PMID- 12464325
TI  - Event-related alpha and theta responses in a visuo-spatial working memory task.
AB  - OBJECTIVE: To explore the reactivity of the theta and alpha rhythms during visuo
      spatial working memory. METHODS: One hundred and seventy-four subjects performed
      a delayed response task. They had to remember the spatial location of a target
      stimulus on a computer screen for a 1 or a 4s retention interval. The target
      either remained visible throughout the entire interval (sensory trials) or
      disappeared after 150ms (memory trials). Changes in induced band power (IBP) in
      the electroencephalogram (EEG) were analyzed in 4 narrow, individually adjusted
      frequency bands between 4 and 12Hz. RESULTS: After presentation of the target
      stimulus, a phasic power increase was found, irrespective of condition and delay
      interval, in the lower (roughly, 4-8Hz) frequency bands, with a posterior
      maximum. During the retention interval, sustained occipital-parietal alpha power
      increase and frontal theta power decrease were found. Most importantly, the
      memory trials showed larger IBP decreases in the theta band over frontal
      electrodes than the sensory trials. CONCLUSIONS: The phasic power increase
      following target onset is interpreted to reflect encoding of the target location.
      The sustained theta decrease, which is larger for memory trials, is tentatively
      interpreted to reflect visuo-spatial working memory processes.

PMID- 12464326
TI  - Dopamine modulates involuntary attention shifting and reorienting: an
      electromagnetic study.
AB  - OBJECTIVE: Dopaminergic function has been closely associated with attentional
      performance, but its precise role has remained elusive. METHODS:
      Electrophysiological and behavioral methods were used to assess the effects of
      dopamine D2-receptor antagonist haloperidol on involuntary attention shifting
      using a randomized, double-blind, placebo-controlled cross-over design. Eleven
      subjects were instructed to discriminate equiprobable 200 and 400ms tones in a
      forced-choice reaction-time (RT) task during simultaneous measurement of whole
      head magnetoencephalography and high-resolution electroencephalography. RESULTS:
      Occasional changes in task-irrelevant tone frequency (10% increase or decrease)
      caused marked distraction on behavioral performance, as shown by significant RT
      increases to deviant stimuli and subsequent standard tones. Furthermore, while
      the standard tones elicited distinct P1-N1-P2-N2-P3 waveforms, deviant tones
      elicited additional mismatch negativity (MMN), P3a, and reorienting negativity
      (RON) responses, indexing brain events associated with involuntary attention
      shifting. While haloperidol did not affect the source loci of the responses of
      magnetic N1 and MMN, the amplitude of the electric P3a and that of RON were
      significantly reduced and the latency of magnetic RON were delayed following
      haloperidol administration. CONCLUSIONS: The present results suggest that
      dopamine modulates involuntary attention shifting to task-irrelevant deviant
      events. It appears that dopamine may disrupt the subsequent re-orienting efforts
      to the relevant task after distraction.

PMID- 12464327
TI  - Non-spatial attentional effects on P1.
AB  - OBJECTIVE: It has been suggested that P1, the earliest endogenous visual
      potential, is influenced primarily by spatial location. However, we have found
      that attention to non-spatial visual features can affect both the latency and
      amplitude of this component. METHODS: A series of studies are reviewed, starting
      with 4 using simple geometric forms, and either serial presentation of single
      stimuli or presentation of stimulus arrays followed by two studies using natural
      complex images. RESULTS: With simple stimuli, latency and amplitude effects are
      seen on the P1, but differ among the paradigms, depending on the demands of the
      task. The data further showed a facilitation effect and that binding occurs in
      parallel with single feature processing. For complex stimuli we found P1 shorter
      to faces than inverted faces, eyes or non-face stimuli, and larger to animal than
      non-animal pictures. The above effects were present in children as well as in
      adults. CONCLUSIONS: These findings demonstrate that very early stages of
      processing can be modified by top-down attentional influences across a range of
      ages and experimental paradigms, concordant with visual processing models showing
      very rapid and dispersed activation with feedback at early cortical levels.

PMID- 12464328
TI  - Temporal integration: intentional sound discrimination does not modulate stimulus
      driven processes in auditory event synthesis.
AB  - OBJECTIVE: Our previous study showed that the auditory context could influence
      whether two successive acoustic changes occurring within the temporal integration
      window (approximately 200ms) were pre-attentively encoded as a single auditory
      event or as two discrete events (Cogn Brain Res 12 (2001) 431). The aim of the
      current study was to assess whether top-down processes could influence the
      stimulus-driven processes in determining what constitutes an auditory event.
      METHODS: Electroencepholagram (EEG) was recorded from 11 scalp electrodes to
      frequently occurring standard and infrequently occurring deviant sounds. Within
      the stimulus blocks, deviants either occurred only in pairs (successive feature
      changes) or both singly and in pairs. Event-related potential indices of change
      and target detection, the mismatch negativity (MMN) and the N2b component,
      respectively, were compared with the simultaneously measured performance in
      discriminating the deviants. RESULTS: Even though subjects could voluntarily
      distinguish the two successive auditory feature changes from each other, which
      was also indicated by the elicitation of the N2b target-detection response, top
      down processes did not modify the event organization reflected by the MMN
      response. CONCLUSIONS: Top-down processes can extract elemental auditory
      information from a single integrated acoustic event, but the extraction occurs at
      a later processing stage than the one whose outcome is indexed by MMN.
      SIGNIFICANCE: Initial processes of auditory event-formation are fully governed by
      the context within which the sounds occur. Perception of the deviants as two
      separate sound events (the top-down effects) did not change the initial neural
      representation of the same deviants as one event (indexed by the MMN), without a
      corresponding change in the stimulus-driven sound organization.

PMID- 12464329
TI  - Spatiotemporal analysis of the neuromagnetic response to rhythmic auditory
      stimulation: rate dependence and transient to steady-state transition.
AB  - OBJECTIVE: Whole head magnetoencephalography was used to investigate the
      spatiotemporal dynamics of neuromagnetic brain activity associated with rhythmic
      auditory stimulation. METHODS: In order to characterize the evolution of the
      auditory responses we applied a Karhunen-Loeve decomposition and k-means cluster
      analysis to globally compare spatial patterns of brain activity at different
      latencies and stimulation rates. Tones were presented binaurally at 27 different
      stimulation rates within a perceptually and behaviorally relevant range from 0.6
      to 8.1 Hz. RESULTS: Over this range, we observed a linear increase of the
      amplitude of the main auditory response at 100 ms latency (N1m) with increasing
      inter-stimulus interval, and qualitative changes of the overall spatiotemporal
      dynamics of the auditory response. In particular, a transition occurred between a
      transient evoked response at low frequencies, and a continuous steady-state
      response at high frequencies. CONCLUSIONS: We show the onset of temporal overlap
      between responses to successive tones that leads to this transition. Response
      overlap begins to occur near 2 Hz, marking the onset of a continuous perceptual
      representation.

PMID- 12464330
TI  - Optimized stimulation and recording parameters of human 'nociception specific'
      blink reflex recordings.
AB  - OBJECTIVE: Few non-invasive methods are available for studying trigeminal
      nociception in humans. The 'nociception specific' blink reflex (nBR) is elicited
      by a preferential stimulation of trigeminal nociceptive fibers and is highly
      sensitive to changes in trigeminal nociception. The aim of this study was to
      establish its optimal stimulation parameters. METHODS: The inter-individual
      variability of R2 responses (41 healthy subjects), symmetry of R2 responses after
      right vs. left sided stimulation (25 subjects), optimal stimulation parameters (3
      groups, each 16 subjects) and re-test reliability over time (15 subjects) were
      studied. RESULTS: The nBR had a R2 response with a latency of 44.7+/-7.3ms, but
      no R1 response. The mean difference of R2 latencies (right vs. left sided
      stimulation) was 0.4+/-2.1(SD)ms, the mean ratio of the R2 response areas (RA)
      was 1.05+/-0.39 (SD). Thus, lateral differences of onset latencies greater than
      4.6ms (0.4+4.2 (2SD)) or >1.83-fold (1.05+0.78 (2SD)) of RA can be assumed as
      outside of normal range. Long inter-block intervals of 7min minimized the
      cumulative habituation of R2 RAs to 23%, onset latencies remained constant. Re
      test reliability over 4 weeks was high both for latencies (Crohnbach's
      alpha=0.85) and RAs (alpha=0.94). CONCLUSIONS: The nBR with the established
      stimulation parameters could be used for studying trigeminal nociception.

PMID- 12464331
TI  - Source localization of MEG sleep spindles and the relation to sources of alpha
      band rhythms.
AB  - OBJECTIVE: First, to determine the distribution of the estimated sources of sleep
      spindles, and alpha and mu rhythms based on whole-head magnetoencephalogram (MEG)
      recordings; second, to scrutinize the physiological relevance of the dipole fit
      algorithm in localizing on-going normal rhythmic activities. METHODS: One hundred
      and fifty-one channels were used to record spontaneous MEG activity during
      wakefulness and superficial sleep in 4 normal subjects. The equivalent dipolar
      sources were estimated by a new 'dipole fit algorithm' and projected on the
      corresponding magnetic resonance images. RESULTS: Equivalent dipoles of MEG
      spindles were distributed over the centro-parietal region. Those of alpha rhythms
      were concentrated around the occipito-parietal sulcus and those of mu rhythms
      were confined to the area around the central sulcus. CONCLUSIONS: MEG sleep
      spindles, and alpha and mu rhythms have distinct spatial distributions of their
      equivalent dipolar sources. This demonstrates that various cortical regions that
      oscillate within the same frequency band have different spatial organizations and
      different functional aspects.

PMID- 12464332
TI  - Does the prion protein gene 129 codon polymorphism influence sleep? Evidence from
      a fatal familial insomnia kindred.
AB  - OBJECTIVE: Experimental and clinical evidence in prion diseases suggests that the
      prion protein gene (PRNP) plays a role in regulating sleep. METHODS: Seventeen
      healthy individuals belonging to a single fatal familial insomnia pedigree, 8
      carriers and 9 non-carriers of the PRNP codon 178 mutation, underwent
      polysomnography and spectral electroencephalographic (EEG) analysis. All were
      also characterized with regard to the codon 129 polymorphism on both PRNP
      alleles. RESULTS: PRNP codon 129 polymorphism exhibited influences on sleep-EEG
      activities. In particular, spindle frequency band power and balance between delta
      and spindle activity were found to correlate with the genotype of PRNP codon 129,
      irrespective of the mutation at codon 178. CONCLUSIONS: Our data suggest that
      PRNP codon 129 polymorphism may also affect sleep in the healthy population and
      warrant further studies in the general population and other sleep disorders.

PMID- 12464333
TI  - EEG in schizophrenic patients: mutual information analysis.
AB  - OBJECTIVE: The aim of the present study is to assess information transmission
      between different cortical areas in schizophrenics by estimating the average
      cross mutual information (A-CMI) and to characterize the dynamical property of
      the cortical areas of schizophrenic patients from multi-channel EEG by
      establishing the auto mutual information (AMI). METHODS: We recorded the EEG from
      16 electrodes in 10 schizophrenic patients and 10 age-matched normal controls. We
      estimated the slope of the AMI to evaluate the complexity of the EEG signal from
      one electrode and the A-CMI values of all 16x16 pairs of electrodes were
      calculated to investigate the information transmission of different cortical
      areas in schizophrenic patients. RESULTS: In T5 and C3 electrodes, the
      schizophrenic patients had lower complexity than normal controls. The
      schizophrenic patients had significantly higher interhemispheric and
      intrahemispheric A-CMI values than the normal controls. CONCLUSIONS: These
      results are consistent with previous findings that suggest left hemispheric
      hypotemporality and inter- and/or intra-hemispheric overconnectivity in
      schizophrenics. Our results of the left hemispheric hypotemporality and the
      increased interhemispheric information transmission in temporal lobe may support
      the hypothesis that the abnormal laterlization in temporal lobe are due to left
      temporal lobe deficit in schizophrenic patients.

PMID- 12464334
TI  - Interictal spike EEG source analysis in hypothalamic hamartoma epilepsy.
AB  - OBJECTIVE: The epilepsy associated with the hypothalamic hamartomas constitutes a
      syndrome with peculiar seizures, usually refractory to medical therapy, mild
      cognitive delay, behavioural problems and multifocal spike activity in the scalp
      electroencephalogram (EEG). The cortical origin of spikes has been widely assumed
      but not specifically demonstrated. METHODS: We present results of a source
      analysis of interictal spikes from 4 patients (age 2-25 years) with epilepsy and
      hypothalamic hamartoma, using EEG scalp recordings (32 electrodes) and realistic
      boundary element models constructed from volumetric magnetic resonance imaging
      (MRIs). Multifocal spike activity was the most common finding, distributed mainly
      over the frontal and temporal lobes. A spike classification based on scalp
      topography was done and averaging within each class performed to improve the
      signal to noise ratio. Single moving dipole models were used, as well as the Rap
      MUSIC algorithm. RESULTS: All spikes with good signal to noise ratio were best
      explained by initial deep sources in the neighbourhood of the hamartoma, with
      late sources located in the cortex. Not a single patient could have his spike
      activity explained by a combination of cortical sources. CONCLUSIONS: Overall,
      the results demonstrate a consistent origin of spike activity in the subcortical
      region in the neighbourhood of the hamartoma, with late spread to cortical areas.

PMID- 12464335
TI  - Bilateral spike-and-wave discharges in a hemi-deafferented cortex.
AB  - We studied a patient with a history of absence attacks in childhood in whom an
      absence status with bilateral spike-and-wave discharges developed after a top-of
      the-basilar syndrome. Surprisingly, even though the ischemic lesion involved the
      left thalamus alone, spike-and-wave discharges were recorded from the two
      hemispheres. Three days after antiepileptic treatment (sodium valproate 500mg 3
      times a day) began, electroenceplalographic recordings and consciousness became
      normal.

PMID- 12464336
TI  - Oscillatory cortical drive to isometrically contracting muscle in Unverricht
      Lundborg type progressive myoclonus epilepsy (ULD).
AB  - OBJECTIVE: We investigated with whole-scalp magnetoencephalography (MEG)
      oscillatory cortical drive to isometrically contracting muscle in 8 genetically
      verified, and thus etiologically homogeneous, Unverricht-Lundborg type
      progressive myoclonus epilepsy (ULD) patients suffering from cortical myoclonus
      and generalized tonic-clonic seizures. The results were compared with those of 8
      healthy control subjects. METHODS: Cortical MEG signals were measured
      simultaneously with surface electromyography (EMG) during isometric contraction
      of the left and right first dorsal interosseus muscles. Cortex-muscle coherence
      and cross-correlograms between MEG and EMG signals were calculated as indicators
      of oscillatory cortical drive to muscle. The cortical areas involved in the
      maximum cortex-muscle coherence were also identified. RESULTS: In patients, the
      strengths of the dominant coherent peaks were 2-4 fold compared with the healthy
      controls. Whereas the coherence was found strictly in the contralateral primary
      motor cortex in controls, additional coherent activity was observed ipsilaterally
      in 5 out of 8 patients. CONCLUSIONS: The remarkably increased MEG-EMG coherence
      in ULD patients suggests altered oscillatory cortical drive to the muscle during
      isometric contraction. We suggest that the enhanced cortex-muscle coherence in
      ULD patients reflects reduced inhibition in the motor cortex, and may contribute
      to disturbed voluntary movements.

PMID- 12464337
TI  - Natural history of ulnar entrapment at elbow.
AB  - OBJECTIVE: No clinical-neurophysiological data on natural history of ulnar
      neuropathy at elbow (UNE) are reported. The aim of the current study is to assess
      the course of untreated UNE. METHODS: We performed a follow-up at 1 year of 30
      neurophysiologically positive UNE, 24 were untreated and 6 were operated on. The
      evaluation was based on a phone interview and sometimes on neurophysiological
      investigation. With regard to management of UNE, at initial evaluation we
      explained to the patients what UNE is and how to avoid posture that can worsen
      nerve compression. RESULTS: Around half of the untreated patients reported
      improvement of symptoms at follow-up. Comparison between baseline and follow-up
      neurophysiological measurements showed a significant spontaneous improvement.
      Most patients reported changing of arm posture after UNE diagnosis. CONCLUSIONS:
      Some UNE cases improve spontaneously without surgical treatment. A part of the
      improvements could be due to the changing of arm postures. We hypothesize that a
      good diagnosis that includes an explanation of the anatomical condition of the
      nerve during postures and movements represents the first therapy for the
      entrapments.

PMID- 12464338
TI  - Imaging of neural conduction block by neuromagnetic recording.
AB  - OBJECTIVE: For the clinical application of neuromagnetic recordings in neural
      conduction block, the patterns of magnetic fields in the region should be
      clarified. Using an experimental in vitro model, the spatiotemporal course of the
      neuromagnetic fields at the site of complete conduction block was examined.
      Additionally, the magnetic compound action fields (CAFs) and electric compound
      action potentials (CAPs) were compared and correlated. METHODS: In a chamber
      containing Ringer's solution, 10 isolated sciatic nerves of rabbits were
      electrically stimulated. Both evoked CAPs and CAFs were measured before and after
      the ligation of the nerve. The sequential positions of the current dipoles and
      the location of the conduction block were estimated by the least-squares search.
      RESULTS: The magnetic contour maps of the CAFs showed a characteristic
      quadrupolar pattern propagating along the nerve. The peak of the leading magnetic
      field ceased and disappeared at the position of the nerve ligation, while the
      trailing magnetic field became attenuated before reaching that position. The
      positions of the conduction blocks were localized by magnetic recordings within a
      difference of 2mm. CONCLUSIONS: The neuromagnetic recordings could visualize the
      change of the magnetic fields at the site of the complete conduction block and
      closely localize that position. SIGNIFICANCE: The neural conduction block was
      visualized and localized by neuromagnetic recordings.

PMID- 12464339
TI  - Observations on intraoperative somatosensory evoked potential (SEP) monitoring in
      the semi-sitting position.
AB  - BACKGROUND: Former case reports suggest that monitoring of median nerve
      somatosensory evoked potentials (M-SEP) is unreliable in patients operated in the
      semi-sitting position due to the occurrence of evoked potential changes unrelated
      to neurological damage. This study was designed to analyze these changes in
      greater detail and confirm that these changes are not caused by neurological
      damage. METHODS: M-SEP monitoring findings of 50 patients with surgery in the
      semi-sitting position were analyzed and compared with a group of 50 patients who
      underwent surgery in the supine position. M-SEP amplitudes and latencies at
      distinct steps of the monitoring procedure were used for further analysis. In 10
      of the 50 semi-sitting patients, M-SEP were recorded additionally after surgery
      with the anesthetized patient in the supine position. RESULTS: Significant M-SEP
      changes occurred in the semi-sitting patients only. An amplitude loss of greater
      than 50% on at least one side was observed in 24 patients. The magnitude and the
      time course of the amplitude loss was considerably variable. A complete loss of
      the evoked potential was not observed in any case. In all 10 patients, M-SEP
      recovered completely when recorded in the supine position. CONCLUSIONS: In about
      half of the patients with M-SEP monitoring in the semi-sitting position, a
      significant amplitude loss occurs which is unrelated to neurological damage and
      presumably caused by subdural gas collections. There is no characteristic pattern
      of M-SEP changes which enables a differentiation of these 'artificial'
      alterations from true events. The only appropriate criterion to indicate an
      impending neurological damage in these patients seems to be a complete loss of
      the M-SEP potential.

PMID- 12464340
TI  - Scalp-recorded Bereitschaftspotential is the result of the activity of cortical
      and subcortical generators--a hypothesis.
AB  - OBJECTIVE: The source of scalp-recorded Bereitschaftspotential (BP) remains a
      subject of ongoing discussion. This paper presents arguments in favour of the
      hypothesis that explains scalp-recorded BP as the result of the activity of both
      cortical and subcortical BP generators. METHODS: Intracranial recordings of BP
      were performed, mostly with depth electrodes in epilepsy surgery candidates. In
      some patients undergoing intracranial exploration, an electrode may have had
      contacts in the subcortical structures. RESULTS: BP is generated in several
      cortical and subcortical structures that are known to be directly or indirectly
      linked with motor control. Cortical sources of BP were displayed contralaterally
      to the movement in the primary motor cortex and somatosensory cortex, and
      bilaterally in the supplementary motor area (SMA), in the preSMA, and in the
      cingulate. A few other generators may be revealed in structures that have not yet
      been sufficiently explored. Subcortical generators of BP were found in the
      putamen, pallidum, caudate, and in the thalamus. In earlier recordings, BP was
      described rostrally to the thalamic region and in the brainstem, i.e. in the pes
      peripedunculi, nucleus peripeduncularis, pulvinar, and medial geniculate.
      CONCLUSIONS: Our observations do not explain the generation of scalp-recorded BP
      by the contribution of either cortical or subcortical sources alone. Intracranial
      cortical recordings contradict a wide distribution of scalp-recorded BP. Widely
      synchronised cerebral electromagnetic activity can be recorded on the scalp. We
      presume that in the case of BP, the weak deep dipoles might reach the scalp, as
      they are produced by a relatively huge mass of subcortical neuronal tissue. We
      strongly suspect that scalp-recorded BP represents a summation of potentials that
      are generated simultaneously in several cortical as well as in several
      subcortical structures.

PMID- 12464341
TI  - Cortico-motor excitability of the lower limb motor representation: a comparative
      study in Parkinson's disease and healthy controls.
AB  - OBJECTIVE: To compare indices of cortico-motor excitability derived from
      transcranial magnetic stimulation (TMS) of the lower limb motor representation in
      patients with Parkinson's diseases (PD) and healthy controls. METHODS: The
      cortico-motor excitability of the lower limb motor area was studied both at rest
      (motor threshold, amplitude of motor evoked potentials (MEPs)) and during active
      contraction of the quadriceps (Quad) muscle (MEPs facilitation and silent period)
      in 10 PD patients (11 legs) and 11 healthy controls using single pulse TMS.
      RESULTS: At rest, the motor threshold was found to be significantly lower and the
      amplitude of MEPs larger in patients than in controls. During active knee
      contraction, patients produced lower levels of MEP facilitation with respect to
      baseline values and the silent period was lengthened in comparison to controls.
      CONCLUSIONS: The present results provide further evidence from the lower limb
      motor area that enhanced cortico-spinal excitability is an important feature in
      the pathophysiology of PD.

PMID- 12464342
TI  - Modulated cortical control of individual fingers in experienced musicians: an EEG
      study. Electroencephalographic study.
AB  - OBJECTIVE: The present research was designed to address the nature of
      interdependency between fingers during force production tasks in subjects with
      varying experience in performing independent finger manipulation. Specifically,
      behavioral and electroencephalographic (EEG) measures associated with
      controllability of the most enslaved (ring) and the least enslaved (index)
      fingers was examined in musicians and non-musicians. METHODS: Six piano players
      and 6 age-matched control subjects performed a series of isometric force
      production tasks with the index and ring fingers. Subjects produced 3 different
      force levels with either their index or ring fingers. We measured the isometric
      force output produced by all 4 fingers (index, ring, middle and little),
      including both ramp and static phases of force production. We applied time-domain
      averaging of EEG single trials in order to extract 4 components of the movement
      related cortical potentials (MRCP) preceding and accompanying force responses.
      RESULTS: Three behavioral findings were observed. First, musicians were more
      accurate than non-musicians at reaching the desired force level. Second,
      musicians showed less enslaving as compared to non-musicians. And third, the
      amount of enslaving increased with the increment of nominal force levels
      regardless of whether the index or ring finger was used as the master finger. In
      terms of EEG measures, we found differences between tasks performed with the
      index and ring fingers in non-musicians. For musicians, we found larger MRCP
      amplitudes at most electrode sites for the ring finger. CONCLUSIONS: Our data
      extends previous enslaving research and suggest an important role for previous
      experience in terms of the independent use of the fingers. Given that a variety
      of previous work has shown finger independence to be reflected in cortical
      representation in the brain and our findings of MRCP amplitude associated with
      greater independence of fingers in musicians, this suggests that what has been
      considered to be stable constraints in terms of finger movements can be modulated
      by experience. SIGNIFICANCE: This work supports the idea that experience is
      associated with changes in behavioral and EEG correlates of task performance and
      may have clinical implications in disorders such as stroke or focal hand
      dystonia. Practice-related procedures offer useful approaches to rehabilitation
      strategies.

PMID- 12464343
TI  - Motor outcome after subcortical stroke: MEPs correlate with hand strength but not
      dexterity.
AB  - OBJECTIVE: Motor evoked potential (MEP) amplitude and threshold are predictors of
      functional outcome in the early stages after stroke, and improvement in these
      parameters usually accompanies motor recovery. The aim of this study in patients
      with subcortical stroke was to determine whether there is a correlation between
      MEP amplitude and threshold and the degree of recovery of strength and dexterity
      in the affected hand. METHODS: MEP amplitude and threshold were measured on the
      affected and unaffected sides in 23 patients who had suffered a subcortical
      ischaemic stroke up to 23 years previously. Grip strength was measured using a
      hand-held dynamometer and dexterity was assessed using a modification of the
      McCarron test battery. RESULTS: Grip strength correlated with both MEP amplitude
      and threshold (r=0.49 and r=-0.54, respectively, P<0.05), whereas the McCarron
      score for motor dexterity did not correlate significantly with either of these
      MEP parameters. CONCLUSIONS: Grip strength and dexterity correlate differentially
      with MEP parameters of excitability and conduction in the corticospinal pathway
      after recovery in patients with subcortical stroke. Grip strength is dependent on
      restoration of corticospinal excitability and conduction whereas additional
      factors such as cortical reorganization may underlie recovery of motor dexterity.

PMID- 12464345
TI  - Reflections and meditations upon complex chromosomal exchanges.
AB  - The application of FISH chromosome painting techniques, especially the recent
      mFISH (and its equivalents) where all 23 human chromosome pairs can be
      distinguished, has demonstrated that many chromosome-type structural exchanges
      are much more complicated (involving more "break-rejoins" and arms) than has
      hitherto been assumed. It is clear that we have been greatly under-estimating the
      damage produced in chromatin by such agents as ionising radiation. This article
      gives a brief historical summary of observations leading up to this conclusion,
      and after outlining some of the problems surrounding the formation of complex
      chromosomes exchanges, speculates about possible solutions currently being
      proposed.

PMID- 12464346
TI  - Genotoxicity of hyperbaric oxygen.
AB  - Hyperbaric oxygen (HBO) treatment is applied as a therapy for a wide variety of
      diseases with symptoms caused by lack of oxygen in the target tissues. However,
      it is known that exposure to high concentrations of oxygen may lead to oxidative
      stress and cause cell and tissue damage. Oxygen toxicity and possible cancer
      promoting effects of HBO therapy have been a matter of serious concern. Although
      a cancer-inducing effect of HBO was not found to date, recent studies clearly
      indicated an induction of oxidative DNA damage in blood cells of healthy subjects
      after HBO under therapeutic conditions. The biological significance of this
      finding has been investigated in a series of in vitro and in vivo tests. This
      review summarizes these studies and critically discusses potential adverse
      genetic effects of HBO therapy. Furthermore, since an induction of anti-oxidative
      defense mechanisms has been determined after HBO exposure, a modified treatment
      regimen of HBO therapy is proposed which avoids genotoxic effects.

PMID- 12464347
TI  - Genotoxicity of streptozotocin.
AB  - Streptozotocin (Streptozocin, STZ, CAS No. 18883-66-4) is a monofunctional
      nitrosourea derivative isolated from Streptomyces achromogenes. It has broad
      spectrum antibiotic activity and antineoplastic properties and is often used to
      induce diabetes mellitus in experimental animals through its toxic effects on
      pancreatic beta cells. STZ is a potent alkylating agent known to directly
      methylate DNA and is highly genotoxic, producing DNA strand breaks, alkali-labile
      sites, unscheduled DNA synthesis, DNA adducts, chromosomal aberrations,
      micronuclei, sister chromatid exchanges, and cell death. This antibiotic was
      found to be mutagenic in bacterial assays and eukaryotic cells. STZ is also
      carcinogenic; a single administration induces tumors in rat kidney, liver, and
      pancreas. Several lines of evidence indicate that free radicals are involved in
      the production of DNA and chromosome damage by this compound. Because of the use
      of STZ as an antineoplastic agent, the study of its genotoxicity has considerable
      practical significance. The purpose of this review is to present our current
      knowledge regarding the genotoxicity of STZ.

PMID- 12464348
TI  - Genetic and environmental factors in cancer and neurodegenerative diseases.
AB  - The aim of this review is to summarise the recent findings in the fields of
      carcinogenesis and neurodegenerative diseases, the both disorders are
      characterised by the contribution of different factors including the inheritance
      of mutated genes, and the exposure to endogenous or exogenous agents during the
      life. We first analysed the causative genes until now discovered in both
      processes, then we focused our attention on the role of environmental exposure,
      susceptibility factors, oxidative stress, apoptosis and aging to the development
      of such disorders. The genotype at a particular locus may account for an inter
      individual susceptibility that can both increase or decrease the risk to develop
      the pathology especially after the exposure to environmental agents. The
      mechanism of apoptosis, that is an excellent strategy in order to eliminate
      damaged cells, seems to be lost during carcinogenesis, while it seems to be
      involved in the neuronal death in a lot of neurodegenerative disorders. Oxidative
      stress can both lead to DNA mutations or to the formation of damaged proteins, so
      being an important risk factor for the initiation and the progression of a
      disease: in fact it may be one of the causes or can arise as a consequence of a
      damage caused by other factors increasing then the first damage. It is well
      established that carcinogenesis is a multi-step process caused by series of
      successive mutations occurring into a cell and conferring to this cell a growth
      advantage, so that age is the largest risk factor for cancer in humans.
      Pathophysiology of neurodegenerative diseases is complex and likely involves
      multiple overlapping and perhaps redundant pathways of neuronal damage,
      characterised by the generation of anomalous proteins, often due to mutations in
      the corresponding gene, and by their subsequent accumulation into or outside
      specific areas of the brain.

PMID- 12464349
TI  - Are some progestins genotoxic liver carcinogens?
AB  - Progestins (progestogens) are classified by the International Agency for Research
      on Cancer (IARC) as possibly carcinogenic to humans. In the last decade evidence
      has shown that a synthetic drug of this family, cyproterone acetate, is activated
      to a reactive species by the liver, and forms DNA adducts and elicits DNA repair
      in hepatocytes from both rats and humans. The response is similar in humans of
      both genders but markedly higher in female than in male rats. The promutagenic
      character of DNA lesions is indicated by the increase in liver of female rats of
      the frequency of micronucleated cells, of mutations, and of enzyme-altered
      preneoplastic foci. Two other synthetic progestins, chlormadinone acetate and
      megestrol acetate, and an aldosterone antagonist, potassium canrenoate, share
      with cyproterone acetate the 17-hydroxy-3-oxopregna-4,6-diene structure. While
      less extensively studied, results so far obtained indicate that they are capable
      of inducing genotoxic effects qualitatively similar to those of cyproterone
      acetate. The majority of progestins have not been systematically tested for
      genotoxicity and the generally negative responses obtained with the standard
      battery of genotoxicity tests might be the consequence of the use of
      inappropriate target cells and/or metabolic activation systems. Cyproterone
      acetate, is activated by the hepatocytes to reactive species of such short half
      life that they react only with the DNA of the cell in which are formed.
      Therefore, it cannot be excluded a priori that other progestins will not display
      genotoxic effects when tested adequately. This hypothesis is supported by the
      knowledge that estrogen-progestin combinations used as oral contraceptives are
      classified by the IARC as carcinogenic to humans due to the increased risk of
      hepatocellular carcinoma. This risk should probably be ascribed to the progestin
      component, since estrogens are carcinogenic to humans due to the increased risk
      of endometrial and possibly of breast cancer but not liver cancer.

PMID- 12464350
TI  - Brca1 and differentiation.
AB  - Breast cancer is one of the most frequent malignancies affecting women. The human
      breast cancer gene 1 (BRCA1) gene is mutated in a distinct proportion of
      hereditary breast and ovarian cancers. Tumourigenesis in individuals with
      germline BRCA1 mutations requires somatic inactivation of the remaining wild-type
      allelle. Although, this evidence supports a role for BRCA1 as a tumour
      suppressor, the mechanisms through which its loss leads to tumourigenesis remain
      to be determined. Neither the expression pattern nor the described functions of
      human BRCA1 and murine breast cancer gene 1 (Brca1) can explain the specific
      association of mutations in this gene with the development of breast and ovarian
      cancer. Investigation of the role of Brca1 in normal cell differentiation
      processes might provide the basis to understand the tissue-restricted properties.

PMID- 12464351
TI  - Genotoxic effects of ethylene oxide, propylene oxide and epichlorohydrin in
      humans: update review (1990-2001).
AB  - Ethylene oxide (EtO), propylene oxide (PO) and epichlorohydrin (ECH) are
      important industrial chemicals widely used as intermediates for various synthetic
      products. EtO and PO are also environmental pollutants. In this review we
      summarize data published during the period 1990-2001 concerning both the
      genotoxic and carcinogenic effects of these epoxides in humans. The use of DNA
      and hemoglobin adducts as biomarkers of exposure and the role of polymorphism, as
      well as confounding factors, are discussed. We have also included recent in vitro
      data comprising genotoxic effects induced by EtO, PO and ECH in mammalian cells.
      The uncertainties regarding cancer risk estimation still persist, in spite of the
      large database collected.

PMID- 12464352
TI  - Selective interaction of bile acids with muscarinic receptors: a case of
      molecular mimicry.
AB  - Bile acids alter regulatory pathways in several cell types. The molecular basis
      for these actions is not fully elucidated, but lithocholyltaurine interacts
      functionally with muscarinic receptors on gastric chief cells. In the present
      report, we demonstrate selective interaction of bile acids with Chinese hamster
      ovary (CHO) cells expressing each of the five muscarinic receptors.
      Lithocholyltaurine decreases binding of a radioligand to muscarinic M3 receptors,
      but not to other muscarinic receptors. Sulfated lithocholyltaurine, the major
      human metabolite, inhibits radioligand binding to muscarinic M1, but not to M2 or
      M3 receptors. Post-receptor actions of lithocholyltaurine include modulation of
      acetylcholine-induced increases in inositol phosphate formation and mitogen
      activated protein (MAP) kinase phosphorylation. Molecular modeling suggests that
      the specific and functional interaction of lithocholyltaurine with muscarinic
      receptors is most likely due to similar shape and surface charge distribution of
      portions of acetylcholine and the bile acid. We propose that bile acids are
      signaling molecules whose effects may be mediated by interaction with muscarinic
      receptors.

PMID- 12464353
TI  - Celiprolol inhibits mitogen-activated protein kinase and endothelin-1 and
      transforming growth factor-beta(1) gene in rats.
AB  - We evaluated the cardioprotective effects of long-term treatment with celiprolol
      (for 5 weeks), a specific beta(1)-adrenoceptor antagonist with a weak beta(2)
      adrenoceptor agonist action, on endothelin-1 and transforming growth factor (TGF)
      beta(1) expression and cardiovascular remodeling in deoxycorticosterone acetate
      (DOCA)-salt hypertensive rats. Upregulated preproendothelin-1, endothelin ET(A)
      receptor, TGF-beta(1), c-fos, and type I collagen expression and extracellular
      signal-regulated kinase activities were suppressed by celiprolol. Celiprolol
      effectively inhibited vascular lesion formation such as medial thickness and
      perivascular fibrosis. These observations suggested that extracellular signal
      regulated kinase and c-fos gene pathway may contribute to the cardiovascular
      remodeling of DOCA rats, and that cardioprotective effects of celiprolol on
      cardiovascular remodeling may be mediated, at least in part, by suppressed
      expression of endothelin-1 and TGF-beta(1).

PMID- 12464354
TI  - Cabergoline prevents necrotic neuronal death in an in vitro model of oxidative
      stress.
AB  - To study if cabergoline, a long-lasting specific dopamine D2 receptor agonist,
      has neuroprotective effects against oxidative stress, we exposed (3 h) SH-SY5Y
      human neuroblastoma cells to tert-butylhydroperoxide (t-BOOH; 500 microM). t-BOOH
      caused a 42+/-4% neuronal death, which was prevented by cabergoline (2 h before)
      in a concentration-dependent manner (EC(50): 1.24 microM). This effect was not
      antagonised by haloperidol (concentration up to 10 microM), and was associated
      with an increased availability of intracellular GSH contents (+30+/-11%) and a
      decrease in the membrane lipid peroxidation (-23+/-9%). Our data suggest that
      cabergoline has neuroprotective effects useful for Parkinson's disease therapy.

PMID- 12464355
TI  - Different strains of rats show different sensitivity to block of long-term
      potentiation by nitric oxide synthase inhibitors.
AB  - Nitric oxide is presumed to play important roles in the induction of synaptic
      plasticity and learning. Previous publications, however, reported contradictory
      results. Block of nitric oxide synthase (NOS) has been shown to impair the
      induction of long-term potentiation of synaptic transmission in some studies.
      Other studies observed a partial block of long-term potentiation depending on
      experimental conditions, while yet other studies did not find an effect of NOS
      inhibitors under any conditions tested. Some reasons for these differences had
      been identified, e.g. the temperature of the slice buffer, the age of the
      animals, and the specific stimulation protocols used. Still, even when taking
      these parameters into account, not all results can be explained. The present
      study compares three strains of rats and observes large differences in
      sensitivity to nitric oxide synthase (NOS) blockers on the induction of long-term
      potentiation. While Wistar rats showed an almost complete block of long-term
      potentiation when using the NOS inhibitors 7-nitro-indazole (30 mg/kg ip) or 1-(2
      trifluoromethylphenyl) imidazole (TRIM; 150 nmol/5 microl icv), 117+/-5 S.E.M. of
      % of baseline slope values of excitatory postsynaptic potentials. Sprague-Dawley
      and Long-Evans rats showed no or only weak effects of drugs on the induction of
      long-term potentiation (166+/-17 S.E.M. of % of baseline slopes in Sprague-Dawley
      rats, 173+/-24 S.E.M. of % of baseline values in Long-Evans rats). The results
      could explain at least some of the discrepancies of the efficacy of NOS
      inhibitors on synaptic plasticity that is found in the literature. Such large
      strain differences suggest that results from studies that use laboratory rats
      could have strain-dependent components and should be generalised cautiously.

PMID- 12464356
TI  - Pharmacological profiles of R-96544, the active form of a novel 5-HT2A receptor
      antagonist R-102444.
AB  - We examined the pharmacology of (2R,4R)-4-hydroxy-2-[2-[2-[2-(3
      methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride (R-96544),
      the active form of a novel 5-HT(2A) receptor antagonist, (2R,4R)-4-lauroyloxy-2
      [2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride
      (R-102444). R-96544 produced a concentration-dependent inhibition of platelet
      aggregation induced by serotonin (5-hydroxytryptamine, 5-HT) alone or in
      combination with ADP in platelets from humans, monkeys, cats, rabbits, rats and
      mice. An intravenous administration of R-96544 to rabbits significantly inhibited
      ex vivo platelet aggregation induced by 5-hydroxytryptamine (5-HT) combined with
      epinephrine. An oral administration of R-102444 to rats also resulted in
      significant inhibition of ex vivo platelet aggregation, whereas R-102444 was
      ineffective in an in vitro platelet aggregation assay. These antiplatelet effects
      of R-96544 and R-102444 were more potent than those of two other 5-HT(2A)
      receptor antagonists, sarpogrelate and its active metabolite (+/-)-1-[2-[2-(3
      methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propanol hydrochloride (M-1). A
      binding study using cat platelet membranes showed that R-96544 has high affinity
      for 5-HT(2A) receptors but no effect on non-serotonergic [3H]ketanserin-binding
      sites. R-96544 caused a parallel shift to the right of concentration-response
      curves for 5-HT in rat caudal artery contraction mediated by 5-HT(2A) receptors.
      Schild plot analysis gave a pA(2) value of 10.4 with a slope near unity (1.04). R
      96544 also inhibited 5-HT(2A) receptor-mediated contraction of guinea pig trachea
      but not 5-HT(3) receptor-mediated contraction of guinea pig ileum and 5-HT(2B)
      receptor-mediated contraction of rat fundus preparation. R-96544 (i.v.)
      attenuated the pressor responses evoked by 5-HT (15 microg/kg, i.v.) but not by
      phenylephrine (5 microg/kg, i.v.) and angiotensin II (0.1 microg/kg, i.v.), after
      ganglionic blockade in anesthetized spontaneously hypertensive rats. These
      results show that R-96544, the active form of R-102444, is a novel 5-HT receptor
      antagonist with potent, competitive, and 5-HT(2A)-selective activity.

PMID- 12464357
TI  - Role of bradykinin B(1) receptors in diabetes-induced hyperalgesia in
      streptozotocin-treated mice.
AB  - Insulin-dependent diabetes mellitus (type-1 diabetes) is an inflammatory
      autoimmune disease associated with vascular permeability changes leading to many
      complications including nephropathy, retinopathy, hypertension, hyperalgesia and
      neuropathy. The bradykinin B(1) receptor was recently found to be upregulated
      during the development of the diabetes and to be involved in its complications.
      Kinins are known to be important mediators of a variety of biological effects
      including cardiovascular homeostasis, inflammation and nociception. In the
      present study, we studied the effect of the selective B(1) receptor agonist, des
      Arg(9)-bradykinin, and its specific antagonists, Ac-Lys-[D-beta Nal(7),
      Ile(8)]des-Arg(9)-bradykinin (R-715) and Ac-Orn-[Oic(2), alphaMe Phe(5), D-beta
      Nal(7), Ile(8)]des-Arg(9)-bradykinin (R-954), on diabetic hyperalgesia. Diabetes
      was induced in male CD-1 mice by injecting a single high dose of streptozotocin
      (200 mg kg(-1), i.p.) and the nociception was assessed using the hot plate and
      the tail flick tests, 1 week following the injection of streptozotocin. Our
      results showed that induction of diabetes by streptozotocin provoked a marked
      hyperalgesia in diabetic mice expressed as about 11% decrease in hot plate
      reaction time and 26% decrease in tail flick reaction time. Following acute
      administration of R-715 (200-800 microg kg(-1), i.p.) and R-954 (50-600 microg
      kg(-1), i.p.), this hyperalgesic activity was blocked and the hot plate and tail
      flick latencies of diabetic mice returned to normal values observed in control
      healthy mice. In addition, the acute administration of des-Arg(9)-bradykinin (200
      600 microg kg(-1), i.p.) significantly potentiated diabetes-induced hyperalgesia,
      an effect that was totally reversed by R-715 (1.6-2.4 mg kg(-1), i.p.) and R-954
      (0.8-1.6 mg kg(-1), i.p.). These results provide a major evidence for the
      implication of the bradykinin B(1) receptors in the development of hyperalgesia
      associated with diabetes and suggest a novel approach to the treatment of this
      diabetic complication using the bradykinin B(1) receptor antagonists.

PMID- 12464358
TI  - MK-801- and ethanol-induced activity in inbred long-sleep and short-sleep mice:
      dopamine and serotonin systems.
AB  - Low doses of (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10
      imine (MK-801; dizocilpine) or ethanol induce less locomotor activation in inbred
      long-sleep (ILS) than short-sleep (ISS) mice. These differences may involve
      altered dopamine and/or 5-hydroxytryptamine (serotonin; 5-HT) neurotransmission.
      To address this possibility, the dopaminergic and serotonergic mechanisms
      underlying the locomotor-stimulant effects of MK-801 and ethanol in ILS and ISS
      mice were studied. Dopamine D1, D2 and 5-HT(2A) receptor antagonists reduced MK
      801-stimulated activity in ILS mice without having any effect in ISS mice. The 5
      HT reuptake inhibitor fluoxetine potentiated MK-801-stimulated activity
      selectively in ILS mice. Strain differences in 5-HT transporters do not explain
      this selective effect of fluoxetine in ILS mice since [3H]citalopram binding and
      [3H]5-HT uptake studies found no differences in the affinity, number or function
      of 5-HT transporters between ILS and ISS mice. Ethanol-induced activity in ISS
      mice was depressed by dopamine D2 and 5-HT(2C) receptor antagonists and enhanced
      by a 5-HT(1A) receptor antagonist. These results suggest that in ILS mice the
      locomotor-stimulant effects of MK-801 require increased dopamine and/or 5-HT
      neurotransmission. Conversely, in ISS mice, the effects of MK-801 appear to be
      monoamine-independent. Thus, even though both MK-801 and ethanol inhibit N-methyl
      D-aspartate receptors, their stimulant effects appear to involve different
      neuronal systems.

PMID- 12464359
TI  - L-NAME reduces infarction, neurological deficit and blood-brain barrier
      disruption following cerebral ischemia in mice.
AB  - The role of nitric oxide (NO) in the development of post-ischemic cerebral
      infarction has been extensively examined, but fewer studies have investigated its
      role in other outcomes. In the present study, we first determined the temporal
      evolution of infarct volume, NO production, neurological deficit and blood-brain
      barrier disruption in a model of transient focal cerebral ischemia in mice. We
      then examined the effect of the nonselective NO-synthase inhibitor N(omega)-nitro
      L-arginine-methylester (L-NAME). L-NAME given at 3 mg/kg 3 h after ischemia
      reduced by 20% the infarct volume and abolished the increase in brain NO
      production evaluated by its metabolites (nitrites/nitrates) 48 h after ischemia.
      L-NAME with this protocol also reduced the neurological deficit evaluated by the
      grip test and decreased by 65% the extravasation of Evans blue, an index of blood
      brain barrier breakdown. These protective activities of L-NAME suggest that NO
      has multiple deleterious effects in cerebral ischemia.

PMID- 12464360
TI  - Discriminative stimulus effects of BAY 38-7271, a novel cannabinoid receptor
      agonist.
AB  - BAY 38-7271 [(-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1
      sulfonate] is a novel, highly potent and selective cannabinoid CB(1)/CB(2)
      receptor agonist with neuroprotective properties. It was the aim of the present
      study to further confirm its cannabinoid CB(1) receptor agonist properties in a
      highly sensitive in vivo assay. Male Wistar rats (n=24) were trained to
      discriminate BAY 38-7271 (0.05 mg/kg, i.p., t-30 min) from vehicle in a fixed
      ratio:10, food-reinforced two-lever standard procedure. The animals acquired the
      discrimination after a median number of 52 training sessions. BAY 38-7271
      generalized dose-dependently when tested after different routes of administration
      (ED(50): 0.018 mg/kg, i.p.; 0.001 microg/kg, i.v.; 0.18 mg/kg, p.o.). A time
      dependency study indicated that the cue (0.05 mg/kg, i.p.) was detectable between
      15 min and 4 h, with a maximum of generalization obtained at 30 min after
      administration. Pretreatment with the selective cannabinoid CB(1) receptor
      antagonist SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4
      dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] completely
      antagonized the effects of BAY 38-7271 (ID(50): 1.1 mg/kg, i.p.). Dose-dependent
      and complete generalization was also obtained after i.p. administration of the
      reference cannabinoid CB(1) receptor agonists HU-210 [(-)-11-OH-Delta(8)
      tetrahydrocannabinol-dimethylheptyl, ED(50): 0.003 mg/kg], CP 55,940 [(-)-cis-3
      [2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol,
      0.007 mg/kg], WIN 55,212-2 [(R)-4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1
      naphtalenylcarbonyl)-6H-pyrrolo [3,2,1-ij] quinolin-6-one, 0.28 mg/kg] and (-)
      Delta(9)-tetrahydrocannabinol (0.34 mg/kg). The present study confirms that BAY
      38-7271 is a highly potent cannabinoid CB(1) receptor agonist in vivo.

PMID- 12464361
TI  - Structural requirements for the interaction of sheep insulin-like factor 3 with
      relaxin receptors in rat atria.
AB  - Relaxin is a peptide with various reproductive and nonreproductive functions. The
      site for the peptide-receptor interaction contains two arginines (Arg) and an
      isoleucine (Ile) or valine (Val) residue in the B-chain with a configuration of 
      Arg-X-X-X-Arg-X-X-Ile/Val-X-. The sheep insulin-like peptide 3 (INSL3), a
      structural homologue of relaxin, also contains the n, n+4 arginines in the B
      chain but they are displaced towards the carboxyl terminus by four residues (-X-X
      X-X-Arg-X-X-Val-Arg-). Human INSL3 increases the activity of human relaxin in
      mouse bioassays. Here, we investigated whether sheep synthetic INSL3 affects the
      relaxin activity in rat atria. INSL3 lacked relaxin-like agonist activity but
      blocked the activity of relaxin and competed for relaxin binding sites at high
      concentrations. We also synthesized analogues of INSL3, with amino acid
      substitutions in the arginine-binding region. Analogues A, D and E, which have
      the arginines in positions identical to relaxin, showed weak relaxin-like agonist
      activity. These results suggest that other sites in the relaxin molecule are
      involved in high-affinity peptide-receptor interaction for the production of the
      relaxin biological responses.

PMID- 12464362
TI  - Coronary reactivity to endothelin-1 during partial ischemia and reperfusion in
      anesthetized goats. Role of nitric oxide and prostanoids.
AB  - To examine the coronary reactivity to endothelin-1 and its interaction with
      nitric oxide or prostanoids during partial coronary ischemia and reperfusion,
      left circumflex coronary artery flow was electromagnetically measured, and
      partial occlusion of this artery was induced for 60 min, followed by reperfusion
      in anesthetized goats (eight non-treated, six treated with N(w)-nitro-L-arginine
      methyl esther (L-NAME) and five treated with meclofenamate). During partial
      occlusion, coronary vascular conductance was reduced by 24-37% (P<0.01), and the
      coronary vasodilatation in response to acetylcholine (3-100 ng) and sodium
      nitroprusside (1-10 microg) was much decreased in every case; the
      vasoconstriction in response to endothelin-1 (1-10 microg) was depressed in non
      treated animals, and this depression was reversed by L-NAME and was accentuated
      by meclofenamate. At 30 min of reperfusion coronary vascular conductance remained
      decreased by 22-27% (P<0.01), and the vasodilatation in response to acetylcholine
      (3-100 ng) and sodium nitroprusside (1-10 microg), as well as the
      vasoconstriction with endothelin-1 (1-10 microg), were as in the control and
      comparable in the three groups of animals. These results suggest: (a) that during
      ischemia, the coronary vasodilator reserve is greatly reduced, and the
      vasoconstriction with endothelin-1 is blunted, with preservation of the
      modulatory role of nitric oxide and involvement of vasoconstrictor prostanoids in
      this vasoconstriction, and (2) that during reperfusion, the coronary vasodilator
      reserve and the coronary reactivity to acetylcholine and endothelin-1 recover,
      but the modulatory role of nitric oxide in this reactivity may be attenuated.

PMID- 12464363
TI  - Effects of evodiamine on gastrointestinal motility in male rats.
AB  - The effects of evodiamine on gastric emptying, gastrointestinal transit, and
      plasma levels of cholecystokinin (CCK) were studied in male rats. Evodiamine,
      isolated from the dry unripened fruit of Evodia rutaecarpa Bentham (a Chinese
      medicine named Wu-chu-yu), has been recommended for abdominal pain, acid
      regurgitation, nausea, diarrhea, and dysmenorrhea. Gastrointestinal motility was
      assessed in rats 15 min after intragastric instillation of a test meal containing
      charcoal and Na(2)51CrO(4). 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 CCK radioimmunoassay (RIA). After administration
      of evodiamine (0.67-6.00 mg/kg), both gastric emptying and gastrointestinal
      transit were inhibited, whereas the plasma concentration of CCK was increased in
      a dose-dependent manner. The selective CCK(1) receptor antagonists, devazepide
      and lorglumide, effectively attenuated the evodiamine-induced inhibition of
      gastric emptying and gastrointestinal transit. L-365,260 (3R-(+)-N-(2,3-dihydro-1
      methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylphenyl)-urea), a
      selective CCK(2) receptor antagonist, did not alter the evodiamine-induced
      inhibition of gastric emptying and gastrointestinal transit. These results
      suggest that evodiamine inhibits both gastric emptying and gastrointestinal
      transit in male rats via a mechanism involving CCK release and CCK(1) receptor
      activation.

PMID- 12464364
TI  - Investigation of the potential modulatory effect of biliverdin, carbon monoxide
      and bilirubin on nitrergic neurotransmission in the pig gastric fundus.
AB  - In porcine gastric fundus, we have investigated the colocalization of the bile
      pigment biosynthetic enzymes heme oxygenase-2 and biliverdin reductase with
      neuronal nitric oxide synthase (nNOS), the effect of carbon monoxide (CO) on
      fundic circular smooth muscle and the possible modulatory effect of the bile
      pigments biliverdin and bilirubin on CO-mediated relaxations and on nitrergic
      relaxation. Heme oxygenase-2 and biliverdin reductase immunoreactivity was
      present in all nNOS containing myenteric neurons. CO induced a concentration
      dependent relaxation of fundic circular smooth muscle strips, which was
      completely blocked by the specific guanylate cyclase inhibitor 1H
      (1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). 3-(5'-hydroxymethyl-2'-furyl)-1
      benzylindazole (YC-1), biliverdin and bilirubin strongly enhanced the amplitude
      of the CO-induced relaxation. Tin protoporphyrin had no effect on electrically
      induced nitrergic relaxation, but spectrophotometric analysis learned that
      incubation of porcine gastric fundus circular muscle strips with tin
      protoporphyrin did not influence heme oxygenase activity. In conclusion, our data
      suggest that nitrergic neurons in the pig gastric fundus are able to produce
      biliverdin and bilirubin, and that these agents potentiate the relaxant effect of
      CO, which is formed concomitantly with biliverdin by heme oxygenase-2.

PMID- 12464365
TI  - Gossypol induces chloride secretion in rat proximal colon.
AB  - The effect of gossypol on electrolyte transport was investigated in rat colon
      mounted in Ussing chambers. The addition of gossypol to the mucosal or serosal
      side led to an increase in mucus secretion, which we did not quantify. Mucosally
      or serosally added gossypol also induced a rise in short circuit current (I(sc))
      and tissue conductance (G(t)). Part of the mucosally added gossypol seemed to be
      bound to the mucus because the effects on I(sc) and G(t) were smaller when
      gossypol was added to the mucosal side. Serosally added gossypol had an effect on
      I(sc) at a concentration of 10 micromol l(-1). Mucus secretion was reduced in low
      Ca(2+) buffer. The increase in I(sc) was diminished by blockers of Cl- channels,
      K+ channels, of the Na+/K+ ATPase and of the Na+/K+/2 Cl- cotransporter.
      Measurements of unidirectional ion fluxes showed that gossypol added to the
      mucosal side had no effect on net Na+ transport, but increased Cl- secretion. The
      effect of mucosally added gossypol was significantly reduced by the use of low Cl
      buffers and abolished when the buffer was additionally depleted of HCO(3)(-).
      Calmodulin antagonists inhibited the effect on secretion. These findings indicate
      that gossypol induces chloride secretion via a calmodulin-dependent mechanism.
      High concentrations of gossypol induced a strong increase in G(t) that could be
      blocked by W7, a blocker of calmodulin-dependent myosin light chain kinase. This
      indicates that the rise in G(t) is not due to an unspecific toxic effect, but
      instead, to specific opening of tight junctions.

PMID- 12464366
TI  - Aerosolized perfluorocarbon reduces adhesion molecule gene expression and
      neutrophil sequestration in acute respiratory distress.
AB  - In acute respiratory distress syndrome, neutrophil migration into the lung plays
      a key role in the development of lung injury. To study the effect of different
      modes of ventilation with perfluorocarbon (FC77), intrapulmonary neutrophil
      accumulation and mRNA expression of E-selectin, P-selectin and intercellular
      adhesion molecule-1 (ICAM-1), mediating leukocyte sequestration, were measured in
      surfactant depleted piglets. After bronchoalveolar lavage, 20 animals either
      received aerosolized perfluorocarbon (Aerosol-PFC), partial liquid ventilation
      (PLV) with perfluorocarbon at functional residual capacity filling volume (FRC
      PLV) or at low volume (LV-PLV) or intermittent mandatory ventilation (control).
      After 2 h of perfluorocarbon application, intermittent mandatory ventilation was
      continued for 6 h. In the Aerosol-PFC group, all measured adhesion molecules
      showed a significantly reduced gene expression compared to controls. FRC-PFC
      treatment was effective in significantly diminishing P-selectin and ICAM-1 mRNA
      expression. Relative lung tissue neutrophil counts were significantly reduced in
      the Aerosol-PFC and the FRC-PLV group. Treatment with aerosolized perfluorocarbon
      is at least as effective as partial liquid ventilation at FRC volume in reducing
      pulmonary adhesion molecule expression and neutrophil accumulation in acute
      respiratory distress syndrome.

PMID- 12464367
TI  - Effect of chronic administration of a CRF(1) receptor antagonist, CRA1000, on
      locomotor activity and endocrine responses to stress.
AB  - Corticotropin-releasing factor (CRF) is involved in the regulation of stress
      responses. The actions of CRF in the brain are mediated through two distinct CRF
      receptor subtypes, CRF(1) and CRF(2) receptors. In the present study, we examined
      the effects in rat of chronic administration of a nonpeptidic CRF(1) receptor
      selective antagonist, CRA1000, 2-[N-(2-methylthio-4-isopropylphenyl)-N
      ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6
      methylpyrimidine), on locomotor activity, feeding behavior and the hypothalamic
      pituitary-adrenal axis. Chronic CRA1000 treatment significantly decreased
      locomotor activity in the dark phase of the diurnal cycle. However, chronic
      CRA1000 treatment showed no effect on food and water intake, or on body weight.
      After a 10-day period of CRA1000 treatment, plasma concentrations of
      adrenocorticotropic hormone (ACTH) and corticosterone in basal conditions and
      under immobilization stress were no different from those in rats treated with
      vehicle. However, CRA1000 administered 2 h before immobilization stress
      significantly reduced ACTH and corticosterone responses to stress with no effect
      on basal ACTH and corticosterone concentrations. These results suggest that
      CRF(1) receptors are involved in the regulation of locomotor activity during the
      dark period, but are not involved in the regulation of feeding behavior under non
      stressful conditions. Furthermore, the results suggest that a 10-day treatment
      with CRA1000 does not affect hypothalamic-pituitary-adrenal axis activity either
      under basal conditions or after acute stress.

PMID- 12464368
TI  - Blockade of glucocorticoid receptors with ORG 34116 does not normalize stress
      induced symptoms in male tree shrews.
AB  - Glucocorticoid receptors play an important role in the regulation of the activity
      of the hypothalamo-pituitary-adrenal axis, and are thought to be involved in the
      pathophysiology of depressive disorders. The present study investigated the
      effect of the specific glucocorticoid receptor antagonist ORG 34116 (a
      substituted 11,21 bisarylsteroid compound) in the tree shrew (Tupaia belangeri)
      chronic psychosocial stress model, an established animal model for depressive
      disorders. Animals were stressed for 10 days before treatment with ORG 34116
      started (25 mg/kg p.o. for 28 days). Stress induced a decrease in body weight,
      which just failed significance, whereas ORG 34116 did not affect body weight in
      stress and control animals. ORG 34116 enhanced the stress-induced increase in the
      concentration of urinary-free cortisol, although no differences between the
      different experimental groups existed during the last week of treatment. In
      stressed animals, ORG 34116 did not affect marking behavior, but decreased
      locomotor activity. Post mortem analysis of 5-HT(1A) receptors revealed a
      decreased affinity of 3[H]-8-OH-DPAT (3[H]-8-hydroxy-2-[di-n
      propylamino]tetralin) binding sites in the hippocampus of animals treated with
      the glucocorticoid receptor antagonist. In conclusion, under our experimental
      conditions, the glucocorticoid receptor antagonist ORG 34116 did not normalize
      the depressive-like symptoms in the psychosocial stress model of male tree
      shrews. This finding, however, does not exclude that specific central,
      neuroendocrine and behavioral features are affected by the compound.

PMID- 12464370
TI  - Social class and mortality in older women.
AB  - In middle-aged people, social class is one of the strongest predictors of
      mortality. However, to date, research prospectively evaluating the relationship
      between social class and mortality in the older persons has produced conflicting
      results. This may be due to the lack of clinical covariates in many analyses. The
      objective of this study was to determine the relationship between social class
      markers-education, income, husband's work history, and personal work history-and
      mortality in a cohort of older women, after adjusting for clinical and behavioral
      factors. The participants were 737 ambulatory, community-living women, age 72 and
      older, followed from 1989 to 1993. In addition to education attained, present
      income, husband's work history, and personal work history, proportional hazard
      models adjusted for age, race, marital status, number of chronic conditions,
      number of medications used, Activities of Daily Living status, Mini-Mental State
      Exam score, physical activity, and alcohol use. In multivariable models personal
      work history was the only social class marker that remained significantly
      associated with mortality. Compared with managers and professionals, women who
      never worked outside the home had a 3.5 greater risk of death (95% CI, 1.6-7.5),
      while women who had worked in partly/unskilled or skilled professions were over
      two and a half times more likely to die; the adjusted hazard ratios were 2.7 (95%
      CI, 1.2-6.4) and 2.7 (95% CI, 1.3-5.7), respectively. In this population of older
      women, personal work history was the only social class marker predictive of
      mortality.

PMID- 12464371
TI  - Alcohol consumption and incidence of dementia in a community sample aged 75 years
      and older.
AB  - To explore the relationship between light to moderate alcohol consumption and
      risk of dementia and Alzheimer's disease in very old people, a community-based
      dementia-free cohort (n = 402) was followed for almost 6 years to detect incident
      dementia using the Diagnostic and Statistical Manual of Mental Disorders, 3rd
      Edition-Revised criteria. Data from the entire cohort and a subpopulation of
      those with baseline Mini-Mental State Examination score > or =24 (n = 317) were
      analyzed with Cox models. In the entire population, light to moderate drinking
      was significantly associated with a decreased risk of incident dementia and
      Alzheimer's disease compared with nondrinking (adjusted relative risk 0.5, 95%
      confidence interval 0.3 to 0.7). In the analysis of the subpopulation, however,
      the inverse association between light to moderate drinking and risk of incident
      dementia and Alzheimer's disease was less evident and no longer statistically
      significant. This study suggested that light to moderate alcohol drinking might
      protect against dementia and Alzheimer's disease among old people, although the
      possibility that such an association may be due to information bias cannot be
      totally ruled out.

PMID- 12464372
TI  - Tiredness in daily activities among nondisabled old people as determinant of
      onset of disability.
AB  - The purpose of this article was to examine whether self-reported tiredness in
      daily activities at age 75 is an independent determinant of onset of disability
      at 5-year follow-up. The investigation is based on two subgroups of nondisabled
      participants of 75 year olds who survived and participated in the follow-up study
      5 years later (n = 510 and 429). Persons who felt tired in their daily activities
      had a larger risk of becoming disabled in mobility (OR = 3.2, 95% CI = 1.4-7.6)
      and in daily activities (OR = 2.1, 95% CI = 1.0-4.2) compared to persons without
      tiredness. In addition, persons with poor cognitive function, little diversity in
      social relations and no physical activity had an independent risk of onset of
      disability. The results indicate that it is important to take it seriously when
      older people complain about tiredness in daily activities, as these people are at
      higher risk of becoming disabled than others.

PMID- 12464373
TI  - The effects of aging and radiation exposure on blood pressure levels of atomic
      bomb survivors.
AB  - The Adult Health Study (AHS) is a longitudinal study that has included biennial
      blood pressure measurements since 1958. In the present study, we applied the
      mixed effects model for serially measured data on the AHS population to (1)
      examine age-related changes in blood pressure and (2) detect possible radiation
      effects. The estimated longitudinal model of systolic blood pressure (SBP)
      depicted a linear increase from 30 to 80 years of age for both sexes. The
      diastolic blood pressure (DBP) rose linearly to about 65 years of age and then
      leveled off. There were marked differences in the longitudinal trends of DBP
      among birth cohorts, particularly for men, with higher DBP levels in the younger
      cohort. The present analysis demonstrated a small but statistically significant
      effect of ionizing radiation on the longitudinal trends of both SBP and DBP. This
      phenomenon is compatible with the degenerative effect of ionizing radiation on
      blood vessels.

PMID- 12464374
TI  - Risk factors for development of systemic lupus erythematosus: allergies,
      infections, and family history.
AB  - We examined risk factors for systemic lupus erythematosus (SLE) in 265 recently
      diagnosed patients in North Carolina and South Carolina and 355 control subjects
      identified through driver's license records and frequency matched to patients by
      age, sex, and state. Analyses were limited to exposures before diagnosis (cases)
      or reference year (control subjects). SLE patients were more likely than control
      subjects to report a history of allergy to medications (odds ratio [OR] 3.1, 95%
      confidence interval [CI], 2.1-4.5), particularly to antibiotics. SLE risk
      increased with history of shingles (OR 2.5, 95% CI 1.1-5.9) and with frequent
      (more than once per year) cold sores in the 3 years before diagnosis (OR 2.8, 95%
      CI 1.4-5.4). There was little association with history of mononucleosis, a marker
      of late infection with Epstein-Barr virus, implanted medical devices, or
      hepatitis B vaccination. History of lupus in parents or siblings was associated
      with an increased risk (OR 3.3, 95% CI 1.2-8.6). Further research is needed to
      clarify whether medication allergies and specific infectious agents are involved
      in the etiology of SLE. Published by Elsevier Science Inc.

PMID- 12464375
TI  - Body mass index (BMI) and waist circumference (WC) as screening tools for
      cardiovascular risk factors in Guadeloupean women.
AB  - Hypertension, dyslipidemia and type 2 diabetes, important cardiovascular risk
      factors, are strongly linked to obesity. Body mass index (BMI) and waist
      circumference (WC) are measures of obesity that can be useful in identifying
      individuals with these risk factors. We assessed which of the two measures is
      more informative at the population level. The study population included 5,149
      consecutive women aged 18 to 74 recruited in an Health Center of Guadeloupe (FWI)
      in 1999. The areas under the ROC curves of BMI and WC and their 95% CI were
      computed and compared. Logistic regression analysis of BMI and WC and the areas
      under the ROC curves in two separate age groups (18-39 years and 40-74 years)
      showed that age modifies the discriminant ability of these parameters in
      identifying the CVD risk factors. Sensitivity equalled specificity at levels
      between 52-70% for BMI and 55-80% for WC. ROC areas for identifying each risk
      factors by BMI varied from 0.52 to 0.84 and by WC from 0.55 to 0.88. For the
      identifying of women with at least one CVD risk factor, in the whole population,
      the areas under the curves for BMI and WC (respectively, 0.71; 95% CI: 0.69-0.73
      and 0.76; 95% CI: 0.74-0.78) were both significantly greater than 0.5. The
      difference between these correlated areas was 0.04, 95% CI [-0.05, -0.03]. The
      lowest values of the areas were noted in detecting women with dyslipidemia and
      the highest in detecting those with type 2 diabetes. Waist circumference, a
      practical tool that had a higher discriminant ability than BMI in identifying
      presence or absence of all these risk factors, appears as the best screening tool
      in this population.

PMID- 12464376
TI  - Relation of self-rated measures of physical activity to multiple risk factors of
      insulin resistance syndrome in young adults: the Bogalusa Heart Study.
AB  - The relation of self-rated measures of physical activity to multiple risk factors
      of insulin resistance syndrome (IRS) was examined in African American (n = 409)
      and white (n = 1,011) young adults aged 20 to 38 years enrolled in the Bogalusa
      Heart Study. Physical activity was assessed in terms of work activity, leisure
      time activity, television watching, and video game playing by a questionnaire.
      Waist circumference, blood pressure, total to high-density lipoprotein
      cholesterol ratio, and insulin resistance index showed a consistent inverse trend
      with leisure-time activity (P < 0.01) and a positive trend with hours of
      inactivity (P < 0.01) after adjusting for age, race, and sex. An inverse
      relationship was seen between leisure-time activity and mean number of risk
      factors (>75th percentile for age, race, and sex) (P < 0.001), whereas a positive
      relationship was seen with hours of inactivity (P < 0.001). Moderately to very
      active individuals versus inactive individuals had a reduced relative risk of
      having > or =3 risk factors (P < 0.05); conversely, excess hours of inactivity
      increased the relative risk (P < 0.05). Thus, leisure-time activity and hours of
      inactivity are important predictors of multiple cardiovascular risk variables of
      IRS in young adults.

PMID- 12464377
TI  - The impact of somatic and cognitive disorders on the functional status of the
      elderly.
AB  - To estimate the relative effects of coexisting nondementia illnesses on the
      probability of functional disability, depending on the presence of cognitive
      impairment or dementia, we used data from the baseline case-control assessment of
      a longitudinal study of aging and dementia. Our study included 668 subjects (345
      nondemented, 98 cognitively impaired, and 225 demented), aged 75 and older.
      Demented subjects had greater disability prevalence on all specific instrumental
      activities of daily living (IADL) and activities of daily living (ADL) items than
      cognitively impaired subjects who, in turn, had greater disability than
      nondemented subjects. Somatic illnesses were found to be associated with
      particular tasks in item specific models; decreasing MMSE was strongly associated
      with the probability of IADL and ADL disability, which increased dramatically in
      the presence of somatic illnesses among cognitively impaired as well as demented
      subjects. Attention to illnesses among cognitively impaired and demented people
      may shed light on remediable factors crucial to their daily functioning.

PMID- 12464378
TI  - Generalized synthesis of evidence and the threat of dissemination bias. the
      example of electronic fetal heart rate monitoring (EFM).
AB  - Assessment of the potential impact of dissemination bias is necessary for meta
      analysis. When evidence is available from studies of different designs, the
      different study types may be affected by dissemination bias to differing degrees.
      The evidence relating to electronic fetal heart rate monitoring (EFM) for
      preventing perinatal mortality is used to explore the feasibility of carrying out
      a dissemination bias assessment in a generalized synthesis of evidence (gse)
      framework. Visual inspection of funnel plots, statistical tests, and methods to
      "adjust" the results of a meta-analysis are all used in an extensive sensitivity
      analysis. The potential impact of dissemination bias on gse models synthesizing
      all the evidence together is also reported. Detailed consideration is given to
      the influence of meta-analysis model choice, and outcome scale used. Using the
      risk difference scale, funnel plots of the observational studies appeared highly
      asymmetric. However, further explorations show these conclusions are not robust
      over use of different outcome measures or different meta-analysis models.
      Researchers should be aware that dissemination bias may affect different sources
      of evidence differently. Although assessments such as those described here are
      recommended, awareness of their lack of robustness to outcome scale and model
      choice is important. Further research into methods to assess dissemination bias
      that are invariant to these factors is needed.

PMID- 12464379
TI  - Human papillomavirus testing for triage of women referred because of abnormal
      smears. a decision analysis considering outcomes and costs.
AB  - The objective of this article was to evaluate the utility of high-risk human
      papillomavirus (HR-HPV) testing for triage of women referred for colposcopy
      because of abnormal smears. We considered women with persistent mild or moderate
      dyskaryosis and women with severe dyskaryosis who were referred for colposcopy.
      For both patient groups we evaluated three alternative management policies: (1)
      conventional management based on histological assessment; (2) HR-HPV-triage with
      direct treatment without prior histologic assessment for HR-HPV-positive women
      and conventional management for HR-HPV-negative women; and (3) direct treatment
      without histologic assessment for all referred women. For each policy the average
      number of medical procedures, doctor visits, and the costs per referred woman
      were calculated. Based on a literature review, the results were tested and
      translated to other patient groups. Per woman with persistent mild or moderate
      dyskaryosis and compared with conventional policy, HR-HPV-triage will avoid 0.51
      colposcopically directed biopsies, but adds 0.05 local treatments of the cervix
      (i.e., loop excision of the transformation zone) and 0.09 outpatient visits, and
      will cost $134 US dollars extra. HPV triage is less efficient in women with
      borderline or mildly dyskaryotic cytology. In women with severe dyskaryosis,
      direct treatment is more efficient as conventional management or HPV triage. The
      decision to introduce HPV testing or direct treatment in women with persistent
      mild or moderate dyskaryosis strongly depends on the relative burden attributed
      to a colposcopically directed biopsy and an outpatient visit compared to loop
      excision of the transformation zone treatment of the cervix. For women with
      severe dyskaryosis, direct treatment should be seriously considered.

PMID- 12464380
TI  - Analysis of nonresponse bias in a population-based case-control study on lung
      cancer.
AB  - The objective of this study was to identify characteristics of nonrespondents and
      late respondents in a population-based case-control study on lung cancer
      conducted in the city of Turin (Italy). Information about demographic and
      socioeconomic variables of 634 cases and 859 controls who responded to an
      interview, as well as of 154 cases and 154 controls who did not respond were
      obtained from census and the public register of Turin. The socioeconomic level of
      nonrespondents was high in cases but low in controls. Late respondent controls
      (i.e., individuals who responded after contact through their general
      practitioner) had socioeconomic characteristics comparable with those of
      nonrespondents, while they were similar to respondents with respect to
      demographic variables. The interview of late respondents halved, from 14 to 7%,
      the magnitude of the bias introduced by nonresponse on the estimate of the
      association between educational level and lung cancer. Nonresponse, associated
      with socioeconomic status, is an important potential source of bias in population
      based case-control studies, which should always be considered and discussed. The
      direction and magnitude of the bias can be quantified. General practitioners may
      contribute to decrease nonresponse bias. Caution should be used in inferring
      characteristics of nonrespondents on the basis of those of late respondents.

PMID- 12464381
TI  - Initial validation of a questionnaire for detecting gastroesophageal reflux
      disease in epidemiological settings.
AB  - There is a high prevalence of gastroesophageal reflux disease (GERD) in the
      general population. Prevalence studies are scarce, and there is a lack of valid
      instruments for measuring them. The aim of this paper is to validate a
      questionnaire for detecting GERD. A validity study design with pathologic GERD
      patients and controls was used. A sample of 240 subjects age and sex paired was
      selected in the ratio of 3:1 (patients to controls). The initial structured
      questionnaire contained a variety of GERD symptoms. Internal consistency,
      interobserver reliability, criteria validity using 24-h esophageal pH monitoring,
      construct validity, and extreme group validation were assessed. Sensitivity,
      specificity, and predictive values were also obtained in different cutoff points
      of the definitive scale. A total of 180 confirmed GERD patients and 60 controls
      were included in the study. Mean age in years was 45 +/- 13, with no statistical
      difference by gender (67% were female). Internal consistency of 0.75 and
      interobserver reliability of 0.87 was achieved in building the scale. Extreme
      group validation was highly significant by assessing the scale score with 24-h
      esophageal pH monitoring (P <.0001). At cutoff point 3 of the scale and with a
      correct classification of subjects of 92.4%, sensitivity, specificity, positive,
      and negative predictive values were 92, 95, 98, and 79%, respectively. The
      conclusion of this article is that a reliable and valid instrument was built to
      detect GERD.

PMID- 12464382
TI  - An experiment of mailing physician surveys on two different issues in joint or
      separate mail.
AB  - High response rates from physicians play an important role in obtaining valid
      data on practice patterns. We wanted to know whether two questionnaires (one on
      hernia surgery and one on perioperative pain management) should better be sent
      out in one letter or two separate letters. We randomized 2,393 surgeons who
      received the two questionnaires either in one letter or by separate mail, in two
      letters, at a time interval of 4 weeks. The response rate for the separate
      mailout was not significantly higher when compared to the joint mailout. The
      differences were 3.3% (95%-CI -0,4% to 7.1%) and 2.2% (95%-CI -1,4% to 5.9%) for
      the two surveys. Due mainly to higher postage costs, the costs per response were
      doubled in the separate mailout group (5.85 Euro versus 2.93 Euro). Sending out
      two surveys separately seems to have only little effect on the response rates.

PMID- 12464383
TI  - Concomitant prescribing of benzodiazepines during antidepressant therapy in the
      elderly.
AB  - A follow-up study was performed in two ambulatory cohorts aged > or =65 to
      investigate whether the prevalence and incidence of anxiolytic/hypnotic
      benzodiazepine drug prescribing is comparable between users of serotonin reuptake
      inhibitors (SSRIs) and users of tricyclic antidepressants (TCAs). The prevalence
      and incidence of benzodiazepines during antidepressant therapy was estimated
      among users of TCAs and SSRIs. Coprescribing of benzodiazepines occurred in 53%
      of the TCA users and 57% of the SSRI users (prevalence RR 1.1; CI(95) 0.9-1.2).
      The average duration of benzodiazepine drug use was >65 days per 100 days of
      antidepressant use. During SSRI therapy, significantly more people started
      benzodiazepine drug therapy than during TCA therapy (incidence rate ratio (RR)
      1.7; CI(95) 1.2-2.4). Analyses repeated 5 years later yielded similar results
      (overall incidence RR(MH) 1.6; CI(95) 1.3-2.0). These data indicate that SSRI use
      is associated with a significantly higher chance of starting benzodiazepines
      compared with TCA use.

PMID- 12464384
TI  - Should scoring rules be based on odds ratios or regression coefficients?

PMID- 12464385
TI  - Intracellular signals involved in the effects of insulin-like growth factors and
      neuregulins on myofibre formation.
AB  - A number of extracellular factors are involved in the embryonic development of
      skeletal muscle and the muscle regeneration that is triggered in response to
      muscle damage. Some of them, such as insulin-like growth factors (IGFs),
      fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), transforming
      growth factor (TGF)-like molecules, leukemia inhibitor factor (LIF) or platelet
      derived growth factors (PDGFs), are involved in the activation of cell
      proliferation that operates before muscle differentiation. In addition, factors
      such as IGFs, neuregulins (NRGs), sonic hedgehog (Shh) or Wnt promote muscle
      differentiation. Here, we review the intracellular signals that are triggered in
      the myogenic effect of IGFs and neuregulin and we describe common pathways. A
      fuller understanding of the signalling pathways triggered by these factors may
      permit the design of new tools for muscle regeneration therapy.

PMID- 12464386
TI  - Voltage-gated sodium channels as primary targets of diverse lipid-soluble
      neurotoxins.
AB  - Voltage-gated Na(+) channels are heteromeric membrane glycoproteins responsible
      for the generation of action potentials. A number of diverse lipid-soluble
      neurotoxins, such as batrachotoxin, veratridine, aconitine, grayanotoxins,
      pyrethroid insecticides, brevetoxins and ciguatoxin, target voltage-gated Na(+)
      channels for their primary actions. These toxins promote Na(+) channel opening,
      induce depolarization of the resting membrane potential, and thus drastically
      affect the excitability of nerve, muscle and cardiac tissues. Poisoning by these
      lipid-soluble neurotoxins causes hyperexcitability of excitable tissues, followed
      by convulsions, paralysis and death in animals. How these lipid-soluble
      neurotoxins alter Na(+) channel gating mechanistically remains unknown. Recent
      mapping of receptor sites within the Na(+) channel protein for these neurotoxins
      using site-directed mutagenesis has provided important clues on this subject.
      Paradoxically, the receptor site for batrachotoxin and veratridine on the voltage
      gated Na(+) channel alpha-subunit appears to be adjacent to or overlap with that
      for therapeutic drugs such as local anaesthetics (LAs), antidepressants and
      anticonvulsants. This article reviews the physiological actions of lipid-soluble
      neurotoxins on voltage-gated Na(+) channels, their receptor sites on the S6
      segments of the Na(+) channel alpha-subunit and a possible linkage between their
      receptors and the gating function of Na(+) channels.

PMID- 12464387
TI  - PDGF inactivates forkhead family transcription factor by activation of Akt in
      glomerular mesangial cells.
AB  - Regulation of the forkhead domain transcription factors by PDGF has not been
      studied. In this report, we investigated the role of PDGF-induced Akt in
      regulating forkhead domain protein FKHRL1 in glomerular mesangial cells. PDGF
      increased phosphorylation of FKHRL1 in a time- and PI 3 kinase-dependent manner.
      Expression of dominant negative Akt by adenovirus-mediated gene transfer blocked
      PDGF-induced FKHRL1 phosphorylation. PDGF inhibited transcription of a forkhead
      DNA binding element-driven reporter gene. This inhibition was mimicked by
      constitutively active myristoylated Akt. Moreover, FKHR1-mediated transcription
      of the reporter gene was completely attenuated by both PDGF and Myr-Akt. One of
      the targets of forkhead transcription factors is the proapoptotic Fas ligand
      (FasL) gene. PDGF, as well as Myr-Akt, inhibited transcription of FasL. In
      contrast, inhibition of PI 3 kinase and dominant negative Akt increased FasL gene
      transcription, suggesting that suppression of PI 3 kinase/Akt signalling may
      induce apoptosis in mesangial cells via upregulation of FasL expression. However,
      expression of dominant negative Akt by adenovirus did not induce apoptosis in
      mesangial cells, suggesting that Akt-independent antiapoptotic mechanisms also
      exist. Together, our data demonstrate for the first time that PDGF inactivates
      forkhead domain transcription factor by Akt-dependent phosphorylation and that
      suppression of Akt signalling is not sufficient to induce apoptosis in mesangial
      cells.

PMID- 12464388
TI  - The Shb adaptor protein causes Src-dependent cell spreading and activation of
      focal adhesion kinase in murine brain endothelial cells.
AB  - The mechanisms leading to focal adhesion kinase (FAK) activation remain obscure.
      We have investigated the role of the adaptor protein Shb in cell spreading and
      the regulation of FAK phosphorylation in immortalised brain endothelial (IBE)
      cells. Fibroblast growth factor 2 (FGF-2) stimulation lead to a direct
      association between Shb and FAK, which was mediated by the phosphotyrosine
      binding (PTB) domain of Shb. IBE cells overexpressing wild-type or R522K Shb
      (with an inactive Src homology 2 (SH2) domain) displayed increased FAK
      phosphorylation as well as enhanced spreading when seeded on collagen. FGF-2
      induced tyrosine phosphorylation of Shb was dependent upon Src activity but
      independent of FAK activation. The use of Rat-1 fibroblasts overexpressing a
      temperature sensitive v-Src (tsLA29) confirmed that active Src enhanced Shb
      phosphorylation. The data indicate that Shb binds directly to FAK and regulates
      its phosphorylation leading to enhanced cell spreading in a Src-dependent manner.

PMID- 12464389
TI  - Growth/differentiation factor-5 induces growth arrest and apoptosis in mouse B
      lineage cells with modulation by Smad.
AB  - Bone morphogenetic proteins, including growth/differentiation factor-5 (GDF-5),
      are multifunctional cytokines. Recent studies of intracellular signal
      transduction mechanisms for the transforming growth factor-beta superfamily have
      focused on Smad proteins. However, scant attention has been given to the
      mechanism by which GDF-5 exerts its negative growth effect on immunological
      competent cells. In the present study, we demonstrated that GDF-5 induced cell
      cycle arrest in the G1 phase before the appearance of apoptosis in mouse B cell
      hybridoma HS-72 cells, while the ectopic expression of Smad6 and Smad7 in HS-72
      cells suppressed the GDF-5-induced G1 cell cycle arrest by abolishing the
      expression of p21(CIP-1/WAF-1) and hypophosphorylation of retinoblastoma protein.
      Moreover, we found that Smad6 and Smad7 suppressed GDF-5-induced apoptosis in HS
      72 cells. These findings indicated that Smad6 and Smad7 exhibit inhibitory
      effects toward GDF-5-mediated signaling in B lineage cells.

PMID- 12464390
TI  - Major occurrence of the new alpha2beta1 isoform of NO-sensitive guanylyl cyclase
      in brain.
AB  - NO-sensitive guanylyl cyclase (GC) acts as the effector molecule for NO and
      therefore plays a key role in the NO/cGMP signalling cascade. Besides the long
      known GC isoform (alpha(1)beta(1)), another heterodimer (alpha(2)beta(1)) has
      recently been identified to be associated with PSD-95 in brain.Here, we report on
      the tissue distribution of all known guanylyl cyclase subunits to elucidate the
      isoform content in different tissues of the mouse. The guanylyl cyclase subunit
      levels were assessed with quantitative real-time PCR, and the most important
      results were verified in Western blots. We demonstrate the major occurrence of
      the alpha(2)beta(1) heterodimer in brain, find a significant amount in lung and
      lower amounts in all other tissues tested. In brain, the levels of the
      alpha(2)beta(1) and alpha(1)beta(1) isoforms were comparable; in all other
      tissues, the alpha(1)beta(1) heterodimer was the predominating isoform. The
      highest guanylyl cyclase content was found in lung; here the GC amounted to
      approximately twice as much as in brain. In sum, the major occurrence of the
      alpha(2)beta(1) heterodimer suggests a special role in synaptic transmission;
      whether this isoform outside the brain also occurs in neuronal networks has to be
      addressed in future studies.

PMID- 12464391
TI  - Endothelin-1 stimulated capacitative Ca2+ entry through ET(A) receptors of a rat
      brain-derived type-1 astrocyte cell line, IA-1g1.
AB  - The present study demonstrated that endotheline-1 (ET-1) stimulated a biphasic
      (transient and sustained) increase in [Ca(2+)](i) and signaling was blocked by
      BQ123 and inhibited by BQ788. RT-PCR analysis revealed that ET(A) was expressed
      more than ET(B) mRNA-suggesting that ET(A) is the major receptor. Simply
      reintroducing Ca(2+) in the buffer stimulated a sustained increase in [Ca(2+)](i)
      and the effect was inhibited by U73122, thapsigargin (TG), miconazole and
      SKF96365. When measured in Ca(2+)-free buffer, the ET-1-stimulated Ca(2+)
      transient decreased by 73% and the reintroduction of Ca(2+) induced a large
      sustained increase in [Ca(2+)](i). These effects were not affected by nifedipine,
      but were inhibited by miconazole and SKF96365-indicating that the sustained
      increase in [Ca(2+)](i) mediated by ET-1 was mostly due to capacitative Ca(2+)
      entry (CCE). The ET-1-induced CCE was inhibited by phorbol ester (PMA) but was
      enhanced by GF109203X; it was also enhanced by 8-bromo-cyclic AMP (8-Br-cAMP) but
      was inhibited by H89. Thus, protein kinase C (PKC) negatively regulated and cAMP
      dependent protein kinase (PKA) positively regulated the ET-1-mediated CCE in
      these cells.

PMID- 12464392
TI  - Norepinephrine induces slow calcium signalling in murine brown preadipocytes
      through the beta-adrenoceptor/cAMP/protein kinase A pathway.
AB  - The mechanism of adrenergically activated calcium signalling in isolated murine
      brown preadipocytes (stromal-vascular fraction) was studied with Fura-2.
      Norepinephrine (NE) generated in preadipocytes a slow Ca(2+)-response (
      approximately 10 nM/min) without a burst and a maximum, whereas in mature brown
      adipocytes, the quick burst reached 1.5 microM [Ca(2+)](i). Thapsigargin, which
      is known to discharge Ca(2+) ions from the IP(3)-sensitive stores, initiated a
      huge capacitative calcium entry in mature brown adipocytes but failed to
      stimulate a response in preadipocytes. The beta-selective antagonist nadolol
      almost completely prevented the effect of NE on [Ca(2+)](i), while the antagonist
      of alpha-adrenoceptors phentolamine caused only a approximately 25% reduction of
      the cellular response. Forskolin or the cell-permeable Br-cAMP caused [Ca(2+)](i)
      rise, which were even higher than with NE. The protein kinase A (PKA) inhibitor N
      [2-(p-bromocynnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89) reduced and the
      phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX), N-cyclohexyl-N
      (2-hydroxyethyl)-4-(6-(1,2-dihydro-2-oxoquinolyloxy))butyramide (OPC-3911), 4-(3
      butoxy-4-methoxybenzyl)-2-imidazolidone (Ro 20-1724) or the protein phosphatase
      inhibitor okadaic acid enhanced the NE-, isoproterenol- or forskolin-initiated
      cellular calcium responses. It was concluded that (i) brown preadipocytes lacked
      a trigger mechanism of initiation of [Ca(2+)](i) rises and (ii) the cAMP- and
      protein kinase A-mediated phosphorylation played an important role in the beta
      adrenoceptor-initiated calcium signalling in these cells. All these features
      distinguish brown adipocyte precursors from differentiated brown adipocytes,
      where calcium signalling is initiated exclusively via alpha(1)-adrenoceptors and
      the trigger mechanism.

PMID- 12464393
TI  - Regulation of membrane-bound PKC in adult cardiac ventricular myocytes.
AB  - Activation of protein kinase C (PKC) is thought to involve translocation to the
      particulate fraction. The present study demonstrates a membrane-associated,
      inactive pool of PKC in adult rat ventricular myocytes. Membranes were isolated
      from stimulated (phorbol 12-myristate 13-acetate (PMA), endothelin-1 (ET-1)) or
      control myocytes and PKC activity determined in the absence (active PKC) or
      presence (total PKC) of PMA. An inactive, PMA-responsive, pool of PKC was
      detected. In intact myocytes, PMA or ET-1 induced a translocation of PKC epsilon
      from the cytosol into the particulate fraction. In contrast, ET-1 decreased both
      total and active PKC in the membranes: this decrease was associated with a loss
      of PKC epsilon immunoreactivity. PMA increased the amount of membrane-associated,
      inactive PKC. Our results demonstrate the presence of a membrane-associated pool
      of PKC in cardiac myocytes that is differentially modulated by ET-1 or PMA.

PMID- 12464394
TI  - Involvement of phosphatidylinositol 3-kinase gamma in neutrophil apoptosis.
AB  - Although phosphoinositide 3-kinases (PI3-K) are known to participate in anti
      apoptotic pathways, their importance in modulating neutrophil apoptosis in vivo
      has not been examined. In these studies, we used neutrophils from mice lacking
      the PI3-Kgamma isoform (PI3-Kgamma-/-) to determine the role that PI3-Kgamma
      occupies in neutrophil apoptosis under in vivo conditions. We found that
      neutrophil apoptosis under basal and LPS-stimulated conditions was increased in
      PI3-Kgamma-/- mice compared to that present in control PI3-Kgamma+/+ animals.
      Neutrophils from PI3-Kgamma-/- mice demonstrated decreased amounts of active,
      serine 473 phosphorylated Akt, phosphorylated CREB, and diminished nuclear
      translocation of NF-kappaB. Levels of the CREB-dependent anti-apoptotic protein
      Mcl-1 and of the NF-kappaB-dependent anti-apoptotic mediator Bcl-x(L) were
      significantly decreased in PI3-Kgamma-/- neutrophils. In contrast, PI3-Kgamma-/-
      neutrophils contained diminished amounts of phosphorylated, inactive forms of the
      pro-apoptotic mediators, Bad, FKHR, and GSK-3beta. These results demonstrate that
      PI3-Kgamma directly participates in multiple in vivo pathways involved in
      regulating neutrophil apoptosis.

PMID- 12464395
TI  - Nuclear convergence of the TGFbeta and cAMP signal transduction pathways in
      murine embryonic palate mesenchymal cells.
AB  - Transforming growth factors beta (TGFbeta) and cyclic AMP (cAMP) both participate
      in growth and differentiation of the developing mammalian secondary palate and
      elicit similar biological responses. Cross-talk between these two signal
      transduction pathways in cells derived from the embryonic palate has been
      demonstrated previously. In the present study, we have examined nuclear
      convergence of these signalling pathways at the level of transcriptional complex
      formation. Biotinylated oligonucleotides encoding a consensus Smad binding
      element (SBE), or a cyclic AMP response element (CRE), were mixed with cell
      extracts from murine embryonic palate mesenchymal (MEPM) cells that were treated
      with either TGFbeta or forskolin. Protein-oligonucleotide complexes were
      precipitated with streptavidin-agarose, and analysed by Western blotting to
      identify proteins in the complex bound to each consensus oligonucleotide. TGFbeta
      treatment of MEPM cells increased the levels of phosphorylated Smad2,
      phosphorylated cAMP response element binding protein (CREB), and the coactivator,
      CREB binding protein (CBP), that were part of a complex bound to the SBE.
      Treatment of cells with forskolin, a stimulator of adenylate cyclase, increased
      the amount of phosphorylated CREB and CBP, but not the amount of phosphorylated
      Smad2 bound in a complex to the SBE. Additionally, the presence of the co
      repressors, c-Ski and SnoN, was demonstrated as part of a complex bound to the
      SBE (but not the CRE). Amounts of c-Ski and SnoN found in the SBE-containing
      complex increased in response to either TGFbeta or forskolin. These results
      demonstrate that phosphorylated CREB forms a complex with the co-activator CBP,
      phosphorylated Smad2 and the co-repressors c-Ski and SnoN on a consensus SBE.
      This suggests cooperative regulation of genes with SBE-containing promoters by
      the cAMP and TGFbeta signalling pathways in the developing palate.

PMID- 12464396
TI  - Modulation of cyclooxygenase-2 on glycine- and glutamate-induced ion currents in
      rat periaqueductal gray neurons.
AB  - Cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid to
      prostaglandins. Two isoforms of COX are known: COX-1 and COX-2. In the present
      study, the modulatory effect of COX-2 on glycine- and glutamate-induced ion
      currents in periaqueductal gray (PAG) neurons was investigated using the nystatin
      perforated patch clamp method. Continuous application of lipopolysaccharides on
      PAG neurons resulted in increased glycine-induced ion current and decreased
      glutamate-induced ion current. In contrast, continuous application of celecoxib,
      selective COX-2 inhibitor, resulted in decreased glycine-induced ion current and
      increased glutamate-induced ion current. These results demonstrate that COX-2
      modulates neuronal activity of PAG, and it can be suggested that COX-2
      participates in the regulation of the descending pain control system in the level
      of PAG neurons.

PMID- 12464397
TI  - A vinca alkaloid enhances morphological dynamics of dendritic spines of
      neocortical layer 2/3 pyramidal cells.
AB  - We imaged neocortical layer 2/3 pyramidal cells in rat brain slices with two
      photon laser scanning microscopy to investigate that spine motility can be
      influenced by the voltage-dependent Na(+) and Ca(2+) channel inhibitor,
      vinpocetine, which exhibited positive cognitive effects in human studies.
      Veratridine, which enhances sodium influx, was also tested on dendritic spine
      motility. Perfusion with vinpocetine, a derivative of vinca alkaloids, caused a
      substantial increase in the structural dynamics of dendritic spines measured by
      the changes in length or the number of new/retracted spines. In contrast,
      enhancement of sodium influx with veratridine failed to change spine motility.
      Our results indicate that the rapid changes in spine shape and size could occur,
      when calcium and sodium influx has been decreased by this vinca alkaloid. Spine
      motility induced by vinpocetine may be associated to microtubule alterations, an
      effect that was described for other vinca alkaloids. On the other hand, the
      potential of vinpocetine to enhance cognition in clinical studies suggests that
      the increased spine motility may be related to cognitive functions.

PMID- 12464398
TI  - Transcriptional biomarkers distinguish between vulnerable periods for
      developmental neurotoxicity of chlorpyrifos: Implications for toxicogenomics.
AB  - The widespread use of organophosphate insecticides has raised concern about
      neurotoxic effects of fetal and childhood exposures. Studies in rats show that
      chlorpyrifos (CPF) elicits CNS cell damage, in part, through noncholinergic
      mechanisms that involve alterations in the expression and function of nuclear
      transcription factors that control cell replication, differentiation, and
      apoptosis. In the current study, we examined mRNAs encoding c-fos and p53, in
      order to determine if changes in these factors correspond to the differential
      susceptibility of forebrain neurons and glia, when exposure is shifted from the
      early neonatal period (postnatal days 1-4) to a later period (days 11-14). The
      early treatment paradigm elicited a significant elevation of c-fos whereas the
      later treatment suppressed c-fos. Neither regimen altered forebrain p53
      expression, but values were elevated in the cerebellum following the later
      treatment; the cerebellum develops later than the forebrain and has its peak of
      neurogenesis postnatally. Our results suggest that a wider profiling of mRNAs
      using genomic arrays would enable screening for developmental neurotoxicants, but
      that regional and temporal profiles will be required in order to draw mechanistic
      conclusions or to identify critical periods of vulnerability.

PMID- 12464399
TI  - Afferent projections to the hamster intergeniculate leaflet demonstrated by
      retrograde and anterograde tracing.
AB  - The intergeniculate leaflet (IGL) is considered involved in nonphotic shifting of
      the circadian clock through a direct connection, the geniculo-hypothalamic tract.
      The brain areas mediating nonphotic arousal to the hamster IGL have not been
      thoroughly investigated by both retrograde and anterograde tracing. We,
      therefore, reinvestigated the IGL afferent connections with the retrograde tracer
      Cholera toxin B and subsequently verified the results with the anterograde tracer
      Phaseolus vulgaris-leucoagglutinin. We also defined a subset of neurons
      projecting to the IGL that were activated by arousal using c-Fos
      immunocytochemistry. Apart from a dense afferent projection from the retina- and
      the contralateral leaflet, there were ipsilateral projections from other
      structures: layer V and VI of the prefrontal cortex, the zona incerta, the
      magnocellular part of the subparafascicular nucleus, the dorsal raphe nucleus,
      the locus coeruleus, and the cuneiform nucleus. Dense bilateral projections to
      the leaflet from the pretectal nuclei were found. Hypothalamic afferents were
      observed dorsal to the suprachiasmatic nuclei, in the retrochiasmatic area (RCh)
      and in the ventromedial hypothalamic nuclei. All of these projections were
      confirmed by anterograde tracing. Furthermore, arousal (wheel-running) induced c
      Fos in neurons projecting to the IGL (prefrontal cortex, RCh, pretectum). Taken
      together, the data strengthen the view that the IGL integrates photic and
      nonphotic information.

PMID- 12464400
TI  - Modulation of glutamate receptor expression by gonadal steroid hormones in the
      rat striatum.
AB  - The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine
      (MK-801) attenuates morphine-induced immediate-early gene expression in the rat
      striatum in a sexually dimorphic manner that depends in part on gonadal steroids.
      To determine if this effect was dependent on modulation of glutamate receptor
      gene expression, we studied the effect of gonadal hormones on levels of the NR1
      subunit of NMDA receptor and the GluR2 subunit of the AMPA-subtype of glutamate
      receptor in the rat striatum, using autoradiographic immunocytochemistry. We
      found that ovariectomy decreased GluR2 immunoreactivity in the striatum, but no
      changes were seen in levels of NR1 following gonadectomy in either sex. Thus, the
      effects of gonadal steroids on NMDA receptor-mediated responses are not due to
      regulation of NR1 expression.

PMID- 12464401
TI  - Possible alteration of tryptophan metabolism following repeated administration of
      sertraline in the rat brain.
AB  - The levels of tryptophan and the serotonin (5-HT) turnover were examined in
      various brain regions of rats after single or repeated treatment with the
      selective 5-HT uptake inhibitor, sertraline. A single administration of
      sertraline (10mg/kg, i.p.) increased tryptophan and 5-HT levels in all the brain
      regions investigated. The levels of 5-hydroxyindolacetic acid (5-HIAA) decreased
      in various brain regions. The 5-HIAA/5-HT ratio as turnover index was
      significantly decreased by a single administration of sertraline in all the brain
      regions investigated. Daily treatment with sertraline (10mg/kg) for 21 days did
      not affect tryptophan and 5-HT levels in various brain regions 1h after last
      injection. The 5-HT turnover was not changed in any of the brain regions
      investigated by a repeated administration of sertraline. In conclusion, the data
      show that the increase in tryptophan levels and the decrease in 5-HT turnover in
      rat brain are attenuated by repeated treatment of sertraline.

PMID- 12464402
TI  - Circadian variation of brain histamine in goldfish.
AB  - Teleosts may make an excellent model to study brain histamine function. Fishes
      are phylogenetically closer to the basic vertebrate blueprint than higher
      vertebrates. They appear to have a simpler histaminergic system in terms of
      central nervous system distribution and, contrary to higher vertebrates, brain
      histamine appears to be strictly neuronal. In this preliminary study, we examined
      circadian variation of brain histamine in goldfish, Carassius auratus, as this
      neurotransmitter correlates with circadian behavior of some mammals. Two groups
      of juvenile goldfish were held in 24 60L aquaria, six fish per aquarium, on
      reversed photoperiods; L:D 12:12 with light onset either at 0700 or 1900h. Fish
      were sampled every 4h. At a sampling time, all the fish in a tank were taken;
      each sampling, for both groups, was done in replicate. Brain histamine was
      determined by immunoassay. There was a significant circadian variation in
      histamine on both photoperiod regimes with the highest levels during the
      photophase. These results support the hypothesis of an early phylogenic role for
      histamine in vertebrate circadian physiology.

PMID- 12464403
TI  - Lithium chloride, administered chronically to rats, does not affect the
      fractional phosphorylation of brain cytosolic phospholipase A2, while reducing
      its net protein level.
AB  - Lithium, used to treat bipolar disorder, has been reported to decrease rat brain
      mRNA and protein levels of cytosolic phospholipase A(2) (cPLA(2)), an enzyme that
      selectively hydrolyzes arachidonic acid from the stereospecifically numbered (sn)
      2 position of membrane phospholipids, and to decrease PLA(2) activity. cPLA(2)
      can be activated by being phosphorylated at its Ser-228, Ser-505, and Ser-727
      sites. In this study, we show that the percent phosphorylated cPLA(2) protein in
      rat brain is unaffected by lithium. Male Fischer-344 rats were fed lithium
      chloride for 6 weeks, so as to produce a therapeutically equivalent brain lithium
      concentration; control rats were fed lithium-free chow under parallel conditions.
      cPLA(2) was immunoprecipitated from brain homogenate and phosphorylated cPLA(2)
      protein was quantified using an anti-phosphoserine antibody, and compared to net
      cPLA(2) protein. The mean ratio of phosphorylated/total cPLA(2) was not changed
      significantly in the lithium-treated compared to the control group. Thus,
      decreased brain PLA(2) enzyme activity caused by chronic lithium is likely a
      consequence only of lithium's downregulation of cPLA(2) transcription.

PMID- 12464404
TI  - Neurokinin-1 versus mu-opioid receptor binding in rat nucleus tractus solitarius
      after single and recurrent intermittent hypoxia.
AB  - G protein-coupled excitatory neurokinin-1 and inhibitory mu-opioid receptors
      exist in respiratory brainstem with their peptides and influence breathing. To
      assess their putative role in respiratory responses to hypoxia, neurokinin-1, and
      mu-opioid receptor binding was determined in the respiratory nucleus tractus
      solitarius of the mature rat after single and recurrent intermittent hypoxia
      versus normoxia. Hypoxia comprised six 5-min bouts of 8% O(2)-92% N(2) interceded
      by 5-min bouts in 21% O(2)-79% N(2) (normoxia), either on 6 consecutive days
      (recurrent intermittent hypoxia) or on the 6th day only (single intermittent
      hypoxia). Controls comprised six daily sessions in normoxia. To examine the
      plasticity in receptor response, brains were collected 5min, 2h, or 24h after the
      last gaseous exposure. Sections from each brainstem underwent quantitative film
      autoradiography with iodinated substance P and DAMGO for neurokinin-1 and mu
      opioid receptors, respectively. Neurokinin-1 receptor binding decreased 5min
      after single and recurrent hypoxia and 2h after recurrent hypoxia, whereas mu
      opioid binding remained unchanged. The binding of both receptors increased 24h
      after recurrent intermittent hypoxia. Neurokinin versus mu-opioid binding
      differences immediately posthypoxia might affect physiological responses to
      episodic hypoxia.

PMID- 12464405
TI  - Catalase prevents elevation of [Ca(2+)](i) induced by alcohol in cultured canine
      cerebral vascular smooth muscle cells: Possible relationship to alcohol-induced
      stroke and brain pathology.
AB  - Several studies have suggested that alcohol-induced brain injury is associated
      with generation of reactive oxygen species (ROS). The recent findings, that
      antioxidants (Vitamin E and pyrrolidine dithiocarbamate (PDTC)) prevent
      intracellular Ca(2+) ([Ca(2+)](i)) overload in cerebral vascular smooth muscle
      cells, induced by alcohol, demonstrate indirectly that ROS formation is related
      to cerebral vascular injury. The present experiments were designed to test the
      hypothesis that catalase, an hydrogen peroxide (H(2)O(2)) scavenging enzyme, can
      prevent or ameliorate alcohol-induced elevation of [Ca(2+)](i). Preincubation of
      cultured canine cerebral vascular smooth muscle cells with catalase (20-1000
      units/ml) didn't produce any apparent changes from controls in resting levels of
      [Ca(2+)](i) after 1-3 days. Exposure of the cerebral vascular cells to culture
      media containing 10-100mM ethanol resulted in significant rises in [Ca(2+)](i)
      (p<0.01). Although exposure of these cells to a low concentration of catalase (20
      units/ml) failed to prevent the increased level of [Ca(2+)](i) induced by
      ethanol, concomitant addition of higher concentrations of catalase (100-1000
      units/ml) and ethanol (10-100mM) inhibited or ameliorated the rises of
      [Ca(2+)](i) induced by ethanol either at 24h or at 3 days, in a concentration
      dependent manner. Catalase, in the range of 100-200 units/ml, inhibited
      approximately 50% of the [Ca(2+)](i) increases caused by ethanol in the first
      24h. Catalase at a concentration of 1000 units/ml inhibited completely excessive
      [Ca(2+)](i) accumulation. The present results when viewed in light of other
      recently published data suggest that H(2)O(2) generation may be one of the
      earliest events triggered by alcohol in alcohol-induced brain-vascular damage,
      neurobehavioral actions and stroke.

PMID- 12464406
TI  - Developmental toxicity of terbutaline: critical periods for sex-selective effects
      on macromolecules and DNA synthesis in rat brain, heart, and liver.
AB  - beta-Adrenoceptors (betaARs) control cell replication/differentiation, and during
      development, signaling is not subject to desensitization. We examined the effects
      of terbutaline, a beta(2)AR agonist used as a tocolytic, on development in rat
      brain regions and peripheral tissues with high betaAR concentrations. Prenatal
      terbutaline (gestational days 17-20) decreased cell numbers (DNA content) in the
      fetal brain and liver. Early postnatal exposure (PN2-5) reduced DNA synthesis in
      early-developing brain regions of females, with sensitization of the effect upon
      repeated terbutaline administration; after multiple terbutaline injections, DNA
      content was reduced in male cerebellum. The cerebellum was targeted later (PN11
      14), exhibiting decreased DNA synthesis in both sexes; in contrast, cardiac DNA
      synthesis decreased after one injection but increased after the fourth daily
      injection. Our results suggest that excessive betaAR stimulation by terbutaline
      alters cell development in brain regions and peripheral tissues, with the net
      effect depending on sex and the timing of exposure. These effects may contribute
      to neuropsychiatric, cognitive, cardiovascular, and metabolic abnormalities
      reported in the offspring of women treated with beta-agonist tocolytics.

PMID- 12464407
TI  - Analysis of spurious bulk waves in ball surface wave device.
AB  - We analyzed the acoustic waves propagating in a sphere to establish a useful
      guideline for the design of NDE apparatus and ball surface acoustic wave (SAW)
      device exploiting the diffraction-free propagation of SAW on a sphere. First, we
      calculated the laser-generated acoustic displacements both under ablation
      condition and under thermoelastic condition and verified experimentally the
      validity of the calculation. Next, the acoustic waves excited by out-of-plane
      stress and those excited by in-plane stress were compared. The results showed
      that when the out-of-plane stress was applied, the relative amplitudes of the
      bulk waves to that of the SAW were larger and the number of bulk waves was larger
      than that when the in-plane stress was applied, while the SAW had similar
      waveforms in each case. The ratio of the relative amplitude of the bulk waves for
      the out-of-plane stress and the in-plane stress was 3.1:1 at phi(1)=90 degrees
      and 1.67:1 at phi(1)=0 degrees. The large amplitude for the out-of-plane stress
      can be explained by wide directivities of bulk waves. Consequently, we found that
      it is necessary for ball SAW device to select a piezoelectric material and form
      of interdigital transducer so that the in-plane stress becomes dominant.

PMID- 12464408
TI  - Non-contact sound velocities and attenuation measurements of several ceramics at
      elevated temperatures.
AB  - Laser ultrasonic technique has been employed to carry out the sound velocities
      and attenuation measurements as a function of temperature in alumina, two kinds
      of silicon nitride and partially stabilized zirconia (PSZ) samples. Accuracy of
      the laser technique used has been checked in terms of the diffraction effect and
      reproducibility of the results. Results of attenuation at room temperature have
      been compared with quartz transducer technique. In PSZ, velocity behavior has
      become non-linear and also, a peak in attenuation has been observed around 500
      degrees C. In one of the silicon nitride sample, which uses glassy sintering
      agent, attenuation has shown a sharp peak around 950 degrees C. Interestingly,
      when the experiment was repeated from 800 to 1000 degrees C, this anomalous
      attenuation peak has disappeared, leaving a background increasing towards higher
      temperatures.

PMID- 12464409
TI  - Open-circuit test of a PZT vibrator and its applications.
AB  - This study investigates a terminal transient response of a Langevin-type PZT
      vibrator theoretically and experimentally to quantify an electrical shock and
      refine an equivalent circuit of the vibrator. The shock is induced immediately
      after an AC sinusoidal voltage of the vibrator is switched off. Then, the
      transient response involves a DC part and an AC part, which approach zero at the
      DC and AC times, respectively, and the vibrator is placed on a sponge in air. To
      do so, we should propose an open-circuit test to find the AC and DC times in
      addition to the maximum amplitude of the transient response. Thus the DC times
      exceeds the AC time, and the AC and DC times are used to estimate the resistances
      in the equivalent circuit presenting the real mechanical and dielectric losses,
      respectively. Therefore, the resistances in the equivalent circuit are sensitive
      to the vibration amplitude, but the inductance and capacitances are not.
      Furthermore, the maximum amplitude is required to cause the shock, and depends on
      the frequency of the source and the open-circuited time, and is about 65 times
      the amplitude of the source.

PMID- 12464410
TI  - Numerical predictions and experiments on the free-plate edge mode.
AB  - In this paper, te edge mode variation is studied with three different methods:
      the reciprocal work method, already used by Torvik [J. Acoust. Soc. Am. 41 (1967)
      346] to model this phenomenon, the S-parameter method and a finite element model
      that are applied for the first time to the study of the edge resonance. Moreover,
      laser probe measurements of the edge mode have also been performed and compared
      to the numerical predictions. The good agreement between the numerical
      predictions and the experimental data allows full understanding of the resonant
      phenomenon. The edge resonance is linked to the strong increase in amplitude of
      two complex Lamb waves, and the edge mode is proved to radiate into the plate as
      the first symmetrical Lamb mode S(0). Displacements at the edge and away from the
      edge have been computed and measured to evaluate the spatial and temporal
      behaviour of the edge mode. The dependence of the edge resonance frequency and
      amplitude on the Poisson coefficient has also been studied.

PMID- 12464411
TI  - Finite element analysis of Rayleigh wave interaction with finite-size, surface
      breaking cracks.
AB  - The interaction of surface acoustic waves with finite-size, surface-breaking,
      semi-circular cracks is studied numerically, and experimentally. We focus on the
      behavior of the reflection coefficient of the Rayleigh wave from such cracks in
      the far field of the crack, when the depth of the crack is comparable to the
      wavelength of the interrogating surface wave. The cases in which the depth of the
      crack is much smaller or much larger compared to the wavelength have been
      extensively investigated by many authors and are not considered here except for
      validating the numerical and experimental results in these regimes. The
      theoretical, finite element, and experimental results presented are in very good
      agreement over the range were the crack depth is much smaller or much larger
      compared to the wavelength of the incident Rayleigh wave. In the transition
      regime, between these two limiting cases, only the finite element and
      experimental data show good agreement since the theoretical predictions are no
      longer applicable. In the high crack depth to wavelength ratio (a/lambda(R))
      regime, the finite element and experimental results close to the crack approach
      the limiting value of the reflection coefficient from a 90 degrees corner.

PMID- 12464413
TI  - Chemical mutagenesis of the parasitic nematode Strongyloides ratti to isolate
      ivermectin resistant mutants.
AB  - We describe a strategy for the mutagenesis of the free-living adult generation of
      Strongyloides ratti and selection of worms carrying new mutations in the
      subsequent F2 generation of infective larvae. We demonstrate that this strategy
      is successful via the selection of infective larvae that are resistant to the
      anthelmintic ivermectin at a concentration of 10 ng/ml. The majority of these
      larvae were unable to give rise to patent infections when used to infect parasite
      naive rats, implying that the majority of the ivermectin resistance mutations
      confer pleiotropic defects on parasitic, but not on free-living, development.

PMID- 12464414
TI  - Identification of a second proliferating cell nuclear antigen in the human
      malarial pathogen Plasmodium falciparum.
AB  - Proliferating cell nuclear antigen seems to exist as a single form in higher
      eukaryotic cells and plays multiple roles in nucleic acid metabolism. We have
      identified a second additional proliferating cell nuclear antigen (PfPCNA2) in
      Plasmodium falciparum on the basis of several lines of evidence. (1) PfPCNA2,
      consisting of 264 amino acid residues with a predicted molecular mass of 30.2kDa,
      shares only 29% identity and 53% similarity with PfPCNA1 at the amino acid level.
      (2) Southern blot analyses revealed that the hybridisation pattern of the Pfpcna2
      gene is completely different from that of the Pfpcna1 gene. (3) Chromosomal
      localisation studies showed that Pfpcna2 is located on chromosome 12 while
      Pfpcna1 is located on chromosome 13. Northern blot analyses revealed two
      different transcripts of Pfpcna2, one expressed in both asexual and sexual
      erythrocytic stages, while the other existed only in the sexual stage, implying
      that PfPCNA2 may play multiple roles in DNA metabolism in different stages of the
      parasite. Recombinant protein of PfPCNA2, overexpressed in Escherichia coli, has
      been purified to near homogeneity and shown to form an oligomer, probably a
      trimer, as revealed by a size-exclusion chromatography and a native gel
      electrophoresis, suggesting that PfPCNA2, like its higher eukaryotic
      counterparts, may serve as a sliding platform which is capable of interaction
      with diverse proteins and regulation of their activities.

PMID- 12464416
TI  - Leishmania major proteophosphoglycans exist as membrane-bound and soluble forms
      and localise to the cell membrane, the flagellar pocket and the lysosome.
AB  - The Leishmania proteophosphoglycan belongs to a family of heterogeneous
      polypeptides of unusual composition and structure. Here we demonstrate the
      presence in the parasite of a membrane-bound hydrophobic form of
      proteophosphoglycan, in addition to the previously described water-soluble form
      secreted into the culture medium. Phosphatidylinositol-specific phospholipase C
      treatment of the hydrophobic form of proteophosphoglycan converted it into a
      water-soluble form, confirming that it has a functional
      glycosylphosphatidylinositol-anchor, compatible with it being the product of the
      proteophosphoglycan1 gene. Immunofluorescence, immunoelectron microscopy and
      surface labelling showed that proteophosphoglycan expression was variable in
      individual cells but that it was present on the surface of both amastigotes and
      promastigotes, in the flagellar pocket, in endosomes and in the multi-vesicular
      tubule which is the newly described lysosome.

PMID- 12464415
TI  - Prostaglandin production from arachidonic acid and evidence for a 9,11
      endoperoxide prostaglandin H2 reductase in Leishmania.
AB  - Lysates of Leishmania promastigotes can metabolise arachidonic acid to
      prostaglandins. Prostaglandin production was heat sensitive and not inhibited by
      aspirin or indomethacin. We cloned and sequenced the cDNA of Leishmania major,
      Leishmania donovani, and Leishmania tropica prostaglandin F(2alpha) synthase, and
      overexpressed their respective 34-kDa recombinant proteins that catalyse the
      reduction of 9,11-endoperoxide PGH(2) to PGF(2alpha). Database search and
      sequence alignment alignment showed that L. major prostaglandin F(2alpha)
      synthase exhibits 61, 99.3, and 99.3% identity with Trypanosoma brucei, L.
      donovani, and L. tropica prostaglandin F(2alpha) synthase, respectively. Using
      polymerase chain reaction amplification, Western blotting, and
      immunofluorescence, we have demonstrated that prostaglandin F(2alpha) synthase
      protein and gene are present in Old World and absent in New World Leishmania, and
      that this protein is localised to the promastigote cytosol.

PMID- 12464417
TI  - Monoclonal antibodies reactive with secreted-excreted products from the amphids
      and the cuticle surface of Globodera pallida affect nematode movement and delay
      invasion of potato roots.
AB  - This paper describes Excreted-secreted proteins (ES) proteins that were
      immunolocalised in the cuticle, amphids and subventral glands of second stage
      juveniles of the two species of potato cyst nematodes (Globodera pallida and
      Globodera rostochiensis). Monoclonal antibodies reactive with these ES proteins
      were used in a bioassay to investigate their effect on nematode movement and on
      their ability to invade potato roots. Antibodies recognising the nematode cuticle
      surface and the amphids affected nematode movement and delayed nematode
      penetration of roots. These effects were temporary, since the nematodes were able
      to recover and infect potato roots. Movement of second stage juveniles treated
      with the antibodies was impaired for the first 30 min after inoculation: the
      juveniles remained close to the point of introduction and moved slowly and
      abnormally. They recovered normal movement after 1-2 h, possibly because the
      turnover rate of the secreted proteins meant that they were no longer blocked by
      the monoclonal antibodies. No effect was observed on second stage juveniles
      treated with an antibody reactive with secretions from the oesophageal glands.
      Nematodes treated with antibodies reactive with the nematode cuticle surface were
      notably more affected than those treated with other antibodies; nematodes failed
      to recover movement when in continuous contact with the antibodies. It is
      possible that the physical presence of the antibodies on the nematode surface
      affected their motility. Nematodes treated with antibodies reactive with
      secretions from the amphids were temporarily unable to move towards potato roots
      and their exploratory behaviour was greatly affected by the antibody treatment.
      Whether these antibodies were able to inhibit temporarily the function of the
      amphids or this effect was due to physical presence of the antibodies blocking
      the amphidial pore remains to be determined.

PMID- 12464418
TI  - Successful in vitro cultivation of Cryptosporidium andersoni: evidence for the
      existence of novel extracellular stages in the life cycle and implications for
      the classification of Cryptosporidium.
AB  - The present study describes the complete development of all life cycle stages of
      Cryptosporidium andersoni in the HCT-8 cell line. The in vitro cultivation
      protocols were the same as those used for the successful growth of all life cycle
      stages of Cryptosporidium parvum (Int. J. Parasitol. 31 (2001) 1048). Under these
      culture conditions, C. andersoni grew and proliferated rapidly with the
      completion of the entire life cycle within 72h post-infection. The developmental
      stages of C. andersoni are larger than those of C. parvum enabling easier
      identification of life cycle stages including a previously unrecognised
      extracellular stage. The presence of this extracellular stage was further
      confirmed following its isolation from the faeces of infected cattle using a
      laser microdissection technique. This stage was present in large numbers and some
      of them were seen undergoing syzgy. Extraction of DNA from the extracellular
      stage, followed by polymerase chain reaction-restriction fragment length
      polymorphism and sequencing of the 18S rDNA confirmed that this is a stage in the
      life cycle of C. andersoni. In vitro, extracellular stages were always observed
      moving over the HCT-8 cells infected with C. andersoni. Comparative observations
      with C. parvum also confirmed the presence of extracellular stages. Extracellular
      stages were recovered from in vitro culture after 5 days post-infection with the
      cattle genotype of C. parvum and from infected mice. At least two morphologically
      different stages (stages one and two) were purified from mice after 72h of
      infection. The presence and morphological characterisation of extracellular
      developmental stages in the life cycle of Cryptosporidium confirms its
      relationship to gregarines and provides important implications for our
      understanding of the taxonomic and phylogenetic affinities of the genus
      Cryptosporidium. The growth of C. andersoni in cell culture now provides a means
      of studying its development, metabolism, and behaviour as well as testing its
      response to different therapeutic agents.

PMID- 12464419
TI  - Functional genomics of gam56: characterisation of the role of a 56 kilodalton
      sexual stage antigen in oocyst wall formation in Eimeria maxima.
AB  - Gam56 (M(r) 56,000) is an antigen found in the sexual (macrogametocyte) stage of
      the intestinal parasite Eimeria maxima that is implicated in protective immunity.
      The gene (gam56) encoding this protein was cloned and sequenced. It is a single
      copy, intronless gene, that localises to a 1,754 bp transcript, and is first
      detected at 120 h p.i. The gene predicts two distinct protein domains; a tyrosine
      serine rich region, composed of amino acids implicated in oocyst wall formation
      in Eimeria spp., and a proline-methionine rich region often detected in
      extensins, protein components of plant cell walls. The tyrosine-serine rich
      region predicts a secondary structure commonly seen in the structural protein
      fibroin, a component of the cocoon of the caterpillar Bombyx mori. The inference
      that gam56 is a structural component of the oocyst wall was confirmed when a
      specific antibody to gam56 recognised the wall forming bodies in
      macrogametocytes, and the walls of oocysts and sporocysts. Together, these data
      identify a developmentally regulated, sexual stage gene in E. maxima that shares
      primary and secondary structure features in common with intrinsic structural
      proteins in other parasites such as Schistosoma mansoni and Fasciola hepatica,
      and other organisms across different phyla, including the caterpillar Bombyx
      mori. In addition, these findings provide evidence for the molecular mechanisms
      underlying oocyst wall formation in Eimeria and the role of gametocyte antigens
      in this process.

PMID- 12464420
TI  - Cloning and characterisation of a highly immunoreactive 37 kDa antigen with multi
      immunoglobulin domains from the swine roundworm Ascaris suum.
AB  - Antigens from larval stages of Ascaris suum have been shown to induce protection
      against challenge infection with infective A. suum eggs. We previously identified
      several antigens that reacted strongly with serum from pigs inoculated with
      infective eggs containing L3. In this study, we isolated an antigen with a
      molecular mass of 37 kDa and a pI of 4.8 (As37) from A. suum infective eggs using
      two-dimensional electrophoresis, and obtained a full-length cDNA by reverse
      transcription-polymerase chain reaction using primers designed based on the
      internal amino acid sequence of As37. The cDNA sequence consisted of 1,540 bp
      coding for a protein of 321 amino acids with a complex domain organisation.
      Simple modular architecture research tool (SMART) analysis indicated that As37
      contains three immunoglobulin domains, indicating that it is a member of
      immunoglobulin superfamily (IgSF). A homology search of GenBank showed that As37
      has significant similarity to Caenorhabditis elegans DIM-1 protein and has low
      similarity to part of the multi-repeat Ig domain from nematode twitchin and
      mammalian skeleton muscle titin, and to members of the IgSF at the amino acid
      sequence level. Localisation analysis revealed that antibodies to Escherichia
      coli-expressed recombinant As37 (rAs37) bound to muscle cells and the hypodermis.
      The antibodies identified a 37 kDa native antigen in human and dog roundworms,
      suggesting that there are As37 homologues in ascarid nematodes. Sera from mice,
      rabbits and pigs immunised with A. suum infective eggs reacted with rAs37 in
      immunoblot analyses. The potential use of rAs37 for protection against A. suum
      infection is discussed.

PMID- 12464421
TI  - Sm60, a mannose-binding protein from Schistosoma mansoni with inflammatory
      property.
AB  - We demonstrate here that a mannose-binding protein from Schistosoma mansoni,
      termed Sm60, was recovered in the mannose-eluted fraction (Man(+)) upon affinity
      chromatography on immobilised mannose of the soluble antigen fraction from adult
      worm tegument and cercariae. Sm60 was detected in the Man(+) fraction as a
      prominent doublet with an apparent molecular mass of 60-66 kDa by SDS-PAGE and
      appeared as a single band with a pI of approximately 6.9 by isoelectrofocusing.
      Sm60 was also detected in preparations of schistosomula extract and soluble egg
      antigens using a mouse polyclonal anti-Sm60 serum on immunoblotting assay. This
      antiserum demonstrated that Sm60 was localised on the tegument of S. mansoni
      adult worm. In order to determine the role of Sm60 in host-parasite interactions,
      we showed that Sm60 induced in vitro migration of human neutrophil in a dose
      dependent manner and in vitro mast cell degranulation. Sm60 triggered these
      activities through its carbohydrate-binding site, since these activities were
      selectively inhibited by 0.2 M D-mannose, but not by 0.2 M D-galactose.
      Furthermore, Sm60 induced in vivo neutrophil migration. In contrast, mast cell
      depleted rats presented a significant reduction of the neutrophil migration
      induced by Sm60 as compared with non-depleted controls. These data suggest that
      in vivo neutrophil migration induced by Sm60 is modulated by mast cell-dependent
      mechanisms. Sm60 might play a key role in the host-parasite interaction, and its
      characterization opens perspective to examine the role of this molecule in the
      biology of S. mansoni.

PMID- 12464422
TI  - Leishmania (Leishmania) amazonensis-induced cutaneous leishmaniasis in the
      primate Cebus apella: a model for vaccine trials.
AB  - A primate model of leishmaniasis was developed with the objective of future
      vaccine testing. Lesion development and immunological parameters were studied
      upon primary and secondary infections. Seven Cebus apella were injected
      subcutaneously with 2 x 10(6) Leishmania (Leishmania) amazonensis promastigotes.
      Erythematous nodules appeared 19-29 days p.i., which disappeared 100 days p.i.
      Four months later, six of the monkeys were challenged with the same inoculum;
      three of them developed erythematous nodules after 7 days p.i., with ulcer
      formation in two of these subjects. The lesions were short-lived and all were
      cured 40 days post challenge. Anti-Leishmania IgG antibodies were detected and
      they increased after the challenge infection. Leishmania antigen-induced
      lymphoproliferation was found 1 month post-primary infection, which coincided
      with IFN-gamma production and lesion development. It decreased to control levels
      afterwards, but at the time of the challenge dose, it was significantly above the
      initial level. After the challenge infection, it first increased then decreased
      sharply at 40 days post-challenge, coinciding with the healing of the lesion. It
      increased again to a higher level at 60 days post-challenge. Leishmania
      (Leishmania) amazonensis-infection in C. apella did not induce complete
      protection against a secondary infection with a homologous parasite although
      specific antibody production and lymphoproliferation with IFN-gamma production
      were observed. This fact indicates that vaccine has to be better than infection
      in the induction of protective immunity, and raises a question on in vitro
      parameters that should be considered as a counterpart of expected protection
      induced by vaccine candidate. In addition, we conclude that this is a useful
      primate model for the evaluation of candidate vaccines.

PMID- 12464423
TI  - Structure-activity relationships of an inhibitory nematode FMRFamide-related
      peptide, SDPNFLRFamide (PF1), on Ascaris suum muscle.
AB  - FMRFamide-related peptides are widespread among the Nematoda. Among them is a
      family of extended PNFLRFamide peptides encoded on the flp-1 peptide precursor
      gene in Caenorhabditis elegans. The most studied peptide from this series is
      SDPNFLRFamide (PF1). Each residue in this peptide was sequentially substituted
      with either alanine or the corresponding d-isomer of the native amino acid in
      order to define structure-function relationships in this peptide using an Ascaris
      suum muscle tension assay. In general, substitutions in the N-terminal
      tetrapeptide had only minor consequences for efficacy, while substitutions in the
      C-terminal tetrapeptide caused more dramatic changes. Such substitutions
      typically markedly diminished efficacy, but d-isomer substitution at either
      position 5 (Phe) or 6 (Leu) converted the inhibitory activity of the prototype
      into excitation. In addition, it has been evident that KPNFLRFamide and
      SDPNFLRFamide, though encoded on flp-1 and sharing a PNFLRFamide hexapeptide, act
      through different receptors. KPNFLRFamide directly gates a chloride channel in A.
      suum muscle cells, while SDPNFLRFamide acts through nitric oxide synthase to open
      K+ channels in the same tissue. The use of K+ channel blockers and nitric oxide
      synthase inhibitors in electrophysiological experiments employing A. suum muscle
      membranes allowed the unambiguous conclusion that the N-terminal lysine is
      absolutely required for activation of the chloride channel and excludes
      interaction with the SDPNFLRFamide receptor.

PMID- 12464424
TI  - Host adaptation and host-parasite co-evolution in Cryptosporidium: implications
      for taxonomy and public health.
AB  - To assess the genetic diversity and evolution of Cryptosporidium parasites, the
      partial ssrRNA, actin, and 70kDa heat shock protein (HSP70) genes of 15 new
      Cryptosporidium parasites were sequenced. Sequence data were analysed together
      with those previously obtained from other Cryptosporidium parasites (10
      Cryptosporidium spp. and eight Cryptosporidium genotypes). Results of this multi
      locus genetic characterisation indicate that host adaptation is a general
      phenomenon in the genus Cryptosporidium, because specific genotypes were usually
      associated with specific groups of animals. On the other hand, host-parasite co
      evolution is also common in Cryptosporidium, as closely related hosts usually had
      related Cryptosporidium parasites. Results of phylogenetic analyses suggest that
      the Cryptosporidium parvum bovine genotype and Cryptosporidium meleagridis were
      originally parasites of rodents and mammals, respectively, but have subsequently
      expanded their host ranges to include humans. Understanding the evolution of
      Cryptosporidium species is important not only for clarification of the taxonomy
      of the parasites but also for assessment of the public health significance of
      Cryptosporidium parasites from animals.

PMID- 12464425
TI  - Trichinella zimbabwensis n.sp. (Nematoda), a new non-encapsulated species from
      crocodiles (Crocodylus niloticus) in Zimbabwe also infecting mammals.
AB  - Since 1995, Trichinella larvae have been detected in 39.5% of farmed crocodiles
      (Crocodylus niloticus) in Zimbabwe. Morphological, biological, biochemical and
      molecular studies carried out on one isolate from a farmed crocodile in 2001
      support the conclusion that this parasite belongs to a new species, which has
      been named Trichinella zimbabwensis n.sp. This species, whose larvae are non
      encapsulated in host muscles, infects both reptiles and mammals. The morphology
      of adults and larvae is similar to that of Trichinella papuae. Adults of T.
      zimbabwensis cross in both directions with adults of T. papuae (i.e. male of T.
      zimbabwensis per female of T. papuae and male of T. papuae per female of T.
      zimbabwensis), producing F1 offspring which produce very few and less viable F2
      larvae. Muscle larvae of T. zimbabwensis, like those of T. papuae, do not infect
      birds. Three allozymes (of a total of 10) are diagnostic between T. zimbabwensis
      and T. papuae, and five are diagnostic between T. zimbabwensis and Trichinella
      pseudospiralis, the third non-encapsulated species. The percentage of the
      pairwise alignment identity between T. zimbabwensis and the other Trichinella
      species for the cytochrome oxidase subunit I gene, the large subunit ribosomal
      DNA (mt-lsrDNA) gene and the expansion segment five, shows that T. zimbabwensis
      is more similar to the two non-encapsulated species T. papuae (91% for cytochrome
      oxidase I; 96% for mt-lsrDNA; and 88% for expansion segment five) and T.
      pseudospiralis (88% for cytochrome oxidase I; 90% for mt-lsrDNA; and 66-73% for
      expansion segment five) than to any of the encapsulated species (85-86% for
      cytochrome oxidase I; 88-89% for mt-lsrDNA; and 71-79% for expansion segment
      five). This is the first non-encapsulated species discovered in Africa. The
      finding of a new Trichinella species that infects both reptiles and mammals
      suggests that the origin of Trichinella parasites dates back further than
      previously believed and can contribute to understanding the phylogeny and the
      epidemiology of the genus Trichinella.

PMID- 12464426
TI  - Aortic arch and pharyngeal phenotype in the absence of BMP-dependent neural crest
      in the mouse.
AB  - Neural crest cells are essential for proper development of a variety of tissues
      and structures, including peripheral and autonomic nervous systems, facial
      skeleton, aortic arches and pharyngeal glands like the thymus and parathyroids.
      Previous work has shown that bone morphogenic protein (BMP) signalling is
      required for the production of migratory neural crest cells that contribute to
      the neurogenic and skeletogenic lineages. We show here that BMP-dependent neural
      crest cells are also required for development of the embryonic aortic arches and
      pharynx-derived glands. Blocking formation or migration of this crest cell
      population from the caudal hindbrain resulted in strong phenotypes in the cardiac
      outflow tract and the thymus. Thymic aplasia or hypoplasia occurs despite
      uncompromised gene induction in the pharyngeal endoderm. In addition, when
      hypoplastic thymic tissue is found, it is ectopically located, but functional in
      thymopoiesis. Our data indicate that thymic phenotypes produced by neural crest
      deficits result from aberrant formation of pharyngeal pouches and impaired
      migration of thymic primordia because the mesenchymal content in the branchial
      arches is below a threshold level.

PMID- 12464427
TI  - Heparin-binding epidermal growth factor and its receptor ErbB4 mediate
      implantation of the human blastocyst.
AB  - The mechanisms that mediate implantation of the human embryo remain poorly
      understood and represent a fundamental problem in reproductive biology. Candidate
      molecules that mediate and facilitate implantation have been identified in animal
      studies, and include heparin binding epidermal growth factor. Here we demonstrate
      a potential function for the transmembrane form of heparin-binding epidermal
      growth factor in mediating blastocyst attachment to the endometrium, in two
      different novel in vitro models for human implantation. Furthermore, we
      demonstrate specific localisation of the heparin-binding epidermal growth factor
      receptor ErbB4, on the surface of the trophectoderm in peri-implantation human
      blastocysts. Our data lead the way for further dissection of the molecular
      mechanisms of implantation of the human embryo, and have implications for
      infertility, in vitro fertilization and contraception.

PMID- 12464428
TI  - Control of Dopa decarboxylase gene expression by the Broad-Complex during
      metamorphosis in Drosophila.
AB  - The induction of the Dopa decarboxylase gene (Ddc) in the epidermis of Drosophila
      at pupariation is a receptor-mediated response to the steroid molting hormone,
      ecdysone. Activity is also dependent on the Broad-Complex (BR-C), an early
      ecdysone response gene that functions during metamorphosis. BR-C encodes a family
      of zinc-finger protein isoforms, BR-C(Z1-Z4). Genetic experiments have shown that
      the Z2 isoform is required for epidermal Ddc to reach maximum expression at
      pupariation. In this paper, we report that BR-C regulates Ddc expression at two
      different developmental stages through two different cis-acting regions. At
      pupariation, BR-C acts synergistically with the ecdysone receptor to up-regulate
      Ddc. DNase I foot printing has identified four binding sites of the predominant
      Z2 isoform within a distal regulatory element that is required for maximal Ddc
      activity. The sites share a conserved core sequence with a set of BR-C sites that
      had been mapped previously to within the first Ddc intron. Using variously
      deleted Ddc genomic regions to drive reporter gene expression in transgenic
      organisms, we show that the intronic binding sites are required for Ddc
      expression at eclosion. At both pupariation and eclosion, BR-C releases Ddc from
      an active silencing mechanism, operating through two distinct cis-acting regions
      of the Ddc genomic domain at these stages. Transgenes, bearing a Ddc fragment
      from which one of the cis-acting silencers has been deleted, exhibit beta
      galactosidase reporter activity in the epidermal cells prior to the appearance of
      endogenous DDC. Our finding that BR-C is required for Ddc activation at eclosion
      is the first evidence to suggest that this important regulator of the early
      metamorphic events, also regulates target gene expression at the end of
      metamorphosis.

PMID- 12464429
TI  - Selective inhibition of protein kinases blocks the formation of a new axis, the
      beginning of budding, in Hydra.
AB  - In Hydra, head regeneration and bud formation appear to be very similar
      processes. The fact that there are genes whose expression is specific for one of
      the two processes suggests that they do not have identical molecular bases. We
      analyzed the signal transduction pathways regulating bud development using
      inhibitors of protein kinase C, Src, PI3K and ERK. The four inhibitors reversibly
      blocked bud formation in Hydra when applied before stage 1. Once the bud reached
      stage 3, three of them had no effect and the bud developed normally. The
      inhibitors blocked the expression of Budhead, an early head marker, and of CnOtx
      which are specific for bud formation. The results are in agreement with the
      central role of a signaling pathway mediated by Src on bud development.

PMID- 12464430
TI  - CRIM1 is involved in endothelial cell capillary formation in vitro and is
      expressed in blood vessels in vivo.
AB  - In endothelial cells that form capillary-like structures in vitro a variety of
      genes is upregulated as we have demonstrated previously. In addition to well
      known genes, we also identified genes never described in endothelial cells
      before. Here, we report the further characterization of one selected gene called
      cysteine-rich motor neuron 1 (CRIM1). CRIM1 is strongly upregulated in
      endothelial cells during tube formation and is expressed by a variety of adherent
      growing cell lines whereas cell lines grown in suspension do not express CRIM1.
      By using antisense technology we were able to inhibit CRIM1 expression and
      demonstrate impaired formation of capillary-like structures in vitro in
      transfected endothelial cells. Furthermore, we show that CRIM1 is a glycosylated
      type I transmembrane protein, that accumulates at sites of close cell-to-cell
      contact upon stimulation. Finally, we found CRIM1 protein to be expressed by
      endothelial cells of the inner lining of blood vessels in vivo. Taken together
      our results imply a possible role of CRIM1 in capillary formation and
      maintainance during angiogenesis.

PMID- 12464431
TI  - Xolloid-related: a novel BMP1/Tolloid-related metalloprotease is expressed during
      early Xenopus development.
AB  - We have identified a novel Tolloid-like metalloprotease, called Xolloid-related
      (Xlr), that is expressed during early Xenopus development. Transcripts for xlr
      are localized to the marginal zone of mid-gastrulae and are most abundant in
      ventral and lateral sectors. At neurula stages xlr is strongly expressed around
      the blastopore and in the pharyngeal endoderm, and more weakly expressed
      throughout the ventral half of the embryo. Transcripts are detected in the
      nervous system, particularly the hindbrain and spinal cord, and tailbud of
      tailbud stage embryos, with weaker expression in the anterior nervous system,
      otic vesicle, heart, and pronephric duct. Transcription of xlr is increased by
      BMP4 and decreased by Noggin and tBR, indicating that xlr is regulated by BMP
      signalling. Injection of xlr mRNA inhibits dorsoanterior development and the
      dorsal axis inducing ability of coinjected chordin, but not noggin or tBR, mRNA.
      Xlr conditioned media cleaves Chordin in vitro, indicating that this protease may
      regulate the availability of Chordin in vivo.

PMID- 12464432
TI  - Xhex-expressing endodermal tissues are essential for anterior patterning in
      Xenopus.
AB  - Two regions expressing Hex in the early gastrula contribute to organizing the
      anterior of the vertebrate embryo. In Xenopus, these include the anterior yolky
      endoderm and the suprablastoporal endoderm (SBE), which is fated to form the
      epithelial lining of the gut. These tissues may correspond to the anterior
      visceral endoderm and anterior definitive endoderm of amniotes. Genetic studies
      in mice have demonstrated the important roles of these tissues in producing
      anterior identity in the adjacent neural ectoderm. In Xenopus, both the anterior
      endoderm and the SBE have anterior inducing properties; furthermore, the SBE can
      organize a full anterior-posterior axis. Inhibition of Xhex function shows that
      both these Xhex-expressing endodermal tissues are required for anterior
      development in Xenopus.

PMID- 12464433
TI  - Movement of bristle precursors contributes to the spacing pattern in Drosophila.
AB  - In Drosophila melanogaster, microchaetes (small bristles) are regularly spaced
      and form five straight rows in the acrostichal region of the adult notum.
      Microchaetes develop from sensory organ precursors that arise as single, evenly
      spaced cells during pupal development. In this article we address the question of
      how the precursor cells remain aligned throughout pupal development, in spite of
      continued division of the intervening epidermal cells. Using in vivo imaging we
      show that bristle precursors move about continuously throughout development,
      covering distances of up to one or two cell diameters. During this process, they
      remain aligned in wild-type flies, suggesting that the movement may be regulated.
      Flies mutant for scabrous (sca) have a disorganised pattern of bristles with
      little or no alignment. In vivo observations of sca mutants indicated that the
      precursor cells move around more than in the wild type, but that, in spite of
      this the precursor cells and resulting bristles never become well aligned. They
      appear to follow a more complex path, suggesting that the movement is not co
      ordinated. Moreover, analysis of the alignment of precursor cells in vivo in wild
      type and sca mutant flies indicate that mutant animals are not able to maintain
      the pattern of precursor cells during development. Analysis of mosaic flies
      confirmed the time-lapse observations and showed furthermore that bristles
      preferentially move towards high levels of Scabrous. We suggest that, by altering
      the properties of epithelial cells in a graded fashion, Scabrous may provide cues
      that allow the precursors to remain evenly spaced after they have segregated.

PMID- 12464434
TI  - The retinoic acid receptors RARalpha and RARgamma are required for inner ear
      development.
AB  - To define the signal transduction pathway of retinoic acid during inner ear
      development, we analyzed the expression patterns of transcripts encoding the
      three retinoic acid receptors (RARalpha, beta, and gamma) and related them to
      phenotypes resulting from single or compound inactivation of these nuclear
      receptors. The expression of all three RARs was observed in the developing mouse
      otocyst as early as embryonic day 10.5 (E10.5)-E12.5 and continued into
      adulthood. Expression domains of the three RAR receptors, however, were largely
      non-overlapping: RARalpha was predominantly expressed in the developing sensory
      epithelium, RARbeta in inner ear mesenchymal tissues and RARgamma in the
      differentiating otic capsule. In the adult, RARalpha and RARgamma transcripts
      were found in the organ of Corti and the spiral ganglion, whereas RARbeta
      transcripts were localized in mesenchyme-derived tissues. RARalpha, beta, and
      gamma null mutant mice, as well as RARalpha/RARbeta and RARbeta/RARgamma combined
      null fetuses, did not present any noticeable morphological abnormalities in the
      inner ear. In contrast, RARalpha/RARgamma null mutants displayed a severe
      hypoplasia of the otocyst that was already visible at E10.5 without any visible
      endolymphatic duct. The hypoplastic otocyst in RARalpha/RARgamma null mutants was
      characterized by impaired chondrocyte differentiation and neural development.
      After the second week of gestation, these mutant fetuses lacked all of the semi
      circular canals and the endolymphatic duct and displayed strong anomalies in the
      inner ear structures. The morphological deficits were generally more severe in
      the cochlear portion than in the vestibular portion of the inner ear. Altogether,
      these results demonstrate that RARalpha and RARgamma play an essential role in
      the initial differentiation of otic placode derivatives, whereas RARbeta plays a
      minimal role in this process.

PMID- 12464435
TI  - The E2F cell cycle regulator is required for Drosophila nurse cell DNA
      replication and apoptosis.
AB  - During Drosophila oogenesis nurse cells become polyploid, enabling them to
      provide the developing oocyte with vast amounts of maternal messages and
      products. The nurse cells then die by apoptosis. In nurse cells, as in many other
      polyploid or polytene tissues, replication is differentially controlled and the
      heterochromatin is underreplicated. The nurse cell chromosomes also undergo
      developmentally induced morphological changes from being polytene, with tightly
      associated sister chromatids, to polyploid, with dispersed sister chromatids. We
      used female-sterile dE2F1 and dDP mutants to assess the role of the E2F cell
      cycle regulator in oogenesis and the relative contributions of transcriptional
      activation versus repression during nurse cell development. We report here that
      E2F1 transcriptional activity in nurse cells is essential for the robust
      synthesis of S-phase transcripts that are deposited into the oocyte. dE2F1 and
      dDP are needed to limit the replication of heterochromatin in nurse cells. In
      dE2F1 mutants the nurse cell chromosomes do not properly undergo the transition
      from polyteny to polyploidy. We also find that dDP and dE2F1 are needed for nurse
      cell apoptosis, implicating transcriptional activation of E2F target genes in
      this process.

PMID- 12464436
TI  - Targeted disruption of the Tab1 gene causes embryonic lethality and defects in
      cardiovascular and lung morphogenesis.
AB  - The transforming growth factor-beta (TGF-beta) superfamily consists of a group of
      secreted signaling molecules that perform important roles in the regulation of
      cell growth and differentiation. TGF-beta activated kinase-1 binding protein-1
      (TAB1) was identified as a molecule that activates TGF-beta activated kinase-1
      (TAK1). Recent studies have revealed that the TAB1-TAK1 interaction plays an
      important role in signal transduction in vitro, but little is known about the
      role of these molecules in vivo. To investigate the role of TAB1 during
      development, we cloned the murine Tab1 gene and disrupted it by homologous
      recombination. Homozygous Tab1 mutant mice died, exhibiting a bloated appearance
      with extensive edema and hemorrhage at the late stages of gestation. By
      histological examinations, it was revealed that mutant embryos exhibited
      cardiovascular and lung dysmorphogenesis. Tab1 mutant embryonic fibroblast cells
      displayed drastically reduced TAK1 kinase activities and decreased sensitivity to
      TGF-beta stimulation. These results indicate a possibility that TAB1 plays an
      important role in mammalian embryogenesis and is required for TAK1 activation in
      TGF-beta signaling.

PMID- 12464437
TI  - The mouse rib-vertebrae mutation is a hypomorphic Tbx6 allele.
AB  - Rib-vertebrae (rv) is an autosomal recessive mutation in mouse that affects
      somite formation, morphology, and patterning. Expression of Notch pathway
      components is affected in the paraxial mesoderm of rv mutant embryos, and rv and
      a null allele of the Notch ligand delta1 show non-allelic non-complementation. By
      fine genetic mapping and complementation testing we have identified Tbx6, a gene
      essential for paraxial mesoderm formation, as the gene mutated in rv. Compound
      heterozygotes carrying a Tbx6 null allele and rv show a phenotype that is milder
      than in homozygous Tbx6 null but more severe than in homozygous rv mutants. Tbx6
      expression is down-regulated in rv mutant embryos. An insertion in the promoter
      region upstream of the transcriptional start is present in the genome of rv
      mutants but not in different strains of mice wild type for Tbx6. Our results
      indicate that rv is a regulatory mutation of Tbx6 causing a hypomorphic
      phenotype.

PMID- 12464440
TI  - Retroperitoneal soft tissue sarcomas: a treatment challenge and a call for
      randomized trials.

PMID- 12464441
TI  - Surgical resection and radiotherapy for primary retroperitoneal soft tissue
      sarcoma.
AB  - METHODS AND MATERIALS: Forty-five patients were consecutively treated for primary
      retroperitoneal soft tissue sarcoma with surgery in combination with radiation
      therapy in the same institution. The median follow-up time was 53 months (7-108).
      RESULTS: Seventeen (38%) patients had clear microscopic margins (R0 resection),
      26 patients (58%) had gross complete surgical excision (R1 resection) and two
      patients (4%) had a macroscopic residual disease (R2 resection). External
      radiotherapy doses ranged from 40.8 to 59.4 Gy (mean and median: 49 Gy).
      Seventeen patients underwent intraoperative radiation therapy (IORT). Moreover,
      11 patients received chemotherapy. The overall 1-, 2-, and 5-year survival for
      all 45 patients were 93, 85 and 60%, respectively. The 1-, 2-, and 5-year
      locoregional relapse-free rate for the whole group was 91, 70 and 40%,
      respectively. In univariate analysis, quality of surgery was the only variable to
      show a significant effect for overall survival (P=0.0386) and for local control
      (P=0.0059). Tumor size and tumor grade had no statistically significant effect.
      For the patients receiving IORT+external beam radiation therapy, no difference
      was observed for survival or locoregional control. The most frequent acute side
      effects treatment complications were radiation-induced nausea or vomiting (42%)
      and moderate enteritis (30%). Significant late morbidity was observed for two
      patients. CONCLUSIONS: This study confirms the feasibility of external
      postoperative radiotherapy with an acceptable level of toxicity. However, the
      high rate of local relapses (especially in field of radiation) does not
      demonstrate the usefulness of radiotherapy at the level of dose used and further
      preferably randomized studies should be planned.

PMID- 12464442
TI  - The risk of second malignancy in men with prostate cancer treated with or without
      radiation in British Columbia, 1984-2000.
AB  - BACKGROUND AND PURPOSE: To describe the risk of second malignancy following a
      diagnosis of prostate cancer, in British Columbia (BC), Canada. To ascertain
      whether that risk changed with the use of radiation therapy. METHODS AND
      MATERIALS: All invasive cases of prostate cancer diagnosed from 1984 through to
      2000 were retrieved from the BC Tumor Registry. Standardized incidence ratios
      (SIRs) were calculated from observed and expected numbers as a percentage.
      Patients were divided into those who received high-dose radiation therapy (>/=45
      Gy, RT group) and those not treated with radiation (non-RT group). RESULTS:
      Overall there was no significant difference between observed and expected second
      cancer rates, SIR=100 (RT group, N=101; non-RT group, N=98, P=n.s.). Individual
      tumour sites at significantly increased risk (P<0.01) included bladder (non-RT
      group, SIR=132), colo-rectal (RT group, SIR=121), pleura (RT group, SIR=228).
      Other sites of possible significance (P<0.05) include sarcoma (RT group, SIR=170)
      and testis (non-RT group, SIR=282). CONCLUSIONS: Increased rates of bladder and
      testis cancers in the non-RT group are likely to be due to increased urologist
      surveillance and the use of therapeutic orchiectomy. Increased rates of
      colorectal cancer in those treated with radiation may be either due to
      surveillance or treatment. Increases in sarcomas in the RT group are probably
      treatment-related. Overall the increased second cancer risk for those undergoing
      radiation therapy was 1 in 220.

PMID- 12464443
TI  - Osteosarcoma as a second malignant neoplasm.
AB  - PURPOSE: The aim of this study is to compare primary and secondary osteosarcomas
      using data from the National Cancer Institute's Surveillance, Epidemiology and
      End Results (SEER) program. METHODS: Osteosarcoma cases were identified in the
      SEER Cancer Incidence Public-Use Database, 1973-96 (1,511 primary and 133
      secondary osteosarcomas). Secondary osteosarcomas were further classified as
      occurring within or outside the previously irradiated field. Comparisons among
      groups were performed by nominal logistic regression. Survival analyses were
      performed using Kaplan-Meir and proportional hazards regression. RESULTS:
      Secondary osteosarcomas were more likely to have a non-extremity primary site and
      an older age at diagnosis (>40 years) (<0.0001 for both). Secondary osteosarcoma
      cases continued to be more likely to have a non-extremity site when excluding
      those occurring within the radiation field. Five-year overall survival was 50%
      lower for secondary osteosarcomas for both extremity and non-extremity sites.
      Primary malignancies associated with secondary osteosarcomas included 14
      lymphomas/leukemias, six sarcomas, 54 carcinomas, and seven other cancers.
      Secondary osteosarcomas occurring within a field of radiation were more likely to
      occur at a younger age, have a malignancy with a primary morphology other than
      carcinoma, a non-limb site, and a longer duration between their primary malignant
      neoplasms and the development of osteosarcoma. No difference in the overall
      survival was noted between secondary osteosarcomas occurring within an irradiated
      field and those that did not. CONCLUSIONS: Secondary osteosarcomas are associated
      with carcinomas especially in the elderly. Although a 50% decreased 5-year
      survival was observed for secondary osteosarcomas in this study, this might not
      reflect the current outcomes with more aggressive therapy.

PMID- 12464444
TI  - Second primary oesophageal cancer following radiation for breast cancer.
AB  - The management of 12 women who presented with a second primary oesophageal cancer
      following radiotherapy for breast cancer was reviewed. It was concluded that nine
      cases fitted the classical description of a radiation-induced malignancy. Most
      cases were successfully managed with combined modality therapy in spite of their
      previous radiotherapy.

PMID- 12464445
TI  - Reproducibility and treatment planning advantages of a carbon fiber relocatable
      head fixation system.
AB  - INTRODUCTION: An all carbon fiber head fixation system, VBH HeadFix Arc
      ('HeadFix') modified to optimize conformal radiation therapy, is described and
      its treatment planning and delivery advantages, positional accuracy and X-ray
      attenuation are presented. MATERIAL AND METHODS: Serial radiation field isocenter
      measurements were made from weekly anterior-posterior (AP) and lateral port films
      taken of 13 children undergoing fractionated external beam radiation therapy for
      primary brain tumors. Measurements were also made of radiation transmission
      through the components of the HeadFix system. RESULTS AND CONCLUSION: The mean
      deviation between simulation and port films in each of the orthogonal directions
      was 0.8-1.2 mm and the mean 3 dimensional deviation was 1.8+/-0.6 mm. The
      modified HeadFix system components attenuate between 2 and 4% of the incident
      beam, allowing a wider range of beam directions for conformal therapy than the
      previously reported system.

PMID- 12464446
TI  - Motivational responses to natural and drug rewards in rats with neonatal ventral
      hippocampal lesions: an animal model of dual diagnosis schizophrenia.
AB  - The high prevalence of substance use disorders in schizophrenia relative to the
      general population and other psychiatric diagnoses could result from
      developmental neuropathology in hippocampal and cortical structures that underlie
      schizophrenia. In this study, we tested the effects of neonatal ventral
      hippocampal lesions on instrumental behavior reinforced by sucrose pellets and
      intravenous cocaine injections. Lesioned rats acquired sucrose self
      administration faster than sham-lesioned rats, but rates of extinction were not
      altered. Lesioned rats also responded at higher rates during acquisition of
      cocaine self-administration, and tended to acquire self-administration faster.
      Higher response rates reflected perseveration of responding during the post
      injection "time-out" periods, and a greater incidence of binge-like cocaine
      intake, which persisted even after cocaine self-administration stabilized. In
      contrast to sucrose, extinction from cocaine self-administration was prolonged in
      lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming
      increased compared with shams. These results suggest that neonatal ventral
      hippocampal lesions facilitate instrumental learning for both natural and drug
      rewards, and reduce inhibitory control over cocaine taking while promoting
      cocaine seeking and relapse after withdrawal. The findings are discussed in terms
      of possible developmental or direct effects of the lesions, and both positive
      reinforcement (substance use vulnerability as a primary disease symptom) and
      negative reinforcement (self-medication) theories of substance use comorbidity in
      schizophrenia.

PMID- 12464447
TI  - Homer 1a gene expression modulation by antipsychotic drugs: involvement of the
      glutamate metabotropic system and effects of D-cycloserine.
AB  - N-methyl-D-aspartate receptor hypofunction has been suggested to play a role in
      the pathophysiology of schizophrenia. New glutamatergic mechanisms involving
      metabotropic receptors have been recently proposed to further expand this
      hypothesis. "Homer" is a family of postsynaptic density proteins functionally and
      physically attached to glutamate metabotropic receptors. We investigated the
      activation of the early gene form of Homer after acute treatment with typical or
      atypical antipsychotic drugs alone or with the adjunction of D-cycloserine. This
      activation was compared with that of c-fos, considered a putative molecular
      marker of brain regions activated by antipsychotics. Male Sprague-Dawley rats
      were treated intraperitoneally with haloperidol (0.8 mg/Kg) or clozapine (15
      mg/Kg) alone or with the adjunction of D-cycloserine (20 mg/Kg). Rats were
      sacrificed ninety minutes after injection and the brains were processed for
      quantitative in situ hybridization histochemistry. Haloperidol induced a
      statistically significant increase of Homer both in caudate-putamen and nucleus
      accumbens compared with controls; clozapine induced Homer significantly only in
      the accumbens. The adjunction of D-cycloserine attenuated the haloperidol-induced
      increase of Homer expression in caudate-putamen and nucleus accumbens and
      attenuated the clozapine-induced increase in the accumbens. The c-fos gene
      expression was potently induced by haloperidol in caudate-putamen and nucleus
      accumbens, and by clozapine only in the accumbens. The adjunction of D
      cycloserine enhanced c-fos expression only for clozapine in both regions of the
      forebrain. These results demonstrate a differential involvement of glutamatergic
      metabotropic system in gene expression modulation induced by typical or atypical
      antipsychotic drugs and may suggest new molecular basis for the augmentation
      strategy by a glycine site partial agonist.

PMID- 12464448
TI  - Evaluation of antidepressant-related behavioral responses in mice lacking the
      serotonin transporter.
AB  - Inhibition of the serotonin transporter (5-HTT) is a principal initial target of
      many antidepressants. However, the contribution of the 5-HTT to their therapeutic
      efficacy is incompletely understood. We utilized a targeted gene mutation
      approach to examine the role of the 5-HTT in the behavioral actions of
      antidepressants. The 5-HTT mutation was bred onto two separate genetic
      backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical,
      neurological and behavioral functions, all measures were normal with the
      exception that 5-HTT -/- mice on the C57BL/6J background showed increased body
      weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background
      showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/-
      mice on the 129S6 background showed a baseline antidepressant-like reduction in
      immobility. In contrast, the same mice showed increased immobility in the forced
      swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on
      the C57BL/6J background showed no baseline antidepressant-related phenotype on
      either test. The behavioral effects of three antidepressants were tested in 5-HTT
      mutant mice (C57BL/6J background) in the tail suspension test. The anti
      immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg),
      were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for
      the behavioral effects of fluoxetine. In contrast, 5-HTT-/- mice retained
      sensitivity to the anti-immobility effects of the norepinephrine reuptake
      inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine
      reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable
      tool for delineating the neuropsychopharmacological actions of antidepressants.

PMID- 12464449
TI  - Conditioned locomotion is not correlated with behavioral sensitization to
      cocaine: an intra-laboratory multi-sample analysis.
AB  - Pre-clinical and clinical studies have demonstrated the importance of associative
      factors in regulating craving for drugs of abuse. To model these conditioned
      effects, we have examine cue-induced conditioned locomotion in rodents. The
      present study involved analysis of several of our prior studies to evaluate the
      relationship between conditioned locomotion and behavioral sensitization using a
      within-subjects analysis. Both are animal models used to study addiction, so it
      is important to know if one is predictive of the other, and more generally, if
      drug effects are predictive of conditioned effects. In all of our studies, Paired
      subjects received cocaine during presentation of conditioned stimuli while
      Unpaired subjects received saline with the stimuli and cocaine at the home cages
      an hour later. Paired subjects typically displayed behavioral sensitization over
      the course of training. After the completion of training, all subjects were
      tested with the conditioned stimuli in the absence of drug and conditioned
      locomotion was measured. The response of Unpaired subjects on the last training
      day was positively correlated with their response on test day, as expected since
      both days were nearly identical (stimuli presented without cocaine). However, for
      Paired subjects, the magnitude of conditioned locomotion on the drug-free test
      day was not positively correlated with the magnitude of behavioral sensitization.
      These results underscore the importance of focusing research on drug-free
      conditioned behaviors when attempting to model conditioned responses to drug
      related cues in human addicts.

PMID- 12464450
TI  - The effects of excitotoxic hippocampal lesions in rats on risperidone- and
      olanzapine-induced locomotor suppression.
AB  - Previous studies have shown that excitotoxic hippocampal lesions in rats
      attenuate the ability of different doses of haloperidol, but not of clozapine, to
      suppress locomotor activity. The purpose of the present study was to determine if
      kainic acid-induced hippocampal damage reduces the degree of locomotor
      suppression produced by two relatively newer antipsychotic drugs, risperidone and
      olanzapine. Young adult male rats received bilateral intracerebroventricular
      infusions of the excitotoxin, kainic acid (KA), or vehicle and were tested for
      locomotor responses to drug treatment 30 days later. Infusions of KA produced
      neuronal loss in the CA3 region of the dorsal hippocampus in every rat. As
      reported previously, KA lesions reduced the ability of haloperidol (0.35 mg/kg)
      to completely suppress the locomotor activity elicited by amphetamine (1.5 mg/kg)
      relative to the effect of haloperidol in non-lesioned controls. Lesioned animals
      treated with a moderate dose of risperidone (1.4 mg/kg) also exhibited
      significantly more locomotor activity after amphetamine treatment in comparison
      to control animals. A trend toward greater activity was also observed in the
      lesioned group relative to the control group after olanzapine (3.0 mg/kg)
      injection (p =.09, 2-tailed). The locomotor effects of lower and higher doses of
      risperidone and olanzapine were not altered by kainic acid lesions. These data
      suggest that the locomotor-suppressive effects of moderate doses of risperidone
      and, perhaps, olanzapine involve hippocampal neurons, but that higher doses of
      each drug can suppress activity in a hippocampal-independent manner.

PMID- 12464451
TI  - The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid
      receptor function.
AB  - Previous studies have demonstrated that antidepressants can enhance
      glucocorticoid receptor (GR) translocation and function, possibly through
      activation of cAMP and downstream cAMP dependent protein kinases. Accordingly, we
      examined GR function in cells treated with rolipram, a phosphodiesterase (PDE)
      type 4 inhibitor that antagonizes cAMP breakdown. Compared with vehicle-treated
      cells, rolipram alone and in combination with dexamethasone significantly
      enhanced GR function as measured in both mouse L929 cells and rat C6 glioma cells
      stably transfected with reporter genes driven by upstream glucocorticoid response
      elements. Rolipram's facilitation of GR function was reversible by the GR
      antagonist, RU486, and was associated with reduced cytosloic GR binding,
      indicating rolipram enhancement of GR nuclear translocation. Finally, rolipram
      potently augmented GR enhancement by the antidepressant, desipramine. These
      findings broaden the potential pathways by which PDE type 4 inhibitors can
      influence cellular function and indicate that these agents may have special
      utility in disorders associated with impaired GR-mediated feedback inhibition.

PMID- 12464452
TI  - R-fluoxetine increases extracellular DA, NE, as well as 5-HT in rat prefrontal
      cortex and hypothalamus: an in vivo microdialysis and receptor binding study.
AB  - The selective serotonin reuptake inhibitor fluoxetine consists of equal amounts
      of R and S stereoisomers. In this study, we investigated the pharmacologic
      properties of the stereoisomers using transporter and receptor binding assays and
      in vivo microdialysis in freely moving rats. Binding to the transporter confirmed
      selectivity of R- and S-fluoxetine for the 5-HT transporter versus the dopamine
      (DA) and norepinephrine (NE) human transporters. Receptor binding studies
      demonstrated significant affinity of R-fluoxetine, but not S-fluoxetine, for
      human 5-HT(2A) and 5-HT(2C) receptor subtypes. Functional GTPgammaS binding
      studies indicated that R-fluoxetine is an antagonist at 5-HT(2A) and 5-HT(2C)
      receptors. In microdialysis studies, acute R- and S-fluoxetine increased
      extracellular levels of 5-HT, DA, and NE in prefrontal cortex (PFC), but R
      fluoxetine caused significantly greater increases of catecholamines. R-fluoxetine
      increased extracellular levels of 5-HT and NE in PFC, nucleus accumbens, and
      hypothalamus, whereas it increased dopamine in PFC and hypothalamus, but not in
      DA-rich nucleus accumbens and striatum, thus indicating a regionally selective
      effect. The unexpected increases of extracellular catecholamines by a selective 5
      HT uptake inhibitor like R-fluoxetine may be due to its antagonism of 5-HT(2C)
      receptors.

PMID- 12464453
TI  - Gamma-hydroxybutyrate reduces GABA(A)-mediated inhibitory postsynaptic potentials
      in the CA1 region of hippocampus.
AB  - Gamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative
      neurotransmitter, derived from gamma-aminobutyric acid (GABA). At micromolar
      concentrations GHB binds to specific high and low affinity binding sites present
      in discrete areas of the brain, while at millimolar concentrations GHB also binds
      to GABA(B) receptors. Previous studies indicated that GHB inhibits both NMDA and
      AMPA receptor mediated excitatory postsynaptic potentials in hippocampal CA1
      pyramidal neurons. This action of GHB occurs in the presence of GABA(B) blockade
      and is antagonized by NCS-382, a specific GHB receptor antagonist, suggesting
      that it is mediated by GHB receptors. In the present study, we have investigated
      the effect of GHB on GABA(A) mediated inhibitory postsynaptic potentials (GABA(A)
      IPSP) elicited in CA1 hippocampal pyramidal neurons by stimulation of Schaffer
      collateral-commissural fibers. We observed that GHB inhibited GABA(A)-IPSPs by
      about 40% at concentrations of 300-600 microM. GHB inhibition was blocked by NCS
      382 (500 microM), which per se failed to modify GABA(A)-IPSPs. Moreover, GHB
      failed to modify cell membrane depolarization induced by the brief pressure
      application of GABA in the presence of tetrodotoxin (TTX), indicating that GHB
      does not inhibit postsynaptic GABA responses. However, GHB reduced the amplitude
      of GABA(A)-IPSPs elicited in pyramidal neurons by paired pulse stimulation and
      enhanced paired pulse facilitation with respect to control condition, suggesting
      that GHB reduces GABA release from nerve terminals. Finally, GHB failed to reduce
      the amplitude of GABA(A)-IPSPs in the presence of BaCl(2), suggesting that the
      effect of GHB is due to GHB receptor-mediated presynaptic inhibition of Ca(2)+
      influx.

PMID- 12464454
TI  - Previous exposure to VTA amphetamine enhances cocaine self-administration under a
      progressive ratio schedule in a D1 dopamine receptor dependent manner.
AB  - The effect of previous exposure to amphetamine (AMPH) in the ventral tegmental
      area (VTA) on the subsequent self-administration of cocaine was assessed. Rats in
      different groups were pre-exposed to three injections into the VTA of either
      saline (0.5 microl/side) or AMPH (2.5 microg/0.5 microl/side). Injections were
      given once every third day. Starting 7-10 days after the last pre-exposure
      injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion)
      under fixed ratio 1 and 2 (FR1 and FR2) schedules and then tested under a
      progressive ratio (PR) schedule of reinforcement for six consecutive days. No
      differences between groups were observed during self-administration training
      under the FR schedules of reinforcement. However, when tested under the PR
      schedule, VTA AMPH pre-exposed rats worked more and, as a result, obtained more
      infusions of cocaine than saline pre-exposed rats. Rats in a separate group pre
      exposed to VTA AMPH but co-infused with the D(1)-like dopamine (DA) receptor
      antagonist SCH23390 (0.25 microg/0.5 microl/side) did not show enhanced cocaine
      self-administration. These rats, as well as others pre-exposed to VTA SCH23390
      alone showed levels of cocaine self-administration similar to saline pre-exposed
      rats. Thus, in a manner paralleling the sensitization of AMPH-induced locomotion
      and nucleus accumbens DA overflow, previous exposure to AMPH in the VTA leads to
      enhanced intravenous self-administration of cocaine and activation of D(1) DA
      receptors in this site during pre-exposure is necessary for the production of
      this effect.

PMID- 12464455
TI  - A role for electrotonic coupling in the striatum in the expression of dopamine
      receptor-mediated stereotypies.
AB  - Stimulation of dopamine (DA) receptors in the striatum evokes a number of
      alterations in motor behavior in rats, as well as causing several alterations in
      cellular physiology, including changes in membrane potential, cell excitability,
      afferent drive, and electrotonic coupling. One cellular property that is potently
      modulated by DA stimulation is electrotonic coupling, a process shown to subserve
      motor pattern generation. To examine whether electrotonic coupling plays a role
      in mediating a specific set of DA receptor-mediated motor behaviors, we tested
      the effects of two inhibitors of gap junction conductance, carbenoxolone (CARB)
      and anandamide (AEA), on apomorphine (APO)-induced motor responses. We then used
      intra-striatal infusions of CARB to determine the role of electrotonic coupling
      specifically in the ventral striatum in the expression of APO-induced behaviors.
      APO (2.5-3.0 mg/kg, i.p.) significantly increased motor activity (a composite
      score) and the frequencies of oral and sniffing stereotypies. APO also disrupted
      grooming initiation and completion. APO-induced oral stereotypies were
      selectively blocked by systemic administration of CARB (7.0, 35.0 mg/kg).
      Moreover, although CARB alone disrupted the initiation and completion of grooming
      sequences, it also partially normalized APO-induced disruptions in grooming. AEA
      (0.5, 1.5 mg/kg) also blocked APO-induced oral stereotypies at the higher dose,
      but differed from CARB in that it did not restore normal grooming behaviors but,
      instead, appeared to "release" locomotion. Bilateral infusion of carbenoxolone
      (50 pmol) into the ventral striatum also blocked the oral stereotypies induced by
      systemic APO. We conclude from these and previous experiments that gap junctions
      play an important role in normal motor behavior, and furthermore that disruption
      of motor behavior in the form of oral and sniffing stereotypies associated with
      systemic APO administration may be a consequence of this heightened electrotonic
      coupling in the striatum. These results may be relevant to diseases and
      pharmacotherapies associated with disruptions of motor and possibly cognitive
      sequencing.

PMID- 12464456
TI  - Cognitive performance of MDMA-treated rhesus monkeys: sensitivity to serotonergic
      challenge.
AB  - Recreational users of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy")
      exhibit poor performance on a number of neurocognitive measures, with tests of
      memory and attention most commonly affected. Cognitive impairments can be
      persistent or possibly permanent, since users who have been abstinent from MDMA
      for many months are also impaired. Repeated treatment of rats or nonhuman
      primates with MDMA has consistently been demonstrated to produce specific,
      lasting depletions of brain serotonin (5-HT) markers, a potential source of such
      cognitive symptoms. We have shown, however, that monkeys treated with a regimen
      of MDMA (4 days, 10 mg/kg i.m., b.i.d.), sufficient to produce a 50% reduction of
      the 5-HT metabolite 5-hydroxyindoleacetic acid in cerebrospinal fluid, do not
      exhibit lasting deficits in a range of cognitive domains. Acute drug challenges
      are often effective at unmasking consequences of amphetamine toxicity. Here, the
      performance of MDMA-treated and control monkeys on tests of spatial working
      memory (self-ordered spatial search), vigilance and reaction time (5-choice
      reaction time), reinforcer efficacy and sustained attention (progressive ratio
      responding) and fine motor control (bimanual motor skill task) was challenged
      with ketanserin (0.1-1.7 mg/kg, i.m.), 1-(3-Chlorophenyl)piperazine
      dihydrochloride (mCPP, 0.03-0.5 mg/kg, i.m.) and (+/-)8-hydroxy-DPAT hydrobromide
      (8-OH-DPAT, 0.032-0.1 mg/kg, i.m.). MDMA-exposed animals exhibited increased
      sensitivity to challenge with mCPP on the reaction time and progressive ratio
      tasks but otherwise were equivalently sensitive to drug challenge. Post-mortem
      analysis demonstrated that 76-93% reductions of 5-HT in neocortex persist 17-20
      months post-MDMA. These observations suggest that large depletions of brain 5-HT
      produced by MDMA can persistently alter behavioral sensitivity to the disrupting
      effects of serotonergic agents.

PMID- 12464457
TI  - Effect of dopamine receptor antagonists on renewal of cocaine seeking by
      reexposure to drug-associated contextual cues.
AB  - We recently found that in rats trained to self-administer a heroin-cocaine
      mixture, exposure to the drug self-administration environment, after extinction
      of the drug-reinforced behavior in a different context, leads to renewal of drug
      seeking. Here we further explored the role of contextual stimuli in drug seeking
      by characterizing the effect of drug-associated environmental stimuli on renewal
      of cocaine seeking. We also investigated whether activation of dopamine receptors
      contributes to context-induced renewal of cocaine seeking by testing the effects
      of selective D1-like (SCH 23390) and D2-like (raclopride) receptor antagonists.
      Rats were trained for 10 days to self-administer cocaine by pressing a lever.
      Next, lever pressing was extinguished in the presence of the discrete cues
      associated with cocaine infusions for 10 days in a context that was distinctively
      different from the drug-taking context. On the test days, rats were pretreated
      with SCH 23390 (0, 5 or 10 microg/kg) or raclopride (0, 50 or 100 microg/kg) and
      non-reinforced lever-pressing behavior was determined either in the extinction
      context (Control group) or the cocaine-associated context (Renewal group).
      Consistent with our previous report, cocaine seeking was renewed when rats were
      exposed to the drug-associated context after extinction in a different context.
      Furthermore, pretreatment with the D1-like or the D2-like receptor antagonists
      attenuated context-induced renewal of cocaine seeking. These data suggest that
      activation of dopamine receptors is involved in reinstatement of cocaine seeking
      induced by exposure to the drug self-administration context.

PMID- 12464458
TI  - Effects of rapid tryptophan depletion on sleep electroencephalogram and mood in
      subjects with partially remitted depression on bupropion.
AB  - Serotonin has been implicated in both sleep and mood regulation. When central
      serotonin was depleted with a tryptophan-free amino acid drink (TFD), some
      studies have reported that the antidepressant benefits were reversed in partially
      remitted patients treated with SSRIs. Other studies showed that the TFD increased
      rapid eye movement (REM) sleep in both normal males and in remitted depression
      patients on selective serotonin reuptake inhibitors (SSRIs) without affecting
      mood. In this study, we administered a TFD to patients with remitted depression
      who were being treated with bupropion, an antidepressant whose mechanism of
      action apparently does not affect the serotonin system. We hypothesized that the
      TFD would increase the propensity for REM sleep without affecting depression
      ratings. Eight partially remitted depression subjects on bupropion were
      administered a TFD and a control drink containing tryptophan in double-blind,
      random order on separate days. The effects of these drinks were monitored with
      sleep electroencephalograms, mood ratings, and plasma tryptophan measures
      comparing baseline, TFD, and control nights. The TFDs reduced REM latency and
      stage 2 percent and increased REM time and percent. Subjective measures of
      elation, vigor, and friendliness significantly decreased on both TFD and control
      drinks but depression ratings did not. Plasma levels of tryptophan decreased with
      the TFD. Although the TFD altered REM sleep, certain mood measures, and plasma
      tryptophan levels, no relapses into depression were seen with our subjects.
      Bupropion alone did not affect sleep measures.

PMID- 12464459
TI  - Amphetamine-induced increases in extracellular dopamine, drug wanting, and
      novelty seeking: a PET/[11C]raclopride study in healthy men.
AB  - Eight healthy men underwent two positron emission tomography (PET)
      [11C]raclopride scans, one following placebo, the second following d-amphetamine
      (0.30 mg/kg, p.o.). PET data were analyzed using: (1) brain parametric maps to
      statistically generate regions of significant change; and (2) a priori identified
      regions of interest (ROI) manually drawn on each individual's co-registered
      magnetic resonance (MR) images. Compared with placebo, d-amphetamine decreased
      [11C]raclopride binding potential (BP) with significant effects in ventral but
      not dorsal striatum. Change in BP in the statistically generated cluster
      correlated with self-reported drug-induced 'drug wanting' (r = 0.83, p =.01) and
      the personality trait of Novelty Seeking-Exploratory Excitability (r = 0.79, p
      =.02). The same associations were seen in the manually drawn ROI in ventral
      striatum but not in dorsal putamen or caudate. Changes in extracellular dopamine
      (DA) did not correlate with mood. Mesolimbic DA might mediate interest in
      obtaining reward rather than reward, per se. Individual differences in
      amphetamine-induced DA release might be related to predispositions to drug and
      novelty seeking.

PMID- 12464460
TI  - Dextroamphetamine modulates the response of the human amygdala.
AB  - Amphetamine, a potent monoaminergic agonist, has pronounced effects on emotional
      behavior in humans, including the generation of fear and anxiety. Recent animal
      studies have demonstrated the importance of monoamines, especially dopamine, in
      modulating the response of the amygdala, a key brain region involved in the
      perception of fearful and threatening stimuli, and the generation of appropriate
      physiological and behavioral responses. We have explored the possibility that the
      anxiogenic effect of amphetamine in humans reflects the drug's influence on the
      activity of the amygdala. In a double-blind placebo controlled study, fMRI
      revealed that dextroamphetamine potentiated the response of the amygdala during
      the perceptual processing of angry and fearful facial expressions. Our results
      provide the first evidence of a specific neural substrate for the anxiogenic
      effects of amphetamine and are consistent with animal models of dopaminergic
      activation of the amygdala.

PMID- 12464461
TI  - Effects of the neuropeptide substance P on sleep, mood, and neuroendocrine
      measures in healthy young men.
AB  - The neuropeptide substance P (SP) has been supposed to be involved in the
      etiopathology of affective disorders, mainly because of the finding of increased
      levels of SP in the cerebrospinal fluid of depressed patients and the preliminary
      evidence of antidepressant effects of SP-receptor antagonists in depressed
      patients. We investigated whether SP may induce changes of sleep, mood and
      neuroendocrine measures that are similar to those in depressed patients. In a
      double-blind, randomized cross-over design, 12 healthy young men were
      investigated in two blocks of three consecutive nights, in which SP or NaCl was
      intravenously infused during the third night. Polysomnographic recordings were
      obtained during all nights and blood samples were drawn every 30 min during the
      third night. Infusion of SP caused a significant worsening of the mood of the
      subjects, led to an increase of REM latency and time awake during the SP-infusion
      intervals, caused increased stage 1 sleep in the first part of the night, and led
      to increased cortisol and thyroid stimulating hormone levels and a trend for
      decreased growth hormone levels. These effects can be interpreted as evidence for
      a central arousing effect of SP. Further studies should focus on the effects of
      substance P in patients with depressive or other psychiatric disorders.

PMID- 12464462
TI  - Is the time course of clozapine response correlated to the time course of
      clozapine plasma levels? A one-year prospective study in drug-resistant patients
      with schizophrenia.
AB  - The relationship between the time course of clinical response to clozapine and
      the time course of clozapine plasma levels has never been investigated. In the
      present study, we assessed prospectively the clinical response to clozapine and
      the plasma levels of the drug and its major metabolites in 32 drug-resistant
      patients with schizophrenia kept on a fixed dose of 600 mg/day for 1 year Four of
      the patients met response criteria at week 4 of treatment. At weeks 8, 12, and
      24, new responders were 7, 6, and 6, respectively. Nine patients never achieved
      clinical response. In responders at week 4, clozapine and clozapine-N-oxide
      plasma levels were significantly higher than in both new responders at weeks 8,
      12, and 24 and nonresponders. In new responders at weeks 8, 12, and 24, in spite
      of a fixed clozapine daily dose, mean drug plasma levels progressively rose up to
      when clinical response occurred; then, the levels remained stable over time.
      Nonresponders exhibited mean clozapine plasma levels constantly below the value
      of 260 ng/ml, with N-demethylation as the preferred metabolic route. The present
      findings show, for the first time, that the time course of the clinical response
      to clozapine may be linked to the time course of plasma levels of clozapine and
      its major metabolites.

PMID- 12464463
TI  - Nicotine and behavioral markers of risk for schizophrenia: a double-blind,
      placebo-controlled, cross-over study.
AB  - We investigated the effect of nicotine on three behavioral markers of risk for
      schizophrenia: sustained attention (using the Continuous Performance Task (CPT)),
      antisaccade performance, and smooth pursuit. Smooth pursuit was investigated in
      two conditions, one in which attention was enhanced (monitoring target changes)
      and one in which attention was not enhanced (no monitoring). Patients with
      schizophrenia (n = 15) and controls (n = 14) were given a 14-mg nicotine patch in
      a double-blind, placebo-controlled, crossover design and plasma nicotine
      concentrations were monitored. Nicotine concentrations were similar in both
      groups. A Group x Drug interaction (p <.02) on CPT hits indicated that nicotine
      improved sustained attention in patients but not in controls. Nicotine
      significantly decreased antisaccade errors (p <.01) in both groups. A Drug x
      Monitoring condition interaction (p <.01) on pursuit gain indicated that nicotine
      significantly increased pursuit gain in the no-monitoring condition in patients
      and controls equally, but did not improve pursuit in the monitoring condition.
      Thus, improvement in pursuit may have been mediated via an effect on attention
      rather than by an effect on oculomotor function per se. In patients, the
      magnitude of improvement in attention on nicotine was correlated with the
      improvement on eye movement tasks. Thus, nicotine improves performance on both
      attention and oculomotor markers of risk for schizophrenia, possibly via common
      mechanisms.

PMID- 12464464
TI  - Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month double
      blind study.
AB  - This multicenter, double-blind, randomized study evaluated the efficacy, safety
      and functional effects of two atypical antipsychotics, amisulpride and
      risperidone, in patients with chronic schizophrenia (DSM IV) with a recent
      worsening of symptoms. It was planned as a non-inferiority trial. 309 patients
      received amisulpride (400-1,000 mg/day) or risperidone (4-10 mg/day) for six
      months. Amisulpride was demonstrated to be not inferior to risperidone with
      respect to the decrease in Positive and Negative Syndrome Scale (PANSS) total
      score from baseline (90% 2-sided confidence interval (-5.6; 4.0)). Symptomatic
      improvement measured with the Brief Psychiatry Rating Scale (BPRS), the PANSS
      positive subscale, and the Bech Rafaelsen Melancholia Scale was similar in both
      groups. Amisulpride was significantly (p <.05) superior to risperidone in terms
      of response (>/=50% improvement in PANSS and BPRS total scores or "very much/much
      improved" on the Clinical Global Impression Scale) and also demonstrated better
      functional effects and subjective response. Both treatments were well tolerated
      and had a similar low incidence of extrapyramidal symptoms; however, amisulpride
      was associated with less weight gain and endocrine/sexual symptoms.

PMID- 12464467
TI  - A message from the president.

PMID- 12464465
TI  - Are differential behavioral responses to smoking and smoking cessation in
      schizophrenia related to nicotinic receptor levels?

PMID- 12464468
TI  - Effects of thermal properties and geometrical dimensions on skin burn injuries.
AB  - A one-dimensional multi-layer model is presented to characterise the skin burn
      process resulting from the application of a high temperature heat source to a
      skin surface. Transient temperatures were numerically calculated using a finite
      difference method to solve the Pennes bioheat equation. A damage function
      denoting the extent of burn injury was then calculated using the Arrhenius
      assumptions. The model was used to predict the effects of thermal physical
      properties and geometrical dimensions on the transient temperature and damage
      function distributions. The results show that the epidermis and dermis
      thicknesses significantly affect the temperature and burn injury distributions,
      while variations of the initial temperatures and the blood perfusion have little
      effect.

PMID- 12464469
TI  - Efficacy of laser debridement with autologous split-thickness skin grafting in
      promoting improved healing of deep cutaneous sulfur mustard burns.
AB  - The consequences of receiving a cutaneous sulfur mustard (SM) burn are prolonged
      wound healing and secondary infection. This study was undertaken to find a
      treatment that promotes quick healing with few complications and minimal
      disfigurement. Multiple deep SM burns (4 cm diameter) were generated on the
      ventrum of weanling pigs and treated at 48 h. Four treatments were compared: (1)
      full-thickness CO(2) laser debridement followed by skin grafting; (2) full
      thickness sharp surgical tangential excision followed by skin grafting, the "Gold
      Standard" used in deep thermal burns management; (3) partial-thickness laser
      ablation with no grafting; and (4) partial-thickness sharp excision with no
      grafting. A computer controlled, raster scanned, high-powered continuous wave
      (cw) CO(2) laser was utilized. Ulceration, wound geometry, and wound contraction
      were evaluated during a 36-day healing period. Histopathological evaluations were
      conducted at the end of the healing period. Engraftment rates were similar
      between both methods of debridement. Laser debridement followed by skin grafting
      was as efficacious in improving the wound healing of deep SM burns as the "Gold
      Standard." Full-thickness laser debridement of these small total body surface
      area (TBSA) burns was time efficient and provided adequate beds for split
      thickness skin grafting. Laser debridement offered additional benefits that
      included hemostatic control during surgery and minimal debridement of normal
      perilesional skin. Mid-dermal debridement by sharp excision or laser ablation
      without grafting produced less desirable results but was better than no
      treatment.

PMID- 12464470
TI  - The influence of apoptosis of mucosal epithelial cells on intestinal barrier
      integrity after scald in rats.
AB  - OBJECTIVE: To study the influence of apoptosis of intestinal epithelial cells
      occurring as a result of reperfusion after burn shock on the intestinal barrier.
      METHODS: Fifty Wistar rats were subjected to a 30% TBSA full thickness burn, and
      normal saline (40 ml/kg) was given intraperitoneally immediately after the injury
      (group A). Ten rats served as a sham control group. The experimental group B
      consisted of 50 rats with identical injuries, but the normal saline was not given
      until 6h after the injury. Apoptosis of intestinal epithelial cells was verified
      by DNA fragmentation, DNA agarose gel electrophoresis, TUNEL and electron
      microscope (EM), and DNA fragmentation rate was expressed as ap%. The D-lactic
      acid in portal vein blood and intestinal diamine oxidase (DAO) were determined to
      evaluate the permeability and integrity of intestinal mucosal epithelium.
      RESULTS: The ap% of intestinal epithelium group B was higher than in that of
      group A (P<0.05 or 0.01), and its amplitude peaked at 12h for both groups.
      Typical DNA ladder pattern was seen in electrophoresis in both groups. Apoptotic
      cells were discerned on the tips of the ileal villi at 3h postscald by TUNEL and
      EM in the group B, and they appeared earlier than in the group A. There was a
      significant positive correlation between the ap% and the level of D-lactic acid
      (group A: r=0.817, P<0.05; group B: r=0.727, P<0.05). On the other hand, a
      significant negative correlation was found between the ap% and the DAO values
      (group A: r=-0.937, P<0.01; group B: r=-0.836, P<0.05). CONCLUSION: Apoptosis
      occurred in enterocytes after scald injury this pathological change might
      contribute to a breach of integrity of intestinal epithelium, leading to a
      compromise in its barrier function. Delayed fluid resuscitation might lead to an
      earlier and higher degree of apoptosis of the intestinal epithelial cells.

PMID- 12464471
TI  - The evaluation of nosocomial infection during 1-year-period in the burn unit of a
      training hospital in Istanbul, Turkey.
AB  - An analysis of the burned patients, admitted to our eight bed burn unit and
      treated between 1 January and 31 December 2000, was performed. Prevalence,
      etiologic agents, length of hospitalization, cost of treatment and mortality
      rates caused by nosocomial infections (NIs) were studied. The study included 63
      patients. Eighteen of these (Group-A) had 24 NI episodes. The most common NI
      observed was burn-wound infection (58.3%), followed by bacteraemia-sepsis
      (16.7%). NIs were not detected in the rest at all (Group B). The mean length of
      hospitalization was 38.5+/-19.7 days in Group A, and 20.3+/-7.6 days in Group B.
      The mean total burned surface area (TBSA) was 43+/-21 in Group A and 29+/-18 in
      Group B, while the most important independent risk factor for NI was TBSA in
      burned patients (OR, 1.08; CI(95), 0.93-1.24). NI prolonged the mean hospital
      stay to 18 days and increased the cost of treatment by 502 US dollars. The most
      common bacteria isolated was Pseudomonas aeruginosa (41.7%) and the second was
      methicillin resistant Staphylococcus aureus (MRSA-25.0%). All of the NI-free
      patients survived, while, five (28.5%) patients with NI died (P<0.01). These
      findings emphasized the need for careful disinfection and conscientious contact
      control procedures in areas that serve immunosupressed individuals, such as
      burned patients.

PMID- 12464472
TI  - Septicaemia after burn injury: a comparative study.
AB  - Seventy-nine (8.4%) patients during June 1992-May 1996 (Group-1) and 68 (7.2%)
      patients from June 1996 to May 2000 (Group-2) who developed septicaemia at the
      burns unit of Al-Babtain Centre for Plastic Surgery and Burns, Kuwait, were
      retrospectively studied and compared. The mean age of 26 years, male
      predominance, flame burns as main aetiology and mean burn percentage of >or=40%
      was observed in both the groups. Both groups revealed extensive flame burn,
      inhalation injury, intubation and difficult resuscitation as the risk factors.
      The proportion of satisfactory resuscitation increased significantly (P<0.001) in
      Group-2. The septicaemia commonly occurred within 2 weeks postburn but the number
      of episodes during 5 days postburn was less in Group-2. The surface wound was
      found to be the likely source of entry of the organisms into the blood stream in
      both the groups. The gram positive organisms were dominant aetiologic factor in
      both groups but an increase frequency of Acnetobacter was found in Group-2. The
      proportion of MRSE and Pseudomonas septicaemia was significantly higher (P<0.01)
      in the Group-1. The rate of survivors, in both the groups was higher among
      operated patients but it was significantly higher (P<0.001) in the Group-1. A
      mortality rate 20.6% in Group-2 decreased against Group-1, which can be
      attributed to better resuscitation, nutritional care, early detection of
      septicaemia, appropriate antibiotics and early wound excision and skin grafting.
      MOF was the cause of death of 60.9% in Group-1 and 85.7% in Group-2. There was no
      role of prophylactic antibiotic in burn patients in the incidence of septicaemia
      and mortality.

PMID- 12464473
TI  - The use of split-thickness dermal grafts to resurface full thickness skin
      defects.
AB  - Coverage of large burns may be difficult when skin graft donor sites are limited.
      This study explored the use of the split-thickness dermal graft (STDG), as an
      alternative to the standard split-thickness skin graft (STSG). STSGs and STDGs
      were compared experimentally by their ability to resurface full thickness skin
      defects in a pig model. Both types of grafts were harvested from the backs of six
      pigs and placed on full thickness wounds. From the same donor site a 0.012in.
      thick STSG and another two 0.012in. thick STDGs were harvested. Thus the deep
      surface of grafts measured 0.012, 0.024 and 0.036in. from the skin surface,
      respectively. All grafts were placed on 6cmx6cm full thickness wounds. The donor
      areas healed at 1 week. Epithelialization of the STDGs, was assessed by
      computerized planimetry, and was 100% at 4 weeks. Graft biopsies revealed that
      STSGs were significant thinner than STDGs at 1 week (P=0.0422, 0.0135), 2 weeks
      (P=0.0240) and 4 weeks (P=0.0516, 0.0425). We conclude that STDGs my provide
      definitive coverage of full thickness skin deficits in a pig wound model.

PMID- 12464474
TI  - Recombinant human growth hormone modulates the hepatic acute-phase response and P
      selectin in burned rats.
AB  - The purpose of this study was to determine the effect of recombinant human growth
      hormone (rhGH) on serum constitutive proteins, cytokines, P-selectin, and insulin
      like growth factor (IGF-1) in the thermally injured rats.Sprague-Dawley rats (64
      males) were given 30% total body surface area full thickness scald burn. They
      were randomly divided to receive either 2.5mg/kg per day im rhGH or saline
      (control). Rats were sacrified on postburn days 1, 2, 5, and 7, and serum
      constitutive proteins, cytokines, P-selectin, and IGF-1 levels were
      measured.Serum IGF-1 levels were increased on days 2, 5, or 7 after burn in rhGH
      treated rats compared with controls (P<0.001, <0.01 and <0.001, respectively).
      Serum transferrin and albumin levels were increased on days 7 after burn in rhGH
      treated rats compared with controls (P<0.05). The cytokines increased after
      thermal injury. The rhGH decreased serum levels of tumor necrosis factor-alpha on
      postburn days 1 compared with controls (P<0.001). Serum levels of interleukin-1
      were decreased on days 1 and 2 after burn in rhGH treated rats compared with
      controls (P<0.001, <0.01, respectively). Rats receiving rhGH showed significantly
      increased P-selectin levels at 5 and 7 postburn days compared with controls
      (P<0.001). Our data indicate that rhGH, given after thermal injury, increased
      albumin, transferrin, IGF-1, and P-selectin levels and decreased serum tumor
      necrosis factor-alpha and interleukin-1 levels.

PMID- 12464475
TI  - Serum concentration of amino-terminal propeptide of type III procollagen (PIIINP)
      as a prognostic marker for skin fibrosis after scar correction in burned
      patients.
AB  - The amino-terminal propeptide of procollagen type III (PIIINP) has been proposed
      as a marker for fibrogenesis in patients with different fibroproliferative
      disorders, e.g. liver and lung fibrosis. In this study, serum concentrations of
      PIIINP were measured by ELISA as a marker for excessive cicatrization in burned
      patients before and after scar correction. All patients were followed 6 months to
      determine a new fibrotic reaction during the wound healing process using the Burn
      Scar Index and to correlate pre- and post-operative concentrations of PIIINP in
      their sera with the risk to develop a new severe tissue fibrosis leading to
      pathological scar formation. Furthermore, PIIINP was determined in the excised
      scar tissue by immunohistochemistry. The study included 38 patients. Nineteen
      patients (8 female, 11 male, average age 48.3+/-18.9 years) had hypertrophic
      scars after major burn injury (TBSA, 21+/-12%; Burn Scar Index, 10.4+/-3.7
      points) and underwent scar correction. Nineteen patients (12 female, 7 male,
      average age 42.3+/-25.5 years) who underwent elective plastic-surgical operations
      served as the control group. Blood samples were drawn immediately before
      operation, at the 1st, 3rd, 7th, and 14th post-operative days, as well as 1st,
      3rd, and 6th months after operation.Pre-operatively, PIIINP was significantly
      elevated (P<0.05) in burned patients who underwent scar correction. There was a
      significant increase (P<0.05) of PIIINP in burned patients from 9.8+/-3.7ng/ml
      pre-operatively to 13.9+/-4.2ng/ml at the 7th post-operation day. Up to 3 months
      after operation, the 6 months after scar correction concentration remained at a
      significantly elevated level compared to pre-operative values. The burned
      patients had a Burn Scar Index of 7.8+/-3.6 points. Pre-operative PIIINP serum
      concentrations correlated with the Burn Scar Index (r(2)=0.7 and 0.68; P<0.05).
      Scar tissue stained intensively positive for PIIINP. There was a significant
      correlation between pre-operative serum values and degree of immunostaining
      (r(2)=0.45; P<0.05). The increased concentration of PIIINP seen in our burned
      patients' sera might serve as a marker for the extent of skin fibrosis and for
      the risk of developing new severe fibrotic reactions after scar correction.

PMID- 12464476
TI  - Effects of full-thickness burns on nociceptor sensitization in anesthetized rats.
AB  - Burn-induced pain is often inadequately managed and its mechanisms, both
      peripheral and central, are poorly understood. To examine peripheral mechanisms,
      the effects of full-thickness burns on individual nociceptive fibers in sural
      nerve of anesthetized rats were studied. Additionally, the study investigated
      whether topical post-burn treatment with the mu-opioid receptor agonist
      loperamide ameliorated burn-induced pathologies. Receptive field (RF) properties
      of C-fibers were determined for 4h before and after producing burns. Burns caused
      profound tissue damage with edema extending beyond the injury site. Injury
      located within or proximal to RFs of nociceptors caused rapid decreases in
      mechanical responsiveness or complete desensitization at the original test site.
      However, post-burn, RF size frequently grew to include areas of newly sensitized
      skin. Transient or prolonged periods of ectopic activity was recorded from some
      nociceptors; this was most prevalent in fibers with RFs proximal to the injury
      site where burn induced background firing in 60% of the population. In most
      cases, loperamide significantly increased mechanical thresholds, prevented
      sensitization of uninjured skin, and reduced discharge.These data indicate that
      full-thickness burns activate and/or sensitize C-nociceptors, thus probably
      leading to pain. As loperamide ameliorates nociceptor activation and
      sensitization, it is an appropriate candidate for burn pain management.

PMID- 12464477
TI  - Epidemiology and mortality of burns in a general hospital of Eastern Sri Lanka.
AB  - This 2-year prospective study examined the epidemiology and mortality of 345
      patients admitted with burn injuries. Sixty-four percent of all burns were
      accidental in nature and at least 25% were self-inflicted. The rest were due to
      assaults or had a doubtful cause. The median age was 22 years. Forty-one percent
      of the accidents were due to the fall of a homemade kerosene bottle lamp. The
      main cause was flames, followed by scalds. Females outnumbered males in all
      categories of burns except cases of assault, and suffered from a higher
      mortality. Most at risk of accidental burns were children between 1 and 4 years,
      who suffered primarily from scalds. Self-inflicted burns were most common among
      women aged 20-29 years. The overall median total body surface area (TBSA) burned
      was 16%. Self-inflicted and 'doubtful' burns were much more extensive and more
      often fatal than accidental ones. The overall mortality rate was 27%. Burns
      involving more than 50% of the body surface area were invariably fatal. Mortality
      was highest in the elderly and in the 20-29 years age group. Burns were the first
      single cause of mortality in the surgical wards. The case is made for the
      establishment of more Burns Units.

PMID- 12464478
TI  - Use of an amphoteric lavage solution for emergency treatment of eye burns. First
      animal type experimental clinical considerations.
AB  - PURPOSE: Severe eye burns occur rarely, but are related to a poor prognosis in
      rehabilitation. As emergency treatment has been identified as decisive factor for
      the prognosis of eye burns, new first aid rinsing solutions should be considered
      carefully in their clinical action. In a first approach, the new drug Diphoterine
      was subjected to a comparison with saline solution to evaluate the effects in a
      model of severe eye burns. METHODS: In a double-masked experiment 16 rabbits
      underwent a severe eye burn of one cornea followed by immediate rinsing with 0.9%
      sodium-chlorine solution (n=8) or Diphoterine (n=8). During 16 days after burn,
      an irrigation therapy with 0.9% saline solution three times daily 160 ml was
      applied in both groups following the recommendation of prolonged irrigation
      therapy performed in our clinic. In a similar setup, 16 eyes were subjected
      alkali burns with measurements of aqueous humor pH within 30s after burn and
      after a period of 5 min rinsing with 500 ml saline 0.9% or Diphoterine,
      respectively. RESULTS: The result of the severe eye burn with an opaque cornea
      was similar in both groups. During rinsing no fibrin precipitates occurred in the
      Diphoterine rinsed group whereas this was detectable in all eyes rinsed with
      saline solution. After 16 days there was no difference between both groups
      indicating no harmful effect of Diphoterine as emergency treatment compared to
      saline 0.9%. After 30s of burn with 1N NaOH and rinsing with 500 ml of the
      specified solutions the anterior chamber pH was 10+/-0 in the saline group and
      9.35+/-0.3 in the Diphoterine group showing efficacy of the buffering capacity of
      Diphoterine. CONCLUSION: Diphoterine proves to be efficient in the primary
      treatment of burns. The anterior chamber pH could be lowered by 5min of rinsing.
      No harmful effects of Diphoterine could be observed compared to rinsing with
      saline solution in the course of an severe alkali burn of the cornea.

PMID- 12464479
TI  - Compartment syndrome in burn patients. A report of five cases.
AB  - Compartment syndrome has been observed in five burn patients. In all five
      patients the diagnosis was delayed and muscle necrosis occurred. Three limbs in
      two patients required amputation because of complete muscle necrosis, and the
      function of limbs in the three other patients was affected to different degrees.
      It is suggested that early limb escharotomies or fasciotomies in patients with
      full-thickness burns is necessary. Dressing should not be very tightly wound in
      limbs that have been grafted and the sensory and motor function of fingers or
      toes must be monitored carefully as well as distal circulation in limbs after
      operation.

PMID- 12464480
TI  - Enzymatic debridement of burn wound with collagenase in children with partial
      thickness burns.
AB  - Seventy-eight pediatric burn patients treated by enzymatic debridement with
      collagenase clostridiopeptidase A (CCA), were compared to 41 patients those burn
      wounds were excised surgically. Patients whose burn wounds were initially
      assessed as partial-thickness at admission were enrolled in the study. Total
      removal of eschar was achieved in 49 of 78 (62.8%) patients by CCA only (group
      D). In 29 patients (37.2%), therapy with CCA was ceased because of the
      development of burn wound infection or a manifest need for grafting of the wound,
      therefore, these patients underwent tangential wound excision (group DS). The
      records of 41 patients, treated by early tangential excision, having similar burn
      wounds by extent and depth with groups D and DS were used as controls (group S).
      There was no significant difference between the time to achieve a clean wound bed
      in groups D, DS and S (mean 7.8, 8, and 7 days, respectively, P>0.05). In group
      D, none of the patients required blood transfusion, except one. Patients in group
      DS were found to have fewer excisions (mean 1.1) when compared to those in group
      S (mean 1.5, P<0.05). The shortest hospital stay was found in group D (12.5 days,
      P<0.01). In conclusion, the use of CCA, provided a short hospital stay, reduced
      the overall need for surgery and blood transfusions in patients with partial
      thickness burns. Thus, CCA should be considered as an initial treatment of choice
      for removal of eschar in children, having a partial-thickness burn wound without
      infection.

PMID- 12464481
TI  - Noninvasive Positive Pressure Ventilation in burns.
AB  - OBJECTIVE: Acute respiratory failure is a common complication of the severely
      burn-injured patient. Endotracheal intubation and mechanical ventilation is
      associated with a high rate of complications. Noninvasive Positive Pressure
      Ventilation (NIPPV) has been shown to be as effective as conventional ventilation
      in improving gas exchange and is associated with fewer complications with
      patients in acute hypercapnic and hypoxaemic respiratory failure. We report our
      experience with NIPPV in 30 burn patients. METHOD: The records of all burn
      patients from 1998 to 2000, where NIPPV was used as part of their management at
      the St. Andrew's Centre for Plastic Surgery and Burns, were reviewed. RESULTS:
      Mean age was 47.56 years (range 12-81). Nine patients were female. Mean burn size
      was 24.4% total body surface area (TBSA) (range 3-54). Inhalation injury was
      confirmed in eight cases. A positive diagnosis of pneumonia was made in 29
      patients. The mean PaO(2)/FiO(2) ratio prior to institution of NIPPV was 28.98Kpa
      (range 8.75-52). Intermittent Positive Pressure Breathing (IPPB) was the most
      common ventilatory mode employed (25 patients) and the face mask was the most
      used interface (18 cases). Twenty-two patients (74%) avoided endotracheal
      intubation and their respiratory function continued to improve after NIPPV was
      discontinued. One patient (3%) died and seven patients (23%) were reintubated.
      Three out of the seven were electively reintubated for burns surgery. CONCLUSION:
      In burn-injured patients with acute respiratory failure, NIPPV appears to be
      effective in supporting respiratory function such that endotracheal intubation
      can be avoided in most cases.

PMID- 12464482
TI  - Severe microstomia due to burn by caustic soda.

PMID- 12464483
TI  - Penile and upper extremity amputation following high-voltage electrical trauma:
      case report.

PMID- 12464484
TI  - Burns in patients with impaired sensibility of the hands--a case of osteomyelitis
      in a neglected thumb burn.

PMID- 12464485
TI  - Burn scar contractures of the feet: efficacy of bilateral simultaneous surgical
      correction.
AB  - Children who sustain large total body surface area (TBSA) burns with involvement
      of the lower extremities frequently sustain injuries to the dorsum of the feet.
      Burn scar contractures of the feet can develop as a sequela of the burn injury.
      Such contractures frequently require surgical correction. Many surgeons proceed
      with staged unilateral corrections when both feet are equally in need of
      operative intervention. The purpose of the study is to determine if the morbidity
      for correction of bilateral dorsal foot contractures is different from that for
      the correction of unilateral dorsal foot contractures.A retrospective review from
      January 1994 to July 1999 was undertaken. Forty-five patients with photographic
      record of burn scar contracture of the feet were identified. Twenty-five patients
      underwent staged unilateral surgical correction and twenty patients underwent
      simultaneous bilateral correction of the feet. All patients underwent surgical
      correction with split thickness skin grafts (STSG). No statistical difference was
      found in terms of mortality, development of contracture, or number of
      reconstructive procedures. However, the length of stay revealed the efficacy of
      the bilateral simultaneous release of the dorsal feet.

PMID- 12464486
TI  - The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid
      resistance in Mycobacterium tuberculosis.
AB  - Mycobacterium tuberculosis has two discrete beta-ketoacyl synthases encoded by
      kasA and kasB that are located in tandem within a five-gene operon that has been
      implicated in isoniazid-sensitivity and mycolic acid synthesis. We have developed
      an in vitro meromycolic acid synthase assay to elucidate the anabolic role of
      these enzymes. Overproduction of KasA and KasB individually and together in M.
      smegmatis enabled cell-free incorporation of [(14)C]malonyl-CoA into lipids whose
      chain length was dependent upon the M. tuberculosis elongating enzyme used. KasA
      specifically elongated palmitoyl-CoA to monounsaturated fatty acids that averaged
      40 carbons in length. KasB hyperproduction in the presence of KasA produced
      longer chain multiunsaturated hydrocarbons averaging 54 carbons in length. These
      products comigrated with a synthetic standard of meromycolic acid and their
      production was sensitive to isoniazid, thiolactomycin, and triclosan. KasA
      mutations associated with isoniazid resistance produced an enzyme that had a
      diminished overall catalytic activity but conferred enhanced resistance to
      isoniazid. In vivo analysis confirmed that overexpression of each of the four
      mutant KasAs enhanced isoniazid resistance when compared to overexpression of
      wild-type KasA. These results suggest discrete anabolic roles for both KasA and
      KasB in mycolic acid synthesis and substantiate the involvement of KasA mutations
      in isoniazid resistance.

PMID- 12464487
TI  - Milk containing Mycobacterium bovis as a source of infection for white-tailed
      deer fawns (Odocoileus virginianus).
AB  - SETTING: White-tailed deer represent the first wildlife reservoir of
      Mycobacterium bovis in the United States. The behavior of does with nursing fawns
      provides several potential mechanisms for disease transmission. Little
      information exists concerning transmission between doe and fawn, specifically
      transmammary transmission. OBJECTIVE: Determine if fawns can become infected by
      ingestion of milk replacer containing M. bovis, thus simulating transmission from
      doe to fawn through contaminated milk. DESIGN: Seventeen, 21-day-old white-tailed
      deer fawns were inoculated orally with 2 x 10(8) CFU (high dose, n=5), 2.5 x
      10(5) to 2.5 x 10(6) CFU (medium dose, n=5), and 1 x 10(4) CFU (low dose, n=5) of
      M. bovis in milk replacer. Dosages were divided equally and fed daily over a 5
      day period. Positive control fawns (n=2) received 1 x 10(5) CFU of M. bovis
      instilled in the tonsillar crypts. Fawns were euthanized and examined 35-115 days
      after inoculation and various tissues collected for bacteriologic and microscopic
      analysis. RESULTS: All fawns in the tonsillar, high oral and medium oral dose
      groups developed generalized tuberculosis involving numerous organs and tissues
      by 35-84 days after inoculation. Three of five fawns in the low-dose oral group
      had tuberculous lesions in the mandibular lymph node, and one of five had lesions
      in the medial retropharyngeal lymph node when examined 115 days after
      inoculation. CONCLUSION: White-tailed deer fawns can become infected through oral
      exposure to M. bovis. Therefore, the potential exists for fawns to acquire M.
      bovis while nursing tuberculous does.

PMID- 12464488
TI  - Optimization of electroporation conditions for Mycobacterium avium.
AB  - Successful transformation and subsequent genetic manipulation of Mycobacterium
      avium requires suitable vectors, efficient transformation systems, and reliable
      selectable markers. A systematic analysis of the parameters involved in the
      transformation of M. avium was performed to optimize DNA transfer. Factors
      examined included the composition of the growth medium, growth medium additives,
      variations in washing of the bacteria prior to electroporation, and conditions of
      electroporation. Of the parameters assayed, the frequency of transformation
      (defined as the number of transformants per 10(6) transformed bacteria) showed
      the greatest increase with the addition of 1.5% glycine to the M. avium culture
      medium and the use of higher concentrations of plasmid DNA. The addition of 0.5 M
      sucrose to the growth medium and wash solution yielded a modest increase in
      transformation frequency, but more importantly afforded greater consistency of
      results between different batches of cells with no decrease in transformation
      yields following freezing and thawing. We also confirmed that gfp could be used
      as a selective marker for M. avium, even as a single copy integrant, and allowed
      for rapid discrimination between false and true transformants. Using this
      protocol, we were able to transform nine of 11 clinical strains of M. avium.

PMID- 12464489
TI  - Selective identification of new therapeutic targets of Mycobacterium tuberculosis
      by IVIAT approach.
AB  - The in vivo induced antigen technology (IVIAT)(1) has been used for the
      identification of open reading frames (ORFs) which could be possible therapeutic
      targets. A recombinant lambdagt11:: Mycobacterium tuberculosis H37Rv expression
      library was screened with pooled TB patient sera preabsorbed with in vitro grown
      M. tuberculosis H37Rv. Preabsorption of pooled TB patient sera allowed
      identification of antigens specifically expressed or upregulated during infection
      and growth in vivo. Six ORFs were identified, of which four (rv0287, rv2402,
      rv3878 and rv1045) were of hypothetical functions. Rv0287 is a probable
      regulatory protein. Rv3878 is present uniquely in M. tuberculosis H37Rv and is a
      part of RDI deletion region of M. bovis BCG, which includes esat 6 region. This
      could be exploited as a tool for diagnosis. Two ORFs were assigned function
      solely on the basis of homology, dnaQ (rv3711c) and lpdA (rv3303c). dnaQ codes
      for the epsilon subunit of DNA polymerase III, which is responsible for the
      proofreading activity of the complex. lpdA codes for dihydrolipoamide
      dehydrogenase, which is a part of many multienzyme complexes such as pyruvate
      dehydrogenase, keto-acid dehydrogenase and alpha-ketoglutarate dehydrogenase.
      These two enzymes appear to be potential targets for drug development.

PMID- 12464490
TI  - The mtp40 gene is not present in Mycobacterium bovis.
AB  - The mtp40 gene was initially reported to be lacking in classical Mycobacterium
      bovis strains, while being specific to classical M. tuberculosis strains. Later
      two clinical isolates reported to be M. bovis were shown to possess the mtp40
      gene (A. Weil, B.B. Plikaytis, W.R. Butler, C.L. Woodley and T.M. Shinnik, J Clin
      Microbiol 1996; 34: 2309-2311). The two strains were, however, not fully
      characterized biochemically or genotypically. By PCR amplification of whole cell
      lysates and subsequent spoligotyping, which classifies isolates within the M.
      tuberculosis complex, the two strains were found to possess the spacers 40-43
      which typically are lacking in classicalM. bovis, but had a spoligotyping pattern
      compatible with M. africanum. We conclude that the two strains, previously
      designated M. bovis, should be designated M. africanum. This reinvestigation has
      implications for the phylogenetic classification of M. bovis.

PMID- 12464491
TI  - Competition in size-structured populations: mechanisms inducing cohort formation
      and population cycles.
AB  - In this paper we investigate the consequences of size-dependent competition among
      the individuals of a consumer population by analyzing the dynamic properties of a
      physiologically structured population model. Only 2 size-classes of individuals
      are distinguished: juveniles and adults. Juveniles and adults both feed on one
      and the same resource and hence interact by means of exploitative competition.
      Juvenile individuals allocate all assimilated energy into development and mature
      on reaching a fixed developmental threshold. The combination of this fixed
      threshold and the resource-dependent developmental rate, implies that the
      juvenile delay between birth and the onset of reproduction may vary in time.
      Adult individuals allocate all assimilated energy to reproduction. Mortality of
      both juveniles and adults is assumed to be inversely proportional to the amount
      of energy assimilated. In this setting we study how the dynamics of the
      population are influenced by the relative foraging capabilities of juveniles and
      adults. In line with results that we previously obtained in size-structured
      consumer-resource models with pulsed reproduction, population cycles primarily
      occur when either juveniles or adults have a distinct competitive advantage. When
      adults have a larger per capita feeding rate and are hence competitively superior
      to juveniles, population oscillations occur that are primarily induced by the
      fact that the duration of the juvenile period changes with changing food
      conditions. These cycles do not occur when the juvenile delay is a fixed
      parameter. When juveniles are competitively superior, two different types of
      population fluctuations can occur: (1) rapid, low-amplitude fluctuations having a
      period of half the juvenile delay and (2) slow, large-amplitude fluctuations
      characterized by a period, which is roughly equal to the juvenile delay. The
      analysis of simplified versions of the structured model indicates that these two
      types of oscillations also occur if mortality and/or development is independent
      of food density, i.e. in a situation with a constant juvenile developmental delay
      and a constant, food-independent background mortality. Thus, the oscillations
      that occur when juveniles are more competitive are induced by the juvenile delay
      per se. When juveniles exert a larger foraging pressure on the shared resource,
      maturation implies an increase not only in adult density, but also in food
      density and consequently fecundity. Our analysis suggests that this correlation
      in time between adult density and fecundity is crucial for the occurrence of
      population cycles when juveniles are competitively superior.

PMID- 12464492
TI  - Statistics for phylogenetic trees.
AB  - This paper poses the problem of estimating and validating phylogenetic trees in
      statistical terms. The problem is hard enough to warrant several tacks: we reason
      by analogy to rounding real numbers, and dealing with ranking data. These are
      both cases where, as in phylogeny the parameters of interest are not real
      numbers. Then we pose the problem in geometrical terms, using distances and
      measures on a natural space of trees. We do not solve the problems of inference
      on tree space, but suggest some coherent ways of tackling them.

PMID- 12464493
TI  - A note on distributions of times to coalescence, under time-dependent population
      size.
AB  - Expressions for marginal distributions of times in the time-varying coalescence
      process are derived. The proposed method allows also for computation of joint
      probability distribution for pairs, triples, etc. of coalescence times. The
      expressions derived are useful for (1) extending several statistics from time
      constant to time-varying case, (2) increasing efficiency and accuracy of
      simulations in time-varying evolution, and (3) debugging coalescence simulation
      software.

PMID- 12464494
TI  - Adaptive peak shifts in a heterogenous environment.
AB  - The problem of moving from one coadapted gene complex to a better one can be
      divided into two steps: first the advantageous combination has to appear and then
      it has to take over the population. Selection can have contrasting effects on the
      two stages. When selection is weak intermediate forms are frequent, and the
      advantageous combination appears easily. Spreading of that advantageous
      combination, on the other hand, tends to be hard, as recombination acts to break
      it. The opposite is true when selection is strong. Spreading is easier, but if
      selection is also strong against the intermediate forms, the appearance of the
      beneficial combination becomes an extremely rare event. This inherent contrast in
      the optimal conditions for the two stages raises the possibility that proximity
      of areas differing in the intensity of selection may significantly shorten the
      expected waiting time for a peak shift. We studied this phenomenon in a haploid
      two-locus diallelic model of two neighboring subpopulations. Our results show
      that limited migration between the two areas might shorten the waiting time for a
      peak shift by orders of magnitude in comparison with either complete isolation or
      complete mixing. Implications for peripheral evolution and speciation are
      discussed.

PMID- 12464495
TI  - Runaway sexual selection with paternal transmission of the male trait and gene
      culture determination of the female preference.
AB  - Sexual selection is modeled with a male viability-reducing trait and a female
      mating preference for that trait both of which are culturally transmitted. Both
      the male trait and the female preference are transmitted only between same-sex
      individuals, so that non-random association between the trait and the preference,
      which would give rise to a Fisherian runaway process, cannot arise. Inclusion of
      an autosomal gene that confers a female predisposition to acquire a certain
      preference is shown to allow the coevolution of the male trait and the female
      preference by a Fisherian process. This holds true even when the female
      preference has a slight viability cost, provided the male cultural transmission
      is not perfect. It is also suggested that a Fisherian process can be more easily
      initiated in these models than in the conventional genetic models. Furthermore, a
      Fisherian process may cause cultural transmission of female preference to evolve.
      Additionally, polymorphism can be maintained at the predisposition locus if
      heterozygous females have a stronger predisposition to acquire the preference
      than homozygotes. Our models may be applicable to the case when the male trait is
      a Y-linked genetic or environmentally determined trait.

PMID- 12464497
TI  - Mechanisms of ventilator-induced lung injury in premature infants.
AB  - Mechanical ventilation in premature infants may injure the lungs or exacerbate
      the pre-existing condition that led to the need for mechanical ventilation.
      Ventilator-induced lung injury (VILI) may be associated with alveolar structural
      damage, pulmonary oedema, inflammation, and fibrosis. This injury is not uniform
      and is associated with surfactant dysfunction. Recovery from VILI includes
      clearance of pulmonary oedema and alveolar structural repair. Mechanisms of VILI
      include high airway pressure (barotrauma), large gas volumes (volutrauma),
      alveolar collapse and re-expansion (atelectotrauma), and increased inflammation
      (biotrauma). Injury to the lung may lead to other organ dysfunction. The
      premature lung is more susceptible to VILI, and lung injury may exacerbate the
      disturbance of lung development that occurs after birth. Therapies targeting
      specific processes in lung injury, and which complement the protective ventilator
      management strategies to avoid atelectotrauma and lung overdistension are an area
      of active research.

PMID- 12464498
TI  - Giving small babies oxygen: 50 years of uncertainty.
AB  - A small landmark trial in 1952 showed that excess oxygen use might well be
      causing a major epidemic of retinal blindness in preterm babies. That a single
      study of just 65 babies was enough to throw doubt on a long-standing treatment
      strategy revealed just how powerful a tool the randomized controlled trial could
      be. Confirmatory evidence from a cooperative trial involving a further 212 babies
      banished all residual doubt just 4 years later, and it remains a major reproach
      that we have still not learnt, after 50 years, how to optimize the delivery of
      oxygen to the preterm baby with further help from this powerful tool. Two well
      conducted trials have recently shown that avoiding subclinical hypoxaemia
      (fractional SaO(2)<92%) in babies more than a month old does nothing to improve
      later growth or development. It is now time the same question was asked of babies
      less than a month old, because we might reduce their need for ventilatory
      support. This is particularly important in babies of less than 28 weeks'
      gestation, who remain, currently, at serious risk of chronic lung disease and
      permanent retinal scarring.

PMID- 12464499
TI  - Respiratory gas conditioning in infants with an artificial airway.
AB  - There is a strong physiological rationale for delivering the inspiratory gas at
      or close to core body temperature and saturated with water vapour to infants with
      an artificial airway undergoing long-term mechanical ventilatory assistance.
      Cascade humidifiers with heated wire ventilatory circuitry may achieve this goal
      safely. Whenever saturated air leaves the humidifier chamber at 37 degrees C and
      condensate accumulates in the circuit, the gas loses humidity and acquires the
      potential to dry airway secretions near the tip of the endotracheal tube. Heat
      and moisture exchangers and hygroscopic condenser humidifiers with or without
      bacterial filters have become available for neonates. They can provide sufficient
      moisture output for short-term ventilation without excessive additional dead
      space or flow-resistive load for term infants. Their safety and efficacy for very
      low birthweight infants and for long-term mechanical ventilation has not been
      established conclusively. A broader application of these inexpensive and simple
      devices is likely to occur with further design improvements. When heated
      humidifiers are appropriately applied, water or normal saline aerosol application
      offers no additional significant advantage in terms of inspiratory gas
      conditioning and may impose a water overload on the airway or even systemically.
      Although airway irrigation by periodic bolus instillation of normal saline
      solution prior to suctioning procedures is widely practised in neonatology,
      virtually no data exist on its safety and efficacy when used with appropriately
      humidified inspired gas. There is no evidence that conditioning of inspired gas
      to core body temperature and full water vapour saturation may promote nosocomial
      respiratory infections.

PMID- 12464500
TI  - Newer experience with CPAP.
AB  - Progress in neonatal intensive care is closely linked to improvements in the
      management of respiratory failure in small infants. Current modalities of
      ventilatory assistance range from more benign continuous positive airway pressure
      (CPAP) to various modes of mechanical ventilation (including high frequency
      ventilation). The advent of less invasive methods of delivering CPAP has
      permitted earlier treatment of infants with respiratory distress syndrome and
      avoided the need for mechanical ventilation. Children's Hospital of New York
      (Columbia University) places all spontaneously breathing infants on nasal prong
      CPAP as the first mode of respiratory support. The early initiation of nasal
      prong CPAP in combination with a tolerance to elevated PCO(2) levels has reduced
      the incidence of chronic lung disease to <5% in infants weighing less than 1500g.
      This report will present an historical review and summarize the experience with
      CPAP at Columbia and other centres. In addition, it reviews the clinical
      applications and physiological effects of CPAP in preterm infants with
      respiratory distress syndrome.

PMID- 12464501
TI  - Clinical applications of pulmonary function and graphics.
AB  - Pulmonary function and mechanics testing are emerging as a valuable tool to aid
      clinical decision making in the management of ventilated infants. Although there
      are as yet no published randomized controlled trials to suggest that pulmonary
      mechanics testing reduces mortality or morbidity, it has--in conjunction with
      clinical, radiological, and blood gas monitoring--changed neonatal ventilation
      from "good judgement" to "informed judgement". It is not surprising that
      pulmonary graphics are increasingly being used as a tool for assessment of
      patient status, therapeutic evaluation, and management guidance of infants who
      become dependent on ventilator. A working knowledge of pulmonary graphics also
      improves understanding of pulmonary physiology and pathophysiology, and their
      responses to mechanical ventilatory support. Recent advances in microprocessor
      technology for on-line analysis of pulmonary mechanics have made such evaluations
      easily available for bedside clinical application.

PMID- 12464502
TI  - Newer techniques of mechanical ventilation: an overview.
AB  - The introduction of newer, state-of-the-art, microprocessor controlled ventilator
      systems provides clinicians with opportunities to apply a number of advanced
      ventilatory modalities which were not previously available for treating newborns.
      Some of these techniques will need further scientific evaluation in controlled
      trials, but this should not preclude their use in clinical settings, as their
      safety has already been proved by "standard setters" for use in neonates. There
      is a firm physiological rationale for their use, and individual centres have
      already acquired substantial experience in the application of these modalities.
      The trend towards increasing sophistication and greater versatility is likely to
      continue, and clinicians involved in the care of sick newborn infants must keep
      abreast of these developments.

PMID- 12464503
TI  - Permissive hypercapnia.
AB  - Although lifesaving, mechanical ventilation can result in lung injury and
      contribute to the development of bronchopulmonary dysplasia. The most critical
      determinants of lung injury are tidal volume and end-inspiratory lung volume.
      Permissive hypercapnia offers to maintain gas exchange with lower tidal volumes
      and thus decrease lung injury. Further physiologic benefits include improved
      oxygen delivery and neuroprotection, the latter through both avoidance of
      accidental hypocapnia, which is associated with a poor neurologic outcome, and
      direct cellular effects. Clinical trials in adults with acute respiratory failure
      indicated improved survival and reduced incidence of organ failure in subjects
      managed with low tidal volumes and permissive hypercapnia. Retrospective studies
      in low birth weight infants found an association of bronchopulmonary dysplasia
      with low PaCO(2). Randomized clinical trials of low birth weight infants did not
      achieve sufficient statistical power to demonstrate a reduction of BPD by
      permissive hypercapnia, but strong trends indicated the possibility of important
      benefits without increased adverse events. Herein, we review the mechanisms
      leading to lung injury, the physiologic effects of hypercapnia, the dangers of
      hypocapnia, and the available clinical data.

PMID- 12464504
TI  - Weaning newborns from mechanical ventilation.
AB  - While there is a relative consensus as to whether mechanical ventilation should
      be initiated, the management of babies during recovery from respiratory failure
      remains largely subjective and is predominantly determined by institutional or
      individual practices or preferences. This can lead to babies either being left on
      the ventilator too long, or extubated too hastily, thus requiring repeated re
      intubation. The current scientific literature fails to provide a uniform view of
      the most appropriate way to wean babies from mechanical ventilation. This might
      stem from a lack of understanding of the relative merits of the different
      techniques of discontinuing mechanical ventilation, given the availability of a
      variety of primary ventilatory modes which were not available to a neonatal
      population before, and limited research into the pathophysiological mechanisms
      responsible for an unsuccessful extubation. The purpose of this paper is to
      review the physiological, mechanical, and clinical principles of weaning, and to
      highlight areas still in need of investigation.

PMID- 12464505
TI  - Alternative strategies for the management of respiratory failure in the newborn-
      clinical realities.
AB  - Following the introduction of surfactant in the early 1990s and the growing use
      of antenatal steroids since that time, the number of infants, term and preterm,
      suffering severe acute respiratory failure has declined. However, such babies do
      still occur and their management causes much debate and concern not least because
      of the recognised high risk of adverse outcome in these babies. This article
      reviews the therapeutic options available when other more routine strategies
      fail.

PMID- 12464506
TI  - Surgical versus medical treatment for severe epilepsy: consequences for
      intellectual functioning in children and adults. A follow-up study.
AB  - We compared the effects of medical and combined surgical and medical treatment of
      refractory epilepsy on intellectual functioning in a group of children (n=13) and
      a group of adults (n=15). The patients were tested with the age-appropriate
      versions of Wechsler's intelligence scales twice prior to and once after epilepsy
      surgery. There were no significant differences between the groups in preoperative
      epilepsy-related variables, including age at onset. The IQ scores were submitted
      to two-way analyses of variance (ANOVA). We also evaluated individual changes in
      IQ scores. Adult patients maintained stable levels of performance after drug
      treatment as well as following surgery, while children declined in Full Scale IQ
      after both kinds of treatment. Children also declined in Performance IQ, but not
      in Verbal IQ after drug treatment, and in Verbal IQ, but not in Performance IQ
      after surgery. Three of six children who underwent a significant decline in Full
      Scale IQ before surgery did not show any further decline postoperatively. We have
      proposed a developmental model to account for the different findings in children
      and adults, and conclude tentatively that refractory, long-standing epilepsy may
      interfere with intellectual development both during drug treatment and following
      combined surgical and medical treatment in children, while the impact of long
      standing refractory epilepsy of similar severity as in children is not strong
      enough to reduce intellectual performance in adults, irrespective of treatment
      modality.

PMID- 12464507
TI  - Socio-demographic characteristics of adolescents with epilepsy in Northern
      Jordan.
AB  - OBJECTIVE: The main objectives of this study were to determine the socio
      demographic characteristics of epilepsy, and to compare these results with
      findings of comparable studies from other parts of the world. METHOD: Initially,
      the target population of this study consisted of 116 patients with epilepsy
      randomly selected, over a 6-month period, from those patients attending the
      neurology clinic at Princess Basma Teaching Hospital (PBTH) in Northern Jordan.
      However, seven patients were dropped from the study and eight others refused to
      participate in the study. A semi-structured clinico-epidemiological questionnaire
      was used to investigate the most significant socio-demographic characteristics of
      this group of adolescent Jordanian patients with epilepsy such as age, sex,
      living status, family history, type of epilepsy, and some other special clinical
      investigations. To further evaluate the significance of a family history of
      epilepsy, the education attainment and employment in these patients with epilepsy
      were compared with a similar number of age, sex matched control cases obtained
      from patients attending the hospital for reasons other than epilepsy. RESULTS:
      Among the study population, the mean age at presentation was 19 years (SD+/-2.7);
      54 were males 47 were females. Fifty three patients had a poor level of education
      because they had less than 10 years of formal education, 29 had an average level
      of education (10-12 years) of formal education, and 19 had achieved a higher
      level of education. Thirty patients were employed, 21 unemployed and 50 were
      students. Twelve patients were living alone and leading independent lives, 88
      patients were living with parents and siblings. One male patient was married and
      living with his wife and children. A positive family history was present in first
      degree relatives in 11 patients as compared to 3 in the control group. Ninety
      eight patients suffered from generalized epilepsy and three from partial
      epilepsy. Sixty seven patients reported an aura and 84 patients had post ictal
      complaints such as sleepiness, headache, or drowsiness. CONCLUSION: Socio
      demographic characteristics of this group of adolescents with epilepsy are
      compatible with the results of the work of others such as Elwes [Neurosurg
      Psychiatr 54 (1991) 200], in the North East of England and Hauser from the Mayo
      clinic in his descriptive study of the epidemiology of epilepsy.

PMID- 12464508
TI  - Crossed cerebellar diaschisis secondary to refractory frontal seizures in
      childhood.
AB  - We report a girl with refractory partial seizures since 7 years of age, secondary
      to right frontal cortical dysplasia, who developed MRI and SPECT abnormalities in
      the contralateral hemicerebellar cortex. These became more marked, leading to
      left hemicerebellar atrophy. Crossed cerebellar diaschisis has been described
      mostly in hemispheric stroke and supratentorial tumours, but less often in
      epilepsy. It is usually a transient phenomenon. This report shows that crossed
      cerebellar diaschisis can develop within two years of seizure onset and evolve
      over time.

PMID- 12464509
TI  - The epilepsy nurse specialist at a tertiary care hospital-improving the interface
      between primary and tertiary care.
AB  - Recent literature suggests that access to an epilepsy nurse specialist (ENS) may
      help improve patients understanding and management of their condition and in
      doing so may decrease morbidity and mortality. This paper describes the role of
      the ENS at a large tertiary referral epilepsy centre, the National Hospital for
      Neurology and Neurosurgery (NHNN) in supporting patients with refractory epilepsy
      in the hospital and community. Approximately 300 patients were referred to the
      ENS in the first 6 months of the service. A questionnaire was posted to 193
      patients, 69% responded. Most patients had multiple seizures each month, took
      polytherapy, underwent frequent antiepileptic drug (AED) dose changes and often
      experienced drug side effects. Sixty percent of patients contacted the ENS for
      urgent medical advice. Important aspects of the service were access by telephone
      to medication advice, information, support and adequate time to discuss issues.
      The ENS improved continuity of, and accessibility to, care for patients, has
      become a key member of the multidisciplinary epilepsy team and has freed up
      scarce medical time.

PMID- 12464510
TI  - Epilepsy--giving the diagnosis. A survey of British paediatric neurologists.
AB  - Adult-centred studies continue to show poor information provision and
      understanding in people with epilepsy. This study explores whether paediatric
      neurologists work within a consultation framework designed to meet information
      needs. A questionnaire on how to give the diagnosis was sent to 32 UK Paediatric
      Neurologists. Consultation content was largely determined intuitively rather than
      on a shared knowledge of the process involved. Little consensus was identified in
      relation to analogy and the usefulness or awareness of available unevaluated
      literature; but most acknowledged the value of a specialist epilepsy nurse. Most
      responses were based on a typical medical agenda but less than 20% addressed
      emotional responses and adaptation. Three approaches were identified-'pro-active'
      (running the risk of overload but recognising the right of parents to
      information), 'reactive' (more individually tailored, but assumes doctors can
      judge parental reactions) and 'drip-feed' (protective and pre-selecting topics to
      meet the situation). Our aim to establish a guideline proved impossible. Further
      study should develop more detailed models of the disclosure process, and identify
      epilepsy explanations that can be consumer-tested.

PMID- 12464511
TI  - Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse
      features associated with higher doses of sodium valproate.
AB  - The risk of an adverse outcome to pregnancy is increased in women with epilepsy.
      This is partly attributable to antiepileptic drugs. Guidelines for the management
      of pregnancy in women with epilepsy generally advise against polytherapy but make
      no distinction between the risks of different drugs. Several recent studies have
      however shown greater risk of adverse outcome in offspring exposed to sodium
      valproate in utero, particularly at higher doses. The outcome of pregnancy was
      monitored to identify antiepileptic drug treatment associated with a poor outcome
      in a mainly prospective study of women attending an outpatient clinic. From
      January 1990 to December 1999 all 69 pregnancies in women referred to the clinic
      were monitored. Drug treatments and other risk factors were recorded. In each
      child dysmorphic features, developmental delay and structural anomalies were
      assessed and graded. Data were analysed for drug- and dosage-dependent
      differences in outcome. In each assessment area a positive association between
      adverse outcome and dose was found for sodium valproate but not for
      carbamazepine. Severe adverse outcomes were found only in children exposed to
      sodium valproate at maternal doses above 1000 mg per day.

PMID- 12464512
TI  - A survey of a novel epilepsy clinic.
AB  - The management of a group of epilepsy patients from primary care, in a
      geographical area with clear epilepsy management guidelines and secondary care
      clinics is surveyed. Suggestions are made to improve liaison between primary and
      secondary care as well as epilepsy management in primary care. All 42 local
      primary care practices were invited to take part in this project. A study day
      providing a broad overview of epilepsy management was held. Those attending were
      expected to identify all patients in their practice with epilepsy using
      diagnostic codes and prescribing data. Nine of the invited 42 practices took part
      in the project, and identified 506 patients prescribed anti-epilepsy drugs
      (AEDs). Three hundred and three patients were invited for review by their
      practice nurse, following exclusion of those prescribed AEDs for other
      conditions, children and those already under specialist review. One hundred and
      sixteen patients attended for review. Seventy-one patients were identified as
      requiring specialist review and a consultant neurologist, epilepsy nurse
      specialist and clinical assistant completed them. Of the 71 patients 31 had
      experienced no seizures for 5 years, 40 had experienced seizures in the past 5
      years, of whom 32 had experienced seizures in the last year. Sixteen were
      suffering at least one seizure per month, and a few had poorly controlled
      epilepsy. Patients were taking mainly Phenytoin, Carbamazepine and Sodium
      valproate. Twenty were taking polytherapy and one no treatment.Fifty-two patients
      reported side effects and 15 poor compliance. Many patients reviewed were
      considered to be taking unnecessary medication and suffering unnecessary side
      effects. There is a need for improved epilepsy management in primary care and
      better liaison between primary and secondary care.

PMID- 12464513
TI  - The associations between epilepsy and depressive illness in secondary care.
AB  - BACKGROUND: The association between epilepsy and depressive illness has long been
      established. However, though various explanations-psychosocial and anatomical
      have been proposed findings from studies are inconsistent and often
      contradictory. AIMS: This study aimed to compare the features of those people
      with epilepsy seen in a secondary care setting who developed a depressive illness
      with those that did not. METHOD: Information regarding the patient's epilepsy,
      history and presence of depressive illness and perceived social functioning was
      gathered from case notes, questionnaire and patient interview. RESULTS: The
      experience of a depressive episode was associated with the presence of a right
      sided lesion, attacks occurring more than once each month, diagnosis made in
      adulthood and a perceived marked effect of the epilepsy on mobility and social
      activity. CONCLUSION: These findings are not all consistent with work already
      carried out in this field. However, they do point to a multifactorial aetiology
      of depressive illness in this group as is the case in the general population.
      Possible explanations for frequently contradictory findings are discussed.

PMID- 12464515
TI  - Low grade glial neoplasms.

PMID- 12464516
TI  - A pathology of the animal spirits -- the clinical neurology of Thomas Willis
      (1621-1675) part I -- background, and disorders of intrinsically normal animal
      spirits.
AB  - Thomas Willis (1621-1675), author of the classical work Cerebri Anatome (1664),
      was arguably the father of the modern era of neurology. As compared with his
      neuroanatomy, relatively little attention has been paid to Willis' clinical
      neurology, as described in his Pathologiae Cerebri (1667) and De Anima Brutorum
      (1672), where he gave a structured account of disease of the nervous system as it
      was known in his day. His account was largely derived from personal observations
      and not from traditional authorities and was based around his concept of the
      animal spirits, a fictitious entity in many ways analogous to the present day
      idea of the nerve impulse. This concept allowed him to develop a pathology of the
      animal spirits which embraced the whole content of the clinical neurology and
      psychiatry of his times. The anatomical and physiological background to Willis'
      concepts of animal spirit dysfunction, and those disorders he regarded as due to
      disturbed function of intrinsically normal animal spirits (mainly headache,
      disorders of consciousness, apoplexy and palsy) are dealt with in the present
      paper. The disorders he attributed to inherently abnormal animal spirits are
      considered in a second part of the paper.

PMID- 12464517
TI  - Racial distribution of intracranial and extracranial atherosclerosis.

PMID- 12464518
TI  - Informed consent without bureaucracy.
AB  - A comparison is drawn between informed consent in medicine and consenting
      practices in other areas of human activity, and an underlying conceptual unity is
      detected in all of these consenting practices. We insist on obtaining consent, in
      medicine and elsewhere, because of the value we place on personal autonomy. The
      conceptual unity of informed consent and consenting practices outside of medicine
      is defended against a series of objections. On the basis of the comparison with
      consenting practices in other areas of human activity, it is argued that
      bureaucratic informed consent processes in medicine are both unnecessary and
      unwarranted.

PMID- 12464519
TI  - A medical class lost at Gallipoli.
AB  - In 1915, the second year of the First World War, one of the big battles was the
      Gallipoli Campaign. Many students of the Istanbul Darulfunun (today Istanbul
      University) and of the Istanbul Men's High School joined the second battalion to
      participate in the defence of the Dardanelles as volunteers. All of the soldiers
      of that battalion died in 19 May 1915. The Medical School of Darulfunun, which
      lost all of the students of the class of 1915, had no student to graduate in
      1921.

PMID- 12464520
TI  - Prospective study of neuropsychological and psychosocial outcome following
      surgical excision of intracerebral arteriovenous malformations.
AB  - In this prospective study the neuropsychological and psychosocial function of 64
      patients undergoing surgical resection of cerebral arteriovenous malformations
      was examined prior to surgery (T1), one month post-surgery (T2) and one year post
      surgery (T3). A mild but widespread cognitive decline was observed pre
      operatively. There was a trend toward decreased neuropsychological function at
      T2. All neuropsychological tests showed a trend toward improvement at T3 compared
      with both pre-operative (generally not statistically significant) and early post
      operative values (generally significant). Patients were assessed for change
      between testing times. At T2 patients were more likely to have deteriorated than
      improved, whereas at T3 the group which had altered from baseline were more
      likely to have improved than deteriorated. Deterioration in some verbal/language
      tasks was more common for left sided AVMs. Outcome did not differ significantly
      for patients presenting with haemorrhage. Psychosocial function was unchanged at
      late follow-up for the majority of patients.

PMID- 12464521
TI  - Fractionated stereotactic radiotherapy for acoustic neuromas: preservation of
      function versus size.
AB  - For larger acoustic neuromas the preservation of cranial nerve function following
      radiosurgery remains a challenge. Fractionated stereotactic radiotherapy (FSR)
      for acoustic neuromas offers both higher total tumour dose (Gy) and potential
      sparing of the facial motor, sensory and auditory cranial nerves. Eighty
      consecutive patients (45 M, 35 F) (age 56.8+/-1.7 years) received FSR for AN and
      have a median follow up of 1.1 years. A prospective schedule permitted increased
      fractionation vs. size. For FSR 70 patients having AN < 3.0 cm in diameter had 5
      daily fractions of 5 Gy (25 Gy total) and 10 patients having AN > or = 3 cm had
      10 daily fractions of 3 Gy (30 Gy total). All treatments were prescribed to the
      80% isodose and given via the dedicated 10 MeV accelerator. For both the larger
      and smaller AN, the percentage decrease in volume was similar. No tumour
      increased in size, no patient developed facial weakness and hearing was
      preserved. Using size-dependent fractionation, FSR may result in both tumour
      control and preservation of normal cranial nerve functions for both large and
      small AN.

PMID- 12464522
TI  - Early experiences of elective stenting for symptomatic stenosis of the M1 segment
      of the middle cerebral artery: reports of three cases and review of the
      literature.
AB  - The role of stenting in the treatment of patients with middle cerebral artery
      stenosis is not defined because of the high risk and difficulty in tracking.
      However, recent improvements in the technology, in particular of small, flexible
      stents and of small, flexible stents with accumulative stenting experience in
      occlusive intracranial disease endovascular treatment of this disease is now
      possible. We treated three patients with a symptomatic stenosis of the M1 segment
      of the middle cerebral artery despite combination anticoagulation therapy. All
      patients were successfully treated with a balloon-expandable S660 coronary stent.
      No procedure-related complications occurred and all patients were discharged and
      remained neurologically stable during the follow-up period (2-12 months). We
      propose stenting as one of the treatment modalities in patients with symptomatic
      stenosis of the M1 segment of the middle cerebral artery in selected cases.
      However, further studies on this new procedure should be done to determine its
      effect on long-term stroke prevention and to compare its safety with other
      treatment options.

PMID- 12464523
TI  - Relationships between event-related potentials and neuropsychological tests in
      neurologically healthy adults.
AB  - The aim of this study was to investigate the relationship between conventional
      neuropsychological tests and an event-related potential (P300). Subjects were 118
      neurologically normal healthy adults 18-74 years old with no history of
      neurological, neurosurgical, or psychiatric disorders. We administered a
      neuropsychological test battery and recorded auditory P300 in all subjects. A
      significant correlation was seen between P300 latency and age, but not between
      amplitude and age. While significant negative correlations were apparent between
      some neuropsychological tests and age and P300 latency, stepwise regression
      analysis to assess the significance of each factor determined that age alone
      correlated with P300 latency. We therefore concluded that P300 measurements
      cannot be replaced by neuropsychological tests; rather, brain function should be
      evaluated by both methods.

PMID- 12464524
TI  - Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary
      progressive multiple sclerosis.
AB  - We have previously shown that patients with primary progressive multiple
      sclerosis (MS) have significantly elevated plasma levels of antibody to GM3
      ganglioside compared to patients with relapsing-remitting MS, healthy subjects
      and patients with other neurological diseases. Anti-GM3 antibody levels were
      elevated also in patients with secondary progressive MS but to a lesser extent
      than in primary progressive MS. As gangliosides are particularly enriched in the
      axonal membrane, these findings suggested that antiganglioside immune responses
      might contribute to the axonal damage in progressive forms of MS. The present
      study was performed to determine whether peripheral blood T cell responses to GM3
      are also increased in progressive MS. Blood was collected from 98 untreated
      patients with MS (40 with relapsing-remitting, 27 with secondary progressive and
      31 with primary progressive MS), 50 healthy subjects and 24 patients with other
      disorders of the CNS, and reactivity to GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and
      sulphatide was assessed by 6-day T cell proliferation assays. Increased T cell
      reactivity to GM3 and GQ1b occurred significantly more often in patients with
      primary progressive MS than in healthy subjects and patients with other CNS
      diseases. These findings suggest that ganglioside-specific T cells may contribute
      to the axonal damage in primary progressive MS.

PMID- 12464525
TI  - Decreased amplitudes in multiple sclerosis patients with normal visual acuity: a
      VEP study.
AB  - Primary demyelination with relative preservation of axons is considered to be one
      pathological hallmark of multiple sclerosis (MS), a chronic inflammatory disease
      of the central nervous system. However, imaging and pathomorphological studies
      have stimulated a recent re-emergence of interest in the axonal,
      neurodegenerative aspect of MS pathology. Axonal injury appears to be a key
      factor of disability and permanent neurological deficit in MS patients. In the
      present electrophysiological study, visual potentials evoked by pattern reversal
      (VEPs) were recorded in 25 MS patients with normal visual acuity and unimpaired
      visual functions. Compared to a control population, VEP amplitudes for two
      different spatial frequencies were significantly decreased. From this
      observation, we conclude that an underlying pathological process threatening
      axonal integrity may not be reliably reflected by clinical parameters due to the
      distinct ability of the visual system to compensate for axonal loss. Pattern VEP
      may thus serve as an objective tool to diagnose and to monitor axonal pathology
      in MS. Focal conduction block due to demyelination as a cause for reduced VEP
      amplitudes can not be fully excluded, but would appear less likely since latency
      prolongation in the MS group was moderate compared to controls.

PMID- 12464526
TI  - Stroke prevention in patients with atrial fibrillation.
AB  - We evaluated the antithrombotic therapy and eligibility for anticoagulation
      before stroke in 30 patients with atrial fibrillation (AF) admitted to a district
      hospital in Kochi, Japan from 1992 to 1998. The mean age was 77+/-10 years old.
      Subtypes of ischemic stroke were classified as possibly cardioembolic in 26 (87%)
      patients and lacunar in four (13%). Eight (26.7%) patients died in the acute
      phase and 15 (50%) were disabled at discharge. Most patients were eligible for
      anticoagulation before stroke because of previously known AF (80%), high risk for
      stroke (80%), absence of contraindications (83.3%), and good clinical compliance
      (90%). The prescription rate of warfarin was, however, less than 20% even in high
      risk patients who needed anticoagulation. In conclusion, underuse of warfarin and
      high eligibility for anticoagulation in stroke patients with AF suggest that the
      chance of stroke prevention may be lost in many patients with AF in clinical
      practice.

PMID- 12464527
TI  - Subarachnoid hemorrhage of unknown origin and the basilar artery configuration.
AB  - It is unclear whether the configuration of the basilar artery (BA) in patients
      with subarachnoid hemorrhage (SAH) of unknown origin is comparable to that in
      normal subjects or whether there are differences which may help to identify the
      origin. We studied the BA configuration in 57 patients with SAH of unknown origin
      (10%), who were identified in a prospectively collected series of 549 SAH
      patients consecutively admitted to our service over a 9-year period. There were
      30 patients (53%) with non-perimesencephalic SAH and 27 with perimesencephalic
      SAH (47%). According to a standardized algorithm we determined, on straight
      anteroposterior digital subtraction angiography (DSA), the width of the proximal
      BA segment at the origin of the anterior inferior cerebellar artery and the width
      of the most distal BA segment between the superior cerebellar arteries and the
      posterior cerebral arteries. Based on these measurements we calculated the distal
      proximal BA ratios and compared them to the ratios obtained in a control group of
      31 patients who had DSA for reasons other than aneurysmal SAH. The mean ratio in
      patients with non-perimesencephalic SAH of unknown origin was 1.150 (range: 1.080
      1.230). In patients with perimesencephalic SAH of unknown origin it was 1.156
      (range: 1.120-1.250). In the control group the mean ratio was 1.163 (range: 1.125
      1.200). There are no variations in the configurations of the BA which could
      possibly explain the cause of this type of SAH or clarify the origin of
      hemorrhage.

PMID- 12464528
TI  - The effectiveness of regional cerebral oxygen saturation monitoring using near
      infrared spectroscopy in carotid endarterectomy.
AB  - Nineteen patients (20 operations) underwent elective carotid endarterectomy
      without arterial shunt. Carotid cross-clamping caused a significant decrease
      (from 61.2% to 49.5%, 19.1% decrease from the preclamp baseline) of the
      ipsilateral cerebral oxygen saturation and it increased to 65.6% after
      declamping. Cross-clamping also caused a significant decrease (from 2.9 Hz to 1.6
      Hz) of the ipsilateral electroencephalogram main frequency and it increased to
      3.6 Hz after declamping. Asymmetry of main frequency which was greater than 0.7
      Hz was observed when that of oxygen saturation decreased more than 25% during
      cross-clamping. The reported data indicate that cerebral oxygen saturation less
      than 54-56.1% and its decrease more than 15.6-18.2% is found to be a predictor of
      neurologic compromise. In this study, the asymmetry of cerebral oxygen saturation
      more than 25% was also found to be a risk. Arterial shunt should be used in
      haemodynamically high risk cases.

PMID- 12464529
TI  - MRI findings in cobalamin deficiency.
AB  - A 55 year old male presented 2 years after a jejuno-iliectomy with weakness of
      all limbs, paraesthesiae, and difficulty in walking. Clinical examination
      revealed loss of posterior column sensations. Investigations were suggestive of a
      deficiency of vitamin B12 and folate. MRI showed a band of hyperintensity on T2
      image, in the dorsal portion of the spinal cord.

PMID- 12464530
TI  - Images in neuroscience: bilateral cerebral venous infarction.

PMID- 12464531
TI  - Cerebrovascular responses to pathophysiological insult in diabetic rats.
AB  - Diabetes mellitus is associated with altered cerebrovascular responsiveness and
      this could contribute to the pathology of stroke in diabetic patients. In these
      studies, we used a model of haemorrhagic stroke (intrastriatal injection of 50
      microl blood) to examine subacute perilesional perfusion and blood-brain barrier
      (BBB) integrity in spontaneously diabetic rats. Volumes of striatal oligaemia
      (blood flow < 35 ml 100 g(-1) min(-1)) were significantly increased (>300%) in
      diabetic rats with intrastriatal blood, compared to either non-diabetic rats with
      blood or control diabetic rats with striatal injection of silicon oil. However,
      the increase in BBB permeability was both qualitatively and quantitatively
      similar in diabetic and control rats. Poorer outcomes following haemorrhagic
      stroke in diabetic patients may thus result from dysfunctional cerebrovascular
      control, and particularly decreased dilatatory reserve.

PMID- 12464532
TI  - Reconstruction of the sellar floor using Bioglue following transsphenoidal
      procedures.
AB  - OBJECTIVE: Cerebrospinal fluid rhinorrhea, pneumocephalus and meningitis are
      serious complications following transsphenoidal excision of sellar, suprasellar
      and parasellar lesions. This study evaluates the use of a new bioadhesive,
      Bioglue as an adjunct in reconstructing the sellar floor and preventing CSF
      fistula and investigates the possible complications associated with its use.
      METHODS: In thirty-two patients (31 pituitary adenomas and 1 meningioma) Bioglue
      was used to help reconstruct the sellar floor after endonasal transsphenoidal
      procedures between January 2001 and April 2002 at the Royal Melbourne Hospital.
      RESULTS: There were no post-operative CSF rhinorrhea, allergic rhinitis,
      meningitis, pneumocranium, granulomas or other complications associated with the
      use of Bioglue. CONCLUSION: This technique of reconstruction of sellar floor
      using Bioglue is simple and time efficient in preventing CSF fistula formation
      following transsphenoidal procedures for sellar region lesions.

PMID- 12464533
TI  - Stent-assisted Guglielmi detachable coils embolisation for the treatment of a
      traumatic carotid cavernous fistula.
AB  - Embolisation of a carotid cavernous fistula by means of a detachable balloon is a
      well-established method for treating carotid cavernous fistulas while preserving
      a patent internal carotid artery. However, failure to embolise the carotid
      cavernous fistula may occur. Herein we describe a stent-assisted Guglielmi
      detachable coil embolisation that completely occludes the fistulous opening
      rather than fills the cavernous sinus. By applying this technique, we
      successfully treated a carotid cavernous fistula, without compromise of the
      parent internal carotid artery when the balloon technique failed.

PMID- 12464534
TI  - Inflammatory myopathies: how to treat the difficult cases.
AB  - The initial approach to the treatment of patients with inflammatory myopathy is
      critical in determining the subsequent course and outcome. Prolonged
      administration of high doses of corticosteroids should be avoided and a second
      line agent such as methotrexate or azathioprine should be introduced earlier
      rather than later. Intravenous immunoglobulin therapy has an important place if
      the myositis remains active, particularly in patients with dermatomyositis, and
      is the treatment of choice in patients with immunodeficiency who are not
      controlled by corticosteroids. In more resistant cases of polymyositis or
      dermatomyositis it may be necessary to use cyclophosphamide, cyclosporin or the
      promising newer immunosuppressive agents mycophenolate mofetil or tacrolimus to
      achieve disease control. The treatment of inclusion body myositis remains
      unsatisfactory but a trial of prednisolone and methotrexate is warranted in
      selected patients.

PMID- 12464535
TI  - Severe amnesia following a unilateral temporal lobe stroke.
AB  - A 60 year old right-handed man developed severe amnesia following a left medial
      temporal stroke as documented by cerebral MRI, MRA and SPECT scans.
      Neuropsychological evaluation 13 weeks after the stroke showed a profound
      retrograde amnesia characterised by memory loss for public facts and events over
      the previous four decades. In addition, autobiographical memory showed selective
      loss of personal episodic memory with relative preservation of personal semantic
      memory. The development of this degree of amnesia with these features following a
      unilateral temporal lobe lesion is unusual. The possible neuroanatomical
      mechanisms underlying the amnesia and how they relate to current theories of
      memory loss are discussed.

PMID- 12464536
TI  - Cerebral lupus in patients whilst on treatment for lupus nephritis with
      cyclosporine.
AB  - Two young female patients who were treated for severe lupus nephritis with
      cyclosporine, developed, while the renal parameters remained stable, signs of
      cerebral lupus (bilateral papiloedema and cranial nerve palsy in one patient and
      grand mal seizures in the second). The first patient responded to plasmapheresis
      and i.v. cyclophosphamide, and the second to temporary increase in prednisone
      with anti-convulsant medication. Both case histories suggest that cyclosporine,
      whilst controlling lupus nephritis, was not able to prevent serious attacks of
      cerebral lupus. This discrepancy might be related to relative inability of the
      drug to reduce antibody production or to the existence of heterogeneous
      pathogenetic mechanisms of lupus in different organ systems.

PMID- 12464537
TI  - Convexity dural chondroma: a case report and review of the literature.
AB  - The majority of intracranial chondromas arise from cartilage rests in the
      synchondrosis at the base of the skull. Chondromas are most commonly found in the
      sellar and parasellar regions, usually located extradurally. In rare instances,
      these tumours originate from the dura mater of the convexity. We report a rare
      case of a chondroma arising from the convexity dura mater. The origin of this
      tumour is analysed and the literature reviewed.

PMID- 12464538
TI  - Chronic sciatica secondary to retroperitoneal pelvic schwannoma.
AB  - Pelvic schwannoma is a rare cause of sciatic pain. We report a case of
      retroperitoneal pelvic schwannoma presenting with chronic sciatica which was
      diagnosed and monitored radiologically for several years before successful
      surgical resection.

PMID- 12464539
TI  - Hamartoma in the internal auditory canal.
AB  - An 11 year old girl presented with hearing loss in her left ear and left
      trigeminal and facial nerve palsy. Radiological examinations revealed an
      enlargement of the left internal acoustic canal and the existence of a mass
      protruding from the canal into the cerebellopontine angle. The partial resection
      of the mass by a suboccipital craniectomy resulted in ceasing the progression of
      her symptoms. Histological diagnosis was hamartoma with cerebellar heterotopia.
      The concurrence of heterotopic cerebellar tissue could help to understand the
      pathogenesis of hamartomas.

PMID- 12464540
TI  - Persistent primitive otic artery with IC-cavernous aneurysm.
AB  - We describe a case of unruptured internal carotid artery aneurysm associated with
      persistent primitive otic artery variant in a 48 year old woman. The aneurysm was
      successfully treated by endovascular embolisation. A possible pathogenesis of
      this rare condition is discussed.

PMID- 12464541
TI  - Totally thrombosed giant P2 aneurysm: a case report and review of literature.
AB  - The diagnosis and treatment of intracranial saccular giant aneurysms is still
      difficult despite developments in neuroradiology, neuroanesthesiology and micro
      neurosurgery. These aneurysms are usually located on major intracranial arteries
      and are rarely on distal branches of these arteries. An extra-axial 4 x 5 cm mass
      lesion in the left mediobasal temporal region was detected on the CT and MRI
      examinations of a 37 year old male patient who was admitted to our institution
      with headache and slight right-sided hemiparesis lasting for 2 months. The lesion
      was avascular on angiography. Surgery proved that the lesion was a totally
      thrombosed giant aneurysm of the P2 segment of posterior cerebral artery (PCA).
      The P2 segment was clipped proximal to the aneurysm with pterional-transsylvian
      approach and the aneurysm was totally excised. Giant aneurysms of the P2 segment
      are rare and 15 cases have been reported in the literature. This report presents
      a rarely seen totally thrombosed giant P2 aneurysms and discusses the
      difficulties in diagnosis and treatment.

PMID- 12464542
TI  - Solitary tuberculoma of the cerebellopontine angle: a rare presentation.
AB  - Central nervous system tuberculoma presenting as a solitary mass in an extrinsic
      location is rare. Due to the increase in incidence of tuberculosis in the western
      world, there is a corresponding increase in CNS tuberculosis. Cerebellopontine
      angle tumours are most commonly acoustic schwannomas or meningiomas. Radiosurgery
      as a primary modality of treatment for many CNS masses without prior pathological
      diagnosis is increasing in popularity. This report shows that a mass in the CP
      angle can closely mimic a tumour radiologically and inappropriate radiation
      treatment was avoided after surgery. Histopathological examination proved it to
      be a tuberculoma. Awareness of this rare presentation of a solitary tuberculoma
      in the CP angle is emphasised.

PMID- 12464543
TI  - Intradural, extramedullary spinal Ewing's sarcoma in childhood.
AB  - We describe an 11 year old girl with progressive paraparesis from a spinal
      tumour. Magnetic resonance imaging showed an intradural, extramedullary mass
      extending from the C7 level to T1. Neither osteolytic nor osteosclerotic changes
      were seen in the vertebral bodies. Extraskeletal Ewing's sarcoma was diagnosed
      histopathologically.

PMID- 12464544
TI  - Familial arachnoid cysts associated with oculopharyngeal muscular dystrophy.
AB  - Cerebral arachnoid cysts that occur in more than one member of a family have been
      rarely reported. These familial cases are important because they imply a genetic
      component in the pathophysiology of these arachnoid cysts. We present an unusual
      family in which two conditions, a genetic myopathy, oculopharyngeal muscular
      dystrophy (OPMD), and arachnoid cysts occur together. OPMD is caused by a
      mutation in the PAPB2 gene that localizes to chromosome 14. In this family, two
      siblings with genetically confirmed OPMD both have left hemispheric intracranial
      arachnoid cysts unassociated with other cerebral abnormalities. The association
      of these two disorders suggests that in this family, a chromosome 14 gene may
      play a role in the development of arachnoid cysts.

PMID- 12464545
TI  - An infant with an intradural lipoma of the cervical spine extending into the
      posterior fossa.
AB  - BACKGROUND: Intradural lipomas of the cervical spine are very rare. These tumours
      show no association with spinal dysraphism. We describe an infant with cervical
      spinal cord lipoma. Surgical decompression of the cord resolved all neurologic
      deficits. CASE DESCRIPTION: An 8 month old female infant presented with retarded
      development of motor function in the limbs, in addition to dysphagia. Computed
      tomography identified a tumour of fat density that extended from the medulla to
      C7. Magnetic resonance imaging showed hyperintensity on both T1- and T2-weighted
      images. A fat-suppression sequence demonstrated an area of signal enhancement in
      the dorsal portion of the tumour following administration of gadolinium. The
      adjacent spinal cord was normal. Partial removal of the tumour was performed
      together with decompressive laminoplasty. The enhancing region proved to be
      fibrous tissue. Motor development resumed in the week following operation.
      CONCLUSION: Retarded motor development was the main manifestation of this
      infant's rare spinal tumour. Neuroimaging was of considerable diagnostic value;
      in particular, fat-suppression magnetic resonance imaging demonstrated details of
      the tumour and surrounding structures. Decompressive laminoplasty and laminectomy
      with partial removal of the tumour was effective in reversing clinical deficits.

PMID- 12464546
TI  - Nocardia brain abscess misinterpreted as cerebral infarction.
AB  - We present the case of a non-immunocompromised man with right-sided hemiparesis
      and aphasia thought to be caused by cerebral infarction, but which in the later
      clinical course evolved to be a nocardia brain abscess that needed surgical
      intervention. Misinterpretation of imaging combined with the absence of clinical
      signs of infection led to inadequate primary treatment

PMID- 12464547
TI  - Arachnoid granulations in the transverse sinuses of a patient with ocular
      melanoma.
AB  - Arachnoid granulations show typical imaging features that allow their distinction
      from dural sinus thrombosis and intrasinus tumor. These features include a mid
      lateral transverse sinus location, focality, common adjacent entering superficial
      veins, origin of attachment, low density on computed tomography (CT),
      isointensity-hypointensity on T1-weighted magnetic resonance imaging (MRI) and
      hyperintensity on T2-weighted MRI. We report the CT and MRI findings of
      incidentally detected bilateral arachnoid granulations in the transverse sinuses
      of a patient with ocular melanoma.

PMID- 12464548
TI  - Dural arteriovenous malformation occurring after craniotomy for pial
      arteriovenous malformation.
AB  - The etiology of dural arteriovenous malformation (AVM) is still uncertain, and
      the occurrence of postoperative dural AVM has rarely been proved
      angiographically. The authors present a case of dural AVM in the jugular and the
      sigmoid sinuses, which developed 1 year after resection of a pial AVM via the
      craniotomy. A possible mechanism underlying this case of dural AVM is discussed.

PMID- 12464550
TI  - Detection of changes in cartilage water content using MRI T2-mapping in vivo.
AB  - OBJECTIVES: Osteoarthritis (OA) is the most prevalent chronic disease in the
      elderly, and it is generally diagnosed at an advanced state when treatment is
      difficult if not impossible. The early form of OA is characterized by an elevated
      water content in the cartilage tissue. The purpose of this study was to verify in
      vivo if changes in the water content of patellar cartilage typically occurring in
      early OA can be detected using T(2) mapping MRI methods. DESIGN: Twenty healthy
      volunteers performed 60 knee bends in order to compress their patellar cartilage
      thereby reducing its water content. MR images of the patellar cartilage were
      acquired immediately following exercise and after 45 min of rest. Patellar
      cartilage thickness and T(2) maps were determined and their difference between
      the time points evaluated. RESULTS: Cartilage thickness increased by 5.4+/-1.5%
      from 2.94+/-0.15 mm to 3.10+/-0.15 mm (P< 0.001) following 45 min of rest, while
      T(2) increased by 2.6+/-1.0% from 23.1+/-0.5 ms to 23.7+/-0.6 ms (P< 0.05).
      CONCLUSION: Small, physiologic changes in the water content of patellar cartilage
      and the concomitant change in proteoglycan and collagen density following
      exercise can be detected using MRI. The proposed T(2)-mapping method, together
      with other non-invasive MR cartilage imaging techniques, could aid in the early
      diagnosis of OA.

PMID- 12464551
TI  - Side differences of knee joint cartilage volume, thickness, and surface area, and
      correlation with lower limb dominance--an MRI-based study.
AB  - OBJECTIVE: To test the hypotheses that absolute side differences in knee joint
      cartilage morphology are substantially smaller than intersubject variability, and
      that systematic side differences are determined by (force) dominance of the lower
      limbs. METHODS: Fifteen healthy volunteers with definite dominance of one lower
      limb were studied. Knees were imaged sagittally with a validated, high-resolution
      MR sequence. Transverse MR images of the thigh and calf were acquired with a spin
      echo sequence. Knee joint cartilage volume, thickness and joint surface areas, as
      well as muscle cross sectional areas were determined with in house post
      processing software. RESULTS: Absolute side differences amounted to 5.0+/-3.7%
      for the knee cartilage volume, 3.8+/-3.1% for cartilage thickness, and 3.4+/-1.7%
      for joint surface areas. The intersubject variability was 24.8%, 14.4%, and
      14.1%, respectively. Volunteers with dominance of one of both lower limbs did not
      display significant side differences in cartilage morphology, but the side
      differences of the thigh musculature correlated positively with side differences
      of knee joint cartilage volume (r=+0.68; P< 0.01). CONCLUSIONS: The results
      advocate the use of cartilage parameters from the contra-lateral limb for
      retrospectively estimating cartilage loss in patients with unilateral
      osteoarthritis (OA), and for determining local risk factors of OA in cross
      sectional epidemiological studies, which are specific to pre-morbid cartilage
      morphology. Functional (force) dominance of one of both lower limbs does not
      explain side differences of articular cartilage morphology, but side differences
      are positively associated with side differences in muscle cross sectional areas.

PMID- 12464552
TI  - Long-term and resegmentation precision of quantitative cartilage MR imaging
      (qMRI).
AB  - OBJECTIVE: Follow up of osteoarthritis (OA) and evaluation of structure modifying
      OA drugs require longitudinal data on cartilage structure. The aim of this study
      was to analyse the long term and resegmentation precision of quantitative
      cartilage analysis with magnetic resonance imaging (qMRI) in vivo, and to relate
      precision errors to the estimated cartilage loss in OA. METHOD: Sagittal MR
      images of the knee were obtained in 14 individuals, four datasets being acquired
      in a first imaging session. In 12 subjects, two further datasets were acquired
      over the next months. Image analysis was performed in the same session for image
      data obtained under short-term and long-term imaging conditions, and in three
      different sessions (months apart) for the first data set (resegmentation
      precision). RESULTS: Long-term precision errors ranged from 1.4% (total knee) to
      3.9% (total femur) for cartilage volume and thickness and were only marginally
      higher than those under short term conditions. In the medial tibia, the error was
      84 mm(3) compared with an estimated loss of >1,200 mm(3) in varus OA. Precision
      errors for resegmentation were somewhat higher, but considerably smaller than the
      intersubject variability. CONCLUSIONS: Scanner drift and changes in imaging or
      patient conditions appear not to represent a critical problem in quantitative
      cartilage analysis with magnetic resonance imaging (qMRI). In longitudinal
      studies, image analysis of sequential data should be performed within the same
      post-processing session. Under these conditions, qMRI promises to be a very
      powerful method to assess structural change of cartilage in OA.

PMID- 12464553
TI  - No loss of cartilage volume over three years in patients with knee osteoarthritis
      as assessed by magnetic resonance imaging.
AB  - OBJECTIVE: Magnetic resonance imaging (MRI) has the potential to provide accurate
      quantification of structural changes in joint disease, with sensitivity to
      change, as it can provide direct visualization of the cartilage and bone. In this
      study, we investigated whether knee cartilage volume, as assessed by MRI, is
      sensitive to change over time in patients with osteoarthritis (OA). DESIGN:
      Sixteen patient volunteers (10 male, six female) with established OA of the knee
      were entered into the study and demographic data recorded. At baseline, 12 months
      and 37+/-2 months, patients underwent simple measures of disease severity, as
      well as extended weight-bearing AP knee X-rays. In addition the patient's index
      knee was imaged using MR at 1.0 T using a 3-D spoiled gradient-echo sequence with
      fat-suppression, repetition time 50 ms, echo time 11 ms, flip-angle 40 degrees,
      sagittal slice thickness 1.56 mm and in-plane pixel resolution 0.55 mm. Manual
      image segmentation was performed on all knee cartilage compartments and the
      respective cartilage volumes determined. RESULTS: Eleven of the original patients
      recruited completed the 3-year study. Radiographic features indicated that the
      majority had a spectrum of well-established OA at entry. The average decrease in
      medial tibiofemoral joint space width was 0.21+/-0.37 mm (mean+/-S.D.).
      Comparison of MR images at baseline and 37+/-2 months indicated little evidence
      of cartilage lesion shape or size change in any of the compartments. There was no
      significant MRI volume change in any of the knee cartilage compartments over the
      course of 1 year. The change in total knee cartilage volume, as measured by MRI,
      was a loss of only 1.6%, or 0.36+/-1.3 ml (mean+/-S.D.), over the 3 years.
      CONCLUSIONS: The failure to identify loss of cartilage volume over 3 years in
      this cohort of patients with established knee OA using MRI challenges the face
      validity of this endpoint to assess structural changes in OA.

PMID- 12464554
TI  - Fibronectin fragments active in chondrocytic chondrolysis can be chemically cross
      linked to the alpha5 integrin receptor subunit.
AB  - OBJECTIVE: To determine whether fibronectin fragments (Fn-f) known to enhance
      cartilage matrix degradation and to alter chondrocyte metabolism, bind on the
      chondrocyte cell surface close enough to the alpha(5)beta(1) fibronectin (Fn)
      receptor to be chemically cross-linked to it. DESIGN: Biotinylated Fn-fs were
      added to chondrocytes, followed by cross-linking with dithiobissulfosuccinimidyl
      propionate, and the resultant alpha(5) complexes trapped on to antialpha(5)
      agarose. Adherent material was analysed by probing with avidin-HRP. In a more
      specific approach in which only proximal targets could be cross-linked,
      photoaffinity labeled Fn-fs or Fn were added to cells, the derivatives activated
      and the cross-linked material analysed. Interaction of biotinylated Fn-fs and Fn
      with insolubilized alpha(5)beta(1) receptor was also visualized and quantified.
      RESULTS: Biotinylated Fn-fs and Fn, but not a control of BSA, were cross-linked
      to alpha(5) protein in the presence of the propionate. Photoaffinity label Fn-f
      and Fn, but not BSA, were cross-linked to alpha(5) protein as well. Interaction
      was decreased by addition of an excess of unlabeled Fn-f or Fn. Fn-fs bound to
      alpha(5)beta(1)-agarose, although the affinity was 30-fold weaker and the
      stoichiometry 20-fold greater when the smallest Fn-f was compared to native Fn.
      CONCLUSIONS: These data are consistent with a role for the alpha(5) subunit in Fn
      f activities and suggest that the Fn-fs bind proximal or directly to alpha(5)
      receptors. The weaker, higher stoichiometry interaction of Fn-fs with receptor
      suggests that fragmentation has allowed de novo interactions not possible in
      native Fn.

PMID- 12464555
TI  - Microarray analysis reveals the involvement of beta-2 microglobulin (B2M) in
      human osteoarthritis.
AB  - OBJECTIVE: To assess whether beta-2 microglobulin (B2M) has effects on articular
      chondrocytes that would implicate B2M involvement in osteoarthritis (OA)
      pathogenesis. METHODS: The mRNA levels of B2M in fetal and osteoarthritic
      chondrocytes were detected by RT-PCR. B2M levels in synovial fluid and tissue
      cultured media from cartilage explants were tested using B2M ELISA kit. Primary
      cultured chondrocytes were used for proliferation and microarray experiments.
      RESULTS: The average B2M level in OA synovial fluid is significantly higher than
      that found in normal synovial fluid. However, there was no significant difference
      in B2M synovial fluid levels amongst differing OA stages. The release of B2M by
      osteoarthritic cartilage was detectable after 24h in culture and continued to
      increase during the 72 h study period. B2M had an inhibitory effect on
      chondrocyte growth at 1.0 microg/ml, and became significantly inhibitory at 10.0
      microg/ml. Genes regulated by B2M were detected through microarray technology.
      Twenty genes were found to be up-regulated by B2M, including collagen type III
      which is known to be up-regulated in OA. Eleven genes were found to be down
      regulated at least two-fold by B2M. CONCLUSION: These results indicate that B2M
      is highly expressed in OA cartilage and synovial fluid compared to normal, and
      suggest that B2M may have effects on chondrocyte function that could contribute
      to OA pathogenesis. Published by Elsevier Science Ltd.

PMID- 12464556
TI  - An in-vitro screening assay for the detection of inhibitors of proinflammatory
      cytokine synthesis: a useful tool for the development of new antiarthritic and
      disease modifying drugs.
AB  - OBJECTIVE: This work targets the development of a new tool to help develop new
      anticytokine drugs that prevent or reduce the progression of arthritic diseases.
      The specific aim of our study was to establish a fast and reliable in vitro
      screening assay of cytokine synthesis inhibitors (TNFalpha, IL-1beta) which shows
      better correlation with enzyme assays than previously reported in vitro assays.
      The test system should be able to detect p38-MAP kinase inhibitors. MATERIAL AND
      METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll
      density gradient centrifugation from human EDTA-potassium whole blood. Cells were
      adjusted at 1 x 10(6) cells/ml. PBMCs were stimulated with lipopolysaccharide
      (LPS; E. coli serotype 026:B6: 1 microg/ml) in the presence of test compound (10(
      5)-10(-8)M) for 4h at 37 degrees C in a 5% CO(2)-incubator. Induced TNFalpha and
      IL-1beta protein were measured by ELISA. RESULTS: The following are
      representative examples of inhibitors which effect cytokine synthesis. Corticoid
      Dexamethasone inhibits IL-1beta and TNFalpha synthesis at IC(50) of 38 nM and 25
      nM, respectively. ERK1/ERK2 inhibitor U0126 effects cytokine synthesis at IC(50)
      of 0.34 microM for IL-1beta production and 0.26 microM for TNFalpha synthesis.p38
      MAP kinase inhibitor SB 203580 inhibits IL-1beta- and TNF-alpha-synthesis
      (IC(50)sof 0.052 microM and 0.46 microM) in the same degree as p38-MAP kinase
      activity (IC(50): 0.34 microM). Same results could be shown for SB 210313, which
      had same efficacy on IL-1beta and TNFalpha biosynthesis (IC(50)'s: 1.88 microM
      and 1.01 microM) and on p38-MAP kinase (IC(50): 6.85 microM). Also for SB 202190
      this correlation in inhibition of IL-1beta and TNFalpha synthesis (IC(50)'s:
      0.055 microM and 1.01 microM) and p38-MAP kinase inhibition (IC(50): 0.088
      microM) could be shown. CONCLUSION: This study shows the screening assay using
      PBMCs stimulated with LPS for IL-1beta and TNFalpha synthesis is a reliable test
      system for the quantification of the effectiveness of new drugs modulating IL
      1beta and TNFalpha synthesis which is mainly mediated by p38-MAP Kinase. These
      assay allows fast detection of IL-1beta and TNFalpha synthesis inhibitors with
      different modes of action, including p38-MAP kinase inhibitors. The results
      obtained with our in-vitro screening assay show good correlation with results
      from enzyme assays.

PMID- 12464557
TI  - Articular cartilage degradation and de-differentiation of chondrocytes by the
      systemic administration of retinyl acetate-ectopic production of osteoblast
      stimulating factor-1 by chondrocytes in mice.
AB  - OBJECTIVE: Vitamin A derivatives are widely used therapeutic agents for the
      treatment of dermatological and rheumatological disorders. Long-standing
      administration of these drugs, in turn, causes skeletal changes including
      ossification of ligaments, premature fusion of epiphyses and abnormalities of
      modeling. Recent in vitro experiments have further suggested that retinoid
      treatment of cultured chondrocytes may cause apoptotic cell death. The present
      study aims to address detailed cartilage changes associated with in vivo
      administration of vitamin A derivatives. METHODS: Retinyl acetate was
      administrated to experimental mice, C3H-Heston, for more than 12 months. Modified
      morphometry on the articular cartilage and fluorescent labeling of the
      subchondral bone were carried out to address the changes in the articular
      cartilage and subchondral bone. In order to address the detailed chondrocytes
      phenotypes, electron microscopy was carried out. Since findings of these studies
      suggested that biological properties of the cartilage matrix might be altered,
      the present study also immunolocalized functional matrix molecules, type I
      collagen and osteoblast-stimulating factor-1 (OSF-1). RESULTS: Histomorphometry
      demonstrated that retinoid administration lead to progressive atrophy of the
      articular cartilage with concomitant proliferation of subchondral bone.
      Furthermore, detailed light and electron microscopy suggested that the
      subchondral bone proliferates into the degenerating cartilage. The affected
      articular cartilage also resembled that of osteoarthritis in terms of ectopic
      type I collagen production. Furthermore, the affected articular cartilage
      produced a developmentally regulated matrix molecule, osteoblast-stimulating
      factor-1 (OSF-1) that is normally expressed in both the fetal cartilage and the
      epiphyseal growth plate cartilage but not in the articular cartilage. CONCLUSION:
      The present results indicate that the systemic retinoid administration may alter
      the biological properties of the articular cartilage.

PMID- 12464558
TI  - Phenotypic differences in murine chondrocyte cell lines derived from mature
      articular cartilage.
AB  - OBJECTIVE: To obtain well characterized immortalized murine chondrocyte cell
      lines. The cell lines were obtained from mature articular chondrocytes, instead
      of embryonal cells which are used in most other studies. METHODS: Pieces of
      articular cartilage were cut from murine patellae and femoral heads. Chondrocytes
      were isolated by digestion with collagenase. These cells were cultured in
      monolayer and immortalized by transfection of the SV40 large T antigen gene. To
      preserve the differentiated phenotype, the resulting clones were cultured in
      three-dimensional carriers, alginate beads. The phenotypes of the cells were
      characterized using the following parameters: Cell morphology (light microscopy),
      messenger RNA (RT-PCR) and protein (immunohistochemistry) levels of extracellular
      matrix molecules. Moreover, responsiveness to interleukin-1(IL-1) was determined
      by measuring production of proteoglycans ((35)S-sulfate incorporation) and of
      nitric oxide (Griess reaction). RESULTS: Sixteen clones were obtained, ten (P1 to
      P10) derived from patellar cartilage, and six (H1 to H6) from femoral head
      cartilage. In seven cell lines (P2, P5, H1, H3, H4, H5, H6) high production of
      type II collagen corresponded with high levels of mRNA of type II collagen (and
      prevalence of the IIB type) and with high IL-1-induced suppression of
      proteoglycan synthesis. Like intact murine articular cartilage, all cell lines
      produced type I and type X collagens, but mRNA levels of both types of collagen
      were never higher in the cell lines as compared with intact cartilage.
      CONCLUSION: Our results demonstrate that it is possible to immortalize mature
      murine articular chondrocytes. Each of the obtained chondrocyte cell lines
      appeared to have a stable phenotype. Both relatively differentiated and
      relatively dedifferentiated chondrocyte cell lines could be identified.

PMID- 12464559
TI  - RNA interference of HIV replication.
AB  - Double-stranded RNA-mediated interference (RNAi) induces sequence-specific post
      transcriptional gene silencing and has emerged as a powerful tool to silence gene
      expression in multiple organisms. In mammalian cells, duplexes of 21 nucleotide
      RNAs, known as short-interfering RNAs (siRNAs), efficiently inhibit gene
      expression. Recent research demonstrates the general use of siRNAs to
      specifically inhibit HIV-1 replication by targeting viral or cellular genes.
      Importantly, RNAi opens a new avenue for gene-based therapeutics.

PMID- 12464560
TI  - Membrane rafts in immunoreceptor signaling: new doubts, new proofs?
AB  - Immunoreceptors are believed to initiate their signaling by association with
      membrane rafts rich in src-family kinases and other signaling molecules. Although
      a recent paper casts doubt over this concept, by exposing drawbacks of a commonly
      used procedure to disturb rafts by cholesterol extraction, several other recent
      papers give further support to the concept.

PMID- 12464561
TI  - Viral immunology: challenges associated with the progression from bench to
      clinic.
AB  - The third in a series of workshops, 'Immunity to Viral Infections', was held at
      the Trudeau Institute, NY, USA from 20-22 September 2002.

PMID- 12464567
TI  - Interleukin is as interleukin does.

PMID- 12464568
TI  - Immunity as a function of the unicellular state: implications of emerging genomic
      data.
AB  - Instead of being greeted as supporting the growing corpus of immunological
      theory, recent advances in the bioinformatic analysis of genomes have often
      surprised the discoverers and failed to attract the attention of immunologists.
      In fact, the view that multicellular immune systems are adaptations of already
      highly evolved unicellular immune systems that are capable of self/not-self
      discrimination can assist our comprehension of phenomena, such as 'junk' DNA,
      genetic polymorphism and the ubiquity of repetitive elements. For instance, the
      'hidden transcriptome', revealed by run-on transcription of genes or repetitive
      elements, contains a diverse repertoire of RNA 'immune receptors' with the
      potential to form double-stranded RNA with viral RNA 'antigens', thus triggering
      intracellular alarms.

PMID- 12464569
TI  - Premature ageing of the immune system: the cause of AIDS?
AB  - The reasons for the failure of the immune system to control HIV-1 infection, and
      the resulting immunodeficiency, remain unclear. HIV-1 persists in its host
      despite vigorous immune responses, including a strong, and probably functional,
      HIV-specific cytotoxic T-lymphocyte response. Interestingly the immunological
      features of HIV-1-infected individuals show many similarities to those seen in
      elderly people without HIV infection. We propose that, through a process of
      continuous immune activation, HIV-1 infection leads to an acceleration of the
      adaptive immune system ageing process, resulting in premature exhaustion of
      immune resources, which participates in the onset of immunodeficiency. This
      hypothesis might shed new light on HIV-1 pathogenesis and could suggest the need
      to reconsider current immunotherapeutic strategies to fight the virus.

PMID- 12464570
TI  - Failing immune control as a result of impaired CD8+ T-cell maturation: CD27 might
      provide a clue.
AB  - Despite readily detectable virus-specific CD8(+) T cells in most HIV-infected
      patients, immune surveillance is eventually lost, leading to progression to AIDS.
      Recently developed insights into human T-cell differentiation have been used to
      study the phenotype of virus-specific T cells in HIV-infected individuals. Based
      on these results, we propose that failing immune control in human viral infection
      could be a result of impaired cytotoxic T-lymphocyte (CTL) maturation into fully
      differentiated effector T cells. Impaired maturation is not confined to HIV
      specific CD8(+) T cells but could also be involved in failing immunity to Epstein
      Barr virus and other viral infections. We postulate that CD27(-) effector CD8(+)
      T cells might be required for adequate control of chronic viral infection and
      prevention of disease development.

PMID- 12464571
TI  - A temporal and spatial summation model for T-cell activation: signal integration
      and antigen decoding.
AB  - Commitment of T cells to cytokine production and proliferation requires sustained
      (up to several hours) T-cell receptor (TCR) signaling that is achieved through
      serial engagement. This article proposes a kinetic model, adopted from neurons,
      which is based on the local temporal summation of successive signals. This model
      offers an explanation for how signals originating from serially triggered TCRs
      are accumulated and integrated over the period required for T-cell activation,
      given that each TCR-evoked signal is rapidly lost. The principal innovation of
      this model is the suggestion that signaling intermediates produced by serially
      triggered TCRs are not simply sustained but are incrementally built up. Several
      phenomena related to T-cell behavior and self-nonself discrimination are
      discussed.

PMID- 12464572
TI  - Lymphocyte kinetics: the interpretation of labelling data.
AB  - DNA labelling provides an exciting tool for elucidating the in vivo dynamics of
      lymphocytes. However, the kinetics of label incorporation and loss are complex
      and results can depend on the method of interpretation. Here we describe two
      approaches to interpreting labelling data. Both seek to explain the common
      observation that the estimated death rate of lymphocytes is higher than their
      estimated proliferation rate. In the first approach, an additional source of
      lymphocytes is postulated. In the second, it is maintained that lymphocyte
      heterogeneity is sufficient to account for the observation. We explain why we
      favour the second approach, arguing that the addition of a large source of
      lymphocytes is unnecessary and difficult to reconcile with what is currently
      known about lymphocyte physiology. We discuss how the choice of model can affect
      data interpretation.

PMID- 12464573
TI  - Contrasting distribution and seasonal dynamics of carbohydrate reserves in stem
      wood of adult ring-porous sessile oak and diffuse-porous beech trees.
AB  - We tested the hypothesis that broad-leaved forest species with contrasting wood
      anatomy and hydraulic system (ring-porous versus diffuse-porous) also differ in
      distribution and seasonal dynamics of carbohydrate reserves in stem wood. Total
      nonstructural carbohydrate (TNC) reserves (starch and sugars) were measured
      enzymatically in the 10 youngest stem xylem rings of adult oak (Quercus petraea
      (Matt.) Liebl.) and beech (Fagus sylvatica L.) trees during an annual cycle.
      Radial distribution of carbohydrates was investigated according to ring age. On
      all dates, oak trees had twofold higher TNC concentration than beech trees (41
      versus 23 mg g(DM)(-1)), with starch accounting for the high TNC concentration in
      oak. Seasonal dynamics of TNC concentration were significantly (P < 0.05) more
      pronounced in oak (20-64 mg TNC g(DM)(-1)) than in beech (17-34 mg TNC g(DM)(
      1)). A marked decrease in TNC concentration was observed in oak trees during bud
      burst and early wood growth, whereas seasonal fluctuations in TNC concentrations
      in beech trees were small. The radial distribution of TNC based on ring age
      differed between species: TNC was restricted to the sapwood rings in oak, whereas
      in beech, it was distributed throughout the wood from the outermost sapwood ring
      to the pith. Although the high TNC concentrations in the outermost rings
      accounted for most of the observed seasonal pattern, all of the 10 youngest xylem
      rings analyzed participated in the seasonal dynamics of TNC in beech trees. The
      innermost sapwood rings of oak trees had low TNC concentrations. Stem growth and
      accumulation of carbon reserves occurred concomitantly during the first part of
      the season, when there was no soil water deficit. When soil water content was
      depleted, stem growth ceased in both species, whereas TNC accumulation was
      negligibly affected and continued until leaf fall. The contrasting dynamics and
      distribution of carbohydrate reserves in oak and beech are discussed with
      reference to differences in phenology, early spring growth and hydraulic
      properties between ring-porous trees and diffuse-porous trees.

PMID- 12464574
TI  - Winter embolism, mechanisms of xylem hydraulic conductivity recovery and
      springtime growth patterns in walnut and peach trees.
AB  - Xylem vessels of Prunus persica Batsch (peach) and Juglans regia L. (walnut) are
      vulnerable to frost-induced embolism. In peach, xylem embolism increased
      progressively over the winter, reaching a maximum of 85% loss of hydraulic
      conductivity (PLC) in early March. Over winter, PLC in walnut approached 100%,
      but the degree of xylem embolism varied during the winter, reflecting the ability
      of walnut to generate positive xylem pressures in winter and spring. In contrast,
      positive xylem pressures were not observed in peach. Controlled freeze-thaw
      experiments showed that frost alone is insufficient to increase embolism in
      peach; evaporative conditions during thawing are also required. However, when
      both species were protected from frost, PLC was zero. At bud break, there was
      complete recovery from embolism in walnut, whereas PLC remained high in peach.
      Three mechanisms responsible for the restoration of branch hydraulic conductivity
      were identified in walnut: the development of stem pressure, the development of
      root pressure and the formation of a new ring of functional xylem, whereas only
      one mechanism was observed in peach (new functional ring). The climatic
      conditions necessary for the manifestation of these mechanisms were investigated.

PMID- 12464575
TI  - Carbon acquisition and water use in a Northern Utah Juniperus osteosperma (Utah
      juniper) population.
AB  - Water use and carbon acquisition were examined in a northern Utah population of
      Juniperus osteosperma (Torr.) Little. Leaf-level carbon assimilation, which was
      greatest in the spring and autumn, was limited by soil water availability. Gas
      exchange, plant water potential and tissue hydrogen stable isotopic ratio
      (deltaD) data suggested that plants responded rapidly to summer rain events.
      Based on a leaf area index of 1.4, leaf-level water use and carbon acquisition
      scaled to canopy-level means of 0.59 mm day(-1) and 0.13 mol m(-2) ground surface
      day(-1), respectively. Patterns of soil water potential indicated that J.
      osteosperma dries the soil from the surface downward to a depth of about 1 m.
      Hydraulic redistribution is a significant process in soil water dynamics. Eddy
      covariance data indicated a mean evapotranspiration rate of 0.85 mm day(-1) from
      March to October 2001, during which period the juniper population at the eddy
      flux site was a net source of CO2 (3.9 mol m(-2) ground area). We discuss these
      results in relation to the rapid range expansion of juniper species during the
      past century.

PMID- 12464576
TI  - Ectomycorrhizal fungi and exogenous auxins influence root and mycorrhiza
      formation of Scots pine hypocotyl cuttings in vitro.
AB  - We studied the ability of the ectomycorrhizal (ECM) fungi, Pisolithus tinctorius
      (Pers.) Coker and Couch and Paxillus involutus (Batsch) Fr. (Strain H), to
      produce indole-3-acetic acid (IAA) and to affect the formation and growth of
      roots on Scots pine (Pinus sylvestris L.) hypocotyl cuttings in vitro. Effects of
      indole-3-butyric acid (IBA) and the auxin transport inhibitor, 2,3,5
      triiodobenzoic acid (TIBA), on rooting and the cutting-fungus interaction were
      also studied. Both fungi produced IAA in the absence of exogenous tryptophan, but
      the mycelium and culture filtrate of Pisolithus tinctorius contained higher
      concentrations of free and conjugated IAA than the mycelium and culture filtrate
      of Paxillus involutus. Inoculation with either fungus or short-term application
      of culture filtrate of either fungus to the base of hypocotyl cuttings enhanced
      root formation. Inoculation with either fungus was even more effective in
      enhancing root formation than treatment of the hypocotyl bases with IBA. Fungal
      IAA production was not directly correlated with root formation, because rooting
      was enhanced more by Paxillus involutus than by Pisolithus tinctorius. This
      suggests that, in addition to IAA, other fungal components play an important role
      in root formation. Treatment with 5 microM TIBA increased the rooting percentage
      of non-inoculated cuttings, as well as of cuttings inoculated with Pisolithus
      tinctorius, perhaps as a result of accumulation of IAA at the cutting base.
      However, the marked reduction in growth of Pisolithus tinctorius in the presence
      of TIBA suggests that the effects of TIBA on rooting are complicated and not
      solely related to IAA metabolism. The high IAA-producer, Pisolithus tinctorius,
      formed mycorrhizas, and the IBA treatment increased mycorrhizal frequency in this
      species, whereas TIBA decreased it. Paxillus involutus did not form mycorrhizas,
      indicating that a low concentration of IAA together with other fungal components
      were sufficient to stimulate formation and growth of the roots, but not the
      formation of ECM symbiosis.

PMID- 12464577
TI  - Impact of needle age on the response of respiration in Scots pine to long-term
      elevation of carbon dioxide concentration and temperature.
AB  - Sixteen 20-year-old Scots pine (Pinus sylvestris L.) trees growing in the field
      were enclosed in environment-controlled chambers that for 4 years maintained: (1)
      ambient conditions (CON); (2) elevated atmospheric carbon dioxide concentration
      [CO2] (ambient + 350 micromol mol-1; EC); (3) elevated temperature (ambient + 2-3
      degrees C; ET); or (4) elevated [CO2] and temperature (EC+ET). Dark respiration
      rate, specific leaf area (SLA) and the concentrations of starch and soluble
      sugars in needles were measured in the fourth year. Respiration rates, on both an
      area and a mass basis, and SLA decreased in EC relative to CON, but increased in
      ET and EC+ET, regardless of needle age class. Starch and soluble sugar
      concentrations for a given needle age class increased in EC, but decreased
      slightly in ET and EC+ET. Respiration rates and SLA were highest in current-year
      needles in all treatments, whereas starch and soluble sugar concentrations were
      highest in 1-year-old needles. Relative to that of older needles, respiration of
      current-year needles was inhibited less by EC, but increased in response to ET
      and EC+ET. All treatments enhanced the difference in respiration between current
      year and older needles relative to that in CON. Age had a greater effect on
      needle respiration than any of the treatments. There were no differences in
      carbohydrate concentration or SLA between needle age classes in response to any
      treatment. Relative to CON, the temperature coefficient (Q10) of respiration
      increased slightly in EC, regardless of age, but declined significantly in ET and
      EC+ET, indicating acclimation of respiration to temperature.

PMID- 12464578
TI  - Effects of light availability on leaf gas exchange and expansion in lychee
      (Litchi chinensis).
AB  - Effects of photosynthetic photon flux density (PPFD) on leaf gas exchange of
      lychee (Litchi chinensis Sonn.) were studied in field-grown "Kwai May Pink" and
      "Salathiel" orchard trees and young potted "Kwai May Pink" plants during summer
      in subtropical Queensland (27 degrees S). Variations in PPFD were achieved by
      shading the trees or plants 1 h before measurement at 0800 h. In a second
      experiment, potted seedlings of "Kwai May Pink" were grown in a heated greenhouse
      in 20% of full sun (equivalent to maximum noon PPFD of 200 micromol m(-2)xs(-1))
      and their growth over three flush cycles was compared with seedlings grown in
      full sun (1080 micromol m(-2)xs(-1)). Young potted plants of "Kwai May Pink" were
      also grown outdoors in artificial shade that provided 20, 40, 70 or 100% of full
      sun (equivalent to maximum PPFDs of 500, 900, 1400 and 2000 micromol m(-2)xs(-1))
      and measured for shoot extension and leaf area development over one flush cycle.
      Net CO2 assimilation increased asymptotically in response to increasing PPFD in
      both orchard trees and young potted plants. Maximum rates of CO2 assimilation
      (11.9 +/- 0.5 versus 6.3 +/- 0.2 micromol CO2 m(-2) s(-1)), dark respiration (1.7
      +/- 0.3 versus 0.6 +/- 0.2 micromol CO2 m(-2) s(-1)), quantum yield (0.042 +/-
      0.005 versus 0.027 +/- 0.003 mol CO2 mol(-1)) and light saturation point (1155
      versus 959 micromol m(-2) s(-1)) were higher in orchard trees than in young
      potted plants. In potted seedlings grown in a heated greenhouse, shoots and
      leaves exposed to full sun expanded in a sigmoidal pattern to 69 +/- 12 mm and
      497 +/- 105 cm(2) for each flush, compared with 27 +/- 7 mm and 189 +/- 88 cm(2)
      in shaded seedlings. Shaded seedlings were smaller and had higher shoot:root
      ratios (3.7 versus 3.1) than seedlings grown in full sun. In the potted plants
      grown outdoors in 20, 40, 70 or 100% of full sun, final leaf area per shoot was
      44 +/- 1, 143 +/- 3, 251 +/- 7 and 362 +/- 8 cm(2), respectively. Shoots were
      also shorter in plants grown in shade than in plants grown in full sun (66 +/- 5
      mm versus 101 +/- 2 mm). Photosynthesis in individual leaves of lychee appeared
      to be saturated at about half full sun, whereas maximum leaf expansion occurred
      at higher PPFDs. We conclude that lychee plants can persist as seedlings on the
      forest floor, but require high PPFDs for optimum growth.

PMID- 12464579
TI  - Effects of long-term, elevated ultraviolet-B radiation on phytochemicals in the
      bark of silver birch (Betula pendula).
AB  - Long-term outdoor experiments were conducted to investigate the effects of
      elevated ultraviolet-B (UV-B, 280-320 nm) radiation on secondary metabolites
      (phenolics and terpenoids) and the main soluble sugars (sucrose, raffinose and
      glucose) in the bark of silver birch (Betula pendula Roth) saplings. Saplings
      were exposed to a constant 50% increase in erythemal UV irradiance (UV-B(CIE);
      based on the CIE (International Commission on Illumination) erythemal action
      spectrum) and a small increase in UV-A radiation (320-400 nm) for three growing
      seasons in an irradiation field in central Finland. Two control groups were used:
      saplings exposed to ambient radiation and saplings exposed to slightly increased
      UV-A radiation. Concentrations of sucrose, raffinose and glucose in bark were
      higher in UV-treated saplings than in saplings grown in ambient radiation,
      indicating that stem carbohydrate metabolism was changed by long-term elevated UV
      radiation. Saplings in the elevated UV-A + UV-B radiation treatment and the UV-A
      radiation control treatment had significantly increased concentrations of certain
      UV-absorbing phenolics, such as salidroside, 3,4'-dihydroxypropiophenone-3
      glucoside, (+)-catechin and (-)-epicatechin compared with saplings in ambient
      radiation. In contrast, the radiation treatments had no effect on the non-UV-B
      absorbing terpenoids, papyriferic acid and deacetylpapyriferic acid. We conclude
      that plant parts, in addition to leaves, accumulate specific phenolic UV-filters
      in response to UV radiation exposure.

PMID- 12464580
TI  - Naphthenic acids inhibit root water transport, gas exchange and leaf growth in
      aspen (Populus tremuloides) seedlings.
AB  - Effects of sodium naphthenates (NAs) on root hydraulic conductivity (Lp) and gas
      exchange processes were examined in aspen (Populus tremuloides Michx.) seedlings
      grown in solution culture. Exposure of roots to NAs for 3-5 weeks significantly
      decreased Lp and stomatal conductance. Root-absorbed NAs also decreased leaf
      chlorophyll concentration, net photosynthesis and leaf growth. Short-term (< or =
      2 h) exposure of excised roots to NAs significantly decreased root water flow
      (Qv) with a concomitant decline in root respiration. We conclude that NAs
      metabolically inhibited Lp, likely by affecting water channel activity, and that
      this inhibition could be responsible for the observed reductions in gas exchange
      and leaf growth.

PMID- 12464581
TI  - Potential mechanisms and consequences of cardiac triacylglycerol accumulation in
      insulin-resistant rats.
AB  - The accumulation of intracellular triacylglycerol (TG) is highly correlated with
      muscle insulin resistance. However, it is controversial whether the accumulation
      of TG is the result of increased fatty acid supply, decreased fatty acid
      oxidation, or both. Because abnormal fatty acid metabolism is a key contributor
      to the pathogenesis of diabetes-related cardiovascular dysfunction, we examined
      fatty acid and glucose metabolism in hearts of insulin-resistant JCR:LA-cp rats.
      Isolated working hearts from insulin-resistant rats had glycolytic rates that
      were reduced to 50% of lean control levels (P < 0.05). Cardiac TG content was
      increased by 50% (P < 0.05) in the insulin-resistant rats, but palmitate
      oxidation rates remained similar between the insulin-resistant and lean control
      rats. However, plasma fatty acids and TG levels, as well as cardiac fatty acid
      binding protein (FABP) expression, were significantly increased in the insulin
      resistant rats. AMP-activated protein kinase (AMPK) plays a major role in the
      regulation of cardiac fatty acid and glucose metabolism. When activated, AMPK
      increases fatty acid oxidation by inhibiting acetyl-CoA carboxylase (ACC) and
      reducing malonyl-CoA levels, and it decreases TG content by inhibiting glycerol-3
      phosphate acyltransferase (GPAT), the rate-limiting step in TG synthesis. The
      activation of AMPK also stimulates cardiac glucose uptake and glycolysis. We thus
      investigated whether a decrease in AMPK activity was responsible for the reduced
      cardiac glycolysis and increased TG content in the insulin-resistant rats.
      However, we found no significant difference in AMPK activity. We also found no
      significant difference in various established downstream targets of AMPK: ACC
      activity, malonyl-CoA levels, carnitine palmitoyltransferase I activity, or GPAT
      activity. We conclude that hearts from insulin-resistant JCR:LA-cp rats
      accumulate substantial TG as a result of increased fatty acid supply rather than
      from reduced fatty acid oxidation. Furthermore, the accumulation of cardiac TG is
      associated with a reduction in insulin-stimulated glucose metabolism.

PMID- 12464582
TI  - Palliation of rectal cancer: expertise and selection are the keys.

PMID- 12464583
TI  - Isolated limb perfusion in elderly melanoma patients.

PMID- 12464584
TI  - Approaching the dilemma between prophylactic bilateral mastectomy or oophorectomy
      for breast and ovarian cancer prevention in carriers of BRCA1 or BRCA2 mutations.

PMID- 12464585
TI  - Significance of micrometastases in colorectal cancer.

PMID- 12464586
TI  - Radical resection of rectal cancer primary tumor provides effective local therapy
      in patients with stage IV disease.
AB  - BACKGROUND: The optimal use of radical surgery to palliate primary rectal cancers
      presenting with synchronous distant metastases is poorly defined. We have
      reviewed stage IV rectal cancer patients to evaluate the effectiveness of radical
      surgery without radiation as local therapy. METHODS: Eighty stage IV patients
      with resectable primary rectal tumors treated with radical rectal surgery without
      radiotherapy were identified. Sixty-one (76%) patients received chemotherapy;
      response information was available for 34 patients. RESULTS: Radical resection
      was accomplished by low anterior resection (n = 65), abdominoperineal resection
      (n = 11), and Hartmann's resection (n = 4). Surgical complications were seen in
      12 patients (15%), with 1 death and 4 reoperations. The local recurrence rate was
      6% (n = 5), with a median time to local recurrence of 14 months. Only one patient
      received pelvic radiotherapy as salvage treatment. One patient required
      subsequent diverting colostomy. Median survival was 25 months. On multivariate
      analysis, the extent of metastasis and response to chemotherapy were determinants
      of prolonged survival. CONCLUSIONS: For patients who present with distant
      metastases and resectable primary rectal cancers, radical surgery without
      radiotherapy can provide durable local control with acceptable morbidity. The
      extent of metastatic disease and the response to chemotherapy are the major
      determinants of survival. Effective systemic chemotherapy should be given high
      priority in the treatment of stage IV rectal cancer.

PMID- 12464587
TI  - Prognostic value of baseline and serial carcinoembryonic antigen and carbohydrate
      antigen 19.9 measurements in patients with pseudomyxoma peritonei treated with
      cytoreduction and hyperthermic intraperitoneal chemotherapy.
AB  - BACKGROUND: Tumor markers are useful for diagnosis and follow-up. We studied the
      prognostic value of baseline and serial carcinoembryonic antigen (CEA) and
      carbohydrate antigen 19.9 (CA19.9) measurements in patients with pseudomyxoma
      peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal
      chemotherapy (HIPEC). METHODS: Sixty-three patients with pseudomyxoma peritonei
      were treated with cytoreductive surgery and HIPEC. The tumor markers CEA and
      CA19.9 were collected before therapy and at 3-month intervals during follow-up.
      RESULTS: Preoperative CEA and CA19.9 levels were increased in, respectively, 75%
      and 58% of the patients. Baseline tumor marker values were related to the extent
      of tumor. Immediately after HIPEC, both tumor markers decreased markedly (P
      <.0001). CA19.9 was shown to be a more useful tumor marker than CEA for follow
      up. During follow-up, a high absolute CA19.9 level (P =.0005) was predictive for
      imminent recurrence. Patients who never attained a normal CA19.9 level showed a
      higher recurrence rate at 1 year (53%; SE, 15%), in comparison to patients who
      did so (6%; SE 4%). The median lead time of increased CA19.9 to recurrence was 9
      months. CONCLUSIONS: The measurement of the tumor marker CA19.9 is useful in
      evaluating therapy in patients with pseudomyxoma peritonei treated with
      cytoreductive surgery and HIPEC. CA19.9 is a prognostic factor for predicting
      recurrent disease.

PMID- 12464588
TI  - Safety and efficacy of isolated limb perfusion in elderly melanoma patients.
AB  - BACKGROUND: Older patients are assumed to have a higher risk of complications
      from isolated limb perfusion (ILP). A study was performed evaluating the safety
      and efficacy of ILP in patients older than 75 years with advanced melanoma of the
      limbs. METHODS: A total of 218 therapeutic ILPs with melphalan with or without
      tumor necrosis factor alpha were performed in 202 patients with advanced
      measurable melanoma and were analyzed retrospectively. Fifty-three patients (28%)
      were 75 years or older. RESULTS: Complete response rates were 56% for those older
      than 75 years and 58% for the younger group (P =.79). Locoregional relapse
      occurred in 56% of the older group versus 51% in the younger group (P =.61). Limb
      toxicity, systemic toxicity, local complications, and long-term morbidity were
      similar in both age groups. Perioperative mortality was low, with one procedure
      related death in the older group. Older patients stayed in the hospital for a
      median of 23 days (younger patients, 19 days; P <.01). CONCLUSIONS: ILP results
      in similar response rates in the elderly with recurrent melanoma, without
      increased toxicity, complications, or long-term morbidity compared with younger
      patients. Older age in itself is not a contraindication for ILP.

PMID- 12464589
TI  - Prognostic importance of lymph node tumor burden in melanoma patients staged by
      sentinel node biopsy.
AB  - BACKGROUND: The objective of this study was to investigate the relationship
      between nodal tumor burden and the outcomes of recurrence and survival in
      sentinel node-positive melanoma patients. METHODS: We reviewed a series of
      sentinel node-positive patients with primary cutaneous melanoma treated with
      completion lymph node dissection (CLND). Microscopic nodal tumor deposits were
      counted and measured with an ocular micrometer. Various measures of tumor burden
      and traditional melanoma prognostic indicators were studied in multivariate Cox
      regression models. RESULTS: Sentinel lymph node and CLND specimens were evaluated
      in 90 node-positive patients. The diameter of the largest lymph node tumor nodule
      and the total lymph node tumor volume were significant predictors of recurrence
      (two-sided P <.0001 for both) and survival (two-sided P =.0018 and P =.0002,
      respectively). A tumor deposit diameter of 3 mm was identified as the most
      significant cut point predictive of recurrence (P <.0001; hazard ratio, 5.18) and
      survival (P <.0001; hazard ratio, 5.43). The 3-year survival probability was.86
      for patients with largest tumor deposit diameters of <or=3 mm and was .27 for
      patients with largest deposit diameters >3 mm (P <.0001). CONCLUSIONS:
      Microstaging of melanoma sentinel lymph node/CLND specimens by using the diameter
      of the largest tumor deposit is a highly significant predictor of early relapse
      and survival.

PMID- 12464590
TI  - Changes in breast cancer therapy because of pathology second opinions.
AB  - BACKGROUND: Examination of pathology slides is a routine part of a breast cancer
      second opinion. The purpose of this study was to determine how often the
      pathologic second opinion (1) altered the diagnosis and (2) resulted in a change
      in the surgical procedure. METHODS: Patients presenting between 1997 and 2001 for
      a second opinion after a biopsy diagnosis of breast cancer (invasive or
      noninvasive) were included in this study. RESULTS: There were 340 patients
      presenting for second opinions regarding 346 breast cancers. Sixty-eight
      pathologic second opinions (20%) did not result in any change in pathology or
      prognostic factors, whereas in the remaining 80%, some change occurred. Major
      changes that altered surgical therapy occurred in 7.8% of cases, and pathology
      review provided additional prognostic information in 40%. Changes were more
      common in in situ carcinoma than invasive carcinoma (P =.004), but biopsy type
      (core vs. excisional biopsy) was not a significant predictor of change in
      pathologic information. CONCLUSIONS: This study confirms the benefit of a
      pathology second opinion to improve preoperative estimates of prognosis and to
      determine the appropriate surgical procedure. Missing information on grade and
      histological subtype was responsible for a large number of cases, suggesting a
      need for widespread application of standardization and quality improvement in
      pathology reporting.

PMID- 12464591
TI  - Intraoperative ultrasound facilitates surgery for early breast cancer.
AB  - BACKGROUND: Mammogram-directed wire localization for nonpalpable cancer requires
      surgeon's time and coordination and some patient discomfort. Up to half of these
      nonpalpable lesions can be visualized by ultrasound. Use of intraoperative
      ultrasound streamlines the process of image-guided surgery. METHODS: We
      prospectively visualized 69 nonpalpable breast cancers between January 1998 and
      July 2001. Ultrasound localization was performed in the operating room
      immediately before definitive surgery. Breast cancers were localized using either
      blue dye or a guide wire. RESULTS: Ultrasound correctly localized all lesions at
      surgery. Negative margins for invasive carcinoma were found in 97% (67 of 69) of
      patients. Re-excisions were performed in only 6% (4 of 69) of patients. Overall
      negative margins were found in 90% (62 of 69) of patients. Most positive margins
      (71%) were due to the presence of noncalcified ductal carcinoma in situ.
      Mastectomy was necessary in 4% of patients, usually due to multifocal invasive
      carcinoma. CONCLUSIONS: Increased familiarity with ultrasound has allowed the
      surgeon to localize breast cancer in the operating room, improving the process of
      image-guided surgery. Ultrasound localization is accurate, time efficient,
      technically feasible, and easier for the patient. The re-excision rate is very
      low and is similar to that for mammographic localization. Intraoperative
      ultrasound localization should be considered whenever a breast cancer needs image
      guided excision.

PMID- 12464592
TI  - Ultrasound-guided lumpectomy of nonpalpable breast cancer versus wire-guided
      resection: a randomized clinical trial.
AB  - BACKGROUND: The wire-guided excision of nonpalpable breast cancer often results
      in tumor resections with inadequate margins. This prospective, randomized trial
      was undertaken to investigate whether intraoperative ultrasound (US) guidance
      enables a better margin clearance than the wire-guided technique in the breast
      conserving treatment of nonpalpable breast cancers. METHODS: Patients with a
      preoperative histological diagnosis of nonpalpable breast cancer that could be
      visualized both with US and mammography were included. Patients were randomized
      to undergo either a wire-guided or a US-guided excision. Adequate margins were
      defined as >or=1 mm. RESULTS: Of 49 included patients, 23 were assigned to
      undergo wire-guided excision and 26 to undergo US-guided excision. One patient
      crossed over to US-guided excision after inadvertent wire displacement. Mean
      tumor diameter, specimen weight, and operating time were similar in both groups.
      The excision was adequate in 24 (89%) of 27 US-guided excisions and 12 (55%) of
      22 wire-guide excisions (P =.007). CONCLUSIONS: US-guided excision seems to be
      superior to wire-guided excision with respect to margin clearance of
      mammographically detected and US-visible nonpalpable breast cancers. Patients do
      not have to undergo the unpleasant wire placement before surgery.

PMID- 12464593
TI  - The clinical significance of cytokeratin-positive cells in lymph nodes at the
      time of mastectomy from patients with ductal carcinoma-in-situ.
AB  - BACKGROUND: We determined the presence or absence of and clinical significance of
      cytokeratin-positive cells in the lymph nodes of patients who had had
      mastectomies for ductal carcinoma-in-situ. METHODS: Two pathologists
      independently assessed the axillary lymph nodes found. All patients had either a
      core or open biopsy performed before the time of mastectomy. The lymph nodes were
      assessed with hematoxylin and eosin stain and immunohistochemistry for
      cytokeratin marker AE1/AE3. The slides were assessed for the presence or absence
      of epithelial cells. As a control, axillary lymph nodes found in prophylactic
      mastectomies were assessed. None of these had had a previous biopsy performed.
      RESULTS: Lymph nodes from all patients demonstrated no obvious epithelial cells
      on hematoxylin and eosin stain. Peripheral sinuses of lymph nodes from six
      patients (23%) who had mastectomies for ductal carcinoma-in-situ contained a few
      cytokeratin-positive cells on immunohistochemistry. The lymph nodes of the
      control group demonstrated no cytokeratin-positive cells. The mean follow-up of
      patients was 5 years, and all patients were alive without recurrence at the time
      of the study. CONCLUSIONS: Epithelial cells may be present in the lymph nodes
      draining a site of recent breast biopsy in the absence of invasive carcinoma,
      indicating that these are an artifact of recent surgery and not of
      micrometastatic disease.

PMID- 12464594
TI  - Isolated limb perfusion with tumor necrosis factor and melphalan for
      nonresectable sSewart-Treves lymphangiosarcoma.
AB  - BACKGROUND: Cutaneous Stewart-Treves lymphangiosarcomas represent a rare group of
      tumors characterized by a high grade of vascularization and by localization in an
      extremity with lymphedema. The multifocality and the localization makes these
      tumors eligible for treatment with isolated limb perfusion (ILP). ILP with tumor
      necrosis factor (TNF) and melphalan is a safe and highly effective procedure that
      can achieve limb salvage in >or=80% of all patients with nonresectable extremity
      soft tissue sarcoma or melanoma. METHODS: In 10 patients with multifocal Stewart
      Treves lymphangiosarcoma of the extremities, 16 ILPs with TNF plus melphalan were
      performed. All patients would have been candidates for exarticulation of the
      extremity. RESULTS: We observed an 87% overall response rate (complete and
      partial responses); one patient had a mixed response, and one patient did not
      respond to the therapy. In nine perfusions (56%), a complete response was
      achieved, and five perfusions (31%) resulted in a partial response. Limb salvage
      was achieved in eight patients (80%), with a mean follow-up duration of 34.8
      months (range, 3 to >or=115 months). Regional toxicity was limited and systemic
      toxicity minimal to moderate, with no toxic deaths. CONCLUSIONS: Multifocal
      Stewart-Treves lymphangiosarcomas in extremities with chronic lymphedema can be
      successfully treated by ILP with TNF and melphalan.

PMID- 12464595
TI  - The prognostic significance of lymph node size in patients with squamous
      esophageal cancer.
AB  - BACKGROUND: The prognosis of patients with esophageal cancer remains dismal, and
      their care poses a great challenge of customizing therapeutic strategies for
      individual patients. Lymph node staging is still less than ideal in esophageal
      cancer patients. Therefore, we investigated a new approach to lymph node
      analysis. METHODS: One hundred eighty-seven patients curatively resected for
      squamous cell cancer of the esophagus were studied. The long diameter of the
      largest metastatic lymph node (MLN) was measured on a histopathologic slide and
      was considered as the MLN size. RESULTS: Patient survival decreased with each
      millimeter increment in MLN size. By using MLN size as the lymph node
      classification criterion, patients with MLN <10 mm had both a significantly
      better overall and cancer-specific survival than those with MLN >or=10 mm.
      Patients with fewer than four MLNs were separated into prognostic groups
      according to the MLN size. Among the several prognostic factors, MLN size
      remained the strongest independent predictor of survival by multivariate
      analysis. This nodal analysis allowed stratification of patients into four stages
      with distinctly different survivals. CONCLUSIONS: This approach supplements
      traditional nodal staging strategies and therefore has potential for guiding the
      development of treatment strategies in this carcinoma.

PMID- 12464596
TI  - DNA-PKcs expression in esophageal cancer as a predictor for chemoradiation
      therapeutic sensitivity.
AB  - BACKGROUND: It would be of considerable benefit to patients with esophageal
      cancer to be able to predict the effect of CRT before therapy, because critical
      side effects could be avoided and the therapeutic cost of CRT-resistant cases
      could be reduced. One of the biological parameters with the potential to indicate
      radioresponse is the DNA double-strand break repair enzyme DNA-PKcs. This study
      aims to clarify the correlation between DNA-PKcs expression and CRT effect.
      METHODS: Sixty-seven patients with progressive esophageal cancer treated with CRT
      were included in this study. The relationship between the expression of DNA-PKcs
      and the effect of CRT was examined by using immunohistochemistry. The
      relationships between DNA-PKcs expression, clinicopathologic parameters, and CRT
      effect were investigated statistically. RESULTS: A significant correlation was
      found between the expression of DNA-PKcs and the effect of CRT (P =.0149). The
      high-DNA-PKcs expression group showed greater therapeutic sensitivity than the
      low-expression group. Clinicopathologic factors had no relationship with DNA-PKcs
      expression or CRT effect. CONCLUSIONS: This study suggests that high expression
      of DNA-PKcs correlates with CRT effect. DNA-PKcs expression could, therefore, be
      useful for predicting the effect of CRT. In addition, these results may make it
      possible to plan therapy taking patients' quality of life into consideration.

PMID- 12464597
TI  - Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E
      succinate.
AB  - BACKGROUND: Relapse of melanoma after surgical treatment remains a significant
      clinical problem in need of novel therapies. Vitamin E succinate (VES) is a
      promising antitumor micronutrient. We evaluated the effect of VES on melanoma
      dormancy and angiogenesis. METHODS: B16F10 melanoma cells were allografted in
      mice. The effect of VES on melanoma dormancy was measured by monitoring tumor
      volume. Tumor vascularity was quantitated with CD31 immunostaining. The
      expression of vascular endothelial growth factor (VEGF), VEGF receptor 1, and
      VEGF receptor 2 in tumors was assessed by the intensity of immunostaining. VES
      effect on secreted VEGF protein and VEGF promoter activity was measured with
      enzyme-linked immunosorbent assay and transient transfection assay, respectively.
      Significance was determined by analysis of variance. RESULTS: VES promoted
      melanoma dormancy (P =.0019) and inhibited melanoma angiogenesis (P <.0001). VES
      also significantly suppressed the expression of VEGF, VEGF receptor 1, and VEGF
      receptor 2 in melanoma tumors (P <.0001). Melanoma VEGF secretion (P =.0077) and
      melanoma VEGF promoter activity (P <.05) were significantly inhibited by VES.
      CONCLUSIONS: VES promotes melanoma dormancy and inhibits melanoma angiogenesis.
      The mechanism of the VES antiangiogenesis effect involves the inhibition of VEGF
      gene transcription. These findings support future studies of VES in the
      prevention of melanoma metastasis.

PMID- 12464598
TI  - Preoperative chemoradiation for rectal cancer: a different perspective.

PMID- 12464599
TI  - Tail-anchored and signal-anchored proteins utilize overlapping pathways during
      membrane insertion.
AB  - Tail-anchored proteins are a distinct class of membrane proteins that are
      characterized by a C-terminal membrane insertion sequence and a capacity for post
      translational integration. Although it is now clear that tail-anchored proteins
      are inserted into the membrane at the endoplasmic reticulum (ER), the molecular
      basis for their integration is poorly understood. We have used a cross-linking
      approach to identify ER components that may be involved in the membrane insertion
      of tail-anchored proteins. We find that several newly synthesized tail-anchored
      proteins are transiently associated with a defined subset of cellular components.
      Among these, we identify several ER proteins, including subunits of the Sec61
      translocon, Sec62p, Sec63p, and the 25-kDa subunit of the signal peptidase
      complex. When we analyze the cotranslational membrane insertion of a comparable
      signal-anchored protein we find the nascent polypeptide associated with a similar
      set of ER components. We conclude that the pathways for the integration of tail
      anchored and signal-anchored membrane proteins at the ER exhibit a substantial
      degree of overlap, and we propose that this reflects similarities between co- and
      post-translational membrane insertion.

PMID- 12464600
TI  - Phosphorylation of key serine residues is required for internalization of the
      complement 5a (C5a) anaphylatoxin receptor via a beta-arrestin, dynamin, and
      clathrin-dependent pathway.
AB  - The human complement 5a (C5a) anaphylatoxin receptor (CD88) is a G protein
      coupled receptor involved in innate host defense and inflammation. Upon agonist
      binding, C5a receptor (C5aR) undergoes rapid phosphorylation on the six serine
      residues present in the C-terminal region followed by desensitization and
      internalization. Using confocal immunofluorescence microscopy and green
      fluorescent protein-tagged beta-arrestins (beta-arr 1- and beta-arr 2-EGFP) we
      show a persistent complex between C5aR and beta-arrestins to endosomal
      compartments. Serine residues in the C5aR C terminus were identified that control
      the intracellular trafficking of the C5aR-arrestin complex in response to C5a.
      Two phosphorylation mutants C5aR-A(314,317,327,332) and C5aR-A(314,317,332,334),
      which are phosphorylated only on Ser(334)/Ser(338) and Ser(327)/Ser(338),
      respectively, recruited beta-arr 1 and were internalized. In contrast, the
      phosphorylation-deficient receptors C5aR-A(334,338) and C5aR-A(332,334,338) were
      not internalized even though observations by confocal microscopy indicated that
      beta-arr 1-EGFP and/or beta-arr 2-EGFP could be recruited to the plasma membrane.
      Altogether the results indicate that C5aR activation is able to promote a loose
      association with beta-arrestins, but phosphorylation of either Ser(334)/Ser(338)
      or Ser(327)/Ser(338) is necessary and sufficient for the formation of a
      persistent complex. In addition, it was observed that C5aR endocytosis was
      inhibited by the expression of the dominant negative mutants of dynamin (K44E)
      and beta-arrestin 1 (beta-arr 1-(319-418)-EGFP). Thus, the results suggest that
      the C5aR is internalized via a pathway dependent on beta-arrestin, clathrin, and
      dynamin.

PMID- 12464601
TI  - Nickel in subunit beta of the acetyl-CoA decarbonylase/synthase multienzyme
      complex in methanogens. Catalytic properties and evidence for a binuclear Ni-Ni
      site.
AB  - The acetyl-CoA decarbonylase/synthase (ACDS) complex catalyzes the central
      reaction of acetyl C-C bond cleavage in methanogens growing on acetate and is
      also responsible for synthesis of acetyl units during growth on C-1 substrates.
      The ACDS beta subunit contains nickel and an Fe/S center and reacts with acetyl
      CoA forming an acetyl-enzyme intermediate presumably directly involved in acetyl
      C-C bond activation. To investigate the role of nickel in this process two forms
      of the Methanosarcina thermophila beta subunit were overexpressed in
      anaerobically grown Escherichia coli. Both contained an Fe/S center but lacked
      nickel and were inactive in acetyl-enzyme formation in redox-dependent
      acetyltransferase assays. However, high activity developed during incubation with
      NiCl(2). The native and nickel-reconstituted proteins both contained iron and
      nickel in a 2:1 ratio, with insignificant levels of other metals, including
      copper. Binding of nickel elicited marked changes in the UV-visible spectrum,
      with intense charge transfer bands indicating multiple thiolate ligation to
      nickel. The kinetics of nickel incorporation matched the time course for enzyme
      activation. Other divalent metal ions could not substitute for nickel in yielding
      catalytic activity. Acetyl-CoA was formed in reactions with CoA, CO, and
      methylcobalamin, directly demonstrating C-C bond activation by the beta subunit
      in the absence of other ACDS subunits. Nickel was indispensable in this process
      too and was needed to form a characteristic EPR-detectable enzyme-carbonyl adduct
      in reactions with CO. In contrast to enzyme activation, EPR signal formation did
      not require addition of reducing agent, indicating indirect catalytic involvement
      of the paramagnetic species. Site-directed mutagenesis indicated that Cys-278 and
      Cys-280 coordinate nickel, with Cys-189 essential for Fe/S cluster formation. The
      results are consistent with an Ni(2)[Fe(4)S(4)] arrangement at the active site. A
      mechanism for C-C bond activation is proposed that includes a specific role for
      the Fe(4)S(4) center and accounts for the absolute requirement for nickel.

PMID- 12464602
TI  - Rapid clearance of sialylated glycoproteins by the asialoglycoprotein receptor.
AB  - The asialoglycoprotein-receptor (ASGP-R) located on liver parenchymal cells was
      originally identified and characterized on the basis of its ability to bind
      glycoproteins bearing terminal galactose (Gal) or N-acetylgalactosamine (GalNAc);
      however, endogenous ligands for the ASGP-R have not to date been definitively
      identified. We have determined that the rat ASGP-R specifically binds
      oligosaccharides terminating with the sequence
      Siaalpha2,6GalNAcbeta1,4GlcNAcbeta1,2Man. Bovine serum albumin chemically
      modified with 10-15 tetrasaccharides with the sequence
      Siaalpha2,6GalNAcbeta1,4GlcNAcbeta1,2Man is cleared from the blood of the rat
      with a half-life of <1 min by a receptor located in the liver. We have isolated
      the receptor and identified it as the ASGP-R. Furthermore, we have determined
      that subunit 1 of the ASGP-R accounts for the binding of terminal
      Siaalpha2,6GalNAcbeta. Based on the newly defined specificity of the rat ASGP-R
      we hypothesize that glycoproteins bearing structures that are selectively
      modified with terminal Siaalpha2,6GalNAcbeta and are released into the blood may
      be endogenous ligands for the rat ASGP-R.

PMID- 12464603
TI  - Bifunctional family 3 glycoside hydrolases from barley with alpha -L
      arabinofuranosidase and beta -D-xylosidase activity. Characterization, primary
      structures, and COOH-terminal processing.
AB  - An alpha-l-arabinofuranosidase and a beta-d-xylosidase, designated ARA-I and XYL,
      respectively, have been purified about 1,000-fold from extracts of 5-day-old
      barley (Hordeum vulgare L.) seedlings using ammonium sulfate fractional
      precipitation, ion exchange chromatography, chromatofocusing, and size-exclusion
      chromatography. The ARA-I has an apparent molecular mass of 67 kDa and an
      isoelectric point of 5.5, and its catalytic efficiency during hydrolysis of 4'
      nitrophenyl alpha-l-arabinofuranoside is only slightly higher than during
      hydrolysis of 4'-nitrophenyl beta-d-xyloside. Thus, the enzyme is actually a
      bifunctional alpha-l-arabinofuranosidase/beta-d-xylosidase. In contrast, the XYL
      enzyme, which also has an apparent molecular mass of 67 kDa and an isoelectric
      point of 6.7, preferentially hydrolyzes 4'-nitrophenyl beta-d-xyloside, with a
      catalytic efficiency approximately 30-fold higher than with 4'-nitrophenyl alpha
      l-arabinofuranoside. The enzymes hydrolyze wheat flour arabinoxylan slowly but
      rapidly hydrolyze oligosaccharide products released from this polysaccharide by
      (1 --> 4)-beta-d-xylan endohydrolase. Both enzymes hydrolyze (1 --> 4)-beta-d
      xylopentaose, and ARA-I can also degrade (1 --> 5)-alpha-l-arabinofuranohexaose.
      ARA-I and XYL cDNAs encode mature proteins of 748 amino acid residues which have
      calculated molecular masses of 79.2 and 80.5 kDa, respectively. Both are family 3
      glycoside hydrolases. The discrepancies between the apparent molecular masses
      obtained for the purified enzymes and those predicted from the cDNAs are
      attributable to COOH-terminal processing, through which about 130 amino acid
      residues are removed from the primary translation product. The genes encoding the
      ARA-I and XYL have been mapped to chromosomes 2H and 6H, respectively. ARA-I
      transcripts are most abundant in young roots, young leaves, and developing grain,
      whereas XYL mRNA is detected in most barley tissues.

PMID- 12464604
TI  - Delta 12-oleate desaturase-related enzymes associated with formation of
      conjugated trans-delta 11, cis-delta 13 double bonds.
AB  - Conjugated linolenic acids are present as major seed oils in several plant
      species. Punicic acid (or trichosanic acid) is a conjugated linolenic acid isomer
      containing cis-delta9, trans-delta11, cis-delta13 double bonds in the C(18)
      carbon chain. Here we report cDNAs, TkFac and PgFac, isolated from Trichosanthes
      kirilowii and Punica granatum, that encode a class of conjugases associated with
      the formation of trans-delta11, cis-delta13 double bonds. Expression of TkFac and
      PgFac in Arabidopsis seeds under transcriptional control of the seed-specific
      napin promoter resulted in accumulation of punicic acid up to approximately 10%
      (w/w) of the total seed oils. In contrast, no punicic acid was found in lipids
      from leaves even when the conjugases were driven under control of the cauliflower
      mosaic virus 35S promoter. In yeast cells grown without exogenous fatty acids in
      the culture medium, TkFac and PgFac expression resulted in punicic acid
      accumulation accompanied by 16:2delta(9cis, 12cis) and 18:2delta(9cis, 12cis)
      production. Thus, TkFac and PgFac are defined as bifunctional enzymes having both
      conjugase and delta12-oleate desaturase activity. Furthermore, we demonstrate
      that 16:2delta(9cis, 12cis) and 18:3delta(9cis, 12cis, 15cis) as well as
      18:2delta(9cis, 12cis) are potential substrates for the conjugases to form trans
      delta11 and cis-delta13 double bonds.

PMID- 12464605
TI  - A novel transcriptional inhibitory element differentially regulates the cyclin D1
      gene in senescent cells.
AB  - Senescent human diploid fibroblasts are unable to initiate DNA synthesis
      following mitogenic stimulation and adopt a unique gene expression profile
      distinct from young or quiescent cells. In this study, a novel transcriptional
      regulatory element was identified in the 5'-untranslated region of the cyclin D1
      gene. We show that this element differentially suppresses cyclin D1 expression in
      young versus senescent fibroblasts. Electrophoretic mobility shift assays
      revealed abundant complexes forming with young cell nuclear extracts compared
      with senescent cell nuclear extracts. Binding was maintained in young quiescent
      cells, showing that loss of this activity was specific to senescent cells and not
      an effect of cell cycle arrest. Site-directed mutagenesis within this cyclin D1
      inhibitory element (DIE) abolished binding activity and selectively increased
      cyclin D1 promoter activity in young but not in senescent cells. Sequences with
      homology to the DIE were found in the 5'-untranslated regions of other genes
      known to be up-regulated during cellular aging, suggesting that protein(s) that
      bind the DIE might be responsible for the coordinate increase in transcription of
      many genes during cellular aging. This study provides evidence that loss of
      transcriptional repressor activity contributes to the up-regulation of cyclin D1,
      and possibly additional age-regulated genes, during cellular senescence.

PMID- 12464606
TI  - Both heads of tissue-derived smooth muscle heavy meromyosin bind to actin in the
      presence of ADP.
AB  - The effect of ADP and phosphorylation upon the actin binding properties of heavy
      meromyosin was investigated using three fluorescence methods that monitor the
      number of heavy meromyosin heads that bind to pyrene-actin: (i) amplitudes of ATP
      induced dissociation, (ii) amplitudes of ADP-induced dissociation of the pyrene
      actin-heavy meromyosin complex, and (iii) amplitudes of the association of heavy
      meromyosin with pyrene-actin. Both heads bound to pyrene-actin, irrespective of
      regulatory light chain phosphorylation or the presence of ADP. This behavior was
      found for native regulated heavy meromyosin prepared by proteolytic digestion of
      chicken gizzard myosin with between 5 and 95% heavy chain cleavage at the actin
      binding loop, showing that two-head binding is a property of heavy meromyosin
      with uncleaved heavy chains. These data are in contrast to a previous study using
      an uncleaved expressed preparation (Berger, C. E., Fagnant, P. M., Heizmann, S.,
      Trybus, K. M., and Geeves, M. A. (2001) J. Biol. Chem. 276, 23240-23245), which
      showed that one head of the unphosphorylated heavy meromyosin-ADP complex bound
      to actin and that the partner head either did not bind or bound weakly. Possible
      explanations for the differences between the two studies are discussed. We have
      shown that unphosphorylated heavy meromyosin appears to adopt a special state in
      the presence of ADP based upon analysis of actin-heavy meromyosin association
      rate constants. Data were consistent with one head binding rapidly and the second
      head binding more slowly in the presence of ADP. Both heads bound to actin at the
      same rate for all other states.

PMID- 12464607
TI  - Nuclear localization of a non-caspase truncation product of atrophin-1, with an
      expanded polyglutamine repeat, increases cellular toxicity.
AB  - Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant
      neurodegenerative disorder similar to Huntington's disease, with clinical
      manifestations including chorea, incoordination, ataxia, and dementia. It is
      caused by an expansion of a CAG trinucleotide repeat encoding polyglutamine in
      the atrophin-1 gene. Both patients and DRPLA transgenic mice have nuclear
      accumulation of atrophin-1, especially an approximately 120-kDa fragment, which
      appears to represent a cleavage product. We now show that this is an N-terminal
      fragment that does not correspond to the previously described caspase-3 fragment,
      or any other known caspase cleavage product. The atrophin-1 sequence contains a
      putative nuclear localization signal in the N terminus of the protein and a
      putative nuclear export signal in the C terminus. We have tested the hypothesis
      that endogenous localization signals are functional in atrophin-1, and that
      nuclear localization and proteolytic cleavage contribute to atrophin-1 cell
      toxicity. In transient cell transfection experiments using a neuroblastoma cell
      line, full-length atrophin-1 with 26 (normal) or 65 (expanded) glutamines
      localized to both nucleus and cytoplasm, with no significant difference in
      toxicity between the normal and mutant proteins. A construct with 65 glutamine
      repeats encoding an N-terminal fragment (which removes an NES) of atrophin-1
      similar in size to the truncation product in DRPLA patient tissue, showed
      increased nuclear labeling, and an increase in cellular toxicity, compared with a
      similar fragment with 26 glutamines. Full-length atrophin-1 with 65 polyglutamine
      repeats and mutations inactivating the NES also yielded increased nuclear
      localization and increased toxicity. These data suggest that truncation enhances
      cellular toxicity of the mutant protein, and that the NES is a relevant region
      deleted during truncation. Furthermore, mutating the NLS in the truncated protein
      shifted atrophin-1 more to the cytoplasm and eliminated the increased toxicity,
      consistent with the idea that nuclear localization enhances toxicity. In none of
      the experiments were inclusions visible in the nucleus or cytoplasm suggesting
      that inclusion formation is unrelated to cell death. These data indicate that
      truncation of atrophin-1 may alter its ability to shuttle between the nucleus and
      cytoplasm, leading to abnormal nuclear interactions and cell toxicity.

PMID- 12464609
TI  - Reconstitution of holin activity with a synthetic peptide containing the 1-32
      sequence region of EJh, the EJ-1 phage holin.
AB  - Pneumococcal EJ-1 phage holin (EJh) is a hydrophobic polypeptide of 85 amino acid
      residues displaying lethal inner membrane disruption activity. To get an insight
      into holin structure and function, several peptides representing the different
      topological regions predicted by sequence analysis have been synthesized.
      Peptides were structurally characterized in both aqueous buffer and membrane
      environments, and their potential to induce membrane perturbation was determined.
      Among them, only the N-terminal predicted transmembrane helix increased the
      membrane permeability. This segment, only when flanked by the positive charged
      residues on its N-terminal side, which are present in the sequence of the full
      length protein, folds into a major alpha-helix structure with a transmembrane
      preferential orientation. Fluorescein quenching experiments of N-terminal-labeled
      peptide evidenced the formation of oligomers of variable size depending on the
      peptideto-lipid molar ratio. The self-assembling tendency correlated with the
      formation of transmembrane pores that permit the release of encapsulated dextrans
      of various sizes. When analyzed by atomic force microscopy, peptide-induced
      membrane lesions are visualized as transbilayer holes. These findings are the
      first evidence for a lytic domain in holins and for the nature of membrane
      lesions caused by them.

PMID- 12464608
TI  - Cooperative interaction of hypoxia-inducible factor-2alpha (HIF-2alpha ) and Ets
      1 in the transcriptional activation of vascular endothelial growth factor
      receptor-2 (Flk-1).
AB  - Interactions between Ets family members and a variety of other transcription
      factors serve important functions during development and differentiation
      processes, e.g. in the hematopoietic system. Here we show that the endothelial
      basic helix-loop-helix PAS domain transcription factor, hypoxia-inducible factor
      2alpha (HIF-2alpha) (but not its close relative HIF-1alpha), cooperates with Ets
      1 in activating transcription of the vascular endothelial growth factor receptor
      2 (VEGF-2) gene (Flk-1). The receptor tyrosine kinase Flk-1 is indispensable for
      angiogenesis, and its expression is closely regulated during development.
      Consistent with the hypothesis that HIF-2alpha controls the expression of Flk-1
      in vivo, we show here that HIF-2alpha and Flk-1 are co-regulated in postnatal
      mouse brain capillaries. A tandem HIF-2alpha/Ets binding site was identified
      within the Flk-1 promoter that acted as a strong enhancer element. Based on the
      analysis of transgenic mouse embryos, these motifs are essential for endothelial
      cell-specific reporter gene expression. A single HIF-2alpha/Ets element conferred
      strong cooperative induction by HIF-2alpha and Ets-1 when fused to a heterologous
      promoter and was most active in endothelial cells. The physical interaction of
      HIF-2alpha with Ets-1 was demonstrated and localized to the HIF-2alpha carboxyl
      terminus and the autoinhibitory exon VII domain of Ets-1, respectively. The
      deletion of the DNA binding and carboxyl-terminal transactivation domains of HIF
      2alpha, respectively, created dominant negative mutants that suppressed
      transactivation by the wild type protein and failed to synergize with Ets-1.
      These results suggest that the interaction between HIF-2alpha and endothelial Ets
      factors is required for the full transcriptional activation of Flk-1 in
      endothelial cells and may therefore represent a future target for the
      manipulation of angiogenesis.

PMID- 12464610
TI  - Inhibition of hemostasis by a high affinity biogenic amine-binding protein from
      the saliva of a blood-feeding insect.
AB  - The saliva of the blood-feeding insect Rhodnius prolixus contains numerous
      pharmacologically active substances. Included among these are a number of
      lipocalin proteins that bind various ligands important in hemostasis and
      inflammation. One such protein is a biogenic amine-binding protein (ABP) that
      binds serotonin, epinephrine, and norepinephrine. Based on amino acid alignments,
      it is most similar to the nitrophorin group of lipocalins found in the same
      insect species. Physiologically, this protein appears to act as both a
      vasodilator and platelet aggregation inhibitor. This protein inhibits smooth
      muscle contraction of the rat uterus in response to serotonin and of the rabbit
      aorta in response to norepinephrine. Platelet aggregation induced by a
      combination of low concentrations of ADP and either serotonin or epinephrine is
      inhibited because of the binding of serotonin and epinephrine. Potentiation of
      aggregation induced by low concentrations of collagen along with serotonin or
      epinephrine is also inhibited. Dissociation constants for biogenic amines were
      measured using isothermal titration calorimetry and the Hummel-Dreyer method of
      equilibrium gel filtration. In this manner, K(d) values of 102, 24, and 345 nm
      were found for serotonin, norepinephrine, and epinephrine, respectively.
      Molecular modeling of ABP suggests that ligand binding is mediated by interaction
      with the side chains of aromatic amino acids and charged residues that line the
      binding pocket.

PMID- 12464611
TI  - Structural features of glycosyltransferases synthesizing major bilayer and
      nonbilayer-prone membrane lipids in Acholeplasma laidlawii and Streptococcus
      pneumoniae.
AB  - In membranes of Acholeplasma laidlawii two consecutively acting
      glucosyltransferases, the (i) alpha-monoglucosyldiacylglycerol (MGlcDAG) synthase
      (alMGS) (EC ) and the (ii) alpha-diglucosyl-DAG (DGlcDAG) synthase (alDGS) (EC ),
      are involved in maintaining (i) a certain anionic lipid surface charge density
      and (ii) constant nonbilayer/bilayer conditions (curvature packing stress),
      respectively. Cloning of the alDGS gene revealed related uncharacterized sequence
      analogs especially in several Gram-positive pathogens, thermophiles and archaea,
      where the encoded enzyme function of a potential Streptococcus pneumoniae DGS
      gene (cpoA) was verified. A strong stimulation of alDGS by phosphatidylglycerol
      (PG), cardiolipin, or nonbilayer-prone 1,3-DAG was observed, while only PG
      stimulated CpoA. Several secondary structure prediction and fold recognition
      methods were used together with SWISS-MODEL to build three-dimensional model
      structures for three MGS and two DGS lipid glycosyltransferases. Two Escherichia
      coli proteins with known structures were identified as the best templates, the
      membrane surface-associated two-domain glycosyltransferase MurG and the soluble
      GlcNAc epimerase. Differences in electrostatic surface potential between the
      different models and their individual domains suggest that electrostatic
      interactions play a role for the association to membranes. Further support for
      this was obtained when hybrids of the N- and C-domain, and full size alMGS with
      green fluorescent protein were localized to different regions of the E. coli
      inner membrane and cytoplasm in vivo. In conclusion, it is proposed that the
      varying abilities to bind, and sense lipid charge and curvature stress, are
      governed by typical differences in charge (pI values), amphiphilicity, and
      hydrophobicity for the N- and (catalytic) C-domains of these structurally similar
      membrane-associated enzymes.

PMID- 12464613
TI  - Synergy of epidermal growth factor and 12(S)-hydroxyeicosatetraenoate on protein
      kinase C activation in lens epithelial cells.
AB  - 12(S)-hydroxyeicosatetraenoic acid (12(S)HETE) is a bioactive metabolite of
      arachidonic acid synthesized by 12-lipoxygenase. The 12-lipoxygenase blocker,
      baicalein, prevents epidermal growth factor (EGF)-induced activation of protein
      kinase C (PKC) alpha and beta in lens epithelial cells, whereas supplementation
      with 12(S)HETE reverses this effect, suggesting that EGF and 12(S)HETE may work
      together to activate PKC. This study investigates the mechanism of PKCbeta
      activation by EGF and 12(S)HETE. 12(S)HETE alone directed translocation of
      PKCbeta through the C1 rather than the C2 domain, without activating
      phosphoinositide 3-kinase (PI3K) or MAPK signaling or increasing intracellular
      calcium concentration. In the presence of baicalein, EGF triggered an asymmetric
      phosphorylation of the EGF receptor initiating signaling through PI3K and MAPK,
      but not PLCgamma. Together, 12(S)HETE and EGF synergistically increased
      phosphorylation of PKCbeta in the activation loop and C terminus as well as
      PKCbeta-specific activity. PI3K inhibitors blocked phosphorylation, but MEK1
      inhibitors did not. Microvesicles containing phosphatidylinositol 3,4,5
      trisphosphate mimicked the action of EGF on PKCbeta activity in the presence of
      12(S)HETE. Kinase-inactive PKCbeta mutations in either activation loop or C
      terminus were effectively translocated by 12(S)HETE, as was PKCbeta in the
      presence of chelerythrine or Go-6983. These findings indicate that
      unphosphorylated PKCbeta is translocated to the membrane by 12(S)HETE and
      phosphorylated by EGF-dependent PI3K signaling, to generate catalytically
      competent PKCbeta.

PMID- 12464612
TI  - Conditional expression of mutant M-line titins results in cardiomyopathy with
      altered sarcomere structure.
AB  - Titin is a giant protein responsible for muscle elasticity and provides a
      scaffold for several sarcomeric proteins, including the novel titin-binding
      protein MURF-1, which binds near the titin M-line region. Another unique feature
      of titin is the presence of a serine/threonine kinase-like domain at the edge of
      the M-line region of the sarcomere, for which no physiological catalytic function
      has yet been shown. To investigate the role(s) of the titin M-line segment, we
      have conditionally deleted the exons MEx1 and MEx2 (encoding the kinase domain
      plus flanking sequences) at different stages of embryonic development. Our data
      demonstrate an important role for MEx1 and MEx2 in early cardiac development
      (embryonic lethality) as well as postnatally when disruption of M-line titin
      leads to muscle weakness and death at approximately 5 weeks of age. Myopathic
      changes include pale M-lines devoid of MURF-1, and gradual sarcomeric
      disassembly. The animal model presented here indicates a critical role for the M
      line region of titin in maintaining the structural integrity of the sarcomere.

PMID- 12464614
TI  - Alzheimer's disease beta-amyloid peptide is increased in mice deficient in
      endothelin-converting enzyme.
AB  - The abnormal accumulation of beta-amyloid (Abeta) in the brain is an early and
      invariant feature in Alzheimer's disease (AD) and is believed to play a pivotal
      role in the etiology and pathogenesis of the disease. As such, a major focus of
      AD research has been the elucidation of the mechanisms responsible for the
      generation of Abeta. As with any peptide, however, the degree of Abeta
      accumulation is dependent not only on its production but also on its removal. In
      cell-based and in vitro models we have previously characterized endothelin
      converting enzyme-1 (ECE-1) as an Abeta-degrading enzyme that appears to act
      intracellularly, thus limiting the amount of Abeta available for secretion. To
      determine the physiological significance of this activity, we analyzed Abeta
      levels in the brains of mice deficient for ECE-1 and a closely related enzyme,
      ECE-2. Significant increases in the levels of both Abeta40 and Abeta42 were found
      in the brains of these animals when compared with age-matched littermate
      controls. The increase in Abeta levels in the ECE-deficient mice provides the
      first direct evidence for a physiological role for both ECE-1 and ECE-2 in
      limiting Abeta accumulation in the brain and also provides further insight into
      the factors involved in Abeta clearance in vivo.

PMID- 12464615
TI  - Cyclic AMP-independent involvement of Rap1/B-Raf in the angiotensin II AT2
      receptor signaling pathway in NG108-15 cells.
AB  - The angiotensin II (Ang II) type 2 (AT(2)) receptor is an atypical seven
      transmembrane domain receptor. Controversy surrounding this receptor concerns
      both the nature of the second messengers produced as well as its associated
      signaling mechanisms. Using the neuronal cell line NG108-15, we have reported
      previously that activation of the AT(2) receptor induced morphological
      differentiation in a p21(ras)-independent, but p42/p44(mapk)-dependent mechanism.
      The activation of p42/p44(mapk) was delayed, sustained, and had been shown to be
      essential for neurite elongation. In the present report, we demonstrate that
      activation of the AT(2) receptor rapidly, but transiently, activated the Rap1/B
      Raf complex of signaling proteins. In RapN17- and Rap1GAP-transfected cells, the
      effects induced by Ang II were abolished, demonstrating that activation of these
      proteins was responsible for the observed p42/p44(mapk) phosphorylation and for
      morphological differentiation. To assess whether cAMP was involved in the
      activation of Rap1/B-Raf and neuronal differentiation induced by Ang II, NG108-15
      cells were treated with stimulators or inhibitors of the cAMP pathway. We found
      that dibutyryl cAMP and forskolin did not stimulate Rap1 or p42/p44(mapk)
      activity. Furthermore, adding H-89, an inhibitor of protein kinase A, or Rp-8-Br
      cAMP-S, an inactive cAMP analog, failed to impair p42/p44(mapk) activity and
      neurite outgrowth induced by Ang II. The present observations clearly indicate
      that cAMP, a well known stimulus of neuronal differentiation, did not participate
      in the AT(2) receptor signaling pathways in the NG108-15 cells. Therefore, the
      AT(2) receptor of Ang II activates the signaling modules of Rap1/B-Raf and
      p42/p44(mapk) via a cAMP-independent pathway to induce morphological
      differentiation of NG108-15 cells.

PMID- 12464616
TI  - Three highly conserved proteins catalyze the conversion of UDP-N-acetyl-D
      glucosamine to precursors for the biosynthesis of O antigen in Pseudomonas
      aeruginosa O11 and capsule in Staphylococcus aureus type 5. Implications for the
      UDP-N-acetyl-L-fucosamine biosynthetic pathway.
AB  - N-Acetyl-l-fucosamine is a constituent of surface polysaccharide structures of
      Pseudomonas aeruginosa and Staphylococcus aureus. The three P. aeruginosa enzymes
      WbjB, WbjC, and WbjD, as well as the S. aureus homologs Cap5E, Cap5F, and Cap5G,
      involved in the biosynthesis of N-acetyl-l-fucosamine have been overexpressed and
      purified to near homogeneity. Capillary electrophoresis (CE), mass spectroscopy
      (MS), and nuclear magnetic resonance spectroscopy have been used to elucidate the
      biosynthesis pathway, which proceeds in five reaction steps. WbjB/Cap5E catalyzed
      4,6-dehydration of UDP-N-acetyl-d-glucosamine and 3- and 5-epimerization to yield
      a mixture of three keto-deoxy-sugars. The third intermediate compound was
      subsequently reduced at C-4 to UDP-2-acetamido-2,6-dideoxy-l-talose by
      WbjC/Cap5F. Incubation of UDP-2-acetamido-2,6-dideoxy-l-talose (UDP-TalNAc) with
      WbjD/Cap5G resulted in a new peak separable by CE that demonstrated identical
      mass and fragmentation patterns by CE-MS/MS to UDP-TalNAc. These results are
      consistent with WbjD/Cap5G-mediated 2-epimerization of UDP-TalNAc to UDP-FucNAc.
      A nonpolar gene knockout of wbjB, the first of the genes associated with this
      pathway, was constructed in P. aeruginosa serotype O11 strain PA103. The
      corresponding mutant produced rough lipopolysaccharide devoid of B-band O
      antigen. This lipopolysaccharide deficiency could be complemented with P.
      aeruginosa wbjB or with the S. aureus homolog cap5E. Insertional inactivation of
      either the cap5G or cap5F genes abolished capsule polysaccharide production in
      the S. aureus strain Newman. Providing the appropriate gene in trans, thereby
      complementing these mutants, fully restored the capsular polysaccharide
      phenotype.

PMID- 12464617
TI  - Caspy, a zebrafish caspase, activated by ASC oligomerization is required for
      pharyngeal arch development.
AB  - The pyrin domain was identified recently in multiple proteins that are associated
      with apoptosis and/or inflammation, but the physiological and molecular function
      of these proteins remain poorly understood. We have identified Caspy and Caspy2,
      two zebrafish caspases containing N-terminal pyrin domains. Expression of Caspy
      and Caspy2 induced apoptosis in mammalian cells that were inhibited by general
      caspase inhibitors. Biochemical analysis revealed that both Caspy and Caspy2 are
      active caspases, but they exhibit different substrate specificity. Caspy, but not
      Caspy2, interacted with the zebrafish orthologue of ASC (zAsc), a pyrin- and
      caspase recruitment domain-containing protein identified previously in mammals.
      The pyrin domains of both Caspy and zAsc were required for their interaction.
      Furthermore, zAsc and Caspy co-localized to the "speck" when co-transfected into
      mammalian cells. Enforced oligomerization of zAsc, but not simple interaction
      with zAsc, induced specific proteolytic activation of Caspy and enhanced Caspy
      dependent apoptosis. Injection of zebrafish embryos with a morpholino antisense
      oligonucleotide corresponding to caspy resulted in an "open mouth" phenotype
      associated with defective formation of the cartilaginous pharyngeal skeleton.
      These studies suggest that zAsc mediates the activation of Caspy, a caspase that
      plays an important role in the morphogenesis of the jaw and gill-bearing arches.

PMID- 12464618
TI  - N-terminal truncation of the dopamine transporter abolishes phorbol ester- and
      substance P receptor-stimulated phosphorylation without impairing transporter
      internalization.
AB  - The structural basis of phosphorylation and its putative role in internalization
      were investigated in the human dopamine transporter (hDAT). Activation of protein
      kinase C (PKC) was achieved either directly by treatment with 4-alpha-phorbol 12
      myristate 13-acetate (PMA) or by activating the Galpha(q)-coupled human substance
      P receptor (hNK-1) co-expressed with hDAT in HEK293 cells and in N2A
      neuroblastoma cells. In both cell lines, activation of the hNK-1 receptor by
      substance P reduced the V(max) for [(3)H]dopamine uptake to the same degree as
      did PMA ( approximately 50 and approximately 20% in HEK293 and N2A cells,
      respectively). In HEK293 cells, the reduction in transport capacity could be
      accounted for by internalization of the transporter, as assessed by cell surface
      biotinylation experiments, and by fluorescence microscopy using enhanced green
      fluorescent protein-tagged hDAT. In HEK293 cells, hNK-1 receptor activation, as
      well as direct PKC activation by PMA, was accompanied by a marked increase in
      transporter phosphorylation. However, truncation of the first 22 N-terminal
      residues almost abolished detectable phosphorylation without affecting the SP- or
      PMA-induced reduction in transport capacity and internalization. In this
      background truncation construct, systematic mutation of all the phosphorylation
      consensus serines and threonines in hDAT, alone and in various combinations, did
      also not alter the effect of hNK-1 receptor activation or PMA treatment in either
      HEK293 or N2A cells. Mutation of a dileucine and of two tyrosine-based motifs in
      hDAT was similarly without effect. We conclude that the major phosphorylation
      sites in hDAT are within the distal N terminus, which contains several serines.
      Moreover, the present data strongly suggest that neither this phosphorylation,
      nor the phosphorylation of any other sites within hDAT, is required for either
      receptor-mediated or direct PKC-mediated internalization of the hDAT.

PMID- 12464619
TI  - A new constitutively active brain PAK3 isoform displays modified specificities
      toward Rac and Cdc42 GTPases.
AB  - p21-activated kinases (PAK) are involved in the control of cytoskeleton dynamics
      and cell cycle progression. Here we report the characterization of a new
      mammalian PAK3 mRNA that contains a 45-bp alternatively spliced exon. This exon
      encodes for 15 amino acids that are inserted in the regulatory domain, inside the
      autoinhibitory domain but outside the Cdc42 and Rac interactive binding domain.
      The transcript of the 68-kDa new isoform named PAK3b is expressed in various
      areas of the adult mouse brain. In contrast to PAK3 without the exon b (PAK3a),
      whose basal kinase activity is weak in resting cells, PAK3b displays a high
      kinase activity in starved cells that is not further stimulated by active
      GTPases. Indeed, we demonstrate that the autoinhibitory domain of PAK3b no longer
      inhibits the kinase activity of PAK3. Moreover, we show that the 15-amino acid
      insertion within the autoinhibitory domain impedes the ability of PAK3b to bind
      to the GTPases Rac and Cdc42 and changes its specificity toward the GTPases.
      Altogether, our results show that the new PAK3b isoform has unique properties and
      would signal differently from PAK3a in neurons.

PMID- 12464620
TI  - Hypertonic stress increases T cell interleukin-2 expression through a mechanism
      that involves ATP release, P2 receptor, and p38 MAPK activation.
AB  - Hypertonic stress (HS) can alter the function of mammalian cells. We have
      reported that HS enhances differentiated responses of T cells by increasing their
      ability to produce interleukin (IL)-2, a finding of clinical interest because
      hypertonic infusions may modulate immune function in patients. HS shrinks cells
      and mechanically deforms membranes, which results in ATP release from many cell
      types. Here we investigate if ATP release is an underlying mechanism through
      which HS augments T cell function. We found that mechanical stress and HS induced
      rapid ATP release from Jurkat T cells. HS and exogenous ATP mobilized
      intracellular Ca(2+), activated p38 MAPK, and increased IL-2 expression. Ca(2+)
      mobilization was attenuated in the presence of EGTA or by removal of
      extracellular ATP with apyrase. Adenosine did not increase IL-2 expression, as
      did ATP. Apyrase, inhibition of P2 receptors, or inhibition of p38 MAPK with
      SB203580 reduced the stimulatory effects of HS, indicating that HS enhances IL-2
      expression through a mechanism that involves ATP release, P2 (perhaps P2X7)
      receptors, and p38 MAPK activation. We conclude that release of and response to
      ATP plays a key role in the mechanism through which hypertonic stress regulates
      the function of T cells.

PMID- 12464621
TI  - Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation
      of the docking protein Gab2.
AB  - We have previously demonstrated that phosphatidylinositol 3-kinase (PI3-kinase)
      is necessary and sufficient to account for epidermal growth factor (EGF)-induced
      mitogenesis in rat primary hepatocytes. A cytosolic Gab2-containing complex
      accounts for >80% of the total EGF-induced PI3-kinase activity (Kong, M.,
      Mounier, C., Wu, J., and Posner, B. I. (2000) J. Biol. Chem. 275, 36035-36042),
      suggesting a key role for Gab2 in EGF-induced mitogenesis. Here, we demonstrate
      that PP1, a selective inhibitor of Src family kinases, blocks the EGF-induced
      Gab2 tyrosine phosphorylation without inhibiting EGF-induced phosphorylation of
      the EGF receptor, ErbB3, or Shc. We also show that Gab2 phosphorylation is
      increased in Csk knockout cells in which Src family kinases are constitutively
      activated. Furthermore, PP1 blocks Gab2-associated downstream events including
      EGF-induced PI3-kinase activation, Akt phosphorylation, and DNA synthesis. We
      demonstrate that Gab2 and Src are constitutively associated. Since this
      association involves the proline-rich sequences of Gab2, it probably involves the
      Src homology 3 domain of Src kinase. Mutation of the proline-rich sequences in
      Gab2 prevented EGF-induced Gab2 phosphorylation, PI3-kinase/Akt activation, and
      DNA synthesis, demonstrating that Gab2 phosphorylation is critical for EGF
      induced mitogenesis and is not complemented by ErbB3 or Shc phosphorylation. We
      also found that overexpression of a Gab2 mutant lacking SHP2 binding sites
      increased EGF-induced Gab2 phosphorylation and the activation of PI3-kinase but
      blocked activation of MAPK. In addition, we demonstrated that the Src-induced
      response was down-regulated by Gab2-associated SHP2. In summary, our results have
      defined the role for Src activation in EGF-induced hepatic mitogenesis through
      the phosphorylation of Gab2 and the activation of the PI3-kinase cascade.

PMID- 12464622
TI  - A diverse family of inositol 5-phosphatases playing a role in growth and
      development in Dictyostelium discoideum.
AB  - Inositol phosphate-containing molecules play an important role in a broad range
      of cellular processes. Inositol 5-phosphatases participate in the regulation of
      these signaling molecules. We have identified four inositol 5-phosphatases in
      Dictyostelium discoideum, Dd5P1-4, showing a high diversity in domain
      composition. Dd5P1 possesses only a inositol 5-phosphatase catalytic domain. An
      unique domain composition is present in Dd5P2 containing a RCC1-like domain. RCC1
      has a seven-bladed propeller structure and interacts with G-proteins. Dd5P3 and
      Dd5P4 have a domain composition similar to human Synaptojanin with a SacI domain
      and OCRL with a RhoGAP domain, respectively. We have expressed the catalytic
      domains and show that these inositol 5-phosphatases have different substrate
      preferences. Single and double gene inactivation suggest a functional redundancy
      for Dd5P1, Dd5P2, and Dd5P3. Inactivation of the gene coding for Dd5P4 leads to
      defects in growth and development. These defects are restored by the expression
      of the complete protein but not by the 5-phosphatase catalytic domain.

PMID- 12464623
TI  - Cross-linking of surface IgM in the Burkitt's lymphoma cell line ST486 provides
      protection against arsenite- and stress-induced apoptosis that is mediated by ERK
      and phosphoinositide 3-kinase signaling pathways.
AB  - The ST486 cell line, derived from a human Burkitt's lymphoma, is a model for
      antigen-induced clonal deletion in germinal center B-lymphocytes, with apoptosis
      induced upon cross-linking of surface IgM. Moreover, this cell line is highly
      sensitive to the induction of apoptosis by many chemicals, including sodium
      arsenite, a significant environmental contaminant with immunotoxic activity. In
      contrast to arsenite and other chemicals, surface IgM cross-linking induces
      apoptosis in ST486 cells with delayed kinetics. Moreover, the initial signaling
      events following IgM stimulation are associated with cell survival and
      proliferation and include activation of the extracellular-signal regulated kinase
      (ERK) and the phosphoinositide 3-kinase (PI3K) pathways. We examined the question
      of whether IgM-mediated activation of the ERK and PI3K pathways can influence the
      apoptotic response of ST486 cells following exposure to arsenite and selected
      drugs with different molecular targets, including cycloheximide, etoposide, and
      camptothecin, and a physical stress, hyperthermia. Our findings show that IgM
      stimulated cells are significantly protected against arsenite and drug-induced
      apoptosis during a window of several hours after surface IgM cross-linking, as
      evidenced by an inhibition of cleavage of poly(ADP-ribose) polymerase and lack of
      morphological changes indicative of apoptosis. Significantly, surface IgM cross
      linking also protects against arsenite-induced mitochondrial depolarization as
      well as caspase-9 cleavage. Furthermore, we demonstrate that this IgM-mediated
      protection requires the activation of the ERK and PI3K pathways, because
      inhibition of either pathway blocks the ability of antigen receptor activation to
      protect against apoptosis. Our study also provides evidence for p90(S6) ribosomal
      kinase as a point of convergence between the two signaling pathways resulting in
      the phosphorylation of the pro-apoptotic Bcl-2 family member Bad at serine 112.
      This investigation demonstrates, for the first time, that specific signals
      transduced by activation of the B-cell receptor protect cells at a common point
      of regulation in the apoptotic pathways for diverse stresses.

PMID- 12464624
TI  - Chimeric photosynthetic reaction center complex of purple bacteria composed of
      the core subunits of Rubrivivax gelatinosus and the cytochrome subunit of
      Blastochloris viridis.
AB  - A gene coding for the photosynthetic reaction center-bound cytochrome subunit,
      pufC, of Blastochloris viridis, which belongs to the alpha-purple bacteria, was
      introduced into Rubrivivax gelatinosus, which belongs to the beta-purple
      bacteria. The cytochrome subunit of B. viridis was synthesized in the R.
      gelatinosus cells, in which the native pufC gene was knocked out, and formed a
      chimeric reaction center (RC) complex together with other subunits of R.
      gelatinosus. The transformant was able to grow photosynthetically. Rapid photo
      oxidization of the hemes in the cytochrome subunit was observed in the membrane
      of the transformant. The soluble electron carrier, cytochrome c(2), isolated from
      B. viridis was a good electron donor to the chimeric RC. The redox midpoint
      potentials and the redox difference spectra of four hemes in the cytochrome
      subunit of the chimeric RC were almost identical with those in the B. viridis RC.
      The cytochrome subunit of B. viridis seems to retain its structure and function
      in the R. gelatinosus cell. The chimeric RC and its mutagenesis system should be
      useful for further studies about the cytochrome subunit of B. viridis.

PMID- 12464625
TI  - Interactions of substrate with calreticulin, an endoplasmic reticulum chaperone.
AB  - Calreticulin is a molecular chaperone found in the endoplasmic reticulum in
      eukaryotes, and its interaction with N-glycosylated polypeptides is mediated by
      the glycan Glc(1)Man(7-9)GlcNAc(2) present on the target glycoproteins. Here, we
      report the thermodynamic parameters of its interaction with di-, tri-, and
      tetrasaccharide, which are truncated versions of the glucosylated arm of
      Glc(1)Man(7-9)GlcNAc(2), determined by the quantitative technique of isothermal
      titration calorimetry. This method provides a direct estimate of the binding
      constants (K(b)) and changes in enthalpy of binding (Delta H(b) degrees ) as well
      as the stoichiometry of the reaction. Unlike past speculations, these studies
      demonstrate unambiguously that calreticulin has only one site per molecule for
      binding its complementary glucosylated ligands. Although the binding of glucose
      by itself is not detectable, a binding constant of 4.19 x 10(4) m(-1) at 279 K is
      obtained when glucose occurs in alpha-1,3 linkage to Man alpha Me as in Glc alpha
      1-3Man alpha Me. The binding constant increases by 25-fold from di- to
      trisaccharide and doubles from tri- to tetrasaccharide, demonstrating that the
      entire Glc alpha 1-3Man alpha 1-2Man alpha 1-2Man alpha Me structure of the
      oligosaccharide is recognized by calreticulin. The thermodynamic parameters thus
      obtained were supported by modeling studies, which showed that increased number
      of hydrogen bonds and van der Waals interactions occur as the size of the
      oligosaccharide is increased. Also, several novel findings about the recognition
      of saccharide ligands by calreticulin vis a vis legume lectins, which have the
      same fold as this chaperone, are discussed.

PMID- 12464626
TI  - Transcriptional regulation of the rat NHE3 gene. Functional interactions between
      GATA-5 and Sp family transcription factors.
AB  - Expression of sodium-hydrogen exchanger isoform 3 (NHE3) in the intestinal and
      renal epithelium plays a critical role in sodium absorption and acid/base
      homeostasis. To decipher rat NHE3 gene regulation, its cis-acting regulatory
      elements and associated transcription factors were characterized by transient
      transfection of Caco-2, IEC-6, Qt6, and Drosophila SL2 cells. Deletion and
      mutational analyses demonstrated that the atypical TATA box located at bp -26/-31
      was not necessary for promoter activity, and that a -20/+8-bp fragment represents
      a functional initiator. Within the 81-bp upstream region, three Sp transcription
      factor binding sites were critical because their mutation drastically reduced
      promoter activity. The roles of Sp1 and Sp3 were further demonstrated by
      electromobility shift assay and by transactivation of the NHE3 promoter in SL2
      cells by forced expression of Sp1 and Sp3. Both of these transcription factors
      were found to act synergistically with GATA-5 bound to a GATA box in exon 1
      (+20/+23 bp). These studies demonstrate that rat NHE3 promoter is initiator
      driven and controlled mainly by Sp1 and Sp3, which functionally interact with
      GATA-5. This interaction represents a novel regulatory mechanism, which is likely
      to participate in a gradient of intestinal gene expression along the crypt-villus
      axis.

PMID- 12464627
TI  - Localization, topology, and function of the LCB1 subunit of serine
      palmitoyltransferase in mammalian cells.
AB  - Serine palmitoyltransferase (SPT), the enzyme catalyzing the initial step in the
      biosynthesis of sphingolipids, comprises two different subunits, LCB1 and LCB2.
      LCB1 has a single highly hydrophobic domain near the N terminus. Chinese hamster
      ovary cell mutant LY-B cells are defective in SPT activity because of the lack of
      expression of an endogenous LCB1 subunit. Stable expression of LCB1 having an
      epitope tag at either the N or C terminus restored SPT activity of LY-B cells,
      suggesting that the epitope tag did not affect the localization or topology of
      LCB1. Indirect immunostaining showed that the N- and C-terminal epitopes are
      oriented toward the lumenal and cytosol side, respectively, at the endoplasmic
      reticulum. Interestingly, there was far less LCB2 in LY-B cells than in wild-type
      cells, and the amount of LCB2 in LY-B cells was restored to the wild-type level
      by transfection with LCB1 cDNA. In addition, overproduction of the LCB2 subunit
      required co-overproduction of the LCB1 subunit. These results indicated that the
      LCB1 subunit is most likely an integral protein having a single transmembrane
      domain with a lumenal orientation of its N terminus in the endoplasmic reticulum
      and that the LCB1 subunit is indispensable for the maintenance of the LCB2
      subunit in mammalian cells.

PMID- 12464628
TI  - Neuronal migration and molecular conservation with leukocyte chemotaxis.

PMID- 12464629
TI  - A common mechanism for mitotic inactivation of C2H2 zinc finger DNA-binding
      domains.
AB  - Many nuclear proteins are inactivated during mitotic entry, presumably as a
      prerequisite to chromatin condensation and cell division. C2H2 zinc fingers
      define the largest transcription factor family in the human proteome. The linker
      separating finger motifs is highly conserved and resembles TGEKP in more than
      5000 occurrences. However, the reason for this conservation is not fully
      understood. We demonstrate that all three linkers in the DNA-binding domain of
      Ikaros are phosphorylated during mitosis. Phosphomimetic substitutions abolished
      DNA-binding and pericentromeric localization. A linker within Sp1 was also
      phosphorylated, suggesting that linker phosphorylation provides a global
      mechanism for inactivation of the C2H2 family.

PMID- 12464630
TI  - A nucleolar mechanism controlling cell proliferation in stem cells and cancer
      cells.
AB  - The unique property of stem cells to self-renew suggests specific mechanisms that
      regulate their cell-cycle progression. In the present study, we identify a novel
      protein, nucleostemin, found in the nucleoli of CNS stem cells, embryonic stem
      cells, and several cancer cell lines and preferentially expressed by other stem
      cell-enriched populations. It contains an N-terminal basic domain and two GTP
      binding motifs. When stem cells differentiate, nucleostemin expression decreases
      rapidly prior to cell-cycle exit both in vitro and in vivo. Depletion or
      overexpression of nucleostemin reduces cell proliferation in CNS stem cells and
      transformed cells. Mutation analysis indicates that excessive nucleostemin,
      particularly mutants that lack the GTP-regulatory domain, prevents cells from
      entering mitosis and causes apoptosis in a p53-dependent manner. The N-terminal
      basic domain specifies nucleolar localization, the p53 interaction, and is
      required for the cell death caused by overexpression. This work describes a novel
      nucleolar mechanism that controls the cell-cycle progression in CNS stem cells
      and cancer cells.

PMID- 12464631
TI  - Cohesin release is required for sister chromatid resolution, but not for
      condensin-mediated compaction, at the onset of mitosis.
AB  - The establishment of metaphase chromosomes is an essential prerequisite of sister
      chromatid separation in anaphase. It involves the coordinated action of cohesin
      and condensin, protein complexes that mediate cohesion and condensation,
      respectively. In metazoans, most cohesin dissociates from chromatin at prophase,
      coincident with association of condensin. Whether loosening of cohesion at the
      onset of mitosis facilitates the compaction process, resolution of the sister
      chromatids, or both, remains unknown. We have found that the prophase release of
      cohesin is completely blocked when two mitotic kinases, aurora B and polo-like
      kinase (Plx1), are simultaneously depleted from Xenopus egg extracts. Condensin
      loading onto chromatin is not affected under this condition, and rod-shaped
      chromosomes are produced that show an apparently normal level of compaction.
      However, the resolution of sister chromatids within these chromosomes is severely
      compromised. This is not because of inhibition of topoisomerase II activity that
      is also required for the resolution process. We propose that aurora B and Plx1
      cooperate to destabilize the sister chromatid linkage through distinct mechanisms
      that may involve phosphorylation of histone H3 and cohesin, respectively. More
      importantly, our results strongly suggest that cohesin release at the onset of
      mitosis is essential for sister chromatid resolution but not for condensin
      mediated compaction.

PMID- 12464632
TI  - Complex transcriptional circuitry at the G1/S transition in Saccharomyces
      cerevisiae.
AB  - In the yeast Saccharomyces cerevisiae, SBF (Swi4-Swi6 cell cycle box binding
      factor) and MBF (MluI binding factor) are the major transcription factors
      regulating the START of the cell cycle, a time just before DNA replication, bud
      growth initiation, and spindle pole body (SPB) duplication. These two factors
      bind to the promoters of 235 genes, but bind less than a quarter of the promoters
      upstream of genes with peak transcript levels at the G1 phase of the cell cycle.
      Several functional categories, which are known to be crucial for G1/S events,
      such as SPB duplication/migration and DNA synthesis, are under-represented in the
      list of SBF and MBF gene targets. SBF binds the promoters of several other
      transcription factors, including HCM1, PLM2, POG1, TOS4, TOS8, TYE7, YAP5, YHP1,
      and YOX1. Here, we demonstrate that these factors are targets of SBF using an
      independent assay. To further elucidate the transcriptional circuitry that
      regulates the G1-to-S-phase progression, these factors were epitope-tagged and
      their binding targets were identified by chIp-chip analysis. These factors bind
      the promoters of genes with roles in G1/S events including DNA replication, bud
      growth, and spindle pole complex formation, as well as the general activities of
      mitochondrial function, transcription, and protein synthesis. Although functional
      overlap exists between these factors and MBF and SBF, each of these factors has
      distinct functional roles. Most of these factors bind the promoters of other
      transcription factors known to be cell cycle regulated or known to be important
      for cell cycle progression and differentiation processes indicating that a
      complex network of transcription factors coordinates the diverse activities that
      initiate a new cell cycle.

PMID- 12464633
TI  - Conserved homeodomain proteins interact with MADS box protein Mcm1 to restrict
      ECB-dependent transcription to the M/G1 phase of the cell cycle.
AB  - Two homeodomain proteins, Yox1 and Yhp1, act as repressors at early cell cycle
      boxes (ECBs) to restrict their activity to the M/G1 phase of the cell cycle in
      budding yeast. These proteins bind to Mcm1 and to a typical homeodomain binding
      site. The expression of Yox1 is periodic and directly correlated with its binding
      to, and repression of, ECB activity. The absence of Yox1 and Yhp1 or the
      constitutive expression of Yox1 leads to the loss of cell-cycle regulation of ECB
      activity. Therefore, the cell-cycle-regulated expression of these repressors
      defines the interval of ECB-dependent transcription. Twenty-eight genes,
      including MCM2-7, CDC6, SWI4, CLN3, and a number of genes required during late M
      phase have been identified that are coordinately regulated by this pathway.

PMID- 12464634
TI  - Cell identity and sexual development in Cryptococcus neoformans are controlled by
      the mating-type-specific homeodomain protein Sxi1alpha.
AB  - Virulence in the human fungal pathogen Cryptococcus neoformans is associated with
      the alpha mating type. Studies to identify the properties of alpha cells that
      enhance pathogenesis have led to the identification of a mating-type locus of
      unusually large size and distinct architecture. Here, we demonstrate that the
      previously identified MATalpha components are insufficient to regulate sexual
      differentiation, and we identify a novel alpha-specific regulator, SXI1alpha. Our
      data show that SXI1alpha establishes alpha cell identity and controls progression
      through the sexual cycle, and we discover that ectopic expression of SXI1alpha in
      a cells is sufficient to drive a/alpha sexual development. SXI1alpha is the first
      example of a key regulator of cell identity and sexual differentiation in C.
      neoformans, and its identification and characterization lead to a new model of
      how cell fate and the sexual cycle are controlled in C. neoformans.

PMID- 12464635
TI  - The DAF-7 TGF-beta signaling pathway regulates chemosensory receptor gene
      expression in C. elegans.
AB  - Regulation of chemoreceptor gene expression in response to environmental or
      developmental cues provides a mechanism by which animals can alter their sensory
      responses. Here we demonstrate a role for the daf-7 TGF-beta pathway in the
      regulation of expression of a subset of chemoreceptor genes in Caenorhabditis
      elegans. We describe a novel role of this pathway in maintaining receptor gene
      expression in the adult and show that the DAF-4 type II TGF-beta receptor
      functions cell-autonomously to modulate chemoreceptor expression. We also find
      that the alteration of receptor gene expression in the ASI chemosensory neurons
      by environmental signals, such as levels of a constitutively produced pheromone,
      may be mediated via a DAF-7-independent pathway. Receptor gene expression in the
      ASI and ASH sensory neurons appears to be regulated via distinct mechanisms. Our
      results suggest that the expression of individual chemoreceptor genes in C.
      elegans is subject to multiple modes of regulation, thereby ensuring that animals
      exhibit the responses most appropriate for their developmental stage and
      environmental conditions.

PMID- 12464636
TI  - CD44 is required for two consecutive steps in HGF/c-Met signaling.
AB  - The tyrosine kinase receptor c-Met and its ligand HGF/SF, ezrin, and splice
      variants of CD44 have independently been identified as tumor metastasis
      associated proteins. We now show that these proteins cooperate. A CD44 isoform
      containing variant exon v6 sequences is strictly required for c-Met activation by
      HGF/SF in rat and human carcinoma cells, in established cell lines as well as in
      primary keratinocytes. CD44v6-deficient tumor cells were unable to activate c-Met
      unless they were transfected with a CD44v6-bearing isoform. Antibodies to two v6
      encoded epitopes inhibited autophosphorylation of c-Met by interfering with the
      formation of a complex formed by c-Met, CD44v6, and HGF/SF. In addition, signal
      transduction from activated c-Met to MEK and Erk required the presence of the
      cytoplasmic tail of CD44 including a binding motif for ERM proteins. This
      suggests a role for ERM proteins and possibly their link to the cortical actin
      cytoskeleton in signal transfer.

PMID- 12464637
TI  - ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5'UTR.
AB  - p27Kip1 restrains cell proliferation by binding to and inhibiting cyclin
      dependent kinases. To investigate the mechanisms of p27 translational regulation,
      we isolated a complete p27 cDNA and identified an internal ribosomal entry site
      (IRES) located in its 5'UTR. The IRES allows for efficient p27 translation under
      conditions where cap-dependent translation is reduced. Searching for possible
      regulators of IRES activity we have identified the neuronal ELAV protein HuD as a
      specific binding factor of the p27 5'UTR. Increased expression of HuD or the
      ubiquitously expressed HuR protein specifically inhibits p27 translation and p27
      IRES activity. Consistent with an inhibitory role of Hu proteins in p27
      translation, siRNA mediated knockdown of HuR induced endogenous p27 protein
      levels as well as IRES-mediated reporter translation and leads to cell cycle
      arrest in G1.

PMID- 12464638
TI  - Trp-dependent auxin biosynthesis in Arabidopsis: involvement of cytochrome P450s
      CYP79B2 and CYP79B3.
AB  - The plant hormone auxin regulates many aspects of plant growth and development.
      Although several auxin biosynthetic pathways have been proposed, none of these
      pathways has been precisely defined at the molecular level. Here we provide in
      planta evidence that the two Arabidopsis cytochrome P450s, CYP79B2 and CYP79B3,
      which convert tryptophan (Trp) to indole-3-acetaldoxime (IAOx) in vitro, are
      critical enzymes in auxin biosynthesis in vivo. IAOx is thus implicated as an
      important intermediate in auxin biosynthesis. Plants overexpressing CYP79B2
      contain elevated levels of free auxin and display auxin overproduction
      phenotypes. Conversely, cyp79B2 cyp79B3 double mutants have reduced levels of IAA
      and show growth defects consistent with partial auxin deficiency. Together with
      previous work on YUCCA, a flavin monooxygenase also implicated in IAOx
      production, and nitrilases that convert indole-3-acetonitrile to auxin, this work
      provides a framework for further dissecting auxin biosynthetic pathways and their
      regulation.

PMID- 12464639
TI  - New agents for cancer prevention.

PMID- 12464640
TI  - Regulation of Epstein-Barr virus lytic cycle activation in malignant and
      nonmalignant disease.

PMID- 12464641
TI  - Investing in prevention: what incentive does the pharmaceutical industry have?

PMID- 12464642
TI  - For Bexxar, FDA meeting offers long-awaited chance at approval.

PMID- 12464643
TI  - Studies expand potential uses of photodynamic therapy.

PMID- 12464644
TI  - Stat Bite: Leading Causes of Death in the United States, 1973 vs. 1999.

PMID- 12464645
TI  - Melanoma treatment activates immune system against cancer.

PMID- 12464646
TI  - Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class
      of apoptosis-inducing agents.
AB  - BACKGROUND: The cyclooxygenase-2 (COX-2) inhibitor celecoxib is thought to act as
      a chemopreventive agent by sensitizing cancer cells to apoptotic signals. Other
      COX-2 inhibitors, such as rofecoxib, are two orders of magnitude less potent than
      celecoxib at inducing apoptosis. The molecular structures of celecoxib and
      rofecoxib were used as starting points to examine the structural features that
      contribute to this discrepancy. METHODS: We used a systematic chemical approach
      to modify the structures of celecoxib and rofecoxib to produce a series of
      compounds that were tested for their effects on the viability of human prostate
      cancer PC-3 cells and their ability to induce apoptosis in these cells. Cell
      viability was measured by the trypan blue dye exclusion assay, and apoptosis was
      measured by an enzyme-linked immunosorbent assay that quantifies DNA cleavage and
      by western blot detection of poly(ADP-ribose) polymerase (PARP) cleavage. Western
      blotting was used to monitor the effects of the compounds on phosphorylation of
      the serine/threonine kinase Akt and extracellular signal-regulated kinase 2
      (ERK2), two components of celecoxib-induced apoptosis signaling. Monte Carlo
      simulations were used to molecularly model the surface electrostatic potential
      and electron density of selected compounds. All statistical tests were two-sided.
      RESULTS: The structural requirements for the induction of apoptosis in PC-3 cells
      were different from those for COX-2 inhibition. Structure-function analysis
      indicated that the induction of apoptosis by compounds derived from COX-2
      inhibitors required a bulky terminal phenyl ring, a heterocyclic system with
      negative electrostatic potential, and a benzenesulfonamide or benzenecarboxamide
      moiety. These derivatives mediated apoptosis by facilitating the
      dephosphorylation of Akt and ERK2, irrespective of their COX-2 inhibitory
      activities. CONCLUSION: A new class of compounds that induce apoptosis by
      targeting Akt and ERK2 signaling pathways in human prostate cancer cells can be
      synthesized by modifying existing COX-2 inhibitors.

PMID- 12464647
TI  - Discrete alterations in the BZLF1 promoter in tumor and non-tumor-associated
      Epstein-Barr virus.
AB  - BACKGROUND: Although the Epstein-Barr virus (EBV) is associated with malignant
      and nonmalignant diseases, its lytic replication is predominantly associated with
      nonmalignant diseases such as acute infectious mononucleosis (IM) or chronic
      active EBV infection. Lytic replication is also associated with type B EBV more
      than with type A EBV. Sustained lytic replication, however, is not compatible
      with tumor growth. We investigated whether control of an EBV lytic regulatory
      gene, BZLF1, differed in these diseases. METHODS: Polymerase chain reaction
      single-strand conformation polymorphism (PCR-SSCP) and direct DNA sequence
      analyses were used to characterize the promoter sequence of BZLF1 (Zp) in 52
      tumors (34 non-Hodgkin's lymphomas, 13 post-transplant lymphoproliferative
      disease samples, and five nasopharyngeal carcinomas), and in peripheral blood
      lymphocytes from seven patients with chronic active EBV, six with IM, and 40
      healthy, EBV-seropositive individuals. All sequences were compared with the
      prototype EBV strain B95.8 sequence. All statistical tests were two-sided.
      RESULTS: Three polymorphic Zp sequences were detected. Among the malignant
      samples, sequence Zp-P, associated with 84% of type A EBV, was identical to that
      of EBV strain B95.8, whereas a second sequence (Zp-V3), associated exclusively
      with type B EBV (P<.001), contained three base substitutions. Among the
      nonmalignant samples, a distinct polymorphism, Zp-V4, containing the
      substitutions detected in Zp-V3 and an additional base change, was identified in
      all samples from chronic active EBV, IM, and healthy individuals, but in none of
      the malignant samples (P<.001). Zp-V4 was independent of the EBV type.
      CONCLUSIONS: Polymorphisms in the regulatory sequences of BZLF1 are
      differentially distributed among malignant and nonmalignant cells and may
      identify EBV subtypes with various lytic activities, including those not
      associated with malignancies.

PMID- 12464648
TI  - Baseline findings of the Italian multicenter randomized controlled trial of "once
      only sigmoidoscopy"--SCORE.
AB  - BACKGROUND: A single sigmoidoscopy examination at around age 60 years has been
      proposed as a cost-effective strategy to prevent colorectal cancer. A multicenter
      randomized controlled trial, the SCORE trial, is in progress in Italy to estimate
      the impact of this strategy on colorectal cancer incidence and mortality and the
      duration of the protective effect. We present the baseline screening outcomes.
      METHODS: A questionnaire was mailed to a random sample of 236 568 people aged 55
      64 years to assess their eligibility for and interest in screening. Those
      reporting a history of colorectal cancer, adenomas, inflammatory bowel disease,
      recent colorectal endoscopy, or two first-degree relatives with colorectal cancer
      were excluded. Eligible, interested respondents were assigned randomly to the
      control group (no further contact) or the intervention group (invitation to
      undergo sigmoidoscopy). Screenees with colorectal cancer, polyps larger than 5
      mm, three or more adenomas, adenomas 5 mm or smaller with a villous component of
      more than 20%, or severe dysplasia were referred for colonoscopy. RESULTS: Of the
      56 532 respondents (23.9% of those invited), 34 292 were enrolled and 17 148 were
      assigned to the screening group. Of those, 9999 attended and 9911 were actually
      examined by sigmoidoscopy. Distal adenomas were detected in 1070 subjects
      (10.8%). Proximal adenomas were detected in 116 of 747 (15.5%) subjects without
      cancer at sigmoidoscopy who then underwent colonoscopy. A total of 54 subjects
      was found to have colorectal cancer, a rate of 5.4 per 1000 (54% of which were
      Dukes' A). The procedures were relatively safe, with two perforations (one in
      9911 sigmoidoscopy exams and one in 775 colonoscopies) and one hemorrhage
      requiring hospitalization after polypectomy during colonoscopy. The pain
      associated with sigmoidoscopy was described as mild or less than expected by
      83.3% of the screenees. CONCLUSION: Sigmoidoscopy screening is generally
      acceptable to recipients and safe. The high yield of advanced adenomas is
      consistent with the projected impact of sigmoidoscopy screening on colorectal
      cancer incidence.

PMID- 12464649
TI  - Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation
      carriers.
AB  - BACKGROUND: Oral contraceptive use has been associated with an increase in the
      risk of breast cancer in young women. We examined whether this association is
      seen in women at high risk of breast cancer because they carry a mutation in one
      of two breast cancer susceptibility genes, BRCA1 and BRCA2. METHODS: We performed
      a matched case-control study on 1311 pairs of women with known deleterious BRCA1
      and/or BRCA2 mutations recruited from 52 centers in 11 countries. Women who had
      been diagnosed with breast cancer were matched to control subjects by year of
      birth, country of residence, mutation (BRCA1 or BRCA2), and history of ovarian
      cancer. All study subjects completed a questionnaire about oral contraceptive
      use. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by
      conditional logistic regression. All statistical tests were two-sided. RESULTS:
      Among BRCA2 mutation carriers, ever use of oral contraceptives was not associated
      with an increased risk of breast cancer (OR = 0.94, 95% CI = 0.72 to 1.24). For
      BRCA1 mutation carriers, ever use of oral contraceptives was associated with a
      modestly increased risk of breast cancer (OR = 1.20, 95% CI = 1.02 to 1.40).
      However, compared with BRCA1 mutation carriers who never used oral
      contraceptives, those who used oral contraceptives for at least 5 years had an
      increased risk of breast cancer (OR = 1.33, 95% CI = 1.11 to 1.60), as did those
      who used oral contraceptives before age 30 (OR = 1.29, 95% CI = 1.09 to 1.52),
      those who were diagnosed with breast cancer before age 40 (OR = 1.38, 95% CI =
      1.11 to 1.72), and those who first used oral contraceptives before 1975 (OR =
      1.42, 95% CI = 1.17 to 1.75). CONCLUSIONS: Among BRCA1 mutation carriers, women
      who first used oral contraceptives before 1975, who used them before age 30, or
      who used them for 5 or more years may have an increased risk of early-onset
      breast cancer. Oral contraceptives do not appear to be associated with risk of
      breast cancer in BRCA2 carriers, but data for BRCA2 carriers are limited.

PMID- 12464650
TI  - Association of HLA class I and II alleles and extended haplotypes with
      nasopharyngeal carcinoma in Taiwan.
AB  - BACKGROUND: Nasopharyngeal carcinoma (NPC), which occurs at a disproportionately
      high rate among Chinese individuals, is associated with Epstein-Barr virus (EBV).
      Human leukocyte antigen (HLA) polymorphisms appear to play a role in NPC, because
      they are essential in the immune response to viruses. We used high-resolution HLA
      genotyping in a case-control study in Taiwan to systematically evaluate the
      association between various HLA alleles and NPC. METHODS: We matched 366 NPC case
      patients to 318 control subjects by age, sex, and geographic residence.
      Participants were interviewed and provided blood samples for genotyping. High
      resolution (polymerase chain reaction-based) genotyping of HLA class I (A and B)
      and II (DRB1, DQA1, DQB1, and DPB1) genes was performed in two phases. In phase
      I, 210 case patients and 183 control subjects were completely genotyped. In phase
      II, alleles associated with NPC in the phase I analysis were evaluated in another
      156 case patients and 135 control subjects. Extended haplotypes were inferred.
      RESULTS: We found a consistent association between HLA-A*0207 (common among
      Chinese but not among Caucasians) and NPC (odds ratio [OR] = 2.3, 95% confidence
      interval [CI] = 1.5 to 3.5) but not between HLA-A*0201 (most common HLA-A2 allele
      in Caucasians) and NPC (OR = 0.79, 95% CI = 0.55 to 1.2). Individuals with HLA
      B*4601, which is in linkage disequilibrium with HLA-A*0207, had an increased risk
      for NPC (OR = 1.8, 95% CI = 1.2 to 2.5) as did individuals with HLA-A*0207 and
      HLA-B*4601 (OR = 2.8, 95% CI = 1.7 to 4.4). Individuals homozygous for HLA-A*1101
      had decreased risks for NPC (OR = 0.24, 95% CI = 0.13 to 0.46). The extended
      haplotype HLA-A*3303-B*5801/2-DRB1*0301-DQB1*0201/2-DPB1*0401, specific to this
      ethnic group, was associated with a statistically significantly increased risk
      for NPC (OR = 2.6, 95% CI = 1.1 to 6.4). CONCLUSIONS: The restriction of the
      association of HLA-A2 with NPC to HLA-A*0207 probably explains previously
      observed associations of HLA-A2 with NPC among Chinese but not Caucasians. The
      extended haplotypes associated with NPC might, in part, explain the higher rates
      of NPC in this ethnic group.

PMID- 12464651
TI  - In vivo antitumor activity of Sindbis viral vectors.
AB  - BACKGROUND: Sindbis virus, a blood-borne virus transmitted by mosquitoes, has
      been used as a vector to efficiently express exogenous genes in vitro and in vivo
      and to induce apoptosis. Because Sindbis virus infects mammalian cells by
      interacting with the high-affinity laminin receptors, which are expressed at
      higher levels in several human cancers than in normal cells, we determined
      whether a Sindbis viral vector could be used to target cancers in vivo. METHODS:
      C.B-17-SCID mice with established xenografts were given daily intraperitoneal
      injections of the Sindbis viral vector SinRep/LacZ containing the bacterial beta
      galactosidase gene. Control mice were untreated or received injections with
      phosphate-buffered saline. Tumor size was measured daily. Expression of beta
      galactosidase and Factor VIII (a marker for endothelial cells) was determined by
      immunohistochemical staining of tumor sections. Apoptosis was analyzed by TUNEL
      (terminal deoxynucleotidyl transferase [TdT]-mediated dUTP nick end labeling)
      staining. C.B-17-SCID beige mice, which lack natural killer (NK) cells, were used
      to assess the importance of NK cells in antitumor efficacy of Sindbis viral
      vectors. RESULTS: Tumors from mice treated with SinRep/LacZ were statistically
      significantly smaller than tumors from control mice. This effect was observed for
      tumor xenografts derived from BHK (kidney, hamster), LS174T (colon, human), HT29
      (colon, human), and CFPAC (pancreas, human) cells. Expression of beta
      galactosidase co-localized with that of Factor VIII in tumor sections. Tumors
      from SinRep/LacZ-treated mice contained more apoptotic cells than tumors from
      control mice. Complete tumor regression was observed in three of five C.B-17-SCID
      mice but in none of five C.B-17-SCID beige mice treated with SinRep/LacZ.
      CONCLUSION: Sindbis viral vectors efficiently targeted tumors in vivo, were
      apparently delivered through the circulation, and were more effective in the
      presence of NK cells.

PMID- 12464652
TI  - HDM2 protein overexpression and prognosis in primary malignant melanoma.
AB  - Overexpression of the oncogene HDM2 is observed in a substantial proportion of
      melanomas, including noninvasive and thin lesions, suggesting that HDM2
      overexpression may be an early event in melanocyte transformation. To determine
      the role of HDM2 in the clinical progression of melanoma, we examined whether its
      expression was associated with patient survival. From November 1972 through
      November 1982, 134 patients with melanoma who participated in the New York
      University Melanoma Cooperative Group were studied, if representative tissues and
      follow-up were available. HDM2 protein expression was assessed
      immunohistochemically. Unexpectedly, we observed that HDM2 overexpression was
      statistically significantly associated with improved disease-free survival
      (relative risk [RR] = 0.47, 95% confidence interval [CI] = 0.24 to 0.89; two
      sided chi(2) P =.021) and overall survival (RR = 0.55, 95% CI = 0.33 to 0.94; two
      sided chi(2) P =.027) in multivariable analysis. HDM2 overexpression appears to
      be an independent predictor of survival for patients with primary melanoma;
      however, larger prospective studies are required for validation.

PMID- 12464653
TI  - Re: Population-based, case-control study of HER2 genetic polymorphism and breast
      cancer risk.

PMID- 12464654
TI  - HER-2/neu oncogene sequence revisited.

PMID- 12464656
TI  - Re: Loss of imprinting of insulin-like growth factor-II (IGF2) gene in
      distinguishing specific biologic subtypes of Wilms tumor.

PMID- 12464657
TI  - Re: Systematic review of psychological therapies for cancer patients: overview
      and recommendations for future research.

PMID- 12464659
TI  - Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces
      mitochondrial injury.

PMID- 12464660
TI  - Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and
      prospects for therapy.

PMID- 12464661
TI  - Rescuing protein conformation: prospects for pharmacological therapy in cystic
      fibrosis.

PMID- 12464662
TI  - Alternative treatment for secretory diarrhea revealed in a new class of CFTR
      inhibitors.

PMID- 12464663
TI  - Neutrophils and lung injury: getting it right.

PMID- 12464664
TI  - Fatty acid oxidation in human skeletal muscle.

PMID- 12464665
TI  - Fatal attraction: chemokines and type 1 diabetes.

PMID- 12464666
TI  - Getting Tie(2)d up in angiogenesis.

PMID- 12464667
TI  - Recombinant angiopoietin-1 restores higher-order architecture of growing blood
      vessels in mice in the absence of mural cells.
AB  - Interactions between endothelial cells (ECs) and perivascular mural cells (MCs)
      via signaling molecules or physical contacts are implicated both in vascular
      remodeling and maintenance of vascular integrity. However, it remains unclear how
      MCs regulate the morphogenic activity of ECs to form an organized vascular
      architecture, comprising distinct artery, vein, and capillary, from a simple mesh
      like network. A clear elucidation of this question requires an experimental model
      system in which ECs are separated from MCs and yet form vascular structures. Here
      we report that injection of an antagonistic mAb against PDGFR-beta into murine
      neonates provides such an experimental system in the retina by completely
      blocking MC recruitment to developing vessels. While a vascular network was
      formed even in the absence of MCs, it was poorly remodeled and leaky. Using this
      vascular system ideal for direct assessment of the activities of MC-derived
      molecules, we show that addition of recombinant modified angiopoietin-1 restored
      a hierarchical vasculature, and also rescued retinal edema and hemorrhage in the
      complete absence of MCs. These observations demonstrate the potential of Ang1 as
      a new therapeutic modality for MC dropout in diseases such as diabetic
      retinopathies.

PMID- 12464668
TI  - Epimorphin expression in intestinal myofibroblasts induces epithelial
      morphogenesis.
AB  - The formation of the crypt-villus axis during gut ontogeny requires continued
      reciprocal interactions between the endoderm and mesenchyme. Epimorphin/syntaxin
      2 (epimorphin) is a mesenchymal protein expressed in the fetal gastrointestinal
      tract during villus morphogenesis. To elucidate its role in gut ontogeny, the
      epimorphin cDNA was transfected, in sense and antisense orientations, into a rat
      intestinal myofibroblast cell line, MIC 216. To determine the effects of
      epimorphin on the epithelium, myofibroblasts were cocultured with the Caco2 cell
      line. Caco2 cells spread in a simple monolayer over antisense-transfected cells
      lacking epimorphin. In contrast, sense-transfected myofibroblasts induced Caco2
      cells to form compact, round clusters with small lumens. These morphologic
      differences were preserved in Transwell cocultures in which cell-cell contact was
      prevented, suggesting that epimorphin's effects were mediated by secreted
      factor(s). To determine the effects of epimorphin on crypt-villus axis formation
      in an in vivo model, rat gut endoderm was combined with epimorphin-transfected
      myofibroblasts and implanted into the chick intracoelomic cavity. The grafts in
      which epimorphin was overexpressed revealed multiple well-formed villi with crypt
      like units, whereas those in which epimorphin expression was inhibited developed
      into round cystic structures without crypts or villi. Of several potential
      secreted morphogens, only the expression of bone morphogenetic protein 4 (Bmp4)
      was increased in the epimorphin-transfected cells. Incubation with noggin
      partially blocked the transfected myofibroblasts' effects on Caco2 colony
      morphology. These results indicate that mesenchymal epimorphin has profound
      effects on crypt-villus morphogenesis, mediated in part by secreted factor(s)
      including the Bmp's.

PMID- 12464669
TI  - Increased production of IL-7 uncouples bone formation from bone resorption during
      estrogen deficiency.
AB  - Postmenopausal bone loss stems from the inability of osteoblastic activity to
      match the increase in osteoclastic bone resorption induced by estrogen
      deficiency. However, the mechanism that uncouples osteoblast from osteoclast
      activities remains unexplained. We show that ovariectomy enhances the production
      of the osteoclastogenic cytokine IL-7, and that its neutralization in vivo
      prevents ovariectomy-induced bone loss. Surprisingly, serum osteocalcin levels, a
      biochemical marker of bone formation, suggested that the bone-sparing effects of
      IL-7 neutralization were due not only to inhibition of bone resorption, but also
      to stimulation of bone formation. Consistent with these data, addition of IL-7 to
      neonatal calvarial organ cultures blocked new bone formation, and injection of IL
      7 into mice in vivo inhibited bone formation as measured by calcein incorporation
      into long bones. The antianabolic effects of IL-7 were consistent with an
      observed downregulation of the osteoblast-specific transcription factor core
      binding factor alpha1/Runx2. Thus, because it targets both the osteoclast and the
      osteoblast pathways, IL-7 is central to the altered bone turnover characteristic
      of estrogen deficiency.

PMID- 12464670
TI  - Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks
      cholera toxin-induced intestinal fluid secretion.
AB  - Secretory diarrhea is the leading cause of infant death in developing countries
      and a major cause of morbidity in adults. The cystic fibrosis transmembrane
      conductance regulator (CFTR) protein is required for fluid secretion in the
      intestine and airways and, when defective, causes the lethal genetic disease
      cystic fibrosis. We screened 50,000 chemically diverse compounds for inhibition
      of cAMP/flavone-stimulated Cl(-) transport in epithelial cells expressing CFTR.
      Six CFTR inhibitors of the 2-thioxo-4-thiazolidinone chemical class were
      identified. The most potent compound discovered by screening of structural
      analogs, CFTR(inh)-172, reversibly inhibited CFTR short-circuit current in less
      than 2 minutes in a voltage-independent manner with K(I) approximately 300 nM.
      CFTR(inh)-172 was nontoxic at high concentrations in cell culture and mouse
      models. At concentrations fully inhibiting CFTR, CFTR(inh)-172 did not prevent
      elevation of cellular cAMP or inhibit non-CFTR Cl(-) channels, multidrug
      resistance protein-1 (MDR-1), ATP-sensitive K(+) channels, or a series of other
      transporters. A single intraperitoneal injection of CFTR(inh)-172 (250 micro
      g/kg) in mice reduced by more than 90% cholera toxin-induced fluid secretion in
      the small intestine over 6 hours. Thiazolidinone CFTR inhibitors may be useful in
      developing large-animal models of cystic fibrosis and in reducing intestinal
      fluid loss in cholera and other secretory diarrheas.

PMID- 12464671
TI  - NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a
      common disease-associated allele.
AB  - Mutations in NPHS2, encoding podocin, have been identified in childhood onset
      focal and segmental glomerulosclerosis (FSGS). The role of NPHS2 in adult disease
      is less well defined. We studied 30 families with FSGS and apparent autosomal
      recessive inheritance and 91 individuals with primary FSGS. We screened family
      members for NPHS2 mutations. NPHS2 mutations appeared to be responsible for
      disease in nine of these families. In six families, the affected individuals were
      compound heterozygotes for a nonconservative R229Q amino acid substitution. This
      R229Q variant has an allele frequency of 3.6% in a control population. In these
      families, R229Q was the only mutation identified on one of the two disease
      associated NPHS2 alleles. We used in vitro-translated podocin and purified
      nephrin to investigate the effect of R229Q on their interaction and found
      decreased nephrin binding to the R229Q podocin. These data suggest that this
      common polymorphism contributes to the development of FSGS. Chromosomes bearing
      the R229Q mutation share a common haplotype defining an approximately 0.2-Mb
      region. R229Q appears to enhance susceptibility to FSGS in association with a
      second mutant NPHS2 allele. Identification of R229Q mutations may be of clinical
      importance, as NPHS2-associated disease appears to define a subgroup of FSGS
      patients unresponsive to corticosteroids.

PMID- 12464672
TI  - A monoclonal thyroid-stimulating antibody.
AB  - The thyrotropin receptor, also known as the thyroid-stimulating hormone receptor
      (TSHR), is the primary antigen of Graves disease. Stimulating TSHR antibodies are
      the cause of thyroid overstimulation and were originally called long-acting
      thyroid stimulators due to their prolonged action. Here we report the successful
      cloning and characterization of a monoclonal antibody (MS-1) with TSHR
      stimulating activity. The thyroid-stimulating activity of MS-1 was evident at IgG
      concentrations as low as 20 ng/ml. MS-1 also competed for radiolabeled TSH
      binding to the native TSHR and was able to compete for TSH-induced stimulation.
      MS-1 recognized a conformational epitope within the TSHR alpha (or A) subunit but
      excluding the receptor cleavage region. Using an assay measuring loss of antibody
      recognition after cleavage we demonstrated that MS-1, in contrast to TSH, was
      unable to enhance TSHR posttranslational cleavage. Since receptor cleavage is
      followed by alpha subunit shedding and receptor degradation, the functional half
      life of the receptor may be extended. The isolation and characterization of MS-1
      provides a novel explanation for the prolonged thyroid stimulation in this
      disease which may be secondary to the lack of receptor cleavage in addition to
      the prolonged half-life of IgG itself.

PMID- 12464673
TI  - CCR4-bearing T cells participate in autoimmune diabetes.
AB  - Chemokine receptor expression is exquisitely regulated on T cell subsets during
      the course of their migration to inflammatory sites. In the present study we
      demonstrate that CCR4 expression marks a pathogenic population of autoimmune T
      cells. CCR4 was found exclusively on memory CD4(+) T cells during the progression
      of disease in NOD mice. Cells expressing the CCR4 ligand TARC (thymus- and
      activation-regulated chemokine) were detected within infiltrated islets from
      prediabetic mice. Interestingly, neutralization of macrophage-derived chemokine
      (MDC) with Ab caused a significant reduction of CCR4-positive T cells within the
      pancreatic infiltrates and inhibited the development of insulitis and diabetes.
      Furthermore, enhanced recruitment of CCR4-bearing cells in NOD mice resulting
      from transgenic expression of MDC resulted in acceleration of clinical disease.
      Cumulatively, the results demonstrate that CCR4-bearing T cells participate in
      the development of such tissue-driven autoimmune reactions.

PMID- 12464674
TI  - Malonyl coenzyme A and the regulation of functional carnitine
      palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle.
AB  - Physiological hyperglycemia with hyperinsulinemia reduces fat oxidation in
      skeletal muscle. The mechanism responsible for this decrease in fat oxidation in
      human muscle is not known and may contribute to the development of insulin
      resistance. We hypothesized that the transfer of long-chain fatty acids (LCFAs)
      into the mitochondria via carnitine palmitoyltransferase-1 (CPT-1) is inhibited
      by increased malonyl coenzyme A (malonyl-CoA) (a known potent inhibitor of CPT-1)
      in human muscle during hyperglycemia with hyperinsulinemia. We studied six
      healthy subjects after an overnight fast and during an induced 5-hour period of
      hyperglycemia with hyperinsulinemia. Muscle fatty acid oxidation was calculated
      using stable isotope methodology combined with blood sampling from the femoral
      artery and vein of one leg. Muscle functional CPT-1 activity was assessed by
      concurrently infusing an LCFA tracer and a CPT-independent medium-chain fatty
      acid tracer. Muscle biopsies were obtained from the vastus lateralis after the
      periods of fasting and hyperglycemia with hyperinsulinemia. Hyperglycemia with
      hyperinsulinemia decreased LCFA oxidation, but had no effect on LCFA uptake or
      medium-chain fatty acid oxidation across the leg. Malonyl-CoA concentration
      significantly increased from 0.13 +/- 0.01 to 0.35 +/- 0.07 nmol/g during
      hyperglycemia with hyperinsulinemia. We conclude that hyperglycemia with
      hyperinsulinemia increases malonyl-CoA, inhibits functional CPT-1 activity, and
      shunts LCFA away from oxidation and toward storage in human muscle.

PMID- 12464675
TI  - Restoration of LDL receptor function in cells from patients with autosomal
      recessive hypercholesterolemia by retroviral expression of ARH1.
AB  - Familial hypercholesterolemia is an autosomal dominant disorder with a gene
      dosage effect that is usually caused by mutations in the LDL receptor gene that
      disrupt normal clearance of LDL. In the homozygous form, it results in a
      distinctive clinical phenotype, characterized by inherited hypercholesterolemia,
      cholesterol deposition in tendons, and severe premature coronary disease. We
      described previously two families with autosomal recessive hypercholesterolemia
      that is not due to mutations in the LDL receptor gene but is characterized by
      defective LDL receptor-dependent internalization and degradation of LDL by
      transformed lymphocytes from the patients. We mapped the defective gene to
      chromosome 1p36 and now show that the disorder in these and a third English
      family is due to novel mutations in ARH1, a newly identified gene encoding an
      adaptor-like protein. Cultured skin fibroblasts from affected individuals exhibit
      normal LDL receptor activity, but their monocyte-derived macrophages are similar
      to transformed lymphocytes, being unable to internalize and degrade LDL.
      Retroviral expression of normal human ARH1 restores LDL receptor internalization
      in transformed lymphocytes from an affected individual, as demonstrated by uptake
      and degradation of (125)I-labeled LDL and confocal microscopy of cells labeled
      with anti-LDL-receptor Ab.

PMID- 12464676
TI  - Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator
      induced lung injury.
AB  - Mortality related to adult respiratory distress syndrome (ARDS) ranges from 35%
      to 65%. Lung-protective ventilator strategies can reduce mortality during ARDS.
      The protective strategies limit tidal volumes and peak pressures while maximizing
      positive end-expiratory pressure. The efficacy of this approach is due to a
      reduction of shear-stress of the lung and release of inflammatory mediators.
      Ventilator-induced lung injury (VILI) is characterized by inflammation. The
      specific mechanism(s) that recruit leukocytes during VILI have not been
      elucidated. Because the murine CXC chemokines KC/CXCL1 and MIP-2/CXCL2/3, via
      CXCR2, are potent neutrophil chemoattractants, we investigated their role in a
      murine model of VILI. We compared two ventilator strategies in C57BL/6 mice: high
      peak pressure and high stretch (high peak pressure/stretch) versus low peak
      pressure/stretch for 6 hours. Lung injury and neutrophil sequestration from the
      high-peak pressure/stretch group were greater than those from the low-peak
      pressure/stretch group. In addition, lung expression of KC/CXCL1 and MIP
      2/CXCL2/3 paralleled lung injury and neutrophil sequestration. Moreover, in vivo
      inhibition of CXCR2/CXC chemokine ligand interactions led to a marked reduction
      in neutrophil sequestration and lung injury. These findings were confirmed using
      CXCR2(-/-) mice. Together these experiments support the notion that increased
      expression of KC/CXCL1 and MIP-2/CXCL2/3 and their interaction with CXCR2 are
      important in the pathogeneses of VILI.

PMID- 12464677
TI  - Induction of the Cdk inhibitor p21 by LY83583 inhibits tumor cell proliferation
      in a p53-independent manner.
AB  - Using microarray analysis, we have detected downregulation of several components
      of the cGMP signaling pathway during replicative senescence of primary human
      diploid fibroblasts (HDFs). Therefore, the effect of pharmacological inhibition
      of cGMP synthesis was analyzed in HDFs. Treatment with 6-anilino-5,8
      quinolinequinone (LY83583, referred to as LY hereafter), a previously described
      inhibitor of guanylate cyclase, induced cellular senescence. Microarray analysis
      revealed that LY treatment induced the Cdk inhibitor p21(WAF1/SDI/CIP1). In
      colorectal cancer cells, transcription of p21 was induced by LY in a p53
      independent manner. Furthermore, p21, but not p53, was required for inhibition of
      proliferation by LY. The lack of p53 involvement suggests that LY does not induce
      DNA damage. Growth inhibition was also observed in malignant melanoma and breast
      cancer cell lines. Functional inactivation of the retinoblastoma tumor-suppressor
      protein, an effector of p21-mediated cell-cycle inhibition, converted LY-induced
      growth arrest to apoptosis. These results suggest that LY, or derivatives, may be
      useful therapeutic agents for the treatment of tumors.

PMID- 12464678
TI  - Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates
      increased cerebral blood flow and stroke protection by corticosteroids.
AB  - Many cellular responses to corticosteroids involve the transcriptional modulation
      of target genes by the glucocorticoid receptor (GR). A rapid, non-nuclear effect
      of GR was found to mediate neuroprotection. High-dose corticosteroids (20 mg/kg
      intraperitoneally), given within 2 hours of transient cerebral ischemia, acutely
      increased endothelial nitric oxide synthase (eNOS) activity, augmented regional
      cerebral blood flow (CBF) by 40% to 50%, and reduced cerebral infarct size by
      32%. These neuroprotective effects of corticosteroids were abolished by the GR
      antagonist RU486 and by inhibition of phosphatidylinositol 3-kinase (PI3K), and
      were absent in eNOS(-/-) mice. To determine the mechanism by which GR activated
      eNOS, we measured the effect of corticosteroids on PI3K and the protein kinase
      Akt. In a ligand-dependent manner, GR activated PI3K and Akt in vitro and in vivo
      caused NO-dependent vasodilation, which was blocked by cotreatment with RU486 or
      the PI3K inhibitor LY294002 but not by transcriptional inhibitors. Indeed, a
      mutant GR, which cannot dimerize and bind to DNA, still activated PI3K and Akt in
      response to corticosteroids. These findings indicate that non-nuclear GR rapidly
      activates eNOS through the PI3K/Akt pathway and suggest that this mechanism
      mediates the acute neuroprotective effects of corticosteroids through
      augmentation of CBF.

PMID- 12464679
TI  - T cell activation causes diarrhea by increasing intestinal permeability and
      inhibiting epithelial Na+/K+-ATPase.
AB  - Inflammatory bowel disease (IBD) is associated with mucosal T cell activation and
      diarrhea. We found that T cell activation with anti-CD3 mAb induces profound
      diarrhea in mice. Diarrhea was quantified by intestinal weight-to-length (wt/l)
      ratios, mucosal Na(+)/K(+)-ATPase activity was determined and ion transport
      changes were measured in Ussing chambers. Anti-CD3 mAb increased jejunal wt/l
      ratios by more than 50% at 3 hours, returning to base line after 6 hours. Fluid
      accumulation was significantly reduced in TNF receptor-1 (TNFR-1(-/-)), but not
      IFN-gamma knockout mice. Anti-CD3 mAb decreased mucosal Na(+)/K(+)-ATPase
      activity, which was blocked by anti-TNF mAb and occurred to a lesser degree in
      TNFR-1(-/-) mice. Neither alpha nor beta subunits of Na(+)/K(+)-ATPase decreased
      in abundance at 3 hours. Intestinal tissue from anti-CD3-treated mice exhibited
      increased permeability to mannitol at 1 hour and decreases in electroneutral
      Na(+) absorption, Na(+)-dependent glucose absorption, and cAMP-stimulated anion
      secretion at 3 hours. Furthermore, enteral fluid accumulation was observed in
      CFTR(-/-) mice, indicating a minor role of active anion secretion. These data
      suggest that diarrhea in IBD is due to TNF-mediated malabsorption rather than to
      secretory processes. T cell activation induces luminal fluid accumulation by
      increasing mucosal permeability and reducing epithelial Na(+)/K(+)-ATPase
      activity leading to decreased intestinal Na(+) and water absorption.

PMID- 12464680
TI  - Importance of free actin filament barbed ends for Arp2/3 complex function in
      platelets and fibroblasts.
AB  - We investigated the effect of actin filament barbed end uncapping on Arp23
      complex function both in vivo and in vitro. Arp23 complex redistributes rapidly
      and uniformly to the lamellar edge of activated wild-type platelets and
      fibroblasts but clusters in marginal actin filament clumps in gelsolin-null
      cells. Treatment of gelsolin-null platelets with the negative dominant N-WASp C
      terminal CA domain has no effect on their residual actin nucleation activity,
      placing gelsolin actin filament severing, capping, and uncapping function
      upstream of Arp23 complex nucleation. Actin filaments capped by gelsolin or the
      gelsolin homolog CapG fail to enhance Arp23 complex nucleation in vitro, but
      uncapping of the barbed ends of these actin filaments restores their ability to
      potentiate Arp23 complex nucleation. We conclude that Arp23 complex contribution
      to actin filament nucleation in platelets and fibroblasts importantly requires
      free barbed ends generated by severing and uncapping.

PMID- 12464681
TI  - Bacillus thuringiensis-toxin resistance management: stable isotope assessment of
      alternate host use by Helicoverpazea.
AB  - Data have been lacking on the proportion of Helicovera zea larvae that develop on
      noncotton host plants that can serve as a refuge from selection pressure for
      adaptation to transgenic cotton varieties that produce a toxin from the bacterium
      Bacillus thuringiensis. We found that individual H. zea moths that develop as
      larvae on cotton and other plants with C3 physiology have a different ratio of
      13C to 12C than moths that develop on plants with C4 physiology, such as corn. We
      used this finding in determining the minimum percentage of moths that developed
      on noncotton hosts in two cotton-growing areas. Our results indicate that local
      corn can serve as a refuge for H. zea in midsummer. Our results contrast
      dramatically with the prevailing hypothesis that the large majority of late
      season moths are produced from larvae feeding on cotton, soybean, and other C3
      plants. Typically, <50% of moths captured in August through October have isotope
      ratios indicative of larval feeding on C3 plants. In one October sample, 100% of
      the moths originated from C4 hosts even though C4 crops were harvested at least 1
      mo earlier, and no common wild C4 hosts were available. These findings support
      other research indicating that many late-season H. zea moths captured in
      Louisiana and Texas are migrants whose larvae developed on corn in more northern
      locations. Our isotope data on moths collected in Texas early in the season
      indicate that the majority of overwintering H. zea do not originate from cotton
      feeding larvae and may be migrants from Mexico. Non-Bt corn in Mexico and the
      U.S. corn belt appears to serve as an important refuge for H. zea.

PMID- 12464682
TI  - A unique molecular chaperone Cosmc required for activity of the mammalian core 1
      beta 3-galactosyltransferase.
AB  - Human core 1 beta3-galactosyltransferase (C1beta3Gal-T) generates the core 1 O
      glycan Galbeta1-3GalNAcalpha1-SerThr (T antigen), which is a precursor for many
      extended O-glycans in animal glycoproteins. We report here that C1beta3Gal-T
      activity requires expression of a molecular chaperone designated Cosmc (core 1
      beta3-Gal-T-specific molecular chaperone). The human Cosmc gene is X-linked
      (Xq23), and its cDNA predicts a 318-aa transmembrane protein ( approximately 36.4
      kDa) with type II membrane topology. The human lymphoblastoid T cell line Jurkat,
      which lacks C1beta3Gal-T activity and expresses the Tn antigen GalNAcalpha1
      SerThr, contains a normal gene and mRNA encoding C1beta3Gal-T, but contains a
      mutated Cosmc with a deletion introducing a premature stop codon. Expression of
      Cosmc cDNA in Jurkat cells restored C1beta3Gal-T activity and T antigen
      expression. Without Cosmc, the C1beta3Gal-T is targeted to proteasomes.
      Expression of active C1beta3Gal-T in Hi-5 insect cells requires coexpression of
      Cosmc. Overexpression of active C1beta3Gal-T in mammalian cell lines also
      requires coexpression of Cosmc, indicating that endogenous Cosmc may be limiting.
      A small portion of C1beta3Gal-T copurifies with Cosmc from cell extracts,
      demonstrating physical association of the proteins. These results indicate that
      Cosmc acts as a specific molecular chaperone in assisting the foldingstability of
      C1beta3Gal-T. The identification of Cosmc, a uniquely specific molecular
      chaperone required for a glycosyltransferase expression in mammalian cells, may
      shed light on the molecular basis of acquired human diseases involving altered O
      glycosylation, such as IgA nephropathy, Tn syndrome, Henoch-Schonlein purpura,
      and malignant transformation, all of which are associated with a deficiency of
      C1beta3Gal-T activity.

PMID- 12464683
TI  - Differential regulation of gene expression by ovariectomy in mouse aorta.
AB  - The purpose of this study was to investigate the effects of ovarian hormones on
      gene expression in the vascular wall. Our approach employed an RT-PCR-based
      cloning strategy of DNA differential display analysis and
      verification/confirmation of differential expression by semi-quantitative PCR and
      real-time PCR. mRNA analysis of normal aortas from intact and ovariectomized
      female C57BL/6J mice, showed altered expression of 20 genes with significant
      (>70%) sequence homology to known genes. Eight were selected for further study
      based on the genes' known function and potential relevance to vascular
      physiology. Differential expression of mRNA for three genes was confirmed by both
      semi-quantitative and real-time RT-PCR using gene-specific primers. Ovariectomy
      downregulated expression of elongation factor-1alpha (3.5-fold), ganglioside
      induced differentiation associated protein (8.2-fold), and NADH:ubiquinone
      oxidoreductase (3.8-fold). Thus, in normal mouse aortas, ovariectomy resulted in
      significant differential downregulation of a number of vascular genes important
      to vascular cell growth and angiogenesis, cellular differentiation, and
      mitochondrial energy metabolism, respectively. These studies have implications
      for our understanding of hormonal regulation of vascular gene expression and the
      therapeutic targeting of specific vascular genetic sequences by female sex
      steroid hormones.

PMID- 12464684
TI  - Hypoxia induces different genes in the lungs of rats compared with mice.
AB  - Different animal species have a varying response to hypoxia. Mice develop less
      pulmonary artery thickening after chronic hypoxia exposure than rats. We
      hypothesized that the lung tissue gene expression pattern displayed in hypoxic
      rats would differ from that of hypoxic mice. We exposed Sprague-Dawley rats and
      C57BL/6 mice to both 1 and 3 wk of hypobaric hypoxia. Although both species
      developed pulmonary hypertension, mice showed less pulmonary vascular remodeling
      than rats. Microarray gene analysis demonstrated a distinct pattern of gene
      expression between mice and rats when exposed to hypoxic conditions. In addition,
      some genes appeared to be more responsive at an earlier time point of 1 wk of
      hypoxia. Hypoxic conditions in the rat induce genes involved in endothelial cell
      proliferation, repression of apoptosis, and vasodilation. Mice exposed to hypoxic
      conditions decrease the expression of genes involved in vasodilation and in
      endothelial cell proliferation. Although we cannot determine whether the
      differential expression of genes during chronic hypoxia is cause or consequence
      of the differential pulmonary vascular remodeling, we propose that a balance
      between over- and under-expression of a selective group of genes may be
      responsible for lung vascular remodeling and vascular tone control.

PMID- 12464685
TI  - Effect of hypoxia on gene expression by human hepatocytes (HepG2).
AB  - The full extent to which hypoxia produces gene expression changes in human cells
      is unknown. We used late-generation oligonucleotide arrays to catalog hypoxia
      induced changes in gene expression in HepG2 cells. Five paired sets of cultures
      were subjected to either control (room air-5% CO(2)) or hypoxic (1% O(2)-5%
      CO(2)) conditions for 24 h, and RNA was analyzed on an Affymetrix cDNA array
      containing approximately 12,600 sequences. A statistically significant change in
      expression was shown by 2,908 sequences (1,255 increased and 1,653 decreased).
      The observed changes were highly concordant with published literature on hypoxic
      stress but showed relatively little overlap (12-22%) with changes in gene
      expression that have been reported to occur after heat stress in other systems.
      Of note, of these 2,908 sequences, only 387 (213 increased and 174 decreased)
      both exhibited changes in expression of twofold or greater and were highly
      expressed in at least three of the five experiments. We conclude that the effect
      of hypoxia on gene expression by HepG2 cells is broad, has a significant
      component of downregulation, and includes a relatively small number of genes
      whose response is truly independent of cell and stress type.

PMID- 12464687
TI  - ENU mutagenesis: a work in progress.

PMID- 12464688
TI  - Of mice and models: improved animal models for biomedical research.
AB  - The ability to engineer the mouse genome has profoundly transformed biomedical
      research. During the last decade, conventional transgenic and gene knockout
      technologies have become invaluable experimental tools for modeling genetic
      disorders, assigning functions to genes, evaluating drugs and toxins, and by and
      large helping to answer fundamental questions in basic and applied research. In
      addition, the growing demand for more sophisticated murine models has also become
      increasingly evident. Good state-of-principle knowledge about the enormous
      potential of second-generation conditional mouse technology will be beneficial
      for any researcher interested in using these experimental tools. In this review
      we will focus on practice, pivotal principles, and progress in the rapidly
      expanding area of conditional mouse technology. The review will also present an
      internet compilation of available tetracycline-inducible mouse models as tools
      for biomedical research (http://www.zmg.uni-mainz.de/tetmouse/).

PMID- 12464689
TI  - Tools for targeted manipulation of the mouse genome.
AB  - In the postgenomic era the mouse will be central to the challenge of ascribing a
      function to the 40,000 or so genes that constitute our genome. In this review, we
      summarize some of the classic and modern approaches that have fueled the recent
      dramatic explosion in mouse genetics. Together with the sequencing of the mouse
      genome, these tools will have a profound effect on our ability to generate new
      and more accurate mouse models and thus provide a powerful insight into the
      function of human genes during the processes of both normal development and
      disease.

PMID- 12464690
TI  - Gene homology resources on the World Wide Web.
AB  - As the amount of information available to biologists increases exponentially,
      data analysis becomes progressively more challenging. Sequence homology has been
      a traditional tool in the researchers' armamentarium; it is a very versatile
      instrument and can be employed to assist in numerous tasks, from establishing the
      function of a gene to determination of the evolutionary development of an
      organism. Consequently, numerous specialized tools have been established in the
      public domain (most commonly, the World Wide Web) to help investigators use
      sequence homology in their research. These homology databases differ both in
      techniques they use to compare sequences as well as in the size of the unit of
      analysis, which can be the whole gene, a domain, or a motif. In this paper, we
      aim to present a systematic review of the inner details of the most commonly used
      databases as well as to offer guidelines for their use.

PMID- 12464691
TI  - What can cardiovascular gene transfer learn from genomics: and vice versa?
AB  - The field of gene transfer has developed in an era of expanding biomedical
      knowledge. The potential for gene transfer to treat cardiovascular disease is
      great, yet identified and unidentified barriers remain. Gene transfer and its
      ultimate application, gene therapy, require extensive details of not only the
      mechanism of disease but the biological implications of the vectors used to
      deliver the therapeutic genes as well. Many of these details are becoming
      available via the study of genomics. Genomics, the study of complete genetic
      sequences, holds the potential for enabling and amplifying the therapeutic hopes
      for gene transfer. Identification of new therapeutic genes, new regulatory
      sequences, and establishing the patterns of gene expression from tissues exposed
      to vectors and transgenes will rapidly advance the application of gene transfer.
      Finally, there are historical and ongoing lessons learned from the development of
      gene transfer that may be applicable to the challenging field of genomics and may
      enable its future success.

PMID- 12464692
TI  - Charting the effects of antioxidant therapy in the diseased brain: focus on
      "vitamin E deficiency and metabolic deficits in neuronal ceroid lipofuscinosis
      described by bioinformatics".

PMID- 12464693
TI  - Heterogeneous allele expression of pulmonary SP-D gene in rat large intestine and
      other tissues.
AB  - Random allele expression has recently been observed for several genes including
      interleukins and genes of the lymphoid system. We studied the hypothesis that the
      surfactant protein D (SP-D) gene, an innate host defense molecule, exhibits
      random allele expression in a tissue-specific manner. SP-D gene expression is
      tissue specific in the 14 tissues studied. Study of SP-D allelic expression in
      several tissues revealed a balanced biallelic (BB) in lung, and, in several
      extrapulmonary tissues, a heterogeneous pattern: BB, imbalanced biallelic (IB),
      and monoallelic (MO). The results from 103 heterozygous rats showed an expression
      profile in large intestine of BB (22%), IB (58%), and MO (20%). Among eight
      families, the percent of BB in siblings varied from 0 to 41%, MO from 0 to 33%,
      and IB from 49 to 83%. The parent-of-origin does not play a role in SP-D allele
      specific expression. However, acquired epigenetic factors, family background, or
      other factors may contribute to the overall pattern of expression.

PMID- 12464694
TI  - Postextinction of conditioned fear: between two CS-related memories.

PMID- 12464695
TI  - Learning directions of objects specified by vision, spatial audition, or auditory
      spatial language.
AB  - The modality by which object azimuths (directions) are presented affects learning
      of multiple locations. In Experiment 1, participants learned sets of three and
      five object azimuths specified by a visual virtual environment, spatial audition
      (3D sound), or auditory spatial language. Five azimuths were learned faster when
      specified by spatial modalities (vision, audition) than by language. Experiment 2
      equated the modalities for proprioceptive cues and eliminated spatial cues unique
      to vision (optic flow) and audition (differential binaural signals). There
      remained a learning disadvantage for spatial language. We attribute this result
      to the cost of indirect processing from words to spatial representations.

PMID- 12464696
TI  - Reduced delayed-rectifier K+ current in the learning mutant rutabaga.
AB  - In the Drosophila mutant rutabaga, short-term memory is deficient and
      intracellular cyclic adenosine monophosphate (cAMP) concentration is reduced. We
      characterized the delayed-rectifier potassium current (IK(DR)) in rutabaga as
      compared with the wild-type. The conventional whole-cell patch-clamp technique
      was applied to cultured Drosophila neurons derived from embryonic neuroblasts.
      IK(DR) was smaller in rutabaga (368 +/- 11 pA) than in wild-type (541 +/- 14 pA)
      neurons, measured in a Ca(2+)-free solution. IK(DR) was clearly activated at
      approximately 0 mV in the two genotypes. IK(DR) typically reached its peak within
      10-20 msec after the start of the pulse (60 mV). There was no difference in
      inactivation of IK(DR) for wild-type (14 +/- 3%) and rutabaga (19 +/- 3%). After
      application of 10 mM TEA, in wild-type, IK(DR) was reduced by 46 +/- 5%, whereas
      in rutabaga, IK(DR) was reduced by 28 +/- 3%. Our results suggest that IK(DR) is
      carried by two different types of channels, one which is TEA-sensitive, whereas
      the other is TEA-insensitive. Apparently, the TEA-sensitive channel is less
      expressed in rutabaga neurons than in wild-type neurons. Conceivably, altered
      neuronal excitability in the rutabaga mutant could disrupt the processing of
      neural signals necessary for learning and memory.

PMID- 12464697
TI  - The differential role of premotor frontal cortex and basal ganglia in motor
      sequence learning: evidence from focal basal ganglia lesions.
AB  - There has been a growing interest in the differential role of various neural
      structures in implicit learning processes. The goal of our study was to clarify
      how focal lesions restricted to the basal ganglia interfere with different
      aspects of implicit visuo-motor sequence learning. A version of the Serial
      Reaction Time Task (SRTT) of Nissen and Bullemer using a 12-trial sequence was
      administered. A total of 20 subjects with focal basal ganglia lesions caused by
      ischemic or hemorrhagic infarction and 20 matched control subjects participated
      in this study. The results indicate that subjects with focal basal ganglia
      lesions showed unimpaired implicit learning of a 12-item motor sequence. Subjects
      with basal ganglia lesions, however, had more difficulties improving their
      general proficiency with the reaction-time task independent of sequence-specific
      learning. We observed a tendency toward smaller regional volumes in the
      cerebellum and left pre-supplementary motor area (pre-SMA) of subjects with basal
      ganglia lesions. Smaller cerebellar and pre-SMA volumes were related to lower
      implicit learning performance in the lesion group. The size of lesions in the
      basal ganglia was not related to sequence-specific implicit learning but had a
      significant influence on subjects' general proficiency for execution of the
      reaction-time task. We propose that implicit learning is achieved by a
      distributed network of cortical and subcortical structures. The basal ganglia
      seem to be responsible for adjusting to the general requirements of a task rather
      than for learning specific associations between stimuli that might be
      accomplished by premotor frontal areas and the cerebellum instead.

PMID- 12464698
TI  - Fimbria-fornix lesions disrupt the dead reckoning (homing) component of
      exploratory behavior in mice.
AB  - Exploration is the primary way in which rodents gather information about their
      spatial surroundings. Thus, spatial theories propose that damage to the
      hippocampus, a structure thought to play a fundamental role in spatial behavior,
      should disrupt exploration. Exploration in rats is organized. The animals create
      home bases that are central to exploratory excursions and returns, and
      hippocampal formation damage alters the organization of exploration by disrupting
      returns. Mice do not appear to readily establish home bases in novel
      environments, thus, for this species, it is more difficult to establish the
      contribution of the hippocampus to exploration. The purpose of the present study
      was threefold: develop a task in which mice center their exploration from a home
      base, determine whether the exploratory behavior is organized, and evaluate the
      role of fimbria-fornix lesions on exploration. Mice were given a novel
      exploratory task in which their nesting material was placed on a large circular
      table. Video records of control and fimbria-fornix mice were made in both light
      and dark (infrared light) conditions. Exploration patterns (outward trips, stops,
      and homeward trips) were reconstructed from the video records. Control mice
      centered their activity on their bedding, from which they made circuitous outward
      trips marked by many stops, and periodic direct returns. The bedding-centered
      behavior and outward trips of the fimbria-fornix mice were similar to those of
      the control mice, but significantly fewer direct return trips occurred. The
      direct homeward trips observed under light and dark conditions were consistent
      with a dead-reckoning strategy, in which an animal computes its present position
      and homeward trajectory from self-movement cues generated on the outward trip.
      Because the fimbria-fornix lesions disrupted the homeward component of
      exploratory trips, we conclude that the fimbria-fornix may contribute to dead
      reckoning in mice. The results also show that the home-bedding methodology
      facilitates the establishment of a home base by mice, thus providing a useful
      methodology for studies with mice.

PMID- 12464699
TI  - Second-order olfactory-mediated fear-potentiated startle.
AB  - Recently, we reported that discrete (4-sec) olfactory cues paired with footshock
      serve as effective conditioned stimuli (CSs) for potentiating the acoustic
      startle response in rats using the fear-potentiated startle paradigm. Because
      odors are such salient cues for the rat, and because of the robust olfactory
      conditioning observed previously, the current studies investigated second-order
      fear conditioning using olfactory and visual cues. In Experiments 1 and 2, we
      used a small number of first-order and second-order training trials on separate
      days to investigate second-order fear-potentiated startle. Significant
      potentiated startle was observed in animals receiving Paired/Paired training in
      both studies, but surprisingly, control animals in the Unpaired/Paired group
      (Exp. 1) also showed significant potentiated startle to a light S2 at testing.
      These findings are addressed in the Discussion. Overall, the results of both
      experiments suggest that olfactory cues serve as efficient S1 and S2 stimuli in
      second-order fear-potentiated startle paradigms when only a small number of first
      and second-order training trials are presented.

PMID- 12464700
TI  - Memory for extinction of conditioned fear is long-lasting and persists following
      spontaneous recovery.
AB  - Conditioned fear responses to a tone paired with footshock rapidly extinguish
      when the tone is presented in the absence of the shock. Rather than erase
      conditioning, extinction is thought to involve the formation of new memory. In
      support of this, extinguished freezing spontaneously recovers with the passage of
      time. It is not known, however, how long extinction memory lasts or whether
      extinction interferes with consolidation of conditioning if given on the same
      day. To address this, we gave rats 7 trials of auditory fear conditioning
      followed 1 h later by 20 extinction trials, and tested for spontaneous recovery
      after a delay of 0, 1, 2, 4, 6, 10, or 14 d. Conditioned freezing to the tone
      gradually recovered with time to reach 100% by day 10. No-extinction controls
      indicated that the increase in freezing with time was not owing to incubation of
      conditioning memory. Complete spontaneous recovery indicates that extinction
      training given 1 h after conditioning does not interfere with the consolidation
      of conditioning memory. Despite complete recovery of freezing, rats showed
      savings in their rate of re-extinction, indicating persistence of extinction
      memory. These data support the idea that conditioning and extinction of fear are
      learned by independent systems, each able to retain a long-term memory.

PMID- 12464701
TI  - How do people solve the "weather prediction" task?: individual variability in
      strategies for probabilistic category learning.
AB  - Probabilistic category learning is often assumed to be an incrementally learned
      cognitive skill, dependent on nondeclarative memory systems. One paradigm in
      particular, the weather prediction task, has been used in over half a dozen
      neuropsychological and neuroimaging studies to date. Because of the growing
      interest in using this task and others like it as behavioral tools for studying
      the cognitive neuroscience of cognitive skill learning, it becomes especially
      important to understand how subjects solve this kind of task and whether all
      subjects learn it in the same way. We present here new experimental and
      theoretical analyses of the weather prediction task that indicate that there are
      at least three different strategies that describe how subjects learn this task.
      (1) An optimal multi-cue strategy, in which they respond to each pattern on the
      basis of associations of all four cues with each outcome; (2) a one-cue strategy,
      in which they respond on the basis of presence or absence of a single cue,
      disregarding all other cues; or (3) a singleton strategy, in which they learn
      only about the four patterns that have only one cue present and all others
      absent. This variability in how subjects approach this task may have important
      implications for interpreting how different brain regions are involved in
      probabilistic category learning.

PMID- 12464702
TI  - Cognitive procedural learning in patients with fronto-striatal lesions.
AB  - Previous studies on the role of prefronto-striatal loop systems for cognitive
      procedural learning (PL) brought inconsistent results. To examine whether the
      integrity of the dorsolateral prefrontal loop is indispensable for normal
      cognitive PL, we examined the acquisition of cognitive skills in 35 patients with
      focal prefrontal lesions, focal caudate lesions, and Huntington's Disease (HD),
      and compared it with a control group. To examine the potential role of the
      processing demands made by the cognitive tasks, a set of tasks was applied whose
      acquisition places demand either on reasoning and problem solving, or on the
      establishment of fast and repetitive processing routines. The Pursuit Rotor task
      was also studied with the aim to re-examine earlier findings of a functional
      segregation of motor and complex prefronto-striatal loops. Deficits of cognitive
      and motor PL were found to be limited to certain tasks and groups. PL of one
      task, which demanded rapid, repetitive processing of visuo-spatial stimuli, was
      impaired in all patient groups. PL of two problem-solving tasks was impaired in
      patients with focal and degenerative caudate lesions only. None of the groups was
      impaired at PL of Mirror Reading, another task demanding rapid and repetitive
      visuo-spatial processing, and none was impaired in a fifth task of language
      skill. Deficits of motor learning were only observed in patients in whom the
      motor loop was affected. These results suggest that the dorsolateral prefronto
      striatal loop is involved in the establishment of cognitive processing routines.
      The comparison of patients with and without caudate lesions suggests that
      disconnection of this circuit is critical. However, the normal acquisition of two
      cognitive tasks even in this group indicates that the integrity of the
      dorsolateral prefrontal loop is not mandatory for normal cognitive PL. We discuss
      these dissociations with regard to the demand profiles of the applied tasks and
      the locations of the lesions.

PMID- 12464703
TI  - Habit and skill learning in schizophrenia: evidence of normal striatal processing
      with abnormal cortical input.
AB  - Different forms of nondeclarative learning involve regionally specific striatal
      circuits. The motor circuit (involving the putamen) has been associated with
      motor-skill learning and the dorsolateral prefrontal cortex (DLPFC) circuit
      (involving the caudate) has been associated with cognitive-habit learning.
      Efforts to differentiate functional striatal circuits within patient samples have
      been limited. Previous studies have provided mixed results regarding striatal
      dependent nondeclarative learning deficits in patients with schizophrenia. In
      this study, a cognitive-habit learning task (probabilistic weather prediction)
      was used to assess the DLPFC circuit and a motor-skill learning task (pursuit
      rotor) was used to assess the motor circuit in 35 patients with schizophrenia and
      35 normal controls. Patients with schizophrenia displayed significant performance
      differences from controls on both nondeclarative tasks; however, cognitive-habit
      learning rate in patients did not differ from controls. There were performance
      and learning-rate differences on the motor-skill learning task between the whole
      sample of patients and controls, however, analysis of a subset of patients and
      controls matched on general intellectual level eliminated learning rate
      differences between groups. The abnormal performance offset between patients with
      schizophrenia and controls in the absence of learning rate differences suggests
      that abnormal cortical processing provides altered input to normal striatal
      circuitry.

PMID- 12464704
TI  - Internalization of inactive EGF receptor into endosomes and the subsequent
      activation of endosome-associated EGF receptors. Epidermal growth factor.
AB  - Despite intensive efforts to understand cell signaling from endosomes, there is
      no direct evidence demonstrating that endosomal signaling is sufficient to
      activate signal transduction pathways or that endosomal signaling can produce
      biological responses. The lack of breakthrough is due in part to the inability to
      generate endosomal signals in isolation from plasma membrane signals. In this
      Protocol, we describe a system in which epidermal growth factor (EGF) receptor
      (EGFR) is specifically activated when it is endocytosed into endosomes. We
      treated cells with EGF in the presence of AG1478, a specific EGFR tyrosine kinase
      inhibitor, and monensin, which blocks recycling of EGFR. This treatment led to
      the internalization of nonactivated EGF-EGFR complex into endosomes. The endosome
      associated EGFR was then activated by removing AG1478 and monensin. During this
      procedure, we did not observe any detectable surface EGFR phosphorylation. We
      also achieved specific activation of endosome-associated EGFR without using
      monensin. Specific activation of endosome-associated EGFR provides a unique tool
      to study endosomal signaling of EGFR. This method may also be applied to other
      receptor tyrosine kinases to study whether they, too, can signal from endosomes.

PMID- 12464705
TI  - Executive summary International Society for Clinical Densitometry position
      development conference Denver, Colorado July 20-22, 2001.
AB  - Bone densitometry is routinely used to assess the skeleton in patients who have
      diseases or conditions that can cause low bone mass. However, there are some
      areas of controversy related to the interpretation of bone densitometry results.
      To address these issues, the International Society for Clinical Densitometry
      (ISCD) convened a Position Development Conference in Denver, Colorado, July 20
      22, 2001. The ISCD is a not-for-profit multidisciplinary society whose main
      mission is to promote quality in the performance and interpretation of bone
      densitometry examinations.

PMID- 12464706
TI  - Position statements of the International Society for Clinical Densitometry:
      methodology.
AB  - Given the need for authoritative positions in areas of controversy in the field
      of bone densitometry, the International Society for Clinical Densitometry (ISCD)
      convened a Position Development Conference in Denver, CO, USA, in July 2001. Four
      general areas were selected on the basis of clinical importance and likelihood of
      reaching agreement. These areas were discussed at length prior to the conference
      by the Scientific Advisory Committee of the ISCD and presented to a panel of
      experts at the conference. The four areas included discussions of (1). the
      regions of interest of central dual X-ray densitometry (DXA), (2). the criteria
      by which a densitometric diagnosis of osteoporosis can be made in men and non
      Caucasian women, (3). the role of serial BMD measurements in patient management,
      and (4). the standards by which bone mass measurements at peripheral sites should
      be used in the diagnosis of osteoporosis. Details of the methodology used at the
      conference are discussed. The following papers explain the results of the
      discussions and describe the official ISCD positions.

PMID- 12464707
TI  - Which central dual X-ray absorptiometry skeletal sites and regions of interest
      should be used to determine the diagnosis of osteoporosis?
AB  - Although central measurement of bone mass by dual X-ray absorptiometry (DXA) is
      viewed by many as the "gold standard" for the diagnosis of osteoporosis in
      patients without previous fragility fracture, controversy remains on how best to
      use central DXA as a tool for diagnosis. Questions concerning the measurement of
      bone mass of the central skeleton were addressed at the International Society for
      Clinical Densitometry Position Development Conference. An expert panel agreed on
      the following positions: First, the diagnosis of osteoporosis should be based on
      the lowest T-score of either the PA spine or hip. Second, both the PA spine and
      hip should be measured. Third, whenever possible, bone mineral density (BMD) of
      the first four lumbar vertebrae should be measured. Fourth, DXA manufacturers
      should use L1-L4 as the default region of interest for their printouts. Fifth,
      BMD of either hip may be measured. Sixth, the lowest T-score of the three sites
      total hip, femoral neck, or trochanter should be considered. Seventh, Ward's area
      should not be used for diagnostic purposes; DXA manufacturers should not include
      this region in the default printout. Eighth, BMD of the forearm should be
      measured if the hip or spine cannot be accurately measured. Finally, lateral
      spine BMD should not be used to diagnose osteoporosis.

PMID- 12464708
TI  - What are the criteria by which a densitometric diagnosis of osteoporosis can be
      made in males and non-Caucasians?
AB  - Osteoporotic fractures are not rare in men or non-Caucasian women. However, for
      these groups, there is no consensus densitometric definition of osteoporosis. As
      is the case in Caucasian women, low bone mineral density (BMD) is associated with
      increased fracture risk among men and non-Caucasian women; thus, a densitometric
      definition of osteoporosis seems feasible. Reaching agreement on criteria for
      diagnosing osteoporosis in men and non-Caucasians was among the goals of the
      International Society for Clinical Densitometry Position Development Conference
      held in July 2001. To this end, the conference recommendation for males is that
      osteoporosis be defined as a BMD T-score of -2.5 or below the young normal mean
      for men. Since the relationship between BMD and fracture risk may differ between
      men and women, it is recommended that T scores in men continue to be derived
      using a male normative database. Similarly, for non-Caucasians, the
      recommendation is to diagnose osteoporosis at or below a T-score of -2.5.
      However, given the difficulty in defining race or ethnic groups, a dearth of
      data, and their conflicting nature correlating BMD with fracture risk in
      different ethnicities, it is recommended that a uniform normative database (not
      adjusted for race) be utilized in the United States for T-score derivation in non
      Caucasians. Note that these are current clinical recommendations, which may
      change as additional data accumulate. Furthermore, there was agreement that the
      following individuals should have their bone density measured: anyone (male or
      female, regardless of race) with prior fragility fractures or with conditions
      widely recognized to increase the risk of bone loss and fracture (such as
      hypogonadism, corticosteroid treatment, hyperparathyroidism, alcohol abuse,
      anticonvulsant use, and prior gastrectomy); women on long-term hormone
      replacement therapy; and in the absence of these conditions, women age 65 and
      older (regardless of race) and men age 70 and older.

PMID- 12464709
TI  - What is the role of serial bone mineral density measurements in patient
      management?
AB  - The ability of dual X-ray absorptiometry (DXA) to monitor bone mineral density
      (BMD) has been well documented in epidemiologic and pharmaceutical trials.
      However, its application to monitoring of patients in clinical practice has been
      subject to recent controversies. Despite these controversies, most clinical
      centers rely on DXA for monitoring of patients, and therefore guidance is needed.
      In this article, we report the positions developed by an expert panel of the
      International Society for Clinical Densitometry on the use of densitometry for
      the serial measurement of bone mass for monitoring change in BMD. The panel found
      DXA to be a precise method of measuring change in BMD if used with an appropriate
      level of least significant change (LSC), at anatomic sites with good precision
      and response to therapy, and at 1- to 2-yr time intervals. Monitoring is
      acceptable for determining when therapy is indicated, and if an agent is not
      therapeutically effective (i.e., when bone loss occurs despite treatment). Each
      densitometry center should perform an in vivo precision study on individuals
      similar to the patient population at the center and determine LSC at a 95%
      confidence level. If such a precision study cannot be performed, benchmark
      precision might be used, although there was no agreement on what values should be
      used. The PA spine is the preferred anatomic site for monitoring. The total hip
      can be used when the spine study is technically invalid. We conclude with
      recommendations for further research.

PMID- 12464710
TI  - What are the standards by which bone mass measurement at peripheral skeletal
      sites should be used in the diagnosis of osteoporosis?
AB  - Measurement of bone mineral density (BMD) at central skeletal sites with dual X
      ray absorptiometry is the "gold standard" both for the diagnosis of osteoporosis
      using the criteria of the World Health Organization (WHO) and for monitoring
      individuals receiving antiresorptive treatment for osteoporosis. Measurement of
      BMD at peripheral sites (peripheral BMD) can be used to assess fracture risk, but
      application of the WHO criteria gives different prevalence values for
      "osteoporosis" with peripheral devices, and different risks for fracture at the
      same cut points. The International Society for Clinical Densitometry Position
      Development Conference panelists reached the following conclusions about
      peripheral BMD testing: First, WHO T-score criteria should not be used with
      peripheral devices. Second, for the identification of a level for peripheral BMD
      measurements above which osteoporosis is unlikely, device-specific cut points for
      peripheral BMD should be identified that have 90% sensitivity for identifying
      patients who have osteoporosis (T-score of -2.5 or below) based on measurements
      of the spine and hip. If central BMD testing is available, patients who have
      peripheral BMD below the 90% sensitivity level should have a central BMD
      measurement. If central BMD testing is not available, peripheral BMD might be
      used for identification of patients who are likely to have osteoporosis. Risk
      based cut points were preferred to prevalence based cut points, and, again,
      device-specific cut points are needed. For patients tested only with a peripheral
      BMD device whose result is intermediate, clinical judgment would be needed.
      Third, peripheral BMD testing should not be used for monitoring patients who are
      taking antiresorptive therapy for osteoporosis. Fourth, peripheral BMD testing
      performs best when used for postmenopausal women. Further research on all these
      issues is needed.

PMID- 12464711
TI  - Foramen ovale recordings: a presurgical investigation in epilepsy.
AB  - The aim of our study was to determine when foramen ovale recordings add useful
      information to scalp EEG recordings and magnetic resonance imaging (MRI) with
      hippocampal measurements. We evaluated the outcome of 79 patients with non
      lesional partial epilepsy with presumed temporal seizure onset. Ictal foramen
      ovale recordings were performed in 16 patients with normal MRI ('MRI-negative
      group') and 41 patients with lateralizing MRI but non-lateralizing scalp EEG
      ('discordant group'). 22 patients with concordant MRI and scalp EEG were not
      investigated with foramen ovale recordings ('concordant group'). The seizure-free
      rate was higher in concordant than discordant patients despite additional
      investigation with foramen ovale electrodes (71 and 55% seizure free,
      respectively). No useful localizing information was added with foramen ovale
      recordings in MRI-negative patients.

PMID- 12464712
TI  - Epidemiological data of multiple sclerosis in the province of Evros, Greece.
AB  - The frequency of multiple sclerosis (MS) in Greece is still debated. Our previous
      epidemiological field survey with a cross-check study of MS on March 31, 1984, in
      the province of Evros in north-eastern Greece showed a prevalence rate of
      10.1/100,000. In 1990, Milonas et al. recorded a prevalence rate of 29.5/100,000
      in northern Greece. So Greece is classified in the medium-frequency zone
      according to Kurtzke. This study was performed to estimate the prevalence of MS
      in the province of Evros and the annual incidence rates from 1974 to 1999.
      Patients were identified from several sources. A clinical follow-up was performed
      in 95% of the cases, and, if clinically indicated, new paraclinical examinations
      were performed and cases classified by Poser's criteria. The prevalence rate of
      the definite MS cases on December 31, 1999, was 38.9/100,000 and places the area
      in the high-risk zone. The mean annual incidence measured in 5-year intervals
      increased from 0.66/100,000 in 1974-1978 to 2.36/100,000 in 1994-1999 (p < 0.01).
      The increase in prevalence can be attributed to other causes than etiological
      changes, but the increase in the annual incidence rate indicates the possibility
      of a variation in risk factors of the disease.

PMID- 12464713
TI  - Frontotemporal dementia: paroxetine as a possible treatment of behavior symptoms.
      A randomized, controlled, open 14-month study.
AB  - Frontotemporal dementia (FTD) represents an important cause for degenerative
      disruption and is increasingly recognized as an important cause (up to 25%) of
      degenerative dementia among late-middle-age individuals. The serotoninergic
      system is tightly bound to frontal circuits, whose degeneration subserves FTD.
      Patients aged 64-68 years, with a diagnosis of FTD, were randomized to receive
      paroxetine up to 20 mg/day (n = 8) or piracetam up to 1,200 mg/day (n = 8). At 14
      months, the patients treated with paroxetine showed significant improvements in
      behavioral symptoms, reflected by a reduction of caregiver stress. Side effects
      were easily tolerable, and there was no dropout. The results are presented with
      an overview of the literature on the topic.

PMID- 12464714
TI  - Crossover comparison of efficacy and preference for rizatriptan 10 mg versus
      ergotamine/caffeine in migraine.
AB  - Rizatriptan is a selective 5-HT(1B/1D) receptor agonist with rapid oral
      absorption and early onset of action in the acute treatment of migraine. This
      randomized double- blind crossover outpatient study assessed the preference for 1
      rizatriptan 10 mg tablet to 2 ergotamine 1 mg/caffeine 100 mg tablets in 439
      patients treating a single migraine attack with each therapy. Of patients
      expressing a preference (89.1%), more than twice as many preferred rizatriptan to
      ergotamine/caffeine (69.9 vs. 30.1%, p < or = 0.001). Faster relief of headache
      was the most important reason for preference, cited by 67.3% of patients
      preferring rizatriptan and 54.2% of patients who preferred ergotamine/caffeine.
      The co-primary endpoint of being pain free at 2 h was also in favor of
      rizatriptan. Forty-nine percent of patients were pain free 2 h after rizatriptan,
      compared with 24.3% treated with ergotamine/caffeine (p < or = 0.001),
      rizatriptan being superior within 1 h of treatment. Headache relief at 2 h was
      75.9% for rizatriptan and 47.3% for ergotamine/caffeine (p < or = 0.001), with
      rizatriptan being superior to ergotamine/caffeine within 30 min of dosing. Almost
      36% of patients taking rizatriptan were pain free at 2 h and had no recurrence or
      need for additional medication within 24 h, compared to 20% of patients on
      ergotamine/caffeine (p < or = 0.001). Rizatriptan was also superior to
      ergotamine/caffeine in the proportions of patients with no nausea, vomiting,
      phonophobia or photophobia and for patients with normal function 2 h after drug
      intake (p < or = 0.001). More patients were (completely, very or somewhat)
      satisfied 2 h after treatment with rizatriptan (69.8%) than at 2 h after
      treatment with ergotamine/caffeine (38.6%, p < or = 0.001). Recurrence rates were
      31.4% with rizatriptan and 15.3% with ergotamine/caffeine. Both active treatments
      were well tolerated. The most common adverse events (incidence > or = 5% in one
      group) after rizatriptan and ergotamine/caffeine, respectively, were dizziness
      (6.7 and 5.3%), nausea (4.2 and 8.5%) and somnolence (5.5 and 2.3%).

PMID- 12464715
TI  - Dopamine agonists induce episodes of irresistible daytime sleepiness.
AB  - We assessed the prevalence and risk factors for irresistible daytime sleepiness
      (IDS) in a cohort of patients with Parkinson's disease (PD) treated with dopamine
      agonists. Seventy consecutive PD patients on dopamine agonists were interviewed.
      IDS was experienced by 24 patients (34.3%). Fifty percent of the pramipexole
      patients, 15.4% of the pergolide patients, 23.1% of the ropinirole patients and
      the 2 patients on bromocriptine experienced IDS. Patients who experienced IDS
      were younger (p = 0.009). Nineteen patients had IDS while driving, 3 sustained a
      motor vehicle crash. Daytime somnolence (p = 0.05) and early arousals (p = 0.001)
      were risk factors and daytime napping (p = 0.007) and benzodiazepines (p = 0.006)
      were protective. Improvement was achieved by changing the dosing schedule, the
      amount of agonist per dose, discontinuing the agonist or accommodating the
      sleepiness. We conclude that dopamine agonists are commonly implicated in IDS.

PMID- 12464716
TI  - Autonomic side effects of botulinum toxin type B treatment of cervical dystonia
      and hyperhidrosis.
AB  - Recently, botulinum toxin type B (BT-B) has become available to treat muscle
      hyperactivity in cervical dystonia (CD). When we started the clinical use of BT
      B, we noticed a side effect profile not seen with botulinum toxin type A (BT-A)
      before. Altogether 30 consecutive patients were included in this open controlled
      study. 24 patients were treated for CD with 11,310 +/- 2,616 mouse units (MU) of
      BT-B (NeuroBloc) and 6 for focal hyperhidrosis (HH) with 4,000-10,000 MU. In 5 of
      them, BT-A (Botox) was used additionally for comparison of effectiveness. In CD,
      side effects consisted of dryness of mouth (total 21, duration 4.4 +/- 2.0 weeks,
      10 severe, 7 moderate, 4 mild), accommodation difficulties (7), conjunctival
      irritation (5), reduced sweating (4), swallowing difficulties (3), heartburn (3),
      constipation (3), bladder voiding difficulties (2), head instability (1), dryness
      of nasal mucosa (1) and thrush (1). In HH, side effects consisted of
      accommodation difficulties (4), dryness of mouth (2) and conjunctival irritation
      (1). Autonomic side effects occur far more often after BT-B than after BT-A.
      Their localization suggests systemic BT-B spread. BT-B should be applied
      carefully in patients with pre-existent autonomic dysfunction, additional
      anticholinergic treatment and in conditions where anticholinergics are
      contraindicated.

PMID- 12464717
TI  - Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O
      methyldopa following a new dual-release and a conventional slow-release
      formulation of levodopa and benserazide in healthy volunteers.
AB  - The objective was to assess the single- and multiple-dose pharmacokinetics of
      levodopa and 3-O-methyldopa following administration of a new dual-release and
      conventional slow-release formulation of levodopa/benserazide in the dose ratio
      of 4:1. In an open-label, two-way cross-over study, 20 healthy volunteers were
      randomized to receive first either Madopar DR or Madopar HBS for 8 days. Then
      they crossed over to the other formulation. A first dose of 200 mg levodopa and
      50 mg benserazide ('250' mg) was given on day 1, '125' mg t.i.d. on the
      subsequent 6 days (days 2-7), followed by '250' mg on day 8. The two treatment
      periods of 8 days were separated by a wash-out period of at least 7 days. Blood
      samples were taken at specific times over a 12-hour period (day 1) or a 36-hour
      period (day 8). Plasma concentrations of levodopa and 3-O-methyldopa were
      measured by high-performance liquid chromatography for pharmacokinetic
      evaluation. The pharmacokinetics of levodopa after a single-dose administration
      (day 1) of Madopar DR and Madopar HBS were significantly different as reflected
      by the respective mean values of maximum plasma concentration (C(max) 1.99 vs.
      0.82 mg x l-1), time to reach maximum concentration (t(max) 0.7 vs. 2.6 h) and
      area under the plasma concentration-time curve (AUC(0- infinity ) 4.52 vs. 3.18
      mg x h x l-1). The respective values after multiple doses (day 8) were: C(max)
      1.98 vs. 0.93 mg x l-1, t(max) 0.7 vs. 2.3 h and AUC(0-infinity ) 4.84 vs. 3.96
      mg x h x l-1. The relative bioavailability (Madopar DR vs. Madopar HBS) was 1.73
      on day 1 and 1.32 on day 8. Bioequivalence could not be demonstrated for log
      transformed data of AUC and C(max) within a predefined range of 80-125 and 70
      143%, respectively. In conclusion, the observed differences in C(max), t(max) and
      AUC are consistent with a faster rate and higher extent of levodopa absorption
      after administration of Madopar DR. Statistical evaluation of these kinetic data
      showed that Madopar DR is not bioequivalent to Madopar HBS.

PMID- 12464718
TI  - Apraxia of tool use: an autopsy case of biparietal infarction.
AB  - Although disorders in the use of single objects have been reported, there have
      been few detailed analyses. We describe the autopsy case of a 65-year-old, right
      handed male patient with severe impairment of actual tool use which was caused by
      biparietal infarctions. He persistently and stably showed a severely defective
      use of actual objects, single or multiple, and relatively well-preserved
      pantomimes of object use and intransitive gestures. He did not have aphasia or
      dementia, and his ability for tool naming and function description was completely
      preserved. The author identified similar patterns of errors about a tool-action(
      target) relationship both in single-object use and multiple-object use. Lesion
      analysis showed cortical infarcts mainly located in the bilateral inferior
      parietal lobules, extending into the temporal lobe on the right side.

PMID- 12464719
TI  - The three-item clock-drawing test: a simplified screening test for Alzheimer's
      disease.
AB  - The Clock-Drawing Test (CDT) has been used to screen for Alzheimer's disease (AD)
      as a supplement to cognitive tests that focus on memory impairment. We examined a
      comprehensive scoring system of the CDT in screening of AD in a Chinese
      population and derived a simplified scoring system. All 403 (144 AD and 259
      nondemented) subjects were administered the CDT, including both the drawing part
      (CDT-D) and the copying part (CDT-C). The Cognitive Abilities Screening
      Instrument and the Clinical Dementia Rating were also administered. Stepwise
      discriminant analysis was used to develop a simplified CDT scoring system. The
      optimal CDT cutoff scores (CDT-D: 10/11; CDT-C: 12/13) show intermediate
      sensitivity (CDT-D: 66.7%; CDT-C: 51.4%) and specificity (CDT-D: 74.5%; CDT-C:
      74.1%). The simplified 3-item CDT scoring system, with a cutoff score of 2/3, has
      a sensitivity of 72.9% and a specificity of 65.6%; it can be used as a quick test
      for AD screening.

PMID- 12464720
TI  - The timing of antiparkinsonian treatment reduction after subthalamic nucleus
      stimulation.
AB  - The objective of this work was to precisely analyse the reduction of the
      antiparkinsonian treatment in 18 consecutive patients with Parkinson's disease
      (PD) operated on for bilateral subthalamic nucleus (STN) stimulation, first after
      1 month of follow-up, then at 1 year postoperatively. Trihexyphenidyle,
      selegiline, entacapone, apomorphine and lisuride could be withdrawn shortly after
      starting STN electrical stimulation. The levodopa mean daily dose was reduced by
      57% at 1 month after surgery and remained stable at 1 year. The mean ropinirole
      and bromocriptine daily dose decrements after surgery corresponded to 54 and 63%,
      respectively, at 1 month and to 77 and 40% at 1 year. At 12 months
      postoperatively, one third of the patients no longer received any
      antiparkinsonian drugs and the others were on monotherapy of either levodopa or
      dopamine agonists or received a combined treatment of a dopaminergic agonist and
      levodopa. In conclusion, STN stimulation allows a major reduction and
      simplification of antiparkinsonian treatment which can usually be achieved during
      the early postoperative period.

PMID- 12464721
TI  - Acute paraneoplastic dysautonomia.

PMID- 12464722
TI  - Characterisation of infant food modifications in the European Union.
AB  - Improvements in the understanding of human milk composition, in dietetic effects
      on physiological outcomes in infants, and in food technology have lead to
      modifications in infant formulas and other dietetic products for infants. In
      Europe, new ingredients may be added to infant formula and follow-on formulas if
      their suitability for particular use by infants from birth has been established
      by generally accepted scientific data. However, there is uncertainty as to the
      nature of the evaluation needed to evaluate whether modifications in dietetic
      products for infants can be regarded as suitable and safe. Moreover, there is no
      agreement on the nature of evidence required to justify the scientific validity
      of potential effects on infant health and well-being, which might provide the
      basis for the communication of such effects to health professionals and
      consumers. Therefore, a scientific workshop was held under the auspices of the
      Child Health Foundation, Munich, Germany, and the European Society for Paediatric
      Gastroenterology, Hepatology and Nutrition to discuss issues arising in this area
      among participants representing academia, infant food industry, consumer
      organisations, the European Commission, and food regulatory bodies of some
      European Union member states. This article summarises the outcomes of this
      workshop. The participants agreed on general concepts of evaluation of
      innovations and on establishing evidence for benefits, but felt that further
      discussion would be necessary on the principles and practicalities involved in
      setting up a central register of clinical trials and of a central repository of
      trial data.

PMID- 12464723
TI  - Feeding patterns in breast-fed and formula-fed infants.
AB  - AIM: The intention of this study performed in healthy breast- and formula-fed
      infants was to characterize physiological feeding patterns as a basis for
      counseling parents to feed their infants on demand. METHODS: Ingested milk
      volumes of 10 breast-fed and 14 formula-fed infants were measured during five 72
      hour investigation periods during the 3rd, 6th, 9th, 13th, and 17th weeks of
      life. RESULTS: A comparable diurnal distribution of feeds was observed in both
      groups during the first 9 weeks of life, with a day-night asymmetry of feeding
      first observed at the age of 6 weeks. Thereafter, formula-fed infants showed a
      further decrease in their nightly milk intake. Within the investigation period,
      the milk volume per feed rose from 100 (range 40-200) g to 140 (range 30-300) g
      in the breast-fed group and from 100 (range 20-200) g to 200 (range 20-450) g in
      formula-fed infants. From the 6th week of life onwards, formula-fed infants had
      significantly higher feeding volumes. CONCLUSIONS: Parents should be informed
      about the variability of infant demands per feed and of feeding at night observed
      in breast-fed infants. The results suggest that feeding patterns similar to those
      of breast-fed infants are difficult to accomplish in formula-fed infants.

PMID- 12464724
TI  - Effects of calcium and phosphorus intake and excretion on bone density in
      postmenopausal women in Hermosillo, Mexico.
AB  - Calcium (Ca) is important in bone formation and as aging progresses, bone loss
      gradually occurs. With the onset of menopause, reduced estrogen levels and
      insufficient Ca in the diet often create serious problems with fractures. Since
      little is known about the diet and other factors related to risk factors in
      postmenopausal women in northern Mexico, it was the objective of this study to
      determine the effects of dietary Ca and phosphorus (P) and their excretion,
      anthropometric measurements, and blood serum estradiol on bone density in women
      aged 45-63 years. No studies are available on the dietary intake of Ca and P and
      the effects on bone mineral density (BMD) in postmenopausal women in northern
      Mexico, so this study reports some of the first data on this population. Women
      with an average age of 55 years showed a positive relation of Ca intake and Ca
      excretion, however, dietary intake of Ca and P had no relation to bone density.
      Age, urinary Ca, Ca/creatinine and years of postmenopause had the highest
      negative correlation. Weight and body mass index had a positive correlation with
      BMD in the forearm and heel. Only 15% of the women met the recommendation of
      1,500 mg/day of Ca. A high Ca/creatinine ratio has been proposed to indicate
      excess Ca excretion and subsequent bone density loss. Thirty-five percent of the
      women exceed the Ca/creatinine indicator of >0.16. In this study, 1% of the
      subjects were classified as osteoporotic and 37% as osteopenic.

PMID- 12464725
TI  - Effect of short-chain fructooligosaccharides and cellulose on cecal enzyme
      activities in rats.
AB  - The effect of fructooligosaccharides (FOS) on cecal enzyme activity was studied.
      Adult male Wistar rats were fed a fiber-free diet supplemented with 5% cellulose,
      a 5% mixture (1:1) of cellulose and FOS or 5% FOS as a source of fiber for 4
      weeks. The cecal content was used to measure azoreductase, beta-glucuronidase,
      beta-glucosidase, nitrate reductase and nitroreductase activities. Cellulose-fed
      diet increased significantly body weight gain, food intake and fecal stool weight
      compared to FOS-fed diet. No differences in food intake between FOS-containing
      diets were found. FOS-containing diets showed statistically higher weight of
      cecal content and weight of cecal wall compared with the cellulose group. There
      were significant differences in cecal enzyme activities between cellulose-fed
      rats and FOS-fed rats. Cellulose-FOS-fed diet decreased significantly
      nitroreductase, beta-glucuronidase and beta-glucosidase enzymes, but did not
      differ statistically in azoreductase and nitrate reductase compared with the
      control group. FOS-fed diet increased significantly reductive enzymes and
      decreased hydrolytic enzymes compared with the cellulose group. The incorporation
      of cellulose in diet seems to affect the prebiotic effect of FOS, since both
      cellulose and FOS are possible substrates for bifidobacteria proliferation. The
      results suggest that a mixture of cellulose and FOS as a source of dietary fiber
      could have a healthier effect on bacterial enzyme activities than each type of
      dietary fiber alone.

PMID- 12464726
TI  - Antihypertensive effects of hydrolysates of wakame (Undaria pinnatifida) and
      their angiotensin-I-converting enzyme inhibitory activity.
AB  - AIM: The angiotensin-I-converting enzyme (ACE) inhibitory and antihypertensive
      activities of wakame hydrolysates have been investigated in several studies.
      METHODS: Wakame (Undaria pinnatifida) was hydrolyzed using 17 kinds of proteases
      and the inhibitory activity of the hydrolysates for ACE was measured. Of these
      hydrolysates 4 with potent ACE inhibitory activity were administered singly and
      orally to spontaneously hypertensive rats (SHR). RESULTS: The systolic blood
      pressure of SHR decreased significantly after single oral administration of
      protease S 'Amano' and proleather FG-F hydrolysates (10 mg protein/kg body
      weight). In a long-term feeding experiment, 7-week-old SHR were fed standard chow
      supplemented with protease S 'Amano'-derived wakame hydrolysates for 10 weeks. In
      SHR fed the 1 and 0.1% wakame hydrolysates, elevation of systolic blood pressure
      was still significantly suppressed for 7 weeks. CONCLUSIONS: The hydrolysates
      derived from wakame by protease S 'Amano' have a powerful ACE-inhibitory activity
      (IC(50) = 86 microg protein/ml) and were effective in spite of their slight
      bitterness as 'physiologically functional food' with antihypertensive activity.

PMID- 12464727
TI  - Effect of ingestion of thermally oxidized sunflower oil on the fatty acid
      composition and antioxidant enzymes of rat liver and brain in development.
AB  - BACKGROUND: The current study was undertaken to assess the effects of oxidized
      sunflower oil ingestion (obtained by heating at 98 degrees C with air
      insufflation during 48 h and incorporated at 5% in a fat-free diet) on liver and
      brain fatty acid composition, and some serum parameters and protective enzymes
      against peroxidation (glutathione peroxidase, glutathione reductase, catalase and
      glucose-6-phosphate dehydrogenase). RESULTS: The main results show that the
      oxidized oil contains 262 mmol/kg of hydroperoxides, 5.7% of the esters are
      oxidized and 50.4% are polymerized. In the liver, we noticed that oxidized oil
      exercises a toxic effect as confirmed by the increase in the thiobarbituric acid
      reactive substance (TBARS) concentration. In the same way, we noticed that
      vitamin E exercises a favorable effect in the preservation against free radicals
      and lipid peroxidation; however, it cannot ensure this protection alone. In the
      liver, only glutathione peroxidase and glutathione reductase activities were
      positively correlated with the TBARS concentration. In the treated groups, we
      also noted changes in the fatty acid profiles of liver and brain homogenates,
      essentially by the appearance of trans fatty acid (18:1 trans) and an increase in
      arachidonic acid content.

PMID- 12464728
TI  - From genotype to phenotype in Leber hereditary optic neuropathy: still more
      questions than answers.

PMID- 12464729
TI  - Lightning strikes twice: Leber hereditary optic neuropathy families with two
      pathogenic mtDNA mutations.
AB  - OBJECTIVE: To report the clinical and mitochondrial genetic analyses of two
      families, each of which carries both the 11778 and 14484 Leber hereditary optic
      neuropathy (LHON) mutations in mitochondrial DNA. METHODS: In addition to
      detailed clinical histories, the complete sequence of the mitochondrial DNA
      (mtDNA) from each family was determined. RESULTS: A small Australian LHON family
      (Vic20) and a family from the United States carry the 11778 and 14484 LHON
      mutations. In addition to the optic neuropathy, one branch of the Baltimore LHON
      pedigree had a high incidence of a fatal infantile encephalopathy. In both
      families, the 14484 LHON mutation was homoplasmic, whereas the 11778 LHON
      mutation was heteroplasmic. CONCLUSIONS: There are no additional mtDNA sequence
      changes that explain the encephalopathy in the Baltimore LHON family, and a
      nuclear gene involvement is an alternative explanation that is supported by the
      available data. The ophthalmological characteristics and penetrance in the 11778
      and 14484 "two-mutation" LHON families are not markedly more severe than those of
      classic LHON families who carry a single mtDNA mutation.

PMID- 12464730
TI  - Contrast letter acuity as a measure of visual dysfunction in patients with
      Friedreich ataxia.
AB  - BACKGROUND: Friedreich ataxia is a progressive neurodegenerative disorder
      affecting afferent cerebellar pathways and other neuronal systems, including
      afferent visual pathways. A systematic clinical outcome measure for examination
      of visual dysfunction in Friedreich ataxia has not been identified. We sought to
      identify a simple, reliable method for assessing clinical and subclinical visual
      dysfunction in patients with Friedreich ataxia. METHODS: Contrast letter acuity
      was measured binocularly in Friedreich ataxia patients and age-matched visually
      asymptomatic volunteers (control group) using the Low-contrast Sloan Letter
      Charts at three different low-contrast levels (5.0%, 1.25%, and 0.6%). Binocular
      high-contrast visual acuity (100% level) was also determined for each
      participant. RESULTS: Despite equal median binocular high-contrast visual
      acuities between the two groups, patients with Friedreich ataxia had
      significantly lower (worse) Low-contrast Sloan Letter Chart scores compared with
      controls, particularly at the lowest contrast levels (1.25% and 0.6%). Ambulation
      status significantly predicted Low-contrast Sloan Letter Charts scores in linear
      regression models accounting for patient age, suggesting a potential
      complementary role for Low-contrast Sloan Letter Chart testing in the assessment
      of disease status as well as visual function in Friedreich ataxia. CONCLUSIONS:
      This study demonstrates that Low-contrast Sloan Letter Chart testing may provide
      a useful clinical outcome measure for Friedreich ataxia and other neuro
      ophthalmologic disorders.

PMID- 12464731
TI  - Nerve sheath tumors of the sellar region.
AB  - Nerve sheath tumors, including schwannomas and neurofibromas, rarely affect the
      sellar region. The authors report two such cases that were mistaken for pituitary
      adenomas on the basis of clinical and imaging features.

PMID- 12464732
TI  - The eyes of mito-mouse: mouse models of mitochondrial disease.
AB  - The recent creation of several mouse models of mitochondrial diseases has
      provided new insights into the understanding of human mitochondrial disorders.
      Whether these animals have clinical or histologic ophthalmologic abnormalities is
      of great interest given the high frequency of such abnormalities in humans with
      mitochondrial disorders. In this article, we describe the currently available
      mouse models for mitochondrial diseases with special emphasis on their ocular
      phenotype. These mouse models demonstrate multiple and varied ophthalmologic
      manifestations.

PMID- 12464733
TI  - Developmental neurogenetics and neuro-ophthalmology.
AB  - The field of developmental neurogenetics has burgeoned over the past decade.
      Through the combined efforts of developmental biologists, geneticists, and
      clinicians, genetic defects resulting in neuro-ophthalmic disorders such as
      holoprosencephaly, microphthalmia, dominant optic atrophy, and optic nerve
      colobomas have been identified and characterized at the molecular level.
      Experimental studies in model organisms are continuing to identify novel genes
      critical for ocular and central nervous system development. Mutations in some of
      these genes have revealed a spectrum of pathology similar to that observed in
      septo-optic dysplasia, Moebius syndrome, and Duane retraction syndrome. This
      review examines our current knowledge of the molecular genetics of neuro
      ophthalmic disease and focuses on several candidate genes for afferent and
      efferent visual system disorders.

PMID- 12464734
TI  - Practical approaches to neurogenetic disease.
AB  - Over the past 15 years, molecular genetic advances have led to new approaches for
      evaluation of neurogenetic disease. New diagnostic tests are available, and in
      some cases new diseases have been defined. However, effective use of these new
      tests still relies on solid clinical assessment to prioritize testing and
      interpret results. This review presents applications of genetic advances to a
      series of neurogenetic disorders, emphasizing the specific uses of genetic
      testing and the clinical questions that may arise. The rapid expansion in
      molecular diagnostics and genomics has fundamentally changed the approach to
      neurogenetic illnesses. Use of molecular biologic techniques has elucidated new
      disease mechanisms and allowed the application of genetic concepts to classically
      nongenetic illnesses. This has led to a wealth of new clinical information and
      created new dilemmas in patient care. In addition, it has brought into common
      usage a series of clinical genetic terms, such as variable expressivity (the
      range of phenotypic features in which the same disease can manifest) and
      anticipation (the progressively earlier age of onset of a specific disease in a
      family). This review provides a practical approach for neurogenetic evaluation of
      individuals who are likely to present in neuro-ophthalmologic practices with
      inherited ataxias, myotonic dystrophy, oculopharyngeal dystrophy, and Parkinson
      disease.

PMID- 12464735
TI  - 14th International Neuro-Ophthalmology Society (INOS) Meeting, Buenos Aires,
      Argentina, May 5-8, 2002.

PMID- 12464736
TI  - Patient education in the Internet era.

PMID- 12464737
TI  - Use of MindMapper software for research domain mapping.
AB  - The application of concept mapping software to facilitate the first steps of the
      research review process is discussed in relation to other software programs
      currently used for research synthesis. MindMapper software was used to develop a
      strategy for organizing the results of a comprehensive literature search into
      discrete categories with relationships among concepts graphically displayed to
      reveal the structure of the research domain. A Mind Map was developed for the
      scholarly literature on Web-based consumer health information. A second Mind Map
      examined the subconcept of barriers to consumer use of the Internet for health
      information. MindMapper has many features that facilitate description of the
      breadth and depth of literature in a domain of inquiry. It also facilitates
      identification of the number and nature of studies underpinning mapped
      relationships among concepts, thus laying the groundwork for systematic research
      reviews and meta-analyses.

PMID- 12464738
TI  - Piloting an information literacy program for staff nurses: lessons learned.
AB  - Intrinsic to all models of evidence-based practice is the need for information
      literacy and the critical assessment of information. As part of a house-wide
      evidence-based practice initiative, the objective of this pilot project was to
      develop the information literacy skills of staff nurses to increase their ability
      to find and assess available electronic resources for clinical decision making.
      An intensive care unit was chosen to pilot a unit-based approach to educate staff
      nurses to perform patient care-related electronic literature searches. An
      additional goal was to determine the effectiveness of unit-based training
      sessions on the frequency and quality of electronic literature searches by
      participating nurses. In addition to the unit-based instruction, nursing and
      library staff collaborated to develop a Web-based tutorial to supplement and
      reinforce the content of the training sessions. A pretest-post-test design was
      used to evaluate the initiative and to assess the effect of the educational
      intervention over time. Among the lessons learned from this pilot study was that
      unit-based instruction presents significant obstacles for effective learning of
      new technological skills for staff nurses.

PMID- 12464739
TI  - Implementing a Web-based information resource at an inner-city community church:
      lessons learned.
AB  - The objective of this project was to develop and implement electronic access to
      HIV/AIDS information resources at Glide Memorial Church in San Francisco, CA.
      This involved developing tailored Web-based access to the relevant information
      for the Glide Clinic patients. In addition, the project deployed workstations in
      2 clinic areas and provided support to clinic patients as they learned to access
      the information resources. This article describes the experience with information
      retrieval in a clinic setting for underserved patients, including lessons
      learned, effective strategies, and anecdotes of effect on patients. Required
      nursing informatics competencies in this particular area are also addressed.

PMID- 12464740
TI  - Creating an interactive interdisciplinary electronic assessment.
AB  - The transition from the paper medical record to a fully computerized patient
      record has not been without pain or dissatisfaction from clinical staff. An often
      heard question is, "Are we working for the computer or is the computer working
      for us?" Documenting patient care activities is a driving force in care planning,
      treatment, and reimbursement. Patient assessments are traditionally detailed and
      at least partially documented during the face-to-face interaction between the
      clinical staff and the patients. Historically, overprinted forms have been
      developed to guide the documentation of the patient responses to the assessment
      and care planning. The overprinted forms are lengthy, cumbersome, and available
      only in hard copy and, therefore, not part of a computerized patient record.
      Tools enabling these overprinted assessments to be part of the computerized
      patient record are now available in the Computerized Patient Record System of the
      Department of Veterans Affairs. This article describes the method used by the
      Butler, PA, Veterans Affairs Medical Center Clinical Information Systems
      Coordinator to transform an existing assessment document into an interactive
      interdisciplinary assessment.

PMID- 12464741
TI  - Predicting NCLEX success with the HESI Exit Exam: fourth annual validity study.
AB  - The fourth annual validity study of the Health Education Systems, Inc. (HESI)
      Exit Exam was designed to examine not only the accuracy of the examination in
      predicting NCLEX success but also the degree of risk for failure of the licensure
      examination associated with specific scoring intervals. A descriptive comparative
      design was used to examine the data provided by schools of nursing regarding
      students' NCLEX outcomes in the 1999-2000 academic year. As in the 3 previous
      studies, the examination was found to be a highly accurate predictor of NCLEX
      success (98.46%). Each scoring interval was significantly different from each of
      the other scoring intervals ( =.001). In fact, for the combined group of
      registered nurse and practical nurse students, the percentage of students who
      failed the NCLEX more than doubled with each successively lower scoring interval.
      These findings provide the information faculties needed to make evidence-based
      decisions regarding students' risks for NCLEX failure. Additionally, frequency
      data were obtained from this survey regarding the use of the examination as a
      benchmark for progression and remediation, and these findings may also be useful
      to faculties that are considering establishing such programs.

PMID- 12464743
TI  - Bone microstructure in osteoporosis: transilial biopsy and histomorphometry.
AB  - The bone fragility of osteoporosis is not fully explained by a deficit in bone
      mass. Histomorphometric examination of transilial bone biopsies has identified
      microstructural defects that-in light of what is known about the mechanical
      properties of structural materials-further compromise bone strength.
      Histomorphometric measures describe the biopsy specimen, the configuration of its
      trabeculae in space, and the extent to which its trabecular lattice is intact. In
      postmenopausal women with established osteoporosis, a deficit of both cortical
      and cancellous bone is typical, i.e., both cortical thickness and cancellous bone
      volume tend to be substantially reduced. Much of the cancellous bone deficit can
      be attributed to loss of entire trabecular elements rather than to generalized
      thinning of trabeculae. Direct measures of trabecular connectivity confirm this
      impression: women with established osteoporosis have fewer trabecular nodes and
      more termini than healthy women, even at the same cancellous bone volume.
      Evidence for accumulated microdamage in transilial biopsies is circumstantial,
      and the phenomenon itself may well be localized to fracture sites.
      Histomorphometric data from transilial biopsies comprise a large body of
      information about the structural and functional character of osteoporosis and
      provide valuable information about the effects of new treatments on bone
      microstructure.

PMID- 12464744
TI  - The Zurich experience: one decade of three-dimensional high-resolution computed
      tomography.

PMID- 12464745
TI  - Magnetic resonance imaging of trabecular bone structure.

PMID- 12464746
TI  - Role of magnetic resonance for assessing structure and function of trabecular
      bone.
AB  - The strength of trabecular bone and its resistance to fracture traditionally have
      been associated with apparent density. This paradigm assumes that neither the
      ultrastructural nor microstructural make-up of the bone is altered during aging
      and osteoporosis. During the past decade there has been growing evidence from
      both laboratory and clinical studies against this view. Recent advances in
      noninvasive imaging technology, notably micro-magnetic resonance imaging (micro
      MRI) and computed tomography, offer an opportunity to test the hypothesis that
      architecture is an independent contributor to bone strength. MRI appears to be
      ideally suited for this task because bone marrow has uniform high signal
      intensity while bone appears with background intensity, thus yielding a binary
      system tomographic system. However, in vivo trabecular bone imaging is hampered
      by the limited signal-to-noise ratio that precludes voxel sizes much smaller than
      trabecular thickness, which would be required to yield a bimodal intensity
      histogram for segmentation of the image into bone and marrow. The resulting
      partial volume blurring leads to fuzzy boundaries. Successful structure analysis
      thus demands more elaborate processing strategies. This article reviews new
      approaches conceived in the authors' laboratory toward acquisition, processing,
      and structural analysis of trabecular bone images in the limited spatial
      resolution regimen of in vivo micro MRI. These methods are shown to provide
      detailed insight into the three-dimensional trabecular network topology and scale
      at the distal radius or distal tibia that typically serve as surrogate sites. The
      micro MRI-derived structural parameters are shown to be associated with the
      bone's biomechanical properties and fracture resistance. Further, the technology
      has advanced to a stage permitting serial studies in laboratory animals and
      humans as a means to evaluate the effects of treatment. The method currently is
      confined to peripheral skeletal sites, and its extension to typical fracture
      sites such as the proximal femur hinges on further advances in detection
      sensitivity.

PMID- 12464747
TI  - Characterization of the integrity of three-dimensional trabecular bone
      microstructure by connectivity and shape analysis using high-resolution magnetic
      resonance imaging in vivo.
AB  - Bone mineral density and bone structure are the main determinants of bone
      strength in osteoporosis. In this study we used high-resolution magnetic
      resonance imaging to visualize the bone microstructure in the finger phalanges in
      vivo and to assess the topological three-dimensional connectivity of the
      trabecular network and the shape of the trabeculae as measures of bone quality.
      We visualized the phalanges of young and elderly healthy volunteers in vivo with
      a spatial resolution of 152 microm x 152 microm x 280 microm. Image processing
      software to quantify three measures of connectedness was developed and tested:
      connectivity, global connectivity density, and local connectivity density. Global
      three-dimensional connectivity ranged from 904 to 1,607 connections. Global
      connectivity density ranged from 2.9 to 4.7 connections per mm with large
      intersubject differences. We found a decrease of local connectivity density with
      growing distance from the joint ranging from 5.1 to 0.2 connections per mm. These
      preliminary results represent a quantitative description of the well-known
      rarefication of the trabecular network when moving from epiphysis to the
      diaphysis. Three-dimensional visualization showed a dense network consisting
      mostly of rod-like trabeculae at the epiphysis changing to a less dense network
      of a few plate-like structures near the medullary canal. An algorithm for the
      quantitative classification of trabecular architecture with regard to plate or
      rod-like shape was tested for feasibility. We conclude that in vivo assessment of
      three-dimensional properties of the trabecular network is possible in human
      phalanges. Determination of connectivity and shape will allow quantification of
      structural aspects of osteoporotic changes and may improve assessment of fracture
      risk.

PMID- 12464748
TI  - High-resolution magnetic resonance imaging to assess trabecular bone structure in
      patients after transplantation: a review.
AB  - After organ transplantation patients have a higher incidence of osteoporotic
      fractures. Bone mineral density (BMD) measurements to assess fracture risk are of
      limited value in these patients. On the other hand, structure-based techniques
      have shown promise. In this review, the use of high-resolution magnetic resonance
      imaging in the analysis of the trabecular bone structure in patients before and
      after renal and cardiac transplantation cross-sectionally is presented. The
      analyses of calcaneal trabecular structure were compared with BMD with regard to
      the prediction of therapy-induced bone loss and osteoporotic fracture status.
      Sagittal and axial T1-weighted spin-echo sequences with a voxel size of 0.2 x 0.2
      x 1 mm were performed at 1.5 T and structure measures analogous to bone
      histomorphometry were calculated. In addition, fracture status of the spine and
      of the peripheral skeleton was assessed. Structure measures showed significant
      differences between healthy controls and patients before and after renal and
      cardiac transplantation (p < 0.01). Osteoporotic fractures were found in
      approximately 35% of the transplant patients; the percentage was higher in the
      cardiac transplants. Structure measures and BMD were lower in patients with
      fractures; differences were more significant in the cardiac transplant patients.
      Using receiver operating characteristic analyses the diagnostic performance in
      differentiating patients with and without fractures was highest when BMD and
      structure measures were combined. Structure measures performed better than BMD in
      the cardiac transplant patients, whereas results were comparable in the renal
      transplant patients. In conclusion, structure measures determined in high
      resolution magnetic resonance images may be useful in assessing changes of
      trabecular bone after organ transplantation and may improve the prediction of
      fracture risk.

PMID- 12464749
TI  - Reorientation of attention in Huntington disease.
AB  - OBJECTIVES AND BACKGROUND: This experiment sought to quantify the extent to which
      patients with Huntington disease (HD) have difficulties in orienting attention,
      via a vibrotactile version of a Posner-type cost-benefit paradigm. METHOD:
      Participants were required to push a button in response to a vibration delivered
      to the index finger of either hand. Prior to each stimulus vibration, a precue
      (valid, neutral, or invalid) was delivered to the finger. Benefits and costs were
      calculated from valid and invalid precues. RESULTS: Although patients with HD
      were overall slower than the controls, their performance was no different; both
      patients and controls demonstrated increased benefits from valid compared with
      invalid and neutral cues. Of interest was the finding that patients, unlike
      controls, performed significantly slower with the cue presented to the left
      compared with the right side. The crossed arm configuration proved to be too
      difficult for the patients with HD, and thus an analysis on these data was not
      permitted. CONCLUSIONS: Patients may experience difficulties in allocating
      attentional resources toward their left nonpreferred hand. Overall, findings
      demonstrate that patients with HD, with minimal caudate damage at early stages of
      disease onset, may not experience problems in their ability to orient attention.

PMID- 12464750
TI  - A multivariate classification study of attentional orienting in patients with
      right hemisphere lesions.
AB  - OBJECTIVE: To characterize patterns of orienting dysfunction that were typical to
      patients with lesions in the right hemisphere (RH). BACKGROUND: Brain lesions in
      the right hemisphere are commonly associated with dysfunction of visual orienting
      (e.g., visual neglect and extinction). In a clinical study of these symptoms, the
      multicomponent nature of attentional orienting calls upon a multivariate
      statistical design with careful selection of neurocognitive variables. METHODS:
      Thirty-eight patients with verified brain lesions and four patients with
      peripheral motor dysfunction after poliomyelitis were included in the study.
      Cognitive function was evaluated in all patients. Three reaction-time (RT)
      measures derived from the cue-target paradigm were selected as features in a data
      driven multivariate classification scheme to generate natural subgroups of
      patients. RESULTS: Four subgroups were generated, with only RH patients allocated
      to two of them. All patients within one of the RH subgroups were characterized by
      a pattern of impairment earlier described as a "disengage failure" by Posner et
      al. ( 5, 6), signs of visual neglect on Behavioral Inattention Test, and a
      severely impaired cognitive function. Results for the other RH subgroup were
      heterogeneous on both experimental and clinical variables. Age and cognitive
      function were found to strongly influence two of the features, but could not
      predict the clusters generated from the RT measures. CONCLUSIONS: The present
      findings show that the cue-target paradigm together with multivariate clustering
      of selected feature variables can serve as a useful tool to explore and
      characterize patients with right hemisphere lesions. Although the concept of
      "disengage failure" was suited to describe the typical RT pattern in patients
      with neglect, other neurocognitive models and concepts can be applied to the
      results in the current study.

PMID- 12464751
TI  - Hypersexuality after pallidal surgery in Parkinson disease.
AB  - OBJECTIVE: To examine the possible association of neuropsychiatric symptoms and
      pallidal surgery for Parkinson disease (PD). BACKGROUND: Parkinson disease may be
      accompanied by a variety of psychiatric symptoms. It is important to distinguish
      these from psychiatric syndromes that are associated with the treatment of PD.
      METHODS: Case description of a patient with PD and a history of right pallidotomy
      who developed a psychiatric syndrome, including prominent hypersexuality, after
      surgical implantation of a deep brain stimulator electrode in the left globus
      pallidus. RESULTS AND CONCLUSIONS: This case demonstrates that patients receiving
      antiparkinson medication may be at risk for the development of psychiatric
      sequelae after pallidal surgery.

PMID- 12464752
TI  - Misdiagnosis of schizophrenia in a patient with psychotic symptoms.
AB  - OBJECTIVE: A case is presented of a 37-year-old black woman with a 5-year history
      of a chronic psychotic illness, diagnosed as schizophrenia, who presented to the
      emergency room complaining of a severe headache, while appearing confused and
      experiencing visual and auditory hallucinations. The purpose of this case study
      is to illustrate the way in which the appellation of schizophrenia can be
      misapplied in a patient with a complicated medical history and poor follow-up
      evaluation and treatment. BACKGROUND: Patients with active psychosis are
      frequently unable to provide a coherent or comprehensive medical history. In the
      absence of obvious indications to the contrary, a diagnosis of a primary
      psychiatric illness is often assumed, especially if this label has been applied
      in the past. However, the differential diagnosis of psychosis is extensive.
      METHODS: This patient was given a complete psychiatric and neurologic evaluation,
      and aspects of the history that had been lost or ignored were uncovered and
      reevaluated. RESULTS: A diagnosis other than schizophrenia was made and another
      treatment, other than antipsychotic drugs, was initiated. The patient responded
      rapidly with improved cognitive function and resolution of her psychotic
      symptoms. CONCLUSIONS: This case serves to illustrate how the absence of a
      careful clinical assessment and historical case review, in patients who have been
      previously labeled as schizophrenic, can perpetuate misdiagnoses and
      inappropriate treatments. It highlights the importance, especially in patients
      with an incomplete medical history, of ruling out all organic causes of psychosis
      to avoid inappropriately labeling someone as having a psychiatric illness.

PMID- 12464753
TI  - Publishing with students--an uncontrolled variable.

PMID- 12464754
TI  - An intervention to increase safety behaviors of abused women: results of a
      randomized clinical trial.
AB  - BACKGROUND: Although intimate partner violence is recognized as a major threat to
      women's health, few interventions have been developed or tested. OBJECTIVE: To
      test an intervention administered to abused women in order to increase safety
      seeking behaviors. METHOD: A two-group clinical trial randomized 75 abused women
      to receive six telephone intervention sessions on safety behaviors. A control
      group of 75 women received standard care. Women in both groups were re
      interviewed at 3 months and 6 months post-initial measurement. RESULTS: Using
      repeated measures analysis of variance (ANOVA), we found significantly [F (2,146)
      5.11, =.007] more adopted safety behaviors reported by women in the intervention
      group than by women in the control group at both the 3-month [F (91,74) = 19.70,
      <.001] and 6-month [F (1,74) = 15.90, <.001] interviews. The effect size (ES) of
      the intervention was large at 3 months (ES = 1.5) and remained substantial at 6
      months (ES = 0.56). DISCUSSION: These findings demonstrate that an intervention
      to increase safety behaviors of abused women is highly effective when offered
      following an abusive incident and remains effective for 6 months.

PMID- 12464755
TI  - Determinants of Medicare home healthcare service use among Medicare recipients.
AB  - BACKGROUND: Medicare reimbursement for home healthcare (HHC) services has changed
      dramatically in recent years. A clear understanding of the determinants of
      Medicare HHC services use is needed so that HHC agencies can meet the demand for
      services from an aging population while remaining financially sound. OBJECTIVES:
      The purpose of the study was to identify the determinants of Medicare HHC service
      within the framework of the Andersen Behavioral Model. METHODS: This cross
      sectional secondary analysis used data from the 1996 Medical Expenditures Panel
      Survey to examine characteristics of 239 subjects who had received Medicare
      reimbursed HHC services. Predisposing characteristics, enabling resources, and
      need characteristics were examined to explain Medicare HHC service use. Two
      criterion measures, annual Medicare expenditures and days of care, were employed
      in hierarchical regression analyses. RESULTS: Variance in annual Medicare
      expenditures was explained by both the predisposing (R(2) =.16, <.001) and need
      characteristics (R(2) =.09, <.001). Variance in days of care was explained by
      predisposing characteristics (R(2) =.12, <.001) and need characteristics (R(2)
      =.15, <.001). The adjusted for the total model was.21 for annual Medicare
      expenditures and.25 for days of care. CONCLUSIONS: While Andersen's Behavioral
      Model is useful in explaining Medicare HHC service use, it may be important to
      use multiple measures as criterion variables since the amount and proportion of
      variance explained differs with the variable used.

PMID- 12464756
TI  - Impact of a psychoeducational intervention on caregiver response to behavioral
      problems.
AB  - BACKGROUND: Eighty percent of persons with Alzheimer's disease and related
      disorders are cared for by family members who often lack adequate support and
      training for this all-consuming job. OBJECTIVE: To evaluate the efficacy of a
      longitudinal, multisite, community-based intervention designed to teach home
      caregivers to manage behavioral problems in persons with Alzheimer's disease.
      METHODS: Usable data were analyzed from 237 caregiver/care recipient dyads (n =
      132 Experimental; n = 105 Comparison). The experimental group received a
      psychoeducational nursing intervention that was conceptually grounded in the
      Progressively Lowered Stress Threshold model (Hall & Buckwalter, 1987). The
      comparison group received routine information and referrals for case management,
      community-based services, and support groups. Although a variety of psychosocial
      outcomes were compared between caregivers in the two groups, this article focuses
      on frequency and response to behavioral problems and functional decline. RESULTS:
      The Progressively Lowered Stress Threshold intervention had a statistically
      significant effect on spousal response to memory/behavioral problems (p <.01) for
      all caregivers and on response to activities of daily living problems (p <.01)
      for spousal caregivers. In addition, nonspouses in the experimental group
      reported a reduction in the frequency of memory/behavioral problems (p <.01). No
      intervention effect on reports of activities of daily living frequencies was
      found for either spouses or nonspouses. CONCLUSIONS: This Progressively Lowered
      Stress Threshold-based intervention had a positive impact on both the frequency
      of and response to problem behaviors among spousal caregivers.

PMID- 12464757
TI  - Efficacy and safety of sucrose for procedural pain relief in preterm and term
      neonates.
AB  - BACKGROUND: Preterm and acutely ill term neonates who are hospitalized in a
      neonatal intensive care unit are subjected to multiple frequent invasive and
      painful procedures aimed at improving their outcome. Although several trials to
      determine the efficacy of sucrose for managing procedural pain in preterm and
      acutely ill term neonates have been developed, these have generally lacked
      methodological rigor and have not provided clinicians with clear practice
      guidelines. OBJECTIVES: To compare the efficacy and safety of three interventions
      for relieving procedural pain associated with heel lances in preterm and term
      neonates, and to explore the influence of contextual factors including sex,
      severity of illness, and prior painful procedures on pain responses. METHODS: In
      a randomized controlled trial, 190 neonates were stratified by gestational age
      and then randomized to receive (a) sucrose and nonnutritive sucking (n = 64), (b)
      sucrose alone (n = 62), or (c) sterile water and nonnutritive sucking (control)
      (n = 64) to evaluate the efficacy (pain response as measured using the Premature
      Infant Pain Profile) (Stevens, Johnson, Petryshen, & Taddio, 1996) and safety
      (adverse events) following a scheduled heel lance during the first week of life.
      Stratification was used to control for the effects of age on pain response.
      RESULTS: Significant differences in pain response existed among treatment groups
      (F = 22.49, p <.001), with the lowest mean Premature Infant Pain Profile scores
      in the sucrose and nonnutritive sucking group. Efficacy of sucrose following a
      heel lance was not affected by severity of illness, postnatal age, or number of
      painful procedures. Intervention group and sex explained 12% of the variance in
      Premature Infant Pain Profile scores. Few adverse events occurred (n = 6), and
      none of them required medical or nursing interventions. CONCLUSIONS: The
      combination of sucrose and nonnutritive sucking is the most efficacious
      intervention for single heel lances. Research on the effects of gestational age
      on the efficacy and safety of repeated doses of sucrose is required.

PMID- 12464758
TI  - A Delphi study to determine informatics competencies for nurses at four levels of
      practice.
AB  - BACKGROUND: Despite its obvious need, a current, research-based list of
      informatics competencies for nurses is not available. OBJECTIVE: To produce a
      research-based master list of informatics competencies for nurses and
      differentiate these competencies by level of nursing practice. METHODS: After a
      comprehensive literature review and item consolidation, an expert panel defined
      initial competencies. Subsequently, a three round Delphi study was conducted to
      validate the items. Participants were expert informatics nurse specialists in the
      United States of America. RESULTS: Of the initial 305 competencies proposed, 281
      competencies achieved an 80% or greater agreement for both importance as a
      competency and appropriateness for the correct practice level. Five competencies
      were rejected. Six competencies were considered valid competencies but the
      appropriate level of practice could not be agreed upon. Thirteen competencies did
      not reach any consensus after the three Delphi rounds. DISCUSSION: The Delphi
      study had a high rate of participation, demonstrating the great level of interest
      and need for a list of informatics competencies for nurses. Out of the initial
      305 competencies, only 24 items were not validated. Respondents commented during
      each round about whether computer skills should be considered informatics
      competencies. The authors propose that computer skills, while not high level, are
      one set of tools within the larger category of informatics competencies. This
      sample of experts did not deem programming skills as necessary for informatics
      nurses. This research study is an initial effort to fill the void of valid and
      reliable informatics competencies. It is the first study to span four levels of
      nurses, create competencies for both entry-level and experienced informatics
      nurse specialists, and examine the categories of computer skills, informatics
      knowledge and informatics skills.

PMID- 12464759
TI  - From "death sentence" to "good cancer": couples' transformation of a prostate
      cancer diagnosis.
AB  - BACKGROUND: While little is known about the couple's process of moving from
      diagnosis of prostate cancer to treatment, it is acknowledged that cancer-and
      prostate cancer in particular-affects the couple, not just the patient. This
      highlighted the need to illuminate this process as a foundation for development
      of nursing interventions. OBJECTIVES: To describe the experience of men who are
      diagnosed with prostate cancer and their wives, from the time of diagnosis
      through staging to the completion of radical prostatectomy. METHODS: A
      qualitative cross-sectional approach was used to elicit couples' experiences from
      diagnosis to the time of the interview including their response to diagnosis,
      their treatment decision-making process, and how the couple moved from the
      decision to have surgery through the staging process to the time that the surgery
      was completed. A total of 20 couples participated. RESULTS: Analysis of the data
      revealed that a number of themes related to the couples' process of moving from
      diagnosis to treatment. Initially, the diagnosis of prostate cancer represented a
      loss of control that led these couples to put themselves through a "crash course"
      on prostate cancer. The information gathered led these couples to conclude that
      prostate cancer was "good cancer." This enabled them to refocus their energies
      and start their "quest for the best" treatment and surgeon. Once this was
      accomplished, the couples began to prepare for surgery that culminated in the
      turning over of complete control to the surgeon and hospital staff at the time of
      surgery. CONCLUSIONS: The participants discovered they were able to manage the
      demands presented by the intrusion of a cancer diagnosis and mount a response to
      what at first threatened to be a "death sentence." By engaging in the challenge
      of gathering a volume of facts and a variety of details, they could make informed
      decisions. Couples were able to regain a sense of control through the engagement
      in decision-making related to treatment, surgeon, and hospital, and through the
      transformation of the meaning of the malignant diagnosis to that of a "good
      cancer."

PMID- 12464760
TI  - Predictive validity of the Braden Scale among Black and White subjects.
AB  - BACKGROUND: The Braden Scale for Predicting Pressure Sore Risk (Braden Scale) has
      been tested for predictive validity, but the cut-off scores for Blacks has not
      been compared to White populations. OBJECTIVES: The purpose of this brief report
      is to determine if the Braden Scale predicts pressure ulcer risk similarly for
      Blacks and Whites. METHOD: A multisite study of the predictive validity of the
      Braden Scale was conducted in nursing homes, tertiary care, and Veteran's
      Administration Medical Centers in three cities (Omaha, Chicago, and Raleigh)
      selected to maximize ethnic diversity. A total of 843 subjects, 666 (79%) White,
      159 (12%) Black were studied. Two nurses independently rated each randomly
      selected subject on admission and every other day until discharge, using the
      Braden Scale or the Skin Assessment Tool. RESULTS: Whites had a higher incidence
      of pressure ulcers (15%) than did Blacks (5%), but there was no statistically
      significant difference in the mean Braden Scale score between groups ( 19.4, 2.8,
      White versus 19.8, 2.75, Black). A score of 18 best predicts risk for both groups
      (sensitivity 70%, specificity 77%, with 75% correct predictions for Whites and
      sensitivity 75%, specificity 76%, with percent correct 76% for Blacks). There was
      no difference in the area under the receiver-operator characteristic (ROC) curves
      (0.75, 0.03, White and 0.82, 0.07, Black subjects, =.005). CONCLUSIONS: A score
      of 18 can be used for identifying Black and White individuals at risk for
      pressure ulcers.

PMID- 12464761
TI  - Multinomial logistic regression.
AB  - BACKGROUND: When the dependent variable consists of several categories that are
      not ordinal (i.e., they have no natural ordering), the ordinary least square
      estimator cannot be used. Instead, a maximum likelihood estimator like
      multinomial logit or probit should be used. OBJECTIVES: The purpose of this
      article is to understand the multinomial logit model (MLM) that uses maximum
      likelihood estimator and its application in nursing research. METHOD: The
      research on "Racial differences in use of long-term care received by the elderly"
      (Kwak, 2001) is used to illustrate the multinomial logit model approach. This
      method assumes that the data satisfy a critical assumption called the
      "independence of irrelevant alternatives." A diagnostic developed by Hausman is
      used to test the independence of irrelevant alternatives assumption. Models in
      which the dependent variable consists of several unordered categories can be
      estimated with the multinomial logit model, and these models can be easily
      interpreted. CONCLUSIONS: This method can handle situations with several
      categories. There is no need to limit the analysis to pairs of categories, or to
      collapse the categories into two mutually exclusive groups so that the (more
      familiar) logit model can be used. Indeed, any strategy that eliminates
      observations or combines categories only leads to less efficient estimates.

PMID- 12464762
TI  - Nurse educator, go home!

PMID- 12464763
TI  - Polanyi's philosophy: a new look at a theoretical framework.

PMID- 12464764
TI  - Use of dyadic role-playing to increase student participation.
AB  - Dyadic role-playing is a way to combine role-playing and dyad work in class to
      increase student participation. The instructor can use warm-up exercises to help
      students reduce their stress, and to recognize the value of role-playing in their
      journeys toward becoming professional nurses. The advantages, limitations, and
      practical considerations regarding dyadic role-playing are also highlighted.

PMID- 12464765
TI  - Using journals for community health students engaged in group work.
AB  - Teaching students concepts integral to community health nursing, such as
      collaboration and partnership, while providing clinical practica in community
      agencies, mandates that students address group process and evaluate self-growth.
      To facilitate reflection on self-learning in the context of collaborative group
      work, faculty and students use a structured, graded, weekly journal. This
      teaching and learning tool serves as a mechanism for assisting students with
      understanding group process.

PMID- 12464766
TI  - Accuracy of references in general readership nursing journals.

PMID- 12464767
TI  - Stakeholder involvement in curriculum planning: responding to healthcare reform.
AB  - Instead of nursing faculty deciding the kind of education needed for a new
      curriculum, views and suggestions were solicited from nurses, doctors, and policy
      makers to help shape the curriculum. When stakeholders are involved in curriculum
      planning, there is a greater likelihood that the needed education is delivered.
      The authors discuss the context, process, outcome, and pros and cons of
      stakeholder involvement.

PMID- 12464768
TI  - The use of handheld technology in nursing education.
AB  - Advances in technology must be integrated into curricula. The authors review the
      process and risks associated with adopting handheld technology and offer
      suggestions for integrating this technology into nursing curricula.

PMID- 12464769
TI  - Web-based teaching in undergraduate nursing programs.
AB  - This study examined faculty perspectives of teaching undergraduate nursing
      courses entirely online via the World Wide Web. More than 80% of the 171 faculty
      completing the online survey indicated spending more time planning and
      implementing a Web course than a traditional course. Forty-seven percent
      preferred online teaching to traditional instruction, and described the
      experience as a success beyond expectation. This positive reaction supports the
      ongoing viability of Web-based instruction in nursing education.

PMID- 12464770
TI  - The seven principles of good practice: applications for online education in
      nursing.
AB  - Traditional education has been studied over time for the purpose of documenting
      what constitutes good practice in teaching. Online education in nursing is still
      relatively new and has not endured the same scrutiny as classroom education. The
      authors discuss how Chickering and Gamson's Seven Principles of Good Practice for
      Undergraduate Education apply to online nursing education and provide practical
      examples of how the principles can be implemented in Web-based nursing courses.

PMID- 12464771
TI  - Nurse manager role in labor contract negotiations.

PMID- 12464772
TI  - Customer service for step-down patients.

PMID- 12464773
TI  - Development of the San Diego Nursing Service-education Consortium for Clinical
      Planning.

PMID- 12464774
TI  - Assessing differences in job satisfaction of nurses in magnet and nonmagnet
      hospitals.
AB  - Is there a difference in the level of job satisfaction among clinical nurses
      employed at magnet versus nonmagnet hospitals, and is it linked to nurse
      executive leadership? To answer these questions, 305 clinical nurses employed at
      magnet and nonmagnet hospitals rated their perceptions of job satisfaction while
      16 leaders from the same hospitals were interviewed for their perception of their
      role in healthcare. The author discusses that differences in job satisfaction
      scores were linked to greater visibility and responsiveness by magnet nurse
      leaders; better support of clinical nurse autonomous decision-making by magnet
      nurse leaders; and greater support of a professional nursing climate at magnet
      hospitals as evidenced by adequate staffing in the workforce.

PMID- 12464775
TI  - Implementing a geriatric resource nurse model.
AB  - The aging of the American population and its effects on healthcare centers
      require strategies and programs to ensure best practices for older patients. The
      authors describe an educational program, modification of a Geriatric Resource
      Nurse Model, and the use of a Geriatric Nurse Practitioner in implementing and
      integrating the clinical, psychosocial, and financial aspects that influence care
      needed by elderly patients and their families.

PMID- 12464776
TI  - The relationship of empowerment and selected personality characteristics to
      nursing job satisfaction.
AB  - PURPOSE: This study reports on a secondary data analysis undertaken to better
      understand the determinants of job satisfaction for hospital nurses. Both
      workplace and personal factors can contribute to job satisfaction. THEORETICAL
      FRAMEWORK: Kanter's theory of structural empowerment and Spreitzer's theory of
      psychological empowerment explain logical outcomes of managerial efforts to
      create structural conditions of empowerment. Selected personal attributes were
      also considered. METHOD AND SAMPLE: Instruments used were 1) Conditions for Work
      Effectiveness Questionnaire; 2) psychological empowerment tool; 3) a mastery
      scale; 4) an achievement scale; and 5) a job satisfaction scale. The sample of
      347 nurses (58% response rate) came from all specialty areas. RESULTS: Structural
      and psychological empowerment predicted 38% of the variance in job satisfaction.
      Achievement and mastery needs were not significant. Other personal attributes can
      be found in future research to improve job satisfaction. CONCLUSIONS: Through
      careful manipulation of the hospital environment, both structural and
      psychological empowerment can be increased, resulting in greater job and patient
      satisfaction and, ultimately, improved patient outcomes.

PMID- 12464777
TI  - Christman's principles for effective management: reflection and challenges for
      action.
AB  - Dr. Luther Christman developed a set of principles essential to effective nursing
      management in 1982. The authors cut through the change and chaos of the past 20
      years to focus on these meaningful principles and encourage readers to reflect
      and enact these principles in their practice.

PMID- 12464778
TI  - Of cells, mice, men and radiobiology.

PMID- 12464779
TI  - A phase I study of 99mTc-hR3 (DiaCIM), a humanized immunoconjugate directed
      towards the epidermal growth factor receptor.
AB  - A phase I trial was conducted to evaluate the safety, tumour and normal tissue
      localization, pharmacokinetics and radiation dosimetry of Tc-hR3, a humanized
      monoclonal antibody directed towards the epidermal growth factor receptor, in 12
      patients with recurrent or metastatic epithelial malignancies. Patients were
      injected intravenously with 3.0 mg or 6.0 mg (1010 MBq) of Tc-hR3. Blood and
      plasma concentrations of radioactivity were measured and a complete 24 h urine
      collection was obtained. Whole-body images were acquired up to 24 h post
      injection and normal organ uptake quantified. Radiation dosimetry was estimated
      using MIRDose. Safety was evaluated by clinical observation,
      biochemical/haematological testing and by measuring immune response to Tc-hR3.
      There were no adverse effects, no changes in biochemical/haematological indices
      and no immune response to Tc-hR3. Tc-hR3 was rapidly cleared from the blood with
      a distribution half-life of 10.8+/-3.8 min. The volume of distribution, and
      clearance, were 180+/-37 ml.kg and 14+/-3 ml.kg.min, respectively. The
      elimination phase could not be discerned due to increasing blood radioactivity at
      later times. About 19-24% was excreted in the urine. Normal tissue uptake was
      mainly in the liver (44-50%), spleen (3-4%) and kidneys (3%). Imaging was
      positive in one patient with squamous cell carcinoma of the mouth and an involved
      cervical lymph node. The whole-body radiation dose from Tc-hR3 was 1.34+/-0.02x10
      mSv.Bq. We conclude that Tc-hR3 exhibited an excellent safety profile. Future
      studies to determine the sensitivity and specificity of imaging with Tc-hR3 in a
      larger group of patients with pre-selection for epidermal growth factor receptor
      positivity are planned.

PMID- 12464780
TI  - Sentinel node localization in patients with non-palpable breast cancer.
AB  - The aim of this study was to demonstrate that radionuclide sentinel node
      detection can be applied to patients with non-palpable breast cancer. One hundred
      and ten consecutive women with unilateral breast cancer were studied. Group 1 was
      made up of 80 patients with palpable breast cancer (mean age, 58 years) and group
      2 of 30 patients with non-palpable breast cancer detected mammographically (mean
      age, 55 years). Tc-nanocolloid (111 MBq) was injected peritumorally in palpable
      tumours, and in the tumour area (ultrasound guided) in non-palpable tumours. At 2
      h post-injection, anterior and lateral scintigrams were obtained from patients in
      the supine position. The location of the sentinel node was marked on the
      patient's skin. Patients with non-palpable tumours were moved to the surgery room
      3 h later, and those with palpable tumours 24 h later. The histopathological
      study included three haematoxylineosin sections and immunochemistry. All patients
      underwent axillary lymphadenectomy. The sentinel node was detected in 67 cases
      (84%) in group 1 and in 28 cases (93%) in group 2. In four patients (5%) in group
      1 and two patients (7%) in group 2, no axillary sentinel node was detected in the
      surgical bed, although it had been seen in scintigraphy. In nine patients (11%)
      in group 1, neither scintigraphic nor surgical detection was successful. Skip
      metastasis was seen in six cases (10%) of palpable tumours and in one case (4%)
      of non-palpable tumours. It can be concluded that non-palpable breast tumours
      cannot be considered an exclusion criterion for sentinel node localization and
      biopsy. Ultrasonography-guided injection, followed by scintigraphic and surgical
      detection of the sentinel node, may help in the management of patients with non
      palpable breast tumours.

PMID- 12464781
TI  - Quantitative radionuclide lymphoscintigraphy predicts outcome of manual lymphatic
      therapy in breast cancer-related lymphedema of the upper extremity.
AB  - Secondary lymphedema is a localized, acquired lymphatic microcirculatory
      disturbance that affects large numbers of patients after breast cancer therapy.
      There is a paucity of objective methods to quantitate lymphatic function and to
      anticipate the response to therapeutic interventions. We applied radionuclide
      lymphoscintigraphy to evaluate lymphatic transport and axillary lymph node
      visualization in women following breast cancer therapy to determine the utility
      of these data in these patients. Lymphoscintigraphy was performed after
      subcutaneous injection of 0.25 mCi of Tc-filtered sulfur colloid. Subcutaneous
      accumulation of radiotracer ('dermal backflow') and the visualization of axillary
      lymph nodes were graded using our own scoring system. The ratio of radioactivity
      within the affected to normal axillae (ARR) was also quantified. Nineteen
      patients with lymphedema after breast cancer therapy were evaluated. The disease
      severity was documented by serial measurements of the limb volume using the
      truncated cone formula. Responses to therapy were quantified after completion of
      the therapy. There was a correlation between the ARR and the percentage reduction
      in edema volume. The lymphoscintigraphic score correlated with the initial arm
      volume excess and with the durationof lymphedema. It can be concluded that
      quantitative and semi-quantitative assessment by radionuclide lymphoscintigraphy
      represents a potentially useful tool for the clinical assessment of upper
      extremity lymphedema.

PMID- 12464782
TI  - Detection of inflammatory lymph nodes in rabbits by 99mTc-HIG lymphoscintigraphy.
AB  - Tc-Human immunoglobulin G ( Tc-HIG) is a well-known radiopharmaceutical for the
      evaluation of inflammatory lesions. Recently, it has been demonstrated as a new
      agent for the visualization of the lymphatic system by our group. Our aim was to
      investigate the feasibility of detection of inflammatory lymph nodes by Tc-HIG
      lymphoscintigraphy. Ten adult New Zealand rabbits were used as group A. In a
      baseline study, 37 MBq Tc-HIG (0.1 ml) was injected into both hind legs of the
      rabbits, and sequential posterior gamma imaging with the rabbits lying prone was
      performed at 5, 15, 30, 60, 90 and 120 min using a single-headed gamma camera
      (Toshiba GCA G01 E). One week later, microorganisms ( ) were injected in a volume
      of 0.1 ml intradermally into the web space between the second and third toes in
      the bilateral hind legs of each rabbit in order to obtain inflammation in the
      popliteal lymph nodes. After 4 days, 37 MBq Tc-HIG (0.1 ml) was injected into the
      hind legs of the rabbits bilaterally, and sequential posterior gamma imaging was
      performed as described above (second study). Another group of 10 adult New
      Zealand rabbits (group B) was injected with the same microorganisms in the right
      hind legs only. After 4 days, scintigraphic imaging was carried out in the same
      way as described above (third study). Regions of interest were drawn over the
      injection sites and popliteal lymph nodes on each image for semiquantitative
      analysis. Count rates for each were calculated and a decay correction was
      applied. Time-activity curves were generated to show the percentage retention of
      radioactivity in each region. After the scintigraphic study, some of the group B
      rabbits were killed by intravenous injection of pentobarbitone (100-150 mg.kg,
      and both left and right lymph nodes were removed for microscopic examination. On
      the scintigrams, lymphatic channels and popliteal lymph nodes were visualized
      within 15 min. In the second study, bilateral popliteal lymph nodes were
      visualized more clearly than in the baseline study. The right popliteal lymph
      nodes of the rabbits were more clearly visualized in the third study.
      Semiquantitative analysis showed a higher percentage uptake of radioactivity in
      the right compared to the left popliteal lymph nodes in group B rabbits.
      Microscopic examination of the tissue sections demonstrated inflammation in the
      right lymph nodes of group B rabbits. In this preliminary study, it was found
      that Tc-HIG is a new promising agent for the demonstration and evaluation of
      inflammatory lymph nodes.

PMID- 12464783
TI  - 99mTc-MIBI and 201Tl SPET in the detection of recurrent brain tumours after
      radiation therapy.
AB  - The purpose of this study was to evaluate whether Tc-hexakis-2
      methoxyisobutylisonitrile ( Tc-MIBI) or Tl single photon emission tomography
      (SPET) could detect recurrent tumours in patients with previous radiation therapy
      for brain tumours. Dual SPET with Tc-MIBI and Tl was performed in 21 patients
      suspected of having recurrent brain tumours. SPET images were acquired 15 min
      (early) and 2 h (delayed) after injection. The ratio of the average counts for
      the region of interest in the lesion area and its mirror image in normal brain
      tissue was obtained. Early and delayed ratios were calculated. On the basis of
      histological and/or clinical findings, the final diagnosis was considered as
      recurrent tumours in 15 patients and radiation necrosis in six. Both ratios using
      Tc-MIBI and Tl were significantly higher in recurrent tumours than in radiation
      necrosis. Based on a cut-off of 5.89 of the early ratio using Tc-MIBI to
      distinguish between recurrent tumours and radiation necrosis, the accuracy was
      90%. Based on a cut-off of 6.77 of the delayed ratio using Tc-MIBI, the accuracy
      was 86%. The corresponding values using cut-offs of 2.40 and 1.85 with Tl were
      90% and 86%, respectively. However, within recurrent tumours, both ratios for Tc
      MIBI were significantly higher than those for Tl. Early Tc-MIBI SPET may be
      especially useful for the detection of recurrent tumours in patients who have
      previously undergone radiation therapy for brain tumours.

PMID- 12464784
TI  - Experience with 123I-iomazenil SPECT in acute cerebral infarction.
AB  - Neuronal cells are susceptible to cerebral ischaemia. As gamma-aminobutyric
      acid(A) (GABA(A)) receptors are specific for neurones, functional receptor
      imaging using I-iomazenil (IMZ), a ligand to the GABA benzodiazepine receptor,
      has been proposed as an imaging modality for the assessment of neuronal
      integrity. However, there is only limited experience with IMZ in patients with
      acute cerebral infarction. Therefore, the aim of this study was to evaluate IMZ
      single photon emission computed tomography (SPECT) in patients with acute
      cerebral ischaemia. IMZ SPECT was performed in 21 patients with acute cerebral
      infarction 7-10 days after stroke onset. Eleven patients underwent systemic
      thrombolysis within 6 h after symptom onset (group 1), whereas 10 patients were
      treated conservatively (group 2). IMZ (150-200 MBq) was injected intravenously
      and imaging was performed using a dedicated four-head SPECT camera at 5 min
      (perfusion) and 90 min (receptor distribution) post-injection, with an
      acquisition time of 50 min each. Images were analysed by visual inspection. Four
      patients showed normal IMZ distribution, and 17 patients showed abnormalities of
      IMZ uptake on both early and late images. In six patients with regional uptake
      deficits, a crossed cerebellar diaschisis was observed on early images.
      Cerebellar inhomogeneity of tracer uptake was absent at the time of late images
      in all six patients. In eight patients, areas of hypoperfusion corresponded
      exactly to the regions of receptor deficiency (match). In five patients,
      preserved neuronal integrity was present in hypoperfused areas (mismatch). In
      four patients, normally or even hyperperfused areas exhibited regional receptor
      deficiency (inverse mismatch). In conclusion, IMZ SPECT demonstrated differences
      between regional perfusion and receptor distribution in about one-half of
      patients 7-10 days after acute cerebral ischaemia. Interesting patterns between
      the early phase (perfusion) and the late phase (receptor distribution) were
      found. These patterns are indicative of the heterogeneous development of cerebral
      ischaemia where, even days after stroke onset, areas of hypoperfusion but
      preserved neuronal integrity may be present. However, the evaluation of the
      potential clinical and therapeutic impact of individual IMZ distribution patterns
      requires further investigation.

PMID- 12464785
TI  - Pulsed Doppler tissue imaging for the assessment of myocardial viability:
      comparison with 99mTc sestamibi perfusion imaging.
AB  - The aim of the present study was to examine whether Doppler tissue imaging
      demonstrated comparable diagnostic performance for the detection of viable
      myocardium compared to myocardial perfusion imaging with Tc hexakis-2
      methoxyisobutylisonitrile (MIBI). We studied 30 patients with old myocardial
      infarction who underwent percutaneous transluminal coronary angioplasty (PTCA).
      Myocardial single photon emission computed tomography (SPECT) with Tc-MIBI and
      two-dimensional echocardiography were carried out within 7 days before PTCA. We
      measured regional Tc-MIBI uptake for each myocardial segment from SPECT and peak
      systolic velocity and a ratio of regional pre-ejection period to regional
      ejection time (PEP/ET) from pulsed Doppler tissue imaging. Biplane left
      ventriculography was performed before interventional procedures and repeated 3
      months after PTCA. Myocardial viability was determined when wall motion was
      improved at least one grade after PTCA. The peak systolic velocity was positively
      correlated with regional Tc-MIBI uptake (R =0.59, P<0.01). The PEP/ET
      demonstrated inverse correlation with Tc-MIBI uptake ( R=-0.59, P<0.01). Peak
      systolic velocity of viable segments was higher than that of non-viable segments
      ( P<0.05). The PEP/ET was lower in viable segments than in non-viable segments (
      P<0.05). Peak systolic velocity and PEP/ET demonstrated high diagnostic accuracy
      for detecting viable myocardium compared with Tc-MIBI perfusion imaging (80% and
      79% vs 90%). These data indicate that measurements of regional peak systolic
      velocity and PEP/ET by Doppler tissue imaging are useful for evaluating
      myocardial viability quantitatively and provide helpful information for a
      clinical judgment in an interventional strategy.

PMID- 12464786
TI  - The value of the TIMI frame count method in the diagnosis of coronary no-reflow:
      a comparison with myocardial perfusion SPECT in patients with acute myocardial
      infarction.
AB  - The state of no-reflow (i.e. inadequate myocardial tissue perfusion despite
      normal arterial flow proven in angiography after pharmacological or mechanical
      interventions) is considered to be a marker of a poor prognosis. Although the
      Thrombolysis in Myocardial Infarction (TIMI) flow grade is a valuable and widely
      used qualitative measure in angiography trials, it is limited by its subjective
      and categorical nature. Recently, the TIMI frame count method (TFC) was proposed
      for detecting no-reflow. In our study we aimed to compare TFC values with
      myocardial perfusion single photon emission computed tomography (SPECT) findings
      to investigate the additional role of the former method in the evaluation of no
      reflow. Twenty patients (16 men and four women; mean age 58+/-9 years) with first
      acute myocardial infarction were included in the study after thrombolytic
      therapy. Coronary angiography (CAG) was performed 5-7 days later. The TIMI flow
      grade and TFC values were determined in angiography examinations. A TIMI flow of
      less than grade 3 and a TFC value >27 were considered to be pathologically
      decreased for coronary artery blood flow. Tc tetrofosmin myocardial rest SPECT
      was carried out 24 h after coronary angiography. SPECT images were scored on a
      four-point scale in 20 myocardial segments and the total defect score was
      calculated from the sum of defect scores in 20 segments. Wall motion was assessed
      using the wall motion score index in echocardiography (ECWSI). The occurrence
      rates of angiographic no-reflow, pathological TFC and perfusion defects in SPECT
      were calculated as 40% (8/20), 47% (8/17; non-measurable in three patients with
      TIMI grade 0), and 55% (11/20), respectively. Perfusion defects were present and
      the TIMI frame count value was increased in all patients with angiographic no
      reflow (TIMI grade <3). The occurrence rate of perfusion defects and increased
      TFC was equal (42%) in all 12 patients having TIMI grade 3 flow. Increased TFC
      was demonstrated in four of five patients having perfusion defects and TIMI grade
      3 flow (80% compatibility with SPECT). TIMI frame count and ECWSI values were
      significantly higher in patients having perfusion defects than in patients with
      normal perfusion ( <0.05). It is concluded that the TIMI frame count is a
      valuable method in the detection of patients with TIMI grade 3 flow, with no
      reflow, and increases the specificity of coronary angiography in the evaluation
      of the response to thrombolytic therapy. A pathologically increased TFC value
      with TIMI grade 3 flow during CAG seems to be a good indication for the use of
      myocardial perfusion SPECT in the definitive diagnosis and/or follow-up of such
      patients.

PMID- 12464787
TI  - SPECT using 99mTc-DTPA for the assessment of disease activity in Graves'
      ophthalmopathy: a comparison with the results from MRI.
AB  - Currently available methods for the estimation of disease activity in the orbits
      of patients with Graves' ophthalmopathy (GO) have the disadvantages of being
      either expensive or time consuming. The aim of this study was to develop a quick,
      reliable method using Tc labelled diethylenetriaminepentaacetic acid (DTPA) and
      four-headed single photon emission computed tomography (SPECT) for this purpose.
      The theoretical basis of the method is that the high capillarization and oedema
      in the orbit may be reflected on Tc-DTPA images in GO. SPECT data of 28 orbits of
      14 patients with GO were compared with magnetic resonance imaging (MRI) T2
      relaxation time scores. Based on the number of 'active' muscles with T2
      relaxation times of more than 70 ms in a given orbit, an MRI score of 0 (no
      active muscle) to 4 (all rectus muscles active) was assigned to the orbit. With
      MRI, 18 orbits were inactive, and 10 were active. Thirty minutes after the
      intravenous administration of 7 MBq.kg Tc-DTPA, 128 projections were acquired by
      a four-headed SPECT. On the sum of six transaxial slices containing the entire
      bulbar region of the skull, a triangle-like region of interest (ROI) was drawn
      (OR ROI). This ROI was 'slipped' to the right temporal region of the brain as
      reference site (B ROI). The count ratios of OR/B were calculated and compared to
      MRI score values. In the group of 18 inactive orbits (an MRI score of zero on
      both sides), in the transaxial plane, the mean OR/B value was 6.4+/-1.17, and in
      the group of 10 active orbits (an MRI score of 1-3) 8.30+/-2.08, the difference
      being significant (P <0.05). Tc-DTPA orbital SPECT is a promising method for the
      estimation of disease activity in the orbits of patients with Graves'
      ophthalmopathy.

PMID- 12464788
TI  - 123I-MIBG radioaerosol lung clearance in COPD patients with fixed and partially
      reversible obstruction to evaluate the functional status of pulmonary adrenergic
      innervation.
AB  - In order to test the hypothesis that a greater sympathetic activity underlies
      partial reversibility of the bronchial obstruction in selected patients with
      chronic obstructive pulmonary disease (COPD), we assessed the pulmonary clearance
      of inhaled I-meta-iodobenzylguanidine ( I-MIBG) radioaerosol in 10 patients with
      fixed and nine with reversible obstruction. The clearance of inhaled I-MIBG is
      known to be inversely related to I-MIBG uptake by adrenergic terminals. Groups
      were matched for age and judged free from confounding comorbidity. The
      penetration index did not distinguish between the groups (fixed obstruction,
      97.39+/-14.59%; reversible obstruction, 89.09+/-19.95%; P=0.659); this excludes
      the possibility that the inequality of tracer penetration could affect I-MIBG
      clearance. The I-MIBG clearance was 140.92+/-7.67 min in patients with fixed
      obstruction and 151.08+/-31.54 min in patients with reversible obstruction (
      P=0.604). In conclusion, COPD patients with fixed and reversible obstruction show
      comparable binding of the tracer to adrenergic pulmonary receptors. Thus, a
      greater receptor responsiveness or post-receptor mechanism probably underlies the
      partial reversibility of bronchial obstruction.

PMID- 12464789
TI  - Diagnosis of bone infections using 99mTc-HMPAO labelled leukocytes.

PMID- 12464792
TI  - A nursing portfolio: documenting your professional journey.
AB  - Professional profiling may enhance one's career development. The opportunities to
      use a current profile abound, and include applying for a new position, a
      leadership role in a professional society, a scholarship or an award, or career
      advancement. The true professional updates the profile on an annual basis,
      emphasizing significant personal and professional accomplishments. Documentation
      and validation of one's credentials may require substantial effort-but such
      effort is worth it. Profiling is a step toward recognition and success.

PMID- 12464793
TI  - Understanding renal dose dopamine.
AB  - Low-dose dopamine is a widely administered drug used often in critical care
      settings to prevent or treat patients with low urinary output. There are new data
      to support that low-dose dopamine may have side effects and not always increase
      renal perfusion to the kidneys. This article is a review of the current use of
      low-dose dopamine, the role of dopamine in the kidneys, and the potential risks
      of infusing this drug to patients.

PMID- 12464794
TI  - The changing face of Canadian home parenteral therapy.
AB  - This article describes the Calgary Health Region Home Parenteral Therapy Program
      (HPTP), which has successfully shifted infusion therapies such as anti
      infectives, analgesics, hydration, vasodilators, glucocorticoids, and iron
      chelating agents from the hospital to patients' homes. Particular attention is
      given to the parenteral administration of anti-infectives, which currently
      accounts for more than 95% of program adult therapy days.

PMID- 12464795
TI  - Current treatments for hepatitis.
AB  - Common viral agents known to cause inflammation of the liver (hepatitis) are
      hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV).
      Some other viral agents that can cause hepatitis are Epstein Barr virus, herpes
      simplex virus, and cytomegalovirus. Some patients infected with these viral
      agents progress to develop chronic viral hepatitis. Approximately 45% of chronic
      hepatitis cases are associated with hepatitis C and approximately 15% are
      associated with hepatitis B. In addition to being a leading cause of chronic
      hepatitis, HCV is most frequently associated with liver cirrhosis and
      hepatocellular carcinoma. Although much has been published about HAV and HBV,
      health professionals have learned about HCV only in recent years. For this
      reason, this article will emphasize the epidemiologic challenges and current
      treatments for hepatitis C; hepatitis A and B will be discussed in brief.

PMID- 12464796
TI  - Ethical reflections on pharmacogenetics and DNA banking in a cohort of HIV
      infected patients.
AB  - The aim of this study was to analyse ethical issues concerning the storage of
      human biological samples to be used in genetic analyses and pharmacogenetic
      research based on a French experience of DNA banking in a cohort of human
      immunodeficiency virus (HIV)-infected patients started on a protease inhibitor
      containing treatment. We describe the ethical issues raised during the
      establishment of a DNA bank, including questions dealing with autonomy, benefit
      to the patient, information sharing and confidentiality as well as guarantees
      concerning the storage and use of DNA. The practical applications of themes
      illustrated theoretically in the literature are discussed. Most of the points
      raised are not specific to HIV, but some of them may be more accurate due to the
      characteristics of the HIV population, which is more involved in the social
      debate through the community life and the increased risk of stigmatization. Our
      results are summarized in the memorandum and consent form presented in the
      Appendices. One issue still open to discussion is the way the results of genetic
      data will be given to the patients. This work should allow other researchers and
      members of evaluation committees to enrich their considerations and should
      stimulate discussion on this topic.

PMID- 12464797
TI  - Differential activation of promutagens by alloenzymes of human sulfotransferase
      1A2 expressed in Salmonella typhimurium.
AB  - Various enzymatically formed sulfuric acid esters are chemically reactive and
      mutagenic. This metabolic activation pathway is not detected in standard in-vitro
      mutagenicity test systems. We describe the construction of Salmonella typhimurium
      TA1538-derived strains expressing alloenzymes *1, *2, *3, *5, *6 of human
      sulfotransferase 1A2 (SULT1A2). The reference compounds, 1-hydroxymethylpyrene (1
      HMP), N-hydroxy-2-acetylaminofluorene (OH-AAF) and 2-hydroxylamino-5
      phenylpyridine (OH-APP), were activated to mutagens in these strains. Their
      activity differed 7- to 16-fold between strains expressing various alloenzymes.
      It was strongest and weakest in the strains expressing the common alloenzymes, *1
      and *2, respectively. The SULT1A2 protein expression levels, and the V(max) and
      K(m) values with the reference substrate 4-nitrophenol, varied 2.5-, 4-, and 110
      fold, respectively, in cytosolic preparations from strains TA1538-SULT1A2*1 and
      *2. Strains with varying protein levels were constructed via insertion of silent
      mutations in the 5'-part of the cDNA. TA1538-SULT1A2*1Z and TA1538-SULT1A2*2Y
      showed equal expression levels of alloenzymes *1 and *2, respectively, which were
      3 times above those of TA1538-SULT1A2*1. The mutagenicity of OH-AAF and OH-APP
      was unchanged in strain TA1538-SULT1A2*1Z versus *1, and moderately increased in
      TA1538-SULT1A2*2Y versus *2. The influence of the protein level was stronger with
      1-HMP. Nevertheless, mutagenic activity of 1-HMP was still 11 times higher in
      TA1538-SULT1A2*1Z than in TA1538-SULT1A2*2Y. Thus, differences in the properties
      between alloenzymes can lead to differences in the activation of promutagens. The
      model compounds were also tested in strains expressing the other ten human SULTs
      identified. Whereas OH-AAF and OH-APP showed the highest mutagenic activities in
      strains expressing SULT1A2, 1-HMP was more potent in strains expressing other
      SULT forms. With the limitation that little is known about the tissue
      distribution and regulation of SULT1A2, the findings suggest that its
      polymorphism may affect the individual susceptibility towards procarcinogens, in
      particular certain aromatic amines and amides.

PMID- 12464798
TI  - Interest of genotyping and phenotyping of drug-metabolizing enzymes for the
      interpretation of biological monitoring of exposure to styrene.
AB  - In the field of occupational and/or environmental toxicology, the measurement of
      specific metabolites in urine may serve to assess exposure to the parent
      compounds (biological monitoring of exposure). Styrene is one of the chemicals
      for which biological monitoring programs have been validated and implemented in
      environmental and occupational medicine. However, inter-individual differences in
      the urinary excretion exist both for the main end-products (mandelic acid and
      phenylglyoxylic acid) and for its specific mercapturic acids
      (phenylhydroxyethylmercapturic acids, PHEMA). This limits to a certain extent the
      use of these metabolites for an accurate assessment of styrene exposure. In a
      group of 26 volunteers selected with relevant genotypes, and exposed to styrene
      vapours (50 mg/m3, 8 h) in an inhalation chamber, we evaluated whether genotyping
      or phenotyping relevant drug-metabolizing enzymes (CYP2E1, EPHX1, GSTM1, GSTT1
      and GSTP1) may help to explain the observed inter-individual variability in the
      urinary metabolite excretion. Peripheral blood lymphocytes were used for
      genotyping and as reporter cells for the phenotyping of CYP2E1 and EPHX1. The
      GSTM1 genotype was clearly the most significant parameter explaining the variance
      in urinary PHEMA excretion (6-fold lower in GSTM1 null subjects; P < 0.0001) so
      that systematic GSTM1 genotyping should be recommended routinely for a correct
      interpretation of PHEMA urinary levels. Variant alleles CYP2E1*6 (7632T>A) and
      His113EPHX1 were associated with a significant reduction of, respectively, the
      expression (P = 0.047) and activity (P = 0.022) of the enzyme in peripheral blood
      lymphocytes. In combination with GSTM1 genotyping, the phenotyping approach also
      contributed to improve the interpretation of urinary results, as illustrated by
      the combined effect of CYP2E1 expression and GSTM1 allelic status that explained
      77% of the variance in PHEMA excretion and allows the recommendation of
      mercapturates as specific and reliable biomarkers of exposure to styrene.

PMID- 12464799
TI  - Identification and functional characterization of new potentially defective
      alleles of human CYP2C19.
AB  - CYP2C19 is a clinically important enzyme responsible for the metabolism of a
      number of therapeutic drugs, such as mephenytoin, omeprazole, diazepam,
      proguanil, propranolol and certain antidepressants. Genetic polymorphisms in this
      enzyme result in poor metabolizers of these drugs. There are racial differences
      in the incidence of the poor metabolizer trait, which represents 13-23% of Asians
      but only 3-5% of Caucasians. In this study, single nucleotide polymorphisms
      (SNPs) in CYP2C19 were identified by direct sequencing of genomic DNA from 92
      individuals from three different racial groups of varied ethnic background,
      including Caucasians, Asians and blacks. Several new alleles were identified
      containing the coding changes Arg114 His (CYP2C19*9), Pro227 Leu (CYP2C19*10),
      Arg150 His (CYP2C19*11), stop491 Cys (CYP2C19*12), Arg410 Cys (CYP2C19*13), Leu17
      Pro (CYP2C19*14) and Ile19 Leu (CYP2C19*15). When expressed in a bacterial cDNA
      expression system, CYP2C19*9 exhibited a modest decrease in the V(max) for 4'
      hydroxylation of -mephenytoin, and no alteration in its affinity for reductase.
      CYP2C19*10 exhibited a dramatically higher K(m) and lower V(max) for mephenytoin.
      CYP2C19*12was unstable and expressed poorly in a bacterial cDNA expression
      system. Clinical studies will be required to confirm whether this allele is
      defective in vivo. CYP2C19*9, CYP2C19*10 and CYP2C19*12 all occurred in African
      Americans, or individuals of African descent, and represent new potentially
      defective alleles of CYP2C19 which are predicted to alter risk of these
      populations to clinically important drugs.

PMID- 12464800
TI  - Canine red blood cell thiopurine S-methyltransferase: companion animal
      pharmacogenetics.
AB  - Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism
      of thiopurine drugs. In humans, a common genetic polymorphism for TPMT is a major
      factor responsible for individual variation in the toxicity and therapeutic
      efficacy of these drugs. Dogs (Canis familiaris) are also treated with thiopurine
      drugs and, similar to humans, they display large individual variations in
      thiopurine toxicity and efficacy. We set out to determine whether dogs might also
      display genetically determined variation in TPMT activity. As a first step, we
      observed that canine red blood cell (RBC) TPMT activity in samples from 145 dogs
      varied over a nine-fold range. That variation was not associated with either the
      age or sex of the animal. Subsequently, we cloned the canine TPMT cDNA and gene.
      The canine cDNA encoded a protein that was 81.2% identical to the enzyme encoded
      by the most common TPMT allele in humans. A genotype-phenotype correlation
      analysis was performed by resequencing the canine gene using DNA samples from 39
      animals selected for high, low or intermediate levels of RBC TPMT activity. We
      observed nine polymorphisms in these 39 DNA samples, including three
      insertion/deletion events and six single nucleotide polymorphisms (SNPs), one of
      which was a nonsynonymous cSNP (Arg97Gln). However, when the variant allozyme at
      codon 97 was expressed in COS-1 cells, it did not display significant differences
      in either basal levels of TPMT activity or in substrate kinetics compared with
      the wild-type allozyme. Six of the nine canine TPMT polymorphisms were associated
      with 67% of the variation in level of RBC TPMT activity in these 39 blood
      samples. When those six SNPs were assayed using DNA from all 145 animals studied,
      40% of the phenotypic variance in the entire population sample could be explained
      by these polymorphisms. Therefore, inheritance is a major factor involved in the
      regulation of variation in RBC TPMT in the dog, just as it is in humans. These
      observations represent a step towards the application of pharmacogenetic and
      pharmacogenomic principles to companion animal drug therapy.

PMID- 12464801
TI  - Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different
      ethnic groups.
AB  - Genetic variation in UDP-glucuronosyltransferase 1A1 (UGT1A1)expression has
      several important clinical implications. UGT1A1 basal transcription is affected
      by a polymorphic (TA)n repeat, and another important regulatory element is the
      phenobarbital-responsive enhancer module (PBREM) which might contain variants
      affecting inducible gene expression. We assessed the extent of linkage
      disequilibrium between the (TA)n polymorphism and variants in the PBREM and
      UGT1A1 promoter. We also investigated the relationship between PBREM-(TA)n
      haplotypes and the glucuronidation rate of the UGT1A1 substrate SN-38. DNAs from
      83 human livers were genotyped for the (TA)n polymorphism and microsomes from the
      same livers were phenotyped for SN-38 glucuronidation. The (TA)n polymorphism was
      genotyped in 24 additional African-Americans included in the Human Variation
      Panel (Coriell Institute). A 606-bp region spanning the PBREM was sequenced in 81
      liver and a subset of 22 Human Variation Panel DNAs and six variants were found.
      The -3279G T and -3156G A variants are common (0.39 and 0.30, respectively). 
      3279G T is more common in Caucasians than African-Americans (P = 0.001). In
      Caucasians, linkage disequilibrium was highly significant between sites -3279, 
      3156, and the (TA)n polymorphism (P < 0.0001). In contrast, in African-Americans,
      only marginal levels of significance were observed between (TA)n and -3279 (P =
      0.02) and between -3279 and -3156 (P = 0.04). Ten promoter haplotypes were
      identified. Haplotype I is the most common (0.39), from which haplotype II (0.15)
      differs at position -3279. SN-38G formation rates were correlated with (TA)n
      genotypes. This study showed that (i) common promoter variants are in linkage
      disequilibrium and (ii) the haplotype structure of promoter is probably different
      between Caucasians and African-Americans.

PMID- 12464802
TI  - Sudden unexpected death in epilepsy: neuropathologic findings.
AB  - Sudden unexpected death in epilepsy refers to sudden death of an individual with
      a clinical history of epilepsy, in whom a postmortem examination fails to uncover
      a gross anatomic, toxicologic, or environmental cause of death. Evidence of
      terminal seizure activity may not be present. One to two percent of natural
      deaths certified by the medicolegal death investigator are attributed to
      epilepsy. Detailed microscopic examination of the brain has increasingly afforded
      the identification of structural changes representative of epileptogenic foci.
      The authors present 70 cases of death attributed to sudden unexpected death in
      epilepsy. These cases were classified as follows: individuals who lacked a gross
      brain lesion, those who had a brain lesion demonstrable at autopsy, and those who
      lacked neuropathologic evaluation because of decomposition or because only an
      external examination was done. All of the subjects had a clinical history of
      seizures. The authors confirm that various microscopic findings, including
      neuronal clusters, increased perivascular oligodendroglia, gliosis, cystic
      gliotic lesions, decreased myelin, cerebellar Bergmann's gliosis, and folial
      atrophy, are present in a higher percentage of the brains of sudden unexpected
      death in epilepsy subjects than in the brains of age- and sex-matched control
      subjects.

PMID- 12464803
TI  - Cyanide fatalities: case studies of four suicides and one homicide.
AB  - Deaths due to cyanide poisoning are relatively rare, largely owing to the
      restricted availability of cyanide. Nevertheless, the authors report five cases
      of cyanide fatalities occurring within a few months. Cyanide is one of the most
      rapidly acting poisons known and is still used for suicide and homicide. The
      discussion focuses on the circumstances, metabolic changes, pathophysiology,
      blood levels, diagnosis, and management of cyanide poisoning.

PMID- 12464804
TI  - Immunohistochemical analysis of forensic evidence from a double homicide.
AB  - We report the use of immunohistochemical staining for analysis of forensic
      evidence from a double homicide. A 38-year-old woman and her 7-year-old daughter
      were murdered by multiple blows to the head and face with a tomahawk, resulting
      in multiple fragments of brain tissue scattered about the murder scene. The
      victims' husband and father was the main suspect, who maintained that he was out
      of town on business during the evening of the murders. However, a shirt taken
      from the suspect's car on the morning after the murders (secured by the police
      before the suspect visited the murder scene) was found to have two small stains.
      DNA analysis on the stains showed the presence of the deceased wife's DNA, and
      immunohistochemical stains on shirt fragments conclusively documented the
      presence of deep central nervous system tissue, providing the critical piece of
      evidence needed to arrest and prosecute the suspect. This report demonstrates
      that shirt or similar cloth fragments can be processed into paraffin blocks and
      subsequently immunostained to search for and classify types of tissue fragments
      that may be present on the fabric.

PMID- 12464805
TI  - Suicide with the latest type of slaughterer's gun.
AB  - The authors describe a case of suicide by a single shot to the head from the
      latest type of captive bolt pistol (which has lateral instead of frontal gas
      outlets), with the aim of finding criteria to identify correctly the lesions
      caused by this type of weapon correctly and to distinguish them from those caused
      by typical firearms.

PMID- 12464806
TI  - Suicide with two guns represents a special type of combined suicide.
AB  - Suicide by simultaneous gunshots with two firearms is rare. The case of a 90-year
      old man who killed himself with two 6.35 mm pistols fired at the temples at the
      same time is presented. The victim was found dead on the terrace of his home; two
      guns and two cartridges were present near the corpse. Cases of suicides with two
      guns published in the literature are compared, and the Italian cases are
      illustrated briefly. The authors describe the circumstances and autopsy findings
      that permitted the assertion that it was a case of suicide and to exclude an
      homicide and show, by figures, the three-dimensional reconstruction of cranial
      shooting injuries. The use of two guns is considered a representation of a
      special type of "combined suicide" or "planned complex suicide."

PMID- 12464807
TI  - Suicide by intracerebellar ballpoint pen.
AB  - Self-inflicted eye injuries among psychiatric patients are relatively common.
      Transorbital penetrating traumas are more rare but if undiagnosed may cause
      lethal intracranial lesions. We report a fatal case of a 25-year-old
      schizophrenic man who introduced a plastic ballpoint pen through his right orbit
      up to the cerebellum. The computed tomography findings were misinterpreted as a
      penetrating track from a bullet. The patient died 4 days after the trauma, and
      the causative object was identified only at autopsy. When no precise information
      about an apparently trivial ocular trauma is available, clinicians and
      investigators must adequately consider, especially in psychiatric patients, the
      possibility of an intracranial penetrating lesion.

PMID- 12464808
TI  - Sudden and unexpected death resulting from splenic artery aneurysm rupture: two
      case reports of pregnancy-related fatal rupture of splenic artery aneurysm.
AB  - Rupture of a splenic artery aneurysm is a rare and usually catastrophic event,
      most commonly associated with pregnancy. In spite of increasingly common reliance
      on abdominal angiography, magnetic resonance imaging, and computerized tomography
      during the past quarter century, clinicians uncommonly recognize any of the
      various splanchnic arterial aneurysms absent premonitory signs or symptoms.
      Accordingly, rupture of a visceral aneurysm, including splenic artery aneurysm,
      typically presents as sudden, unexpected obtundation or death. As a consequence,
      the initial recognition and diagnosis of splenic artery aneurysm rupture take
      place only at autopsy. This report presents two such cases of sudden death
      resulting from splenic artery aneurysm in a pregnant woman and a postpartum
      woman, respectively.

PMID- 12464809
TI  - Anticoagulant-related iliopsoas muscle bleeding leading to fatal exsanguination:
      report of two autopsy cases.
AB  - Two cases of massive iliopsoas muscle bleeding leading to fatal exsanguination
      are presented. Both patients (two women, 61 and 74 years old, respectively)
      received oral anticoagulation with phenprocoumon. The intramuscular bleeding
      occurred spontaneously in women of relatively good physical condition.
      Intriguingly, phenprocoumon concentrations were within the therapeutic range
      (1.55 microg/ml and 1.26 microg/ml, respectively) as detected by toxicologic
      analysis. These cases demonstrate that severe bleeding in the iliopsoas muscle
      has to be considered in all patients receiving anticoagulant medication, even in
      those who have coagulation parameters within the therapeutic range. Especially in
      older patients with a high degree of comorbidity or in patients receiving
      analgesic drugs, the potential of fatal outcome of iliopsoas muscle bleeding
      seems to be of clinicopathologic relevance.

PMID- 12464810
TI  - The response of relatives to medicolegal investigations and forensic autopsy.
AB  - Relatives of deceased persons, on whose body a forensic autopsy had been
      performed at the Institute of Forensic Science, Bern, Switzerland, were
      interrogated by a questionnaire. The aim was to investigate the attitude of
      relatives toward medicolegal investigation procedures in general and toward
      forensic autopsy in particular. A great majority of the relatives showed a
      positive or indifferent attitude toward a forensic autopsy. They showed a great
      interest in autopsy results and wished to be informed. It was concluded that
      information given before the autopsy is important for better understanding and
      can, if properly given, improve the relatives' acceptance and collaboration
      regarding forensic investigations. By contrast, a lack of information before the
      autopsy and about the autopsy results can cause further suffering on behalf of
      the bereaved. A forensic autopsy can be of great benefit for relatives and can
      help them to cope with a tragic loss.

PMID- 12464811
TI  - Change in the postmortem formation of hypostasis in skin preparations 100
      micrometers thick.
AB  - Twenty-three paired skin samples from 19 autopsies without putrefaction were
      taken from areas of livor mortis that (1). did not blanch with finger pressure
      and (2). blanched with strong pressure by tweezers. Three-dimensional microscopic
      viewing of 100-microm benzidine-stained skin sections demonstrated small blood
      vessels filled with red blood cells. The diameters of the clumps of red blood
      cells were greater in the sections from non-blanched areas than in the blanched
      areas, suggesting that fixation of hypostasis soon after death depends on
      sedimentation of intravascular red blood cells and passive dilatation of small
      vessels rather than on postmortem hemolysis.

PMID- 12464812
TI  - Suicide by blunt force trauma.
AB  - Suicide by self-inflicted blunt force injury is rare. The authors report a case
      of a 48-year-old man who initially appeared to have died of a homicidal beating.
      The pertinent autopsy findings consisted of blunt force closed head injury
      combined with numerous cutaneous abrasions and contusions of the entire body.
      Further inquiries confirmed a medical history of paranoid schizophrenia and a
      previous attempt at suicide. This case represents an extreme example of severe
      blunt trauma sustained during fatal self-mutilation and masquerading as a
      homicide. It also underscores the importance of correlating a thorough background
      investigation with autopsy findings in determining the appropriate manner of
      death.

PMID- 12464813
TI  - Pulmonary siderophages and unexpected infant death.
AB  - It has been proposed that the presence of siderophages in the lungs of infants
      who die unexpectedly should be considered a marker of a previous hypoxic event,
      which may preclude a diagnosis of sudden infant death syndrome. The authors
      retrospectively reviewed all infant deaths (<1 year old) going to autopsy at the
      Denver Office of the Medical Examiner from January 1999 to January 2001. Lung
      sections were stained with Prussian blue, and siderophages were counted in 20
      high-power fields per lobe sampled. Cell counts were performed by two independent
      pathologists who were blinded to history and cause of death, with good
      reproducibility. Iron stain results were then categorized by average number of
      siderophages per 20 high-power field (category 1 = <5, category 2 = 5-100,
      category 3A = 100-500, category 3B = >100 in a single lobe, category 4 = >500).
      The results were subsequently correlated to case history, autopsy findings, and
      cause/manner of death. Forty-three cases were reviewed. The causes of death
      included sudden infant death syndrome (16), asphyxia (5), undetermined (6), and
      other (16). Those deaths were categorized by the above criteria as follows:
      category 1. (32), category 2. (6), category 3. (4), and category 4. (1). All
      sudden infant death syndrome deaths were in category 1. Categories 1 and 2 also
      included deaths in which hypoxia might have been present before death because of
      such factors as pneumonia and congenital heart disease. Categories 3 and 4
      included a known homicidal asphyxia in which repeated episodes of intentional
      smothering were documented, 2 probable asphyxias, 1 nonaccidental trauma, and 1
      undetermined. All 5 cases had questionable circumstances surrounding the death of
      the infant. Pulmonary siderophages were described in only 1 of the 43 autopsy
      reports. It was concluded that pulmonary siderophages can be markedly increased
      in cases of repeated asphyxia. Siderophages may also be increased in cases where
      hypoxia may have been present for another reason, but not to the same degree.
      Siderophages are not increased in sudden infant death syndrome. Because iron
      laden macrophages often are not recognized on routine examination with
      hematoxylin and eosin staining, iron stains may be helpful in the evaluation of
      infant deaths. If siderophages are present in increased amounts without an
      obvious explanation, further investigation is warranted.

PMID- 12464814
TI  - Childhood sporting deaths.
AB  - Exercise-induced collapse and sudden death are unusual in childhood. For this
      reason, a study was undertaken of a series of 12 cases of sudden death in
      childhood occurring during physical exertion associated with sporting activities.
      The age range was 7 to 16 years (mean 12.3 years, M:F ratio 5:1). Deaths resulted
      from trauma associated with the sporting activity, from an idiosyncratic response
      to exertion, or from exacerbation of a known underlying disease. Trauma was
      directly fatal (n = 4: vascular trauma in 1, head injury in 2, drowning in 1),
      exacerbated an underlying medical condition (n = 1: hypertrophic obstructive
      cardiomyopathy), or followed collapse from underlying organic disease (n = 1:
      drowning in epilepsy). Deaths after exertion occurred when there was an
      unexpected response to underlying occult disease (n = 4: aortic stenosis in 1,
      cerebral arteriovenous malformation in 1, hypertrophic obstructive cardiomyopathy
      in 1, coronary atherosclerosis in 1) or to preexisting known disease (n = 2:
      surgically corrected transposition of the great vessels in 1, asthma in 1). The
      fatal episodes often resulted from a complex interplay of a variety of factors,
      including physical exertion, possible trauma, and underlying organic disease.
      Testing of other family members may be indicated in cases where a rare, possibly
      familial, disease is found. Evaluation of cases required descriptions of
      activities before death, information from the medical history of the deceased,
      and detailed findings from the autopsy.

PMID- 12464815
TI  - Sudden death resulting from epidermoid cyst of the brain.
AB  - Epidermoid cysts of the brain are rare tumor-like lesions, most often of
      maldevelopmental origin. They are benign in nature, causing symptoms depending on
      their localization. Surgical resection leads to excellent results. A case is
      reported of a 68-year-old-man who died suddenly and unexpectedly. Postmortem
      examination revealed signs of central dysregulation and a bifrontal epidermoid
      cyst. To the authors' knowledge, death resulting from epidermoid cyst of the
      brain has not been reported so far.

PMID- 12464816
TI  - Circumstances and macropathologic findings in 1590 consecutive cases of bodies
      found in water.
AB  - The diagnosis of drowning relies primarily on critical examination of the
      subject's individual characteristics, circumstances, and postmortem
      macropathologic changes. In this retrospective study, based on 1590 consecutive
      cases of bodies found in water and undergoing autopsy at the Department of
      Forensic Medicine, University of Helsinki, from 1976 to 1998, the frequency of
      circumstantial data and macropathologic changes crucial for the diagnosis of
      drowning were determined. The fatal events were eyewitnessed in 403 cases
      (25.3%), and suicide notes were found in 83 cases (5.2%). External foam, frothy
      fluid in airways, and overlap of the anterior margins of lungs were found in 275
      (17.3%), 739 (46.5%), and 669 (42.1%) of the cases, respectively, but no one of
      these changes, tested against dry-land controls, were specific for drowning. The
      association of external foam and overlap of the lung margins was exclusive of
      drowning but was observed in only 176 cases (11.1%). After cross-analysis, 964
      (60.6%) of the cases had no circumstantial data or macromorphologic pathologic
      findings that allowed a definite diagnosis of drowning. The diagnostic problems
      in putative drowning cases, based on this study sample, have not been overrated.
      Studies to investigate and improve the reliability of complementary methods for
      the diagnosis of drowning are warranted.

PMID- 12464817
TI  - Population study of six short tandem repeat loci in Antalya, Turkey.
AB  - Population studies of six short tandem repeat loci were carried out in a sample
      of unrelated Turkish individuals living in Antalya province, southwest Turkey.
      After electrophoresis in polyacrylamide gels, 8 alleles could be identified for
      THO1, 6 for TPOX and CSF1PO, 9 for VWA, 7 for FES, and 14 for F13A01. There was a
      significant deviation from the Hardy-Weinberg equilibrium between observed and
      expected values for FES and TPOX loci.

PMID- 12464818
TI  - Fatal salmonella aortitis with mycotic aneurysm rupture.
AB  - Salmonellae most commonly cause uncomplicated cases of gastroenteritis but have a
      predilection for damaged blood vessels, especially those damaged by
      atherosclerosis. The abdominal aorta is most frequently affected. The most
      serious complication of aortitis is mycotic aneurysm formation with subsequent
      rupture. The authors present the case of a 61-year-old man who was found
      unresponsive at home 3 days after discharge from the hospital for treatment of
      gastroenteritis with bacteremia. Postmortem examination revealed a ruptured
      mycotic aneurysm with a large retroperitoneal hematoma. Numerous gram-negative
      rods were embedded in the wall of the aorta and surrounding inflammatory
      infiltrate, compatible with the patient's previously isolated. Whereas abdominal
      aortic aneurysm rupture is most commonly associated with atherosclerosis, the
      isolation of from blood cultures, coupled with radiographic evidence of gas
      surrounding the aorta, should raise the suspicion of infectious aortitis. Whereas
      fatal rupture of an aortic aneurysm secondary to atherosclerosis alone or in
      conjunction with aortitis will not have an impact on the manner of death,
      infections are reportable and thus have public health implications.

PMID- 12464819
TI  - Multiple regression models for age estimation by assessment of morphologic dental
      changes according to teeth source.
AB  - The aims of this study were twofold: (1). to measure parameters that contribute
      significantly to estimates of dental age, using a combination of classic methods
      and a computer-assisted image analysis procedure to avoid the bias inherent in
      observer subjectivity; and (2). to develop new mathematical regression models for
      age prediction according to postmortem interval. Two different populations were
      studied. Forty-three permanent teeth (Group I), extracted for valid clinical
      reasons, were taken from patients 25-79 years of age. The other population group
      (Group II) was composed of 37 healthy erupted permanent teeth obtained from human
      skeletal remains (age 22-82 years) with a postmortem interval ranging from 21 to
      37 years. Morphologic age-related changes were investigated by measuring
      variables on intact and half-sectioned teeth. Multiple regression analyses were
      performed with age as the dependent variable for each sample source. In fresh
      extracted teeth, the variables that made the greatest contributions to
      predictions of age were dental attrition, dentin color, and translucency width,
      the latter measured with a computer-assisted image analysis method. In teeth from
      human skeletal remains, the variables that made the greatest contributions to age
      calculation were cementum apposition, pulp length measured by computer-assisted
      image analysis, dental attrition, root translucency, and dental color. We
      conclude by recommending different regression models to calculate age depending
      on the postmortem interval.

PMID- 12464820
TI  - Comparative study of efficiency of dental methods for identification of burn
      victims in two bus accidents in Spain.
AB  - This article deals with the usefulness and limitations of dental identification
      methods of human burn victims of two buses accidents in Spain. The first accident
      happened in Bailen in 1996 and involved 28 badly burned Spanish victims. In the
      second, in Illescas in 1997, 8 Japanese and 2 Spanish victims lost their lives.
      In both accidents, postmortem forensic procedures for identification were used,
      including external and internal examination, routine photographs, and dental
      examination. Dental identification was established in 57% of the cases in the
      Bailen accident and 80% in the Illescas accident. The success rate of dental
      identification varies considerably depending on the nature of the accident, the
      nationality and country of residence of the victims, the incidence of dental
      treatment, the availability of adequate dental records, and the degree of dental
      injuries. A discussion of procedures and methods for identification recommended
      when dealing with burn victims is included.

PMID- 12464821
TI  - Delayed rupture of a vertebral artery as an uncommon cause of fatal subarachnoid
      hemorrhage: case report.

PMID- 12464822
TI  - Investigation and reporting practices for drownings: implications for injury
      prevention research in new york state.
AB  - The New York State Department of Health conducted a study of drownings among New
      York State residents. A total of 883 drownings between 1988 and 1994 met study
      criteria. Medical examiner, coroner, police, and hospital records were obtained
      to supplement death certificate data. Although police reports were an important
      source of information, acquiring police records was labor intensive and time
      consuming and would be unnecessary if ME/Cs used standard death investigation
      guidelines and a uniform reporting form. The authors compared International
      Classification of Diseases-9 E codes listed on death certificates with
      information from supplementary data sources. Appropriate International
      Classification of Diseases-9 E codes were often not used in cases for which a
      specific code was available. In some cases, a code was assigned that failed to
      correctly reflect information provided on the death certificate. More frequently,
      the description provided by the medical examiner or coroner did not permit the
      use of a more specific code. The role of alcohol could not be assessed for 38% of
      drowning victims because toxicology testing was not performed, results were not
      made available by the medical examiner or coroner, or samples were collected 24
      hours or more after the time of the drowning. Investigation and reporting
      practices that would benefit injury prevention research are suggested.

PMID- 12464823
TI  - Globalization of forensic medicine.

PMID- 12464824
TI  - Forensic medicine in france.

PMID- 12464825
TI  - Lipids, lipoproteins, and exercise.
AB  - PURPOSE: Dose-response relationships between exercise training volume and blood
      lipid changes suggest that exercise can favorably alter blood lipids at low
      training volumes, although the effects may not be observable until certain
      exercise thresholds are met. METHODS AND RESULTS: Plasma triglyceride reductions
      are often observed after exercise training regimens requiring energy expenditures
      similar to those characterized to increase high-density lipoprotein cholesterol
      (HDL-C). Thresholds established from cross-sectional and longitudinal exercise
      training studies indicate that 15 to 20 miles/week of brisk walking or jogging,
      which elicit between 1,200 to 2,200 kcals of energy expenditure per week, is
      associated with triglyceride reductions of 5 to 38 mg/dL and HDL-C increases of 2
      to 8 mg/dL. Exercise training seldom alters total cholesterol and low-density
      lipoprotein cholesterol (LDL-C) unless dietary fat intake is reduced and body
      weight loss is associated with the exercise training program, or both. Thus, for
      most individuals, the positive effects of regular exercise are exerted on blood
      lipids at low training volumes and accrue so that noticeable differences
      frequently occur with energy expenditures of 1,200 to 2,200 kcals/week.
      CONCLUSIONS: It appears that weekly exercise caloric expenditures that meet or
      exceed the higher end of this range are more likely to produce the desired lipid
      changes. Regarding hyperlipidemic disorders, the primary means for intervention
      is pharmacologic, whereas diet modification, weight loss, and exercise, although
      important, are viewed as adjunctive therapies. Because much is known about the
      exercise training-induced plasma lipid and lipoprotein modifications as well as
      the mechanisms responsible for these changes, rehabilitation professionals can
      better develop a comprehensive medical management plan that optimizes
      pharmacologic, reduced dietary fat intake, weight loss, and exercise
      interventions.

PMID- 12464826
TI  - Prognostic value of exercise tests in male veterans with chronic coronary artery
      disease.
AB  - PURPOSE: The authors evaluate the prognostic value of treadmill testing in a
      large consecutive series of patients with chronic coronary artery disease.
      Exercise testing is widely performed, but analyses of the prognostic value of
      test results have largely concentrated on patients referred for the diagnosis of
      coronary artery disease, patients after an acute coronary event or procedure, or
      patients with congestive heart failure. METHODS: All patients referred for
      evaluation at two university-affiliated Veterans Affairs Medical Centers who
      underwent exercise treadmill tests for clinical indications between 1987 and 2000
      were determined to be dead or alive using the Social Security Death Index after a
      mean 5.8-year follow-up. Patients without established heart disease and those
      with congestive heart failure were excluded, leaving the target population of
      those with a history myocardial infarction or coronary intervention. Clinical and
      exercise test variables were collected prospectively according to standard
      definitions; testing and data management were performed in a standardized fashion
      using a computer-assisted protocol. All-cause mortality was used as the endpoint
      for follow-up. Standard survival analysis was performed including Kaplan Meier
      curves and the Cox Hazard Model. RESULTS: Of the 1,473 patients with coronary
      artery disease who had exercise testing, 273 (19%) patients had a
      revascularization procedure (Revascularization group); 813 (55%) had a history of
      myocardial infarction, diagnostic Q waves (MI group), or both; and 387 (26%) had
      a history of myocardial infarction or Q wave and revascularization (Combined
      group). Mean age of the patients was 61.8 +/- 9 years. A total of 401 deaths
      occurred during a mean follow-up of 5.8 years with an annual mortality rate of
      4.5%. Only two variables, age and maximal exercise capacity, were independently
      and statistically associated with time to death in all three groups and were the
      strongest predictors of all cause mortality. CONCLUSION: A simple score based on
      METs, age, and history of myocardial infarction or diagnostic Q waves can
      stratify prognosis in patients with chronic coronary artery disease. The score
      enabled the identification of a group at low risk (32% of the cohort) with an
      annual mortality rate of 2%, a group at intermediate risk (42% of the cohort)
      with an annual mortality rate of about 4%, and a group at high risk (26% of the
      cohort) with an average annual mortality rate of approximately 7%.

PMID- 12464827
TI  - Simplifying prognostication and decision making using exercise testing.

PMID- 12464828
TI  - Effects of cardiac rehabilitation on self-reported health status after coronary
      artery bypass surgery.
AB  - PURPOSE: To examine the effectiveness of cardiac rehabilitation on health status
      following coronary artery bypass surgery. METHODS: A prospective cohort study of
      patients having coronary artery bypass surgery at 14 centers in the state of
      Washington. Baseline clinical and demographic data were collected, as was
      information from the Rand Short Form, 36 (SF-36), the Seattle Angina
      Questionnaire, and other questions regarding health status before surgery and at
      6 and 12 months after surgery. In the 12-month follow-up survey, subjects were
      asked to complete questions pertaining to their participation in postdischarge
      cardiac rehabilitation programs. RESULTS: A total of 947 subjects from 13 centers
      received 1-year follow-up surveys, with 75% responding. Of these, 691 (95%)
      answered questions about participation in cardiac rehabilitation programs. SF-36
      and Seattle Angina Questionnaire scores improved significantly after surgery for
      both cardiac rehabilitation participants and nonparticipants. Although more than
      90% of subjects who participated in the cardiac rehabilitation programs stated
      that they were beneficial, for eight SF-36 domains and five Seattle Angina
      Questionnaire domains, no significant associations were found with participation
      in cardiac rehabilitation. When the participation status was defined as only
      those participants who completed at least 8 weeks of cardiac rehabilitation, only
      1 of 13 health status domains favored cardiac rehabilitation. Responses to a
      series of questions about perceptions of change in general and cardiac-specific
      health did not differ among participants and nonparticipants. CONCLUSIONS:
      Although patients report favorable impressions of cardiac rehabilitation after
      coronary artery bypass surgery, it does not appear to provide a measurable
      benefit in self-reported health status beyond that achieved from the
      revascularization procedure itself.

PMID- 12464829
TI  - The case for cardiac rehabilitation after coronary revascularization: achieving
      realistic outcome assessments.

PMID- 12464830
TI  - Exercise consultation improves short-term adherence to exercise during phase IV
      cardiac rehabilitation: a randomized, controlled trial.

PMID- 12464831
TI  - Neurobehavioral improvement after brief rehabilitation in patients with chronic
      obstructive pulmonary disease.
AB  - PURPOSE: Depressive symptoms, physiologic function, and cognition were examined
      in patients with chronic obstructive pulmonary disease (COPD) after 3 weeks of
      rehabilitation. METHODS: Patients with COPD completed measures of depression,
      neuropsychological function, exercise, and spirometry before and after a 3-week
      rehabilitation program. The 30 rehabilitation patients with COPD were compared
      with 29 untreated patients with COPD and 21 healthy controls similar in age,
      education, and gender. RESULTS: A significant group by time interaction effect
      was found on the Beck Depression Inventory (BDI). A significant interaction
      effect was also found on the 6-minute walk. Patients in the COPD rehabilitation
      program had decreased depressive symptoms and increased 6-minute walk distance
      compared with the untreated groups. Across the 3 groups, no significant
      interaction effects were found on neuropsychological tests. However, clinically
      significant improvement in sustained visual attention, verbal retention, and
      visuospatial ability were reported in the most impaired patients with COPD in the
      rehabilitation group. CONCLUSION: Compared with control groups, decline in
      depressive symptoms and increased exercise capacity occurred in patients with
      COPD after brief rehabilitation. Clinical improvement in visual attention, verbal
      memory, and visuospatial functions occurred in the impaired patients with COPD
      participating in treatment. Neurobehavioral improvements after such a brief
      rehabilitation intervention are relevant for clinical care and warrant continued
      investigation in well-designed clinical trials.

PMID- 12464832
TI  - Feasibility of using a computer-assisted intervention to enhance the way women
      with breast cancer communicate with their physicians.
AB  - This study was conducted to evaluate the feasibility of using a computer
      intervention to enhance communication between healthcare professionals and women
      with breast cancer. Additional aims were to measure the extent to which women
      achieved their preferred decisional roles and satisfaction with the clinical
      medical appointment. This two-arm randomized clinical trial design included a
      convenience sample of 749 women with breast cancer attending 3 urban Canadian
      outpatient oncology clinics. Most women were older than 50 years and had a high
      school diploma or greater (57%). Women in the control group completed measures of
      decision preference before their clinic appointments. Women in the intervention
      group were encouraged to use the information and decision preference profiles
      generated by the computer program at their clinic appointments. Levels of
      involvement in decision making and satisfaction were measured after the clinic
      appointments. Results showed that although the majority of women in both groups
      did assume their preferred roles in decision making, a significantly higher
      proportion of women in the intervention group reported playing a more passive
      role than originally planned. Both groups reported high satisfaction levels.
      Future research is required to study how this computer intervention could be used
      by clinicians to provide information and decision support to these women.

PMID- 12464833
TI  - Stress and coping strategies of patients with cancer. A Korean study.
AB  - Cancer is a potential life-threatening illness that engenders considerable
      psychologic distress, requiring persistent coping for the treatment procedures.
      In this cross-sectional descriptive study stress levels and coping strategies of
      257 cancer patients residing in South Korea are addressed. Lazarus and Folkman's
      theory of stress and coping was used as the theoretical framework. The data were
      collected from November 1999 to March 2000 by face-to-face interviews. Study
      participants were primarily male (62.6%) and married (91.4%). Cancer of the
      gastrointestinal system was the most prevalent type of cancer (31.3%). Women and
      the patients in the third-stage of cancer showed higher stress but less coping
      than other groups. Stress was negatively correlated with both problem-focused
      coping and emotion-focused coping. Korean patients with cancer used emotion
      focused coping strategies more than problem-focused coping strategies.

PMID- 12464834
TI  - Relaxation and imagery for anxiety and depression control in community patients
      with advanced cancer.
AB  - A community-based nursing study was conducted in Sydney, Australia, to compare
      the effects of progressive muscle relaxation and guided imagery on anxiety,
      depression, and quality of life in people with advanced cancer. In this study, 56
      people with advanced cancer who were experiencing anxiety and depression were
      randomly assigned to 1 of 4 treatment conditions: (1) progressive muscle
      relaxation training, (2) guided imagery training, (3) both of these treatments,
      and (4) control group. Subjects were tested before and after learning muscle
      relaxation and guided imagery techniques for anxiety, depression, and quality of
      life using the Hospital Anxiety and Depression scale and the Functional Living
      Index-Cancer scale. There was no significant improvement for anxiety; however,
      significant positive changes occurred for depression and quality of life.

PMID- 12464835
TI  - Nurses' attitudes toward truthful communication with patients with cancer. A
      Greek study.
AB  - The purpose of this study was to examine Greek nurses' attitudes toward truth
      telling practices when working with cancer patients and their psychological
      status regarding the difficulties they face in their day-to-day communication
      with these patients. A self-administered questionnaire composed of 19 questions,
      including both multi-item scales and single-item measures, was designed for the
      study. For this study, 200 nurses were asked to participate, of whom 148 (74%)
      completed and returned the questionnaire. The questionnaire is self-administered,
      formulated after a thorough review of the relevant literature. The pretesting was
      carried out using the alpha model of reliability and the Cochran Chi Square test
      (Q-test), which was 545.46 (P < .0001) and showed a Cronbach alpha coefficient of
      0.7148. A large percentage of the respondents (75.7%) believe that only some
      patients with cancer should be told the truth of their diagnosis and prognosis,
      although a larger percentage (89.1%) believe that the truth should be told to the
      relatives. Most of the respondents (66.2%) reported that is difficult to engage
      in open communication with the patients, because their academic education did not
      sufficiently train them in communication skills. Although 83.78% of the nurse
      respondents do not reveal that the disease is incurable, 86 (58.1%) believe that
      only the patient's physician should reveal the truth. These results indicate that
      although many Greek nurses believe that the patients should be informed and know
      their condition, lack of training in communication skills is a major obstacle to
      achieving this. Finally, this self-assessment questionnaire may provide
      acceptable and valid assessment of Greek nurses' perceptions and attitudes on
      truth telling.

PMID- 12464836
TI  - A Phase III study on the efficacy of topical aloe vera gel on irradiated breast
      tissue.
AB  - The aim of the study was to see if topical aloe vera gel would be beneficial in
      reducing the identified skin side-effects of radiation therapy, including
      erythema, pain, itching, dry desquamation, and moist desquamation, when compared
      with aqueous cream. The secondary aim was to assess the effect of other factors
      known to predict severity of radiation skin reaction, ie, breast size, smoking
      habit, and one or more drainages of lymphocele after surgery, on other skin side
      effects. A Phase III study was conducted involving 225 patients with breast
      cancer after lumpectomy or partial mastectomy, who required a course of radiation
      therapy using tangential fields. Patients were randomized to either topical aloe
      vera gel or topical aqueous cream to be applied 3 times per day throughout and
      for 2 weeks after completion of radiation treatment. Weekly skin assessments were
      performed by nursing staff. Aqueous cream was significantly better than aloe vera
      gel in reducing dry desquamation and pain related to treatment. Subjects with D
      cup or larger size breasts experienced significantly more erythema, regardless of
      treatment arm. For subjects who had undergone lymphocele drainage, the aloe vera
      group experienced significantly more pain than the aqueous cream group. Within
      the aqueous cream arm, smokers were significantly more likely to experience
      itching within the treatment field than were nonsmokers. Within the aloe vera
      arm, subjects who had undergone one or more lymphocele drainages after surgery
      were significantly more likely to experience erythema and itching within the
      treatment field than those who did not have drainage. In this study, aloe vera
      gel did not significantly reduce radiation-induced skin side effects. Aqueous
      cream was useful in reducing dry desquamation and pain related to radiation
      therapy.

PMID- 12464837
TI  - Symptom management and successful outpatient transplantation for patients with
      multiple myeloma.
AB  - This retrospective descriptive study compared symptoms and symptom management in
      patients who completed autologous peripheral blood stem cell transplantation
      without hospital admission with those of patients who required unplanned hospital
      admission during the transplantation period. The sample consisted of 87 patients
      with multiple myeloma treated as outpatients during a 16-month period. Medical
      records and electronic database records review for each patient provided data on
      patient characteristics, medical factors, and symptoms/symptom management.
      Neither age, gender, religion, payer source, treatment on or off protocol, nor
      positive blood culture made a difference in hospital admission. The percentage of
      outpatient visits that included documented teaching on self-care made a
      significant difference (P = .008). Longitudinal analyses of patients' documented
      symptoms before admission compared with nonadmitted patients captured changes
      over time in symptoms/symptoms management. Overall, the patients' symptoms were
      managed well. Significant differences were fatigue, measured as the percentage of
      usual energy (P = .017), and the amount of oral hydration in a 24-hour period (P
      < .001). Results call attention to the role that fatigue and the amount of oral
      hydration may have in unplanned hospital admissions and to the importance of
      teaching on self-care.

PMID- 12464838
TI  - Complications of radiation therapy for head and neck cancers. The patient's
      perspective.
AB  - Newer treatments for head and neck cancers, including altered fractionation and
      the use of concomitant radiotherapy and chemotherapy, may provide better local
      regional tumor control rates; however, patients may experience more frequent and
      more severe acute toxicities that result in considerable suffering. Through this
      study, we sought a better understanding of patients' experiences when undergoing
      radiotherapy. Personal interviews were conducted with 33 individuals who had
      received radiotherapy for head and neck cancers. These individuals described
      their treatment experiences and identified the most troublesome and debilitating
      side effects of radiotherapy. Overall, lethargy and weakness, dry mouth, mouth
      sores and pain, taste changes, and sore throat were the most frequently reported
      troublesome or debilitating side effects. The single most debilitating side
      effect was oropharyngeal mucositis that was characterized by patients as sore
      throat, and mouth sores and pain; both negatively affected the patient's ability
      to eat and drink, causing many patients to experience significant weight loss.
      Trends toward more aggressive management of head and neck cancers underscore the
      need for new and effective therapies for oropharyngeal mucositis occurring in
      patients receiving radiotherapy.

PMID- 12464839
TI  - Overcoming patient-related barriers to cancer pain management for home care
      patients. A pilot study.
AB  - The purpose of this pilot study was to explore the effectiveness of a pain
      education program to overcome patient-related barriers in managing cancer pain
      for Taiwanese home care patients with cancer. The pain education program was
      developed based on previous studies of Taiwanese patient-related barriers to
      cancer pain management. The Barriers Questionnaire-Taiwan form, the Brief Pain
      Inventory, the Medication Adherence Questionnaire, and a demographic
      questionnaire were used for data collection. The sample consisted of 18 patients
      in the experimental group and 19 patients in the control group. Descriptive
      statistics, tests, and paired tests were used to analyze the data. Results of
      this study revealed that patients who received the pain educational program had
      significantly greater reduction in Barriers Questionnaire-Taiwan form scores and
      more improvement in medication adherence compared with patients who did not
      participate in the program. When compared to pretest scores, patients scores
      after receiving the pain education intervention showed significant improvement on
      the Barriers Questionnaire-Taiwan form, medication adherence, pain intensity, and
      pain interference. The results of this study support the effectiveness of the
      pain education program on overcoming the barriers to cancer pain management for
      Taiwanese home care patients with cancer.

PMID- 12464840
TI  - Men with cancer. Changes in attempts to master the self-image as a man and as a
      parent.
AB  - Little is known about men's experience of how cancer affects their role as a
      father. The aim of this study was to gain an understanding of changes in these
      men's everyday family lives. The study had an interpretative descriptive design,
      utilizing the concept of transition as a fore structure. Eight men with different
      types of blood cancer and with children living at home were recruited for the
      study. Interviews, guided by the main components of the concept of transition,
      provided qualitative data for analysis. Through the interpretative process, the
      central theme--change in self-image as a man and as a parent--was generated. This
      theme consists of the subthemes gaining control, balancing emotions, subjective
      well-being, being open or not toward the family, and challenges in family life
      and to family well-being. The time after diagnosis influenced the process of
      transition. Self-image changes are more obvious shortly after diagnosis. Further
      study is needed to identify how nurses and other clinicians can assess the
      family's needs and support the parental role, especially in consideration of the
      findings of this study.

PMID- 12464841
TI  - Solving family-related barriers to truthfulness in cases of terminal cancer in
      Taiwan. A professional perspective.
AB  - The study investigated the puzzling factors and solutions of family-related
      barriers to truthfulness with patients with terminal cancer through a nationwide
      survey conducted in Taiwan. Two-hundred twenty-nine valid questionnaires were
      retrieved (91.6%) from 250 palliative care workers at 15 Taiwan hospices. Most of
      the respondents were nursing staff (72.5%), and only 38 respondents were
      physicians (16.6%). Canonical correlation analysis was used to examine the
      association between the puzzling factors and solutions, which revealed that the
      value of the first variate was 0.39 (P < .05). Results showed that the puzzling
      factors of barriers and canonical loadings were families do not know how to tell
      the truth (.85), families believe it is unnecessary to tell aged patients the
      truth (.71), and patients can be happier without knowing the truth (.70). The
      valid solutions correlated significantly with the above puzzling factors and were
      ranked in the following order: communicate with and encourage families to accept
      patients' prognoses (.83), discuss the sickness gently with patients and
      determine what patients know (.76), and tell the families about the possible
      emotional reactions in patients and how to provide support (.72). In conclusion,
      for solving family-related barriers to truthfulness in cases of terminal cancer,
      the results suggest that health professionals communicate with families first and
      discuss the possible emotional reactions from patients, give patients enough time
      to reflect on their sicknesses and discuss further what patients have been told,
      and then disclose information based on patients' expectations and support them.

PMID- 12464842
TI  - A contemporary statement on practice and education.

PMID- 12464843
TI  - How are you facilitating advance directives in your clinical nurse specialist
      practice?

PMID- 12464844
TI  - Just what are we treating--addiction or pain?

PMID- 12464845
TI  - Dealing with colon cancer: one woman's emotional journey.
AB  - Although death is inevitable, it continues to remain a taboo issue for society. A
      failure to discuss the unavoidable may represent a safeguard to avoid dealing
      with mortality and related fears. Many patients who are terminally ill spend
      their days feeling alone, misunderstood, and afraid. Kubler-Ross attempted to
      strip death of its negative connotations and to provide a venue for the
      terminally ill to have a voice. Using information from more than 200 clinical
      interviews, Kubler-Ross revealed a trend in emotions over time in most, but not
      all, of her patients, which enabled her to formulate a model of coping with death
      that included 5 interdependent emotional stages: denial, anger, bargaining,
      depression, and acceptance. This model has become the most widely accepted and
      popularized model on death and dying, often cited as the Five Stages of Grief."
      However, given the lack of research concerning Kubler-Ross's model, completing
      work in this area seems warranted. The purpose of this case study was to examine
      one individual's emotional journey after being diagnosed with terminal colon
      cancer. More specifically, the goals were twofold: (1) to provide the participant
      with a voice and to allow her story to be told by examining the major external
      events (ie,surgery, chemotherapy) occurring since the diagnosis that affected her
      emotional and physical well-being and (2) to determine whether the participant's
      emotional journey paralleled Kubler-Ross's model, to what extent, and whether new
      emotions or stages occurred. The participant, a 50-year-old female, was diagnosed
      with stage 4 Duke Stage D colon cancer. Qualitative information was collected in
      face-to-face interviews, newspaper articles about the participant, and e-mail
      correspondence (as form letters to a group of friends and supporters) and
      subsequently analyzed for trends. The overall results revealed clear existence of
      the 5 stages of grief as outlined in the Kubler-Ross model. Analyses also
      revealed that the stages often overlapped or occurred simultaneously.
      Additionally, the participant regressed to earlier stages when subjected to
      negative external factors. Four other highly salient emotions were also prevalent
      throughout the participant's experience with colon cancer, namely joy, fear,
      hope, and numbness. The findings from this case study help to validate Kubler
      Ross's stages. Further, the importance of the voice of the participant cannot be
      overemphasized. This case study clearly depicts the unique thoughts and emotions
      during one woman's struggle with colon cancer, sentiments that are often
      overlooked in quantitative analysis.

PMID- 12464846
TI  - Clinical nurse specialist practice: addressing populations with HIV/AIDS.
AB  - Clinical nurse specialists (CNSs) in public health and human immunodeficiency
      virus/acquired immune deficiency syndrome are needed to eliminate healthcare
      disparities, especially with African American women, ages 25-44. This population
      of women accounts for 64% of acquired immunodeficiency syndrome cases reported
      among women, and most of these women need nursing care in community settings.
      Epidemiologic data and nursing research findings demonstrate an urgent need for
      nurses with advanced practice competencies in human immunodeficiency
      virus/acquired immune deficiency syndrome. The competencies identified by the
      National Association of Clinical Nurses Specialists in 3 spheres of influence
      direct care, nursing personnel, and organizations/networks-are used to describe
      clinical nurse specialist competencies as they relate to this population.
      Leininger's Sunrise Model serves as a framework to help this population preserve,
      accommodate, and repattern behaviors for the prevention and treatment of human
      immunodeficiency virus/acquired immune deficiency syndrome.

PMID- 12464847
TI  - Using self-regulation theory to develop an intervention for cancer-related
      fatigue.
AB  - Fatigue is a common and distressing symptom for patients undergoing cancer
      treatment, with reported incidences as high as 96%. According to self-regulation
      theory, inadequate management of the symptom of fatigue may lead to increased
      fatigue distress among patients with cancer. The purpose of this article is to
      describe a theory-based educational intervention developed to help patients
      manage their fatigue more effectively, with the goal of decreasing the distress
      that fatigue causes for patients receiving outpatient cancer treatment. Further,
      this article describes the role of self-regulation theory in guiding intervention
      development to reduce fatigue distress and improve outcomes for patients with
      cancer. The intervention is designed to be delivered before the patient's first
      cancer treatment.

PMID- 12464848
TI  - Nurse specialist profile.

PMID- 12464849
TI  - The influence of greed and power on health and life. Graham Greene's The Third
      Man.

PMID- 12464850
TI  - [Clinical implications of acoustic neuromas growth rate in volumetric study].
AB  - OBJECTIVE: The pattern of neuroma growth is of great importance in choosing the
      appropriate management. This paper tests the clinical impact of tumor growth rate
      assessed by volumetry. There is a conviction that some slowly growing tumors
      could be observed for many years. METHOD AND PATIENTS: Volume measurements were
      performed on T1- weighted MR images (spin echo sequences) after injection of
      gadolinium using a special dedicated software. The studied group included 17
      patients in whom at least two MRI examinations were carried out and tumor growth
      was confirmed. The intervals between initial and the first follow-up examination
      were 14.2 months on the average. In 7 cases tumor evolution was observed in 2
      periods (3 MRI studies) and in 4 cases in 3 periods (4 MRI studies). RESULTS: The
      growth rate depended on tumors volume and clinical stage (P<0.01). Small tumors
      can be observed more safely than advanced tumors because their increase in mass
      is lower. CONCLUSION: The observation with the tumoral volume measurements
      appears to be a useful and accurate tool to estimate the tumor growth rate. The
      growth rate is a major factor for choosing the appropriate management.

PMID- 12464851
TI  - [Acute Mastoiditis in Children: a series of 38 Cases].
AB  - OBJECTIVE: We reviewed retrospectively the clinical, radiological and therapeutic
      findings in 38 infants and children with acute mastoiditis. MATERIAL AND METHODS:
      From 1988 to 2001, 38 children (mean age 36 months) were treated for acute
      mastoiditis and periostitis or retroauricular abscess. RESULTS: Diagnosis was
      usually made on the basis of typical retroauricular signs (60% of the cases), but
      was sometimes delayed owing to inappropriate antibiotics in 16 cases (42%) or
      atypical presentation in 3 (8%). Twenty-four children (70%) had no
      otolaryngological history. Pneumococci were isolated in most of the cases (n=15,
      57%) with 13% having penicillin-resistant pneumococci. Lateral sinus
      thrombophlebitis was the most frequent complication, observed in 3 children (8%).
      Mastoiditis revealed congenital or acquired cholesteatoma in 4 children, who were
      all four infected with Gram-negative bacteria. Intravenous antibiotic therapy was
      associated with antroatticotomy in 36 children. CONCLUSION: Despite emergence of
      new antibiotic resistance, the annual rate of mastoiditis has remained unchanged,
      remaining a serious complication of middle ear acute otitis. Cholesteatoma should
      be suspected in case of Gram-negative bacteria or in older children.

PMID- 12464852
TI  - [Adenocarcinomas of the ethmoid sinuses. Epidemiological data].
AB  - OBJECTIVE: The relationship between adenocarcinomas of the ethmoid (ADKE) and
      wood-dust exposure has been well established. Sino-nasal cancer in wood-workers
      has been added to the list of occupational disorders in France, as prescribed
      disease number 47-Bq. PATIENTS AND METHODS: Our data set consisted of 207 cases
      with sino-nasal cancer (from January 1985 to January 2001). Among these cases,
      67.1% were adenocarcinoma. A wood dust exposure has been reported in 96.4% cases.
      The mean duration of wood dust exposure was 30 years. The mean latency between
      the end of the exposure and the diagnostic was 10.6 years. RESULTS: Our
      epidemiological data confirmed those from the biomedical literature. The
      occupations at greatest risk are furniture workers, sawmill workers, carpentry
      workers, and other wood product workers. Two components of exposure - duration
      and average level - contributed independently to the overall elevated risk. The
      risk is greater among men who were employed in jobs with the highest wood dust
      exposure and increases with the duration of exposure. CONCLUSIONS: The
      preinvasive stages of ADKE (mucostasis/cuboid metaplasia/dysplasia) are still an
      unverified hypothesis. ADKE were observed in workers who use "hard" woods. The
      chemical nature of the carcinogenic factor(s) in wood dust is not known. The
      factors responsible for induction of ADKE in hard wood-workers probably exist in
      the wood-dust itself. Tannins were suggested as possible contributing agents to
      induction of ADKE. In addition to wood dust, exposures may include formaldehyde.
      Given these facts, it should be possible to define preventive measures, so that
      incidence of ADKE in professional wood and leather workers should decrease.

PMID- 12464853
TI  - [Current aspects of laryngeal tuberculosis: a report of four cases].
AB  - OBJECTIVE: Laryngeal tuberculosis is a rare condition. This new clinical pattern
      of tuberculosis should be recognized by clinicians. METHODS: We report our
      experience with four cases of laryngeal tuberculosis. RESULTS: The principal
      differences in the disease pattern are an increase in the number of cases of
      primary laryngeal tuberculosis without any evident pulmonary involvement and the
      declining number of pseudotumor forms with an larger number of nonspecific
      laryngeal localizations. CONCLUSION: Tuberculosis should be entertained as a
      possible diagnosis in patients with nonspecific laryngeal disease. The diagnosis
      is confirmed by identification of granulomatous inflammation and acid-fast
      bacilli. New culture techniques and molecular biology methods such as polymerase
      chain reaction allow early identification of Mycobacterium tuberculosis.

PMID- 12464854
TI  - [Parapharyngeal chondrosarcoma and Ollier's disease: a case report and review of
      the literature].
AB  - OBJECTIVES: Ollier's disease is a constitutional pathology of unknown etiology.
      It is characterized by bone dysplasia generating numerous enchondromas. The
      malignant degeneration of this dysplasia is well known. The aim of this article
      is to study the diagnostic, therapeutic and prognostic characteristics of these
      lesions. MATERIAL AND METHODS: We report a case of parapharyngeal chondrosarcoma
      extended to the base of the skull in a patient with Ollier's disease. The
      treatment was a surgical removal by a cervicotransoral incision combined with a
      preauricular incision and with a mastoidectomy. It was therefore possible to
      control the skull base, the parapharyngeal space, the infratemporal fossa and the
      major neurovascular structures. The removal of the lesion was completed at the
      level of the clivus and sphenoid with optics (30 and 70 degrees ). We discuss
      this treatment and the follow up on the bases of literature data. RESULTS: The
      neoplastic degeneration of enchondromas is estimated between 25 to 50% of cases.
      The most frequent location is the pelvic bones. Chondrosarcomas are slow growing
      tumors and their metastatic potential is less significant as we note it in our
      case report. Their diagnostic is essentially based on histological criteria's and
      their treatment is surgical. CONCLUSION: Chondrosarcomas of the ENT area
      occurring with Ollier's disease is rare. Their prognostic is good if the surgical
      treatment is well done.

PMID- 12464855
TI  - [Prenatal diagnosis at 25 weeks gestation and neonatal management of a vallecular
      cyst].
AB  - Due to the anatomical location, vallecular cyst is a rare but well-recognized
      cause of upper airway obstruction and death in newborn. This cyst can be
      accurately diagnosed by echography in utero and by MR imaging. Prenatal diagnosis
      allows for early consultation with surgical specialist, so that the time and
      place of the delivery can be addressed for neonatal preoperative planning. We
      report the first prenatal diagnosis of a vallecular cyst at 25 weeks of
      gestation. At birth, the cyst was drained and then marsupialized. We believed
      that, in cases of oropharyngeal tumors discovered in utero, elective delivery
      should be realised in a tertiary referral center in which emergency ventilation
      and tracheostomy are possible.

PMID- 12464856
TI  - [Endonasal plasmocytoma: diagnosis and management].
AB  - Plasmocytomas are either medullary (disseminated form) or extramedullary with or
      without bone infiltration (located form). Plasmocytoma is not a common tumor but
      extramedullary forms mostly occur in the upper respiratory tract without specific
      manifestations. OBJECTIVE: The aim of this study is to discuss the management
      (diagnostic and therapeutic) and the follow-up of extramedullary nasal
      plasmocytoma. MATERIAL AND METHODS: We report a case of a 71-year-old patient
      with unilateral nasal obstruction manifestation. RESULTS: Endonasal biopsy
      concluded plasma cell tumor without extension on CT scan. Treatment consisted of
      external nasal surgery and radiotherapy. CONCLUSION: Diagnosis of solitary
      extramedullary plasmocytoma can only be confirmed when the presence of systemic
      disease is excluded by performing clinical, biological (marrow bone biopsy) and
      radiological investigations. The treatment should be based on surgery with
      complementary radiotherapy if there is a skull base erosion. Long term follow-up
      is necessary because of the high risk of diffuse marrow involvement (multiple
      myeloma) which may occur after a long delay.

PMID- 12464857
TI  - [Questions to the experts].

PMID- 12464858
TI  - Resident debt and the American College of Surgeons.

PMID- 12464859
TI  - The SUS loan repayment program for surgeon/scientists: will it work?

PMID- 12464860
TI  - SUS extramural educational loan repayment for physicians/scientists.

PMID- 12464861
TI  - Adjusting surgical mortality rates for patient comorbidities: more harm than
      good?
AB  - Background. Studies of medical admissions have questioned the validity of using
      claims data to adjust for preexisting medical conditions (comorbidities), but the
      impact of using comorbidities from claims data to risk-adjust mortality rates for
      high-risk surgery is not well characterized. The purpose of this study was to
      evaluate the relationship between comorbidities and mortality in administrative
      data in surgical populations and identify better risk-adjustment methods.
      Methods. Using the national Medicare database (1994-1997), we identified
      admissions for elective abdominal aortic aneurysm repair (140,577) and
      pancreaticoduodenectomy (10,530). We calculated the relative risk of mortality
      (adjusted for age, sex, race, and admission acuity) for 5 chronic conditions that
      are known (from clinical series) to increase the risk of postoperative mortality
      and are commonly used in claims-based risk-adjustment models. To explore the
      potential value of alternative risk-adjustment strategies, we examined
      relationships between surgical mortality and comorbidities using diagnosis codes
      identified from previous admissions. Results. Overall, in-hospital mortality for
      elective abdominal aortic aneurysm (AAA) repair and pancreaticoduodenectomy were
      5.1% and 10.4%, respectively. For both procedures, 3 of the 5 comorbidities were
      associated with decreased risk of mortality: prior myocardial infarction (MI) [RR
      = 0.38; 95% confidence interval (CI), 0.33-0.43 for AAA; RR = 0.38; 95% CI, 0.21
      0.69 for pancreaticoduodenectomy), malignancy (RR = 0.67; 95% CI, 0.59-0.76 for
      AAA; RR = 0.74; 95% CI, 0.45-1.21 for pancreaticoduodenectomy], and diabetes (RR
      = 0.76; 95% CI, 0.64-0.84 for AAA; RR = 0.59; 95% CI, 0.49-0.69 for
      pancreaticoduodenectomy). Using comorbidities identified from prior admissions
      increased the mortality risk estimates for prior MI (RR = 1.22; 95% CI, 1.08-1.38
      for AAA; RR = 0.80; 95% CI, 0.49-1.30 for pancreaticoduodenectomy) and diabetes
      (RR = 1.41; 95% CI, 1.25-1.59 for AAA; RR = 0.94; 95% CI, 0.78-1.14 for
      pancreaticoduodenectomy). Conclusions. Because comorbidities coded on the index
      admission appear protective, incorporating them in risk-adjustment models for
      studies comparing surgical performance may penalize providers for taking care of
      sicker patients. When available, comorbidity information from prior
      hospitalizations may be more useful for risk adjustment.

PMID- 12464862
TI  - Financial returns on specialty training for surgeons.
AB  - BACKGROUND: Because of recent changes in physician reimbursement and managed care
      penetration, we wanted to examine the financial returns that medical students
      might anticipate when considering different careers. METHODS. We used standard
      financial techniques to calculate the return on educational investment for 5
      surgical specialties (general surgery, otolaryngology, ophthalmology, orthopedic
      surgery, and urology) and primary care medicine between 1992 and 1998. RESULTS:
      The annual yield on specialty training fell for all specialties examined, from an
      average of 15% to 3% for primary care specialties, and from an average of 36% to
      19% for surgical specialties. The difference in the average future hourly income
      between a given specialty and general practice decreased for all surgical
      specialties (for general surgery, from $12.03 in 1992 to $9.89 in 1998;
      otolaryngology, from $21.37 to $5.56; ophthalmology, from $14.12 to $7.15;
      orthopedic surgery, from $21.16 to $18.91), except urology (from $13.81 in 1992
      to $14.84 in 1998). Returns became negative for primary care medicine, dropping
      from $1.72 to -$1.21. CONCLUSION: Efforts to create a "level playing field"
      within medicine have resulted in decreased returns on educational investment
      across all specialties. Financial returns and the incentives they create should
      be carefully considered as part of health care reform.

PMID- 12464863
TI  - Invited commentary: how do we recruit bright and selflessly capable students into
      the gratifying profession of surgery?

PMID- 12464864
TI  - Preoperative oral arginine and n-3 fatty acid supplementation improves the
      immunometabolic host response and outcome after colorectal resection for cancer.
AB  - BACKGROUND: Previous trials showed that perioperative immunonutrition improved
      outcome in patients with gastrointestinal cancer. This study was designed to
      appraise the impact of the simple preoperative oral arginine and n-3 fatty acids
      supplementation on immune response, gut oxygenation, and postoperative
      infections. METHODS: Two hundred patients with colorectal neoplasm were
      randomized to: (a) oral intake for 5 days before surgery of a formula enriched
      with arginine and n-3 fatty acids (pre-op group; n = 50); (b) same preoperative
      treatment prolonged after surgery by jejunal infusion (peri-op group; n = 50);
      (c) oral intake for 5 days before surgery of a standard isoenergetic,
      isonitrogenous formula (control group; n = 50); and (d) no supplementation before
      and after operation (conventional group; n = 50). The immune response was
      measured by phagocytosis ability of polymorphonuclear cells and delayed
      hypersensitivity response to skin tests. Gut oxygenation and microperfusion were
      assessed by polarographic probes and laser Doppler flowmetry, respectively.
      RESULTS: The 4 groups were comparable for demographics, comorbidity, and surgical
      variables. The 2 groups receiving immunoutrients (pre-op and peri-op) had a
      significantly better immune response, gut oxygenation, and microperfusion than
      the other 2 groups. Intent-to-treat analysis showed an overall infection rate of
      12% in pre-op, 10% in peri-op, 32% in control, and 30% in conventional groups (P
      <.04 pre-op and peri-op vs control and conventional). CONCLUSION: Preoperative
      oral arginine and n-fatty acids improves the immunometabolic response and
      decreases the infection rate. Postoperative prolongation with such supplemented
      formula has no additional benefit.

PMID- 12464865
TI  - Invited commentary: new roles for immune-enhancing diets.

PMID- 12464866
TI  - Recovery after uncomplicated laparoscopic cholecystectomy.
AB  - BACKGROUND: After laparoscopic cholecystectomy, the duration of convalescence is
      2 to 3 weeks with an unclear pathogenesis. This study was undertaken to analyze
      postoperative recovery after uncomplicated elective laparoscopic cholecystectomy.
      METHODS: Twenty-four consecutive unselected employed patients were followed up
      prospectively from 1 week before to 1 week after outpatient laparoscopic
      cholecystectomy. Daily computerized monitoring of physical motor activity and
      sleep duration and night sleep fragmentation (actigraphy), subjective sleep
      quality, pulmonary function, pain, and fatigue were registered. Treadmill
      exercise performance (preoperatively and at postoperative days 2 and 8) and
      nocturnal pulse oximetry at the patients' homes (preoperatively and postoperative
      nights 1-3) were completed. RESULTS: Median age was 41 years (range, 21-56).
      Compared with preoperatively, levels of physical motor activity, fatigue, and
      pain scores were normalized 2 days after operation. Subjective sleep quality was
      significantly worsened on the first postoperative night, and sleep duration was
      significantly increased on the first 2 postoperative nights. There were no
      significant perioperative changes in actigraphy night sleep fragmentation,
      incidence of self-reported awakenings or nightmares/distressing dreams, exercise
      performance, or nocturnal oxygenation. Pulmonary peak flow measurements were
      normalized the day after operation. CONCLUSION: After uncomplicated outpatient
      laparoscopic cholecystectomy, there is no pathophysiologic basis for recommending
      a postoperative convalescence of more than 2 to 3 days in otherwise healthy
      younger patients.

PMID- 12464867
TI  - New strategies to prevent laparoscopic bile duct injury--surgeons can learn from
      pilots.
AB  - BACKGROUND: Injury to the bile ducts is the most important complication of
      laparoscopic cholecystectomy (LC), affecting approximately 2000 patients annually
      in the United States. Traditional surgical teaching fails to provide adequate
      extrabiliary reference points. A "person approach" of blame and shame (as
      distinct from a "system approach") has evidently been unsuccessful in controlling
      this problem. New strategies are needed. High-reliability organizations such as
      aviation and the nuclear power industry have well-developed system-based error
      prevention programs; the application to laparoscopic operations of some
      principles used in these programs merits evaluation. In addition, some time
      honored teaching of steps to safeguard the bile duct needs to be re-examined.
      METHODS: A review of the literature and of 34 cases of bile duct injury referred
      to the author was carried out. Traditional surgical teaching was evaluated to
      identify reasons why it has failed to prevent bile duct injury. New extrabiliary
      reference points were used. Error prevention strategies derived from the aviation
      and maritime industries were modified for application to LC. These principles
      have been applied in a prospective study of 2000 successive LCs carried out on 1
      surgical unit, including operations by surgical trainees. RESULTS: The literature
      and case review indicated that misidentification of biliary anatomy was the major
      cause of bile duct injury and the injury was unrecognized by the operating
      surgeon in 3 out of 4 cases, suggesting that traditional surgical teaching
      provides inadequate reference points to prevent duct misidentification, that
      spatial disorientation analogous to navigation errors occurs, and that systemic
      factors predisposing to error are present. Several principles used in navigation
      were applied. "Human factors," educational principles derived from aviation crew
      resource management training, were applied. No bile duct injuries occurred in the
      2000 LC operations. Eight patients had biliary leakage develop but all recovered
      without further surgical intervention. CONCLUSIONS: Laparoscopic bile duct injury
      continues to occur at an unacceptable rate. New strategies involving a system
      approach and using principles adopted by the aviation and maritime industries
      were applied in 2000 consecutive LCs without bile duct injury. The application in
      the operating room of commonly taught navigation principles, the use of
      extrabiliary reference points such as Rouviere's sulcus, and the introduction of
      human factors education for surgeons reduces the frequency of bile duct injury.

PMID- 12464868
TI  - Medial pancreatectomy: a multi-institutional retrospective study of 53 patients
      by the French Pancreas Club.
AB  - BACKGROUND: The results of medial pancreatectomy have been previously reported
      anecdotally. The purpose of the study was to provide short- and long-term results
      of MP in a large multicenter collective series. METHODS: From 1990 to 1998, 53
      patients (mean age +/- SD = 49 +/- 15 years) underwent medial pancreatectomy for
      primary cystic neoplasms of pancreas (n = 19), endocrine neoplasms (n = 17),
      intraductal papillary mucinous neoplasms (IPMN) (n = 6), fibrotic stenosis of the
      Wirsung's duct (n = 4), or other benign (n = 4) or malignant (n = 3) diseases.
      The proximal (right) pancreatic remnant was sutured (n = 53), and the distal
      (left) remnant was either anastomosed to a jejunal loop (n = 26), to the stomach
      (n = 25), or oversewn (n = 2). Medial pancreatectomy was indicated in 3 patients
      (6%) because of failed enucleation, in 3 (6%) to prevent worsening of preexisting
      diabetes, or to prevent de novo diabetes in a patient with chronic pancreatitis,
      and deliberately in the 47 others. RESULTS: The length of the resected pancreas
      was 5.0+/- 2.2 cm (range, 2-15). One patient (2%) died from a pancreatic fistula
      and portal thrombosis. Three patients were reoperated on because of complications
      related to the left pancreas, which was partially or totally resected. Pancreatic
      fistula developed in 16 patients (30%). Mean delay for the return of oral feeding
      was related to the presence of a pancreatic fistula. At follow-up (median = 26
      months, range, 12-131), 1 pancreatic recurrence and 1 de novo diabetes occurred
      in patients without IPMN. In patients with IPMN, the rates of pancreatic
      recurrence and diabetes were 40% (2/5), respectively. CONCLUSIONS: Medial
      pancreatectomy effectively preserves long-term endocrine function and is
      associated with a low risk of local recurrence, except in patients with IPMN.
      However, there is a high risk (30%) of PF after medial pancreatectomy.

PMID- 12464869
TI  - Assessment of routine elimination of postoperative nasogastric decompression
      after Roux-en-Y gastric bypass.
AB  - BACKGROUND: Anastomotic disruption after surgical intervention is an infrequent
      complication, but may lead to severe morbidity and mortality when it occurs. Of
      the various gastric procedures, the Roux-en-Y gastric bypass (RYGB) has one of
      the highest risks for anastomotic leakage. Consequently, a nasogastric tube (NGT)
      is frequently placed when these operations are performed. Most studies examining
      the outcomes for patients without postoperative NGTs have been relatively small
      with groups of patients undergoing a variety of operations. Assessing the
      incidence of anastomotic leaks by routine elimination of postoperative NGTs
      requires a large number of patients. In this study, we assessed the safety and
      efficacy of routine elimination of NGTs in a large cohort of patients undergoing
      a single operation. METHODS: We reviewed our experience with 1067 patients who
      underwent RYGB at the UCLA medical center. Fifty-six patients had NGTs routinely
      placed before the implementation of a standard protocol, which eliminated
      postoperative NGT decompression. The complication rate for the RYGB patient
      cohort with and without postoperative NGT was compared. RESULTS: We found no
      difference in the complication rates between the 2 groups (Fisher exact test; P
      =.21). CONCLUSIONS: Our findings suggest that routine placement of an NGT after
      RYGB is unnecessary.

PMID- 12464870
TI  - Recovery of liver function in two-third partial hepatectomized rats evaluated by
      L-[1-13C]phenylalanine breath test.
AB  - BACKGROUND: We have previously reported that by means of a breath test with
      intravenously administered L-[1-13C] phenylalanine (13Cphe), hepatopathy could be
      quantitatively evaluated by measuring expiratory 13CO2 levels in a short period.
      It is known that phenylalanine hydroxylase activity (PAHA) plays an important
      role in phenylalanine metabolism. We examined the relationship between changes in
      PAHA and the results of the 13Cphe breath test during hepatic regeneration in a
      rat model of 70% hepatectomy, to assess their usefulness for evaluating hepatic
      regeneration. METHODS: Male Wistar rats (Shizvoka Laboratory Animal Center,
      Hamamatsu, Japan) weighing 230 to 290 g were subjected to 70% hepatectomy under
      anesthesia with sodium pentobarbital. One, 2, 3, 5, 7, and 14 days
      postoperatively, 30 mg/kg 13Cphe was intravenously injected into the femoral
      vein, and the increase in exhaled 13CO2 (Delta 13CO2) was measured for 15
      minutes. Simple laparotomy was performed in control rats. After the breath test,
      the regenerated liver was removed and weighed. The amount of DNA, amount of
      hepatic tissue total protein (TP), and PAHA were determined. RESULTS: The r
      between liver weight/body weight and PAHA, between DNA and PAHA, and between TP
      and PAHA were 0.832, 0.720, and 0.758, respectively. Breath test graphs revealed
      that liver weight/body weight, DNA, and TP showed the best correlations with the
      peak value of Delta 13CO2 (liver weight/body weight percentage, r = 0.801; DNA, r
      = 0.660; TP, r = 0.706), and r between PAHA and peak value was 0.638.
      CONCLUSIONS: These results suggest that measurement of PAHA in regenerated liver
      is an effective method for following up liver function after hepatic resection.
      Moreover, the 13Cphe breath test may also be useful to evaluate liver function
      after partial hepatectomy.

PMID- 12464871
TI  - Adenovirus-mediated delivery of a soluble form of the VEGF receptor Flk1 delays
      the growth of murine and human pancreatic adenocarcinoma in mice.
AB  - BACKGROUND: Because pancreatic adenocarcinoma is poorly responsive to
      chemotherapy and radiation therapy, novel treatments such as antiangiogenic gene
      therapy may have use in the adjuvant treatment of this malignancy. We evaluated
      the antitumor effects of the in vivo administration of an adenovirus vector
      encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial
      growth factor, in 3 murine models of pancreatic adenocarcinoma. METHODS: In a
      first model, immunocompetent C57Bl/6 mice were injected subcutaneously with
      Panc02 murine pancreatic adenocarcinoma cells before treatment. In a second
      model, immunodeficient severe combined immunodeficiency mice were injected
      subcutaneously with BxPc-3 human pancreatic adenocarcinoma cells before
      treatment. In a third model, C57Bl/6 mice were injected with Panc02 cells through
      an intrasplenic route before treatment, in an effort to model metastatic disease.
      In each model, half the tumor-bearing mice were injected intravenously with 10(9)
      Flk1-Fc adenovirus particles and half with control adenovirus. RESULTS: In
      subcutaneous tumor models, Ad Flk1-Fc-treated animals were found to have 75%
      smaller murine and 78% smaller human pancreatic tumor volumes, relative to tumor
      volumes of Ad Fc-treated animals, 6 weeks after vector administration. In animals
      injected with tumor through the intrasplenic route, pathologic and histologic
      analyses made 10 days after injection of tumor revealed hepatic, pancreatic, and
      splenic tumors, together with a desmoplastic response consistent with pathologic
      findings in human pancreatic cancer. Cohorts of these tumor-bearing mice treated
      with Ad Flk1-Fc demonstrated significantly longer survival and decreased liver
      replacement with tumor at the time of death, relative to animals treated with Ad
      Fc. CONCLUSION: A recombinant adenovirus encoding soluble Flk-1 inhibited
      pancreatic tumor growth in mice. These studies suggest that the delivery of gene
      products such as Flk1-Fc through in vivo gene transfer may be useful in the
      future treatment of patients with pancreatic cancer.

PMID- 12464872
TI  - Characterization of incisional wound healing in inducible nitric oxide synthase
      knockout mice.
AB  - BACKGROUND: Excisional wound healing in inducible nitric oxide synthase knockout
      (iNOS-KO) mice has been previously shown to be impaired compared with their
      background strain controls. Incisional wounds were created in this experiment in
      both types of animals and paradoxically were found to heal with the same rapidity
      and breaking strength in both groups. METHODS: Dorsal 2.5 cm incisional wounds
      were created in iNOS-KO mice, as well as their parental strain controls
      (C57BL/6J). Standardized polyvinyl alcohol sponges were implanted in the wounds
      to allow for measurement of collagen deposition. Animals were harvested on
      postoperative days (PODs) 3, 5, 7, 10, 14, and 28, and their wounds subjected to
      tensiometric breaking strength analysis. Nonisotopic in situ hybridization
      quantitative analysis for iNOS, endothelial NOS (eNOS), basic fibroblast growth
      factor (bFGF), transforming growth factor-beta1 (TGF-beta1), vascular endothelial
      growth factor (VEGF), and interleukin-4 (IL-4) expression in the wounds was
      performed. Hydroxyproline levels were quantitated in the harvested polyvinyl
      alcohol sponges. Data were analyzed with the Students t test. RESULTS: No
      significant differences were found in breaking strengths or levels of
      hydroxyproline (and thus collagen) in iNOS-KO versus wild-type wounds at all
      tested time points. Flawed iNOS expression levels in iNOS-KO animals were similar
      to (functional) iNOS expression in wild-types. eNOS and bFGF expression nearly
      doubled on POD 7 in iNOS-KO incisions (P =.002, and.002), respectively and
      remained 200% to 300% elevated thereafter. TGF-beta1 expression was increased
      approximately 50% to 100% in iNOS-KO wounds on PODs 5 and 7 (P =.006 and.01,
      respectively). VEGF and IL-4 expression was elevated by 25% to 100% in wild-type
      compared with iNOS-KO animals at all time points (P <.01). CONCLUSIONS: The
      overexpression of TGF-beta1 and eNOS may represent mechanisms in iNOS-KO mice to
      compensate for their loss of functional iNOS, resulting in incisional wound
      healing equivalent to controls. Their impaired expression of VEGF and IL-4, on
      the other hand, may partially explain the delayed excisional wound healing noted
      in these animals.

PMID- 12464873
TI  - The effects of preconditioning on the oxidative stress in small-bowel
      autotransplantation.
AB  - BACKGROUND: One determining factor in intestinal transplantation is the extreme
      sensitivity of the small bowel to ischemia-reperfusion injury. This study
      investigated the effect of ischemic preconditioning prior to autotransplantation.
      METHODS: Total orthotopic intestinal autotransplantation was performed in 40
      mongrel dogs. In 4 groups (GI-GIV), grafts were stored for 3 hours in cold Euro
      Collins (GI,GIII) and University of Wisconsin (GII,GIV) solutions. In GIII and
      GIV, before preservation, preconditioning was induced by 4 cycles (5-min ischemia
      + 10-min reperfusion). Bowel samples were collected after laparotomy (control),
      at the end of preservation and reperfusion periods. We determined oxidative
      stress markers (reduced glutathione [GSH], superoxide dismutase [SOD]),
      production of oxygen free radicals, activity of nuclear factor-kappaB (NF
      kappaB), and DNA damage. RESULTS: In the non-preconditioned groups, GSH
      concentration increased slightly, while SOD activity decreased significantly
      during reperfusion. In the preconditioned groups, GSH increased markedly, and
      better preservation of SOD was observed. The number of oxygen free radicals
      increased during reperfusion mainly in non-preconditioned groups. Activation of
      NF-kappaB peaked by 1 hour, and decreased 3 hours after preconditioning. We
      observed DNA-damaged cells in all groups. CONCLUSIONS: Our findings confirm that
      preconditioning prior to preservation can moderate the severity of oxidative
      stress and activate the endogenous cellular adaptation in bowel tissue.

PMID- 12464874
TI  - Pharyngolaryngoesophagectomy for well-differentiated papillary thyroid carcinoma
      widely invading the upper aerodigestive tract.

PMID- 12464875
TI  - Gastrointestinal metastasis to the breast.
AB  - BACKGROUND: Although primary breast cancer is common, metastatic disease to the
      breast, especially primary gastrointestinal cancer, is rare. Routine pathologic
      examination may be helpful in determining the true diagnosis, but can be
      misleading. METHODS: To determine whether a signet ring carcinoma was a primary
      malignancy of the gastrointestinal tract metastatic to the breast or vice versa,
      histochemical analysis was performed for Her-2/NEU, gross cystic disease fluid
      protein-15, estrogen receptor, progesterone, carcinoembryonic antigen,
      cytokeratin 7, and cytokeratin 20. RESULTS: Positive staining for
      carcinoembryonic antigen and cytokeratin 20 (and negative staining for the breast
      cancer antigens), and the clinical criteria favors the diagnosis of
      gastrointestinal carcinoma metastatic to the mammary gland. CONCLUSIONS: Because
      the prognosis of therapy for metastatic cancer to the breast differs from that of
      primary breast cancer, it is imperative that the correct diagnosis be
      established. Immunohistochemistry for carcinoembryonic antigen and cytokeratin 20
      are particularly useful. Metastatic gastrointestinal carcinoma to the breast is a
      rare lesion but needs to be at least included in the differential diagnosis of
      breast masses, especially in patients with a history of gastrointestinal cancer.

PMID- 12464876
TI  - Arterial hypertension due to primary adrenal hydatid cyst.

PMID- 12464877
TI  - End-stage skeletal manifestations of severe hyperparathyroidism.

PMID- 12464878
TI  - Lymphedema praecox of the lower extremity.

PMID- 12464879
TI  - Nina.

PMID- 12464880
TI  - Hemorrhagic acalculous cholecystitis associated with hemodialysis.

PMID- 12464881
TI  - Supernumerary intravagal parathyroid hyperplasia.

PMID- 12464882
TI  - Left liver plus caudate lobe graft with complete revascularization.

PMID- 12464884
TI  - Hockey groin syndrome.

PMID- 12464886
TI  - Apical periodontitis: a very prevalent problem.

PMID- 12464887
TI  - Clinical implications of the smear layer in endodontics: a review.
AB  - It has been recognized for many years that root canal instrumentation produces a
      smear layer that covers the surfaces of prepared canal walls. This layer contains
      inorganic and organic substances such as fragments of odontoblastic processes and
      necrotic debris. There is a lack of agreement regarding the effect of the smear
      layer on the quality of instrumentation and obturation, but the smear layer
      itself may be infected and may protect the bacteria within the dentinal tubules.
      Various methods have been used to remove the smear layer. Conflicting results
      have been obtained from numerous in vitro studies regarding the significance of
      the presence or the removal of the smear layer.

PMID- 12464888
TI  - Functional fixation of autotransplanted tooth germs by using bioresorbable
      membranes.
AB  - OBJECTIVE: The purpose of this study was to evaluate the contribution of a
      bioresorbable membrane placement to the healing of immature teeth after
      autotransplantation of tooth buds. STUDY DESIGN: Six cases were selected: 2
      transplantations of wisdom teeth, 2 for premolar agenesis, 1 for ectopia, and 1
      premolar in an incisor position. The crown of each tooth germ and the marginal
      alveolar bone were covered with a resorbable membrane. RESULTS: The radicular
      edification was nearly complete, neither ankylosis nor inflammatory resorption
      was observable, the pulp vitality was preserved, and the periodontal integration
      was identical to that of other teeth. The membrane ensured contention and
      stabilization of the transplant, allowed functional stimulation, permitted
      protection of the coagulum and periodontal cells, and kept the epithelium at a
      distance. CONCLUSIONS: The transplantations of immature teeth were improved by
      the use of a resorbable membrane, which caused an optimal functional fixation of
      the transplanted tooth.

PMID- 12464889
TI  - Soft tissue profile changes of the midface in patients with cleft lip and palate
      following maxillary distraction osteogenesis: a preliminary study.
AB  - OBJECTIVE: The purpose of this study was to examine preoperative to postoperative
      changes of soft tissue profiles in the midface of cleft patients who underwent
      maxillary distraction. STUDY DESIGN: Nine cleft patients were examined
      (distraction group). Lateral cephalograms were obtained preoperatively and 6
      months after distraction. Changes in the positions of soft and hard tissue
      landmarks, the nasolabial angle, and facial height were investigated and compared
      with those in 9 other cleft patients who underwent conventional maxillary
      advancement (conventional group). RESULTS: Anterior changes of the soft and hard
      tissue landmarks were significantly larger in the distraction group than in the
      conventional group. The distraction group tended to have larger increases in the
      nasolabial angle and subnasal length, as well as a higher anterior movement ratio
      for soft to hard tissue. CONCLUSIONS: These results suggest that, in the
      midfacial profile changes of cleft patients who underwent maxillary distraction,
      not only is advancement of soft and hard tissue large, but also anterior movement
      ratio for soft to hard tissue is relatively high.

PMID- 12464890
TI  - A 3-dimensional finite-element analysis investigating the biomechanical behavior
      of the mandible and plate osteosynthesis in cases of fractures of the condylar
      process.
AB  - OBJECTIVE: The condylar region is one of the most frequent sites for mandibular
      fractures, with direct application of miniplates being the most commonly used
      open-fixation technique today. Yet, anatomic and biomechanical limitations
      continue to make this application technically challenging with a considerable
      complication rate. We sought to analyze such incongruencies with respect to the
      complex biomechanical behavior of the mandible. STUDY DESIGN: Individual human
      mandible geometry, the specific bone density distribution, and the position and
      orientation of the masticatory muscles were evaluated by performing computed
      tomography scans and a sequential dissection of the cadaver mandible. Three
      dimensional finite-element analysis was performed for different fracture sites,
      osteosynthesis plates, and loading conditions. RESULTS: Osteosynthesis of
      fractures of the condylar neck with 1 or 2 miniplates of a diameter of 2.35 x
      1.00 mm was found to be an insufficient fixation method. This also applies for
      plates (3.60 x 1.54 mm), according to Pape et al,(8) when used in singular
      fashion (high condylar neck fractures excepted). In cases of singular occlusal
      contacts in the molar region (particularly at the contralateral side of the
      fracture), the highest stress values inside the mandible and osteosynthetic
      devices could be observed. With even the static yield limit of titanium being
      exceeded in such cases, consecutive rapid failure of the miniplates becomes most
      likely when loading of the condylar region caused by bite forces cannot be
      prevented. CONCLUSION: We strongly recommend the use, whenever possible, of 2
      plates in the manner described by Pape et al(8) for osteosynthesis of fractures
      of the condylar neck in combination with bicortically placed screws. The
      stiffness of a singular osteosynthesis plate made of titanium in a diametrical
      dimension of approximately 5.0 x 1.75 mm was found to be equivalent to the
      physiological bone stiffness in the investigated fracture sites. The actual
      stiffness of such a fixation plate is approximately 3 times higher than the
      stiffness of devices commonly in use.

PMID- 12464891
TI  - An analysis of oral surgical dental visits by provider type, 1996.
AB  - OBJECTIVE: The choice by consumers of the professional from whom they receive
      specific types of care is influenced by many factors. This study examines the
      roles that socioeconomic and racial factors play in deciding whether a generalist
      or oral and maxillofacial surgeon provides routine exodontia care in a community.
      STUDY DESIGN: The 1996 Medical Expenditure Panel Survey sampled 10,500 households
      consisting of 21,571 individuals. The combined full-year 1996 response rate of
      the Medical Expenditure Panel Survey sample through the third round was 70%. An
      analysis was undertaken of surgical dental services and type of provider for each
      of several socioeconomic and demographic categories. All estimates and statistics
      reported were computed, taking into account the complex sampling design of the
      Medical Expenditure Panel Survey, with the use of the software package SUDAAN.
      RESULTS: Data analyzed in this study reveal that the majority of oral surgical
      visits for all patients are to a generalist and not an oral and maxillofacial
      surgeon. In addition, nonwhite patients, patients from lower-income households,
      and patients with less education are more likely to receive surgical care from a
      generalist than from a specialist. On the other hand, white patients, patients
      from higher-income households, and patients with more education are more likely
      to receive surgical care from a specialist than from a generalist. CONCLUSIONS:
      Socioeconomic status and race seem to play a role in whether patients receive
      oral surgical care from a general dentist or an oral and maxillofacial surgeon.

PMID- 12464892
TI  - Monitoring ammonia to assess halitosis.
AB  - OBJECTIVE: This study examined the applicability of ammonia monitoring for
      assessing halitosis. STUDY DESIGN: The actual degree of halitosis was determined
      by using an organoleptic test in 61 subjects aged 28 +/- 10 years (mean +/- SD).
      Levels of volatile sulfur compounds and ammonia were determined by using gas
      chromatography and ammonia monitoring, respectively. Levels of ammonia and methyl
      mercaptan produced by bacteria in dental plaque and tongue-coating samples
      obtained from 25 subjects were quantified. In addition, changes in ammonia levels
      were measured before and after removing tongue coating or dental plaque. RESULTS:
      There was no significant correlation between the organoleptic score and the
      ammonia level measured with ammonia monitoring, whereas there was a significant
      correlation between ammonia level and the total level of volatile sulfur
      compounds measured with gas chromatography. Significant correlations were also
      observed between ammonia level and levels of methyl mercaptan produced by
      bacteria in dental plaque and tongue coating. Furthermore, the ammonia level
      decreased after the removal of tongue coating and dental plaque. CONCLUSION:
      These results indicate that measuring ammonia levels is useful for assessing
      halitosis, specifically for halitosis arising from a lack of oral hygiene.

PMID- 12464893
TI  - Resolution of oral non-Hodgkin's lymphoma by reduction of immunosuppressive
      therapy in a renal allograft recipient: a case report and review of the
      literature.
AB  - A case of oral non-Hodgkin's lymphoma arising in a patient with insulin-dependent
      diabetes who had undergone renal allograft transplantation is described. The
      resolution of the disease was achieved by a reduction in her immunosuppressive
      therapy. The differential diagnosis is discussed, and the management of
      posttransplantation lymphoproliferative disorders is reviewed.

PMID- 12464894
TI  - Oral lichen sclerosus et atrophicus: a case report.
AB  - Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory mucocutaneous
      disease usually affecting the female genitalia. Involvement of the oral mucosa is
      extremely rare but is sometimes the only manifestation of the disease. A review
      of the literature has disclosed only 10 histopathologically verified cases of
      oral LSA. We present another case with a solitary oral LSA lesion and summarize
      the current knowledge about this rare oral mucosal lesion.

PMID- 12464895
TI  - Oral lesions as the first clinical sign of microscopic polyangiitis: a case
      report.
AB  - Microscopic polyangiitis (MPA) is defined as a systemic necrotizing vasculitis
      that clinically and histologically affects small-sized vessels without
      granulomata. The main clinical feature of MPA is renal involvement characterized
      by rapidly progressing glomerulonephritis. We report a case of oral lesions,
      initially thought to be associated with Wegener's granulomatosis, as the first
      sign of MPA in an otherwise healthy man. To our knowledge, this is the first
      published case of MPA-associated oral lesions.

PMID- 12464896
TI  - The prevalence of herpes simplex virus shedding and infection in the oral cavity
      of seropositive patients undergoing head and neck radiation therapy.
AB  - OBJECTIVE: Herpes viruses are characterized by their ability to establish and
      maintain a latent infection that can reactivate. Only 2 preliminary studies have
      examined herpes simplex virus (HSV) reactivation in patients receiving head and
      neck radiotherapy. The role of radiation therapy in the reactivation of a latent
      virus has not been established. The purpose of the present study was to evaluate
      the incidence of HSV reactivation in patients receiving radiation treatment for
      head and neck malignancies. METHODS: Twenty patients, 19 of whom were HSV
      seropositive, undergoing head and neck radiation therapy were assessed weekly
      before and during radiation therapy, and HSV cultures were completed during
      cancer treatment. RESULTS: Only 3.6% of the cultures were positive for HSV during
      radiation therapy. HSV was cultured in 4 men receiving a mean of 6,000 cGy to the
      head and neck area. Recovery from HSV was seen in patients nearing completion of
      radiation therapy. CONCLUSIONS: The results of this study suggest that HSV
      reactivation is not common during radiation therapy. Therefore, this study does
      not support prophylaxis of HSV in patients undergoing head and neck irradiation.

PMID- 12464897
TI  - Thymidylate synthase and dihydropyrimidine dehydrogenase expression in oral
      squamous cell carcinoma: an immunohistochemical and clinicopathologic study.
AB  - OBJECTIVE: Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5
      FU), and dihydropyrimidine dehydrogenase (DPD) is the first enzyme that
      metabolizes 5-fluorouracil. Until now, only the enzyme activities of TS and DPD
      have been investigated; however, there are few reports about the
      immunohistochemistry of TS and DPD and none regarding oral carcinoma. The purpose
      of this article was to investigate the expression of TS and DPD in oral squamous
      cell carcinoma. STUDY DESIGN: In this study, 109 oral squamous cell carcinomas
      were investigated for the immunohistochemical expression of TS and DPD proteins.
      RESULTS: The expressions of TS in carcinoma cases was significantly higher than
      in controls (P <.05, t test). DPD was expressed both in carcinomas and in areas
      adjacent to the carcinomas. There was no correlation between the clinical factors
      and the TS labeling index or between the clinical factors and the DPD labeling
      index (DPD-LI). Pathologically, DPD-LI was significantly different in both the
      World Health Organization classification and Anneroth's classification. The TS
      labeling index was significantly correlated with the Ki-67 LI (P <.05, Pearson's
      correlation coefficient). Although TS showed no correlation between tegafur
      uracil response and TS labeling index, there was a significant correlation
      between the tegafur-uracil response and DPD-LI. CONCLUSIONS: TS may reveal tumor
      cell proliferation, but DPD-LI may correlate with a response to anticancer drug
      treatment.

PMID- 12464898
TI  - Proliferation and invasion factors in HIV-associated dysplastic and nondysplastic
      oral warts and in oral squamous cell carcinoma: an immunohistochemical and RT-PCR
      evaluation.
AB  - OBJECTIVE: Oral warts arising in human immunodeficiency virus (HIV) infection
      occasionally show marked epithelial dysplasia. However, anecdotal evidence
      suggests that they do not progress to oral squamous cell carcinoma (SCC).
      Therefore, we evaluated lesions for expression of proteins (tenascin-C, beta6
      integrin, and matrix metalloproteinase-1[MMP1]) that have been identified as
      important in the invasive phase of oral SCC. STUDY DESIGN: Twenty-two oral
      dysplastic warts from 22 patients and 5 oral SCCs were stained for human
      papillomavirus (HPV) antigen, proliferation protein Ki-67, tenascin-C, beta6, and
      MMP1 by immunohistochemical methods. For comparison, 5 nondysplastic warts each
      from HIV-positive and HIV-negative patients and 5 normal mucosa specimens were
      included. Sections were semiquantitatively assessed, and results were compared.
      Because MMP1 was the lowest or least expressed interface protein, MMP1 mRNA was
      quantitatively assessed from formalin-fixed paraffin-embedded tissue in selected
      cases with quantitative reverse transcription-polymerase chain reaction. RESULTS:
      Twenty of 22 dysplastic warts stained positive for human papillomavirus common
      antigen, and all warts showed high proliferative fractions similar to SCCs.
      Tenascin-C and beta6 were variably expressed by the dysplastic warts but were
      consistently expressed at high levels in the SCCs. MMP1 protein levels were
      negative or low in 20 of 22 in dysplastic warts, but were elevated in 4 of 5
      SCCs. MMP1 mRNA analysis indicated that message was low in 4 dysplastic warts and
      also suggested that protein translation was incomplete in 3 of the warts.
      CONCLUSION: We conclude that invasion-associated proteins are underexpressed in
      oral dysplastic warts in HIV-positive men. However, until these patients are
      followed for extended periods, the risk of development of SCC from oral
      dysplastic warts remains unknown.

PMID- 12464899
TI  - Immunohistochemical study of the orthokeratinized odontogenic cyst: a comparison
      with the odontogenic keratocyst.
AB  - OBJECTIVE: Orthokeratinized odontogenic cyst (OOC) is a developmental cyst that
      occurs in the maxilla and the mandible and is defined by the World Health
      Organization as the uncommon orthokeratinized type of odontogenic keratocyst
      (OKC). However, studies have shown that OOC has peculiar clinicopathologic
      aspects and biologic behavior when compared with other developmental odontogenic
      cysts, especially OKCs. Therefore, in this study, the immunohistochemical profile
      of the OOC was delineated and compared with that of the OKC. STUDY DESIGN: Twelve
      cases of OOC were submitted to a panel of antibodies composed of cytokeratins
      (10, 13, and 14) and extracellular matrix proteins: fibronectin, types I and III
      collagen, and tenascin. For comparative means, 12 cases of OKC also were
      submitted to the same panel of antibodies. RESULTS: The results obtained showed
      that OOCs expressed cytokeratin 10 and showed variable expression of cytokeratins
      13 and 14. Fibronectin and collagen types I and III also were expressed in OOC in
      a fibrillar aspect. OKC showed only the superficial keratin layer positive to
      cytokeratin 10 and the basal and suprabasal layers with variable expression of
      cytokeratin 14, and cytokeratin 13 was present in the upper epithelial layers.
      The extracellular matrix proteins showed a nonfibrillar expression. Tenascin was
      immunoexpressed only in OKC. CONCLUSION: The immunohistochemical profile of the
      studied cysts clearly showed that OOC presents a well-formed cystic enveloping,
      whereas the OKC profile is compatible with a more aggressive biologic behavior.

PMID- 12464900
TI  - Mucinous adenocarcinoma of probable minor salivary gland origin.
AB  - Mucinous adenocarcinoma is characterized by large pools of extracellular mucin.
      The tumor has been reported in the nasal cavity, paranasal sinus, breast, colon,
      stomach, prostate, skin, and lung. Mucinous adenocarcinoma also arises as a
      primary tumor of the major salivary glands. However, its occurrence is
      exceedingly rare and has only recently been recognized. Only 9 cases in the major
      salivary glands have been reported. We present an additional case of MAC in the
      maxilla that was considered to have developed from a palatal minor salivary
      gland.

PMID- 12464901
TI  - Congenital immature teratoma of the tongue: an autopsy case.
AB  - Congenital immature teratoma of the tongue is a very rare form of extragonadal
      teratoma. We report an infant autopsy case of a huge congenital immature teratoma
      protruding from the tongue of a female infant born to a woman at 28 weeks'
      gestation of her first pregnancy. The mass obstructed the infant's mouth and
      produced hydroamnios. Maternal alpha-fetoprotein serum level was elevated and the
      infant's tumor was identified before birth by ultrasonography. The pregnancy was
      terminated by cesarean section.

PMID- 12464902
TI  - Identification of bacteria in acute endodontic infections and their antimicrobial
      susceptibility.
AB  - OBJECTIVE: The purpose of the study was to identify the bacterial composition of
      the microbiota from acute endodontic abscesses/cellulitis and their antimicrobial
      susceptibilities. STUDY DESIGN: Purulence from 17 patients with acute endodontic
      abscesses/cellulitis was obtained by needle aspiration and processed under
      anaerobic conditions. Bacteria were isolated and identified by biochemical or
      molecular methods. The antimicrobial susceptibility of isolated bacteria was
      determined by using the Etest. RESULTS: All 17 aspirates contained a mix of
      microorganisms. A total of 127 strains of bacteria were isolated. Of 127 strains,
      80 strains were anaerobes and 47 strains were aerobes. The mean number of strains
      per sample was 7.5 (range, 3 to 13). The average number of viable bacteria was
      6.37 x 10(7) (range, 10(4) to 10(8)) colony-forming units/mL. Strict anaerobes
      and microaerophiles were the dominant bacteria in 82% (14 of 17) of the cases.
      The genera of bacteria most frequently encountered were Prevotella and
      Streptococcus. Prevotella and Peptostreptococcus were frequently found to
      dominate the mixture. The combination of Prevotella and Streptococcus was found
      in 53% (9 of 17). The previously reported uncultured Prevotella clone PUS9.180
      was frequently identified. The percentage of bacteria susceptible/intermediate
      for each antibiotic in this study was penicillin V, 81% (95 of 118);
      metronidazole, 88% (51 of 58); amoxicillin, 85% (100 of 118); amoxicillin +
      clavulanic acid, 100% (118 of 118); and clindamycin, 89% (105 of 118).
      CONCLUSIONS: The present results confirm the existence of mixed infection with
      the predominance of anaerobic bacteria in acute endodontic abscesses/cellulitis.
      The frequency of uncultured Prevotella clone PUS9.180 suggests the possible key
      role of this Prevotella species in acute endodontic infections. Penicillin V
      still possesses antimicrobial activity against the majority of bacteria isolated
      from acute endodontic infections. However, if penicillin V therapy has failed to
      be effective, the combination of penicillin V with metronidazole or amoxicillin
      with clavulanic acid is recommended. Switching to clindamycin is another good
      alternative.

PMID- 12464903
TI  - Tissue-dissolving capacity and antibacterial effect of buffered and unbuffered
      hypochlorite solutions.
AB  - OBJECTIVE: The goal of this study was to compare the dissolving potential of
      Dakin's solution with that of equivalent buffered and unbuffered sodium
      hypochlorite solutions on fresh and decayed tissues. In addition, the
      antimicrobial effect of Dakin's solution and equivalent unbuffered hypochlorite
      was tested. STUDY DESIGN: Tissue specimens were obtained from freshly dissected
      pig palates. Unbuffered 2.5% and 0.5% sodium hypochlorite solutions and 0.5%
      solutions buffered at a pH of 12 and a pH of 9 (Dakin's solution) were tested on
      fresh and decayed tissue. Tissue decay was assessed histologically. Antimicrobial
      testing was performed with Enterococcus faecalis in dentin blocks and on filter
      papers. RESULTS: The 2.5% NaOCl solution was substantially more effective than
      the three 0.5% solutions in dissolving the test tissues. Buffering had little
      effect on tissue dissolution, and Dakin's solution was equally effective on
      decayed and fresh tissues. No differences were recorded for the antibacterial
      properties of Dakin's solution and an equivalent unbuffered hypochlorite
      solution. CONCLUSIONS: In contrast to earlier statements, the results of this
      study do not demonstrate any benefit from buffering sodium hypochlorite with
      sodium bicarbonate according to Dakin's method. An irrigation solution with less
      dissolving potential may be obtained by simply diluting stock solutions of NaOCl
      with water.

PMID- 12464904
TI  - Fractal analysis of mandibular bony healing after orthognathic surgery.
AB  - OBJECTIVES: We evaluated the radiographic changes to the operational sites after
      orthognathic surgery by using fractal analysis. STUDY DESIGN: Panoramic
      radiographs from 35 patients who underwent orthognathic surgery on the mandible
      without any complications during the osseous healing process were selected. The
      radiographs taken before the operation (stage 0) and 1 or 2 days (stage 1), 1
      month (stage 2), 6 months (stage 3), and 12 months (stage 4) after the operation
      were digitized at 600 dpi with 256 gray levels. The fractal dimension was
      calculated by means of a tile-counting method in the region of interest centered
      on the operational site and was statistically analyzed according to its stages.
      RESULTS: The fractal dimension was decreased immediately after the operation and
      increased gradually according to the time lapse (P <.05). The fractal dimension
      in the region of interest 12 months postoperatively was similar to that
      preoperatively. CONCLUSION: This result suggests that fractal dimension can be
      used to evaluate the bony healing process after orthognathic surgery.

PMID- 12464905
TI  - Correlating carotid artery stenosis detected by panoramic radiography with
      clinically relevant carotid artery stenosis determined by duplex ultrasound.
AB  - OBJECTIVE: We sought to assess the utility of panoramic radiography as an adjunct
      screening tool for detecting significant asymptomatic carotid artery stenosis.
      The specific aim was to correlate calcifications seen in the region of the
      carotid bifurcation with clinically relevant carotid artery stenosis as
      determined by duplex ultrasound (DUS). STUDY DESIGN: Routine dental panoramic
      films of patients 55 and older (n = 778) at the University of Rochester Eastman
      Dental Center were retrospectively reviewed for calcifications around the carotid
      bifurcation. Patients with such calcifications were referred for DUS, and raw
      data were interpreted by a vascular surgeon blinded to the radiographic findings.
      Groups were compared by using the chi(2) test. RESULTS: Twenty-seven patients
      (3.5%) had suggestive radiographic calcifications on one or both sides, 20 of
      whom consented to DUS. Clinically significant carotid stenoses (>50% lumenal
      narrowing) were present in 50% of the sides with calcification compared with 21%
      of the sides without (P =.08, chi(2)). Three patients (15% of those screened with
      DUS) had stenoses greater than 80% and underwent 4 carotid endarterectomies as a
      direct result of screening. CONCLUSIONS: Data suggest that clinically significant
      stenosis may exist if calcifications are observed on panoramic radiographs.
      Incidental examination of this area carries a minimal cost and appears beneficial
      as a screening tool for carotid disease, although definitive testing must follow.

PMID- 12464906
TI  - Follicular/desmoplastic hybrid ameloblastoma with radiographic features of
      concomitant fibro-osseous and solitary cystic lesions.
AB  - We report a case of ameloblastoma radiographically suggestive of a complication
      of fibro-osseous and solitary cystic lesions. A 35-year-old woman was referred to
      our hospital for treatment, complaining of swelling in the left premolar region
      of the mandible. Radiological findings indicated a mixed radiopaque and
      radiolucent lesion in the region of the left mandibular canine and first premolar
      as well as a solitary cystic lesion in the mandibular second premolar region.
      Following biopsy, resection of mandible was performed under general anesthesia.
      Histopathologic examination identified follicular-type ameloblastoma with partial
      desmoplastic findings. Conventional radiography and computed tomography were not
      useful in indicating the relationship between the mixed and solitary cystic
      lesions. However, magnetic resonance imaging was instrumental in elucidating this
      relationship.

PMID- 12464907
TI  - Cyclic variation of myocardial signal intensity in real-time myocardial perfusion
      imaging.
AB  - BACKGROUND: The presence of cyclic intensity variation during real-time
      myocardial perfusion imaging (RTPI) has been controversially discussed. We
      investigated whether cyclic intensity variation is systematically found during
      RTPI and whether such variations are related to regional functional parameters.
      METHODS: Intraoperative RTPI were obtained in 12 pigs before, during, and after
      left descending coronary artery occlusion with 60 mL/h SonoVue infusion.
      Furthermore, RTPI was performed in 14 patients after slow bolus injection of 0.7
      mL of Optison. Instantaneous regional systolic to diastolic (S/D) myocardial
      intensity ratios were calculated after high mechanical index bubble destruction.
      S/D ratios were correlated with A- and beta-values, and fractional area
      shortening. RESULTS: Systematic cyclic S/D changes were present in both
      experimental settings showing significantly higher systolic values (animals, S/D
      1.28 +/- 0.44; patients, S/D 1.25 +/- 0.7). Cyclic S/D variation was not related
      to fractional area shortening, or A- or beta-values (all r < 0.3, not
      significant). CONCLUSION: Consistent cyclic changes in myocardial contrast
      intensity can be measured both in intraoperative animals and in patients, showing
      higher systolic values. S/D ratios are not related to regional functional
      parameters.

PMID- 12464908
TI  - Quantitative parameters of myocardial perfusion with contrast echocardiography in
      human beings: Influence of triggering mode.
AB  - To facilitate quantitation of myocardial contrast echocardiography (MCE) in human
      beings, dual- or triple-triggered flash imaging has been advocated. However, the
      effect of this modality on quantitative blood-flow parameters of MCE is not
      known. Accordingly, MCE was quantitated in 71 myocardial regions of 22 patients
      (age: 57 +/- 16 years) during continuous infusion of Optison (12-18 mL/h). Two
      sets of images with end-systolic gating (1:1, 1:2, 1:3, 1:4, 1:6, and 1:8) from
      the apical 4-chamber view were acquired: single and dual triggering for the first
      15 patients; and single and triple triggering for the other 7 patients. During
      gated imaging, MCE of the first, second, and third frame were quantitated. Curves
      of intensity versus pulsing intervals were fitted to an exponential function: y =
      A (1-e(-betat)). Where beta is myocardial blood velocity or the rate of rise of
      myocardial contrast intensity (MCI), and A is myocardial blood volume or the
      plateau of MCI reached. Continuous imaging, and the second and third frame in 1:1
      gating only, provided similar intensity to precontrast imaging. Beyond 1:1
      gating, MCI of the second frame in dual triggering mode gradually increased with
      incremental pulsing interval. This was still present but less pronounced in
      triple triggering. During dual and triple triggering, a lower beta was observed
      compared with single triggering. Application of image subtraction with the flash
      procedure further decreased beta, A, and the A(*)beta product, a quantitative
      parameter of blood flow by MCE. Thus, flash subtraction imaging alters the
      quantitative parameters of myocardial blood velocity and flow derived from MCE.
      Continuous imaging, and the second or third frame in flash imaging at 1:1 gating
      only, result in MCI similar to precontrast imaging and can be used for background
      subtraction to quantitate MCE parameters.

PMID- 12464909
TI  - Effect of destructive pulse duration on the detection of myocardial perfusion in
      myocardial contrast echocardiography: In vitro and in vivo observations.
AB  - Myocardial perfusion is detected with contrast echocardiography by comparing a
      contrast-enhanced image with a baseline obtained before contrast injection (true
      baseline) or after myocardial bubble destruction after a high-power destructive
      pulse (postdestructive pulse baseline). Although it is assumed that all bubbles
      are destroyed by a destructive pulse insuring optimal contrast detection, this
      assumption has not been tested. In 18 participants we compared the videointensity
      (VI) differences among the contrast-enhanced image, the postdestructive pulse
      baseline, and the true baseline using both triggered high-mechanical index
      imaging and real-time imaging. VI difference was significantly greater for the
      true baseline with both techniques at all ventricular levels. The benefit of
      using a true baseline was less when the duration of the destructive pulse was
      increased. Similarly, we quantified VI in a flow phantom using continuous Optison
      (commercially available perfluoropropane-filled albumin microbubbles) (Amersham,
      Princeton, NJ) infusion and variable durations of destructive pulses. VI
      decreased with the duration of the destructive pulse and reached a plateau after
      a duration of 8 to 15 frames. The plateau reached after a long destructive pulse
      was dependent on flow rate and concentration and never reached a true baseline,
      unless concentration (<100 microL/L) and flow rate (<0.5 cm/s) were very low. IN
      CONCLUSION: (1) in clinical studies, the difference in VI between contrast
      enhanced and baseline images is greater when true baseline is used; (2) the
      longer the destructive pulse, the closer the postdestructive pulse baseline to
      true baseline; and (3) this effect exists in all regions of the left ventricle.

PMID- 12464910
TI  - Heterogeneity of contrast effect during intermittent second harmonic myocardial
      contrast echocardiography in healthy patients.
AB  - Intermittent harmonic imaging with contrast is increasingly used to detect
      perfusion defects in patients with coronary disease. To achieve this, image
      homogeneity and the ability to visualize segments on the lateral and distal
      portions of the imaging field are important. The objective of this study was to
      evaluate whether the use of specific postprocessing algorithms, such as
      background subtraction with color coding and parametric display, allows for
      improved image homogeneity compared with conventional intermittent second
      harmonic imaging. For this purpose, 20 participants who were free of cardiac
      abnormalities and in whom myocardial perfusion should by definition be
      homogeneously distributed, underwent contrast echocardiography during the
      constant intravenous infusion of 1.0 +/- 0.3 mL/min of perfluorocarbon-enhanced
      sonicated dextrose albumin. End-systolic ECG-triggered images were obtained from
      the apical 4-chamber view at pulsing intervals of 300-ms 1, 3, 5, and 8 cardiac
      cycles. For analysis, each set of images was aligned, averaged, background
      subtracted, and color coded. Pulsing intervals versus videointensity plots were
      then generated for each pixel in the images and fitted to an exponential function
      to produce parametric images of beta (an index of microbubble velocity) and A (a
      measure of myocardial blood volume). The heterogeneity of the contrast effect was
      evaluated by computing the coefficients of variation in each image. Contrast
      heterogeneity was >20% with all 4 methods. However, it was greater in gray-scale
      second harmonic (39 +/- 13%) and color-coded (47 +/- 16%) images than in
      parametric images of beta and A (24 +/- 14 and 24 +/- 8%, respectively; both P
      <.05 vs gray-scale second harmonic and color-coded images). With all 4 methods,
      basal- and apical-lateral segments contributed most to image heterogeneity,
      albeit significantly less so with parametric imaging. In conclusion, our data
      indicate that myocardial opacification is frequently heterogeneous in healthy
      participants, particularly when using gray-scale second harmonic and background
      subtracted with color-coding imaging. Parametric imaging allows reduction, albeit
      incomplete, of the heterogeneity of the contrast effect and therefore improves
      image quality.

PMID- 12464911
TI  - A new echocardiographic method for the assessment of the severity of aortic
      regurgitation: color M-mode flow propagation velocity.
AB  - PURPOSE: Echocardiographic Doppler methods widely used in assessment of the
      severity of aortic regurgitation (AR) are considered sensitive and reliable.
      However, they all have limitations for quantitation of AR. The color M-mode
      Doppler flow propagation velocity (FPV) method has been shown to provide useful
      insights in the evaluation of left ventricular diastolic function and appears to
      be minimally affected with preload changes. Clinical data regarding the value of
      FPV in the determination of the significance of valvular insuffiencies are
      lacking. The purpose of this study was to evaluate the use of FPV in measurement
      of the severity of AR and to compare its reliability with angiography and other
      echocardiographic methods. METHODS: Twenty-nine patients (13 male, 16 female) who
      had cardiac catheterization for various reasons before echocardiographic
      evaluation were included. The mean age was 53.6 +/- 13.4 years. At the time of
      cardiac catheterization, the degree of AR was assessed as mild in 10 patients, as
      moderate in 12, and as severe in 7. In all patients, FPV measurements of AR were
      obtained with color M-mode Doppler in the apical 5-chamber view. Regurgitation
      jet height and its ratio to left ventricular outflow obtained in the parasternal
      long axis with color flow Doppler, pressure half-time, and slope of AR obtained
      with continuous wave Doppler in apical 5-chamber view were other
      echocardiographic methods chosen for comparison. RESULTS: The mean values of FPV
      were 93.1 +/- 18.4 cm/s, 49.8 +/- 8.0 cm/s, and 31.7 +/- 4.9 cm/s in severe,
      moderate, and mild AR groups, respectively (P <.001). Significant correlation was
      observed between angiographic grades, FPV, pressure half-time, slope, and jet
      height and ratio to left ventricular outflow (P <.0001, r = 0.93; P <.0001, r = 
      0.81; P <.0001, r = 0.76; P <.0001, r = 0.92, respectively). CONCLUSION: FPV is a
      simple, practical, and reliable method for the quantification of AR.

PMID- 12464912
TI  - Left ventricular inflow propagation velocity: comparisons between pulsed wave and
      color M-mode Doppler echocardiography.
AB  - Sixty-six participants (age 58 +/- 16 years) were included for evaluation of the
      relationship between color M-mode and pulsed wave Doppler left ventricular inflow
      propagation velocity (LVIPVcmm and LVIPVpw, respectively). LVIPVpw was measured
      through the application of the range ambiguity phenomenon, and LVIPVcmm was
      obtained by manually tracing the first aliasing velocity during the early
      filling. The variability for LVIPVpw measurements was significantly less than
      that for LVIPVcmm measurements. There was a significant correlation (r = 0.678, P
      <.001) between LVIPVcmm and LVIPVpw for all study participants. However, LVIPVpw
      was greater than LVIPVcmm, especially when the inflow propagation time was
      relatively short. Age was the only determinant of both LVIPVcmm and LVIPVpw in
      the control group. As for the patients with diseases retarding inflow
      propagation, age remained its determinant. However, its impact decreased and the
      end-systolic dimension and fractional shortening of the left ventricle, instead,
      turned out to be its major determinant. In conclusion, LVIPVpw measurements are
      more reproducible than LVIPVcmm measurements. LVIPVpw correlates with LVIPVcmm
      and their difference significantly correlates with left ventricular inflow
      propagation time.

PMID- 12464913
TI  - Diagnostic value of mitral annular velocity for constrictive pericarditis in the
      absence of respiratory variation in mitral inflow velocity.
AB  - Respiratory variation of 25% or more in transmitral early diastolic filling (E)
      velocity is a well-recognized diagnostic feature of constrictive pericarditis
      (CP) that is useful for distinguishing it from restrictive cardiomyopathy.
      However, a subset of patients with CP do not exhibit the typical respiratory
      change. Recent data showed that mitral annular (E') velocity measured by Doppler
      tissue echocardiography (DTE) is markedly reduced in patients with restrictive
      cardiomyopathy whereas E' velocity is well-preserved in CP. This study evaluated
      the role of DTE for the diagnosis of CP when there is no characteristic
      respiratory variation of E velocity. From September 1999 to March 2001, 19
      patients (17 men, 2 women; mean age, 57 +/- 13 years) with surgically confirmed
      CP underwent comprehensive echocardiography preoperatively, including pulsed wave
      and DTE examination with simultaneous recording of respiration. Nine (47%) of the
      19 patients had less than 25% respiratory variation in E velocity. There was no
      significant difference in mitral inflow peak velocity, deceleration time, early
      to-late ventricular filling ratio, and E' velocity between patients with and
      patients without respiratory variation of E velocity of 25% or more. Regardless
      of the presence or absence of a significant respiratory variation of E velocity,
      E' velocity was relatively normal (mean, 12 +/- 4 cm/s) in all patients with CP.
      In conclusion, E' velocity is well preserved in patients with isolated CP even
      when there is no characteristic respiratory variation of E velocity. Thus, when
      the respiratory variation in Doppler E velocity is blunted or absent during the
      evaluation of suspected CP in patients with restrictive mitral inflow velocity,
      preserved E' velocity shown by DTE should support the diagnosis of CP over a
      primary myocardial disease.

PMID- 12464914
TI  - Analysis of the myocardial velocities in patients with mitral stenosis.
AB  - BACKGROUND: Pure mitral stenosis (MS) affects left-ventricular performance as a
      result of myocardial and functional factors. We planned this study to evaluate
      the effect of MS on right- and left-ventricular functions using Doppler tissue
      imaging (DTI). METHODS: A total of 46 patients with an established diagnosis of
      MS (mean age: 41 +/- 11 years), and 40 age-matched healthy individuals (mean age:
      40 +/- 9 years) were included in this study. Echocardiography equipped with DTI
      function was performed on each participant. The mitral valve area was measured.
      Myocardial velocities were recorded at 4 different sites (septum, lateral,
      anterior, and inferior) of the left ventricle, and the right-ventricular free
      wall annulus by DTI. The positive systolic velocity when the mitral and tricuspid
      ring moved toward the cardiac apex, and 2 negative diastolic velocities when the
      mitral annulus moved toward the base away from the apex (1 during the early phase
      of diastole and another in the late phase of diastole [A(m)]) were measured. The
      early diastolic velocity/A(m) ratio was calculated for each wall. The mean of
      systolic and diastolic myocardial velocities of the left ventricle was
      calculated. Patients with pure MS were compared with healthy participants, and
      the relationship of DTI variables with mitral valve area was evaluated. RESULTS:
      The myocardial velocities of the left ventricle indicating left-ventricular
      function were found to be significantly lower in patients with pure MS. Right
      ventricular annulus velocities, on the other hand, were similar in both groups. A
      significant positive correlation could be established between mitral valve area
      and mean positive systolic velocity, A(m) of the left ventricle, and right
      ventricular A(m) (r = 0.50, P <.001; r = 0.48, P =.001; r = 0.45, P =.002,
      respectively), whereas a significant negative correlation (r = -0.42, P =.004)
      was established for right-ventricular early diastolic velocity/A(m) ratio.
      CONCLUSION: This first study where pure MS was evaluated by DTI shows that MS
      affects left-ventricular performance on long axis. The results indicate that the
      decrease in left-ventricular performance is caused by both functional and
      myocardial factors.

PMID- 12464915
TI  - Time interval from the initiation of the electrocardiographic P wave to the start
      of left atrial appendage ejection flow: A novel method for predicting atrial
      fibrillation recurrence.
AB  - OBJECTIVE: The incidence of paroxysmal and persistent atrial fibrillation (AF)
      recurrence is high and unpredictable. In this study, a novel noninvasive method
      that was thought to reflect the interatrial conduction time was investigated to
      predict AF recurrence. This method was on the basis of the measurement of time
      interval from initiation of the electrocardiographic P wave to the start of left
      atrial (LA) appendage (LAA) ejection flow (P-LAA). METHODS AND RESULTS: Forty
      five consecutive patients (age, 61 +/- 11 years; 20 male) with newly diagnosed AF
      (mean duration, 132 hours; range: 6 hours-3 months) who converted to in sinus
      rhythm spontaneously or with cardioversion were studied prospectively.
      Transthoracic and transesophageal echocardiography were performed to measure LA
      size, mechanical functions, LAA ejection velocity, and P-LAA. Transesophageal
      echocardiography was performed for the measurement of P-LAA 1 to 2 days after
      conversion to in sinus rhythm. The patients were followed up for a period of 163
      +/- 72 days for the recurrence of AF. AF recurred in 17 (38%) patients after a
      mean time of 81 +/- 67 days. P-LAA was significantly higher in patients with AF
      recurrence (123 +/- 36 vs 92 +/- 24 milliseconds, P =.0047) and multiple
      regression analysis indicated that P-LAA was an independent predictor of AF
      recurrence. Multiple regression analysis revealed no significant differences in
      LA size parameters, or in clinical and LA mechanical function parameters recorded
      after restoration of in sinus rhythm between patients with and without AF
      recurrence. CONCLUSION: P-LAA may be considered to be an independent predictor of
      recurrent AF.

PMID- 12464916
TI  - Automated calculation of the Tei index from signal averaged left ventricular
      acoustic quantification wave forms.
AB  - The Tei index is a combined measurement of systolic and diastolic left
      ventricular (LV) performance and may be more useful for the diagnosis of global
      cardiac dysfunction than either systolic or diastolic measures alone. We sought
      to determine whether the Tei index could be accurately calculated from LV area
      waveforms generated with automated border detection. Twenty-four patients were
      studied in 3 groups: systolic dysfunction, diastolic dysfunction, and normal. The
      Tei index was calculated both from Doppler tracings and from analysis of LV area
      waveforms. Excellent agreement was found between Doppler-derived timing intervals
      and the Tei index with those obtained from averaged LV area waveforms. A
      significant difference was seen in the Tei index, computed with both Doppler and
      automated border detection techniques, between the normal group and those with LV
      systolic dysfunction and subjects with isolated diastolic dysfunction. This study
      validates the use of LV area waveforms for the automated calculation of the Tei
      index.

PMID- 12464917
TI  - Myocardial viability independently influences left ventricular diastolic function
      in the early phase after acute myocardial infarction.
AB  - BACKGROUND: After acute myocardial infarction, a broad range of left ventricular
      (LV) end-diastolic pressure (LVEDP) is expected because of chamber remodeling.
      However, intrinsic characteristics of the infarcted tissue (necrosis or
      viability) may also play a role. We aimed to evaluate whether myocardial
      viability (Mviab) has an influence on LVEDP. METHODS: One hundred twenty-three
      consecutive patients with acute myocardial infarction underwent low-dose
      dobutamine echocardiography (5-10 microg/kg/min) to assess Mviab. Mviab was
      quantitatively evaluated by the variation of Delta wall motion score index.
      Patients underwent left heart catheterization with recording of LVEDP and a
      complete echocardiographic examination with measurement of LV volumes, ejection
      fraction, and mass. RESULTS: The overall population (81% male; mean age 58 +/- 10
      years) was divided into 2 groups according to the presence (group 1; 66 patients)
      or absence (group 2; 57 patients) of Mviab. LVEDP was higher in patients without
      Mviab (16 +/- 8 vs 20 +/- 7 mm Hg; P =.02). The multivariate analysis showed that
      Delta wall motion score index correlated with LVEDP (P =.01) independent of wall
      motion score index and LV end-systolic volume. CONCLUSIONS: After acute
      myocardial infarction, LVEDP shows wide variability and is independently
      associated with Mviab.

PMID- 12464918
TI  - Comparison of simultaneous invasive and noninvasive measurements of pressure
      gradients in congenital aortic valve stenosis.
AB  - PURPOSE: Congenital aortic valve stenosis is a common problem in pediatric
      cardiology. The catheter peak to peak systolic gradient is the accepted standard
      used for prognosis and intervention, but noninvasive correlation in pediatric
      patients is frequently associated with underestimation or overestimation of this
      gradient. The purpose of this study was to compare different noninvasive
      measurements with simultaneous catheter gradients to identify which best predicts
      the catheter peak to peak gradient. METHODS: Twenty-five simultaneous Doppler and
      catheter measurements of aortic stenosis gradient were performed in 14 children
      (all 14 before valvuloplasty and 11 after valvuloplasty). Noninvasive estimates
      of pressure gradient were compared with catheter measurements with linear
      regression and Bland-Altman analysis. RESULTS: The Doppler peak instantaneous
      pressure gradient overestimated the catheter peak to peak gradient but correlated
      well with the catheter peak instantaneous gradient. The Doppler mean systolic
      gradient correlated well with the catheter peak to peak gradient at low gradients
      and underestimated higher catheter gradients but agreed well at all levels with
      the catheter mean gradient. The modification of a catheter-derived correlation
      equation produced good correlation with the catheter peak to peak gradient
      (slope, 1.14; intercept, -1.8; R, 0.92), as did the use of estimated pressure
      recovery (slope, 1.04; intercept, 5.0; R, 0.94), calculated from a defined fluid
      mechanic equation. CONCLUSION: The catheter peak to peak gradient can be
      accurately estimated noninvasively using estimated pressure recovery or
      correlation equations incorporating Doppler measurements.

PMID- 12464919
TI  - Noncompressibility of myocardium during systole with freehand three-dimensional
      echocardiography.
AB  - BACKGROUND: Measures of ventricular performance, such as the ejection fraction,
      assume that myocardium is noncompressible and does not change volume
      significantly from end diastole to end systole. Although this principle is widely
      accepted as true, little data exist in the literature to support it. Freehand 3
      dimensional (3D) echocardiography has previously been shown to be highly accurate
      for measurement of myocardial mass and volume. Therefore, we hypothesized that it
      has sufficient accuracy to test the validity of this assumption. We measured
      myocardial volume at end diastole and end systole in 2 groups of subjects with
      hypertrophy. METHODS: Forty-one healthy young adult athletes and 17 adult
      patients with hypertension, hypertrophy, normal ejection fraction, and heart
      failure symptoms underwent examination with freehand 3D echocardiography.
      Endocardial and epicardial surfaces at end diastole and end systole were
      reconstructed, and their volumes were computed. From these surface volumes,
      myocardial volume at end diastole and end systole and epicardial stroke volume
      and endocardial stroke volume were calculated. These volumes were compared with
      the 2 sample paired t test. RESULTS: Myocardial volume was constant from diastole
      to systole (174.7 +/- 45.3 mL versus 174.6 +/- 45.8 mL; P = not significant), and
      endocardial and epicardial stroke volumes were identical (76.0 +/- 17.4 mL versus
      76.0 +/- 17.1 mL; P = not significant). The average absolute difference between
      the end-diastolic and end-systolic myocardial volumes was 1.9 mL, or less than
      1.1% of end-diastolic volume. CONCLUSION: Myocardial volume measured with
      freehand 3D echocardiography does not change significantly during systole.
      Myocardial volume may be considered noncompressible for purposes of measurement
      of ventricular function with freehand 3D echocardiography. Comparison of end
      diastolic and end-systolic myocardial volumes may be used for quality assurance
      in performing 3D reconstructions.

PMID- 12464920
TI  - Use of intravascular ultrasound to measure local compliance of the pediatric
      pulmonary artery: in vitro studies.
AB  - BACKGROUND: The accurate measurement of local pulmonary artery compliance in
      pediatric pulmonary hypertension is an important step toward further
      understanding the biomechanical and hemodynamic aspects of the disease. The
      emergence of intravascular ultrasound (IVUS) imaging techniques promises the
      ability to make such measurements clinically. However, the use of IVUS for
      compliance measurements has not been validated. Furthermore, confusion exists
      regarding the most appropriate method to measure compliance. METHODS: This study
      validated IVUS measurements against a laser micrometer standard for 4 elastic
      tubes of varying compliance. Two methods of quantifying local compliance were
      explored: The pressure-strain modulus (E(p)), (E(p)(g/cm(2)) = DeltaP x
      R(d)/DeltaR (Where DeltaP is pulse pressure, R(d) is diastolic radius, and DeltaR
      is systolic minus diastolic radii) and the dynamic compliance (C(dyn)),
      (C(dyn)(%/100 mm Hg) = [DeltaD/(DeltaP x D(d))] x 10(4) Where DeltaD is systolic
      minus diastolic diameters and D(d) is diastolic diameter. RESULTS: IVUS diameter
      measurements agreed well with laser micrometer data although slight
      overestimation (mean = 3.67% +/- 2.78%) was present. Mean values of E(p) ranged
      from 353.3 g/cm(2) to 2676.0 g/cm(2); mean C(dyn) values ranged from 5.7%
      diametric change/100 mm Hg to 39.5% diametric change/100 mm Hg for all tube
      models. Although mean values of E(p) and C(dyn) could be distinguished among the
      various tubes, the extremely large measurement uncertainty for E(p) precluded
      statistical differentiation. The uncertainty in E(p) increased inversely with the
      diametric change, indicating a potential limitation of E(p) associated with
      stiffening arteries. CONCLUSIONS: We conclude that C(dyn) is a more robust mean
      of quantifying pediatric pulmonary artery compliance, especially as arteries
      stiffen with chronic pulmonary hypertension.

PMID- 12464921
TI  - Conversion to digital technology improves efficiency in the pediatric
      echocardiography laboratory.
AB  - BACKGROUND: Although the videotape method (VTM) is commonly used to record and
      intrepret ecocardiographic images, many pediatric echocardiographers are
      considering acquiring to, interpreting from, and storing their images to digital
      disk using the single-beat digital acquisition method (SBM). The paucity of image
      redundancy using SBM should translate into improved laboratory efficiency
      compared with VTM, but hard data are lacking. The purpose of this study was to
      test the hypothesis that the time to acquire images to videotape using VTM and to
      disk using SBM would be the same for normal hearts and corresponding congenital
      heart diseases, but interpretation times would be shorter using SBM. METHODS: We
      measured the times to acquire and interpret 403 echocardiograms using standard
      VTM from Children's Hospital in Cincinnati, Ohio, and 352 echocardiograms
      acquired using SBM from Children's Hospital in San Diego, Calif. Diagnostic
      categories at each site included: (1) normal, (2) simple shunt or isolated valve
      disease, and (3) multiple-lesion disease. RESULTS: As a group, SBM
      echocardiograms included more hemodynamic measurements and took more time to
      acquire (P <.037), but less time to read (P <.001) than corresponding images
      acquired using VTM. Using SBM, it took more time to acquire normals and isolated
      valve or shunt lesions, whereas the average time to acquire multiple-lesion
      disease was the same using both VTM and SBM. With SBM, in contrast,
      interpretation times were significantly less for all corresponding diagnoses.
      CONCLUSION: SBM studies took longer to acquire because more hemodynamic
      measurements were acquired, but they were read in less time than corresponding
      VTM studies even though all videotapes were replayed in search fast-forward mode.
      Pediatric echocardiographers can increase their laboratory efficiency by
      converting from VTM to SBM.

PMID- 12464922
TI  - Noncompaction of ventricular myocardium: a study of twelve patients.
AB  - We report 12 patients with ventricular noncompaction who were
      echocardiographically identified at our institution since 1991. The mean age at
      presentation was 3.5 years. Five patients had isolated noncompaction. Three of
      them had subnormal left ventricular systolic function at presentation.
      Noncompaction was associated with complex congenital heart defect in 3 patients.
      Four patients had simple congenital heart defects: pulmonary stenosis,
      coarctation of aorta with aberrant origin of right subclavian artery, ventricular
      septal defect, and partial anomalous pulmonary venous return. The observed rhythm
      abnormalities were Wolff-Parkinson-White syndrome and paroxysmal supraventricular
      tachycardia, bigemini ventricular extrasystoles, and left bundle branch block. A
      transvenous pacemaker was implanted in a patient because of complete heart block.
      Noncompaction of the ventricular myocardium is rare. Our patients clearly
      represent the clinical and morphological spectrum of this disorder. Distinct
      morphological features can be diagnosed on 2-dimensional echocardiography.

PMID- 12464923
TI  - Pulmonary artery compression by a saphenous vein graft aneurysm and contrast
      echocardiography using an agitated mixture of ten percent air, ten percent blood,
      and ten percent saline.
AB  - This case illustrates the use of intravenous injection of an agitated mixture of
      10% air, 10% blood, and 80% saline during intraoperative transesophageal
      echocardiography in a patient with a saphenous vein graft aneurysm compressing
      the main pulmonary artery.

PMID- 12464924
TI  - Intracardiac echocardiography using the AcuNav ultrasound catheter during
      percutaneous balloon mitral valvuloplasty.
AB  - During the past 10 years, there has been a trend toward and an interest in the
      use of catheter-based interventions to perform procedures that were once only
      approached surgically. The problem with the catheter-based approach has been
      procedure-related complications. Improved imaging of cardiac structures while
      undertaking interventional procedures may help to prevent or allow for early
      identification of these complications. Transesophageal echocardiography has been
      used during catheter-based procedures as a guide, and has both advantages and
      disadvantages. Intracardiac echocardiography is a relatively new imaging
      technique that also provides an enhanced view of cardiac structures and may also
      allow for the safe and efficient performance of catheter-based procedures. We
      report the first case of successful percutaneous balloon mitral valvuloplasty
      done under ultrasound guidance using an intracardiac echocardiography catheter
      (10F, 5-10 MHz) (Acunav). The strengths and weaknesses of this approach are
      described and compared with transesophageal echocardiography and older
      intracardiac echocardiography devices.

PMID- 12464925
TI  - Intraoperative transesophageal echocardiographic assessment of acute prosthetic
      aortic valve regurgitation after mitral valve replacement: value of the deep
      transgastric long-axis view.
AB  - The transesophageal echocardiographic assessment of prosthetic aortic valve
      function is made more difficult by the presence of a mechanical mitral valve
      prosthesis because echocardiographic views conventionally used to assess the
      aortic valve function are obscured by acoustic shadowing and artifacts. We report
      the use of intraoperative transesophageal echocardiography in a patient who
      developed severe prosthetic aortic valve regurgitation after implantation of a
      mechanical mitral valve, in whom conventional multiplane midesophageal views
      failed to reveal aortic regurgitation owing to acoustic shadowing and artifacts
      from the prosthetic mitral valve. We report the value of the deep transgastric
      long-axis view of the aortic valve that provided an unobstructed view of the left
      ventricular outflow tract, and clearly demonstrated severe aortic regurgitation
      as a result of interference with the prosthetic aortic valve mechanism by the
      implanted mitral valve prosthesis. This case also emphasizes the importance of a
      comprehensive intraoperative transesophageal examination, including that of
      surrounding structures, to detect iatrogenic complications during mitral valve
      replacement.

PMID- 12464926
TI  - Obstruction of right ventricular outflow tract by extended cardiac metastasis
      from esophageal cancer.
AB  - We report a patient in whom there was right ventricular outflow tract obstruction
      by extended metastasis from esophageal cancer. A 65-year-old man was admitted to
      the hospital for evaluation of recent onset of weight loss and heart murmur.
      Esophagogram and endoscopy showed a 10-cm, ulcerative, infiltrative esophageal
      cancer. This esophageal cancer was histologically proven to be a squamous cell
      carcinoma. To assess the cardiac metastasis, echocardiography, magnetic resonance
      imaging, coronary angiography, and endomyocardial biopsy were performed. The
      magnetic resonance imaging, echocardiography, and right ventriculography revealed
      a 7-cm lobulated mass extending to the right ventricular outflow tract, right
      ventricle, septum, and anterior wall of the left ventricle. Interestingly, the
      feeding vessels of the tumor were identified by echocardiography and coronary
      angiography. Histologically, the cardiac tumor was proven to be have the same
      pathologic findings as esophageal cancer, compatible with carcinomatous
      metastasis.

PMID- 12464928
TI  - Update on current concepts of the molecular basis of beta2-adrenergic receptor
      signaling.
AB  - The proposed manner by which beta(2)-adrenergic receptors signal has dramatically
      changed from earlier concepts that centered on a lock-and-key mechanism in which
      the receptor acts as a simple switch. We now know that beta(2)-adrenergic
      receptors spontaneously toggle to an activated state (R*) and that the
      equilibrium between R (the inactive state) and R* can be altered by ligands. In
      addition, the R* conformation is likely to consist of multiple subspecies that
      may favor certain signaling pathways or regulatory events. Changes in agonist
      structure alter the abundance of certain subspecies of R*. Indeed,
      multifunctional coupling is common with many G-protein-coupled receptors and can
      be modulated pharmacologically to attain specific outcomes. In addition to
      providing the basis for development of new beta-agonists for unique signaling,
      these properties can be extended such that beta(2)-adrenergic receptors, or
      highly modified "designer" receptors, can be used for gene therapy with highly
      specific effects.

PMID- 12464929
TI  - Novel beta2-adrenergic receptor signaling pathways.
AB  - The beta(2)-adrenergic receptor (beta(2)AR) is perhaps the most thoroughly
      investigated of all G-protein-coupled receptors. Although the classical pathway
      of beta(2)AR signaling involves agonist-promoted binding of the receptor to the
      heterotrimeric guanosine triphosphate-binding protein G(s), activation of
      adenylyl cyclase, and production of cyclic adenosine monophosphate (cAMP),
      current evidence suggests that beta(2)AR signaling is regulated by interaction
      with multiple proteins. These interactions fall into 3 major groups: guanosine
      triphosphate-binding proteins such as G(s) and G(i); protein kinases such as the
      cAMP-dependent protein kinase, protein kinase C, G-protein-coupled receptor
      kinases, and tyrosine kinases; and adaptor proteins such as arrestins, A-kinase
      anchoring proteins, and the Na(+)/H(+)-exchanger regulatory factor. This review
      discusses these various interactions with particular emphasis on their role in
      regulating beta(2)AR signaling and trafficking.

PMID- 12464930
TI  - Transgenic techniques to delineate cell-specific effects of beta2-adrenergic
      receptors in the lung.
AB  - Many, if not most, of the different cell types within the lung have been shown to
      express beta(2)-adrenergic receptors (beta(2)ARs) on the cell surface. beta(2)ARs
      have thus been implicated in the regulation of many aspects of lung function.
      However, the physiologic and therapeutic relevance for many of these cell
      specific responses has been difficult to establish because of confounding effects
      that result from the simultaneous activation of receptors on multiple cell types
      in an in vivo environment. It has been recognized in in vitro models that
      overexpression of G-protein-coupled receptors such as the beta(2)ARs can increase
      the number of spontaneously active receptors (R*) and thereby promote autonomous
      signal transduction or enhanced agonist sensitivity. With transgenic techniques,
      high levels of receptor expression and activation can also be attained in vivo.
      By further using cell-specific promoters to direct expression, it is possible to
      express beta(2)ARs in select cell types of a heterogeneous organ such as the
      lung. In this manner, activation of receptor signaling is limited to the targeted
      cell. Promoter-directed transgenesis can therefore be a useful tool to delineate
      cell-specific beta(2)AR-mediated effects in the lung.

PMID- 12464931
TI  - Effects of beta2-adrenergic receptor overexpression on alveolar epithelial active
      transport.
AB  - beta-Adrenergic receptor (betaAR) agonists accelerate the clearance of edema from
      the alveolar airspace by increasing the function of epithelial transport
      proteins, including epithelial Na(+) channels and Na,K-adenosinetriphosphatases.
      To improve our understanding of the role of the beta(2)AR in regulating alveolar
      fluid clearance, we used an adenoviral-mediated gene transfer strategy to effect
      significant increases in membrane-bound beta(2)AR number and function in the
      alveolar epithelium of normal rats. Alveolar fluid clearance in beta(2)AR
      overexpressing lungs, measured by means of an isolated lung model in the absence
      of catecholamine supplementation, was 100% greater than in controls. These
      findings were associated with significant increases of epithelial Na(+) channel
      function and Na,K-adenosine triphosphatase function in the peripheral lung.
      Experiments performed with adrenalectomized rats, a beta(2)-agonist (procaterol),
      and a nonspecific beta-antagonist (propranolol) indicate that overexpression
      maximally up-regulates beta(2)-adrenergic-responsive alveolar fluid clearance and
      improves responsiveness to endogenous catecholamines. Mechanistic studies in
      human lung epithelial cells (A549) indicate that receptor overexpression prevents
      homologous receptor desensitization, possibly by overwhelming endogenous
      regulatory pathways. Our studies demonstrate that overexpression of beta(2)AR in
      lung epithelial cells can be used to study the role and regulation of alveolar
      beta(2)ARs. They also suggest a therapeutic role for the beta(2)AR in the
      treatment of pulmonary edema.

PMID- 12464932
TI  - Molecular interactions between glucocorticoid and catecholamine signaling
      pathways.
AB  - To study the mechanism underlying glucocorticoid regulation of the beta(1)
      adrenergic receptor (beta(1)AR), we identified a 43-bp region (-1274 to -1232
      from the translation start site) that contains a novel glucocorticoid regulatory
      unit (GRU) that confers glucocorticoid responsiveness. The sequence encompassing
      the GRU is (5')TAATTA(3'), which is a core-binding motif for the homeodomain
      proteins; an E-box ((5')CACGTG(3')) binding site for the Myc/Max family proteins,
      and an overlapping glucocorticoid response element half-site ((5')TGTTCT(3')). We
      showed that the half-site is critical for GRU-protein interactions, which also
      require binding of proteins to the E-box and the homeodomain region. Expression
      of proteins binding to the GRU was shown to be developmentally regulated, being
      high in embryonic hearts, reduced in newborn hearts, and undetectable in adult
      hearts. Overexpression of c-myc antisense significantly reduced glucocorticoid
      responsiveness of the beta(1)AR gene. We further demonstrated that
      transcriptional regulation of the beta(1)AR gene is closely related to that of
      the c-myc gene and that the beta(1)AR may be a potential target of c-myc. We
      conclude that the ovine beta(1)AR gene contains a novel, functional GRU and that
      the nuclear factors that transactivate through this element may have important
      developmental implications.

PMID- 12464933
TI  - Cytokine regulation of beta-adrenergic responses in airway smooth muscle.
AB  - Decreased responsiveness to beta-adrenergic receptor agonists is a characteristic
      feature of human asthma. One explanation for this observation is that cytokines
      released in the asthmatic airway have direct effects on airway smooth muscle
      cells that reduce the ability of the cells to relax in response to beta-agonists.
      This review summarizes data indicating that both inflammatory cytokines, such as
      IL-1beta and TNF-alpha, and Th2 cytokines, such as IL-13 and IL-5, have the
      capacity to decrease the ability of cultured airway smooth muscle cells to relax
      or to generate cyclic AMP in response to beta-agonists, such as isoproterenol.
      These effects are observed in smooth muscle from human airways and airway smooth
      muscle of other species. In human airway smooth muscle, the effects of IL-1beta
      and TNF-alpha appear to be mediated through expression of cyclooxygenase-2,
      whereas the effect of IL-13 requires activation of the extracellular signal
      regulated kinase-mitogen-activated protein kinase pathway. IL-1beta and TNF-alpha
      also inhibit the ability of beta-agonists to drive airway smooth muscle gene
      expression through pathways dependent on cyclic AMP response elements.
      Understanding the mechanistic basis for the effects of these cytokines may prove
      to be an important step in improving the efficacy of beta-agonists for the
      treatment of asthma.

PMID- 12464934
TI  - Molecular interactions between glucocorticoids and long-acting beta2-agonists.
AB  - beta(2)-Adrenergic receptor agonists and glucocorticoids are the two most
      effective treatments for asthma, and used in combination they are more effective
      than either alone. Glucocorticoids mediate their anti-inflammatory effects
      through the action of activated glucocorticoid receptors (GRs), with the level of
      activity being related to the number of nuclear receptors. Glucocorticoids can
      upregulate the synthesis of several genes in human lung cells through interaction
      with specific DNA binding regions (glucocorticoid response elements) within the
      promoter region of glucocorticoid-responsive genes. Many of the down-regulating
      effects of GRs on the synthesis of cytokines and other inflammatory mediators are
      due to repression of other transcription factors, such as activator protein-1 and
      nuclear factor kappaB. GR functions such as nuclear localization and gene
      activation can be regulated by phosphorylation status. Long-acting beta(2)
      agonists may affect GR nuclear localization through modulation of GR
      phosphorylation and furthermore through priming of GR functions within the
      nucleus by modifying GR or GR-associated protein phosphorylation. Glucocorticoids
      in turn may regulate beta(2)-adrenergic receptor function by increasing its
      expression, acting through glucocorticoid response elements, and, importantly, by
      restoring G-protein-beta(2)-receptor coupling and inhibiting beta(2)-receptor
      downregulation, thereby preventing desensitization.

PMID- 12464935
TI  - Airway smooth muscle: an immunomodulatory cell.
AB  - Asthma is characterized in part by reversible airflow obstruction,
      hyperresponsiveness, and inflammation. Chronic obstructive pulmonary disease,
      which includes chronic bronchitis, emphysema, and possibly bronchiectasis, is
      defined as predominantly irreversible airflow obstruction associated with
      abnormal airway inflammation. Traditional concepts concerning airway inflammation
      have focused on trafficking leukocytes and on the effects of inflammatory
      mediators, cytokines, and chemokines secreted by these cells. Airway smooth
      muscle, the major effector cell responsible for bronchomotor tone, has been
      viewed as a target tissue responding to neurohumoral control and inflammatory
      mediators. New evidence, however, suggests that airway smooth muscle may secrete
      cytokines and chemokines and express cellular adhesion molecules that are
      important in modulating submucosal airway inflammation. Other new evidence
      suggests that beta-adrenergic agents may inhibit some but not all of the
      inflammatory responses. In certain circumstances, increasing levels of cyclic
      adenosine monophosphate in the cytosol of airway smooth muscle promote the
      secretion of other cytokines or chemokines. The cellular and molecular mechanisms
      that regulate the immunomodulatory functions of airway smooth muscle may offer
      new and important therapeutic targets in treating these common lung diseases.

PMID- 12464936
TI  - Effects of beta-agonists on airway epithelial cells.
AB  - beta-Adrenergic receptor (betaAR) agonists exert a variety of effects on airway
      epithelial cells. Among their best known actions is their ability to increase
      ciliary beat frequency, mediated by cyclic adenosine monophosphate (cAMP)
      production, stimulation of protein kinase A (PKA), and phosphorylation of an
      outer dynein arm light chain. Submucosal glands express betaARs, and beta
      agonists may stimulate secretion of mucus from airways, although human data are
      controversial. beta-Agonists may also affect ion transport across epithelial
      cells by opening apical ion channels such as the cystic fibrosis transmembrane
      regulator. This effect, likely to occur in submucosal glands, can influence water
      fluxes across the airway epithelium and may have profound influences on mucus
      hydration. betaAR activation can increase intracellular calcium in some ciliated
      cells, thereby stimulating ciliary beating and possibly influencing
      transepithelial ion transport. betaAR-mediated activation of cAMP-dependent
      protein kinase accelerates epithelial cell migration, thereby enhancing
      epithelial wound repair. beta-Agonists reduce the ultrastructural damage seen
      with infection and potentiate secretion of certain cytokines from epithelial
      cells while inhibiting secretion of others. Finally, beta-agonists may have
      effects on airway epithelial cells that are mediated through betaARs but do not
      require cAMP production. The signaling mechanisms of some beta-agonist effects
      are not well understood but are important to our understanding of airway
      epithelial cell growth, differentiation, and function.

PMID- 12464937
TI  - Effects of beta2-agonists on resident and infiltrating inflammatory cells.
AB  - beta(2)-adrenergic receptors are present on inflammatory cells such as mast
      cells, monocytes, eosinophils, T-lymphocytes, and neutrophils implicated in the
      pathophysiology of respiratory disease. Short-acting beta(2)-agonists (eg,
      albuterol) and long-acting beta(2)-agonists (eg, salmeterol, formoterol) inhibit
      cell activation, inflammatory mediator release, and cell recruitment and survival
      mechanisms in vitro, with evidence of cellular specificity in response. In some
      cases, these effects can be observed in vivo, particularly with the long-acting
      agents. Reductions in inflammatory cell numbers, activation status in airway
      tissue, and inflammatory markers in sputum, bronchoalveolar lavage fluid, and
      blood have been reported after administration of clinical doses of salmeterol and
      formoterol. The inflammatory cell inhibitory activity of beta(2)-agonists is
      increased in the presence of corticosteroids, resulting in additive and/or
      synergistic effects on mediator release, adhesion molecule expression, and
      cellular proliferation. In vivo, the combination of long-acting beta(2)-agonist
      and corticosteroid exhibits an anti-inflammatory effect greater than that of the
      agonist alone, as well as a reduction in airway vascularity, a component of
      remodeling, that corticosteroids alone cannot produce.

PMID- 12464938
TI  - Effect of beta-adrenergic agonists on mucociliary clearance.
AB  - The mucociliary clearance apparatus, an important defense mechanism for clearing
      the lung of bacteria and foreign particulate matter, is a well-coordinated system
      consisting of airway secretory cells that produce a sol and gel (or mucus) fluid
      layer on the airway surface and ciliated cells that propel the mucus out of the
      lung towards the mouth. In vivo mucociliary clearance rates can be measured by
      following the rate of egress of deposited, radiolabeled markers by gamma camera.
      Short-acting beta-adrenergic agonists have been shown to enhance mucociliary
      clearance rates to varying degrees in patients with various lung diseases (eg,
      asthma, chronic bronchitis, and cystic fibrosis), although the enhancement is
      generally less than that seen in the normal lung. Limited data on the in vivo
      dose-response relationships of these mucociliary clearance effects suggest that
      larger doses are required for enhancement of mucociliary clearance than are
      needed for bronchodilatation. Little is known about chronic effects, but studies
      with dosing for up to a week also suggest an enhancement of mucociliary
      clearance, primarily by agonists that are lipophilic. Issues for future research
      include the effects of the newer long-acting beta-agonists, large versus small
      airway effects, and combination effects with other inhaled therapeutic agents
      (eg, steroids and ion-channel blockers).

PMID- 12464939
TI  - The effect of inhaled beta2-agonists on clinical outcomes in chronic obstructive
      pulmonary disease.
AB  - The major clinical outcomes measured in evaluating the responses to
      pharmacotherapy in patients with chronic obstructive pulmonary disease (COPD)
      include the severity of dyspnea, exercise capacity, exacerbations, and health
      status. Various studies have demonstrated that testing for acute bronchodilator
      reversibility in the pulmonary function laboratory does not predict the clinical
      responses to a trial of bronchodilator therapy in patients with COPD. Separate
      studies have shown that inhaled albuterol, both a single dose (300 microg) and 2
      weeks of therapy (200 microg/4x/day), reduces dyspnea. There is more published
      information available about the effects of long-acting (>/=12 hours' duration of
      action) inhaled beta(2)-agonists because of greater interest in considering
      clinical outcomes at the time of drug testing. In one randomized clinical trial,
      formoterol reduced symptoms (as recorded in a home diary) and improved health
      status. Nine clinical studies have examined the effects of salmeterol on clinical
      outcomes. Salmeterol reduced the perception of breathlessness (in 6 of 9 studies)
      and improved health status (in 3 of 4 studies). These results collectively
      demonstrate that long-acting inhaled beta(2)-agonists not only relax bronchial
      smooth muscle but also provide important clinical benefits in symptomatic
      patients with COPD.

PMID- 12464940
TI  - Effects of beta2-agonists on airway tone and bronchial responsiveness.
AB  - In evaluating the clinical consequences of beta(2)-agonist therapy, it is
      important to consider the possibility of reduced asthma control and increased
      bronchial responsiveness with regular or long-term use. Some studies have noted
      reductions in protective effects but not complete loss of protection with short
      acting beta(2)-agonist therapy. These reductions vary, depending on the use of
      nonspecific, indirect, or immunologic challenges, but it appears there is a
      greater loss of protective effect against indirect stimuli. Tachyphylaxis to the
      bronchodilatatory effects of long-acting beta(2)-agonists appears to be minimal.
      Individuals homozygous for arginine at locus 16 of the beta(2)-adrenergic
      receptor gene have a decline in pulmonary function during beta(2)-agonist use,
      and they are at greater risk of asthma exacerbations during beta(2)-agonist
      therapy than patients with other genotypes. Important questions for further
      research are whether small differences in tachyphylaxis and bronchoprotection
      have relevant clinical effects and to what extent tachyphylaxis and tolerance to
      bronchoprotection are caused by pharmacogenetic interactions.

PMID- 12464941
TI  - beta-Agonists and metabolism.
AB  - This review presents recent concepts of how beta-agonists affect glucose
      homeostasis by modulating insulin secretion, liver metabolism, and uptake of
      glucose into muscle, with attention to the influence of hypoglycemia on beta
      agonist sensitivity and the effects of beta(3)-adrenergic receptor (beta(3)AR)
      polymorphisms on adipocyte metabolism. Specific beta(2)-agonist effects on the
      pancreatic beta cell result in increased insulin secretion, yet other mechanisms,
      such as increased glucagon secretion and hepatic effects, cause an overall
      increase in serum glucose and an apparent decrease in insulin sensitivity. Human
      studies confirm the presence of beta(2)ARs on pancreatic beta cells. Intensive
      treatment of diabetes mellitus with insulin, especially in type 1 diabetes, has
      led to increased incidence of hypoglycemia. Repeated episodes of hypoglycemia
      lead to unawareness of neuroglycopenia, a major limitation to intensive
      treatment. Hypoglycemic unawareness is associated with reduced beta-agonist
      sensitivity. Scrupulous avoidance of hypoglycemia over many weeks to months can
      restore beta-agonist sensitivity and improve detection of hypoglycemia. beta
      agonists have also been employed to prevent hypoglycemia. beta-agonists can
      increase thermogenesis and lipolysis, leading to increased energy expenditure and
      decreased fat stores. While beta(1)ARs and beta(2)ARs mediate many of these
      actions, it is likely that beta(3)ARs in the adipocyte membrane also play an
      important role. Specific beta(3)AR subtypes have been associated with obesity and
      the metabolic syndrome.

PMID- 12464942
TI  - Variability in beta-adrenergic receptor response in the vasculature: Role of
      receptor polymorphism.
AB  - beta-adrenergic receptors (betaARs) are important in determining vascular tone.
      Stimulation of beta(2)ARs in the vasculature produces vasodilatation, which acts
      to counteract the vasoconstriction produced by endogenous sympathetic agonists.
      Impaired vasodilatation occurs in human hypertension and in Blacks. It is now
      clear that receptor polymorphism may contribute to some of the variability seen
      in vascular response. beta(2)AR haplotypes determine the desensitization response
      to chronic agonist exposure in vivo and result in altered vasodilatory responses.

PMID- 12464943
TI  - Adverse effects of beta-agonists.
AB  - Short-acting beta-adrenergic receptor agonists have pharmacologically predictable
      dose-related and potency-related adverse effects, including tachycardia and
      tremor, and they also affect serum potassium and glucose. These effects all show
      tolerance with continued exposure. The potential for arrhythmia is increased by
      comorbidity and hypoxemia. Nonpharmacologically predictable effects include
      airway hyperresponsiveness to nonspecific and specific stimuli, including
      allergen and exercise, and increased airway inflammation. Genetic variants of the
      beta-adrenergic receptor alter susceptibility to adverse effects of beta-agonists
      on airway function. The impact of the enantiomers of beta-agonists on adverse
      effects remains unclear. The two epidemics of asthma death among young people
      were temporally associated with introduction of potent short-acting beta-agonists
      (isoproterenol and fenoterol) and appear to be related to adverse effects of
      these drugs on airway function and airway hyperresponsiveness rather than to
      cardiotoxicity. Compared with short-acting agents, long-acting beta-agonists show
      similar but less pronounced pharmacologically predictable effects, and they have
      not been shown to increase airway hyperresponsiveness in adults. Postmarketing
      surveillance studies have not suggested significant adverse effects of long
      acting beta-agonists on morbidity and mortality.

PMID- 12464945
TI  - Biology and clinical relevance of naturally occurring antimicrobial peptides.
AB  - Within the last decade, several peptides have been discovered on the basis of
      their ability to inhibit the growth of potential microbial pathogens. These so
      called antimicrobial peptides participate in the innate immune response by
      providing a rapid first-line defense against infection. Recent advances in this
      field have shown that peptides belonging to the cathelicidin and defensin gene
      families are of particular importance to the mammalian immune defense system.
      This review discusses the biology of these molecules, with emphasis on their
      structure, processing, expression and function. Current evidence has shown that
      both cathelicidins and defensins are multifunctional and that they act both as
      natural antibiotics and as signaling molecules that activate host cell processes
      involved in immune defense and repair. The abnormal expression of these peptides
      has also been associated with human disease. Current and future studies are
      likely to implicate the presence of antimicrobial peptides in several unexplained
      human inflammatory disorders and to provide novel therapeutic approaches to the
      treatment of disease.

PMID- 12464946
TI  - Choice of a medication to treat asthma: is an improvement in symptoms sufficient
      for deciding?

PMID- 12464947
TI  - Current issues with influenza vaccination in egg allergy.
AB  - Influenza infection, with its accompanying morbidity and mortality, represents a
      major public health concern yearly to the elderly and high-risk groups, including
      asthmatic patients. Active prevention with vaccination consistently falls short
      of reaching optimal immunization rates in all risk groups. Asthmatic patients and
      others with concomitant egg allergy might be denied active immunization because
      of the risk of inducing adverse reactions with a vaccine derived from egg embryo
      tissue. Evidence supports the relatively safe administration of influenza vaccine
      to individuals with egg allergy in whom vaccination is indicated when specific
      protocols are followed under the supervision of experienced physicians. A
      practical protocol that includes incremental dosing of influenza vaccine is
      presented to guide clinicians in influenza vaccination in this high-risk group.

PMID- 12464948
TI  - Asthma and the CCAAT-enhancer binding proteins: a holistic view on airway
      inflammation and remodeling.
AB  - Asthma is an airway disease with increasing prevalence characterized by
      intermittent reversible airway obstruction, airway inflammation, and airway wall
      remodeling. The disease is generally triggered by inhalation of allergens, but
      nonallergic asthma triggers are quite common. The pathogenesis of asthma is well
      documented, and a great deal of research has been carried out to elucidate the
      underlying mechanisms. A multitude of articles have focused on cells alleged to
      be involved in the pathogenesis, including circulating cells from the immunologic
      compartment (ie, eosinophils and T lymphocytes) and resident cells, such as
      fibroblasts, airway smooth muscle cells, and, more recently, the airway
      epithelium. Despite the enormous amount of research, it is still unclear what
      exactly causes asthma. A general feature of most studies is an enhanced
      activation status of asthmatic cells, suggesting a general defect with respect to
      regulation of cellular responses. Here we discuss the ubiquitous transcription
      factor family of CCAAT-enhancer binding proteins (C/EBPs) and its involvement in
      inflammation and proliferation. We propose that an imbalance of C/EBP isoform
      expression might lead to an enhanced activity of asthmatic cells and provide an
      overall hypothesis that both airway inflammation and remodeling can be conceived
      as the result of an imbalance of C/EBP isoform expression.

PMID- 12464949
TI  - Effects of montelukast and beclomethasone on airway function and asthma control.
AB  - BACKGROUND: Maintaining asthma control is a major objective of therapy.
      Traditionally, the effectiveness of asthma therapy has been judged primarily by
      its effect on airway function rather than on multiaspect asthma control.
      OBJECTIVE: An inhaled corticosteroid and a leukotriene receptor antagonist were
      compared to determine whether they provided equivalent effects, as judged by days
      of asthma control. METHODS: In a randomized, multicenter, double-blind, placebo
      controlled, parallel-group study, asthmatic patients (n = 782) with FEV(1)
      percent predicted values of between 50% and 85% and a weekly average beta-agonist
      use of more than 2 puffs per day were randomized to receive montelukast (10 mg
      daily), beclomethasone (200 microg twice daily), or placebo treatment for 6 weeks
      in a double-dummy fashion. We examined the distribution of the primary end point:
      percentage of days of asthma control. Secondary end points included FEV(1),
      albuterol use, occurrence of an asthma attack, asthma flare-up, rescue
      corticosteroid use, sustained asthma control, and adverse experiences. RESULTS:
      The percentage of days of asthma control was almost identical between the
      montelukast and beclomethasone groups (98% overlap in the distribution).
      Montelukast was at least equal to beclomethasone, and both were greater than
      placebo on the basis of frequency of asthma attacks, asthma flare-ups, and rescue
      corticosteroid use. Beclomethasone had a greater effect than montelukast and both
      treatments were better than placebo at improving FEV(1). CONCLUSIONS: Montelukast
      was as effective as beclomethasone, as judged by indices of clinical control
      other than FEV(1). When evaluating the outcome of montelukast therapy, FEV(1)
      might underestimate clinical effectiveness.

PMID- 12464950
TI  - Changes in sputum counts and airway hyperresponsiveness after budesonide:
      monitoring anti-inflammatory response on the basis of surrogate markers of airway
      inflammation.
AB  - BACKGROUND: Airway hyperresponsiveness (AHR) to pharmacologic stimuli and sputum
      eosinophils might be useful in the individual adjustment of long-term asthma
      management. However, it is not clear whether inhaled glucocorticosteroids (GCSs)
      provide greater protection against specific surrogate markers of airways
      inflammation than other means. In addition, detailed longitudinal assessment of
      changes in airway response with inhaled GCSs has never been carried out.
      OBJECTIVES: We compared changes in AHR to inhaled methacholine and adenosine 5'
      monophosphate (AMP) after budesonide treatment in a randomized, double-blind,
      placebo-controlled, crossover study of patients with mild-to-moderate asthma.
      Subsequently, we undertook a separate study to examine the time course of the
      changes in AHR in more detail and the changes in sputum cell counts in relation
      to budesonide treatment. METHODS: In the phase 1 of the study, patients undertook
      bronchial provocation studies with increasing doubling concentrations of
      methacholine (0.06 to 16 mg/mL) and AMP (3.125 to 800 mg/mL) before and after
      budesonide 0.8 mg/daily for 3 weeks. The bronchial responses to the inhaled
      agonists were expressed as the provocative concentration causing a 20% decline in
      FEV(1) (PC(20)). In phase 2 of the study, patients attended the laboratory on 12
      separate occasions to investigate changes in PC(20) methacholine, PC(20) AMP, and
      sputum cell counts before, during, and after withdrawal of therapy with inhaled
      budesonide 0.8 mg/daily for 6 weeks. RESULTS: Budesonide treatment for 3 weeks
      significantly attenuated the constrictor response by 0.8 +/- 0.3 doubling doses
      for methacholine and by 2.6 +/- 0.5 doubling doses for AMP. These changes were
      significantly different from each other (P =.003). Significant variation in
      PC(20) methacholine (P <.05) value, PC(20) AMP (P <.001) value, percentage of
      sputum eosinophils (P <.001), and percentage of sputum epithelial cells (P <.001)
      were observed throughout the longitudinal assessment of changes in airway
      response to budesonide. Compared with the other surrogate markers, PC(20) AMP
      appears to be useful in promptly detecting early inflammatory changes of the
      asthmatic airways; a significant change of 1.6 +/- 0.3, 2.2 +/- 0.3, and 2.8 +/-
      0.3 doubling doses of PC(20) AMP was observed at 1, 4, and 6 weeks, respectively,
      in the course of budesonide treatment. CONCLUSIONS: The present findings
      underline the exquisite selectivity of diverse surrogate markers of airway
      inflammation in response to inhaled budesonide. When compared with that to the
      other markers, AHR to inhaled AMP is an early and sensitive indicator of the
      beneficial anti-inflammatory effects of topical GCSs.

PMID- 12464951
TI  - Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis.
AB  - BACKGROUND: Chronic rhinosinusitis (CRS) is the most common chronic disease that
      is frequently refractory to treatment. OBJECTIVE: We sought to establish the
      safety and demonstrate the clinical efficacy of intranasal antifungal drug
      therapy in patients with CRS in a pilot trial. METHODS: A prospective open-label
      trial used amphotericin B as a medical treatment in 51 randomly selected patients
      with CRS. The antifungal agent was applied intranasally as 20 mL of a 100
      microg/mL solution twice daily. The outcome was measured by using their symptoms
      and by using an endoscopic scoring system in all patients. In addition,
      pretreatment and posttreatment coronal computed tomographic scans of the nose and
      sinuses were available for evaluation in 13 patients. RESULTS: By using
      amphotericin B, improvement of sinusitis symptoms was observed in 38 (75%) of 51
      patients. Endoscopically, 18 (35%) of 51 patients became disease free, and an
      additional 20 (39%) of 51 had improvement of at least one stage (P <.001). No
      effect was seen in 13 (25%) of 51 patients. The available computed tomographic
      scans before and after treatment demonstrated a significant reduction in the
      inflammatory mucosa thickening that had occluded the paranasal sinuses (P <.0001
      in maxillary sinus). CONCLUSION: This open-label pilot trial demonstrates that
      direct mucoadministration of an antifungal drug appears to be both safe and
      effective in the treatment of patients with CRS. Therefore controlled and blinded
      trials are indicated to clarify the novel role of intranasal antifungal drugs in
      the treatment of CRS.

PMID- 12464952
TI  - CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic
      asthma.
AB  - BACKGROUND: We have previously demonstrated that CpG oligodeoxynucleotides (CpG
      ODNs) protect against eosinophilia and airway hyperresponsiveness in murine
      models of allergen-induced asthma. Acute inflammation is hypothesized to induce
      chronic airway responses, but no previous studies have evaluated the effects of
      CpG-ODNs on allergen-induced airway remodeling. Because remodeling is thought to
      be responsible for many of the long-term adverse effects on asthmatic patients,
      we evaluated whether CpG-ODNs might similarly prevent these changes using a
      murine model of recurrent allergen exposure. OBJECTIVE: The purpose of this study
      was to evaluate the effect of CpG-ODNs on chronic inflammatory changes and airway
      remodeling by using a murine model of chronic allergen-induced asthma. METHODS:
      C57BL/6 mice were sensitized to ovalbumin (OVA) and subsequently exposed to
      nebulized OVA by means of inhalation 3 times weekly for 6 weeks. Some mice
      received CpG-ODNs by means of intraperitoneal injection at the time of
      sensitization. At the end of the exposure period, mice were evaluated for the
      development of airway inflammation, airway hyperresponsiveness, and airway
      remodeling. RESULTS: OVA-sensitized mice exposed to recurrent airway challenge
      with OVA have chronic inflammation, persistent airway hyperresponsiveness, and
      evidence of airway remodeling, including subepithelial collagen deposition and
      goblet cell hyperplasia-metaplasia. These changes are significantly reduced in
      mice treated with CpG-ODNs. Interestingly, mice treated with CpG-ODNs exhibit
      increased levels of bronchoalveolar lavage transforming growth factor beta,
      suggesting that regulatory T cells might be responsible for some of these
      protective effects. CONCLUSION: CpG-ODNs are effective not only in preventing
      acute inflammation but also appear to reduce markers of airway remodeling that
      develop after chronic allergen exposure.

PMID- 12464953
TI  - Expression of Smad7 in bronchial epithelial cells is inversely correlated to
      basement membrane thickness and airway hyperresponsiveness in patients with
      asthma.
AB  - BACKGROUND: Smad7 is an intracellular antagonist of transforming growth factor
      beta (TGF-beta) signaling, which could determine the intensity or duration of the
      TGF-beta signal. Because TGF-beta has been implicated in the development of
      airway remodeling in asthma on the basis of its strong capacity to induce
      extracellular matrix production, it is possible that Smad7 also plays some roles
      in the regulation of the process. OBJECTIVE: We sought to determine the
      relationships between Smad7 expression in bronchial biopsy samples from asthmatic
      subjects and clinicopathologic features. METHODS: Bronchial biopsy specimens were
      obtained from 40 asthmatic subjects and 6 healthy control subjects. Expression
      levels of Smad7 on a histologic section were estimated by immunohistochemical
      staining. In addition, the roles of Smad7 in TGF-beta-mediated transcriptional
      responses were studied by in vitro studies. RESULTS: Smad7 immunoreactivity was
      detected mainly in bronchial epithelial cells in control and asthmatic subjects.
      Interestingly, asthmatic subjects exhibited less Smad7 immunoreactivity in
      bronchial epithelial cells than normal subjects. Expression levels of Smad7 in
      bronchial epithelial cells were inversely correlated with basement membrane
      thickness and airway hyperresponsiveness in asthmatic subjects. In addition,
      abrogation of endogenous Smad7 expression through use of an antisense
      oligonucleotide enhanced transcriptional responses to TGF-beta, whereas
      overexpression of Smad7 inhibited TGF-beta-induced plasminogen activator
      inhibitor 1production in a human bronchial epithelial cell line, BEAS2B cells.
      CONCLUSION: These findings suggest that Smad7 is a key molecule that defines the
      susceptibility of bronchial epithelial cells to TGF-beta action and that
      regulation of Smad7 expression in bronchial epithelial cells might be related to
      the development of airway remodeling and airway hyperresponsiveness in asthma.

PMID- 12464954
TI  - Atrial natriuretic peptide gene transfer by means of intranasal administration
      attenuates airway reactivity in a mouse model of allergic sensitization.
AB  - Atrial natriuretic peptide (ANP) is a bronchodilator; however, the short half
      life of ANP in vivo limited its therapeutic utility to treat asthma. The efficacy
      of intranasally administered plasmid DNA-expressing ANP (pANP; amino acid 99-126;
      Acc. No. XM131840) on the prevention of allergen-induced airway
      hyperresponsiveness (AHR) was examined in this study by using a mouse model of
      asthma. Ovalbumin-sensitized mice were treated with pANP versus control plasmids,
      and AHR was monitored after ovalbumin challenge for 5 weeks on 10-day intervals
      starting 4 days after gene transfer. Mice administered pANP demonstrated
      significantly less AHR for 20 days after treatment. The results demonstrate that
      pANP gene transfer protects against AHR and might be useful in the treatment of
      asthma.

PMID- 12464955
TI  - Kinetics and mode of peptide delivery via the respiratory mucosa determine the
      outcome of activation versus TH2 immunity in allergic inflammation of the
      airways.
AB  - BACKGROUND: Specific immunotherapy involving systemic injection of allergen,
      though highly effective, can cause severe side effects due to IgE-mediated
      activation of effector cells. Allergen-derived peptides might provide a safer
      alternative. We have investigated the use of mucosally delivered peptide to
      induce CD4(+) T(H)2 cell tolerance and thus protect against allergen-induced
      airway inflammation. OBJECTIVE: The purpose of this study was to investigate
      whether intranasal administration of an allergen-derived peptide, either alone or
      adsorbed to chitosan, can prevent the induction of T(H)2-mediated pulmonary
      inflammation after sensitization and challenge of the airways with allergen.
      METHODS: Mice were given (intranasally) a peptide containing an immunodominant
      epitope of the Dermatophagoides pteronyssinus (Der p) 1 allergen, either as
      soluble antigen or adsorbed to chitosan, before sensitization and allergen
      challenge. Pulmonary inflammation, antigen-specific CD4(+) T-cell responses, and
      antibody levels in sera were then determined. RESULTS: Mice given peptide
      adsorbed to chitosan had significant reductions in airway eosinophilia, which
      correlated with reduced levels of IL-4 and IL-5 in the bronchoalveolar lavage
      fluid. There was decreased recruitment of activated CD4(+) T cells into the
      airways after allergen challenge, which correlated with a loss of Der p 1
      specific T-cell cytokine responses in the periphery and the localized production
      of IL-10 by antigen-specific T cells in bronchial lymph nodes. Induction of
      peripheral T-cell tolerance was preceded by transient T-cell activation and IFN
      gamma production. CONCLUSION: Our data demonstrate that suppression of airway
      inflammation by intranasal administration of peptide antigen adsorbed to chitosan
      is initiated by transient T-cell activation and maintained by the production of
      IL-10 by antigen-specific T cells in the draining lymph nodes.

PMID- 12464956
TI  - Site-specific sensitization in a murine model of allergic rhinitis: role of the
      upper airway in lower airways disease.
AB  - BACKGROUND: Allergic rhinitis (AR) is the most common atopic disease with strong
      links to asthma. We have developed a murine model of AR to study nasal,
      bronchial, and systemic immune response to local allergen stimulation.
      OBJECTIVES: The purpose of this study was to develop and characterize a murine
      model of AR. METHODS: Six- to 8-week-old BALB/c mice were sensitized by means of
      intranasal (local) application of ovalbumin (OVA) or systemic intraperitoneal
      injection. They were then challenged with intranasal OVA, and allergic response
      was assessed. RESULTS: Intranasal particle deposition was found to be exclusively
      in the nares. All sensitized animals showed increased levels of OVA-specific
      serum IgE and IgG after challenge, although the timing to maximal response varied
      with the route and dose of allergen used. Histology of the upper and lower
      airways showed marked eosinophilic infiltration, and analysis of bronchoalveolar
      lavage fluid showed increased IL-5 and PMN infiltrates after challenge.
      CONCLUSION: Using exclusive local sensitization and challenge of mouse nares, we
      were able to demonstrate inflammatory changes in both the upper and lower
      airways, even though distribution of allergen particles appeared to be only in
      the nares of these animals. This provides further evidence for the importance of
      the upper airway in lower airways disease. We have shown that the route of
      administration greatly affects the characteristics of the subsequent immune
      responses.

PMID- 12464957
TI  - TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and
      bronchial submucosa is a feature of asthma and eosinophilic bronchitis.
AB  - BACKGROUND: Asthma is characterized by variable airflow obstruction and airway
      hyperresponsiveness in association with airway inflammation under the influence
      of T(H)2 cytokines. Eosinophilic bronchitis has similar immunopathology to asthma
      but without disordered airway physiology. Whether eosinophilic bronchitis is
      associated with increased expression of T(H)2 cytokines is unknown. OBJECTIVE: We
      sought to assess the expression of T(H)2 cytokines in eosinophilic bronchitis.
      METHODS: Expression of activation markers and chemokine receptors from blood and
      bronchoalveolar lavage (BAL) fluid T cells and the T(H)2 cytokine expression from
      these T cells and bronchial mucosa biopsy specimens were assessed from subjects
      with eosinophilic bronchitis, subjects with asthma, and healthy control subjects.
      RESULTS: The proportion of resting (stimulated) CD4 BAL fluid T cells expressing
      intracellular IL-4 was significantly higher in the subjects with eosinophilic
      bronchitis 7.2% (11.4%) and subjects with asthma 5.3% (5.5%) than in healthy
      control subjects 2.8% (3.9%) (P =.03). The number of IL-4(+) (P <.001) and IL
      5(+) (P =.003) cells per square millimeter of bronchial submucosa was
      significantly higher in the disease groups than in the healthy control subjects.
      Expression of intracellular IFN-gamma was significantly higher in stimulated
      blood CD8 T cells from subjects with eosinophilic bronchitis (24%) and asthma
      (17%) than in the healthy control subjects (5%; P =.003). There were no between
      group differences in expression of IFN-gamma in the BAL fluid T cells or in the
      bronchial submucosa and no differences in expression of activation markers or
      chemokine receptors. CONCLUSION: These findings support the concept of asthma as
      a disease associated with activation of T(H)2 lymphocytes in the airway and
      provide evidence that these cytokines play a role in the development of airway
      inflammation in eosinophilic bronchitis but suggest that the release of T(H)2
      cytokines is not sufficient for the elaboration of disordered airway physiology
      in asthma.

PMID- 12464958
TI  - Differential roles of IL-16 and CD28/B7 costimulation in the generation of T
      lymphocyte chemotactic activity in the bronchial mucosa of mild and moderate
      asthmatic individuals.
AB  - BACKGROUND: IL-16 is an important T-cell chemotactic cytokine in asthmatic
      airways; its release from allergen-stimulated bronchial mucosa in mild asthma has
      been shown to be dependent on CD28/B7 costimulation. OBJECTIVE: We have extended
      our previous studies to investigate the role of IL-16 and CD28/B7 costimulation
      in T-lymphocyte chemotactic activity (TLCA) released from the bronchial mucosa in
      more severe asthma. METHODS: TLCA was determined in the supernatants of induced
      sputum and allergen-stimulated bronchial mucosal explants from healthy volunteers
      and volunteers with mild and moderately severe asthma by means of a Boyden
      chamber technique. The contribution of IL-16 to the activity was evaluated
      through use of a neutralizing monoclonal antibody; the contribution of CD28/B7
      costimulation to allergen-induced release of TLCA was determined through use of
      CTLA4-Ig fusion protein and neutralizing monoclonal antibodies to CD80 (B7.1) and
      CD86 (B7.2). RESULTS: Induced sputum and unstimulated explants from asthmatic
      subjects generated significant spontaneous TLCA (P <.05). Both mild and moderate
      asthmatic explants showed significantly elevated Dermatophagoides pteronyssinus 
      induced release of TLCA, but only in mild asthma could sputum and allergen
      stimulated explant TLCA be inhibited by anti-IL-16 (median inhibition, 39% and
      59%; P <.05). In addition, allergen released significant quantities of IL-16 from
      mild asthmatic explants (P <.05) but not from moderate asthmatic explants.
      Antibodies to the CD28 counter-ligands CD80 and CD86 inhibited allergen-induced
      release of TLCA in mild asthmatic explants by 94% (P <.05) and 62%, but TLCA
      release from moderate asthmatic explants was unaffected by CTLA4-Ig. CONCLUSION:
      These results show that TLCA release in moderate asthmatic airways, in contrast
      to mild asthmatic airways, is not dependent on CD28/B7 costimulation and does not
      involve IL-16.

PMID- 12464959
TI  - The distribution of individual threshold doses eliciting allergic reactions in a
      population with peanut allergy.
AB  - BACKGROUND: Hidden peanut in consumer products can endanger patients with peanut
      allergy. Individual threshold doses for eliciting allergic reactions need to be
      elucidated to assess the risks for development of allergic reactions after
      accidental ingestion of peanut in a population with peanut allergy. OBJECTIVE: We
      sought to determine the distribution of individual threshold doses in a
      population with peanut allergy and to correlate these thresholds to the severity
      of peanut-induced symptoms. METHODS: Twenty-six adult patients with a convincing
      history of peanut-related symptoms, a specific IgE level of 0.7 kU/L or greater,
      or a positive skin prick test response of 2+ or greater to peanut were included.
      These patients underwent double-blind, placebo-controlled food challenges with
      increasing doses of peanut. A threshold dose could be established when objective
      or repetitive subjective reactions occurred after active doses. RESULTS: All
      patients had subjective oral symptoms (n = 26), prior subjective gastrointestinal
      symptoms (n = 14), or objective symptoms (n = 5). Reactions started within 30
      minutes after ingestion of peanut, but in 2 patients additional symptoms were
      delayed by 1 to 2 hours. Threshold doses for allergic reactions ranged from a
      dose as low as 100 microg up to 1 g of peanut protein. Fifty percent of the study
      population (95% CI, 30%-70%) already had an allergic reaction after ingestion of
      3 mg of peanut protein. Patients with severe symptoms had lower threshold doses
      compared with those of patients with mild symptoms (P =.027). CONCLUSIONS: A
      substantial part of a population with peanut allergy will react to very low
      amounts of peanut, requiring accurate declaration of peanut content in consumer
      products. This is even more important because patients with severe reactions
      react to lower doses than patients with mild symptoms.

PMID- 12464960
TI  - The atopic dog as a model of peanut and tree nut food allergy.
AB  - BACKGROUND: Animal models are needed that mimic human IgE-mediated peanut and
      tree nut allergy. Atopic dogs have been previously used in a model of food
      allergy to cow's milk, beef, wheat, and soy, with the demonstration of specific
      IgE production and positive oral challenges similar to those seen in human
      subjects. OBJECTIVE: We sought to sensitize dogs to peanut, walnut, and Brazil
      nut and to assess whether sensitization is accompanied by clinical reactions and
      whether there is cross-reactivity among the different preparations. METHODS:
      Eleven dogs were sensitized subcutaneously by using an established protocol with
      1 microg each of peanut, English walnut, or Brazil nut protein extracts in alum
      first at birth and then after modified live virus vaccinations at 3, 7, and 11
      weeks of age. The dogs were sensitized to other allergens, including soy and
      either wheat or barley. Intradermal skin tests, IgE immunoblotting to nut
      proteins, and oral challenges were performed with ground nut preparations.
      RESULTS: At 6 months of age, the dogs' intradermal skin test responses were
      positive to the nut extracts. IgE immunoblotting to peanut, walnut, and Brazil
      nut showed strong recognition of proteins in the aqueous preparations. Each of
      the 4 peanut- and the 3 Brazil nut-sensitized dogs and 3 of the 4 walnut
      sensitized dogs reacted on oral challenge with the corresponding primary
      immunogen at age 2 years. None of the peanut-sensitized dogs reacted clinically
      with walnut or Brazil nut challenges. One of the walnut-sensitized dogs had
      delayed (overnight) vomiting to Brazil nut. CONCLUSIONS: On the basis of
      measurements of the mean amount of allergen eliciting a skin test response in
      dogs, the hierarchy of reactivity by skin testing is similar to the clinical
      experience in human subjects (peanut > tree nuts > wheat > soy > barley). Cross
      reactivity, which was not apparent between soy and peanut or tree nuts or between
      peanut and tree nuts, was slight between walnut and Brazil nut. The results give
      further support to the dog as a model of human food allergy.

PMID- 12464961
TI  - Rush Hymenoptera venom immunotherapy: a safe and practical protocol for high-risk
      patients.
AB  - BACKGROUND: Hymenoptera venom immunotherapy in allergic patients is a well
      established treatment modality for the prevention of systemic anaphylactic
      reactions caused by insect stings. A variety of therapy regimens exists, from
      conventional to rush and ultrarush modalities that operate on continuous or
      intermittent schedules. OBJECTIVE: The aim of this study was to report the 8-year
      experience with our rush venom immunotherapy regimen in predominantly high-risk
      patients and to compare data on safety and convenience with the results of 26
      studies published from 1978 to 2001. METHODS: One hundred one patients allergic
      to bee, yellow jacket, or hornet venom were treated with rush Hymenoptera venom
      immunotherapy. Diagnosis and selection of patients for venom immunotherapy were
      carried out according to the recommendations of the European Academy of
      Allergology and Clinical Immunology. We used a 4-day regimen, and the incidence
      and nature of systemic reactions (SRs) were documented. Fifty-two patients were
      treated with honeybee venom, and 49 were treated with yellow jacket venom.
      RESULTS: One hundred (99%) patients reached the maintenance dose. We observed 8
      injection-related SRs (0.47% of all injections given) in 7 (6.9%) patients. The
      number of SRs was higher in patients treated with bee venom extract (12%)
      compared with in patients receiving yellow jacket venom extract (2%). There was
      no significant difference in the risk of SRs between female and male patients.
      The incidence of SRs was considerably lower than the average of 17.8% reported in
      the literature. CONCLUSION: With a rush immunotherapy regimen over a time period
      of 8 years in predominantly high-risk patients, the incidence of SRs was low,
      despite the high number of patients with bee venom allergy, who are more likely
      to have side effects. Epinephrine as rescue medication was never necessary, and
      the regimen proved to be safe and convenient for both the patients and the
      medical staff.

PMID- 12464962
TI  - CD4 CD25 regulatory T cells are not functionally impaired in adult patients with
      IgE-mediated cow's milk allergy.

PMID- 12464963
TI  - Anaphylaxis after ingestion of gummy bears.

PMID- 12464964
TI  - Food additives intolerance: a possible cause of perennial rhinitis.

PMID- 12464965
TI  - Are all IGIVs the same?

PMID- 12464966
TI  - Usefulness of specific skin tests in the diagnosis of hypersensitivity
      pneumonitis.

PMID- 12464967
TI  - Combined mediator blockade or topical corticosteroids for seasonal allergic
      rhinitis.

PMID- 12464970
TI  - Enteropathogenic and enterohemorrhagic Escherichia coli infections: emerging
      themes in pathogenesis and prevention.
AB  - Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E coli (EHEC) are
      important causes of infectious diarrhea, particularly among pediatric
      populations. While EPEC is a significant health threat in the developing world,
      EHEC causes sporadic but deadly outbreaks of hemorrhagic colitis and hemolytic
      uremic syndrome in North America and other developed areas. The present review
      discusses emerging themes in the pathogenesis of EPEC and EHEC, including the
      discovery and characterization of novel bacterial proteins that are injected by
      the pathogen into host cells. Recent advances have also been made in the
      development of relevant animal models, while bacterial virulence factors are
      being investigated as potential vaccination targets for humans and animals. It is
      hoped that these new areas of study will not only further our knowledge of the
      pathogenesis of EPEC- and EHEC-induced disease but also provide opportunities for
      reducing infection rates and improving treatment options in the future.

PMID- 12464971
TI  - Tabulation of myeloid, lymphoid and intestinal malignancies in Crohn's disease.
AB  - A variety of malignant complications occur in Crohn's disease, and previous
      studies have recorded an increased intestinal cancer risk. The present
      investigation tabulated myeloid and lymphoid malignancies compared with
      intestinal cancers in 1000 consecutively evaluated patients with Crohn's disease
      who were followed over an extended period by a single clinician. Myeloid and
      lymphoid neoplasms were present in 0.5% of patients, while cancer in the
      intestinal tract was detected in 1%. Most of these patients with a malignancy had
      Crohn's disease for a prolonged period of more than 20 years and had negative
      outcomes, including death or presentations with advanced disease. In this cohort,
      lymphoma was not detected in a single patient after definition of Crohn's
      disease, possibly reflecting the limited use of immunosuppressives or infused
      biological agents in this clinical practice. Bypassed rectal 'stumps' were
      associated with subsequent colorectal cancer in half of all males with colon
      cancer in this series, suggesting an important risk factor following colectomy in
      Crohn's disease. Epithelial dysplasia was detected in only a single male patient
      before colorectal cancer, implying that this histopathological marker may be a
      poor predictor of subsequent colon cancer development in Crohn's disease, an
      inflammatory bowel disease process that is typically patchy or focal in
      distribution in the intestinal tract.

PMID- 12464972
TI  - Inhibitory effect of polaprezinc on the inflammatory response to Helicobacter
      pylori.
AB  - Helicobacter pylori-infected gastrointestinal mucosa is frequently infiltrated by
      polymorphonuclear leukocytes (PMN) and monocytes, and these invading cells have
      been implicated in gastrointestinal mucosal inflammation. To clarify the efficacy
      of polaprezinc, a chelate compound consisting of zinc and L-carnosine, against H
      pylori-induced inflammation including PMN infiltration, the in vitro effects of
      this drug on interleukin (IL)-8 production by an established gastric cancer cell
      line (MKN 45 cells) and on PMN-endothelial cell adhesive interactions was
      investigated. Polaprezinc and zinc sulphate inhibited IL-8 production by MKN 45
      cells in response to stimulation with H pylori water extract (HPE) in a dose
      dependent manner from 10(-7) M to 10(-5) M. In addition, the expression of CD11b
      and CD18 on PMN and PMN-dependent adhesion to endothelial cells elicited by HPE
      was inhibited by polaprezinc and zinc sulphate in a concentration-dependent
      manner. L-carnosine did not have any effects on IL-8 production or PMN
      endothelial cell interactions. These results suggest that polaprezinc, mainly the
      zinc component, may inhibit H pylori-induced PMN-mediated gastric inflammation by
      attenuating CD11b/CD18 expression on PMN and IL-8 production from gastric
      epithelial cells.

PMID- 12464973
TI  - Tumour necrosis factor-alpha and nitric oxide mediate apoptosis by D
      galactosamine in a primary culture of rat hepatocytes: exacerbation of cell death
      by cocultured Kupffer cells.
AB  - BACKGROUND: Prostaglandin E1 (PGE1) reduces cell death in experimental and
      clinical liver dysfunction. OBJECTIVES: Whether PGE1 protects against D
      galactosamine (D-GalN)-associated hepatocyte cell death by the regulation of
      tumour necrosis factor-alpha (TNF-alpha) and/or nitric oxide (NO) in hepatocytes
      or cocultured Kupffer cells was examined. METHODS: Anti-TNF-alpha antibodies were
      used to evaluate the role of TNF-alpha during D-GalN cytotoxicity and its
      protection by PGE1 in cocultured hepatocytes and Kupffer cells. Cell apoptosis
      and necrosis were assessed by DNA fragmentation and lactate dehydrogenase
      release, respectively. Nitrite+nitrate (NOx), as NO end products, and TNF-alpha
      concentrations were measured in the culture medium. The role of NO was determined
      by measuring inducible NO synthase (iNOS) expression and the effect of its
      inhibition during d-GalN cytotoxicity and its protection by PGE1. RESULTS: D-GalN
      enhanced hepatocyte cell death associated with high TNF-alpha and NOx levels in a
      culture medium. Anti-TNF-alpha and iNOS inhibition suggested that TNF-alpha was
      mediating apoptosis, but not necrosis, through the stimulation of NO production.
      The antiapoptotic activity of PGE1 was associated with a reduction of NO
      production, but was blocked by iNOS inhibition. This apparent contradiction was
      explained by the ability of PGE1 to enhance iNOS expression shortly after its
      administration and inhibit it later during d-GalN treatment. Anti-TNF-alpha
      antibodies did not reduce the exacerbation of d-GalN-associated cell death in
      hepatocytes by cocultured Kupffer cells. CONCLUSION: TNF-alpha mediates D-GalN
      induced apoptosis via NO production in cultured hepatocytes. The protective
      effect of PGE1 against D-GalN-induced apoptosis is probably through the induction
      of low iNOS expression that was followed by a reduction of iNOS expression and NO
      production induced by the hepatotoxin. The exacerbation of hepatocyte cell death
      by Kupffer cells was not related to TNF-alpha and NO.

PMID- 12464974
TI  - Sexual abuse in irritable bowel syndrome: to ask or not to ask -- that is the
      question.
AB  - BACKGROUND: Irritable bowel syndrome (IBS) is a common and costly disorder in
      Canada. The paucity of medical treatment underscores the importance of examining
      every element of the management approach. Data exist supporting an increased
      prevalence of abuse among individuals with IBS. Importantly, the pathophysiology
      underlying the link between abuse and IBS is increasingly understood. Treatment
      recommendations by opinion leaders support an abuse inquiry. However, many
      clinicians view abuse inquiry as an ethical dilemma. METHOD: Canadian
      gastroenterologists were surveyed to determine current practice patterns and to
      identify barriers to inquiry. Barriers cited by clinicians were explored within
      an ethical context. RESULTS: Abuse inquiry is not universally practised in
      Canada. Fifty-four per cent of the membership of Canadian Association of
      Gastroenterologists responded to the survey. They reported inquiring into abuse
      histories in approximately 50% of patients with IBS. The frequency of inquiry
      declined when male patients were considered. The primal barriers cited were time
      constraints (25%), personal comfort with abuse issues (25%) and lack of resources
      for addressing the abuse (33%). Importantly, only a minority (10%), cited abuse
      history as irrelevant to the management of the patient. INTERPRETATION:
      Physicians identify significant barriers to pursuing an inquiry into abuse.
      However, a minority cited 'clinical irrelevance' as a primal barrier, the
      implicit statement being that the abuse history has clinical relevance. This view
      is consistent with opinion leaders and published treatment recommendations.
      Therefore, by not inquiring into the abuse history, physicians are not fulfilling
      their ethical responsibility to the patient. Physicians need to resolve their
      barriers to inquiry. Furthermore, they need to familiarize themselves with
      treatment recommendations and include this review in their consultation.

PMID- 12464975
TI  - Leptomeningeal carcinomatosis secondary to gastroesophageal adenocarcinoma: a
      case report and review of the literature.
AB  - BACKGROUND: Leptomeningeal carcinomatosis (LC) is a rare metastatic complication
      of solid tumours. It has been mainly described in association with breast cancer,
      lung cancer and melanoma. CASE PRESENTATION: A patient presenting with
      progressive solid food dysphagia with documented adenocarcinoma of the lower
      esophagus and gastroesophageal junction is reported. One month after the initial
      diagnosis, the patient developed gradual onset of increasing headache and
      progressive decrease in the level of consciousness. Computed tomography of the
      head showed evidence of meningeal enhancement, and cerebrospinal fluid
      examination showed the presence of adenocarcinoma cells, making the diagnosis of
      LC. The patient died one month after LC was diagnosed. DISCUSSION: LC is a poor
      prognostic sign in solid organ malignancies. It usually presents with headache,
      altered level of consciousness and focal neurological deficits. Diagnosis is
      established by finding malignant cells in the cerebrospinal fluid and supported
      by marked meningeal enhancement on computed tomography of the brain. A review of
      the English literature found only three reported cases of LC secondary to
      esophageal malignancy. CONCLUSION: A case of LC complicating esophageal and
      gastroesophageal junction malignancy is described. A high index of suspicion and
      early diagnosis may influence the poor outcome of these patients.

PMID- 12464976
TI  - Serum levels of triglyceride and insulin resistance in patients with nonalcoholic
      steatohepatitis.

PMID- 12464978
TI  - Abuse: an integrated and coordinated health sector response is needed.

PMID- 12464980
TI  - Pulmonary site porcine bioprosthesis: evaluation at 14 years.

PMID- 12464981
TI  - Celebrating lies.

PMID- 12464982
TI  - Preventing thrombosis: update of first-line therapy in the management of non-ST
      segment elevation acute coronary syndromes.
AB  - Non-ST segment elevation acute coronary syndrome (NSTE ACS) has a high rate of
      recurrence. Both antithrombotic and antiplatelet agents in association with
      coronary revascularization play an important role in the prevention of an adverse
      outcome. Acetylsalicylic acid, heparin and low molecular weight heparin
      (especially enoxaparin), and the intravenous small-molecule glycoprotein IIb/IIIa
      inhibitors, are of proven value. Recently, clopidogrel has been shown to reduce
      recurrent ischemic events, both early and during the first year after the index
      ACS. Furthermore, two recent trials have shown that an early invasive strategy is
      preferable to a conservative approach in the higher risk patient. As yet, no
      study has shown either the efficacy or the safety of combining all these
      treatment modalities in the management of the NSTE ACS patient. The initial
      choice of antithrombotic and antiplatelet agents and a strategy for early
      revascularization is made after considering the risk of recurrent acute ischemic
      events. For patients destined to have an early invasive strategy, it is desirable
      to choose an anti-thrombotic/antiplatelet combination that will reduce events
      before revascularization, enhance the revascularization procedure and not be
      associated with excessive bleeding. A risk-determined algorithm is presented,
      which applies observations made at the time of presentation to decide the optimal
      management for the individual patient.

PMID- 12464983
TI  - Ischemia Management with Accupril post bypass Graft via Inhibition of angiotensin
      coNverting enzyme (IMAGINE): a multicentre randomized trial - design and
      rationale.
AB  - BACKGROUND: Coronary artery bypass grafting (CABG) remains the revascularization
      treatment of choice for patients with severely symptomatic or life-threatening
      coronary artery disease (CAD). However, 9% to 25% of the patients undergoing CABG
      will suffer a recurrent ischemic event such as death, recurrent infarction,
      angina or repeat revascularization. The pathophysiological processes particular
      to the CABG procedure that may affect graft endothelial function are most active
      in the early phase after surgery. Angiotensin-converting enzyme (ACE) inhibition
      has been shown to be effective in reducing or preventing ischemic events in
      patients with and without left ventricular dysfunction, and in those at high risk
      for CAD. Nonetheless, no large clinical trail has investigated this role of ACE
      inhibition in preventing ischemic events early after CABG. OBJECTIVE: The
      Ischemia Management with Accupril post bypass Graft via Inhibition of angiotensin
      coNverting Enzyme (IMAGINE) study addressed whether ACE inhibition initiated
      early after CABG improves short and long term outcomes in patients after CABG.
      PATIENTS AND METHODS: This multicentre, multinational trial recruited 2204
      patients with an uncomplicated course early after CABG from 55 to 65 medical care
      facilities in Canada, The Netherlands, Belgium and France. Eligible patients with
      normal left ventricular function were randomly assigned to placebo or quinapril
      (titrated up to 40 mg daily where possible) within seven to 10 days after CABG.
      All patients were followed up closely for a minimum of 12 months after random
      placement. The median treatment period is expected to be approximately 27 months.

PMID- 12464984
TI  - Increased P wave dispersion: a new finding in patients with syndrome X.
AB  - The present clinical study was undertaken in patients with syndrome X, namely
      angina with normal coronary arteries, to investigate the presence of increased P
      wave dispersion by comparing patients with coronary artery disease (CAD) and
      healthy control subjects. Three groups were studied - group A, 21 patients (48 6
      years) with syndrome X; group B, 16 patients (56 9 years) with CAD; and group C,
      16 healthy subjects (49 8 years). Patients with CAD were older than those in
      groups A and C (P=0.005 and P=0.035, respectively). All groups demonstrated
      similar PQ, QRS and RR intervals. Group B had a lower minimum P wave duration
      than group C (P=0.05). P wave dispersion in group A was found to be higher than
      that in groups B and C (P=0.018 and P=0.0001, respectively). Patients with
      syndrome X demonstrated increased P wave dispersion compared to patients with CAD
      and healthy subjects. High sympathetic tone or autonomic imbalance observed in
      patients with syndrome X may affect intra-atrial and interatrial conduction
      times, and leave them prone to develop atrial arrhythmias.

PMID- 12464985
TI  - Effects of nitroprusside on cardiac norepinephrine spillover and isovolumic left
      ventricular relaxation in the normal and failing human left ventricle.
AB  - BACKGROUND: Left ventricular isovolumic relaxation responses to changes in
      afterload or preload may be mediated, in part, by reflex changes in sympathetic
      nervous system activity. PATIENTS AND METHODS: The authors examined whether
      changes in left ventricular isovolumic relaxation during changes in load were
      associated with changes in cardiac norepinephrine spillover. Six patients with
      normal left ventricular function and 12 patients with congestive heart failure
      secondary to left ventricular systolic dysfunction were studied. Measurements of
      left ventricular isovolumic relaxation (Tau) were obtained using a high fidelity
      left ventricular pressure manometer, before, during and after infusion of
      nitroprusside. Total body and cardiac norepinephrine spillover were measured
      using a radiotracer infusion. RESULTS: Nitroprusside caused significant
      reductions in systemic arterial and left ventricular end-diastolic pressures,
      changes that were similar in the two groups. In people with normal left
      ventricular systolic function, these changes were associated with significant
      increases in both systemic and cardiac sympathetic activity, but no change in
      Tau. In the group with congestive heart failure, cardiac norepinephrine spillover
      did not change; however, there was a significant increase in the rate of left
      ventricular isovolumic relaxation. CONCLUSION: This study confirms that in the
      failing human left ventricular, isovolumetric relaxation is sensitive to changes
      in loading conditions induced by the nitrosovasodilator nitroprusside.
      Importantly, this load sensitivity is not associated with reflex increases in
      cardiac sympathetic activity.

PMID- 12464986
TI  - Donor management in cardiac transplantation.
AB  - The most important limitation in organ transplantation is donor availability.
      Canada is facing a serious situation with respect to organ donation rates and
      transplantation. The number of patients listed for heart transplant continues to
      increase while the number of available donors has plateaued. Several steps can be
      taken to address this growing mismatch. The proper identification and assessment
      of potential donors together with improvements in medical management may increase
      the donor pool. Additionally, the use of marginal donors and the development of
      new organ preservation techniques may lead to an increase in the number of
      potential heart transplants in Canada. This paper summarizes the identification,
      evaluation and management of heart transplant donors, and defines strategies to
      improve procurement activity in heart transplantation.

PMID- 12464987
TI  - Pacemaker-induced superior vena cava syndrome: a case report and review of
      management strategy.
AB  - A case of pacemaker-induced superior vena cava syndrome is presented with its
      management. A review of the physiopathology and therapeutic options is presented
      for this unusual clinical syndrome.

PMID- 12464989
TI  - Hypertension in pregnancy: Canadian momentum.

PMID- 12464990
TI  - The anatomy of guidelines.

PMID- 12464991
TI  - Aboriginal women and menopause.
AB  - OBJECTIVE: To determine the characteristics of menopause in Aboriginal women, in
      particular Canadian Aboriginal women. METHODS: An extensive review of articles
      extracted from both medical and non-medical databases was undertaken. The search
      strategy combined the key word "menopause" with any of the following terms:
      Aboriginals, Native Americans, Natives, Indians, Metis, Inuit, Eskimo, and
      Indigenous people. RESULTS: A total of 29 records were found, 13 of which had
      results relevant to the objective of the study. These articles suggest that
      menopause may have a positive effect on the lives of Aboriginal women with
      respect to increasing their freedom within the community. Aboriginal women appear
      to experience fewer vasomotor symptoms than other North American women.
      CONCLUSION: More research needs to be done to determine the effect menopause has
      on Canadian Aboriginal women and their coexisting diseases such as cardiovascular
      disease, hypertension, and diabetes mellitus. This work will allow health care
      providers to make more informed decisions on managing Aboriginal women's
      transition through menopause in areas such as hormone replacement therapy.

PMID- 12464992
TI  - Fall in mean arterial pressure and fetal growth restriction in pregnancy
      hypertension: an updated metaregression analysis.
AB  - OBJECTIVE: To update our previous analysis of randomized controlled trials in
      pregnancy hypertension, which discerned that greater treatment-induced decreases
      in maternal mean arterial pressure (MAP) appear to adversely affect fetal growth.
      METHODS: We conducted an English-language computer search of MEDLINE,
      Hypertension in Pregnancy, the relevant Cochrane reviews, and the bibliographies
      of retrieved papers, review articles, and standard obstetric and toxicology
      texts. Metaregression analysis was used to compare the change in MAP from
      enrollment to delivery with birth weight. RESULTS: Seven new trials with 335
      women were added to the 27 trials with 2305 women previously reported. No new
      trials reported on the frequency of small for gestational age infants. Treatment
      induced mean difference in MAP was associated with lower mean birth weight
      (slope: -17.55 [SD 6.67], r2 = 0.19, Spearman's non-parametric p = 0.031,
      Pearson's parametric p = 0.013). Therefore, over the range of reported mean
      differences in MAP, a 10 mm Hg fall in MAP was associated with a 176 g decrease
      in birth weight, and 19% of the birth weight difference between trials could be
      explained by differential blood pressure control. CONCLUSION: These results
      strengthen the association between blood pressure control and restricted fetal
      growth, and reinforce the need for new data to elucidate optimal antihypertensive
      use for mild to moderate pregnancy hypertension.

PMID- 12464993
TI  - The management of thrombophilia during pregnancy: a Canadian survey.
AB  - OBJECTIVE: To determine current Canadian practice patterns in the management of
      pregnant women with thrombophilia. METHODS: Physician members of the Society of
      Obstetricians and Gynaecologists of Canada (SOGC) who provide obstetrical care
      were invited to complete a closed-ended questionnaire in which they were
      presented 5 clinical scenarios involving thrombophilic pregnancies and asked to
      give their management recommendations. The 5 scenarios presented in the survey
      were of a pregnant woman with (1) asymptomatic factor V Leiden (FVL), (2)
      asymptomatic FVL and a family history of venous thromboembolism (VTE), (3) FVL
      and recurrent fetal loss, (4) FVL and a previous VTE, or (5) antiphospholipid
      antibody syndrome and recurrent fetal loss. RESULTS: Of the 1448 eligible SOGC
      members invited, 18 had moved with no forwarding address, and 662 (46.3% of the
      remainder) responded. The majority (65%) of the respondents were obstetricians
      and 51% of them had a university-affiliated practice. In scenario 1, 26% of
      physicians indicated they would recommend some form of antepartum
      thromboprophylaxis, whereas in the remaining four scenarios, 58% to 84% would
      definitely recommend antepartum thromboprophylaxis. CONCLUSION: Most clinicians
      favour intervening with thromboprophylaxis in pregnant thrombophilic women rather
      than observing without prophylaxis. This tendency spans a wide range of clinical
      scenarios, despite a lack of evidence to support such decisions. This survey
      highlights the need to provide clinicians and women with evidence for the safety
      and effectiveness of prophylaxis, before these interventions become the default
      recommendation by clinicians caring for this prevalent group of women.

PMID- 12464994
TI  - Acute uterine inversion: a review of 40 cases.
AB  - OBJECTIVE: To determine the incidence, complications, and risk of recurrence of
      acute uterine inversion. METHODS: A retrospective chart review was conducted of
      all cases of acute uterine inversion recorded at the Grace Maternity Hospital in
      Halifax, Nova Scotia, from 1977 to 2000. RESULTS: During the 24-year period
      studied, 40 cases of acute uterine inversion occurred following 125,081 births.
      The incidence of acute uterine inversion following vaginal birth was 1 in 3737,
      and following Caesarean section, 1 in 1860. Post-partum hemorrhage complicated
      65% of cases of acute uterine inversion, and 47.5% required blood transfusion.
      There was no recurrence in 26 subsequent deliveries. Following the institution of
      active management of the third stage of labour in 1988, the incidence of acute
      uterine inversion following vaginal delivery fell 4.4-fold. CONCLUSION: Acute
      uterine inversion is rare but accompanied by high risk of postpartum hemorrhage
      and the need for blood transfusion. Active management of the third stage of
      labour may reduce the incidence of uterine inversion.

PMID- 12464995
TI  - The quality of obstetrical clinical practice guidelines promulgated by a
      specialty society.
AB  - OBJECTIVE: To review the methodologic quality of all obstetrical clinical
      practice guidelines developed by the Society of Obstetricians and Gynaecologists
      of Canada (SOGC) from 1992 to August 2001. METHODS: Three reviewers independently
      assessed each of 37 guidelines according to a validated and reliable 37-item
      appraisal tool. A mean "global" score as well as three "dimension" scores were
      calculated for each guideline. The appraisal tool assessed each document
      according to three dimensions, which related to the rigour of its development
      (Dimension 1), its context and content (Dimension 2), and its application
      (Dimension 3). A repeated-measures analysis of variance was used to derive the
      interclass correlation coefficient. RESULTS: Mean global quality scores ranged
      from 8.1% to 54.0%. Only two guidelines were given a mean global score above 50%
      and 21 of the guidelines (56.8%) had mean global scores of less than 30%. Mean
      dimension scores were 19.9% for Dimension 1, relating to rigour of development,
      47.3% for Dimension 2, relating to context and content, and 27.2% for Dimension
      3, relating to application. The interclass correlation coefficient using a fixed
      effects model was 0.72, reflecting reasonable agreement between the reviewers.
      CONCLUSION: Both the mean global scores and mean dimension-specific scores for
      the obstetrical clinical practice guidelines were lower than optimal. We were
      unable to reveal statistically significant improvements in guideline quality over
      time given the limited number of documents, but the scores for more recently
      drafted guidelines appear generally higher than earlier guidelines. This finding
      is consistent with new editorial policy adopted by the SOGC regarding guideline
      development. A broader review should be conducted by the SOGC on guidelines in
      development and under revision.

PMID- 12464996
TI  - Ovarian thecoma associated with a large quantity of ascites and elevated serum CA
      125 and CA 15-3.
AB  - BACKGROUND: Elevation of tumour marker CA (cancer antigen) 125 associated with
      Meigs' or atypical Meigs' syndrome is widely recognized. Other tumour markers are
      available to assist in distinguishing between benign and malignant ovarian masses
      in the preoperative diagnosis. CASE PRESENTATION: A 57-year-old woman presented
      with a suspicious pelvic mass and abundant ascites. Preoperative tumour markers
      CA 125 and CA 15-3 were elevated at 1750 U/mL and 60 U/mL, respectively. The
      woman underwent surgery, and 9 L of straw-coloured ascites were drained along
      with a solid-cystic ovarian mass. The final pathology disclosed an ovarian
      thecoma. Six months later, both tumour markers were normal. CONCLUSION: This
      first report of 2 elevated tumour markers associated with atypical Meigs'
      syndrome cautions us not to rely on tumour markers to differentiate benign from
      malignant masses.

PMID- 12464998
TI  - The lure of the 80-hour work week.

PMID- 12464997
TI  - NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of
      Weaver syndrome but are rare in other overgrowth phenotypes.
AB  - Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive
      facial appearance, height and head circumference >97th percentile, advanced bone
      age, and developmental delay. Weaver syndrome is characterized by the same
      criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb
      chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause
      of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of
      cases. We evaluated 75 patients with childhood overgrowth, for intragenic
      mutations and large deletions of NSD1. The series was phenotypically scored into
      four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was
      typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but
      with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and
      patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor
      Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8
      nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1
      functions. The truncating mutations were spread throughout NSD1, but there was
      evidence of clustering of missense mutations in highly conserved functional
      domains between exons 13 and 23. There was a strong correlation between presence
      of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in
      group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4
      had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1
      mutations, all between amino acids 2142 and 2184. We conclude that intragenic
      mutations of NSD1 are the major cause of Sotos syndrome and account for some
      Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.

PMID- 12464999
TI  - Clinical evaluation of patients with temporomandibular joint implants.
AB  - PURPOSE: An undetermined number of patients with temporomandibular joint (TMJ)
      symptoms have been treated with intra-articular disc implants composed of Teflon
      ethylene/propylene or Teflon polytetrafluoroethylene and aluminum oxide (Proplast
      Teflon; Vitek, Houston, TX). These implants have shown the potential to fragment
      in situ resulting in nonbiodegradable particles that stimulate a giant cell
      reaction and lead to degeneration of local structures, pain, and limitation of
      mandibular opening. We examined the possible relationship between TMJ implants
      and persistent pain, responses to sensory stimuli, quality of life, and systemic
      immune dysfunction. PATIENTS AND METHODS: This case series (32 patients) were
      referred from university-based orofacial pain centers and private practices from
      across the United States. Laboratory and clinical assessments evaluated orofacial
      pain symptoms, neurologic function, clinical signs and symptoms of rheumatologic
      disease, physical function, systemic measures of immune function, and behavioral
      measures. RESULTS: We found that TMJ implant patients appeared to have altered
      sensitivity to sensory stimuli, a higher number of tender points with a diagnosis
      of fibromyalgia, increased self-report of chemical sensitivity, higher
      psychologic distress and significantly lower functional ability. Systemic illness
      or autoimmune disease was not evident in this series of TMJ implant patients.
      CONCLUSIONS: Significant problems were noted on clinical assessment of TMJ
      implant patients. This is a US government work. There are no restrictions on its
      use.

PMID- 12465000
TI  - Long-term study of temporomandibular joint surgery with alloplastic implants
      compared with nonimplant surgery and nonsurgical rehabilitation for painful
      temporomandibular joint disc displacement.
AB  - PURPOSE: The purpose of this study was to determine the long-term objective and
      subjective outcomes of temporomandibular joint (TMJ) implant surgery for the
      treatment of painful TMJ disc displacement using temporary Silastic (Dow Corning
      Corporation, Midland, MI), permanent Silastic, or Proplast (Vitek, Houston, TX)
      implants to replace the disc. These cases were compared with other cases of the
      same diagnosis treated with either nonsurgical rehabilitation or nonimplant
      surgery involving discectomy or disc repair procedures. MATERIALS AND METHODS: A
      cross-sectional study was conducted among 466 patients who received treatment for
      unilateral or bilateral TMJ disc displacement before January 1, 1990. The 5
      treatment groups noted above were compared for long-term outcomes. Objective
      outcome measurements for jaw function were performed using a calibrated examiner
      and the Craniomandibular Index (CMI). Subjective (self-reported) outcomes were
      obtained relative to jaw function (Mandibular Function Impairment Questionnaire
      [MFIQ]), symptom severity (Symptom Severity Index [SSI]), and the impact of pain
      (Global Pain Impact [GPI] scale). RESULTS: The results, adjusted for gender,
      baseline tomogram score, and baseline symptom scores, showed that the nonsurgical
      rehabilitation group (n = 159) and the group having TMJ surgery without implants
      (n = 149) had statistically better results than the group who underwent surgery
      with a Proplast implant (n = 94). These between-group differences included both
      objective signs (CMI), and subjective reports of jaw function (MFIQ), symptom
      severity (SSI), and global pain impact (GPI). The MFIQ score associated with the
      nonsurgical rehabilitation group was also statistically better than for the
      Silastic implant groups, including both the temporary (n = 31) and permanent (n =
      33) implants. Clinical differences between groups were slight. CONCLUSION: This
      study suggests that the use of interpositional disc implants in TMJ surgery is
      not associated with improved outcomes when compared with nonimplant surgery or
      nonsurgical rehabilitation.

PMID- 12465002
TI  - Treatment of orbital floor blowout fractures with conchal auricular cartilage
      graft: a report on 14 cases.
AB  - PURPOSE: We sought to present follow-up on 14 cases in which conchal cartilage
      graft was used to span small orbital floor defects (up to 2 x 2 cm). MATERIALS
      AND METHODS: Fourteen patients with orbital floor blowout fractures were included
      in the study; in 8 cases, there was associated fracture of the inferior orbital
      rim. The decision to proceed surgically was based on the presence of at least one
      of the following conditions: diplopia, enophthalmos, herniation of orbital
      tissues through gaps in the orbital floor bone, and concomitant displacement of
      bone fragments of the inferior orbital rim. Auricular cartilage was used in all
      cases. Access to the orbital floor was via subtarsal incision unless a laceration
      was present and useable. RESULTS: The incidence of clinical signs during follow
      up and the surgical complications found (1 case of entropion, 1 case of palpebral
      edema) are fully comparable with those reported in the literature; they do not
      appear to be correlated to the use of a cartilage graft. CONCLUSIONS: The use of
      auricular cartilage has wide application for small orbital floor defects. The
      conchal graft is easy to harvest. It provides an optimal support function for the
      globe with minimum donor-site morbidity. A graft of adequate size ensures
      adequate stability.

PMID- 12465003
TI  - Combined approach to impacted parotid stones.
AB  - PURPOSE: This article describes the use of combined endoscopic and ultrasound
      approach to locate and to extract impacted parotid stones, which cannot be
      retrieved by intraoral approach alone. PATIENTS AND METHODS: A total of 12
      parotid glands from 7 women and 5 men (age range, 35 to 62 years) with parotid
      sialoliths were treated with the combined method. Eleven of 12 of the procedures
      were performed under local anesthesia in an outpatient clinic. The identification
      of the calculi was done in 5 patients with 1.3-mm sialoendoscope (Nahlieli
      Sialoendoscope; Karl Storz, Tuttlingen, Germany) in 6 patients with the aid of
      high-resolution ultrasound, and in 1 patient the location was combined endoscopy
      and ultrasound. The removal of the calculi was performed extraorally via minimal
      incision. The indications for the combined approach were 1) calculus in the
      posterior third of the Stensen's duct with too narrow duct anterior to it, 2)
      obstruction of the posterior or middle third of the Stensen's ducts leading to
      the calculus, 3) large (>5-mm) stones in the middle or posterior part of the duct
      that cannot be dilated for intraductal removal, and 4) intraparenchymal stones.
      RESULTS: Of the 12 patients, 9 had complete removal (75%); in 1 case with 3
      sialoliths, we removed 2 and the gland remained asymptomatic. In 7 cases, the
      glands returned to function, 3 glands became atrophic with no function, but the
      gland remained asymptomatic. The aesthetic results were satisfactory in all
      cases, no major complications were noted. CONCLUSIONS: Combined endoscopic
      ultrasound approach is another minimal invasive technique for identification and
      removal of impacted parotid sialolithiasis.

PMID- 12465004
TI  - Condylar and temporomandibular joint disc positions after mandibular osteotomy
      for prognathism.
AB  - PURPOSE: The purpose of this study was to compare the changes in
      temporomandibular joint (TMJ) morphology and clinical symptoms after sagittal
      split ramus osteotomy (SSRO) and intraoral vertical ramus osteotomy (IVRO) with
      and without a Le Fort I osteotomy. PATIENTS AND METHODS: Of 43 patients with a
      diagnosed jaw deformity, 20 underwent IVRO without internal fixation and 23
      underwent SSRO with rigid internal fixation. Some operations were performed in
      combination with a Le Fort I osteotomy. The TMJ symptoms and joint morphology,
      including the disc position, were assessed preoperatively and postoperatively
      using magnetic resonance imaging (MRI) and axial cephalography. RESULTS: A
      significant difference in the direction of condylar rotation was seen in
      horizontal axial cephalography images (P <.01). Fewer or no TMJ symptoms were
      reported postoperatively by 88% of the patients who underwent IVRO with or
      without a Le Fort I osteotomy and by 66.7% of patients who underwent SSRO with or
      without a Le Fort I osteotomy. In sagittal images, no change was seen in anterior
      disc displacement after SSRO; however, improvement was seen in 44.4% of patients
      with anterior disc displacement who underwent IVRO with or without a Le Fort I
      osteotomy. CONCLUSION: These results suggest that SSRO does not improve anterior
      disc displacement; IVRO improves anterior disc displacement in the initial
      postsurgical period, and both procedures may improve TMJ symptoms.

PMID- 12465006
TI  - Management of fractured mandibles without the use of intermaxillary wire
      fixation.
AB  - PURPOSE: The aims of this retrospective clinical study were to compare the
      management of unilateral angle fractures of the mandible using the traditional
      approach of open reduction with internal fixation (ORIF) and intermaxillary wire
      fixation (IMF) with the technique of ORIF without IMF. PATIENTS AND MATERIALS:
      Thirty-one patients who presented with isolated unilateral angle fractures of the
      mandible were randomly divided into 2 treatment groups. Both groups underwent
      open reduction with a single upper border miniplate and screw fixation (ORIF).
      Eleven of the 31 patients in the study had IMF to aid in the fracture reduction,
      and 20 patients had no IMF so the fracture was reduced by hand manipulation.
      Records of operating and discharge times, postreduction radiographs, and occlusal
      outcomes were examined and tabulated. RESULTS: Patients in both treatment groups
      were closely matched in terms of age, gender, site of injury (ie, isolated angle
      fracture of mandible), and incidence of teeth in the fracture line. The mean
      operating time for traditional ORIF with IMF of angle fractures of the mandible
      was 98.5 minutes, and these patients were discharged an average of 1.82 days
      after surgery. The mean operating time for ORIF of angle fractures of the
      mandible without the use of IMF was 40.2 minutes, and these patients were
      discharged an average of 1.35 days after surgery. Postoperative outcomes in terms
      of the postreduction anatomic alignment of the fractures and functional occlusion
      at 6 weeks were similar in the 2 treatment groups. CONCLUSIONS: We found that the
      use of IMF for the management of angle fractures of the mandible is unnecessary
      provided there is a skilled assistant present to help manually reduce the
      fracture site for plating. Discarding the use of IMF not only helps improve
      patient comfort but also reduces the operating time by up to 1 hour and
      accelerates discharge times by up to half a day.

PMID- 12465008
TI  - Long-term follow-up of the CAD/CAM patient fitted total temporomandibular joint
      reconstruction system.
AB  - PURPOSE: The purpose of this study was the assessment of the long-term safety and
      effectiveness of the Techmedica (Camarillo, CA) CAD/CAM Total Temporomandibular
      Joint Reconstruction System (now called the TMJ Concepts Patient Fitted Total
      Temporomandibular Joint Reconstruction System, Ventura, CA). PATIENTS AND
      METHODS: A survey was mailed to the available addresses of 170 (79%) of the 215
      patients who had been implanted with the Techmedica System devices between 1990
      and 1994. Seventy-nine (46%) surveys were returned by the US Postal Service as
      undeliverable. Three patients (1.4%) were reported as deceased in returns from
      relatives. Therefore, of the remaining 91 possible responses, 60 (65.9%) were
      returned. Fifty-eight (58) surveys, considered complete and valid (96.7%),
      representing 97 (39 bilateral, 19 unilateral) devices with a mean follow-up of
      107.4 +/- 15.5 months (range, 60 to 120 months) were analyzed. Subjective data
      related to pain, mandibular function, diet consistency, and present quality of
      life were collected using visual analog scales. Objective measures of mandibular
      interincisal opening and lateral excursions were obtained from direct
      measurements using the Therabite (Therabite, Philadelphia, PA) measuring scale
      provided in the survey with instructions as to its use. RESULTS: Analysis of the
      subjective data at 10 years revealed a 76% reduction in mean pain scores and a
      68% increase in mean mandibular function and diet consistency scores (P <.0001).
      Analysis of objective data revealed a 30% improvement in mandibular range of
      motion after 10 years (P =.0009). Long-term quality of life improvement scores
      were statistically related to the number of prior temporomandibular joint
      operations the patients had undergone. CONCLUSION: These data indicate that the
      CAD/CAM Patient Fitted Total Temporomandibular Joint Reconstruction System has
      proved to be a safe and effective long-term management modality in the patient
      population surveyed for this study.

PMID- 12465009
TI  - Comparison of calcium alginate film with collagen membrane for guided bone
      regeneration in mandibular defects in rabbits.
AB  - PURPOSE: We sought to compare calcium alginate film (CAF) with collagen membrane
      (CM) regarding their effects on guided bone regeneration. MATERIALS AND METHODS:
      Circular bone defects with 5-mm diameter were created in the region anterior to
      both mandibular angles in 34 rabbits. The defects on one side were covered with a
      CAF, and the contralateral side with CM. Healing condition was analyzed with
      gross, radiographic, electromicroscopic, histologic, and immunohistochemical
      studies and image pattern analysis system after 1, 2, 4, 6, and 8 weeks. RESULTS:
      CM absorbed more slowly but collected fewer osteoinductive factors (P <.05) in
      the early period. CAF induced dense bone formation, whereas CM produced less
      newly formed bone. CONCLUSION: CAF is more efficacious than CM in guided bone
      regeneration in this animal model.

PMID- 12465010
TI  - Expression of type 2 nitric oxide synthase and vascular endothelial growth factor
      in oral dysplasia.
AB  - PURPOSE: The small molecule nitric oxide (NO), produced by a family of enzymes
      called NO synthase (NOS), has a diverse array of functions in both physiologic
      and pathologic states. Prolonged production of NO by the isoform NOS2 has been
      implicated in human cancer progression. NO has an important role in angiogenesis,
      being both an upstream signal and a downstream effector molecule to vascular
      endothelial growth factor (VEGF). The latter group of proteins are crucial for
      vascular endothelial cell proliferation and permeability. The expression of VEGF
      increases with cancer progression. Because angiogenesis is a prerequisite for the
      development of invasive cancer, this immunohistochemical study investigated the
      expression of NOS2 and VEGF in oral epithelial dysplasia. MATERIALS AND METHODS:
      An immunohistochemical study was performed using monoclonal antibodies to NOS2
      and VEGF on archival formalin-fixed, paraffin-embedded tissue of 33 cases of oral
      dysplasia. RESULTS: A significant correlation was found between NOS2 and VEGF
      expression in oral dysplasia (P <.001). Expression of both NOS2 and VEGF also
      correlated with the severity of dysplasia (P <.001, P <.002). CONCLUSIONS: These
      findings may provide further understanding to the complex transformation of oral
      epithelial dysplasia to invasive carcinoma and the role of angiogenesis in this
      process.

PMID- 12465011
TI  - Growth of the mandible after replacement of the mandibular condyle: an
      experimental investigation in Macaca mulatta.
AB  - PURPOSE: The study goal was to investigate growth of the mandible after
      temporomandibular joint reconstruction in juvenile monkeys. MATERIALS AND
      METHODS: Sixteen juvenile monkeys (Macaca mulatta) were used as experiment
      subjects. Animals were equally divided into 4 experimental groups based on the
      method of temporomandibular joint reconstruction after bilateral condylar
      excision via extraoral vertical ramus osteotomies. Group Condyle animals had
      their condylar segments immediately replaced to serve as surgical controls. Group
      Bone animals were reconstructed with a bony strut. Group sternoclavicular joint
      (SCJ) animals were reconstructed with the sternal end of their clavicles. Group
      costochondral junction (CCJ) animals were reconstructed with costochondral
      junction of ribs. Standardized lateral cephalometric radiographs with the aid of
      tantalum bone markers were used to evaluate mandibular growth. Twenty animals
      were used as controls and were allowed to grow undisturbed for an 18-month period
      (Group Control). RESULTS: All animals showed good mandibular function and a Class
      I molar relationship after an 18-month follow-up period. Statistical and graphic
      comparisons showed no significant difference in mandibular growth among any of
      the groups. CONCLUSIONS: The results of this investigation suggest that, within
      the limits of this model, the choice of autograft for condyle replacement may be
      irrelevant.

PMID- 12465013
TI  - Large cervical mass in an 8-month-old infant.

PMID- 12465014
TI  - Management of the pregnant oral and maxillofacial surgery patient.

PMID- 12465015
TI  - Metastatic chordoma to the mandibular condyle: an anterior surgical approach.

PMID- 12465016
TI  - Subacute necrotizing sialadenitis in the buccal mucosa.

PMID- 12465017
TI  - Metastatic esophageal adenocarcinoma involving the maxilla.

PMID- 12465018
TI  - Ophthalmoplegia and ptosis as onset symptoms of an isolated primary mucocele of
      the sphenoid sinus.

PMID- 12465019
TI  - Postobstructive pulmonary edema in an obese child after an oral surgery procedure
      under general anesthesia: a case report.

PMID- 12465020
TI  - Comma incision for impacted mandibular third molars.

PMID- 12465021
TI  - Alveolar ridge osteogenesis using 2 intraosseous distractors: uniform and
      nonuniform distraction.

PMID- 12465022
TI  - Paradental cyst: vital tooth pulp tests "nonvital".

PMID- 12465023
TI  - Future trends in OMS surgical practice.

PMID- 12465025
TI  - Aspects of nucleosomal positional flexibility and fluidity.
AB  - Nucleosomes have been considered until recently to be stable and uniquely
      localized particles. We focus here on two properties of nucleosomes that are
      emerging as central attributes of their functions: mobility and multiplicity of
      localization. The biological relevance of these phenomena is based on the fact
      that chromatin functions depend on the relative stability of nucleosomes, on
      their covalent or conformational modifications, their dynamics, their
      localization, and the density of their distribution. In order to understand these
      complex behaviors both the structure of the nucleosome core particles and the
      informational rules governing their interaction with defined DNA sequences are
      here taken into consideration. The fact that nucleosomes solve the problem of how
      to locate a specific interaction site on a potentially infinite combination of
      sequences, with interactions recurring to a controlled level of informational
      ambiguity and stochasticity, is discussed. Nucleosomes have been shown to slide
      along DNA. This novel facet of their behavior and its implications in chromatin
      remodeling are reviewed.

PMID- 12465026
TI  - Lipoconjugates for the noncovalent generation of microarrays in biochemical and
      cellular assays.
AB  - The generation of microarrays by functionalization of hydrophobic glass surfaces
      with conjugates of triacylated lipophilic end-groups and with a peptide or hapten
      as a test substance is presented. Immobilization on the hydrophobic surfaces
      through the triacylated anchor group is fully orthogonal to the reactivity of
      functional groups within the test substances. The technique is therefore free of
      risk that reactions of these functional groups may influence the biological
      activity of the test compounds in screening applications. In addition, no
      preactivation of either the surface or the compounds is required. Reagents and
      substrates may be stored at ambient conditions for long periods of time. The
      lipoconjugates are administered from aqueous solution enabling automated
      nanopipetting down to spot dimensions of 100 microm across. The microstructures
      are stable with respect to the conditions of biochemical assays and applications
      in cell biology. Due to the hydrophobicity of the nonfunctionalized surfaces,
      standard blocking protocols used in microtiter-plate testing can be employed,
      thereby inhibiting nonspecific binding of assay reagents. Generation of these
      microstructures on hydrophobic glass slides or coverslips enables highly
      sensitive multichannel read-outs with high-resolution fluorescence microscopy.

PMID- 12465027
TI  - Mutational analysis of the kinetics and thermodynamics of transcription factor NF
      kappaB homodimerisation.
AB  - Dimeric transcription factors of the NF-kappaB/Rel family are sequence-specific
      DNA-binding proteins that mediate the inducible expression of immunologically
      important eukaryotic genes by competing for kappaB sites. The kinetic and
      thermodynamic components of these interactions were probed by mutation of the
      subunit interface of the p50 homodimer, a paradigm for other family members.
      Guided by the crystal structure, we selected the side chains of five key residues
      (R255, Y270, L272, A311 and V313) for individual and combinatorial truncation,
      with the aim of generating a mutant panel. Homodimerisation was assessed
      indirectly by measurement of DNA binding with an optical biosensor in order to
      unmask the relative contributions of each residue. Surface plasmon resonance
      revealed that a unanimous bias for a palindromic kappaB site over an asymmetric
      one was mainly the result of a slower dissociation rate for the DNA/homodimer
      complex in the case of the palindromic kappaB site. Y270 and L272 were
      individually the most critical residues in homodimerisation. DNA binding was
      abolished when all five residues were substituted, which reinforces the notion
      that only a subset of residues contributes crucial dimer-forming contacts. The
      role of Y270 was unique, since its mutation to glycine dramatically slowed both
      the association and dissociation rates for DNA binding. Surprisingly, R255 was
      shown to be of little importance in the stability of the p50 homodimer, despite
      its apparent participation in a salt bridge at the dimer interface. Our results
      suggest that binding modes inferred from structural data should be treated
      cautiously.

PMID- 12465028
TI  - A structural model of the complex formed by phospholamban and the calcium pump of
      sarcoplasmic reticulum obtained by molecular mechanics.
AB  - Phospholamban (PLN) is an intrinsic membrane protein of 52 amino acids that
      modulates the activity of the reticular Ca(2+) ion pump. We recently solved the
      three-dimensional structure of chemically synthesized, unphosphorylated,
      monomeric PLN (C41F) by high-resolution nuclear magnetic resonance spectroscopy
      in chloroform/methanol. The structure is composed of two alpha-helical regions
      connected by a beta turn (Type III). We used this structure and the
      crystallographic structure of the sarcoplasmic reticulum calcium pump (SERCA)
      recently determined by Toyoshima and co-workers and modeled into its E(2) form by
      Stokes (1KJU) or by Toyoshima (1FQU). We applied restrained and unrestrained
      energy optimizations and used the AMBER molecular mechanics force field to model
      the complex formed between PLN and the pump. The results indicate that
      transmembrane helix 6 (M6) of the SERCA pump is energetically favored, with
      respect to the other transmembrane helices, as the PLN binding partner within the
      membrane and is the only one of these helices that also permits contact between
      the N-terminal residues of PLN and the critical cytosolic binding loop region of
      the pump. This result is in agreement with published biochemical data and with
      the predictions of previous mutagenesis work on the membrane sector of the pump.
      The model reveals that PLN does not span the entire width of the membrane, that
      is, its hydrophobic C-terminal end is located near the center of the
      transmembrane region of the SERCA pump. The model also shows that interaction
      with M6 is stabilized by additional contacts made by PLN to M4. The contact
      between the N-terminal portion of PLN and the pump is stabilized by a number of
      salt and hydrogen-bond bridges, which may be abolished by phosphorylation of PLN.
      The contacts between the cytosolic portions of PLN and the pump are only observed
      in the E(2) conformation of the pump. Our model of the complex also offers a
      plausible structural explanation for the preference of protein kinase A for
      phosphorylation of Ser16 of PLN.

PMID- 12465029
TI  - Glycopeptide specificity of helper T cells obtained in mouse models for
      rheumatoid arthritis.
AB  - Five protected analogues of beta-D-galactosyl-(5R)-5-hydroxy-L-lysine were
      prepared, in which the galactosyl moiety was modified by monodeoxygenation or
      inversion of stereochemistry at C-4. The building blocks were used in the solid
      phase synthesis of a set of glycopeptides related to the peptide fragment CII256
      273 from type II collagen. Evaluation of the glycopeptides revealed that T-cell
      hybridomas obtained in collagen-induced arthritis (CIA), which is a common mouse
      model for rheumatoid arthritis, recognized the galactosyl moiety with high
      specificity for individual hydroxy groups. Moreover, T-cell hybridomas obtained
      in a humanized variant of CIA were also found to recognize the glycopeptides in
      an equally carbohydrate-specific manner. The results allowed the generation of
      models of the complexes formed between the appropriate class II major
      histocompatibility complex (MHC) molecule, glycopeptide, and the T-cell receptor,
      that is, of an interaction that is critical for the stimulation of T cells in the
      arthritis models. In the structural models, peptide side chains anchor the
      glycopeptide in pockets in the class II MHC molecule, whereas the galactosylated
      hydroxylysine residue forms the key contacts with the T-cell receptor.
      Importantly, the results also suggest that a T-cell response towards glycopeptide
      fragments from type II collagen could play an important role in the development
      of rheumatoid arthritis in humans.

PMID- 12465030
TI  - Novel paromamine derivatives exploring shallow-groove recognition of ribosomal
      decoding-site RNA.
AB  - Natural aminoglycoside antibiotics recognize an internal loop of bacterial
      ribosomal-decoding-site RNA by binding to the deep groove of the RNA structure.
      We have designed, synthesized, and tested RNA-targeted paromamine derivatives
      that exploit additional interactions on the shallow groove face of the decoding
      site RNA. An in vitro transcription-translation assay of a series of 6'
      derivatives showed the 6'-position to be very sensitive to substitution. This
      result suggests that the group at the 6'-position plays a pivotal role in RNA
      target recognition.

PMID- 12465031
TI  - Dissecting the streptavidin-biotin interaction by phage-displayed shotgun
      scanning.
AB  - Shotgun scanning the streptavidin-biotin interaction identifies long-range
      hydrophobic interactions that contribute to one of the strongest naturally
      occurring noncovalent protein-ligand interactions. The femtomolar dissociation
      constant for this interaction makes it a useful model system to dissect the
      forces that govern high-affinity molecular recognition between proteins and small
      molecules. Shotgun scanning combines the diversity and in vitro binding selection
      of phage-displayed libraries with a binomial mutagenesis strategy. Libraries
      consist of proteins with the residues in multiple positions mutated to give a 1:1
      ratio of alanine:wild type. Here, we use shotgun scanning to determine the
      functional contribution of the 38 C-terminal residues of streptavidin to the high
      affinity interaction with biotin. The library pools were subjected to three
      rounds of selection for functional streptavidin variants that bind biotin and
      statistical analysis was used to assess side-chain contributions to biotin
      binding. The results demonstrate the utility of shotgun scanning for the
      dissection of receptor-small-molecule interactions. While shotgun scanning
      results were largely consistent with previous single-point, site-directed
      mutagenesis studies for residues in direct contact with biotin, residues distant
      from the biotin binding site have not previously been explored. Key streptavidin
      residues identified by shotgun scanning as contributors to the interaction with
      biotin include those with side chains that fill the beta barrel, residues at the
      tetramer interface, and second-sphere residues, which are reinforced by long
      distance propagation of hydrophobic interactions.

PMID- 12465032
TI  - Tight binding of the antitumor drug ditercalinium to quadruplex DNA.
AB  - The structural selectivity of the DNA-binding antitumor drug ditercalinium was
      investigated by competition dialysis with a series of nineteen different DNA
      substrates. The 7H-pyridocarbazole dimer was found to bind to double-stranded DNA
      with a preference for GC-rich species but can in addition form stable complexes
      with triplex and quadruplex structures. The preferential interaction of the drug
      with four-stranded DNA structures was independently confirmed by electrospray
      mass spectrometry and a detailed analysis of the binding reaction was performed
      by surface plasmon resonance (SPR) spectroscopy. The BIAcore SPR study showed
      that the kinetic parameters for the interaction of ditercalinium with the human
      telomeric quadruplex sequence are comparable to those measured with a duplex
      sequence. Slow association and dissociation were observed with both the
      quadruplex and duplex structures. The newly discovered preferential binding of
      ditercalinium to the antiparallel quadruplex sequence d(AG(3)[T(2)AG(3)](3))
      provides new perspectives for the design of drugs that can bind to human
      telomeres.

PMID- 12465033
TI  - Stereochemical course of Escherichia coli RNase H.
AB  - A new enzymatic method has allowed the assignment of the stereochemistry of E.
      coli RNase-H-assisted hydrolysis of RNA labelled within the scissile bond with
      (R(p))-phosphorothioate. This method is based on a stereospecific, two-step
      enzymatic conversion of cytidine 5'-[(18)O]phosphorothioate into the
      corresponding 5'-alpha-[(18)O]thiotriphosphate, which is then further used for
      stereospecific transfer of cytidine 5'-[(18)O]phosphorothioate to the 3'-OH group
      of a short oligonucleotide with the aid of terminal deoxyribonucleotidyl
      transferase. Matrix-assisted laser desorption/ionisation time-of-flight mass
      spectrometry of the resulting elongated primer revealed that RNase-H-assisted
      hydrolysis proceeds with inversion of configuration at the phosphorus atom. This
      result is discussed in the context of current knowledge of the architecture of
      the active site of the enzyme.

PMID- 12465034
TI  - A parallel synthesis scheme for generating libraries of DNA polymerase substrates
      and inhibitors.
AB  - We report a combinatorial approach aimed at producing in a single step a large
      family of nucleoside triphosphate derivatives that could be tested for their
      ability to be substrates for DNA polymerases. We propose as a unique triphosphate
      building block a nucleotide with a hydrazine function anchored to an imidazole
      ring. Condensation between the 5'-triphosphate derivative of 1-(2-deoxy-beta-D
      erythro-pentofuranosyl)-imidazole-4-hydrazide (dY(NH(2))TP) and any aldehyde or
      ketone, followed by reduction of the intermediate hydrazones dXmTP, resulted in
      the corresponding hydrazides (dXnTP). Following this scheme, a series of
      aldehydes having various aromatic parts yielded a number of adducts dY(NHR)TP.
      Vent (exo-) DNA polymerase is found to be able to catalyse the single
      incorporation of these bulky triphosphate derivatives. Subsequent extensions of
      the modified pairs with canonical triphosphates resulted mainly in abortive
      elongations at primer+2, except after the incorporation of dY(NHben)TP and, to a
      lesser extent, dY(NHphe)TP opposite C. These results illustrate the potential of
      this parallel synthetic scheme for generating new substrates or inhibitors of
      replication in a single step.

PMID- 12465035
TI  - Improving antisense oligonucleotide binding to human serum albumin: dramatic
      effect of ibuprofen conjugation.

PMID- 12465036
TI  - A signal released by an endophytic attacker acts as a substrate for a rapid
      defensive reaction of the red alga Chondrus crispus.

PMID- 12465037
TI  - A short Aib/Ala-based peptide helix is as stable as an Ala-based peptide helix
      double its length.

PMID- 12465038
TI  - Fluorinated protective groups for on-resin quantification of solid-phase
      oligosaccharide synthesis with 19F NMR spectroscopy.

PMID- 12465041
TI  - TNFalpha downregulates PPARdelta expression in oligodendrocyte progenitor cells:
      implications for demyelinating diseases.
AB  - TNFalpha has been implicated in several demyelinating disorders, including
      multiple sclerosis (MS) and X-adrenoleukodystrophy (X-ALD). TNFalpha abundance is
      greatly increased in the areas surrounding damaged regions of the central nervous
      system of patients with MS and X-ALD, but its role in the observed demyelination
      remains to be elucidated. A class of nuclear receptors, the peroxisome
      proliferator-activated receptors (PPARs), has been implicated in several
      physiological and pathological processes. In particular, PPARdelta has been shown
      to promote oligodendrocyte (OL) survival and differentiation and PPARgamma has
      been implicated in inflammation. In the present study, we investigate on the
      effects of TNFalpha on OLs during differentiation in vitro. The results obtained
      show that TNFalpha treatment impairs PPARdelta expression with concomitant
      decrease of lignocerolyl-CoA synthase and very-long-chain fatty acid beta
      oxidation as well as plasmalogen biosynthesis. We propose a hypothetical model
      possibly explaining the perturbation effects of proinflammatory cytokines on
      myelin synthesis, maturation, and turnover.

PMID- 12465042
TI  - Induction of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide-stimulated
      primary astrocytes is mediated by extracellular signal-regulated protein kinase
      1/2 (Erk1/2).
AB  - In the present study, we investigated whether the activation of protein kinase C
      (PKC) and extracellular signal-regulated kinase 1/2 (Erk1/2) are involved in the
      induction of MMP-9 in lipopolysaccharide (LPS)-stimulated primary astrocytes. The
      expression of MMP-9 but not MMP-2 was increased by LPS. LPS treatment induced
      activation of Erk1/2 within 30 min, which was dose-dependently inhibited by
      PD98059, a specific inhibitor of the Erk kinase (MEK). In this condition, PD98059
      blocked the increase in MMP-9 protein and mRNA level as well as gelatin-digesting
      activity. Inhibition of PKC activity blocked the LPS-induced activation of Erk1/2
      as well as MMP-9 expression. In addition, activation of PKC by phorbol myristoyl
      acetate (PMA) activated Erk1/2 with concomitant increase in MMP-9 production.
      Moreover, treatment of PD98059 dose-dependently decreased the PMA-induced MMP-9
      expression. The results from the present study suggest that induction of MMP-9 by
      LPS in rat primary astrocytes is mediated, at least in part, by the sequential
      activation of PKC and Erk1/2. The Erk1/2-mediated MMP-9 induction may provide
      insights into the regulation of MMP-9 production in CNS, which may occur in vivo
      in pathological situations such as CNS inflammation.

PMID- 12465043
TI  - Spatiotemporal gradient of oligodendrocyte differentiation in chick optic tectum
      requires brain integrity and cell-cell interactions.
AB  - The development of oligodendrocytes in the chicken optic tectum (OT) was studied
      in vivo and in vitro by analyzing expression of myelin-associated glycoprotein
      (MAG) with a monoclonal antibody. MAG(+) cells first appeared in the anterior OT
      on embryonic day (E) 12, were present throughout the anterior half on E15, and
      eventually filled the tectum on E17. This spatiotemporal appearance of MAG(+)
      oligodendrocytes resembled two streams of cells entering the OT along the
      afferent and efferent axonal layers. However, experiments determined that this
      appearance of MAG immunoreactivity was the result of a gradient of
      oligodendrocyte differentiation and was not cell migration. First, retroviral
      vector labeling of OT progenitors in vivo on E3 resulted in labeled
      oligodendrocytes in late embryos. In addition, pieces of OT from as early as E3
      kept in culture for a week developed numerous MAG(+) oligodendrocytes. Pieces of
      both anterior and posterior E7 OT developed MAG(+) oligodendrocytes after 3 days
      in culture, well ahead of their normal schedule in vivo. BrdU incorporation
      studies revealed that these cells were not born in culture, but merely
      differentiated. Monolayer cultures made from dissociated E10 or later OT cells
      developed MAG(+) oligodendrocytes, but monolayers made from E7 OT cells did not.
      These experiments demonstrate that oligodendrocyte progenitors were present in
      the OT as early as E3, that they could differentiate precociously, and that their
      normal progressive differentiation in situ must be due to removal of inhibitory
      constraints rather than the onset of inductive factors. Also, certain cell-cell
      interactions occur between E7 and E10, which cannot be disrupted if
      oligodendrocyte differentiation is to occur.

PMID- 12465044
TI  - Mitochondrial localization of glucocortocoid receptor in glial (Muller) cells in
      the salamander retina.
AB  - Glucocorticoid hormones regulate the transcription of nuclear genes by way of
      their receptors. In addition, these hormones modulate mitochondrial gene
      transcription by mechanisms that remain poorly understood. Using
      immunofluorescence labeling in isolated Muller and photoreceptor cells and in
      intact salamander retina, we found that the glucocorticoid receptor (GR) is
      localized in both cell types. Confocal laser scanning microscopy and double
      staining with cytochrome oxidase (COX) showed that GR is localized in the
      mitochondria of Muller cells, but not in the mitochondria of photoreceptors. GR
      also colocalizes with glutamine synthetase (GS) in the cytoplasm of Muller cells.
      GR is also localized in the microvilli of the distal process of Muller cells and
      in the synaptic terminal of photoreceptors. Pre-incubation of Muller cells with 1
      microM dexamethasone (DEX) for 7 h led to greater than 50% inhibition of the
      glutamate-induced increase in mitochondrial NADH. This late effect of
      glucocorticoids on glutamate metabolism could be ascribed, in part, to a direct
      action of steroid hormones on mitochondrial metabolism.

PMID- 12465045
TI  - Loss of microglial ramification in microglia-astrocyte cocultures: involvement of
      adenylate cyclase, calcium, phosphatase, and Gi-protein systems.
AB  - Reduction in microglial branching is a common feature in brain pathology and
      culminates in the transformation into small, rounded, microglia-derived
      phagocytes in the presence of neural debris. The molecular factors responsible
      for this transformation are unknown. Here we explored the effect of different
      classes of intra- and extracellular stimuli in vitro on the morphology of
      ramified microglia cultured on a confluent astrocyte substrate. These studies
      showed a strong dose-dependent effect for the Ca(2+) ionophore calcimycine/A21837
      (50 microM) and for dibutyryl-cAMP (1 mM), with a loss of microglial
      ramification. Direct activation of the adenylate cyclase with forskolin (0.1 mM)
      also led to the disappearance of microglial branching. Okadaic acid (70 nM), the
      inhibitor of protein phosphatases 1 and 2A (PP1/PP2A), and pertussis toxin (12.5
      microg/ml), a G(i)-protein inhibitor, also showed similar effects. No effect was
      observed for dibutyryl-cGMP or for UTP; addition of ATP had a moderate effect,
      but only at very high, probably nonphysiological concentrations (100 mM).
      Extracellular matrix components such as keratatan-sulfate, integrin receptor
      blockers, the disintegrins kistrin, echistatin, and flavoridin, or the serine
      protease thrombin all had no effect. Addition of prostaglandin D(2) (PGD(2)), a
      molecule produced by activated microglial cells, had a transforming effect, but
      at concentrations two orders of magnitude higher than that of established PGD(2)
      receptors. In summary, addition of agents causing intracellular elevation of
      Ca(2+) and cAMP or inhibition of G(i)-proteins and phosphatases to ramified
      microglia cultured on top of confluent astrocytes leads to a rapid loss of
      microglial branching. Signaling cascades controlled by these molecules may play
      an important role in the regulation of this common physiological process in the
      injured brain.

PMID- 12465046
TI  - Activation of microglia: a neuroinflammatory role for CAP37.
AB  - Recent evidence suggests that inflammation and immune function in the central
      nervous system (CNS) may play a considerable role in the progression of many
      neurodegenerative diseases. It is known that microglia, the CNS equivalent of
      peripheral blood monocytes, may be instrumental in causing neurotoxicity.
      However, the mediator(s) that activates microglia to produce toxic substances
      that orchestrate cell death has yet to be elucidated. We have identified a novel
      inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa
      (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known
      to be a potent activator and regulator of monocyte function in the systemic
      circulation. We hypothesize that CAP37, a mediator previously shown to recruit
      and activate monocytes in the systemic circulation, may also play a role in CNS
      inflammation by modulating microglial function. Here we demonstrate that CAP37 is
      a chemoattractant for microglia and that CAP37-treated microglia express class II
      major histocompatibility antigens and produce proinflammatory cytokines and
      chemokines. We conclude that CAP37 has the ability to activate microglial cells
      and suggest that it has the potential to serve as a neuroinflammatory molecule.

PMID- 12465047
TI  - Transplanted multipotential neural precursor cells migrate into the inflamed
      white matter in response to experimental autoimmune encephalomyelitis.
AB  - Transplanted neural precursor cells remyelinate efficiently acutely demyelinated
      focal lesions. However, the clinical value of cell transplantation in a chronic,
      multifocal disease like multiple sclerosis will depend on the ability of
      transplanted cells to migrate to the multiple disease foci in the brain. Here, we
      expanded newborn rat neural precursor cells in spheres and transplanted them
      intracerebroventricularly or intrathecally in rats. The cells were labeled by the
      nuclear fluorescent dye Hoechst or by incubation with BrdU to enable their
      identification at 2 days and 2 weeks after transplantation, respectively. Spheres
      consisted of PSA-NCAM(+), nestin(+), NG2(-) undifferentiated precursor cells that
      differentiated in vitro into astrocytes, oligodendrocytes, and neurons. Spheres
      that were transplanted into intact rats remained mostly in the ventricles or in
      the spinal subarachnoid space. Following transplantation at peak of experimental
      autoimmune encephalomyelitis, cells migrated into the brain or spinal cord
      parenchyma, exclusively into inflamed white matter but not into adjacent gray
      matter regions. After 2 weeks, many transplanted cells had migrated into distant
      white matter tracts and acquired specific markers of the astroglial and
      oligodendroglial lineages. Thus, the inflammatory process may attract targeted
      migration of transplanted precursor cells into the brain parenchyma.

PMID- 12465048
TI  - Role of enteric glial cells in inflammatory bowel disease.
AB  - Enteric glial cells (EGCs) represent an extensive but relatively poorly described
      cell population within the gastrointestinal tract. Accumulating data suggest that
      EGCs represent the morphological and functional equivalent of CNS astrocytes
      within the enteric nervous system (ENS). The EGC network has trophic and
      protective functions toward enteric neurons and is fully implicated in the
      integration and the modulation of neuronal activities. Moreover, EGCs seem to be
      active elements of the ENS during intestinal inflammatory and immune responses,
      sharing with astrocytes the ability to act as antigen-presenting cells and
      interacting with the mucosal immune system via the expression of cytokines and
      cytokine receptors. Transgenic mouse systems have demonstrated that specific
      ablation of EGC by chemical ablation or autoimmune T-cell targeting induces an
      intestinal pathology that shows similarities to the early intestinal
      immunopathology of Crohn's disease. EGCs may also share with astrocytes the
      ability to regulate tissue integrity, thereby postulating that similar
      interactions to those observed for the blood-brain barrier may also be partly
      responsible for regulating mucosal and vascular permeability in the
      gastrointestinal tract. Disruption of the EGC network in Crohn's disease patients
      may represent one possible cause for the enhanced mucosal permeability state and
      vascular dysfunction that are thought to favor mucosal inflammation.

PMID- 12465049
TI  - Formation of a beta1 integrin signaling complex in Schwann cells is independent
      of rho.
AB  - Schwann cell adhesion to basal lamina is essential for peripheral nerve
      development. beta(1) integrin receptors for extracellular matrix cooperate with
      other receptors to transmit signals that coordinate cell cycle progression and
      initiation of differentiation, including myelin-specific gene expression. In
      Schwann cell/sensory neuron cocultures, beta(1) integrins complex with focal
      adhesion kinase (FAK), fyn kinase, paxillin, and schwannomin in response to basal
      lamina adhesion. To study the assembly of this signaling complex in Schwann cells
      (SCs), we induced beta(1) integrin clustering on suspended cells using an
      immobilized antibody and recovered a complex containing beta(1) integrin, FAK,
      paxillin, and schwannomin. In adherent subconfluent cells, the proteins
      colocalized to filopodia, ruffling membranes and focal contacts. We assessed the
      role of rhoGTPase in the process of integrin complex assembly by introducing C3
      transferase (C3T), a rho inhibitor, into the cells. Although C3T caused dose
      dependent morphological abnormalities, FAK, paxillin, and schwannomin were able
      to coimmunoprecipitate with beta(1) integrin. Additionally, colocalization of
      FAK, paxillin, and schwannomin with beta(1) integrin in filopodia and small focal
      contacts remained unchanged. We conclude that SCs do not require active rho to
      recruit signaling and structural proteins to beta(1) integrins clustered at the
      plasma membrane. Rho is required to establish large focal adhesions and to spread
      and stabilize plasma membrane extensions.

PMID- 12465050
TI  - Dystonia: a disorder of motor programming or motor execution?
AB  - For some time, dystonia has been seen as purely a motor disorder. Relatively
      novel concepts published approximately 10 years ago also presumed that in the
      development of dystonic dyskinesias, only motor behaviour was abnormal.
      Neurophysiological observations of various types of dystonic disorders, which
      were performed using sophisticated electromyography, polymyography, H-reflex
      examination, long-latency reflex, etc., as well as new insights into the
      behaviour of dystonia, have urged the inclusion of sensory (particularly
      somatosensory) mechanisms into the pathophysiological background of dystonia. The
      major role has been considered to be played by abnormal proprioceptive input by
      means of the Ia proprioceptive afferents, with the source of this abnormality
      found in the abnormal processing of muscle spindle afferent information. However,
      neurophysiological investigations have also provided evidence that the
      abnormality in the central nervous system is located not only at the spinal and
      subcortical level, but also at the cortical level; specifically, the cortical
      excitability and intracortical inhibition have been revealed as abnormal. This
      evidence was revealed by SEP recordings, paired transcranial magnetic stimulation
      recordings, and BP and CNV recordings. The current concept of dystonic movement
      connects the abnormal function of somatosensory pathways and somatosensory
      analysers with the dystonic performance of motor action, which is based on the
      abnormality of sensorimotor integration.

PMID- 12465051
TI  - The power of cueing to circumvent dopamine deficits: a review of physical therapy
      treatment of gait disturbances in Parkinson's disease.
AB  - Gait disturbances are among the primary symptoms of Parkinson's disease (PD) and
      contribute significantly to a patient's loss of function and independence.
      Standard treatment includes antiparkinsonian drugs, primarily levodopa. In
      addition to the standard drug regime, physical therapy is often prescribed to
      help manage the disease. In recent years, there have been promising reports of
      physical therapy programs combined with various types of sensory cueing for PD.
      In this brief review of the literature, we summarize the evidence regarding the
      clinical efficacy of different physical therapy programs for PD, specifically
      with respect to improving gait. We also discuss the potential therapeutic
      mechanisms of sensory cueing and review the studies that have used cueing in the
      treatment of gait in PD. This review of the literature shows two key findings:
      (1) despite its relatively long history, the evidence supporting the efficacy of
      conventional physical therapy for treatment of gait in PD is not strong; and (2)
      although further investigation is needed, sensory cueing appears to be a powerful
      means of improving gait in PD.

PMID- 12465052
TI  - Parkinson's disease and dementia with Lewy bodies: one disease or two?
AB  - Parkinson's disease (PD) and dementia with Lewy bodies (DLB) have clinical
      features in common and are both characterized neuropathologically by the presence
      of Lewy bodies (LBs). We conducted a clinicopathological correlation pilot study
      to better understand whether PD and DLB represent two distinct nosological
      entities or rather exist along the spectrum of a single LB disease. A
      neuropathologist blinded to clinical diagnoses evaluated brains with largely pure
      LB pathology to determine LB distribution and frequency. Research clinicians
      blinded to LB distribution and frequency determined consensus clinical diagnoses.
      Clinical features separated cases into two groups, one having features most
      compatible with PD and the other with DLB. The groups were distinguishable mainly
      by the time course of clinical symptoms. Although the presence of neocortical LBs
      was more common in the group of patients with clinical features of DLB,
      neocortical LBs were also present in 1 member of the PD group and even in the
      clinically normal control subject. Thus, there appear to be two clinical
      syndromes, distinguished mainly by the time course of symptoms. The mechanisms
      responsible for the different clinical presentations are not known, and the issue
      of whether PD and DLB represent two distinct diseases remains unsettled.

PMID- 12465053
TI  - Selective loss of pyramidal neurons in the pre-supplementary motor cortex in
      Parkinson's disease.
AB  - The nonprimary motor cortices have not previously been studied in Parkinson's
      disease, despite the selective pattern of dysfunction observed in these regions.
      In particular, the pre-supplementary motor region is consistently underactive,
      with successful treatments correlating with increased excitatory drive to
      nonprimary motor regions. This finding could suggest a primary cortical
      abnormality in the pre-supplementary motor area (pre-SMA) in Parkinson's disease.
      We analysed and compared neuronal number in the pre-SMA and dorsolateral premotor
      cortical regions in 5 cases of Parkinson's disease and 5 controls. For each
      cortical region, the total neuronal number as well as the estimated numbers of
      subpopulations of interneurons and pyramidal neurons was quantified using
      previously published unbiased techniques. The results showed a significant loss
      of cortico-cortical projecting pyramidal neurons in the pre-SMA with no loss of
      other pyramidal neurons or interneurons either in this region or in the
      dorsolateral premotor region. These findings indicate a highly selective loss of
      pyramidal cells in the pre-SMA in Parkinson's disease, consistent with previous
      imaging findings in this disease. Our results implicate the degeneration of the
      premotor projection from the pre-SMA, along with dopaminergic basal ganglia
      dysfunction, in the pathogenesis of Parkinson's disease.

PMID- 12465054
TI  - Levodopa but not ropinirole induces an internalization of D1 dopamine receptors
      in parkinsonian rats.
AB  - Levodopa therapy in Parkinson's disease is mediated by dopamine receptors and, in
      a recent study, we showed that a Dl full agonist can induce an internalization of
      D1 dopamine receptors. The aim of the present study was to determine whether
      levodopa or a dopamine agonist such as ropinirole can also induce the
      internalization of D1 dopamine receptors in the striatum of control and
      hemiparkinsonian rats. The distribution of D1 dopamine receptors was analyzed by
      immunohistochemistry using a specific antibody. In control animals and 6
      hydroxydopamine (6-OHDA)-lesioned animals treated with saline, D1 dopamine
      receptors were localized at the level of the plasma membrane. In contrast, in
      both lesioned and nonlesioned animals receiving a single dose of levodopa, but
      not in animals receiving ropinirole, D1 dopamine receptors were internalized in
      the cytoplasm. This result is likely explained by the fact that ropinirole binds
      to non-D1 dopamine receptors, whereas levodopa, which increases dopamine levels,
      indirectly acts on both D1 and D2 receptors. Ropinirole is consequently less
      likely to desensitize D1 dopamine receptors than levodopa and, thus, to reduce
      the efficacy of the treatment.

PMID- 12465055
TI  - Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the
      MPTP-lesioned nonhuman primate model of Parkinson's disease.
AB  - Long-term treatment with levodopa in Parkinson's disease results in the
      development of motor fluctuations, including reduced duration of antiparkinsonian
      action and involuntary movements, i.e., levodopa-induced dyskinesia. Cannabinoid
      receptors are concentrated in the basal ganglia, and stimulation of cannabinoid
      receptors can increase gamma-aminobutyric acid transmission in the lateral
      segment of globus pallidus and reduce glutamate release in the striatum. We thus
      tested the hypothesis that the cannabinoid receptor agonist nabilone (0.01, 0.03,
      and 0.10 mg/kg) would alleviate levodopa-induced dyskinesia in the 1-methyl-4
      phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -lesioned marmoset model
      of Parkinson's disease. Coadministration of nabilone (0.1 mg/kg) with levodopa
      was associated with significantly less total dyskinesia (dyskinesia score, 12;
      range, 6-17; primate dyskinesia rating scale) than levodopa alone (22; range, 14
      23; P < 0.05). This effect was more marked during the onset period (0-20 minutes
      post levodopa). There was no reduction in the antiparkinsonian action of
      levodopa. Furthermore, the intermediate dose of nabilone used (0.03 mg/kg)
      increased the duration of antiparkinsonian action of levodopa by 76%. Thus,
      cannabinoid receptor agonists may be useful in the treatment of motor
      complications in Parkinson's disease.

PMID- 12465056
TI  - Switching of movement direction is central to parkinsonian bradykinesia in sit-to
      stand.
AB  - Patients with Parkinson's disease (PD) are known to manifest slowness in
      movements. We sought to identify the particular kinematic and kinetic disorders
      that contribute to the slowness in performing sit-to-stand in these patients. Two
      inter-related studies were carried out. In the first study, 20 patients with PD
      and 20 control subjects were instructed to perform sit-to-stand at a natural
      speed. In the second study, 15 control subjects were instructed to simulate the
      slower speed of sit-to-stand of the patients identified in the first study.
      Kinematic and kinetic data were recorded by a PEAK motion analysis system and two
      force platforms. The results showed that patients with PD generated smaller peak
      horizontal and vertical velocities during the task. They took a longer time to
      complete each individual phase as well as the whole movement of sit-to-stand.
      Patients also produced smaller peak hip flexion and ankle dorsiflexion joint
      torques and had prolonged time-to-peak torques from sit-to-stand onset. When
      control subjects simulated the patients' speed of sit-to-stand, there was no
      difference in all the kinematic and kinetic data between groups. The only
      exception was that they exhibited a shorter transition time between peak
      horizontal velocity (flexion phase) and seat-off (extension phase) than the
      patients. This study demonstrated that the slowness of PD patients during sit-to
      stand at a natural speed could be attributed to inadequate peak hip flexion and
      ankle dorsiflexion torques, a prolonged torque production, as well as a
      difficulty in switching from the flexion to extension direction during sit-to
      stand. As the latter difficulty persisted when the control subjects performed the
      task at a speed similar to that of the patients, our findings suggest that a
      fundamental problem of patients with Parkinson's disease could be a switch
      between movement directions.

PMID- 12465057
TI  - Practice effects in three-dimensional sequential rapid aiming in Parkinson's
      disease.
AB  - One hypothesized role of the basal ganglia, based largely on findings in
      Parkinson's disease (PD) patients, is the control of movement sequences. We
      examined changes in performance with practice of a movement sequence in PD
      patients and age-matched controls (n = 8 per group). Subjects practiced a complex
      three-dimensional sequential aiming task over 2 days, completing 180 trials, with
      the goal to minimize response time within specified accuracy limits. The results
      indicated that both groups became faster in planning the movement, and both
      groups moved more quickly through the sequence with practice. The PD group's
      decrease in movement time occurred primarily within the first 45 trials, whereas
      the control group continued to improve through the first 150 trials. Flight time
      (time between targets) to a small target decreased with practice in both groups,
      but flight time to a large target decreased only in the control group. This
      finding indicates that error corrective processes are more amenable to practice
      than ballistic processes in people with PD. There was little evidence that either
      group improved their performance by planning shorter (lower) trajectories, but
      rather increased mean velocity. Contact time (time on target) decreased with
      practice in both groups, and there were no group differences. These data indicate
      that practice can improve performance, both in planning and in specific execution
      processes.

PMID- 12465058
TI  - Large French-Canadian family with Lewy body parkinsonism: exclusion of known
      loci.
AB  - The identification of rare, large families with Parkinson's disease (PD) has
      provided important clues that have contributed to our understanding of this
      complex disorder. We have identified a large French-Canadian kindred that spans
      five generations consisting of more than 90 individuals. A total of 65
      individuals now have been examined, had venous blood drawn, and DNA extracted.
      Two-point and multipoint linkage analysis was performed to assess linkage to
      known PD genes or loci. Within the third and fourth generations of this family
      there are 10 living, plus 3 deceased members with well-documented levodopa
      responsive parkinsonism. Autopsy results on 1 member demonstrated the loss of
      pigmented neurons in the substantia nigra and the presence of alpha-synuclein
      positive Lewy bodies. Four of the PD patients have prominent postural and kinetic
      tremors that preceded their parkinsonism by up to 10 years. Two other individuals
      within the family have prominent isolated postural and kinetic tremors without
      parkinsonism. The alpha-synuclein(4q21.3-23), Parkin(6q25.2-27), PARK3 (2p13),
      PARK4, and ubiquitin carboxy terminal hydrolase-L1 (4p14-16.3) and PARK6 and
      PARK7 (1p35-36) loci were excluded in this kindred using closely linked markers.
      The clinical and pathological features of this family are consistent with the
      diagnosis of PD. This family further demonstrates the known genetic heterogeneity
      in PD and is large enough that a genome-wide screen has been undertaken in an
      effort to identify a novel PD gene.

PMID- 12465059
TI  - Resource use and costs in a Swedish cohort of patients with Parkinson's disease.
AB  - We estimated resource use and costs in patients with Parkinson's disease (PD),
      thereby providing baseline data for future economic evaluations of therapeutic
      interventions. Data were collected from medical records of a South Swedish cohort
      of 127 PD patients during 1 year (1996) and a mailed questionnaire inquiring
      about cost-related consequences and resource use in 1996 and in 2000. Annual
      costs were calculated based on prevalence and expressed in SEK (monetary value of
      the year 2000). Direct health care costs averaged approximately SEK 29,000 (
      approximately USD 2,900; EUR 3,200) per patient per year, of which drugs were the
      most costly component. Nonmedical direct costs were higher than direct health
      care costs, averaging approximately SEK 43,000 ( approximately USD 4,300; EUR
      4,800) per patient per year, and costs due to lost production were approximately
      SEK 52,000 ( approximately USD 5,200; EUR 5,800) per patient per year. The mean
      total annual cost for PD in our sample approximated SEK 124,000 ( approximately
      USD 12,400; EUR 13,800) per patient. These findings are roughly within the same
      range as estimates from other countries and show that PD causes a considerable
      societal burden. In addition to other outcomes, evaluations of the economic
      implications of new therapeutic interventions are highly warranted. In this
      perspective, the present study provides valuable baseline data.

PMID- 12465060
TI  - Memory and executive function impairment predict dementia in Parkinson's disease.
AB  - We analyzed the association of neuropsychological test impairment at baseline
      with the development of dementia in idiopathic Parkinson's disease (PD) patients.
      A cohort of nondemented PD patients from northern Manhattan, NY was followed
      annually with neurological and neuropsychological evaluations. The
      neuropsychological battery included tests of verbal and nonverbal memory,
      orientation, visuospatial ability, language, and abstract reasoning. The
      association of baseline neuropsychological tests scores with incident dementia
      was analyzed using Cox proportional hazards models. The analysis controlled for
      age, gender, education, duration of PD, and the total Unified Parkinson's Disease
      Rating Scale motor score at baseline. Forty-five out of 164 patients (27%) became
      demented during a mean follow-up of 3.7 +/- 2.3 years. Four neuropsychological
      test scores were significantly associated with incident dementia in the Cox
      model: total immediate recall (RR: 0.92, 95% CI: 0.87-0.97, P = 0.001) and
      delayed recall (RR: 0.73, 95% CI: 0.59-0.91, P = 0.005) of the Selective
      Reminding Test (SRT), letter fluency (RR: 0.87, 95% CI: 0.77-0.99, P = 0.03), and
      Identities and Oddities of the Mattis Dementia Rating Scale (RR: 0.85, 95% CI:
      0.73-0.98, P = 0.03). When the analysis was performed excluding patients with a
      clinical dementia rating of 0.5 (questionable dementia) at baseline evaluation,
      total immediate recall and delayed recall were still predictive of dementia in
      PD. Our results indicate that impairment in verbal memory and executive function
      are associated with the development of dementia in patients with PD.

PMID- 12465061
TI  - Motor response to levodopa and the evolution of motor fluctuations in the first
      decade of treatment of Parkinson's disease.
AB  - Thirty-four patients with Parkinson's disease were followed for a mean period of
      8 years from the time of initiation of levodopa medication. Levodopa response was
      charted from the starting point of pharmacological treatment to give a
      longitudinal point of view of the changes that evolve as the disease progresses.
      Objective measurements of the motor response to levodopa test-doses were made at
      approximately three yearly intervals. Motor fluctuations developed in 58% of the
      patient group after a mean treatment period of 35 months. Dyskinesia developed in
      parallel with fluctuations but appeared on average 7 months before symptomatic
      wearing-off effects of levodopa doses. The patients with motor fluctuations had
      significantly better responses to levodopa. By contrast, nonfluctuators were more
      prone to develop increasing midline motor disability affecting speech, gait and
      balance. Comparison of test-dose and pretreatment scores suggested that a
      substantial long-duration response to levodopa remains after many years of
      treatment, and that lateralized motor deficits show a stronger long duration
      response than midline ones. Motor fluctuations are a consequence of disease
      progression but their early development is, on balance, associated with better
      long-term functional ability because these patients have the greater capacity to
      respond to pharmacological treatment.

PMID- 12465062
TI  - Apomorphine monotherapy in the treatment of refractory motor complications of
      Parkinson's disease: long-term follow-up study of 64 patients.
AB  - Continuous subcutaneous infusion of apomorphine is now increasingly recognized as
      an effective treatment for refractory off periods and peak-dose dyskinesias in
      Parkinson's disease. We have reviewed our experience with apomorphine infusions,
      after a strategy decision in 1995 based on emerging preclinical data, to treat
      all patients with steady-state plasma levels of apomorphine throughout the waking
      day, minimizing additional pulsatile stimulation either by oral dopaminergic
      medication or bolus parenteral injections of apomorphine. Sixty-four patients
      have been treated with apomorphine pumps and 45 of these successfully converted
      to monotherapy, managing to discontinue all other forms of dopaminergic
      stimulation during the daytime treatment period with apomorphine. Patients were
      followed up for a mean of 33.8 months (range, 4-108 months) and clinical data
      analyzed retrospectively. The mean maintenance dose of apomorphine was 98 mg per
      24 hours (monotherapy group: 103 mg/24 hours; polytherapy group: 93 mg/24 hours),
      which did not significantly increase at final follow-up. There was a mean maximum
      dyskinesia reduction of 64% (S.D. = 20) in the monotherapy group, compared to 30%
      (S.D. = 33) in those continuing on polytherapy (P < 0.001), despite a maintained
      increase in on time (monotherapy group: 55%, P < 0.005; polytherapy group: 50%, P
      = 0.05). Fifteen patients failed to successfully convert to monotherapy but
      benefited nonetheless, and only 3 failed apomorphine infusional therapy
      altogether. Reasons for failure were mixed, including difficulty with compliance
      and adverse effects such as daytime somnolence, skin complications, and painful
      dystonias. There was a significantly higher success rate in patients able to
      manage the treatment either independently or with the help of their caregiver.
      These results confirm that subcutaneous apomorphine monotherapy can reset peak
      dose dyskinesia threshold in levodopa-treated patients and further reduce off
      period disability after all available forms of oral medication, including long
      acting dopamine agonists, have been tried.

PMID- 12465063
TI  - Diagnosing multiple system atrophy with greater accuracy: combined analysis of
      the clonidine-growth hormone test and external anal sphincter electromyography.
AB  - The clonidine-growth hormone test (CGHT) has been proposed as a means of
      differentiating multiple system atrophy (MSA) from idiopathic Parkinson's disease
      (PD). However, it is controversial whether the CGHT is valid. We sought to
      confirm the validity of the CGHT and to compare the diagnostic accuracy of the
      CGHT with that of external anal sphincter electromyelography (Sph-EMG) for MSA.
      We performed the CGHT and the Sph-EMG on 21 PD patients, 23 patients with
      probable MSA of parkinsonian type (MSA-p), and 22 patients with probable MSA of
      cerebellar type (MSA-c). We compared the sensitivity, specificity, and positive
      and negative predictive values (PPV and NPV) of CGHT, Sph-EMG, and a combination
      of the two tests. We also evaluated the correlations of Unified Parkinson's
      Disease Rating Scale (UPDRS) scores with the results of the two tests. There was
      no significant difference between the UPDRS scores for the PD and MSA-p groups.
      Serum growth hormone concentrations after clonidine significantly increased in PD
      (mean increase +/- SEM, 4.19 +/- 0.92 ng/ml; P < 0.0001), but remained unchanged
      in both MSA-p (0.83 +/- 0.61 ng/ml) and MSA-c (1.45 +/- 0.58 ng/ml). The growth
      hormone responses to clonidine in MSA-p were significantly different from those
      in PD (P < 0.05). Abnormal, denervated Sph-EMG was observed in 95.7% of MSA-p,
      86.4% of MSA-c, and 33.3% of PD patients. Compared to Sph-EMG, the CGHT was less
      sensitive but more specific in both MSA-p and MSA-c. The result of neither test
      correlated with the severity of parkinsonism. Interestingly, combining the
      results of the CGHT and Sph-EMG markedly increased the specificity (85.7% in the
      CGHT and 66.7% in Sph-EMG vs. 95.2% in the combination study) and the PPV in both
      MSA-p (85.7% and 75.9% vs. 94.4%) and MSA-c (82.4% and 73.1% vs. 91.7%). We
      confirm that the CGHT can distinguish MSA-p from PD. Its sensitivity is lower and
      its specificity higher than Sph-EMG. Compared to either test alone, combined
      testing with the CGHT and Sph-EMG increased specificity and PPV, thereby
      enhancing accuracy in the diagnosis of MSA.

PMID- 12465064
TI  - Application of the International Cooperative Ataxia Scale rating in multiple
      system atrophy.
AB  - We assessed the International Cooperative Ataxia Scale (ICARS) as a means of
      extracting and rating cerebellar signs in multiple system atrophy (MSA). Cross
      sectional analysis of internal consistency, factor structure, and correlation
      with parkinsonism severity (Unified Parkinson's Disease Rating Scale [UPDRS] III)
      of the ICARS, in 50 unselected MSA patients (mean age, 67.6 years; mean disease
      duration, 5.5 years), 50 age-matched and disease duration-matched Parkinson'
      disease (PD) patients, and 50 control subjects. Fifteen patients (30%) had MSA-C
      (cerebellar subtype) and 35 (70%) MSA-P (parkinsonism subtype), and 66% had at
      least one cerebellar sign. The total ICARS score was much higher (fivefold) in
      MSA compared to PD patients. The ICARS score was twofold higher in MSA-C than in
      MSA-P patients. MSA-C patients had a higher score than MSA-P mainly on posture
      and gait disturbances and kinetic functions subscores. All the ICARS items were
      significantly more severe in MSA than in PD patients, who in turn scored higher
      than the controls. In MSA, internal consistency was excellent (Cronbach = 0.93).
      Factor structure analysis revealed four clinically distinct subscores, in
      accordance with the scale structure, which accounted for 70% of the variance. The
      ICARS showed less consistency and accuracy in PD patients; however, the ICARS
      scores significantly correlated with the UPDRS-III scores in both MSA and PD
      patients. The ICARS appears a useful tool to extract and rate the severity of
      cerebellar signs in MSA; however, it is clearly contaminated by parkinsonian
      features.

PMID- 12465065
TI  - Progressive supranuclear palsy diagnosis and confounding features: report on 16
      autopsied cases.
AB  - We evaluated 16 (15 men, 1 woman) autopsy-verified progressive supranuclear palsy
      (PSP) cases during 31 years (1969-2000) for clinical diagnosis and the course of
      the disease. The onset was gait difficulty or postural instability in 9 (56.3%),
      general motor slowing in 3 (18.8%), and tremor in 2. One case had onset with
      cognitive decline and 1 as hemidystonia. Four cases had supranuclear
      ophthalmoplegia (SNO) at the first assessment and were diagnosed as PSP. By last
      assessment, PSP diagnosis was made in 4 additional cases, but in 8 (50%) who
      never manifested ophthalmoplegia (mean 9.8 years after onset), PSP diagnosis was
      not made. Other manifestations included bulbar symptoms in 13 (81.3%), and
      cognitive impairment in 10 (62.5%) during the course of illness. Fifteen cases
      received levodopa, amantadine, anticholinergics, dopamine agonists, and
      selegiline in different combinations with symptomatic benefit in 9 of 15 (60%).
      Five had some improvement on levodopa alone and 3 showed more improvement when a
      dopamine agonist was added to levodopa. In general, the benefit was minimal and
      occurred only early in the course of illness. The mean age at onset was 63.7
      (range, 53-85) years. Mean duration at PSP diagnosis was 4.8 (range, 2-11) years.
      Mean survival was 8.6 (range, 3-24) years and mean age at death was 72.3 (range,
      60-89) years. When the different diagnostic criteria recommended in the
      literature were used, the accuracy of clinical diagnosis did not improve
      substantially.

PMID- 12465066
TI  - Tc-99m ethylene cysteinate dimer SPECT in the differential diagnosis of
      parkinsonism.
AB  - Positron emission tomography (PET) and network analysis have been used to
      identify a reproducible pattern of regional metabolic covariation that is
      associated with idiopathic Parkinson's disease (PD). The activity of this PD
      related pattern can be quantified in individual subjects and used to discriminate
      PD patients from atypical parkinsonians. Because PET is not commonly available,
      we sought to determine whether similar discrimination could be achieved using
      more routine single photon emission computed tomography (SPECT) perfusion
      methods. Twenty-three subjects with PD (age, 63 +/- 9 years), 22 subjects with
      multiple system atrophy (MSA; age, 64 +/- 7 years), and 20 age-matched healthy
      controls (age, 62 +/- 13 years) underwent SPECT imaging of regional cerebral
      perfusion with Tc-99m ethylene cysteinate dimer (ECD). Using network analysis, we
      determined whether a PD-related pattern existed in the SPECT data, and whether
      its expression discriminated PD from MSA patients. Additionally, we compared the
      accuracy of group discrimination achieved by this pattern with that of the PET
      derived PD-related pattern applied to the SPECT data. Network analysis of the
      SPECT data identified a significant pattern characterized by relative increases
      in cerebellar, lentiform, and thalamic perfusion covarying with decrements in the
      frontal operculum and in the medial temporal cortex. Subject scores for this
      pattern discriminated PD patients from controls (P < 0.01) and from MSA patients
      (P < 0.03). Subject scores for the PET-derived PD-related pattern computed in the
      individual SPECT scans more accurately distinguished PD patients from controls (P
      < 0.005) and from MSA patients (P = 0.0002). A significant PD-related covariance
      pattern can be identified in SPECT perfusion data. Moreover, the disease related
      pattern identified previously with PET can be applied to individual SPECT
      perfusion scans to provide group discrimination between PD patients, healthy
      controls, and individuals with MSA. Because of significant individual subject
      overlap between groups, however, the clinical utility of this method in the
      differential diagnosis of Parkinsonism remains uncertain.

PMID- 12465067
TI  - Phenomenology of "Lubag" or X-linked dystonia-parkinsonism.
AB  - X-linked dystonia-parkinsonism (XDP), or Lubag syndrome, is known to cause
      progressive dystonia, with or without parkinsonism, among Filipino male adults
      with maternal roots from the Philippine island of Panay. We present
      cinematographic material of 11 cases of Lubag carrying the XDP haplotypes who
      manifest with a wide spectrum of movement disorders, including dystonia, tremor,
      parkinsonism, myoclonus, chorea, and myorhythmia. Because of overlapping
      features, Lubag patients are commonly misdiagnosed as idiopathic dystonia,
      essential tremor, Parkinson's disease, or Parkinson's-plus syndromes. Thus, it is
      imperative to elicit an exhaustive family history in any Filipino male adult who
      presents with a movement disorder.

PMID- 12465068
TI  - Athetosis I: historical considerations.

PMID- 12465069
TI  - Athetosis II: the syndrome of mild athetoid cerebral palsy.
AB  - We describe 8 patients who presented with continuous, irregular movements
      occurring independently in individual fingers and, in some cases, toes, in the
      setting of mild dystonia present since early childhood and not associated with
      major disability. The finger movements varied from low-amplitude quivering or
      wriggling to larger amplitude movements in the plane of abduction-adduction as
      well as flexion-extension; they were asymmetrical but not unilateral. Quivering
      or working of the facial muscles was seen in 5 patients. Most patients reported
      worsening of the movements over the years, but there was no other evidence of a
      progressive neurological disease. We classify the movement disorder as athetosis
      as described by Hammond and Shaw and the syndrome as mild athetoid cerebral
      palsy.

PMID- 12465070
TI  - Long-term efficacy of botulinum toxin A in treatment of various movement
      disorders over a 10-year period.
AB  - Although botulinum toxin A (BTX) has been licensed in Canada for treatment of
      various movement disorders since 1990, few clinical studies regarding its long
      term efficacy and side effects have been reported. We conducted a retrospective
      analysis of 235 patients who received BTX from our movement disorders clinic over
      a 10-year period (January 1990 to December 1999). A total of 2,616 treatment
      cycles (multiple injections) were administered to 235 patients with cervical
      dystonia (CD), hemifacial spasm (HS), blepharospasm (BP), and other movement
      disorders. Substantial benefit at 5 years was seen in most patients (90% in BP,
      88% in HS, 63% in CD, 100% in jaw closing and lower limb dystonia, and 56% in
      writer's cramp). Benefit was maintained for up to 10 years in CD, HS, and BP
      data, with a 75.8% benefit reported. Twenty-eight percent of patients
      discontinued treatment during the follow-up period due to a variety of reasons.
      Of these, 9.1% of patients developed primary resistance, and 7.5% of patients
      secondary resistance. Adverse effects, mostly minor, developed in 27% of patients
      at any one time, occurring over 4.5% of treatment cycles. These were most
      frequently reported in blepharospasm (22 of 36 patients in 40 cycles), followed
      by hemifacial spasm (21 of 70 patients in 46 cycles), and cervical dystonia (17
      of 106 in 28 cycles). Only 1.3% of patients discontinued therapy due intolerable
      adverse effects. The results show that BTX is a safe and effective treatment of
      various types of movement disorders, and most side effects are well tolerated.
      Discontinuation for any reason was also low after 5 years. Efficacy was
      maintained after long periods of treatment with high degree of patient
      satisfaction.

PMID- 12465071
TI  - Clinical relevance of electrophysiological tests in the assessment of patients
      with Huntington's disease.
AB  - Assessment programs recently designed to follow-up patients with Huntington's
      disease (HD) in therapeutic trials have not included electrophysiological testing
      in the list of mandatory examinations. This omission is likely due to the current
      lack of data establishing a clear correlation between the electrophysiological
      results and those of clinical assessment. We address this issue in a cohort of 36
      patients at relatively early stages of the disease (I and II).
      Electrophysiological studies comprised the recording of palmar sympathetic skin
      responses (SSRs), blink reflexes (BRs), thenar long latency reflexes (LLRs),
      cortical somatosensory evoked potentials (SEPs), and electromyographic silent
      periods evoked by transcranial magnetic stimulation (SPs). Results were analyzed
      with reference to disease duration and staging and to specific cognitive,
      psychiatric, and motor alteration. SEPs were the most and very sensitive markers,
      because they were abnormal in 94% of patients. Except for LLRs, alteration of
      electrophysiological results increased in parallel to the evolution of the
      disease. Except for LLRs and SSR latency, electrophysiological results correlated
      with those of specific clinical examinations. In particular, an increased BR
      latency or a reduced amplitude of the N20 component of SEPs correlated with the
      extent of bradykinesia, whereas a reduced amplitude of SSRs or of the N30
      component of SEPs correlated with hyperkinesia. Overall, electrophysiological
      tests, in particular SEPs and BRs, appeared sensitive and interesting in the
      follow-up of HD patients and correlated with various clinical parameters,
      suggesting that these easy to perform and noninvasive repeatable examinations
      could be added fruitfully to the assessment programs for HD.

PMID- 12465072
TI  - Polymorphisms in iron-responsive binding protein 2 and lack of association with
      sporadic Parkinson's disease.
AB  - Mice with targeted disruptions in the iron-responsive binding protein 2 (IRP2)
      gene accumulate iron in distinct regions of the brain and develop
      neurodegenerative characteristics resembling Parkinson's disease after 6 months
      of age. To determine whether polymorphisms in IRP2 predispose humans to
      Parkinson's disease (PD), we sequenced the IRP2 gene of subjects with sporadic PD
      and normal controls. Three polymorphisms which result in an amino acid change
      were identified: L159V, F272L, and T560I. The L159V and T560I polymorphisms,
      identified in an African-American PD subject, were found in the African-American
      population at an allele frequency of 0.102 (n = 1,236) and 0.111 (n = 1,228),
      respectively, and were not associated with an increased prevalence of PD. The
      F272L polymorphism was found in a normal 58-year-old, Caucasian subject whose
      father had PD, but it was not observed in 38 additional patients with sporadic
      PD. The F272L polymorphism occurred at an allele frequency of 0.0014 (n = 1,384)
      in the normal Caucasian population. Additional F272L heterozygous subjects
      identified in the normal population did not have a family or personal history of
      PD. We conclude that these IRP2 polymorphisms do not play an important role in
      the development of sporadic cases of PD. It remains to be determined whether
      other polymorphisms in IRP2 play a role in familial PD.

PMID- 12465073
TI  - Case-control study of dopamine transporter-1, monoamine oxidase-B, and catechol-O
      methyl transferase polymorphisms in Parkinson's disease.
AB  - We investigated the association of Parkinson's disease (PD) with dopamine
      transporter-1 (DAT1), monoamine oxidase-B (MAO-B), and catechol-O
      methyltransferase (COMT) gene polymorphisms. Overall, we observed no significant
      association of PD with the DAT1-3'-variable numbers of tandem repeats, the MAO-B
      (GT)(n), and the COMT-Val108Met gene polymorphisms in a sample of 319 unrelated
      PD cases and 196 control subjects. Analyses stratified by sex, age at
      examination, family history of PD, and ethnic origin also yielded negative
      findings, with three exceptions. We found statistically significant associations
      of PD with MAO-B polymorphisms in older patients and with a COMT polymorphism in
      younger subjects and in women. These significant differences at the two-tailed
      alpha level of 0.05 and restricted to subgroup analyses may have a biological
      basis or may be chance findings.

PMID- 12465074
TI  - Beginning-of-dose and rebound worsening in MPTP-treated common marmosets treated
      with levodopa.
AB  - A wide range of motor fluctuations develop in Parkinson's disease (PD) patients
      after prolonged levodopa (L-dopa) treatment, but few experimental models exist in
      which these can be investigated. We report on motor fluctuations occurring in
      MPTP-treated common marmosets (Callithrix jacchus) treated repeatedly with L
      dopa. All animals showed an improvement in motor function in response to L-dopa,
      and rapidly developed peak-dose dyskinesia. During the period of L-dopa action,
      brief periods of immobility were occasionally observed. After acute L-dopa
      challenge, animals exhibited a worsening of motor function before improvement,
      and after the beneficial response to L-dopa declined, motor performance showed
      rebound worsening to below-baseline values. Before L-dopa challenge and during
      wearing-off and rebound worsening, leg dystonias were observed. Although these
      findings cannot necessarily be generalized to all MPTP-treated nonhuman primates,
      they demonstrate that MPTP-treated marmosets show a range of different motor
      fluctuations analogous to those seen in PD patients chronically treated with L
      dopa. Therefore, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated
      primates can provide a model in which the pathophysiology of treatment
      complications can be investigated.

PMID- 12465075
TI  - Sublingual atropine for sialorrhea secondary to parkinsonism: a pilot study.
AB  - Sialorrhea is a relatively common symptom in idiopathic Parkinson's disease and
      related conditions for which most of the accepted treatments are either highly
      invasive or may cause substantial systemic side effects. This study describes an
      open-label pilot study of sublingual atropine drops for the treatment of
      sialorrhea in 7 patients (6 with Parkinson's disease, 1 with progressive
      supranuclear palsy). Participants demonstrated statistically significant declines
      in saliva production, both objectively and subjectively. Self-reported drooling
      severity showed a significant decline between baseline and 180 minutes, t(6) =
      3.240 P < 0.025 (eta(2) = 0.636), and between baseline and 1 week, t(6) = 4.583 P
      < 0.005 (eta(2) = 0.778). Objectively measured saliva production decreased
      significantly between baseline and the 1-week follow-up, t(6) = 2.711 P < 0.05
      (eta(2) = 0.551). Delirium occurred in 1 patient (concurrent with a urinary tract
      infection), and 2 patients experienced worsening of hallucinations (active
      hallucinosis was concealed by both individuals to allow participation in the
      trial). The remaining trial participants did not experience any anticholinergic
      side effects. This trial shows that, in selected patient populations, sublingual
      atropine is a simple and inexpensive treatment for sialorrhea associated with
      parkinsonism.

PMID- 12465076
TI  - An imaging study of parkinsonism among African-Caribbean and Indian London
      communities.
AB  - We previously reported on 131 parkinsonian patients of African-Caribbean and
      Indian origin attending movement disorders clinics in six London Hospitals, of
      whom approximately 20% manifested atypical parkinsonism with a late-onset,
      akinetic-rigid predominant syndrome, postural instability and minimal resting
      tremor refractory to levodopa therapy and dopamine agonists (see Hu et al.,
      Neurology 2000;54[Suppl.3]: A188 and Hu et al., Mov Disord
      2000;15[Suppl.3]:S212). To better elucidate the phenotype of these atypical
      patients (18)FDG/(18)F-dopa positron emission tomography (PET) were performed in
      a subgroup to look for cortical and striatal metabolic changes suggestive of
      multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal
      degeneration (CBD), or dementia with Lewy bodies. Magnetic resonance imaging
      (MRI) rating of cerebral vascular lesion load, putaminal atrophy, and
      neuropsychological testing were also performed. Discriminant function analysis of
      (18)F-dopa/(18)FDG striatal metabolism in 43 patients failed to separate atypical
      ethnic minority from typical Caucasian Parkinson's disease (PD) patients.
      Additionally, atypical Indian and African-Caribbean patients did not show
      cortical reductions in glucose metabolism suggestive of PSP, CBD, or DLB.
      Cerebral vascular lesion load rated in these patients did not differ between
      atypical and typical PD groups, and none of the atypical patients had MRI changes
      suggestive of MSA or PSP. Our results suggest the atypical parkinsonian phenotype
      seen in African-Caribbean and Indian patients represents a levodopa-refractory
      form of PD separate from MSA or PSP in most patients.

PMID- 12465077
TI  - Juvenile parkinsonism as a manifestation of systemic lupus erythematosus: case
      report and review of the literature.
AB  - Involvement of the central nervous system in systemic lupus erythematosus (SLE)
      has been well described. It usually includes psychiatric disturbance, seizures,
      and cranial nerve disorders. Movement disorders are less common, chorea being the
      one most frequently described. A parkinsonian syndrome may be an extremely rare
      manifestation of cerebral lupus. We report on a case of juvenile parkinsonism as
      a manifestation of SLE and review the literature.

PMID- 12465078
TI  - Neurophysiological investigations in patients with primary writing tremor.
AB  - The pathophysiology of primary writing tremor (PWT) is still unknown: it has been
      classified as a focal form of essential tremor and as a tremulous form of
      writer's cramp. We studied cortical and spinal excitability in patients with PWT
      and compared the results with published data of patients with essential tremor,
      and writer's cramp. We used electrical stimulation of median and radial nerve to
      study reciprocal inhibition of forearm antagonist muscles and paired transcranial
      magnetic stimulation at short and long interstimulus intervals (ISIs) to assess
      intracortical excitability. Both studies were conducted on patients with PWT and
      on control subjects. The early (presynaptic) and late (disynaptic) phases of
      reciprocal inhibition were normal as was intracortical excitability at short and
      long ISIs. Our study suggests that the pathophysiology of PWT is different from
      that of writer's cramp and partially also from that of essential tremor.

PMID- 12465079
TI  - Cooling improves the writing performance of patients with writer's cramp.
AB  - Cooling of hand and forearm muscles by immersion in 15 degrees C cold water for 5
      minutes improved the writing performance of patients with writer's cramp. Since
      abnormal processing of muscle spindle afferent discharges contributes to the
      pathology of writer's cramp, this effect might result from a reduction in muscle
      spindle activity by lowering muscle temperature. Cooling is a simple, cheap, and
      safe procedure, providing temporary relief for patients with writer's cramp.

PMID- 12465080
TI  - Progressive delayed-onset dystonia after cerebral anoxic insult in adults.
AB  - The basal ganglia, especially the globi pallidi (GP), are highly vulnerable to
      generalized cerebral anoxia/hypoxia. We report on 2 new cases with delayed-onset
      generalized dystonia due to cerebral anoxia. The onset of dystonia in both of our
      patients was delayed by about 2 months. In both cases, the unusual feature was
      the progressive worsening and the spread of dystonia over many years after
      delayed onset. Dystonia progressed for 16 years in Case 1 and for 4 years in Case
      2. Furthermore, initial magnetic resonance imaging (MRI) scan of Case 1 showed
      mild changes of the internal capsule sparing the basal ganglia. Years later, in
      line with clinical progression, the follow-up MRI scan showed isolated bilateral
      lesions involving the entire GP. MRI scans in Case 2 showed bilateral lesions of
      caudate and lentiform nuclei. There may be several mechanisms underlying delayed
      and progressive symptoms after time-limited brain anoxia. We hypothesize that
      anoxia-induced excitotoxicity resulting in mitochondrial dysfunction and
      subsequent apoptosis may explain, at least partly, the delayed-onset and
      progressive extrapyramidal syndromes seen in these patients.

PMID- 12465081
TI  - Presumed rapid eye movement behavior disorder in Machado-Joseph disease
      (spinocerebellar ataxia type 3).
AB  - Rapid eye movement behavior disorder (RBD) is a recently recognized sleep
      disorder in which patients are occasionally not paralyzed during the dream
      portions of sleep. When not idiopathic, this state has been associated primarily
      with parkinsonian conditions but also with a small number of medications and
      other neurodegenerative disorders. Dopamine deficiency may play a role in some
      patients. This report describes the occurrence of a syndrome that appears to be
      RBD in 6 of 7 patients followed with Spinocerebellar ataxia type 3 (Machado
      Joseph disease). Polysomnography was normal in 1 patient. Two of these patients
      had had single photon emission computed tomographic imaging of the dopamine
      transporter 1 year previously.

PMID- 12465082
TI  - Metric characteristics of the drug-induced extrapyramidal symptoms scale
      (DIEPSS): a practical combined rating scale for drug-induced movement disorders.
AB  - The metric properties of the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS)
      were examined in 182 subjects treated with antipsychotics. Inter-rater
      reliability, test-retest reliability, and concurrent validity with other rating
      scales for EPS were high. Four factors were identified and the optimal diagnostic
      cut-off scores were obtained. These results suggest that the DIEPSS is a reliable
      and valid multidimensional rating scale.

PMID- 12465083
TI  - Cabergoline plasma concentration is increased during concomitant treatment with
      itraconazole.
AB  - We report on 2 patients with idiopathic Parkinson's disease who experienced
      marked improvement in symptoms following the addition of itraconazole to current
      cabergoline treatment. Plasma levels of cabergoline were analyzed in one of the
      patients and increased to approximately 300% during treatment with itraconazole,
      which paralleled major clinical improvement.

PMID- 12465084
TI  - Entacapone-induced hepatotoxicity and hepatic dysfunction.
AB  - We describe 2 patients with Parkinson's disease who developed hepatotoxicity
      associated with the use of entacapone, a novel, mainly peripheral acting
      inhibitor of catechol-D-methyltransferase. Hepatotoxicity resolved rapidly with
      discontinuation of the drug. Analysis of causality in a further case initially
      linked to entacapone exposure was confounded by conflicting serial adverse
      reaction reports.

PMID- 12465085
TI  - Clozapine withdrawal symptoms in a Parkinson's disease patient.
AB  - Abrupt clozapine withdrawal can cause rebound psychosis and severe somatic
      symptoms in psychiatric patients. We report on the case of an advanced
      Parkinson's disease patient who developed myoclonus, tremor, rigidity,
      hyperreflexia, and stupor after abrupt clozapine withdrawal. The patient's
      symptoms resolved with treatment with cyproheptadine. This clinical picture
      suggests serotonergic rebound as an explanation for the patient's symptoms,
      although other pharmacological mechanisms are possible. Clozapine should be
      gradually withdrawn over a period of 1 to 2 weeks when possible, and abruptly
      discontinued only when necessary.

PMID- 12465086
TI  - Hemiballism after subthalamotomy in patients with Parkinson's disease: report of
      2 cases.
AB  - The occurrence of persistent hemiballism after subthalamotomy for Parkinson's
      disease (PD) has not been described as frequently as mild or transient
      dyskinesia. We report on 2 patients with advanced PD who developed hemiballism
      and/or dyskinesia after subthalamotomy. One patient with a small lesion confined
      to the subthalamic nucleus (STN) developed persistent hemiballism; the other with
      a larger lesion involving the STN and also the zona incerta presented with a
      transient dyskinesia in a single limb. We conclude that a precise STN lesion
      might bear a potential risk of persistent hemiballism.

PMID- 12465087
TI  - Transient mania with hypersexuality after surgery for high frequency stimulation
      of the subthalamic nucleus in Parkinson's disease.
AB  - Among 30 Parkinson's disease patients who received high frequency stimulation of
      the subthalamic nucleus, 5 developed remarkable disorders of mood or sexual
      behavior after the implant. We describe 2 men who developed mania and
      hypersexuality a few days after the implant that lasted for some months and then
      gradually disappeared spontaneously.

PMID- 12465088
TI  - Steele-Richardson-Olszewski syndrome in a patient with a single C212Y mutation in
      the parkin protein.
AB  - Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of
      unknown aetiology, most frequently sporadic. Familial cases of SROS have been
      described. An intronic polymorphism of the tau gene is associated with sporadic
      SROS and mutations of the tau gene are present in atypical cases of SROS. The
      role of tau has been excluded in other families with pathology proven SROS,
      suggesting that this syndrome may have multiple causes. An 82-year-old patient,
      father of 3 children with autosomal recessive juvenile parkinsonism due to
      combined heterozygous mutations of the parkin gene, developed clinical features
      of SROS 2 years before death. The diagnosis was confirmed by pathology. He
      carried the C212Y mutation of the parkin gene and was homozygous for the A0
      polymorphism and for the H1 haplotype. The role of parkin in the processing of
      tau is discussed.

PMID- 12465089
TI  - Hemichorea as an initial manifestation of moyamoya disease: reversible striatal
      hypoperfusion demonstrated on single photon emission computed tomography.
AB  - We describe a case with unilateral moyamoya disease that showed progressive
      hemichorea as an initial manifestation. Single photon emission computed
      tomography showed perfusion defect in the contralateral basal ganglia although
      magnetic resonance imaging was unremarkable. Hemichorea improved along with
      normalization of perfusion after bypass surgery, suggestive of striatal
      hypoperfusion as the cause of hemichorea.

PMID- 12465090
TI  - Unilateral pallidal stimulation for segmental cervical and truncal dystonia:
      which side?
AB  - We present a 24-year-old man with idiopathic segmental cervical and truncal
      dystonia of juvenile onset. His condition improved after unilateral stimulation
      of the internal globus pallidus ipsilateral to the contracting
      sternocleidomastoid muscle.

PMID- 12465091
TI  - Further case of paroxysmal exercise-induced dystonia and some insights into
      pathogenesis.
AB  - Cerebrospinal fluid (CSF) analysis of pterin and monamine metabolites was
      performed before and after an attack in a patient with paroxysmal exercise
      induced dystonia. A twofold increase in CSF homovanillic acid and 5
      hydroxyindoleacetic acid after an attack was measured. This finding lends support
      to the hypothesis that increased dopaminergic transmission contributes to the
      clinical features of the hyperkinetic movement disorders.

PMID- 12465092
TI  - Forty-one year follow-up of childhood-onset opsoclonus-myoclonus-ataxia:
      cerebellar atrophy, multiphasic relapses, and response to IVIG.
AB  - We report on an adult with opsoclonus-myoclonus-ataxia syndrome experiencing
      widely spaced neurological relapses, who was followed for 41 years. His responses
      to treatment are described.

PMID- 12465093
TI  - Hereditary chin trembling: a new family with exclusion of the chromosome 9q13-q21
      Locus.
AB  - Hereditary chin trembling is a rare autosomal dominant condition that has been
      linked to chromosome 9q13-21 in one kindred. We describe a four-generation family
      with this condition and, using linkage analysis, have excluded the 9q13-21 region
      as causing the chin trembling in this family.

PMID- 12465094
TI  - Holmes' tremor and neuroparacoccidioidomycosis: a case report.
AB  - We report on a case of neuroparacoccidioidomycosis that presented with a midbrain
      mass lesion associated with Holmes' tremor. The difficulties of pharmacological
      treatment of such tremor are emphasized.

PMID- 12465095
TI  - Oculo-auricular phenomenon secondary to vestibular dysfunction.
AB  - The oculo-auricular phenomenon consists of coactivation of the ocular rectus
      lateralis and the posterior muscles of both ears (transverse auriculae and
      obliquus auriculae muscles). This coactivation produces a bilateral curling of
      auricles during extreme lateral gaze that can be observed in as much as an 80% of
      the normal population. We herein describe a 26-year-old man who presented a
      transient oculo-auricular phenomenon in the course of a vestibular vertigo.

PMID- 12465096
TI  - Early-onset parkinsonism in cerebrotendinous xanthomatosis.

PMID- 12465097
TI  - Chorea in motor neuron disease.

PMID- 12465100
TI  - Dynamic activity-induced manganese-dependent contrast magnetic resonance imaging
      (DAIM MRI).
AB  - Activity-induced manganese-dependent contrast (AIM) MRI is a hemodynamic
      independent functional MRI method that used manganese ion as an MR-detectable
      contrast agent. In AIM, MnCl(2) is infused intra-arterially after the blood-brain
      barrier (BBB) is opened with a hyperosmolar agent. Upon functional stimulation of
      the brain, Mn(2+) accumulates in the active region(s) by entering active cells
      through voltage-gated Ca(2+) channels, causing local signal increases in T(1)
      weighted images. The contrast of AIM MRI depends strongly on the depth of
      anesthesia, and the low levels used in somatosensory stimulation studies can lead
      to significant nonspecific accumulation of manganese ion throughout the brain.
      The purpose of this study was to produce an AIM functional map of somatosensory
      stimulation, which separates the stimulation-specific signal increase from the
      nonspecific activation due to light anesthesia. A dynamic AIM (DAIM) paradigm was
      developed, which used sequential MR scans during MnCl(2) infusion, prior to and
      following functional stimulation of the brain. Stimulation-specific functional
      maps were produced using time-course analysis. The new method was tested during
      glutamate administration and electric stimulation of the rat forepaw. It was
      shown that DAIM maps are better confined to the specific region of brain
      activated by somatosensory stimulation as compared to AIM MRI.

PMID- 12465101
TI  - FIESTA-ET: high-resolution cardiac imaging using echo-planar steady-state free
      precession.
AB  - This work describes a technique that combines multishot echo-planar imaging (EPI)
      with steady-state free precession (SSFP, also known as TrueFISP, FIESTA, and
      balanced FFE) for multislice, cine MR imaging of the heart. Unlike recently
      reported methods, the technique presented here (FIESTA-ET) is high-resolution and
      does not require offline reconstruction or postprocessing. It is therefore
      suitable for use on standard clinical scanners. FIESTA-ET was compared with
      conventional FIESTA imaging in 10 volunteers and quantitative analyses of
      myocardial signal-to-noise ratios (SNR) and ventricular volumes were performed.
      While providing comparable image quality, FIESTA-ET required half the acquisition
      time per slice of conventional FIESTA. Because multiple slices could be imaged in
      a single breathhold, the entire heart could be scanned in less than 2 min.
      Although the FIESTA-ET images exhibited an unexpected increase (P < 0.0005) in
      myocardial SNR of 16% over FIESTA, the volumetric measurements showed excellent
      correlation.

PMID- 12465102
TI  - Reproducibility of localized 2D correlated MR spectroscopy.
AB  - The test-retest reliability of two-dimensional (2D) correlated spectroscopy
      (COSY) was studied on a whole-body 1.5T MRI scanner. Single-voxel localized 2D
      proton spectra were recorded in vitro as well as in vivo using a recently
      implemented localized chemical shift correlated spectroscopic (L-COSY) sequence.
      A total of 40 in vitro and 40 human brain (10 volunteers, four times each) 2D L
      COSY spectra were recorded. The coefficients of variation (CVs) of selected brain
      metabolites (raw volume integrals) recorded in 10 healthy volunteers were less
      than 9% for creatine, choline, and N-acetyl aspartate, and less than 17% for myo
      inositol, glutamine/glutamate, aspartate, and threonine/lactate. The 2D
      metabolite ratios and the raw volume integrals of 2D diagonal and cross peaks in
      healthy human brain were very well reproduced. The intraclass correlation
      coefficients were greater than 0.4 (P < 0.05) for the major metabolites,
      indicating that the 2D peak volumes were stable enough within individuals to
      detect reliable differences between normal subjects.

PMID- 12465103
TI  - Brain metabolite composition during early human brain development as measured by
      quantitative in vivo 1H magnetic resonance spectroscopy.
AB  - Biochemical maturation of the brain can be studied noninvasively by (1)H magnetic
      resonance spectroscopy (MRS) in human infants. Detailed time courses of cerebral
      tissue contents are known for the most abundant metabolites only, and whether or
      not premature birth affects biochemical maturation of the brain is disputed.
      Hence, the last trimester of gestation was observed in infants born prematurely,
      and their cerebral metabolite contents at birth and at expected term were
      compared with those of fullterm infants. Successful quantitative short-TE (1)H
      MRS was performed in three cerebral locations in 21 infants in 28 sessions
      (gestational age 32-43 weeks). The spectra were analyzed with linear combination
      model fitting, considerably extending the range of observable metabolites to
      include acetate, alanine, aspartate, cholines, creatines, gamma-aminobutyrate,
      glucose, glutamine, glutamate, glutathione, glycine, lactate, myo-inositol,
      macromolecular contributions, N-acetylaspartate, N-acetylaspartylglutamate, o
      phosphoethanolamine, scyllo-inositol, taurine, and threonine. Significant effects
      of age and location were found for many metabolites, including the previously
      observed neuronal maturation reflected by an increase in N-acetylaspartate.
      Absolute brain metabolite content in premature infants at term was not
      considerably different from that in fullterm infants, indicating that prematurity
      did not affect biochemical brain maturation substantially in the studied
      population, which did not include infants of extremely low birthweight.

PMID- 12465104
TI  - Anomalous nuclear magnetic relaxation of aqueous solutions of ferritin: an
      unprecedented first-order mechanism.
AB  - Ferritin, the iron-storing protein, speeds up proton transverse magnetic
      relaxation in aqueous solutions. This T(2) shortening is used in MRI to quantify
      iron in the brain and liver. Current theoretical models underestimate the
      relaxation enhancement by ferritin at imaging fields, and they do not predict the
      measured dependence of the rate enhancement on the magnetization of the
      particles. Here it is shown that a proton exchange dephasing model (PEDM)
      overcomes these limitations by allowing a first-order relaxation mechanism. The
      PEDM considers proton exchange between bulk water and exchangeable protons
      located at the surface of the hydrated iron oxide nanometric core of the protein.
      Relaxation is shown to depend on the distribution of the frequency shifts of the
      adsorption sites; the observed properties agree with a Lorentzian distribution.
      Computer simulations utilizing recent Mossbauer spectroscopy data show that the
      distribution of these shifts is effectively Lorentzian.

PMID- 12465105
TI  - Magnetic resonance relaxivity of dendrimer-linked nitroxides.
AB  - The relaxivity and bioreduction rates of eight dendrimer-linked nitroxides
      varying in the number of nitroxides per molecule were measured and the potential
      use of these compounds as MR contrast agents was demonstrated. The T(1) and T(2)
      relaxivities, measured at room temperature and 1.5 T, varied linearly with the
      number of nitroxides per molecule for compounds with up to 16 nitroxides per
      molecule. Fourth-generation polypropylenimide- (DAB) and third-generation
      polyamidoamine- (PAMAM) dendrimer-linked nitroxides were found to have greater
      relaxivity than gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). The
      greater number of nitroxides per dendrimer increased relaxivity over that of a
      single nitroxide, allowing a decreased dose to achieve differential contrast with
      MR evaluations. Rates of nitroxide bioreduction were below detection threshold
      using EPR spectroscopy for generation 2 dendrimers and higher. A pilot assessment
      of in vivo cartilage uptake that compared intraarticular injection of three
      structurally different dendrimer-linked nitroxides with Gd-DTPA and with saline
      demonstrated high affinity of the DAB-dendrimer-linked nitroxides for normal
      rabbit articular cartilage. From these results, it is evident that target
      specific dendrimer-linked nitroxides can be designed.

PMID- 12465106
TI  - Magnetization structure contrast based on intermolecular multiple-quantum
      coherences.
AB  - In vivo and ex vivo MRI based on intermolecular multiple-quantum coherences
      (iMQC) is predicted to provide a fundamentally different source of contrast for
      MRI. This article investigates the dependence of image contrast upon the choice
      of correlation distance for a heterogeneous material. A closely packed array of
      parallel hollow cylinders was used to demonstrate signal intensity variations
      when the correlation distance becomes comparable to the gap size between the
      cylinders. The observed effects agree well with three-dimensional calculations of
      the time evolution of magnetization under the nonlinear Bloch equations.

PMID- 12465107
TI  - How does blood oxygen level-dependent (BOLD) contrast correlate with oxygen
      partial pressure (pO2) inside tumors?
AB  - Blood oxygen level-dependent (BOLD) contrast-based functional MRI (fMRI) has been
      reported as a method to assess the evolution of tumor oxygenation after hyperoxic
      treatments, because of its sensitivity to changes in blood flow and
      deoxyhemoglobin content. However a number of questions remain: 1) In view of
      tumor heterogeneity, how good is the correlation between the MR parameters in
      gradient-echo imaging (signal intensity (SI) or effective transverse relaxation
      time (T(*)(2))) and local tumor oxygen partial pressure (pO(2))? 2) Is the
      magnitude of the change in SI or T(*)(2) a quantitative marker for variation in
      pO(2)? 3) Is initial T(*)(2) a good marker for initial pO(2)? To address these
      questions, murine tumors were imaged during respiratory challenges at 4.7 Tesla,
      using fiber-optic microprobes to simultaneously acquire tumor pO(2) and
      erythrocyte flux. The BOLD signal response (SI and T(*)(2)) was temporally
      correlated with changes in pO(2). However, the magnitude of the signal bore no
      absolute relation to pO(2) across tumors, i.e., a given change in SI corresponded
      to a 25 mmHg pO(2) change in one tumor, but to a 100 mmHg change in another. The
      initial T(*)(2) value did not reliably predict tumor oxygenation at the beginning
      of the experiment. In conclusion, the major advantages of the technique include
      noninvasiveness, high spatial resolution, and real-time detection of pO(2)
      fluctuations. Information afforded by the BOLD imaging technique is qualitative
      in nature and may be combined with other techniques capable of providing an
      absolute measure of pO(2).

PMID- 12465108
TI  - Transient relationships among BOLD, CBV, and CBF changes in rat brain as detected
      by functional MRI.
AB  - The transient relationship between arterial cerebral blood flow (CBF(A)) and
      total cerebral blood volume (CBV(T)) was determined in the rat brain. Five rats
      anesthetized with urethane (1.2 g/kg) were examined under graded hypercapnia
      conditions (7.5% and 10% CO(2) ventilation). The blood oxygenation level
      dependent (BOLD) contrast was determined by a gradient-echo echo-planar imaging
      (GE-EPI) pulse sequence, and CBV(T) changes were determined after injection of a
      monocrystalline iron oxide nanocolloid (MION) contrast agent using an iron dose
      of 12 mg/kg. The relationship between CBV(T) and CBF(A) under transient
      conditions is similar to the power law under steady-state conditions. In
      addition, the transient relationship between CBV(T) and CBF(A) is region
      specific. Voxels with > or =15% BOLD signal changes from hypercapnia (7.5% CO(2)
      ventilation) have a larger power index (alpha = 3.26), a larger maximum possible
      BOLD response (M = 0.85), and shorter T(*)(2) (32 ms) caused by deoxyhemoglobin,
      compared to voxels with <15% BOLD signal changes (alpha = 1.82, M = 0.16, and
      T(*)(2) = 169 ms). It is suggested that the biophysical model of the BOLD signal
      can be extended under the transient state, with a caution that alpha and M values
      are region-specific. To avoid overestimation of the cerebral metabolic rate of
      oxygen changes seen using fMRI, caution should be taken to not include voxels
      with large veins and a large BOLD signal.

PMID- 12465109
TI  - Water ADC, extracellular space volume, and tortuosity in the rat cortex after
      traumatic injury.
AB  - The diffusion parameters in rat cortex were studied 3-35 days following a
      cortical stab wound, using diffusion-weighted MR to determine the apparent
      diffusion coefficient of water (ADC(W)) in the tissue, and the real-time
      iontophoretic tetramethylammonium (TMA) method to measure the extracellular space
      (ECS) diffusion parameters: ECS volume fraction alpha and the ADC of TMA(+)
      (ADC(TMA)). Severe astrogliosis was found close to the wound, and mild
      astrogliosis was found in the ipsilateral but not the contralateral cortex.
      Chondroitin sulfate proteoglycan (CSPG) expression was increased throughout the
      ipsilateral cortex. In the hemisphere contralateral to the wound, alpha,
      ADC(TMA), and ADC(W) were not significantly different from control values. ECS
      volume fraction was increased only in the vicinity of the wound, in the region of
      cell death and severe astrogliosis, at 3 and 7 days after injury. However, both
      ADC(TMA) and ADC(W) were significantly decreased after lesion in the vicinity of
      the wound as well as in the rest of the ipsilateral hemisphere distant from the
      wound. Thus, both ADC(W) and ADC(TMA) decreased in regions wherein alpha did not
      change but CSPG increased. An increase in extracellular matrix expression may
      therefore impose diffusion barriers for water as well as for TMA molecules.

PMID- 12465110
TI  - Automatic selection of mask and arterial phase images for temporally resolved MR
      digital subtraction angiography.
AB  - For time-resolved background-subtracted contrast-enhanced magnetic resonance
      angiography, the bright and sparse arterial signal allows unique identification
      of contrast bolus arrival in the arteries. This article presents an automatic
      filtering algorithm using such arterial characterization for selecting arterial
      phase images and mask images to generate an optimal summary arteriogram. A paired
      double-blinded comparison demonstrated that this automatic algorithm is as
      effective as the manual process.

PMID- 12465111
TI  - Application of sensitivity-encoded echo-planar imaging for blood oxygen level
      dependent functional brain imaging.
AB  - The benefits of sensitivity-encoded (SENSE) echo-planar imaging (EPI) for
      functional MRI (fMRI) based on blood oxygen level-dependent (BOLD) contrast were
      quantitatively investigated at 1.5 T. For experiments with 3.4 x 3.4 x 4.0 mm(3)
      resolution, SENSE allowed the single-shot EPI image acquisition duration to be
      shortened from 24.1 to 12.4 ms, resulting in a reduced sensitivity to geometric
      distortions and T(*)(2) blurring. Finger-tapping fMRI experiments, performed on
      eight normal volunteers, showed an overall 18% loss in t-score in the activated
      area, which was substantially smaller than expected based on the image signal-to
      noise ratio (SNR) and g-factor, but similar to the loss predicted by a model that
      takes physiologic noise into account.

PMID- 12465112
TI  - Method for efficient fast spin echo Dixon imaging.
AB  - In order to satisfy the Carr-Purcell-Meiboom-Gill (CPMG) condition, echo shift as
      dictated in fast-spin-echo (FSE)-based Dixon imaging was previously achieved by
      applying a time shift to the readout gradient and the data acquisition window.
      Accordingly, interecho spacing is increased, which entails increased image
      blurring and, in multislice imaging, a significant reduction in the slice
      coverage for a given imaging time. In this work, a new method is developed by
      which the echo shift is induced by "sandwiching" in time the readout gradient
      with a pair of small gradients of equal area and of opposite polarity. While data
      with non-zero phase shifts between water and fat signals are collected as
      fractional echoes, no increase in echo spacing is necessary with the modified
      acquisition strategy, and increased time efficiency is therefore achieved. In
      order to generate separate water-only and fat-only images in data processing, a
      set of low-resolution images are first reconstructed from the central symmetric
      portion (either 128 x 128 or 64 x 64) of the acquired multipoint Dixon data. High
      resolution images using all the acquired data, including some partial Fourier
      reconstructed images, are then phase demodulated using the phase errors
      determined from the low-resolution images. The feasibility of the technique is
      demonstrated using a water and fat phantom as well as in clinical patient
      imaging.

PMID- 12465113
TI  - Band artifacts due to bulk motion.
AB  - Band artifacts due to bulk motion were investigated in images acquired with fast
      gradient echo sequences. A simple analytical calculation shows that the width of
      the artifacts has a square-root dependence on the velocity of the imaged object,
      the time taken to acquire each line of k-space and the field of view in the phase
      encoding direction. The theory furthermore predicts that the artifact width can
      be reduced using parallel imaging by a factor equal to the square root of the
      acceleration parameter. The analysis and results are presented for motion in the
      phase- and frequency-encoding directions and comparisons are made between
      sequential and centric ordering. The theory is validated in phantom experiments,
      in which bulk motion is simulated in a controlled and reproducible manner by
      rocking the scan table back and forth along the bore axis. Preliminary cardiac
      studies in healthy human volunteers show that dark bands may be observed in the
      endocardium in images acquired with nonsegmented fast gradient echo sequences.
      The fact that the position of the bands changes with the phase-encoding direction
      suggests that they may be artifacts due to motion of the heart walls during the
      image acquisition period.

PMID- 12465114
TI  - Finite difference time domain (FDTD) method for modeling the effect of switched
      gradients on the human body in MRI.
AB  - Numerical modeling of the eddy currents induced in the human body by the pulsed
      field gradients in MRI presents a difficult computational problem. It requires an
      efficient and accurate computational method for high spatial resolution analyses
      with a relatively low input frequency. In this article, a new technique is
      described which allows the finite difference time domain (FDTD) method to be
      efficiently applied over a very large frequency range, including low frequencies.
      This is not the case in conventional FDTD-based methods. A method of implementing
      streamline gradients in FDTD is presented, as well as comparative analyses which
      show that the correct source injection in the FDTD simulation plays a crucial
      rule in obtaining accurate solutions. In particular, making use of the derivative
      of the input source waveform is shown to provide distinct benefits in accuracy
      over direct source injection. In the method, no alterations to the properties of
      either the source or the transmission media are required. The method is
      essentially frequency independent and the source injection method has been
      verified against examples with analytical solutions. Results are presented
      showing the spatial distribution of gradient-induced electric fields and eddy
      currents in a complete body model.

PMID- 12465115
TI  - Interleaved pulsed MAMBA: a new parallel slice imaging method.
AB  - A method of acquiring slices in parallel is described which uses interleaved sets
      of pulsed B(0) field coils to generate discrete regions of uniform field within
      the main magnetic field known as interleaved MAMBA (multiple acquisition micro
      B(0) array). Simulations of a number of coil designs were performed using the
      Biot-Savart law. A six-step coil was built and interfaced to a 0.17 T Niche MRI
      system and the field steps measured using an imaging technique. Measured field
      steps were in good agreement with the values predicted by simulation. The coil
      design was then scaled up by a factor of three, interfaced to a 1.5 T whole-body
      MRI system, and scans of the hands and arms of volunteers were acquired from up
      to four field steps using standard spin and gradient echo sequences. Images were
      also acquired simultaneously from two field steps with no frequency encode
      aliasing and one excitation. The one-dimensional interleaved pulsed MAMBA step
      field technique shows great promise for enabling many slices to be acquired
      simultaneously along the axis of the coil for rapid volumetric studies without
      the need for multiple shot Hadamard encoding. Extension of interleaved coil
      design to two or three dimensions is feasible, which could provide full spatial
      coverage combined with ultra-rapid data acquisition.

PMID- 12465116
TI  - Consequences of nitric oxide generation in epileptic-seizure rodent models as
      studied by in vivo EPR.
AB  - The role of nitric oxide (NO) in epileptogenesis was studied in
      pentylenetetrazole (PTZ)-treated animals using in vivo and ex vivo EPR
      spectroscopy. NO generation was measured directly in the brain of a PTZ-induced
      mouse in vivo by an L-band EPR spectrometer. An elevation in NO production in the
      brain was observed during convulsions, and more NO was generated in the tonic
      seizure vs. the clonic seizure. NO content in several brain tissues (including
      the cerebral cortex (CR), cerebellum (CL), olfactory bulb (OB), hippocampus (HI),
      and hypothalamus (HT)) of PTZ-doped rats was analyzed quantitatively ex vivo by X
      band EPR. To test the involvement of NO in seizure development, pharmacological
      analyses were performed using the NO synthase (NOS) inhibitors N(G)-nitro-L
      arginine (L-NNA), N(G)-monomethyl-L-arginine (L-NMMA), and 3-bromo-7
      nitroindazole (3Br-7NI). All of these inhibitors suppressed the convulsions,
      holding them at the clonic level, and prevented development of a tonic convulsion
      in rats doped with up to 80 mg/kg PTZ. 3Br-7NI completely inhibited NO
      production, but L-NNA and L-NMMA showed only 70% inhibition of NO production in
      PTZ-doped rats. In order to examine the contributions of NO in convulsions, rats
      were treated with anticonvulsants (phenytoin and diazepam) before PTZ treatment.
      Both drugs completely suppressed tonic convulsion in PTZ-doped rats at doses up
      to 80 mg/kg, but NO levels were similar to those detected in a clonic convulsion.
      These results support the notion that NO does not directly induce a clonic
      convulsion, but may be generated as a consequence of onset of seizure.

PMID- 12465117
TI  - Mapping of the B1 field distribution of a surface coil resonator using EPR
      imaging.
AB  - Surface coil resonators have been widely used to perform topical EPR
      spectroscopy. They are usually positioned adjacent to or implanted within the
      body. For EPR applications these resonators have a number of important advantages
      over other resonator designs due to their ease of sample accessibility,
      mechanical fabrication, implementation of electronic tuning and coupling
      functions, and low susceptibility to sample motions. However, a disadvantage is
      their B(1) field inhomogeneity, which limits their usefulness for 3D imaging
      applications. We show that this problem can be addressed by mapping and
      correcting the B(1) field distribution. We report the use of EPR imaging (EPRI)
      to map the B(1) distribution of a surface coil resonator. We show that EPRI
      provides a fast, accurate, and reliable technique to evaluate the B(1)
      distribution. 3D EPRI was performed on phantoms, prepared using three different
      saline concentrations, to obtain the B(1) distribution. The information obtained
      from the phantoms was used to correct the images of living animals. With the use
      of this B(1) correction technique, surface coil resonators can be applied to
      perform 3D mapping of the distribution of free radicals in biological samples and
      living systems.

PMID- 12465118
TI  - A method for measuring cerebral glucose metabolism in vivo by 13C-NMR
      spectroscopy.
AB  - Current methods for estimating the rate of cerebral glucose utilization
      (CMR(glc)) typically measure metabolic activity for 40 min or longer subsequent
      to administration of [(13)C]glucose, 2-[(14)C]deoxyglucose, or 2
      [(18)F]deoxyglucose. We report preliminary findings on estimating CMR(glc) for a
      period of 15 min by use of 2-[6-(13)C]deoxyglucose. After a 24-hr fast, rats were
      anesthetized, infused with [1-(13)C]glucose for 50 min, and injected with 2-[6
      (13)C]deoxyglucose (500 mg/kg). During the subsequent 12.95 min the estimated
      value of CMR(glc) was 0.6 +/- 0.4 micromol/min/g (mean +/- SD, N = 7), in
      agreement with values reported for anesthetized rats studied with the 2
      [(14)C]deoxyglucose method and other (13)C-NMR methods that measure CMR(glc). In
      rats injected with bicuculline methiodide (a known stimulant of CMR(glc)),
      CMR(glc) increased by more than 75% during 12.95 min following injection of
      bicuculline (Wilcoxon signed rank test, P = 0.042, N = 8).

PMID- 12465119
TI  - Relaxivity and diffusion of gadolinium agents in cartilage.
AB  - Prior work indicates that the distribution of Gd(DTPA)(2-) (as measured by T(1))
      is a good surrogate measure of the distribution of gycosaminoglycan (GAG) in
      cartilage. In addition to the measured T(1) in the presence of Gd(DTPA)(2-), the
      precision of the measurement of Gd(DTPA)(2-) concentration depends on the T(1)
      without Gd(DTPA)(2-) (T(o)(1)), and the relaxivity (r) of Gd(DTPA)(2-) in
      cartilage, parameters that are influenced by cartilage composition. These
      parameters were measured in native and GAG-depleted cartilage in order to
      estimate the bounds on the values one might expect for cartilage in arbitrary
      states of degeneration. The range of T(o)(1) was 0.3 sec; the range of r was 0.6
      (mM*s)(-1) at 8.5 T and 1.4 (mM*s)(-1) at 2 T. These data suggest that Gd(DTPA)(2
      ) will be underestimated (and GAG overestimated) if the values for T(o)(1) and r
      are assumed to be those of native cartilage. (For example, in a severe case a 90%
      loss of GAG would be underestimated as a 70% loss.) Gd(HPDO3A) was investigated
      as a nonionic "control agent" and found to have relaxivity and diffusion
      properties that were comparable to Gd(DTPA)(2-) (r(Gd(HPDO3A))/r(Gd(DTPA))
      approximately 1; D(Gd(HPDO3A))/D(Gd(DTPA)) approximately 0.85). Since Gd(HPDO3A)
      distributes uniformly through cartilage (independent of GAG), the distribution of
      T(1) with Gd(HPDO3A) can be used as a surrogate measure of variations in T(o)(1)
      and r, if present. From the perspective of transport, if Gd(HPDO3A) has fully
      penetrated the cartilage, Gd(DTPA)(2-) would have in the same time frame.
      Therefore, the data confirm the efficacy of using Gd(HPDO3A) as a "control agent"
      for dGEMRIC.

PMID- 12465120
TI  - Application of image registration to measurement of intervertebral rotation in
      the lumbar spine.
AB  - In this study, the precision and accuracy of a new method for measuring axial
      rotations of the lumbar vertebrae, which are thought to be increased in patients
      with degenerative spinal instability, were estimated. A standard image
      registration algorithm involving a user-selected center of rotation was adapted
      for this purpose. Accuracy was tested on a phantom containing a rotating lumbar
      vertebra. Calculated rotations were compared to the known values. Images were
      also obtained in subjects, using a tilting table that provided rotation between
      thorax and hips. For these measurements precision was estimated by varying the
      center of rotation. In the phantom the method had an accuracy of 0.2 degrees. In
      the human subject measurements the precision was 0.60-1.5 degrees. The method
      measured rotations of lumbar vertebrae with sufficient accuracy and precision to
      detect clinically significant differences in patients with back pain.

PMID- 12465121
TI  - Phased array ghost elimination (PAGE) for segmented SSFP imaging with interrupted
      steady-state.
AB  - Steady-state free precession (SSFP) has recently proven to be valuable for
      cardiac imaging due to its high signal-to-noise ratio and blood-myocardium
      contrast. Data acquired using ECG-triggered, segmented sequences during the
      approach to steady-state, or return to steady-state after interruption, may have
      ghost artifacts due to periodic k-space distortion. Schemes involving several
      preparatory RF pulses have been proposed to restore steady-state, but these
      consume imaging time during early systole. Alternatively, the phased-array ghost
      elimination (PAGE) method may be used to remove ghost artifacts from the first
      several frames. PAGE was demonstrated for cardiac cine SSFP imaging with
      interrupted steady-state using a simple alpha/2 magnetization preparation and
      storage scheme and a spatial tagging preparation.

PMID- 12465122
TI  - Can MTR be used to assess cartilage in the presence of Gd-DTPA2-?
AB  - Magnetization transfer (MT) and T(1) and T(2) relaxation of normal, trypsinized,
      and interleukin-1beta (IL-1beta)-treated cartilage were measured in the absence
      and presence of Gd-DTPA(2-). Without the addition of Gd-DTPA(2-), neither T(1)
      nor T(2) showed any significant change with cartilage damage. However, with Gd
      DTPA(2-), trypsinized cartilage exhibited substantially shorter T(1) than normal
      cartilage, as expected due to the glycosaminoglycan (GAG) loss in these samples,
      and associated increased Gd-DTPA(2-) concentration. The T(2) results were
      similar, but less dramatic. The MT pseudo first-order exchange rate, RM(0B), did
      not depend on the contrast agent concentration, as expected, and was
      significantly faster for trypsinized and slower for IL-1beta-treated cartilage.
      In both cases, the MT fraction of the macromolecular pool M(0B) decreased while
      only trypsinized cartilage showed an increase in MT exchange rate R. The MT ratio
      (MTR) decreased with increasing Gd-DTPA(2-) concentration. However,
      interpretation of the MTR results in the presence of Gd-DTPA(2-) was complicated
      due to competing effects of increased longitudinal relaxivity and MT exchange.
      Therefore, in a cartilage sample with an unknown degree of GAG depletion and some
      collagen damage, a full MT analysis might be used to probe the molecular state of
      cartilage, but it would not be possible to use a simple MTR measurement after the
      administration of Gd-DTPA(2-) to differentially determine the amount of cartilage
      degradation in the sample.

PMID- 12465123
TI  - Signal behavior in continuously ramped 2D TrueFISP for whole-body imaging.
AB  - A fast and robust imaging technique was developed based on a single-slice
      TrueFISP acquisition using a slice excitation frequency that is incremented, or
      spatially "ramped," with each repetition. The short acquisition time of single
      slices allows artifact-free imaging during free breathing, which demonstrates the
      potential use of this technique for whole-body screening. Overlapping positioning
      of consecutively acquired slices was used to provide gapless volume coverage in
      free-breathing measurements. The image contrast of ramped TrueFISP was analyzed
      in detail using simulations and experiments. A high ramp speed results in an
      increased overall signal intensity and in a modification of the known T(2)/T(1)
      contrast towards a proton density-weighted contrast. A further increase in
      imaging speed is achieved with z-interleaved phase-encoding trajectories based on
      weighted transitions between adjacent views.

PMID- 12465124
TI  - Remote control of catheter tip deflection: an opportunity for interventional MRI.
AB  - This study seeks to exploit the high magnetic field environment of a clinical MRI
      scanner and demonstrate the technical feasibility of developing a catheter whose
      tip can be remotely oriented within the magnetic field by applying a DC current
      to a coil wound around the catheter tip to generate a magnetic moment and
      consequent deflection. To achieve arbitrary three-dimensional deflections, a
      three-axis coil was wound on a 1.5 Fr cylindrical catheter. By applying DC
      currents in the 100 mA range, this catheter was successfully guided through a 3D
      phantom maze, mimicking the vasculature, under MR imaging guidance. Feasibility
      was demonstrated that the strong ambient magnetic field of the MR scanner offers
      a special opportunity to develop simple devices that can be remotely steered to
      sites of clinical interest.

PMID- 12465125
TI  - RF heating due to conductive wires during MRI depends on the phase distribution
      of the transmit field.
AB  - In many studies concerning wire heating during MR imaging, a "resonant wire
      length" that maximizes RF heating is determined. This may lead to the
      nonintuitive conclusion that adding more wire, so as to avoid this resonant
      length, will actually improve heating safety. Through a theoretical analysis
      using the method of moments, we show that this behavior depends on the phase
      distribution of the RF transmit field. If the RF transmit field has linear phase,
      with slope equal to the real part of the wavenumber in the tissue, long wires
      always heat more than short wires. In order to characterize the intrinsic safety
      of a device without reference to a specific body coil design, this maximum-tip
      heating phase distribution must be considered. Finally, adjusting the phase
      distribution of the electric field generated by an RF transmit coil may lead to
      an "implant-friendly" coil design.

PMID- 12465126
TI  - Introduction to this issue: disability, public policy, and employment.

PMID- 12465127
TI  - Public policy and employment of people with disabilities: exploring new
      paradigms.
AB  - A "sea change" in public attitudes, legislation, and political power at the end
      of the 20th century in the United States has helped set the stage in the early
      21st century for the entry of people with disabilities into the labor force.
      Major pieces of federal legislation have altered national policy with the
      intention of maximizing the work force participation of people with disabilities.
      At the same time, a new theoretical paradigm of disability has emerged, which
      emphasizes community inclusion, accommodation, and protection of civil rights.
      This "New Paradigm" of disability can be applied in concert with rigorous
      behavioral science methodologies to shed light on the outcomes of recent federal
      policy changes regarding the labor force participation of people with
      disabilities. In so doing, social science can be used in more meaningful ways to
      understand both the intended and unintended consequences of federal policy.

PMID- 12465128
TI  - Does U.S. federal policy support employment and recovery for people with
      psychiatric disabilities?
AB  - Evidence suggests that a high percentage of people with a psychiatric disability
      can recover--find meaningful work, develop positive relationships, and
      participate fully in their communities. Evidence also suggests that work is an
      essential component of recovery. However, few people with a serious psychiatric
      disability are actually employed and most of those who are employed work only
      part-time at barely minimum wages. To assess the impact of federal programs such
      as Social Security Disability Insurance, vocational rehabilitation, medical
      insurance, and psychiatric services upon employment, we conducted a qualitative
      study of 16 employed and 16 unemployed individuals with psychiatric disabilities.
      All of our participants had disabilities severe enough to qualify them for Social
      Security Disability benefits. They told us that current federal policies and
      practices encouraged employment and integration of only a few participants, in a
      particular stage of their recovery, and placed significant barriers in the
      employment path of others.

PMID- 12465129
TI  - Accounting for unemployment among people with mental illness.
AB  - Persons diagnosed with a serious mental illness experience significantly high
      rates of unemployment compared with the general population. The explanations for
      this situation have included a focus on the symptoms associated with these
      disorders, a focus on the lack of effective vocational rehabilitation programs
      for this population, and, most recently, a focus on employer discrimination and
      the financial disincentives to employment in various public policies. The authors
      of this manuscript review the evolution in thought pertaining to the labor market
      experiences of persons with a serious mental illness and propose as an additional
      set of factors that should be considered, those labor market liabilities that
      this population shares with others without disabilities who experience similar
      employment histories. The authors conclude that the inclusion of these factors in
      our understanding of issues that persons with serious mental illness face in the
      competitive labor market will likely lead to a further evolution in program and
      policy development.

PMID- 12465130
TI  - Dead end jobs or a path to economic well being? The consequences of non-standard
      work among people with disabilities.
AB  - How do non-standard jobs affect the economic well-being of workers with
      disabilities, and what happens when non-standard workers use disability lawsuits
      to challenge discrimination and improve their economic opportunities? This study
      uses data from the Current Population Survey, the Survey of Income and Program
      Participation, and a Lexis search of legal cases to help answer these questions.
      Temporary employment, independent contracting, and part-time employment are
      almost twice as likely among workers with disabilities as among those without
      disabilities. Non-standard workers with disabilities receive lower pay and fewer
      benefits due both to the types of job they hold, and disability gaps within job
      types, which contribute to their high poverty rates. They would continue to have
      high poverty rates even if these pay gaps were eliminated, however, because they
      work fewer hours than non-standard workers without disabilities and are
      concentrated in lower-paying occupations. In attempting to improve their
      opportunities through disability lawsuits, non-standard workers prevail in only a
      small minority of cases. Several policy implications of the lawsuits and survey
      data are discussed.

PMID- 12465131
TI  - Applicability of the ADA to "Ticket to Work" employment networks. Americans with
      Disabilities Act.
AB  - This article examines the applicability of the antidiscrimination provisions of
      the Americans with Disabilities Act (ADA) of 1990 to The Ticket to Work and Work
      Incentives Improvement Act (TWWIIA) passed in 1999. Among other policy changes,
      under the Ticket to Work program, eligible recipients of disability insurance
      (SSDI) and supplemental income (SSI) receive a voucher or "ticket" to obtain
      services from qualified employment networks (ENs). ENs provide employment
      services and supports to designated beneficiaries and must meet certain
      qualification requirements. The ADA is applicable to ENs in several ways:
      primarily, in the EN's responsibility to provide appropriate access and services
      to program participants. This article discusses application of the ADA to the
      Ticket Program as ENs begin to serve program beneficiaries.

PMID- 12465132
TI  - Employment of persons with disabilities in information technology jobs:
      literature review for "IT works".
AB  - This article reviews relevant literature as to the labor pool of qualified
      individuals with disabilities and employment in information technology (IT)
      sector jobs. First, the article reviews the empirical literature on barriers to
      employment in IT for persons with disabilities. The examination then is extended
      to studies of barriers to employment for individuals with disabilities in other
      employment sectors. Findings illustrate the limited experiences that IT and non
      IT companies have in employing and accommodating employees with disabilities.
      Implications are discussed for enhancing the employment of qualified workers with
      disabilities in IT through research, education, training, and mentoring programs.

PMID- 12465133
TI  - Cruise ships and kayaks: welfare and rehabilitation approaches for women with
      disabilities in poverty.
AB  - Women with disabilities have low employment rates and about one-third live in
      poverty. They represent half of the population using either services of the
      vocational rehabilitation (VR) system or the welfare system, and many use both.
      Although both systems have made gains in improving their employment status,
      neither comprehensively addresses the needs of this population. Welfare policy
      has encouraged state level innovation and moved large numbers of people into
      employment in as little as five years. State welfare agencies offer a range of
      services specifically addressing the needs of families with children. VR agencies
      have decades of specific experience assisting people with disabilities gain
      employment. Welfare reform has been the cruise ship moving large numbers of
      people across an ocean. VR agencies have been the kayak builders designing
      specialized small craft to move specific people along tributaries. What can they
      learn from each other?

PMID- 12465134
TI  - Evolution of disability in late 19th century America: Civil War pensions for
      Union Army veterans with musculoskeletal conditions.
AB  - This article examines the evolution of musculoskeletal (MSK) disability and its
      impact on mortality and work patterns in the late 19th century in America, in the
      context of the Civil War disability policy scheme. The study was conducted on
      17,702 Union Army (UA) Civil War veterans. Of these, 10,789 were examined and
      diagnosed with major MSK conditions, rheumatism, sciatica, and spinal curvature,
      between 1862 and 1907. Analyses examine MSK (i) prevalence rates by birth cohort
      and age group; (ii) fatality rates as compared with other disabilities; (iii)
      risk rates by occupation type; and (iv) lifespan for MSK patients. MSK conditions
      are commonly claimed disabilities within the Civil War data set, with prevalence
      rates increasing with age. Regression studies show that working in clerical and
      professional (relative to manual labor) occupations decreases the likelihood of
      being examined for and diagnosed with MSK conditions. MSK patients examined at
      older ages tended to have longer lifespan than those examined at younger ages.
      The findings suggest that changes in age, environmental, and occupational
      conditions during the late 19th century affected MSK condition prevalence and the
      average lifespan of MSK patients. Implications for contemporary disability policy
      are discussed.

PMID- 12465135
TI  - The Video Suggestibility Scale for Children: how generalizable is children's
      performance to other measures of suggestibility?
AB  - This study explored the generalizability of the Video Suggestibility Scale for
      Children (VSSC), which was developed by Scullin and colleagues (Scullin & Ceci,
      2001; Scullin & Hembrooke, 1998) as a tool for discriminating among children
      (aged three to five years) who have different levels of suggestibility. The VSSC
      consists of two subscales; Yield (a measure of children's willingness to
      acquiesce to misleading questions) and Shift (a measure of children's tendency to
      change their responses after feedback from the interviewer). Children's (N = 77)
      performance on each of the subscales was compared with their performance using
      several other measures of suggestibility. These measures included children's
      willingness to assent to a false event as well as the number of false interviewer
      suggestions and false new details that the children provided when responding to
      cued-recall questions about an independent true-biased and an independent false
      (non-experienced) event. An independent samples t-test revealed that those
      children who assented to the false event generated higher scores on the Yield
      measure. Hierarchical regression analyses revealed that Yield was a significant
      predictor of the number of false details reported about the false activity, but
      not the true-biased activity. There was no significant relationship between the
      Shift subscale and any of the dependent variables. The potential contribution of
      the VSSC for forensic researchers and practitioners is discussed.

PMID- 12465136
TI  - Feigning not equal malingering: a case study.
AB  - Researchers and scholars assert that feigning should not be equated with
      malingering. Some practicing clinicians doing the everyday work of forensic
      assessment may view this as merely an academic distinction. This case study
      illustrates that a high level of certainty about feigning must not be considered
      indicative of malingering. The case also contrasts two models for assessing
      malingering and highlights the need for forensic examiners to present assessment
      of-malingering data clearly and cautiously.

PMID- 12465137
TI  - WOMAC: a 20-year experiential review of a patient-centered self-reported health
      status questionnaire.

PMID- 12465138
TI  - The hand: a second face?

PMID- 12465139
TI  - Pharmacogenetics for the individualization of treatment of rheumatic disorders
      using azathioprine.

PMID- 12465140
TI  - Metacarpophalangeal arthroplasty in rheumatoid arthritis: what determines
      satisfaction with surgery?
AB  - OBJECTIVE: In patients with rheumatoid arthritis (RA), it is unclear what
      determines satisfaction with metacarpophalangeal (MCP) joint replacement surgery.
      Previous studies have focused primarily on objective outcomes, such as range of
      motion (ROM) or strength, although some subjective measures have been examined.
      We investigate which outcomes most strongly correlate with patient satisfaction.
      METHODS: We assembled a retrospective cohort of 26 RA patients who received a
      total of 160 MCP silastic spacer implants. Patients answered a telephone survey,
      and 18/26 patients were examined. The strength of association between specific
      outcome variables and patient satisfaction with surgery was measured using
      Spearman correlations. RESULTS: Patients had a mean age of 64.8 years and 77%
      were female. The mean time since surgery was 5.5 years. The strongest determinant
      of patient satisfaction was postoperative hand appearance (Spearman r > or =
      0.60). Pain was also highly correlated with satisfaction with surgery (Spearman r
      > or = 0.46). Ability to perform activities of daily living and portions of the
      Jebsen Hand Function Test were moderately correlated with patient satisfaction.
      Most other measures of hand strength and ROM showed only minimal correlation with
      patients' overall satisfaction with surgery. CONCLUSION: Overall satisfaction
      with silastic spacer surgery in this cohort of RA patients was most influenced by
      postoperative hand appearance and by pain. While objective measures of surgical
      outcomes are valuable reflections of technical success, they are not important
      determinants of patient satisfaction. The criteria used to assess MCP
      arthroplasty results should be revised to better capture the outcomes that appear
      to matter most to patients.

PMID- 12465141
TI  - Adverse effects of sulfasalazine in patients with rheumatoid arthritis are
      associated with diplotype configuration at the N-acetyltransferase 2 gene.
AB  - OBJECTIVE: N-acetyltransferase 2 (NAT2) is a key enzyme for the acetylation of
      sulfasalazine (SSZ). We examine whether there was a correlation between diplotype
      configurations (combinations of 2 haplotypes for a subject) at the NAT2 gene and
      the adverse effects of SSZ used for the treatment of rheumatoid arthritis (RA).
      METHODS: The findings from 144 patients with RA who had been treated with SSZ
      were collected from our outpatient department and used for a retrospective study.
      Haplotype analysis was performed by the maximum-likelihood estimation based on
      the EM algorithm using the obtained polymorphism data. RESULTS: Sixteen patients
      (11.1%) had experienced adverse effects from SSZ, the most common being allergic
      reactions including rash and fever. The slow acetylators who had no NAT2*4
      haplotype had experienced adverse effects more frequently (62.5%) than the fast
      acetylators who had at least one NAT2*4 haplotype (8.1%) (p < 0.001, OR 7.73, 95%
      CI 3.54-16.86). In 25% of the slow acetylators, the adverse effects were so
      severe that they were hospitalized. CONCLUSION: Genotyping the NAT2 gene followed
      by estimation of diplotype configuration before administration of SSZ is likely
      to reduce the frequency of adverse effects in Japanese patients with RA.

PMID- 12465142
TI  - Expression analysis of the glucocorticoid receptor and the nuclear factor-kB
      subunit p50 in lymphocytes from patients with rheumatoid arthritis.
AB  - OBJECTIVE: To study a possible relationship between expression of the
      transcription factor glucocorticoid receptor (GR), which mediates
      antiinflammatory effects, and the transcription factor p50, which mediates
      proinflammatory effects, in peripheral blood mononuclear cells (PBMC) of patients
      with rheumatoid arthritis (RA). METHODS: Expression analysis of GR and nuclear
      factor-kB subunit p50 in PBMC was performed by semiquantitative immunoblotting.
      RESULTS: GR and p50 expression in PBMC were significantly increased in patients
      with RA who had never received corticosteroids. In contrast, GR density is
      decreased in glucocorticoid treated RA patients. In addition, a dependency
      between increased GR expression and increased p50 expression was found.
      CONCLUSION: The pathogenesis of RA is not reflected in diminished GR expression
      but rather in an increased expression level of GR, as well as increased p50
      expression in PBMC. Corticosteroids as the major therapeutic drugs result in a
      reduction of these increased GR and p50 expression levels.

PMID- 12465143
TI  - Practical pharmacogenetics: the cost effectiveness of screening for thiopurine s
      methyltransferase polymorphisms in patients with rheumatological conditions
      treated with azathioprine.
AB  - OBJECTIVE: Thiopurine S-methyltransferase (TPMT), which catalyzes the
      inactivation of azathioprine (AZA), exhibits genetic polymorphism that results in
      dose related, serious toxicities (mainly hematological cytopenias) in 10-15% of
      individuals treated with AZA. Polymerase chain reaction (PCR) tests provide a
      sensitive, specific means of prospectively identifying these patients before AZA
      therapy and minimizing toxicity through dosage reduction. Our objective was to
      model the cost effectiveness of the 2 alternative AZA treatment strategies in
      rheumatologic conditions: (1) utilizing PCR to determine polymorphisms leading to
      TPMT deficiencies prior to AZA therapy with a reduction in dose; and (2) no
      testing. The analysis was conducted from a third party payer perspective over one
      year. METHODS: A decision analytic model was applied to map the costs and
      outcomes of patients under both strategies. Data applied to the model included
      the positive and negative predictive values of the PCR, the probabilities of
      adverse events due to AZA, and the costs associated with their management.
      Sources of data included published clinical trials, diagnostic test evaluations,
      surveillance trials, and economic evaluations. RESULTS: Dose related toxicities
      resulted in AZA discontinuation rates of 10-20%. The usual dosing strategy cost
      $677 Cdn per patient, whereas the genotype directed dosing strategy cost $663 Cdn
      per patient. In the genotype dosing strategy, the number needed to treat to avoid
      one adverse event over 6 months was 20. Thus, the genotype based dosing strategy
      dominated the usual dosing strategy. One-way sensitivity analyses revealed that
      the estimates were robust to ranges of +/- 30% for the costs, the properties of
      the PCR test, and the probability of adverse events. CONCLUSION: The introduction
      of PCR testing to identify TPMT polymorphisms prior to AZA treatment may
      represent good value in certain health care settings.

PMID- 12465144
TI  - Autoantibodies in early seropositive rheumatoid arthritis, before and during
      disease modifying antirheumatic drug treatment.
AB  - OBJECTIVE: Autoantibodies observed in patients with rheumatoid arthritis (RA)
      during clinical trials of immunomodulating agents may cause concern about
      possible induction of autoimmunity by the therapeutic intervention. We determined
      the frequency and variability of selected autoantibodies in patients with early
      rheumatoid factor (RF) positive RA during a prospective observational study.
      METHOD: The study cohort consisted of 276 patients with active RA and with RF >
      or = 40 IU, who were enrolled between January 1, 1993, and April 1, 2000, before
      starting disease modifying antirheumatic drug (DMARD) therapy (average duration
      of symptoms, 7 mo). During an average of 3.5 years followup, a panel of
      autoantibodies was determined at entry, 6 months, 12 months, and yearly
      thereafter, in addition to routine clinical, radiographic, and laboratory
      assessments. After enrollment, patients were treated with DMARD at the discretion
      of their rheumatologists. RESULTS: At entry before any DMARD therapy, antinuclear
      antibody (ANA; by HEp-2) values were negative in 31%, borderline (8 IU/ml) in
      26%, and > 8 (mean 65.5 IU/ml) in 41%. Tender and swollen joint counts, Disease
      Activity Score, and RF values were significantly higher in those with ANA > 8.
      During followup 726 paired serial specimens were available; 12.5% changed from
      negative to positive ANA and 12.3% from positive to negative. Additional
      autoantibodies were present in specimens of 20% of the subjects; 8% had 2 and
      1.4% had 3 other autoantibodies. Anti-dsDNA was detected in 13 (5.5%) patients; 4
      changed from negative to positive and one from positive to negative. SSA IgG and
      SSB IgG autoantibodies were both present in one of these patients. Ribosomal P
      protein autoantibodies were noted in 2 other patients, but Sm (Smith) and
      uRNP/snRNP IgG autoantibodies were not present in any patient. No patient had a
      diagnosis of systemic lupus erythematosus. Antithyroid peroxidase (20 patients),
      parietal cell (15), smooth muscle (14), reticulin (9), mitochondrial (5),
      striational (2), SSB (2) and SCL-70 (1) autoantibodies were detected in some
      specimens. Seven patients were diagnosed with hypothyroidism, one with chronic
      thyroiditis, one with hepatitis C, and 9 with malignancies. CONCLUSION: In
      patients with early RF positive RA the frequent occurrence of autoantibodies
      before and during treatment with standard DMARD may make it difficult to
      attribute their presence to new therapies.

PMID- 12465145
TI  - Contemporary disease modifying antirheumatic drugs (DMARD) in patients with
      recent onset rheumatoid arthritis in a US private practice: methotrexate as the
      anchor drug in 90% and new DMARD in 30% of patients.
AB  - OBJECTIVE: To describe therapies with disease modifying antirheumatic drugs
      (DMARD) and biological agents in patients with early rheumatoid arthritis (RA)
      who were receiving routine clinical care in 2001 in a private practice of 5
      rheumatologists in Nashville, TN, USA. METHODS: A cohort of 232 patients with
      initial symptoms of RA in 1998 or later were enrolled between February and
      October 2001 into a longterm observational study, designed to evaluate treatments
      and longterm outcomes of RA. The baseline evaluation included review of all DMARD
      that had been taken since disease onset, clinical measures on a multidimensional
      health assessment questionnaire, joint counts, and laboratory measures. RESULTS:
      Among the 232 patients, methotrexate (MTX) was the first DMARD used in 192
      patients (82.8%), including 3 in combinations. Since initiation of the first
      DMARD to the study visit, over a median interval of 12.1 months, 125 (66.1%)
      patients of the 189 whose initial DMARD was MTX as a single DMARD continued MTX
      as a single DMARD, 43 (22.8%) had another DMARD or biological agent added in
      combination with MTX, and 21 (11.1%) discontinued MTX. Since the onset of RA,
      89.2% of the patients had taken MTX, 15.9% hydroxychloroquine, 3.9%
      sulfasalazine, 22.0% leflunomide, 9.5% etanercept, 4.3 infliximab, and 87.0%
      prednisone. CONCLUSION: After a median duration of 12.1 months of DMARD therapy,
      almost 90% of patients with recent onset RA took MTX as the anchor drug. More
      than 60% took MTX as a single DMARD or in combination with traditional DMARD,
      while 30% took leflunomide, etanercept, or infliximab, usually in combination
      with MTX.

PMID- 12465146
TI  - The use of infliximab in academic rheumatology practice: an audit of early
      clinical experience.
AB  - OBJECTIVE: To audit a first clinical experience of treating rheumatic disease
      patients with infliximab in the setting of an academic tertiary care rheumatology
      practice. METHODS: The infusion history of patients referred to the McGill
      University Health Centre during the first 18 month period of a special access
      program for treatment with infliximab, a tumor necrosis factor-a antibody, was
      audited for disease characteristics, dosing schedule for infliximab, concomitant
      treatments, response rate, and side effect profile. RESULTS: Forty-one patients
      received a total of 300 infusions of infliximab over a period of 9 +/- 5 months
      (mean +/- standard deviation). Rheumatic disease indications were rheumatoid
      arthritis in 30, spondyloarthropathy in 6, psoriatic arthritis in 2, juvenile
      onset polyarthritis in 2, and scleroderma in one. Disease duration was 17 +/- 11
      years. Concomitant treatment with steroids and methotrexate was present in 68%
      and 54%, respectively. Infliximab treatment was continued beyond 5 infusions or
      22 weeks in 63%. Of the 26 patients continuing treatment, adjustment to dosing
      and/or interval schedule of infusions was made in 58%. The clinical response rate
      was moderately to greatly improved in 96%. Severe side effects considered
      directly related to the treatment were observed in 6 (15%) patients; less severe
      side effects, which did not preclude continuation of treatment but frequently
      required medical intervention, were noted in 93%. CONCLUSION: Infliximab is a
      valuable treatment for patients with resistant rheumatic diseases in the short
      term. Both the serious, and the frequent, more benign complication rate observed
      in this group of patients should alert physicians to be vigilant in the routine
      care of patients treated with infliximab.

PMID- 12465147
TI  - Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of
      patients with systemic lupus erythematosus.
AB  - OBJECTIVE: To study the relationship between antiphospholipid antibodies (aPL)
      and the incidence of venous thrombosis (VT) among patients with systemic lupus
      erythematosus (SLE). METHODS: The study population consisted of 678 patients with
      SLE enrolled in the Hopkins Lupus Cohort. Medical records were reviewed to
      identify the occurrence of VT prior to cohort entry. During cohort participation,
      VT was diagnosed by ultrasound or venography. Lupus anticoagulant [LAC, Russell
      viper venom time (RVVT) assay] and anticardiolipin (aCL, polyclonal assay) status
      of each subject was determined on a quarterly basis. The Kaplan-Meier approach
      was used to estimate probability of having a VT over time since SLE diagnosis.
      The association between the most recently measured values of LAC and aCL on the
      subsequent risk of VT was estimated using Cox proportional hazards models.
      RESULTS: Counting only first occurrences, the rate of VT was 5.1 cases per 1000
      person-years. Of those with a mean RVVT greater than 37 s during followup, an
      estimated 42% will develop a VT within 20 years of SLE diagnosis [95% confidence
      interval (CI) 21% to 63%, p < 0.0001 compared to those with lower RVVT]. The
      immediate risk (hazard) of deep venous thrombosis increased 34% with each 5
      second prolongation of the RVVT test, based on the most recent assessment of
      RVVT, controlling for gender and cholesterol [p = 0.0022, 95% CI 11% to 61%]. Of
      those with a mean polyclonal aCL greater than 2.3 units, 34% developed a VT
      within 20 years of SLE diagnosis (95% CI 11% to 57%, p = 0.0097 compared to those
      with lower aCL). The immediate risk (hazard) of deep venous thrombosis was not
      significantly associated with the most recent assessment of aCL. CONCLUSION: This
      large prospective study indicates that patients with SLE are at substantial risk
      for VT over time. Both the presence of a LAC and of polyclonal aCL are associated
      with the risk of VT, but LAC is a better predictor of risk than is aCL.

PMID- 12465148
TI  - Expression of cyclin B1 and cyclin dependent kinase inhibitor p21 in lymphocytes
      in patients with systemic lupus erythematosus.
AB  - OBJECTIVE: The roles of cyclins and cyclin dependent kinase (CDK) inhibitors of
      lymphocytes in the pathogenesis of systemic lupus erythematosus (SLE) are
      unclear. We measured the expression of cyclin B1 and CDK inhibitor p21 in
      peripheral blood lymphocytes (PBL) from patients with SLE and controls. METHODS:
      PBL from 40 SLE patients with renal disease (RSLE), 40 SLE patients without renal
      disease (SLE), and 28 healthy control subjects were cultured with
      phytohemagglutinin (PHA). Bivariate distribution of cyclin B1 or p21 expression
      versus cellular DNA content was assessed by flow cytometry. RESULTS: Expression
      of p21 in lymphocytes was significantly lower in patients with RSLE and with SLE
      than controls (RSLE vs controls and SLE vs controls, both p < 0.001). Expression
      of cyclin B1 was similar in all groups. The percentages of RSLE lymphocytes in
      G0/G1 and S phase were significantly reduced and elevated, respectively, compared
      with controls. CONCLUSION: Downregulated p21 in PHA stimulated PBL from patients
      with SLE may be closely related to aberration of cell division in SLE
      lymphocytes.

PMID- 12465149
TI  - Defining lupus cases for clinical studies: the Boston weighted criteria for the
      classification of systemic lupus erythematosus.
AB  - OBJECTIVE: The 1982 American College of Rheumatology (ACR) revised criteria for
      the classification of systemic lupus erythematosus (SLE), updated in 1997, have
      become the standard for establishing eligibility of subjects for epidemiologic
      and clinical lupus studies. These criteria may exclude patients with limited
      disease, restricting the generalizability of research findings. We developed and
      evaluated the ability of a weighted classification system to identify a broader
      spectrum of patients with lupus. METHODS: We constructed the Boston Weighted
      Criteria system for the classification of SLE, updating that developed in 1984.
      Using a hospital billing database, we identified 27l patients seen in our
      rheumatology clinic for possible SLE and reviewed medical records for all ACR
      criteria and the treating rheumatologist's diagnosis. We compared both the Boston
      Criteria and the treating rheumatologist's diagnosis to the updated 1982 ACR
      criteria; we also compared the Boston Criteria to the treating rheumatologist's
      diagnosis. RESULTS: The Boston Criteria identified 190/271 patients as having
      SLE, the rheumatologist's diagnosis identified 179/271, and the ACR criteria
      identified 171/271. The Boston Criteria had a sensitivity of 93% and specificity
      of 69% compared to the ACR criteria, and would identify 7% more patients.
      CONCLUSION: The Boston Criteria identify a larger number of patients compared
      with the current ACR criteria, while retaining face validity. This reflects the
      inclusion of patients with objective findings of SLE but less than 4 ACR
      criteria. Our Boston Criteria system could minimize selection bias and increase
      the generalizability of clinical SLE studies.

PMID- 12465150
TI  - Prevalence of factors influencing cancer risk in women with lupus: social habits,
      reproductive issues, and obesity.
AB  - OBJECTIVE: There is mounting evidence that hematological malignancies are
      increased in systemic lupus erythematosus (SLE), and the risk of certain solid
      tumors may also be increased. The pathogenesis may be different for the 2
      processes: risk of hematological malignancies in SLE may be due to chronic
      lymphocyte stimulation, while risk of solid tumors may be influenced by factors
      such as obesity and reproductive habits. We aimed to determine prevalence in a
      lupus cohort of selected factors that influence the risk of cancer, and to
      compare this prevalence to that of the general population. METHODS: Subjects were
      women followed in the Montreal General Hospital Lupus Clinic. We administered a
      postal survey of factors known to be associated with lung and aerodigestive
      cancers (smoking, alcohol use) as well as factors associated with breast and
      gynecologic cancers (nulliparity, use of oral contraceptives, and hormone
      replacement therapy). For patients who had died or been lost to followup, data
      were abstracted from clinic records. Information about nonsteroidal
      antiinflammatory drug (NSAID) use (a potentially protective factor for colorectal
      cancer) was also collected. Obesity prevalence was established from the clinic
      database. Comparison figures were obtained from the 1996-1997 National Population
      Health Survey data for Quebec women and age adjusted, where possible. RESULTS:
      Compared to the general population, the lupus population had lower prevalence of
      current use of oral contraceptives, and greater prevalence of obesity and
      nulliparity. The average number of pack-years among smokers was also greater in
      the lupus cohort. CONCLUSION: Solid cancer incidence in SLE may be influenced by
      established cancer risk factors such as smoking, obesity, and reproductive
      history.

PMID- 12465151
TI  - Specific antibody response after influenza immunization in systemic lupus
      erythematosus.
AB  - OBJECTIVE: To determine the efficacy of influenza virus vaccine in patients with
      systemic lupus erythematosus (SLE). METHODS: The study population comprised 24
      patients with SLE who received the split-virion, inactivated vaccine containing
      15 micro g hemagglutinin (HA)/dose of each of A/Beijing/262/95(H1N1),
      A/Sydney/05/97(H3N2), and B/Harbin/07/94. Hemagglutination inhibition (HI)
      antibodies were tested using the HI test according to a standard World Health
      Organization procedure. Immune response was defined as 4-fold or greater rise in
      HI antibodies 6 weeks after vaccination. Geometric mean titers (GMT) were
      calculated to assess the immunity of the whole group. RESULTS: All patients were
      women. Prior to vaccination, the percentage of SLE patients with protective
      levels of HI antibodies and the GMT of HI antibodies were similar to those of age
      matched healthy women. Six weeks after vaccination, 75% of the patients had
      immune response to at least one of the 3 antigens; 58.3% and 62.5% of the
      patients responded to A/Sydney/05/97(H3N2) and B/Harbin/07/94, respectively.
      However, only 37.5% of the patients responded to A/Beijing/262/95(H1N1). Six
      weeks after immunization, the SLE patients generated immune response against a
      mean number of 1.5 of the 3 influenza vaccines. There was a trend toward a lower
      immune response in patients with age > or = 50 years, prednisone dosage > or = 10
      mg daily, and who used azathioprine. However, methotrexate therapy was not
      associated with decreased response. CONCLUSION: The immune response to influenza
      vaccine of patients with SLE is lower than that seen in adults in the general
      population, in particular among older patients and those treated with
      immunosuppressive therapy.

PMID- 12465152
TI  - Upregulated expression of transforming growth factor-beta receptors in dermal
      fibroblasts of skin sections from patients with systemic sclerosis.
AB  - OBJECTIVE: To investigate the expression levels of transforming growth factor
      beta (TGF-beta) receptors in the skin of patients with systemic sclerosis (SSc).
      METHOD: We examined expressions of TGF-beta type I and type II receptors (TGF
      betaRI and TGF-betaRII) in skin sections of 5 patients with SSc and 5 healthy
      controls using in situ hybridization and immunohistochemical analysis. RESULTS:
      The expression levels of both TGF-betaRI and TGF-betaRII were elevated in the
      dermal fibroblasts of skin sections from patients with SSc in comparison to
      control skin sections in in situ hybridization and in immunohistochemical
      stainings. The numbers of fibroblasts expressing TGF-betaRI and TGF-betaRII in
      the SSc skin sections were increased in comparison to controls. The inflammatory
      cells around the vessels also expressed TGF-betaRI and TGF-betaRII intensively in
      the SSc skin sections. CONCLUSION: These results suggest that the autocrine TGF
      beta signaling due to the overexpression of TGF-betaRI and TGF-betaRII in dermal
      fibroblasts is involved in the pathogenesis of dermal fibrosis in patients with
      SSc.

PMID- 12465153
TI  - Increased circulating concentrations of the counteradhesive proteins SPARC and
      thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet
      and endothelial cell activation.
AB  - OBJECTIVE: To determine whether circulating concentrations of the counteradhesive
      proteins SPARC (secreted protein acidic and rich in cysteine) and thrombospondin
      1 (TSP-1) are elevated in scleroderma (systemic sclerosis, SSc). The relationship
      of these counteradhesive proteins to measures of platelet and endothelial cell
      activation was examined. METHODS: Plasma from 45 patients with SSc (26 limited
      form, 19 diffuse) and 22 age and sex matched controls was assayed for SPARC, TSP
      1, beta-thromboglobulin (betaTG), and platelet factor 4 (PF4), 2 distinct
      platelet a-granule products, and soluble E-selectin, a marker of endothelial cell
      activation. RESULTS: The mean (+/- SE) SPARC concentration was greater in
      patients with limited SSc (124.0 +/- 9.6 ng/ml) compared to controls (66.8 +/-
      8.0 ng/ml) (p = 0.0005), whereas in patients with diffuse SSc (74.1 +/- 7.9
      ng/ml) it was not. Elevated SPARC concentrations in the limited SSc group could
      not be ascribed to either platelet or endothelial cell activation. TSP-1
      concentrations were also increased in SSc patients (n = 29) compared to controls
      (n = 11) (2.98 +/- 0.12 vs 2.4 +/- 0.21 log transformed ng/ml; p < 0.02). Unlike
      SPARC, TSP-1 concentrations correlated with both betaTG (r = 0.57, p = 0.0014)
      and PF4 (r = 0.41, p = 0.026) levels, indicating that increased TSP-1 could, in
      part, be explained through elevated platelet a-granule release in SSc patients.
      Plasma levels of betaTG, PF4, and E-selectin were each similarly elevated (p <
      0.003) in patients with both limited and diffuse SSc compared to controls.
      CONCLUSION: That circulating SPARC and TSP-1 are elevated in patients with SSc
      raises the possibility that counteradhesive proteins, which regulate vascular
      organization and remodeling, might contribute to the pathogenesis of SSc
      vasculopathy.

PMID- 12465154
TI  - Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study
      in 84 patients.
AB  - OBJECTIVE: To compare the risk of ovarian failure and the fertility of women
      treated with intravenous cyclophosphamide (IVCY) according to the underlying
      inflammatory disease. METHODS: Review of the data of 84 consecutive women: 56
      with systemic lupus erythematosus (SLE), 28 with other diseases, mainly Wegener's
      granulomatosis and systemic vasculitides. RESULTS: The mean age at IVCY
      initiation was 29 +/- 10 years (range 13-53). The mean dosage was 0.9 +/- 0.14 g
      per pulse (range 0.5-1), and the mean number of pulses 13 +/- 6.5 (range 3-42).
      With a mean followup of 5.1 +/- 3.7 years, 23 women developed amenorrhea, with a
      mean duration of 4 +/- 3.6 months between IVCY initiation and amenorrhea.
      Amenorrhea was sustained in 19 women (13 with SLE and 6 with other diseases, NS).
      The mean age at ovarian failure onset was 40 +/- 7.6 years. The risk of ovarian
      failure correlated with the age at IVCY institution (p < 0.0001), and was
      independent of underlying inflammatory disease. Eighteen women (13 with SLE and 5
      with other diseases) became pregnant during or after CY therapy, with a total of
      22 pregnancies. The mean age at IVCY initiation, and the mean number of IVCY
      (maximum 40 pulses) before pregnancy were similar in women with SLE and those
      with other diseases. Six pregnancies occurred during IVCY therapy, which ended in
      induced abortion (n = 3), spontaneous abortion (n = 1), and normal pregnancy
      after IVCY withdrawal (n = 2) in women who wished to keep their pregnancy despite
      the risk of teratogenicity. Sixteen pregnancies occurred 2.9 +/- 2.1 years (range
      1-9) after IVCY withdrawal. They ended in: 3 induced abortions indicated for
      severe morphological anomalies (n = 2) and for SLE relapse (n = 1), 3 spontaneous
      miscarriages, and 10 deliveries of healthy newborns. CONCLUSION: The risk of
      ovarian failure depends essentially on the age at IVCY initiation. Pregnancy may
      occur during IVCY therapy, and an efficient contraception is mandatory. After
      IVCY withdrawal, pregnancy is possible with a favorable outcome in two-thirds of
      the cases.

PMID- 12465155
TI  - Inflammatory joint manifestations are prevalent in psoriasis: prevalence study of
      joint and axial involvement in psoriatic patients, and evaluation of a psoriatic
      and arthritic questionnaire.
AB  - OBJECTIVE: To examine the prevalence of inflammatory manifestations, such as
      peripheral arthritis, axial disease, undifferentiated spondyloarthropathy (uSpA)
      and enthesopathies in patients with psoriasis, and to evaluate a psoriatic and
      arthritic questionnaire (PAQ) to identify patients with arthritis. Methods. An
      evaluation of a questionnaire (PAQ) in a hospital- and community-based population
      of 276 psoriatic patients, and clinical, radiological, and laboratory examination
      of the 202 patients answering the questionnaire and willing to participate in the
      subsequent study. Results. Ninety-seven patients (48%) were identified as having,
      or having had, inflammatory manifestations (peripheral arthritis, axial disease,
      uSpA, and enthesopathies). Sixty-seven patients (33%) had peripheral arthritis
      and/or axial disease, 30 of whom had not previously been diagnosed. A total PAQ
      score of 4 out of 8 was the best cutoff value detecting arthritis with a
      sensitivity of 60% and a specificity of 62.2%. A positive answer to the question
      "Have you ever thought you might have arthritis?" in combination with morning
      stiffness in peripheral joints for at least 60 min, had a sensitivity of 30% and
      a specificity of 91.1% and was significantly associated with peripheral arthritis
      and/or axial disease in multiple logistic regression analysis. Conclusion. We
      found a high prevalence of inflammatory joint/axial disease in this group of
      psoriatic patients. Almost half the patients with peripheral arthritis and/or
      axial disease had not previously been diagnosed. The PAQ did not, either as a
      total score or by combining questions, discriminate for arthritis in this
      population with psoriasis.

PMID- 12465156
TI  - Dutch patients with familial and sporadic ankylosing spondylitis do not differ in
      disease phenotype.
AB  - OBJECTIVE: To assess potential differences in the phenotypic expression between
      familial and sporadic ankylosing spondylitis (AS). METHODS: Clinical data from
      the patient record forms were compared between 55 patients with AS from multicase
      families (i.e., families in which > or = 2 first-degree relatives have the
      disease) (familial AS) and 110 sex and age matched patients with AS who did not
      have a first-degree relative with the disease (sporadic AS). RESULTS: Between
      familial and sporadic AS no differences were found in age at disease onset, age
      at diagnosis, or prevalences of peripheral arthritis and acute anterior uveitis.
      CONCLUSION: Potential differences in genetic makeup are not reflected in
      differences in the phenotypic expression of familial and sporadic AS.

PMID- 12465157
TI  - Supplementary vitamin E does not affect the loss of cartilage volume in knee
      osteoarthritis: a 2 year double blind randomized placebo controlled study.
AB  - OBJECTIVE: To determine whether vitamin E affects change in cartilage volume in
      patients with knee osteoarthritis (OA). METHODS: In a double blind, placebo
      controlled trial, 136 patients with knee OA (American College of Rheumatology
      clinical and radiographic criteria) were randomized to receive vitamin E (500 IU)
      or placebo for 2 years. Tibial cartilage volume was measured by magnetic
      resonance imaging at the beginning and end of the study. RESULTS: Baseline
      characteristics were similar in the 2 groups (67 vitamin E, 69 placebo); there
      were more women in the vitamin E group, 42 (63%) vs 33 (48%) in the placebo
      group. One hundred seventeen subjects (59 vitamin E, 58 placebo) completed the
      study. Loss of medial and lateral tibial cartilage was similar in subjects
      treated with vitamin E and placebo (mean +/- SD: medial 157 +/- 209 vs 187 +/-
      220 micro m3 placebo, p = 0.51; lateral 186 +/- 258 vs 251 +/- 216 micro m3, p =
      0.19). There were no significant differences between the vitamin E and placebo
      treated groups in improvement of symptoms from baseline. Dietary levels of
      antioxidants (vitamin C, beta carotene, retinol equivalents) had no effect on
      cartilage volume loss. CONCLUSION: Vitamin E does not appear to have a beneficial
      effect in the management of knee OA: it does not affect cartilage volume loss or
      symptoms.

PMID- 12465158
TI  - Comparison of a computer based method and the classical manual method for
      radiographic joint space width assessment in hip osteoarthritis.
AB  - OBJECTIVE: To compare the intraobserver reliability and the sensitivity to change
      of 2 techniques evaluating the cartilage breakdown in hip osteoarthritis (OA).
      METHODS:  DESIGN: 3 year longitudinal study. PARTICIPANTS: patients with painful
      hip OA. OUTCOME: coxofemoral joint space width (JSW) at baseline and at 3 year
      followup was measured on anteroposterior weight-bearing radiographs by 2 methods:
      a manual method to obtain JSW at the narrowest point (minimal JSW) using a 0.1 mm
      graduated magnifying glass and a computer based method to obtain minimal and
      average JSW. STATISTICAL ANALYSIS: Two assessments, at one month interval, of
      each pair of films; evaluation of the intraobserver reliability using the
      intraclass coefficient of correlation, and the Bland and Altman approach,
      obtaining the smallest detectable difference (SDD). For each technique,
      percentage of progressors was evaluated, i.e., the percentage of patients with
      change greater than the SDD. Evaluation of sensitivity to change was performed
      using the standardized response mean (SRM), with 95% CI calculated using the
      jackknife method. RESULTS: Twenty-five pairs of films were evaluated. There were
      no statistically significant differences between the 3 analyses in the calculated
      intraclass coefficients of correlation, percentage of progressors, or SRM.
      CONCLUSION: These results suggest that both techniques are reliable and sensitive
      enough to detect changes in a relevant percentage of patients with hip OA after a
      3 year followup.

PMID- 12465159
TI  - Radiographic methods in knee osteoarthritis: a further comparison of semiflexed
      (MTP), schuss-tunnel, and weight-bearing anteroposterior views for joint space
      narrowing and osteophytes.
AB  - OBJECTIVE: Current radiographic evaluation of knee osteoarthritis (OA) depends
      primarily on the presence and severity of joint space narrowing (JSN) and
      osteophytes. Radiographic JSN is a function of the actual JSN caused by articular
      cartilage loss and the observable JSN artifactually caused when the tibial and
      femoral surfaces diverge due to variations in patient's knee position. Views
      yielding the greatest JSN are the most accurate. Osteophytes are also dependent
      on positioning. This study investigated the consequences of positioning on JSN
      and osteophytes in clinical studies in which the outcome of OA knee is scored.
      METHODS: In total, 1105 patients underwent 1175 paired radiographic examinations
      using weight-bearing (WB) standard anterior-posterior (AP) extended knee views
      (AP-WB), semiflexed WB posterior-anterior views with the knee in contact with the
      film and the 1st metatarsophalangeal (MTP) joint under the film plane (MTP)
      (method of Buckland-Wright), and WB PA views with the tip of the great toe at the
      film plane, 20 degrees of knee flexion and 5 degrees downward angulation of the x
      ray tube (schuss-tunnel view). Careful attention was given to proper positioning.
      JSN and osteophytes were scored on a 0-3 scale. RESULTS: JSN was significantly
      greater by the MTP and schuss-tunnel methods than by the AP-WB method, but no
      difference was found between the MTP and schuss-tunnel methods. In addition,
      disagreement was identified in 34% of MTP and AP-WB scores. In 69.3% of
      disagreements the scores were more abnormal in the MTP view. When the
      disagreements were studied, the mean MTP score was 1.68 compared to 1.12 for the
      AP-WB score. Fifty-seven knees were scored as 3 by the MTP view and as 2 by the
      AP-WB, and 8 knees were scored as 3 by the AP-WB view and 2 by the MTP view.
      Little difference in osteophytes was noted among the 3 methods, although fewer
      osteophytes were identified by the schuss-tunnel method than the AP-WB method.
      CONCLUSION: Using the clinical reading methods of this study, the MTP and schuss
      tunnel views were equivalent when compared to each other. When compared with the
      AP-WB view, the schuss-tunnel view resulted in a lower osteophyte score. These
      results, based on clinical readings, are similar to previous computerized
      analyses that indicated that the MTP and schuss-tunnel views were superior to the
      AP-WB, but that the MTP view was superior to the schuss-tunnel view.

PMID- 12465160
TI  - Interleukin 17, a nitric oxide-producing cytokine with a peroxynitrite
      independent inhibitory effect on proteoglycan synthesis.
AB  - OBJECTIVE: To compare the potency of 2 cytokines, interleukin 17 (IL-17) and IL
      1beta, on rat cartilage proteoglycan synthesis with special attention to nitric
      oxide (NO) and peroxynitrite formation. METHODS: Chondrocytes in alginate beads
      were stimulated with human recombinant (rh) IL-17 (0.03 to 300.0 ng/ml) and/or
      rhIL-1beta (0.25 to 25.0 ng/ml) in the presence or not of L-NMMA or CuDips.
      Alternatively, rats were injected with either IL-17 (10.0 micro g) or IL-1beta
      (1.0 micro g) into each knee joint. NO concentrations were determined by a
      spectrofluorimetric assay, proteoglycan synthesis by 35SO4-2 incorporation,
      peroxynitrite generation by immunostaining for 3-nitrotyrosine, and IL-1beta mRNA
      expression by reverse transcription-polymerase chain reaction. RESULTS: IL-17
      inhibited proteoglycan synthesis and increased NO production, both in vitro and
      in vivo, without inducing expression of IL-1beta mRNA in cartilage. Additive
      effects were observed when IL-17 was combined with low concentrations of IL-1.
      Surprisingly, a similar NO synthesis between IL-1 and IL-17 led to a less
      suppressive effect of IL-17 on cartilage anabolism than with IL-1. Both in vitro
      and in vivo, peroxynitrite formation was extensive with IL-1beta, but negligible
      or nonexistent with IL-17. L-NMMA and CuDips completely corrected the suppressive
      effect of IL-1beta on proteoglycan synthesis, unlike with IL-17. CONCLUSION:
      These data showed that NO is weakly involved in the IL-17 mediated inhibition of
      proteoglycan synthesis in rat. NO overload may not be predictive of any
      inhibitory effect on cartilage anabolism, but instead superoxide is a key
      regulator of NO contribution to chondrocyte dysfunction. Since IL-17 is a NO
      producing cytokine with additive effects when combined with IL-1, it may play a
      pivotal role in cartilage destruction during rheumatoid arthritis, for which
      infiltrating cells produce high levels of superoxide and proinflammatory
      cytokines.

PMID- 12465161
TI  - Are there distinctive inflammatory flares after hylan g-f 20 intraarticular
      injections?
AB  - OBJECTIVE: This survey was designed to examine features of a group of patients
      with acute painful joint effusions following hylan G-F 20 (Synvisc) knee
      injections. METHODS: Eight patients with painful local reactions after
      intraarticular hylan G-F 20 injections for knee osteoarthritis were evaluated
      clinically, with detailed synovial fluid analysis, and followed for outcome.
      RESULTS: Leukocyte counts ranged from 3150 to 103,000/mm3. Crystals were seen in
      one patient. Inflammatory knee effusions occurred from 1 to 48 h after
      injections, but never with first injections. Synovial fluid volumes were 30 to 71
      mm(3). Three patients had shiny clumps (not further characterized) that were
      noted in leukocytes on Wright stained smears. Most patients were treated with
      aspiration and depot steroids. Five of the 8 patients had moderate or greater
      improvement at 6 months. CONCLUSION: The majority of the occasional dramatic
      episodes of inflammation after hylan G-F 20 injection do not seem to be related
      to crystals. No detrimental lasting results were noted. The absence of post-hylan
      flares following the first intraarticular injection in this small series suggests
      that sensitization to or accumulation of hylan G-F 20 or its breakdown products
      may play an etiologic role in these flares.

PMID- 12465162
TI  - The determinants of change in patella cartilage volume in osteoarthritic knees.
AB  - OBJECTIVE: The rate of change in patella articular cartilage and factors
      influencing it, in subjects with osteoarthritis (OA), is unknown. We performed a
      cohort study to determine this. METHODS: One hundred ten subjects with OA had
      baseline skyline and lateral radiographs and magnetic resonance imaging (MRI) on
      their knee. They were followed 2 years later with a repeat MRI of the same knee.
      Patella and tibial cartilage volume was measured at baseline and followup. Risk
      factors assessed at baseline were tested for their association with change in
      patella cartilage volume over time. RESULTS: The annual percentage loss of
      patella cartilage was 4.5 +/- 4.3%. Sex, body mass index (BMI), and pain score at
      baseline were associated with an increase in cartilage loss. The rate of patella
      cartilage loss was greater in women than men, 5.3% versus 3.5% (p < 0.03),
      independent of age, BMI, and pain score. No association was seen between change
      in patellar cartilage volume and change in either medial or lateral tibial
      cartilage volume (r = 0.02, p = 0.86 and r = 0.08, p = 0.43, respectively).
      CONCLUSION: In OA, patella cartilage volume is lost at 4.5 +/- 4.3% per year. The
      main factors affecting this are sex, BMI, and baseline pain score. The poor
      correlation between patella cartilage loss and cartilage loss in the tibial
      compartment suggests that the pathogenetic mechanisms for OA in the
      patellofemoral and tibiofemoral joint may differ. Further work will be required
      to determine whether the rate of patella cartilage loss in OA is steady or
      phasic, and to determine which factors can be modified to reduce cartilage loss.

PMID- 12465163
TI  - The effects of exercise and education, individually or combined, in women with
      fibromyalgia.
AB  - OBJECTIVE: To examine the effectiveness of a supervised aerobic exercise program,
      a self-management education program, and the combination of exercise and
      education for women with fibromyalgia (FM). METHODS: One hundred fifty-two women
      were randomized into one of 4 groups: exercise-only, education-only, exercise and
      education, or control. The duration of the study was 12 weeks. All subjects were
      analyzed at 3 times: before study, immediately upon completion, and 3 months
      after completion of the intervention program on measures of disability, self
      efficacy, fitness, tender point count, and tender point tenderness. Of the 152
      women, complete data were available for 95 and 69 who complied with the protocol.
      In order to determine the group time interaction, a 2 way analysis of variance
      with repeated measures was used for each measure. RESULTS: The only significant
      group time interaction was reported with the compliance analysis for the Self
      Efficacy Coping with Other Symptoms subscale and the Six Minute Walk. If the
      program was followed, the combination of a supervised exercise program and group
      education provided persons with FM with a better sense of control over their
      symptoms. Fitness improved in the 2 groups undergoing supervised aerobic exercise
      programs. However, the improvement in fitness was maintained at followup in the
      exercise-only group and not the combined group. Conclusion. Subjects receiving
      the combination of exercise and education and who complied with the treatment
      protocol improved their perceived ability to cope with other symptoms. In
      addition, a supervised exercise program increased walking distance at post-test,
      an increase that was maintained at followup in the exercise-only group. Results
      demonstrate the challenges with conducting exercise and education studies in
      persons with FM.

PMID- 12465164
TI  - Stochastic processes in the causation of rheumatic disease.
AB  - OBJECTIVE: Rheumatic disorders arise in certain individuals depending on the
      interaction of genetic and environmental factors, the contribution for each
      varying with the specific rheumatic disorder. However, a third variable, i.e.,
      random or stochastic processes, may be important, but this has been poorly
      studied. We examined 3 rheumatic disorders to determine whether a simple
      stochastic process might be consistent with the incidence data. METHODS: A
      questionnaire and clinical survey of patients with ankylosing spondylitis,
      rheumatoid arthritis, and systemic sclerosis was performed to determine age at
      onset of first symptom. Population data were obtained from the Australian Bureau
      of Statistics. Computer modeling of the equation dN/dt = kP0 tr-1exp(-ktr/r) was
      performed, where dN/dt is the age-specific incidence rate, P0 is the proportion
      of population at risk, t is the age at onset, k is a constant, and r is the
      number of random events that must occur before the disease manifests. RESULTS:
      Analysis of the age-specific incidence for each of these 3 rheumatic disorders
      was consistent with the stochastic model, where r varied from 4 to 9. CONCLUSION:
      An examination of the age-specific incidence suggests that only a small number of
      random events need to occur in a predisposed population to allow the emergence of
      the rheumatic disorder. These random events might be environmental (e.g.,
      infections or exposure to toxins) or due to acquired genetic changes (e.g.,
      somatic mutations involving pivotal immune or growth/repair genes).

PMID- 12465165
TI  - Longterm followup of childhood lupus nephritis.
AB  - OBJECTIVE: To determine the longterm outcome in children with onset of lupus
      nephritis before 18 years of age. METHODS: Sixty-seven patients with onset of
      lupus nephritis prior to age 18 were identified. The mean followup time was 11
      years (range 5-19). The mean age at diagnosis was 13.2 years (range 4-17). The
      male:female ratio was 1:3.8. Renal biopsies were classified using the WHO
      classification. Fifteen patients had Class II, 8 patients Class III, 32 patients
      Class IV, and 11 patients Class V and one patient refused biopsy. The cohort
      consists of the 66 patients who had a renal biopsy. Five patients received
      cyclophosphamide (CYC) and 17 received azathioprine (AZA) as part of the initial
      treatment of Class IV nephritis. Eight additional patients received CYC because
      of a flare of disease while receiving AZA, and 8 other patients received AZA
      because of a flare of disease while taking prednisone therapy. RESULTS: Four
      patients died; 6 developed endstage renal disease (ESRD); all but one of the
      patients who died and/or had ESRD had WHO Class IV [diffuse proliferative
      glomerulonephritis (DPGN)]; only 2 Caucasians developed ESRD, although 16 out of
      36 Caucasians had DPGN; serum creatinine at followup was normal in 84% of the
      survivors; presently 70% of the patients take less than 7.5 mg prednisone/day and
      62% do not take cytotoxic drugs. No patient is currently treated with CYC. All 8
      patients with Class III nephritis were taking medication at last followup.
      CONCLUSION: The longterm outcome in this group of children with lupus nephritis,
      in whom AZA was the most commonly used immunosuppressive agent, was excellent,
      with 94% patient survival at a mean followup of 11 years. Our results suggest
      that non-Caucasian patients with pediatric onset lupus nephritis may be at
      increased risk for renal failure compared to Caucasians.

PMID- 12465166
TI  - Aerobic fitness in children with juvenile idiopathic arthritis: a systematic
      review.
AB  - OBJECTIVE: To determine whether children with juvenile idiopathic arthritis (JIA)
      have lower physical fitness compared to healthy children, and to determine the
      clinical relevance of this impairment. METHODS: A systematic literature search
      was performed using MEDLINE, CINAHL, EMBASE and SPORTDiscus. The appropriate
      titles were identified and the data were extracted from these publications. The
      maximal oxygen consumption (VO2peak; in ml.kg-1.min-1) during a maximal exercise
      test until volitional exhaustion was used as the main outcome for this review.
      RESULTS: Nine studies were identified in the literature. Data from 5 studies (144
      patients) were pooled in a metaanalysis. The VO2peak of the patients with JIA was
      21.8% (95% CI 13.7, 29.9) lower than that of healthy children (p < 0.0001).
      CONCLUSION: The results of the metaanalysis suggest that children with JIA have
      moderate to heavy impairment in physical fitness as represented by maximal oxygen
      consumption compared to healthy children.

PMID- 12465167
TI  - Chronic arthritis associated with chromosome deletion 22q11.2 syndrome.

PMID- 12465168
TI  - Churg-strauss syndrome in a group of patients receiving fluticasone for asthma.

PMID- 12465169
TI  - Brachial plexopathy as a presenting symptom of giant cell arteritis.

PMID- 12465170
TI  - The role of cardiac magnetic resonance imaging in antiphospholipid syndrome.

PMID- 12465171
TI  - Eosinophilia, arthritis, and soft tissue swellings.

PMID- 12465172
TI  - Use of prognostic markets to guide biologic therapies for rheumatoid arthritis.

PMID- 12465173
TI  - Removal of hyaline articular cartilage reduces lymphocyte infiltration and
      activation in rheumatoid synovial membrane.

PMID- 12465174
TI  - Should we be reading this journal?

PMID- 12465175
TI  - False positive elevation of cardiac troponin I in seropositive rheumatoid
      arthritis.

PMID- 12465176
TI  - Antineutrophil cytoplasmic antibodies a "Red Flag" in patients with systemic
      sclerosis.

PMID- 12465177
TI  - [Nurses and Europe. Standardization of diplomas].

PMID- 12465178
TI  - [A successful expatriation, Helen Harding].

PMID- 12465179
TI  - [Independent practice in Belgium].

PMID- 12465180
TI  - Radical-molecule complexes: changing our perspective on the molecular mechanisms
      of radical-molecule reactions and their impact on atmospheric chemistry.
AB  - The strong binding energies for radical-molecule complexes allow these unique
      systems to influence both the photochemical and reaction pathways for both
      chemical and atmospherically important reactions. This Minireview summarizes the
      work that has been presented in the literature and also introduces new radical
      molecule complexes that may play important roles in new chemistry.

PMID- 12465181
TI  - Cooling mechanisms of the planetary thermospheres: the key role of O atom
      vibrational excitation of CO2 and NO.
AB  - Cooling due to infrared emissions from O atom excited CO2 and NO is a critically
      important process in the thermal budget of the terrestrial thermosphere.
      Increasing CO2 density due to human activity makes the role of its emission
      particularly worthy of quantitative evaluation. Furthermore, the O atom excited
      15 microns CO2 emission has a unique role in the lower thermosphere of Venus
      where it is the only significant cooling mechanism; it is also an important
      process in the Martian thermosphere. The experimental and theoretical status of
      these rate coefficients is reviewed and the unsatisfactory current state of
      knowledge is pointed out.

PMID- 12465183
TI  - Magnetic circular dichroism of 5,10,15,20-tetraphenylsapphyrin.
AB  - Magnetic circular dichroism (MCD) spectra were obtained for the inverted and
      "normal" forms of doubly protonated 5,10,10,20-tetraphenylsapphyrin and for the
      inverted neutral form. In all these species, the same pattern of the signs of
      Faraday B terms, [+, -, +, -], is revealed for the four lowest singlet electronic
      transitions. This sequence is opposite to that observed in sapphyrins that are
      unsubstituted at the meso positions. The results can be accounted for by the
      reversed patterns of the orbital energy splittings in the two highest occupied pi
      orbitals (delta HOMO) and the two lowest unoccupied pi orbitals (delta LUMO).
      Indeed, the application of the perimeter model leads to the prediction that in
      the parent sapphyrin, delta HOMO < delta LUMO, whereas the opposite becomes true
      after fourfold phenyl substitution at the meso positions. These predictions are
      corroborated by the results of quantum-chemical calculations. The calculated
      values of delta HOMO-delta LUMO are quite small, which places sapphyrin close to
      the case of the so-called "soft chromophore", for which delta HOMO = delta LUMO.
      Titration of solutions containing the neutral chromophore with bases and acids
      leads to parallel changes in the electronic absorption and MCD spectra that
      indicate presence of the anionic and singly protonated species.

PMID- 12465184
TI  - Polymeric membranes for aromatic/aliphatic separation processes.
AB  - For the membrane-based separation of benzene/cyclohexane mixtures, the
      pervaporation properties of different 6FDA (4,4'-hexafluoroisopropylidene
      diphthalic anhydride) based copolyimide membranes have been investigated. In
      order to obtain high permeability as well as high selectivity copolyimides were
      synthesised using a combination of 4MPD (2,3,5,6-tetramethyl-1,4-phenylene
      diamine) and 6FpDA (4,4'-hexafluoro-isopropylidene dianiline) as well as DABA
      (3,5-diaminobenzoic acid) as monomers. Cross-linking is possible with this type
      of copolyimides and necessary to reduce swelling effects, which often occur with
      polymeric membranes and lead to a deterioration of the separation characteristics
      in aromatic/aliphatic separation processes. In order to find the most suitable
      membrane material, the polymer structure, the crosslinking agents, as well as the
      crosslinking methods have been varied. The separation characteristics have been
      determined by sorption and pervaporation experiments. Sorption experiments have
      been carried out at 60 degrees C using benzene, toluene and ethylbenzene as
      aromatic components and cyclohexane, cyclohexene, hexane and heptane as aliphatic
      solvents. Pervaporation experiments have been performed at 60 degrees C using
      benzene/cyclohexane mixtures with benzene concentrations covering the whole
      concentration range. It has been found that crosslinked copolyimide membranes
      show excellent chemical resistance, strongly reduced swelling behaviour and
      higher selectivity in aromatic/aliphatic separation compared to conventional
      membrane materials.

PMID- 12465185
TI  - The kinetics of cyclization reactions on polyaromatics from first principles.
AB  - Ab initio density functional theory calculations are presented on cyclization
      reactions of polyaromatics involved in coke formation during the thermal cracking
      of hydrocarbons. During coke formation, cyclization can take place at various
      sites, differing from each other by the local polyaromatic structure. This local
      structure also determines the minimum number of carbon atoms that must be added
      to allow the formation of a new ring. Kinetic parameters are calculated for the
      various ring-closure reactions by means of transition state theory. The
      activation energy is largely affected by the local structure of the polycyclic
      aromatic hydrocarbon, whereas the frequency factor varies significantly in terms
      of the length of the attached alkyl chain. The calculations, as presented, give a
      microscopic insight into the mechanisms that contribute to barrier formation and
      to the value of the frequency factor. The relative importance of cyclization at
      different sites, under conditions typical for an industrial cracking unit is
      studied on the basis of the calculated rate constants at various temperatures.
      The results suggest that the nature of coke formation is autocatalytic: the
      larger the macroradicals, the faster the subsequent reactions that lead to
      further growth of the polyaramatic surface. This type of calculation is the first
      step towards the development of structural relations for the kinetic parameters
      in terms of the local structure of the coke matrix.

PMID- 12465187
TI  - A novel route to molecular self-assembly: self-intermixed monolayer phases.

PMID- 12465188
TI  - Membrane-suspended nanocompartments based on ordered pores in alumina.

PMID- 12465190
TI  - New insights into the spatial distribution of aluminium in various mesoporous
      aluminosilicates.

PMID- 12465191
TI  - Near-edge fine structures in electron energy loss spectra: are CaB2C2 and LaB2C2
      isotypic?

PMID- 12465192
TI  - Chemically assembled single-wall carbon nanotubes and their electrochemistry.

PMID- 12465193
TI  - ABC's of stroke prevention. A guide for RNs.

PMID- 12465194
TI  - Stroke: call 911. Nursing recognition & response.
AB  - Stroke is the third leading cause of death and primary cause of disability in the
      United States. In 1997 the National Institute of Neurological Disorders and
      Stroke presented a national symposium hailing the use of tPA in minimizing
      disability from stroke. Guidelines detailing eligibility for tPA were published,
      clinical treatment pathways were developed, outcomes were identified, and public
      education campaigns initiated to teach the warning signs of stroke. Yet, five
      years later, it is estimated that less than 5% of stroke victims are treated with
      tPA.

PMID- 12465195
TI  - Pain control = big challenge.

PMID- 12465196
TI  - It's not "hip" to be delirious.

PMID- 12465197
TI  - Bathing. Pleasure or pain?
AB  - Bathing creates some of the highest levels of discomfort in the lives of
      individuals diagnosed with dementia. The present study measured the frequency of
      14 agitated behaviors during bathing in 15 elderly residents with dementia
      residing in a continuing care center. Each resident was observed for four
      sessions of two different bathing methods, the conventional tub bath and a
      modification of the bed bath, known as the Thermal bath. The summed frequencies
      of all agitated behaviors was significantly less for the Thermal bath than the
      tub bath. This overall effect was greater in men than women and in one particular
      behavior, shivering. The results suggest that for individuals with dementia the
      Thermal bath offers a viable alternative to the conventional tub method. Further
      research may clarify other parameters, such as cost effectiveness and long-term
      effects of the use of non-rinse cleansers for elderly individuals.

PMID- 12465198
TI  - Evidence-based protocol. Wandering.

PMID- 12465199
TI  - Documentation of delirium in elderly patients with hip fracture.
AB  - This study determined the accuracy of diagnosis and documentation of delirium in
      the medical and nursing records of 55 elderly patients with hip fracture (mean
      age = 78.4, SD = 8.4). These records were reviewed retrospectively on a patient's
      discharge for diagnosis of delirium, and for description of clinical indicators
      or symptoms of delirium. Additionally, all patients were monitored by one of the
      research members on days 1, 3, 5, 8, and 12 postoperatively for signs of
      delirium, as measured by the Confusion Assessment Method (CAM). Clinicians were
      blinded to the purpose of the study. According to the CAM criteria, the incidence
      of delirium was 14.5% on postoperative Day 1; 9.1% on postoperative Day 3; 10.9%
      on postoperative Day 5; 7.7% on postoperative Day 8; and 5.6% on postoperative
      Day 12. For those same days, no formal diagnosis of delirium or a description of
      clinical indicators was found in the medical records. In the nursing records, a
      false-positive documentation of 8.5%, 4%, 4.1%, 4.2%, and 5.9%, respectively was
      noted. False-negative documentation was found in 87.5%, 80%, 66.7%, 75%, and 50%
      of the cases on the respective days. Documentation of essential symptoms--namely
      onset and course of the syndrome--and disturbances in consciousness, attention,
      and cognition, were seldom or never found in the nursing records. However,
      behaviors of the hyperactive variant of delirium and which are known to interfere
      with nursing care were documented more often (e.g., 13.4% restless, 10.3% fidget
      with materials, 7.2% annoying behavior). Both medical and nursing records showed
      poor documentation and under-diagnosis of delirium. However, a correct diagnosis
      and early recognition of delirium may enhance the management of this syndrome.

PMID- 12465200
TI  - Influenza. Past, present, and future.
AB  - Influenza is a viral infection of the respiratory tract spread by airborne
      transmission. Vaccination remains the best strategy for influenza prevention, and
      is especially recommended for high-risk groups, such as residents of nursing or
      residential homes, as well as those with diabetes, chronic renal failure, or
      chronic respiratory conditions. The clinician must realize the importance of
      active surveillance in addition to symptomatology interpretation and diagnostic
      testing to reliably and efficiently diagnose influenza. Active surveillance
      allows the clinician to monitor regional patterns of influenza movement to know
      when influenza is present in any given area. Surveillance data allows the
      practitioner to effectively time vaccination programs and implement prophylaxis
      protocols as indicated. An influenza management protocol ensuring the prompt
      recognition and management of influenza outbreaks should be devised and
      implemented for high-risk facilities. Managing clients with influenza requires
      prompt diagnosis and initiation of therapy, including use of antivirals available
      for the prevention or treatment of influenza. Because of the severity of
      morbidity and mortality caused by the influenza virus among older adults in
      particular, it is imperative that gerontological nurses have expert knowledge
      related to influenza. The clinician who participates in active influenza
      surveillance, promotes vaccination programs, implements influenza management
      protocols, and stays abreast of recent breakthroughs in the arena of influenza
      research--such as the development of neuraminidase inhibitors--will be able to
      contribute to diminishing the morbidity and mortality impact associated with
      influenza.

PMID- 12465201
TI  - Perceptions of a senior citizens' Wellness Center. The community's voice.
AB  - Health promotion encompasses an important role in the nursing care of all
      individuals across the life span. The literature indicates senior citizens tend
      to be the age group most actively involved in health promotion activities. Not
      only do senior citizens, as an age group, participate more frequently in health
      promotion activities, but also they tend to seek out health promotion
      opportunities. A center for community residing senior citizens, funded by the
      provincial health department for 4 years, was initiated to promote health and
      wellness among the senior citizens and to delay the onset of disability. To
      evaluate the outcomes of the Wellness Center, the qualitative methodology of this
      study used the focus group approach. The participants in the focus groups
      comprised health professionals and community groups with some involvement with
      the Wellness Center. In their discussions, participants identified the Center as
      providing health promotion services different from those currently existing in
      the health care system. The participants agreed the Center was essential to
      promote healthy lifestyles for senior citizens.

PMID- 12465202
TI  - Long-term care and insurance.

PMID- 12465203
TI  - Office workers and video display terminals: physical, psychological and ergonomic
      factors.
AB  - The purpose of the pilot study was to examine the psychological and physical
      symptoms reported by video display terminal (VDT) and non-VDT users in relation
      to intensity and duration of VDT exposure, ergonomic characteristics of the work
      station, workers' perceptions of the working environments, medical conditions,
      job satisfaction, and mood states. Thirty VDT users and 16 non VDT users were
      selected from four departments of a major radiopharmaceutical company for
      participation in the cross-sectional study. Self-administered questionnaires were
      utilized to obtain information on symptoms, medical conditions, job satisfaction,
      mood states, and the working environments. Objective measurements were obtained
      to provide information on the various ergonomic components of the work station.
      The study corroborated findings reported in previous studies, whereby eye related
      symptoms were associated with VDT usage. A higher percentage of symptoms were
      reported among VDT users even when they had more control over their work
      stations. These workers expressed higher levels of job satisfaction, and lower
      levels of tension, fatigue, confusion, anger, and depression than non-VDT users.
      Most importantly, a trend in symptomatology was identified, whereby symptoms
      appeared to increase as duration of VDT exposure increased.

PMID- 12465204
TI  - Obstructive sleep apnea.

PMID- 12465205
TI  - HIPAA update: administrative simplification and national standards.

PMID- 12465206
TI  - Physical activity determinants in adults. Perceived benefits, barriers, and self
      efficacy.
AB  - The determinants of physical activity in adults were explored in this study.
      Explanatory variables included perceived benefits of and perceived barriers to
      physical activity, and perceived self efficacy for physical activity. Inactive
      participants were asked to identify barriers to activity, and active participants
      cited cues prompting them to adopt a physically active lifestyle. Data were
      collected from 137 adults obtained from work sites, an evening college program,
      and church groups. Overall, participants were physically active. Self efficacy
      was the only variable to predict physical activity. Race (i.e., being White) and
      body mass index (i.e., being overweight) explained perceived barriers to
      activity. The primary reason for inactivity was lack of time, and the most
      frequently cited cues to activity were dissatisfaction with one's weight or
      appearance. Few nursing studies have attempted to increase participants' levels
      of self efficacy. However, the occupational health nurse is in a unique position
      to increase workers' perceived self efficacy for activity and, in turn, their
      activity levels.

PMID- 12465207
TI  - Preventing young worker fatalities. The Fatality Assessment and Control
      Evaluation (FACE) Program.
AB  - During the period between 1992 through 1998, the Bureau of Labor Statistics
      identified an average of 67 work related deaths of individuals younger than 18
      each year. This article describes the Fatality Assessment and Control Evaluation
      (FACE) program and summarizes indepth data collected on 59 young worker
      fatalities in 26 states. These investigations were conducted between May 1986 and
      February 2002. Young workers ranged in age from 9 to 17 years, with a mean age of
      15.3 years: 21 were working in the agriculture, forestry, and fishing industry;
      12 in construction; 10 in manufacturing; 8 in services; and 8 in the retail
      industry. The majority worked as laborers. Ninety-three percent were young men.
      Each investigation resulted in the formulation and dissemination of strategies to
      help prevent future similar occurrences. As an example of state FACE activities,
      the article describes the Wisconsin FACE program's efforts to foster
      collaboration between regulatory agencies, researchers, educators, and
      occupational safety and health professionals, and to integrate efforts aimed at
      improving safety for young workers.

PMID- 12465208
TI  - Improving employee communication in the clinical setting. A nurse's perspective.
AB  - 1. Integrating public relations techniques with clinical competence promotes
      employee satisfaction (and appreciation). 2. Described techniques improve the
      employee's clinic interaction, perception of the nurses' understanding care, and
      involvement in the treatment. 3. Nurses should incorporate the service industry's
      "tricks of the trade" to deal with dissatisfied employees. These include point of
      impact intervention, blameless apology, and broken record.

PMID- 12465209
TI  - Applying research to practice. Practical guidelines for occupational health
      nurses.
AB  - Much has been written about the research practice gap--and there is no doubt this
      gap exists in occupational health nursing. It is an irony that the professionals
      who would benefit most from occupational health and safety research may be the
      ones who do not participate in or contribute to research. Closing the gap
      requires a commitment on the part of both practitioners and researchers. It
      behooves occupational health nurses to constantly seek ways to make the
      connection--to forge relationships that can continue to advance the specialty.
      Researchers must increase their efforts to conduct research in "real world"
      conditions, because this research is most likely to improve practice.
      Practitioners must be willing to familiarize themselves with research so they can
      become active participants in the ongoing effort to find answers to troubling
      occupational health and safety problems. Rosenheck (2001) presents an interesting
      perspective on the barriers to eliminating the research practice gap. He purports
      that, although professionals often are highly respectful of scientific endeavors,
      in reality, "daily decision making is shaped more by power structures, ingrained
      routines, and established resource configuration than by current scientific
      findings." In most organizations, standard operating procedures and behavioral
      norms are the major influences on workplace practices; scientific evidence plays
      a minor role (Rosenheck, 2001). Several reasons can be found for this lack of
      reliance on research as a basis for practice. Studies may demonstrate
      effectiveness among large groups. However, practitioners may not see the
      relevance or applicability of such studies to individuals or small groups of
      clients. Also, practitioners may fear that the implementation of new strategies
      will require more oversight than they are able to provide. Another logistical
      barrier is the application of the research may require the collaboration of
      multiple individuals--dynamic environments with extensive turnover may result in
      constant personnel changes and diminished commitments on the part of the team.
      Applying research to practice requires thoughtful and careful strategizing.
      Success depends on the commitment of key people within the organization to see
      the activities through from planning to implementation to evaluation. The
      involvement and support of management is crucial to a successful outcome. In many
      cases, the benefits of the research many not be readily apparent. However, if
      management perceives the potential value and the eventual "pay offs," they are
      more likely to allocate funds and other resources needed to assure the research
      is supported to its completion. Finding the time and resources to read and apply
      research in the occupational setting is a formidable task. However, the
      importance of a scientific base to occupational nursing practice is becoming
      increasingly evident. Occupational health nurses must become effective observers
      who recognize the value of research findings contributing to more effective
      practice. They must develop strategies for sharing information and for learning
      from others' experiences, and through this process, demystify the research
      process and become better research consumers. If occupational health nurses are
      to maximize their abilities to achieve their most important health and safety
      goals and to provide cost effective, quality services, they must develop
      strategies to enable them to use findings from relevant, well designed, practice
      oriented research studies.

PMID- 12465210
TI  - Case study methods for occupational health inquiry.

PMID- 12465211
TI  - Culture perspectives.
AB  - All cultures have had means and techniques that express their immediate aims. The
      thing that interests me is that today, painters do not have to go to a subject
      matter outside of themselves. They work from a different source. They work from
      within. It seems to me that the modern artist cannot express this age, the
      airplane, the atom bomb, the radio, in the old form of the Renaissance or of any
      of the old cultures.

PMID- 12465212
TI  - Infant massage as a component of developmental care: past, present, and future.
AB  - Infant massage has been practiced for centuries by segments on the continents of
      Africa and South America and in the Far East. Infant massage is a relatively new
      modality in North America. Numerous studies support its use in preterm infants,
      who have exhibited decreased stress levels, increased weight gain, and improved
      motor function when compared with non-massaged controls. Research has recently
      turned to the benefits of massage in the cocaine-exposed population and in those
      with human immunodeficiency virus. Massage in ill preterms has been targeted for
      clinical testing.

PMID- 12465213
TI  - Aromatherapy: mythical, magical, or medicinal?
AB  - Aromatherapy, a branch of herbology, is one of the fastest growing therapies in
      the world today. Historically, essential oils are best used in the form of
      massage or bath oils or inhalations. Frequently, it is reported that aromatherapy
      leaves one feeling uplifted, stimulated, invigorated, or rejuvenated, depending
      on the oil used. When inhaled, the various aromas penetrate the bloodstream via
      the lungs causing physiologic changes. In turn, the limbic system, which controls
      our emotions and memories, is affected. Some consider aromatherapy as mystical or
      magical; others, however, are attempting to validate empirically this ancient
      therapy as medicinal.

PMID- 12465214
TI  - Pet therapy research: a historical review.
AB  - From its unpretentious beginnings in pastoral England to the current interest in
      scientific research and trials of its use, pet therapy is clearly drawing
      attention to its benefits. Throughout the 40-year history of pet therapy, nursing
      and nursing research has been at the very heart. The growing body of research in
      pet therapy reflects nursing's own evolutionary process. This article reviews the
      history of pet therapy and discusses the growing body of research illustrating
      the healing power of animal use.

PMID- 12465215
TI  - From exercise to physical activity.
AB  - Recommendations for regular exercise have been evident in the nursing literature
      since the early 1900s. Health professionals and popular media have promoted
      vigorous exercise for positive health benefits since the 1960s. The concept of
      exercise as it appeared in the nursing literature during the early part of the
      20th century is closer to the concept of physical activity of today--regular,
      moderate-intensity activities that become part of one's lifestyle. Nurses are in
      a unique position to counsel individuals, families, and communities on the
      importance of regular physical activity and to correct misconceptions that only
      vigorous exercise has health benefits.

PMID- 12465216
TI  - Transcending circumstance: seeking Holism at Auschwitz.
AB  - We all have things we do to try to cope with the stress that modern life brings.
      Usually, those things enable us to live our lives to the fullest. But how do
      people cope with events that cause extraordinary suffering? The Holocaust was
      full of just such events. Despite the horror of what happened to those imprisoned
      at Auschwitz, there is evidence that the interventions that promote healing today
      also were helpful during the Holocaust. A review of these interventions, such as
      art, music, and humor, brings hope for our lives, both for now and in the future.

PMID- 12465217
TI  - Do soy isoflavones lower cholesterol, inhibit atherosclerosis, and play a role in
      cancer prevention?
AB  - This article is designed to help nursing professionals advise patients about the
      role of soy in the prevention and treatment of heart disease, breast cancer, and
      prostate cancer. Soy protein lowers total cholesterol, low-density lipoprotein
      cholesterol, and triglycerides in humans and inhibits atherosclerosis in animals.
      In cell culture studies and animal research, the soy isoflavone genistein offers
      protection from breast cancer and prostate cancer because it prevents cancer
      initiation, slows promotion, and impedes cancer progression. This article
      synthesizes the current research concerning soy phytoestrogens and the prevention
      and treatment of heart disease, breast cancer, and prostate cancer. Nursing
      professionals may use this information when counseling patients.

PMID- 12465218
TI  - Understanding the effects of nurses on the process by which patients develop
      hospital satisfaction.
AB  - An understanding of the process by which hospital patients evaluate their nurses
      could be very useful. However, no theory-based model exists in the nursing
      literature to explain the relationship among patients' hospital rooms, locus of
      causality, patients' evaluation of nurses, and hospital satisfaction. This
      article proposes a model to help fill this void. It also presents empirical
      evidence supporting the model--a study finding that patients' evaluation of their
      hospital rooms and their perception of locus of causality affected their
      evaluations of nurses. The results suggest patients' evaluation of their nurses
      and rooms are two key variables that affect their overall hospital satisfaction.
      However, patients' evaluation of nurses appears to have a much greater influence
      on hospital satisfaction than does patients' evaluation of their rooms.

PMID- 12465219
TI  - Families' use of religion/spirituality as a psychosocial resource.
AB  - The hospitalization of a child is stressful for a family. Turning to
      religion/spirituality (R/S) is a potential coping mechanism. Using an integration
      of Antonovsky's salutogenic model and human ecological theory, this study sought
      to determine if there is a relationship between the use of R/S as a psychosocial
      resource and the ability of the family to cope with the stress of child
      hospitalization. Although findings were inconclusive, a majority of families
      believed that R/S was important in helping them cope and that their beliefs and
      practices influenced their choice to use R/S as a resource. Implications for
      health care providers and administrators are discussed.

PMID- 12465220
TI  - Investigation of gastrointestinal transport by magnetic marker localization.
AB  - The method of magnetic marker monitoring MMM with a biomagnetic measurement
      system allows the tracking of the transport of solid drug forms with high
      spatiotemporal resolution. This technique enables to display the path and the
      disintegration of the magnetic marked pharmaceutical dosage form via the decrease
      of its magnetic moment. The method was used to assess exogenous factor on the
      esophageal transport of orally administered solid drug forms in five healthy
      volunteers. In a drug delivery study we have applied the MMM to monitor the path
      of a tablet during the gastrointestinal passage and to visualize the
      disintegration in the small intestine by the magnetic moment of the tablet. The
      signal to noise ratio of the measurement data was improved by ICA filtering.

PMID- 12465221
TI  - [Brief causal relations in EEG based on adaptive Granger causality].
AB  - Commonly, coherence and correlation are used to describe interrelations between
      EEG signals. But, on this basis, the investigation of causality or direction of
      interrelations is not possible. The general idea of causality between two signals
      may be expressed in terms of upgrading the predictability of one signal bye the
      knowledge of the past of the other signal. The best established approach in this
      context is the so-called Granger causality. The study present an adaptive
      estimation of Granger causality, which allows to detect dynamic causal relations
      within time intervals of less 100 ms. The time-variant Granger causality is
      applied to EEG data of the Stroop task. It could be shown, that conflict
      situation generates a dense web of directed interactions from posterior to
      anterior cortical areas.

PMID- 12465222
TI  - Considerations on noise of electrodes in combination with amplifiers for
      bioelectrical signal recording.
AB  - Detection of weak bioelectrical signals needs a recording system with a very low
      system noise. In this paper, the noise of electrodes as well as the influence of
      different combinations of electrodes and amplifiers on the system noise was
      investigated. As a first result the electrodes noise is similar to the noise of a
      passive electronic part with the same impedance. For smaller electrodes a
      reduction of the electrode impedance will reduce the system noise, also for
      larger electrodes the electrode itself is not the dominant noise source, so that
      an improvement of the amplifier is the way to get a better system. A special
      amplifier was tested with iridium and platinum black electrodes of different
      sizes.

PMID- 12465223
TI  - [A method for analysis of muscle activity during electric stimulation].
AB  - The measurement of the surface-EMG during electrical stimulation requires the
      suppression of the stimulus pulse close to the source. This is necessary because
      of the discharge currents spreading within the human body caused by the
      stimulation pulse and the drift effects at the electrodes distorting the EMG
      signal. A measurement-system will be presented, which splits the EMG in a
      detection and a processing path. A special converter keeps the base line at zero
      level. The detection path sets the gain of the recording amplifier and identifies
      the stimulation pulse to control its suppression. The processing of the EMG is
      conducted in the main path way. By these means the EMG including M-wave is
      undistorted and unbiased presented. The results will be discussed taking the
      physiology relevance into account.

PMID- 12465224
TI  - [Magnetoneurographic registration of evoked summation action fields over lumbar
      vertebrae following transcutaneous tibial nerve stimulation].
AB  - Goal of this study was the development of a protocol for the registration of
      evoked magnetic fields over the lumbar spine using off-the-shelf equipment. Three
      subjects in a sitting position with their torso bent slightly forward were
      stimulated at the tibial nerve with a commercially available stimulator.
      Neuromagnetic fields were registered over a circular, 800 cm2 area of the
      lumbosacral spine using a 61-channel 4D-Neuroimaging biomagnetometer. After
      appropriate signal processing, dipolar magnetic fields with a field strength 5-17
      fT peak-to-peak amplitude were detected in three out of four registrations.
      Location and orientation of these fields concurred with the expected evoked
      compound action currents along the course of the nerve fibers.

PMID- 12465225
TI  - [Measuring eyelid reflex with electroblepharography].
AB  - Safety regulations concerning the handling of low power lasers in the visible
      region (Class 2, according to DIN EN 60825-1) assume that the eye is protected by
      the eye-blink reflex, which should have completed within 250 ms during laser
      impact into the eye. A method has been developed to determine the temporal
      progression of the blink reflex by measuring the biosignal of the upper eyelid
      movement. In this procedure, which we call Electroblepharography (EBG), the
      electrical signal of the eyelid muscle is gained by means of self adherent
      electrode pads and is evaluated and charted after analog signal processing in the
      EBG-device. The graphical representation of the biopotential corresponds to the
      temporal position of the upper eyelid. Characteristic values as latency-time,
      position and velocity of the eyelid can be deduced.

PMID- 12465226
TI  - [Fiberoptic measurement of myocardial contraction--correlation of the signal with
      hemodynamic values].
AB  - In addition to the intracardial ECG, the mechanical myocard contraction should be
      used as another input signal for cardiac pacemakers and implantable
      defibrillators. Therefore a fiberoptical measurement system was designed. A
      sensor-fiber was placed in the coronary venous system. An opto-electronic system
      converts the optical losses, caused by bending of the fiber, into a proportional
      voltage. This method allows measuring of the left ventricular myocard contraction
      strength. By theoretical calculations it was shown, that a good correlation of
      the sensor-signal and the left ventricular radius can be expected. Additional
      investigations using an isolated beating pig heart were performed. A high
      correlation of the sensor-signal and the left ventricular stroke volume was
      shown.

PMID- 12465227
TI  - [Quantitative analysis of cardiovascular interactions in patients with
      cardiomyopathy and after myocardial infarct].
AB  - The aim of this study was to detect pathological changes of the complex
      autonomous regulation of ecg, blood pressure and respiration (synchronously
      recordings of 30 minutes) in patients with cardiac diseases. We investigated the
      cardiovascular and cardiorespiratory linear and nonlinear interactions in 10
      patients with dilative cardiomyopathy (dcm) and in 10 patients after myocardial
      infarction (mi). We compared results from the classical linear correlation
      function analysis with results from the mutual information method
      (transinformation) for analysis of nonlinear and linear interactions. Both
      methods yield high significant parameters (p < 0.01). Thus, we found both linear
      and nonlinear interactions with partly different specificity in patients with dcm
      and mi compared to healthy subjects (ref).

PMID- 12465228
TI  - Simulation methods for the online extraction of ECG parameters under
      Matlab/Simulink.
AB  - The classification of cardiac pathologies in the human ECG greatly depends on the
      reliable extraction of characteristic features. This work presents a complete
      simulation environment for testing ECG classification algorithms under
      Matlab/Simulink. Evaluation of algorithm performance is undertaken in full
      compliance with the ANSI/AAMI standards EC38 and EC57, and ranges from beat-to
      beat analysis to the comparison of episode markers (e.g., for VT/VF detection
      algorithms). For testing the quality of waveform boundary detection, our own
      testing methods have been implemented in compliance with existing literature.

PMID- 12465229
TI  - [Differentiation between vital heart muscle tissue and infarct scar using
      magnetocardiography].
AB  - Magnetocardiography provides touchless information about myocardial excitation
      propagation and repolarization. This evolving diagnostic technique has been used
      so far to risk-stratify patients in terms of sudden cardiac death and to detect
      myocardial ischemia. We evaluated its potential to assess myocardial viability in
      patients with coronary artery disease. Magnetocardiography was performed using a
      shielded prototype 49-channel LTS SQUID system. A specific algorithm was
      developed to calculate automatically a set of magnetocardiographic parameters.
      Regional myocardial viability was determined using 18F-labeled fluoro-2
      deoxyglucose positron emission tomography. We found that magnetocardiography may
      contribute essentially to discriminate between viable myocardium and infarct
      scar.

PMID- 12465230
TI  - [Analysis of cardiovascular regulation after heart operation].
AB  - Baroreflex sensitivity, heart rate and blood pressure variability have been
      proven to predict fatal outcome in patients after acute myocardial infarction.
      This study aims at investigating the time dependent alterations in cardiovascular
      control to find new predictive parameters for arrhythmic events after surgery. 25
      male patients with coronary heart disease following an aortocoronary bypass
      surgery were examined. The results show significant alterations in sympathetic
      and vagal mediated regulation. The extubation after 6 hours seems to influence
      primarily the sympathetic activation. Obviously, there is a vagal suppression 20
      h after surgery, while the sympathetic tonus works in a normal range. This
      unbalanced interaction of the autonomous system seems to be a reason for the high
      incidence of atrial tachycardias in the early period after cardiac surgery.

PMID- 12465231
TI  - Model based analysis of the heart rate and blood pressure relationship.
AB  - The main intention of this contribution is to measure the coupling between
      bivariate time series using the dual sequence method to estimate the baroreflex
      as well as a nonlinear regression approach, namely the maximal correlation
      method, to get a better understanding of the underlying processes. The data we
      analyse are heart rate and blood pressure variability time series from 27
      patients with dilated cardiomyopathy as well as from a control group of 27 age-
      and sex-matched healthy subjects. The results strongly indicate and confirm the
      mechanisms of respiratory sinus arrhythmia in heart rate. Revealing the coupling
      direction and the strength of coupling between heart rate and blood pressure via
      optimal transformations in addition to the baroreflex estimation seems to be a
      very promising approach.

PMID- 12465232
TI  - [Hardware implementation in VT/VF detection algorithms for AED (automatic
      external defibrillators)].
AB  - The automatic external defibrillator (AED) should carry out the diagnosis of the
      patient in a cardiac emergency when medical professionals are not present. The
      decision about defibrillation should be made without the help of first responder.
      To fulfill these requirements special algorithms are needed. In this article the
      structure of such an algorithm and also hardware implementation problems are
      described.

PMID- 12465233
TI  - [Databank for support of comprehensive study evaluations of signals for
      anesthesia monitoring].

PMID- 12465234
TI  - [Heart rate and blood pressure interaction in normotensive and chronic
      hypertensive pregnancy].
AB  - Pregnancy has impact on autonomic control. Since hypertensive pregnancy disorders
      are a major cause of maternal mortality we investigated the baroreflex
      sensitivity (BRS) in chronic hypertensive pregnant women (CH), normotensive
      pregnant (PRE) and non-pregnant (NPRE) women. In addition to the traditional
      'sequence method' we used joint symbolic dynamics (JSD). BRS was significantly
      reduced in all pregnancies compared with NPRE (p < 0.00001) but there was no
      significant difference between CH and PRE. Contrary, the JSD measures revealed
      significant differences (p < 0.00001) in the heart rate and blood pressure
      interactions between PRE and CH. In conclusion, JSD measures uncovered a
      different gestation related adaptation of autonomic regulation in women with
      chronic.

PMID- 12465235
TI  - [Measurement of flow mediated vasodilation (FMD) using kalman-filtering].
AB  - Brachial artery flow-mediated vasodilation is increasingly used as a measure of
      endothelial function. High resolution ultrasound provides a noninvasive method to
      observe this flow-mediated vasodilation by monitoring the diameter of the artery
      over time. In the past, the diameter had to be measured in tedious postprocessing
      routines, usually by the examiner himself. We present a system, which is able to
      process ultrasound rf-data in realtime. On that system, we implemented a kalman
      filter, which makes the tracking of both vessel walls possible. The diameter can
      be calculated accurately, taking into account process noise as well as
      measurement noise.

PMID- 12465236
TI  - Mobile patient simulator for resuscitation training with automatic external
      defibrillators.
AB  - Resuscitation training has to be performed under most realistic conditions. This
      includes both usual CPR measures (breathing and chest compressions) and advanced
      measures, e.g. the usage of an Automatic External Defibrillator (AED). Almost all
      currently available simulators for ECG signals used in such trainings have a
      rather limited variety of available ECG signals. The trainer also has to change
      between different rhythms manually, resulting in a less realistic training
      environment. The development will result in mobile ECG simulator which can
      automatically react to events in the resuscitation process according to pre
      programmed scenarios. It also has potential to simulate other physiological
      parameters like thorax impedance in the future.

PMID- 12465237
TI  - [Continuous bilateral auscultation as perioperative monitoring of ventilation:
      comparison of 2 systems for registering respiratory sounds].

PMID- 12465238
TI  - [High resolution EEG and whole head MEG].
AB  - A low-noise multichannel EEG-Amplifier-System has been designed and analyzed,
      which is electromagnetically compatible with SQUIDs. The EEG- together with the
      MEG-System is operated inside the quiet environment of a magnetically shielded
      room, hence no electrical 50 Hz-Artifact is detectable. Measurements pointed out
      that the influence of amplifier- and electrochemical-noise of electrodes to
      averaged EEG-spectral densities is less than 1% within the frequency range 0.5 to
      70 Hz. Thermal noise of the skin-electrode-interface, equivalent to a resistor of
      30 k omega, only begins to take effect above 20 Hz, suggesting that there is no
      need of skin abrasion.

PMID- 12465239
TI  - [Improving SNR (signal to noise ratio) in multichannel EEG recording].
AB  - The main problem in measurements of the focal VEP (Visual Evoked Potential) is
      its weak SNR (Signal-to-Noise Ratio). The most common method for enhancement of
      the SNR is the stimulus synchronized averaging. For study of single responses
      other ways in SNR improvement are needed. In this contribution a new method based
      on space-time selective measurement is introduced, which can be interpreted as
      beaming a signal source. Since the anatomical structures of sources generating
      the focal VEP are known in general and if the electrode positions are of
      sufficient density over the visual cortex, a source beamer can be realized by
      controlling the channels' delays.

PMID- 12465240
TI  - [Approximate entropy of anesthesia EEG: compromise between calculation time and
      clinical validity].
AB  - Approximate entropy, a measure of regularity, can be used to analyze the
      electroencephalogram of patients in general anesthesia to discriminate between
      different states of consciousness. EEG burst suppression patterns reflect a state
      of deep anesthesia. Due to the instationary character of this EEG pattern
      approximate entropy values do not correctly classify the patient state. Possible
      solutions to this problem may be limited by the demand of computing power for
      entropy calculation and the reaction time following changes in patient state.
      Different approaches for an online monitoring application are examined.

PMID- 12465241
TI  - Time-delayed decorrelation for the identification of cardiac artifact components
      in MEG data.
AB  - The time-delayed decorrelation (TDD) Independent Component Analysis (ICA) applied
      to continuous multichannel magnetoencephalographic (MEG) recordings is a
      straightforward calculation in the time domain: Its main ingredient is a
      calculation of the correlation between signals having different time shifts with
      respect to each other. The equivalent mathematical representation in the
      frequency domain and a simple simulation show that TDD exploits different complex
      frequency spectra of the sources. Applying ICA to 80-channel whole head MEG data
      obtained under visual stimulation we can assign five of the 80 source components
      to the cardiac artifact. Their complex spectra exhibit a randomly distributed
      phase showing that TDD is capable of isolating quasi-periodic signals even for
      the case of an unspecified phase.

PMID- 12465242
TI  - MEG-analysis using the Hilbert transform.
AB  - Event-related fields (ERFs) measured by magnetoencephalography (MEG) upon visual
      stimulation are analysed by Hilbert transformation. The Hilbert transform of real
      valued measured ERF is an analytic complex signal, represented by phase and
      amplitude. The temporal behaviour of the derivative of the phase, i.e. the
      instantaneous frequency, allows to distinguish time intervals containing
      meaningful signal from noise. On the basis of both phase and amplitude, energies
      and latencies of single event ERFs can be determined.

PMID- 12465243
TI  - [Course and intraindividual reproducibility of heart rate variability].

PMID- 12465244
TI  - [Time variant bispectral analysis based on adaptive recursive Fourier
      transformation].
AB  - An appropriate investigation of quadratic phase couplings (QPC) in non-stationary
      signals requires time-variant methods of bispectral analysis. A new approach for
      time-variant estimation of power spectrum and bispectrum based on an adaptively,
      recursively estimated Fourier transform (ADFT) is presented in this paper. A
      reduced calculation effort and the possibility of the calculation of the
      bispectrum for selected frequency triples are important advantages of this
      method. Because of the recursive calculation, the ADFT is convenient for
      analysing ongoing signals. This will be demonstrated for simulated and real
      biomedical signals.

PMID- 12465245
TI  - [Spectral heart rate variability analysis in probands--age dependence and active
      orthostasis].

PMID- 12465246
TI  - [Integration of the Aasalid test in an online measurement system for evaluating
      cerebral autoregulation].
AB  - An important question during the intensive care of patients with subarachnoid
      hemorrhage and craniocerebral trauma is the evaluation of the cerebral
      autoregulation (CA). The so called Aaslid-Test is a standard method which allows
      the cerebral autoregulation to be classified. As the results under repetitive
      conditions show a high variation, it has not been yet possible to draw
      statistically proved conclusions concerning the performance of the CA. To improve
      the test results the measuring conditions are discussed and systematized. The
      algorithms of the Aaslid-Test have been implemented to an online measuring
      system. The error bandwidth has been estimated. To avoid systematically occurring
      errors an enhanced measuring protocol is provided.

PMID- 12465247
TI  - Applications of autofluorescence for characterisation of biological systems
      (biomonitoring).
AB  - We describe a system capable of measuring the laser induced fluorescence emission
      of two coenzymes (NADH and FAD) via an optical fibre for in vivo monitoring of
      anatomical, physiological or pathological changes in biological systems. This
      optical technique permits the measurement of changes in the metabolism of cells
      in real-time and is nearly non-destructive. We present results of examinations on
      the localisation of transitions between different tissue and the monitoring of
      the oxygenation level (ischemia) in muscle or changes in the cellular activity of
      bacteria in a bioreactor.

PMID- 12465248
TI  - [Optical rhinometry--a method for objective assessment of nasal provocation].

PMID- 12465249
TI  - Field trials with low power lasers concerning the blink reflex.
AB  - Laser belonging to class 2 emit in the visible part of the spectrum. The power is
      limited to 1 mW in the CW mode. Up to now the protection of the eyes has been
      supposed to be given by the blink reflex for incidentally intrabeam viewing in
      many regulations. In 3 field trials with 519 test persons we have shown that only
      15.9% at 670 nm, 17.2% at 635 nm, and 20.3% at 532 nm had a blink reflex under
      laser irradiation. An analysis of the results showed neither significant
      differences concerning the age and the gender of the test persons nor whether
      they were wearer of glasses or right sighted. The frequent lack of the blink
      reflex demands organizational measures like instruction using laser class 2 in
      medical and other applications.

PMID- 12465250
TI  - Comparing light sensitivity, linearity and step response of electronic cameras
      for ophthalmology.
AB  - PURPOSE: To develop and test a procedure to measure and compare light
      sensitivity, linearity and step response of electronic cameras. METHODS: The
      pixel value (PV) of digitized images as a function of light intensity (I) was
      measured. The sensitivity was calculated from the slope of the P(I) function, the
      linearity was estimated from the correlation coefficient of this function. To
      measure the step response, a short sequence of images was acquired. During
      acquisition, a light source was switched on and off using a fast shutter. The
      resulting PV was calculated for each video field of the sequence. RESULTS: A CCD
      camera optimized for the near-infrared (IR) spectrum showed the highest
      sensitivity for both, visible and IR light. There are little differences in
      linearity. The step response depends on the procedure of integration and read
      out.

PMID- 12465251
TI  - [Determination of tissue optical parameters using HF modulation spectroscopy].
AB  - Radio frequency modulation spectroscopy is a capable method to determine tissue
      optical parameters in-vivo. For the eventual purpose of clinical measurements we
      have developed and tested an rf laser spectroscopy device which enables a
      measurement of the spatial amplitude and phase shift profiles of backscattered
      modulated laser light. Spectral absorption and scattering coefficients are
      computed by inverse formulas derived from analytical solutions of the diffusion
      model of light transport in a semi-infinite geometry.

PMID- 12465252
TI  - [Bipolar , active electrode for 4-channel recording of dynamic surface EMG during
      electric stimulation].
AB  - In this paper we present an electrode for measuring the surface electromyogram
      (EMG) that combines high quality of signal recording with the ease of use in
      clinical routine. Additional requirements have been the use of the electrode in
      combination with electrical stimulation and under dynamic conditions like
      walking. Special focus was put on the minimization of movement artifacts by
      integration of a dual impedance transformer (active electrode) and by a self
      adjusting fixation of the two contacts of the electrode via proprietary springs.
      An elaborate preparation of the skin is not necessary due to a very high input
      impedance of the amplifier. A special circuit for overvoltage protection makes
      the electrode suitable for use in the presence of high voltage stimulation pulses
      without the risk of destroying the FET-input stages.

PMID- 12465253
TI  - [HeiDATAProViT--a universal software tool for evaluating biomedical data].
AB  - Evaluation of large sets of biomedical data can be divided into three universal
      stages: 1. archiving of clinical data together with data obtained from
      measurements, 2. processing of numerical data using signal processing algorithms
      and 3. visualizing the results. In this paper a software is presented which
      tightly integrates a data base under MS Access and the possibilities for data
      processing and visualization offered by Matlab. This software tool provides an
      interface between a data base containing large sets of biomedical data and an
      extensible pool of evaluation and visualization procedures. It can serve both as
      an instrument for data processing in clinical routine and an important component
      for evaluation of measurement data in any medical research project.

PMID- 12465254
TI  - Interactive PC-based volume rendering of CT datasets.
AB  - In radiology, the reading of large CT volumes is a time consuming task.
      Interactive volume rendering (iVRT) is a promising new technique. Using dedicated
      hardware (VP1000, Terarecon Inc.) it can now be realized on a standard PC in a
      cost effective manner. For this purpose, a program built using the Visualization
      Toolkit with integrated functionality for the VP 1000 is used for almost real
      time iVRT (8-9 frames/second). It is possible to embed opaque and translucent
      polygon surfaces (e.g., segmented structures). By interactively varying the
      opacity, color and gradient transfer functions as well as using freely placable
      cutting planes, the visualization can easily be adapted to different diagnostic
      needs.

PMID- 12465255
TI  - [Clinical benefit of compensation of motion artefacts in contrast media enhanced
      MRI mammography].
AB  - This article discusses the diagnostic benefit of methods for the compensation of
      motion artefacts in dynamic MRT-Mammography with a contrast agent. Our algorithms
      for motion compensation perform a locally rigid registration of cubic sub-volumes
      and a locally affine deformation of tetrahedral sub-volumes from a Delaunay
      Triangulation. Within an extensive clinical study, these fast, automatic, and
      robust algorithms have been applied to 64 MRT-Mammography datasets from the
      radiological practice of Dr. Friedburg. The comparison of corrected datasets with
      original data and the statistical evaluation of results show a significantly
      improved quality of difference images, particularly at the presence of large
      motion artefacts.

PMID- 12465256
TI  - [Biplane angiographic volumetry of the right and left heart ventricle with
      optical image pairing].
AB  - Compared to single plane angiographic systems, biplane systems offer the
      possibility of a merged evaluation of the two x-ray projections. A computer
      program was developed that allows the assessment of enddiastolic and endsystolic
      volumes and frame-by-frame analysis of the left and right ventricle based on
      representing the biplane angiograms as optimal paired images. Optimal pairing
      means the magnifications are fitted, resulting in identical scales for objects
      located in the isocenter of the gantry; furthermore the images are rotated such
      that paired epipolar lines in both planes represent the same cross section of a
      centered object. The improved border tracing is proved by comparing the vertical
      extents from the lateral and frontal projection of the right ventricle. The
      standard deviation of the differences were significantly (p < 0.01) reduced as
      compared to the generally used unpaired evaluation.

PMID- 12465257
TI  - [Comparison of the accuracy of 3-dimensional fusion algorithms].
AB  - Recently many algorithms for matching three-dimensional medical data have been
      developed. Inter- and intramodal fusion of data adds valuable information for
      planning, controlling and evaluating therapies. This work presents a procedure to
      evaluate the accuracy of fusion algorithms by numerical means. In contrast to the
      usual way of visual inspection the developed software tools allow automatic
      numerical--and thus objective--evaluation of different algorithms using simulated
      realistic volume data. It is therefore possible to conduct reproducible
      comparisons of different matching methods. These tools also proved to be very
      valuable during the development and optimisation of an algorithm employing
      normalised mutual information.

PMID- 12465258
TI  - Comparative analysis of locally adaptive image enhancement for 3D ultrasound
      images.
AB  - In this article we compare methods for locally adaptive preprocessing of 3D
      ultrasound (US) images and their different capabilities of enhancing
      diagnostically important anatomical structures. We show that suitability and
      optimization of methods depend on the objective of the preprocessing task, e.g.,
      slice representation or volume rendering. This article analyzes which features
      should be used to control the enhancement algorithm For slice representations
      optimization of local statistics is appropriate to maintain diagnostically
      important structures. Features with good region separation properties are
      preferable for volume rendering tasks. We demonstrate our results with US images
      from clinical examinations.

PMID- 12465259
TI  - Visualization of anatomical structures of epigastric organs by use of
      automatically segmented 3-D ultrasound image volumes--first results.
AB  - The detection and the staging of tumors and their metastases in parenchymatous
      organs of the epigastric organs today is improved by the enormous increase of
      imaging system's efficiency. For an increasing number of findings, which shall be
      dissected in intention to cure, the feasibility of diagnostics and therapy
      planning based on sonograms was investigated. In 3-D US image volumes of approx.
      20 patients, characteristic anatomical structures (e.g., vessels, abscesses,
      tumors) were detected by specifically adapted automatic computer-based
      segmentation and visualized. The detection of pathological findings, their
      quantification and their spatial assignment to anatomical main structures was
      essentially simplified by 3-D image acquisition and 2-D and 3-D visualization of
      segmented images.

PMID- 12465260
TI  - [Hough transformation for image processing in eye tracking recording].

PMID- 12465261
TI  - [Optimizing histological image data for 3-D reconstruction using an image
      equalizer].
AB  - Bone cells form a wired network within the extracellular bone matrix. To analyse
      this complex 3D structure, we employed a confocal fluorescence imaging procedure
      to visualize live bone cells within their native surrounding. By means of newly
      developed image processing software, the "Image-Equalizer", we aimed to enhanced
      the contrast and eliminize artefacts in such a way that cell bodies as well as
      fine interconnecting processes were visible.

PMID- 12465262
TI  - [Error assessment of color management in digital images in telemedicine].

PMID- 12465263
TI  - Automatic image matching for breast cancer diagnostics by a 3D deformation model
      of the mamma.
AB  - X-ray mammograms and MR volumes provide complementary information for early
      breast cancer diagnosis. The breast is deformed during mammography, therefore the
      images can not be compared directly. A registration algorithm is investigated to
      fuse the images automatically. A finite element simulation was applied to a MR
      image of an underformed breast and compared to a compressed breast using
      different tissue models and boundary conditions. Based on the results a set of
      patient data was registered. To archive the requested accuracy distinguishing
      between the different tissue types of the breast was not necessary. A linear
      elastic model was sufficient. It was possible to simulate the deformation with an
      average deviation of approximately of the size of a voxel in the MRI data and
      retrieve the position of a lesion with an error of 3.8 mm in the patient data.

PMID- 12465264
TI  - [Supporting primary stent implantation by angiographic length measurement].
AB  - In this study a procedure for online measurement of a coronary segment length
      during primary stenting is presented. The spatial segmental axis is calculated
      from a biplane angiogram and the corresponding projection data by simple
      delineation of the proximal and distal segment sites in each image. In a clinical
      evaluation the length error, projectional foreshortening and time frame during
      measurement of 222 stents or carrier balloons were calculated. The overall
      percentage length error was 3.3(+)-2.4%. The device length imaged with a mean
      projectional foreshortening of 18(+)-20% was measured within 18(+)-4 s. The
      procedure yields the accurate length of coronary segments within a short
      computation time taking projectional foreshortening into account.

PMID- 12465265
TI  - [Real time eye tracking with the CMOS 2 camera system].

PMID- 12465266
TI  - Active medical implants and occupational safety--measurement and numerical
      calculation of interference voltage.
AB  - Low frequency electric and magnetic fields may interfere with implanted cardiac
      pacemakers causing a life-threatening malfunction of the device. In order to
      assess the safety of workers in the vicinity of industrial electrical devices the
      interference voltage at the input port of a pacemaker is an important measure. In
      order to investigate the coupling of fields emanating from electrical devices a
      numerical method for the calculation of interference voltages is presented and
      applied to the investigation of homogeneous electric and magnetic fields in the
      frequency range from 50 Hz to 1 MHz. Implantation of the pacemaker in the right
      pectoral, left pectoral and abdominal area using a realistic model of the human
      body as well as different grounding conditions are considered. The numerical
      method is successfully validated by measurements and shows good agreement with
      results in the literature.

PMID- 12465267
TI  - Magnetic resonance imaging with implanted neurostimulators: numerical calculation
      of the induced heating.
AB  - Magnetic resonance imaging (MRI) is still contraindicated in patients with
      implanted active medical devices, as the applied radiofrequency (RF) fields can
      lead to significant heating of the implants and the electrodes. A head model with
      an implanted deep brain stimulation electrode (DBS) was exposed to a continuous
      RF-field similar to the excitational field used in MRI at a frequency of 64 MHz.
      In this study a two-step procedure for the accurate estimation of electrode
      heating during MRI is presented. First the energy loss was calculated in the
      frequency domain during an applied RF-pulse. Then a thermodynamic algorithm
      taking heat transfer mechanisms into account was used. The applied method showed
      to be numerically stable and gave more accurate results than first calculated
      using a simple worst-case approximation.

PMID- 12465268
TI  - Development of a cost-effective and MRI compatible temperature measurement
      system.
AB  - A reliable temperature measurement system working inside a MRI-system is required
      in order to determine the amount of local temperature rise during application of
      radiofrequency fields on medical implants and thus to ensure patient safety.
      Hence the aim of this study was to develop a cost-effective temperature
      measurement system suitable for use in a MRI system to investigate this heating
      having mainly phantom experiments in mind. Three active temperature measurement
      systems were set up, the first using a PTC as the temperature sensor, the other
      two with platinum resistors of 100 omega and 1000 omega. Interference tests in a
      MRI systems were performed. It could be shown that a stable temperature
      measurement at a resolution of 0.1 degree C could be established.

PMID- 12465269
TI  - [A method for worst-case study of coupling between medical equipment].
AB  - The increasing use of electronic devices in operating theatres and intensive-care
      units leads to possible interactions of such devices and consequently to serious
      immunity problems. This paper presents a numerical near field worst-case-study of
      the coupling between coagulators and ECG devices under consideration of the human
      body. For this purpose a special body model has been developed which meets the
      geometrical dimensions given in DIN 33402 part 2. The model's electrical
      properties correspond to a weighted average of those of different tissues of the
      human body. Different parameters (coagulation frequency, positions of electrodes,
      etc.) are considered.

PMID- 12465270
TI  - Wound diagnostics with microwaves.
AB  - The reflection of electromagnetic waves on material surfaces is very depending on
      the electric and magnetic properties of these materials, on their structure and
      on the surface texture. Therefore the different layers and dielectric properties
      of healthy and unsound body tissue also show different reflection behavior
      towards incidentating electromagnetic waves. By analyzing the reflected signals
      of incident electromagnetic waves, it is possible to get information about the
      inner structure of the reflecting body tissue. This effect could then be used for
      a contactless analysis of body tissue e.g. to gain crucial medical information
      about healing processes. In this paper the results of several full wave
      simulations of various tissue structures are presented and the significance and
      usability of this method is shown.

PMID- 12465271
TI  - [Endoscopic 3-D imaging--measuring biological surfaces].
AB  - The precise endoscopical measurement of topometrical structures of organs will
      overcome limitations in present minimal invasive surgery and lead to new
      operation techniques. This paper describes a research project concerning an
      endoscopical 3D-measurement system based on optical techniques. We will introduce
      prototype endoscopes for minimal invasive 3D-measurements and the applied
      photogrammetrical algorithms for acquiring the topometrical structures. The
      influence of major organ surface properties on the measurement will be discussed
      and first results will be presented.

PMID- 12465272
TI  - Retinal Vessel Analyzer (RVA)--design and function.
AB  - The Retinal Vessel Analyzer (RVA) is a measuring device for online measurement of
      the diameter of retinal vessels in relation to time and locations along the
      vessel. It is furthermore provided with several tools for analyzing the measured
      data. The fundamental components consist of a fundus camera with CCD measuring
      camera attached and an advanced image-processing unit. The measurement range is
      from 90 microns, temporal resolution is 40 ms and measurement resolution is less
      than 1 micron. Systematic error of non-linearity is S < or = 1.6%,
      reproducibility is given by variation coefficient: short term vcs = 1.5%, long
      term vcl = 2.8%.

PMID- 12465273
TI  - Retinal Vessel Analysis--new possibilities.
AB  - Retinal Vessel Analysis is a new technique to assess behavior of large retinal
      vessels based on diameter measurements. The Retinal Vessel Analyzer (RVA)
      measures continuously on-line obtaining data in relation to time and local
      position. Possible analysis tools include (a) Time Course Analysis of
      physiological, pathological, or therapy induced changes; (b) Local Course
      Analysis to recognize local narrow or wide vessel segments along the vessel; (c)
      Vasomotoric Analysis to determine vasomotions and blood pressure related diameter
      changes; (d) Functional Analysis to examine dynamic behavior e.g. the ability to
      autoregulate and (e) Functional Imaging to visualize functional parameters of
      vessels in single vessel segments. RVA is thus able to recognize and study
      different autoregulation mechanisms.

PMID- 12465274
TI  - [Patent protection in modern medical technology].
AB  - Inventions related to medical treatments and devices are due to specific
      regulations in the German, European and US patent Law much more difficult to
      obtain than inventions in the field of ordinary mechanics. In particular,
      inventions related to treatments of the human or animal body are excluded from
      patentability. In order to obtain at least some patent protection for such
      inventions the wording of the claims as well as the wording of the specification
      and preferred embodiments is very important. Patent protection is in most cases
      the only remedy to return the investment spent for the research. To maximize the
      possibility of patent protection in many countries, the timing of publication of
      the research result and filing of the patent application must be coordinated.

PMID- 12465275
TI  - [Progress management in medical technology: better products faster in use].

PMID- 12465276
TI  - [Initial chronic results of flexible sieve electrodes as interface to nerve
      stumps].
AB  - Since more than 20 years, nerve stumps have been interfaced with sieve-like
      microsystems with integrated electrodes in experimental studies. In most cases,
      silicone tubes have been assembled on the microsystems to adapt the nerve and
      deliver a guidance structure for regeneration. Flexible, polyimide-based sieve
      electrodes with integrated fixation aids have been implanted chronically in an
      animal model. They have been adapted between the transsected ends of the sciatic
      nerve of rats and on the proximal stump in an amputation model. First
      electrophysiological experiments proved the functional reinnervation. Combining
      embryonic motor neurons with the sieve electrode, we propose a biohybrid system
      that is under investigation to functionally interface the distal part of a
      transsected peripheral nerve.

PMID- 12465277
TI  - Selective stimulation of pig radial nerve: comparison of 12-polar and 18-polar
      cuff electrodes.
AB  - Aiming at the development of an implantable neuroprosthesis for restoration of
      hand function in tetraplegic patients (C5/C6), we examined and compared the
      stimulation performance of two different neural electrode designs. Our studies on
      the radial nerve of adult pigs proved the feasibility of selective control of
      different forearm muscles by using only one multichannel nerve cuff electrode.
      The results gained by applying a 12-polar cuff electrode design were poor, while
      the potential of an 18-polar design was very encouraging.

PMID- 12465278
TI  - [A modular method for automated evaluation of gait analysis data].
AB  - A modular methodology for automated gait data evaluation: The aim of Instrumented
      Gait Analysis is to measure data such as joint kinematics or kinetics during gait
      in a quantitative way. The data evaluation for clinical purposes is often
      performed by experienced physicians (diagnosis of specific motion dysfunction,
      planning and validation of therapy). Due to subjective evaluation and complexity
      of the pathologies, there exists no objective, standardized data analysis method
      for these tasks. This article covers the development of a modular, computer-based
      methodology to quantify the degree of pathological gait in comparison to normal
      behavior, as well as to automatically search for interpretable gait abnormalities
      and to visualize the results. The outcomes are demonstrated with two different
      patient groups.

PMID- 12465279
TI  - [Initial results with the Munich knee simulator].
AB  - In orthopaedics more than 50 different clinical knee joint evaluation tests exist
      that have to be trained in orthopaedic education. Often it is not possible to
      obtain sufficient practical training in a clinical environment. The training can
      be improved by Virtual Reality technology. In the frame of the Munich Knee Joint
      Simulation project an artificial leg with anatomical properties is attached by a
      force-torque sensor to an industrial robot. The recorded forces and torques are
      the input for a simple biomechanical model of the human knee joint. The robot is
      controlled in such way that the user gets the feeling he moves a real leg. The
      leg is embedded in a realistic environment with a couch and a patient on it.

PMID- 12465280
TI  - [Reha-Stepper locomotion therapy in early rehabilitation of paraplegic patients].
AB  - Treadmill training with partial body weight support was shown to significantly
      improve the constitution and gait capacity of incomplete spinal cord injured
      (SCI) persons. The main requirement for application of this therapy is a
      sufficient capacity of the cardiovascular system. Most of the SCI patients do not
      comply with this requirement in the first few weeks after spinal cord injury,
      where spinal reflexes are frequently missing (spinal shock). To offer SCI
      patients a locomotion therapy at this early stage of rehabilitation we developed
      a novel, active tilt-table, the Reha-Stepper, that moves the lower limbs in an
      almost physiological manner in terms of kinematic and kinetic parameters. The
      tilt of the device can be continuously increased from horizontal to almost
      upright position adapted to the status of the patient.

PMID- 12465281
TI  - [Bicycle ergometer for rehabilitation].
AB  - In patients that are in rehabilitation the physical ability is measured with
      stationary cycle ergometers. A new ergometer, that can be mounted easily to a
      bicycle, allows the mobile measurement independent of the location. The principle
      is based on the simultaneous measurement of chain force and chain velocity. One
      component of the chain force is measured, that is generated by the change of the
      chain's direction by pulleys. The velocity of the chain is measured by the
      rotational speed of one of the pulleys. The new ergometer is easy to attach and
      remove. The measured values are digitized, numerically processed and recorded.
      Through a GSM-Modem these data are transmitted to a remote central host computer
      and allow the control/evaluation of the patient's performance.

PMID- 12465282
TI  - [Local temperature distribution in HF thermotherapy in an ex-vivo liver model].

PMID- 12465283
TI  - [Model construction for reperfusion of the isolated pig liver].
AB  - In recent years thermal ablation of liver tumors as a minimally invasive method
      became a promising alternative to conventional strategies such as chemotherapy or
      resection of liver tissue. Thereby an electrode is placed inside the tumor
      delivering energy in the form of high frequency current into the target volume to
      achieve and maintain a tissue temperature between 60 and 100 degrees C. Cells
      exposed to this thermic stress undergo coagulation necrosis and are irreversibly
      damaged. To protect vital liver structures from heat, it is necessary to develop
      an online temperature monitoring system. An experimental setup perfusing isolated
      pig livers under physiological conditions with 0.9% NaCl solution was established
      to develop and evaluate the measuring technique.

PMID- 12465284
TI  - [First experiences with a miniaturized heart-lung-machine].
AB  - Conventional heart-lung-machines (HLM) used for many cardiosurgical procedures
      lead to an impaired function of nearly all organs. This deleterious effect may be
      reduced by miniaturized HLMs. Therefore we report on our first experiences in 9
      patients (4 women, 5 men) undergoing beating heart coronary artery bypass
      grafting from 10/01 to 04/02 in our department employing a miniaturized HLM with
      the Deltastream extracorporeal rotary blood pump. Eight patients had an
      uneventful postoperative course, one patient died on the first postoperative day.
      Using this miniaturized HLM beating heart coronary artery bypass grafting was
      successful in all patients. Further studies are necessary to support these
      results.

PMID- 12465285
TI  - [Initial clinical experiences with a plasma impermeable capillary and a radial
      pump as a biventricular heart replacement].
AB  - A 3 month old infant was treated because of acute lung failure after VSD- and ASD
      occlusion with an extracorporal membrane oxygenation. The system performance was
      monitored over a period of 21 days. A Biomedicus 540 centrifugal pump served as
      the drive. The HILITE 800 LT infant oxygenator was chosen for oxygenation because
      this product is equipped with a plasma tight fiber. An oxygenator's application
      with an average of 128 hours lay, as expected, relatively high. Plasma leaks were
      not noticed. A change of pump head though became necessary due to high hemolysis
      after every 51 hs.

PMID- 12465286
TI  - Measurement method for the assessment of transmission properties of implantable
      hearing aids.
AB  - Over the last five years the Symphonix Vibrant soundbridge (VSB), an implantable
      hearing device, has proven an effective alternative treatment modality for
      patients suffering from moderate to severe sensorineural hearing loss. The
      results from the majority of our 40 patients are very encouraging but reveal
      clinical variations in benefit influenced by the coupling of the transducer to
      the ossicular chain. This study describes a set-up for measuring the sound
      pressure level in the external auditory canal when the middle ear implant is
      activated. The reverse transfer function allows the transducer performance to be
      determined both intra- and postoperatively. The sound pressure level shows a
      strong correlation with the stapes footplate displacement and free-field
      audiometry.

PMID- 12465287
TI  - Image-guided navigation for minimal invasive approaches in craniomaxillofacial
      surgery.
AB  - The use of minimally invasive procedures in maxillofacial surgery will require
      new technologies involving surgical navigation and techniques. The aim of our
      studies is to improve the efficacy of image-guided navigation in combination with
      endoscopically assisted techniques for minimally invasive craniomaxillofacial
      procedures. Prospective evaluation was made of all patients who underwent
      surgical procedures using image-guided navigation. The most common type of
      operations performed were endoscopically assisted interventions within the
      paranasal sinuses, fracture treatment, the resection of bone lesions and further
      miscellaneous interventions. Our experience to date suggest that image-data based
      techniques are eminently applicable, providing a feasible alternative to
      conventional surgical treatment.

PMID- 12465288
TI  - [Monitoring for determining etiology of dialysis-associated and dialysis-induced
      arrhythmias].

PMID- 12465289
TI  - [Remote controlled drug release in the alimentary tract by local power deposition
      in alternating magnetic fields].
AB  - Remote controlled release of agents in the alimentary tract is an important task
      of gastroenterology and pharmacy. We investigated two different methods of drug
      release by heating locally restricted parts in medical capsules: hysteresis
      losses of magnetite powder and eddy current losses of metals in alternating
      magnetic fields. The comparison of our experimental results with theoretically
      derived expectations show that both methods are suitable techniques if special
      technical conditions are met. In order to demonstrate the feasibility of simple
      constructions, we used a gelatin capsule, consisting of two parts which were kept
      together by a belt of wax and a small copper coil. This capsule was placed in
      water and the belt was heated in an alternating magnetic field until melting and
      releasing a test fluid after about 60 s.

PMID- 12465290
TI  - Numerical calculations of switched magnetic field gradients during magnetic
      resonance imaging.
AB  - During magnetic resonance imaging (MRI) pulse-sequences the human body is exposed
      to switched magnetic gradient fields. These gradients become stronger and are
      switched faster for fast imaging. Effects resulting from these fields with
      trapezoidal waveforms are on the one hand sensory perception of induced currents
      and on the other hand muscular and cardiac stimulation. All three components of
      the current density induced by gradient pulse sequence were analysed in a high
      resolution model of the human torso. The evaluation of the calculated data was
      performed thoroughly in the region of the heart muscle of the torso model to find
      out how different waveforms of the switched gradient field influence strength and
      direction of induced currents.

PMID- 12465291
TI  - Thermal heating of human tissue induced by electromagnetic fields of magnetic
      resonance imaging.
AB  - The paper presents a simulation of the transient temperature distribution in the
      human body caused by induced eddy currents during magnetic resonance imaging
      (MRI). In a first simulation the validity of the used heat conduction equation
      was proven using a simple example of a cool-down-process of a sphere. Thereafter
      the heating of a phantom model with an implanted electrode placed in a MRI-System
      (active body coil) was examined. The resulting increase in temperature was
      compared with existing measurements. Finally the implications of the heating of
      the tissue are discussed based on the observed experimental and numerical
      results.

PMID- 12465292
TI  - [Modeling light distribution in nasal tissue structures].
AB  - There are different applications in the field of optical diagnostics in which the
      theories explaining the light transport in tissue do not lead to simple solutions
      for complicate geometric conditions. In these cases the Monte Carlo method
      provides a powerful tool to solve this problem statistically. In order to
      simulate the light transport in the nasal region a model was created which
      includes the structure depending on the swelling of the mucous membrane as well
      as the Monte Carlo model. Using this model it is possible to evaluate the
      measured values qualitatively. However, due to the long distance between light
      source and detector the statistical error becomes a major problem for reliable
      statements.

PMID- 12465293
TI  - [Reducing MRI artefacts by controlled combinations of para- and diamagnetic
      materials].
AB  - A theoretical mathematical model of dual-component paramagnetic and diamagnetic
      material to cancel metal-induced magnetic resonance imaging (MRI) artifacts was
      investigated and evaluated. The magnetization produced by material causes
      gradient linearity distortion. By using materials with opposing paramagnetic and
      diamagnetic properties it is supposed to compensate these effects. Therefore the
      interferences by paramagnetic and diamagnetic materials on images in a closed 1.5
      Tesla high field magnetic resonance imaging system was experimentally examined
      for different types of sequences and correlated to their magnetic susceptibility.
      Basing on this results the concept of dual-component materials to solve the
      problems of MRI--artifacts was theoretically checked by using the finite element
      method and experimentally in the MRI.

PMID- 12465294
TI  - Simulation of a birdcage and a ceramic cavity HF-resonator for high magnetic
      fields in magnetic resonance imaging.
AB  - The aim of this work was the 3D-simulation of a dielectric resonator for high
      field-MRI. A 12-rod-bird-cage-resonator was simulated in a first step, in order
      to verify the capability of the commercial simulation software MAFIA to simulate
      homogeneous, transversal B-fields in resonators. The second step was the
      simulation of frequency-independent dielectric ceramic resonators for static
      magnetic field strengths of 7 T and 12 T (294 MHz and 504 MHz respectively). The
      results were compared to the measured results of a manufactured TiO2- and a Al2O3
      resonator. Only minor deviations showed up. These results led to the conclusion
      that dielectric resonators for high field MRI can be optimised using numerical
      field calculation software.

PMID- 12465295
TI  - Development and characterisation of a ceramic HF-resonator for the MR-tomography.
AB  - Future trends in magnetic resonance imaging (MRI) lead to higher magnetic field
      strengths of the static magnetic fields and as an implication of that to much
      higher frequencies. Nowadays a common model of a send-receive coil is the
      birdcage resonator. However it is very difficult to find an optimal L/C-relation
      for the capacities and inductivities at frequencies above 300 MHz. The idea is to
      build a completely new send-receive resonator without discrete network elements.
      The solution presented in this work is the development of a fully ceramic
      resonator with a high dielectric constant (between 30-100) and a low loss factor
      (tan delta approximately 10(3)). This approach has shown to produce a stable
      transversal magnetic field at the desired MR-frequencies above 300 MHz.

PMID- 12465296
TI  - [A system for simulating heart movement].

PMID- 12465297
TI  - [SOP-surgical operation planning].
AB  - Our active research project DFG Eu-49/1-2 strives to the reconstruction of bone
      defects basing on the individual craniofacial implants prefabricated within the
      TICC-processing-chain. In cases of disease of the bone the defect is to plan and
      the bone has to be resected. The planning of the defect is done on CT- and CAD
      data. The common visualisation of this different data-types (CT-data as pixel- or
      voxel-data on the one hand and CAD-data as geometry-data on the other hand) was
      not possible in the used application. The development of "Surgical Operation
      Planning" (SOP) results in an application between CT-visualisation and CAD
      application and allows the common visualisation and planning for defect
      reconstructions.

PMID- 12465298
TI  - [Finite element simulation of the dilatation of coronary vascular implants].
AB  - Intravascular stents are small tube-like structures expanded into stenotic
      arteries to restore blood flow. The stent is mounted on a balloon catheter and
      delivered to the site of blockage. First the balloon is inflated, so the stent
      expands and is pressed against the stenotic wall of the coronary artery. After
      balloon deflation the stent remains in the coronary artery and the balloon is
      removed. In this paper, the finite element method is used to simulate the
      expansion and recoil after ballOon deflation of the stent as well as the cyclic
      loading of the stent caused by the changing blood pressure.

PMID- 12465299
TI  - Hyperelastic description of elastomechanic properties of the heart: a new
      material law and its application.
AB  - Knowledge concerning passive mechanic cardiac properties is necessary to model
      behavior of whole hearts. Commonly, a continuum mechanics based description is
      chosen in conjunction with the finite element method. The aim of this work is to
      summarize, derive and evaluate hyperelastic material laws for inhomogeneous,
      anisotropic myocardium. Hence, different material laws were set up and their
      parameters were determined taking measurement data in literature into account.
      The material laws were compared from a theoretical and numerical point of view.
      Furthermore, the application of continuum mechanics based methods is evaluated
      concerning aspects of numerical solution and spatial discretisation. In further
      work the laws will be implemented and integrated in an existing software
      environment, which allows the calculation of deformations in complex geometries.

PMID- 12465300
TI  - Modeling force development in the sarcomere in consideration of electromechanical
      coupling.
AB  - Models of the cellular force development simulate the contractive behavior of the
      sarcomere. In conjunction with electrophysiological models they can contribute to
      a better comprehension of physiology and pathologies. Aim of this study is to
      examine the coupling of cellular electrophysiological processes and force
      development. For that a graphical user interface was developed to simplify the
      parameterization and calculation of the models as well as to present the results
      graphically. A feedback mechanism is introduced to pay attention to close
      connections between force development and intracellular processes. On basis of
      various tests with different boundary conditions, new force models are developed,
      parameterized, validated and compared with models in literature. In future
      studies the results will be tested in multiple cell organization.

PMID- 12465301
TI  - [Detector quantum efficiency of various roentgen imaging chains].

PMID- 12465302
TI  - [Influence of heart rate on image quality and detection of coronary stenoses with
      multislice spiral CT].
AB  - Multi-slice spiral CT (MSCT) permits the detection of coronary stenoses. We
      investigated the influence of the patient's heart rate (HR) during the scan on
      stenosis detection and the presence of motion artifacts. In 100 patients MSCT was
      performed and retrospectively ECG-gated cross-sectional images were
      reconstructed. 115 of 400 coronary arteries (29%) were unevaluable due to motion
      artifacts (84/115) or other reasons (31/115). In evaluable arteries, sensitivity
      was 91% (51/56 high grade stenoses detected), specificity was 89%. With
      increasing HR, the number of unevaluable arteries increased and overall
      sensitivity for stenosis detection decreased from 62% (HR < or = 70 bpm) to 33%
      (HR > 70 bpm). MSCT permits detection of coronary stenoses, but evaluability and
      accuracy decrease with increasing HR.

PMID- 12465303
TI  - [Texture-based image segmentation in medical volume images].

PMID- 12465304
TI  - [Quantitative evaluation of cavitation bubble fields induced by lithotripter
      shock waves].
AB  - Extracorporeal shock wave lithotripsy is the world-wide standard therapy for
      renal stones. The rare-faction phase of the shock wave can induce cavitation
      within the body. Cavitation contributes to stone disintegration but also to
      medical side effects. The aim of this study was to evaluate the spatial and size
      distribution of the cavitation bubble fields. To this end, the bubble fields were
      photographed digitally and evaluated automatically by image processing. The
      influence of various medium (water) and shock wave parameters was investigated.
      Water purity, i.e. the number of cavitation nuclei, was the most critical medium
      parameter which has to be controlled. At oxygen levels higher than 4 mg/l,
      cavitation increased rapidly when high shock wave frequencies of 2 Hz were used.

PMID- 12465305
TI  - Design of a system for contact-free measurement of the conductivity of biological
      tissue.
AB  - The electrical impedance of tissue can give important informations about the
      viability of the tissue. A non-invasive and contact-free measuring system using
      an inductive sensor is presented. Using a single pick-up coil the system is not
      sensitive enough for measuring the small changes in conductivity of biological
      tissue. Employing a gradiometer instead of a single pick-up coil can improve the
      resolution of the system. The developed data acquisition system is realized using
      four parts: A lock-in-amplifier, providing a sinusoidal signal and measuring the
      signal of the sensor, a power amplifier, driving the excitation coil of the
      sensor, the inductive sensor and a preamplifier for buffering a reference signal
      and amplifying the output signal of the sensor. In this paper the focus is on the
      hardware that was set up. Results of measurements on inhomogeneous phantoms are
      shown.

PMID- 12465306
TI  - [Realization of a measurement module for determining pH value in perfusion
      cultures].
AB  - For cultivating animal cells in bioreactors the maintenance of a fixed pH-value
      is of elementary importance. In a perfused cell culture system the pH-value is
      measured by electrochemical flow rate sensors. For the acceptance of a technical
      solution the integration in complex workplaces is necessary, thereby small size
      and low costs are the main features. For that a special measurement module was
      developed, consisting of measuring amplifier and microcontroller component with
      CAN-Bus-interface.

PMID- 12465307
TI  - Development of a current-controlled defibrillator for clinical tests.
AB  - The work presented here is only a part of the development for a new current
      controlled defibrillator. In the diploma thesis "Development and construction of
      a current-controlled defibrillator for clinical tests" the most important part
      was the control and safety of the defibrillator. To ensure a safe circuit design,
      a risk-analysis and a Failure Mode and Effects Analysis (FMEA) were necessary.
      Another major part was the programming of a microcontroller in embedded C and a
      programmable logic device in Very High Speed Integrated Circuit Description
      Language (VHDL). The circuit had to be constructed, and the defibrillator was
      optically decoupled from the laptop for safety reasons. The waveform-data can be
      transmitted to the microcontroller from the laptop, and the logged data is then
      transmitted back.

PMID- 12465308
TI  - [Development of a multi-function instrument for laparoscopic surgery].

PMID- 12465309
TI  - [Actuator design and control exemplified by a urologic implant].
AB  - The state of the art concerning the use of actuators and sensors and the
      intelligent microprocessor-based control will be discussed on the basis of a
      novel urological implant, a fine tuned, sensor controlled artificial sphincter. A
      set of powerful actuators with a reaction time lower than 10 ms have been
      realised due to an appropriate design of components. This has been achieved at a
      supply voltage of 4.2 V and a power input lower than 0.1 mW. An optimal
      reliability as well as the comfort in operating the implant by the physician and
      the patient was gained by the use of different data technologies being adapted to
      the implanted system.

PMID- 12465310
TI  - [Construction and optimal design of a dynamic heart phantom for simulation of
      motion artefacts in PET scan].

PMID- 12465311
TI  - [Diagnosis of arterial vascular diseases using classification of peripheral and
      cardiac impedance signals].

PMID- 12465312
TI  - [Evaluation of measurement systems for determining therapeutic effectiveness of
      anti-decubitus ulcer devices].
AB  - Interface pressure measurement is today a most used technique for laboratory
      evaluation of support surfaces in prevention of pressure sores. This article
      describes the results of an experimental comparative evaluation of four modern
      pressure mapping systems (Tekscan, Xsensor, Novel and FSA) using a special
      loading device. The tests generated data on numerical accuracy, linearity and
      hysteresis. The results show that the accuracy of pressure mapping systems is
      still limited and results obtained from different systems can not be directly
      compared.

PMID- 12465313
TI  - [Validation of simultaneously acquired blood pressure data by statistical
      coincidence determination of heart rate variability and blood pressure
      variability].
AB  - We report on the comparison of simultaneous non-invasive measurements of finger
      blood pressure obtained at both hands with two Portapres systems. We investigated
      the impact of altering the measurement location on heart rate and blood pressure
      variability (HRV,BPV) parameters. Two 30 minutes recordings were done twice in 21
      volunteers swapPing the systems. HRV and BPV parameters meanNN, sdNN, HF/P and Fw
      Shannon were determined. Left and right side corresponding parameters were
      compared by U-test and correlations. Coincidence matrices were analysed by
      Mahalanobis distance. The minimal total divergence in HRV was 4.8%, in systolic
      BPV 6.7% and diastolic BPV 12.1%. These estimates recommend those parameters for
      multi-center studies that are insensitive to the measurement location.

PMID- 12465314
TI  - [Coating material of parlene C as encapsulation material for biomedical micro
      implants].
AB  - Biomedical microsystems attain to contact with environments like blood,
      ephitHelium and saline solutions therefore they need an encapsulation. Parylene
      seems to be a suitable polymer to cover the implants and protect them against
      moisture and aggressive environment. This paper describes the characterisation of
      Parylene C coatings and its possibilities to protect implants. Beside the
      encapsulation of biomedical microsystems the manufacturing of fexible electrodes
      and the cytotoxicity behavior of RIE etched Parylene layers was investigated.

PMID- 12465315
TI  - [Comparative analysis of in vitro test procedures for evaluating
      hemocompatibility of cardiovascular stents].
AB  - Within the scope of this study existing in vitro techniques for testing the
      hemocompatibility of coronary stents were analysed and optimised. Static and
      quasi-stationary systems were compared to a pulsed flow model with respect to
      platelet activity. The streamlines were visualized by dye injection. Blood flow
      was measured by ultrasonic Doppler velocity meter and electromagnetic flow meter.
      Uncoated stainless steel (316 L) stents were tested. Surrogate parameters of the
      hemocompatibility were the change in surface morphology after blood contact and
      the rise of biomechanical activation markers as C3a and beta-thromboglobulin. The
      results were correlated to the stent design and to the flow characteristics of
      the test systems.

PMID- 12465316
TI  - [Design strategy for balloon-expandable stents made of biodegradable polymers
      using finite element analysis].
AB  - Stents made of biodegradable polymers have first been suggested to treat
      cardiovascular diseases more than ten years ago. Despite the enormous potential
      of local drug delivery there is no biodegradable coronary stent available today.
      Some of the problems concern the insufficient mechanical properties of the stent
      designs. Therefore a design strategy was developed to improve the mechanical
      properties of balloon-expandable polymer stents. Starting with compiling the
      possible geometric strut forms we proceeded to design strut features exhibiting
      an improved deformation behaviour. The addition of functional structures to
      improve certain stent characteristics led to stent designs, whose mechanical
      properties, recoil and collaps behaviour, were determined by 3D Finite Element
      Analysis. Finally, a mechanical in vitro testing of these stent prototypes was
      conducted.

PMID- 12465317
TI  - [Developing and establishing a monophasic action potential electrode].

PMID- 12465318
TI  - Signalprocessing in transmission pulse hemometry.
AB  - Supplying organs and body tissues with sufficient oxygen is one of the most
      important vital human functions. Commercial pulse oximeters compute the
      functional oxygen saturation from relative values (reduced hemoglobin and
      oxyhemoglobin). Methemoglobin (MetHb) and carboxyhemoglobin (COHb) are not taken
      into account, since they are considered to be reduced hemoglobin and
      oxyhemoglobin (RHb, HbO2). The total hemoglobin concentration is not included,
      and is determined by invasive methods. In this work, a non-invasive pulse
      oximeter is developed, which finds the entire hemoglobin concentration
      photometrically, and measures the fractional oxygen saturation and pulse rate.
      The signal of transmitted light I is processed according to the Lambert-Beer-law.
      The signal decays exponentially with the thickness d of the irradiated sample and
      its absorption coefficient alpha (I = I0 e -alpha d), where I0 is the incident
      light intensity.

PMID- 12465319
TI  - [Optimizing radiation parameters for heart catheter examinations in children].

PMID- 12465320
TI  - [Variability of ventilation parameters of home ventilation equipment].
AB  - The performance of pressure- and volume controlled ventilators used for invasive
      and non-invasive ventilation in the home were tested on a patient lung model. In
      order to determine the influence of tidal volume preset, breathing rate,
      resistance, compliance and leakage to the variability of delivered tidal volume
      and peak airway pressure a factorial plan with adapted analysis of variance was
      used. The influence of tidal volume preset, compliance and leakage to the
      delivered tidal volume is significant. The peak airway pressure depends hardly on
      the influence factors. All tested ventilators meet the legal demands. But in some
      clinical situations there are considerable deviations of the breathing parameters
      depending on the brand. In conclusion ventilators of different brands are not
      interchangeable.

PMID- 12465321
TI  - [Assessment of radiation exposure caused by transmission scans in SPECT: an
      anthropomorphic dosimetry study].
AB  - Transmission measurements are performed in SPECT to correct for attenuation of
      the gamma quanta in the body. In this study, we measured the additional radiation
      dose caused by transmission scans using a field of collimated 153Gd rod sources.
      Two measurement series were performed with an anthropomorphic phantom and
      thermoluminescence dosimeters. For a typical SPECT study, we found a mean dose
      rate of 2.2 +/- 0.8 micro Sievert per hour (range: 1.2-3.9 micro Sievert per
      hour). For a measurement time of 20 min, this corresponds to a mean equivalent
      patient radiation dose of 0.73 micro Sievert. Thus, the radiation exposure caused
      by transmission scans can be neglected compared to the radiopharmaceutical dose
      and may not be considered as a limiting factor for the clinical application of
      attenuation correction in SPECT.

PMID- 12465322
TI  - The wireless monitoring of vital parameters: a design study.
AB  - This project shows the way vital parameters can be transmitted and visualized
      with no connecting cables necessary to the PDA. This was realized using a sensor
      developed with an integrated Bluetooth interface and a PDA, also equipped with
      Bluetooth. This radio connection can span up to 10 m, and parameters, such as
      pulse frequency, oxygen saturation in blood, ECG measurements and plethysmograms,
      can be transmitted. Using the software introduced in this work, the transmitted
      measurements can be displayed numerically or graphically on the PDA. The software
      simultaneously checks for any limits and sends a warning message if these limits
      are exceeded. All received data are additionally documented.

PMID- 12465323
TI  - Miniaturized module for the wireless transmission of measurements with Bluetooth.
AB  - The wiring of patients for obtaining medical measurements has many disadvantages.
      In order to limit these, a miniaturized module was developed which digitalizes
      analog signals and sends the signal wirelessly to the receiver using Bluetooth.
      Bluetooth is especially suitable for this application because distances of up to
      10 m are possible with low power consumption and robust transmission with
      encryption. The module consists of a Bluetooth chip, which is initialized in such
      a way by a microcontroller that connections from other bluetooth receivers can be
      accepted. The signals are then transmitted to the distant end. The maximum bit
      rate of the 23 mm x 30 mm module is 73.5 kBit/s. At 4.7 kBit/s, the current
      consumption is 12 mA.

PMID- 12465324
TI  - XML-based synchronization of mobile medical devices.
AB  - Today, mobile computing provides enough resources to be used in medical
      applications. Patient treatment is a process that involves multiple partners. All
      those partners need access to common patient-data and need to make changes to the
      patients' health record. Therefore, data that the partners collect and change
      with mobile devices has to be synchronized on a central server to form the master
      patient record. Data conflicts resulting from the synchronization have to be
      solved automatically. Our project describes a solution for XML-based data
      replication and synchronization for mobile health applications.

PMID- 12465325
TI  - [Measuring hypoxic and hypercapnic respiratory response in patients with
      obstructive sleep apnea].
AB  - The gas composition of breathing air is a very important stimulus for the control
      of breathing. The different partial pressures of O2 and CO2 independently trigger
      individually different reactions (respiratory response), which can be measured as
      a change of respiratory minute volume. Investigations of the respiratory control
      in patients with obstructive sleep apnoea (OSA) have up to now been restricted to
      an analysis of the breathing patterns at night. Therefore we have developed a
      computer-controlled device which allows a flexible composition of the air to be
      inhaled using a regulated feet-back circle. With this system it is possible to
      produce a hypercapnia test as well as a hyperoxia and an isocapnic hypoxia test.
      The simultaneous recording of all relevant respiratory parameters (AF, AMV,
      ETCO2, SpO2, FiO2) and the parallel recording of continuous blood pressure allow
      a quantitative description of the respiratory regulation of patients with OSA
      with exactly defined tests.

PMID- 12465326
TI  - [Dependence of nocturnal bronchial obstruction on sleep position].
AB  - Patients with bronchial obstructions often have problems to stay asleep at night.
      The interaction between sleep position and bronchial obstructions has not been
      investigated until now. A total of 20 patients was included in this study. All
      patients were recorded one night in our sleep laboratory with a parallel
      recording of lung sounds using a commercial Pulmotrack 1010 system. The bronchial
      obstructions were lower in lateral position than in supine position for both
      tracheal and chest sounds (p = 0,083 and p = 0,036; n.s.). This effect seemed to
      be especially high in patients with many obstruction episodes. From our results
      we can conclude that there is a small dependence of bronchial obstructions from
      sleep position. Further investigations are needed to verify this result.

PMID- 12465327
TI  - [Development of a CAN (controller area network) bus for modules of a perfused
      cell culture system].
AB  - For computer-aided data acquisition and automated running of experiments in cell
      cultivation reactors networking of all sensoric and actoric devices is required.
      A low cost and high performance solution to this demand can be found by using the
      widely established CAN (Controller Area Network) bus. If standard PCs running MS
      Windows are used to control this network special measures have to be taken to
      prevent loss of data caused by differences in the computing power of the PC on
      one hand and microcontroller-based devices on the other.

PMID- 12465328
TI  - [Expanding control possibilities of myoelectric hand prostheses].
AB  - Raising control possibilities of myoelectric prostheses--The control of hand
      prostheses is based on the surface scan of myoelectric voltage caused by muscle
      contractions in an amputees arm stump. So far available prostheses only perform
      up to two different grip types. This paper introduces a control scheme that is
      able to execute a variety of grip types dependent on the patient's control
      signals. Therefore a platform is presented to adapt control parameters especially
      to the patients anatomy. Developed algorithms are flashed on a microcontroller,
      processing data online and controlling a new generation of prostheses (FZK
      prosthesis, Forschungszentrum Karlsruhe).

PMID- 12465329
TI  - [Effect of post-extrasystole potentiation on blood pressure and heart rate
      regulation].
AB  - Noninvasive finger arterial blood pressure and ECG were recorded for 30 min in
      patients with idiopathic dilated cardiomyopathy (IDC) and healthy control
      subjects (CON) for the investigation of blood pressure and heart rate regulation
      following a premature ventricular complex (PVC). The potentiation of blood
      pressure amplitude of the postextrasystolic beat was fivefold increased in IDC
      compared with CON (48.7 +/- 32.6% vs. 9.8 +/- 5.4%, p < 0.01). PVC starts a
      baroreflex response, which last about 10 s in physiological regulation. In
      contrast, the baroreflex response in IDC is immediately suppressed by the
      augmented potentiation of the blood pressure amplitude from the first
      postextrasystolic beat. Thus, the regulation after PVC is determined by the PVC
      itself and postextrasystic potentiation.

PMID- 12465330
TI  - Parameter extraction of ECG signals in real-time.
AB  - In order for a mobile ECG recorder to be able to classify a heart rhythm online,
      the significant parameters must be extracted. The relevant parameters are the
      beginning, peak and end of the QRS-complex, the P- and T-waves, the ST-segment
      and other significant intervals, such as the RR-interval. The aim of the
      development was, firstly, stable, real-time-capable QRS detection, which finally
      achieved values for sensitivity of 98.9% and a positive predictivity of 99.9% on
      standard ECG databases. Also, a filter-based detection of P- and T-waves was
      implemented, which can also be performed in real-time on a microcontroller
      platform.

PMID- 12465331
TI  - Evaluation and optimization of different spectral estimation methods for EEG
      signals.
AB  - The goal of this work was the evaluation of various spectral estimation methods
      with regard to their suitability for classifying EEG data. A test environment was
      implemented in which the algorithms are optimized and evaluated using various
      artificial and real EEG data. The methods are based on autoregressive approaches,
      as well as from FFT, wavelet, and matching pursuit-based spectral estimations.
      The evaluation showed that the quality of the results strongly correlate with the
      computational effort of the algorithm. The matching pursuit algorithm (MP) was
      implemented and further optimized since it had the best test result and had good
      scalability. Even under a sufficiently low runtime, it still gave good results.

PMID- 12465332
TI  - [Miniaturized components and systems for cardiovascular and tissue therapy].

PMID- 12465333
TI  - The Ruhr Center of Competence for Medical Enginnering (Kompetenzzentrum
      Medizintechnik Ruhr KMR, Bochum).
AB  - The profile and the projects of the Ruhr-Center of Competence for Medical
      Engineering at the Ruhr-University Bochum (Germany) will be described. Main topic
      of the KMR is medical ultrasound with emphasis on image based tissue
      characterization including elastography and multimodality concepts, mainly in
      combination with other non-ionizing imaging modalities. Project aims are early
      detection of cancer (skin, prostate), vessel and perfusion diagnostics (early
      detection of arteriosclerosis, cardiac arteries, stroke), and intraoperative
      navigation using ultrasound.

PMID- 12465334
TI  - [Thuringen ophthalmological innovation].

PMID- 12465335
TI  - [Competence center for cardiovascular implants. Hannover Medimplant].

PMID- 12465336
TI  - Competence Center for Miniaturised Monitoring and Intervention Systems MOTIV.
AB  - In the national Competence Center, the whole value chain, from the idea to the
      development of a product ready for the market, is brought together. MOTIV has
      underlined three focus point: It wants to improve the therapy and therapy
      control, to develop intelligent microimplants and to create innovative telematic
      home healthcare concepts.

PMID- 12465337
TI  - [Visions and strategies in the European research area. "Technology for the
      Information Society"].
AB  - A new generation of EU research is expected to take life at the end of 2002. One
      of the new elements of the Sixth Framework Programme (FP6), which is essential
      for the realisation of the European Research Area (ERA), will be the use of new
      instruments for funding research, such as Integrated Projects (IP) and Networks
      of Excellence (NoE). Integrated Projects will contribute to strengthening
      European competitiveness and solve major societal problems, by mobilising a
      critical mass of research and development resources and skills existing in
      Europe. Networks of Excellence will contribute to strengthening European
      scientific and technological excellence though a better integration of research
      capacities across Europe.

PMID- 12465338
TI  - [Heart assist systems with integrated microsensors (HIM 2)].
AB  - The use of intracardiac pump systems is leading to more physiological support for
      coronary surgery patients. But the currently available micro blood pump with an
      integrated micro pressure sensor and an outer diameter of 6.5 mm is not suitable
      for a transfemoral placement of the device. Therefore a significantly smaller
      pump with an outer diameter of 4 mm (12F) is been developed and tested. To
      transfer the sensor technology in this, for the first time the MID (moulded
      interconnected device) technology is applied in a medical device. In a first step
      MID is used to integrate a smaller pressure sensor on the existing blood pump.
      The result should help to find a new packaging and connecting solution for
      integration of the miniaturized sensor on the 4 mm pump.

PMID- 12465339
TI  - [Personal Health Monitoring System with innovative microsystem technical sensor
      (status report)].

PMID- 12465340
TI  - IMEX--a new knowledge platform for microsystems in medicine.
AB  - The development of medical applications is driven in the context of steadily
      growing needs and the requirement of lowering the overall costs. Microsystems
      will have an extremely important impact on medical technology in the future. The
      great challenges for the wider usage of microstructures in health application are
      biocompatibility and mass production. Especially SME's need help to overcome
      these problems by free access to knowledge, availability of standards and
      contacts to partners. IMEX is a new knowledge platform funded by the Federal
      Ministry of Education and Research in Germany. In setting up an active network of
      institutes and companies IMEX sets up a knowledge base and starts
      standardisation.

PMID- 12465341
TI  - ["Computer- and Sensor-Assisted Surgery" Special Research Area 414--goals and
      concepts].
AB  - This paper presents an overview of our research in computer assisted surgery
      within the "Sonderforschungsbereich 414--Information Technology in Medicine:
      Computer and Sensor Supported Surgery". The overall goal is to achieve improved
      operation methods including higher quality, more safety and also more economy due
      to shorter operation time and less postoperative treatment. The SFB 414 is
      divided into three different sections focusing on projects concerning the heart,
      projects supporting cranio-facial interventions and interconnecting projects that
      serve both categories.

PMID- 12465342
TI  - Perfusion-contractility matching during Fontan circulation.
AB  - We investigated the relationship between coronary perfusion pressure (CPP) and
      myocardial contractility and the effects of an acute elevation of right atrial
      pressure (RAP) on this relationship in an experimental model of Fontan
      circulation in 6 anesthetized open-chest dogs with isolated perfused coronary
      arteries. The relationship between CPP and Ees could be described by biphasic J
      shaped curves which were nearly identical before and under Fontan circulation.
      While above a "critical" CPP (72 +/- 9 mmHg vs. 81 +/- 8 mmHg, n.s.) the changes
      of CPP did not affect Ees, below this level the decrease of CPP resulted in a
      progressive decrease of Ees. Under Fontan circulation, the progressive increase
      of RAP did not influence Ees at CPP = 100 mmHg, led to a moderate decrease of Ees
      at CPP = 75 mmHg and severe decrease at CPP = 60 mmHg. Thus, both coronary
      arterial and venous pressure affect myocardial contractility after Fontan
      procedure.

PMID- 12465343
TI  - [Multi-value regulatory systems for extracorporeal circulation].
AB  - Extracorporeal perfusion is the standard technique in cardiac surgery. It is
      controlled by perfusionists on the basis of their clinical experience and on the
      available data collected pre- and intra-operatively. But in spite of intensive
      monitoring postoperative complications occur. An appropriate control of the heart
      lung machine (HLM) using an "autopilot" might improve the quality of heart
      surgery and decrease postoperative complications. Hence, a mathematical model of
      a human circulatory system has been developed which provides much more
      information about haemodynamics, blood gases and acid-base status than standard
      monitoring. It has been implemented on a system which is capable of integrating
      measured data as input parameters in real-time in the simulation. Now, soft- and
      hardware control concepts based on the human circulatory system have to be
      developed which are able to control the HLM.

PMID- 12465344
TI  - Evaluation of models.
AB  - Evaluation of models describing computer based technology is crucial for further
      evolution of medical progress. In this project, the research sites of the
      Sonderforschungsbereich 414 "Computer and sensor aided surgery" were linked for
      evaluation purposes. Topics of flow, morphology, function, and robotics in the
      field of cardiac and oromaxillofacial surgery are addressed. Key methods are
      animal models, phantoms, image processing and clinical studies in the setting of
      exactly defined circumstances. As an example, 3D evaluation of myocardial edema
      is presented. Heterogeneity of 3D distribution of induced myocardial edema was
      validated. Temporal dynamics of edema is described as an example. Based on such
      models, diagnostic and operation relevant planning data are offered to cardiac
      surgeons.

PMID- 12465345
TI  - [Clinical applications of 3-D and 4-D imaging in echocardiography].

PMID- 12465346
TI  - [Electrophysiological modeling of the heart as a basis in therapeutic
      interventions].

PMID- 12465347
TI  - [Computer-assisted reconstruction of coronary vessels].
AB  - End stage coronary artery disease with linear stenosis of the main vessels
      despite several coronary interventions is a current challenge for surgical
      treatment. As the long term results are mainly determined by the pathology of the
      coronary vessels a simple revascularisation with arterial or venous grafts
      provides no adequate solution of the problem. An exactly controlled 3D
      reconstruction of the coronary vessels enabling selective thrombendarteriectomy
      (TEA) seems to be a new approach, that may be limited by neointimal
      hyperproliferation of the coronary vessels. Intraoperative brachytherapy may be a
      tool to inhibit this process.

PMID- 12465348
TI  - Problems of interactive segmentation.
AB  - Computer-assisted surgery makes a patient-individual treatment feasible, aiming
      at decreased surgical risk and reduced recovery time of patients. At present, in
      areas of application, e.g., heart surgery as well as craniofacial surgery, its
      use is still limited to complex cases due to the high effort. In surgical
      planning, it is caused by extensive medical image analysis, including tissue
      classification. Especially, the classification (or segmentation) requires a lot
      of manual intervention. For a long time research has been devoted solely to
      computational aspects of segmentation, where usability aspects has been out of
      scope. This article focuses on the major problems of interactive segmentation and
      provides consequences on the segmentation process towards a solution.

PMID- 12465349
TI  - [Processing medical image data for head surgery].
AB  - Three-dimensional models of the patient's anatomy are the basis for modern
      applications in computer-assisted surgery or radiology. To create these models
      the data is processed in a series of steps that transforms the initial raw data
      (generally CT/MRT volume images) into the three-dimensional models (e.g. triangle
      meshes). In doing so, a multitude of parameters adjustments, interactions and
      decisions are necessary to be made by the physician in order to create the models
      adapted to the specific needs of the patient and to the surgery. The quality of
      the models therefore strongly depends on that process chain. As a result of the
      high requirements on the quality and security of a clinical application the
      quality of the models itself and the capability to use them flexibly are
      essential. This work present a method to adjust and optimise the creation of the
      models and to asses their quality afterwards.

PMID- 12465350
TI  - [Surgery planning in head surgery].

PMID- 12465351
TI  - [Robot-assisted surgical suite].

PMID- 12465352
TI  - [Expanded reality in head surgery].
AB  - The preoperative planning of complex craniofacial surgical interventions is
      increasingly realized with the aid of appropriate planning systems in order to
      achieve high precision, minimal invasion and protection of risk areas. But the
      most important step from the planning to the actual intervention consists of
      providing the planning data intraoperatively in a reasonable and easy to handle
      way. In this regard, augmented reality is one of the most challenging and
      promising techniques to solve this problem. In this paper we present two
      different systems based on see-through glasses resp. a common video projector to
      directly visualize the planning data in the surgeon's field of view. The work is
      funded by the 'Deutsche Forschungsgemeinschaft (DFG)' and Stryker Leibinger
      Freiburg/Germany.

PMID- 12465353
TI  - The value of permanent follow-up of implantable pacemakers--first results of an
      European trial.
AB  - A clinical study investigates the use of Home Monitoring (HM) in pacemaker
      therapy. For 3 months patients are supervised by daily automatic HM messages.
      Endpoints are the technical feasibility and the clinical benefit of HM. Ninety
      three patients have currently been included and followed for 72 +/- 30 days.
      Three patients were excluded due to insufficient mobile net coverage at their
      living sites. For the other patients, 5311 of 5911 messages were successfully
      registered. Interrupts in the sequence of messages occurred 331 times. Two
      hundred ten of these (63%) lasted just 1 day, 14 interrupts (4%) lasted 5 or more
      days. Two patients did not show any interrupts, 34 patients (38%) had interrupts
      of 3 and more days. The clinical benefit of Home Monitoring was found in the
      remote detection of arrhythmia and lead dislocation.

PMID- 12465354
TI  - [Telereha--special challenges for telemedicine in geriatric rehabilitation].
AB  - Modern telecommunication technology has the potential to improve the quality of
      life for elders with physical and mental impairments as well as for their
      caregiving relatives. This can be viewed as an opportunity to establish and
      maintain instant and personalized access to various medical services in a
      situation where increasing needs are opposed to decreasing resources. However, it
      is not yet clear whether telematics is adequate, efficient, and effective in
      supporting care for geriatric patients. Results of a tele-rehabilitation project
      ("TeleReha", conducted at the Berlin Geriatric Center) which comprised mobility
      impaired patients caregiving relatives and geriatric professionals, showed that
      participants regard telecommunicational and communicational needs.

PMID- 12465355
TI  - ["Saar Stroke Teleservice--pilot study for stroke after care with a home care
      platform].
AB  - In the German region Saarland a pilot trial has been conducted for the post
      clinical telecare and rehabilitation of stroke patients in there homes by a
      cooperative network of local healthcare providers. For that purpose an e-home
      care platform has been developed by a combine of Fraunhofer institutes under the
      leadership of the Fraunhofer Institute for Biomedical Engineering. A network
      formed by a clinic, 2 general practitioners and an advice centre cared for 18
      patients using the so-called PHS Homecare Platform for telemonitoring and virtual
      visits by videophone. (PHS: Personal Health Service--A research initiative of the
      Fraunhofer Society in the years 1996-2001). In the underlying feasibility study
      the telecare of stroke patients in the context of the German healthcare system
      has been tested and the e-home care platform has been evaluated.

PMID- 12465356
TI  - The Karlsruhe TeleHomeCare concept.
AB  - Chronically ill and care-intensive patients are those who account for a large
      share of the cost and work that service providers invest in the health sector.
      With the introduction of DRGs (Diagnoses Related Groups), hospitals will work on
      shortening hospitalization periods, thereby increasing the demand for outpatient
      care capacities. To prevent a quality decline due to early hospital release,
      partners in research an industry have joined in an effort to develop a platform
      for patients to be treated at home with service quality equal to in-hospital
      standards.

PMID- 12465357
TI  - [Can costs be lowered by post-hospital patient management with telecare].
AB  - The idea of Televisite is to equip the patients with a camera and a communication
      panel at the time of their discharge from the hospital. In that way patients and
      physicians are able to continue the treatment and the rehabilitation program. An
      easy to handle interface helps the patient to answer simple questions or to send
      voice recordings, pictures or videos via a service centre to the doctor in
      attendance. This concept has the great advantage that the patients has to visit
      the physician in the office or in the hospital only when absolute required.
      Routine checks can be done by telecommunication. Thus the efficiency of the
      system may significantly contribute to lower costs in the health care system.

PMID- 12465358
TI  - Recording and transmission of digital wound images with the help of a mobile
      device.
AB  - The goal of this project is to develop a mobile device for transmitting images
      for the aftercare of surgical patients within the framework of the competence
      center TELTRA. After designing and evaluating different platforms and cameras, it
      was decided to develop for a compact flash camera card and an HSCSD modem which
      is based on and can be plugged into a pocket PC. The recorded images are sent
      with the help of a Java program from the pocket PC over an IrDA interface to the
      HSCSD mobile telephone, and then to the web server, where it is saved in a
      digital patient record.

PMID- 12465359
TI  - [@HOME is a new Eu-Project in Tele Home care].
AB  - @Home is a robust platform for real-time remote monitoring of patients at their
      home by doctors at the hospital. Health monitoring sensors, which have the
      capability to measure quick and easy vital parameters such as blood pressure,
      pulse rate, temperature, oxygen saturation (SpO2), as well as ECG 12 leads are
      used. Additionally, an advantage of the platform is that all the sensors are
      wearable and the patient is able to walk around indoors or outdoors. Moreover,
      the sensors are able to convey the recorded data over Bluetooth, a short-range
      wireless communication, to any Bluetooth enabled device such as Desktop computer
      or a Pocket PC.

PMID- 12465360
TI  - ["Skill mix" and "grade mix" today and in the future].

PMID- 12465361
TI  - [Justice and good nursing care].
AB  - In this article the value orientations of justice and of the good are analysed in
      their concrete meanings for nursing proceeding. Firstly, the usual interpretation
      of justice in the practice field which reduces it to economical justice of
      distribution, is criticized. A stronger orientation of justice to the criterion
      of adequacy is proposed as an alternative. This would make possible a synthesis
      between the two demands of a just care and of a good care and would permit the
      mediation of two value orientations that often seem to be irreconcilable in
      nursing practice. The definition of the contents of good care attributes high
      importance to the aspect of relation. Because the nursing relation is in its
      essence an asymmetrical relation, the dimension of power has a decisive
      importance in this context. This leads to the question which kind of conditions
      must be created to give nurses the opportunity to use the power that they get
      from their function in a responsible way and to cultivate an attitude of non
      indifference toward those who need their help.

PMID- 12465362
TI  - [Inpatient postpartum nursing: evaluation of "holistic" and "traditional" nursing
      processes in the post partum period].
AB  - During the last years one could observe a change in the organisation of
      postpartum care at hospitals in Germany. Maternity hospitals implement new models
      of care which they call "holistic", "integrated" or "family centered" care. The
      reasons for the implementation are various. The desire for an optimal care has
      surely to be mentioned in the first place, but social changes and changes in
      health politics like the shortening of the lengths of hospital stay after a
      normal birth and the demand for quality assurance are also very important. But
      what does the "new model of care" mean for mothers, their children and their
      families and for the staff? What effects have the new models of care in
      comparison with the traditional ones? Will the goals be achieved? A formative
      programme evaluation was chosen in order to investigate these questions. To do
      justice to the research plan, to the complexity of the field of research and to
      produce valid results, three qualitative methods were applied: (keywords:
      triangulation: time triangulation, within-method-triangulation): participant
      observation, problem-oriented interview according to Witzel and document
      analysis. The evaluation of the data followed the method of qualitative content
      analysis developed by Mayring. As a whole, the results suggest that the new model
      of care has not produced the changes and not left the impression and effects on
      the mothers and the staff the hospital and the supporters had hoped for.

PMID- 12465363
TI  - [Movement as interaction--systemic-constructivist approach to movement and
      consequences for nursing care]].
AB  - The article starts off by analysing the problem that practice of nursing care and
      its training primarily keep to a mechanistic understanding of movement which is
      based on the scientific stimulus-response-model. Following this understanding it
      is argued that subjective dimensions of movement are thus neglected, ignoring
      patients' needs and demands. In order to reach a complex understanding of
      movement systemic and constructivist perspectives are introduced. Hence
      consequences for nurses' development of motorical propositions are developed.
      Interventions focussed on movements are to be designed as movement dialogues in
      which patients and nurses must find a consensus. In this process nurses'
      propositions can be seen as suggestions while patients' responses can be taken as
      counter suggestions.

PMID- 12465364
TI  - [Attitude of cancer patients to fatigue: patient attitude in Switzerland and
      England].
AB  - In the course of a cancer trajectory, many patients suffer from distressing
      fatigue. In past years, research has shown that care givers tend to underestimate
      or even to ignore this frequent phenomenon. Despite increasing knowledge, fatigue
      seems to remain an orphan topic in symptom management. AIM: A qualitative
      research strategy was used to explore the perception of cancer patients regarding
      the awareness of fatigue in professionals and the way they deal with it. Patients
      also evaluated the usefulness of some currently available information material
      about fatigue. METHODS: The expert-opinion of cancer patients in Switzerland and
      England was analysed. Convenient sampling guided the selection process of seven
      patients in each country. A tape-recorded focus-group interview served as method
      to collect and transcribe data. Data were analysed according to the framework
      analyses by Richie & Spencer. RESULTS: Results were very similar in both
      countries. Patients stated a great need for more information regarding fatigue.
      They feel that care givers are not sufficiently aware of it and that a specific
      support is not part of current standard practice. The information material was
      well received and generally judged as very good and helpful. CONCLUSIONS:
      Communication barriers in professionals as well as in patients continue to exist.
      Patients wish to be better informed by care givers. The available information
      material serves well to support this information as they provide words for the
      unmentioned phenomenon. Far more professional fatigue education is needed to
      raise care givers' awareness.

PMID- 12465365
TI  - [Nursing care dependence in the hospital. A descriptive study].
AB  - The findings indicate no clinical relevant difference relating to care dependency
      between men and women in any age group. The extent of care dependency grows with
      the patients' age in both genders. A crucial increase of care dependency is found
      after the age of 80. Because the variance of means on the care dependency scales
      increases with age generalizations of the results are restricted. Patients with
      cardiovascular diseases and patients with injuries and poisoning are more
      dependent on care than patients with other medical diagnoses. Patients with
      muscle-skeletal illnesses show the least degree of care dependency. The findings
      according to medical disciplines reveal patients who are in intensive care as the
      group most dependent on care with geriatric and neurological patients following.
      There is no difference of care dependency means between patients who were
      operated and patients who had not undergone an operation.

PMID- 12465367
TI  - [Prescriptions in international common denomination drugs, a future headache for
      nurses?].

PMID- 12465368
TI  - [Society for Professional Nursing Interests organizes to defend the profession].

PMID- 12465369
TI  - [Screening for diabetes campaign].

PMID- 12465370
TI  - [Pain and injury from dressing removal, the nurses' point of view].

PMID- 12465371
TI  - [Hospital and communication].

PMID- 12465372
TI  - [From negligence to malpractice in institutions].

PMID- 12465373
TI  - [Negligence and role change].

PMID- 12465374
TI  - [Nursing strategy. Discernment in daily professional practice].

PMID- 12465375
TI  - ["Do what I say, not what I do"].

PMID- 12465376
TI  - [Nursing strategy. Practice analysis groups].

PMID- 12465377
TI  - [The sanctioning of malpractice in the act of nursing care].

PMID- 12465378
TI  - [From "too bad" to time taken].

PMID- 12465379
TI  - [When the transfer of patient information doesn't work well...].

PMID- 12465380
TI  - [Prevention, a necessity for the future of our practice].

PMID- 12465381
TI  - [A. Classification of antibiotics. 5/12 The aminosides].

PMID- 12465382
TI  - [Which response to professional burnout syndrome?].

PMID- 12465383
TI  - [Sacral decubitus in a tetraplegic patient].

PMID- 12465384
TI  - [Prevention of cancer].
AB  - Both the cancer incident rate and mortality rate are increasing in Japan. Well
      balanced and strategic measures effectively combining primary and secondary
      preventions are required. In this article, primary prevention measures, such as
      smoking control and improvement of dietary habits, and secondary prevention
      measures, such as new methods of cancer screening are discussed. The importance
      of establishing a Center for Cancer Prevention and Screening is also discussed.

PMID- 12465385
TI  - [Mass screening of gastric cancer--limits and prospects].
AB  - Now we have two methods for gastric cancer screening. One is radiological study
      and another is pepsinogen test. The efficacy of radiological study has been
      established by the curve of mortality rate of gastric cancer through these four
      decades. But it is problem for this study that the number of the participants has
      reduced and the patients who take the examination have been fixed. On the other
      hand, pepsinogen test is very easy and cheap to take the results. But the
      efficacy of this is not established, because this test started only twelve years
      before. According to our research, both tests have the pros and cons. So it is
      necessary to use both methods to do mass screening of gastric cancer. The capsule
      endoscopy, which was developed in these years, has held great possibility. It
      will be used practically near future.

PMID- 12465386
TI  - [Mass surveys for detection of colorectal cancer].
AB  - In Japan, an immunochemical fecal occult test is the first step in mass surveys
      for detection of a colorectal cancer. A person with false-negative fecal occult
      blood has early cancer and/or cancer less than 3 cm in diameter. If the end of
      the mass survey is mp cancer (cancer involvement to the colonic wall), the false
      negative rate for colorectal cancer is less than 10%. A person with a positive
      reaction on the fecal occult test is taken forward to the second step. The second
      step in the mass survey consists of barium enema or/and endoscopy. Endoscopic
      false-negative cancers are located behind the physical flexure section or the
      colonic haustra. Radiologic false-negative cancers are type II cancer or cancer
      less than 1 cm in diameter or on the right side of the colon. In our experience,
      we have rarely overlooked cancer more than 2.1 cm in diameter by colonoscopy or
      barium enema. Most mp cancers are more than 2 cm in diameter. Thus, with
      colonoscopy or radiology we overlooks less than 10% of mp cancer.

PMID- 12465387
TI  - [Lung cancer screening--its efficacy and limitations].
AB  - Although the purpose of cancer screening is to decrease the number of cancer
      deaths, the efficacy of some cancer screening programs has not been proved. This
      article describes the authorized method for the lung cancer screening system in
      Japan, and introduces papers reporting the efficacy of lung cancer screening. The
      problems in the present lung cancer screening system in Japan are also discussed.

PMID- 12465388
TI  - [Breast cancer].
AB  - In Japan the mortality and incidence rates of breast cancer have been increasing.
      In 2000, the number of breast cancer deaths in female was 9,171. In 1996, the
      aged adjusted incidence rate of breast cancer was 38.9, top among all of female
      cancers and the estimated number of female breast cancer patients was 29,448 in
      Japan. Therefore, efficient breast cancer screening system is urgently needed. In
      April 2000, breast screening using biennial mammography in combination with
      clinical breast examination instead of annual clinical breast examination alone
      was introduced for women aged 50 and over in Japan. However, the compliance of
      screening using mammography was less than 1% in the fiscal 2000 year. On the
      other hand, the compliance of screening with clinical breast examination alone
      was 6.5% in same period. These compliances were significantly lower than that of
      about 65% in the USA. Given the importance of the control of quality in screening
      mammography, a central committee for the quality control of mammographic
      screening has been established in order to educate doctors and radiographers and
      to assess image apparatus in each facility. As of April 2002, 1,409 out of 1,978
      doctors that participated in the training program had obtained either grade A
      (instructor level) or grade B (adequate level). Gotzche and Olsen reassessed
      previous meta-analyses of screening mammography and concluded that screening for
      breast cancer with mammography was unjustified. Subsequently, reviews by U. S.
      Preventive Services Task Forces and the WHO reconfirmed the effectiveness of
      screening mammography in reducing breast cancer mortality. These controversies
      show the importance of assessment of screening mammography effectiveness in
      Japan.

PMID- 12465389
TI  - [Problem of uterine and ovarian cancer mass screening].
AB  - We express the mass screening data of uterine cervical cancer, endometrial
      cancer, and ovarian cancer in Japan. The increase in cervical cancer mass
      screening rate, correlate well with decreasing mortality for uterine cancer, but
      mortality is re-increasing now. It is concern to increase of uterine cervical
      dysplasia and cervical cancer of young women. Then, we need to start the
      screening for more young women. The detect ratio of uterine corpus cancer is
      increasing now. Then, we need to change the object, and introduce new screening
      method for example, trans vaginal echogram. Ovarian cancer screening method is
      not establishment, but mortality rate in patients with ovarian cancer will be
      increase in future. Trans vaginal echogram is the better method for the
      screening. On the economical reason, we have a tendency the cancer screenings are
      neglected. It is important to watch the policy of health carefully.

PMID- 12465390
TI  - [Neo-adjuvant chemotherapy with carmofur for colorectal cancer--a multi
      institutional randomized controlled study].
AB  - The efficacy and safety of preoperative chemotherapy with carmofur (HCFU) for
      colorectal cancer were evaluated in a randomized controlled study involving 63
      institutes in the Kanto area. Patients aged 75 or younger with Dukes' B or C
      colorectal cancer were eligible if curative surgery was expected. In the end, 326
      were eligible from 405 consecutive colorectal cancer patients. Patients in both
      the control (n = 162) and the new treatment group (n = 164) were given
      intravenous mitomycin C (MMC) 6 mg/m2 on day 0 and 7 after surgery and HCFU 300
      mg/day orally from day 14 for a year. Patients in the new treatment group were
      also given oral HCFU for 14 days or more prior to surgery. All 326 patients were
      followed for 5 years or longer. Five-year overall and disease-free survival rates
      were not significantly different between the two groups (75.4% and 71.6% for the
      control, and 71.8% and 71.5% for the study group, respectively). In the subset
      analysis, neither cancer site nor nodal status affected the differences in
      overall- and disease-free survival rates between the groups. The present findings
      show no additional efficacy of preoperative chemotherapy with HCFU in survival
      from advanced colorectal cancer. Further investigations in terms of patient
      selection, treatment regimen, combined use of radiotherapy, and other factors
      would be required to determine the significance of preoperative chemotherapy
      against advanced colorectal cancer.

PMID- 12465391
TI  - [Clinical and diagnostic significance of abdominal CT for peritoneal metastases
      in patients with primary gastric cancer].
AB  - The clinical and diagnostic significance of abdominal computed tomography (CT)
      was evaluated in 123 patients with primary gastric adenocarcinoma and
      disseminated peritoneal metastases. The peritoneal metastases were diagnosed by
      CT findings such as ascites (30.1%), wall thickness of the intestine (1.6%),
      increase in fat density of peritoneal fat tissue (4.9%), peritoneal nodules
      (2.4%), and hydronephrosis (4.9%). The overall diagnosis of peritoneal metastasis
      was 37.4%. The CT findings of peritoneal metastases were significantly correlated
      with anemia, poor performance status, distant metastases, P3, and resectability
      of the primary tumor. The survival of the patients with positive findings was
      significantly poor (150 days of median survival), compared with those without
      findings (230 days). The abdominal CT thus provides information for diagnosis of
      peritoneal metastases and on the prognosis in patients with primary gastric
      cancer.

PMID- 12465392
TI  - [Phase I study of gemcitabine (GEM) and docetaxel (TXT) combination chemotherapy
      for unresectable non-small-cell lung cancer].
AB  - A phase I study of gemcitabine (GEM) and docetaxel (TXT) combination chemotherapy
      was performed for unresectable non-small-cell lung cancer. Chemotherapy consisted
      of a fixed dose of GEM (1,000 mg/m2) on day 1, 8 and an escalated dose of TXT
      (50, 60, 70 mg/m2) on day 8 every 21 days, > or = 2 courses. Nine patients were
      entered (each dose level: 3 patients). Leukopenia, neutropenia, GOT increase, GPT
      increase, anorexia, fatigue, fever, and alopecia occurred, but no dose-limiting
      toxicity was found at any dose level and no MTD was reached. The recommended dose
      for the phase II study is GEM 1,000 mg/m2 and TXT 70 mg/m2 with consideration of
      application to outpatients and continuing courses.

PMID- 12465393
TI  - [Combined chemoendocrine therapy using adriamycin, cyclophosphamide and high dose
      toremifene in patients with recurrent breast cancer].
AB  - We studied a new chemoendocrine therapy against recurrent breast cancer in order
      to evaluate its efficacy and toxicity. Sixteen eligible patients were treated
      with the therapy consisting of adriamycin/cyclophosphamide (AC) plus toremifene
      (TOR). Adriamycin (20 mg/m2) was administered intravenously on days 1 and 8, and
      cyclophosphamide (100 mg/body) was given orally on days 1 to 14 every 4 weeks.
      TOR (120 mg/day) was given orally daily. The median age of the patients was 52
      years; 6 were premenopausal and 10 postmenopausal. As post-operative adjuvant
      therapy, anthracycline chemotherapy and tamoxifen were given to 4 and 9 patients,
      respectively. AC therapy was administered for 8.5 cycles (median). Four complete
      responses (25%), 8 partial responses (37.5%), 4 no change (25%) (including 2 long
      NC), and 2 progressive disease (12.5%) were obtained, for an overall response
      rate of 62.5%. The median duration of time to progression and survival were 13.2
      months (0.7-30.4 months) and 22.8 months (13.7-44.8 + months), respectively. The
      frequent toxicities were leukopenia, nausea/vomiting, and alopecia, but these
      were clinically well tolerated. Our results suggest that the addition of high
      dose TOR to AC therapy is useful in the treatment of recurrent breast cancer.

PMID- 12465394
TI  - [Combination chemotherapy of paclitaxel followed by nedaplatin for human ovarian
      cancer].
AB  - The antitumor activity of a combination of paclitaxel (TXL) followed by
      nedaplatin (NDP) against SK-OV-3 human ovarian cancer was evaluated. We also
      compared the antitumor activity of TXL plus NDP with that of TXL plus carboplatin
      (CBDCA) or TXL plus cisplatin (CDDP). TXL was injected i.v. daily for four days
      and either NDP, CBDCA or CDDP was injected i.v. once after the TXL treatment,
      into tumor-bearing mice. The sequential administration of TXL prior to NDP
      resulted in enhanced inhibition of tumor growth in comparison with either TXL or
      NDP monotherapy. The combination in TXL plus NDP was synergistic and superior to
      that of TXL plus CDDP or TXL plus CBDCA therapy. Histological tests demonstrated
      that the fraction of BrdU-incorporated cells in tumor tissue was significantly
      inhibited by the combination of TXL with NDP. These results demonstrated the
      antitumor efficacy of TXL with NDP against human ovarian cancer and suggest the
      clinical effectiveness of combination of TXL with NDP.

PMID- 12465395
TI  - Asian trends in prostate cancer hormone therapy.
AB  - The first Conference on Asian Trends in Prostate Cancer Hormone Therapy was held
      in September 2001 to serve as a forum for Asian urologists to compare data on
      prostate cancer and discuss issues regarding the use of hormone therapy. The
      conference revealed that due to various cultural and philosophical factors,
      differences exist in prostate cancer management among the Asian countries. In
      addition, a lack of databases on hormone therapy was exposed in some countries.
      It was noted that many decisions in the treatment of prostate cancer are
      influenced by the strategies adopted in Western countries, and that attempts to
      formulate uniform guidelines for the Asian region have hitherto been
      unsuccessful. The main findings of the conference are reported in this review.

PMID- 12465396
TI  - [A case of metastatic breast cancer responding to weekly paclitaxel and high-dose
      toremifene administrated alternately].
AB  - A 64-year-old woman underwent muscle-preserving mastectomy for breast cancer in
      April 1999. She developed multiple lung metastases 3 months later. The metastases
      partially responded to 10 cycles of CAF (cyclophosphamide, adriamycin, 5
      fluorouracil). However, her lung metastases worsened again 7 months later and CAF
      was not effective (progressive disease). We therefore began administration of low
      dose paclitaxel (80 mg/m2/week) and high-dose toremifene (120 mg/day) alternately
      in April 2001. This alternative therapy brought a marked decrease in the lung
      metastases. After 4 cycles of this treatment, lung metastatic findings had
      disappeared from her chest X-ray. This alternative therapy is potentially
      effective against metastatic breast cancer.

PMID- 12465397
TI  - [A case of thymic carcinoma responded to intra-arterial chemotherapy combined
      with radiation therapy].
AB  - A 70-year-old male complained of pain in the left neck. A tumor of about 8 cm in
      diameter was detected by contrast CT in the region extending from the anterior to
      upper mediastinum. For definitive diagnosis, biopsy was performed under CT
      guidance, and the patient was diagnosed as having anaplastic carcinoma in the
      thymus (T4, N1, M0, stage IVb). Since surgical treatment was judged to be
      impossible because of infiltration into large blood vessels, the patient
      underwent chemotherapy by intra-arterial injection (CDDP, ADM) and radiotherapy
      (45 Gy), and obtained a CR. Metastasis to the spleen was detected during the
      follow-up period, but a CR was obtained by chemotherapy by intra-arterial
      injection (CDDP) and systemic chemotherapy (TXL). Generally, the prognosis for
      carcinoma in the thymus is poor, and the prognosis for anaplastic carcinoma in
      the thymus is considered especially poor. However, chemotherapy by intra-arterial
      injection of carcinostatics such as CDDP can be applied to patients in whom
      surgical treatment is impossible.

PMID- 12465398
TI  - [A case of vulval extramammary Paget's disease associated with pancreatic cancer
      that was successfully treated with chemotherapy].
AB  - We report the case of an 84-year-old woman with vulval extramammary Paget's
      disease associated with pancreatic cancer who was successfully treated. At first,
      biweekly low-dose FP (cisplatin 10 mg/body, 5-fluorouracil 250 mg/body) was
      administered by intravenous infusion. Next, we attempted a regimen of gemcitabine
      (1,000 mg/body) was administered weekly by intravenous infusion. As a result, the
      size of the pruritic lesion of the vulva was reduced more than 50%, and the serum
      level of CA19-9 decreased clearly. These treatments would be a valid option in
      certain cases of pancreas cancer and extramammary Paget's disease.

PMID- 12465399
TI  - [A case of pancreatic tail cancer with peritoneal carcinosis treated with
      gemcitabine hydrochloride].
AB  - This paper reports a case of pancreatic tail cancer with peritoneal carcinosis
      that showed a good response to gemcitabine hydrochloride. A 52-year-old man, who
      had undergone a gastrojejunostomy for pancreatic tail cancer with peritoneal
      carcinosis, was referred to our hospital for anticancer therapy. Laboratory data
      on admission disclosed hypoalbuminemia and a high level of serum CA19-9 (156
      IU/ml). These findings indicated that the patient was in a cancer cachexic
      condition. Gemcitabine hydrochloride treatment (1,000 mg/m2/week x 3/4 weeks) was
      started. Ascites disappeared after 2 courses of treatment, and the tumor was
      reduced (62% of the reduction rate) after 5 courses of treatment. Furthermore,
      the serum CA19-9 level and serum albumin value returned to normal, and
      performance status was improved to grade 1. The patient has been well for 15
      months after the diagnosis of pancreatic tail cancer with peritoneal carcinosis.
      Gemcitabine hydrochloride may have not only reduced the tumor volume and improved
      cancer cachexic condition, but also prolonged the survival time in this case.

PMID- 12465400
TI  - [A patient with hepatocellular carcinoma with intraperitonial lymph node
      metastases in whom oral UFT treatment was markedly effective].
AB  - We report a patient with hepatocellular carcinoma (HCC) with intraperitoneal
      lymph node metastases in whom UFT (uracil + tegafur) was markedly effective. The
      patient was a 70-year-old woman with chronic hepatitis C, who developed HCC
      mainly infiltrating the medial segment of the liver. Arterial infusion
      chemotherapy and embolization were performed, and radiofrequency ablation was
      also conducted. Despite these interventions, the serum alpha-fetoprotein level
      continued to increase, and reached a level as high as 208,000 ng/ml by the second
      month of treatment. Abdominal computed tomography (CT) revealed no recurrence in
      the liver, but multiple metastases to intraperitoneal lymph nodes were
      identified. UFT-E treatment was initiated at the dose of 400 mg/day. A subsequent
      abdominal CT revealed complete disappearance of the intraperitoneal lymph node
      metastases 2 months after the start of UFT treatment. The serum alpha-fetoprotein
      level returned to normal 4 months after the start of UFT treatment. We consider
      that the patient described here is a good example to illustrate the remarkable
      effectiveness of UFT in the treatment of metastatic HCC.

PMID- 12465401
TI  - [A case of AFP-producing gastric cancer with multiple liver metastases responding
      to CPT-11 and cisplatin combination chemotherapy].
AB  - A case of AFP-producing gastric cancer successfully treated with CPT-11 and
      cisplatin combined therapy is reported together with a review of the literature.
      A 52-year-old male was admitted with complaints of upper abdominal pain and body
      weight loss. Gastric cancer with multiple liver metastases was diagnosed based on
      endoscopy and computed tomography findings. The patient's serum AFP level was
      697,100 ng/ml and a biopsy specimen showed AFP-positive tumor cells
      immunohistochemically. He was treated with a combination chemotherapy consisting
      of CPT-11 (70 mg/m2) on day 1 and 15, and cisplatin (80 mg/m2) on day 1, repeated
      every 4 weeks. The primary lesion of the stomach and the liver metastases were
      remarkably reduced, and the serum level of AFP decreased to 18 ng/ml after 5
      cycles of this treatment. No severe side effects were seen during this treatment.
      This result suggests that combination chemotherapy consisting of CPT-11 and
      cisplatin may be effective and safe for patients with AFP-producing gastric
      cancer with multiple liver metastases.

PMID- 12465402
TI  - [Postoperative adjuvant immunochemotherapy using Lentinan for advanced gastric
      carcinoma patients with metastasis in the regional lymph nodes and serosal
      invasion].
AB  - Six patients with gastric cancer, stage IIIA to IV, received intraabdominal
      cisplatin (CDDP) at laporotomy. This was followed by postoperative intravenous
      infusion of mitomycin C (MMC), CDDP or fluorouracil (5-FU). When these patients
      recovered to the extent that permitted oral medication, an immunochemotherapeutic
      regimen containing either oral UFT (uracil and tegafur) or 5'-deoxy-5
      fluorouridine (5'-DFUR), plus intravenous Lentinan (LNT) was administered for a
      period ranging from one and a half to two years. This postoperative
      immunochemotherapy was successful in all 6 patients. No relapse has been observed
      in any of them for at least 4 years. These findings indicate that the
      chemotherapeutic strategy of administering intraabdominal CDDP immediately after
      surgery, followed by postoperative immunochemotherapy with pyrimidine-fluoride
      products plus Lentinan on an outpatient basis may be useful in the treatment of
      T3 or T4 gastric carcinoma with metastasis in the regional lymph nodes.

PMID- 12465403
TI  - [A case of recurrent advanced gastric cancer suggesting the efficacy of TS-1 and
      CDDP combination chemotherapy].
AB  - The patient, a 53-year-old male, underwent radical surgery for advanced gastric
      cancer (stage IV). On the second day after surgery, adjuvant chemotherapy
      consisting of 250 mg/day 5-FU (i.v.) for 14 days, followed by 450 mg/day of UFT-E
      for about 12 months, was initiated. About 21 months after surgery (7 months after
      cessation of medication), the CA19-9 level had risen (136 U/ml). After 26 months,
      the patient experienced a backache and his CEA and CA19-9 levels had risen 11.7
      ng/ml and 869 U/ml, respectively. The results from an imaging examination were
      suggestive of multiple bone metastases and para-aortic lymphatic metastasis.
      Chemotherapy was resumed with only TS-1 (100 mg/day). Because the tumor markers
      (TM) continued to rise, he was hospitalized and the medication was combined with
      daily administration of 10 mg of CDDP (TS-1 + CDDP protocol). When the total dose
      of CDDP reached 160 mg, there was a dramatic drop in the TM (surrogate marker)
      level. The patient was discharged and medication of TS-1 and 10 mg/day of CDDP
      twice a week was continued on an outpatient basis. Five months after the initial
      administration of FP, the CEA and CA19-9 returned to normal levels (4.3 ng/ml and
      33 U/ml, respectively). Metastases to the para-aortic lymph nodes had disappeared
      and the sites of bone metastases were reduced in size. The patient was able to
      resume his full social activities. Since that time, a second-line therapy has
      been added. Currently (about two years after the recurrence), he is still
      undergoing therapy with TS-1 + CDDP.

PMID- 12465404
TI  - [A case of advanced gastric cancer showing complete response to chemotherapy of
      peroral carcinostatic only].
AB  - The patient was a 68-year-old woman. She was referred to our hospital because of
      advanced gastric cancer. Endoscopic examination showed that the tumor was located
      in the Subcardia, with its oral margin invading the esophagus. Histologic
      examination of biopsy specimen led to a diagnosis of moderately to poorly
      differentiated adenocarcinoma. Apparent lymph node swellings (No. 7, No. 11) on
      enhanced CT examination indicated the metastasis of the gastric cancer.
      Consulting with her family, we decided to treat the cancer with chemotherapy
      using the peroral carcinostatic "UFT", and started it on November 18, 1997.
      Follow-up endoscopic examination confirmed that the tumor was reduced in size
      immediately after starting chemotherapy, and then finally disappeared on December
      10, 1999. Since then, there has been no recurrence of the tumor. This is a rare
      case of gastric cancer showing complete response to chemotherapy using a peroral
      carcinosatatic alone.

PMID- 12465405
TI  - [A case of effective weekly paclitaxel administration for metastatic gastric
      cancer].
AB  - We report a case of effective weekly paclitaxel (TXL) administration for
      metastatic gastric cancer. 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. A 74-year-old man was diagnosed with recurrence 49
      months after surgery for gastric cancer. He was treated with 5-fluorouracil and
      cisplatin, and thrombocytopenia (grade 3) and creatinin elevation (grade 1) were
      observed and assessed as progressive disease 2 months after the treatment. We
      attempted weekly TXL administration and after 5 courses assessed the patient as
      having a partial response. The treatment is ongoing. The toxic event was
      leukopenia (grade 2), with no episode of thrombocytopenia. The patient did not
      complain of nausea or vomiting, and his quality of life was fair during the
      treatment. Weekly TXL administration is a useful treatment for metastatic gastric
      cancer.

PMID- 12465406
TI  - [A case of multiple liver metastases from colon cancer successfully treated with
      modified pharmacokinetic modulating chemotherapy using Leucovorin].
AB  - A 51-year-old man underwent right hemicolectomy due to ascending colon cancer
      with multiple liver metastases. Administration of modified pharmacokinetic
      modulating chemotherapy (PMC) using Leucovorin (intravenous infusion of 5-FU, 600
      mg/m2/24 hours; oral administration of UFT, Taiho Pharmaceutical Co., Tokyo,
      Japan, 400 mg/day; and Isovorin, Wyeth Lederle Co., Tokyo Japan, 250 mg/body) was
      started postoperatively. Two months of modified PMC produced a drastic tumor
      reduction without any adverse reactions such as diarrhea or myelosuppression
      observed. At present the patient continues to tolerate the chemotherapy and is
      being followed as an outpatient clinic. This case suggests the usefulness of
      modified PMC using Leucovorin for progressive recurrent colon cancer.

PMID- 12465407
TI  - [Two patients with recurrent colon cancer who underwent surgery following a
      combination of irinotecan and UFT].
AB  - One patient with pulmonary metastasis from colon cancer and one with para-aortic
      lymph node metastasis were treated with a combination of irinotecan and UFT.
      Irinotecan (100 mg/m2) was given by 24-hour intravenous infusion on day 1, and
      UFT (600 mg/day) was given orally on days 3 to 7 and days 10 to 14 of a 2-week
      course, which was then repeated. In the patient with pulmonary metastasis, the
      lesions in the lung resolved after 7 courses of chemotherapy. Surgery was
      performed after 10 courses. The patient with para-aortic lymph node metastasis
      had a partial response after 4 courses of chemotherapy, and underwent surgery
      after 6 courses. The only adverse effects were grade 2 myelosuppression and hair
      loss, none of which were severe enough to require treatment. With this
      chemotherapy regimen, patients are admitted for two days biweekly for 24-hour
      intravenous infusion of CPT-11. Thus, most of the treatment can be performed on
      an outpatient basis. The combination of irinotecan and UFT is expected to be
      useful for metastatic or recurrent colon cancer.

PMID- 12465408
TI  - [Adverse reactions to TS-1 for outpatients with recurrent head and neck cancer].
AB  - To examine the adverse reactions to TS-1 for patients with recurrent head and
      neck cancer, five patients with locoregional recurrences and two with distant
      metastasis were enrolled in the present study and took TS-1 as outpatients. All
      patients underwent irradiation with or without surgery before administration of
      TS-1. One patient was given 100 mg of TS-1 daily, and six patients were given 120
      mg of TS-1 daily. Thirteen courses consisted of the regimen of four weeks of TS-1
      administration followed by two weeks of intermission, nine courses consisted of
      the regimen of two weeks of administration followed by one week of intermission,
      and seven courses consisted of the regimen of two weeks of administration
      followed by two weeks of intermission. Anemia, leukopenia, neutropenia, and liver
      dysfunction were often observed as adverse reactions to TS-1 administration.
      Grade 3 bilirubinemia was observed in only one course, but other adverse
      reactions consisted of grade 1 or grade 2. Almost all adverse reactions returned
      to normal after the cessation of drug administration. Based on these results, we
      conclude that TS-1 is a safe drug for the treatment of outpatients with recurrent
      head and neck cancer.

PMID- 12465409
TI  - Evaluation of cell viability by double-staining fluorescence assay.
AB  - Various methods are available for the assessment of cell viability. Recently,
      interest has centered on methods using fluorescent dyes. In this work, we used a
      double-staining assay, involving the use of rhodamin 123, which stains the
      mitochondria of viable cells, and propidium iodide, which stains the nuclei of
      dead cells, to investigate their use in assessing the viability of cells. We
      added adriamycin to NIH 3T3 cells and double-stained the cells that adhered to
      the dish and those that were suspended in the culture solution, and observed the
      results over time. We found that nearly all the adherent cells were stained with
      rhodamin 123 alone. However, the suspended cells in the control group accounted
      for most of the double-stained cells, and when adriamycin was added, most were
      stained with PI alone.

PMID- 12465410
TI  - [A high-throughput SNP typing system for genome-wide association studies].
AB  - SNPs are useful markers for identifying genes responsible for and/or associated
      with common diseases, and for directing personalized medical care. Furthermore,
      because they are so frequent in the genome and can be genotyped quite easily,
      SNPs can serve as markers for a whole genome association study. However, one of
      the most difficult issues to be solved for whole-genome association studies using
      SNPs is reduction of the amount of genomic DNA for genotyping. The presently
      available technologies require too much genomic DNA to be practical. To overcome
      this problem, we combined the Invader assay with multiplex PCR performed in the
      presence of Taq polymerase antibody as well as a novel 384-well card system that
      reduces the reaction volume. We amplified 96 genomic DNA fragments simultaneously
      in a single tube, and analyzed each SNP using the Invader assay. Since we used 10
      20 nanograms of genomic DNA as a template for multiplex PCR, the amount needed to
      assay one SNP was only 0.1-0.2 nanograms. Our results strongly indicate the
      feasibility of undertaking genome-wide association studies using blood samples of
      only 5-10 milliliters. Using these technologies, which allow us to perform as
      many as 450,000 typings in one day, our system should let us identify the genes
      responsible for many diseases and/or pharmacological responsiveness.

PMID- 12465411
TI  - [Post launch studies].
AB  - Evidence Based Medicine (EBM) is a growing concept in Japan as it is elsewhere.
      Central to improving the use of EBM is generation of data through well conducted
      controlled clinical studies. There are many problems associated with conduct of
      clinical studies after launch in Japan, and many initiatives are ongoing to
      improve the situation. Development of Clinical Research Coordinators (CRO) and
      central Data Management centers are key to improving the quality of clinical
      research in Japan. Currently Japan has an undeveloped legal system with regard to
      post-launch trials and off-label use of registered drugs. There is no
      reimbursement for off-label and various restrictions imposed on the recipients of
      the Ministry of Health, Labour and Welfare's (MHLW) funds. Maybe the biggest
      problem is the high cost of post-marketing studies sponsored by pharmaceutical
      manufacturers. A high quality system to support post launch clinical studies need
      a solid financial base. There is a need for a suitable review system for
      investigator initiated multi-centre studies, as the current IRB system is not
      sufficient. There are also challenges regarding the differences, perceived or
      real, in treatment practice and available registrations in Japan and in the West,
      causing problems in choosing suitable comparators and study designs. At the
      present time it is not clear whether investigator initiated trials will be
      acceptable for registration purposes in Japan. The agreed first priority is to
      build a suitable and strong infrastructure within the academic community to
      support researchers to investigate important questions with or without
      pharmaceutical company support. Despite all these issues, several groundbreaking
      projects are under way throughout Japan, in many different areas and by different
      collaborative groups, some with government support. In fact, researcher-initiated
      clinical trials achieved a rapid growth in Japan in the past year.

PMID- 12465412
TI  - Alastair McGowan--the thinking man's A&E consultant?

PMID- 12465413
TI  - Mergers, reconfigurations, and how to survive them.

PMID- 12465414
TI  - A "new order" of nursing practice.

PMID- 12465415
TI  - The "not-so-brief" debriefing.

PMID- 12465416
TI  - Office-based surgery: advantages, disadvantages, and the nurse's role.
AB  - Office-based surgery is a growing trend in surgical services offered to many
      patients, however, it is not without risk. In knowing the facts about office
      based surgery, nurses will be able to assist our patients in the most appropriate
      decisions regarding their surgical care. This article will present the
      indications, advantages, and limitations of office-based surgery, as well as the
      nurse's role in this environment.

PMID- 12465417
TI  - Anesthesia's new frontier: ensuring patient safety in the office setting.
AB  - Advancements in technology and pharmacology, as well as improved techniques and
      instrumentation have allowed for much greater flexibility in how and where
      surgical and anesthesia care can be provided safely. Many procedures now take but
      a fraction of the time they used to take to complete and can be performed with
      minimal risk of blood loss and far less postoperative pain. Office-based surgery
      has emerged as a safe and viable alternative to traditional in-hospital surgery.
      This article provides an overview of the comprehensive "Standards for Office
      Based Anesthesia Practice" developed by the American Association of Nurse
      Anesthetists (AANA).

PMID- 12465418
TI  - A practical guide to achieving AAAASF accreditation.
AB  - As time goes on, more professional societies and individual states are mandating
      stricter standards for office surgical facilities to ensure quality of care. As
      the nurse is often the person who coordinates accreditation efforts within the
      facility, he or she needs to be "savvy" regarding the implementation and
      maintenance of these standards. The American Association for Accreditation of
      Ambulatory Surgery Facilities (AAAASF) criteria are discussed with strategies and
      rationale for implementation.

PMID- 12465419
TI  - American Society of Plastic Surgeons office-based surgery accreditation
      crosswalk.

PMID- 12465420
TI  - How states regulate office surgery--a primer.

PMID- 12465421
TI  - Developing a performance improvement program.
AB  - In today's health care environment, the focus has shifted to quality in every
      aspect of patient care, with this emphasis coming from patients, employers,
      insurance companies, and regulatory and accreditation agencies. Developing a
      performance improvement (PI) program to document quality of care can promote a
      safe environment and improve patient outcomes. There are helpful resources such
      as the Web, books, magazines, and continuing education resources that can provide
      structure and guide in the development of the PI program.

PMID- 12465422
TI  - Needlestick Safety and Prevention Act.
AB  - The Occupational Safety and Health Administration (OSHA) is now enforcing the new
      Needlestick Safety and Prevention Act. Updated enforcement procedures [CPL 2
      2.69] for the revised Bloodborne Pathogen Standard were distributed to OSHA
      inspectors in tlate 2001. Facilities that have not implemented safer medical
      devices with engineered sharp injury protection are at risk for an OSHA citation.
      Any facility or organization that employs individuals who might reasonably
      experience occupational exposure to blood or other potentially infectious
      materials must comply with the regulation, even if the facility has never had a
      needlestick injury. This article will present the new regulations and discuss who
      is affected by the regulations.

PMID- 12465423
TI  - Off-hours, in-office surgery: when customer service backfires.

PMID- 12465424
TI  - Theorized improvisation--a new type of leadership.

PMID- 12465425
TI  - Office education: sharing your knowledge.
AB  - The author's passion for plastic surgery nursing emerged from a life-changing
      experience involving skin grafting and skin reconstruction on her face from basal
      cell carcinoma. After many more skin cancer excisions, she decided to leave the
      hospital environment to pursue further study and work in the field of dermatology
      and wound care. This helped to expand her specialized knowledge of skin
      anatomy/physiology and prepare for a career in plastic/reconstructive surgery.
      During her masters degree program, the author developed educational guidelines
      and materials to facilitate her new role in plastic surgery as a
      nurse/patient/community educator. She finished her masters degree in nursing
      education and completed her clinical preceptor/internship with two board
      certified plastic and reconstructive surgeons in December of 2000.

PMID- 12465426
TI  - Eleven years intraoperative ATG bolus. A list of successes.
AB  - Induction therapy for organ transplantation using monoclonal antibodies has been
      in recent years reevaluated. Results from various centers indicate the value of
      such therapy, especially in sensitized patients undergoing kidney transplantation
      as well as in simultaneous kidney--pancreas transplant patients. Author presents
      the experience of eleven years of intraoperative ATG bolus administration in the
      Berlin--Friedrichshain Kidney Transplantation Center.

PMID- 12465427
TI  - Mechanisms of ischemic preconditioning and its application in transplantation.
AB  - Ischemic preconditioning is a phenomenon of increased tissue resistance to
      ischemic injury evoked by brief intermittent periods of ischemia. Since its
      discovery in 1986, extensive studies were undertaken to explain its mechanisms
      and induce protection pharmacologically. There is convincing evidence on
      adenosine receptors, ATP-dependent potassium channels, nitric oxide and tyrosine
      kinases pathways involvement in the process. Universal ability of various tissues
      to adopt protection from short-time ischemia and reperfusion makes clinical
      applications of the phenomenon, including field of transplantation medicine,
      highly appealing. This review summarizes known physiological pathways of ischemic
      preconditioning. Trials on protection against cold ischemia and other transplant
      related issues of preconditioning are also presented.

PMID- 12465428
TI  - Experience with ATG short course high dose induction therapy in a series of 112
      enteric drained pancreatic transplants.
AB  - BACKGROUND: New immunosuppressive protocols and advanced surgical technique
      resulted in a major improvement in the outcome of pancreatic transplantation.
      PATIENTS AND METHODS: 112 enteric drained whole pancreas transplants (PTx)
      performed at the Innsbruck University Hospital between 3.1997 and 10.2001 were
      retrospectively analysed. Prophylactic immunosuppression consisted of FK506, MMF
      and steroids. A short course of high dose ATG induction was given additionally.
      Perioperative antimicrobial prophylaxis consisted of Amoxicillin/Clavulanic (32
      PTx), Pipercillin/Tazobactam (68 PTx), quinolones (10 PTx) or macrolide (2 PTx).
      64 patients additionally received fluconazole. RESULTS: Actuarial patient,
      pancreas and kidney graft survival at one year were 96.4%, 86.7% and 95.3%,
      surgical complication rate was 28%, rejection rate 40%. Eight grafts were lost
      due to intraabdominal infection, seven due to rejection. Median perioperative
      observation days (OD) were 29 (range 14-125), patients were on antibiotics for
      68% of OD, and developed fever on 33% of OD. Incidence of CMV infection was 42%
      (but only five patients developed CMV disease), HSV 24%, intraabdominal infection
      22%, UTI 11%, wound infection 9% and pneumonia: 5%. CONCLUSION: ATG short course
      induction is well tolerated after enteric drained PTx. Infection represents a
      frequent and at least for IA sepsis serious complication after PTx with enteric
      drainage.

PMID- 12465430
TI  - DNA from rejecting donor organs can be detected in recipient lymphoid and non
      lymphoid tissues.
AB  - Rejecting tissue and organ grafts shed cellular debris from damaged cells.
      Cellular debris contains fragments of nuclei with their genetic material. The
      question arises what is the fate of donor DNA in recipient fluids and tissues. Is
      it enzymatically disintegrated and becomes a waste product or it is utilized by
      recipient cells. We have shown, using sex-mismatched transplants and the Sry-gene
      fragment PCR detection method, that at the time of rejection recipient tissue
      contain donor DNA. The concentration of donor DNA did not parallel the
      concentration of live donor passenger cells. There were differences in donor DNA
      concentration depending on whether heart, skin or BMC were transplanted.
      Moreover, there was more donor DNA in recipient tissues than in control syngeneic
      transplants. Interestingly, a relatively high donor DNA concentration was
      detected in syngeneic recipients reflecting the extent of non-immune pre
      transplantation ischemic damage of the graft.

PMID- 12465429
TI  - Freedom from rejection and stable kidney function are excellent criteria for
      steroid withdrawal in tacrolimus-treated kidney transplant recipients.
AB  - OBJECTIVES: This prospective, randomized, multicentre study investigated the
      efficacy and safety of two tacrolimus-based regimens and their potential to
      withdraw steroids. METHODS: In total 489 patients were randomised to receive
      either tacrolimus and MMF (n = 243) or tacrolimus and azathioprine (n = 246)
      concomitantly with steroids in both treatment groups. The initial oral dose of
      tacrolimus was 0.2 mg/kg/day, MMF dose was 1 g/day, azathioprine was administered
      at 1-2 mg/day. Steroids were tapered from 20 mg/day to 5 mg/day. From month 3
      onwards, steroids were withdrawn in patients who were free from steroid-resistant
      rejection and who had serum creatinine concentrations < 160 mumol/L. Study
      duration was 6 months. RESULTS: Patient survival at month 6 was 98.3% (Tac/MMF/S)
      and 98.4% (Tac/Aza/S), graft survival at 6 month was 95.0% (Tac/MMF/S) and 93.5%
      (Tac/Aza/S). The 6-month incidences of biopsy-proven acute rejection were 18.9%
      (Tac/MMF/S) compared with 26.8% (Tac/Aza/S), p = 0.038. The 6-month incidences of
      steroid-resistant acute rejection were 2.1% (Tac/MMF/S) and 4.9% (Tac/Aza/S), p =
      ns. At the end of month 3, steroid withdrawal was performed in 60.5% (Tac/MMF/S)
      and 48.8% (Tac/Aza/S) of patients, p < 0.01. During months 4-6, 2.7% of patients
      in the Tac/MMF group had a biopsy-confirmed acute rejection compared with 0.8% of
      patients in the Tac/Aza group. In patients who continued to receive steroids, the
      incidences of biopsy-proven acute rejections during months 4-6 were 3.5%
      (Tac/MMF/S) and 7.1% (Tac/Aza/S). At study end, the steroid-free patients had an
      excellent kidney function, the median serum creatinine concentration was 119.5
      mumol/L (Tac/MMF) and 115.1 mumol/L (Tac/Aza); the median serum creatinine of the
      total study group was 130.5 mumol/L (Tac/MMF/S) and 132.8 mumol/L (Tac/Aza/S).
      CONCLUSION: Both tacrolimus regimens are efficacious and safe. The combination of
      Tacrolimus and MMF achieved a lower rejection rate and permitted a higher
      proportion of steroid-free patients. The overall incidence of acute rejection was
      low and kidney function was good.

PMID- 12465431
TI  - Serum cytokine concentration after liver lobe harvesting for transplantation.
AB  - OBJECTIVE: To investigate cytokine concentration after liver lobe harvesting for
      transplantation in order to prove that it is a relatively safe surgical procedure
      with limited tissue injury. MATERIAL AND METHODS: Study was performed in 17
      healthy liver donors and 6 patients with benign liver tumors. Serum levels of IL
      6, IL-1ra and sTNFRI were measured before surgery and on the days 1, 3 and 7
      thereafter, by immunoassay (ELISA). RESULTS: There was a significant increase in
      serum concentrations of IL-6 on day 1-7 (from 2.4 pg/ml to 315.1 +/- 526, 47.3 +/
      48 and 15.3 +/- 15 pg/ml; p = 0.0002, p = 0.0006, p = 0.003), for IL-1ra on day
      1-3 (from 472.5 +/- 436 pg/ml to 2072.6 +/- 3511 and 715.5 +/- 268 pg/ml; p =
      0.001, p = 0.004), and for sTNFRI on day 1-3 (from 1075.7 +/- 338.0 pg/ml to
      1601.4 +/- 317.0 and 1528.9 +/- 402.0 pg/ml; p = 0.0006, p = 0.003), following
      liver harvesting. No significant difference was observed between pre and
      postoperative IL-6 serum concentration, whereas IL-1ra and sTNFRI were elevated
      only on day 3 after liver resection (p = 0.02, p = 0.04). A significantly higher
      level of sTNFRI was seen in patients after liver resection, as compared to liver
      donors on day 1 (p = 0.01), 3 (p = 0.03) and 7 (p = 0.0006) after surgery,
      whereas on day 3 (p = 0.03) and 7 (p = 0.01) when IL-1ra was measured.
      CONCLUSION: The short period of elevated concentrations of IL6, sTNFRI and IL1ra
      after harvesting of lobes for transplantation and a relatively low serum level of
      these cytokines indicate that this type of procedure does not evoke any major
      postoperative SIRS-type reaction as seen not infrequently after resection of
      liver for primary or secondary liver pathology.

PMID- 12465432
TI  - Induction of long-term peripheral microchimerism in non-human primates in a model
      of xenogeneic peripheral tolerance induction.
AB  - Xenotransplantation represents a promising solution to the ever increasing
      shortage of donor organs in allotransplantation. However, due to different and
      stronger modes of rejection, successful xenotransplantation will require
      different organ-protective regimes from those used in allogeneic transplantation
      today. Since one can not simply increase the dosage of the drugs used,
      immunomodulation or tolerance induction of the recipient would be the most
      desirable approach. Transfusion of donor leukocytes has been shown to
      downregulate recipient responses or even induce peripheral tolerance in small
      animal models. Since the infusion of donor cells represents a relatively simple
      approach, as one can purify and compose the inoculum exactly before infusion, we
      studied whether this approach can be successfully employed in a preclinical swine
      to non-human primate model of peripheral tolerance induction/immunomodulation. In
      our model, baboons underwent sequential column adsorption and complement
      blockade. The animals received only initial immunosuppression with
      cyclophosphamide. No further immunosuppression was given. Subsequently all
      animals received 1-3 x 10(10) porcine splenocytes i.v. Development and
      maintenance of chimerism was analyzed by sequential flow cytometric and PCR
      analyses. Other parameters studied included effects of the preparatory induction
      protocol. We could show that a low level of chimerism is maintained in these
      animals for up to 1.5 years, despite the fact that they received no additional
      immunosuppression after the initial one. At no time of the experiment did any
      animal display symptoms of poor health. Thus we demonstrate that the concept of
      donor leukocyte transfusion is transferable into preclinical xenotransplantation.
      We are currently conducting organ transplantation experiments into animals thus
      treated to directly analyze the immunomodulatory effect of the donor cells.

PMID- 12465433
TI  - High duodeno-jejunal anastomosis as a safe method of enteric drainage in
      simultaneous pancreas and kidney transplantation.
AB  - One of the key issues in successful pancreas transplantation is uncomplicated
      drainage of pancreas exocrine secretion. OBJECTIVE: The aim of the study is to
      present results of side-to-side high duodeno-jejunal anastomosis as routine
      method of enteric drainage in simultaneous pancreas kidney transplantation (SPK).
      METHODS: 30 diabetic patients underwent SPK at the Department of Surgery, Ruhr
      University Bochum in 2001. The pancreas was drained using a portion of duodenal
      segment anastomosed to the first loop of jejunum about 20-40 cm distal to the
      Treitz ligament. RESULTS: Early relaparotomy was required in 20% patients. The
      mean time of first relaparotomy was 5.5 (range 1-11) days after transplantation.
      In 10% of cases graft pancreatectomy was necessary. Perioperative mortality was
      3.3%. Currently 83.3% patients are insulin-free and 86.6% patients are free of
      dialysis. CONCLUSIONS: These data suggest, that side-to-side high duodeno-jejunal
      anastomosis is a safe method of drainage of pancreas exocrine secretion in SPK.

PMID- 12465434
TI  - Application of recombinant activated factor VII for treatment of impaired
      haemostasis during liver transplantation in recipients with Wilson's disease--a
      report of two cases.
AB  - Recombinant activated factor VII (rFVIIa, NovoSeven, Novo Nordisk A/S, Denmark)
      is a treatment used to prevent and arrest intra- and postoperative bleeding in
      patients with haemophilia A or B complicated by circulating anticoagulants
      (inhibitors of FVIII and FIX) and in patients without haemophilia who
      spontaneously develop inhibitors of FVIII, i.e. in acquired haemophilia. Patients
      who qualify for liver transplantation due to liver dysfunction may have varying
      degrees of coagulation impairment and thus carry an elevated risk of massive
      bleeding and have worse prognosis. The authors administered recombinant activated
      factor VII to two patients with coagulation abnormalities in the course of
      Wilson's disease during liver transplantation.

PMID- 12465435
TI  - Testing security.

PMID- 12465436
TI  - Who should provide consumer health portals?

PMID- 12465437
TI  - Mercy Health Partners consolidates sites and then creates portal.

PMID- 12465438
TI  - Advocate Health Care moves to personalized Web marketing approach.

PMID- 12465439
TI  - Study looks at how technology can improve quality of care.

PMID- 12465440
TI  - Testing times. Rhiannon Sanders talks to the editor.

PMID- 12465441
TI  - Gene variant linked to Alzheimer's and Parkinson's predicts diabetic neuropathy.

PMID- 12465442
TI  - Bayer diagnostics completes acquisition of visible genetics.

PMID- 12465443
TI  - Prometheus Laboratories Inc. obtains license to patent for pharmacogenetic test.

PMID- 12465444
TI  - ILEX oncology acquires CD52 diagnostic rights for Campath.

PMID- 12465445
TI  - Serum levels of S-100B protein predict active metastatic disease melanoma.

PMID- 12465446
TI  - CD 31: marker of angiogenesis and a prognostic factor in adult soft tissue
      sarcomas.

PMID- 12465447
TI  - Centocor to focus on immune-mediated inflammatory disorders.

PMID- 12465448
TI  - Transgenomic in collaboration to develop diagnostic test for PXE.

PMID- 12465449
TI  - Enabling pharmacogenomics: survey shows researchers looking for new solutions.

PMID- 12465450
TI  - Integration of molecular diagnostics with therapeutics: implications for drug
      discovery and patient care.
AB  - The Introduction of targeted therapeutics into clinical practice has created
      major opportunities for further development of the molecular diagnostics
      industry. Emerging genomic and proteomic technologies and information are now
      resulting in the molecular subclassification of disease as the basis for
      diagnosis, prognosis and therapeutic selection. The ultimate goals of
      personalized medicine are to take advantage of a molecular understanding of
      disease, both to optimize drug development and direct preventive resources and
      therapeutic agents at the right population of people while they are still well.
      Single nucleotide polymorphisms identification and genotyping have uncovered
      predisposition markers from cancer and heart disease as well in the prediction of
      both drug efficacy and toxicity. Pharmacogenomic and pharmacodynamic assays are
      being developed to enhance the speed and decrease the cost of drug development,
      as well as reduce side effects and increase response rates in a variety of
      diseases. The traditional trial and error practice of medicine is progressively
      eroding in favor of more precise marker-assisted diagnosis and safer and more
      effective molecularly guided treatment of disease. For the diagnostics industry
      this represents an unprecedented opportunity for integration, increased value and
      commercial opportunities for molecularly-derived tests.

PMID- 12465451
TI  - Rolling-circle amplification in DNA diagnostics: the power of simplicity.
AB  - Due to its robustness and simplicity, the rolling replication of circular DNA
      probes holds a distinct position in DNA diagnostics among other isothermal
      methods of target, probe or signal amplification. Major rolling-circle
      amplification approaches to DNA detection via posthybridization probe/signal turn
      by-turn enhancement are briefly overviewed here with an emphasis on the new
      concepts and latest progress in the field, including the single-molecule and
      single-mutation detection assays as exemplary applications. Underlying
      mechanisms, current controversies and principal advantages of rolling-circle
      amplification are also considered. Possible future directions for the further
      advancement of this diagnostic methodology are outlined.

PMID- 12465452
TI  - SELDI proteinchip MS: a platform for biomarker discovery and cancer diagnosis.
AB  - Identification and understanding the structures, interactions and functions of
      all of a cell's proteins is one of the major goals of the postgenome era. The
      genome project has produced a wealth of information that is greatly expounding
      the genetic basis of cancer. However, it falls short in not allowing for accurate
      prediction of what is happening at the protein level in a cancer cell or a body
      fluid proteome. It is the hope that, by deciphering the alterations in the cancer
      proteome, biomarkers and patterns of biomarkers will be found that will lead to
      improvements in early detection, diagnosis and treatment monitoring. To achieve
      this goal, rapid high-throughput proteomic technologies will be required. The
      SELDI ProteinChip Biomarker mass spectrometry system appears to have potential in
      this effort, both for biomarker discovery and as a potential clinical diagnostic
      assay platform.

PMID- 12465453
TI  - Detection of oncogenes in the diagnosis of cancers with active oncogenic
      signaling.
AB  - Releasing individuals from susceptibility to and anxiety about the development of
      cancer is an eventual goal of cancer research. This owes much to rapid progress
      in molecular oncology that is supported by advances in technology. Cancers of the
      colon and rectum, pancreas and lung that share certain clinical and molecular
      oncological characteristics represent timely and important target of this field.
      Of the genes altered in these types of cancers, the best documented is K-ras.
      Currently highlighted along with this oncogene is beta-catenin, which has roles
      in both cell adhesion and transformation. Molecular diagnosis and susceptibility
      assessment targeting of such oncogenes will be promising for improvement in
      treatment and prevention of cancer, thereby contributing to human healthcare.
      Here we review recent knowledge on molecular diagnosis of sporadic cancers, with
      focus on K-ras and beta-catenin oncogenes.

PMID- 12465454
TI  - Venous thromboembolism: implications for gene-based diagnosis and technology
      development.
AB  - Venous thromboembolism is an hypercoagulable state that frequently reflects a
      complex interplay between inherited, acquired and environmental factors. The
      overall incidence of venous thromboembolism, which increases with age, is
      approximately 1:1000 in the US and Western Europe. In addition to known risk
      factors such as pregnancy and cancer, genetic variants can also increase the
      venous thromboembolism risk. Once such genetic variant, FV Leiden is
      characterized by single-point mutation and has been found in approximately 20% of
      idiopathic venous thromboembolism cases. The discovery of FV Leiden unleashed an
      increased interest in the genetics of venous thromboembolism as well as other
      cardiovascular diseases. Because FV Leiden was not only defined by only one
      common single nucleotide polymorphism but was also widely prevalent, impetus for
      the development of novel mutation detection methodologies and platforms for DNA
      analysis in both the clinical and research laboratory was greatly accelerated. An
      overview of this technology and its relationship to the genetics of venous
      thromboembolism is reviewed.

PMID- 12465455
TI  - Molecular diagnosis of myocardial disease.
AB  - Myocardial disorders are major causes of morbidity and mortality, including heart
      failure, sudden death and the need for heart transplantation. The two most common
      forms of myocardial disorders, dilated cardiomyopathy and hypertrophic
      cardiomyopathy are paradigms of left ventricular systolic dysfunction and
      diastolic dysfunction. The genetics of these disorders are increasingly
      understood with the sarcomere playing a central role in the development of HCM
      and the link between sarcomere and sarcolemma being key to the development of
      DCM. In this review, the genetics of the myocardial diseases will be described.

PMID- 12465456
TI  - Prenatal genetic diagnosis of Down's syndrome.
AB  - Down's syndrome is a common cause of birth defects and mental retardation.
      Prenatal screening and diagnosis of Down's syndrome is important to any pregnant
      woman interested in the health of her fetus and is of particular concern to the
      growing number of advanced maternal age women who are at increased risk of an
      affected pregnancy. Prenatal screening tests, performed in the first and second
      trimester, are based on maternal age, serum tests and fetal ultrasound.
      Definitive diagnosis requires amniocentesis or chorionic villus sampling.
      Hopefully, these invasive tests can, one day, be replaced with safer methods of
      obtaining fetal cells. Molecular genetic techniques are augmenting traditional
      chromosome analysis, broadening the range of identifiable genetic disorders and
      allowing earlier results.

PMID- 12465457
TI  - PCR for the diagnosis of toxoplasmosis after hematopoietic stem cell
      transplantation.
AB  - Toxoplasma gondii is a ubiquitous pathogen that causes significant morbidity and
      mortality in immunocompromised patients. Although relatively uncommon,
      toxoplasmosis is increasingly recognized as a severe complication of
      hematopoietic stem cell transplantation. Timely and accurate diagnosis of this
      treatable infection is critical. PCR-based testing has become the preferred
      method for diagnosis, occasionally replacing tissue biopsy. This article reviews
      the clinical, diagnostic and therapeutic aspects of toxoplasmosis in the setting
      of hematopoietic stem cell transplantation and the current and future role of PCR
      based testing for early detection and diagnosis.

PMID- 12465458
TI  - Detection of myelin basic protein in cerebrospinal fluid.
AB  - Radioimmunoassay for myelin basic protein in cerebrospinal fluid is commonly used
      as a biochemical marker of demyelination in multiple sclerosis patients. A
      sensitive enzyme-linked immunosorbent assay for myelin basic protein has been
      recently developed, which can make a clinical evaluation of myelin basic protein
      in cerebrospinal fluid of patients with multiple sclerosis and other neurological
      diseases. Most multiple sclerosis patients with acute exacerbation had markedly
      high myelin basic protein. Longitudinal studies of multiple sclerosis patients
      showed that myelin basic protein in CSF increases rapidly in agreement with acute
      relapse and then rapidly declines and disappears. Significantly higher
      cerebrospinal fluid myelin basic protein levels in human T-cell lymphotropic
      virus Type I-associated myelopathy/tropical spastic paraparesis patients were
      also detected. This enzyme-linked immunosorbent assay system can be used
      routinely to measure myelin basic protein in cerebrospinal fluid as a useful
      diagnostic indicator, not only for central active demyelination as in multiple
      sclerosis but, also for spinal cord demyelination as in human T-cell lymphotropic
      virus Type I-associated myelopathy/tropical spastic paraparesis.

PMID- 12465459
TI  - Introduction to retroviruses and retroviral vectors.
AB  - As various viral vector systems for gene transfer are developed, interest in
      using such systems in applied settings continues to grow. This Chapter is
      designed to provide background information for readers interested in learning
      about lentiviral vector systems for gene transfer applications but who lack a
      background in retrovirology. To assist those readers who are unfamiliar with
      retroviral vector systems, basic outlines of the retroviral replication cycle and
      of characteristics of retroviral vector systems are introduced here in order to
      present and define concepts and terms that are discussed in subsequent Chapters.

PMID- 12465460
TI  - HIV-1 replication.
AB  - In general terms, the replication cycle of lentiviruses, including HIV-1, closely
      resembles that of other retroviruses. There are, however, a number of unique
      aspects of HIV replication; for example, the HIVs and SIVs target receptors and
      coreceptors distinct from those used by other retroviruses. Lentiviruses encode a
      number of regulatory and accessory proteins not encoded by the genomes of the
      prototypical "simple" retroviruses. Of particular interest from the gene therapy
      perspective, lentiviruses possess the ability to productively infect some types
      of non-dividing cells. This chapter, while reiterating certain points discussed
      in Chapter 1, will attempt to focus on issues unique to HIV-1 replication. The
      HIV-1 genome encodes the major structural and non-structural proteins common to
      all replication-competent retroviruses (Fig. 1, and Chapter 1). From the 5'- to
      3'-ends of the genome are found the gag (for group-specific antigen), pol (for
      polymerase), and env (for envelope glycoprotein) genes. The gag gene encodes a
      polyprotein precursor whose name, Pr55Gag, is based on its molecular weight.
      Pr55Gag is cleaved by the viral protease (PR) to the mature Gag proteins matrix
      (also known as MA or p17), capsid (CA or p24), nucleocapsid (NC or p7), and p6.
      Two spacer peptides, p2 and p1, are also generated upon Pr55Gag processing. The
      pol-encoded enzymes are initially synthesized as part of a large polyprotein
      precursor, Pr160GagPol, whose synthesis results from a rare frameshifting event
      during Pr55Gag translation. The individual pol-encoded enzymes, PR, reverse
      transcriptase (RT), and integrase (IN), are cleaved from Pr160GagPol by the viral
      PR. The envelope (Env) glycoproteins are also synthesized as a polyprotein
      precursor (Fig. 1). Unlike the Gag and Pol precursors, which are cleaved by the
      viral PR, the Env precursor, known as gp160, is processed by a cellular protease
      during Env trafficking to the cell surface, gp160 processing results in the
      generation of the surface (SU) Env glycoprotein gp120 and the transmembrane (TM)
      glycoprotein gp41. gp120 contains the determinants that interact with receptor
      and coreceptor, while gp41 not only anchors the gp120/gp41 complex in the
      membrane (Fig. 2), but also contains domains that are critical for catalyzing the
      membrane fusion reaction between viral and host lipid bilayers during virus
      entry. Comparison of env sequences from a large number of virus isolates revealed
      that gp120 is organized into five conserved regions (C1-C5) and five highly
      variable domains (V1-V5). The variable regions tend to be located in disulfide
      linked loops. gp41 is composed of three major domains: the ectodomain (which
      contains determinants essential for membrane fusion), the transmembrane anchor
      sequence, and the cytoplasmic tail. In addition to the gag, pol, and env genes,
      HIV-1 also encodes a number of regulatory and accessory proteins. Tat is critical
      for transcription from the HIV-1 LTR and Rev plays a major [figure: see text]
      role in the transport of viral RNAs from the nucleus to the cytoplasm. Vpu, Vif,
      Vpr and Nef have been termed "accessory" or "auxiliary" proteins to reflect the
      fact that they are not uniformly required for virus replication. The functions of
      these very interesting proteins will be discussed in more detail at the end of
      this chapter. HIV replication proceeds in a series of events that can be divided
      into two overall phases: "early" and "late" (Fig. 3). Although some events occur
      in a concerted or simultaneous fashion, the replication cycle can be viewed most
      simply as proceeding in an ordered, step-wise manner. In this chapter, each step
      in virus replication will be considered; additional information can be obtained
      from the more detailed reviews and primary references that are cited.

PMID- 12465461
TI  - Determinants for lentiviral infection of non-dividing cells.
AB  - Lentiviruses share the common characteristic of infecting non-dividing target
      cells, distinguishing them from the oncogenic retroviruses which only
      productively infect dividing cells. The search for determinants for infection of
      non-dividing cells has produced a number of candidates. From HIV-1, the viral
      proteins matrix, integrase and Vpr have all been implicated. A structural
      determinant, the central DNA flap, has also been implicated. The supporting
      evidence for each of these proposed determinants will be examined and compared to
      how other viruses, non-retroviruses, transport their genomes to the nucleus. With
      currently available data, integrase and the central DNA flap appear to be the key
      players, and yet the mechanism for infection of non-dividing cells remains
      undefined.

PMID- 12465462
TI  - HIV-1 vector systems.
AB  - Human immunodeficiency virus type 1 (HIV-1) based gene transfer systems are
      gaining in popularity due to their ability to transduce terminally differentiated
      and non-dividing cells. Oncoretroviral vectors based on Moloney murine leukemia
      virus (MoMLV), on the other hand, can only transduce dividing cells. The reasons
      for increased ability of lentivirus vectors to transduce such cells has been
      attributed to several of the viral proteins (integrase, matrix and Vpr) that are
      purported to be involved in the nuclear import of the pre-integration complex
      (PIC). Nuclear import is also augmented by a unique triple stranded DNA region
      created during reverse transcription of the incoming viral RNA in the target cell
      (discussed in chapter 3). This chapter deals with the rationale behind the design
      of human immunodeficiency virus type 1 (HIV-1) based packaging systems with an
      emphasis on some recent advances in the field for the creation of safe and
      efficient HIV-1 based vectors. The review covers trans-acting proteins and cis
      sequences required for the deployment of HIV-1 vectors for gene transfer. This is
      a rapidly advancing field that with further refinements may soon allow the
      utilization of HIV-1 based and/or other lentivirus vectors in a clinical setting.

PMID- 12465463
TI  - HIV-2 and SIV vector systems.
AB  - Lentiviral vectors have received much attention in recent years due to their
      ability to efficiently transduce non-dividing cells. Of the lentiviruses HIV-2
      and SIV offer several unique benefits as the basis for lentiviral vector design.
      HIV-1, HIV-2 and SIV remain the only known primate lentiviruses, and consequently
      are among the most extensively studied viruses known. Substantial effort has been
      devoted towards identifying the pathogenic determinants of the primate
      lentiviruses and towards understanding their replication within primates. Of the
      primate lentiviruses, the pathogenicity and rates of transmission of HIV-2 and
      SIV fall far below that of HIV-1, potentially providing vectors based upon HIV
      2/SIV with a greater degree of biosafety. Last, and perhaps most importantly, HIV
      2 and SIV are viruses which may be studied within non-human primate models
      susceptible to AIDS-like disease, making vectors based upon these viruses
      accessible to substantial preclinical evaluation. We approach this Chapter
      presenting information regarding the basic biology of HIV-2 and SIV and conclude
      by pointing to how unique features of HIV-2 and SIV are well suited to vector
      design, hoping to leave the reader with a greater appreciation of the potential
      these viruses offer within the field of gene transfer applications.

PMID- 12465464
TI  - FIV vector systems.
AB  - Why is feline immunodeficiency virus (FIV) such an appealing candidate for gene
      therapy vector development? Phylogenetic analysis suggests FIV is only distantly
      related to the primate lentiviruses, and despite repeated exposure, neither
      seroconversion nor other detectable evidence of human infection occurs. FIV
      naturally infects diverse Felidae worldwide, including the domestic cat. Here,
      the disease progression parallels the immunodeficiency caused by HIV, and for
      that reason, FIV and the cat provide an excellent model for anti-virals and AIDS
      vaccine research. Simple genome organization also facilitates vector development
      and analysis: FIV has only three accessory/regulatory proteins. To overcome FIV's
      cat-specific tropism, feline vectors are equipped with hybrid LTRs, since the FIV
      LTR shows low activity in human cells. Recombinant FIV vectors generate titers
      comparable to other lentiviral systems, are capable of incorporating heterologous
      envelopes and efficiently transduce dividing and nondividing cells in the
      presence and absence of the accessory proteins in vitro. Compared to HIV vectors,
      FIV vector development is still in its infancy, but initial in vivo data in
      various species and tissues indicate long-term gene expression at therapeutic
      levels, and thus FIV vectors hold great promise. Future efficacy studies in
      animal models and primates will determine the FIV vectors' suitability for gene
      therapy. The design of recombinant FIV vectors incorporates safety features
      described for primate lentiviral vectors with the benefit that biosafety testing
      of FIV vectors can occur in the natural host. Currently, FIV vectors are
      generated in a transient fashion, but the availability of a stable producer
      system amenable to better characterization and scale-up will considerably
      increase the potential for use of FIV vectors in the clinic.

PMID- 12465465
TI  - EIAV, CAEV and other lentivirus vector systems.
AB  - Lentiviruses that infect non-primates make up a diverse collection of viruses.
      Although these viruses have some features in common with HIV and other primate
      viruses, differences in genome organization and viral gene function have made the
      successful derivation of vectors from non-primate lentiviruses unpredictable.
      This Chapter discusses the construction and application of gene transfer systems
      derived from four non-primate lentiviruses including equine infectious anemia
      virus (EIAV), caprine arthritis encephalitis virus (CAEV), visna virus, and
      Jembrana disease virus (JDV).

PMID- 12465466
TI  - Safety considerations in vector development.
AB  - The inadvertent production of replication competent retrovirus (RCR) constitutes
      the principal safety concern for the use of lentiviral vectors in human clinical
      protocols. Because of limitations in animal models to evaluate lentiviral vectors
      for their potential to recombine and induce disease, the vector design itself
      should ensure against the emergence of RCR in vivo. Issues related to RCR
      generation and one approach to dealing with this problem are discussed in this
      chapter. To assess the risk of generating RCR, a highly sensitive biological
      assay was developed to specifically detect vector recombination in transduced
      cells. Analysis of lentiviral vector stocks has shown that recombination occurs
      during reverse transcription in primary target cells. Rejoining of viral protein
      coding sequences of the packaging construct and cis-acting sequences of the
      vector was demonstrated to generate env-minus recombinants (LTR-gag-pol-LTR).
      Mobilization of recombinant lentiviral genomes was also demonstrated but was
      dependent on pseudotyping of the vector core with an exogenous envelope protein.
      5' sequence analysis has demonstrated that recombinants consist of U3, R, U5, and
      the psi packaging signal joined with an open gag coding region. Analysis of the
      3' end has mapped the point of vector recombination to the poly(A) tract of the
      packaging construct's mRNA. The state-of-the-art third generation packaging
      construct and SIN vector also have been shown to generate env-minus proviral
      recombinants capable of mobilizing retroviral DNA when pseudotyped with an
      exogenous envelope protein. A new class of HIV-based vector (trans-vector) was
      recently developed that splits the gag-pol component of the packaging construct
      into two parts: one that expresses Gag/Gag-Pro and another that expresses Pol (RT
      and IN) fused with Vpr. Unlike other lentiviral vectors, the trans-vector has not
      been shown to form recombinants capable of DNA mobilization. These results
      indicate the trans-vector design prevents the generation of env-minus recombinant
      lentivirus containing a functional gag-pol structure (LTR-gag-pol-LTR), which is
      absolutely required for retroviral DNA mobilization and the emergence of RCR.
      Quality assurance based on monitoring for RCR may have limitations as a predictor
      of safety in vivo, especially in the long term. The demonstration of lentivirus
      infection via alternative entry mechanisms supports this notion. Therefore, the
      approach of monitoring trans-vector stocks for env-minus recombinant virus in
      vitro as a surrogate marker for the possible emergence of RCR in vivo should
      represent a significant advancement in vector safety quality assurance.

PMID- 12465467
TI  - Prospects for gene therapy using HIV-based vectors.
AB  - Recombinant vectors derived from murine leukemia virus (MLV) have been widely
      used to introduce genes in human gene therapy clinical trials and have shown the
      potential for medical applications and the promise of significantly improving
      medical therapies. Yet, the demonstrated limitations of these vectors support the
      need for continued development of improved vectors. The intrinsic properties
      associated with the MLV genome and its life cycle do not favor the successful
      application of this vector system in certain human gene transfer applications.
      Since MLV integrates randomly into the host genome, transgene expression is
      frequently affected by the flanking host chromatin. MLV insertions can often
      result in silencing or position effect variation of gene expression either
      immediately after insertion or following cell expansion in culture or in vivo.
      Migration of the MLV pre-integration complex from the cytoplasm into the nucleus
      of infected cells requires mitosis for nuclear membrane breakdown. Since a
      majority of human cells exist in a quiescent state in vivo, it is unlikely that
      direct in vivo gene delivery into target tissues can be achieved with the MLV
      vector system. Finally, insertion of tissue-specific cis-regulatory sequences to
      direct transgene expression frequently results in either the rearrangement of the
      vector sequence or disruption of the cis-regulatory sequence functions. The long
      terminal repeat (LTR) of MLV, which contains a ubiquitously active
      enhancer/promoter element, may partially account for this problem. Together,
      these problems pose a major obstacle for the use of MLV vectors in the treatment
      of human diseases. This Chapter discusses some of the potential targets to which
      HIV vectors might be applied in clinical settings and some of the issues
      surrounding use of HIV vectors in gene transfer clinical trials.

PMID- 12465468
TI  - Ethical considerations in the use of lentiviral vectors for genetic transfer.
AB  - This chapter will outline the various concerns which have been raised in
      scientific, bioethics, and lay communities about the use of lentiviral vectors
      for purposes of gene therapy. Many of these concerns are ranged around gene
      therapy itself; others are concerns particular to using this sort of vector for
      genetic modification of human cells. These concerns are outlined within the
      chapter, and arguments are given in favor and against various approaches to these
      concerns. Lastly, it is noted throughout that at this stage of research into gene
      therapy, the most practical approach to these dilemmas is to maintain awareness
      of the ethical problems and provide information to those concerned with all
      aspects of the development of this set of technologies.

PMID- 12465469
TI  - Nursing research and development.

PMID- 12465470
TI  - The anatomical exhibition of real human bodies.
AB  - It is impossible not to be stunned, and dwarfed, and inspired, and horrified, and
      amazed by the sight of the horse, complete with human rider, rearing high above
      your head. It is not so much the size of the model--more that both horse and man
      are real.

PMID- 12465471
TI  - Informed consent. The global picture.
AB  - All patients have the right to decline, and therefore must have the opportunity
      to give, informed consent for medical photography. This must be documented in
      order to comply with the Caldicott recommendations on data protection and patient
      confidentiality, and in doing so meet clinical standards of care. If
      confidentiality is breached, or consent is not obtained, the legal charge would
      be trespass to the person.

PMID- 12465472
TI  - The scrub practitioner and the first assistant role.
AB  - An audit of the activities undertaken by scrub nurses was performed at Ninewells
      Hospital, Dundee during November 1999. The result showed that a high percentage
      of scrub practitioners are undertaking first assistant activities. In order to
      prepare staff for their role within specialised areas of practice an ongoing
      program of Fitness for Practice modules is being developed collaboratively
      between Tayside University Hospitals Trust and the University of Dundee. This
      article describes their experiences.

PMID- 12465473
TI  - Chromophore design for photorefractive organic materials.
AB  - During the last years, significant progress has been achieved in understanding
      the mechanism of the photorefractive effect in amorphous organic materials. New
      chromophores could be devised which provided a substantial increase in the
      electrooptical response and lead to photorefractive materials with unprecedented
      refractive index modulation (delta n = 10(-2) at E = 28 V micron-1) and two-beam
      coupling gain. These improvements could only be accomplished by optimizing the
      electronic structure of highly conjugated merocyanine dyes to perfectly balanced
      dyes in the charge resonance limit (such as aminothienyl oxopyridone (ATOP) and
      indoline dimethine oxopyridone (IDOP) derivatives), considering effects of
      supramolecular ordering (dipolar aggregation), and adjusting the compatibility of
      the dyes to photoconducting polymers (like poly-N-vinylcarbazole). In particular,
      optimized glass-forming dyes (such as 2BNCM and ATOP-4) combine the dual
      functionalities of charge transport and electrooptical response and exhibit
      photorefractivity even in absence of any additional photoconductor.

PMID- 12465474
TI  - Comparison of hydride, hydrogen atom, and proton-coupled electron transfer
      reactions.
AB  - A comparison of hydride, hydrogen atom, and proton-coupled electron transfer
      reactions is presented. Herein, hydride and hydrogen atom transfer refer to
      reactions in which the electrons and protons transfer between the same donor and
      acceptor, while proton-coupled electron transfer (PCET) refers to reactions in
      which the electrons and protons transfer between different centers. Within these
      definitions, hydride and hydrogen atom transfer reactions are typically
      electronically adiabatic, hence evolving on a single electronic surface. In
      contrast, PCET reactions are often electronically nonadiabatic since the electron
      transfers a longer distance through a proton transfer interface. For all three
      types of reactions, solute reorganization is important, particularly the hydrogen
      donor--acceptor mode. Solvent reorganization is critical for hydride transfer and
      PCET, which involve significant solute charge redistribution, but not for
      hydrogen atom transfer. Theoretical descriptions and simulation methodology for
      all three types of reactions are presented, as well as experimentally relevant
      applications to hydride transfer in enzymes and PCET in solution.

PMID- 12465476
TI  - Metallic oxygen.

PMID- 12465475
TI  - On spectroscopy, control, and molecular information processing.
AB  - Implementing a logic machine on a single molecule was recently discussed with
      experimental roadmarks. Lasers were used to control the input and sometimes also
      the output of information with additional processing done via inter- and
      intramolecular dynamics. We examine the special requirements for an experiment
      that mimics a logic circuit. We use two-photon processes as physical examples of
      our considerations and discuss both combinational and sequential logic machines.

PMID- 12465477
TI  - Femtochemistry of Norrish type-I reactions: III. Highly excited ketones-
      theoretical.
AB  - Time-dependant density functional theory (TDDFT) and ab initio methods (CASSCF
      and CASMP2) are applied here for the investigation of the excited-state potential
      energy surfaces of ketones studied experimentally in the accompanying paper,
      number IV in the series. The aim is to provide a general and detailed physical
      picture of the Norrish type-I reaction from S0 and S1 potentials (papers I and
      II) and from higher-energy potentials (papers III and IV). Particular focus here
      is on reactions following excitation to the 3s, 3p, and 3d Rydberg state and to
      the (nz-->pi*) and (pi-->pi*) valence states. It is shown that the active
      orbitals in the CASSCF calculations can be chosen so that accurate results are
      obtained with a small active space. Dynamic corrections of the state-specific
      CASSCF energies at the multireference MP2 level do not improve the results for
      the Rydberg states but are significant for the valence states. The geometries of
      the Rydberg states are similar to the ground state; the S1 and other valence
      states are not. A common property of the valence states is the elongated CO bond
      and the pyramidalization of the carbonyl carbon atom. As a consequence, these
      valence states cross all Rydberg states along the CO stretching coordinate and
      provide an efficient pathway down to the 3s Rydberg states (S2) through a series
      of conical intersections (CIs). The nonadiabatic coupling vector of the CI
      between the (pi-->pi*) and the 3s Rydberg states guides energy channeling into
      the asymmetric CC-stretching mode. The energy demand for the CC bond breakage
      (Norrish type-I) on the S2 surface is lower than that of the CI leading to the S1
      state. This CC bond breakage leads to a linear excited state acetyl radical (3s
      Rydberg). Crossing a small barrier the 3s acyl radical can access a CI leading
      either to a second CC bond breakage or to a hot ground-state acetyl radical. The
      barriers for the Norrish type-I reaction on the various excited-state surfaces
      can be rationalized within the framework of valence-bond theory. The dynamic
      picture of the Norrish type-I reactions is now clear: The excitation to high
      energy states leads to the nonconcerted breakage of the alpha-CC bonds by an
      "effective downhill" potential in space involving the active excitation center
      CO, CC stretching, and CCO bending nuclear motions, but not, as usually thought,
      a direct repulsive potential along the CC bond. In our accompanying paper (part
      IV), it is shown that the results from the experimental investigations of Norrish
      type-I reactions on the femtosecond timescale are consistent with these
      theoretical results.

PMID- 12465478
TI  - Femtochemistry of Norrish type-I reactions: IV. Highly excited ketones-
      experimental.
AB  - Femtosecond dynamics of Norrish type-I reactions of cyclic and acyclic ketones
      have been investigated in real time for a series of 13 compounds using
      femtosecond-resolved time-of-flight mass spectrometry. A general physical
      description of the ultrafast processes of ketones excited into a high-lying
      Rydberg state is presented. It accounts not only for the results that are
      presented herein but also for the results of previously reported studies. For
      highly excited ketones, we show that the Norrish type-I reaction is nonconcerted,
      and that the first bond breakage occurs along the effectively repulsive S2
      surface involving the C-C bond in a manner which is similar to that of ketones in
      the S1 state (E. W.-G. Diau et al. ChemPhysChem 2001, 2, 273-293). The
      experimental results show that the wave packet motion out of the initial Franck
      Condon region and down to the S2 state can be resolved. This femtosecond (fs)
      internal conversion from the highly excited Rydberg state to the S2 state
      proceeds through conical intersections (Rydberg-valence) that are accessed
      through the C=O stretching motion. In one of these conical intersections, the
      internal energy is guided into an asymmetric stretching mode. This explains the
      previously reported pronounced nonstatistical nature of the reaction. The second
      bond breakage involves an excited-state acyl radical and occurs on a time scale
      that is up to one order of magnitude longer than the first. We discuss the
      details regarding the ion chemistry, which determines the appearance of the mass
      spectra that arise from ionization on the fs time scale. The experimental results
      presented here, aided by the theoretical work reported in paper III, provide a
      unified picture of Norrish reactions on excited states and on the ground-state
      potential energy surfaces.

PMID- 12465479
TI  - Dodecahedral clathrate structures and magic numbers in alkali cation
      microhydration clusters.
AB  - Using global geometry optimization based on our specialized version of Genetic
      Algorithms, we have examined the global and most important local minimum energy
      structures of water microsolvation clusters of potassium and cesium cations
      within the common TIP4P/OPLS model. Together with our earlier results on the
      corresponding sodium case, this work constitutes a first step towards a
      theoretical elucidation of "magic numbers" of solvating molecules and proposed
      special structures occurring in these systems. In particular, the actual role of
      dodecahedral cage structures is examined. Within the present model, they do not
      occur in sodium microsolvation, in agreement with the absence of the magic number
      20 for this system. For potassium and cesium microsolvation, dodecahedral cages
      do occur but their actual structures are far from ideal and their importance
      appears to be overrated. We offer simple explanations for structural features and
      trends, and for magic numbers smaller than 20.

PMID- 12465480
TI  - Solid-state electrolysis in CuBr thin films: observation and modelling of fractal
      growth.

PMID- 12465481
TI  - Biological and physical applications of water-based metal nanoparticles
      synthesised in organic solution.

PMID- 12465482
TI  - Ring currents in the porphyrins: a four-orbital model.

PMID- 12465483
TI  - Laser-induced growth of Ag nanoparticles from aqueous solutions.

PMID- 12465484
TI  - Control over the structure of ice and water by block copolymer additives.

PMID- 12465485
TI  - Photovoltaic devices from fullerene--oligophenyleneethynylene conjugates.

PMID- 12465486
TI  - Bose-Einstein condensation in a dilute gas: the first 70 years and some recent
      experiments (Nobel Lecture).
AB  - Bose-Einstein condensates of dilute gases offer a rich field to study fundamental
      quantum-mechanical processes, manipulation of the speed at which light
      propogates, observation of atomic pair-formation and superfluidity, or even
      simulating white dwarf stars. Still more radical applications are on the horizon.
      However, their initial creation was a masterpiece of experimental physics. After
      an initial process of laser cooling (which itself won its developers the 1997
      Nobel Prize), atoms in a magnetic-optical trap must be safely transferred into a
      purely magnetic trap, where the condensation process begins at 170 nK and 20 nK a
      pure condensate of 2000 atoms could be created. More astonishingly, Wieman and
      Cornell showed these low temperatures could be achieved in "bench scale"
      equipment rather than the massive pieces normally demanded by cryoscience. For
      their 1995 discovery of this new state of matter, they were awarded the 2001
      Nobel Prize in Physics.

PMID- 12465487
TI  - Cold molecules.
AB  - During the last years there has been a rapidly growing interest in the field of
      cold molecules. This has obviously been inspired by the spectacular successes in
      the closely related field of cold atoms, which have recently been recognized by
      the award of the 2001 Nobel Prize in Physics to Cornell, Ketterle, and Wieman.
      But molecules have much more to offer than simply extending the experiments
      already performed with atoms to more complex species.

PMID- 12465488
TI  - Langmuir-Blodgett assembly of one-dimensional nanostructures.
AB  - The Langmuir-Blodgett technique has been used to assemble one-dimensional
      nanoscale building blocks. Various superstructures can be obtained as a result of
      different interactions between the individual nanostructures and different
      surface pressure applied. The general assembly behavior is exemplified here with
      BaCrO4, BaWO4, Au nanorods, and Mo3Se3 nanowires.

PMID- 12465489
TI  - Opening a new vista in solid-state science: tuning electronic properties by gate
      induced doping.

PMID- 12465490
TI  - Study of the nature of improper blue-shifting hydrogen bonding and standard
      hydrogen bonding in the X3CH...OH2 and XH...OH2 complexes (X = F, Cl, Br, I): A
      correlated Ab initio study.
AB  - Weak hydrogen bonding was studied in the XH...OH2 and X3CH...OH2 complexes (X =
      F, Cl, Br, I) using the correlated MP2 ab initio method with relativistic
      Stuttgart/Dresden pseudopotentials and basis set (SDD). The accuracy of the
      method was tested for selected nonrelativistic complexes by performing MP2
      calculations with all-electron basis sets (6-311G** and TZVPP). The
      characteristics of bonding in the hydrogen halide complexes correspond to the
      standard H-bonding (an elongation of the X-H bond and red shift of its stretch
      frequency), whereas those in the X3CH...OH2 complexes (X = F, Cl) are typical of
      improper blue-shifting H-bonding (a contraction of the CH bond and blue shift of
      the respective stretch frequency). A natural bond orbital analysis revealed some
      important differences between both classes of complexes: a) the electron density
      transfer (EDT) in the former complexes is considerably larger than that in the
      latter complexes: b) the EDT in the former complexes is almost completely
      directed to the sigma*-antibonding orbital of the XH bond, which causes a
      weakening of this bond, its elongation, and a concomitant decrease of the XH
      stretch frequency. In the latter complexes, only a small portion of the EDT goes
      to the sigma*-antibonding orbital of the CH bond of the proton donor and a larger
      part is transferred to the remote (nonparticipating) part of the proton donor. As
      a consequence, the structural reorganization of the proton donor occurred,
      leading to the contraction of the C-H bond. The fact that a small red shift of
      the C-H stretch frequency was found in bromoform-water and iodoform-water
      complexes was explained by the competition of both the above-mentioned mechanisms
      with dominating passage of electron density to the sigma*-antibonding orbital of
      the C-H bond. For an explanation of all the geometric features of both types of
      complexes, it is however necessary to consider both charge transfer and
      electrostatic effects. The electrostatic effects fail sometimes to interpret the
      geometry changes in the proton donor.

PMID- 12465491
TI  - Two-dimensional molecular electronics circuits.
AB  - Addressing an array of bistable [2]rotaxanes through a two-dimensional crossbar
      arrangement provides the device element of a current-driven molecular electronic
      circuit. The development of the [2]rotaxane switches through an iterative,
      evolutionary process is described. The arrangement reported here allows both
      memory and logic functions to use the same elements.

PMID- 12465492
TI  - Synthesis, EPR and ENDOR of [60]fulleropyrrolidine bisadducts with nitroxide
      addends: magnitude and sign of the exchange interaction.

PMID- 12465493
TI  - Electron-deficient columnar plastic crystals.

PMID- 12465494
TI  - Hole mobility in DNA: effects of static and dynamic structural fluctuations.

PMID- 12465495
TI  - A cylindrical polymer: a stack of discotic triphenylene within comblike
      polymethacrylate.

PMID- 12465496
TI  - Superlattice and magnetism directed by the size and shape of nanocrystals.

PMID- 12465497
TI  - Biomolecular and supramolecular kinetics in the submicrosecond time range: the
      fluorazophore approach.
AB  - Fluorophores based on the azo chromophore 2,3-diazabicyclo[2.2.2]oct-2-ene,
      referred to as fluorazophores, display an exceedingly long fluorescence lifetime
      and undergo quenching upon contact with efficient hydrogen or electron donors.
      These photophysical and photochemical properties allow several uncommon
      applications to biomolecular and supramolecular kinetic studies in the
      submicrosecond time range. Examples for kinetics of host-guest complexation, end
      to-end contact formation in polypeptides, and lateral diffusion in membrane
      models are described. Principal requirements for these types of kinetic
      measurements and the dependence of the kinetics of diffusion-controlled reactions
      on the dimensionality of the system are discussed.

PMID- 12465498
TI  - Visible-light photocatalysis by modified titania.

PMID- 12465499
TI  - [FeII(bpy)3]2+/TiO2-codoped zeolites: synthesis, characterization, and first
      application in photocatalysis.
AB  - TiO2-codoped [FeII(bpy)3]2+/zeolite Y systems are revealed to be efficient
      photocatalysts for photochemically enhanced Fenton processes. Preparation,
      characterization, and tests using 2,4-xylidine as a model pollutant are
      described, and a first mechanistic hypothesis explaining the rather high
      photochemical reactivity of the catalyst system is given.

PMID- 12465500
TI  - Geometry optimisation of aluminium clusters using a genetic algorithm.
AB  - The application of a Genetic Algorithm, for optimising the geometry of aluminium
      clusters with 21-55 atoms bound by the many-body Murrell-Mottram potential, is
      described. In this size regime, a number of different structural motifs are
      identified--face-centred cubic, hexagonal close packed, decahedral and
      icosahedral structures. The larger clusters consist of hollow icosahedral
      geometric shells, with Al55 having a centred icosahedral structure. Evolutionary
      Progress Plots for Al19 and Al38 reveal how the best structure evolves from
      generation to generation upon operation of the Genetic Algorithm.

PMID- 12465501
TI  - Coupled electrorotation: two proximate microspheres spin in registry with an AC
      electric field.
AB  - We report a novel approach to micro- and nanoparticle rotation, uniting the fine
      translational control afforded by optical trapping with the flexibility and
      simplicity of dipole-field-induced coupled electrorotation (CER). Fluorescence
      imaging using a microparticle photopatterning technique was combined with optical
      trapping to quantify both the senses and speeds of rotation for individual pairs
      of particles. Laser tweezers allowed controlled positioning of a pair of
      particles within a dipole field while simultaneously providing an axis about
      which the particles rotated. The particle-particle interactions inherent in CER
      offer several distinct advantages compared with electrorotation in multipole
      fields. Results from several investigations highlight the utility of this
      approach, including quantification of rotation in spheres as small as 750 nm in
      diameter, observation of rotation rates as high as 1800 rpm, fabrication of
      coupled electrorotational "antigears", trapping and rotation of sphere dimers,
      and exploitation of the registry of sphere rotation to probe the dielectric
      properties of immobile objects.

PMID- 12465502
TI  - Kinetics of the photoferroelectric effect in chiral smectic-C liquid crystals
      studied by time-resolved measurements of spontaneous electric polarization and
      director tilt angle.
AB  - The origin of the photoferroelectric effect in liquid crystals, where the
      spontaneous polarization of a chiral ferroelectric smectic-C* (SmC*) host phase
      is changed by the E,Z-photoisomerization of azobenzene dopant molecules, was
      investigated by kinetic studies on the molecular isomerization and the subsequent
      changes in the SmC* order parameters, the director tilt angle, and the
      spontaneous electric polarization. The photoresponse of a liquid-crystal mixture
      consisting of 5 mol% 4,4'-bis-[(2-methyl)butyloxy]azobenzene dissolved in the
      SmC* host phase FLC 6430 was studied at low UV-light intensities (lambda = 366
      nm, 15 microW cm-2) using an electrooptical technique that measured the desired
      parameters with a time resolution of about 1 s. The time-resolved measurements of
      optical absorption, tilt angle, and spontaneous polarization during the thermal
      reisomerization after ending the sample irradiation showed that the photoinduced
      changes in the spontaneous polarization simultaneously followed the molecular
      isomerization with the same rate constant and activation energy, while the
      director tilt angle remained basically unchanged. Minor changes in the tilt are
      explained by the local heating of the sample due to the optical absorption. Since
      the photoinduced change in polarization was observed at constant tilt, we
      conclude that in the limit of low UV intensity the photoferroelectric effect
      originates from a photo-induced change of the bilinear coupling coefficient
      between the polarization and the tilt. In the molecular theory of chiral SmC*
      liquid crystals, the coupling coefficient is related to the bias of molecular
      rotations. This bias may be considerably disturbed by the formation of the bent Z
      isomers during the photoisomerization.

PMID- 12465503
TI  - On the "ozone deficit problem": what are Ox and HOx catalytic cycles for ozone
      depletion hiding?
AB  - Studies on the role of vibrational excitation in the reactants for the O2 + O2,
      OH + O2, and HO2 + O2 reactions show that they can be important sources of ozone
      in the stratosphere, particularly at conditions of local thermodynamic
      disequilibrium. The results suggest that the Ox and HOx cycles commonly viewed as
      catalytic sinks of ozone may actually lead to its production, and hence help to
      clarify the "ozone deficit problem". This paper also presents an explanation for
      the general overestimation of the OH abundance in the upper stratosphere and
      lower mesosphere through standard HOx chemistry.

PMID- 12465504
TI  - Kinetic resonance Raman spectroscopy of the Briggs-Rauscher oscillator.

PMID- 12465505
TI  - Binding kinetics of the toroid-shaped PCNA to DNA strands on a 27 MHz quartz
      crystal microbalance.

PMID- 12465506
TI  - Anchoring of liquid crystals on surface-initiated polymeric brushes.

PMID- 12465507
TI  - Excited-state photophysics of an acridine derivative selectively intercalated in
      duplex DNA.

PMID- 12465508
TI  - Formation of single-walled carbon nanotube thin films on electrodes monitored by
      an electrochemical quartz crystal microbalance.

PMID- 12465509
TI  - Photochemical response of electronically reconfigurable molecule-based switching
      tunnel junctions.

PMID- 12465510
TI  - The dynamics of the H + H2O reaction.
AB  - This article reviews the history and recent progress in the study of the dynamics
      of the H + H2O reaction, which has become a benchmark for experimental research
      in the field of gas-phase reaction dynamics. The dynamics of H + H2O is discussed
      in terms of the different observable properties: integral cross-sections, rate
      coefficients, product state distributions, differential cross-sections, and
      vector correlations. It is shown how experimental measurements and first
      principle theoretical calculations have revealed the interesting microscopic
      aspects of this elementary chemical reaction.

PMID- 12465511
TI  - Holographic data storage--the materials challenge.

PMID- 12465512
TI  - An investigation of the photoinduced changes of absorption of high-performance
      photoaddressable polymers.
AB  - Recently, a novel class of photoaddressable polymers (PAPs) has been reported,
      which allows for reversible photorecording with values of the photoinduced
      birefringence in excess of 0.2. These polymers are copolymers of methacrylate
      type monomers with a mesogenic and a nonmesogEnic photoactive azobenzene in the
      side chain. This report presents a detailed analysis of the three-dimensional
      photoinduced reorientation of side chains within thin layers of PAP materials,
      utilizing polarized UV/Visible spectroscopy, infrared, and photothermal
      deflection spectroscopy (PDS). The three-dimensional orientation distribution
      before and after illumination with 514 nm polarized light was investigated by
      angle-dependent UV/Vis absorption spectroscopy. As-prepared samples possess an
      uniaxial orientation with the photoactive units being preferentially aligned
      within the plane of the substrate layer. These films become biaxial upon
      photoalignment with polarized light incident normal to the substrate plane. For
      PAP materials containing mesogenic side chains, the out-of-plane absorption stays
      nearly unchanged, proving that the photoinduced reorientation occurs mainly
      within the layer plane. For a homopolymer bearing only a nonmesogenic azobenzene
      in the side chain, photobleaching is observed, associated with a disease in
      absorption in all three principle directions. This finding can be understood in
      terms of an orientational coupling between the photodegradation product and the
      active azobenzene units. Photodegradation was well established by infrared
      spectroscopy. Photothermal deflection spectroscopy has been performed to manifest
      photoinduced changes in the transparent wavelength region of the PAP material,
      below the absorption edge. In contrast to the pronounced optical changes in the
      UV/Vis and IR spectra, the absorption in this range remains nearly unchanged.
      This result provides evidence that the polymers can be well applied for
      holographic storage in thick-layer devices.

PMID- 12465513
TI  - Magneto-optical measurements of chromophore/semiconductor nanocrystalline
      superstructures.
AB  - The magneto-optical properties of chromophore/semiconductor nanocrystalline
      superstructures were examined using optically detected magnetic resonance (ODMR)
      and time-resolved photo-luminescence (PL) spectroscopy. The samples consisted of
      CdS or PbS nanocrystals separated by conjugated organic chains, forming three
      dimensional superstructures. The ODMR measurements revealed that the
      magnetooptical properties of the superstructures are mainly controlled by the
      individual characteristic of the nanocrystals. The ODMR spectra were compared
      with simulated curves generated by the diagonalization of a spin Hamiltonian,
      indicating the existence of the following luminescence events. a) Recombination
      between electron-hole pairs trapped at a stoichiometric defect (metal or sulfur
      vacancies) or oxygen adatom sites at the surface of the nanocrystals. These
      electron-hole pairs showed anistropic g-factors and weak exchange interactions.
      b) Bound exciton emission, from strongly coupled electron-hole pairs trapped at
      intrinsic stoichiometric or structural defects at the core of the nanocrystals.
      The existence of the two overlapping luminescence events is further confirmed by
      the acceptance of biexponential PL decay processes.

PMID- 12465514
TI  - In situ ESR/Vis/NIR spectroelectrochemistry of [60]fullerene: the origin of ESR
      "spikes" and the reactivity of pristine fullerene anions.

PMID- 12465515
TI  - Electron transfer studies on self-assembled monolayers of helical ferrocenoyl
      oligoproline-cystamine bound to gold.

PMID- 12465516
TI  - Alumination pathways to mesoporous aluminosilicates with high-temperature
      hydrothermal stability.

PMID- 12465517
TI  - Cavity-ringdown spectroscopy studies of the B2 sigma+<--X2 sigma+ Rsystem of AIO.

PMID- 12465518
TI  - Atomic level study of LiMn2O4 as electrode in lithium batteries.

PMID- 12465519
TI  - Redox targeting of oligonucleotides anchored to nanocrystalline TiO2 films for
      DNA detection.

PMID- 12465520
TI  - Determination of the fractal characteristic of nanofiber-network formation in
      supramolecular materials.

PMID- 12465521
TI  - Control of liquid-crystalline properties by base pairing of adenine and thymine.

PMID- 12465522
TI  - Ethics in action. Family presence during codes.

PMID- 12465523
TI  - Staff collaboration boosts adoption of best practices.

PMID- 12465524
TI  - What if you're stuck by a needle?

PMID- 12465525
TI  - Reshaping the future for overweight kids.

PMID- 12465526
TI  - A new age for childhood diseases. Down syndrome.

PMID- 12465527
TI  - Less morphine, or more?

PMID- 12465528
TI  - Traumatic brain injury: help for the family.

PMID- 12465529
TI  - When your beliefs run counter to care.

PMID- 12465530
TI  - Tobacco settlement funds--intent vs. actuality.

PMID- 12465531
TI  - A year with the AFL-CIO.

PMID- 12465533
TI  - Life support treatment.

PMID- 12465534
TI  - The power of listening.

PMID- 12465535
TI  - The role of the HCA.

PMID- 12465536
TI  - Psoriasis.
AB  - Psoriasis affects patients to varying degrees, and may seriously impair their
      quality of life. Treatments minimise symptoms but cannot cure the condition.

PMID- 12465537
TI  - Developing self-directed training for intravenous cannulation.
AB  - Nurses are frequently called upon to insert intravenous cannulae. Traditional
      training has involved a study day followed by supervised practice, but in one
      trust, many nurses failed to continue cannulation afterwards. A flexible system
      of training, using videos and workbooks was introduced, which has enabled nurses
      to build a portfolio of clinical skills at their own pace.

PMID- 12465538
TI  - Practical issues in the management of highly exuding wounds.
AB  - Many different types of wound dressings are available. It is important that
      nurses know what sort of dressing is appropriate for a patient's highly exuding
      wound as using the wrong dressing can lead to repeated dressing changes and
      soiling of clothes and bedding and will undermine the patient's faith in care.
      This paper provides a practical guide to the effective use of products.

PMID- 12465539
TI  - A breast unit care pathway: enhancing the role of the nurse.
AB  - The second of two papers on the development of patient care pathways focuses on
      the experience of one hospital's breast unit. Nurses have taken over tasks
      previously carried out by clinicians, particularly in pre-assessment, preparing
      for discharge and follow-up, family history clinics and seroma aspiration. There
      are key lessons for other units and conditions.

PMID- 12465540
TI  - Assessing patients with actual or potential erectile dysfunction.
AB  - Asking question about sexuality forms part of the nursing assessment but is often
      overlooked because of the embarrassment of both nurse and patient. However,
      failure to identify erection problems, either actual or potential, can result in
      distress, making eventual treatment more difficult. A prompt assessment and
      referral to an erectile dysfunction clinic are required.

PMID- 12465541
TI  - Comprehensive critical care within the independent health-care sector.
AB  - With the development of a concordat between the NHS and the private sector, this
      paper describes how one private health-care provider has taken steps to improve
      the theoretical and practical training of ward nurses caring for the growing
      number of high-dependency patients in this setting. A critical care training
      programme has been set up, with promising early results.

PMID- 12465542
TI  - An investigation into the accuracy of different types of thermometers.
AB  - The traditional mercury-in-glass thermometer carries the potential risk of glass
      breakage and mercury spillage and health-care professionals have sought an
      alternative. This study examined the accuracy of three other types of temperature
      measurement device--disposable, digital and tympanic--when compared with standard
      mercury thermometer readings.

PMID- 12465543
TI  - Ethical considerations in research from a cancer nurse's perspective.
AB  - Much progress has been made to protect patients who act as subjects in clinical
      research trials, but there are still difficulties in ensuring that the interests
      of the individual are not sacrificed in favour of the greater long-term good of
      the many. This paper argues that informed consent and providing adequate
      information for the patient are essential, but only part of the picture.

PMID- 12465544
TI  - Robotic surgery: is it for you?
AB  - Robotic surgery has indeed arrived. The approved device in the United States, the
      Intuitive Surgical System's daVinci System, is installed in about 80 hospitals
      worldwide. That number is rising rapidly. Once other companies, Computer Motion
      for example, receive Food and Drug Administration approval for their systems, the
      number of robotic-equipped operating rooms will begin to increase enormously. The
      current outcry regarding the expense of these systems is certainly not without
      merit. However, I would urge surgeons interested or even just curious about these
      systems to try one in a laboratory setting. The ease of accomplishing difficult
      tasks and the vividness of the 3-dimensional imaging create an experience that is
      both extremely impressive and enjoyable. There are currently no data to justify
      the expense of these systems in terms of patient outcomes or reduced
      complications. Such data will take a great deal of time and effort to accumulate.
      However, having become accustomed to the robotic system, this surgeon would have
      difficult moving back to standard laparoscopic instrumentation. Imagine during a
      standard open operation that your scrub assistant rubbed grease on your glasses
      and took away your favorite forceps and needle holder and gave you clumsy
      instruments 18 inches too long with less-than-reliable action at the tips. With
      enough struggling you would be able to accomplish the operation, and perhaps over
      time, even become facile with subpar instruments. However, you would certainly
      rather see well and have the instruments that you know work best in your hands.
      It would be very difficult to design a study to prove that your patients are
      better off when you use your normal instruments and clean glasses as opposed to
      fogging glasses and difficult-to-use instruments. But, you would know that there
      is a difference. That in large part is the feeling of surgeons who have had the
      good fortune of becoming accustomed to the current robotic systems for minimally
      invasive surgery. They can see much better and can manipulate tissue much better.
      Most of them are also convinced that when they can see better and manipulate
      tissue better, the outcomes for their patients are better. Is robotic surgery
      right for you? The answer is complex and has a myriad of elements. This author
      would suggest that a great start in determining the answer would be to try the
      current systems and keep track of both the literature and the technical evolution
      regarding these systems as time progresses.

PMID- 12465545
TI  - Intraductal papillary mucinous neoplasms of the pancreas.

PMID- 12465546
TI  - Laparoscopic bariatric surgery.

PMID- 12465547
TI  - Intestinal transplantation: a coming of age.

PMID- 12465548
TI  - Current management of necrotizing pancreatitis.
AB  - Although necrotizing pancreatitis remains a devastating disease, progress during
      the past 2 decades has significantly reduced morbidity and mortality. Early
      recognition of severe disease, using scoring systems or clinical signs, is
      essential to successful therapy. Standard therapy for patients with severe
      disease includes early invasive monitoring and resuscitation, prophylactic
      antibiotics, nutrition, and serial CT scanning and FNA to identify infected
      necrosis. Recent data suggest that with few exceptions, patients with pancreatic
      necrosis can be managed with a conservative strategy, reserving surgery or other
      forms of intervention for documented infection. Such a policy must be flexible,
      however. Infection may develop late after weeks of sterility, and repeated FNAs
      are necessary. Conservative management produces a subset of patients with
      persistent pain, malaise, and an inability to tolerate a diet or return to
      activities of daily life. These patients with organized necrosis do well with
      delayed debridement. Although there may still be a subset of patients with
      sterile necrosis who might benefit from earlier debridement, we have not yet
      identified a marker for this group.

PMID- 12465549
TI  - Is nonoperative management of abdominal gunshot wounds reasonable?

PMID- 12465550
TI  - The surgeon as a risk factor.

PMID- 12465551
TI  - The current status of sentinel lymph node biopsy for breast cancer.

PMID- 12465552
TI  - The current management of postoperative bile duct strictures.

PMID- 12465553
TI  - The status of gene therapy for surgical disease.

PMID- 12465554
TI  - Local excision of rectal tumors.
AB  - Local excision of rectal cancer is done with the goal of cure or palliation with
      minimal morbidity. Careful patient selection is paramount to avoid local
      recurrence. Endorectal sonography has brought accuracy to the preoperative
      staging of rectal cancer. Patients with ultrasound stage T1 carcinoma of the
      distal rectum and well-differentiated or moderately well-differentiated histology
      can be offered local excision, with expected low morbidity and a low risk of
      recurrence. Pathologic examination of the entire specimen determines favorable or
      unfavorable histologic features, and is the basis for final decisions made on
      therapy. The role of adjuvant therapy after local excision is still being
      defined. Preoperative chemoradiation followed by local excision appears promising
      for patients with more advanced or very distal tumors who have a complete
      pathologic response to the neoadjuvant therapy.

PMID- 12465555
TI  - The current status of percutaneous tracheotomy.

PMID- 12465556
TI  - The role of epidural analgesia and anesthesia in surgical outcomes.
AB  - Recent clinical evidence suggests that EAA used in combination with general
      anesthesia has a beneficial effect on surgical outcome compared with general
      anesthesia and systemic analgesia. Those complications with clear evidence of a
      reduced incidence in prospective, randomized studies are shown in Table 2. The
      benefits are greatest in high-risk patients who receive thoracic epidural
      blockade with local anesthetic agents. Besides reducing the incidence of certain
      major complications, the adjunctive use of EAA reduces ICU care, hastens
      recovery, and has cost savings.

PMID- 12465557
TI  - Positron emission tomography in surgical oncology.

PMID- 12465558
TI  - The current role of angioplasty in carotid disease.

PMID- 12465560
TI  - The prevalence of disability among children: paradigms and estimates.
AB  - Every examination of disability among children must first grapple with definition
      of disability. The challenges to identifying disability among children involve
      not only determining the appropriate paradigm for defining disability, but also
      applying that paradigm to children in a meaningful way. This discussion of the
      prevalence of disability among children starts by examining the various paradigms
      utilized to identify disability and how they are interpreted when applied to
      children. Estimates of the prevalence of childhood disability, under different
      definitions of disability are presented. The goal of the discussion is to
      illustrate the sensitivity of the estimates of disability prevalence to the
      particular definition and data set used. Finally, the potential influence of the
      choice of paradigm on further measurement and service delivery is outlined.

PMID- 12465561
TI  - Health maintenance and management in childhood disability.
AB  - Health and health-related needs of children with disabilities are very broad in
      scope, and it is impossible to adequately cover all aspects in a single article.
      This article has tried, however, to highlight the issues common to disability,
      and lay the groundwork for the development of health maintenance guidelines for
      this population. The prevalence of childhood disability is on the rise, yet life
      expectancies are improving, and it is not uncommon for children even with severe
      disabilities to live well into adulthood. The ICIDH2 paradigm shift to focus on
      health and function rather than impairment and disability fits well with the
      national initiative to promote health for all. There is a paucity of information
      on the impact of childhood interventions on health in adulthood, yet it would be
      prudent to surmise that early interventions will be effective. Directed attention
      to the basic health needs and preventive measures for the management of children
      with disabilities is required. This can be difficult because the management of a
      child with disability is dynamic and challenging, and health care providers may
      find their time and energies consumed with just managing the more obvious and
      striking disability-related problems. The widespread ramifications of disability
      on both the individual and society, call for teamwork between family, health care
      providers, and the community. Although the specific needs of such a diverse group
      vary widely; as a group, children with disabilities have many common needs. These
      include the need for basic health maintenance and health promotion measures such
      as nutrition, immunizations and physical fitness, as well as coordination of
      services, psychologic and family support, technical assistance, funding
      resources, communication between health and education fields, and access to a
      "medical home," the site for primary care of the child. As a tree is bent, so it
      will grow. Efforts to promote growth and maximize opportunities for development,
      to inculcate healthy eating habits, to encourage exercise and socialization
      behaviors, and to strengthen the bond between the child with disability, family,
      and community will help minimize disability-related problems in adulthood. As
      children with disabilities are drawn into the mainstream of the concept of
      health, we should start to see the much awaited change in societal attitudes
      toward disability. The conditions resulting in childhood disability are many
      varied. Rather than developing condition specific health guidelines, it would be
      more advantageous to use a general health framework of anticipatory guidance,
      growth, development, medical management, psychologic and vocational counseling,
      and resource planning. Working off this framework, health maintenance and
      promotion measures can then be further individualized to suit the child and
      family's specific needs.

PMID- 12465562
TI  - PICUBASICS: an on-line resource for the diagnosis and management of acute illness
      in children with chronic conditions and disabilities.
AB  - Children with disabilities and chronic conditions are more likely than their
      healthy peers to be admitted to emergency rooms, to be hospitalized, and to
      require pediatric intensive care. Although many of these admissions are
      attributable to disease burden, a significant percentage are unscheduled stays
      for an acute illness that is directly related to a known condition. Such
      admissions are foreseeable, and therefore may be avoidable. An understanding of
      typical patterns of events that lead to acute illness in children with chronic
      conditions might suggest strategies to prevent these illnesses or to minimize the
      severity of unpreventable illnesses when they occur. When viewed as a marker for
      avoidable morbidity, an "unanticipated" hospitalization of a child with a chronic
      condition or disability thus provides an important opportunity for health care
      quality improvement at the community level.

PMID- 12465563
TI  - Osteoporosis in children who have disabilities.
AB  - Children who have disabilities are at increased risk for osteoporosis during
      childhood. This not only puts them at risk for fractures during childhood but
      also during adulthood. Peak bone mass, which helps predict osteoporosis in
      adulthood, is never attained in children who have a disability. Care providers of
      this group of children must be aggressive in the prevention and treatment of
      osteoporosis. A thorough laboratory evaluation and DXA studies may be undertaken
      on all disabled children who are at risk for osteoporosis. Although medications
      have shown promise in the treatment of decreased bone mass, their efficacy in
      children who have disabilities must be evaluated in larger, controlled studies.
      Nonpharmocologic treatments also necessitate further exploration.

PMID- 12465564
TI  - Adolescent sexuality and disability.
AB  - Regardless of what our beliefs about sex and disability may be, as health care
      providers we can promote the health and well being of our patients with
      disabilities in several ways. First and perhaps foremost, physical and
      programmatic barriers to accessing general health care including routine
      gynecologic care must be dramatically reduced. The promise of Title III of the
      Americans with Disabilities Act must be aggressively extended to our health care
      system to ensure equal access to routine health care for all. Second, knowledge
      of community resources that can support the healthy development and exercise of
      responsible and satisfying sexuality is critical. For example, health care
      providers should know about adaptive and assistive technologies as well as the
      use of personal care assistants to support the healthy although sometimes
      nontypical expression of one's sexuality. Centers for Independent Living are
      community resources that are often underutilized by the medical profession. These
      centers--run by and for people with disabilities--are likely resources and allies
      for providing education, role models, and peer mentoring around relationships,
      intimacy, sexuality, sexual expression, and parenting with a disability. Finally,
      sex education is a must and should include the following: Basic facts of life,
      reproduction, and sexual intercourse; Human growth and development Human
      reproduction and anatomy Self-pleasuring/masturbation and the use of sexual aids
      Intimacy and privacy Pregnancy and child birth Contraception and abortion Family
      life and parenthood Sexual response and consensual sex Sexual orientation Sexual
      abuse HIV/AIDS and other sexually transmitted diseases. The question should not
      be whether sex education is provided to persons with disabilities, but rather how
      it is most effectively provided. Health sex education must include the
      development of effective communication skills, decision-making skills,
      assertiveness, and the ability to say "no." It must also include ways to create
      satisfying relationships. For more information about sex education as it relates
      to people with disabilities, the following abbreviated resource list may be
      helpful: http://www.sexualhealth.com http://www.lookingglass.com Ludwig S,
      Hingsburger, D. Being sexual: an illustrated series on sexuality and
      relationships. SIECCAN, 850 Coxwell, Aven., East York, Ontario, M4C 5R1 Tel: 416
      466-5304; Fax: 416-778-0785. Sexuality Information and Education Council of the
      United States (SIECUS), 130 West 42nd Street, Suite 350, New York, NY 10036. Tel:
      212-819-9770. National Information Center for Children and Youth with
      Disabilities (NICHCY), P.O. Box 1492, Washington, DC 20013; Tel/TTY: 800-695
      0285; Fax: 202-884-8641; Internet: www.nichcy.org Non-Latex Supplies (Ask your
      pharmacist if not available) Trojan-Supra: http://www.trojancondoms.com Durex
      Avanti: http://www.durex.com Female Health Company-FC Female Condom
      http://www.femalehealth.com Pasante--EzOn http://www.postalcondoms.co.uk
      (available in Canada and U.K.).

PMID- 12465565
TI  - Pain management in a pediatric rehabilitation setting.
AB  - This article reviews the current understanding of pain evaluation as applied to
      children who have chronic illness and disabilities. Utilizing a collaborative
      medical approach, psychiatric principles of management are discussed. Case
      scenarios are presented to outline application of general strategies of clinical
      management.

PMID- 12465566
TI  - Injury prevention for children with disabilities.
AB  - Little injury data exists for children who have disabilities. There is an urgent
      need to address injury prevention and to improve safety standards for this group.
      Understanding the epidemiology of injuries will allow clinicians to accurately
      advise patients and their families on individual risks and counsel them in steps
      to take to reduce those risks. Safety information must be tailored to consider
      each child's functional impairments. All children who have disabilities are at
      risk for maltreatment. Open discussion of this problem is warranted given the
      immensity of the problem. Identifying parental concerns and supporting parents in
      the use of respite resources are appropriate. For children who have problems in
      mobility, falls are the number one concern. Collaboration with reliable vendors
      and therapists that adhere to standards for safe seating is essential for
      reducing the risk of wheelchair tips and falls. In addition, therapists should be
      directed to provide mobility training for activities from safe transfers to
      street crossing in a community setting. Parents should be counseled to approach
      their child's injury risk based on the child's cognitive and behavioral level
      rather than their chronological level. Knowledge of the child's developmental
      quotient or intelligence quotient will also allow the clinician to accurately
      formulate an injury prevention plan. Many children will always need supervision
      for tasks that put them in situations of injury risk (i.e., swimming, street
      crossing, bathing). Sensorineural deficits such as blindness or deafness create
      significant alterations in negotiating the environment and an increased risk of
      injury. Awareness of the special needs for fire risk reduction and street safety
      are critical in this population. The collection of injury data is critical to
      define the scope of the problem and to influence changes in policy and the
      development of technical standards. Educational efforts focused on safety should
      include pediatricians, rehabilitative therapists, social workers, teachers,
      parents, and--most importantly--the empowerment of children as they age injury
      free into adults. SUGGESTED STRATEGIES: A national injury surveillance system for
      children who have disabilities should be developed to identify injury risk
      factors for children with disabilities. Children with disabilities should be
      monitored as a separate risk group in data collection regarding injuries. Parents
      should be aware of the cognitive level of their child and its influence on their
      injury risk. Crash testing on passenger restraints should include crash dummies
      whose physical characteristics resemble those of children who have disabilities.
      Families should have an emergency evacuation plan with specific consideration of
      their disabled child in the event of an emergency. Risk of burns to insensate
      skin and risks of thermal and friction trauma should be discussed when
      appropriate. The fire department and the police department should be notified of
      the presence of a child who has a disability in the home. Parents must be aware
      of the risk of falls to children who are mobile but cognitively impaired and to
      those in wheelchairs regardless of cognitive ability. Hospitals must have Child
      Protective Services teams with specific training in abuse to children with
      disabilities. Discussion of maltreatment risk should be addressed during routine
      office visits and appropriate resources should be made available to provide
      support to families. Educational programs should be developed to alert providers
      to the risks of abuse of children who have disabilities.

PMID- 12465567
TI  - Exercise and sports for children who have disabilities.
AB  - This article focuses on the exercise needs of children who have disabilities, how
      these needs differ from able-bodied children, and what medical concerns are
      relevant for a given disability. The information presented also discusses some
      preventative options related to individual sports and a discussion of various
      organized recreational and competitive opportunities available both nationally
      and internationally. In addition, a listing of major disabled sports
      organizations is provided for reference.

PMID- 12465568
TI  - Physical activity, metabolic issues, and assessment.
AB  - Considering the important health consequences of physical activity and aerobic
      capacity, current guidelines recommend that all individuals should be physically
      active all or most days of the week. Relatively little is known about physical
      activity patterns or aerobic capacity of individuals who have disabilities, but
      existing data clearly show a disturbing pattern of low levels of physical
      activity and aerobic capacity in most, if not all, populations who have
      disabilities. More research is needed on all populations who have disabilities,
      not only documenting current levels of physical activity and aerobic capacity but
      also investigating potential strategies for improvement. Unfortunately, the
      techniques available for measuring physical activity have significant
      shortcomings. DLW shows considerable promise, but it is expensive and not
      appropriate for population studies. All other techniques have significant
      shortcomings in regard to tracking individual physical activity patterns, but
      they might provide valuable insight regarding group behavior. Although maximal
      exercise testing is the gold standard for measuring aerobic capacity, this
      technique is difficult to use in many populations that have disabilities. Few
      protocols have been validated for use with individuals who have disabilities, and
      indiscriminant use of protocols developed for nondisabled populations is
      inappropriate when testing individuals who have disabilities. Submaximal testing
      could be of considerable utility, but few protocols have been validated. For most
      populations that have disabilities, submaximal tests designed to predict VO2peak
      are not valid, given the altered disability-specific physiological responses,
      which usually result in gross overpredictions. Submaximal tests designed to
      compare (either intra or inter individual comparisons) physiological responses at
      predetermined submaximal work rates show considerable promise. Both populations
      of children who have disabilities that are discussed herein exhibit low levels of
      physical activity and aerobic capacity, which is consistent with most of the
      literature for any group that has disabilities. Although the mechanisms for
      producing lower levels of activity and aerobic capacity differ among children who
      have mental retardation and children who have CP, the outcome is similar in both
      populations. Appropriate testing methodology differs between these populations,
      and the different mechanisms involved demonstrate the disability-specific nature
      of research in children who have disabilities, which also illustrates the
      difficulty of producing general guidelines for exercise and physical activity
      interventions. Current data clearly show the need for improving both physical
      activity patterns and aerobic capacity in most children who have disabilities.
      Failure to accomplish this goal will ultimately have considerable negative health
      outcomes for individuals who have disabilities.

PMID- 12465569
TI  - Strategies for clinical motion analysis based on functional decomposition of the
      gait cycle.
AB  - In this article the authors have developed a strategy for clinical gait analysis
      that takes advantage of the functional subdivisions that naturally occur during
      the gait cycle. By organizing the contributions of several investigators, the
      authors have identified the important critical events that must occur during each
      phase of gait and related those features to specific gait measurements that are
      routinely available from modern motion analysis laboratories. In addition, the
      authors have provided examples of how findings from a motion laboratory can be
      used to suggest possible interventions that can improve or restore absent or
      abnormal critical events, thereby improving the overall gait performance of the
      patient with gait pathology. While this condensed version of motion analysis
      strategies is not sufficiently comprehensive to address all individuals who have
      gait pathology, the authors hope that it serves as a suitable introduction to
      this challenging field.

PMID- 12465570
TI  - Facts and myths about therapeutic interventions in cerebral palsy: integrated
      goal development.
AB  - This article explores a variety of myths and facts about therapy for children who
      have cerebral palsy. Current evidence is used to refute popular myths and debunk
      harmful ones. A way of integrating interventions is suggested and a planning
      process for timing interventions is proposed.

PMID- 12465572
TI  - The employment service and vacancy durations.
AB  - In the literature, there are few examples of studies analyzing the impact of
      labor market programs on vacancies. This article presents the results of a study
      of the impact of personnel increase at Swedish employment offices on vacancy
      durations. The evaluation method in the study is quasi-experimental. The main
      results of the study are as follows: (a) The increase of employment office staff
      members reduced their vacancy durations by approximately 2 days, and the
      probability that a vacancy is cancelled from the register is 1.17 times higher
      for the program offices; and (b) this effect is too small for the increase of
      staff members to represent a socially efficient use of resources and for a
      positive outcome in a public finance context.

PMID- 12465571
TI  - Measuring risk and protective factors for substance use, delinquency, and other
      adolescent problem behaviors. The Communities That Care Youth Survey.
AB  - Risk and protective factors predictive of adolescent problem behaviors such as
      substance abuse and delinquency are promising targets for preventive
      intervention. Community planners should assess and target risk and protective
      factors when designing prevention programs. This study describes the development,
      reliability, and validity of a self-report survey instrument for adolescents ages
      11 to 18 that measures an array of risk and protective factors across multiple
      ecological domains as well as adolescent problem behaviors. The instrument can be
      used to assess the epidemiology of risk and protection in youth populations and
      to prioritize specific risk and protective factors in specific populations as
      targets for preventive intervention.

PMID- 12465573
TI  - The role of postsecondary education in welfare reform. Ohio's JOBS Student
      Retention Program.
AB  - The 1996 federal welfare reform legislation encourages quick employment over
      education and training for the nation's welfare recipients. However, some argue
      that a one-size-fits-all approach ignores the heterogeneity of this population.
      This article presents findings from a net impact evaluation of Ohio's JOBS
      Student Retention Program (JSRP), a program designed to facilitate success for
      public assistance recipients at 2-year community or technical colleges. The
      authors evaluate this policy using state administrative data sets. The analyses
      consist of unadjusted and regression-adjusted comparisons of means for the JSRP
      group and a constructed comparison group. Outcomes examined include program
      completion, employment, earnings, and welfare recipiency. Focusing on the most
      recent 11 of 16 quarters of data available, the average increase in quarterly
      earnings was 8.45% for program participants and 12.91% for program completers.
      The results indicate that encouraging postsecondary education for some welfare
      recipients will boost earnings capacity and therefore long-term self-sufficiency.

PMID- 12465574
TI  - The effect of active parental consent on the ability to generalize the results of
      an alcohol, tobacco, and other drug prevention trial to rural adolescents.
AB  - The authors report the effect of active parental consent on sample bias among
      rural seventh graders participating in a drug abuse prevention trial. Students
      obtaining active consent from their parents to complete the survey were of higher
      academic standing, missed fewer days of school, and were less likely to
      participate in the special education program at their school as compared to
      students who did not return a parental consent form. However, students with
      consent were not significantly different from students whose parents actively
      declined. The sample obtained under active parental consent represents students
      less at risk for problem behaviors than would have been obtained under passive
      consent procedures.

PMID- 12465575
TI  - The developmental course of gender differentiation: conceptualizing, measuring,
      and evaluating constructs and pathways.
AB  - Gender differentiation is pervasive, and understanding how and why it develops is
      important for both theoretical and practical reasons. The work described here is
      rooted in constructivist accounts of gender differentiation. Past research
      provides considerable support for constructivist predictions concerning (a)
      developmental changes in gender attitudes and (b) the relation between gender
      attitudes and information processing. Little work, however, has addressed the
      more fundamental question of how children's developing gender attitudes about
      others are related to developing gender characterizations of self. The focus of
      the current Monograph is on this other-self relation during middle childhood. A
      brief review of past theory and empirical work on gender differentiation is
      provided. It is argued that a major explanation of the limitations and
      inconsistencies evident in earlier work may be traced to restrictions in the
      measures available to assess key constructs. A conceptual analysis of the
      specific limitations of past measures is presented. The Monograph then offers
      alternative models of the developmental relation between attitudes toward others
      and characterization of self (the attitudinal and the personal pathway models),
      and identifies conditions expected to influence the strength of the observed
      other-self relation. Four studies establish the reliability and validity of a
      suite of measures that provides comparable methods for assessing attitudes toward
      others (attitude measures, or AM) and sex typing of self (personal measures, or
      PM) in three domains: occupations, activities, and traits (or OAT). Parallel
      forms are provided for adults (the OAT-AM and OAT-PM) and for children of middle
      school age, roughly 11-13 years old (the COAT-AM and COAT-PM). A fifth study
      provides longitudinal data from children tested at four times, beginning at the
      start of grade 6 (approximately age 11 years) and ending at the close of grade 7
      (approximately age 13 years). These data are used to examine the developmental
      relation between children's sex typing of others and sex typing of the self, and
      to test the predictions concerning the factors hypothesized to affect the
      strength of the relation between the two types of sex typing. Overall, the data
      supported the conceptual distinctions among individuals' (a) gender attitudes
      toward others, (b) feminine self, and (c) masculine self, and, additionally,
      revealed some intriguing differences across domains. Interestingly, the data
      concerning the other-self relation differed by sex of participant. Among girls,
      analyses of concurrent relations showed that those girls who held fewer
      stereotypes of masculine activities for others showed greater endorsement of
      masculine items for self, a finding compatible with both the other-to-self
      attitudinal pathway model and the self-to-other personal pathway model. The
      prospective regression analyses, however, showed no effects. That is,
      preadolescent girls' gender attitudes about others did not predict their later
      self-endorsements, nor did self-endorsements predict later attitudes. Data from
      boys showed a strikingly different pattern, one consistent with the self-to-other
      personal pathway model: There was no evidence of concurrent other-self relations,
      but prospective analyses indicated that preadolescent boys who endorsed greater
      numbers of feminine traits as self-descriptive early in grade 6 developed
      increasingly egalitarian gender attitudes by the end of grade 7. The Monograph
      closes with discussions of additional implications of the empirical data, of
      preliminary work on developing parallel measures for younger children, and of the
      need to design research that illuminates the cognitive-developmental mechanisms
      underlying age-related changes in sex typing.

PMID- 12465576
TI  - Outlier changes might shock you.

PMID- 12465577
TI  - Reprocessing. Opened but unused: FDA mulls policy.

PMID- 12465578
TI  - Medical/surgical advances. The unkindest cut.

PMID- 12465579
TI  - Patient safety. Jump on board.

PMID- 12465580
TI  - IT/wireless. Peace and quiet.

PMID- 12465581
TI  - Wanted: women only..

PMID- 12465582
TI  - 1Q[3a]. Does employer-sponsored health care have a future? .

PMID- 12465583
TI  - Patient safety. Quest for quality: lessons learned, challenges met.

PMID- 12465584
TI  - E-mail minus 'e-mail'. California study shows that online communication can
      benefit patients, physicians and payers.

PMID- 12465585
TI  - America's uninsured. Rethinking the problem that won't go away.
AB  - Even as the number of uninsured Americans surpasses 41 million and continues to
      climb, the issue is not a front-burner concern with policy-makers, the public or
      even many providers. Why does this seeming apathy--and political paralysis-
      prevail and what will it take to galvanize health care stakeholders to action?

PMID- 12465586
TI  - Dueling priorities.
AB  - The Institute of Medicine report on medical errors and the resulting attention
      from the public and health care purchasers pushed patients safety to the
      forefront of providers' quality initiatives. Now, some health care leaders say
      the preoccupation with safety is wrongheaded and could detract from broad efforts
      to improve care.

PMID- 12465587
TI  - The complex business of neuroscience.
AB  - It's a clinical line that usually takes a back seat to higher-profile services
      like cardiology, oncology and orthopedics. But hospitals are starting to pay more
      attention to neuroscience for a number of reasons, including its tertiary nature
      and the high volume of imaging studies involved. More importantly, it usually
      generates a profit.

PMID- 12465588
TI  - The dynamics of satisfaction.
AB  - As hospitals wrestle with workforce and quality issues, employee and patient
      satisfaction have been elevated to core priorities. The Baptist Healthcare
      Leadership Institute shows how the two are intertwined and how hospitals can
      improve satisfaction levels.

PMID- 12465589
TI  - Healthy news.
AB  - Hospitals are a cornerstone of community health programs, but cannot bear that
      burden alone. A new organization aims to bridge the gap between health care
      insiders and outsiders.

PMID- 12465590
TI  - Prospective analysis of peer and parent influences on smoking initiation among
      early adolescents.
AB  - The nature and relative importance of psychosocial influences on smoking
      initiation among early adolescents are topics of substantial research interest.
      Students (n = 1081) from four middle schools were surveyed at the beginning and
      end of the sixth grade. Baseline predictors were regressed on smoking initiation
      at end of sixth grade. In bivariate, logistic regression analyses association
      with problem behaving peers, perceived prevalence, and depression were positively
      associated and adjustment to school, perceived social competence, parent
      expectations, parental monitoring, and parental involvement were negatively
      associated with smoking initiation. In multivariate logistic regression analyses
      controlling for sex, race, and school, peer affiliation and perceived prevalence
      were positively associated, whereas social competence and parental monitoring
      were negatively associated with smoking initiation. A significant interaction
      between parental involvement and peer affiliation indicated that among teens with
      problem behaving friends only those with parents who were relatively uninvolved
      were are at increased risk for smoking initiation. This finding held for boys,
      girls, Whites, Blacks, and teens living in single parent families. These findings
      provide evidence that antecedent parenting behaviors may protect early
      adolescents against smoking even in the context of negative peer affiliation.

PMID- 12465591
TI  - Corneal sensitivity 10 years after epikeratoplasty.
AB  - PURPOSE: To assess corneal sensitivity in patients 10 or more years after
      epikeratoplasty for myopia, aphakia, hyperopia, and keratoconus. METHODS: A total
      of 45 eyes of 33 patients (age range at examination 33 to 55 yr) were included in
      the study. Corneal sensitivity thresholds using an electromagnetic aesthesiometer
      (Draeger) were measured at various locations on the lenticule and the recipient
      cornea. Measurements were evaluated regarding the corrective purpose, surgical
      technique, age, and gender of the patients and the area of measurements. RESULTS:
      The mean corneal sensitivity threshold in the center of the epikeratoplasty
      lenticule was significantly lower than on the peripheral recipient cornea (320.0
      +/- 365.1 x 10(-5) N versus 0.1 +/- 0.5 x 10(-5) N). Corneal sensitivity at the 3
      and 9 o'clock positions was significantly higher compared to the values at the 6
      and 12 o'clock positions on the lenticule. No correlations of these values with
      age, gender, type, and primary indications for the surgery were observed.
      CONCLUSIONS: These results indicate a relative hypesthesia of the epikeratoplasty
      lenticule as compared to the peripheral host cornea, even 10 years after surgery.
      In our patients no clinically significant changes were observed that could be
      attributed to the reduced sensitivity over this follow-up period.

PMID- 12465592
TI  - Quality of dredged material in the river Seine basin (France). II.
      Micropollutants.
AB  - Dredging rivers is needed to ensure safe navigable waters, rivers and waterways.
      To anticipate the management of dredged materials in the case of the river Seine
      basin, the quality of the sediments in the river is checked every 3 years before
      dredging operations. The river Seine Basin is heavily submitted to pollution
      pressure from nearby industrial activities and urban expansion of Paris and its
      region. Here, the micropollutant content of the sediment sampled in 1996, 1999
      and 2000 before dredging is discussed compared to regulatory standards. The
      results indicate that most of the sediment samples from the river Seine basin are
      lightly to moderately contaminated with organic and inorganic micropollutants
      (heavy metals, PAH, PCB), which makes the management after dredging easier. This
      pollution is strongly correlated with the organic matter content and to the fine
      fraction (<50 microm) of the sediment. These results can lead to other management
      options than the ones already used in the river Seine basin: (1) dumping of
      lightly to moderately polluted sediments in quarries; and (2) physical treatment
      (sieving, hydrocycloning) of contaminated sediments issued from 'hot spots'.

PMID- 12465593
TI  - Tropical malabsorption.
AB  - Tropical malabsorption remains an important clinical problem for both the
      indigenous population of tropical countries and for short-term visitors and
      longer-term residents from the industrialized world. In young children,
      persistent diarrhea and malabsorption can result in severe retardation of growth
      and development. The most common cause is an intestinal infection notably the
      small intestinal protozoa including Giardia intestinalis, Cryptosporidium parvum,
      Isospora belli, Cyclospora cayetanensis, and the microsporidia. Tropical sprue
      still remains an important diagnostic option but is less common than it was 20 to
      30 years ago. It is important to attempt to make a specific microbiological
      diagnosis as this will influence the choice of antibiotic. However, if laboratory
      facilities are not available, it is possible to offer empirical therapy although
      this may involve a trial of more than one antibiotic.

PMID- 12465594
TI  - [Molecular mechanism in Sjogren syndrome: T cell receptors and autoantigens].

PMID- 12465595
TI  - [The androgen receptor: molecular pathology].
AB  - Androgens play a crucial role in the development, maintenance and regulation of
      male phenotype and reproductive physiology through the androgen receptor, a
      transcription factor. Testosterone or dihydrotestosterone binding induces a trans
      conformation of the androgen receptor and allows its translocation into the
      nucleus, where it recognizes specific DNA sequences. Recent developments in
      molecular genetics, as well as structural analysis of the androgen receptor,
      allow a better understanding of the structure/function relationship of this
      nuclear receptor. Molecular analyses of androgen insensitivity syndrome, as well
      as hormone-resistant prostate cancer, Kennedy's disease and isolated male
      infertility, have been proved useful as privileged models for this purpose. In
      the absence of identified AR receptor mutations in androgen insensitivity
      syndromes, abnormalities of transcriptional cofactor should be considered.
      Finally, identification of androgen-dependent genes will be helpful for
      evaluating the degree of the molecular defect of androgen action within target
      cells.

PMID- 12465596
TI  - Acta Cytologica 40 years ago. Volume VI, number 6, 1962.

PMID- 12465597
TI  - Ranula--this term is probably one of the oldest in surgery, and its etymology is
      not very obvious...

PMID- 12465598
TI  - [MR aortofemorography versus DSA: prospective evaluation].
AB  - PURPOSE: To determine how far MRA of lower limbs obviates the need for pre
      therapeutic DSA. MATERIALS AND METHOD: Three-step 3-D gadolinium enhanced
      aortofemorography with a moving bed was prospectively compared to DSA in 49
      consecutive patients (40 males, 9 females; age range 38-80 years; mean age 64
      years). According to Leriche and Fontaine's clinical gradation of lower limb
      ischemia, 5 patients were graded I, 37 graded II, 4 graded III, and 3 graded IV.
      Two observers graded stenoses for DSA and three for MRA. Cohen's kappa statistics
      were used to evaluate interobserver variability using MRA, as well as to compare
      MRA to DSA. In addition, sensitivity, specificity, positive and negative
      predictive values of MRA for the assessment of stenosis superior to 80% were
      calculated by using DSA as a gold standard, respectively for arterial trunks
      above and below the level of the knees. RESULTS: Overall accuracy of MRA was 92%.
      Comparison of DSA and MRA yielded a kappa value of 0.87 (0.95 for arterial trunks
      located above the level of the knees and 0.75 below). Interobserver agreement was
      very good. Sensitivity, specificity, positive and negative predictive values of
      MRA for the diagnosis of > 80% stenosis were respectively 98, 98, 85 and 99%
      above the level of the knees and 87, 91, 77 and 96% below the knees. CONCLUSION:
      MRA can be considered as valuable technique for the evaluation of peripheral
      arterial obstructive disease, especially for stenosis located above the level of
      the knees.

PMID- 12465599
TI  - [Burkitt's lymphoma of the appendix].
AB  - We report the case of a 12-year-old European boy presenting with an appendicular
      Burkitt's lymphoma. He complained of right lower abdominal pain mimicking acute
      appendicitis. Ultrasonography and abdominal CT showed an appendicular mass which
      features were strongly suspicious for malignancy. This case emphasizes the
      importance of medical imaging to characterize appendicular lesions and to select
      the surgical technique. Accurate diagnosis was obtained histologically on
      resected specimen.

PMID- 12465601
TI  - Case 1: assessment. Congenital cystic adenomatoid malformation type 2.

PMID- 12465602
TI  - Case 2: assessment. Vocal cord dysfunction.

PMID- 12465603
TI  - Case 3: assessment. Exercise-induced inspiratory laryngeal stridor.

PMID- 12465600
TI  - The macrophage growth factor CSF-1 in mammary gland development and tumor
      progression.
AB  - Colony stimulating factor 1 (CSF-1), a major regulator of the mononuclear
      phagocytic lineage, is expressed in more than 70% of human breast cancers and its
      expression is correlated with poor prognosis. Studies of CSF-1 null mutant mice
      demonstrated that CSF-1 plays an important role in normal mammary ductal
      development as well as in mammary tumor progression to metastasis. CSF-1
      regulates these processes through the recruitment and regulation of macrophages,
      cells that become associated with mammary tumors and the terminal end buds at the
      end of the growing ducts. This phenomenon suggests that the tumors subvert normal
      developmental processes to allow invasion into the surrounding stroma, a process
      that gives the tumor access to the vasculature and consequently the promotion of
      metastasis. In addition, soluble CSF-1 secreted from the tumor acts to divert
      antitumor macrophage responses and suppresses the differentiation of mature tumor
      antigen-presenting dendritic cell This review discusses these observations in
      detail and attempts to fit them into a larger picture of CSF-1 and macrophage
      action in the regulation of normal mammary gland development and tumor
      progression.

PMID- 12465604
TI  - Case 4: assessment. Early chronic lung disease.

PMID- 12465605
TI  - Case 5: assessment. Allergic tubular interstitial nephritis.

PMID- 12465606
TI  - Why there hasn't been an anthrax outbreak.

PMID- 12465607
TI  - Progestogen-only pills (POPs) and body weight.

PMID- 12465608
TI  - The death of Kipling's daughter.

PMID- 12465609
TI  - International readership.

PMID- 12465610
TI  - Lipochitooligosaccharide-induced tobacco cells release a peptide as mediator of
      the glycolipid signal.

PMID- 12465611
TI  - Further information and recommendations to prevent perforation with the frameless
      GyneFix IUD.

PMID- 12465612
TI  - Potent inhibition of human immunodeficiency virus type 1 replication by an
      intracellular anti-Rev single-chain antibody.

PMID- 12465613
TI  - Neuropathy associated with Norplant.

PMID- 12465614
TI  - Blood pressure measurement--does anyone do it right?: An assessment of
      reliability of equipment in use and the measurement techniques of clinicians.

PMID- 12465615
TI  - An early manuscript in the history of American comparative psychology: Lewis
      Henry Morgan's "Animal Psychology" (1857).
AB  - Lewis Henry Morgan (1818-1881) is best known as the 1st ethnographer of Native
      American culture, but he also wrote on animal psychology, beginning in 1843, some
      50 years before the founding of comparative psychology as a scientific
      discipline. Although not an evolutionist, Morgan argued that animals possess many
      human mental abilities, such as reason and moral judgment, and he rejected the
      scientific utility of the concept of instinct, a view that did not gain much
      currency in psychology until the rise of behaviorism in the 1920s. This 1857
      manuscript, which is in the Lewis Henry Morgan Papers at the University of
      Rochester in Rochester, New York, formed the basis for the last chapter of his
      1868 monograph on the American beaver but gives additional information on his
      sources and an expanded criticism of the concept of instinct.

PMID- 12465616
TI  - [Stereotactically and sonographically guided vacuum-assisted breast biopsy: a
      national consensus for Austria].

PMID- 12465617
TI  - Australian influences on Elton Mayo: the construct of Revery in industrial
      society.
AB  - Elton Mayo was born in Australia and spent most of his first 42 years living in
      that country. This article explores the Australian context in which he developed
      his views views of Australia compared with that of the United States during the
      time that Mayo developed his approach to psychology and the role of workers in
      industry. In addition, the social context in which Mayo established his career
      was shaped by significant political events in Australia. The construct of revery,
      which describes a specific state of consciousness, is central to Mayo's early
      theorizing and was developed by Mayo partly in reaction to political and
      industrial conflict occurring in Australia.

PMID- 12465618
TI  - [Breast Imaging Reporting and Data System (BI-RADS)--German version].

PMID- 12465619
TI  - Maintaining health insurance during a recession: likely COBRA eligibility.
AB  - Findings from The Commonwealth Fund 2001 Health Insurance Survey.

PMID- 12465620
TI  - From the Centers for Disease Control and Prevention. 25th anniversary of the last
      case of naturally acquired smallpox.

PMID- 12465621
TI  - From the Centers for Disease Control and Prevention. Adverse events associated
      with 17D-derived yellow fever vaccination--United States, 2001-2002.

PMID- 12465622
TI  - From the Centers for Disease Control and Prevention. Investigations of West Nile
      virus infections in recipients of blood transfusions.

PMID- 12465623
TI  - Orientalism in Euro-American and Indian psychology: historical representations of
      "natives" in Colonial and postcolonial contexts.
AB  - The author examines the historical role of Euro-American psychology in
      constructing Orientalist representations of the natives who were colonized by the
      European colonial powers. In particular, the author demonstrates how the power to
      represent the non-Western "Other" has always resided, and still continues to
      reside, primarily with psychologists working in Europe and America. It is argued
      that the theoretical frameworks that are used to represent non-Westerners in
      contemporary times continue to emerge from Euro-American psychology. Finally, the
      author discusses how non-Western psychologists internalized these Orientalist
      images and how such a move has led to a virtual abandonment of pursuing "native"
      forms of indigenous psychologies in Third World psychology departments.

PMID- 12465624
TI  - The gnu mutation of Drosophila causes inappropriate DNA synthesis in unfertilized
      and fertilized eggs.
AB  - Drosophila melanogaster embryos whose mothers are homozygous for the maternal
      effect lethal mutation gnu (GNU embryos) under DNA synthesis but no nuclear
      division; this leads to the formation of a small number of giant nuclei in the
      syncytial blastoderm. We have shown previously that many components of the
      mitotic apparatus are present and functional in GNU embryos, and the primary
      lesion of the gnu mutation has therefore remained obscure. Here, we report that
      fertilization is not necessary for GNU eggs to develop. Giant nuclei originate
      from the products of female meiosis, and we see autonomously replicating
      centrosomes that must be maternally derived. If GNU eggs are inseminated,
      however, the male pronucleus also undergoes DNA replication. Our observations
      suggest that the GNU cytoplasm permits DNA synthesis in a relatively unregulated
      manner. In embryos from females homozygous for gnu and the female sterile haploid
      mutation mh, we find replication of DNA derived from the male pronucleus. This
      contrasts with embryos from mothers homozygous for mh alone, in which this does
      not occur. We propose that the gnu gene product participates in the repression of
      DNA synthesis found in unfertilized eggs.

PMID- 12465625
TI  - Privacy legislation and research.

PMID- 12465626
TI  - Privacy legislation and research.

PMID- 12465627
TI  - Chronic fatigue syndrome clinical practice guidelines: psychological factors.

PMID- 12465628
TI  - Chronic fatigue syndrome clinical practice guidelines: psychological factors.

PMID- 12465629
TI  - Should we still give our asthmatic patients written individualised management
      plans?

PMID- 12465630
TI  - The right to health care, the social contract, and health reform in the United
      States.

PMID- 12465631
TI  - Ethics and health care reform: institutional contributions.

PMID- 12465632
TI  - Funding health care with an employer mandate: efficiency and equity concerns.

PMID- 12465633
TI  - A nursing home's good faith duty "to" care: redefining a fragile relationship
      using the law of contract.

PMID- 12465634
TI  - Recommendations for lightning protection in sport.

PMID- 12465635
TI  - The ADA--a little used tool to remedy nursing home discrimination.

PMID- 12465636
TI  - Treating medical charts near the end of life: how legal anxieties inhibit good
      patient deaths.

PMID- 12465637
TI  - Women's sexual exploitation in therapy.
AB  - The incidence of therapist-patient sex is disturbingly high, and the obstacles to
      seeking legal redress against a sexually abusive therapist are numerous. The
      defence of consent is one of the most serious obstacles. Generally no physical
      coercion is involved; and the patient often believes she is consenting at the
      time in which sexual relations occur. The author explores how the defence of
      consent has been construed to bar women from succeeding in malpractice and sexual
      assault suits against sexually abusive therapists. Her thesis is that an
      understanding of the nature and dynamics of the therapeutic relationship leads to
      the conclusion that free and informed consent is not possible in this context.
      The author concludes with a discussion of whether a mandatory reporting law,
      requiring therapists to file a report with the relevant licencing authorities
      when they become aware that a current patient has engaged in sexual relations
      with a former therapist, would be desirable.

PMID- 12465638
TI  - Sex discrimination and insurance for contraception.
AB  - Unintended pregnancy is a serious problem in the United States. Most private
      insurance plans do not pay for contraception even though they pay for other
      prescription drugs and devices. This Article argues that this pattern constitutes
      sex discrimination and is prohibited by Title VII of the Civil Rights Act of
      1964, as amended by the Pregnancy Discrimination Act. It discusses the reasons
      this issue has been neglected and suggests ways federal and state officials might
      remedy this common form of gender discrimination.

PMID- 12465639
TI  - Asymptomatic HIV as a disability under the Americans with Disability Act.
AB  - The Americans with Disability Act (ADA) does not state whether it prohibits
      discrimination against individuals who are infected with HIV but asymptomatic.
      Some courts have held that the language of the ADA is unambiguous and does not
      cover asymptomatic HIV as a disability because the virus is not an "impairment"
      that substantially limits a "major life activity." Other courts have looked
      behind the statutory language and found that Congress intended to protect
      asymptomatic individuals with HIV because the virus impairs one's ability to
      procreate and/or engage in sexual relations. This Comment argues that
      asymptomatic individuals with HIV are indeed protected under the ADA, but that
      the analytic framework thus far employed by the courts is flawed. Asymptomatic
      HIV is a protected disability not because it is independently debilitating, but
      because the prejudices and fears of other may prevent HIV-infected persons from
      fully participating in society. The ADA was enacted to prevent exactly this type
      of discrimination.

PMID- 12465640
TI  - Arguing the "obvious" in Wisconsin: why state regulation of assisted reproductive
      technology has not come to pass, and how it should.

PMID- 12465641
TI  - Metaphorical imagination: the moral and legal status of fetuses and embryos.

PMID- 12465642
TI  - Women in labor: some issues about informed consent.
AB  - Women wishing hospital admission for childbirth are asked to sign very general
      pre-admission consent forms. The use of such forms suggests that women in labor
      are considered incompetent to give informed consent. This paper explores some of
      the problems with advance directives and general consent, and argues that since
      women in labor are not generally incompetent, it is not appropriate to require
      this kind of consent of them.

PMID- 12465643
TI  - Solving an "appalling" problem: social reformers and the campaign for the Alberta
      Sexual Sterilization Act, 1928.
AB  - In this article, the author examines the campaign leading up to the passage of
      the Sexual Sterilization Act in Alberta in 1928. The author asserts that the
      passage of this Act was the result of the influence of a few elite individuals,
      particularly those involved with the United Farm Women of Alberta social reform
      movement, and may not have been reflective of widespread favourable public
      sentiment. While there were serious misgivings regarding the passage of the
      Sexual Sterilization Act, the legislation was ultimately successful because of
      the pressing problems of inadequate mental facilities and budgetary constraints.
      The author discusses the legislation's eventual repeal in 1972 due to public
      denunciation of eugenic measures, concerns about liability, and the threat posed
      to individual liberties. This article was the winner of the William Morrow Essay
      Contest in 1999.

PMID- 12465644
TI  - In vitro fertilization and embryos: the need for international guidelines.

PMID- 12465645
TI  - The European total ban on human cloning: an analysis of the Council of Europe's
      actions in prohibiting human cloning.

PMID- 12465646
TI  - Genetic dilemmas and the child's right to an open future.

PMID- 12465647
TI  - From Baby M. to Jaycee B.: fathers, mothers, and children in the brave new world.

PMID- 12465648
TI  - Legal and ethical issues involved when counseling minors in nonschool settings.
AB  - Many counselors in non-school settings will work with children at some time
      during their practice; therefore, it is essential that they understand the legal
      and ethical issues relevant to working with minors. Major court cases and
      legislation are presented, and 4 critical ethical issues--counselor competence,
      the client's rights to confidentiality and informed consent, and duties related
      to child abuse--are addressed. Suggestions for working ethically with minors in
      order to limit legal liability are presented.

PMID- 12465649
TI  - Genetic privacy and the law: an end to genetics exceptionalism.
AB  - While the proliferation of human genetic information promises to achieve many
      public benefits, the acquisition, use, retention, and disclosure of genetic data
      threatens individual liberties. States (and to a lesser degree, the federal
      government) have responded to the anticipated and actual threats of privacy
      invasion and discrimination by enacting several types of genetic-specific
      legislation. These laws emphasize the differences between genetic information and
      other health information. By articulating these differences, governments afford
      genetic data an "exceptional" status. The authors argue that genetic
      exceptionalism is flawed for two reasons: (1) strict protections of autonomy,
      privacy, and equal treatment of persons with genetic conditions threaten the
      accomplishment of public goods; and (2) there is no clear demarcation separating
      genetic data from other health data; other health data deserve protections in a
      national health information infrastructure. The authors present ideas for
      individual privacy protections that balance the societal need for genetic
      information and the claims for privacy by individuals and families.

PMID- 12465650
TI  - The futility of futility?: on life, death, and reasoned public policy.

PMID- 12465651
TI  - Wrong map: why public science can't really be public.

PMID- 12465652
TI  - [Ideal BCG inoculation as part of the future tuberculosis prevention programs].

PMID- 12465653
TI  - Intercomparison of translocation and dicentric frequencies between laboratories
      in a follow-up of the radiological accident in Estonia.
AB  - PURPOSE: To perform an interlaboratory comparison of FISH chromosome painting and
      to study the time-course of translocations and dicentrics in three accident
      victims exposed to radiation. Also, to use the data in the validation of the FISH
      technique as a retrospective dosimeter. MATERIALS AND METHODS: Twelve blood
      samples were collected during 4 years from three subjects exposed to radiation in
      an accident in Estonia in 1994 involving gamma-radiation from a 137Cs source. Two
      of the subjects were exposed during approximately 7 h, both receiving a
      protracted dose of about 1 Gy and also localized exposure. The third subject
      received a protracted whole-body dose of 2.7 Gy during 4 weeks as well as a short
      term partial-body dose. Preparations from 48-h metaphase cultures were painted by
      the FISH technique using routine methods and probe cocktails in four
      laboratories. Samples from each subject were analysed in two different
      laboratories that used different combinations of whole chromosome probes. The
      PAINT nomenclature was applied when recording chromosome aberrations. RESULTS:
      The intercomparison of FISH analysis data showed reasonable similarities between
      laboratories, the largest discrepancy being 21% in the frequency of two-way
      translocations in subject 3. Half-time calculations, based on combined data sets
      from two laboratories, showed that dicentrics decreased rapidly with half-times
      of approximately 2 years. In all cases, the initial dicentric yields were lower
      than the initial translocation yields. During the 4-year follow-up, the
      frequencies of all translocations in cells containing only simple rearrangements
      fell on average to about 65% of their initial value. Two-way translocations were
      slightly more persistent than all translocations. The average half-time was about
      8 years for two-way translocations and around 6 years for all translocations.
      Cells containing complex rearrangements were few in number and they disappeared
      with time. In general, the inclusion of complex cells caused a more rapid fall in
      aberration yield. CONCLUSIONS: In general, the results imply that relatively
      consistent scoring data were obtained with different chromosome painting
      protocols. They also support the idea that the reduction of translocations with
      time is associated with partial-body irradiation.

PMID- 12465654
TI  - Limits imposed by ionizing radiation on the long-term survival of trapped
      bacterial spores: beta radiation.
AB  - PURPOSE: A model is presented for determining the survival time T(F) of a
      fraction F of a population of bacterial spores trapped within a fluid inclusion
      and subject to genetic damage from beta radiation. METHODS: The limiting factor
      to survival is the production of double-strand breaks (DSB) in the DNA resulting
      from single-track cleaving and from the cumulative effects of single-strand
      breaks (SSB) induced by the presence of ionizing radiation in the environment.
      The model considers the probability that radicals and ions formed by the passage
      of high-energy particles will interact with a DNA molecule and induce damage.
      RESULTS: The survival time T(F) for a fraction F of a trapped population is a
      weak function of both F and the length L in base pairs of the genome. For
      irradiation due to a beta source trapped with the spores within the inclusion,
      the survival time is also inversely proportional to the concentration of the
      radionuclide, the dominant factor in limiting survival time. CONCLUSIONS: The
      predictions of the model are consistent with measured DSB formation rates, the
      observed survival of trapped spores over time periods as long as 250 Ma, and
      track structure models which address low physical dose rates.

PMID- 12465655
TI  - Dietary sodium modification and experimental radiation nephropathy.
AB  - PURPOSE: To determine whether suppression of the renin-angiotensin system (RAS)
      with high dietary sodium (salt) has the same beneficial effect on radiation
      nephropathy as suppression of the RAS with angiotensin-converting-enzyme (ACE)
      inhibitors or angiotensin II (AII) receptor antagonists. MATERIALS AND METHODS:
      Normal and irradiated rats were placed on high- or low-salt diets and assessed
      for effects on blood pressure, on AII levels and on the development of radiation
      nephropathy. RESULTS: In unirradiated animals, a high-salt diet suppressed AII
      and caused hypertension, while a low-salt diet produced no detectable effects.
      Use of a high-salt diet 3-9 weeks after irradiation exacerbated radiation-induced
      hypertension but attenuated the development of radiation nephropathy. Continuous
      use of a high-salt diet slowed the progression of radiation nephropathy, but
      eventually exacerbated radiation-induced hypertension and accelerated renal
      failure. Use of a high-salt diet in animals with established radiation
      nephropathy was deleterious. A low-salt diet had no effect on the development of
      radiation nephropathy. CONCLUSIONS: These studies provide further support for the
      hypothesis that the beneficial effect of AII receptor antagonists, ACE inhibitors
      and high dietary sodium in the prophylaxis of radiation nephropathy is due to
      their suppression of the RAS, not to their anti-hypertensive effects.

PMID- 12465656
TI  - Adaptive response and the influence of ageing: effects of low-dose irradiation on
      cell growth of cultured glial cells.
AB  - PURPOSE: To examine the molecular mechanism of radiation adaptive response (RAR)
      for the growth of cultured glial cells and to investigate the influence of ageing
      on the response. MATERIALS AND METHODS: Glial cells were cultured from young and
      older rats (1 and 24 months). RAR for the growth of glial cells conditioned with
      a low dose of X-rays and subsequently exposed to a high dose of X-rays was
      examined for cell number and BrdU incorporation. Involvement of the subcellular
      signalling pathway factors in RAR was investigated using their inhibitors,
      activators, and mutated and knockout glial cells. RESULTS: RAR was observed in
      cells cultured from young rats but was not in cells from older animals. The
      inhibitors of protein kinase C (PKC) and DNA-dependent protein kinase (DNA-PK) or
      phosphatidylinositol 3-kinase (PI3K) suppressed RAR. The activators of PKC
      instead of low-dose irradiation also caused RAR. Moreover, glial cells cultured
      from severe combined immunodeficiency (scid) mice (CB-17 scid) and ataxia
      telangiectasia mutated (Atm) knockout mice showed no RAR. CONCLUSION: The results
      indicated that PKC, ATM, DNAPK and/or PI3K were involved in RAR for growth and
      BrdU incorporation of cultured glial cells and RAR decreased with ageing.

PMID- 12465657
TI  - Radiation effects on circulating and endothelial cell interactions studied by
      quantitative real-time videomicroscopy.
AB  - PURPOSE: To quantify in vitro the functional consequences of irradiation on the
      interactions between leukocytes or platelets and endothelial cells (EC) in
      flowing whole blood using a parallel-plate flow chamber and real-time
      videomicroscopy. MATERIALS AND METHODS: The parallel-plate flow chamber was
      calibrated to determine the dynamic parameters of the flow channel. Fluorescent
      labelled whole blood was perfused at wall shear rates of 25, 75 and 500 s(-1)
      over a monolayer of human microvascular EC-lung (HMVEC-L) with or without
      irradiation at 10 Gy. The adhesion of leukocytes and platelets on EC was
      quantified by videomicroscopy and image analysis. RESULTS: Calibration of the
      parallel-plate flow chamber showed that flow in the chamber was laminar and
      steady and had a parabolic velocity profile, thus simulating physiological flow
      conditions. Flow assay revealed that rolling, mean rolling velocity and firm
      adhesion of leukocytes was increased following irradiation of EC. Irradiation
      also favoured platelet adhesion to EC. CONCLUSIONS: The results of an in vitro
      flow assay with whole blood showed that under physiological flow conditions,
      irradiation affected the function of EC; pro-inflammatory and thrombogenic
      responses were enhanced, which may contribute to in vivo radiation-induced
      vascular occlusion and fibrosis.

PMID- 12465658
TI  - Case-control study on the use of cellular and cordless phones and the risk for
      malignant brain tumours.
AB  - PURPOSE: To investigate the use of cellular and cordless phones and the risk for
      malignant brain tumours. MATERIALS AND METHODS: A case-control study was
      performed on 649 patients aged 20-80 years of both sexes with malignant brain
      tumour diagnosed from 1 January 1997 to 30 June 2000. All patients were alive
      during the time of the study and had histopathology verified brain tumours. One
      matched control to each case was selected from the Swedish Population Register.
      The study area was the Uppsala-Orebro, Stockholm, Linkoping and Goteborg medical
      regions of Sweden. RESULTS: Exposure was assessed by a questionnaire answered by
      588 (91%) cases and 581 (90%) controls. Phone usage was defined as 'ever use' and
      usage starting within 1 year before diagnosis was disregarded. Overall, no
      significantly increased risks were found: analogue cellular phones yielded an
      odds ratio (OR)=1.13, 95% confidence interval (CI)=0.82-1.57, digital cellular
      phones OR=1.13, CI=0.86-1.48, and cordless phones OR=1.13, CI=0.85-1.50. For
      ipsilateral (same side) radiofrequency exposure, analogue mobile phones gave
      OR=1.85, CI=1.16-2.96, for all malignant brain tumours. For astrocytoma, this
      risk was OR=1.95, CI=1.12-3.39. For all malignant brain tumours, digital mobile
      phones yielded OR=1.59, CI=1.05-2.41, and cordless phones yielded OR=1.46,
      CI=0.96-2.23, in the analysis of ipsilateral exposure. CONCLUSION: The
      ipsilateral use of an analogue cellular phone yielded a significantly increased
      risk for malignant brain tumours.

PMID- 12465659
TI  - Effects of 7 Hz-modulated 450 MHz electromagnetic radiation on human performance
      in visual memory tasks.
AB  - PURPOSE: The aim was to examine low-level 7 Hz-modulated 450 MHz radiation
      effects on human performance in visually presented neuropsychological tasks
      associated with attention and short-term memory. MATERIALS AND METHODS: A
      homogeneous group of 100 subjects (37 female, 63 male) were randomly assigned to
      either the exposed (10-20 min, 0.158 mW cm(-2)) or the sham-exposed group. A
      battery of three different tests measured attention and short-term memory. Task 1
      involved alternately selecting black digits from 1 to 25 in ascending order and
      white digits from 24 to 1 in descending order. The time spent on the task and the
      number of errors were recorded and analysed. Task 2 involved viewing a picture of
      12 objects during 3 s, followed by a list of 24 words. The subject was required
      to select words representing previously presented objects. In task 3, an array of
      letters in 10 rows (60 in each row) was presented, and the subject was required
      to identify all examples of a particular two-letter combination. RESULTS: The
      results of tasks 1 and 3 showed a significant increase in variances of errors
      (p<0.05) in the exposed versus the sham-exposed group. The results of task 2
      indicated a significant decrease in errors (p<0.05) in the exposed group.
      CONCLUSIONS: The data provide additional evidence that acute low-level exposure
      to microwaves modulated at 7 Hz can affect cognitive processes such as attention
      and short-term memory.

PMID- 12465660
TI  - Problems in scoring radiation-induced chromatid breaks. Comments on the paper:
      The XRCC2 human repair gene influences recombinational rearrangements leading to
      chromatid breaks.

PMID- 12465661
TI  - Some limitations of the application of the NTCP model describing the response of
      organs with 'relatively serial' structure.

PMID- 12465662
TI  - Fractionating the neglected space: the relevance of reference frames for defining
      left and right in spatial neglect.

PMID- 12465663
TI  - Dyslexia and the cerebellar deficit hypothesis.

PMID- 12465664
TI  - Cerebellar abnormalities in developmental dyslexia: cause, correlate or
      consequence?

PMID- 12465665
TI  - Pure retrograde amnesia following a mild head trauma: a neuropsychological and
      metabolic study.
AB  - After a minor closed head injury, a 33-year-old man acquired extensive retrograde
      amnesia (RA) covering the previous ten years and concerning autobiographical,
      semantic and procedural memories. The patient's learning abilities remained
      excellent and he recovered considerable information from his wife, the media and
      personal documents. This relearned information did not, however, provide a sense
      of personal experience in the first weeks. CT and MRI failed to show brain
      damage, but EEG and SPECT examination showed a marked right temporal dysfunction.
      After three months the patient had almost completely recovered from RA.
      Interestingly, a parallel recovery was observed in the second SPECT obtained at
      this period. There was clearly a blockade of retrieval, while the stored engrams
      were probably intact. The mechanisms underlying such a functional amnesia are
      discussed in the light of previous reports of amnesia without brain lesions.

PMID- 12465666
TI  - Multiple reference frames in neglect? An investigation of the object-centred
      frame and the dissociation between "near" and "far" from the body by use of a
      mirror.
AB  - In this single case study of a man (AE) who suffered a right hemisphere stroke we
      showed the co-existence of neglect within different spatial frames: (a) In left
      hemispace and (b) in 'far' versus 'near' space, both as defined from the
      patient's viewpoint, as well as (c) for the left side of an object (as defined
      from an object-centred view). In the experiment, AE's latencies to name the
      colour of two cubes, each located in one hemispace, were measured. In some
      conditions, the cubes were placed on a table but in other conditions each cube
      was held in one hand of an experimenter who could either face the patient or show
      the cubes while her back was turned towards him. One prediction was that AE would
      show longer latencies for cubes in left hemispace; however, if object-centred
      neglect also occurred, then latencies should be even longer for cubes held in the
      experimenter's left hand. In order to reveal the presence of neglect for 'far'
      versus 'near' space, the cubes could also be positioned either near to (i.e.
      reaching distance) or far from the patient (i.e., several metres out of reach),
      by moving the table or the experimenter. Finally, in some conditions, AE looked
      at the cubes into a mirror that was positioned far away from his body. Because
      external objects seen in a mirror can be 'near' the patient's body, the patient
      actually looked at a 'far' location (i.e. the surface of the mirror) to see an
      object that is 'near'. The experiment confirmed the presence of all forms of
      neglect, since AE not only named the colour of a cube seen in his left hemispace
      more slowly than in right hemispace, but latencies increased for a cube held by
      the experimenter in her left hand and in left hemispace (both when the left hand
      was seen directly or as a mirror reflection). Finally, AE's performance was worse
      for 'far' than 'near' locations, when the cubes were physically located near his
      body (i.e., within "grasping" space) but seen in the mirror.

PMID- 12465667
TI  - Evidence for a neuroanatomical difference within the olivo-cerebellar pathway of
      adults with dyslexia.
AB  - Recent behavioural evidence has indicated that cerebellar impairment may be
      strongly associated with dyslexia. Previous neuroanatomical research has shown
      the presence of anomalies within the cerebral cortex of brains of dyslexic
      people. This paper reports equivalent analyses on the cerebella of the same brain
      specimens. Cross sectional areas and cell packing densities of Purkinje cells in
      the cerebellar cortex, and cells in the inferior olivary and dentate nuclei of
      four dyslexic and four control brains were measured using the dissector method. A
      significant difference in mean cell area in medial posterior cerebellar cortex
      was identified, with the dyslexic cells having larger mean area. Furthermore,
      analysis of cell size distributions not only confirmed the significant
      differences in the posterior lobe, with an increased proportion of large neurons
      and fewer small neurons for the dyslexics, but also revealed significant
      differences in the anterior lobe, again with a pattern of more large and fewer
      small cells. Similar distributional differences were seen in the inferior olive.
      No differences were found in the flocculonodular lobe or the dentate nucleus.
      While caution is necessary in generalising from the results given the small
      number of specimens, together with the age difference, the neuroanatomical data
      established here provides further converging evidence of cerebellar abnormality
      in dyslexia.

PMID- 12465668
TI  - Patterns of phonological errors as a function of a phonological versus an
      articulatory locus of impairment.
AB  - We present the case of two aphasic patients: one with fluent speech, MM, and one
      with dysfluent speech, DB. Both patients make similar proportions of phonological
      errors in speech production and the errors have similar characteristics. A closer
      analysis, however, shows a number of differences. DB's phonological errors
      involve, for the most part, simplifications of syllabic structure; they affect
      consonants more than vowels; and, among vowels, they show effects of
      sonority/complexity. This error pattern may reflect articulatory difficulties.
      MM's errors, instead, show little effect of syllable structure, affect vowels at
      least as much as consonants and, and affect all different vowels to a similar
      extent. This pattern is consistent with a more central impairment involving the
      selection of the right phoneme among competing alternatives. We propose that, at
      this level, vowel selection may be more difficult than consonant selection
      because vowels belong to a smaller set of repeatedly activated units.

PMID- 12465669
TI  - The selective impairment of arithmetical procedures.
AB  - The theoretical distinction between arithmetic facts and procedures was first
      made by Groen and Parkman (1972). This was confirmed with a neuropsychological
      single case described by Warrington (1982) who had impaired arithmetical facts
      but well preserved arithmetical procedures. Since this time there have been
      several patients described who showed a selective impairment of arithmetic facts.
      There have also been reports of cases with impaired arithmetical procedures.
      However, there has not yet been a case reported with the selective impairment of
      procedures in the context of intact arithmetic facts. This paper describes a
      patient, SR, with probable Alzheimer's dementia who had well preserved addition,
      multiplication and subtraction facts but who nevertheless had severe difficulties
      with a range of arithmetical procedures such as multidigit sums, decimals and
      fractions. The implications of this case for current theoretical models are
      discussed.

PMID- 12465670
TI  - Asymmetric functional roles of right and left ventromedial prefrontal cortices in
      social conduct, decision-making, and emotional processing.
AB  - The aim of this study was to begin to parse the relative contributions of the
      right and left ventromedial prefrontal cortices (VMPC) in regard to social
      conduct, decision-making, and emotional processing. We hypothesized that the
      right VMPC is a critical component of the neural systems that subserve such
      functions, whereas the left VMPC is not. Seven participants with focal, stable
      unilateral lesions to the right (n = 4) or left (n = 3) VMPC were studied with
      procedures designed to measure social conduct, decision-making, and emotional
      processing and personality. The right-sided participants had profound
      disturbances of social and interpersonal behavior and of the ability to maintain
      gainful employment; they had defective performance and impaired anticipatory skin
      conductance responses during the Gambling Task; most had profound abnormalities
      of emotional processing and personality, and met criteria for "acquired
      sociopathy." By contrast, the left-sided participants had normal social and
      interpersonal behavior; they had stable employment; they performed normally and
      had normal skin conductance responses on the Gambling Task; they had normal
      emotional processing; and their personalities were unchanged from premorbid
      status. The marked deficits in social conduct, decision-making, and emotional
      processing in participants with unilateral right VMPC lesions are reminiscent in
      kind of those that have been reported in connection with bilateral VMPC lesions,
      albeit perhaps of lesser severity. The findings provide preliminary evidence that
      insofar as social, decision-making, and emotional functions are concerned, the
      right-sided component of the VMPC system may be critical, whereas the left-sided
      component may be less important.

PMID- 12465671
TI  - Two cases of functional focal retrograde amnesia with impairment of object use.
AB  - We report on two patients, TH and KN, with focal retrograde amnesia (FRA). Their
      memory loss regarding life events extended to their whole lives, whereas they
      could acquire and retain new information. They also showed prominent deficits in
      production and comprehension of common words. In addition, at least in the
      testing situation, they were impaired in their recognition and use of familiar
      objects. Although both cases of FRA followed an episode that can cause brain
      pathology, MRI revealed no structural abnormality in either patient. Stressful
      situations preceding the onset were evident in KN, but not in TH. We discuss
      their impairments of object knowledge from a neuropsychological perspective, and
      we interpret the etiology of their condition as a functional rather than a
      psychogenic amnesia.

PMID- 12465672
TI  - Recognition of emotion from facial, prosodic and written verbal stimuli in
      Parkinson's disease.
AB  - Although the basal ganglia are thought to be important in recognizing emotion,
      there is contradictory evidence as to whether patients with Parkinson's disease
      (PD) have deficits in recognizing facial expressions. In addition, few studies
      have examined their ability to recognize emotion from non-visual stimuli, such as
      voices. We examined the ability of PD patients and age-matched controls to
      recognize emotion in three different modalities: facial, prosodic, and written
      verbal stimuli. Compared to controls, PD patients showed deficits in recognizing
      fear and disgust in facial expressions. These impairments were not seen in their
      recognition of prosodic or written verbal stimuli. This modality-specific deficit
      suggests that the neural substrates for recognizing emotion from different
      modalities are not fully identical.

PMID- 12465673
TI  - Disentangling the "organic" from the "psychic" was as difficult in 1910 as it is
      today--a commentary on Liepmann (1910).

PMID- 12465674
TI  - Contribution to the understanding of the amnesic symptom complex (Beitrag zur
      Kenntnis des Amnestischen Symptomenkomplexes). 1910 [classical article].

PMID- 12465675
TI  - Why are our similarities so different? A reply to Humphreys and Riddoch.

PMID- 12465676
TI  - Functional retrograde amnesia--mnestic block syndrome.

PMID- 12465677
TI  - Organic retrograde amnesia.

PMID- 12465678
TI  - Mechanisms in 'pure retrograde amnesia': functional, physiological or
      pathophysiological?

PMID- 12465679
TI  - The "psychogenic" versus "organic" conundrum of pure retrograde amnesia: is it
      still worth pursuing?

PMID- 12465680
TI  - Does focal retrograde amnesia exist and if so, what causes it?

PMID- 12465681
TI  - Pure retrograde amnesia exists but what is the explanation?

PMID- 12465682
TI  - What does psychogen mean?

PMID- 12465683
TI  - Diffuse lung disease remains a challenging dilemma for radiologists today despite
      the advances in our imaging technologies.

PMID- 12465684
TI  - Clinical approach to interstitial lung disease.
AB  - The term interstitial lung disease (ILD) encompasses a large variety of entities.
      The clinical diagnosis is often difficult and is a multidisciplinary process.
      Achieving the correct diagnosis often involves 3 elements: a clinical impression,
      radiologic evaluation, and a pathologic opinion. All 3 components play a critical
      role. Frequently, the goal is differentiating idiopathic pulmonary fibrosis (IPF)
      from more treatable entities. This article provides an overview of the input
      provided by the 3 specialties cited earlier, as well as the interrelationship
      among these specialties in the diagnosis of ILD. Additional consideration is
      given to the decision-making process involved in determining when to obtain a
      biopsy specimen from a patient with ILD, and a review of current treatment
      strategies.

PMID- 12465685
TI  - Pathologist's approach to diffuse lung disease.
AB  - The pathologic diagnosis of diffuse lung disease is based on the recognition of
      specific patterns closely correlated with the clinical history and the radiologic
      findings. The current pathologic classification of the idiopathic interstitial
      pneumonias is in flux, with the new creation of cellular and fibrotic subtypes of
      nonspecific interstitial pneumonia and further refinements in the criteria for
      usual interstitial pneumonia, desquamative interstitial pneumonia, and
      respiratory bronchiolitis-associated lung disease. The radiologist plays a
      pivotal role in the diagnosis of these conditions by using high-resolution
      computed tomography. The radiologist also provides an important service by
      guiding the clinician or surgeon, based on the site and extent of disease, in
      obtaining a sample that will provide the pathologist with appropriate diagnostic
      material. This article reviews the current pathologic criteria for the
      classification of idiopathic interstitial pneumonias, smoking-related disorders,
      hypersensitivity pneumonitis, as well as the lymphoproliferative disorder
      lymphocytic interstitial pneumonitis, with a focus on differential diagnoses.

PMID- 12465686
TI  - Radiographic approach to multifocal consolidation.
AB  - Consolidation in the lung is seen on radiographs or computed tomography (CT) as
      increased areas of attenuation that obscure the underlying pulmonary vasculature.
      There are numerous causes of multifocal consolidative opacities. If the symptoms
      are acute (days to weeks), the most common causes include edema, pneumonia, and
      hemorrhage. Depending on the patient's history, signs, and symptoms, the less
      common causes such as radiation pneumonitis or acute eosinophilic syndrome may be
      considered. If the symptoms are more chronic (weeks to months), the differential
      may include alveolar proteinosis, neoplasms such as lymphoma or bronchoalveolar
      cell carcinoma, granulomatous or inflammatory conditions, and lipoid pneumonia.
      In this article, we review and discuss characteristic radiographic and clinical
      findings that can aid the radiologist in prioritizing the differential
      considerations when faced with multifocal parenchymal consolidative disease.

PMID- 12465687
TI  - Approach to ground-glass opacification of the lung.
AB  - There area number of diseases that present with ground-glass opacification of the
      lung as a primary manifestation on chest radiography and thin-section computed
      tomography (CT). These diseases cannot be clearly categorized into the classic
      classification scheme of airspace and interstitial disease because there are
      features of both categories seen in the imaging and histologic findings. Ground
      glass opacification has, therefore, been categorized as nonspecific by many
      radiologists. The fact that both the airspaces and interstitial tissues are often
      involved should have little importance when evaluating radiographs or high
      resolution CT (HRCT) images. The role of the radiologist is evolving and is
      becoming more significant in the clinical evaluation of a patient presenting with
      so-called interstitial lung disease. In this article, an approach is described
      that hopefully will lead to an effective and narrow differential diagnosis when a
      radiologist is confronted with ground-glass opacification. The critical features
      in evaluating such cases include: (1) the duration of clinical symptoms; (2) the
      presence or absence of lung fibrosis, especially honeycombing; (3) the patient's
      history of smoking; and (4) the distribution of the disease. Each of these
      features is considered in this article in conjunction with the diseases that lead
      to ground-glass opacification. The recent thinking regarding nonspecific
      interstitial pneumonia and usual interstitial pneumonia also is discussed.

PMID- 12465688
TI  - Radiographic evaluation of diffuse interstitial lung disease: review of a dying
      art.
AB  - The chest radiographic interpretation of interstitial lung disease is discussed
      by using a pattern approach. Patterns discussed are the Peripheral Reticular,
      Linear, Cystic, Nodular, and Ground-glass. The radiographic characteristics of
      each pattern are described, and the causes of each pattern are reviewed with
      attention to their usual clinical presentation. An understanding of the
      characteristic radiographic manifestations of various interstitial lung diseases
      can lead to improved diagnosis.

PMID- 12465689
TI  - The radiological spectrum of small-airway diseases.
AB  - The small airways of the lungs are an often misunderstood and confusing anatomic
      location teeming with an array of similar-appearing disease processes that can be
      daunting even to the most experienced radiologist. This article shows that an
      understanding of small-airway anatomy and accurate pattern recognition can allow
      one to determine useful clinical differential diagnoses. The ability to recognize
      mosaic lung attenuation, and the presence of centrilobular nodules and reticular
      opacities (tree-in-bud), with or without ground glass, is of critical importance
      in evaluating this portion of the lung. In addition, we attempt to further show
      how high-resolution computed tomography (HRCT) scanning has opened the deep
      recesses of the lung to the thoracic radiologist, allowing for a more meaningful
      radiologic contribution to the clinical care of patients with unexplained
      pulmonary symptomatology.

PMID- 12465690
TI  - Distribution of lung disease.
AB  - Radiologists rely on imaging patterns to arrive at a diagnosis. The different
      morphological patterns in the lungs are well known, but less emphasis has
      traditionally been placed on the pattern of distribution. This important feature
      greatly assists in the differential diagnosis regarding many pulmonary diseases
      and is the focus of this article. Chest radiographs often result in a narrow
      differential if one understands the regional differences and microenvironments
      within the lung and takes into consideration the ancillary imaging findings. High
      resolution computed tomography offers additional information at the level of the
      secondary pulmonary lobule to fine-tune the distribution pattern and,
      consequently, the differential diagnosis. Disease distribution is often as
      important as the morphologic appearance of the disorder. This article will
      approach pulmonary diseases from the perspective of distribution patterns,
      highlighting the more common patterns. The goal of this review article is to give
      radiologists a conceptual framework that may be applied in their daily work
      environment.

PMID- 12465691
TI  - A categorical approach to thoracic imaging.

PMID- 12465692
TI  - How well do general practitioners deliver palliative care? A systematic review.
AB  - General practitioners (GPs) deliver the majority of palliative care to patients
      in the last year of life. This article seeks to examine the nature of GP care,
      perceptions of the GPs themselves and others of that care, the adequacy of
      palliative care training, issues relating to accessibility of GPs to palliative
      care patients, and strategies that may be of use in encouraging more effective
      delivery of palliative care by GPs. Medline and PubMed databases from 1966 to
      2000 were searched, and 135 references identified. Sixty-six of these described
      studies relevant to GP palliative care. GPs value this part of their work. Most
      of the time, patients appreciate the contribution the GP makes to palliative care
      particularly if the GP is accessible, takes time to listen, allows patient and
      carer to ventilate their feelings, and is seen to be making efforts made
      regarding symptom relief. However, reports from bereaved relatives suggest that
      palliative care is performed less well in the community than in other settings.
      GPs express discomfort about their competence to perform palliative care
      adequately. They tend to miss symptoms which are not treatable by them, or which
      are less common. However, with appropriate specialist support and facilities, GPs
      have been shown to deliver sound and effective care. GP comfort working with
      specialist teams increases with exposure to this form of patient management, as
      does the understanding of the potential other team members have in contributing
      to the care of the patient. Formal arrangements engaging GPs to work with
      specialist teams have been shown to improve functional outcomes, patient
      satisfaction, improve effective use of resources and improve effective physician
      behaviour in other areas of medicine. Efforts by specialist services to develop
      formal involvement of GPs in the care of individual patients, may be an effective
      method of improving GP palliative care skills and appreciation of the roles
      specialist services can play.

PMID- 12465693
TI  - Analyses of nursing home residents in hospice care using the minimum data set.
AB  - OBJECTIVE: To present comprehensive profiles of residents in hospice care at
      admission to the nursing home using the Minimum Data Set (MDS). DESIGN AND
      SETTING: We analysed 40,622 MDS admission assessments for nursing home residents
      in hospice care. The MDS contains resident-focused data on pain, cognitive
      patterns, physical function, disease diagnoses, medications, nutrition, and
      specific treatments received. RESULTS: About four in five recently admitted
      hospice residents had 'do not resuscitate' orders and only 27% had a living will.
      Over 70% of recently admitted hospice residents experienced pain, with almost one
      half experiencing daily pain. Over one half of those hospice residents in pain
      experienced moderate pain and almost one third experienced horrible or
      excruciating pain. About 57% of recently admitted hospice patients had cancer, 21
      % had congestive heart failure, 20% had emphysema/chronic obstructive pulmonary
      disease, and 18% had depression. About one in two recently admitted hospice
      residents exhibited at least moderate impairment in cognitive function.
      CONCLUSIONS: There is a need to improve pain management, advanced directives, and
      mental health services for residents dying in nursing homes.

PMID- 12465694
TI  - The provision of palliative care in nursing homes and residential care homes: a
      survey of clinical nurse specialist work.
AB  - The provision of end-of-life care within nursing and residential care homes is of
      concern to policy makers and specialist palliative care providers. There is
      evidence of an increasing number of initiatives involving clinical nurse
      specialists (CNS) with the care of residents within these care settings, but the
      extent to which this is occurring in the UK has not been documented. A survey of
      730 community CNS in palliative care was undertaken to describe the extent to
      which these practitioners are involved with the care of residents in nursing and
      residential care homes and the nature of this work. Although 92% of the CNS
      surveyed had worked with nursing homes and 80% of the CNS with residential care
      homes, the responses showed that this work was primarily reactive and undertaken
      infrequently. The majority of the work undertaken by CNS involved caring for
      patients with malignant conditions with a clinical focus addressing the
      management of physical symptoms.

PMID- 12465695
TI  - Differences in assessment of symptoms and quality of life between patients with
      advanced cancer and their specialist palliative care nurses in a home care
      setting.
AB  - This study examined differences in the assessment of symptoms and quality of life
      (QoL) between patients with advanced cancer living at home and their specialist
      palliative care nurses. Nurses introduced a recently validated outcome measure,
      the Palliative Care Outcome Scale (POS), to patients referred to their hospice at
      their first or second home visit. The POS has two components: a patient
      questionnaire mirrored almost exactly by a staff questionnaire, which are both
      completed independently. The POS contains 10 core questions examining aspects of
      symptom control and QoL. Of the 338 patients referred during the study period,
      174 (51%) were eligible for inclusion in the study. Of these, 55 (32%) pairs of
      patient and nurse questionnaires were returned and suitable for assessment. Not
      all questionnaires were returned by nurse and patient to form a matched pair.
      There was good agreement and correlation between patients and nurses in the
      assessment of pain and symptom control. However, important differences were found
      in other areas explored including anxiety levels of patients and their families,
      personal thoughts, practical matters and information received. The study confirms
      the importance of evaluating the needs, feelings and concerns of patients with
      advanced cancer cared for at home and highlights both the significance and
      necessity of the patient's contribution to any such assessment.

PMID- 12465696
TI  - Deaths from heart failure in general practice: implications for palliative care.
AB  - Trial and observational research indicates a high one-year mortality with a
      significant potential for specialist palliative care for patients with heart
      failure. A community observational study was undertaken in two general practices,
      with a total population of 21,000. There were three objectives: to determine the
      prevalence of symptomatic heart failure, to document mortality in the cohort over
      six and 12 months, and to establish the population in which a palliative care
      approach was adopted. A search of the computerized medical records yielded 548
      patients with symptomatic heart failure (2.6% of the total study population).
      Over a six-month period, 31 patients (6% of the cohort) died and over a 12-month
      period 64 patients (12% of the cohort) died. 'Sudden death' was recorded in the
      records of 14 patients and death from coexisting malignancy was recorded in seven
      patients. A palliative care approach in patients not dying suddenly or of
      malignancy was recorded in 21 cases (33% of the total deaths). The findings do
      not indicate a high mortality in patients with symptomatic heart failure in
      general practice. The role of specialist palliative care in many cases would
      appear to be limited by the difficulty in predicting prognosis. In a significant
      number of cases, general practitioners appear to be aware of the need for a
      palliative care approach in patients dying of heart failure.

PMID- 12465697
TI  - Loss of weight and loss of appetite in advanced cancer: a problem for the
      patient, the carer, or the health professional?
AB  - This paper aims to examine the loss of weight and loss of appetite as 'problems'
      experienced by patients with advanced cancer and those that care for them. It
      reports the results of a systematic search of the literature and presents the
      findings as a narrative review. Research to date has focused upon charting the
      prevalence and incidence of these symptoms, but little empirical work has been
      conducted to investigate how patients and carers experience these problems. There
      is some evidence to suggest that anorexia may be more distressing for those
      caring for the patient than the person suffering from the symptom itself.
      Understanding the reason for this anguish requires an appreciation of the meaning
      of food refusal and constitutes the first step towards informing the development
      of effective interventions. Such exploratory work is mandatory if health
      professionals wish to move beyond speculation and deliver interventions that
      provide meaningful benefits for the cancer patient and their family.

PMID- 12465698
TI  - An assessment of the efficacy and tolerability of a 'double dose' of normal
      release morphine sulphate at bedtime.
AB  - This study was a prospective, randomized, open, crossover study comparing a
      double dose (DD) of normal-release (NR) morphine at bedtime with a single dose
      (SD) of NR morphine at bedtime and 4 h later. Twenty patients completed the
      study. Four patients required breakthrough analgesia during the SD phase of the
      study, whilst 11 patients required breakthrough analgesia during the DD phase of
      the study (P = 0.01 6). Moreover, all of the pain scores were worse during the DD
      phase (overnight pain, P < 0.01; morning pain, P < 0.01), and some of the opioid
      related side effect scores were worse during the DD phase (xerostomia, P = 0.033;
      vivid dreams, P = 0.05). This study does not support the European Association for
      Palliative Care (EAPC) recommendations on the use of a double dose of NR morphine
      at bedtime.

PMID- 12465699
TI  - Self-reports are not related to objective assessments of cognitive function and
      sedation in patients with cancer pain admitted to a palliative care unit.
AB  - Cancer patients often report complaints of cognitive impairment and sedation. It
      is not well known if subjective complaints reflect objective assessments of
      cognitive function (CF) and sedation. We obtained self-reports of sedation and CF
      from 29 patients admitted to a palliative care unit and receiving morphine
      treatment. Sedation was reported on a verbal rating scale (VRS) and CF was
      reported using the EORTC QLQ-C30 health-related quality-of-life questionnaire CF
      scale. The self-reports were compared with objective assessments of sedation and
      CF by applying the Observer's Assessment of Alertness/Sedation (OAA/S) scale and
      Mini Mental State Examination (MMS), respectively. The assessments were repeated
      for seven patients who were readmitted to the palliative care unit. The patient
      self-reports of memory, concentration and sedation were dichotomized into
      noncomplainers and complainers. The percentages of complainers were 54%, 46% and
      37% for memory, concentration and sedation, respectively. Patients who complained
      from difficulties with concentration or memory did not score differently from
      noncomplainers on objective assessments of CF (MMS score), but had a
      significantly higher level of fatigue. Patients complaining from sedation did not
      score differently from noncomplainers on objective assessments of sedation (OAA/S
      score). We observed no significant correlations between EORTC QLQ-C30 CF scale
      scores and MMS scores, or between VRS sedation scores and OAA/S scores. The study
      demonstrates a lack of relationship between patient self-reports and objective
      methods for assessing sedation and cognitive failure. This finding illustrates
      the importance of differentiating between observations and patient self-reports.
      The results also question the validity of patient self-reports for measurements
      of cognitive failure and sedation.

PMID- 12465700
TI  - Palliative venting gastrostomy in malignant intestinal obstruction.
AB  - This retrospective clinical study reports on the experience of palliative venting
      gastrostomy (PVG) in an integrated acute teaching hospital and hospice-based
      palliative care service over a seven-year period (1989-97). PVG was performed for
      51 patients with refractory nausea and vomiting resulting from varying degrees
      and levels of persisting or intermittent malignant bowel obstruction. There were
      32 females and 19 males; the mean age was 61 years (range 25-86 years). All
      patients had advanced and incurable cancer with intra-abdominal spread,
      originating from the following primary sites: colon and rectum (27), ovary (16),
      breast (2), pancreas (2), and other (4). The venting gastrostomy tube was
      inserted endoscopically by a railroading technique in 46 patients (using a 16- to
      20-French Dobhoff PEG tube), at open laparotomy in four cases and under
      radiological (abdominal computerized tomography) control in one case. Endoscopic
      insertion was attempted and abandoned for technical reasons in a further two
      cases. The median survival of all 51 patients from the time of gastrostomy
      insertion was 17 days (range 1-190). In 47/51 (92%), the symptoms of nausea and
      vomiting were relieved by the procedure, and these patients experienced
      restoration of some level of oral soft food and fluid intake. Twenty patients
      were discharged home, and six died at home. In a small group of highly selected
      patients, for whom pharmacological measures failed to palliate the effects of
      malignant bowel obstruction, PVG was shown to be a safe and effective means of
      abolishing or substantially improving vomiting. Provided that the intervention is
      appropriate to the given clinical situation and acceptable to the patient, it
      should be considered.

PMID- 12465701
TI  - Resistance amongst yeasts isolated from the oral cavities of patients with
      advanced cancer.
AB  - The aim of this study was to determine the prevalence of in vitro resistance
      amongst yeasts isolated from the oral cavities of patients with advanced cancer.
      The National Committee for Clinical Laboratory Standards' broth microdilution
      method was used to determine the sensitivities to fluconazole, itraconazole,
      ketoconazole, and nystatin, whilst the Etest method was used to determine the
      sensitivity to amphotericin B. The prevalence of in vitro resistance was:
      amphotericin B, 2%; fluconazole, 8%; itraconazole, 22%; ketoconazole, 7%;
      nystatin, 0%. Moreover, 28% of the yeasts was resistant to one or more of the
      azole group of anti-fungal drugs. The results of this study suggest that azole
      resistance may become a clinical problem in palliative care.

PMID- 12465702
TI  - Palliative physicians persuade procurators fiscal.
AB  - Mesothelioma caused by occupational exposure to asbestos is well recognized and
      sufferers who have been employed in a prescribed occupation can claim
      compensation. Stringent criteria must be fulfilled in order to establish the link
      between occupational exposure and mesothelioma, and to this end the procurator
      fiscal is involved after the patient's death, both to elucidate the individual
      situation and 'for the common good'. Problems were experienced locally by the use
      of uniformed police officers, as the appointed Crown agents, as interviewers of
      recently bereaved relatives, irrespective of the degree of tact and sensitivity
      shown. The likelihood of an autopsy was also distressing. It is important to
      recognize the role of the procurator fiscal and to ensure that workers'
      compensation procedures exist and are followed. However, in order to minimize
      grief and distress to relatives, discussion took place with the local procurator
      fiscal. He was appreciative of the issues raised and practice has now changed
      substantially. In particular, police officers are no longer required to interview
      relatives either for the purpose of identification or to ascertain the deceased's
      occupational history. A pro forma has been produced and agreed locally to obviate
      the need for medical staff to be interviewed by police officers. Following
      subsequent discussion with the Crown Office our local arrangements have been
      incorporated in Crown Office guidance for national use.

PMID- 12465703
TI  - Religious faith and support at the end of life: a comparison of first generation
      black Caribbean and white populations.

PMID- 12465704
TI  - Artificial hydration during the last week of life in patients dying in a district
      general hospital.

PMID- 12465705
TI  - A pilot study to evaluate the effect of reflexology on mood and symptom rating of
      advanced cancer patients.

PMID- 12465706
TI  - Do we need palliative care audit in developing countries?

PMID- 12465707
TI  - Novel use of L-dOPA in the treatment of anorexia and asthenia associated with
      cancer.

PMID- 12465708
TI  - Resuscitation or not?

PMID- 12465709
TI  - The use of fentanyl and alfentanil sprays for episodic pain.

PMID- 12465710
TI  - "Power quality system," a new system of quality management for globalization:
      towards innovation and competitive advantages.
AB  - Knowledge Management (KM) addresses the critical issues of organizational
      adoption, survival and competence in the face of an increasingly changing
      environment. KM embodies organizational processes that seek a synergistic
      combination of the data and information processing capabilities of information
      and communication technologies (ICT), and the creative and innovative capacity of
      human beings to improve ICT In that role, knowledge management will improve
      quality management and avoid or minimize losses and weakness that usually come
      from poor performance as well as increase the competitive level of the company
      and its ability to survive in the global marketplace. To achieve quality, all
      parties including the clients, company consultants, contractors, entrepreneurs,
      suppliers, and the governing bodies (i.e., all involved stake-holders) need to
      collaborate and commit to achieving quality. The design based organizations in
      major business and construction companies have to be quality driven to support
      healthy growth in today's competitive market. In the march towards vision 2020
      and globalization (i.e., the one world community) of many companies, their design
      based organizations need to have superior quality management and knowledge
      management to anticipate changes. The implementation of a quality system such as
      the ISO 9000 Standards, Total Quality Management, or Quality Function Deployment
      (QFD) focuses the company's resources towards achieving faster and better results
      in the global market with less cost. To anticipate the needs of the marketplace
      and clients as the world and technology change, a new system, which we call Power
      Quality System (PQS), has been designed. PQS is a combination of information and
      communication technologies (ICT) and the creative and innovative capacity of
      human beings to meet the challenges of the new world business and to develop high
      quality products.

PMID- 12465711
TI  - Accreditation at the US EPA-NEIC. National Enforcement Investigations Center.
AB  - The US Environmental Protection Agency-National Enforcement Investigations Center
      (NEIC) of Denver, Colorado is the specialty technical arm of the Office of
      Enforcement and Compliance Assurance (OECA) within the US EPA. NEIC is a center
      for technical support nationwide to state, local, tribal, and federal
      environmental enforcement and compliance assurance programs. NEIC is a source of
      expertise for technical analysis, compliance monitoring, engineering evaluations,
      forensic laboratory activities, information management, computer forensics, and
      witness testimony. Effective 1 February 2001, NEIC was granted accreditation for
      overall environmental measurement activities that include field sampling, field
      measurements and monitoring, and laboratory measurements. NEIC became the first
      and only environmental forensic center in the United States to be granted this
      type of accreditation. The accreditation criteria incorporates nationally and
      internationally accepted forensic and quality management standards. Awarded by
      the National Forensic Science Technology Center (NFSTC), the NEIC Accreditation
      Standard was developed for conducting environmental measurements while adhering
      to forensic requirements in specific areas. The NEIC Accreditation Standard is
      based on ISO/IEC Guide 25 and ANSI/ASQC E4-1994, and it references specific
      aspects of the American Society of Crime Laboratory Directors/Laboratory
      Accreditation Board (ASCLD/LAB) Manual.

PMID- 12465712
TI  - Can non-regulators audit Independent Ethic Committees (IEC), and if so, how?
AB  - A number of guidelines and directives have reinforced the need for a more
      formalised approach to Independent Ethic Committees (IECs) and support the need
      to audit IECs. The key elements of an audit of an IEC are reviewed within the
      context of the European Guidelines for Auditing Independent Ethics Committees
      published by the European Forum for Good Clinical Practice (EFGCP). Auditing
      requirements in these recent guidelines and the EU Clinical Trial Directive are
      discussed as well as the methodology and type of documentation and SOPs that
      should be present at an audit. It is argued that both inspectorates and
      independent auditors need to conduct such audits to improve the overall global
      standard.

PMID- 12465713
TI  - A new insight into the Taguchi method.
AB  - To obtain high quality products at low cost and in a short time is an economical
      and technological challenge to today's engineering community. Design of
      Experiments based on the Taguchi approach is a powerful technique to attain this
      objective. In some processes, it is necessary to consider not only two factors
      but also the ratio of their levels 'as a factor.' This paper introduces a new
      look at the Taguchi method that makes it possible, by choosing the proper levels,
      to evaluate the ratio of two factors as a new factor in the same orthogonal
      array. An experiment to study four three-level factors was designed, and a case
      study is presented to illustrate the ratio of the two three-level factors as a
      new factor using the same L9 orthogonal array.

PMID- 12465714
TI  - Cloning of cellulose synthesis related genes from Acetobacter xylinum ATCC23769
      and ATCC53582: comparison of cellulose synthetic ability between strains.
AB  - About 14.5 kb of DNA fragments from Acetobacter xylinum ATCC23769 and ATCC53582
      were cloned, and their nucleotide sequences were determined. The sequenced DNA
      regions contained endo-beta-1,4-glucanase, cellulose complementing protein,
      cellulose synthase subunit AB, C, D and beta-glucosidase genes. The results from
      a homology search of deduced amino acid sequences between A. xylinum ATCC23769
      and ATCC53582 showed that they were highly similar. However, the amount of
      cellulose production by ATCC53582 was 5 times larger than that of ATCC23769
      during a 7-day incubation. In A. xylinum ATCC53582, synthesis of cellulose
      continued after glucose was consumed, suggesting that a metabolite of glucose, or
      a component of the medium other than glucose, may be a substrate of cellulose. On
      the other hand, cell growth of ATCC23769 was twice that of ATCC53582. Glucose is
      the energy source in A. xylinum as well as the substrate of cellulose synthesis,
      and the metabolic pathway of glucose in both strains may be different. These
      results suggest that the synthesis of cellulose and the growth of bacterial cells
      are contradictory.

PMID- 12465715
TI  - Evolutionary re-organisation of a large operon in adzuki bean chloroplast DNA
      caused by inverted repeat movement.
AB  - We have sequenced two sections of chloroplast DNA from adzuki bean (Vigna
      angularis), containing the junctions between the inverted repeat (IR) and large
      single copy (LSC) regions of the genome. The gene order at both junctions is
      different from that described for other members of the legume family, such as
      Lotus japonicus and soybean. These differences have been attributed to an
      apparent 78-kb inversion that spans nearly the entire LSC region and which is
      present in adzuki and its close relative, the common bean. This 78-kb
      rearrangement broke the large S10 operon of ribosomal proteins into two smaller
      operons, one at each end of the LSC, without affecting the gene content of the
      genome. It disrupted the physical and transcriptional relationship between the
      six-gene rpl23-rpl14 cluster and the four-gene rps8-rpoA cluster that is
      conserved in most land plants. Analysis of the endpoints of the rearrangement
      indicates that it probably occurred by means of a two-step process of expansion
      and contraction of the IR and not by a 78-kb inversion.

PMID- 12465716
TI  - Search for and analysis of single nucleotide polymorphisms (SNPs) in rice (Oryza
      sativa, Oryza rufipogon) and establishment of SNP markers.
AB  - We searched for SNPs in 417 regions distributed throughout the genome of three
      Oryza sativa ssp. japonica cultivars, two indica cultivars, and a wild rice (O.
      rufipogon). We found 2800 SNPs in approximately 250,000 aligned bases for an
      average of one SNP every 89 bp, or one SNP every 232 bp between two randomly
      selected strains. Graphic representation of the frequency of SNPs along each
      chromosome showed uneven distribution of polymorphism-rich and -poor regions, but
      little obvious association with the centromere or telomere. The 94 SNPs that we
      found between the closely related cultivars 'Nipponbare' and 'Koshihikari' can be
      converted into molecular markers. Our establishment of 213 co-dominant SNP
      markers distributed throughout the genome illustrates the immense potential of
      SNPs as molecular markers not only for genome research, but also for molecular
      breeding of rice.

PMID- 12465717
TI  - Universal fluorescent labeling (UFL) method for automated microsatellite
      analysis.
AB  - We have devised a novel method for automated microsatellite analysis using
      "universal" fluorescent labeling. This system is based on polymerase chain
      reactions driven by sequence-specific primers and a reporter primer labeled with
      a fluorescent dye at its 5' end. The forward sequence-specific primer is designed
      with a tag region bearing no homology to any human genomic sequence.
      Complementary tag sequences act as templates for the 6-carboxyfluorescein-labeled
      reporter primer, and those products can be analyzed with an autosequencer. The
      results we achieved with this assay system were consistent with the results of
      conventional assays using radioisotope-labeled primers, and diagnosis required
      less time. Furthermore, the fluorescent-labeled reporter primer is "universal" in
      that it can be used with different sequence-specific primers designed to carry
      the appropriate tag sequence at their 5'-ends. Our observations suggest that the
      "universal" fluorescent labeling method is an efficient tool for analyzing
      sequence variations in human DNA.

PMID- 12465718
TI  - Prediction of the coding sequences of mouse homologues of KIAA gene: I. The
      complete nucleotide sequences of 100 mouse KIAA-homologous cDNAs identified by
      screening of terminal sequences of cDNA clones randomly sampled from size
      fractionated libraries.
AB  - We have been conducting a human cDNA project to predict protein-coding sequences
      in long cDNAs (> 4 kb) since 1994. The number of these newly identified human
      genes exceeds 2000 and these genes are known as KIAA genes. As an extension of
      this project, we herein report characterization of cDNAs derived from mouse KIAA
      homologous genes. A primary aim of this study was to prepare a set of mouse. KIAA
      homologous cDNAs that could be used to analyze the physiological roles of KIAA
      genes in mice. In addition, comparison of the structures of mouse and human KIAA
      cDNAs might enable us to evaluate the integrity of KIAA cDNAs more convincingly.
      In this study, we selected mouse KIAA-homologous cDNA clones to be sequenced by
      screening a library of terminal sequences of mouse cDNAs in size-fractionated
      libraries. We present the entire sequences of 100 cDNA clones thus selected and
      predict their protein-coding sequences. The average size of the 100 cDNA
      sequences reached 5.1 kb and that of mouse KIAA-homologous proteins predicted
      from these cDNAs was 989 amino acid residues.

PMID- 12465719
TI  - Microscopic colitis: a clinical and pathological review.

PMID- 12465720
TI  - Gastro-oesophageal reflux in obese subjects: influence of overweight, weight loss
      and chronic gastric balloon distension.
AB  - BACKGROUND: Gastro-oesophageal reflux is an obesity-related health risk assumed
      to improve after weight loss. Prolonged intragastric balloon distension might
      oppose this. The purpose of the study was to investigate the prevalence of gastro
      oesophageal reflux in untreated obese subjects and to study the consequences of
      weight loss with or without intragastric balloon treatment. METHODS: Patients
      participating in a randomized double-blind, sham-controlled trial received
      balloon or sham treatment for the first 13 weeks. Thereafter, all subjects
      received a balloon for the remaining year. Twenty-four-hour pH recordings were
      made at the start, after 13 weeks of balloon or sham treatment, after 26 and 52
      weeks of balloon treatment and 13 weeks after balloon removal. RESULTS: Group
      wise, pH data of 42 untreated patients (BMI 43.4 kg/m2) were highly abnormal. On
      an individual level, 22 subjects (52%) had some evidence of reflux, 17 patients
      (40%) showed pathological total reflux times and 8 (19%) had combined total,
      upright and supine reflux with grade B reflux oesophagitis in only one patient.
      Albeit poorly, oesophageal acid exposure was related to body weight and visceral
      fat distribution. A reduction in acid reflux was observed in sham-treated weight
      losing subjects, whereas in balloon-treated subjects supine reflux and duration
      of the longest reflux increased. In the second 13-week period, the initially
      improved pH values worsened by balloon placement in sham-treated subjects. Values
      in balloon-balloon-treated subjects stabilized. After 52 weeks, acid reflux
      levelled off at pretreatment values and further improved after balloon removal.
      At these times, decreased visceral fat masses correlated significantly with
      diminished oesophageal exposure to acid. CONCLUSIONS: Obesity predisposed to
      gastro-oesophageal reflux. Body weight loss and, strikingly, visceral fat loss
      resulted in improved reflux parameters. Adverse effects on acid reflux by gastric
      balloon distension wore off over time.

PMID- 12465721
TI  - Studies on the relationship between esophageal acid exposure, mucosal lesions and
      heartburn using an acid exposure sensor.
AB  - BACKGROUND: In vitro studies of a recently developed acid exposure sensor show
      that the sensor response (SR) to acid <pH 4 is linearly determined by the
      duration and degree of acidity. The aim was to determine whether SR correlates
      with the severity of acid-induced esophageal mucosal lesions and acid-induced
      heartburn. METHODS: HCl pH 1.5 or saline was infused into the feline esophagus
      for 5-20 min. Simultaneously, sensor measurements were performed below the
      infusion port. The histological damage was scored by an independent pathologist.
      In 15 normal subjects, HCl pH 1 was infused into the esophagus and the severity
      of the heartburn (0-5) was scored at 5-min intervals. In 10 subjects who
      experienced heartburn during acid perfusion, initial perfusion with HCl was
      repeated during heartburn induction time minus 5 min, followed by perfusion with
      the subject's own gastric juice, titrated to pH 2; heartburn severity was again
      scored at 5-min intervals. Acid exposure sensors positioned below the infusion
      port were removed at heartburn scores 1, 2 and 3. RESULTS: A good correlation was
      found between SR and the histological score for mucosal damage in the cat
      esophagus (r = 0.64, P < 0.005). There was a good relation between heartburn
      severity score and acid exposure time (r = 0.84, P < 0.001), and a significant
      but weaker relation between heartburn severity and SR. CONCLUSION: In cats, there
      is a good relation between the severity of acid-induced esophageal mucosal
      lesions and SR. In men, there is a significant correlation between the severity
      of acid-induced heartburn and the simultaneously measured SR. Therefore, SR
      measurement has the potential of yielding clinically relevant information in the
      investigation of GERD.

PMID- 12465722
TI  - Long-term stress and Helicobacter pylori infection independently induce gastric
      mucosal lesions in C57BL/6 mice.
AB  - BACKGROUND: Long-term psychological stresses may have a role in the pathogenesis
      of peptic ulcer. However, the interaction between stress and Helicobacter pylori
      infection in the development of peptic ulcer is not established. The aim of this
      study was to elucidate the roles of long-term stress and H. pylori infection in
      the development of gastric mucosal lesions in mice. METHODS: The Sydney strain
      (SS1) of H. pylori was inoculated into the stomach of C57BL/J6 mice. Twelve weeks
      later, mice with or without H. pylori infection were exposed to long-term
      repeated water-immersion-restraint stress (WIRS) for 12 h per day, 3 times per
      week, for 8 weeks. Gastric mucosal lesions were evaluated both macroscopically
      (ulcer index) and microscopically (Updated Sydney System). RESULTS: The long-term
      WIRS induced mild inflammation, oedema, interstitial haemorrhage and superficial
      erosions in the stomach of mice both with and without H. pylori infection. The
      degree of mucosal inflammation or atrophy in H. pylori-infected mice was not
      influenced by the stress. In the mice without H. pylori infection, the ulcer
      index of the stressed mice was greater than that of non-stressed mice (1.66 +/-
      0.39 versus 0.17 +/- 0.08, P = 0.007). In the mice with H. pylori infection, the
      ulcer index (mean +/- s(x)) of the stressed mice was also greater than that of
      non-stressed mice (2.31 +/- 0.59 versus 0.64 +/- 0.22, P = 0.027). CONCLUSIONS:
      The present study showed that long-term stress can induce gastric mucosal
      inflammation and erosions, and this effect may occur independently of H. pylori
      infection.

PMID- 12465723
TI  - Seven-day triple therapy with omeprazole, amoxycillin and clarithromycin for
      Helicobacter pylori infection in haemodialysis patients.
AB  - BACKGROUND: Triple therapy is accepted as the treatment of choice for
      Helicobacter pylori eradication, but there is no consensus on how long the
      therapy should be maintained in haemodialysis (HD(+)) patients. Our aims in this
      study were to evaluate the safety and efficacy of the 7-day triple therapy in
      HD(+) patients. METHOD: Forty-seven HD(+) and 55 HD(-) patients with dyspepsia
      underwent endoscopy. The prevalence of H. pylori was detected by Giemsa stain,
      followed by the urea breath test (UBT). H. pylori(+) patients were scheduled to
      undergo 7-day triple therapy and the success of eradication was investigated by
      UBT. RESULTS: Forty-five (44%) patients were positive for H. pylori. Forty of
      them underwent triple therapy and 39 (98%) patients completed the treatment.
      Eradication was successful in 32 (82%) and unsuccessful in 7 (18%) patients.
      There was no significant difference between these groups in age, gender,
      endoscopic findings or HD, and only previous treatment was significant for
      eradication failure by univariate and multivariate logistic regression analysis.
      Side effects were observed in 2 (15%) of 13 HD(+) and 3 (11%) of 27 HD(-)
      patients, and one HD(-) patient had to stop medication because of severe nausea
      and vomiting. The eradication rate was 93% (28/30) in patients without previous
      treatment. The triple therapy was unsuccessful in 7 patients, and 4 of them again
      underwent 7-day triple therapy, but all resulted in failure. CONCLUSIONS: Seven
      day triple therapy is safe and effective for primary treatment of H. pylori
      infection in both HD(+) and HD(-) patients, but a new treatment is necessary for
      patients with previous treatment.

PMID- 12465724
TI  - Are dyspepsia management guidelines coherent with primary care practice?
AB  - BACKGROUND: Spontaneous physician behaviour can affect guideline applicability,
      implementation strategies and application costs, particularly in relation to
      widespread pathologies chiefly managed by general practitioners (GPs). Of the
      array of dyspepsia management guidelines, the closest to general practice, partly
      owing to proposing committee composition, are the European Society for Primary
      Care Gastroenterology (ESPCG) guidelines. METHODS: To evaluate variability in
      dyspepsia management among GPs in Padua and divergence in spontaneous
      prescriptive behaviour from the ESPCG dyspepsia guideline, we prospectively
      studied the behaviour of 39 GPs over a 3-month period of outpatient activity,
      through questionnaires on each consultation. Test-group representativeness was
      preliminarily defined in terms of antisecretory drug expenditure. RESULTS: 1790
      forms on dyspepsia-related consultations were studied in a population of 51,193
      registered patients; 1264 patients with a history of dyspeptic pathology
      consulted their GP (19% duodenal ulcer (DU), 9% gastric ulcer (GU), 54% gastro
      oesophageal reflux disease (GERD), 32% non-ulcer dyspepsia (NUD), 1%
      cholelithiasis), while 526 patients presented with symptoms of dyspepsia with no
      previous gastroscopy (EGDS) (42% were aged <45 years), of whom 42% had twice
      consulted their GP. Empirical management by prescription of symptomatic drugs was
      the most common procedure in DU (33%), GU (73%) and NUD (74%) relapses.
      Helicobacter pylori eradication therapy was prescribed in only 2% of patients
      with a history of organic or functional dyspepsia. 145 patients with
      uninvestigated dyspepsia were referred for second-level endoscopy and 43 for H.
      pylori testing. Forty-four percent of endoscopies prescribed for uninvestigated
      patients did not comply with the ESPCG guideline; full compliance would have
      determined a 105% rise in endoscopies. Prescriptive variability between GPs was
      high (based on the Goodman-Kruskal (0.41, P < 0.001) and Cramer tests (V = 0.51,
      P < 0.005)) and agreement between observed and expected prescriptions according
      to ESPCG criteria was as low as V = 0.11. On the basis of the most frequently
      observed behaviours, we developed three options of the ESPCG guideline and
      compared them to spontaneous prescriptions. CONCLUSIONS: Highest compliance
      emerged where the clinical approach for all patients with uninvestigated
      dyspepsia was symptomatic therapy at first presentation followed by a different
      attitude at second presentation, setting a higher cut-off age than in the
      guideline (which in our case proved, on mathematical calculation, to be 55
      years).

PMID- 12465725
TI  - Clinical findings and anti-neuronal antibodies in coeliac disease with
      neurological disorders.
AB  - BACKGROUND: Little is known about the clinical and immunological features of
      coeliac disease patients with neurological disorders. In a large series of adult
      coeliac disease patients, we investigated the prevalence of neurological
      disorders and anti-neuronal antibodies, along with the clinical course. METHODS:
      Neurological symptoms were investigated in 160 consecutive patients (120 F, 40 M)
      with biopsy-proven coeliac disease. Anti-neuronal antibodies to central/enteric
      nervous systems were investigated in all neurological patients, 20 unaffected
      ones and 20 controls. RESULTS: Thirteen (8%) patients had neurological disorders,
      including epilepsy (n = 3), attention/memory impairment (n = 3), cerebellar
      ataxia (n = 2), peripheral neuropathy (n = 2), multiple sclerosis (n = 1),
      Moyamoya disease (n = 1) and Steinert's disease (n = 1). No significant
      demographic or clinical differences (gastrointestinal or other gluten-related
      signs) were found between patients with and without neurological involvement. In
      all but 2 of the 13 cases, the neurological disorder preceded diagnosis ofcoeliac
      disease. Neurological symptoms improved or disappeared in 7 patients who started
      a gluten-free diet within 6 months after neurological onset, and in none of 4
      patients who began later. Prevalence of central nervous system anti-neuronal
      antibodies was significantly higher in neurological (61%) than in other patients
      (5%) (P = 0.0007) or controls (0%) (P = 0.00001). CONCLUSIONS: Coeliac disease
      can sometimes present in the guise of a neurological disorder, which may greatly
      improve when a gluten-free diet is started promptly. Therefore, the possible
      presence of coeliac disease needs to be carefully considered in patients with
      cerebellar ataxia, epilepsy, attention/memory impairment or peripheral
      neuropathy.

PMID- 12465726
TI  - Autoantibodies to human tissue transglutaminase: superior predictors of coeliac
      disease.
AB  - BACKGROUND: Using selected sample populations, we compared sensitivity and
      specificity of autoantibodies to guinea pig and human tissue transglutaminase to
      assess if the human antigen is superior for predicting coeliac disease. METHODS:
      Four commercial enzyme-linked immunoassay kits using human tissue
      transglutaminase as antigen were used to measure autoantibody levels in serum
      samples from untreated adult coeliacs (n = 32). They were from a series of 130
      cases diagnosed between 1997 and 1999 and chosen to bias the group towards
      subjects with negative autoantibodies when measured with guinea pig tissue
      transglutaminase as antigen. Samples from 38 control subjects (biased towards
      false-positive levels with guinea pig antigen) were used to compare specificity.
      We also assessed if human antigen kits could differentiate between levels in
      normal subjects and in selective IgA deficiency. RESULTS: Sensitivity for coeliac
      disease in this selected group using the human antigen kits ranged from 88% to
      100%. Three kits showed significantly higher specificity (82%-97%, P < 0.05) than
      the guinea pig antigen kit (71%) for the samples studied. No kit achieved
      complete separation between normal autoantibody levels and lower levels in
      selective IgA deficiency. CONCLUSIONS: All human antigen kits showed
      significantly higher sensitivity for coeliac disease compared to guinea pig
      antigen (P < 0.001). Receiver operating characteristic curves confirmed the
      superior diagnostic accuracy of the human antigen kits.

PMID- 12465727
TI  - Expression of osteopontin (Eta-1) in Crohn disease of the terminal ileum.
AB  - BACKGROUND: The causes of Crohn disease (CD) are still regarded as unknown, but
      impaired mucosal immunoregulation with activation of T-helper-1 (Th-1) cytokine
      responses is probably involved and may contribute to the morphological changes.
      We investigated a possible role of osteopontin (Opn) in the pathogenesis of CD.
      This glycoprotein has been suggested to be involved in the generation of Th-1
      type immune responses; moreover, it carries anti-inflammatory activities.
      METHODS: Ileal samples from CD patients--both actively inflamed and inactive
      areas as well as unaffected intestinal specimens from controls (normal ileum)-
      were investigated by Western blot analysis, immunohistochemistry and in situ
      hybridization. RESULTS: In normal gut, Opn was found to be regularly expressed by
      plasma cells (CD 38) and a subset of lamina propria mononuclear cells (MNC) as
      well as by intestinal epithelial cells (IEC). In active CD, immunohistochemistry
      and in situ hybridization analysis revealed a loss of Opn expression by IEC
      adjacent to ulcerative lesions, whereas especially plasma cells (CD 38) in the
      vicinity of such lesions were found to express the molecule. In addition, a
      slight overexpression of Opn protein was found in metaplastic crypts. However,
      quantitative analysis of total Opn protein in the ileal mucosa of CD patients did
      not reveal any difference vis-a-vis control tissues. CONCLUSIONS: The
      constitutive expression of Opn in normal gut indicates that it is involved in
      intestinal immune homeostasis. Downregulation of Opn expression in IEC might
      favour the disintegration of the epithelial barrier. The expression of Opn in
      lamina propria plasma cells could contribute to disease chronification, probably
      by affecting cell survival.

PMID- 12465728
TI  - CTLA4 gene polymorphisms in Dutch and Chinese patients with inflammatory bowel
      disease.
AB  - BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by chronic
      intestinal inflammation as a result of an exaggerated T-cell response. CTLA4, a
      receptor of activated T cells, has an inhibitory function in regulating T-cell
      activation. Since CTLA4 gene polymorphisms have been associated with several
      autoimmune diseases, the aim was to study these gene polymorphisms in patients
      with IBD in two different populations. METHODS: The C-318T polymorphism in the
      promoter region and A+49G polymorphism in exon I of the CTLA4 gene were
      investigated by a PCR-SSP method. We studied 139 unrelated patients with
      ulcerative colitis (UC), 163 patients with Crohn disease (CD) and 174 healthy
      controls of Dutch Caucasian origin as well as 35 patients with UC and 62 healthy
      controls from the Chinese Han population. RESULTS: No significant differences in
      the distribution of allele, genotype and haplotype frequencies were observed
      between C-318T and A+49G gene polymorphisms and IBD in Dutch Caucasians and UC in
      the Chinese Han population. Although the haplotypes of the C-318T and A+49G
      polymorphisms were distributed differently between Dutch Caucasian and Chinese
      Han populations, there were no differences in the subgroups of patients with CD
      classified according to age, localization and behaviour in the Vienna
      classification and in those with UC classified according to age at onset, disease
      extension and presence of colectomy in the Dutch patients. However, the CTLA4-318
      genotype CC was more frequent in patients with CD over 40 years (93%) than in
      younger patients (74%) (P = 0.045). CONCLUSION: C-318T and A+49G CTLA4 gene
      polymorphisms and their haplotypes are not associated in Dutch Caucasian patients
      with IBD and in Chinese patients with UC.

PMID- 12465729
TI  - Siblings and the risk of inflammatory bowel disease.
AB  - BACKGROUND: Environmental exposures in early life have been implicated in the
      aetiology of inflammatory bowel disease (IBD). Siblings are used as proxy markers
      to characterize patterns of exposure relevant to the risk of IBD. METHODS: Some
      15,823 patients with ulcerative colitis and 12,668 with Crohn disease from the
      Swedish In-patient Register were compared with 79,546 and 63,035 controls,
      respectively, in a case-control study. Multiple logistic regression was used to
      investigate associations with older and younger siblings, and adjustment was made
      for sex, year of birth, mother's age, region and, additionally, father's social
      class. RESULTS: Older siblings are associated with a graded increased risk for
      ulcerative colitis (P for trend <0.001) and an adjusted odds ratio of 1.15 (95%
      CI 1.07-1.24) for three or more older siblings. Younger siblings are associated
      with a graded decreased risk for Crohn disease (P for trend <0.001) with an
      adjusted odds ratio of 0.83 (0.76-0.90) for three or more younger siblings. The
      greatest protective association with Crohn disease was seen for younger siblings
      born within 2 years of the subject. Older maternal age is independently
      associated with a decreased risk of Crohn disease, with P for trend <0.001.
      Additional adjustment for social class did not substantially alter the results.
      CONCLUSIONS: Having siblings is associated with the risk and phenotype of
      developing IBD, possibly through their influence on patterns of antigenic
      exposure in early life. The association of maternal age with Crohn disease may
      reflect age-related changes in maternal immune profile.

PMID- 12465730
TI  - Influence of alcohol consumption on the association between serum lipids and
      colorectal adenomas.
AB  - BACKGROUND: There have been no reports that low serum cholesterol levels increase
      the risk of colorectal adenoma, although many studies have shown that they do
      increase the risk of colorectal cancer. Alcohol intake, which is associated with
      a risk of colorectal adenomas, and serum cholesterol levels are closely related.
      The purpose of this study was to evaluate the influence of alcohol consumption on
      the association between serum cholesterol levels and colorectal adenoma. METHODS:
      The subjects were 1,349 male patients who underwent both barium enema examination
      and total colonoscopy. They answered a questionnaire regarding their alcohol
      consumption history, and their blood samples were analysed. The subjects were
      divided into three groups: those with no tumour (with neither adenoma nor
      adenocarcinoma), those with adenoma and those with adenocarcinoma. Among the
      groups, the serum total cholesterol and triglyceride levels were compared in all
      the patients, in the patients who did not drink daily and in the patients who
      did. RESULTS: In all the patients, the serum cholesterol and triglyceride levels
      did not differ between the patients with and those without adenoma. In the daily
      drinkers, the serum cholesterol and triglyceride levels were significantly lower
      in patients with adenoma than in those without. CONCLUSIONS: Significantly lower
      levels of serum cholesterol and triglycerides were found in daily drinkers with
      adenoma than in those without.

PMID- 12465731
TI  - Differentiation of pancreatic tumours by conventional ultrasound, unenhanced and
      echo-enhanced power Doppler sonography.
AB  - BACKGROUND: Echo-enhanced power Doppler sonography (power Doppler sonography
      after injection of a contrast agent) is a non-invasive and increasingly used
      procedure for differentiating between pancreatic tumours. However, the diagnostic
      accuracy of this method compared to conventional ultrasound or unenhanced power
      Doppler sonography has never been investigated in a large prospective controlled
      study. METHODS: 137 patients were included in the study, selected from 190
      consecutive patients with a mean age of 60 years (range 16-85) who presented at
      our department in the period January 1998 through June 2001 with clinical
      suspicion of a pancreatic tumour. Sonography was performed by an experienced
      examiner blind to the patients' clinical diagnoses. The exact diagnosis was based
      on histological evidence from biopsy examination (surgical and fine needle
      biopsy) or on a follow-up of at least 18 months. RESULTS: Of the 137 patients, 47
      had pancreatic cancer; 41 had masses associated with pancreatitis; 17 had
      neuroendocrine tumours; 12 had cystic lesions of the pancreas; and 10 had other
      pancreatic diseases. A normal pancreas was found in 10 patients. The sensitivity
      of echo-enhanced power Doppler sonography with respect to diagnosing pancreatic
      carcinoma was 87% and its specificity 94%. The corresponding values for chronic
      pancreatitis were 85% and 99%, respectively. CONCLUSIONS: Echo-enhanced power
      Doppler sonography has a high sensitivity and specificity in the differential
      diagnosis of pancreatic tumours. However, histology is the standard of reference.

PMID- 12465732
TI  - Renal functional reserve is well maintained in patients with advanced liver
      cirrhosis and ascites.
AB  - BACKGROUND: Glomerular filtration rate (GFR) and effective renal plasma flow
      (ERPF) in healthy humans can be induced by amino acid stimulation. The rise in
      GFR from baseline to maximum is referred to as the renal functional reserve
      (RFR). Recently, we showed that the RFR is preserved in patients with compensated
      cirrhosis despite impaired renal function. In the present study, we evaluated RFR
      in decompensated cirrhotics with ascites. METHODS: Steady-state inulin- and para
      aminohippurate (PAH) clearances were performed at rest and during amino acid
      infusion in 22 patients with decompensated liver cirrhosis and ascites. RESULTS:
      Baseline GFR and ERPF (means +95% confidence intervals) were: GFR 25.2 (21.1
      29.2) ml min(-1), ERPF 266.6 (229.7-303.5). Amino acid infusion significantly
      increased GFR by 67% (38.3-95.8) to 34.6 (29.2-40.0) ml min(-1) (means + (95%
      confidence intervals), P < 0.001) and ERPF by 29% (11.9-46.3) to 326.3 (274.1
      378.5) ml min(-1) (P = 0.002). Renal vascular resistance dropped by 13.4% (3.3
      23.5) from 29.4 (24.8-33.9) mmHg ml(-1) min(-1) to 26.4 (22.0-30.7) mmHg ml(-1)
      min(-1) (P = 0.036). The improved kidney function was accompanied by a decrease
      in systemic aldosterone levels (P < 0.05). CONCLUSION: In patients with liver
      cirrhosis and ascites, amino acid infusion improves kidney function. Trials are
      warranted to test the long-term effects of amino acid infusions in patients with
      hepatorenal syndrome.

PMID- 12465733
TI  - Effects of acute pancreatic duct obstruction on pancreatic perfusion: implication
      of acute pancreatic duct decompression.
AB  - BACKGROUND: Acute pancreatitis can result in pancreatic ischaemia and necrosis.
      Pancreatic duct (PD) obstruction may be the first step causing ischaemia in acute
      pancreatitis. Nitric oxide donors can attenuate acute pancreatitis through
      improvement in compromised pancreatic perfusion (PP). In this study, we
      determined if (1) PD obstruction altered PP and (2) PD decompression or L
      arginine administration reversed this change. METHODS: Fifteen Australian possums
      were randomly assigned to two groups: Animals in group A (n = 6) were subjected
      to 30 min of PD obstruction and 60 min of PD decompression. Animals in group B (n
      = 9) were subjected to 120 min PD ligation and 60 min PD decompression. A subset
      group B (n = 6) were subjected to intravenous L-arginine (100 microg/kg) at the
      end of 120 min of ligation and at the end of PD decompression. The PP (Laser
      Doppler fluxmetry), PD pressure and blood pressure were continuously monitored.
      RESULTS: PD pressure increased from 2.9 +/- 2.5 to 18.1 +/- 4.9 mmHg following PD
      ligation. PP was reduced to 67.1% +/- 4.5% (P<0.01) and 46.2% +/- 7.5% (P<0.001)
      of baseline following 30 and 120 min of PD ligation, respectively. Following 60
      min of PD decompression, PP was restored to 89.1% +/- 13.4% (P<0.02) of the
      baseline in the 30-min group. However, following 120 min PD ligation, PP remained
      depressed. L-arginine administration after 120 min of PD ligation transiently
      increased PP from 46.2% +/- 7.5% to 81.1% +/- 8.6% (P<0.03) of baseline. This
      effect was reproduced if L-arginine was administered at the end of decompression
      (P<0.05). CONCLUSION: In patients with acute pancreatitis due to obstructive
      causes, early decompression of the PD may prevent early pancreatic ischaemia.

PMID- 12465734
TI  - Gastric bile monitoring: an in vivo and in vitro study of Bilitec reliability.
AB  - BACKGROUND: It has been claimed that the combination of bile and hydrochloride
      acid (HCl) has a noxious effect on intestinal mucosa. The aim was to study the
      reliability of the Bilitec 2001 method inmonitoring the presence of bile in
      repeated tests and at different pH and water dilutions. METHODS: 24-h esophageal
      pH and gastric Bilitec monitoring were performed twice with an interval of 6
      weeks in 23 patients with symptomatic gastroesophageal reflux (GER). In vitro
      tests of pH and Bilitec recordings were peformed with different mixtures of bile,
      HCl and water. RESULTS: Gastric bile was present in 37% of the recording time,
      28% during day time and 47% during nights. No significant difference was found
      between the two test occasions. The maximum bile concentration in the stomach was
      significantly lower in patients with severe pathological GER than in those with
      normal GER. When concentrated bile was diluted with the same volume of HCl, the
      pH level fell below 4. The maximum absorption limit with Bilitec in concentrated
      bile was gradually reduced with decreasing pH. The Bilitec technique recorded the
      presence of bile even at a pH of 1.4, but not if the bile was diluted with water
      at a ratio of 1:100 or more. CONCLUSIONS: Bilitec gastric recordings show the
      same clinical result when repeated under standardized conditions. The Bilitec
      technique is not reliable for monitoring the amount and concentration of bile in
      the stomach. Bile reflux cannot be monitored with the pH recording technique.

PMID- 12465735
TI  - Reduced diffusion in liver cirrhosis is related to impairment of protein liver
      synthesis.

PMID- 12465736
TI  - Nimesulide-induced severe hemolytic anemia and acute liver failure leading to
      liver transplantation.
AB  - We present the case of a 63-year-old woman who had undergone 7 months of
      treatment with Nimesulide (100 mg/b.i.d.) for symptomatic osteoarthritis. The
      patient was admitted to our unit with a clinical picture of progressive jaundice
      over 3 weeks. Clinical and analytical studies revealed acute liver failure, this
      being confirmed by liver biopsy, which showed submassive necrosis. Serological
      tests for different viral agents causing hepatitis were all negative. In
      addition, she presented a picture of severe haemolytic anaemia resistant to
      several treatments and needed multiple transfusions. Twenty-three days after
      admission, the patient presented hepatic encephalopathy and received an
      orthotopic liver transplant on day 25. The evolution after transplantation was
      good and the patient continues in good health with no evidence of haemolysis
      almost 2 years later. Liver toxicity due to Nimesulide is well known, but to our
      knowledge the occurrence of haemolytic anaemia has not been related to this drug
      previously. For these reasons, Nimesulide has been restricted or removed from the
      market in several countries in recent months.

PMID- 12465737
TI  - Intrahepatic heterogeneity of hepatic venous pressure gradient in human cirrhosis
      again.

PMID- 12465738
TI  - Familial occurrence of microscopic colitis: an opportunity to study the
      relationship between microscopic colitis and coeliac disease?

PMID- 12465739
TI  - Drug-induced liver injury associated with antinuclear antibodies.

PMID- 12465740
TI  - Long-term variability of bone turnover markers in patients with non-metastatic
      breast cancer.
AB  - Variability of bone marker measurements is a major problem in their clinical
      application. Most studies on marker variability have been performed in healthy
      subjects and over relatively short intervals of time. We prospectively evaluated
      the long-term variability of bone markers in 102 postmenopausal women diagnosed
      with primary breast cancer. During follow up (8-48, median 30 mo.), no patient
      developed bone metastases or other skeletal disease. Patients were seen every 3
      months and exactly timed blood/urine specimens were obtained. All analyses were
      performed after study end by the same technician, using a single batch of
      reagents per analyte. The coefficient of variation was calculated as CV (%) =
      square root(sigma(CVi2)/n) (CVi = SD/mean x 100; n = n of CVi). The least
      significant change (LSC) was then LSC (%) = Z x CV x square root(2). Z = 1.96 for
      a 95% confidence interval (LSC-95). In a subset of n = 10 patients with no
      potential interference during follow-up, lowest CVs were recorded for serum (s)
      calcium (5%), sTAP (12%) and sBAP (14%). The LSC-95 for these markers were 14%,
      33% and 39%, respectively. Highest CVs were seen with urine (56%) and serum (42%)
      CTX (LSC-95: 155%, 117% resp.). We conclude that in breast cancer patients
      without bone metastases, long-term variability varied greatly between markers.
      For certain markers, the LSC seems considerably higher than previously reported.

PMID- 12465741
TI  - Markers of bone turnover do not predict bone metastases in breast cancer.
AB  - Markers of bone turnover are often elevated in patients with prevalent bone
      metastases (BM). To test whether bone markers may be used as early indicators of
      developing BM, we prospectively studied 113 women with primary breast cancer. At
      the time of study inclusion, none of the women had BM, skeletal disease or was on
      bone active drugs. During follow-up (8-52, median 30 mo.), pt. were seen every 3
      mo. and blood/urine specimens were obtained. Eleven patients developed BM (BM+)
      and each of them was matched to 4 women remaining free of BM (BM-). Markers were
      serum (s) calcium, sTAP, sBAP, sOC, sPICP, sNTX, sCTX and urinary (u) PYD, uDPD,
      uNTX, uCTX. All analyses were done in single batches after study end. At any
      given point in time, marker levels in the BM+ group did not differ from those in
      the BM- group. Levels at baseline did not predict later BM (OR 0.14-1.01, all
      ns). 93% of all changes in bone markers were below the least significant change,
      as defined in an independent group of similar patients. The remaining 7% of
      values could not be associated in a consistent pattern with the occurrence of BM.
      We conclude that in patients with primary breast cancer, biochemical markers of
      bone turnover can not be used to predict or diagnose incident BM. This lack in
      diagnostic validity is mainly attributable to the high overall and long-term
      variability of the currently used bone markers.

PMID- 12465742
TI  - New assays for intact parathyroid hormone and their clinical relevance for the
      diagnosis of hyperparathyroidism.

PMID- 12465743
TI  - Serum erythropoietin concentrations in patients with anemia--preliminary
      hemoglobin-related reference ranges.
AB  - Serum erythropoietin (EPO) determination is useful in the diagnosis of renal
      anemia. In anemic patients with normal renal function increased EPO
      concentrations are typically found, however, so far hemoglobin-related reference
      ranges for serum EPO had not been established. In a cross-sectional manner we
      determined serum EPO in 280 patients with anemia and normal serum concentrations
      of creatinine and urea. Each 70 consecutive anemic patients with hemoglobin
      concentrations within four intervals were included (<8 g/dL; 8.1-9.0 g/dL; 9.1
      10.0 g/dL; 10.1-11.0 g/dL). 97 patients were from surgical disciplines, 183 were
      from internal disciplines. Serum EPO was determined by use of an automated
      sandwich immunoassay that is standardized according to the WHO 2nd IRP 67/343.
      The ranges between the 20th and 80th percentile of EPO concentrations for the
      four specified hemoglobin intervals were as follows: Hb <8 g/dL, EPO 61.8-366
      IU/L; Hb 8.1-9.0 g/dL, EPO 43.3-242 IU/L; Hb 9.1-10.0 g/dL, EPO 31.8-113 IU/L; Hb
      10.1-11.0 g/dL, EPO 22.3-71.2 IU/L. Since no complete diagnostic evaluation of
      the patients' renal and respiratory functions was performed in this cross
      sectional study we propose the 20th percentile of EPO concentrations as a
      preliminary hemoglobin-related reference range; serum EPO concentrations below
      this percentile speak for a contribution of EPO deficiency in the individual
      etiology of anemia.

PMID- 12465744
TI  - Endogenous regulation of insulin secretion by UCP2.
AB  - Uncoupling protein 2 (UCP2) expression is more-or-less ubiquitous, in tissues of
      diverse function. Its presence in adipose and muscle is postulated to be involved
      in regulation of energy expenditure and nutrient partitioning, particularly that
      of fats. In pancreatic islet beta cells, induction of UCP2 is shown to inhibit
      glucose-stimulated insulin secretion. Thus, insufficient insulin secretion in
      models of type 2 diabetes is associated with elevated UCP2 expression in islets.
      The evidence for such a role for UCP2 in the regulation of insulin secretion in
      islets is reviewed.

PMID- 12465745
TI  - Molecular diagnostics of solid malignant tumours.
AB  - Three groups of genes have been identified which play a major role in determining
      the origin and spread of cancer: Oncogenes support the growth of tumour cells in
      a manner which does not depend on the tissue environment. They occur as proto
      oncogenes in the genome of every cell in the body. If only one allele is
      excessively or inappropriately activated by mutation, they can change the
      phenotype of the cell lastingly and initiate malignant growth. Tumour suppressor
      genes hamper the growth of cells with DNA mutations. Both alleles must be mutated
      in the genome in order to block production of functional protein and to allow
      mutations to be passed on in their DNA to daughter cells. With an existing
      predisposition to cancer, one of the alleles is already mutated. The malignoma
      develops after a mutation occurs in the second allele. Mutator genes are
      responsible for maintaining the integrity of the genome and reliably transmitting
      the genetic code. A functional loss of both alleles increases error rates during
      DNA-replication. This can lead to mutations in oncogenes or tumour suppressor
      genes, and contribute to the origin or spreading of a malignoma. Tumour-modifier
      genes might turn out to be the genetic factors underlying the origin or even
      prevention of malignomas caused mainly by environmental factors. From experiments
      on mice it is known that these genes may be responsible for the incomplete
      penetrance of hereditary tumours. Demonstration of these genes using molecular
      diagnostic procedures will promote opportunities and knowledge in the field of
      oncology.

PMID- 12465746
TI  - IgD myeloma: clinical, biological and laboratory features.
AB  - The study of IgD myeloma remains a challenging field. In terms of the initial
      detection of the IgD paraprotein, great care must be exercised in the
      interpretation of electrophoresis patterns and immunoglobulin profiles.
      Laboratory staff have a very important role to play in this, as it is likely that
      many IgD myeloma cases are uncovered following the involvement of laboratory
      staff. They must help to ensure that suggestive electrophoresis and
      immunoglobulin levels are properly investigated and that Bence Jones myeloma is
      not diagnosed without excluding the presence of an IgD paraprotein. In clinical
      terms, IgD myeloma remains a rare but aggressive tumour affecting younger people
      and with presenting features that include most of those common to all myeloma
      cases. However, renal problems, amyloidosis and the occurrence of Bence Jones
      lambda light chain proteinuria complicate matters to a far greater extent than in
      most other forms of the disease. There are now increasing numbers of case reports
      describing patients with associative symptoms and only time will tell whether
      these relationships are predictive or useful in nature. It is important however,
      given the rarity of the condition, that these cases continue to be reported.
      There do not appear to be any treatment regimes that are specifically tailored
      for IgD myeloma and the response to chemotherapy does not seem to differ from
      other forms of the disease. However, the management of any associated renal
      failure will always remain a challenge, I suspect. The progress being made in the
      treatment of myeloma as a whole, is bound to have a positive impact on the
      treatment of IgD myeloma.

PMID- 12465747
TI  - Leukocyte counts in cerebrospinal fluid with the automated hematology analyzer,
      Technicon H*3.
AB  - BACKGROUND: Presently, the counting of leukocytes in cerebrospinal fluid (CSF) is
      still performed manually. This requires sufficiently experienced medical
      technologists. At present, specific automated systems for CSF cell counting are
      not available. In this study, we evaluated the use of the automated hematology
      analyzer, Technicon H*3 in the analysis of cerebrospinal fluid (CSF). METHODS: We
      tested the hematology analyzer, Technicon H*3, which was not designed for CSF
      analysis. Sixty CSF samples were analyzed by the analyzer, Technicon H*3. Then
      the counts obtained were compared with the manual microscopic method. RESULTS:
      Linearity was tested by both plasma and normal saline solution (NSS). Concerning
      the NSS dilution, a good correlation can be observed at theoretical number of WBC
      > 30 cells/microL and so did the plasma dilution. The results of the comparison
      of both methods used for the determination of total leukocytes in the CSF gave a
      good correlation (r = 0.984). Concerning the determinations of neutrophils and
      lymphocytes, the correlation coefficients were 0.855 and 0.835, respectively.
      CONCLUSIONS: According to our study, the use of this automated analyzer for cell
      counting in CSF is probably feasible. The high degree of accuracy and linearity
      that is offered by the analyzer should prompt us and the manufacturers to remedy
      the interfering factors as described by improving the algorithms. Once this is
      done, these analyzers may be very useful for cell counts in CSF.

PMID- 12465748
TI  - Serum erythropoietin levels in pediatric patients with beta
      thalassemia/hemoglobin E.
AB  - Presently, the assays for serum erythropoietin (EPO) seem valuable tools for
      clinical research, but their roles in routine clinical practice remain undefined.
      Some studies mentioned that serum EPO measurements, which are now easily and
      reliably performed, should be used in monitoring the therapy of beta-thalassemia
      major. Here, we report our experience in the determination of serum EPO in
      children with beta-thalassemia/Hb E and also compared the results with those in
      hemoglobin E trait, beta-thalassemia/Hb E as well as healthy non-anemic controls
      of similar age. Fifty five transfusion-dependent beta-thalassemia/Hb E, fifteen
      hemoglobin E trait, five beta-thalassemia trait cases and twenty five controls
      were studied for their serum EPO levels. The mean (S.D.) EPO concentrations were
      19.94 (17.40) U/L for the controls, 16.13 (8.47) U/L for the hemoglobin E trait,
      24.40 (8.20) U/L for the beta-thalassemia trait and 372.19 (432.04) U/L for the
      beta-thalassemia/Hb E cases. The mean EPO concentration for the normal controls
      was near to that of the hemoglobin E trait (P = 0.06) and beta-thalassemia trait
      (P = 0.25) but eighteen times less than that for the beta-thalassemia major cases
      (P<0.0005).

PMID- 12465749
TI  - How to make things work again--troubleshooting using the GC-IDMS determination of
      triacylglycerols as an example.
AB  - This article describes the process of "repairing" a method which has gone out of
      control, using the gas-chromatographic isotope-dilution mass spectrometric (GC
      IDMS) determination of total glycerides in serum, measured as glycerol. The
      original method used 13C2-glycerol as aqueous internal standard and 12C
      tripalmitin dissolved in toluene as external standard. The modified method used
      tripalmitin as internal and external standard, the former being labelled
      uniformly on the glycerol moiety of tripalmitin (13C3-tripalmitin). In addition,
      glycerol-free human serum albumin was added to the external standards to "trap"
      the glycerol physically during evaporation of the extraction solvent after
      alkaline hydrolysis. The modified method was more stable than the original one
      and the intensity of the MS-signal in the modified method was at least 100 times
      stronger in the external standards than in the original method. The precision of
      the modified method in measuring total glycerides in serum samples (as total
      glycerol) was better than in the original method, the coefficients of variation
      being under 1.5% at concentrations between 0.8 and 3.5 mmol/l.

PMID- 12465750
TI  - Chemoprevention of prostate cancer.
AB  - Chemoprevention is prevention of cancer by administering natural or synthetic
      chemicals. Anti-androgens are among the promising chemopreventive agents for
      prostate cancer because prostate epithelium is androgen dependent. A National
      Cancer Institute supported large, randomized, clinical prostate cancer
      chemoprevention trial has been conducted to test the efficacy of finasteride, an
      inhibitor of 5-a-reductase, which converts testosterone to 5-hydroxy
      testosterone. Now the focus is on micronutrients and phytochemicals, which have
      potential preventive effects against prostate cancer. Lycopene, soy isoflavones,
      vitamin E and selenium are among the most promising nutritional chemopreventive
      agents. Another NCI supported large clinical chemoprevention trial was recently
      started to investigate the efficacy of selenium and vitamin E, alone or in
      combination in the prevention of prostate cancer. Inclusion of appropriate
      biomarkers in clinical trials will help elucidate the mechanisms by which genetic
      and epigenetic pathways of carcinogenesis are modulated by nutrients and
      phytochemicals.

PMID- 12465751
TI  - Prostate brachytherapy.
AB  - Prostate brachytherapy has been practiced for nearly 100 years in various forms.
      However, technological advances over the past 20 years in imaging, computing, and
      devices have propelled this technique into the mainstream of prostate cancer
      treatments. A discussion of radiobiology principles is important to the
      understanding of modern brachytherapy technique. For low risk tumors,
      brachytherapy may be administered as monotherapy. For high risk tumors
      combination therapy with external beam therapy is indicated. Androgenablation
      therapy is used for hormonal downsizing or for select high risk tumors. Diseases
      free survival appears similar to that seen with other definitive therapies for
      clinically localized prostate cancer. The short term morbidity of the procedure
      includes significant obstructive and irritative voiding symptoms. Future
      brachytherapy goals are discussed.

PMID- 12465752
TI  - Fast neutron irradiation for prostate cancer.
AB  - The purpose of this study was to summarize the progress made using fast neutron
      irradiation in the treatment of prostate cancer at Wayne State University between
      1991 and the year 2001. The results of three Phase II studies and one Phase III
      st udy involving nearly 700 patients is summarized in this paper. The Phase II
      studies weredose finding studies looking at doses of 15, 9, 10, and 11 nGy,
      respectively. The randomized protocol was a study of sequence looking at the
      results of treating patients with neutron first versus neutron radiation last.
      The results demonstrated that the best combination of tumor control probabilities
      and normal tissue complications was found in a mix of approximately 50% neutrons
      and 50% photons. Thus, the standard doses become 10 nGy and 40 Gy of photons. The
      randomized trial demonstrated that the sequence has significant importance and
      the disease-free survival was 93% for patients treated with neutrons first versus
      73% for patients treated with neutrons last. There was no difference in the rate
      of acute or chronic complications. Finally, an analysis was performed
      demonstrating which patients may best benefit from the use of neutron
      irradiation. It was shown that patients with one, two, or three adverse risk
      factors had a significant improvement in disease-free survival when part of the
      treatment included neutron radiation versus standard photon radiation alone.
      Neutron radiation can be delivered safely with effort to see that it is superior
      to that which can be achieved by conformal photon irradiation by itself. Future
      work will be done to expand the role of neutron radiation in other clinical
      disease sites.

PMID- 12465753
TI  - Prostate cancer gene therapy: past experiences and future promise.
AB  - Gene therapy has been used to target prostate cancer with excellent pre-clinical
      efficacy but limited clinical efficacy. The concept of delivering genetic
      material to prostate cancer cells to alter their phenotype and ultimately their
      behavior has been demonstrated in the laboratory over the last decade.
      Translating those pre-clinical findings into novel therapies for prostate cancer
      has been difficult. The stigma of gene therapy and the aggressive regulation of
      clinical trials involving transfer of genetic material to patients are two major
      impediments to clinical successes in gene therapy. This review hopes to provide a
      snapshot of prior gene transfer protocol findings and forecast the exciting
      future directions investigators are heading.

PMID- 12465754
TI  - Vitamin D-related therapies in prostate cancer.
AB  - Calcitriol or 1,25-dihydroxycholecalciferol (vitamin D) is classically known for
      its effects on bone and mineral metabolism. Epidemiological data suggest that low
      vitamin D levels increase the risk and mortality from prostate cancer. Calcitriol
      is also a potent anti-proliferative agent in a wide variety of malignant cell
      types including prostate cancer cells. In prostate model systems (PC-3, LNCaP,
      DU145, MLL) calcitriol has significant anti-tumor activity in vitro and in vivo.
      Calcitriol's effects are associated with an increase in cell cycle arrest,
      apoptosis, differentiation and in the modulation of growth factor receptors.
      Calcitriol induces a significant G0/G1 arrest and modulates p21(Waf/Cip1) and
      p27(Kip1), the cyclin dependent kinase inhibitors. Calcitriol induces PARP
      cleavage, increases the bax/bcl-2 ratio, reduces levels of phosphorylated mitogen
      activated protein kinases (P-MAPKs, P-Erk-1/2) and phosphorylated Akt (P-Akt),
      induces caspase-dependent MEK cleavage and up-regulation of MEKK-1, all potential
      markers of the apoptotic pathway. Glucocorticoids potentiate the anti-tumor
      effect of calcitriol and decrease calcitriol-induced hypercalcemia. In
      combination with calcitriol, dexamethasone results in a significant time- and
      dose-dependent increase in VDR protein and an enhanced apoptotic response as
      compared to calcitriol alone. Calcitriol can also significantly increase
      cytotoxic drug-mediated anti-tumor efficacy. As a result, phase I and II trials
      of calcitriol either alone or in combination with the carboplatin, paclitaxel, or
      dexamethasone have been initiated in patients with androgen-dependent and 
      independent prostate cancer and advanced cancer. Patients were evaluated for
      toxicity, maximum tolerated dose (MTD), schedule effects, and PSA response. Data
      from these studies indicate that high-dose calcitriol is feasible on an
      intermittent schedule, the MTD is still being delineated and dexamethasone or
      paclitaxel appear to ameliorate toxicity. Studies continue to define the MTD of
      calcitriol whichcan be safely administered on this intermittent schedule either
      alone or with other agents and to evaluate the mechanisms of calcitriol effects
      in prostate cancer.

PMID- 12465755
TI  - Osteoporosis and other adverse body composition changes during androgen
      deprivation therapy for prostate cancer.
AB  - Osteoporosis and other body composition changes are important complications of
      androgen deprivation therapy (ADT) for prostate cancer. Bilateral orchiectomy and
      gonadotropin-releasing hormone agonist treatment decrease bone mineral density
      and increase fracture risk. Other factors including diet and lifestyle may
      contribute tobone loss in men with prostate cancer. Estrogens play an important
      role in male bone metabolism. Androgen deprivation therapy with estrogens
      probably causes less bone loss than bilateral orchiectomy or gonadotropin
      releasing hormone agonist treatment. Bicalutamide monotherapy increases serum
      estrogen levels and may also spare bone. Lifestyle modification including smoking
      cessation, moderation of alcohol use, and regular weight bearing exercise are
      recommended to decrease treatment-related bone loss. Supplemental calcium and
      vitamin D are also recommended. Pamidronate (Aredia), an intravenous
      bisphosphonate, prevents bone loss during ADT. Other bisphosphonates are probably
      effective but have not been studied in hypogonadal men. Androgen deprivation
      therapy increases fat mass and decreases muscle mass. These body composition
      changes may contribute to treatment-related decreases in physical capacity and
      quality of life.

PMID- 12465756
TI  - Metastasis in soft tissue sarcomas: prognostic criteria and treatment
      perspectives.
AB  - Soft tissue sarcomas (STSs) are rare tumors, notorious for early hematogenous
      metastasizing. Metastatic disease is seldom amenable to curative treatment;
      therefore new treatment modalities are required. Treatment-related and tumor
      related prognostic factors can be assessed to estimate the risk for subsequent
      metastases, as will be discussed. By this means, high-risk patients can be
      defined; they are the candidates for clinical trials mandatory for treatment
      development. The metastatic process as well as the reaction to chemotherapy
      depends on the biological make-up of the tumor. Current chemotherapy regimens do
      not improve the survival rates of patients with metastatic disease, due to
      resistance mechanisms of tumor cells. New drugs with direct access to the cell
      death machinery in tumor cells might contribute to more effective treatment of
      STS patients.

PMID- 12465757
TI  - In vitro anti-aggregatory effects of the GP IIb/IIIa antagonist eptifibatide on
      feline platelets.

PMID- 12465758
TI  - Ehrlichiosis in cats.

PMID- 12465759
TI  - Molecular evidence supporting Ehrlichia canis-like infection in cats.
AB  - Currently, the pathogenic role of Ehrlichia canis in cats has been proposed
      predominantly on the basis of the serologic evidence of natural infection and the
      infrequent detection of morulae-like structures within the cytoplasm of
      leukocytes in cats. The purpose of this report was to provide molecular evidence
      supporting E. canis-like infection in 3 cats that had clinical manifestations
      consistent with canine ehrlichiosis but lacked antibodies to E. canis antigens.
      Serum from all 3 cats contained antinuclear antibodies (ANAs). The predominant
      disease manifestation was polyarthritis in 1 cat and bone marrow hypoplasia or
      dysplasia. accompanied by pancytopenia or anemia and thrombocytopenia, in 1 cat
      each. The alignment of E. canis partial 16S ribosomal DNA (rDNA: 382 nucleotide
      positions), amplified from EDTA blood samples from each cat, was identical to
      each other and was identical to a canine isolate of E. canis (GenBank accession
      number AF373613). In 1 cat, concurrent treatment with corticosteroids may have
      interfered with the therapeutic effectiveness of doxycycline for the elimination
      of E. canis-like infection. To further define the spectrum of ehrlichiosis in
      cats, polymerase chain reaction (PCR) testing may be necessary until serologic
      testing is thoroughly validated in experimentally or naturally infected cats. In
      addition, until E. canis has been isolated from cats and several tissue culture
      isolates are available from disparate geographic regions for detailed comparative
      genetic study, the molecular evidence presented in this study supporting E. canis
      like infection in cats must be interpreted with caution.

PMID- 12465760
TI  - Stenosis hemodynamics: from physical principles to clinical indices.
AB  - Clinical evaluation of patients with aortic stenosis entails hemodynamic
      determinations and interpretations that depend on complex blood flow patterns.
      Although pressure gradient and Doppler velocity are intrinsically adjusted for a
      wide range of species and body size, they are highly flow-dependent indices that
      can vary among patients with physically identical stenosis areas and within
      individuals between determinations. Other indices, such as the Gorlin area, are
      adjusted for flow. All stenosis indices derived from hemodynamic measurements,
      however, must exhibit some degree of flow dependence because of fundamental
      aspects of fluid dynamics that affect the blood velocity profile. The Gorlin
      effective orifice area is an index that sacrifices adjustment for body size. This
      hinders comparisons over a range of patient species, breed, and size because it
      may be problematic to determine what effective orifice area is appropriate for a
      given individual. One potential solution is to compare the effective area of an
      individual's normal tract, if one exists, to the tract in question as a ratio,
      the effective orifice area ratio (EOAR). The EOAR can be estimated from the ratio
      of flow velocity integrals (FVIs) of the 2 outflow tracts. Clinical data and
      experience are lacking, but theoretical advantages of the index include intrinsic
      adjustment for both body size and flow rate. Aortic stenosis is a complex,
      multifactorial disease, and selection of an optimal hemodynamic severity index
      may not result in adequate prognostic criteria for segregation of patient risk
      and treatment groups.

PMID- 12465761
TI  - Collagenolytic activity in bronchoalveolar lavage fluid in canine pulmonary
      eosinophilia.
AB  - We studied and characterized the collagenolytic matrix metalloproteinases (MMP-8
      and MMP-13) in the pathogenesis of canine pulmonary eosinophilia (PE). Twenty
      dogs with PE and 16 healthy control dogs underwent similar clinical examination
      and collection of bronchoalveolar lavage fluid (BALF). Analyses of total cell and
      differential cell counts and collagen I degradation with and without aminophenyl
      mercuric acetate (APMA) treatment were performed. Correlations between cell
      counts and percentage of degraded collagen I in BALF were studied. Collagenase
      activity detected in BALF was characterized by Western immunoblotting for
      collagenase-2 (MMP-8) and collagenase-3 (MMP-13), and their cellular location was
      studied by immunocytochemical means. Collagenolytic activity was significantly
      increased in cell-free and native BALF of PE dogs compared to healthy controls.
      APMA treatment had no significant effect on BALF collagenase activity, indicating
      that collagenolytic activity occurred in diseased BALF in vivo in active form.
      Western immunoblotting identified the presence of MMP-8 and MMP-13
      immunoreactivities, of which the latter was converted to active form. Major
      immunoreactivity for MMP-8 was observed in macrophages and epithelial cells, and
      major immunoreactivity for MMP-13 was observed in macrophages. A significant
      positive correlation was noted between the percentage of degraded collagen I and
      the counts of eosinophils, macrophages, lymphocytes, and mast cells. These
      findings suggest that the up-regulation of collagenolysis eventually contributes
      to pulmonary tissue destruction in canine PE.

PMID- 12465762
TI  - Copper-associated liver disease in Dalmatians: a review of 10 dogs (1998-2001).
AB  - This retrospective study summarizes 10 Dalmatians suspected of having hepatic
      copper toxicosis. Hepatic copper toxicosis can result from either a primary
      metabolic defect in hepatic copper metabolism or from altered hepatic biliary
      excretion of copper. An inherited copper-associated hepatopathy has been
      documented in Bedlington Terriers, and there is evidence for familial copper
      associated liver disease in West Highland White (WHW) Terriers and Skye Terriers.
      Nine of the 10 Dalmatians in this study presented for gastrointestinal clinical
      signs, including anorexia and vomiting. All animals had increased alanine
      aminotransferase (ALT) enzyme activity, and 9 of 10 had increased alkaline
      phosphatase (ALP) enzyme activity. The relative increase in ALT activity was much
      greater than the relative increase in ALP activity, suggesting a predominantly
      hepatocellular rather than cholestatic liver disease. The mean hepatic copper
      concentration for 9 Dalmatians was 3,197 microg/g dry weight liver (dwl) (normal,
      <450 microg/g). In 5 of these 9 dogs, hepatic copper concentrations exceeded
      2,000 microg/g dwl. Necroinflammatory alterations associated with copper-laden
      parenchymal cells were the notable histopathologic finding. The inflammatory
      infiltrate was either primarily lymphocytic or neutrophilic. Morphologic features
      of cholestasis generally were not prominent except in those dogs with severe
      pathology. These findings lend support to the hypothesis that a primary metabolic
      defect in hepatic copper metabolism occurs in the Dalmatian breed. The mechanism
      and genetic basis of this condition require further study.

PMID- 12465763
TI  - Intestinal permeability and absorption in dogs with traumatic injury.
AB  - The objectives of this study were to assess the feasibility of using urinary
      recovery of sugars to evaluate intestinal permeability and absorption in dogs
      with traumatic injury and to determine if intestinal permeability and absorption
      are altered in dogs with traumatic injury. After a 6-hour fast, a sugar solution
      containing lactulose, rhamnose, 3-0-methyl-D-glucose, and xylose was administered
      via nasoesophageal tube. Urine was collected and quantitated over the 6-hour
      study period via closed collection urinary catheters. Urinary sugar recoveries
      were measured by high-pressure anion exchange liquid chromatography and pulsed
      amperometric detection. Urinary sugar recoveries in the trauma group at 24, 48,
      and 72 hours after trauma were compared to normal controls. In addition, severity
      of trauma was compared to urinary sugar recoveries. Twelve client-owned dogs with
      traumatic injury and 6 healthy controls were enrolled in the study. Lactulose
      recovery and the lactulose:rhamnose recovery ratio were significantly higher in
      the trauma group at 48 hours but were no longer different from controls by 72
      hours. Xylose recovery was significantly higher in the trauma group when compared
      to controls at 72 hours, whereas 3-O-methyl-D-glucose recovery was significantly
      lower in the trauma group at 24 hours. The xylose: 3-O-methyl-D-glucose ratio was
      higher in the trauma group at all time points. Significant correlation was found
      between severity of trauma and xylose and 3-O-methyl-D-glucose recoveries 24
      hours after injury. Results of this study support the hypothesis that intestinal
      permeability and absorption are altered in dogs with traumatic injury.

PMID- 12465764
TI  - Audiograms estimated from brainstem tone-evoked potentials in dogs from 10 days
      to 1.5 months of age.
AB  - The objective of this study was to build audiograms from thresholds of brainstem
      tone-evoked potentials in dogs and to evaluate age-related change of the
      audiogram in puppies. Results were obtained from 9 Beagle puppies 10-47 days of
      age. Vertex to mastoid brainstem auditory-evoked potentials in response to 5.1
      millisecond Hanning-gated sine waves with frequencies octave-spaced from 0.5 to
      32 kHz were recorded. Three dogs were examined at 10, 13, 19, 25, and 45 days.
      Four other dogs were examined at 16 days. Data from 7 dogs between 42 and 47 days
      of age were pooled to obtain audiogram reference values in 1.5-month-old puppies.
      The best auditory threshold lowered from above 60 dB sound pressure level (SPL)
      to values close to 0 dB SPL between 13 and 25 days of age and then stabilized.
      The audible frequency range widened, including 32 kHz in all tested dogs from the
      19th day. In the 7 1.5-month-old puppies, the mean auditory threshold decreased
      by 11 dB per octave from 0.5 to 2 kHz. The auditory threshold was lowest and held
      the same value from 2 to 8 kHz. The mean auditory threshold increased by 20 dB
      per octave from 8 to 32 kHz. Near threshold, click-evoked potentials test only a
      small part of the audible frequency range in dogs. Use of tone-evoked potentials
      may become a powerful tool in investigating dogs with possible partial hearing
      loss, including during the auditory system maturation period.

PMID- 12465765
TI  - Neonatal cerebellar ataxia in Coton de Tulear dogs.
AB  - A neonatal ataxia syndrome was observed in Coton de Tulear dogs. Seven affected
      pups (32%; 7/22) of both genders came from 5 different litters with
      phenotypically normal parents. Neurologic examination revealed normal mental
      status, head titubation, intention tremors, and severe gait, stance, and ocular
      ataxia beginning at 2 weeks of age. One of the pups was able to walk with
      assistance, but most of the affected pups were unable to stand and used
      propulsive movements ("swimming") for goal-oriented activities. They frequently
      would fall to lateral recumbency with subsequent decerebellate posturing and
      paddling. Ocular motor abnormalities included fine vertical tremors at rest and
      saccadic dysmetria. The condition was nonprogressive at least until 4 months of
      age. No specific abnormalities were identified in routine laboratory screening of
      blood and urine. Cerebrospinal fluid (CSF) analysis was normal in 1 dog, and a
      mild increase in protein concentration was observed in a second dog. CSF organic
      and amino acid concentrations were within normal limits. Magnetic resonance
      imaging and computed tomography of the brain, electromyography, motor nerve
      conduction studies, and brain stem auditory-evoked potentials were within normal
      limits. Postmortem examinations were performed on 5 affected dogs between 2 and 4
      months of age. Routine light microscopic and immunocytochemical examination of
      brain, spinal cord, peripheral nerve, and muscle did not disclose any gross or
      histologic lesions. Compared with the cerebellum from an age-matched normal dog,
      the cerebellum from an affected dog showed synaptic abnormalities, including loss
      of presynaptic terminals and organelles associated with parallel fiber
      varicosities within the molecular layer and increased numbers of lamellar bodies
      in Purkinje cells. An autosomal recessive trait affecting development of the
      cerebellum is suspected.

PMID- 12465766
TI  - Retrospective analysis of spinal arachnoid cysts in 14 dogs.
AB  - Spinal cord dysfunction secondary to spinal arachnoid cysts (SACs) has been
      reported previously in dogs. This retrospective study reviews the clinical signs,
      radiographic findings, and outcome after surgical resection of SACs in 14 dogs.
      Plain vertebral column radiographs and myelography were done in all dogs.
      Computed tomography (CT) was done in 7 dogs and magnetic resonance (MR) imaging
      in 3 dogs. Affected dogs were between 1 and 12 years of age, and 8 of 14 were
      Rottweilers. Abnormalities detected on neurological examination depended on the
      location of the SAC. Five dogs had bilobed or multiple SACs. SACs were located in
      the cervical vertebral column in 11 dogs and in the thoracic vertebral column in
      4 dogs. All dogs had dorsally or dorsolaterally located SACs. Two dogs also had
      additional ventrally located SACs. Spinal cord compression secondary to
      intervertebral disc extrusion or protrusion was demonstrated at the site of the
      SACs in 2 dogs. Surgical resection of the SACs was completed in all dogs. Eleven
      dogs were available for follow-up. Five weeks postoperatively, 7 dogs improved in
      neurological function, with some residual ataxia and paresis in 6 of these dogs.
      Neurological function had deteriorated in 4 dogs. It was concluded from this
      study that Rottweilers have a higher incidence of SACs than other breeds of dog.
      Furthermore, bilobed or multiple SACs can occur commonly, and myelography
      effectively localized SACs in dogs. Surgical resection of SACs resulted in
      improvement in neurological function in the majority of treated dogs.

PMID- 12465767
TI  - Temporohyoid osteoarthropathy in 33 horses (1993-2000).
AB  - A retrospective study of the medical records of 33 horses was performed to
      determine the clinical and diagnostic abnormalities associated with temporohyoid
      osteoarthropathy. Data collected from medical records included signalment,
      presenting complaints, history, physical examination findings, laboratory data,
      results of diagnostic imaging studies, and treatments. Follow-up information was
      obtained from a review of case records; by telephone conversation with the owner,
      veterinarian, or trainer; or by both methods. Of 33 horses with temporohyoid
      osteoarthropathy, 29 presented with facial nerve (cranial nerve VII) deficits and
      23 presented with vestibulocochlear nerve (cranial nerve VIII) deficits. Guttural
      pouch endoscopy was more reliable than radiography for diagnosis. Of horses with
      unilateral clinical signs, 22.6% actually had bilateral disease. Magnetic
      resonance imaging and computed tomography identified the lesions in all horses in
      which these tests were performed. Of 30 horses for which follow-up information
      was obtained, 20 (67%) were alive. Eight horses were euthanized and 1 died
      because of problems associated with temporohyoid osteoarthropathy. Nineteen of 20
      surviving horses (95%) were considered by the owner or trainer to be suitable for
      athletic use. Twelve surviving horses (60%) had residual facial nerve deficits;
      11 horses (55%) had residual vestibulocochlear nerve deficits. Horses with
      temporohyoid osteoarthropathy have a fair prognosis for return to some type of
      athletic function, but there is risk of acute death. The majority of horses would
      be expected to have some residual cranial nerve dysfunction, and it could take a
      year or longer for maximal improvement to occur.

PMID- 12465768
TI  - Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for
      dogs with lymphoma.
AB  - The purpose of this study was to compare a maintenance-free chemotherapy protocol
      based on CHOP (H from hydroxydaunorubicin = doxorubicin, O from Oncovin =
      vincristine) to a similar protocol with a maintenance phase for the treatment of
      canine lymphoma. Fifty-three dogs with multicentric lymphoma were treated with a
      6-month modified version of the University of Wisconsin (UW)-Madison chemotherapy
      protocol (UW-25). Disease-free interval (DFI) and survival were compared to a
      historical control group of 55 dogs treated with a similar protocol with a
      prolonged maintenance phase. Remission rate for the study dogs was 94.2%
      (complete remission = 92.3%, partial remission = 1.9%). DFI and survival between
      the 2 groups did not differ significantly, with median DFI and survival of the
      study dogs equal to 282 and 397 days compared to 220 and 303 days for the control
      dogs (P = .2835 and .3365, respectively). Univariate analysis identified substage
      b (P = .0087), German Shepherd breed (P = .0199), and body weight > 18 kg (P =
      .0016) as significant for worse survival. Longer survival was associated with
      thrombocytopenia (P = .0436). Multivariate analysis revealed that substage (P =
      .0388) and weight (P = .0125) retained significance for DFI, whereas substage (P
      = .0093), thrombocytopenia (P = .0150), and weight (P = 0 .0050) retained
      significance for survival. Overall, the protocol was well tolerated by the dogs,
      with 41.5% (22/53) requiring a treatment delay or dose modification, but only
      9.4% (5/53) needing hospitalization. The 6-month chemotherapy protocol based on
      CHOP with no maintenance phase provides similar DFI and survival times when
      compared to a similar protocol with a prolonged maintenance phase.

PMID- 12465769
TI  - Treatment of fibroadenomatous hyperplasia in cats with aglepristone.
AB  - Fibroadenomatous hyperplasia (FAH) is characterized by a rapid proliferation of
      mammary stroma and duct epithelium of 1 or more glands and predominantly affects
      younger female cats. Endogenous progesterone and exogenous progestogens play an
      important role in the genesis of FAH. The presence of progesterone receptors in
      fibroadenomatous tissue allows for targeted endocrine therapy with progesterone
      receptor blockers. We report on 22 young cats with FAH, none of which had
      responded to the withdrawal of progestogens or ovariectomy. The common signs were
      tachycardia (11 cats); skin ulceration, painful mammary glands, or both (16
      cats); lethargy (8 cats); and anorexia (4 cats). The cats were treated with
      subcutaneous injections of the progesterone receptor blocker aglepristone on 1 (7
      cats, 20 mg/kg) or 2 consecutive days (15 cats, 10 mg/kg/d) once weekly. All but
      1 cat responded with a complete and lasting remission of signs after 1-4 weeks of
      treatment. Two cats had a short-term skin irritation at the site of the
      aglepristone injection. Two pregnant cats with FAH aborted after treatment with
      aglepristone and subsequently developed endometritis. In conclusion, the results
      of this study demonstrate that FAH in cats can be treated successfully with the
      progesterone receptor blocker aglepristone.

PMID- 12465770
TI  - The immunophenotype of blood and cerebrospinal fluid mononuclear cells in dogs.
AB  - Inflammatory neurologic diseases are common in dogs, but establishing a
      definitive diagnosis often is difficult. Nucleated cell number and type in
      cerebrospinal fluid (CSF) rarely are suggestive of an etiologic agent. We
      speculated that CSF leukocyte immunophenotyping would be a useful adjunct in the
      investigation of canine inflammatory neurologic diseases by yielding more
      specific etiologic information. The goals of this study were to establish the
      feasibility of flow cytometric evaluation of individual canine CSF samples and to
      identify the cell distribution in healthy dogs. The mononuclear cell populations
      of paired blood and CSF samples from 23 healthy dogs were characterized by
      labeling of cells with antibodies against CD4, CD8alpha, CD21, and CD14 molecules
      and by flow cytometric analysis of their expression. The mean proportion of CD4+
      and CD21+ cells was significantly higher in blood than in the CSF (P < .002 and P
      < .001, respectively). In contrast, the mean proportion of CD14+ and CD8a+ cells
      was not significantly different between blood and CSF (P = .5 and p = .9,
      respectively). These findings demonstrate differences in the distribution and
      function of mononuclear cells in the circulating venous and subarachnoid
      compartments in the dog.

PMID- 12465771
TI  - bcl-2 and MIB-1 labeling indexes in cats with lymphoma.
AB  - Immunohistochemistry was used to examine feline lymphoid tumors for bcl-2 and MIB
      1 expression. Tumor tissues from 29 cats were selected to represent 2 groups-
      cats that did not respond to chemotherapy and cats that responded to therapy.
      Median bcl-2 immunoreactivity was 60%, and median MIB-1 reactivity was 47%. There
      was no significant difference in median survival time between cats with tumors
      with high levels of bcl-2 expression and those with low levels of expression.
      There was no significant difference in median survival time between cats with
      tumors with high levels of MIB-1 expression and those with low levels of
      expression. Mean bcl-2 immunoreactivity was significantly (P = .0004) higher in
      low-grade (73.2%) than in high-grade (16.9%) lymphomas, whereas the mean MIB-1
      immunoreactivity was significantly (P = .0201) higher in high-grade (61.2%)
      lymphomas than in low-grade (35.0%) lymphomas. The mean bcl-2 immunoreactivity
      was significantly (P = .0042) greater in T-cell lymphomas (66.8%) than in B-cell
      lymphomas (22.8%), whereas the mean MIB-1 immunoreactivity was significantly (P =
      .0052) lower in T-cell lymphomas (36.4%) than in B-cell lymphomas (65.2%).
      Although expression of bcl-2 and MIB-1 did not appear to be linked to responses
      to chemotherapy in cats with lymphoma, the data suggest a possible role for these
      regulatory proteins in the biology of feline lymphomas.

PMID- 12465772
TI  - Liposome-encapsulated doxorubicin (Doxil) and doxorubicin in the treatment of
      vaccine-associated sarcoma in cats.
AB  - The purpose of this randomized, multicenter study was to evaluate the toxicity
      and efficacy of liposome-encapsulated doxorubicin (LED) and doxorubicin (DOX) in
      the treatment of feline vaccine-associated sarcoma (VAS). Cats were divided
      according to their disease status into a microscopic arm (no evidence of gross
      disease) and a macroscopic arm (evidence of gross disease). Each arm was
      randomized to receive either LED (1-1.5 mg/kg i.v. q3 weeks) or DOX (1 mg/kg i.v.
      q3 weeks). Thirty-three cats were entered in the macroscopic arm of the study
      with an overall response rate of 39% (5 complete response and 8 partial response)
      and a median time to progression of 84 days. Response rates were not different
      between LED and DOX. Seventy-five cats were entered into the microscopic arm.
      When compared to a similar historical control population treated with surgery
      alone, the cats receiving chemotherapy had a prolonged median disease-free
      interval (388 days versus 93 days). No difference in efficacy was detected
      between LED and DOX. LED at 1.5 mg/kg induced delayed nephrotoxicosis in 23%,
      necessitating a decrease in the recommended dosage to 1 mg/kg, and cutaneous
      toxicosis in 21.7% of treated cats. This study showed that both DOX and LED are
      efficacious in the treatment of VAS and should be considered in the treatment of
      this tumor.

PMID- 12465773
TI  - Efficacy of sodium borate in the prevention of fatty liver in dairy cows.
AB  - The effects of sodium borate (100 mg/kg body weight, p.o., 15 days) from a month
      before expected calving until a month after calving were evaluated in dairy cows
      susceptible to fatty liver. Cows received either sodium borate (n = 13) or no
      treatment (n = 10). All cows had mild fatty livers and increased plasma
      triglycerides and very low density lipoprotein (VLDL) concentrations at the
      beginning of the experiment. The control group of cows developed significant
      fatty liver after calving, and 2 of them had severe fatty liver associated with
      clinical and biochemical abnormalities. There were no clinicopathological signs
      related to sodium borate administration. Serum triglycerides and VLDL
      concentrations before calving decreased significantly at calving and after
      calving in controls, and they were within the normal range only after calving.
      There were significant alterations during the experiment in some hematological
      and chemical variables between groups, within period, but they were within the
      normal range. Unlike treated cows, serum triglycerides and VLDL concentrations
      correlated with liver fat content after calving in untreated cows. Our results
      document that sodium borate decreases the degree of fatty liver in dairy cows
      during early lactation.

PMID- 12465774
TI  - Intravenous lidocaine and small-intestinal size, abdominal fluid, and outcome
      after colic surgery in horses.
AB  - Twenty-eight horses with the diagnosis of an intestinal disorder requiring
      surgical intervention were randomly assigned to lidocaine (n = 13) or saline
      (control, n = 15) treatment groups. After induction of anesthesia, treated horses
      received a loading dose of 2% lidocaine (0.65 mg/kg) intravenously, followed by a
      continuous rate of infusion of 1% lidocaine (0.025 mg/kg/min) until the
      discontinuation of anesthesia. Upon recovery from anesthesia, a 2nd loading dose
      of 2% lidocaine (1.3 mg/kg) was administered, followed by an infusion of 1%
      lidocaine (0.05 mg/kg/min) for 24 hours postoperatively. The control group
      received equivalent volumes of saline. Lidocaine-treated horses had significantly
      better minimum jejunal cross-sectional area scores (P = .011), minimum jejunal
      diameter scores (P = .002), and intestinal ultrasound index (IUI) (P = .007).
      Peritoneal fluid was detected by percutaneous ultrasound examination in 8 of the
      15 control animals but in none of the treated animals (P = .003). Failure to
      obtain fluid via abdominocentesis was significantly more frequent for lidocaine
      treated horses (P = .025). No significant differences between the groups were
      found in the presence of gastrointestinal sounds, time to passage of 1st feces,
      number of defecations in the 1st 24 hours, presence of gastric reflux, duodenal
      or jejunal wall thickness, maximum duodenal or jejunal diameter or cross
      sectional area, minimum duodenal diameter or cross-sectional area, duodenal and
      jejunal intraluminal echogenicity, small-intestinal contractions per minute, rate
      of complications, or outcome. On the basis of this study, lidocaine infusion may
      have some desirable effects on jejunal distension and peritoneal fluid
      accumulation and was well tolerated perioperatively in horses with colic. The low
      incidence of small-intestinal lesions and gastric reflux in the study makes it
      difficult to assess the use of lidocaine in the prevention of postoperative ileus
      (POI).

PMID- 12465775
TI  - Treatment with pergolide or cyproheptadine of pituitary pars intermedia
      dysfunction (equine Cushing's disease).
AB  - Medical records of 27 horses (including 13 ponies) treated with pergolide or
      cyproheptadine for pituitary pars intermedia dysfunction were reviewed to
      determine the effect of treatment on plasma ACTH, insulin, and glucose
      concentrations and clinical signs. Prior to treatment, the most common clinical
      signs were laminitis, hirsutism, and abnormal body fat distribution. The median
      pergolide dose was 3.0 microg/kg p.o. q24h (range, 1.7-5.5 microg/kg). All horses
      treated with cyproheptadine were given 0.25 mg/kg p.o. q24h. After pergolide
      treatment, ACTH concentrations (n = 20; median = 30.4 pg/ml; range, 4.2-173) were
      significantly lower (P < .01) than those in horses treated with cyproheptadine (n
      = 7; median = 141.0 pg/ml: range, 10-1,230). Among horses treated with pergolide,
      there was a correlation between ACTH concentration after treatment and the
      duration of treatment (P < .001) and pergolide dose (P = .04). Significantly (P =
      .02) more owners of horses treated with pergolide (85%, 17/20) reported an
      improvement in clinical signs compared to owners of horses treated with
      cyproheptadine (28%, 2/7).

PMID- 12465776
TI  - Dr Cheryl Chrisman receives ACVIM's highest honor--the Kirk Award. American
      College of Veterinary Internal Medicine.

PMID- 12465777
TI  - Why Medicare cannot promulgate a national coverage rule: a case of regula mortis.
AB  - For over twenty-five years, Medicare has tried to promulgate a rule to implement
      the broad congressional directive to pay only for items and services that are
      "reasonable and necessary." A rule would clarify legal authority and describe
      specific criteria for evaluation of new technology in Medicare. This case study
      is an intractable example of a larger issue of regula mortis or dead rule. Regula
      mortis occurs when a mobilized interest group blocks legitimate administrative
      agency action, causing a regulatory stalemate. In this case, the medical device
      industry has prevented the implementation of a rule. The article diagnoses the
      condition of regula mortis, explains its effects in the Medicare case, and draws
      on principles of administrative law to propose remedies to break the logjam.
      While the case of coverage criteria is important in its own right, it has wider
      relevance. All health systems must grapple with the challenge of evaluating new
      technologies. Medicare efforts provide a starting point for the policy
      discussion. In our current political environment, regula mortis may be an
      increasingly common phenomenon and the proposed cures for it broadly applicable.

PMID- 12465778
TI  - Policy feedback and public opinion: the role of employer responsibility in social
      policy.
AB  - This study extends the literature on policy feedback and explores the extent to
      which public attitudes reflect learning from past government initiatives. We
      analyze the ways in which feedback mechanisms affecting public attitudes may
      differ from those earlier identified in the literature. We apply this general
      analytic framework to help explain variation in public attitudes toward private
      employer involvement in health care, explore possible causal pathways, and offer
      some preliminary empirical tests of these hypotheses. There are different levels
      of public support for the notion of employer obligation involving medical care,
      long-term care, and the treatment of substance abuse. Our evidence suggests that
      lessons about the performance of institutions in each of these policy domains
      represent the most important effect of existing policy on public attitudes.
      Furthermore, these differences correspond to what one would expect based on our
      model of policy feedback and cannot be explained by other plausible sources of
      policy legitimacy.

PMID- 12465779
TI  - The role of group interest, identity, and stigma in determining mental health
      policy preferences.
AB  - Public attitudes toward mental health present an interesting puzzle. While mental
      health is one aspect of general health and well-being, it receives less support
      for government spending increases than does health care. One explanation lies
      with the stigma that is attached to mental illness. This stigma produces more
      negative attitudes on policy issues related to persons with mental illness such
      as government spending for mental health. However, group identification, as
      defined by personal experience or a family member who has experienced a mental
      illness, may have a strong effect on these attitudes. Using data from the 1996
      General Social Survey's module on mental health. I examine this and other
      hypotheses and find evidence that group identification increases the likelihood
      of increased support for government spending for mental health. These robust
      findings exist even in quantitative models, which include politically relevant
      variables and measure identification with mental illness in two different ways.
      These findings suggest that mental health is policy for the few because those
      most supportive of government spending increases are persons who share the common
      identity of experiencing mental illness.

PMID- 12465780
TI  - Risk, response, and mental health policy: learning from the experience of the
      United Kingdom.
AB  - Policy makers in the United States and the United Kingdom recognize that mentally
      disordered offenders present special challenges to law enforcement, mental
      health, and social service systems, as well as the community. Although various
      policy initiatives have advanced over the past twenty years to improve the
      management of mentally disordered offenders, mental health policy has chronically
      failed in both countries. Because safety concerns have emerged as the mental
      health system has been "deinstitutionalized," debate is growing about whether the
      community-care approach works-for the community. This study argues that mental
      health policy fails because policy makers focus on the wrong risks and design
      policies that manage these risks in ways that increase the possibility of adverse
      clinical and economic outcomes. The argument made here uses the case of persons
      with severe mental illness in the United Kingdom as an example of the complex
      relationship between risk and policy making in democratic governance. Emphasis is
      on the nature of risk in mental health policy and how government responds to
      policy and political risks. Mental health policy in Britain is then analyzed in
      terms of its response to and management of risks. Mental health policy has
      historically mismanaged the risk issue in the United Kingdom and as such has set
      in motion the growing community-care backlash. The path to a better outcome lies
      in the responsible management of the right risks. Lessons from the United Kingdom
      experience can be usefully applied to mental health issues in many industrial
      democracies.

PMID- 12465781
TI  - Compensation for medical injury in New Zealand: does "'no-fault" increase the
      level of claims making and reduce social and clinical selectivity?
AB  - The issues of patient safety and quality of care have gained policy attention
      with a growing appreciation of the scale and impact of medical injury in health
      systems. While the focus is clearly on the prevention of iatrogenic injury, the
      question of patient compensation is now also considered important, if only
      because in fault-based tort systems the fear of litigation may itself be a
      barrier to the disclosure and open discussion of medical error. No-fault systems,
      by contrast, do not require proof of culpability, and thus may both reduce
      barriers to compensation and increase disclosure of error. Little evidence,
      however, is available on the performance of such systems. This article reports on
      the analysis of two data sources-a sample of hospital admissions and a complete
      set of compensation claims for medical injury. Both are for the same year and
      region of New Zealand, a country that has maintained a no-fault system of
      accident compensation for a quarter of a century. Just over 2 percent of hospital
      admissions were associated with an adverse event that was potentially compensable
      under scheme criteria. While the claims process was well targeted, the level of
      claims making and receipt was low, with the ratio of successful claims to
      potentially compensable events being approximately 1:30. Comparison of social and
      clinical characteristics of the two data sets revealed a degree of selectivity.
      Compared with the hospital events, the typical successful claimant was younger
      and female and was much more likely to have experienced a surgical adverse event
      that, while unexpected, was not due to substandard care. It is concluded that, in
      interpreting these results, account needs to be taken of a number of features
      unique to the New Zealand system. These include: the limited payoff for a
      compensation claim (no pain and suffering or lump sum, free hospital care); the
      relative complexity of the grounds for claim (either rarity and severity or
      practitioner error); and a history of limited litigation for medical error. This
      suggests that, while the New Zealand system is well targeted, cheap, and free of
      financial and legal barriers, a change in legal doctrine alone has not in itself
      been sufficient to remove completely the selective and low level of claims making
      traditionally associated with patient compensation under tort.

PMID- 12465782
TI  - A new gypsum-based technique to reduce methane and phophorus release from
      sediments of eutrophied lakes: (gypsum treatment to reduce internal loading).
AB  - The release of nutrients from the sediment into the water column, i.e. internal
      nutrient loading, is an important problem in the restoration of eutrophied lakes.
      The ebullition of gases, mainly methane, has been identified as the key process
      in nutrient transportation in the internal loading. We studied whether methane
      production in lake sediment and the release of nutrients into the water column
      could be prevented by the addition of gypsum (CaSO4 x 2H2O). Three different
      gypsum products were examined in a controlled laboratory microcosm with a
      continuous water flow. The addition of gypsum (especially Fe-gypsum) into the
      sediment increased the redox potentials and reduced methane production and
      release of phosphorus from the sediments during an incubation period of 3 months.
      Gypsum evidently acted as a slow-releasing source of sulphate in sediment, which
      likely enhanced the activity of sulphate-reducing bacteria and improved the
      overall mineralisation rate of organic matter. The liberation of H2S and
      phosphate, which might be an undesired consequence of increased sulphate
      reduction rates was prevented by the application of Fe-containing gypsum likely
      as a result of the formation of pyrite and apatite minerals.

PMID- 12465783
TI  - Effect of low ORP in anoxic sludge zone on excess sludge production in oxic
      settling-anoxic activated sludge process.
AB  - This paper studied the effect of oxidation-reduction potential (ORP) in the
      anoxic sludge zone on the excess sludge production in the oxic-settling-anoxic
      process (OSA process), a modified activated sludge process. Two pilot-scale
      activated sludge systems were employed in this study: (1) an OSA process that was
      modified from a conventional activated sludge process by inserting a sludge
      holding tank or namely the "anoxic" tank in the sludge return line; and (2) a
      conventional process used as the reference system. Each was composed of a
      membrane bioreactor to serve the aeration tank and solid/liquid separator. Both
      systems were operated with synthetic wastewater for 9 months. During the
      operation, the OSA system was operated with different ORP levels (+100 to -250
      mV) in its anoxic tank. It has been confirmed that the OSA system produced much
      less excess sludge than the reference system. A lower ORP level than +100 mV in
      the anoxic tank is in favor of the excess sludge reduction. When the ORP level
      decreased from +100 to -250 mV the sludge reduction efficiency was increased from
      23% to 58%. It has also been found that the OSA system performed better than the
      reference system with respect to the chemical oxygen demand removal efficiency
      and sludge settleability. The OSA process may present a potential low-cost
      solution to the excess sludge problem in an activated sludge process because
      addition of a sludge holding tank is only needed.

PMID- 12465784
TI  - Effect of residual chlorine on the analysis of geosmin, 2-MIB and MTBE in
      drinking water using the SPME technique.
AB  - The effect of chlorine on the analysis of three organic compounds (geosmin, 2
      methylisoborneol (2-MIB) and methyl tert-butyl ether (MTBE)) in drinking water is
      elucidated. Three fibers for solid-phase microextraction (SPME) were employed for
      the extraction of the organic compounds from drinking water samples with and
      without free residual chlorine present. A gas chromatograph coupled with a mass
      spectrometer was used to analyze the compounds trapped by the fibers. The
      presence of chlorine substantially reduces the observed geosmin, 2-MIB, and MTBE
      concentrations. Depending on the analyte and chlorine concentrations, an
      experimental error of 10-70% may be observed due to the presence of free residual
      chlorine. The impact is larger for lower organic compound concentrations, and
      under higher residual chlorine conditions. To counteract the effect from residual
      chlorine, sodium thiosulfate was used to dechlorinate the water. After
      dechlorination the experimental error was less than 10%, suggesting that
      dechlorination is necessary when applying SPME for the extraction of organic
      compounds from chlorinated drinking water.

PMID- 12465785
TI  - Remediation of PCE-contaminated aquifer by an in situ two-layer biobarrier:
      laboratory batch and column studies.
AB  - The industrial solvent tetrachloroethylene (PCE) is among the most ubiquitous
      chlorinated compounds found in groundwater contamination. The objective of this
      study was to develop an in situ two-layer biobarrier system consisting of an
      organic-releasing material layer followed by an oxygen-releasing material layer.
      The organic-releasing material, which contained sludge cakes from a domestic
      wastewater treatment plant, is able to release biodegradable organics
      continuously. The oxygen-releasing material, which contained calcium peroxide, is
      able to release oxygen continuously upon contact with water. The first organic
      releasing material layer was to supply organics (primary substrates) to
      reductively dechlorinate PCE in situ. The second oxygen-releasing material layer
      was to release oxygen to aerobic biodegrade or cometabolize PCE degradation
      byproducts from the first anaerobic layer. Batch experiments were conducted to
      design and identify the components of the organic and oxygen-releasing materials,
      and evaluate the organic substrate (presented as chemical oxygen demand (COD)
      equivalent) and oxygen release rates from the organic-releasing material and
      oxygen-releasing materials, respectively. The observed oxygen and COD release
      rates were approximately 0.0368 and 0.0416 mg/d/g of material, respectively. A
      laboratory-scale column experiment was then conducted to evaluate the feasibility
      of this proposed system for the bioremediation of PCE-contaminated groundwater.
      This system was performed using a series of continuous-flow glass columns
      including a soil column, an organic-releasing material column, two consecutive
      soil columns, and an oxygen-releasing material column, followed by two other
      consecutive soil columns. Anaerobic acclimated sludges were inoculated in the
      first four columns, and aerobic acclimated sludges were inoculated in the last
      three columns to provide microbial consortia for contaminant biodegradation.
      Simulated PCE-contaminated groundwater with a flow rate of 0.25 L/d was pumped
      into this system. Effluent samples from each column were analyzed for PCE and its
      degradation byproducts. Results show that up to 99% of PCE removal efficiency was
      obtained in this passive system. Thus, the biobarrier treatment scheme has the
      potential to be developed into an environmentally and economically acceptable
      remediation technology for the in situ treatment of PCE-contaminated aquifer.

PMID- 12465786
TI  - Modeling the ozonation of 2,4-dichlorophoxyacetic acid through a kinetic
      approach.
AB  - The ozonation of herbicide 2,4-dichlorophoxyacetic acid (2,4-D) was studied and
      modeled at different initial pH levels and initial concentrations. The
      degradation rate of 2,4-D was found to increase with the initial pH level and
      decrease with initial 2,4-D concentration. A two-stage ozonation of 2,4-D was
      observed, in which the initial stage of ozonation was slightly faster than the
      second stage due to the higher initial (saturated) ozone concentration; under
      these circumstances, the direct molecular ozone oxidation was likely to
      predominate. At the second stage, the indirect radical oxidation became more
      significant in determining the overall 2,4-D oxidation, and the reaction was more
      pH-dependent. A mathematic model associated with the analytical solutions
      consisting of direct and indirect oxidations contributed by the molecular ozone
      and free radical is proposed. The proposed model is capable of predicting the
      decay of 2,4-D quantitatively by ozonation at different initial pH levels and
      initial 2,4-D concentrations.

PMID- 12465787
TI  - Solar disinfection (SODIS): simulation of solar radiation for global assessment
      and application for point-of-use water treatment in Haiti.
AB  - Haiti and other developing countries do not have sufficient meteorological data
      to evaluate if they meet the solar disinfection (SODIS) threshold of 3-5 h of
      solar radiation above 500 W/m2, which is required for adequate microbial
      inactivation in drinking water. We have developed a mathematical model based on
      satellite-derived daily total energies to simulate monthly mean, minimum, and
      maximum 5-h averaged peak solar radiation intensities. This model can be used to
      assess if SODIS technology would be applicable anywhere in the world. Field
      measurements were made in Haiti during January 2001 to evaluate the model and
      test SODIS efficacy as a point-of-use treatment option. Using the total energy
      from a measured solar radiation intensity profile, the model recreated the
      intensity profile with 99% agreement. NASA satellite data were then used to
      simulate the mean, minimum, and maximum 5-h averaged peak intensities for Haiti
      in January, which were within 98.5%, 62.5%, and 86.0% agreement with the measured
      values, respectively. Most of the discrepancy was attributed to the heterogeneous
      nature of Haiti's terrain and the spatial resolution of the NASA data. Additional
      model simulations suggest that SODIS should be effective year-round in Haiti.
      Actual SODIS efficacy in January was tested by the inactivation of total
      coliform, E. coli, and H2S-producing bacteria. Exposure period proved critical.
      One-day exposure achieved complete bacterial inactivation 52% of the time, while
      a 2-day exposure period achieved complete microbial inactivation 100% of the
      time. A practical way of providing people with cold water every morning that has
      undergone a 2-day exposure would be to rotate three groups of bottles every
      morning, so two groups are out in the sun and one is being used for consumption.

PMID- 12465788
TI  - Acidogenesis of gelatin-rich wastewater in an upflow anaerobic reactor: influence
      of pH and temperature.
AB  - The influence of temperature and pH on the acidification of a synthetic gelatin
      based wastewater was investigated using an upflow anaerobic reactor. Gelatin
      degradation efficiency and rate, degree of acidification, and formation rate of
      volatile fatty acids and alcohols all slightly increased with temperature.
      Temperature affected the acidogenesis of gelatin according to the Arrhenius
      equation with an activation energy of 1.83 kcal/mol. Compared with temperature,
      pH had a more significant effect on the acidogenesis. Gelatin degradation
      efficiency substantially increased with pH, from 60.0% at pH 4.0 to 97.5% at pH
      7.0. The degree of acidification increased from 32.0% at pH 4.0 to 71.6% at pH
      6.5, but dropped to 66.8% when pH increased to 7.0. The optimum pH for the
      overall acidogenic activity was found to be 6.0, close to 5.9, the optimum pH
      calculated using a semi-empirical model. Operation at pH of 4.0-5.0 favored the
      production of propionate, hydrogen, whereas the operation at pH 6.0-7.0
      encouraged the production of acetate, butyrate, and i-butyrate. The region
      between pH 5.0 and 6.0 was the transition zone.

PMID- 12465789
TI  - Analysis of photosynthetic activity in the most polluted stretch of river Ganga.
AB  - As a result of the increasing anthropogenic activities in the gangetic plain,
      Ganga water quantity as well as quality has declined over the years. A major
      effort to clean Ganga, named Ganga Action Plan (GAP) was instituted by the
      Government of India in 1984. The emphasis in GAP was on the reduction of organic
      load on the river through interception, diversion and treatment of wastewater
      reaching the river, thus maintaining the biochemical oxygen demand (BOD) and
      dissolved oxygen (DO) levels of river within the acceptable limits. A major
      criticism of GAP is that the significance of river ecology has not been addressed
      adequately during its conception and implementation. One of the important aspects
      from this perspective is the photosynthetic activity in the river Ganga. It has
      been postulated that photosynthetic activity plays an important role in
      maintaining high levels of DO in Ganga, and as a result the river can assimilate
      high organic loads without appreciable depletion in dissolved oxygen levels.
      Objective of the present study was to assess the photosynthetic activity and
      oxygen production rates in the river and correlate these values with various
      water quality parameters. Most polluted stretch of Ganga, which is known as the
      Kannauj-Kanpur stretch was chosen for this study. Based on the results of the
      study, it was concluded that despite implementation of phase I of GAP, and
      consequent diversion and reduction of organic loading to the river, both BOD and
      DO levels in the river has increased in the entire Kannauj-Kanpur stretch, except
      at Jajmau, where anaerobically treated effluent is discharged to the river. The
      nitrogen levels have also increased in the entire Kannauj-Kanpur stretch.
      Dissolved oxygen (DO) and alkalinity in the river water vary diurnally at all
      sites. Chlorophyll-a levels and oxygen production rates due to photosynthesis
      appear to be positively influenced by phosphate levels in the river water.
      Chlorophyll-a levels appear to be negatively correlated to the Ammonical and
      total Total Kjeldahl Nitrogen (TKN) content in the river water, suggesting the
      possibility of release of nutrients due to algal death and decomposition under
      certain circumstances.

PMID- 12465790
TI  - Pilot-plant comparative study of peracetic acid and sodium hypochlorite
      wastewater disinfection.
AB  - Peracetic acid (PAA) use in wastewater disinfection was assessed by examining its
      performances in a pilot plant fed by the effluent from a conventional activated
      sludge treatment plant. The influence of PAA initial concentrations (0.5-4.0
      mg/l) and contact times (8-38 min) on the presence of seven microorganisms (total
      coliforms, fecal coliforms, fecal streptococci, Escherichia coli, Pseudomonas
      sp., Salmonella sp., and bacteriophages anti-E. coli) and on residual biocide and
      halogenated organic compound (AOXs) concentrations were evaluated. The data so
      obtained were compared to the corresponding results acquired using sodium
      hypochlorite (HYP) in the same experimental conditions. The biocide effect of PAA
      against total and fecal coliforms, E. coli, Pseudomonas sp. and Salmonella sp.
      was similar to that shown by HYP. The former disinfectant was, however, less
      efficient than the latter in the reduction of fecal streptococci and
      bacteriophages anti-E. coli. In both cases the biocide quantities initially
      introduced in the sewage resulted in the presence of significant concentrations
      at the end of the contact time. No significant variation of AOX content was
      detected in the effluent treated with PAA, whereas a progressive increment of
      such compounds was found when increasing quantities of HYP were added to the
      sewage.

PMID- 12465791
TI  - Rough set-based hybrid fuzzy-neural controller design for industrial wastewater
      treatment.
AB  - Recent advances in control engineering suggest that hybrid control strategies,
      integrating some ideas and paradigms existing in different soft computing
      techniques, such as fuzzy logic, genetic algorithms, rough set theory, and neural
      networks, may provide improved control performance in wastewater treatment
      processes. This paper presents an innovative hybrid control algorithm leading to
      integrate the distinct aspects of indiscernibility capability of rough set theory
      and search capability of genetic algorithms with conventional neural-fuzzy
      controller design. The methodology proposed in this study employs a three-stage
      analysis that is designed in series for generating a representative state
      function, searching for a set of multi-objective control strategies, and
      performing a rough set-based autotuning for the neural-fuzzy logic controller to
      make it applicable for controlling an industrial wastewater treatment process.
      Research findings in the case study clearly indicate that the use of rough set
      theory to aid in the neural-fuzzy logic controller design can produce relatively
      better plant performance in terms of operating cost, control stability, and
      response time simultaneously, which is effective at least in the selected
      industrial wastewater treatment plant. Such a methodology is anticipated to be
      capable of dealing with many other types of process control problems in waste
      treatment processes by making only minor modifications.

PMID- 12465792
TI  - Substrate characterisation for a subsurface reactive barrier to treat colliery
      spoil leachate.
AB  - Subsurface permeable reactive barriers (PRB) have been used to successfully treat
      acidic mine drainage in Canada and offer great potential for doing the same in
      the United Kingdom. A PRB for the treatment of colliery spoil leachate from a
      site near Newcastle upon Tyne, UK, has been designed. The selection of the
      reactive media to be used is of paramount importance, with particular reference
      to permeability and reactivity. A number of reactive media mixtures containing
      varying proportions of cattle slurry screenings, green waste compost, calcite
      limestone chips and pea gravel were prepared and their respective permeabilities
      and reactivities were investigated. Media mixtures containing 50% 10 mm grade
      calcite limestone chips showed better alkalinity addition and metals removal than
      a blank containing 50% pea gravel. A media mixture containing 50% limestone chips
      and 50% green waste compost showed a 24 h period to achieve maximum addition of
      alkalinity and maximum removal of acidity and metals. Mixtures containing 25%
      green waste compost and 25% slurry screenings achieved maximum addition/removal
      in 4 h. The likely presence of iron sulphide in samples drawn from test vessels
      during both test runs indicates that bacterial sulphate reduction is occurring in
      this composite.

PMID- 12465793
TI  - Characteristics and fates of soluble microbial products in ceramic membrane
      bioreactor at various sludge retention times.
AB  - The formation and fate of soluble microbial products (SMP) in membrane bioreactor
      (MBR) was investigated at various sludge retention times (SRT) for 170 days. The
      SMP concentration was estimated by feeding glucose, which could be completely
      degraded, and by measuring the dissolved organic carbon (DOC) of the effluent
      from MBR. Under the conditions of SRT of 20 days, influent DOC of 112 mg/l and
      HRT of 6 h, the produced SMP was 4.7 mg DOC/l of which 57% was removed or
      retained by the membrane. DOC of MBR supernatant increased during 100 days and
      then gradually decreased. Specific UV absorbance showed that the accumulated
      compounds had a portion of larger, more aromatic, more hydrophobic and double
      bond-rich organics, which originated from the decayed biomass. Molecular weight
      distributions of SMP in MBR supernatant showed that the acclimated microorganisms
      in a long SRT could decompose high molecular weight organics, it caused the shift
      of molecular weight distributions of SMP to a lower range. During the operation
      period, enumeration of active cells in the MBR showed that microbial inhibitions
      by accumulated SMP was not observed.

PMID- 12465794
TI  - The accumulation of potentially toxic elements in edible body tissues of lambs
      grazing after a single application of sewage sludge.
AB  - The application of sewage sludge to grassland can lead to the accumulation of
      potentially toxic elements (PTEs) at the soil surface that may be ingested,
      together with soil and herbage, by grazing ruminants. To investigate the extent
      to which the method of application of sludge to grassland might influence the
      accumulation of PTEs in body tissues of grazing sheep, two experiments were
      undertaken using grassland overlying two contrasting types of soil. At both
      sites, plots were either untreated or given liquid digested sludge in a single
      application in either autumn or spring by surface spreading or by injection.
      Weaned lambs were grazed on the experimental sites for 149 days (Experiment 1) or
      160 days (Experiment 2). Muscle, kidney and liver tissues were assayed for
      concentrations of PTEs at each slaughter date. Applications of sludge were
      reflected in elevated concentrations of Pb and Cu in soil in Experiment 1 only (P
      < 0.05). Total loadings of PTEs for the treated grasslands did not exceed UK
      statutory limits to annual additions to soil. No significant differences were
      observed in the concentrations of PTEs in herbage between untreated and treated
      sites, with the exception of the concentration of Cu in herbage after surface
      application in the spring (Experiment 2). At the end of Experiment 1 the
      concentration of Cd tended to be higher in kidney tissues of lambs grazed on the
      pastures amended with sludge in the autumn compared to lambs grazed on untreated
      pastures. No other treatment effects were evident. Concentrations of PTEs in
      edible tissues of lambs grazed on grassland given a single dose of sludge were
      generally low and unlikely to pose a significant risk to the food chain. However,
      reduced food intake was observed in lambs grazed on grassland which had received
      sludge recently, indicating that the 21-day UK statutory no-grazing period should
      be reviewed in relation to grassland given sewage sludge in the spring.

PMID- 12465795
TI  - Preliminary assessment of transport processes influencing the penetration of
      chlorine into wastewater particles and the subsequent inactivation of particle
      associated organisms.
AB  - The diffusion of a chemical disinfectant into wastewater particles may be viewed
      as a serial two-step process involving transport through a macroporous network of
      pathways to micropores that lead into dense cellular regions. Previous research
      reveals that ultraviolet (UV) light penetration into wastewater particles is
      limited primarily to macropores, resulting in a residual concentration of
      targeted organisms in post-disinfected effluents that reflects the number of
      organisms embedded in the dense cellular regions of particles. Conversely,
      chlorine was demonstrated as part of this research to penetrate into both the
      macroporous and microporous network of pathways, implying that the application of
      chlorine may be designed feasibly to achieve a desired level of inactivation of
      particle-associated organisms. In the short term, a disinfection model previously
      developed for UV irradiation may be used to assess the inactivation of particle
      associated organisms with chlorine. However, in the long-term, a more rigorous
      and complete understanding of the transport of chemical disinfectants into
      particles can be explored utilizing existing mathematical expressions commonly
      used to model mass transport into porous media. The parameters of interest in
      this modeling approach include the reaction rate of chlorine with particulate
      material, the diffusion rate of chlorine within a particle, the mass-transfer
      rate coefficient across the particle's boundary, and the particle porosity.

PMID- 12465796
TI  - DOC removal by multi-stage ozonation-biological treatment.
AB  - Multi-stage ozonation-biological treatment process for dissolved organic carbon
      (DOC) removal was evaluated to apply for drinking water treatment. Waters with
      different types of DOC were used, i.e. a reservoir water for drinking water
      supply, a secondary effluent from a municipal wastewater treatment plant and a
      solution of humic substances extracted from leaf mold. The multi-stage ozonation
      biological treatment process was compared with conventional single-stage
      ozonation-biological treatment process. Amount of DOC removed in biological
      treatment was defined as amount of biodegradable dissolved organic carbon (BDOC)
      in influent of biological treatment. DOC removal in the multi-stage ozonation
      biological treatment was higher than that in the conventional single-stage
      ozonation-biological treatment with the same total ozonation time for the
      reservoir water and humic substances solution. Moreover, three- or four-stage
      ozonation for 5 min followed by biological treatment (total ozonation time 15 or
      20 min) showed higher removal of DOC than the single-stage ozonation (60 min) and
      biological treatment. The higher DOC removal in the multi-stage treatment was due
      to the production of BDOC by ozonation. The long-term ozonation was not effective
      to produce BDOC because most of ozone was utilized to oxidize BDOC produced in
      the early stage of ozonation. In the multi-stage treatment, ozonation was
      effective to decompose refractory DOC and to produce BDOC because BDOC was
      removed by biological treatment. However, multi-stage ozonation-biological
      treatment was not effective for the secondary effluent. The reason seems to be
      high concentration of ozone scavengers in that water and low reactivity of DOC
      for ozone.

PMID- 12465797
TI  - Gravitational sedimentation of flocculated waste activated sludge.
AB  - The sedimentation characteristics of flocculated wastewater sludge have not been
      satisfactorily explored using the non-destructive techniques, partially owing to
      the rather low solid content (ca. 1-2%) commonly noted in the biological
      sediments. This paper investigated, for the first time, the spatial-temporal
      gravitational settling characteristics of original and polyelectrolyte
      flocculated waste activated sludge using Computerized Axial Tomography Scanner.
      The waste activated sludge possessed a distinct settling characteristic from the
      kaolin slurries. The waste activated sludges settled more slowly and reached a
      lower solid fraction in the final sediment than the latter. Flocculation markedly
      enhanced the settleability of both sludges. Although the maximum achievable solid
      contents for the kaolin slurries were reduced, flocculation had little effects on
      the activated sludge. The purely plastic rheological model by Buscall and White
      (J Chem Soc Faraday Trans 1(83) (1987) 873) interpreted the consolidating
      sediment data, while the purely elastic model by Tiller and Leu (J. Chin. Inst.
      Chem. Eng. 11 (1980) 61) described the final equilibrated sediment. Flocculation
      produced lower yield stress during transient settling, thereby resulting in the
      more easily consolidated sludge than the original sample. Meanwhile, the
      flocculated activated sludge was stiffer in the final sediment than in the
      original sample. The data reported herein are valuable to the theories
      development for clarifier design and operation.

PMID- 12465798
TI  - Arsenic removal using a polymeric/inorganic hybrid sorbent.
AB  - A fixed-bed sorption process can be very effective in removing trace
      concentrations of arsenic from contaminated groundwater provided: the sorbent is
      very selective toward both As(III) and As(V) species; the influent and treated
      water do not warrant any additional pre- or post- treatment; pH and composition
      of the raw water with respect to other electrolytes remain unchanged besides
      arsenic removal, and the sorbent is durable with excellent attrition resistance
      properties. In addition, the sorbent should be amenable to efficient regeneration
      for multiple reuse. This study reports the results of an extensive investigation
      pertaining to arsenic removal properties of a polymeric/inorganic hybrid sorbent.
      Each hybrid sorbent particle is essentially a spherical macroporous cation
      exchanger bead within which agglomerates of nanoscale hydrated Fe oxide (HFO)
      particles have been uniformly and irreversibly dispersed using a simple chemical
      thermal treatment. The new sorbent, referred to as hybrid ion exchanger or HIX,
      combines excellent mechanical and hydraulic properties of spherical polymeric
      beads with selective As(III) and As(V) sorption properties of HFO nanoparticles
      at circum-neutral pH. Comparison of the results of fixed-bed column runs between
      the new sorbent and the polymeric anion exchanger confirmed that both As(V) and
      As(III) were removed very selectively with HIX. Equally important, no pH
      adjustment, pre- or post-treatment was warranted. Besides the absence of arsenic,
      the treated water composition was identical to that of influent water. HIX was
      amenable to efficient in situ regeneration with caustic soda and could
      subsequently be brought into service following a short rinse with carbon dioxide
      sparged water. During fixed-bed column runs, intraparticle diffusion was
      identified as the primary rate-limiting step for both As(III) and As(V) sorption.
      Repeated use of the same HIX particles during various laboratory investigations
      provided strong evidence that the new sorbent possesses excellent attrition
      resistance properties and retains its arsenic removal capacity over cycles.

PMID- 12465799
TI  - Congruence in the performance of model nitrifying activated sludge plants located
      in Germany, Scotland and Spain.
AB  - A laboratory model nitrifying activated sludge plant treating OECD synthetic
      sewage was designed and constructed by each of three laboratories in Germany,
      Scotland and Spain in order to produce a sludge inoculum for 5 rapid toxicity
      bioassays. The plants were run for 3 years and produced sludge for the
      microbially based bioassays Vibrio fischeri bioluminescence, ATP luminescence and
      respiration, and, nitrification and enzyme inhibition. Although the initial
      sludge inoculum for the plants differed, as did some of the running conditions
      such as temperature regime, the sludge produced within the different countries
      had similar characteristics with respect to sludge age, total suspended solids
      and volatile suspended solids. Nitrification was generally maintained over the 3
      year period although there were occasions when the process was inconsistent.
      Nitrification recovery was afforded by reseeding with a nitrifying sludge from a
      local wastewater treatment works (WWTW) or imposition of starvation conditions
      for a period of time. The sludge produced was used to carry out toxicity testing
      and results compared well with those using sludge from a WWTW. Overall, the use
      of sludge generated in the laboratory could be used for toxicity testing negating
      the need to resort to the use of natural WWTW sludge, which may contain a range
      of toxic substances due to uncontrolled industrial and domestic inputs and an
      unbalanced microbial consortium.

PMID- 12465800
TI  - Monitoring and kinetic study of ammonia oxidation using dissolved oxygen
      electrode and NAD(P) H fluorometer.
AB  - The ammonia oxidation of a mixed culture enriched from a wastewater treatment
      plant sludge was monitored by a DO probe and a nicotinamide adenine dinucleotide
      (phosphate) (NAD(P)H) fluorometer. Under fixed aeration, DO reflected ammonia
      oxidation effectively. According to the DO profiles and the total ammonia
      concentrations analyzed experimentally, the ammonia oxidation kinetics of the
      enriched culture was determined. The ammonia oxidation rate was found sensitive
      to pH, especially at low total ammonia concentrations. At high concentrations of
      total ammonia, the maximum ammonia oxidation rate occurred at pH 7.6+/-0.1. At
      low concentrations, the pH sensitivity intensified significantly and the apparent
      optimal pH shifted higher with decreasing total ammonia concentrations, because
      NH3 molecules were the true substrate for ammonia oxidation and more NH4+ ions
      were converted to NH3 molecules at higher pH. The ammonia oxidation kinetics was
      therefore developed according to the concentration of NH3 molecules, instead of
      the commonly used total ammonia concentration. The kinetics followed Michaelis
      Menten behavior for both DO and NH3 concentration: the maximum rate was 16.7+/
      0.7 mg NH3-N/(g TSS-h) and the Michaelis constants for DO and NH3 were (14+/-2)%
      air saturation and (4.4+/-0.4) x 10(-2) (mg NH3-N/L), respectively. It was also
      concluded from the study that with or without exogenous organic substances, the
      NAD(P)H fluorescence of the enriched nitrifying culture was undetectable. The
      fluorescence did not respond to addition or depletion of substrate (ammonia,
      glucose, or acetate), change between aerobic and anaerobic conditions, or even
      KCN addition to kill the culture.

PMID- 12465801
TI  - Diversity of nitrifying bacteria in full-scale chloraminated distribution
      systems.
AB  - Chloramination for secondary disinfection of drinking water often promotes the
      growth of nitrifying bacteria in the distribution system due to the ammonia
      introduced by chloramine formation and decay. This study involved the application
      of molecular biology techniques to explore the types of ammonia-oxidizing
      bacteria (AOB) and nitrite-oxidizing bacteria (NOB) present in several full-scale
      chloraminated systems. The results of AOB community characterization indicated
      the ubiquitous detection of representatives from the Nitrosomonas genus, with
      Nitrosospira constituting a negligible or small fraction of the AOB community in
      all but one sample. Cloning and sequencing demonstrated the presence of AOB
      representatives within the Nitrosomonas oligotropha cluster, a phylogenetic
      subgroup of AOB from which isolates demonstrate a high affinity for ammonia. For
      the NOB communities, Nitrospira were detected in most of the samples, while
      Nitrobacter were only detected in a few samples. These results provide insight
      into the types of AOB responsible for nitrification episodes in full-scale
      chloraminated systems, which should help direct future studies aimed at
      characterizing relevant AOB growth and inactivation properties. Furthermore, the
      detection of NOB in most of the samples suggests a need to evaluate the
      contribution of biological nitrite oxidation relative to chemical oxidation in
      these systems.

PMID- 12465802
TI  - The sensitivity of fixed-bed biological perchlorate removal to changes in
      operating conditions and water quality characteristics.
AB  - Flow rate, electron donor addition, and biomass control were evaluated in order
      to optimize perchlorate (ClO4-) removal from drinking water using biologically
      active carbon (BAC) filtration. Influent dissolved oxygen (DO) was lowered from
      ambient conditions to approximately 2.5 mg/L for all experiments using a nitrogen
      sparge. When influent nitrate concentration was 0-2.0 mg/L, 1.6-2.8 mg/L as
      carbon of acetate or ethanol was required to achieve and sustain the complete
      removal of 50 microg/L perchlorate in a BAC filter. Most or all of the exogenous
      acetate and ethanol was removed during biofiltration. When a 72-h electron donor
      feed failure was simulated, a maximum perchlorate breakthrough of 18 microg/L was
      observed and, once electron donor was reapplied, 9 days were required to
      reestablish complete perchlorate removal. During a 24-h electron donor feed
      failure simulation, the maximum effluent perchlorate concentration detected was
      6.7 microg/L. Within 24 h of reactivating the electron donor, the filter regained
      its capacity to consistently remove 50 microg/L perchlorate to below detection.
      Although biomass growth diminished the filter's ability to consistently remove
      perchlorate, a cleaning procedure immediately restored stable, complete
      perchlorate removal. This cleaning procedure was required approximately every 50
      days (4800 bed volumes) when influent DO concentration was 2.5 mg/L. Empty-bed
      contact time (EBCT) experiments showed that 80% perchlorate removal was achieved
      using a 5-min EBCT, and complete perchlorate removal was observed for an EBCT of
      9 min. It was also demonstrated that BAC filtration consistently removed
      perchlorate to below detection for influent perchlorate concentrations ranging
      from 10 to 300 microg/L, influent sulfate concentrations between 0 and 220 mg/L,
      influent pH values of 6.5-9.0, and operating temperatures of 5-22 degrees C.

PMID- 12465803
TI  - Particle-associated microorganisms in stormwater runoff.
AB  - This research investigated the effects of blending and chemical addition before
      analysis of the concentration of microorganisms in stormwater runoff from a
      single summer storm to determine whether clumped or particle-associated organisms
      play a significant role. The standard membrane filtration method was used to
      enumerate the microorganisms. All organisms, except for Escherichia coli, showed
      an increase in the measured concentration after blending samples at 22,000 rpm
      with or without the chemical mixture. Other than fecal streptococci, the organism
      concentrations decreased with the addition of the Camper's solution in both
      blended and unblended samples before analyses. There was a statistically
      significant interaction between the effects of Camper's solution and the effects
      of blending for all the organisms tested, except for total coliform. Blending did
      not alter the mean particle size significantly. The results show no correlation
      between increased total coliform, fecal coliform, and fecal streptococcus
      concentrations and the mean particle size.

PMID- 12465804
TI  - Adsorption of cobalt from aqueous solutions onto sepiolite.
AB  - Adsorption of Co(II) ions from aqueous sepiolite suspensions has been
      systematically investigated as a function of several variables including
      activation conditions, solid to liquid ratio, pH and temperature. The results are
      analyzed to identify the mechanism of cobalt uptake by sepiolite. Both
      abstraction and real adsorption isotherms were constructed to isolate the
      precipitation of cobalt from the real adsorption. Also, for the first time a
      plausible correlation between the released Mg(II) ions from sepiolite matrix and
      those adsorbed Co(II) ions is made. A one to one ion exchange mechanism is found
      to describe the results. The data obtained from adsorption isotherms at different
      temperatures were fitted to various adsorption models to calculate thermodynamic
      quantities such as the free energy of adsorption, heat of adsorption and entropy
      of adsorption. The thermodynamic data indicate that Co(II) adsorption onto
      sepiolite is entropically driven and characterized by physical adsorption.

PMID- 12465805
TI  - Detection of tannic acid at trace level in industrial wastewaters using a highly
      sensitive chemiluminescence method.
AB  - A novel flow injection procedure was developed for the determination of tannic
      acid in industrial wastewaters based on the enhancement by tannic acid of the
      chemiluminescence from luminol-K3Fe(CN)6-OH- system. The method has the merits of
      higher sensitivity, higher selectivity, wider linear range, simpler
      instrumentation. It is applicable for the determination of tannic acid in the
      range of 3.0 x 10(-10)-1.0 x 10(-7) mol/L with a detection limit of 1.0 x 10(-10)
      mol/L. The relative standard deviation is 2.7% for the determination of 1.0 x 10(
      8) mol/L tannic acid (n = 11). The method has been successfully used to determine
      tannic acid at trace level in industrial wastewaters from brewery and tannery.

PMID- 12465806
TI  - Simulation of bioremediation of chlorophenols in a sandy aquifer.
AB  - Bioremediation of consecutive spills of phenol, 2-chlorophenol (2-MCP), 2,4,6
      trichlorophenol (2,4,6-TCP) and pentachlororphenol as single pollutants was
      investigated in eight pilot plant scale sand columns system (100 cm l, 6 cm ID),
      simulating the conditions, which could be created in the saturated zone of a
      pristine aquifer following an accidental spill. Bioremediation in this study
      consisted of re-circulating local groundwater through the polluted site in a
      controlled manner following a closed-loop configuration. Intrinsic microbial
      development was enhanced by adding the necessary nutrients. Consecutive
      accidental spills of 480-mg phenol/kg soil; 140-mg 2-MCP/kg; 14-mg 2,4,6-TCP/kg
      soil and 17-mg pentachlorophenol (PCP)/kg soil under saturated conditions and a
      continuous specific discharge of 0.56 cm min(-1) were simulated. Degradation
      curves demonstrated first-order kinetics. Biodegradation rates (k1) were
      influenced by consecutive exposures. Calculated rate constants for biodegradation
      for sole substrate experiments were in the range of 0.06-0.15 day(-1), 0.21-1.20
      day(-1), 0.04-2.28 day(-1) and 0.01-0.03 day(-1) for phenol, 2-MCP, 2,4,6-TCP and
      PCP, respectively. The acclimation of the aquifer to simulated consecutive
      accidental spills was found to be directly proportional to the cumulative load of
      each single chlorophenol. A relationship between the octanol water partitioning
      (Kow) values and the experimental degradation rates (k1) was found.

PMID- 12465807
TI  - Having the benefits of those who have gone before us.

PMID- 12465808
TI  - The failure of pet microchip data to be entered onto the NSW Companion Animal
      Database.

PMID- 12465809
TI  - Only six veterinary pathologists training in Australia.

PMID- 12465810
TI  - Peer review--what is it? Why use it?

PMID- 12465811
TI  - Babesia gibsoni infection in three dogs in Victoria.
AB  - Small intraerythrocytic parasites were observed in the blood of three related
      male American Pit Bull Terriers. Two of the dogs, both less than 1-year-old, were
      anaemic at the time of initial examination and the third, an adult and sire of
      the two younger dogs, had a normal haemogram and low parasitaemia. The
      morphological appearance of the erythrocyte inclusions, analysis of a 450-bp
      region of the 18S rRNA gene and antibody titres provided evidence that this
      parasite was Babesia gibsoni, a species not previously reported in Australia.

PMID- 12465812
TI  - Long QT syndrome in dogs with tick toxicity (Ixodes holocyclus).
AB  - OBJECTIVE: To evaluate cardiac electrical function in dogs with tick toxicity.
      DESIGN: A prospective clinical investigation of 39 client-owned dogs treated for
      naturally occurring tick toxicity. PROCEDURE: An ECG was performed on each dog on
      several occasions; at admission to hospital with tick toxicity, 24 h later, at
      discharge from hospital when clinically normal and approximately 12 months later.
      RESULTS: The mean QT interval corrected for heart rate (QTc) was prolonged at
      admission, 24 h and at discharge compared to the QTc measured 12 months later. T
      wave morphology was altered in dogs at admission. All other parameters were
      within normal limits. CONCLUSIONS: The prolonged QTc interval and altered T wave
      morphology of dogs with tick toxicity reflects delayed cardiac repolarisation and
      is comparable with long QT syndrome (LQTS) in people who are predisposed to
      polymorphic ventricular tachycardia and sudden death. Resolution of ECG changes
      lagged behind clinical recovery.

PMID- 12465813
TI  - Pea mania: deranged behaviour in cattle grazing a pea crop (Pisum sativum var
      arvense).
AB  - Hypersensitivity to external stimuli, progressing in some animals to manic
      behaviour, occurred in a cattle herd that grazed a crop of field peas (Pisum
      sativum var arvense) in the pre-flowering stage. Haematological and biochemical
      analyses eliminated hypomagnesaemia and ketosis as diagnoses. Other than two
      steers euthanased due to injuries sustained during manic episodes, all affected
      animals survived, recovering over 3 days when moved to alternative pasture. No
      necropsies were conducted. No microbial pathogens or endophytes were found on or
      in the plants. A previously reported incident in Victoria in 1987 in cattle
      grazing peas appeared to be of a similar nature. Environmental factors leading to
      these incidents were not clearly identified.

PMID- 12465814
TI  - Characterisation of the first Australian isolate of Neospora caninum from cattle.
AB  - OBJECTIVE: To isolate Neospora caninum from a congenitally infected calf.
      PROCEDURE: A calf was obtained from a N. caninum infected dam maintained in a
      dairy herd of Holstein-Friesian cattle located on the south coast of NSW near
      Nowra. The calf was euthanased and samples collected for serology and pathology.
      Samples of brain and spinal cord of the calf were homogenised and injected into
      immunocompromised mice in an attempt to recover protozoa by in vivo culture.
      Sequential passage of brain homogenate through IFNgammaPKO mice was performed and
      tissue culture flasks were inoculated with brain homogenate. Parasites were
      identified by electron microscopy and DNA sequencing. The antigen profile of the
      isolate was analysed using Western blotting. Pathogenicity was examined in BALB/c
      mice and transmission of the parasite during pregnancy was examined in Qs mice.
      RESULTS: The calf was seropositive for N. caninum and histopathological
      examination of sections of cerebrum identified lesions consistent with a very
      mild infection with N. caninum. The parasites isolated using tissue culture were
      identified as N. caninum, based on the sequence of the ribosomal DNA and electron
      microscopy. The antigen profile of the new isolate was similar to that of the NC
      Liverpool isolate, but quite different from that of Toxoplasma gondii. In BALB/c
      mice inoculated with the new isolate, severe clinical signs developed in only
      three of ten infected mice, compared with six of ten mice infected with NC
      Liverpool. Mild to moderate nonsuppurative encephalitis was observed in BALB/c
      mice infected with the new isolate, compared with mice infected with NC
      Liverpool, that developed severe nonsuppurative encephalitis. Transplacental
      transmission of the isolate arising from an acute infection during pregnancy
      occurred in about 87% of pups. CONCLUSION: This is the first isolation of bovine
      Neospora caninum in Australia. This isolate, called NC-Nowra, appears to be a
      less virulent form and may prove to be a suitable candidate for vaccine
      development.

PMID- 12465815
TI  - The role of handouts, note-taking and overhead transparencies in veterinary
      science lectures.
AB  - OBJECTIVE: To study student and staff views of the role and use of handouts, note
      taking and overhead transparencies in veterinary science lectures at the
      University of Queensland METHODS: The Nominal Group Technique was used to help
      develop a questionnaire, which was completed by 351 students (a response rate of
      84%) and 35 staff (76%) from the 5 years of the veterinary course. The data were
      analysed using the SAS statistical computer package. RESULTS: Staff and students
      held different views as to the frequency with which handouts should be used,
      their educational value, and whether they should be complete or partial. Fewer
      students than staff agreed that handouts discourage further reading in a subject.
      Almost all staff and students saw the central functions of note-taking to be
      provision of notes for subsequent revision and encoding information given by the
      lecturer. More students than staff however, considered that note-taking in
      lectures interferes with understanding. Staff and students held similar views as
      to the uses of overheads in lectures. Interestingly however, more staff than
      students agreed that overheads often contain too much information. CONCLUSION:
      Both students and staff saw the central role of note-taking as providing a set of
      good notes for revision. Generally students preferred that this information be
      provided in the form of partial or complete handouts, while staff preferred
      students to take notes and to read outside lectures. Surprisingly, more staff
      than students felt that overhead transparencies often contained too much
      information. Note-taking, handouts and overhead transparencies need to be linked
      in a coherent educational strategy to promote effective learning.

PMID- 12465816
TI  - Comparison of copper heptonate with copper oxide wire particles as copper
      supplements for sheep on pasture of high molybdenum content.
AB  - OBJECTIVE: To assess the effectiveness of intramuscular injection of copper
      heptonate (CuHep) and an oral dose of copper oxide wire particles (COWP) in
      preventing Cu inadequacy in adult and young sheep on pasture of high Mo content.
      DESIGN: Field experiments with flocks of mature Merino wethers and crossbred
      weaners. PROCEDURE: Adult wethers were given 25 or 37.5 mg Cu as CuHep, 2.5 g
      COWP or no Cu treatment. The weaners were given 12.5 or 25 mg Cu as CuHep, 1.25 g
      COWP or no Cu treatment. At intervals over the next 12 (adults) or 8 (weaners)
      months the sheep were weighed and samples of blood and liver were collected for
      trace element assay. Wool samples collected from the adults at the end of the
      experiment were assessed for physical characteristics. RESULTS: The higher dosage
      of CuHep raised liver Cu above control group values for at least 9 months in
      adults and 3 months in weaners. The lower dosage of CuHep was similarly effective
      for 3 months in adults but was without effect in weaners. In adults the response
      to COWP matched that to the higher dosage of CuHep; in weaners it was greater,
      lasting at least 5 months. No changes indicative of Cu deficiency, apart from a
      depressed body weight in adults, were seen. CONCLUSIONS: In sheep on pasture of
      high Mo content a single intramuscular injection of CuHep providing 37.5 mg Cu to
      adults or 25 mg Cu to weaners will raise liver Cu reserves for at least 9 and 3
      months respectively and may be an acceptable alternative to COWP for preventing
      seasonal Cu deficiency in sheep in southern Australia.

PMID- 12465817
TI  - Pathogenesis studies with Australian bat lyssavirus in grey-headed flying foxes
      (Pteropus poliocephalus).
AB  - OBJECTIVE: To examine the susceptibility of the grey-headed flying fox (Pteropus
      poliocephalus) to Australian bat lyssavirus (ABL), and to provide preliminary
      observations on the pathogenesis of the disease in flying foxes. PROCEDURE: Ten
      flying foxes were inoculated intramuscularly with ABL, and four with a bat
      associated rabies virus. Inoculated animals were observed daily, and clinical
      samples collected every 9 to 14 days. Animals with abnormal clinical signs were
      euthanased, and samples collected for histological, serological, virological and
      immunohistological examinations. At 3 months post inoculation (PI), all survivors
      were euthanased, and each submitted to a similar examination. RESULTS: Three ABL
      inoculated flying foxes, and two rabies-inoculated animals developed abnormal
      clinical signs between 15 and 24 days PI. All three ABL-inoculated animals had
      histological lesions consistent with a lyssavirus infection, and lyssaviral
      antigen was identified in the central nervous system (CNS) of each. Virus was
      isolated from the brain of two affected animals. Of the rabies-inoculated flying
      foxes, both had histological lesions and viral antigen in the CNS. Virus was
      recovered from the brain of only one. None of the five affected flying foxes
      developed anti-lyssavirus antibodies, but, by 3 months PI, five of the seven ABL
      inoculated survivors, and one of the two rabies virus-inoculated survivors, had
      seroconverted. The dynamics of the immune responses were quite variable.
      CONCLUSIONS: The response of flying foxes to ABL, administered by a peripheral
      route of inoculation, was similar to that of bats inoculated peripherally with
      bat-derived rabies viruses.

PMID- 12465818
TI  - Annual leave accrual: strategies for reduction.

PMID- 12465819
TI  - Exercise minotaur.

PMID- 12465820
TI  - Response to the declining numbers of veterinarians in the bush.

PMID- 12465821
TI  - Mail-out from the state's Veterinary Surgeon's Board detailing the circumstances
      under which surgical de-barking is permitted.

PMID- 12465822
TI  - Sarcoptic mange is a serious problem in common wombats.

PMID- 12465823
TI  - Primary glaucoma in Burmese cats.
AB  - OBJECTIVE: To document the clinical signs and management of primary glaucoma in
      Burmese cats. DESIGN: A retrospective study of six affected Burmese cats, from
      1996 to 2001. Procedure Six Burmese cats diagnosed with primary glaucoma were
      managed over periods varying from 3 months to 4.5 years. Clinical details were
      obtained from practice records. Gonioscopic examination of the drainage or
      iridocorneal angle in eyes of these affected cats was made. RESULTS: Six desexed
      female Burmese cats (ages 7.0 to 10.5 years) presented with complaints of either
      unilateral (n = 4) or bilateral (n = 2) red eye, dilated pupil or enlarged eye.
      In one of the affected cats, one eye had been enucleated prior to the
      commencement of the study, thus a total of 11 eyes were examined. Clinically, all
      affected eyes (n = 8) had injected episcleral blood vessels and elevated
      intraocular pressure. Gonioscopy revealed the presence of nine narrow and two
      closed iridocorneal angles. Medical therapy included topical 2% dorzolamide (n =
      8), 0.5% timolol maleate (n = 1), 0.005% latanoprost (n = 1) and 0.5-1.0%
      prednisolone acetate (n = 8). Surgery was performed in six eyes using either
      diode laser (n = 5) and/or cryothermy (n = 2) and one eye was eviscerated, with
      implantation of a prosthesis. With therapy, five affected eyes maintained vision
      and normal intraocular pressure, one eye remained blind with normal intraocular
      pressure, one eye remained blind with elevated intraocular pressure and one eye
      was eviscerated. CONCLUSIONS: The Burmese cat may be predisposed to primary
      narrow-angle glaucoma. Early diagnosis and continuous antiglaucoma therapy can
      help control intraocular pressure and maintain vision.

PMID- 12465824
TI  - Arthroscopic management of septic polyarthritis in a dog.
AB  - A 4 1/2-month-old male Neapolitan Mastiff was presented with a history of severe
      non weight-bearing lameness, depression and anorexia, following 6 weeks of
      intermittent thoracic limb lameness that had deteriorated in the previous 72
      hours. Haematogenous septic polyarthritis involving the right elbow joint and
      left glenohumeral joint was diagnosed, with blood and joint cultures revealing a
      Pasteurella species. Arthroscopy was utilised to facilitate joint evaluation and
      effect drainage of both joints. Clinical remission was achieved within 48 hours.
      Arthroscopy provided a minimally invasive yet thorough joint examination, lavage,
      and drainage of fibrinopurulent debris, thereby allowing early postoperative
      mobility and minimal morbidity.

PMID- 12465825
TI  - Diaphragmatic hernia in a bitch. 1937.

PMID- 12465826
TI  - 2002: Hiatal hernia in a puppy.
AB  - A sliding hiatal hernia (where the terminal oesophagus, oesophagogastric junction
      and part of the stomach move cranially through a diaphragmatic defect) was
      diagnosed in a 4-month-old, Shar-Pei puppy presented for evaluation of
      regurgitation. The diagnosis was confirmed using radiography. Herniorraphy
      consisted of repositioning the stomach within the abdomen, plicating the
      diaphragmatic hiatus and performing a tube gastropexy to the left abdominal wall.
      Veterinary practitioners should have a high index of suspicion of hiatal hernia
      in young puppies, particularly Shar-Peis and British Bull Dogs, that present with
      persistent vomiting or regurgitation.

PMID- 12465827
TI  - Haematological changes during tetracosactrin response testing in normal dogs.

PMID- 12465828
TI  - Confirmation of the existence of two distinct genetic groups of infectious bursal
      disease virus in Australia.
AB  - OBJECTIVE: To characterise infectious bursal disease viruses (IBDVs) prevalent at
      major commercial sites throughout Australia and to compare the nucleic acid
      sequences of local strains of IBDV with those of characterised overseas strains.
      DESIGN: Samples of bursae were collected from 20 broiler farms that belonged to
      different poultry companies in New South Wales (NSW), Queensland (Qld), Victoria
      (Vic), Westem (WA) and South Australia (SA). METHOD: Bursae were collected from
      broilers between 24 and 35 days of age. Bursal tissue was homogenised and tested
      for the presence of IBDV antigen using four monoclonal antibodies (Mabs) which
      detect antigenic variation in IBDV strains. The nucleotide sequences of the
      hypervariable region (HVR) within the VP2 gene of IBDVs was determined and the
      deduced amino acid sequences compared with three vaccine strains and six
      previously characterised Australian IBDV strains. The deduced amino acid
      sequences were also compared with the published amino acid sequences of overseas
      strains. The phylogenetic relationships between Australian strains and overseas
      strains were then determined. RESULTS: IBDV was detected in birds from 14 out of
      20 farms sampled. Typing with four Mabs showed that all viruses from Vic (6) and
      SA (10) were antigenic variants, whereas all viruses from NSW (29), Qld (4) and
      WA (5) were classical-like strains. Nucleotide sequencing of one sample from each
      of the 14 farms on which IBDV was detected confirmed results obtained with Mabs.
      The amino acid sequences of all Australian viruses differed from the amino acid
      sequences of foreign IBDV strains. Phylogenetic analysis showed that Australian
      IBDV viruses belonged to two distinct genetic groups. Very virulent (vv) IBDV
      strains belonged to a third genetic group, and overseas classical and variant
      strains belonged to a fourth genetic group. CONCLUSIONS: The results confirmed
      previous findings that there are two groups of IBDV strains circulating in
      commercial broilers in Australia. The majority are classical-like strains that
      are antigenically and genetically similar to vaccine strains 002/73 and V877.
      These classical strains were prevalent in broilers in three states, NSW, Qld and
      WA. The second group of strains are antigenic variants that were only found in
      broilers in two states, Vic and SA. All Australian IBDVs characterised to date
      are genetically distinct and can be differentiated from all other overseas
      strains. This enables identification of incursion of any exotic strain into
      Australian poultry, be it classical, US variant or wIBDV strains.

PMID- 12465829
TI  - Genotyping cattle for inherited congenital myoclonus and maple syrup urine
      disease.
AB  - OBJECTIVE: To develop a routine procedure for establishing the inherited
      congenital myoclonus (ICM) genotype of cattle and to obtain an estimate of the
      prevalence of heterozygotes for ICM and maple syrup urine disease (MSUD) in
      Australian Poll Herefords. DESIGN: A mismatch amplification procedure was
      developed to genotype for ICM. The ICM and MSUD genotypes of subjects from a
      'neuraxial oedema' experimental breeding herd were investigated. Tail hair roots
      were used as a source of target DNA to determine the ICM and MSUD genotypes of
      455 Poll Hereford bulls. RESULTS: An Acc I mismatch procedure was found to be
      suitable to genotype cattle for the ICM alleles using tail hair roots as the
      source of DNA. Based on the prevalence of heterozygotes among saleyard and sale
      bulls in the early 1990s, and contemporary slaughter bulls, the frequencies of
      the alleles responsible for ICM and MSUD were estimated to be between 0.01 and
      0.02. CONCLUSION: This survey demonstrates that the mutations responsible for ICM
      and MSUD are present in the Australian Poll Hereford population. PCR tests could
      be used to advantage in differential diagnosis of neurological disease in newly
      born calves and in selection of Poll Hereford seed stock.

PMID- 12465830
TI  - The efficacy of formulations of triclabendazole and ivermectin in combination
      against liver fluke (Fasciola hepatica) and gastro-intestinal nematodes in cattle
      and sheep and sucking lice species in cattle.
AB  - OBJECTIVE: To assess the efficacy of two formulations of triclabendazole and
      ivermectin in combination against liver fluke (Fasciola hepatica), gastro
      intestinal nematodes and sucking louse species in cattle and sheep. PROCEDURE: A
      study of 540 cattle and 428 sheep at 18 sites throughout Victoria and New South
      Wales was undertaken. At each site, one group of cattle or sheep was treated with
      a combined formulation (Fasimec Cattle or Fasimec Sheep), another received
      ivermectin and triclabendazole separately. In trials on lice infestation, an
      additional group remained untreated. Samples for faecal egg counts were collected
      on days -7, 0 (treatment day), +7, +14 and +21 after treatment. Lice assessments
      were carried out on days -7, 0, +7, +14, +28, +42 and +56. RESULTS: Both
      treatments were highly efficacious (> 98% efficacy) against liver fluke in cattle
      and sheep, against three sucking lice species of cattle and against gastro
      intestinal nematodes in sheep. There was also no significant difference between
      treatments in efficacy. Against gastro-intestinal nematodes, Fasimec Cattle was
      significantly (P < 0.01) more effective than the separately applied ivermectin
      and triclabendazole treatment. Mean efficacy for the Fasimec Cattle and
      Ivomec/Fasinex 120 groups respectively, was 97.6% and 94.2% on Day +7, 98.9% and
      91% on Day +14 and 98.5% and 92.6% on Day +21. CONCLUSION: The efficacy of
      Fasimec' Cattle and Fasimec Sheep was at least equal to that of currently
      registered products (with the same active ingredients) used to control these
      parasites.

PMID- 12465831
TI  - The use of fluorescein as a contrast medium to enhance intradermal skin tests in
      cats.

PMID- 12465832
TI  - Detection of Haemobartonella felis (Candidatus Mycoplasma haemofelis) in
      Australia that is similar to the 'Ohio' strain.

PMID- 12465833
TI  - Gamma(delta) T-cell lymphoma in a cow.

PMID- 12465834
TI  - Effect of mixing on biomethanation of cattle-manure slurry.
AB  - The benefits and extent of mixing required during biomethanation of cattle-manure
      slurry was studied by investigating the effect of: 1) continuous and intermittent
      mixing, 2) agitator impeller speed and position; 3) not providing assisted
      mixing; 4) mixing on production of extracellular polymeric substances; and 5)
      mixing on the ultimate anaerobic biodegradability. Biomethanation was not
      adversely affected: during intermittent mixing; or when only sufficient mixing
      was provided to maintain off-bottom suspension of digester contents; or by
      doubling impeller speed. In fact continuous digestion of cattle-manure slurry
      without mechanical stirring was superior in terms of gas production. This can be
      attributed to increased loss of active volatile solids during stirring. Moreover,
      long-term batch digestion studies showed that the rate of biomethanation in a
      continuously stirred digester was inferior to that of a non-stirred one. Mixing
      was found to decrease production of extracellular polymeric substances (EPS). The
      presence of an increased level of EPS during the quiescent state could indicate
      increased attachment of cells to each other, resulting in larger agglomerates
      with better settling properties thus increasing biomass retention time.

PMID- 12465835
TI  - Removal of heavy metals from contaminated water by petiolar felt-sheath of palm.
AB  - The ability of a reticulated fibrous network of palm petiolar felt-sheath (PPF)
      to remove toxic metals such as Cd, Cu and Zn from contaminated water was
      investigated as a new biosorbent system. PPF was found to sequester metal ions
      efficiently from dilute aqueous solutions with a selectivity order of Cd > Cu >
      Zn. The extent of adsorption was found to be dependent on pH, metal ion
      concentration and amount of biosorbent. The metal uptake was completed in a short
      time and contact of 30 min was observed to be optimum. The adsorption of all the
      three metals followed Langmuir isotherm. The bound metal ions were successfully
      desorbed and the PPF fibrous-biomass remained effective during five adsorption
      desorption cycles. Present studies suggest that PPF has potential to be used in
      the removal/recovery of heavy metal ions from aqueous solutions.

PMID- 12465836
TI  - Maturity degree of composts from municipal solid wastes evaluated by differential
      scanning calorimetry.
AB  - Differential scanning calorimetry (DSC) in association with chemical analysis was
      applied to assess the maturity reached by the organic fraction of Municipal Solid
      Wastes (MSW) subjected to composting processes with manual and fixed aeration and
      sampled at different composting times. Thermograms showed that the difference in
      the treatments, i.e., the manual aeration and the fixed aeration, had no relevant
      effect on the stabilization and maturation of OM in the substrates. Common
      thermal effects observed were: a low temperature endotherm assigned to
      dehydration and/or loss of peripheral polysaccharides chains; a medium
      temperature exotherm assigned to loss of peptidic structures, and a high
      temperature exotherm assigned to oxydation and polycondensation of aromatic
      nuclei of the molecule. Results obtained suggest that in the experimental
      conditions used, a shorter time of composting (about 30 d) appears adequate, in
      order to limit the extended mineralization of OM, whereas a prolonged composting
      time (up to 132 d) would produce a compost of poor quality with high ash content
      and low OM content.

PMID- 12465837
TI  - Importance of surface diffusivities in pesticide adsorption kinetics onto
      granular versus powdered activated carbon: experimental determination and
      modeling.
AB  - Three pesticides (atrazine, bromoxynil and diuron) and two granular activated
      carbons are involved in equilibrium and kinetic adsorption experiments.
      Equilibrium is represented by Freundlich isotherm law and kinetic is described by
      the Homogeneous Surface Diffusion Model, based on external mass transfer and
      intraparticle surface diffusion. Equilibrium and long-term experiments are
      conducted to compare Powdered Activated Carbon and Granular Activated Carbon.
      These first investigations show that crushing GAC into PAC improves the
      accessibility of the adsorption sites without increasing the number of these
      sites. In a second part, kinetics experiments are carried out using a
      Differential Column Batch Reactor. Thanks to this experimental device, the
      external mass transfer coefficient k(f) is calculated from empirical correlation
      and the effect of external mass transfer on adsorption is likely to be minimized.
      In order to obtain the intraparticle surface diffusion coefficient D. for these
      pesticides, comparisons between experimental kinetic data and simulations are
      conducted and the best agreement leads to the Ds coefficient. This procedure
      appears to be an efficient way to acquire surface diffusion coefficients for the
      adsorption of pesticides onto GAC. Finally it points out the role of surface
      diffusivity in the adsorption rate. As a matter of fact, even if the amount of
      the target-compound that could be potentially adsorbed is really important, its
      surface diffusion coefficient may be small, so that its adsorption may not have
      enough contact time to be totally achieved.

PMID- 12465838
TI  - Transport of toxic organic aerosol pollutants from Yugoslavia to Greece during
      the operation "Allied Force".
AB  - Between March 24 and June 10, 1999 a large number of chemicals were ejected into
      the atmosphere because of air strikes on chemical industries and oil storage
      facilities in former Yugoslavia. Chemicals released into the atmosphere under
      suitable meteorological conditions can be transported across borders to large
      distances. The releases may have contained not only conventional air pollutants
      but also semi-volatile organic compounds (SOCs) which include dioxins, furans,
      PCBs and PAHs, all known to be hazardous to health. A measuring programme was
      initiated at Democritus University Thrace, Greece to monitor the chemical
      characteristics of atmospheric aerosol during February, March and April 1999.
      Particulate matter (aerosol) was collected on filters and was analysed using high
      resolution gas chromatography coupled to high-resolution mass spectrometry for
      their content in SOCs. In the present work we show evidence of two events with
      three to twenty fold increased SOCs in the atmosphere of Northern Greece which
      were associated with air masses transported from the conflict area, following the
      destruction of chemical plants and oil storage facilities.

PMID- 12465839
TI  - Comparison of activated sludge processes at different temperatures: 35 degrees C,
      27-55 degrees C, and 55 degrees C.
AB  - The performance of mesophilic (35 degrees C; referred to as R1) and thermophilic
      (55 degrees C; R3) laboratory activated sludge processes (ASPs) as well as ASP
      with a fluctuating temperature (27-56 degrees C; R2) was compared. During the 124
      day runs, in R1 and R3 hydraulic retention time was gradually reduced from 18 h
      to 3 h, corresponding to an increase in volumetric loading rate from 2 to 10 kg
      soluble COD m(-3) d(-1); in R2 hydraulic retention time was gradually reduced
      from 18 to 4.5 h, corresponding to an increase in volumetric loading rate from 2
      to 7.5 kg soluble COD m(-3) d(-1). R1 removed on average 85% of soluble COD (GF50
      filtered) that was approximately 10% more than R3. In R2 SCOD removal was
      dependent on the operating temperature, being comparable to R1 and R3 at
      respective temperature. However, the COD for 0.45 microm-filtered (bacteria-free)
      effluent samples was lower for R3 than for R1, indicating the role of free
      bacteria on effluent quality. Furthermore, 24 h post-aeration of R3 effluent at
      35 degrees C decreased SCOD (GF50-filtrated) markedly (43% removal), whereas at
      55 degrees C no SCOD removal occurred, which suggest mesophilic post-treatment
      ability to remove thermophilically recalcitrant matter or, more probably, the
      ability of free bacteria to aggregate more efficiently under lower temperatures.
      The results indicate that temperature may not be as crucial a factor in high
      temperature biological wastewater treatment as previously believed. On the other
      hand, in thermophilic ASP the importance of solids separation is emphasized.

PMID- 12465840
TI  - Reductive dechlorination of PCE and TCE by vitamin B12 and ZVMs.
AB  - The reductive dechlorination of tetrachloroethene (PCE) and trichloroethene (TCE)
      catalyzed by vitamin B12 was examined when zero valent metals (ZVMs) were used as
      bulk electron donors in batch reactors. UV-visible spectra showed that zinc
      reduces vitamin B12 Co(III) to vitamin B12 Co(I) through B12 Co(II) and iron
      reduces vitamin B12 Co(III) to vitamin B12 Co(II). Thus iron, the most popular
      ZVM reductant, does not have enough reduction potential toreduce vitamin B12 to
      the super-reduced vitamin B12(I), which has been shown to be an active species in
      reductive dechlorination. Dechlorination of PCE and TCE by iron and zinc in the
      presence of vitamin B12 showed that the zinc and vitamin B12 combination greatly
      enhances the reaction rates for both PCE and TCE, but iron and vitamin B12 result
      in an increase in reactivity only for PCE degradation, not for TCE degradation in
      comparison with metals only. This result indicates vitamin B12(I) is active
      towards both PCE and TCE degradation while vitamin B12(II) is active only towards
      PCE. Calculated activation energies for the dechlorination of PCE in the presence
      of Vitamin B12 showed that vitamin B12 lowered the activation energy about 40-60
      kJ mol(-1) for both metals.

PMID- 12465841
TI  - Modelling of an activated primary settling tank including the fermentation
      process and VFA elutriation.
AB  - A complete model of a primary settler including both sedimentation and biological
      processes is presented. It is a one-dimensional model based on the solids flux
      concept and the conservation of mass that uses the Takacs model for the settling
      velocity, which is corrected by a compression function in the lower layers. The
      biological model is based on the ASM2 and enlarged with the fermentation model
      proposed by this research group. The settler was split in ten layers and the flux
      terms in the mass balance for each layer is obtained by means of the settling
      model. A pilot plant has been operated to study the primary sludge fermentation
      and volatile fatty acids (VFA) elutriation in a primary settler tank. The model
      has been tested with pilot plant experimental data with very good results. It has
      been able to simulate the VFA production in the settler and their elutriation
      with the influent wastewater for all the studied experiments. The developed model
      is easily applicable to secondary settlers and thickeners, also taking into
      account biological activity inside them.

PMID- 12465842
TI  - Removal of some heavy metal cations from aqueous solutions by spruce sawdust. I.
      Study of the binding mechanism through batch experiments.
AB  - The biosorption of five metal ions, cadmium, copper, nickel, lead and zinc in
      single component solutions and a multicomponent mixture in aqueous solutions by
      spruce sawdust is reported. A comparative study, performed through batch
      experiments, between the cationic release of sawdust in ultra pure water and in a
      metallic solution leads to an understanding of the heavy metal ion fixation
      mechanism on sawdust. An empirical model is developed in order to distinguish
      between a sorption phenomenon purely based on ion exchange from one in which
      physical adsorption is involved. Thus, the difference in cations released between
      the two solutions corresponds to the metal ions which bind to anionic sites by
      displacing protons from acidic groups and existing cations (natural components of
      the sawdust) from anionic sites. Metal ion binding capacities of spruce sawdust
      reach values ranging from 2.1 to 4.3x10(-2) meq g(-1) in single metal ion
      solutions with the following relative preference: Zn < Ni < Cd << Cu < Pb. Our
      results show variable contributions of the different cations of the sawdust in
      the ion exchange mechanism in which calcium, naturally present in the sawdust,
      accounts for about 65% of the biosorption of the metal ions studied. The study
      also indicates the possibility of desorbing the loaded metal ions with a calcium
      solution.

PMID- 12465843
TI  - Sorption mechanism of Co2+ ions by AlPO4.
AB  - Sorption studies were conducted for Co2+ ions on AlPO4 at different
      concentrations and temperatures. Sorption of Co2+ was found to increase with
      increase in concentration and temperature. To determine the mechanism of the
      sorption process, dissolution of AlPO4 in the presence of Co2+ ions and
      desorption studies were performed which indicated the mechanism of sorption to be
      the ion exchange followed by precipitation. FTIR studies were also employed to
      confirm the proposed mechanism.

PMID- 12465844
TI  - The effects of change in volatile fatty acid (VFA) composition on methanogenic
      upflow filter reactor (UFAF) performance.
AB  - The effects of changes in composition of a volatile fatty acid mixture (namely
      acetic, propionic and butyric acids) fed to a methanogenic upflow filter reactor
      (UFAF) were investigated in terms of reactor chemical oxygen demand (COD) removal
      efficiency and biogas production level. A mixed substrate consisting of differing
      proportions of VFAs (on a COD basis) was fed to the reactor in semi-continuous
      mode under constant organic loading rate (OLR) and hydraulic retention time
      (HRT). At an OLR of 1.2 kg COD m(-3) x d and HRT of 4 days, increasing propionic
      acid concentrations of about 312 mg l(-1), 617 mg l(-1), 951 mg l(-1) and 1242 mg
      l(-1) fed to the reactor provided COD removal rates and biogas production levels
      of, 84.70%-1301 ml d(-1), 80.80%-1214 ml d(-1), 73.65%-1071 ml d(-1) and 65.53%
      942 ml d(-1), respectively, indicating inhibitory effects of propionic acid on
      the methanogenic ecosystem. Subsequent introduction of butyric acid (247 mg l(
      1)) in addition to propionic acid (891 mg l(-1)) increased the performance of the
      UFAF, yielding 76.10% COD removal and 1075 ml d(-1) of biogas production. The
      instability observed in the system towards the end of the study probably
      originated from operating the reactor at relatively high VFA concentrations for a
      long period of time. Change in VFA composition did not seem to have significant
      effects on the effluent MLVSS/MLSS ratio. The upflow anaerobic filter reactor
      adapted to variations in feed composition in a short period of time.

PMID- 12465845
TI  - Nitrite removal in a submerged biofilter.
AB  - Nowadays submerged filters seem to be the preferred technology for
      denitrification purposes. Optimisation of biological nitrogen has recently been
      tried based the nitrate shunt in order to save two of the involved steps. Former
      studies have shown that a build-up of nitrite can be achieved by an appropriate
      control of the nitrification process either in suspended cultures or in fixed
      cultures. An experimental plan was conducted to study the effect of different
      types of carbon source (acetate, ethanol and urban wastewater) on the performance
      of a submerged down flow biofilter, as well as the influence of the hydraulic
      loading. Results have shown that maximum nitrogen removal rates were similar for
      acetate and ethanol attaining values significantly higher than for urban waste
      water. On the other hand, nitrogen massic loading appeared to be the limiting
      factor for efficiency rather than hydraulic loading.

PMID- 12465846
TI  - A self-regulated fed-batch reactor. Part II--Results obtained with a ready
      biodegradable substrate and an acclimatized mixed culture.
AB  - Following the development of the self-regulated fed-batch reactor, a few
      experiments were carried out with performance demonstration purposes. Results
      indicate that biodegradation kinetic constants are quite easy and that a large
      range of possibilities for the reactor application can be envisaged.

PMID- 12465847
TI  - Diapause induction and termination in the predatory mite Euseius finlandicus in
      peach orchards in northern Greece.
AB  - The course of diapause induction as well as of diapause termination in females of
      the predatory mite Euseius (Amblyseius) finlandicus Oudemans (Acari:
      Phytoseiidae) in Northern Greece was determined by transferring females during
      winter and early spring from peach trees to a short day (LD 8:16) or a long day
      (LD 16:8) photoperiod both at 20 degrees C. The first diapause females were found
      in mid September and by the first week of October all the females were in
      diapause. The mean number of days required for diapause termination under the
      short day photoperiod LD 8:16 was gradually reduced from 93.7 days in the
      beginning of October to less than 20 days in mid February and early March. Under
      the long day photoperiod of LD 16:8 diapause was terminated in less than 20 days
      irrespective of the date of collection. These results indicate that by mid
      February photoperiodic sensitivity of females was lost and diapause was
      terminated. However, females were found in their overwintering sites until the
      second half of March, probably because of the prevailing relatively low
      temperatures and lack of adequate food.

PMID- 12465848
TI  - Chemistry of the oil gland secretion of Collohmannia gigantea (Acari: Oribatida).
AB  - The chemistry of the lemon-scented oil gland secretion of Collohmannia gigantea,
      a middle-derivative mixonomatan oribatid mite, was investigated by gas
      chromatography - mass spectrometry. Gas chromatographic profiles of whole body
      extracts of C. gigantea revealed two distinct chromatographic zones, the first
      containing a set of six volatile compounds, comprising the lemon-scented
      monoterpene aldehydes neral and geranial, the scented monoterpene ester neryl
      formate, a distinctly scented aromatic aldehyde (2-hydroxy-6-methyl-benzaldehyde
      = 2,6-HMBD), and the two non-scented hydrocarbons, tridecane and pentadecane. All
      six components appeared to be present in steady relative proportions in scenting
      mites only, indicating their unity within the scented secretion. In contrast, the
      components of the second chromatographic zone were less volatile and found in
      both, scenting and nonscenting mites. Chemically, they represent a set of fatty
      acids of already known cuticular origin. The secretion bouquet of the first
      chromatographic zone was linked with oil glands by histochemical means: large
      amounts of aldehydes were present only in oil gland reservoirs, not in any other
      region of the mite body. While chemical profiles of oil gland secretions of
      several dozen astigmatid mites are known, only one other oribatid oil gland
      composition, from a desmonomatan species, has been elucidated, being almost the
      same as that of C. gigantea. Moreover, all components of these two secretions are
      widely distributed amongst astigmatid mite species and may also be common in a
      restricted set of middle-derivative oribatids. These findings are consistent with
      the idea of astigmatid mite origin from a mixonomatan-desmonomatan group.

PMID- 12465849
TI  - Presence of chitinase in adult Varroa destructor, an ectoparasitic mite of Apis
      mellifera.
AB  - The enzyme spectrum of an ectoparasitic mite of the honeybee. Varroa destructor
      (Anderson and Trueman) was studied using a semi-quantitative method, especially
      designed for complex samples which have not been purified. Exopeptidases and
      phosphatases are shown present. A chitinase and enzymes able to transform beta
      carbohydrates are also present with a large range in the intensity of the
      reaction. The role of the chitinase can be related to the supply of nutritional
      needs or/and the piercing and sucking behaviour of the adult parasite. Chitinase
      activity could be one factor influencing the balance between the parasite and its
      host.

PMID- 12465850
TI  - Phylogenetic relationships in rhinonyssid mites (Acari: Rhinonyssidae) based on
      mitochondrial 16S rDNA sequences.
AB  - A 390 bp region of the 16S rDNA gene was sequenced from six species of
      rhinonyssid mites (Tinaminyssus columbae, T. minisetosum, Sternostoma turdi, S.
      sternahirundo, S. fulicae and Ptilonyssus euroturdi) and two subspecies
      (Tinaminyssus melloi melloi and Tinaminyssus melloi streptopeliae) to examine the
      level of sequence variation and the taxonomic levels to show utility in phylogeny
      estimation. Furthermore, two different geographic locations of T. m. melloi and
      T. m. streptopeliae were analyzed to detect variation between populations.
      Molecular data revealed the existence of two distinct groups in the genus
      Tinaminyssus parasitic on columbiform birds. These results are in agreement with
      those reported by some authors using morphological characters. Sternostoma turdi
      parasitizing aerial birds appeared to be phylogenetically separated from other
      species of this genus isolated from aquatic birds. Moreover, our study addresses
      the validity of the subspecies status of T. melloi streptopeliae. This region of
      the mitochondrial 16S rDNA gene is a useful marker for inferring phylogenetic
      relationships among closely related rhinonyssid species, but not for more
      distantly related taxa.

PMID- 12465851
TI  - Short-term changes in consumption and oviposition rates of Neoseiulus
      californicus strains (Acari: Phytoseiidae) after a diet shift.
AB  - Short-term effects on consumption and oviposition rates of four strains of
      Neoseiulus californicus (McGregor) after a diet shift were evaluated. The new
      feeding conditions experienced by the predators were six fixed densities of eggs
      or protonymphs of Tetranychus urticae Koch placed on excised strawberry leaflet
      discs and maintained under laboratory conditions (25 +/- 1 degrees C, 75-85% RH,
      16L: 8D). The observations were made on the first and the fifth day of the
      experiment. The phytoseiids came from three long-term mass-reared strains fed on
      T. urticae, Dermatophagoidesfarinae Hughes, or Quercus spp. pollen, respectively.
      The fourth strain was collected directly in a strawberry field. Time since diet
      transfer can be added to the factors (i.e. feeding history and prey density)
      already known to affect the functional and numerical responses of N.
      californicus, both when it feeds on prey eggs and protonymphs. If consumption
      rates were averaged over all strains and densities, 9.04 and 11.41 eggs, and 6.97
      and 6.48 protonymphs were consumed on the first and the fifth day, respectively.
      If the same was done for oviposition rates, predators feeding on eggs produced
      1.46 and 2.36 eggs/female/day, whereas predators feeding on protonymphs produced
      1.35 and 2.29 eggs/female/day. Time had the greatest impact on the functional
      response of the strain that had previously fed on tetranychids, while an effect
      of time on the numerical response was detectable in all strains.

PMID- 12465852
TI  - Comparative effectiveness of an integrated pest management system and other
      control tactics for managing the spider mite Tetranychus ludeni (Acari:
      Tetranychidae) on eggplant.
AB  - The effect of an integrated pest management (IPM) package, host plant resistance,
      Chrysoperla carnea predation and neem oil were evaluated against the spider mite
      Tetranychus ludeni on eggplant (Solanum melongena L.) fields in 1996 and 1997, by
      estimating the mite population density and yield levels. Compared with the IPM
      package (Panruti local, C. carnea plus neem oil), the standard (susceptible)
      eggplant variety (MDU1) grown by farmers and treated with an acaricide (dicofol)
      had significantly higher mite densities. The predator C. carnea was recorded in
      significantly lower numbers in plots with the standard variety compared to a
      resistant variety (panruti local) with the full IPM package. Eggplant yield level
      and crop value were highest in the IPM-treated plots followed by Panruti local
      plus C. carnea. The standard variety treated with an acaricide had the lowest
      yield and value. These results indicated the usefulness of host plant resistance
      complemented by biorational control agents, such as C. carnea and neem oil, that
      these are suitable components in an IPM programme for managing the spider mite in
      endemic areas.

PMID- 12465853
TI  - Studies on survival and water balance of unfed adult Dermacentor marginatus and
      D. reticulatus ticks (Acari: Ixodidae).
AB  - The water content, the survival time at various relative humidities (r.h.) and
      the critical equilibrium activity of unfed adult Dermacentor marginatus and D.
      reticulatus ticks were investigated at a constant temperature of 20 degrees C. It
      was also examined whether these ticks use liquid water to compensate water loss.
      Both Dermacentor spp. showed no significant differences in water content in
      relation to body mass. The mean water content of D. marginatus and D. reticulatus
      was 54.6% and 54.7%, respectively, in females and 56.3% and 57.0%, respectively,
      in males. The survival time of unfed adults prolonged with decreasing saturation
      deficits. On average, males survived longer than females and D. marginatus ticks
      survived mostly longer than D. reticulatus ticks. The 50% mortality period ranged
      between 40 d at 33% r.h. and 420 d at 95% r.h. in D. marginatus, and between 43 d
      at 33 r.h. and 366 d at 95% r.h. in D. reticulatus. The critical equilibrium
      activity of unfed adults was estimated to be 0.84 for both species and was
      independent of sex. When dehydrated adult D. marginatus and D. reticulatus ticks
      were offered liquid water, only a few slightly gained weight while most further
      lost weight. Liquid water was not attractive for dehydrated or non-dehydrated
      ticks and drinking was not observed. After submerging in water for 2 d, most of
      the dehydrated ticks had gained weight.

PMID- 12465854
TI  - Cockroach allatostatin-like immunoreactivity in the synganglion of the American
      dog tick Dermacentor variabilis (Acari: Ixodidae).
AB  - Using immunocytochemistry based on a monoclonal antibody against Diploptera
      punctata allatostatin I and horseradish peroxidase-diaminobenzidine reaction, the
      presence of allatostatin-like immunoreactivity is demonstrated in the synganglion
      of Dermacentor variabilis females. The immunoreactive cells are located in the
      protocerebral, cheliceral, palpal, stomodeal, postesophageal, and opisthosomal
      regions of the synganglion. Strongly immunoreactive granules accumulate in the
      boundary area of the subganglia in the preesophageal part of the synganglion.
      This suggests that the immunoreactive materials may be released directly from
      there. In addition, a putative neurohemal area is found in the anterior area of
      the opisthosomal ganglion, where abundant immunoreactive materials are stored.
      Weak immunoreactivity and fewer immunoreactive cells are seen in newly molted
      females compared with one month old, unfed females. Thus, the immunoreactive
      products may be depleted during molting and synthesized in females before
      feeding.

PMID- 12465855
TI  - Listening to Mothers: the first national U.S. survey of women's childbearing
      experiences.

PMID- 12465858
TI  - Evidence-based practice.

PMID- 12465857
TI  - The nursing shortage: refocusing on the mission.

PMID- 12465859
TI  - Cyclic perimenstrual pain and discomfort: the scientific basis for practice.
AB  - OBJECTIVE: To review and organize the science related to cyclic perimenstrual
      pain and discomfort for the fifth research-based practice project of the
      Association of Women's Health, Obstetric and Neonatal Nurses. DATA SOURCES:
      Computerized searches in CINAHL, MEDLINE, and the Cochrane Library, as well as
      hand searches of cited references. Keywords included cyclic pelvic pain, comfort,
      pain guidelines, and dysmenorrhea. DATA EXTRACTION: All relevant articles prior
      to 1999 were considered. Thirty-three research-based articles (1992-1999) were
      reviewed for relevance by the science team as part of the fifth research-based
      practice project of the Association of Women's Health, Obstetric and Neonatal
      Nurses. DATA SYNTHESIS: The literature review and synthesis resulted in a cogent
      description of cyclic perimenstrual pain and discomfort and the development of
      three nursing diagnoses: perimenstrual cyclic pelvic pain, perimenstrual
      discomfort, and perimenstrual negative affect. Cyclic pelvic pain is a new
      concept, developed by the science team during the project. Perimenstrual cyclic
      pelvic pain is an acute, subjective experience defined by pelvic pain that
      presents in a repeating time frame associated with the menstrual cycle. It is
      usually clustered with other discomforts and appreciably affects a woman's
      quality of life. Because the science about interventions is complex and
      extensive, data synthesis led to organization of the interventions within seven
      categories. CONCLUSIONS: Translation of research into practice is essential.
      Cyclic perimenstrual pain and discomfort is an important clinical issue, yet the
      science had not previously been comprehensively reviewed with the mission to
      translate it for nursing practice. Translation of this complex literature was
      accomplished though an innovative clinical practice guideline and subsequently
      evaluated in nursing practice through the research-based practice project.

PMID- 12465860
TI  - Being with woman: A guiding concept for the care of laboring women.
AB  - OBJECTIVE: To review the literature concerning the midwifery concept of being
      with woman and the related nursing concepts of presence and social support during
      childbirth. DATA SOURCES: Literature in the English language from 1985 through
      2000, using MEDLINE and CINAHL. DATA EXTRACTION: Discussion of articles from
      relevant journals and textbooks were included. Pertinent older sources, which
      enhanced the understanding of the concepts, were reviewed. DATA SYNTHESIS: Being
      with woman is defined as the provision of emotional, physical, spiritual, and
      psychological presence/support by the caregiver as desired by the laboring woman.
      Ample evidence exists for including being with woman as a central concept of the
      model of care for women in labor. The qualitative review indicates that women
      value and desire the attributes of the concept during childbirth. The qualitative
      and quantitative literature demonstrate beneficial physiological and
      psychological outcomes for women who experience being with woman. CONCLUSIONS:
      Obstetric units would be wise to incorporate the being with woman model of care
      as routine policy for the care of laboring women by midwives and nurses. Being
      with woman provides psychological and physiological benefits for women, client
      satisfaction, and potential cost savings.

PMID- 12465861
TI  - Telephone social support for low-income pregnant women.
AB  - OBJECTIVE: To assess whether social support can be provided to low-income
      pregnant women by telephone. DESIGN: A qualitative pilot study. SETTING: Nonurban
      prenatal clinics. PARTICIPANTS: Convenience sample of 20 pregnant women who were
      eligible for Medicaid, spoke English, were at least 24 weeks gestation, and had a
      telephone or access to a telephone. RESULTS: The Baby-Beep pilot program provides
      strong evidence that a telephone social support intervention is feasible and
      highly acceptable to a group of low-income pregnant women. Through the use of the
      telephone, a strong rapport appeared to develop between the health care provider
      and the women because nonverbal cues were eliminated. The study also found that
      collaboration between mental health nurses and prenatal care providers could help
      create safe, cost-effective psychosocial care for pregnant women. CONCLUSION: The
      Baby-Beep pilot study provides important information about one way to deliver
      social support to low-income women who may have little or no social support and
      feel alienated in a clinical setting.

PMID- 12465862
TI  - What influences a woman to choose vaginal birth after cesarean?
AB  - OBJECTIVE: To discover what influences women in the decision to deliver via
      vaginal birth after cesarean (VBAC). DESIGN: Descriptive and qualitative,
      influenced by principles of phenomenology and using content analysis to describe
      the lived experiences of women who choose VBAC. SETTING: Women were recruited
      from a postpartum unit in a hospital in the rural southeastern United States.
      PARTICIPANTS: Five women who had delivered via VBAC within 2 to 4 months before
      the study. RESULTS: The major influences that affect a woman's decision to choose
      VBAC are described. The dominant themes found were the woman's sense of control
      in the decision-making process; physician encouragement for VBAC; and delivery
      type outcome advantages, incorporating physical and emotional factors.
      CONCLUSION: Women are influenced by internal and external factors in their
      decision to choose VBAC. Their choices come from their personal experiences and
      should be encouraged by health care providers during all aspects of the
      childbearing process.

PMID- 12465863
TI  - Men of diverse cultures: knowledge and attitudes about breastfeeding.
AB  - OBJECTIVE: The purpose of this study was three-fold: (a) to describe the
      knowledge of and attitudes on breastfeeding of men from diverse racial
      backgrounds, (b) to determine the relationship between knowledge and attitude
      toward breastfeeding, and (c) to determine the relationship between specified
      demographic variables and men's knowledge or attitudes on breastfeeding. DESIGN:
      Descriptive SETTING: An inner-city teaching hospital and its associated prenatal
      clinic located in the southern United States. PARTICIPANTS: One hundred men from
      diverse cultures who spoke either English or Spanish, were 18 years of age or
      older, and were present at either the hospital maternity units or associated
      prenatal clinic. RESULTS: Eighty-one percent (81%) of the men in this study
      indicated that they would prefer their infants to be breastfed. Ethnicity and age
      were found to be linked to attitudes and knowledge of breastfeeding. CONCLUSIONS:
      This study demonstrated that men had a strong desire that their infants be
      breastfed and wanted to be included in decisions concerning breastfeeding.

PMID- 12465864
TI  - Prenatal smoking and alterations in newborn heart rate during transition.
AB  - OBJECTIVE: To evaluate the effects of prenatal cigarette smoke exposure on
      newborn heart rate following the physiologic challenge of birth. DESIGN:
      Nonexperimental, comparative. PARTICIPANTS: A convenience sample of 130 full
      term, healthy newborns who were born at a suburban medical center. MAIN OUTCOME
      MEASURES: Cotinine is the major metabolite of nicotine and was measured in venous
      cord blood. The heart rate was monitored at 1 minute intervals during the first 4
      hours of life. Infants were categorized into three groups based on the cotinine
      level: < 0.05 ng/ml (n = 68), 0.05-6.0 ng/ml (n = 39), and > 6.0 ng/ml (n = 23).
      These levels corresponded, respectively, to no exposure, passive, and active
      exposure of the mother to nicotine. RESULTS: A one-way ANOVA was significant for
      maximum heart rate, F(2, 127) = 9.26, p = .001; range of heart rate, F(2, 127) =
      5.4, p = .006; and variance of heart rate, F(2, 127) = 5.24, p = .007. Post hoc
      multiple comparisons found that newborns with cotinine levels > 6.0 ng/ml
      differed significantly from infants with cotinine levels < 0.05 ng/ml and 0.05
      6.0 ng/ml in maximum heart rate, range of heart rate, and variance of heart rate.
      CONCLUSIONS: These findings suggest that newborns with cotinine levels > 6.0
      ng/ml have a limited ability to maximize and vary their heart rate. Cardiac
      output in the newborn is primarily dependent on heart rate. If unable to maximize
      cardiac output during times of stress, the newborn is potentially at an increased
      risk for morbidity and possible mortality.

PMID- 12465865
TI  - Calculating the risks and benefits of disclosure in African American women who
      have HIV.
AB  - OBJECTIVE: To identify the processes involved in and the patterns of disclosure
      of their HIV diagnosis reported by African American women. DESIGN: Qualitative
      descriptive. SETTING: Southeastern United States; nurse visits in the homes of
      the participants. PARTICIPANTS: Forty-eight African American women who were HIV
      positive and were primary caretakers of young children. MAIN OUTCOME MEASURE:
      Field notes were analyzed using content analysis. RESULTS: Once the women learned
      they had HIV, they were faced with the issue of determining "what is at stake" in
      telling others of their diagnosis. This dilemma was characterized by the threat
      of stigma, feelings of shame, and the concurrent need for support. The women
      determined a calculus of disclosure in determining to whom and when to reveal
      their HIV diagnosis. This calculus involved a careful evaluation of the risks and
      benefits involved in disclosing their illness. Risks of telling were fueled by
      societal and experienced stigma associated with HIV, whereas the benefits were
      primarily fueled by personal needs. The calculus of disclosure was a recursive
      process, with decisions made and remade over time. Disclosure patterns ranged
      from secretive to full disclosure. CONCLUSIONS: Issues related to stigma and
      therefore to disclosure of a diagnosis of HIV are highly relevant to HIV-positive
      African American women. Nurses have an important role in supporting women
      regarding their disclosure decisions.

PMID- 12465866
TI  - Factors affecting a woman's intent to adopt hormone replacement therapy for
      menopause.
AB  - OBJECTIVE: To explore the relationship of attitude toward menopause, knowledge of
      menopause, social support for hormone replacement therapy (HRT), and self
      efficacy for HRT with intention to adopt HRT for menopause. DESIGN: A prospective
      design, to explore the relationship between predictors and the criterion, intent
      to adopt HRT. SETTING: The participants were recruited from clinic sites in rural
      Nebraska and Wyoming. PARTICIPANTS: A convenience sample of 167
      perimenopausal/menopausal women ages 39 to 58. MAIN OUTCOME MEASURE: Multiple
      regression was used to examine the relationships between predictors and the
      criterion, intent to adopt HRT. RESULTS: Self-efficacy was found to predict
      intent to adopt HRT to a higher degree than the other predictors of support and
      knowledge. The combined influence of all three predictors affected intent to
      adopt HRT to a greater degree than any of the variables independently, R2 = .45.
      CONCLUSIONS: This study provides evidence that self-efficacy, support, and
      knowledge may affect a woman's intent to adopt HRT. A higher priority needs to be
      placed on enhancing a menopausal woman's self-efficacy, support, and knowledge to
      facilitate adoption of HRT.

PMID- 12465867
TI  - Evaluating the level of evidence of qualitative research.
AB  - Guidelines for evaluating the levels of evidence based on quantitative research
      are well established. However, the same cannot be said for the evaluation of
      qualitative research. This article discusses a process members of an evidence
      based clinical practice guideline development team with the Association of
      Women's Health, Obstetric and Neonatal Nurses used to create a scoring system to
      determine the strength of qualitative research evidence. A brief history of
      evidence-based clinical practice guideline development is provided, followed by
      discussion of the development of the Nursing Management of the Second Stage of
      Labor evidence-based clinical practice guideline. The development of the
      qualitative scoring system is explicated, and implications for nursing are
      proposed.

PMID- 12465868
TI  - The FDA recommendations on fish intake during pregnancy.
AB  - The U.S. Food and Drug Administration recommends that pregnant women, women of
      childbearing age, and young children avoid eating shark, swordfish, mackerel, and
      tilefish. These fish often harbor high levels of methylmercury, a potent human
      neurotoxin. Methylmercury readily crosses the placenta and has the potential to
      significantly damage the fetal nervous system. Health care providers are
      responsible for educating women about the hazards of methylmercury and the Food
      and Drug Administration recommendation.

PMID- 12465869
TI  - Supportive care during labor: a guide for busy nurses.
AB  - Removing the barriers to the provision of supportive nursing care during labor
      will require much effort by multidisciplinary teams within each institution. Yet
      even without such reform, an individual nurse can easily provide crucial elements
      of supportive care. This article suggests many practical techniques that nurses
      can use to support women during the stresses of labor. Each requires only a
      minute or two, and all are partly based on recruiting and teaching the partner to
      carry out some of them.

PMID- 12465870
TI  - Effects of labor support on mothers, babies, and birth outcomes.
AB  - Supportive care and childbirth have been connected for all of recorded history.
      The impact of supportive care on health outcomes, however, has only been
      investigated over the last few decades. Research provides powerful evidence of
      improved outcomes for mothers and babies when mothers are supported in labor.
      These outcomes include, but are not limited to, lower rates of analgesia and
      anesthesia use, lower operative birth rates, shorter labors, fewer newborns with
      5-minute Apgar scores less than 7, increased maternal satisfaction with the
      birthing process, and much more. Intrapartum nurses must be knowledgeable of the
      research that is directly related to critical aspects of their care, such as
      labor support. This article provides an overview of the quantitative research
      related to the effect of labor support on birth and maternal and fetal outcomes
      during childbirth. By understanding and applying this research in clinical
      practice, bedside nurses may improve outcomes and transform intrapartum care.

PMID- 12465871
TI  - Mothers' experiences of labor support: exploration of qualitative research.
AB  - OBJECTIVE: To review and synthesize qualitative research studies of women's
      perceptions of professional labor support. DATA SOURCES: Journal articles dated
      from 1990 to 2001. Search terms included labor support, labor and delivery,
      childbirth, birth, and caring during labor. Qualitative studies and combined
      quantitative/qualitative studies with open-ended questions were included. STUDY
      SELECTION: The focus of the 17 studies was laboring women's rather than nurses'
      perceptions of labor support or care during labor. DATA EXTRACTION: Data
      describing methods, samples, and findings were extracted from study reports. DATA
      SYNTHESIS: Similarities reported in the study findings were synthesized using a
      model of labor support. Synthesis of the study findings was reported using
      exemplary statements in the words of women who experienced labor support.
      Categories included expectations of labor support, physical comfort, caring and
      emotional support, interpersonal communication style, communication of
      information and instructions, advocacy, and competence of the professional.
      CONCLUSIONS: There were a limited number of qualitative studies of labor support.
      Professional labor support was influenced by the interpersonal communication
      style of the caregiver. Cultural differences existed in caregiver actions
      considered supportive.

PMID- 12465872
TI  - More than support: nursing interventions provided to women in labor.
AB  - OBJECTIVE: To describe the type and quantity of interventions provided to women
      in the first stage of labor. DESIGN: Descriptive, observational. SETTING: An
      intrapartum nursing unit in a Pacific Northwest medical center. PARTICIPANTS:
      Participants were 24 registered nurses employed on the intrapartum nursing unit
      and 75 women in labor with singleton pregnancies at 36 weeks or more gestation.
      Seventy-five 2-hour episodes of care that included one registered nurse assigned
      to a woman in labor were the units of analysis. MAIN OUTCOME MEASURES: Observed
      surveillance, indirect care, and supportive care interventions recorded during
      the episode of care during the first stage of labor. RESULTS: Nurses spent an
      average of 58.9% of the observed time in direct or indirect care of the study
      patient and provided an average of 169.9 interventions. Nurses spent 31.5% of the
      observed time providing at least one supportive care intervention with or without
      a simultaneous surveillance and/or indirect care intervention. CONCLUSION: Nurses
      provided supportive care more frequently than previous work sampling studies have
      suggested. This supportive care was frequently done in conjunction with other,
      more technical nursing care interventions. Integration of supportive care with
      other direct and indirect care interventions may offer the best model for
      providing high-quality intrapartum nursing care.

PMID- 12465873
TI  - Beyond holding hands: the modern role of the professional doula.
AB  - This article illustrates the five main aspects of the doula's role: providing
      specific labor support skills; offering guidance and encouragement; assisting
      mothers to cover gaps in their care; building a team relationship; and
      encouraging communication between patient, nursing staff, and medical caregivers.
      The roles of both nurses and doulas are discussed, including the complementary
      nature of their roles, and also strategies for preventing conflict between doulas
      and nurses. A modern perspective on birth plans and the doula movement are
      included.

PMID- 12465874
TI  - Edwardsiella ictaluri invasion of IEC-6, Henle 407, fathead minnow and channel
      catfish enteric epithelial cells.
AB  - Invasion of Edwardsiella ictaluri into cultured mammalian, fish and enzymatically
      harvested catfish enteric epithelial cells is described. Gentamicin survival
      assays were used to demonstrate the ability of this catfish pathogen to invade
      IEC-6 (origin: rat small intestinal epithelium), Henle 407 (origin: human
      embryonic intestinal epithelium), fathead minnow (FHM, minnow epithelial cells)
      and trypsin/pepsin-harvested channel catfish enteric epithelial cells. Invasion
      of all cell types occurred within 2 h of contact at 26 degrees C, in contrast to
      Escherichia coli DH5 alpha, which did not invade cells tested. Eight Edwardsiella
      ictaluri isolates from diseased catfish and the ATCC (American Type Culture
      Collection) strain were evaluated for invasion efficiency using FHM cells. All
      isolates were invasive, but at differing efficiencies. Invasion blocking assays
      using chemical blocking agents were performed on a single isolate (LA 89-9) using
      IEC-6 epithelial cells. Preincubation of IEC-6 cells with cytochalasin D
      (microfilament depolymerizer) and monodansylcadaverine (blocks receptor-mediated
      endocytosis) significantly reduced invasion by E. ictaluri, whereas exposure to
      colchicine (microtubule depolymerizer) had no effect on bacterial
      internalization. Results indicate that actin polymerization and receptor-mediated
      endocytosis are involved in uptake of E. ictaluri by IEC-6 epithelial cells.
      Invasion trials using freshly harvested cells from the intestine of the natural
      host, Ictalurus punctatus, show that invasion occurs, but at a low efficiency.
      This is possibly due to loss of outer membrane receptors during enzymatic cell
      harvest. This study provides the first documentation of the invasion of cultured
      mammalian and fish cells by E. ictaluri, and identifies possible mechanisms used
      for intracellular access. Additionally, the study describes several functional in
      vitro invasion models using commercially available cell lines as well as cells
      from the natural host (channel catfish, I. punctatus).

PMID- 12465875
TI  - Cell-surface properties of Lactococcus garvieae strains and their immunogenicity
      in the yellowtail Seriola quinqueradiata.
AB  - The cell-surface properties of strains of Lactococcus garvieae were examined. Two
      capsular types were found, one with a highly developed capsule (KG9408) and one
      with a micro-capsule (MS93003) carrying fimbriae-like components projecting from
      the cell surface. One strain (NSS9310) had neither cell capsular nor fimbriae
      like structures on its cell surface. The strains with the highly developed
      capsule were more virulent to fish than either the micro-capsular or non-capsular
      strains. The KG9408, MS93003 and NSS9310 strains could be clearly differentiated
      by their susceptibility to bacteriophages. Protection against L. garvieae
      infection was induced in the yellowtail Seriola quinqueradiata by immunization
      with formalin-killed L. garvieae KG9408 and MS93003 cells. Although protection
      was also induced by immunization with NSS9310, the level of protection was
      significantly lower than that with KG9408 and MS93003 vaccines. Passive
      immunization with yellowtail immune sera raised against KG9408 and MS93003
      conferred strong protection on yellowtail with rapid bacterial clearance after
      challenge with L. garvieae. Immunoblotting analysis of protein antigens extracted
      from L. garvieae strains using rabbit anti-KG9408 and anti-MS93003 sera and
      yellowtail anti-KG9408 and anti-MS93003 sera indicated that some bands in KG9408
      and MS93003 strains were not detectable in NSS9310.

PMID- 12465876
TI  - Immature stages and re-description of Henneguya suprabranchiae (Myxosporea:
      Myxobolidae), an intestinal parasite of the catfish Clarias gariepinus in the
      River Nile, Egypt.
AB  - A new morphological description, supported by light microscopy photographs, is
      presented for various immature stages and for mature Henneguya suprabranchiae
      Landsberg, 1987 spores infecting the intestine of the Nile catfish Clarias
      gariepinus, Burchell, 1822 (Syn.: C. lazera). Large cysts of 2 to 4.5 mm
      diameter, containing immature and mature stages, were present in the outer layer
      of the intestine. They caused severe damage to the smooth muscle and atrophy due
      to the increased size and resultant pressure of the plasmodial mass. From
      September 2000 to April 2001, 21 infected fishes were detected, with a parasite
      prevalence of 21.2%. Nine immature stages were distinguished, and these have been
      measured, sketched and described. In addition, caudal process development was
      recorded. The mature spores are re-described and compared with previous
      descriptions of H. suprabranchiae spores. The main new morphological
      characteristics described are the number of polar filament coils, triangular
      thickening of the sporoplasm base, and a suture line visible only in lateral
      view.

PMID- 12465877
TI  - Comparison of in vitro-cultured and wild-type Perkinsus marinus. I. Pathogen
      virulence.
AB  - Perkinsus marinus is a highly contagious pathogen of the eastern oyster
      Crassostrea virginica. Until recently, transmission studies have employed wild
      type parasites isolated directly from infected oysters. Newly developed methods
      to propagate P. marinus in vitro have led to using cultured parasites for
      infection studies, but results suggest that cultured parasites are less virulent
      than wild-type parasites In this paper, we report results of experiments designed
      to quantify differences between wild-type and cultured P. marinus virulence and
      to test the following hypotheses: (1) in vitro-cultured parasites are less
      virulent than wild-type parasites; (2) virulence decreases gradually during in
      vitro culture; (3) virulence of in vitro cultures can be restored by in vivo
      passage; (4) virulence changes with culture phase. Our results demonstrate that
      parasites freshly isolated from infected hosts are much more virulent than those
      propagated in culture, indicating a potential deficiency in the culture medium
      used. Virulence was lost immediately in culture and, for that reason, the
      practice of repassing cultured cells through the host to restore virulence does
      not work for P. marinus. Virulence was also associated with culture phase: log
      phase parasites were significantly more virulent than those obtained from lag- or
      stationary-phase cultures.

PMID- 12465878
TI  - Comparison of in vitro-cultured and wild-type Perkinsus marinus. II. Dosing
      methods and host response.
AB  - Endoparasites must breach host barriers to establish infection and then must
      survive host internal defenses to cause disease. Such barriers may frustrate
      attempts to experimentally transmit parasites by 'natural' methods. In addition,
      the host's condition may affect a study's outcome. The experiments reported here
      examined the effect of dosing method and host metabolic condition on measures of
      virulence for the oyster parasite Perkinsus marinus. Oysters, Crassostrea
      virginica, were challenged with wild-type and cultured forms of P. marinus via
      feeding, shell-cavity injection, gut intubation and adductor-muscle injection.
      For both parasite types, adductor-muscle injections produced the heaviest
      infections followed by shell-cavity injection, gut intubation, and feeding. There
      was no difference in parasite burdens between oysters fed cultured cells by acute
      vs chronic dosing, and parasite loads stabilized over time, suggesting a dynamic
      equilibrium between invasion and elimination. P. marinus distribution among
      tissues of challenged oysters indicated that parasites invaded the mantle and
      gill, as well as the gut, which has been considered the primary portal of entry.
      Frequency distributions of P. marinus in oysters challenged with 3 different
      culture phases indicated an aggregated distribution among hosts and suggested
      that stationary-phase parasites were easiest for the oyster to control or
      eliminate and log-phase parasites were the most difficult. Host metabolic
      condition also affected experimental outcomes, as indicated by increased
      infection levels in oysters undergoing spawning and/or exposed to low oxygen
      stress.

PMID- 12465879
TI  - Comparison of in vitro-cultured and wild-type Perkinsus marinus. III. Fecal
      elimination and its role in transmission.
AB  - Perkinsus marinus, a pathogen of the eastern oyster Crassostrea virginica, is
      transmitted directly among oysters. Previous studies found viable P. marinus
      parasites in the feces and pseudofeces of oysters within hours of injection with
      parasites, suggesting that the parasite may be voided from live oysters and
      subsequently dispersed in the water column. The experiments described here were
      designed to quantify P. marinus shed in the feces and pseudofeces of
      experimentally infected oysters. The results indicated that parasites were shed
      in 2 phases. A 'decreasing' phase occurred within 2 wk of challenge and before
      net parasite proliferation began in the host. An 'increasing' phase occurred
      after P. marinus had begun replicating. The quantity of P. marinus recovered in
      the feces and pseudofeces of exposed oysters was only about 5 % of the dose
      administered. In vitro-cultured P. marinus were eliminated at a greater rate than
      wild-type P. marinus and the fraction discharged was not associated with culture
      phase. Oysters that were continuously dosed with P. marinus in their food
      gradually lost the ability to discard the parasite in pseudofeces. The quantity
      of P. marinus shed in feces of infected oysters was correlated with both the P.
      marinus body burden and subsequent survival time, suggesting that noninvasive
      fecal counts could predict infection intensity and survival. The results indicate
      that in an epizootic, shedding of P. marinus via feces is relatively small
      compared to the potential number released by cadavers of heavily infected
      oysters, but that fecal discharge may be important in transmission before
      infections become lethal.

PMID- 12465880
TI  - Detection of hepatopancreatic parvovirus in Thai shrimp Penaeus monodon by in
      situ hybridization, dot blot hybridization and PCR amplification.
AB  - Hepatopancreatic parvovirus (HPV) infects the hepatopancreas in penaeid shrimp
      and retards their growth. The DNA sequence of HPV from Thai shrimp Penaeus
      monodon (HPVmon) differs from HPV of Penaeus chinensis (HPVchin) by approximately
      30%. In spite of this difference, commercial PCR primers (DiagXotics) developed
      from HPVchin to yield a 350 bp PCR product do give a 732 bp product with HPVmon
      DNA template. On the other hand, the sensitivity of HPVmon detection with these
      primers and with hybridization probes designed for HPVchin is significantly lower
      than it is with HPVchin. To improve sensitivity for HPVmon detection, we used the
      sequence of the 732 bp HPVmon PCR amplicon described above to develop specific
      PCR primers (H441F and H441R) and hybridization probe. The primers could detect
      as little as 1 fg of purified HPVmon DNA while the 441 bp digoxygenin-labeled PCR
      product gave strong, specific reactions with in situ hybridization and with
      hybridization blots. In contrast, negative results were obtained using DNA from
      all other pathogens tested and from DNA of P. monodon. Supernatant solution from
      boiled, fresh shrimp fecal and postlarval samples homogenized in 0.025%
      NaOH/0.0125% SDS could be used to detect as little as 0.1 pg HPVmon DNA by the
      PCR reaction. By dot blot hybridization, a visible signal was obtained with
      purified HPVmon DNA at 0.01 pg, but detection in spiked feces and postlarval
      samples was only 1 and 0.1 pg, respectively.

PMID- 12465881
TI  - Uptake of foreign ferritin in platy Xiphophorus maculatus (Poeciliidae:
      Teleostei).
AB  - The ability and capacity of various tissues in platy Xiphophorus maculatus L. to
      take up horse-spleen ferritin injected into the blood stream are described.
      Ferritin was injected intraperioneally, and the cellular uptake was demonstrated
      as Prussian blue precipitations in tissues treated with acid ferrocyanide
      solutions. Ferritin was detected within the heart endocardial cells and
      macrophages in the trunk kidney and spleen, 1/4 h after the injection, i.e.
      foreign ferritin was taken up very rapidly by these cells. When the time elapsed
      between the ferritin injection and sacrifice exceeded 6 h, these cells, and also
      macrophages in the gill and intestine, were almost completely filled with
      ferritin. At these stages, however, the amounts of Prussian blue precipitations
      per volume unit of the tissue were much larger in the heart than in the other
      organs studied in the present work, i.e. the endocardial tissue seems to play an
      important role in the clearance of the blood circulation in this species. We
      suggest that this tissue in platy is specialized to endocytose waste and foreign
      macromolecules, including pathogenic particles, from the blood stream. The
      eosinophilic and neutrophilic granulocytes do not appear to take up foreign
      ferritin, i.e. these cells may play no endocytotic role in the clearance of
      foreign macromolecules in platy.

PMID- 12465882
TI  - Life before the clock: modeling circadian evolution.
AB  - A feedback loop that functions via transcription and translation is thought to be
      the mechanistic core of circadian rhythmicity. Numerous modeling efforts
      incorporate the identified components and their modifications to recreate the
      circadian clock in computer simulations. Several issues remain problematic,
      including the lack of precise quantitative kinetics and the likely existence of
      additional, as-yet-undiscovered components. Even without these complications,
      models and flow charts of the circadian system have reached high complexity. They
      attempt to reconcile all observations without violating current views and
      concepts. In this article, the authors consider the mechanisms that may have
      preceded the circadian system in evolution. Given that cellular metabolism and
      biochemistry were presumably already interconnected in cascading feedback
      reactions prior to the appendage of the transcription/translation feedback loop,
      a coordinated response to exogenous changes would be advantageous over
      unsystematic responses. The authors hypothesize that those mechanisms that
      allowed synchronization in spite of metabolic complexity form the basis for the
      evolution of circadian properties and are as fundamental to the circadian system
      as the transcriptional/translational feedback loop.

PMID- 12465883
TI  - Origins of circadian rhythmicity.

PMID- 12465884
TI  - Mapping quantitative trait loci affecting circadian photosensitivity in retinally
      degenerate mice.
AB  - It is known that retinally degenerate C57BL/6J (rd/rd) mice have unattenuated
      circadian photosensitivity. However, the authors have previously found that CBA/J
      (rd/rd) mice that carry the same rd mutation have attenuated circadian
      photosensitivity compared to normal CBA/N (+/+) mice. In the present study, a
      quantitative trait locus (QTL) analysis using C57BL/6J (rd/rd) and CBA/J (rd/rd)
      mice was conducted in order to identify the genes affecting circadian
      photosensitivity of the rd mice. As a result, several putative QTLs onthree
      separate chromosomes (8, 12, 17) were detected, which indicates that circadian
      photosensitivity in rd mice is altered by multiple genes. Identification of these
      genes may provide new insights into the understanding of regulation of circadian
      photoentrainment and sleep-wake disorders.

PMID- 12465885
TI  - Restoration of self-sustained circadian rhythmicity by the mutant clock allele in
      mice in constant illumination.
AB  - Mice mutant for the Clock gene display abnormal circadian behavior characterized
      by long circadian periods and a tendency to become rapidly arrhythmic in constant
      darkness (DD). To investigate whether this result is contingent on the absence of
      light, the authors studied the circadian behavior of homozygous Clock mutant mice
      under conditions of both constant light and DD. Fourteen of 15 Clock/Clock mice
      stayed rhythmic in constant light of 70 to 170 lux, where 10 of 15 wild-type mice
      became arrhythmic. In contrast, only 5 of 15 Clock/ Clock mice and 15 of 15 wild
      type mice remained rhythmic after 60 cycles when released in DD (dim red light of
      < 1.5 lux) after 8 days of entrainment. The restoration of self-sustained
      rhythmicity by the Clock allele cannot be attributed to reduced sensitivity of
      the system to light It underscores the fact that self-sustainment is not a secure
      guide to functional organization.

PMID- 12465886
TI  - Circadian rhythm of iguana electroretinogram: the role of dopamine and melatonin.
AB  - The amplitude of the b-wave of the electroretinogram (ERG) varies with a
      circadian rhythm in the green iguana; the amplitude is high during the day(or
      subjective day) and low during the night (or subjective night). Dopamine and
      melatonin contents in the eye are robustly rhythmic under constant conditions;
      dopamine levels are high during the subjective day, and melatonin levels are high
      during the subjective night. Dopamine and melatonin affect the amplitude of the b
      wave in an antagonistic and phase-dependent manner: dopamine D2-receptor agonists
      injected intraocularly during the subjective night produce high-amplitude b-waves
      characteristic of the subjective day, whereas melatonin injected intraocularly
      during the subjective day reduces b-wave amplitude. Sectioning the optic nerve
      abolishes the circadian rhythms of b-wave amplitude and of dopamine content. The
      results of this study suggest that in iguana, a negative feedback loop involving
      dopamine and melatonin regulates the circadian rhythm of the ERG b-wave amplitude
      that is at least in part generated in the brain.

PMID- 12465887
TI  - Sleep processes exert a predominant influence on the 24-h profile of heart rate
      variability.
AB  - Adverse cardiovascular events are known to exhibit 24-h variations with a peak
      incidence in the morning hours and a nonuniform distribution during the night.
      The authors examined whether these 24-h variations could be related to circadian
      or sleep-related changes in heart rate (HR) and in HR variability (HRV). To
      differentiate the effect of circadian and sleep-related influences, independent
      of posture and of meal ingestion, seven normal subjects were studied over 24 h,
      once with nocturnal sleep from 2300 to 0700 h and once after a night of sleep
      deprivation followed by 8 h of daytime sleep from 0700 to 1500 h. The subjects
      were submitted to constant conditions (continuous enteral nutrition and bed
      rest). HRV was calculated every 5 min using two indexes: the standard deviation
      of normal R-R intervals (SDNN) and the ratio of low-frequency to low-frequency
      plus high-frequency power. Sleep processes exerted a predominant influence on the
      24-h profiles of HR and HRV, with lowest HRV levels during slow wave sleep, high
      levels during REM sleep and intrasleep awakenings, and abrupt increases in HR at
      each transition from deeper sleep to lighter sleep or awakenings. The circadian
      influence was smaller, except for SDNN, which displayed a nocturnal increase of
      140% whether the subjects slept or not. This study demonstrates that 24-h
      variations in HR and HRV are little influenced by the circadian clock andare
      mainly sleep-stage dependent. The results suggest an important role for exogenous
      factors in the morning increase in cardiovascular events. During sleep, the
      sudden rises in HR at each transition from deeper sleep to lighter sleep or
      awakenings might precipitate the adverse cardiac events.

PMID- 12465888
TI  - Photic resetting of the human circadian pacemaker in the absence of conscious
      vision.
AB  - Ocular light exposure patterns are the primary stimuli for entraining the human
      circadian system to the local 24-h day. Many totally blind persons cannot use
      these stimuli and, therefore, have circadian rhythms that are not entrained.
      However, a few otherwise totally blind persons retain the ability to suppress
      plasma melatonin concentrations after ocular light exposure, probably using a
      neural pathway that includes the site of the human circadian pacemaker,
      suggesting that light information is reaching this site. To test definitively
      whether ocular light exposure could affect the circadian pacemaker of some blind
      persons and whether melatonin suppression in response to bright light correlates
      with light-induced phase shifts of thecircadian system, the authorsperformed
      experiments with 5 totally blind volunteers using a protocol known to induce
      phase shifts of the circadian pacemaker in sighted individuals. In the 2 blind
      individuals who maintained light-induced melatonin suppression, the circadian
      system was shifted by appropriately timed bright-light stimuli. These data
      demonstrate that light can affect the circadian pacemaker of some totally blind
      individuals--either by altering the phase of the circadian pacemaker or by
      affecting its amplitude. They are consistent with data from animal studies
      demonstrating that there are different neural pathways and retinal cells that
      relay photic information to the brain: one for conscious light perception and the
      other for non-image-forming functions.

PMID- 12465889
TI  - Circadian adaptation to night-shift work by judicious light and darkness
      exposure.
AB  - In this combined field and laboratory investigation, the authors tested the
      efficacy of an intervention designed to promote circadian adaptation to night
      shift work. Fifteen nurses working permanent night schedules (> or = 8 shifts/ 15
      days) were recruited from area hospitals. Following avacation period of > or = 10
      days on a regular daytime schedule, workers were admitted to the laboratory for
      the assessment of circadian phase via a 36-h constant routine. They returned to
      work approximately 12 night shifts on their regular schedules under one of two
      conditions. Treatment group workers (n = 10, mean age +/- SD = 41.7 +/- 8.8
      years) received an intervention including 6 h of intermittent bright-light
      exposure in the workplace (approximately 3,243 lux) and shielding from bright
      morning outdoor light with tinted goggles (15% visual light transmission).
      Control group workers (n = 9, mean age +/- SD = 42.0 +/- 7.2 years) were observed
      in their habitual work environments. On work days, participants maintained
      regular sleep/wake schedules including a single 8-h sleep/darkness episode
      beginning 2 h after the end of the night shift. A second 36-h constant routine
      was performed following the series of night shifts. In the presence of the
      intervention, circadian rhythms of core body temperature and salivary melatonin
      cycles were delayed by an average (+/- SEM) of -9.32 +/- 1.06 h and -11.31 +/-
      1.13 h, respectively. These were significantly greater than the phase delays of 
      4.09 +/- 1.94 h and -5.08 +/- 2.32 h displayed by the control group (p = 0.03 and
      p = 0.02, respectively). The phase angle between circadian markers and the
      shifted schedule was reestablished to its baseline position only in the treatment
      group of workers. These results support the efficacy of a practical intervention
      for promoting circadian adaptation to night-shift work under field conditions.
      They also underline the importance of controlling the overall pattern of exposure
      to light and darkness in circadian adaptation to shifted sleep/wake schedules.

PMID- 12465890
TI  - Saturation of enzyme kinetics in circadian clock models.
AB  - From the mathematical study of simple models for circadian rhythm, the authors
      identified a clear effect of saturation in the enzyme kinetics on the promotion
      or suppression of a sustained oscillation. In the models, a clock gene (per gene)
      is transcribed to produce mRNAs, which are translated to produce proteins in the
      cytosol which are then transported to the nucleus and suppress the transcription
      of the gene. The negative feedback loop with a long time delay creates sustained
      oscillation. All the enzymatic reactions (e.g., degradation, translation, and
      modification) are assumed to be of Michaelis-Menten type. The reaction rate
      increases with the amount of substrate but saturates when it is very large. The
      authors prove mathematically that the saturation in any of the reactions included
      in the feedback loop (in-loop reaction steps) suppresses the oscillation, whereas
      the saturation of both degradation steps and the back transport of the protein to
      cytosol (branch reaction steps) makes the oscillation more likely to occur. In
      the experimental measurements of enzyme kinetics and in published circadian clock
      simulators, in-loop reaction steps have a small saturation index whereas branch
      reaction steps have a large saturation index.

PMID- 12465891
TI  - A porphyrin C-nucleoside incorporated into DNA.
AB  - [reaction: see text] A free porphyrin coupled on 2-deoxy-D-ribose was synthesized
      and incorporated into DNA via phosphoramidite chemistry. Substitution at the ends
      of a 5'-modified self-complementary duplex was found to be thermally and
      thermodynamically stabilizing. The porphyrin moiety strongly intercalates in the
      duplex when located near the center, and retains its fluorescence properties in
      DNA.

PMID- 12465892
TI  - Synthesis of enantiomerically pure 2,2,3,4,5-pentasubstituted pyrrolidines by
      phenylsulfanyl migration.
AB  - [reaction: see text] Enantiomerically pure 2,2,3,4,5-pentasubstituted
      pyrrolidines can be prepared, in high overall yield, from alpha,beta-unsaturated
      esters. Asymmetry is introduced via a Michael addition, and additional
      stereogenic centers are introduced by an aldol reaction. A novel stereospecific
      ring-forming reaction, proceeding via a thiiranium (episulfonium) ion, yields
      pyrrolidines from beta-hydroxy sulfides. In this manner, 2,2,3,4,5
      pentasubstituted pyrrolidines, containing three contiguous stereogenic centers
      around the ring, can be prepared in 44% overall yield from ethyl crotonate.

PMID- 12465893
TI  - A facile synthesis of cis-1-methyl-1,2,3,3a,4,8b- hexahydropyrrolo[3,2
      f]pyrindine, an annulated nicotine analog.
AB  - [reaction: see text] The title compound, 2, has been synthesized in 45% overall
      yield in six steps from 3-bromopyridine. The hexahydropyrrolo[3,2-f]pyrindine
      skeleton was constructed from key intermediate 5, via intramolecular azomethine
      ylide-alkene [3 + 2] cycloaddition. The present work constitutes a general method
      for rapid assembly of other related tricyclic nicotine analogues.

PMID- 12465894
TI  - UCS1025A and B, new antitumor antibiotics from the fungus Acremonium species.
AB  - [structure: see text] UCS1025A and B, novel pentacyclic polyketides with an
      unprecedented furopyrrolizidine skeleton, were isolated from the fungus
      Acremonium sp. KY4917. The structures and stereochemistry were elucidated by a
      combination of two-dimensional NMR and X-ray crystallographic analysis. UCS1025A
      showed unique chemical equilibria involving three tautomeric isomers and
      exhibited antimicrobial activity and antiproliferative activity against human
      tumor cell lines.

PMID- 12465895
TI  - Computer-aided design of chiral ligands. Part III. A novel ligand for asymmetric
      allylation designed using computational techniques.
AB  - [reaction: see text] Computer-aided design protocols to identify new chiral
      ligands for reactions proceeding through well-defined transition states are
      outlined. Ligand families are discovered via computational screening of large
      structural databases such as the Cambridge Structural Database. Using this
      method, a novel cis-decalin ligand has been identified as a chiral auxiliary for
      the allylboration of aldehydes. Synthesis, resolution, and evaluation revealed
      that this new auxiliary provided the aldehyde facial approach upon which the
      design was predicated.

PMID- 12465896
TI  - High-affinity peptide nucleic acid oligomers containing tricyclic cytosine
      analogues.
AB  - [structure: see text] Peptide nucleic acid (PNA) monomers containing the
      tricyclic cytosine analogues phenoxazine, 9-(2-aminoethoxy)phenoxazine (G-clamp),
      and 9-(3-aminopropoxy)phenoxazine (propyl-G-clamp) have been synthesized. The
      modified nucleobases were incorporated into PNA oligomers using Boc-chemistry for
      solid-phase synthesis. PNAs containing single G-clamp modifications exhibit
      significantly enhanced affinity toward RNA and DNA targets relative to unmodified
      PNA while maintaining mismatch discrimination. These PNA G-clamp modifications
      exhibit the highest increase in affinity toward nucleic acid targets reported so
      far for PNA modifications.

PMID- 12465897
TI  - Poly(ethylene glycol) (PEG) as a reusable solvent medium for organic synthesis.
      Application in the Heck reaction.
AB  - [reaction: see text] PEG has been used as a solvent medium for regioselective
      Heck reactions with easy recyclability of solvent and Pd catalyst for the first
      time.

PMID- 12465898
TI  - Total synthesis of sphingofungin F.
AB  - [reaction: see text] A concise, stereocontrolled synthesis of sphingofungin F was
      achieved. Key features involve diastereoselective oxazoline formation catalyzed
      by palladium(0), MgBr(2)-promoted gamma-alkoxy allylic stannane addition, and
      palladium(0)-catalyzed coupling of a vinyl iodide with an organozinc reagent.

PMID- 12465899
TI  - Template-assisted preferential formation of a syn photodimer in a pyrophosphate
      induced self-assembly of a thymine-functionalized isothiouronium receptor.
AB  - [reaction: see text] The effect of anion templation is investigated for the
      photodimerization of a thymine-functionalized isothiouronium receptor. The
      receptor forms a photodimer at the thymine moiety in methanol upon UV
      irradiation, while the isothiouronium moiety works as an oxoanion binding site
      via a two-point hydrogen-bonding motif. As compared to the case of a free
      receptor, the presence of pyrophosphate (PPi) resulted in the preferential
      formation of the syn-type photodimer, which would be desirable for recognizing
      the templated PPi.

PMID- 12465900
TI  - Ketene dithioacetals in the aza-Diels-Alder reaction with N-arylimines: a
      versatile approach to tetrahydroquinolines, 2,3-dihydro-4-quinolones, and 4
      quinolones.
AB  - [reaction: see text] The first successful use of ketene dithioacetals as
      dienophiles in the aza-Diels-Alder reaction with N-arylimines is described. Among
      the ketene dithioacetals tested, 1,4-benzodithiafulvenes are most effective in
      assembling the tetrahydroquinoline core. Subsequent chemical manipulations
      provide a concise and divergent approach to the synthesis of 2,3
      tetrahydroquinolines, 2,3-dihydro-4-quinolones, and 4-quinolones.

PMID- 12465901
TI  - Photochemistry on soluble polymer supports: synthesis of nucleosides.
AB  - [reaction: see text] A new soluble polymer support synthesis of nucleosides is
      described. The photochemical ring expansion of cyclobutanones in the presence of
      poly(ethylene glycol) (PEG) results in polymer-supported ribosides. These
      photoadducts can be cleaved from the polymer under Vorbruggen coupling conditions
      with TMS-protected purines and pyrimidines to give ribonucleosides. The method
      has been extended to include modified PEGs with dendritic end-groups in order to
      improve the loading levels for these coupling reactions.

PMID- 12465902
TI  - Novel tunable CuX(2)-mediated cyclization reaction of cyclopropylideneacetic
      acids and esters for the facile synthesis of 4-halomethyl-2(5H)-furanones and 4
      halo-5,6-dihydro-2H-pyran-2-ones.
AB  - [reaction: see text] A mixture of cyclopropylideneacetic acids (or esters) and
      CuBr(2) (or CuI/I(2)) in aqueous acetonitrile afforded 4-substituted 2(5H)
      furanones or 3,4-substituted 5,6-dihydro-2H-pyran-2-ones in moderate to good
      yields. The selectivity of the reaction greatly depended on the reaction
      temperature.

PMID- 12465903
TI  - An efficient copper catalyst for the formation of sulfones from sulfinic acid
      salts and aryl iodides.
AB  - [reaction: see text] A novel copper-catalyzed method for the coupling of sulfinic
      acid salts and aryl iodides is described. A variety of methyl and diaryl sulfones
      have been formed in excellent yields.

PMID- 12465904
TI  - Synthesis of the C20-C26 building block of halichondrins via a regiospecific and
      stereoselective S(N)2' reaction.
AB  - [reaction: see text] A regiospecific and stereoselective S(N)2' reaction to
      convert the trisylate into the vinyl iodide is presented. The homoallylic alcohol
      is used to direct the delivery of LiCu(Me)(2).

PMID- 12465905
TI  - Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: stoichiometric process.
AB  - [reaction: see text] Via an X-ray analysis, the sulfonamide bearing R(1) = i-Pr,
      R(2) = Me, and R(3) = Me is shown to be a tridentate ligand to a Cr(III) salt.
      This class of ligands, represented by R(1) = t-Bu, R(2) = 2-naphthyl, and R(3) =
      Me, is effective to achieve an asymmetric Ni/Cr-mediated coupling reaction and,
      with the C14-C38 segment of halichondrins, its synthetic potential has been
      demonstrated. A possible mechanism is suggested for the process.

PMID- 12465906
TI  - Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: catalytic process.
AB  - [reaction: see text] The stable, crystalline Cr(III)/sulfonamide complex 1a is
      shown to be an effective catalyst for the Ni/Cr-mediated coupling reaction. A
      possible mechanism is suggested for the process. 1a is also effective for other
      Cr-mediated coupling reactions. With this catalyst, a concise and efficient
      synthesis of the C14-C26 segment of halichondrins has been developed.

PMID- 12465907
TI  - Synthesis and properties of novel thiophene-based conjugated homologues: 9,9
      diphenylfluorene-capped oligothiophenes.
AB  - [reaction: see text] A series of novel 9,9-diarylfluorene-capped oligothiophenes
      were synthesized by Suzuki coupling reactions in good yields. The color of the
      emissions can be controlled by varying the conjugation length of the
      oligothiophene core. The bulky and rigid terminal groups of the resulting
      oligomers are significantly beneficial for their high morphological and thermal
      stability. These new oligothiophenes exhibit intriguing reversible oxidation and
      reduction redox behavior.

PMID- 12465908
TI  - Discodermolide/Dictyostatin hybrids: synthesis and biological evaluation.
AB  - [structure: see text] Two hybrid analogues of discodermolide and dictyostatin (3,
      26) have been designed and synthesized. These are the first macrocyclic analogues
      of discodermolide and biological activities were evaluated and compared with
      linear discodermolide analogues.

PMID- 12465909
TI  - Enantioselective syntheses of colletodiol, colletol, and grahamimycin A.
AB  - [reaction: see text] The enantioselective synthesis of colletodiol has been
      achieved in 11 steps from methyl 1,3,5-octatrienoate and 16 total steps from both
      ethyl sorbate and methyl 1,3,5-octatrienoate. The route relies upon an enantio-
      and regioselective Sharpless dihydroxylation and a palladium-catalyzed reduction
      to form a 5-hydroxy-1-enoate and an 7-hydroxy-1,3-dienoate. These esters were
      further functionalized, coupled, and macrolactonized to provide colletodiol after
      deprotection. Grahamimycin A and colletol were synthesized in one and two steps,
      respectively, from colletodiol.

PMID- 12465910
TI  - CeCl(3) x 7H(2)O-NaI catalyzed hydrooxacyclization of unsaturated 3-hydroxy
      esters.
AB  - [reaction: see text] Cerium(III) chloride heptahydrate and sodium iodide in
      boiling acetonitrile promote cyclization of 3-hydroxyalkenoic acids esters giving
      5-substituted tetrahydrofuranacetic acid esters and 6-substituted
      tetrahydropyranacetic acid esters in fair to good yield and with complete
      retention of the absolute configuration of the starting 3-hydroxy ester.

PMID- 12465911
TI  - Synthesis of the unnatural amino acid AGDHE, a constituent of the cyclic
      depsipeptides callipeltins A and D.
AB  - [reaction: see text] The novel amino acid residue (2R,3R,4S)-4-amido-7-guanidino
      2,3-dihydroxyheptanoic acid (AGDHE, 3), a constituent of the cyclic depsipeptides
      callipeltins A and D, and its (2S,3S,4S) diastereomer were synthesized from a
      protected L-ornithine derivative in 13 steps (15% overall yield), and its
      configurational assignment was reexamined by (1)H NMR.

PMID- 12465912
TI  - Directed evolution experiments reveal mutations at cycloartenol synthase residue
      His477 that dramatically alter catalysis.
AB  - [reaction: see text] Cycloartenol synthase cyclizes and rearranges oxidosqualene
      to the protosteryl cation and then specifically deprotonates from C-19. To
      identify mutants that deprotonate differently, randomly generated mutant
      cycloartenol synthases were selected in a yeast lanosterol synthase mutant. A
      novel His477Asn mutant was uncovered that produces 88% lanosterol and 12%
      parkeol. The His477Gln mutant produces 73% parkeol, 22% lanosterol, and 5%
      Delta(7)-lanosterol. These are the most accurate lanosterol synthase and parkeol
      synthase that have been generated by mutagenesis.

PMID- 12465913
TI  - An efficient method for cyclopentene annulation onto alpha,beta-unsaturated
      ketones: W(CO)(5)(L)-catalyzed 5-endo-dig cyclization of 6-siloxy-5-en-1-ynes.
AB  - [reaction: see text] A highly efficient method for the cyclopentene annulation
      onto alpha,beta-unsaturated ketones is described. Indium-mediated 1,4
      propargylation onto alpha,beta-unsaturated ketones in the presence of tert
      butyldimethylsilyl triflate and dimethyl sulfide gives the 6-siloxy-5-en-1-yne
      derivatives, which undergo W(CO)(5)(L)-catalyzed 5-endo-dig cyclization to give
      the corresponding cyclopentene derivatives in good yield.

PMID- 12465914
TI  - Synthesis of photoactive p-azidotetrafluorophenylalanine containing peptide by
      solid-phase Fmoc methodology.
AB  - [structure: see text] N-Fmoc-L-p-azidotetrafluorophenylalanine was prepared from
      achiral starting materials using an acetamidomalonate synthesis and enzymatic
      resolution. A photoactive peptide containing this fluorinated residue could be
      assembled using solid-phase Fmoc chemistry.

PMID- 12465915
TI  - A novel chiral ferrocenyl phosphine ligand from sugar: applications in Rh
      catalyzed asymmetric hydrogenation reactions.
AB  - [structure: see text] A new chiral ferrocenyl diphosphine ligand 3 was
      synthesized from readily available D-mannitol. Rh-complex with this ligand showed
      high enantioselectivity and reactivity in the asymmetric hydrogenation of
      dehydroamino acid derivatives and itaconic acid derivatives. Up to over 99% ee
      and 10 000 TON were achieved with this catalytic system.

PMID- 12465916
TI  - Pyrrolidine-5,5-trans-lactams. 1. Synthesis and incorporation into inhibitors of
      hepatitis C virus NS3/4A protease.
AB  - [reaction: see text] In this, the first of two letters, we outline the use of the
      pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based
      inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of
      the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals
      (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and
      a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(
      )(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV
      assay.

PMID- 12465917
TI  - Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray crystal structure data in the
      optimization of P3 and P4 substituents.
AB  - [reaction: see text] In this, the second of two letters, we describe the
      elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the
      requirements for optimal substitution of the pyrrolidine and lactam nitrogen
      atoms. Central to the strategy is the use of rapid iterative synthesis in
      conjunction with X-ray crystal structure determination of ligand-protein
      complexes.

PMID- 12465918
TI  - A new strategy toward the total synthesis of stachyflin, a potent anti-influenza
      A virus agent: concise route to the tetracyclic core structure.
AB  - [reaction: see text] A new strategy directed toward the total synthesis of
      stachyflin, a potent and novel anti-influenza A virus agent isolated from a
      microorganism, has been presented through the enantioselective synthesis of the
      tetracyclic core structure. The synthetic method features a BF(3) x Et(2)O
      induced domino epoxide-opening/rearrangement/cyclization reaction as the key
      step.

PMID- 12465919
TI  - Synthesis of a new fluorescent probe specific for catechols.
AB  - [reaction: see text] The synthesis of a new fluorescent probe, specific for the
      catechol moiety, has been conducted by preparation of alpha,alpha
      dibromomalonamides containing an appropriate fluorophore. N,N'-Bis-anthracen-9
      ylmethyl-2,2-dibromomalonamide reacted with various catechols in the presence of
      cesium carbonate to generate highly fluorescent derivatives.

PMID- 12465920
TI  - Synthesis of corroles bearing up to three different meso substituents.
AB  - [reaction: see text] We have developed a new method that affords
      regioisomerically pure corroles possessing up to three different substituents at
      the meso positions. The corrole formation reaction involves the acid-catalyzed
      condensation of a dipyrromethane-dicarbinol with pyrrole followed by oxidation
      with DDQ. ABC-Type corroles were synthesized for the first time according to this
      procedure.

PMID- 12465921
TI  - Highly enantioselective hydrogenation of enol acetates catalyzed by Ru-TunaPhos
      complexes.
AB  - [reaction: see text] The chiral disphosphines with tunable dihedral angles
      (TunaPhos) have been used for asymmetric hydrogenation of enol acetates and
      dihedral-angle-dependent enantioselectivities were observed. C2-TunaPhos has been
      proved to be effective for Ru-catalyzed asymmetric hydrogenation of electron
      deficient and other enol acetates.

PMID- 12465922
TI  - Synthesis of trans-(3S)-amino-(4R)-alkyl- and -(4S)-aryl-piperidines via ring
      closing metathesis reaction.
AB  - [reaction: see text] trans-(3S)-Amino piperidines bearing various alkyl and aryl
      substituents at the C-4 position were synthesized via a ring-closing metathesis
      reaction. The absolute stereochemistry was controlled using a protected D-serine
      as a starting material. Stereoselective hydrogenation of allylamines provided
      trans-(3S)-amino-(4R)-alkyl- and -(4S)-aryl-piperidines. This procedure presents
      the first method for the asymmetric synthesis of 4-substituted 3-amino
      piperidines.

PMID- 12465923
TI  - Synthesis of novel cyclic oligosaccharides: beta-1,6-thio-linked
      cycloglucopyranosides.
AB  - [structure: see text] A protocol for the synthesis of novel cyclic beta-1,6-S
      linked glucopyranosides is developed. The key intermediate is a linear
      thiooligosaccharide bearing an iodo group at C-6 of the nonreducing sugar and a
      thioacetyl group at the anomeric center of the reducing end sugar. The crucial
      macrocyclization step was achieved through base-promoted intramolecular S(N)2
      glycosylation in remarkably high yields (92-95%) and with well-controlled
      stereochemistry.

PMID- 12465924
TI  - Rhodium(II,II) dimer as an efficient catalyst for aziridination of sulfonamides
      and amidation of steroids.
AB  - [reaction: see text] Unsaturated sulfonamides underwent direct intramolecular
      aziridination catalyzed by Rh(2)(OAc)(4) with PhI(OAc)(2) and Al(2)O(3) to give
      the corresponding aziridine products in excellent yields (up to 98%) and with
      good to excellent conversions. High turnovers (up to 1375) were achieved. The
      intermolecular rhodium-catalyzed amidation of cholesteryl acetate with PhI=NTs or
      PhI(OAc)(2)/NH(2)R as the nitrogen source exhibited both excellent regio- and
      alpha-selectivity (alpha/beta ratio up to 9:1).

PMID- 12465925
TI  - Stereodivergent approach to beta-hydroxy alpha-amino acids from C(2)-symmetrical
      alk-2-yne-1,4-diols.
AB  - [reaction: see text] A new stereodivergent route to erythro- and threo-beta
      substituted serines from a common C(2)-symmetrical alk-2-yne-1,4-diol is
      described. Stereocontrol in such an acyclic system is achieved by taking
      advantage of symmetry. Stereoselective alkyne reduction to either (Z)- or (E)
      olefin allows selection of the stereochemistry of alpha-carbon in the final amino
      acid by using a Pd(0)-catalyzed process. This strategy has been applied to the
      synthesis of (2S,3S)-3-hydroxyleucine.

PMID- 12465926
TI  - The stereocontrolled total synthesis of (-)-O-methylpallidinine.
AB  - [reaction: see text] The stereocontrolled total synthesis of (-)-O
      methylpallidinine, a naturally occurring Morphinan alkaloid with a B/C-trans
      hydrophenanthrene framework, has been achieved starting from the chiral
      bicyclo[3.2.1]octenone building block by employing a single-step
      dihydrophenanthrene formation reaction as the key step.

PMID- 12465927
TI  - One-pot asymmetric synthesis of beta-cyanohydroxymethyl alpha-amino acid
      derivatives: formation of three contiguous stereogenic centers.
AB  - [reaction: see text] One-pot asymmetric Mannich-hydrocyanation reactions are
      described. Reaction of unmodified aldehydes with N-PMP-protected alpha-imino
      ethyl glyoxylate in the presence of catalytic amounts of L-proline followed by
      the addition of Et(2)AlCN provided highly enantiomerically pure beta
      cyanohydroxymethyl alpha-amino acid derivatives possessing three contiguous
      stereogenic centers as single diastereomers (93-99% ee). Control of reaction
      temperature during the cyanation step directed whether cyclization of the
      products to lactones occurred.

PMID- 12465928
TI  - Concerning the origin of the high beta-selectivity of glycosidation reactions of
      2-deoxy-2-iodo-glucopyranosyl trichloroacetimidates.
AB  - [structure: see text] Studies on the glycosidation reactions of conformationally
      constrained glycosyl imidates 8a and 8b were performed to evaluate the possible
      involvement of "conformationally inverted" oxonium ion intermediates in
      glycosidation reactions with 2-deoxy-2-iodo-glucopyranosyl donors. The
      mechanistic implications of this study are discussed, and intermediates 23 and 24
      are invoked to rationalize the observed beta-selectivities.

PMID- 12465929
TI  - Diastereoselective synthesis of highly substituted tetrahydropyran-4-ones.
AB  - [reaction: see text] Aldol reactions of beta-ketoesters with aldehydes followed
      by a tandem Knoevenagel condensation, with a further equivalent of aldehyde, and
      intramolecular Michael addition produces single diastereomers of highly
      substituted tetrahydropyran-4-ones.

PMID- 12465930
TI  - Transition metal-catalyzed cyclopropanation of alkenes in water: catalyst
      efficiency and in situ generation of the diazo reagent.
AB  - [reaction: see text] A cyclopropanation reaction involving ethyl diazoacetate and
      olefins proceeds with surprisingly high efficiency in aqueous media using Rh(II)
      carboxylates. Nishiyama's Ru(II) Py-box and Katsuki's Co(II) Salen complexes that
      allow for highly enantioselective cyclopropanations in organic solvents can also
      be applied to aqueous cyclopropanations with similar results. In situ generation
      of ethyl diazoacetate and cyclopropanation also proceeds efficiently. A
      chemoselective O-H insertion is also possible in water when hydrophobic catalysts
      and alcohols are used.

PMID- 12465931
TI  - Cyclopentadithiophene (CPDT) dimer dication: bipolaron model for
      quaterthiophenes.
AB  - [structure: see text] Cyclopentadithiophene (CPDT) dimers in which both 3,3' and
      4' ',3' " positions were bridged with 1,3-dioxalane, carbonyl, or
      dicyanovinylidene were prepared. These compounds have small HOMO-LUMO gaps (1.03
      2.25 eV). The electrochemical oxidation of a dicyanovinylidene-bridged CPDT dimer
      gave a dication that had a quinoid-like structure.

PMID- 12465932
TI  - SmI(2)-promoted oxidation of aldehydes in the presence of electron-rich
      heteroatoms.
AB  - [reaction: see text] The Evans-Tishchenko reaction provides an efficient and
      practical solution for the oxidation of aldehydes possessing sensitive electron
      rich heteroatoms to the corresponding esters. Careful selection of the
      sacrificial beta-hydroxy ketone provides considerable subsequent flexibility to
      access the desired carboxylic acid.

PMID- 12465933
TI  - Synthesis and thermolysis of heterocyclic 3-aza-3-ene-1,5-diynes(1).
AB  - [reaction: see text] Simple, acyclic 3-aza-3-ene-1,5-diynes undergo an aza
      Bergman rearrangement to a fleeting 2,5-didehydropyridine (2,5-ddp) intermediate
      that rapidly ring-opens to beta-alkynylacrylonitrile products. In an effort to
      access longer-lived 2,5-ddp intermediates, we have prepared heterocyclic 3-aza-3
      ene-1,5-diynes. The thermolysis of one such heterocyclic aza-enediyne does not
      afford products derived from trapping a 2,5-ddp intermediate but rather
      cyclopropanes that appear to arise from a carbene intermediate and a product that
      appears to be a trapping product from a 2,3-ddp intermediate.

PMID- 12465934
TI  - A highly abbreviated synthesis of pentalenene by means of the squarate ester
      cascade.
AB  - [reaction: see text] The sequential addition of 5-methylcyclopentyllithium and
      propynyllithium to diisopropyl squarate results in the efficient formation of a
      functionalized angular triquinane having two of its five-membered rings
      substituted precisely as in the target sesquiterpene. Only seven additional steps
      are then required to access pentalenene.

PMID- 12465935
TI  - Practical total synthesis of ciguatoxin CTX3C by improved protective group
      strategy.
AB  - [structure: see text] Ciguatoxin CTX3C is a representative congener of
      ciguatoxins, which are known to be the principal causative agents of ciguatera
      seafood poisoning. The structure of CTX3C spans more than 3 nm and is
      characterized by 13 ether rings. In this paper, an improved total synthesis of
      CTX3C is reported. Alteration of the protective group from benzyl ether to 2
      naphthylmethyl (NAP) ether drastically increases the yield for final global
      deprotection and has provided a sufficient amount of sample for further
      biological studies.

PMID- 12465936
TI  - A new 1,1'-binaphthyl-based catalyst for the enantioselective phenylacetylene
      addition to aromatic aldehydes without using a titanium complex.
AB  - [reaction: see text] A novel 1,1'-binaphthyl compound containing bulky 3,3'-aryl
      substituents is found to catalyze the reaction of a terminal alkyne with various
      aromatic aldehydes under mild conditions to generate chiral propargyl alcohols
      with 80-94% ee. Unlike the previously reported 1,1'-binaphthyl catalysts, this
      new compound does not require the use of a titanium complex and the pre
      preparation of an alkynylzinc. This has greatly simplified the experimental
      procedure for this reaction.

PMID- 12465937
TI  - Reinvestigation of mucohalic acids, versatile and useful building blocks for
      highly functionalized alpha,beta-unsaturated gamma-butyrolactones.
AB  - [reaction: see text] Mucohalic acids (mucochloric acid (1, 3,4-dichloro-5-hydroxy
      5H-furan-2-one) and mucobromic acid (2, 3,4-dibromo-5-hydroxy-5H-furan-2-one))
      are inexpensive, commercially available starting materials with multiple
      functional groups. These compounds have been modified by way of reduction
      followed by Suzuki cross-coupling reactions involving arylboronic acids to afford
      highly functionalized alpha,beta-unsaturated gamma-butyrolactones in excellent
      yield. The synthetic utility of these building blocks was effectively
      demonstrated through preparation of the antiinflammatory drug Vioxx.

PMID- 12465938
TI  - Diphenylmethylidenecyclobuta[a]cyclopropa[d]benzene: synthesis and spectral
      characterization.
AB  - [reaction: see text] The first derivative of the novel and highly strained
      rocketene (cyclobuta[a]cyclopropa[d]benzene) 5, namely, the C4 diphenyl
      substituted exocyclic alkene 8, has been prepared in 16% overall yield as a
      yellow oil with properties fully consistent with its highly strained nature.

PMID- 12465939
TI  - Enantioselective deprotonation of meso-cycloheptanone derivative: application to
      the synthesis of a potential intermediate for pseudomonic acid B.
AB  - [reaction: see text] A novel synthetic path to a potential intermediate for the
      synthesis of pseudomonic acid B was established by employing enantioselective
      deprotonation of a meso-cycloheptanone derivative bearing hydroxy groups at the
      3,4,5,6-positions with lithium (S,S')-alpha,alpha'-dimethyldibenzylamide as a key
      step.

PMID- 12465940
TI  - Dissections: self-assembled aggregates that spontaneously reconfigure their
      structures when their environment changes.
AB  - This Communication describes a new strategy for the design of adaptive structures
      based on reconfigurable mesoscale self-assembly. Several sets of millimeter-scale
      objects have been designed that can self-assemble into two different, regular
      aggregates at the interface between an aqueous solution and perfluorodecalin; the
      choice between the two aggregates is determined by the density of the aqueous
      phase.

PMID- 12465941
TI  - Triangular and tetrahedral array of silver(I) ions by a novel disk-shaped
      tridentate ligand: dynamic control of coordination equilibrium of the silver(I)
      complexes.
AB  - A disk-shaped tridentate ligand 1 arranges silver(I) ions in a two-dimensional
      triangular and a three-dimensional tetrahedral fashion in the metal-ligand
      ratios, 3:2 and 1:1, respectively. The resulting sandwich-type (Ag312) and
      tetrahedral (Ag414) architectures are in a dynamic equilibrium in solution.

PMID- 12465942
TI  - A new approach to hybrid nanocomposite materials with periodic structures.
AB  - Hybrid core-shell polymer-semiconductor or polymer-metal microspheres were used
      in the "bottom-top" approach to production of nanocomposite materials with
      periodic structures. In the first step CdS and Ag nanocrystals were synthesized
      in situ on the surface of polymer microspheres using ion exchange between the
      counter ions in the electrical double layer of latex beads and ions in the liquid
      medium. In the second step a low-Tg polymeric shell was synthesized on the
      surface of hybrid particles, which upon annealing of the periodic array of three
      layer microbeads formed a matrix. The proposed strategy employing hybrid
      microspheres as the functional structural blocks shows a new way to produce
      optically responsive materials with periodicity commensurable with the wavelength
      of light, an intrinsic property of photonic crystals.

PMID- 12465943
TI  - Enzymatic formation of an unnatural hexacyclic C35 polyprenoid by bacterial
      squalene cyclase.
AB  - A C35 polyprene in which a farnesyl C15 unit is connected in a head-to-head
      fashion to a geranylgeranyl C20 unit was enzymatically converted to an unnatural
      hexacyclic polyprenoid by squalene:hopene cyclase from Alicyclobacillus
      acidocaldarius. This is the first demonstration of the remarkable ability of the
      squalene cyclizing enzyme to perform construction of unnatural hexacyclic
      skeleton. The cyclization of the C35 polyprene was initiated by a proton attack
      on the terminal double bond of the C15 unit and proceeded without rearrangement
      of carbon and hydrogen. The substrate should be folded in chair-chair-chair-chair
      boat-boat conformation to achieve the stereochemistry of the cyclization product.

PMID- 12465944
TI  - Dithiane additions to vinyl epoxides: steric control over the SN2 and SN2'
      manifolds.
AB  - High chemoselectivity can be achieved in the addition of lithium dithiane anions
      to vinyl epoxides exploiting the steric nature of the dithiane substituent.
      Unencumbered dithiane anions afford SN2 adducts, whereas sterically encumbered
      anions lead primarily to SN2' adducts. Furthermore, the SN2' addition occurs syn
      to the vinyl epoxide.

PMID- 12465945
TI  - Alkyne adducts of [W2(OCH2tBu)8]n (M = M): comparisons of bridging and terminal
      addition products.
AB  - Alkynes are found to react with [W2(OCH2tBu)8] (M = M) in hydrocarbon solvents at
      room temperature or 45 degrees C to give 1:1 adducts. These are shown to be
      either bridged (mu-PhCCH and mu-MeCCMe) or terminal-bound (eta2-PhCCMe) in the
      solid state by single-crystal X-ray crystallography. In solution NMR spectroscopy
      reveals that bridged and terminal species exist in equilibrium for MeCCH, MeCCMe,
      and PhCCMe. By NMR spectroscopy the PhCCH and Me3SiCCH adducts are present in
      solution in bridging and terminally bonded species, respectively. The
      interconversion of bridged and terminal-bound adducts is chemically rapid but
      slow on the NMR time scale even though each type of adduct shows fluxional
      behavior. Calculations employing density functional theory have been carried out
      on alkyne adducts of the model template W2(OCH3)8 and reveal very small
      differences in energy between a mu-skewed structure and one having a terminal
      eta2-alkyne.

PMID- 12465946
TI  - A small molecule with osteogenesis-inducing activity in multipotent mesenchymal
      progenitor cells.
AB  - Purmorphamine, which is a 2,6,9-trisubstituted purine compound, was discovered
      through cell-based high-throughput screening from a heterocycle combinatorial
      library. It differentiates multipotent mesenchymal progenitor cells into an
      osteoblast lineage. It will serve as a unique chemical tool to study the
      molecular mechanisms of osteogenesis of stem cells and bone development.

PMID- 12465947
TI  - Chiral self-discrimination in a M3L2 subphthalocyanine cage.
AB  - A tris(3-pyridyl)-substituted C3 symmetric subphthalocyanine (SubPc) was
      dimerized into a M3L2 cage in the presence of a stoichiometric amount of
      (en)Pd(NO3)2. NMR studies demonstrated the recognition event to be accompanied by
      chiral self-discrimination between the two enantiomers of the SubPc. Moreover,
      the specificity is such that only one of four possible isomers was detected in
      solution.

PMID- 12465948
TI  - A potent and highly selective sulfotransferase inhibitor.
AB  - In the present work, we have used a newly developed, fluorescence-based assay to
      screen a library of >30 000 compounds as potential beta-arylsulfotransferase-IV
      inhibitors. A total of 11 inhibitors were discovered. Most of the compounds
      discovered showed low micromolar inhibition, but one of the compounds showed
      potent inhibition (Ki = 96 nM). The most potent of these inhibitors was tested
      against a variety of other purine binding enzymes and showed remarkable
      specificity.

PMID- 12465949
TI  - A chlorine isotope effect for enzyme-catalyzed chlorination.
AB  - Several chlorinated organic compounds (COCs) that have been detected in a wide
      range of human, animal, and environmental samples may be derived from natural or
      anthropogenic sources. To determine whether the Cl isotope ratios of these
      compounds could be used to differentiate sources, we investigated the chlorine
      isotope effect for enzyme-catalyzed chlorination. Two aromatic substrates, 1,3,5
      trimethylbenzene (TMB) and 3,5-dimethylphenol (DMP), were treated with a
      chloroperoxidase isolated from the fungus Caldariomyces fumago. A kinetic isotope
      effect (KIE) (in terms of k35/k37) was calculated to be 1.012 for TMB and 1.011
      for DMP. A similar reaction, but not catalyzed, with hypochlorite yielded a much
      smaller KIE. These results indicate that a substantial KIE exists for this
      process. Furthermore, natural COCs synthesized by this enzymatic pathway may have
      Cl isotope ratios that will be easily distinguished from anthropogenic COCs.

PMID- 12465950
TI  - Molecular rectification through electric field induced conformational changes.
AB  - A new approach for the design of a molecular rectifier is proposed. Using a
      simple model, we have shown that conformational changes induced by the electric
      field may lead to a rectifying junction. The simplest possible rectifier of this
      kind presents two almost isoenergetic conformations, with different conductances
      and dipole moments. A simple equation allows for the estimation of the range of
      molecular parameters and temperatures that lead to an effective rectification.
      Examples show that rectification based on this mechanism is also possible at room
      temperature.

PMID- 12465951
TI  - An efficient enantioselective fluorination of various beta-ketoesters catalyzed
      by chiral palladium complexes.
AB  - Reflecting the importance of fluorinated organic compounds in medicinal
      chemistry, development of an efficient method for catalytic enantioselective
      fluorination is increasingly desirable. Using a novel palladium complex 2 (1-2.5
      mol %), various beta-ketoesters including cyclic and acyclic substrates were
      fluorinated with excellent enantioselectivity in the range of 83-94% ee. It is
      environmentally advantageous that this reaction proceeds well in solvents such as
      EtOH, rather than usual organic solvents. Furthermore, the product was
      successfully tranformed into both alpha-fluoro beta-hydroxy and beta-amino acid
      derivatives, which should be extremely useful in developing novel drugs.

PMID- 12465952
TI  - Observations of different triplet conformations in time-resolved infrared spectra
      of alkyl phenylglyoxylates.
AB  - Two different conformations of the triplet state of alkyl phenylglyoxylates were
      observed by means of time-resolved step-scan FT-IR spectroscopy. The amplitude of
      the peak corresponding to the sterically hindered conformation decreases as the
      size of the alkyl group increases. Both conformations exhibit similar reactivity
      in intermolecular hydrogen abstraction, but only one of them undergoes Norrish
      Type II photoelimination.

PMID- 12465953
TI  - Oxygen-oxygen bond homolysis in a novel titanium(IV) alkylperoxide complex,
      Cp2Ti(OOtBu)Cl.
AB  - Cp2TiCl2 reacts with NaOOtBu to form the new titanium peroxide complex,
      Cp2Ti(OOtBu)Cl (1), which has been characterized both in solution and in the
      solid state. This complex is surprisingly unreactive towards olefins and
      phosphines, as it does not directly transfer an oxygen atom. Instead,
      decomposition occurs via initial homolysis of the oxygen-oxygen bond, yielding a
      tert-butoxyl radical. Decomposition of 1 in the presence of phosphines yields
      either phosphine oxides (e.g., OPPh3) or phosphinites (e.g., tBuOPEt2), products
      that result from tBuO* + PR3. O-O bond homolysis is surprising because the Ti(IV)
      center is d0 and cannot be oxidized, where all previous clear examples of
      homolytic cleavage of metal peroxide complexes are facilitated by oxidation of
      the metal center.

PMID- 12465954
TI  - Non-covalent synthesis in aqueous solution of discrete multi-porphyrin aggregates
      with programmable stoichiometry and sequence.
AB  - This unprecedented calixarene templated, noncovalent synthesis of multi-porphyrin
      complexes in aqueous solution makes it possible to plan the nature,
      stoichiometry, and sequence of porphyrins. The proposed method presents the same
      accuracy of the covalent approach and a 100% yield, but it is not as time
      consuming as the latter method.

PMID- 12465955
TI  - Direct detection of radical cations of NADH analogues.
AB  - The radical cation of an NADH analogue (BNAH: 1-benzyl-1,4-dihydronicotinamide)
      has been successfully detected as the transient absorption and ESR spectra in the
      thermal electron transfer from BNAH to Fe(bpy)33+ (bpy = 2,2'-bipyridine). The
      ESR spectra of the radical cations of BNAH and the dideuterated compound (BNAH
      4,4'-d2) indicate that the observed radical cation is the keto form rather than
      the enol form in the tautomerization. The deprotonation rate and the kinetic
      isotope effects of the keto form of BNAH*+ were determined from the kinetic
      analysis of the electron-transfer reactions.

PMID- 12465956
TI  - Self-directed assembly of photoactive hybrid silicates derived from an azobenzene
      bridged silsesquioxane.
AB  - Hybrid silicate materials derived from organo-bridged silsesquioxane precursors,
      RO3-Si-R'-Si-OR3, where R and R' are organic ligands, represent a remarkably
      diverse class of nanocomposites capable of forming both Si-O-Si and Si-C-Si bonds
      with molecular scale homogeneity. Recently, in an effort to better control their
      structure and function, surfactant-directed self-assembly or self-directed
      assembly has been used to synthesize hierarchical organo-bridged
      polysilsesquioxanes that exhibit order over multiple length scales. Here we
      report the synthesis and self-directed assembly of an optically active azobenzene
      bridged silsesquioxane, 4,4'-bis(3-triethoxysilylpropylureido)azobenzene 1.
      Hydrogen-bonding interactions between the three active centers of the bis-ureide
      groups (-NH-CO-NH) combined with pi-pi interactions between the azobenzene groups
      serve to self-assemble 1 into a highly ordered lamellar mesostructure in which
      the d-spacing is optically controlled through photoisomerization of the
      azobenzene moiety before or after assembly.

PMID- 12465957
TI  - Enantioselective synthesis of (-)-codeine and (-)-morphine.
AB  - A new synthetic strategy for the synthesis of the opiate and amaryllidaceae
      alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set
      the stereochemistry. The pivotal tricyclic intermediate is available in six steps
      from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1
      carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth
      Horner phosphate reagent. This intermediate requires only two steps to convert to
      (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of
      codeine/morphine is formed. The final ring formation involves a novel visible
      light-promoted hydroamination. Thus, six steps are required to convert the
      pivotal tricyclic intermediate into codeine, which has been demethylated in high
      yield to morphine.

PMID- 12465958
TI  - Catalytic asymmetric epoxidation of alpha,beta-unsaturated amides: efficient
      synthesis of beta-aryl alpha-hydroxy amides using a one-pot tandem catalytic
      asymmetric epoxidation-Pd-catalyzed epoxide opening process.
AB  - The catalytic asymmetric epoxidation of alpha,beta-unsaturated amides using Sm
      BINOL-Ph3As=O complex was succeeded. Using 5-10 mol % of the asymmetric catalyst,
      a variety of amides were epoxidized efficiently, yielding the corresponding
      alpha,beta-epoxy amides in up to 99% yield and in more than 99% ee. Moreover, the
      novel one-pot tandem process, one-pot tandem catalytic asymmetric epoxidation-Pd
      catalyzed epoxide opening process, was developed. This method was successfully
      utilized for the efficient synthesis of beta-aryl alpha-hydroxy amides, including
      beta-aryllactyl-leucine methyl esters. Interestingly, it was found that
      beneficial modifications on the Pd catalyst were achieved by the constituents of
      the first epoxidation, producing a more suitable catalyst for the Pd-catalyzed
      epoxide opening reaction in terms of chemoselectivity.

PMID- 12465959
TI  - Enantioselective total synthesis of (-)-strychnine using the catalytic asymmetric
      Michael reaction and tandem cyclization.
AB  - The enantioselective total synthesis of (-)-strychnine was accomplished through
      the use of the highly practical catalytic asymmetric Michael reaction (0.1 mol %
      of (R)-ALB, more than kilogram scale, without chromatography, 91% yield and >99%
      ee) as well as a tandem cyclization that simultaneously constructed B- and D
      rings (>77% yield). Moreover, newly developed reaction conditions for thionium
      ion cyclization, NaBH3CN reduction of the imine moiety in the presence of Lewis
      acid to prevent ring opening reaction, and chemoselective reduction of the
      thioether (desulfurization) in the presence of exocyclic olefin were pivotal to
      complete the synthesis. The described chemistry paves the way for the synthesis
      of more advanced Strychnos alkaloids.

PMID- 12465960
TI  - The Trp cage: folding kinetics and unfolded state topology via molecular dynamics
      simulations.
AB  - Using over 75 mus of molecular dynamics simulation, we have generated several
      thousand folding simulations of the 20-residue Trp cage at experimental
      temperature and solvent viscosity. A total of 116 independent folding simulations
      reach RMSDcalpha values below 3 A RMSDcalpha, some as close as 1.4 A RMSDcalpha.
      We estimate a folding time of 5.5+/-3.5 mus, a rate that is in reasonable
      agreement with experimental kinetics. Finally, we characterize both the folded
      and unfolded ensemble under native conditions and note that the average topology
      of the unfolded ensemble is very similar to the topology of the native state.

PMID- 12465961
TI  - Catalyzed collapse and enhanced hydrogen storage of BN nanotubes.
AB  - The novel morphology of BN nanotubes with a collapsed structure has been
      discovered by a metal-catalyzed treatment. The collapse causes the dramatic
      enlargement of a specific surface area of BN nanotubes and remarkably enhances
      the hydrogen storage capacity of BN nanotubes.

PMID- 12465962
TI  - Highly enantioselective rhodium-catalyzed hydrogenation of beta-dehydroamino acid
      derivatives using monodentate phosphoramidites.
AB  - New and very easily accessible monodentate phosphoramidite ligands have been
      developed that lead to excellent ee's and full conversions in the hydrogenation
      of (E)- and (Z)-beta-dehydroamino acid derivatives with both aliphatic and
      aromatic side chains. Particularly, two different catalytic systems were
      established for (E)-beta-(acylamino)acrylates (98-99% ee) and (Z)-beta
      (acylamino)acrylates (92-95% ee) based on phosphoramidites 2 and 3, respectively.

PMID- 12465963
TI  - The reaction mechanism of xanthine oxidase: evidence for two-electron chemistry
      rather than sequential one-electron steps.
AB  - Current research on xanthine oxidase has favored a mechanism involving base
      catalyzed proton abstraction from a Mo-OH group, allowing nucleophilic attack on
      the substrate and hydride transfer from the substrate to Mo=S group in the active
      site. During the course of this reaction mechanism, the molybdenum redox cycles
      from MoVI to MoIV, with reoxidation of the MoIV speices to form the EPR active
      MoV intermediate. However, it has also been suggested that the reaction occurs in
      two subsequent one-electron steps. We have determined kinetic parameters kred and
      kred/Kd for a variety of plausible substrates as well as the one-electron
      reduction potentials for these substrates. Our data indicate no correlation
      between these kinetic parameters and their one-electron reduction potentials, as
      would be expected if the enzyme were using two subsequent one-electron reduction
      steps. Our results provide additional support to current evidence for the favored
      two-electron reduction mechanism.

PMID- 12465964
TI  - Stephacidin A and B: two structurally novel, selective inhibitors of the
      testosterone-dependent prostate LNCaP cells.
AB  - Two novel antitumor alkaloids, Stephacidin A and B, were isolated from the solid
      fermentation of Aspergillus ochraceus WC76466. Both alkaloids exhibit in vitro
      cytotoxicity against a number of human tumor cell lines; however, stephacidin B
      demonstrated more potent and selective antitumor activities, especially against
      prostate testeosterone-dependent LNCaP cells with IC50 value of 60 nM. The
      structures of stephacidin A and B were established on the basis of the NMR data
      and X-ray crystallography. With 15 rings and 9 chiral centers, stephacidin B
      represents one of the most structurally complex and novel alkaloids occurring in
      nature.

PMID- 12465965
TI  - Reaction mechanism of soluble epoxide hydrolase: insights from molecular dynamics
      simulations.
AB  - Molecular dynamics simulations have been performed to gain insights into the
      catalytic mechanism of the hydrolysis of epoxides to vicinal diols by soluble
      epoxide hydrolase (sEH). The binding of a substrate, 1S,2S-trans-methylstyrene
      oxide, was studied in two conformations in the active site of the enzyme. It was
      found that only one is likely to be found in the active enzyme. In the preferred
      conformation the phenyl group of the substrate is pi-sandwiched between two
      aromatic residues, Tyr381 and His523, whereas the other conformation is pi
      stacked with only one aromatic residue, Trp334. Two simulations were carried out
      to 1 ns for each conformation to evaluate the protonation state of active site
      residue His523. It was found that a protonated histidine is essential for keeping
      the active site from being disrupted. Long time scale, 4 ns, molecular dynamics
      simulation was done for the structure with the most likely combination of binding
      conformation and protonation state of His523. Near Attack Conformers (NACs) are
      present 5.3% of the time and nucleophilic attack on either epoxide carbon atom,
      approximately 75% on C(1) and approximately 25% on C(2), is found. A maximum of
      one hydrogen bond between the epoxide oxygen and either of the active site
      tyrosines, Tyr465 and Tyr381, is present, in agreement with experimental
      mutagenesis results that reveal a slight loss in activity if one tyrosine is
      mutated and essential loss of all activity upon double mutation of the two
      tyrosines in question. It was found that a hydrogen bond from Tyr465 to the
      substrate oxygen is essential for controlling the regioselectivity of the
      reaction. Furthermore, a relationship between the presence of this hydrogen bond
      and the separation of reactants was found. Two groups of amino acid segments were
      identified each as moving collectively. Furthermore, an overall anti-correlation
      was found between the movements of these two individually collectively moving
      groups, made up by parts of the cap-region, including the two tyrosines, and the
      site of the catalytic triad, respectively. This overall anti-correlated
      collective domain motion is, perhaps, involved in the conversion of E.NAC to
      E.TS.

PMID- 12465966
TI  - Roles of the proximal hydrogen bonding network in cytochrome P450cam-catalyzed
      oxygenation.
AB  - Structural and functional roles of the hydrogen bonding network that surrounds
      the heme-thiolate coordination of P450(cam) from Pseudomonas putida were
      investigated. A hydrogen bond between the side chain amide of Gln360 and the
      carbonyl oxygen of the axial Cys357 was removed in Q360L. The side chain hydrogen
      bond and the electrostatic interaction between the polypeptide amide proton of
      Gln360 and the sulfur atom of Cys357 were simultaneously removed in Q360P. The
      increased electron donation of the axial thiolate in Q360L and Q360P was
      evidenced by negative shifts of their reduction potentials by 45 and 70 mV,
      respectively. Together with the results on L358P in which the amide proton at
      position 358 was removed (Yoshioka, S., Takahashi, S., Ishimori, K., Morishima,
      I. J. Inorg. Biochem. 2000, 81, 141-151), we propose that the side chain hydrogen
      bond and the electrostatic interaction of the amide proton with the thiolate
      ligand cause approximately 45 and approximately 35 mV of positive shifts,
      respectively, of the redox potential of the heme in P450(cam). The resonance
      Raman spectra of the ferrous-CO form of the Q360 mutants showed a downshifted Fe
      CO stretching mode at 482 approximately 483 cm(-)(1) compared with that of wild
      type P450(cam) at 484 cm(-)(1). The Q360 mutants also showed the upshift by 4
      approximately 5 cm(-)(1) of the Fe-NO stretching mode in the ferrous-NO form.
      These Raman results indicate the increase in the sigma-electron donation of the
      thiolate ligand in the reduced state of the Q360 mutants and were in contrast to
      the increased pi-back-donation of the thiolate in L358P having an upshifted Fe-CO
      stretching mode at 489 cm(-)(1). The catalytic activities of the Q360 mutants for
      the unnatural substrates were similar to those of the wild-type enzyme,
      indicating that the increased sigma-electron donation does not promote the O-O
      bond heterolysis in the Q360 mutants, although the increased pi-electron donation
      in L358P promoted the heterolysis of the O-O bond. We conclude that the functions
      of the proximal hydrogen bonding network in P450(cam) are to stabilize the heme
      thiolate coordination, and to regulate the redox potential of the heme iron.
      Furthermore, we propose that the pi-electron donation, not the sigma-electron
      donation, of the thiolate ligand promotes the heterolysis of the O-O bond of
      dioxygen.

PMID- 12465967
TI  - Guanine of the third strand of C.G*G triplex serves as an effective hole trap.
AB  - We have examined the structural and electronic effects of the one-electron
      oxidation of the C.GG triplex, where G is located in a quite different
      environment from the G of duplex DNA. Upon photoirradiation of an external
      photosensitizer (riboflavin) with the C.GG triplex, oxidative DNA cleavage
      occurred exclusively at guanine repeat sequences in the third strand of triple
      helix DNA. Hole transport through the C.GG triplex also occurred, resulting in
      selective cleavage at G in the third strand. Thus, the hole generated in the
      duplex can migrate to GGG in the third strand and is trapped exclusively at Gs in
      the third strand. These experimental results, together with molecular orbital
      calculations, suggest that the origin of the selective strand cleavage can be
      explained as follows: (i) guanine repeat sequences in the third strand are more
      easily oxidized than in duplex DNA and (ii) in their radical cation states, G of
      the third strand rapidly deprotonates and reacts with oxygen and/or water,
      leading to strand cleavage. These results indicate that the oxidative damage
      preferentially occurred at Gs of the third strand owing to thermodynamic and
      kinetic features of the one-electron oxidation of the C.GG triplex.

PMID- 12465968
TI  - Position-specific incorporation of a fluorophore-quencher pair into a single
      streptavidin through orthogonal four-base codon/anticodon pairs.
AB  - Four-base codon strategy was applied to incorporate a fluorophore-quencher pair
      into specific positions on a single protein; beta-anthraniloyl-L-alpha,beta
      diaminopropionic acid (atnDap) was employed as a fluorophore and p
      nitrophenylalanine (ntrPhe) as a quencher. Their positions were directed by the
      CGGG/CCCG and GGGC/CCCG four-base codon/anticodon pairs and two doubly mutated
      streptavidins, i.e., ((52)atnDap, (84)ntrPhe) and ((54)ntrPhe, (84)atnDap)
      mutants were synthesized through Escherichia coli in vitro protein synthesizing
      systems. Intramolecular photoinduced electron transfer (ET) was observed as the
      decrease of intensity in steady-state fluorescence spectroscopy and as the
      shortening of fluorescence decaytimes. The quenching data indicated that the ET
      rate reflects the detailed structure of the protein.

PMID- 12465969
TI  - Exploring nucleoside hydrolase catalysis in silico: molecular dynamics study of
      enzyme-bound substrate and transition state.
AB  - The mechanism of action of inosine-uridine nucleoside hydrolase has been
      investigated by long-term molecular dynamics (MD) simulation in TIP3P water using
      stochastic boundary conditions. Five MD studies have been performed with enzyme
      substrate complex (E.S), enzyme substrate complex with protonated His241 (EH.S),
      enzyme transition state complex (E.TS), enzyme transition state complex with
      protonated His241 (EH.TS), and His241Ala transition state complex E(H241A).TS.
      Special attention has been given to the role of His241, which has been considered
      as the general acid catalyst to assist departure of the leaving nucleobase on the
      basis of its location in the active site in the X-ray crystal structure (). Yet
      on the basis of the location in the active site, Tyr229 is closer to the aniline
      ring of pAPIR as compared to His241. On initiation of MD simulations, His241 does
      not approach the nucleobase in the structures of EH.S, E.S, EH.TS, and E.TS. In
      the solvated enzyme, Tyr229, which is a member of the hydrogen bonding network
      inosine O2'.Asp14.His241.Tyr229.inosine N7, serves as a proton source to the
      leaving nucleobase. The loss of significant activity of His241Ala mutant is shown
      to be related to the disruption of the above hydrogen bonded network and the
      distancing of Tyr229 from inosine N7. The structures of the enzyme complexes with
      substrate or TS are not visibly altered on protonation of His241, a most unusual
      outcome. The bell-shaped pH dependence upon pK(app)'s of 7.1 and 9.1 may be
      attributed to the necessity of the dissociation of Asp10 or Asp15 and the acid
      form of Tyr229, respectively. In TS, the residue Ile81 migrated closer, whereas
      Arg233 moved away from the nucleobase. The probability of ribooxocarbenium ion
      stabilization by Asn168 and Asp14 is discussed. The Asp14-CO(2)(-) is hydrogen
      bonded to the ribose 2'-OH for 96% of the MD simulation time. Nucleophilic
      addition of water138 to ribooxocarbenium ion is suggested to be assisted by the
      proton shuttle from water138 --> Asp10 --> Asp15 --> water pool. An
      anticorrelation motion between Tyr229-OH and Asn168-OD1 in EH.S and E.S is
      observed. The relationship of this anticorrelated motion to mechanism, if any,
      deserves further exploration, perhaps the formation of a near attack
      conformation.

PMID- 12465970
TI  - Hybridization of mismatched or partially matched DNA at surfaces.
AB  - We investigate how probe density influences hybridization for unlabeled target
      oligonucleotides that contain mismatched sequences or targets that access
      different binding locations on the immobilized probe. We find strong probe
      density effects influencing not only the efficiency of hybridization but also the
      kinetics of capture. Probe surfaces are used repeatedly, and the potentially
      large contributions of sample-to-sample variations in surface heterogeneity and
      nonspecific adsorption are addressed. Results of kinetic, equilibrium, and
      temperature-dependent studies, obtained using in-situ surface plasmon resonance
      (SPR) spectroscopy, show that hybridization for surface immobilized DNA is quite
      different from the well-studied solution-phase reaction. Surface hybridization
      depends strongly on the target sequence and probe density. Much of the data can
      be explained by the presence of steric crowding at high probe density; however,
      the behavior of mismatched sequences cannot be understood using standard models
      of hybridization even at the lowest density studied. In addition to unusual
      capture kinetics observed for the mismatched targets, we find that the binding
      isotherms can be fit only if a heterogeneous model is used. For mismatched
      targets, the Sips model adequately describes probe-target binding isotherms; for
      perfectly matched targets, the Langmuir model can be used.

PMID- 12465971
TI  - Hydroxylation of methane by non-heme diiron enzymes: molecular orbital analysis
      of C-H bond activation by reactive intermediate Q.
AB  - The electronic structures of key species involved in methane hydroxylation
      performed by the hydroxylase component of soluble methane monooxygenase (sMMO),
      as proposed previously on the basis of high-level density functional theory, were
      investigated. The reaction starts with initial approach of methane at one of the
      bridging oxo atoms in intermediate Q, a di(mu-oxo)diiron(IV) unit. This step is
      accompanied by a proton-coupled outer-sphere transfer of the first electron from
      a C-H sigma-bond in methane to one of the metal centers. The second electron
      transfer, also an outer-sphere electron transfer process, occurs along a two
      component reaction pathway. Both redox reactions are strongly coupled to
      structural distortions of the diiron core. The electronic consequence and driving
      force of these distortions are intuitively explained by using the computed Kohn
      Sham orbitals in the broken-symmetry framework to incorporate the experimentally
      observed antiferromagnetic coupling of the unpaired electrons at the metal
      centers. The broken-symmetry orbital scheme is essential for describing the C-H
      bond activation process in a consistent and complete manner, enabling derivation
      of both an intuitive and quantitative understanding of the most salient
      electronic features that govern the details of the hydroxylation.

PMID- 12465972
TI  - Side chain orientation from methyl 1H-1H residual dipolar couplings measured in
      highly deuterated proteins.
AB  - High-level deuteration is a prerequisite for the study of high molecular weight
      systems using liquid-state NMR. Here, we present new experiments for the
      measurement of proton-proton dipolar couplings in CH(2)D methyl groups of (13)C
      labeled, highly deuterated (70-80%) proteins. (1)H-(1)H residual dipolar
      couplings (RDCs) have been measured in two alignment media for 57 out of 70
      possible methyl containing residues in the 167-residue flavodoxin-like domain of
      the E. coli sulfite reductase. These data yield information on the orientation of
      the methyl symmetry axis with respect to the molecular alignment frame. The
      alignment tensor characteristics were obtained very accurately from a set of
      backbone RDCs measured on the same protein sample. To demonstrate that accurate
      structural information is obtained from these data, the measured methyl RDCs for
      Valine residues are analyzed in terms of chi(1) torsion angles and stereospecific
      assignment of the prochiral methyl groups. On the basis of the previously
      determined backbone solution structure of this protein, the methyl RDC data
      proved sufficient to determine the chi(1) torsion angles in seven out of nine
      valines, assuming a single-rotamer model. Methyl RDCs are complementary to other
      NMR data, for example, methyl-methyl NOE, to determine side chain conformation in
      high molecular weight systems.

PMID- 12465973
TI  - Enzymatic phosphorylation of unnatural nucleosides.
AB  - In an effort to expand the genetic alphabet, a number of unnatural, predominantly
      hydrophobic, nucleoside analogues have been developed which pair selectively in
      duplex DNA and during enzymatic synthesis. Significant progress has been made
      toward the efficient in vitro replication of DNA containing these base pairs.
      However, the in vivo expansion of the genetic alphabet will require that the
      unnatural nucleoside triphosphates be available within the cell at sufficient
      concentrations for DNA replication. We report our initial efforts toward the
      development of an unnatural in vivo nucleoside phosphorylation pathway that is
      based on nucleoside salvage enzymes. The first step of this pathway is catalyzed
      by the D. melanogaster nucleoside kinase, which catalyzes the phosphorylation of
      nucleosides to the corresponding monophosphates. We demonstrate that each
      unnatural nucleoside is phosphorylated with a rate that should be sufficient for
      the in vivo replication of DNA.

PMID- 12465974
TI  - Enantioselective formation of a dynamic hydrogen-bonded assembly based on the
      chiral memory concept.
AB  - In this paper, we report the enantioselective formation of a dynamic noncovalent
      double rosette assembly 1a(3).(CYA)(6) composed of three 2-pyridylcalix[4]arene
      dimelamines (1a) and six butylcyanuric acid molecules (BuCYA). The six 2-pyridyl
      functionalities of the assembly interact stereoselectively with chiral
      dicarboxylic acids 3a-e via two-point hydrogen-bonding interactions. One of the
      two enantiomeric assemblies (P- or M-) 1a(3).(CYA)(6) is formed in excess as the
      result of the complexation of the chiral diacids, resulting in formation of
      optically active assemblies. The complexations with dibenzoly tartaric acids D-3a
      and L-3a (3 equivalent), respectively, leading to the formation of diastereomeric
      assemblies (P)-1a(3).(BuCYA)(6).(D-3a)(3) and (M)-1a(3).(BuCYA)(6).(L-3a)(3) with
      90% diastereomeric excess. The diastereomeric excess in (M)-1a(3).(BuCYA)(6).(L
      3a)(3) is "memorized" when L-3a is removed by precipitation with ethlylenediamine
      (EDA). The assembly (M)-1a(3).(BuCYA)(6) is still optically active (90%
      enantiomeric excess), although none of its individual components are chiral. (M)
      1a(3).(BuCYA)(6) has a high kinetic stability toward racemization (E(a) = 119 kJ
      mol(-)(1), half-life of (M)-1a(3).(BuCYA)(6) is ca. 1 week at 20 degrees C).

PMID- 12465975
TI  - Photophysical properties of porphyrin tapes.
AB  - The novel fused Zn(II)porphyrin arrays (Tn, porphyrin tapes) in which the
      porphyrin macrocycles are triply linked at meso-meso, beta-beta, beta-beta
      positions have been investigated by steady-state and time-resolved spectroscopic
      measurements along with theoretical MO calculations. The absorption spectra of
      the porphyrin tapes show a systematic downshift to the IR region as the number of
      porphyrin pigments increases in the arrays. The fused porphyrin arrays exhibit a
      rapid formation of the lowest excited states (for T2, approximately 500 fs) via
      fast internal conversion processes upon photoexcitation at 400 nm (Soret bands),
      which is much faster than the internal conversion process of approximately 1.2 ps
      observed for a monomeric Zn(II)porphyrin. The relaxation dynamics of the lowest
      excited states of the porphyrin tapes were accelerated from approximately 4.5 ps
      for the T2 dimer to approximately 0.3 ps for the T6 hexamer as the number of
      porphyrin units increases, being explained well by the energy gap law. The
      overall photophysical properties of the porphyrin tapes were observed to be in a
      sharp contrast to those of the orthogonal porphyrin arrays. The PPP-SCI
      calculated charge-transfer probability indicates that the lowest excited state of
      the porphyrin tapes (Tn) resembles a Wannier-type exciton closely, whereas the
      lowest excited state of the directly linked porphyrin arrays can be considered as
      a Frenkel-type exciton. Conclusively, these unique photophysical properties of
      the porphyrin tapes have aroused much interest in the fundamental photophysics of
      large flat organic molecules as well as in the possible applications as electric
      wires, IR sensors, and nonlinear optical materials.

PMID- 12465976
TI  - Stereoselective synthesis of pamamycin-607.
AB  - A macrodiolide antibiotic pamamycin-607 was synthesized by joining two hydroxy
      acid components. Three cis-2, 5-disubstituted tetrahydrofuran rings in the
      molecule were stereoselectively prepared by radical cyclization reactions of beta
      alkoxyvinyl ketone intermediates and a beta-alkoxymethacrylate substrate. The key
      step of the synthesis is characterized by the predominant threo product formation
      in the radical cyclization reaction of a beta-alkoxymethacrylate intermediate.

PMID- 12465977
TI  - Investigation of the [Sm(N(SiMe(3))(2))(2)] reducing system in THF. Rate and
      mechanistic studies.
AB  - The reductant [Sm(N(SiMe(3))(2))(2)] was examined by cyclic voltammetry and UV
      vis spectroscopy. Rate constants and activation parameters for the reduction of 1
      iodobutane, 2-butanone, and methylacetoacetate by [Sm(N(SiMe(3))(2))(2)] were
      measured in THF by stopped-flow absorption decay experiments. Comparison with
      SmI(2) and SmI(2)-HMPA shows that the redox potential of [Sm(N(SiMe(3))(2))(2)]
      is intermediate between the SmI(2)-based reductants, yet it reduces alkyl iodides
      and ketones at a faster rate than the powerful combination of SmI(2) and HMPA.
      The activation data for reduction of alkyl iodides and ketones by
      [Sm(N(SiMe(3))(2))(2)] are consistent with highly ordered transition states
      having low activation barriers. All of these results taken together suggest that
      the mechanism of reduction of alkyl iodides and ketones by [Sm(N(SiMe(3))(2))(2)]
      has more inner-sphere character than reduction by SmI(2) or Sm-(HMPA) complexes.
      The change in the ET mechanism is attributed to the unique structure of the
      [Sm(N(SiMe(3))(2))(2)] complex.

PMID- 12465978
TI  - First and efficient synthesis of phosphonodifluoromethylene analogues of
      nucleoside 3'-phosphates: crucial role played by sulfur in construction of the
      target molecules.
AB  - Phosphoric esters of secondary alcohols are ubiquitous in biological systems.
      However, despite the obvious interest of the corresponding difluoromethylene
      phosphonates as isopolar mimics, a single example of such an analogue featuring
      this particular substitution pattern has so far been reported in the literature,
      due to synthetic problems associated with their preparation. The lithium salt of
      diethyl difluoromethylphosphonothioate 28d provides a solution to this problem,
      as demonstrated by an 8-step synthesis of all five fully protected analogues of
      nucleoside 3'-phosphates in 9-18% overall yield, from readily available ketones.
      Sulfur is shown to play a crucial role in the introduction of the phosphorus
      substituted difluoromethylene unit onto the furanose ring. Complete
      diastereoselectivity is observed in the three steps of the process requiring
      stereocontrol. The key conversion of the P=S bond into its oxygenated analogue is
      simply achieved by use of m-chloroperoxybenzoic acid. It is noteworthy that the
      synthesis can be carried out on large scale: a 31-g batch of compound 26b has
      been prepared. The deprotected nucleoside 3'-phosphate analogues can be liberated
      from their precursors as exemplified by the conversion of 7b, 8b, and 9b into the
      corresponding difluorophosphonic acids, isolated in the form of their disodium
      salts.

PMID- 12465979
TI  - The role of surface free energy on the formation of hybrid bilayer membranes.
AB  - The interaction of small phospholipid vesicles with well-characterized surfaces
      has been studied to assess the effect of the surface free energy of the
      underlying monolayer on the formation of phospholipid/alkanethiol hybrid bilayer
      membranes (HBMs). The surface free energy was changed in a systematic manner
      using single-component alkanethiol monolayers and monolayers of binary mixtures
      of thiols. The binary surfaces were prepared on gold by self-assembly from binary
      solutions of the thiols HS-(CH(2))(n)()-X (n = 11, X = CH(3) or OH) in THF.
      Surface plasmon resonance (SPR), electrical capacitance, and atomic force
      microscopy (AFM) measurements were used to characterize the interaction of
      palmitoyl,oleoyl-phosphatidylcholine (POPC) vesicles with the surfaces. For all
      surfaces examined, it appears that the polar part of surface energy influences
      the nature of the POPC assembly that associates with the surface. Comparison of
      optical, capacitance, and AFM data suggests that vesicles can remain intact or
      partially intact even at surfaces with a contact angle with water of close to 100
      degrees. In addition, comparison of the alkanethiols of different chain lengths
      and the fluorinated compound HS-(CH(2))(2)-(CF(2))(8)-CF(3) that characterize
      with a low value of the polar part of the surface energy suggests that the
      quality of the underlying monolayer in terms of number of defects has a
      significant influence on the packing density of the resulting HBM layer.

PMID- 12465980
TI  - Effects of phosphine ligand chelation on the reactivity of monomeric parent amido
      ruthenium complexes: synthesis and reactivity of such a complex bearing
      monodentate ligands.
AB  - The parent amido complex cis-(PMe(3))(4)Ru(H)(NH(2)) (2) has been prepared via
      the deprotonation of [cis-(PMe(3))(4)Ru(H)(NH(3))(+)][BPh(4)(-)]. The amido
      complex is a somewhat weaker base than the DMPE analogue trans
      (DMPE)(2)Ru(H)(NH(2)) but is still basic enough to quantitatively deprotonate
      fluorene and reversibly deprotonate 1,3-cyclohexadiene and toluene. Complex 2
      exhibits very labile phosphine ligands, two of which can be replaced by DMPE to
      yield the mixed complex cis-(PMe(3))(2)(DMPE)Ru(H)(NH(2)). Because of the ligand
      lability, 2 also undergoes hydrogenolysis and rapid exchange with labeled NH(3).
      The amide complex reacts with alkyl halides to yield E2 and S(N)2 products, along
      with ruthenium hydrido halide complexes including the ruthenium fluoride cis
      (PMe(3))(4)Ru(H)(F). Ruthenium hydrido ammonia halide ion pair intermediates [cis
      (PMe(3))(4)Ru(H)(NH(3))(+)][X(-)] are observed in some deprotonation and E2
      reactions, and measurement of the equilibrium constants for NH(3) displacement
      from these complexes suggests that they benefit from significant hydrogen bonding
      between X(-) and NH(3) groups. Cumulenes also react with complex 2 to afford the
      products of insertion into an NH bond. The rates of neither these NH insertion
      reactions nor the reversible deprotonation reactions show any dependence on the
      concentration of PMe(3) present, suggesting that these reactions take place
      directly at the NH(2) group and do not involve precoordination of substrate to
      the metal center.

PMID- 12465981
TI  - Organic triplet emissions of arylacetylide moieties harnessed through
      coordination to [Au(PCy(3))]+. Effect of molecular structure upon
      photoluminescent properties.
AB  - A family of mono- and binuclear Cy(3)P-supported gold(I) complexes containing
      various pi-conjugated linear arylacetylide ligands, including the two homologous
      series (Cy(3)P)Au(Ctbd1;CC(6)H(4))(n)()(-)(1)(Ctbd1;CPh) and
      (Cy(3)P)Au(Ctbd1;CC(6)H(4))(n)()Ctbd1;CAu(PCy(3)) (n = 1-4), have been prepared.
      X-ray crystal analyses revealed no intermolecular aurophilic interactions in
      their crystal lattice. The lowest-energy singlet transitions are predominately
      intraligand in nature and exhibit both phenyl and acetylenic (1)(pipi) character.
      Strong photoluminescence is detected in solid and solution states under ambient
      conditions, with lifetimes in the microsecond regime. For complexes with a single
      arylacetylide group, only phosphorescence from the arylacetylide (3)(pipi) state
      is observed. Vibrational spacings in the solid-state emission spectra can be
      attributed to a combination of phenyl ring deformation and symmetric phenyl ring
      and Ctbd1;C stretches. Additional delayed-fluorescence emission is recorded for
      complexes with multiple p-arylacetylide units, and this is attributed to a
      triplet-triplet annihilation process. The phosphorescence energy of these
      complexes are readily modified by altering the length of the conjugated
      arylacetylide system, while the intensity of phosphorescence relative to
      fluorescence decreases when the p-arylacetylide chain is elongated. Information
      regarding the nature and relative energies of arylacetylide singlet and triplet
      excited states has been derived from the two homologous series and extrapolated
      to polymeric arylacetylide species. The (3)(pipi) excited-state reduction
      potentials E degrees [Au(+)/Au] (Au = 1a, 2, and 4) are estimated to be -1.80, 
      1.28, and -1.17 V versus SSCE, respectively.

PMID- 12465982
TI  - DNA dynamics in a water drop without counterions.
AB  - Because of its polyionic character, the DNA double helix is stable and
      biologically active only in salty aqueous media where its charge is compensated
      by solvent counterions. Monovalent metal ions are ubiquitous in DNA environment,
      and they are usually considered as the possible driving force of sequence
      dependent modulations of DNA structure that make it recognizable by proteins. In
      an effort to directly examine this hypothesis, MD simulations of DNA in a water
      drop surrounded by vacuum were carried out, which relieves the requirement of
      charge neutrality. Surprisingly, with zero concentration of counterions, a
      dodecamer DNA duplex appears metastable, and its structure remains similar to
      that observed in experiment, including the minor groove narrowing in the
      dodecamer d(CGCGAATTCGCG)(2) often considered as the most evident cation effect.
      It is suggested that the same computational approach will allow one to simulate
      dynamics of long DNA chains more efficiently than with periodical boundary
      conditions.

PMID- 12465983
TI  - Odd carbon long linear chains HC2n+1H (n = 4-11): properties of the neutrals and
      radical anions.
AB  - The optimized geometries, adiabatic electron affinities, vertical electron
      affinities, vertical electron detachment energies (for the anions), and IR-active
      vibrational frequencies have been predicted for the long linear carbon chains
      HC(2)(n)()(+1)H (n = 4-11). The B3LYP density functional combined with DZP and
      TZ2P basis sets was used in this theoretical study. These methods have been
      extensively calibrated versus experiment for the prediction of electron
      affinities (Chem. Rev. 2002, 102, 231). The computed physical properties are
      discussed and compared with the even carbon chains HC(2)(n)()H. The predicted
      electron affinities form a remarkably regular sequence: 2.12 eV (HC(9)H), 2.42 eV
      (HC(11)H), 2.66 eV (HC(13)H), 2.85 eV (HC(15)H), 3.01 eV (HC(17)H), 3.14 eV
      (HC(19)H), 3.25 eV (HC(21)H), and 3.35 eV (HC(23)H). These electron affinities
      are as much as 0.4 eV higher than those for analogous even carbon chains. The
      predicted structures display an intermediate cumulene-polyacetylene type of
      bonding, with the inner carbons appearing cumulenic and the outer carbons
      polyacetylenic.

PMID- 12465984
TI  - A classification of covalent, ionic, and metallic solids based on the electron
      density.
AB  - The electron density of crystals contains all of the information required to
      complete a classification of their bonding types. We propose here a set of three
      different indexes, flatness, charge transfer, and molecularity, easily obtained
      from the experimental or theoretical electron density, which give rise to a
      classification in close resemblance to the classical van Arkel-Ketelaar diagrams.

PMID- 12465985
TI  - Electrical contacting of flavoenzymes and NAD(P)+-dependent enzymes by
      reconstitution and affinity interactions on phenylboronic acid monolayers
      associated with Au-electrodes.
AB  - The preparation of integrated, electrically contacted, flavoenzyme and NAD(P)(+)
      dependent enzyme-electrodes is described. The reconstitution of apo-glucose
      oxidase, apo-GOx, on a FAD cofactor linked to a pyrroloquinoline quinone (PQQ)
      phenylboronic acid monolayer yields an electrically contacted enzyme monolayer
      (surface coverage 2.1 x 10(-)(12) mol cm(-)(2)) exhibiting a turnover rate of 700
      s(-)(1) (at 22 +/- 2 degrees C). The system is characterized by microgravimetric
      quartz-crystal microbalance analyses, Faradaic impedance spectroscopy, rotating
      disk electrode experiments, and cyclic voltammetry. The performance of the enzyme
      electrode for glucose sensing is described. Similarly, the electrically contacted
      enzyme-electrodes of NAD(P)(+)-dependent enzymes malate dehydrogenase, MalD, and
      lactate dehydrogenase, LDH, are prepared by the cross-linking of affinity
      complexes generated between the enzymes and the NADP(+) and NAD(+) cofactors
      linked to a pyrroloquinoline quinone phenylboronic acid monolayer, respectively.
      The MalD enzyme-electrode (surface coverage 1.2 x 10(-)(12) mol cm(-)(2))
      exhibits a turnover rate of 190 s(-)(1), whereas the LDH enzyme-electrode
      (surface coverage 7.0 x 10(-)(12) mol cm(-)(2)) reveals a turnover rate of 2.5 s(
      )(1). Chronoamperometric experiments reveal that the NAD(+) cofactor is linked to
      the PQQ-phenylboronic acid by two different binding modes. The integration of the
      LDH with the two NAD(+) cofactor configurations yields enzyme assemblies
      differing by 1 order of magnitude in their bioelectrocatalytic activities.

PMID- 12465986
TI  - Direct observation of deuterium migration in crystalline-state reaction by single
      crystal neutron diffraction IV. "Hula-twist" rotation of a long alkyl radical
      produced by photoirradiation.
AB  - When the crystal of [(R)-1,2
      bis(ethoxycarbonyl)ethyl](pyridine)bis(dimethylglyoximato)cobalt(III) was exposed
      to a xenon lamp, the chiral 1,2-bis(ethoxycarbonyl)ethyl group was partly
      inverted to the opposite configuration and finally the racemic group was produced
      with retention of the single crystal form. To make clear the mechanism, the
      hydrogen atom bonded to the chiral carbon of the chiral group was exchanged with
      the deuterium atom and the crystal was exposed to the xenon lamp for 3 days. The
      crystal after irradiation was analyzed by neutron diffraction. About 33% of the
      (R)-isomers were inverted to the (S) isomers in a crystal. The deuterium atom in
      the (S)-isomer was bonded to the same chiral carbon atom. This result clearly
      indicates that the inversion proceeds in the three steps; (i) the Co-C bond was
      homolytically cleaved by photoirradiation and the 1,2-bis(ethoxycarbonyl)ethyl
      radical and Co(II) were produced, (ii) the radical rotated by 180 degrees
      directing the C-D bond to the cobalt atom and the opposite plane of the radical
      faced to the cobalt atom, and (iii) the radical made a bond with Co(II). Because
      the peripheral atoms of the long radical occupy approximately the same positions
      in the process of the radical rotation, the crystal was not decomposed. The above
      rotation is a good example of hula-twist rotation in the process of
      photoisomerization of polyenes such as rhodopsin.

PMID- 12465987
TI  - Toward the optical tongue: flow-through sensing of tannin-protein interactions
      based on FTIR spectroscopy.
AB  - The interaction of polyphenols (tannins) with proline-rich proteins (gelatin) has
      been studied using an automated flow injection system with Fourier transform
      infrared spectroscopic detection to gain insight into chemical aspects related to
      astringency. In the perception of astringency, a major taste property in red
      wines and other beverages such as beer, tea, or fruit juices, an interaction
      between proline-rich salivary proteins and tannins present in the sample takes
      place. To study this interaction, agarose beads carrying gelatin (a proline-rich
      protein) were placed in the IR flow cell in such a way that the beads were probed
      by the IR beam. Using an automated flow system, we injected samples in a carrier
      stream and flushed over the proteins in a highly reproducible manner.
      Simultaneously, any retardation due to tannin-protein interactions taking place
      inside the flow cell was monitored by infrared spectroscopy. Tannins of different
      sources (grapes, wooden barrels, formulations used in wine making) were
      investigated, and their flow-through behavior was characterized. Significant
      differences in their affinity toward gelatin could be observed. Furthermore,
      because of small but characteristic differences in the IR spectrum, it is
      possible to distinguish condensed from hydrolyzable tannins. Nonastringent
      substances such as alcohols, sugars, and acids did not show retention on gelatin.
      The selectivity of the flow-through sensor was also demonstrated on the example
      of red and white wine. In contrast to white wine, where no interaction could be
      observed, in red wine a major interaction of the red wine tannins was found.

PMID- 12465988
TI  - Intramolecular cycloadditions of cyclobutadiene with olefins.
AB  - Intramolecular cycloadditions between cyclobutadiene and olefins can provide
      highly functionalized cyclobutene-containing products. The outcome of the
      reaction depends on the nature of the tether connecting the two reactive partners
      in the cycloaddition. Electronically unactivated olefins attached to
      cyclobutadiene through a three-atom, heteroatom-containing tether yield
      successfully the desired cycloadducts, whereas the corresponding substrates
      without a heteroatom linkage or with a longer tether are less prone to undergo
      the intramolecular cycloaddition. Calculations were used to help uncover some of
      the factors that influence the course of the cycloaddition. Successful
      intramolecular reactions usually require either electronic activation of the
      dienophile, conformational restriction of the tether, or a slower oxidation
      protocol. In general, a facile intermolecular dimerization of cyclobutadiene is
      the major process that competes with the intramolecular cycloaddition.

PMID- 12465989
TI  - C3-symmetrical supramolecular architectures: fibers and organic gels from
      discotic trisamides and trisureas.
AB  - Hydrogen bonded C(3)-symmetrical molecules that associate into supramolecular
      stacks are described. Structural mutation on these molecules has been performed
      to elucidate the contribution of the different secondary interactions (hydrogen
      bonding, pi-pi stacking) to the self-assembly of the disks into chiral stacks.
      Twelve C(3)-symmetrical molecules have been investigated, six of which contain
      three central amide functionalities (1a-f) and six of which contain three central
      urea groups (2a-f). Peripheral groups of the disks are "small", "medium", or
      "large", half of them being achiral and the other half being chiral, to enable
      investigation of the supramolecular architectures with CD spectroscopy. In all of
      the cases, elongated, helical stacks are formed in apolar solution, except for
      the "medium" amide disks 1c/d. The elongated stacks of the C(3)-symmetrical disks
      form gels, which are visualized by AFM and SANS, and this confirms the
      directionality of the interactions. For the "large" urea disk, 2f, fibers with a
      length of up to 2 microm are observed. Temperature dependent and "sergeants-and
      soldiers" CD measurements reveal that the urea stacks are much more rigid than
      the corresponding amide ones. In case of the "medium" urea disks, 2c/d, a true
      rigid rod, is formed. Where amide disks immediately reach their thermodynamic
      equilibrium, kinetic factors seem to govern urea aggregation. In a number of
      experiments aimed at reversibility with the urea stacks, hysteresis is observed,
      implying that these urea disks initially form a poorly defined stack, which
      subsequently transforms slowly into a well-defined, chiral architecture.

PMID- 12465990
TI  - Catalytic role of gold in gold-based catalysts: a density functional theory study
      on the CO oxidation on gold.
AB  - Gold-based catalysts have been of intense interests in recent years, being
      regarded as a new generation of catalysts due to their unusually high catalytic
      performance. For example, CO oxidation on Au/TiO(2) has been found to occur at a
      temperature as low as 200 K. Despite extensive studies in the field, the
      microscopic mechanism of CO oxidation on Au-based catalysts remains
      controversial. Aiming to provide insight into the catalytic roles of Au, we have
      performed extensive density functional theory calculations for the elementary
      steps in CO oxidation on Au surfaces. O atom adsorption, CO adsorption, O(2)
      dissociation, and CO oxidation on a series of Au surfaces, including flat
      surfaces, defects and small clusters, have been investigated in detail. Many
      transition states involved are located, and the lowest energy pathways are
      determined. We find the following: (i) the most stable site for O atom on Au is
      the bridge site of step edge, not a kink site; (ii) O(2) dissociation on Au (O(2)
      ->2O(ad)) is hindered by high barriers with the lowest barrier being 0.93 eV on a
      step edge; (iii) CO can react with atomic O with a substantially lower barrier,
      0.25 eV, on Au steps where CO can adsorb; (iv) CO can react with molecular O(2)
      on Au steps with a low barrier of 0.46 eV, which features an unsymmetrical four
      center intermediate state (O-O-CO); and (v) O(2) can adsorb on the interface of
      Au/TiO(2) with a reasonable chemisorption energy. On the basis of our
      calculations, we suggest that (i) O(2) dissociation on Au surfaces including
      particles cannot occur at low temperatures; (ii) CO oxidation on Au/inactive
      materials occurs on Au steps via a two-step mechanism: CO+O(2)-->CO(2)+O, and
      CO+O-->CO(2); and (iii) CO oxidation on Au/active-materials also follows the two
      step mechanism with reactions occurring at the interface.

PMID- 12465991
TI  - Ab initio QM/MM dynamics simulation of the tetrahedral intermediate of serine
      proteases: insights into the active site hydrogen-bonding network.
AB  - Ab initio QM/MM dynamics simulation is employed to examine the stability of the
      tetrahedral intermediate during the deacylation step in elastase-catalyzed
      hydrolysis of a simple peptide. An extended quantum region includes the catalytic
      triad, the tetrahedral structure, and the oxyanion hole. The calculations
      indicate that the tetrahedral intermediate of serine proteases is a stable
      species on the picosecond time scale. On the basis of geometrical and dynamical
      properties, and in agreement with many experimental and theoretical studies, it
      is suggested that the crucial hydrogen bonds involved in stabilizing this
      intermediate are between Asp-102 and His-57 and between the charged oxygen of the
      intermediate and the backbone N-H group of Gly-193 in the oxyanion hole. The
      mobility of the imidazolium ring between O(w) and O(gamma), two of the oxygens of
      the tetrahedral structure, shows how the intermediate could proceed toward the
      product state without a "ring-flip mechanism", proposed earlier on the basis of
      NMR data. In addition to the proposed C(epsilon)(1)-H.O hydrogen bond between the
      imidazolium ring and the backbone carbonyl of Ser-214, we observe an alternative
      C(epsilon)(1)-H.O hydrogen bond with the backbone carbonyl of Thr-213, that can
      stabilize the intermediate during the imidazolium movement. Proton hopping occurs
      between Asp-102 and His-57 during the simulation. The proton is, however, largely
      localized on the nitrogen, and hence it does not participate in a low-barrier
      hydrogen bond. The study also suggests factors that may be implicated in product
      release: breaking the hydrogen bond of the charged oxygen with the backbone of
      Ser-195 in the oxyanion hole and a loop opening between residues 216-225 that
      enables the breaking of a hydrogen bond in subsite S(3).

PMID- 12465992
TI  - Density functional theory study of enantiospecific adsorption at chiral surfaces.
AB  - Density functional theory calculations are carried out for the adsorption of a
      chiral molecule, (S)- and (R)-HSCH(2)CHNH(2)CH(2)P(CH(3))(2), on a chiral
      surface, Au(17 11 9)(S)(). The S-enantiomer is found to bind more strongly than
      the R-enantiomer by 8.8 kJ/mol, evidencing that the chiral nature of the kink
      sites at the Au(17 11 9) surface leads to enantiospecific binding. The adsorption
      of two related chiral molecules, HSCH(2)CHNH(2)COOH ("cysteine") and
      HSCH(2)CHNH(2)CH(2)NH(2), does not, however, lead to enantiospecific binding. The
      results of the density functional calculations are broken down into a local
      binding model in which each of the chiral molecule's three contact points with
      the surface provides a contribution to the overall adsorption bond strength. The
      enantiospecific binding is demonstrated to originate from the simultaneous
      optimization of these three local bonds. In the model, the deformation energy
      costs of both the molecule and the surface are further included. The model
      reveals that the molecule may undergo large deformations in the attempt to
      optimize the three bonds, while the surface deforms to a lesser extent. The most
      favorable binding configurations of each enantiomer are, however, characterized
      by small deformation energies only, justifying a local binding picture.

PMID- 12465993
TI  - Electron affinities of Al(n) clusters and multiple-fold aromaticity of the square
      Al4(2-) structure.
AB  - The concept of aromaticity was first invented to account for the unusual
      stability of planar organic molecules with 4n + 2 delocalized pi electrons.
      Recent photoelectron spectroscopy experiments on all-metal MAl(4)(-) systems with
      an approximate square planar Al(4)(2-) unit and an alkali metal led to the
      suggestion that Al(4)(2-) is aromatic. The square Al(4)(2-) structure was
      recognized as the prototype of a new family of aromatic molecules. High-level ab
      initio calculations based on extrapolating CCSD(T)/aug-cc-pVxZ (x = D, T, and Q)
      to the complete basis set limit were used to calculate the first electron
      affinities of Al(n)(), n = 0-4. The calculated electron affinities, 0.41 eV (n =
      0), 1.51 eV (n = 1), 1.89 eV (n = 3), and 2.18 eV (n = 4), are all in excellent
      agreement with available experimental data. On the basis of the high-level ab
      initio quantum chemical calculations, we can estimate the resonance energy and
      show that it is quite large, large enough to stabilize Al(4)(2-) with respect to
      Al(4). Analysis of the calculated results shows that the aromaticity of Al(4)(2-)
      is unusual and different from that of C(6)H(6). Particularly, compared to the
      usual (1-fold) pi aromaticity in C(6)H(6), which may be represented by two Kekule
      structures sharing a common sigma bond framework, the square Al(4)(2-) structure
      has an unusual "multiple-fold" aromaticity determined by three independent
      delocalized (pi and sigma) bonding systems, each of which satisfies the 4n + 2
      electron counting rule, leading to a total of 4 x 4 x 4 = 64 potential resonating
      Kekule-like structures without a common sigma frame. We also discuss the 2-fold
      aromaticity (pi plus sigma) of the Al(3)(-) anion, which can be represented by 3
      x 3 = 9 potential resonating Kekule-like structures, each with two localized
      chemical bonds. These results lead us to suggest a general approach (applicable
      to both organic and inorganic molecules) for examining delocalized chemical
      bonding. The possible electronic contribution to the aromaticity of a molecule
      should not be limited to only one particular delocalized bonding system
      satisfying a certain electron counting rule of aromaticity. More than one
      independent delocalized bonding system can simultaneously satisfy the electron
      counting rule of aromaticity, and therefore, a molecular structure could have
      multiple-fold aromaticity.

PMID- 12465994
TI  - Manipulation and characterization of xenon-metalloporphyrin complexation with a
      scanning tunneling microscope.
AB  - The formation of a series of Xe-CuEtioI [Cu(II) etioporphyrin I] complexes on
      Cu(001) surface was identified by scanning tunneling microscopy (STM) at
      cryogenic condition. The binding sites of xenon to CuEtioI molecule were directly
      revealed by high-resolution STM images in combination with controlled
      manipulation. The interaction between xenon atoms and CuEtioI in the on-top
      configuration is suggestive of a charge-induced dipole interaction. The
      structural parameters obtained with the STM complement results from spectroscopic
      studies of van der Waals complexes.

PMID- 12465997
TI  - Current trachoma treatment methodologies: focus on advancements in drug therapy.
AB  - Currently, there are approximately 6 million people with irreversible blindness
      as a result of chronic follicular conjunctivitis with subsequent corneal scarring
      caused by Chlamydia trachomatis, also known as trachoma. On the basis of the
      clinical studies evaluated, the most widely tested effective pharmacological
      treatments for trachoma today are topical tetracycline 1% to be applied to both
      eyes twice daily for 6 weeks or a single oral dose of azithromycin 20 mg/kg (up
      to 1g). Although chemotherapy can generate prompt therapeutic response and
      surgery can reverse the repercussions of these infections, these conditions will
      persist through reinfections. Implementing proper personal hygiene and
      environmental improvement measures for the control of infection transmission will
      be essential in reducing the potentially devastating results of trachoma
      infections.

PMID- 12465998
TI  - Emerging concepts in periodontal therapy.
AB  - Conventional periodontal therapy consists of mechanical scaling and root planing,
      and surgical treatment. This is still the mainstay of periodontal treatment.
      Adjunctive antimicrobial treatments, both systemic and local delivery, are
      becoming more sophisticated and useful in the treatment of recurrent
      periodontitis. Also very promising are adjunctive treatments that modulate the
      host response and decrease levels of destructive pro-inflammatory cytokines or
      matrix metalloproteinases. Smoking is a major risk factor for periodontitis and
      has a profound impact on the progression of periodontal bone and attachment loss.
      In the interest of improved periodontal health patients should be encouraged to
      stop smoking. Finally bacterial endotoxins that stimulate the release of pro
      inflammatory cytokines can have systemic effects and may lead to pre-term, low
      birthweight babies, and cardiovascular diseases such as atherosclerosis,
      myocardial infarction and stroke. Health professionals need to be cognisant of
      the effect dental health can have on systemic diseases and refer for treatment
      when appropriate to ensure that optimum oral and systemic health is achieved for
      their patients.

PMID- 12465999
TI  - A guide to drug use during percutaneous coronary intervention.
AB  - The past decade has seen major advances in adjunctive pharmacotherapy for
      percutaneous coronary intervention. Pharmacological therapeutic advances have
      resulted from a greater understanding of the pathophysiological mechanisms
      underlying platelet activation and aggregation, thrombin generation and thrombus
      formation. Specifically, refinements in the use of unfractionated heparin,
      developments in the use of low molecular weight heparins and direct antithrombin
      agents as well as improvement in both oral and parenteral adjunctive antiplatelet
      therapies have occurred and are reviewed herein.

PMID- 12466000
TI  - Postoperative ileus: progress towards effective management.
AB  - The pathogenesis of postoperative ileus (PI) is multifactorial, and includes
      activation of inhibitory reflexes, inflammatory mediators and opioids (endogenous
      and exogenous). Accordingly, various strategies have been employed to prevent PI.
      As single-modality treatment, continuous postoperative epidural analgesia
      including local anaesthetics has been most effective in the prevention of PI.
      Choice of anaesthetic technique has no major impact on PI. Minimally invasive
      surgery reduces PI, in accordance with the sustained reduction in the
      inflammatory responses, while the effects of early institution of oral nutrition
      on PI per se are minor. Several pharmacological agents have been employed to
      resolve PI (propranolol, dihydroergotamine, neostigmine, erythromycin, cisapride,
      metoclopramide, cholecystokinin, ceruletide and vasopressin), most with either
      limited effect or limited applicability because of adverse effects. The
      development of new peripheral selective opioid antagonists is promising and has
      been demonstrated to shorten PI significantly. A multi-modal rehabilitation
      programme including continuous epidural analgesia with local anaesthetics,
      enforced nutrition and mobilisation may reduce PI to 1-2 days after colonic
      surgery.

PMID- 12466002
TI  - Etoricoxib.
AB  - Etoricoxib is a cyclo-oxygenase (COX)-2-selective NSAID with a higher COX-1 to
      COX-2 selectivity ratio than the other COX-2-selective NSAIDs rofecoxib,
      valdecoxib or celecoxib. In patients with rheumatoid arthritis, improvements in
      tender and swollen joint counts and patient and investigator global assessment of
      disease activity were significantly greater in etoricoxib than in placebo
      recipients in two studies. Etoricoxib was also significantly more effective than
      naproxen in one of these studies. In patients with osteoarthritis of the hip or
      knee, etoricoxib was significantly more effective than placebo and had similar
      efficacy to naproxen with regards to improvements in pain and physical function
      scores and patient global assessment of disease status scores in two studies.
      Etoricoxib had similar efficacy to diclofenac in patients with osteoarthritis of
      the knee. Single-dose etoricoxib relieved pain in patients with postoperative
      dental pain in two studies. Similar scores assessing total pain relief over 8
      hours (TOPAR8) were reported in etoricoxib and naproxen sodium or ibuprofen
      recipients, and higher TOPAR8 scores were reported with etoricoxib than with
      paracetamol (acetaminophen)/codeine. Pain relief was significantly better with
      etoricoxib than placebo in two studies in patients with chronic low back pain.
      Etoricoxib had similar efficacy to indomethacin in a study in patients with acute
      gout, and single-dose etoricoxib had similar efficacy to naproxen sodium in a
      study in women with primary dysmenorrhoea. Compared with non-COX-selective
      NSAIDs, etoricoxib was associated with significantly fewer upper gastrointestinal
      (GI) perforations, ulcers or bleeds, and was significantly less likely to result
      in treatment discontinuation because of NSAID-type GI symptoms or any GI
      symptoms.

PMID- 12466006
TI  - Voriconazole: in the treatment of invasive aspergillosis.
AB  - Voriconazole, a broad-spectrum triazole antifungal agent, inhibits the cytochrome
      P450-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the fungal
      membrane and stopping fungal growth. The drug shows excellent in vitro activity
      against Aspergillus spp., including itraconazole- and amphotericin B-resistant A.
      fumigatus isolates. At 12 weeks, 52.8% of voriconazole recipients achieved a
      successful outcome (complete or partial response) versus 31.6% of amphotericin B
      recipients in a randomised, nonblind trial in 392 patients (aged > or =12 years)
      with invasive aspergillosis. Patients received intravenous voriconazole (6 mg/kg
      once every 12 hours on day 1, then 4 mg/kg once every 12 hours for > or =7 days;
      patients could then be switched to oral voriconazole 200mg once every 12 hours)
      or intravenous amphotericin B (1 to 1.5 mg/kg/day for > or=14 days). At the
      investigators' discretion, those who failed to respond to or experienced toxicity
      with the initial randomised drug could be switched to other licensed antifungal
      therapy. Voriconazole was generally well tolerated. The most common treatment
      related adverse events were transient visual disturbances (approximately 30% of
      patients) and skin rashes (6%). Voriconazole was generally better tolerated than
      amphotericin B; voriconazole recipients experienced significantly (p < 0.02 both
      comparisons) fewer treatment-related adverse events or serious adverse events.
      The incidence of visual disturbances was significantly (p < 0.001) higher with
      voriconazole than amphotericin B treatment.

PMID- 12466001
TI  - Prospects for the prevention and reversal of type 1 diabetes mellitus.
AB  - Type 1 (insulin-dependent) diabetes mellitus results from selective immune
      mediated destruction of pancreatic islet beta cells. Strategies to prevent or
      reverse the development of diabetes can be divided into three groups, depending
      on whether they focus on beta-cell protection, regeneration or replacement.
      Prevention of immune beta-cell destruction involves either halting the immune
      attack directed against beta cells or making beta cells better able to withstand
      immune attack, for example, by making them resistant to free radical damage. The
      recent identification of beta-cell growth factors and development of stem cell
      technologies provides an alternative route to the reversal of diabetes, namely
      beta-cell regeneration. Interestingly, stem cell-derived islets appear to be less
      sensitive to recurrent immune destruction that is normally seen in response to
      islet transplantation. The last alternative is beta-cell replacement or
      substitution. This covers a wide range of interventions including human whole
      pancreas transplantation, xenotransplantation, genetically modified beta cells,
      mechanical insulin sensing and delivery devices, and the artificial pancreas.
      This review describes recent advances in each of these research areas and aims to
      provide clinicians with an idea of where and when an effective strategy to
      prevent or reverse diabetes development will become available.

PMID- 12466009
TI  - Stavudine once daily.
AB  - Stavudine administered once daily is a nucleoside analogue reverse transcriptase
      inhibitor. The efficacy (reduction in viral load and increase in CD4+ lymphocyte
      counts from baseline) of stavudine once daily-containing triple therapy was
      similar to that of stavudine immediate release (IR)-containing triple therapy in
      the treatment of antiretroviral-naive patients with HIV infection in two 48-week,
      randomised, double-blind trials. In the largest trial (n = 783), 80% of patients
      receiving stavudine 75 or 100mg once daily in combination with lamivudine 150mg
      twice daily and efavirenz 600mg once daily, and 75% of patients receiving
      stavudine IR 30 or 40mg twice daily-containing combination therapy, had HIV RNA
      levels reduced to below the limit of quantification at 48 weeks (<400 copies/ml;
      intent-to-treat analysis). These findings are supported by those from the smaller
      trial in 150 patients. Stavudine once daily triple therapy was well tolerated,
      with the incidence of adverse events being similar to that with stavudine IR.
      Grades 2-4 treatment related adverse events occurring in > or =3% of patients in
      either group were dizziness, rash, abnormal dream, headache, insomnia, fatigue
      and peripheral neurological symptoms. Peripheral neurological symptoms occurred
      in 3% of patients receiving long-term treatment with stavudine once daily and 6%
      of patients receiving stavudine IR in a combined analysis.

PMID- 12466013
TI  - Bisoprolol: a review of its use in chronic heart failure.
AB  - Bisoprolol is a highly selective beta(1)-adrenoceptor antagonist. Administration
      of bisoprolol to patients with chronic heart failure is associated with increases
      in left ventricular function and reductions in heart rate; increases in heart
      rate variability are also seen. Two major randomised, double-blind, placebo
      controlled, multicentre trials have examined the clinical efficacy of bisoprolol
      in combination with ACE inhibitors and diuretics in patients with stable chronic
      heart failure (New York Heart Association class III or IV): the Cardiac
      Insufficiency Bisoprolol Study (CIBIS; n = 641) and CIBIS II (n = 2 647). All
      cause mortality (primary endpoint) was significantly lower in bisoprolol than in
      placebo recipients in CIBIS II (11.8 vs 17.3%) and was reduced by bisoprolol
      regardless of dosage. All-cause mortality was also lower in CIBIS (16.6 vs 20.9%)
      although the difference did not achieve statistical significance. In a meta
      analysis of CIBIS and CIBIS II (n = 3 288), a relative reduction of 29% in the
      incidence of all-cause mortality was seen in bisoprolol versus placebo
      recipients; this analysis also demonstrated that bisoprolol reduces mortality in
      patients with chronic heart failure regardless of aetiology or severity. In CIBIS
      II, there were significantly fewer cardiovascular deaths, admissions to hospital
      for any reason, or cardiovascular deaths or cardiovascular hospitalisations
      (combined endpoint) in bisoprolol, compared with placebo, recipients (secondary
      endpoints). Compared with standard treatment alone, the addition of bisoprolol
      was a cost-effective option in chronic heart failure in UK, French, German and
      Swedish pharmacoeconomic studies. Bisoprolol is generally well tolerated in
      patients with chronic heart failure. In CIBIS II, adverse events occurring more
      commonly in bisoprolol than placebo recipients, regardless of causal relationship
      with the study medication, included dizziness, bradycardia, hypotension and
      fatigue. Bisoprolol recipients were less likely than placebo recipients to
      experience worsening of heart failure, dyspnoea or tachycardia. In both CIBIS and
      CIBIS II there was no significant difference between bisoprolol and placebo
      recipients in the incidence of permanent treatment withdrawal. In conclusion,
      adding the highly selective beta(1)-blocker bisoprolol to a treatment regimen
      comprising an ACE inhibitor and a diuretic significantly improves survival in
      patients with stable chronic heart failure and reduces the need for
      hospitalisation. The use of bisoprolol in this disorder is generally well
      tolerated and is cost effective. Thus, bisoprolol should be considered a standard
      treatment option when selecting a beta-blocker for use in combination with ACE
      inhibitors and diuretics in patients with stable, moderate to severe chronic
      heart failure.

PMID- 12466014
TI  - Comparison of the extrapancreatic action of gamma-linolenic acid and n-3 PUFAs in
      the high fat diet-induced insulin resistance [corrected].
AB  - OBJECTIVE: The effect of dietary borage oil (rich in the gamma-linolenic acid
      [GLA]) on insulin sensitivity and lipid metabolism was compared with that of fish
      oil (rich in n-3 polyunsaturated fatty acids [PUFAs]) in high fat (HF) diet
      induced insulin resistance (IR) of rats. METHODS: Male Wistar rats were fed ad
      libitum for 3 weeks a standard laboratory chow (Controls) or high fat diet
      consisting of 70-cal % fat. In addition, a group of rats was fed high fat (HF)
      diet where a part of saturated fat was replaced with fish oil as a source of n-3
      PUFAs (HF+FO), or borage oil as a source of GLA (HF+GLA). In vivo insulin action
      was assessed by the euglycemic hyperinsulinemic clamp. Glucose, insulin, free
      fatty acids (FFA), triglycerides (Tg) and glycerol levels in blood and tissue
      depots were also measured. RESULTS: Increased levels of Tg, FFA and glycerol in
      circulation after HF diet were accompanied by their raised accumulation in
      insulin sensitive tissues. FO feeding lowered the concentration of all lipids in
      serum and prevented their accumulation in both tissues. On the other hand GLA
      supplementation into the high fat diet did not suppress increased levels of Tg,
      FFA and glycerol in circulation and tissue depots as well. FO feeding
      significantly reduced HF diet-induced in vivo IR, while GLA supplementation did
      not improve the in vivo insulin sensitivity in HF diet induced insulin
      resistance. CONCLUSIONS: 1. Substitution of FO into the high fat diet led to an
      improvement of in vivo insulin action; 2. this insulin sensitizing effect of FO
      was accompanied by a decrease of circulating Tg, FFA and glycerol levels in the
      postprandial state and by a lower lipid content in liver and skeletal muscle. 3.
      on the opposite, GLA treatment failed to improve in vivo insulin action; and 4.
      was associated with an adverse effect on lipid levels both in circulation and
      tissue depots.

PMID- 12466015
TI  - Bed rest immobilization with various oral sodium supply: plasma hormones and body
      fluids.
AB  - OBJECTIVE: To answer the question if plasma hormone concentrations (plasma renin
      activity--PRA, vasopressin--pAVP, and aldosterone concentration) due to
      antiorthostatic immobilization (8 days -6 degree head-down tilt bed rest--HDBR)
      are altered by oral salt load, we provided constant sodium supply during 4 days
      ambulatory conditions followed by 8 days HDBR in 10 normotensive men. METHODS: A
      low' (LS: 143 10 mM) and high' (HS: 434+/-17 mM Na+/d excreted) sodium treatment
      were provided in randomized order, separated > or = 1 mo. Before and at the end
      of HDBR, hemodynamic variables and thoracic impedance were determined, and blood
      was taken for aldosterone and PRA, venous hematocrit, and plasma mass density.
      Extracellular fluid volume and pAVP were determined every second day. Whole body
      electrical impedance spectroscopy was employed to assess changes in extracellular
      volume, hormone determinations were done with radioimmunoassay, mass density
      measurements with the mechanical oscillator technique. RESULTS: Extracellular
      volume decreased with HDBR (LS: -4.0%, p=0.002; HS: -5.8%, p=0.018) without
      significant difference between salt treatments. Resting hormone levels were not
      altered by HDBR, but pAVP was lower (5.5+/-0.1 pg/ml) in HS than in LS (7.2+/-0.3
      pg/ml) as was plasma aldosterone (HS: 69+/-7 pg/ml, LS: 180+/-24 pg/ml). On the
      other hand, HDBR reduced extracellular volume by ?5% irrespective of dietary
      sodium supply. CONCLUSIONS: Our data support the hypothesis that hormonal
      activities are more affected by oral salt load than by simulated short-term space
      flight, and suggest that the reduction of extracellular fluid volume due to head
      down bed rest is not influenced by moderate changes of dietary sodium supply.

PMID- 12466016
TI  - New views on the role of endothelin (minireview).
AB  - Endothelin was isolated and identified in 1988 by Yanagisawa et al. The
      endothelin family consists of 21 amino acid isoforms endothelin-1, endothelin-2
      and endothelin-3. Endothelin receptors are present in many internal organs, e.g.
      heart, adrenals, kidneys, lung tissue, central nervous system. ET-1 is the main
      isoform which is synthesized in endothelial cells, muscular coat of arterial wall
      as well as in heart, kidney and central nervous system. Endothelins affect
      multiple organ systems and are involved in the pathogenesis of many diseases.
      Moreover, ET-1 raises blood pressure, induces vascular and myocardial
      hypertrophy. This paper is also concerned with endothelin receptor blockers which
      mediate relaxation of resistance arteries and, since they show a hypotensive
      effect, can be useful in many cardiovascular diseases.

PMID- 12466018
TI  - Failure to increase glucose consumption through the pentose-phosphate pathway
      results in the death of glucose-6-phosphate dehydrogenase gene-deleted mouse
      embryonic stem cells subjected to oxidative stress.
AB  - Mouse embryonic stem (ES) glucose-6-phosphate (G6P) dehydrogenase-deleted cells (
      G6pd delta), obtained by transient Cre recombinase expression in a G6pd -loxed
      cell line, are unable to produce G6P dehydrogenase (G6PD) protein (EC 1.1.1.42).
      These G6pd delta cells proliferate in vitro without special requirements but are
      extremely sensitive to oxidative stress. Under normal growth conditions, ES G6pd
      delta cells show a high ratio of NADPH to NADP(+) and a normal intracellular
      level of GSH. In the presence of the thiol scavenger oxidant, azodicarboxylic
      acid bis[dimethylamide], at concentrations lethal for G6pd delta but not for wild
      type ES cells, NADPH and GSH in G6pd delta cells dramatically shift to their
      oxidized forms. In contrast, wild-type ES cells are able to increase rapidly and
      intensely the activity of the pentose-phosphate pathway in response to the
      oxidant. This process, mediated by the [NADPH]/[NADP(+)] ratio, does not occur in
      G6pd delta cells. G6PD has been generally considered essential for providing
      NADPH-reducing power. We now find that other reactions provide the cell with a
      large fraction of NADPH under non-stress conditions, whereas G6PD is the only
      NADPH-producing enzyme activated in response to oxidative stress, which can act
      as a guardian of the cell redox potential. Moreover, bacterial G6PD can
      substitute for the human enzyme, strongly suggesting that a relatively simple
      mechanism of enzyme kinetics underlies this phenomenon.

PMID- 12466019
TI  - Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic
      steatosis and abnormal hepatic choline metabolite concentrations despite
      ingesting a recommended dietary intake of choline.
AB  - Choline is an essential nutrient for humans and is derived from the diet as well
      as from de novo synthesis involving methylation of phosphatidylethanolamine
      catalysed by the enzyme phosphatidylethanolamine N -methyltransferase (PEMT).
      This is the only known pathway that produces new choline molecules. We used mice
      with a disrupted Pemt-2 gene (which encodes PEMT; Pemt (-/-)) that have
      previously been shown to possess no hepatic PEMT enzyme. Male, female and
      pregnant Pemt (-/-) and wild-type mice ( n =5-6 per diet group) were fed diets of
      different choline content (deficient, control, and supplemented). Livers were
      collected and analysed for choline metabolites, steatosis, and apoptotic
      [terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling
      (TUNEL)] positive cells. We found that, in livers of Pemt (-/-) mice fed any of
      the diets, there was hepatic steatosis and significantly higher occurrence of
      TUNEL positive cells compared with wild-type controls. In male, female and
      pregnant mice, liver phosphatidylcholine concentrations were significantly
      decreased in Pemt (-/-) choline deficient and in Pemt (-/-) choline control
      groups but returned to normal in Pemt (-/-) choline supplemented groups.
      Phosphocholine concentrations in liver were significantly diminished in knockout
      mice even when choline was supplemented to above dietary requirements. These
      results show that PEMT normally supplies a significant portion of the daily
      choline requirement in the mouse and, when this pathway is knocked out, mice are
      unable to attain normal concentrations of all choline metabolites even with a
      supplemental source of dietary choline.

PMID- 12466020
TI  - The N-terminus of the human copper transporter 1 (hCTR1) is localized
      extracellularly, and interacts with itself.
AB  - We have used indirect immunofluorescense studies and glycosylation-site insertion
      and deletion mapping to characterize the topology of human copper transporter 1
      (hCTR1), the putative human high-affinity copper-import protein. Both approaches
      indicated that hCTR1 contains three transmembrane domains and that the N-terminus
      of hCTR1, which contains several putative copper-binding sites, is localized
      extracellularly, whereas the C-terminus is exposed to the cytosol. Based on
      previous observations that CTR1 proteins form high-molecular-mass complexes, we
      investigated directly whether CTR1 proteins interact with themselves. Yeast two
      hybrid studies showed that interaction of yeast, mouse, rat and human CTR1 occurs
      at the sites of their N-terminal domains, and is not dependent on the copper
      concentration in the growth media. Analysis of deletion constructs indicated that
      multiple regions in the N-terminus are essential for this self-interaction. In
      contrast, the N-terminal tail of the presumed low-affinity copper transporter,
      hCTR2, does not interact with itself. Taken together, these results suggest that
      CTR1 spans the membrane at least six times, permitting formation of a channel,
      which is consistent with its proposed role as a copper transporter.

PMID- 12466021
TI  - Tyrosinases from crustaceans form hexamers.
AB  - Tyrosinases, which are widely distributed among animals, plants and fungi, are
      involved in many biologically essential functions, including pigmentation,
      sclerotization, primary immune response and host defence. In the present study,
      we present a structural and physicochemical characterization of two new
      tyrosinases from the crustaceans Palinurus elephas (European spiny lobster) and
      Astacus leptodactylus (freshwater crayfish). In vivo, the purified crustacean
      tyrosinases occur as hexamers composed of one subunit type with a molecular mass
      of approx. 71 kDa. The tyrosinase hexamers appear to be similar to the
      haemocyanins, based on electron microscopy. Thus a careful purification protocol
      was developed to discriminate clearly between tyrosinases and the closely related
      haemocyanins. The physicochemical properties of haemocyanins and tyrosinases are
      different with respect to electronegativity and hydrophobicity. The hexameric
      nature of arthropod tyrosinases suggests that these proteins were the ideal
      predecessors from which to develop the oxygen-carrier protein haemocyanin, with
      its allosteric and co-operative properties, later on.

PMID- 12466022
TI  - Urea signalling to immediate-early gene transcription in renal medullary cells
      requires transactivation of the epidermal growth factor receptor.
AB  - Signalling by physiological levels of urea (e.g. 200 mM) in cells of the
      mammalian renal medulla is reminiscent of activation of a receptor tyrosine
      kinase. The epidermal growth factor (EGF) receptor may be transactivated by a
      variety of G-protein-coupled receptors, primarily through metalloproteinase
      dependent cleavage of a membrane-anchored EGF precursor. In the murine inner
      medullary collecting duct (mIMCD3) cell line, urea (200 mM) induced prompt (1-5
      min) tyrosine phosphorylation of the EGF receptor. Pharmacological inhibition of
      EGF receptor kinase activity with AG1478 or PD153035 blocked urea-inducible
      transcription and expression of the immediate-early gene, Egr-1. AG1478 blocked,
      either fully or partially, other hallmarks of urea signalling including Elk-1
      activation and extracellular signal-regulated kinase phosphorylation. EGF
      receptor kinase inhibition also blocked the cytoprotective effect of urea
      observed in the context of hypertonicity-inducible apoptosis. EGF receptor
      transactivation was likely to be attributable to metalloproteinase-dependent
      ectodomain shedding of an EGF receptor agonist because both specific and non
      specific inhibitors of metalloproteinases blocked the urea effect. Heparin
      binding EGF (HB-EGF), in particular, was implicated because the diphtheria toxin
      analogue and highly specific antagonist of HB-EGF, CRM197, also blocked urea
      inducible transcription. In aggregate, these data indicate that signalling in
      response to urea in renal medullary cells requires EGF receptor transactivation,
      probably through autocrine action of HB-EGF.

PMID- 12466023
TI  - Cyclooxygenase-2 is a neuronal target gene of NF-kappaB.
AB  - BACKGROUND: NF-kappaB is implicated in gene regulation involved in neuronal
      survival, inflammmatory response and cancer. There are relatively few neuronal
      target genes of NF-kappaB characterized. RESULTS: We have identified the neuronal
      cyclooxygenase-2 (COX-2) as a NF-kappaB target gene. In organotypic hippocampal
      slice cultures constitutive NF-kappaB activity was detected, which was correlated
      with high anti-COX-2 immunoreactivity. Aspirin a frequently used painkiller
      inhibits neuronal NF-kappaB activity in organotypic cultures resulting in a
      strong inhibition of the NF-kappaB target gene COX-2. Based on these findings,
      the transcriptional regulation of COX-2 by NF-kappaB was investigated. Transient
      transfections showed a significant increase of COX-2 promoter activity upon
      stimulation with PMA, an effect which could be obtained also by cotransfection of
      the NF-kappaB subunits p65 and p50. In the murine neuroblastoma cell line NB-4,
      which is characterized by constitutive NF-kappaB activity, COX-2 promoter
      activity could not be further increased with PMA or TNF. Constitutive promoter
      activity could be repressed upon cotransfection of the inhibitory subunit IkappaB
      alpha. EMSA and mutational analysis conferred the regulatory NF-kappaB activity
      to the promoter distal kappaB-site in the human COX-2 promoter. CONCLUSIONS: NF
      kappaB regulates neuronal COX-2 gene expression, and acts as an upstream target
      of Aspirin. This extends Aspirin's mode of action from a covalent modification of
      COX-2 to the upstream regulation of COX-2 gene expression in neurons.

PMID- 12466024
TI  - An initial biochemical and cell biological characterization of the mammalian
      homologue of a central plant developmental switch, COP1.
AB  - BACKGROUND: Constitutive photomorphogenic 1 (COP1) has been defined as a central
      regulator of photomorphogenic development in plants, which targets key
      transcription factors for proteasome-dependent degradation. Although COP1
      mammalian homologue has been previously reported, its function and distribution
      in animal kingdom are not known. RESULTS: Here we report the characterization of
      full-length human and mouse COP1 cDNAs and the genomic structures of the COP1
      genes from several different species. Mammalian COP1 protein binds to
      ubiquitinated proteins in vivo and is itself ubiquitinated. Furthermore,
      mammalian COP1 is predominantly nuclear localized and exists primarily as a
      complex of over 700 kDa. Through mutagenesis studies, we have defined a leucine
      rich nuclear export signal (NES) within the coiled-coil domain of mammalian COP1
      and a nuclear localization signal (NLS), which is composed of two clusters of
      positive-charged amino acids, bridged by the RING finger. Disruption of the RING
      finger structure abolishes the nuclear import, while deletion of the entire RING
      finger restores the nuclear import. CONCLUSIONS: Our data suggest that mammalian
      COP1, similar to its plant homologue, may play a role in ubiquitination.
      Mammalian COP1 contains a classic leucine-rich NES and a novel bipartite NLS
      bridged by a RING finger domain. We propose a working model in which the COP1
      RING finger functions as a structural scaffold to bring two clusters of positive
      charged residues within spatial proximity to mimic a bipartite NLS. Therefore, in
      addition to its well-characterized role in ubiquitination, the RING finger domain
      may also play a structural role in nuclear import.

PMID- 12466025
TI  - Group I aptazymes as genetic regulatory switches.
AB  - BACKGROUND: Allosteric ribozymes (aptazymes) that have extraordinary activation
      parameters have been generated in vitro by design and selection. For example,
      hammerhead and ligase ribozymes that are activated by small organic effectors and
      protein effectors have been selected from random sequence pools appended to
      extant ribozymes. Many ribozymes, especially self-splicing introns, are known
      control gene regulation or viral replication in vivo. We attempted to generate
      Group I self-splicing introns that were activated by a small organic effector,
      theophylline, and to show that such Group I aptazymes could mediate theophylline
      dependent splicing in vivo. RESULTS: By appending aptamers to the Group I self
      splicing intron, we have generated a Group I aptazyme whose in vivo splicing is
      controlled by exogenously added small molecules. Substantial differences in gene
      regulation could be observed with compounds that differed by as little as a
      single methyl group. The effector-specificity of the Group I aptazyme could be
      rationally engineered for new effector molecules. CONCLUSION: Group I aptazymes
      may find applications as genetic regulatory switches for generating conditional
      knockouts at the level of mRNA or for developing economically viable gene
      therapies.

PMID- 12466026
TI  - Localised necrosis of scrotum (Fournier's gangrene) in a spinal cord injury
      patient - a case report.
AB  - BACKGROUND: Men with spinal cord injury (SCI) appear to have a greater incidence
      of bacterial colonisation of genital skin as compared to neurologically normal
      controls. We report a male patient with paraplegia who developed rapidly
      progressive infection of scrotal skin, which resulted in localised necrosis of
      scrotum (Fournier's gangrene). CASE PRESENTATION: This male patient developed
      paraplegia at T-8 level 21 years ago at the age of fifteen years. He has been
      managing his bladder by wearing a penile sheath. He noticed redness and swelling
      on the right side of the scrotum, which rapidly progressed to become a black
      patch. A wound swab yielded growth of methicillin-resistant Staphylococcus aureus
      (MRSA). Necrotic tissue was excised. Culture of excised tissue grew MRSA. A
      follow-up wound swab yielded growth of MRSA and mixed anaerobes. The wound was
      treated with regular application of povidone-iodine spray. He made good progress,
      with the wound healing gradually. CONCLUSION: It is likely that the presence of a
      condom catheter, increased skin moisture in the scrotum due to urine leakage,
      compromised personal hygiene, a neurogenic bowel and subtle dysfunction of the
      immune system contributed to colonisation, and then rapidly progressive infection
      in this patient. We believe that spinal cord injury patients and their carers
      should be made aware of possible increased susceptibility of SCI patients to
      opportunistic infections of the skin. Increased awareness will facilitate prompt
      recourse to medical advice, when early signs of infection are present.

PMID- 12466027
TI  - Choosing marginal or random-effects models for longitudinal binary responses:
      application to self-reported disability among older persons.
AB  - BACKGROUND: Longitudinal studies with binary repeated outcomes are now widespread
      in epidemiology. The statistical analysis of these studies presents difficulties
      and standard methods are inadequate. METHODS: We consider strategies for
      modelling binary repeated responses and focus on two specific issues: the choice
      between marginal and random-effects models, and the choice of the time point
      origin. These issues are addressed using the example of self-reported disability
      in older women assessed annually for 6 years. The indicator of disability
      "needing help to go outdoors or home-confined" is used. RESULTS: In view of the
      observed associations between the responses for consecutive years, the baseline
      response was considered as a covariate. We compared the marginal and random
      effects models first when only the influence of time and age is analysed and
      second when individual risk factors are studied in an aetiological perspective.
      There were substantial differences between the parameter estimates. They were due
      to differences between specific concepts related to the two models and the large
      between-individual heterogeneity revealed by the analysis. CONCLUSIONS: A random
      effects model appears to be most suitable for the analysis of self-reported
      disability in older women.

PMID- 12466028
TI  - A double-blind, randomized parallel-group, efficacy and safety study of
      intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus
      imipramine in patients with major depressive disorder.
AB  - S-adenosyl-L-methionine (SAMe) is a natural substance which constitutes the most
      important methyl donor in transmethylation reactions in the central nervous
      system. Several clinical trials have shown that SAMe possesses an antidepressant
      activity. This multicentre study was carried out to confirm both efficacy and
      safety of SAMe in the treatment of major depression. SAMe was given
      intramuscularly (i.m.) at a dose of 400 mg/d, double-blind, vs. 150 mg/d oral
      Imipramine (IMI) in patients with a diagnosis of major depressive episode, with a
      baseline score on the 21-item Hamilton Depression Rating Scale (HAMD) of >or=18.
      A total of 146 patients received SAMe whereas 147 received IMI for a period of 4
      wk. The two main efficacy measures were endpoint HAMD score and percentage of
      responders to Clinical Global Impression (CGI) at week 4. Secondary efficacy
      measures were the final Montgomery-Asberg Depression Rating Scale (MADRS) scores
      and the response rate intended as a fall in HAMD scores of at least 50% with
      respect to baseline. The analysis of safety and tolerability was conducted in all
      treated patients. SAMe and IMI did not differ significantly on any efficacy
      measure, either main or secondary. Adverse events were significantly less in
      patients treated with SAMe compared to those treated with IMI. These data show
      400 mg/d i.m. SAMe to be comparable to 150 mg/d oral IMI in terms of
      antidepressive efficacy, but significantly better tolerated. These findings
      suggest interesting perspectives for the use of SAMe in depression.

PMID- 12466029
TI  - Brain monoamines and early visual information-processing speed.
AB  - Visual inspection time (IT) is a measure of information-processing speed, which
      correlates reliably with psychometric intelligence. Pharmacological research into
      IT indicates that manipulation of the cholinergic system modulates performance on
      the IT task, however the contribution of other neurotransmitters to this modality
      remains unclear. This study was designed to examine the effects of low brain
      serotonin and catecholamine availability on IT using the established method of
      amino-acid precursor depletion. Female participants (n=13) completed three
      experimental sessions; tryptophan depletion (TD); tyrosine/phenylalanine
      depletion (TPD); and a balanced control condition (B) in a randomized, double
      blind cross-over design. IT assessments were performed at baseline and approx. 5
      h post-mixture administration. IT scores were unaffected by either of the
      treatment conditions. These findings suggest that monoamines, whilst implicated
      in various forms of cognition are not central to IT, which measures the
      efficiency of perceptual intake and information-processing speed.

PMID- 12466030
TI  - Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic
      stress disorder.
AB  - Dysfunction of glutamatergic neurotransmission may be relevant to the
      pathogenesis of post-traumatic stress disorder (PTSD). Preclinical and clinical
      evidence suggests that PTSD symptoms could be alleviated following enhancement of
      neurotransmission mediated at the N-methyl-D-aspartate (NMDA) subtype of
      glutamate receptors. Eleven patients with chronic PTSD participated in a double
      blind, placebo-controlled, cross-over trial with 50 mg/d D-cycloserine which acts
      as a partial agonist at the glycine regulatory site on the NMDA receptor. D
      cycloserine treatment resulted in significant improvements in numbing, avoidance,
      and anxiety symptoms; however, similar effects were also observed during placebo
      treatment. In addition, D-cycloserine treatment resulted in a significant
      (p=0.03), reduction in the perseverative error scores as measured by the
      Wisconsin Card Sorting Test. This pilot study is the first to assess the efficacy
      of a NMDA receptor modulator for PTSD treatment and its results warrant further,
      larger-scale investigation.

PMID- 12466031
TI  - Generalized anxiety disorder: comorbidity, comparative biology and treatment.
AB  - Generalized anxiety disorder (GAD) is a severe and chronic anxiety disorder
      characterized by uncontrollable worrying and somatic anxiety (tension, insomnia
      and hypervigilance). It is a common condition, with lifetime prevalence rates for
      DSM-IV GAD in the general population of approx. 5-6% being reported. In addition,
      like other anxiety disorders, GAD also shows comorbidity with depression and most
      of the other anxiety disorders. This article reviews data on the prevalence of
      GAD, its comorbidity with depression, and its social and economic impact.
      Proposed neurobiological mechanisms for GAD are discussed, since an understanding
      of these may help in the development of future therapies. Finally, current
      pharmacological and non-pharmacological treatment options for GAD are reviewed,
      with particular attention being paid to published clinical-trial data.

PMID- 12466032
TI  - Introduction to the special section.
AB  - This Special Section of the International Journal of Neuropsychopharmacology
      presents papers which review the current status of the relationship between the
      inflammatory response system (IRS) and major 'endogenous' and 'organic' (due to a
      medical condition) depression. Studies published over the last 11 years and
      reviewed in this Special Section begin to test the necessary conditions which are
      needed to accept the hypothesis that an activation of the IRS is involved in the
      pathophysiology and aetiology of 'endogenous' and 'organic' depression. This
      hypothesis suggests that some types of 'endogenous' and 'organic' depression may
      be related to IRS activation, such as an increased production of pro-inflammatory
      cytokines, such as interleukin-1beta (IL-1beta), IL-6, tumour necrosis factor
      alpha (TNF-alpha) and interferon-gamma (IFN)-gamma. These cytokines are stress
      sensitive, may cause depression, they have specific effects on brain systems
      involved in the pathogenesis of major depression, such as the serotonergic system
      and the hypothalamic-pituitary-adrenal (HPA) axis, and their production may be
      suppressed by antidepressants. Future research should examine whether anti
      inflammatory drugs are effective in the treatment of depression and whether
      naturally occurring variants of the 'IRS' genes confer susceptibility to the
      development of the depressive phenotype through altered function of the
      respective gene products.

PMID- 12466033
TI  - Immune dysregulation in major depression: a critical review of existing evidence.
AB  - It is now well established that depression is associated with immune
      dysregulation. It is not, however, known whether this immune dysregulation plays
      a role in the pathophysiology of major depression or whether it increases the
      susceptibility of the depressed patient to immune-related disorders. This article
      presents a critical review of existing evidence for immune dysregulation in major
      depression, including changes in leucocyte trafficking, lymphocyte function, and
      markers of immune activation. Possible mediators of immune dysregulation in major
      depression are briefly discussed. Finally, the relationship between major
      depression and several medical conditions such as infection, allergy and
      autoimmune disorders, cardiovascular diseases, cancer and AIDS is critically
      reviewed.

PMID- 12466034
TI  - Changes in the immune system in rodent models of depression.
AB  - This review summarizes some of the evidence which implicates an increase in the
      peripheral and central secretion of pro-inflammatory cytokines in the behavioural
      changes seen in some stress-induced and brain lesion models of depression.
      Following a consideration of the role of cytokines in the periphery and the
      brain, evidence is presented suggesting that pro-inflammatory cytokines alter the
      function of monoamine neurotransmitters which have been implicated in severe
      stress and in major depression. These changes occur in the presence of elevated
      glucocorticoid concentrations which suggests that immune activation is correlated
      with a decrease in the sensitivity of the glucocorticoid receptors on immune
      cells in addition to those occurring in the brain. The review concludes with a
      brief account of the various rodent models of depression in which evidence of
      immune activation as been demonstrated.

PMID- 12466035
TI  - Cytokines as a stressor: implications for depressive illness.
AB  - Stressful events have been implicated in the provocation of depressive illness.
      Inasmuch as immunological challenge, and particularly cytokine administration,
      engender neuroendocrine and central neurochemical changes reminiscent of those
      provoked by psychogenic stressors, it was suggested that immune activation may
      also contribute to affective illness. The present report provides a brief
      overview of the neurochemical sequelae of acute and repeated interleukin-1beta
      (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and IL-2 treatment,
      describes some of the synergisms associated with these treatments, as well as
      their potential interactions with psychogenic stressors. In addition, a
      discussion is provided concerning the fact that cytokines, like stressors, may
      have time-dependent proactive effects, so that re-exposure to the treatments
      provoke greatly augmented neurochemical changes (sensitization). Given that the
      effects of cytokines are evident within hypothalamic, as well as
      extrahypothalamic sites, including various limbic regions, it is suggested that
      cytokines may impact on emotional changes, including depression.

PMID- 12466036
TI  - The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans.
AB  - Administration of the cytokines interferon-alpha and interleukin-2 is used for
      the treatment of various disorders, such as hepatitis C and various forms of
      cancer. The most serious side-effects are symptoms associated with depression,
      including fatigue, increased sleepiness, irritability, loss of appetite as well
      as cognitive changes. However, great differences exist in the prevalence of the
      development of depressive symptoms across studies. Differences in doses and
      duration of therapy may be sources of variation as well as individual differences
      of patients, such as a history of psychiatric illness. In addition, sensitization
      effects may contribute to differential responses of patients to the
      administration of cytokines. In animals administration of pro-inflammatory
      cytokines induces a pattern of behavioural alterations called 'sickness
      behaviour' which resembles the vegetative symptoms of depression in humans.
      Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor
      tryptophan in depressed people support a role for 5-HT in the development of
      depression. In addition, evidence exists for a dysregulation of the noradrenergic
      system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression.
      Some mechanisms exist which make it possible for cytokines to cross the blood
      brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma
      and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by
      stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral
      depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic
      activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the
      HPA axis. Altogether, administration of cytokines may induce alterations in the
      brain resembling those found in depressed patients, which leads to the hypothesis
      that cytokines induce depression by their influence on the 5-HT, noradrenergic
      and HPA system.

PMID- 12466037
TI  - Cytokine-induced changes in mood and behaviour: implications for 'depression due
      to a general medical condition', immunotherapy and antidepressive treatment.
AB  - Several lines of evidence indicate that cytokine-mediated communication pathways
      between the immune system and the brain are involved in the pathophysiology of
      depression: (1) . Depression is highly prevalent in various medical conditions,
      including infectious, autoimmune and neurodegenerative diseases. This clinical
      association cannot be attributed solely to psychological distress, and it
      probably reflects direct activation of illness-induced physiological processes.
      (2). Experiments in humans and in animals demonstrate that exposure to cytokines
      induces depressive-like mood and behavioural alterations. (3). Cytokine
      immunotherapy in cancer and hepatitis patients elicits a major depressive episode
      in a large percentage of the patients. (4). Several types of depression that are
      not directly associated with a physical disease (e.g. major depression,
      melancholia, dysthymia) were also associated with cytokine hypersecretion. (5).
      Antidepressant drugs possess anti-inflammatory characteristics, which may partly
      account for their therapeutic effect. Congruently, antidepressants were found to
      reverse cytokine-induced major depression in humans and depressive-like
      behaviours in animals. (6). Cytokines affect brain systems that were implicated
      in the aetiology of depression, including the hypothalamus-pituitary-adrenal axis
      and monoaminergic systems. These conclusions strongly suggest that during medical
      conditions elevated levels of cytokines directly contribute to the induction of
      depression. Therefore, illness-associated depression should not be underestimated
      (in terms of prevalence and severity), and should be treated with antidepressant
      drugs, which may act on the specific physiological mechanisms of this disorder.

PMID- 12466038
TI  - Effects of antidepressants on the production of cytokines.
AB  - There is now evidence that major depression is associated with an up-regulation
      of the inflammatory response system (IRS). One of the major factors in this IRS
      activation is the hyperproduction of pro-inflammatory cytokines. Recently, a
      number of studies examined whether there is a causative role of these
      inflammatory mediators in the aetiology of major depression. Studies with animal
      models and cytokine immune therapy in humans suggest that pro-inflammatory
      cytokines induce depressive symptomatology. Moreover, these depressive symptoms
      can be effectively reversed by antidepressant treatment. Thus, it may be
      suggested that antidepressants suppress pro-inflammatory cytokine production
      and/or action, resulting in improvement of depressive symptoms. The influence of
      antidepressants on cytokine production has been examined in culture systems in
      vitro, and in animal models of depression - in which cytokine production is
      induced by endotoxin administration. Results suggest that antidepressants of
      several classes decrease the production of pro-inflammatory cytokines such as
      interferon-gamma and tumour necrosis factor-alpha, and increase that of
      interleukin-10, an anti-inflammatory cytokine. Further, the effect of
      antidepressive treatment on cytokine secretion and on plasma levels of cytokines
      in depressed patients has been studied. Unfortunately, different approaches to
      examine cytokine production and different techniques to measure cytokines in
      plasma are used in these studies. Despite this, current data indicate a
      normalization of cytokine plasma levels and cytokine production after
      antidepressant treatment. It is clear, however, that more research is warranted
      and we strongly argue the need for higher standardization in the methodology used
      to examine the cytokine network in depressed patients.

PMID- 12466039
TI  - Venlafaxine and reversible blepharoedema.

PMID- 12466040
TI  - Emotional blunting, sexual dysfunction and SSRIs.

PMID- 12466042
TI  - Tetrandrine and related bis-benzylisoquinoline alkaloids from medicinal herbs:
      cardiovascular effects and mechanisms of action.
AB  - Tetrandrine (TET), a bis-benzylisoquinoline alkaloid purified and identified an
      active ingredient in a Chinese medicinal herb, radix stephanae tetrandrae, has
      been used traditionally for the treatment of congestive circulatory disorder and
      inflammatory diseases. TET, together with a few of its structural analogues, has
      long been demonstrated to have antihypertensive action in clinical as well as
      animal studies. Presumably, the primary anti-hypertensive action of TET is due to
      its vasodilatory properties. TET prevents or inhibits vascular contraction
      induced by membrane depolarization with KCl or alpha-adrenoceptor activation with
      phenylephrine (PE). TET (30 micromol/L) also inhibits the release of endothelium
      derived nitric oxide (NO) as well as NO production by inducible NO synthase. TET
      apparently inhibits multiple Ca2+ entry pathways as demonstrated in cell types
      lacking the L-type Ca2+ channels. In cardiac muscle cells, TET inhibits both L-
      and T-type Ca2+ channels. In addition to its actions on cardiovascular tissues,
      TET may also exert its anti-hypertensive action via a Ca2+-dependent manner on
      other tissues intimately involved in the modulation of blood pressure control,
      such as adrenal glands. In adrenal glomerulosa cells, KCl- or angiotensin II
      induced aldosterone synthesis is highly dependent on extracellular Ca2+.
      Steroidogenesis and Ca2+-influx in bovine adrenal glomerulosa cells have been
      shown to be potently inhibited by TET. In bovine adrenal chromaffin cells, TET
      inhibits Ca2+ currents via L- and N-type channels as well as other unidentified
      channels with IC50 of 10 micromol/L. Other than the Ca2+ antagonistic effects,
      TET also interacts with the alpha-adrenergic receptors and muscarinic receptors
      based on functional as well as radioligand binding studies. Apart from its
      functional effects, TET and related compounds also exert effects on tissue
      structures, such as remodelling of hypertrophied heart and inhibition of
      angiogenesis, probably by causing apoptotic responses. TET is also known for its
      anti-inflammatory and anti-fibrogenic actions, which make TET and related
      compound potentially useful in the treatment of lung silicosis, liver cirrhosis,
      and rheumatoid arthritis.

PMID- 12466043
TI  - Effects of tetrandrine on cardiovascular electrophysiologic properties.
AB  - Tetrandrine (Tet) is one of the best characterized Ca2+ channel blocker of plant
      origin. It can affect cardiovascular electrophysiologic properties in following
      field: inhibit the contractility, +/-dt/dpmax, and automaticity of myocardium,
      prolong the FRP, and exert concentration-dependent negative inotropic and
      chronotropic effects without altering cardiac excitability. Tet directly blocks
      both T-type and L-type calcium current in ventricular cells and vascular smooth
      muscle cells, but it does not shift the I-V relationship curve of ICa. All its
      effects would be beneficial in the treatment of angina, arrhythmias, and other
      cardiovascular disorders. Tet also directly inhibits the activity of BKCa channel
      in endothelial cell line and also inhibits Ca2+-release-activated channels in
      vessel endothelial cells, which might significantly contribute to the change of
      endothelial cell activity.

PMID- 12466044
TI  - Effects of tetrandrine on cardiac and vascular remodeling.
AB  - Tetrandrine (Tet) is an alkaloid isolated from the Chinese herb Radix of
      Stephaniae tetrandrae S Moore. Cardiac and vascular remodeling confers a very
      definite risk of increased cardiovascular morbidity and mortality. Remodeling
      reversal has been achieved in human and experimental animals treated with some
      antihypertensive drugs but not all. This review will focus on cardiovascular
      remodeling and therapeutic effects of Tet. Three models, SHR, RHR (high renin),
      and DOCA-Salt HR (low renin) were used. Left ventricular and vascular remodeling
      had been developed in rats with 8-week untreated hypertension. Tet was
      administrated by ig 50 mg/kg/d for 9 weeks. Tet lowered SBP, left ventricular
      weight to body weight ratio, vascular media thickness, media to lumen ratio,
      cardiac and vascular wet weight, and collagen content. Tet decreased markedly the
      density and total number of dihydropyridine binding sites and also decreased Ca2+
      overload in myocardium and vessels. Tet improved haemodynamic changes during
      remodeling special diastolic function such as LV compliance and stiffness,
      increased cardiac myosin ATPase activity and Na+-K+, Ca2+ ATPase activity, and
      normalized vascular reactivity. Tet inhibited proliferation of vascular smooth
      muscle cells, induced and sensitized VSMCs to pro-apoptosis stimulation, improved
      the endothelial function, and increased NO production. These results suggest that
      Tet was not only an anti-hypertensive drug but also an excellent drug to reverse
      cardiac and vascular remodeling.

PMID- 12466045
TI  - Cardiovascular pharmacological effects of bisbenzylisoquinoline alkaloid
      derivatives.
AB  - Tetrandrine, dauricine, daurisoline and neferine are bisbenzylisoquinoline
      alkaloid derivatives isolated from Chinese traditional medicine and herbs. The
      cardiovascular pharmacological effects and the mechanism of actions of these
      compounds were reviewed. Tetrandrine isolated from Stephania tetrandra S Moore
      possesses antihypertensive and antiarrhythmic effects. The antihypertensive
      effects of tetrandrine have been demonstrated in experimental hypertensive
      animals and in hypertensive patients. Recent studies showed that in addition to
      its calcium antagonistic effect, tetrandrine interacted with M receptors.
      Modulation by M receptor is one of the pharmacological mechanisms of
      cardiovascular effects of tetrandrine. Dauricine and daurisoloine were isolated
      from Menispermum dauricum DC. The antiarrhythmic effects of dauricine have been
      verified in different experimental arrhythmic models and in cardiac arrhythmic
      patients. Dauricine blocked the cardiac transmembrane Na+,K+ and Ca2+ ion
      currents. Differing from quinidine and sotalol, which exhibited reverse use
      dependent effect, dauricine prolonged APD in a normal use-dependent manner in
      experimental studies. The antiarrhythmic effect of daurisoline and neferine which
      is an alkaloid isolated from Nelumbo nucifera Gaertn, and their mechanisms of
      actions have also been studied. The antiarrhythmic effect of daurisoline is more
      potent than that of dauricine.

PMID- 12466046
TI  - Immunomodulatory effects and mechanisms of plant alkaloid tetrandrine in
      autoimmune diseases.
AB  - Autoimmune diseases characterized by activation of immune effector cells and
      damage of target organs are currently treated with a combination of several
      disease-modifying antirheumatic drugs (DMARDs) that preserve different
      immunomodulatory mechanisms. Such a combination treatment strategy not only
      provides synergistic effects but also reduces side effects from individual drug.
      Tetrandrine (Tet), purified from a creeper Stephania tetrandra S Moore, is a bis
      benzylisoquinoline alkaloid and has been used to treat patients with silicosis,
      autoimmune disorders, and hypertension in Mainland China for decades. The
      accumulated studies both in vitro and in vivo reveal that Tet preserves a wide
      variety of immunosuppressive effects. Importantly, the Tet-mediated
      immunosuppressive mechanisms are evidently different from some known DMARDs. The
      synergistic effects have also been demonstrated between Tet and other DMARDs like
      FK506 and cyclosporin. These results highlight Tet a very potential candidate to
      be considered as one of DMARDs in the treatment of autoimmune diseases,
      especially rheumatoid arthritis. This review summarizes evidence-based in vivo
      and in vitro studies on this potential Chinese immunosuppressive herb.

PMID- 12466047
TI  - Potential role of tetrandrine in cancer therapy.
AB  - Tetrandrine, a bisbenylisoquinoline alkaloid isolated from the dried root of
      Stephenia tetrandra S Moore, exhibits very broad pharmacological actions,
      including anti-tumor activity. The beneficial effects of tetrandrine on tumor
      cell cytotoxicity and radiosensitization, multidrug resistance, normal tissue
      radioprotection, and angiogenesis are most promising and deserve great attention.
      Tetrandrine has potential either as a tumoricidal agent or as an adjunct to
      chemotherapy and radiotherapy. To evaluate the potential clinical efficacy of
      tetrandrine for cancer therapy, more mechanism-based pharmacological,
      pharmacokinetic, and pharmacodynamic studies are required.

PMID- 12466048
TI  - Pharmacological actions of tetrandrine in inflammatory pulmonary diseases.
AB  - Tetrandrine is a principle from a traditional Chinese medicine of the root of
      Stephania tetrandra S Moore approved by State Drugs Administration of China as a
      new drug for the treatment of silicosis. Except for its antiinflammatory,
      antifibrogenetic, immunomodulating effects and antioxidant effects, tetrandrine
      presents antiallergic effects, inhibitory effects on pulmonary vessels and airway
      smooth muscle contraction, and platelet aggregation via its nonspecific calcium
      channel antagonism that suggested its potential in the treatment of asthma,
      pulmonary hypertension and chronic obstructive pulmonary disease (COPD). In
      general, the clinical results to date with tetrandrine in asthma and pulmonary
      hypertension have been exciting. The last 10 years have witnessed great leaps
      forward in our understanding of the molecular biology and biochemistry of chronic
      inflammatory diseases as well as the treatment drugs, which may create
      opportunities for future therapeutic innovation, development of tetrandrine
      derivatives or new extracts from other Chinese medicine. The current article
      briefly reviews the basic and clinical pharmacology of tetrandrine as well as the
      in vitro and in vivo data supporting the view that tetrandrine is as a novel drug
      for the treatment of silicosis, asthma and pulmonary hypertension.

PMID- 12466049
TI  - Effects of tetrandrine on smooth muscle contraction induced by mediators in
      pulmonary hypertension.
AB  - AIM: In attempt to characterize tetrandrine on pulmonary hypertension, biological
      activities induced by a range of mediators implicated in the pathogenesis of
      pulmonary hypertension were investigated. METHODS: Pulmonary artery rings and
      tracheal segments were contracted with couples of bioactive substances in which a
      series experiments including effects of tetrandrine on calcium agonist,
      endothelin, thromboxane A2, angiotensin II, neuropeptide Y, histamine, 5-methyl
      furmethide were performed, the influences of tetrandrine in the concentration of
      1 to 30 micromol/L were investigated. RESULTS: Tetrandrine inhibited calcium
      agonist BayK8644, endothelin-1 and thromboxane A2 mimetic U46619, angiotensin II-
      and neuropeptide Y-induced contractile responses with depression of the maximal
      contraction of pulmonary artery rings in a varying extent. Tetrandrine inhibited
      leukotriene E4-induced concentration-response curve in a competitive antagonist
      manner with a pKB of (5.29+/-0.11) without any influence leukotriene C4,
      leukotriene D4, histamine, and 5-methyl furmethide induced contractile responses
      of guinea pig trachea. CONCLUSION: Tetrandrine may produce multiple
      pharmacological effects against calcium channel antagonist, U46619, endothelin
      1,angiotension II, and neuropeptide Y induced vasoconstriction in rat pulmonary
      arteries in varying extent and inhibition of leukotriene E4 rather than C4, D4,
      histamine, and 5-methyl furmethide induced contractile responses on rat tracheal
      segments. These pharmacological characteristics are considered to contribute to
      its antihypertensive action during pulmonary hypertension.

PMID- 12466050
TI  - Effect of tetrandrine on free intracellular calcium in cultured calf basilar
      artery smooth muscle cells.
AB  - AIM: To study the effects of tetrandrine (Tet) on extracellular Ca2+ influx and
      intracellular Ca2+ release in cultured calf basilar artery smooth muscle cells.
      METHODS: Free intracellular calcium was examined by a system of measurement of AR
      CM-MIC, using Fura 2-AM as a fluorescent indicator. RESULTS: In the presence of
      extracellular Ca2+ 1.3 mmol/L, no significant effect of Tet on resting [Ca2+]i
      was found. KCl 20, 40, and 60 mmol/L triggered a sustained rise in [Ca2+]i,
      pretreatment with Tet inhibited the elevation of [Ca2+]i induced by KCl in
      concentration-dependent manner, Tet at high concentration (100 micromol/L) almost
      abolished the rise of [Ca2+]i evoked by KCl. Caffeine 10 mmol/L only produced a
      transient increase of [Ca2+]i, which spontaneously declined back to resting
      levels. Tet 10-30 micromol/L had no effect on caffeine-induced [Ca2+]i transient
      peak. Tet at high concentration (100 micromol/L), however, reduced the [Ca2+]i
      transient peak induced by caffeine. Phenylephrine (PE) 10 mmol/L produced a rapid
      transient peak and a distinct sustained elevation in [Ca2+]i in the presence of
      extracellular Ca2+. In the absence of extracellular Ca2+ containing egtazic acid
      (EGTA), PE only produced a rapid transient peak in [Ca2+]i. Pretreatment of Tet
      (10-100 micromol/L) inhibited the sustained elevation in [Ca2+]i induced by PE in
      a concentration-dependent manner. However, only 100 micromol/L of Tet inhibited
      the transient peak in [Ca2+]i induced by PE both in the presence of extracellular
      Ca2+ 1.3 mmol/L and in the absence of extracellular Ca2+ containing EGTA.
      CONCLUSION: Tet inhibited the Ca2+ influx from the extracellular site via voltage
      activated Ca2+ channel and PE-receptor-operated Ca2+ channel. At a high
      concentration, Tet may inhibit the Ca2+ release from sarcoplasmic reticulum (SR)
      or refilling of intracellular calcium store in cerebral artery smooth muscle
      cells.

PMID- 12466051
TI  - Morinda citrifolia (Noni): a literature review and recent advances in Noni
      research.
AB  - Morinda citrifolia L (Noni) has been used in folk remedies by Polynesians for
      over 2000 years, and is reported to have a broad range of therapeutic effects,
      including antibacterial, antiviral, antifungal, antitumor, antihelmin, analgesic,
      hypotensive, anti-inflammatory, and immune enhancing effects. In order to reveal
      the nutritional and medicinal value of the Noni plant, and to summarize
      scientific evidence that supports the Polynesians' claim, a literature review and
      recent advances in Noni research is given below.

PMID- 12466052
TI  - Effects of natural products on ischemic heart diseases and cardiovascular system.

PMID- 12466053
TI  - Effect of Korea red ginseng on cerebral blood flow and superoxide production.
AB  - AIM: To investigate the effects of Korea red ginseng (KRG) on the cerebral
      perfusion rate in the rats and the generation of superoxide anion in the
      endothelial cells. METHODS: The cerebral perfusion rate was measured using laser
      doppler flowmetry before and after the administration of crude saponin (CS) and
      saponin-free fraction (SFF) of KRG in the anesthetized rats. The superoxide
      generation was measured by the method based on lucigenin-enhanced
      chemiluminescence in the cultured endothelial cells. RESULTS: The relative
      cerebral perfusion rate (rCBF) was significantly increased by the intraperitoneal
      injection of CS (100 mg/kg) in the rats, but SFF had no effect on the rCBF.
      Chronic treatment with CS for 7 d significantly inhibited the decrease of
      forebrain cerebral blood flow induced by clamping both carotid arteries in the
      rats. Furthermore, CS (0.1 g/L) significantly suppressed NADPH-induced superoxide
      generation in the human umbilical vein endothelial cells (P <0.01). CONCLUSION:
      The present study demonstrated that crude saponin fraction of KRG enhanced
      cerebral blood flow in rats. Furthermore, crude saponin fraction of KRG abrogated
      the NADPH-driven superoxide generation in endothelial cells.

PMID- 12466054
TI  - Protective effects of trilinolein extracted from panax notoginseng against
      cardiovascular disease.
AB  - Trilinolein is a triacylglycerol purified from a commonly used traditional
      Chinese medicine Panax notoginseng. Trilinolein has been reported to provide a
      number of beneficial effects including reducing thrombogenicity and arrhythmias
      and increasing erythrocyte deformability. Additionally, trilinolein has been
      reported to be an antioxidant, which can counteract free radical damage
      associated with atherogenesis, and myocardial damage seen with ischaemia and
      reperfusion. These pharmacologic effects may explain the perceived benefits
      derived from treating circulatory disorders with the herb over the centuries.

PMID- 12466055
TI  - Contents of four active components in different commercial crude drugs and
      preparations of danshen (Salvia miltiorrhiza).
AB  - AIM: To detect the contents of four active components of Salvia miltiorrhiza in
      various commercially available danshen crude drugs and preparations. METHODS:
      Commercially available danshen crude drugs from different sources, as well as
      danshen pills and intravenous injection preparations containing danshen alone or
      in combination with other herbs were collected. The composition of these danshen
      samples was analyzed using HPLC. Specifically, the amounts of magnesium
      tanshinoate B (MTB), danshensu, isotanshinone HA, and cryptotanshinone were
      determined. In some of these samples, the content of MTB was further confirmed by
      liquid chromatography-tandem mass spectrometer (LC-MS)/MS method. RESULTS: There
      were great variations in the amount of the four active ingredients in the
      commercially available danshen crude drugs and drug preparations in this study.
      The amount of MTB was the highest among the four components measured in the crude
      drugs. However, the amounts of MTB in all danshen preparations were much lower
      than those in crude drugs. The 2 lipophilic components, isotanshinone HA and
      cryptotanshinone, were very low or not detectable in both injection and oral
      preparations. CONCLUSION: MTB can be used to standardize the various forms of
      danshen crude drugs and drug preparations from different sources. In view of the
      variation in the amounts of MTB and other components, improvement in the
      production methods of danshen preparations is essential to ensure consistent
      amount of its active ingredients and reproducible pharmacological actions.

PMID- 12466056
TI  - Are herbal medicinal products less teratogenic than Western pharmaceutical
      products.
AB  - AIM: To determine the use and teratogenicity of herbal medicinal products (HMP).
      METHODS: A retrospective study was conducted in a University hospital to compare
      the difference in the pattern of use and fetal outcomes between pregnant women
      who took HMP and Western pharmaceutical products (WPP). RESULTS: From 1995 Jan to
      2001 Dec, 61 and 372 women took HMP and WPP one month before or during their
      current pregnancies respectively. There was an increase in the prevalence of
      pregnant women who took HMP from 0 % in 1995 to 0.8 % in 2001. Among HMP users,
      51.6 %, 82.8 % and 58.6 % of them had low monthly family income (<15 000), low
      education level (secondary education or below) and were unemployed respectively.
      In comparison to WPP, pregnant women used smaller number of HMP (1.4 vs 3.0, P <
      0.01) at a later gestation (4.8 weeks vs 3.1 weeks, P <0.01) and within a shorter
      duration (11.1 d vs 47.9 d, P < 0.01). The prevalence of congenital fetal
      abnormalities in the group of women who took HMP (3.3 %) was not significantly
      higher than that who took WPP (0.8 %). There were no and two abnormal fetal
      karyotypes in the former and latter group respectively. No and ten women in the
      former and latter group underwent termination of pregnancy for anxiety
      respectively. The proportions of silent miscarriage in the former and latter
      group were similar (6.6 % vs 5.4 %). CONCLUSION: Pregnant users of HMP were from
      lower socio-economical status. There was no significant difference in the
      teratogenicity between HMP and WPP.

PMID- 12466057
TI  - Effects of Kampo medicine, keishi-ka shakuyaku-to (TJ-60) on alteration of
      diacylglycerol metabolism in gastrointestinal smooth muscle of diabetic rats.
AB  - AIM: To examine the effects of Kampo medicine, keishi-ka-shakuyaku-to (TJ-60) on
      the signal transduction in diabetic gastrointestinal dysfunction. METHODS:
      Experimental diabetic models were prepared using streptozotocin (STZ)-treated
      Wistar rats. Randomly selected STZ rats were treated with insulin (12 U/kg/d) or
      TJ-60 (1% of food intake). Diacylglycerol (DG) and DG kinase activities were
      quantified in isolated aortic smooth muscle tissue. RESULTS: One of the key
      element of the PI-turnover, DG kinase activity in resting state in gastric smooth
      muscle was significantly increased compared to the control value, and carbachol
      (CCh)-induced response was not detectable, but it was detected in the control
      rats. On the other hand resting activity in ileum did not differ from the
      control, but the CCh-induced responses were suppressed. Treatment with TJ-60
      indicated resistant effects for the alteration of DG kinase activities in
      diabetic intestinal tissues. In order to reveal the mechanism of the effects,
      total content of DG was measured, because the DG plays important role in the PI
      turnover and the DG converted from not only PI but also incorporated glucose
      under high glucose condition. Patterns of the change in DG levels were similar to
      those in DG kinase. These results indicate that the effect of TJ-60 occurs at the
      cellular level of DG. CONCLUSION: Dysfunction of gastrointestinal smooth muscle
      in diabetes is mediated by an alternation of DG and DG kinase. TJ-60 influences
      the alteration and relief the dysfunction.

PMID- 12466058
TI  - Increase of insulin sensitivity in diabetic rats received die-huang-wan, a herbal
      mixture used in Chinese traditional medicine.
AB  - AIM: Effects on insulin sensitivity of die-huang-wan, the herbal mixture widely
      used to treat diabetic disorder in Chinese traditional medicine, were
      investigated in vivo. METHODS: The obese Zucker rats were employed as insulin
      resistant animal model. Also, insulin-resistance was induced by the repeated
      intraperitoneal injections of long-acting human insulin at 0.5 U/kg three times
      daily into adult male Wistar rats. Insulin resistance was identified using the
      loss of tolbutamide (10 mg/kg) or electroacupuncture (EA)-induced plasma glucose
      lowering action. The plasma glucose concentration was examined by glucose oxidase
      assay. RESULTS: The plasma glucose-lowering action induced by tolbutamide was
      significantly enhanced in obese Zucker rats receiving the repeated administration
      of die-huang-wan at dosage of 26 mg/kg for 3 d. Furthermore, administration of
      die-huang-wan delayed the formation of insulin resistance in rats that were
      induced by the daily repeated injection of human long-acting insulin at 0.5 U/kg
      three times daily and identified by the loss of tolbutamide- or EA-induced
      hypoglycemia. In streptozotocin-induced diabetic rats, oral administration of
      metformin at 320 mg/kg once daily made an increase of the response to exogenous
      short-acting human insulin 15 d later. This is consistent with the view that
      metformin can increase insulin sensitivity. Similar treatment with die-huang-wan
      at an effective dose (26.0 mg/kg) also increased the plasma glucose lowering
      action of exogenous insulin at 10 d later. The effect of die-huang-wan on insulin
      sensitivity seems to produce more rapidly than that of metformin. CONCLUSION: The
      present study found that oral administration of die-huang-wan increased insulin
      sensitivity and delayed the development of insulin resistance in rats.

PMID- 12466059
TI  - (-)epicatechin induces and modulates endothelium-dependent relaxation in isolated
      rat mesenteric artery rings.
AB  - AIM: The present study was aimed to examine the role of endothelial nitric oxide
      in the relaxant response to green tea (-)epicatechin and its modulation of
      endothelium-mediated relaxation in the isolated rat mesenteric artery rings.
      METHODS: Changes in the isometric tension were measured with Grass force
      displacement transducers. RESULTS: The (-)epicatechin-induced relaxation was
      largely dependent on the presence of intact endothelium and was reversed by NG
      nitro-L-arginine methyl ester 10 micromol/L or methylene blue 10 micromol/L, the
      inhibitors of nitric oxide-mediated relaxation. L-Arginine at 1 mmol/L
      antagonized the effect of L-NAME or methylene blue. Pretreatment of endothelium
      intact rings with (-)epicatechin 10 micromol/L enhanced the relaxation induced by
      endothelium-dependent vasodilator, acetylcholine, while this concentration did
      not influence the endothelium-independent relaxation induced by sodium
      nitroprusside in the endothelium-denuded artery rings. CONCLUSION: The results
      indicate that the endothelium-dependent vasodilation by (-)epicatechin is mainly
      mediated through nitric oxide and low concentration of (-)epicatechin augments
      endothelium-dependent vasorelaxation in the rat mesenteric arteries.

PMID- 12466060
TI  - Huperzine B protects rat pheochromocytoma cells against oxygen-glucose
      deprivation-induced injury.
AB  - AIM: To test the ability of huperzine B (HupB) to alleviate injury from oxygen
      glucose deprivation (OGD) in the rat pheochromocytoma line PC12 cells. METHODS:
      After OGD for 3 h and reoxygenation for 24 h, neuronal morphology was observed by
      phase-contrast microscopy; cell survival was quantified by the reduction of MTT;
      malondialdehyde (MDA) was determined by the thiobarbituric acid; superoxide
      dismutase (SOD) was assayed by a modification of the xanthine/xanthine oxidase;
      and lactate (LA) was measured according to Marbach and Weil. RESULTS: OGD for 3 h
      and reoxygenation for 24 h triggered death in nearly 70 % of cells, along with
      major changes in morphology and biochemistry including elevated level of MDA, SOD
      activity, and LA content. Cells pretreated with HupB 1-100 micromol/L for 2 h
      showed significantly improved survival and reduced biochemical and morphologic
      signs of toxicity. CONCLUSION: HupB protected PC12 cells against OGD-induced
      injury, most likely by alleviating disturbances of oxidative and energy
      metabolism.

PMID- 12466061
TI  - Importance of blood pressure variability in organ protection in spontaneously
      hypertensive rats treated with combination of nitrendipine and atenolol.
AB  - AIM: To study the importance of reduction of blood pressure variability (BPV) in
      the organ protection of long-term treatment with combination of nitrendipine and
      atenolol, which was abbreviated as Nile, in spontaneously hypertensive rats
      (SHR). METHODS: Combination of nitrendipine (10 mg/kg/d) and atenolol (20
      mg/kg/d) was given in SHR chow for 12 weeks. Blood pressure (BP) was then
      recorded during 24 h in conscious state. After the determination of baroreflex
      sensitivity (BRS), rats were killed for organ-damage evaluation. RESULTS: Long
      term treatment with Nile significantly decreased BP and BPV, ameliorated impaired
      BRS, and obviously diminished end-organ damage in SHR. The indices of left
      ventricular and aortic hypertrophy, and glomerulosclerosis score were all
      positively related to BP and BPV, and negatively related to BRS in untreated and
      Nile-treated SHR. Multiple-regression analysis showed that decrease in left
      ventricular and aortic hypertrophy was mainly related to the decrease in systolic
      BPV, and amelioration in renal lesion was mainly determined by increase in BRS.
      CONCLUSION: Long-term treatment with Nile possessed obvious organ protection in
      SHR. Besides the BP reduction, the decrease in BPV and the restoration of BRS may
      importantly contribute to this organ protection.

PMID- 12466068
TI  - [Neonate with Down syndrome and persistent condensation in the middle lobe].

PMID- 12466069
TI  - [Brucellosis-induced splenic abscess].

PMID- 12466070
TI  - [Is limitation of medical intervention ethical?].

PMID- 12466071
TI  - [Should Anales Espanoles de Pediatria publish studies that do not contain
      informed consent?].

PMID- 12466072
TI  - [End-of-life decision-making in critical care].
AB  - Introduction Termination of artificial life-support in critically-ill patients
      without chance of recovery or with severe damage is frequent in the intensive
      care unit (UCI). Patients and methodsWe studied the present situation concerning
      the withdrawal of life support in Spain using data collected over 10 years in
      referral hospitals with pediatric ICUs. Forty-nine patients were included, of
      which 43 had chronic diseases.ResultsThe most frequent causes of admission to the
      pediatric ICU in this type of patiens was respiratory failure followed by
      cardiovascular surgery. The family seemed to be a key element when taking a
      decision although in a few cases the medical team acted paternalistically. The
      most common ways of limiting life-support were withholding or withdrawing some
      treatments (mainly mechanical ventilation and vasoactive drugs) and implementing
      do-not-resuscitate orders. Sedation and suitable pain management were widely used
      in terminal care. After the decision to limit life-support was made, six patients
      were discharged from the pediatric ICU. ConclusionsAlthough each case should be
      treated individually, because of the wide variation found in the limitation of
      life-support, we suggest the need for common guidelines that could help the
      decision-making process.

PMID- 12466073
TI  - [Effects of corticosteroids in the management of Duchenne muscular dystrophy: our
      experience].
AB  - Objective To evaluate the clinical course in patients with Duchenne muscular
      dystrophy admitted to our department who received corticosteroid treatment and to
      compare their course with that in patients who did not receive corticosteroid
      treatment.Patients and methodsWe performed a retrospective study of 20 pediatric
      patients with a diagnosis of Duchenne muscular dystrophy who were offered
      corticosteroid treatment: 10 patients received deflazacort and 10 refused the
      treatment. The MRC muscular strength scale and Vignos' functional scale were used
      to evaluate clinical course, which was compared in both groups.ResultsUntreated
      patients showed progressive worsening. Corticosteroid-treated patients showed
      disease stabilization both in muscular strength and functional performance. In
      addition, muscular balance improved in 70 % of these patients, but only 2 %
      showed functional improvement. The positive effect of steroid treatment had a
      mean duration of 12 months. Loss of independent gait occurred at similar ages in
      both groups (10.3 vs. 10.5 years). The results of Achilles' tendon surgery were
      poor.ConclusionsCorticosteroids produced clinical stabilization and improved
      muscular strength. Functional improvement was not significant, including loss of
      gait, probably because this loss also depends on an increase in joint
      contracture. Good coordination among multiprofessional teams is essential to
      achieve optimal results.

PMID- 12466074
TI  - [Incidence of childhood tuberculosis in southern Pontevedra (Spain)].
AB  - Background Epidemiological pattern of tuberculosis in Galicia is closer to that
      in developing countries than to that in Europe.ObjectivesThe aim of the present
      study was to determine the incidence and development of childhood tuberculosis,
      to analyze its clinical presentation and to quantify accurate diagnoses of
      pulmonary tuberculosis.MethodsObservational descriptive retrospective study in
      children aged 0-14 years old admitted to the Tuberculosis Unit of Vigo from 1
      January 1995 to 31 December 1999.ResultsA total of 146 patients were included;
      144 initial cases (98.63 %), one relapse (0.68 %), one withdrawal/recovery (0.68
      %) and none with chronic disease or treatment failure. The incidence rate of
      tuberculosis showed no significant variations, changing from 46.08 x 5 in 1995 to
      24.81 x 5 in 1998. The incidence rate was higher in younger children and was
      111.38 x 5 in 1995 in children aged 0-4 years old. There were 78 boys (54.42 %)
      and 68 girls (46.75 %). A total of 51.36 % of the patients were from urban areas
      and 48.68 % were from rural areas. The most common location was the lung, with
      132 cases (83.54 %). The diagnosis of pulmonary tuberculosis was accurate in 59 %
      of the patients and this percentage rose to 90.3 % in the group of patients aged
      0-2 years old.ConclusionsIncidence of childhood tuberculous disease is high,
      especially in children aged 0-4 years old. A high percentage of diagnoses of
      pulmonary tuberculosis were accurate.

PMID- 12466075
TI  - [Influence of Gilbert's syndrome on serum bilirubin levels and gallstone
      formation in children with chronic hemolytic disease].
AB  - To determine whether Gilbert's syndrome increases the risk of gallstone formation
      in children with chronic hemolytic disease, we studied 44 children with this
      diagnosis. Gallstones were detected by abdominal ultrasonography. This took place
      annually in scheduled examinations or in the context of acute abdominal pain. In
      all patients, the mean values of hemoglobin, reticulocyte and serum bilirubin in
      the chronic phase were recorded. In addition, TA insertion in the A(TA)nTATAA
      motif within the promoter region of the enzyme uridine-diphosphate-glucuronyl
      transferase (UGT1A1) was screened, since this is typically associated with GS.We
      found 10 (22.7 %) homozygotes for the mutated allele TA*7/TA*7, 12 (27.3 %)
      TA*6/TA*6 heterozygotes and 22 (50 %) homozygotes for the wild-type allele
      TA*6/TA*6. No statistically significant differences were found in the values of
      hemoglobin (Kruskal-Wallis test 2.496; p > 0.05) or in reticulocyte count
      (Kruskal-Wallis test 1.696; p > 0,05) between the three groups of patients,
      suggesting a similar degree of hemolysis. Patients with the UGT1A1 TA*7/TA*7
      genotype showed higher mean serum bilirubin levels than did patients who were
      homozygous for the wild-type allele (Mann-Whitney test 35.5; p < 0.05). None of
      the patients with the TA*6/TA*6 genotype developed gallstones, whereas this
      complication was found in 2 of 12 (16.6 %) heterozygotes and 6 of 10 (60 %)
      homozygotes for the allele with TA insertion. In this latter group, 4 patients
      presented acute pancreatitis as a consequence of gallstone formation.The
      association between increased bilirubin load due to chronic hemolytic disease and
      diminished hepatic conjugation leads to raised serum bilirubin levels and
      consequently to an increased risk of gallstone formation. Therefore, we recommend
      screening for Gilbert's syndrome in children in the initial phases of chronic
      hemolytic diseases.

PMID- 12466076
TI  - [Influence of primary care personnel on breastfeeding duration].
AB  - Background Breastfeeding duration in Spanish neonates does not fulfill the
      recommendations of the World Health Organization.ObjectiveTo report the results
      of a policy of breastfeeding support in a primary care center.Material and
      methodsWe performed a before-and-after intervention study of all mothers of
      children born in Ulldecona who decided to breast feed in 1992, 1993, 1996 and
      1997 (control group: 125 infants), and from August 1999-August 2001 (72 infants).
      Study variable: in May 1999 a breastfeeding support policy was initiated in the
      primary care center.ResultsBreastfeeding duration increased (in the control group
      the mean duration of exclusive breastfeeding was 18.8 weeks; from 1999 to 2001 it
      was 28 weeks). Negative factors for breastfeeding were the birth of twins,
      introduction of a supplement, and education (there was an inverse relationship
      between greater education and breastfeeding duration). Duration of breastfeeding
      was longer in Moroccan mothers. Sex, gestational age, weight, type of delivery,
      separation between mother and neonate, maternal age, previous children, and work
      outside the home did not influence breastfeeding duration. Simple lineal
      regression revealed that the intervention was effective (P 0.046). Early
      hypogalactia and breast problems decreased, and voluntary weaning increased (P <
      0.001).ConclusionThe primary care team plays key role in the maintenance of
      breastfeeding and in the well-being of the mother and neonate.

PMID- 12466077
TI  - [Obstructive sleep apnea syndrome in children: the responsibility of
      pediatricians].
AB  - Although obstructive sleep apnea syndrome (OSAS) in children is a frequent and
      potentially serious respiratory disorder, it has a reliable diagnosis and
      treatment is highly effective. OSAS is a respiratory sleep-related disorder that
      forms part of sleep apnea-hypoapnea syndrome. The syndrome affects between 1 %
      and 3 % of children. In addition to its cardiopulmonary complications, it can
      retard growth and increase the risk of hyperactivity and learning difficulties.
      It has also been associated with attention deficit disorder and hyperactivity.
      When OSAS is suspected, up-to-date nocturnal polysomnography is the gold standard
      for the diagnosis and quantification of severity of childhood OSAS. In most
      children the treatment of choice is adenotonsillectomy, which has a success rate
      of more than 85 %. We provide an up-to-date review of the evidence on the
      clinical features, etiology, complications and treatment of OSAS in children. The
      main objective of this review is to alert pediatricians to their essential role
      in the early detection of this syndrome, especially among children who snore, and
      to provide a clinical practice guideline for the diagnosis and definitive
      treatment of these children.

PMID- 12466078
TI  - [Decisions on limiting treatment in critically-ill neonates: a multicenter
      study].
AB  - Backgrounds Some patients with a poor prognosis cause serious doubts about the
      real benefit of life-sustaining treatment. In some cases the possibility of
      limiting those treatments is raised. Such end-of-life decisions provoke ethical
      dilemmas and questions about procedure.ObjectivesTwo determine the frequency of
      end-of-life decisions in neonates, patient characteristics, and the criteria used
      by those taking decisions.Patients and methodsWe performed a multicenter,
      descriptive, prospective study. Neonates from 15 neonatal intensive care units
      who died during their stay in the hospital between 1999 and 2000, as well as
      those in whom end-of-life decisions were taken, were included. End-of-life
      decisions were defined as clinical decisions to withhold or withdraw life
      sustaining treatment.ResultsA total of 330 patients were included. End-of-life
      decisions were taken in 171 (52 %); of these, 169 (98.8 %) died. The remaining
      159 patients (48.2 %) died without treatment limitation. The main disorders
      involving end-of-life decisions were congenital malformation (47 %), neurologic
      disorders secondary to perinatal asphyxia and intracranial hemorrhage
      periventricular leukomalacia (37 %). Of the 171 neonates, treatment was withheld
      in 80 and vital support was withdrawn in 91. The most frequently withdrawn life
      sustaining treatment was mechanical ventilation (68 %). The criteria most
      commonly used in end-of-life decisions were poor vital prognosis (79.5 %), and
      current and future quality of life (37 % and 48 % respectively). The patient's
      external factors such as unfavorable family environment or possible negative
      consequences for familial equilibrium were a factor in 5 % of
      decisions.ConclusionsThe present study, the first of this type performed in
      Spain, reveals little-known aspects about the clinical practice of withholding
      and/or withdrawing life-sustaining treatment in critically ill neonates. End-of
      life decisions were frequent (52 %) and were followed by death in most of the
      patients (98,8 %). The main criteria in decision-making were poor vital prognosis
      and the patient's current and future quality of life.

PMID- 12466079
TI  - [Prone versus what?].
AB  - Background It has been known for many years that the risk of sudden infant death
      syndrome (SIDS) is reduced by the supine sleeping position. Campaigns are
      required to increase awareness of this finding among all those involved in
      childcare (parents, relatives, kindergarten staff, health professionals
      etc.).ObjectiveTo determine knowledge of the best sleeping position among health
      professionals (physicians and nurses) and the parents of healthy
      neonates.Material and methodThe study was performed in a tertiary maternity
      hospital. A voluntary, anonymous questionnaire containing an item on the best
      sleeping position for neonates was distributed. The influence of parental age,
      occupation, education, and previous children was analyzed.ResultsThe side
      position was the most frequent answer among parents both in the first
      questionnaire (50.9 %) and in the second (46.8 %). Health professionals preferred
      the supine position (63.3 %). Parents who gave the right answer had a higher mean
      age, were more likely to work outside the home and to be better educated. The
      existence of previous children did not influence the answer.ConclusionsIn some
      maternity hospitals, parents still believe the side sleeping position to be best
      for their children. To provide an example in maternity wards, all health
      professionals should accept the supine position as the best for preventing SIDS.

PMID- 12466080
TI  - [Sleeping position to prevent sudden infant death syndrome in Latin-american and
      Caribbean hospitals].
AB  - Background The prone sleeping position for sleeping has been identified as the
      principal risk factor for sudden infant death syndrome (SIDS).ObjectiveThe aim of
      this study was to determine the prevalence of different sleeping positions and
      other risk factors for SIDS and to identify the advice given to parents in
      several maternity units in Latin America and the Caribbean through a specially
      designed questionnaire.MethodsDescriptive cross-sectional study based in
      hospitals. All the countries in Latin America and the Caribbean were contacted
      through the Pan American Health Organization and responses were obtained from 16
      countries.ResultsTwo hundred thirteen hospitals answered the survey. The
      preferred sleeping position for healthy infants was prone in 8.5 % of the
      hospitals, side in 48.8 %, and supine in 25.2 %. In 17.5 % of the hospitals no
      position was preferred or the answers were inconsistent.Concerning the
      recommendations given to parents on the best position for their infants at home,
      25.7 % recommended the supine position, 7.6 % the prone position, 59.0 % the side
      position while 7.6 % made no recommendations.ConclusionsThe results of this study
      show that in the hospitals surveyed there is a policy of not placing healthy
      neonates in the prone position. However, the most frequent position was the side,
      which is not advisable as it increases the risk of SIDS. To reduce in the
      incidence of SIDS, campaigns to increase the use of the supine position should be
      carried out in hospitals and among the general public.

PMID- 12466081
TI  - [Causes of neonatal death in the community of Valencia (Spain)].
AB  - Objectives To describe the causes of neonatal mortality in the Community of
      Valencia (VC) and to compare two registration systems for causes of death: that
      of the Spanish Society of Neonatology and that of the Word Health Organization's
      "Statistical Bulletin of Deaths (SBD)".MethodsData related to death from the
      SSN's mortality form, which orders all the diagnoses according to their severity,
      and data from the SBD, which uses sequential criteria (basic, intermediate or
      immediate cause of death) were obtained. Both systems were joined in a single
      form. Data from 19 hospitals in the Community of Valencia (1998-99) were
      collected. Two features were compared: a) "single cause of death" meaning the
      first diagnosis of the SSN system versus the "basic cause" of the SBD; and b)
      "multidiagnosis", which compares all the diagnoses mentioned anywhere in either
      of the two systems.ResultsA total of 206 neonatal deaths were included. When
      using the "basic cause" criterion the most common causes of death were
      malformations (31 %), respiratory distress syndrome (20 %) and extreme
      prematurity (10 %). However, when applying the "first diagnosis" criterion, the
      most common causes were respiratory distress syndrome (34 %), malformations (33
      %) and asphyxia (9 %). These differences were statistically significant. When the
      causes of death were compared using the "multidiagnosis" criterion the
      differences were greater.ConclusionsThe two systems differ qualitatively and
      quantitatively. The SSN form is useful for studying prevalent morbidity among
      deaths as well as other parameters, but it may fail to identify the causes of
      death. The SBD uses more explicit criteria for the causes of death. Thus, both
      systems should be complementary.

PMID- 12466082
TI  - [Isolated non-compaction of the ventricular myocardium].
AB  - Isolated non-compaction of the ventricular myocardium is a rare disorder of
      endomyocardial morphogenesis characterized by numerous, excessively prominent
      ventricular trabeculations, probably due to arrest of normal endomyocardial
      embryogenesis. We report two cases of isolated non-compaction of the ventricular
      myocardium.The first patient had a brother who died in the first year of life
      after heart transplantation due to refractory heart failure caused by restrictive
      biventricular cardiomyopathy associated with a right ventricular diverticulum.
      This could have been a case of isolated non-compaction of the ventricular
      myocardium that was not diagnosed. The patient, who is 8 years old, is
      asymptomatic and echocardiogram (ECG) showed multiple prominent ventricular
      trabeculations in the apical portion of the left ventricle, slightly depressed
      systolic and diastolic function and restrictive ventricular filling pattern.The
      second patient is a 7-year-old boy who presents recurrent syncopes. ECG showed
      multiple prominent ventricular trabeculations, restrictive ventricular filling
      pattern and normal systolic function. The Holter ECG recording showed multiple
      premature ventricular complexes and nonsustained ventricular tachycardia. An
      implantable subcutaneous Holter recorder was inserted, which was associated with
      an episode of aborted sudden death and polymorphic ventricular tachycardia
      followed by asystole. The patient was then treated with an implantable
      defibrillator.

PMID- 12466083
TI  - [Nijmegen breakage syndrome associated with pulmonary lymphoma].
AB  - Nijmegen breakage syndrome is a rare autosomal recessive disorder characterized
      by a peculiar dysmorphic syndrome (microcephaly, "bird-like" facies, short
      stature), combined immunodeficiency with recurrent infections, X-ray
      hypersensitivity and predisposition to malignancy, mainly lymphomas, as a
      consequence of chromosome instability due to anomalies in the repair of double
      stranded DNA breaks.We present a 6-year-old boy with Nijmegen breakage syndrome,
      who developed a large B-cell non-Hodgkin's lymphoma, localized in the lung
      without nodal involvement.

PMID- 12466084
TI  - [Cutaneous involvement as the form of presentation in B-cell lymphoblastic
      leukemia/lymphoma].
AB  - Primary cutaneous involvement in B-cell lymphoblastic leukemia/lymphoma is rare
      in childhood. We present the case of an eleven and a half year old girl who, five
      months prior to being referred to our center, had undergone surgery to remove a
      small gluteal tumor diagnosed histopathologically as lymphoid proliferation
      suggestive of large cell lymphoma. On examination the presence of small nodes
      close to the scar where the tumor had previously been removed was observed.
      Hemogram revealed 2.7 x 9/l white blood cells with 0.5 x 9/l neutrophils; the
      remaining series and complementary investigations were normal. Bone marrow
      aspiration revealed 52 % blastic cells with immunophenotype and morphological
      characteristics of common (B-cell) acute lymphoblastic leukemia with L2 subtype
      in the French-American-British (FAB) classification. Ten months after finishing
      polychemotherapy, the patient is now in complete remission. We would like to
      highlight that a small slow-growing cutaneous node could be the presenting form
      of lymphoblastic lymphoma or acute lymphoblastic leukemia.

PMID- 12466085
TI  - [Multicenter studies and clinical trials in special populations].

PMID- 12466086
TI  - [Natural surfactants: Are there really any differences?].

PMID- 12466087
TI  - [Natural surfactants: Yes, there really are differences].

PMID- 12466088
TI  - [Retarted intrauterine growth versus small for gestational age].

PMID- 12466089
TI  - [Spontaneous neonatal chylothorax and cistyc hygroma].

PMID- 12466090
TI  - [Scurvy associated with celiac disease].

PMID- 12466091
TI  - [Pascual-Castroviejo syndrome II: Association of facial hemangioma, posterior
      fossa malformation and congenital heart defect].

PMID- 12466092
TI  - [Postherpetic neuralgia as a reason for nephrologic consultation].

PMID- 12466093
TI  - [Succinylcholine-induced rhabdomyolosis].

PMID- 12466094
TI  - [Considerations in the diagnosis and treatment of congenital vascular tumors].

PMID- 12466095
TI  - Glutamate receptors in plants.
AB  - Ionotropic glutamate receptors function in animals as glutamate-gated non
      selective cation channels. Numerous glutamate receptor-like (GLR) genes have been
      identified in plant genomes, and plant GLRs are predicted, on the basis of
      sequence homology, to retain ligand-binding and ion channel activity. Non
      selective cation channels are ubiquitous in plant membranes and may function in
      nutrient uptake, signalling and intra-plant transport. However, there is little
      evidence for amino acid gating of plant ion channels. Recent evidence suggests
      that plant GLRs do encode non-selective cation channels, but that these channels
      are not gated by amino acids. The functional properties of these proteins and
      their roles in plant physiology remain a mystery. The problems surrounding
      characterization and assignation of function to plant GLRs are discussed in this
      Botanical Briefing, and potential roles for GLR proteins as non-selective cation
      channels involved in metabolic signalling are described.

PMID- 12466096
TI  - Plastid and stromule morphogenesis in tomato.
AB  - By using green fluorescent protein targeted to the plastid organelle in tomato
      (Lycopersicon esculentum Mill.), the morphology of plastids and their associated
      stromules in epidermal cells and trichomes from stems and petioles and in the
      chromoplasts of pericarp cells in the tomato fruit has been revealed. A novel
      characteristic of tomato stromules is the presence of extensive bead-like
      structures along the stromules that are often observed as free vesicles, distinct
      from and apparently unconnected to the plastid body. Interconnections between the
      red pigmented chromoplast bodies are common in fruit pericarp cells suggesting
      that chromoplasts could form a complex network in this cell type. The potential
      implications for carotenoid biosynthesis in tomato fruit and for vesicles
      originating from beaded stromules as a secretory mechanism for plastids in
      glandular trichomes of tomato is discussed.

PMID- 12466097
TI  - Infection of tubercles of the parasitic weed Orobanche aegyptiaca by
      mycoherbicidal Fusarium species.
AB  - Progression of the infection by host-specific strains of Fusarium oxysporum and
      Fusarium arthrosporioides of Orobanche aegyptiaca (Egyptian broomrape) tubercles
      attached to tomato roots was tracked using light, confocal and electron
      microscopy. Mycelia transformed with the gene for green fluorescent protein were
      viewed using a confocal microscope. Fungal penetration was preceded by a rapid
      loss of starch, with approx. 10 % remaining at 9 h and no measurable starch at 24
      h. Penetration into the Orobanche tubercles began by 12 h after inoculation.
      Hyphae penetrated the outer six cell layers by 24 h, reaching the centre of the
      tubercles by 48 h and infecting nearly all cells by 72 h. Most of the infected
      tubercles were dead by 96 h. Breakdown of cell walls and the disintegration of
      cytoplasm in and around the infected cells occurred between 48 and 96 h. Lignin
      like material increased in tubercle cells of infected tissues over time, but did
      not appear to be effective in limiting fungal penetration or spread. Callose,
      suberin, constitutive toxins and phytoalexins were not detected in infected
      tubercles, suggesting that there are no obvious defence mechanisms to overcome.
      Both Fusarium spp. pathogenic on Orobanche produced fumonisin-like ceramide
      synthase inhibitors, while fusaric acid was produced only by F. oxysporum in
      liquid culture. The organisms do not have sufficient virulence for field use
      (based on glasshouse testing), suggesting that virulence should be transgenically
      enhanced or additional isolates sought.

PMID- 12466098
TI  - Study of homeosis in the flower of Philodendron (araceae): a qualitative and
      quantitative approach.
AB  - This study deals specifically with floral organogenesis and the development of
      the inflorescence of Philodendron squamiferum and P. pedatum. Pistillate flowers
      are initiated on the lower portion of the inflorescence and staminate flowers are
      initiated on the distal portion. An intermediate zone consisting of sterile male
      flowers and atypical bisexual flowers with fused or free carpels and staminodes
      is also present. This zone is located between the sterile male and female floral
      zones. In general, the portion of bisexual flowers facing the male zone forms
      staminodes, and the portion facing the female zone develops an incomplete
      gynoecium with few carpels. The incomplete separation of some staminodes from the
      gynoecial portion of the whorl shows that they belong to the same whorl as the
      carpels. There are two levels of aberrant floral structures in Philodendron: The
      first one is represented by the presence of atypical bisexual flowers, which are
      intermediates between typical female flowers and typical sterile male flowers.
      The second one is the presence of intermediate structures between typical carpels
      and typical staminodes on a single atypical bisexual flower. The atypical
      bisexual flowers of P. squamiferum and P. pedatum are believed to be a case of
      homeosis where carpels have been replaced by sterile stamens on the same whorl. A
      quantitative analysis indicates that in both species, on average, one staminode
      replaces one carpel.

PMID- 12466099
TI  - Initial net CO2 uptake responses and root growth for a CAM community placed in a
      closed environment.
AB  - To help understand carbon balance between shoots and developing roots, 41 bare
      root crassulacean acid metabolism (CAM) plants native to the Sonoran Desert were
      studied in a glass-panelled sealable room at day/night air temperatures of 25/15
      degrees C. Net CO(2) uptake by the community of Agave schottii, Carnegia
      gigantea, Cylindropuntia versicolor, Ferocactus wislizenii and Opuntia
      engelmannii occurred 3 weeks after watering. At 4 weeks, the net CO(2) uptake
      rate measured for south-east-facing younger parts of the shoots averaged 1.94
      micro mol m(-2) s(-1) at night, considerably higher than the community-level
      nocturnal net CO(2) uptake averaged over the total shoot surface, primarily
      reflecting the influences of surface orientation on radiation interception
      (predicted net CO(2) uptake is twice as high for south-east-facing surfaces
      compared with all compass directions). Estimated growth plus maintenance
      respiration of the roots averaged 0.10 micro mol m(-2) s(-1) over the 13-week
      period, when the community had a net carbon gain from the atmosphere of 4 mol C
      while the structural C incorporated into the roots was 23 mol. Thus, these five
      CAM species diverted all net C uptake over the 13-week period plus some existing
      shoot C to newly developing roots. Only after sufficient roots develop to support
      shoot water and nutrient requirements will the plant community have net above
      ground biomass gains.

PMID- 12466100
TI  - Size distribution, growth and inter-year variation in sex expression of Bischofia
      javanica, an invasive tree.
AB  - Flowering activity and sex expression of Bischofia javanica Blume were
      investigated for 3 years. B. javanica is an invasive dioecious tree of
      subtropical forests on the Bonin Islands in the western Pacific of Japan. The sex
      ratio showed a significant male bias (1.25-2.33). Smaller trees were
      significantly male biased, whereas larger trees showed no significant difference
      in sex expression, suggesting that males tend to be more precocious in sexual
      reproduction. We found evidence for sex changes in B. javanica; these have not
      been reported previously. Most of the 1,653 census trees remained non-flowering
      (58.1 %); 3.7 % of them showed sex changes, and the percentage of trees
      repeatedly flowering as males and females was 10.5 and 3.4 %, respectively. Sex
      changes were observed in both directions but a larger percentage of male trees
      became female. Flowering frequency and sex expression were significantly related
      to tree size (i.e. diameter at breast height). Over the 3 years, trees that were
      consistent females were the largest; inconsistent trees (switching sex between
      years) were intermediate in size, whereas consistent males were the smallest.
      There were no significant differences in relative growth rate (RGR) among trees
      of different sex or flowering frequencies. These results suggest that the
      maintenance of female reproduction is not related to changes in RGR of diameter
      but to flowering frequency or the reversal to the male form, dependent upon the
      internal resource status of individual trees.

PMID- 12466101
TI  - Fructokinase and hexokinase from pollen grains of bell pepper (Capsicum annuum
      L.): possible role in pollen germination under conditions of high temperature and
      CO2 enrichment.
AB  - The processes of pollen grain development and germination depend on the uptake
      and metabolism of pollen sugars. In pepper (Capsicum annuum L.), initial sugar
      metabolism includes sucrose hydrolysis by invertase and subsequent
      phosphorylation of glucose and fructose by hexose kinases. The main objective of
      this study was to investigate changes in fructokinase (EC 2.7.1.4) and hexokinase
      (EC.2.7.1.1) activities in pepper flowers during their development, and to study
      the possible roles of these enzymes in determining pollen germination capacity
      under high temperature and under CO(2) enrichment, previously shown to modify
      sugar concentrations in pepper pollen (Aloni et al., 2001 Physiologia Plantarum
      112: 505-512). Fructokinase (FK) activity was predominant in pepper pollen, and
      increased during pollen maturation. Pollen hexokinase (HK) activity was low and
      did not change throughout pollen development. High-temperature treatment
      (day/night, 32/26 degrees C) of pepper plants reduced the percentage of pollen
      that germinated compared with that under normal temperatures (26/22 degrees C),
      and concomitantly reduced the activity of FK in mature pollen. High temperature
      also reduced FK and HK activity in the anther. Under high ambient CO(2) (800
      micro l l(-1)) pollen FK activity was enhanced. The results suggest that pollen
      and anther FK may play a role in the regulation of pollen germination, possibly
      by providing fructose-6-phosphate for glycolysis, or through conversion to UDP
      glucose (UDPG) to support the biosynthesis of cell wall material for pollen tube
      growth. High temperature stress and CO(2) enrichment may influence pollen
      germination capacity by affecting these pathways.

PMID- 12466102
TI  - Gender variation of sequential inflorescences in a monoecious plant Sagittaria
      trifolia (Alismataceae).
AB  - In protogynous plants, female flowers of early blooming plants are at a
      reproductive disadvantage because they cannot set fruit due to the lack of
      available pollen. To study this phenomenon, gender expression of the monoecious
      herb Sagittaria trifolia was investigated over the entire flowering season in two
      field and two cultivated populations in Hubei and Hunan Provinces, China. In
      racemes of S. trifolia, flowers open sequentially from bottom to top, with female
      flowers opening first followed by male flowers. This creates a temporal
      separation of sexes in the species. Under field conditions small plants are often
      male, with production of both male and female flowers increasing with plant size.
      Femaleness increased among sequential inflorescences since female flower
      production increased whereas male flower production did not. Seed production was
      greater in large inflorescences because they contain more female flowers, and the
      number of ovules increased in female flowers at basal positions within the
      raceme. A consistent pattern of high seed set was observed in flowers from both
      field and cultivated populations. About 1 % of unfertilized ovules resulted from
      no pollination and 2 % of the seeds produced were only partly developed due to
      resource limitation. In the first inflorescence of the six experimental
      populations, 6.7-40.0 % of individuals produced only male flowers, and female
      flowers of 1.9-6.5 % individuals were aborted. The occurrence of male flowers in
      early blooming inflorescences could be an adaptive strategy to conserve resources
      and enhance pollination of female flowers in protogynous S. trifolia.

PMID- 12466103
TI  - Abscisic acid catabolism in maize kernels in response to water deficit at early
      endosperm development.
AB  - To further our understanding of the greater susceptibility of apical kernels in
      maize inflorescences to water stress, abscisic acid (ABA) catabolism activity was
      evaluated in developing kernels with chirally separated (+)-[(3)H]ABA. The
      predominant pathway of ABA catabolism was via 8'-hydroxylase to form phaseic
      acid, while conjugation to glucose was minor. In response to water deficit
      imposed on whole plants during kernel development, ABA accumulated to higher
      concentrations in apical than basal kernels, while both returned to control
      levels after rewatering. ABA catabolism activity per gram fresh weight increased
      about three-fold in response to water stress, but was about the same in apical
      and basal kernels on a fresh weight basis. ABA catabolism activity was three to
      four-fold higher in placenta than endosperm, and activity was higher in apical
      than basal kernels. In vitro incubation tests indicated that glucose did not
      affect ABA catabolism. We conclude that placenta tissue plays an important role
      in ABA catabolism, and together with ABA influx and compartmentation, determine
      the rate of ABA transport into endosperms.

PMID- 12466104
TI  - The effect of heat stress on tomato pollen characteristics is associated with
      changes in carbohydrate concentration in the developing anthers.
AB  - Continuous exposure of tomato 'Trust' to high temperatures (day/night
      temperatures of 32/26 degrees C) markedly reduced the number of pollen grains per
      flower and decreased viability. The effect of heat stress on pollen viability was
      associated with alterations in carbohydrate metabolism in various parts of the
      anther during its development. Under control, favourable temperature conditions
      (28/22 degrees C), starch accumulated in the pollen grains, where it reached a
      maximum value 3 d before anthesis; it then diminished towards anthesis. During
      anther development, the concentration of total soluble sugars gradually increased
      in the anther walls and in the pollen grains (but not in the locular fluid),
      reaching a maximum at anthesis. Continuous exposure of the plants to high
      temperatures (32/26 degrees C) prevented the transient increase in starch
      concentration and led to decreases in the concentrations of soluble sugars in the
      anther walls and the pollen grains. In the locular fluid, however, a higher
      soluble sugar concentration was detected under the high-temperature regime
      throughout anther development. These results suggest that a major effect of heat
      stress on pollen development is a decrease in starch concentration 3 d before
      anthesis, which results in a decreased sugar concentration in the mature pollen
      grains. These events possibly contribute to the decreased pollen viability in
      tomato.

PMID- 12466105
TI  - Low temperature-induced modifications in cell ultrastructure and localization of
      phenolics in winter oilseed rape (Brassica napus L. var. oleifera L.) leaves.
AB  - Acclimation of winter oilseed plants in the cold (i.e. at temperatures >0 degrees
      C) followed by short exposure to sub-lethal freezing temperatures resulted in
      pronounced ultrastructural changes of leaf epidermal and mesophyll cells. The
      following major changes were observed upon acclimation at 2 degrees C: increased
      thickness of cell walls; numerous invaginations of plasma membranes; the
      appearance of many large vesicles localized in the cytoplasm in close proximity
      to the central vacuole; the occurrence of abundant populations of microvesicles
      associated with the endoplasmic reticulum (ER) cisternae or located in the
      vicinity of dictyosomes; and the occurrence of paramural bodies and myelin-like
      structures. In addition, large phenolic deposits were observed in the vicinity of
      the plasma membrane and membrane-bound organelles such as chloroplasts, large
      vesicles or cytoplasm/tonoplast interfaces. Transient freezing (-5 degrees C for
      18 h) of the cold-acclimated leaves led to reversible disorganization of the
      cytoplasm and to pronounced structural changes of the cellular organelles.
      Chloroplasts were swollen, with the stroma occupying one half of their volume and
      the thylakoid system being displaced to the other half. Large phenolic aggregates
      disappeared but distinct layers of phenolic deposits were associated with
      mitochondrial membranes and with chloroplast envelopes. In frost-thawed cells
      recovered at 2 degrees C for 24 h, dictyosomes and dictyosome- or ER-derived
      small vesicles reappeared in the ribosome-rich cytoplasm. Aberrations in the
      structure of chloroplasts and mitochondria were less pronounced. Few phenolic
      deposits were seen as small grains associated with chloroplast envelopes and
      vesicle membranes. These observations demonstrate that plants undergo different
      changes in cell ultrastructure depending on whether they are subjected to
      chilling or freezing temperatures. Results are discussed in relation to membrane
      recycling and the possible role of phenolics during the first and second stages
      of plant acclimation at low temperature.

PMID- 12466106
TI  - Morphological and ultrastructural diversity of orbicules in relation to
      evolutionary tendencies in apocynaceae s.L.
AB  - Minute granules of sporopollenin, called orbicules, can be observed on the
      innermost tangential and/or radial walls of secretory tapetum cells. Orbicules
      were investigated in 62 species (50 genera) of Apocynaceae s.l. using light
      microscopy, scanning electron microscopy and transmission electron microscopy.
      Orbicules were found in 43 species (34 genera) distributed amongst the
      subfamilies Rauvolfioideae, Apocynoideae, Periplocoideae, and in the genus
      Riocreuxia (Asclepiadoideae). Absence of orbicules is apparent in Secamonoideae
      and Asclepiadoideae (except Riocreuxia). The orbicule types described are based
      on observed morphological and ultrastructural variation. Of the six orbicule
      types previously described, Type I and Type II orbicules are lacking. In the
      majority of species, Type III orbicules were recorded in addition to Types IV, V
      and VI. In this study we suggest that embedded Type VI orbicules are more
      derived. A correlation between orbicule typology and evolutionary tendencies in
      Apocynaceae s.l. palynology was found. A trend was observed from the presence of
      Type III orbicules in the majority of species belonging to the basal group of
      genera characterized by colporate to porate single pollen grains, or 3-6-porate
      tetrads, towards the more derived embedded Type VI orbicules in the more advanced
      Periplocoideae genera with multiporate tetrads or pollinia. Orbicule data have
      proven not to be useful for evaluating tribal delimitation within the Apocynaceae
      s.l. contrary to the Rubiaceae and Loganiaceae s.l.

PMID- 12466107
TI  - Comparative analysis of growth rings in perennial forbs grown in an Alpine
      restoration experiment.
AB  - Recent studies have demonstrated that growth rings are widespread in the roots of
      forbs, and there is evidence that the rings are formed annually. However, the
      annual nature and development of the growth rings has not yet been examined in
      comparative experimental studies. In this study growth rings were analysed in the
      main roots of four alpine forbs (Lotus alpinus, Trifolium thalii, Silene
      willdenowii and Potentilla aurea) that were grown in an alpine restoration
      experiment for 6 years. All individuals of L. alpinus and T. thalii, and some
      individuals of S. willdenowii showed six clearly demarcated growth rings,
      demonstrating that the rings were formed annually. P. aurea did not show
      distinguishable growth rings. In L. alpinus and T. thalii there were fluctuations
      in growth ring width that were consistent between individuals and also between
      species, and matched variations in climatic growth conditions. Results of the
      present study indicate that conclusions drawn from previous studies suggesting
      that growth rings in the roots of forb species are most likely formed annually
      are also valid for alpine plants. In terms of annual ring width patterns, this
      study also provides the first strong evidence for consistent responses of
      different forb species and individuals to commonly experienced variations in
      habitat conditions.

PMID- 12466108
TI  - Cellulose orientation in the outer epidermal wall of angiosperm roots:
      implications for biosystematics.
AB  - The net orientation of cellulose fibrils in the outer epidermal wall of the root
      elongation zone of 57 angiosperm species belonging to 29 families was determined
      by means of Congo Red fluorescence and polarization confocal microscopy. The
      angiosperms can be divided in three groups. In all but four plant families, the
      net orientation of the cellulose fibrils is transverse to the root axis. Three
      families, the Poaceae, Juncaceae and Cyperaceae, have a totally different
      organization. In the root elongation zone of these plants, the net orientation of
      cellulose fibrils in the outer epidermal wall is parallel with the root axis. In
      roots of one family, the Arecaceae, an elongation zone in the literal sense of
      the word is absent and cellulose fibrils are randomly oriented.

PMID- 12466110
TI  - Effect of fixatives and tissue processing on the content and integrity of nucleic
      acids.
AB  - Clinical and molecular medicines are undergoing a revolution based on the
      accelerated advances in biotechnology such as DNA microarrays and proteomics.
      Answers to fundamental questions such as how does the DNA sequence differ between
      individuals and what makes one individual more prone for a certain disease are
      eagerly being sought in this postgenomic era. Several government and nonprofit
      organizations provide the researchers access to human tissues for molecular
      studies. The tissues procured by the different organizations may differ with
      respect to fixation and processing parameters that may affect significantly the
      molecular profile of the tissues. It is imperative that a prospective
      investigator be aware of the potential contributing factors before designing a
      project. The purpose of this review is to provide an overview of the methods of
      human tissue acquisition, fixation, and preservation. In addition, the parameters
      of procurement and fixation that affect the quality of the tissues at the
      molecular level are discussed.

PMID- 12466111
TI  - Genes involved in breast cancer progression: analysis of global changes in gene
      expression or retroviral tagging?

PMID- 12466112
TI  - Disease-associated prion protein in vessel walls.
AB  - Human prion diseases like Creutzfeldt-Jakob disease are infectious, inherited, or
      sporadic neurodegenerative disorders, characterized by the accumulation of an
      abnormal isoform of the host-encoded prion protein. This affects nervous tissue
      in sporadic Creutzfeldt-Jakob disease and, additionally, in lymphoid tissue in
      bovine spongiform encephalopathy-linked variant Creutzfeldt-Jakob disease.
      Experimental studies have established the involvement of cells of the lymphoid
      and peripheral nervous system in the transport of prions to their target central
      nervous system tissue. To evaluate the role of vessel wall-associated mobile
      cells, we obtained formalin-fixed tissue blocks from various brain regions and/or
      basal arteries from sporadic, variant and iatrogenic Creutzfeldt-Jakob disease,
      and unselected control cases. We demonstrate disease-associated prion protein
      deposits in intracranial vessel walls, in sporadic and variant Creutzfeldt-Jakob
      disease by performing immunohistochemical staining and paraffin-embedded tissue
      blotting. Using double immunofluorescence, these deposits co-localize with HLA-DR
      and S-100 immunoreactive cells in the intima, which are components of the
      vascular-associated dendritic cell network, as well as with HLA-DR and CD-68
      immunopositive macrophages of the intima and media. We conclude that mobile cells
      in vessel walls like dendritic and monocyte/macrophage lineage cells may be
      involved in spread of disease-associated prion protein and possibly also of
      infectivity.

PMID- 12466113
TI  - Lens defects and age-related fiber cell degeneration in a mouse model of
      increased AbetaPP gene dosage in Down syndrome.
AB  - Early-onset cataract and Alzheimer's disease occur with high frequency in Down
      syndrome (trisomy 21), the most common chromosome duplication in human live
      births. Previously, we used in vivo and lens organ culture models to demonstrate
      Alzheimer pathophysiology in oxidative stress-related lens degeneration.
      Currently, well-characterized Alzheimer transgenic mouse models are used to
      extend these findings. Here, we report on mice carrying a complete copy of a wild
      type human AbetaPP (hAbetaPP) gene from the Down syndrome critical region on
      chromosome 21. hAbetaPP mice produce fiber cell membrane defects similar to those
      described in human cataracts and increased age-related lens degeneration.
      hAbetaPP expression and mRNA alternative splicing in human and mouse lens and
      cornea favor longer, potentially more amyloidogenic forms. Endogenous mouse
      AbetaPP expression is increased in transgenic lenses, consistent with the cycle
      of oxidative stress proposed in the mechanism of Alzheimer pathophysiology.
      Alternative splicing previously designated as neuron-specific occurs in human
      lens and cornea, and is maintained by hAbetaPP expressed in mouse tissues. These
      present data implicate AbetaPP in fiber cell formation and in early-onset
      cataracts in Down syndrome. Finally, our findings provide further support for our
      hypothesis that Alzheimer pathophysiology contributes to the cataract formation
      that is increasing in the aging population.

PMID- 12466114
TI  - Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with
      poor clinical outcome.
AB  - While several prognostic factors have been identified in breast carcinoma, the
      clinical outcome remains hard to predict for individual patients. Better
      predictive markers are needed to help guide difficult treatment decisions. In a
      previous study of 78 breast carcinoma specimens, we noted an association between
      poor clinical outcome and the expression of cytokeratin 17 and/or cytokeratin 5
      mRNAs. Here we describe the results of immunohistochemistry studies using
      monoclonal antibodies against these markers to analyze more than 600 paraffin
      embedded breast tumors in tissue microarrays. We found that expression of
      cytokeratin 17 and/or cytokeratin 5/6 in tumor cells was associated with a poor
      clinical outcome. Moreover, multivariate analysis showed that in node-negative
      breast carcinoma, expression of these cytokeratins was a prognostic factor
      independent of tumor size and tumor grade.

PMID- 12466115
TI  - Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations.
AB  - Craniopharyngioma is a rare tumor occurring in the sellar region comprising 3% of
      all intracranial tumors. To elucidate the contribution of beta-catenin gene
      mutation to tumorigenesis, we examined genetic alterations and expression of beta
      catenin in 10 cases of adamantinomatous and 6 cases of papillary
      craniopharyngiomas. Beta-catenin gene mutations were found in all of the
      adamantinomatous and none of the papillary craniopharyngiomas.
      Immunohistochemically, all cases of adamantinomatous craniopharyngioma showed
      cytoplasmic and nuclear expression of beta-catenin. In contrast, papillary
      craniopharyngiomas showed exclusively membranous expression. The results suggest
      that adamantinomatous- and papillary-type craniopharyngiomas are not only
      clinicopathologically, but also genetically, distinctive variants. Mutation of
      the beta-catenin gene therefore seems to play an important role in the
      tumorigenesis of adamantinomatous craniopharyngioma. Among the adamantinomatous
      type tumors, beta-catenin-positive mesenchymal cells were observed in two cases.
      Microdissection-based mutational analysis revealed that these mesenchymal cells
      also harbor the same beta-catenin gene mutations as those of epithelial cells,
      suggesting their tumorous nature. Thus, at least a subset of adamantinomatous
      craniopharyngioma is considered to be biphasic.

PMID- 12466116
TI  - Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4
      deficient mice.
AB  - Carbon tetrachloride (CCl(4)) intoxification in rodents is a commonly used model
      of both acute and chronic liver injury. Recently, we showed that mice in which
      FGFR4 was ablated from the germline exhibited elevated cholesterol metabolism and
      bile acid synthesis coincident with unrepressed levels of cytochrome P450 7A
      (CYP7A), the rate-limiting enzyme in cholesterol disposal. Of the four fibroblast
      growth factor (FGF) receptor genes expressed in adult liver, FGFR4 is expressed
      specifically in mature hepatocytes. To determine whether FGFR4 plays a broader
      role in liver-specific metabolic functions, we examined the impact of both acute
      and chronic exposure to CCl(4) in FGFR4-deficient mice. Following acute CCl(4)
      exposure, the FGFR4-deficient mice exhibited accelerated liver injury, a
      significant increase in liver mass and delayed hepatolobular repair. Chronic
      CCl(4) exposure resulted in severe fibrosis in livers of FGFR4-deficient mice
      compared to normal mice. Analysis at both mRNA and protein levels indicated an 8
      hour delay in FGFR4-deficient mice in the down-regulation of cytochrome P450 2E1
      (CYP2E1) protein, the major enzyme whose products underlie CCl(4)-induced injury.
      These results show that hepatocyte FGFR4 protects against acute and chronic
      insult to the liver and prevents accompanying fibrosis. The results show that
      FGFR4 acts by promotion of processes that restore hepatolobular architecture
      rather than cellularity while limiting damage due to prolonged CYP2E1 activity.

PMID- 12466117
TI  - Differential expression of LIGHT and its receptors in human placental villi and
      amniochorion membranes.
AB  - mRNA encoding LIGHT (homologous to lymphotoxins, exhibits inducible expression,
      competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed
      by T lymphocytes), a member of the tumor necrosis factor superfamily of ligands,
      as well as mRNAs encoding LIGHT receptors [HVEM, LTbetaR, and TR6 (DcR3)] are
      present in placentas and cytotrophoblast cells at term. To establish translation
      of these messages and determine directions for functional studies, term
      placentas, amniochorion membranes, and purified cytotrophoblast cells were
      evaluated by immunoblotting and immunohistochemistry. Ligand and receptor
      proteins were identified in lysates from all three sources although the soluble
      receptor, TR6, was scarce in placentas and all receptors were in low abundance in
      cytotrophoblast cells. These results were confirmed and cell type-specific
      expression was documented by immunohistochemistry. Ligand and receptor proteins
      were differentially expressed according to cell type. For example, HVEM was
      identified on syncytiotrophoblast but not in villous mesenchymal cells; amnion
      epithelial cells were positive for all proteins whereas chorion membrane
      cytotrophoblasts exhibited none. Because LIGHT is a powerful cytokine that can
      alter gene expression and promote apoptosis, these experiments suggest that
      ligand-receptor interactions may critically influence structural and functional
      aspects of human placentas through as yet undefined autocrine/paracrine pathways.

PMID- 12466118
TI  - Bile acid-induced Mallory body formation in drug-primed mouse liver.
AB  - Chronic cholestasis is associated with retention of bile acids and profound
      cytoskeletal alterations in hepatocytes including Mallory body (MB) formation.
      The mechanisms responsible for MB formation in cholestatic liver diseases are
      unclear. The aim of our study was to determine the relevance of cholestasis and
      bile acids for MB formation. For this purpose mice received a 3,5
      diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diet for 2.5 months to
      induce MB formation. After recovery from DDC intoxication for 4 weeks followed by
      disappearance of MBs, these drug-primed mice were subjected to DDC refeeding,
      common bile duct ligation (CBDL), and feeding of a cholic acid (CA)-supplemented
      diet for 7 days, respectively. Cytokeratin (CK) 8 and CK 18 expression was
      studied by competitive reverse transcriptase-polymerase chain reaction and
      Western blot analysis. Cytoskeletal alterations of hepatocytes and MB formation
      were monitored by immunofluorescence microscopy and immunohistochemistry using CK
      , ubiquitin-, and MB-specific antibodies. Like DDC refeeding, both CBDL and CA
      feeding of drug-primed mice significantly increased CK 8 and CK 18 mRNA and
      protein levels (with excess of CK 8) and resulted in ubiquitination and abnormal
      phosphorylation of CKs. Furthermore, CBDL and CA feeding resulted in rapid
      neoformation of MBs in drug-primed mice. It is concluded that MB formation in
      cholestatic liver diseases may be triggered by the action of potentially toxic
      bile acids.

PMID- 12466119
TI  - The molecular basis for hereditary porcine membranoproliferative
      glomerulonephritis type II: point mutations in the factor H coding sequence block
      protein secretion.
AB  - Porcine membranoproliferative glomerulonephritis type II in piglets of the
      Norwegian Yorkshire breed is considered the first animal model of human dense
      deposit disease. Porcine dense deposit disease is caused by the absence of the
      complement regulator factor H in plasma. Here we report the molecular basis for
      this absence. Single nucleotide exchanges at position C1590G and T3610G in the
      coding region of the factor H gene result in amino acid exchanges at nonframework
      residues L493V and I1166R that are located within SCR 9 and SCR 20, respectively.
      Apparently the L493V mutation represents a polymorphism whereas the I1166R causes
      the physiological consequences a block in protein secretion. Expression analysis
      shows comparable mRNA levels for factor H in liver tissue derived from both
      affected and healthy animals. In affected piglets, factor H protein is detected
      in increased amounts in liver cells. Factor H accumulates inside the hepatocytes
      and is not released as shown by Western blot analysis and immunohistochemistry.
      These data demonstrate that single amino acid exchanges of two nonframework amino
      acids either alone or in combination block protein secretion of factor H. This
      observation is also of interest for other human diseases in which factor H is
      involved, such as human factor H-associated form of hemolytic uremic syndrome.

PMID- 12466120
TI  - Osteopontin inhibits mineral deposition and promotes regression of ectopic
      calcification.
AB  - Ectopic calcification, the abnormal calcification of soft tissues, can have
      severe clinical consequences especially when localized to vital organs such as
      heart valves, arteries, and kidneys. Recent observations suggest that ectopic
      calcification, like bone biomineralization, is an actively regulated process.
      These observations have led a search for molecular determinants of ectopic
      calcification. A candidate molecule is osteopontin (OPN), a secreted
      phosphoprotein invariantly associated with both normal and pathological mineral
      deposits. In the present study, OPN was found to be a natural inhibitor of
      ectopic calcification in vivo. Glutaraldehyde-fixed aortic valve leaflets showed
      accelerated and fourfold to fivefold greater calcification after subcutaneous
      implantation into OPN-null mice compared to wild-type mice. In vitro and in vivo
      studies suggest that OPN not only inhibits mineral deposition but also actively
      promotes its dissolution by physically blocking hydroxyapatite crystal growth and
      inducing expression of carbonic anhydrase II in monocytic cells and promoting
      acidification of the extracellular milieu. These findings suggest a novel
      mechanism of OPN action and potential therapeutic approach to the treatment of
      ectopic calcification.

PMID- 12466121
TI  - Cathepsin-L, a key molecule in the pathogenesis of drug-induced and I-cell
      disease-mediated gingival overgrowth: a study with cathepsin-L-deficient mice.
AB  - Drug-induced gingival overgrowth, the chronic side effect of calcium antagonists,
      is frequently seen due to the increase in patients with hypertension, although
      the etiology of the disease is largely unknown. I-cell disease, which accompanies
      gingival overgrowth, is characterized by a deficiency in UDP-N-acetyl-glucosamine
      and is classified as one of the lysosomal storage diseases. Here, we hypothesized
      that a common mechanism may underlie the etiology of gingival overgrowth seen in
      patients treated with calcium antagonist and in patients with I-cell disease. A
      calcium antagonist, nifedipine, specifically suppressed cathepsin-L activity and
      mRNA expression, but not that of cathepsin-B in cultured gingival fibroblasts.
      The activity of cathepsin-L was suppressed up to 50% at 24 hours after treatment
      of the cells with the reagent. The selective suppression of cathepsin-L activity
      appeared not to be dependent on Ca(2+), since treatment of the cells with
      thapsigargin suppressed both cathepsin-B and -L activity. Mice deficient in the
      cathepsin-L gene manifested enlarged gingivae. Histological observation of the
      gingivae demonstrated typical features of acanthosis, a phenotype very similar to
      that of experimentally induced gingival overgrowth. Since cathepsin-L deficiency
      was reported to be associated with thickening of the skin, impaired cathepsin-L
      activity may play a key role in the establishment of skin and gingival
      abnormalities seen in I-cell disease. In addition, reduced cathepsin-L activity
      may play an important role in inducing drug-induced gingival overgrowth.

PMID- 12466122
TI  - Anti-thrombin is expressed in the benign prostatic epithelium and in prostate
      cancer and is capable of forming complexes with prostate-specific antigen and
      human glandular kallikrein 2.
AB  - Anti-thrombin, a member of the serpin family and an inhibitor of thrombin and
      blood coagulation factor Xa, was recently shown to inhibit angiogenesis and tumor
      growth. In the present study, we examined the expression of anti-thrombin in
      benign and malignant prostate gland. Using immunohistochemistry, anti-thrombin
      was found in prostate epithelium and stroma cells. Tissue microarrays of tumors
      (n = 112) and three different prostate cancer cell lines (PC-3, LNCaP, and DU
      145) were all positive for anti-thrombin. Abundant expression in a population of
      prostatic tumor cells was further evidenced by in situ hybridization experiments.
      The immunostaining for anti-thrombin was confined to the cytoplasm, was most
      intense in Gleason grade 3 tumors, and in part overlapped with that of prostate
      specific antigen. Western blotting of benign and malignant tissue homogenates
      revealed a predominant 58-kd anti-thrombin immunoreactive component. In vitro,
      anti-thrombin formed complexes more readily with human kallikrein 2, particularly
      in the presence of heparin, and less efficiently with prostate-specific antigen.
      Both complexes could be recognized by polyclonal and monoclonal IgGs against anti
      thrombin. We conclude that anti-thrombin is widely expressed in prostate cancer
      but is gradually lost in tumors of high Gleason grade. Anti-thrombin may act as a
      local anti-angiogenic factor, the effect of which is partially lost in poorly
      differentiated prostatic tumors.

PMID- 12466123
TI  - Loss of the EP2 prostaglandin E2 receptor in immortalized human keratinocytes
      results in increased invasiveness and decreased paxillin expression.
AB  - Prostaglandin E(2) (PGE(2)) receptor subtype EP(2), which is coupled to cAMP
      metabolism, is known to mediate proliferation of primary human keratinocytes in
      vitro. The effect of gain or loss of EP(2) receptors in immortalized human
      keratinocytes (HaCat cells) was examined. HaCat keratinocytes were transfected
      with sense or anti-sense constructs of the EP(2) receptor. Loss or gain of EP(2)
      expression was documented by immunoblot and associated changes in agonist
      stimulated cAMP production. Loss or gain of EP(2) receptor expression correlated
      with alterations in plating efficiencies but with modest affects on growth. When
      cell lines were studied in an organ culture model, anti-sense clones were highly
      invasive compared with vector controls and sense transfectants. A marked increase
      in prostaglandin production is commonly seen in malignant lesions. Because
      prostaglandin receptors are known to undergo ligand-induced receptor down
      regulation, we sought to determine whether EP(2) receptor down-regulation results
      in increased invasiveness. In vector controls, invasiveness was reproduced by
      ligand-dependent EP(2) receptor down-regulation as assessed by
      immunohistochemistry. In addition, loss of EP(2) receptor expression was
      associated with decreased paxillin expression, a critical component of focal
      adhesion assembly. Thus, down-regulation of EP(2) receptors represents a
      potential mechanism for neoplastic progression to an invasive phenotype.

PMID- 12466124
TI  - Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule
      formation.
AB  - Extensive formation of nonfollicular sterile pustules on erythematous background
      combined with fever and peripheral blood leukocytosis are the characteristics of
      acute generalized exanthematous pustulosis. This uncommon eruption most often is
      an allergic reaction because of drugs such as aminopenicillins and sulfonamides
      inter alia. We recently demonstrated the important role of drug-specific T cells
      in the pathogenesis of this disease, showing that they produce high amounts of
      the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a
      special subgroup of T cells, differing from the usual Th1 and Th2 subsets. In
      this study we use immunohistochemistry as well as cytotoxicity assays (4- and 18
      hour assays) and fluorescence-activated cell-sorting analysis of drug-specific
      circulating T cells and of cells eluted from the skin of five patients with acute
      generalized exanthematous pustulosis, to analyze whether cytotoxic T-cell
      functions are important in the pathogenesis of this disease, in particular for
      the formation of vesicles. The data reveal that drug-specific CD4(+) as well as
      CD8(+) T cells both are activated and cytotoxic; perforin/granzyme B and to a
      variable degree the Fas/FasL-killing mechanism is involved in tissue destruction.
      These features allow the formation of vesicles. Additional secretion of
      interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the
      vesicles and transform them into pustules.

PMID- 12466125
TI  - Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein
      kinases in Lewy body diseases.
AB  - A better understanding of cellular mechanisms that occur in Parkinson's disease
      and related Lewy body diseases is essential for development of new therapies. We
      previously found that 6-hydroxydopamine (6-OHDA) elicits sustained extracellular
      signal-regulated kinase (ERK) activation that contributes to neuronal cell death
      in vitro. As subcellular localization of activated kinases affect accessibility
      to downstream targets, we examined spatial patterns of ERK phosphorylation in 6
      OHDA-treated cells and in human postmortem tissues representing the full spectrum
      of Lewy body diseases. All diseased human cases exhibited striking granular
      cytoplasmic aggregates of phospho-ERK (P-ERK) in the substantia nigra (involving
      28 +/- 2% of neurons), which were largely absent in control cases (0.3 +/- 0.3%).
      Double-labeling studies and examination of preclinical cases suggested that these
      P-ERK alterations could occur relatively early in the disease process.
      Development of granular cytoplasmic P-ERK staining in 6-OHDA-treated cells was
      blocked by neuroprotective doses of catalase, supporting a role for oxidants in
      eliciting neurotoxic patterns of ERK activation. Evidence of nuclear
      translocation was not observed in degenerating neurons. Moreover, granular
      cytoplasmic P-ERK was associated with alterations in the distribution of
      downstream targets such as P-RSK1, but not of P-Elk-1, suggesting functional
      diversion of ERK-signaling pathways in Lewy body diseases.

PMID- 12466126
TI  - Sustained expression of homeobox D10 inhibits angiogenesis.
AB  - Homeobox (Hox) genes are master regulatory genes that direct organogenesis and
      maintain differentiated tissue function. As HoxD3 and HoxB3 promote angiogenesis,
      we investigated whether endothelial cells use other Hox genes to maintain a
      mature quiescent phenotype. HoxD10 expression was higher in quiescent as compared
      to tumor-associated angiogenic endothelium. Microarray analysis of HoxD10
      overexpressing endothelial cells revealed a pattern of gene expression consistent
      with a nonangiogenic phenotype. Moreover, sustained expression of HoxD10 impaired
      endothelial cell migration and blocked angiogenesis induced by basic fibroblast
      growth factor and vascular endothelial growth factor in the chick chorioallantoic
      membrane in vivo. HoxD10-overexpressing human endothelial cells also failed to
      form new vessels when implanted into immunocompromised mice. These results
      indicate a role for HoxD10 in maintaining a nonangiogenic state in the
      endothelium.

PMID- 12466127
TI  - Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of
      transforming growth factor-beta1 via G-protein signal transduction in aortic
      valve interstitial cells.
AB  - Clinical disorders associated with increased serotonin [5-hydroxytryptamine (5
      HT)] levels, such as carcinoid syndrome, and the use of serotonin agonists, such
      as fenfluoramine have been associated with a valvulopathy characterized by
      hyperplastic valvular and endocardial lesions with increased extracellular
      matrix. Furthermore, 5-HT has been demonstrated to up-regulate transforming
      growth factor (TGF)-beta in mesangial cells via G-protein signal transduction. We
      investigated the hypothesis that increased exposure of heart valve interstitial
      cells to 5-HT may result in increased TGF-beta1 expression and activity because
      of serotonin receptor-mediated signal transduction with activation of Galphaq,
      and subsequently up-regulation of phospholipase C. Thus, in the present study we
      performed a clinical-pathological investigation of retrieved carcinoid and normal
      valve cusps using immunohistochemical techniques to detect the presence of TGF
      beta1 and other proteins associated with TGF-beta expression, including TGF-beta
      receptors I and II, latent TGF-beta-associated peptide (LAP), and alpha-smooth
      muscle actin. Carcinoid valve cusps demonstrated the unusual finding of
      widespread smooth muscle actin involving the interstitial cells in the periphery
      of carcinoid nodules; these same cells were also positive for LAP. Normal valve
      cusps were only focally positive for smooth muscle actin and LAP. In sheep aortic
      valve interstitial cell cultures 5-HT induced TGF-beta1 mRNA production and
      increased TGF-beta1 activity. 5-HT also increased collagen biosynthesis at the
      dosages studied. Furthermore, TGF-beta1 added to SAVIC cultures increased the
      production of sulfated glycan and hyaluronic acid. In addition, overexpression of
      Galphaq using an adenoviral expression vector for a constitutively active Galphaq
      mutant (Q209L-Galphaq) resulted in increased phospholipase C activity as well as
      up-regulation of TGF-beta expression and activity. These results strongly support
      the view that G-protein-related signal transduction is involved in 5-HT up
      regulation of TGF-beta1. In conclusion, 5-HT-associated valve disease may be, in
      part, because of TGF-beta1 mechanisms.

PMID- 12466128
TI  - Frequent deletion of Fas gene sequences encoding death and transmembrane domains
      in nasal natural killer/T-cell lymphoma.
AB  - Nasal natural killer (NK)/T-cell lymphoma (NL) frequently co-expresses Fas (Apo
      1/CD95) and Fas ligand (FasL), but the tumor cells seldom undergo apoptosis. To
      determine the reason for failure of apoptosis, we examined Fas mRNA expression in
      23 NL cases by reverse transcriptase-polymerase chain reaction and sequenced the
      entire coding region of the Fas gene in 15 of these cases for which the full
      length Fas cDNA could be amplified. The reverse transcriptase-polymerase chain
      reaction analysis revealed that all of the 23 cases expressed Fas mRNA and the
      sequencing results showed that in addition to the commonly expressed wild-type
      Fas mRNA and four alternative splice variants detected in 7 cases, mutant Fas
      transcripts were present in 9 of the 15 (60%) cases sequenced. With confirmation
      of some Fas mutations at the gene level, 12 deletions in nine cases and one
      insertion in one case were eventually identified. To rule out any potential
      polymerase chain reaction artifacts, the same protocol was used to examine 10
      reactive tonsils as a control. No aberrant transcripts associated with deletions
      were detected in these tonsils except for three alternative splice variants. All
      of the deletion variants detected in NL contained N-terminal preligand assembly
      domain but not C-terminal death domain and/or transmembrane domain. Co-detection
      of the wild-type allele and the mutated Fas alleles without the death domain
      suggested that a dominant-negative mechanism could block the apoptosis signaling.
      Moreover, loss of the transmembrane domain could protect the tumor cells from apo
      ptosis by producing a soluble form of the Fas receptor. The actuarial 3-year
      survivals leveled off at 15% for patients carrying the Fas mutations and/or
      splice variants in the lesions and 49% for those carrying the wild type only, but
      the difference did not reach statistical significance on the univariate analysis
      (P = 0.396). Taken together, the findings in this study suggest that frequent Fas
      gene mutations in NL can result in resistance to apoptosis and may contribute to
      the pathogenesis of NL by adding to the tumor immune privilege.

PMID- 12466129
TI  - Genomic imbalances in pediatric intracranial ependymomas define clinically
      relevant groups.
AB  - The outcome of pediatric ependymomas is difficult to predict based on clinical
      and histological parameters. To address this issue, we have performed a
      comparative genomic hybridization screen of 42 primary and 11 recurrent pediatric
      ependymomas and correlated the genetic findings with clinical outcome. Three
      distinct genetic patterns were identified in the primary tumors and confirmed by
      hierarchical cluster analysis. The first group of structural tumors, showed few,
      mainly partial imbalances (n = 19). A second numerical group showed 13 or more
      chromosome imbalances with a nonrandom pattern of whole chromosome gains and
      losses (n = 5). The remaining tumors (n = 18) showed a balanced genetic profile
      that was significantly associated with a younger age at diagnosis (P < 0.0001),
      suggesting that ependymomas arising in infants are biologically distinct from
      those occurring in older children. Multivariate analysis showed that the
      structural group had a significantly worse outcome compared to tumors with a
      numerical (P = 0.05) or balanced profile (P = 0.02). Moreover genetic group and
      extent of surgical resection contributed significantly to outcome whereas
      histopathology, age, and other clinical parameters did not. We conclude that
      patterns of genetic imbalances in pediatric intracranial ependymomas may help to
      predict clinical outcome.

PMID- 12466130
TI  - Bacterial colonization and the expression of inducible nitric oxide synthase in
      murine wounds.
AB  - The expression of inducible nitric oxide synthase (iNOS) in two different murine
      wound models was investigated. Animals were subjected to either full-thickness
      linear skin incision with subcutaneous implantation of sterile polyvinyl alcohol
      sponges, or to 1.5 x 1.5-cm dorsal skin excision. Reverse transcriptase
      polymerase chain reaction detected iNOS mRNA in all cell samples retrieved from
      the sponges. Immunoblotting of lysates of inflammatory cells harvested from the
      sponges failed to detect iNOS protein, and immunohistochemistry of the incisional
      wound was mildly positive. Inflammatory cells of excisional wounds stained
      strongly positive for iNOS. Cutaneous wounds were found to be colonized with
      Staphylococcus aureus. The detection of iNOS in cells from sponges inoculated in
      vivo with heat-killed bacteria and the reduction of immunohistochemical signal
      for iNOS in excisional wounds of animals treated with antibiotics support a role
      of bacteria in the induction of iNOS in wounds. The expression of iNOS in
      excisional wounds requires interferon-gamma and functional lymphocytes because
      interferon-gamma knockout and SCID-Beige mice exhibited attenuated iNOS staining
      in excisional wounds. The expression of iNOS in the inflammatory cells of murine
      wounds is a response to bacterial colonization and not part of the normal repair
      process elicited by sterile tissue injury.

PMID- 12466131
TI  - Nipah virus infection: pathology and pathogenesis of an emerging paramyxoviral
      zoonosis.
AB  - In 1998, an outbreak of acute encephalitis with high mortality rates among pig
      handlers in Malaysia led to the discovery of a novel paramyxovirus named Nipah
      virus. A multidisciplinary investigation that included epidemiology,
      microbiology, molecular biology, and pathology was pivotal in the discovery of
      this new human infection. Clinical and autopsy findings were derived from a
      series of 32 fatal human cases of Nipah virus infection. Diagnosis was
      established in all cases by a combination of immunohistochemistry (IHC) and
      serology. Routine histological stains, IHC, and electron microscopy were used to
      examine autopsy tissues. The main histopathological findings included a systemic
      vasculitis with extensive thrombosis and parenchymal necrosis, particularly in
      the central nervous system. Endothelial cell damage, necrosis, and syncytial
      giant cell formation were seen in affected vessels. Characteristic viral
      inclusions were seen by light and electron microscopy. IHC analysis showed
      widespread presence of Nipah virus antigens in endothelial and smooth muscle
      cells of blood vessels. Abundant viral antigens were also seen in various
      parenchymal cells, particularly in neurons. Infection of endothelial cells and
      neurons as well as vasculitis and thrombosis seem to be critical to the
      pathogenesis of this new human disease.

PMID- 12466132
TI  - Targeted inactivation of the mouse guanylin gene results in altered dynamics of
      colonic epithelial proliferation.
AB  - Heat-stable enterotoxin (STa), elaborated by enterotoxigenic Echerichia coli, is
      a worldwide cause of secretory diarrhea in infants and travelers. Both STa and
      guanylin, a peptide structurally similar to STa, increase intracellular cGMP
      levels after binding to the same intestinal receptor, guanylate cyclase C (GC-C).
      Distinct from its role as an intestinal secretagogue, guanylin may also have a
      role in intestinal proliferation, as guanylin expression is lost in intestinal
      adenomas. To determine the function of guanylin in intestinal epithelia, guanylin
      null mice were generated using a Cre/loxP-based targeting vector. Guanylin null
      mice grew normally, were fertile and showed no signs of malabsorption. However,
      the levels of cGMP in colonic mucosa of guanylin null mice were significantly
      reduced. The colonic epithelial cell migration rate was increased and increased
      numbers of colonocytes expressing proliferating cell nuclear antigen (PCNA) were
      present in crypts of guanylin null mice as well. The apoptotic index was similar
      in guanylin null mice and littermate controls. We conclude from these studies
      that loss of guanylin results in increased proliferation of colonic epithelia. We
      speculate that the increase in colonocyte number is related to decreased levels
      of cGMP and that this increase in proliferation plays a role in susceptibility to
      intestinal adenoma formation and/or progression.

PMID- 12466133
TI  - Transforming growth factor-beta1 is up-regulated by podocytes in response to
      excess intraglomerular passage of proteins: a central pathway in progressive
      glomerulosclerosis.
AB  - Chronic diseases of the kidney have a progressive course toward organ failure.
      Common pathway mechanisms of progressive injury, irrespectively of the etiology
      of the underlying diseases, include glomerular capillary hypertension and
      enhanced passage of plasma proteins across the glomerular capillary barrier
      because of impaired permselective function. These changes are associated with
      podocyte injury and glomerular sclerosis. Direct evidence for causal roles is
      lacking, particularly for the link between intraglomerular protein deposition and
      sclerosing reaction. Because transforming growth factor-beta1 (TGF-beta1) is the
      putative central mediator of scarring, we hypothesized that TGF-beta1 can be up
      regulated by protein overload of podocytes thereby contributing to sclerosis. In
      rats with renal mass reduction, protein accumulation in podocytes as a
      consequence of enhanced transcapillary passage preceded podocyte
      dedifferentiation and injury, increase in TGF-beta1 expression in podocytes, and
      TGF-beta1-dependent activation of mesangial cells. Angiotensin-converting enzyme
      inhibitor prevented both accumulation of plasma proteins and TGF-beta1
      overexpression in podocytes and sclerosis. Albumin load on podocytes in vitro
      caused loss of the synaptopodin differentiation marker and enhanced TGF-beta1
      mRNA and protein. Conditioned medium of albumin-stimulated podocytes induced a
      sclerosing phenotype in mesangial cells, an effect mimicked by TGF-beta1 and
      blocked by anti-TGF-beta1 antibodies. Thus, the passage of excess plasma proteins
      across the glomerular capillary wall is the trigger of podocyte dysfunction and
      of a TGF-beta1-mediated mechanism underlying sclerosis. Agents to reduce TGF
      beta1, possibly combined with angiotensin blockade, should have priority in novel
      approaches to treatment of progressive nephropathies.

PMID- 12466134
TI  - Replication and clearance of respiratory syncytial virus: apoptosis is an
      important pathway of virus clearance after experimental infection with bovine
      respiratory syncytial virus.
AB  - Human respiratory syncytial virus is an important cause of severe respiratory
      disease in young children, the elderly, and in immunocompromised adults.
      Similarly, bovine respiratory syncytial virus (BRSV) is causing severe, sometimes
      fatal, respiratory disease in calves. Both viruses are pneumovirus and the
      infections with human respiratory syncytial virus and BRSV have similar clinical,
      pathological, and epidemiological characteristics. In this study we used
      experimental BRSV infection in calves as a model of respiratory syncytial virus
      infection to demonstrate important aspects of viral replication and clearance in
      a natural target animal. Replication of BRSV was demonstrated in the luminal part
      of the respiratory epithelial cells and replication in the upper respiratory
      tract preceded the replication in the lower respiratory tract. Virus excreted to
      the lumen of the respiratory tract was cleared by neutrophils whereas apoptosis
      was an important way of clearance of BRSV-infected epithelial cells. Neighboring
      cells, which probably were epithelial cells, phagocytized the BRSV-infected
      apoptotic cells. The number of both CD4(+) and CD8+ T cells increased during the
      course of infection, but the T cells were not found between the epithelial cells
      of the bronchi up until apoptosis was no longer detected, thus in the bronchi
      there was no indication of direct contact-dependent T-cell-mediated cytotoxicity
      in the primary infection.

PMID- 12466135
TI  - Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its
      signaling pathway in aortic valve interstitial cells.
AB  - Serotonin [5-hydroxytryptamine (5-HT)]-mediated cardiac valvular disease has been
      commonly observed in patients with carcinoid tumors. Previous research by others
      using reverse transcriptase-polymerase chain reaction demonstrated that aortic
      valve cells expressed predominantly 5-HT(2A/2B) receptors (5-HT(2A)R). Related
      investigations by our group using sheep aortic valve interstitial cell (SAVIC)
      cultures demonstrated that 5-HT both up-regulates transforming growth factor
      (TGF)-beta1 expression and activity, and also results in increased phospholipase
      C (PLC) activity. Thus, the present study investigated the hypothesis that the 5
      HT signaling pathway in SAVICs involves 5-HT(2)Rs with associated G-protein
      signal transduction. The objectives were to functionally characterize in SAVIC
      cultures the native serotonin receptor subtypes using specific agonists and
      antagonists, and to delineate the serotonin-signaling pathway. 5-HT
      administration caused a marked stimulation of PLC activity. SAVIC studies of
      specific agents that target the 5-HT(2)R subtypes indicate that this response
      seemed to be mediated predominantly by 5-HT(2A)Rs. Furthermore, the sheep 5
      HT(2A)R was identified by reverse transcriptase-polymerase chain reaction with
      sequence confirmation including comparisons to pig and human 5-HT(2A)R.
      Extracellular signal-regulated kinase (Erk 1/2) is a signaling molecule
      downstream from the 5-HT(2A)R. Both a protein kinase C inhibitor, GF109203X, and
      a Src inhibitor, PP1, attenuated 5-HT-stimulated Erk 1/2 activation. However, a 5
      HT(2A)R antagonist, MDL 100907, inhibited 5-HT up-regulation of PLC and TGF
      beta1, while having far less pronounced effects on Erk 1/2. In conclusion, these
      studies of the signal transduction activity of SAVICs in response to 5-HT have
      demonstrated that the 5-HT(2A)Rs are the most functionally active of the 5
      HT(2)Rs in this cell type. Furthermore, 5-HT(2A)Rs are also involved in 5-HT up
      regulation of active TGF-beta. 5-HT also mediated strong Erk 1/2 signaling via
      the MAP-kinase pathway, which was only in part because of 5-HT(2A)R activity.
      Thus, major 5-HT Erk 1/2 signaling beyond that controlled by 5-HT(2)Rs must
      involve other serotonin receptor types and/or secondary signaling events.

PMID- 12466136
TI  - CD44 deficiency leads to enhanced neutrophil migration and lung injury in
      Escherichia coli pneumonia in mice.
AB  - CD44 is a major cell-surface receptor for hyaluronic acid (HA), a
      glycosaminoglycan component of extracellular matrix. HA-CD44 interactions have
      been implicated in leukocyte extravasation into an inflammatory site. This study
      examined the role of CD44 in acute inflammatory responses during pneumonias
      induced by Escherichia coli and Streptococcus pneumoniae using CD44-deficient
      mice. In E. coli-induced pneumonia, neutrophil accumulation in the lungs and
      edema formation was increased by 84% and 88%, respectively, in CD44-deficient
      mice compared to wild-type mice. In contrast, no difference was observed between
      these genotypes in S. pneumoniae-induced pneumonia, and the HA content in the
      lungs decreased after instillation of S. pneumoniae, but not E. coli, in both
      genotypes. Studies to determine the mechanisms for this enhanced response showed
      that: 1) neutrophil apoptosis was not different between these two genotypes in
      either type of pneumonia; 2) CD44 deficiency resulted in enhanced mRNA expression
      of several inflammatory genes; and 3) CD44-deficient neutrophils migrated through
      Matrigel in response to chemoattractants faster and in greater numbers than wild
      type neutrophils in vitro and this increase was in part dependent on HA content
      in the Matrigel. These data demonstrate that CD44 deficiency results in enhanced
      inflammation in E. coli but not S. pneumoniae-induced pneumonia, suggesting a
      previously unrecognized role for CD44 in limiting the inflammatory response to E.
      coli.

PMID- 12466138
TI  - Acceleration of mouse mammary tumor virus-induced murine mammary tumorigenesis by
      a p53 172H transgene: influence of FVB background on tumor latency and
      identification of novel sites of proviral insertion.
AB  - We previously showed that a mammary-specific dominant-negative p53 transgene (WAP
      p53(172H)) could accelerate ErbB2-induced mammary tumorigenesis in mice, but was
      not tumorigenic on its own. To identify other genes that cooperate with WAP
      p53(172H) in tumorigenesis, we performed mouse mammary tumor virus (MMTV)
      proviral mutagenesis. We derived F1, N2, and N4/N5 mice from p53(172H) transgenic
      FVB mice backcrossed onto MMTV+ C3H/He mice. Results show the latency of MMTV
      tumorigenesis is correlated with FVB contribution. F1 tumors had the shortest
      latency (217 days), had a higher rate of metastasis, and were less differentiated
      than the N2 and N4/N5 tumors. The latency was 269 days in N2 mice, and lengthened
      to 346 days in N4/N5 mice. p53(172H) significantly accelerated MMTV tumorigenesis
      only in N2 mice, indicating cooperativity between p53(172H) and MMTV in this
      cohort. To identify genes that may be causally involved in MMTV-induced mammary
      tumorigenesis, we identified 60 sites of proviral insertion in the N2 tumors.
      Among the insertions in p53(172H) transgenic tumors were 10 genes not previously
      found as sites of MMTV insertion including genes involved in signaling (Pdgfra,
      Pde1b, Cnk1), cell adhesion (Cd44), angiogenesis (Galgt1), and transcriptional
      regulation (Olig1, Olig2, and Uncx4.1). These may represent cellular functions
      that are likely not deregulated by mutation in p53.

PMID- 12466137
TI  - Constitutive nuclear factor-kappaB activity is crucial for human retinoblastoma
      cell viability.
AB  - Retinoblastoma (Rb) is the most common intraocular malignancy of childhood.
      Although systemic and intrathecal chemotherapy with local and cranial
      radiotherapy have improved overall survival, the prognosis for patients with
      central nervous system involvement is still poor. We investigated the role of the
      transcription factor nuclear factor (NF)-kappaB, which promotes cell survival in
      several other models, in the pathophysiology of Rb. The human Rb cell lines Y79
      and WERI-Rb1 were treated with the cell permeable peptide SN50, that specifically
      inhibits the transcriptional activity of NF-kappaB by blocking its translocation
      into the nucleus. We found that NF-kappaB inhibition up-regulated Bax; down
      regulated the anti-apoptotic proteins Bcl-2, A1, and cIAP-2; and induced loss of
      the mitochondrial transmembrane potential and caspase-independent, calpain
      dependent apoptosis in Rb cells. Inhibition of the p38 kinase sensitized cells to
      SN50-induced cell death, whereas insulin-like growth factor-1 activated NF-kappaB
      and attenuated the proapoptotic effect of SN50. Finally, NF-kappaB inhibition
      sensitized Rb cells to doxorubicin. In conclusion, inhibition of NF-kappaB
      activity in Rb cells leads to loss of mitochondrial transmembrane potential and
      caspase-independent, calpain-dependent apoptosis. Therapeutic strategies
      targeting NF-kappaB could be beneficial in the clinical management of Rb, either
      alone or in combination with conventional chemotherapy.

PMID- 12466139
TI  - Insulin-regulated increase of soluble vascular adhesion protein-1 in diabetes.
AB  - Vascular adhesion protein-1 (VAP-1) is one of the molecules on the endothelial
      cell membrane, which may guide inflammatory cells into atherosclerotic lesions.
      This dual function molecule may also contribute to the pathogenesis of
      atherosclerosis and other vasculopathies via its enzymatic activity that oxidizes
      primary amines to produce their corresponding aldehydes, hydrogen peroxide, and
      ammonium. Because VAP-1 also exists in a soluble form, we analyzed its potential
      usefulness as a biomarker to monitor and predict the extent of ongoing
      atherosclerotic processes. Soluble VAP-1 (sVAP-1) levels were determined from the
      sera of 136 Finnish men with established coronary heart disease and in 275
      controls using sandwich enzyme immunoassays and correlated to multiple risk
      factors for coronary events. Intriguingly, sVAP-1 showed a statistically
      significant correlation with diabetes in both cohorts. We then collected patients
      with type 1 diabetes and observed that sVAP-1 levels were highly elevated when
      the patients were metabolically compromised. On normalization of their blood
      glucose and ketone body levels by exogenous insulin, their sVAP-1 concentration
      rapidly decreased to control levels. Intravenous glucose tolerance and
      hyperinsulinemic clamp tests further showed that elevation of blood glucose per
      se did not increase sVAP-1 levels, but rather, sVAP-1 was inversely correlated
      with circulating insulin concentrations. In conclusion insulin appears to
      regulate shedding or clearance of VAP-1, and an increase in sVAP-1 because of
      absolute or relative insulin deficiency may be directly involved in the
      pathogenesis of diabetic angiopathy.

PMID- 12466140
TI  - Improved contractile function of the mdx dystrophic mouse diaphragm muscle after
      insulin-like growth factor-I administration.
AB  - Limited knowledge exists regarding the efficacy of insulin-like growth factor I
      (IGF-I) administration as a therapeutic intervention for muscular dystrophies,
      although findings from other muscle pathology models suggest clinical potential.
      The diaphragm muscles of mdx mice (a model for Duchenne muscular dystrophy) were
      examined after 8 weeks of IGF-I administration (1 mg/kg s.c.) to test the
      hypothesis that IGF-I would improve the functional properties of dystrophic
      skeletal muscles. Force per cross-sectional area was approximately 49% greater in
      the muscles of treated mdx mice (149.6 +/- 9.6 kN/m(2)) compared with untreated
      mice (100.1 +/- 4.6 kN/m(2), P < 0.05), and maintenance of force over repeated
      maximal contraction was enhanced approximately 30% in muscles of treated mice (P
      < 0.05). Diaphragm muscles from treated mice comprised fibers with approximately
      36% elevated activity of the oxidative enzyme succinate dehydrogenase, and
      approximately 23% reduction in the proportion of fast IId/x muscle fibers with
      concomitant increase in the proportion of type IIa fibers compared with untreated
      mice (P < 0.05). The data demonstrate that IGF-I administration can enhance the
      fatigue resistance of respiratory muscles in an animal model of dystrophin
      deficiency, in conjunction with enhancing energenic enzyme activity. As
      respiratory function is a mortality predictor in Duchenne muscular dystrophy
      patients, further evaluation of IGF-I intervention is recommended.

PMID- 12466141
TI  - Induction of colitis in mice deficient of Peyer's patches and mesenteric lymph
      nodes is associated with increased disease severity and formation of colonic
      lymphoid patches.
AB  - Inflammatory bowel disease is associated with immune activation in Peyer's
      patches and mucosal lymph nodes. The role of these organs in dextran sodium
      sulfate (DSS)-induced colitis was investigated. We used mice lacking Peyer's
      patches and/or lymph nodes because of lymphotoxin-alpha gene deficiency or
      treatment in utero with lymphotoxin-beta-receptor IgG and tumor necrosis factor
      receptor-I (55)-IgG fusion proteins. Mice lacking Peyer's patches and lymph nodes
      because of lymphotoxin-alpha deficiency or in utero fusion protein treatment
      developed more severe colitis than control mice as indicated by more severe
      intestinal shrinking, longer colonic ulcers, and higher histological disease
      scores. Oral DSS triggered the formation of colonic submucosal lymphoid patches
      in these mice and caused an increase in the number of submucosal lymphoid patches
      in mice treated in utero with the fusion proteins. Mice lacking Peyer's patches
      only showed more submucosal lymphoid patches whereas intestinal length and
      histological disease score were similar to control mice. In conclusion, more
      severe DSS-induced colitis correlates with the loss of the mesenteric lymph
      nodes. However, neither the absence of Peyer's patches nor the presence of
      colonic lymphoid patches were correlated with increased disease severity.

PMID- 12466142
TI  - Shock-induced neutrophil mediated priming for acute lung injury in mice:
      divergent effects of TLR-4 and TLR-4/FasL deficiency.
AB  - Acute lung injury (ALI) leading to respiratory distress is a common sequela of
      shock/trauma, however, modeling this process in mice with a single shock or
      septic event is inconsistent. One explanation is that hemorrhage is often just a
      "priming insult," thus, secondary stimuli may be required to "trigger" ALI. To
      test this we carried out studies in which we assessed the capacity of hemorrhage
      alone or hemorrhage followed by septic challenge (CLP) to induce ALI. Lung edema,
      bronchoalveolar lavage interleukin (IL)-6, alveolar congestion, as well as lung
      IL-6, macrophage inflammatory protein (MIP)-2, and myeloperoxidase (MPO) activity
      were all increased in mice subjected to CLP at 24 but not 72 hours following
      hemorrhage. This was associated with a marked increase in the susceptibility of
      these mice to septic mortality. Peripheral blood neutrophils derived from 24
      hours post-hemorrhage, but not Sham animals, exhibited an ex vivo decrease in
      apoptotic frequency and an increase in respiratory burst capacity, consistent
      with in vivo "priming." Subsequently, we observed that adoptive transfer of
      neutrophils from hemorrhaged but not sham-hemorrhage animals to neutropenic
      recipients reproduce ALI when subsequently septically challenged, implying that
      this priming was mediated by neutrophils. We also found marked general increases
      in lung IL-6, MIP-2, and MPO in mice deficient for toll-like receptor (TLR-4) or
      the combined lack of TLR-4/FasL. However, the TLR-4 defect markedly attenuated
      neutrophil influx into the lung while not altering the change in local
      cytokine/chemokine expression. Alternatively, the combined loss of FasL and TLR-4
      did not inhibit the increase in MPO and exacerbated lung IL-6/MIP-2 levels even
      further.

PMID- 12466144
TI  - Cyclooxygenase blockade and exogenous glutamine enhance sodium absorption in
      infected bovine ileum.
AB  - We have previously shown that prostanoids inhibit electroneutral sodium
      absorption in Cryptosporidium parvum-infected porcine ileum, whereas glutamine
      stimulates electroneutral sodium absorption. We postulated that glutamine would
      stimulate sodium absorption via a cyclooxygenase (COX)-dependent pathway. We
      tested this hypothesis in C. parvum-infected calves, which are the natural hosts
      of cryptosporidiosis. Tissues from healthy and infected calves were studied in
      Ussing chambers and analyzed via immunohistochemistry and Western blots.
      Treatment of infected tissue with selective COX inhibitors revealed that COX-1
      and -2 must be blocked to restore electroneutral sodium absorption, although the
      transporter involved did not appear to be the expected Na(+)/H(+) exchanger 3
      isoform. Glutamine addition also stimulated sodium absorption in calf tissue, but
      although this transport was electroneutral in healthy tissue, sodium absorption
      was electrogenic in infected tissue and was additive to sodium transport
      uncovered by COX inhibition. Blockade of both COX isoforms is necessary to
      release the prostaglandin-mediated inhibition of electroneutral sodium uptake in
      C. parvum-infected calf ileal tissue, whereas glutamine increases sodium uptake
      by an electrogenic mechanism in this same tissue.

PMID- 12466145
TI  - Impairment of TGF-beta signaling in T cells increases susceptibility to
      experimental autoimmune hepatitis in mice.
AB  - In autoimmune hepatitis, strong TGF-beta1 expression is found in the inflamed
      liver. TGF-beta overexpression may be part of a regulatory immune response
      attempting to suppress autoreactive T cells. To test this hypothesis, we
      determined whether impairment of TGF-beta signaling in T cells leads to increased
      susceptibility to experimental autoimmune hepatitis (EAH). Transgenic mice of
      strain FVB/N were generated expressing a dominant-negative TGF-beta type II
      receptor in T cells under the control of the human CD2 promoter/locus control
      region. On induction of EAH, transgenic mice showed markedly increased portal and
      periportal leukocytic infiltrations with hepatocellular necroses compared with
      wild-type mice (median histological score = 1.8 +/- 0.26 vs. 0.75 +/- 0.09 in
      wild-type mice; P < 0.01). Increased IFN-gamma production (118 vs. 45 ng/ml) and
      less IL-4 production (341 vs. 1,256 pg/ml) by mononuclear cells isolated from
      transgenic livers was seen. Impairment of TGF-beta signaling in T cells therefore
      leads to increased susceptibility to EAH in mice. This suggests an important role
      for TGF-beta in immune homeostasis in the liver and may teleologically explain
      TGF-beta upregulation in response to T cell-mediated liver injury.

PMID- 12466143
TI  - Generation of a syngeneic mouse model to study the effects of vascular
      endothelial growth factor in ovarian carcinoma.
AB  - Vascular endothelial growth factor (VEGF) performs multifaceted functions in the
      tumor microenvironment promoting angiogenesis, suppressing anti-tumor immune
      response, and possibly exerting autocrine functions on tumor cells. However,
      appropriate syngeneic animal models for in vivo studies are lacking. Using
      retroviral transfection and fluorescence-activated cell sorting, we generated a
      C57BL6 murine ovarian carcinoma cell line that stably overexpresses the murine
      VEGF164 isoform and the enhanced green fluorescent protein. VEGF164
      overexpression dramatically accelerated tumor growth and ascites formation,
      significantly enhanced tumor angiogenesis, and substantially promoted the
      survival of tumor cells in vivo. In vitro, VEGF164 overexpression significantly
      enhanced cell survival after growth factor withdrawal and conferred resistance to
      apoptosis induced by cis-platin through an autocrine mechanism. VEGF/green
      fluorescent protein-expressing tumors were not recognized by the adaptive immune
      system. After vaccination, a specific anti-tumor T-cell response was detected,
      but tumor growth was not inhibited. This engineered murine carcinoma model should
      prove useful in the investigation of the role of VEGF in modulating the tumor
      microenvironment and affecting the complex interactions among angiogenesis
      mechanisms, anti-tumor immune mechanisms, and tumor cell behavior at the natural
      state or during therapy in ovarian carcinoma.

PMID- 12466146
TI  - Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing
      substance action.
AB  - We tested the hypothesis that hepatic nitric oxide (NO) and glutathione (GSH) are
      involved in the synthesis of a putative hormone referred to as hepatic insulin
      sensitizing substance HISS. Insulin action was assessed in Wistar rats using the
      rapid insulin sensitivity test (RIST). Blockade of hepatic NO synthesis with N(G)
      nitro-l-arginine methyl ester (l-NAME, 1.0 mg/kg intraportal) decreased insulin
      sensitivity by 45.1 +/- 2.1% compared with control (from 287.3 +/- 18.1 to 155.3
      +/- 10.1 mg glucose/kg, P < 0.05). Insulin sensitivity was restored to 321.7 +/-
      44.7 mg glucose/kg after administration of an NO donor, intraportal SIN-1 (5
      mg/kg), which promotes GSH nitrosation, but not after intraportal sodium
      nitroprusside (20 nmol x kg(-1) x min(-1)), which does not nitrosate GSH. We
      depleted hepatic GSH using the GSH synthesis inhibitor l-buthionine-[S,R]
      sulfoximine (BSO, 2 mmol/kg body wt ip for 20 days), which reduced insulin
      sensitivity by 39.1%. Insulin sensitivity after l-NAME was not significantly
      different between BSO- and sham-treated animals. SIN-1 did not reverse the
      insulin resistance induced by l-NAME in the BSO-treated group. These results
      support our hypothesis that NO and GSH are essential for insulin action.

PMID- 12466147
TI  - Effects of NF-kappa B inhibition on mesenteric ischemia-reperfusion injury.
AB  - Mesenteric ischemia-reperfusion injury is a serious complication of shock.
      Because activation of nuclear factor-kappaB (NF-kappaB) has been implicated in
      this process, we treated rats with vehicle or the IkappaB-alpha inhibitor BAY 11
      7085 (25 mg/kg ip) 1 h before mesenteric ischemia-reperfusion (45 min of ischemia
      followed by reperfusion at 30 min or 6 h) and examined the ileal injury response.
      Vehicle-treated rats subjected to ischemia-reperfusion exhibited severe mucosal
      injury, increased myeloperoxidase (MPO) activity, increased expression of
      interleukin-6 and intercellular adhesion molecule 1 protein, and a biphasic peak
      of NF-kappaB DNA-binding activity during the 30-min and 6-h reperfusion courses.
      In contrast, BAY 11-7085-pretreated rats subjected to ischemia-reperfusion
      exhibited less histological injury and less interleukin-6 and intercellular
      adhesion molecule 1 protein expression at 30 min of reperfusion but more
      histological injury at 6 h of reperfusion than vehicle-treated rats subjected to
      ischemia-reperfusion. Studies with phosphorylation site-specific antibodies
      demonstrated that IkappaB-alpha phosphorylation at Ser(32),Ser(36) was induced at
      30 min of reperfusion, whereas tyrosine phosphorylation of IkappaB-alpha was
      induced at 6 h of reperfusion. BAY 11-7085 inhibited the former, but not the
      latter, phosphorylation pathway, whereas alpha-melanocyte-stimulating hormone,
      which is effective in limiting late ischemia-reperfusion injury to the intestine,
      inhibited tyrosine phosphorylation of IkappaB-alpha. Thus NF-kappaB appears to
      play an important role in the generation and resolution of intestinal ischemia
      reperfusion injury through different activation pathways.

PMID- 12466148
TI  - Intestinal alkaline phosphatase release is not associated with chylomicron
      formation.
AB  - Intestinal alkaline phosphatase (IAP) is one of the major sources of alkaline
      phosphatase in circulation. It is secreted into the intestinal lumen, serum, and
      lymph. After the ingestion of lipid, lymphatic alkaline phosphatase secretion
      increases significantly. We have found that the nonabsorbable fat olestra is
      unable to stimulate lymphatic alkaline phosphatase secretion. We also found that
      the hydrophobic surfactant Pluronic L-81, which blocks chylomicron formation,
      fails to inhibit this increase in lymphatic alkaline phosphatase secretion. These
      results suggest that it is the lipid uptake into the mucosa and/or
      reesterification to form triacylglycerols, but not the formation of chylomicrons,
      that is necessary for the stimulation of the secretion of alkaline phosphatase
      into the lymph.

PMID- 12466149
TI  - Growth factor stimulation of matrix metalloproteinase expression and myoblast
      migration and invasion in vitro.
AB  - We investigated the role of growth factors and fibronectin on matrix
      metalloproteinase (MMP) expression and on migration and invasion of mouse
      skeletal myoblasts in vitro. None of the growth factors tested significantly
      affected MMP-1 or MMP-2 activity as revealed by gelatin zymography, but both
      basic FGF (bFGF) and tumor necrosis factor (TNF)-alpha significantly increased
      MMP-9 activity (10- and 30-fold, respectively). The increase in secreted MMP-9
      activity with TNF-alpha stimulation was due at least in part to an increase in
      MMP-9 gene transcription, because an MMP-9 promoter construct was approximately
      fivefold more active in TNF-alpha-treated myoblasts than in control myoblasts, as
      well as an increase in MMP-9 proteolytic activation. However, whereas
      fibronectin, bFGF, hepatocyte growth factor, and TGF-beta1 significantly
      augmented migration of mouse myoblasts, TNF-alpha did not, nor did PDGF-BB or IGF
      I. Fibronectin and bFGF also significantly augmented invasion of myoblasts across
      a Matrigel barrier, and plasmin cotreatment potentiated whereas N-acetyl cysteine
      suppressed the effects of bFGF and fibronectin on myoblast migration and
      invasion. Finally, transient transfection with an MMP-9 overexpression construct
      had only minimal effects on myoblast migration/invasion, whereas overexpression
      of either MMP-2 or MMP-1 significantly augmented myoblast migration and invasion.
      These observations support the hypothesis that MMP activity is a necessary
      component of growth factor-mediated myoblast migration but suggest that other
      consequences of growth factor signaling are also necessary for migration to
      occur.

PMID- 12466150
TI  - Tumor necrosis factor regulates intestinal epithelial cell migration by receptor
      dependent mechanisms.
AB  - Altered mucosal integrity and increased cytokine production, including tumor
      necrosis factor (TNF), are the hallmarks of inflammatory bowel disease (IBD). In
      this study, we addressed the role of TNF receptors (TNFR) on intestinal
      epithelial cell migration in an in vitro wound closure model. With mouse TNFR1 or
      TNFR2 knockout intestinal epithelial cells, gene transfection, and
      pharmacological inhibitors, we show a concentration-dependent receptor-mediated
      regulation of intestinal cell migration by TNF. A physiological TNF level (1
      ng/ml) enhances migration through TNFR2, whereas a pathological level (100 ng/ml)
      inhibits wound closure through TNFR1. Increased rate of wound closure by TNFR2 or
      inhibition by TNFR1 cannot be explained by either increased proliferation or
      apoptosis, respectively. Furthermore, inhibiting Src tyrosine kinase decreases
      TNF-induced focal adhesion kinase (FAK) tyrosine phosphorylation and cellular
      migration. We therefore conclude that TNFR2 activates a novel Src-regulated
      pathway involving FAK tyrosine phosphorylation that enhances migration of
      intestinal epithelial cells.

PMID- 12466151
TI  - Polyamines regulate Rho-kinase and myosin phosphorylation during intestinal
      epithelial restitution.
AB  - Polyamines are required for the early phase of mucosal restitution that occurs as
      a consequence of epithelial cell migration. Our previous studies have shown that
      polyamines increase RhoA activity by elevating cytosolic free Ca(2+)
      concentration ([Ca(2+)](cyt)) through controlling voltage-gated K(+) channel
      expression and membrane potential (E(m)) during intestinal epithelial
      restitution. The current study went further to determine whether increased RhoA
      following elevated [Ca(2+)](cyt) activates Rho-kinase (ROK/ROCK) resulting in
      myosin light chain (MLC) phosphorylation. Studies were conducted in stable Cdx2
      transfected intestinal epithelial cells (IEC-Cdx2L1), which were associated with
      a highly differentiated phenotype. Reduced [Ca(2+)](cyt), by either polyamine
      depletion or exposure to the Ca(2+)-free medium, decreased RhoA protein
      expression, which was paralleled by significant decreases in GTP-bound RhoA, ROCK
      1, and ROKalpha proteins, Rho-kinase activity, and MLC phosphorylation. The
      reduction of [Ca(2+)](cyt) also inhibited cell migration after wounding.
      Elevation of [Ca(2+)](cyt) induced by the Ca(2+) ionophore ionomycin increased
      GTP-bound RhoA, ROCK-1, and ROKalpha proteins, Rho-kinase activity, and MLC
      phosphorylation. Inhibition of RhoA function by a dominant negative mutant RhoA
      decreased the Rho-kinase activity and resulted in cytoskeletal reorganization.
      Inhibition of ROK/ROCK activity by the specific inhibitor Y-27632 not only
      decreased MLC phosphorylation but also suppressed cell migration. These results
      indicate that increase in GTP-bound RhoA by polyamines via [Ca(2+)](cyt) can
      interact with and activate Rho-kinase during intestinal epithelial restitution.
      Activation of Rho-kinase results in increased MLC phosphorylation, leading to the
      stimulation of myosin stress fiber formation and cell migration.

PMID- 12466152
TI  - Serine/threonine phosphorylation regulates HNF-4alpha-dependent redox-mediated
      iNOS expression in hepatocytes.
AB  - Nitric oxide (NO), endogenously synthesized by inducible NO synthase (iNOS),
      serves antioxidant and antiapoptotic functions in settings characterized by
      oxidative stress and proinflammatory cytokines such as sepsis and shock. However,
      the redox-sensitive mechanisms regulating hepatocyte expression of iNOS are
      largely unknown. In interleukin-1beta (IL-1beta)-stimulated hepatocytes exposed
      to superoxide, we demonstrate that hepatocyte nuclear factor-4alpha (HNF-4alpha)
      acts as an activator of redox-associated hepatocyte iNOS expression at the level
      of protein, mRNA, and promoter activation. In the absence of HNF-4alpha, this
      redox-mediated enhancement is ablated. HNF-4alpha functional activity is
      associated with a unique serine/threonine kinase-mediated phosphorylation
      pattern. This suggests that a redox-sensitive kinase pathway targets HNF-4alpha
      to augment hepatocyte iNOS expression. Previous studies have not addressed a
      redox-dependent kinase signaling pathway that targets HNF-4alpha and enhances
      hepatocyte iNOS gene transcription. A unique pattern of phosphorylation
      determines HNF-4alpha activity as a trans-activator of IL-1beta-mediated
      hepatocyte iNOS expression in the presence of oxidative stress.

PMID- 12466154
TI  - Effect of a growth hormone receptor antagonist on proliferative diabetic
      retinopathy.

PMID- 12466155
TI  - Refractive status and vision profile survey in a contact lens trial.

PMID- 12466158
TI  - Protecting the integrity of the Board's examinations.

PMID- 12466159
TI  - The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV.
      Local treatment failure and enucleation in the first 5 years after brachytherapy.
      COMS report no. 19.
AB  - OBJECTIVE: To describe the frequency and predictors of local treatment failure
      and enucleation after iodine 125 (I(125)) brachytherapy in patients with
      choroidal melanoma treated and followed up in a large randomized clinical trial.
      DESIGN: Prospective, noncomparative, interventional case series within a
      randomized, multicenter clinical trial. PARTICIPANTS: Patients enrolled in the
      Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus
      brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm
      in apical height and no more than 16.0 mm in longest basal dimension. METHODS:
      I(125) brachytherapy was administered via episcleral plaque according to a
      standard protocol. Follow-up ophthalmic evaluations, including ophthalmic
      ultrasound and fundus photography, were performed according to a standard
      protocol at baseline, every 6 months thereafter for 5 years, and subsequently at
      annual intervals. Survival analysis methods were used to estimate the cumulative
      risk of postirradiation treatment failure and enucleation. Factors associated
      with treatment failure and enucleation of plaqued eyes were evaluated using Cox
      proportional hazards analysis. MAIN OUTCOME MEASURES: Reports of enucleation and
      of local treatment failure, defined as tumor growth, recurrence, or extrascleral
      extension, derived from clinical reports based on echographic and photographic
      documentation. RESULTS: As of September 30, 2000, 638 of the 650 patients
      randomized to brachytherapy and so treated had been followed up for 1 year or
      longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were
      enucleated during the first 5 years after brachytherapy, and treatment failure
      was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients
      undergoing enucleation by 5 years was 12.5% (95% confidence interval [CI], 10.0%
      15.6%); the risk of treatment failure was 10.3% (95% CI, 8.0%-13.2%). Treatment
      failure was the most common reason for enucleation within 3 years of treatment;
      beyond 3 years, ocular pain was most common. Risk factors for enucleation were
      greater tumor thickness, closer proximity of the posterior tumor border to the
      foveal avascular zone, and poorer baseline visual acuity in the affected eye.
      Risk factors for treatment failure were older age, greater tumor thickness, and
      proximity of the tumor to the foveal avascular zone. Local treatment failure was
      associated weakly with reduced survival after controlling for baseline tumor and
      personal characteristics (adjusted risk ratio, 1.5; P = 0.08). CONCLUSIONS: Local
      treatment failure and enucleation were relatively infrequent events after I(125)
      brachytherapy within the COMS. Treatment failure typically occurred early and was
      associated weakly with poorer survival. The COMS randomized trial documented the
      absence of a clinically or statistically significant difference in survival for
      patients randomly assigned to enucleation versus brachytherapy. This analysis
      documents the efficacy of brachytherapy to achieve sustained local tumor control
      and to conserve the globe.

PMID- 12466160
TI  - Complex microcirculation patterns detected by confocal indocyanine green
      angiography predict time to growth of small choroidal melanocytic tumors: MuSIC
      Report II.
AB  - PURPOSE: Multiple independent laboratories have confirmed the histologic
      observation that some tumor microcirculation patterns (MCPs) in uveal melanomas
      are associated strongly with death resulting from metastatic disease. Because
      these patterns are imageable with confocal indocyanine green angiography (ICG),
      we designed a prospective study to evaluate whether these angiographically
      detectable MCPs predict time to tumor growth. DESIGN: Observational case series,
      prospective, non-randomized. PARTICIPANTS: Ninety-eight patients with unilateral,
      small, choroidal melanocytic tumors. METHODS: The following information and tumor
      characteristics were recorded for each patient: demographic parameters, best
      corrected visual acuity, intraocular pressure, related visual symptoms, location
      and dimension of tumor, pigmentation, orange pigment, drusen, tumor-associated
      hemorrhage, subretinal fluid, and confocal ICG angiographically determined
      microcirculation patterns-silent (avascularity), normal (preexisting normal
      choroidal vessels within the tumor), straight vessels, parallel without and with
      cross-linking, arcs without and with branching, loops, and networks. MAIN OUTCOME
      MEASURES: Time to growth of the tumor, with growth defined as an increase in the
      maximal apical tumor height of 0.5 mm measured by standardized A-scan
      ultrasonography, photographic documentation of an increase of the largest basal
      diameter of at least 1.5 mm, advancement of one tumor border of at least 0.75 mm,
      or a combination thereof. RESULTS: Twenty-eight of the 98 tumors in this study
      (29%) met the predetermined criteria for tumor growth. The median time to growth
      was 127 days (range, 51-625 days). The following tumor characteristics were
      significantly associated with time to tumor growth: flashes (P = 0.0224), orange
      pigment (P = 0.012), subretinal fluid (P < 0.001), maximum basal tumor diameter
      at initial examination (P = 0.015), maximum apical tumor height (P < 0.001),
      parallel with cross-linking MCP (P < 0.001), arcs with branching MCP (P = 0.006),
      loops (P < 0.001), and networks (P < 0.001). Of these, the angiographic
      documentation of any of the complex MCPs (parallel with cross-linking, arcs with
      branching, loops, networks, or a combination thereof) showed the strongest
      association with the time to tumor growth in a Cox proportional hazard model.
      CONCLUSIONS: The characteristics of our patient cohort are comparable by clinical
      and echographic parameters with cohorts for predicting tumor growth, described
      previously in the literature. In addition, we detected a novel clinical predictor
      of tumor growth: the confocal ICG angiographic detection of complex MCPs.

PMID- 12466161
TI  - Effect of technique on intraocular pressure after combined cataract and glaucoma
      surgery: An evidence-based review.
AB  - TOPIC: To analyze the literature pertaining to the techniques used in combined
      cataract and glaucoma surgery, including the technique of cataract extraction,
      the timing of the surgery (staged procedure versus combined procedure), the
      anatomic location of the operation, and the use of antifibrosis agents. CLINICAL
      RELEVANCE: Cataract and glaucoma are both common conditions and are often present
      in the same patient. There is no agreement concerning the optimal surgical
      management of these disorders when they coexist. METHODS/LITERATURE REVIEWED:
      Electronic searches of English language articles published since 1964 were
      conducted in Pub MED and CENTRAL, the Cochrane Collaboration's database. These
      were augmented by a hand search of six ophthalmology journals and the reference
      lists of a sample of studies included in the literature review. Evidence grades
      (A, strong; B, moderate; C, weak; I, insufficient) were assigned to the evidence
      that involved a direct comparison of alternative techniques. RESULTS: The
      preponderance of evidence from the literature suggests a small (2-4 mmHg) benefit
      from the use of mitomycin-C (MMC), but not 5-fluorouracil (5-FU), in combined
      cataract and glaucoma surgery (evidence grade B). Two-site surgery provides
      slightly lower (1-3 mmHg) intraocular pressure (IOP) than one-site surgery
      (evidence grade C), and IOP is lowered more (1-3 mmHg) by phacoemulsification
      than by nuclear expression in combined procedures (evidence grade C). There is
      insufficient evidence to conclude either that staged or combined procedures give
      better results or that alternative glaucoma procedures are superior to
      trabeculectomy in combined procedures. CONCLUSIONS: In the literature on surgical
      techniques and adjuvants used in the management of coexisting cataract and
      glaucoma, the strongest evidence of efficacy exists for using MMC, separating the
      incisions for cataract and glaucoma surgery, and removing the nucleus by
      phacoemulsification.

PMID- 12466163
TI  - Chronic angle-closure with glaucomatous damage: long-term clinical course in a
      North American population and comparison with an Asian population.
AB  - PURPOSE: To study the long-term clinical course of North American chronic angle
      closure glaucoma (CACG) patients with optic disc damage and visual field loss in
      the presence of an angle closed at least partially by peripheral anterior
      synechiae and to compare it with a similar group of Singaporean patients. DESIGN:
      A retrospective, interventional case-control study series. PARTICIPANTS: Fifty
      one patients (80 eyes) diagnosed with CACG with glaucomatous optic nerve head and
      visual field damage at a New York hospital from January 1990 through December
      1994. All study eyes underwent laser peripheral iridotomy (LPI). METHODS: The
      presenting features, management, and subsequent long-term intraocular pressure
      (IOP) outcome were analyzed and compared with 65 Asian patients (83 eyes) from a
      Singapore hospital who were similarly diagnosed during the same period. MAIN
      OUTCOME MEASURES: The long-term outcome after LPI was assessed in terms of IOP
      and the requirement for additional therapy. RESULTS: The mean presenting IOP was
      higher in the Singapore eyes (40 +/- 15 mmHg) compared with the New York eyes (31
      +/- 12.5 mmHg). All 80 New York eyes (100%) and 78 of 83 Singapore eyes (94%)
      required further treatment to control IOP during follow-up. Of the eyes with a
      subsequent rise in IOP, 33 of 80 eyes (41.3%) compared with 34 of 83 eyes (41.0%)
      of the Singapore patients were controlled with additional topical medication. Of
      the New York eyes, 25 of 80 (31.3%) eventually underwent filtering surgery,
      compared with 44 of 83 (53.0%) in the Singapore study. The other 22 eyes (27.5%)
      in the New York group went on to additional laser procedures, peripheral
      iridoplasty, laser trabeculoplasty, or a combination thereof, after which IOPs
      were controlled and no surgery was required. There was no similar comparison for
      the Singapore group, because these eyes went directly on to surgery. CONCLUSIONS:
      Despite the presence of a patent LPI, most eyes with CACG presenting with
      elevated IOP and having both optic disc and visual field damage in both
      populations required further treatment to control IOP. Results in the American
      population are similar to that reported in Asian patients.

PMID- 12466164
TI  - Rate and pattern of visual field decline in primary open-angle glaucoma.
AB  - PURPOSE: To study the rate and pattern of visual field decline in primary open
      angle glaucoma. DESIGN: Retrospective observational case series. PARTICIPANTS:
      Forty eyes of 40 patients with primary open-angle glaucoma that were followed
      longitudinally with serial Goldmann visual fields for a minimum period of 8 years
      in an academic institution. Eyes with any other ocular disease except for mild
      cataract were excluded. METHODS: Visual fields obtained with worse than 20/50
      Snellen visual acuity from cataract were excluded from analysis. In the remainder
      (671 Goldmann visual fields), the I4e isopter was quantified manually using a
      grid template previously described by Esterman. The visual field was divided into
      central and peripheral, superior and inferior, and nasal and temporal regions,
      all centered at the blind spot. The rate of visual field decline was estimated
      for each visual field region (including the four quadrants: superonasal [SN],
      superotemporal [ST], inferotemporal [IT], and inferonasal [IN]) using linear
      regression. Asymmetry of visual field progression was determined by comparing the
      rates of progression among the four quadrants. Pertinent clinical factors were
      evaluated for association with the asymmetry of visual field progression. MAIN
      OUTCOME MEASURES: Rates of visual field decline for the entire visual field and
      each region. Long-term clinical outcome measures, including visual acuity,
      cataract and cup-to-disc ratio progression, intraocular pressures, and medical
      and surgical interventions were also studied. RESULTS: The rate of visual field
      change was -1.3% per year for the entire visual field. The rates of visual field
      section change (in % per year) were -1.3 (central), -1.4 (peripheral), -1.5
      (superior), -1.2 (inferior), -1.4 (nasal), -1.2 (temporal), -1.8 (SN), -1.3 (IT),
      -1.2 (IN), and -1.1 (ST). About half the patients showed symmetric visual field
      decline, whereas others showed a more asymmetric pattern. Asymmetric visual field
      progression was associated with the presence of disc hemorrhage, overall rate of
      visual field progression, and surgical intervention for glaucoma. CONCLUSIONS: In
      this group of selected patients with primary open-angle glaucoma with a long-term
      follow-up, all sections of the visual field declined over time. Disc hemorrhage
      was associated with more asymmetric visual field progression, implicating focal
      damage to the optic disc.

PMID- 12466165
TI  - Changes in intraocular pressure and ocular perfusion pressure after latanoprost
      0.005% or brimonidine tartrate 0.2% in normal-tension glaucoma patients.
AB  - OBJECTIVE: To evaluate and compare the effects of latanoprost 0.005% once daily
      and brimonidine tartrate 0.2% twice daily in patients with normal-tension
      glaucoma (NTG). DESIGN: A randomized, open-label, crossover study. PARTICIPANTS:
      Twenty-eight NTG patients with progressive visual field defects/optic disc
      excavation, new disc hemorrhage, or field defects that threatened fixation.
      INTERVENTION: Patients were randomly allocated to one of two groups. Patients in
      group 1 were treated with latanoprost, lubricant, and brimonidine for 4 weeks
      each, whereas patients in group 2 were treated with brimonidine, lubricant, and
      latanoprost for 4 weeks each. MAIN OUTCOME MEASURES: Intraocular pressure (IOP),
      pulse rate, and blood pressure were measured at 8 am, 12 noon, and 4 pm after
      each 4-week treatment. Ocular perfusion pressure (OPP) was calculated. RESULTS:
      Latanoprost and brimonidine reduced the average IOP by 3.6 +/- 1.9 mmHg (P <
      0.001) and 2.5 +/- 1.3 mmHg (P < 0.001), respectively, with a significant
      difference between the two regimens (P = 0.009). Both drugs significantly reduced
      IOP at each time point. Latanoprost decreased IOP significantly more than did
      brimonidine at 8 am (11.7 +/- 2.2 mmHg vs. 13.7 +/- 2.1 mmHg, P = 0.004) and 4 pm
      (11.4 +/- 2.1 mmHg vs. 13.2 +/- 2.9 mmHg, P = 0.004), but IOP was equal between
      the two agents at 12 noon (11.5 +/- 2.6 mmHg vs. 11.5 +/- 2.3 mmHg, P = 0.967).
      IOP was maintained at 12 mmHg or lower in 18 (66.7%) of 27 patients after
      treatment with latanoprost and in 9 (33.3%) of 27 patients after treatment with
      brimonidine. Latanoprost monotherapy reduced IOP by 30% in 8 patients (29.6%),
      but brimonidine monotherapy did not reduce IOP by that much in any of the
      patients. OPP increased after latanoprost treatment (P < 0.001) but did not
      increase after brimonidine treatment (P = 0.355). There was no significant change
      in pulse rate or blood pressure. CONCLUSIONS: Both latanoprost and brimonidine
      reduce IOP in NTG patients. Brimonidine has a peak IOP-lowering effect equal to
      that of latanoprost but produces a higher mean diurnal IOP than does latanoprost
      because of its shorter effect. Latanoprost might favorably alter optic disc blood
      perfusion by increasing OPP.

PMID- 12466166
TI  - Phacoemulsification in eyes with functioning filtering blebs: a prospective
      study.
AB  - OBJECTIVE: To evaluate the effect of phacoemulsification on intraocular pressure
      (IOP) control in eyes with a previous functioning filtering bleb and no glaucoma
      medication. DESIGN: Prospective, nonrandomized comparative (self-controlled)
      trial. PARTICIPANTS: Forty-seven patients (49 eyes) who underwent
      phacoemulsification after successful trabeculectomy, with at least 12 months of
      follow-up. INTERVENTION: Clear corneal phacoemulsification and implantation of a
      foldable intraocular lens in eyes that underwent a previous successful
      trabeculectomy. The time between both procedures was always greater than 1 year.
      MAIN OUTCOME MEASURES: Preoperative and postoperative IOP, the number of glaucoma
      medications, bleb appearance, and visual acuity were recorded at each follow-up
      examination. Success was defined as no need for glaucoma medications, bleb
      needling, or further glaucoma surgery for IOP control after phacoemulsification.
      Preoperative and intraoperative factors were evaluated for an association with
      postoperative failure using Kaplan-Meier survival analysis. RESULTS: The mean (+/
      standard deviation) IOP before phacoemulsification was 12.24 (+/- 4.68) mmHg,
      and it increased 3.94, 3.76, 1.39, 2.04, and 1.57 mmHg on the first postoperative
      day, after 1, 6, and 12 months, and at the last visit, respectively. At each
      interval, the mean IOP was significantly higher than the preoperative value (P =
      0.000, 0.000, 0.049, 0.01, and 0.01, respectively). Nevertheless, the mean IOP
      after phacoemulsification was always lower than before trabeculectomy (P =
      0.000). At the last visit, glaucoma medication was required in 17 eyes (34.7%).
      The success rates after phacoemulsification were 83.6%, 68.2%, and 55.7% at 6
      months and 1 and 2 years, respectively (Kaplan-Meier survival analysis). The
      number of glaucoma medications used increased at all follow-up visits (P <
      0.005). Bleb size decreased after phacoemulsification (P = 0.000). An IOP before
      phacoemulsification of greater than 10 mmHg was associated with postoperative
      failure (P = 0.002). Similarly, bleb failure and the need for glaucoma medication
      were associated with higher IOPs before phacoemulsification. CONCLUSIONS:
      Phacoemulsification significantly increased IOP and the number of glaucoma
      medications in eyes with preexisting functioning filtering blebs. Eyes with
      higher IOPs before phacoemulsification had worsened postoperative IOP control and
      bleb failure.

PMID- 12466167
TI  - Outcome of Baerveldt glaucoma drainage implants for the treatment of uveitic
      glaucoma.
AB  - OBJECTIVE: To evaluate the efficacy and safety of Baerveldt glaucoma drainage
      devices in the management of uveitic glaucoma. DESIGN: Retrospective,
      noncomparative case series. PARTICIPANTS: Twenty-four eyes of 24 patients who
      underwent implantation of Baerveldt glaucoma drainage devices between 1996 and
      2000 for the treatment of uveitic glaucoma refractory to medical therapy.
      INTERVENTION: Implantation of Baerveldt glaucoma drainage device. MAIN OUTCOME
      MEASURES: Control of intraocular pressure (IOP), number of glaucoma medications
      needed for adequate IOP control, visual acuity, complications associated with the
      surgery, and the effect of subsequent surgery on the ability of the device to
      control IOP. Success was defined as IOP >/=5 and </=21 mmHg with or without
      antiglaucoma medications and without need for further glaucoma surgery, loss of
      light perception, or phthisis. RESULTS: Cumulative life-table success rates were
      95.8% at 3 months and 91.7% at 6 months, 12 months, and 24 months. The mean
      postoperative follow-up was 20.8 months. The IOP was reduced from a preoperative
      mean of 30.5 +/- 8.96 mmHg with 3.1 +/- 0.99 antiglaucoma medications to a
      postoperative mean at 6 months or 1 year of 13.0 +/- 4.6 mmHg (P < 0.001) with
      0.8 +/- 0.8 antiglaucoma medications (P < 0.001). At last follow-up 14 of 24 eyes
      (58.3%) required no antiglaucoma medications. Best-corrected visual acuity
      improved or remained within 2 lines of preoperative visual acuity in 19 (79.2%)
      eyes. The most common complications were choroidal effusions in four (16.7%),
      hypotony in three (12.5%) eyes, cystoid macular edema in three (12.5%) eyes, and
      failure of corneal grafts in two (8.3%). Seven of 22 eyes (31.8%) in which
      successful control of IOP with the Baerveldt implant was achieved underwent
      subsequent nonglaucoma-related incisional surgery. None of these eyes (0%) lost
      IOP control after the subsequent procedure. CONCLUSIONS: The Baerveldt glaucoma
      drainage device offers reasonable safety and effectiveness for the control of IOP
      in eyes with uveitis and refractory glaucoma.

PMID- 12466168
TI  - The minimum occlusion trial for the treatment of amblyopia.
AB  - OBJECTIVE: To determine whether the traditional regimen of three intervals of
      full-time occlusion (FTO) for amblyopia without any measurable improvement in
      visual acuity constitutes an adequate trial. DESIGN: Retrospective,
      noncomparative, interventional case series. PARTICIPANTS: Sixty-four children
      younger than 10 years of age with unilateral amblyopia. METHODS: The medical
      records of patients treated for amblyopia in a university outpatient clinic were
      reviewed. Patients who underwent one FTO interval without an improvement in
      visual acuity followed by at least one additional FTO interval were included in
      the study. MAIN OUTCOME MEASURES: Improvement in visual acuity. RESULTS: Sixty
      four patients underwent 81 occlusion trials consisting of one FTO interval
      without improvement followed by one or more FTO intervals. Visual acuity improved
      after the second FTO interval in 25 (31%) of the trials. Of the 44 occlusion
      trials consisting of two FTO intervals without improvement, visual acuity
      improved after the third FTO interval in 12 (27%) of the trials. Of the 11
      occlusion trials consisting of three FTO intervals without improvement followed
      by one or more additional FTO intervals, acuity did not improve with any of the
      trials. CONCLUSIONS: A minimum of three intervals of FTO is necessary to
      determine whether an amblyopia patient will be unresponsive to occlusion therapy.
      After three FTO intervals without improvement, additional FTO is unlikely to
      result in an improvement in visual acuity.

PMID- 12466169
TI  - A cost-utility analysis of therapy for amblyopia.
AB  - OBJECTIVE: Evaluation of the incremental cost-effectiveness of therapy for
      amblyopia. DESIGN: Cost-utility reference-case analysis. METHODS: A cost-utility
      analysis was performed from a third-party insurer perspective by using decision
      analysis, evidence-based data from the literature, and patient preference-based
      time trade-off utility values. DATABASE: Patient-derived time trade-off ocular
      utility values and the American Academy of Ophthalmology Preferred Practice
      Pattern guidelines for the treatment of amblyopia. INTERVENTION: Treatment of
      childhood amblyopia using medical and surgical therapies per the American Academy
      of Ophthalmology Preferred Practice Pattern. MAIN OUTCOME MEASURE: Dollars (year
      2001 nominal U.S. dollars) expended per quality-adjusted life-year ($/QALY)
      gained. RESULTS: Treatment for amblyopia resulted in a $/QALY gained of $2281
      with a discount rate of 3% for costs and outcomes. Sensitivity analysis, varying
      costs and utility values by 10%, resulted in a $/QALY gained range from $2053 to
      $2509. CONCLUSIONS: When compared with other interventions in health care,
      therapy for amblyopia seems to be highly cost-effective. This information is
      increasingly important for health care policy makers.

PMID- 12466170
TI  - Dietary antioxidant intake and incidence of early age-related maculopathy: the
      Blue Mountains Eye Study.
AB  - OBJECTIVE: To investigate associations between dietary intake, including modest
      supplement intake, of antioxidant vitamins and zinc at baseline and the 5-year
      incidence of early age-related maculopathy (ARM). DESIGN: Population-based cohort
      study. PARTICIPANTS: From 1992 through 1994, 3654 persons aged 49 years or more
      (82% of those eligible) living in two postcode areas west of Sydney, Australia,
      were examined for the Blue Mountains Eye Study baseline. Five years later, 2335
      persons (75% of known survivors) were reexamined. METHODS: A 145-item Food
      Frequency Questionnaire (FFQ) was used to assess nutrient intakes. Of the 2335
      people who attended a follow-up visit, 1989 (85%) had completed a FFQ at
      baseline. The nutrients examined in this study included: alpha-carotene, beta
      carotene, beta-cryptoxanthin, lutein and zeaxanthin, lycopene, retinol, vitamin
      A, vitamin C, and zinc. MAIN OUTCOME MEASURES: Early ARM was assessed by masked
      grading of stereo retinal photographs. Definitions for incidence closely followed
      those used in the Beaver Dam Eye Study. RESULTS: Early ARM developed in 192
      persons (8.7% 5-year incidence) who did not have either late or early ARM at
      baseline. Of these, 159 persons completed the FFQ at baseline. After adjusting
      for age, gender, family history of ARM, and smoking status at baseline, no
      associations, or any trends suggesting possible association, were found between
      baseline intake of the nutrients examined, apart from vitamin C, and the 5-year
      incidence of early ARM. Compared with the lowest quintile, increasing baseline
      intakes of vitamin C, from diet and supplements, was associated with an increased
      risk of incident early ARM (odds ratio [OR], 1.7; 95% confidence interval [CI],
      1.0-3.0; and OR, 2.3; 95% CI, 1.3-4.0 for the fourth and fifth quintiles,
      respectively). CONCLUSIONS: Our cohort study of an older population could not
      find evidence of protection associated with usual dietary antioxidant or zinc
      intakes (including use of supplements) on the 5-year incidence of early ARM.

PMID- 12466171
TI  - Retinal detachment in East Africa.
AB  - PURPOSE: To report the causes of retinal detachment in an African setting and the
      outcome after surgery. DESIGN: Noncomparative interventional case series.
      PARTICIPANTS: A total of 361 eyes in 345 patients. METHODS: Data were collected
      from patients' case notes. A minimum of 2 months' follow-up was available for 254
      eyes. Risk factors for poor anatomic or visual outcome were analyzed by logistic
      regression. MAIN OUTCOME MEASURES: Primary anatomic success, which was defined as
      an attached retina at least 2 months after the initial surgery, without any
      additional interventions; final anatomic success, defined as an attached retina
      at least 2 months after the latest intervention; and visual outcome, defined as
      the corrected visual acuity at least 2 months after the last operation. RESULTS:
      The macula was detached at presentation in 332 (91.9%) eyes. In 203 (56.2%) eyes,
      the retina had been detached for >1 month. Proliferative vitreoretinopathy (PVR)
      grade C1 or worse-was present in 63 (17.5%) eyes. Thirty eyes (8.3%) had giant
      retinal tears. Ninety-five patients (27.5%) were blind (<20/400 in the better
      eye) at presentation. The retina was successfully reattached with 1 operation in
      186 (73.2%) eyes. The most frequent cause of primary failure was missed breaks or
      new breaks. The final anatomic success rate in eyes observed for at least 8 weeks
      after the last operation was 88.2%. Giant retinal tear and PVR were significant
      independent predictors of anatomic failure. In eyes with successfully reattached
      retinas, 63.9% achieved 20/200 vision or better. Among successfully reattached
      macula-off detachments, risk factors for a poor visual outcome (<20/200) were
      macular hole, duration of retinal detachment >1 month, and poor preoperative
      acuity. Of 74 blind patients with 2 months' follow-up, only 23 (31.1%) remained
      blind at the latest follow-up. CONCLUSIONS: Retinal detachment is a treatable
      cause of blindness in Africa. Despite late presentation and complex pathology,
      surgical repair is frequently successful and often restores navigational vision.
      Greater emphasis should be given to the recognition and treatment of retinal
      detachment in regional training programs for ophthalmologists and primary eye
      care workers.

PMID- 12466172
TI  - Photodynamic therapy for symptomatic choroidal hemangioma: visual and anatomic
      results.
AB  - OBJECTIVE: To document the anatomic and functional outcome of photodynamic
      therapy (PDT) in symptomatic choroidal hemangioma DESIGN: Prospective,
      noncomparative, interventional case series. PARTICIPANTS: Fifteen patients with
      circumscribed choroidal hemangioma of the posterior pole presenting with
      progressive vision loss caused by exudation into the macular area. INTERVENTION:
      PDT using 6 mg/m(2) body surface area verteporfin and a light dose of 100 J/cm(2)
      at 692 nm was performed. One to four treatments with a single laser spot were
      applied in 6-week intervals. A standardized evaluation was provided before and at
      6-week intervals after each treatment, at 3, 6, and 12 months, and a mean follow
      up 19 months after the last application. MAIN OUTCOME MEASURES: Functional tests
      included best-refracted visual acuity (Early Treatment of Diabetic Retinopathy
      Study criteria) and scanning laser scotometry. Anatomic results were documented
      by ophthalmoscopy, fluorescein/indocyanine green angiography, and
      ultrasonography. RESULTS: A complete regression of the vascular mass was achieved
      in all eyes after the last course of one to four consecutive treatments. Tumors
      (mean height, 3.8 mm) responded with a reproducible decrease in size to each
      treatment, with the most intensive effect seen after the first application.
      Progressive occlusion of the angiomatous net without recanalization was
      documented angiographically. Two patients had stable vision with resolution of
      metamorphopsia; 13 patients demonstrated visual recovery. An overall visual
      acuity (VA) improvement of an average of 3 lines was documented, with a mean VA
      level of 20/125 before treatment and 20/80 after therapy. Visual fields showed
      withdrawal of central scotomas from the macula. No recurrence was seen during a
      follow-up for up to 50 months. CONCLUSIONS: PDT using verteporfin offers a safe
      and effective option to treat choroidal hemangiomas. Complete anatomic regression
      with persistent absence of leakage is associated with substantial improvements in
      vision.

PMID- 12466173
TI  - Preoperative and postoperative assessment by multifocal electroretinography in
      the management of optic disc pits with serous macular detachment.
AB  - PURPOSE: To evaluate the macular function by means of multifocal
      electroretinogram (MF ERG) in eyes with congenital optic disc pit and serous
      macular detachment. The evaluation was performed before and after the successful
      surgical intervention. DESIGN: Nonrandomized, comparative (self-controlled),
      interventional trial. PARTICIPANTS: Ten patients (10 eyes) with optic disc pit
      with serous macular detachment were treated with the macular buckling procedure
      and followed up from March 1999 through May 2001. METHODS: In all patients
      included in the study, MF ERG was recorded before and after treatment. For
      recording, the VERIS III system (Visual Evoked Response Imaging System; Tomey,
      Nagoya, Japan) was used. MAIN OUTCOME MEASURES: The retinal response densities
      were studied before and after treatment in areas 1 and 2 and were compared with
      visual acuity. RESULTS: The MF ERG before treatment showed decreased retinal
      response densities in all 10 cases. Twelve months after the surgical
      intervention, the electrical response densities in areas 1 (foveal area) and 2
      (parafoveal area) improved. Further improvement was noted in 3 of the 10 patients
      who completed a follow-up of 18 months after treatment. In 8 of the 10 patients,
      postoperative visual acuity also increased. In the remaining two patients, visual
      acuity did not change after treatment, despite improvement of the retinal
      response densities. CONCLUSIONS: In eyes with congenital optic disc pit with
      serous macular detachment, the decrease in retinal electrophysiologic response
      before treatment was not limited to the fovea, but also involved the perifoveal
      area. In all 10 eyes 12 months after treatment, the electrical activities in
      areas 1 and 2 improved. This improvement was not always followed by an increase
      in visual acuity. In 2 of the 10 patients, visual acuity remained unchanged. The
      values of retinal response densities before treatment cannot be used alone as a
      prognostic factor for the postoperative functional retinal results. It should
      also be stressed that the results of this study cannot be compared with the
      results of studies where spontaneous resolution of the macular detachment
      occurred.

PMID- 12466174
TI  - Vitrectomy for diabetic traction retinal detachment using the multiport
      illumination system.
AB  - OBJECTIVE: To examine the visual and anatomic results of bimanual vitrectomy
      surgery with the multiport illumination system (MIS) in eyes with advanced
      diabetic traction retinal detachment. DESIGN: Retrospective, noncomparative
      interventional case series. PARTICIPANTS: Sixty-seven consecutive eyes in 62
      patients having vitrectomy with the MIS. METHODS: During surgery, the vitreous,
      the posterior hyaloid membrane, and fibrovascular proliferative tissue were
      removed by using bimanual dissection made possible by the MIS. MAIN OUTCOME
      MEASURES: Retinal reattachment rate, visual function, and postoperative
      complications were compared with previously published series of vitrectomy for
      diabetic traction retinal detachment. RESULTS: With a minimum of 6 months of
      follow-up, complete retinal reattachment was achieved in 62 eyes (93%), and
      macular attachment was achieved in all 67 eyes. Vision was stabilized or improved
      in 51 eyes (72%), and 5/200 vision was achieved in 47 eyes (70%). No unique
      complications, such as incision-related retinal tears, occurred. CONCLUSION: MIS
      allows bimanual surgery during vitrectomy for diabetic traction retinal
      detachment, with good visual and anatomic results.

PMID- 12466175
TI  - Lasik enhancements: a comparison of lifting to recutting the flap.
AB  - PURPOSE: To compare the visual outcomes and incidence of complications of lifting
      with recutting the lamellar flap in laser in situ keratomileusis (LASIK)
      enhancement surgery. DESIGN: Retrospective case-control study. PARTICIPANTS: Two
      hundred twelve consecutive eyes undergoing a LASIK enhancement procedure at a
      single surgery location during a 5-year period. METHODS: Charts of participants
      were obtained and outcome measures obtained. MAIN OUTCOME MEASURES: Uncorrected
      visual acuity, best-corrected visual acuity, refractive error, complications.
      RESULTS: Relifting of flaps was performed in 164 of 212 eyes (77.4%), and
      recutting of flaps was performed in 48 of 212 eyes (22.6%). There were no
      significant differences in early visual outcomes between the two groups. At 1
      year patients had significantly better uncorrected vision if the flap was lifted
      rather than recut (20/24.7 vs. 20/31.3, P < 0.008). In addition, the flap lift
      group had a significantly more stable refraction at 1 year than did the recut
      group (change in spherical equivalent: +0.05 diopters (D) vs. -0.57 D). The
      incidence of complications did not significantly differ between the two groups.
      CONCLUSIONS: LASIK enhancement surgery can be performed safely and effectively by
      either lifting or recutting a flap. Lifting the flap may show better long-term
      stability of refractive error and uncorrected acuity.

PMID- 12466177
TI  - Scleral fixation of secondary foldable multifocal intraocular lens implants in
      children and young adults.
AB  - OBJECTIVE: To assess the feasibility of transscleral fixation of a foldable,
      multifocal intraocular lens (IOL) as an alternative form of optical correction to
      monofocal IOL implantation in aphakic children and young adults intolerant of
      contact lenses in the absence of sufficient capsular support. STUDY DESIGN:
      Prospective, nonrandomized, comparative trial. PARTICIPANTS: Twenty-six eyes of
      26 unilateral aphakic patients in the age group 6 to 29 years (mean, 13.2 years)
      at two university institutions with more than 6 months of follow-up.
      INTERVENTIONS: Anterior vitrectomy and secondary scleral-fixated foldable IOL
      implantation were performed in all cases. In 12 patients, a zonal-progressive
      optic multifocal IOL (Array SA40-N; Allergan, Irvine, CA) was implanted, whereas
      14 patients received a monofocal IOL (SI40NB; Allergan). The follow-up ranged
      from 6 to 20 months (mean, 13.4 months). RESULTS: Preoperative patient
      demographics, mean postoperative spherical equivalent, astigmatism, and
      uncorrected and best-corrected distance visual acuity (BCDVA) were similar in the
      two groups. After surgery, BCDVA within one Snellen line of the preoperative
      BCDVA was achieved by 83% of the multifocal group and by 85% of the monofocal
      group. Patients with a multifocal IOL achieved a significantly better uncorrected
      near visual acuity than patients with monofocal IOL (019 versus 0.34; P = 0.02).
      With distance correction only, mean near visual acuity was 0.25 versus 0.44 (P =
      0.01). Best-corrected near visual acuity was approximately 0.18 for both groups
      (P = 0.77), with +1.32 diopters (D) for the multifocal group and +2.54 D for the
      monofocal group (P = 0.001). Spectacle dependency differed significantly between
      the two groups, with 10 patients (71%) of the monofocal group commonly requiring
      an additional plus add for near tasks compared with two patients (16%) in the
      multifocal group (P = 0.001). The Lang test showed stereopsis to be superior in
      the multifocal group (P = 0.04). Complications encountered were: pressure
      increase in three eyes (11.5%), which was permanent in one case (3.8%); marked
      postoperative anterior chamber reaction in four eyes (15.4%); IOL decentration in
      five eyes (19.2%), one (3.8%) requiring surgical reintervention; and suture
      erosion through the conjunctiva in two eyes (7.4%). There was no statistically
      significant difference between the two groups. CONCLUSIONS: Secondary scleral
      fixated multifocal IOL implantation was as successful as monofocal IOL
      implantation in achieving BCDVA comparable with preoperative BCDVA. Moreover,
      stereopsis, uncorrected and distance-corrected near visual acuities were better
      in the multifocal patients than in the monofocal eyes. Multifocal IOL seems a
      viable alternative to monofocal scleral fixation in children and young patients
      with contact lens-intolerant aphakia.

PMID- 12466178
TI  - Descemet's membrane detachment after cataract surgery: management and outcome.
AB  - OBJECTIVE: To analyze the possible causes of Descemet's membrane detachment (DMD)
      and the treatment and outcome of patients after cataract surgery. DESIGN:
      Retrospective noncomparative interventional case series. PARTICIPANTS: Fifteen
      eyes of 12 patients. METHODS: We reviewed clinical data on 15 eyes of 12 patients
      with nonscrolled DMD after cataract surgery who presented to the Cornea Service
      at Wills Eye Hospital from 1986 to 2001. Institutional review board/ethics
      committee approval was obtained. MAIN OUTCOME MEASURES: Visual acuity and
      reattachment of Descemet's membrane. RESULTS: Cataract procedures involved nine
      clear-corneal eyes, four limbal incisions, one trabeculectomy/combined
      phacoemulsification, and one extracapsular cataract extraction. From 1986 to
      1990, we had 1 patient; from 1991 to 1995, no patients; and from 1996 to 2001, 11
      patients (including all clear-corneal eyes). Of the 15 eyes, 8 resolved with
      medical treatment alone, with a mean time to resolution of 9.8 weeks. One patient
      was lost to follow-up while improving on medical treatment, and another required
      a penetrating keratoplasty (PK) after medical treatment failed. Five eyes
      received anterior-chamber SF(6) gas injection. Of these eyes, three DMDs
      resolved, one underwent repeated injection (not improving after 10 weeks), and
      another required a PK. CONCLUSIONS: Referrals for DMD seem to be increasing. This
      may be explained by the increase in clear-corneal cataract procedures. Medical
      treatment seems to be adequate in many cases and may be appropriate initial
      therapy. When needed, SF(6) gas injection may also be successful, but not in all
      cases.

PMID- 12466179
TI  - Epithelial downgrowth after clear cornea phacoemulsification: report of two cases
      and review of the literature.
AB  - OBJECTIVE: To report two cases of diffuse epithelial downgrowth after clear
      cornea phacoemulsification and to review the different treatment options for this
      ominous disease. DESIGN: Two interventional case reports. METHODS: Retrospective
      review of two eyes from two different patients in whom epithelial downgrowth
      developed 7 and 3 months after uneventful clear cornea phacoemulsification. In
      the first case, the epithelial invasion seemed to be growing from the temporal
      incision site onto the corneal endothelium toward the visual axis. Cryotherapy
      was applied to the affected cornea, with control of the growing membrane. A
      penetrating keratoplasty was performed to restore visual function. In the second
      patient, the membrane was attached to the iris and posterior cornea and was
      confirmed by diagnostic argon laser photocoagulation. This case was surgically
      treated with en bloc excision and a corneoscleral graft. MAIN OUTCOME MEASURES:
      Visual acuity at the final follow-up visit. RESULTS: Surgical treatment of the
      epithelial downgrowth was different for both patients. In the postoperative
      period, a best-corrected visual acuity of 20/60 and 20/30 was achieved in each
      case. No regrowth of the membrane was observed. CONCLUSIONS: Treatment of
      epithelial downgrowth is controversial. We present two cases of epithelialization
      of the anterior chamber with either clinical or histologic confirmation after
      clear cornea sutureless phacoemulsification. Surgical treatment should be
      attempted promptly to obtain a good visual prognosis.

PMID- 12466180
TI  - Corneal thickness indices discriminate between keratoconus and contact lens
      induced corneal thinning.
AB  - PURPOSE: To evaluate two indices generated from measurements obtained from the
      Orbscan Corneal Topography System (CTS; Orbscan, Inc., Salt Lake City, UT) to
      distinguish contact lens-induced corneal thinning from keratoconus. The corneal
      thickness index (CTI) was used to compare central and peripheral corneal
      thicknesses. The discriminant function 1 (DF1) was used to evaluate corneal
      thickness and central keratometry measurements. DESIGN: Case-control study.
      PARTICIPANTS: Fifty-four patients with keratoconus or suspected keratoconus, 75
      contact lens wearers, and 67 normal controls. METHODS: In the initial model
      building study, the central and peripheral corneal thickness and central
      keratometry (K) readings were evaluated retrospectively in 1 eye each of 23
      patients with clinically defined keratoconus, 31 contact lens wearers, and 43
      normal patients with the Orbscan CTS. Two methods (corneal thickness index [CTI]
      and discriminant function 1 [DF1]) were evaluated for their efficacy in
      classifying these conditions. The CTI was designed as the ratio between mean
      peripheral corneal thickness and the central corneal thickness, and the formula
      for the DF1 was as follows: DF1 = 0.044 x central thickness - 0.030 x nasal
      thickness + 9.210 x CTI - 0.157 x Max K - 8.9. In the subsequent validation
      study, the results were verified in a separate group of keratoconus patients (n =
      23), keratoconus suspects (n = 8), contact lens wearers (n = 44), and normal
      patients (n = 24). MAIN OUTCOME MEASURES: Corneal thickness index (CTI) and
      discriminant function 1 (DF1). RESULTS: The corneal thickness in patients with
      keratoconus and contact lens wearers was significantly thinner than that of
      normal eyes in the central and eight peripheral measured sites (P < 0.001). The
      corneal thickness in contact lens wearers was significantly greater than in
      keratoconus patients in the inferotemporal (P = 0.013), inferior (P = 0.003), and
      central (P < 0.001) sites and was borderline different in the superior site (P =
      0.07). In the model-building study, the CTI in keratoconus patients (1.28 +/-
      0.15) was significantly greater than in contact lens-wearing (1.10 +/- 0.03; P <
      0.001) and normal eyes (1.09 +/- 0.04; P < 0.001). The CTI was not significantly
      different between normal and contact lens-wearing eyes (P = 0.68). A CTI value of
      1.16 or more showed a sensitivity of 91% and specificity of 99% in
      differentiating keratoconus from contact lens-wearing and normal eyes. The DF1
      value was significantly lower in keratoconic eyes than in contact lens-wearing
      and normal eyes. A DF1 value of -0.6 showed a 96% sensitivity and 99% specificity
      in differentiating keratoconus from contact lens-wearing and normal eyes. Similar
      results were obtained in the validation study. CONCLUSIONS: Corneal thickness
      indices generated from the Orbscan CTS appear to be sensitive and specific for
      diagnosing keratoconus. These indices may prove to be clinically useful
      parameters for distinguishing keratoconus from contact lens-induced corneal
      thinning.

PMID- 12466181
TI  - Anti-tumor necrosis factor-alpha therapy with infliximab as an alternative to
      corticosteroids in the treatment of human leukocyte antigen B27-associated acute
      anterior uveitis.
AB  - OBJECTIVE: To evaluate the potentials of infliximab, a mouse-human chimeric
      immunoglobulin G1 monoclonal antibody that binds both the soluble form and the
      membrane-bound precursor of tumor necrosis factor-alpha (TNF-alpha), thus
      inhibiting a broad range of biologic activities of TNF-alpha, in the therapy of
      patients with acute HLA B27-associated anterior uveitis. DESIGN: Prospective
      noncomparative case series. PARTICIPANTS: Seven consecutive patients with acute
      onset of HLA B27-associated anterior uveitis, with at least three anterior
      chamber cells. INTERVENTION: Infliximab IV (Centocor, Malvern, PA) at a dosage of
      10 mg/kg body weight was used as the only anti-inflammatory drug. MAIN OUTCOME
      MEASURES: Anterior chamber cells and flare were evaluated before infliximab
      treatment and at defined time points after treatment. C-reactive protein (CRP)
      levels were assessed in all patients before IV delivery of infliximab and were re
      evaluated after 1 week. RESULTS: Patients were observed for a mean period of 17
      +/- 0.8 months. Seven patients received a single infliximab infusion of 10 mg/kg
      body weight. One patient received a second infusion 3 weeks after the first
      because of a uveitis flare-up. The median duration (+/- standard deviation) of
      uveitis was 8 +/- 12 days. All patients responded to infliximab with immediate
      improvement of clinical symptoms and a rapid decrease in anterior chamber cells.
      Total resolution of the uveitis was achieved with infliximab as the sole anti
      inflammatory drug in all but one patient, who also showed systemic inflammatory
      activity, as indicated by a threefold increase in the serum CRP level. A relapse
      was seen in four patients after a median period of 5 +/- 6.4 months. CONCLUSION:
      Infliximab proved to be a powerful therapeutic agent in acute HLA B27-associated
      uveitis and may therefore be a future alternative or supplement to steroid
      treatment. Larger controlled studies on the efficacy and dosage of infliximab in
      different forms of anterior uveitis will nonetheless be needed to evaluate the
      effectiveness of anti-TNF-alpha treatment in acute, as well as chronic, uveitis.

PMID- 12466182
TI  - Orbital lymphoma misdiagnosed as scleritis.
AB  - OBJECTIVE: To describe two patients in whom orbital lymphoma was misdiagnosed and
      treated as scleritis. DESIGN: Two case reports with clinicopathologic
      correlation. METHODS: Each patient underwent clinical, radiologic, and histologic
      assessment. MAIN OUTCOME MEASURE: Histologic confirmation of the diagnosis of
      orbital lymphoma. RESULTS: The two patients who had been diagnosed and treated as
      having scleritis were found to have orbital lymphoma. CONCLUSION: The
      differential diagnosis for scleritis should include lymphoma.

PMID- 12466183
TI  - Orbital presentation of posttransplantation lymphoproliferative disorder: a small
      case series.
AB  - OBJECTIVE: To describe a small series of patients with orbital presentation of
      posttransplantation lymphoproliferative disorder (PTLD). DESIGN: Retrospective,
      interventional case series. PARTICIPANTS: Three patients with orbital
      presentation of histologically diagnosed PTLD. METHODS: Review of medical
      records. MAIN OUTCOME MEASURES: Measured parameters included vision, proptosis,
      and tumor extent. RESULTS: Three cases of orbital PTLD are described. In two of
      the cases, the tumor initially demonstrated orbital signs and symptoms, whereas
      in the third case, orbital and systemic signs were synchronous. Two of three
      patients had disseminated disease discovered at the time of presentation. One
      adult patient had synchronous presentation of PTLD in the orbit and prostate. One
      pediatric patient had tumor dissemination to the liver at the time of
      presentation. The PTLD tumors were classified histologically as diffuse large
      cell lymphoma of monomorphic or immunoblastic type in all three cases. Treatment
      included local irradiation, decreased immunosuppression, and antilymphocyte
      monoclonal antibodies. CONCLUSIONS: Orbital presentation is a rare manifestation
      of PTLD. However, ophthalmologists must consider this diagnosis carefully in
      organ transplant recipients with subtle orbital signs and symptoms at
      presentation. Early detection may alter prognosis. In each case presented, the
      diagnosis was established via lesion biopsy and subsequent histologic or flow
      cytometric evaluation, or both.

PMID- 12466184
TI  - Incidence of ocular injuries in motor vehicle crash victims with concomitant air
      bag deployment.
AB  - OBJECTIVE: To report the incidence of ocular and nonocular trauma in patients
      admitted to the Henry Ford Hospital via the emergency room since 1994 after a
      motor vehicle crash (MVC) with and without air bag deployment. DESIGN: A
      retrospective cohort study. METHODS: The Henry Ford Hospital Trauma Registry
      database was reviewed for patients involved in MVCs with and without air bag
      deployment since 1994. RESULTS: From 1994 to 1999, there were only seven air bag
      related ocular injuries, representing 4.4% of all MVC-related ocular injuries.
      From 1997 to 1999, MVC-related ocular injuries with and without air bags
      represented 5.0% and 12.7%, respectively, of all MVC-related injuries. For that
      same period, the death rate and average Injury Severity Score for MVCs with air
      bag deployment were 3.4% and 10.75, compared with 8% and 14.5, respectively, for
      MVCs without air bag deployment. CONCLUSIONS: MVC-related ocular injuries
      associated with air bag deployment are rare, and the incidence of ocular injuries
      associated with MVCs was lower when air bags were deployed.

PMID- 12466185
TI  - Squamous metaplasia of the canaliculi associated with 5-fluorouracil: a
      clinicopathologic case report.
AB  - OBJECTIVE: To illustrate a newly recognized histopathologic change in a patient
      with canalicular obstruction after weekly administration of 5-fluorouracil for
      colon cancer. DESIGN: Interventional case report. METHODS: A full-thickness
      section of canaliculus was obtained during surgical repair. MAIN OUTCOME MEASURE:
      Histopathologic changes in the specimen. RESULTS: The prominent histologic
      feature of the canalicular specimen was severe squamous metaplasia with narrowing
      of the lumen. CONCLUSION: Canalicular obstruction may follow systemic use of 5
      fluorouracil due to squamous metaplasia.

PMID- 12466186
TI  - Automated perimetry: a report by the American Academy of Ophthalmology.
AB  - OBJECTIVE: The purpose of this document is to summarize and evaluate the
      effectiveness of new automated perimetry tests and algorithms in diagnosing
      glaucoma and detecting disease progression. METHODS: A literature search on
      automated perimetry retrieved over 300 citations from 1994 to 2001, of which 71
      were selected as relevant to this assessment. The quality of the evidence
      obtained from these studies was assessed by the methodologist. RESULTS: The four
      automated perimetry techniques described in this assessment are short wavelength
      automated perimetry (SWAP), frequency doubling technology perimetry (FDT), high
      pass resolution perimetry (HPRP), and motion automated perimetry (MAP). The
      algorithms described are Swedish interactive threshold algorithm (SITA) and SITA
      fast. With the exception of SWAP, these techniques and algorithms reduce testing
      time and inconsistent patient performance when compared with conventional full
      threshold testing. CONCLUSIONS: Short wavelength automated perimetry detected
      visual field loss earlier than standard threshold automated perimetry, with a
      sensitivity and specificity of about 88% and 92% respectively. However, it is a
      lengthy, demanding test, is sensitive to media opacities, and has a greater
      magnitude of long-term fluctuation compared with standard threshold automated
      perimetry, which make it difficult to assess disease progression accurately. When
      compared to standard threshold automated perimetry, FDT perimetry showed
      sensitivity and specificity greater than 97% for detecting moderate and advanced
      glaucoma, and sensitivity of 85% and specificity of 90% for early glaucoma. As
      FDT perimetry has a short testing time and is resistant to blur and pupil size,
      it may be a useful screening tool. In a longitudinal study, high-pass resolution
      perimetry was more effective than standard threshold automated perimetry in
      monitoring progressive glaucomatous loss, detecting progression at a median of 12
      months earlier in 54% of patients studied. Motion automated perimetry
      demonstrated usefulness in detecting early glaucomatous visual loss in a
      longitudinal study. Studies on SITA demonstrated greater sensitivity and
      reproducibility and less intertest variability when compared to standard full
      threshold testing and a 50% reduction in testing times. A study comparing
      standard full threshold, SITA, and SITA fast found a sensitivity of 95% for the
      first two techniques and 93% for SITA fast. Long-term follow-up studies are
      needed to assess the ability of these techniques to detect progression of
      glaucoma over time.

PMID- 12466187
TI  - Male contraception.
AB  - The provision of safe, effective contraception has been revolutionized in the
      past 40 yr following the development of synthetic steroids and the demonstration
      that administration of combinations of sex steroids can be used to suppress
      ovulation and, subsequently, other reproductive functions. This review addresses
      the current standing of male contraception, long the poor relation in family
      planning but currently enjoying a resurgence in both scientific and political
      interest as it is recognized that men have a larger role to play in the
      regulation of fertility, whether seen in geopolitical or individual terms.
      Condoms and vasectomy continue to be popular at particular phases of the
      reproductive lifespan and in certain cultures. Although not perfect
      contraceptives, condoms have the additional advantage of offering protection from
      sexually transmitted infection. The hormonal approach may have acquired the
      critical mass needed to make the transition from academic research to
      pharmaceutical development. Greatly increased understanding of male reproductive
      function, partly stimulated by interest in ageing and the potential benefits of
      androgen replacement, is opening up other avenues for investigation taking
      advantage of nonhormonal regulatory pathways specific to spermatogenesis and the
      reproductive tract.

PMID- 12466189
TI  - Modulation of growth factor/cytokine synthesis and signaling by 1alpha,25
      dihydroxyvitamin D(3): implications in cell growth and differentiation.
AB  - Distinct from its classic functions in the regulation of calcium and phosphorus
      metabolism as a systemic hormone, 1alpha,25-dihydroxyvitamin D(3)
      [1alpha,25(OH)(2)D(3)] is involved in the local control and regulation of
      cellular growth and differentiation in various tissues, including epidermis
      (keratinocytes) and bone (osteoblasts and osteoclasts). In this review, the
      impact of 1alpha,25(OH)(2)D(3) on growth factor/cytokine synthesis and signaling
      is discussed, particularly as it pertains to bone cells and keratinocytes.
      1alpha,25(OH)(2)D(3) not only regulates growth factor/cytokine synthesis but may
      also alter growth factor signaling. Recently discovered examples for such
      interactions are the interactions between the vitamin D receptor and the mothers
      against decapentaplegic-related proteins that function downstream of TGFbeta
      receptors. Inhibitory effects of 1alpha,25(OH)(2)D(3) on keratinocytes through
      TGFbeta activation and IL-1alpha, IL-6, and IL-8 suppression may provide a
      rationale for its beneficial effects in the treatment of hyperproliferative skin
      disorders, whereas stimulatory effects through the epidermal growth factor
      related family members and platelet-derived growth factor may be operative in its
      beneficial effects in skin atrophy and wound healing. Modulation of cytokines and
      growth factors by 1alpha,25(OH)(2)D(3) during bone remodeling plays an important
      role in the coupling of osteoblastic bone formation with osteoclastic resorption
      to maintain bone mass.

PMID- 12466190
TI  - Genetic analysis of the mammalian transforming growth factor-beta superfamily.
AB  - Members of the TGF-beta superfamily, which includes TGF-betas, growth
      differentiation factors, bone morphogenetic proteins, activins, inhibins, and
      glial cell line-derived neurotrophic factor, are synthesized as prepropeptide
      precursors and then processed and secreted as homodimers or heterodimers. Most
      ligands of the family signal through transmembrane serine/threonine kinase
      receptors and SMAD proteins to regulate cellular functions. Many studies have
      reported the characterization of knockout and knock-in transgenic mice as well as
      humans or other mammals with naturally occurring genetic mutations in superfamily
      members or their regulatory proteins. These investigations have revealed that TGF
      beta superfamily ligands, receptors, SMADs, and upstream and downstream
      regulators function in diverse developmental and physiological pathways. This
      review attempts to collate and integrate the extensive body of in vivo mammalian
      studies produced over the last decade.

PMID- 12466191
TI  - Cellular actions of the insulin-like growth factor binding proteins.
AB  - In addition to their roles in IGF transport, the six IGF-binding proteins
      (IGFBPs) regulate cell activity in various ways. By sequestering IGFs away from
      the type I IGF receptor, they may inhibit mitogenesis, differentiation, survival,
      and other IGF-stimulated events. IGFBP proteolysis can reverse this inhibition or
      generate IGFBP fragments with novel bioactivity. Alternatively, IGFBP interaction
      with cell or matrix components may concentrate IGFs near their receptor,
      enhancing IGF activity. IGF receptor-independent IGFBP actions are also
      increasingly recognized. IGFBP-1 interacts with alpha(5)beta(1) integrin,
      influencing cell adhesion and migration. IGFBP-2, -3, -5, and -6 have heparin
      binding domains and can bind glycosaminoglycans. IGFBP-3 and -5 have carboxyl
      terminal basic motifs incorporating heparin-binding and additional basic residues
      that interact with the cell surface and matrix, the nuclear transporter importin
      beta, and other proteins. Serine/threonine kinase receptors are proposed for
      IGFBP-3 and -5, but their signaling functions are poorly understood. Other cell
      surface IGFBP-interacting proteins are uncharacterized as functional receptors.
      However, IGFBP-3 binds and modulates the retinoid X receptor-alpha, interacts
      with TGFbeta signaling through Smad proteins, and influences other signaling
      pathways. These interactions can modulate cell cycle and apoptosis. Because
      IGFBPs regulate cell functions by diverse mechanisms, manipulation of IGFBP
      regulated pathways is speculated to offer therapeutic opportunities in cancer and
      other diseases.

PMID- 12466192
TI  - Activation of the knirps locus links patterning to morphogenesis of the second
      wing vein in Drosophila.
AB  - The adjacent knirps (kni) and knirps-related (knrl) genes encode functionally
      related zinc finger transcription factors that collaborate to initiate
      development of the second longitudinal wing vein (L2). kni and knrl are expressed
      in the third instar larval wing disc in a narrow stripe of cells just anterior to
      the broad central zone of cells expressing high levels of the related spalt
      genes. Here, we identify a 1.4 kb cis-acting enhancer element from the kni locus
      that faithfully directs gene expression in the L2 primordium. We find that three
      independent ri alleles have alterations mapping within the L2-enhancer element
      and show that two of these observed lesions eliminate the ability of the enhancer
      element to direct gene expression in the L2 primordium. The L2 enhancer can be
      subdivided into distinct activation and repression domains. The activation domain
      mediates the combined action of the general wing activator Scalloped and a
      putative locally provided factor, the activity of which is abrogated by a single
      nucleotide alteration in the ri(53j) mutant. We also find that misexpression of
      genes in L2 that are normally expressed in veins other than L2 results in
      abnormal L2 development. These experiments provide a mechanistic basis for
      understanding how kni and knrl link AP patterning to morphogenesis of the L2 vein
      by orchestrating the expression of a selective subset of vein-promoting genes in
      the L2 primordium.

PMID- 12466193
TI  - Grainy head controls apical membrane growth and tube elongation in response to
      Branchless/FGF signalling.
AB  - Epithelial organogenesis involves concerted movements and growth of distinct
      subcellular compartments. We show that apical membrane enlargement is critical
      for lumenal elongation of the Drosophila airways, and is independently controlled
      by the transcription factor Grainy head. Apical membrane overgrowth in grainy
      head mutants generates branches that are too long and tortuous without affecting
      epithelial integrity, whereas Grainy head overexpression limits lumenal growth.
      The chemoattractant Branchless/FGF induces tube outgrowth, and we find that it
      upregulates Grainy head activity post-translationally, thereby controlling apical
      membrane expansion to attain its key role in branching. We favour a two-step
      model for FGF in branching: first, induction of cell movement and apical membrane
      growth, and second, activation of Grainy head to limit lumen elongation, ensuring
      that branches reach and attain their characteristic lengths.

PMID- 12466194
TI  - Two modes of recruitment of E(spl) repressors onto target genes.
AB  - The decision of ectodermal cells to adopt the sensory organ precursor fate in
      Drosophila is controlled by two classes of basic-helix-loop-helix transcription
      factors: the proneural Ac and Sc activators promote neural fate, whereas the
      E(spl) repressors suppress it. We show here that E(spl) proteins m7 and mgamma
      are potent inhibitors of neural fate, even in the presence of excess Sc activity
      and even when their DNA-binding basic domain has been inactivated. Furthermore,
      these E(spl) proteins can efficiently repress target genes that lack cognate DNA
      binding sites, as long as these genes are bound by Ac/Sc activators. This
      activity of E(spl)m7 and mgamma correlates with their ability to interact with
      proneural activators, through which they are probably tethered on target
      enhancers. Analysis of reporter genes and sensory organ (bristle) patterns
      reveals that, in addition to this indirect recruitment of E(spl) onto enhancers
      via protein-protein interaction with bound Ac/Sc factors, direct DNA binding of
      target genes by E(spl) also takes place. Irrespective of whether E(spl) are
      recruited via direct DNA binding or interaction with proneural proteins, the co
      repressor Groucho is always needed for target gene repression.

PMID- 12466195
TI  - EcR isoforms in Drosophila: testing tissue-specific requirements by targeted
      blockade and rescue.
AB  - The three Drosophila EcR isoforms differ only at their N termini; thus, they
      share the conserved ligand-binding domain transcriptional activation function
      (AF2) and only differ in the unconserved A/B region, which contains a second,
      isoform-specific, activation function (AF1). We have developed a dominant
      negative mutant EcR (EcR-DN), expressed it in flies with the GAL4/UAS system, and
      used it to block ecdysone signaling in eight tissues or groups of tissues.
      Localized EcR-DN arrests ecdysone-dependent development in the target cells and
      often--because of a molting checkpoint--arrests development globally.
      Simultaneously expressing individual wild-type EcR isoforms in the same target
      tissues suppresses the EcR-DN phenotype and identifies the rescuing isoform as
      sufficient to support the development of the target. Every isoform, and even an N
      terminal truncated EcR that lacks any AF1, supports development in the fat body,
      eye discs, salivary glands, EH-secreting neurosecretory cells and in the dpp
      expression domain, implying that AF1 is dispensable in these tissues. By
      contrast, only EcR-A is able to support development in the margins of the wing
      discs, and only EcR-B2 can do so in the larval epidermis and the border cells of
      the developing egg chamber. In light of our results, the simplest explanations
      for the widespread spatial and temporal variations in EcR isoform titers appear
      untenable.

PMID- 12466196
TI  - The Drosophila pho-like gene encodes a YY1-related DNA binding protein that is
      redundant with pleiohomeotic in homeotic gene silencing.
AB  - Polycomb group proteins (PcG) repress homeotic genes in cells where these genes
      must remain inactive during Drosophila and vertebrate development. This
      repression depends on cis-acting silencer sequences, called Polycomb group
      response elements (PREs). Pleiohomeotic (Pho), the only known sequence-specific
      DNA-binding PcG protein, binds to PREs but pho mutants show only mild phenotypes
      compared with other PcG mutants. We characterize pho-like, a gene encoding a
      protein with high similarity to Pho. Pho-like binds to Pho-binding sites in vitro
      and pho-like, pho double mutants show more severe misexpression of homeotic genes
      than do the single mutants. These results suggest that Pho and Pho-like act
      redundantly to repress homeotic genes. We examined the distribution of five PcG
      proteins on polytene chromosomes from pho-like, pho double mutants. Pc, Psc, Scm,
      E(z) and Ph remain bound to polytene chromosomes at most sites in the absence of
      Pho and Pho-like. At a few chromosomal locations, however, some of the PcG
      proteins are no longer present in the absence of Pho and Pho-like, suggesting
      that Pho-like and Pho may anchor PcG protein complexes to only a subset of PREs.
      Alternatively, Pho-like and Pho may not participate in the anchoring of PcG
      complexes, but may be necessary for transcriptional repression mediated through
      PREs. In contrast to Pho and Pho-like, removal of Trithorax-like/GAGA factor or
      Zeste, two other DNA-binding proteins implicated in PRE function, does not cause
      misexpression of homeotic genes or reporter genes in imaginal disks.

PMID- 12466197
TI  - Development of the Drosophila genital disc requires interactions between its
      segmental primordia.
AB  - In both sexes, the Drosophila genital disc comprises three segmental primordia:
      the female genital primordium derived from segment A8, the male genital
      primordium derived from segment A9 and the anal primordium derived from segments
      A10-11. Each segmental primordium has an anterior (A) and a posterior (P)
      compartment, the P cells of the three segments being contiguous at the lateral
      edges of the disc. We show that Hedgehog (Hh) expressed in the P compartment
      differentially signals A cells at the AP compartment border and A cells at the
      segmental border. As in the wing imaginal disc, cell lineage restriction of the
      AP compartment border is defined by Hh signalling. There is also a lineage
      restriction barrier at the segmental borders, even though the P compartment cells
      of the three segments converge in the lateral areas of the disc. Lineage
      restriction between segments A9 and A10-11 depends on factors other than the Hh,
      En and Hox genes. The segmental borders, however, can be permeable to some
      morphogenetic signals. Furthermore, cell ablation experiments show that the
      presence of all primordia (either the anal or the genital primordium) during
      development are required for normal development of genital disc. Collectively,
      these findings suggest that interaction between segmental primordia is required
      for the normal development of the genital disc.

PMID- 12466198
TI  - Mechanisms of cell positioning during C. elegans gastrulation.
AB  - Cell rearrangements are crucial during development. In this study, we use C.
      elegans gastrulation as a simple model to investigate the mechanisms of cell
      positioning. During C. elegans gastrulation, two endodermal precursor cells move
      from the ventral surface to the center of the embryo, leaving a gap between these
      ingressing cells and the eggshell. Six neighboring cells converge under the
      endodermal precursors, filling this gap. Using an in vitro system, we observed
      that these movements occurred consistently in the absence of the eggshell and the
      vitelline envelope. We found that movement of the neighbors towards each other is
      not dependent on chemotactic signaling between these cells. We further found that
      C. elegans gastrulation requires intact microfilaments, but not microtubules. The
      primary mechanism of microfilament-based motility does not appear to be through
      protrusive structures, such as lamellipodia or filopodia. Instead, our results
      suggest an alternative mechanism. We found that myosin activity is required for
      gastrulation, that the apical sides of the ingressing cells contract, and that
      the ingressing cells determine the direction of movement of their neighboring
      cells. Based on these results, we propose that ingression is driven by an
      actomyosin-based contraction of the apical side of the ingressing cells, which
      pulls neighboring cells underneath. We conclude that apical constriction can
      function to position blastomeres in early embryos, even before anchoring
      junctions form between cells.

PMID- 12466199
TI  - Molecular identification of distinct neurogenic and melanogenic neural crest
      sublineages.
AB  - Clonal and lineage analyses have demonstrated that although some neural crest
      cells have the ability to generate multiple cell types and display self-renewal
      ability, other crest cells generate a single or limited repertoire of cell types.
      However, it is not yet clear when, and in what order, crest cells become
      specified to adopt a particular fate. We report that the receptor tyrosine
      kinases TrkC and C-Kit are expressed by distinct neural crest subpopulations in
      vitro. We then analyzed the lineages of individual receptor-expressing crest
      cells and found that TrkC-expressing cells that have just emerged from the neural
      tube give rise to clones containing neurons or glial cells, or both, but never
      produce melanocytes. A short time later, TrkC-expressing cells only generate pure
      neuronal clones. By contrast, from their earliest appearance in neural tube
      outgrowths, C-Kit-expressing cells invariably give rise to clones containing only
      melanocytes. Our results directly demonstrate that distinct neurogenic and
      melanogenic sublineages diverge before or soon after crest cells emerge from the
      neural tube, that fate-restricted precursors are present in nascent neural crest
      populations and that these sublineages can be distinguished by their cell type
      specific expression of receptor tyrosine kinases.

PMID- 12466201
TI  - The Drosophila trithorax group gene tonalli (tna) interacts genetically with the
      Brahma remodeling complex and encodes an SP-RING finger protein.
AB  - The trithorax group genes are required for positive regulation of homeotic gene
      function. The trithorax group gene brahma encodes a SWI2/SNF2 family ATPase that
      is a catalytic subunit of the Brm chromatin-remodeling complex. We identified the
      tonalli (tna) gene in Drosophila by genetic interactions with brahma. tna
      mutations suppress Polycomb phenotypes and tna is required for the proper
      expressions of the Antennapedia, Ultrabithorax and Sex combs reduced homeotic
      genes. The tna gene encodes at least two proteins, a large isoform (TnaA) and a
      short isoform (TnaB). The TnaA protein has an SP-RING Zn finger, conserved in
      proteins from organisms ranging from yeast to human and thought to be involved in
      the sumoylation of protein substrates. Besides the SP-RING finger, the TnaA
      protein also has extended homology with other eukaryotic proteins, including
      human proteins. We show that tna mutations also interact with mutations in
      additional subunits of the Brm complex, with mutations in subunits of the
      Mediator complex, and with mutations of the SWI2/SNF2 family ATPase gene kismet.
      We propose that Tna is involved in postranslational modification of transcription
      complexes.

PMID- 12466200
TI  - Dlx proteins position the neural plate border and determine adjacent cell fates.
AB  - The lateral border of the neural plate is a major source of signals that induce
      primary neurons, neural crest cells and cranial placodes as well as provide
      patterning cues to mesodermal structures such as somites and heart. Whereas
      secreted BMP, FGF and Wnt proteins influence the differentiation of neural and
      non-neural ectoderm, we show here that members of the Dlx family of transcription
      factors position the border between neural and non-neural ectoderm and are
      required for the specification of adjacent cell fates. Inhibition of endogenous
      Dlx activity in Xenopus embryos with an EnR-Dlx homeodomain fusion protein
      expands the neural plate into non-neural ectoderm tissue whereas ectopic
      activation of Dlx target genes inhibits neural plate differentiation.
      Importantly, the stereotypic pattern of border cell fates in the adjacent
      ectoderm is re-established only under conditions where the expanded neural plate
      abuts Dlx-positive non-neural ectoderm. Experiments in which presumptive neural
      plate was grafted to ventral ectoderm reiterate induction of neural crest and
      placodal lineages and also demonstrate that Dlx activity is required in non
      neural ectoderm for the production of signals needed for induction of these
      cells. We propose that Dlx proteins regulate intercellular signaling across the
      interface between neural and non-neural ectoderm that is critical for inducing
      and patterning adjacent cell fates.

PMID- 12466202
TI  - The guanine nucleotide exchange factor C3G is necessary for the formation of
      focal adhesions and vascular maturation.
AB  - The Ras signalling pathway has major roles in normal cell function and
      oncogenesis. C3G is a guanine nucleotide exchange factor for members of the Ras
      family of GTPases. We generated a mouse strain with a hypomorphic C3G allele.
      C3G(gt/gt) mutant embryos died of vascular defects around E11.5 due to
      haemorrhage and vascular integrity defects. Vascular supporting cells did not
      develop appropriately. C3G-deficient fibroblasts responded to PDGF-BB abnormally,
      exhibited cell adhesion defects and lacked paxillin and integrin-beta1-positive
      cell adhesions. In contrast, integrin-beta3-positive cell adhesions formed
      normally. These results show that C3G is required for (1) vascular myogenesis,
      (2) the formation of paxillin- and integrin beta1-positive, but not integrin
      beta3-positive, cell adhesions and (3) normal response to PDGF, necessary for
      vascular myogenesis.

PMID- 12466203
TI  - DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and
      for functional integrity of germ cell DNA in the mouse.
AB  - Ercc1 is essential for nucleotide excision repair (NER) but, unlike other NER
      proteins, Ercc1 and Xpf are also involved in recombination repair pathways. Ercc1
      knockout mice have profound cell cycle abnormalities in the liver and die before
      weaning. Subsequently Xpa and Xpc knockouts have proved to be good models for the
      human NER deficiency disease, xeroderma pigmentosum, leading to speculation that
      the recombination, rather than the NER deficit is the key to the Ercc1 knockout
      phenotype. To investigate the importance of the recombination repair functions of
      Ercc1 we studied spermatogenesis and oogenesis in Ercc1-deficient mice. Male and
      female Ercc1-deficient mice were both infertile. Ercc1 was expressed at a high
      level in the testis and the highest levels of Ercc1 protein occurred in germ
      cells following meiotic crossing over. However, in Ercc1 null males some germ
      cell loss occurred prior to meiotic entry and there was no evidence that Ercc1
      was essential for meiotic crossing over. An increased level of DNA strand breaks
      and oxidative DNA damage was found in Ercc1-deficient testis and increased
      apoptosis was noted in male germ cells. We conclude that the repair functions of
      Ercc1 are required in both male and female germ cells at all stages of their
      maturation. The role of endogenous oxidative DNA damage and the reason for the
      sensitivity of the germ cells to Ercc1 deficiency are discussed.

PMID- 12466205
TI  - Early determination and long-term persistence of adult-generated new neurons in
      the hippocampus of mice.
AB  - New neurons are continually generated in the adult hippocampus, but the important
      question, whether adult neurogenesis is transient or leads to the lasting
      presence of new neurons, has not yet been answered. Dividing cells were labeled
      with bromodeoxyuridine (BrdU) and were investigated by means of
      immunofluorescence and confocal microscopy at several time-points 1 day to 11
      months thereafter. BrdU-labeled neurons remained stable in number and in their
      relative position in the granule cell layer over at least 11 months. This finding
      implies that the addition of new neurons is not transient and that their final
      number and localization are determined early. By contrast, expression of immature
      markers beta-III-tubulin and doublecortin in BrdU-labeled cells, peaked early
      after division and was not detectable after 4 weeks. In transgenic mice
      expressing enhanced green fluorescent protein under the nestin promoter none of
      the BrdU/nestin-positive cells early after division expressed the mature marker
      NeuN, confirming that no dividing neurons were detected. These new data suggest
      that new neurons are recruited early from the pool of proliferating progenitor
      cells and lead to a lasting effect of adult neurogenesis.

PMID- 12466204
TI  - 'Cyclic alopecia' in Msx2 mutants: defects in hair cycling and hair shaft
      differentiation.
AB  - Msx2-deficient mice exhibit progressive hair loss, starting at P14 and followed
      by successive cycles of wavelike regrowth and loss. During the hair cycle, Msx2
      deficiency shortens anagen phase, but prolongs catagen and telogen. Msx2
      deficient hair shafts are structurally abnormal. Molecular analyses suggest a
      Bmp4/Bmp2/Msx2/Foxn1 acidic hair keratin pathway is involved. These structurally
      abnormal hairs are easily dislodged in catagen implying a precocious exogen.
      Deficiency in Msx2 helps to reveal the distinctive skin domains on the same
      mouse. Each domain cycles asynchronously - although hairs within each skin domain
      cycle in synchronized waves. Thus, the combinatorial defects in hair cycling and
      differentiation, together with concealed skin domains, account for the cyclic
      alopecia phenotype.

PMID- 12466206
TI  - Hypogonadotropic hypogonadism and peripheral neuropathy in Ebf2-null mice.
AB  - Olf/Ebf transcription factors have been implicated in numerous developmental
      processes, ranging from B-cell development to neuronal differentiation. We
      describe mice that carry a targeted deletion within the Ebf2 (O/E3) gene. In Ebf2
      null mutants, because of defective migration of gonadotropin releasing hormone
      synthesizing neurons, formation of the neuroendocrine axis (which is essential
      for pubertal development) is impaired, leading to secondary hypogonadism. In
      addition, Ebf2(-/-) peripheral nerves feature defective axon sorting,
      hypomyelination, segmental dysmyelination and axonal damage, accompanied by a
      sharp decrease in motor nerve conduction velocity. Ebf2-null mice reveal a novel
      genetic cause of hypogonadotropic hypogonadism and peripheral neuropathy in the
      mouse, disclosing an important role for Ebf2 in neuronal migration and nerve
      development.

PMID- 12466207
TI  - A critical role for elastin signaling in vascular morphogenesis and disease.
AB  - Vascular proliferative diseases such as atherosclerosis and coronary restenosis
      are leading causes of morbidity and mortality in developed nations. Common
      features associated with these heterogeneous disorders involve phenotypic
      modulation and subsequent abnormal proliferation and migration of vascular smooth
      muscle cells into the arterial lumen, leading to neointimal formation and
      vascular stenosis. This fibrocellular response has largely been attributed to the
      release of multiple cytokines and growth factors by inflammatory cells.
      Previously, we demonstrated that the disruption of the elastin matrix leads to
      defective arterial morphogenesis. Here, we propose that elastin is a potent
      autocrine regulator of vascular smooth muscle cell activity and that this
      regulation is important for preventing fibrocellular pathology. Using vascular
      smooth muscle cells from mice lacking elastin (Eln(-/-)), we show that elastin
      induces actin stress fiber organization, inhibits proliferation, regulates
      migration and signals via a non-integrin, heterotrimeric G-protein-coupled
      pathway. In a porcine coronary model of restenosis, the therapeutic delivery of
      exogenous elastin to injured vessels in vivo significantly reduces neointimal
      formation. These findings indicate that elastin stabilizes the arterial structure
      by inducing a quiescent contractile state in vascular smooth muscle cells.
      Together, this work demonstrates that signaling pathways crucial for arterial
      morphogenesis can play an important role in the pathogenesis and treatment of
      vascular disease.

PMID- 12466209
TI  - Introduction. Computation in cortical columns.

PMID- 12466210
TI  - Interlaminar connections in the neocortex.
AB  - This review summarizes the local circuit, interlaminar connections in adult
      mammalian neocortex. These were first demonstrated with anatomical techniques,
      which indicate some of the exquisite spatial precision present in the circuitry.
      Details, such as the class(es) of neurons targeted by some of these projections,
      have begun to be added in studies that combine paired/triple intracellular
      recordings with dye-filling of connected neurons. Clear patterns are emerging
      from these studies, with 'forward' projections from layer 4 to 3 and from 3 to 5
      targeting both selected pyramidal cells and interneurons, while 'back'
      projections from layer 5 to 3 and from 3 to 4 target only interneurons. To place
      these data in a wider context, the major afferent inputs to and efferent outputs
      from each of the layers are discussed first.

PMID- 12466211
TI  - Anatomical substrates for functional columns in macaque monkey primary visual
      cortex.
AB  - In this review we re-examine the concept of a cortical column in macaque primary
      visual cortex, and consider to what extent a functionally defined column reflects
      any sort of anatomical entity that subdivides cortical territory. Functional
      studies have shown that columns relating to different response properties are
      mapped in cortex at different spatial scales. We suggest that these properties
      first emerge in mid-layer 4C through a combination of thalamic afferent inputs
      and local intracortical circuitry, and are then transferred to other layers in a
      columnar fashion, via interlaminar relays, where additional processing occurs.
      However, several properties are not strictly columnar since they do not appear in
      all cortical layers. In contrast to the functional column, an anatomically based
      cortical column is defined most clearly in terms of the reciprocal connections it
      makes, both via intra-areal lateral connections and inter-areal
      feedback/feedforward pathways. The column boundaries are reinforced by interplay
      between lateral inhibition spreading beyond the column boundary and disinhibition
      within the column. The anatomical column acts as a functionally tuned unit and
      point of information collation from laterally offset regions and feedback
      pathways. Thalamic inputs provide the high-contrast receptive field sizes of the
      column's neurons, intra-areal lateral connections provide their low contrast
      summation field sizes, and feedback pathways provide surround modulation of
      receptive fields responses.

PMID- 12466212
TI  - Fast-spike interneurons and feedforward inhibition in awake sensory neocortex.
AB  - 'Fast-spike' interneurons of layer 4 mediate thalamocortical feedforward
      inhibition and can, with some confidence, be identified using extracellular
      methods. In somatosensory barrel cortex of awake rabbits, these 'suspected
      inhibitory interneurons' (SINs) have distinct receptive field properties: they
      respond to vibrissa displacement with very high sensitivity and temporal
      fidelity. However, they lack the directional specificity that is clearly seen in
      most of their ventrobasal thalamocortical afferents. Several lines of evidence
      show that layer-4 SINs receive a potent and highly convergent and divergent
      functional input from topographically aligned thalamocortical neurons. Whereas
      the unselective pooling of convergent thalamocortical inputs onto SINs generates
      sensitive and broadly tuned inhibitory receptive fields, the potent divergence of
      single thalamocortical neurons onto many SINs generates sharply synchronous (+/-1
      ms) activity (because of coincident EPSPs). Synchronous discharge of these
      interneurons following thalamocortical impulses will generate a synchronous
      feedforward release of GABA within the barrel. Thalamocortical impulses will,
      therefore, generate only a brief 'window of excitability' during which spikes can
      occur in the post-synaptic targets of fast-spike interneurons. This fast,
      synchronous, highly sensitive and broadly tuned feed-forward inhibitory network
      is well suited to suppress spike generation in spiny neurons following all but
      the most optimal feedforward excitatory inputs.

PMID- 12466213
TI  - Cortical damping: analysis of thalamocortical response transformations in rodent
      barrel cortex.
AB  - In the whisker-barrel system, layer IV excitatory neurons respond preferentially
      to high-velocity deflections of their principal whisker, and these responses are
      inhibited by deflections of adjacent whiskers. Thalamic input neurons are
      amplitude and velocity sensitive and have larger excitatory and weaker inhibitory
      receptive fields than cortical neurons. Computational models based on known
      features of barrel circuitry capture these and other differences between thalamic
      and cortical neuron response properties. The models' responses are highly
      sensitive to thalamic firing synchrony, a finding subsequently confirmed in real
      barrels by in vivo experiments. Here, we use dynamic systems analysis to examine
      how barrel circuitry attains its sensitivity to input timing, and how this
      sensitivity explains the transformation of receptive fields between thalamus and
      cortex. We find that strong inhibition renders the net effect of intracortical
      connections suppressive or damping, distinguishing it from previous amplifying
      models of cortical microcircuits. In damping circuits, recurrent excitation
      enhances response tuning not by amplifying responses to preferred inputs, but by
      enabling them to better withstand strong inhibitory influences. Dense
      interconnections among barrel neurons result in considerable response
      homogeneity. Neurons outside the barrel layer respond more heterogeneously,
      possibly reflecting diverse networks and multiple transformations within the
      cortical output layers.

PMID- 12466214
TI  - Decoding neuronal population activity in rat somatosensory cortex: role of
      columnar organization.
AB  - The present study asks in what way the activity of a neuronal population
      responding to a sensory stimulus could be most efficiently decoded, or 'read
      off', by the target neurons. A simple solution to this problem has been proposed 
      pooling the activity of responding neurons. However, pooling can be inefficient
      if sensory information is encoded by the 'label' of each neuron firing a spike.
      We have tested the efficiency of pooling by quantifying the extent to which
      information about a sensory stimulus is diminished when the identity of the
      individual neurons is lost by pooling. Analyzing the response of small groups of
      neurons in rat barrel cortex to single-whisker deflection, we found that pooling
      neurons within the same column is efficient for representing stimulus position;
      it causes a loss of only 1% of the information about whether the principal
      whisker was stimulated, and a loss of 5-12% of the finer information about which
      of nine possible whiskers (the principal and its neighbors) was stimulated. Cross
      column pooling led to larger information losses, in the range of 25-55%. Thus, to
      decode stimulus position from the discharge of barrel cortex populations,
      'downstream' neurons could pool the activity arising from neurons of the same
      column, while maintaining the activity arising from neurons of separate columns
      at least partially segregated. Since such parcellation is present in some of the
      projections from barrel cortex, these findings suggest that columnar organization
      of barrel cortex serves to facilitate decoding of the location of the stimulated
      whisker.

PMID- 12466215
TI  - Closed-loop neuronal computations: focus on vibrissa somatosensation in rat.
AB  - Two classes of neuronal architectures dominate in the ongoing debate on the
      nature of computing by nervous systems. The first is a predominantly feedforward
      architecture, in which local interactions among neurons within each processing
      stage play a less influential role compared with the drive of the input to that
      stage. The second class is a recurrent network architecture, in which the local
      interactions among neighboring neurons dominate the dynamics of neuronal activity
      so that the input acts only to bias or seed the state of the network. The study
      of sensorimotor networks, however, serves to highlight a third class of
      architectures, which is neither feedforward nor locally recurrent and where
      computations depend on large-scale feedback loops. Findings that have emerged
      from our laboratories and those of our colleagues suggest that the vibrissa
      sensorimotor system is involved in such closed-loop computations. In particular,
      single unit responses from vibrissa sensory and motor areas show generic
      signatures of phase-sensitive detection and control at the level of
      thalamocortical and corticocortical loops. These loops are likely to be
      components within a greater closed-loop vibrissa sensorimotor system, which
      optimizes sensory processing.

PMID- 12466216
TI  - Synaptic physiology and receptive field structure in the early visual pathway of
      the cat.
AB  - How does the cortical circuitry analyze the visual scene? Here we explore the
      earliest levels of striate cortical processing: the first stage, where
      orientation sensitivity emerges, and the second stage, where stimulus selectivity
      is further refined. The approach is whole cell recording from cat in vivo.
      Neurons in the lateral geniculate nucleus of the thalamus have circular receptive
      fields whose subregions, center and surround are concentrically arranged and have
      the reverse sign, on or off. These neurons supply cortical simple cells, whose
      receptive fields have on and off subregions that are elongated and lie side by
      side. Feedforward models hold that orientation sensitivity depends on this
      thalamocortical change in receptive field structure and an arrangement within
      subregions such that stimuli of the reverse contrast evoke synaptic responses of
      the opposite polarity-push-pull. Our work provides support for feedforward models
      and emphasizes that push-pull is key in the geniculostriate pathway, preserved
      from retina by thalamic relay cells and reiterated, point by point, by cortical
      simple cells. Also, we help define the cortical push-pull circuit by identifying
      inhibitory simple cells. Lastly, separate experiments that compare the first and
      second levels of cortical processing suggest that differences in the synaptic
      physiology of connections at the two (thalamocortical versus intracortical)
      stages underlie differential selectivity for properties such as motion.

PMID- 12466217
TI  - Cortical columns: a multi-parameter examination.
AB  - Columnar structure in the cerebral cortex has been demonstrated in numerous
      studies. However, in the visual system, it is not clear from imaging, basic
      physiological and anatomical approaches how multiple stimulus parameters are
      related within columns. We have analyzed recordings from pairs of neurons in the
      striate cortex of the cat using various spatial and temporal parameters. We find
      that most parameters are clustered within inferred columns with the exception of
      spatial phase. Diversity of phase could be useful for serial processing in
      central visual pathways.

PMID- 12466218
TI  - Understanding layer 4 of the cortical circuit: a model based on cat V1.
AB  - This paper reviews theoretical and experimental results on the processing of
      layer 4, the input-recipient layer, of cat primary visual cortex (V1). A wide
      range of experimental data can be understood from a model in which response
      tuning of layer 4 cells is largely determined by a local interplay of feedforward
      excitation (from thalamus) and feedforward inhibition (from layer 4 inhibitory
      interneurons driven by thalamus). Feedforward inhibition dominates excitation,
      inherits its tuning from the thalamic input and sharpens the tuning of excitatory
      cells. At least a strong component of the feedforward inhibition received by a
      cell is spatially opponent to the excitation it receives, meaning that inhibition
      is driven by dark in regions of the visual field in which excitation is driven by
      light, and vice versa. The idea of opponent inhibition can be generalized to mean
      inhibition driven by input patterns that are strongly anti-correlated with the
      patterns that excite a cell. This paper argues that dominant feedforward opponent
      inhibition may be a general principle of cortical layer 4. This leads to the
      suggestion that the properties that show columnar organization--invariance across
      the vertical depth of cortex--may be properties that are shared by 'opposite'
      (anticorrelated) stimulus pairs. This contrasts with the more common idea that a
      column represents a set of cells that all share similar stimulus preferences.

PMID- 12466219
TI  - Columnar transformations in auditory cortex? A comparison to visual and
      somatosensory cortices.
AB  - Auditory cortical columns have been studied for decades, but intracolumnar
      processing in auditory cortex is still poorly understood, relative to what is
      known about such processing in visual cortex and somatosensory cortex. While
      there are certainly striking similarities in cortical structure across the
      modalities, investigations of auditory cortex anatomy and synaptic physiology
      have also found important differences from the columnar organization of other
      sensory cortices. In vitro and in vivo studies of thalamocortical transformations
      in the auditory system have begun to reveal the functional significance of these
      differences, and have defined the earliest stages of auditory cortical
      processing. However, the question of what transformations are performed within
      auditory cortical columns remains unresolved. Attempts to find laminar
      differences in auditory cortex, which could provide the key to understanding
      columnar transformations, have so far produced contradictory and inconclusive
      results. Direct analogies to primary visual and somatic sensory cortices would
      suggest that response properties such as bandwidth, inhibitory sideband
      structure, preferred modulation rate and modulation phase sensitivity might vary
      across layers in auditory cortex. While such analogies could prove useful as
      guidelines for future research, the best hope for understanding auditory columnar
      transformations may lie instead with a more modality-specific, functional
      approach.

PMID- 12466220
TI  - Columns for complex visual object features in the inferotemporal cortex:
      clustering of cells with similar but slightly different stimulus selectivities.
AB  - Cells in the inferotemporal cortex (area TE) selectively respond to complex
      visual object features and those that respond to similar features cluster in a
      columnar region elongated vertical to the cortical surface. What are the
      functional roles of the column structure in the inferotemporal cortex?
      Selectivity of cells within a column is similar but not identical. If we
      emphasize the similarity among cells within a column, we can regard the columns
      as units for description of object features. The variety of stimulus selectivity
      in a column may work as a tool to disregard subtle changes in input images when
      the system is directed to invariant recognition. Alternatively, if we emphasize
      the differences in selectivity of cells within a column, the columns can be
      compared to differential amplifiers, each of which represents variety within a
      group of features. The enormous number of objects present in nature can be
      efficiently described by combining outputs of the multiple differential
      amplifiers in the inferotemporal cortex. The two modes may work in parallel, with
      a graded balance changing according to the behavioral context. Determining
      whether or not these hypotheses are valid will require further studies.

PMID- 12466221
TI  - Towards a theory of the laminar architecture of cerebral cortex: computational
      clues from the visual system.
AB  - One of the most exciting and open research frontiers in neuroscience is that of
      seeking to understand the functional roles of the layers of cerebral cortex. New
      experimental techniques for probing the laminar circuitry of cortex have recently
      been developed, opening up novel opportunities for investigating how its six
      layered architecture contributes to perception and cognition. The task of trying
      to interpret this complex structure can be facilitated by theoretical analyses of
      the types of computations that cortex is carrying out, and of how these might be
      implemented in specific cortical circuits. We have recently developed a detailed
      neural model of how the parvocellular stream of the visual cortex utilizes its
      feedforward, feedback and horizontal interactions for purposes of visual
      filtering, attention and perceptual grouping. This model, called LAMINART, shows
      how these perceptual processes relate to the mechanisms that ensure the stable
      development of cortical circuits in the infant, and to the continued stability of
      learning in the adult. The present article reviews this laminar theory of visual
      cortex, considers how it may be generalized towards a more comprehensive theory
      that encompasses other cortical areas and cognitive processes, and shows how its
      laminar framework generates a variety of testable predictions.

PMID- 12466222
TI  - Endomorphin analogues containing D-Pro2 discriminate different mu-opioid receptor
      mediated antinociception in mice.
AB  - The antagonistic actions of D-Pro(2)-endomorphins on inhibition of the paw
      withdrawal response by endomorphins were studied in mice. D-Pro(2)-endomorphin-1
      and D-Pro(2)-endomorphin-2, injected intrathecally (i.t.), had no significant
      effect on the nociceptive thermal threshold alone. When D-Pro(2)-endomorphin-1
      (0.05-0.1 pmol) was injected simultaneously with i.t. endomorphin-1 (5.0 nmol) or
      endomorphin-2 (5.0 nmol), antinociception induced by endomoprhin-1 was reduced
      significantly, whereas endomorphin-2-induced antinociception was not affected by
      D-Pro(2)-endomorphin-1. Antinociception induced by i.t. endomorphin-2 (5.0 nmol)
      was reduced significantly by its analogue, D-Pro(2)-endomorphin-2 (100 pmol), but
      not by D-Pro(2)-endomorphin-1. D-Pro(2)-endomorphin-1. D-Pro(2)-endomorphin-1
      also antagonized the antinociceptive effect of i.t. DAMGO, a mu-opioid receptor
      agonist, whereas D-Pro(2)-endomorphin-2 failed to reduce the effect of DAMGO.
      These results suggest that endomorphin analogues containing D-Pro(2) are able to
      discriminate the antinociceptive actions of mu(1)- and mu(2)-opioid receptor
      agonists at the spinal cord level.

PMID- 12466223
TI  - Nociceptive sensitization by the secretory protein Bv8.
AB  - 1 The small protein Bv8, isolated from amphibian skin, belongs to a novel family
      of secretory proteins (Bv8-Prokineticin family, SWISS-PROT: Q9PW66) whose
      orthologues have been conserved throughout evolution, from invertebrates to
      humans. 2 When injected intravenously or subcutaneously (from 0.06 to 500 pmol
      kg(-1)) or intrathecally (from 6 fmol to 250 pmol) in rats, Bv8 produced an
      intense systemic nociceptive sensitization to mechanical and thermal stimuli
      applied to the tail and paws. 3 Topically delivered into one rat paw, 50 fmol of
      Bv8 decreased by 50% the nociceptive threshold to pressure in the injected paw
      without affecting the threshold in the contralateral paw. 4 The two G-protein
      coupled prokineticin receptors, PK-R1 and PK-R2, were expressed in rat dorsal
      root ganglia (DRG) and in dorsal quadrants of spinal cord (DSC) and bound Bv8 and
      the mammalian orthologue, EG-VEGF, with high affinity. In DSC, PK-R1 was more
      abundant than PK-R2, whereas both receptors were equally expressed in DRG. IC(50)
      of Bv8 and EG-VEGF to inhibit [(125)I]-Bv8 binding to rat DRG and DSC were 4.1+/
      0.4 nM Bv8 and 76.4+/-7.6 nM EG-VEGF, in DRG; 7.3+/-0.9 nM Bv8 and 330+/-41 nM EG
      VEGF, in DSC. 5 In the small diameter neurons (<30 microm) of rat DRG cultures,
      Bv8 concentrations, ranging from 0.2 to 10 nM, raised [Ca(2+)](i) in a dose
      dependent manner. 6 These data suggest that Bv8, through binding to PK receptors
      of DSC and primary sensitive neurons, results in intense sensitization of
      peripheral nociceptors to thermal and mechanical stimuli.

PMID- 12466224
TI  - Nitric oxide inhibits uptake of dopamine and N-methyl-4-phenylpyridinium (MPP+)
      but not release of MPP+ in rat C6 glioma cells expressing human dopamine
      transporter.
AB  - 1. Conflicting results have been reported regarding the influence of nitric oxide
      (NO) and peroxynitrite on dopamine (DA) uptake and release. In the present study,
      effects of NO donors were studied in rat C6 glioma cells expressing human DA
      transporter. 2. [(3)H]-DA uptake was inhibited by S-nitroso-thiol S-nitroso-N
      acetylpenicillamine, spermine/NO, diethylamine/NO (DEA/NO), (Z)-1-[N-(3
      ammoniopropyl)-N-(n-propyl)-amino]/NO (PAPA/NO), and 3-morphosynodiomine (SIN-1)
      in a rank order correlating with their half lives as NO donors, whereas no effect
      was observed for diethylenetriamine/NO and dipropylenetriamine/NO, which release
      NO very slowly. 3. Hydroxycobalamin, a NO scavenger, but not superoxide dismutase
      and catalase, enzymes that metabolize superoxide and hydrogen peroxide,
      respectively, abolished the inhibitory effect of DEA/NO and SIN-1, indicating
      that they inhibit DA uptake through a mechanism related to the production of NO
      but unrelated to the formation of peroxynitrite. In consonance, peroxynitrite did
      not alter DA uptake in the present system. 4. DEA/NO and PAPA/NO reduced [(3)H]
      MPP(+) uptake, whereas the release of [(3)H]-MPP(+) was not modified,
      demonstrating that NO can inhibit uptake of DA transporter substrate without
      accelerating DA transporter-mediated reverse transport of substrate under the
      same conditions.

PMID- 12466225
TI  - Molecular pharmacology of the human prostaglandin D2 receptor, CRTH2.
AB  - 1. The recombinant human prostaglandin D(2) (PGD(2)) receptor, hCRTH2, has been
      expressed in HEK293(EBNA) and characterized with respect to radioligand binding
      and signal transduction properties. High and low affinity binding sites for
      PGD(2) were identified in the CRTH2 receptor population by saturation analysis
      with respective equilibrium dissociation constants (K(D)) of 2.5 and 109 nM. This
      revealed that the affinity of PGD(2) for CRTH2 is eight times less than its
      affinity for the DP receptor. 2. Equilibrium competition binding assays revealed
      that of the compounds tested, only PGD(2) and several related metabolites bound
      with high affinity to CRTH2 (K(i) values ranging from 2.4 to 34.0 nM) with the
      following rank order of potency: PGD(2)>13,14-dihydro-15-keto PGD(2)>15-deoxy
      Delta(12,14)-PGJ(2)>PGJ(2)>Delta(12)-PGJ(2)>15(S)-15 methyl-PGD(2). This is in
      sharp contrast with the rank order of potency obtained at DP :
      PGD(2)>PGJ(2)>Delta(12)-PGJ(2)>15-deoxy-Delta(12,14)-PGJ(2) >>>13,14-dihydro-15
      keto-PGD(2). 3. Functional studies demonstrated that PGD(2) activation of
      recombinant CRTH2 results in decrease of intracellular cAMP in a pertussis toxin
      sensitive manner. Therefore, we showed that CRTH2 can functionally couple to the
      G-protein G(alphai/o). PGD(2) and related metabolites were tested and their rank
      order of potency followed the results of the membrane binding assay. 4. By
      Northern blot analysis, we showed that, besides haemopoietic cells, CRTH2 is
      expressed in many other tissues such as brain, heart, thymus, spleen and various
      tissues of the digestive system. In addition, in situ hybridization studies
      revealed that CRTH2 mRNA is expressed in human eosinophils. Finally, radioligand
      binding studies demonstrated that two eosinophilic cell lines, butyric acid
      differentiated HL-60 and AML 14.3D10, also endogenously express CRTH2.

PMID- 12466226
TI  - Antibodies and a cysteine-modifying reagent show correspondence of M current in
      neurons to KCNQ2 and KCNQ3 K+ channels.
AB  - 1. KCNQ K(+) channels are thought to underlie the M current of neurons. To probe
      if the KCNQ2 and KCNQ3 subtypes underlie the M current of rat superior cervical
      ganglia (SCG) neurons and of hippocampus, we raised specific antibodies against
      them and also used the cysteine-alkylating agent N-ethylmaleimide (NEM) as an
      additional probe of subunit composition. 2. Tested on tsA-201 (tsA) cells
      transfected with cloned KCNQ1-5 subunits, our antibodies showed high affinity and
      selectivity for the appropriate subtype. The antibodies immunostained SCG neurons
      and hippocampal sections at levels similar to those for channels expressed in tsA
      cells, indicating that KCNQ2 and KCNQ3 are present in SCG and hippocampal
      neurons. Some hippocampal regions contained only KCNQ2 or KCNQ3 subunits,
      suggesting the presence of M currents produced by channels other than KCNQ2/3
      heteromultimers. 3. We found that NEM augmented M currents in SCG neurons and
      KCNQ2/3 currents in tsA cells via strong voltage-independent and modest voltage
      dependent actions. Expression of individual KCNQ subunits in tsA cells revealed
      voltage-independent augmentation of KCNQ2, but not KCNQ1 nor KCNQ3, currents by
      NEM indicating that this action on SCG M currents likely localizes to KCNQ2. Much
      of the voltage-independent action is lost after the C242T mutation in KCNQ2. 4.
      The correspondence of NEM effects on expressed KCNQ2/3 and SCG M currents, along
      with the antibody labelling, provide further evidence that KCNQ2 and KCNQ3
      subunits strongly contribute to the M current of neurons. The site of NEM action
      may be important for treatment of diseases caused by under-expression of these
      channels.

PMID- 12466227
TI  - Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding
      cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension.
AB  - 1. Chronic hypoxic treatment of rats (to induce pulmonary hypertension, PHT) for
      14 days increased cGMP-inhibited cAMP specific phosphodiesterase (PDE3) and cGMP
      binding cGMP specific phosphodiesterase (PDE5) activities in pulmonary arteries.
      The objective of this study was to establish the molecular basis for these
      changes in both animal and cell models of PHT. In this regard, RT-PCR and
      quantitative Western blotting analysis was applied to rat pulmonary artery
      homogenates and human pulmonary "artery" smooth muscle cell (HPASMC) lysates. 2.
      PDE3A/B gene transcript levels were increased in the main, first, intrapulmonary
      and resistance pulmonary arteries by chronic hypoxia. mRNA transcript and protein
      levels of PDE5A2 in the main and first branch pulmonary arteries were also
      increased by chronic hypoxia, with no effect on PDE5A1/A2 in the intra-pulmonary
      and resistance vessels. 3. The expression of PDE3A was increased in HPASMCs
      maintained under chronic hypoxic conditions for 14 days. This may be mediated via
      a protein kinase A-dependent mechanism, as treatment of cells with Br-cAMP (100
      microM) mimicked chronic hypoxia in increasing PDE3A expression, while the PKA
      inhibitor, H8 peptide (50 microM) abolished the hypoxic-dependent increase in
      PDE3A transcript. 4. We also found that the treatment of HPASMCs with the
      inhibitor of kappaB degradation Tosyl-Leucyl-Chloro-Ketone (TLCK, 50 microM)
      reduced PDE5 transcript levels, suggesting a role for this transcription factor
      in the regulation of PDE5 gene expression. 5. Our results show that increased
      expression of PDE3 and PDE5 might explain some changes in vascular reactivity of
      pulmonary vessels from rats with PHT. We also report that NF-kappaB might
      regulate basal PDE5 expression.

PMID- 12466228
TI  - 4-aminopyridine- and dendrotoxin-sensitive potassium channels influence
      excitability of vagal mechano-sensitive endings in guinea-pig oesophagus.
AB  - 1. Distension-sensitive vagal afferent fibres from the guinea-pig oesophagus were
      recorded extracellularly in vitro. Most recorded units were spontaneously active
      firing at 3.2+/-0.3 Hz (n=41, N=41) and had low thresholds (less than 1 mm) to
      circumferential stretch. Dynamic and adapted phases of stretch-evoked firing, as
      well as a silent period were linearly dependent on the amplitude of stretch. 2.
      High K+ (7-12 mM) Krebs solution dose-dependently increased both spontaneous and
      stretch-evoked firing and reduced the duration of the silent period. 3.
      Charybdotoxin (ChTX, 100 nM) slightly increased spontaneous and stretch-evoked
      firing and decreased the silent period, while neither iberiotoxin (100 nM) nor
      apamin (0.5 microM) had significant effects. omega-Conotoxin GVIA (0.5 microM)
      did not significantly affect firing of vagal mechanoreceptors. 4. In the majority
      of single units, 4-aminopyridine (4-AP) concentration-dependently (EC(50)
      approximately 28 microM) increased spontaneous firing, strongly reduced the
      silent period but did not affect stretch (3 mm)-induced firing. Firing evoked by
      1-2 mm was increased by 4-AP. 5. Alpha-dendrotoxin (DnTX, 300 nM) and DnTX K (30
      nM) slightly increased spontaneous and stretch-evoked firing. There was no
      additive effect on spontaneous firing when ChTX and DnTX K were applied
      simultaneously. 6. Barium (100 microM) increased stretch-induced firing, probably
      due to an increase in intramural tension. Glibenclamide (10 microM) had no effect
      on spontaneous or stretch-induced firing. 7. The results indicate that voltage
      gated 4-AP- and dendrotoxin-sensitive K+ channels are the main type of K+
      channels that influence excitability of vagal mechano-sensitive endings of the
      guinea-pig oesophagus. They were involved in control of spontaneous firing and in
      stretch-induced firing evoked by moderate stretch, but none of the K+ channels
      appeared to be involved in adaptation to maintained stretch by their slowly
      adapting vagal mechanoreceptors.

PMID- 12466229
TI  - Inhibitory mechanism of xestospongin-C on contraction and ion channels in the
      intestinal smooth muscle.
AB  - 1. Xestospongin-C isolated from a marine sponge, Xestospongia sp., has recently
      been shown to be a membrane-permeable IP(3) receptor inhibitor. In this study we
      examined the effects of this compound on smooth muscle from guinea-pig ileum. 2.
      In guinea-pig ileum permeabilized with alpha-toxin, xestospongin-C (3 microM)
      inhibited contractions induced by Ca(2+) mobilized from sarcoplasmic reticulum
      (SR) with IP(3) or carbachol with GTP, but not with caffeine. 3. In intact smooth
      muscle tissue, xestospongin-C (3-10 microM) inhibited carbachol- and high-K+
      induced increases in [Ca(2+)](i) and contractions at sustained phase. 4. It also
      inhibited voltage-dependent inward Ba(2+) currents in a concentration-dependent
      manner with an IC(50) of 0.63 microM. Xestospongin-C (3-10 microM) had no effect
      on carbachol-induced inward Ca(2+) currents via non-selective cation channels;
      but it did reduce voltage-dependent K+ currents in a concentration-dependent
      manner with an IC(50) of 0.13 microM. 5. These results suggest that xestospongin
      C inhibits the IP(3) receptor but not the ryanodine receptor in smooth muscle SR
      membrane. In intact smooth muscle cells, however, xestospongin-C appears to
      inhibit voltage-dependent Ca(2+) and K+ currents at a concentration range similar
      to that at which it inhibits the IP(3) receptor. Xestospongin-C is a selective
      blocker of the IP(3) receptor in permeabilised cells but not in cells with intact
      plasma membrane.

PMID- 12466230
TI  - Beta 2 adrenergic receptor 5' haplotypes influence promoter activity.
AB  - 1. Transcriptional control of the human beta(2) adrenergic receptor gene (ADRB2)
      predominantly resides within a 549 base pair region immediately 5' to the start
      of translation. Within this region, four naturally occurring polymorphisms, -468
      C-->G, -367 T-->C, -47 T-->C, and -20 T-->C, have been identified. 2. To
      determine the individual site and haplotype effects of these polymorphisms, we
      generated 16 luciferase-based mutant constructs which were transiently
      transfected into HEK293 cells, and measured ADRB2 promoter-driven luciferase
      activity. 3. Two of the 16 mutant constructs, GCCT (-468G, -367C, -47C, -20T) and
      CTCT, showed a highly significant 3 fold decrease in luciferase induction
      relative to the reference CTTT. These haplotype effects could not be accounted
      for by the separate and additive effects of each site. 4. These findings indicate
      that promoter polymorphisms interact to significantly alter beta(2) adrenergic
      receptor expression, and should be examined further for their association with
      disease-related phenotypes.

PMID- 12466231
TI  - Smooth muscle 5-HT2A receptors mediating contraction of porcine isolated proximal
      stomach strips.
AB  - 1. The aim of this study was to characterize the 5-HT receptors involved in the 5
      HT-induced contraction of longitudinal muscle (LM) strips of porcine proximal
      stomach. This was done in a classical organ bath set-up for isotonic measurement.
      2. The concentration-contraction curve to 5-HT was not modified by 5-HT(3) and 5
      HT(4) receptor antagonism. Methysergide, ketanserin and mesulergine antagonized
      the curve to 5-HT. Concomitantly, increasing concentrations of ketanserin and
      mesulergine progressively revealed a biphasic nature of the 5-HT curve.
      Ketanserin antagonized the low-affinity receptor while it did not modify the high
      affinity receptor. 3. Tetrodotoxin did not influence the concentration
      contraction curve to 5-HT neither in the absence nor presence of ketanserin,
      indicating that nerves are not involved. 4. Ketanserin competitively antagonized
      the monophasic concentration-response curve to alpha-Methyl-5-HT, yielding a
      Schild slope that was not significantly different from unity. After constraining
      the Schild slope to unity, a pK(B) estimate of 8.23+/-0.90 was obtained. This
      affinity estimate of ketanserin closely approximates previously reported
      affinities at 5-HT(2A) receptors. 5. In the presence of ketanserin (0.1 microM;
      exposing the high-affinity receptor), a wide range of 5-HT receptor antagonists
      covering all 5-HT receptors known, was tested. Only methysergide and ritanserin
      inhibited the response to 5-HT, thus expressing affinity for the high-affinity
      receptor. This did not reveal the identity of the receptor involved. 6 It can be
      concluded that 5-HT induces pig proximal stomach (LM) contraction via 5-HT(2A)
      receptors located on smooth muscle. A ketanserin-insensitive phase of
      contractions could not be characterized between the actually known classes of 5
      HT receptors with the pharmacological tools that were used.

PMID- 12466232
TI  - In vivo measurement of nitric oxide production in porcine gut, liver and muscle
      during hyperdynamic endotoxaemia.
AB  - 1. During prolonged endotoxaemia, an increase in arginine catabolism may result
      in limiting substrate availability for nitric oxide (NO) production. These
      effects were quantitated in a chronically instrumented porcine endotoxaemia
      model. 2. Ten days prior to the beginning of the experiments, pigs were
      catheterized. On day 0, pigs received a continuous infusion of endotoxin (3
      microg kg(-1) h(-1)) over 24 h and were saline resuscitated. Blood was drawn from
      the catheters at 0 and 24 h during primed-infusion of (15)N(2)-arginine and P
      aminohippurate to assess (15)N(2)-arginine to (15)N-citrulline conversion and
      plasma flow rates, respectively, across the portal-drained viscera, liver and
      hindquarter. 3. During endotoxin infusion a hyperdynamic circulation with
      elevated heart rate, cardiac index and decreased mean arterial pressure was
      achieved, characteristic of the human septic condition. 4. Endotoxin induced NO
      production by the portal-drained viscera and the liver. The increased NO
      production was quantitatively matched by an increase in arginine disposal.
      Nitrite/nitrate levels remained unchanged during endotoxaemia. 5. Despite an
      increased arginine production from the hindquarter and an increased whole-body
      arginine appearance rate during endotoxin infusion, the plasma arginine
      concentration was lower in endotoxin-treated animals than in controls. 6 On a
      whole-body level, the muscle was found to serve as a major arginine supplier and,
      considering the lowered arginine plasma levels, seems critical in providing
      arginine as precursor for NO synthesis in the splanchnic region.

PMID- 12466233
TI  - Divergent mechanisms of action of the inflammatory cytokines interleukin 1-beta
      and tumour necrosis factor-alpha in mouse cremasteric venules.
AB  - 1. Protein synthesis dependency and the role of endogenously generated platelet
      activating factor (PAF) and leukotriene B(4) (LTB(4)) in leukocyte migration
      through interleukin-1beta (IL-1beta)- and tumour necrosis factor-alpha (TNFalpha)
      stimulated mouse cremasteric venules was investigated using established
      pharmacological interventions and the technique of intravital microscopy. 2.
      Based on previously obtained dose-response data, 30 ng rmIL-1beta and 300 ng
      rmTNFalpha were injected intrascrotally (4 h test period) to induce comparable
      levels of leukocyte firm adhesion and transmigration in mouse cremasteric
      venules. 3. Co-injection of the mRNA synthesis inhibitor, actinomycin D (0.2 mg
      kg(-1)), with the cytokines significantly inhibited firm adhesion (49+/-13.6%)
      and transmigration (67.2+/-4.2%) induced by IL-1beta, but not TNFalpha. 4. In
      vitro, TNFalpha (1-100 ng ml(-1)), but not IL-1beta, stimulated L-selectin
      shedding and increased beta(2) integrin expression on mouse neutrophils, as
      quantified by flow cytometry. 5. The PAF receptor antagonist, UK-74,505
      (modipafant, 0.5 mg kg(-1), i.v.), had no effect on adhesion induced by either
      cytokine, but significantly inhibited transmigration induced by IL-1beta (66.5+/
      4.5%). 6. The LTB(4) receptor antagonist, CP-105,696 (100 mg kg(-1), p.o.),
      significantly inhibited both IL-1beta induced adhesion (81.4+/-15.2%) and
      transmigration (58.7+/-7.2%), but had no effect on responses elicited by
      TNFalpha. Combined administration of the two antagonists had no enhanced
      inhibitory effects on responses induced by either cytokine. 7. The data indicate
      that firm adhesion and transmigration in mouse cremasteric venules stimulated by
      IL-1beta, but not TNFalpha, is protein synthesis dependent and mediated by
      endogenous generation of PAF and LTB(4). Additionally, TNFalpha but not IL-1beta,
      can directly stimulate mouse neutrophils in vitro. The findings provide further
      evidence to suggest divergent mechanisms of actions of IL-1beta and TNFalpha, two
      cytokines often considered to act via common molecular/cellular pathways.

PMID- 12466234
TI  - Functional characterization of tachykinin NK1 receptors in the mouse uterus.
AB  - 1. Contractility studies were undertaken to determine the nature of the receptors
      mediating responses to tachykinins in uteri of oestrogen-treated mice. 2. In the
      presence of thiorphan (3 microM), captopril (10 microM), and bestatin (10
      microM), substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) produced
      concentration-related contractions of uterine preparations. The order of potency
      was SP > or =NKA>NKB. 3. Neither atropine (0.1 microM) nor l-NOLA (100 microM),
      nor indomethacin (10 microM) alone or in combination with either ranitidine (10
      microM) or mepyramine (10 microM), affected responses to SP. These findings
      indicate that SP actions are not mediated or modulated through the release of
      acetylcholine, nitric oxide, prostanoids or histamine. 4. In the presence of
      peptidase inhibitors, the tachykinin NK(1) receptor-selective agonist
      [Sar(9)Met(O(2))(11)]SP, produced a concentration-dependent contractile effect.
      The tachykinin NK(2) and NK(3) receptor-selective agonists
      [Lys(5)MeLeu(9)Nle(10)]NKA(4-10) and [MePhe(7)]NKB were relatively inactive. The
      potencies of SP analogues in which Glu replaced Gln(5) and/or Gln(6) were similar
      to that of SP. 5. The tachykinin NK(1) receptor-selective antagonist, SR140333
      (10 nM), alone or combined with the tachykinin NK(2) receptor-selective
      antagonist, SR48968 (10 nM), shifted log concentration curves to SP, NKA and NKB
      to the right. SR140333 (10 nM) reduced the effect of [Sar(9)Met(O(2))(11)]SP.
      SR48968 did not affect responses to SP or [Sar(9)Met(O(2))(11)]SP, but reduced
      the effect of higher concentrations of NKA and shifted the log concentration
      response curve to NKB to the right. The tachykinin NK(3) receptor-selective
      antagonist, SR 142801 (0.3 microM), had little effect on responses to SP and NKB.
      6. We conclude that the tachykinin NK(1) receptor mediates contractile effects of
      SP, NKA and NKB and [Sar(9)Met(O(2))(11)]SP in myometrium from the oestrogen
      primed mouse. The tachykinin NK(2) receptor may also participate in the responses
      to NKA and NKB.

PMID- 12466235
TI  - L-arginyl-3,4-spermidine is neuroprotective in several in vitro models of
      neurodegeneration and in vivo ischaemia without suppressing synaptic
      transmission.
AB  - 1. Stroke is the third most common cause of death in the world, and there is a
      clear need to develop new therapeutics for the stroke victim. To address this
      need, we generated a combinatorial library of polyamine compounds based on sFTX
      3.3 toxin from which L-Arginyl-3,4-Spermidine (L-Arg-3,4) emerged as a lead
      neuroprotective compound. In the present study, we have extended earlier results
      to examine the compound's neuroprotective actions in greater detail. 2. In an in
      vitro ischaemia model, L-Arg-3,4 significantly reduced CA1 cell death when
      administered prior to induction of 60 min of ischaemia as well as when
      administered immediately after ischaemia. Surprisingly, L-Arg-3,4 continued to
      prevent cell death significantly when administration was delayed for as long as
      60 min after ischaemia. 3. L-Arg-3,4 significantly reduced cell death in
      excitotoxicity models mediated by glutamate, NMDA, AMPA, or kainate. Unlike
      glutamate receptor antagonists, 300 microM L-Arg-3,4 did not suppress synaptic
      transmission as measured by evoked responses in acute hippocampal slices. 4. L
      Arg-3,4 provided significant protection, in vitro, in a superoxide mediated
      injury model and prevented an increase of superoxide production after AMPA or
      NMDA stimulation. It also decreased nitric oxide production after in vitro
      ischaemia and NMDA stimulation, but did so without inhibiting nitric oxide
      synthase directly. 5. Furthermore, L-Arg-3,4 was significantly neuroprotective in
      an in vivo model of global forebrain ischaemia, without any apparent neurological
      side-effects. 6. Taken together, these results demonstrate that L-Arg-3,4 is
      protective in several models of neurodegeneration and may have potential as a new
      therapeutic compound for the treatment of stroke, trauma, and other
      neurodegenerative diseases.

PMID- 12466236
TI  - Effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels:
      stereoselective bupivacaine block.
AB  - 1 Levobupivacaine and ropivacaine are the pure S(-) enantiomers of N-butyl- and N
      propyl-2',6'-pipecoloxylidide, developed as less cardiotoxic alternatives to
      bupivacaine. In the present study, we have analysed the effects of
      levobupivacaine, ropivacaine and bupivacaine on HERG channels stably expressed in
      CHO cells. 2 The three drugs blocked HERG channels in a concentration-, time- and
      state-dependent manner. Block measured at the end of 5 s pulses to -10 mV induced
      by 20 microM bupivacaine (52.7+/-2.0%, n=15) and ropivacaine (55.5+/-2.7%, n=13)
      was similar (P>0.05) and both lower than that induced by levobupivacaine (67.5+/
      4.2%, n=11) (P<0.05). 3 Dextrobupivacaine (20 microM) was less potent (47.2+/
      5.2%, n=10) than levobupivacaine (P<0.05), indicating stereoselective HERG
      channel block. 4. Block induced by the three local anaesthetics exhibited a steep
      voltage dependence in the range of channel activation. In all cases, block
      measured at the maximum peak current at a test potential of 0 mV after promoting
      recovery from inactivation (I-->O) was lower than that observed at the end of 5-s
      pulses (I+O). 5. Levobupivacaine, ropivacaine and bupivacaine accelerated HERG
      inactivation kinetics, slowed the recovery from inactivation and shifted the
      inactivation curve towards more negative membrane potentials. The three local
      anaesthetics induced a rapid time-dependent decline after using a protocol that
      quickly activates HERG channels. 6. All these results suggest that: (1) these
      drugs bind to the open and the inactivated states of HERG channels, (2) they
      stabilize HERG channels in the inactivated state, and (3) block induced by
      bupivacaine enantiomers is stereoselective.

PMID- 12466237
TI  - The use of Tris-lipidation to modify drug cytotoxicity in multidrug resistant
      cells expressing P-glycoprotein or MRP1.
AB  - 1. Increasing the lipophilicity is a strategy often used to improve a compound's
      cellular uptake and retention but this may also convert it into a substrate for
      an ATP-dependent transporter such as P-glycoprotein or the multidrug resistance
      associated protein (MRP1), which are involved in cellular efflux of drugs. Tris
      Lipidation of compounds is a convenient way of modifying drug lipophilicity and
      generating an array of derivatives with diverse properties. 2. To determine the
      effect of Tris-Lipidation on a drug's cytoxicity in multidrug resistant cells,
      various glycyl-Tris-mono- (GTP1), di- (GTP2) and tri-palmitate (GTP3) derivatives
      were prepared of the cancer chemotherapeutic drugs chlorambucil and methotrexate,
      and of the anti-HIV drug AZT. The cytotoxicity of these derivatives and their
      parent compounds was determined in the CEM/VLB(100) cells with increased P
      glycoprotein expression, the CEM/E1000 cells that overexpress MRP1 and the
      parent, drug-sensitive CCRF-CEM cells. 3. Increasing the lipophilicity of AZT
      increased its cytotoxicity in the sensitive CCRF-CEM parental cell line while
      decreased cytotoxicity was observed for the methotrexate derivatives. For the
      chlorambucil derivatives, both increased (GTP1) and decreased (GTP2) cytotoxicity
      occurred in the CCRF-CEM cells. With the exception of AZT-GTP1, all GTP1 and GTP2
      derivatives of chlorambucil, methotrexate and AZT had decreased cytotoxicity in
      the P-glycoprotein-expressing CEM/VLB(100) cells while chlorambucil-GTP1,
      methotrexate-GTP2 and methotrexate-GTP3 were the only compounds with decreased
      cytotoxicity in the MRP1-overexpressing CEM/E1000 cells. 4. The number of
      palmitate residues, the position of derivatisation and the type of linkage all
      may affect the P-glycoprotein and MRP1 substrate properties. 5. Tris-Lipidation
      may therefore provide a useful way of manipulating the pharmacokinetic properties
      of drugs.

PMID- 12466238
TI  - The antimigraine 5-HT 1B/1D receptor agonists, sumatriptan, zolmitriptan and
      dihydroergotamine, attenuate pain-related behaviour in a rat model of trigeminal
      neuropathic pain.
AB  - 1. Peripheral lesion to the trigeminal nerve may induce severe pain states.
      Several lines of evidence have suggested that the antimigraine effect of the
      triptans with 5-HT(1B/1D) receptor agonist properties may result from inhibition
      of nociceptive transmission in the spinal nucleus of the trigeminal nerve by
      these drugs. On this basis, we have assessed the potential antinociceptive
      effects of sumatriptan and zolmitriptan, compared to dihydroergotamine (DHE), in
      a rat model of trigeminal neuropathic pain. 2. Chronic constriction injury was
      produced by two loose ligatures of the infraorbital nerve on the right side.
      Responsiveness to von Frey filament stimulation of the vibrissal pad was used to
      evaluate allodynia. 3. Two weeks after ligatures, rats with a chronic
      constriction of the right infraorbital nerve displayed bilateral mechanical hyper
      responsiveness to von Frey filament stimulation of the vibrissal pad with a mean
      threshold of 0.38+/-0.04 g on the injured side and of 0.43+/-0.04 g on the
      contralateral (left) side (versus > or =12.5 g on both sides in the same rats
      prior to nerve constriction injury). 4. Sumatriptan at a clinically relevant dose
      (100 microg kg(-1), s.c.) led to a significant reduction of the mechanical
      allodynia-like behaviour on both the injured and the contralateral sides (peak
      effects 6.3+/-1.1 g and 4.4+/-0.7 g, respectively). A more pronounced effect was
      obtained with zolmitriptan (100 microg kg(-1), s.c.) (peak-effects: 7.4+/-0.9 g
      and 3.2+/-1.3 g) whereas DHE (50-100 microg kg(-1), i.v.) was less active (peak
      effect approximately 1.5 g). 5. Subcutaneous pretreatment with the 5-HT(1B/1D)
      receptor antagonist, GR 127935 (3 mg kg(-1)), prevented the anti-allodynia-like
      effects of triptans and DHE. Pretreatment with the 5-HT(1A) receptor antagonist,
      WAY 100635 (2 mg kg(-1), s.c.), did not alter the effect of triptans but
      significantly enhanced that of DHE (peak effect 4.3+/-0.5 g). 6. In a rat model
      of peripheral neuropathic pain, which consisted of a unilateral loose
      constriction of the sciatic nerve, neither sumatriptan (50-300 microg kg(-1)) nor
      zolmitriptan (50-300 microg kg(-1)) modified the thresholds for paw withdrawal
      and vocalization in response to noxious mechanical stimulation. 7. These results
      support the rationale for exploring the clinical efficacy of brain penetrant 5
      HT(1B/1D) receptor agonists as analgesics to reduce certain types of trigeminal
      neuropathic pain in humans.

PMID- 12466239
TI  - Modulation of the release of endogenous adenosine by cannabinoids in the
      myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum.
AB  - 1. Interactions between the cannabinoid system and the adenosine system were
      investigated in the myenteric plexus-longitudinal muscle (MPLM) of the guinea-pig
      ileum. 2. Electrically-evoked contractions of the MPLM were inhibited in a
      concentration dependent manner by exogenous adenosine and the adenosine receptor
      agonist 2-chloroadenosine. These inhibitory effects were reversed by the
      selective A(1) receptor antagonist DPCPX (20 nM). 3. Preincubation of the MPLM
      with the cannabinoid receptor agonist CP55,940 (1 nM) or the endogenous
      cannabinoid ligand anandamide caused a significant leftward shift in the
      concentration-effect curves to adenosine and 2-chloroadenosine. 4. Electrically
      evoked contractions of the MPLM were inhibited in a concentration dependent
      manner by the adenosine uptake inhibitor dipyridamole. This inhibition was
      reversed by DPCPX (20 nM). 5. Pretreatment with CP55,940 (1 nM) or anandamide (10
      microM) significantly reduced the inhibition produced by dipyridamole, an effect
      which was completely reversed by the selective CB(1) receptor ligand SR141716
      (100 nM). 6. Electrically evoked adenosine release, measured in real time by
      means of adenosine-specific biosensors, was inhibited by CP55,940 (10 nM). This
      inhibition was blocked when CP55,940 was applied in the presence of SR141716 (100
      nM). 7. These results confirm the presence of presynaptic CB(1) and A(1)
      receptors in the guinea-pig MPLM, and suggest that CB(1) receptor stimulation
      reduces electrically-evoked adenosine release. Overall the data raise the
      possibility that the cannabinoid system plays a role in the modulation of
      adenosine transmission in the MPLM.

PMID- 12466240
TI  - Oxidative and non-oxidative mechanisms of neuronal cell death and apoptosis by L
      3,4-dihydroxyphenylalanine (L-DOPA) and dopamine.
AB  - 1. The present study was designed to evaluate the nature of intervening agents in
      L-DOPA- and dopamine-induced neurotoxicity in Neuro-2A cells. 2. In the absence
      of cells and in conditions of light protection, at 37 degrees C, L-DOPA or
      dopamine (1 mM) in culture medium degraded spontaneously in a time-dependent
      manner, this being prevented by ascorbic acid (200 microM) and other
      antioxidants, namely glutathione (1 mM), N-acetyl-L-cysteine (1 mM), sodium
      metabisulphite (200 microM), but not N-ter-butyl-alpha-phenylnitrone (1 mM) and
      deferoxamine (100 microM). 3. The viability of Neuro-2A cells declined following
      treatment with L-DOPA or dopamine in a concentration- and time-dependent manner.
      The decrease in cell viability by L-DOPA (10+/-4% of control) or dopamine (15+/
      4% of control) was markedly attenuated by antioxidants (ascorbic acid,
      glutathione, N-acetyl-L-cysteine and sodium metabisulphite). Autoxidation of L
      DOPA or dopamine was accompanied by the formation of H(2)O(2) in a time-dependent
      manner, this being completely prevented by ascorbic acid at 24 h or markedly
      reduced at 48 h. 4. Protective effects of 100 U ml(-1) catalase (40+/-1% of
      control) against L-DOPA-induced cell death were lower than those conferred by 200
      microM ascorbic acid (70+/-3% of control). Catalase-induced protection (59+/-5%
      of control) against dopamine-induced cell death was similar to that conferred by
      200 microM ascorbic acid (57+/-4% of control). L-DOPA-induced neuronal cell death
      was also accompanied by increases in caspase-3 activity, this being insensitive
      to ascorbic acid. Dopamine-induced increase in caspase-3 activity occurred only
      when autoxidation of the amine was prevented by ascorbic acid. 5. It is suggested
      that in addition to generation of H(2)O(2) and quinone formation, L-DOPA- and
      dopamine-induced cell death may result from induction of apoptosis, as evidenced
      by increases in caspase-3 activity. Dopamine per se induces apoptosis by a
      mechanism independent of oxidative stress, as evidenced by the fact that
      increases in caspase-3 activity occurred only when autoxidation of the amine was
      prevented.

PMID- 12466241
TI  - The effects of the cyclosporin A, a P-glycoprotein inhibitor, on the
      pharmacokinetics of baicalein in the rat: a microdialysis study.
AB  - 1. Baicalein is a bioactive flavonoid isolated from the root of Scutellaria
      baicalensis Georgi, a medicinal herb that has been used since ancient times to
      treat bacterial infections. As little is known concerning its pharmacokinetics,
      this study focussed on its pharmacokinetics as well as the possible roles of the
      multidrug transporter P-glycoprotein on its distribution and disposition. 2.
      Three microdialysis probes were simultaneously inserted into the jugular vein,
      the hippocampus and the bile duct of male Sprague-Dawley rats for sampling in
      biological fluids following the administration of baicalein (10, 30 and 60 mg kg(
      1)) through the femoral vein. The P-glycoprotein inhibitor cyclosporin A was used
      to help delineate its roles. 3. The study design consisted of two groups of six
      rats in parallel: control rats which received baicalein alone and the cyclosporin
      A treated-group in which the rats were injected cyclosporin A, a P-glycoprotein
      inhibitor, 10 min prior to baicalein administration. 4. Cyclosporin A treatment
      resulted in a significant increase in elimination half-life, mean residence time
      and area under the concentration versus time curve (AUC) of unbound baicalein in
      the brain. However, AUC in the bile was decreased. 5. The decline of baicalein in
      the hippocampus, blood and bile suggested that there was rapid exchange and
      equilibration between the peripheral compartment and the central nervous system.
      In addition, the results indicated that baicalein was able to penetrate the blood
      brain barrier as well as undergoing hepatobiliary excretion. 6. Although no
      direct transport studies were undertaken and multiple factors may affect BBB
      penetration and hepatobiliary excretion, strong association of the involvement of
      P-glycoprotein in these processes is indicated.

PMID- 12466242
TI  - Excitatory motor innervation in the canine rectoanal region: role of changing
      receptor populations.
AB  - 1. Motor innervation in the canine rectoanal region was examined in isolated
      strips of the circular muscle layer. Contractile responses to electrical field
      stimulation began at lower frequencies and were more persistent in the internal
      anal sphincter (IAS) than in the rectum. 2. Motor innervation to the IAS was
      almost exclusively sympathetic, since it was blocked by guanethidine (Guan 3
      microM) while the response in the proximal rectum was approximately 50%
      muscarinic, and sensitive to the M(3) selective antagonist 4-diphenylacetoxy-N
      methylpiperidine (4-DAMP, 0.1 microM) and 50% tachykinergic, and sensitive to the
      neurokinin 2 (NK(2)) receptor antagonist GR 94800 (1 microM). From IAS to rectum
      there was a gradual shift in the relative contribution of intrinsic and extrinsic
      neural innervation. 3. Responses to exogenously applied transmitters exhibited a
      similar pattern to that observed with motor innervation. Norepinephrine (NE) was
      most potent in the IAS and acetylcholine (ACh) and NK-A were most potent in the
      proximal rectum. The responses were inhibited by prazosin, 4-DAMP and GR 94800
      respectively. 4. A gradient in the density of adrenergic alpha(1), muscarinic and
      NK(2) receptors also existed from IAS to rectum as determined by measuring the
      binding of [(3)H]-prazosin, [(3)H]-quinuclidinyl benzilate ([(3)H]-QNB and [(3)H]
      SR-48968 to smooth muscle membranes. 5. In summary, these data suggest that the
      shift in motor innervation in the rectoanal region is achieved in part by changes
      in receptor populations available for activation by sympathetic and enteric motor
      neurons.

PMID- 12466243
TI  - Identification, regulation and role of tissue inhibitor of metalloproteinases-4
      (TIMP-4) in human platelets.
AB  - 1. Matrix metalloproteinase-2 (MMP-2) released during activation of human
      platelets by aggregating agents and cancer cells is known to stimulate platelet
      aggregation. 2. The expression, activity and role of tissue inhibitors of
      metalloproteinases (TIMPs), natural inhibitors of MMPs, in isolated human
      platelets were investigated. 3. Western blot, reverse zymography, immunogold
      electron microscopy, aggregometry (collagen-, thrombin and HT-1080 human
      fibrosarcoma cells-induced aggregation), flow cytometry and the release of (14)C
      serotonin from labelled platelets recruited to the aggregate were used to
      characterize the presence and function of platelet TIMPs. 4. TIMP-4 (23 kDa) has
      been identified as the major MMP inhibitor (12-16 ng per 10(8) platelets) in
      human platelets. Platelets expressed lower (<1 ng per 10(8) platelets) amounts of
      TIMP-1. No other TIMPs were detected using Western blot analysis. 5. TIMP-4 co
      localized with MMP-2 in resting platelets and was released upon platelet
      aggregation induced by collagen and thrombin. 6. Collagen resulted also in the
      release of higher molecular weight (60 kDa) complexes of TIMP-4. 7. The release
      of TIMP-4 was reduced by prostacyclin and S-nitroso-glutathione (GSNO), an NO
      donor. 8. Human recombinant TIMP-4 (rTIMP-4), but not human rTIMP-1, inhibited
      partially both platelet aggregation and recruitment. 9. The recombinant TIMP-4
      potentiated the recruitment inhibitor effects of GSNO. 10. TIMP-4 was not
      released during platelet aggregation induced by HT-1080 cells. 11. Human rTIMP-4
      exerted a biphasic effect on HT-1080 cells-induced aggregation. 12. Thus, TIMP-4
      is the major intraplatelet MMP inhibitor and it is involved in regulation of
      platelet aggregation and recruitment.

PMID- 12466244
TI  - Pharmacological evidence for a novel cysteinyl-leukotriene receptor subtype in
      human pulmonary artery smooth muscle.
AB  - 1. To characterize the cysteinyl-leukotriene receptors (CysLT receptors) in
      isolated human pulmonary arteries, ring preparations were contracted with
      leukotriene C(4) (LTC(4)) and leukotriene D(4) (LTD(4)) in either the absence or
      presence of the selective CysLT(1) receptor antagonists, ICI 198615, MK 571 or
      the dual CysLT(1)/CysLT(2) receptor antagonist, BAY u9773. 2. Since the
      contractions induced by the cysteinyl-leukotrienes (cysLTs) in intact
      preparations failed to attain a plateau response over the concentration range
      studied, the endothelium was removed and the tissue treated continuously with
      indomethacin (Rubbed+INDO). In these latter preparations, the pEC(50) for LTC(4)
      and LTD(4) were not significantly different (7.61+/-0.07, n=20 and 7.96+/-0.09,
      n=22, respectively). However, the LTC(4) and LTD(4) contractions were markedly
      potentiated when compared with data from intact tissues. 3. Leukotriene E(4)
      (LTE(4)) did not contract human isolated pulmonary arterial preparations. In
      addition, treatment of preparations with LTE(4) (1 microM; 30 min) did not modify
      either the LTC(4) or LTD(4) contractions. 4. Treatment of preparations with the S
      conjugated glutathione (S-hexyl-GSH; 100 microM, 30 min), an inhibitor of the
      metabolism of LTC(4) to LTD(4), did not modify LTC(4) contractions. 5. The
      pEC(50) values for LTC(4) were significantly reduced by treatment of the
      preparations with either ICI 198615, MK 571 or BAY u9773 and the pK(B) values
      were: 7.20, 7.02 and 6.26, respectively. In contrast, these antagonists did not
      modify the LTD(4) pEC(50) values. 6. These findings suggest the presence of two
      CysLT receptors on human pulmonary arterial vascular smooth muscle. A CysLT(1)
      receptor with a low affinity for CysLT(1) antagonists and a novel CysLT receptor
      subtype, both responsible for vasoconstriction. Activation of this latter
      receptor by LTC(4) and LTD(4) induced a contractile response which was resistant
      to the selective CysLT(1) antagonists (ICI 198615 and MK 571) as well as the non
      selective (CysLT(1)/CysLT(2)) antagonist, BAY u9773.

PMID- 12466245
TI  - Characterization of a charybdotoxin-sensitive intermediate conductance Ca2+
      activated K+ channel in porcine coronary endothelium: relevance to EDHF.
AB  - 1. This study characterizes the K(+) channel(s) underlying charybdotoxin
      sensitive hyperpolarization of porcine coronary artery endothelium. 2. Two forms
      of current-voltage (I/V) relationship were evident in whole-cell patch-clamp
      recordings of freshly-isolated endothelial cells. In both cell types, iberiotoxin
      (100 nM) inhibited a current active only at potentials over +50 mV. In the
      presence of iberiotoxin, charybdotoxin (100 nM) produced a large inhibition in
      38% of cells and altered the form of the I/V relationship. In the remaining
      cells, charybdotoxin also inhibited a current but did not alter the form. 3.
      Single-channel, outside-out patch recordings revealed a 17.1+/-0.4 pS
      conductance. Pipette solutions containing 100, 250 and 500 nM free Ca(2+)
      demonstrated that the open probability was increased by Ca(2+). This channel was
      blocked by charybdotoxin but not by iberiotoxin or apamin. 4. Hyperpolarizations
      of intact endothelium elicited by substance P (100 nM; 26.1+/-0.7 mV) were
      reduced by apamin (100 nM; 17.0+/-1.8 mV) whereas those to 1-ethyl-2
      benzimidazolinone (1-EBIO, 600 microM, 21.0+/-0.3 mV) were unaffected (21.7+/-0.8
      mV). Substance P, bradykinin (100 nM) and 1-EBIO evoked charybdotoxin-sensitive,
      iberiotoxin-insensitive whole-cell perforated-patch currents. 5 A porcine
      homologue of the intermediate-conductance Ca(2+)-activated K(+) channel (IK1) was
      identified in endothelial cells. 6. In conclusion, porcine coronary artery
      endothelial cells express an intermediate-conductance Ca(2+)-activated K(+)
      channel and the IK1 gene product. This channel is opened by activation of the
      EDHF pathway and likely mediates the charybdotoxin-sensitive component of the
      EDHF response.

PMID- 12466246
TI  - Inhibition of striatal and retinal dopamine release via nociceptin/orphanin FQ
      receptors.
AB  - 1. We determined the effects of nociceptin/orphanin FQ and the NOP receptor
      ligands acetyl-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2) (Ac-RYYRIK-NH(2)) and naloxone
      benzoylhydrazone on transmitter release in vitro. 2. The electrically evoked
      tritium overflow from guinea-pig and mouse striatal slices and guinea-pig retinal
      discs preincubated with [(3)H]-dopamine was inhibited by nociceptin/orphanin FQ
      (pEC(50) 7.9, 7.6 and 8.6; E(max) 30, 50 and 55%). Ac-RYYRIK-NH(2) 0.032 microM
      and naloxone benzoylhydrazone 5 microM antagonized the effect of
      nociceptin/orphanin FQ in striatal slices of the guinea-pig (apparent pA(2) 9.1
      and 6.8) and the mouse (apparent pA(2) 9.2 and 7.5) and strongly attenuated the
      effect of nociceptin/orphanin FQ 0.1 microM in guinea-pig retinal discs. Ac
      RYYRIK-NH(2) 0.032 microM did not affect the evoked overflow by itself whereas
      naloxone benzoylhydrazone 5 microM inhibited it in each tissue. 3. The
      electrically evoked tritium overflow from mouse brain cortex slices preincubated
      with [(3)H]-noradrenaline was inhibited by nociceptin/orphanin FQ (pEC(50) 7.9,
      E(max) 85%), Ac-RYYRIK-NH(2) (pEC(50) 8.3, E(max) 47%) but not affected by
      naloxone benzoylhydrazone 5 microM. Ac-RYYRIK-NH(2) and naloxone benzoylhydrazone
      showed apparent pA(2) values of 8.6 and 6.9. 4. In conclusion, the inhibitory
      effect of nociceptin/orphanin FQ on dopamine release in the striatum and retina
      and on noradrenaline release in the cerebral cortex is mediated via NOP
      receptors. Ac-RYYRIK-NH(2) behaves as an extremely potent NOP receptor antagonist
      in the striatum and retina and as a partial agonist in the cortex.

PMID- 12466247
TI  - 20-Hydroxyeicosatetraenoic acid potentiates stretch-induced contraction of canine
      basilar artery via PKC alpha-mediated inhibition of KCa channel.
AB  - 1. The present study was undertaken to elucidate whether PKCalpha plays a role in
      the mechanism of the stretch-induced contraction potentiated by 20
      hydroxyeicosatetraenoic acid (20-HETE). The effects of 20-HETE on the canine
      basilar artery were compared with those of iberiotoxin, a blocker of large
      conductance Ca(2+)-activated K(+) channels (K(Ca) channels), as this blocker was
      shown earlier to sensitize these arteries to mechanical stretch. 2. Slow stretch
      at rates of 0.1 to 3 mm s(-1) did not produce any contraction in normal
      physiological solution. 3. In the presence of 20-HETE, the slow stretch could
      produce contraction, which was inhibited by nicardipine, a 1,4-dihydropyridine
      Ca(2+) channel blocker, and gadolinium, a blocker of stretch-activated cation
      channels. 4. 20-HETE inhibited whole-cell K(+) current and depolarized the
      membrane by approximately 10 mV. These effects of 20-HETE were similar to those
      of iberiotoxin. 5. Calphostin C, an inhibitor of protein kinase C (PKC),
      inhibited the action of 20-HETE, but not that of iberiotoxin. 6. In response to
      20-HETE PKCalpha isoform was translocated from the cytosol to the membrane
      fraction, which translocation was inhibited by calphostin C. 7. These results
      suggest that 20-HETE induced sensitization of the canine basilar artery to
      stretch was caused by PKCalpha-mediated inhibition of K(Ca) channel activity.

PMID- 12466248
TI  - Presynaptic cross-talk of beta-adrenoreceptor and 5-hydroxytryptamine receptor
      signalling in the modulation of glutamate release from cerebrocortical nerve
      terminals.
AB  - 1. The presynaptic interactions between facilitatory beta-adrenoreceptors and
      inhibitory 5-hydroxytryptamine (5-HT) receptors modulating glutamate release from
      cerebrocortical nerve terminals were examined. 2. 4-aminopyridine (4-AP, 1 mM)
      evoked glutamate release was facilitated by the membrane permeant cyclic-3',5'
      adenosine monophosphate (cAMP) analogue, 8-bromo-cAMP (8-Br-cAMP), used to
      directly activate cAMP-dependent protein kinase (PKA). 3. The beta-adrenoreceptor
      agonist, isoprenaline (ISO), effected a concentration-dependent potentiation of 4
      AP-evoked glutamate release which was abolished by the beta-adrenoreceptor
      antagonist, propranolol, and the PKA inhibitor, Rp-cyclic-3',5'-adenosine
      monophosphothioate (Rp-cAMPS). 4. 5-HT receptor activation by 100 microM 5-HT
      produced an inhibition of 4-AP-evoked glutamate release in nerve terminals. The
      inhibitory effect of 5-HT could be mimicked by the selective 5-HT(1A) receptor
      agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and antagonized by 1-(2
      methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN-190). 5. When 5-HT (or 8-OH
      DPAT) was used in conjunction with ISO or 8-Br-cAMP, the beta-adrenoreceptor- and
      PKA-mediated potentiation of glutamate release was abrogated. 6. The inhibitory
      crosstalk of 5-HT(1A) receptors to beta-adrenoceptor-mediated facilitation of
      glutamate release was abolished in the presence of NAN-190. 7. Examination of
      voltage-dependent Ca(2+) influx revealed that, while ISO and 5-HT alone caused a
      respective potentiation and diminution of the 4-AP-evoked increase in
      [Ca(2+)](c), the co-presence of 5-HT abolished the ISO mediated potentiation of
      Ca(2+) influx. 8. Together, these results suggest that beta-adrenoreceptors and 5
      HT(1A) receptors coexist on the cerebrocortical nerve terminals and that the
      cross-talk between the two receptor signalling pathways occurs at a locus
      downstream from cAMP production, possibly at the level of voltage-dependent
      Ca(2+) influx.

PMID- 12466249
TI  - Hormonal-dependent recruitment of Na+,K+-ATPase to the plasmalemma is mediated by
      PKC beta and modulated by [Na+]i.
AB  - 1. The present study demonstrates that stimulation of hormonal receptors of
      proximal tubule cells with the serotonin-agonist 8-hydroxy-2-(di-n-propylamino)
      tetraline (8-OH-DPAT) induces an augmentation of Na(+),K(+)-ATPase activity that
      results from the recruitment of enzyme molecules to the plasmalemma. 2. Cells
      expressing the rodent wild-type Na(+),K(+)-ATPase alpha-subunit had the same
      basal Na(+),K(+)-ATPase activity as cells expressing the alpha-subunit S11A or
      S18A mutants, but stimulation of Na(+),K(+)-ATPase activity was completely
      abolished in either mutant. 3. 8-OH-DPAT treatment of OK cells led to PKC(beta)
      dependent phosphorylation of the alpha-subunit Ser-11 and Ser-18 residues, and
      determination of enzyme activity with the S11A and S18A mutants indicated that
      both residues are essential for the agonist-dependent stimulation of Na(+),K(+)
      ATPase activity. 4. When cells were treated with both dopamine and 8-OH-DPAT, an
      activation of Na(+),K(+)-ATPase was observed at basal intracellular sodium
      concentration (approximately 9 mM), and this activation was gradually reduced and
      became a significant inhibition as the concentration of intracellular sodium
      gradually increased from 9 to 19 mM. Thus, besides the antagonistic effects of
      dopamine and 8-OH-DPAT, intracellular sodium modulates whether an activation or
      an inhibition of Na(+),K(+)-ATPase is produced.

PMID- 12466250
TI  - Iodinated contrast media induce neutrophil apoptosis through a mitochondrial and
      caspase mediated pathway.
AB  - Iodinated contrast media (ICM) can induce apoptosis (programmed cell death) in
      renal, myocardial and endothelial cells. Following intravascular injection,
      circulating immune cells are exposed to high concentrations of ICM. As
      neutrophils constitutively undergo apoptosis we hypothesized that ICM may
      adversely affect neutrophil survival. Our aim was to investigate the effect of
      ICM on neutrophil apoptosis. Neutrophils were isolated from healthy subjects and
      cultured in vitro with ionic (diatrizoate and ioxaglate) and non-ionic (iohexol
      and iotrolan) ICM. The effect of ICM on neutrophil apoptosis in both unstimulated
      and lipopolysaccharide-stimulated neutrophils was determined by annexin V flow
      cytometry. The influence of physicochemical properties of the different ICM on
      apoptosis of neutrophils was also studied. We further investigated the effects of
      ICM on key intracellular signal pathways, including p38 mitogen-activated protein
      kinase (MAPK) by Western blotting, and mitochondrial depolarization and caspase
      activity by flow cytometry. Isoiodine concentrations (20 mg ml(-1)) of ionic
      (diatrizoate 69.6+/-2.9%; ioxaglate 58.9+/-2.0%) and non-ionic (iohexol 57.3+/
      2.9%; iotrolan 57.1+/-2.6%) ICM significantly induced neutrophil apoptosis over
      control levels (47.7+/-1.4%). The apoptotic effect of ICM was influenced by their
      chemical structure, with ionic ICM having a more significant (p<0.01) apoptotic
      effect than non-ionic ICM (p<0.05). Furthermore, ICM reversed the anti-apoptotic
      effect of lipopolysaccharide (1000 ng ml(-1)) treated neutrophils to control
      levels (23.0+/-3.5% to 61.2+/-5.3%; n=4; p<0.05). These agents induce apoptosis
      through a p38 MAPK independent pathway that results in mitochondrial
      depolarization, and is dependent on caspase activation. As neutrophils play a
      central role in host response to infection and injury, ICM, through induction of
      neutrophil apoptosis, could have a significant deleterious effect on host immune
      defence and resolution of an inflammatory response.

PMID- 12466251
TI  - Renal cortical retention of contrast medium on delayed CT and nephropathy
      following transcatheter arterial chemoembolisation in patients with high serum
      creatinine level.
AB  - The aim of this study was to investigate the prevalence of renal cortical
      retention (RCR) of contrast media seen on delayed CT, and nephropathy following
      transarterial chemoembolisation (TACE) in high-risk patients. The findings of 18
      patients with abnormally high serum creatinine levels who underwent TACE were
      reviewed. Nephropathy was defined as an increase in serum creatinine level of
      more than 44 micromol l(-1), or more than 25%, on day 1, 3, 7 or 14. RCR was
      defined as mild (CT value >50) or severe (CT value >100). RCR was seen in 16
      cases (89%) and in seven cases (39%) of post-TACE nephropathy. Patients without
      severe RCR did not develop nephropathy post-TACE, whereas 50% of those with such
      retention did (p=0.19). Delayed CT appears to have the potential as an early
      detector of nephropathy post-TACE in high-risk patients.

PMID- 12466252
TI  - Shrinkage of the distal renal artery 1 year after stent placement as evidenced
      with serial intravascular ultrasound.
AB  - The objective of this study was to determine the quantitative intravascular
      ultrasound (IVUS) and angiographic changes that occur during 1 year follow-up
      after renal artery stent placement, given that restenosis continues to be a
      limitation of renal artery stent placement. 38 consecutive patients with
      symptomatic renal artery stenosis treated with Palmaz stent placement were
      studied prospectively. IVUS and angiography were performed at the time of stent
      placement and at 1 year follow-up. At follow-up, angiographic restenosis was seen
      in 14% of patients. The lumen area in the stent, seen with IVUS, was
      significantly decreased from 24+/-5.6 mm(2) to 17+/-5.6 mm(2) (p<0.001) solely
      due to plaque accumulation. The distal main renal artery showed a significant
      decrease in lumen area owing to a significant vessel area decrease from 39+/-14.0
      mm(2) to 29+/-9.3 mm(2) (p<0.001) without plaque accumulation. Angiographic
      analysis confirmed this reduction in luminal diameter and showed that the distal
      renal artery diameter at follow-up was significantly smaller than before stent
      placement (86+/-23.0% vs 104+/-23.9% of the contralateral renal artery diameter;
      p=0.003). Besides plaque accumulation in the stent, unexplained shrinkage of the
      distal main renal artery was evidenced with IVUS and angiography 1 year following
      stent placement.

PMID- 12466253
TI  - Colour Doppler and grey scale ultrasound features of HIV-related vascular
      aneurysms.
AB  - Atypical aneurysms of large elastic arteries owing to human immunodeficiency
      virus (HIV) vasculopathy are a well described complication of acquired
      immunodeficiency syndrome (AIDS). However, there are no reports describing the
      ultrasound features of these lesions. We performed a retrospective review of
      ultrasound images of 12 patients presenting with 39 HIV-related aneurysms over a
      2 year period. Of these there were a total of 12 patients with symptomatic
      lesions comprising the superficial femoral artery (n=5), the origin of the
      internal carotid artery (n=3), the popliteal artery (n=2), the common femoral
      artery (n=1) and the common iliac artery (n=1). The remainder were asymptomatic
      and were demonstrated radiologically. The ultrasound features of large
      symptomatic HIV-related femoral and carotid aneurysms were typical of
      pseudoaneurysms with a defect or "blow-out" in the vessel wall and turbulent
      pulsatile flow. Of note was the presence of marked thickening of the vessel
      adjacent to the aneurysm and hyperechoic "spotting" of the arterial wall. These
      ultrasound features described may be unique to HIV vasculopathy.

PMID- 12466254
TI  - Two-view screening and extending the age range: the balance of benefit and risk.
AB  - The UK Breast Screening Programme intends to introduce two-view screening on all
      screening rounds, and also to extend the normal screening age range at its upper
      end from the present 64 years to 70 years. The implications of these changes for
      cancer detection:induction ratios and for benefit/risk ratios are discussed. It
      is shown that both ratios remain much greater than 1.0 at all screening ages.
      This is also true for younger women, subject to provisos regarding starting ages
      for annual screening as described in previous papers. The requirements for
      optimization in a breast screening programme are also discussed. It is suggested
      that benefit (rather than the benefit/risk ratio) should be maximized provided
      that benefit exceeds risk.

PMID- 12466255
TI  - Diagnostic agreement of two calcaneal ultrasound devices: the Sahara bone
      sonometer and the Achilles+.
AB  - Quantitative ultrasound for the assessment of skeletal status is an evolving
      method in the diagnosis of osteoporosis. In this cross-sectional study we
      investigated the diagnostic agreement between the Sahara bone sonometer and the
      Achilles+ with respect to broadband ultrasound attenuation (BUA), speed of sound
      (SOS) and stiffness/quantitative ultrasound index (QUI). 309 healthy females
      without diseases or medications known to influence bone metabolism (with the
      exception of oestrogen) were recruited at two participating centers (Erlangen and
      Berlin). 33% of subjects were taking oestrogens. There was no significant
      difference in BUA, SOS, and stiffness/QUI between oestrogen and non-oestrogen
      takers. In vivo precision (expressed as root mean square coefficient of
      variation) was calculated from two repeat measurements and analyzed in both
      centres. Mean values were 1.57% (BUA Achilles+), 3.64% (BUA Sahara), 0.35% (SOS
      Achilles+), 0.39% (SOS Sahara), 2.22% (stiffness Achilles+) and 3.04% (QUI
      Sahara). Between the two devices we observed a strong correlation for SOS
      (r=0.89, p<0.01) and stiffness/QUI (r=0.83, p<0.01), and a moderate correlation
      for BUA (r=0.68, p<0.01). All parameters were moderately negatively associated
      with age (r=-0.38 to -0.48; p<0.01 for all correlations). Kappa (kappa) scores
      used to report diagnostic agreement were calculated for tertiles and "equivalent
      T-scores". The tertiles divide the cohort on both scanners into the same number
      of subjects above and below a given T-score. Diagnostic agreement using tertiles
      was poor to moderate (kappa< or =0.51). Diagnostic agreement using equivalent T
      score agreement, again, was poor to moderate for BUA but fair to good for SOS and
      stiffness/QUI (0.59< or =kappa< or =0.73). We conclude that diagnostic agreement
      between the two devices is at best comparable to the agreement of a dual X-ray
      absorptiometry measurement using the same densitometer at two different skeletal
      sites. It is therefore insufficient to compare directly two measurements of an
      individual patient on both ultrasound devices. Standardization of quantitative
      ultrasound is very much needed.

PMID- 12466256
TI  - Assessment of tumour response to chemotherapy for metastatic colorectal cancer:
      accuracy of the RECIST criteria.
AB  - Evaluation of tumour size modifications in response to treatment is a critical
      issue in the management of advanced malignancies. In 1981, the World Health
      Organization (WHO) established guidelines for tumour response assessment. These
      WHO1981 criteria were recently simplified in a revised version, named RECIST
      (Response Evaluation Criteria in Solid Tumours), which uses unidimensional
      instead of bidimensional measurements, a reduced number of measured lesions,
      withdrawal of the progression criteria based on isolated increase of a single
      lesion, and different shrinkage threshold for definitions of tumour response and
      progression. In order to validate these new guidelines, we have compared results
      obtained with both classifications in a prospective series of 91 patients
      receiving chemotherapy for metastatic colorectal cancer. Data from iterative
      tomographic measurements were fully recorded and reviewed by an expert panel. The
      overall response and progression rates according to the WHO1981 criteria were 19%
      and 58%, respectively. Using RECIST criteria, 16 patients were reclassified in a
      more favourable subgroup, the overall response rate being 28% and the progression
      rate 45% (non-weighted kappa concordance test 0.72). When isolated increase of a
      single measurable lesion is not taken into account for progression with the
      WHO1981 criteria, only 7 patients were reclassified and the kappa test was
      satisfying, i.e. > or =0.75, for the whole population as well as for each of the
      responding and progressive subgroups. Since it provides concordant results with a
      simplified method, the use of RECIST criteria is recommended for evaluation of
      treatment efficacy in clinical trials and routine practice.

PMID- 12466257
TI  - A study of hypoxic cell radiosensitizer applied to Ehrlich ascite tumour: a
      comparison of FC43 emulsion and pentoxyfilline.
AB  - In this study, we examined the effects of various combinations of treatments
      involving radiation, injections of perfluorochemicals (FC-43 emulsion) and
      injections of pentoxifylline on the growth delay of Ehrlich ascite tumours.
      Ehrlich ascite tumour cells were transplanted into the legs of ddY-strain mice.
      Tumour-bearing mice were divided into seven groups: group 1, no treatment; group
      2, irradiated only; group 3, injected with FC-43 emulsion and kept in a carbogen
      atmosphere; group 4, injected with pentoxifylline and nicotinamide; group 5,
      injected with FC-43 emulsion, kept in a carbogen atmosphere and irradiated; group
      6, injected with pentoxifylline and nicotinamide and irradiated; and group 7,
      injected with FC-43 emulsion, pentoxifylline and nicotinamide, kept in a carbogen
      atmosphere and irradiated. When 20 Gy irradiation was applied, tumour growth
      delay was 11 days in group 2, 20 days in group 5, 22 days in group 6, and 24 days
      in group 7. For a growth delay of 20 days, the dose modifying factor was 1.95+/
      0.04 (standard deviations) in group 5, 1.97+/-0.09 standard deviations in group
      6, and 2.01+/-0.07 standard deviations in group 7. It was concluded that FC-43
      emulsion and pentoxifylline did not have an interactive effect.

PMID- 12466258
TI  - Case report: An unusual arrival of a hydrocoele.
AB  - Acute hydrocoele is a previously unreported complication of herniography that may
      be explained on the basis of inguinal-scrotal embryology.

PMID- 12466259
TI  - Case report: Aneurysmal bone cyst of the ethmoid bone.
AB  - Aneurysmal bone cysts (ABCs) are benign, slow growing expansile lesions usually
      found in long bones or vertebrae. Plain radiography reveals expansion of bone and
      cortical thinning. MRI may assist in diagnosis by virtue of its ability to
      demonstrate blood-fluid levels, which is a characteristic finding in these
      lesions. Very few cases of ABC of the paranasal sinuses have been reported in the
      literature. We present MRI findings of ABC of the ethmoid sinus in a 19-year-old
      male.

PMID- 12466260
TI  - Pictorial review: Colour Doppler ultrasound flow patterns in the portal venous
      system.
AB  - Doppler ultrasound is a well established method for assessment of the portal
      venous system to detect the direction of portal blood flow. It is helpful for non
      invasive diagnosis of intra-abdominal portosystemic shunts, especially in
      patients with cirrhosis. Less attention has been paid to other influences on
      portal venous flow, e.g. tricuspid regurgitation, increased hepatic out-flow
      resistance, respiratory cycle. The aim of this pictorial review is to describe
      the spectrum of physiological and pathological Doppler ultrasound flow patterns
      in the portal venous system.

PMID- 12466261
TI  - A lump in the head: giant osteoma.

PMID- 12466262
TI  - Signal recognition particle (SRP)-mediated targeting and Sec-dependent
      translocation of an extracellular Escherichia coli protein.
AB  - Hemoglobin protease (Hbp) is a hemoglobin-degrading protein that is secreted by a
      human pathogenic Escherichia coli strain via the autotransporter mechanism.
      Little is known about the earliest steps in autotransporter secretion, i.e. the
      targeting to and translocation across the inner membrane. Here, we present
      evidence that Hbp interacts with the signal recognition particle (SRP) and the
      Sec-translocon early during biogenesis. Furthermore, Hbp requires a functional
      SRP targeting pathway and Sec-translocon for optimal translocation across the
      inner membrane. SecB is not required for targeting of Hbp but can compensate to
      some extent for the lack of SRP. Hbp is synthesized with an unusually long signal
      peptide that is remarkably conserved among a subset of autotransporters. We
      propose that these autotransporters preferentially use the co-translational
      SRP/Sec route to avoid adverse effects of the exposure of their mature domains in
      the cytoplasm.

PMID- 12466263
TI  - Calcium modulates promoter occupancy by the Entamoeba histolytica Ca2+-binding
      transcription factor URE3-BP.
AB  - The Entamoeba histolytica upstream regulatory element 3-binding protein (URE3-BP)
      binds to the URE3 sequence of the Gal/GalNAc-inhibitable lectin hgl5 and
      ferredoxin 1 (fdx) gene promoters. This binding can be inhibited in vitro by
      addition of calcium. Two EF-hand motifs, which are associated with the ability to
      bind calcium, are present in the amino acid sequence of URE3-BP. Mutation of the
      second EF-hand motif in URE3-BP resulted in the loss of calcium inhibition of DNA
      binding as monitored by electrophoretic mobility shift assay. Chromatin
      immunoprecipitation assays revealed that URE3-BP was physically bound to the hgl5
      and fdx promoters in vivo. Parasite intracellular calcium concentrations were
      altered by changes in extracellular calcium. Promoter occupancy was lost when
      intracellular calcium levels were increased by coordinate increases in
      extracellular calcium. Increased intracellular calcium also resulted in decreased
      levels of URE3-BP mRNA. Together these results demonstrate that changes in
      extracellular calcium result in changes in URE3-BP mRNA and in the ability of
      URE3-BP to bind to URE3-containing promoters. Modulation of URE3-BP by calcium
      may represent an important mechanism of control of gene expression in E.
      histolytica.

PMID- 12466264
TI  - Platelet-activating factor acetylhydrolase, and not paraoxonase-1, is the
      oxidized phospholipid hydrolase of high density lipoprotein particles.
AB  - Paraoxonase-1 (PON1), an high density lipoprotein (HDL)-associated
      organophosphate triesterase, suppresses atherosclerosis in an unknown way.
      Purified PON1 protects lipoprotein particles from oxidative modification and
      hydrolyzes pro-atherogenic oxidized phospholipids and the inflammatory mediator
      platelet-activating factor (PAF). We find human PON1 acted as a phospholipase
      A(2) but not as a phospholipase C or D through cleavage of phosphodiester bonds
      as expected. PON1 requires divalent cations, but EDTA did not block the
      phospholipase A(2) activity of PON1. In contrast, a serine esterase inhibitor
      abolished phospholipase activity even though PON1 has no active-site serine
      residues. PAF acetylhydrolase, an oxidized phospholipid phospholipase A(2), is a
      serine esterase associated with specific HDL particles. Western blotting did not
      reveal detectable amounts of PAF acetylhydrolase in PON1 preparations, although
      very low amounts of PAF acetylhydrolase might still account for PON1
      phospholipase A(2) activity. We revised the standard PON1 purification by first
      depleting HDL of PAF acetylhydrolase to find PON1 purified in this way no longer
      hydrolyzed oxidized phospholipids or PAF. Serum from a donor with an inactivating
      mutation in the PAF acetylhydrolase gene did not hydrolyze oxidized phospholipids
      or PAF, yet displayed full paraoxonase activity. We conclude that PAF
      acetylhydrolase is the sole phospholipase A(2) of HDL and that PON1 has no
      phospholipase activity toward PAF or pro-atherogenic oxidized phospholipids.

PMID- 12466265
TI  - Isolation and functional characterization of N-methyltransferases that catalyze
      betaine synthesis from glycine in a halotolerant photosynthetic organism
      Aphanothece halophytica.
AB  - Glycine betaine (N,N,N-trimethylglycine) is an important osmoprotectant and is
      synthesized in response to abiotic stresses. Although almost all known
      biosynthetic pathways of betaine are two-step oxidation of choline, here we
      isolated two N-methyltransferase genes from a halotolerant cyanobacterium
      Aphanothece halophytica. One of gene products (ORF1) catalyzed the methylation
      reactions of glycine and sarcosine with S-adenosylmethionine acting as the methyl
      donor. The other one (ORF2) specifically catalyzed the methylation of
      dimethylglycine to betaine. Both enzymes are active as monomers. Betaine, a final
      product, did not show the feed back inhibition for the methyltransferases even in
      the presence of 2 m. A reaction product, S-adenosyl homocysteine, inhibited the
      methylation reactions with relatively low affinities. The co-expressing of two
      enzymes in Escherichia coli increased the betaine level and enhanced the growth
      rates. Immunoblot analysis revealed that the accumulation levels of both enzymes
      in A. halophytica cells increased with increasing the salinity. These results
      indicate that A. halophytica cells synthesize betaine from glycine by a three
      step methylation. The changes of amino acids Arg-169 to Lys or Glu in ORF1 and
      Pro-171 to Gln and/or Met-172 to Arg in ORF2 significantly decreased V(max) and
      increased K(m) for methyl acceptors (glycine, sarcosine, and dimethylglycine) but
      modestly affected K(m) for S-adenosylmethionine, indicating the importance of
      these amino acids for the binding of methyl acceptors. Physiological and
      functional properties of methyltransferases were discussed.

PMID- 12466266
TI  - Regulation of estrogen receptor alpha-mediated transcription by a direct
      interaction with protein phosphatase 2A.
AB  - Estrogen receptor alpha (ERalpha) mediates the effects of estrogen by altering
      gene expression following hormone binding. It has recently been shown that kinase
      mediated phosphorylation of ERalpha also transcriptionally activates the receptor
      in the absence of estrogen. We now report that ERalpha-dependent gene expression
      also is regulated by protein phosphatase 2A (PP2A). ERalpha co-immunoprecipitates
      with enzymatically active PP2A. ERalpha binds directly to the catalytic subunit
      of PP2A, which dephosphorylates serine 118 of the receptor. Amino acids 176-182
      in the A/B domain of ERalpha are required for the interaction between PP2A and
      the receptor. Phosphatase inhibition disrupts the ERalpha-PP2A complex and
      induces formation of an ERalpha-activated mitogen-activated protein kinase
      complex, phosphorylation of ERalpha on serine 118, and transcriptional
      activation. These findings demonstrate that estrogen receptors exist in complexes
      with phosphatases as well as kinases. We propose a new model of ligand
      independent activation of estrogen receptors in which the level of
      phosphorylation of ERalpha, and hence its transcriptional activation, is
      determined by the net effect of these counterregulatory pathways.

PMID- 12466267
TI  - Unusual thermal and conformational properties of the rhodopsin congenital night
      blindness mutant Thr-94 --> Ile.
AB  - Naturally occurring point mutations in the opsin gene cause the retinal diseases
      retinitis pigmentosa and congenital night blindness. Although these diseases
      involve similar mutations in very close locations in rhodopsin, their progression
      is very different, with retinitis pigmentosa being severe and causing retinal
      degeneration. We report on the expression and characterization of the recently
      found T94I mutation associated with congenital night blindness, in the second
      transmembrane helix or rhodopsin, and mutations at the same site. T94I mutant
      rhodopsin folded properly and was able to bind 11-cis-retinal to form
      chromophore, but it showed a blue-shifted visible band at 478 nm and reduced
      molar extinction coefficient. Furthermore, T94I showed dramatically reduced
      thermal stability, extremely long lived metarhodopsin II intermediate, and highly
      increased reactivity toward hydroxylamine in the dark, when compared with wild
      type rhodopsin. The results are consistent with the location of Thr-94 in close
      proximity to Glu-113 counterion in the vicinity of the Schiff base linkage and
      suggest a role for this residue in maintaining the correct dark inactive
      conformation of the receptor. The reported results, together with previously
      published data on the other two known congenital night blindness mutants, suggest
      that the molecular mechanism underlying this disease may not be structural
      misfolding, as proposed for retinitis pigmentosa mutants, but abnormal
      functioning of the receptor by decreased thermal stability and/or constitutive
      activity.

PMID- 12466268
TI  - Identification of a new murine tumor necrosis factor receptor locus that contains
      two novel murine receptors for tumor necrosis factor-related apoptosis-inducing
      ligand (TRAIL).
AB  - Tumor necrosis factor (TNF) ligand and receptor superfamily members play critical
      roles in diverse developmental and pathological settings. In search for novel TNF
      superfamily members, we identified a murine chromosomal locus that contains three
      new TNF receptor-related genes. Sequence alignments suggest that the ligand
      binding regions of these murine TNF receptor homologues, mTNFRH1, -2 and -3, are
      most homologous to those of the tumor necrosis factor-related apoptosis-inducing
      ligand (TRAIL) receptors. By using a number of in vitro ligand-receptor binding
      assays, we demonstrate that mTNFRH1 and -2, but not mTNFRH3, bind murine TRAIL,
      suggesting that they are indeed TRAIL receptors. This notion is further supported
      by our demonstration that both mTNFRH1:Fc and mTNFRH2:Fc fusion proteins
      inhibited mTRAIL-induced apoptosis of Jurkat cells. Unlike the only other known
      murine TRAIL receptor mTRAILR2, however, neither mTNFRH2 nor mTNFRH3 has a
      cytoplasmic region containing the well characterized death domain motif. Coupled
      with our observation that overexpression of mTNFRH1 and -2 in 293T cells neither
      induces apoptosis nor triggers NFkappaB activation, we propose that the mTnfrh1
      and mTnfrh2 genes encode the first described murine decoy receptors for TRAIL,
      and we renamed them mDcTrailr1 and -r2, respectively. Interestingly, the overall
      sequence structures of mDcTRAILR1 and -R2 are quite distinct from those of the
      known human decoy TRAIL receptors, suggesting that the presence of TRAIL decoy
      receptors represents a more recent evolutionary event.

PMID- 12466269
TI  - Solution structure of heavy meromyosin by small-angle scattering.
AB  - Elucidation of x-ray crystal structures for the S1 subfragment of myosin afforded
      atomic resolution of the nucleotide and actin binding sites of the enzyme. The
      structures have led to more detailed hypotheses regarding the mechanisms by which
      force generation is coupled to ATP hydrolysis. However, the three-dimensional
      structure of double-headed myosin consisting of two S1 subfragments has not yet
      been solved. Therefore, to investigate the overall shape and relative
      orientations of the two heads of myosin, we performed small-angle x-ray and
      neutron scattering measurements of heavy meromyosin containing all three light
      chains (LC(1-3)) in solution. The resulting small-angle scattering intensity
      profiles were best fit by models of the heavy meromyosin head-tail junction in
      which the angular separation between heads was less than 180 degrees. The S1
      heads of the best fit models are not related by an axis of symmetry, and one of
      the two S1 heads is bent back along the rod. These results provide new
      information on the structure of the head-tail junction of myosin and indicate
      that combining scattering measurements with high resolution structural modeling
      is a feasible approach for investigating myosin head-head interactions in
      solution.

PMID- 12466270
TI  - Characterization of the motor activity of mammalian myosin VIIA.
AB  - Myosin VIIA was cloned from rat kidney, and the construct (M7IQ5) containing the
      motor domain, IQ domain, and the coiled-coil domain as well as the full-length
      myosin VIIA (M7full) was expressed. The M7IQ5 contained five calmodulins. Based
      upon native gel electrophoresis and gel filtration, it was found that M7IQ5 was
      single-headed, whereas M7full was two-headed, suggesting that the tail domain
      contributes to form the two-headed structure. M7IQ5 had Mg(2+)-ATPase activity
      that was markedly activated by actin with K(actin) of 33 microm and V(max) of
      0.53 s(-1) head(-1). Myosin VIIA required an extremely high ATP concentration for
      ATPase activity, ATP-induced dissociation from actin, and in vitro actin
      translocating activity. ADP markedly inhibited the actin-activated ATPase
      activity. ADP also significantly inhibited the ATP-induced dissociation of myosin
      VIIA from actin. Consistently, ADP decreased K(actin) of the actin-activated
      ATPase. ADP decreased the actin gliding velocity, although ADP did not stop the
      actin gliding even at high concentration. These results suggest that myosin VIIA
      has slow ATP binding or low affinity for ATP and relatively high affinity for
      ADP. The directionality of myosin VIIA was determined by using the polarity
      marked dual fluorescence-labeled actin filaments. It was found that myosin VIIA
      is a plus-directed motor.

PMID- 12466271
TI  - A second class of peroxidases linked to the trypanothione metabolism.
AB  - Trypanosoma brucei, the causative agent of African sleeping sickness, has three
      nearly identical genes encoding cysteine homologues of classical selenocysteine
      containing glutathione peroxidases. The proteins are expressed in the mammalian
      and insect stages of the parasite. One of the genes, which contains a
      mitochondrial as well as a glycosomal targeting signal has been overexpressed.
      The recombinant T. brucei peroxidase has a high preference for the
      trypanothione/tryparedoxin couple as electron donor for the reduction of
      different hydroperoxides but accepts also T. brucei thioredoxin. The apparent
      rate constants k(2)' for the regeneration of the reduced enzyme are 2 x 10(5) m(
      1) s(-1) with tryparedoxin and 5 x 10(3) m(-1) s(-1) with thioredoxin. No
      saturation kinetics was observed and the rate-limiting step of the overall
      reaction is reduction of the hydroperoxide. With glutathione, the peroxidase has
      marginal activity and reduction of the enzymes becomes limiting with a k(2)'
      value of 3 m (-1) s(-1). The T. brucei peroxidase, in contrast to the related
      Trypanosoma cruzi enzyme, also accepts hydrogen peroxide as substrate. The
      catalytic efficiency of the peroxidase studied here is comparable with that of
      the peroxiredoxin-like tryparedoxin peroxidases, which shows that trypanosomes
      possess two distinct peroxidase systems both dependent on the unique dithiol
      trypanothione.

PMID- 12466272
TI  - Regulation of nuclear receptor transcriptional activity by a novel DEAD box RNA
      helicase (DP97).
AB  - We have identified a novel DEAD box RNA helicase (97 kDa, DP97) from a breast
      cancer cDNA library that interacts in a hormone-dependent manner with nuclear
      receptors and represses their transcriptional activity. DP97 has RNA-dependent
      ATPase activity, and mapping studies localize the interacting regions of DP97 and
      nuclear receptors to the C-terminal region of DP97 and the hormone
      binding/activation function-2 region of estrogen receptors (ER), as well as
      several other nuclear receptors. Repression by DP97 maps to a small region (amino
      acids 589-631) that has homology to a repression domain in the corepressor
      protein NCoR2/SMRTe. This region of DP97 is necessary and sufficient for its
      intrinsic repression activity. The N-terminal helicase region of DP97 is,
      however, dispensable for its transcriptional repressor activity. The knockdown of
      endogenous cellular DP97 by antisense DP97 or RNA interference (siRNA for DP97)
      results in significant enhancement of the expression of estradiol-ER-stimulated
      genes and attenuation of the repression of genes inhibited by the estradiol-ER.
      This implies that endogenous DP97 normally dampens stimulation and intensifies
      repression of estradiol-ER-regulated genes. Our findings add to the growing
      evidence that RNA helicases can associate with nuclear receptors and function as
      coregulators to modulate receptor transcriptional activity.

PMID- 12466273
TI  - Platelet factor 4 enhances the binding of oxidized low-density lipoprotein to
      vascular wall cells.
AB  - Accumulation of low-density lipoprotein (LDL)-derived cholesterol by macrophages
      in vessel walls is a pathogenomic feature of atherosclerotic lesions. Platelets
      contribute to lipid uptake by macrophages through mechanisms that are only
      partially understood. We have previously shown that platelet factor 4 (PF4)
      inhibits the binding and degradation of LDL through its receptor, a process that
      could promote the formation of oxidized LDL (ox-LDL). We have now characterized
      the effect of PF4 on the binding of ox-LDL to vascular cells and macrophages and
      on the accumulation of cholesterol esters. PF4 bound to ox-LDL directly and also
      increased ox-LDL binding to vascular cells and macrophages. PF4 did not stimulate
      ox-LDL binding to cells that do not synthesize glycosaminoglycans or after
      enzymatic cleavage of cell surface heparan and chondroitin sulfates. The effect
      of PF4 on binding ox-LDL was dependent on specific lysine residues in its C
      terminus. Addition of PF4 also caused an approximately 10-fold increase in the
      amount of ox-LDL esterified by macrophages. Furthermore, PF4 and ox-LDL co
      localize in atherosclerotic lesion, especially in macrophage-derived foam cells.
      These observations offer a potential mechanism by which platelet activation at
      sites of vascular injury may promote the accumulation of deleterious lipoproteins
      and offer a new focus for pharmacological intervention in the development of
      atherosclerosis.

PMID- 12466274
TI  - Bimodal protection of DNA by Mycobacterium smegmatis DNA-binding protein from
      stationary phase cells.
AB  - Some members of the DNA-binding protein from stationary phase cells (Dps) family
      of proteins have been shown to play an important role in protecting
      microorganisms from oxidative or nutritional stress. Dps homologs have been
      identified in various bacteria such as Escherichia coli, Bacillus subtilis, and
      Listeria innocua. Recently we have reported the presence of a Dps homolog, Ms
      Dps, in Mycobacterium smegmatis. Ms-Dps was found to have a nonspecific DNA
      binding ability. Here we have detected two stable oligomeric forms of Ms-Dps in
      vitro, a trimeric and a dodecameric form. Interestingly, the conversion of Dps
      from a trimeric to a dodecameric form takes place upon incubation at 37 degrees C
      for 12 h. These two oligomeric forms differ in their DNA binding properties. The
      dodecameric form is capable of DNA binding and forming large crystalline arrays
      with DNA, whereas the trimeric form cannot do so. However, even in the absence of
      DNA binding, the trimeric form has the capacity to protect the DNA against
      Fenton's-mediated damage. The protection is afforded by the ferroxidase activity
      of the trimer. However, the trimeric form cannot protect DNA from DNaseI attack,
      for which a direct physical shielding of DNA by the dodecamer is required. Thus
      we suggest that Ms-Dps provides a bimodal protection of DNA by its two different
      oligomeric forms.

PMID- 12466275
TI  - Isolation and characterization of T4 bacteriophage gp17 terminase, a large
      subunit multimer with enhanced ATPase activity.
AB  - Phage T4 terminase is a two-subunit enzyme that binds to the prohead portal
      protein and cuts and packages a headful of concatameric DNA. To characterize the
      T4 terminase large subunit, gp17 (70 kDa), gene 17 was cloned and expressed as a
      chitin-binding fusion protein. Following cleavage and release of gp17 from
      chitin, two additional column steps completed purification. The purification
      yielded (i) homogeneous soluble gp17 highly active in in vitro DNA packaging (
      approximately 10% efficiency, >10(8) phage/ml of extract); (ii) gp17 lacking
      endonuclease and contaminating protease activities; and (iii) a DNA-independent
      ATPase activity stimulated >100-fold by the terminase small subunit, gp16 (18
      kDa), and modestly by portal gp20 and single-stranded binding protein gp32
      multimers. Analyses revealed a preparation of highly active and slightly active
      gp17 forms, and the latter could be removed by immunoprecipitation using
      antiserum raised against a denatured form of the gp17 protein, leaving a
      terminase with the increased specific activity (approximately 400 ATPs/gp17
      monomer/min) required for DNA packaging. Analysis of gp17 complexes separated
      from gp16 on glycerol gradients showed that a prolonged enhanced ATPase activity
      persisted after exposure to gp16, suggesting that constant interaction of the two
      proteins may not be required during packaging.

PMID- 12466276
TI  - Sorting of encystation-specific cysteine protease to lysosome-like peripheral
      vacuoles in Giardia lamblia requires a conserved tyrosine-based motif.
AB  - Encystation-specific cysteine protease (ESCP) was the first membrane-associated
      protein described to be part of the lysosome-like peripheral vacuoles in the
      intestinal parasite Giardia lamblia. ESCP is homologous to cathepsin C enzymes of
      higher eukaryotes, but is distinguished from other lysosomal cysteine proteases
      because it possesses a transmembrane domain and a short cytoplasmic tail.
      Tyrosine-based motifs within tails of membrane proteins are known to participate
      in endosomal/lysosomal protein sorting in higher eukaryotes. In this study, we
      show that a YRPI motif within the ESCP cytoplasmic tail is necessary and
      sufficient to mediate ESCP sorting to peripheral vacuoles in Giardia. Deletion
      and point mutation analysis demonstrated that the tyrosine residue is critical
      for ESCP sorting, whereas amino acids located at the Y+1 (Arg), Y+2 (Pro), and
      Y+3 (Ile) positions show minimal effect. Loss of the motif resulted in surface
      localization, whereas addition of the motif to a variant-specific surface protein
      resulted in lysosomal localization. Although Giardia trophozoites lack a
      morphologically discernible Golgi apparatus, our findings indicate that this
      parasite directs proteins to the lysosomes using a conserved sorting signal
      similar to that used by yeast and mammalian cells. Because Giardia is one of the
      earliest branching protist, these results demonstrate that sorting motifs for
      specific protein traffic developed very early during eukaryotic evolution.

PMID- 12466277
TI  - Salt dependence of DNA binding by Thermus aquaticus and Escherichia coli DNA
      polymerases.
AB  - DNA binding properties of the Type 1 DNA polymerases from Thermus aquaticus (Taq,
      Klentaq) and Escherichia coli (Klenow) have been examined as a function of [KCl]
      and [MgCl(2)]. Full-length Taq and its Klentaq "large fragment" behave similarly
      in all assays. The two different species of polymerases bind DNA with sub
      micromolar affinities in very different salt concentration ranges. Consequently,
      at similar [KCl] the binding of Klenow is approximately 3 kcal/mol (150x) tighter
      than that of Taq/Klentaq to the same DNA. Linkage analysis reveals a net release
      of 2-3 ions upon DNA binding of Taq/Klentaq and 4-5 ions upon binding of Klenow.
      DNA binding of Taq at a higher temperature (60 degrees C) slightly decreases the
      ion release. Linkage analysis of binding versus [MgCl(2)] reports the ultimate
      release of approximately 1 Mg(2+) ion upon complex formation. However, the
      MgCl(2) dependence for Klenow, but not Klentaq, shows two distinct phases. In 10
      mm EDTA, both polymerase species still bind DNA, but their binding affinity is
      significantly diminished, Klenow more than Klentaq. In summary, the two
      polymerase species, when binding to identical DNA, differ substantially in their
      sensitivity to the salt concentration range, bind with very different affinities
      when compared under similar conditions, release different numbers of ions upon
      binding, and differ in their interactions with divalent cations.

PMID- 12466278
TI  - Effects of endogenous DNA base lesions on transcription elongation by mammalian
      RNA polymerase II. Implications for transcription-coupled DNA repair and
      transcriptional mutagenesis.
AB  - The blockage of transcription elongation by RNA polymerase II (pol II) is thought
      to be a trigger for transcription-coupled repair in the pathway of nucleotide
      excision repair. Purified pol II and oligo(dC)-tailed templates containing a
      single non-bulky DNA lesion on the transcribed strand such as an
      apurinic/apyrimidinic (AP) site, uracil, or 8-oxoguanine (8-oxoG) were used for
      transcription elongation assays. In this system pol II could bypass both the AP
      site and uracil without pausing and insert cytosine opposite the AP site and
      either guanine or adenine opposite to uracil. Thus, the AP site on the DNA
      templates could lead to correct transcription only if depurination at guanine
      occurred, whereas uracil generated either the correct transcriptional product or
      an incorrect one with a G:C to A:T transition. In the case of 8-oxoG, pol II
      stalled at the lesion, but sometimes bypassed it and inserted a cytosine residue
      or the incorrect adenine residue leading to a G:C to T:A transversion. These
      findings indicate that 8-oxoG lesions caused a blockage of transcription
      elongation and/or the misincorporation of a ribonucleotide by pol II, implying
      the initiation of transcription-coupled repair of 8-oxoG and/or transcriptional
      mutagenesis.

PMID- 12466279
TI  - Selective strand annealing and selective strand exchange promoted by the N
      terminal domain of hepatitis delta antigen.
AB  - We have previously shown that the N-terminal domain of hepatitis delta virus
      (NdAg) has an RNA chaperone activity in vitro (Huang, Z. S., and Wu, H. N. (1998)
      J. Biol. Chem. 273, 26455-26461). Here we investigate further the basis of the
      stimulatory effect of NdAg on RNA structural rearrangement: mainly the formation
      and breakage of base pairs. Duplex dissociation, strand annealing, and exchange
      of complementary RNA oligonucleotides; the hybridization of yeast U4 and U6 small
      nuclear RNAs and of hammerhead ribozymes and cognate substrates; and the cis
      cleavage reaction of hepatitis delta ribozymes were used to determine directly
      the role of NdAg in RNA-mediated processes. The results showed that NdAg could
      accelerate the annealing of complementary sequences in a selective fashion and
      promote strand exchange for the formation of a more extended duplex. These
      activities would prohibit NdAg from modifying the structure of a stable RNA, but
      allow NdAg to facilitate a trans-acting hammerhead ribozyme to find a more
      extensively matched target in cognate substrate. These and other results suggest
      that hepatitis delta antigen may have a biological role as an RNA chaperone,
      modulating the folding of viral RNA for replication and transcription.

PMID- 12466280
TI  - The cytotoxic activity of ribosome-inactivating protein saporin-6 is attributed
      to its rRNA N-glycosidase and internucleosomal DNA fragmentation activities.
AB  - Saporin-6 produced by the plant Saponaria officinalis belongs to the family of
      single chain ribosome-inactivating proteins. It potently inhibits protein
      synthesis in eukaryotic cells, by cleaving the N-glycosidic bond of a specific
      adenine in 28 S rRNA, which results in the cell death. Saporin-6 has also been
      shown to be active on DNA and induces apoptosis. In the current study, we have
      investigated the roles of rRNA depurination and the activity of saporin-6 on
      genomic DNA in its cytotoxic activity. The role of putative active site residues,
      Tyr(72), Tyr(120), Glu(176), Arg(179), and Trp(208), and two invariant residues,
      Tyr(16) and Arg(24), proposed to be important for structural stability of saporin
      6, has been investigated in its catalytic and cytotoxic activity. These residues
      were mutated to alanine to generate seven mutants, Y16A, R24A, Y72A, Y120A,
      E176A, R179A, and W208A. We show that for the RNA N-glycosidase activity of
      saporin-6, residues Tyr(16), Tyr(72), and Arg(179) are absolutely critical;
      Tyr(120) and Glu(176) can be partially dispensed with, whereas Trp(208) and
      Arg(24) do not appear to be involved in this activity. The residues Tyr(72),
      Tyr(120), Glu(176), Arg(179), and Trp(208) were found to be essential for the
      genomic DNA fragmentation activity, whereas residues Tyr(16) and Arg(24) do not
      appear to be required for the DNA fragmentation. The study shows that saporin-6
      possesses two catalytic activities, namely RNA N-glycosidase and genomic DNA
      fragmentation activity, and for its complete cytotoxic activity both activities
      are required.

PMID- 12466281
TI  - Identification of the LIM protein FHL2 as a coactivator of beta-catenin.
AB  - Beta-catenin is a key mediator of the Wnt pathway, which plays a critical role in
      embryogenesis and oncogenesis. As a transcriptional activator, beta-catenin binds
      the transcription factors, T-cell factor and lymphoid enhancer factor, and
      regulates gene expression in response to Wnt signaling. Abnormal activation of
      beta-catenin has been linked to various types of cancer. In a yeast two-hybrid
      screen, we identified the four and a half of LIM-only protein 2 (FHL2) as a novel
      beta-catenin-interacting protein. Here we show specific interaction of FHL2 with
      beta-catenin, which requires the intact structure of FHL2 and armadillo repeats 1
      9 of beta-catenin. FHL2 cooperated with beta-catenin to activate T-cell
      factor/lymphoid enhancer factor-dependent transcription from a synthetic reporter
      and the cyclin D1 and interleukin-8 promoters in kidney and colon cell lines. In
      contrast, coexpression of beta-catenin and FHL2 had no synergistic effect on
      androgen receptor-mediated transcription, whereas each of these two coactivators
      independently stimulated AR transcriptional activity. Thus, the ability of FHL2
      to stimulate the trans-activating function of beta-catenin might be dependent on
      the promoter context. The detection of increased FHL2 expression in
      hepatoblastoma, a liver tumor harboring frequent beta-catenin mutations, suggests
      that FHL2 might enforce beta-catenin transactivation activity in cancer cells.
      These findings reveal a new function of the LIM coactivator FHL2 in
      transcriptional activation of Wnt-responsive genes.

PMID- 12466282
TI  - Regulation of phosducin-like protein by casein kinase 2 and N-terminal splicing.
AB  - Phosducin-like protein (PhLP) is a member of the phosducin family of G-protein
      betagamma-regulators and exists in two splice variants. The long isoform PhLP(L)
      and the short isoform PhLP(S) differ by the presence or absence of an 83-amino
      acid N terminus. In isolated biochemical assay systems, PhLP(L) is the more
      potent Gbetagamma-inhibitor, whereas the functional role of PhLP(S) is still
      unclear. We now report that in intact HEK 293 cells, PhLP(S) inhibited Gbetagamma
      induced inositol phosphate generation with approximately 20-fold greater potency
      than PhLP(L). Radiolabeling of transfected HEK 293 cells with [(32)P] revealed
      that PhLP(L) is constitutively phosphorylated, whereas PhLP(S) is not. Because
      PhLP(L) has several consensus sites for the constitutively active kinase casein
      kinase 2 (CK2) in its N terminus, we tested the phosphorylation of the
      recombinant proteins by either HEK cell cytosol in the presence or absence of
      kinase inhibitors or by purified CK2. PhLP(L) was a good CK2 substrate, whereas
      PhLP(S) and phosducin were not. Progressive truncation and serine/threonine to
      alanine mutations of the PhLP(L) N terminus identified a serine/threonine cluster
      (Ser-18/Thr-19/Ser-20) within a small N-terminal region of PhLP(L) (amino acids 5
      28) as the site in which PhLP(L) function was modified in HEK 293 cells. In
      native tissue, PhLP(L) also seems to be regulated by phosphorylation because
      phosphorylated and non-phosphorylated forms of PhLP(L) were detected in mouse
      brain and adrenal gland. Moreover, the alternatively spliced isoform PhLP(S) was
      also found in adrenal tissue. Therefore, the physiological control of G-protein
      regulation by PhLP seems to involve phosphorylation by CK2 and alternative
      splicing of the regulator.

PMID- 12466283
TI  - The core domain of chemokines binds CCR5 extracellular domains while their amino
      terminus interacts with the transmembrane helix bundle.
AB  - CCR5 is a functional receptor for various inflammatory CC-chemokines, including
      macrophage inflammatory protein (MIP)-1alpha and RANTES (regulated on activation
      normal T cell expressed and secreted), and is the main coreceptor of human
      immunodeficiency viruses. The second extracellular loop and amino-terminal domain
      of CCR5 are critical for chemokine binding, whereas the transmembrane helix
      bundle is involved in receptor activation. Chemokine domains and residues
      important for CCR5 binding and/or activation have also been identified. However,
      the precise way by which chemokines interact with and activate CCR5 is presently
      unknown. In this study, we have compared the binding and functional properties of
      chemokine variants onto wild-type CCR5 and CCR5 point mutants. Several mutations
      in CCR5 extracellular domains (E172A, R168A, K191A, and D276A) strongly affected
      MIP-1alpha binding but had little effect on RANTES binding. However, a MIP/RANTES
      chimera, containing the MIP-1alpha N terminus and the RANTES core, bound to these
      mutants with an affinity similar to that of RANTES. Several CCR5 mutants
      affecting transmembrane helices 2 and 3 (L104F, L104F/F109H/F112Y, F85L/L104F)
      reduced the potency of MIP-1alpha by 10-100 fold with little effect on activation
      by RANTES. However, the MIP/RANTES chimera activated these mutants with a potency
      similar to that of MIP-1alpha. In contrast, LD78beta, a natural MIP-1alpha
      variant, which, like RANTES, contains a proline at position 2, activated these
      mutants as well as RANTES. Altogether, these results suggest that the core
      domains of MIP-1alpha and RANTES bind distinct residues in CCR5 extracellular
      domains, whereas the N terminus of chemokines mediates receptor activation by
      interacting with the transmembrane helix bundle.

PMID- 12466284
TI  - Interrogating a high-density SNP map for signatures of natural selection.
AB  - Identifying genomic regions that have been targets of natural selection remains
      one of the most important and challenging areas of research in genetics. To this
      end, we report an analysis of 26,530 single nucleotide polymorphisms (SNPs) with
      allele frequencies that were determined in three populations. Specifically, we
      calculated a measure of genetic differentiation, F(ST), for each locus and
      examined its distribution at the level of the genome, the chromosome, and
      individual genes. Through a variety of analyses, we have found statistically
      significant evidence supporting the hypothesis that selection has influenced
      extant patterns of human genetic variation. Importantly, by contrasting the F(ST)
      of individual SNPs to the empirical genome-wide distribution of F(ST), our
      results are not confounded by tenuous assumptions of population demographic
      history. Furthermore, we have identified 174 candidate genes with distribution of
      genetic variation that indicates that they have been targets of selection. Our
      work provides a first generation natural selection map of the human genome and
      provides compelling evidence that selection has shaped extant patterns of human
      genomic variation.

PMID- 12466285
TI  - Evidence for a fast, intrachromosomal conversion mechanism from mapping of
      nucleotide variants within a homogeneous alpha-satellite DNA array.
AB  - Assuming that patterns of sequence variants within highly homogeneous centromeric
      tandem repeat arrays can tell us which molecular turnover mechanisms are
      presently at work, we analyzed the alpha-satellite tandem repeat array DXZ1 of
      one human X chromosome. Here we present accurate snapshots from this dark matter
      of the genome. We demonstrate stable and representative cloning of the array in a
      P1 artificial chromosome (PAC) library, use samples of higher-order repeats
      subcloned from five unmapped PACs (120-160 kb) to identify common variants, and
      show that such variants are presently in a fixed transition state. To
      characterize patterns of variant spread throughout homogeneous array segments, we
      use a novel partial restriction and pulsed-field gel electrophoresis mapping
      approach. We find an older large-scale (35-50 kb) duplication event supporting
      the evolutionarily important unequal crossing-over hypothesis, but generally find
      independent variant occurrence and a paucity of potential de novo mutations
      within segments of highest homogeneity (99.1%-99.3%). Within such segments, a
      highly nonrandom variant clustering within adjacent higher-order repeats was
      found in the absence of haplotypic repeats. Such variant clusters are hardly
      explained by interchromosomal, fixation-driving mechanisms and likely reflect a
      fast, localized, intrachromosomal sequence conversion mechanism.

PMID- 12466286
TI  - Distribution and characterization of regulatory elements in the human genome.
AB  - The regulation of transcription and subsequent gene splicing are crucial to
      correct gene expression. Although a number of regulatory sequences involved in
      both processes are known, it is not clear how general their functions are in the
      genomic context, nor how the regulatory regions are distributed throughout the
      genome. Here we study the distribution of known mutagenic elements within human
      introns and exons to deduce the properties of regions essential for splicing and
      transcription. We show that intronic splicing regulators are generally found
      close to the splice sites, but may be found as far as 200 nucleotides away from
      the splice junctions. Similarly, sequences important for splicing may be located
      as far as 125 nucleotides away from the junctions, within exons. We characterize
      several types of simple repetitive sequences and low-complexity regions that are
      overrepresented close to both intron ends and are likely to play important roles
      in the splicing process. We show that the first introns within most genes play a
      particularly important regulatory role that is most likely, however, to be
      involved in transcription control. We also study the distribution of two known
      regulatory motifs, the GGG trinucleotide and the CpG dinucleotide, and deduce
      their respective importance to splicing and transcription regulation.

PMID- 12466287
TI  - Selecting for functional alternative splices in ESTs.
AB  - The expressed sequence tag (EST) collection in dbEST provides an extensive
      resource for detecting alternative splicing on a genomic scale. Using genomically
      aligned ESTs, a computational tool (TAP) was used to identify alternative splice
      patterns for 6400 known human genes from the RefSeq database. With sufficient EST
      coverage, one or more alternatively spliced forms could be detected for nearly
      all genes examined. To identify high (>95%) confidence observations of
      alternative splicing, splice variants were clustered on the basis of having
      mutually exclusive structures, and sample statistics were then applied. Through
      this selection, alternative splices expected at a frequency of >5% within their
      respective clusters were seen for only 17%-28% of genes. Although intron
      retention events (potentially unspliced messages) had been seen for 36% of the
      genes overall, the same statistical selection yielded reliable cases of intron
      retention for <5% of genes. For high-confidence alternative splices in the human
      ESTs, we also noted significantly higher rates both of cross-species conservation
      in mouse ESTs and of validation in the GenBank mRNA collection. We suggest
      quantitative analytical approaches such as these can aid in selecting useful
      targets for further experimental characterization and in so doing may help
      elucidate the mechanisms and biological implications of alternative splicing.

PMID- 12466288
TI  - Haplotype and linkage disequilibrium architecture for human cancer-associated
      genes.
AB  - To facilitate association-based linkage studies we have studied the linkage
      disequilibrium (LD) and haplotype architecture around five genes of interest for
      cancer risk: ATM, BRCA1, BRCA2, RAD51, and TP53. Single nucleotide polymorphisms
      (SNPs) were identified and used to construct haplotypes that span 93-200 kb per
      locus with an average SNP density of 12 kb. These markers were genotyped in four
      ethnically defined populations that contained 48 each of African Americans, Asian
      Americans, Hispanic Americans, and European Americans. Haplotypes were inferred
      using an expectation maximization (EM) algorithm, and the data were analyzed
      using D', R(2), Fisher's exact P-values, and the four-gamete test for
      recombination. LD levels varied widely between loci from continuously high LD
      across 200 kb to a virtual absence of LD across a similar length of genome. LD
      structure also varied at each gene and between populations studied. This
      variation indicates that the success of linkage-based studies will require a
      precise description of LD at each locus and in each population to be studied. One
      striking consistency between genes was that at each locus a modest number of
      haplotypes present in each population accounted for a high fraction of the total
      number of chromosomes. We conclude that each locus has its own genomic profile
      with regard to LD, and despite this there is the widespread trend of relatively
      low haplotype diversity. As a result, a low marker density should be adequate to
      identify haplotypes that represent the common variation at a locus, thereby
      decreasing costs and increasing efficacy of association studies.

PMID- 12466289
TI  - Retroposed new genes out of the X in Drosophila.
AB  - New genes that originated by various molecular mechanisms are an essential
      component in understanding the evolution of genetic systems. We investigated the
      pattern of origin of the genes created by retroposition in Drosophila. We
      surveyed the whole Drosophila melanogaster genome for such new retrogenes and
      experimentally analyzed their functionality and evolutionary process. These
      retrogenes, functional as revealed by the analysis of expression, substitution,
      and population genetics, show a surprisingly asymmetric pattern in their origin.
      There is a significant excess of retrogenes that originate from the X chromosome
      and retropose to autosomes; new genes retroposed from autosomes are scarce.
      Further, we found that most of these X-derived autosomal retrogenes had evolved a
      testis expression pattern. These observations may be explained by natural
      selection favoring those new retrogenes that moved to autosomes and avoided the
      spermatogenesis X inactivation, and suggest the important role of genome position
      for the origin of new genes.

PMID- 12466290
TI  - Domain regulation of imprinting cluster in Kip2/Lit1 subdomain on mouse
      chromosome 7F4/F5: large-scale DNA methylation analysis reveals that DMR-Lit1 is
      a putative imprinting control region.
AB  - Mouse chromosome 7F4/F5, where the imprinting domain is located, is syntenic to
      human 11p15.5, the locus for Beckwith-Wiedemann syndrome. The domain is thought
      to consist of the two subdomains Kip2 (p57(kip2))/Lit1 and Igf2/H19. Because DNA
      methylation is believed to be a key factor in genomic imprinting, we performed
      large-scale DNA methylation analysis to identify the cis-element crucial for the
      regulation of the Kip2/Lit1 subdomain. Ten CpG islands (CGIs) were found, and
      these were located at the promoter sites, upstream of genes, and within
      intergenic regions. Bisulphite sequencing revealed that CGIs 4, 5, 8, and 10 were
      differentially methylated regions (DMRs). CGIs 4, 5, and 10 were methylated
      paternally in somatic tissues but not in germ cells. CGI8 was methylated in
      oocyte and maternally in somatic tissues during development. Parental-specific
      DNase I hypersensitive sites (HSSs) were found near CGI8. These data indicate
      that CGI8, called DMR-Lit1, is not only the region for gametic methylation but
      might also be the imprinting control region (ICR) of the subdomain.

PMID- 12466291
TI  - Diversity in nucleotide binding site-leucine-rich repeat genes in cereals.
AB  - The diversity of the largest group of plant disease resistance genes, the
      nucleotide binding site-leucine-rich repeat (NBS-LRR) genes, was examined in
      cereals following polymerase chain reaction (PCR) cloning and database mining.
      NBS-LRR genes in rice are a large and diverse class with more than 600 genes, at
      least three to four times the complement of Arabidopsis. Most occur in small
      families containing one or a few cross-hybridizing members. Unlike in Arabidopsis
      and other dicots, the class of NBS-LRR genes coding for a Toll and mammalian
      interleukin-1 receptor (TIR) domain were not amplified during the evolution of
      the cereals. Genes coding for TIR domains are present in the rice genome, but
      have diverged from the NBS-LRR genes. Most cereal genes are similar in structure
      to the members of the non-TIR class of dicots, although many do not code for a
      coiled-coil domain in their amino termini. One unique class of cereal genes, with
      ~50 members, codes for proteins similar to the N-termini and NBS domains of
      resistance genes but does not code for LRR domains. The resistance gene
      repertoire of grasses has changed from that of dicots in their independent
      evolution since the two groups diverged. It is not clear whether this reflects a
      difference in downstream defense signaling pathways.

PMID- 12466292
TI  - A nonsense mutation in the FMO3 gene underlies fishy off-flavor in cow's milk.
AB  - Fish-odor syndrome or Trimethylaminuria (OMIM #602079) in humans is an inborn
      error of metabolism associated with a characteristic fishy body odor due to
      elevated levels of trimethylamine (TMA) in body fluids. It is caused by loss-of
      function mutations in FMO3 encoding flavin-containing mono-oxygenase 3. A fishy
      off-flavor is occasionally observed in cow's milk and it has been established
      recently that this phenotype is due to elevated TMA levels. Here, we report that
      fishy off-flavor in cow's milk is caused by a nonsense mutation (R238X) in the
      bovine FMO3 ortholog. RT-PCR analysis indicated that the mutant transcript is
      present in a very low amount. The mutation was found to be surprisingly common (q
      = 0.155) in one breed of cattle.

PMID- 12466293
TI  - Extreme pathway lengths and reaction participation in genome-scale metabolic
      networks.
AB  - Extreme pathways are a unique and minimal set of vectors that completely
      characterize the steady-state capabilities of genome-scale metabolic networks. A
      framework is provided to mathematically characterize extreme pathway length and
      to study how individual reactions participate in the extreme pathway structure of
      a network. The length of an extreme pathway is the number of reactions that
      comprise it. Reaction participation is the percentage of extreme pathways that
      utilize a given reaction. These properties were computed for the production of
      individual amino acids and protein production in Helicobacter pylori and
      individual amino acid production in Haemophilus influenzae. Reaction
      participation classifies the reactions into groups that are always, sometimes, or
      never utilized for the production of a target product. The utilized reactions can
      be further grouped into correlated subsets of reactions, some of which are non
      obvious, and which may, in turn, suggest regulatory structure. The length of the
      extreme pathways did not correlate with product yield or chemical complexity. The
      distributions of extreme pathway lengths in H. pylori were also very different
      from those in H. influenzae, showing a distinct systemic difference between the
      two organisms, despite overall similar metabolic networks. Reaction participation
      and extreme pathway lengths thus serve to elucidate systemic biological features.

PMID- 12466294
TI  - Large functional range of steady-state levels of nuclear and mitochondrial
      transcripts coding for the subunits of the human mitochondrial OXPHOS system.
AB  - We have measured, by reverse transcription and real-time quantitative PCR, the
      steady-state levels of the mitochondrial and nuclear transcripts encoding several
      subunits of the human oxidative phosphorylation (OXPHOS) system, in different
      normal tissues (muscle, liver, trachea, and kidney) and in cultured cells (normal
      fibroblasts, 143B osteosarcoma cells, 143B206 rho(0) cells). Five mitochondrial
      transcripts and nine nuclear transcripts were assessed. The measured amounts of
      these OXPHOS transcripts in muscle samples corroborated data obtained by others
      using the serial analysis of gene expression (SAGE) method to appraise gene
      expression in the same type of tissue. Steady-state levels for all the
      transcripts were found to range over more than two orders of magnitude. Most of
      the time, the mitochondrial H-strand transcripts were present at higher levels
      than the nuclear transcripts. The mitochondrial L-strand transcript ND6 was
      usually present at a low level. Cultured 143B cells contained significantly
      reduced amounts of mitochondrial transcripts in comparison with the tissue
      samples. In 143B206 rho(0) cells, fully depleted of mitochondrial DNA, the levels
      of nuclear OXPHOS transcripts were not modified in comparison with the parental
      cells. This observation indicated that nuclear transcription is not coordinated
      with mitochondrial transcription. We also observed that in the different tissues
      and cells, there is a transcriptional coregulation of all the investigated
      nuclear genes. Nuclear OXPHOS gene expression seems to be finely regulated.

PMID- 12466295
TI  - The human Hox-bearing chromosome regions did arise by block or chromosome (or
      even genome) duplications.
AB  - Many chromosome regions in the human genome exist in four similar copies,
      suggesting that the entire genome was duplicated twice in early vertebrate
      evolution, a concept called the 2R hypothesis. Forty-two gene families on the
      four Hox-bearing chromosomes were recently analyzed by others, and 32 of these
      were reported to have evolutionary histories incompatible with duplications
      concomitant with the Hox clusters, thereby contradicting the 2R hypothesis.
      However, we show here that nine of the families have probably been translocated
      to the Hox-bearing chromosomes more recently, and that three of these belong to
      other chromosome quartets where they actually support the 2R hypothesis. We
      consider 13 families too complex to shed light on the chromosome duplication
      hypothesis. Among the remaining 20 families, 14 display phylogenies that support
      or are at least consistent with the Hox-cluster duplications. Only six families
      seem to have other phylogenies, but these trees are highly uncertain due to
      shortage of sequence information. We conclude that all relevant and analyzable
      families support or are consistent with block/chromosome duplications and that
      none clearly contradicts the 2R hypothesis.

PMID- 12466296
TI  - Gene expression profiling of embryo-derived stem cells reveals candidate genes
      associated with pluripotency and lineage specificity.
AB  - Large-scale gene expression profiling was performed on embryo-derived stem cell
      lines to identify molecular signatures of pluripotency and lineage specificity.
      Analysis of pluripotent embryonic stem (ES) cells, extraembryonic-restricted
      trophoblast stem (TS) cells, and terminally-differentiated mouse embryo
      fibroblast (MEF) cells identified expression profiles unique to each cell type,
      as well as genes common only to ES and TS cells. Whereas most of the MEF-specific
      genes had been characterized previously, the majority (67%) of the ES-specific
      genes were novel and did not include known differentiated cell markers.
      Comparison with microarray data from embryonic material demonstrated that ES
      specific genes were underrepresented in all stages sampled, whereas TS-specific
      genes included known placental markers. Investigation of four novel TS-specific
      genes showed trophoblast-restricted expression in cell lines and in vivo, whereas
      one uncharacterized ES-specific gene, Esg-1, was found to be exclusively
      associated with pluripotency. We suggest that pluripotency requires a set of
      genes not expressed in other cell types, whereas lineage-restricted stem cells,
      like TS cells, express genes predictive of their differentiated lineage.

PMID- 12466297
TI  - Rapid mapping of zebrafish mutations with SNPs and oligonucleotide microarrays.
AB  - Large-scale genetic screens in zebrafish have identified thousands of mutations
      in hundreds of essential genes. The genetic mapping of these mutations is
      necessary to link DNA sequences to the gene functions defined by mutant
      phenotypes. Here, we report two advances that will accelerate the mapping of
      zebrafish mutations: (1) The construction of a first generation single nucleotide
      polymorphism (SNP) map of the zebrafish genome comprising 2035 SNPs and 178 small
      insertions/deletions, and (2) the development of a method for mapping mutations
      in which hundreds of SNPs can be scored in parallel with an oligonucleotide
      microarray. We have demonstrated the utility of the microarray technique in
      crosses with haploid and diploid embryos by mapping two known mutations to their
      previously identified locations. We have also used this approach to localize four
      previously unmapped mutations. We expect that mapping with SNPs and
      oligonucleotide microarrays will accelerate the molecular analysis of zebrafish
      mutations.

PMID- 12466298
TI  - A novel method for SNP detection using a new duplex-specific nuclease from crab
      hepatopancreas.
AB  - We have characterized a novel nuclease from the Kamchatka crab, designated duplex
      specific nuclease (DSN). DSN displays a strong preference for cleaving double
      stranded DNA and DNA in DNA-RNA hybrid duplexes, compared to single-stranded DNA.
      Moreover, the cleavage rate of short, perfectly matched DNA duplexes by this
      enzyme is essentially higher than that for nonperfectly matched duplexes of the
      same length. Thus, DSN differentiates between one-nucleotide variations in DNA.
      We developed a novel assay for single nucleotide polymorphism (SNP) detection
      based on this unique property, termed "duplex-specific nuclease preference"
      (DSNP). In this innovative assay, the DNA region containing the SNP site is
      amplified and the PCR product mixed with signal probes (FRET-labeled short
      sequence-specific oligonucleotides) and DSN. During incubation, only perfectly
      matched duplexes between the DNA template and signal probe are cleaved by DSN to
      generate sequence-specific fluorescence. The use of FRET-labeled signal probes
      coupled with the specificity of DSN presents a simple and efficient method for
      detecting SNPs. We have employed the DSNP assay for the typing of SNPs in
      methyltetrahydrofolate reductase, prothrombin and p53 genes on homozygous and
      heterozygous genomic DNA.

PMID- 12466299
TI  - Generalized gap model for bacterial artificial chromosome clone fingerprint
      mapping and shotgun sequencing.
AB  - We develop an extension to the Lander-Waterman theory for characterizing gaps in
      bacterial artificial chromosome fingerprint mapping and shotgun sequencing
      projects. It supports a larger set of descriptive statistics and is applicable to
      a wider range of project parameters. We show that previous assertions regarding
      inconsistency of the Lander-Waterman theory at higher coverages are incorrect and
      that another well-known but ostensibly different model is in fact the same. The
      apparent paradox of infinite island lengths is resolved. Several applications are
      shown, including evolution of the probability density function, calculation of
      closure probabilities, and development of a probabilistic method for computing
      stopping points in bacterial artificial chromosome shotgun sequencing.

PMID- 12466300
TI  - A scalable high-throughput chemical synthesizer.
AB  - A machine that employs a novel reagent delivery technique for biomolecular
      synthesis has been developed. This machine separates the addressing of individual
      synthesis sites from the actual process of reagent delivery by using masks placed
      over the sites. Because of this separation, this machine is both cost-effective
      and scalable, and thus the time required to synthesize 384 or 1536 unique
      biomolecules is very nearly the same. Importantly, the mask design allows scaling
      of the number of synthesis sites without the addition of new valving. Physical
      and biological comparisons between DNA made on a commercially available
      synthesizer and this unit show that it produces DNA of similar quality.

PMID- 12466301
TI  - A strategy to retrieve the whole set of protein modules in microbial proteomes.
AB  - Protein homology is often limited to long structural segments that we have
      previously called modules. We describe here a suite of programs used to catalog
      the whole set of modules present in microbial proteomes. First, the Darwin AllAll
      program detects homologous segments using thresholds for evolutionary distance
      and alignment length, and another program classifies these modules. After
      assembling these homologous modules in families, we further group families which
      are related by a chain of neighboring unrelated homologous modules. With the
      automatic analysis of these groups of families sharing homologous modules in
      independent multimodular proteins, one can split into their component parts many
      fused modules and/or deduce by logic more distant modules. All detected and
      inferred modules are reassembled in refined families. These two last steps are
      made by a unique program. Eventually, the soundness of the data obtained by this
      experimental approach is checked using independent tests. To illustrate this
      modular approach, we compared four proteobacterial proteomes (Campylobacter
      jejuni, Escherichia coli, Haemophilus influenzae, and Helicobacter pylori). It
      appears that this method might retrieve from present-day proteins many of the
      modules which can help to trace back ancient events of gene duplication and/or
      fusion.

PMID- 12466302
TI  - A unified framework for mapping quantitative trait loci in bivalent tetraploids
      using single-dose restriction fragments: a case study from alfalfa.
AB  - The development of statistical methodologies for quantitative trait locus (QTL)
      mapping in polyploids is complicated by complex polysomic inheritance. In this
      article, we propose a statistical method for mapping QTL in tetraploids
      undergoing bivalent formation at meiosis by using single-dose restriction
      fragments. Our method is based on a unified framework, one that uses chromosome
      bivalent pairing configuration and gametic recombination to discern different
      mechanisms of gamete formation. Our bivalent polyploid model can not only provide
      a simultaneous estimation of the linkage and chromosome pairing configuration-a
      cytological parameter of evolutionary and systematic interest-but also enhances
      the precision of estimating QTL effects and position by correctly characterizing
      gene segregation during polyploid meiosis. By using our method and a linkage map
      constructed in a previous study, we successfully identify several QTL affecting
      winter hardiness in bivalent tetraploid alfalfa. Moreover, our results reveal
      significant preferential chromosome pairing at meiosis in an F1 hybrid
      population, which indicates the importance of reassessing the traditional view of
      random chromosome segregation in alfalfa.

PMID- 12466303
TI  - Extension and integration of the gene ontology (GO): combining GO vocabularies
      with external vocabularies.
AB  - Structured vocabulary development enhances the management of information in
      biological databases. As information grows, handling the complexity of
      vocabularies becomes difficult. Defined methods are needed to manipulate, expand
      and integrate complex vocabularies. The Gene Ontology (GO) project provides the
      scientific community with a set of structured vocabularies to describe domains of
      molecular biology. The vocabularies are used for annotation of gene products and
      for computational annotation of sequence data sets. The vocabularies focus on
      three concepts universal to living systems, biological process, molecular
      function and cellular component. As the vocabularies expand to incorporate terms
      needed by diverse annotation communities, species-specific terms become
      problematic. In particular, the use of species-specific anatomical concepts
      remains unresolved. We present a method for expansion of GO into areas outside of
      the three original universal concept domains. We combine concepts from two
      orthogonal vocabularies to generate a larger, more specific vocabulary. The
      example of mammalian heart development is presented because it addresses two
      issues that challenge GO; inclusion of organism-specific anatomical terms, and
      proliferation of terms and relationships. The combination of concepts from
      orthogonal vocabularies provides a robust representation of relevant terms and an
      opportunity for evaluation of hypothetical concepts.

PMID- 12466304
TI  - Highly efficient modification of bacterial artificial chromosomes (BACs) using
      novel shuttle vectors containing the R6Kgamma origin of replication.
AB  - Bacterial artificial chromosome (BAC) mediated transgenesis has proven to be a
      highly reliable way to obtain accurate transgene expression for in vivo studies
      of gene expression and function. A rate-limiting step in use of this technology
      to characterize large numbers of genes has been the process with which BACs can
      be modified by homologous recombination in Escherichia coli. We report here a
      highly efficient method for modifying BACs by using a novel set of shuttle
      vectors that contain the R6Kgamma origin for DNA replication, the E. coli RecA
      gene for recombination, and the SacB gene for negative selection. These new
      vectors greatly increased the ease with which one can clone the shuttle vectors,
      as well as screen for co-integrated and resolved clones. Furthermore, we simplify
      the shuttle vector cloning to one step by incorporation of a "built-in"
      resolution cassette for rapid removal of the unwanted vector sequences. This new
      system has been used to modify a dozen BACs. It is well suited for efficient
      production of modified BACs for use in a variety of in vivo studies.

PMID- 12466306
TI  - Genetics of essential hypertension: from families to genes.
AB  - Family studies demonstrated the contribution of genetic factors to the
      development of primary hypertension. However, the transition from this
      phenomenologic-biometric approach to the molecular-genetic one is more difficult.
      This last approach is mainly based on the Mendel paradigm; that is, the
      dissection of the poligenic complexity of hypertension is brought about on the
      assumption that the individual genetic variants underlying the development of
      hypertension must be more frequent in hypertensive patients than in controls and
      must cosegregate with hypertension in families. The validity of these assumptions
      was clearly demonstrated in the so-called monogenic form of hypertension.
      However, because of the network of the feedback mechanisms regulating BP, it is
      possible that that the same gene variant may have an opposite effect on BP
      according to the genetic and environmental backgrounds. Independent groups of
      observations (acute BP response to saline infusion, incidence of hypertension in
      a population follow-up of 9 yr, age-related changes on BP) discussed in this
      review suggest a positive answer to this question. Therefore the impact of a
      given genetic variant on BP level must be evaluated within the context of the
      appropriate genetic epistatic interactions. A negative finding or a minor genetic
      effect in a general population may become a major gene effect in a subset of
      people with the appropriate genetic and environmental backgrounds.

PMID- 12466307
TI  - The kidney as a sensor of cardiovascular risk in essential hypertension.
AB  - Renal damage as a consequence of uncontrolled arterial hypertension is well
      recognized. Antihypertensive therapy has come to very significantly decrease the
      vascular damage in the kidneys of hypertensive patients. However, prevalence of
      mild renal insufficiency remains present in a significant proportion of the
      hypertensive population. This is accompanied by a marked increase in
      cardiovascular risk, as a consequence of the clustering of other cardiovascular
      risk factors and of insufficiently controlled BP. Prevention and protection of
      renal and cardiovascular damage in these patients will be one of the most
      relevant tasks in the future.

PMID- 12466308
TI  - Microalbuminuria, cardiovascular, and renal risk in primary hypertension.
AB  - Microalbuminuria is defined as abnormal urinary excretion of albumin between 30
      and 300 mg/d. It can be measured accurately by several widely available and
      sensitive methods. This abnormality can be found in 8 to 15% of nondiabetic
      patients with primary hypertension, although its prevalence varies greatly in the
      literature, likely due to differences in the methods used to detect it and to the
      criteria applied in the selection of patients. The pathogenetic mechanisms
      leading to the development of microalbuminuria are still not completely known. BP
      load and increased systemic vascular permeability, possibly due to early
      endothelial damage, seem to play a major role. Increased urinary albumin
      excretion has been associated with several unfavorable metabolic and nonmetabolic
      risk factors and subclinical hypertensive organ damage. In fact, a higher
      prevalence of concentric left ventricular hypertrophy and subclinical impairment
      of left ventricular performance, as well as the presence of carotid
      atherosclerosis, have been reported in patients with microalbuminuria. These
      associations might per se justify a greater incidence of cardiovascular events.
      Long-term longitudinal studies have recently confirmed the unfavorable prognostic
      significance of microalbuminuria in hypertensive patients. It has also been
      hypothesized that microalbuminuria might be a forerunner of overt renal damage in
      primary hypertension. Clinical studies, however, have shown conflicting results,
      and this hypothesis has to be considered tempting but speculative at present. In
      conclusion, microalbuminuria is a specific, integrated marker of cardiovascular
      risk and target organ damage in primary hypertension and one that is suitable for
      identifying patients at higher global risk. A wider use of this test in the
      diagnostic work-up of hypertensive patients is recommended.

PMID- 12466309
TI  - The renin-angiotensin system as a risk factor and therapeutic target for
      cardiovascular and renal disease.
AB  - The renin-angiotensin system (RAS) plays an important homeostatic role in BP
      regulation, water and salt balance, and tissue growth control under physiologic
      conditions. On the other hand, a pivotal involvement of the RAS in the
      pathophysiology of cardiovascular and renal disease is extensively supported by
      both basic and clinical evidence. In particular, it is today recognized that
      angiotensin II (AngII), the biologic effector of the RAS, may prompt a number of
      relevant structural and functional abnormalities through the activation of a
      complex of cellular effects mostly mediated via its binding with the AT(1)
      subtype receptors. The key role of these AngII-linked mechanisms of disease is
      strongly corroborated by large interventional studies. In fact, pharmacologic
      interference with RAS activity, by both preventing AngII formation with
      angiotensin-converting enzyme inhibitors or antagonizing its binding to cell
      membrane receptors by selective antagonists, is associated with highly beneficial
      outcomes in major disease conditions (hypertension, diabetes, renal failure,
      heart failure, myocardial infarction, stroke, and others). This article briefly
      reviews the current views on the biologic organization of RAS evidence supporting
      a pathogenic role of the RAS activity in promoting cardiac, vascular, and renal
      disease, and finally provides the basis for considering inhibition of RAS
      activity a major target for therapeutic interventions in these conditions.

PMID- 12466305
TI  - Assembly, verification, and initial annotation of the NIA mouse 7.4K cDNA clone
      set.
AB  - A set of 7407 cDNA clones (NIA mouse 7.4K) was assembled from >20 cDNA libraries
      constructed mainly from early mouse embryos, including several stem cell
      libraries. The clone set was assembled from embryonic and newborn organ libraries
      consisting of ~120,000 cDNA clones, which were initially re-arrayed into a set of
      ~11,000 unique cDNA clones. A set of tubes was constructed from the racks in this
      set to prevent contamination and potential mishandling errors in all further re
      arrays. Sequences from this set (11K) were analyzed further for quality and clone
      identity, and high-quality clones with verified identity were re-arrayed into the
      final set (7.4K). The set is freely available, and a corresponding database was
      built to provide comprehensive annotation for those clones with known identity or
      homology, and has been made available through an extensive Web site that includes
      many link-outs to external databases and analysis servers.

PMID- 12466310
TI  - Atherosclerotic renal artery stenosis: epidemiology, cardiovascular outcomes, and
      clinical prediction rules.
AB  - Atherosclerotic renal artery stenosis is the most common primary disease of the
      renal arteries, and it is associated with two major clinical syndromes, ischemic
      renal disease and hypertension. The prevalence of this disease in the population
      is undefined because there is no simple and reliable test that can be applied on
      a large scale. Renal artery involvement in patients with coronary heart disease
      and/or heart failure is frequent, and it may influence cardiovascular outcomes
      and survival in these patients. Suspecting renal arterial stenosis in patients
      with recurrent episodes of pulmonary edema is justified by observations showing
      that about one third of elderly patients with heart failure display
      atherosclerotic renal disease. Whether interventions aimed at restoring arterial
      patency may reduce the high mortality in patients with heart failure is still
      unclear because, to date, no prospective study has been carried out in these
      patients. Increased awareness of the need for cost containment has renewed the
      interest in clinical cues for suspecting renovascular hypertension. In this
      regard, the DRASTIC study constitutes an important attempt at validating clinical
      prediction rules. In this study, a clinical rule was derived that predicted renal
      artery stenosis as efficiently as renal scintigraphy (sensitivity: clinical rule,
      65% versus scintigraphy, 72%; specificity: 87% versus 92%). When tested in a
      systematic and quantitative manner, clinical findings can perform as accurately
      as more complex tests in the detection of renal artery stenosis.

PMID- 12466311
TI  - Hypertension and atherosclerotic renal artery stenosis: diagnostic approach.
AB  - Atherosclerotic renovascular disease needs noninvasive diagnostic tools to apply
      to patients having clinical characteristics that can suggest its presence. Color
      Doppler ultrasonography is a noninvasive, inexpensive diagnostic procedure that
      is capable, in an experienced hand, of accurately screening for renovascular
      disease. Magnetic resonance angiography and spiral computed tomography
      angiography play an ancillary role in detecting atheromatous renovascular
      disease. Captopril-enhanced renography and scintigraphy and the resistive index
      at Doppler sonography may be very useful in patients with renal artery stenosis
      for predicting the response to revascularization.

PMID- 12466312
TI  - Treatment of atherosclerotic renal artery stenosis.
AB  - The increasing prevalence of atherosclerotic renal artery stenosis (ARAS) has
      prompted in recent years a more aggressive treatment of this condition for
      reducing BP and for preserving the jeopardized renal function. Percutaneous
      transluminal renal angioplasty (PTRA), alone or in conjunction with stent
      implantation, may be useful for both these goals. However, despite the
      methodological improvements that make this procedure much safer than surgery,
      caution must be applied before PTRA is extended to all patients with ARAS.
      Indeed, PTRA is associated with a 23% rate of major/minor complications and with
      a 20% rate of restenosis, even in arteries implanted with stent. Moreover the
      cure rate of hypertension achievable with PTRA is, at best, around 10%, with a
      40% rate of improvements. Even for rescuing the ischemic kidney, PTRA/stent
      implantation are not always effective; only 35% of patients with ARAS have some
      improvement in renal function. These data indicate that there is an urgent need
      of rigorous criteria for selecting among the many patients with ARAS those who
      may actually benefit from the dilation procedure.

PMID- 12466313
TI  - Halting the progression of chronic nephropathy.
AB  - The incidence of end-stage renal disease (ESRD) is increasing worldwide. In the
      United States alone, there were 372,000 patients requiring renal replacement
      therapy in the year 2000 and is expected to rise to 650,000 by the year 2010. The
      trends in Europe and Japan are forecasted to follow a similar path. These
      increases represent a significant burden to countries worldwide; not only due to
      the financial costs of providing ESRD care, but also because of lost productivity
      and significant morbidity and mortality for the affected patients. There is
      clearly a pressing need for the aggressive identification and early treatment of
      patients with nephropathy to prevent progression to ESRD. Research in the last 25
      yr has made great advances in the understanding of the progression of chronic
      renal disease in diabetic and nondiabetic proteinuric nephropathy. There are now
      effective treatment options that can slow the progression of chronic
      nephropathies in many individuals, and ongoing research has raised the
      tantalizing prospect of the reversal of renal disease progression.

PMID- 12466314
TI  - Is it the agent or the blood pressure level that matters for renal protection in
      chronic nephropathies?
AB  - Some antihypertensive agents may be capable of reducing chronic renal
      insufficiency (CRI) progression because they halt some of the pathogenic
      mechanisms involved in renal damage. Although this effect seems to be partially
      independent of BP reduction, it is still unclear whether these drugs are really
      superior to other antihypertensive agents when the BP values recommended by the
      present guidelines are actually achieved. This is particularly true when
      considering that, in published trials, target and achieved BP values were
      constantly higher than those nowadays recommended. Furthermore, in the majority
      of these studies, patients treated with ACE-inhibitors (ACE-I) or Angiotensin II
      receptor antagonists (ATIIRA) achieved lower BP values than those in control
      groups and BP values during 24 h were not recorded. Anyway, taking into account
      the role of baseline and follow-up BP values, the treatment effect remained
      significant in almost all of the multivariate models. These findings suggest that
      the renoprotective effect of these agents (ACE-I, ATIIRA) is partially
      independent of better BP control. However, caution should be paid in attributing
      true biologic renoprotective properties to drugs just on the basis of statistical
      adjustments of BP values, although robustly performed, without being aware of
      what those BP values actually reflect.

PMID- 12466315
TI  - Renoprotection: a matter of blood pressure reduction or agent-characteristics?
AB  - Data from recent clinical trials show that lowering of BP reduces the rate of
      renal function loss in chronic renal disease. There is evidence supporting the
      assertion that BP lowering obtained by intervention in the renin-angiotensin
      aldosterone system (RAAS) has an additive renoprotective effect in both diabetic
      and nondiabetic renal diseases. However, to dissociate BP-dependent and non-BP
      dependent action of RAAS blockade, the relevant trials are in many cases flawed
      by design, resulting in BP differences between the comparative antihypertensive
      strategies. This review discusses whether the relevant literature allows for the
      conclusion that RAAS intervention has renoprotective effects in addition to its
      effects on BP. In particular, the main evidence for a specific renoprotective
      action of RAAS blockade is provided by its consistent antiproteinuric action,
      which cannot completely be attributed to the reduction in BP. Indeed, other
      strategies that lower proteinuria without having an antihypertensive effect, such
      as lowering dietary protein intake or the use of non-steroidal antiinflammatory
      drugs, appear to have a renoprotective effect as well. Interestingly, a
      consistent finding across different intervention studies is that the more
      proteinuria is reduced the better the kidney appears to be protected. Therefore,
      it is concluded that agent-characteristics of RAAS intervention (i.e.,
      antiproteinuric properties) independently influence renal function loss in
      addition to its BP-lowering effect. Future studies should further explore the
      renoprotective benefit of non-antihypertensive intervention measures, alone and
      in combination with antihypertensive strategies.

PMID- 12466316
TI  - Conventional therapy and newer drug classes for cardiovascular protection in
      hypertension.
AB  - Recently published actively controlled outcome trials in hypertension compared
      conventional therapy (diuretics and beta-blockers) with newer antihypertensive
      drug classes, including angiotensin-converting enzyme inhibitors, calcium channel
      blockers, alpha-blockers, and angiotensin II antagonists. In a quantitative
      overview of nine trials including 62,605 randomized patients, it was found that
      conventional therapy and newer drug classes had similar long-term efficacy in
      preventing cardiovascular complications of hypertension. BP lowering largely
      accounted for most, if not all, of the observed benefits in cardiovascular
      outcome. These findings emphasize the desirability of lowering BP as much as
      possible to maximize the reduction in cardiovascular complications. Furthermore,
      several clinical trials have been specifically designed to highlight specific
      mechanisms of action of the newer drugs by measuring intermediate end points,
      such as carotid intima-media thickening or renal dysfunction, or by studying
      subgroups of patients with specific disorders, such as diabetes mellitus. In
      these trials, calcium channel blockers were more effective than conventional
      therapy in preventing carotid intima-media thickening and mild renal dysfunction,
      whereas use of calcium channel blockers or angiotensin-converting enzyme
      inhibitors was associated with a lower incidence of diabetes mellitus in some
      studies. However, whether or not these specific effects of the newer drugs on
      intermediary and/or metabolic end points in the long run also lead to fewer
      cardiovascular complications remains to be proved.

PMID- 12466317
TI  - Cardiovascular and renal protection in type 2 diabetes mellitus: the role of
      calcium channel blockers.
AB  - The most important factor that prevents the progression of renal damage in
      diabetes mellitus, beside the improvement of blood glucose control, is tight BP
      control. The tenet of tight BP control may be defined as the lowest BP level one
      can accomplish using antihypertensive therapy that is at the same time compatible
      with the absence of untoward side effects. In fact, both the Framingham Heart
      Study in nondiabetic normal subjects and the United Kingdom Prospective Diabetes
      Study in type 2 diabetic patients showed that systolic values as low as 108 to
      111 mmHg and diastolic values as low as 70 to 71 mmHg are significantly
      associated with decreased cardiovascular mortality and morbidity. However, 45 to
      50% of the patients with type 2 diabetes mellitus and hypertension have systolic
      BP levels above 140 mmHg during antihypertensive therapy, particularly when using
      monotherapy. Thus the issue regarding the choice of which drugs one should use to
      treat hypertension became critical from a clinical point of view. Pharmaceutical
      compounds, which inhibit the renin-angiotensin system, have become the first
      choice treatment in patients with diabetes mellitus and incipient and advanced
      renal complications. The present brief review analyzes the effects of calcium
      channel blockers (CCB) on cardiovascular and renal complications in diabetes
      mellitus. The review discussed those studies that directly and blindly compared
      CCB with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin II
      AT(1) receptor blockers (ARB). Furthermore, size of the population recruited in
      each trial was used as a criterion of priority in the selection of the reports
      from the available literature. From the point of view of cardiovascular
      complications, the results of these studies showed a slightly better benefit of
      CCB on stroke, whereas ACE inhibitors better prevented the occurrence of
      myocardial infarction and congestive heart failure. On the other hand, recent
      observations demonstrated that also ACE inhibitors and ARB are effective in the
      primary and secondary prevention of stroke, although these studies did not
      directly compare these compounds with CCB. With regard to the outcome of renal
      complications, both ARB and ACE inhibitors more effectively prevented the
      progression of renal damage among the patients with overt nephropathy than CCB.
      On the contrary, both CCB and ACE inhibitors were equally effective on blunting
      the decay of GFR in diabetic patients who do not have overt proteinuria. However,
      ACE inhibitors and ARB more markedly decreased the rate of albumin excretion rate
      in the range of both microalbuminuria and macroalbuminuria. Recent advances in
      the understanding of the pathogenesis of abnormalities of albumin excretion rate
      and of atherosclerosis are also discussed. Both mechanical stress, mainly
      secondary to systolic hypertension, and elevated circulating and tissue levels of
      angiotensin II, partially independent from each other, cause excessive generation
      of superoxide compounds. This chain reaction of events in turn leads to disorders
      of structural components of glomerular filter and to damage of the vascular wall.
      Systolic BP control (<130 mmHg) is not adequately accomplished in the majority of
      the patients treated only with ACE inhibitors and ARB, even in association with
      diuretics. Poor BP control may lead to excessive systemic mechanical stress at
      the vascular level despite satisfactory inhibition of angiotensin II effects. In
      conclusion, one can suggest that CCB are useful and often indispensable
      pharmaceutical compounds, beside ACE inhibitors and ARB, to accomplish tight BP
      control (<130/85 mmHg), a target that is unlikely to be successfully maintained
      in the overall population of type 2 diabetic patients only by ACE inhibitors or
      ARB, as monotherapy. However, ACE inhibitors and ARB might be considered first
      choice drugs in the treatment of hypertension in diabetes mellitus, mainly
      because of a better renoprotection.

PMID- 12466318
TI  - Renal and cardiovascular protection in type 2 diabetes mellitus: angiotensin II
      receptor blockers.
AB  - Aggressive treatment of hypertension is effective in reducing both microvascular
      and macrovascular complications in type 2 diabetes, and target BP less than
      130/85 or 130/80 mmHg are now recommended. Inhibition of renin angiotensin
      aldosterone system (RAAS) plays an essential role in the treatment of
      hypertension and diabetes-related complications. Studies focusing on renal end
      points suggest that angiotensin-converting enzyme inhibitors (ACE-I) are more
      effective than other traditional agents in reducing the onset of clinical
      proteinuria in both type 1 and type 2 diabetic patients with incipient
      nephropathy, mainly in normotensive ones (secondary prevention). However, several
      small trials in type 2 diabetic patients with overt nephropathy (tertiary
      prevention) failed to demonstrate a specific renoprotective role for ACE-I, at
      variance with type 1 diabetes. Three recent large trials address the question of
      whether angiotensin II receptor blockers (ARB) prevent the development of
      clinical proteinuria or delay the progression of nephropathy in type 2 diabetes.
      The IRMA study showed that irbesartan is more effective than conventional therapy
      in preventing the development of clinical proteinuria and in favoring the
      regression to normoalbuminuria for comparable BP control in patients with
      incipient nephropathy. The IDNT and RENAAL trials showed that ARB are more
      effective than traditional antihypertensive therapies in reducing progression
      toward end-stage renal failure (ESRF) in type 2 diabetic patients with overt
      nephropathy independently of changes in BP. Moreover, a reduction in
      hospitalizations for heart failure was demonstrated for ARB-treated patients
      compared with placebo. Furthermore, the LIFE study showed that losartan is more
      effective than conventional therapy in reducing cardiovascular morbidity and
      mortality in a cohort of diabetic patients with hypertension and left ventricular
      hypertrophy. In conclusion, ARB seem to be effective in both preventing renal
      damage and reducing progression toward ESRF in type 2 diabetic patients. Thus,
      the guidelines for the prevention and treatment of diabetic nephropathy are now
      changed. In type 1 diabetes ACE-I are the first-choice drug; in type 2 diabetes,
      ARB are considered first-choice drugs in secondary prevention as well as ACE-I
      and have been now elected the unique first-choice drug in tertiary prevention of
      ESRF. Finally, ARB should be considered as the first-choice drug in
      cardiovascular prevention too, as well as ACE-I.

PMID- 12466319
TI  - Growth hormone treatment and neoplasia-coincidence or consequence?

PMID- 12466320
TI  - Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a
      perspective for the 21st century.

PMID- 12466321
TI  - Early clinical development of pharmaceuticals for type 2 diabetes mellitus: from
      preclinical models to human investigation.

PMID- 12466322
TI  - The molecular pathogenesis of hereditary and sporadic adrenocortical and
      adrenomedullary tumors.
AB  - Modern imaging modalities lead to frequent detection of adrenal masses, most of
      them incidental findings. Although the majority of adrenocortical and
      adrenomedullary tumors are benign, there are no reliable clinical and laboratory
      markers to distinguish most of them from malignant neoplasms. The molecular
      mechanisms underlying the pathogenesis of these tumors have recently begun to be
      unraveled. A fruitful avenue for the elucidation of tumorigenesis has been the
      study of adrenal tumors that are manifestations of hereditary or postzygotic
      genetic syndromes, because one knows the "first hit", i.e. the primary gene
      defect. In contrast, in sporadic adrenal tumors the first hit, possibly a somatic
      mutation of a tumor-related gene, is unknown, and therefore the sequence of
      genetic alterations is difficult to establish. In this article we review in
      addition to our own work the literature on molecular aspects of adrenocortical
      and adrenomedullary tumorigenesis.

PMID- 12466323
TI  - The genetics of autoimmune thyroid disease.

PMID- 12466324
TI  - Local biosynthesis of sex steroids in bone.

PMID- 12466325
TI  - Human osteoblast-like cells express predominantly steroid 5alpha-reductase type
      1.
AB  - In previous studies we established that human bone and human osteoblast-like
      cells (hOB cells) cultured from bone express 5alpha-reductase (5alpha-R)
      activity, as demonstrated by the conversion of testosterone and androstenedione
      to their corresponding 5alpha-reduced metabolites, 5alpha-dihydrotestosterone
      (DHT) and 5alpha-androstanedione. Two 5alpha-R isozymes (types 1 and 2) have been
      identified in various tissues. As their nature in bone is unknown, we
      investigated which isozymes were expressed in first passage hOB cells cultured
      from bone specimens obtained from six donors (five women and one man). For
      comparison, 5alpha-reductase isozyme expression in genital skin fibroblasts
      cultured from foreskin of three males was determined. Pharmacological and
      biochemical studies using selective inhibitors of the 5alpha-R isozymes were
      performed, and gene expression was assessed by RT-PCR. In hOB cells, LY191704, a
      potent nonsteroidal selective inhibitor of 5alpha-R type 1, and the 4-azasteroid
      17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one (a dual
      inhibitor of 5alpha-R types 1 and 2) inhibited 5alpha-R activity with a 50%
      inhibitory concentration (IC(50)) of approximately 4 nM. Finasteride, a selective
      inhibitor of 5alpha-R type 2, blocked 5alpha-R activity with an IC(50) of
      approximately 60 nM. The IC(50) of progesterone, a physiological substrate for
      5alpha-R, was approximately 200 nM. In genital skin fibroblasts, LY191704
      inhibited 5alpha-R with an IC(50) of more than 5000 nM, whereas finasteride and
      17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one effectively
      inhibited 5alpha-R with IC(50) of approximately 4 nM. Experiments to determine
      5alpha-reductase activity in homogenates of hOB cells as a function of pH showed
      very low activity at pH 5.5, but a broad shoulder of activity from pH 6.0-9.0,
      which was not inhibited by finasteride, but was nearly completely blocked by
      LY191704. RT-PCR revealed that 5alpha-R type 1 and 2 mRNAs were expressed in both
      bone and genital skin fibroblasts. Based on our pharmacological and biochemical
      studies, it appears that 5alpha-R activity in hOB cells is catalyzed
      predominantly by the type 1 rather than the type 2 isozyme. This expression
      pattern is in contrast to that in genital skin fibroblasts, where the activity of
      the type 2 isozyme prevails. As in most androgen target tissues DHT is
      biologically more active as an androgen than testosterone, DHT is formed in bone
      by 5alpha-R type 1 action from circulating testosterone, and bone cells also
      express the androgen receptor, local DHT production may play a physiological role
      in human bone homeostasis.

PMID- 12466326
TI  - The macroprolactin problem.

PMID- 12466327
TI  - Gross variability in the detection of prolactin in sera containing big big
      prolactin (macroprolactin) by commercial immunoassays.
AB  - A high molecular mass form of prolactin (PRL), macroprolactin, accumulates in the
      sera of some subjects. Although macroprolactin exhibits limited bioactivity in
      vivo, it retains immunoreactivity. We examined the frequency of
      macroprolactinemia in clinical practice and the ability of immunoassay systems to
      distinguish between macroprolactin and monomeric PRL. Of 300 hyperprolactinemic
      sera identified, 71 normalized following treatment of sera with polyethylene
      glycol, indicating that 24% of hyperprolactinemia could be accounted for by
      macroprolactin. Ten of these macroprolactinemic sera were circulated to 18
      clinical laboratories. Two sets of PRL measurements of the 10 untreated sera were
      obtained from each of the nine most commonly used immunoassay systems. Across the
      nine assay systems, differences in the PRL estimates ranged from 2.3- to 7.8
      fold. Elecsys users reported the highest PRL levels. Somewhat lower values were
      reported for DELFIA systems followed by Immuno-1, AxSYM, and Architect assays.
      The Immulite 2000 assay generated PRL levels equivalent to approximately 50% of
      those reported by the high-reading methods. The lowest PRL levels were reported
      by Access, ACS:180, and Centaur systems. To avoid confusion caused by the
      frequent presence of macroprolactin accounting for hyperprolactinemia, secondary
      screening for the presence of macroprolactin is recommended.

PMID- 12466328
TI  - Intrahepatically transplanted islets--strangers in a strange land.

PMID- 12466329
TI  - Low revascularization of experimentally transplanted human pancreatic islets.
AB  - Pancreatic islets are avascular immediately after transplantation. Although the
      islets are rapidly revascularized, it is uncertain whether the revascularization
      produces an adequate oxygenation of the transplanted islet tissue. We measured
      pO(2), blood flow and vascular density in mouse or human islets 1 month after
      transplantation to nude mice. Tissue pO(2) was measured with Clark
      microelectrodes. Blood perfusion was measured with laser-Doppler flow cytometry,
      whereas vascular density was determined in histological specimens stained for the
      lectin Bandeiraea simplicifolia (BS-1). Both the transplanted mouse and human
      islets had a pO(2) 15-20% of that in endogenous mouse islets. Moreover, the
      vascular density of the transplanted islets was decreased compared with that of
      endogenous mouse and human islets. Graft blood perfusion was approximately 50% of
      renal cortex blood flow. A negative correlation was found between donor age and
      blood perfusion of the human islet grafts. A similar correlation was seen between
      donor age and the total vascular density of these grafts. In conclusion,
      transplanted human islets had a markedly decreased vascular density and pO(2)
      compared with endogenous islets. This has potential implications for clinical
      islet transplantations, because poor vascular engraftment may significantly
      increase the number of islets needed to obtain insulin independence.

PMID- 12466330
TI  - Histopathological study of intrahepatic islets transplanted in the nonhuman
      primate model using edmonton protocol immunosuppression.
AB  - While islet cell transplantation is a promising way to restore insulin
      independence to patients with type I diabetes mellitus, a detailed histological
      analysis of the transplanted, intraportal islets has not yet been reported.
      Rhesus macaques underwent total pancreatectomy, then had allogeneic isolated
      islets infused into their portal vein, followed by daclizumab, tacrolimus, and
      sirolimus to prevent islet rejection. Islets were evenly distributed among the
      liver lobes. Liver sections from a primate given allogeneic islets 5 d earlier
      did not display any islet capillary formation, whereas intrahepatic islets
      transplanted 30 and 90 d before euthanasia showed an abundant capillary supply.
      Localized hepatocellular glycogenosis was observed surrounding the islets in a
      primate with functioning islets 7 months post transplant. Liver sections from a
      primate that rejected islets transplanted 2 months prior displayed only islet
      remnants with prominent local lymphohistiocytic inflammation and an occasional
      capillary. We conclude that islets develop an abundant vascular supply within 30
      d following transplant and because capillaries persist even following rejection,
      that the vascular cells are likely from the recipient. While transplanted islets
      were not vascularized early post transplant, the primates remained insulin
      independent. The long-term consequence of islets in the liver, marked by the
      glycogenosis, remains unknown and warrants further study.

PMID- 12466332
TI  - A 43-year-old male with untreated panhypopituitarism due to absence of the
      pituitary stalk: from dwarf to giant.
AB  - A 43-yr-old male was referred because of an x-ray made after a fall, which showed
      open epiphysis of the arm. The man had always been short for his age; during
      childhood he once consulted a pediatrician because of short stature, but
      thereafter he never sought medical attention. At age 18 yr he was not allowed to
      join the army because of his height of 147 cm. He continued to grow steadily and
      finally reached 193 cm. He had no complaints and considered himself reasonably
      fit. Physical examination showed a disproportional man with a body mass index of
      29.3 kg/m(2) and Tanner stage P1G1. Laboratory investigations showed hormone
      levels consistent with multiple pituitary deficiency, with dynamic tests
      consistent with hypothalamic or pituitary stalk disease. Magnetic resonance
      scanning of the brain showed a small anterior pituitary remnant, no pituitary
      stalk, and an ectopic neurohypophysis. This case of untreated panhypopituitarism
      shows a particular growth curve with an average growth velocity of 2 cm/yr,
      resembling patients with estrogen receptor mutation or aromatase deficiency. A
      literature study of other adult patients with untreated panhypopituitarism shows
      a variable growth pattern. Some speculations about possible reasons for this
      variability in clinical characteristics are presented.

PMID- 12466333
TI  - Thyroid acropachy: report of 40 patients treated at a single institution in a 26
      year period.
AB  - Thyroid acropachy is an extreme manifestation of autoimmune thyroid disease. It
      presents with digital clubbing, swelling of digits and toes, and periosteal
      reaction of extremity bones. It is almost always associated with ophthalmopathy
      and thyroid dermopathy. During a 26-yr period at our institution, of 178 patients
      with thyroid dermopathy, 40 had acropachy. Clubbing associated with thyroid
      dermopathy (pretibial myxedema) was seen in 35 patients. Clubbing usually was not
      a patient complaint and was noted only by clinical observers. Four of eight
      patients with hand and extremity radiographs had periosteal reaction. Seven had
      associated extremity and joint pain; this pain was absent at long-term follow-up.
      Half of the patients required systemic corticosteroid therapy, 53% required
      transantral or transfrontal orbital decompression for severe ophthalmopathy, and
      18% had the elephantiasic form of dermopathy. Cigarette-smoking rates were 81%
      for women and 75% for men (mean, 28 pack-years). All 13 patients who had thyroid
      stimulating Ig measurement had high titers. Long-term follow-up (median, 12.5 yr)
      revealed that acropachy was not a complaint in follow-up visits or
      questionnaires. The data suggest that thyroid acropachy is an indicator of
      severity of ophthalmopathy and dermopathy. It is a source of clinical concern
      only if dermopathy is persistent and severe.

PMID- 12466334
TI  - Effect of discontinuation of long-term growth hormone treatment on carbohydrate
      metabolism and risk factors for cardiovascular disease in girls with Turner
      syndrome.
AB  - GH treatment increases insulin levels in girls with Turner syndrome (TS), who are
      already predisposed to develop diabetes mellitus and other risk factors for
      developing cardiovascular disease. Therefore, in the present study, we
      investigated carbohydrate metabolism and several other risk factors that may
      predict development of cardiovascular disease in girls with TS after
      discontinuation of long-term GH treatment. Fifty-six girls, participating in a
      randomized dose-response study, were examined before, during, and 6 months after
      discontinuing long-term GH treatment with doses of 4 IU/m(2).d ( approximately
      0.045 mg/kg.d), 6 IU/m(2).d, or 8 IU/m(2).d. After a minimum of 4 yr of GH
      treatment, low-dose micronized 17beta-estradiol was given orally. Mean (SD) age
      at 6 months after discontinuation of GH treatment was 15.8 (0.9) yr. Mean
      duration of GH treatment was 8.8 (1.7) yr. Six months after discontinuation of GH
      treatment, fasting glucose levels decreased and returned to pretreatment levels.
      The area under the curve for glucose decreased to levels even lower than
      pretreatment level (P < 0.001). Fasting insulin levels and the area under the
      curve for insulin decreased to levels just above pretreatment level (P < 0.001
      for both), although being not significantly different from the control group. No
      dose-dependent differences among GH dosage groups were found. At 6 months after
      discontinuation, impaired glucose tolerance was present in 1 of 53 girls (2%),
      and none of the girls developed diabetes mellitus type 1 or 2. Compared with
      pretreatment, the body mass index SD-score had increased (P < 0.001), and the
      systolic and diastolic blood pressure SD-score had decreased significantly at 6
      months after discontinuation of GH treatment (P < 0.001 for both) although
      remaining above zero (P < 0.001, P < 0.05, and P < 0.005, respectively). Compared
      with pretreatment, total cholesterol (TC) did not change after discontinuation of
      GH treatment, whereas the atherogenic index [AI = TC/high-density lipoprotein
      cholesterol (TC/HDL-c)] and low-density lipoprotein cholesterol (LDL-c) had
      decreased; and both HDL-c and triglyceride levels increased (P < 0.001 for AI,
      LDL-c, and HDL-c; P < 0.05 for triglyceride). Compared with the control group,
      AI, serum TC, and LDL-c levels were significantly lower (P < 0.001 for all),
      whereas HDL-c levels were significantly higher (P < 0.05). In conclusion, after
      discontinuation of long-term GH treatment in girls with TS, the GH-induced
      insulin resistance disappeared, blood pressure decreased but remained higher than
      in the normal population, and lipid levels and the AI changed to more cardio
      protective values.

PMID- 12466335
TI  - Effects of oral androstenedione administration on serum testosterone and
      estradiol levels in postmenopausal women.
AB  - Androstenedione is a steroid hormone and an intermediate in the synthetic pathway
      of both testosterone and estradiol in men and women. It is available without
      prescription and taken with the expectation that it may have beneficial effects
      on strength, general well-being, libido, and quality of life. Although studies
      have shown that oral androstenedione increases serum testosterone and estradiol
      levels in men, the hormonal effects of androstenedione in postmenopausal women
      are unknown. We randomly assigned 30 healthy postmenopausal women to receive 0,
      50, or 100 mg androstenedione as a single oral dose. After androstenedione
      administration, we made hourly measurements of serum androstenedione, estrone,
      estradiol, and testosterone concentrations during 12 h of frequent blood
      sampling. The mean change (+/-SD) in serum androstenedione area under the curve
      (AUC) was greater in both the 50-mg (79 +/- 39%) and 100-mg dose groups (242 +/-
      184%) than in the control group (-29 +/- 28%) (P < 0.0001 for controls vs. 50-mg
      group and controls vs. 100-mg group). The mean change in serum androstenedione
      AUC was also greater in the 100-mg than 50-mg dose group (P = 0.0026). The mean
      change in serum estrone AUC was greater in both the 50-mg (108 +/- 72%) and 100
      mg dose groups (116 +/- 119%) than in the control group (-5 +/- 19%), although
      the control vs. 100-mg group comparison did not quite meet statistical
      significance (P < 0.0001 for controls vs. 50-mg group, P = 0.0631 controls vs.
      100-mg group). The mean change in serum estradiol AUC remained stable after
      supplementation in all groups without any between-group differences observed (-11
      +/- 17%, 2.8 +/- 34%, -11 +/- 27%, for the control, 50-mg, and 100-mg groups,
      respectively). The mean change in serum testosterone AUC was greater in both the
      50-mg (185 +/- 146%) and 100-mg dose groups (457 +/- 601%) than in the control
      group (-27 +/- 13%) (P < 0.0001 for controls vs. 50-mg group and for controls vs.
      100-mg group). The mean change in testosterone AUC was also greater in the 100-mg
      dose group than 50-mg dose group (P = 0.0257). There was considerable individual
      variability in the changes of serum androstenedione, estrone, and testosterone
      levels in the treated groups with peak serum testosterone levels exceeding the
      upper limit of normal in 4 of 10 women in the 50-mg dose group and 6 of 10 in the
      100-mg dose group. We concluded that the acute administration of both 50-mg and
      100-mg of androstenedione increases serum testosterone and estrone levels, but
      not estradiol levels, in postmenopausal women. If these hormonal effects are
      sustained during long-term administration, regular use of this supplement by
      postmenopausal women could thus cause both beneficial and adverse effects.

PMID- 12466336
TI  - Increased insulin-like growth factor (IGF)-II and IGF/IGF-binding protein ratio
      in prepubertal constitutionally tall children.
AB  - The height of subjects with constitutionally tall stature (CTS) is at least 2 SD
      above the mean of subjects of the same age and sex. Apart from a few discordant
      data on the role of GH and its direct mediator, IGF-I, no studies have been
      conducted on other components of the IGF system, which also condition the
      bioavailability and activity of IGF-I. We, therefore, investigated the
      possibility that other components of the IGF system might play a role in
      determining the increased growth velocity seen in CTS. To this end, we evaluated
      the behavior not only of IGF-I but also of IGF-II, IGF-binding protein (IGFBP)-3,
      and acid-labile subunit, the subunits that constitute the main IGF complex in
      circulation (150-kDa complex), as well as of IGFBP-1 and IGFBP-2, which are
      negatively regulated by GH and, like IGFBP-3, able to influence the
      bioavailability of the IGFs. The study was performed on 22 prepubertal subjects
      affected by CTS (16 males and 6 females), aged 2.8-13.3 yr (6.8 +/- 0.5 yr, mean
      +/- SEM). Thirty-seven normal prepubertal subjects (16 males and 21 females) aged
      between 2.2 and 13.3 yr (6.7 +/- 0.5 yr), who were comparable in socioeconomic
      and nutritional terms, served as controls. From the auxological point of view,
      subjects with CTS differed significantly from controls only in terms of growth
      velocity (HV-SD score; CTS, 1.8 +/- 0.3; controls, 0.4 +/- 0.2; P < 0.0001) and
      height (H-SD score; CTS, 3.1 +/- 0.1; controls, 0.4 +/- 0.2; P < 0.0001). The
      results demonstrated that the concentrations of IGF-I (27.3 +/- 2.0 nmol/liter),
      IGFBP-3 (66.9 +/- 3.8), and acid-labile subunit (216.8 +/- 13.6) in CTS-affected
      subjects were not significantly different from those determined in controls (25.0
      +/- 2.9, 74.4 +/- 4.1, and 241.0 +/- 11.9, respectively). By contrast, IGF-II
      levels proved significantly higher in CTS subjects (IGF-II: 87.2 +/- 3.4 vs. 52.4
      +/- 2.3, P < 0.0001). Chromatographic analysis, performed after acid treatment of
      pooled sera, showed only the presence of normal 7.5-kDa IGF-II in both CTS
      subjects and controls. In comparison with controls, CTS children showed a lower
      concentration of IGFBP-1 (1.6 +/- 0.3 vs. 4.1 +/- 0.7, P = 0.03) and a higher
      concentration of IGFBP-2 (14.3 +/- 1.8 vs. 9.6 +/- 1.1, P = 0.03). The IGFs (IGF
      I and -II)/IGFBPs (-1 + -2 + -3) molar ratio was significantly higher (P <
      0.0001) in CTS children than in controls. In particular, the IGF-II/IGFBP ratio
      (P < 0.0001) was responsible for the excess of the IGF peptide in relation to the
      concentrations of IGFBPs and, therefore, for the increase in the potentially
      bioactive free form of the IGFs. Moreover, the IGFBP-3/IGF molar ratio was
      significantly reduced, being less than 1 in CTS subjects (0.6 +/- 0.1 vs. 1.1 +/-
      0.1), so that a quantity of IGF peptides lack sufficient IGFBP-3 to form the 150
      kDa complex with which are normally sequestered in the vascular compartment. The
      data show that in CTS: 1) the most GH-dependent components of the IGF system are
      normal, consistent with the finding of a normal GH secretory state; 2) the less
      GH-dependent IGF-II is significantly increased, in agreement with the finding of
      a relationship between high levels of IGF-II and overgrowth in some syndromes;
      and 3) the IGF/IGFBP molar ratio is increased, and, therefore, a greater
      availability of free IGF for target tissues may be responsible for overgrowth in
      CTS.

PMID- 12466337
TI  - High circulating ghrelin: a potential cause for hyperphagia and obesity in prader
      willi syndrome.
AB  - Prader-Willi syndrome (PWS) is a genetic disorder occurring in 1 of 10,000-16,000
      live births and is characterized by excessive appetite with progressive massive
      obesity as well as short stature and mental retardation. Most patients have GH
      deficiency and hypogonadotropic hypogonadism. The causes of the hyperphagia and
      abnormal GH secretion are unknown. To determine whether ghrelin, a novel GH
      secretagogue with orexigenic properties, is elevated in PWS, we measured fasting
      plasma ghrelin concentration; body composition (dual-energy x-ray
      absorptiometry); and subjective ratings of hunger (visual analog scale) in seven
      subjects (6 males and 1 female; age, 26 +/- 7 yr; body fat, 39 +/- 11%, mean +/-
      SD) with PWS (diagnosis confirmed by genetic test) and 30 healthy subjects
      (reference population, 15 males and 15 females; age, 32 +/- 7 yr; body fat, 36 +/
      11%) fasted overnight. All subjects were weight stable for at least 6 months
      before admission to the study. The mean plasma ghrelin concentration was higher
      in PWS than in the reference population (307 +/- 164 vs. 109 +/- 24 fmol/ml; P <
      0.001), and this difference remained significant after adjustment for percentage
      body fat (P < 0.001). Plasma ghrelin was also higher (P = 0.0004) in PWS than in
      five healthy subjects fasted for 36 h. A positive correlation was found between
      plasma ghrelin and subjective ratings of hunger (r = 0.71; P = 0.008).
      Furthermore, in subjects with PWS, the concentration of the hormone was not
      different before and after ingestion of 2 ml and a satiating amount of the same
      liquid meal (ghrelin concentrations: 307 +/- 164 vs. 306 +/- 205 vs. 260 +/- 134
      fmol/ml, respectively; ANOVA for repeated measures, P = 0.56). This is the first
      evidence that ghrelin, a novel orexigenic hormone, is elevated in subjects with
      PWS. Our finding suggests that ghrelin may be responsible, at least in part, for
      the hyperphagia observed in PWS.

PMID- 12466338
TI  - Neurosurgical treatment of Nelson's syndrome.
AB  - Total bilateral adrenalectomy remains the definitive procedure for cure in
      Cushing's disease. It is complicated by the development of Nelson's syndrome, the
      treatment of which remains troublesome. We report the long-term follow-up, median
      17 yr (range, 8-22 yr), of 13 patients (3 males and 10 females) treated with
      pituitary surgery for Nelson's syndrome at a median age of 35 yr (range, 21-67
      yr). The presence of a pituitary mass lesion necessitated neurosurgery in all.
      Preoperatively, the median plasma ACTH level was 664 pmol/liter (range, 92-3665
      pmol/liter); this fell to 29 pmol/liter (range, <2 to 1124 pmol/liter)
      postoperatively (P < 0.0005). Cutaneous hyperpigmentation was reduced in all and
      resolved in 11 patients. The pituitary tumor bulk was clearly reduced in 12
      patients. There was no perioperative mortality. No patient developed a visual
      field defect attributable to surgery. New anterior pituitary hormone deficiency
      occurred in seven patients, and permanent diabetes insipidus occurred in five
      patients. At latest follow-up, the median plasma ACTH is 73 pmol/liter (range, <2
      to 7759 pmol/liter); six patients have levels of less than 44 pmol/liter and also
      have a resolution of their pigmentation and no evidence of a recurrence of a
      pituitary mass lesion. We conclude that pituitary surgery is an efficacious
      treatment for mass lesions associated with Nelson's syndrome, has long-term
      benefit with minimal side effects, and must be considered in the management of
      this distressing complication.

PMID- 12466339
TI  - Combined stimulation of adrenocorticotropin and compound-S by single dose
      metyrapone test as an outpatient procedure to assess hypothalamic-pituitary
      adrenal function.
AB  - The metyrapone test is used to test the hypothalamic-pituitary-adrenocortical
      axis. The present study aims to assess the diagnostic accuracy of combined
      stimulation of ACTH and compound-S (CMP-S). In addition, we analyzed the safety
      and practicability of this test as an outpatient procedure. A total of 327
      metyrapone tests were analyzed retrospectively in 185 patients (mean age, 50.3 +/
      15.2 yr). One hundred thirteen patients had one test, and 72 patients had
      between 2 and 6 tests over 1-3 yr. Most patients suffered from pituitary adenomas
      (60 macroadenomas, 63 microadenomas) or other pituitary lesions (n = 29).
      Metyrapone (2 g) was given at 2400 h as an outpatient procedure. Blood samples
      for analysis of ACTH, CMP-S, and cortisol were taken at 0730 h. Stimulation of
      adrenal CMP-S and cortisol by pituitary ACTH demonstrated a dose-response curve
      with the shape of half a geometric parabola. CMP-S reached a plateau when ACTH
      rose above 175 ng/liter [r = 0.661, P < 0.0001 for ACTH <175 ng/liter; r = 0.083,
      P = not significant (NS) for ACTH >175 ng/liter], cortisol flattened at ACTH
      levels above 230 ng/liter (r = 0.633; P < 0.0001 for ACTH < 230 ng/liter; P = NS
      for ACTH >230 ng/liter). Alternatively, the sum of CMP-S plus cortisol also
      flattened when ACTH rose above 230 ng/liter (r = 0.696; P < 0.0001 for ACTH <230;
      P = NS for ACTH > 230 ng/liter). Receiver operating curve analysis defining a cut
      off for ACTH at 150 ng/liter demonstrated a sensitivity of 47% and 67% at a cut
      off level for CMP-S at 200 or 260 nmol/liter, respectively. The respective
      specificity was 82% and 68% for CMP-S. This compared with a sensitivity of 71%
      and specificity of 69% if the sum of CMP-S plus cortisol of 450 nmol/liter were
      used as cut-off. The response curve between CMP-S and ACTH implies a maximally
      stimulated adrenal cortex at circulating ACTH levels above 175 ng/liter. Single
      measurement of CMP-S using the cut-off at 200 nmol/liter, as suggested in the
      literature, yields a poor sensitivity of only 47% compared with ACTH. Despite the
      relatively high cross-reactivity of CMP-S in the cortisol assay, the sum of CMP-S
      and cortisol levels with a cut-off value of 450 nmol/liter yields a better
      diagnostic accuracy compared with CMP-S alone.

PMID- 12466340
TI  - Impact of estrogen replacement therapy in a male with congenital aromatase
      deficiency caused by a novel mutation in the CYP19 gene.
AB  - Recent reports of the impact of estrogen receptor alpha and aromatase deficiency
      have shed new light on the importance of estrogen for bone formation in man. We
      describe a novel mutation of the CYP19 gene in a 27-yr-old homozygous male of
      consanguinous parents. A C to A substitution in intron V, at position -3 of the
      splicing acceptor site before exon VI of the CYP19 gene, is the likely cause of
      loss of aromatase activity. The mRNA of the patient leads to a frameshift and a
      premature stop codon 8 nucleotides downstream the end of exon V. Both parents
      were shown to be heterozygous for the same mutation. Apart from genua valga,
      kyphoscoliosis, and pectus carniatus, the physical examination was normal
      including secondary male characteristics with normal testicular size. To
      substitute for the deficiency, the patient was treated with 50 micro g
      transdermal estradiol twice weekly for 3 months, followed by 25 micro g twice
      weekly. After 6 months estrogen levels (<20 at baseline and 45 pg/ml at 6 months;
      normal range, 10-50) and estrone levels (17 and 34 ng/ml; normal range, 30-85)
      had normalized. Bone maturation progressed and the initially unfused carpal and
      phalangeal epiphyses began to close within 3 months and were almost completely
      closed after 6 months. The bone age, assessed by roentgenographic standards for
      bone development by Gruelich and Pyle, was 16.5 at baseline and 18-18.5 yr after
      6 months of treatment. Bone density of the distal radius (left), assessed by
      quantitative computed tomography, increased from 52 to 83 mg/cm(3) (normal range,
      120-160) and bone mineral density of the lumbar spine, assessed by dual-energy x
      ray-absorptiometry, increased from 0.971 to 1.043 g/cm(2) (normal range, >1.150).
      Osteocalcin as a bone formation parameter increased from 13 to 52 micro g/l
      (normal range, 24-70) and aminoterminal collagen type I telopeptide as a bone
      resorption parameter increased from 62.9 to 92.4 nmol/mmol creatinine (normal
      range, 5-54). Semen analysis revealed oligoazoospermia (17.4 million/ml; normal
      >20) at baseline. After 3 months of treatment, the sperm count increased (23.1
      million/ml) and decreased rapidly (1.1 million/ml) during the following 3 months.
      The sperm motility was reduced at baseline and decreased further during
      treatment. Area under the curve of insulin, C-peptide, and blood glucose levels
      during oral glucose tolerance test decreased after 6 months (insulin: 277 vs. 139
      micro U/ml.h; C-peptide 52 vs. 15 ng/m.h; area under the curve glucose: 17316 vs.
      12780 mg/d.min). Triglycerides (268 vs. 261 mmol/liter) and total cholesterol
      levels (176 vs. 198 mmol/liter) did not change significantly, but the low-density
      lipoprotein/high-density lipoprotein ratio decreased from 5.37 to 3.56 and
      lipoprotein (a) increased from 19.9 to 60.0 mg/dl (normal range, <30). In this
      rare incidence of estrogen deficiency, estrogen replacement demonstrated its
      importance for bone mineralization and maturation and glucose metabolism in a
      male carrying a novel mutation in the CYP19 gene.

PMID- 12466341
TI  - Effect of fluvastatin slow-release on low density lipoprotein (LDL) subfractions
      in patients with type 2 diabetes mellitus: baseline LDL profile determines
      specific mode of action.
AB  - The objective of this study was to determine the effect of slow-release (XL)
      fluvastatin on low density lipoprotein (LDL) subfractions in type 2 diabetes. A
      multicenter, double-blind, randomized, parallel-group comparison of fluvastatin
      XL 80 mg (n = 42) and placebo (n = 47), each given once-daily for 8 wk, in 89
      patients with type 2 diabetes (HbA1c: 7.2 +/- 1.0%, LDL cholesterol (LDL-C): 3.4
      +/- 0.7 mmol/liter, high density lipoprotein cholesterol: 1.1 +/- 0.3 mmol/liter,
      and triglycerides (TG): 2.4 +/- 1.4 mmol/liter). At baseline and on treatment,
      plasma lipoproteins were isolated and quantified. Eight weeks of fluvastatin
      treatment decreased total cholesterol (-23.0%, P < 0.001), LDL-C (-29%, P <
      0.001) and TG (-18%, P < 0.001), compared with placebo. At baseline, there was a
      preponderance of dense LDL (dLDL) (apolipoprotein B in LDL-5 plus LDL-6 > 25
      mg/dl) in 79% of patients, among whom fluvastatin decreased all LDL subfractions,
      reductions in dLDL being greatest (-28%, P = 0.001; cholesterol in dLDL -29%). In
      patients with low baseline dLDL (apolipoprotein B in LDL-5 plus LDL-6 </= 25
      mg/dl), but a preponderance of buoyant LDL (LDL-1 through LDL-3), fluvastatin
      significantly decreased only these subfractions. Fluvastatin 80 mg XL, once
      daily, decreased total cholesterol and total LDL-C. In patients with atherogenic
      dLDL, absolute changes of dLDL were most pronounced, emphasizing the value of
      fluvastatin treatment in type 2 diabetes. The antiatherogenic potential of
      fluvastatin in type 2 diabetes may thus be greater than that expected from its
      effects on LDL-C and TG alone.

PMID- 12466342
TI  - Bone involvement in eugonadal male patients with adrenal incidentaloma and
      subclinical hypercortisolism.
AB  - Adrenal incidentalomas (AI) are not associated, by definition, with clinically
      evident syndromes; however, some AI patients may show biochemical indexes of
      subclinical hypercortisolism (SH). Previous data on female AI patients indicated
      that SH may lead to bone loss, at least at spine. No data are available on bone
      involvement in samples of only AI male patients. We measured bone metabolism and
      bone mineral density at spine and femur by dual-energy x-ray absorptiometry in 38
      consecutive eugonadal male AI patients and 38 healthy matched control subjects.
      Patients were subdivided according to the presence or absence of SH (group SH+
      and group SH-, respectively). Mean Z-score levels of spinal bone mineral density
      measured by dual-energy x-ray absorptiometry were lower (P < 0.05) in group SH+ (
      0.42 +/- 1.62) in comparison with group SH- (0.6 +/- 1.13) and controls (0.47 +/-
      1.06). Thus, in order for the most appropriate management to be individually
      tailored, bone mass evaluation is strongly indicated in AI male patients with SH,
      irrespective of their gonadal status.

PMID- 12466343
TI  - Prevalence and clinical picture of celiac disease in Turner syndrome.
AB  - A multicenter study of Turner syndrome (TS) patients was carried out to estimate
      the prevalence of celiac disease (CD) and to detect clinical characteristics and
      laboratory data of affected patients. Three hundred eighty-nine girls with TS
      were screened by IgA antigliadin antibodies and/or antiendomysial antibodies.
      Intestinal biopsy was offered to positive cases. CD was diagnosed in 25 patients.
      In celiac subjects, anemia, anorexia, and delayed growth (with respect to Italian
      TS curves) were frequently present; whereas distended abdomen, chronic diarrhea,
      constipation, and vomiting occurred more rarely. In addition, low serum iron
      levels, hemoglobinemia, and high values of aminotransferases were observed. Ten
      patients showed classic CD, 8 showed atypical symptoms, and 7 showed a silent CD.
      In 11 symptomatic patients, the diagnosis of CD was made at the onset of
      symptoms, whereas 7 of them showed a median delay of 79 months in diagnosis.
      Other autoimmune disorders were observed in 40% of the patients. Our study
      confirms the high prevalence (6.4%) of CD in a large series of TS patients.
      Moreover, the subclinical picture in 60% of the cases, the diagnostic delay, and
      the incidence of other autoimmune disorders suggest that routine screening of CD
      in TS is indicated.

PMID- 12466344
TI  - Effects of chronic iodine excess in a cohort of long-term American workers in
      West Africa.
AB  - A cross-sectional survey of 102 Peace Corps volunteers in Niger, West Africa, in
      1998 had previously demonstrated a high rate of thyroid dysfunction and goiter
      attributable to excess iodine from their water filters. The Peace Corps
      volunteers were followed-up a mean of 30 wk after they ceased using iodine-based
      water filtration systems. Goiter was present in 44% of subjects during excess
      iodine ingestion and in 30% after removal of excess iodine. Mean serum iodine
      decreased from 293 micro g/liter during excess iodine ingestion to 84 micro
      g/liter after cessation of excess iodine. Mean total serum T(4) values increased
      from 100.4 to 113.3 nmol/liter (7.8 to 8.8 micro g/dl). Mean serum free T(4)
      increased from 32.2 to 34.7 pmol/liter (2.5 to 2.7 ng/dl). Mean serum TSH
      decreased from 4.9 to 1.8 mU/liter. Mean serum thyroid peroxidase antibody levels
      decreased from 33,000 to 22,000 IU/liter (33 to 22 IU/ml). We found that during
      prolonged excess iodine exposure there were marked increases in serum total
      iodine concentrations, and the prevalence of goiter, elevated serum TSH values,
      and elevated serum thyroid peroxidase antibody values increased. The prevalence
      of all abnormalities decreased after removal of excess iodine from the drinking
      water system.

PMID- 12466345
TI  - Effects of pioglitazone in nondiabetic patients with arterial hypertension: a
      double-blind, placebo-controlled study.
AB  - Hypertension is often associated with insulin resistance, dyslipidemia and
      obesity, which indicate a prediabetic state and increased risk of cardiovascular
      disease. Pioglitazone treatment of patients with type 2 diabetes reduces insulin
      resistance and improves lipid profiles. The present double-blind placebo
      controlled study is the first study to report effects of pioglitazone in non
      diabetic patients with arterial hypertension. Following a one week run-in, 60
      patients were randomized to receive either pioglitazone (45 mg/day) or placebo
      for 16 weeks. Insulin sensitivity (M-value) increased by 1.2 +/- 1.7 mg/min/kg
      with pioglitazone compared with 0.4 +/- 1.4 mg/min/kg (P = 0.022) with placebo.
      HOMA index was decreased (-22.5 +/- 45.8) by pioglitazone but not by placebo
      (+0.8 +/- 26.5; P < 0.001). Decreases in fasting insulin and glucose were
      significantly (P = 0.002 and P = 0.004, respectively) greater with pioglitazone
      than placebo. Body weight did not change significantly with either treatment. HDL
      cholesterol was increased and apolipoprotein B was decreased to a significantly
      greater extent with pioglitazone. There was a significantly (P = 0.016) greater
      decrease from baseline in diastolic blood pressure with pioglitazone. These
      changes would suggest improved glucose metabolism and a possible reduction in
      risk of cardiovascular disease with pioglitazone treatment of non-diabetic
      patients with arterial hypertension.

PMID- 12466346
TI  - Poorly controlled type I diabetes mellitus in young men selectively suppresses
      luteinizing hormone secretory burst mass.
AB  - Alterations in the reproductive axis function are present to a variable extent in
      patients with type 1 diabetes mellitus (IDDM). Results from studies in IDDM men
      have yielded discrepant findings, which may reflect nonuniform patient selection
      criteria, age, diabetic status, duration of the disease and differences in
      sampling protocols. To more clearly define the impact of early diabetic
      alterations in the male reproductive axis, we applied a combined strategy of
      patient selection restricted to young men with relatively short duration of IDDM,
      dual control groups, multiparameter deconvolution analysis to assess LH secretory
      activity, and assessment of time-dependent changes in human chorionic
      gonadotropin (hCG)-stimulated serum testosterone concentrations. Three groups of
      subjects were studied: 11 young men with poorly controlled IDDM, 9 well
      controlled diabetics, and 9 healthy men. All volunteers underwent blood sampling
      at 10-min intervals before and after 2 consecutive iv pulses of 10 micro g GnRH.
      On a separate day, 40 IU/kg hCG were given im, and blood samples were collected
      before hCG administration, every 60 min thereafter for 6 h, and then 24, 48, and
      72 h after the injection. Mean serum LH concentrations across the basal 6-h
      sampling period were significantly (P < 0.05) decreased in men with poorly
      controlled IDDM (11 +/- 1.6 IU/liter) compared with those in well controlled
      diabetics (19 +/- 1.8 IU/liter) and healthy controls (19 +/- 1.5 IU/liter).
      Multiple parameter deconvolution analysis revealed a 50% reduction in the mass of
      LH secreted per burst and the pulsatile LH secretion rate in poorly controlled
      IDDM (mass of LH secreted/burst, 7 +/- 1.1 vs. 12 +/- 2.1 and 13 +/- 1.5
      IU/liter; LH secretion rate, 47 +/- 6.3 vs. 78 +/- 10 and 87 +/- 11 IU/liter.6 h;
      poorly controlled vs. well controlled IDDM and healthy controls, respectively; P
      < 0.05 for both parameters). Uncontrolled IDDM patients had significantly (P <
      0.05) lower integrated serum LH concentrations after the first and second GnRH
      pulses (first GnRH pulse, 4460 +/- 770 vs. 7250 +/- 1200 and 5120 +/- 910
      IU/liter; second pulse, 4700 +/- 615 vs. 7640 +/- 881 and 7100 +/- 1230 IU/liter;
      poorly controlled vs. well controlled IDDM and healthy men, respectively) and
      markedly attenuated LH secretory burst mass after the second GnRH stimulus (49 +/
      8.8 vs. 90 +/- 13 and 83 +/- 19 IU/liter; poorly controlled vs. well controlled
      IDDM and healthy controls, respectively). The biological to immunological ratio
      of LH released in baseline conditions was higher in uncontrolled IDDM patients
      (0.81 +/- 0.10) than in controlled IDDM (0.37 +/- 0.08) and healthy controls
      (0.48 +/- 0.06; P < 0.01), whereas LH released in response to exogenous GnRH
      exhibited comparable ratios among the three study cohorts. Baseline serum
      testosterone levels as well as absolute and incremental responses to exogenous
      hCG did not differ by degree of metabolic control. Collectively, these results
      indicate that the function of the hypothalamic-gonadotrope axis is compromised in
      young men with poorly controlled IDDM, such that the amplitude of spontaneous
      pulsatile and exogenous GnRH-stimulated LH secretion is attenuated. This central
      hypogonadotropism is paradoxically associated with the presence in the
      circulation of gonadotropin molecules with enriched biological activity, which is
      evidently sufficient to temporarily maintain normal total testosterone
      concentrations in the earlier stages of IDDM.

PMID- 12466347
TI  - Regulation of insulin-like growth factor binding protein-1 during protracted
      critical illness.
AB  - IGF binding protein-1 (IGFBP-1), an important regulator of IGF bioavailability,
      has been shown to correlate with mortality in critically ill patients. In the
      liver, IGFBP-1 is transcriptionally repressed by insulin, and it is therefore a
      potential marker of hepatic insulin sensitivity. We have recently shown that,
      compared with conventional treatment, maintenance of normoglycemia with intensive
      insulin therapy decreased morbidity and mortality of continuously fed critically
      ill patients. This study compares the effect of conventional and intensive
      insulin therapy on IGFBP-1 and assesses its predictive value for mortality. In
      363 patients who were dependent on intensive care for more than 7 d and were
      randomly assigned to either conventional or intensive insulin therapy, serum
      IGFBP-1 levels were measured on admission, on d 1, 8, 15, 22, and 29, and on the
      day of intensive care unit discharge or death. In addition, IGFBP-1 and
      phosphoenolpyruvate carboxykinase mRNA levels were measured by real-time RT-PCR
      in postmortem liver biopsies obtained from 74 patients who died in the intensive
      care unit. Although intensive insulin treatment lowered glycemia, it had no
      effect on IGFBP-1 serum levels. Instead, serum IGFBP-1 concentration was
      significantly higher in patients who ultimately died, and it differentiated
      nonsurvivors from survivors 3 wk before death. The predictive value of serum
      IGFBP-1 for mortality was similar to that of the APACHE-II score. Like
      circulating IGFBP-1, hepatic mRNA levels of IGFBP-1 and the similarly insulin
      regulated gene, phosphoenolpyruvate carboxykinase, were not significantly
      different between conventional and intensive insulin therapy groups. These data
      suggest that hepatic insulin resistance in prolonged critically ill patients,
      reflected by high serum IGFBP-1 levels, is not overcome by intensive insulin
      therapy, and that this may affect patient outcome.

PMID- 12466348
TI  - Interleukin-1beta induces phosphodiesterase 4B2 expression in human myometrial
      cells through a prostaglandin E2- and cyclic adenosine 3',5'-monophosphate
      dependent pathway.
AB  - Intrauterine infections are important etiological factors of preterm labor. They
      trigger an increase in proinflammatory cytokines, in particular IL-1beta, that
      induces a cascade of events resulting in the production of potent effectors of
      myometrial contractility, such as the prostaglandin E(2) (PGE(2)). Within the
      smooth muscle cells, contractility is under the control of cAMP content, partly
      regulated by cAMP-phosphodiesterase 4 (PDE4), the predominant family of PDEs
      expressed in human myometrium. In the present study, using a model of
      inflammation of human myometrial cells in culture, we demonstrated that exposing
      the cells to IL-1beta resulted in a significant up-regulation of PDE4 activity
      through an increase in PDE4B2 mRNA and protein levels. The IL-1beta-induced PDE4
      activity occurs after an increase in PGE(2) production and subsequent cAMP
      augmentation. Pretreatment with indomethacin or NS 398 completely blocked this
      long-term effect of IL-1beta, revealing a PGE(2)-dependent pathway. Accordingly,
      our results demonstrated that the PDE4B2 variant can participate in the
      regulation of the inflammatory reaction that occurs at term or in preterm labor
      and leads to myometrial contractions. Knowing the myorelaxant effect of PDE4
      inhibitors and the implication of the PDE4B2 in the inflammatory process, this
      isoform may be an appropriate target for discovering antiinflammatory drugs to
      manage infection-induced preterm deliveries.

PMID- 12466349
TI  - Estrogen receptor alpha and beta expression in theca and granulosa cells from
      women with polycystic ovary syndrome.
AB  - A defining characteristic of dominant follicles is high estradiol concentrations.
      Abnormal expression of estrogen receptors (ERs) could contribute to poor
      follicular development and ovulatory failure in polycystic ovary syndrome (PCOS).
      The aim of this study was to determine whether there are differences in ERalpha
      and ERbeta expression in granulosa cells (GC) and theca cells (TC) from women
      with PCOS, compared with regularly cycling women. GC and TC were obtained by
      microdissection from 12 polycystic and 23 normal ovaries. ERalpha and ERbeta mRNA
      and protein expression were measured by semiquantitative RT-PCR and Western blot,
      respectively. In control ovaries, both GC and TC ERalpha mRNAs were higher in
      small antral (SA) than in dominant follicles. ERalpha mRNA was similar in PCOS
      and size-matched control follicles. In control follicles, ERalpha protein
      concentrations were higher in GC than in TC. In GC, the ERalpha concentrations
      were comparable among SA, dominant, and PCOS follicles. In TC, ERalpha
      concentrations were lower in dominant follicles but were markedly increased in
      PCOS. In control ovaries, GC and TC expression of ERbeta mRNA was higher in SA,
      compared with dominant follicles. In PCOS, ERbeta mRNA was intermediate between
      SA and dominant follicles in both GC and TC. In GC, the ERbeta protein
      concentrations followed the same pattern as mRNA expression; but in TC ERbeta,
      protein in PCOS was equivalent to that in dominant follicles. The results of this
      study demonstrate that there are significant alterations in the expression of
      ERalpha and ERbeta in PCOS that may be related to abnormal follicular
      development.

PMID- 12466350
TI  - Estrogenicity of isoflavones on human endometrial stromal and glandular cells.
AB  - Endometrium consists of different cell populations such as epithelial and stromal
      cells and is mainly regulated by sex steroids. Isoflavones are plant-derived
      estrogenic compounds that have estrogenic and antiestrogenic properties in a cell
      specific manner. We hypothesized that one of the potential health benefits of
      isoflavones may be their ability to regulate endometrial cell function. The
      present study was conducted to assess estrogenic and/or antiestrogenic effects of
      isoflavones (genistein, genistin, daidzein, and daidzin) in cultured human
      endometrial stromal and glandular (Ishikawa) cells by MTT colorimetric cell
      proliferation assay, proliferating cell nuclear antigen expression, and alkaline
      phosphatase activity assays. Experiments were performed in a time- (24-96 h) and
      concentration-dependent (10(-12) to 10(-5) M) manner. All isoflavones used in the
      present study induced endometrial stromal and Ishikawa cell proliferation when
      compared with control (vehicle) group in a time- (at 48 h and afterward) and
      concentration-dependent manner (at 10(-8) M and above) (P < 0.05). However,
      isoflavones (at 10(-8) and above concentrations) were also antiestrogenic when
      combined with estradiol (E(2)) (P < 0.05). The isoflavones revealed a weak
      estrogenic activity (39-67% less than E(2)) as assessed by alkaline phosphatase
      activity (P < 0.05), but when administered together with E(2), they antagonized
      estrogen induced alkaline phosphatase activity by 36-89% (P < 0.05). We conclude
      that, although isoflavones alone have weak estrogenic effects on endometrial
      stromal and glandular cells, in the presence of E(2) they act as antiestrogens.

PMID- 12466351
TI  - Demonstration of enhanced potency of a chimeric somatostatin-dopamine molecule,
      BIM-23A387, in suppressing growth hormone and prolactin secretion from human
      pituitary somatotroph adenoma cells.
AB  - In acromegaly, the combination of somatostatin (SS) and dopamine (DA) agonists
      has been shown to enhance suppression of GH secretion. In the present study, a
      new chimeric molecule, BIM-23A387, which selectively binds to the SS subtype 2
      receptor (sst(2); K(i) = 0.10 nM) and to the DA D2 receptor (D2DR; K(i) = 22.1
      nM) was tested in cultures prepared from 11 human GH-secreting tumors for its
      ability to suppress GH and prolactin (PRL) secretion. The chimeric compound was
      compared with individual sst(2) and D2DR agonists of comparable activity at the
      individual receptors. All tumors expressed both sst(2) and D2DR mRNAs (0.8 +/-
      0.2 and 4.7 +/- 0.7 copy/copy beta-glucuronidase mRNA, respectively). In cell
      cultures from seven octreotide-sensitive tumors, the maximal inhibition of GH
      release induced by the individual sst(2) and D2DR analogs and by BIM-23A387 was
      similar. However, the mean EC(50) for GH suppression by BIM-23A387 (0.2 pM) was
      50 times lower than that of the individual sst(2) and D2DR analogs, either used
      individually or combined. Similar data were obtained in four tumors that were
      only partially responsive to octreotide. The inhibition of GH release by BIM
      23A387 was only partially reversed by the D2R2 antagonist, sulpiride, or by the
      sst(2) antagonist, BIM-23454. Only when both antagonists were combined was the GH
      suppressive effect of BIM-23A387 totally reversed. Finally, BIM-23A387 produced a
      mean 73 +/- 6% inhibition of PRL in six mixed GH plus PRL tumors. These data
      demonstrate an enhanced potency of the chimeric molecule, BIM-23A387, in
      suppressing GH and PRL secretion from acromegalic tumors, which cannot be
      explained merely on the basis of binding affinity for SS and/or DA receptors.

PMID- 12466352
TI  - Amino acids stimulate translation initiation and protein synthesis through an Akt
      independent pathway in human skeletal muscle.
AB  - Studies in vitro as well as in vivo in rodents have suggested that amino acids
      (AA) not only serve as substrates for protein synthesis, but also as nutrient
      signals to enhance mRNA translation and protein synthesis in skeletal muscle.
      However, the physiological relevance of these findings to normal humans is
      uncertain. To examine whether AA regulate the protein synthetic apparatus in
      human skeletal muscle, we infused an AA mixture (10% Travesol) systemically into
      10 young healthy male volunteers for 6 h. Forearm muscle protein synthesis and
      degradation (phenylalanine tracer method) and the phosphorylation of protein
      kinase B (or Akt), eukaryotic initiation factor 4E-binding protein 1, and
      ribosomal protein S6 kinase (p70(S6K)) in vastus lateralis muscle were measured
      before and after AA infusion. We also examined whether AA affect urinary nitrogen
      excretion and whole body protein turnover. Postabsorptively all subjects had
      negative forearm phenylalanine balances. AA infusion significantly improved the
      net phenylalanine balance at both 3 h (P < 0.002) and 6 h (P < 0.02). This
      improvement in phenylalanine balance was solely from increased protein synthesis
      (P = 0.02 at 3 h and P < 0.003 at 6 h), as protein degradation was not changed.
      AA also significantly decreased whole body phenylalanine flux (P < 0.004). AA did
      not activate Akt phosphorylation at Ser(473), but significantly increased the
      phosphorylation of both eukaryotic initiation factor 4E-binding protein 1 (P <
      0.04) and p70(S6K) (P < 0.001). We conclude that AA act directly as nutrient
      signals to stimulate protein synthesis through Akt-independent activation of the
      protein synthetic apparatus in human skeletal muscle.

PMID- 12466353
TI  - Serum inhibin B in polycystic ovary syndrome: regulation by insulin and
      luteinizing hormone.
AB  - Inhibin B is a product of the granulosa cells of growing preantral and antral
      follicles. Despite the large ovarian volume and increased follicle number
      typically detected in women with polycystic ovary syndrome (PCOS), previous
      studies demonstrate that inhibin B is not elevated as would be expected in PCOS,
      but is inversely correlated with body mass index (BMI). We therefore hypothesized
      that inhibin B levels in women with PCOS are regulated by a factor related to
      BMI. Thus, LH, sex steroids, and metabolic parameters were measured in 50
      anovulatory PCOS subjects in pools constituted from equal aliquots of serum drawn
      every 10 min for 4 h and were correlated with inhibin B. Based on the results of
      these correlative studies, inhibin B regulation by human chorionic gonadotropin
      (hCG) and insulin was tested directly. In PCOS subjects, inhibin B correlated
      inversely with BMI (r = -0.413; P < 0.004) and fasting insulin (r = -0.409; P <
      0.004). Inhibin B also correlated directly with pool LH (r = 0.419; P < 0.003),
      LH pulse amplitude (r = 0.512; P < 0.0001), and SHBG (r = 0.429; P < 0.003). The
      relationships demonstrated for inhibin B were not demonstrated for inhibin A, nor
      were they evident in normal subjects. To determine whether the correlations
      represent regulation of inhibin B, i.e. stimulation of inhibin B by LH or
      suppression by insulin, two interventional studies were performed. In the first
      study hCG (5000 U) was administered to PCOS subjects (n = 15) to mimic the
      effects of LH. Inhibin B was not increased, but was significantly reduced 24 h
      after hCG administration (223.8 +/- 21.3 vs. 152.4 +/- 15.9 pg/ml; P < 0.0005).
      In the second study, diazoxide (100 mg every 8 h) was administered for 3 d to
      PCOS subjects (n = 9). Inhibin B increased (85.4 +/- 12.4 to 136.6 +/- 18.8
      pg/ml; P < 0.05) in association with a decrease in the insulin area under the
      curve (104 +/- 29 to 83 +/- 22 nmol/liter.min; P < 0.05) induced by diazoxide. In
      PCOS subjects, inhibin B demonstrated significant relationships with BMI and
      factors related to BMI, including LH, insulin, and SHBG. Although LH was
      associated with inhibin B, hCG administration suppressed inhibin B secretion
      after 24 h, whereas short-term insulin suppression increased inhibin B. These
      findings suggest that both increased LH and insulin may account for the relative
      suppression of inhibin B in patients with PCOS.

PMID- 12466354
TI  - Ca2+-activated, large conductance K+ channel in the ovary: identification,
      characterization, and functional involvement in steroidogenesis.
AB  - Progesterone production by the corpus luteum is a process vital for reproduction.
      In humans its secretion is stimulated by the placental hormone human chorionic
      gonadotropin (hCG), and this stimulatory action can also be observed in cultured
      human luteinized granulosa cells (GCs). We now provide evidence that opening of a
      Ca(2+)-activated K(+) channel, the BK(Ca), is crucially involved in this process.
      Immunohistochemistry and RT-PCR revealed the presence of the pore-forming alpha
      subunit in human luteinized GCs and in luteal cells of human, macaque, and rat,
      implying that BK(Ca) channels are important throughout species. Blocking of
      BK(Ca) channels by iberiotoxin attenuated hCG-induced progesterone secretion. The
      inhibitory action of iberiotoxin suggests that BK(Ca) channels are activated in
      the course of hCG-induced steroidogenesis. In search of physiological activators
      we used an electrophysiological approach and could preclude a direct regulation
      of channel activity by hCG or GC-derived steroids (progesterone and 17beta
      estradiol). Instead, the peptide hormone oxytocin and an acetylcholine (ACh)
      agonist, carbachol, evoked transient BK(Ca) currents and membrane
      hyperpolarization. These two molecules are both secreted by GCs and act via
      raised intracellular Ca(2+) levels. The release of oxytocin is stimulated by hCG,
      and a similar mechanism is likely in the case of ACh. We conclude that BK(Ca)
      channel activity in GCs is mediated by components of the intraovarian signaling
      system, thereby interlinking a systemic hormonal and a local neuroendocrine
      system in control of steroidogenesis.

PMID- 12466355
TI  - Adiposity and hyperinsulinemia in Indians are present at birth.
AB  - We studied body size and cord blood leptin and insulin concentrations in newborn
      urban Indian (Pune, India) and white Caucasian (London, UK) babies to test the
      hypothesis that the adiposity and hyperinsulinemia of Indians are present at
      birth. Indian babies (n = 157) were lighter in weight compared with white
      Caucasian babies [n = 67; median weight, 2805 g vs. 3475 g, respectively; P <
      0.001, adjusted for gestational age and sex; -1.52 SD score; confidence interval
      (CI), -1.66, -1.42] and had smaller abdominal (-2.39 SD score; CI, -2.52, -2.09),
      midarm (-1.47 SD score; CI, -1.58, -1.34), and head (-1.23 SD score; CI, -1.42, 
      1.13) circumferences. However, their skinfolds were relatively preserved:
      subscapular (central) skinfold (-0.32 SD score; CI, -0.43, -0.20) was better
      preserved than triceps (peripheral) skinfold (-0.86 SD score; CI, -0.97, -0.75).
      Cord plasma leptin (median, 6.2 ng/ml Pune and 6.4 ng/ml London) and insulin
      (median, 34.7 pmol/liter Pune and 20.8 pmol/liter London) concentrations were
      comparable in the two populations but were higher in Indians when adjusted for
      birth weight, confirming relative adiposity and hyperinsulinemia of Indian
      babies. Indian mothers were smaller in all respects, compared with white
      Caucasian mothers, except subscapular skinfold, which was similar in the two
      populations. Our results support the intrauterine origin of adiposity, central
      adiposity, and hyperinsulinemia in Indians. Further research should concentrate
      on elucidating genetic and environmental influences on fetal growth and body
      composition. Prevention of insulin resistance syndrome in Indians will need to
      address regulation of fetal growth in addition to prevention of obesity in later
      life.

PMID- 12466356
TI  - Pedigree analysis of constitutional delay of growth and maturation: determination
      of familial aggregation and inheritance patterns.
AB  - To investigate the genetic basis of constitutional delay of growth and maturation
      (CD), 41 families of CD probands underwent interviews regarding pubertal timing,
      and 12 additional families had history data analyzed from medical records. The
      family histories of the 53 probands (40 boys and 13 girls) were assessed for
      pubertal delay using both strict criteria (pubertal delay >or=2 SD beyond the
      mean) and relaxed criteria (pubertal delay >or=1 SD beyond the mean). These
      pedigrees were compared with 25 control pedigrees. Mean age of menarche was 14.3
      +/- 1.4 yr for mothers of CD probands vs. 12.7 +/- 1.4 yr for mothers of controls
      (P < 0.0001). Thirty-eight percent of CD mothers met the strict 2 SD criteria,
      and an additional 29% met the relaxed 1 SD criteria for pubertal delay. By
      contrast, among the control mothers, 12% met the strict and an additional 8% met
      the relaxed criteria (P < 0.0001 for comparison with CD mothers). CD fathers were
      also more likely than the control fathers to have a history of pubertal delay.
      For first-degree relatives, the estimated relative risk of meeting the 2 SD and 1
      SD criteria for delay in CD vs. control pedigrees were 4.8 and 4.9, respectively;
      estimated relative risk for second-degree relatives were 3.2 and 4.4,
      respectively. Inheritance patterns varied, but many families showed an apparent
      autosomal dominant pattern, with or without incomplete penetrance. Although many
      genes may underlie CD, the inheritance patterns suggest that there are also
      single genes with major effects whose penetrance is likely affected by genetic or
      environmental modifiers. The future identification of these major and modifying
      genes is an exciting prospect that would improve our understanding of the factors
      that regulate human pubertal timing and modulate the human reproductive endocrine
      axis.

PMID- 12466357
TI  - Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with
      glucose intolerance.
AB  - Recent evidence suggests that increased cortisol secretion, altered cortisol
      metabolism, and/or increased tissue sensitivity to cortisol may link insulin
      resistance, hypertension, and obesity. Whether these changes are important in
      type 2 diabetes mellitus (DM) is unknown. We performed an integrated assessment
      of glucocorticoid secretion, metabolism, and action in 25 unmedicated lean male
      patients with hyperglycemia (20 with type 2 diabetes and 5 with impaired glucose
      intolerance by World Health Organization criteria) and 25 healthy men, carefully
      matched for body mass index, age, and blood pressure. Data are mean +/- SE.
      Patients with hyperglycemia (DM) had higher HbA(1c) (6.9 +/- 0.2% vs. 6.0 +/-
      0.1%, P < 0.0001) and triglycerides. Cortisol secretion was not different, as
      judged by 0900 h plasma cortisol and 24 h total urinary cortisol metabolites.
      However, the proportion of cortisol excreted as 5alpha- and 5beta-reduced
      metabolites was increased in DM patients. Following an oral dose of cortisone 25
      mg, generation of plasma cortisol by hepatic 11beta-hydroxysteroid dehydrogenase
      type 1 (11beta-HSD 1) was impaired in DM patients (area under the curve, 3617 +/-
      281 nM.2 h vs. 4475 +/- 228; P < 0.005). In contrast, in sc gluteal fat biopsies
      from 17 subjects (5 DM and 12 controls) in vitro 11beta-HSD 1 activity was not
      different (area under the curve, 128 +/- 56% conversion.30 h DM vs. 119 +/- 21, P
      = 0.86). Sensitivity to glucocorticoids was increased in DM patients both
      centrally (0900 h plasma cortisol after overnight 250 micro g oral dexamethasone
      172 +/- 16 nM vs. 238 +/- 20 nM, P < 0.01) and peripherally (more intense forearm
      dermal blanching following overnight topical beclomethasone; 0.56 +/- 0.92 ratio
      to vehicle vs. 0.82 +/- 0.69, P < 0.05). In summary, in patients with glucose
      intolerance, cortisol secretion, although normal, is inappropriately high given
      enhanced central and peripheral sensitivity to glucocorticoids. Normal 11beta-HSD
      1 activity in adipose tissue with impaired hepatic conversion of cortisone to
      cortisol suggests that tissue-specific changes in 11beta-HSD 1 activity in
      hyperglycemia differ from those in primary obesity but may still be susceptible
      to pharmacological inhibition of the enzyme to reduce intracellular cortisol
      concentrations. Thus, altered cortisol action occurs not only in obesity and
      hypertension but also in glucose intolerance, and could therefore contribute to
      the link between these multiple cardiovascular risk factors.

PMID- 12466358
TI  - The effects of gonadotropin-releasing hormone (GnRH) I and GnRH II on the
      urokinase-type plasminogen activator/plasminogen activator inhibitor system in
      human extravillous cytotrophoblasts in vitro.
AB  - The regulated expression of the urokinase-type plasminogen activator (uPA) and
      plasminogen activator inhibitor (PAI-1) is believed to modulate the invasive
      capacity of human trophoblastic cells in vitro and in vivo. To date, the factors
      capable of regulating the expression of uPA and PAI-1 in these cells remain
      poorly characterized. In these studies, we have examined the ability of the
      classical mammalian GnRH I and the second form of GnRH (GnRH II) to regulate uPA
      and PAI-1 mRNA and protein expression levels in primary cultures of human
      extravillous cytotrophoblasts using quantitative competitive PCR and ELISA,
      respectively. Both GnRH I and II increased uPA and concomitantly decreased PAI-1
      mRNA and protein expression levels in our extravillous cytotrophoblast cultures
      in a dose- and time-dependent manner. Cetrorelix, a peptide GnRH antagonist
      specific for the GnRH I receptor, was capable of inhibiting the regulatory
      effects of GnRH I, but not GnRH II on uPA and PAI-1 expression levels in primary
      cell cultures. Taken together, these observations suggest that GnRH I and GnRH II
      may facilitate trophoblast invasion by increasing the ratio of uPA/PAI-1
      expression via interactions with two distinct GnRH receptors.

PMID- 12466359
TI  - Insulin sensitivity and the insulin-like growth factor system in prepubertal boys
      with premature adrenarche.
AB  - Girls with premature adrenarche (PA), similar to women with polycystic ovarian
      syndrome, display alterations in the IGF system, may have impaired insulin
      sensitivity, and demonstrate unfavorable lipid profiles. Girls with PA are also
      at increased risk for functional ovarian hyperandrogenism. Metabolic studies in
      boys with PA, however, are limited. The objective of this study was to determine
      whether boys with PA show alterations in insulin sensitivity and the IGF system.
      We studied an ethnically heterogeneous group of 19 prepubertal boys: 11 with PA
      (age, 8.2 +/- 0.7 yr; body mass index (BMI)-Z score, 1.8 +/- 1.1) and 8 controls
      (age, 7.9 +/- 0.8 yr; BMI-Z score, 1.2 +/- 1.0). Fasting levels of glucose,
      insulin, proinsulin (P(0)), hemoglobin A1c, testosterone, SHBG, delta4
      androstenedione, dehydroepiandrosterone sulfate, LH, FSH, IGF-I, IGF-binding
      protein-1, IGF-binding protein-3, free IGF-I, and lipids were measured. Ten of 11
      boys with PA and six of eight controls underwent standard oral glucose tolerance
      testing. The insulin response to this test was measured by the insulin area under
      the curve. Measures of insulin sensitivity were calculated as the fasting glucose
      to insulin ratio, quantitative insulin sensitivity check index, and composite
      insulin sensitivity index. All values were adjusted for BMI-Z score. Total IGF-I,
      P(0), ratio of P(0) and fasting insulin level, and log insulin area under the
      curve were higher, and SHBG was lower in the boys with PA, compared with
      controls. Decreased insulin sensitivity was suggested by decreased composite
      insulin sensitivity index. A trend toward greater triglycerides was observed in
      the boys with PA, compared with the controls. Prepubertal boys with PA show
      differences in the IGF system and decreased insulin sensitivity, independent of
      obesity, as observed in girls with PA. These findings suggest that both boys and
      girls with PA should be monitored for the development of insulin resistance and
      associated complications, including diabetes mellitus and cardiovascular disease.

PMID- 12466360
TI  - Tranilast inhibits the proliferation of uterine leiomyoma cells in vitro through
      G1 arrest associated with the induction of p21(waf1) and p53.
AB  - Uterine leiomyoma is a mesenchymal tumor composed of smooth muscle cells with
      fibrous tissues and many mast cells. Tranilast is known to suppress fibrosis or
      to work as a mast cell stabilizer and is reported to inhibit proliferation of
      vascular smooth muscle cells. In this study, we examined the effects of tranilast
      on cultured human leiomyoma cells in vitro to evaluate whether this agent has the
      potential to inhibit the growth of uterine leiomyomas. Tranilast inhibited the
      proliferation of cultured leiomyoma cells in a dose-dependent manner without any
      cytotoxic effect or induction of apoptosis. In association with the inhibitory
      effect, tranilast induced the cyclin-dependent kinase (CDK) inhibitor p21(waf1)
      and tumor suppressor gene p53 and decreased CDK2 activity. These results suggest
      that tranilast arrests the proliferation of uterine leiomyoma cells at the G0/G1
      phase, through the suppression of CDK2 activity via an induction of p21(waf1) and
      p53. Tranilast was concluded to be a potent agent to inhibit proliferative
      activity of uterine leiomyoma cells.

PMID- 12466362
TI  - Inhibin B: a marker for the functional state of the seminiferous epithelium in
      patients with azoospermia factor C microdeletions.
AB  - Testicular production of inhibin B is believed to be dependent on the presence of
      germ cells within the seminiferous tubules. However, this association has
      recently been questioned in patients with deletions of azoospermia factor (AZF)
      on the Y chromosome. We have addressed this problem in 442 unselected
      infertile/subfertile patients (excluding obstructive and iatrogenic forms) who
      were analyzed for Yq microdeletions. AZFc microdeletions were found in 16
      patients (3.8% of the total infertile group, but 9% of the subgroup with
      azoospermia or severe oligozoospermia with sperm concentration <1 x 10(6)/ml).
      The reproductive hormone profiles in patients with AZFc microdeletions were
      analyzed and compared with those in infertile patients without microdeletions and
      those in fertile control individuals. The mean serum inhibin B concentration in
      the patients with AZFc microdeletions (39.5 +/- 36.0 pg/ml) was significantly
      lower than that in the group of infertile patients without microdeletions (134.6
      +/- 88.5 pg/ml). However, no significant difference was found compared with that
      in a matched group of infertile patients with comparably low sperm counts (72.6
      +/- 75.5 pg/ml). Bilateral testicular biopsies in the AZFc-deleted patients
      revealed a variable histological pattern suggestive of a progressive depletion of
      seminiferous epithelium. An association between testicular pathology and the
      reproductive hormone profile was found; the more severe forms had lower inhibin B
      and higher FSH levels. Importantly, if Sertoli cell-only tubules were prevalent
      in the biopsy, inhibin B was invariably undetectable. In patients with bilateral
      spermatocytic arrest, inhibin B remained within the normal range, which is
      consistent with a role of spermatocytes in the maintenance of inhibin B
      secretion. Our data support the view that, in contrast to recently published
      data, in patients with AZF microdeletions the serum concentration of inhibin B is
      dependent upon the functional interaction between Sertoli cells and spermatocytes
      and/or spermatids.

PMID- 12466363
TI  - Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with
      insulin resistance and androgen levels.
AB  - In addition to its orexigenic properties, ghrelin has been shown to modulate the
      secretory pattern of pituitary hormones, and it may exert direct effects on
      peripheral organs such as the gonads and endocrine pancreas. To study possible
      interactions among ghrelin, glucose homeostasis, and the reproductive system, we
      investigated 10 obese women with polycystic ovary syndrome (OB-PCOS) in
      comparison with 10 age- and body mass index-matched obese subjects (OB). Plasma
      levels of insulin, glucose, androgens, and ghrelin were measured at baseline
      condition and after 7 months of therapy (hypocaloric diet + metformin or
      placebo). Plasma ghrelin levels were lower in OB-PCOS than in OB (P < 0.05). A
      strong negative correlation between ghrelin and androstenedione levels was found
      in both populations at baseline (OB-PCOS: P < 0.01; OB: P < 0.001) and after
      therapy (OB-PCOS: P < 0.01; OB: P < 0.05), whereas no correlation was found
      between ghrelin and other androgens. In both groups, the markers of insulin
      resistance in fasting and stimulated conditions (glucose/insulin ratio,
      homeostasis model insulin resistance index, homeostasis model applied to the oral
      glucose tolerance test) demonstrated decreased insulin sensitivity. However, a
      negative correlation between plasma ghrelin and all these markers was observed
      only in the OB-PCOS group (P < 0.05). Accordingly, a negative correlation between
      ghrelin variation and treatment-induced changes of the glucose/insulin ratio,
      HOMA-R, and HOMA(OGTT) was observed only in the OB-PCOS group (P < 0.05). In
      conclusion, OB-PCOS women have lower ghrelin levels than those expected based on
      the presence of obesity. Only in OB-PCOS, ghrelin negatively correlates with
      insulin sensitivity. In addition, regardless of the presence of PCOS, a marked
      negative correlation exists between ghrelin and androstenedione levels,
      suggestive of an interaction between ghrelin and steroid synthesis or action.

PMID- 12466364
TI  - Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not
      increased in human obesity.
AB  - Central obesity is associated with increased morbidity and mortality.
      Preadipocyte proliferation and differentiation contribute to increases in adipose
      tissue mass, yet the mechanisms that underlie these processes remain unclear.
      Patients with glucocorticoid excess develop a reversible form of central obesity,
      but circulating cortisol levels in idiopathic obesity are invariably normal. We
      have hypothesized that the enzyme 11beta-hydroxysteroid dehydrogenase type 1
      (11beta-HSD1), by converting inactive cortisone to active cortisol in adipose
      tissue, might be an important autocrine regulator of fat mass. Paired omental and
      sc fat biopsies were obtained from 32 women (median age, 43 yr; range, 28-65;
      median body mass index, 27.5 kg/m(2); range, 19.7-39.2) undergoing elective
      abdominal surgery. 11beta-HSD1 activity and mRNA levels were assessed in whole
      tissue and in isolated preadipocytes and adipocytes using specific enzyme assays
      and real-time PCR. Preadipocyte proliferation was measured using tritiated
      thymidine incorporation. Whole adipose tissue 11beta-HSD1 mRNA levels did not
      differ between omental and sc samples (P = 0.73). In addition, mRNA levels did
      not correlate with body mass index (omental: r = 0.1; P = 0.6; sc: r = 0.15; P =
      0.4). In keeping with earlier studies, 11beta-HSD1 mRNA levels were higher in
      omental compared with sc preadipocytes. However, in cultured omental
      preadipocytes, 11beta-HSD1 activity inversely correlated with body mass index (r
      = -0.47; P = 0.03). In omental preadipocytes, both cortisol and cortisone
      decreased proliferation (P < 0.05). Inhibition of 11beta-HSD1 with glycyrrhetinic
      acid partially reversed the cortisone-induced decrease in preadipocyte
      proliferation (P < 0.05). Enhanced preadipocyte proliferation within omental
      adipose tissue as a consequence of decreased 11beta-HSD1 mRNA levels and activity
      may contribute to increases in visceral adipose tissue mass in obese patients.

PMID- 12466365
TI  - Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of
      nitric oxide synthase, is elevated in hyperthyroid patients.
AB  - Cardiovascular manifestations are frequent findings in patients with thyroid
      hormone disorders. Nitric oxide (NO) plays a key role in vascular, endothelial
      mediated relaxation. NO is synthesized from L-arginine by NO synthase, an enzyme
      inhibited by endogenous compounds, mainly asymmetric dimethylarginine [asymmetric
      N(G),N(G)-dimethyl-L-arginine (ADMA)]. The aim of our work was to investigate
      whether plasma L-arginine and dimethylarginine concentrations and NO production
      are altered in hypo- and hyperthyroid patients, compared with control subjects. L
      arginine, ADMA and symmetric dimethylarginine were analyzed by HPLC. NO was
      measured as plasma nitrite plus nitrate (NO(x)) concentration by a colorimetric
      method based on Griess reagent. L-arginine, ADMA, and symmetric dimethylarginine
      plasma levels in the hypothyroid group were similar to those of the control
      group; whereas in hyperthyroidism, these values were significantly increased.
      However, the L-arginine/ADMA ratio was decreased in hyperthyroid patients,
      resulting in diminished NO(x) production. When all subjects were analyzed
      together, free T(4) levels were directly correlated with ADMA and inversely
      correlated with NO(x).

PMID- 12466366
TI  - Variation in the amount of T antigen and N-acetyllactosamine oligosaccharides in
      human cervical mucus secretions with the menstrual cycle.
AB  - It has been hypothesized that the carbohydrate portion of mucins present in the
      endocervical canal plays an important role in conferring specific physicochemical
      properties (e.g. viscosity and hydration) to the mucus gel through the menstrual
      cycle. Our recent finding showing an increase in the amount of MUC5B mucin
      protein at midcycle has raised the question of whether the mucin O-glycan content
      also varies to confer specific hydrodynamic properties to secreted mucins during
      ovulation. Using lectins as carbohydrate probes, we have identified two common
      mucin oligosaccharide structures, T antigen and N-acetyllactosamine, within
      secretory granules in human endocervical glands during the proliferative phase of
      the menstrual cycle. Analysis of endocervical secretions by enzyme-linked lectin
      assay revealed that the amounts of T antigen and N-acetyllactosamine are maximal
      at midcycle. Lectin blot assay of immunoprecipitated MUC5B demonstrated that the
      mucin is a carrier of the T antigen and N-acetyllactosamine oligosaccharides in
      cervical mucus secretions. The amounts of T antigen and N-acetyllactosamine
      oligosaccharides on MUC5B increased during the first half of the cycle, peaked at
      midcycle, and dramatically dropped at the end of the cycle. The peak in MUC5B
      mucin protein and carbohydrate content coincides with the change in mucus
      character that occurs at midcycle. The role of O-glycans on mucins may be to hold
      water within the endocervical canal during ovulation to facilitate sperm
      migration.

PMID- 12466367
TI  - Single and combined effects of growth hormone and testosterone administration on
      measures of body composition, physical performance, mood, sexual function, bone
      turnover, and muscle gene expression in healthy older men.
AB  - We examined the effects of GH and/or testosterone (T) administration on body
      composition, performance, mood, sexual function, bone turnover, and muscle-gene
      expression in healthy older men. Ten men [mean (SEM) age, 68 (2.5) yr; height,
      171.5 (2.4) cm; and weight, 80 (3.0) kg] completed each of the following 1-month,
      double-blind interventions after a baseline (B) study in randomized order with an
      intervening 3-month washout: transdermal T patch (5.0 mg/daily); recombinant
      human GH (6.25 micro g/kg sc daily); and combined hormones (GHT). ANOVA with
      repeated measures was used to evaluate interventional effects. Integrated serum
      GH concentrations [mean (SEM)] were elevated comparably by GH and GHT: [B = 363
      (55), GH = 1107 (120), T = 459 (131), and GHT = 1189 (46) micro g/liter.min; P <
      0.0001]. Serum IGF-I concentrations also increased commensurately after GH and
      GHT: [B = 168 (14), GH = 285 (16), T = 192 (25), and GHT = 294 (25) micro
      g/liter; P < 0.0001]. GHT administration increased total estradiol: [B = 110
      (20), GH = 106 (13), T = 129 (13), and GHT = 153 (17) pmol/liter; P < 0.02], and
      both T and GHT elevated free T: [B = 12 (2.1), GH = 11 (1.5), T = 22 (2.8), and
      GHT = 24 (2.5) pg/ml; P < 0.0001]. No significant changes occurred in strength,
      flexibility, percentage body fat, or sexual function and mood. However, fat-free
      mass increased under combined GHT exposure: [B = 55 (1.3), GH = 56 (1.1), T = 55
      (1.5), GHT = 57 (1.7) kg; P < 0.03]. Balance improved in response to GH
      intervention (P < 0.05), as did 30-m walk time during T and GHT interventions [B
      = 6.6 (0.3), GH = 6.2 (0.7), T = 5.9 (0.3), GHT = 5.5 (0.3) sec; P = 0.04] and
      stair climb time for all three interventions [B = 32.2 (1.4), GH = 29.8 (1.2), T
      = 30.5 (1.4), and GHT = 29.9 (1.2) sec (P = 0.0034), wherein the effects of GH,
      T, and GHT were different from that of B]. Muscle IGF-I gene expression increased
      by 1.9-fold during GH administration and by 2.3-fold during GHT administration (P
      < 0.05, compared with B). Myostatin and androgen receptor gene expression were
      not affected. Serum osteocalcin increased in response to the GH and GHT
      interventions: [B = 4.8 (0.52), GH = 5.7 (0.54), T = 4.7 (0.33), and GHT = 5.5
      (0.39); P <0.009]. There were no significant adverse events during 30 patient
      months of intervention. We conclude that 1 month of GH and/or T administration
      improves certain measures of balance and physical performance in older men and
      increases muscle IGF-I gene expression.

PMID- 12466368
TI  - A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg
      multiple endocrine neoplasia type 2A kindred presenting with an
      adrenocorticotropin-producing pheochromocytoma.
AB  - Multiple endocrine neoplasia type 2 (MEN 2) comprises a heterogeneous group of
      neoplasic disorders that most commonly have a single missense substitution of the
      RET protooncogene (RET) involving exons 10 and 11. It was previously reported a
      MEN 2A kindred in which the father presented with a rare phenotype consisting of
      bilateral ACTH-producing pheochromocytoma and medullary thyroid carcinoma. We
      recently performed mutational analysis of the father and his 4 children using a
      denaturing gradient gel electrophoresis approach and PCR-amplified genomic DNA,
      followed by direct sequencing or restriction fragment length polymorphism
      testing. All 4 children showed a RET sequence variation. The common exon 11
      Cys(634)Arg RET mutation was present in 2 of the 4 children who had undergone
      thyroidectomy for C cell disease. The remaining 2 children, who did not harbor
      the Cys(634)Arg mutation and are negative for C cell and adrenal disease, carry a
      previously unreported Val(648)Ile missense change in RET exon 11. This novel
      substitution was not found in the unaffected mother or in 200 control alleles.
      Both RET variants were present in the father affected with MEN 2A and the unusual
      ACTH-producing pheochromocytoma. We speculate that the double RET mutation may
      have modified and contributed to the rare MEN 2A phenotype in the father.

PMID- 12466369
TI  - Differential regulation of adiponectin secretion from cultured human omental and
      subcutaneous adipocytes: effects of insulin and rosiglitazone.
AB  - Adiponectin is an adipocyte-derived plasma protein with insulin-sensitizing and
      antiatherosclerotic properties. Because adipose tissue depots differ in the
      strength of their association with the adverse metabolic consequences of obesity,
      we studied the secretion of adiponectin in vitro from paired samples of isolated
      human omental and sc adipocytes and its regulation by insulin and rosiglitazone.
      Cells were incubated for 12 or 24 h with and without treatment with 100 nM
      insulin, 8 micro M rosiglitazone, or both combined; adiponectin secreted into the
      culture medium was measured by a RIA with a human adiponectin standard and
      normalized for cellular DNA content. Secretion of adiponectin by omental cells
      was generally higher than sc cells and showed a strong negative correlation with
      body mass index (r = -0.78;P = 0.013). In contrast, secretion from the sc cells
      was unrelated to body mass index. Compared with sc-derived adipocytes,
      adiponectin secretion from omental cells was increased by insulin or
      rosiglitazone alone and was up to 2.3-fold higher following combined treatment
      with insulin and rosiglitazone, whereas secretion from sc adipose cells was
      unaffected by these treatments. These data suggest that reduced secretion from
      the omental adipose depot may account for the decline in plasma adiponectin
      observed in obesity. Furthermore, enhanced adiponectin secretion from fat cells
      derived from the visceral compartment in response to rosiglitazone alone or in
      combination with insulin may play a role in some of the systemic insulin
      sensitizing and antiinflammatory properties of the thiazolidinediones.

PMID- 12466370
TI  - Growth hormone blunts protein oxidation and promotes protein turnover to a
      similar extent in abdominally obese and normal-weight women.
AB  - Abdominally obese individuals have reduced 24-h plasma GH concentrations. Their
      normal plasma IGF-I levels may reflect GH hypersensitivity. Alternatively,
      obesity-associated hyposomatotropism may cause less biological effect in target
      tissues. We therefore determined whole-body responsiveness to the anabolic
      effects of GH in abdominally obese (OB) and normal weight (NW) premenopausal
      women. A 1-h iv infusion of GH or placebo was randomly administered to six NW
      (body mass index, 21.1 +/- 1.9 kg/m(2)) and six OB (body mass index, 35.5 +/- 1.5
      kg/m(2)) women in a cross-over design. Endogenous insulin, glucagon and GH
      secretion was suppressed by infusion of somatostatin. Whole-body protein turnover
      was measured using a 10-h infusion of [(13)C]-leucine. GH administration induced
      a similar plasma GH peak in NW and OB women (49.8 +/- 10.4 vs. 45.1 +/- 5.6
      mU/liter). GH, compared with placebo infusion, increased nonoxidative leucine
      disposal, P < 0.0001) and endogenous leucine appearance (R(a), P = 0.0004) but
      decreased leucine oxidation (P = 0.0051). All changes were similar in both
      groups. Accordingly, whole-body GH responsiveness, defined as the maximum
      response of nonoxidative leucine disposal, leucine R(a), and oxidation per unit
      of GH, was not different in OB and NW women (0.25 +/- 0.18 vs. 0.19 +/- 0.17
      micro mol/kg.h, 0.21 +/- 0.23 vs. 0.13 +/- 0.17 micro mol/kg.h, and -0.10 +/-
      0.08 vs. -0.08 +/- 0.05 micro mol/kg.h, respectively). These results indicated
      that whole-body tissue responsiveness to the net anabolic effect of GH is similar
      in OB and NW women. Hence, we inferred that hyposomatotropism may promote amino
      acid oxidation and blunt protein turnover in abdominal obesity. However,
      hyposomatotropism cannot account for all anomalous features of protein metabolism
      in abdominally obese humans.

PMID- 12466371
TI  - Differential expression of the adenylyl cyclase-stimulatory guanosine
      triphosphate-binding protein G(s)alpha in the human myometrium during pregnancy
      and labor involves transcriptional regulation by cyclic adenosine 3',5'
      monophosphate and binding of phosphorylated nuclear proteins to multiple GC boxes
      within the promoter.
AB  - G(s)alpha is the G protein subunit that stimulates adenylyl cyclase activity in
      the myometrium during pregnancy, raising intracellular levels of the smooth
      muscle relaxant cAMP. The promoter region of the gene encoding G(s)alpha is GC
      rich and contains multiple putative binding sites for the specificity protein
      (Sp) transcription factor family. In electrophoretic mobility shift assays, four
      of these Sp sites were bound by recombinant Sp1 protein. Binding was dependent on
      phosphorylation of Sp1 by protein kinase A. Phosphorylated Sp1-4 proteins were
      observed in extracts of cultured human myometrial cells, but in electrophoretic
      mobility shift assays G(s)alpha promoter sequence binding by Sp1 was not
      apparent. Instead, these assays showed phosphorylation-dependent G(s)alpha
      promoter binding by lower molecular weight myometrial proteins that could not be
      supershifted by antibodies specific to Sp1-4 proteins. To investigate the
      regulation of G(s)alpha expression, the GC-rich promoter region was used to
      direct transcription of a firefly luciferase reporter gene in transient
      transfection assays of primary human myometrial cell cultures, COS-7 and HEK 293
      cells. Reporter gene expression was found to follow a biphasic response to
      forskolin and 8-bromo-cAMP, with an initial, concentration-dependent increase in
      luciferase activity, followed by a prolonged decrease. In myometrial cells, this
      pattern was also seen in response to treatment with human chorionic gonadotropin.

PMID- 12466372
TI  - Activity and protein expression of the Na+/H+ exchanger is reduced in
      syncytiotrophoblast microvillous plasma membranes isolated from preterm
      intrauterine growth restriction pregnancies.
AB  - Regulation of syncytiotrophoblast intracellular pH is critical to optimum
      enzymatic and transport functions of the placenta. Previous studies of Na(+)/H(+)
      exchanger (NHE) activity in the placenta from pregnancies complicated by
      intrauterine growth restriction (IUGR) have produced conflicting results. The
      possible role of altered placental pH regulation in the development of acidosis
      in some fetuses subjected to IUGR remains to be fully established. We
      investigated the activity and protein expression of the NHE in
      syncytiotrophoblast microvillous (MVM) plasma membranes isolated from preterm and
      term placentas obtained from uncomplicated and IUGR pregnancies. Western blotting
      showed that the expression of NHE isoforms 1, 2, and 3 was approximately 10-fold
      greater in MVM than in basal plasma membrane (BM). Immunohistochemistry localized
      NHE-1 and NHE-2 to MVM and BM and NHE-3 to the MVM, BM, and cytoplasm of the
      syncytiotrophoblast. NHE-1 expression in MVM from preterm IUGR placentas was
      reduced by 55%, compared with gestational age-matched controls (P < 0.05, n = 6
      and n = 16, respectively), whereas NHE-1 expression was unaltered in term IUGR
      placentas (n = 8). The activity (amiloride-sensitive Na(+) uptake) of NHE in MVM
      from IUGR preterm placentas was reduced by 48% (P < 0.05, n = 6). In contrast,
      MVM NHE activity was unchanged in term IUGR (n = 7). Using Northern blotting, no
      difference could be demonstrated in NHE-1 mRNA expression between IUGR and
      control groups. The reduced activity and expression of NHE in MVM of preterm IUGR
      placentas may compromise placental function and may contribute to the development
      of fetal acidosis in preterm IUGR fetuses.

PMID- 12466373
TI  - 11beta-hydroxysteroid dehydrogenase types 1 and 2: an important pharmacokinetic
      determinant for the activity of synthetic mineralo- and glucocorticoids.
AB  - The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) system plays a pivotal role
      in glucocorticoid (GC) and mineralocorticoid (MC) action. Although 11beta-HSD
      activities are important determinants for the efficacy of synthetic MCs and GCs,
      corresponding pharmacokinetic data are scanty. Therefore, we characterized 11beta
      HSD profiles for a wide range of steroids often used in clinical practice. 11beta
      HSD1 and 11beta-HSD2 were selectively examined in 1) human liver and kidney
      cortex microsomes, and 2) Chinese hamster ovarian cells stably transfected with
      11beta-HSD1 or 11beta-HSD2 expression vectors. Both systems produced concordant
      evidence for the following conclusions. Oxidation of steroids by 11beta-HSD2 is
      diminished if they are fluorinated in position 6alpha or 9alpha (e.g. in
      dexamethasone) or methylated at 2alpha or 6alpha (in methylprednisolone) or
      16alpha or 16beta, by a methylene group at 16 (in prednylidene), methyloxazoline
      at 16, 17 (in deflazacort), or a 2-chlor configuration. Whereas the methyl groups
      also decrease reductase activity (steric effects), fluorination increases
      reductase activity (negative inductive effect), leading to a shift to reductase
      activity. This may explain the strong MC activity of 9alpha-fluorocortisol and
      should be considered in GC therapy directed to 11beta-HSD2-expressing tissues
      (kidney, colon, and placentofetal unit). 11beta-HSD2 oxidation of prednisolone is
      more effective than that of cortisol, explaining the reduced MC activity of
      prednisolone compared with cortisol. Reduction by 11beta-HSD1 is diminished by
      16alpha-methyl, 16beta-methyl, 2alpha-methyl, and 2-chlor substitution, whereas
      it is increased by the Delta(1)-dehydro configuration in prednisone, resulting in
      higher hepatic first pass activation of prednisone compared with cortisone. To
      characterize a GC or a MC as substrate for the different 11betaHSDs may be
      essential for an optimized steroid therapy.

PMID- 12466374
TI  - Anovulation in eumenorrheic, nonobese adolescent girls born small for gestational
      age: insulin sensitization induces ovulation, increases lean body mass, and
      reduces abdominal fat excess, dyslipidemia, and subclinical hyperandrogenism.
AB  - Adolescent girls born small for gestational age (SGA) are at risk for
      anovulation, hyperinsulinism, subclinical hyperandrogenism, dyslipidemia, and
      central adiposity. Hyperinsulinemic insulin resistance has been proposed as a key
      pathogenetic factor underpinning these associations. We have tested this
      hypothesis in an intervention study by assessing the effects of insulin
      sensitization (metformin treatment, 850 mg/d for 3 months) in eumenorrheic,
      nonobese, anovulatory SGA adolescents [n = 13; mean birth weight, 2.3 kg; age, 15
      yr; body mass index (BMI), 20.5 kg/m(2); >or=3 yr post-menarche] who were in a
      steady state (over approximately 6 months) for BMI, hyperinsulinism, subclinical
      hyperandrogenism, and dyslipidemia, and who presented a deficit of lean body mass
      and an excess of (truncal and abdominal) fat mass. Metformin treatment was
      accompanied by a drop in fasting insulin and serum androgens and by a less
      atherogenic lipid profile (all P <or= 0.01). After 3 months on metformin, all
      identified aberrations in body composition were attenuated, the most marked
      changes (P < 0.0001) being a reduction of the excess in abdominal fat and of the
      deficit in lean body mass; BMI remained unaltered. Finally, 6 of 13 girls became
      ovulatory after about 6 wk on metformin, and 9 of 13 (69%) ovulated within 11 wk
      on metformin. In conclusion, these observations corroborate the notion that
      anovulation, an excess of abdominal fat mass, and a deficit of lean mass in
      nonobese SGA adolescents are essentially underpinned by hyperinsulinemic insulin
      resistance, and that sensitization to insulin is an effective approach to correct
      these abnormalities and, conceivably, to prevent them.

PMID- 12466375
TI  - Eutopic overexpression of vasopressin v1a receptor in adrenocorticotropin
      independent macronodular adrenal hyperplasia.
AB  - Arginine vasopressin (AVP) stimulates cortisol secretion through its vascular
      type V(1a) receptor in the adrenal glands, in addition to stimulating ACTH
      secretion through pituitary V(3) receptor. Because hyper-response of plasma
      cortisol to vasopressin is documented in some patients with Cushing's syndrome
      due to adrenal adenoma (CS) or ACTH-independent macronodular adrenocortical
      hyperplasia (AIMAH), we analyzed the expression of V(1a), V(2), V(3) receptor and
      AVP mRNA in human adrenal tissues by quantitative competitive RT-PCR or real-time
      PCRs. V(1a) receptor mRNA levels (ratio against glyceraldehyde 3-phosphate
      dehydrogenase) were 0.378 +/- 0.143 (mean +/- SE) in preclinical CS (n = 5) and
      0.630 +/- 0.072 in AIMAH (n = 4), which were significantly higher than those
      (0.046 +/- 0.012; n = 9) in control adrenals, whereas those in overt CS (0.143 +/
      0.048; n = 10) or aldosterone-producing adenomas (0.069 +/- 0.018; n = 12) were
      similar to control adrenals. Although ectopic expression of V(2) or V(3) receptor
      was detected in half of AIMAH cases, the absolute levels were low. Furthermore,
      V(1a) receptor mRNA levels in the adjacent adrenal glands (0.190 +/- 0.039, n =
      9) of aldosterone-producing adenomas were higher than those in control adrenals
      and in the corresponding tumor portions (0.079 +/- 0.024). In contrast, there
      were no significant differences in AVP mRNA levels among these groups. These
      results suggest that eutopic V(1a) receptor overexpression is involved in the
      etiology of AIMAH and a subset of adrenal adenomas causing overt or preclinical
      Cushing's syndrome. Our results imply a possible association of V(1a) receptor
      expression with adrenal hyperplasia.

PMID- 12466376
TI  - Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by
      three novel missense CYP17 mutations identified in patients with P450c17
      deficiency.
AB  - The microsomal enzyme cytochrome P450c17 is an important regulator of
      steroidogenesis. The enzyme has two functions: 17alpha-hydroxylase and 17,20
      lyase activities. These functions determine the ability of adrenal glands and
      gonads to synthesize 17alpha-hydroxylated glucocorticoids (17alpha-hydroxylase
      activity) and/or sex steroids (17,20-lyase activity). Both enzyme functions
      depend on correct steroid binding, but it was recently shown that isolated lyase
      deficiency can also be caused by mutations located in the redox partner
      interaction domain. In this article we present the clinical history and molecular
      analysis of two patients with combined 17alpha-hydroxylase/17,20-lyase deficiency
      and four patients with isolated 17,20-lyase deficiency. In these six patients,
      four missense CYP17 mutations were identified. Two mutations were located in the
      steroid-binding domain (F114V and D116V), and the other two mutations were found
      in the redox partner interaction domain (R347C and R347H). We investigated the
      activity of these mutated proteins by transfection experiments in COS-1 cells
      using pregnenolone, progesterone, or their hydroxylated products as a substrate
      and measuring 17alpha-hydroxylase- and 17,20-lyase-dependent metabolites in the
      medium. The mutations in the steroid-binding domain (F114V and D116V) of P450c17
      caused combined, complete (F114V), or partial (D116V) 17alpha-hydroxylase and
      17,20-lyase deficiencies, whereas mutations in the redox partner interaction
      domain (R347C and R347H) displayed less severe 17alpha-hydroxylase deficiency,
      but complete 17,20-lyase deficiency. These findings are consistent with the
      clinical data and support the observation that the redox partner interaction
      domain is essential for normal 17,20-lyase function of P450c17.

PMID- 12466377
TI  - Administration of insulin-like growth factor I to rhesus monkeys does not augment
      gonadotropin-stimulated ovarian steroidogenesis.
AB  - Although it is well established that IGF-I is able to amplify the actions of FSH
      and LH on ovarian cells in vitro, little information is available regarding the
      effects of IGF-I on ovarian function in vivo. To address this question, rhesus
      monkeys whose spontaneous gonadotropin secretion was interrupted with a GnRH
      antagonist received continuous iv infusions of saline, IGF-I (240 microg/kg.d),
      or IGF-I (240 microg/kg.d) plus human GH (hGH) (200 microg/kg.d) 7 d before and
      continuing throughout a 15-d iv infusion of hFSH and hLH during which serum LH
      concentrations were maintained at 7-10 mIU/ml and FSH concentrations were
      incrementally increased every 3 d from 7.5 to 17.5 mIU/ml. Serum estradiol
      concentrations in saline-treated control animals did not differ (P > 0.05) from
      animals treated with IGF-I + hGH. In contrast, serum estradiol levels in IGF-I
      treated animals were significantly less (P < 0.05) than those of control or IGF-I
      + hGH-treated animals. Serum androstenedione levels did not differ among the
      three treatment groups. Analysis of follicular fluids on the final day of
      gonadotropin infusion indicated that intrafollicular IGF-I concentrations
      paralleled serum IGF-I concentrations in all treatment groups. Measurement of the
      ratio of IGF-I to IGF-binding protein-3 in follicular fluids indicated that there
      was not a disproportionate increase in I-binding protein-3 in animals infused
      with either IGF-I alone or IGF-I + hGH. Concentrations of GH in follicular fluids
      of IGF-I treated animals were less than control animals suggesting that the
      diminished responsiveness of ovaries to FSH in the IGF-I treatment group may have
      been due to reduced GH.

PMID- 12466379
TI  - Expression of interleukin-10 and its receptor is up-regulated in early pregnant
      versus cycling human endometrium.
AB  - Previous reports suggest that systemic and/or placental presence of T helper 2
      type cytokines would be supportive of normal pregnancy. Among these cytokines, IL
      10 is thought to be produced at the feto-maternal interface to control fetal
      ablating immune responses. However, expression of IL-10 in nonhemopoietic
      maternal cells of the human uterus has not been characterized in detail. Thus, we
      studied the expression and modulation of the cytokine and its receptor in human
      endometrial cells obtained in different phases of the cycle and in early
      pregnancy. Both cycling and pregnant endometrium express the genes for IL-10 and
      its receptor, but secretion of the cytokine was significantly increased in
      decidual cultures compared with that by endometrial cells in both proliferative
      and secretory phases of the cycle. Similarly, the expression of IL-10 receptor
      mRNA was up-regulated in early decidua compared with that in menstrual cycle
      dependent endometrium. IL-1beta, but not gonadal steroid hormones, was able to
      directly increase endometrial/decidual IL-10 production. Based on the activity of
      IL-10 in other nonhemopoietic cell populations, we also evaluated its potential
      effects on TNFalpha secretion and proliferation of endometrial/decidual cells,
      but we were unable to demonstrate any direct role of IL-10 as a regulator of
      these specific functions. It is evident that IL-10 and its receptor are normal
      constituents of endometrium and early decidua, and their up-regulation during
      early pregnancy may participate in the T helper type 2 predominance at the feto
      maternal interface. The inability of the cytokine to exert autocrine effects on
      TNFalpha secretion and proliferation of decidual cells leads to speculation that
      the cytokine acts mostly as a paracrine mediator able to affect maternal immune
      responses.

PMID- 12466380
TI  - Impact of experimental blockade of peripheral growth hormone (GH) receptors on
      the kinetics of endogenous and exogenous GH removal in healthy women and men.
AB  - Organs that respond to and metabolize GH are enriched in cognate high-affinity
      receptors. However, whether isologous receptors mediate the de facto access of
      ligand to cellular degradative pathways is not known. To address this query, we
      assessed the distribution and whole-body elimination kinetics of (endogenous and
      exogenous) GH before and after administration of a novel, potent, and selective
      recombinant human (rh) GH receptor antagonist peptide, pegvisomant. Sixteen
      healthy young adults (nine men and seven women) participated in a double-blind,
      prospectively randomized, within-subject cross-over study. The intervention
      comprised a single sc injection of placebo vs. a high dose of pegvisomant (1
      mg/kg sc) timed 62 and 74 h before the overnight sampling and daytime infusion
      sessions, respectively. The half-life, metabolic clearance rate (MCR), and
      distribution volume of GH were quantitated by way of: 1) deconvolution analysis
      of serum GH concentration time series collected every 10 min for 10 h; 2)
      exponential regression analysis of the decay of GH concentrations after a 6-min
      iv pulse of rhGH (1 and 10 micro g/kg); 3) calculation of the MCR during constant
      iv infusion of rhGH (0.5 and 5.0 micro g/kg every 2 h); and 4) exponential
      fitting of the elimination time-course of GH concentrations following cessation
      of each constant infusion. Concentrations of GH and pegvisomant were measured in
      separate, noncross-reactive, two-site monoclonal, immunofluorometric assays.
      Pegvisomant concentrations averaged 4860 +/- 480 micro g/liter (+/-SEM) across
      the infusion interval, thus exceeding low steady state GH concentrations by 3000
      fold. Inhibitory efficacy of the GH receptor antagonist peptide was affirmed by
      way of a 34% reduction in the serum total IGF-I concentration, i.e., from 257 +/-
      37 (placebo) to 170 +/- 24 (drug) micro g/liter (P < 0.001); and a reciprocal 77%
      elevation of the (10-h) mean GH concentration, i.e., from 1.3 +/- 0.23 (placebo)
      to 2.3 +/- 0.42 (drug) micro g/liter (P = 0.003). ANOVA disclosed that prior
      administration of pegvisomant (compared with placebo) did not alter: 1) the
      calculated half-life (minutes) of secreted GH, which averaged 15 +/- 1.3
      (placebo) and 14 +/- 0.69 (drug); 2) the half-time of disappearance (minutes) of
      an iv pulse of rhGH, 15 +/- 1.0 (placebo) and 13 +/- 0.5 (drug) (for the 10 micro
      g/kg dose); 3) the distribution volume (milliliters per kilogram) of rhGH, 59 +/-
      6.2 (placebo) and 58 +/- 3.5 (drug); 4) the steady state GH concentration
      (micrograms per liter) attained during constant iv infusion of rhGH (at a rate of
      5 micro g/kg every 2 h), 18.2 +/- 2.4 (placebo) and 18.3 +/- 2.3 (drug); 5) the
      half-life (minutes) of elimination of GH from equilibrium, 16 +/- 0.98 (placebo)
      and 16 +/- 1.8 (drug); and 6) the steady state MCR (liters per kilogram per day)
      of rhGH, 3.8 +/- 0.32 (placebo) and 3.5 +/- 0.31 (drug). In ensemble, the present
      data refute the a priori postulate that vascular-accessible GH receptors
      determine the in vivo pseudoequilibrium kinetics of GH disappearance in the
      human.

PMID- 12466381
TI  - Is the short follicular phase in older women secondary to advanced or accelerated
      dominant follicle development?
AB  - This study sought to determine whether the shortened follicular phase in
      ovulatory older women is secondary to advanced (i.e. earlier) or accelerated
      (i.e. more rapid) folliculogenesis. Normal ovulatory women, aged 40-45 yr (n =
      15) and 20-25 yr (n = 13), underwent daily venipuncture and transvaginal
      ultrasonography throughout the follicular phase of a spontaneous menstrual cycle
      (control cycle) and after pituitary down-regulation with a GnRH agonist (study
      cycle). As expected, the older subjects in the control cycles demonstrated an
      elevated d 3 FSH and a shortened follicular phase compared with the younger
      subjects. After release from hypothalamic-pituitary-ovarian axis suppression, the
      early follicular phase FSH peak occurred earlier (6.8 vs. 9.8 d; P < 0.01) and
      was of a greater magnitude (12.1 vs. 6.5 mIU/ml; P < 0.01) in the older subjects.
      The time from release of suppression until the subsequent LH surge was also
      shorter (17.5 vs. 20.8 d; P < 0.01) in the older group. However, the time from
      FSH peak to LH surge was similar in the older and younger groups (10.7 vs. 11.0
      d; P = 0.74). Compared with younger women, older subjects had normal follicular
      phase levels of estradiol and inhibin A and lower levels of inhibin B in both
      control and study cycles. We conclude that the shortened follicular phase
      observed in older ovulatory women is due to earlier dominant follicle selection,
      independent of hormonal influences from the preceding luteal phase.

PMID- 12466382
TI  - Characterization of morphological and cytoskeletal changes in trophoblast cells
      induced by insulin-like growth factor-I.
AB  - IGF-I and IGF-II were appeared to play major roles in the adhesive and migratory
      events that are considered to be crucial in the implantation process. The purpose
      of this study was to determine the effects of IGF-I on trophoblast adhesion to
      extracellular matrix. Trophoblast cells obtained from early gestation at
      artificial abortion were incubated with the indicated doses of IGF-I at the
      indicated times. Trophoblast cells were treated with IGF-I in the presence or
      absence of RGD peptide and an antibody against alpha-subunit of IGF-I receptor
      (alphaIR3). Morphometric and morphological changes were studied using light and
      electron microscopy. Furthermore, vinculin, actin stress fibers, phosphorylated
      focal adhesion kinase (FAK), phosphotyrosine, and paxillin were immunolocalized
      in trophoblast cells after IGF-I treatment in the presence or absence of
      alphaIR3. Immunoprecipitation and anti-phosphotyrosine immunoblotting were
      carried out to detect the phosphorylated FAK and phosphorylated paxillin contents
      of the IGF-I-treated and untreated trophoblast cells. The results showed that IGF
      I promoted trophoblast adhesion to fibronectin substrate in a time- and dose
      dependent manner, and addition of RGD peptide and alphaIR3 monoclonal antibody
      abolished the effects of IGF-I in these cells. Morphological studies exhibited an
      increase in the lamellipodia formation upon IGF-I treatment, and confocal images
      of immunofluorescent staining revealed localization of phosphorylated FAK,
      paxillin, and vinculin at focal adhesions as well as redistribution of actin
      microfilaments and formation of actin stress fibers inside the cell. Western
      blotting, using antiphosphotyrosine demonstrated proteins with molecular masses
      of 125 kDa (FAK) and 68 kDa (paxillin) present in the IGF-I-treated cells, which
      were lacking in the control groups. In conclusion, these findings suggest that
      IGF-I can stimulate lamellipodia formation and promote adhesion of trophoblast
      cells to extracellular matrix by activating their adhesion molecules that must be
      activated within the implantation window.

PMID- 12466383
TI  - Systemic distribution of steroid sulfatase and estrogen sulfotransferase in human
      adult and fetal tissues.
AB  - Estrogens play a key role in various target tissues. Enzymes involved in the
      biosynthesis and metabolism of these sex steroids also regulate estrogenic
      actions in these tissues. Estrone sulfate (E1S) is a major circulating plasma
      estrogen that is converted into the biologically active estrogen, estrone (E1),
      by steroid sulfatase (STS). E1 is also sulfated and reverted into E1S by estrogen
      sulfotransferase (EST). These two enzymes have recently been shown to play
      important roles in the in situ estrogen actions of various sex steroid-dependent
      human tumors. However, the distribution of STS and EST in normal adult and fetal
      human tissues remains largely unknown. Therefore, in this study, in addition to
      examining the tissue distribution of both STS and EST mRNA in human adult and
      fetal tissues using RT followed by quantitative PCR, we studied the activity of
      these enzymes using (3)H-labeled E1/E1S as substrates in the homogenates of
      various human adult tissues. We also examined the localization of STS and EST
      protein in human adult and fetal tissues using immunohistochemistry, and that of
      EST mRNA in the adult kidney using laser dissection microscopy and PCR. STS mRNA,
      enzyme activity, and immunoreactivity were either absent or detected at very low
      levels in all adult and fetal tissues examined in this study. EST mRNA
      expression, however, was detected in all of the tissues examined, except for
      adult spleen and pancreas. EST enzyme activities were consistent with those of
      mRNA expression in the great majority of the tissues examined. Marked EST
      immunoreactivity was detected in hepatocytes, adrenal gland (adult, zona
      fasciculate to the reticularis; fetus, fetal zone), and epithelial cells of the
      gastrointestinal tract, smooth muscle cells of the tunica media in aorta, Leydig
      cells of the testis, and syncytiotrophoblast of the placenta. Patterns of EST
      immunolocalization were similar between adult and fetal human tissues, but EST
      immunoreactivity was detected in the urinary tubules of adult kidney, whereas in
      the fetal kidney, it was localized in the interstitial cells surrounding the
      urinary tubules. In the adult kidney, the presence of EST mRNA was also confirmed
      in the cells of urinary tubules using laser dissection microscopy and RT-PCR.
      Although the number of human tissues available for examination in this study was
      limited, our results suggest that between the enzymes involved in estrogen
      activation or inactivation, EST and not STS is the more widely expressed enzyme
      in various peripheral tissues in humans. We speculate that EST may play an
      important role in protecting peripheral tissues from possible excessive
      estrogenic effects.

PMID- 12466386
TI  - Close juxtapositions between luteinizing hormone-releasing hormone-immunoreactive
      neurons and corticotropin-releasing factor-immunoreactive axons in the human
      diencephalon.
AB  - Gonadal functions are modulated by corticotropin-releasing factor (CRF) in the
      rat via direct suppression of LH-releasing hormone (LHRH) release. Although there
      is evidence of direct morphological contacts between the LHRH and CRF
      immunoreactive (-IR) structures in the rat hypothalamus, little is known about
      the morphological base of CRF-influenced LHRH release in man. Thus, we studied
      the distribution of the CRF-IR and LHRH-IR systems in the human diencephalon and
      revealed putative CRF-LHRH juxtapositions using double label
      immunohistochemistry. LHRH-IR cells were present mainly in the infundibular
      region and the medial preoptic area. CRF-IR neuronal structures were observed in
      the periventricular area, paraventricular nucleus, infundibular region, and
      median eminence. CRF-LHRH juxtapositions were found mainly in the infundibulum
      and median eminence. Few juxtapositions were detected in the medial preoptic
      area. In these regions, black diaminobenzidine/silver-labeled CRF-IR fibers
      abutted fusiform brown diaminobenzidine-labeled LHRH neurons, usually forming
      multiple contacts. Examination of semithin sections of these close associations
      with the aid of oil immersion revealed no cleft between CRF-IR nerve terminals
      contacting LHRH-IR structures. These findings suggest that the juxtapositions
      between the LHRH-IR and CRF-IR neurons may be functional synapses forming the
      morphological substrate of the CRF-controlled LHRH secretion. Moreover, the wide
      distribution of CRF-IR elements suggests that CRF controls other diencephalic
      functions as well.

PMID- 12466384
TI  - The mitogenic potential of heparin-binding epidermal growth factor in the human
      endometrium is mediated by the epidermal growth factor receptor and is modulated
      by tumor necrosis factor-alpha.
AB  - Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal
      growth factor (EGF) family, is implicated in a variety of biological processes,
      including reproduction. Previous studies describe increased levels of HB-EGF in
      the human endometrium during the midsecretory stage of the menstrual cycle,
      suggesting a function for HB-EGF in implantation of the human blastocyst. Here we
      have investigated the expression and function of the soluble and transmembrane
      forms of HB-EGF in the human endometrium. We show that the expression of the
      transmembrane form of HB-EGF in the human endometrium is modulated according to
      the stage of the menstrual cycle. We present data demonstrating that both the
      soluble and transmembrane forms of HB-EGF induce DNA synthesis in human
      endometrial stromal cells. Furthermore, TNFalpha has a cooperative effect on HB
      EGF, EGF, TGFalpha, and betacellulin-induced DNA synthesis in stromal cells,
      suggesting roles for the EGF family and TNFalpha in regeneration and maturation
      of human endometrium. Induction of DNA synthesis by HB-EGF and its modulation by
      TNFalpha in endometrial stromal cells are mediated by the EGF receptor and not
      the HB-EGF receptor ErbB4. Our data suggest key functions for HB-EGF, TNFalpha,
      and the EGF receptor in endometrial maturation, via autocrine/paracrine and
      juxtacrine pathways, in preparation for embryo implantation.

PMID- 12466387
TI  - Estradiol and interleukin-1beta exert a synergistic stimulatory effect on the
      expression of the chemokine regulated upon activation, normal T cell expressed,
      and secreted in endometriotic cells.
AB  - Endometriosis, commonly associated with intraperitoneal inflammation, is estrogen
      dependent. Possible links between the immunoinflammatory and endocrine changes
      observed in endometriotic women have been poorly understood. In this study, we
      report that estradiol (E(2)) and IL-1beta exert a synergistic stimulatory action
      on RANTES (regulated upon activation, normal T cell expressed, and secreted)
      expression by endometriotic cells. Treatment of endometriotic cells with IL-1beta
      had a dose-dependent effect on RANTES protein secretion and mRNA steady state
      levels, whereas cell treatment with E(2) or progesterone had no detectable
      effect. Interestingly, treatment of endometriotic cells with E(2) before
      stimulation with IL-1beta resulted in a further increase in RANTES protein
      secretion and mRNA steady state levels, compared with IL-1beta alone, whereas
      treatment with progesterone did not significantly affect cell responsiveness to
      IL-1beta. Assessment of RANTES mRNA half-life revealed that cell pretreatment
      with E(2) enhanced RANTES mRNA stability and increased gene transcription as
      shown by run-on analysis. Immunohistochemical analysis of RANTES in endometriotic
      tissue showed immunostaining to be predominant in the stroma with no noticeable
      differences in tissues from the proliferative and secretory phase of the
      menstrual cycle. This appears to be consistent with the cell culture data and
      indicates that RANTES expression in endometriotic tissue is not subject to cyclic
      variation. These findings reveal a new regulatory mechanism by which IL-1beta
      produced by activated macrophages can in synergy with ovarian and locally
      produced E(2) lead to enhanced macrophage and T-lymphocyte recruitment, thereby
      exacerbating the local immunoinflammatory process. Furthermore, the findings
      provide a further evidence for a close relationship between the endocrine and
      immunological changes observed in endometriosis.

PMID- 12466388
TI  - Pathophysiology of androgen insensitivity syndromes: molecular and structural
      approaches of natural and engineered androgen receptor mutations at amino acid
      743.
AB  - To decipher the clues of genotype-phenotype mapping in androgen insensitivity
      syndromes (AIS), we integrated clinical, molecular, and structural data in an
      investigation into the characteristics of androgen receptor (AR) ligand binding
      and activation. We looked for residues substituted in AIS that are conserved
      among the different AR species but that diverge in the other steroid receptors,
      thus suggesting a role in androgen binding specificity. Of the residues fitting
      these characteristics, we focused on the glycine at position 743, for which
      natural substitutions (glutamic acid and valine) have been associated with
      different androgen resistance phenotypes. The consequences of both substitutions
      were evaluated along with the minimal glycine to alanine mutation. The gradual
      impairment of binding and trans-activation efficiencies in AR mutants ranging
      from alanine to valine and subsequently glutamic acid were highlighted by in
      vitro experiments. Structural analyses showed the consequences of these
      substitutions at the atomic level and suggested a difference in local
      organization among the nuclear receptor superfamily. Overall, this integrative
      approach provides a useful tool for further investigations into the AR structure
      function relationship in AIS.

PMID- 12466389
TI  - Human endometrial epithelial cells express ephrin A1: possible interaction
      between human blastocysts and endometrium via Eph-ephrin system.
AB  - Eph receptor tyrosine kinases and their cell membrane-bound ligands, ephrins, are
      well known to function in cell-to-cell interaction and to play an important role
      in cell migration and adhesion during embryonic development in mammals. To
      investigate the involvement of the Eph-ephrin system in human embryo
      implantation, the expression of Eph receptors and ephrins was examined in human
      blastocysts and the endometrium. Immunohistochemical examination showed that
      ephrin A1 was expressed on human endometrial luminal and glandular epithelial
      cells in both the proliferative (cycle d 8-13; n = 8) and secretory (cycle d 18
      24; n = 7) phases. RT-PCR analysis of isolated endometrial epithelial cells and
      stromal cells showed that ephrin A1 mRNA was predominantly expressed in
      endometrial epithelial cells. Northern blot analysis also confirmed the
      expression of ephrin A1 mRNA in the endometrium. In addition, nested RT-PCR
      analysis revealed the mRNA expression of Eph A1, one of the representative
      receptors for ephrin A1, in human blastocysts obtained from patients undergoing
      in vitro fertilization treatment. These findings indicate a possible interaction
      between human blastocysts and endometrial epithelial cells via the Eph-ephrin
      system. Because intracytoplasmic signals are induced by Eph receptors after
      ephrin stimulation, this system may be involved in the activation process of the
      human embryo during the implantation period.

PMID- 12466390
TI  - Small guanosine triphospatase RhoA and Rho-associated kinase as regulators of
      trophoblast migration.
AB  - The small guanosine triphosphatase Rho controls cell adhesion and motility
      through reorganization of the actin cyto-skeleton and regulation of actomyosin
      contractility. Among the putative target molecules of Rho, a Rho-associated
      coiled coil-forming protein kinase (ROCK) is thought to participate in Rho
      mediated cell adhesion and motility. In the present study, we explored the
      expression and function of RhoA and ROCK in human trophoblast cells. The
      colocalization of RhoA, cytokeratin 8/18, and cytokeratin 7 in some cells located
      in the decidual stromal region indicated that extravillous trophoblast cells
      expressed RhoA. In double staining for RhoA and ROCK in human chorionic villi,
      RhoA staining was strongly positive in the cytoplasm of cytotrophoblasts, whereas
      ROCK stained in the cytoplasm of cytotrophoblasts and syncytiotrophoblasts. Both
      RhoA and ROCK were stained in cytoplasma of cultured human cytotrophoblast.
      Cultured human trophoblast cells contained actin stress fibers that were lost
      after treatment with C3, an exoenzyme produced by Clostridium botulinum. Y-27632,
      a selective ROCK inhibitor, suppressed RhoA-induced formation of actin stress
      fibers and formation of focal contact in trophoblast cells. The trophoblast
      reacquired actin stress fibers and focal contact after withdrawal of Y-27632.
      Cultured human cytotrophoblast cells from 7-9 wk of gestation migrated into a
      fibronectin-coated membrane. Both C3 exoenzyme and Y-27632 inhibited
      cytotrophoblast migration in a dose-dependent manner. In conclusion, cyto
      trophoblasts express RhoA and ROCK in their cytoplasm, and RhoA-ROCK is involved
      in their assembly of actin stress fibers. Suppression of RhoA-ROCK reduces
      trophoblast migration. These findings suggest that RhoA-ROCK signaling is a key
      regulator of trophoblast cell migration.

PMID- 12466391
TI  - Nasolacrimal drainage system obstruction from radioactive iodine therapy for
      thyroid carcinoma.
AB  - Ophthalmic complications of (131)I therapy, including ocular dryness, have been
      recently investigated and described. However, nasolacrimal drainage system
      obstruction (NDSO), complicating (131)I therapy, has not been previously well
      appreciated or characterized. One of our patients developed bilateral complete
      nasolacrimal duct obstruction after (131)I therapy that prompted awareness of
      this potential complication. Over 16 months, 423 patients with epithelial-derived
      thyroid cancer were provided routine clinical care; 390 of these patients had
      received (131)I ablation or therapy, and 10 patients subsequently reported
      epiphora. All had evidence of NDSO disease after a mean cumulative (131)I dose of
      17,279 +/- 2,923 MBq (467 +/- 79 mCi), with a mean individual (131)I dose of
      6,660 +/- 555 MBq (180 +/- 15 mCi). Symptoms appeared 6.5 +/- 1.4 (range, 3-16)
      months after the last (131)I dose, whereas the mean time from symptom onset to
      correct diagnosis was 18 +/- 5 months. A causal relationship between (131)I
      administration and NDSO is strongly suspected. Patients reporting epiphora should
      be evaluated promptly by an oculoplastic surgeon.

PMID- 12466392
TI  - Prediction of insulin sensitivity in nonobese women with polycystic ovary
      syndrome.
AB  - Insulin resistance is a frequent (although not constant) abnormality in both
      obese and nonobese women with polycystic ovary syndrome (PCOS). It plays a key
      role in the predisposition to type 2 diabetes, which is the most important health
      consequence of the syndrome. Identification of patients with insulin resistance
      is significant both for follow-up and for therapeutic reasons. The aim of the
      study was to evaluate the relationships between insulin sensitivity, measured by
      euglycemic clamp, and both endocrine and metabolic indices and to identify the
      best model for predicting insulin sensitivity. A total of 41 nonobese women
      fulfilling the diagnostic criteria for PCOS were enrolled in the study. None of
      the androgens correlated with the insulin sensitivity index. All clamp parameters
      correlated with SHBG, triglycerides, and body mass index, although no correlation
      was found with waist to hip ratio or waist circumference. The close relationship
      between insulin sensitivity and SHBG was documented by factor analysis and by its
      presence in all prediction models as the most significant (or even the single)
      predictor of the insulin sensitivity index. IN CONCLUSION: 1) a decreased level
      of SHBG can be used as a single reliable parameter in the prediction of insulin
      sensitivity in nonobese women with PCOS; and 2) waist to hip ratio, waist
      circumference, and androgen concentrations have no predictive value.

PMID- 12466393
TI  - Increased 25-hydroxyvitamin D3 1alpha-hydroxylase and reduced 25-hydroxyvitamin
      D3 24-hydroxylase expression in parathyroid tumors--new prospects for treatment
      of hyperparathyroidism with vitamin d.
AB  - Vitamin D analogues are in clinical use for prevention and treatment of secondary
      hyperparathyroidism (HPT) in chronic renal failure. Despite recent advances there
      is a need for vitamin D derivatives with maintained parathyroid hormone
      suppressive activity and less hypercalcemic and hyperphosphatemic toxicity. Here
      we show coincident increased expression of the vitamin D activating enzyme 25
      hydroxyvitamin D(3) 1alpha-hydroxylase (1alpha-hydroxylase) and reduced
      expressions of the 1,25(OH)(2)D(3) catabolizing enzyme 25-hydroxyvitamin D(3)
      1alpha-hydroxylase (1alpha-hydroxylase) in the majority of investigated
      parathyroid adenomas and secondary hyperplastic glands. In addition, this
      relationship was found for the mitochondrial CYP27A enzyme (25-hydroxylase), a
      potential physiological vitamin D(3) 25-hydroxylase. These findings should be
      considered in future development of vitamin D analogues for treatment of HPT.

PMID- 12466394
TI  - Fasting and post-glucose ghrelin levels in SGA infants: relationships with size
      and weight gain at one year of age.
AB  - Wide ranges in postnatal weight gain are seen in infants born small for
      gestational age (SGA); most show some catch-up growth and this may be driven by
      increased appetite. Ghrelin, the natural ligand of the GH secretagogue receptor,
      has potent orexigenic effects. In adults circulating ghrelin levels are increased
      in anorexia, decreased in obesity and show post prandial suppression. The aim of
      the present study was to test the hypothesis that rate of weight gain over the
      first year in SGA infants may relate to variable suppression of circulating
      ghrelin levels. Serum ghrelin levels were measured in 1 y old infants born SGA (n
      = 85) and in control infants born adequate for gestatitional age (AGA) (n = 22)
      fasting and 10 minutes after intravenous (iv) glucose (0.5 g/Kg of 25% dextrose).
      Sex- and gestational age-adjusted SD scores (SDS) for body weight were calculated
      at birth and at 1 y, and delta weight SDS between 0-1 y was calculated as an
      index of postnatal weight gain. In both SGA and AGA groups, ghrelin levels
      reduced from fasting (mean +/- SE: 104.4 +/- 6.4 fmol/ml) to 10 minutes post-iv
      glucose (82.7 +/- 5.3, p < 0.005). There were no differences in ghrelin levels
      between SGA and AGA infants (fasting or post-iv glucose). However, in SGA infants
      ghrelin levels post-glucose, but not fasting, were psitively related to current
      length (r = 0.28, p < 0.05), weight (r = 0.23, p < 0.05) and to change in weight
      SDS 0-1 y (r = 0.22, p < 0.05). SGA infants who showed poor catch-up growth
      showed a larger decline in ghrelin concentrations post-iv glucose. In conclusion,
      circulating ghrelin levels rapidly decreased after iv glucose. Higher ghrelin
      levels or lower reductions in circulating levels following iv glucose were seen
      in SGA infants who showed greater infancy weight gain, suggesting that sustained
      orexigenic drive could contribute to postnatal catch-up growth.

PMID- 12466395
TI  - The quantitative insulin sensitivity check index QUICKI predicts the onset of
      type 2 diabetes better than fasting plasma insulin in obese subjects: a 5-year
      follow-up study.
AB  - The aim of the present study was to evaluate the predictive value of QUICKI and
      fasting plasma insulin (FPI0 as predictors of the onset of type 2 diabetes
      mellitus. We performed a five-year follow-up study in a sample of middle-aged
      subjects with at least one of the following risk factors; hypertension defined as
      systolic blood pressure >or=160 mmHg and/or diastolic blood pressure >or=90 mmHg
      or medication for hypertensin, obesity defined as a body mass index >or=30
      kg/m(2) and/or a waist-to-hip ratio >or=1.00 in men and >or=0.88 in women, or a
      family history of type 2 DM. When the QUICKI index was used to compare the
      tertile with the lowest risk to the tertile of the highest risk of obese
      subjects. Odd's Ratio (OR) for type 2 diabetes was 7.77 (95% CI 1.39-202.24). For
      FPI, the respective OR's were 2.84 (95% CI 0.82-9.82) and 3.96 (95% CI 1.02
      15.48). QUICKI and fasting insulin did not have a statistically significant
      predictive value among non-obese subjects. Concerning QUICKI, the subjects in the
      tertiles at the medium and highest risk had a higher risk for type 2 DM than the
      corresponding tertiles of FPI among obese subjects.

PMID- 12466398
TI  - Actinobacillus actinomycetemcomitans.

PMID- 12466399
TI  - The accuracy and efficacy of screening tests for Chlamydia trachomatis: a
      systematic review.
AB  - Screening women for lower genital tract infection with Chlamydia trachomatis is
      important in the prevention of pelvic inflammatory disease, ectopic pregnancy and
      infertility. This systematic review aims to state clearly which of the available
      diagnostic tests for the detection of C. trachomatis would be most effective in
      terms of clinical effectiveness. The review included all studies published from
      1990 onward that evaluated diagnostic tests in asymptomatic, young, sexually
      active populations. Medline and Embase were searched electronically and key
      journals were hand-searched. Further studies were identified through the Internet
      and contact with experts in the field. All studies were reviewed by two reviewers
      and were scored by Irwig's assessment criteria. Additional quality assessment
      criteria included a documented sexual history and recording of previous
      chlamydial infection. The reviews were subjected to meta-analysis and meta
      regression. The 30 studies that were included examined three types of DNA-based
      test--ligase chain reaction (LCR), PCR and gene probe--as well as enzyme immuno
      assay (EIA). The results showed that while specificities were high, sensitivities
      varied widely across the tests and were also dependent on the specimen tested.
      Pooled sensitivities for LCR, PCR, gene probe and EIA on urine were 96.5%, 85.6%,
      92% and 38%, respectively, while on cervical swabs the corresponding
      sensitivities of PCR, gene probe and EIA were 88.6%, 84% and 65%. Meta-analysis
      demonstrated that DNA amplification techniques performed best for both urine and
      swabs in low prevalence populations. We conclude that nucleic acid amplification
      tests used on non-invasive samples such as urine are more effective at detecting
      asymptomatic chlamydial infection than conventional tests, but there are few data
      to relate a positive result with clinical outcome.

PMID- 12466400
TI  - Variation in the persistence of Escherichia coli O157:H7 in experimentally
      inoculated 6-week-old conventional lambs.
AB  - Six-week-old lambs were inoculated orally with 10(9) cfu of an antibiotic
      resistance marked four-strain mixture of enterohaemorrhagic Escherichia coli
      (EHEC) O157:H7 to investigate faecal excretion and intestinal colonisation. In
      the first experiment, three E. coli O157:H7 isolates were not detected in the
      faeces of any lambs beyond day 8 post inoculation (pi), or from any of the
      tissues derived from inoculated animals. One strain, 140065 Nal(r), was isolated
      from the caecum and colon of one lamb on day 9 pi, from the rectum of another on
      day 22 pi and persisted in the faeces for up to 28 days pi. All animals remained
      clinically normal throughout the study period and histological evidence of
      adhesion of E. coli O157:H7 to the intestinal mucosa was not found. In a separate
      experiment, four 6-week-old lambs were inoculated orally with 10(9) cfu of E.
      coli O157:H7 strain 140065 Nal(r) alone. Faecal samples were positive for this
      strain until the end of the experiment (day 19 pi). This strain was also
      recovered from the gastrointestinal tract of lambs on days 6, 18 and 19 pi, but
      was not isolated at day 17 pi. When sampled separately, rectum and terminal colon
      contents contained higher numbers of the inoculated strain than the intestinal
      tissue at these sites. Animals inoculated with O157:H7 strain 140065 Nal(r) alone
      produced soft faeces from day 5 pi onwards. Although attaching and effacing
      lesions were observed in the caecum, proximal colon and rectum in one animal on
      day 18 pi, the adherent bacteria did not stain with antiserum raised against the
      O157 antigen.

PMID- 12466401
TI  - Isolation from a sheep of an attaching and effacing Escherichia coli O115:H- with
      a novel combination of virulence factors.
AB  - Attaching and effacing (AE) lesions were observed in the caecum, proximal colon
      and rectum of one of four lambs experimentally inoculated at 6 weeks of age with
      Escherichia coli O157:H7. However, the attached bacteria did not immunostain with
      O157-specific antiserum. Subsequent bacteriological analysis of samples from this
      animal yielded two E. coli O115:H(-) strains, one from the colon (CO) and one
      from the rectum (RC), and those bacteria forming the AE lesions were shown to be
      of the O115 serogroup by immunostaining. The O115:H(-)isolates formed
      microcolonies and attaching and effacing lesions, as demonstrated by the
      fluorescence actin staining test, on HEp-2 tissue culture cells. Both isolates
      were confirmed by PCR to encode the epsilon (epsilon) subtype of intimin.
      Supernates of both O115:H(-) isolates induced cytopathic effects on Vero cell
      monolayers, and PCR analysis verified that both isolates encoded EAST1, CNF1 and
      CNF2 toxins but not Shiga-like toxins. Both isolates harboured similar sized
      plasmids but PCR analysis indicated that only one of the O115:H(-) isolates (CO)
      possessed the plasmid-associated virulence determinants ehxA and etpD. Neither
      strain possessed the espP, katP or bfpA plasmid-associated virulence
      determinants. These E. coli O115:H(-) strains exhibited a novel combination of
      virulence determinants and are the first isolates found to possess both CNF1 and
      CNF2.

PMID- 12466402
TI  - Production of serum antibodies that recognise epitopes located on the R3 region
      of Escherichia coli core lipopolysaccharides by patients infected with strains of
      enterohaemorrhagic E. coli.
AB  - Antibody-antigen cross-reactions were examined with sera from patients with
      Escherichia coli O157 infection and lipopolysaccharide (LPS) purified from a
      range of enterohaemorrhagic E. coli (EHEC) including those belonging to
      serogroups O26, O103, O111, O145 and O157. Six of 10 patients infected with an
      O157 EHEC produced serum antibodies that cross-reacted with common LPS-core
      epitopes, which were expressed by 23 of 33 strains of EHEC examined. These common
      LPS-core epitopes were also present on strains of E. coli O26 which did not
      produce verocytotoxin. These cross-reacting antibodies did not influence the
      basic immunoblotting procedures used for the routine serodiagnosis of infections
      with E. coli O157.

PMID- 12466403
TI  - Passive protection against Burkholderia pseudomallei infection in mice by
      monoclonal antibodies against capsular polysaccharide, lipopolysaccharide or
      proteins.
AB  - Burkholderia pseudomallei, the aetiological agent of melioidosis, is endemic in
      south-east Asia and northern Australia, where it is an important cause of human
      disease. There is no vaccine available and antibiotic therapy is associated with
      high relapse rates. A panel of seven monoclonal antibodies (MAbs) that recognise
      capsular polysaccharide, lipopolysaccharide or proteins was produced and their
      ability to protect mice passively against experimental melioidosis was evaluated.
      The MAbs were capable of protecting mice against intra-peritoneal challenge with
      10(4) cfu/250 MLD of a virulent strain of B. pseudomallei (NCTC 4845), when
      pooled, and four of the MAbs were individually protective. However, at a higher
      B. pseudomallei challenge level of 10(6) cfu none of the MAbs afforded protection
      and only the anti-exopolysaccharide MAbs produced a significantly delayed time to
      death.

PMID- 12466404
TI  - Determination of quorum-sensing signal molecules and virulence factors of
      Pseudomonas aeruginosa isolates from contact lens-induced microbial keratitis.
AB  - The virulence of Pseudomonas aeruginosa in contact lens-induced microbial
      keratitis has been linked to various extracellular and cell-associated bacterial
      products, such as proteases and toxins. Recently, a group of bacterial signal
      molecules, N-acyl-homoserine lactones (AHLs), has been reported to play an
      important role in the regulation of the production of several bacterial virulence
      factors in P. aeruginosa. The aim of this study was to determine the signal
      molecules produced by P. aeruginosa keratitis strains, and to elucidate any
      possible correlation between the production of signal molecules and the
      expression of phenotypic characteristics, including protease production,
      bacterial invasion and acute cytotoxic activity. The presence and profiles of
      AHLs in ocular P. aeruginosa isolates were analysed by a combination of thin
      layer chromatography and bioassay. All 17 keratitis isolates produced AHLs. There
      were differences both in the amounts and the types of AHL production in the
      various phenotypes of isolates. High levels of AHLs were found among the isolates
      with high protease activity and invasiveness. Acutely cytotoxic isolates
      displayed low AHL and protease activities. Invasive strains were more common than
      cytotoxic strains from keratitis patients. These results suggest that quorum
      sensing systems of P. aeruginosa display a complexity even within the same
      species, and the production of certain AHL signal molecules may be associated
      with certain phenotypes in P. aeruginosa.

PMID- 12466405
TI  - Recombinant GroES in combination with CpG oligodeoxynucleotides protects mice
      against Mycobacterium avium infection.
AB  - The groES gene of Mycobacterium avium strain 485 was cloned and expressed in
      Escherichia coli and the recombinant GroES protein was purified by affinity
      chromatography. The GroES preparation showed high purity by electrophoresis and
      immunoblotting. Immuno-electron microscopy showed that GroES was located both in
      the cytoplasm and on the surface of the mycobacterial cells and thus is readily
      available to interact with the host immune system. BALB/c mice were immunised
      intranasally with recombinant GroES, alone or in combination with a synthetic
      oligodeoxynucleotide containing unmethylated CpG motifs, and tested for
      protection against infection with M. avium. Neither GroES nor CpG alone provided
      any protection against subsequent challenge with M. avium, whereas a combination
      of the two significantly protected the lungs and spleen against colonisation by
      M. avium after intranasal challenge with a low dose of the organism. This
      indicates that intranasal administration of GroES and CpG oligodeoxynucleotides
      increases the resistance of BALB/c mice to M. avium infection.

PMID- 12466406
TI  - N-acetyl-D-galactosamine specific lectin of Eikenella corrodens induces
      intercellular adhesion molecule-1 (ICAM-1) production by human oral epithelial
      cells.
AB  - During the acute inflammatory response in periodontitis, gingival epithelial
      cells are considered to play important roles in the recruitment of inflammatory
      cells to the site of infection through the secretion of chemokines. However,
      little is known about the expression of molecules that are involved in the
      interaction between the epithelium and neutrophils following bacterial
      attachment. Earlier work reported that periodontopathogenic Eikenella corrodens
      strain 1,073 up-regulated the expression and secretion of chemokines such as
      interleukin-8 (IL-8) from KB cells (a human oral epithelial cell line derived
      from a human oral epidermoid carcinoma). To elucidate the mechanism of the
      transmigration of neutrophils through the epithelium, the present study
      investigated the expression of adhesion molecules on KB cells in response to E.
      corrodens attachment. Adhesion molecule gene expression was assessed by RT-PCR
      and adhesion proteins expressed on KB cell surfaces were determined by cell-based
      ELISA and FACS. In RT-PCR, ICAM-1 mRNA levels were significantly increased within
      1 h in response to exposure to E. corrodens and continued to increase over the 12
      h period of study. In ELISA, increased surface ICAM-1 expression was paralleled
      by increased ICAM-1 mRNA levels. Furthermore, the increases in ICAM-1 expression
      on epithelial cells infected with E. corrodens were observed to be due to the N
      acetyl-D-galactosamine (GalNAc) specific bacterial lectin-like substance of E.
      corrodens (EcLS), which was one of the adhesins of E. corrodens. This is the
      first study to report that a bacterial lectin-like substance increased the
      expression of ICAM-1 on gingival epithelial cells.

PMID- 12466407
TI  - Comparison of 16S rDNA-based PCR and checkerboard DNA-DNA hybridisation for
      detection of selected endodontic pathogens.
AB  - Molecular methods have been used recently to investigate the bacteria encountered
      in human endodontic infections. The aim of the present study was to compare the
      ability of a 16S rDNA-based PCR assay and checkerboard DNA-DNA hybridisation in
      detecting Actinobacillus actinomycetemcomitans, Bacteroides forsythus,
      Peptostreptococcus micros, Porphyromonas endodontalis, Por. gingivalis and
      Treponema denticola directly from clinical samples. Specimens were obtained from
      50 cases of endodontic infections and the presence of the target species was
      investigated by whole genomic DNA probes and checkerboard DNA-DNA hybridisation
      or taxon-specific oligonucleotides with PCR assay. Prevalence of the target
      species was based on data obtained by each method. The sensitivity and
      specificity of each molecular method was compared with the data generated by the
      other method as the reference--a value of 1.0 representing total agreement with
      the chosen standard. The methods were also compared with regard to the prevalence
      values for each target species. Regardless of the detection method used, T.
      denticola, Por. gingivalis, Por. endodontalis and B. forsythus were the most
      prevalent species. If the checkerboard data for these four species were used as
      the reference, PCR detection sensitivities ranged from 0.53 to 1.0, and
      specificities from 0.5 to 0.88, depending on the target bacterial species. When
      PCR data for the same species were used as the reference, the detection
      sensitivities for the checkerboard method ranged from 0.17 to 0.73, and
      specificities from 0.75 to 1.0. Accuracy values ranged from 0.6 to 0.74. On the
      whole, matching results between the two molecular methods ranged from 60% to
      97.5%, depending on the target species. The major discrepancies between the
      methods comprised a number of PCR-positive but checkerboard-negative results.
      Significantly higher prevalence figures for Por. endodontalis and T. denticola
      were observed after PCR assessment. There was no further significant difference
      between the methods with regard to detection of the other target species.

PMID- 12466408
TI  - Development of a PCR assay specific for Peptostreptococcus anaerobius.
AB  - Peptostreptococcus anaerobius is a gram-positive anaerobic coccus that is widely
      distributed in the normal human flora. The organism has also been implicated as a
      causative agent of several systemic infections, including endocarditis and
      infections of the genitourinary and gastrointestinal tracts. Its role in oral
      disease is less well defined, although it has been implicated in periodontal
      disease, gingivitis and root canal infections. Identification of P. anaerobius in
      clinical samples is currently reliant upon traditional culture and biochemical
      methods. The aim of this study was to develop a novel PCR assay for the detection
      of P. anaerobius and to attempt detection of this organism in oral samples. PCR
      primers specific for P. anaerobius DNA were developed by alignment of bacterial
      16S ribosomal RNA gene sequences and selection of sequences specific at their 3'
      ends for P. anaerobius. When used in a PCR assay, positivity for P. anaerobius
      DNA was indicated by the amplification of a 943-bp product. The primers were
      shown to be specific for P. anaerobius DNA, as no PCR products were obtained when
      genomic DNA from a wide range of other Peptostreptococcus species and other oral
      bacteria were used as templates. The PCR assay was then applied to the detection
      of P. anaerobius DNA in subgingival plaque samples from adult periodontitis
      patients and pus aspirates from subjects with acute dento-alveolar abscesses. All
      of 60 subgingival plaque samples from 16 patients were negative for P. anaerobius
      DNA. None of the 43 pus samples analysed contained P. anaerobius DNA. These
      results suggest that P. anaerobius is not a major pathogen in adult periodontitis
      and dento-alveolar abscesses. The PCR assay is a more rapid, sensitive and
      specific alternative to culture-based methods for identification of P. anaerobius
      in clinical samples.

PMID- 12466409
TI  - The epidemic wave of meningococcal disease in Spain in 1996-1997: probably a
      consequence of strain displacement.
AB  - During 1996 and 1997 an epidemic wave of meningococcal disease took place in
      Spain. Initial studies described the antigenic expression of the epidemic strain
      as C:2b:P1.2,5 and proposed that it was a variant of the previously identified
      Spanish C:2b:non-subtypable epidemic strain. To clarify this hypothesis, 1036
      C:2b:P1.2(5) and 76 C:2b:NST isolates obtained during 1992-1999 were analysed by
      pulsed-field gel electrophoresis. The majority of the C:2b:P1.2,5 and C:2b:P1.2
      isolates showed one of two very closely related profiles. During the epidemic
      period, 80% of the C:2b:NST strains showed these two pulsotypes. However, before
      the epidemic wave, most of these C:2b:NST strains (60%) showed a profile that was
      found infrequently among C:2b:P1.2,5 and C:2b:P1.2 isolates. A similar evolution
      was observed in C:2b:P1.5 isolates. Thirty-four C:2b:P1.2(5) and 10 C:2b:NST
      isolates, exhibiting representative pulsotypes, were subjected to multi-locus
      sequence typing. Isolates belonging to both A4 and ET-37 lineages were
      identified. These data point to the possibility that the A4 cluster has displaced
      the ET-37 complex among serogroup C meningococci in Spain.

PMID- 12466410
TI  - Population structure and antibiotic resistance of Acinetobacter DNA group 2 and
      13TU isolates from hospitals in the UK.
AB  - A total of 287 Acinetobacter isolates belonging to DNA groups 2 (A. baumannii)
      and 13TU was collected consecutively from 46 hospitals and typed by randomly
      amplified polymorphic DNA fingerprinting with primers DAF-4 and ERIC-2. With a
      similarity coefficient of >/=72% as a cut-off value, 37 clusters of genotypically
      similar isolates (genotypes) were recognised. Four major clusters, found in 15,
      12, 12 and 8 hospitals respectively, accounted for 42% of isolates, but only
      three of these predominant clusters were associated with outbreaks of infection
      in individual hospitals. Many of the isolates were resistant to multiple
      antibiotics, including expanded-spectrum beta-lactam agents, aminoglycosides,
      tetracyclines and fluoroquinolones, but >98% remained susceptible to carbapenems
      and colistin. Overall, the study demonstrated that a heterogeneous population of
      Acinetobacter DNA group 2 and 13TU isolates, frequently showing multiple
      resistance to antibiotics, was causing infections in UK hospitals, and that four
      predominant genotypes appeared to have disseminated among geographically distinct
      locations.

PMID- 12466411
TI  - Molecular fingerprinting of fusidic acid- and rifampicin-resistant strains of
      methicillin-resistant Staphylococcus aureus (MRSA) from Malaysian hospitals.
AB  - The emergence and spread of multiresistant methicillin-resistant Staphylococcus
      aureus (MRSA) strains, especially those resistant to fusidic acid and rifampicin,
      in Malaysian hospitals is of concern. In this study DNA fingerprinting by PFGE
      was performed on fusidic acid- and rifampicin-resistant isolates from Malaysian
      hospitals to determine the genetic relatedness of these isolates and their
      relationship with the endemic MRSA strains. In all, 32 of 640 MRSA isolates from
      9 Malaysian hospitals were resistant to fusidic acid and rifampicin. Seven PFGE
      types (A, ZC, ZI, ZJ, ZK, ZL and ZM) were observed. The commonest type was type
      ZC, seen in 72% of isolates followed by type A, seen in 13%. Each of the other
      types (ZI, ZJ, ZK, ZL and ZM) was observed in a single isolate. Each type, even
      the commonest, was found in only one hospital. This suggests that the resistant
      strains had arisen from individual MRSA strains in each hospital and not as a
      result of the transmission of a common clone.

PMID- 12466412
TI  - Improved molecular identification of Thermoactinomyces spp. associated with
      mushroom worker's lung by 16S rDNA sequence typing.
AB  - Mushroom worker's lung (MWL) is a hypersensitivity pneumonitis or allergic
      alveolitis caused by a type III IgG-mediated immunopathogenic inflammatory
      reaction in the host due to the inhalation of several thermophilic organisms,
      including Thermoactinomyces spp. It is difficult to distinguish phenotypically
      the eight species of this genus; therefore, this study sought to develop an
      improved molecular means of identifying Thermoactinomyces spp. associated with
      MWL by partial 16S rDNA PCR amplification and direct sequencing. Hypervariable
      regions within the 16S rRNA gene, which could be employed as signature sequences
      of the eight individual species, were identified and employed with highly
      conserved flanking primers to allow initial PCR amplification, before direct DNA
      sequencing of the 16S rDNA amplicons. A novel 24-mer 16S rDNA oligonucleotide
      upstream primer was designed from in silico alignments of all Thermoactinomyces
      spp. and was employed in combination with downstream (reverse) 16S rDNA primers.
      This permitted the successful identification of all four isolates associated with
      mushroom workers' lung. The method may be useful in the identification of
      Thermoactinomyces spp. associated with allergic alveolitis or pneumonitis
      associated with occupational exposure in agricultural and horticultural
      environments.

PMID- 12466413
TI  - Microsatellite analysis of environmental and clinical isolates of the opportunist
      fungal pathogen Aspergillus fumigatus.
AB  - Microsatellite analysis was used to examine the genetic relatedness of 111
      clinical and environmental isolates of the opportunist human pathogenic fungus
      Aspergillus fumigatus from Ontario, Canada. Forty-three A. fumigatus isolates
      were from clinical sources and 68 from environmental sources. Phylogenetic
      analysis of the genotypes revealed that there were no geographical or temporal
      associations of clinical or environmental genotypes. In fact, several of the
      environmental and clinical isolates showed identical (clonal) genotypes from
      disparate geographical areas. However, a locus by locus examination revealed that
      there were several significant differences in allele frequencies between clinical
      and environmental isolates. There may be linkage of certain microsatellite loci
      with genes affecting virulence in A. fumigatus. A susceptible individual may be
      equally predisposed to infection by any isolate of A. fumigatus. However, under
      transient selection as a pathogen, genes encoding alleles for enhanced virulence
      may not assort independently from microsatellite loci. A dynamic equilibrium may
      exist between random recombination of loci in the natural environment and
      selection for virulence factors during host infection cycles.

PMID- 12466414
TI  - Dual Candida albicans and Cryptococcus neoformans fungaemia in an AIDS presenter:
      a unique disease association in the highly active antiretroviral therapy (HAART)
      era.
AB  - A case report of a patient who discovered his HIV infection concurrently with an
      advanced immunodeficiency and a dual Candida albicans and Cryptococcus neoformans
      fungaemia is discussed with reference to the changing epidemiology and clinical
      features of HIV infection and AIDS in the highly active antiretroviral therapy
      (HAART) era. The tendency to develop multiple concomitant AIDS-defining illnesses
      at the time of first hospitalisation seems to be an increasing feature in
      patients who remain unaware of or neglect their HIV disease and who are still at
      risk of opportunist infections even with the availability of HAART.

PMID- 12466415
TI  - Coding of sound intensity in the chick cochlear nerve.
AB  - Tuning curves, spontaneous activity, and rate-intensity (RI) functions were
      obtained from units in the chick cochlear nerve. The characteristic frequency
      (CF) was determined from each tuning curve. The shape of each RI function was
      subjectively evaluated and assigned to one of four RI types. The breakpoint,
      discharge rate at the highest SPLs, and slopes of the primary and secondary
      segments were quantified for each function. The CF and RI type were then related
      to these variables. A new RI function was observed in which the discharge
      activity in the secondary segment diminished as stimulus level increased above
      the breakpoint. This function was called a "sloping-down" type. In 959 units,
      saturating, sloping-up, sloping-down, and straight RI types were identified in
      39.2, 35.5, 12.6, and 12.7% of the sample, respectively. The slope of the primary
      segment was nearly the same in each of the four types and averaged 5.48 S. s(-1).
      dB(-1) across all units. The slopes of the secondary segments formed four
      groupings when segregated by RI type based on the subjective assignments and
      averaged 0.03, 1.22, -0.90, and 3.95 S. s(-1). dB(-1) in the saturating, sloping
      up, sloping-down, and straight types, respectively. The data describing the
      secondary segments of all units were fit with a multi-compartment polynomial and
      showed a continuous distribution that segregated, with some overlap, into the
      different RI categories. The proportion of RI types, as well as the secondary and
      primary slopes were approximately constant across CFs. In addition, it would
      appear that the other parameters that define the four types were, for the most
      part, homogeneously distributed across the frequency axis of the chick inner ear.
      Finally, a comparison of RI functions having a common CF suggested that the
      compressive nonlinearity that determines RI type may be a phenomenon localized to
      individual hair cells in the bird ear.

PMID- 12466416
TI  - Synaptically evoked GABA transporter currents in neocortical glia.
AB  - The presence, magnitude, and time course of GABA transporter currents were
      investigated in electrophysiologically characterized neocortical astrocytes in an
      in vitro slice preparation. On stimulation with a bipolar-tungsten stimulating
      electrode placed nearby, the majority of cells tested displayed long-lasting GABA
      transporter currents using both single and repetitive stimulation protocols.
      Using subtype-specific GABA transporter antagonists, long-lasting GABA
      transporter currents were identified in neocortical astrocytes that originated
      from at least two subtypes of GABA transporters: GAT-1 and GAT-2/3. These
      transporter currents displayed slow rise times and long decay times, contrasting
      the time course observed for glutamate transporter currents, and are indicative
      of a long extracellular time course of GABA as well as a role for glial GABA
      transporters during synaptic transmission.

PMID- 12466417
TI  - Free radical-mediated cell damage after experimental status epilepticus in
      hippocampal slice cultures.
AB  - Generation of free radicals may have a key role in the nerve cell damage induced
      by prolonged or frequently recurring convulsions (status epilepticus).
      Mitochondrial function may also be altered due to production of free radicals
      during seizures. We therefore studied changes in field potentials (fp) together
      with measurements of extracellular, intracellular, and intramitochondrial calcium
      concentration ([Ca(2+)]e, [Ca(2+)]i, and [Ca(2+)]m, respectively), mitochondrial
      membrane potential (deltapsi), NAD(P)H auto-fluorescence, and dihydroethidium
      (HEt) fluorescence in hippocampal slice cultures by means of simultaneous
      electrophysiological and microfluorimetric measurements. As reported previously,
      each seizure-like event (SLE) resulted in mitochondrial depolarization associated
      with a delayed rise in oxidation of HEt to ethidum, presumably indicating ROS
      production. We show here that repeated SLEs led to a decline in intracellular and
      intramitochondrial Ca(2+) signals despite unaltered Ca(2+) influx. Also,
      mitochondrial depolarization and the NAD(P)H signal became smaller during
      recurring SLEs. By contrast, the ethidium fluorescence rises remained constant or
      even increased from SLE to SLE. After about 15 SLEs, activity changed to
      continuous afterdischarges with steady depolarization of mitochondrial membranes.
      Staining with a cell death marker, propidium iodide, indicated widespread cell
      damage after 2 h of recurring SLEs. The free radical scavenger, alpha-tocopherol,
      protected the slice cultures against this damage and also reduced the ongoing
      impairment of NAD(P)H production. These findings suggest involvement of reactive
      oxygen species (ROS) of mitochondrial origin in the epileptic cell damage and
      that free radical scavenging may prevent status epilepticus-induced cell loss.

PMID- 12466418
TI  - Investigation of the neuronal aggregate generating seizures in the rat tetanus
      toxin model of epilepsy.
AB  - A key question in epilepsy is the organization and size of the neuronal networks
      necessary for generating seizures. Hypotheses include: a single focal neuronal
      network drives seizure discharges across the brain, which may or may not be
      identical with the circuits that generate interictal spikes; or multiple neuronal
      networks link together in re-entrant loops or other long-range networks. It
      remains unclear whether any of these hypotheses apply to spontaneous seizures in
      freely moving animals. We used the tetanus toxin chronic model of epilepsy to
      test the different predictions made by each hypothesis about the propagation and
      interaction of epileptic discharges during seizures. Seizures could start in
      either the injected or noninjected dorsal hippocampus, suggesting that seizures
      have multifocal onsets in the tetanus toxin model. During seizures, individual
      bursts propagated in either direction, both between the right and left dorsal
      hippocampi, and between CA3 and the dentate gyrus in the same hippocampus. These
      findings argue against one site "driving" seizures or seizures propagating around
      a limbic loop. Specifically, the side leading each burst switched a median of
      three times during the first 20 s of a seizure. Analysis of bursts during
      seizures suggested that the network at each recording site acted like a neuronal
      oscillator. Coupling of population spikes in right and left CA3 increased during
      the early part of seizures, but the cross-correlation of their whole-discharge
      waveforms changed little over the same period. Furthermore, the polarity of the
      phase difference between population spikes did not follow the phase difference
      for complete discharges. We concluded that the neuronal aggregate necessary for
      seizures in our animals comprises multiple spatially distributed neuronal
      networks and that the increased synchrony of the output (population spike firing)
      of these networks during the early part of seizures may contribute to seizure
      generation.

PMID- 12466419
TI  - Modulation of noxious and non-noxious spinal mechanical transmission from the
      rostral medial medulla in the rat.
AB  - Modulatory influences on spinal mechanical transmission from the rostral medial
      medulla (RMM) were studied. Noxious stimulation, produced by von Frey-like
      monofilaments, and non-noxious stimulation, produced by a soft brush, was applied
      to the glabrous skin of the hind foot. At 28 sites in RMM, electrical stimulation
      facilitated responses to noxious mechanical stimulation at low intensities (5-25
      microA) and inhibited responses of the same neurons at greater intensities (50
      100 microA) of stimulation. At 24 and 9 other sites in RMM, stimulation at all
      intensities only inhibited or only facilitated, respectively, responses to
      noxious mechanical stimulation of the hind foot. Stimulus-response functions to
      mechanical stimulation were shifted leftward by low intensities and decreased by
      high intensities of stimulation. Inhibitory influences were found to descend in
      the dorsolateral funiculi; facilitatory effects were contained in the ventral
      spinal cord. Descending modulation of non-noxious brush stimulation revealed
      biphasic facilitatory-inhibitory effects (9 sites in RMM), only inhibitory
      effects (14 sites) and only facilitatory effects (8 sites). The effects of
      electrical stimulation were replicated by intra-RMM administration of glutamate;
      a low concentration (0.25 nmol) facilitated and a greater concentration (2.5
      nmol) inhibited spinal mechanical transmission, providing evidence that cells in
      RMM are sufficient to engage descending influences. Descending modulatory effects
      were specific for the site of stimulation, not for the spinal neuron, because
      modulation of the same neuron was different from different sites in RMM. These
      results show that spinal mechanical transmission, both noxious and non-noxious,
      is subject to descending influences, including facilitatory influences that may
      contribute to exaggerated responses to peripheral stimuli in some chronic pain
      states.

PMID- 12466420
TI  - Long-term neuromodulatory regulation of a motor pattern-generating network:
      maintenance of synaptic efficacy and oscillatory properties.
AB  - Rhythm generation by the pyloric motor network in the stomatogastric ganglion
      (STG) of the spiny lobster requires permissive neuromodulatory inputs from other
      central ganglia. When these inputs to the STG are suppressed by cutting the
      single, mainly afferent stomatogastric nerve (stn), pyloric neurons cease to
      burst and the network falls silent. However, as shown previously, if such a
      decentralized quiescent ganglion is maintained in organ culture, pyloric network
      rhythmicity returns after 3-4 days and, although slower, is similar to the motor
      pattern expressed when the stn is intact. Here we use current- and voltage-clamp,
      primarily of identified pyloric dilator (PD) neurons, to investigate changes in
      synaptic and cellular properties that underlie this transition in network
      behavior. Although the efficacy of chemical synapses between pyloric neurons
      decreases significantly (by <or=50%) after STG decentralization, the fundamental
      change leading to rhythm recovery occurs in the voltage-dependent properties of
      the neurons themselves. Whereas pyloric neurons, including the PD, lateral
      pyloric, and pyloric cell types, are unable to generate burst-producing membrane
      potential oscillations in the short-term absence of extrinsic modulatory inputs,
      in long-term decentralized ganglia, the same cells are able to oscillate
      spontaneously, even after experimental isolation in situ from all other elements
      in the pyloric network. In PD neurons this reacquisition of rhythmicity is
      associated with a net reduction in outward tetraethylammonium-sensitive ionic
      currents that include a delayed-rectifier type potassium current (I(Kd)) and a
      calcium-dependent K(+) current, I(KCa). By contrast, long-term STG
      decentralization caused enhancement of a hyperpolarization-activated inward
      current that resembles I(h). These results are consistent with the hypothesis
      that modulatory inputs sustain the modulation-dependent rhythmogenic character of
      the pyloric network by continuously regulating the balance of membrane
      conductances that underlie neuronal oscillation.

PMID- 12466421
TI  - Inter-ictal- and ictal-like epileptic discharges in the dendritic tree of
      neocortical pyramidal neurons.
AB  - Dendritic mechanisms have been implied to play a key role in the formation of
      epileptic discharges. However, presently only a handful of direct dendritic
      recordings have been reported during epileptic discharges. In this study, I
      performed simultaneous voltage recordings from the soma and apical dendrite of
      the same neuron combined with calcium-imaging measurements to investigate inter
      ictal- and ictal-like epileptic discharges in dendrites of layer 5 pyramidal
      neurons. Neocortical brain slices treated with bicuculline (BCC) produced both
      isolated "inter-ictal" paroxysymal depolarization shift (PDS) responses and
      electrographic seizures. Concomitant voltage recordings from the soma and apical
      dendrite revealed that PDS responses developed in both the apical dendrites and
      soma. However, the two responses differed from one another. In apical dendrites,
      the PDS was significantly higher in amplitude and shorter in duration compared
      with the somatic PDS. The PDS response in dendrites had a peak amplitude of 68.9
      +/- 2.2 (SD) mV, peak voltage value of 9.3 +/- 2.7 mV, and half-width of 203.8 +/
      38.4 ms. In contrast, the somatic PDS had a peak amplitude of 48.7 +/- 2.7 mV,
      peak voltage value of -11.9 +/- 3.1 mV, and half-width of 247.8 +/- 57.3 ms (P <
      0.01, n = 18). In addition the apical dendritic PDS always preceded the somatic
      counterpart in all 18 neurons examined. Concomitant calcium-imaging measurements
      showed the PDS evoked large calcium influx into the entire dendritic tree
      including the apical tuft, basal, and oblique dendrites. The PDS evoked
      [Ca(2+)](i) were not uniform along the dendritic tree, being highest in the
      oblique dendrites (71.3 +/- 14.5 microM) and lowest at the distal tuft branches
      (9.3 +/- 0.7 microM). The PDS responses persisted after blockade of voltage-gated
      sodium channels by intracellular QX-314 but became narrower (by 69.6 +/- 9.7%)
      following intracellular administration of the voltage-gated calcium channel
      blocker D600. Electrographic seizures recorded in the soma and apical dendrites
      were composed of recurrent bursts. The initial bursts represented PDS responses.
      During the seizure the amplitude of bursts gradually attenuated and reached an
      average value of 26 +/- 13% of the initial ictal PDS burst. Double recordings
      during electrographic seizures revealed the initial one to four ictal bursts
      appeared first at the apical dendrite while later ictal bursts were always
      observed first at the soma. In conclusion, the results of this study show "inter
      ictal" PDS responses originated in the apical dendritic tree, were partially
      mediated by voltage-gated calcium channels and spread throughout the dendritic
      tree including the fine tuft, basal, and oblique dendrites. During electrographic
      seizures the origin of epileptic bursts shifted from the apical dendritic tree to
      the soma-basal region.

PMID- 12466422
TI  - Mechanisms of neuronal hyperexcitability caused by partial inhibition of Na+-K+
      ATPases in the rat CA1 hippocampal region.
AB  - Extra- and intracellular records were made from rat acute hippocampal slices to
      examine the effects of partial inhibition of Na(+)-K(+)-ATPases (Na(+)-K(+)
      pumps) on neuronal hyperexcitability. Bath application of the low-affinity
      cardiac glycoside, dihydroouabain (DHO), reversibly induced interictal-like
      epileptiform bursting activity in the CA1 region. Burst-firing was correlated
      with inhibition of the pumps, which was assayed by changes in [K(+)](o) uptake
      rates measured with K(+)-ion-sensitive microelectrodes. Large increases in
      resting [K(+)](o) did not occur. DHO induced a transient depolarization (5-6 mV)
      followed by a long-lasting hyperpolarization (approximately 6 mV) in CA1
      pyramidal neurons, which was accompanied by a 30% decrease in resting input
      resistance. Block of an electrogenic pump current could explain the
      depolarization but not the hyperpolarization of the membrane. Increasing
      [K(+)](o) from 3 to 5.5 mM minimized these transient shifts in passive membrane
      properties without preventing DHO-induced hyperexcitability. DHO decreased
      synaptic transmission, but increased the coupling between excitatory postsynaptic
      potentials and spike firing (E-S coupling). Monosynaptic inhibitory postsynaptic
      potential (IPSP) amplitudes declined to approximately 25% of control at the peak
      of bursting activity; however, miniature TTX-resistant inhibitory postsynaptic
      current amplitudes were unaffected. DHO also reduced the initial slope of the
      intracellular excitatory postsynaptic potential (EPSP) to approximately 40% of
      control. The conductances of pharmacologically isolated IPSPs and EPSPs in high
      Ca/high-Mg-containing saline were also reduced by DHO by approximately 50%. The
      extracellular fiber volley amplitude was reduced by 15-20%, suggesting that the
      decrease in neurotransmission was partly due to a reduction in presynaptic fiber
      excitability. DHO enhanced a late depolarizing potential that was superimposed on
      the EPSP and could obscure it. This potential was not blocked by antagonists of
      NMDA receptors, and blockade of NMDA, mGlu, or GABA(A) receptors did not affect
      burst firing. The late depolarizing component enabled the pyramidal cells to
      reach spike threshold without changing the actual voltage threshold for firing.
      We conclude that reduced GABAergic potentials and enhanced E-S coupling are the
      primary mechanisms underlying the hyperexcitability associated with impaired
      Na(+)-K(+) pump activity.

PMID- 12466423
TI  - Taste responses of neurons in the hamster solitary nucleus are modulated by the
      central nucleus of the amygdala.
AB  - Previous studies have shown a modulatory influence of forebrain gustatory areas,
      such as the gustatory cortex and lateral hypothalamus, on the activity of taste
      responsive cells in the nucleus of the solitary tract (NST). The central nucleus
      of the amygdala (CeA), which receives gustatory afferent information, also exerts
      descending control over taste neurons in the parabrachial nuclei (PbN) of the
      pons. The present studies were designed to investigate the role of descending
      amgydaloid projections to the NST in the modulation of gustatory activity.
      Extracellular action potentials were recorded from 109 taste-responsive cells in
      the NST of urethan-anesthetized hamsters and analyzed for a change in
      excitability following electrical and chemical stimulation of the CeA. Electrical
      stimulation of the CeA orthodromically modulated 36 of 109 (33.0%) taste
      responsive NST cells. An excitatory response was observed in 33 (30.28%) cells.
      An initial decrease in excitability to electrical stimulation of the CeA,
      suggestive of postsynaptic inhibition, was observed in three (2.75%) NST taste
      cells. NST cells modulated by the CeA were significantly less responsive to taste
      stimuli than cells that were not. Many of these cells were under the modulatory
      influence of the contralateral CeA (28/36 = 77.8%) as well as the ipsilateral
      (22/36 = 61.1%); 14 (38.9%) were excited bilaterally. Latencies for excitation
      were longer after ipsilateral than after contralateral CeA stimulation.
      Microinjection of DL-homocysteic acid (DLH) into the CeA mimicked the effect of
      electrical stimulation on each of the nine cells tested: DLH excited eight and
      inhibited one of these electrically activated NST cells. Application of
      subthreshold electrical stimulation to the CeA during taste trials increased the
      taste responses of every CeA-responsive NST cell (n = 7) tested with this
      protocol. These effects would enhance taste discriminability by increasing the
      signal-to-noise ratio of taste-evoked activity.

PMID- 12466424
TI  - Characterization and developmental changes of Na+ currents of petrosal neurons
      with projections to the carotid body.
AB  - Carotid body chemoreceptors transduce a decrease in arterial oxygen tension into
      an increase in spiking activity on the sinus nerve, and this response increases
      with postnatal age over the first week or two of life. Previous work from our
      laboratory has suggested a major role of axonal Na(+) channels in the initiation
      of afferent spiking activity. Using RT-PCR of the petrosal ganglia we identified
      Na(+) channel TTX-S isoforms Na(v)1.1, Na(v)1.6, and Na(v)1.7 and the TTX
      resistant (TTX-R) isoforms Na(v)1.8 and Na(v)1.9 at high levels.
      Electrophysiologic recordings (at 3 ages: 3 days, 9 days, 18-20 days) of neurons
      that project to the carotid body exhibited predominantly fast-inactivating sodium
      currents, with a bimodal recovery from inactivation at -80 mV (fast component
      approximately 8 ms; slow component approximately 90 ms). Developmental age had
      little effect with no change in peak current density (approximately 1.4 nA/pF)
      and was associated with a slight, but significant increase in the speed of
      recovery from inactivation at -140 and -120 mV but not at other potentials.
      Assuming that the same Na(+) channel complement is present at the nerve terminal
      as at the soma, the association of a sensory modality (chemoreception) with a
      relatively uniform Na(+) channel profile suggests that the rapid kinetics of TTX
      S channels may be essential for some aspects of chemoreceptor function beyond
      mediating simple axonal conduction.

PMID- 12466425
TI  - Postsynaptic muscarinic M1 receptors activate prefrontal cortical EEG of C57BL/6J
      mouse.
AB  - Recent pharmacological studies exploring the functional roles of muscarinic
      cholinergic receptor (mAChR) subtypes in prefrontal cortex of C57BL/6J (B6) mouse
      have provided evidence for a presynaptic M2 autoreceptor. The B6 mouse was chosen
      for these studies because it is a genetically well-characterized model that also
      provides the genomic background for many genetically modified mice. In addition
      to increasing ACh release, one functional consequence of pharmacologically
      blocking the cortical M2 autoreceptor is activation of the contralateral
      prefrontal cortical EEG. To date, the mechanisms through which M2 autoreceptor
      antagonism causes cortical EEG activation have not been investigated. The present
      study tested the hypothesis that, in the B6 mouse, prefrontal cortical ACh
      activates the contralateral prefrontal EEG via postsynaptic M1 receptors. This
      hypothesis was tested in 15 mice using in vivo microdialysis delivery of
      muscarinic antagonists with simultaneous quantification of ACh release, number of
      7- to 14-Hz EEG spindles, and fast Fourier transformation analysis of prefrontal
      EEG. Dialysis delivery of the nonsubtype selective muscarinic antagonist
      scopolamine (10 nM) significantly (P = 0.01) increased ACh release. Quantitative
      EEG analysis showed that scopolamine did not alter contralateral prefrontal
      cortical EEG. To differentiate mAChR subtypes mediating pre- versus postsynaptic
      responses, additional experiments used muscarinic antagonists with different
      affinities for the five mAChR subtypes. Microdialysis delivery of 3 nM AF-DX 116,
      a muscarinic antagonist with relatively high affinity for the M2 and M4 subtypes,
      significantly (P < 0.01) increased prefrontal cortical ACh release and activated
      EEG in the contralateral prefrontal cortex. EEG activation was characterized by a
      significant decrease in number of 7- to 14-Hz EEG spindles (P < 0.0001) and power
      (Vrms) of EEG slow waves (P < 0.05). Microdialysis delivery of 3 nM AF-DX 116
      plus 3 nM pirenzepine, a relatively selective M1 and M4 muscarinic antagonist,
      also significantly (P < 0.01) increased ACh release but did not decrease the
      number of EEG spindles and did not change EEG slow waves. The differential EEG
      and ACh responses to dialysis delivery of the muscarinic antagonists support the
      conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the M1 subtype
      are a primary site by which ACh activates the EEG.

PMID- 12466426
TI  - Dopamine enhancement of NMDA currents in dissociated medium-sized striatal
      neurons: role of D1 receptors and DARPP-32.
AB  - Dopamine (DA), via activation of D1 receptors, enhances N-methyl-D-aspartate
      (NMDA)-evoked responses in striatal neurons. The present investigation examined
      further the properties of this enhancement and the potential mechanisms by which
      this enhancement might be effected. Dissociated medium-sized striatal neurons
      were obtained from intact rats and mice or mutant mice lacking the DA and cyclic
      adenosine 3',5' monophosphate (cAMP)-regulated phosphoprotein of M(R) 32,000
      (DARPP-32). NMDA (10-1,000 microM) induced inward currents in all neurons. In
      acutely dissociated neurons from intact rats or mice, activation of D1 receptors
      with the selective agonist, SKF 81297, produced a dose-dependent enhancement of
      NMDA currents. This enhancement was reduced by the selective D1 receptor
      antagonist SKF 83566. Quinpirole, a D2 receptor agonist alone, produced small
      reductions of NMDA currents. However, it consistently and significantly reduced
      the enhancement of NMDA currents by D1 agonists. In dissociated striatal neurons,
      in conditions that minimized the contributions of voltage-gated Ca(2+)
      conductances, the D1-induced potentiation was not altered by blockade of L-type
      voltage-gated Ca(2+) conductances in contrast to results in slices. The DARPP-32
      signaling pathway has an important role in D1 modulation of NMDA currents. In
      mice lacking DARPP-32, the enhancement was significantly reduced. Furthermore,
      okadaic acid, a protein phosphatase 1 (PP-1) inhibitor, increased D1-induced
      potentiation, suggesting that constitutively active PP-1 attenuates D1-induced
      potentiation. Finally, activation of D1 receptors produced differential effects
      on NMDA and gamma aminobutyric acid (GABA)-induced currents in the same cells,
      enhancing NMDA currents and inhibiting GABA currents. Thus simultaneous
      activation of D1, NMDA, and GABA receptors could predispose medium-sized spiny
      neurons toward excitation. Taken together, the present findings indicate that the
      unique potentiation of NMDA receptor function by activation of the D1 receptor
      signaling cascade can be controlled by multiple mechanisms and has major
      influences on neuronal function.

PMID- 12466427
TI  - Mechanical response properties of A and C primary afferent neurons innervating
      the rat intracranial dura.
AB  - The intracranial dura receives a small-fiber sensory innervation from the
      trigeminal ganglion that is thought to be involved in some types of headaches,
      including migraine. Mechanical response properties of dural afferent neurons were
      examined to investigate variation across the population in the properties of
      threshold, slope, adaptation, and incidence of mechanosensitivity. Dural afferent
      neurons were recorded in the trigeminal ganglion of urethan-anesthetized rats and
      were identified by their constant-latency response to dural shock. Neurons were
      classified as fast A (>5 m/s), slow A (5 >or= conduction velocity (CV) >or= 1.5
      m/s), or C (<1.5 m/s), based on response latency to dural shock. Mechanical
      receptive fields were identified by stroking or indenting the outer surface of
      the dura. Stimulus-response curves were obtained from responses to 2-s constant
      force indenting stimuli of graded intensities delivered to the dural receptive
      field with a servo force-controlled mechanical stimulator. The slow A population
      had the highest percentage of mechanosensitive units (97%) as well as the highest
      slopes and the lowest thresholds. Thus by all three criteria, the slow As had the
      highest mechanosensitivity. Conversely, the fast A population had the lowest
      mechanosensitivity in that it had the lowest percentage of mechanosensitive units
      (66%), the lowest slopes, and the highest thresholds. The C population was
      intermediate with respect to all three properties but was much more similar to
      the slow As than to the fast As. All three fiber classes showed a negative
      correlation between slope and threshold. The majority of neurons showed a slowly
      adapting response to a maintained 2-s stimulus. Adapting neurons could be
      subdivided based on whether the fitted exponential curve decayed to zero or to a
      nonzero plateau; the latter group contained the most sensitive neurons in that
      they had the lowest thresholds and highest slopes. Nonadapting neurons generally
      had lower initial firing rates than adapting neurons. Fast A neurons exhibited
      greater and more rapid adaptation than slow A and C neurons. Neurons with the
      lowest slopes, regardless of CV, had relatively rapid adaptation. The more slowly
      conducting portion of the C population was distinguished from the other C neurons
      by a number of properties: more mechanically insensitive neurons, higher
      thresholds, and more nonadapting neurons. These differences in mechanical
      response properties may be related in part to differences in membrane currents
      involved in impulse generation that have been described in subpopulations of
      dorsal root ganglion cells.

PMID- 12466428
TI  - Effects of intrathecal glutamatergic drugs on locomotion I. NMDA in short-term
      spinal cats.
AB  - Excitatory amino acids (EAA) have been reported to induce fictive locomotion in
      different in vitro and in vivo preparations in a variety of species through their
      actions on both N-methyl-D-aspartate (NMDA), and non-NMDA receptors. NMDA-induced
      intrinsic membrane properties such as intrinsic motoneuronal membrane
      oscillations and plateau potentials have been suggested to play a role in the
      generation of locomotion. There is, however, no information on the ability of
      NMDA in triggering spinal locomotion in awake behaving animals. Because most of
      the previous work on the induction of locomotion has concentrated on
      monoaminergic drugs, mainly noradrenergic drugs, the aim of this study is to
      examine the potential of NMDA in initiating locomotion in chronic spinal cats
      within the first week after spinalization. Five cats chronically implanted with
      an intrathecal cannula and electromyographic (EMG) electrodes were used. EMG
      activity synchronized to video images of the hindlimbs were recorded. The results
      show that during the early posttransection period (within the 1st week
      postspinalization), NMDA did not trigger robust locomotion as did noradrenergic
      drugs. The predominant effects of NMDA were a general hyperexcitability reflected
      by fast tremor, toe fanning, and an increase in small alternating hindlimb
      movements with no foot placement nor weight support. During the intermediate
      phase posttransection (6-8 days), when the cats were able to make some
      rudimentary steps with foot placement, NMDA significantly enhanced the locomotor
      performance, which lasted for 24-72 h postinjection. NMDA was also found to
      increase the excitability of the cutaneous reflex transmission only in early
      spinal cats. One possible hypothesis for the ineffectiveness of NMDA in
      triggering locomotion in early spinal cats could be attributed to the widespread
      activation of NMDA receptors on various neuronal elements involved in the
      transmission of afferent pathways that in turn may interfere with the expression
      of locomotion. The marked effects of NMDA in intermediate-spinal cats suggest
      that NMDA receptors play an important role in locomotion perhaps through its role
      on intrinsic membrane properties of neurons in shaping and amplifying spinal
      neuronal transmission or by augmenting the sensory afferent inputs. The long-term
      effects mediated by NMDA receptors have been reported in the literature and may
      involve mechanisms such as induction of long-term potentiation or interactions
      with neuropeptides. The effects of NMDA injection in intact cats and long-term
      chronic spinal cats will be addressed in a forthcoming companion paper.

PMID- 12466429
TI  - Relationship between membrane potential oscillations and rhythmic discharges in
      identified hippocampal theta-related cells.
AB  - Intracellular recordings of cells, classified according to the criteria of Colom
      and Bland as phasic theta-ON or phasic theta-OFF cells, were carried out in the
      dorsal region of the hippocampal formation in urethan-anesthetized rats. Cells
      were studied during two spontaneously occurring hippocampal field conditions,
      asynchrony, termed large-amplitude irregular activity, and synchrony, termed
      theta. During the spontaneous cycling between these two field states, the effect
      of four levels of intracellular depolarizing and hyperpolarizing constant current
      injections on the amplitude and phase of membrane potential oscillations (MPOs)
      and the rate and pattern of cell discharges was assessed. Labeled CA1 pyramidal
      cells and bistratified cells met the criteria for classification as phasic theta
      ON cells and labeled CA1 pyramidal layer basket cells, mossy hilar cells, and
      granule cells met the criteria for classification as phasic theta-OFF cells. MPOs
      were recorded in CA1 pyramidal cells, CA1 layer basket cells, mossy interneurons,
      and granule cells only during theta field activity, their onset in theta-ON cells
      signaled by a depolarizing shift of 5-10 mV and in theta-OFF cells by a
      hyperpolarizing shift of 5-10 mV, in membrane potential. The effect of current
      injections in phasic theta-ON and theta-OFF cells during the theta field
      condition revealed that MPO amplitude was voltage dependent and frequency was
      voltage independent. There were no phase changes observed in phasic theta-ON
      cells during current injections; however, amplitude analysis revealed an inverted
      U-shaped curve asymmetrically distributed around the average value of the
      membrane potential occurring during the spontaneous theta (no current) control
      condition. The occurrence and rate of rhythmical cell discharges in CA1 pyramidal
      phasic theta-ON cells during the theta condition was precisely controlled within
      a critical range of membrane potential values from approximately -57 to -68 mV,
      corresponding to a range of MPO amplitudes of approximately 4-7 mV. Outside the
      critical range, rhythmic cell discharges were abolished. Membrane potential
      oscillations in CA1 pyramidal layer basket cells underwent an approximate 180
      degrees phase reversal when the membrane potential was depolarized above -65 mV.
      The occurrence and rate of rhythmic cell discharges in CA1 pyramidal layer basket
      cell phasic theta-OFF cells during the theta condition was precisely controlled
      within a critical range of membrane potential values from approximately -62 to 
      60 mV, corresponding to a range of MPO amplitudes of approximately 7-7.5 mV.
      Outside the critical range, cell discharges were absent or occurred singly.

PMID- 12466430
TI  - Pentobarbital depressant effects are independent of GABA receptors in auditory
      thalamic neurons.
AB  - Pentobarbital, a general anesthetic, has received extensive study for its ability
      to potentiate inhibition at GABA(A) subtype of receptors for GABA. Using whole
      cell current-clamp techniques and bath applications, we determined the effects of
      pentobarbital and GABA receptor antagonists on the membrane properties and tonic
      or burst firing of medial geniculate neurons in thalamic slices. Pentobarbital
      (0.01-200 microM) induced depressant effects in 50 of 66 neurons (76%).
      Pentobarbital hyperpolarized neurons by a mean of 3 mV and decreased the number
      of action potentials in tonic firing, evoked by current pulse injection from near
      the resting potential. Pentobarbital also decreased burst firing or low threshold
      Ca(2+)-spikes, evoked by current pulse injection into neurons at potentials
      hyperpolarized from rest. The blockade of tonic and burst firing, as well as low
      threshold Ca(2+)-spikes, was surmountable by increasing the amplitude of input
      current. The GABA(A) receptor antagonists, bicuculline (100 microM) and
      picrotoxinin (50-100 microM), did not block the depressant effects of
      pentobarbital (10 microM). The GABA(B) receptor antagonist, saclofen (200
      microM), and GABA(C) receptor antagonist, (1,2,3,6-tetrahydropyridine-4
      yl)methylphosphinate (10-50 microM), did not significantly alter the depressant
      effects. Pentobarbital produced excitatory effects (0.1-50 microM) on 11 neurons
      (17%) but had no effects on 5 neurons (7%). The excitation consisted of
      approximately 3 mV depolarization, increased tonic and burst firing and the rate
      of rise and amplitude of low threshold Ca(2+) spikes. These effects were
      associated with a increase in input resistance. In contrast, the depressant
      effects of pentobarbital correlated to a decreased input resistance measured with
      hyperpolarizing current pulse injection (IC(50) = 7.8 microM). Pentobarbital
      reduced Na(+)-dependent rectification on depolarization and lowered the slope
      resistance over a wide voltage range. Tetrodotoxin eliminated both Na(+)
      dependent rectification and the pentobarbital-induced decrease in membrane
      resistance at depolarized voltages in two-thirds of the neurons. The
      pentobarbital-induced decrease in membrane resistance at voltages hyperpolarized
      from rest was not evident during co-application with Cs(+), known to block the
      hyperpolarization-activated rectifiers. In summary, the pentobarbital acted at
      low concentrations to depress thalamocortical neurons. The depression resulted
      from decreased rectification on depolarization, which no longer boosted
      potentials over threshold, and an increased conductance that shunted spike
      generation. The depressant effects of pentobarbital did not involve known types
      of GABA receptor interactions.

PMID- 12466431
TI  - Somatostatin depresses long-term potentiation and Ca2+ signaling in mouse dentate
      gyrus.
AB  - The selective loss of somatostatin (SST)-containing interneurons from the hilus
      of the dentate gyrus is a hallmark of epileptic hippocampus. The functional
      consequence of this loss, including its contribution to postseizure
      hyperexcitability, remains unclear. We address this issue by characterizing the
      actions of SST in mouse dentate gyrus using electrophysiological techniques.
      Although the majority of dentate SST receptors are located in the outer molecular
      layer adjacent to lateral perforant path (LPP) synapses, we found no consistent
      action of SST on standard synaptic responses generated at these synapses.
      However, when SST was present during application of high-frequency trains that
      normally generate long-term potentiation (LTP), the induction of LTP was
      impaired. SST did not alter the maintenance of LTP when applied after its
      induction. To examine the mechanism by which SST inhibits LTP, we recorded from
      dentate granule cells and examined the actions of this neuropeptide on synaptic
      transmission and postsynaptic currents. Unlike findings in the CA1 hippocampus,
      we observed no postsynaptic actions on K(+) currents. Instead, SST inhibited
      Ca(2+)/Ba(2+) spikes evoked by depolarization. This inhibition was dependent on N
      type Ca(2+)currents. Blocking these currents also blocked LTP, suggesting a
      mechanism through which SST may inhibit LTP. Our results indicate that SST
      reduction of dendritic Ca(2+) through N-type Ca(2+) channels may contribute to
      modulation of synaptic plasticity at LPP synapses. Therefore the loss of SST
      function postseizure could result in abnormal synaptic potentiation that
      contributes to epileptogenesis.

PMID- 12466432
TI  - Task differences with the same load torque alter the endurance time of submaximal
      fatiguing contractions in humans.
AB  - Endurance time, muscle activation, and mean arterial pressure were measured
      during two types of submaximal fatiguing contractions that required each subject
      to exert the same net muscle torque in the two tasks. Sixteen men and women
      performed isometric contractions at 15% of the maximum voluntary contraction
      (MVC) force with the elbow flexor muscles, either by maintaining a constant force
      while pushing against a force transducer (force task) or by supporting an
      equivalent inertial load while maintaining a constant elbow angle (position
      task). The endurance time for the force task (1402 +/- 728 s) was twice as long
      as that for the position task (702 +/- 582 s, P < 0.05), despite a similar
      reduction in the load torque at exhaustion for each contraction. The rate of
      increase in average electromyographic activity (EMG, % peak MVC value) for the
      elbow flexor muscles was similar for the two tasks. However, the average EMG was
      greater at exhaustion for the force task (22.4 +/- 1.2%) compared with the
      position task (14.9 +/- 1.0%, P < 0.05). In contrast, the rates of increase in
      the mean arterial pressure, the rating of perceived exertion, anterior deltoid
      EMG, and fluctuations in motor output (force or acceleration) were greater for
      the position task compared with the force task (P < 0.05). Furthermore, the rate
      of bursts in EMG activity, which corresponded to the transient recruitment of
      motor units, was greater for the brachialis muscle during the position task.
      These results indicate that the briefer endurance time for the position task was
      associated with greater levels of excitatory and inhibitory input to the motor
      neurons compared with the force task.

PMID- 12466433
TI  - Development of GABA(A) receptor-mediated inhibitory postsynaptic currents in
      hippocampus.
AB  - Hippocampal CA1 pyramidal cells receive two kinetic classes of GABA(A) receptor
      mediated inhibition: slow dendritic inhibitory postsynaptic currents
      (GABA(A,slow) IPSCs) and fast perisomatic (GABA(A,fast)) IPSCs. These two classes
      of IPSCs are likely generated by two distinct groups of interneurons, and we have
      previously shown that the kinetics of the IPSCs have important functional
      consequences for generating synchronous firing patterns. Here, we studied
      developmental changes in the properties of GABA(A,fast) and GABA(A,slow)
      spontaneous, miniature, and evoked IPSCs (sIPSCs, mIPSCs, and eIPSCs,
      respectively) using whole cell voltage-clamp recordings in brain slices from
      animals aged P10-P35. We found that the rate of GABA(A,slow) sIPSCs increased by
      over 70-fold between P11 and P35 (from 0.0017 to 0.12 s(-1)). Over this same age
      range, we observed a >3.5-fold increase in the maximal amplitude of GABA(A,slow)
      eIPSCs evoked by stratum lacunosum-moleculare (SL-M) stimuli. However, the rate
      and amplitude of GABA(A,slow) mIPSCs remained unchanged between P10 and P30,
      suggesting that the properties of GABA(A,slow) synapses remained stable over this
      age range, and that the increase in sIPSC rate and in eIPSC amplitude was due to
      increased excitability or excitation of GABA(A,slow) interneurons. This
      hypothesis was tested using bath application of norepinephrine (NE), which we
      found at low concentrations (1 microM) selectively increased the rate of
      GABA(A,slow) sIPSCs while leaving GABA(A,fast) sIPSCs unchanged. This effect was
      observed in animals as young as P13 and was blocked by coapplication of
      tetrodotoxin, suggesting that NE was acting to increase the spontaneous firing
      rate of GABA(A,slow) interneurons and consistent with our hypothesis that
      developmental changes in GABA(A,slow) IPSCs are due to changes in presynaptic
      excitability. In contrast to the changes we observed in GABA(A,slow) IPSCs, the
      properties of GABA(A,fast) sIPSCs remained largely constant between P11 and P35,
      whereas the rate, amplitude, and kinetics of GABA(A,fast) mIPSCs showed
      significant changes between P10 and P30, suggesting counterbalancing changes in
      action potential-dependent GABA(A,fast) sIPSCs. These observations suggest
      differential developmental regulation of the firing properties of GABA(A,fast)
      and GABA(A,slow) interneurons in CA1 between P10 and P35.

PMID- 12466434
TI  - The rat lumbosacral spinal cord adapts to robotic loading applied during stance.
AB  - Load-related afferent information modifies the magnitude and timing of hindlimb
      muscle activity during stepping in decerebrate animals and spinal cord-injured
      humans and animals, suggesting that the spinal cord mediates load-related
      locomotor responses. In this study, we found that stepping on a treadmill by
      adult rats that received complete, midthoracic spinal cord transections as
      neonates could be altered by loading the hindlimbs using a pair of small robotic
      arms. The robotic arms applied a downward force to the lower shanks of the
      hindlimbs during the stance phase and measured the position of the lower shank
      during stepping. No external force was applied during the swing phase of the
      step. When applied bilaterally, this stance force field perturbed the hindlimb
      trajectories so that the ankle position was shifted downward during stance. In
      response to this perturbation, both the stance and step cycle durations
      decreased. During swing, the hindlimb initially accelerated toward the normal,
      unperturbed swing trajectory and then tracked the normal trajectory. Bilateral
      loading increased the magnitude of the medial gastrocnemius electromyographic
      (EMG) burst during stance and increased the amplitude of the semitendinosus and
      rectus femoris EMG bursts. When the force field was applied unilaterally, stance
      duration decreased in the loaded hindlimb, while swing duration was decreased in
      the contralateral hindlimb, thereby preserving interlimb coordination. These
      results demonstrate the feasibility of using robotic devices to mechanically
      modulate afferent input to the injured spinal cord during weight-supported
      locomotion. In addition, these results indicate that the lumbosacral spinal cord
      responds to load-related input applied to the lower shank during stance by
      modifying step timing and muscle activation patterns, while preserving normal
      swing kinematics and interlimb coordination.

PMID- 12466435
TI  - Movement-related neuronal activity reflecting the transformation of coordinates
      in the ventral premotor cortex of monkeys.
AB  - We examined how the transformation of coordinates from visual to motor space is
      reflected by neuronal activity in the ventral premotor cortex (PMv) of monkeys.
      Three monkeys were trained to reach with their right hand for a target that
      appeared on a screen. While performing the task, the monkeys wore prisms that
      shifted the image of the target 10 degrees, left or right, or wore no prisms, for
      a block of 200 trials. The nine targets were located in the same positions in
      visual space regardless of whether the prisms were present. Wearing the prisms
      required the monkeys to initiate a movement in a direction that was different
      from the apparent target location. Thus using the prisms, we could dissociate
      visual space from motor space. While the monkey performed the behavioral task, we
      recorded neuronal activity in the left PMv and primary motor cortex (MI), and
      various kinds of task-related neuronal activity were found in the motor areas.
      These included neurons that changed their activity during a reaction time (RT)
      period (the period between target presentation and movement onset), which were
      called "movement-related neurons" and selected for analysis. In these neurons,
      activity during a movement time (MT) period was also compared. Using general
      linear models for our statistical analysis, the neurons were then classified into
      four types: those whose activity was consistently dependent on location of
      targets in the visual coordinates regardless of whether the prisms were present
      or absent (V type); those that were consistently dependent on target location in
      the motor coordinates only; those that had different activity for both of the
      motor and visual coordinates; and those that had nondifferential activity for the
      two types of coordinates. The proportion of the four types of the neurons
      differed significantly between the PMv and MI. Most remarkably, neurons with V
      type activity were almost exclusively recorded in the PMv and were almost
      exclusively found during the RT period. Such activity was never observed in an
      electromyogram of the working forelimb. Based on these observations, we postulate
      that the V and other types may represent the various intermediate stages of the
      transformation of coordinates and that the PMv plays a crucial role in
      transforming coordinates from visual to motor space.

PMID- 12466436
TI  - Effects of a cross-modal manipulation of attention on somatosensory cortical
      neuronal responses to tactile stimuli in the monkey.
AB  - The role of attention in modulating tactile sensitivity in primary (SI) and
      secondary somatosensory cortex (SII) was addressed using a cross-modal
      manipulation of attention, somatosensory versus visual. Two adult monkeys (Macaca
      mulatta) were trained to perform two tasks: tactile discrimination of a change in
      the texture of a surface presented to digits 3 and 4 and visual discrimination of
      a change in the intensity of a light. In each trial, standard texture (2 mm
      spatial period, SP) and visual stimuli were presented. These were followed by an
      increase in SP and/or luminance. Each trial was preceded by an instruction cue
      (colored light) that directed the animal to attend and respond to the change in
      one modality while ignoring any change in the other modality. The two tasks were
      interleaved during the recording, on a trial-by-trial basis. Extracellular
      recordings were made from 178 neurons (SI, 102; SII, 76), all with a cutaneous
      receptive field on the stimulated digit tips. Discharge was quantified in both
      tasks during the instruction, the standard-stimuli, and the texture-change
      periods. The results showed that selective attention to tactile stimuli had
      qualitatively and quantitatively greater and earlier effects in SII than SI.
      Twenty-four of 102 SI cells showed a significant change in discharge with the
      direction of attention. For almost all cells (20/24), discharge was enhanced when
      attention was directed toward the tactile stimuli; the effects were most frequent
      in the analysis interval that encompassed the change in SP (16/24). A
      significantly higher proportion of SII cells were attention-sensitive (47/76).
      The effects were concentrated in the texture-change period (39/47) but also
      included earlier periods in the trial (instruction period, n = 15; standard
      stimuli period, n = 32). Attention-related modulation that spanned all three
      intervals (n = 11) likely reflected baseline changes in discharge. For the
      texture-sensitive cells (43 in SI, 37 in SII), the mean change in discharge
      frequency (post texture change - pre-texture change) in each task was
      significantly increased in SII but not SI with selective attention. The results
      are consistent with a two-stage modulation of parietal cortical discharge, an
      initial stage (SI) in which there is some enhancement of sensory responses to the
      salient feature, the texture change, and a second stage (SII) in which baseline
      changes occur, along with further feature selection. These controls may be
      independently exerted on SI and SII, or they may reflect top-down controls from
      SII to SI.

PMID- 12466437
TI  - Mechanisms of dopamine activation of fast-spiking interneurons that exert
      inhibition in rat prefrontal cortex.
AB  - Prefrontal cortical dopamine (DA) modulates pyramidal cell excitability directly
      and indirectly by way of its actions on local circuit GABAergic interneurons. DA
      modulation of interneuronal functions is implicated in the computational
      properties of prefrontal networks during cognitive processes and in
      schizophrenia. Morphologically and electrophysiologically distinct classes of
      putative GABAergic interneurons are found in layers II-V of rat prefrontal
      cortex. Our whole cell patch-clamp study shows that DA induced a direct, TTX
      insensitive, reversible membrane depolarization, and increased the excitability
      of fast-spiking (FS) interneurons. The DA-induced membrane depolarization was
      reduced significantly by D1/D5 receptor antagonist SCH 23390, but not by the D2
      receptor antagonist (-)sulpiride, D4 receptor antagonists U101958 or L-745870,
      alpha1-adrenoreceptor antagonist prazosin, or serotoninergic receptor antagonist
      mianserin. The D1/5 agonists SKF81297 or dihydrexidine, but not D2 agonist
      quinpirole, also induced a prolonged membrane depolarization. Voltage-clamp
      analyses of the voltage-dependence of DA-sensitive currents, and the effects of
      changing [K(+)](O) on reversal potentials of DA responses, revealed that DA
      suppressed a Cs(+)-sensitive inward rectifier K(+) current and a resting leak
      K(+) current. D1/D5, but not D2 agonists mimicked the suppressive effects of DA
      on the leak current, but the DA effects on the inward rectifier K(+) current were
      not mimicked by either agonist. In a subgroup of FS interneurons, the slowly
      inactivating membrane outward rectification evoked by depolarizing voltage steps
      was also attenuated by DA. Collectively, these data showed that DA depolarizes FS
      interneurons by suppressing a voltage-independent 'leak' K(+) current (via D1/D5
      receptor mechanism) and an inwardly rectifying K(+) current (via unknown DA
      mechanisms). Additional suppression of a slowly inactivating K(+) current led to
      increase in repetitive firing in response to depolarizing inputs. This D1-induced
      increase in interneuron excitability enhances GABAergic transmission to PFC
      pyramidal neurons and could represent a mechanism via which DA suppresses
      persistent firing of pyramidal neurons in vivo.

PMID- 12466438
TI  - Differential dependence of LTD on glutamate receptors in the auditory cortical
      synapses of cortical and thalamic inputs.
AB  - Pyramidal neurons in the auditory cortex (AC) receive glutamatergic inputs from
      the medial geniculate body (MGB inputs) and other pyramidal neurons (pyramidal
      inputs). We found that the induction of long-term depression (LTD) in
      supragranular layers was only partially suppressed by 50 microM D-(-)-2-amino-5
      phosphonovalerate (APV), an antagonist of N-methyl-D-aspartate (NMDA) receptors
      (NMDARs), and 500 microM (+)-alpha-methyl-4-carboxyphenylglycine (MCPG), an
      antagonist of metabotropic glutamate receptors (mGluRs). However, LTD was not
      observed in the mixture of APV and MCPG. We hypothesized that the mixed
      dependence of LTD on glutamate receptors could be attributed to the heterogeneity
      of MGB inputs and pyramidal inputs. To test this hypothesis, the angle of slicing
      and other recording conditions were adjusted so that postsynaptic potentials were
      recorded in normal slices, but not in the slices prepared from the rats with MGB
      lesion. In these experiments, LTD was suppressed by MCPG alone. The conditions
      were adjusted to minimize the contribution of MGB inputs in field potentials. In
      these experiments, the induction of LTD was suppressed by APV alone.
      Interestingly, the induction of LTD was partially suppressed by 20 microM
      nifedipine, a blocker of L-type Ca(2+) channels, in the slices prepared from the
      rats with MGB lesions, but not in normal slices. These findings suggest that the
      induction of LTD requires activation of mGluRs in the synapses of MGB inputs and
      of NMDARs in the synapses of pyramidal inputs.

PMID- 12466439
TI  - Responses of primate caudal parabrachial nucleus and Kolliker-fuse nucleus
      neurons to whole body rotation.
AB  - The caudal aspect of the parabrachial (PBN) and Kolliker-Fuse (KF) nuclei receive
      vestibular nuclear and visceral afferent information and are connected
      reciprocally with the spinal cord, hypothalamus, amygdala, and limbic cortex.
      Hence, they may be important sites of vestibulo-visceral integration,
      particularly for the development of affective responses to gravitoinertial
      challenges. Extracellular recordings were made from caudal PBN cells in three
      alert, adult female Macaca nemestrina through an implanted chamber. Sinusoidal
      and position trapezoid angular whole body rotation was delivered in yaw, roll,
      pitch, and vertical semicircular canal planes. Sites were confirmed
      histologically. Units that responded during rotation were located in lateral and
      medial PBN and KF caudal to the trochlear nerve at sites that were confirmed
      anatomically to receive superior vestibular nucleus afferents. Responses to whole
      body angular rotation were modeled as a sum of three signals: angular velocity, a
      leaky integration of angular velocity, and vertical position. All neurons
      displayed angular velocity and integrated angular velocity sensitivity, but only
      60% of the neurons were position-sensitive. These responses to vertical rotation
      could display symmetric, asymmetric, or fully rectified cosinusoidal spatial
      tuning about a best orientation in different cells. The spatial properties of
      velocity and integrated velocity and position responses were independent for all
      position-sensitive neurons; the angular velocity and integrated angular velocity
      signals showed independent spatial tuning in the position-insensitive neurons.
      Individual units showed one of three different orientations of their excitatory
      axis of velocity rotation sensitivity: vertical-plane-only responses, positive
      elevation responses (vertical plane plus ipsilateral yaw), and negative elevation
      axis responses (vertical plane plus negative yaw). The interactions between the
      velocity and integrated velocity components also produced variations in the
      temporal pattern of responses as a function of rotation direction. These findings
      are consistent with the hypothesis that a vestibulorecipient region of the PBN
      and KF integrates signals from the vestibular nuclei and relay information about
      changes in whole-body orientation to pathways that produce homeostatic and
      affective responses.

PMID- 12466440
TI  - Capacity of vertical VOR adaptation in squirrel monkey.
AB  - Squirrel monkeys were trained using newly developed visual-vestibular mismatch
      paradigms to test the asymmetrical simultaneous induction of vertical
      vestibuloocular reflex (VOR) gain changes in opposite directions (high and low)
      either in the upward and downward directions or in response to high- and low
      frequency stimuli. The first paradigm consists of sinusoidal head movement [A
      sin(omegat)] and a full rectified sinusoidal optokinetic stimulus [+/-|A
      sin(omegat)|], whereas the second paradigm consists of the sum of two sinusoids
      with different frequencies [A sin(omega(1)t) + A sin(omega(2)t) for head motion
      and +/-[A sin(omega(1)t) - A sin(omega(2)t)] for the optokinetic stimulus,
      omega(1) = 0.1pi, omega(2) = 5pi]. The first paradigm induced a half rectified
      sinusoidal eye-velocity trace, i.e., suppression of the VOR during upward head
      motion and enhancement during downward head motion or vise versa, whereas the
      second paradigm induced suppression of the VOR at the low-frequency omega(1) and
      enhancement at the high-frequency omega(2) or vise versa. After 4 h of exposure
      to these paradigms, VOR gains of up and down or high and low frequency were
      modified in opposite directions. We conclude that the monkey vertical VOR system
      is capable of up-down directionally differential adaptation as well as high-low
      frequency differential adaptation. However, experiments also suggest that these
      gain controls are not completely independent because the magnitudes of the gain
      changes during simultaneous asymmetrical training were less than those achieved
      by symmetrical training or training in only one of the two components, indicating
      an influence of the gain controls on each other. These results confine the
      adaptive site(s) responsible for vertical VOR motor learning to those that can
      process up and downward or low- and high-frequency head signal separately but not
      completely independently.

PMID- 12466441
TI  - Prolongation of hippocampal miniature inhibitory postsynaptic currents in mice
      lacking the GABA(A) receptor alpha1 subunit.
AB  - GABA(A) receptors (GABA(A)-Rs) are pentameric structures consisting of two alpha,
      two beta, and one gamma subunit. The alpha subunit influences agonist efficacy,
      benzodiazepine pharmacology, and kinetics of activation/deactivation. To
      investigate the contribution of the alpha1 subunit to native GABA(A)-Rs, we
      analyzed miniature inhibitory postsynaptic currents (mIPSCs) in CA1 hippocampal
      pyramidal cells and interneurons from wild-type (WT) and alpha1 subunit knock-out
      (alpha1 KO) mice. mIPSCs recorded from interneurons and pyramidal cells obtained
      from alpha1 KO mice were detected less frequently, were smaller in amplitude, and
      decayed more slowly than mIPSCs recorded in neurons from WT mice. The effect of
      zolpidem was examined in view of its reported selectivity for receptors
      containing the alpha1 subunit. In interneurons and pyramidal cells from WT mice,
      zolpidem significantly increased mIPSC frequency, prolonged mIPSC decay, and
      increased mIPSC amplitude; those effects were diminished or absent in neurons
      from alpha1 KO mice. Nonstationary fluctuation analysis of mIPSCs indicated that
      the zolpidem-induced increase in mIPSC amplitude was associated with an increase
      in the number of open receptors rather than a change in the unitary conductance
      of individual channels. These data indicate that the alpha1 subunit is present at
      synapses on WT interneurons and pyramidal cells, although differences in mIPSC
      decay times and zolpidem sensitivity suggest that the degree to which the alpha1
      subunit is functionally expressed at synapses on CA1 interneurons may be greater
      than that at synapses on CA1 pyramidal cells.

PMID- 12466442
TI  - Developmental changes in short-term synaptic depression in the neonatal mouse
      spinal cord.
AB  - We examined age-dependent changes in short-term synaptic depression of
      monosynaptic excitatory postsynaptic potentials (EPSPs) recorded in lumbar
      motoneurons in hemisected spinal cords of neonatal Swiss-Webster mice between
      postnatal day 2 (P2) and 12 (P12). We used four paradigms that sample the input
      output dependence on stimulation history in different but complementary ways: 1)
      paired-pulse depression; 2) steady-state depression during constant frequency
      trains; 3) modulation during irregular stimulation sequences; and 4) recovery
      after high-frequency conditioning trains. Paired-pulse synaptic depression
      declined more than steady-state depression during 10-pulse trains at frequencies
      from 0.125 to 8 Hz in this age range. Depression during sequences of irregular
      stimulations that more closely mimic physiological activation also declined with
      postnatal age. On the other hand, the overall rate of synaptic recovery after a 4
      Hz conditioning train exhibited surprisingly little change between P2 and P12.
      Control experiments indicated that these observations depend primarily, if not
      exclusively, on changes in presynaptic transmitter release. The data were
      examined using quantitative models that incorporate factors that have been
      suggested to exist at more specialized central synapses. The model that best
      predicted the observations included two presynaptic compartments that are
      depleted during activation, plus two superimposed processes that enhance
      transmitter release by different mechanisms. One of the latter produced rapidly
      decaying enhancement of transmitter release fraction. The other mechanism
      indirectly enhanced the rate of renewal of one of the depleted presynaptic
      compartments. This model successfully predicted the constant frequency and
      irregular sequence data from all age groups, as well as the recovery curves
      following short, high-frequency tetani. The results suggest that a reduction in
      release fraction accounts for much of the decline in synaptic depression during
      early postnatal development, although changes in both enhancement processes also
      contribute. The time constants of resource renewal showed surprisingly little
      change through the first 12 days of postnatal life.

PMID- 12466443
TI  - Sustained firing of alpha and gamma hind limb motoneurons induced by stimulation
      of the pudendal nerve.
AB  - Axons from receptors in the cat vaginal wall run in the sensory pudendal nerve
      (SPN), and brief (<10 s) vaginal probing (VP) in the decerebrate cat produces a
      long-lasting (>1 min) contraction of the triceps surae (TS) muscles. The aim of
      the present project was to find out whether brief SPN stimulation also produces
      sustained TS response and, eventually, to study the mechanisms involved in it.
      Decerebrate female cats were used. In some cats, TS electromyography (EMG) and
      tension response were recorded; stimulation of left SPN with single or repetitive
      trains of shocks produced a bilateral TS response that outlasted the stimulus >1
      min as VP did. In paralyzed cats (pancuronium; Panc), intracellular recordings
      were made from hind limb motoneurons (MNs). SPN stimulation produced a
      depolarization <or=5 s long and occasional cell firing only lasting <2.5 s; this
      is in contrast with the prolonged TS postdischarge seen in nonparalyzed cats. If
      MNs were depolarized below the firing threshold by current injection, about half
      of them showed bistable firing that could last several minutes in response to SPN
      train. It is suggested that MNs might hyperpolarize after Panc injection. Before
      Panc injection, SPN train produced long-lasting (>1 min) electroneurographic
      (ENG) postdischarge in a small filament of the medial gastrocnemius (MG) nerve;
      the MG EMG postdischarge was also recorded. Large spikes (LS) and small spikes
      (SS) were distinguished in the ENG. During the postdischarge, LS frequency and
      the integrated EMG activity correlated well (r > 0.9); no correlation was found
      between SS and EMG. After Panc injection, LS postdischarge was absent but the SS
      postdischarge remained. LS followed by EMG potential were also evoked by brief TS
      stretch (reflex LS); single shocks to SPN only elicited SS that were not followed
      by EMG potential. It is concluded that alpha axons and gamma axons produced LS
      and SS, respectively, and that SPN activates gamma axons. It is proposed that, in
      the nonparalyzed cats, the stimulation of SPN with trains of shocks might cause
      an increase in the afferent inflow from muscle spindles to alpha MNs through the
      sustained firing of gamma MNs. The increased excitatory inflow would depolarize
      alpha MNs and allow bistable MN firing; Panc would decrease this inflow by
      blocking transmission to the spindle fibers.

PMID- 12466444
TI  - Impairment of synaptic vesicle exocytosis and recycling during neuromuscular
      weakness produced in mice by 2,4-dithiobiuret.
AB  - Chronic treatment of rodents with 2,4-dithiobiuret (DTB) induces a neuromuscular
      syndrome of flaccid muscle weakness that mimics signs seen in several human
      neuromuscular disorders such as congenital myasthenic syndromes, botulism, and
      neuroaxonal dystrophy. DTB-induced muscle weakness results from a reduction of
      acetylcholine (ACh) release by mechanisms that are not yet clear. The objective
      of this study was to determine if altered release of ACh during DTB-induced
      muscle weakness was due to impairments of synaptic vesicle exocytosis,
      endocytosis, or internal vesicular processing. We examined motor nerve terminals
      in the triangularis sterni muscles of DTB-treated mice at the onset of muscle
      weakness. Uptake of FM1-43, a fluorescent marker for endocytosis, was reduced to
      approximately 60% of normal after either high-frequency nerve stimulation or K(+)
      depolarization. Terminals ranged from those with nearly normal fluorescence
      ("bright terminals") to terminals that were poorly labeled ("dim terminals").
      Ultrastructurally, the number of synaptic vesicles that were labeled with
      horseradish peroxidase (HRP) was also reduced by DTB to approximately 60%;
      labeling among terminals was similarly variable. A subset of DTB-treated
      terminals having abnormal tubulovesicular profiles in their centers did not
      respond to stimulation with increased uptake of HRP and may correspond to dim
      terminals. Two findings suggest that posttetanic "slow endocytosis" remained
      qualitatively normal: the rate of this type of endocytosis as measured with FM1
      43 did not differ from normal, and HRP was observed in organelles associated with
      this pathway- coated vesicles, cisternae, as well as synaptic vesicles but not in
      the tubulovesicular profiles. In DTB-treated bright terminals, end-plate
      potential (EPP) amplitudes were decreased, and synaptic depression in response to
      15-Hz stimulation was increased compared with those of untreated mice; in dim
      terminals, EPPs were not observed during block with D-tubocurarine. Nerve
      stimulation-induced unloading of FM1-43 was slower and less complete than normal
      in bright terminals, did not occur in dim terminals, and was not enhanced by
      alpha-latrotoxin. Collectively, these results indicate that the size of the
      recycling vesicle pool is reduced in nerve terminals during DTB-induced muscle
      weakness. The mechanisms by which this reduction occurs are not certain, but
      accumulated evidence suggests that they may include defects in either or both
      exocytosis and internal vesicular processing.

PMID- 12466445
TI  - Regional analysis of whole cell currents from hair cells of the turtle posterior
      crista.
AB  - The turtle posterior crista is made up of two hemicristae, each consisting of a
      central zone containing type I and type II hair cells and a surrounding
      peripheral zone containing only type II hair cells and extending from the planum
      semilunatum to the nonsensory torus. Afferents from various regions of a
      hemicrista differ in their discharge properties. To see if afferent diversity is
      related to the basolateral currents of the hair cells innervated, we selectively
      harvested type I and II hair cells from the central zone and type II hair cells
      from two parts of the peripheral zone, one near the planum and the other near the
      torus. Voltage-dependent currents were studied with the whole cell, ruptured
      patch method and characterized in voltage-clamp mode. We found regional
      differences in both outwardly and inwardly rectifying voltage-sensitive currents.
      As in birds and mammals, type I hair cells have a distinctive outwardly
      rectifying current (I(K,L)), which begins activating at more hyperpolarized
      voltages than do the outward currents of type II hair cells. Activation of I(K,L)
      is slow and sigmoidal. Maximal outward conductances are large. Outward currents
      in type II cells vary in their activation kinetics. Cells with fast kinetics are
      associated with small conductances and with partial inactivation during 200-ms
      depolarizing voltage steps. Almost all type II cells in the peripheral zone and
      many in the central zone have fast kinetics. Some type II cells in the central
      zone have large outward currents with slow kinetics and little inactivation.
      Although these currents resemble I(K,L), they can be distinguished from the
      latter both electrophysiologically and pharmacologically. There are two varieties
      of inwardly rectifying currents in type II hair cells: activation of I(K1) is
      rapid and monoexponential, whereas that of I(h) is slow and sigmoidal. Many type
      II cells either have both inward currents or only have I(K1); very few cells only
      have I(h). Inward currents are less conspicuous in type I cells. Type II cells
      near the torus have smaller outwardly rectifying currents and larger inwardly
      rectifying currents than those near the planum, but the differences are too small
      to account for variations in discharge properties of bouton afferents innervating
      the two regions of the peripheral zone. The large outward conductances seen in
      central cells, by lowering impedances, may contribute to the low rotational gains
      of some central-zone afferents.

PMID- 12466446
TI  - Functional analysis of whole cell currents from hair cells of the turtle
      posterior crista.
AB  - Controlled currents were used to study possible functions of voltage-sensitive,
      outwardly rectifying conductances. Results were interpreted with linearized
      Hodgkin-Huxley theory. Because of their more hyperpolarized resting potentials
      and lower impedances, type I hair cells require larger currents to be depolarized
      to a given voltage than do type II hair cells. "Fast" type II cells, so-called
      because of the fast activation of their outward currents, show slightly
      underdamped responses to current steps with resonant (best) frequencies of 40-85
      Hz, well above the bandwidth of natural head movements. Reflecting their slower
      activation kinetics, type I and "slow" type II cells have best frequencies of 15
      30 Hz and are poorly tuned, being critically damped or overdamped. Linearized
      theory identified the factors responsible for tuning quality. Our fast type II
      hair cells show only modestly underdamped responses because their steady-state I
      V curves are not particularly steep. The even poorer tuning of our type I and
      slow type II cells can be attributed to their slow activation kinetics and large
      conductances. To study how ionic currents shape response dynamics, we
      superimposed sinusoidal currents of 0.1-100 Hz on a small depolarizing steady
      current intended to simulate resting conditions in vivo. The steady current
      resulted in a slow inactivation, most pronounced in fast type II cells and least
      pronounced in type I cells. Because of inactivation, fast type II cells have
      nearly passive response dynamics with low-frequency gains of 500-1,000 Momega. In
      contrast, type I and slow type II cells show active components in the vestibular
      bandwidth and low-frequency gains of 20-100 and 100-500 Momega, respectively. As
      there are no differences in the responses to sinusoidal currents for fast type II
      cells from the torus and planum, voltage-sensitive currents are unlikely to be
      responsible for the large differences in gains and response dynamics of afferents
      innervating these two regions of the peripheral zone. The low impedances and
      active components of type I cells may be related to the low gains and modestly
      phasic response dynamics of calyx-bearing afferents.

PMID- 12466447
TI  - Reduced endplate currents underlie motor unit dysfunction in canine motor neuron
      disease.
AB  - Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant
      degenerative disorder of motor neurons. In homozygous animals, motor units
      produce decreased force output and fail during repetitive activity. Previous
      studies suggest that decreased efficacy of neuromuscular transmission underlies
      these abnormalities. To examine this, we recorded muscle fiber endplate currents
      (EPCs) and found reduced amplitudes and increased failures during nerve
      stimulation in homozygotes compared with wild-type controls. Comparison of EPC
      amplitudes with muscle fiber current thresholds indicate that many EPCs from
      homozygotes fall below threshold for activating muscle fibers but can be raised
      above threshold following potentiation. To determine whether axonal abnormalities
      might play a role in causing motor unit dysfunction, we examined the postnatal
      maturation of axonal conduction velocity in relation to the appearance of tetanic
      failure. We also examined intracellularly labeled motor neurons for evidence of
      axonal neurofilament accumulations, which are found in many instances of motor
      neuron disease including HCSMA. Despite the appearance of tetanic failure between
      90 and 120 days, average motor axon conduction velocity increased with age in
      homozygotes and achieved adult levels. Normal correlations between motor neuron
      properties (including conduction velocity) and motor unit properties were also
      observed. Labeled proximal motor axons of several motor neurons that supplied
      failing motor units exhibited little or no evidence of axonal swellings. We
      conclude that decreased release of transmitter from motor terminals underlies
      motor unit dysfunction in HCSMA and that the mechanisms determining the
      maturation of axonal conduction velocity and the pattern of correlation between
      motor neuron and motor unit properties do not contribute to the appearance or
      evolution of motor unit dysfunction.

PMID- 12466448
TI  - Reduced neuromuscular quantal content with normal synaptic release time course
      and depression in canine motor neuron disease.
AB  - Hereditary canine spinal muscular atrophy is an autosomal dominant version of
      motor neuron disease in which motor units exhibit extensive dysfunction before
      motor terminal or axonal degeneration appear. We showed in a previous paper that
      motor endplate currents (EPCs) are reduced and that failures of nerve-evoked EPCs
      appear in the homozygote medial gastrocnemius (MG) muscle in which failing motor
      units are also found, suggesting a presynaptic deficit of ACh release. To examine
      this further, we performed a detailed analysis of synaptic release properties in
      the MG muscle of homozygotes and compared the results with data from genetically
      normal control animals. We found that the amplitude of miniature EPCs (mEPC) did
      not differ between homozygote and normal synapses, indicating that quantal
      content is reduced at homozygote motor terminals. Consistent with this,
      deconvolution analysis showed that the maximum release rates at homozygote motor
      terminals were significantly reduced relative to normal. This analysis also
      demonstrated that the time course of quantal release at homozygote synapses did
      not differ from normal. The extent of quantal release depression during high
      frequency activation in homozygotes did not differ from normal despite the
      significant reduction of quantal content and maximum release rate. Surprisingly,
      the absolute amount of posttetanic potentiation was not decreased at homozygotes
      motor terminals despite the differences in quantal content. We conclude that
      failure of homozygote motor unit force during repetitive activity is due to a
      unique combination of low quantal content and normal release depression and
      suggest that the primary deficit in homozygote motor terminals is a reduced
      supply of readily releasable quanta.

PMID- 12466449
TI  - Muscarinic and nicotinic presynaptic modulation of EPSCs in the nucleus accumbens
      during postnatal development.
AB  - We have studied the modulatory effects of cholinergic agonists on excitatory
      postsynaptic currents (EPSCs) in nucleus accumbens (nAcb) neurons during
      postnatal development. Recordings were obtained in slices from postnatal day 1
      (P1) to P27 rats using the whole cell patch-clamp technique. EPSCs were evoked by
      local electrical stimulation, and all experiments were conducted in the presence
      of bicuculline methchloride in the bathing medium and with QX-314 in the
      recording pipette. Under these conditions, postsynaptic currents consisted of
      glutamatergic EPSCs typically consisting of two components mediated by
      AMPA/kainate (KA) and N-methyl-D-aspartate (NMDA) receptors. The addition of
      acetylcholine (ACh) or carbachol (CCh) to the superfusing medium resulted in a
      decrease of 30-60% of both AMPA/KA- and NMDA-mediated EPSCs. In contrast, ACh
      produced an increase ( approximately 35%) in both AMPA/KA and NMDA receptor
      mediated EPSCs when administered in the presence of the muscarinic antagonist
      atropine. These excitatory effects were mimicked by the nicotinic receptor
      agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) and blocked by the
      nicotinic receptor antagonist mecamylamine, showing the presence of a cholinergic
      modulation mediated by nicotinic receptors in the nAcb. The antagonistic effects
      of atropine were mimicked by pirenzepine, suggesting that the muscarinic
      depression of the EPSCs was mediated by M(1)/M(4) receptors. In addition, the
      inhibitory effects of ACh on NMDA but not on AMPA/KA receptor-mediated EPSC
      significantly increased during the first two postnatal weeks. We found that,
      under our experimental conditions, cholinergic agonists produced no changes on
      membrane holding currents, on the decay time of the AMPA/KA EPSC, or on responses
      evoked by exogenous application of glutamate in the presence of tetrodotoxin, but
      they produced significant changes in paired pulse ratio, suggesting that their
      action was mediated by presynaptic mechanisms. In contrast, CCh produced
      consistent changes in the membrane and firing properties of medium spiny (MS)
      neurons when QX-314 was omitted from the recording pipette solution, suggesting
      that this substance actually blocked postsynaptic cholinergic modulation.
      Together, these results suggest that ACh can decrease or increase glutamatergic
      neurotransmission in the nAcb by, respectively, acting on muscarinic and
      nicotinic receptors located on excitatory terminals. The cholinergic modulation
      of AMPA/KA and NMDA receptor-mediated neurotransmission in the nAcb during
      postnatal development could play an important role in activity-dependent
      developmental processes in refining the excitatory drive on MS neurons by gating
      specific inputs.

PMID- 12466450
TI  - Stimulus-evoked modulation of sensorimotor pyramidal neuron EPSPs.
AB  - Sensory cortical neurons display substantial receptive field dynamics during and
      after persistent sensory drive. Because a cell's response properties are
      determined by the inputs it receives, receptive field dynamics are likely to
      involve changes in the relative efficacy of different inputs to the cell. To test
      this hypothesis, we have investigated if brief repetitive stimulus drive in vitro
      alters the efficacy of two types of corticocortical inputs to layer V pyramidal
      cells. Specifically, we have used whole cell recordings to measure the effect of
      repetitive electrical stimulation at the layer VI/white matter (WM) border on the
      synaptic response of layer V pyramidal cells to corticocortical input evoked by
      electrical stimulation of layer I or layer II/III and emulated by local
      application of glutamate. Repetitive stimulation (10 Hz for 3 s) at the layer
      VI/WM border transiently potentiated excitatory postsynaptic potentials (EPSPs)
      evoked by electrical stimulation of layer II/III by 97 +/- 12% (mean +/- SE). The
      recovery of EPSP amplitude to its preconditioning value was well-described by a
      single-term decaying exponential with a time constant of 7.2 s. The same layer
      VI/WM conditioning train that evoked layer II/III EPSP potentiation frequently
      caused an attenuation of layer I EPSPs. Similarly, subthreshold postsynaptic
      responses to local glutamate application in layers II/III and I were potentiated
      and attenuated, respectively, by the conditioning stimulus. Potentiation and
      attenuation could be evoked in the same cell by repositioning the glutamate
      puffer pipette in the appropriate layer. The conditioning stimulus that led to
      the transient modification of upper layer EPSP efficacy also evoked a slow
      depolarization in glial cells. The membrane potential of glial cells recovered
      with a time course similar to the dissipation of the potentiation effect,
      suggesting that stimulus-evoked changes in extracellular potassium (ECK) play a
      role in layer II/III EPSP potentiation. Consistent with this proposal, increasing
      the bath concentration of ECK caused a substantial increase of layer II/III EPSP
      amplitude. EPSP potentiation was sensitive to postsynaptic membrane potential
      and, more importantly, was significantly weaker for synaptic currents than for
      synaptic potentials, suggesting that it involves the recruitment of a
      postsynaptic voltage-dependent mechanism. Two observations suggest that layer
      II/III EPSP potentiation may involve the recruitment of postsynaptic sodium
      channels: EPSP potentiation was strongly reduced by intracellular application of
      N-(2,6-dimethyl-phenylcarbamoylmethyl) triethylammonium bromide (QX-314) and
      responses to local glutamate application were potentiated by high ECK in the
      presence of cadmium but not in the presence of tetrodotoxin. The results
      demonstrate a novel way in which brief periods of repetitive stimulus drive are
      accompanied by rapid, transient, and specific alterations in the functional
      connectivity and information processing characteristics of sensorimotor cortex.

PMID- 12466451
TI  - A computational model of muscle recruitment for wrist movements.
AB  - To execute a movement, the CNS must appropriately select and activate the set of
      muscles that will produce the desired movement. This problem is particularly
      difficult because a variety of muscle subsets can usually be used to produce the
      same joint motion. The motor system is therefore faced with a motor redundancy
      problem that must be resolved to produce the movement. In this paper, we present
      a model of muscle recruitment in the wrist step-tracking task. Muscle activation
      levels for five muscles are selected so as to satisfy task constraints (moving to
      the designated target) while also minimizing a measure of the total effort in
      producing the movement. Imposing these constraints yields muscle activation
      patterns qualitatively similar to those observed experimentally. In particular,
      the model reproduces the observed cosine-like recruitment of muscles as a
      function of movement direction and also appropriately predicts that certain
      muscles will be recruited most strongly in movement directions that differ
      significantly from their direction of action. These results suggest that the
      observed recruitment behavior may not be an explicit strategy employed by the
      nervous system, but instead may result from a process of movement optimization.

PMID- 12466453
TI  - Postsynaptic dorsal column and cuneate correlations in the raccoon: a re
      evaluation by parallel-cascade analysis.
AB  - In a previous study, we reported evidence for correlations between the firing of
      postsynaptic dorsal column (PSDC) neurons and cuneate neurons with overlapping
      receptive fields on the glabrous skin of the raccoon forepaw. The evidence was
      based on cross-correlation and frequency response analyses of spontaneously
      firing neurons. However, cross-correlation without white noise Gaussian analog
      inputs or Poisson distributed pulse train inputs is difficult to interpret
      because of the inherent convolution with the autocorrelation of the unknown input
      signals. While the data suggested positive correlations in the spinocuneate
      direction for most neuron pairs, we could not estimate the temporal
      characteristics of these putative connections. We have now re-analyzed these data
      using a parallel-cascade method to estimate the first- and second-order kernels
      of a Volterra series approximation to the spinocuneate system. This unbiased
      analysis suggests that a positive correlation occurs after about 5 ms, probably
      followed by a negative correlation at about 12 ms. Second-order kernels also had
      repeatable structure, indicating dual pathways with time separations of at least
      10 ms.

PMID- 12466452
TI  - Adaptive changes in early and late blind: a FMRI study of verb generation to
      heard nouns.
AB  - Literacy for blind people requires learning Braille. Along with others, we have
      shown that reading Braille activates visual cortex. This includes striate cortex
      (V1), i.e., banks of calcarine sulcus, and several higher visual areas in
      lingual, fusiform, cuneus, lateral occipital, inferior temporal, and middle
      temporal gyri. The spatial extent and magnitude of magnetic resonance (MR)
      signals in visual cortex is greatest for those who became blind early in life.
      Individuals who lost sight as adults, and subsequently learned Braille, still
      exhibited activity in some of the same visual cortex regions, especially V1.
      These findings suggest these visual cortex regions become adapted to processing
      tactile information and that this cross-modal neural change might support Braille
      literacy. Here we tested the alternative hypothesis that these regions directly
      respond to linguistic aspects of a task. Accordingly, language task performance
      by blind persons should activate the same visual cortex regions regardless of
      input modality. Specifically, visual cortex activity in blind people ought to
      arise during a language task involving heard words. Eight early blind, six late
      blind, and eight sighted subjects were studied using functional magnetic
      resonance imaging (fMRI) during covert generation of verbs to heard nouns. The
      control task was passive listening to indecipherable sounds (reverse words)
      matched to the nouns in sound intensity, duration, and spectral content.
      Functional responses were analyzed at the level of individual subjects using
      methods based on the general linear model and at the group level, using voxel
      based ANOVA and t-test analyses. Blind and sighted subjects showed comparable
      activation of language areas in left inferior frontal, dorsolateral prefrontal,
      and left posterior superior temporal gyri. The main distinction was bilateral,
      left dominant activation of the same visual cortex regions previously noted with
      Braille reading in all blind subjects. The spatial extent and magnitude of
      responses was greatest on the left in early blind individuals. Responses in the
      late blind group mostly were confined to V1 and nearby portions of the lingual
      and fusiform gyri. These results confirm the presence of adaptations in visual
      cortex of blind people but argue against the notion that this activity during
      Braille reading represents somatosensory (haptic) processing. Rather, we suggest
      that these responses can be most parsimoniously explained in terms of linguistic
      operations. It remains possible that these responses represent adaptations which
      initially are for processing either sound or touch, but which are later
      generalized to the other modality during acquisition of Braille reading skills.

PMID- 12466454
TI  - Movement rate effect on activation and functional coupling of motor cortical
      areas.
AB  - We investigated changes in the activation and functional coupling of bilateral
      primary sensorimotor (SM1) and supplementary motor (SMA) areas with different
      movement rates in eight normal volunteers. An auditory-cued repetitive right
      thumb movement was performed at rates of 0.5, 0.75, 1, 2, 3, and 4 Hz. As a
      control condition, subjects listened to pacing tones with no movements.
      Electroencephalogram (EEG) was recorded from 28 scalp electrodes and
      electromyogram was obtained from the hand muscles. The event-related changes in
      EEG band-power (ERpow: activation of each area) and correlation (ERcor:
      functional coupling between each pair of cortical areas) were computed every 32
      ms. Modulations of ERpow and ERcor were inspected in alpha (8-12 Hz) and beta (16
      20 Hz) bands. Motor cortical activation and coupling was greater for faster
      movements. With increasing movement rate, the timing relationship between
      movement and tone switched from synchronization (for 0.5-1 Hz) to syncopation
      (for 3-4 Hz). The results suggested that for slow repetitive movements (0.5-1
      Hz), each individual movement is separately controlled, and EEG activation and
      coupling of the motor cortical areas were immediately followed by transient
      deactivation and decoupling, having clear temporal modulation locked to each
      movement. In contrast, for fast repetitive movements (3-4 Hz), it appears that
      the rhythm is controlled and the motor cortices showed sustained EEG activation
      and continuous coupling.

PMID- 12466455
TI  - Ionic currents underlying fast action potentials in the obliquely striated muscle
      cells of the octopus arm.
AB  - The octopus arm provides a unique model for neuromuscular systems of flexible
      appendages. We previously reported the electrical compactness of the arm muscle
      cells and their rich excitable properties ranging from fast oscillations to
      overshooting action potentials. Here we characterize the voltage-activated ionic
      currents in the muscle cell membrane. We found three depolarization-activated
      ionic currents: 1) a high-voltage-activated L-type Ca(2+) current, which began
      activating at approximately -35 mV, was eliminated when Ca(2+) was substituted by
      Mg(2+), was blocked by nifedipine, and showed Ca(2+)-dependent inactivation. This
      current had very rapid activation kinetics (peaked within milliseconds) and slow
      inactivation kinetics (tau in the order of 50 ms). 2) A delayed rectifier K(+)
      current that was totally blocked by 10 mM TEA and partially blocked by 10 mM 4
      aminopyridine (4AP). This current exhibited relatively slow activation kinetics
      (tau in the order of 15 ms) and inactivated only partially with a time constant
      of ~150 ms. And 3) a transient A-type K(+) current that was totally blocked by 10
      mM 4AP and was partially blocked by 10 mM TEA. This current exhibited very fast
      activation kinetics (peaked within milliseconds) and inactivated with a time
      constant in the order of 60 ms. Inactivation of the A-type current was almost
      complete at -40 mV. No voltage-dependent Na(+) current was found in these cells.
      The octopus arm muscle cells generate fast (~3 ms) overshooting spikes in
      physiological conditions that are carried by a slowly inactivating L-type Ca(2+)
      current.

PMID- 12466456
TI  - Contrast dependence of response normalization in area MT of the rhesus macaque.
AB  - Contrast normalization is a process whereby responses of neurons are scaled
      according to the total amount of contrast in a region of the image nearby the
      receptive field of a neuron. This process allows neurons to code for informative
      scene or object attributes in a manner unaffected by changes in illumination.
      Evidence for normalization is seen in striate and extrastriate cortex from
      experiments where multiple stimuli are presented with a single receptive field
      (RF). Neuronal responses in such experiments are smaller than that predicted by
      linear summation, revealing the presence of normalization. While the presence of
      normalization is often clear, its mechanism is less so. To study the mechanism of
      normalization, we measured the interaction between pairs of brief local stimuli
      (spatial Gabor functions) within the RFs of cells in the middle temporal (MT or
      V5) area of monkeys and varied both the location and contrast of the stimuli. We
      found response summed approximately linearly when contrast was low but rapidly
      became normalized as stimulus contrast increased. The rapid transition to
      effective normalization at low contrasts suggested cooperativity in the
      normalization, and a model embodying such a cooperative step provided a good
      account of our data.

PMID- 12466457
TI  - Changes of AI receptive fields with sound density.
AB  - Primates engage in auditory behaviors under a broad range of signal-to-noise
      conditions. In this study, optimal linear receptive fields were measured in alert
      primate primary auditory cortex (A1) in response to stimuli that vary in
      spectrotemporal density. As density increased, A1 excitatory receptive fields
      systematically changed. Receptive field sensitivity, expressed as the expected
      change in firing rate after a tone pip onset, decreased by an order of magnitude.
      Spectral selectivity more than doubled. Inhibitory subfields, which were rarely
      recorded at low sound densities, emerged at higher sound densities. The ratio of
      excitatory to inhibitory population strength changed from 14.4:1 to 1.4:1. At low
      sound densities, the sound associated with the evocation of an action potential
      from an A1 neuron was broad in spectrum and time. At high sound densities, a
      spike-evoking sound was more likely to be a spectral or temporal edge and was
      narrower in time and frequency range. Receptive fields were used to predict
      responses to a novel high-noise-density stimulus. The predictions were highly
      correlated with the actual responses to the 2-s complex sound excerpt. The
      structure of prediction failures revealed that neurons with prominent inhibitory
      fields had relatively poor linear predictions. Further, the finding that
      stochastic variance is limiting in prediction even after averaging 150
      repetitions means that high-fidelity representations of simple sounds in A1 must
      be distributed over at least hundreds of neurons. Auditory context alters A1
      responses across multiple parameter spaces; this presents a challenge for
      reconstructing neural codes.

PMID- 12466458
TI  - Long-term voltage-sensitive dye imaging reveals cortical dynamics in behaving
      monkeys.
AB  - A novel method of chronic optical imaging based on new voltage-sensitive dyes
      (VSDs) was developed to facilitate the explorations of the spatial and temporal
      patterns underlying higher cognitive functions in the neocortex of behaving
      monkeys. Using this system, we were able to explore cortical dynamics, with high
      spatial and temporal resolution, over period of <or=1 yr from the same patch of
      cortex. The visual cortices of trained macaques were stained one to three times a
      week, and immediately after each staining session, the monkey started to perform
      the behavioral task, while the primary and secondary visual areas (V1 and V2)
      were imaged with a fast optical imaging system. Long-term repeated VSD imaging
      (VSDI) from the same cortical area did not disrupt the normal cortical
      architecture as confirmed repeatedly by optical imaging based on intrinsic
      signals. The spatial patterns of functional maps obtained by VSDI were
      essentially identical to those obtained from the same patch of cortex by imaging
      based on intrinsic signals. On comparing the relative amplitudes of the evoked
      signals and differential map obtained using these two different imaging
      methodologies, we found that VSDI emphasizes subthreshold activity more than
      imaging based on intrinsic signals, that emphasized more spiking activity. The
      latency of the VSD-evoked response in V1 ranged from 46 to 68 ms in the different
      monkeys. The amplitude of the V2 response was only 20-60% of that in V1. As
      expected from the anatomy, the retinotopic responses to local visual stimuli
      spread laterally across the cortical surface at a spreading velocity of 0.15-0.19
      m/s over a larger area than that expected by the classical magnification factor,
      reaching its maximal anisotropic spatial extent within approximately 40 ms. We
      correlated the observed dynamics of cortical activation patterns with the
      monkey's saccadic eye movements and found that due to the slow offset of the
      cortical response relative to its onset, there was a short period of simultaneous
      activation of two distinct patches of cortex following a saccade to the visual
      stimulus. We also found that a saccade to a small stimulus was followed by direct
      transient activation of a cortical region in areas of V1 and V2, located
      retinotopically within the saccadic trajectory.

PMID- 12466459
TI  - Local application of dopamine inhibits pyramidal tract neuron activity in the
      rodent motor cortex.
AB  - Cortical neurons respond in a variety of ways to locally applied dopamine,
      perhaps because of the activation of different receptors within or among
      subpopulations of cells. This study was conducted to assess the effects of
      dopamine and the receptor subtypes that mediate the responses of a specific
      population of neurons, the pyramidal tract neurons (PTNs) in the rodent motor
      cortex. The specific subfamilies of dopamine receptors expressed by PTNs also
      were determined. PTNs were identified by antidromic stimulation in intact
      animals. Extracellular recordings of their spontaneous activity and glutamate
      induced excitation were performed with multi-barrel pipettes to allow
      simultaneous recording and iontophoresis of several drugs. Prolonged (30 s)
      application of dopamine caused a progressive, nonlinear decrease in spontaneous
      firing rates for nearly all PTNs, with significant reductions from baseline
      spontaneous activity (71% of baseline levels) occurring between 20 and 30 s of
      iontophoresis. The D1 selective (SCH23390) and the D2 selective (eticlopride)
      antagonists were both effective in blocking dopamine-induced inhibition in nearly
      all PTNs. Mean firing levels were maintained within 3% of baseline levels during
      co-application of the D1 antagonist with dopamine and within 11% of baseline
      levels during co-application of the D2 antagonist and dopamine. SCH23390 was
      ineffective however, in 2 of 16 PTNs, and eticlopride was ineffective in 3 PTNs.
      The dopamine blockade by both antagonists in most neurons, along with the
      selective blockade by one, but not the other antagonist in a few neurons indicate
      that the overall population of PTNs exhibits a heterogeneous expression of
      dopamine receptors. The firing rate of PTNs was significantly enhanced by
      iontophoresis of glutamate (mean = 141% of baseline levels). These increases were
      attenuated significantly (mean= 98% of baseline) by co-application with dopamine
      in all PTNs, indicating dopaminergic interactions with glutamate transmission.
      The expression of dopamine receptors was studied with dual-labeling techniques.
      PTNs were identified by retrograde labeling with fast blue and the D1a, D2, or D5
      receptor proteins were stained immunohistochemically. Some, but not all PTNs,
      showed labeling for D1a, D2, or D5 receptors. The D1a and D2 receptor
      immunoreactivity was observed primarily in the somata of PTNs, whereas D5
      immunoreactivity extended well into the apical dendrites of PTNs. In accordance
      with findings of D1 and D2 receptor antagonism of dopamine's actions, the
      identification of three DA receptor subtypes on PTNs suggests that dopamine can
      directly modulate PTN activity through one or more receptor subtypes.

PMID- 12466460
TI  - Dynamics of abducens nucleus neuron discharges during disjunctive saccades.
AB  - In this report, we provide the first characterization of abducens nucleus neuron
      (ABN) discharge dynamics during horizontal disjunctive saccades. These movements
      function to rapidly transfer the visual axes between targets located at different
      eccentricities and depths. Our primary objective was to determine whether the
      signals carried by ABNs during these movements are appropriate to drive the
      motion of the eye to which they project. We also asked whether ABNs encode eye
      movements similarly during disjunctive saccades and disjunctive fixation. To
      address the first objective we 1) assessed whether we could predict the discharge
      dynamics of individual neurons during disjunctive saccades based on their
      discharge properties during conjugate saccades and 2) directly estimated the
      sensitivity of individual neurons to either the ipsilateral/contralateral eye or
      the conjugate/vergence position and velocity using bootstrap statistics. Our main
      finding was that during disjunctive saccades in the direction ipsilateral to the
      recording site (ON-direction), the majority of ABNs preferentially encoded the
      velocity and the position of the ipsilateral eye. The remaining neurons
      predominantly encoded the conjugate motion of the eyes (i.e., were equally
      sensitive to the motion of both eyes). Generally, ipsilateral/contralateral eye
      based models better described neuronal discharges than conjugate/vergence based
      models, yet both model structures yielded similar conclusions. Moreover, the
      preferred eye of individual neurons based on their position and velocity
      sensitivities were generally well matched. We also found that for saccades in the
      OFF-direction, the pausing behavior of ABNs was similar during conjugate and
      disjunctive saccades, with the exception that for movements of small amplitudes,
      more ABNs paused during conjugate saccades. Finally, we found that putative
      motoneurons and internuclear neurons encoded ON- and OFF-direction disjunctive
      saccades in a similar manner. To address our second objective, we compared the
      discharge properties of individual ABNs during disjunctive saccades and
      disjunctive fixation. Good coherence was observed between the preferred eye of
      individual ABNs during the two behaviors. Taken together, our results indicate
      that although individual ABNs can encode the motion of both eyes to various
      degrees, the population drive of ABNs accounts for most of the movement of the
      ipsilateral eye during disjunctive saccades and disjunctive fixation.

PMID- 12466461
TI  - Motion adaptation in area MT.
AB  - In many sensory systems, exposure to a prolonged stimulus causes adaptation,
      which tends to reduce neural responses to subsequent stimuli. Such effects are
      usually stimulus-specific, making adaptation a powerful probe into information
      processing. We used dynamic random dot kinematograms to test the magnitude and
      selectivity of adaptation effects in the middle temporal area (MT) and to compare
      them to effects on human motion discrimination. After 3 s of adaptation to a
      random dot pattern moving in the preferred direction, MT neuronal responses to
      subsequent test patterns were reduced by 26% on average compared with adaptation
      to a static pattern. This reduction in response magnitude was largely independent
      of what test stimulus was presented. However, adaptation in the opposite
      direction changed responses less often and very inconsistently. Therefore motion
      adaptation systematically and profoundly affects the neurons in MT representing
      the adapted direction, but much less those representing the opposite direction.
      In human psychophysical experiments, such adapting stimuli affected direction
      discrimination, biasing choices away from the adaptation direction. The magnitude
      of this perceptual shift was consistent with the magnitude of the changes seen in
      area MT, if one assumes that a motion comparison step occurs after MT.

PMID- 12466462
TI  - Brain responses associated with the Valsalva maneuver revealed by functional
      magnetic resonance imaging.
AB  - The Valsalva maneuver, a test frequently used to evaluate autonomic function,
      recruits discrete neural sites. The time courses of neural recruitment relative
      to accompanying cardiovascular and breathing patterns are unknown. We examined
      functional magnetic resonance imaging signal changes within the brain to repeated
      Valsalva maneuvers and correlated these changes with physiological trends. In 12
      healthy subjects (age, 30-58 yr), a series of 25 volumes (20 gradient echo echo
      planar image slices per volume) was collected using a 1.5-Tesla scanner during a
      60-s baseline and 90-s challenge period consisting of three Valsalva maneuvers.
      Regions of interest were examined for signal intensity changes over baseline and
      challenge conditions in cardiorespiratory-related regions. In addition, whole
      brain correlations between signal intensity and heart rate and airway load
      pressure were performed on a voxel-by-voxel basis. Significant signal changes,
      correlated with the time course of load pressure and heart rate, emerged within
      multiple areas, including the amygdala and hippocampus, insular and lateral
      frontal cortices, dorsal pons, dorsal medulla, lentiform nucleus, and fastigial
      and dentate nuclei of the cerebellum. Signal intensities peaked early in the
      Valsalva maneuver within the hippocampus and amygdala, later within the dorsal
      medulla, pons and midbrain, and deep cerebellar nuclei, and last within the
      lentiform nuclei and the lateral prefrontal cortex. The ventral pontine signals
      increased during the challenge, but not in a fashion correlated to load pressure
      or heart rate. Sites showing little or no correlation included the vermis and
      medial prefrontal cortex. These data suggest an initiating component arising in
      rostral brain areas, a later contribution from cerebellar nuclei, basal ganglia,
      and lateral prefrontal cortex, and a role for the ventral pons in mediating
      longer term processes.

PMID- 12466463
TI  - Correlated discharges among putative pyramidal neurons and interneurons in the
      primate prefrontal cortex.
AB  - Neurophysiological recordings have revealed that the discharges of nearby
      cortical cells are positively correlated in time scales that range from
      millisecond synchronization of action potentials to much slower firing rate co
      variations, evident in rates averaged over hundreds of milliseconds. The presence
      of correlated firing can offer insights into the patterns of connectivity between
      neurons; however, few models of population coding have taken account of the
      neuronal diversity present in cerebral cortex, notably a distinction between
      inhibitory and excitatory cells. We addressed this question in the monkey
      dorsolateral prefrontal cortex by recording neuronal activity from multiple micro
      electrodes, typically spaced 0.2-0.3 mm apart. Putative excitatory and inhibitory
      neurons were distinguished based on their action potential waveform and baseline
      discharge rate. We tested each pair of simultaneously recorded neurons for
      presence of significant cross-correlation peaks and measured the correlation of
      their averaged firing rates in successive trials. When observed, cross
      correlation peaks were centered at time 0, indicating synchronous firing
      consistent with two neurons receiving common input. Discharges in pairs of
      putative inhibitory interneurons were found to be significantly more strongly
      correlated than in pairs of putative excitatory cells. The degree of correlated
      firing was also higher for neurons with similar spatial receptive fields and
      neurons active in the same epochs of the behavioral task. These factors were
      important in predicting the strength of both short time scale (<5 ms)
      correlations and of trial-to-trial discharge rate covariations. Correlated firing
      was only marginally accounted for by motor and behavioral variations between
      trials. Our findings suggest that nearby inhibitory neurons are more tightly
      synchronized than excitatory ones and account for much of the correlated
      discharges commonly observed in undifferentiated cortical networks. In contrast,
      the discharge of pyramidal neurons, the sole projection cells of the cerebral
      cortex, appears largely independent, suggesting that correlated firing may be a
      property confined within local circuits and only to a lesser degree propagated to
      distant cortical areas and modules.

PMID- 12466464
TI  - Single-unit activity related to bimanual arm movements in the primary and
      supplementary motor cortices.
AB  - Single units were recorded from the primary motor (MI) and supplementary motor
      (SMA) areas of Rhesus monkeys performing one-arm (unimanual) and two-arm
      (bimanual) proximal reaching tasks. During execution of the bimanual movements,
      the task related activity of about one-half the neurons in each area (MI:
      129/232, SMA: 107/206) differed from the activity during similar displacements of
      one arm while the other was stationary. The bulk of this "bimanual-related"
      activity could not be explained by any linear combination of activities during
      unimanual reaching or by differences in kinematics or recorded EMG activity. The
      bimanual-related activity was relatively insensitive to trial-to-trial variations
      in muscular activity or arm kinematics. For example, trials where bimanual arm
      movements differed the most from their unimanual controls did not correspond to
      the ones where the largest bimanual neural effects were observed. Cortical
      localization established by using a mixture of surface landmarks,
      electromyographic recordings, microstimulation, and sensory testing suggests that
      the recorded neurons were not limited to areas specifically involved with
      postural muscles. By rejecting this range of alternative explanations, we
      conclude that neural activity in MI as well as SMA can reflect specialized
      cortical processing associated with bimanual movements.

PMID- 12466465
TI  - Vestibular convergence patterns in vestibular nuclei neurons of alert primates.
AB  - Sensory signal convergence is a fundamental and important aspect of brain
      function. Such convergence may often involve complex multidimensional
      interactions as those proposed for the processing of otolith and semicircular
      canal (SCC) information for the detection of translational head movements and the
      effective discrimination from physically congruent gravity signals. In the
      present study, we have examined the responses of primate rostral vestibular
      nuclei (VN) neurons that do not exhibit any eye movement-related activity using
      0.5-Hz translational and three-dimensional (3D) rotational motion. Three distinct
      neural populations were identified. Approximately one-fourth of the cells
      exclusively encoded rotational movements (canal-only neurons) and were
      unresponsive to translation. The canal-only central neurons encoded head rotation
      in SCC coordinates, exhibited little orthogonal canal convergence, and were
      characterized with significantly higher sensitivities to rotation as compared to
      primary SCC afferents. Another fourth of the neurons modulated their firing rates
      during translation (otolith-only cells). During rotations, these neurons only
      responded when the axis of rotation was earth-horizontal and the head was
      changing orientation relative to gravity. The remaining one-half of VN neurons
      were sensitive to both rotations and translations (otolith + canal neurons).
      Unlike primary otolith afferents, however, central neurons often exhibited
      significant spatiotemporal (noncosine) tuning properties and a wide variety of
      response dynamics to translation. To characterize the pattern of SCC inputs to
      otolith + canal neurons, their rotational maximum sensitivity vectors were
      computed using exclusively responses during earth-vertical axis rotations (EVA).
      Maximum sensitivity vectors were distributed throughout the 3D space, suggesting
      strong convergence from multiple SCCs. These neurons were also tested with earth
      horizontal axis rotations (EHA), which would activate both vertical canals and
      otolith organs. However, the recorded responses could not be predicted from a
      linear combination of EVA rotational and translational responses. In contrast,
      one-third of the neurons responded similarly during EVA and EHA rotations,
      although a significant response modulation was present during translation. Thus
      this subpopulation of otolith + canal cells, which included neurons with either
      high- or low-pass dynamics to translation, appear to selectively ignore the
      component of otolith-selective activation that is due to changes in the
      orientation of the head relative to gravity. Thus contrary to primary otolith
      afferents and otolith-only central neurons that respond equivalently to tilts
      relative to gravity and translational movements, approximately one-third of the
      otolith + canal cells seem to encode a true estimate of the translational
      component of the imposed passive head and body movement.

PMID- 12466466
TI  - Differential adaptation of the linear and nonlinear components of the horizontal
      vestibuloocular reflex in squirrel monkeys.
AB  - Previous work in squirrel monkeys has demonstrated the presence of linear and
      nonlinear components to the horizontal vestibuloocular reflex (VOR) evoked by
      high-acceleration rotations. The nonlinear component is seen as a rise in gain
      with increasing velocity of rotation at frequencies more than 2 Hz (a velocity
      dependent gain enhancement). We have shown that there are greater changes in the
      nonlinear than linear component of the response after spectacle-induced
      adaptation. The present study was conducted to determine if the two components of
      the response share a common adaptive process. The gain of the VOR, in the dark,
      to sinusoidal stimuli at 4 Hz (peak velocities: 20-150 degrees /s) and 10 Hz
      (peak velocities: 20 and 100 degrees /s) was measured pre- and postadaptation.
      Adaptation was induced over 4 h with x0.45 minimizing spectacles. Sum-of-sines
      stimuli were used to induce adaptation, and the parameters of the stimuli were
      adjusted to invoke only the linear or both linear and nonlinear components of the
      response. Preadaptation, there was a velocity-dependent gain enhancement at 4 and
      10 Hz. In postadaptation with the paradigms that only recruited the linear
      component, there was a decrease in gain and a persistent velocity-dependent gain
      enhancement (indicating adaptation of only the linear component). After
      adaptation with the paradigm designed to recruit both the linear and nonlinear
      components, there was a decrease in gain and no velocity-dependent gain
      enhancement (indicating adaptation of both components). There were comparable
      changes in the response to steps of acceleration. We interpret these results to
      indicate that separate processes drive the adaptation of the linear and nonlinear
      components of the response.

PMID- 12466467
TI  - Cellular activity in the supplementary eye field during sequential performance of
      multiple saccades.
AB  - To investigate how single neurons in the supplementary eye field (SEF)
      participate in sequential performance of multiple saccades, we analyzed
      presaccadic activity while monkeys were performing three saccades in six
      different orders from memory. The saccades in each sequence were separated by a
      fixation period and initiated from the same fixation point with intervening
      return saccades. We found that the majority of the presaccadic activity of the
      SEF neurons differed significantly depending on the numerical position of
      saccades in each sequence (rank order). This rank-order selectivity was found in
      parallel with the selectivity for the sequence of three saccades. Our data
      suggest a role for SEF neurons in the coding of temporally ordered saccadic eye
      movements.

PMID- 12466468
TI  - The formation and function of extracellular enveloped vaccinia virus.
AB  - Vaccinia virus produces four different types of virion from each infected cell
      called intracellular mature virus (IMV), intracellular enveloped virus (IEV),
      cell-associated enveloped virus (CEV) and extracellular enveloped virus (EEV).
      These virions have different abundance, structure, location and roles in the
      virus life-cycle. Here, the formation and function of these virions are
      considered with emphasis on the EEV form and its precursors, IEV and CEV. IMV is
      the most abundant form of virus and is retained in cells until lysis; it is a
      robust, stable virion and is well suited to transmit infection between hosts. IEV
      is formed by wrapping of IMV with intracellular membranes, and is an intermediate
      between IMV and CEV/EEV that enables efficient virus dissemination to the cell
      surface on microtubules. CEV induces the formation of actin tails that drive CEV
      particles away from the cell and is important for cell-to-cell spread. Lastly,
      EEV mediates the long-range dissemination of virus in cell culture and, probably,
      in vivo. Seven virus-encoded proteins have been identified that are components of
      IEV, and five of them are present in CEV or EEV. The roles of these proteins in
      virus morphogenesis and dissemination, and as targets for neutralizing antibody
      are reviewed. The production of several different virus particles in the VV
      replication cycle represents a coordinated strategy to exploit cell biology to
      promote virus spread and to aid virus evasion of antibody and complement.

PMID- 12466469
TI  - Herpes simplex virus type 1 mutants containing the KOS strain ICP34.5 gene in
      place of the McKrae ICP34.5 gene have McKrae-like spontaneous reactivation but
      non-McKrae-like virulence.
AB  - Herpes simplex virus type 1 (HSV-1) strain McKrae is neurovirulent in rabbits
      infected by the ocular route, causing fatal encephalitis in approximately 50% of
      the animals, and has a high-level spontaneous reactivation phenotype, with 10% of
      rabbit eyes containing reactivated virus at any given time. In contrast, HSV-1
      strain KOS is completely avirulent (no rabbits die) and has a completely negative
      spontaneous reactivation phenotype. Mutations of the ICP34.5 gene can reduce the
      neurovirulence of HSV-1 strains McKrae and 17syn(+) by up to 100000-fold. ICP34.5
      mutants also have reduced spontaneous reactivation phenotypes. To determine
      whether differences in the ICP34.5 gene might be involved in the reduced
      neurovirulence and spontaneous reactivation phenotypes of KOS compared with
      McKrae, we constructed chimeric viruses containing the KOS ICP34.5 gene in place
      of the McKrae ICP34.5 gene. Rabbits ocularly infected with the chimeric viruses
      had a high spontaneous reactivation phenotype indistinguishable from McKrae. In
      contrast, neurovirulence of the chimeric viruses was decreased compared with
      McKrae. Thus, one or more 'defects' in the KOS ICP34.5 gene appeared to be at
      least partially responsible for the reduced neurovirulence of KOS compared with
      McKrae. However, there appeared to be no 'defect' in the KOS ICP34.5 function
      required for efficient spontaneous reactivation.

PMID- 12466470
TI  - Stability and circularization of herpes simplex virus type 1 genomes in
      quiescently infected PC12 cultures.
AB  - Herpes simplex virus type 1 (HSV-1) DNA has been shown to exist as a linear,
      double-stranded molecule in the virion and as a non-linear (endless), episomal,
      nucleosomal form in latently infected trigeminal ganglia. The kinetics of the
      formation and appearance of endless viral genomes and the stability of linear
      genomes in neuronal cells are not well understood. Nerve growth factor (NGF)
      differentiated PC12 cells can sustain long-term, quiescent infections with HSV-1.
      In this report, the structure and stability of HSV-1 viral DNA in NGF
      differentiated PC12 cells was studied as a function of time following infection
      using both wild-type and replication-defective virus. Unexpectedly,
      unencapsidated linear genomes were stable in the nucleus of NGF-differentiated
      PC12 cells for up to 2-3 weeks following infection, beyond the period at which
      there is no detectable viral gene expression. However, following infection with
      wild-type HSV, the majority of quiescent viral genomes were in an endless form
      after 3-4 weeks. These data suggest that the stability and fate of HSV-1 DNA in
      non-mitotic neuronal-like cells is different from that in productively infected
      cells and thus there is a significant cellular role in this process. The
      relevance to the virus life-cycle in neurones in vivo is discussed.

PMID- 12466471
TI  - Herpes simplex virus 1 ICP0 co-localizes with a SUMO-specific protease.
AB  - Early during infection, the herpes simplex regulatory protein ICP0 promotes the
      proteasome-dependent degradation of a number of cellular proteins and the loss of
      a number of SUMO-1-modified protein isoforms, including PML. Recently, ICP0 has
      been shown to induce the accumulation of conjugated ubiquitin and function as a
      ubiquitin E3 ligase. However, certain aspects of the biochemistry, cell biology
      and the links between SUMO-1 conjugation/deconjugation and protein degradation
      remain unclear. For example, it is not currently known whether SUMO-1
      deconjugation is a prerequisite for ubiquitination or degradation and, if so, by
      what mechanism this may occur. To help address these questions, a SUMO-specific
      protease (SENP1) was cloned and its expression and localization in relation to
      ICP0 examined. A cell line was established which constitutively expresses SUMO-1
      to facilitate studies of localization and biochemistry. SENP1 localized to the
      nucleus mainly in discrete subdomains, a subset of which co-localized with the
      PML bodies. Both ICP0 and SENP1 protease promoted the loss of SUMO-1 from the
      nucleus, observed both for the endogenous species and the cell line expressing
      the epitope-tagged SUMO-1. The tagged SUMO-1 was recruited into high molecular
      mass conjugates in the cell line, and expression of SENP1 promoted loss of these
      species, including the modified species of PML. Finally, in co-transfection
      experiments ICP0 promoted the recruitment of SENP1 to nuclear domains, a result
      which was also observed early during infection. The significance of these
      findings is discussed in relation to the function of ICP0.

PMID- 12466472
TI  - The latency-related gene of bovine herpesvirus-1 can inhibit the ability of bICP0
      to activate productive infection.
AB  - Transfection of bovine cells with bovine herpesvirus-1 genomic DNA yields low
      levels of infectious virus. Cotransfection with the bICP0 gene enhances
      productive infection and virus yield because bICP0 can activate viral gene
      expression. Since the latency-related (LR) gene overlaps and is antisense to
      bICP0, the effects of LR gene products on productive infection were tested. The
      intact LR gene inhibited productive infection in a dose-dependent fashion but LR
      protein expression was not required. Further studies indicated that LR gene
      sequences near the 3' terminus of the LR RNA are necessary for inhibiting
      productive infection. When cotransfected with the bICP0 gene, the LR gene
      inhibited bICP0 RNA and protein expression in transiently transfected cells.
      Taken together, these results suggest that abundant LR RNA expression in sensory
      neurons is one factor that has the potential to inhibit productive infection and
      consequently promote the establishment and maintenance of latency.

PMID- 12466473
TI  - Augmentation of cellular immune responses to bovine herpesvirus-1 glycoprotein D
      by vaccination with CpG-enhanced plasmid vectors.
AB  - The potential of CpG-enhanced plasmid DNA vectors encoding a truncated secreted
      form of bovine herpesvirus-1 (BHV-1) glycoprotein D (tgD) to induce enhanced
      immune responses in cattle was investigated. We created tgD expression plasmids
      containing 0, 40 or 88 copies of the hexamer 5' GTCGTT 3', a known pan-activating
      CpG motif in several species. The total tgD-specific IgG titre of calves
      immunized with these plasmids did not correlate with the CpG content of the
      plasmid backbone. However, the pBISIA88-tgD-vaccinated group showed a
      significantly lower IgG1:IgG2 ratio than calves immunized with pBISIA40-tgD or
      pMASIA-tgD, which has no CpG motifs inserted. Antigen-specific lymphocyte
      proliferation and IFN-gamma secretion by peripheral blood mononuclear cells
      correlated positively with the CpG content of the vectors. In contrast, calves
      that received a killed BHV-1 vaccine had an IgG1-predominant isotype and low
      lymphocyte proliferation and IFN-gamma levels. Following challenge, the pBISIA88
      tgD-immunized group developed the greatest anamnestic response, the highest BHV-1
      neutralization titres in serum and a significantly lower level of virus shedding
      than the saline control group. However, there were no significant differences in
      clinical symptoms of infection between the DNA-immunized groups and the saline
      control group. These data indicate that CpG-enhanced plasmids induce augmented
      immune responses and could be used to vaccinate against pathogens requiring a
      strong cellular response for protection.

PMID- 12466474
TI  - Human cytomegalovirus infection induces cellular thymidylate synthase gene
      expression in quiescent fibroblasts.
AB  - Productive infection of non-proliferating cells by cytomegalovirus (CMV) requires
      the coordinated stimulation of host biochemical pathways that prepare cells to
      synthesize DNA. Here we illustrate the ability of human CMV (HCMV) to stimulate
      cellular thymidylate synthase (TS) gene expression in quiescent human embryonic
      lung fibroblasts. TS mRNA and protein levels are nearly undetectable in quiescent
      cells, but are greatly increased following HCMV infection. Inhibition of TS
      activity was shown to impair HCMV DNA synthesis, demonstrating that TS
      upregulation is required for efficient HCMV replication in quiescent cells. The
      increase in TS gene expression was due to an increase in gene transcription,
      since the expression of a reporter gene driven by the human TS promoter was
      strongly induced by HCMV infection. Deletion analysis of the human TS promoter
      identified two positive elements that are important for this increased
      transcription. We have previously shown that murine CMV (MCMV) stimulates the
      mouse TS promoter by a mechanism that depends on the presence of an E2F element
      in the promoter region. However, deletion of the two potential E2F binding sites
      in the human TS promoter did not prevent the virus-induced increase in TS
      promoter activity. Our data suggest that HCMV activates human TS gene
      transcription by mechanisms that are independent of E2F and different from those
      used by MCMV to stimulate the mouse TS promoter.

PMID- 12466475
TI  - Epstein-Barr virus replication in tongue epithelial cells.
AB  - Epstein-Barr virus (EBV) persistently infects B-cells in humans and can be shed
      into the saliva. The cellular source of infectious virus is uncertain. Hairy
      leukoplakia, an AIDS-associated lesion of the tongue, supports EBV replication in
      epithelial cells. However, the general significance of this observation has
      remained doubtful. Using immunohistochemistry and in situ hybridization, we
      demonstrate evidence of EBV replication in tongue epithelial cells in 4 of 168
      samples from 84 autopsy cases. Thus, in patients who do not have AIDS, squamous
      epithelial cells of the tongue rarely support EBV replication. However, all
      individuals with evidence of EBV replication were either on immunosuppressive
      therapy or were terminally ill cancer patients, suggesting that an impairment of
      the immune system may have allowed EBV replication to occur at this site. Thus,
      our findings are consistent with the idea that EBV replication in oropharyngeal
      epithelial cells is an infrequent event.

PMID- 12466476
TI  - Ovine herpesvirus 2 lytic cycle replication and capsid production.
AB  - Ovine herpesvirus 2 (OvHV-2) causes malignant catarrhal fever in cattle, pigs and
      deer. We have observed intact circular and linear OvHV-2 genomes in infected T
      cell lines derived from cows and rabbits. Bovine T cell lines were predominantly
      latently infected but rabbit T cell lines supported OvHV-2 productive cycle gene
      expression and virus capsids were demonstrated for the first time.

PMID- 12466477
TI  - Infection of wild-type Autographa californica multicapsid nucleopolyhedrovirus
      induces in vivo apoptosis of Spodoptera litura larvae.
AB  - Direct evidence of in vivo apoptosis of Spodoptera litura larvae was demonstrated
      by haemocoel inoculation with wild-type Autographa californica multicapsid
      nucleopolyhedrovirus (AcMNPV) budded virus (BV). In sharp contrast to natural
      infection, cadavers did not melt, liquefy and melanize. Typical morphological
      changes of apoptosis in insect haemocytes post-infection, including blebbing of
      the cell surface, chromatin margination and condensation, vacuolization of the
      cytoplasm and formation of apoptotic bodies, were observed by light and electron
      microscopy. Total DNAs extracted from virus-infected haemocytes showed DNA
      ladders. Cleavage of chromatin DNA by endogenous endonucleases were detected in
      the cells of most tissues cells, including epithelial cells and fat body cells,
      using terminal dUTP nick end labelling assays. Virogenic stroma and viral
      nucleocapsids could be seen in the nuclei of a few haemocytes. Yields of BV and
      OV (occluded virus) produced from the infected S. litura larvae were much lower
      than from the infected S. exigua larvae. These data suggest that host apoptotic
      responses to virus infection reduce AcMNPV spread at the level of the organism
      and that apoptosis could be a host-range limiting factor for baculovirus
      infections.

PMID- 12466478
TI  - Characterization of pif, a gene required for the per os infectivity of Spodoptera
      littoralis nucleopolyhedrovirus.
AB  - During plaque purification of Spodoptera littoralis nucleopolyhedrovirus in S.
      littoralis Sl52 cell culture, a deletion mutant virus was isolated. Analysis of
      the biological properties of this mutant virus revealed an absence of per os
      infectivity of the occluded virus. Infectivity by injection of the non-occluded
      (budded) virus is not different between the wild-type and the deleted virus.
      Restriction analysis of the mutant virus genome revealed a 4.5 kb deletion within
      the NotI D fragment. The observed phenotype was mapped to the deleted region by
      rescue experiments. The deletion was characterized and the equivalent DNA
      fragment on the wild-type virus was sequenced. By co-transfecting the DNA of the
      deleted virus with plasmids derived from the wild-type virus, it was possible to
      determine that ORF 7 in this fragment is responsible for the observed phenotype.
      ORF 7, called pif (per os infectivity factor), is homologous to ORF 119 of
      Autographa californica nucleopolyhedrovirus. Similar ORFs are present in all
      sequenced baculoviruses. The product of this gene is an occlusion body-derived
      virion structural protein required only for the first steps of larva infection,
      as viruses being produced in cells expressing the gene but not containing it in
      their genomes are able to produce successful infections.

PMID- 12466479
TI  - Characterization of HLA DR13-restricted CD4(+) T cell epitopes of hepatitis B
      core antigen associated with self-limited, acute hepatitis B.
AB  - The HLA DR13 allele has been associated with a self-limited course of hepatitis B
      virus infection, possibly through the induction of a more vigorous hepatitis B
      core antigen (HBcAg) and/or hepatitis B e antigen-specific CD4(+) T cell
      response. HBcAg-specific CD4(+) T cell responses were investigated in three HLA
      DR13-positive subjects with self-limited, acute hepatitis B. HBcAg-specific,
      short-term T cell lines derived from these three subjects showed a dominant
      recognition of HBcAg peptides spanning aa 1-20 (P1), 11-30 (P2), 41-60 (P5), 111
      131 (P12) and 141-160 (P15). In order to characterize these epitopes in more
      detail, CD4(+) T cell clones and cell lines were generated using HBcAg.
      Surprisingly, 11 of 12 T cell clones examined recognized P15; one recognized P10
      (aa 91-111). Of four T cell lines, two recognized P15 and two recognized P5. By
      peptide mapping, the minimal epitope of P15 was located to residues
      (147)TVVRRRGRSP(156).

PMID- 12466480
TI  - Structural relationship between nucleocapsid-binding activity of the rabies virus
      phosphoprotein (P) and exposure of epitope 402-13 located at the C terminus.
AB  - The structural changes of the nominal phosphoprotein (P) of rabies virus using a
      monoclonal antibody, mAb #402-13, was investigated. This mAb recognized a linear
      epitope that was mapped roughly to a C-terminal region of the P protein, ranging
      from aa 256 to 297. The P gene products were detected by the mAb in immunoblot
      assays, the products of which were produced either in BHK-21 cells or in
      Escherichia coli cells. The mAb, however, detected very low levels of P gene
      products in immunoprecipitation assays. The mAb recognized the nucleocapsid (NC)
      associated P proteins but recognized free P protein and free N-P complex produced
      in the infected cells much less efficiently. When the P proteins were released
      from the NC, however, they were no longer recognized by the mAb. Similar results
      were obtained from BHK-21 cells co-transfected with P and N cDNAs. Furthermore,
      studies with C-terminally truncated P protein mutants revealed that the NC
      binding ability of the P protein was dependent on the presence of the C-terminal
      epitope region. From these results, it is thought that the 402-13 epitope region
      is concealed when the P protein is present in a free form or free N-P complex but
      is exposed when it is associated with the NC. The C-terminal epitope region
      seemed to be essential for the P protein to be associated with the NC but not for
      the formation of free N-P complexes with newly synthesized N protein.

PMID- 12466481
TI  - Studies on the different conditions for rabies virus neutralization by monoclonal
      antibodies #1-46-12 and #7-1-9.
AB  - Virus-neutralizing activity of two monoclonal antibodies (mAbs), #7-1-9 and #1-46
      12, against rabies virus glycoprotein (G) was compared. Although these mAbs
      affected the virion's ability to bind to host cells similarly, a big difference
      was found in the titres of virus neutralization (1:7132 and 1:32 for mAbs #1-46
      12 and #7-1-9, respectively, at a concentration of 10 micro g protein/ml).
      Although no big difference in virion-binding affinity between the two mAbs was
      found, the number of antibodies required for virus neutralization was very low,
      </=20 molecules for mAb #1-46-12 and >/=250 molecules for mAb #7-1-9. In the
      latter case, the mAbs cover a major part of the virion surface and cause steric
      hindrance of viral receptor-binding activity. The infectivity of an epitope
      preserved escape mutant virus (R-61) was not affected by the binding of high
      numbers of mAb #1-46-12 to the virion, which implies that mAb binding does not
      mask the receptor-binding site of the viral spikes. Based on these results, it is
      hypothesized that mAb #1-46-12 affected virus infectivity by a mechanism
      different from covering the virion spikes. Possible virus-neutralizing mechanisms
      by low numbers of mAb #1-46-12 in comparison to that of mAb #7-1-9 are discussed.

PMID- 12466482
TI  - Role of G protein and protein kinase signalling in influenza virus budding in
      MDCK cells.
AB  - Recently, we have shown that influenza virus budding in MDCK cells is regulated
      by metabolic inhibitors of ATP and ATP analogues (Hui & Nayak, Virology 290, 329
      341, 2001 ). In this report, we demonstrate that G protein signalling stimulators
      such as sodium fluoride, aluminium fluoride, compound 48/80 and mastoparan
      stimulated the budding and release of influenza virus. In contrast, G protein
      signalling blockers such as suramin and NF023 inhibited virus budding.
      Furthermore, in filter-grown lysophosphatidylcholine-permeabilized virus-infected
      MDCK cells, membrane-impermeable GTP analogues, such as guanosine 5'-O-(3
      thiotriphosphate) or 5'-guanylylimidodiphosphate caused an increase in virus
      budding, which could be competitively inhibited by adding an excess of GTP. These
      results suggest that the G protein is involved in the regulation of influenza
      virus budding. We also determined the role of different protein kinases in
      influenza virus budding. We observed that specific inhibitors or activators of
      protein kinase A (H-89 and 8-bromoadenosine 3',5'-cyclic monophosphate) or of
      protein kinase C (bisindolylmaleimide I and Ro-32-0432) or of
      phosphatidylinositol 3-kinase (LY294002 and wortmannin) did not affect influenza
      virus budding. However, the casein kinase 2 (CK2) inhibitor 5,6-dichloro-1-beta-D
      ribofuranosylbenzimidazole decreased virus budding. We further observed an
      increase in the CK2 activity during the replication cycle of influenza virus,
      although Western blot analysis did not reveal any increase in the amount of CK2
      protein in virus-infected cells. Also, in digitonin-permeabilized MDCK cells, the
      introduction of CK2 substrate peptides caused a down-regulation of virus budding.
      These results suggest that CK2 activity also regulates influenza virus budding.

PMID- 12466483
TI  - Role of overlapping glycosylation sequons in antigenic properties, intracellular
      transport and biological activities of influenza A/H2N2 virus haemagglutinin.
AB  - The haemagglutinin (HA) protein of influenza A/H2N2 virus possesses five
      oligosaccharide attachment sites, two of which have overlapping glycosylation
      sequons at positions 20-23 (NNST) and 169-172 (NNTS). Here, the role of these two
      oligosaccharide attachment sites is investigated with regard to antigenic
      property, intracellular transport and biological activity of the HA protein.
      Glycosylation-site HA mutants with mutation(s) in their overlapping glycosylated
      sequons, each of which had one or two oligosaccharide attachment sites removed,
      were constructed. Comparison of electrophoretic mobility between the wt and
      mutant HA proteins showed that both Asn residues 20 and 21 and Asn residues 169
      and 170 could be used for glycosylation. Analysis of reactivity of the mutants
      with anti-HA monoclonal antibodies suggested that amino acid changes at these two
      positions result in a conformational change of the HA molecule. Even if
      oligosaccharide chains linked to Asn 20 or 21 and Asn 169 or 170 are eliminated,
      the antigenic properties, intracellular transport and biological activities are
      not influenced strongly. Thus it is reasonable to conclude that the two
      overlapping glycosylation sequons at positions 20-23 and 169-172 are conserved
      among all of the HAs of influenza A/H2N2 viruses because conservation of the
      amino acid sequence itself rather than that of N-glycosylation is essential for
      the formation of the proper conformation, intracellular transport and biological
      activities of the H2 subtype HA.

PMID- 12466484
TI  - Complete nucleotide sequence of chikungunya virus and evidence for an internal
      polyadenylation site.
AB  - In this study, the complete genomic sequence of chikungunya virus (CHIK; S27
      African prototype) was determined and the presence of an internal polyadenylation
      [I-poly(A)] site was confirmed within the 3' non-translated region (NTR) of this
      strain. The complete genome was 11805 nucleotides in length, excluding the 5' cap
      nucleotide, an I-poly(A) tract and the 3' poly(A) tail. It comprised two long
      open reading frames that encoded the non-structural (2474 amino acids) and
      structural polyproteins (1244 amino acids). The genetic location of the non
      structural and structural proteins was predicted by comparing the deduced amino
      acid sequences with the known cleavage sites of other alphaviruses, located at
      the C-terminal region of their virus-encoded proteins. In addition, predicted
      secondary structures were identified within the 5' NTR and repeated sequence
      elements (RSEs) within the 3' NTR. Amino acid sequence homologies, phylogenetic
      analysis of non-structural and structural proteins and characteristic RSEs
      revealed that although CHIK is closely related to o'nyong-nyong virus, it is in
      fact a distinct virus. The existence of I-poly(A) fragments with different
      lengths (e.g. 19, 36, 43, 91, 94 and 106 adenine nucleotides) at identical
      initiation positions for each clone strongly suggests that the polymerase of the
      alphaviruses has a capacity to create poly(A) by a template-dependant mechanism
      such as 'polymerase slippage', as has been reported for vesicular stomatitis
      virus.

PMID- 12466485
TI  - The first hydrophobic domain of the hepatitis C virus E1 protein is important for
      interaction with the capsid protein.
AB  - The interaction between the hepatitis C virus capsid protein and the envelope
      protein E1 has been demonstrated previously in vivo. To determine the binding
      region of the E1 protein with the capsid protein, this interaction was
      characterized in vitro. This study shows that the interaction between these
      proteins should occur in the endoplasmic reticulum membrane rather than in the
      cytosol and that the first hydrophobic domain of the E1 protein (aa 261-291) is
      important for the interaction with the capsid protein.

PMID- 12466486
TI  - Intracellular localization and determination of a nuclear localization signal of
      the core protein of dengue virus.
AB  - In dengue virus (DEN) particles, the core protein is a structural protein of the
      nucleocapsid. The core protein is known to be present in the nucleus of DEN
      infected cells but there have been conflicting reports as to whether it is also
      present in the nucleolus. To clarify this, the intracellular location of the core
      protein was examined using a monoclonal antibody, 15B11, which was produced in
      this study. Immunofluorescence staining with this antibody demonstrated that the
      core protein first appeared in the cytoplasm and then in the nuclei and nucleoli
      of infected cells. Nuclear localization of the core protein was determined to be
      independent of other DEN proteins, since recombinant core proteins still entered
      the nuclei and nucleoli of cells transfected with only the core protein gene.
      Three putative nuclear localization signal motifs have been predicted to be
      present on the core protein. Deletion of the first one (KKAR), located at aa 6-9,
      and mutation of the second one (KKSK), located at aa 73-76, did not eliminate the
      nuclear localization property of the core protein. The third motif with a
      bipartite structure, RKeigrmlnilnRRRR, located at aa 85-100, was determined to be
      responsible for the nuclear localization of the core protein, since the core
      protein without this motif was located exclusively in the cytoplasm of DEN
      infected cells and that this motif mediated nuclear localization of a normally
      cytoplasmic protein.

PMID- 12466487
TI  - Genetic recombination in wild-type poliovirus.
AB  - Poliovirus isolates were screened for recombinants by combined analysis of two
      distant polymorphic segments of the poliovirus genome (one in the capsid and the
      other in the polymerase-coding region). Using a restriction fragment length
      polymorphism (RFLP) assay, a high number of recombinant genomes was found among
      vaccine-derived strains excreted by poliovirus vaccine vaccinees or vaccine
      associated paralytic poliomyelitis cases. Some of these subjects carried a wild
      type poliovirus (non-vaccine-specific) nucleotide sequence in the 3' part of the
      genome. Using a similar approach, a collection of wild-type poliovirus strains
      isolated in South India between 1985 and 1993 was screened for recombinants.
      Genotypes were defined by the parallel application of RFLP assays and genomic
      sequencing of the capsid protein VP1 and the 3D polymerase polypeptide. Analyses
      revealed several instances where the position of an isolate on the phylogenic
      tree for the capsid protein-coding segment did not agree with its position on the
      tree for the polymerase-coding region. In this way, several wild-type/wild-type
      and wild-type/vaccine recombinants could be identified, indicating that
      recombination is encountered commonly in the natural evolution of poliovirus
      strains.

PMID- 12466488
TI  - Conservation of L and 3C proteinase activities across distantly related
      aphthoviruses.
AB  - The foot-and-mouth disease virus (FMDV) leader (L) proteinase is an important
      virulence determinant in FMDV infections. It possesses two distinct catalytic
      activities: (i) C-terminal processing at the L/VP4 junction; and (ii) induction
      of the cleavage of translation initiation factor eIF4G, an event that inhibits
      cap-dependent translation in infected cells. The only other member of the
      Aphthovirus genus, equine rhinitis A virus (ERAV), also encodes an L protein, but
      this shares only 32% amino acid identity with its FMDV counterpart. Another more
      distantly related picornavirus, equine rhinitis B virus (ERBV), which is not
      classified as an aphthovirus, also encodes an L protein. Using in vitro
      transcription and translation analysis, we have shown that both ERAV and ERBV L
      proteins have C-terminal processing activity. Furthermore, expression of ERAV L,
      but not ERBV L, in BHK-21 cells resulted in the efficient inhibition of cap
      dependent translation in these cells. We have shown that the ERAV and FMDV L
      proteinases induce cleavage of eIF4GI at very similar or identical positions.
      Interestingly, ERAV 3C also induces eIF4GI cleavage and again produces distinct
      products that co-migrate with those induced by FMDV 3C. The ERBV L proteinase
      does not induce eIF4GI cleavage, consistent with its inability to shut down cap
      dependent translation. We have also shown that another unique feature of FMDV L,
      the stimulation of enterovirus internal ribosome entry site (IRES) activity, is
      also shared by the ERAV L proteinase but not by ERBV L. The functional
      conservation of the divergent ERAV and FMDV proteinases indicates the likelihood
      of a similar and important role for these enzymes in the pathogenesis of
      infections caused by these distantly related aphthoviruses.

PMID- 12466489
TI  - Genetic variation and immunohistochemical differences among geographic isolates
      of Taura syndrome virus of penaeid shrimp.
AB  - Taura syndrome virus (TSV) is an important virus infecting penaeid shrimp in the
      western hemisphere. Genetic variation and immunohistochemical differences of 20
      TSV isolates collected from the USA, Taiwan, Mexico and Nicaragua were compared.
      Capsid protein genes CP1 (546 bp) and CP2 (584 bp) were amplified by RT-PCR and
      the cDNAs were sequenced. Pairwise comparison of nucleotide sequences showed a 0
      2.4% difference in CP1 and a 0-3.5% difference in CP2. Phylogenetic analyses
      clustered the TSV isolates into two groups: one contained USA, Taiwan and some
      Mexican isolates, the other contained Mexican isolates only. Immunohistochemical
      analysis using a TSV-specific monoclonal antibody produced positive results for
      the USA and Taiwan isolates but negative results for the Mexican and Nicaraguan
      isolates. Molecular and immunohistochemical data suggest the existence of at
      least two TSV strains, one of which might have evolved following contact with a
      new penaeid host, Penaeus stylirostris.

PMID- 12466490
TI  - Sequence analysis and genomic organization of Aphid lethal paralysis virus: a new
      member of the family Dicistroviridae.
AB  - The complete nucleotide sequence of the genomic RNA of an aphid-infecting virus,
      Aphid lethal paralysis virus (ALPV), has been determined. The genome is 9812 nt
      in length and contains two long open reading frames (ORFs), which are separated
      by an intergenic region of 163 nt. The first ORF (5' ORF) is preceded by an
      untranslated leader sequence of 506 nt, while an untranslated region of 571 nt
      follows the second ORF (3' ORF). The deduced amino acid sequences of the 5' ORF
      and 3' ORF products respectively showed similarity to the non-structural and
      structural proteins of members of the newly recognized genus Cripavirus (family
      Dicistroviridae). On the basis of the observed sequence similarities and
      identical genome organization, it is proposed that ALPV belongs to this genus.
      Phylogenetic analysis showed that ALPV is most closely related to Rhopalosiphum
      padi virus, and groups in a cluster with Drosophila C virus and Cricket paralysis
      virus, while the other members of this genus are more distantly related.
      Infectivity experiments showed that ALPV can not only infect aphid species but is
      also able to infect the whitefly Trialeurodes vaporariorum, extending its host
      range to another family of the order Hemiptera.

PMID- 12466491
TI  - Development of infectious transcripts and genome manipulation of Black queen-cell
      virus of honey bees.
AB  - The South African isolate of Black queen-cell virus (BQCV), a honey bee virus,
      was previously found to have an 8550 nucleotide genome excluding the poly(A)
      tail. Its genome contained two ORFs, a 5'-proximal ORF encoding a putative
      replicase protein and a 3'-proximal ORF encoding a capsid polyprotein. Long
      reverse transcription (RT)-PCR was used to produce infectious transcripts for
      BQCV and to manipulate its genome. Primers were designed for the amplification of
      the complete genome, the in vitro transcription of infectious RNA and PCR
      directed mutagenesis. An 18-mer antisense primer was designed for RT to produce
      full-length single-stranded cDNA (ss cDNA). Unpurified ss cDNA from the RT
      reaction mixture was used directly as a template to amplify the full genome by
      long high-fidelity PCR. The SP6 promoter sequence was introduced into the sense
      primer to transcribe RNA directly from the amplicon. RNA was transcribed in vitro
      with and without the presence of a cap analogue and injected directly into bee
      pupae, which were then incubated for 8 days. In vitro transcripts were infectious
      but the presence of a cap analogue did not increase the amount of virus
      recovered. A single base mutation abolishing an EcoRI restriction site was
      introduced by fusion-PCR, to distinguish viral particles recovered from
      infectious transcripts from wild-type virus (wtBQCV). Mutant virus (mutBQCV) and
      wtBQCV were indistinguishable by electron microscopy and Western blot analysis.
      The EcoRI restriction site was present in wtBQCV and not in mutBQCV.

PMID- 12466492
TI  - Capacity of simian immunodeficiency virus strain mac Nef for high-affinity Src
      homology 3 (SH3) binding revealed by ligand-tailored SH3 domains.
AB  - The simian immunodeficiency virus (SIV) Nef protein contains a consensus Src
      homology 3 (SH3) binding motif. However, no SH3-domain proteins showing strong
      binding to SIV Nef have yet been found, and its potential capacity for high
      affinity SH3 binding has therefore remained unproven. Here we have used phage
      display-assisted protein engineering to develop artificial SH3 domains that bind
      tightly to SIV strain mac (SIVmac) Nef. Substitution of six amino acids in the RT
      loop region of Hck-SH3 with the sequence E/DGWWG resulted in SH3 domains that
      bound in vitro to SIVmac Nef much better than the natural Hck- or Fyn-SH3
      domains. These novel SH3 domains also efficiently associated with SIVmac Nef when
      co-expressed in 293T cells and displayed a strikingly differential specificity
      when compared with SH3 domains similarly targeted for binding to human
      immunodeficiency virus type 1 (HIV-1) Nef. Thus, SIVmac Nef is competent for high
      affinity SH3 binding, but its natural SH3 protein partners are likely to be
      different from those of HIV-1 Nef.

PMID- 12466493
TI  - Implication of caspases during maedi-visna virus-induced apoptosis.
AB  - Maedi-visna virus (MVV) causes encephalitis, pneumonia and arthritis in sheep. In
      vitro, MVV infection and replication lead to strong cytopathic effects
      characterized by syncytia formation and subsequent cellular lysis. It was
      demonstrated previously that MVV infection in vitro induces cell death of sheep
      choroid plexus cells (SCPC) by a mechanism that can be associated with apoptotic
      cell death. Here, the relative implication of several caspases during acute
      infection with MVV is investigated by employing diverse in vitro and in situ
      strategies. It was demonstrated using specific pairs of caspase substrates and
      inhibitors that, during in vitro infection of SCPC by MVV, the two major pathways
      of caspase activation (i.e. intrinsic and extrinsic pathways) were stimulated:
      significant caspase-9 and -8 activities, as well as caspase-3 activity, were
      detected. To study the role of caspases during MVV infection in vitro, specific,
      cell-permeable, caspase inhibitors were used. First, these results showed that
      both z-DEVD-FMK (a potent inhibitor of caspase-3-like activities) and z-VAD-FMK
      (a broad spectrum caspase inhibitor) inhibit caspase-9, -8 and -3 activities.
      Second, both irreversible caspase inhibitors, z-DEVD-FMK and z-VAD-FMK, delayed
      MVV-induced cellular lysis as well as virus growth. Third, during SCPC in vitro
      infection by MVV, cells were positively stained with FITC-VAD-FMK, a probe that
      specifically stains cells containing active caspases. In conclusion, these data
      suggest that MVV infection in vitro induces SCPC cell death by a mechanism that
      is strongly dependent on active caspases.

PMID- 12466494
TI  - Cauliflower mosaic virus is preferentially acquired from the phloem by its aphid
      vectors.
AB  - Cauliflower mosaic virus (CaMV) is transmitted in a non-circulative manner by
      aphids following the helper strategy. Helper proteins P2 and P3 act as a bridge
      between virions and the aphid cuticle. Electronic monitoring of aphid stylet
      activities (EPG technique), transmission tests and electron microscopy showed
      that CaMV is preferentially acquired from the phloem by its most common aphid
      vectors, Brevycorine brassicae and Myzus persicae. We also found that CaMV is
      semipersistently transmitted and that the rate of acquisition does not follow a
      typical bimodal curve. Instead, the virus could be acquired from non-phloem
      tissues at a low and fairly constant rate after one or more intracellular
      punctures within a few minutes, but the probability of acquisition rose
      significantly when aphids reached the phase of committed ingestion from the
      phloem. The acquisition rate of CaMV did not increase with increasing number of
      intracellular punctures, but the total duration of intracellular puncture was one
      of the variables selected by the stepwise logistic regression model used to fit
      the data that best explained acquisition of CaMV. Furthermore, aphids reaching
      the phloem faster had a higher probability of acquiring the virus. Our results
      support the hypothesis that multiple intracellular punctures of epidermal and
      mesophyll cells result in loading aphids with the CaMV-encoded aphid transmission
      factor (P2), and that aphids, in most cases, subsequently acquire CaMV particles
      during phloem sap ingestion. Consistently, immunoelectron microscopy showed that
      P3-virions are frequently found in the sieve element lumen, whereas P2 could not
      be detected.

PMID- 12466495
TI  - Systemic movement of a movement-deficient strain of Cucumber mosaic virus in
      zucchini squash is facilitated by a cucurbit-infecting potyvirus.
AB  - Zucchini squash (Cucurbita pepo) is a systemic host for most strains of the
      cucumovirus Cucumber mosaic virus (CMV), although the long-distance movement of
      the M strain of CMV (M-CMV) is inhibited in some cultivars. However, co-infection
      of zucchini plants with M-CMV and the potyvirus Zucchini yellow mosaic virus
      strain A (ZYMV-A) allowed M-CMV to move systemically, as demonstrated by tissue
      print analysis. These doubly infected plants exhibited severe synergism in
      pathology. Infection of zucchini squash by M-CMV and an attenuated strain of ZYMV
      (ZYMV-AG) showed a milder synergy in pathology, in which ZYMV-AG also facilitated
      the long-distance movement of M-CMV similar to that promoted by ZYMV-A. Variation
      in the extent of synergy in pathology by the two strains of ZYMV did not
      correlate with differences in levels of accumulation of either virus. Thus, the
      extent of synergy in pathology is at least in part independent of the resistance
      neutralizing function of the potyvirus.

PMID- 12466496
TI  - Characterization of a protein from Rice tungro spherical virus with serine
      proteinase-like activity.
AB  - The RNA genome of Rice tungro spherical virus (RTSV) is predicted to be expressed
      as a large polyprotein precursor (Shen et al., Virology 193, 621-630, 1993 ). The
      polyprotein is processed by at least one virus-encoded protease located adjacent
      to the C-terminal putative RNA polymerase which shows sequence similarity to
      viral serine-like proteases. The catalytic activity of this protease was explored
      using in vitro transcription/translation systems. Besides acting in cis, the
      protease had activity in trans on precursors containing regions of the 3' half of
      the polyprotein but did not process a substrate consisting of a precursor of the
      coat proteins. The substitution mutation of Asp(2735) of the RTSV polyprotein had
      no effect on proteolysis; however, His(2680), Glu(2717), Cys(2811) and His(2830)
      proved to be essential for catalytic activity and could constitute the catalytic
      centre and/or substrate-binding pocket of the RTSV 3C-like protease.

PMID- 12466497
TI  - Stability in vitro of the 69K movement protein of Turnip yellow mosaic virus is
      regulated by the ubiquitin-mediated proteasome pathway.
AB  - Plant viruses move to adjacent cells with the use of virus-encoded cell-to-cell
      movement proteins. Using proteins produced by in vitro translation, we present
      evidence that the '69K' movement protein of Turnip yellow mosaic virus (TYMV) is
      recognized as a substrate for the attachment of polyubiquitin chains and for
      subsequent rapid and selective proteolysis by the proteasome, the ATP-dependent
      proteolytic system present in reticulocyte lysate. Truncation of the 69K protein
      suggests the existence of two degradation signals within its sequence. We propose
      that selective degradation of virus movement proteins may contribute to the
      previously reported transient nature of their accumulation during infection.

PMID- 12466498
TI  - Thermostability of mouse-passaged BSE and scrapie is independent of host PrP
      genotype: implications for the nature of the causal agents.
AB  - Five experimentally maintained strains of scrapie and BSE agents have been
      passaged in two PrP genotypes of mice. Brain macerates were autoclaved at 126
      degrees C and the levels of surviving infectivity were measured by titration.
      There was a large difference in the survival properties of transmissible
      spongiform encephalopathy (TSE) infectivity between TSE strains. PrP genotype had
      little effect. Phenotypic properties of the TSE strains were not affected with
      the exception that with one strain (ME7), incubation periods of the heated sample
      were longer than the controls given equivalent doses. It is concluded that PrP is
      probably not responsible for differences in thermostability between strains. More
      likely, a host-independent molecule which differs in covalent structure between
      strains accounts for these properties.

PMID- 12466499
TI  - Sets meeting isometric copies of the lattice Z2 in exactly one point.
AB  - The construction of a subset S of (2) such that each isometric copy of (2) (the
      lattice points in the plane) meets S in exactly one point is indicated. This
      provides a positive answer to a problem of H. Steinhaus [Sierpinski, W. (1958)
      Fund. Math. 46, 191-194].

PMID- 12466500
TI  - Mosaic organization and heterogeneity in frequency of allelic recombination of
      the Plasmodium vivax merozoite surface protein-1 locus.
AB  - The organization and allelic recombination of the merozoite surface protein-1
      gene of Plasmodium vivax (PvMsp-1), the most widely prevalent human malaria
      parasite, were evaluated in complete nucleotide sequences of 40 isolates from
      various geographic areas. Alignment of 31 distinct alleles revealed the mosaic
      organization of PvMsp-1, consisting of seven interallele conserved blocks flanked
      by six variable blocks. The variable blocks showed extensive variation in repeats
      and nonrepeat unique sequences. Numerous recombination sites were distributed
      throughout PvMsp-1, in both conserved blocks and variable block unique sequences,
      and the distribution was not uniform. Heterozygosity of PvMsp-1 alleles was
      higher in Asia (0.953 +/- 0.009) than in Brazil (0.813 +/- 0.047). No identical
      alleles were shared between Asia and Brazil, whereas all but one variable block
      nonrepeat sequence found in Brazil occurred in Asia. These observations suggest
      that P. vivax populations in Asia are ancestral to Brazilian populations, and
      that PvMsp-1 has heterogeneity in frequency of allelic recombination events.
      Recurrent origins of new PvMsp-1 alleles by repeated recombination events were
      supported by a rapid decline in linkage disequilibrium between pairs of
      synonymous sites with increasing nucleotide distance, with little linkage
      disequilibrium at a distance of over 3 kb in a P. vivax population from Thailand,
      evidence for an effectively high recombination rate of the parasite. Meanwhile,
      highly reduced nucleotide diversity was noted in a region encoding the 19-kDa C
      terminal epidermal growth factor-like domain of merozoite surface protein-1, a
      vaccine candidate.

PMID- 12466501
TI  - Scanning surface confocal microscopy for simultaneous topographical and
      fluorescence imaging: application to single virus-like particle entry into a
      cell.
AB  - We have developed a method for simultaneous recording of high-resolution
      topography and cell surface fluorescence in a single scan which we call scanning
      surface confocal microscopy. The resolution of the system allows imaging of
      individual fluorescent particles in the nanometer range on fixed or live cells.
      We used this technique to record the interaction of single virus-like particles
      with the cell surface and demonstrated that single particles sink into the
      membrane in invaginations reminiscent of caveolae or pinocytic vesicles. This
      method provides a technique for elucidating the interaction of individual viruses
      and other nanoparticles, such as gene therapy vectors, with target cells.
      Furthermore, this technique should find widespread application for studying the
      relationship of fluorescently tagged molecules with components of the cell plasma
      membrane.

PMID- 12466502
TI  - The average distances in random graphs with given expected degrees.
AB  - Random graph theory is used to examine the "small-world phenomenon"; any two
      strangers are connected through a short chain of mutual acquaintances. We will
      show that for certain families of random graphs with given expected degrees the
      average distance is almost surely of order log nlog d, where d is the weighted
      average of the sum of squares of the expected degrees. Of particular interest are
      power law random graphs in which the number of vertices of degree k is
      proportional to 1kbeta for some fixed exponent beta. For the case of beta > 3, we
      prove that the average distance of the power law graphs is almost surely of order
      log nlog d. However, many Internet, social, and citation networks are power law
      graphs with exponents in the range 2 < beta < 3 for which the power law random
      graphs have average distance almost surely of order log log n, but have diameter
      of order log n (provided having some mild constraints for the average distance
      and maximum degree). In particular, these graphs contain a dense subgraph, which
      we call the core, having n(clog log n) vertices. Almost all vertices are within
      distance log log n of the core although there are vertices at distance log n from
      the core.

PMID- 12466503
TI  - Stabilizing the integrin alpha M inserted domain in alternative conformations
      with a range of engineered disulfide bonds.
AB  - Conformational movement of the C-terminal alpha7 helix in the integrin inserted
      (I) domain, a major ligand-binding domain that adopts an alpha/beta Rossmann
      fold, has been proposed to allosterically regulate ligand-binding activity.
      Disulfide bonds were engineered here to reversibly lock the position of the
      alpha7 helix in one of two alternative conformations seen in crystal structures,
      termed open and closed. Our results show that pairs of residues with Cbeta atoms
      farther apart than optimal for disulfide bond stereochemistry can be successfully
      replaced by cysteine, suggesting that backbone movement accommodates disulfide
      formation. We also find more success with substituting partially exposed than
      buried residues. Disulfides stabilizing the open conformation resulted in
      constitutively active alphaMbeta2 heterodimers and isolated alphaM inserted
      domains, which were reverted to an inactive form by dithiothreitol reduction. By
      contrast, a disulfide stabilizing the closed conformation resulted in inactive
      alphaMbeta2 that was resistant to activation but became activatable after
      dithiothreitol treatment.

PMID- 12466504
TI  - Evidence for vestibular regulation of autonomic functions in a mouse genetic
      model.
AB  - Physiological responses to changes in the gravitational field and body position,
      as well as symptoms of patients with anxiety-related disorders, have indicated an
      interrelationship between vestibular function and stress responses. However, the
      relative significance of cochlear and vestibular information in autonomic
      regulation remains unresolved because of the difficulties in distinguishing the
      relative contributions of other proprioceptive and interoceptive inputs,
      including vagal and somatic information. To investigate the role of cochlear and
      vestibular function in central and physiological responses, we have examined the
      effects of increased gravity in wild-type mice and mice lacking the POU
      homeodomain transcription factor Brn-3.1 (Brn-3bPou4f3). The only known phenotype
      of the Brn-3.1(-/-) mouse is related to hearing and balance functions, owing to
      the failure of cochlear and vestibular hair cells to differentiate properly.
      Here, we show that normal physiological responses to increased gravity (2G
      exposure), such as a dramatic drop in body temperature and concomitant circadian
      adjustment, were completely absent in Brn-3.1(-/-) mice. In line with the lack of
      autonomic responses, the massive increase in neuronal activity after 2G exposure
      normally detected in wild-type mice was virtually abolished in Brn-3.1(-/-) mice.
      Our results suggest that cochlear and vestibular hair cells are the primary
      regulators of autonomic responses to altered gravity and provide genetic evidence
      that these cells are sufficient to alter neural activity in regions involved in
      autonomic and neuroendocrine control.

PMID- 12466505
TI  - Atrial fibrillation--rhythm or rate control.

PMID- 12466506
TI  - A comparison of rate control and rhythm control in patients with atrial
      fibrillation.
AB  - BACKGROUND: There are two approaches to the treatment of atrial fibrillation: one
      is cardioversion and treatment with antiarrhythmic drugs to maintain sinus
      rhythm, and the other is the use of rate-controlling drugs, allowing atrial
      fibrillation to persist. In both approaches, the use of anticoagulant drugs is
      recommended. METHODS: We conducted a randomized, multicenter comparison of these
      two treatment strategies in patients with atrial fibrillation and a high risk of
      stroke or death. The primary end point was overall mortality. RESULTS: A total of
      4060 patients (mean [+/-SD] age, 69.7+/-9.0 years) were enrolled in the study;
      70.8 percent had a history of hypertension, and 38.2 percent had coronary artery
      disease. Of the 3311 patients with echocardiograms, the left atrium was enlarged
      in 64.7 percent and left ventricular function was depressed in 26.0 percent.
      There were 356 deaths among the patients assigned to rhythm-control therapy and
      310 deaths among those assigned to rate-control therapy (mortality at five years,
      23.8 percent and 21.3 percent, respectively; hazard ratio, 1.15 [95 percent
      confidence interval, 0.99 to 1.34]; P=0.08). More patients in the rhythm-control
      group than in the rate-control group were hospitalized, and there were more
      adverse drug effects in the rhythm-control group as well. In both groups, the
      majority of strokes occurred after warfarin had been stopped or when the
      international normalized ratio was subtherapeutic. CONCLUSIONS: Management of
      atrial fibrillation with the rhythm-control strategy offers no survival advantage
      over the rate-control strategy, and there are potential advantages, such as a
      lower risk of adverse drug effects, with the rate-control strategy.
      Anticoagulation should be continued in this group of high-risk patients.

PMID- 12466507
TI  - A comparison of rate control and rhythm control in patients with recurrent
      persistent atrial fibrillation.
AB  - BACKGROUND: Maintenance of sinus rhythm is the main therapeutic goal in patients
      with atrial fibrillation. However, recurrences of atrial fibrillation and side
      effects of antiarrhythmic drugs offset the benefits of sinus rhythm. We
      hypothesized that ventricular rate control is not inferior to the maintenance of
      sinus rhythm for the treatment of atrial fibrillation. METHODS: We randomly
      assigned 522 patients who had persistent atrial fibrillation after a previous
      electrical cardioversion to receive treatment aimed at rate control or rhythm
      control. Patients in the rate-control group received oral anticoagulant drugs and
      rate-slowing medication. Patients in the rhythm-control group underwent serial
      cardioversions and received antiarrhythmic drugs and oral anticoagulant drugs.
      The end point was a composite of death from cardiovascular causes, heart failure,
      thromboembolic complications, bleeding, implantation of a pacemaker, and severe
      adverse effects of drugs. RESULTS: After a mean (+/-SD) of 2.3+/-0.6 years, 39
      percent of the 266 patients in the rhythm-control group had sinus rhythm, as
      compared with 10 percent of the 256 patients in the rate-control group. The
      primary end point occurred in 44 patients (17.2 percent) in the rate-control
      group and in 60 (22.6 percent) in the rhythm-control group. The 90 percent (two
      sided) upper boundary of the absolute difference in the primary end point was 0.4
      percent (the prespecified criterion for noninferiority was 10 percent or less).
      The distribution of the various components of the primary end point was similar
      in the rate-control and rhythm-control groups. CONCLUSIONS: Rate control is not
      inferior to rhythm control for the prevention of death and morbidity from
      cardiovascular causes and may be appropriate therapy in patients with a
      recurrence of persistent atrial fibrillation after electrical cardioversion.

PMID- 12466508
TI  - Mass treatment to eliminate filariasis in Papua New Guinea.
AB  - BACKGROUND: The global initiative to eradicate bancroftian filariasis currently
      relies on mass treatment with four to six annual doses of antifilarial drugs. The
      goal is to reduce the reservoir of microfilariae in the blood to a level that is
      insufficient to maintain transmission by the mosquito vector. METHODS: In nearly
      2500 residents of Papua New Guinea, we prospectively assessed the effects of four
      annual treatments with a single dose of diethylcarbamazine plus ivermectin or
      diethylcarbamazine alone on the incidence of microfilariae-positive infections,
      the severity of lymphatic disease, and the rate of transmission of Wuchereria
      bancrofti by mosquitoes. Random assignment to treatment regimens was carried out
      according to the village of residence, and villages were categorized as having
      moderate or high rates of transmission. RESULTS: The four annual treatments with
      either drug regimen were taken by 77 to 86 percent of the members of the
      population who were at least five years old; treatments were well tolerated. The
      proportion with microfilariae-positive infections decreased by 86 to 98 percent,
      with a greater reduction in areas with a moderate rate of transmission than in
      those with a high rate. The respective aggregate frequencies of hydrocele and leg
      lymphedema were 15 percent and 5 percent before the trial began, and 5 percent
      (P<0.001) and 4 percent (P=0.04) after five years. Hydrocele and leg lymphedema
      were eliminated in 87 percent and 69 percent, respectively, of those who had
      these conditions at the outset. The rate of transmission by mosquitoes decreased
      substantially, and new microfilariae-positive infections in children were almost
      completely prevented over the five-year study period. CONCLUSIONS: Annual mass
      treatment with drugs such as diethylcarbamazine can virtually eliminate the
      reservoir of microfilariae and greatly reduce the frequency of clinical lymphatic
      abnormalities due to bancroftian filariasis. Eradication may be possible in areas
      with moderate rates of transmission, but longer periods of treatment or
      additional control measures may be necessary in areas with high rates of
      transmission.

PMID- 12466509
TI  - Images in clinical medicine. Tuberculosis with atlantoaxial and craniovertebral
      Pott's disease.

PMID- 12466510
TI  - Global drug-resistance patterns and the management of latent tuberculosis
      infection in immigrants to the United States.
AB  - BACKGROUND: In the United States, an increasingly disproportionate burden of
      tuberculosis among the foreign-born population has led to calls for improvements
      in the detection and treatment of latent infection in new immigrants. Current
      treatment guidelines do not take into account global differences in drug
      resistance patterns or their implications for the treatment of immigrants. The
      use of multinational surveillance systems to guide the management of latent
      infection according to region-specific drug-resistance profiles could improve the
      efficiency of efforts to reduce the burden of tuberculosis in immigrants to the
      United States. METHODS: We constructed a decision-analysis model by using a
      hypothetical cohort of all documented immigrants entering the United States from
      developing nations. Region-specific drug-resistance profiles were derived from
      data on 30,388 cases of infection. The model examined the effectiveness and cost
      effectiveness of four strategies: no intervention or tuberculin skin testing
      followed by treatment with isoniazid, treatment with rifampin, or treatment with
      rifampin plus pyrazinamide for those with a positive test result. RESULTS: A
      strategy of detecting and treating latent tuberculosis infection was cost-saving
      among immigrants from Mexico, Haiti, sub-Saharan Africa, South Asia, and
      developing nations in East Asia and the Pacific. This strategy was highly cost
      effective among immigrants from other developing nations. Rifampin plus
      pyrazinamide was the preferred strategy for treating latent infection in
      immigrants from Vietnam, Haiti, and the Philippines. CONCLUSIONS: For new
      immigrants to the United States from developing nations, a strategy of detecting
      and treating latent tuberculosis infection would lead to substantial health and
      economic benefits. Because of the high prevalence of resistance to isoniazid,
      treatment with a rifampin-containing regimen should be strongly considered for
      immigrants from Vietnam, Haiti, and the Philippines.

PMID- 12466511
TI  - Clinical practice. Latent tuberculosis infection.

PMID- 12466512
TI  - Genetic testing.

PMID- 12466513
TI  - Clinical problem-solving. The unusual suspect.

PMID- 12466514
TI  - Management of atrial fibrillation--radical reform or modest modification?

PMID- 12466515
TI  - Major progress toward eliminating lymphatic filariasis.

PMID- 12466516
TI  - Obesity and the risk of heart failure.

PMID- 12466517
TI  - Drug resistance among patients recently infected with HIV.

PMID- 12466518
TI  - Risperidone in children with autism and serious behavioral problems.

PMID- 12466519
TI  - Cardiac pacing for sinus-node dysfunction.

PMID- 12466520
TI  - Variant cystic fibrosis phenotypes in the absence of CFTR mutations.

PMID- 12466521
TI  - Availability of neonatal intensive care and neonatal mortality.

PMID- 12466522
TI  - Cardiomyopathy with mitochondrial damage associated with nucleoside reverse
      transcriptase inhibitors.

PMID- 12466523
TI  - Images in clinical medicine. Tuberculous mastoiditis and cerebral tuberculoma.

PMID- 12466525
TI  - The 3' untranslated region of human vimentin mRNA interacts with protein
      complexes containing eEF-1gamma and HAX-1.
AB  - Previously, we have shown that the vimentin 3' untranslated region (3'UTR)
      contains a highly conserved region, which is sufficient for the perinuclear
      localization of a reporter mRNA. This region was shown to specifically bind
      protein(s) by band shift analyses. UV-cross-linking studies suggest these
      proteins are 46- and 35-kDa in mass. Here, we have used this sequence as 'bait'
      to isolate RNA binding proteins using the yeast three-hybrid method. This
      technique relies on a functional assay detecting bona fide RNA-protein
      interaction in vivo. Three cDNA isolates, HAX-1, eEF-1gamma and hRIP, code for
      proteins of a size consistent with in vitro cross- linking studies. In all cases,
      recombinant proteins were capable of binding RNA in vitro. Although hRIP is
      thought to be a general mRNA binding protein, this represents an unreported
      activity for eEF-1gamma and HAX-1. Moreover, HAX-1 binding appears to be specific
      to vimentin's 3'UTR. Both in vivo synthesized eEF-1gamma and HAX-1 proteins were
      'pulled out' of HeLa whole cell extracts by binding to a RNA affinity column
      comprised of vimentin's 3'UTR. Moreover, size-fractionation of extracts results
      in the separation of large complexes containing either eEF-1gamma or HAX-1. Thus,
      in addition to their known functions, both eEF-1gamma and HAX-1 are RNA binding
      proteins, which suggests new roles in mRNA translation and/or perinuclear
      localization.

PMID- 12466526
TI  - The caudal homeodomain protein activates Drosophila E2F gene expression.
AB  - The Drosophila caudal homeobox gene is required for definition of the
      anteroposterior axis and for gut development, and CDX1 and CDX2, human homologs,
      play crucial roles in the regulation of cell proliferation and differentiation in
      the intestine. Most studies have indicated tumor suppressor functions of Cdx2,
      with inhibition of proliferation, while the effects of Cdx1 are more
      controversial. The influence of Drosophila Caudal on cell proliferation is
      unknown. In this study, we found three potential Caudal binding sequences in the
      5'-flanking region of the Drosophila E2F (DE2F) gene and showed by transient
      transfection assays that they are involved in Caudal transactivation of the dE2F
      gene promoter. Analyses with transgenic flies carrying an E2F-lacZ fusion gene,
      with and without mutation in the Caudal binding site, indicated that the Caudal
      binding sites are required for expression of dE2F in living flies. Caudal-induced
      E2F expression was also confirmed with a GAL4-UAS system in living flies. In
      addition, ectopic expression of Caudal with heat-shock promotion induced
      melanotic tumors in larvae. These results suggest that Caudal is involved in
      regulation of proliferation through transactivation of the E2F gene in
      Drosophila.

PMID- 12466527
TI  - Analysis of histone acetyltransferase and histone deacetylase families of
      Arabidopsis thaliana suggests functional diversification of chromatin
      modification among multicellular eukaryotes.
AB  - Sequence similarity and profile searching tools were used to analyze the genome
      sequences of Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces
      pombe, Caenorhabditis elegans and Drosophila melanogaster for genes encoding
      three families of histone deacetylase (HDAC) proteins and three families of
      histone acetyltransferase (HAT) proteins. Plants, animals and fungi were found to
      have a single member of each of three subfamilies of the GNAT family of HATs,
      suggesting conservation of these functions. However, major differences were found
      with respect to sizes of gene families and multi-domain protein structures within
      other families of HATs and HDACs, indicating substantial evolutionary
      diversification. Phylogenetic analysis identified a new class of HDACs within the
      RPD3/HDA1 family that is represented only in plants and animals. A similar
      analysis of the plant-specific HD2 family of HDACs suggests a duplication event
      early in dicot evolution, followed by further diversification in the lineage
      leading to Arabidopsis. Of three major classes of SIR2-type HDACs that are found
      in animals, fungi have representatives only in one class, whereas plants have
      representatives only in the other two. Plants possess five CREB-binding protein
      (CBP)-type HATs compared with one to two in animals and none in fungi. Domain and
      phylogenetic analyses of the CBP family proteins showed that this family has
      evolved three distinct types of CBPs in plants. The domain architecture of CBP
      and TAF(II)250 families of HATs show significant differences between plants and
      animals, most notably with respect to bromodomain occurrence and their number.
      Bromodomain-containing proteins in Arabidopsis differ strikingly from animal
      bromodomain proteins with respect to the numbers of bromodomains and the other
      types of domains that are present. The substantial diversification of HATs and
      HDACs that has occurred since the divergence of plants, animals and fungi
      suggests a surprising degree of evolutionary plasticity and functional
      diversification in these core chromatin components.

PMID- 12466528
TI  - Bacillus subtilis tau subunit of DNA polymerase III interacts with bacteriophage
      SPP1 replicative DNA helicase G40P.
AB  - Genetic evidence suggests that the Bacillus subtilis dnaX gene only encodes for
      the tau subunit of both DNA polymerases III (Pol IIIs). The B.subtilis full
      length protein and their mutant derivatives tau(373- 563) (lacking the N
      terminal, domains I-III or amino acid residues 1-372) and tau(1-372) (lacking the
      C-terminal region or amino acids 373-563) have been purified. The tau protein
      forms tetramers, tau(373- 563) forms dimers, whereas tau(1-372), depending on the
      ionic strength, forms trimers or tetramers in solution. In the absence of single
      stranded (ss) DNA and a nucleotide cofactor, tau interacts with the SPP1
      hexameric replicative G40P DNA helicase in solution or with G40P-ATP bound to
      ssDNA, with a 1:1 stoichiometry. G40P(109-442), lacking the N-terminal amino acid
      residues 1-108, interacts with the C-terminal moiety of tau. The data indicate
      that the interaction of G40P with the tau subunit of Pol III, is relevant for the
      loading of the Pol IIIs into the SPP1 G38P-promoted open complex.

PMID- 12466529
TI  - Elucidation of structure-function relationships in the protein subunit of
      bacterial RNase P using a genetic complementation approach.
AB  - RNase P is a ribonucleoprotein involved in tRNA biosynthesis in all living
      organisms. Bacterial RNase P is comprised of a catalytic RNA subunit and a lone
      protein cofactor which plays a supporting, albeit essential, role in the tRNA
      processing reaction in vivo. In this study, we have searched various databases to
      identify homologs of the protein subunit of RNase P from diverse bacteria and
      used an alignment of their primary sequences to determine the most highly
      conserved residues, and thereby extend earlier predictions of which residues
      might play an important role in RNA recognition. By employing a genetic
      complementation assay, we have also gained insights into structure- function
      relationships in the protein subunit of bacterial RNase P.

PMID- 12466530
TI  - Localisation of the human hSuv3p helicase in the mitochondrial matrix and its
      preferential unwinding of dsDNA.
AB  - We characterised the human hSuv3p protein belonging to the family of
      NTPases/helicases. In yeast mitochondria the hSUV3 orthologue is a component of
      the degradosome complex and participates in mtRNA turnover and processing, while
      in Caenorhabditis elegans the hSUV3 orthologue is necessary for viability of
      early embryos. Using immunofluorescence analysis, an in vitro mitochondrial
      uptake assay and sub-fractionation of human mitochondria we show hSuv3p to be a
      soluble protein localised in the mitochondrial matrix. We expressed and purified
      recombinant hSuv3p protein from a bacterial expression system. The purified
      enzyme was capable of hydrolysing ATP with a K(m) of 41.9 micro M and the
      activity was only modestly stimulated by polynucleotides. hSuv3p unwound partly
      hybridised dsRNA and dsDNA structures with a very strong preference for the
      latter. The presented analysis of the hSuv3p NTPase/helicase suggests that new
      functions of the protein have been acquired in the course of evolution.

PMID- 12466531
TI  - Human topoisomerase I cleavage complexes are repaired by a p53-stimulated
      recombination-like reaction in vitro.
AB  - Several studies have shown that human topoisomerase I (htopoI) cleaves in the
      vicinity of various DNA lesions and thereby forms covalent intermediates known as
      'cleavage complexes'. Such complexes are detrimental to cells if they are not
      repaired. Therefore, it is generally accepted that repair pathways must exist for
      such lesions. We have demonstrated that a htopoI cleavage complex can be
      recognized by a second topoisomerase I molecule and thereby perform a so-called
      htopoI 'double cleavage' in vitro. In addition, we found that the double cleavage
      reaction was stimulated by p53. Here we show that the double cleavage reaction
      results in the removal of the original htopoI cleavage complex and the generation
      of a single-stranded gap of approximately 13 nt. This gap supports a sequence
      dependent DNA recombination reaction mediated by the second htopoI molecule.
      Furthermore, we show that p53 strongly stimulates the recombination reaction. We
      suggest that this reaction may represent a novel p53-dependent topoisomerase I
      induced recombination repair (TIRR) pathway for htopoI cleavage complexes.

PMID- 12466532
TI  - Characterization of the frameshift stimulatory signal controlling a programmed -1
      ribosomal frameshift in the human immunodeficiency virus type 1.
AB  - Synthesis of the Gag-Pol protein of the human immunodeficiency virus type 1 (HIV
      1) requires a programmed -1 ribosomal frameshifting when ribosomes translate the
      unspliced viral messenger RNA. This frameshift occurs at a slippery sequence
      followed by an RNA structure motif that stimulates frameshifting. This motif is
      commonly assumed to be a simple stem-loop for HIV-1. In this study, we show that
      the frameshift stimulatory signal is more complex than believed and consists of a
      two-stem helix. The upper stem-loop corresponds to the classic stem-loop, and the
      lower stem is formed by pairing the spacer region following the slippery sequence
      and preceding this classic stem-loop with a segment downstream of this stem-loop.
      A three-purine bulge interrupts the two stems. This structure was suggested by
      enzymatic probing with nuclease V1 of an RNA fragment corresponding to the
      gag/pol frameshift region of HIV-1. The involvement of the novel lower stem in
      frameshifting was supported by site-directed mutagenesis. A fragment encompassing
      the gag/pol frameshift region of HIV-1 was inserted in the beginning of the
      coding sequence of a reporter gene coding for the firefly luciferase, such that
      expression of luciferase requires a -1 frameshift. When the reporter was
      expressed in COS cells, mutations that disrupt the capacity to form the lower
      stem reduced frameshifting, whereas compensatory changes that allow re-formation
      of this stem restored the frameshift efficiency near wild-type level. The two
      stem structure that we propose for the frameshift stimulatory signal of HIV-1
      differs from the RNA triple helix structure recently proposed.

PMID- 12466533
TI  - Circle ligation of in vitro assembled chromatin indicates a highly flexible
      structure.
AB  - Evidence is provided that some condensed linker histone-containing chromatin
      structures are highly flexible in solutions containing 2 mM Mg2+. Chromatin
      assembled in vitro +/- histone H5 on a 6.3 kb linear DNA fragment in 90 mM NaCl
      using the polyglutamic acid method sedimented fairly homogeneously. The H5
      containing sample had s(20, w) values that were 58-69% greater than the sample
      lacking H5. Chromatin assembled on linear pUC19 plasmid DNA was treated with T4
      DNA ligase in solutions containing 2 mM Mg2+ over a range of DNA concentrations.
      It was found that the intramolecular DNA ends of the chromatin could be joined
      together more efficiently than the intramolecular ends of the naked DNA at the
      higher DNA concentrations. This result could not be attributed to the effective
      reduction in DNA length by nucleosome formation. The chromatin structures formed
      did not have naked DNA tails extending from the ends as assessed by exonuclease
      III digestion. Chromatin assembled on DNA shortened by up to 420 bp gave very
      similar results, suggesting that the structure was a flexible one, rather than a
      rigid one having DNA ends that were fortuitously juxtaposed.

PMID- 12466534
TI  - An upstream open reading frame impedes translation of the huntingtin gene.
AB  - Expansion of a CAG tract within the huntingtin gene, leading to the production of
      a protein with an expanded polyglutamine tract, is responsible for Huntington's
      disease. We show here that the 5' untranslated region (UTR) of the huntingtin
      gene plays an important role in controlling the synthesis of huntingtin. In
      particular, the 5' UTR contains an upstream open reading frame (uORF) encoding a
      21 amino acid peptide. We demonstrate that the presence of this uORF negatively
      influences expression from the huntingtin mRNA. Our results suggest a role for
      the uORF in limiting ribosomal access to downstream initiation sites. Mechanisms
      involving the post-transcriptional regulation of huntingtin are not well
      understood, and this may be an important way of regulating huntingtin protein
      levels.

PMID- 12466535
TI  - A single amino acid substitution in DNA-PKcs explains the novel phenotype of the
      CHO mutant, XR-C2.
AB  - We recently described a CHO DSBR mutant belonging to the XRCC7 complementation
      group (XR-C2) that has the interesting phenotype of being radiosensitive, but
      having only a modest defect in VDJ recombination. This cell line expresses only
      slightly reduced levels of DNA-PKcs but has undetectable DNA-PK activity. Limited
      sequence analyses of DNA-PKcs transcripts from XR-C2 revealed a point mutation
      that results in an amino acid substitution of glutamic acid for glycine six
      residues from the C-terminus. To determine whether this single substitution was
      responsible for the phenotype in XR-C2 cells, we introduced the mutation into a
      DNA-PKcs expression vector. Whereas transfection of this expression vector
      significantly restores the VDJ recombination deficits in DNA-PKcs-deficient
      cells, radioresistance is not restored. Thus, expression of this mutant form of
      DNA-PKcs in DNA-PKcs- deficient cells substantially recapitulates the phenotype
      observed in XR-C2, and we conclude that this single amino acid substitution is
      responsible for the non-homologous end joining deficits observed in XR-C2.

PMID- 12466536
TI  - Difference between deoxyribose- and tetrahydrofuran-type abasic sites in the in
      vivo mutagenic responses in yeast.
AB  - We have analyzed the mutagenic specificity of an abasic site in DNA using the
      yeast oligonucleotide transformation assay. Oligonucleotides containing an abasic
      site or its analog were introduced into B7528 or its derivatives, and nucleotide
      incorporation opposite abasic sites was analyzed. Cytosine was most frequently
      incorporated opposite a natural abasic site (O) ('C-rule'), followed by thymine.
      Deletion of REV1 decreased the transformation efficiency and the incorporation of
      cytosine nearly to a background level. In contrast, deletion of RAD30 did not
      affect them. We compared the mutagenic specificity with that of a tetrahydrofuran
      abasic site (F), an abasic analog used widely. Its mutation spectrum was clearly
      different from that of O. Adenine, not cytosine, was most favorably incorporated.
      However, deletion of REV1 decreased the transformation efficiency with F
      containing oligonucleotide as in the case of O. These results suggest that the
      bypass mechanism of F is different from that of O, although the bypasses in both
      cases are dependent on REV1. We also found that the mutagenic specificity of F
      can be affected by not only the adjacent bases, but also a base located two
      positions away from F.

PMID- 12466537
TI  - The vertebrate protein CTCF functions as an insulator in Saccharomyces
      cerevisiae.
AB  - Insulators are elements that shelter genes from the effects of silencers or
      enhancers. CTCF is the only vertebrate protein that has a recognized role in
      transcriptional insulation, but how it exerts its effect is unknown. In an
      attempt to better understand how CTCF functions, we have used an insulation assay
      in Saccharomyces cerevisiae. We show that CTCF acts as an insulator in yeast,
      where it can efficiently block the spreading of repressive telomeric chromatin.
      We identify two domains of the protein that are responsible for this activity: a
      short and very potent N-terminal domain, as well as the C-terminus of the
      protein.

PMID- 12466538
TI  - Sequence-dependent folding of DNA three-way junctions.
AB  - Three-way DNA junctions can adopt several different conformers, which differ in
      the coaxial stacking of the arms. These structural variants are often dominated
      by one conformer, which is determined by the DNA sequence. In this study we have
      compared several three-way DNA junctions in order to assess how the arrangement
      of bases around the branch point affects the conformer distribution. The results
      show that rearranging the different arms, while retaining their base sequences,
      can affect the conformer distribution. In some instances this generates a
      structure that appears to contain parallel coaxially stacked helices rather than
      the usual anti-parallel arrangement. Although the conformer equilibrium can be
      affected by the order of purines and pyrimidines around the branch point, this is
      not sufficient to predict the conformer distribution. We find that the folding of
      three-way junctions can be separated into two groups of dinucleotide steps. These
      two groups show distinctive stacking properties in B-DNA, suggesting there is a
      correlation between B-DNA stacking and coaxial stacking in DNA junctions.

PMID- 12466539
TI  - Outersphere and innersphere coordinated metal ions in an aminoacyl-tRNA
      synthetase ribozyme.
AB  - Metal ions are essential cofactors for various ribozymes. Here we dissect the
      roles of metal ions in an aminoacyl-tRNA synthetase-like ribozyme (ARS ribozyme),
      which was evolved in vitro. This ribozyme can charge phenylalanine on tRNA in
      cis, where it is covalently attached to the 5'-end of tRNA (i.e. a form of
      precursor tRNA), as well as in trans, where it can act as a catalyst. The
      presence of magnesium ion is essential for this ribozyme to exhibit full
      catalytic activity. Metal-dependent kinetics, as well as structural mappings
      using Tb3+ in competition with Mg2+ or Co(NH3)6(3+), identified two potential
      metal-binding sites which are embedded near the tRNA-binding site. The high
      affinity metal-binding site can be filled with either Mg2+ or Co(NH3)6(3+) and
      thus the activity relies on a metal ion that is fully coordinated with water or
      ammonium ions. This site also overlaps with the amino acid-binding site,
      suggesting that the metal ion plays a role in constituting the catalytic core.
      The weak metal-binding site is occupied only by a metal ion(s) that can form
      innersphere contacts with ligands in the ribozyme and, hence, Mg2+ can enhance
      ribozyme activity, but Co(NH3)6(3+) cannot. The experiments described in this
      work establish the roles of metal ions that have distinct coordination properties
      in the ARS ribozyme.

PMID- 12466540
TI  - Antisense inhibition of gene expression in cells by oligonucleotides
      incorporating locked nucleic acids: effect of mRNA target sequence and chimera
      design.
AB  - Use of antisense oligonucleotides is a versatile strategy for achieving control
      of gene expression. Unfortunately, the interpretation of antisense-induced
      phenotypes is sometimes difficult, and chemical modifications that improve the
      potency and specificity of antisense action would be useful. The introduction of
      locked nucleic acid (LNA) bases into oligonucleotides confers exceptional
      improvement in binding affinity, up to 10 degrees C per substitution, making LNAs
      an exciting option for the optimization of antisense efficacy. Here we examine
      the rules governing antisense gene inhibition within cells by oligonucleotides
      that contain LNA bases. LNA- containing oligomers were transfected into cells
      using cationic lipid and accumulated in the nucleus. We tested antisense gene
      inhibition by LNAs and LNA-DNA chimeras complementary to the 5'-untranslated
      region, the region surrounding the start codon and the coding region of mRNA, and
      identified effective antisense agents targeted to each of these locations. Our
      data suggest that LNA bases can be used to develop antisense oligonucleotides and
      that their use is a versatile approach for efficiently inhibiting gene expression
      inside cells.

PMID- 12466541
TI  - Hybridization of 2'-O-methyl and 2'-deoxy molecular beacons to RNA and DNA
      targets.
AB  - Molecular beacons are stem-loop hairpin oligonucleotide probes labeled with a
      fluorescent dye at one end and a fluorescence quencher at the other end; they can
      differentiate between bound and unbound probes in homogeneous hybridization
      assays with a high signal-to-background ratio and enhanced specificity compared
      with linear oligonucleotide probes. However, in performing cellular imaging and
      quantification of gene expression, degradation of unmodified molecular beacons by
      endogenous nucleases can significantly limit the detection sensitivity, and
      results in fluorescence signals unrelated to probe/target hybridization. To
      substantially reduce nuclease degradation of molecular beacons, it is possible to
      protect the probe by substituting 2'-O-methyl RNA for DNA. Here we report the
      analysis of the thermodynamic and kinetic properties of 2'-O-methyl and 2'-deoxy
      molecular beacons in the presence of RNA and DNA targets. We found that in terms
      of molecular beacon/target duplex stability, 2'-O-methyl/RNA > 2'-deoxy/RNA > 2'
      deoxy/DNA > 2'-O-methyl/DNA. The improved stability of the 2'-O-methyl/RNA duplex
      was accompanied by a slightly reduced specificity compared with the duplex of 2'
      deoxy molecular beacons and RNA targets. However, the 2'-O-methyl molecular
      beacons hybridized to RNA more quickly than 2'-deoxy molecular beacons. For the
      pairs tested, the 2'-deoxy-beacon/DNA-target duplex showed the fastest
      hybridization kinetics. These findings have significant implications for the
      design and application of molecular beacons.

PMID- 12466542
TI  - Intron gain and loss in the evolution of the conserved eukaryotic recombination
      machinery.
AB  - Intron conservation, intron gain or loss and putative intron sliding events were
      determined for a set of three genes (SPO11, MRE11 and DMC1) involved in basic
      aspects of recombination in eukaryotes. These are ancient genes and present in
      nearly all of the major kingdoms. MRE11 is of bacterial origin and can be found
      in all kingdoms. DMC1 is a specialized homolog of the bacterial RecA protein,
      whereas the SPO11 gene is of archaebacterial origin. Only unique homologs of
      SPO11 are found in animals and fungi whereas three distantly related SPO11 copies
      are present in plant genomes. A comparison of the respective intron positions and
      phases of all genes was performed, demonstrating that a quarter of the intron
      positions were perfectly conserved over more than 1 000 000 000 years. Regarding
      the remaining three quarters of the introns we found insertions to be about three
      times more frequent than deletions. Aligning the introns of the three different
      SPO11 homologs of Arabidopsis thaliana we propose a conclusive model of their
      evolution. We postulate that at least one duplication event occurred shortly
      after the divergence of plants from animals and fungi and that a respective
      homolog has been retained in a protist group, the apicomplexa.

PMID- 12466543
TI  - Methylation of Xenopus CIRP2 regulates its arginine- and glycine-rich region
      mediated nucleocytoplasmic distribution.
AB  - Cold-inducible RNA-binding protein (CIRP) was originally found in mammalian cells
      as a protein that is overexpressed upon a temperature downshift. Recently, we
      identified a Xenopus homolog of CIRP, termed xCIRP2, as a major cytoplasmic RNA
      binding protein in oocytes. In this study we found by yeast two-hybrid screening
      that the Xenopus homolog of protein arginine N-methyltransferase 1 (xPRMT1)
      interacted with xCIRP2. We found that an arginine- and glycine-rich region of
      xCIRP2, termed the RG4 domain, was a target of xPRMT1 for methylation in vitro.
      xCIRP2 expressed in cultured cells accumulated in the nucleus as does mammalian
      CIRP. Interestingly, the RG4 domain was necessary for nuclear localization of
      xCIRP2. RG4-mediated nuclear accumulation of xCIRP2 was diminished in the
      presence of transcription inhibitors, suggesting that nuclear localization of
      xCIRP2 was dependent on ongoing transcription with RNA polymerase II. Analysis of
      interspecies heterokaryons revealed that xCIRP2 was capable of nucleocytoplasmic
      shuttling and the RG4 domain functioned as a nucleocytoplasmic shuttling signal.
      Methylation by overexpressed xPRMT1 caused cytoplasmic accumulation of xCIRP2.
      Possible implications of the relationship between regulation of intracellular
      localization and multiple functions of xCIRP2 will be discussed.

PMID- 12466544
TI  - Regulation of site-specific recombination by the C-terminus of lambda integrase.
AB  - Site-specific recombination catalyzed by bacteriophage lambda integrase (Int) is
      essential for establishment and termination of the viral lysogenic life cycle.
      Int is the archetype of the tyrosine recombinase family whose members are
      responsible for DNA rearrangement in prokaryotes, eukaryotes and viruses. The
      mechanism regulating catalytic activity during recombination is incompletely
      understood. Studies of tyrosine recombinases bound to their target substrates
      suggest that the C-termini of the proteins are involved in protein-protein
      contacts that control the timing of DNA cleavage events during recombination. We
      investigated an Int truncation mutant (W350) that possesses enhanced
      topoisomerase activity but greater than 100-fold reduced recombination activity.
      Alanine scanning mutagenesis of the C-terminus indicates that two mutants, W350A
      and I353A, cannot perform site-specific recombination although their DNA binding,
      cleavage and ligation activities are at wild-type levels. Two other mutants,
      R346A and R348A, are deficient solely in the ability to cleave DNA. To explain
      these results, we have constructed a homology-threaded model of the Int structure
      using a Cre crystal structure. We propose that residues R346 and R348 are
      involved in orientation of the catalytic tyrosine that cleaves DNA, whereas W350
      and I353 control and make intermolecular contacts with other Int proteins in the
      higher order recombination structures known as intasomes. These results suggest
      that Int and the other tyrosine recombinases have evolved regulatory contacts
      that coordinate site-specific recombination at the C-terminus.

PMID- 12466545
TI  - Functional domains involved in the interaction between Orc1 and transcriptional
      repressor AlF-C that bind to an origin/promoter of the rat aldolase B gene.
AB  - The promoter of the rat aldolase B (AldB) gene functions in vivo as an origin of
      DNA replication in the cells in which transcription of the gene is repressed.
      Previously, we identified two closely related DNA-binding proteins, AlF-C1 and
      AlF-C2, which repressed the AldB gene promoter. We also reported that the binding
      site of these proteins, site C, is one of the required DNA elements of the AldB
      gene origin/promoter for autonomously replicating activity in transfected cells.
      In the present study, we show that AlF-C1 and AlF-C2 bind directly to Orc1, a
      subunit of the origin recognition complex (ORC). Deletion analyses revealed a
      functional domain in AlF-C2 for binding to Orc1, which is located separately from
      the DNA-binding domain. In addition, we found a novel protein-interacting domain
      in Orc1 required for the binding of AlF-C2, which was conserved in human, mouse
      and Chinese hamster, but not in Drosophila, frog and yeast. Thus, it is assumed
      that in mammalian cells, sequence- specific DNA-binding proteins are involved in
      recruiting ORC to regulate replication initiation and/or transcription
      repression.

PMID- 12466546
TI  - HapScope: a software system for automated and visual analysis of functionally
      annotated haplotypes.
AB  - We have developed a software analysis package, HapScope, which includes a
      comprehensive analysis pipeline and a sophisticated visualization tool for
      analyzing functionally annotated haplotypes. The HapScope analysis pipeline
      supports: (i) computational haplotype construction with an expectation
      maximization or Bayesian statistical algorithm; (ii) SNP classification by
      protein coding change, homology to model organisms or putative regulatory
      regions; and (iii) minimum SNP subset selection by either a Brute Force Algorithm
      or a Greedy Partition Algorithm. The HapScope viewer displays genomic structure
      with haplotype information in an integrated environment, providing eight
      alternative views for assessing genetic and functional correlation. It has a user
      friendly interface for: (i) haplotype block visualization; (ii) SNP subset
      selection; (iii) haplotype consolidation with subset SNP markers; (iv)
      incorporation of both experimentally determined haplotypes and computational
      results; and (v) data export for additional analysis. Comparison of haplotypes
      constructed by the statistical algorithms with those determined experimentally
      shows variation in haplotype prediction accuracies in genomic regions with
      different levels of nucleotide diversity. We have applied HapScope in analyzing
      haplotypes for candidate genes and genomic regions with extensive SNP and
      genotype data. We envision that the systematic approach of integrating functional
      genomic analysis with population haplotypes, supported by HapScope, will greatly
      facilitate current genetic disease research.

PMID- 12466547
TI  - Rearrangement of a 1,3-trans-[Pt(NH3)2[(GXG)-N7G,N7G]] intrastrand cross-link
      into interstrand cross-links within RNA duplexes.
AB  - The cross-linking reaction described previously in the DNA and 2'-O-methyl RNA
      series is extended to RNA duplexes. A 17mer single-stranded RNA containing the
      1,3-trans-[Pt(NH3)2[(GAG)-N7G,N7G]] intrastrand chelate, named G*AG* (*
      indicating a platinated base) gives, upon pairing with the complementary RNA
      strand, the G*AG/CUC* interstrand cross-link. The rate of the reaction in 200 mM
      NaClO4 is similar to that observed for DNA-RNA duplexes. It depends on the added
      Na+ or Mg2+ cation and on its concentration. RNA duplexes containing GA/GA or
      AG/AG tandem mismatches in the rearrangement triplet core were also studied. The
      major interstrand cross-links, G*AG/CGA* and G*AG/AGC*, are accompanied by a
      minor one involving the central G of the CGA or AGC complementary sequence
      G*AG/CG*A and G*AG/AG*C. In 200 mM NaClO4, the G*A/GA tandem mismatch does not
      modify the rate of the cross-linking rearrangement whereas the AG*/AG mismatch
      slows it down by a factor of four. Our results reflect the predominance of the
      local structure of the rearrangement core over the nucleophility of the cross
      linking base. They also show that the reaction could be used to trap tertiary
      structures of naturally occurring RNAs, including those with the commonly
      encountered GA/GA mismatch.

PMID- 12466548
TI  - Detection of novel members, structure-function analysis and evolutionary
      classification of the 2H phosphoesterase superfamily.
AB  - 2',3' Cyclic nucleotide phosphodiesterases are enzymes that catalyze at least two
      distinct steps in the splicing of tRNA introns in eukaryotes. Recently, the
      biochemistry and structure of these enzymes, from yeast and the plant Arabidopsis
      thaliana, have been extensively studied. They were found to share a common active
      site, characterized by two conserved histidines, with the bacterial tRNA-ligating
      enzyme LigT and the vertebrate myelin-associated 2',3' phosphodiesterases. Using
      sensitive sequence profile analysis methods, we show that these enzymes define a
      large superfamily of predicted phosphoesterases with two conserved histidines
      (hence 2H phosphoesterase superfamily). We identify several new families of 2H
      phosphoesterases and present a complete evolutionary classification of this
      superfamily. We also carry out a structure- function analysis of these proteins
      and present evidence for diverse interactions for different families, within this
      superfamily, with RNA substrates and protein partners. In particular, we show
      that eukaryotes contain two ancient families of these proteins that might be
      involved in RNA processing, transcriptional co-activation and post
      transcriptional gene silencing. Another eukaryotic family restricted to
      vertebrates and insects is combined with UBA and SH3 domains suggesting a role in
      signal transduction. We detect these phosphoesterase modules in polyproteins of
      certain retroviruses, rotaviruses and coronaviruses, where they could function in
      capping and processing of viral RNAs. Furthermore, we present evidence for
      multiple families of 2H phosphoesterases in bacteria, which might be involved in
      the processing of small molecules with the 2',3' cyclic phosphoester linkages.
      The evolutionary analysis suggests that the 2H domain emerged through a
      duplication of a simple structural unit containing a single catalytic histidine
      prior to the last common ancestor of all life forms. Initially, this domain
      appears to have been involved in RNA processing and it appears to have been
      recruited to perform various other functions in later stages of evolution.

PMID- 12466549
TI  - A Hoogsteen base pair embedded in undistorted B-DNA.
AB  - Hoogsteen base pairs within duplex DNA typically are only observed in regions
      containing significant distortion or near sites of drug intercalation. We report
      here the observation of a Hoogsteen base pair embedded within undistorted,
      unmodified B-DNA. The Hoogsteen base pair, consisting of a syn adenine base
      paired with an anti thymine base, is found in the 2.1 A resolution structure of
      the MATalpha2 homeodomain bound to DNA in a region where a specifically and a non
      specifically bound homeodomain contact overlapping sites. NMR studies of the free
      DNA show no evidence of Hoogsteen base pair formation, suggesting that protein
      binding favors the transition from a Watson-Crick to a Hoogsteen base pair.
      Molecular dynamics simulations of the homeodomain-DNA complex support a role for
      the non-specifically bound protein in favoring Hoogsteen base pair formation. The
      presence of a Hoogsteen base pair in the crystal structure of a protein-DNA
      complex raises the possibility that Hoogsteen base pairs could occur within
      duplex DNA and play a hitherto unrecognized role in transcription, replication
      and other cellular processes.

PMID- 12466550
TI  - Crystal structure of d(GCGAAAGCT) containing a parallel-stranded duplex with homo
      base pairs and an anti-parallel duplex with Watson-Crick base pairs.
AB  - A DNA fragment d(GCGAAAGCT), known to adopt a stable mini-hairpin structure in
      solution, has been crystallized in the space group I4(1)22 with the unit-cell
      dimensions a = b = 53.4 A and c = 54.0 A, and the crystal structure has been
      determined at 2.5 A resolution. The four nucleotide residues CGAA of the first
      half of the oligomer form a parallel duplex with another half through the homo
      base pairs, C2:C2+ (singly-protonated between the Watson- Crick sites), G3:G3
      (between the minor groove sites), A4:A4 (between the major groove sites) and
      A5:A5 (between the Watson-Crick sites). The two strands remaining in the half of
      the parallel duplex are split away in different directions, and they pair in an
      anti-parallel B-form duplex with the second half extending from a neighboring
      parallel duplex, so that an infinite column is formed in a head-to-tail fashion
      along the c-axis. It seems that a hexa-ammine cobalt cation supports such a
      branched and bent conformation of the oligomer. One end of the parallel duplex is
      stacked on the corresponding end of the adjacent parallel duplex; between them,
      the guanine base of the first residue is stacked on the fourth ribose of another
      duplex.

PMID- 12466551
TI  - Skip interacts with the retinoblastoma tumor suppressor and inhibits its
      transcriptional repression activity.
AB  - Ski interacting protein (Skip) plays an important role in the transforming
      activity of both v-Ski and EBNA2 (Epstein-Barr virus encoded latency protein) and
      is involved in EBNA2 and NotchIC activation of CBF1-repressed promoters. We have
      previously shown that Skip acts as a transcriptional co-activator on a number of
      cellular and viral promoters. Here, we report that Skip also interacts with pRb
      and, in cooperation with Ski, can overcome pRb-induced transcriptional
      repression. We show a strong and direct interaction between pRb and Skip, and we
      map the site of interaction to amino acid residues 171-353 of the evolutionarily
      conserved SNW domain of Skip. Furthermore, the combination of Skip and Ski can
      successfully overcome the G1 arrest and flat cell phenotype induced by pRb. Taken
      together, these studies suggest that one potential function of the Skip-Ski
      complex is to overcome the growth-suppressive activities of pRb.

PMID- 12466552
TI  - Substitution of an essential adenine in the U1A-RNA complex with a non-polar
      isostere.
AB  - The RNA recognition motif (RRM) binds to single-stranded RNA target sites of
      diverse sequences and structures. A conserved mode of base recognition by the RRM
      involves the simultaneous formation of a network of hydrogen bonds with the base
      functional groups and a stacking interaction between the base and a highly
      conserved aromatic amino acid. We have investigated the energetic contribution of
      the functional groups involved in the recognition of an essential adenine, A6, in
      stem-loop 2 of U1 snRNA by the N-terminal RRM of the U1A protein. Previously, we
      found that elimination of individual hydrogen bond donors and acceptors on A6
      destabilized the complex by 0.8-1.9 kcal/mol, while mutation of the aromatic
      amino acid (Phe56) that stacks with A6 to Ala destabilized the complex by 5.5
      kcal/mol. Here we continue to probe the contribution of A6 to complex stability
      through mutation of both the RNA and protein. We have removed two hydrogen
      bonding functional groups by introducing a U1A mutation, Ser91Ala, and replacing
      A6 with tubercidin, purine, or 1-deazaadenine. We find that the complex is
      destabilized an additional 1.2-2.6 kcal/mol by the elimination of the second
      hydrogen bond donor or acceptor. Surprisingly, deletion of all of the functional
      groups involved in hydrogen bonds with the U1A protein by substituting adenine
      with 4-methylindole reduced the binding free energy by only 2.0 kcal/mol.
      Experiments with U1A proteins containing mutations of Phe56 suggested that
      improved stacking interactions due to the greater hydrophobicity of 4
      methylindole than adenine may be partly responsible for the small destabilization
      of the complex upon substitution of 4-methylindole for A6. The data imply that
      hydrophobic interactions can compensate energetically for the disruption of the
      complex hydrogen-bonding network between nucleotide and protein.

PMID- 12466553
TI  - G-quartets assembly within a G-rich DNA flap. A possible event at the center of
      the HIV-1 genome.
AB  - Stretches of guanines can associate in vitro through Hoogsteen hydrogen bonding
      to form four-stranded structures. In the HIV-1 central DNA flap, generated by
      reverse transcriptase at the end of retrotranscription, both the two 99 nt-long
      overlapping (+) strands contain two adjacent tracts of guanines. This study
      demonstrates that oligonucleotides containing these G-clusters form highly stable
      G-quadruplexes of various structures in vitro, whose formation was controlled by
      an easy and reversible protocol using sodium hydroxide. Among these sequences, a
      G'2 hairpin dimer was the most stable structure adopted by the 5'-tail of the (+)
      downstream strand. Since the two (+) strands of the HIV-1 central DNA flap hold
      these G-clusters, and based on the properties of reverse branch migration in DNA
      flaps, constructions using HIV-1 sequences were assembled to mimic small DNA
      flaps where the G-clusters are neighbors. G-quartets were successfully probed in
      such flaps. They were induced by potassium and by a dibenzophenanthroline
      derivative already known to stabilize them. Such results suggest some function(s)
      for G-quartets associated with a DNA flap in the HIV-1 pre-integration steps, and
      argue for their transient formation during the processing of G-rich DNA flaps at
      the time of replication and/or repair.

PMID- 12466554
TI  - Translesion replication of benzo[a]pyrene and benzo[c]phenanthrene diol epoxide
      adducts of deoxyadenosine and deoxyguanosine by human DNA polymerase iota.
AB  - Human DNA polymerase iota (poliota) is a Y-family polymerase whose cellular
      function is presently unknown. Here, we report on the ability of poliota to
      bypass various stereoisomers of benzo[a]pyrene (BaP) diol epoxide (DE) and
      benzo[c]phenanthrene (BcPh) DE adducts at deoxyadenosine (dA) or deoxyguanosine
      (dG) bases in four different template sequence contexts in vitro. We find that
      the BaP DE dG adducts pose a strong block to poliota-dependent replication and
      result in a high frequency of base misincorporations. In contrast,
      misincorporations opposite BaP DE and BcPh DE dA adducts generally occurred with
      a frequency ranging between 2 x 10(-3) and 6 x 10(-4). Although dTMP was inserted
      efficiently opposite all dA adducts, further extension was relatively poor, with
      one exception (a cis opened adduct derived from BcPh DE) where up to 58%
      extension past the lesion was observed. Interestingly, another human Y-family
      polymerase, polkappa, was able to extend dTMP inserted opposite a BaP DE dA
      adduct. We suggest that poliota might therefore participate in the error-free
      bypass of DE-adducted dA in vivo by predominantly incorporating dTMP opposite the
      damaged base. In many cases, elongation would, however, require the participation
      of another polymerase more specialized in extension, such as polkappa.

PMID- 12466555
TI  - The complete genomic sequence of Mycoplasma penetrans, an intracellular bacterial
      pathogen in humans.
AB  - The complete genomic sequence of an intracellular bacterial pathogen, Mycoplasma
      penetrans HF-2 strain, was determined. The HF-2 genome consists of a 1 358 633 bp
      single circular chromosome containing 1038 predicted coding sequences (CDSs), one
      set of rRNA genes and 30 tRNA genes. Among the 1038 CDSs, 264 predicted proteins
      are common to the Mycoplasmataceae sequenced thus far and 463 are M.penetrans
      specific. The genome contains the two-component system but lacks the essential
      cellular gene, uridine kinase. The relatively large genome of M.penetrans HF-2
      among mycoplasma species may be accounted for by both its rich core proteome and
      the presence of a number of paralog families corresponding to 25.4% of all CDSs.
      The largest paralog family is the p35 family, which encodes surface lipoproteins
      including the major antigen, P35. A total of 44 genes for p35 and p35 homologs
      were identified and 30 of them form one large cluster in the chromosome. The
      genetic tree of p35 paralogs suggests the occurrence of dynamic chromosomal
      rearrangement in paralog formation during evolution. Thus, M.penetrans HF-2 may
      have acquired diverse repertoires of antigenic variation-related genes to allow
      its persistent infection in humans.

PMID- 12466556
TI  - PSKH1, a novel splice factor compartment-associated serine kinase.
AB  - Small nuclear ribonucleoprotein particles (snRNPs) and non-snRNP splicing factors
      containing a serine/arginine-rich domain (SR proteins) concentrate in splicing
      factor compartments (SFCs) within the nucleus of interphase cells. Nuclear SFCs
      are considered mainly as storage sites for splicing factors, supplying splicing
      factors to active genes. The mechanisms controlling the interaction of the
      various spliceosome constituents, and the dynamic nature of the SFCs, are still
      poorly understood. We show here that endogenous PSKH1, a previously cloned
      kinase, is located in SFCs. Migration of PSKH1-FLAG into SFCs is enhanced during
      co-expression of T7-tagged ASF/SF2 as well as other members of the SR protein
      family, but not by two other non-SR nuclear proteins serving as controls. Similar
      to the SR protein kinase family, overexpression of PSKH1 led to reorganization of
      co-expressed T7-SC35 and T7-ASF/SF2 into a more diffuse nuclear pattern. This
      redistribution was not dependent on PSKH1 kinase activity. Different from the SR
      protein kinases, the SFC-associating features of PSKH1 were located within its
      catalytic kinase domain and within its C-terminus. Although no direct interaction
      was observed between PSKH1 and any of the SR proteins tested in pull-down or
      yeast two-hybrid assays, forced expression of PSKH1-FLAG was shown to stimulate
      distal splicing of an E1A minigene in HeLa cells. Moreover, a GST-ASF/SF2 fusion
      was not phosphorylated by PSKH1, suggesting an indirect mechanism of action on SR
      proteins. Our data suggest a mutual relationship between PSKH1 and SR proteins,
      as they are able to target PSKH1 into SFCs, while forced PSKH1 expression
      modulates nuclear dynamics and the function of co-expressed splicing factors.

PMID- 12466557
TI  - Discovery of RNA structural elements using evolutionary computation.
AB  - RNA molecules fold into characteristic secondary and tertiary structures that
      account for their diverse functional activities. Many of these RNA structures, or
      certain structural motifs within them, are thought to recur in multiple genes
      within a single organism or across the same gene in several organisms and provide
      a common regulatory mechanism. Search algorithms, such as RNAMotif, can be used
      to mine nucleotide sequence databases for these repeating motifs. RNAMotif allows
      users to capture essential features of known structures in detailed descriptors
      and can be used to identify, with high specificity, other similar motifs within
      the nucleotide database. However, when the descriptor constraints are relaxed to
      provide more flexibility, or when there is very little a priori information about
      hypothesized RNA structures, the number of motif 'hits' may become very large.
      Exhaustive methods to search for similar RNA structures over these large search
      spaces are likely to be computationally intractable. Here we describe a powerful
      new algorithm based on evolutionary computation to solve this problem. A series
      of experiments using ferritin IRE and SRP RNA stem-loop motifs were used to
      verify the method. We demonstrate that even when searching extremely large search
      spaces, of the order of 10(23) potential solutions, we could find the correct
      solution in a fraction of the time it would have taken for exhaustive
      comparisons.

PMID- 12466559
TI  - Probing triplex formation by EPR spectroscopy using a newly synthesized spin
      label for oligonucleotides.
AB  - Spin labels have been extensively used to study the dynamics of oligonucleotides.
      Spin labels that are more rigidly attached to a base in an oligonucleotide
      experience much larger changes in their range of motion than those that are
      loosely tethered. Thus, their electron paramagnetic resonance spectra show larger
      changes in response to differences in the mobility of the oligonucleotides to
      which they are attached. An example of this is 5-(2,2,5,5-tetramethyl-3
      ethynylpyrrolidine-1-oxyl)-uridine (1). How ever, the synthesis of this modified
      DNA base is quite involved and, here, we report the synthesis of a new spin
      labeled DNA base, 5-(2,2,6,6-tetramethyl-4-ethynylpiperidyl-3-ene-1-oxyl)-uridine
      (2). This spin label is readily prepared in half the number of steps required for
      1, and yet behaves in a spectroscopically analogous manner to 1 in
      oligonucleotides. Finally, it is shown here that both spin labels 1 and 2 can be
      used to detect the formation of both double-stranded and triplex DNA.

PMID- 12466558
TI  - Proteomic analysis of human metaphase chromosomes reveals topoisomerase II alpha
      as an Aurora B substrate.
AB  - The essential Aurora B kinase is a chromosomal passenger protein that is required
      for mitotic chromosome alignment and segregation. Aurora B function is dependent
      on the chromosome passenger, INCENP. INCENP, in turn, requires sister chromatid
      cohesion for its appropriate behaviour. Relatively few substrates have been
      identified for Aurora B, so that the precise role it plays in controlling mitosis
      remains to be elucidated. To identify potential novel mitotic substrates of
      Aurora B, extracted chromosomes were prepared from mitotically-arrested HeLa S3
      cells and incubated with recombinant human Aurora B in the presence of
      radioactive ATP. Immunoblot analysis confirmed the HeLa scaffold fraction to be
      enriched for known chromosomal proteins including CENP-A, CENP-B, CENP-C, ScII
      and INCENP. Mass spectrometry of bands excised from one-dimensional
      polyacrylamide gels further defined the protein composition of the extracted
      chromosome fraction. Cloning, fluorescent tagging and expression in HeLa cells of
      the putative GTP-binding protein NGB/CRFG demonstrated it to be a novel mitotic
      chromosome protein, with a perichromosomal localisation. Identi fication of the
      protein bands corresponding to those phosphorylated by Aurora B revealed
      topoisomerase II alpha (topo IIalpha) as a potential Aurora B substrate. Purified
      recombinant human topo IIalpha was phosphorylated by Aurora B in vitro,
      confirming this proteomic approach as a valid method for the initial definition
      of candidate substrates of key mitotic kinases.

PMID- 12466560
TI  - Monitoring mis-acylated tRNA suppression efficiency in mammalian cells via EGFP
      fluorescence recovery.
AB  - A reporter assay was developed to detect and quantify nonsense codon suppression
      by chemically aminoacylated tRNAs in mammalian cells. It is based on the cellular
      expression of the enhanced green fluorescent protein (EGFP) as a reporter for the
      site-specific amino acid incorporation in its sequence using an orthogonal
      suppressor tRNA derived from Escherichia coli. Suppression of an engineered amber
      codon at position 64 in the EGFP run-off transcript could be achieved by the
      incorporation of a leucine via an in vitro aminoacylated suppressor tRNA.
      Microinjection of defined amounts of mutagenized EGFP mRNA and suppressor tRNA
      into individual cells allowed us to accurately determine suppression efficiencies
      by measuring the EGFP fluorescence intensity in individual cells using laser
      scanning confocal microscopy. Control experiments showed the absence of natural
      suppression or aminoacylation of the synthetic tRNA by endogenous aminoacyl-tRNA
      synthetases. This reporter assay opens the way for the optimization of essential
      experimental parameters for expanding the scope of the suppressor tRNA technology
      to different cell types.

PMID- 12466561
TI  - Sequence tagged microsatellite profiling (STMP): improved isolation of DNA
      sequence flanking target SSRs.
AB  - Sequence tagged microsatellite profiling (STMP) enables the rapid development of
      large numbers of co-dominant DNA markers, known as sequence tagged
      microsatellites (STMs). Each STM is amplified by PCR using a single primer
      specific to the conserved DNA sequence flanking the microsatellite repeat in
      combination with a universal primer that anchors to the 5'-ends of the
      microsatellites. It is also possible to convert STMs into conventional
      microsatellite, or simple sequence repeat (SSR), markers that are amplified using
      a pair of primers flanking the repeat sequence. Here, we describe a modification
      of the STMP procedure to significantly improve the capacity to convert STMs into
      conventional SSRs and, therefore, facilitate the development of highly specific
      DNA markers for purposes such as marker-assisted breeding. The usefulness of this
      technique was demonstrated in bread wheat.

PMID- 12466562
TI  - Polyamine-assisted rapid and clean cleavage of oligonucleotides from cis-diol
      bearing universal support.
AB  - Polyamine-assisted deprotection conditions have been developed for the rapid and
      clean cleavage of oligonucleotide chains from a cis-diol group bearing universal
      polymer support, making it compatible with modern oligonucleotide synthesis via
      all types of phosphoramidite synthons, including base labile protecting group
      bearing synthons as well. The synthesized oligonucleotides were found to be
      comparable with the corresponding standard oligomers with respect to their
      retention time on HPLC, mass on MALDI-TOF and biological activity in PCR
      amplification.

PMID- 12466563
TI  - Predicting the success of primer extension genotyping assays using statistical
      modeling.
AB  - Using an empirical panel of more than 20 000 single base primer extension (SNP
      IT) assays we have developed a set of statistical scores for evaluating and rank
      ordering various parameters of the SNP-IT reaction to facilitate high-throughput
      assay primer design with improved likelihood of success. Each score predicts
      either signal magnitude from primer extension or signal noise caused by
      mispriming of primers and structure of the PCR product. All scores have been
      shown to correlate with the success/failure rate of the SNP-IT reaction, based on
      analysis of assay results. A logistic regression analysis was applied to combine
      all scored parameters into one measure predicting the overall success/failure
      rate of a given SNP marker. Three training sets for different types of SNP-IT
      reaction, each containing about 22 000 SNP markers, were used to assign weights
      to each score and optimize the prediction of the combined measure. c-Statistics
      of 0.69, 0.77 and 0.72 were achieved for three training sets. This new
      statistical prediction can be used to improve primer design for the SNP-IT
      reaction and evaluate the probability of genotyping success for a given SNP based
      on analysis of the surrounding genomic sequence.

PMID- 12466564
TI  - Construction and selection of bead-bound combinatorial oligonucleoside
      phosphorothioate and phosphorodithioate aptamer libraries designed for rapid PCR
      based sequencing.
AB  - Chemically synthesized combinatorial libraries of unmodified or modified nucleic
      acids have not previously been used in methods to rapidly select oligonucleotides
      binding to target biomolecules such as proteins. Phosphorothioate
      oligonucleotides (S-ODNs) or phosphorodithioate oligonucleotides (S2-ODNs) with
      sulfurs replacing one or both of the non-bridging phosphate oxygens bind to
      proteins more tightly than unmodified oligonucleotides and have the potential to
      be used as diagnostic reagents and therapeutics. We have applied a split
      synthesis methodology to create one-bead one-S-ODN and one-bead one-S2-ODN
      libraries. Binding and selection of specific beads to the transcription factor NF
      kappaB p50/p50 protein were demonstrated. Sequencing both the nucleic acid bases
      and the positions of any 3'-O-thioate/dithioate linkages was carried out by using
      a novel PCR-based identification tag of the selected beads. This approach allows
      us to rapidly and conveniently identify S-ODNs or S2-ODNs that bind to proteins.

PMID- 12466565
TI  - Quantitative codon optimisation of DNA libraries encoding sub-random peptides:
      design and characterisation of a novel library encoding transmembrane domain
      peptides.
AB  - Codons for amino acids sharing similar chemical properties seem to cluster on the
      genetic codon table. Such a geographical distribution of the codons was exploited
      to create chemically synthesised DNA that encodes peptide libraries containing
      only a subset of the 20 natural amino acids. The frequency of each amino acid in
      the subset was further optimised by quantitatively manipulating the ratio of the
      four phosphoamidites during chemical synthesis of the libraries. Peptides encoded
      by such libraries show a reduced complexity and could be enriched in peptides of
      a desired property, which are thus more suitable when screening for functional
      peptides. Proof of concept for the codon-biased design of peptide libraries was
      shown by design, synthesis, and characterisation of a transmembrane peptide
      library that contains >80% transmembrane peptides, representing a 160-fold
      enrichment compared with a fully randomised library.

PMID- 12466566
TI  - Stringent doxycycline dependent control of CRE recombinase in vivo.
AB  - The strategy of modulating gene activities in vivo via CRE/loxP recombination
      would greatly profit from subjecting the recombination event to an independent
      and stringent temporal control. Here, we describe a transgenic mouse line, LC-1,
      where the expression of the cre and luciferase gene is tightly controlled by the
      Tet system. Using the R26R mouse line as indicator for CRE activity, and mouse
      lines expressing tetracycline controlled transactivators (tTA/rtTA) in various
      tissues, we show that; (i) in the non-induced state CRE recombinase is tightly
      controlled throughout the development and adulthood of an animal; (ii) upon
      induction, efficient recombination occurs in the adult animal in all tissues
      where tTA/rtTA is present, including hepatocytes, kidney cells, neurons and T
      lymphocytes; and (iii) no position effect appears to be caused by the LC-1 locus.
      Moreover, using the novel rTA(LAP)-1 mouse line, we show that in hepatocytes,
      complete deletion of the loxP-flanked insert in R26R animals is achieved less
      than 48 h after induction. Thus, the LC-1 mouse appears suitable for exploiting
      two rapidly increasing collections of mouse lines of which one provides tTA/rtTA
      in specific cell types/tissues, and the other a variety of loxP-flanked genes.

PMID- 12466567
TI  - Detection of pseudouridine and other modifications in tRNA by cyanoethylation and
      MALDI mass spectrometry.
AB  - Mass spectrometry plays a central role in the characterisation of modified
      nucleotides, but pseudouridine is a mass-silent post-transcriptional modification
      and hence not detectable by direct mass spectrometric analysis. We show by the
      use of matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry that
      pseudouridines in tRNA can be specifically cyanoethylated by acrylonitrile
      without affecting the uridines. The tRNA was cyanoethylated and then subjected to
      digestion with either RNase A or RNase T1. Cyanoethylated digestion fragments
      were identified by mass spectrometric comparison of untreated and acrylonitrile
      treated samples, where the addition of one acrylonitrile resulted in a mass
      increment of 53.0 Da. The exact modified nucleotide could be identified by tandem
      mass spectrometry on the cyanoethylated digestion fragment. The methodology was
      used to identify additional one 4-thiouridine and one pseudouridine in
      tRNA(TyrII) from Escherichia coli. Furthermore, we observed that RNase A is
      highly tolerant towards nucleotide modifications, only being inhibited by 2'-O
      methylation, whereas RNase T1 cleavage is affected by most nucleotide
      modifications.

PMID- 12466568
TI  - National Oral Health Care Program.

PMID- 12466569
TI  - Foreign body aspiration.
AB  - OBJECTIVE: To analyze the clinical and radiological profile of foreign body
      aspiration in children reaching a tertiary care center and identify areas of
      possible interventions for proper management of such cases. SETTING: Tertiary
      level teaching hospital. SUBJECTS: Case records of patients suspected to have
      foreign body aspiration over the past four years were analyzed. Clinico
      radiological features, types and location of foreign bodies were studied.
      RESULTS: Of 75 children who underwent rigid bronchoscopy, 70 had tracheo
      bronchial foreign bodies. History of choking was elicited in 90 percent cases. In
      30 percent cases chest radiographs were non-contributory, while the commonest
      finding (63 percent) was distal emphysema. Over three-fourth of the cases were
      below the age of 2 years. Vegetative foreign bodies, mainly peanuts, were
      commonly present. In many cases, referral was delayed as the diagnosis was missed
      initially. CONCLUSION: Foreign body aspiration remains a common unintentional
      childhood injury due to improper exposure of young children to otherwise
      innocuous looking nuts and other small objects.

PMID- 12466570
TI  - Adrenal insufficiency of critical illness.

PMID- 12466571
TI  - Circulating adhesion molecule levels in childhood asthma.
AB  - The present study aims at comparing the levels of circulating forms of E
      selectin, ICAM-1 and VCAM-1 in 10 patients with acute asthma, 10 stable atopic
      asthmatics, 10 nonatopic stable asthmatics and 10 age-matched healthy children.
      sE-selectin levels of patients with acute asthma were found to be significantly
      higher than that of the other three groups. The insignificant rise in sICAM-1
      levels was attributed to the usage of inhaler corticosteroids. Serum sE-selectin
      and sICAM-1 seem to be promising serological markers for monitoring disease
      activity in childhood asthma.

PMID- 12466572
TI  - Effect of deworming on nutritional status of ascaris infested slum children of
      Dhaka, Bangladesh.
AB  - This randomized double blind community trial was conducted on Ascaris infested
      children (n = 85) aged 2 to 12 years and was aimed to study the impact of
      deworming on nutritional status, in an urban slum of Dhaka, Bangladesh. The
      change of weight gain was significantly higher in children given anthelmintics
      than those given placebo (0.92 kg vs. 0.54 kg). A multiple linear regression
      model shows that after controlling sex, deworming and height were positively
      correlated while age and weight were negatively correlated with weight change.

PMID- 12466573
TI  - Dengue fever epidemic in Chennai--a study of clinical profile and outcome.
AB  - Children with dengue fever presenting to the Institute of Social Pediatrics,
      Government Stanley Hospital, during the months of October to December 2001, were
      prospectively followed up for clinical profile and outcome. Commonest clinical
      features were fever, vomiting, bleeding, body pain and hepatomegaly. Elevated
      liver enzymes and low platelet counts were common laboratory findings in dengue.
      Hepatomegaly, positive tourniquet test, elevated haematocrit and thrombocytopenia
      were more common in DHF and DSS group. Retro-orbital pain was slightly more in
      DHF and DSS groups and there was a tendency for DSS to present at an earlier age.
      There was no correlation between platelet counts and bleeding in classical dengue
      cases.

PMID- 12466574
TI  - Clinical and bacteriological profile of neonatal septicemia in a tertiary level
      pediatric hospital in Bangladesh.
AB  - The present article is a descriptive analysis of clinical and bacteriological
      profile of neonatal septicemia in a tertiary care hospital in Bangladesh. Eighty
      six neonates with suspected sepsis were enrolled, out of which 30 were culture
      positive. Clinical presentation was non-specific. Majority (70%) of the cultures
      isolated gram negative bacilli, most commonly E.coli and Klebsiella. These
      isolates were most often sensitive to gentamicin, ciprofloxacin, and third
      generation cephalosporins. Twelve out of 30 culture positive cases died.

PMID- 12466575
TI  - An indigenously developed method for sweat collection and estimation of chloride
      for diagnosis of cystic fibrosis.
AB  - An indigenously developed method for sweat collection and titration method for
      estimation of chloride was validated. The mean difference in estimated chloride
      value from the known strength of saline in 50 samples was -1.04 +/- 4.13 mEq/L
      (95% CI: -0.07 to 2.28). The mean difference in the estimated chloride values
      between two observers when the test was performed on known strengths of saline
      solution was -2.5 +/- 4.24 mEq/L (95% CI: -3.67 to 1.33). The inter observer
      variability between two observers when the test was performed on sweat samples
      obtained from 50 individuals was -1.12 +/- 4.34 mEq/L (95% CI: -2.23 to 0.8 ).
      Sweat weight of more than 100 mg could be collected in first attempt in 602 of
      757 (80%) patient with an average sweat weight of 230 mg. This inexpensive method
      of sweat collection and chloride estimation has acceptable accuracy and
      repeatability and can be used in resource poor setting for making a diagnosis of
      cystic fibrosis.

PMID- 12466576
TI  - Giant solitary parathyroid adenoma presenting with bone disease.

PMID- 12466577
TI  - Urinoma.

PMID- 12466578
TI  - Partial 15q22 trisomy due to segregation of maternal 10;15 reciprocal
      translocation.

PMID- 12466579
TI  - Cornelia De Lange syndrome.

PMID- 12466580
TI  - Infantile cortical hyperostosis.

PMID- 12466581
TI  - Melnick-Fraser syndrome.

PMID- 12466582
TI  - Primary atypical pneumonia in children.

PMID- 12466584
TI  - Hydatid disease of lungs unusual cause of hemoptysis.

PMID- 12466585
TI  - Low birth weight and maturity: a future marriage of convenience?

PMID- 12466587
TI  - Is Hib vaccination required at all in India?

PMID- 12466589
TI  - Reporting trend of infectious diseases through case reports and brief reports
      published in Indian Pediatrics.

PMID- 12466590
TI  - Antipyretic effect of nimesulide and paracetamol in children.

PMID- 12466592
TI  - Steroids in perinatology.

PMID- 12466594
TI  - Foreign body in the larynx.

PMID- 12466595
TI  - Polymorphism in Cs[AgZn(NCS)4].
AB  - The title compound, caesium silver zinc tetrathiocyanate, crystallizes in two
      polymorphic forms, in space groups P2(1)/n and C2/c. Both structures form a
      continuous three-dimensional network. The structure in C2/c contains a
      delocalized Ag atom in a binuclear-like anion, where two [Ag(NCS)(4)] units
      (delocalized Ag as an average) share two common NCS(-) ligands.

PMID- 12466596
TI  - The channel structure of the mercury(II) selenite(IV) oxide hydrate
      HgSeO3.HgO.1/6H2O.
AB  - The main building units of the title compound, dimercury(II) selenite(IV) oxide
      hydrate, are strongly distorted [Hg1O(6)] and [Hg2O(7)] polyhedra, and a
      pyramidal Se(IV)O(3) group. Slightly corrugated hexagonal rings made up of six
      [Hg1O(6)] octahedra spread parallel to the ab plane and are connected via
      [Hg2O(7)] polyhedra parallel and perpendicular to this direction, which results
      in a three-dimensional arrangement with channels propagating parallel to the c
      axis. The Se(IV)O(3) groups are situated below and above the rings and bridge
      both types of Hg atoms. The non-bonding orbitals are stereochemically active and
      protrude into the channels of the three-dimensional network. Additional water
      molecules are located at the centres of the channels and show weak interactions
      with the Se(IV) lone pairs and the O atoms of the Se(IV)O(3) groups.

PMID- 12466597
TI  - Dichloro[N,N-dimethyl-1-(1-methyl-1H-tetrazol-5-yl-kappaN4)methanamine
      kappaN]copper(II).
AB  - The title compound, [CuCl(2)(C(5)H(11)N(5))], is the first structurally
      characterized molecular chelate complex involving an alpha-aminoalkyltetrazole.
      There are two complex molecules in the asymmetric unit. The ligand molecules are
      bidentate. Both Cu atoms reveal rather distorted square-planar coordinations. The
      complex molecules are linked together by van der Waals interactions only.

PMID- 12466598
TI  - trans-Carbonyliodotris(triphenylstibine-kappaSb)rhodium(I).
AB  - The crystal structure of the title compound, [RhI(C(18)H(15)Sb)(3)(CO)],
      represents a rare example of a crystallographically characterized five-coordinate
      Rh(I)-SbPh(3) complex. The compound crystallizes with the I-Rh-CO core on a
      threefold rotation axis, with three crystallographically equivalent
      triphenylstibine ligands. Selected geometric parameters are: Rh-I = 2.7159 (8),
      Rh-Sb = 2.5962 (4), Rh-C(CO) = 1.825 (6) and C(CO)-O 1.153 (6) A, and Sb-Rh-I =
      89.374 (10) and Sb-Rh-C(CO) = 90.626 (10) degrees. The cone angle of the SbPh(3)
      ligand was determined as 137 degrees, according to the Tolman model.

PMID- 12466599
TI  - An organometallic RhIII complex with a distorted octahedral structure:
      (acetonitrile-kappaN)dimethyl(1,4,7-trimethyl-1,4,7-triazacyclononane
      kappa3N,N',N")rhodium(III) tetraphenylborate.
AB  - In the title compound, [Rh(CH(3))(2)(C(2)H(3)N)(C(9)H(21)N(3))](C(24)H(20)B), the
      geometry around the Rh(III) centre is distorted octahedral, with elongated Rh-N
      bonds trans to the metal-bonded methyl groups. The metal-containing cations are
      located in channels formed by an anionic supramolecular mesh, in which aromatic
      pi-pi interactions between anionic [B(Ph)(4)](-) units play a major role.

PMID- 12466600
TI  - Retroracemization using new forms of Belokon's original ligand: intermediate NiII
      complexes of N-((2-[N-(S)-alkylprolylamino]phenyl)phenylmethylene)-(S)
      phenylalanine (alkyl is 2-picolyl, 3-picolyl or ethyl).
AB  - In the title compounds, [N-(phenyl(2-[N-(S)-(2
      picolyl)prolylamino]phenyl)methylene)-(S)-phenylalaninato]nickel(II),
      [Ni(C(33)H(30)N(4)O(3))], (I), [N-(phenyl(2-[N-(S)-(3
      picolyl)prolylamino]phenyl)methylene)-(S)-phenylalaninato]nickel(II) hemihydrate,
      [Ni(C(33)H(30)N(4)O(3))].0.5H(2)O, (II), and [N-((2-[N-(S)
      ethylprolylamino]phenyl)phenylmethylene)-(S)-phenylalaninato]nickel(II),
      [Ni(C(29)H(29)N(3)O(3))], (III), the Ni(II) centres have approximate square
      planar coordination geometries from N(3)O donor sets. The picolyl N atoms in (I)
      and (II) are too remote from the metal centres to interact significantly, but the
      metal coordination geometries experience tetrahedral distortion and/or
      displacement of the metal centre from the N(3)O plane. These are linked to
      conformational differences between the ligands of the symmetry-independent
      complexes (Z' = 2), which in turn are related to molecular packing. In (III),
      where a less sterically demanding ethyl group replaces the picolyl substituents,
      there are none of the distortions or displacements seen in (I) and (II).

PMID- 12466601
TI  - Bis(tetraphenylphosphonium) bis[cis-1,2-bis(methoxycarbonyl)ethylenedithiolato
      kappa2S,S']nickelate(II) and bis(tetraphenylphosphonium) bis[cis-1,2
      bis(methoxycarbonyl)ethylenedithiolato-kappa2S,S']nickelate(III) iodide.
AB  - The crystal structures of the title compounds,
      (C(24)H(20)P)(2)[Ni(C(6)H(6)O(4)S(2))(2)], (I), and
      (C(24)H(20)P)(2)[Ni(C(6)H(6)O(4)S(2))(2)]I, (II), in the diamagnetic reduced (2-)
      and paramagnetic oxidized (1-) states, are reported at 200 and 293 K,
      respectively. In both compounds, the Ni atom lies on an inversion centre and the
      NiS(4) coordination is thus required to be exactly planar. In the diamagnetic
      complex, (I), the Ni-S distances are 2.1818 (7) and 2.1805 (6) A, while they are
      2.1481 (6) and 2.1392 (5) A in the paramagnetic complex, (II). This results from
      both the different complex core oxidation states and the different conformations
      of the methoxycarbonyl groups.

PMID- 12466602
TI  - Cobalt(II) and nickel(II) complexes of isoquinoline-1-carboxylate.
AB  - trans-Diaquabis(isoquinoline-1-carboxylato-kappa(2)N,O)cobalt(II) dihydrate,
      [Co(C(10)H(6)NO(2))(2)(H(2)O)(2)].2H(2)O, and trans-diaquabis(isoquinoline-1
      carboxylato-kappa(2)N,O)nickel(II) dihydrate,
      [Ni(C(10)H(6)NO(2))(2)(H(2)O)(2)].2H(2)O, contain the same isoquinoline ligand,
      with both metal atoms residing on a centre of symmetry and having the same
      distorted octahedral coordination. In the former complex, the Co-O(water) bond
      length in the axial direction is 2.167 (2) A, which is longer than the Co
      O(carboxylate) and Co-N bond lengths in the equatorial plane [2.055 (2) and 2.096
      (2) A, respectively]. In the latter complex, the corresponding bond lengths for
      Ni-O(water), Ni-O(carboxylate) and Ni-N are 2.127 (2), 2.036 (2) and 2.039 (3) A,
      respectively. Both crystals are stabilized by similar stacking interactions of
      the ligand, and also by hydrogen bonds between the hydrate and coordinated water
      molecules.

PMID- 12466603
TI  - A ruthenium(II)-porphyrin-carbene complex with a weakly bonded methanol ligand.
AB  - The title diphenylcarbene porphyrin complex (diphenylcarbenyl-kappaC)(methanol
      kappaO)(5,10,15,20-tetra-p-tolylporphyrinato-kappa(4)N)ruthenium(II) methanol
      solvate, [Ru(C(13)H(10))(C(48)H(36)N(4))(CH(4)O)].CH(4)O, has a six-coordinate Ru
      atom with a methanol molecule as the second axial ligand. The carbene fragment is
      slightly distorted from an ideal sp(2) configuration, with a C(phenyl)-C(carbene)
      C(phenyl) angle of 112.2 (3) degrees. The Ru-C bond length of 1.845 (3) A is
      comparable with other carbene complexes. The two phenyl rings of the carbene
      ligand are perpendicular to the carbene plane. Methanol solvate molecules link
      the methanol ligands of adjacent porphyrin complexes via hydrogen bonds.

PMID- 12466604
TI  - [5-Benzyl-3-phenyl-2-(2-pyridyl-kappaN)thiazolidin-4-one
      kappaS]dichloropalladium(II).
AB  - The palladium(II) centre in the title compound, [PdCl(2)(C(21)H(18)N(2)OS)], is
      coordinated to the pyridyl N atom and to the thiazolidinone S atom of the 5
      benzyl-3-phenyl-2-(2-pyridyl)thiazolidin-4-one ligand, resulting in a five
      membered chelate ring. Two cis-chloro ligands complete the square-planar
      coordination environment of the metal. Although the geometry at the Pd centre is
      essentially planar, the N-Pd-S bite angle of 85.20 (8) degrees causes deviations
      in the cis angles from the ideal value of 90 degrees. Opposite enantiomers form
      one-dimensional chains in the cell via a short S.O intermolecular interaction.

PMID- 12466605
TI  - trans-Bis[1-methyl-3-(p-nitrophenyl)triazenido 1-oxide
      kappa2N3,O]dipyridinenickel(II).
AB  - In the centrosymmetric title complex, [Ni(C(7)H(7)N(4)O(3))(2)(C(5)H(5)N)(2)],
      the coordination geometry about the Ni(2+) ion is octahedral, with two
      deprotonated 1-methyl-3-(p-nitrophenyl)triazenide 1-oxide ions, viz.
      [O(2)NC(6)H(4)NNN(O)CH(3)](-), acting as bidentate ligands (four-electron
      donors). Two neutral pyridine (py) molecules complete the coordination sphere in
      positions trans to each other. The triazenide 1-oxide ligand is almost planar,
      the largest interplanar angle of 8.80 (12) degrees being between the phenyl ring
      of the p-nitrophenyl group and the plane defined by the N(3)O moiety. The Ni
      N(triazenide), Ni-O and Ni-N(py) distances are 2.0794 (16), 2.0427 (13) and
      2.1652 (18) A, respectively.

PMID- 12466606
TI  - [2,2'-(1,3,5,8,10,12-Hexaazacyclotetradecane-3,10-diyl)diethanol
      kappa4N1,N5,N8,N12]bis(thiocyanato-kappaS)copper(II).
AB  - In the crystal structure of the title compound, [Cu(NCS)(2)(C(12)H(30)N(6)O(2))],
      the Cu atom lies on an inversion centre and has an elongated octahedral
      coordination, with Cu-N distances of 2.004 (2) and 2.015 (2) A, and a Cu-S
      distance of 2.9696 (10) A. The 2,2'-ethanol chains are axially oriented. The
      molecules are linked to form a three-dimensional network via O-H.N, N-H.O and N
      H.S hydrogen bonds.

PMID- 12466607
TI  - catena-Poly[tris(ethylenediamine-kappa2N,N')nickel(II) [[trithiocyanato-kappa3N
      sodium(I)]-mu-aqua-kappa2O:O]].
AB  - The title complex, ([Ni(C(2)H(8)N(2))(3)][Na(NCS)(3)(H(2)O)])(n), consists of
      discrete [Ni(en)(3)](2+) dications (en is ethylenediamine) and polymeric
      [(H(2)O)(0.5)Na(NCS)(3)(H(2)O)(0.5)](n)(2n-) anions. The compound crystallizes in
      space group P-3c1. The Ni(II) atom lies on a threefold axis and has a distorted
      octahedral coordination geometry. The Na(+) cation also lies on a site with
      imposed crystallographic threefold symmetry and is coordinated by the thiocyanate
      N atoms (the thiocyanates are in general positions), by one water molecule with
      crystallographically imposed 32 symmetry and by a second water molecule with
      crystallographically imposed -3 symmetry. The unique Na atom thus has trigonal
      bipyramidal coordination. The O atoms of the water molecules bridge the Na(+)
      cations to form one-dimensional polymeric chains in the crystal structure. The
      [Ni(en)(3)](2+) dications are distributed around and between the chains and are
      linked to them via N-H.S hydrogen bonds.

PMID- 12466608
TI  - A lariat-functionalized copper(II) diimine-dioxime complex.
AB  - The dimeric title copper(II) complex, diaqua-1kappaO,2kappaO-bis[3,9-dimethyl-6
      (2-pyridylmethyl)-4,8-diazaundeca-3,8-diene-2,10-dione dioximato(1-)]
      1k(4)N(2),N(4),N(8),N(10);1:2kappa(5)O(2):N(2),N(4),N(8),N(10)-dicopper(II)
      diperchlorate, [Cu(2)(C(17)H(24)N(5)O(2))(2)](ClO(4))(2), crystallizes with one
      Cu atom in a square-pyramidal environment and the other Cu atom displaying a
      distorted octahedral coordination. In each case, the four N atoms in the core of
      the ligand (two imine and two oxime N atoms) form the base of the pyramid, with a
      water molecule at an apex. The two parts of the dimer are linked by an
      interaction [2.869 (2) A] between one of the Cu atoms and one of the oxime O
      atoms coordinated to the second Cu atom, and also by a hydrogen bond between the
      apical water molecule on the second Cu atom and the pyridyl N atom from the
      coordination sphere of the first Cu atom. The pyridyl N atoms of the lariat arms
      are not coordinated to either of the Cu atoms. Thus, this potentially
      pentadentate ligand is only tetradentate when coordinated to Cu(II).

PMID- 12466609
TI  - Lead tartrate from X-ray powder diffraction data.
AB  - The structure of lead tartrate, Pb(2+).C(4)H(4)O(6)(2-), has been solved from X
      ray powder diffraction data. The cation exhibits ninefold coordination and the
      tartrate groups are linked through Pb.O contacts to form a three-dimensional
      network.

PMID- 12466610
TI  - Monosodium [1-hydroxy-2-(1H-imidazol-3-ium-4-yl)ethane-1,1-diyl]bis(phosphonate)
      tetrahydrate (monosodium isozoledronate).
AB  - The title compound, Na(+).C(5)H(9)N(2)O(7)P(2)(-).4H(2)O, is an isomer of
      zoledronate, a potent bone antiresorptive bisphosphonate drug having significant
      activity against several parasitic protozoa. The crystal structure of
      isozoledronate consists of bisphosphonate dimers coordinated by two Na(+) ions.
      The dimers are held together through an extensive hydrogen-bonding network. The
      crystals exhibit non-merohedral twinning that roughly superimposes the a and b
      axes, and inverts the c axis.

PMID- 12466611
TI  - Solvent-metal interactions in bis[1,2-dicarba-closo-dodecaboran(12)-1
      yl]mercury(II) dichloromethane solvate and bis[1,12-dicarba-closo-dodecaboran(12)
      1-yl]mercury(II) tetrahydrofuran solvate.
AB  - The title compounds, bis[1,2-dicarba-closo-dodecaboran(12)-1-yl]mercury(II)
      dichloromethane solvate, [Hg(C(2)B(10)H(11))(2)].CH(2)Cl(2), (I), and bis[1,12
      dicarba-closo-dodecaboran(12)-1-yl]mercury(II) tetrahydrofuran solvate,
      [Hg(C(2)B(10)H(11))(2)].C(4)H(8)O, (II), were prepared in excellent yields using
      a robust synthetic procedure involving the reaction of HgCl(2) with the
      appropriate monolithiocarborane. X-Ray analysis of the products revealed strong
      interactions between the Hg atoms in both complexes and the respective lattice
      solvent. The distances between the Hg(II) centers and the Cl atoms of the
      dichloromethane solvent molecule in the ortho-carborane derivative, (I), and the
      O atom of the tetrahydrofuran molecule in the para-carborane complex, (II), are
      shorter than the sums of the van der Waals radii for Hg and Cl (3.53 A), and Hg
      and O (3.13 A), respectively, indicating moderately strong interactions. There
      are two crystallographically independent molecules in the asymmetric unit of both
      compounds, which, in each case, are related by differing relative positions of
      the cages.

PMID- 12466612
TI  - A novel one-dimensional coordination polymer, catena-poly[[diaquacobalt(II)]-mu
      (2,2'-bipyridyl-3,3'-dicarboxylato-kappa4N,N':O,O')].
AB  - The title compound, [Co(C(12)H(6)N(2)O(4))(H(2)O)(2)](n), has been hydrothermally
      synthesized and structurally characterized. It consists of polymeric chains of
      [Co(mu-(2,2'-bipyridyl-3,3'-dicarboxylato-kappa(4)N,N':O,O'))(H(2)O)(2)] units,
      in which each Co(II) cation is octahedrally coordinated by two chelating pyridyl
      N atoms, two chelating carboxyl O atoms from different carboxylate groups of
      another bipyridyl ligand, and two water molecules as terminal ligands. A
      crystallographic twofold axis parallel to the chain axis, passes through the Co
      atom.

PMID- 12466613
TI  - A novel one-dimensional coordination polymer with Cd2+ and
      diethylenetriaminepentaacetic acid.
AB  - catena-Poly[[[bis[diaqua(4,4'-bipyridine)cadmium(II)]-bis[mu-(N"
      carboxymethyldiethylenetriamine-N,N,N',N"-tetraacetato)cadmium(II)]]-mu-4,4'
      bipyridine] tetradecahydrate],
      [Cd(4)(C(14)H(19)N(3)O(10))(2)(C(10)H(8)N(2))(3)(H(2)O)(4)].14H(2)O or
      [Cd(4)(HDTPA)(2)(BPY)(3)(H(2)O)(4)].14H(2)O, where BPY is 4,4'-bipyridine and
      HDTPA(4-) is N"-carboxymethyldiethylenetriamine-N,N,N',N"-tetraacetate, consists
      of a one-dimensional coordination polymer formed from a secondary building unit
      which comprises four Cd centres. The chain structure of the title compound was
      obtained by the use of a multidentate organic ligand, N,N,N',N",N"
      diethylenetriaminepentaacetic acid (H(5)DTPA), which forms multiple chelate rings
      with the Cd metal centres. An extended network is formed via hydrogen bonds.

PMID- 12466614
TI  - Hexaamminecobalt(III) aquabis(nitrilotriacetato-kappa4N,O,O',O")gadolinate(III)
      octahydrate.
AB  - Crystals of the title compound,
      [Co(NH(3))(6)][Gd(C(6)H(6)NO(6))(2)(H(2)O)].8H(2)O, were synthesized in and
      collected from aqueous solution. The hexaamminecobalt(III) cation has the
      expected octahedral geometry, while the Gd coordination sphere has the geometry
      of a tricapped trigonal prism, with the two nitrilotriacetate N atoms and one
      water molecule occupying the capping positions.

PMID- 12466615
TI  - Ammonium 4-nitrophenylarsonate.
AB  - In the crystal structure of the title compound,
      (NH(4))[AsO(2)(OH)(C(6)H(4)NO(2))], the 4-nitrophenylarsonate anions and ammonium
      cations are linked through hydrogen bonds to form infinite chains along the b
      axis. The hydroxyl O atom of the 4-nitrophenylarsonate anion acts as both an
      acceptor and a donor of hydrogen bonds. All atoms are located in general
      positions.

PMID- 12466616
TI  - catena-Poly[[tetraaquairon(II)]-mu-succinato-kappa2O:O'].
AB  - The title complex, ([Fe(C(4)H(4)O(4))(H(2)O)(4)])(n), is an infinite polymeric
      compound bridged by the succinate dianion. Two carboxylate groups coordinate in a
      monodentate manner to the Fe(II) atom, in a trans fashion, with an O-Fe-O bond
      angle of 175.72 (6) degrees and Fe-O distances of 2.0886 (14) and 2.1008 (15) A.
      One of the uncoordinated carboxylate O atom forms an intramolecular hydrogen bond
      with a coordinated water molecule. Extensive hydrogen bonding between parallel
      polymeric complex chains results in a three-dimensional supramolecular structure.

PMID- 12466617
TI  - trans-4-Acetylcyclohexanecarboxylic acid and (+/-)-trans-2
      acetylcyclohexanecarboxylic acid: hydrogen-bonding patterns in two isomeric keto
      acids.
AB  - Both title compounds, C(9)H(14)O(3), display carboxyl-dimer hydrogen-bonding
      patterns. The 4-acetyl isomer adopts a chiral conformation with negligible
      disordering of the methyl and carboxyl groups and forms centrosymmetric dimers
      across the b and c edges of the chosen cell [O.O = 2.667 (3) A and O-H.O = 175
      degrees ]. Intermolecular C-H.O close contacts were found for both carbonyl
      groups. In the 2-acetyl isomer, there is no intramolecular interaction between
      the carboxyl and acetyl groups and the hydrogen bonding involves centrosymmetric
      carboxyl dimerization across the ab and ac faces of the chosen cell [O.O = 2.668
      (2) A and O-H.O = 173 degrees ]. The carboxyl group is negligibly disordered, but
      significant rotational disordering was found for the acetyl methyl group. An
      intermolecular C-H.O close contact was found involving the ketone group.

PMID- 12466618
TI  - C-H...N and C-H...pi interactions in 2-ethoxy-4,6-diphenylpyridine-3
      carbonitrile.
AB  - The title compound, C(20)H(16)N(2)O, has two molecules in the asymmetric unit and
      the crystal structure shows that the central pyridine ring of each molecule has a
      flat boat conformation. The terminal C atom in one of the molecules is disordered
      over two positions, with relative occupancies of 0.594 (14) and 0.398 (14).
      Intermolecular C-H.N and C-H.pi interactions and pi-pi stacking, along with
      intramolecular C-H.N and C-H.pi interactions, help to stabilize the structure.

PMID- 12466619
TI  - Trimethyl[3-methyl-1-(o-tolenesulfonyl)indol-2-ylmethyl]ammonium iodide and
      benzyl[3-bromo-1-(phenylsulfonyl)indol-2-ylmethyl]tolylamine.
AB  - The title compounds, C(20)H(25)N(2)O(2)S(+).I(-), (I), and C(29)H(25)BrN(2)O(2)S,
      (II), respectively, both crystallize in space group P-1. The pyrrole ring
      subtends an angle with the sulfonyl group of 33.6 degrees in (I) and 21.5 degrees
      in (II). The phenyl ring of the sulfonyl substituent makes a dihedral angle with
      the best plane of the indole moiety of 81.6 degrees in (I) and 67.2 degrees in
      (II). The lengthening or shortening of the C-N bond distances in both compounds
      is due to the electron-withdrawing character of the phenylsulfonyl group. The S
      atoms are in distorted tetrahedral configurations. The molecular structures are
      stabilized by C-H.O and C-H.I interactions in (I), and by C-H.O and C-H.N
      interactions in (II).

PMID- 12466620
TI  - 2-(Pyrrolidin-1-yl)-1,4-naphthoquinone and 2-phenylsulfanyl-3-(pyrrolidin-1-yl)
      1,4-naphthoquinone.
AB  - The structure of 2-(pyrrolidin-1-yl)-1,4-naphthoquinone,
      C(14)H(12.95)Cl(0.05)NO(2), (I), is actually a 0.95:0.05 mixture including 2
      chloro-3-(pyrrolidin-1-yl)-1,4-naphthoquinone as a minor impurity, but (I) was
      resolved as a single molecule containing a Cl atom with 5% occupancy at the 3
      position. Compound (I) was prepared from the fully chloro-substituted analogue in
      an attempt to produce the disubstituted pyrrolidinyl derivative. 2-Phenylsulfanyl
      3-(pyrrolidin-1-yl)-1,4-naphthoquinone, C(20)H(17)NO(2)S, (II), was also prepared
      from 2-chloro-3-(pyrrolidin-1-yl)-1,4-naphthoquinone, using a strong exocyclic
      nucleophile. The structure of (II) differs from previous structures of 2,3
      dichloro-1,4-naphthoquinone and its derivatives in that the naphthoquinone ring
      is non-planar.

PMID- 12466621
TI  - Azadirachtol, a tetranortriterpenoid from neem kernels.
AB  - The title compound, dimethyl (-)-(2aR,3R,4R,4aS,5R,7aS,8R,10S,10aR)-3,8,10
      trihydroxy-4-[(2R,6R)-2-hydroxy-11-methyl-5,7,10
      trioxatetracyclo[6.3.1.0(2,6)0(9,11)]dodec-3-en-9-yl]-4
      methylperhydroisobenzofurano[5,4,3a-cd]isobenzofuran-5,10a-diacetate,
      C(28)H(36)O(13), which exhibits higher antifeedant activity than azadirachtin-A,
      a known potent antifeedant, was isolated from neem kernels. The asymmetric unit
      of the structure contains two independent molecules, which differ in the
      conformations of their functional groups and also in the conformations of some of
      the rings. The relative orientation between the decalin and furanyl moieties is
      similar to that observed in the majority of azadirachtin structures, but is
      different from that in azadirachtin-A. The two symmetry-independent molecules are
      linked into dimeric units by intermolecular O-H.O hydrogen bonds.

PMID- 12466622
TI  - 4,1',6'-Trichloro-4,1',6'-trideoxysucrose monohydrate.
AB  - At 160 K, the glucopyranosyl ring in 1,6-dichloro-1,6-dideoxy-beta-D
      fructofuranosyl 4-chloro-4-deoxy-alpha-D-glucopyranoside monohydrate,
      C(12)H(19)Cl(3)O(8).H(2)O, has a near ideal (4)C(1) chair conformation, while the
      fructofuranosyl ring has a (4)T(3) conformation. The conformation of the sugar
      molecule is quite different to that of sucralose, particularly in the
      conformation about the glycosidic linkage, which affects the observed pattern of
      intramolecular hydrogen bonds. A complex series of intermolecular hydrogen bonds
      links the sugar and water molecules into an infinite three-dimensional framework.

PMID- 12466623
TI  - 5-[Acetamido(phenyl)methyl]-5-methylimidazolidine-2,4-dione.
AB  - The title compound, alternatively named N-[(4-methyl-2,5-dioxoimidazolidin-4
      yl)(phenyl)methyl]acetamide, C(13)H(15)N(3)O(3), crystallizes in the
      centrosymmetric space group P2(1)/c with one molocule in the asymmetric unit. The
      imidazolidine-2,4-dione system is essentially planar, as evidenced by NMR
      studies. The dihedral angle between the planes of the imidazolidine and phenyl
      rings is 23.3 (1) degrees, while the dihedral angle between the acetamide side
      chain and the imidazolidine ring is 60.7 (1) degrees. The molecular structure and
      packing is stabilized by C-H.O and N-H.O interactions. Intermolecular hydrogen
      bonds form cyclic dimers, with graph-set descriptor R(2)(2)(8), and a chain of
      C(7).

PMID- 12466624
TI  - 2,3,3',6-Tetra-O-acetyl-4,1',6'-trichloro-4,1',4',6'-tetradeoxygalactosucrose.
AB  - At 160 K, one of the Cl atoms in the furanoid moiety of 3-O-acetyl-1,6-dichloro
      1,4,6-trideoxy-beta-D-fructofuranosyl 2,3,6-tri-O-acetyl-4-chloro-4-deoxy-alpha-D
      galactopyranoside, C(20)H(27)Cl(3)O(11), is disordered over two orientations,
      which differ by a rotation of about 107 degrees about the parent C-C bond. The
      conformation of the core of the molecule is very similar to that of 3-O-acetyl
      1,4,6-trichloro-1,4,6-trideoxy-beta-D-tagatofuranosyl 2,3,6-tri-O-acetyl-4-chloro
      4-deoxy-alpha-D-galactopyranoside, particularly with regard to the conformation
      about the glycosidic linkage.

PMID- 12466625
TI  - Ethyl 3,5-dimethyl-4-phenyl-1H-pyrrole-2-carboxylate.
AB  - In the title compound, C(15)H(17)NO(2), the ethoxycarbonyl group is anti with
      respect to the pyrrole N atom. The angle between the planes of the phenyl and
      pyrrole rings is 48.26 (9) degrees. The molecules are joined into dimeric units
      by a strong hydrogen bonds between pyrrole N-H groups and carbonyl O atoms. The
      geometry of the isolated molecule was studied by ab initio quantum mechanical
      calculations, employing both molecular orbital Hartree-Fock (MO-HF) and density
      functional theory (DFT) methods. The minimum energy was achieved for a
      conformation where the angle between the planes of the phenyl and pyrrole rings
      is larger, and that between the ethoxycarbonyl and pyrrole planes is smaller than
      in the solid-state molecule.

PMID- 12466626
TI  - 2-Hydroxy-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium-4-yl)benzoate
      monohydrate.
AB  - The title molecule, C(13)H(13)N(3)O(3).H(2)O, is in the form of a monohydrated
      zwitterion. The tetrahydropyridinium ring adopts an envelope conformation and is
      nearly coplanar with the plane of the imidazoline ring. The water solvate
      molecule plays an important role as a bridge between zwitterions, forming
      molecular chains running along the c direction, which are interconnected by N-H.O
      hydrogen bonds into molecular ribbons. The crystal packing is further stabilized
      by another N-H.O and one O-H.N hydrogen bond, which interconnect the molecular
      ribbons.

PMID- 12466627
TI  - 16-[3-Methoxy-4-(2-piperidin-1-ylethoxy)benzylidene]-17-oxoandrost-5-en-3beta-yl
      acetate monohydrate.
AB  - The title compound, C(36)H(49)NO(5).H(2)O, has the outer two six-membered rings
      of the steroid nucleus in chair conformations. The central ring B of the steroid
      nucleus is in an 8beta,9alpha-half-chair conformation, while ring D of the
      steroid adopts a slightly distorted 13beta,14alpha-half-chair conformation. The
      piperidine ring is in a chair conformation. The methoxybenzylidene moiety has an
      E configuration with respect to the carbonyl group at position 17. Intermolecular
      O-H.O and O-H.N hydrogen bonds link the steroid and water molecules into chains
      which run parallel to the b axis.

PMID- 12466628
TI  - 2,4-Diamino-5-(1-naphthyl)-3,5-diaza-1-azoniaspiro[5.5]undeca-1,3-diene chloride.
AB  - The title salt, C(18)H(22)N(5)(+).Cl(-), is a member of a new series of
      lipophilic 4,6-diamino spiro-s-triazines which are potent inhibitors of
      dihydrofolate reductase. The protonated triazine ring deviates from planarity,
      whereas the cyclohexane ring adopts a chair conformation. A rather unusual
      hydrogen-bonding scheme exists in the crystal. There is a centrosymmetric
      arrangement involving two amino groups and two triazine ring N atoms, with graph
      set R(2)(2)(8) and an N.N distance of 3.098 (3) A, flanked by two additional
      R(3)(2)(8) systems, involving two amino groups, a triazine ring N atom and a Cl(
      ) anion, with N.Cl distances in the range 3.179 (2)-3.278 (2) A. Furthermore, the
      Cl(-) anion, the protonated triazine ring N atom and an amino group form a
      hydrogen-bonding system with graph-set R(2)(1)(6).

PMID- 12466629
TI  - Redetermination of (6R,7S,9S,11S)-(-)-sparteinium monoperchlorate.
AB  - The structure of the title compound, C(15)H(27)N(2)(+).ClO(4)(-), consists of a
      monoprotonated sparteinium cation and a perchlorate anion. The two tertiary N
      atoms of the cation, one perchlorate O atom and a H atom form a bifurcated
      hydrogen bond, the four hydrogen-bonding atoms being nearly in the same plane.

PMID- 12466630
TI  - Hydrogen-bonded one-dimensional networks in 1:1 complexes of N,N'-bis(2
      pyridyl)aryldiamines with anilic acid.
AB  - The 1:1 complexes N,N'-bis(2-pyridyl)benzene-1,4-diamine-anilic acid (2,5
      dihydroxy-1,4-benzoquinone) (1/1), C(16)H(14)N(4).C(6)H(4)O(4), (I), and N,N'
      bis(2-pyridyl)biphenyl-4,4'-diamine-anilic acid (1/1),
      C(22)H(18)N(4).C(6)H(4)O(4), (II), have been prepared and their solid-state
      structures investigated. The component molecules of these complexes are connected
      via conventional N-H.O and O-H.N hydrogen bonds, leading to the formation of an
      infinite one-dimensional network generated by the cyclic motif R(2)(2)(9). The
      anilic acid molecules in both crystal structures lie around inversion centres and
      the observed bond lengths are typical for the neutral molecule. Nevertheless, the
      pyridine C-N-C angles [120.9 (2) and 120.13 (17) degrees for complexes (I) and
      (II), respectively] point to a partial H-atom transfer from anilic aicd to the
      bispyridylamine, and hence to H-atom disorder in the OHN bridge. The
      bispyridylamine molecules of (I) and (II) also lie around inversion centres and
      exhibit disorder of their central phenyl rings over two positions.

PMID- 12466632
TI  - Management of recurrent depression in primary care.

PMID- 12466633
TI  - Peptic ulcer disease and neuroticism in the United States adult population.
AB  - BACKGROUND: The goal of the current study was to determine the association
      between personality factors and peptic ulcer disease (PUD) among adults in the
      general population. METHOD: Data were drawn from the Midlife Development in the
      United States Survey (MIDUS), a representative household survey of the adult
      population (ages 25-74; n = 3,032) of the United States. Multiple logistic
      regression analyses were used to determine the association between the big five
      personality factors and PUD, adjusting for differences in sociodemographic
      characteristics, psychiatric and physical comorbidity. RESULTS: Neuroticism was
      associated with significantly increased odds of PUD [OR = 1.5 (95% CI: 1.03,
      2.4)], which persisted after controlling for differences in sociodemographic
      characteristics, cigarette smoking, perception of poor health, comorbid mental
      disorders and physical illnesses. This relationship was specific to neuroticism.
      CONCLUSIONS: These findings are consistent with and extend previous clinical and
      epidemiologic data by providing evidence of an independent association between
      neuroticism and PUD among adults in the general population. Future work
      investigating the relationship between neuroticism and the development of PUD in
      prospective data, including objective measures of physical and mental health
      status, may contribute to our understanding of this association.

PMID- 12466634
TI  - Suicidal tendencies and body image and experience in anorexia nervosa and
      suicidal female adolescent inpatients.
AB  - BACKGROUND: The aim of this study was to assess the relationship between body
      image and suicidal tendencies in anorexia nervosa (AN). METHODS: Three groups of
      hospitalized female adolescents--nonsuicidal AN, suicidal psychiatric and
      nonsuicidal psychiatric patients, as well as a community control group with no
      psychiatric disturbances were compared with regard to suicidal tendencies (in the
      form of attitudes to life and death), body image and experience, depression and
      anxiety. RESULTS: The AN and suicidal patients showed less attraction to but more
      repulsion by life, and more attraction to and less repulsion by death compared
      with the other two groups. The AN and suicidal patients were also different from
      either one or both control groups in showing more negative attitudes and feelings
      towards their bodies, lower sensitivity to body clues, less body control, and
      elevated depression and anxiety. These between-group differences in suicidal
      tendencies were retained after controlling for age, body mass index, the
      different body image dimensions, anxiety and depression. CONCLUSIONS: Our
      findings suggest that female AN inpatients with no evidence of overt suicidal
      behavior demonstrate elevated suicidal tendencies that are similar to those of
      suicidal psychiatric inpatients. These self-destructive tendencies are highly
      associated with a pervasive sense of disturbance of body image and experience.

PMID- 12466635
TI  - Bulimia and impulsive behaviour in middle adolescence.
AB  - BACKGROUND: In clinical samples, bulimia seems to be associated with various
      dyscontrol behaviours suggesting weakness in impulse control. Population studies
      of adolescents, however, are needed. We evaluated the association between self
      reported bulimic behaviour and a number of dyscontrol behaviours, namely
      bullying, truancy, excessive drinking and sexual disinhibition among adolescents
      aged 14-16. This is the first study on bulimia and impulsivity in a large non
      selected adolescent population sample. METHODS: A self-report questionnaire was
      administered to a representative population sample of 14- to 16-year-old
      adolescents (pupils of the 8th and the 9th grades of secondary school in four
      different regions in Finland). 4,453 girls and 4,334 boys aged 14-16
      participated. The participation rate was 85.5%. RESULTS: Bulimic behaviour was
      associated with bullying, truancy, excessive drinking and sexual disinhibition
      among both sexes. Odds ratios for bulimic-type eating pathology according to each
      of these behaviours varied between 1.7 and 4.1. The more dyscontrol behaviours
      occurred simultaneously, the more likely was bulimic-type eating pathology.
      CONCLUSIONS: There is an association between bulimic behaviour and dyscontrol
      behaviours in the general population of adolescent girls and boys.

PMID- 12466636
TI  - Increased probability of remaining in remission from panic disorder with
      agoraphobia after drug treatment in patients who received concurrent cognitive
      behavioural therapy: a follow-up study.
AB  - BACKGROUND: Many short-term trials suggested that the combination of
      psychotherapy with medication might be more effective than either treatment
      alone. However, only few studies examined the long-term effectiveness of this
      combination. METHODS: A private practice sample of consecutive patients with DSM
      III-R panic disorder with agoraphobia who achieved remission after drug treatment
      with or without concurrent cognitive-behavioural psychotherapy were followed up.
      Patients were assessed before treatment, after treatment and at each follow-up
      contact with the Marks-Sheehan Phobia Scale, the Hamilton Anxiety Rating Scale,
      and the Hamilton Depression Rating Scale. Kaplan-Meier survival analysis was
      performed on the time to panic disorder relapse. Cox regression analysis was used
      to control for the possible confounding effect of factors other than treatment.
      RESULTS: Of patients who received medication alone (n = 32), 25 (78.1%) relapsed,
      prevalently (65.6%) during the first year. The estimated mean survival time was
      12 months (95% CI 7-17). Of patients who received integrated treatment (n = 21),
      only 3 (14.3%) relapsed. The estimated mean survival time was 65 months (95% CI
      44-86). Treatment was the only variable associated with the occurrence of
      relapse, with a hazard ratio of 12.6 (95% CI 2.5-63.3) for patients who received
      only medication. CONCLUSIONS: Some methodological limitations, such as treatment
      allocation by preference, suggest caution in the interpretation of our results.
      However, the long-term therapeutic advantage of integrated treatment over
      medication alone was large and independent from known prognostic factors. The
      long-term effectiveness of integrated treatment should be tested with a
      randomised controlled trial.

PMID- 12466637
TI  - Treating medication-resistant panic disorder: predictors and outcome of cognitive
      behavior therapy in a Brazilian public hospital.
AB  - BACKGROUND: In Brazil, treatment of panic disorder is most frequently initiated
      with pharmacotherapy, but only half of the patients can be expected to be panic
      free after medication. Studies have suggested that individual or group cognitive
      behavior therapy (CBT) is an effective treatment strategy for panic patients who
      have failed to respond to pharmacotherapy. METHODS: Thirty-two patients diagnosed
      with panic disorder with agoraphobia having residual symptoms despite being on an
      adequate dose of medication were treated with 12 weeks of group CBT. The outcome
      was evaluated for panic frequency and severity, generalized anxiety, and global
      severity. Comorbid conditions, a childhood history of anxiety, and defense
      mechanism styles were assessed as potential predictors of treatment response.
      RESULTS: Twenty-nine patients completed the 12-week protocol. Treatment was
      associated with significant reductions in symptom severity on all outcome
      measures (p < 0.001). Patients with depression had a poorer outcome of the
      treatment (p = 0.01) as did patients using more neurotic (p = 0.002) and immature
      defenses (p = 0.05). CONCLUSION: Consistent with previous reports, we found that
      CBT was effective for our sample of treatment-resistant patients. Among these
      patients, depression as well as neurotic defense style was associated with a
      poorer outcome. The use of CBT in Brazil for treatment-resistant and other panic
      patients is encouraged.

PMID- 12466638
TI  - A longitudinal study of hormonal reactions accompanying life events in recently
      resettled refugees.
AB  - BACKGROUND: Refugees constitute a growing section of the general population in
      many countries. It is therefore important to study which factors in everyday life
      are important to recently resettled refugees after they have been granted
      residence. METHODS: Life events from a checklist, as well as categories derived
      from written responses to open-ended questions were analysed (repeated-measures
      ANOVA). Changes over time in mean serum/plasma concentrations of cortisol,
      thyroxine, prolactin, and dehydroepiandrosterone sulphate (DHEA-S) were compared
      in subjects with and without the reported events. RESULTS: Distress in
      significant others (close friends or first-degree relatives) and a perception of
      excessive demands in everyday life were associated with increases in serum
      cortisol. Events associated with decreased levels of prolactin were typically
      situations of strain in relation to authorities or individuals to which the
      subjects were in a position of dependency. DHEA-S changed in opposite directions
      in post-traumatic stress disorder (PTSD) and non-PTSD subjects. DHEA-S also
      changed with positive events. CONCLUSIONS: Distress in significant others and a
      too demanding everyday life lead to significant changes in the stress-responsive
      hormones cortisol, prolactin and DHEA-S. Since DHEA-S behaves differently in
      PTSD, this condition is a potential confounder in studies of DHEA-S with an
      unknown proportion of PTSD among participants.

PMID- 12466639
TI  - Radioprotectants: current status and new directions.
AB  - The ability to prevent radiotherapy-induced toxicity without affecting antitumor
      efficacy has the potential to enhance the therapeutic benefit for cancer patients
      without increasing their risk of serious adverse effects. Among the currently
      available cytoprotective agents capable of protecting normal tissue against
      damage caused by either chemo- or radiotherapy, only amifostine has been shown in
      clinical trials to reduce radiation-induced toxicity. Most notably, it reduces
      the incidence of xerostomia, which is a clinically significant long-term toxicity
      arising in patients undergoing irradiation of head and neck cancers. In vitro
      studies with the active metabolite of amifostine (WR-1065) have shown it to
      prevent both radiation-induced cell death and radiation-induced mutagenesis. The
      potential of this agent to prevent secondary tumors, as well as other radiation
      induced toxicities is now the focus of ongoing research. Among other novel
      approaches to radioprotection being explored are methods to increase levels of
      the antioxidant mitochondrial enzyme manganese superoxide dismutase (MnSOD). In
      addition, the use of epoetin alfa, alone or in combination with cytoprotectants
      (e.g., amifostine), to treat radiation-induced anemia is also being investigated.
      The objective of developing newer cytoprotective therapies is to improve the
      therapeutic ratio by reducing the acute and chronic toxicities associated with
      more intensive and more effective anticancer therapies.

PMID- 12466640
TI  - Prevalence of anemia in cancer patients undergoing radiotherapy: prognostic
      significance and treatment.
AB  - As the antitumor activity of radiation is mediated via its interaction with
      oxygen to form labile free radicals, the intratumoral oxygen level has an
      important influence on the ability of radiation therapy to kill malignant cells.
      By decreasing the oxygen-carrying capacity of the blood, anemia may result in
      tumor hypoxia and may have a negative influence on the outcome of radiotherapy
      for various malignancies, even for small tumors not normally assumed to be
      hypoxic. In addition, anemia also has a negative effect on the quality of life of
      cancer patients, as evidenced by worsening fatigue. As a high proportion (about
      50%) of cancer patients undergoing radiotherapy are anemic prior to or during
      treatment, strategies to correct anemia and/or the resultant tumor hypoxia are
      increasingly being considered an important component of treatment. In particular,
      epoetin alfa (recombinant human erythropoietin), which has proved an effective
      and well-tolerated means of raising hemoglobin levels in anemic patients
      receiving radiotherapy, potentially could reverse the negative prognostic
      influence of a low hemoglobin in patients with certain malignancies. Radiation
      oncologists need to be aware of the possibility of anemia in cancer patients
      undergoing radiotherapy so that timely intervention can be instituted whenever
      anemia is diagnosed.

PMID- 12466641
TI  - Raising hemoglobin: an opportunity for increasing survival?
AB  - Although the association between low hemoglobin levels and poorer outcomes in
      radiation oncology has long been recognized, anemia is often overlooked and
      untreated. However, a growing body of clinical evidence now indicates that low
      hemoglobin levels during radiation treatment are associated with decreased
      response and survival following radiotherapy. For example, a large Canadian
      retrospective study in patients receiving radical radiotherapy for cervical
      cancer showed that the 5-year survival rate was 19% higher in those whose
      hemoglobin during radiation treatment was =12 g/dl compared to those with levels
      <12 g/dl. The data suggest that clinical trials need to be performed to determine
      whether increasing hemoglobin levels leads to improved local control and
      survival. The mechanism by which low hemoglobin levels could cause poorer
      outcomes is not well understood and needs further elucidation. It is postulated
      that lower hemoglobin levels resulting in decreased oxygen carrying capacity may
      lead to increased tumor hypoxia, radiation resistance and increased tumor
      angiogenesis. The interrelationship of low hemoglobin levels, hypoxia, tumor
      angiogenesis and survival is explored in this article.

PMID- 12466642
TI  - New chemotherapeutic agents: update of major chemoradiation trials in solid
      tumors.
AB  - The institution of combined modality therapy for unresected solid tumors has
      resulted in significant improvements in tumor control and survival benefit
      compared with radiotherapy (RT) alone. A number of chemotherapy agents that can
      enhance the effectiveness of RT, such as cisplatin and 5-fluorouracil, are now
      considered standard treatment for patients with a number of cancer types. There
      is growing interest in a number of additional agents that have also been found to
      have radiosensitizing ability. These include paclitaxel, docetaxel, irinotecan,
      gemcitabine, and vinorelbine, as well as biologic agents. Other agents may be of
      value because they act to counter dose-limiting toxicities associated with RT.
      This article provides an update of some important, recently completed and ongoing
      clinical trials evaluating novel chemoradiation protocols, with examples taken
      primarily from studies conducted by the Radiation Therapy Oncology Group (RTOG).
      Theoretical approaches to the development of new agents and combined modality
      regimens are also discussed.

PMID- 12466643
TI  - An Assessment of House Staff's Knowledge of Alcohol and Substance Abuse Utilizing
      Standardized Patients.
AB  - Utilizing standardized patients (SPs), house staff knowledge of alcohol and
      substance abuse was assessed in residents just prior to their starting their
      first graduate year of training. A total of 345 residents from 13 different
      residencies in eight institutions participated in this program. Each resident was
      assigned four SP cases. The reliability of these encounters ranged from 0.63 to
      0.74. Of the participating residents, 22% were United States medical graduates
      (USMGs) and 78% were international medical graduates (IMGs). A considerable
      proportion of both USMGs and IMGs failed to ask appropriate questions concerning
      alcohol and drug use or identify the presence of risk factors associated with
      such use. Residents' scores on cases primarily dealing with general medical
      issues, as compared to those dealing with substance abuse, were consistently
      higher. Knowledge of basic information concerning substance abuse and opioids was
      deficient in over 50% of those tested. These findings suggest that residents
      about to start their clinical training are not sufficiently prepared to address
      patients presenting with alcohol and other drug problems.

PMID- 12466644
TI  - Sexual Trauma, Substance Abuse, and Treatment Success in a Sample of African
      American Women Who Smoke Crack Cocaine.
AB  - The purpose of this descriptive study was to examine the relationship among
      sexual trauma, severity of substance use, and treatment success for African
      American women who smoke crack cocaine. Using a convenience sample of 208 African
      American women with a history of crack smoking, participants were interviewed for
      2 to 4 hr and asked a variety of questions about their health, relationships,
      sexuality, and drug use. Women with a history of sexual trauma (N = 134) reported
      being addicted to more substances than women who had not been sexually
      traumatized (N = 74), despite the fact that the two groups did not differ on the
      number of substances used. Differences in the self-reported level of substance
      abuse was corroborated with external evidence of group differences in substance
      abuse severity. Women with a history of sexual trauma, compared to women without
      such a history, were admitted to the hospital or emergency room more often for
      health issues related to their substance use and were more likely to be negligent
      in caring for their children because of their drug use. We also found evidence to
      suggest that there are differences in treatment success between the two groups;
      women with a history of sexual trauma reported having been to substance abuse
      treatment programs more often than women without such a history. These findings
      are discussed in light of the particular treatment needs of women with a history
      of sexual trauma.

PMID- 12466645
TI  - Training Community-Based Clinicians in Screening and Brief Intervention for
      Substance Abuse Problems: Translating Evidence into Practice.
AB  - Screening and brief intervention in general health care settings are efficacious
      but have not been widely adopted. Our objective was to assess the effect of an
      educational intervention on clinicians' substance abuse-related clinical
      practices. The study was a telephone survey of practicing physicians, nurses,
      psychologists, physician's assistants, and social workers who attended a half-day
      continuing education course on one of four occasions. The course covered the
      stages of behavioral change and motivational counseling, using primarily role
      play with standardized patients. Of 87 course attendees, 70 (80%) completed the
      interview. Months to years after the course, most (91%) reported that the course
      made an impact on their practice. Most (78%) of respondents reported that they
      frequently or always asked new patients who drank alcohol a formal screening
      questionnaire such as the CAGE, and 94% frequently or always assessed their
      substance abusing patients' readiness to change. Most respondents reported that
      since taking the course they were more likely (1) to screen patients for alcohol
      or drug related problems (86%) and (2) to ask patients about their substance
      abuse on a follow-up visit (96%). After exposure to an active-learning half-day
      continuing education course, clinicians reported improvement with and high rates
      of desirable substance abuse-related clinical practices up to 5 years later.
      Continuing education efforts that incorporate active learning directed toward
      practicing clinicians show promise for improving rates of brief intervention for
      alcohol and other drug abuse.

PMID- 12466646
TI  - Predictors of Treatment Outcomes for Substance-Abusing Women: A Retrospective
      Study.
AB  - This study examined whether client characteristics at admission predict
      Retention, Abstinence, and utilization of Required Services and Specialized
      Services for pregnant women in outpatient and residential substance abuse
      treatment. Retrospective data were collected with the Psychosocial History (PSH),
      a structured clinical interview that is an expansion of the Addiction Severity
      Index, designed specifically to assess substance abusing women. The PSH was
      administered at intake for 183 pregnant women admitted to outpatient (n = 133) or
      residential (n = 50) treatment. Factor analysis reduced predictors to five
      factors with composite scores, and multiple regression procedures determined
      client characteristics that predict treatment outcomes. The findings suggest the
      complexity of predicting treatment outcomes for pregnant women. Significant
      predictors were composites of variables that encompassed all aspects of women's
      personal and family lives including medical and psychiatric needs, family and
      parenting issues, housing, victimization, and clients' perceived needs for
      treatment and assistance in all of these areas. The results suggest the need for
      a holistic approach to substance abuse treatment and continued exploration of a
      broad range of psychosocial assessments at intake in order to develop substance
      abuse treatment programs that effectively address multiple aspects of women's
      lives.

PMID- 12466647
TI  - Cocaine, Crime, Family History of Deviance-Are Psychosocial Correlates Related to
      These Phenomena in Male Cocaine Abusers?
AB  - This paper examines relationships among deviant behaviors such as cocaine abuse,
      crime, and family history of deviance; demographics; and psychological
      characteristics such as aggression, sensation seeking, confidence to resist
      taking cocaine and risk taking tendency to use cocaine in different situations;
      psychiatric symptoms (e.g., depression, anxiety, obsessive-compulsiveness,
      somatization, attention deficit); and social characteristics such as social
      adjustment. The sample consisted of men, mean age 35 years, who were veterans of
      the armed services. Canonical correlation analysis showed three significant
      canonical variates: The first indicated that verbal aggression, general sensation
      seeking, and a problem index for situations involving urges to use cocaine were
      positively related to number of times arrested and negatively related to age. The
      second revealed that experience seeking and problem indices for situations
      involving urges to use cocaine and for those involving pleasant times, were
      positively related to last cocaine use consumption level, total lifetime grams of
      cocaine used, and alcohol problems of the immediate family. The third showed that
      verbal aggression and a problem index for risk situations for use involving
      pleasant times were positively related, and experience seeking was negatively
      related, to number of times arrested, number of times incarcerated in the
      previous 30 days, age, and last cocaine use level. The implications of the
      associations found among these variables are discussed as they pertain to
      prevention, treatment, and future research.

PMID- 12466648
TI  - Gender Differences in HIV Risk Behaviors among Young Adults and Adolescents
      Entering a Massachusetts Detoxification Center.
AB  - We examined gender differences in HIV risk behaviors among young substance
      abusers 17 through 25 years of age. A voluntary and confidential survey inquiring
      about HIV-related risk behaviors was administered to clients (N = 200
      respondents) on intake at a drug detoxification center in Massachusetts. Female
      respondents were more likely than males to report having shared their needles (p
      < 0.01), having had sex in exchange for drugs or money (p < 0.01), sex with an
      HIV-infected partner (p < 0.01), and sex with an injection-drug user (p < 0.01).
      They were also more likely to report having been diagnosed with an STD (p <
      0.01). Nineteen percent of females (compared to 32% of males) reported always
      having used condoms for vaginal sex (p = 0.08), and 16% of females compared to
      35% of males reported always having used condoms for anal sex (p = 0.06). In our
      cohort of substance-abusing youth, adolescent and young adult females were more
      likely than males to report unsafe injection-drug use and sexual practices. The
      results of this study suggest that programs designed to decrease HIV risk among
      high-risk substance abusers in detoxification centers should be gender specific.

PMID- 12466649
TI  - Prevalence of Personality Disorders among Cocaine and Heroin Addicts.
AB  - Using the MCMI-III, we studied rates of personality disorders among 443 inpatient
      drug abusers (i.e., 160 opiate addicts and 283 cocaine addicts). For both samples
      the disorders of antisocial (60%), passive-aggressive (negativistic) (34%), and
      depressive personality disorders (32%) showed higher prevalence rates. Previous
      studies (N = 13) using different measures (e.g., SCID, SDIP, MCMI-I) reported
      similar findings in terms of overall prevalence of specific personality
      disorders, although actual rates varied by population.

PMID- 12466650
TI  - Chronic Drug Use and Crime.
AB  - This paper used bivariate and multivariate analyses to estimate the relationships
      between chronic drug use and various measures of criminal activity. The data for
      these analyses were derived from the 1993 (1) and 1995 (2) National Household
      Surveys on Drug Abuse (NHSDA). Measures of criminal justice system contact and
      criminal activity included ever arrested, arrested during the previous year,
      commission of a predatory crime (e.g., assault, fighting) during the previous
      year, and commission of a property crime (e.g., theft, property damage, car
      theft, breaking and entering) during the previous year. The analysis was
      conducted separately for males, females, and age groups, and it distinguished
      between chronic drug users, nonchronic drug users, and nondrug users. The results
      consistently showed a significant linear relationship between criminal activity
      and frequency of drug use. These findings have implications regarding the
      potential reduction in predatory and property crime that could occur from a
      decrease in drug use. Significant differences in criminal behavior between
      chronic drug users and other cohorts may signal a critical need to develop
      targeted interventions for this particular type of drug user.

PMID- 12466651
TI  - Innovative Clinical Addiction Research Training Track in Preventive Medicine.
AB  - Medical education related to identification, diagnosis and management of alcohol
      and other drug problems receives inadequate attention in the undergraduate
      curriculum and during residency training. This article describes the design,
      implementation, and evaluation of a new track in Clinical Addiction Research
      Training (CART) in a General Preventive Medicine (GPM) residency program. CART is
      comprised of a new course in Addiction Medicine, new practicum sites in addiction
      medicine research and treatment, and a CART-designated resident. An Advisory
      Group of educators, researchers, scholars, and administrators in addiction
      medicine, has provided guidance and support for this new track. Evaluation of the
      CART track suggested improvements in residents' knowledge and attitudes.
      Residents engaged in high caliber clinical addiction research projects. The
      development of the CART track within the GPM residency is an approach that can be
      integrated into other specialties, such as internal medicine, family practice,
      and adolescent medicine, to develop residents' interest and expertise in the
      addictive behaviors.

PMID- 12466652
TI  - An Integrated Approach for Dually Diagnosed Patients in a Substance Abuse
      Treatment Program: Case Presentation.
AB  - Patients with co-occurring psychiatric and substance use disorders experience
      worse social and clinical outcomes and are in need of adequate and simultaneous
      treatment for both disorders. The case presented illustrates the diversity of
      psychosocial, health, and behavioral problems and the complexity of treatment of
      a dually diagnosed patient. The authors discuss the benefits of using an
      integrated approach in an addiction treatment setting. The authors also review
      the importance of an integrated treatment model for populations with inadequate
      health care resources who are at high risk for medical and psychiatric
      complications.

PMID- 12466653
TI  - Alcohol Withdrawal, Psychological Symptoms, and Treatment Success.
AB  - Twenty-nine chronic male alcoholics were examined with the Profile of Mood States
      (POMS). Tests with the POMS scale were carried out on the ward on Days 1 and 5
      and after 21 days of sobriety. Our aim was to study the mood change in chronic
      alcoholics during detoxification and after 3 weeks of sobriety compared with a
      standard group (college students) and with psychiatric outpatients. A further aim
      was to study whether the patients who later underwent a Minnesota treatment
      program(n = 6) differed in mood compared with those who did not. An improvement
      was observed over time regarding all six POMS factors. The results for Day 21
      were generally better than the expected normal values for the POMS profile sheet
      with regard to both psychiatric outpatients and college norms. The follow-up
      based on the patients' records 1.5-2 years after the detoxification occasion in
      question showed that 18 patients had been hospitalized, generally for alcohol
      detoxification. The 6 patients who participated in a Minnesota treatment program
      had no documented relapses. A comparison of these 6 patients with the rest showed
      that the former had significantly lower values on five of the subscales.

PMID- 12466654
TI  - Course and Severity of Substance Abuse in Women with Comorbid Eating Disorder.
AB  - The objective of this study is to ascertain whether the course and severity of
      Substance Abuse among female patients with comorbid Substance Related Disorder
      and Eating Disorder (SRD-ED) is similar to or different from the course and
      severity of SRD among female patients with Substance Related Disorder but no
      Eating Disorder (SRD). Subjects were voluntary patients, obtained in two
      addiction programs located within departments of psychiatry in two state
      university medical centers, and included 66 women with SRD-ED and 211 women with
      SRD. Data were collected on demography, course and severity of SRD, and
      associated biomedical conditions. SRD-ED patients were significantly younger and
      more apt to be single, more highly educated, living with family and friends,
      employed, and of higher socioeconomic status. SRD-ED and SRD patients were more
      similar than different on most indicators of course and severity, although
      several clinical differences prevailed. These clinical differences were primarily
      ascribed to age. In most respects, patients with comorbid SRD-ED manifest course
      and severity of SRD similar to patients with SRD. Demographic differences between
      the two groups can mostly be ascribed to the younger mean age of SRD-ED patients
      rather than to the comorbid ED. Some biomedical problems are related to the
      specific consequences of ED.

PMID- 12466655
TI  - Psychiatry Residents' Opinions of a Substance Abuse Rotation in a VA Hospital
      General Internal Medicine Unit.
AB  - Written optional evaluation forms were devised to gather psychiatry residents'
      opinions regarding their substance use disorder rotation in a general internal
      medicine unit. Over a 4-year period 24 residents completed that rotation and 83%
      (N = 20) completed the form. Of the responding residents, 95% (N = 19) rated an
      above-average satisfaction with the rotation and 90% (N = 18) would recommend the
      rotation to other residents. All respondents 100% (N = 20) reported that the
      rotation met its stated training objectives. Considering the recent changes in
      the delivery of health care with its focus toward primary care and away from
      specialty care, these findings raise the possibility of incorporating the
      substance abuse training of psychiatry residents into the primary care setting of
      general internal medicine.

PMID- 12466656
TI  - MCMI-III Scores on Substance Abusers With and Without Histories of Suicide
      Attempts.
AB  - Sixty-eight patients with a history of suicide attempt were compared to 340
      patients without a history of suicide attempt using the MCMI-III, a frequently
      used test for measuring personality disorders. Patients with a suicide attempt
      history scored higher on Schizoid, Avoidant, Depression, Dependent, Passive
      Aggressive (Negativistic), Self-Defeating, and Paranoid and significantly lower
      on Histrionic and Compulsive and scored higher on all clinical syndrome scales
      except for Drug Dependence and Delusional Disorder. Logistic regression correctly
      predicted the no-suicide-history group with 97% accuracy, but only accurately
      predicted 16% of the patients with a suicide attempt history. A discriminant
      function analysis correctly predicted 90% of the patients with a suicidal attempt
      history and 63% of the patients with no history of suicide attempt. Results
      suggest that MCMI-III scores may be able to detect patients with a history of
      suicide attempt, using multivariate statistics.

PMID- 12466657
TI  - Changes in Alcohol Use and Drinking Problems in Relation to Role Transitions in
      Different Stages of the Life Course.
AB  - Older and younger generations are compared with respect to changes in alcohol use
      and alcohol-related problems associated with role transitions in the life course,
      using data from a 9-year follow-up study in the Netherlands. Transitions in
      several role domains are summarized in an index for structure of everyday life.
      It was hypothesized that role transitions involving an increase in structure of
      everyday life would lead to a decrease in drinking and in problems. As expected,
      the association of the index with alcohol use and alcohol related problems was
      negative among the younger generation. However, contrary to expectation, the
      association was positive among the older generation. It is concluded that the
      role-theoretic framework from which our expectations were derived should be
      amended when used for research among older people. More specific attention to the
      content of social roles and associated resources and coping mechanisms available
      at older age is recommended.

PMID- 12466658
TI  - Client's Perceived Need for Treatment and Its Impact on Outcome.
AB  - Objectives. Based on the concept of "stage of change," this study examines the
      relationship between patients' motivation for substance abuse treatment and their
      posttreatment improvements in the areas measured by the Addiction Severity Index
      (ASI; alcohol, drug, medical, psychiatric). We attempt to answer the following
      questions: Do clients' perceptions of "need for drug, alcohol, psychiatric, and
      medical treatment" at admission predict their improvements on these problems at 6
      month follow-up? How do clients' perceived needs contribute to their use of
      treatment and their reported change? Methods. Clinical interview data (N = 696)
      collected using the ASI from the Target Cities Project in the city of
      Philadelphia in 1993 and 1995. Results. Clients' motivation made a substantial
      difference in their improvement following treatment in all problem areas. Clients
      who said treatment was even slightly important on the ASI at admission made more
      changes than clients who reported that treatment was "not at all" important. Even
      when the motivation groups were approximately equated for lifetime problem
      severity there was still a significant effect of recent motivation as expressed
      on the ASI. Conclusions. These data are consistent with other findings from the
      "stage of change" literature suggesting that treatment is only important for
      patients who are ready or at least somewhat motivated to receive it. These
      findings underscore the importance of efforts to increase patients' readiness for
      treatment in order to achieve better treatment effects.

PMID- 12466659
TI  - Psychosocial Functioning of People with Substance Abuse and Bipolar Disorders.
AB  - This study assessed whether a secondary diagnosis of a substance use disorder in
      hospitalized people with bipolar disorder was associated with poorer outcomes on
      self-reported measures of mood (Profile of Mood States), subjective distress
      (Behavior and Symptom Identification Scale), and coping resources (Coping
      Resources Inventory), and with specific patient characteristics. Sixty-two
      patients with bipolar disorder and a secondary diagnosis of a substance use
      disorder and 60 patients with only a bipolar disorder diagnosis participated.
      Patients with bipolar disorder and a secondary diagnosis of a substance use
      disorder perceived significantly more impairment on all three measures than did
      patients without the secondary diagnosis. Moreover, the background
      characteristics of a history of violence, past or current involvement with the
      criminal justice system, and not having an antipsychotic medication prescribed
      during hospitalization had the strongest association with having a secondary
      diagnosis of a substance use disorder among the characteristics examined. These
      findings suggest the existence of a subgroup of patients with substance abuse and
      bipolar disorders who have substantial psychosocial impairment and probably
      require more intense treatment.

PMID- 12466660
TI  - Computer-Generated Written Behavioral Contracts with Problem Drinkers in Primary
      Medical Care.
AB  - Problem drinking is common among patients in primary medical care, but often
      unrecognized. Brief physician interventions can be helpful, but several barriers
      hinder their adoption in practice, notably a lack of time. We conducted a
      randomized pilot study of written behavioral contracts that patients wrote with
      help from a computer program. In eight family medicine practices, 2684 patients
      were approached and 2399 screened with the Alcohol Use Disorders Identification
      Test (AUDIT). Of those, 186 screened positive, 154 were eligible, and 80
      enrolled. Follow-up interviews were completed with 69 (86%). At 12 months, the
      AUDIT and Addiction Severity Index alcohol scores decreased nonsignificantly more
      in the intervention group than in the controls. The study demonstrated that
      computer-based interventions are acceptable to patients and physicians, feasible
      in busy primary care practices, and have effect sizes comparable to those of
      physician-based interventions. Computer-based interventions may be an effective
      and efficient tool to enhance identification of and intervention with problem
      drinkers in primary care.

PMID- 12466661
TI  - Alcohol Consumption and Alcohol Problems Among Women in European Countries.
AB  - Traditionally, less research has been conducted on women's drinking as compared
      to men's. But women's drinking has been shown to differ from men's in terms of
      consumption patterns and in factors determining heavy and problematic drinking.
      Thus, special efforts are needed to increase knowledge in this field. This
      article introduces a set of papers from the recently completed concerted action
      project "Alcohol Consumption and Alcohol Problems among Women in European
      Countries," supported by the European Commission. The aim of the study was to
      examine and compare the drinking patterns and problems of women in 9 European
      countries. This was done by comparing alcohol consumption and alcohol problem
      rates within and between countries and between men and women and among women. The
      project also developed recommendations for much needed standardized measures of
      alcohol consumption and alcohol problems for use in European alcohol
      epidemiological research.

PMID- 12466662
TI  - Drinking Cultures and the Position of Women in Nine European Countries.
AB  - Nine European countries involved in the Biomed Project "Alcohol Consumption and
      Alcohol Problems Among Women in European Countries" are described in relation to
      sociodemographic characteristics and drinking patterns. The populations of the
      nine countries, especially women, have become much older during the period 1950
      1995. Also, women tend to have fewer children, and at an older age, so that the
      percentage of the younger age groups is decreasing. If we connect this to the
      fact that women now are more a part of the labor force than before, we might
      infer that the observed decrease in gender difference in alcohol use is to be
      explained in relation to economic factors. In terms of drinking patterns, a broad
      division can be made between two wide regions: (a) the northern dry area, where
      beer is the leading beverage, consumed on weekends and outside mealtimes; and (b)
      the southern, or Mediterranean, wet area, where wine is the main beverage,
      usually drunk at meals. However, the dispersion in alcohol consumption found
      among the study countries in 1961 declined considerably by 1997. In this respect,
      European countries are getting more similar, so that we may consider this
      phenomenon a "convergence" of alcohol drinking in Europe. More generally, changes
      from a more traditional drinking pattern to a novel one from another country may
      be due to several factors, one of which is the increasing relevance of women in
      the drinking context. On the treatment side, such a relevance is nowadays visible
      through the better availability of both health services and nonstatutory
      organizations to take care of women affected with alcohol-related problems.

PMID- 12466663
TI  - Women's Roles and Women's Drinking: A Comparative Study in Four European
      Countries.
AB  - The present study analyzes the influence of role combinations on heavy drinking
      in four European countries: Finland, France, Germany, and Switzerland. Data sets
      come from nationally representative surveys. A growing number of studies have
      investigated the influence of social roles on alcohol consumption. Different
      theories such as role accumulation, role overload, and role deprivation aim to
      explain the association between roles and poor mental health, including heavy
      alcohol consumption. The results show that roles and role combinations influence
      heavy drinking differently in each country. The findings also indicate that the
      social position of women in a country is strongly connected to the differing
      associations between specific role combinations and heavy drinking across
      countries. No single role theory can be applied cross-culturally. Large-scale
      surveys are needed to test statistically the association between role
      combinations and heavy drinking.

PMID- 12466664
TI  - Life Stage, Alcohol Consumption Patterns, Alcohol-Related Consequences, and
      Gender.
AB  - This paper presents findings from a European collaborative study. A common
      framework for reanalysis of existing data was devised. Alcohol-related problems
      encountered were classified as "internal" and "external." Logistic regression
      analyses were then conducted to predict lifetime presence of any internal
      problem, any external problem, and any problem at all. The predictor variables
      were gender, life stage (corresponding roughly to young, middle and older age),
      past year's drinking level in four categories of grams of alcohol per month, and
      past year's "binge" drinking. All four predictor variables were associated with
      the presence of alcohol-related problems, with women and retired people having
      fewer problems and heavy drinkers and binge drinkers having more. At all levels
      of alcohol consumption, men were more likely than women to experience at least
      one adverse consequence. Internal problems were more common than external
      problems. Country differences are discussed and recommendations are made for
      further studies.

PMID- 12466665
TI  - Mortality 5 Years After Detoxification and Counseling as Indicated by
      Psychometric Tests.
AB  - Residential detoxification of substance abusers, using medication to alleviate
      withdrawal symptoms, often fails to ensure further abstention and predict which
      clients have the greatest risk of morbidity after detoxification. Prolonging the
      detoxification period with a counseling period has been shown to enhance
      compliance to counseling. Sixty-one (61) substance abusers (mean age: 31.3 years;
      22 women) with a mean length of abuse of 16 years in 1993-1994 were tested using
      two psychometric tests and then followed up in 1999 according to mortality. Mean
      value on Antonovsky's Sense of Coherence (SOC) scale was 2.98 and on Hopkins
      Symptom Checklist (HSCL-24) was 2.06, indicating postdetoxification coping
      problems and distress. Thirteen (13) abusers died during follow-up. Cox
      regression of mortality showed increased risk in men, and also an increased risk
      of dying in the observation period with lower SOC score (p <.01), but not with
      increasing HSCL-24 score. Logistic regression indicated a 3.6 times higher risk
      of dying in the observation period if the SOC score was 1 point lower (on a scale
      range from 1 to 5). An increased mortality in drug addicts leaving the facility
      with an SOC value below 3.00 after a 4-week detoxification and counseling stay is
      thus strongly supported by the data. Antonovsky's SOC scale thus seems to be a
      good indicator of future mortality.

PMID- 12466666
TI  - Alexithymia in Egyptian Substance Abusers.
AB  - Alexithymia is thought of as a trait that predisposes to drug abuse. Moreover, it
      is suggested to be related to type of the substance abused, with the worst-case
      scenario including a worse prognosis as well as tendency to relapse or even not
      to seek treatment at all. To address this important subject in Egyptian patients,
      a sample of 200 Egyptian substance abusers was randomly selected from inpatients
      in the Institute of Psychiatry, Ain Shams University, Egypt. The study also
      included 200 group-matched controls. DSM-IV criteria were used for assessment of
      substance use disorders, and toxicologic urine analysis was used to confirm the
      substances of abuse. Toronto Alexithymia Scale (TAS)-Arabic version was used for
      assessment of alexithymia. It was found that alexithymia was significantly more
      prevalent in the substance use disorders group as compared to healthy controls.
      It was also found that among the substance use disorders group, alexithymics
      reported more polysubstance abuse, more opiate use (other than heroin IV), lower
      numbers of hospitalizations, lower numbers of reported relapses, and a lower
      tendency to relapse as a result of internal cues compared to patients without
      alexithymia. Statistically significant associations were also found between
      alexithymia and more benzodiazepine abuse and nonpersistence in treatment. The
      results suggest that alexithymia should be targeted in a treatment setting for
      substance use disorders.

PMID- 12466667
TI  - Alcohol Consumption Estimates in Surveys in Europe: Comparability and Sensitivity
      for Gender Differences.
AB  - The comparability of general population studies on alcohol from nine European
      countries is evaluated from three points of view: (1) methodologic aspects
      influencing alcohol estimates, (2) variation between countries in coverage of
      sales estimates of alcohol consumption, and (3) associations between type of
      question used to measure alcohol consumption and gender differences in alcohol
      consumption. With respect to methodologic aspects, it was found that the studies
      differed on most of the 10 points included in this comparison. The coverage of
      sales estimates by surveys varies between 39% (Germany) and 56% (France). With
      respect to type of question and gender differences, it was found that more
      elaborate sets of questions on alcohol consumption are associated with smaller
      gender differences in the prevalence of heavy drinking (>600 g 100% alc/mo). It
      is concluded that the methodologic differences between studies and the
      differences in sales coverage do not allow cross-national comparison of survey
      estimates of alcohol consumption of different European countries. Compared with
      more elaborate sets of questions on alcohol consumption, simple questions on
      alcohol consumption are likely to underestimate gender differences in the
      prevalence of heavier drinking.

PMID- 12466668
TI  - Investigating Gender Convergence in Alcohol Consumption in Finland, Germany, The
      Netherlands, and Switzerland: A Repeated Survey Analysis.
AB  - Since the 1970s there has been concern that women may have started to adopt the
      drinking behaviors of men, a process seen as the result of emancipation in which
      women increasingly move into professions and/or lifestyles similar to those of
      men. This is called the convergence hypothesis. The present analysis investigated
      a possible closing of the gender gap and includes four countries that had
      national survey data for at least two time points: Finland (1984, 1992), Germany
      (1984, 1990), The Netherlands (1981, 1989), and Switzerland (1987, 1992).
      Significant convergence could be found only in Finland, which consisted of a
      greater increase of Finnish women becoming current drinkers and of a greater
      relative increase in the women's mean consumption. The fact that gender
      convergence was found only for Finland could be due not only to the longer
      observation period, but also to the egalitarian position of women and the
      changing drinking culture of the country.

PMID- 12466669
TI  - Alcohol-Related Mortality in Europe: A Tentative Analysis from the EU Project
      "Alcohol Consumption and Alcohol Problems among Women in European Countries"
AB  - Mortality data were collected for eight of the nine study countries in the BIOMED
      II concerted action "Alcohol Consumption and Alcohol Problems among Women in
      European Countries": Finland, France, Germany, Italy, The Netherlands, the United
      Kingdom (Scotland), Sweden, and Switzerland. An analysis of mortality that is
      limited to causes of death that are fully attributable to alcohol (DAA) results
      in a large underestimation of alcohol-related mortality (ARM) rates in all study
      countries and especially among females. These estimates can be improved by
      including an analysis of selected causes of death that are indirectly
      attributable to alcohol. This produces geographic and time-trend variability of
      ARM rates that are more congruent with alcohol drinking levels and trends. From
      this study, it is evident that when German data are analyzed separately for the
      former German Democratic Republic (GDR) and the former Federal Republic of
      Germany (FRG), two distinct ARM patterns result. The authors underline
      methodologic limits of this study and recommend procedures for a more reliable
      calculation of European ARM estimates

PMID- 12466670
TI  - Gender Differences in Drinking Patterns in Nine European Countries: Descriptive
      Findings.
AB  - Gender differences in drinking patterns in nine European countries (the Czech
      Republic, Finland, France, Germany, Italy, The Netherlands, Scotland, Sweden, and
      Switzerland) were examined using data from surveys conducted in the late 1980s
      and early 1990s. Drinking patterns were analyzed with regard to sociodemographic
      variables such as age, education, employment, marital status, and parenthood. Age
      was closely related to drinking in every society, but the patterns were different
      in different societies. Women with higher education tended to consume more
      alcohol than women with lower education in many societies, whereas a similar
      pattern was not found among men. Unemployment seemed to be more strongly related
      to women's drinking than to that of men. Divorced men consistently consumed the
      most alcohol in every country. Parenthood was profoundly and consistently
      associated across societies with women's monthly consumption and prevalence of
      heavy drinking.

PMID- 12466671
TI  - Stages of Change Assessments in Alcohol Problems: Agreement Across Self- and
      Clinician-Reports.
AB  - A number of self-report scales and "algorithms" have been developed to measure
      stage of change in alcohol problems. These methods rely on client self-reports,
      but an alternative approach is to use clinician judgments. The purpose of this
      investigation was to compare approaches including a newly developed Readiness to
      Change Questionnaire - Clinician Version (RCQ-CV). Clients being assessed for
      alcohol treatment (N = 64) completed SOCRATES, the Readiness to Change
      Questionnaire (RCQ), a social desirability scale, and a stage of change
      algorithm. Clinicians completed the RCQ-CV and provided a simple assessment of
      stage of change. The agreement among the alternative methods was generally good
      with the continuous measures, including agreement between scales, between clients
      and clinicians, and between experienced clinicians and trainees. Agreement among
      categorical stage assignments was poor. The RCQ-CV shows promise as a clinical
      and research tool.

PMID- 12466672
TI  - Medical Education About the Care of Addicted Incarcerated Persons: A National
      Survey of Residency Programs.
AB  - In June 1998, there were 1.8 million inmates in correctional facilities for
      adults; 1.2 million in state and federal prisons and 600,000 in municipal/county
      jails (668 persons per 100,000 U.S. population). Rates of TB, AIDS, mental
      illness, and substance abuse are 2-13 times higher in persons living in jails and
      prisons. This study was designed to assess the level of training offered to
      residents in seven medical specialties in the care of addicted incarcerated
      persons. The study design involved two stages. The first entailed a mailed survey
      to 1,831 residency directors in family medicine, internal medicine, osteopathic
      medicine, pediatrics, obstetrics and gynecology, psychiatry, and emergency
      medicine. The second stage was a telephone interview, about substance use
      disorders, of faculty listed by the residency directors as teaching residents.
      The mailed survey was completed by 1,205 residency directors (66%). The 769
      faculty from those identified programs, who participated in the telephone
      interview, reported that only 14% of their residency programs offered lectures or
      conferences on the care of incarcerated persons, yet 44% of the programs had
      residents caring for incarcerated persons with substance abuse problems, in a
      clinical setting. Only 22% offered clinical experiences for residents in a
      correctional facility.We recognize that our survey of correctional health and
      substance abuse training is limited, but as such, a greater number of respondents
      to our survey do not teach residents addiction medicine topics pertaining to
      prevention, evaluation, intervention, and management of the addicted criminal
      offender/patient in a correctional setting or give adequate clinical exposure to
      this special population. The data suggests a need to develop and implement
      educational programs on medical care for this high-risk and expanding population.

PMID- 12466673
TI  - Integrating Substance Abuse Content into an HIV Risk-Reduction Intervention: A
      Pilot Study with Middle School-Aged Hispanic Students.
AB  - A pilot study of a school-based HIV/AIDS risk reduction program with integrated
      components on substance abuse was conducted to determine: 1) its effectiveness in
      Hispanic, middle school-aged children and 2) if differences in effectiveness are
      found in students who report risky behaviors. Activity-oriented training on
      decision-making, HIV/AIDS illness, risky behaviors, and abstinence was provided
      to 125 students. Participants were classified into risk groups, based on reported
      sexual and alcohol/drug (AOD) activity. Effectiveness was analyzed by comparing
      the risk group's knowledge, beliefs, and perceived-risk scores pre/post-program
      in sexual activity, AOD use, disease course, and casual contact categories. This
      program improved some knowledge, few beliefs, and few perceived risks. The
      perceived-risk scores of the high-risk group did not reflect their higher risk
      for HIV/AIDS. School-based programs should measure actual HIV/AIDS risks,
      including AOD, to identify participants who need focused interventions. Further
      research is needed to understand how AOD influences risky sexual behaviors, and
      what content and interventions are useful.

PMID- 12466674
TI  - Internet Program Development Leading to Certification in Substance Abuse
      Prevention.
AB  - The purpose of this project was to develop a multidisciplinary educational
      program that would provide information needed to work more efficiently in
      substance abuse prevention and prepare the learner for certification examination.
      Because prevention service providers are scattered throughout the state, country,
      and global community, an educational program had to be easily accessible. The
      solution was to develop a web-based curriculum that could be accessed anywhere in
      the world. One that would meet not only state requirements, but also would
      conform to international certification criteria. Qualitative analysis was used to
      categorize broad content areas of university course offerings, core functions
      considered vital by the state, and various educational programs in substance
      abuse throughout the country. As themes and subthemes emerged, clusters of
      essential components were retrieved and divided into four groupings. These
      groupings later translated into four distinct modules, each containing four to
      six components of study. A pilot group of 17 people were recruited throughout the
      state. These service providers took the web-based program over a period of 3
      months and then participated in a special administration of an international
      certification exam. Results showed a 94% pass rate for the pilot group as
      compared with a national 32%.

PMID- 12466675
TI  - The Relationship of Stress and Coping Methods to Adolescent Marijuana Use.
AB  - As the use of marijuana among adolescents remains high, more effective
      interventions are needed. We conducted this cross-sectional survey at an
      outpatient, university-based, adolescent clinic to determine the prevalence of
      marijuana use in an inner-city adolescent population and to examine the
      relationship of stress and coping methods to marijuana user status (never user,
      experimenter, and frequent user). The subjects were 918 adolescents aged 12-21
      years. Lifetime use in this population was 59% (n = 611) with 18.4% (n = 191)
      reporting frequent weekly use. Almost all (97%) marijuana users acknowledged
      marijuana use by friends. Stepwise logistic regression analysis showed that
      negative life events, greater use of the negative coping method of anger and less
      frequent use of the positive coping method of parental support were significantly
      and independently related to marijuana user status. In the presence of high peer
      use, exploring parent-child relationships and use of anger coping and intervening
      accordingly may decrease marijuana use.

PMID- 12466676
TI  - Violence Among Comorbid and Noncomorbid Severely Mentally Ill Adults: A Pilot
      Study.
AB  - This pilot study examined the relationship between substance dependence and
      violence in a sample of severely mentally ill adults. Subjects were 42
      psychiatric outpatients enrolled in a clinical case management program in San
      Francisco, California. Almost 40% of the participants reported perpetrating at
      least one violent act in the past 12 months. Comorbid participants were over
      4(1/2) times more likely to commit a violent act in the past 12 months than
      noncomorbid participants. Substance dependence was also more frequently
      associated with perpetration of a violent act by female than by male participants
      and by Caucasian than by African American participants. Comorbid mentally ill
      participants appear more likely to perpetrate violent acts than those with mental
      illness alone. The dangers of substance dependence in terms of the perpetration
      of violence may not be in mental illness or substance dependence alone but in
      their co-occurrence. Further investigation is needed to assess risk factors for
      violence and victimization in multiple environmental and situational domains. It
      will be important to explore the moderating effects of gender and race on the co
      occurrence of mental illness, substance dependence, and the perpetration of
      violent acts.

PMID- 12466677
TI  - Effects of Cigarette Smoking on Psychopathology Scores in Patients With
      Schizophrenia: An Experimental Study.
AB  - Cigarette smoking and/or nicotine administration have been shown to transiently
      ameliorate several psychophysiological deficits in patients with schizophrenia
      such as indicators of deficient sensory gating and attention, but acute effects
      of smoking on positive and negative symptoms in schizophrenia have not been
      evaluated in experimental paradigms. The current study assessed whether smoking
      of cigarettes, after 6-12 h abstinence, transiently alters the expression of
      negative and/or positive symptoms in patients with schizophrenia who have a
      history of regular smoking. In a double-blind, placebo controlled study patients
      with schizophrenia participated in two sessions in which they smoked either
      cigarettes moderately high in nicotine content or denicotinized cigarettes. They
      were interviewed pre-and postsmoking to obtain ratings of PANSS and SANS scales,
      and had blood pressure and pulse serially recorded before and after smoking.
      Pulse rate and blood pressure were slightly higher after smoking in the high
      nicotine cigarette session. Negative symptom scores on both scales were
      significantly lower after cigarette smoking compared to same-day predrug
      baseline, but there were no differences in active versus denicotinized cigarette
      drug effects. These results suggest that acute smoking of cigarettes reduces
      negative symptoms in patients with schizophrenia in this experimental paradigm.
      Future work needs to identify the mechanism responsible for this behavioral
      effect.

PMID- 12466678
TI  - The Prevalence of Cigarette Smoking in an Acute Inpatient Physical Medicine and
      Rehabilitation Population.
AB  - The purpose of this study was to determine the prevalence of cigarette smoking
      among patients before and after discharge from an acute inpatient physical
      medicine and rehabilitation unit and to assess smokers' interest in and desire
      for smoking cessation. A consecutive sample of inpatients (n = 233) admitted over
      a 5-month period to a regional rehabilitation inpatient center for acute
      rehabilitation treatment was surveyed for their smoking patterns. Ten percent of
      patients admitted to rehabilitation were active smokers prior to their
      hospitalization. In spite of reporting high motivation to stop smoking, half were
      not interested in participating in a smoking cessation program if one were
      offered to them. Following discharge from inpatient rehabilitation, 54% of a
      small sample of patients who could be contacted had resumed smoking (all within 4
      weeks of being home). Given the prevalence of smoking in this population and its
      adverse consequences on health and quality of life, we suggest that
      rehabilitation professionals actively address this health problem during the
      patient's hospitalization.

PMID- 12466679
TI  - A Comparison of Clonidine and Buprenorphine in the Outpatient Treatment of Opiate
      Withdrawal.
AB  - The opiate withdrawal syndrome, although not life threatening, is a major
      obstacle in the treatment of opiate dependence. Over a 12 week period, 124
      patients (63% female, 66% African American and mean age 32.6 years) underwent 5
      day treatment for opiate withdrawal. Patients treated in the first 6 weeks (n =
      69) received clonidine based treatment (0.1 mg every 6 h with one dose received
      on-site each day and the others taken home), while patients treated in the latter
      6 weeks (n = 65) received buprenorphine 0.3 mg IM daily. Both groups received
      supportive medications for diarrhea, cramps, aches, and nausea, had clonidine
      patches placed on day 4, and were offered naltrexone upon completion. Based on
      age, gender, and race the two treatment groups were similar. The completion rate
      was 75.4% for buprenorphine group and 47.5% for the clonidine group, (p =.001).
      In conclusion, buprenorphine was superior to clonidine in enabling opiate
      dependent patients to successfully complete an outpatient detoxification program.

PMID- 12466680
TI  - The Effects on Facilitators of a Substance Abuse Education Program.
AB  - This retrospective-anecdotal study was conducted to determine if involvement in a
      learner-centered continuing education program in substance abuse prevention would
      influence the careers and work-related activities of thefacilitators. A
      questionnaire was sent to 33 individuals who served as facilitators of a large
      substance abuse prevention education project. Of the 31 who responded, 21 (67.7%)
      indicated that serving as a facilitator resulted in either "major changes" or
      "some changes" to their careers, and 25 (80.6%) felt that they were "much more
      likely" or "more likely" to incorporate substance abuse prevention activities
      into their work. Teaching in substance abuse education programs may cause changes
      in the career paths and work-related activities of the facilitators.
      Investigators may need to incorporate evaluations of the effects of a particular
      program on the intended learners as well as the facilitators.

PMID- 12466681
TI  - Active and Former Injection Drug Users Report of HIV Risk Behaviors During
      Periods of Incarceration.
AB  - American prisons have increasing numbers of inmates incarcerated for drug
      offenses. This population is at high risk for HIV-infection and may continue HIV
      transmission risk behaviors while incarcerated. We find that 31% of injection
      drug users with a history of imprisonment had used illicit drugs in prison, and
      nearly half of these persons had injected drugs while incarcerated. Male gender
      and number of times incarcerated were associated with drug use in prison.
      Interventions for drug-using prisoners that are advocated in some European
      prisons, such as needle exchange programs and methadone maintenance, need
      attention in the United States.

PMID- 12466682
TI  - Development of an Instrument to Assess Problem Behavior in First Grade Students
      Prenatally Exposed to Cocaine. Part II: Validation.
AB  - In Part I, the initial development of a preliminary tool, the PROBS-14, was
      reported. The tool was developed and initially tested through a consensus process
      that tapped the perceptions of early education teachers. Concurrent validity
      between the PROBS-14 and the Conners' Teacher Rating Scale (CTRS) was established
      with factor analysis, yielding a hyperactivity-conduct factor, composed of PROBS
      items and all but two of the CTRS subscales, and a central processing factor,
      composed of PROBS items and the remaining CTRS scales. The purpose of Part II was
      to further establish concurrent validity of the PROBS-14 with known pediatric
      behavior measures (TRF, CTRS) and to ascertain if the PROBS-14 better predicts a
      cocaine behavioral effect. A sample of 468 African American children with known
      cocaine exposure (n = 200) and control status (n = 268) were evaluated. Factor
      analyses produced results similar to those reported in Part I, with PROBS items
      accounting for problem behavior variance beyond that accounted for by the TRF,
      and more specific than that accounted for by the CTRS. Additionally, children
      prenatally exposed to cocaine, particularly those exposed late in pregnancy,
      differed significantly from controls on the PROBS total, central processing
      scale, and several PROBS items. The PROBS instrument offers a promising brief
      measure of child problem behaviors with adequate concurrent and predictive
      validity, and which outperforms the TRF and CTRS in discriminating prenatal
      cocaine exposure status.

PMID- 12466683
TI  - Factors Affecting the Short-Term Prognosis of Alcohol Dependent Patients
      Undergoing Inpatient Detoxification.
AB  - Stable measures of psychological functioning require a considerable period of
      abstinence. However, the duration of inpatient detoxification programs has
      decreased dramatically in most health care systems, posing a novel challenge for
      clinical evaluation of patients. The present study was carried out to examine
      whether factors predicting short-term prognosis can be identified in alcohol
      dependent subjects during early stages of inpatient detoxification. Self-reports
      of mood states were obtained, and executive cognitive functioning was examined.
      Outcome was studied at 2-3 months. No correlation was found between self-reported
      symptoms of depression, hopelessness, and anxiety, and percentage of nondrinking
      days. A significant positive correlation was found between Wisconsin Card Sorting
      Test (WCST) performance and short-term prognosis measured by this parameter.
      Thus, in addition to transient withdrawal-related effects, impairments of WCST
      performance in early stages of alcohol detoxification may reflect more long
      standing deficits in problem-solving strategies, of possible relevance for
      matching patients to treatment services.

PMID- 12466684
TI  - Methadone Anonymous: A 12-Step Program for Methadone Maintained Heroin Addicts.
AB  - Methadone Anonymous (MA) is a new 12-step fellowship developed for methadone
      maintained heroin addicts. A total of 53 MA members completed a survey assessing
      factors related to methadone maintenance treatment program (MMTP) entry, drug
      use, MA participation, beliefs concerning effectiveness of MMTP and MA, and level
      of social cohesiveness. Length of time in MA was associated with a decreased use
      of alcohol, cocaine, and marijuana. Clients rated components of MA to be
      significantly more helpful to recovery than MMTP treatment components.
      Affiliation to five MA members known best by the respondents was significantly
      greater than affiliation to non-MA members. Length of time in MA was positively
      associated with MA affiliation. Social affiliation and endorsement of 12-step
      principles were positively correlated. These findings suggest that MA
      participation has benefits not available in professionally driven MMTP, and
      should be further studied.

PMID- 12466685
TI  - Faculty Rating of Learning Objectives for an Undergraduate Medical Curriculum in
      Substance Abuse.
AB  - The purpose of this study is to describe medical faculty's ratings of learning
      objectives related to substance abuse. A comprehensive set of learning objectives
      was drafted. The Associate Dean at each of Ontario's five medical schools was
      asked to select two faculty members from each clinical discipline who were
      involved in undergraduate medical education. The selected faculty were sent a
      survey asking them to rate 282 objectives according to their importance for
      undergraduate education in their discipline, using a 5-point scale. Sixty-eight
      out of 90 surveys were returned. For statistical analysis, disciplines were
      placed into two groups, Group 1 (internal medicine, surgery, emergency medicine,
      and anesthesia) and Group 2 (family medicine, psychiatry, and pediatrics). The
      mean ratings of Group 1 were significantly higher than Group 2 (p < 0.001) for
      five sets of objectives: attitudes, epidemiology, screening and assessment,
      nonmedical interventions, and specific populations (women, the elderly, and
      adolescents). Group 1 gave mean ratings above 4 to all themes except
      epidemiology, inpatient care, and medical complications. In contrast, Group 2
      gave mean ratings above 4 to only three themes: physician substance abuse
      problems, withdrawal, and medical complications. The marked differences in
      learning objectives between disciplines suggest that a discipline-specific
      approach is needed for curricular development in substance abuse.

PMID- 12466686
TI  - Clinically relevant?

PMID- 12466687
TI  - Concussions among university football and soccer players.
AB  - OBJECTIVE: A study to examine the incidence and characteristics of concussions
      among Canadian university athletes during 1 full year of football and soccer
      participation. DESIGN: Retrospective survey. PARTICIPANTS: Three hundred eighty
      Canadian university football and 240 Canadian university soccer players reporting
      to 1999 fall training camp. Of these, 328 football and 201 soccer players
      returned a completed questionnaire. MAIN OUTCOME MEASURES: Based on self-reported
      symptoms, calculations were made to determine the number of concussions
      experienced during the previous full year of football or soccer participation,
      the duration of symptoms, the time for return to play, and any associated risk
      factors for concussions. RESULTS: Of all the athletes who returned completed
      questionnaires, 70.4% of the football players and 62.7% of the soccer players had
      experienced symptoms of a concussion during the previous year. Only 23.4% of the
      concussed football players and 19.8% of the concussed soccer players realized
      they had suffered a concussion. More than one concussion was experienced by 84.6%
      of the concussed football players and 81.7% of the concussed soccer players.
      Examining symptom duration, 27.6% of all concussed football players and 18.8% of
      all concussed soccer players experienced symptoms for at least 1 day or longer.
      Tight end and defensive lineman were the positions most commonly affected in
      football, while goalies were the players most commonly affected in soccer.
      Variables that increased the odds of suffering a concussion during the previous
      year for football players included a history of a traumatic loss of consciousness
      or a recognized concussion in the past. Variables that increased the odds of
      suffering a concussion during the previous year for soccer players included a
      past history of a recognized concussion while playing soccer and being female.
      CONCLUSIONS: University football and soccer players seem to be experiencing a
      significant amount of concussions while participating in their respective sports.
      Variables that seem to increase the odds of suffering a concussion during the
      previous year for football and soccer players include a history of a recognized
      concussion. Despite being relatively common, symptoms of concussion may not be
      recognized by many players.

PMID- 12466688
TI  - Therapeutic patellar taping changes the timing of vasti muscle activation in
      people with patellofemoral pain syndrome.
AB  - OBJECTIVE: To examine the effect of the application of tape over the patella on
      the onset of electromyographic (EMG) activity of vastus medialis obliquus (VMO)
      relative to vastus lateralis (VL) in participants with and without patellofemoral
      pain syndrome (PFPS). DESIGN: Randomised within subject. SETTINGS: University
      laboratory. PARTICIPANTS: Ten participants with PFPS and 12 asymptomatic
      controls. INTERVENTIONS: Three experimental taping conditions: no tape,
      therapeutic tape, and placebo tape. MAIN OUTCOME MEASURES: Electromyographic
      onset of VMO and VL assessed during the concentric and eccentric phases of a
      stair stepping task. RESULTS: When participants with PFPS completed the stair
      stepping task, the application of therapeutic patellar tape was found to alter
      the temporal characteristics of VMO and VL activation, whereas placebo tape had
      no effect. In contrast, there was no change in the EMG onset of VMO and VL with
      the application of placebo or therapeutic tape to the knee in the asymptomatic
      participants. CONCLUSIONS: These data support the use of patellar taping as an
      adjunct to rehabilitation in people with PFPS.

PMID- 12466689
TI  - Wrist pain in young gymnasts: frequency and effects upon training over 1 year.
AB  - OBJECTIVE: To determine the frequency and characteristics of wrist pain in young,
      nonelite gymnasts over a 1-year training period, and to describe the effects of
      chronic wrist upon gymnastics training. DESIGN: Prospective cohort study.
      SETTING: Los Angeles-based gymnastics club. PARTICIPANTS: Forty-seven nonelite
      female and male gymnasts between 5 and 16 years of age. ASSESSMENTS: Each subject
      completed an interview-based questionnaire and received a physical exam at the
      study onset and at the end of 1 year of training. The questionnaire detailed
      training habits and elicited a history and description of wrist pain. MAIN
      OUTCOME MEASURES: The frequency of wrist pain and several measures of training
      were reported at the study onset and at 1 year. Gymnasts with wrist pain were
      compared with those who were pain-free. MAIN RESULTS: Wrist pain was reported by
      57% (27 of 47) of subjects at the study onset. Eighty-nine percent (24 of 27)
      reported wrist pain both at the study onset and 1 year later. Nineteen gymnasts
      (40%) were pain-free at each collection. The floor exercise, the pommel horse,
      and the balance beam were most frequently associated with wrist pain symptoms.
      Multivariate analysis revealed that adolescent gymnasts between 10 and 14 years
      of age were significantly more likely to report wrist pain at each survey than
      those who were either above or below this age range (p = 0.03). Forty-two percent
      of subjects with wrist pain at each survey reported that the symptoms interfered
      with training. Only five gymnasts with wrist pain were seen by physicians.
      Training intensity increased in gymnasts with and without wrist pain. The
      relative increase within each group was statistically significant among pain-free
      gymnasts (p = 0.003), but was not for those with wrist pain (p = 0.08).
      CONCLUSIONS: Wrist pain among young, nonelite gymnasts is common, and appears to
      persist with continued training in the vast majority of those who report
      symptoms. Adolescent gymnasts between 10 and 14 years of age training at this
      level are significantly more likely to have wrist pain. Wrist pain appears to
      have a negative effect upon training, based upon both self-report and training
      intensity measures; however, more study is needed with respect to this issue.

PMID- 12466690
TI  - Upper extremity injuries in snowboarding and skiing: a comparative study.
AB  - OBJECTIVES: To determine the types and causes of upper extremity injuries
      sustained while snowboarding. DESIGN: A prospective survey of snowboarders with
      upper extremity injuries, especially fractures and dislocations. PARTICIPANTS:
      Between 1995 and 2000, we analyzed and interviewed 6,837 injured snowboarders and
      2,175 injured skiers, and a total of 2,742 snowboarders and 361 skiers with
      fractures or dislocations of the upper extremities were studied. RESULTS: The
      ratio of upper extremity injuries to all injury types was significantly higher in
      snowboarders (40%, p < 0.001). Shoulder dislocations accounted for 5.5% of all
      injuries in skiers but 71% of all dislocations. In comparison, 6.5% of
      snowboarders' injuries were shoulder dislocations, representing 50% of all
      dislocations. It was noted that dislocation of the elbow joint was a more
      characteristic injury of snowboarders (30%) than of skiers (3%). The most
      frequently fractured site in skiers was the clavicle (32% of all fractures), and
      in snowboarders, it was the wrist (62% of all fractures). The most frequently
      affected side of the snowboarders' upper extremity was the left, with the
      exception of wrist fractures. With the exception of wrist fractures, the edge
      side that caused the accident was the opposite of the side that was injured. Most
      snowboarders did not have initial instruction from professional instructors (93%)
      and did not use protective equipment (87%). CONCLUSIONS: The results of this
      study indicate that the upper extremity injuries are much more common in
      snowboarders than skiers. In particular, upper extremity fractures in
      snowboarders are three times more common than in skiers. Furthermore, in
      snowboarding, wrist fractures have a different underlying cause compared with
      other upper extremity injuries.

PMID- 12466691
TI  - Survey analysis to assess the effectiveness of the bull tough helmet in
      preventing head injuries in bull riders: a pilot study.
AB  - OBJECTIVE: The purpose of this pilot study was to assess the effectiveness of the
      Bull Tough helmet (Bull Tough, Seguin, TX) in preventing head injuries to bull
      riders. The hypothesis was that this helmet is effective in diminishing the
      incidence of head injuries in bull riders. DESIGN: This study was a retrospective
      study. METHODS: Surveys were mailed to 320 purchasers of the Bull Tough helmet.
      Participants were asked to recall the numbers of rides performed in 1999 while
      wearing the helmet and the number of rides performed in 1999 while not wearing
      the helmet. In addition, they were asked to provide the number and severity of
      head injuries suffered in 1999 both while wearing the helmet and while not
      wearing the helmet. SETTING: Participants responding to the survey were bull
      riders from the United States and Canada. PARTICIPANTS: Eighty-one riders
      responded to the survey. MAIN OUTCOME MEASUREMENTS: The primary outcome
      measurements were planned before data collection began and included the incidence
      of head injuries to bull riders both while wearing the helmet and while not
      wearing the helmet. RESULTS: While not wearing a helmet, the incidence of head
      injury was 1.54% per ride (11 head injuries/713 rides). While wearing the helmet,
      the incidence of head injury was 0.80% per ride (28 head injuries/3,518 rides).
      Using the X(2) test, the p value was 0.0570. CONCLUSIONS: This study supports the
      hypothesis that the Bull Tough helmet diminishes the incidence of head injury in
      bull riders.

PMID- 12466692
TI  - Test-retest reliability of glenohumeral internal and external rotator strength.
AB  - OBJECTIVE: To establish test-retest reliability for a strength testing protocol
      of the glenohumeral internal and external rotator muscles using a KinCom
      (Chattanooga Group, Hixson, TN) isokinetic dynamometer. DESIGN: Prospective test
      retest reliability study. SETTING: Rehabilitation research laboratory.
      PARTICIPANTS: Fourteen volunteers between the ages of 27 and 35 years
      participated in the study. Subjects had no history of traumatic shoulder injury
      and no overuse-based shoulder pain interfering with activity within the last 6
      months. Nine of the 14 subjects were not participating in more than 6 hours
      weekly of arm-based sporting activities, while the remaining five subjects were
      involved in swim training at workout volumes of no greater than 3000 m per week.
      INTERVENTION: Subjects performed three test sessions of four maximal repetitions
      each of concentric and eccentric shoulder internal and external rotation
      bilaterally in a standardized sitting position. An average of 5.9 days occurred
      between consecutive test sessions (range, 2-21 days). MAIN OUTCOME MEASURES:
      Average torque data were collected for concentric and eccentric internal and
      external rotation tests bilaterally. Intraclass correlation coefficients were
      calculated to compare the data across sessions. Pearson product moment
      correlation coefficients were calculated to assess reliability between sessions.
      RESULTS: High test-retest reliability, ranging from 0.82 to 0.97, was
      demonstrated for all tests. CONCLUSIONS: The results indicate that a reliable
      test protocol has been determined for shoulder internal and external rotation
      strength testing on the KinCom isokinetic dynamometer.

PMID- 12466693
TI  - Preliminary comparison of bromelain and Ibuprofen for delayed onset muscle
      soreness management.
AB  - OBJECTIVE: The purpose of this study was to determine whether a common bromelain
      regimen or common ibuprofen regimen are effective in resolving pain and muscle
      dysfunction associated with delayed onset muscle soreness of the elbow flexors.
      DESIGN: A randomized, double-blinded, repeated measures design was used for this
      study. SETTING: The study was performed in the Sports Injury Research Lab at an
      NCAA Division I university. PARTICIPANTS: Forty subjects who had not participated
      in an upper body resistance-training program 3 months prior to the study,
      suffered pain or injury in the nondominant arm, or experienced an adverse
      response to nonsteroidal anti-inflammatory drugs or pineapple (bromelain source)
      were recruited. Thirty-nine subjects finished the study. INTERVENTIONS: Active
      range of motion (ROM), perceived pain, and peak concentric torque measurements of
      the nondominant arm were taken prior to and 24, 48, 72, and 96 hours following an
      eccentric exercise protocol of the elbow flexors. Subjects were assigned to one
      of four treatment groups (bromelain 300 mg t.i.d., ibuprofen 400 mg t.i.d.,
      placebo t.i.d., and control) and began treatment immediately following the
      exercise protocol. MAIN OUTCOME MEASURES: No differences among treatments were
      observed for any of the dependent variables at any time. ROM deficits and pain
      peaked between 48 and 72 hours. Peak torque deficiencies were observed between 24
      and 72 hours. CONCLUSIONS: Ingestion of bromelain and ibuprofen had no effect on
      elbow flexor pain, loss of ROM, or loss of concentric peak torque as a result of
      an eccentric exercise regimen.

PMID- 12466694
TI  - Community-based exercise assessment in children with high risk for type 2
      diabetes.
AB  - OBJECTIVE: To assess the risk factors for a group of children at high risk for
      type 2 diabetes using a proven medical model and incorporating a community
      friendly standardized fitness assessment tool. DESIGN: All children in school
      (kindergarten to grade eight) in an isolated First Nation community were enrolled
      to be screened for diabetes, risk factors, and fitness level. SETTING: Beausoleil
      First Nation community is an Ojibway community situated on Christian Island in
      Georgian Bay, Ontario, Canada. PARTICIPANTS: All children attending Christian
      Island Elementary School, a total of 101 students from kindergarten to grade
      eight. INTERVENTIONS: Capillary blood glucose fasting and 2 hours after 75-g
      simple carbohydrate meal, height and weight (calculated BMI), blood pressure,
      aerobic capacity, abdominal strength and endurance, upper body strength, trunk
      extensor strength and flexibility, and upper body flexibility. OUTCOME
      MEASUREMENTS: Applicability of tests to assess disease, risk factors, and fitness
      level. RESULTS: Eight children were found to have abnormal capillary blood
      glucose and required further laboratory investigations. Significant risk factors
      for type 2 diabetes were identified. The screening exercise assessment identified
      specific areas below that considered a healthy fitness zone. CONCLUSIONS: The
      screening assessment identified medical areas of concern in capillary blood
      glucose, blood pressure, and body mass index. The fitness testing identified
      areas of concern in aerobic capacity, upper body strength, abdominal strength and
      endurance, and flexibility. The fitness testing was First Nation community
      friendly.

PMID- 12466695
TI  - A moderate dose of pseudoephedrine does not alter muscle contraction strength or
      anaerobic power.
AB  - OBJECTIVE: To investigate the effect of an acute oral administration of
      pseudoephedrine (PSE) on muscle function, fatigue, and anaerobic power output.
      DESIGN AND MATERIALS: Healthy males (N = 10) and females (N = 10) were allocated
      to receive both a placebo and PSE (120 mg) using a randomized, double-blind,
      crossover experimental design. Each subject had their maximal voluntary
      contraction strength and fatigability measured for both handgrip and ankle dorsi
      flexion. Following the strength measurements, a 30-second maximal cycle test was
      performed to determine lower extremity anaerobic power and fatigue. Plasma
      lactate was measured before and after exercise. RESULTS: There were no
      significant differences in any of the outcome variables between the placebo and
      PSE trials. CONCLUSIONS: These results demonstrated that a 120 mg dose of PSE did
      not enhance force production, time to fatigue, fatigue index, or power output in
      young men or women. Therefore, there does not appear to be an ergogenic benefit
      from the ingestion of 120 mg PSE in high-intensity exercise performance.

PMID- 12466696
TI  - Weight changes, sodium levels, and performance in the South African Ironman
      Triathlon.
AB  - OBJECTIVE: To establish relationships between body weight changes and serum
      sodium during and after an Ironman Triathlon, and postrace fluid status and
      rectal temperature, including the incidence of hyponatremia. DESIGN: Descriptive
      research. SETTING: The 2000 South African Ironman Triathlon, in which each
      athlete swam 3.8 km, cycled 180 km, and ran 42.2 km. PARTICIPANTS: All entrants
      in the race were invited to participate in the study. METHODS: Athletes were
      weighed at registration, immediately prerace, immediately postrace, and 12 hours
      later. Blood samples were drawn at registration and immediately postrace. Rectal
      temperatures were measured postrace. RESULTS: Starting body weight was
      significantly related to total finishing time (r = 0.27) and to cycling (r =
      0.20) and running (r = 0.28) time. Body weight decreased significantly (p <
      0.0001) during the race and had not returned to prerace values 12 hours later (p
      < 0.0001). Percentage change in body weight was unrelated to postrace rectal
      temperatures and inversely related to the postrace serum sodium concentrations (r
      = -0.45). Postrace serum sodium concentrations fell within a normal distribution
      (141.8 +/- 3.1 mmol.L(-1), mean +/- SD) and were negatively correlated to overall
      triathlon time (r = -0.22). Three sodium values (0.6%) were below 135 mmol.L(-1).
      Percentage change in body weight was unrelated to time in the marathon leg.
      CONCLUSIONS: Percentage change in body weight was linearly related to postrace
      serum sodium concentrations but unrelated to postrace rectal temperature or
      performance in the marathon. There was no evidence that in this study, more
      severe levels of weight loss or dehydration were related to either higher body
      temperatures or impaired performance.

PMID- 12466697
TI  - Management of splenic rupture and return-to-play decisions in a college football
      player.

PMID- 12466699
TI  - Use of multiple arterial grafts and its effect on long-term outcome.

PMID- 12466700
TI  - Outcomes in single versus bilateral internal thoracic artery grafting in coronary
      artery bypass surgery.
AB  - The authors analyzed the early outcomes in two groups of patients undergoing
      coronary artery bypass grafting (CABG) with single versus bilateral internal
      thoracic arteries (ITA) in their institution. One thousand sixty-nine patients
      underwent CABG with single or bilateral ITAs from 1990 to 2000. Of these
      patients, 911 (85.2%) had single ITA and 158 had bilateral ITA (14.8%). The
      incidence of tobacco abuse was 40.3% in the single ITA group and 56.7% in the
      double ITA group (P = 0.0001). The incidence of perioperative myocardial
      infarction, renal failure, reoperation for bleeding, stroke, or operative
      mortality did not differ in the two groups. There was a 4.4% incidence of
      mediastinitis in the bilateral ITA group versus 2.2% in the single ITA group (P =
      0.0602). Early outcomes after bilateral ITA grafting for CABG are similar to
      single ITA grafting. Careful judgment should be exercised in selecting patients
      for bilateral ITA grafting, particularly if the patient smokes.

PMID- 12466701
TI  - Robotics and coronary artery surgery.
AB  - Significant progress in cardiac surgery, and specifically the surgical management
      of coronary artery disease, has been due in large part to enabling technology.
      Robotic systems have been recently developed and refined for use in cardiac
      surgery to facilitate, among other procedures, a totally endoscopic approach to
      coronary artery bypass surgery. These systems enhance precision through
      endoscopic approaches by specifically addressing the inherent limitations of
      conventional endoscopic coronary microsurgical instrumentation via computerized,
      digital interface, telemanipulation technology. With a combined experience of 125
      patients, several groups have independently demonstrated the clinical feasibility
      of totally endoscopic coronary artery bypass with two commercially available
      robotic telemanipulation systems. Additional enabling technology is needed to
      overcome the challenges currently limiting development and widespread application
      of totally endoscopic off-pump multivessel coronary artery bypass surgery.

PMID- 12466702
TI  - Role of low-molecular-weight heparin in the management of acute coronary
      syndromes.
AB  - In the past few years, several clinical trials with low-molecular-weight heparins
      in acute coronary syndromes without ST-segment elevation have been published. In
      the acute phase of treatment, enoxaparin obtained better results than
      unfractionated heparin, but dalteparin and nadroparin did not. Enoxaparin also
      obtained better results than tinzaparin. From these results, it can be assumed
      that the efficacy of enoxaparin is higher than that of dalteparin and nadroparin.
      However, because low-molecular-weight heparins have not been compared head to
      head (except in the case of enoxaparin and tinzaparin), and given the differences
      between studies in patient selection criteria, design, treatment strategies, and
      efficacy variables, it cannot be concluded that one low-molecular-weight heparin
      is superior to another in the acute phase of treatment. Prolonged dalteparin
      treatment suggests a benefit, particularly for patients at high risk (defined as
      those with high troponin levels), and it can also be useful in patients waiting
      for invasive procedures.

PMID- 12466703
TI  - A multifaceted search for the presence of high-risk, vulnerable plaque.

PMID- 12466704
TI  - Biologic aspects of vulnerable plaque.
AB  - Atherosclerosis and its thrombotic complications are the major cause of morbidity
      and mortality in the industrialized world. The progression of atherosclerotic
      plaques in coronary circulation is modulated by several risk factors. It is now
      clear that plaque composition is a major determinant of plaque disruption and
      superimposed thrombosis. Plaque vulnerability, defined as the propensity of
      plaques to disrupt, is further determined by intrinsic and extrinsic triggering
      factors. After disruption, the fatty core of the plaque and its high content of
      tissue factor provide a powerful substrate for the activation of the coagulation
      cascade. Plaque disruption can be clinically silent or cause symptoms of ischemia
      depending on thrombus burden and the degree of vessel occlusion. In addition,
      plaque disruption and subsequent healing are recognized to play key roles in the
      rapid plaque progression. This review looks at the mechanisms underlying the
      development and progression of atherosclerotic plaques, factors leading to plaque
      rupture and subsequent thrombosis, and their clinical consequences as potential
      targets for future research.

PMID- 12466705
TI  - Vulnerable atherosclerotic plaque: emerging challenge for animal models.
AB  - A recent shift in the clinical paradigm of acute coronary syndromes led to a
      burst of activity in developing animal models related to plaque vulnerability. In
      the present review, animal models of spontaneous and induced plaque rupture,
      thrombosis, and hemorrhage and "vulnerability endpoints" in conventional models
      of atherosclerosis are discussed. These endpoints include readouts related to
      biomechanical properties of the plaques, collagen turnover, underlying
      inflammation, and lipid accumulation. Challenges in model validation are
      emphasized. Development of new animal models and new tools of monitoring plaque
      vulnerability will facilitate design of plaque-stabilizing therapies.

PMID- 12466706
TI  - Angioscopy and ischemic heart disease.
AB  - Angioscopy allows direct visualization of the coronary artery lumen and provides
      detailed information regarding the surface characteristics of the vessel wall and
      specific lesions causing acute coronary syndromes. Disruption of a plaque,
      ulceration, tears, fissures, lipid-rich or fibrous lesions, and luminal or mural
      thrombus can be readily detected in vivo. Characterization of culprit lesions in
      various coronary syndromes reveals the different mechanisms of ischemia. The
      predominant lesion in acute myocardial infarction is an ulcerated, yellow plaque
      with thrombus. In unstable angina, different substrates can be seen, from the
      lipid-rich lesion with thrombus to the fibrous smooth plaque, reflecting a varied
      physiopathology. Because of its ability to detect superficial lipid pools,
      angioscopy may be valuable for the detection of vulnerable plaques.

PMID- 12466707
TI  - Identification of high-risk atherosclerotic plaques: a survey of spectroscopic
      methods.

PMID- 12466708
TI  - Characterizing arterial plaque with optical coherence tomography.
AB  - Many imaging technologies have been pivotal in the reduction of mortality
      associated with coronary artery disease over the last 50 years. However, there
      are several areas where coronary disease could benefit from high-resolution
      imaging. Recently, optical coherence tomography (OCT) has been introduced for
      micron scale intravascular imaging. OCT is analogous to ultrasonography,
      measuring the intensity of back-reflected infrared light rather than sound.
      First, its resolution, at 4 to 20 microm, is higher than that of any currently
      available imaging technology. Second, acquisition rates are near video speed.
      Third, unlike ultrasonography, OCT catheters consist of simple fiber optics and
      contain no transducers within their frame. This makes imaging catheters both
      inexpensive and small, the current smallest cross-sectional diameter being 0.014
      inches. Fourth, OCT systems are compact and portable. Finally, it can be combined
      with a range of spectroscopic techniques. This article reviews the application of
      OCT to intracoronary imaging.

PMID- 12466709
TI  - Intravascular thermography: a novel approach for detection of vulnerable plaque.

PMID- 12466710
TI  - Cardiac magnetic resonance imaging: a "one-stop-shop" evaluation of myocardial
      dysfunction.
AB  - A faster and more precise method for determining hibernating myocardium remains
      the holy grail of noninvasive cardiac imaging. Nuclear or echocardiogram-based
      imaging techniques have been the key modalities for evaluating important markers
      of cardiac viability. Advances in hardware and software for cardiac magnetic
      resonance imaging (CMRI) have transformed this valuable research tool into an
      important part of current noninvasive cardiac imaging. Due to its high spatial
      resolution and large field of view, CMRI offers unsurpassed images of the heart
      and its function. A combination of dobutamine stress function, vasodilator
      induced stress perfusion, and delayed hyperenhancement of contrast within the
      injured myocardium has become a one-stop shop in the routine assessment of
      cardiac viability following transient ischemic insult or myocardial infarction.

PMID- 12466711
TI  - Carotid artery stenting: acute and long-term results.
AB  - The objective of this study was to evaluate the safety and efficacy of carotid
      artery stenting (CAS) in high-risk patients. Carotid endarterectomy (CEA) has
      been shown to be more effective than medical therapy but has limitations. CAS may
      be a reasonable alternative, particularly in high-risk patients. The authors
      evaluated prospectively the safety and efficacy of CAS in 299 consecutive
      patients who underwent CAS of 343 extracranial carotid arteries. Of the patients
      enrolled, 210 (70%) would have been excluded from the major trials of CEA, and 84
      (28%) were referred by vascular surgeons. This series represents a very high-risk
      group that included patients with unstable angina, previous ipsilateral CEA,
      contralateral carotid occlusion, and other severe comorbid illnesses. Seventy
      four (25%) patients were aged 80 years or more. All patients had independent
      neurologic examination before and after the procedure. Three hundred seventy-six
      stents were deployed in 343 arteries. Procedural success was 99%. Mean stenosis
      was 75 +/- 12% before and 7 +/- 8% after the procedure. Ninety-two patients had
      coronary intervention. Only 56 (19%) patients were North American Symptomatic
      Carotid Endarterectomy Trial (NASCET) eligible. During the initial
      hospitalization and 30 days post-CAS, there were two (0.6%) major and seven
      (2.3%) minor strokes. There were no myocardial infarctions or deaths during or
      within 30 days of CAS. None of the NASCET-eligible patients had a stroke. At a
      mean follow-up period of 26 +/- 13 months, eight (2.7%) patients had asymptomatic
      restenosis. No additional major strokes or neurologic deaths occurred. In
      conclusion, CAS is feasible, can be performed even in high-risk patients, and is
      associated with a low restenosis rate.

PMID- 12466712
TI  - Genetic basis of thoracic aortic aneurysms and dissections.
AB  - The major diseases affecting the aorta are aortic aneurysms and dissections,
      which are classified based on anatomic location. Diseases affecting the ascending
      aorta, such as thoracic aortic aneurysms and type I and II dissections, are
      primarily associated with medial necrosis on pathologic examination. Medial
      necrosis is characterized by fragmentation and loss of elastic fibers, loss of
      smooth muscle cells, and interstitial collections of collagenous tissue and
      basophilic ground substance. Medial necrosis occurs as part of the normal aging
      of the aorta but is accelerated by other conditions, including hypertension and
      genetic alterations that predispose persons to these aortic diseases. The
      etiologies of many of the genetic syndromes, such as Marfan syndrome, that
      predispose persons to thoracic aortic aneurysms and dissections are understood.
      Studies are just beginning to elucidate the genes that predispose persons without
      known syndromes to these aortic diseases, and a major locus for this condition,
      termed the TAAD1 locus, has been mapped to 5q13-14. Future characterization of
      this gene and others will enhance the ability to determine persons at risk for
      aortic aneurysms and dissections and will define molecular mechanisms involved in
      the pathogenesis of this disorder.

PMID- 12466713
TI  - An economic evaluation of a school-based sexually transmitted disease screening
      program.
AB  - BACKGROUND: A school-based sexually transmitted disease (STD) screening program
      was implemented in eight New Orleans public high schools to detect chlamydia and
      gonorrhea. GOAL: The goal was to assess the incremental cost-effectiveness of
      replacing non-school-based screening with the school-based screening program.
      STUDY DESIGN: A decision-analysis model was constructed to compare costs and
      cases of expected pelvic inflammatory disease (PID) in the school-based screening
      scenario versus a non-school-based screening scenario. Cost-effectiveness was
      quantified and measured as cost per case of PID prevented. RESULTS: Under base
      case assumptions, at an intervention cost of $86,449, the school screening
      program prevented an estimated 38 cases of PID, as well as $119,866 in treatment
      costs for PID and its sequelae, resulting in savings of $1524 per case of PID
      prevented. Results remained cost-saving over a reasonable range of model
      parameter estimates. CONCLUSIONS: The New Orleans school-based chlamydia
      screening program was cost-effective and cost-saving and could be cost-effective
      in other settings. School-based screening programs of this type are likely to be
      a cost-effective use of public funds and can reduce the burden of STDs among
      adolescents.

PMID- 12466714
TI  - Epidemics due to imported syphilis in Finland.
AB  - BACKGROUND: Russia and other states of the former Soviet Union experienced a huge
      increase in syphilis beginning in the early 1990s. At first these epidemics were
      not well known in neighboring countries such as Finland. STUDY DESIGN: In 1995
      the incidence of syphilis in Finland doubled to 3.3/100,000 and a local cluster
      of 18 cases was detected in the city of Tampere. The reasons for this epidemic
      were analyzed and the occurrence of syphilis was carefully monitored up to 2001.
      RESULTS: The main reason for the increased incidence in Finland was the import of
      syphilis from Russia; only a few cases were acquired from Estonia or elsewhere.
      The source partners of Finnish men who contracted syphilis abroad were mostly sex
      workers or other casual partners. Mobile prostitution to Finland was not involved
      in the transmission. Most syphilis cases were found sporadically in southern
      Finland, in areas where foreign travel is frequent. Secondary transmission in
      Finland was usually limited to one or two partners. The only isolated cluster was
      further away and developed due to unawareness of the risk of syphilis by the
      cases and local healthcare providers. From 1995 onward, syphilis was carefully
      monitored by national reporting and a special sexually transmitted disease (STD)
      surveillance network, and the incidence remained at a constant level even though
      travel to and from Russia more than tripled. Nationwide serologic surveillance in
      STD and maternity clinics and among blood donors showed no major changes in the
      prevalence of syphilis. CONCLUSION: An epidemic of syphilis imported mainly by
      heterosexual men from Russia caused one sporadic cluster in Finland in 1995.
      Thereafter, general awareness by the public and healthcare providers about the
      risks of contracting syphilis from abroad, in addition to effective use of
      national surveillance and notification systems, was needed to protect the country
      from further spread of syphilis to an endemic infection.

PMID- 12466715
TI  - Acceptability of sexually transmitted infection screening among women in short
      term substance abuse treatment.
AB  - BACKGROUND: Substance abuse treatment centers provide an opportunity to offer
      sexually transmitted infection (STI) screening to a high-risk and hard-to-reach
      population. GOAL: The goal was to assess STI prevalence, risk factors, and
      acceptability of STI screening among females at substance abuse treatment centers
      with use of urine testing by ligase chain reaction and self-collected swab
      specimens. STUDY DESIGN: Adult, female inpatients were offered free testing and
      treatment for chlamydia infection, gonorrhea, and trichomonas infection.
      Interviews were conducted to collect risk behavior data. RESULTS: Eighty-six
      percent of inpatients (180/209) accepted testing. Twenty-three percent (41/177)
      had an STI. Of those with an STI, 90% (37/41) had trichomonas infection. All 41
      infected patients received treatment. Drug use before sex, exchange of sex for
      money/drugs, and any gynecological complaint were significantly associated with
      infection. Most women were uninsured (76%). Only 45% had undergone a medical
      examination in the past year. CONCLUSION: STI screening is highly acceptable
      among women in substance abuse treatment centers. Substance users are at high
      risk for STIs and may not otherwise receive medical care.

PMID- 12466716
TI  - Adolescent condom use and perceptions of risk for sexually transmitted diseases:
      a prospective study.
AB  - BACKGROUND: The authors' previous research has shown that in cross-sectional
      analysis, partner-specific perceptions of risk for gonorrhea and chlamydial and
      HIV infection correlated with partner-specific intentions to use condoms. GOAL:
      The goal was to determine whether partner-specific measures of perception of risk
      for STDs (PRSTD) predict partner-specific condom use 6 months later among high
      risk and low-risk youth. STUDY DESIGN: Youths aged 14 to 19 years were recruited
      from an STD clinic (n = 236) and an HMO teen clinic (n = 306) and were
      interviewed at baseline and at 6 months about PRSTD, attitudes about condoms,
      self-efficacy, normative expectations, and condom use. RESULTS: PRSTD with a main
      sex partner was an independent predictor of condom use with a main sex partner in
      the STD clinic cohort (odds ratio = 2.5; 95% CI = 1.1-6.2). There was no
      association between PRSTD with a casual sex partner and condom use in this cohort
      or between PRSTD for main or casual sex partners and condom use in the HMO teen
      clinic cohort. CONCLUSION: Interventions that target high-risk adolescents should
      focus on PRSTD with a main sex partner.

PMID- 12466717
TI  - Distribution of human papillomavirus types in cervicovaginal washings from women
      evaluated in a sexually transmitted diseases clinic.
AB  - BACKGROUND: Women evaluated for sexually transmitted diseases (STDs) may be at
      increased risk for human papillomavirus (HPV) infection, a condition associated
      with cervical dysplasia. The distribution of HPV types in such a population is
      unknown. GOAL: The goal was to determine the prevalence of HPV infection, the
      distribution of HPV types, and the type distribution in relation to cervical
      dysplasia in women in an STD clinic. STUDY DESIGN: Cervicovaginal lavage and
      Papanicolaou smear specimens were obtained from 295 women. Lavage specimens were
      analyzed for HPV by polymerase chain reaction/reverse blot strip assay. RESULTS:
      Cervical cytologic findings were abnormal for 19.7% of women. HPV DNA was
      detected in 49.2% of women (high-risk HPV in 42.4%). HPV positivity correlated
      with the degree of cytologic abnormality. In women with dysplasia, HPV types 16,
      66, 83, 56, 52, and 59 were commonly detected. Specimens containing abundant HPV
      DNA occurred most often in women with dysplasia. CONCLUSIONS: HPV infection was
      common in women attending an STD clinic. Numerous individual HPV types were
      associated with cervical dysplasia, including "low-risk" types.

PMID- 12466718
TI  - Prevalence monitoring in syphilis surveillance: results from a multicenter
      research program.
AB  - BACKGROUND: Syphilis seroprevalence data can be used as an independent measure of
      syphilis trends and to augment syphilis case report data for program planning.
      The prevalence of reactive syphilis serology in jails, delivery rooms, and drug
      treatment centers was examined from 1995 to 1999. Prevalence was evaluated by age
      and gender at each site and compared with county primary and secondary syphilis
      case rates. Annual prevalence of high titer-reactive serology in jails was
      compared with primary and secondary syphilis case rates. GOAL: The goal was to
      examine trends in syphilis seroprevalence and to evaluate the relationship of
      trends in seroprevalence to reported cases. STUDY DESIGN: This was a cross
      sectional survey. RESULTS: Prevalence of reactive serology and high titer
      reactive serology was lowest among women in delivery rooms (2.9% and 0.4%,
      respectively) and highest among women in jails (11.1% and 4.1%, respectively),
      indicating substantial recently treated or active infection among women in jails.
      Trends in high titer-reactive serology were similar to primary and secondary
      syphilis case rates. CONCLUSION: The prevalence of high titer-reactive serology
      can provide valuable information about community syphilis morbidity for use in
      prevention and control programs.

PMID- 12466719
TI  - High prevalence of Neisseria gonorrhoeae and multiple sexually transmitted
      diseases among rural women in the Eastern Highlands Province of Papua New Guinea,
      detected by polymerase chain reaction.
AB  - BACKGROUND: In a previous community-based study among rural women in the Eastern
      Highlands Province (EHP) of Papua New Guinea we determined that the prevalences
      of Trichomonas vaginalis infection, Chlamydia trachomatis infection, and syphilis
      were 46%, 26%, and 4%, respectively. Surprisingly, however, the prevalence of
      Neisseria gonorrhoeae infection was only 1%, which we considered low in
      consideration of the high prevalence of other sexually transmitted diseases
      (STDs). The aim of the current study was to reexamine samples that were collected
      in that survey and retest them with use of polymerase chain reaction (PCR). STUDY
      DESIGN: Using a cluster-sampling method, we surveyed 201 women aged 15 to 45
      years in a population of approximately 19,000 people. In addition, 243 other
      women living in the same area who wished to be screened for STDs were included in
      the study. METHODS: Endocervical samples that were stored frozen at -80 degrees C
      were retested with multiplex PCR (M-PCR) for the detection of both N gonorrhoeae
      and C trachomatis and with a separate PCR for the detection of T vaginalis.
      RESULTS: A total of 373 samples that were still available were analyzed. The
      prevalences of T vaginalis, C trachomatis, and N gonorrhoeae infections were
      42.6%, 26.5%, and 18.2%, respectively; 59.8% of the women had at least one STD,
      while 21.7% had mixed infections, 5.9% of them with all three pathogens.
      CONCLUSIONS: STDs are very common among rural women in the EHP of Papua New
      Guinea and often present as multiple infections.

PMID- 12466720
TI  - Characterization of ciprofloxacin resistance in Neisseria gonorrhoeae isolates in
      Canada.
AB  - BACKGROUND: Ciprofloxacin (500 mg orally, single dose) is one of the recommended
      therapies for gonorrhea in Canada. In Canada, the first ciprofloxacin-resistant
      (CipR) Neisseria gonorrhoeae strain was isolated in 1993. Antimicrobial
      susceptibilities of N gonorrhoeae isolates were monitored as part of a national
      surveillance program to ensure efficacy of antimicrobial therapies. GOAL: The
      goal was to determine the characteristics of ciprofloxacin resistance in Canadian
      gonococcal isolates. STUDY DESIGN: Susceptibility testing was performed on
      gonococcal strains from different provinces in Canada to determine the prevalence
      of CipR strains and their distribution. The CipR strains were further
      differentiated according to auxotype (A), serotype (S), plasmid profile (P), and
      pulsed-field gel electrophoresis (PFGE) profile. DNA sequencing and DNA
      microarray technology were used to determine mutations in gyrA and parC. RESULTS:
      In Canada, between 1997 and 1999, 4.8% of resistant strains (130 of 2687
      antibiotic-resistant N gonorrhoeae isolates) were CipR (MICs of 1-32 microg/l)
      and belonged to 48 A/S/P classes. Sixty-eight of the strains that were not
      differentiated by A/S/P were subtyped into 47 classes with PFGE. DNA sequencing
      and DNA microarray showed that the most common mutations had amino acid
      substitutions of Ser-->Phe at codon 91 and Asp-->Gly at codon 95 of the gyrA and
      Ser-->Arg at codon 87 of parC. CONCLUSION: The CipR strains isolated in Canada
      are phenotypically and genotypically diverse, indicating that they were imported
      from overseas and not endemic in Canada. Mutations in gyrA and parC previously
      only identified by DNA sequencing were successfully identified with DNA
      microarray technology. DNA microarray technology could be an alternative tool for
      identifying point mutations in resistance genes or other epidemiologic markers
      when clinical laboratories replace culture methods with rapid and automated
      molecular methods for diagnosis.

PMID- 12466721
TI  - Spotting the future.

PMID- 12466722
TI  - Detection of a novel Tet M determinant in tetracycline-resistant Neisseria
      gonorrhoeae from Uruguay, 1996-1999.
AB  - BACKGROUND: Determination of the diversity within the tet(M) sequence from N
      gonorrhoeae is a useful epidemiologic tool for monitoring the movement or
      importation of strains within a geographic region. Only two distinct tet(M) genes
      in clinical gonococcal isolates have been described up to now: the Dutch and the
      American types. GOAL: The study involved surveillance of the tet(M) gene types in
      high-level-tetracycline-resistant gonococcal isolates from Uruguay during the
      period 1996 to 1999. STUDY DESIGN: Among 181 gonococcal isolates, those showing
      MICs >/=16 microg/ml to tetracycline were analyzed for detection and
      characterization of the tet(M) gene by a polymerase chain reaction (PCR) and
      further HpaII restriction fragment polymorphism methods, respectively. The
      plasmid content and antibiogram were determined. RESULTS: Twenty-two of 181
      isolates (12%) exhibited high levels of resistance to tetracycline (MICs >/=16
      microg/ml) and harbored a putative 25.2-Mda plasmid that contained the tet(M)
      gene. A high percentage of isolates (95%; 21/22) presented the Dutch type tet(M)
      gene. One isolate from 1999 revealed a new restriction pattern. Such a pattern
      had been previously noted in 1991. This new restriction pattern has not been
      described previously as occurring in isolates of N gonorrhoeae. The tet(M)
      amplimer sequence showed 100% identity with a previously described tet(M)
      carrying plasmid from N meningitidis. CONCLUSION: A new HpaII restriction pattern
      of the tet(M) gene is present in low frequency. The tet(M) sequence was different
      from the gonococcal tet(M) sequences already known and not typable with the use
      of a differential PCR assay. Accordingly, with the genetic diversity already
      present within the tet(M) sequence of N gonorrhoeae isolates, we should be aware
      of the sensitivity of the PCR assays in use for tetracycline-resistant N
      gonorrhoeae detection.

PMID- 12466723
TI  - The ecology of sex work and drug use in Saratov Oblast, Russia.
AB  - BACKGROUND: The Russian Federation is experiencing epidemics of drug-injection
      associated HIV infection and high rates of syphilis and other sexually
      transmitted infections (STIs). GOAL: The goal of the study was to present the
      results of a rapid assessment focusing on sex workers (SWs) and drug users that
      was conducted in the Saratov Oblast in May 2000. STUDY DESIGN: We used four data
      collection techniques during this rapid assessment: review of available
      literature; in-depth interviews; naturalistic observations; and focus group
      discussions. RESULTS: Sex work in Saratov/Engels is more differentiated, with
      more categories of SWs, pimps with well-defined functions, and clearly formed
      escort services. In Balakovo, sex work is confined to individual women who are
      working as freelancers, most of whom are drug users. In the past 2 years, the
      drug of choice has shifted to heroin. The potential epidemiologic impact of sex
      work on the general population is defined in terms of the number of SW contacts
      per 100,000 population per year, which ranges from 32,800 to 730,000. Further
      elaboration of this simple measure is discussed. CONCLUSION: Our understanding of
      core group structure and characteristics, core-periphery contacts, and the impact
      of these on the spread of STI needs to be enhanced; comparative empirical data on
      such parameters need to be collected across societies.

PMID- 12466724
TI  - Gonorrhea surveillance: the missing links.

PMID- 12466725
TI  - Condom effectiveness: factors that influence risk reduction.

PMID- 12466726
TI  - The epidemiological and control implications of HIV transmission probabilities
      within partnerships.
AB  - BACKGROUND: The spread of HIV is in part determined by the probability of
      transmission within a sexual partnership. GOAL: The goal of the study was to
      examine the relationship between the per-partnership and per-act transmission
      probability and explore how different assumptions influence the measurement of
      cofactors and interventions. STUDY DESIGN: We defined the mathematical
      relationship between the transmission probability of HIV per sex act and per
      partnership for the proposed biologic mechanisms. For completeness we included
      the original assumption of a per-partnership transmission probability and also
      the simple binomial model, which cannot be ruled out completely because of
      potential measurement error in discordant partner studies. RESULTS: A constant
      per-act or per-partnership transmission probability provides unsatisfactory
      models of the observed relationship between the number of sex acts and the
      likelihood of transmission. Either there is extreme heterogeneity in the
      transmission likelihood between partnerships or the transmission likelihood
      within a partnership decreases over time. These models cause the relative risk
      for a partnership in which a cofactor STD is present to decrease more rapidly
      than would be expected. The transmission probability per-partnership is
      substantially reduced only when there is a dramatic reduction in unprotected acts
      (e.g., condom use) or the transmission probability per act (e.g., due to
      antiretrovirals or STD treatment). Combining interventions can sometimes generate
      a more-than-additive impact, particularly with extreme heterogeneity. CONCLUSION:
      More empirical studies are needed to develop realistic models of transmission
      providing quantitative understanding of the HIV transmission process.

PMID- 12466727
TI  - Prevalence of gonococcal and chlamydial infections and sexual risk behavior among
      youth in Addis Ababa, Ethiopia.
AB  - BACKGROUND: No community-based study on the magnitude of sexually transmitted
      diseases (STDs) has ever been conducted among young people in Ethiopia. GOAL: To
      assess the magnitude of Chlamydia trachomatis and Neisseria gonorrhoeae
      infections and status of sexual risk behavior among youths (15-24 years old) in
      Addis Ababa, Ethiopia. STUDY DESIGN: Youths in or out of school residing in two
      (of the six) administrative zones in Addis Ababa served as the study population.
      Participants filled out a self-administered questionnaire related to sexuality
      and its sociocultural determinants. First-void urine (FVU) was analyzed for
      gonorrhea and chlamydial infection by polymerase chain reaction (PCR). RESULTS: A
      total of 561 youths took part in the study. Urine PCR was performed for 522 of
      them. Nine subjects (1.7%) were found to have and N gonorrhoeae and C trachomatis
      infections. There were five cases (1.0%) involving each agent. Double infection
      was noted in one female subject. All but one of the infections were detected
      among the out-of-school youths (chi-square = 4.5; < 0.05). None of these subjects
      complained of symptoms suggestive of an active STD. One-third (188/561) reported
      having had sexual intercourse. The prevalence among sexually active youths was
      thus 4.8% (9/188) for both infections combined (2.7% for each agent). While 7/52
      (13.5%) of the sexually active females were found to also have STDs, only 2/136
      (1.5%) of the males had an STD (chi-square = 8.0; < 0.01). Report of sexual
      activity was significantly associated with being male, an age of >/=20 years, out
      of-school status, and report of alcohol/khat (amphetamine-like substance)
      consumption. Females reported less condom use, whether they were in or out of
      school and independent of age. CONCLUSIONS: Out-of-school youths, especially
      females, took more sexual risk and were exceedingly susceptible to STDs. This
      calls for alternative group-targeted strategies for sex education, disease
      prevention, and STD screening and management.

PMID- 12466728
TI  - Findings from STD screening of adolescents and adults entering corrections
      facilities: implications for STD control strategies.
AB  - BACKGROUND: Persons entering corrections facilities are at high risk for sexually
      transmitted diseases (STDs) because of risky sexual behavior and lack of access
      to routine screening. GOAL: The goal of the study was to develop a national
      picture of STD prevalence in this population. STUDY DESIGN: We analyzed
      information on age, race/ethnicity, urethral symptoms (men only), and test
      results for approximately 85,000 chlamydia, 157,000 gonorrhea, and 293,000
      syphilis tests for persons entering 23 jails and 12 juvenile detention centers in
      13 US counties from 1996 through 1999. RESULTS: At adult jails in nine counties,
      the median percentage of persons with reactive syphilis tests by county was 8.2%
      (range, 0.3-23.8%) for women and 2.5% (range, 1.0-7.8%) for men. At juvenile
      detention facilities in five counties, the median positivity for chlamydial
      infection was 15.6% (range, 8.0-19.5%) for adolescent girls and 7.6% (range, 2.8
      8.9%) for adolescent boys; the median positivity for gonorrhea was 5.2% (range,
      3.4-10.0%) for adolescent girls and 0.9% (range, 0.7-2.6%) for adolescent boys.
      Of adolescent boys testing positive for chlamydial infection at three juvenile
      facilities, approximately 97% did not report symptoms; of adolescent boys
      positive for gonorrhea, 93% did not report symptoms. CONCLUSION: STD positivity
      among persons entering corrections facilities is high. Most chlamydial and
      gonococcal infections are asymptomatic and would not be detected without routine
      screening. Monitoring the prevalence of STDs in this population is useful for
      planning STD prevention activities in corrections facilities and elsewhere in the
      community.

PMID- 12466729
TI  - Sexually transmitted diseases in Manitoba: evaluation of physician treatment
      practices, STD drug utilization, and compliance with screening and treatment
      guidelines.
AB  - BACKGROUND AND GOAL: There is little information in Manitoba on the utilization
      of drugs for sexually transmitted disease (STD) treatment and the extent to which
      physicians comply with STD screening and treatment guidelines. This study was
      undertaken to provide such information to inform policy and program development.
      METHODS: Physicians providing STD care were asked to complete a simple record for
      each new STD index client or contact seen. This information was subsequently
      linked with data from provincial diagnostic and treatment databases. RESULTS:
      Between October 1997 and September 1998, there were 2535 reports of STD
      treatments. Only about 25% of drugs provided by the provincial health department
      to physicians for STD treatment could be accounted for on the basis of the
      treatment reports received. Seventy-four percent of all treatments provided were
      presumptive ones for urethral or cervical infection or pelvic inflammatory
      disease (PID), and 14.4% of these were associated with subsequent positive tests
      for Chlamydia trachomatis or Neisseria gonorrhoeae. About three quarters of
      presumptive treatments were in compliance with provincial guidelines, as were
      most etiology-based treatments for chlamydial infection and 72% of etiology-based
      treatments for gonorrhea. Noncompliance with guidelines was commonly due to
      presumptive treatment that covered only C trachomatis, nonrecommended treatment
      for N gonorrhoeae, and incorrect treatment of PID. Only about 25% of women and 4%
      of men aged 15 to 24 years who visited a physician in 1997 were tested for C
      trachomatis. CONCLUSION: Increased educational efforts are required to improve
      physician compliance with STD screening and treatment guidelines, as well as
      ensure the appropriate use of STD drugs provided. Opportunities are being missed
      for screening for C trachomatis among young people, the majority of whom are seen
      regularly by a physician.

PMID- 12466730
TI  - Management of hypertensive emergencies of pregnancy by hydralazine bolus
      injection vs continuous drip--a comparative study.
AB  - This prospective study was conducted at Dhaka Medical College and Hospital,
      Bangladesh. The objective was to identify the time required to control high blood
      pressure levels in obstetric patients by injection of hydralazine in a bolus
      intravenous dose vs continuous drip. Seventy-seven patients with eclampsia and
      hypertensive emergencies comprised the target population. Patients were managed
      either by hydralazine drip in normal saline (existing official protocol, n = 33)
      or hydralazine bolus injection (as experiment, n = 44) until diastolic blood
      pressure fell to 90-95 mmHg. Results were compared. Student's t-test was done for
      statistical significance, and a P value of <.05 was considered as significant.
      The groups were similar with respect to maternal age and their mean systolic and
      diastolic blood pressure at the time of enrollment. Patients who received bolus
      injection required less time to achieve the therapeutic goal (65.23 +/- 23.38
      minutes) than continuous drip (186.36 +/- 79.77 minutes; P <.001). The
      experimental group also required significantly lower doses (6.68 +/- 1.66 mg) in
      comparison to that required by control group (20.07 +/- 11.38 mg; P <.001). There
      was no overshoot hypotension in either group. The data suggest that hydralazine
      bolus dose is equally safe and more effective than continuous drip in the
      management of hypertensive emergencies in pregnancy.

PMID- 12466731
TI  - Effects of estrogens and selective estrogen receptor modulators on indicators of
      cardiovascular health in postmenopausal women.

PMID- 12466732
TI  - Insulin and oral antidiabetic agents for treatment of polycystic ovary syndrome.
AB  - Insulin plays a major role in polycystic ovary syndrome (PCOS). Insulin
      resistance and resultant hyperinsulinemia stimulate both the ovary and adrenal to
      produce androgens. Oral antidiabetic agents have been used to alleviate the
      symptoms and to induce ovulation in women with PCOS. This review focuses on the
      relation between insulin and PCOS and discusses the use of oral antidiabetic
      agents.

PMID- 12466733
TI  - Effect of long-term continuous combined hormone replacement therapy with
      estradiol valerate and either dienogest or norethisterone acetate on mammographic
      density in postmenopausal women.
AB  - INTRODUCTION: The potential effect of hormone replacement therapy (HRT) on the
      appearance of the breast on screening mammography is of considerable interest and
      may have important practical implications. OBJECTIVE: The aim of this study was
      to evaluate the changes in the mammographic breast density during long-term
      continuous combined HRT with 2 different preparations. MATERIAL AND METHODS:
      Nineteen patients were studied. Fifteen were treated with Climodien (Schering, 2
      mg estradiol and 2 mg dienogest [E2/dienogest]), and 4 patients were treated with
      Kliogest (Novo Nordisk, 2 mg estradiol and 1 mg norethisterone acetate
      [E2/NETA]). All were followed with yearly mammography for 4 years. RESULTS:
      Increase in the mammographic density was noted in 3 patients (15.8%). The change
      was evident after the first year of treatment with no further change during the
      rest of the study period. CONCLUSIONS: Long-term therapy with continuous combined
      HRT (E2/dienogest or E2/NETA) increased breast density in 3/19 (15.8%) of the
      patients. Our results suggest that the effect of these HRT preparations on
      mammographic density may be less significant than suggested by the results of
      similarly designed trials evaluating different HRT preparations.

PMID- 12466734
TI  - Healthcare utilization among women with physical disabilities.
AB  - BACKGROUND: Current published data indicate barriers and deficiencies in
      healthcare for women with physical disabilities. Yet, information regarding the
      influence of secondary conditions and demographic variables on the actual
      utilization of general health and rehabilitative services is limited. This
      research examined this issue. DESIGN: Survey research SETTING: Metropolitan
      Philadelphia region PARTICIPANTS: 170 women between 21 and 65 years of age with
      physical disabilities RESULTS: Most (96%) women had seen a general healthcare
      provider (eg, personal physician or gynecologist) in the past 6 months, with 60%
      reporting seeing such a provider 3 or more times. Despite this high frequency,
      many women had not had routine preventive gynecologic cancer screening services
      in the past 5 years. Additionally, respondents reported experiencing on average
      12 secondary complications in the past year that moderately impaired their
      functioning. Many of these complications (fatigue, spasticity, deconditioning,
      joint pain, depression, social isolation) are preventable. Despite these
      complications, only about half of the women had seen a rehabilitative service
      provider (eg, physical therapist, mental health worker) in the past 6 months.
      Women who saw their general healthcare provider most frequently were more likely
      to also be receiving services from a rehabilitative service provider. CONCLUSION:
      General healthcare providers are frequently seeing women with physical
      disabilities. Healthcare providers have the ability and opportunity to enhance
      the health and wellness of this population. Particular attention should be
      focused on providing preventive healthcare services, including gynecologic cancer
      screenings and prevention and management of secondary conditions that accompany
      disability.

PMID- 12466735
TI  - The risk of cardiovascular disease with second- and third-generation oral
      contraceptives.

PMID- 12466736
TI  - Single-sex psychiatric services to protect women.
AB  - BACKGROUND: Most psychiatric services (eg, inpatient units, day therapy centers,
      outpatient clinics, and community clinics) are not currently segregated by sex,
      but recent developments--such as increasing psychiatric acuity and increasing
      numbers of comorbidities--have raised the level of violence and perceived threat
      in psychiatric facilities and have made a proportion of the more vulnerable
      patients feel unsafe. AIM: The purpose of this review is to examine the concept
      of vulnerability as it applies to female psychiatric patients and to review the
      literature on the determinants of violence in psychiatric facilities and on
      preferences among psychiatric patients with respect to same-sex vs mixed-sex
      psychiatric services. RESULTS: Literature from Great Britain and from disability
      organizations supports same-sex facilities as options for women who feel unsafe
      in mixed-sex facilities. Outcomes with respect to violent incidents have not been
      evaluated. CONCLUSIONS: Same-sex psychiatric facilities need to be implemented in
      a variety of communities and careful research conducted to examine potential
      benefits in specific populations.

PMID- 12466737
TI  - Leptin--a new member of the bone builders' club?

PMID- 12466738
TI  - Reflections on the WHI findings: avoiding a pill scare and taking sensible steps
      forward.

PMID- 12466739
TI  - Be careful of what you wish for: putting the WHI Estrogen/Progestin and HERS II
      Trials in perspective.

PMID- 12466740
TI  - Use of combination hormone replacement therapy in light of recent data from the
      Women's Health Initiative.

PMID- 12466741
TI  - Why individualizing hormone therapy is crucial: putting the results of the WHI
      trial into perspective.

PMID- 12466742
TI  - An alternative view on mothers holding stillborn babies.

PMID- 12466743
TI  - Are delayed and misdirected episiotomies predisposing factors for pelvic floor
      muscle dysfunction and third-degree tears?

PMID- 12466744
TI  - Novel technique: radiofrequency coagulation--a treatment alternative for early
      stage hemorrhoids.
AB  - BACKGROUND: For early-stage hemorrhoids, in which bleeding is the primary
      symptom, conventional approaches to management include injection of sclerosing
      solutions, band ligation, and infrared coagulation. In our study, we used the
      radiofrequency coagulation technique as an alternative strategy to treat early
      stage hemorrhoids. MATERIALS AND METHODS: A total of 210 patients with bleeding
      hemorrhoids were treated with radiofrequency coagulation at the Gupta Nursing
      Home in Nagpur, India. RESULTS: Follow-up was at 2 weeks, 3 months, and 12 months
      after procedure. Results were recorded as follows: (1) Bleeding--Twenty-eight
      (13%) patients had recurrence of bleeding during the observation period. (2) Pain
      -Some degree of discomfort was reported by all patients within the first 48
      hours. (3) Retention of urine--Only 1 patient had retention of urine; this
      patient was 74 years old and had an enlarged prostate. (4) Discharge--Thirty-four
      (16%) patients complained of discharge in the first 2 weeks after procedure. (5)
      Return to work--Seventy percent (n = 145) of patients resumed their duties after
      48 hours; the remainder required 1 additional day. (6) Sepsis--There were no
      reports of postprocedure sepsis. (7) Sphincter function--None of the patients
      experienced problems with continence or stenosis. Overall patient satisfaction
      was 84% (n = 177). CONCLUSION: Although these initial results of coagulation of
      hemorrhoids by radiofrequency appear quite exciting and encouraging, long-term
      follow-up is needed to assess the duration of relief and potential side effects.
      Continued work in this area will likely provide promising new dimensions in the
      effective management of early-stage hemorrhoids in which bleeding is the main
      symptom. A separate, randomized trial was carried out to assess the difference in
      efficacy between infrared coagulation and radiofrequency coagulation in 100
      patients with early-stage hemorrhoids. Radiofrequency coagulation was found to be
      more effective than infrared coagulation in terms of recurrence of bleeding,
      asymptomatic recurrences of hemorrhoids, and overall satisfaction of technique.

PMID- 12466745
TI  - EUS-guided pancreatic pseudocyst drainage: review and experience at Harbor-UCLA
      Medical Center.
AB  - Pancreatic pseudocyst, the most common cystic lesion of the pancreas, is a
      localized collection of fluid rich in amylase within or adjacent to the pancreas
      and enclosed by a nonepithelialized wall, occurring as a result of acute or
      chronic pancreatitis, pancreatic trauma, or pancreatic duct obstruction.
      Currently, at least 3 major forms of therapy are available: percutaneous
      drainage, surgical intervention, and endoscopic drainage. Controversy exists
      concerning which of these techniques should be offered to the patient as initial
      therapy. Three options exist for the surgical management of pancreatic
      pseudocysts: excision, external drainage, and internal drainage. Surgery, which
      traditionally was the major treatment approach for pancreatic pseudocysts, has
      been challenged by newer endoscopic techniques. Given the low complication and
      mortality rates and the high success rate of endoscopic drainage when compared
      with surgery, surgical intervention should be reserved only for certain cases.
      Addition of endoscopic ultrasonography (EUS) for endoscopic drainage is a new and
      exciting development and may decrease the risks associated with endoscopic
      drainage. We report our experience of 14 cases of EUS-guided pancreatic
      pseudocyst drainage and review the literature for advantages and disadvantages of
      these pancreatic pseudocyst drainage procedures. Complications, recurrence,
      success, and mortality rates for each procedure are described. Our approach to
      pancreatic pseudocyst management is described in the form of an algorithm.

PMID- 12466746
TI  - Genetic testing for breast and ovarian cancer for women with a family history of
      breast cancer: weighing conflicting evidence about oral contraceptives.

PMID- 12466747
TI  - Air travel and venous thrombosis: how much help might aspirin be?
AB  - There has been considerable attention focused recently on the risk of deep venous
      thrombosis (DVT) associated with air travel. Despite the lack of evidence among
      air travelers, a single dose of aspirin has been widely recommended as a means of
      preventing such thrombosis. We have calculated the potential benefit of aspirin
      by applying the data for aspirin in preventing DVT in hip fracture patients to
      the estimated rates of travel-related DVT. If the rate of travel-related DVT is
      20 per 100,000 travelers, then we will have to treat 17,000 people with aspirin
      to prevent 1 additional DVT.

PMID- 12466748
TI  - A note on indirect hemagglutination (IHA) antibody titers among hospitalized
      patients in Thailand with amebic liver abscesses.
AB  - Amebic hepatic abscess is a tropical disease with a wide spectrum of clinical
      presentations. A retrospective case review was performed on 39 hospitalized
      patients in Thailand with the diagnosis of amebic liver abscess. A total of 23
      men (59%) and 16 women (41%), with a mean age of 44.56 +/- 21.81 years (range, 10
      to 88 years), were involved in the study. The average duration of present illness
      was 7.33 +/- 0.83 days. Abscesses were discovered in the right lobe in 29
      patients (74.4%), in the left lobe in 3 patients (7.7%), and in both lobes in 7
      patients (17.9%). Thirty patients had single abscesses (76.9%) and 9 patients had
      multiple abscesses (23.1%). On admission, the average white blood count was 17.37
      +/- 6.34 x 1000 WBC/mm3, serum albumin was 2.86 +/- 0.61 g/dL, prothrombin time
      was 16.52 +/- 5.8 seconds, serum aspartate transaminase (AST) was 92.62 +/-
      118.74 U/L, serum alanine transaminase (ALT) was 83.74 +/- 107.84 U/L, serum
      alkaline phosphatase (ALP) was 407.68 +/- 343.42 U/L, and serum bilirubin was
      2.44 +/- 2.08 g/dL. Average indirect hemagglutination (IHA) titer of the cases
      was 1:1190.35 +/- 895.42 (range, 1:256 to 2048). Concerning the multiple logistic
      regression analysis, no significant correlation was found between antibody titer
      and the other parameters. Of interest, pathogenic organisms were detected in
      stool in only 2 cases. This study shows the usefulness of serologic study in
      diagnosis of amebic liver abscess.

PMID- 12466749
TI  - High prevalence of Fasciolopsis buski in an endemic area of liver fluke infection
      in Thailand.
AB  - There is a high prevalence of Fasciolopsis buski in Sawasdee Village in the Nam
      Som District, Udonthani Province in northeastern Thailand, an endemic area of
      liver fluke infection. From stool examination of 183 villagers participating in
      the study, the authors detected a fluke parasitic infection rate of 14.8% (27
      cases). Of interest, the authors found a similar high prevalence of both
      Opisthorchis viverrini (16 cases, 8.7%) and F buski (13 cases, 7.1%). This region
      is the endemic area of liver fluke, not of F buski. The surrounding environment
      is the hill area of Nayoong Namsom mountain, which is not a suitable area for F
      buski larvae. However, the village has been inhabited by a number of immigrants
      from various regions of Thailand over the past few years. The F buski can be
      carried by these people, possibly explaining the migration of the fluke parasite
      to this setting. The nonendemic parasite infection was also detected at high
      prevalence in the community. Wide spectrum control for various parasitic
      infections in villages like Sawasdee is necessary.

PMID- 12466750
TI  - Elevated end-tidal carbon dioxide during thoracoscopy.
AB  - We report a case of a patient with right pleural effusion who, during video
      assisted thoracoscopy for biopsy and diagnosis, developed a sudden rise in end
      tidal carbon dioxide (EtCO2) after a small tear of the lung tissue. The purpose
      of this case report is to highlight this rare complication and to discuss
      possible alternative differential diagnosis.

PMID- 12466751
TI  - Implications of the autonomy theory of nicotine dependence.

PMID- 12466752
TI  - Update on hepatitis B treatment.

PMID- 12466753
TI  - Dysphagia in a patient with rheumatoid arthritis and iron deficiency anemia.

PMID- 12466754
TI  - Biochemical relapse in prostate cancer: is PSA promoting stress and anxiety?

PMID- 12466755
TI  - New targeted therapies for lung cancer: expectations and reality.

PMID- 12466756
TI  - Immunotherapy of solid tumors: nonmyeloablative allogeneic stem cell
      transplantation.

PMID- 12466757
TI  - Highlights from the XXV International Congress of the World Federation of
      Hemophilia. May 19-24, 2002, Seville, Spain.

PMID- 12466758
TI  - Head and neck cancer carcinoma: new directions for treatment.

PMID- 12466759
TI  - Head and neck cancer: advances in radiation treatment.

PMID- 12466760
TI  - Diagnosis of bipolar disorders: focus on bipolar disorder I and bipolar disorder
      II.
AB  - Bipolar disorders are currently divided into 4 entities: bipolar I, bipolar II,
      cyclothymic disorder, and bipolar disorder not otherwise specified, as described
      in the fourth edition of the Diagnostic and Statistical Manual of Mental
      Disorders (DSM-IV). These subtypes of bipolar disorders cover a spectrum of
      severities, frequencies, and durations of manic and depressive symptoms. The
      differential diagnosis among these and with regard to other disorders with
      similar symptom features remains the foundation for treatment of bipolar
      disorders. It is clear that much diversity exists within these major subtypes,
      such that designations like "rapid cycling" and "bipolar III" are being put
      forward and probed for clinical relevance. Some of the concerns and advantages of
      including these less-established manifestations of bipolar disorders in our
      diagnostic thinking are discussed here, and the utility and drawbacks of our
      current diagnostic protocols are considered.

PMID- 12466761
TI  - Drug development.

PMID- 12466762
TI  - Current status of antiretroviral treatment interruption and intermittent therapy
      strategies.

PMID- 12466763
TI  - New developments in the management of hepatitis B virus/HIV coinfection.

PMID- 12466764
TI  - Young HIV-infected adults are at greater risk for medication nonadherence.
AB  - This study sought to estimate rates of adherence to nucleoside reverse
      transcriptase inhibitors (NRTIs) during the first year of administration in the
      California Medicaid (Medi-Cal) population. A retrospective analysis of pharmacy
      claims data regarding NRTI prescription refills was employed to estimate
      adherence and persistence with therapy throughout 1 year in treatment-naive
      individuals. Adherence was defined as the proportion of days on which drugs were
      taken during the first 365 days of therapy, and persistence was assessed
      according to whether prescriptions were refilled over time within a tolerable
      threshold (60 days). A total of 2614 men and 1174 women exhibited a mean overall
      adherence rate of 53.0%, and 35.6% of individuals were persistent with therapy
      throughout the year. No differences in persistence or adherence rates by sex were
      detected (P =.30). The proportion of individuals with adherence of 80% or better
      was 26%. Age was found to be significant in adherence and persistence by chi
      square examination (P =.001). We conclude that nonadherence can be a critical
      issue during the first year following initiation of therapy. Comprehensive
      adherence support programs may be required to maximize adherence, especially
      among subjects aged 18-24 years, and should be made available early in the course
      of therapy, or before it is initiated.

PMID- 12466765
TI  - Enhancing adherence to antiretrovirals: strategies and regimens.

PMID- 12466766
TI  - Venlafaxine in the treatment of painful peripheral diabetic neuropathy in a
      uremic patient undergoing hemodialysis.

PMID- 12466768
TI  - Criticism of Tom Houston's review of tobacco: a cultural history of how an exotic
      plant seduced civilization.

PMID- 12466769
TI  - High prevalence of HBsAg seropositivity in Hilltribers in the Mae Jam district in
      northern Thailand.

PMID- 12466770
TI  - Hepatic fibrosis--role of hepatic stellate cell activation.
AB  - Hepatic fibrosis is a reversible wound healing response characterized by
      accumulation of extracellular matrix (ECM), or "scar," that follows chronic but
      not self-limited liver disease. The ECM components in fibrotic liver are similar
      regardless of the underlying cause. Activation of hepatic stellate cells is the
      central event in hepatic fibrosis. These perisinusoidal cells orchestrate an
      array of changes including degradation of the normal ECM of liver, deposition of
      scar molecules, vascular and organ contraction, and release of cytokines. Not
      only is hepatic fibrosis reversible, but it is also increasingly clear that
      cirrhosis may be reversible as well. The exact stage at which fibrosis/cirrhosis
      becomes truly irreversible is not known. Antifibrotic therapies will soon be a
      clinical reality. Emerging therapies will be targeted to those patients with
      reversible disease. The paradigm of stellate cell activation provides an
      important framework for defining therapeutic targets.

PMID- 12466771
TI  - Groningen Manipulation Study. The effect of manipulation of the structures of the
      shoulder girdle as additional treatment for symptom relief and for prevention of
      chronicity or recurrence of shoulder symptoms. Design of a randomized controlled
      trial within a comprehensive prognostic cohort study.
AB  - BACKGROUND: We present the design of the Groningen Manipulation Study. This
      randomized controlled trial is part of the Dutch Shoulder Disability Study, a
      comprehensive prognostic cohort study on shoulder disorders, with randomized
      controlled interventions in subcohorts. OBJECTIVE: To evaluate the effectiveness
      of manipulative treatment of the structures of the shoulder girdle, in addition
      to standard treatment by the general practitioner for relief of shoulder symptoms
      and prevention of persistent or recurrent shoulder symptoms. METHODS: A total of
      250 patients with shoulder symptoms and a functional limitation of the shoulder
      girdle will be included from 30 general practices in Groningen, The Netherlands.
      All participating patients receive standard treatment by the general practitioner
      and will be randomly allocated to additional manipulative treatment. Evaluation
      measurements take place 6, 12, 26, and 52 weeks after randomization. CONCLUSION:
      The short-term primary outcome measure is the proportion of patients with relief
      of shoulder complaints and the long-term primary outcome is the proportion of
      patients without persistent or recurrent shoulder symptoms. Dependent and
      independent variables include a structured medical history, a physical
      examination of the shoulder and shoulder girdle, and a measure of the mobility of
      the cervico-thoracic spine with a 6-degree-of-freedom electromagnetic tracking
      device.

PMID- 12466772
TI  - Is the sagittal configuration of the cervical spine changed in women with chronic
      whiplash syndrome? A comparative computer-assisted radiographic assessment.
AB  - OBJECTIVE: To reveal whether women with chronic whiplash-associated disorder
      (WAD) symptoms, grade I-II, demonstrate regional and/or segmental radiographic
      signs of altered cervical lordosis. DESIGN: Case-control study. SETTING:
      Radiography department at a university hospital. PARTICIPANTS: Three age-balanced
      groups comprising 120 women. The case group included women with chronic whiplash
      syndrome (n = 41), and the control group included women with chronic insidious
      onset neck pain (n = 39) and an asymptomatic group (n = 40), who were given
      baseline data. The sample was referred from informed doctors and
      physiotherapists. INTERVENTION: The women sat in a standardized sitting position
      and radiographs were taken in a lateral position with fluoroscopic control for
      alignment. OUTCOME MEASURES: Two distinct measurements were taken; 1 of the
      angles of the upper and lower cervical curvatures, respectively, and 1 of the
      angles between the inferior borders of each pair of vertebrae in the lower
      cervical spine. The 3 groups were compared on the ratio of the lower to upper
      cervical spine angles and on the mean angular values for each segment in the
      cervical spine. RESULTS: The whiplash group showed a decreased ratio between the
      lower versus upper cervical spine but comparisons between groups were not
      statistically significant. The whiplash group was in a significantly more flexed
      position at the C4-C5 level compared with the asymptomatic group (P =.007). The
      reliability measures have to be strengthened to render these results definitely
      conclusive. CONCLUSION: The whiplash group exhibited a different configuration of
      cervical lordosis. This is clinically important and needs to be studied more
      closely.

PMID- 12466773
TI  - Vertebral arteries and cervical movement: Doppler ultrasound velocimetry for
      screening before manipulation.
AB  - OBJECTIVE: It has been proposed that Doppler velocimetry, which is noninvasive,
      quick, and relatively inexpensive, should be used when the screening vertebral
      arteries before manipulation to reduce the risk of cervical manipulation-related
      injury to these vessels. The objective of this analysis of the literature is to
      study the evidence of the suitability of Doppler velocimetry for this purpose.
      DATA SELECTION: Studies were examined that dealt with the incidence of stroke
      after manipulation, the proposed mechanisms for this clinical entity, the
      validity of the provocational tests that have been used in screening before
      manipulation, the validity and reliability of Doppler velocimetry of vertebral
      arteries, and the biomechanics of vertebral arteries. RESULTS: There is a
      suspicion of increased risk for vertebrobasilar stroke for vertebral arteries
      that have markedly reduced patency in the neutral position and/or stenosis during
      cervical rotation. There is evidence that provocational tests lack validity and
      that Doppler velocimetry is valid in assessing the patency of vertebral arteries
      in the neutral position and during cervical rotation. Interexaminer reliability
      of the Doppler technique has been shown to be high. Doppler ultrasound screening
      also seems to be able to provide an indirect assessment of the mechanical
      stresses to the artery during cervical movements. CONCLUSION: There is strong
      evidence to suggest that Doppler velocimetry should be included in the screening
      of vertebral arteries before manipulation.

PMID- 12466774
TI  - Carotid artery blood flow during premanipulative testing.
AB  - BACKGROUND: Cervical manipulation is used millions of times every year. Concern
      about cerebrovascular accidents (CVAs) is common, but actual cases are rarely
      reported. Premanipulative tests are presumed to identify patients at risk of CVA.
      In an earlier study we found no significant changes in the vertebral artery blood
      flow of patients with a positive premanipulative test with different head
      positions. Consequently, we questioned whether there is a role for
      premanipulative testing to identify patients at risk of CVAs. OBJECTIVE: The aim
      of this study was to examine whether instead, blood flow velocity in the internal
      carotid arteries changes with head position in patients with a positive
      premanipulative test, potentially giving contraindication to cervical
      manipulation. METHODS: In a prospective study private practicing chiropractors
      from 3 Danish counties referred patients with a positive premanipulative test for
      an examination of cervical artery blood flow. Premanipulative testing was
      performed by an experienced chiropractor, and flow velocities were measured in
      both vertebral and internal carotid arteries by color duplex sonography at a
      university hospital vascular laboratory. RESULTS: A total of 11 consecutive
      patients with a positive premanipulative test were referred. Two of these were
      excluded because we could not reproduce any symptoms at repeat premanipulative
      testing before the vascular examination. In the remaining 9 patients we found no
      significant difference with different head positions in peak flow velocity or
      time-averaged mean flow velocity in the internal carotid arteries. Blood flow did
      not cease in 1 single patient despite a positive premanipulative test in all.
      CONCLUSION: It appears that a positive premanipulative test is not associated
      with a change in peak flow velocity or time-averaged mean flow velocity in either
      the carotid or the vertebral arteries. If premanipulative testing is used solely
      for the detection of vascular insufficiency as a potential substrate for CVAs
      after cervical manipulation, we believe that premanipulative testing is of little
      clinical value.

PMID- 12466775
TI  - A compilation of chiropractic and complementary/alternative medicine (CAM) data
      from public-use national surveys: report on a health-services research resource
      for the chiropractic and CAM scientific community.
AB  - BACKGROUND: Federally funded national surveys are routinely conducted to provide
      reliable, valid, and relevant data on health and health care, and these "public
      use" survey data are typically made available for further study by the wider
      scientific community. The full potential for using such data to examine the
      delivery, utilization, organization, and costs of chiropractic or
      complementary/alternative (CAM) health care remains largely untapped. OBJECTIVE:
      To report on a project that identifies and indexes public-use survey databases
      that contain explicit reference to chiropractic and CAM health care, and compiles
      that information into a web-based resource for the scientific community. METHODS:
      Review of database source collections. RESULTS: The utility and efficiency of
      secondary analyses as a cost-effective research strategy are well appreciated
      within the larger health-services research community, creating many possible
      opportunities for productive cooperative research endeavors across scientific
      disciplines. CONCLUSION: The Chiropractic and Complementary/Alternative
      Compilation User's Manual is available for free download at
      http://w3.palmer.edu/carber/manualhome.asp, or by following the links at the
      Palmer Center for Chiropractic Research homepage.

PMID- 12466776
TI  - Accuracy and reliability of a new, protractor-based neck goniometer.
AB  - OBJECTIVES: To assess the reliability of the SpinT, a new protractor-based
      device, for measuring active cervical spine ranges of motion. In addition, to
      compare the accuracy of the Cervical Ranges of Motion (CROM) instrument and SpinT
      measurements of rotation about the Y axis with and without tilt, the former
      motion occurring during natural rotation of the head. STUDY DESIGN: Interexaminer
      reliability, intraexaminer reliability, and accuracy trials were conducted.
      METHODS: Two examiners made 2 individual measurements of each of the individual
      cervical ranges of motion of 23 patients (15 men, 8 women; aged 21 to 42 years)
      with no cervical symptoms. The patients were asked to move their necks to end
      range while they sat upright. The accuracy of the CROM instrument and SpinT
      goniometers was assessed with a testing instrument capable of rotating and/or
      tilting to preset angles and upon which either device could be positioned.
      RESULTS: There was excellent agreement between the SpinT measurements of rotation
      about the Y axis compared with the readings from the testing platform regardless
      of the angle of tilt, whereas the CROM instrument displayed poor concordance when
      the tilt exceeded 5 degrees. The reliability trials generally yielded close
      agreement between the examiners, especially regarding measurements of rotation
      left and right and extension and revealed higher concordance regarding
      intraexaminer results. CONCLUSION: This study indicates that SpinT measurements
      of active cervical ranges of motion are reliable and that the SpinT goniometer
      accurately measures rotation with associated tilt.

PMID- 12466777
TI  - Contents for chiropractors' athletic event emergency bags.
AB  - BACKGROUND: Chiropractors are providing health care at a growing number of
      athletic events. With this increased participation it is critical that
      chiropractors be adequately prepared for these events with the proper knowledge,
      skill, and equipment to provide emergency care. OBJECTIVE: The objective was to
      recommend an inventory of items that should be included in a chiropractor's event
      site emergency bag, based on the best available evidence. DATA SOURCES: A pilot
      search was conducted by searching MEDLINE to retrieve articles regarding
      emergency supplies used at athletic events. Key terms were then taken from the
      pilot search and used to conduct a systematic search and review of the
      literature. STUDY SELECTION: Articles were included if they were published in
      English and discussed athletic event-site emergency first aid and supplies.
      Articles published in non-peer-reviewed publications were excluded. DATA
      EXTRACTION: Items recommended for event-site emergency care bags were extracted
      from 19 studies and reviewed by an expert panel of sports chiropractors. Expert
      rankings from a Likert scale were then averaged for each item. DATA SYNTHESIS:
      Items are categorized as recommended, possibly recommended, or not recommended
      based on expert rankings and frequency counts of citations. RESULTS: The most
      recommended items were latex gloves, penlights, and oral airways. An inventory of
      169 items with citations and ratings is included in this review. CONCLUSION: This
      is the first evidence-based article to delineate appropriate first aid and
      emergency equipment for sports chiropractors. This article has utility for
      educators who teach emergency care for athletic events and for practitioners who
      would like to have a clear inventory for their emergency bags.

PMID- 12466778
TI  - Stroke after chiropractic manipulation as a result of extracranial postero
      inferior cerebellar artery dissection.
AB  - OBJECTIVE: To describe a case of dissection of the postero-inferior cerebellar
      artery (PICA) after cervical manipulation. CLINICAL FEATURES: After cervical
      manipulation, a 42-year-old woman had a cerebellar syndrome related to an infarct
      in the area supplied by the PICA, confirmed by computed tomography of the brain.
      Cerebral angiography showed a normal appearance of the vertebral artery, a
      cervical extradural origin of PICA, and a dissection of the latter at the C1-C2
      level. INTERVENTION AND OUTCOME: Anticoagulant treatment with heparin was
      implemented. A positive outcome was achieved after 3 weeks. CONCLUSION:
      Anatomical variations of the vertebral arteries and their branches are not
      infrequent and may constitute a predisposing factor to complications after neck
      manipulation.

PMID- 12466779
TI  - Demarcation of vascular lesions on heart and brain SPECT: fabric art
      representation.

PMID- 12466780
TI  - Exercise myocardial perfusion imaging in elderly patients.
AB  - BACKGROUND: Exercise myocardial perfusion imaging (MPI) has significant value for
      risk stratification, but most patients studied have been middle-aged. In
      particular, the value of exercise MPI in elderly patients with interpretable
      electrocardiographic (ECG) stress test results has not been well defined. MEHODS
      AND RESULTS: Clinical, ECG stress test, MPI, and follow-up data for 626
      outpatients aged 65 years or older with interpretable electrocardiograms
      undergoing symptom-limited exercise MPI between 1992 and 1996 were analyzed.
      Follow-up was 97% complete after 4.4 +/- 1.3 years. After exclusion of the 27
      patients who underwent revascularization within 90 days of MPI, there were 361
      men and 217 women, aged 70.7 +/- 4.4 years. By univariate analysis, male sex,
      increasing age, an abnormal rest ECG result, lower exercise tolerance and lower
      peak exercise heart rates, exercise ST-segment depression, left ventricular
      dilatation, and the number of ischemic regions predicted death or myocardial
      infarction. By multivariable modeling, only increasing patient age, male sex,
      limitation of exercise tolerance, and the number of ischemic segments by MPI were
      predictive of subsequent death or myocardial infarction. CONCLUSIONS: In elderly
      patients referred for exercise MPI, age, sex, exercise tolerance, and MPI
      ischemia provide significant prognostic information.

PMID- 12466781
TI  - Safety and feasibility of atropine added to submaximal exercise stress testing
      with Tl-201 SPECT for the diagnosis of myocardial ischemia.
AB  - BACKGROUND: We aimed to assess whether atropine administration is safe and
      feasible in patients unable to reach the minimal heart rate (HR) required (80% of
      age-predicted HR) in myocardial scintigraphic studies after exercise stress
      testing (EST). METHODS AND RESULTS: We studied 108 patients who underwent
      myocardial perfusion scintigraphy after EST; 0.5 mg of atropine was administered
      to those showing signs of fatigue before reaching minimal HR (group A, n = 44).
      The scintigraphic results for group A were compared with those of patients who
      spontaneously achieved minimal HR (group B, n = 64). Coronary angiographic
      results, if available, and clinical follow-up were also compared. In group A,
      atropine increased HR by 13.7 +/- 7.4 beats/min. The percentage of maximal age
      related HR achieved was 83.3% +/- 7.5%; 74% achieved minimal HR. No major adverse
      effects occurred. When groups A and B were compared, baseline and peak HR, rate
      pressure product, and maximal metabolic equivalents achieved were higher in group
      B. There were no differences in number of perfusion studies positive for ischemia
      (group A, 26/44, and group B, 30/64; P =.2), coronary lesions, or clinical follow
      up. CONCLUSIONS: Atropine added to EST in patients who cannot achieve their 80%
      age-related HR is a safe and potentially useful method for myocardial perfusion
      studies.

PMID- 12466782
TI  - Safety and feasibility of cardiac FDG SPECT following oral administration of
      Acipimox, a nicotinic acid derivative: Comparison of image quality with
      hyperinsulinemic euglycemic clamping in nondiabetic patients.
AB  - BACKGROUND: Image quality of cardiac fluorine-18-deoxyglucose (FDG) studies is
      highly dependent on the metabolic conditions during the study; hyperinsulinemic
      euglycemic clamping ensures adequate image quality. However, the approach is time
      consuming. Data in a small number of patients suggest that oral administration of
      a nicotinic acid derivative (Acipimox, 250 mg; Byk, The Netherlands) results in
      good image quality. METHODS AND RESULTS: The safety and image quality of cardiac
      FDG single photon emission computed tomography studies after Acipimox
      administration were evaluated (21 patients, group 2); the results were compared
      with studies performed during hyperinsulinemic euglycemic clamping (69 patients,
      group 1). Image quality was assessed visually and quantitatively with use of
      heart-to-lung, heart-to-liver, and myocardium-to-background ratios. Blood samples
      were drawn at baseline and at the time of FDG injection to determine levels of
      glucose, free fatty acids, and insulin. Baseline characteristics of group 1 and 2
      patients were comparable. No side effects occurred in group 1. Four patients in
      group 2 (19%) had paroxysmal flushing. Image quality, assessed visually, was good
      in 100% of group 1 patients and in 86% of group 2 patients. Images were
      uninterpretable in only 1 patient in group 2 (5%). All quantitative parameters of
      image quality (heart-to-lung, heart-to-liver, and myocardium-to-background
      ratios) were comparable between group 1 and 2 patients. Baseline plasma levels of
      all substrates were comparable between groups. At the time of FDG injection,
      plasma levels of glucose and free fatty acids were comparable between groups;
      insulin was higher in group 1 patients. CONCLUSIONS: Cardiac FDG single photon
      emission computed tomography after Acipimox is a simple and safe approach that
      renders comparable image quality to that obtained during hyperinsulinemic
      euglycemic clamping.

PMID- 12466783
TI  - Gated SPECT in patients with hypertrophic obstructive cardiomyopathy undergoing
      transcoronary ethanol septal ablation.
AB  - BACKGROUND: Transcoronary ethanol septal ablation (TESA) is a novel treatment for
      obstructive hypertrophic cardiomyopathy (HOCM). Our objective was to evaluate the
      use of gated single photon emission computed tomography (SPECT) in patients with
      HOCM and the effects of TESA on myocardial perfusion. METHODS AND RESULTS: We
      performed gated SPECT and Doppler echocardiography before and 6 weeks after TESA
      in 30 patients with severe HOCM. The lung-to-heart and septal-to-lateral wall
      count-activity ratios were calculated. Before ablation, SPECT showed perfusion
      abnormalities in only 6 patients. Asymmetric septal hypertrophy was noted in 21
      patients (70%). In patients with a lung-to-heart ratio greater than 0.50 before
      ablation, the ratio decreased from 0.56 +/- 0.04 to 0.45 +/- 0.08 after ablation
      (P <.01). The septal-to-lateral wall ratio also decreased significantly after
      ablation. Mean Doppler pressure gradient across the left ventricular outflow
      tract decreased from 52 +/- 39 mm Hg to 13 +/- 13 mm Hg (P <.01) immediately
      after ablation and to 10 +/- 21 mm Hg 6 weeks later (P <.01). There were no
      significant changes in left ventricular ejection fraction by gated SPECT after
      the procedure. SPECT studies done after ablation showed fixed septal defects in
      29 of 30 patients (96.7%). The defects involved the basal and mid septum in 100%
      and 38% of patients, respectively, and ranged in size from 2% to 30% of the left
      ventricle (mean, 8.8% +/- 7.0%). CONCLUSIONS: TESA is an effective technique for
      relieving left ventricular outflow obstruction in patients with HOCM. Myocardial
      gated SPECT can identify the presence and location of infarction after TESA.

PMID- 12466784
TI  - Immunohistochemical-scintigraphic correlation of sympathetic cardiac innervation
      in postischemic left ventricular aneurysms.
AB  - BACKGROUND: This study was conceived to explore the correspondence between
      scintigraphic imaging of the sympathetic innervation of human postischemic left
      ventricular aneurysms and direct immunohistochemical localization of the nerve
      fibers in the same area. MATERIALS AND METHODS: In 7 patients undergoing left
      ventricular aneurysmectomy for postischemic ventricular aneurysm, the findings of
      thallium 201 and metaiodobenzylguanidine myocardial scintigraphy were compared
      with direct immunohistochemical localization of the nerve fibers in the same
      area. This comparison showed good correspondence between scintigraphic and
      immunohistochemical data, although scintigraphy failed to detect areas of minimal
      sympathetic innervation. Moreover, microscopic analysis showed sympathetic nerve
      fibers with peculiar morphology and distribution in the aneurysmal zone.
      CONCLUSION: There is a good correspondence between immunohistochemical and
      scintigraphic imaging in the detection of sympathetic cardiac nerves in human
      left ventricular aneurysms; a morphologically abnormal sympathetic reinnervation
      can be found in the aneurysmal area (although denervation can persist in some
      zones).

PMID- 12466785
TI  - Carvedilol improves left ventricular function in heart failure patients with
      idiopathic dilated cardiomyopathy and a wide range of sympathetic nervous system
      function as measured by iodine 123 metaiodobenzylguanidine.
AB  - BACKGROUND: Carvedilol treatment reduces the mortality rate in patients with
      congestive heart failure. It is not known whether carvedilol treatment is
      effective in heart failure patients with substantial cardiac sympathetic nerve
      dysfunction. The goal of this study was to determine the effect of chronic
      carvedilol treatment in patients with cardiac sympathetic nerve dysfunction of
      varying severity. METHODS AND RESULTS: In 22 congestive heart failure patients
      with idiopathic cardiomyopathy, sympathetic nerve function was assessed before
      and after 7.2 +/- 2.7 months of carvedilol treatment with the use of iodine 123
      metaiodobenzylguanidine (MIBG) imaging, radionuclide ventriculography, and
      transmyocardial norepinephrine sampling. Patients with relatively advanced
      impairment of cardiac sympathetic nerve function, as manifested by a baseline I
      123 MIBG ratio lower than 1.40, had a statistically significant improvement in I
      123 heart-mediastinum ratio with carvedilol treatment, from 1.26 +/- 0.12 to 1.39
      +/- 0.20 (P =.004). Of 10 patients with a baseline I-123 MIBG ratio lower than
      1.40, 9 had an increase in the heart-mediastinum ratio with carvedilol treatment.
      Left ventricular ejection fraction increased from 25.4% +/- 7.8% to 37.3% +/-
      14.7% (P <.001), with no difference between patients with relatively advanced
      versus relatively preserved cardiac sympathetic nerve function. CONCLUSION: Most
      patients with congestive heart failure show a favorable response in left
      ventricular function to carvedilol treatment, regardless of the baseline level of
      cardiac sympathetic nervous system function, as assessed by neuronal imaging with
      I-123 MIBG. Patients with relatively advanced impairment of baseline I-123 MIBG
      uptake are most likely to show evidence of improved cardiac sympathetic nervous
      system function in response to carvedilol therapy.

PMID- 12466786
TI  - Quantitative fluorine 18 deoxyglucose uptake by myocardial positron emission
      tomography in rats.
AB  - BACKGROUND: In vivo quantitative assessment of positron emission tomography (PET)
      with 2-deoxy-2-[fluorine 18]fluorodeoxyglucose (FDG) for rat heart has not been
      explored because of the theoretical limitation of spatial resolution. Our
      objective was to assess whether FDG uptake measured by PET is correlated with
      tissue radioactivity of FDG in rat heart directly measured by an automated gamma
      counter. METHODS AND RESULTS: Ten Sprague-Dawley rats were used for
      echocardiographic assessment and FDG-PET. Rats were sacrificed immediately after
      PET scanning, and the radioactivity of FDG in 4 segmental tissue samples of the
      middle transverse section was measured. Quantitative PET values in a total of 40
      regions of interest, in which partial volume effect was corrected based on the
      phantom study and wall thickness obtained by echocardiogram, were compared with
      radioactivity of the corresponding 40 tissue samples. Linear regression analysis
      revealed that tissue radioactivity of FDG was well correlated with the
      quantitative PET value (Y = 1.17X; r = 0.985, P <.0001). CONCLUSIONS:
      Quantitative FDG-PET for rat heart is a reliable approach for assessing glucose
      metabolism in vivo after correction is made for partial volume effect. These
      results can be used for various models of heart disease with repeated studies
      over the disease process in the same animal.

PMID- 12466787
TI  - Application of pixel truncation to reduce intensity artifacts in myocardial SPECT
      imaging with Tc-99m tetrofosmin.
AB  - BACKGROUND: Technetium 99m-labeled radiopharmaceuticals accumulate in the liver
      and gallbladder, where they generate intensity artifacts that can result in
      misdiagnosis of myocardial single photon emission computed tomography (SPECT)
      images. This study identifies and eliminates factors affecting the magnitude and
      appearance of intensity artifacts in a gallbladder-heart phantom. METHODS AND
      RESULTS: The myocardium and background compartments of a phantom were filled with
      Tc-99m at concentrations of 320 and 26.1 kBq/mL, respectively. A disposable
      plastic syringe containing 5 mL of Tc-99m as a model of the gallbladder was fixed
      in a position lateral to the heart phantom. Artifact intensity was determined on
      SPECT images over a specific activity range in the syringe (28.6, 6.6, and 0.2
      MBq/mL). Among 72 projection images, those with maximal heart counts in the
      region of interest were selected. Counts above and below 110% of the maximal
      heart count in all projection images were excluded and reconstructed,
      respectively. At 28.6 and 6.6 MBq/mL, excessive artifacts generated cold pixels
      immediately around the source, whereas lower activity (0.2 MBq/mL) caused the
      artifacts to disappear. Truncating the counts in the gallbladder caused the
      intensity artifacts at specific activities of 28.6 and 6.6 MBq/mL to disappear.
      CONCLUSIONS: The magnitude and appearance of intensity artifacts depend on
      contrast between extracardiac activities in the same slices of the heart in
      myocardial SPECT images with Tc-99m tetrofosmin, and pixel truncation can
      eliminate them.

PMID- 12466788
TI  - Myocardial ischemia in Kawasaki disease: evaluation with dipyridamole stress
      technetium 99m tetrofosmin scintigraphy.
AB  - BACKGROUND: The coronary artery abnormalities in Kawasaki disease (KD) often
      cause myocardial ischemia. Previous publications have described the use of
      thallium 201 myocardial perfusion imaging to determine the extent of ischemia in
      patients with KD. The technetium perfusion agents offer better resolution and may
      offer additional information about ventricular function in these patients. This
      study was performed to evaluate myocardial perfusion in patients with KD through
      use of technetium 99m tetrofosmin (TF) in conjunction with dipyridamole
      vasodilator stress. METHODS AND RESULTS: Eighty-six patients with KD aged 11.5 +/
      6.4 years and 20 age-matched control patients without heart disease were
      studied. Among 86 patients with KD, significant coronary artery stenosis
      (>or=75%) was observed in 20, coronary aneurysm without stenosis in 37, and no
      coronary lesions in 29. After administration of high-dose dipyridamole infusion
      (0.70 mg/kg), 74 to 370 MBq TF was injected and 148 to 740 MBq TF was injected at
      rest 4 hours later. Single photon emission computed tomography images were
      obtained more than 30 minutes after TF injection. Regional myocardial
      hypoperfusion was observed in 18 patients who had coronary artery stenosis of 75%
      or greater (sensitivity, 90%, and specificity, 100%). Two patients did not
      demonstrate ischemic changes in coronary artery stenosis in group I; one had good
      collateral flow. There were no TF injection-related complications. CONCLUSIONS:
      Tetrofosmin myocardial perfusion imaging can detect regional hypoperfusion in
      children with KD.

PMID- 12466789
TI  - The physiology of lipoproteins.
AB  - The seminal studies of Brown and Goldstein (Science 1986;232:34-47) coupled with
      the findings of the Framingham study revolutionized our understanding of the
      metabolic basis for vascular disease. These studies led to the widespread use of
      the coronary risk lipid profile, which uses the total cholesterol/high-density
      lipoprotein (HDL) ratio (or low-density lipoprotein [LDL]/HDL ratio) in
      predicting risk for vascular disease and as a tool for therapeutic management of
      patients at risk for vascular disease. However, although these methods are
      predictive of coronary artery disease (CAD) in general, it is also well known
      that the extent of occlusive disease and CAD varies greatly between individuals
      with similar cholesterol and HDL lipid profiles. For this reason, the National
      Cholesterol Education Program Expert Panel revised these guidelines and now
      recommends monitoring LDL and HDL cholesterol in the context of coronary heart
      disease risk factors and "risk equivalents." In addition, more recent findings
      indicate that specific alterations in individual lipoprotein subclasses may
      account for the variations in CAD in subjects with similar lipid profiles. For
      example, a preponderance of small, dense LDL particles correlates with a marked
      increase in risk for myocardial infarction independent of LDL levels. In
      particular, the association of small, dense LDL with elevated triglycerides
      (large, less dense VLDL) and reduced HDL has been defined as the atherogenic
      lipoprotein profile, and the key metabolic defect driving this profile may be
      elevated levels of triglycerides, specifically large, less dense VLDL. In an
      attempt to explain the physiologic basis for lipoprotein variations, this review
      describes the basic metabolic scheme underlying the traditional view of
      lipoprotein metabolism and physiology. It then examines the identity and role of
      the various lipoprotein subfractions in an attempt to distill a working model of
      how lipoprotein abnormalities might account for vascular disease in general and
      the metabolic syndrome in particular.

PMID- 12466790
TI  - Brain, behavior, mental stress, and the neurocardiac interaction.

PMID- 12466791
TI  - Transient ischemic dilation: a powerful diagnostic and prognostic finding of
      stress myocardial perfusion imaging.

PMID- 12466792
TI  - Safety and feasibility of atropine added to submaximal exercise stress testing
      with Tl-201 SPECT for the diagnosis of myocardial ischemia.

PMID- 12466793
TI  - And what do we tell our elders?

PMID- 12466794
TI  - Prognostic value of perfusion-FDG mismatch in ischemic cardiomyopathy.

PMID- 12466795
TI  - Contrast echocardiography.

PMID- 12466796
TI  - An electoral lecture.

PMID- 12466797
TI  - Coping with a budget reversal.

PMID- 12466798
TI  - Promoting animal research.

PMID- 12466799
TI  - Surgeons struggle with ethical nightmare of face transplants.

PMID- 12466800
TI  - Europe urged to provide boost for bioterror research.

PMID- 12466801
TI  - Prion data suggest BSE link to sporadic CJD.

PMID- 12466802
TI  - US pushes fish farming into deep water.

PMID- 12466803
TI  - Pathogen-tracking questioned.

PMID- 12466804
TI  - Funding freeze leaves eastern Germany out in the cold.

PMID- 12466805
TI  - Postdoc positions axed as economic crisis takes its toll.

PMID- 12466806
TI  - Field trials excluded from UK crop appraisal.

PMID- 12466807
TI  - Royal Institution's director blasts scientific sexism.

PMID- 12466810
TI  - Mouse genome: The real deal.

PMID- 12466811
TI  - Mouse genome: The real deal.

PMID- 12466812
TI  - Mouse genome: a forage in the junkyard.

PMID- 12466813
TI  - Piecing it all together.

PMID- 12466814
TI  - US embryo rules support 'right-to-life' agenda.

PMID- 12466815
TI  - Would you give up your grant for sustainability?

PMID- 12466816
TI  - Towards taxonomy's 'glorious revolution'.

PMID- 12466817
TI  - DNA committee is model for bioterrorism debate.

PMID- 12466818
TI  - Modelling a new angle on understanding cancer.

PMID- 12466819
TI  - Deserted by our geographical sense.

PMID- 12466824
TI  - Laser technology: ultraviolet upset.

PMID- 12466825
TI  - Immunology: education and promiscuity.

PMID- 12466826
TI  - Condensed-matter physics: Rabi flopping sees the light.

PMID- 12466828
TI  - Conservation biology: lone wolf to the rescue.

PMID- 12466829
TI  - Hydrodynamics: bend and survive.

PMID- 12466831
TI  - Animal communication: tree-hole frogs exploit resonance effects.

PMID- 12466832
TI  - Mathematics: What is the best way to lace your shoes?

PMID- 12466833
TI  - Laser-Raman spectroscopy: images of the Earth's earliest fossils?

PMID- 12466835
TI  - Palaeontology: thermal alteration of the Earth's oldest fossils.

PMID- 12466836
TI  - Drag reduction through self-similar bending of a flexible body.
AB  - The classical theory of high-speed flow predicts that a moving rigid object
      experiences a drag proportional to the square of its speed. However, this
      reasoning does not apply if the object in the flow is flexible, because its shape
      then becomes a function of its speed--for example, the rolling up of broad tree
      leaves in a stiff wind. The reconfiguration of bodies by fluid forces is common
      in nature, and can result in a substantial drag reduction that is beneficial for
      many organisms. Experimental studies of such flow-structure interactions
      generally lack a theoretical interpretation that unifies the body and flow
      mechanics. Here we use a flexible fibre immersed in a flowing soap film to
      measure the drag reduction that arises from bending of the fibre by the flow.
      Using a model that couples hydrodynamics to bending, we predict a reduced drag
      growth compared to the classical theory. The fibre undergoes a bending
      transition, producing shapes that are self-similar; for such configurations, the
      drag scales with the length of self-similarity, rather than the fibre profile
      width. These predictions are supported by our experimental data.

PMID- 12466837
TI  - Multiple ionization of atom clusters by intense soft X-rays from a free-electron
      laser.
AB  - Intense radiation from lasers has opened up many new areas of research in physics
      and chemistry, and has revolutionized optical technology. So far, most work in
      the field of nonlinear processes has been restricted to infrared, visible and
      ultraviolet light, although progress in the development of X-ray lasers has been
      made recently. With the advent of a free-electron laser in the soft-X-ray regime
      below 100 nm wavelength, a new light source is now available for experiments with
      intense, short-wavelength radiation that could be used to obtain deeper insights
      into the structure of matter. Other free-electron sources with even shorter
      wavelengths are planned for the future. Here we present initial results from a
      study of the interaction of soft X-ray radiation, generated by a free-electron
      laser, with Xe atoms and clusters. We find that, whereas Xe atoms become only
      singly ionized by the absorption of single photons, absorption in clusters is
      strongly enhanced. On average, each atom in large clusters absorbs up to 400 eV,
      corresponding to 30 photons. We suggest that the clusters are heated up and
      electrons are emitted after acquiring sufficient energy. The clusters finally
      disintegrate completely by Coulomb explosion.

PMID- 12466838
TI  - Non-framework cation migration and irreversible pressure-induced hydration in a
      zeolite.
AB  - Zeolites crystallize in a variety of three-dimensional structures in which oxygen
      atoms are shared between tetrahedra containing silicon and/or aluminium, thus
      yielding negatively charged tetrahedral frameworks that enclose cavities and
      pores of molecular dimensions occupied by charge-balancing metal cations and
      water molecules. Cation migration in the pores and changes in water content
      associated with concomitant relaxation of the framework have been observed in
      numerous variable-temperature studies, whereas the effects of hydrostatic
      pressure on the structure and properties of zeolites are less well explored. The
      zeolite sodium aluminosilicate natrolite was recently shown to undergo a volume
      expansion at pressures above 1.2 GPa as a result of reversible pressure-induced
      hydration; in contrast, a synthetic analogue, potassium gallosilicate natrolite,
      exhibited irreversible pressure-induced hydration with retention of the high
      pressure phase at ambient conditions. Here we report the structure of the high
      pressure recovered phase and contrast it with the high-pressure phase of the
      sodium aluminosilicate natrolite. Our findings show that the irreversible
      hydration behaviour is associated with a pronounced rearrangement of the non
      framework metal ions, thus emphasizing that they can clearly have an important
      role in mediating the overall properties of zeolites.

PMID- 12466839
TI  - The role of volatiles in magma chamber dynamics.
AB  - Many andesitic volcanoes exhibit effusive eruption activity, with magma volumes
      as large as 10(7)-10(9) m(3) erupted at rates of 1-10 m(3) x s(-1) over periods
      of years or decades. During such eruptions, many complex cycles in eruption rates
      have been observed, with periods ranging from hours to years. Longer-term trends
      have also been observed, and are thought to be associated with the continuing
      recharge of magma from deep in the crust and with waning of overpressure in the
      magma reservoir. Here we present a model which incorporates effects due to
      compressibility of gas in magma. We show that the eruption duration and volume of
      erupted magma may increase by up to two orders of magnitude if the stored
      internal energy associated with dissolved volatiles can be released into the
      magma chamber. This mechanism would be favoured in shallow chambers or volatile
      rich magmas and the cooling of magma by country rock may enhance this release of
      energy, leading to substantial increases in eruption rate and duration.

PMID- 12466840
TI  - The role of parasites in sympatric and allopatric host diversification.
AB  - Exploiters (parasites and predators) are thought to play a significant role in
      diversification, and ultimately speciation, of their hosts or prey. Exploiters
      may drive sympatric (within-population) diversification if there are a variety of
      exploiter-resistance strategies or fitness costs associated with exploiter
      resistance. Exploiters may also drive allopatric (between-population)
      diversification by creating different selection pressures and increasing the rate
      of random divergence. We examined the effect of a virulent viral parasite (phage)
      on the diversification of the bacterium Pseudomonas fluorescens in spatially
      structured microcosms. Here we show that in the absence of phages, bacteria
      rapidly diversified into spatial niche specialists with similar patterns of
      diversity across replicate populations. In the presence of phages, sympatric
      diversity was greatly reduced, as a result of phage-imposed reductions in host
      density decreasing competition for resources. In contrast, allopatric diversity
      was greatly increased as a result of phage-imposed selection for resistance,
      which caused populations to follow divergent evolutionary trajectories. These
      results show that exploiters can drive diversification between populations, but
      may inhibit diversification within populations by opposing diversifying selection
      that arises from resource competition.

PMID- 12466841
TI  - Calcium activation of BK(Ca) potassium channels lacking the calcium bowl and RCK
      domains.
AB  - In many physiological systems such as neurotransmitter release, smooth muscle
      relaxation and frequency tuning of auditory hair cells, large-conductance calcium
      activated potassium (BK(Ca)) channels create a connection between calcium
      signalling pathways and membrane excitability. BK(Ca) channels are activated by
      voltage and by micromolar concentrations of intracellular calcium. Although it is
      possible to open BK(Ca) channels in the absence of calcium, calcium binding is
      essential for their activation under physiological conditions. In the presence of
      intracellular calcium, BK(Ca) channels open at more negative membrane potentials.
      Many experiments investigating the molecular mechanism of calcium activation of
      the BK(Ca) channel have focused on the large intracellular carboxy terminus, and
      much evidence supports the hypothesis that calcium-binding sites are located in
      this region of the channel. Here we show that BK(Ca) channels that lack the whole
      intracellular C terminus retain wild-type calcium sensitivity. These results show
      that the intracellular C terminus, including the 'calcium bowl' and the RCK
      domain, is not necessary for the calcium-activated opening of these channels.

PMID- 12466842
TI  - CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.
AB  - The long-term persistence of pathogens in a host that is also able to maintain
      strong resistance to reinfection, referred to as concomitant immunity, is a
      hallmark of certain infectious diseases, including tuberculosis and
      leishmaniasis. The ability of pathogens to establish latency in immune
      individuals often has severe consequences for disease reactivation. Here we show
      that the persistence of Leishmania major in the skin after healing in resistant
      C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T
      cells. These cells constitute 5-10% of peripheral CD4+ T cells in naive mice and
      humans, and suppress several potentially pathogenic responses in vivo,
      particularly T-cell responses directed against self-antigens. During infection by
      L. major, CD4+CD25+ T cells accumulate in the dermis, where they suppress-by both
      interleukin-10-dependent and interleukin-10-independent mechanisms-the ability of
      CD4+CD25- effector T cells to eliminate the parasite from the site. The
      sterilizing immunity achieved in mice with impaired IL-10 activity is followed by
      the loss of immunity to reinfection, indicating that the equilibrium established
      between effector and regulatory T cells in sites of chronic infection might
      reflect both parasite and host survival strategies.

PMID- 12466846
TI  - Mining the mouse genome.

PMID- 12466847
TI  - Comparative genomics: the mouse that roared.

PMID- 12466848
TI  - Single nucleotide polymorphisms: tackling complexity.

PMID- 12466849
TI  - Functional genomics: a time and place for every gene.

PMID- 12466850
TI  - Initial sequencing and comparative analysis of the mouse genome.
AB  - The sequence of the mouse genome is a key informational tool for understanding
      the contents of the human genome and a key experimental tool for biomedical
      research. Here, we report the results of an international collaboration to
      produce a high-quality draft sequence of the mouse genome. We also present an
      initial comparative analysis of the mouse and human genomes, describing some of
      the insights that can be gleaned from the two sequences. We discuss topics
      including the analysis of the evolutionary forces shaping the size, structure and
      sequence of the genomes; the conservation of large-scale synteny across most of
      the genomes; the much lower extent of sequence orthology covering less than half
      of the genomes; the proportions of the genomes under selection; the number of
      protein-coding genes; the expansion of gene families related to reproduction and
      immunity; the evolution of proteins; and the identification of intraspecies
      polymorphism.

PMID- 12466852
TI  - The mosaic structure of variation in the laboratory mouse genome.
AB  - Most inbred laboratory mouse strains are known to have originated from a mixed
      but limited founder population in a few laboratories. However, the effect of this
      breeding history on patterns of genetic variation among these strains and the
      implications for their use are not well understood. Here we present an analysis
      of the fine structure of variation in the mouse genome, using single nucleotide
      polymorphisms (SNPs). When the recently assembled genome sequence from the
      C57BL/6J strain is aligned with sample sequence from other strains, we observe
      long segments of either extremely high (approximately 40 SNPs per 10 kb) or
      extremely low (approximately 0.5 SNPs per 10 kb) polymorphism rates. In all
      strain-to-strain comparisons examined, only one-third of the genome falls into
      long regions (averaging >1 Mb) of a high SNP rate, consistent with estimated
      divergence rates between Mus musculus domesticus and either M. m. musculus or M.
      m. castaneus. These data suggest that the genomes of these inbred strains are
      mosaics with the vast majority of segments derived from domesticus and musculus
      sources. These observations have important implications for the design and
      interpretation of positional cloning experiments.

PMID- 12466851
TI  - Analysis of the mouse transcriptome based on functional annotation of 60,770 full
      length cDNAs.
AB  - Only a small proportion of the mouse genome is transcribed into mature messenger
      RNA transcripts. There is an international collaborative effort to identify all
      full-length mRNA transcripts from the mouse, and to ensure that each is
      represented in a physical collection of clones. Here we report the manual
      annotation of 60,770 full-length mouse complementary DNA sequences. These are
      clustered into 33,409 'transcriptional units', contributing 90.1% of a newly
      established mouse transcriptome database. Of these transcriptional units, 4,258
      are new protein-coding and 11,665 are new non-coding messages, indicating that
      non-coding RNA is a major component of the transcriptome. 41% of all
      transcriptional units showed evidence of alternative splicing. In protein-coding
      transcripts, 79% of splice variations altered the protein product. Whole
      transcriptome analyses resulted in the identification of 2,431 sense-antisense
      pairs. The present work, completely supported by physical clones, provides the
      most comprehensive survey of a mammalian transcriptome so far, and is a valuable
      resource for functional genomics.

PMID- 12466853
TI  - Numerous potentially functional but non-genic conserved sequences on human
      chromosome 21.
AB  - The use of comparative genomics to infer genome function relies on the
      understanding of how different components of the genome change over evolutionary
      time. The aim of such comparative analysis is to identify conserved, functionally
      transcribed sequences such as protein-coding genes and non-coding RNA genes, and
      other functional sequences such as regulatory regions, as well as other genomic
      features. Here, we have compared the entire human chromosome 21 with syntenic
      regions of the mouse genome, and have identified a large number of conserved
      blocks of unknown function. Although previous studies have made similar
      observations, it is unknown whether these conserved sequences are genes or not.
      Here we present an extensive experimental and computational analysis of human
      chromosome 21 in an effort to assign function to sequences conserved between
      human chromosome 21 (ref. 8) and the syntenic mouse regions. Our data support the
      presence of a large number of potentially functional non-genic sequences,
      probably regulatory and structural. The integration of the properties of the
      conserved components of human chromosome 21 to the rapidly accumulating
      functional data for this chromosome will improve considerably our understanding
      of the role of sequence conservation in mammalian genomes.

PMID- 12466854
TI  - Human chromosome 21 gene expression atlas in the mouse.
AB  - Genome-wide expression analyses have a crucial role in functional genomics. High
      resolution methods, such as RNA in situ hybridization provide an accurate
      description of the spatiotemporal distribution of transcripts as well as a three
      dimensional 'in vivo' gene expression overview. We set out to analyse
      systematically the expression patterns of genes from an entire chromosome. We
      chose human chromosome 21 because of the medical relevance of trisomy 21 (Down's
      syndrome). Here we show the expression analysis of all identifiable murine
      orthologues of human chromosome 21 genes (161 out of 178 confirmed human genes)
      by RNA in situ hybridization on whole mounts and tissue sections, and by
      polymerase chain reaction with reverse transcription on adult tissues. We
      observed patterned expression in several tissues including those affected in
      trisomy 21 phenotypes (that is, central nervous system, heart, gastrointestinal
      tract, and limbs). Furthermore, statistical analysis suggests the presence of
      some regions of the chromosome with genes showing either lack of expression or,
      to a lesser extent, co-expression in specific tissues. This high resolution
      expression 'atlas' of an entire human chromosome is an important step towards the
      understanding of gene function and of the pathogenetic mechanisms in Down's
      syndrome.

PMID- 12466855
TI  - A gene expression map of human chromosome 21 orthologues in the mouse.
AB  - The DNA sequence of human chromosome 21 (HSA21) has opened the route for a
      systematic molecular characterization of all of its genes. Trisomy 21 is
      associated with Down's syndrome, the most common genetic cause of mental
      retardation in humans. The phenotype includes various organ dysmorphies,
      stereotypic craniofacial anomalies and brain malformations. Molecular analysis of
      congenital aneuploidies poses a particular challenge because the aneuploid region
      contains many protein-coding genes whose function is unknown. One essential step
      towards understanding their function is to analyse mRNA expression patterns at
      key stages of organism development. Seminal works in flies, frogs and mice showed
      that genes whose expression is restricted spatially and/or temporally are often
      linked with specific ontogenic processes. Here we describe expression profiles of
      mouse orthologues to HSA21 genes by a combination of large-scale mRNA in situ
      hybridization at critical stages of embryonic and brain development and in silico
      (computed) mining of expressed sequence tags. This chromosome-scale expression
      annotation associates many of the genes tested with a potential biological role
      and suggests candidates for the pathogenesis of Down's syndrome.

PMID- 12466856
TI  - A shift in the ethos of modern medicine.

PMID- 12466857
TI  - Outcome of primary chest packing and delayed sternal closure for intractable
      bleeding following heart surgery.
AB  - Post-operative bleeding is a life-threatening complication encountered following
      cardiac surgery. In cases where bleeding cannot be controlled by correcting
      clotting derangements and using standard surgical techniques, packing the chest
      may be an important salvation method. The aim was to determine the outcome of
      patients having primary chest packing in theatre for intractable bleeding
      following heart surgery. The method used was retrospective analysis of patients'
      medical records. Over a 9-year period, 6890 patients had open-heart surgery at
      the Manchester Royal Infirmary. Twenty (0.29%) of these patients had their chests
      packed prior to leaving theatre, 19 for uncontrolled bleeding, and one for
      inaccessible bleeding. Five (25%) of these patients required one further packing.
      The majority of patients (85%) survived. None developed a sternal wound
      infection. The conclusion drawn was that chest packing could be a life-saving
      procedure following heart surgery.

PMID- 12466858
TI  - Intrapericardial teratoma in a twin with severe failure to thrive.
AB  - We report on one affected twin who presented with cough, dyspnoea and severe
      failure to thrive. He was found to have gross cardiomegaly on chest X-ray. This
      proved to be due to an intrapericardial teratoma with an associated pericardial
      effusion. The operation on this rare tumour was successful.

PMID- 12466859
TI  - 'Quadrileaflet' mitral valve associated with paravalvular aneurysms and
      complicated by mitral incompetence: a case report of a rare pathology identified
      by 2-dimensional echocardiography.
AB  - A case is reported of a rare pathology involving the left atrioventricular valve
      with excessively developed scallops in association with subvalvular aneurysms,
      together with an acquired, probably HIV-related, chronic effusive pericarditis.
      The possible aetiology is discussed.

PMID- 12466860
TI  - Coronary heart disease in Western populations?

PMID- 12466861
TI  - Any hopes of falls in coronary heart disease in Western populations? Little
      chance of reducing its occurence.

PMID- 12466862
TI  - The dilemma of fracture treatment in developing countries.

PMID- 12466863
TI  - A crossover comparison of four peripheral bone-site measurements to identify
      central osteopenia and osteoporosis in women.
AB  - The objective of this study was to assess the ability of four peripheral bone
      measurement sites to predict low bone mineral density of the lumbar spine,
      femoral neck, and total hip as defined by the WHO classification, and to evaluate
      their role as a screening procedure for central dual-energy X-ray absorptiometry
      (DXA). One thousand three hundred white women patients aged 58.3+/-13.9 years
      were enrolled. Correlations between the peripheral and central sites were
      moderate, varying between 0.51 and 0.67. In receiver-operating characteristic
      (ROC) analysis, the areas under the curve for the peripheral sites revealed a few
      small, but significant, differences between sites. The optimal cut-point was
      derived from the ROC data for each site to assess its value as a screening
      parameter. These proved to be unsatisfactory, because the average number of false
      positives and false negatives were 18% and 24%, respectively. A proposal is made
      which entails two cut-points, one for an acceptable percentage of false negatives
      and the other for an acceptable number of false positives. Patients with t-scores
      between these cut-points would be referred for central DXA for classification.
      The result is a substantial decrease in the number of false negatives, i.e.,
      patients who would be candidates for treatment. The contentious issue is what
      proportion of supplemental DXAs is considered logistically and economically
      acceptable for any of the peripheral site measurements to be useful.

PMID- 12466864
TI  - Factors affecting the surgical results of expansive laminoplasty for cervical
      spondylotic myelopathy.
AB  - We studied the outcome of expansive laminoplasty in 37 patients with cervical
      spondylotic myelopathy. Patients were divided into two groups according to the
      recovery rate (RR) - a 'good' group ( n=19), and a 'fair' group ( n=18). Patients
      in the good group showed a greater pre-operative Japanese Orthopaedic Association
      (JOA) score, a greater compression ratio, and a larger Pavlov ratio ( P<0.05).
      The presence of high signal intensity on MRI proved to be of no prognostic
      importance.

PMID- 12466865
TI  - Suprascapular nerve entrapment. A meta-analysis.
AB  - We performed a review of the literature between 1959 and 2001. We found 88 cases
      of suprascapular nerve entrapment, which fulfilled our inclusion criteria.
      Suprascapular nerve entrapment is rare and mainly occurs in patients under 40
      years of age. Males are more likely to suffer from a ganglion compressing the
      nerve than females. If the patient's history reveals a trauma, it is more likely
      that the ligament is compromising the nerve. Ganglions usually cause isolated
      infraspinatus atrophy, whereas a combined atrophy of the supra- and infraspinatus
      muscles is more common in cases in which the nerve is compressed by the ligament.

PMID- 12466866
TI  - Acetabular roof reconstruction with pedicled iliac graft.
AB  - Reconstruction of the acetabular roof in patients with hip dysplasia shows
      disappointing mid-term results due to insufficient incorporation and collapse of
      the bone graft. We have developed a new reconstructive method using a pedicled
      iliac graft. We simulated surgical reconstruction of the acetabular roof in ten
      cadaver specimens. The purpose was to evaluate whether the deep circumflex artery
      was long enough to allow transfer of the graft without requiring micro-vascular
      anastomosis. In all cadavers, the length of the pedicle was sufficient to reach
      any desired position of the acetabular roof. The use of such a pedicled
      structural graft may provide good primary stability and allow local bony
      remodelling and incorporation under load.

PMID- 12466867
TI  - A biomechanical study on fixation stability with twin hook or lag screw in
      artificial cancellous bone.
AB  - The twin hook has been developed as an alternative to the conventional lag screw
      to be combined with a barrelled side-plate in the treatment of trochanteric hip
      fractures. With two oppositely directed apical hooks introduced into the
      subchondral bone of the femoral head, the twin hook provides different
      stabilising properties to the lag screw. The femoral head purchase of the twin
      hook and the lag screw were compared in a biomechanical study using artificial
      cancellous bone, and responses to axial and torsional loading was determined. A
      distinct yield point in load and torque was noted for the lag screw, representing
      failure of the laminas supporting the threads. For the twin hook, gradual
      increase of load and torque occurred during impaction of the bone supporting the
      hooks. The peak loads and torques were higher for the lag screw, but were similar
      for both devices after 8 mm deformation. The stiffness was higher for the lag
      screw, but in counter-clockwise rotation the stiffness for the lag screw was
      negligible. The twin hook appeared to provide fixation stability comparable to
      that offered by the lag screw, but with conceivable advantages in terms of a
      deformation response involving bone impaction and gradually increasing stability.

PMID- 12466868
TI  - Mid-term results and migration behaviour of a ti-alloy cemented stem.
AB  - Between 1991 and 1994, 147 patients (154 hips) underwent a primary cemented total
      hip replacement using the Ultima ti-alloy, collarless, double-tapered stem and a
      UHMWPE cup. The average age at operation was 66.4 years. Ninety-one patients (97
      hips) were available for review with an average follow-up of 76 months. The
      Harris hip score had improved from pre-operative average of 43.1 (12.5-65.0) to
      the latest score of 88.9 (67.5-100). There were 11 revisions in total, eight of
      which were for aseptic stem loosening. The results of Kaplan-Meier survival
      analysis, based on stem revision for aseptic loosening as an end-point, was 92%
      at 8 years. Early stem migration analysis at 2 years was possible in 114 cases
      using digitised radiographs analysed by the EBRA method. Sixty-three stems had
      not migrated and 35 migrated less than 2 mm with only one of these ending in
      failure. Sixteen stems showed early migration of more than 2 mm and five of these
      failed. Early stem migration is predictive of stem failure. Osteolytic lesions
      occurred in 12 femurs and four of these stems failed.

PMID- 12466869
TI  - Why are we still using pre-operative skin traction for hip fractures?
AB  - We performed a prospective randomised trial to evaluate the efficacy of pre
      operative skin traction for proximal femoral fractures in 311 patients. We found
      a significant difference in pain score on the evening of admission and the first
      morning after admission between the groups with traction compared the group
      without. However, there was no corresponding increase in analgesic requirement
      during this period. The peak pain score pattern also was different in our
      population. No other objective benefit can be shown from using skin traction, and
      its routine use should be abandoned.

PMID- 12466870
TI  - A comparative study of trochanteric fractures treated with the Gamma nail or the
      proximal femoral nail.
AB  - The aim of the present paper is to compare the results obtained using two
      osteosynthesis systems developed for the surgical treatment of fractures of the
      trochanteric region of the femur, based on the principles of closed
      intramedullary nailing: the Gamma nail and the proximal femoral nail (PFN). A
      prospective study is presented of 125 trochanteric fractures of the femur treated
      with PFN and 125 treated with the Gamma nail in our service between the years
      1997 and 2000, with the prerequisite of a minimum follow-up of 1 year. Fractures
      were classified according to the AO system, the most commonly recorded subtype
      encountered being the A2. Clinical and radiographic controls were performed upon
      admission and in the post-operative follow-up at 1, 3, 6, and 12 months, the
      corresponding assessment protocol being completed on each occasion. Of the 250
      patients, 179 were women and the rest men. The average age was 78.9 years. Both
      systems enabled early mobilisation and walking in most of our patients. There
      were no significant differences in the use of either nail in terms of the
      recovery of previous functional capacity, nor in terms of the time required for
      fracture healing (12 weeks on average). With regard to the more significant
      technical complications recorded, shaft fractures and the cutting-out phenomenon
      were more common with the use of the Gamma nail, while secondary varus occurred
      at a greater rate when using the PFN.

PMID- 12466871
TI  - Lateral and anterior plating of intra-articular distal femoral fractures treated
      via an anterior approach.
AB  - Thirty-five patients with 36 displaced distal femoral fractures (16 AO-type C2
      and 19 AO-type C3) were treated with an anterior approach and double plating and
      followed for an average of 7 (3-44) months. Bone grafting with allograft and
      demineralized bone matrix was used. Postoperative therapy included immediate ROM
      and non-weight bearing for 12 weeks. Two patients died during hospitalization and
      one was lost to follow-up. Reductions were near anatomic in all but three
      patients. Uneventful healing by 16 weeks occurred in 24/36 fractures. Double
      plating via the anterolateral approach minimized stripping of the medial side and
      improved controlled access to the distal femur.

PMID- 12466872
TI  - Quadriceps torque curve pattern in patients with anterior cruciate ligament
      injury.
AB  - We measured torque curve pattern and quadriceps muscle strength with the knee
      slightly flexed in 48 patients with an anterior cruciate ligament injury, and
      analyzed the factors associated with reduced quadriceps strength. Strength was
      measured under isokinetic contraction, and concentric and eccentric contractions
      were studied. Strength was significantly lower in the injured knee, which also
      showed abnormal patterns of torque curve. In addition to the rapid downward slope
      pattern usually associated with concentric contraction, there was a concave
      pattern during eccentric contraction.

PMID- 12466873
TI  - Tibial reconstruction using a non-vascularised fibular transfer.
AB  - A non-vascularised contralateral fibular transfer was performed on seven patients
      with non-union of the tibia and a sclerosed segmental bone defect following
      injury. The average follow-up was 2.7 years with a minimum of 2 years. The
      operation was successful in achieving fracture union in six patients, with an
      average time to union of 4.5 months (range: 3-6). Shortening of up to 2.4 cm was
      found in two patients and mild residual ankle stiffness in one. This procedure is
      successful and simple when compared to microvascular and Ilizarov techniques.

PMID- 12466874
TI  - Effects of prophylactic ankle supports on pronation during gait.
AB  - We performed a gait analysis of 12 healthy subjects in order to analyse the rear
      foot pronation-supination angle and the shift of centre of pressure (COP) during
      walking. We used a video system and a force plate and examined the effects of
      semi-rigid Air-Stirrup brace, lace-up cloth RocketSoc brace, ankle taping and no
      bracing. Both the lace-up cloth brace and taping increased the maximum pronation
      angle during the stance phase. The lace-up cloth brace alone was associated with
      a larger maximum pronation velocity. With the lace-up cloth brace and taping, the
      COP was more laterally placed, allowing greater leverage about the subtalar axis
      and thus increasing the tendency toward pronation. The two braces and the tape
      did not similarly affect ankle joint biomechanics during gait. The ability to
      reduce excessive amounts of pronation is an important design consideration for
      prophylactic ankle supports.

PMID- 12466875
TI  - Triacylglycerols in prokaryotic microorganisms.
AB  - Triacylglycerols (TAG) are fatty acid triesters of glycerol; there are diverse
      types of TAG with different properties depending on their fatty acid composition.
      The occurrence of TAG as reserve compounds is widespread among eukaryotic
      organisms such as yeast, fungi, plants and animals, whereas occurrence of TAG in
      bacteria has only rarely been described. However, accumulation of TAG seems to be
      widespread among bacteria belonging to the actinomycetes group, such as species
      of Mycobacterium, Streptomyces, Rhodococcus and Nocardia. Fatty acids in
      acylglycerols in cells of Rhodococcus opacus PD630 accounted for up to 87% of the
      cellular dry weight. TAG biosynthesis, justifying an oleaginous status, seems to
      be restricted mainly to this group of bacteria, but occurs to a minor extent also
      in a few other bacteria. The compositions and structures of bacterial TAG vary
      considerably depending on the microorganism and on the carbon source, and unusual
      acyl moieties, such as phenyldecanoic acid and 4,8,12 trimethyl tridecanoic acid,
      are also included. The principal function of bacterial TAG seems to be as a
      reserve compound. Other functions that have been discussed include regulation of
      cellular membrane fluidity by keeping unusual fatty acids away from membrane
      phospholipids, or acting as a sink for reducing equivalents. In recent years,
      basic aspects of the physiology and biochemistry of bacterial TAG accumulation,
      and the molecular biology of the lipid inclusion bodies have been reported. TAG
      are used for nutritional, therapeutic and pharmaceutical purposes and serve as a
      source of oleochemicals.

PMID- 12466876
TI  - Impact of the first Streptomyces genome sequence on the discovery and production
      of bioactive substances.
AB  - An important addition to the field of bacterial genomics is the recent
      publication of the complete genome sequence of Streptomyces coelicolor. This
      strain has been for some decades the model organism for streptomycetes and other
      filamentous actinomycetes, Gram-positive bacteria highly valuable for their
      ability to produce thousands of bioactive metabolites, many of which have found
      important applications in medicine and agriculture. We discuss here the impacts
      that the S. coelicolor genome sequence is likely to have on the production of
      bioactive metabolites by current industrial strains, on the possible development
      of future superhost(s) for the production of valuable drugs, and on the search
      for new bioactive substances from microbial sources.

PMID- 12466877
TI  - An overview on fermentation, downstream processing and properties of microbial
      alkaline proteases.
AB  - Microbial alkaline proteases dominate the worldwide enzyme market, accounting for
      a two-thirds share of the detergent industry. Although protease production is an
      inherent property of all organisms, only those microbes that produce a
      substantial amount of extracellular protease have been exploited commercially. Of
      these, strains of Bacillus sp. dominate the industrial sector. To develop an
      efficient enzyme-based process for the industry, prior knowledge of various
      fermentation parameters, purification strategies and properties of the
      biocatalyst is of utmost importance. Besides these, the method of measurement of
      proteolytic potential, the selection of the substrate and the assay protocol
      depends upon the ultimate industrial application. A large array of assay
      protocols are available in the literature; however, with the predominance of
      molecular approaches for the generation of better biocatalysts, the search for
      newer substrates and assay protocols that can be conducted at micro/nano-scale
      are becoming important. Fermentation of proteases is regulated by varying the C/N
      ratio and can be scaled-up using fed-batch, continuous or chemostat approaches by
      prolonging the stationary phase of the culture. The conventional purification
      strategy employed, involving e.g., concentration, chromatographic steps, or
      aqueous two-phase systems, depends on the properties of the protease in question.
      Alkaline proteases useful for detergent applications are mostly active in the pH
      range 8-12 and at temperatures between 50 and 70 degrees C, with a few exceptions
      of extreme pH optima up to pH 13 and activity at temperatures up to 80-90 degrees
      C. Alkaline proteases mostly have their isoelectric points near to their pH
      optimum in the range of 8-11. Several industrially important proteases have been
      subjected to crystallization to extensively study their molecular homology and
      three-dimensional structures.

PMID- 12466878
TI  - Effects of inoculum size and age on biomass growth and paclitaxel production of
      elicitor-treated Taxus yunnanensis cell cultures.
AB  - Suspension cultures of Taxus yunnanensis cells were inoculated with cells of
      different culture ages (12-24 days) at various densities [50-250 g fresh weight
      (fw)/l], and treated (on day 7) with a mixture of elicitors, including Ag(+),
      chitosan and methyl jasmonate. The biomass productivity (during the production
      stage) increased dramatically with inoculum size, but decreased with inoculum age
      over 16 days. The volumetric yield and productivity of taxol (paclitaxel) also
      increased with inoculum size, while the specific taxol yield (per cell) was
      mainly dependent on inoculum age, with an optimum of 20 days, during the early
      stationary phase. The highest taxol yield and productivity, 39.8 mg/l and 1.9
      mg/l per day, respectively, were obtained with a 20-day-old inoculum at 200 g
      fw/l. Taxol excretion by the cells increased with inoculum age but decreased with
      inoculum size. The elicitor-induced activities of catalase (CAT) and
      phenylalanine ammonia-lyase (PAL) also depended mainly on inoculum age; higher
      PAL activity and lower CAT activity were obtained with an older inoculum,
      corresponding to a higher taxol yield. The results show that both inoculum size
      and age are important variables for taxol production, though the latter more
      profoundly influences elicitor-induced taxol biosynthesis of the cells. Inoculum
      size and age are also interrelated and should be optimized together in a two
      stage culture process.

PMID- 12466879
TI  - Bioprocessing strategies for improving hen egg-white lysozyme (HEWL) production
      by recombinant Aspergillus niger HEWL WT-13-16.
AB  - Hen egg-white lysozyme (HEWL) production by recombinant Aspergillus niger HEWL WT
      13-16 from a cDNA under the control of the A. niger glucoamylase promoter was
      used as a model system. The fungal mycelium was either immobilized on porous
      Celite 560 micro-carrier or grown in suspension as pelleted and dispersed forms.
      The objective was to reduce the protease activity that adversely affects the
      expressed HEWL. Free suspension culture at uncontrolled pH served as the
      benchmark. The control of pH during growth at pH 4.0 gave rise to a greater than
      five-fold reduction of protease activity in suspension culture. An additional
      38.5% decrease in protease activity was achieved in mycelial-pellet cultures in
      comparison to a 40.9% decrease in protease activity obtained with Celite 560
      beads in an airlift vessel at controlled pH. The specific HEWL yields were 5.8,
      5.0 and 4.1 mg/g dry wt. for the free suspension, mycelial-pellet, and Celite-560
      immobilized cultures, respectively.

PMID- 12466880
TI  - Production of heterologous thermostable glycoside hydrolases and the presence of
      host-cell proteases in substrate limited fed-batch cultures of Escherichia coli
      BL21(DE3).
AB  - Metabolic stress is a phenomenon often discussed in conjunction with recombinant
      protein production in Escherichia coli. This investigation shows how heterologous
      protein production and the presence of host cell proteases is related to: (1)
      Isopropyl-beta- D-thiogalactopyranoside (IPTG) induction, (2) cell-mass
      concentration at the time of induction, and (3) the presence of metabolites
      (glutamic acid or those from tryptone soy broth) during the post-induction phase
      of high cell density fed-batch cultivations. Two thermostable xylanase variants
      and one thermostable cellulase, all originating from Rhodothermus marinus, were
      expressed in E. coli strain BL21 (DE3). A three-fold difference in the specific
      activity of both xylanase variants [between 7,000 and 21,000 U/(g cell dry
      weight)], was observed under the different conditions tested. Upon induction at
      high cell-mass concentrations employing a nutrient feed devoid of the metabolites
      above, the specific activity of the xylanase variants, was initially higher but
      decreased 2-3 h into the post-induction phase and simultaneously protease
      activity was detected. Furthermore, protease activity was detected in all induced
      cultivations employing this nutrient feed, but was undetected in uninduced
      control cultivations (final cell-mass concentration of 40 g/l(-1)), as well as in
      induced cultivations employing metabolite-supplemented nutrient feeds. By
      contrast, maximum specific cellulase activity [between 700 and 900 U/(g cell dry
      weight)] remained relatively unaffected in all cases. The results demonstrate
      that detectable host cell proteases was not the primary reason for the decrease
      in post-induction activity observed under certain conditions, and possible causes
      for the differing production levels of heterologous proteins are discussed.

PMID- 12466881
TI  - Maximizing production of Penicillium cyclopium partial acylglycerol lipase.
AB  - Penicillium cyclopium partial acylglycerol lipase production was maximized in
      shaken batch culture. The effect of inoculum size and substrate concentration on
      the lipase activity released in the culture medium was visualized using a surface
      response methodology based on a Doehlert experimental design. The main advantage
      of this approach is the low number of experiments required to construct a
      predictive model of the experimental domain. Substrate percentage (corn steep,
      w/v) ranged from 0.1% to 1.9% and inoculum from 100 spores/ml to 3,200 spores/ml.
      We determined that an optimal set of experimental conditions for high lipase
      production was 1.0% substrate and 3,200 spores/ml, with initial pH 5.0,
      temperature 25 degrees C and shaking speed 120 rpm. Between the conditions giving
      the minimum and the maximum lipase production, we observed a three-fold increase
      in both the predicted and the measured values.

PMID- 12466882
TI  - A novel beta-N-acetylglucosaminidase of Clostridium paraputrificum M-21 with high
      activity on chitobiose.
AB  - A beta- N-acetylglucosaminidase gene ( nag3A) from Clostridium paraputrificum M
      21 was cloned in Escherichia coli. The nag3A gene consists of an open reading
      frame of 1,239-bp, encoding 413 amino acids with a deduced molecular weight of
      45,531 Da. Nag3A is a single domain enzyme containing a family 3 glycoside
      hydrolase catalytic domain. Nag3A was purified from recombinant E. coli and
      characterized. The enzyme hydrolyzed chitooligomers such as di- N
      acetylchitobiose, tri- N-acetylchitotriose, tetra- N-acetylchitotetraose, penta-
      N-acetylchitopentaose, hexa- N-acetylchitohexaose, ball-milled chitin, and
      synthetic substrates such as 4-methylumbelliferyl N-acetyl beta- D-glucosaminide
      [4-MU-(GlcNAc)], but had no activity at all against p-nitrophenyl-beta- D
      glucoside, p-nitrophenyl-beta- D-xyloside, or p-nitrophenyl-beta- D
      galactosamine. The enzyme was optimally active at 50 degrees C and pH 7.0, and
      the apparent K(m) and V(max) values for 4-MU-(GlcNAc) were 7.9 micro M and 21.8
      micro mol min(-1) mg protein(-1), respectively. SDS-PAGE, zymogram, and
      immunological analyses suggested that this enzyme is induced by ball-milled
      chitin.

PMID- 12466883
TI  - Gene cloning, sequencing, and characterization of a family 9 endoglucanase (CelA)
      with an unusual pattern of activity from the thermoacidophile Alicyclobacillus
      acidocaldarius ATCC27009.
AB  - A gene encoding a beta-1,4-glucanase (CelA) belonging to subfamily E1 of family 9
      of glycoside hydrolases was cloned and sequenced from the gram-positive
      thermoacidophile Alicyclobacillus acidocaldarius strain ATCC27009. The translated
      protein contains an immunoglobulin-like domain but lacks a cellulose-binding
      domain. The enzyme, when overproduced in Escherichia coli and purified, displayed
      a temperature optimum of 70 degrees C and a pH optimum of 5.5. CelA contained one
      zinc and two calcium atoms. Calcium and zinc are likely to be important for
      temperature stability. The enzyme was most active against substrates containing
      beta-1,4-linked glucans (lichenan and carboxy methyl cellulose), but also
      exhibited activity against oat spelt xylan. A striking pattern of hydrolysis on p
      nitrophenyl-glycosides was observed, with highest activity on the cellobioside
      derivative, some on the cellotetraoside derivative, and none on the glucoside and
      cellotrioside derivatives. Unmodified cellooligosaccharides were also hydrolyzed
      by CelA. No signal peptide for transport across the cytoplasmic membrane was
      detected. This, together with the substrate specificity displayed, near neutral
      pH optimum and irreversible inactivation at low pH, suggests a role for CelA as a
      cytoplasmic enzyme for the degradation of imported oligosaccharides.

PMID- 12466884
TI  - 3-Phosphoglycerate dehydrogenase from Corynebacterium glutamicum: the C-terminal
      domain is not essential for activity but is required for inhibition by L-serine.
AB  - The serA gene of Corynebacterium glutamicum coding for 3-phosphoglycerate
      dehydrogenase (PGDH) was isolated and functionally characterized. It encodes a
      polypeptide of 530 aminoacyl residues (aa), which is substantially longer than
      the corresponding Escherichia coli polypeptide of 410 aa. The difference is
      largely due to an additional stretch of aa in the carboxy- (C)-terminal part of
      the polypeptide. Overexpression of serA in C. glutamicum results in a 16-fold
      increase in specific PGDH activity to 2.1 U/mg protein, with activity being
      inhibited by high concentrations of L-serine. A set of muteins that were
      progressively truncated at the C-terminal end was constructed. When
      overexpressed, mutein SerADelta197 showed a specific PGDH dehydrogenase activity
      of 1.3 U/mg protein, with the activity no longer being sensitive to L-serine. Gel
      filtration experiments showed that wild type PGDH is a homotetramer, whereas
      mutein SerADelta197 constitutes a dimer. Thus, the specific regulatory features
      of C. glutamicum PGDH are due to the C-terminal part of the polypeptide, which
      can be deleted with almost no effect on the catalytic activity of the enzyme.

PMID- 12466885
TI  - Construction of engineered CHO strains for high-level production of recombinant
      proteins.
AB  - We constructed engineered CHO strains that can be used for high-level production
      of foreign proteins by gene-targeting. After transfecting dihydroforate reductase
      (DHFR)-deficient CHO cells with a plasmid carrying a loxP-green fluorescent
      protein (GFP) fusion gene and a DHFR gene, we screened colonies by fluorescent
      intensity. We selected 16 clones that expressed high levels of GFP and carried
      one copy of the plasmid in their chromosomes and treated them with methotrexate
      (MTX) to examine their ability for DHFR-mediated gene amplification. Two clones,
      MK1 and MK2, showed increased GFP expression upon gene amplification. In those
      clones, the loxP-GFP gene was integrated at a transcription-active, DHFR
      mediated, gene-amplifiable locus in the chromosomes. A gene-targeting vector,
      carrying a loxP-fused hygromycin-resistance gene, was constructed to target
      desired genes in chromosomal loxP by Cre recombinase-mediated site-specific
      recombination. Using this cell-vector system, we could reproducibly obtain high
      producers of recombinant proteins by gene-targeting and gene amplification. In
      human monoclonal antibody production, after gene-targeting of loxP in MK2 and
      gene amplification with MTX, the MTX-resistant colonies showed high levels of
      antibody production. The most productive clone was able to produce 160 mg/l in 7
      days in a low-protein medium in a spinner-flask.

PMID- 12466886
TI  - Stimulation of chymosin secretion by simultaneous expression with chymosin
      binding llama single-domain antibody fragments in yeast.
AB  - We studied the effect of coexpression of chymosin and chymosin-binding llama
      single-domain antibody fragments (VHHs) on the secretion of chymosin by
      Saccharomyces cerevisiae cells. A VHH expression library containing chymosin
      specific VHHs was obtained by immunization of a llama and coexpressed with
      chymosin in yeast. From this library, we obtained two VHH clones that stimulated
      chymosin secretion by screening colonies for the level of chymosin secreted.
      These VHHs bound biotinylated chymosin in an immunoblot procedure but failed to
      bind chymosin in ELISA, suggesting that their interaction with chymosin was of
      low affinity. In a second approach, chymosin-specific VHHs were first selected
      using phage display and then coexpressed with chymosin in yeast cells. Screening
      yeast cells for higher levels of chymosin secretion resulted in 11 VHHs. Sequence
      analysis revealed that these 11 VHHs formed four sets of related VHHs that were
      different from the previously isolated two VHHs. Although binding of VHHs to
      chymosin could not be demonstrated in ELISA using soluble VHHs, it could be
      unambiguously demonstrated for clones isolated by phage display, using phage
      displayed VHHs. Finally, quantitative Western blot analysis of chymosin amounts
      demonstrated that coexpression with VHH domains can stimulate the level of
      secreted chymosin 1.5- to 6-fold.

PMID- 12466887
TI  - Use of a histone H4 promoter to drive the expression of homologous and
      heterologous proteins by Penicillium funiculosum.
AB  - Two genes encoding histone H4 (H4.1 and H4.2) from Penicillium funiculosum have
      been cloned and characterised. Structurally, the histone H4.1 gene is divergently
      linked to the histone H3 gene and the two genes are separated by approximately
      800 bp. The transcription of the histone H4.1 and H4.2 genes in P. funiculosum
      appears to be distinctively regulated. Histone H4.1 mRNA showed a high steady
      state level during the early stages of batch culture that decreased as growth
      reached the stationary phase. In contrast, the expression of the histone H4.2
      gene was lower than that of H4.1 throughout batch growth and increased gradually
      with time. In order to expand the industrial application of P. funiculosum as a
      host for the production of heterologous proteins, the promoter of the histone
      H4.1 gene was successfully used to drive the expression of an intracellular
      bacterial enzyme, beta-glucuronidase, and a secreted homologous enzyme, xylanase
      C. The constitutive secretion of xylanase C was achieved in the absence of other
      xylanases by batch fermentation in the presence of glucose.

PMID- 12466888
TI  - Escherichia coli cells penetrated by chrysotile fibers are transformed to
      antibiotic resistance by incorporation of exogenous plasmid DNA.
AB  - A suspension of recipient Escherichia coli cells in stationary phase, chrysotile
      asbestos, and pUC18 donor DNA spread over the surface of a Luria-Bertani agar
      plate using a streak bar several times, resulted in intracellular uptake of the
      plasmid DNA by the E. coli cells. The transformation efficiency was highest with
      a duration of cell exposure to chrysotile of more than 60 s and an agar
      concentration of 2%. To improve chrysotile-mediated transformation efficiency, we
      systematically optimized various conditions and parameters. In comparison to
      chrysotile exposure without cations, exposure with cations produced up to 100
      fold more transformants. Optimized conditions resulted in 10(6) transformants/
      micro g pUC18 DNA. The drastic physical change due to 'quick drying on the
      surface of the agar plate' when cells were exposed to chrysotile, was essential
      for chrysotile-mediated transformation. We suggest that DNA uptake mediated by
      chrysotile asbestos is the result of a mechanical physical transformation of E.
      coli, since the E. coli cells are not chemically competent. Electron microscopy
      of cells exposed to chrysotile suggested penetration of the E. coli membrane by
      chrysotile fibers. It is suggested that E. coli transformation by the plasmid DNA
      was the result of penetration by chrysotile fibers to which plasmid DNA is bound
      or adsorbed.

PMID- 12466889
TI  - Long anchor using Flo1 protein enhances reactivity of cell surface-displayed
      glucoamylase to polymer substrates.
AB  - We investigated the influence of anchor length on the reactivity to polymer
      substrate of enzyme displayed on yeast cell surfaces. Using various lengths [42,
      102, 146, 318, 428, and 1,326 amino acids (aa)] of the C-terminal region of the
      Saccharomyces cerevisiae Flo1 protein (Flo1p), which plays a major role in yeast
      flocculation, six display systems with various anchor lengths were constructed.
      In these systems, the target protein was displayed on the yeast cell surface
      under the control of the 5'-upstream region of the isocitrate lyase gene of
      Candida tropicalis ( UPR-ICL). Cell-surface display of Rhizopus oryzae
      glucoamylase by these systems was induced and confirmed in all systems by
      immunofluorescence microscopy and immunoblotting. Flow-cytometer measurement of
      the fluorescence intensity of immunofluorescence-labeled yeast cells displaying
      glucoamylase indicated that glucoamylase displayed with longer anchors,
      especially those of 428 and 1,326 aa in length, had higher reactivity to
      antibodies. The reactivity of starch to displayed glucoamylase, which was
      evaluated by plate assay, increased with anchor length, as did the cell growth
      rate in starch-containing medium. These results indicate that cell-surface
      display systems using 428- and 1,326-aa length anchors of Flo1p are effective for
      the display of enzymes on the outer surface of yeast cells.

PMID- 12466890
TI  - PAH utilization by Pseudomonas rhodesiae KK1 isolated from a former manufactured
      gas plant site.
AB  - Pseudomonas rhodesiae KK1 was isolated from a former manufactured-gas plant site,
      due to its ability to grow rapidly in a mixture of polycyclic aromatic
      hydrocarbons (PAHs). Radiorespirometric analysis revealed that strain KK1 was
      found to be able to mineralize anthracene, naphthalene and phenanthrene. Notably,
      phenanthrene-grown cells were able to mineralize anthracene much more rapidly
      than naphthalene-grown cells. Comparative analysis of amino acid sequences from
      17 randomly selected dioxygenases capable of hydroxylating unactivated aromatic
      nuclei indicated that the enzymes for catabolism of PAHs, such as naphthalene and
      phenanthrene, might exist redundantly in strain KK1. Northern hybridization for
      cells grown on naphthalene or phenanthrene, using the putative naphthalene or
      phenanthrene dioxygenase gene fragment as a probe, suggested that the enzyme for
      naphthalene catabolism might share some homology in deduced amino acid sequences
      with phenanthrene dioxygenases. Also, it was found that three lipids (17:0 cyclo,
      18:1 omega7c, 19:0 cyclo) increased in response to both naphthalene and
      phenanthrene, while the shift of other lipids varied from substrate to substrate.

PMID- 12466891
TI  - Cell-adhered conjugated linoleic acid regulates isomerization of linoleic acid by
      resting cells of Propionibacterium freudenreichii.
AB  - The microbiological isomerization of linoleic acid (LA) to conjugated linoleic
      acid (CLA) was studied in resting cell suspensions of a propionibacterium and
      micellar LA to identify factors critical in the isomerization efficiency. These
      suspensions, containing cells 5x10(10) colony-forming units ml(-1) and 510 micro
      g LA ml(-1), isomerized about 90% of LA to CLA. However, the yield was not
      improved with higher amounts of micellar LA, suggesting that the cells had a
      fixed capacity to carry out the isomerization. This was explained by the fact
      that the CLA formed had a tendency to accumulate in the cell mass rather than in
      the aqueous micellar phase during the isomerization. Concomitantly, cell
      viability and isomerization rates were gradually reduced. Upon cessation of the
      reaction, about 46% of all the CLA formed was in the cell material. This
      accumulation to the cells was prevented by adding the detergent in excess to that
      required for micellization of LA. Then the cells remained viable, but the rate of
      isomerization was drastically lowered, due to impaired availability of LA from
      the fortified micellar phase to the cells. It was concluded that the phase
      distribution of substrate and product plays a critical role in the
      microbiological production of CLA.

PMID- 12466892
TI  - Enzymatic hydrolysis and physical characterization of commercial celluloses and
      cellulose-based ion-exchange powdered mixed resins.
AB  - Commercial celluloses (BH20, Epicote, FC+) and their cellulose-containing
      powdered mixed resins (PMR) were evaluated using enzymatic and physical methods.
      Samples were hydrolyzed with purified Trichoderma viride cellulase extract and
      measured for released reducing sugar using the dinitrosalicylic acid method.
      Physical characterization was performed with gross specific surface areas (GSSA)
      and relative crystalline indices (RCI). In addition, FC+ was exposed to physical
      and chemical processing commonly encountered in spent PMR processing to determine
      potential effects on reducing sugar release in high intensity containers.
      Reducing sugar released from the celluloses by T. viride cellulase ranged from
      135.37 to 244.48 mg day(-1); the celluloses were highly crystalline, ranging from
      82.47 to 84.57%; and the GSSA medians for the celluloses ranged from 1,298.60
      cm(2) g(-1) to 2,493.20 cm(2) g(-1). Most processing treatments on the FC+
      reduced the amount of reducing sugar released and increased RCI. Cellulose
      hydrolysis rates did not show a strong correlation with the physical
      characterization. These results suggest that (1) celluloses and PMR can serve as
      abundant sources of bioavailable carbon in water treatment systems, and (2) the
      use of correlative physical characteristics to evaluate a cellulose-based
      commercial product may not accurately predict microbial activity; a complementary
      microbial test such as cellulose hydrolysis with cellulase may prove useful.

PMID- 12466893
TI  - Mono- and dimeric ferulic acid release from brewer's spent grain by fungal
      feruloyl esterases.
AB  - Ultraflo L, a beta-glucanase preparation from Humicola insolens sold for reducing
      viscosity problems in the brewing industry, exhibited activity against the methyl
      esters of ferulic, caffeic, p-coumaric and sinapic acids, displaying mainly type
      B feruloyl esterase activity. Ultraflo also contained the ability to release 65%
      of the available ferulic acid (FA) together with three forms of diferulate from
      brewer's spent grain (BSG). An "esterase-free" Ultraflo preparation greatly
      enhanced the ability of a feruloyl esterase from Aspergillus niger, AnFAEA, to
      release FA (from 23 to 47%) and its dimeric forms, especially the 8,5' benzofuran
      form, from BSG. While total release of these phenolic acids was not observed,
      this synergistic enhancement of ferulate release demonstrates that FA and its
      dimeric forms present in BSG require the addition of more than a xylanase. This
      suggests either that FA is not solely attached to arabinoxylan in the barley cell
      wall, or that the cell wall polysaccharides in BSG hinder the accessibility of
      enzymes to the ferulates, due to processing treatments.

PMID- 12466894
TI  - Examination of the highly diverse CD4(+) T-cell repertoire directed against an
      influenza peptide: a step towards TCR proteomics.
AB  - We combined several recent technological advances in immunology and molecular
      biology to identify and sequence a large number of T-cell receptor (TCR) genes
      specific for a particular antigen. We utilized class II MHC tetramers and
      interferon-gamma surface capture to isolate from samples of peripheral blood the
      population of CD4(+) T cells responding to a peptide derived from influenza
      hemagglutinin and restricted by HLA-DR1. Detailed analysis of hundreds of clones
      from three different patients revealed an extremely diverse repertoire, with
      little overlap between patients. We observed no dominant usage of particular
      Vbeta segments nor any clear CDR3 sequence motif in the responding T cells, but
      most of the clones appear to utilize acidic residues in the CDR1 and CDR3
      regions, presumably to interact with the exposed basic residues in the MHC
      peptide complex. This methodology could be expanded to a large scale to identify
      the generalized rules governing TCR-MHC engagement and factors which shape the T
      cell repertoire after vaccination and in autoimmune pathologies.

PMID- 12466895
TI  - Cloning of S4D-SRCRB, a new soluble member of the group B scavenger receptor
      cysteine-rich family (SRCR-SF) mapping to human chromosome 7q11.23.
AB  - The scavenger receptor cysteine-rich superfamily (SRCR-SF) is a highly conserved
      group of membrane and/or secreted proteins related to the innate and adaptive
      immune system. Here, we report the cloning of the gene encoding human S4D-SRCRB,
      a novel soluble member of the SRCR-SF, which is composed of four group B SRCR
      domains separated by Pro-, Ser- and Thr-rich polypeptides. The longest cDNA
      sequence found is 2,806 bp in length and encodes a mature protein of 528 aa, with
      a predicted molecular mass of M(r) 55,600. The S4D-SRCRB gene is located at
      Chromosome 7q11.23, telomeric to the Williams-Beuren syndrome deletion. It
      extends over 20 kb and consists of 11 exons, with each SRCR domain being encoded
      by a single exon. Northern blot analysis indicated that S4D-SRCRB has a broad
      tissue distribution and is expressed as two major mRNA species: one of 2.8 kb,
      with a restricted tissue expression pattern (mainly kidney and placenta), and
      another of 1.5 kb, with a broader distribution. A similar mRNA expression pattern
      was observed during the analysis of several tumor cell lines. The highest degree
      of similarity found between S4D-SRCRB and other group B SRCR-SF members was with
      human DMBT1 (a mosaic protein composed of fourteen SRCR domains, which is
      involved in innate defense and epithelia polarization) and chicken 18-B (a
      turpentine-induced soluble acute-phase protein composed of four SRCR domains).
      Our data indicate that S4D-SRCRB constitutes a novel SRCR-SF member, which could
      be involved in basic homeostatic functions such as innate host defense.

PMID- 12466896
TI  - Cloning of interleukin-4 delta2 splice variant (IL-4delta2) in chimpanzee and
      cynomolgus macaque: phylogenetic analysis of delta2 splice variant appearance,
      and implications for the study of IL-4-driven immune processes.
AB  - The human interleukin-4 ( IL-4) gene produces an exon 2-lacking alternative
      splice variant, termed IL-4delta2, and described as a naturally occurring
      antagonist of IL-4-driven activity. We report the isolation of an IL-4delta2 cDNA
      from chimpanzee ( Pan troglodytes) bone marrow samples and cynomolgus macaque (
      Macaca fascicularis) activated peripheral lymph node cells. The complete IL-4
      cDNA sequence from chimpanzee is also provided for the first time. The
      phylogenetic analysis of several known IL-4 sequences revealed a highly conserved
      structure of coding regions among primates, suggesting that alternative IL-4
      transcript splicing may be a process shared by other simian and potentially pro
      simian species as well. Extension of the study to other mammalian species led us
      to the assumption that generation of IL-4 splice variants may be common to
      primates, lagomorphs (rabbit), and rodents of the sciuridae family (woodchuck),
      but is unlikely to occur in mice and rats (muridae), for which IL-4 splice
      variants have indeed never been described. Potential implications of
      alternatively spliced cytokine products with possible antagonistic or competitive
      inhibitory function, for the choice of suitable animal models of IL-4-regulated
      immune processes, are discussed. This study also indicates the importance of
      considering alternative splicing when defining cytokine bioassays, most
      particularly in the present context of transcriptomics, involving the
      generalization of sequence-based detection methods such as quantitative reverse
      transcription PCR.

PMID- 12466897
TI  - Identification, cloning, and sequencing of different cytokine genes in four
      species of owl monkey.
AB  - Non-human primates could prove to be suitable models for the study of infectious
      diseases such as malaria, tuberculosis, and hepatitis; the molecules of their
      immune systems are in the process of being fully characterized. Due to the
      relevance of cytokines in the modulation of the immune response, a molecular
      analysis of these proteins in non-human primates from the Aotus genus was carried
      out. Peripheral blood mononuclear cells from four species of Aotusmonkey were
      obtained and their mRNAs for interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon
      gamma (IFN), and tumor necrosis factor (TNF)-alpha were characterized. This study
      shows a high degree of conservation between nucleotide and amino acid sequences
      of cytokines from different Aotus species and those from humans. The TNF-alpha
      molecules were identical in amino acid sequences for both.

PMID- 12466898
TI  - Induction of the rainbow trout MHC class I pathway during acute IHNV infection.
AB  - Interferons are essential for establishing cytotoxic T-lymphocyte immunity
      against viral pathogens through different mechanisms including the modulation of
      antigen presentation to T-cell subsets. At the present time, interferons have yet
      to be isolated from teleost fish. We have developed a salmonid model to examine
      whether MHC gene regulation is modulated during acute viral infection in trout,
      an event attributable to interferons in mammals. During peak infection with
      infectious hematopoietic necrosis virus, induction of STAT-1, PSMB9A and ABCB2
      mRNA was evident in all tissues within infected fish, as compared with controls.
      In addition, MHC class Ia and beta(2) microglobulin (beta(2)m) transcript levels
      were enhanced within the experimental group but surprisingly, splenic and
      pronephric class IIB mRNA expression was virtually absent. A time-course study
      looking at 24, 72 and 192 h post-infection was then performed to determine the
      overall kinetics of this response. STAT-1 and PSMB9A message levels increased
      early during the immune response and remain at relatively high levels until the
      final time point. MHC class Ia expression is not consistently upregulated until
      midway in the response. MHC class IIB transcripts are downregulated by 72 h in
      the spleen and pronephros and then partially restored by 192 h. Finally, analysis
      of the putative promoter regions for PSMB9A and ABCB2 identified interferon (IFN)
      regulatory factory (IRF-1) and INF-gamma (GAS) activation sites that may be
      involved in the regulation of these genes during viral infection.

PMID- 12466899
TI  - Cloning novel immune-type inhibitory receptors from the rainbow trout,
      Oncorhynchus mykiss.
AB  - Novel immune-type receptor ( NITR) genes that encode two extracellular
      immunoglobulin domains and cytoplasmic immunoreceptor tyrosine-based inhibition
      motifs (ITIMs) have been described previously in three lineages of bony fish. In
      the current study, four ITIM-containing NITR cDNAs are identified in the rainbow
      trout ( Oncorhynchus mykiss), and their expression patterns and genomic
      complexity are characterized. The ITIM-containing NITR2 gene maps 1.3 cM from an
      ITIM-containing C-type lectin receptor ( TCL-2) on linkage group XXI. A
      comprehensive, phylogenetic analysis of NITRs from rainbow trout and three other
      major lineages of bony fish defines conserved families of NITRs and suggests an
      ancient lineage of distinct groups of genes. Several probable scenarios that
      explain the origins of variant forms of NITRs are described.

PMID- 12466901
TI  - Outcomes and consequences: the therapeutic index redefined.

PMID- 12466900
TI  - Alternatively spliced forms of MICA and MICB lacking exon 3 in a human cell line
      and evidence of presence of similar RNA in human peripheral blood mononuclear
      cells.
AB  - MICA and MICB genes encode MHC class I chain-related proteins, which are
      polymorphic, do not appear to present peptides or associate with beta(2)
      microglobulin, and are expressed predominantly in epithelial cells, endothelial
      cells, fibroblasts and several cultured cell lines. Alternatively spliced
      isoforms are known to exist for HLA-A and B, as well as HLA-G and the MHC class I
      related gene, MR1. In the course of cloning MICA and MICB cDNA from the colon
      carcinoma cell line HCT 116, it was observed that two kinds of cDNAs were
      obtained: a 1161-bp cDNA, representing full-length MICA or MICB, and a shorter
      variant of 873 bp. The sequences of these short cDNAs were those of the correct
      MICA or MICB alleles but lacking exon 3. They were found in 7 of 72 clones
      examined or about 10% and were called MICA2 and MICB2. MICA1 and MICA2 were
      transfected into Chinese hamster ovary cells and found to be expressed both in
      the cells and on their surface. PCR with a primer based on a sequence formed by
      the joining of exons 2 and 4 allowed detection of the isoform RNA in different
      cells including freshly prepared normal PBMC.

PMID- 12466902
TI  - Analysis of collagen in parametrium and vaginal apex of women with and without
      uterine prolapse.
AB  - Our objective was to compare the amount of collagen in parametrium and vaginal
      apex between women with uterine prolapse at pre- and postmenopause, and in women
      without prolapse. The study included 22 premenopausal women without prolapse
      (group A), 10 premenopausal women with prolapse (group B), and 23 postmenopausal
      women with prolapse (group C) (total 55). Patients in group A underwent abdominal
      hysterectomy for uterine leiomyoma, and patients in groups B and C underwent
      vaginal hysterectomy. During the surgical procedure we obtained biopsies from the
      lateral parametrium and vaginal apex. The tissue was stained for histological
      analysis with picrosirius. We observed a lower amount of collagen in the
      parametrium of women with uterine prolapse, both in menacme and in postmenopause,
      than in the parametrium of women without prolapse. We observed no statistically
      significant difference in vaginal apex between the groups.

PMID- 12466903
TI  - Management of the very weak pelvic floor. Is there a point?
AB  - Conservative treatment in the form of pelvic muscle exercises is effective in the
      treatment of stress urinary incontinence. There are no studies specifically
      looking at women who have extremely weak pelvic muscles and their response to
      conservative treatment. This study looks at the effectiveness of pelvic muscle
      therapy in women with very weak pelvic muscles. Out of 965 women attending the
      bladder clinic at Kirwan Hospital, 219 were assessed to have weak pelvic muscles
      by digital palpation. All patients were subjected to a detailed urogynecological
      questionnaire, a frequency/volume chart, and clinical assessment. All patients
      were then given detailed verbal and written instructions on good bladder habits,
      including posture, dietetic habits and pelvic muscle exercises. Of the 219 women,
      163 were able to complete their treatment and presented for review. Out of 163
      women 118 (72%) reported a subjective improvement; 89 (54%) demonstrated an
      objective improvement in pelvic muscle strength.

PMID- 12466904
TI  - Do pessaries prevent the progression of pelvic organ prolapse?
AB  - Pessaries are used for the management of pelvic organ prolapse, but it is unknown
      whether a pessary will prevent progression of this condition. The purpose of this
      study was to describe the course of pelvic organ prolapse among women using a
      pessary for at least 1 year. Among 56 consecutive women fitted with a pessary, 19
      (33.9%) continued its use under our care for at least 1 year. We compared
      baseline and follow-up examinations, using the Pelvic Organ Prolapse Quantitation
      examination system. At baseline, 16 (84.2%) had stage 3 or 4 prolapse. After 1
      year we observed a significant improvement in the stage of disease ( P = 0.045,
      Wilcoxon signed rank test). Four women (21.1%, 95% confidence interval -0.2,
      43.7%) had an improvement in stage. No women had worsening in stage of prolapse.
      These data suggest that there may be a therapeutic effect associated with the use
      of a supportive pessary.

PMID- 12466905
TI  - Voiding dysfunction following TVT procedure.
AB  - The aim of the study was to assess the incidence of abnormal voiding in patients
      who had undergone tension-free vaginal tape (TVT) placement. Women who had
      undergone a TVT sling procedure for stress or mixed incontinence more than 3
      months previously reported their voiding habits (frequency, urgency, nocturia,
      urinary stream quality and incontinence) over the previous 3 days. A pelvic
      examination and ultrasound postvoid residual (PVR) were performed. Normal voiding
      was classified as a PVR <100 ml, frequency of six or fewer voids per day and two
      or fewer per night, and a urinary stream considered normal by the patient.
      Subjects were classified as either 'normal' (group 1) or 'abnormal' (group 2)
      voiders. Demographic factors, pre-operative urodynamic testing and concomitant
      surgical procedures were compared between groups. From September 1999 to November
      2000, 59 women underwent a TVT procedure. Two were excluded from analysis
      [cervical malignancy (1), interstitial cystitis (1)]. There were no healing
      abnormalities and no patients displayed a positive empty bladder stress test.
      Forty-two (74%) women were included in group 1 and 15 (26%) in group 2. Urinary
      continence was reported by 49 (86%): 93% in group 1 and 67% in group 2. Factors
      highly correlated with postoperative voiding dysfunction included abnormal
      preoperative uroflow pattern and configuration (P = 0.007), preoperative low peak
      flow rate <15 ml/s (P = 0.049), preoperative vault prolapse or enterocele (P =
      0.001), concurrent vault suspension surgery (P = 0.03) and postoperative urinary
      tract infection (UTI) (P = 0.0006). Preoperative urinary retention (postvoid
      residual >100 ml) or detrusor instability, age and body mass index differences
      were not statistically significant. Multivariate analysis revealed that
      preoperative abnormal uroflow and postoperative UTI were related to group 2 (P =
      0.02). Our conclusions were that the TVT sling procedure has success and voiding
      dysfunction rates similar to those of other proven anti-incontinence procedures.
      Various factors were shown to be associated with postoperative voiding
      difficulties. Tension-free placement of the tape may not prevent the development
      of post-operative voiding dysfunction.

PMID- 12466906
TI  - Effects of epidural analgesia on pelvic floor function after spontaneous
      delivery: a longitudinal retrospective study.
AB  - The aim of the study was to assess the effects of epidural analgesia on pelvic
      floor function. Eighty-two primiparous women (group 1, consisting of 41 given an
      epidural, and group 2 of 41 not given an epidural) were investigated during
      pregnancy and at 2 and 10 months after delivery by a questionnaire, clinical
      examination, and assessment of bladder neck behavior, urethral sphincter function
      and intravaginal/intra-anal pressures. The prevalence of stress urinary
      incontinence was similar in both groups at 2 months (24% vs. 17%, P = 0.6) and 10
      months (22% vs. 7%, P = 0.1), as was the prevalence of decreased sexual vaginal
      response at 10 months (27% vs. 10%, P = 0.08). Bladder neck behavior, urethral
      sphincter function and intravaginal and intra-anal pressures showed no
      significant differences between the two groups. Ten months after spontaneous
      delivery, there were no significant differences in the prevalence of stress
      urinary incontinence and decreased sexual vaginal response, or in bladder neck
      behavior, urethral sphincter function and pelvic floor muscle strength between
      women who had or had not had epidural analgesia.

PMID- 12466907
TI  - Urodynamics in climacteric women with urinary incontinence: correlation with
      route of delivery.
AB  - The aim of this study was to compare the urodynamic findings among climacteric
      women complaining of urinary incontinence who had only vaginal deliveries with
      those who had only cesarean sections. The study group comprised 30 climacteric
      women with complaints of urinary incontinence consulting at the Menopause
      Outpatient Clinic, State University of Campinas, submitted to anamneses and
      complete urodynamic testing. Nineteen women had had only vaginal deliveries and
      11 were delivered only by cesarean section. Vaginal delivery was significantly
      associated with a reduced normal and strong desire to void and maximum
      cystometric capacity compared to women who delivered only by Cesarean section.
      Detrusor instability was four to five times more frequent among women who had had
      only vaginal deliveries. There was no difference between the two groups
      concerning uroflowmetry parameters. Climacteric women with urinary incontinence
      who had had only vaginal deliveries are at a higher risk of urodynamic
      abnormalities.

PMID- 12466908
TI  - Percentage of hysterectomy for pelvic organ prolapse in five ethnic groups.
AB  - The aim of this study was to determine whether there are differences in the
      percentage of hysterectomies performed for pelvic organ prolapse between five
      ethnic groups. Using archived data from January 1984 to January 2000, multiple
      logistic regression was used to adjust for age and the age-adjusted percentages
      were compared to Caucasians as odds ratios. A total of 6401 hysterectomies were
      identified, and 832 (13%) were performed for pelvic organ prolapse. The
      differences in the age-adjusted percentages were significant. The Japanese
      (P<0.001), Chinese (P<0.001) and Hawaiian (P<0.05) percentages were lower and
      those of the Filipinos were not significantly different from those of Caucasians
      below age 60. The age-adjusted odds ratios of hysterectomy for pelvic organ
      prolapse relative to Caucasians for Japanese, Chinese and Hawaiians were from 0.5
      to 0.7. The differences begin to disappear after age 60. A significantly lower
      percentage of hysterectomies for pelvic organ prolapse were done in Japanese,
      Hawaiian and Chinese women. The odds ratios in Filipino women increased after age
      60.

PMID- 12466909
TI  - Second tension-free vaginal tape procedure and mesh retensioning: two
      possibilities of treatment of recurrent-persistent genuine stress urinary
      incontinence after a primary tension-free vaginal tape procedure.

PMID- 12466910
TI  - Vesical calculus: a complication of intravesical migration of intrauterine
      contraceptive device.
AB  - Intravesical migration of an intra-uterine contraceptive device (IUCD) in a 28
      year-old woman resulted in recurrent urinary tract infections. She received
      antibiotic treatment from her general practitioner but had no investigations
      done. Later on she became pregnant and investigations revealed that the thread of
      IUCD was missing and there was a vesical calculus. After she had delivered the
      baby, a pelvic X-ray was taken and showed a vesical calculus on the IUCD. Both
      calculus and IUCD were removed cystoscopically.

PMID- 12466911
TI  - Pregnancy in patients with spina bifida and urinary diversion.
AB  - With better medical care the mortality and morbidity associated with spina bifida
      are improving and more such patients are reaching reproductive age. Significant
      problems may be encountered in the management of pregnancy in spina bifida,
      especially in patients with previous abdominal operations for the management of
      neuropathic bladder dysfunction. We report successful pregnancy outcomes in 2
      such patients, both with urinary diversions, with combined obstetric and
      urological care. We also review the existing literature on the subject.

PMID- 12466912
TI  - IUGA Guidelines for Training in Urogynecology and Reconstructive Pelvic Surgery
      (URPS).

PMID- 12466913
TI  - Arbuscular mycorrhizal distribution in relation to microsites on recent volcanic
      substrates of Mt. Koma, Hokkaido, Japan.
AB  - Mycorrhizae occur in most terrestrial ecosystems and are crucial to understanding
      community structure and function. However, their role in primary succession is
      poorly understood. This study examined the mycorrhizal colonization of six plant
      species in relation to microsite types on recent volcanic substrates on the
      summit of Mt. Koma, Hokkaido, Japan. The six microsites were flat, rill, near
      rock, Carextussock, Polygonum patch and Salix patch. Carex oxyandra was
      nonmycorrhizal and Agrostis scabra and Campanula lasiocarpa were arbuscular
      mycorrhizal (AM) at all microsites examined. Agrostis AM colonization levels did
      not differ across microsites. Near rock Campanula roots contained significantly
      more hyphae than at flat and Polygonum patch microsites, and rill and Carex
      tussock Campanula more arbuscules than at Polygonum patches. Penstemon frutescens
      was found to be facultatively mycotrophic with AM colonization occurring in roots
      of Penstemon growing in Carex tussocks, Polygonum patches and near rocks.
      Polygonum weyrichii was found to be ectomycorrhizal. Polygonum located in rills
      and in Polygonum and Salix patches were more colonized than Polygonum in Carex
      patches. Salix reinii was heavily ectomycorrhizal.

PMID- 12466914
TI  - Phosphorus, arbuscular mycorrhizal fungi and performance of the wetland plant
      Lythrum salicaria L. under inundated conditions.
AB  - The role of arbuscular mycorrhizal (AM) fungi in aquatic and semi-aquatic
      environments is poorly understood, although they may play a significant role in
      the establishment and maintenance of wetland plant communities. We tested the
      hypothesis that AM fungi have little effect on plant response to phosphorus (P)
      supply in inundated soils as evidenced by an absence of increased plant
      performance in inoculated (AM+) versus non-inoculated (AM-) Lythrum salicaria
      plants grown under a range of P availabilities (0-40 mg/l P). We also assessed
      the relationship between P supply and levels of AM colonization under inundated
      conditions. The presence of AM fungi had no detectable benefit for any measures
      of plant performance (total shoot height, shoot dry weight, shoot fresh weight,
      root fresh weight, total root length or total root surface area). AM+ plants
      displayed reduced shoot height at 10 mg/l P. Overall, shoot fresh to dry weight
      ratios were higher in AM+ plants although the biological significance of this was
      not determined. AM colonization levels were significantly reduced at P
      concentrations of 5 mg/l and higher. The results support the hypothesis that AM
      fungi have little effect on plant response to P supply in inundated conditions
      and suggest that the AM association can become uncoupled at relatively high
      levels of P supply.

PMID- 12466915
TI  - Influence of liming, inoculum level and inoculum placement on root colonization
      of subterranean clover.
AB  - Arbuscular mycorrhizal (AM) fungi differ in their response to soil pH. Thus,
      change in soil pH may influence the relative abundance of mycorrhizal fungi
      inside roots. Root colonization by two AM fungi was studied in relation to
      addition of lime (CaCO3), quantity of inoculum and inoculum placement. Addition
      of CaCO3 to an acid soil decreased the colonization of roots by Acaulospora
      laevis but increased colonization by Glomus invermaium when both fungi were
      present. In acid soil (pH 4.7), almost all roots were colonized by A. laevis,
      while G. invermaium was dominant when soil pH was increased to pH 7.3. This
      occurred regardless of whether the inoculum was banded or mixed throughout the
      soil. There was no effect of CaCO3 on the relative abundance of fungi inside
      roots at intermediate rates of CaCO3 application (pH 5.3-6.3) when both fungi
      were inoculated together. In this experiment, both fungi colonized roots at all
      levels of CaCO3 when inoculated alone, except for A. laevis at the highest level
      of CaCO3. We conclude that soil pH affects the competitive ability of these two
      AM fungi during mycorrhiza formation primarily by affecting hyphae growth in soil
      and thus the relative abundance of hyphae at the root surface and subsequently
      inside the root.

PMID- 12466916
TI  - Morphological types of arbuscular mycorrhizal fungi in roots of understory plants
      in Japanese deciduous broadleaved forests.
AB  - Morphological types of arbuscular mycorrhizal (AM) fungi in roots of understorey
      plants were examined in three different Japanese deciduous broadleaved forests.
      In total, 43 species belonging to 33 genera from 27 families were examined for
      the morphological types of AM. The number of flowering plant species having Paris
      type AM was greater than those having Arum-type AM in each plot. This tendency
      was more prominent in herbaceous plants than woody plants with nine species
      having Paris-type associations among ten herbaceous plant species examined.
      Therefore, it is suggested from the ecological point of view that Paris-type
      associations could be advantageous for the herbaceous understorey plants growing
      slowly in these environments. The influence of plant identity on the
      morphological types of AM was also discussed by arranging the plants examined
      with the morphological types in a current plant phylogeny scheme. In this study,
      some new records on the morphological types of AM in some new plant families were
      obtained including the first report of a typical Arum-type AM in gymnosperms.

PMID- 12466917
TI  - Does percent root length colonization and soil hyphal length reflect the extent
      of colonization for all AMF?
AB  - Percent root length colonization may not be an appropriate measure of root
      colonization by arbuscular mycorrhizal fungi (AMF) in all cases. We suggest that
      AMF will differ in how well percent root length colonization measures the amount
      of AMF colonization in the root due to differences among AMF in hyphal structure
      and hyphal aggregation. Although soil hyphal length accounts for hyphal density,
      we suggest that it does not consider differences in hyphal structure in
      measurements of external colonization and thus might also misrepresent the true
      amount of AMF in the soil. To test these suggestions, we measured and compared
      percent root length colonization and soil hyphal length with root ergosterol and
      soil ergosterol, respectively, for 21 different species of AMF from three
      families in a greenhouse experiment. Percent root length colonization predicted
      intra-radical colonization best for Glomaceae and Acaulosporaceae isolates, while
      soil hyphal length best represented soil ergosterol for Gigasporaceae isolates.
      The results show that conventional methods for estimating AMF colonization are
      not universal for all AMF. Caution is advised when drawing inferences for
      different groups of AMF.

PMID- 12466918
TI  - The effect of drought on mycorrhizas of beech (Fagus sylvatica L.): changes in
      community structure, and the content of carbohydrates and nitrogen storage bodies
      of the fungi.
AB  - In a water-exclusion experiment, five different ecotypes of beech (Fagus
      sylvatica L.; representing regions of different environmental and climatic
      conditions in Baden-Wurttemberg, Germany) were subjected to drought conditions of
      different severity between July and September of two consecutive years. Drought
      stress as characterised by the water content and the pre-dawn water potential of
      the leaves was related to the degree of mycorrhization, the type of
      ectomycorrhiza, and the physiological properties of individual fungus/plant
      interactions at the fine roots of different beech ecotypes. Our data show that
      decreased soil water availability did not significantly change either the degree
      of fungal colonisation of beech roots (measured by the amount of ergosterol) or
      the number of ectomycorrhizal types per root system. Drought did, however, have
      an influence on the composition of the ectomycorrhizal community, and different
      mycorrhizal types responded to drought differently in terms of their patterns of
      occurrence/abundance. While the abundance of the dominant mycorrhizal types,
      formed with Byssocorticium atrovirens and Lactarius subdulcis, was not affected,
      drought increased the abundance of mycorrhiza formed between beech and Xerocomus
      chrysenteron. A detailed analysis of plant and fungal carbohydrates in
      mycorrhizas indicated that different drought intensities led to distinguishable
      responses. In plants exhibiting a pre-dawn water potential of down to -1.96 MPa,
      drought caused the accumulation of sucrose, glucose and fructose, and of fungus
      specific compounds such as mannitol and arabitol in mycorrhizal roots at the
      expense of, e.g. trehalose. The accumulation of sugar alcohols, which constitute
      compatible solutes known to counteract drought stress, was species-specific.
      Mycorrhizas with X. chrysenteron formed large amounts of arabitol, while those
      with L. subdulcis accumulated mannitol. Sustained partitioning of carbon towards
      the mycorrhizal fungi under drought was also reflected by an increase of nitrogen
      storage in the fungal vacuoles. In treatments where the pre-dawn water potential
      reached values of as low as -2.4 MPa, such alterations were no longer found. In
      such plants, the starch and soluble sugars content was generally reduced, which
      also resulted in a lack of increase in protective, fungus-specific sugar
      alcohols. In summary, the data show that, within certain limits, an increase in
      drought causes a shift in plant/fungus communities. The shift in the pattern of
      fungus-specific compounds could possibly be used as a sensitive measure of
      physiological stress imposed on this symbiosis.

PMID- 12466919
TI  - Inoculation of field-established mulberry and papaya with arbuscular mycorrhizal
      fungi and a mycorrhiza helper bacterium.
AB  - The effects of soil inoculation with arbuscular mycorrhizal (AM) fungi and a
      mycorrhiza helper bacterium (MHB) were investigated on mulberry and papaya plants
      already established in the field. Ten-year-old mulberry plants (var. M5) were
      inoculated with Glomus fasciculatum and 1.5-year-old papaya plants (var. Solo)
      were inoculated with a mixed culture of G. mosseae and G. caledonium with or
      without Bacillus coagulans at two levels of P fertilizer. Growth, P uptake, yield
      and AM colonization levels were monitored. Leaf yield in mulberry and fruit yield
      in papaya were minimal in uninoculated plants given 50% recommended P. However,
      crop yields of both mulberry and papaya inoculated with AM fungi alone or
      together with the bacterium and given 50% recommended P were statistically on a
      par with that of uninoculated plants given 100% recommended P. As inoculation of
      B. coagulans increased mycorrhiza levels in AM fungal-inoculated plants, this may
      be included in the class of MHB. Thus, mulberry and papaya already established in
      the field may respond to AM inoculation and MHB may increase symbiosis
      development by efficient AM fungi.

PMID- 12466920
TI  - Cognitive control of attention and action: issues and trends.

PMID- 12466921
TI  - Attentional control: brief and prolonged.
AB  - The attention system can be viewed as a collection of modules each of which
      contains two components: the expression of attention and the controlling
      operations that produce that expression. Current theories place sites of
      attentional control in the anterior cortex and sites of expression in the
      posterior cortex. Attention to a particular location or appearance of an object
      is itself controlled by instruction from a supervisory system, by the pointing of
      an arrow cue, and by bottom-up abrupt onsets of stimuli. The control of attention
      is regulated by cognitive activities such a cognitive load, error monitoring, and
      current goals. A new development of the triangular circuit theory, together with
      supporting data, suggest the existence of two modes of activity in columns of
      attentional expression: brief enhancement of pulse processing that selects
      information, and prolonged fast oscillations that sustain attention during
      preparatory and maintenance attention. It is proposed that the direct pathway of
      the triangular circuit controls the selection of information in the brief
      attention mode while the indirect pathway through the thalamus controls the
      production of fast oscillations in the prolonged attention mode.

PMID- 12466922
TI  - Oculomotor capture and Inhibition of Return: evidence for an oculomotor
      suppression account of IOR.
AB  - Previous research has shown that when subjects search for a particular target
      object the sudden appearance of a new object captures the eyes on a large
      proportion of trials. The present study examined whether the onset affects the
      oculomotor system even when the eyes move directly towards the target. Using a
      modified version of the oculomotor paradigm (see Theeuwes, Kramer, Hahn, & Irwin,
      1998) we show that when the eyes moved to the target object, subsequent saccades
      were inhibited from moving to a location at which a new object had previously
      appeared (inhibition-of-return; IOR). Whether or not a saccade to the onset was
      executed had no effect on the size of the inhibition. In particular conditions,
      the trajectories of saccades to the target objects were slightly curved in the
      opposite direction of the onset. The data are interpreted in the context of a
      novel hypothesis regarding oculomotor IOR.

PMID- 12466923
TI  - Action-based and vision-based selection of input: two sources of control.
AB  - In the first part of this paper we review evidence suggesting that there exists a
      mechanism that selects input on the basis of its similarity to the required
      action. This response-based input selection differs from the more established
      space- and object-based input selection in that it is not constrained by the
      structure of the input. Our evidence suggests that the two-choice Stroop effect
      is caused by this response-based selection mechanism. By contrast, it is known
      that the flanker effect is determined by the space- and object- based selection
      mechanisms. We explore whether the conflict resolution of the Stroop and flanker
      tasks is different as well by embedding these two tasks in a PRP (Psychological
      Refractory Period) paradigm. We show that the Stroop and the PRP effects are
      additive whereas the flanker and the PRP effects are underadditive, suggesting
      that the processes in charge of the conflict resolution in the Stroop and the
      flanker tasks are indeed different. We discuss possible reasons for this
      difference, and discuss possible ways in which the response-based mechanism can
      be implemented in information processing models.

PMID- 12466924
TI  - Control of stimulus-response translation in dual-task performance.
AB  - In contradiction to stimulus-response- (S-R-) translation bottleneck models of
      dual-task control, stimulus processing in a primary task is affected by its
      compatibility with the response in a secondary, later performed task (Hommel,
      1998a)- an indication of parallel S-R translation. Here we show that this
      backward-compatibility effect is independent of working-memory load, whether this
      is induced by an extra memory task (Experiment 1) or by increasing the number of
      S-R alternatives in the primary task (Experiment 2). However, backward effects
      occur even when the secondary task is no longer carried out (Experiment 3) and
      they are strongly affected by the inconsistency of previously used S-R mappings
      (Experiment 4). These findings suggest that S-R translation is (or can be)
      capacity-independent and automatic even under multiple-task conditions, and that
      it is mediated by direct S-R associations that emerge after only little practice.

PMID- 12466925
TI  - All-or-none bottleneck versus capacity sharing accounts of the psychological
      refractory period phenomenon.
AB  - The goal of the present experiment was to test the predictions of Central
      Bottleneck and Central Capacity Sharing models. According to the Central
      Bottleneck model, dual task interference, as observed in the PRP paradigm, is
      caused by an all-or-none bottleneck in information processing. The Central
      Capacity Sharing model postulates that dual task interference is caused by a
      capacity limited process that can allocate capacity in a graded fashion. The
      Central Bottleneck model predicts no change in RT1 with decreasing SOA, whereas
      the Central Capacity Sharing model predicts that RT1 will increase with
      decreasing SOA and that the slope of the RT1 SOA effect will depend upon the
      difficulty of task 2. Subjects were required to perform a tone pitch judgement
      and shape-matching task in rapid succession. Task order was randomized and the
      SOA between the first and second stimulus varied from 50 to 1250 ms. Results from
      this experiment favour the Central Capacity Sharing model. The results were then
      run through simulations of both the Central Bottleneck and Central Capacity
      Sharing models. Results from the simulations also favoured the Central Capacity
      Sharing model. As the difficulty of the second task increased, more capacity was
      allocated to it, confirming the prediction that as task 2 difficulty increases,
      the RT1 SOA slope increases. The proportion of capacity allocated to the first
      task varied from.78 to.91 indicating that capacity can be allocated in a graded
      fashion.

PMID- 12466926
TI  - Functional decay of memory for tasks.
AB  - Correct performance often depends on remembering the task one has been instructed
      to do. When the task periodically changes, memory for the current task must decay
      (lose activation) to prevent it from interfering with memory for the next task
      when that is encoded. Three task-switching experiments examine this decay
      process. Each shows within-run slowing, a performance decline occurring as memory
      for the current task decays. In experiment 1, slowing is attenuated when memory
      for the task is optional, suggesting that memory is indeed causal. Experiment 2
      finds slowing despite a flat hazard rate for task instructions, suggesting that
      slowing is not an artifact of instruction anticipation. Experiment 3 finds
      slowing in the familiar alternating-runs paradigm (Rogers & Monsell, 1995),
      suggesting that it may lurk elsewhere. A process model of activation explains
      within-run slowing and relates it to switch cost and "restart cost" (Allport &
      Wylie, 2000) in functional terms.

PMID- 12466927
TI  - Representing task context: proposals based on a connectionist model of action.
AB  - Representations of task context play a crucial role in shaping human behavior.
      While the nature of these representations remains poorly understood, existing
      theories share a number of basic assumptions. One of these is that task
      representations are discrete, independent, and non-overlapping. We present here
      an alternative view, according to which task representations are instead viewed
      as graded, distributed patterns occupying a shared, continuous representational
      space. In recent work, we have implemented this view in a computational model of
      routine sequential action. In the present article, we focus specifically on this
      model's implications for understanding task representation, considering the
      implications of the account for two influential concepts: (1) cognitive
      underspecification, the idea that task representations may be imprecise or vague,
      especially in contexts where errors occur, and (2) information-sharing, the idea
      that closely related operations rely on common sets of internal representations.

PMID- 12466928
TI  - Micro- and macro-adjustments of task set: activation and suppression in conflict
      tasks.
AB  - Macro- and micro-adjustment of task set was studied using distributional analyses
      of performance data (reaction time and accuracy) obtained in a new experiment
      using the Simon task. Macro-adjustments involved the long-term strategic
      modifications in response to the relative probability of conflict trials, while
      micro-adjustment involved trial-by-trial modifications invoked by the commission
      of incidental errors. These adjustments were examined in detail in distributional
      analyses of RT and accuracy, which have been shown to be particularly useful in
      studying the role of activation and suppression in conflict tasks. The
      modification of behavioral strategies incurred by the commission of errors and by
      the relative probability that the irrelevant location corresponded to the
      incorrect response was found to involve a reduced location-driven direct response
      activation (as reflected in the early portions of the delta plots for accuracy)
      and a stronger selective suppression of that direct activation (as reflected in
      the delta plot slopes for RT). When the probability of conflict trials was high,
      the effects of irrelevant location were already precluded by macro-adjustment, so
      that error commission had no further micro-adjustment effect on subsequent
      behavior. These patterns were not disclosed by analysis of overall performance.

PMID- 12466929
TI  - Executive control in the Simon effect: an electromyographic and distributional
      analysis.
AB  - Manual responses to lateralized stimuli are faster for spatially congruent
      stimulus-response associations than for incongruent associations, even if the
      stimulus location is irrelevant. This effect, however, decreases as reaction time
      increases. Recent data suggest that such a decrease reflects online, within-trial
      executive control. The present study was aimed at testing this hypothesis by
      analyzing the electromyographic activity of muscles involved in response
      execution. We focused on the particular trials in which an activation of the
      muscle involved to the incorrect response preceded the execution of the correct
      response. A sequential effect analysis, along with an analysis of the reaction
      time distributions, revealed that after such dual-activation trials, executive
      control was reinforced. In addition, a distribution analysis of the reaction
      times associated with such trials compared to the trials without incorrect
      activation, revealed online, within-trial changes in executive control. Arguments
      against a late motor locus of the effect of the irrelevant stimulus location are
      also provided. These results are discussed in terms of current models of
      cognitive control.

PMID- 12466930
TI  - Cardiac timing and the central regulation of action.
AB  - The central control of information processing necessarily entails a selection
      between actions that are implicit in different processing streams. We argue that
      this selection for action also adjusts the autonomic support for action. When
      actions are transiently undefined during the transition between actions, the time
      between heartbeats increases (heart rate transiently slows). This is particularly
      clear when actions are imminent but their identity is undefined, e.g. due to a
      delay while prepotent actions are inhibited in order to map a required action. We
      review results from a number of experiments supporting this perspective. These
      results suggest that central inhibition of representations of action influences
      heartbeat timing as well as more peripheral inhibition of overt responses. Given
      that inhibitory processes characteristic of central response selection induce
      transient heartbeat slowing, then this change is an interesting converging
      measure of the state of central response selection in combination with
      performance measures.

PMID- 12466931
TI  - Frank-Starling law of the heart and the cellular mechanisms of length-dependent
      activation.

PMID- 12466932
TI  - Characteristics of single cells isolated from the atrioventricular node of the
      adult guinea-pig heart.
AB  - To date, data regarding the cellular electrophysiology of the atrioventricular
      node (AVN) have derived from AVN cells isolated from the rabbit heart. The aim of
      this study was to characterise for the first time the electrophysiological
      properties of single cells isolated from the AVN of the guinea-pig heart. Cells
      were isolated from the AVN region by a combination of enzymatic and mechanical
      dispersion. Mean (+/-SEM) cell dimensions were 110.8+/-2.3 microm in length by
      11.4+/-1.3 micro m in width (n=76 cells). Electrophysiological recordings were
      made using the whole-cell patch-clamp technique at 37 degrees C. Mean cell
      capacitance was 25.1+/-0.9 pF (n=43) and mean cell input resistance was 1,377+/
      178 Muomega (n=21). Spontaneously active cells exhibited action potentials
      characteristic of cardiac pacemaker tissue. Under whole-cell voltage clamp, the
      mean 'zero current' potential was -39.7+/-4.1 mV (n=21). Voltage commands of 500
      ms duration to a range of test potentials from a holding potential of -40 mV
      revealed a number of distinct current components. At potentials positive to -40
      mV an early inward current was observed that exhibited a bell-shaped current
      voltage (I-V) relation, typical of L-type calcium current. A delayed outward
      current that increased progressively with test potential magnitude was also
      observed. Analysis of the outward current 'tails' on repolarisation to -40 mV
      showed this to be comprised of two components with half-maximal activation
      voltages of -17.2+/-1.8 mV, and +27.1+/-3.6 mV (n=13). 'Transient outward'
      current appeared absent from guinea-pig AVN cells. Hyperpolarising test pulses
      activated net inward current, for which three components could be observed: a
      barium-sensitive (100 microM Ba(2+)) inwardly rectifying current evident at the
      start of the voltage command and prominent at potentials negative to the
      diastolic potential range; a time-dependent, hyperpolarisation-activated current,
      and a residual background current. On repolarisation to -40 mV, a large inward
      current spike typical of cardiac Na current was observed in some cells. Notably,
      the following electrophysiological characteristics of guinea-pig AVN cells are
      distinct from those characteristics previously reported for the rabbit AVN: (1)
      an absence of transient outward current, (2) the presence of two components of
      delayed outward current, and (3) the presence of a Ba(2+)-sensitive inwardly
      rectifying current at negative voltages. The guinea-pig AVN isolated cell
      preparation may be valuable in providing additional insights into the cellular
      electrophysiology of this important region of the heart.

PMID- 12466933
TI  - Developmental expression and functional significance of Kir channel subunits in
      ureteric bud and nephron epithelia.
AB  - Kir channel subunit expression during development of the rat collecting-duct
      epithelium was quantified by RT-PCR of primary monolayer cultures. mRNAs of the
      vascular-type K(ATP) (K(NDP)) channel-forming subunits Kir6.1/SUR2 were highly
      expressed in early ureteric bud generations (embryonic day E14) and downregulated
      thereafter, while Kir1.1b (ROMK2) mRNA increased fourfold during cortical
      collecting duct (CCD) maturation. As assessed by immunohistochemistry, Kir6.1
      protein was abundant in the apical and basolateral plasma membranes of early
      ureteric buds and trunks (E15 to postnatal day P1), downregulated thereafter and
      not detectable in CCD and outer medullary collecting ducts (OMCD) (P7). During
      nephron development, Kir6.1 protein was expressed ubiquitously on plasma
      membranes of early nephron stages from mesenchymal condensations to S-shaped
      bodies. After fusion of nephron and CCD, Kir6.1 protein was restricted to the
      apical membrane of proximal tubule. The Kir6/SUR2 channel opener, pinacidil (100
      microM/2 days), increased tubulogenesis in organ culture by a factor of 3. Cell
      proliferation of human embryonic kidney cells (HEK 293) which endogenously
      express Kir6.1/SUR2 mRNA was stimulated by pinacidil in a dose-dependent manner,
      an effect that was partially abolished by glibenclamide (3 microM). In summary,
      Kir6.1/SUR2 channel subunits are highly expressed during early development of
      ureteric bud and nephron epithelia where Kir6.1/SUR2 activity regulates cell
      proliferation.

PMID- 12466934
TI  - Functional motor microdomains of the outer hair cell lateral membrane.
AB  - The outer hair cell (OHC) of the mammalian inner ear is a highly partitioned
      neuroepithelial cell whose lateral membrane is devoted to electromotility, a fast
      mechanical length change owing to the motor protein, prestin. Spatially
      restricted measures of prestin-derived nonlinear capacitance or gating charge,
      using either electrical amputation or discrete membrane mechanical deformation,
      were used to determine that functional variation exists within the extensive
      lateral membrane of the cell. This was evidenced by variation in the motor's
      operating voltage range and sensitivity among microdomains within the lateral
      membrane. That is, localized regions of the membrane evidenced Boltzmann
      distributions of motor charge whose midpoint voltage and slope differed from
      those obtained for the whole cell. These data highlight the functional
      independence of microdomains and imply that measured whole cell characteristics
      may differ from the microscopic characteristics of elementary motors.

PMID- 12466935
TI  - Hypobaric hypoxia-reoxygenation diminishes band 3 protein functions in human
      erythrocytes.
AB  - We have previously shown that subjects exposed to acute hypobaric hypoxia display
      an erythrocyte membrane protein band 3 with an increased susceptibility to
      proteolytic degradation. We suggested it was due to an oxidative damage of band
      3. We now report that exposure to hypobaric hypoxia followed by reoxygenation
      affects protein band 3 functions such as anion transport and binding of
      glyceraldehyde-3P-dehydrogenase. Transport capacity was assessed with the
      fluorescent probe 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino] ethanesulfonate
      (NBD-taurine). Binding capacity was evaluated from the activity of the membrane
      associated enzyme. Healthy young men were exposed for 20 min to hypobaric
      hypoxia, simulating an altitude of 4,500 m above sea level and after
      recompression band 3 function was assessed. An inhibition of band 3 anion
      transport function and a decrease in the binding of glyceraldehyde-3P
      dehydrogenase to band 3 were observed. Evidence is given supporting the
      hypothesis that functional alteration of band 3 is due to its oxidative
      modification originated as a consequence of the exposure to hypobaric hypoxia and
      further reoxygenation.

PMID- 12466936
TI  - Involvement of the ryanodine-sensitive Ca2+ store in GLP-1-induced Ca2+
      oscillations in insulin-secreting HIT cells.
AB  - We investigated intracellular Ca(2+) ([Ca(2+)](i)) oscillations evoked by
      glucagon-like peptide 1 (GLP-1) in relation to the ryanodine receptor (RyR) and
      Ca(2+)-induced Ca(2+)release (CICR) mechanism in pancreatic B cell HIT. GLP-1
      produced [Ca(2+)](i) oscillations in the cells, both in media with and without
      Ca(2+), an effect inhibited by ruthenium red and mimicked by 8-Br-cAMPS. In
      addition, the GLP-1-evoked [Ca(2+)](i) rise was initiated at the local
      intercellular peripheral cytoplasm, and a resultant expansion of the
      intercellular space was also observed. Caffeine induced [Ca(2+)](i) elevation in
      the medium with or without Ca(2+), an effect inhibited by ruthenium red. GLP-1
      evoked [Ca(2+)](i) oscillations were also enhanced by IBMX, and eliminated by Rp
      8-Br-cAMPS or 20 microM H-89 treatments whereas they were unaffected by 2 microM
      H-89 treatment. Forskolin caused a transient elevation in [Ca(2+)](i) that was
      reduced by Rp-8-Br-cAMPS, 2 microM or 20 microM H-89. Our results indicate that
      GLP-1 initially generated a local [Ca(2+)](i) elevation at the peripheral
      cytoplasm, subsequently producing [Ca(2+)](i) oscillations that were inhibited by
      ruthenium red, involving ryanodine-sensitive and cAMP-activated CICR mechanisms.
      The cytoplasmic levels of cAMP as well as local Ca(2+) might be responsible for
      [Ca(2+)](i) oscillations.

PMID- 12466937
TI  - Rapid insulin-induced exocytosis in white rat adipocytes.
AB  - Insulin is believed to increase glucose permeability of adipocytes by regulating
      the incorporation of glucose transporters into the plasma membrane by exocytosis.
      This process involves fusion of membrane-bound cellular compartments with the
      plasma membrane, thus influencing the plasma membrane area. However, insulin
      induced changes in plasma membrane area have not yet been demonstrated. In the
      present study we monitored fluorescence intensity with a confocal microscope to
      study the effect of insulin on adipocyte plasma membrane area. After cell
      isolation and adhesion to a glass cover-slip, adipocytes were stained with the
      dye FM1-43, a membrane area reporter. At rest, the rate of fluorescence intensity
      increase was initially high, but gradually stabilized at 2%/min. This steady
      increase in fluorescence is due to a slow rate of exocytosis coupled to
      endocytosis, since the removal of FM1-43 from the bath did not abolish FM1-43
      fluorescence. Insulin addition caused an abrupt increase of fluorescence
      intensity of 4%/min, which was significantly higher than in controls. These
      results suggest rapid, insulin-induced incorporation of new membrane into the
      plasma membrane by exocytosis.

PMID- 12466938
TI  - Two-photon chloride imaging in neurons of brain slices.
AB  - Two-photon laser scanning microscopy has been used successfully for imaging
      activity-dependent changes of intracellular calcium and sodium levels. Here we
      introduce a simple technique for two-photon chloride imaging in intact neurons.
      It involves the use of the membrane-permeable Cl(-) indicator dye MQAE [N-(6
      methoxyquinolyl) acetoethyl ester]. Brief incubation with MQAE produced a robust
      loading of cells in slices from various brain regions including hippocampus,
      cortex and cerebellum. In contrast to conventional fluorescence measurements
      using MQAE, two-photon imaging was not affected in a major way by dye bleaching
      and phototoxic damage. Instead, it allowed prolonged recordings of time-resolved
      changes in intracellular chloride concentration in somata and dendrites. As an
      example of an application we imaged GABA-mediated Cl(-) transients in pyramidal
      cells of cortical and hippocampal slices as well as in cerebellar Purkinje
      neurons. By combining Cl(-) imaging with the gramicidin-based perforated-patch
      clamp technique we showed that changes in MQAE fluorescence are proportional to
      the magnitudes of GABA-evoked transmembrane Cl(-) fluxes. Thus, MQAE-based two
      photon microscopy promises to be a valuable technique for many applications
      requiring chloride imaging in single cells.

PMID- 12466939
TI  - Developmental and food-access-dependent changes in effector systems activated by
      leptin.
AB  - In small mammals leptin reduces fat stores not only by inhibiting food intake but
      also by disinhibiting metabolic cold defense. Presuming that postnatal age and
      feeding regime set the conditions for either mode of leptin action, we compared
      the caloric equivalents of changes in fat mass, metabolic rate (MR) and food
      intake (FI) induced by 10-day treatments with leptin, in rats treated from
      postnatal days 7, 15, 25 onward and in adult mice that were free-feeding or food
      restricted. Whereas MR changes are known to dominate from postnatal days 7-16,
      changes in MR explained only about 50% and 30% of the leptin-induced changes in
      fat mass between days 15-24 and days 25-34, respectively. In adult mice of
      similar body weights, leptin-induced reductions in fat mass under free-feeding
      conditions were due only to FI decreases but due only to MR increases under food
      restricted conditions. Thus, the same leptin treatment induces the same
      percentage decrease in body fat content by driving the two effectors differently,
      depending on age and feeding conditions. Consequently, in assessing the effects
      of leptin under various physiological conditions, short-term measurements of FI
      or MR alone are not sufficient. Instead, determination of the resultant decreases
      in total body fat is required.

PMID- 12466940
TI  - Intracerebroventricular infusion of a triglyceride emulsion leads to both altered
      insulin secretion and hepatic glucose production in rats.
AB  - We investigated here whether non-esterified fatty acids (NEFA) influence insulin
      secretion and action through a direct effect on central nervous system sites
      involved in the control of glucose homeostasis. Normal Wistar rats received a 48
      h intracerebroventricular infusion of either a 10% triglyceride (Intralipid,
      IL)/heparin emulsion (IL/h) or saline/heparin solution (control). At 48 h,
      insulin secretion as measured by an intravenous glucose tolerance test, was more
      elevated in IL/h than in control rats. Pancreatic noradrenaline turnover was
      decreased by 57% in IL/h rats, suggesting low pancreatic sympathetic output that
      could account partly for the elevated insulin secretion. The time course of
      glycaemia was similar in both groups, suggesting insulin resistance. Euglycaemic
      hyperinsulinaemic clamps were imposed to assess peripheral and hepatic insulin
      sensitivity. At each insulin concentration glucose utilization was increased to a
      similar extent in both groups, whereas hepatic glucose production decreased much
      less in IL/h than in control rats. Hepatic insulin insensitivity could be related
      partly to activation of the hypothalamic-pituitary-adrenocortical axis, since
      plasma corticosterone concentration was significantly increased in IL/h rats
      compared with controls. Our data indicate that lipids may alter both insulin
      secretion and hepatic sensitivity to insulin through their effect on central
      nervous system.

PMID- 12466941
TI  - Basolateral adrenoceptor activation mediates noradrenaline-induced Cl- secretion
      in M-1 mouse cortical collecting duct cells.
AB  - Noradrenaline (NA) released from efferent renal sympathetic nerves may directly
      affect renal tubular transport. Here we examined the effect of NA on
      transepithelial ion transport of cultured M-1 mouse cortical collecting duct
      cells using equivalent short-circuit current ( I(SC)) measurements. Steady-state
      I(SC) averaged 87.5+/-2.9 microA cm(-2) (n=185) and was reduced by 97.1+/-0.1%
      (n=80) by apical amiloride (100 microM) confirming that the predominant
      electrogenic transport across M-1 monolayers is sodium absorption via the
      epithelial sodium channel (ENaC). Basolateral addition of NA (10 microM) induced
      a biphasic change in I(SC) characterized by an initial transient peak increase of
      18.1+/-0.9 microA cm(-2) with a subsequent decline to a plateau 1.4+/-0.3 microA
      cm(-2) (n=20) above baseline. Apical application of NA had no effect. The
      response to basolateral NA was concentration dependent and was preserved in the
      presence of apical amiloride. In contrast, the response was largely reduced in
      the presence of apical diphenylamine-2-carboxylic acid (1 mM) and in the absence
      of extracellular Cl(-). The peak response to NA was reduced in the presence of
      the alpha-adrenoceptor antagonist phentolamine (100 microM), whereas the beta
      antagonist propranolol (100 microM) reduced the secondary plateau phase while
      failing to influence the peak response. The alpha(1)-adrenoceptor-selective
      antagonists prazosin (10 nM) and corynanthine (1 microM) reduced the NA-induced
      peak response by about 75% and 70%, respectively, while the alpha(2)-adrenoceptor
      antagonist yohimbine (100 nM) was ineffective. We conclude that in M-1 cells NA
      stimulates Cl(-) secretion probably involving both alpha(1)- and beta
      adrenoceptors located basolaterally.

PMID- 12466942
TI  - Ryanodine receptors and the mediation of Ca2+-dependent anion secretion across
      rat colon.
AB  - The properties of the Na(+)-Ca(2+) exchanger in isolated crypts from rat colon
      were studied using the Fura-2 imaging technique. The transport mode of the
      exchanger was reversed by replacing extracellular Na(+) by the impermeable
      cation, N-methyl-D-glucamine (NMDG(+)), so that the transporter mediated a Ca(2+)
      influx into the cells. Depletion of intracellular Ca(2+) stores by inhibitors of
      sarcoplasmatic endoplasmatic calcium ATPases (SERCA), i.e., cyclopiazonic acid
      (10(-5) mol l(-1)) or thapsigargin (10(-6) mol l(-1)), reduced the increase in
      [Ca(2+)](i) evoked by superfusion with NMDG(+), suggesting a cross-talk between
      the exchanger and the Ca(2+) stores. However, measurement of Ca(2+) influx with
      the Mn(2+) quench technique revealed that the activity of the exchanger was
      independent of the filling state of the stores. Instead, the obvious inhibition
      of the [Ca(2+)](i)response by SERCA blockers was due to a reduction of Ca(2+)
      induced Ca(2+) release after inhibition of store-refilling. The functional
      presence of ryanodine receptors was demonstrated by the increase in
      [Ca(2+)](i)evoked by ryanodine (10(-7) to 3x10(-4) mol l(-1)) in a concentration
      dependent manner. This effect was mimicked by cADP ribose (10(-5) mol l(-1)) in
      crypts permeabilized with saponin (10 mg l(-1)). Ruthenium red (5x10(-5) mol l(
      1)) or high concentrations of ryanodine (3x10(-4) mol l(-1)) inhibited this
      response. In Ussing chamber experiments ruthenium red (5x10(-4) mol l(-1)) or a
      high concentration of ryanodine (10(-3) mol l(-1)) inhibited the increase in
      short-circuit current evoked by the cholinergic agonist, carbachol (5x10(-5) mol
      l(-1)). Consequently, Ca(2+)-induced Ca(2+) release may act as kind of amplifier
      during Ca(2+)-dependent Cl(-) secretion in order to maintain a long-lasting
      increase in the intracellular Ca(2+) concentration.

PMID- 12466943
TI  - Cardiac output decline in prolonged dynamic exercise is affected by the exercise
      mode.
AB  - The aim of this study was to compare the cardiovascular responses to prolonged
      submaximal cycling and running. Eleven males [maximal oxygen uptake (VO(2max)):
      3.58+/-0.15 l min(-1) for running and 3.84+/-0.16 l min(-1) for cycling; mean+/
      SE] either cycled (C) or ran (R) for 90 min at 60% of mode-specific VO(2max), on
      two randomly assigned occasions. Cardiac output declined after 85 min of exercise
      in C (-1.9+/-0.5 l min(-1), P<0.01) but not in R, as a result of a more
      pronounced decrease in stroke volume in the former exercise mode (-22.7+/-3.8 ml
      beat(-1) vs -14.3+/-1.9 ml beat(-1), P<0.01) since heart rate did not differ
      between trials. Stroke volume responses were despite a higher level of
      dehydration (-3.3+/-0.2% in R vs -2.8+/-0.2% in C, P<0.05) and hyperthermia in R
      (39.6+/-0.1 vs 38.8+/-0.1 degrees C in C at 90 min, P<0.01). Finally, mean skin
      blood flow was lower in R than C (72+/-8 vs 89+/-10%; P<0.05). In conclusion,
      stroke volume and cardiac output decline was more pronounced in cycling than in
      running despite lower dehydration and rectal temperature in the former exercise
      mode.

PMID- 12466944
TI  - Divergent expression and localization of aquaporin 5, an exocrine-type water
      channel, in the submandibular gland of Sprague-Dawley rats.
AB  - By Western blot analysis, the expression level of aquaporin (AQP) 5 in the
      submandibular gland (SMG) was found to be different among individual rats of the
      Sprague-Dawley (SD) strain. Such differences were observed for AQP5 but not for
      AQP1 and consequently the SD strain was divided into two groups, one expressing a
      high level of AQP5 and the other a low one. The difference in average intensity
      of expression between the two groups was more than twofold. Immunohistochemical
      analysis of the SMG demonstrated that the AQP5 protein was localized in the basal
      and apical/lateral plasma membrane of acinar cells in rats expressing the high
      level of AQP5. In the rat expressing the low level, however, this channel protein
      was localized strongly in the apical/lateral plasma membrane, but only very
      weakly in the basal membrane of the acinar cells. Such a diverse localization of
      AQP5 was confirmed by Western blotting as well. Breeding between brother and
      sister was repeated for two times within high expressers and low expressers to
      obtain the third generation progenies (F2); the AQP5 level of the SMG in the
      third generation (F2 rats) from high expressers was significantly higher than the
      F2 from low expressers. Our present study suggests the existence of genetic
      variation in the expression of a water channel protein, AQP5, in rats.

PMID- 12466945
TI  - Glutamine transport in isolated epithelial intestinal cells. Identification of a
      Na+-dependent transport mechanism, highly specific for glutamine.
AB  - L-glutamine transport was evaluated in isolated cells from the guinea-pig small
      intestine by measuring [(3)H]- L-glutamine uptake. Villous and crypt cells
      expressed Na(+)-dependent and Na(+)-independent transport mechanisms. Glutamine
      transport systems were identified using various amino acids and analogues as
      inhibitors. In both villous and crypt cells, 2-(methylamino)-isobutyrate (MeAIB),
      a system A inhibitor, did not inhibit Na(+)-dependent glutamine influx. 2
      Aminobicyclo(2,2,1)heptane-2-carboxylate (BCH), a system B(0) and B(0,+)
      substrate, had no effect on Na(+)-dependent influx. Serine, cysteine and
      threonine, system ASC inhibitors, reduced Na(+)-dependent influx by 50%.
      Asparagine, but not histidine, system N inhibitors, reduced Na(+)-dependent
      glutamine influx by 50%, however the effect of asparagine was not additive to
      that of threonine. The remaining Na(+)-dependent glutamine influx (50%) was only
      inhibited by glutamine itself, by Na(+) substitution ( N-methyl-glucamine, K(+),
      Li(+)) or by external pH reduction. Phenyl-acetyl-glutamine (PAG), a synthetic
      amino acid analogue, also inhibited this Na(+)-dependent, threonine-insensitive
      glutamine influx (IC(50) 2.45 mM). The Na(+)-independent uptake was partially
      inhibited by BCH, a system L inhibitor, and other neutral amino acids, but was
      not affect by PAG. Our results suggest that glutamine is transported in both
      villous and crypt cells by the Na(+)-independent system L, by the Na(+)-dependent
      system ASC and by an as yet undescribed Na(+)-dependent transport mechanism,
      highly specific for glutamine.

PMID- 12466946
TI  - Biophysical properties of heteromultimeric erg K+ channels.
AB  - The three ether-a-go-go-related gene (erg) K(+) channel subunits are able to form
      heteromultimers within their subfamily. The functional importance of this finding
      is indicated by in situ hybridization experiments showing that the different erg
      subunits have overlapping expression patterns in several regions of the brain. To
      investigate the biophysical properties of heteromultimeric erg channels,
      concatemers of two erg subunits were constructed and expressed heterologously in
      Chinese hamster ovary (CHO) cells. The resulting currents were measured using the
      patch-clamp technique. The heteromultimers exhibited an intermediate potential
      dependence of activation compared with the corresponding wild-type (WT) erg
      channels. In contrast, the time course of activation was clearly dominated by the
      faster activating subunit. The kinetics of recovery from inactivation and the
      deactivation kinetics of all heteromultimers were similar to those of WT erg1
      channels, the rat homologue of the human erg1 K(+) channel (HERG), even if erg1
      was not part of the concatemer. Taken together, the biophysical properties of
      heteromultimeric erg channels result in larger current amplitudes upon both
      depolarization and repolarization. Thus, through heteromeric assembly erg
      channels may contribute significantly to different physiological functions such
      as setting and stabilizing the resting membrane potential and modulation of
      action potential frequency.

PMID- 12466947
TI  - Skeletal muscle mitochondrial efficiency and uncoupling protein 3 in overeating
      rats with increased thermogenesis.
AB  - To establish whether changes in skeletal muscle mitochondrial efficiency
      contribute to increased energy expenditure and decreased metabolic efficiency of
      overeating rats with increased thermogenesis, we measured basal proton leak,
      fatty acid-induced uncoupling and uncoupling protein 3 (UCP3) content in
      subsarcolemmal and intermyofibrillar skeletal muscle mitochondria.
      Intermyofibrillar, but not subsarcolemmal, mitochondria from rats with increased
      thermogenesis exhibited a lower proton leak compared with controls. In both
      mitochondrial populations from rats with increased thermogenesis, fatty acid
      induced uncoupling was increased significantly and a small recoupling effect of
      GDP was detected. In addition, intermyofibrillar and subsarcolemmal mitochondria
      from rats with increased thermogenesis showed higher UCP3 contents than controls.
      These results point out that metabolic efficiency in subsarcolemmal and
      intermyofibrillar mitochondria from rats with increased thermogenesis is
      differently regulated. In fact, in intermyofibrillar mitochondria both basal
      proton leak and fatty acid-induced uncoupling are altered, while in
      subsarcolemmal mitochondria only fatty acid-induced uncoupling increases. Both
      mitochondrial populations in skeletal muscle cells from rats with increased
      thermogenesis display an increased fatty acid-induced uncoupling and UCP3
      content, which could contribute to avoiding obesity.

PMID- 12466948
TI  - Blockades of mitogen-activated protein kinase and calcineurin both change fibre
      type markers in skeletal muscle culture.
AB  - Activation of either the calcineurin or the extracellular signal-regulated kinase
      (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that
      both pathways can regulate fibre phenotypes in skeletal muscle. We investigated
      the effect of calcineurin blockade with cyclosporin A and mitogen-activated
      protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC)
      isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7
      days of treatment in primary cultures of spontaneously twitching rat skeletal
      muscle. U0126 treatment significantly decreased MHC Ibeta mRNA levels and
      significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA
      levels when compared to control. In addition, U0126 treatment significantly
      increased lactate dehydrogenase, creatine kinase, hexokinase, malate
      dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase activities above control
      values while a significant reduction in the percentage of pyruvate dehydrogenase
      in the active form was also observed. Calcineurin blockade significantly
      decreased both MHC Ibeta and embryonal mRNA levels below control and
      significantly increased MHC IIX mRNA levels. Significant increases in the
      activities of both lactate dehydrogenase and creatine kinase above control values
      were also seen following cyclosporin A treatment. In conclusion, the results
      suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre
      genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses
      fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre
      type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in
      the active form suggests that the ERK1/2 pathway may also be involved in
      regulation of the phosphorylation state of this enzyme.

PMID- 12466949
TI  - Characterisation of the ionic currents in freshly isolated rat ureter smooth
      muscle cells: evidence for species-dependent currents.
AB  - To better understand excitability, and hence contraction, the ionic currents
      underlying the action potential were identified and characterised in
      enzymatically isolated smooth muscle cells of the rat ureter. Using the whole
      cell patch-clamp, under voltage-clamp conditions with K(+) in the pipette, three
      types of responses occurred to depolarisation: (1) sustained outward current and
      spontaneous transient outward currents (STOCs); (2) inward current; and (3) fast
      outward current. Investigation using different voltage protocols and
      pharmacological blockers and agonists revealed the presence of three outward and
      two inward currents. The outward currents were: (1) a sustained BK current,
      sensitive to low concentrations of tetraethylammonium (TEA) and featuring bursts
      of STOCs superimposed on it; (2) a fast, transient, A-type K current sensitive to
      4-aminopyridine; and (3) a TEA and Ca(2+)-insensitive, late K(+) rectifier
      current. The inward currents were: (1) a fast L-type Ca(2+) channel current
      sensitive to nifedipine, Cd(2+) and potentiated by Ba(2+); and (2) a Ca(2+)
      sensitive Cl(-) channel, which was inhibited by niflumic acid and Ba(2+), and
      produced a large tail current upon repolarisation at the end of the voltage step.
      The I- V relationships and peak amplitudes of all the currents are described. The
      finding of a K(+) rectifier and Ca(2+)-activated Cl(-) channel distinguish the
      rat ureteric cells from those of the guinea-pig. Thus, as well as the previously
      established difference in sarcoplasmic reticulum Ca(2+)-release mechanisms, there
      is also a species difference in ion channel expression in this tissue. We relate
      these currents to their possible contribution to the characteristically extremely
      long lasting action potential in the rat ureter.

PMID- 12466950
TI  - From stress and strain to spikes: mechanotransduction in spider slit sensilla.
AB  - This review focuses on the structure and function of a single mechanoreceptor
      organ in the cuticle of spiders. Knowledge emerging from the study of this organ
      promises to yield general principles that can be applied to mechanosensation in a
      wide range of animal systems. The lyriform slit sense organ on the antero-lateral
      leg patella of the spider Cupiennius salei is unusual in possessing large sensory
      neurons, whose cell bodies are close to the sites of sensory transduction, and
      accessible to intracellular recording during mechanotransduction. This situation,
      combined with recent technical developments, has made it possible to observe and
      experiment with all the major stages of mechanosensation. Important findings
      include the approximate size, number and ionic selectivity of the ion channels
      responsible for mechanotransduction, the types of voltage-activated ion channels
      responsible for action potential encoding, and the mechanisms controlling the
      dynamic properties of transduction and encoding. Most recently, a complex
      efferent system for peripheral modulation of mechanosensation has been discovered
      and partially characterized. Much remains to be learned about mechanosensation,
      but the lyriform slit sense organ system continues to offer important
      opportunities to advance our understanding of this crucial sense.

PMID- 12466951
TI  - Mechanoreceptors innervating soft cuticle in the abdomen of the hermit crab,
      Pagurus pollicarus.
AB  - Mechanoreceptors in the soft cuticle of the 4th abdominal segment of the hermit
      crab, Pagurus pollicarus, that are associated with reflex activation of abdominal
      postural motoneuron, were studied to determine whether their properties are
      consistent with a feedback control of abdominal stiffness. Three classes of
      receptors were identified: (1) setal dome receptors, (2) hypodermal receptors,
      and (3) funnel-canal receptors. The hypodermal receptors, which have the largest
      extracellular action potentials, were selected for further study. Their axons
      innervate the entire ipsilateral half of a segment; receptive fields of receptors
      with different amplitudes show extensive overlap. They are phasic and show
      significant adaptation; at higher frequencies they signal displacement rather
      than velocity. Although they are activated by changing muscle tension, their
      threshold for cuticular displacement is much lower than for forces generated by
      postural muscles. These features suggest that they are primarily involved in
      signaling cuticular displacement and shearing forces as they contact the
      columella of the shell in which the hermit crab lives.

PMID- 12466952
TI  - Serotonin precursor (5-hydroxytryptophan) has a profound effect on the post
      copulatory time-fixed sexually refractory stage in the male cricket, Gryllus
      bimaculatus DeGeer.
AB  - This study addresses a potentially general basis of measuring time in a
      biological timer. Here, we examined the effects of biogenic amines on the time
      fixed post-copulatory sexually refractory stage (ca. 1 h) which is defined as the
      time interval between spermatophore protrusion and the onset of a calling or a
      mating response in the reproductive cycle of the male cricket. For subcuticular
      injection of amines (0.15 ml, 10(-2) mol l(-1)), the interval of the refractory
      stage was shortened by octopamine, serotonin, 5-hydoxytryptophan and N-acetyl
      serotonin but was unchanged by tryptophan, melatonin or 5-hydroxyindol-3-acetic
      acid. The effect of 5-hydoxytryptophan was most potent (maximum shortening, 38%)
      and long lasting (ca. 4.5 h) while other amines effected only the injected cycle.
      Injection of 5-hydoxytryptophan (180 nl, 10(-2) mol l(-1)) into the terminal
      abdominal ganglion also decreased the interval to a similar extent. Simultaneous
      injection of 5-hydoxytryptophan with the inhibitor of the serotonin synthesis
      enzyme reduced the 5-hydoxytryptophan effect suggesting that this effect results
      from synthesis of serotonin from 5-hydoxytryptophan. The protein synthesis
      inhibitor cycloheximide had no effect on the interval. These results suggest that
      the reproductive timer is regulated by serotonergic neurons in the terminal
      abdominal ganglion without protein synthesis during the interval of the time
      fixed sexually refractory stage.

PMID- 12466953
TI  - A push-pull set of elastic strand stretch receptor neurons for the swimmeret in
      an isopod Bathynomus doederleini.
AB  - There coexist two types of neuronal terminal processes attaching to elastic
      strands at the socket of the swimmeret in Bathynomus doederleini. One of the
      processes, stretch receptor I is derived from the 1st nerve root of the abdominal
      ganglion. The other, stretch receptor II is derived from the 2nd nerve root of
      the ganglion. Both axons of stretch receptors are very thick (30-60 micro m) at
      sites before the terminal arborization. Cell bodies of the stretch receptors are
      located in the ganglion of their own segments. The neuronal cell body of the
      stretch receptor I is located at the anterior half of the hemiganglion
      ipsilateral to the periphery, and the neuronal cell body of the stretch receptor
      II at the posterior half of the hemiganglion contralateral to the periphery.
      Their signaling modalities in response to swimmeret movements were analyzed from
      intracellular recordings from the cell bodies. Stretch receptor I produced a
      sustained hyperpolarizing potential in response to protraction of the swimmeret.
      Stretch receptor II produced a sustained depolarizing potential in response to
      the protraction, and moreover, generated spike potentials on the rising phase of
      the depolarizing potential according to its height and steepness. Both the
      stretch receptors are a push-pull set of elastic strand stretch receptors for the
      angular position and velocity of swimmeret movements.

PMID- 12466955
TI  - Temperature preferences of male field crickets ( Gryllus integer) alter their
      mating calls.
AB  - Temperature affects the mating displays of many ectothermic animals, yet almost
      no information exists on the temperature preferences of ectotherms while they are
      displaying for mates. This study investigated the preferences of displaying male
      field crickets ( Gryllus integer) for microhabitats of different temperatures. G.
      integer males attract sexually receptive females by calling from cracks in the
      ground. We collected data from the field on the temperature of male calling sites
      (cracks in the ground), on the amount of herbaceous cover (which affects crack
      temperature) surrounding calling sites, and on the temporal properties of male
      calls at different temperatures. Laboratory experiments demonstrated that males
      prefer warmer sites and confirmed that temperature influences mating calls. We
      conclude that males of this ectothermic species prefer to call for mates from
      warmer sites, and that microhabitat choice on the basis of temperature affects
      their mating calls, and potentially their reproductive success.

PMID- 12466954
TI  - Olfactory discrimination of structurally similar alcohols by cockroaches.
AB  - The capability of the cockroach Periplaneta americana to discriminate odors of
      structurally similar aliphatic alcohols was studied by using an operant
      conditioning paradigm. Cockroaches were trained to discriminate three odors: one
      odor associated with sucrose solution (reward) and two odors associated with NaCl
      solution (non-reward). After training, their odor preferences were tested by
      counting the number of visits to each odor source. We tested the capability of
      cockroaches to discriminate (1) three normal aliphatic alcohols with different
      numbers of carbon (1-pentanol, 1-hexanol and 1-octanol), (2) three C6 aliphatic
      alcohols (1-hexanol, 2-hexanol and trans-2-hexen-1-ol), (3) binary mixtures of
      two of these three alcohols and their components, and (4) 1-hexanol solution of
      three different concentrations (1, 10 and 100 micro g micro l(-1)). Cockroaches
      exhibited higher preferences for the odors associated with reward in these tests,
      and we therefore conclude that cockroaches can discriminate these odors. However,
      discrimination of 1-hexanol and trans-2-hexen-1-ol and their binary mixture was
      imperfect, in that some statistical tests suggested significant level of
      discrimination but other tests did not. In addition, the cockroaches learned to
      associate a 1-hexanol solution of the highest or lowest concentration with
      sucrose reward but failed to learn to associate 1-hexanol of an intermediate
      concentration with reward.

PMID- 12466956
TI  - Effects of a red-tide toxin on fish hearing.
AB  - Red tides are formed from blooms of marine algae. Among them, the dinoflagellate
      ( Karenia brevis) that is responsible for Florida red tides can release many
      types of natural toxins, which cause massive kills of marine animals, including
      endangered species, and threaten human health. This study was to investigate
      whether or not a neurotoxin, brevetoxin-3, purified from Florida red tides
      affects hearing sensitivity of a teleost fish, the goldfish ( Carassius auratus).
      LD(50) of the goldfish that were intraperitoneally injected with brevetoxin-3 was
      0.068 microg g(-1). Evoked auditory brainstem responses were recorded, and
      hearing threshold was determined using a correlation method. By comparing
      thresholds of fish before and after a sublethal-dose injection (0.064 microg g(
      1)) of the toxin, we found that brevetoxin-3 significantly reduces auditory
      sensitivity up to 9 dB at low frequencies (100 Hz and 500 Hz), but not at a high
      frequency (2,000 Hz). Reduction of hearing sensitivity was recovered within 24 h.
      To our knowledge, this is the first study showing a natural red-tide toxin causes
      minor hearing loss in vertebrates. Results of the study indicate that brevetoxin
      3 could affect hearing capabilities of marine animals that survived exposure to
      red tides. Mechanisms of the toxin-induced reduction of hearing sensitivity are
      discussed.

PMID- 12466957
TI  - The role of GABAergic inhibition in shaping directional selectivity of bat
      inferior collicular neurons determined with temporally patterned pulse trains.
AB  - This study examined the role of GABAergic inhibition in shaping directional
      selectivity of neurons in the inferior colliculus of the big brown bat, Eptesicus
      fuscus. When determined with temporally patterned pulse trains at different pulse
      repetition rates, 93 inferior colliculus neurons displayed three types of
      directional selectivity curves. A directionally selective curve always showed a
      maximum to a certain azimuthal angle (the best angle). A hemifield curve showed a
      maximum to a range of contralateral azimuthal angles. A non-directional curve did
      not show a maximum to any particular azimuthal angles. Directional selectivity
      curves of 42% neurons changed from hemifield or non-directional to directionally
      selective and the best angles of 16-21% neurons shifted toward the midline with
      increasing pulse repetition rate of pulse trains. Directional selectivity curves
      of most (74%) neurons that discharged impulses to each pulse of a pulse train
      also became sharper with increasing pulse repetition rate of pulse trains.
      Bicuculline application produced more pronounced broadening of directional
      selective curves of inferior colliculus neurons at higher than at lower pulse
      repetition rates. As a result, pulse repetition rate-dependent directional
      selectivity of inferior colliculus neurons was abolished. Possible mechanisms and
      biological significance of these findings are discussed.

PMID- 12466958
TI  - Anti-apoptotic and oncogenic properties of the dsRNA-binding protein of vaccinia
      virus, E3L.
AB  - The vaccinia virus (VV) E3L gene encodes a dsRNA binding protein that inhibits
      activation of the IFN-induced, dsRNA-dependent protein kinase, (PKR), the 2-5A
      synthetases/RNase L system and other dsRNA dependent pathways, thus leading to
      efficient VV replication. To analyse E3L effects over cellular metabolism in a
      virus-free system, we have generated stable mouse 3T3 cell lines expressing E3L.
      Expression of E3L in NIH3T3 cells results in inhibition of eIF-2alpha
      phosphorylation and Ikappa(B)alpha degradation in response to dsRNA. Antiviral
      responses induced by IFN-alpha/beta were partially impaired in 3T3-E3L cells, as
      determined by a viability assay upon VSV infection. E3L expression also confers
      resistance to dsRNA-triggered apoptosis. Interestingly, cells expressing E3L grew
      faster than control cells, and showed increased expression of cyclin A and
      decreased levels of p27(Kip1). E3L cooperated with H-ras in a focus formation
      assay, and NIH3T3 E3L cells formed solid tumors when injected in nude mice.
      Overall, our findings reveal that interference of E3L protein with several
      cellular pathways, results in promotion of cellular growth, impairment of
      antiviral activity and resistance to apoptosis.

PMID- 12466959
TI  - Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for
      transcriptional repression.
AB  - The potential tumor suppressor protein prohibitin can prevent cell proliferation
      and this required its binding to the Rb protein. Prohibitin could repress the
      transcriptional activity of E2F family members and this required a part of the
      marked box region of E2F. The sub-cellular localization of prohibitin has been
      variously attributed to the mitochondria as well as the inner cell membrane. Here
      we show that a subset of prohibitin molecules are present in the nucleus where it
      co-localizes with the Rb protein. Deletion of a putative amino-terminal membrane
      docking domain of prohibitin had no effect on its ability to suppress cell
      proliferation or inhibit E2F activity. Our experiments show that a 53 amino-acid
      stretch of E2F1 is sufficient for being targeted by prohibitin; fusion of this
      region to GAL4-VP16 construct could make it susceptible to prohibitin-mediated,
      but not Rb-mediated repression. Prohibitin, like Rb, could repress transcription
      from SV40 and major late promoters when recruited directly to DNA. Prohibitin
      mediated transcriptional repression required histone-deacetylase activity, but
      unlike Rb, additional co-repressors like N-CoR are also involved. Repression by
      prohibitin correlates with histone deacetylation on promoters and this was
      reversed by IgM stimulation of cells; IgM did not affect Rb-mediated repression
      or deacetylation of the promoters. Prohibitin thus appears to repress E2F
      mediated transcription utilizing different molecular mediators and facilitate
      channeling of specific signaling pathways to the cell cycle machinery.

PMID- 12466960
TI  - Histone H1(S)-3 phosphorylation in Ha-ras oncogene-transformed mouse fibroblasts.
AB  - Phosphorylation of linker histone H1(S)-3 (previously named H1b) and core histone
      H3 is elevated in mouse fibroblasts transformed with oncogenes or constitutively
      active mitogen-activated protein kinase (MAPK) kinase (MEK). H1(S)-3
      phosphorylation is the only histone modification known to be dependent upon
      transcription and replication. Our results show that the increased amounts of
      phosphorylated H1(S)-3 in the oncogene Ha-ras-transformed mouse fibroblasts was a
      consequence of an elevated Cdk2 activity rather than the reduced activity of a H1
      phosphatase, which our studies suggest is PP1. Induction of oncogenic ras
      expression results in an increase in H1(S)-3 and H3 phosphorylation. However, in
      contrast to the phosphorylation of H3, which occurred immediately following the
      onset of Ras expression, there was a lag of several hours before H1(S)-3
      phosphorylation levels increased. We found that there was a transient increase in
      the levels of p21(cip1), which inhibited the H1 kinase activity of Cdk2. Cdk2
      activity and H1(S)-3 phosphorylated levels increased after p21(cip1) levels
      declined. Our studies suggest that persistent activation of the Ras-MAPK signal
      transduction pathway in oncogene-transformed cells results in deregulated
      activity of kinases phosphorylating H3 and H1(S)-3 associated with transcribed
      genes. The chromatin remodelling actions of these modified histones may result in
      aberrant gene expression.

PMID- 12466961
TI  - Inhibition of constitutively active Stat3 suppresses proliferation and induces
      apoptosis in glioblastoma multiforme cells.
AB  - Glioblastoma multiforme (GBM), the most common and malignant central nervous
      system tumor in humans, is highly proliferative and resistant to apoptosis.
      Stat3, a latent transcription factor being activated by aberrant cytokine or
      growth factor signaling, acts as a suppressor of apoptosis in a number of cancer
      cells. Here we report that GBM tumors and cell lines contain high levels of
      constitutively activated Stat3 when compared with normal human astrocytes, white
      matter, and normal tissue adjacent to tumor. The persistent activation of Stat3
      is in part, attributable to an autocrine action of interleukin-6 in the GBM cell
      line U251. Janus kinase inhibitor AG490 inhibits Stat3 activation with a
      concomitant reduction in steady-state levels of Bcl-X(L), Bcl-2 and Mcl-1
      proteins and induces apoptosis in U251 cells as revealed by Poly (ADP-ribose)
      polymerase cleavage and Annexin-V staining. Expression of a dominant negative
      mutant Stat3 protein or treatment with AG490 markedly reduces the proliferation
      of U251 cells by inhibiting the constitutive activation of Stat3. These results
      provide evidence that constitutive activation of Stat3 contributes to the
      pathogenesis of glioblastoma by promoting both proliferation and survival of GBM
      cells. Therefore, targeting Stat3 signaling may provide a potential therapeutic
      intervention for GBM.

PMID- 12466962
TI  - Beta-catenin-mediated transactivation and cell-cell adhesion pathways are
      important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in
      colon cancer cells.
AB  - The development of nontoxic natural agents with chemopreventive activity against
      colon cancer is the focus of investigation in many laboratories. Curcumin
      (feruylmethane), a natural plant product, possesses such chemopreventive
      activity, but the mechanisms by which it prevents cancer growth are not well
      understood. In the present study, we examined the mechanisms by which curcumin
      treatment affects the growth of colon cancer cells in vitro. Results showed that
      curcumin treatment causes p53- and p21-independent G(2)/M phase arrest and
      apoptosis in HCT-116(p53(+/+)), HCT-116(p53(-/-)) and HCT-116(p21(-/-)) cell
      lines. We further investigated the association of the beta-catenin-mediated c-Myc
      expression and the cell-cell adhesion pathways in curcumin-induced G(2)/M arrest
      and apoptosis in HCT-116 cells. Results described a caspase-3-mediated cleavage
      of beta-catenin, decreased transactivation of beta-catenin/Tcf-Lef, decreased
      promoter DNA binding activity of the beta-catenin/Tcf-Lef complex, and decreased
      levels of c-Myc protein. These activities were linked with decreased Cdc2/cyclin
      B1 kinase activity, a function of the G(2)/M phase arrest. The decreased
      transactivation of beta-catenin in curcumin-treated HCT-116 cells was
      unpreventable by caspase-3 inhibitor Z-DEVD-fmk, even though the curcumin-induced
      cleavage of beta-catenin was blocked in Z-DEVD-fmk pretreated cells. The curcumin
      treatment also induced caspase-3-mediated degradation of cell-cell adhesion
      proteins beta-catenin, E-cadherin and APC, which were linked with apoptosis, and
      this degradation was prevented with the caspase-3 inhibitor. Our results suggest
      that curcumin treatment impairs both Wnt signaling and cell-cell adhesion
      pathways, resulting in G(2)/M phase arrest and apoptosis in HCT-116 cells.

PMID- 12466964
TI  - Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation.
AB  - During the last decade, several novel members of the Epidermal Growth Factor
      family of peptide growth factors have been identified. Most prominent among these
      are the Neuregulins or Heregulins. To date, four different Neuregulin genes have
      been identified (Neuregulin1-4) and several different splicing isoforms have been
      identified for at least two of these genes (Neuregulin1 and Neuregulin2). While
      Neuregulin1 isoforms have been extensively studied, comparatively little is known
      about Neuregulin3, Neuregulin4, or the Neuregulin2 isoforms. Indeed, there has
      been no systematic comparison of the activities of these molecules. Here we
      demonstrate that Neuregulin2alpha and Neuregulin2beta stimulate ErbB3 tyrosine
      phosphorylation and coupling to biological responses. In contrast, Neuregulin3
      and Neuregulin4 fail to activate ErbB3 signaling. Furthermore, Neuregulin2beta,
      but not Neuregulin2alpha, stimulates ErbB4 tyrosine phosphorylation and coupling
      to biological responses. Finally, both Neuregulin3 and Neuregulin4 stimulate
      modest amounts of ErbB4 tyrosine phosphorylation. However, whereas Neuregulin3
      stimulates a modest amount of ErbB4 coupling to biological responses, Neuregulin4
      fails to stimulate ErbB4 coupling to biological responses. This suggests that
      there are qualitative as well as quantitative differences in ErbB family receptor
      activation by Neuregulin isoforms.

PMID- 12466963
TI  - Complex regulation of acetylcholinesterase gene expression in human brain tumors.
AB  - To study the regulation of acetylcholinesterase (AChE) gene expression in human
      brain tumors, 3' splice variants of AChE mRNA and potentially relevant
      transcription factor mRNAs were labeled in primary astrocytomas and melanomas.
      AChE-S and AChE-R mRNA, as well as Runx1/AML1 mRNA accumulated in astrocytomas in
      correlation with tumor aggressiveness, but neither HNF3beta nor c-fos mRNA was
      observed in melanoma and astrocytomas. Immunohistochemistry demonstrated nuclear
      Runx1/AML1 and cellular AChE-S and AChE-R in melanomas, however, only AChE-S, and
      not the secreted AChE-R variant, was retained in astrocyte tumor cells.
      Runx1/AML1 revealed weak linkage with ACHE promoter sequences, yet enhanced ACHE
      gene expression in co-transfected COS1 cells. The p300 co-activator and the ACHE
      promoter's distal enhancer facilitated this effect, which was independent of much
      of the Runx1/AML1 trans-activation domain. Surprisingly, GASP, a fusion product
      of green fluorescence protein (GFP) and ASP(67), a peptide composed of the 67 C
      terminal amino acid residues of AChE-S, localized to COS1 cell nuclei. However,
      GARP, the corresponding fusion product of GFP with a peptide having the 51 C
      terminal residues of AChE-E or GFP alone, remained cytoplasmic. Runx1/AML1
      exhibited improved nuclear retention in GASP-expressing COS1 cells, suggesting
      modulated nuclear localization processes. Together, these findings reveal brain
      tumor-specific regulation of both expression and cellular retention of variant
      ACHE gene products.

PMID- 12466965
TI  - Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor.
AB  - Beta-catenin signaling may contribute to prostate cancer (CaP) progression.
      Although beta-catenin is known to upregulate T cell factor (TCF) target gene
      expression in CaP cells, recent evidence demonstrates its capacity to enhance
      ligand-dependent androgen receptor (AR) function. Thus, we wished to further
      understand the interaction between these two pathways. We find in both CaP cells
      (CWR22-Rv1, LAPC-4, DU145) and non-CaP cells (HEK-293, TSU, SW480, HCT-116) that
      beta-catenin/TCF-related transcription (CRT), as measured by activation of a
      synthetic promoter and that of cyclin D1, is inhibited by androgen treatment.
      This inhibition is AR-dependent, as it only occurs in cells expressing AR
      endogenously or transiently, and is abrogated by AR antagonists. Additional
      analyses convey that the ligand-dependent nature of CRT suppression depends on
      transactivation-competent AR in the nucleus, but not on indirect effects stemming
      from AR target gene expression. Given the recent work identifying an AR/beta
      catenin interaction, and from our finding that liganded AR does not prompt gross
      changes in the constitutive nuclear localization of TCF4 or mutant beta-catenin,
      we hypothesized that transcription factor (i.e. AR and TCF) competition for beta
      catenin recruitment may explain, in part, androgen-induced suppression of CRT. To
      address this idea, we expressed an AR mutant lacking its DNA-binding domain
      (DBD). This receptor could not orchestrate ligand-dependent CRT repression,
      thereby providing support for those recent data implicating the AR DBD/LBD as
      necessary for beta-catenin interaction. Further supporting this hypothesis,
      TCF/LEF over-expression counteracts androgen-induced suppression of CRT, and
      requires beta-catenin binding activity to do so. Interestingly, TCF4 over
      expression potently antagonizes AR function; however, this inhibition may occur
      independently of beta-catenin/TCF4 interaction. These results from TCF4 over
      expression analyses, taken together, provide further evidence that AR-mediated
      suppression of CRT is a consequence of limiting amounts of beta-catenin, and not
      AR target gene expression. Our analyses point to a reciprocal balance between AR
      and CRT function that may shape critical processes during normal prostate
      development and tumor progression.

PMID- 12466966
TI  - Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product,
      regulates Rho activation, cell adhesion and migration.
AB  - Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome
      characterized by seizures, mental retardation, autism, and tumors of the brain,
      kidney, heart, retina, and skin. TSC is caused by mutations in either TSC1 or
      TSC2, both of which are tumor suppressor genes. Hamartin, the protein product of
      TSC1, was found to interact with the ezrin-radixin-moesin family of cytoskeletal
      proteins and to activate the small GTPase Rho. To determine whether tuberin, the
      TSC2 product, can also activate Rho, we stably expressed full-length human
      tuberin in two cell types: MDCK cells and ELT3 cells. ELT3 cells lack endogenous
      tuberin expression. We found that expression of human tuberin in both MDCK and
      ELT3 cells was associated with an increase in the amount of Rho-GTP, but not in
      Rac1-GTP or cdc42-GTP. Tuberin expression increased cell adhesion in both cell
      types, and decreased chemotactic cell migration in ELT3 cells. In MDCK cells,
      there was a decrease in the amount of total Focal Adhesion Kinase (FAK) and an
      increase in the fraction of phosphorylated FAK. These findings demonstrate for
      the first time that tuberin activates Rho and regulates cell adhesion and
      migration. Pathways involving Rho activation may have relevance to the clinical
      manifestations of TSC, including pulmonary lymphangioleiomyomatosis.

PMID- 12466967
TI  - The Sp1 transcription factor contributes to the tumor necrosis factor-induced
      expression of the angiogenic factor thymidine phosphorylase in human colon
      carcinoma cells.
AB  - Thymidine phosphorylase (TP; also known as platelet-derived endothelial cell
      growth factor, PD-ECGF) is an angiogenic factor that is chemotactic for
      endothelial cells and has been found to induce neovascularization in vivo. TP is
      frequently overexpressed in human solid tumors, where its expression has been
      correlated with increased tumor microvessel density, invasion, and metastasis,
      and shorter patient survival. In this report, TP activity in the WiDr colon
      carcinoma cell line was found to be induced 100-fold by tumor necrosis factor
      (TNFalpha), a secretory product of activated macrophages that has indirect
      angiogenic activities. Increased TP activity was accompanied by increased TP mRNA
      levels and without an increase in mRNA stability. TNFalpha-induced TP mRNA levels
      were reduced by mithramycin, a DNA-binding transcription inhibitor specific for
      GC-rich sequences. Transcriptional regulation by TNFalpha was confirmed by
      transient transfection of WiDr with upstream TP sequences in a luciferase
      reporter construct. Deletion analysis of the reporter pinpointed two regions of
      the TP promoter with regulatory elements for both TNFalpha-inducible and basal
      expression, and they contained, respectively, three and one consensus binding
      sites for the Sp1-family of transcription factors. One additional region
      contributed only to basal TP expression, and it contained three Sp1 sites.
      TNFalpha-induced TP expression decreased when point mutations were made in three
      of the four Sp1 sites postulated to contribute to both basal and TNFalpha
      inducible expression. Electrophoretic mobility shift assays further demonstrated
      binding of nuclear Sp1 to these three sites. Sp1-binding activity was also
      increased in cells treated with TNFalpha. These studies establish a role for Sp1
      in the regulation of expression of the angiogenic factor TP in colon cancer WiDr
      cells.

PMID- 12466968
TI  - Loss of the cell cycle inhibitors p21(Cip1) and p27(Kip1) enhances tumorigenesis
      in knockout mouse models.
AB  - Events that contribute to tumor formation include mutations in the ras gene and
      loss or inactivation of cell cycle inhibitors such as p21(Cip1) and p27(Kip1). In
      our previous publication, we showed that mice expressing the MMTV/v-Ha-ras
      transgene developed tumors earlier and at higher multiplicities in the absence
      than in the presence of p21(Cip1). To further evaluate the combinatorial role of
      genetic alterations and loss of cell cycle inhibitors in tumorigenesis, we
      performed two companion studies. In the first study, wild type and p21(Cip1)-null
      mice were exposed to the chemical carcinogen, urethane. Similar to its effects in
      v-Ha-ras mice, loss of p21(Cip1) accelerated tumor onset and increased tumor
      multiplicity in urethane-treated mice. Lung tumors were the predominant tumor
      type in urethane-treated mice regardless of p21(Cip1) status. In the second
      study, tumor formation was monitored in v-Ha-ras mice expressing or lacking
      p27(Kip1). Unlike p21(Cip1), the absence of p27(Kip1) had no effect on the timing
      or multiplicity of tumor formation, which was largely restricted to mammary and
      salivary glands. However, once tumors appeared, they grew faster in p27(Kip1)
      null mice than in p27(Kip1)-wild type mice. Increases in growth rate were
      particularly striking for salivary tumors in ras/p27(-/-) mice. Loss of
      p21(Cip1), on the other hand, had no effect on tumor growth rate in v-Ha-ras
      mice. Collectively, our data suggest that p21(Cip1) suppresses tumor formation
      elicited by multiple agents and that p21(Cip1) and p27(Kip1) suppress tumor
      formation in different ways.

PMID- 12466969
TI  - Activation of MAPK signaling pathway is essential for Id-1 induced serum
      independent prostate cancer cell growth.
AB  - The helix-loop-helix protein Id-1 has been suggested to play a positive role in
      cell proliferation and tumorigenesis of many types of human cancers. However,
      little is known about the molecular mechanism involved in the function of Id-1.
      In this study, using four stable Id-1 transfectant clones, we investigated the
      involvement of MAPK signaling pathway in the Id-1 induced serum independent
      prostate cancer cell growth. Our results demonstrated that both transient and
      stable ectopic Id-1 expression in prostate cancer LNCaP cells led to activation
      of the Raf/MEK1/2 signaling pathway. In addition, inhibition of MEK1/2
      phosphorylation by one of its inhibitors, PD098059, resulted in the decreased
      cell cycle S phase fraction and cell growth rate, suggesting that activation of
      MAPK signaling pathway is essential for Id-1 induced prostate cancer cell
      proliferation. Furthermore, treatment with antisense oligonucleotide
      complementary to Id-1 mRNA in PC-3 and DU145 cells resulted in a decreased Id-1
      expression which was accompanied by decreased Egr-1 protein. Our results suggest
      for the first time that the function of Id-1 is associated with MAPK signaling
      pathway activation and indicate a possible novel mechanism in which Id-1
      regulates prostate cancer cell growth and tumorigenesis.

PMID- 12466970
TI  - Expression of the transcription factor Ets-1 is an independent prognostic marker
      for relapse-free survival in breast cancer.
AB  - The transcription factor Ets-1 regulates the expression of several angiogenic and
      extracellular matrix remodeling factors, and might be implicated in disease
      progression of breast cancer. In the present study, the prognostic value of Ets-1
      expression was assessed by quantitative real-time fluorescence RT-PCR in 123
      sporadic primary breast cancer samples of patients with a median follow-up time
      of 62 months. Ets-1 expression levels correlated significantly with VEGF and PAI
      1 in the same tissue. In univariate (P=0.0011) and multivariate (P=0.005)
      analyses, Ets-1 expression showed significant prognostic value for relapse-free
      survival. Ets-1 is a strong, independent predictor of poor prognosis in breast
      cancer. This seems - at least in part - to be attributable to its role in
      transcriptional regulation of factors involved in angiogenesis (VEGF), and
      extracellular matrix remodeling (PAI-1).

PMID- 12466971
TI  - Loss of expression of death-inducing signaling complex (DISC) components in lung
      cancer cell lines and the influence of MYC amplification.
AB  - We have previously reported that the key apoptosis related gene caspase 8 (CASP8)
      is frequently silenced in small cell lung cancer (SCLC) tumors and cell lines
      usually, but not always, by aberrant promoter methylation. Because CASP8 is a key
      component of the death-inducing signaling complex (DISC) when specific death
      receptors (including DR4, DR5, FAS) are activated by their specific ligands
      (TRAIL/FASL), we examined expression of the components of the DISC complex in
      lung cancer cell lines. MYC family members are frequently amplified (MYC+ve) in
      SCLC, and MYC is a potent inducer of apoptosis. We examined 34 SCLC lines (12 of
      which were MYC+ve) and 22 NSCLC lines. CASP8 gene expression was frequently lost
      (79%) at message and protein levels in SCLC but not in non-SCLC (NSCLC). MYC
      amplification was present in 45% of SCLC cell lines, which had lost CASP8
      expression, but not in any of the CASP8 positive lines. The frequency of CASP8
      loss was significantly higher in MYC+ve SCLC compared to MYC-ve SCLC or in NSCLC.
      Analyses of other DISC components showed significantly higher rates of loss of
      expression of CASP10, DR5, FAS and FASL in SCLC compared to NSCLC. The loss of
      expression of proapoptotic DISC components was significantly higher in MYC+ve
      SCLC cell lines and these lines were completely resistant to TRAIL. Expression of
      CASP10 (a caspase closely related to CASP8) was frequently absent at the protein
      level in both SCLC and NSCLC lines. Expression of c-FLIP (proteolytically
      inactive homolog of CASP8) was inversely related to expression of CASP8. Our
      major conclusions are: (a) The death receptor pathway is differently inactivated
      at multiple levels in lung cancer cell lines; and (b) MYC amplification in SCLC
      is associated with inactivation of most components of the DISC complex, with
      resistance to TRAIL and with expression of c-FLIP. These findings may have
      considerable clinical and therapeutic implications.

PMID- 12466972
TI  - Stable and unstable pools of Myc protein exist in human cells.
AB  - The oncoprotein transcription factor Myc plays a crucial role in the control of
      cell growth and proliferation. Consistent with its potent growth-promoting
      properties, cells have evolved a number of mechanisms to limit the activity and
      accumulation of the Myc protein. One of the most striking of these mechanisms is
      ubiquitin (Ub)-mediated proteolysis, which typically destroys Myc within minutes
      of its synthesis. Here we show that, despite the extreme instability of the Myc
      protein, cells contain a pool of Myc that is metabolically stable. Entry of Myc
      into the stable pool is signaled by an element within the carboxy-terminus of the
      protein, and is a cell-specific process that is regulated during mitosis and by
      interaction with Max. These data demonstrate that - even for a rapidly turned
      over protein such as Myc - metabolically stable and unstable forms of a protein
      can co-exist in cells, and suggest that the rate of destruction of Myc molecules
      is linked to their specific functions.

PMID- 12466973
TI  - Identification of radiation-specific responses from gene expression profile.
AB  - The responses to ionizing radiation (IR) in tumors are dependent on cellular
      context. We investigated radiation-related expression patterns in Jurkat T cells
      with nonsense mutation in p53 using cDNA microarray. Expression of 2400 genes in
      gamma-irradiated cells was distinct from other stimulations like anti-CD3,
      phetohemagglutinin (PHA) and concanavalin A (ConA) in unsupervised clustering
      analysis. Among them, 384 genes were selected for their IR-specific changes to
      make 'RadChip'. In spite of p53 status, every type of cells showed similar
      patterns in expression of these genes upon gamma-radiation. Moreover, radiation
      induced responses were clearly separated from the responses to other genotoxic
      stress like UV radiation, cisplatin and doxorubicin. We focused on two IR-related
      genes, phospholipase Cgamma2 (PLCG2) and cytosolic epoxide hydrolase (EPHX2),
      which were increased at 12 h after gamma-radiation in RT-PCR. TPCK could suppress
      the induction of these two genes in either of Jurkat T cells and PBMCs, which
      might suggest the transcriptional regulation of PLCG2 and EPHX2 by NF-kappaB upon
      gamma-radiation. From these results, we could identify the IR-specific genes from
      expression profiling, which can be used as radiation biomarkers to screen
      radiation exposure as well as probing the mechanism of cellular responses to
      ionizing radiation.

PMID- 12466974
TI  - Deregulation of cyclin E2 expression and associated kinase activity in primary
      breast tumors.
AB  - The increased expression of G(1) cyclins has been associated with the many types
      of human tumors. In primary solid tumors however, the expression and activity of
      cyclin E2, the newest member of the G(1) cyclin family, is largely unknown. In
      this study we have analysed the expression of the E-type cyclins in primary solid
      tumors from breast, lung, uterus, ovary, colon, and rectal tissues. Relative gene
      expression was analysed by quantitative real-time reverse transcription
      polymerase chain reaction (Taqman). The levels of cyclin E1 and cyclin E2 were
      significantly elevated (23 vs 38%, respectively) in primary breast tumor samples
      relative to normal breast tissue controls. We also observed an inverse
      correlation between the expression of cyclin E1/E2 and estrogen receptor in
      breast tumors. Our results demonstrate that the expression and associated
      catalytic activity for both cyclin E1 and cyclin E2 is elevated in primary breast
      tumors when compared to normal breast tissue. The increased level of cyclin E2 in
      breast tumors suggests that, similar to cyclin E1, it may contribute to the
      pathogenesis of breast cancer.

PMID- 12466976
TI  - Kangaroo genetics leap ahead.

PMID- 12466977
TI  - Islands of genetic novelty.

PMID- 12466978
TI  - What maintains male-sterility factors in plant populations?

PMID- 12466982
TI  - Effective size of populations with heritable variation in fitness.
AB  - The effective size of monogamous populations with heritable variation in fitness
      is formulated, and the expression obtained is compared with a published equation.
      It is shown that the published equation for dioecious populations is
      inappropriate for most animal and human populations, because the derivation is
      implicitly based on the assumption that zygotes are produced by random union of
      gametes, each from conceptual male and female gametic pools. A convenient
      equation for practical use is proposed, and the application is illustrated with
      the estimation of the effective size of a rural human community in Japan.

PMID- 12466983
TI  - Extensive population subdivision of the cuttlefish Sepia officinalis (Mollusca:
      Cephalopoda) around the Iberian Peninsula indicated by microsatellite DNA
      variation.
AB  - The Atlantic Ocean-Mediterranean Sea junction has been proposed as an important
      phylogeographical area on the basis of concordance in genetic patterns observed
      at allozyme, mtDNA and microsatellite DNA markers in several marine species. This
      study presents microsatellite DNA data for a mobile invertebrate species in this
      area, the cuttlefish Sepia officinalis, allowing comparison of this relatively
      new class of DNA marker with previous allozyme results, and examination of the
      relative effects on gene flow of the Strait of Gibraltar and the Almeria-Oran
      oceanographic front. Genetic variation at seven microsatellite loci screened in
      six samples from NE Atlantic and Mediterranean coasts of the Iberian Peninsula
      was high (mean Na = 9.6, mean H(e) = 0.725). Microsatellites detected highly
      significant subpopulation structuring (F(ST)= 0.061; R(ST) = 0.104), consistent
      with an isolation-by-distance model of low levels of gene flow. Distinct and
      significant clinal changes in allele frequencies between Atlantic and
      Mediterranean samples found at five out of seven loci, however indicate these
      results might be also consistent with an alternative model of secondary contact
      and introgression between previously isolated and divergent populations, as
      previously proposed for other marine species from the Atlantic-Mediterranean
      area. A pronounced 'step' change between SW Mediterranean samples associated with
      the Almeria-Oran front suggests this oceanographic feature may represent a
      contemporary barrier to gene flow.

PMID- 12466984
TI  - Increased fecundity of malathion-specific resistant beetles in absence of
      insecticide pressure.
AB  - Despite that resistance frequency is assumed to decline when selective pressure
      is relaxed, the stability of resistance frequency has been observed in some
      insects in the absence of insecticide. In the red flour beetle, Tribolium
      castaneum, the first case of malathion-resistance was reported in the early
      1960s. The malathion-specific resistant phenotype has now almost completely
      replaced the susceptible one in red flour beetle populations. In the present
      study, several life-history traits that could influence the fitness of the
      insects were compared between insecticide-susceptible and malathion-specific
      resistant populations of the red flour beetle. On average, egg fertility and egg
      to-adult development time did not differ between susceptible and resistant
      populations. However, the fecundity of resistant females was greater than that of
      susceptible ones. Generally, differences in development time between insecticide
      resistant and susceptible populations are considered as having more effect on
      fitness than do differences in fecundity. However, the observed increased female
      fecundity may participate, in combination with the previously observed increased
      male reproductive success, to the development and the stability of malathion
      specific resistance in T. castaneum.

PMID- 12466985
TI  - The population genetics of sporophytic self-incompatibility in Senecio squalidus
      L. (Asteraceae) I: S allele diversity in a natural population.
AB  - Twenty-six individuals of the sporophytic self-incompatible (SSI) weed, Senecio
      squalidus were crossed in a full diallel to determine the number and frequency of
      S alleles in an Oxford population. Incompatibility phenotypes were determined by
      fruit-set results and the mating patterns observed fitted a SSI model that
      allowed us to identify six S alleles. Standard population S allele number
      estimators were modified to deal with S allele data from a species with SSI.
      These modified estimators predicted a total number of approximately six S alleles
      for the entire Oxford population of S. squalidus. This estimate of S allele
      number is low compared to other estimates of S allele diversity in species with
      SSI. Low S allele diversity in S. squalidus is expected to have arisen as a
      consequence of a disturbed population history since its introduction and
      subsequent colonisation of the British Isles. Other features of the SSI system in
      S. squalidus were also investigated: (a) the strength of self-incompatibility
      response; (b) the nature of S allele dominance interactions; and (c) the relative
      frequencies of S phenotypes. These are discussed in view of the low S allele
      diversity estimates and the known population history of S. squalidus.

PMID- 12466986
TI  - The genetic structure of endangered populations in the Cranberry Fritillary,
      Boloria aquilonaris (Lepidoptera, Nymphalidae): RAPDs vs allozymes.
AB  - The genetic population structure of the Cranberry Fritillary Boloria aquilonaris
      was studied using both RAPDs (random amplified polymorphic DNA) and allozymes. In
      Belgium, B. aquilonaris has a naturally fragmented distribution that has been
      accentuated due to human activity during the last century. The genetic population
      structure of this butterfly was analysed at the regional (several Ardenne
      uplands) and at the landscape level (several populations within an Ardenne
      upland). Both population genetic markers confirmed results from a previous CMR
      study at the landscape scale. At the regional scale however, important
      incongruences were observed between RAPDs and allozymes. The average gene
      diversity for the RAPD data was twice that of the allozyme data. The degree of
      population subdivision was also much greater for RAPDs than for allozymes. The
      UPGMA clusters produced by each of these markers differed significantly. We
      believe that, given the higher rate of mutation of RAPDs and the greater number
      of loci assayed by this method, RAPDs reveal a more accurate and recent
      population genetic structure than allozymes.

PMID- 12466987
TI  - Gamera, a family of LINE-like repetitive sequences widely distributed in medaka
      and related fishes.
AB  - A family of repetitive sequences, designated Gamera, has been identified in the
      genome of the Hainan medaka fish Oryzias curvinotus, a closely related species to
      the common medaka fish O. latipes. Sequencing and Southern blot analyses of this
      family revealed: (1) amino acid sequence similarity to reverse transcriptase
      domains of long interspersed nuclear elements (LINEs); (2) 5' truncation of
      dispersed copies; and (3) the disruption of another genetic element, indicating a
      past transposition event. These results suggest that Gamera belongs to the LINE
      superfamily. Gamera is widely distributed in the genus Oryzias, and the
      phylogenetic relationship might indicate its presence in the common ancestor of
      the genus.

PMID- 12466988
TI  - Effect of acetone feeding on alcohol dehydrogenase activity in the olive fruit
      fly, Bactrocera oleae.
AB  - The purpose of this study is to demonstrate a clear connection between the
      presence of acetone in larval diet and alcohol dehydrogenase (ADH) activity in
      laboratory raised populations of Bactrocera oleae. ADH activity of B. oleae is
      depressed in acetone-impregnated diets. At the same time the change of activity
      is accompanied by a change in the relative proportions of the multiple forms of
      ADH. The bulk of activity in the most cathodally migrating form is lost, and all
      the activity becomes localized in the less cathodally migrating forms of the
      enzyme. Moreover, ADH activity, expressed in vivo, appears to drop after exposure
      to acetone, as shown by the fact that larvae become less sensitive to pentenol
      poisoning. Our results show clear selective differences imposed by acetone on
      three homozygous genotypes involving the ADH alleles F, S and I in B. oleae. The
      directions of these differences were found to vary with the fitness component
      under test. Acetone treatment seems to affect developmental time and larva's
      viability as well as allele frequencies of ADH under artificial rearing. The
      effect of acetone on the maintenance of ADH polymorphism in artificially reared
      populations of B. oleae is further discussed.

PMID- 12466989
TI  - Sex-dependent synaptic behaviour in triploid turbot, Scophthalmus maximus
      (Pisces, Scophthalmidae).
AB  - A surface-spreading synaptonemal complex (SC) technique was used to analyse
      spermatocytes and oocytes of triploid turbot (Scophthalmus maximus) in order to
      visualise the process of chromosome synapsis. The most conspicuous characteristic
      of triploid oocytes is that, in the trivalents, the lateral elements of the SC
      were frequently associated in threes, either completely along the length of the
      trivalent, or partially, forming a variety of forked structures. In these nuclei,
      synapsis usually occurred among homologous chromosomes and the number of
      bivalents observed was significantly higher than that expected under the
      assumption of random chromosome association among all partners. However, the
      frequency of trivalents was very low in triploid spermatocytes, triple synapsis
      being also scarce. In these nuclei chromosomes that were excluded from homologous
      synapsis become engaged in random SC formation, and, therefore a considerable
      number of non-homologous associations are produced. The causes of the synaptic
      differences observed in triploid males and females of turbot and their possible
      relation to the sterility displayed by these animals are discussed.

PMID- 12466991
TI  - The common quantitative genetic basis of wing morphology and diapause occurrence
      in the cricket Gryllus veletis.
AB  - A covariation between wing morphology and diapause occurrence has been observed
      in many insect species, but the genetic basis of this covariation has never been
      established. This study measures the heritability of, and genetic correlation
      between, these two ecologically important threshold traits in the cricket Gryllus
      veletis. A total of 81 full-sib families were reared in the laboratory to
      estimate these parameters. A comparison of laboratory and field samples showed
      that these two traits are highly plastic. The heritability of wing morphology was
      0.25 (0.09), the heritability of diapause occurrence was 0.77 (0.11) and the
      genetic correlation between them was 0.61 (0.19). These estimates did not differ
      between males and females. The significance of these quantitative genetic
      parameters is discussed with reference to the monomorphism of natural populations
      of G. veletis for diapause occurrence and with reference to the trade-off between
      the ability to disperse by flight and the ability to diapause found in at least
      one closely related species. A survey of the literature reveals that genetic
      correlations between diapause occurrence or wing morphology and various other
      traits are common in insects, suggesting that these two traits are often
      genetically integrated in insect life-histories.

PMID- 12466990
TI  - Restricted matrilineal gene flow and regional differentiation among Atlantic
      salmon (Salmo salar L.) populations within the Bay of Fundy, eastern Canada.
AB  - Matrilineal phylogenetic divergence among Atlantic salmon stocks of the Bay of
      Fundy in south eastern Canada is investigated. Sequence variation in two regions
      of the mitochondrial ND1 gene, encompassing 710 base pairs, is described for 168
      salmon from 11 rivers. Mean overall haplotype and nucleotide diversity (h and pi)
      observed are 0.5014 and 0.00095, respectively. Nested clade analysis (NCA) and
      molecular analysis of variance (AMOVA) both point to highly restricted gene flow
      among rivers and show the haplotype distribution to be geographically structured.
      Variation among predefined regions of the Bay (16%) is greater than among
      populations within these regions (14%) The main regional differentiation occurs
      between rivers of the geographically isolated inner Minas Basin and those
      elsewhere in the Bay. Differentiation most probably reflects the pattern and
      nature of the historical processes associated with post-glacial colonisation of
      the area by salmon following the last Pleistocene glacial maximum c. 180,00 yrs
      BP.

PMID- 12466992
TI  - Sexual selection on multivariate phenotype in wild and mass-reared Ceratitis
      capitata (Diptera: Tephritidae).
AB  - Males with a larger thorax and narrower face were found to be favoured by
      directional sexual selection in a previous field cage experiment where Ceratitis
      capitata males from the Seib 6-96 genetic sexing strain competed with wild males
      from Alto Valle (Patagonia) for the possession of wild females. Targets of sexual
      selection, however, might differ between wild and laboratory females as a
      response to adaptation to mass-rearing conditions. To evaluate possible
      divergences on the targets of sexual selection as a by-product of adaptation to
      mass-rearing conditions, field cage tests were performed with both wild and
      laboratory females. To avoid possible bias due to correlation among the measured
      traits (eye length [EL], face width [FW], head width [HW], and thorax length
      [TL]), a multivariate analysis was applied. Consistent with the previous
      experiment, the results indicated that TL and FW are probable targets of
      directional sexual selection independently of female strain. However, laboratory
      females were less selective than wild ones. Additionally, correlational sexual
      selection was detected acting on the multivariate phenotype. The effects of
      correlational selection overlap with those of directional selection on each
      single trait. The analysis of mating pair characteristics showed patterns that do
      not match the expectations for a random mating system. The current analysis
      indicates that during mating pair formation two processes overlap. On the one
      hand, sexual selection favours males with larger size (TL) and narrower faces
      (FW). This effect occurs in both wild and laboratory females. In addition,
      assortative mating based on both phenotype and origin was also observed.

PMID- 12466993
TI  - Gene introgression into Coffea arabica by way of triploid hybrids (C. arabica x
      C. canephora).
AB  - Interspecific triploid hybrid plants between the tetraploid species Coffea
      arabica L. and the diploid species C. canephora P. were backcrossed to C.
      arabica. Although characterised by a low production and an important fruit
      dropping, all attempted crosses (ie, 6) generated BC(1) progenies. Flow
      cytometric analysis of the nuclear DNA content revealed that most of the BC1
      individuals were nearly tetraploid. Among the male gametes produced by the
      interspecific triploid hybrids, those presenting a high number of chromosomes
      appeared strongly favoured. Only pollen mother cells having nearly 22 chromosomes
      were effective, the others leading to deficient endosperm and fruit dropping.
      Molecular markers (ie, microsatellite and AFLP) combined with evaluations of
      morphological characteristics and resistance to leaf rust were applied to verify
      the occurrence of gene transfer from C. canephora into C. arabica, and to
      estimate the amount of introgression present in BC(1) individuals. The results
      reveal a strong deficiency in the C. canephroa alleles indicating a severe
      counter-selection against the introgression of genetic material from C. canephora
      into C. arabica by way of triploid hybrids. However, introgressants displaying
      desirable traits such as a high resistance to leaf rust were obtained. The low
      level of introgression could be an advantage by facilitating the recovery of the
      recurrent parent and possibly reducing the number of required backcrosses. On the
      other hand, this could be a limitation when attempting the transfer of a complex
      trait or several simply inherited traits.

PMID- 12466994
TI  - [Proceedings of the 10th Gastroenterology Seminar. 10-11 January 2003, Leipzig,
      Germany].

PMID- 12466995
TI  - [Barrett metaplasia: how dangerous is it really?].

PMID- 12466996
TI  - [Drug therapy versus endoscopic surgery of esophageal reflux].

PMID- 12466997
TI  - [Early esophageal carcinoma: diagnosis and endoscopic therapy].

PMID- 12466998
TI  - [Helicobacter pylori infection--current status in clinical practice and
      prospects].

PMID- 12466999
TI  - [Therapy of complicated ulcer--hemorrhage, perforation and obstruction caused by
      benign inflammatory or post-inflammatory stenosis].

PMID- 12467000
TI  - [Current therapy concepts of stomach lymphoma].

PMID- 12467001
TI  - [Gallstones: pathogenesis and therapy].

PMID- 12467002
TI  - [Diagnosis and therapy of primary biliary cirrhosis and primary sclerosing
      cholangitis].

PMID- 12467003
TI  - [Therapy of viral hepatitis].

PMID- 12467004
TI  - [Gene therapy of hereditary liver diseases].

PMID- 12467005
TI  - ["Liver transplantation: whom to place on the waiting list and when?--10th
      Gastroenterology Seminar, 10-11 January 2003].

PMID- 12467006
TI  - [Autoimmune hepatitis].

PMID- 12467007
TI  - [Hepatic encephalopathy].

PMID- 12467008
TI  - [Therapy of portal hypertension].

PMID- 12467009
TI  - [Molecular pathogenesis of pancreatitis].

PMID- 12467010
TI  - [Conservative therapy of chronic pancreatitis].

PMID- 12467011
TI  - [Endoscopic therapy of acute pancreatitis].

PMID- 12467012
TI  - [Pathogenesis of pancreatic carcinoma].

PMID- 12467013
TI  - [Current aspects of diagnosis and therapy of pancreatic carcinoma].

PMID- 12467014
TI  - [Surgical management of pancreatic carcinoma].

PMID- 12467015
TI  - [Etiology and molecular pathogenesis of Crohn disease].

PMID- 12467016
TI  - [Drug therapy of chronic inflammatory bowel diseases: what is new?].

PMID- 12467017
TI  - [Continence preserving surgery in inflammatory bowel disease -- possibilities and
      limitations].

PMID- 12467018
TI  - [Current aspects of chemotherapy in gastrointestinal oncology].

PMID- 12467019
TI  - [Colon carcinoma--a preventable disease? Strategies for chemoprevention].

PMID- 12467021
TI  - Role of the central and peripheral nervous system in the ovarian function.
AB  - This review attempts to give a comprehensive overview of ovarian innervation,
      considering the whole nervous system and its different levels that may modify the
      ovarian function. The connection between the ovary and the central nervous system
      through the autonomic pathways, including the peripheral ganglia, is highlighted.
      The evidence obtained over the last years highlights the role of the superior
      ovarian nerve (SON) in the ovarian phenomena. Besides, the effect on the ovary of
      conventional neurotransmitters and others such as indolamines and peptides, which
      have been found in this organ, are discussed. Various reproductive diseases have
      been studied almost exclusively from the endocrine point of view. It is evident
      that a better knowledge about the role of the neural factors involved in the
      ovarian physiology may facilitate the understanding of some of these. A review of
      the concepts and an update of some experimental designs is made that permits
      clarifying several aspects of the relationship between the neural system and the
      ovary. At present, there is no doubt that the innervation of the ovary is
      involved in several physiological aspects of this gland function. However, the
      relationship of some levels of the nervous system and the ovary offer a wide
      avenue for future research.

PMID- 12467022
TI  - Supraspinal connections of the ovary: structural and functional aspects.
AB  - This review summarizes our recent studies using the viral transneuronal tracing
      technique to identify sites in the central nervous system (CNS) that are
      connected with the ovary. A neurotropic virus (pseudorabies virus) was injected
      into the ovary and various times after the inoculation the spinal cord and brain
      were examined for virus-infected neurons identified by immunocytochemistry. Such
      neurons could be detected in well-defined cell groups of the spinal cord
      (intermediolateral cell column), brain stem (vagal nuclei, area postrema,
      parapyramidal nucleus, caudal raphe nuclei, A1, A5, A7 noradrenergic cell groups,
      locus coeruleus, Barrington's nucleus, periaqueductal gray), hypothalamus
      (paraventricular nucleus, anterior hypothalamus, arcuate nucleus, zona incerta),
      and, at longer survival time, in some telencephalic structures (amygdala, bed
      nucleus of the stria terminalis). These findings provided the first
      neuromorphological evidence for the existence of a multisynaptic neuronal pathway
      between the brain and the ovary presumably involved in the neuronal control of
      the organ. The observations indicate that there is a significant overlap of CNS
      structures connected with the ovary, the testis, other organs and organ systems,
      suggesting similar neuronal circuitries of the autonomic nervous system
      innervating the different organs. The known descending neuronal connections
      between the CNS structures labeled from the ovary by the viral transneuronal
      tracing technique and the findings suggesting a pituitary independent interplay
      between certain cerebral structures such as the hypothalamus, the amygdala, and
      the ovary are also summarized in this review.

PMID- 12467023
TI  - Intrinsic neurons in the mammalian ovary.
AB  - Mammalian ovarian function is under endocrine and neural control. Although the
      extrinsic innervation of the ovary has been implicated in the control of both
      ovarian development and mature function, it is now clear that, from rats to
      humans, the ovary is endowed with a network of intrinsic neurons displaying
      diverse chemical phenotypes. This article describes the presence of these
      intrinsic neurons in the ovary of different mammalian species, and discusses the
      possible functions that they may have in the regulation of ovarian physiology.

PMID- 12467024
TI  - Localization of calretinin in the rat ovary and in relation to nerve cell bodies
      in dorsal root and paravertebral ganglia projecting to the ovary.
AB  - Retrograde tracing with True Blue was combined with immunocytochemistry to
      determine the source of any calretinin-immunoreactive (CR-ir) nerves projecting
      to the rat ovary. In the ovary, a strong signal for calretinin immunoreactivity
      was localized in interstitial gland cells; however, no intraovarian CR-ir nerves
      could be demonstrated. When the superior ovarian nerve was isolated, cut, and
      True Blue applied to the proximal end, the fluorescent dye was retrogradely
      transported to a population of cells located in T-12, T-13, and L-1 dorsal root
      and paravertebral ganglia. There was virtually no dual labeling of cells in these
      ganglia with calretinin (< 0.009% dual labeling in dorsal root and <0.014% in
      paravertebral ganglia). However, greater than two-thirds of the True Blue-labeled
      cells were immediately adjacent to CR-ir cells in dorsal root ganglia. This
      arrangement is suggestive of a paracrine mechanism between CR-ir cells and cells
      projecting to the ovary. In paravertebral ganglia, 63% of cells projecting to the
      ovary were surrounded completely or partially by beaded CR-ir nerve fibers. The
      source of these fibers (sensory or preganglionic sympathetic) is unknown but
      hypothesized to be preganglionic. Collectively, these observations suggest a
      participatory role for calretinin in ovarian function, either directly via
      effects on the interstitial gland or indirectly by influencing neurons projecting
      to the ovary.

PMID- 12467025
TI  - Changes in sympathetic nerve activity of the mammalian ovary during a normal
      estrous cycle and in polycystic ovary syndrome: Studies on norepinephrine
      release.
AB  - Although it has been known for many years that the ovary is innervated by
      catecholaminergic nerve fibers and much experimental evidence has strengthened
      the notion that catecholamines are physiologically involved in the control of
      ovarian function, scarce evidence has been presented as to the role of
      sympathetic activity in ovarian pathologies that affect reproductive function.
      The purpose of this article is to provide a succinct overview of the findings in
      this area and discuss them relative to the pathology of polycystic ovary
      syndrome, the most common ovarian pathology in women during their reproductive
      years.

PMID- 12467026
TI  - Ovarian acetylcholine and muscarinic receptors: hints of a novel intrinsic
      ovarian regulatory system.
AB  - More than two decades ago, the degrading enzyme of the neurotransmitter
      acetylcholine (ACH) was reported in nerve fibers of the rat ovary. Subsequently,
      it was assumed that ACH is a neurotransmitter of ovarian nerves, although the
      sole presence of the degrading enzyme, ACH-esterase, does not allow such a
      conclusion. That ACH may be involved in the complex regulation of ovarian
      functions, including hormone production, was indicated by studies using, for
      example, granulosa cells (GCs). The lack of detailed information about both
      source(s) and functions of ACH in the ovary prompted us to examine sites of
      ovarian ACH-synthesis and ACH-receptor-bearing target cells. We also started to
      identify functions of ACH in cultured human GCs. While ovarian innervation and
      recently described neuron-like cells of the ovary were not immunoreactive for the
      ACH-synthesizing enzyme, choline-acetyl transferase (CHAT), we found
      immunoreactivity in GCs of rodents and primates. Isolated human and rat GCs
      produced ACH and contained the vesicular ACH transporter (VACHT). These results
      indicate that endocrine GCs are an unexpected non-neuronal source of ACH in the
      ovary. Moreover, these cells and GCs in vivo contain ACH-receptors of the
      muscarinic subtype (MR), namely M1R and M5R. In contrast, oocytes express M3R. MR
      of human GCs are functional and cholinergic stimulation is linked to rapid
      increases in intracellular Ca(++) levels. M1/5R activation also led to increased
      cell proliferation of human GCs in vitro and this stimulatory effect was found to
      be associated with rapid disruption of gap junction communication. Ongoing
      studies begin to identify regulation of ion channels and altered gene expression
      as consequences of MR stimulation. Thus, our results outline first details of an
      unexpected intraovarian, non-neuronal cholinergic system, and suggest that it may
      be involved in the regulation of cell proliferation in the ovary.

PMID- 12467027
TI  - Neurotrophic control of ovarian development.
AB  - Substantial evidence now exists indicating that the neurotrophins, a family of
      growth factors required for the survival, development, and differentiation of
      various neuronal populations of the nervous system, are also important for the
      development of nonneuronal tissues. Such a function was first suggested by
      studies showing the presence of high-affinity neurotrophin receptors in a variety
      of nonneuronal tissues including those of the cardiovascular, endocrine, immune,
      and reproductive systems. Within the latter, the gonads appear to be a
      preferential site of neurotrophin action as suggested by the presence in the
      mammalian ovary of at least four of the five known neurotrophins and all of the
      neurotrophin receptors thus far identified. While the various functions that the
      neurotrophins may have in the ovary are still being elucidated, it is now clear
      that in addition to recruiting the ovarian innervation, they play a direct role
      in the regulation of two different maturational periods that are critical for the
      acquisition of female reproductive function: early follicular development and
      ovulation. Neurotrophins facilitate the development of newly formed follicles by
      promoting the initial differentiation and the subsequent growth of primordial
      follicles. These actions appear to be related to the ability of neurotrophins to
      sustain the proliferation of both mesenchymal and granulosa cells, and to induce
      the synthesis of follicle stimulating hormone (FSH) receptors. At the time of the
      first ovulation, neurotrophins contribute to the ovulatory cascade by increasing
      prostaglandin E(2) release, reducing gap junction communication, and inducing
      cell proliferation within the thecal compartment of preovulatory follicles.

PMID- 12467028
TI  - Preovulatory rise of NGF in ovine follicular fluid: possible involvement in the
      control of oocyte maturation.
AB  - Since nerve growth factor (NGF) is produced in vitro by granulosa cells after
      gonadotropin stimulation, the present research has been designed to investigate
      whether this neurotropin is involved in the events triggered by the gonadotropin
      surge that lead the follicle to ovulate a mature oocyte. To this aim, NGF levels
      in follicular fluid, collected before or 20 hours after the gonadotropin surge,
      was measured by ELISA. To evaluate whether NGF may have a non-neurotropic effect
      on follicle cells, the presence of NGF receptors was investigated by
      immunohistochemistry and further evaluated by analysing the tyrosine
      phosphorylation pattern after NGF stimulation in vitro. The effect of NGF on the
      degree of cumulus expansion, cumulus-oocyte metabolic coupling, and meiotic
      maturation was finally studied by using the culture of follicle-enclosed oocyte.
      The results demonstrate that GnRH causes a dramatic rise of NGF in large
      follicles. Immunohistochemistry revealed a discrete positivity for trkA receptors
      localised in cumulus cells. Tyrosine phosphorylation pattern confirms that
      somatic cells are capable to transduce NGF signal. By contrast, all the oocytes
      examined were negative for trkA and did not change the phosphorylation pattern
      after NGF. In vitro NGF (100 ng/ml) induced a marked cumulus expansion and a
      progressive cumulus-oocyte uncoupling similar to that produced by gonadotropins.
      The addition of NGF also caused the resumption of meiosis in more than 70% of the
      oocytes analysed with an effect that is only slightly less pronounced than that
      of gonadotropins (80%). The increase in NGF secretion following gonadotropin
      surge suggests that this neurotropin may be involved in the control of oocyte
      maturation.

PMID- 12467029
TI  - System for combined three-dimensional morphological and molecular analysis of
      thick tissue specimens.
AB  - We present a new system for simultaneous morphological and molecular analysis of
      thick tissue samples. The system is composed of a computer-assisted microscope
      and a JAVA-based image display, analysis, and visualization program that allows
      acquisition, annotation, meaningful storage, three-dimensional reconstruction,
      and analysis of structures of interest in thick sectioned tissue specimens. We
      describe the system in detail and illustrate its use by imaging, reconstructing,
      and analyzing two complete tissue blocks that were differently processed and
      stained. One block was obtained from a ductal carcinoma in situ (DCIS) lumpectomy
      specimen and stained alternatively with Hematoxilyn and Eosin (H&E), and with a
      counterstain and fluorescence in situ hybridization (FISH) to the ERB-B2 gene.
      The second block contained a fully sectioned mammary gland of a mouse, stained
      for histology with H&E. We show how the system greatly reduces the amount of
      interaction required for the acquisition and analysis and is, therefore, suitable
      for studies that require morphologically driven, wide-scale (e.g., whole gland)
      analysis of complex tissue samples or cultures.

PMID- 12467030
TI  - Determination of chloride efflux by X-ray microanalysis versus MQAE-fluorescence.
AB  - The importance of chloride channels for the cell is demonstrated by a number of
      serious human diseases that are due to mutations in chloride channels. The most
      well-known of these diseases is cystic fibrosis. Investigations into the
      mechanisms of the disease and possible treatments require the study of chloride
      fluxes at the level of individual cells. The present study compares two methods
      for studies of chloride transport: X-ray microanalysis and MQAE fluorescence with
      image analysis. As an experimental system, the cAMP-activated chloride channel in
      cultured respiratory epithelial cells was chosen. Both methods showed that
      stimulation with the cAMP-elevating agents forskolin and IBMX decreased the
      chloride content of the cells by about 20-27%. Inducing a driving force for
      chloride by replacing extracellular chloride by nitrate resulted in a chloride
      efflux that was significantly increased in the presence of forskolin and IBMX.
      This study shows that X-ray microanalysis and MQAE fluorescence are adequate and
      comparable methods for measuring cAMP-dependent chloride transport in individual
      cells.

PMID- 12467031
TI  - Confocal laser scanning microscopy to study formation and properties of
      polyelectrolyte nanocapsules derived from CdCO3 templates.
AB  - Three-dimensional confocal laser scanning microscopy (CLSM) was used as an
      essential investigation method to obtain information about the formation and
      morphological characteristics of nanocapsules. Nanocapsules are built by layer-by
      layer deposition of alternatively charged polyelectrolytes on templates forming
      nanostructured hollow shells. CLSM is unique in allowing for monitoring of the
      core dissolution process in real time and for studying nanocapsule functioning in
      hydrated conditions within a three-dimensional and temporal framework. Since we
      are also interested in the identification of other possible templates, we briefly
      report on the use of yeast cells as biocolloidal cores monitored by means of two
      photon microscopy. Here we focus our attention on the use of CdCO(3) crystals as
      template candidates for the preparation of stable capsules. Both cubic and
      spherical CdCO(3) cores have been produced. Cubic cores exhibit higher
      monodispersity and smaller size compared to spherical ones. Capsules templated on
      these cores have a higher surface-to-volume ratio that is valuable for
      applications related to drug delivery, functional properties of the shells and
      adsorption of proteins, and other biologically relevant molecules. Microsc. Res.
      Tech. 59:536-541, 2002.

PMID- 12467035
TI  - Stereospecific substitution at alpha-carbon to trifluoromethyl group: application
      to optically active fluorinated amino acid syntheses.
AB  - This account summarizes how we performed the intramolecular nucleophilic
      substitutions of the hydroxy groups at alpha-position to trifluoromethyl group.
      The origin of the steric hindrance of the trifluoromethyl group was found to be
      the electrostatic repulsive force between the nucleophile and the negatively
      charged fluorine atoms.

PMID- 12467036
TI  - Stereoselective C-glycosidation of unprotected D-glycals with trimethylsilyl
      cyanide.
AB  - Unprotected glycals reacted with trimethylsilyl cyanide in the presence of a
      catalytic amount of a palladium compound to yield the 2,3-unsaturated glycosyl
      cyanides in high yield and in alpha-selectivity.

PMID- 12467037
TI  - Cross-pinacol-type coupling reactions between alpha,beta-unsaturated ketones and
      aldehydes with low-valent metals.
AB  - Treatment of an alpha,beta-unsaturated ketone and an aldehyde with chromium(II)
      chloride and R(3)SiCl in DMF gives cross-pinacol-type coupling products, 1,2
      diols selectively. The anti/syn ratios of the produced 1,2-diols are shown to
      depend on the reaction temperature: at lower temperatures, the anti adduct is
      produced selectively, but at higher temperatures, the anti/syn ratios gradually
      decrease. When a combination of manganese and a catalytic amount of lead are used
      instead of chromium(II), 1,6-diketone, a dimer of the alpha,beta-unsaturated
      ketone, is produced selectively.

PMID- 12467038
TI  - Asymmetric oxidation of racemic 2-substituted 1,3-oxathianes.
AB  - Racemic 2-substituted 1,3-oxathianes were oxidized with good to high enantiomer
      differentiation by using urea hydrogen peroxide addition compound as oxidant in
      the presence of a catalytic amount of di-mu-oxo Ti(salen) complex, giving the
      corresponding sulfoxides diastereoselectively.

PMID- 12467039
TI  - Practical asymmetric Mukaiyama-Michael reaction of benzalacetone derivatives
      catalyzed by allo-threonine-derived oxazaborolidinone.
AB  - In the presence of 2,6-diisopropylphenol and t-BuOMe (1 equiv. each), asymmetric
      Mukaiyama-Michael reaction of a variety of benzalacetone derivatives 2 with silyl
      ketene acetal 3 is efficiently catalyzed by O-(2-naphthoyl)-N-tosyl-(L)-allo
      threonine-derived B-phenyloxazaborolidinone 1 (10 mol%) to give the corresponding
      adducts 5 in 60-90% ee.

PMID- 12467040
TI  - Highly diastereoselective addition of silyldihalomethyllithiums to chiral alkyl
      esters.
AB  - Treatment of benzoate, formate, or trifluoroacetate esters with
      silyldibromomethyllithiums provides alkyl silyl mixed acetals via the 1,3
      rearrangement of a silyl group from carbon to oxygen. A high level of asymmetric
      induction onto the acetal carbon is observed when chiral alkyl esters are
      employed. The stereochemical assignment of the silyl acetal 13j was accomplished
      on the basis of X-ray crystallographic analysis. A one-pot synthesis of a three
      component coupling product R(1)C(OR(2))(OSiMe(2)-t-Bu)CX(2)E' (X = Cl, Br) by
      sequential additions of an ester (R(1)CO(2)R(2)) and the second electrophile was
      achieved.

PMID- 12467041
TI  - Stereocontrolled addition of enolates to chiral 2-acyl-1,3-oxathiane derivatives.
AB  - Both enantiomers of 3-hydroxyalkanoates and -alkanones were prepared by the
      diastereocontrolled addition of enolates to ketones containing (R)-6-methyl-1,3
      oxathiane moiety as a chiral auxiliary; a formation of enolate from samarium(II)
      iodide and alpha-bromoamide is also discussed.

PMID- 12467042
TI  - 1,2-Silyl-migrative cyclization of vinylsilanes bearing an amino group.
AB  - In the presence of an acid catalyst, alpha-alkyl-substituted (Z)-vinylsilanes 1,
      bearing a tosylamino group, were smoothly cyclized to trans-2-alkyl-3
      silylpiperidines 2 (1,2-silyl-migration products) and (2R*, 1'S*)-2-(1'
      silylalkyl)pyrrolidines 3. The elaboration of the reaction conditions enabled the
      selective preparation of each cyclized product. The acid-catalyzed cyclization of
      (Z)-vinylsilane 5, whose methylene tether is shorter than that of 1 by one
      carbon, formed only the 1,2-silyl-migration product 6 with high trans
      selectivity. These cyclizations were found to proceed in a stereospecific manner.

PMID- 12467043
TI  - Interpretation of enantioresolution in nordeoxycholic acid channels based on the
      four-location model.
AB  - Nordeoxycholic acid (NDCA) forms three kinds of host frameworks, M1, M2, and M3,
      with channels where aliphatic alcohols (1-7) are accommodated. (13)C-NMR studies
      clarified that racemic alcohols 1- or 2-6 are enclosed in the M1- or M2-type
      channel with lower than 15% enantiomeric excess, respectively, while 3-methyl-2
      pentanol (7) is done in the M3-type with 47% ee. These inclusion phenomena can be
      explained due to the Difference Fourier maps of electron densities of their
      enantiomers in the channels. In addition, analysis of the manner of packing
      indicates that four locations in the channels should be fixed for the
      enantioresolution of the alcohols. These results support the four-location model,
      which has been proposed by Mesecar et al.(20) with respect to enantioresolution
      on protein surfaces.

PMID- 12467044
TI  - Kinetically controlled optical resolution of racemic norbornene aldehyde
      derivatives.
AB  - A new method for obtaining optically pure 5-norbornene 2-endo-aldehyde
      derivatives was developed. The reaction of a diastereomeric mixture of the ene
      acetals 2 and 2', derived from racemic norbornene aldehydes (+/-)-1 and chiral
      nonracemic (S,S)-hydrobenzoin 7, with NBS (0.5-0.6 eq.) in the presence of H(2)O
      proceeded in a kinetically controlled manner to give the optically pure hydroxy
      aldehydes 3 along with the intact ene acetals 2'. Both compounds 3 and 2' were
      converted into the optically pure norbornene aldehydes 1 and ent-1, respectively.
      This method opens the way to produce various types of 5-norbornene 2-endo
      aldehydes with 3-exo- or 3-endo-substituents in optically pure forms.

PMID- 12467045
TI  - Catalytic enantioselective allylation of ketones with novel chiral bis
      titanium(IV) catalyst.
AB  - Our recently designed chiral bis-titanium(IV) catalyst can be successfully
      utilized for the catalytic enantioselective allylation of ketones with
      tetraallyltin. The high asymmetric induction is achievable in the case of
      aromatic ketones.

PMID- 12467046
TI  - Remote chirality transfer in nucleophilic catalysis with N-(4-pyridinyl)-L
      proline derivatives.
AB  - Chiral nucleophilic catalysts 5-15 were prepared starting from L-proline.
      Catalysts 9 and 14 promoted acylative kinetic resolution of racemic amino alcohol
      derivative 16 with selectivity factors of 8.1 and 11, respectively, at ambient
      temperature. Since chiral elements are not present in the catalytically active
      pyridine ring in these catalysts, chirality transfer from the remote stereogenic
      center to the reactive site (N-acylpyridinium) is suggested to be responsible for
      the differentiation between enantiomers.

PMID- 12467047
TI  - Preparation of chiral stationary phase for HPLC based on immobilization of
      cellulose 3,5-dimethylphenylcarbamate derivatives on silica gel.
AB  - The immobilization of cellulose 3,5-dimethylphenylcarbamate derivatives having a
      polymerizable vinyl group, i.e., 4-vinylphenylcarbamate or 2
      methacyloyloxyethylcarbamate, on silica gel was examined under various
      conditions. The immobilization was basically conducted through the radical
      copolymerization of the derivatives with a vinyl monomer. Several factors, such
      as the vinyl monomer content and the type and amount of the vinyl group of
      cellulose derivatives, were varied. The introduction of a vinyl group onto the
      silica surface resulted in a more efficient immobilization of the cellulose
      phenylcarbamate derivatives on the silica gel. As the content of the vinyl group
      on the cellulose derivatives was reduced, the immobilization became more
      difficult, although the obtained phase exhibited higher chiral recognition
      abilities. These immobilized CSPs could be stably used with the eluent containing
      10% chloroform, which cannot be used for the phase prepared by coating the
      derivatives on silica gel. Some racemates were better resolved on the immobilized
      CSP by using chloroform as a component of the eluent.

PMID- 12467048
TI  - Asymmetric catalysis with self-organized chiral lanthanum complexes: practical
      and highly enantioselective epoxidation of alpha,beta-unsaturated ketones.
AB  - A highly efficient and practical method for obtaining alpha,beta-epoxy ketones
      with high optical purities was developed. The chiral lanthanum complex self
      organized in situ from lanthanum triisopropoxide, (R)-BINOL, triarylphosphine
      oxide, and alkyl hydroperoxide (1:1:1:1) was found to catalyze the epoxidation of
      alpha,beta-unsaturated ketones with tert-butyl hydroperoxide or cumene
      hydroperoxide at room temperature to give the corresponding epoxy ketones in high
      enantioselectivities (up to >99% enantiomeric excess (ee)). A remarkably high
      asymmetric amplification, a positive nonlinear effect, was observed in the
      epoxidation of chalcone, which strongly suggests the formation of a dinuclear
      peroxide-involved mu-complex as the active catalyst.

PMID- 12467049
TI  - Asymmetric carbon-carbon bond-forming reaction at the 2-position of a piperidine
      skeleton.
AB  - An asymmetric carbon-carbon bond-forming reaction at the 2-position of a
      piperidine skeleton was exploited. This method consisted of a reaction between 1
      (4-methoxybenzoyl)-3,4-didehydro-2-methoxypiperidines and dimethyl malonate
      catalyzed by Cu(II)-chiral 2,2'-isopropylidenebis(4-phenyl-2-oxazoline) to afford
      a 2-substituted piperidine skeleton with moderate enantioselectivity.

PMID- 12467050
TI  - Enantioselective electrochemical oxidation of enol acetates using a chiral
      supporting electrolyte.
AB  - Anodic oxidation of 1-acetoxy-3,4-dihydronaphthalene (1) and alpha-acetoxy-beta
      alkylstyrenes (3) at -78 degrees C in a mixed solvent of acetonitrile (CH(3)CN),
      tetrahydrofuran (THF), and acetic acid (AcOH) containing (S)-tetraethylammonium
      camphorsulfonate as a chiral supporting electrolyte brought about
      enantioselective formation of the corresponding 2-acetoxy-1-tetralones (2) and
      (R)-2-acetoxy-1-phenyl-1-alkanone (4) with maximum enantiomeric excess (ee) of
      44% and 21%, respectively. Introduction of a 7-methoxy group into 1 and increase
      in bulkiness of a beta-alkyl group in 3 resulted in improvement of
      enantioselectivity of the reactions.

PMID- 12467051
TI  - Synthesis of new chiral bis(isoxazoline) ligands containing spiro[5.5]undecane
      skeleton.
AB  - New chiral bis(isoxazoline) ligands bearing a spiro[5.5]undecane skeleton were
      designed and synthesized in five steps from diethyl malonate (3). These ligands
      showed a coordinating ability to Cu(II) as chiral ligands. A complex of (+)
      (M*,S*,R*)-[5.5]-SPRIX 2b and Cu(OTf)(2) catalyzed the conjugate addition of
      diethyl-zinc to 2-cyclohexenone (8) to give (S)-3-ethyl-cyclohexanone (9) in 93%
      yield with 54% ee.

PMID- 12467052
TI  - Molecular design of DABNTf as a highly efficient resolving reagent for racemic Pd
      complex with Tropos biphenylphosphine (BIPHEP) ligand: circular dichroism (CD)
      spectra of enantiopure BIPHEP-Pd complex.
AB  - The racemic Pd complexes with chirally flexible (tropos) biphenylphosphine
      (BIPHEP) ligands can be resolved but transformed into the enantio- and diastereo
      pure complex. The enantiopure metal complex of BIPHEP ligand is thus obtained
      through enantiomer-selective complexation of a racemic BIPHEP-Pd complex with
      enantiopure 1,1'-binaphthyl-2,2'-di(triflyl)amide, DABNTf. The differential CD
      spectra of the enantiopure BIPHEP-Pd complex is also reported.

PMID- 12467053
TI  - Stereospecific synthesis of aldoses based on the epoxide-opening reaction with
      double inversion of the configuration.
AB  - A new synthetic methodology for aldoses and aldonitols was developed in which two
      stereospecific epoxide-opening reactions with double inversion of the
      configuration, i.e., the ring-opening reaction of epoxy sulfides with
      phenylboronic acid and the stereospecific interconversion of trans- and cis-epoxy
      sulfides, were designed as the key steps. The synthetic potential of the new
      methodology was exemplified by the highly stereoselective synthesis of two
      pentose-derived sugars, arabitol and adonitol (ribitol).

PMID- 12467056
TI  - Sequelae of axillary lymph node dissection in older women with stage 1 and 2
      breast carcinoma.
AB  - BACKGROUND: There are few data on the long-term sequelae of axillary dissection
      among older breast carcinoma patients. We describe the impact of axillary
      dissection in a cohort of older women. METHODS: A longitudinal cohort of 571
      patients with Stage 1 and 2 breast carcinoma, 67 years and older, diagnosed
      between 1995 and 1997 from 29 hospitals in five regions, and followed for 2
      years. Data were collected from patients and medical charts. The primary outcome
      was posttreatment quality of life. Generalized estimation equation longitudinal
      modeling was used to evaluate the outcome, controlling for baseline function,
      comorbidity, age, clinical status, and other factors. RESULTS: Sixty percent of
      women reported arm problems at some time in the 2 years after surgery. The
      cumulative risk of having arm problems 2 years posttreatment was three times
      higher (95% confidence interval 1.94-4.67) for women who underwent axillary
      surgery compared with women without axillary surgery, controlling for covariates.
      The effects of having axillary dissection and arthritis were multiplicative 2
      years postsurgery. Arm problems were, in turn, the primary determinate of lower
      physical and mental functioning (P = 0.0001 and 0.04, respectively), controlling
      for other factors. Undergoing axillary dissection did not lessen fears about
      recurrence. CONCLUSIONS: Arm problems after axillary dissection have a consistent
      negative impact on quality of life, suggesting that the risks may outweigh the
      potential benefits in this population.

PMID- 12467057
TI  - Relation of regimens of combined hormone replacement therapy to lobular, ductal,
      and other histologic types of breast carcinoma.
AB  - BACKGROUND: The incidence of invasive lobular carcinoma has been increasing among
      postmenopausal women in some parts of the United States. Part of this may be due
      to changes in classification over time. However, the use of combined (estrogen
      and progestin) hormone replacement therapy (CHRT) also has increased during the
      last decade and may account in part for the increase in invasive lobular breast
      carcinoma. METHODS: A large, multicenter case-control study of Caucasian and
      African-American women who were diagnosed at age < 65 years with their first
      invasive breast tumor from July 1, 1994 through April 30, 1998 was conducted. In
      person interviews were conducted with 1749 postmenopausal patients, and their
      responses were compared with the responses of 1953 postmenopausal control women
      identified through random-digit dialing who met the study criteria of being
      postmenopausal at the time of diagnosis. Polytomous logistic regression was used
      to calculate the odds ratio (OR) as an estimate of the relative risk and to
      compute the 95% confidence interval (95%CI) associated with the use of various
      regimens of hormone replacement therapy (HRT) among women diagnosed with ductal
      breast carcinoma, lobular (or mixed lobular and ductal) breast carcinoma, and a
      grouping of other histologic types of breast carcinoma. RESULTS: Ever use of
      unopposed estrogen therapy (ERT) was not associated with an increase in the risk
      of any histologic type of breast carcinoma. The risk of invasive lobular breast
      carcinoma and the risk of breast carcinoma of the grouping of other histologies
      increased among women currently using CHRT (OR, 2.2; 95%CI, 1.4-3.3; and OR, 1.9;
      95%CI, 1.0-3.4, respectively). The risk increase was greater for the mixed
      lobular-ductal type than for the pure lobular type of breast carcinoma, although
      the difference was not statistically significant. There was some indication that
      >or= 5 years of continuous CHRT (>or= 25 days per month of progestin) was
      associated with a higher risk of lobular breast carcinoma (OR, 2.5; 95%CI, 1.4
      4.3) compared with sequential CHRT (< 25 days per month of progestin; OR, 1.5;
      95%CI, 0.8-2.6). Current use of continuous CHRT was only moderately associated
      with risk of ductal breast carcinoma. CONCLUSIONS: Postmenopausal women who take
      CHRT appear to be at an increased risk of lobular breast carcinoma. Data from
      this study suggest that neither ERT use nor CHRT substantially increase the risk
      of ductal breast carcinoma among women age < 65 years.

PMID- 12467058
TI  - Advanced age and adjuvant tamoxifen prescription in early-stage breast carcinoma
      patients.
AB  - BACKGROUND: Adjuvant tamoxifen is recommended for all women with estrogen
      receptor-positive breast carcinoma without regard for age. We investigated age
      dependent variations in adjuvant tamoxifen prescription patterns in a cohort of
      women 80 years of age and older. METHODS: We studied 92 women diagnosed at four
      U.S. sites with primary, early-stage breast carcinoma. Each woman consented to a
      medical record review and participated in two telephone interviews. We compared
      the proportion of tamoxifen prescriptions received by women 85-92 years of age
      with those received by women 80-84 years of age. Relative risks (RR) and 95%
      confidence intervals (95% CI) were generated using generalized estimating
      equations. Confounding by demographic, disease, and treatment characteristics was
      assessed. RESULTS: Before adjustment, patients 85-92 years of age were 28% less
      likely to receive a tamoxifen prescription compared with patients 80-84 years of
      age (RR = 0.72, 95% CI 0.57-0.91). In this sample, patients not prescribed
      tamoxifen had substantially more comorbidity. After adjusting the crude finding
      for comorbidity, the RR was 0.74 (95% CI 0.58-0.93). In addition, the oldest
      patients and those not prescribed tamoxifen were significantly less likely to be
      married or have living children. After adjusting the crude finding for these two
      factors, the RR was 0.75 (95% CI 0.59-0.95). There was no confounding by the
      other demographic, disease, or treatment covariates assessed. CONCLUSION: Given
      the increasing longevity of the oldest old, undertreatment with adjuvant
      tamoxifen may put older breast carcinoma patients at an increased risk of disease
      recurrence and breast carcinoma mortality.

PMID- 12467059
TI  - Decreased expression of DFF45/ICAD is correlated with a poor prognosis in
      patients with esophageal carcinoma.
AB  - BACKGROUND: DNA fragmentation factor 45 (DFF45)/inhibotor of caspase activated
      DNAse (ICAD) forms a complex with DFF40/CAD and inhibits its DNA cleaving
      function during apoptosis. DFF45 also functions as a chaperone for native DFF40
      and is necessary for its function. It has been indicated that defects in the
      apoptotic pathway may exist in neoplastic cells. METHODS: The authors
      investigated mRNA expression of DFF45 in a series of 46 esophageal squamous cell
      carcinoma (ESCC) specimens using polymerase chain reaction amplification. The
      results were correlated with the patients' clinicopathologic characteristics.
      RESULTS: DFF45 mRNA expression was significantly lower in tumors with higher
      pathologic stage, higher tumor status (T status), lymph node metastasis, or more
      extensive lymphatic invasion. Patients who had low DFF45 mRNA expression
      (indicated by the ratio of DFF45 mRNA expression in tumor to DFF45 mRNA
      expression in normal esophageal mucosa [tumor:normal] < 1) had a significantly
      shorter survival after undergoing surgery compared with patients who had high
      DFF45 mRNA expression (tumor:normal > 1, P = 0.0006; log-rank test, P = 0.0003;
      median follow-up, 14.6 months). CONCLUSIONS: Patients with ESCC with decreased
      DFF45 mRNA expression levels had a poor prognosis compared with patients who had
      high DFF45 mRNA expression levels.

PMID- 12467060
TI  - A survival-stratification model of human colorectal carcinomas with beta-catenin
      and p27kip1.
AB  - BACKGROUND: The stabilization and nuclear translocation of beta-catenin are early
      events in the majority of sporadic colorectal carcinomas (CRC). beta-catenin up
      regulates c-Myc and cyclin D1, which antagonize the association of the cyclin
      dependent kinase (Cdk) inhibitor, p27(kip1), with Cdk2, thus allowing cell cycle
      progression through G1 to S-phase. Lack of p27 is a significant predictor of poor
      survival in a series of 136 CRC specimens. A combination of molecules in the same
      pathway may be a better prognostic factor. METHODS: The expression of beta
      catenin, c-Myc, and cyclin D1 in relation to patients' survival and
      clinicopathologic parameters in the same series was evaluated by
      immunohistochemistry. RESULTS: Intense nuclear overexpression of beta-catenin,
      but not a lack of cell membrane or cytoplasmic expression, is a significant
      predictor of poor survival by both univariate (P = 0.0029) and multivariate
      analyses (P = 0.004, risk ratio =3.8), suggesting that beta-catenin is retained
      in the nucleus to function as an oncogene. None of the patients with high nuclear
      beta-catenin and low p27 expression survived 5 years or more whereas 65% of
      patients with all other combinations of the two markers survived (P < 0.0001).
      This combination is also a significant and independent prognostic factor (P =
      0.001; risk ratio = 9.7). Overexpression of c-Myc is associated with higher
      mortality rates, but the expression of cyclin D1 has no prognostic significance.
      CONCLUSIONS: The combined expression of beta-catenin and p27 can stratify
      patients into markedly different survival groups, possibly via their antagonistic
      effects on metastasis promotion.

PMID- 12467061
TI  - Telomerase reverse transcriptase subunit immunoreactivity: a marker for high
      grade prostate carcinoma.
AB  - BACKGROUND: Telomerase, a ribonucleoprotein complex that maintains telomeric DNA,
      has been detected in 67-93% of prostate carcinomas by telomeric repeat
      amplification protocol assay (involving polymerase chain reaction). One study
      used in situ hybridization in nine patients; however, to date, no
      immunohistochemical results have been published. METHODS: From two hospitals, the
      authors compiled data on 62 patients who underwent prostatectomy from January
      1996 to May 2001. Representative tissue sections were immunostained with a
      polyclonal antibody to telomerase reverse transcriptase (TERT), the catalytic
      subunit of telomerase. Staining was evaluated by two observers and was correlated
      with grade, stage, and biochemical failure. There were 28 sections from low-grade
      to intermediate-grade tumors (Gleason score, 3-6), 14 sections with a Gleason
      score of 3 + 4 = 7, 9 sections with a Gleason score of 4 + 3 = 7, and 11 sections
      from high-grade tumors (Gleason score, 8-10). RESULTS: From low-grade to high
      grade tumors, the four groups described above disclosed nuclear reactivity in
      64%, 100%, 100%, and 100% of sections, respectively. Mean percentages of 5%, 15%,
      40%, and 51% of nuclei were reactive in the respective groups (P < 0.0001) with
      intratumoral heterogeneity. The percent of reactive tumor nuclei was not
      correlated with pathologic stage (P = 0.32) or margin status (P = 0.35). The
      basal cell layer in sections of high-grade prostatic intraepithelial neoplasia
      (HGPIN) and benign/atrophic acini was reactive; secretory cells were reactive in
      13 of 34 HGPIN foci (38%) in 1-20% of nuclei and were never reactive in benign
      acini. Lymphocytes and skeletal muscle were reactive. Weak, nonspecific,
      cytoplasmic staining was noted in benign and tumor acini. CONCLUSIONS: Like
      cytokeratin 34betaE12, nuclear anti-TERT reactivity is a basal cell marker in
      nonneoplastic prostatic acini. Anti-TERT reactivity is acquired by secretory
      cells in tumorigenesis, but consistent reactivity is restricted to high-grade
      carcinoma (Gleason primary pattern >or=4). This histologic evidence suggests that
      higher grade tumors have maximally activated telomerase and may be most
      responsive to antitelomerase therapy.

PMID- 12467062
TI  - Urinary levels of urokinase-type plasminogen activator and its receptor in the
      detection of bladder carcinoma.
AB  - BACKGROUND: The authors found previously that plasma levels of urokinase-type
      plasminogen activator (uPA) and its receptor (uPAR) were elevated in patients
      with bladder carcinoma and were associated with features of biologically
      aggressive disease. In the current study, they tested the hypothesis that
      elevated urinary levels of uPA and uPAR would predict the presence of bladder
      malignancy by comparing the performance of uPA and uPAR with the performance of
      bladder wash-out cytology in the noninvasive diagnosis of bladder tumors.
      METHODS: An enzyme-linked immunosorbent assay was used to compare levels of uPA
      and uPAR in urine that was collected before cystoscopy from 122 patients with
      bladder carcinoma and from 107 participants in a control group. Seventy-two
      patients had clinical Tis or Ta transitional cell carcinoma, and 50 patients had
      invasive disease (>or= T1); 85 patients had clinical Grade 1-2 tumors, and 37
      patients had Grade 3 tumors. For cytology, only high grade was considered
      positive. RESULTS: Urinary levels of uPA and uPAR were higher in patients with
      bladder carcinoma compared with levels in the control group (P < 0.001 and P =
      0.016, respectively). However, only uPA levels were elevated in patients with
      abnormal urinary cytology (P = 0.006). After controlling for cytology (odds ratio
      [OR], 10.182; 95% confidence interval [95%CI], 4.451-23.291; P < 0.001), uPAR (P
      for trend = 0.168), and age (P = 0.091), those in the highest quartile for uPA
      had an increased risk of bladder carcinoma compared with those in the lowest
      quartile (OR, 3.022; 95%CI, 1.295-7.054; P for trend = 0.031). CONCLUSIONS: The
      current findings suggest that urinary levels of uPA, but not uPAR, are related to
      the risk of bladder carcinoma. The study confirmed the central role of urinary
      cytology in the noninvasive diagnosis of bladder carcinoma.

PMID- 12467063
TI  - Which dimensions of health-related quality of life are altered in patients
      attending the different gynecologic oncology health care settings?
AB  - BACKGROUND: We evaluated the feasibility of measuring health-related quality of
      life (HRQOL) in a gynecologic oncology clinic by using an instrument that is
      nonspecific for cancer patients. Our aim was to study whether the HRQOL
      perception of cancer patients differed from general population norms for the same
      age and gender and if it varied across cancer type, cancer status, age, health
      care setting, and reason for the encounter. METHODS: Participants in this study
      included 115 women between the ages of 21 and 83 years who were referred to a
      university hospital for ovarian, endometrial, and cervical carcinoma. They
      completed the SF-36 questionnaire. Mean results for the entire sample, for
      different disease status (primary vs. progressive/recurrent disease), and reason
      for encounter (surgery, preoperative, postoperative, palliative chemotherapy, and
      follow-up) were compared with age-specific expected mean values for each SF-36
      scale, based on published Italian reference values for the healthy population.
      RESULTS: Patients' attitude to the questionnaire was generally good. Mean values
      on the SF-36 scales varied. Role (Physical and Emotional) scales showed the
      highest differences from the expected age-specific values in all situations.
      Patients with primary disease showed little or no differences for the other six
      scales from the expected values, whereas a significant 10-point mean decrease in
      every SF-36 scale was recorded for patients with progressive/recurrent disease. A
      biologic interaction among cervical carcinoma, age, and disease status was found
      in multivariate models, showing worst scores for patients with
      progressive/recurrent cervical carcinoma on almost all scales. CONCLUSIONS:
      Administration of generic HRQOL questionnaires in specialist health care delivery
      settings is feasible and well accepted and may help physicians and nurses to look
      beyond "what's wrong" in their patients.

PMID- 12467064
TI  - Elevated focal adhesion kinase expression facilitates oral tumor cell invasion.
AB  - BACKGROUND: Understanding the molecular mechanisms of metastasis is critical with
      respect to oral tumorigenesis. The focal adhesion kinase (FAK) is an
      intracellular tyrosine kinase associated with the regulation of cell growth,
      migration, and survival. The purpose of the current study was to determine
      whether elevated FAK expression in oral malignancies was associated with
      increased invasiveness and oral carcinoma. METHODS: Immunohistochemical analysis
      was used to assess levels of FAK expression in archived oral carcinoma tissue
      samples. Invasion assays after transfections were used to assess the effect of
      increased FAK expression on invasive potential of oral tumor cells. RESULTS: The
      human oral carcinoma cell line SCC25 was significantly more invasive (P < 0.05)
      and expressed higher levels of FAK compared with the less invasive human oral
      carcinoma cell line SCC15. FAK expression was 3.0-fold higher in the SCC15 cell
      line and 5.0-fold higher in the SCC25 cell line compared with normal epithelial
      cells. In the highly invasive SCC25 cell line, FAK expression was 1.5-fold higher
      compared with the less invasive SCC15 cell line. FAK immunostaining in oral
      tumors was significantly more intense compared with the immunostaining in
      surrounding normal epithelium or chronic mucositis. Overexpression of FAK in low
      invading SCC15 cells resulted in a 4.5-fold increase in the rate of invasion
      compared with untransfected or neotransfected control SCC15 cell lines and a
      nearly 1.5-fold greater rate compared with the highly invasive untransfected
      SCC25 cell line. CONCLUSIONS: The current results suggest that enhanced
      expression of FAK in oral carcinoma cells may lead to a selective growth
      advantage and increased invasive potential of the primary oral tumor.

PMID- 12467065
TI  - Chemotherapy with gemcitabine-containing regimens for locally recurrent or
      metastatic nasopharyngeal carcinoma.
AB  - BACKGROUND: Results from Phase II trials conducted in Asia have shown that
      gemcitabine alone (GEM) or with cisplatin (GC) is active among patients with
      metastatic or locally recurrent nasopharyngeal carcinoma (NPC). METHODS: At the
      Princess Margaret Hospital (PMH), Toronto, 32 patients with NPC were treated with
      GEM (n = 18) or GC (n = 14) from January 2000 to October 2001. Patients either
      received 1000 mg/m(2) GEM on Days 1, 8, and 15 every 28 days as a single agent,
      or with cisplatin (CG) given on day 2 at 70 mg/m(2). RESULTS: Most patients (91%)
      were of Southeast Asian ancestry and 29 (91%) had Type 2 (World Health
      Organization 1991 classification) nonkeratinizing histology. Sixteen of the GEM
      (89%) and five (36%) of the GC patients had received chemotherapy before entering
      the study. Median follow-up was 32 weeks (range, 2-97 weeks) for both groups. In
      the GEM group, there were five (28%) partial responses (PR) and one (6%) complete
      response (CR), giving an overall response rate of 34% (95% confidence interval
      [CI], 13.59). In the GC group, there were two (14%) CRs and seven PRs (50%),
      giving an overall response of 64% (95% CI, 35-87). Hematologic toxicity was dose
      limiting but uncomplicated. Nonhematologic toxicity included one patient with
      reversible reactivation of hepatitis, one with Grade 3 cisplatin-related sensory
      neuropathy, and three with cardiovascular events that were possibly related to
      chemotherapy. The median duration of response for the GEM and GC patients was 17
      and 24 weeks and the 1-year survival rate was 48% (95% CI, 18-78) and 69% (95%
      CI, 40-99), respectively. Median survival has not been reached. CONCLUSIONS: Our
      study confirms that GEM is an active and tolerable drug for patients with NPC.

PMID- 12467066
TI  - Loss of adhesion-regulated proteinase production is correlated with invasive
      activity in oral squamous cell carcinoma.
AB  - BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common malignancy of
      the oral cavity. However, the cellular and biochemical factors that underlie
      locoregional and distant spread of the disease are poorly understood. Invasion of
      OSCC requires multiple cellular events including dissolution of cell-cell
      junctions, basement membrane attachment, extracellular matrix proteolysis, and
      migration. METHODS: We evaluated these properties in vitro using premalignant
      gingival keratinocytes (ppl26) and two OSCC lines (SCC15 and SCC68). Expression
      of adhesion molecules integrins and cadherins, cytoplasmic intermediate filaments
      (IF) vimentin and keratin as well as matrix degrading proteins were evaluated.
      Moreover, regulation of protease production by adhesion molecules was tested.
      RESULTS: All cell lines contained comparable levels of the epithelial cell-cell
      adhesion molecule, E-cadherin. Differential expression of cytoplasmic IF was
      evident between premalignant pp126 cells and OSCC cell lines. Expression levels
      of the alpha3beta1 integrin, utilized for attachment to laminin-5 and other
      matrix proteins, was high in SCC68 cells, moderate in SCC15 cells, and low in
      ppl26 cells. alpha3beta1 integrin clustering up-regulates expression of urinary
      type plasminogen activator (uPA) in ppl26 cells via a mechanism involving ERK
      activation. Both ppl26 and SCC15 cells were responsive to alpha3beta1 clustering,
      resulting in enhanced uPA expression. However, basal uPA levels were high in
      SCC68 cells and integrin clustering did not further stimulate uPA production. ERK
      was constitutively activated in SCC68 cells and treatment of cells with an
      inhibitor of ERK activation (PD98059) reduced uPA expression. Consistent with the
      enhanced proteolytic potential, SCC68 cells readily penetrated Matrigel and
      invasion was blocked by an anticatalytic uPA antibody. CONCLUSIONS: These data
      suggest that loss of adhesion-regulated proteinase production may lead to
      elevated pericellular proteinase activity and coincident alterations in
      cytoskeletal IF protein expression, thereby contributing to the invasive
      potential of OSCC.

PMID- 12467067
TI  - An elevated serum beta-2-microglobulin level is an adverse prognostic factor for
      overall survival in patients with early-stage Hodgkin disease.
AB  - BACKGROUND: The relative importance of prognostic factors in patients with early
      stage Hodgkin disease remains controversial. The purpose of this study was to
      evaluate prognostic factors among patients who received chemotherapy before
      radiotherapy. METHODS: From 1987 to 1995, 217 consecutive patients ranging in age
      from 16 to 88 years (median, 28 years) with Ann Arbor Stage I (n = 55) or II (n =
      162) Hodgkin disease underwent chemotherapy before radiotherapy at a single
      center. Most were treated on prospective studies. Patients received a median of
      three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine,
      and prednisone (NOVP), doxorubicin, bleomycin, vinblastine, and dacarbazine
      (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP),
      cyclophosphamide, vinblastine, procarbazine, prednisone, doxorubicin, bleomycin,
      dacarbazine, and CCNU (CVPP/ABDIC), or other chemotherapeutic regimens were given
      to 160, 18, 15, 10, and 14 patients, respectively. The median radiotherapy dose
      was 40 Gy. Serum beta-2-microglobulin (beta-2M) levels ranged from 1.0 to 4.1
      mg/L (median, 1.7 mg/L; upper limit of normal, 2.0 mg/L). We studied univariate
      and multivariate associations between survival and the following clinical
      features: serum beta-2M level above 1.25 times the upper limit of normal (n =
      12), male gender (n = 113), hypoalbuminemia (n = 11), and bulky mediastinal
      disease (n = 94). RESULTS: Follow-up of surviving patients ranged from 0.9 to
      13.4 years (median, 6.6 years) and 92% were observed for 3.0 or more years.
      Nineteen patients have died. Only elevation of the serum beta-2M level was an
      independent adverse prognostic factor for overall survival (P = 0.0009).
      CONCLUSIONS: The prognostic significance of a simple, widely available, and
      inexpensive blood test, beta-2M, has not been studied routinely in patients with
      Hodgkin disease and should be tested prospectively in large, cooperative group
      trials.

PMID- 12467068
TI  - Serum insulin-like growth factor I evaluation as a useful tool for predicting the
      risk of developing hepatocellular carcinoma in patients with hepatitis C virus
      related cirrhosis: a prospective study.
AB  - BACKGROUND: Although experimental studies have demonstrated an important role of
      insulin-like growth factor I (IGF-I) in hepatocarcinogenesis, the clinical data
      about IGF-I in patients with hepatocellular carcinoma (HCC) are scarce and
      controversial. To the authors' knowledge, this is the first prospective study
      investigating the longitudinal correlation between modifications in serum IGF-I
      levels and the development of HCC in a cohort of patients with hepatitis C virus
      (HCV)-related cirrhosis. METHODS: One hundred fourteen consecutive patients with
      HCV-related Child Grade A cirrhosis were followed prospectively at the Second
      University of Naples for 56.4 +/- 12.0 months with ultrasound examinations of the
      liver and serum alpha-fetoprotein determination every 6 months. At each clinical
      evaluation, the severity of disease was graded according to the established Child
      Pugh scoring system. Serum IGF-I levels were measured prospectively at the study
      entry and at least every 12 months throughout follow-up. RESULTS: Twenty patients
      (19.2%) developed HCC during follow-up. Eleven of these patients had persistent
      Child Grade A cirrhosis for the whole study, whereas the other 9 patients
      developed HCC after their cirrhosis progressed from Child Grade A to Grade B. In
      patients who remained free of HCC for the whole study, serum IGF-I concentrations
      did not modify significantly during follow-up. Conversely, in patients who
      developed HCC, IGF-I levels decreased significantly during follow-up (from 72.6
      +/- 29.9 microg/L to 33.8 +/- 14.5 microg/L; P = 0.001). In these patients, the
      significant decrease occurred both in patients with persistent Child Grade A
      cirrhosis and in patients with cirrhosis that progressed from Child Grade A to
      Grade B. The reduction in IGF-I level preceded the diagnosis of HCC by 9.3 +/-
      3.1 months. CONCLUSIONS: This prospective study demonstrates that, in patients
      with HCV-related cirrhosis, 1) the development of HCC is accompanied by a
      significant reduction of serum IGF-I levels independent of the grade of
      impairment of liver function; and 2) modification of the IGF-I level precedes the
      morphologic appearance of HCC, permitting a precocious diagnosis of the tumor.

PMID- 12467069
TI  - Modified scar grade: a prognostic indicator in small peripheral lung
      adenocarcinoma.
AB  - BACKGROUND: Several studies have shown the prognostic value of desmoplasia for
      lung adenocarcinomas. The authors evaluated the density and extent of desmoplasia
      by modifying the scar grade, as well as the prognostic impact on patient
      survival. METHODS: Modified scar grade was defined as follows: Grade 1, no
      desmoplasia; Grade 2, sparse desmoplastic reaction; Grade 3, dense desmoplastic
      reaction with diameter of 10 mm or less; Grade 4, dense desmoplastic reaction
      with diameter exceeding 10 mm. In addition, the prognostic impact of conventional
      histologic factors and modified scar grade was analyzed in 239 cases of small
      peripheral lung adenocarcinoma (maximum dimension, </= 30 mm) for which long-term
      follow-up data were available. RESULTS: The 5 and 10-year survival rates
      according to the modified scar grade were 100% and 100% for Grade 1 lung
      adenocarcinoma (n = 29); 91.7% and 83.7% for Grade 2 (n = 61); 67.6% and 52.7%
      for Grade 3 (n = 78); and 50.0% and 37.5% for Grade 4 (n = 71), respectively. A
      significant difference in patient survival was found between Grade 1 or 2 versus
      Grade 3 or 4 (P < 0.0001, by log rank test). Multivariate analysis showed that
      modified scar grade was an independent prognostic factor (P = 0.0176), as were
      pathologic stage (P = 0.0293), lymph node metastasis (P = 0.0191), lymphatic
      permeation (P = 0.0022), and pleural involvement (P = 0.0452). Modified scar
      grade also had a significant impact on survival in various subsets of patients,
      including those with pathologic Stage IA disease, patients with tumors of
      diameter 20 mm or less, or patients with mixed subtype tumors with a
      bronchioloalveolar component. CONCLUSIONS: Modified scar grade is a useful
      prognostic factor in patients with small lung adenocarcinomas. Tumors with a
      sparse fibroblastic reaction (modified scar Grade 2) may represent early invasive
      cancers or invasive cancers with low malignant potential, which should be
      distinguished from frankly invasive cancers (modified scar Grade 3 or 4).

PMID- 12467070
TI  - A multicenter phase II study of the intravenous administration of liposomal
      tretinoin in patients with acquired immunodeficiency syndrome-associated Kaposi's
      sarcoma.
AB  - BACKGROUND: A multicenter trial was conducted to determine the efficacy and
      toxicity of escalating dosages of liposomal tretinoin (all-trans-retinoic acid)
      administered once or three times weekly in patients with acquired
      immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma. METHODS: Seventy-six
      patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma
      were randomized to receive the study drug either once (n = 30) or 3 times weekly
      (n = 46). The starting dosage was 60 mg/m(2), which was escalated to 90 mg/m(2)
      and then 120 mg/m(2) if the drug was well tolerated (<or= Grade 2 toxicities
      [according to the Southwest Oncology Group toxicity scale]). Four weeks of
      therapy constituted 1 cycle; patients could receive up to 8 cycles and those who
      completed 8 cycles were given the option of receiving extended therapy. Clinical
      response was defined as complete response (CR), partial response (PR), or stable
      disease (SD). RESULTS: Efficacy was assessed after the completion of 3 treatment
      cycles; 28.9% of patients (22 of 76 patients) responded (no CRs, 1 PR, and 21
      SDs). Among the patients receiving treatment 3 times weekly, 16 of 49 patients
      (32.7%) achieved a clinical response at the end of the third treatment cycle (no
      CRs, 1 PR, and 15 SDs). Concomitant or prior use of protease inhibitors did not
      appear to affect the patient's response to treatment (P = 0.183). CONCLUSIONS:
      Liposomal tretinoin is a new therapeutic agent that has been reported to have
      some clinical activity in patients with AIDS-associated Kaposi sarcoma. A three
      times-per-week dosing schedule was noted to be more effective compared with a
      once-a-week schedule without any significant difference in toxicity reported.

PMID- 12467071
TI  - Long-term cognitive outcome, brain computed tomography scan, and magnetic
      resonance imaging in children cured for acute lymphoblastic leukemia.
AB  - BACKGROUND: Prevention of meningeal recurrence achieved by intrathecal
      methotrexate (MTX) and systemic chemotherapy is part of standard acute
      lymphoblastic leukemia (ALL) treatment. Cranial irradiation has been a routine
      part of past protocol treatment but is currently reserved only for select subsets
      of patients. Central nervous system (CNS) prophylaxis may cause brain
      abnormalities such as intracerebral calcifications, cerebral atrophy, and white
      matter alterations. In addition, long-term neuropsychologic sequelae following
      CNS prophylaxis have been investigated marginally in children cured for ALL.
      METHODS: To explore possible correlations between neuroimaging findings and
      neuropsychologic outcome, we used detailed cognitive tests to evaluate 21
      children with ALL who received cranial irradiation (range, 18-24 Gy) plus
      intrathecal MTX as CNS prophylaxis. All children were followed prospectively once
      a year by cerebral computed tomographic scan and magnetic resonance imaging. All
      patients had continuous complete disease remission for at least 4 years and
      cognitive tests were performed after neuroradiologic examinations. RESULTS: White
      matter abnormalities were associated with poor performance only in a task
      exploring visual motor integration in about 50% of patients. Intracerebral
      calcifications correlate with the number of intrathecal MTX doses and with low
      scores in total intellectual quotient, performance intellectual quotient, and
      significant impairment in attention and visual motor integration tests. Girls are
      more vulnerable to the effects of CNS prophylaxis, whereas age at treatment and
      radiotherapy dose are not relevant to neuropsychologic outcome. CONCLUSIONS: Our
      results indicate the need for careful follow-up of children's cognitive abilities
      because global intellectual measures often fail to detect specific disorders that
      may cause learning difficulties. Moreover, as the clinical implications of
      neuroimaging findings are often limited, periodic extensive evaluation by
      specific neurocognitive tests of mental abilities is recommended to detect early
      signs of cognitive impairment.

PMID- 12467072
TI  - p53 codon 72 polymorphism (C/G) and the risk of human papillomavirus-associated
      carcinomas in China.
AB  - BACKGROUND: Human papillomavirus (HPV) plays an important role in the development
      of carcinomas at various body sites. It was found previously that the p53 codon
      72 polymorphism (C/G) is a high-risk factor for the development HPV-associated
      cervical carcinoma. However, it still was considered controversial in several
      studies of cervical and esophageal carcinoma. METHODS: In the current study, the
      authors used an allele specific polymerase chain reaction (PCR) method to analyze
      correlation between the p53 codon 72 (C/G) polymorphism and HPV-associated,
      noncancerous esophageal epithelium as well as esophageal, ovarian, and breast
      carcinoma in the Chinese population. Esophageal balloon cytology examination
      samples were obtained from high-incidence and low-incidence populations for
      esophageal carcinoma in Anyang (Henan Province). RESULTS: Thirty-six of 48
      esophageal balloon samples from the high-incidence population were HPV positive,
      and 13 of 33 esophageal balloon samples from the low-incidence population were
      HPV positive. Thirty-nine of 62 esophageal carcinoma samples from Anyang Tumor
      Hospital were HPV positive. Twenty-six of 39 ovarian carcinoma samples from the
      Second Affiliated Hospital of Inner Mongolia Medical College were HPV positive.
      Nineteen of 82 breast carcinoma samples from Beijing Cancer Hospital were HPV
      positive. It is noteworthy that the distribution of the p53 codon 72 Arg
      homozygous genotype in HPV positive samples of esophageal epithelium, ovarian
      carcinoma, and breast carcinoma was significantly higher compared with HPV
      negative tumor samples. (P < 0.05). CONCLUSIONS: The current results suggest that
      the p53 codon 72 Arg homozygous genotype is one of the high-risk genetic factors
      for HPV-associated malignancies among the Chinese population.

PMID- 12467073
TI  - Histopathologic grading of medulloblastomas.

PMID- 12467080
TI  - Is paleoanthropology science? Naming new fossils and control of access to them.
AB  - Progress in paleoanthropology is impeded when new fossil materials are published
      but unavailable for comparative study, as is too often the case. In this
      commentary, we review the stages of description and analysis that new fossils
      must undergo and conclude that it is disingenuous to argue that fossils have not
      been properly "published" when descriptions and new names formulated in
      accordance with the International Code of Zoological Nomenclature have appeared
      in leading scientific journals. Once such names and descriptions have been
      published, it is imperative that the original fossils concerned be available to
      the scientific community for comparative analysis, for by the very nature of
      science, no statement about such fossils, however carefully prepared by the
      original describers (or anyone else), can be regarded as definitive. Science is a
      system of provisional knowledge that constantly requires re-examination and
      testing. It cannot function as a system in which assertions have to be left
      unchallenged for want of free access to the primary data.

PMID- 12467081
TI  - Human dissection: an approach to interweaving the traditional and humanistic
      goals of medical education.
AB  - Anatomy remains one of the core courses of medical school, but the time devoted
      to it is decreasing. To accommodate the explosion of medical knowledge, educators
      search to streamline the curriculum. Because it is time-consuming, dissection
      comes under increased scrutiny. Even in the face of these pressures to reduce
      course hours, I would like to propose broadening, not reducing, the
      responsibilities of the anatomy instructor. Anatomy instructors can play a
      crucial role in helping medical schools meet the critical need to cultivate
      humanistic values, especially in the arena of end-of-life care. Anatomy can--and
      should--play an important role in a curriculum-wide effort to address this issue.
      Just as dissection remains an essential technique to teach three-dimensional
      concepts, the cadaver dissection lab is an ideal place to introduce concepts of
      humanistic care. The lab evokes the students' memories, speculations, and fears
      about serious illness in themselves, their families, and loved ones. Some
      programs address these reactions with supplemental activities, such as
      journaling, essay writing, and small group discussion. Valuable as these
      activities may be, anatomy instructors can achieve more by recognizing their role
      as a mentor, who can integrate humanistic values into traditional course
      objectives in a way that adds little time to the curriculum. The attitude of the
      instructor in ministering to the students' needs as they undertake the
      emotionally charged task of dissection can provide a model for how the students
      will respond, in turn, to the hopes and fears of their patients-and to their own
      reactions to dying. This approach will allow students to implement and practice
      humanistic values immediately, laying a foundation for their clinical training.

PMID- 12467082
TI  - The Modular Resource Center: integrated units for the study of the anatomical
      sciences in a problem-based curriculum.
AB  - The Modular Resource Center (MRC) at the College of Veterinary Medicine at
      Cornell University was created in 1993 as a way to provide visual resources in
      support of a newly implemented problem-based curriculum in which the anatomical
      sciences are taught primarily in the first tutorial-based course, The Animal
      Body. Over two dozen modules have been created specifically in support of this
      course, whereas additional modules have been created in support of other basic
      science courses. The basic unit of organization of the MRC is a module presented
      in a carrel that provides students a way to study, either alone or in groups, a
      given topic. The topic is presented through a script and an integrated set of
      anatomical materials including plastinated dissected specimens, vascular casts,
      skeletal preparations, models, radiographs, histological slides, and photo- and
      electron micrographs. The key feature of this resource center is that it is not a
      museum; rather it is more analogous to an interactive library, that can be used
      for reference, study, and review, not only by veterinary students but also by
      faculty, interns, residents, and undergraduates. A unique aspect is that all
      materials have been made by veterinary students working with faculty during the
      summer. Although started as a resource in support of a tutorial-based curriculum,
      the MRC has evolved over a decade into an anatomy resource that would be highly
      valued in any curricular format.

PMID- 12467083
TI  - Relationship of acupuncture points and meridians to connective tissue planes.
AB  - Acupuncture meridians traditionally are believed to constitute channels
      connecting the surface of the body to internal organs. We hypothesize that the
      network of acupuncture points and meridians can be viewed as a representation of
      the network formed by interstitial connective tissue. This hypothesis is
      supported by ultrasound images showing connective tissue cleavage planes at
      acupuncture points in normal human subjects. To test this hypothesis, we mapped
      acupuncture points in serial gross anatomical sections through the human arm. We
      found an 80% correspondence between the sites of acupuncture points and the
      location of intermuscular or intramuscular connective tissue planes in postmortem
      tissue sections. We propose that the anatomical relationship of acupuncture
      points and meridians to connective tissue planes is relevant to acupuncture's
      mechanism of action and suggests a potentially important integrative role for
      interstitial connective tissue.

PMID- 12467084
TI  - The interaction of spatial reference frames and hierarchical object
      representations: evidence from figure copying in hemispatial neglect.
AB  - In copying or drawing a figure, patients with hemispatial neglect following right
      parietal lobe lesions typically produce an adequate representation of parts on
      the right of the figure while omitting the corresponding features on the left.
      The neglect of information occupying contralateral locations is influenced by
      multiple spatial reference frames and by the hierarchical structure of the
      object(s) in the figure. The present work presents a computational
      characterization of the interaction among these influences to account for the way
      in which neglect manifests in copying. Empirical data are initially collected
      from brain-damaged and normal control subjects during two figure-copying tasks in
      which the hierarchical complexity and orientation of the displays to be copied
      are manipulated. In the context of the model, neglect is simulated by a "lesion"
      (monotonic drop-off along gradient from right to left) that can affect
      performance in both object- and viewer-centered reference frames. The effect of
      neglect in both these frames, coupled with the hierarchical representation of the
      object(s), provides a coherent account of the copying behavior of the patients
      and may be extended to account for the copying performance of other patients
      across a range of objects and scences.

PMID- 12467085
TI  - Updating of locations during whole-body rotations in patients with hemispatial
      neglect.
AB  - Posterior parietal cortex lesions have been associated with both hemispatial
      neglect and spatial-updating deficits. Currently, the relation between these
      processes remains poorly understood. We tested the ability of parietal patients
      with neglect to update remembered target locations during passive whole-body
      rotations. The rotations and manual pointing responses were executed with and
      without vision. During the rotation, the remembered location stayed on the same
      side of the body midline or crossed the midline. Parietal patients generally
      underestimated rotations, as compared with control groups, but updated targets
      equally well on either side of the body midline, regardless of the amount of
      updating required. Once parietal patients have localized a target, they can use
      self-motion information to update its location, even if it passes into the region
      they typically neglect. This lack of contralesional updating effects contrasts
      with impairments in eye position updating found in previous work with parietal
      patients.

PMID- 12467086
TI  - A single-system interpretation of dissociations between recognition and
      categorization in a task involving object-like stimuli.
AB  - In previous research (Reed, Squire, Patalano, Smith, & Jonides, 1999), amnesic
      patients performed at near normal levels in a categorization task involving
      stimuli with discrete features, but showed impaired recall of the features. These
      results were taken as evidence of the existence of separate memory systems for
      categorization and recall/recognition. The present research addresses a single
      system account of this dissociation. In Experiment 1, results closely matching
      the dissociation pattern were obtained when normal participants' classification
      and recognition performance was tested either immediately or after a week delay.
      In addition, formal modeling of the data suggested that participants use only a
      few of the dimensions in the categorization task, whereas they must use many
      dimensions in the cued-recall task. In Experiment 2, we found that many
      participants could perform the categorization task without any exposure to the
      training sequence. These results suggest that different memory demands across the
      two tasks may be responsible for the observed dissociation--separate memory
      systems are not necessarily involved.

PMID- 12467087
TI  - PET evidence for multiple strategies of categorization.
AB  - It is widely held that people use multiple strategies to categorize their
      experiences in the world. We conducted a pair of neuroimaging experiments to
      identify the neural correlates of two of these strategies--rule application and
      exemplar similarity. Participants were instructed to perform either a rule- or an
      exemplar-based categorization task while changes in cerebral blood flow were
      measured using positron emission tomography. Patterns of neural activity were
      consistent with the predictions of cognitive models of rule-versus exemplar-based
      categorization and with existing neuroscience data. The identification of
      strategy-specific neural patterns offers future researchers a diagnostic tool for
      assessing strategy use in other situations.

PMID- 12467088
TI  - Testosterone increases analgesia, anxiolysis, and cognitive performance of male
      rats.
AB  - Preliminary evidence suggests that testosterone (T) may have anxiety-reducing and
      cognitive-enhancing properties in animals and people. Performance in a number of
      affective and cognitive behavioral tasks was examined in intact, T-depleted, and
      T-depleted and T-replaced male rats. Rats that were gonadally intact (n = 33),
      gonadectomized (GDX; n = 30), or GDX with silastic capsules of T implanted (n =
      28) were tested through a battery of affective tasks (horizontal crossing, open
      field, elevated plus-maze, emergence, holeboard, social interaction, tailflick,
      pawlick, and defensive burying) and in the inhibitory avoidance task for
      cognitive performance. An additional 6 rats per group had plasma androgen
      concentrations measured and were determined to be physiological for intact rats,
      supraphysiological for T-implanted rats, and near the nadir for GDX rats.
      Testosterone implants produced analgesia as shown by the increased tailflick
      latencies of the GDX rats with silastic capsules of T implanted, relative to
      intact or GDX rats. Testosterone also produced anxiolysis. Intact rats spent more
      time interacting with a conspecific and less time burying an electrified prod
      than did the GDX or T-implanted rats. Intact rats or GDX rats with T implants
      also spent more time on the open arms of the elevated plus-maze than did GDX
      rats. Testosterone also enhanced cognitive performance in the inhibitory
      avoidance task. Intact rats had longer crossover latencies in the inhibitory
      avoidance task relative to GDX rats; GDX rats with T implants had longer
      crossover latencies relative to GDX or intact rats. Together, these data
      demonstrate that endogenous T or administration of T produced analgesia and
      enhanced affect and cognitive performance of adult male rats.

PMID- 12467089
TI  - Is cross-modal integration of emotional expressions independent of attentional
      resources?
AB  - In this study, we examined whether integration of visual and auditory information
      about emotions requires limited attentional resources. Subjects judged whether a
      voice expressed happiness or fear, while trying to ignore a concurrently
      presented static facial expression. As an additional task, the subjects had to
      add two numbers together rapidly (Experiment 1), count the occurrences of a
      target digit in a rapid serial visual presentation (Experiment 2), or judge the
      pitch of a tone as high or low (Experiment 3). The visible face had an impact on
      judgments of the emotion of the heard voice in all the experiments. This cross
      modal effect was independent of whether or not the subjects performed a demanding
      additional task. This suggests that integration of visual and auditory
      information about emotions may be a mandatory process, unconstrained by
      attentional resources.

PMID- 12467090
TI  - Correlation between cortisol level and serotonin uptake in patients with chronic
      stress and depression.
AB  - In a recent study (Tafet, Toister-Achituv, & Shinitzky, 2001), we demonstrated
      that cortisol induces an increase in the expression of the gene coding for the
      serotonin transporter, associated with a subsequent elevation in the uptake of
      serotonin. This stimulatory effect, produced upon incubation with cortisol in
      vitro, was observed in peripheral blood lymphocytes from normal subjects. In the
      present work we investigated the cortisol-induced increase in serotonin uptake in
      lymphocytes from hypercortisolemic patients, including subjects with major
      depressive disorder (n = 8), and subjects with generalized anxiety disorder (n =
      12), in comparison with a control group of normal healthy subjects (n = 8). A
      significant increase in serotonin uptake (+37% + 14, M + SD) was observed in the
      control group, whereas neither the generalized anxiety disorder nor the major
      depression group exhibited changes in serotonin uptake upon incubation with
      cortisol. It is likely that under chronic stress or depression, the capacity for
      increase in serotonin transporter has reached its limit due to the chronically
      elevated blood cortisol level. The physiological and diagnostic implications of
      this observation are discussed.

PMID- 12467091
TI  - Temporal order and processing acuity of visual, auditory, and tactile perception
      in developmentally dyslexic young adults.
AB  - We studied the temporal acuity of 16 developmentally dyslexic young adults in
      three perceptual modalities. The control group consisted of 16 age- and IQ
      matched normal readers. Two methods were used. In the temporal order judgment
      (TOJ) method, the stimuli were spatially separate fingertip indentations in the
      tactile system, tone bursts of different pitches in audition, and light flashes
      in vision. Participants indicated which one of two stimuli appeared first. To
      test temporal processing acuity (TPA), the same 8-msec nonspeech stimuli were
      presented as two parallel sequences of three stimulus pulses. Participants
      indicated, without order judgments, whether the pulses of the two sequences were
      simultaneous or nonsimultaneous. The dyslexic readers were somewhat inferior to
      the normal readers in all six temporal acuity tasks on average. Thus, our results
      agreed with the existence of a pansensory temporal processing deficit associated
      with dyslexia in a language with shallow orthography (Finnish) and in well
      educated adults. The dyslexic and normal readers' temporal acuities overlapped so
      much, however, that acuity deficits alone would not allow dyslexia diagnoses. It
      was irrelevant whether or not the acuity task required order judgments. The
      groups did not differ in the nontemporal aspects of our experiments. Correlations
      between temporal acuity and reading-related tasks suggested that temporal acuity
      is associated with phonological awareness.

PMID- 12467092
TI  - Parameters of remembering and forgetting in the transition from infancy to early
      childhood.
AB  - The ability to recall is something that most intact adults take for granted. For
      much of the last century, this feature of mental life was not considered to
      extend to very young children. There now is evidence that 1- to 2-year-olds are
      able to recall specific events after delays of several months. Over the short
      term, 1- to 2-year-olds' recall is affected by the same factors that affect older
      children's recall; it is not clear whether similar effects are apparent over the
      long term. Moreover, although age-related increases in long-term recall are
      assumed, there have been few empirical tests of the question. We examined recall
      by 14- to 32-month-olds for events experienced at 13 to 20 months. Using elicited
      imitation of novel multistep event sequences we examined effects of (a) delay
      length, (b) age at the time of experience, (c) temporal structure of events, (d)
      mode of experience of events, and (e) availability of verbal reminders, on long
      term recall. Participants were 360 children enrolled at 13 (n = 90), 16 (n =
      180), and 20 (n = 90) months. All of the 13-month-olds and half of the 16-month
      olds were tested on 3-step event sequences; all of the 20-month-olds and half of
      the 16-month-olds were tested on 4-step event sequences. Within each age and step
      length group, equal numbers of children were tested after intervals of 1, 3, 6,
      9, and 12 months (n = 18 per cell). Children were tested on a variety of sequence
      types. For half of the events, imitation was permitted prior to the delay; for
      the other half, children were not permitted imitation. At delayed testing,
      children experienced a recall period during which they were cued by the event
      related props alone, followed by a period in which recall was cued both by the
      event-related props and by verbal labels for the event sequences. Within step
      length groups, the length of time for which older and younger children showed
      evidence of memory did not differ. Nevertheless, when the children were prompted
      by the event-related props alone, there were age-related differences in the
      robustness of children's memories (as indexed by higher levels of recall for
      older children relative to younger children). When the children were prompted by
      the props and by verbal labels for the event sequences, at the longer retention
      intervals, there were age-related differences in the robustness of children's
      memories and in the reliability with which recall was evidenced (as indexed by
      the larger numbers of older children evincing recall). Age-related effects were
      particularly apparent on children's ordered recall. Across the entire age range,
      the children were similarly affected by the variables of sequence type,
      opportunity for imitation, and verbal reminding.

PMID- 12467093
TI  - Historical and future trends in studying the development of long-term retention.

PMID- 12467094
TI  - Across the great divide: bridging the gap between understanding of toddlers' and
      older children's thinking.
AB  - Research on very young children's cognitive development differs greatly from
      research on cognitive development in older children. The differences include the
      questions that are asked, the methods that are used to address them, the measures
      that are employed to provide relevant evidence, and the level of detail at which
      children's knowledge is represented. The research approaches are so different
      that they create an impression that infants' and toddlers' thinking differs
      qualitatively from that of preschoolers and older children. This impression,
      however, may reflect differences in research approaches rather than differences
      in children's thinking. In the present study, we attempted to bridge this gap by
      applying to toddlers a type of process analysis that has proved fruitful in
      studies of older children. Overlapping waves theory, trial-by-trial strategy
      assessments, and microgenetic methods were used to analyze 1.5- and 2.5-year
      olds' problem solving and learning. The results demonstrated that changes in
      toddlers' strategies could be assessed reliably on a trial-by-trial basis, that
      the changes followed the basic form predicted by the overlapping waves model, and
      that analyses of toddlers' strategies could tell us a great deal about both
      qualitative and quantitative aspects of their learning. A componential analysis
      of learning that previously had been applied to older children also proved useful
      for understanding toddlers' learning. The analysis specified that cognitive
      change frequently involves five components: acquisition of new strategies;
      strengthening of the strategies in their original context; improved mapping of
      strategies onto novel problems; increasingly refined choices among variants of
      the strategies; and increasingly skillful execution of the strategies.
      Independent measures of these components indicated that strategic development in
      toddlers involves improvements in all five components. Analyses of individual
      differences in learning showed that the effects of distal variables, such as age
      and sex, could be partially explained in terms of their influence on mastery of
      the components, but that the distal variables exercised additional direct effects
      as well. The process of learning in toddlers closely resembled that of older
      children in other ways as well. Like older children, toddlers use multiple
      strategies over the course of learning; their choices among strategies are quite
      adaptive from early on; their choices become progressively more adaptive as they
      gain experience with the task; they switch strategies not only from trial to
      trial but within a single trial; their transfer of learning from one problem to
      the next is primarily influenced by structural relations between problems but
      also is influenced by superficial features; they show utilization deficiencies
      early in learning that they gradually overcome; and they show individual
      differences in learning that fall into a few qualitatively distinct categories.
      Perhaps most striking, the 1.5- and 2.5-year-olds emerged as active learners, who
      continued to work out the lessons of previous instruction in the absence of
      further instruction. That is, they integrated the lessons of their own problem
      solving efforts with the previous instruction in ways that magnified the initial
      effects of the instruction. Overall, the findings indicated that the gap can be
      bridged; that theories, methods, measures, and representations of knowledge
      typically used with older children can improve our understanding of toddlers'
      problem solving and learning as well.

PMID- 12467095
TI  - A key bridge to understanding the development of thinking and problem solving.

PMID- 12467096
TI  - Breaking the language barrier: an emergentist coalition model for the origins of
      word learning.
AB  - How do children learn their first words? The field of language development has
      been polarized by responses to this question. Explanations range from
      constraints/principles accounts that emphasize the importance of cognitive
      heuristics in language acquisition, to social-pragmatic accounts that highlight
      the role of parent-child interaction, to associationistic accounts that highlight
      the role of "dumb attentional mechanisms" in word learning. In this Monograph, an
      alternative to these accounts is presented: the emergentist coalition theory. A
      hybrid view of word learning, this theory characterizes lexical acquisition as
      the emergent product of multiple factors, including cognitive constraints, social
      pragmatic factors, and global attentional mechanisms. The model makes three
      assumptions: (a) that children cull from multiple inputs available for word
      learning at any given time, (b) that these inputs are differentially weighted
      over development, and (c) that children develop emergent principles of word
      learning, which guide subsequent word acquisition. With few exceptions, competing
      accounts of the word learning process have examined children who are already
      veteran word learners. By focusing on the very beginnings of word learning at
      around 12 months of age, however, it is possible to see how social and cognitive
      factors are coordinated in the process of vocabulary development. After
      presenting a new method for investigating word learning, the development of
      reference is used as a test case of the theory. In 12 experiments, with children
      ranging in age from 12 to 25 months of age, data are described that support the
      emergentist coalition model. This fundamentally developmental theory posits that
      children construct principles of word learning. As children's word learning
      principles emerge and develop, the character of word learning changes over the
      course of the 2nd year of life.

PMID- 12467097
TI  - Pushing the limits on theories of word learning.

PMID- 12467098
TI  - Making the most of summer school: a meta-analytic and narrative review.
AB  - Summer schools serve multiple purposes for students, families, educators, and
      communities. The current need for summer programs is driven by changes in
      American families and by calls for an educational system that is competitive
      globally and embodies higher academic standards. A research synthesis is reported
      that used both meta-analytic and narrative procedures to integrate the results of
      93 evaluations of summer school. Results revealed that summer programs focusing
      on remedial or accelerated learning or other goals have a positive impact on the
      knowledge and skills of participants. Although all students benefit from summer
      school, students from middle-class homes show larger positive effects than
      students from disadvantaged homes. Remedial programs have larger effects when the
      program is relatively small and when instruction is individualized. Remedial
      programs may have more positive effects on math than on reading. Requiring parent
      involvement also appears related to more effective programs. Students at all
      grade levels benefit from remedial summer school, but students in the earliest
      grades and in secondary school may benefit most. These and other findings are
      examined for their implications for future research, public policy, and the
      implementation of summer programs. Based on these results, our recommendations to
      policy makers are that summer programs (a) contain substantial components aimed
      at teaching math and reading and (b) include rigorous evaluations, but also (c)
      permit local control of curricula and delivery systems. Funds should be set aside
      to foster participation in summer programs, especially among disadvantaged youth.
      Program implementers should (a) begin summer program planning earlier in the
      year, (b) strive for continuity of staffing and programs across years, (c) use
      summer school in conjunction with summer staff development opportunities, and (d)
      begin integrating summer school experiences with those that occur during the
      regular school year.

PMID- 12467099
TI  - Recognition memory in amnesia: effects of relaxing response criteria.
AB  - In two experiments, using the remember/know paradigm, we examined whether
      recognition memory in amnesic patients can be improved by instructing patients to
      relax their response criterion. Experiment 1 was modeled after a study by
      Dorfman, Kihlstrom, Cork, and Misiaszek (1995), in which direct instructions to
      respond more leniently led to an increase in recognition accuracy in patients
      with ECT-induced amnesia. We failed to extend this finding to patients with
      global amnesia, but the manipulation was unsuccessful in control subjects as
      well. In Experiment 2, response criterion was manipulated indirectly by providing
      information about the alleged base rate of study items on the recognition test.
      This manipulation led to a criterion shift in control subjects and enhanced
      discriminability in amnesic patients. Analysis of "remember" and "know" responses
      suggests that improved accuracy in amnesia was associated with enhanced
      familiarity-based recognition.

PMID- 12467100
TI  - Behavioral and neurophysiological correlates of episodic coding, proactive
      interference, and list length effects in a running span verbal working memory
      task.
AB  - Updating refers to (1) discarding items from, (2) repositioning items in, and (3)
      adding items to a running working memory span. Our behavioral and fMRI
      experiments varied three factors: trial length, proactive interference (PI), and
      group integrity. Group integrity reflected whether the grouping of items at the
      encoding stage was violated at discarding. Behavioral results were consistent
      with the idea that updating processes have a relatively short refractory period
      and may not fatigue, and they revealed that episodic information about group
      context is encoded automatically in working memory stimulus representations. The
      fMRI results did not show evidence that updating requirements in a task recruit
      executive control processes other than those supporting performance on
      nonupdating trials. They did reveal an item-accumulation effect, in which signal
      increased monotonically with the number of items presented during the trial,
      despite the insensitivity of behavioral measures to this factor. Behavioral and
      fMRI correlates of PI extended previous results and rejected an alternative
      explanation of PI effects in working memory.

PMID- 12467101
TI  - Focal retrograde amnesia and the episodic-semantic distinction.
AB  - This article reports a review of focal retrograde amnesia (FRA), or the
      phenomenon of organically based severe memory loss restricted to retrograde, or
      pretraumatic, memory. Cases of FRA are classified according to the type of memory
      loss: episodic, semantic, or both. A few different clusters of the disorder were
      identified. Lesions to either the anterior temporal lobes or the posterior/visual
      cortex can result in an FRA that devastates retrograde episodic memory, while
      having smaller effects on semantic memory. A number of left-hemisphere patients
      have FRA confined to semantic memory. There are several additional examples of
      FRA following minor cerebral trauma that disrupts either episodic memory alone or
      both episodic and semantic memory that are not accompanied by evidence of
      structural brain lesions. We discuss these different profiles of FRA and their
      implications for the understanding of memory retrieval.

PMID- 12467102
TI  - A computational model of mechanisms controlling experience-dependent
      reorganization of representational maps in auditory cortex.
AB  - Cortical representations of sound can be modified by repeatedly pairing
      presentation of a pure tone with electrical stimulation of neuromodulatory
      neurons located in the basal forebrain (Bakin & Weinberger, 1996; Kilgard &
      Merzenich, 1998a). We developed a computational model to investigate the possible
      effects of basal forebrain modulation on map reorganization in the auditory
      cortex. The model is a self-organizing map with acoustic response characteristics
      mimicking those observed in the mammalian auditory cortex. We simulated the
      effects of basal forebrain modulation, using parameters intrinsic to the self
      organizing map, such as the learning rate (controlling the adaptability of map
      nodes) and the neighborhood function (controlling the excitability of map nodes).
      Previous research has suggested that both parameters can be useful for
      characterizing the effects of neuromodulation on plasticity (Kohonen, 1993; Myers
      et al., 1996; Myers, Ermita, Hasselmo, & Gluck, 1998). The model successfully
      accounts for experimentally observed effects of pairing basal forebrain
      stimulation with the presentation of a single tone, but not of two tones,
      suggesting that auditory cortical plasticity is constrained in ways not accounted
      for by current theories. Despite this limitation, the model provides a useful
      framework for describing experience-induced changes in auditory representations
      and for relating such changes to variations in the excitability and adaptability
      of cortical neurons produced by neuromodulation.

PMID- 12467103
TI  - Tracking the influence of reflexive attention on sensory and cognitive
      processing.
AB  - Previously, we demonstrated that reflexive attention facilitates early visual
      processing during form discrimination (Hopfinger & Mangun, 1998). In the present
      study, we tested whether reflexive facilitation of early visual processing will
      be generated when task load is low (simple luminance detection). Target stimuli
      that were preceded at short cue-to-target intervals by irrelevant visual events
      (cues) elicited an enhanced sensory (P1) event-related potential (ERP) component
      as well as an enhanced longer latency, cognitive ERP component (P300). At long
      cue-to-target intervals, facilitation in these ERP components was no longer
      observed, and, although inhibition of return (IOR) was observed in reaction
      times, the ERPs did not show an inhibition of sensory processing. These results
      provide converging evidence that reflexive attention transiently facilitates
      neural processing of visual inputs at multiple stages of analysis (i.e., sensory
      processing and higher order cognitive processing) but question the view that IOR
      is manifest at the earliest visual cortical stages of analysis.

PMID- 12467104
TI  - Conjunctive representations, the hippocampus, and contextual fear conditioning.
AB  - The context in which events occur can be represented as both (1) a set of
      independent features, the feature representation view, and (2) a set of features
      bound into a unitary representation, the conjunction representation view. It is
      assumed that extrahippocampal (e.g., neocortical) areas provide a basis for
      feature representations, but the hippocampal formation makes an essential
      contribution to the automatic storage of conjunctive representations. We develop
      this dual-representation view and explore its implications for hippocampal
      contributions to contextual fear conditioning processes. To this end, we discuss
      how our framework can resolve some of the conflicts in the recent literature
      relating the hippocampus to contextual fear conditioning. We also present new
      data supporting the role of a key mechanism afforded by conjunctive
      representations--pattern completion (the ability of a subset of a memory pattern
      to activate the complete memory)--in contextual fear conditioning. As is implied
      by this mechanism, we report that fear can be conditioned to the memory
      representation of a context that is not actually present at the time of shock.
      Moreover, this result is predicted by our computational model of cortical and
      hippocampal function. We suggest that pattern completion demonstrated in animals
      and by our model provides a mechanistic bridge to human declarative memory.

PMID- 12467105
TI  - Of mice and men: virtual Hebb-Williams mazes permit comparison of spatial
      learning across species.
AB  - We developed a computer-generated virtual environment to test humans, for the
      first time, on the Hebb-Williams mazes. The goal was to provide a standardized
      test that could be used to directly compare human performance with that of
      C57BL/6J mice performing in real versions of the mazes. Such a comparison seems
      crucial if conclusions regarding genetic manipulations of rodents are to be
      mapped onto human cognitive disorders. The learning curves across species were
      strikingly similar, lending support to the rodent model of human spatial memory.
      Humans learned faster than rodents in both the acquisition and the test portions
      of the protocol, and females of both species were less efficient in solving these
      problems than males. These results represent the first modern comparison of human
      and rodent learning that uses the same test of spatial problem solving.

PMID- 12467106
TI  - Differential effects of glucose on modulation of emotional and nonemotional
      spatial memory tasks.
AB  - Research examining the memory-enhancing effects of glucose in humans has been
      limited to mnemonic tasks lacking affective components, even though glucose may
      be a mechanism for emotion-induced memory enhancement. This limitation does not
      permit analysis of interactions between the enhancing properties of emotional
      stimuli and glucose. Participants were administered either glucose or saccharin
      15 min prior to completing a neutral or emotional spatial memory task.
      Performance under three glycemic conditions (100 mg/kg or 50 g glucose, or
      placebo) for the two sets of emotional stimuli revealed a significant
      interaction. Both 100-mg/kg and 50-g doses of glucose resulted in impaired
      performance for emotional stimuli. For neutral stimuli, a 100-mg/kg dose enhanced
      memory, whereas a 50-g dose showed no effect. Results indicate that the enhancing
      effects of emotional stimuli may be attenuated by the consumption of glucose and
      suggest that recent food consumption should be considered in paradigms examining
      memory.

PMID- 12467107
TI  - Enhancement of serotonin uptake by cortisol: a possible link between stress and
      depression.
AB  - Stress and depression are characterized by elevation of circulating cortisol, as
      well as by changes in physiological functions. In this study, we addressed the
      possibility that elevated cortisol is also associated with the origin and
      development of depression. We report here that cortisol at the nM-microM
      concentration range induces a substantial increase in serotonin uptake both in
      vitro, by human peripheral blood lymphocytes (PBLs) and cortical neuronal cells,
      and in vivo, by rabbit PBLs, owing to promotion of synthesis of the serotonin
      transporter. These findings offer a novel molecular mechanism for depression
      associated with stress. Accordingly, the elevated cortisol induced by stress
      increases serotonin uptake, under both rest and nerve stimulation, which is
      overtly expressed in symptoms of depression.

PMID- 12467108
TI  - Modification of the human blink reflex by transient and sustained features of
      acoustic prestimulation.
AB  - The effects of acoustic stimuli whose onsets and durations were controlled to
      vary their transient and sustained features on the size of a subsequently
      elicited blink reflex were examined in humans. Prestimuli both with and without
      transient features inhibited the reflex when they preceded the eliciting stimulus
      by brief lead intervals, showing that acoustic transients are sufficient, but not
      necessary, for reflex inhibition. Inhibition evoked by transient and sustained
      stimulus features showed partial summation, and inhibition evoked by stimuli with
      only transient and with transient and sustained features showed similar decay
      functions with increasing lead intervals. Blink augmentation was found at longer
      lead intervals early but not late in a session, and was more evident in women
      than men. Prestimuli with only transient features were more effective than those
      with both transient and sustained features, showing that sustained stimulus
      energy at the time of reflex elicitation is not only not necessary for blink
      augmentation, but also diminishes it.

PMID- 12467109
TI  - Functional neuroimaging studies of category specificity in object recognition: a
      critical review and meta-analysis.
AB  - Functional neuroimaging studies in which the cortical organization for semantic
      knowledge has been addressed have revealed interesting dissociations in the
      recognition of different object categories, such as faces, natural objects, and
      manufactured objects. The present paper critically reviews these studies and
      performs a meta-analysis of stereotactic coordinates to determine whether
      category membership predicts patterns of brain activation across different
      studies. This meta-analysis revealed that, in the ventral temporal cortex,
      recognition of manufactured objects activates more medial aspects of the fusiform
      gyrus, as compared with natural object or face recognition. Face recognition
      activates more inferior aspects of the ventral temporal cortex, as compared with
      manufactured object recognition. The recognition task used--viewing, matching, or
      naming--also predicted brain activation patterns. Specifically, matching tasks
      recruit more inferior occipital regions than do either naming or viewing tasks,
      whereas naming tasks recruit more anterior ventral temporal sites than do either
      viewing or matching tasks. These findings indicate that the cognitive demands of
      a particular recognition task are as predictive of cortical activation patterns
      as is category membership.

PMID- 12467110
TI  - Interactions between frontal cortex and basal ganglia in working memory: a
      computational model.
AB  - The frontal cortex and the basal ganglia interact via a relatively well
      understood and elaborate system of interconnections. In the context of motor
      function, these interconnections can be understood as disinhibiting, or
      "releasing the brakes," on frontal motor action plans: The basal ganglia detect
      appropriate contexts for performing motor actions and enable the frontal cortex
      to execute such actions at the appropriate time. We build on this idea in the
      domain of working memory through the use of computational neural network models
      of this circuit. In our model, the frontal cortex exhibits robust active
      maintenance, whereas the basal ganglia contribute a selective, dynamic gating
      function that enables frontal memory representations to be rapidly updated in a
      task-relevant manner. We apply the model to a novel version of the continuous
      performance task that requires subroutine-like selective working memory updating
      and compare and contrast our model with other existing models and theories of
      frontal-cortex-basal-ganglia interactions.

PMID- 12467111
TI  - Dissociation of the neural systems for working memory maintenance of verbal and
      nonspatial visual information.
AB  - Working memory for names and faces was investigated to ascertain whether verbal
      and nonspatial visual information is maintained in working memory by separate
      neural systems. The subjects performed a delayed match-to-sample task for famous
      or unfamous faces and names and a sensorimotor control task. Several occipital,
      temporal, parietal, and prefrontal areas were activated during all memory delays,
      in comparison with the control delays. Greater delay activity for unfamous faces
      than for names was obtained in the right fusiform gyrus, right inferior frontal
      gyrus (IFG), right IFG/precentral gyrus, and right medial superior frontal gyrus,
      whereas greater delay activity for unfamous names than for faces was observed in
      the precuneus, left insula/postcentral gyrus, and left IFG/precentral gyrus.
      There was no significant difference in the prefrontal activity in the comparison
      between famous faces and names. Greater delay activity for famous names than for
      faces was obtained in visual association and parietal areas. The results indicate
      that there is a functional dissociation based on information type within the
      neural system that is responsible for working memory maintenance of verbal and
      nonspatial visual information.

PMID- 12467112
TI  - Posttraining androgens' enhancement of cognitive performance is temporally
      distinct from androgens' increases in affective behavior.
AB  - Steroid hormone-induced variations in spatial learning and memory tasks have been
      reported. In this study, androgens' effects in various cognitive and affective
      tasks were investigated in order to determine whether any observed differences in
      cognitive performance could be due to affective changes produced by the hormones.
      Ovariectomized rats (N = 72) received 0.0, 3.0, or 7.5 mg/kg subcutaneously, of
      testosterone (T), dihydrotestosterone (DHT), or 5 alpha-androstane-3 alpha,17
      beta-diol (3 alpha-Diol) suspended in 10% ethanol/sesame oil v/v. For the
      cognitive tasks (Y maze, inhibitory avoidance, and object recognition), subjects
      were injected after training trials. For the affective tasks (open field,
      elevated plus maze, and tailflick), subjects were injected 1 or 24 h before
      testing. Posttraining injections that produced physiological concentrations of
      androgens--T, DHT, and 3 alpha-Diol--1 h later increased the percentage of
      correct choices in the Y maze, the latencies to cross to the shock-associated
      side of the inhibitory avoidance chamber, and percentage of time exploring novel
      objects 24 h later, when androgen levels were no longer increased. Administration
      of T, DHT, and 3 alpha-Diol also increased the number of entries into the center
      squares of a brightly lit open field, open-arm time in the elevated plus maze,
      and tailflick latencies 1 but not 24 h following administration. These findings
      suggest that these androgens, when administered following training, can enhance
      cognitive performance in the tasks investigated 24 h later when androgen levels
      nadir, but overt changes in the affective behaviors examined occurred at the time
      of physiological concentrations 1 h but not 24 h following androgen
      administration. These findings suggest posttraining androgens can enhance
      consolidation and cognitive performance, independent of their anxiolytic actions.

PMID- 12467113
TI  - Face recognition and emotional valence: processing without awareness by
      neurologically intact participants does not simulate covert recognition in
      prosopagnosia.
AB  - Covert face recognition in neurologically intact participants was investigated
      with the use of very brief stimulus presentation to prevent awareness of the
      stimulus. In Experiment 1, skin conductance response (SCR) to photographs of
      celebrity and unfamiliar faces was recorded; the faces were displayed for 220
      msec and for 17 msec in a within-participants design. SCR to faces presented for
      220 msec was larger and more likely to occur with familiar faces than with
      unfamiliar faces. Face familiarity did not affect the SCR to faces presented for
      17 msec. SCR was larger for faces of good than for faces of evil celebrities
      presented for 17 msec, but valence did not affect SCR to faces displayed for 220
      msec. In Experiment 2, associative priming was found in a face familiarity
      decision task when the prime face was displayed for 220 msec, but no facilitation
      occurred when primes were presented for 17 msec. In Experiment 3, participants
      were able to differentiate evil and good faces presented without awareness in a
      two-alternative forced-choice decision. The results provide no evidence of
      familiarity detection outside awareness in normal participants and suggest that,
      contrary to previous research, very brief presentation to neurologically intact
      participants is not a useful model for the types of covert recognition found in
      prosopagnosia. However, a response based on affective valence appears to be
      available from brief presentation.

PMID- 12467114
TI  - Single-cue delay eyeblink conditioning is unrelated to awareness.
AB  - We examined the importance of awareness for eyeblink conditioning by directly
      comparing single-cue delay eyeblink conditioning and single-cue trace eyeblink
      conditioning. During single-cue delay conditioning, participants who became aware
      of the stimulus contingencies early in the conditioning session conditioned no
      better than those who became aware later in the session or did not become aware.
      Thus, the level of awareness was unrelated to the overall level of conditioning
      across the session. In contrast, awareness of the stimulus contingencies early in
      the session predicted the success of single-cue trace conditioning. These data,
      together with earlier findings, show that awareness is irrelevant to single-cue
      delay eyeblink conditioning but is critical for single-cue trace eyeblink
      conditioning. The findings from the present study are related to previous
      findings for differential (CS+ and CS-) eyeblink conditioning and awareness.

PMID- 12467115
TI  - Prolactin in rats is attenuated by conspecific touch in a novel environment.
AB  - Prolactin is released in response to physical and psychological stress, the
      latter of which involves an animal's interpretation of its environment as
      potentially dangerous. This interpretation might be altered by social buffering,
      as defined by the presence of a social partner. In support of this claim, I
      previously found that the presence of a conspecific during exposure to the open
      field caused lower levels of prolactin in juvenile rats than did exposure to the
      open field alone. Because testing with a conspecific allowed the animals to
      touch, physical contact may have been necessary for the reduction of prolactin.
      To test this hypothesis, juvenile male and female rats in the present study were
      exposed to the open field (1) alone, (2) with a conspecific separated by a
      Plexiglas partition, or (3) with a conspecific without a partition. Touch was
      necessary to reduce stress as measured by prolactin levels.

PMID- 12467116
TI  - Can enantiomorphic crystals like quartz play a role in the origin of
      homochirality on earth?
AB  - This communication reviews the possible actions of enantiomorphic crystals on the
      surface of Earth as sources of homochirality of organic compounds. The discovery
      of asymmetric adsorption and asymmetric catalysis involving optically active
      quartz crystals has led some authors to conclude that this source of asymmetry
      played an important role as a source of homochirality in nature, a concept that
      later proved erroneous. Moreover, data regarding the preponderance in nature of l
      quartz crystals have been used to confirm calculations of the parity violation
      energy difference (PVED) for l-quartz and, hence, to explain the prevalence of L
      amino acids and D-sugars in living matter. As discussed here, quartz and other
      enantiomorphs such as sodium chlorate can produce chiral intermediates active in
      autocatalytical processes. Our most recent compilation of the literature,
      however, reveals that the distribution of d- and l-quartz crystals at the surface
      of the Earth when all possible locations are included is quite random. Although
      quartz can serve as an effective asymmetric inductor in autocatalytic processes,
      it cannot be the source of homochirality of living matter because of the random
      occurrence of the two types of enantiomorphs. The calculations of PVED values for
      quartz therefore lack a sound physical basis.

PMID- 12467117
TI  - Nitrogen reduction under hydrothermal vent conditions: implications for the
      prebiotic synthesis of C-H-O-N compounds.
AB  - Dinitrogen is reduced in dilute hydrogen sulfide (H2S) solutions to ammonium at
      120 degrees C. Experiments with dissolved dinitrogen (partial pressure 50 bar) in
      a 12 x 10(-3) mol/L H2S(aq) solution yield approximately 10(-5) mol/L NH4+ within
      2-7 days. These yields are consistent with the equilibrium NH4+ concentration for
      the N-S-H system under these conditions. The formation of ammonium is catalyzed
      by the presence of freshly precipitated iron monosulfide. These results indicate
      that dinitrogen can be reduced at moderate temperatures in hydrothermal vent
      systems. Abiotic nitrogen reduction could have taken place within primordial
      hydrothermal vents, supplying some ammonia for the synthesis of C-H-O-N compounds
      via abiotic processes. The yield of ammonia via dinitrogen reduction by hydrogen
      sulfide, however, is so low that it is doubtful this process could have produced
      enough ammonia to sustain prebiotic hydrothermal synthesis of C-H-O-N compounds
      in or around vent systems.

PMID- 12467118
TI  - Assessing the plausibility of life on other worlds.
AB  - As the field of astrobiology matures and search strategies for life on other
      worlds are developed, the need to analyze in a systematic way the plausibility
      for life on other planetary systems becomes increasingly apparent. We propose the
      adoption of a simple plausibility of life (POL) rating system based on specific
      criteria. Category I applies to any body shown to have conditions essentially
      equivalent to those on Earth. Category II applies to bodies for which there is
      evidence of liquid water and sources of energy and where organic compounds have
      been detected or can reasonably be inferred (Mars, Europa). Category III applies
      to worlds where conditions are physically extreme but possibly capable of
      supporting exotic forms of life unknown on Earth (Titan, Triton). Category IV
      applies to bodies that could have seen the origin of life prior to the
      development of conditions so harsh as to make its perseverance at present
      unlikely but conceivable in isolated habitats (Venus, Io). Category V would be
      reserved for sites where conditions are so unfavorable for life by any reasonable
      definition that its origin or persistence there cannot be rated a realistic
      probability (the Sun, gas giant planets). The proposed system is intended to be
      generic. It assumes that life is based on polymeric chemistry occurring in a
      liquid medium with uptake and degradation of energy from the environment. Without
      any additional specific assumptions about the nature of life, the POL system is
      universally applicable.

PMID- 12467119
TI  - Martian water: are there extant halobacteria on Mars?
AB  - On Earth, life exists in all niches where water exists in liquid form for at
      least a portion of the year. On Mars, any liquid water would have to be a highly
      concentrated brine solution. It is likely, therefore, that any present-day
      Martian microorganisms would be similar to terrestrial halophiles. Even if
      present-day life does not exist on Mars, it is an interesting speculation that
      ancient bacteria preserved in salt deposits could be retrieved from an era when
      the climate of Mars was more conducive to life.

PMID- 12467120
TI  - Brines in seepage channels as eluants for subsurface relict biomolecules on Mars?
AB  - Water, vital for life, not only maintains the integrity of structural and
      metabolic biomolecules, it also transports them in solution or colloidal
      suspension. Any flow of water through a dormant or fossilized microbial community
      elutes molecules that are potentially recognizable as biomarkers. We hypothesize
      that the surface seepage channels emanating from crater walls and cliffs in Mars
      Orbiter Camera images results from fluvial erosion of the regolith as low
      temperature hypersaline brines. We propose that, if such flows passed through
      extensive subsurface catchments containing buried and fossilized remains of
      microbial communities from the wet Hesperian period of early Mars (approximately
      3.5 Ga ago), they would have eluted and concentrated relict biomolecules and
      delivered them to the surface. Life-supporting low-temperature hypersaline brines
      in Antarctic desert habitats provide a terrestrial analog for such a scenario. As
      in the Antarctic, salts would likely have accumulated in water-filled depressions
      on Mars by seasonal influx and evaporation. Liquid water in the Antarctic cold
      desert analogs occurs at -80 degrees C in the interstices of shallow hypersaline
      soils and at -50 degrees C in salt-saturated ponds. Similarly, hypersaline brines
      on Mars could have freezing points depressed below -50 degrees C. The presence of
      hypersaline brines on Mars would have extended the amount of time during which
      life might have evolved. Phototrophic communities are especially important for
      the search for life because the distinctive structures and longevity of their
      pigments make excellent biomarkers. The surface seepage channels are therefore
      not only of geomorphological significance, but also provide potential
      repositories for biomolecules that could be accessed by landers.

PMID- 12467121
TI  - Large, colorful, or noisy? Attribute- and modality-specific activations during
      retrieval of perceptual attribute knowledge.
AB  - Position emission tomography was used to investigate whether retrieval of
      perceptual knowledge from long-term memory activates unique cortical regions
      associated with the modality and/or attribute type retrieved. Knowledge about the
      typical color, size, and sound of common objects and animals was probed, in
      response to written words naming the objects. Relative to a nonsemantic control
      task, all the attribute judgments activated similar left temporal and frontal
      regions. Visual (color, size) knowledge selectively activated the right posterior
      inferior temporal (PIT) cortex, whereas sound judgments elicited selective
      activation in the left posterior superior temporal gyrus and the adjacent
      parietal cortex. All of the attribute judgments activated a left PIT region, but
      color retrieval generated more activation in this area. Size judgments activated
      the right medial parietal cortex. These results indicate that the retrieval of
      perceptual semantic information activates not only a general semantic network,
      but also cortical areas specialized for the modality and attribute type of the
      knowledge retrieved.

PMID- 12467122
TI  - The role of explicit memory processes in cross-modal priming: an investigation of
      stem completion priming in amnesia.
AB  - To clarify the role of explicit memory processes in cross-modal priming, two
      experiments examined the status of cross-modal stem completion priming in
      amnesia. Experiment 1 used a standard behavioral paradigm in which stems
      corresponding to studied and unstudied words were intermixed. Amnesic patients
      showed intact within- and cross-modal priming, but, in contrast to controls, they
      recognized very few of their completions as having been on the study list. This
      finding suggests that memorial awareness is not necessary for cross-modal priming
      to occur. Experiment 2 used a paradigm modeled after functional imaging studies,
      in which stems corresponding to studied and unstudied words were blocked. Amnesic
      patients showed intact within-modal priming, but impaired cross-modal priming.
      This finding is consistent with the notion that a blocked format induces
      voluntary retrieval strategies in normal participants.

PMID- 12467123
TI  - Effects of dorsal-striatum lesions and fimbria-fornix lesions on the problem
      solving strategies of rats in a shallow water maze.
AB  - In solving a spatial problem, animals can use a place, cue, or response strategy.
      The present research was designed to evaluate the role of dorsal striatum (DS) in
      spatial problem solving and to compare it with that of fimbria fornix (FF). Rats
      were trained with a place + cue task in a shallow pool, then were divided into
      three groups (DS, FF, control), and lesions were made in the corresponding areas.
      After retraining, four probe tests were given: Test 1 (start position moved),
      Test 2 (goal and start positions moved), Test 3 (invisible goal), and Test 4
      (curtain test). The test results suggest that the DS and Control groups performed
      the original task by using the place strategy, whereas the FF group used the cue
      strategy, which strongly implies that the DS group was impaired in the use of the
      cue strategy. This research also provides evidence supporting the usefulness of a
      shallow pool in evaluating animal behavior.

PMID- 12467124
TI  - An fMRI study of imagined self-rotation.
AB  - In the present study, functional magnetic resonance imaging was used to examine
      the neural mechanisms involved in the imagined spatial transformation of one's
      body. The task required subjects to update the position of one of four external
      objects from memory after they had performed an imagined self-rotation to a new
      position. Activation in the rotation condition was compared with that in a
      control condition in which subjects located the positions of objects without
      imagining a change in self-position. The results indicated similar networks of
      activation to other egocentric transformation tasks involving decisions about
      body parts. The most significant area of activation was in the left posterior
      parietal cortex. Other regions of activation common among several of the subjects
      were secondary visual, premotor, and frontal lobe regions. These results are
      discussed relative to motor and visual imagery processes as well as to the
      distinctions between the present task and other imagined egocentric
      transformation tasks.

PMID- 12467125
TI  - The role of taxonomies in the study of human memory.
AB  - The idea that memory is not unitary but is instead composed of multiple systems
      has a long history and has been debated with particular vigor in the last 20
      years. Nevertheless, whether or not there are multiple memory systems remains
      unsettled. In this article, we suggest that psychologists wishing to classify
      memory can learn from biological systematics, the discipline that creates
      taxonomies of species. In so doing, we suggest that psychologists have made two
      assumptions in classifying memory: that features of memory are perfectly
      correlated, and that there is a straightforward mapping between taxonomy and
      theory. We argue that these assumptions are likely to be incorrect, but we also
      argue that there is a place for taxonomy in the study of memory. Taxonomies of
      memory are organizational schemes for data--they are descriptive, not explanatory
      -and so can inspire theory, although they cannot serve as theories themselves.

PMID- 12467126
TI  - Visually guided facial actions in rhesus monkeys.
AB  - We trained 2 monkeys to display facial actions in response to corresponding
      arbitrary visual cues. Each monkey executed the task successfully, and each
      displayed two different facial actions corresponding to either hand-sign or color
      cues. More than 90% of the responses were correct for each monkey. These results
      provide evidence that monkeys can execute facial actions in response to
      conditioned visual cues in the absence of social context. These data suggest that
      facial actions of monkeys are flexible enough for use in further laboratory
      investigations--for example, in studies on the neural mechanisms underlying the
      execution of actions.

PMID- 12467127
TI  - The effects of lesions to the rat hippocampus or rhinal cortex on olfactory and
      spatial memory: retrograde and anterograde findings.
AB  - The role of the hippocampal system in retrograde and anterograde amnesia was
      investigated by using a novel olfactory-guided paradigm and a traditional test of
      spatial learning. In the retrograde study, rats were trained on a sequence of two
      choice olfactory discriminations in the weeks prior to receiving neurotoxic
      lesions of the hippocampus or aspiration lesions of the perirhinal-entorhinal
      cortex. Memory tests for preoperatively learned discriminations revealed no
      statistical impairment for subjects with damage to the hippocampus on a problem
      learned remote in time from surgery (i.e., 4 weeks +) or on the two recently
      learned discriminations (i.e., 1-3 weeks prior to surgery). The performance of
      subjects with perirhinal-entorhinal damage provided an important comparison for
      subjects with specific hippocampal lesions. Despite showing intact memory for the
      remotely learned problem, perirhinal-entorhinal damage resulted in numerically
      (although not significantly) weaker performance on postoperative tests of
      retention for the discriminations learned in the 3 weeks prior to surgery. In the
      anterograde portion of the study, long-term memory for newly acquired
      discriminations was spared in subjects with damage to the hippocampus, whereas
      subjects in the perirhinal-entorhinal lesion group again showed the weakest
      memory performance on these tests of 5-day retention. Postoperative water maze
      learning was uniformly impaired in subjects with damage to the hippocampus and
      perirhinal-entorhinal cortex, thus confirming the effect of these lesions and
      supporting the involvement of these brain areas in spatial processes. These
      findings further dissociate the specific involvement of the hippocampus in tasks
      of a spatial-relational nature versus nonrelational tasks, such as discrimination
      learning and recognition memory (e.g., Duva et al., 1997; Eichenbaum, 1997;
      Eichenbaum, Schoenbaum, Young, & Bunsey, 1996). Moreover, the results suggest
      that damage to the hippocampus itself does not contribute to retrograde or
      anterograde memory impairments for all types of information, whereas the data
      suggest a more important role for the perirhinal-entorhinal cortex in recognition
      memory, irrespective of modality.

PMID- 12467128
TI  - Inhibiting progesterone metabolism in the hippocampus of rats in behavioral
      estrus decreases anxiolytic behaviors and enhances exploratory and
      antinociceptive behaviors.
AB  - Blocking progesterone's metabolism to 5 alpha-pregnan-3 alpha-ol-20-one (3
      alpha,5 alpha-THP) with finasteride, a 5 alpha-reductase inhibitor, and effects
      on anxiolytic, exploratory, and antinociceptive behaviors of rats in behavioral
      estrus were examined. Rats in behavioral estrus received finasteride systemically
      (SC), to the hippocampus, or to control implant sites, the nucleus accumbens (NA)
      or ventral tegmental area (VTA), and were tested in horizontal crossing, open
      field, elevated plus-maze, emergence, holeboard, social interaction, tailflick,
      pawlick, and defensive freezing tasks. Finasteride, SC or intrahippocampally,
      reduced 3 alpha,5 alpha-THP in the hippocampus relative to vehicle implants or
      finasteride to the NA or VTA. Systemic or intrahippocampal finasteride decreased
      central entries in the open field and open-arm time on the elevated plus-maze and
      increased freezing in response to shock relative to vehicle. Finasteride to the
      hippocampus decreased emergence latencies and increased social interaction,
      pawlick, and tailflick latencies relative to all other groups. Finasteride to the
      hippocampus of rats in behavioral estrous decreased anxiolysis and enhanced
      exploration and analgesia. In summary, these data demonstrate that decreases in
      anxiolytic behavior of behavioral estrous rats can be produced by reductions in 3
      alpha,5 alpha-THP in the hippocampus, which suggest that elevations in 3 alpha,5
      alpha-THP in the hippocampus may give rise to anxiolysis seen during behavioral
      estrus.

PMID- 12467129
TI  - Effect of lateralized gaps in noise on the cutaneous blink reflex in humans.
AB  - The early (R1) and late (R2) components of the cutaneous blink reflex in right
      handed humans were recorded in three experiments to examine the lateral symmetry
      of a simple excitatory process in their brainstem pathways and of the control of
      the excitability of the pathways by gaps in acoustic noise. Experiment 1 showed
      that a stimulus below R1-elicitation threshold increased the excitability of the
      right R1 pathway more than the left but that the rate of decay was similar on
      both sides. Experiment 2 showed that a brief unilateral gap in noise affected the
      R1 and R2 reflex pathways bilaterally. Experiment 3 showed that R2 varied with
      gap duration and that gaps to the left and right ears had indistinguishable
      effects. The finer temporal resolution of events in the right sensory field of
      right-handers seen in psychophysical judgments is not seen in the descending
      control of brainstem excitability.

PMID- 12467131
TI  - Types of dietary fat and soy minimally affect hormones and biomarkers associated
      with breast cancer risk in premenopausal women.
AB  - Fourteen premenopausal women participated in a randomized, crossover controlled
      feeding study of three diets, each two menstrual cycles long. We compared a high
      saturated fat Western diet (control diet) with two other diets: the control diet
      plus soy protein (soy diet) and the control diet with polyunsaturated fat (PUFA
      diet) replacing most of the saturated fat. We measured reproductive and serum
      hormones, urinary estrogen metabolites and isoflavonoids, and menstrual cycle
      length. In the follicular phase, prolactin concentrations significantly decreased
      by 3.6 micrograms/dl (P = 0.047), follicle-stimulating hormone concentrations
      slightly increased by 0.1 IU/l (P = 0.076), and cortisol concentrations slightly
      decreased by 81.8 nmol/l (P = 0.088) with the PUFA diet vs. the control diet. The
      soy diet slightly increased menstrual cycle length by 1.8 +/- 0.7 days (P =
      0.088) and significantly increased (P < 0.0001) urinary isoflavonoid excretion.
      These well-controlled diets did not affect serum estrogens or urinary estrogen
      metabolites, suggesting that type of fat or consumption of soy with a high
      saturated fat diet may not alter breast cancer risk by these mechanisms.

PMID- 12467132
TI  - Calcium or resistant starch does not affect colonic epithelial cell proliferation
      throughout the colon in adenoma patients: a randomized controlled trial.
AB  - Patients with a history of sporadic adenomas have increased epithelial cell
      proliferative activity, an intermediate risk marker for colorectal cancer.
      Reduction of proliferation by dietary intervention may reflect a decreased
      colorectal cancer risk. To evaluate whether calcium or resistant starch could
      reduce proliferative activity throughout the colon, we performed a randomized
      controlled trial in 111 sporadic adenoma patients. Patients received two
      placebos, 1 g of calcium + placebo, or 30 g of amylomaize (19 g of resistant
      starch) + placebo. After 2 mo, biopsies were collected from the cecum, transverse
      and sigmoid colon, and rectum during colonoscopy. Epithelial cell proliferation
      was determined by dividing the number of 5-bromo-2-deoxyuridine-labeled nuclei by
      the total number of nuclei x 100 (labeling index, LI). LI of luminal, mid, and
      basal compartments was determined. Twenty-five patients dropped out. In the
      remaining 86 patients (28 treated with placebo, 30 with calcium + placebo, and 28
      with resistant starch + placebo), no difference was observed in total LI, the LI
      of the three compartments, or the crypt length in the four areas of the
      colorectum. Colonic epithelial cell proliferative activity throughout the colon
      of sporadic adenoma patients is not affected by supplementation with 1 g of
      calcium or 19 g of resistant starch.

PMID- 12467133
TI  - Dietary calcium and vitamin D intake and risk of colorectal cancer: a prospective
      cohort study in women.
AB  - Although laboratory data and a few adenoma prevention trials suggest that calcium
      supplementation may reduce the risk of colorectal neoplasia, the results of
      observational studies of calcium intake and colorectal cancer risk are
      contradictory. However, few studies have examined the association among women or
      effects in specific colon subsites. Women with colorectal cancer diagnosed
      through 31 December 2000 were identified by linkage to regional cancer
      registries. During an average 11.3 yr of follow-up of 61,463 women, we observed
      572 incident cases of colorectal cancer. Using data obtained from a 67-item food
      frequency questionnaire and Cox proportional hazards models to estimate rate
      ratios and 95% confidence intervals, we found an inverse association between
      dietary calcium intake and colorectal cancer risk. Women with the highest calcium
      intake (median 914 mg/day) had a reduced risk of colorectal cancer (rate ratio =
      0.72, 95% confidence interval = 0.056-0.93, P for trend = 0.02) compared with
      women with the lowest intake (median 486 mg/day). Furthermore, our results
      suggest that the inverse association may be strongest in relation to distal
      cancers and among older women. The association with dairy products was less
      clear, suggesting that calcium intake per se is more important than specific
      calcium sources. Vitamin D intake was not clearly associated with risk. In sum,
      our data suggest that high calcium intake may lower colorectal cancer risk.

PMID- 12467134
TI  - A population-based case-control study on fruit and vegetable intake and lung
      cancer: a paradox effect?
AB  - A population-based case-control study was carried out in Northwest Spain to
      analyze the effect of fruit and vegetable intake on the appearance of lung
      cancer. A non-significant protective association was found for overall
      consumption of leafy green and other vegetables, with consumption once a day or
      more vs. less than once a week yielding odds ratios of 0.63 [95% confidence
      interval (CI) = 0.24-1.63] for leafy green vegetables and 0.64 (95% CI = 0.30
      1.36) for other vegetables. A significant protective association was found for
      potato consumption. No protective associations were recorded for fruit, whether
      overall or singly; instead, fruit consumption once a day or more vs. less than
      once a week registered a risk of 2.16 (95% CI = 1.02-4.58). Although the
      possibility that this effect may be due to a phenomenon of reverse causation
      cannot be ruled out, these results could support other reports and hypotheses
      which indicate that the protective effect of fruit might not be as pronounced as
      generally thought.

PMID- 12467130
TI  - Most effective colon cancer chemopreventive agents in rats: a systematic review
      of aberrant crypt foci and tumor data, ranked by potency.
AB  - Potential chemopreventive agents for colorectal cancer are assessed in rodents.
      We speculated that the magnitude of the effect is meaningful and ranked all
      published agents according to their potency. Data were gathered systematically
      from 137 articles with the aberrant crypt foci (ACF) end point and from 146
      articles with the tumor end point. The potency of each agent to reduce the number
      of ACF is listed in one table and the potency of each agent to reduce the tumor
      incidence in another table. Both tables are shown in this review and on a website
      with sorting abilities (http://www.inra.fr/reseau-nacre/sci
      memb/corpet/indexan.html). Potency was estimated as the ratio of the value in
      control rats to the value in treated rats. From each article, only the most
      potent agent was kept, except in articles reporting the effect of more than seven
      agents. Among the 186 agents in the ACF table, the median agent reduced the
      number of ACF by one-half. The most potent agents to reduce azoxymethane-induced
      ACF were Pluronic, polyethylene glycol, perilla oil with beta-carotene, and
      sulindac sulfide. Among the 160 agents in the tumor table, the median agent
      reduced the tumor incidence in rats by one-half. The most potent agents to reduce
      the incidence of azoxymethane-induced tumors were celecoxib, a protease inhibitor
      from soy, difluoromethylornithine with piroxicam, polyethylene glycol, and a
      thiosulfonate. For the 57 agents present in both tables, a significant
      correlation (r) was found between the potencies against ACF and tumors (r = 0.45,
      P < 0.001); without celecoxib, a major outlying point in the correlation, r =
      0.68 (P < 0.001, n = 56). In conclusion, this review gathers most known
      chemopreventive agents, ranks the most promising agents against colon
      carcinogenesis in rats or mice, and further supports the use of ACF as a
      surrogate end point for tumors in rats.

PMID- 12467135
TI  - Conjugated linoleic acid isomers and mammary cancer prevention.
AB  - There is increasing evidence that individual isomers of conjugated linoleic acid
      (CLA) may have unique biological or biochemical effects. A primary objective of
      this study was to determine whether there might be differences in the anticancer
      activity of 9,11-CLA and 10,12-CLA. This was achieved by evaluating the reduction
      in premalignant lesions and carcinomas in the mammary gland of rats that had been
      treated with a single dose of methylnitrosourea and given 0.5% of either highly
      purified CLA isomer in the diet. Our results showed that the anticancer
      efficacies of the two isomers were very similar. At 6 wk after carcinogen
      administration, the total number of premalignant lesions was reduced by 33-36%.
      At 24 wk, the total number of mammary carcinomas was reduced by 35-40%. The
      concentration of each CLA isomer and its respective metabolites was analyzed in
      the mammary fat pad. Tissue level of 10,12-CLA was much lower than that of 9,11
      CLA. The pool of metabolites from each isomer was very similar between the two
      groups and represented only a small fraction of total conjugated diene fatty
      acids. Feeding of 9,11-CLA resulted in minimal changes in other unsaturated fatty
      acids. In contrast, feeding of 10,12-CLA produced a wider spectrum of
      perturbations. Small but significant increases in 16:1 and 16:2 were detected;
      these were accompanied by decreases in 20:2, 20:3, 20:4, 22:4, and 22:6. The
      above observation suggests that 10,12-CLA might be more potent than 9,11-CLA in
      interfering with elongation and desaturation of linoleic and linolenic acids. In
      summary, our study showed that, at the 0.5% dose level, the anticancer activity
      of 9,11-CLA and 10,12-CLA was very similar, even though accumulation of 10,12-CLA
      in the mammary tissue was considerably less than that of 9,11-CLA. These
      confounding changes of the other unsaturated fatty acids in contributing to the
      effect of 10,12-CLA need to be clarified.

PMID- 12467136
TI  - Timing of supplementation with the antioxidant N-acetyl-L-cysteine reduces tumor
      multiplicity in novel, cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras)
      transgenic mice but has no impact on malignant progression.
AB  - Epidemiological studies support the protective role of dietary antioxidants in
      preventing cancer. However, emerging evidence suggests that antioxidant
      supplements may actually exacerbate carcinogenesis. We explored this paradox in a
      model containing two common genotypic characteristics of human cancers. We
      selected p53 haploinsufficient Tg.AC (v-Ha-ras) mice as a model, because it
      contains an activated, carcinogen-inducible ras oncogene and an inactivated p53
      tumor suppressor gene. These mice develop chemically induced benign and malignant
      skin tumors rapidly. Mice were fed basal diet with or without 3% N-acetyl-L
      cysteine (NAC) before and after topical application of the carcinogen
      benzo[a]pyrene (64 micrograms twice per week for 7 wk) until 50% of mice within a
      group displayed at least one lesion. Half each of mice fed the basal and the NAC
      supplemented diet were then switched to the alternate diet. Mice fed the NAC
      supplemented diet or switched from the NAC-supplemented to the basal diet
      displayed 38% and 26% reductions, respectively, in tumor multiplicity and a 15%
      reduction if switched from the basal to the NAC-supplemented diet. Although
      latency was unaffected, NAC induced a lag in tumor incidence, which exceeded 90%
      at 10 wk for all groups. The timing of NAC supplementation did not affect
      malignant progression. Thus dietary NAC was chemoprotective by slowing
      tumorigenesis but did not affect malignant conversion.

PMID- 12467137
TI  - Effects of body weight gain reduction resulting from chemopreventive agent
      treatment on mammary gland morphology.
AB  - Moderate reductions (< or = 15%) in body weight gain, similar to those observed
      after administration of some chemopreventive agents in chemically induced mammary
      cancer models, will result in decreased mammary cancers (up to 55%). The
      objective of this study was to determine whether changes in mammary gland
      differentiation, proliferation, apoptosis, and estradiol and progesterone levels
      are affected by moderate reductions in body weight induced after chemopreventive
      agent treatment and dietary restriction. The body weights of female Sprague
      Dawley rats were reduced by dietary restrictions to match those of rats receiving
      4-hydroxyphenylretinamide (4-HPR) at a dose known to inhibit methylnitrosourea
      (MNU)-induced mammary cancers. 4-HPR supplementation or dietary restrictions
      began 1 wk before MNU administration at 50 days of age. Mammary gland
      differentiation, proliferation, apoptosis, and serum levels of estradiol and
      progesterone were measured at 50, 57, and 71 days of age. Casein expression,
      proliferating cellular nuclear antigen expression, and apoptosis were not
      significantly different from controls in the dietary-restricted group.
      Proliferating cellular nuclear antigen expression was significantly lower in 4
      HPR-treated animals than in controls at 57 days of age. The diameter of the
      mammary gland ducts was smaller at 71 days of age in the treatment groups. A
      decrease in estradiol levels for each group was observed at 50 days of age, but
      not at later time points. Progesterone levels were reduced in the 4-HPR group,
      but not in the dietary-restricted group, during each time period. It would appear
      that the observed decrease in mammary cancers observed with moderate reductions
      in body weight gain might be due to multiple related factors different from those
      related to 4-HPR treatment.

PMID- 12467138
TI  - Antineoplastic activity of Solidago virgaurea on prostatic tumor cells in an SCID
      mouse model.
AB  - Solidago virgaurea (goldenrod) has traditionally been used as an anti
      inflammatory herbal medicine for the treatment of various symptoms, including
      prostatic diseases. The plant has also been reported to have antibacterial,
      spasmolytic, and carminative properties. During the course of our screening for
      antineoplastic activities in various herbal plants, we found that the extract of
      S. virgaurea exhibits strong cytotoxic activities on various tumor cell lines.
      The active component mostly resides in the leaves of the plant and is soluble in
      water. When the extract was fractionated by a Sephadex G-100 column, the active
      fraction corresponded to a molecular weight of approximately 40,000. This
      cytotoxic activity is effective on various tumor cell lines, including human
      prostate (PC3), breast (MDA435), melanoma (C8161), and small cell lung carcinoma
      (H520). To examine the effect of the cytotoxic activity on tumor cells in vivo,
      we used the rat prostate cell line (AT6.1) and an SCID mouse model. AT6.1 cells
      were injected into the flank of SCID mice, and then the G-100 fraction of S.
      virgaurea was administered intraperitoneally or subcutaneously every 3 days. The
      size of the tumor was measured for up to 25 days. The growth of the tumor was
      significantly suppressed by the G-100 fraction at 5 mg/kg without any apparent
      side effects. Therefore, S. virgaurea is considered to be promising as an
      antineoplastic medicine with minimal toxicities.

PMID- 12467139
TI  - Induction of tumor necrosis factor production and antitumor effect by cabbage
      extract.
AB  - The effect of cabbage extract on the production of tumor necrosis factor and its
      implication in the antitumor effect were examined in vitro and in vivo. Cabbage
      extract stimulated the production of tumor necrosis factor by rat spleen cells
      and showed cytotoxic activity in a rat ascites hepatoma cell line (AH109A) when
      hepatoma cells were cultured with cabbage-stimulated spleen cells. When the
      extract was adminstered orally to AH109A-bearing rats in combination with
      lipopolysaccharide injection, the hepatoma weights were reduced to one-half of
      the vehicle control. The cytotoxic activity of tumor-infiltrating macrophages was
      induced by simultaneous treatment with cabbage extract and lipopolysaccharide.
      These results indicate that cabbage extract contains macrophage-stimulating
      component(s) and can implement the antitumor effect by stimulating the
      cytotoxicity of tumor-infiltrating macrophages.

PMID- 12467140
TI  - Induction of histone acetylation and inhibition of growth of mouse
      erythroleukemia cells by S-allylmercaptocysteine.
AB  - Growth-inhibitory effects on DS19 mouse erythroleukemia cells were seen in the
      micromolar concentration range with allicin and S-allylmercaptocysteine and in
      the millimolar range with allyl butyrate, allyl phenyl sulfone, and S-allyl
      cysteine. Increased acetylation of histones was induced by incubation of cells
      with the allyl compounds at concentrations similar to those that resulted in the
      inhibition of cell proliferation. The induction of histone acetylation by S
      allylmercaptocysteine was also observed in Caco-2 human colon cancer cells and
      T47D human breast cancer cells. In contrast to the effect on histone acetylation,
      there was a decrease in the incorporation of phosphate into histones when DS19
      cells were incubated with 25 microM S-allylmercaptocysteine. Histone deacetylase
      activity was inhibited by allyl butyrate, but there was little or no effect with
      the allyl sulfur compounds examined in this study. A similar degree of
      downregulation of histone deacetylase and histone acetyltransferase was observed
      when DS19 cells were incubated with S-allylmercaptocysteine or allyl
      isothiocyanate. The induction of histone acetylation by S-allylmercaptocysteine
      was not blocked by a proteasome inhibitor. The mechanism by which S
      allylmercaptocysteine induces histone acetylation remains to be characterized. It
      may be related in part to metabolism to allyl mercaptan, which is a more
      effective inhibitor of histone deacetylase.

PMID- 12467141
TI  - Mutagenicity of food-derived carcinogens and the effect of antioxidant vitamins.
AB  - The food-derived heterocyclic amines (HCAs) 2-amino-3-methylimidazo[4,5
      f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8
      dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine (PhIP) are mutagenic in the Ames test and produce
      tumors in laboratory animals, including monkeys. These HCAs have also been shown
      to induce gene mutations in vivo. To assess the antimutagenic effects of dietary
      antioxidant vitamins, beta-carotene, ascorbic acid (vitamin C), and alpha
      tocopherol (vitamin E), on food-borne mutagenes/carcinogens, we evaluated the
      mutagenic activity of the compounds alone or combined with antioxidant vitamins.
      We utilized the rat lymphocyte mutation assay at the hypoxanthine guanine
      phosphoribosyl transferase (Hprt) locus. Female Fischer 344 rats treated with
      different doses (0, 2.5, 5.0, 25.0, and 50.0 mg/kg) of the carcinogens were
      sacrificed 5 wk after mutagen treatment. Although IQ and MeIQ slightly increased
      mutation frequency (MF) at some doses, a significant (P < 0.0009) increase in MF
      was found in animals exposed to MeIQx at 25 mg/kg. PhIP was the most mutagenic of
      the HCAs, with increases (P < 0.0001) in MF detected at all dose levels compared
      with controls. Because PhIP was the most mutagenic, it was selected for studies
      using the dietary antioxidant vitamins. Addition of antioxidant vitamins, singly
      or in a mixture, caused a significant (P < 0.0001) decrease in PhIP-induced Hprt
      MF. Vitamin E was the most effective at decreasing Hprt MF. In addition, we
      determined whether carcinogen metabolism would be affected by ingestion of
      vitamins. The activities of endogenous detoxification enzymes, glutathione S
      transferase and glutathione peroxidase (GPx), were thus examined. Intake of beta
      carotene and vitamin C without the carcinogen resulted in an increase (P < 0.05)
      in GPx activity. Also a modest increase in GPx activity was seen in animals that
      received the antioxidant mixture alone. Although the mechanisms of action of the
      antioxidants remain to be determined, the results indicate that dietary-derived
      HCA treatment induced MF in rat lymphocytes and suggest that antioxidants in food
      or taken as supplements could, in part, counteract such mutagenic activities.

PMID- 12467142
TI  - Mutagenicity of tocopheryl quinones: evolutionary advantage of selective
      accumulation of dietary alpha-tocopherol.
AB  - We have shown that phenolic antioxidant tocopherols are oxidized to nonarylating
      alpha-tocopheryl quinone (alpha-TQ) and arylating gamma- and delta-TQ
      electrophiles. The arylating quinones stimulate apoptosis and are highly
      cytotoxic in mammalian cells. Some xenobiotic phenolic antioxidants are mutagens,
      and it has been suggested that their arylating quinone metabolites are the active
      agents in mutagenesis related to carcinogenesis. We found that neither alpha- nor
      gamma-TQ was directly genotoxic in supercoiled-to-nicked circular DNA
      conversions, but these agents interacted with the cytomegalovirus reporter-driven
      plasmid and enhanced luciferase transfection, with gamma-TQ > alpha-TQ. The Ames
      test, using gamma-TQ and a number of Salmonella strains, showed no evidence of
      bacterial mutagenesis. gamma-TQ was highly cytotoxic and alpha-TQ slightly
      cytotoxic in eukaryocyte AS52 cells. A guanosine phosphoribosyltransferase gene
      assay showed that gamma-TQ was highly mutagenic and alpha-TQ slightly mutagenic
      in AS52 cells. A review of the literature identified associations where a
      decrease in dietary gamma-tocopherol (gamma-T) diminishes and an increase in
      dietary gamma-T and its quinone enhances carcinogenicity. Humans and other
      omnivores selectively accumulate alpha-tocopherol, even though gamma-T is their
      principal dietary tocopherol. We suggest that this selectivity confers an
      evolutionary advantage by limiting tissue gamma-T, a putative precursor of the
      mutagen gamma-TQ.

PMID- 12467143
TI  - To computerize or not to computerize the patient care record: that is the
      question.
AB  - The advantages and disadvantages of the Computerized Patient Record (CPR) with
      respect to the conventional paper medical record are discussed. The eight
      elements of an ideal CPR are described: (1) ability to directly capture data from
      all patient care sources in a variety of formats, (2) ability to assimilate and
      present data rapidly in a flexible and integrated fashion in all areas of the
      institution where patient care is provided and chart review or abstraction is
      done, (3) making patient safety features an intrinsic part of the CPR, (4)
      portability of the record, (5) appropriate privacy and security safeguards that
      do not restrict patient care, (6) ability to rapidly extract data for tasks that
      are not direct patient care activities, (7) sensible algorithms to determine what
      data need to become a permanent part of the CPR, and (8) the system must have
      exceedingly high reliability. The author concludes that improvements in patient
      care will be accomplished through the use of a CPR and, consequently, this
      technology will become the norm for the inpatient medical record within the next
      decade.

PMID- 12467144
TI  - The social impact of medicine. Chapter 1.
AB  - This paper, an overview of medical history, is based on a course I taught at the
      University of Delaware's Academy of Life Long Learning, "Medicine, the Old and
      the New." It will not be a chronology of medical events and discoveries, but a
      discussion of the social aspects of medicine, how medicine affected the everyday
      lives of people, from the religion-based medicine of antiquity to the super
      scientific medicine of today. It will consist of 25 chapters. Dr. Peter V. Rocca,
      Editor-in-Chief of the Delaware Medical Journal (DMJ), is planning to publish one
      chapter in each successive issue of the DMJ.

PMID- 12467145
TI  - The Board of Medical Practice.

PMID- 12467146
TI  - The autopsy as an outcome and performance measure.

PMID- 12467147
TI  - [Biomedical research and conflicts of interest].
AB  - "PLURAL" RESEARCH: Research is no longer an individual activity but is now
      "plural" and therefore induces conflicts of interests. Using conflicts of
      interests as an analytical grid, as such, allows to shrug off value judgements.
      Good and evil are no more at stake and interests enlightened the actions of the
      various parties. SOME EXAMPLES: The patient versus patients leading to the
      paradigmatic case of sacrifice. Is it allowed to sacrifice one human being on
      purpose to increase the benefit of many? Researcher (the agent of science) versus
      physician (the agent of the patient). Patients versus patients (struggle for
      funding). Manufacturers versus researchers. The simplifying view of "big
      investors" versus "immaculate research" is superimposed on the metaphor of
      Goliath versus David. HYPOTHESIS: Truly the point here argued is that it is not
      an ethical and individual concern but an organizational issue. The key question
      is: therefore what kind of rule, what kind of organization should lead to
      increase efficacy and to reduce tension among the parties involved?

PMID- 12467148
TI  - [Waiting time and satisfaction of patients attending the emergency surgery unit
      of a university hospital center].
AB  - OBJECTIVE: The emergency department of a university hospital centre receives
      40,000 patients per year. A study was conducted in its surgical unit to assess
      the existing dysfunctions and to develop corrective measures. METHOD: The method
      used was that of a prospective survey, based on two questionnaires: one on the
      waiting time, provided by each patient and by the different participants and one
      distributed to the consultants to measure their satisfaction with regard to the
      services rendered. The data were analysed using multivariate methods. RESULTS:
      The questionnaire "waiting time" was completed for 812 patients. The median time
      spent in the emergency department was of 100 minutes, 47% of patients saw a
      physician less than 15 minutes after their arrival. The median medical time was
      of 45 minutes. The prescription of supplementary examinations significantly
      increased the time spent in the department (p < 0.01). Two hundred and twenty
      persons completed the "perception" questionnaire. Forty percent of patients
      considered that they had to wait too long, the time spent waiting for a medical
      examination was too long for 27.7%; 62.5% of the consultants were not informed of
      the foreseeable waiting time and the reasons for this delay. The participants
      were well cared for in 95.4% of cases, and well informed on the possible
      evolution of their lesions (88.4% of cases). The recommendations on leaving the
      department were clearly explained for 93.7%, 98.6% of the persons interviewed had
      been received kindly and 96.5% would return to the department if they needed to.
      CONCLUSION: This study revealed the insufficient information provided on the
      waiting time and the reasons for this delay. The availability of a nurse to
      welcome and assist the patients would improve these parameters. Posters should be
      displayed with information on the foreseeable waiting time. During a meeting to
      present the results of this study, all the staff were made aware of this problem.

PMID- 12467149
TI  - ["The 5 words": a simple and sensitive test for the diagnosis of Alzheimer's
      disease].
AB  - OBJECTIVE: Alzheimer's disease (AD) is under-diagnosed in France. Today only an
      estimated 50% of patients are identified. Diagnosis of AD is particularly
      difficult because the amnesic syndrome, characteristic of the disease, is often
      confused with memory dysfunction that is frequent during the process of aging.
      The improvement in the diagnostic conditions of AD relies on the availability of
      a simple and reliable tool for screening memory disorders of organic origin.
      METHOD: The 5-word test studies the recall of a short list, which the physician
      ensures the patient has registered. Its construction permits the identification
      of patients exhibiting objective memory disorders. A validation study has been
      conducted in 86 patients suffering from AD and 126 persons complaining of
      functional memory disorders. RESULTS: The study has shown the sensitivity (91%)
      and specificity (87%) of the 5-word test in identifying patients with AD.
      CONCLUSION: This is a rapid (2 minutes) and simple test that is easy to use in
      medical practice for the screening of AD.

PMID- 12467150
TI  - [Necrotic eosinophilic angiitis with ileal perforation and peritonitis secondary
      to abdominal angiostrongyliasis].
AB  - INTRODUCTION: Abdominal angiostrongyliasis caused by the filiform nematode
      Angiostrongylus costaricensis, is an endemic disease in Central and South
      America. A case of necrotic eosinophilic angeitis with ileum perforation and
      peritonitis due to abdominal angiostrongyliasis is reported. OBSERVATION: A 32
      year-old man, living in a Paris suburb, underwent segmentary resection of the
      ileum with end to end anastomosis for perforation with generalized peritonitis.
      The anatomopathological examination revealed eosinophilic necrotic lesions with
      thrombosis on the borders of the ileum perforation. The discovery of a section of
      A. costaricensis in the lumen of a nearby muscular artery initiated an
      epidemiological survey, revealing that the patient had visited French Guyana 2
      months earlier. DISCUSSION: Angiostrongylus costaricensis is a nematode
      parisiting certain forest rodents that become its permanent host. The
      intermediate hosts are earth molluscs or slugs of the same family. Humans are
      accidentally infected following ingestion of vegetables infested with L3 larvae
      or slugs carrying the disease. The clinical symptomatology is unspecific:
      prolonged fever, anorexia, and right iliac fossa pain with eosinophilia of the
      blood. Often benign, the progression of abdominal angiostrongylosis is punctuated
      by complications: occlusive syndrome, generalised peritonitis due to intestinal
      perforation and mass syndrome. Hemorrhage, infarct, pseudo-tumoural fibrosis and
      ulcers represent the surgical or macroscopic rearrangements. In the tissue, 4
      lesions characterize abdominal angiostrongylosis: eosinophilic necrotic angeitis,
      foreign body granulomas, eosinophilia in the digestive wall, and the presence of
      A. costaricensis in the lumen of the vessels. There is presently no medical
      treatment and surgery is the only therapeutic option.

PMID- 12467151
TI  - [A psychiatric form of dengue after a visit to Djibouti].

PMID- 12467152
TI  - [Adult ascaris in the intrahepatic bile ducts].

PMID- 12467153
TI  - [Cushing's syndrome during pregnancy].
AB  - The rare association of Cushing's syndrome and pregnancy is explained by the
      amenorrhea and sterility inherent to the syndrome. In the literature, 125 cases
      have been reported: 30 cases of early diagnosis and 95 others diagnosed in the
      second half of pregnancy. AT THE START OF PREGNANCY: When hypercorticism exists
      before pregnancy it is hardly secretory. Its diagnosis, at an early stage, is not
      hindered by the hormone modifications of pregnancy. Its aetiological treatment
      raises the problem of the compatibility in pursuing the latter. IN THE SECOND
      HALF OF PREGNANCY: The positive and aetiological diagnoses of Cushing's syndrome
      are difficult and its prevalence may therefore be underestimated. The evocative
      clinical signs are unspecific: excessive weight gain, hypertension of pregnancy
      and gestational diabetes. The 24-hour free hypercortisoluria and the absence of
      dexamethasone inhibition are of little diagnostic value after the 14th week of
      amenorrhea. The positive diagnosis therefore relies essentially on the abolition
      of the circadian rhythm of cortisol. The biological hyperandrogenia commonly
      observed is not discriminating. Adrenal aetiologies are frequent. Imaging must be
      performed to eliminate an adrenocortical tumor. PROGNOSIS: The maternal prognosis
      depends on the hypertension, preeclampsia, diabetes and the complications of
      Cushing's syndrome. It depends on the activity of the hypercorticism and its
      early aetiological treatment, which must not be delayed after pregnancy. The
      foetal prognosis depends on the maternal prognosis. It is represented by preterm
      delivery, hypotrophy and death of the foetus in utero. The therapeutic management
      must be symptomatic and aetiologic, maternal and obstetrical.

PMID- 12467154
TI  - [The effect of angiotensin-converting enzyme inhibitors on the progression of
      chronic renal failure].
AB  - SEVERAL MECHANISMS: The progression in renal failure first implies hemodynamic
      mechanisms and among which angiotensin II has a central role, but also an
      increase in proteinuria and the induction of many inflammatory and mitogenic
      mediators that enhance fibrosis (TGF-beta), an effect stimulating the thrombotic
      mechanism. Among these factors of progression in renal failure, hypertension and
      proteinuria are the two major factors. Proteinuria is "nephrotoxic" and leads to
      glomerular and tubulo-interstitial lesions. THE ROLE OF ANGIOTENSIN-CONVERTING
      ENZYME INHIBITORS: Angiotensin-converting enzyme inhibitors (ACE) affect the
      different mechanisms that lead to glomerulosclerosis: antihypertensive effect,
      with the normalisation of blood pressure having demonstrated its determining role
      in the production of nephrosis in various epidemiological studies; hemodynamic
      effect with a decrease in glomerular capillary pressure, in the filtration
      fraction, and inhibition of the bradykinin deterioration; antiproteinuric effect
      superior to that of other anti-hypertensive drugs (excepting angiotensin II
      receptor antagonists). Two indications ACE inhibitors have demonstrated their
      efficacy in slowing the progression of renal failure in two large pathological
      fields: diabetic nephropathy in which this effect is demonstrated in type I
      diabetes, although the results are not as obvious in type II diabetes in which
      the nephropathy is multi-factor. The recent French and American recommendations
      are that ACE inhibitors should be used in first intention in diabetic
      nephropathies and aimed at tight blood pressure control; non-diabetic
      nephropathies Two pivotal studies have demonstrated the efficacy of ACE
      inhibitors in nephropathies whatever their type. These data have led to propose
      ACE inhibitors in first intention in patients exhibiting chronic nephropathies,
      whether hypertensive or not THE COMBINATION WITH OTHER HYPERTENSIVE DRUGS:
      Calcium channel blockers have a beneficial trophic effect in renoprotection and
      can be combined with ACE inhibitors, particularly in the case of diabetic
      nephropathies. ACE inhibitors and angiotensin II-receptor antagonists have
      comparable effect on hemodynamics and glomerulosclerosis factors. Clinically, the
      decrease in proteinuria is identical. Endothelin antagonists have also been
      studied in renoprotection and appear to have a beneficial effect when combined
      with ACE inhibitors. GLOBALLY: ACE inhibitors remain the only treatment with
      demonstrated long-term efficacy in the progression of chronic renal failure.
      However, the concept of renoprotection needs to be widened to all the factors
      implied in the progression of chronic renal failure, and ACE inhibitors only
      represent one aspect of treatment. The role of angiotensin II-receptor
      antagonists, alone or combined, is clearly promising.

PMID- 12467155
TI  - [Evolution of Escherichia coli resistance to antibiotics (interview by Delphine
      Bonfils)].

PMID- 12467156
TI  - [Fever, large eyes and confusion; the anticholinergic syndrome].
AB  - A 52-year-old woman was in a confused state and had difficulty walking and
      swallowing, as well as dysarthria. That same day she had consumed some berries,
      which she thought were bilberries, but she had instead eaten Atropa belladonna
      (deadly nightshade). She made a spontaneous and full recovery within a few days.
      A 3-year-old boy, with amblyopia, was vomiting, had difficulty walking and had a
      temperature of 39 degrees C. He was agitated and had a warm, red skin and dilated
      pupils that did not respond to light. A suspected intoxication with a
      parasympathicolytic agent was confirmed upon an empty bottle of atropine eye
      drops being found at his home. The boy made a full recovery following treatment
      with physostigmine. It is important to consider an anticholinergenic intoxication
      in the case of patients who are confused, have difficulty speaking, large fixed
      pupils and fever. A specific anamnesis with respect to medicines, eye drops and
      berries or plants consumed can confirm the diagnosis. It is important to
      recognise an anticholinergic intoxication because without treatment, the outcome
      can be fatal.

PMID- 12467157
TI  - [The Dutch College of General Practitioners' practice guideline, "Vaginal
      bleeding"; reaction from a general practice perspective].
AB  - The most important changes in the first revised version of the Dutch College of
      General Practitioners' practice guideline 'Vaginal bleeding' are the passages
      about the progesterone-containing 'intra-uterine device' (IUD), the combination
      of progesterone and oestrogen by prescribing, for example, a sub-50-pill for the
      treatment of menorrhagia, and advising the patient to undergo a transvaginal
      ultrasound to determine the amount of build-up in the endometrium. Vacuum
      aspiration of the endometrium to establish the cause of menorrhagia is not
      mentioned. This first revised version can contribute to the quality of care in
      general practice.

PMID- 12467158
TI  - [The Dutch College of General Practitioners' practice guideline, "Vaginal
      bleeding"; reaction from a gynaecological perspective].
AB  - The Dutch College of General Practitioners' practice guideline 'Vaginal bleeding'
      is a useful instrument for general practitioners. The changes in the present
      version are based on recent developments in diagnostic and therapeutic
      possibilities, such as (hydro-)ultrasonography to diagnose intracavitary
      abnormalities, progesterone-containing 'intra-uterine devices' (IUDs) and
      endoscopic techniques for destroying the endometrium. The recommendation to
      prescribe cyclical progestogens in the case of hypermenorrhoea is not supported
      by randomised studies. On balance, this guideline provides clear and useful
      advice for the treatment of abnormal vaginal blood loss.

PMID- 12467159
TI  - [Summary of the standard "Vaginal bleeding" (first revision) of the Dutch College
      of General Practitioners].
AB  - In the first revised version of the Dutch College of General Practitioners'
      practice guideline 'Vaginal bleeding' a distinction is made between excessive
      (cyclical), irregular, breakthrough and postmenopausal bleeding. The diagnostic
      guidelines are aimed at identifying possible causes. However, in a considerable
      number of patients no underlying cause is found and the bleeding is assumed to be
      caused by hormonal fluctuations, for instance shortly after the menarche or
      premenopausal. Other causes can be: myomas, an intra-uterine device (IUD),
      medication, or endometrial carcinoma. Furthermore, lesions of the perineum, vulva
      or vagina, a pelvic inflammatory disease, Chlamydia infection, cervical
      carcinoma, imminent abortion or ectopic pregnancy also have to be excluded. In
      this practice guideline, the management guidelines are limited to the treatment
      of bleeding from the endometrium. In most cases bleeding caused by hormonal
      fluctuations is self-limiting. However, symptomatic treatment with progestogens
      or sub-50 oral contraceptives is possible. NSAIDs taken during the first three
      days of menstruation are the second-choice treatment in women with excessive
      bleeding. Tranexamic acid or a levonorgestrel-releasing IUD are other
      possibilities. Postmenopausal women with vaginal bleeding, first of all have to
      be examined by means of a cervical smear and transvaginal ultrasonography, to
      exclude an endometrial carcinoma. They can initially be reassured if the
      ultrasonography reveals an endometrial thickness of 4 mm or less. In the case of
      persistent or recurrent vaginal bleeding, they should still be referred to a
      gynaecologist.

PMID- 12467160
TI  - [How to treat a patient with indications for an infectious viral hemorrhagic
      fever].
AB  - Lassa, Ebola, Marburg and Crimean-Congo haemorrhagic fever viruses are the most
      important causes of viral haemorrhagic fever which is transmitted from person to
      person through contact with blood or excreta. A non-specific fever may be the
      initial symptom of viral haemorrhagic fever. By means of carefully noting where
      the patient has travelled, possible exposure to ill persons, vectors or an animal
      reservoir, and the incubation period (< or = 21 days versus longer), it is
      possible to estimate the risk of infection with one of these viruses. Using this
      approach it is possible to diagnose high-risk patients in good time and to take
      appropriate measures.

PMID- 12467161
TI  - [From gene to disease; from SDHD, a defect in the respiratory chain, to
      paragangliomas and pheochromocytomas].
AB  - Hereditary paragangliomas are rare benign tumours arising from neuroectodermal
      tissue in the head and neck region. In families with paraganglioma, occasionally
      adrenal and extra-adrenal pheochromocytomas are found. Paragangliomas, adrenal
      and extra-adrenal pheochromocytomas may be caused by mutations in the SDHB, SDHC
      and SDHD genes encoding different subunits of mitochondrial respiratory chain
      complex II. Most paraganglioma cases in the Netherlands are caused by SDHD
      mutations. Presymptomatic DNA diagnosis is available for families with
      paragangliomas caused by SDHD mutations.

PMID- 12467162
TI  - [Diagnostic image (114). A woman with pulse-synchronous tinnitus. Glomus tumor in
      the ear].
AB  - A 58-year-old woman with pulse-synchrone tinnitus was diagnosed with a glomus
      tumour in the right middle ear.

PMID- 12467163
TI  - [Coronary bypass surgery in 1971-80 and 1995-96: increased age and comorbidity,
      unchanged survival rates and fewer early reoperations 1 and 5 years
      postoperatively].
AB  - OBJECTIVE: To describe the characteristics of patients undergoing coronary bypass
      surgery (CABG) over the past 30 years and the outcome after 1 and 5 years.
      DESIGN: Retrospective. METHOD: All 1041 patients who had undergone a first CABG
      in the Thorax centre of the Erasmus Medical Centre in Rotterdam during the period
      from 1 July 1971 through 31 May 1980 (group I) were compared with all patients
      who had also undergone such a first operation during the period between 1
      September 1995 and 31 December 1996 (group II). Data on the patients, the
      operations, any reoperations and the mortality were obtained from patient
      records, from general practitioners and from municipal archives. Cumulative
      percentages of survival and of not having reCABG or percutaneous transluminal
      coronary angioplasty (PTCA) were analysed by using the Kaplan-Meier-method.
      RESULTS: The patients in group I were 11 years younger on average than those in
      group II and there were more men (group I: 88%, group II: 76%). The patients in
      group II had more comorbidity than those in group I. The actuarial perioperative
      mortality was 1.2% in group I and 1.6% in group II. The overall 5-year mortality
      was significantly lower in group I than in group II (9.1% vs. 11.0%). After
      adjustment for the baseline characteristics, however, the patients in group II
      had a lower risk of mortality. Coronary revascularisation in the first 5 years
      was required more often in group I than in group II (7.4% vs. 4.2%). Independent
      predictors of a higher 5-year mortality were: a reduced ejection fraction (both
      groups), more extensive vascular disease (group I), chronic pulmonary disease,
      renal function disorders and diabetes mellitus (all group II), while treatment
      for hyperlipidaemia had a favourable effect on survival. CONCLUSION: The age and
      comorbidity of the operated patients had increased over the years, while the
      chance of survival was no less than before and there was less chance of an early
      reoperation.

PMID- 12467164
TI  - [Percutaneous transluminal coronary angioplasty in 1980-85 and 1995-96: more
      frequent multivessel disease, fewer reoperations and no change in mortality 1 and
      5 years postoperatively].
AB  - OBJECTIVE: To describe the characteristics of patients undergoing coronary
      angioplasty (PTCA) over the past 20 years and the outcome after 1 and 5 years.
      DESIGN: Prospective follow-up study. METHODS: All patients who underwent a first
      PTCA in the Thorax centre of the Erasmus Medical Centre in Rotterdam during the
      period from 1 September 1980 through 30 November 1985 (group I) were compared
      with all patients who likewise underwent such a first PTCA during the period
      between 1 September 1995 and 31 December 1996 (group II). Data on the patients,
      the operations, any reoperations and the mortality were obtained from patient
      records, general practitioners and municipal archives. Cumulative percentages of
      survival and of not having rePTCA or coronary artery bypass surgery (CABG) were
      analysed by using the Kaplan-Meier-method. RESULTS: Group I consisted of 856
      patients and group II of 840 patients. The percentage of males decreased over the
      years from 80% to 69%. The average age increased from 56 to 60 years; the oldest
      patient in group I was 75 years and the oldest in group II was 87 years. The
      percentage of patients with multivessel disease increased from 36% to 44%. Stent
      implantation occurred in 55% of the patients in group II (0% in group I). The
      necessity for urgent CABG due to unsuccessful PTCA decreased from 9.4% to 1%.
      After 1 year, the percentage of coronary revascularisations was 28.8% in group I
      and 22.6% in group II (p = 0.01). The perioperative mortality and the 5-year
      survival were not significantly different in the two groups (group I: 1.3% and
      90%; group II: 2.4% and 88%, respectively). For both groups, higher age, a
      smaller ejection fraction, more extensive vascular disease and no treatment with
      statins were independent predictors of a higher mortality after 5 years. In group
      II, renal function disorders were the most important predictor of higher
      mortality.

PMID- 12467165
TI  - [A man with fatal Lassa fever following a stay in Sierra Leone].
AB  - A 48-year-old-man returned to the Netherlands from Sierra Leone and was admitted
      with nausea, crampy abdominal pain, myalgia, arthralgia, headache and watery
      diarrhoea. This was the first case of Lassa fever diagnosed in the Netherlands
      since 1980. Despite treatment with ribavirin, the patient died on the 16th day of
      illness. Prompt diagnosis of Lassa fever is critical for the timely
      administration of ribavirin which improves diagnosis considerably, and for the
      timely implementation of isolation measures. Recently, a reverse transcriptase
      polymerase chain reaction (RT-PCR) has become available for the rapid diagnosis
      of acute Lassa fever, which was implemented to diagnose this patient.

PMID- 12467166
TI  - [Epidemic of methicillin-resistant Staphylococcus aureus due to the transfer of 2
      Dutch burn patients from a hospital outside of the Netherlands; who suffers the
      consequences?].
AB  - Two burns patients who were transferred to the Central Military Hospital Utrecht
      from a foreign hospital, were found to be colonised with MRSA. During their 5
      week hospitalisation, 21 healthcare workers and one patient became colonised with
      the same MRSA strain, despite isolation precautions. The department was closed
      for 29 days; 96 admissions were cancelled and 1411 screening cultures for MRSA
      were performed. Colonised healthcare workers were temporarily unable to work and
      additional costs were incurred for disposables and cleaning procedures. The
      resultant bill for this outbreak was approximately [symbol: see text] 122,500.
      MRSA outbreaks occur in hospitals with some degree of regularity, but the strong
      dispersal during this epidemic was exceptional. The transfer of possible MRSA
      colonised patients from hospitals outside of the Netherlands sometimes faces
      opposition due to the considerable demands it makes on a hospital's personnel,
      organisation and finances. If this were to be compensated, then the currently
      successful Dutch MRSA policy could be coupled with a willingness to accept
      patients from hospitals outside of the Netherlands.

PMID- 12467167
TI  - [Acute appendicitis].

PMID- 12467168
TI  - [Acute appendicitis].

PMID- 12467169
TI  - [Acute appendicitis].

PMID- 12467170
TI  - N.Y. Methodist tops annual reports. Seventeen competitors recognized for
      excellent products.
AB  - NewYork Methodist Hospital, Brooklyn, N.Y., takes the top award for this year's
      competition. Running close behind are The Children's Hospital of Philadelphia,
      second place; and Evangelical Community Hospital, Lewisburg, Pa., third place.
      While there are considerable differences among these institutions and their
      approaches to an annual report, they share some common qualities: all are
      attractive products which meet their objectives. They all produce strong,
      positive impressions through clear language and imagery. Incidentally, New York
      Methodist was the very first hospital to submit a report in this year's
      competition--a factor which played no part in the judging for awards!

PMID- 12467171
TI  - These reports focus on the 'people' side of healthcare. Designers find effective
      ways to portray the human angle.
AB  - Because we received so many entries in the "healthcare system" category, judges
      agreed to divide the category in half according to the total budget as stated on
      the entry form. First place winner is Baptist Health South Florida, Coral Gables,
      Fla. Second is Alegent Health, Omaha, Neb. A tie was declared for third place,
      with the honors going to Spectrum Health, Grand Rapids, Mich.; and Stamford
      Health System, Stamford, Conn.

PMID- 12467172
TI  - Healthcare systems winners produced at lower costs. Quantity, methods of
      distribution account for cost differences.
AB  - Memorial Healthcare System, Hollywood, Fla. is the winner in this category, with
      second place going to Sparrow Health System, Lansing, Mich. Third place winner,
      Cape Fear Valley Health Systems, Fayetteville, N.C., also enjoyed the lowest cost
      per-copy.

PMID- 12467173
TI  - These regional hospitals use reports to broaden awareness. Both winners benefit
      from highly creative designs.
AB  - Nebraska Health System, Omaha, Neb., takes top billing here, with an annual
      report that builds on the success of an extensive advertising campaign. Second
      place winner is Grinnell Regional Medical Center, Grinnell, Iowa, using a
      "blueprint" theme to commemorate the completion of new construction.

PMID- 12467174
TI  - Making an impression on readers. Quality and achievement are reflected in their
      reports.
AB  - Widely different approaches are used by first place winner, Rush-Presbyterian-St.
      Luke's Medical Center, Chicago; and second-place Hackensack University Medical
      Center, Hackensack, N.J. Happily, both effectively achieve their objectives.

PMID- 12467175
TI  - M.D. Anderson report celebrates people, 60 years of history. Anne Arundel,
      Integris review cancer programs.
AB  - Always a winner, the report by The University of Texas, M.D. Anderson Cancer
      Center, Houston, takes first-place in this category, with second place going to
      Anne Arundel Medical Center, Annapolis, Md., and third to Integris Oncology
      Services, Oklahoma City, Okla.

PMID- 12467176
TI  - Community hospitals employ reports to generate warmth. Easy-to-read productions
      take a light touch with finances.
AB  - Gila Regional Medical Center, Silver City, N.M., took first honors in this
      category with a tabloid newspaper insert. Second-place winner, Hurley Medical
      Center, Flint, Mich., has a "touching" report prepared by the Hurley Foundation.

PMID- 12467177
TI  - Does abstinence make the heart grow fonder?

PMID- 12467178
TI  - Adolescent pregnancy in the United States.
AB  - The rates of adolescent pregnancies and births in the United States are higher
      than those in most industrialized nations. Fortunately, the rates of sexual
      activity, pregnancies, and births have declined in the last few years.
      Contraceptive use has increased and the induced abortion rate and ratio have also
      declined. The decrease in sexual activity and the increase in contraceptive use
      are usually attributed, at least in part, to fear of contracting HIV/AIDS. Other
      contributing factors may be health education programs, a changing moral climate,
      new contraceptives, and the improved economy. The decrease in sexual activity and
      increase in contraceptive use have led to the decline in the pregnancy and birth
      rates. The decline in induced abortions is probably due to legislation
      restricting access to abortion for minors, harassment of abortion facilities, and
      violence against abortion providers. Programs to prevent adolescent pregnancies
      and births have traditionally focused on health education and provision of
      contraceptive services. Recently there has been increased emphasis, supported by
      federal funds, on teaching about the value of abstinence. Another new approach
      has been youth development programs that provide adolescents with opportunities
      to interact with caring adults outside of their families and to build self
      esteem, a sense of self-worth, and skills.

PMID- 12467179
TI  - Reducing the rate of teen pregnancy in Canada: a framework for action.
AB  - In partnership with the Young/Single Parent Support Network of Ottawa-Carleton
      and Timmin's Native Friendship Centre, the Canadian Institute of Child Health has
      completed a framework to reduce the rate of teen pregnancy in Canada. The final
      document is called Pro-Action, Postponement, and Preparation/Support: A Framework
      for Action to Reduce the Rate of Teen Pregnancy in Canada. The objectives were to
      learn what is currently being done and what needs to be done on this issue across
      the country, and to explore the potential role of projects funded by the federal
      Canada Action Program for Children (CAPC) and Canada Prenatal Nutrition Program
      (CPNP) in reducing the rate of teen pregnancy. Being an extremely complex and
      sensitive issue, the report was a culmination of a number of research methods:
      over 40 key informants from diverse backgrounds and expertise were interviewed to
      determine the scope of the problem and potential solutions; a detailed literature
      review identified existing date and documentation on the topic, using both
      Canadian and international studies; youth surveys and focus groups were conducted
      in both on-reserve Aboriginal communities and non-Aboriginal communities.

PMID- 12467180
TI  - Socio-cultural factors influencing adolescent pregnancy in rural Nepal.
AB  - Early child bearing is a widely observed phenomenon in Nepal. However, little
      information is available in regard to its contributing factors. This
      retrospective exploratory study was carried out to determine factors contributing
      to adolescent pregnancy in rural Nepal. Cluster sampling technique was used to
      select the study settings. The findings on variable contributing to pregnancy
      from the sample of 575 mothers, who had their first pregnancy at an age below 19
      years, were compared with the findings from an equal number of mothers who had
      their first pregnancy at the age of 20 years or above. The adolescent mothers
      were married at a comparatively younger age with a mean age of 15.9 years.
      Parents or elders, with/without the girl's consent, decided the majority of
      adolescent marriages. The age at marriage exposed women to early pregnancy
      regardless of who decided the marriage. Comparatively, most adolescent mothers
      were from a low social class, engaged in agricultural work, and they had low
      literacy rate. Majorities of the mothers from both groups had no prior knowledge
      about conception until they conceived. Peers were the main source of information
      regarding conception. Although the majority of the respondents knew at least one
      method of contraception, less than 1% had used it before their first pregnancy.
      To conclude, early pregnancy had put the adolescent mothers at the risk of
      unwanted pregnancy and obstetric complications. Women empowerment through
      compulsory girls' education would be the most effective strategy to prepare them
      for late marriage, planned and delayed pregnancy, and better motherhood.

PMID- 12467181
TI  - Mobile outreach services for young people.
AB  - Camden & Islington Healthbus has been providing a mobile advice and information
      outreach service to young people aged 12-25 years in a deprived area of London
      since 1996. Advantages of this service include that it is free and confidential,
      it enables young people to access advice from adult professionals who are not
      part of their daily lives, and opening hours are flexible and convenient with a
      friendly and informal setting. The service focuses mainly on sexual health, but
      will also cover relationships, drugs, growing up, diet and nutrition, and self
      esteem. The Healthbus does not offer a comprehensive range of services, but
      encourages young people to use other providers effectively. Initially, the
      Healthbus offered emergency and oral contraception and pregnancy testing, but
      these services have ceased due to limited use and data-protection requirements.
      The focus has since shifted to health education and risk awareness. Facilities
      include 1-1 counselling, a touch screen computer, leaflets and condoms. Informal
      evaluation has shown that young people feel comfortable and confident in using
      the Healthbus service. A notable success has been that the Healthbus attracts as
      many young men as young women. A number of practical issues should be taken into
      consideration when planning and managing a mobile outreach service.

PMID- 12467182
TI  - A case control study of a deprivation triangle: teenage motherhood, poor
      educational achievement and unemployment.
AB  - Teenage motherhood has been linked with poor health, poor educational attainment,
      poor employment prospects and socio-economic deprivation. Much of the evidence
      has come from large surveys and the nature of these inter-relationships remains
      unclear. A case-control study was designed to compare the educational and
      employment experiences of teenage mothers with those of an age matched sample of
      peers from a similar social background and to test the feasibility of carrying
      out this type of research within primary care. Participants were identified from
      records in 36 GP practices in the Greater Belfast area. First time teenage
      mothers with one child aged 9-15 months at the time of interview were selected.
      Teenage mothers were matched with a control group of nulliparous teenagers in
      respect of age and postcode and registered with the same practice. Questionnaires
      were administered in their home or at their health centre. Data were analysed
      using SPSS for Windows Version 6. Teenage mothers were less likely than controls
      to have gained passes in school leaving examinations. None of the mothers was in
      full time education compared with 35% of the controls. Excluding those in
      education or training, more of the control group were employed at the time of
      study (82% v 11%). It is concluded that teenage mothers with one child report
      poorer educational attainment and employment status than their nulliparous peers
      from a similar social background with similar educational opportunities.
      Attention must be paid to these findings when planning policy to help teenage
      mothers and avoid perpetuation of a cycle of socio-economic deprivation.

PMID- 12467183
TI  - Sexual Health Advice Centre.
AB  - This paper describes how some members of the Genito-Urinary Medicine Department
      of Addenbrookes Hospital, Cambridge surveyed local teenagers to ascertain whether
      they would be interested in attending a walk-in young persons sexual health
      clinic or accessing a sexual health website. Britain has the highest teenage
      birth rate in Western Europe and an increasing number of sexually transmitted
      infections in youngsters. A questionnaire was sent to all schools in the
      Cambridge area with nineteen responses. The results of the questionnaire showed
      that the majority of girls who answered expressed an interest in seeking advice
      at a teenage clinic, while the boys preferred to obtain information over the
      telephone or via a website. It is important for health professionals to be
      sensitive to the views of patients and potential patients, when it comes to
      providing new clinical services.

PMID- 12467184
TI  - The experience of young people with contraceptive consultations and health care
      workers.
AB  - In the United Kingdom, services for contraceptive consultation and family
      planning were first opened in the 1960s. Early and relevant information to
      adolescents is of importance. The aim of this paper was to examine young people's
      attitudes towards and experiences of consultations with health care providers
      about contraception, taking account of the context of their contraceptive use.
      Young people aged 16-21 years were recruited to the study from health services
      (young people's contraceptive and sexual health clinics and a termination of
      pregnancy clinic), secondary schools and community projects (a youth club, a
      young mothers' support group, a community education project and a young women
      offenders unit). As part of the needs' assessment, in-depth interviews and focus
      groups were conducted. Thirty-two young male and females were interviewed.
      Knowledge about contraception, sexually transmitted infections and the risk of
      pregnancy was often high. Many respondents noted that in a five to ten minute
      consultation there was not the time to discuss personal factors that may affect
      contraceptive decision making and effective use of methods. Many described a
      feeling of being rushed through the service and did not feel they had the
      opportunity to ask questions. What young people said they wanted from
      consultations with health care workers and their experiences of the consultation
      process often conflicted. They wanted the time and opportunity to discuss their
      options. Often the young men, who were accessing services, described how
      initially they had gone in to collect condoms, but once they knew the clinic and
      staff would consider making an appointment. It is concluded that young people
      want to be given choices and information regarding contraception that fit their
      lifestyles. Improving the structures of contraceptive and sexual health services
      for young people will help to remove some of the barriers that prevent some young
      people from accessing them. However, it is just as important that barriers in the
      service delivery are tackled to ensure young people receive effective
      contraceptive advice.

PMID- 12467185
TI  - Community-based adolescent health services in Israel: from theory to practice.
AB  - Despite their engagement in health-risk behaviors and their health-related
      concerns, adolescents have the lowest rate of health service utilization of any
      age group. Time constraints during routine medical encounters generally leave
      little opportunity for professional screening for health-risk behaviors or for
      discussing psychosocial problems. In addition, providers express low levels of
      perceived competency in areas such as sexuality, eating disorders or drug abuse.
      To address these needs, a walk-in Adolescent Health Service was established by
      the Sheba Medical Center to provide diagnosis and short-term treatment for
      individual adolescents, as well as counseling and support for local care
      providers. A three-way model of cooperation and partnership was developed and
      implemented. A professional and financial partnership with local authorities were
      established to help define the particular needs of the community's youth and to
      improve the ability to reach youth with special health needs. The partnership
      along with the main medical provider (Kupat Holim Clalit) helped define local
      health needs, served as a referral source of patients with unmet health needs,
      and improved the continuity of care. The regional medical center (Sheba Medical
      Center) provided supervision and consultation for the medical staff of the
      service, as well as a referral center for patients. It was emphasized that the
      service staff was intended as a professional source for the primary physician and
      should not be considered a rival. The core staff included a specialist in
      adolescent medicine, gynecologist, mental health specialist and social worker. A
      structured intake procedure was developed for assessing health concerns and
      problems of adolescents in the context of a community clinic. Findings from the
      first years of services showed that the first 547 female adolescents demonstrated
      that a majority of adolescents presented with primary complaints of a somatic
      nature, while one third were diagnosed with psychosocial problems and one-fifth
      with a sexuality-related problem. A considerable percentage of those diagnosed
      with psychosocial or sexuality-related problems had not stated these issues as
      their "reason for encounter". This additional increment probably represents the
      contribution of the Health Concern Checklist (HCC), in which the adolescent was
      asked to mark each item for which she had concerns or would like to receive
      further information. The HCC can help primary care physicians as well as
      adolescent medical specialists approach the teenage patient and initiate
      productive communication. A practical approach to confidential health care for
      adolescents: The issue of confidentiality has not been sufficiently clarified by
      Israeli law or by the medical community. The need for confidentiality was
      strongly felt in the adolescent health service. A policy which provides all
      adolescents with the opportunity to meet with a physician and receive health
      guidance or advice at least once, even without parental knowledge or consent, was
      formulated and implemented. If parental consent was not feasible, the minor was
      allowed to give informed consent for medical and psychosocial care for
      himself/herself, with certain limitations.

PMID- 12467186
TI  - Effectiveness of current therapy of bacterial vaginosis.
AB  - The study was conducted in order to evaluate effectiveness of the treatment of
      bacterial vaginosis (BV) with different therapeutic regimes according to
      recommendations of the World Health Organization (WHO). During a one-year period
      (February 2000-February 2001) the Sexually Transmitted Diseases (STD) Center was
      visited by 482 women aged 14-51. The diagnosis of BV was established by standard
      methods: Amsel's clinical criteria and Gram stain of vaginal discharge. The first
      line treatment was oral Metronidazole 2 g single dose. Second line was
      Metronidazole 500 mg twice daily orally for 7 days or oral Clindamycin 300 mg
      twice daily for seven days. BV was confirmed in 74 women (15.4%). Most often it
      was observed in women aged 17-30 years of age. Thirty-three (44.6% of total) were
      young women 14-21 years of age. Thirty-one (42%) women received a follow-up
      examination and of those, 11 (38.7%) needed a repeat treatment for BV due to
      unsatisfactory results of this treatment. It is concluded that treatment of BV
      with standard methods was not always effective with no significant difference
      between women under 21 years and older women found in regards to response to
      treatment. Besides antibiotic treatment, the so-called Probiotics (Lactobacillus
      acidophilus) can be taken into consideration as an alternative treatment.
      Additional research about the therapeutic effect of this type of drugs is needed.

PMID- 12467187
TI  - Improved continuation rate of depot-medroxyprogesterone acetate in adolescent
      mothers.
AB  - Poor compliance and high discontinuation rates of Depot-Medroxyprogesterone
      Acetate (DMPA) and other contraceptive methods are major factors in the
      continuing problem of adolescent pregnancy. In this study we attempted to
      determine if providing comprehensive health care for teen mothers and their
      babies would improve continuation rates of DMPA. Patients who started DMPA
      between 1/1/96 and 1/1/99 were included. Teen mothers and their babies received
      all their health care in this clinic, supported by State funding. Key elements
      regarding DMPA in this clinic were continuity of care, phone and mail reminders
      of appointments, free DMPA for patients without insurance, counseling at each
      visit and available evening clinic. In the study period a total of 299 (age 13-22
      years) patients were started on DMPA. Fifty-one percent were white, 47% black and
      2% others. Sixty-three percent were single, 20% married, 3% cohabitating and 14%
      undetermined (missing data). Seventy-eight percent had one baby and 22% more than
      one. A total of 189 patients (63.2%) continued to be compliant after one year of
      use and 101 patients (33.8% of total) continued beyond the second year. The most
      common side effect reported was bleeding or spotting (32%), However only seven
      patients (2.3%) discontinued use because of it. It is concluded that continuity
      of care (same staff and providers on each visit), regular counseling, flexible
      hours (evening appointments), financial ease (free DMPA and no visit charge for
      those without insurance), combined Teen-Tot health visits and regular reminders
      of appointments may help improve compliance and continuation rates in teen
      mothers leading to better success in preventing repeat teen pregnancy.

PMID- 12467188
TI  - Teenagers at risk of unintended pregnancy: identification of practical risk
      markers for use in general practice from a retrospective analysis of case records
      in the United Kingdom.
AB  - The United Kingdom has one of the highest teenage pregnancy rates in Western
      Europe with a high proportion of unintended pregnancies resulting in termination.
      General practice is one source of contraceptive and sexual advice for teenagers
      but it is difficult to target young women most at risk. This study was performed
      to determine whether it was possible to identify any markers that could alert
      general practitioners to the need to give appropriate opportunistic preventive
      advice. This was a retrospective case-control study in which the general practice
      medical records of young women with a recorded history of termination of
      pregnancy resulting from conception between the ages of 13-19 years inclusive
      were examined for details of consultations and contraceptive provision prior to
      conception. Where appropriate, comparison was made with an age and practice
      matched control group. A total of 53 cases were identified and compared with 159
      controls. In the 12 months prior to conception approximately half of the cases
      had discussed contraception and two-fifths had been prescribed oral
      contraception. A significantly higher proportion of cases than controls had
      consulted for emergency contraception and also for urinary tract symptoms. Weaker
      associations were also found with younger age of starting contraception, and also
      recorded side-effects or dissatisfaction with contraception. Lapsed contraception
      and previous pregnancy were noted as other potential markers of risk. The
      findings from this study may assist primary care professionals in focussing
      opportunistic sexual health interventions at some teenagers who are at higher
      risk of unintended pregnancy.

PMID- 12467189
TI  - Adolescent pregnancy in Israel.
AB  - Teenage or adolescent pregnancy requires the extensive involvement of health care
      workers in respect to the medical and social aspects of pregnancy, delivery, and
      later care of both mother and child. Trends in adolescent pregnancy over the last
      few years from the United States, Canada, and the United Kingdom are presented
      and related to data from Israel. Adolescent pregnancy in Israel has been on the
      decline, but in 1999 it was still 3.4% of all live births (131,936 children) with
      more pregnancies in this group among the non-Jewish population (7.2%) than in the
      Jewish population (1.7%).

PMID- 12467190
TI  - Adolescent health policy.

PMID- 12467191
TI  - Youth health in Canada.
AB  - Youth Health in Canada is at a favorable level and adolescents have access to a
      reasonable standard of health care services. The framework is evolving in
      response to changing concepts and to the participation of youth themselves. The
      role of the academic and research leadership in Canada is described. The youth
      population is healthy and contributes in a positive way to the national fabric
      and the needs of the majority are adequately met. However, there are sub
      populations of youth, who continue to warrant a special focus and are deserving
      of the attention of youth health professionals. Youth health in Canada is
      emerging as an adaptation of the American Adolescent Medicine model of the early
      1960s. It is a challenging multidisciplinary field in which should play a
      significant role in shaping its future. Its mandate will be to exercise
      leadership in addressing the changing needs of the general adolescent population
      and bringing renewed focus to the special needs of identifiable sub-populations.

PMID- 12467192
TI  - Towards an integrated adolescent health policy in Israel.
AB  - The principle health issues of Israeli adolescents are largely related to health
      risk behaviors, and are therefore preventable. Deciding which public health
      interventions are of highest priority ought to be determined according to the
      relative importance of these issues among Israeli youth. Violence in the schools
      and dieting to lose weight are highly prevalent in this population, with
      unintentional accidents, smoking and other substance abuse, and reproductive
      health being other important issues. Special health planning considerations that
      take into account Israel's unique population mix are necessary. Israel does not
      yet have a comprehensive, integrated health policy for youth. Nevertheless,
      legislation has been enacted that provides universal national health insurance,
      as well as preventive school health services to all school children from the 1st
      to 9th grade under the Ministry of Health's responsibility, setting the
      foundations for such a comprehensive youth health policy. In addition, policy
      makers and health care providers have recently recognized the need for a pro
      active approach regarding health service development for adolescents. In this
      article, we give an overview of current Israeli health policies that impact upon
      the adolescent population, and propose seven priority areas that should be
      addressed in order to advance the health of youth in this country.

PMID- 12467193
TI  - Anorexia nervosa: a multifactorial disease of nutritional origin?
AB  - Nutrition in general, with infant and child nutrition in particular, have changed
      in the past century through altered farming practices and eating habits. Food
      intake in childhood can influence the expression of the genetic potential. In
      this paper it is attempted to show how childhood zinc deficiency, aggravated in
      puberty by high energy/low zinc ratio of the diet and stresses of various kinds,
      can influence both mental and physical development and ultimately lead to the
      development of anorexia nervosa.

PMID- 12467194
TI  - The importance of the measurement of the circumference of arm, arm muscle area
      and skinfold thickness during puberty.
AB  - Several methods are available to study lean and adipose tissue component of the
      upper arm, but the use of a specific technique is mostly determined by time and
      financial expense. Besides, anthropometric techniques (arm muscle area, mid-arm
      circumference and the triceps skinfold thickness), which are the most practical,
      simple, inexpensive and noninvasive, x-ray, ultrasound scanning, computed
      tomography (CT), or magnetic resonance images (MRI) are also used to determine
      separate measures of muscles, adipose tissue, and bone area. These radiographic
      methods are expensive and suitable only for research studies. This short review
      will try to stress the importance of the measurement of the circumference of arm,
      arm muscle area and skinfold thickness during puberty and adolescence.

PMID- 12467195
TI  - The violent and homicidal adolescent. Hearts darkened before time.
AB  - The problem of adolescent violence and homicide continues to be one of the most
      urgent and difficult problems facing clinicians and agencies that provide
      services to youth. This article describes research based typologies of adolescent
      murderers. In addition, it is suggested that such youth typically do not respond
      to a traditional, verbally oriented psychotherapy model. A therapy model that is
      based upon art and creative therapies that incorporates cognitive behavioral
      therapy interventions is outlined.

PMID- 12467196
TI  - Attitudes towards people with mental illness. Effects of a training program for
      secondary school students.
AB  - This article reports a control study on the influence of a training program on
      attitude change towards people with mental illness. One hundred and seventeen
      students from 13 schools formed school-based mental health clubs, which composed
      the treatment group. They were given a mental health training program at
      different schools. The comparison group consisted of 102 secondary school
      students who had received no intervention. Students of both groups were assessed
      before the commencement, at the last session, and seven months after completion
      of the program with an OMICC (Opinion about Mental Illness in Chinese Community)
      scale developed by the authors. The study revealed significant positive changes,
      which could last a longer period of time, in specific attitudes on separatism and
      stigmatization of people with mental illness among students after the training
      program.

PMID- 12467197
TI  - Adolescent medicine for medical students. A study of knowledge and performance
      among medical students in Brazil.
AB  - The objective of the study was to elaborate and apply an evaluation instrument
      designed to evaluate acquisition of knowledge and performance of medical students
      in the field of adolescent medicine. METHODS: Study carried out during one year,
      with a total of 103 fifth-year medical students of a Brazilian medical school,
      divided into four groups. INSTRUMENTS: Questionnaire, pre and post-test, record
      of individual evaluation, exam marks and average of teachers' concepts. Each
      group was submitted to a test with a differentiated number of questions, though
      proportionality in the distribution of themes was maintained. Statistical
      analysis used the chi-square test or verisimilitude ratio test; means, standard
      deviations and analysis of variance; Turkey's test of multiple comparisons; and
      multivariate technique for repeated measurements. Values of p < 0.05 were
      considered statistically significant. RESULTS: The distribution of themes in
      tests and comparative analysis of tudents' mean score in the Pre-test did not
      reveal any statistically significant difference (p = 1.0; p = 0.08). A positive
      correlation was observed between performance evaluated by the research instrument
      and that measured by formal instruments of the course (r = 0.45; r = 0.68). There
      was an increase in acquisition of knowledge, with a positive correlation between
      scores of the Pre and Post-Test and between Post-Test-Pre-Test difference/Exam (r
      = 0.43; r = 0.27). CONCLUSIONS: The instrument was shown to be appropriate for
      evaluating the teaching of adolescent medicine at pregraduate level. There was
      increase in acquisition of knowledge. The methodology used can be a reference
      point for works with similar objectives.

PMID- 12467198
TI  - Osteocalcin. A biochemical marker of bone turnover during puberty.
AB  - During bone remodelling, osteocalcin is produced by osteoblasts and its level
      increases during the events characterized by rapid bone turnover. Osteocalcin is
      a bone matrix protein, which is specific for bone metabolism and it is not
      influenced by metabolic bone disorders. Osteocalcin is an important marker of
      bone turnover in physiological and pathological conditions. Physiologically,
      serum osteocalcin was increased in children, particularly during the first year
      of life and during puberty, when evolution of the concentration was related to
      rapidity of physical growth. Evidence of a correlation with growth rates comes
      from the observation that serum osteocalcin levels parallel the height velocity
      curve, with higher values in childhood and during adolescence, that later fall to
      adult values. There are previous studies reporting that there is age- and sex
      dependent change in serum osteocalcin levels in children and adolescents with a
      pattern resembling height velocity curves for children and serum osteocalcin
      elevation coincides with the pubertal growth spurt. These findings demonstrate
      that pubertal development and sex should be taken into account rather than
      chronological age when serum levels of osteocalcin are evaluated. In most of the
      studies relationships among osteocalcin and chronological age and bone age, but
      not pubertal developmental stage (sexual maturation stage) were investigated. The
      aim of our study was to determine whether osteocalcin is a useful marker for the
      pubertal growth spurt period. In this study, osteocalcin levels in male
      adolescents were examined in relation to their sexual maturation stage and age.
      According to our findings, the follow up of osteocalcin levels in relation to
      sexual maturation stages could be a new method to determine the phase of the
      pubertal growth spurt. An increase or decrease in osteocalcin levels on
      consecutive measurements may indicate the child's entering accelerated or
      decelerated stages of the growth spurt, respectively. We emphasize that the
      follow up of adolescent growth is made by determination of the sexual maturation
      stage, and not by age. Osteocalcin is a highly specific, reliable and useful
      marker for evaluation of the growth spurt and is not influenced by nonosseous
      disorders.

PMID- 12467199
TI  - Children and homicide.
AB  - Child homicide is as old as human history. It can be classified into intra- and
      extra familial child homicide. Different forms of homicide are discussed, and
      research findings show that in the age group 0-3 years the majority of cases were
      within the family. After age 12 years, it is primarily extra familial. With
      increased age of the child the phenomenon of child perpetrators is seen to be
      manifested in school homicide and juvenile crime. Risk factors are mentioned and
      pediatricians and family physicians should be aware of these in order to try
      preventive measures.

PMID- 12467200
TI  - Disability and Israel.

PMID- 12467201
TI  - Physicians as barriers to successful transitional care.
AB  - There has been a dramatic increase in the number of sufferers of chronic
      childhood diseases surviving into adulthood. Effective transition of these
      children from paediatric to adult medical services is a considerable challenge. A
      lack of integrated planning for this event can present barriers to successful
      transition. These barriers may be generated by the patient, his family or by
      political or logistical factors. However, physicians themselves can also become
      barriers in this process. Paediatricians may resist the transition process as
      they lack confidence in their adult colleagues. Emotional, academic, financial
      and cultural issues will also influence both child and adult physician's attitude
      to the hand-over of care. Increasingly poor understanding of their disease
      process by Paediatric trained doctors, makes transfer of care essential for
      adolescents. The move towards a culture of personal responsibility for health
      care is also crucial for the promotion of the maturing patient's independence.
      Development of adolescent services and closer links between the services could do
      much to enhance the transition experience of emerging adults.

PMID- 12467202
TI  - A review of the female athlete triad (amenorrhea, osteoporosis and disordered
      eating).
AB  - The number of women participating in organized sports has increased dramatically
      over the past 30 years. The female athlete triad is a condition seen with
      increasing frequency in young athletes and is characterized by the triad of
      amenorrhea, disordered eating and osteoporosis. The triad is caused by an
      imbalance between energy intake and energy expenditure and can be associated with
      significant medical morbidity. It occurs most frequently in sports emphasizing a
      lean appearance. Early recognition and intervention are essential. In an
      adolescent athlete, amenorrhea should be considered an indicator of a potential
      problem and should not simply be attributed to a consequence of training. The
      athlete should be evaluated for an underlying eating disorder and tested for
      osteoporosis. Principles of treatment include reducing the intensity of training
      until menses resume, increasing caloric intake, ensuring adequate calcium and
      vitamin D intake, encouraging weight-bearing exercise where appropriate, and
      consideration of hormone replacement therapy. Prevention, through education will
      help ensure the health and safety of young female athletes.

PMID- 12467203
TI  - The influence of the sexual stages of adolescent boys on the circumference of the
      arm, muscle area and skinfold measurements.
AB  - The purpose of this study was to detect the changes in the circumference of the
      arm, skinfold thickness (SFT), arm muscle area (AMA) and arm fat area (AFA),
      during the sexual development of healthy adolescent boys. This study was done
      with 74 adolescent boys, aged 9-17 years, with no chronic diseases, no
      developmental delay, no current medication with height ages appropriate for their
      bone ages, and body mass indexes between 50-75 percentiles. Body weight and
      height, the circumference of the arm and the SFT were measured. Body mass index,
      AMA and AFA were calculated. The mean arm circumference and AMA increased
      significantly from Tanner stage 1 to 5. AMA was significantly and positively
      correlated with age, weight, height, body mass index, arm circumference, SFT.
      After adjusting for Tanner stages, AMA was not correlated with age. A significant
      negative correlation was found between AMA and arm fat area. In the present
      study, it was seen that the sexual stages affected the circumference of arm, AMA,
      and the skinfold thickness in healthy adolescent boys, who were appropriate for
      their bone ages, and had good nutritional status. Further studies are required to
      detect the effect of pubertal stage on arm anthropometry in different nutritional
      status including obesity and malnutrition.

PMID- 12467204
TI  - Adolescent injury mortality in New Zealand and opportunities for prevention.
AB  - Injury is recognised internationally as the major threat to adolescent health.
      The purpose of this study was to describe the epidemiology of adolescent fatal
      injury in New Zealand, and to examine opportunities for prevention. National
      mortality data were searched to identify all 15-19 year-olds, who died from
      injuries in the period 1986-1995. Leading causes of injury were reviewed in light
      of known risk factors, injury mortality rates in other industrialised countries,
      and available prevention strategies. The results showed that injury accounted for
      2,095 deaths (72.8 per 100,000 person years). Males comprised 77% of victims
      (110.6 per 100,000 person years), and there was a three-fold increase in
      mortality from age 15 (35.3 per 100,000 person years) to 19 years (106.4 per
      100,000 person years). The leading causes of death were road traffic crashes
      (42.6 per 100,000 person years), suicide (16.4 per 100,000 person years), and
      unintentional drowning (3.6 per 100,000 person years). The Graduated Driver
      Licensing System addresses a range of risk factors for adolescent road traffic
      crashes. Despite inadequate enforcement, early indications are that it has
      yielded modest reductions in injury. Hazardous drinking is implicated in the high
      rates of road traffic crashes and drownings, and given recent liberalization of
      supply-side policies, proactive identification of hazardous drinkers followed by
      brief intervention holds promise as a prevention measure. Suicide accounts for an
      increasing rate of adolescent deaths in New Zealand. The effect of national
      policies to address a range of suicide risk factors remains to be fully
      evaluated.

PMID- 12467205
TI  - Evaluation of hearing ability in Danish children at the time of school start and
      at the end of school.
AB  - Since previous studies have shown reduced hearing ability in children and
      adolescents at school start, this study was undertaken to evaluate the hearing
      ability in Danish children at the time of start and end of school. Children
      starting school in 1977, 1987, and 1997 from four minor municipalities in North
      Jutland County, Denmark were evaluated for hearing ability by a review of 1,605
      school health records. We found a higher prevalence of impaired hearing ability
      in children who started school 1987 and 1997 compared to those who started school
      1977. Reduced hearing was typically at high frequencies. At the end of school,
      hearing ability of the year group 1977 was just as poor as for the year group
      1987. Whether reduced hearing can influence the learning abilities of these
      children should be evaluated by further studies including information on the
      exposure to noise.

PMID- 12467206
TI  - Seat belt use among teenagers in two Israeli family practices.
AB  - Motor vehicle accidents are the leading cause of deaths among Israeli teenagers.
      Despite the efficacy of seat belt use in reducing mortality, and legislation
      requiring seat belt use in all car positions, a large proportion of Israeli
      adolescents do not consistently use seat belts. Differential data regarding front
      and rear seat belt use in this population are not available. The objective of
      this study was to determine the rates of front and rear seat belt use among a
      sample of Israeli teenagers in the primary care setting. Seventy-eight teenagers
      attending preventive adolescent health visits in two Israeli family practice
      clinics completed questionnaires that included questions regarding seat belt use.
      Structured counseling by the family nurse was provided following completion of
      the questionnaire. Sixty-four percent of the teenagers reported using front seat
      belts all of the time, while only 8% used rear seat belts all of the time.
      Infrequent or non-use of rear seat belts was more prevalent among 10th than among
      7th graders. It is concluded that public health strategies in addition to
      legislation are needed to optimize seat belt use among Israeli teenagers. Health
      education regarding seat belt use--with an emphasis on rear seat belts--can and
      should be incorporated into adolescent preventive health visits in the primary
      care setting.

PMID- 12467207
TI  - Retrospective analysis of youth evaluated for suicide attempt or suicidal
      ideation in an emergency room setting.
AB  - Suicide is the third leading cause of death in adolescents and a major
      contributor to morbidity in this age group. The objective of this study was to
      look at the demographics, major stressors and factors leading to attempting
      suicide as well as the methods of attempted suicide in adolescents admitted to
      two hospitals in a medium size city. Medical records were reviewed of adolescents
      admitted to two area hospitals for attempted suicide between 7/1/97-12/31/99.
      Coroner's data on completed suicide were also reviewed. In the study period a
      total of 287 persons aged 21 years or under were admitted for attempted suicide.
      Mean age was 16.9 years (range 7-21). 53.4% of the total were females and 46.6
      were males with the majority of the total being Caucasians (75.6%). Interpersonal
      conflicts were the most common stressors preceding the attempt; fight with
      parents 20%, end of a relationship 12%, fight with a significant other 8%.
      Financial difficulties were the culprit in 10% of the cases. Abuse was not
      clearly recorded in 64% of cases. In cases where documentation was clear, 60%
      reported sexual and 67% physical abuse. Nearly half of the patients had a prior
      psychiatric diagnosis with prior suicide attempt and depression being most common
      at 27 and 18% respectively. Overdose was the most common method utilized. There
      were 20 completed adolescent suicides in the area with firearms as the method
      used in all of them. It is concluded that suicide continues to be a major problem
      in adolescents. Access to guns may be a detrimental factor in completing suicide.
      Health care providers may help identify those at risk by routinely screening all
      adolescents for depression and suicide.

PMID- 12467208
TI  - Prevalence of obesity in adolescents and the impact of sexual maturation stage on
      body mass index in obese adolescents.
AB  - OBJECTIVE: Puberty is a high-risk period for the development of obesity. The aim
      of this study was to determine the prevalence of obesity in adolescents admitted
      to an outpatient adolescent clinic and investigate the relationships between the
      increase of body mass index and sexual maturation stages in obese adolescents.
      MATERIAL AND METHODS: We recruited 6,462 adolescents, aged 9-16 years, admitted
      to the outpatient clinic of our Adolescent Unit, between May 1999 and September
      2000. BMI was calculated as weight per height with weight in kilograms and height
      in meters. Adolescents with a BMI > or = 95th percentile for age and sex were
      defined as obese, with BMI's > or = 90th percentile but < 95th percentile were
      defined as overweight and considered at risk for obesity. Obese adolescents, with
      endocrine problems identified to cause obesity, were excluded from this study.
      Pearson correlation coefficients were used to assess the relationships between
      BMI and age. The differences between the sexual maturation stages were evaluated
      with Mann-whitney U Test. RESULTS: Out of 6,462 cases screened, 151 obese
      adolescents were found. Prevalence of obesity for the total sample surveyed was
      estimated at 2.3%. BMI values were significantly correlated with age in both
      sexes. In girls, only the increase of BMI values from stage I to stage II was
      found to be statistically significant. In boys, BMI values did not differ
      significantly between the sexual maturation stages but the number of obese cases
      were high in stages I and II. DISCUSSION AND CONCLUSION: The pubertal growth
      spurt (timing determined by sexual maturation stage) effects the amount of fat
      accumulation and the distribution of fat in different ways in boys and girls. So,
      not only the age and sex but also the sexual maturation stage has to be taken
      into account while evaluating the BMI values for investigating the risk of
      obesity in puberty.

PMID- 12467209
TI  - Brainstem auditory evoked response in adolescents with acoustic mycotic neuroma
      due to environmental exposure to toxic molds.
AB  - Indoor air contamination with toxic opportunistic molds is an emerging health
      risk worldwide. Some of the opportunistic molds include: Stachybotrys chartarum,
      Aspergillus species (A. fumigatus, A. flavus, A. niger, A. versicolor etc.),
      Cadosporium, Alternaria, Penicillium, Trichoderma, Fusarium graminearum etc.
      These molds flourish in homes that are moist and damp. Reports of floods are now
      evident in many parts of the world. With these global changes in climatic
      conditions that favor the opportunistic mode of living among these molds, some
      health authorities are beginning to feel concerned about the diversity and the
      extent to which opportunistic molds can cause adverse health effects in humans.
      Mycotoxicosis is the collective name for all the diseases caused by toxic molds.
      Frequently, we have cases of acoustic neuroma due to mycotoxicity in our Center.
      Mycotic neuroma probably has not been reported before and the application of
      brainstem auditory evoked response (BAER) techniques in acoustic mycotic neuroma
      have not been reported either. The aim of this study, therefore, was to report
      cases and measurements of acoustic mycotic neuroma in adolescents using the
      brainstem auditory evoked response. The patients' case history, clinical
      neurological and neurobehavioral questionnaires were assessed. Then, the BAERs
      were recorded between Cz and Ai, with a second channel, Cz-Ac. The case histories
      and the questionnaires were analyzed in conjunction with the outcome of the
      objective brainstem auditory evoked response measurements. The prevalent
      subjective findings in the patients were headaches, memory loss, hearing loss,
      lack of concentration, fatigue, sleep disturbance, facial swelling, rashes,
      nosebleeds, diarrhea, abdominal pains and respiratory difficulties. Objective
      BAER showed overall abnormalities in all the patients. Although the waveform
      abnormalities varied, 1-3 interpeak latencies were abnormal in all the patients.
      Overall results showed the presence of acoustic mycotic neuroma and confirmed the
      sensitivity and usefulness of BAER in screening acoustic mycotic neuroma and
      sensorineural auditory dysfunction.

PMID- 12467210
TI  - Soluble type II transforming growth factor-beta receptor attenuates expression of
      metastasis-associated genes and suppresses pancreatic cancer cell metastasis.
AB  - Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that frequently
      metastasizes and that overexpresses transforming growth factor-beta s (TGF-beta
      s). To determine whether TGF-beta s can act to enhance the metastatic potential
      of PDAC, PANC-1 human pancreatic cancer cells were transfected with an expression
      construct encoding a soluble type II TGF-beta receptor (sT beta RII) that blocks
      cellular responsiveness to TGF-beta 1. When injected s.c. in athymic mice, PANC-1
      clones expressing sT beta RII exhibited decreased tumor growth in comparison with
      sham-transfected cells and attenuated expression of plasminogen activator
      inhibitor 1 (PAI-1), a gene associated with tumor growth. When tested in an
      orthotopic mouse model, these clones formed small intrapancreatic tumors that
      exhibited a suppressed metastatic capacity and decreased expression of
      plasminogen activator inhibitor 1 and the metastasis-associated urokinase
      plasminogen activator. These results indicate that TGF-beta s act in vivo to
      enhance the expression of genes that promote the growth and metastasis of
      pancreatic cancer cells and suggest that sT beta RII may ultimately have a
      therapeutic benefit in PDAC.

PMID- 12467211
TI  - Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor.
AB  - DNA topoisomerase II has been shown to be an important therapeutic target in
      cancer chemotherapy. Here, we describe studies on the antitumor activity of a
      novel topoisomerase II inhibitor, ER-37328 [12,13-dihydro-5-[2
      (dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1- jk]carbazole-4,6,10(5H,11H)
      trione hydrochloride]. ER-37328 inhibited topoisomerase II activity at 10 times
      lower concentration than etoposide in relaxation assay and induced double-strand
      DNA cleavage within 1 h in murine leukemia P388 cells, in a bell-shaped manner
      with respect to drug concentration. The maximum amount of DNA cleavage was
      obtained at 2 microM. Like etoposide, ER-37328 (2 microM) induced topoisomerase
      II-DNA cross-linking in P388 cells. A spectroscopic study of ER-37328 mixed with
      DNA demonstrated that ER-37328 has apparent binding activity to DNA. ER-37328
      showed potent growth-inhibitory activity against a panel of 21 human cancer cell
      lines [mean (50% growth-inhibitory concentration) GI50 = 59 nM]. COMPARE analysis
      according to the National Cancer Institute screening protocol showed that the
      pattern of the growth-inhibitory effect of ER-37328 was similar to that of
      etoposide, but different from that of doxorubicin. Studies on etoposide-,
      amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)]-, and
      camptothecin-resistant P388 cell lines showed that: (a) etoposide- and m-AMSA
      resistant P388 cell lines were partially resistant to ER-37328 compared with the
      parental cell line; and (b) a camptothecin-resistant cell line showed no cross
      resistance to ER-37328. In addition, ER-37328 overcame P-glycoprotein-mediated
      resistance. In vivo, ER-37328 produced potent tumor regression of Colon 38
      carcinoma inoculated s.c., and its activity was superior to that of etoposide or
      doxorubicin. These results indicate that ER-37328 inhibits topoisomerase II
      activity through the formation of topoisomerase II-DNA cleavable complex and has
      potent antitumor activity both in vitro and in vivo.

PMID- 12467212
TI  - Identification of a novel synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana
      1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung
      cancer cells.
AB  - Lung cancer continues to be the leading cause of cancer-related death in the
      United States. Therefore, new agents targeting prevention and treatment of lung
      cancer are urgently needed. In the present study, we demonstrate that a novel
      synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me)
      is a potent inducer of apoptosis in human non-small cell lung carcinoma (NSCLC)
      cells. The concentrations required for a 50% decrease in cell survival (IC50)
      ranged from 0.1 to 0.3 microM. CDDO-Me induced rapid apoptosis and triggered a
      series of effects associated with apoptosis including a rapid release of
      cytochrome c from mitochondria, activation of procaspase-9, -7, -6, and -3, and
      cleavage of poly(ADP-ribose) polymerase and lamin A/C. Moreover, the caspase-3
      inhibitor Z-DEVD-FMK and the pan caspase inhibitor Z-VAD-FMK suppressed CDDO-Me
      induced apoptosis. These results indicate that CDDO-Me induced apoptosis in human
      NSCLC cells via a cytochrome c-triggered caspase activation pathway. CDDO-Me did
      not alter the level of Bcl-2 and Bcl-xL proteins, and no correlation was found
      between cell sensitivity to CDDO-Me and basal Bcl-2 expression level.
      Furthermore, overexpression of Bcl-2 did not protect cells from CDDO-Me-induced
      apoptosis. These results suggest that CDDO-Me induces apoptosis in NSCLC cells
      irrespective of Bcl-2 expression level. In addition, no correlation was found
      between cell sensitivity to CDDO-Me and p53 status, suggesting that CDDO-Me
      induce a p53-independent apoptosis. Our results demonstrate that CDDO-Me may be a
      good candidate for additional evaluation as a potential therapeutic agent for
      human lung cancers and possibly other types of cancer.

PMID- 12467213
TI  - Molecular and cellular characterization of imexon-resistant RPMI8226/I myeloma
      cells.
AB  - Imexon is an aziridine-containing iminopyrrolidone with selective growth
      inhibitory potency for multiple myeloma. Our previous research indicates that
      imexon induces mitochondrial alterations, oxidative stress, and apoptosis. This
      drug represents an interesting model drug with a nonmyelosuppressive profile to
      study the basic mechanisms leading to antitumor activity and resistance. The
      major purpose of this study was to characterize an imexon-resistant RPMI8226/I
      cell line that was developed from RPMI8226 cells by continuous exposure to
      imexon. No significant differences were observed in the sensitivity to several
      cytotoxic drugs, including mitoxantrone, mitomycin C, melphalan, methotrexate,
      cytarabine, cisplatin, vincristine, and paclitaxel, in the imexon-resistant
      cells. However, RPMI8226/I cells were cross-resistant to arsenic trioxide,
      doxorubicin, fluorouracil, etoposide, irinotecan, and especially IFN-alpha. The
      data from DNA microarray and Western blot analyses indicated that the levels of
      antiapoptotic proteins Bcl-2 and thioredoxin-2, which reside mainly in the
      mitochondria, are increased in RPMI8226/I cells. In addition, increased levels of
      lung resistance protein were detected in imexon-resistant cells. Expression of P
      glycoprotein was not detected in RPMI8226/I cells. No loss of mitochondrial
      membrane potential or increase in the levels of reactive oxygen species was
      observed in RPMI8226/I cells after exposure to imexon; however, the levels of
      glutathione are increased in the RPMI8226/I cells. Transmission electron
      microscopy revealed significant changes in the mitochondrial morphology of
      RPMI8226/I cells, whereas no ultrastructural changes were observed in other
      cellular compartments. Imexon-resistant RPMI8226/I myeloma cells appear to have a
      unique mechanism of resistance that is associated with morphological alterations
      of mitochondria, increased protection against oxidative stress, elevated levels
      of glutathione, and enhanced expression of antiapoptotic mitochondrial proteins.

PMID- 12467214
TI  - Disulfiram induces apoptosis in human melanoma cells: a redox-related process.
AB  - Melanoma is highly resistant to conventional chemotherapy. We have demonstrated
      that redox regulation in melanoma cells is aberrant, and redox-modulating agents
      can induce cell apoptosis. We have currently explored the effect of disulfiram
      (DSF), a member of the dithiocarbamate family, on apoptosis of melanoma cells in
      vitro. Human metastatic melanoma cells c81-46A, c81-61, and c83-2C were treated
      with DSF and apoptosis measured. DSF, at a dose of 25-50 ng/ml, consistently
      caused a 4-6-fold increase in apoptosis. The same dose of DSF did not
      significantly affect apoptosis in melanocytes. Coincubation of N-acetyl-cysteine
      reversed the DSF-induced apoptosis. Buthionine sulfoximine (BSO), an inhibitor of
      gamma-glutamyl-cysteine synthetase, as a single agent caused a approximately 2
      fold increase in apoptosis when incubated with melanoma cells for 4 days. BSO
      slightly enhanced the level of apoptosis induced by DSF (4-10% higher than DSF
      alone). Intracellular glutathione was remarkably depleted with BSO treatment. DSF
      did not cause glutathione depletion; however, the ratio of reduced and oxidized
      glutathione was significantly decreased (14% of control), and N-acetyl-cysteine
      partially restored the ratio to 30% of control. There was a transient (2-fold)
      elevation of intracellular superoxide level after 24 h of DSF treatment (before
      the overt apoptosis). The intracellular H2O2 level progressively decreased with
      time. DSF decreased the mitochondrial membrane polarization in a time-dependent
      manner, and there was a significant inverse correlation between apoptosis and
      mitochondrial membrane polarization. We propose that DSF-induced apoptosis is
      redox related but involves a different mechanism from BSO-induced apoptosis in
      tumor cells. Our findings have provided new data for additional understanding of
      drug-induced apoptosis in melanoma cells and suggests an alternative therapeutic
      approach to melanoma.

PMID- 12467215
TI  - P-glycoprotein modulates ceramide-mediated sensitivity of human breast cancer
      cells to tubulin-binding anticancer drugs.
AB  - Alterations in metabolism of ceramide (Cer) to the noncytotoxic metabolite
      glucosylceramide have been implicated in the multidrug resistance (MDR)
      phenomenon. This observation has been made with tumor cells that also overexpress
      P-glycoprotein (Pgp), raising the possibility that Pgp plays a role in regulating
      Cer metabolism. We investigated the effect of the glucosylceramide synthase
      inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) on the
      chemosensitivity of two wild-type and multidrug-resistant human breast tumor cell
      lines. Subtoxic concentrations of PDMP sensitized drug-selected MCF7/AdrR and Pgp
      overexpressing MDA435/LCC6MDR1 (MDR1 gene-transfected) cell lines to Taxol and
      vincristine but did not alter the chemosensitivity of the wild-type cells.
      Evaluation of Taxol uptake indicated that the effect of PDMP was not due to
      membrane permeability alterations because anticancer drug accumulation was
      unaffected by PDMP. Whereas both multidrug-resistant cell lines overexpress Pgp,
      only the MCF7/AdrR cell line overexpresses the glucosylceramide synthase enzyme.
      This difference enabled us to distinguish between sensitization effects
      associated with Cer metabolism versus Pgp-mediated transport. Interestingly, when
      Pgp function was blocked, the PDMP effect was reduced 3-fold in MCF7/AdrR cells
      and was no longer observed in the MDA435/LCC6MDR1 cells. These observations imply
      that Cer metabolism and apoptosis effects are regulated not only by enzymes that
      convert Cer to nontoxic metabolites but also by Pgp-mediated transport. Given the
      intracellular distribution patterns of Pgp, we propose that this effect is
      related to glucosylceramide translocation across the Golgi bilayer. We have
      applied this model to the situation of Cer metabolism-based chemosensitization
      and demonstrate that MDR modulation strategies aimed primarily at altering drug
      transport mechanisms can influence other MDR mechanisms such as glycosphingolipid
      metabolism. This work highlights the relationship between drug transport and Cer
      metabolism in the context of chemosensitization and cautions against making
      oversimplified assumptions that these mechanisms act independently.

PMID- 12467216
TI  - Conservation of the class I beta-tubulin gene in human populations and lack of
      mutations in lung cancers and paclitaxel-resistant ovarian cancers.
AB  - The goal of this study was to determine the prevalence of sequence variants in
      the class I beta-tubulin (clone m40) gene and their occurrence in human tumors
      and cancer cell lines. DNA was isolated from 93 control individuals representing
      a wide variety of ethnicities, 49 paclitaxel-naive specimens (16 ovarian cancers,
      17 non-small cell lung cancers, and 16 ovarian cancer cell lines), and 30
      paclitaxel-resistant specimens (9 ovarian cancers, 9 ovarian cancer cell lines,
      and 12 ovarian cancer xenografts in nude mice). Denaturing high-performance
      liquid chromatography and direct sequence analysis detected two silent
      polymorphisms in exon 4, Leu217Leu (CTG/CTA) and Gly400Gly (GGC/GGT), with minor
      allele frequencies of 17 and 0.5%, respectively. Five nucleotide substitutions
      and one single-base deletion were detected in introns 1, 2, and 3 and in the 3'
      untranslated region. Analysis of 49 paclitaxel-naive and 30 paclitaxel-resistant
      specimens revealed no additional polymorphisms in the coding region. In addition,
      no amino acid replacements were found in chimpanzee, gorilla, and orangutan in
      comparison to human. Our data demonstrate a very high degree of sequence
      conservation in class I beta-tubulin, suggesting that all residues are important
      in tubulin structure and function. Individual variation in response to treatment
      with paclitaxel is not likely to be caused by genetic variations in the beta
      tubulin drug target. Moreover, acquired mutations in class I beta-tubulin are
      unlikely to be a clinically relevant cause of drug resistance.

PMID- 12467217
TI  - Cellular and molecular pharmacology of oxaliplatin.
AB  - Oxaliplatin, a diaminocyclohexane-containing platinum, has a spectrum of activity
      and mechanisms of action and resistance that appear to be different from those of
      other platinum-containing compounds, notably cisplatin. The first part of this
      review describes the differences between oxaliplatin and cisplatin in terms of
      their spectrum of activity and adduct formation and then goes on to discuss
      molecular and cellular experimental data that potentially explain them.
      Particular emphasis is placed on the differential role of DNA repair mechanisms.
      In addition, the anticancer effects of oxaliplatin are optimized when it is
      administered in combination with other anticancer agents, such as 5-fluorouracil,
      gemcitabine, cisplatin, or carboplatin; topoisomerase I inhibitors; and taxanes.
      In vitro and preclinical combination data that could optimize oxaliplatin-based
      chemotherapy are also reviewed.

PMID- 12467218
TI  - Microarray analysis: a comparative approach.

PMID- 12467219
TI  - Preclinical evaluation of amino acid prodrugs of novel antitumor 2-(4-amino-3
      methylphenyl)benzothiazoles.
AB  - Novel 2-(4-aminophenyl)benzothiazoles (e.g., compounds 1 and 2) possess highly
      selective, potent antitumor properties in vitro and in vivo. Elucidation of the
      mechanism of action of this structurally simple class of compounds has occurred
      in parallel with selection of a candidate clinical agent. Antitumor
      benzothiazoles induce and are biotransformed by cytochrome P 450 1A1 to putative
      active, as well as inactive metabolites. Metabolic inactivation of the molecule
      has been thwarted by isosteric replacement of hydrogen with fluorine atoms at
      positions around the benzothiazole nucleus. Amino acid conjugation to the
      exocyclic primary amine function of 2-(4-aminophenyl)benzothiazoles has been used
      to overcome limitations posed by drug lipophilicity. Water soluble, chemically
      stable prodrugs rapidly and quantitatively revert to their parent amine in mice,
      rats, and dogs in vivo. Plasma concentrations of 2-(4-amino-3-methylphenyl)-5
      fluorobenzothiazole (2) regenerated from the lysylamide prodrug (2b), sufficient
      to elicit cytocidal activity against ZR-75-1 and T47D human mammary carcinoma
      cell lines persist > 6 h. The growth of breast (MCF-7) and ovarian (IGROV-1)
      xenograft tumors is significantly retarded by 2b. Manageable toxic side effects
      are reported from preclinically efficacious doses of 2b. Cytochrome P 450 1A1
      protein expression, selectively induced in sensitive carcinoma cells, was
      detected in MCF-7 and IGROV-1 tumors 24 h after treatment of mice with 2b (20
      mg/kg). The lysyl amide prodrug of 2-(4-amino-3-methylphenyl)-5
      fluorobenzothiazole is potentially suitable for clinical evaluation.

PMID- 12467220
TI  - Inhibition of growth of human prostate cancer xenograft by transfection of p53
      gene: gene transfer by electroporation.
AB  - To date, there is no effective therapy for hormone-independent prostate cancer.
      Therefore, as a new strategy for refractory cancer, gene therapy is showing
      increasing promise. In this study, we attempted to use a nonviral gene transfer
      system, in vivo electroporation, in prostate cancer cell PC-3 xenografts with the
      wild-type p53 (wt-p53) gene, as gene therapy for hormone-independent prostate
      cancer. To evaluate this in vivo gene transfer method, the beta-galactosidase
      gene was transfected into xenografts by electroporation. Then, the efficiency of
      transfection of exogenous p53 gene by electroporation was confirmed by reverse
      transcription-PCR, which indicated that p53 mRNA was present in samples from
      xenografts. Next, to estimate the reduction of prostate cancer xenografts by this
      method, we measured the size of PC-3 xenografts in nude mice after
      electroporation with the wt-p53 gene. The growth of tumors was markedly
      suppressed by wt-p53 gene transfection by electroporation compared with
      transfection of mutated type p53 gene (P = 0.0027) or vector only (P = 0.0015).
      Furthermore, histological specimens revealed increased apoptotic cell death in
      p53-transfected tumors. These results suggest that it is possible to transfer wt
      p53 into prostate cancer xenografts using electroporation and to suppress the
      growth of tumors; they, furthermore, suggest that this system might be used for
      local advanced hormone-independent prostate cancer.

PMID- 12467221
TI  - The cyclin-dependent kinase inhibitor flavopiridol disrupts sodium butyrate
      induced p21WAF1/CIP1 expression and maturation while reciprocally potentiating
      apoptosis in human leukemia cells.
AB  - Interactions between the cyclin-dependent kinase inhibitor flavopiridol (FP) and
      the histone deacetylase inhibitor sodium butyrate (SB) have been examined in
      human leukemia cells (U937) in relation to differentiation and apoptosis. Whereas
      1 mM of SB or 100 nM of FP minimally induced apoptosis (4% and 10%, respectively)
      at 24 h, simultaneous exposure of U937 cells to these agents dramatically
      increased cell death (e.g., approximately 60%), reflected by both morphological
      and Annexin/propidium iodide-staining features, procaspase 3 activation, and
      poly(ADP-ribose) polymerase cleavage. Similar interactions were observed in human
      promyelocytic (HL-60), B-lymphoblastic (Raji), and T-lymphoblastic (Jurkat)
      leukemia cells. Coadministration of FP opposed SB-mediated accumulation of cells
      in G0G1 and differentiation, reflected by reduced CD11b expression, but instead
      dramatically increased procaspase-3, procaspase-8, Bid, and poly(ADP-ribose)
      polymerase cleavage, as well as mitochondrial damage (e.g., loss of mitochondrial
      membrane potential and cytochrome c release). FP also blocked SB-related p21WAF1
      CIP1 induction through a caspase-independent mechanism and triggered the caspase
      mediated cleavage of p27KIP1 and retinoblastoma protein. The latter event was
      accompanied by a marked reduction in retinoblastoma protein/E2F1 complex
      formation. However, FP did not modify the extent of SB-associated acetylation of
      histones H3 and H4. Treatment of cells with FP/SB also resulted in the caspase
      mediated cleavage of Bcl-2 and caspase-independent down-regulation of Mcl-1.
      Levels of cyclins A, D1, and E, and X-linked inhibitor of apoptosis also declined
      in SB/FP-treated cells. Finally, FP/SB coexposure potently induced apoptosis in
      two primary acute myelogenous leukemia samples. Together, these findings
      demonstrate that FP, when combined with SB, induces multiple perturbations in
      cell cycle and apoptosis regulatory proteins, which oppose leukemic cell
      differentiation but instead promote mitochondrial damage and apoptosis.

PMID- 12467222
TI  - Enhanced antitumor activity of combined pretargeted radioimmunotherapy and
      paclitaxel in medullary thyroid cancer xenograft.
AB  - A significant antitumor effect associated with moderate toxicity was obtained
      previously with anticarcinoembryonic antigen x antidiethylene-triaminepentaacetic
      acid (DTPA)-indium F6-734 bispecific antibody and iodine-131-labeled DTPA-indium
      bivalent hapten in an animal model of medullary thyroid cancer (MTC). The purpose
      of this study was to determine whether the cytotoxic agents doxorubicin and
      paclitaxel, also known as radiosensitizers, improve efficacy of pretargeted
      radioimmunotherapy (RIT) in experimental MTC. Nude mice bearing TT MTC xenograft
      were treated with F6-734 and iodine-131-labeled DTPA-indium bivalent hapten
      injected 48 h apart with or without doxorubicin or paclitaxel. The maximum
      tolerated dose (MTD) of RIT was 92.5 MBq (as determined previously) and that of
      doxorubicin and paclitaxel 200 and 1000 micrograms, respectively. A control group
      received no treatment. Animal weight, hematotoxicity, tumor volume, and serum
      calcitonin were monitored for 5 months. Tumor growth inhibition induced by drugs
      alone, RIT alone, or combined therapy was characterized by measuring relative
      tumor volume 20, 40, and 60 days after treatment to detect additivity or
      synergism. Mean tumor volume doubling time (MTVDT) was 13 +/- 4 days in the
      control group, 15 +/- 8 days in the group treated with the MTD of doxorubicin,
      and 32 +/- 13 days in the group treated with the MTD of paclitaxel. After RIT
      alone at 92.5 MBq, MTVDT was 86 +/- 22 days. After RIT at 74 MBq (80% of MTD),
      MTVDT was 56 +/- 10 days. MTVDT was not significantly different from this value
      after RIT plus doxorubicin, 60 +/- 16 days (65 and 100% of the respective single
      agent MTDs). Combination of RIT with paclitaxel (65 and 100% of the respective
      single-agent MTDs) prolonged the suppression of tumor growth. One complete
      response was observed, and MTVDT was 114 +/- 44 days. This value was
      significantly longer than the value obtained with RIT alone at 74 MBq (P < 0.05)
      or with RIT combined with doxorubicin (P < 0.02). The change in serum calcitonin
      levels paralleled those in tumor volume. Analysis of dose-response curves at days
      20 and 40 showed additivity between RIT and paclitaxel, and analysis at day 60
      suggested a synergistic effect. In conclusion, addition of doxorubicin did not
      improve RIT efficacy, whereas paclitaxel improved RIT efficacy significantly
      without increasing toxicity.

PMID- 12467223
TI  - Profiling novel sulfonamide antitumor agents with cell-based phenotypic screens
      and array-based gene expression analysis.
AB  - A series of small molecules from sulfonamide-focused libraries have been
      evaluated in these laboratories to discover novel antitumor agents. Cell-based
      screens using flow cytometric analysis revealed the presence of two distinct
      classes of cell cycle inhibitors in this series; one (including E7010 and ER
      67865) arrested mitosis by preventing tubulin polymerization; and the other
      (including E7070 and ER-68487) caused a decrease in the S-phase fraction along
      with cell cycle perturbation in G1 and/or G2 via an unknown mechanism(s). To
      further characterize both classes of antitumor sulfonamides with respect to their
      effects on gene expression, we used oligonucleotide microarray analysis for
      representative compounds. Consistent with the phenotypic observations,
      essentially the same transcription profiles were found between E7010 and ER-67865
      and also between E7070 and ER-68487. However, there was very little overlap
      between genes affected by E7010 and E7070. As a characteristic expression change
      for microtubule-depolymerizing agents, the down-regulation of alpha-tubulin
      transcripts was evident in both E7010- and ER-67865-treated cells. On the other
      hand, E7070 and ER-68487 repressed significantly the expression of a variety of
      genes involved in metabolic processes, cell cycle progression, immune response,
      and signal transduction. Of the compounds examined, E7010 and E7070 have
      progressed to clinical trials, demonstrating some objective responses in the
      Phase I setting. Described herein is profiling of novel anticancer drug
      candidates from the sulfonamide class based on phenotypic screens and gene
      expression analysis. This includes a translational research that may suggest
      potentially useful markers for pharmacodynamic drug assessment in clinic.

PMID- 12467224
TI  - UCN-01 (7-hydroxystaurosporine) inhibits DNA repair and increases cytotoxicity in
      normal lymphocytes and chronic lymphocytic leukemia lymphocytes.
AB  - Elevated DNA repair processes represent resistance mechanisms to the treatment of
      malignancies with alkylating agents. Recently, the cell cycle checkpoint
      abrogator, UCN-01, was reported to inhibit nucleotide excision repair in cell
      free systems. We hypothesized that if UCN-01 was combined with DNA-damaging
      agents, UCN-01 might inhibit the damage repair processes, thereby enhancing
      cytotoxicity in quiescent cells. Here, we investigated the effect of UCN-01 on
      DNA repair and viability of quiescent normal lymphocytes and chronic lymphocytic
      leukemia lymphocytes treated with UV or the cyclophosphamide prodrug 4
      hydroperoxycyclophosphamide (4-HC). DNA damage repair kinetics were determined as
      DNA single strand breaks by the alkaline single cell gel electrophoresis (comet)
      assay and by [3H]thymidine incorporation. Pretreatment with UCN-01 inhibited DNA
      repair initiated by UV or 4-HC in normal lymphocytes as well as chronic
      lymphocytic leukemia lymphocytes in a concentration-dependent manner at
      clinically relevant levels (50-300 nM). This inhibition was demonstrated by the
      decreases in incision capability, DNA resynthesis, and in rejoining, suggesting
      that UCN-01 inhibits the multiple sites of the repair processes. The higher UCN
      01 concentration (300 nM) maximized the inhibitory effects and enhanced the UV-
      or 4-HC-induced cytotoxicity, as determined by annexin V binding or Hoechst 33342
      staining. This enhancement was not obtained by the lower concentrations that
      incompletely inhibited the repair, suggesting the close association between the
      inhibition of the repair and the enhancement of the cytotoxicity. Our findings
      suggest that UCN-01 may be a good candidate for combination strategies of cancer
      treatment.

PMID- 12467225
TI  - Bivalent disulfide-stabilized fragment variable immunotoxin directed against
      mesotheliomas and ovarian cancer.
AB  - We have used protein engineering to generate a stable bivalent fragment variable
      (Fv) molecule from the antimesothelin antibody SS, in which the VH and VL domains
      of the Fv are linked to each other by a disulfide bond, and the two Fvs are
      connected by a flexible 15-amino acid (Gly4-Ser)3 linker. The SS (dsFv)2 molecule
      is fused to a M(r) 38,000 truncated form of Pseudomonas exotoxin to generate a
      bivalent, disulfide stabilized, (dsFv)2 immunotoxin. The immunotoxin was
      expressed in Escherichia coli, refolded in vitro, and purified to approximately
      95% purity with a high yield of > 10%. Binding studies demonstrated that the
      (dsFv)2 molecule has 40 times higher apparent affinity for recombinant mesothelin
      than a monovalent dsFv molecule. The (dsFv)2 immunotoxin was 4-10-fold more
      cytotoxic to three mesothelin antigen-positive cell lines than the monovalent
      dsFv immunotoxin. However, when tested in mice bearing tumor cells expressing
      mesothelin, the antitumor activity of the bivalent immunotoxin is very similar to
      the activity of the lower affinity monovalent immunotoxin. Our data indicate that
      increasing affinity of an antibody fragment does not necessarily lead to higher
      antitumor activity of an immunotoxin in vivo.

PMID- 12467226
TI  - The effects of the novel, reversible epidermal growth factor receptor/ErbB-2
      tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor
      derived cell lines in vitro and in vivo.
AB  - The epidermal growth factor receptor (EGFR) and ErbB-2 transmembrane tyrosine
      kinases are currently being targeted by various mechanisms in the treatment of
      cancer. GW2016 is a potent inhibitor of the ErbB-2 and EGFR tyrosine kinase
      domains with IC50 values against purified EGFR and ErbB-2 of 10.2 and 9.8 nM,
      respectively. This report describes the efficacy in cell growth assays of GW2016
      on human tumor cell lines overexpressing either EGFR or ErbB-2: HN5 (head and
      neck), A-431 (vulva), BT474 (breast), CaLu-3 (lung), and N87 (gastric). Normal
      human foreskin fibroblasts, nontumorigenic epithelial cells (HB4a), and
      nonoverexpressing tumor cells (MCF-7 and T47D) were tested as negative controls.
      After 3 days of compound exposure, average IC50 values for growth inhibition in
      the EGFR- and ErbB-2-overexpressing tumor cell lines were < 0.16 microM. The
      average selectivity for the tumor cells versus the human foreskin fibroblast cell
      line was 100-fold. Inhibition of EGFR and ErbB-2 receptor autophosphorylation and
      phosphorylation of the downstream modulator, AKT, was verified by Western blot
      analysis in the BT474 and HN5 cell lines. As a measure of cytotoxicity versus
      growth arrest, the HN5 and BT474 cells were assessed in an outgrowth assay after
      a transient exposure to GW2016. The cells were treated for 3 days in five
      concentrations of GW2016, and cell growth was monitored for an additional 12 days
      after removal of the compound. In each of these tumor cell lines, concentrations
      of GW2016 were reached where outgrowth did not occur. Furthermore, growth arrest
      and cell death were observed in parallel experiments, as determined by
      bromodeoxyuridine incorporation and propidium iodide staining. GW2016 treatment
      inhibited tumor xenograft growth of the HN5 and BT474 cells in a dose-responsive
      manner at 30 and 100 mg/kg orally, twice daily, with complete inhibition of tumor
      growth at the higher dose. Together, these results indicate that GW2016 achieves
      excellent potency on tumor cells with selectivity for tumor versus normal cells
      and suggest that GW2016 has value as a therapy for patients with tumors
      overexpressing either EGFR or ErbB-2.

PMID- 12467227
TI  - The pro-apoptotic protein, Bik, exhibits potent antitumor activity that is
      dependent on its BH3 domain.
AB  - The Bcl-2 homology 3 (BH3) domain is present in most members of the Bcl-2 protein
      family and is required to confer the death-inducing properties of pro-apoptotic
      members, including Bax, Bak, Bad, and Bik, in cell-based assay systems. To
      determine whether the BH3 domain possesses a similar role in tumor tissues in
      vivo, we overexpressed the wild-type Bik protein and its BH3-deleted counterpart,
      using adenoviral technology, in chemoresistant human tumor prostate (PC-3) and
      colon (HT-29) cell lines growing in vitro and in vivo. Bik caused apoptosis in
      both PC-3 and HT-29 cells in vitro by inducing the release of cytochrome c from
      mitochondria to cytoplasm, resulting in the catalytic activation of caspases 9,
      7, and 3 and cleavage of poly(ADP-ribose) polymerase and DNA fragmentation. When
      the BH3 domain was deleted from the Bik protein, no effect on mitochondrial
      activity or cell morphology could be observed. Furthermore, intratumoral
      injection of an adenovirus vector expressing the Bik gene, but not the deleted
      BH3 Bik gene, suppressed the growth of PC-3 and HT-29 xenografts established in
      nude mice. Histological examination of tumors from mice treated with the wild
      type Bik adenoviral construct demonstrated cellular debris, terminal
      deoxynucleotidyl transferase-mediated dUTP nick end labeling positive staining,
      and morphological changes associated with apoptosis. In contrast, tissue sections
      obtained from tumors treated with the BH3-deleted Bik adenoviral construct showed
      no evidence of apoptosis. Thus, our results suggest that the BH3 domain is
      required for the antitumor activity of the Bik protein and provides a novel
      therapeutic approach for cancer therapy.

PMID- 12467228
TI  - Design and synthesis of fluoroquinophenoxazines that interact with human
      telomeric G-quadruplexes and their biological effects.
AB  - In this study we have identified a new structural motif for a ligand with G
      quadruplex interaction that results in biological effects associated with G
      quadruplex-interactive compounds. Fluoroquinolones have been reported to possess
      weak telomerase inhibitory activity in addition to their better known bacterial
      gyrase poisoning. Starting with a fluoroquinobenzoxazine, which has modest
      potency in a human topoisomerase II assay, we have designed a more potent
      inhibitor of telomerase that has lost its topoisomerase II poisoning activity.
      This fluoroquinophenoxazine (FQP) interacts with G-quadruplex structures to
      inhibit the progression of Taq polymerase in a G-quadruplex polymerase stop
      assay. In addition, we demonstrate by 1H NMR studies that this compound interacts
      with telomeric G-quadruplex structures by external stacking to the G-tetrad with
      both the unimolecular fold-over and the parallel G-quadruplex structures. A
      photocleavage assay confirms the FQP interaction site, which is located off
      center of the external tetrad but within the loop region. Molecular modeling
      using simulated annealing was performed on the FQP-parallel G-quadruplex complex
      to determine the optimum FQP orientation and key molecular interactions with the
      telomeric G-quadruplex structure. On the basis of the results of these studies,
      two additional FQP analogues were synthesized, which were designed to test the
      importance of these key interactions. These analogues were evaluated in the Taq
      polymerase stop assay for G-quadruplex interaction. The data from this study and
      the biological evaluation of these three FQPs, using cytotoxicity and a sea
      urchin embryo system, were in accord with the predicted more potent telomeric G
      quadruplex interactions of the initial lead compound and one of the analogues. On
      the basis of these structural and biological studies, the design of more potent
      and selective telomeric G-quadruplex-interactive compounds can be envisaged.

PMID- 12467229
TI  - The histone deacetylase inhibitor sodium butyrate induces DNA topoisomerase II
      alpha expression and confers hypersensitivity to etoposide in human leukemic cell
      lines.
AB  - The differentiating agent and histone deacetylase inhibitor, sodium butyrate
      (NaB), was shown previously to cause a transient, 3-17-fold induction of human
      DNA topoisomerase II alpha (topo II alpha) gene promoter activity and a 2-fold
      increase in topo II alpha protein early in monocytic differentiation of HL-60
      cells. This observation has now been extended to other short chain fatty acids
      and aromatic butyrate analogues, and evidence is presented that human topo II
      alpha promoter induction correlates closely with histone H4 acetylation status.
      Because increased topo II alpha expression is associated with enhanced efficacy
      of topo II-poisoning antitumor drugs such as etoposide, the hypothesis tested in
      this report was whether NaB pretreatment could sensitize HL-60 myeloid leukemia
      and K562 erythroleukemia cells to etoposide-triggered DNA damage and cell death.
      A 24-72 h NaB treatment (0.4-0.5 mM) induced topo II alpha 2-2.5-fold in both HL
      60 and K562 cells and caused a dose-dependent enhancement of etoposidestimulated,
      protein-linked DNA complexes in both cell lines. At concentrations with minimal
      effects on cell cycle kinetics (0.4 mM in HL-60; 0.5 mM in K562), NaB
      pretreatment also modestly enhanced etoposidetriggered apoptosis in HL-60 cells,
      as determined morphologically after acridine orange/ethidium bromide staining,
      and substantially increased K562 growth inhibition and poly(ADP-ribose)polymerase
      cleavage after etoposide exposure. Therefore, a temporal window may exist whereby
      a differentiating agent may sensitize experimental leukemias to a cytotoxic
      antitumor agent. These results indicate that histone deacetylase inhibitors
      should be investigated for etoposide sensitization of other butyrate-responsive
      hematopoietic and nonhematopoietic tumor lines in vitro and in vivo.

PMID- 12467230
TI  - Combination of thymidine phosphorylase gene transfer and deoxyinosine treatment
      greatly enhances 5-fluorouracil antitumor activity in vitro and in vivo.
AB  - We reported previously that 5-fluorouracil (FUra) efficacy could be enhanced by
      increasing tumoral thymidine phosphorylase (TP) activity. Potentiated TP yield
      was achieved by either transfecting cells with human TP gene (A. Evrard et al.,
      Br. J. Cancer, 80: 1726-1733, 1999) or associating FUra with 2'-deoxyinosine (d
      Ino), a modulator providing the tumors with TP cofactor deoxyribose 1-phosphate
      (J. Ciccolini et al., Clin. Cancer Res., 6: 1529-1535, 2000). The purpose of the
      present work was to study the effects of a combined modulation (TP gene transfer
      + use of d-Ino) on the sensitivity to FUra of the LS174T human colorectal cell
      line. Results showed a near 4000 times increase of cell sensitivity in vitro
      after double (genetic + biochemical) modulation. This potentiation of tumor
      response was accompanied by a total change in the FUra anabolic pathway with a
      5000% increase of cytosolic fluorodeoxyuridine monophosphate, a stronger and
      longer inhibition of thymidylate synthase, and 300% augmentation of DNA damage.
      Besides, whereas thymidine failed to inhibit FUra cytotoxicity in LS174T wild
      type cells, the potentiation of the antitumor activity observed in the modulating
      regimen was partly reversed by thymidine, indicative of thymidylate synthase as
      the main drug target. The impact of this double modulation was next investigated
      in xenograft-bearing nude mice. Results showed that whereas FUra alone was
      completely ineffective on wild-type tumor growth, the size of TP-transfected
      tumors in animals treated with the FUra/d-Ino combination was reduced by 80% (P <
      0.05). Our results suggest that FUra exhibits stronger antiproliferative activity
      when activated via TP through the DNA pathway and that high tumoral TP activity
      therefore leads to enhanced sensitivity to fluoropyrimidines.

PMID- 12467231
TI  - Synergistic interaction of lovastatin and paclitaxel in human cancer cells.
AB  - The hydroxymethylglutaryl-CoA reductase inhibitor lovastatin is used widely to
      treat hypercholesterolemia and has been shown to have cell cycle-specific
      effects. In these studies, we have examined the effects of combining lovastatin
      and paclitaxel (Taxol), a microtubule-stabilizing agent, in the human leukemia
      K562 and HL-60 cell lines. Isobologram analysis of cytotoxicity assays revealed
      that there is a synergistic interaction between the two agents in both cell
      lines. Cell cycle analyses showed that lovastatin enhances paclitaxel-induced G2
      M arrest in both cell lines. In addition, Annexin V apoptotic studies revealed
      that lovastatin enhances paclitaxel-induced apoptosis in HL-60 cells. Lovastatin
      did not affect levels of [3H]paclitaxel in cells. Whereas lovastatin induced an
      accumulation of unmodified Ras and caused an up-regulation of both RhoB and
      Rap1A, paclitaxel was found to have no effect on the isoprenylated proteins.
      Studies of the centromere-associated protein mitosin revealed that treatment with
      lovastatin and paclitaxel resulted in increased mitosin levels and that
      lovastatin altered the association of mitosin with condensed chromosomes. These
      findings provide insight into the mechanisms underlying the cell cycle effects of
      lovastatin and support the development of a novel therapeutic strategy directed
      toward altering deleterious cell proliferation.

PMID- 12467232
TI  - Horseradish peroxidase-mediated gene therapy: choice of prodrugs in oxic and
      anoxic tumor conditions.
AB  - We have previously proposed the plant enzyme horseradish peroxidase (HRP) and the
      plant hormone indole-3-acetic acid (IAA) as an enzyme/prodrug combination for
      cancer gene therapy. In the current study, we evaluated the potential of HRP/IAA
      for gene-directed enzyme/prodrug therapy in three human tumor cell lines (T24
      bladder carcinoma, MCF-7 breast adenocarcinoma, and FaDu nasopharyngeal squamous
      carcinoma) and one endothelial cell line (HMEC-1). The action of 10 IAA analogues
      in combination with HRP was studied in vitro in normoxic conditions as well as in
      the extreme tumor conditions of anoxia. Compounds characterized by prompt
      normoxic or anoxic cytotoxic activation and high HRP transfectant killing or
      selectivity were identified. Some variations were observed in the response of
      cells of different origin, with IAA, 1-Me-IAA, and 5-Br-IAA representing the most
      promising candidates for HRP gene therapy. In particular, 5-Br-IAA showed a very
      prompt and selective activation in anoxia. A strong bystander effect was produced
      by activated IAA and analogues because 70-90% cell kill was obtained when only 5%
      of the cells expressed the HRP enzyme. These results indicate that HRP/IAA
      represents an effective system for enzyme/prodrug-based anticancer approaches,
      and further improvements could be achieved by the use of novel IAA derivatives.

PMID- 12467233
TI  - Mutations in beta-tubulin map to domains involved in regulation of microtubule
      stability in epothilone-resistant cell lines.
AB  - The epothilones (Epos) are a group of natural products isolated from the
      myxobacterium, Sorangium cellulosum. They have a mechanism of action similar to
      that of Taxol, i.e., they stabilize microtubules and induce the formation of
      microtubule bundles in cells. Because they are simpler in structure than Taxol
      and preserve their activity in P-glycoprotein-expressing cells, they are being
      studied as potential antitumor drugs. In this work, a series of Epo-resistant
      A549 and HeLa cell lines have been selected and analyzed. Class I beta-tubulin,
      the major isotype of beta-tubulin in these Epo-resistant cell lines, has been
      sequenced in a search for mutations. In the Epo B-resistant A549 cells, there is
      a mutation at beta 292 from Gln to Glu, in the Epo A-resistant HeLa cell line
      there is a mutation at beta 173 from Pro to Ala, and in the Epo B-resistant HeLa
      cell line there is a heterozygous mutation at beta 422 from Tyr to a mixture of
      Tyr and Cys. These mutations are close to the M-loop, the nucleotide-binding
      site, and the microtubule-associated protein binding sites, respectively. It is
      likely that these mutations in beta-tubulin provide cells with a mechanism of
      resistance to the Epos and taxanes. Among these resistant cell lines, A549.EpoB40
      is hypersensitive to microtubule-destabilizing drugs, such as vinblastine and
      colchicine, and HeLa.EpoB1.8 is dependent on the Epos or taxanes for growth. Our
      studies provide evidence that the M-loop, the GTP binding site, and the
      microtubule-associated protein binding sites at the COOH terminus in beta-tubulin
      are critical for the regulation of microtubule stability.

PMID- 12467234
TI  - Dual role of glutathione in modulating camptothecin activity: depletion
      potentiates activity, but conjugation enhances the stability of the topoisomerase
      I-DNA cleavage complex.
AB  - Depletion of glutathione (GSH) in MCF-7 and MDA-MB-231 cell lines by pretreatment
      with the GSH synthesis inhibitor buthionine sulfoximine potentiated the activity
      of 10,11-methylenedioxy-20(S)-camptothecin, SN-38 [7-ethyl-10-hydroxy-20(S)
      camptothecin], topotecan, and 7-chloromethyl-10,11-methylenedioxy-20(S)
      camptothecin (CMMDC). The greatest potentiation was observed with the alkylating
      camptothecin CMMDC. Buthionine sulfoximine pretreatment also increased the number
      of camptothecin-induced DNA-protein crosslinks, indicating that GSH affects the
      mechanism of action of camptothecin. We also report that GSH interacts with CMMDC
      to form a stable conjugate, 7-(glutathionylmethyl)-10,11-methylenedioxy-20(S)
      camptothecin (GSMMDC), which is formed spontaneously in buffered solutions and in
      MCF-7 cells treated with CMMDC. GSMMDC was synthesized and found to be nearly as
      active as 10,11-methylenedioxy-20(S)-camptothecin in a topoisomerase (topo) I
      mediated DNA nicking assay. The resulting topo I cleavage complexes were
      remarkably stable. In cell culture, GSMMDC displayed potent growth-inhibitory
      activity against U937 and P388 leukemia cell lines. GSMMDC was not active against
      a topo I-deficient P388 cell line, indicating that topo I is its cellular target.
      Peptide-truncated analogues of GSMMDC were prepared and evaluated. All three
      derivatives [7-(gamma-glutamylcysteinylmethyl)-10,11-methylenedioxy-20(S)
      camptothecin, 7-(cysteinylglycylmethyl)-10,11-methylenedioxy-20(S)-camptothecin,
      and 7-(cysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin] displayed topo I
      and cell growth-inhibitory activity. These results suggest that 7-peptidyl
      derivatives represent a new class of camptothecin analogues.

PMID- 12467235
TI  - Effect of O6-benzylguanine on nitrogen mustard-induced toxicity, apoptosis, and
      mutagenicity in Chinese hamster ovary cells.
AB  - O6-Benzylguanine (BG) inactivates O6-alkylguanine-DNA alkyltransferase (AGT),
      resulting in an increase in the sensitivity of cells to the toxic effects of O6
      alkylating agents. BG significantly enhances the cytotoxicity and decreases the
      mutagenicity of nitrogen mustards [i.e., phosphoramide mustard (PM), melphalan,
      and chlorambucil], a group of alkylating agents not known to produce O6-adducts
      in DNA. The enhancement is observed in cells irrespective of AGT activity.
      Exposure of Chinese hamster ovary cells to 100 microM BG results in enhancement
      in the cytotoxicity of PM (300 microM), chlorambucil (40 microM), and melphalan
      (10 microM) by 9-, 7-, and 18-fold, respectively. In contrast, mutation frequency
      after treatment with 300 microM PM is decreased from 259 mutants/10(6) cells to
      22 mutants/10(6) cells when cells are pretreated with BG. The enhancement of
      toxicity of these bis-alkylating agents appears to involve cross-link formation,
      because neither cytotoxicity nor mutagenicity of a monoalkylating PM analogue is
      significantly altered when combined with BG. Enhanced cytotoxicity and decreased
      mutagenicity is concomitant with a dramatic increase in the number of cells
      undergoing apoptosis when BG is combined with PM, melphalan, or chlorambucil at
      72-94 h after treatment. Cell cycle analysis demonstrates that BG alone or
      combined with nitrogen mustards arrests cells in G1 phase of the cell cycle. At
      16 h after treatment, 11 and 57% of cells treated with PM alone or with BG plus
      PM are in G1 phase, respectively. Our data suggest that treatment with BG causes
      G1 arrest and drives noncycling cells treated with nitrogen mustards into
      apoptosis, thus protecting against mutagenic DNA damage introduced by nitrogen
      mustards.

PMID- 12467236
TI  - Inhibition of Kirsten-ras expression in human colorectal cancer using rationally
      selected Kirsten-ras antisense oligonucleotides.
AB  - Kirsten-ras is frequently mutated in colorectal cancers and may be an important
      therapeutic target, particularly because we have previously shown that
      acquisition of a mutation is associated with a poorer outcome. Understanding the
      role of Kirsten-ras and the consequences of inhibiting its activity or expression
      will contribute to our comprehension of colorectal cancer biology and may help to
      rationalize the choice of molecular targets suitable for therapeutic
      manipulation. Therefore we undertook a simple screen, incubating a library of
      oligonucleotides with Kirsten-ras mRNA and RNase H to identify an antisense
      oligonucleotide that effectively inhibited Kirsten-ras expression. We show for
      the first time in a human colon cancer cell line that inhibition of Kirsten-ras
      expression inhibits constitutive phosphorylation of Erk1/2, but not c-Akt,
      suggesting that in these cells constitutive phosphorylation of Erk 1/2 is
      dependent upon Kirsten-ras. Successful inhibition of Kirsten-ras had little
      effect on cell number or cell death and there was no evidence for accumulation of
      cells in any particular phase of the cell cycle. Kirsten-ras inhibition
      significantly reduced secretion of VEGF-A165 into the culture medium. Gene
      expression profiling by microarray detected altered expression of a number of
      genes. Of particular interest for future studies was the altered expression of
      genes encoding products involved in protein trafficking and the potential effects
      of these changes on cell adhesion. Our results suggest that, at least in this
      model, Kirsten-ras may contribute to malignancy predominantly through effects on
      angiogenesis, invasion, and metastasis, and that therapies directed at Kirsten
      ras, including antisense approaches, may have particular utility through these
      mechanisms.

PMID- 12467237
TI  - The novel isocoumarin 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl)
      propionic acid (NM-3) induces lethality of human carcinoma cells by generation of
      reactive oxygen species.
AB  - 2-(8-Hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3) is an
      isocoumarin derivative that has recently entered clinical trials for evaluation
      as a p.o.-bioavailable, antiangiogenic molecule. NM-3 induces endothelial cell
      death at low microM concentrations by a nonapoptotic mechanism. The present
      studies have assessed the direct effects of NM-3 on human carcinoma cells. The
      results demonstrate that NM-3 treatment is associated with the generation of
      reactive oxygen species and loss of clonogenic survival. In concert with these
      findings, we show that exposure to NM-3 is associated with increases in
      expression of the p53 tumor suppressor. In human MCF-7 and ZR-75-1 breast cancer
      cells, NM-3 induces the p21 cyclin-dependent kinase inhibitor, cell cycle arrest
      at G1-S-phase, and necrotic cell death. Moreover, human PA-1 ovarian carcinoma
      and HeLa cervical carcinoma cells respond to NM-3 with the induction of apoptosis
      by a reactive oxygen species-dependent mechanism. These findings demonstrate that
      NM-3 has direct effects on carcinoma cells at clinically achievable
      concentrations and that this agent could be effective in targeting both the tumor
      and its vasculature.

PMID- 12467238
TI  - The role of natural killer cells in adenovirus-mediated p53 gene therapy.
AB  - Adenovirus-mediated gene therapy is a promising new approach for treatment of
      ovarian cancer. In animal models, complete elimination of cancer cells is often
      achieved, although the therapeutic gene has not been delivered to all these
      cells. This is referred to as a bystander effect, because tumor cells near those
      that receive the therapeutic gene are also eliminated. Several mechanisms have
      been proposed for the bystander effect, including intercellular communication
      within the tumor via gap junctions, apoptosis, antiangiogenesis, cytokines or
      other soluble mediators, and immunological mechanisms. There are two well
      documented antitumor effector cell populations in athymic nude mice: macrophages
      and natural killer (NK) cells. We hypothesize that peritoneal populations of NK
      cells in nude mice treated with adenoviruses are involved in the observed
      bystander effect in this in vivo model. We investigated the role of NK cells as
      immunological mediators for the bystander effect using the p53 tumor suppressor
      as the therapeutic anticancer gene. Most ovarian cancer cell lines tested were
      sensitive to lysis by NK cells, although different ovarian cancer cell lines
      exhibited different sensitivities to NK cell-mediated lysis. To determine the
      importance of NK cells in the overall efficacy and in the bystander effect of
      gene therapy, NK cells were depleted in mice by administration of anti-NK1.1
      monoclonal antibodies. To study the efficacy of NK depletion, C57BL/6 (nu/nu)
      mice were given injections i.v. by a single tail vein injection or i.p. with
      increasing doses of anti-NK1.1 IgG. All doses of anti-NK1.1 antibody, from 100
      500 micrograms, essentially eliminated cytotoxic NK activity. To assess the
      duration of depletion after a single dose of anti-NK1.1 IgG, a time-course
      experiment was performed. NK 1.1 antibody was effective in completely depleting
      cytotoxic NK cell activity in the mice for up to 7 days, whether given as 500
      micrograms (i.p.) or 200 micrograms (i.v.). Flow cytometric analysis performed on
      peritoneal cell populations confirmed depletion of NK cells by approximately 80%.
      Finally, a survival study was performed, in which animals were depleted of NK
      cells. In this experiment, NK cell-depleted mice were injected with anti-NK1.1
      IgG, and control mice were mice were treated with normal saline. Two days later,
      all mice were inoculated with a lethal i.p. dose of NIH:OVCAR-3 ovarian cancer
      cells. After 3 days, the mice were divided into two treatment groups; one
      treatment group received three consecutive daily i.p. injections of Ad-CMV-p53
      (SCH58500), and the second treatment group received three consecutive daily i.p.
      injections of control adenovirus construct, rAd-null. All of the NK cell-depleted
      animals, whether treated with rAd-null or with Ad-CMV-p53 (SCH58500) were dead of
      disease by 116 and 138 days, respectively, after initiation of adenovirus
      treatment, and no statistically significant difference in survival was observed
      (P = 0.349). A significant survival advantage was seen in control (NK-competent)
      mice treated with rAd-null (P = 0.04), although all were dead of disease by day
      184. Importantly, control NK-competent mice treated with Ad-CMV-p53 (SCH58500)
      showed no tumor growth or ascites production, and all animals survived. These
      results indicate that immunological mechanisms involving natural killer cells
      play an important role in the bystander effect involving adenovirus-p53 gene
      therapy for ovarian cancer.

PMID- 12467240
TI  - Cell adhesion is a key determinant in de novo multidrug resistance (MDR): new
      targets for the prevention of acquired MDR.
AB  - Clinical circumvention of multidrug resistance (MDR) is a Sisyphian task faced in
      the treatment of many cancers. Identification of several mechanisms of acquired
      MDR has led to the development of chemosensitizing agents that counter specific
      mechanisms of MDR. Initial successes in therapy using "chemosensitizers" often
      culminate in relapse due to the multifactorial nature of acquired MDR. Therefore,
      it may be important to design therapeutic strategies that focus on mechanisms
      that allow for cell survival after initial treatments, before the acquisition of
      MDR. It has been proposed that extracellular effectors such as cytokines, matrix
      components, and adjacent cells may provide sanctuary to cancer cells by
      preventing stress-induced cell death. This review focuses on research implicating
      the cancer cell environment as a particularly important determinant in the
      emergence of drug resistance. More specifically, we will discuss the role of
      direct contact between cancer cells and the extracellular matrix or with adjacent
      cells as extrinsic effectors of de novo MDR. Cell adhesion has been demonstrated
      to prevent cell death through a number of mechanisms. Identification of cell
      adhesion-mediated drug resistance as an initial or de novo effector of MDR
      suggests that therapies targeting interactions between cancer cells and their
      environment may lead to the sensitization of cancer cells to chemotherapy or
      radiotherapy before the emergence of acquired mechanisms of MDR.

PMID- 12467239
TI  - DNA methylation profiles of lung tumors.
AB  - Aberrant methylation of CpG islands in promoter regions of tumor cells is one of
      the major mechanisms for silencing of tumor suppressor genes. We determined the
      frequency of aberrant promoter methylation of the p16, adenomatous polyposis coli
      (APC), H-cadherin (CDH13), glutathione S-transferase P1 (GSTP1), O6-methylguanine
      DNA-methyltransferase (MGMT), retinoic acid receptor beta-2 (RAR beta), E
      cadherin (CDH1), and RAS association domain family 1A (RASSF1A) genes in 198
      tumors consisting of small cell lung cancers [SCLCs (n = 43)], non-small cell
      lung cancers [NSCLCs (n = 115)], and bronchial carcinoids (n = 40). The profile
      of methylated genes in the two neuroendocrine tumors (SCLC and carcinoids) were
      very different from that of NSCLC. However, whereas the overall pattern of
      aberrant methylation of carcinoids was similar to that of SCLC, carcinoids had
      lower frequencies of methylation for some of the genes tested. There were also
      significant differences in the methylation profiles between the two major types
      of NSCLC, adenocarcinoma and squamous cell carcinoma. We performed cluster
      analysis and found that SCLCs clustered with other SCLCs and carcinoids but not
      with NSCLCs, whereas the NSCLCs tended to cluster together. Within NSCLCs,
      adenocarcinomas and squamous cell carcinomas clustered with their respective
      histological types. Finally, we compared the methylation profiles of SCLC and
      NSCLC tumors and their respective cell lines (n = 44). In general, methylation
      frequencies were higher in tumor cell lines, but these differences were seldom
      significant. Thus, tumor cell lines appear to be suitable models to study
      aberrant DNA methylation. We conclude that SCLC, carcinoids, squamous cell
      carcinomas, and adenocarcinomas of the lung have unique profiles of aberrant
      methylation. Our findings should help us understand differences in the
      pathogenetic mechanisms of lung cancers.

PMID- 12467241
TI  - Evolution of the TIR, tolls and TLRs: functional inferences from computational
      biology.
AB  - The mammalian toll-like receptors (TLRs) are products of an evolutionary process
      that began prior to the separation of plants and animals. The most conserved
      protein motif within the TLRs is the TIR, which denotes Toll, the Interleukin-1
      receptor, and plant disease Resistance genes. To trace the ancestry of the TLRs,
      it is desirable to draw upon the sequences of TIR domains from TLRs of diverse
      vertebrate species, including species with known dates of divergence (i.e.,
      representatives of Mammalia and Aves) in order to establish a relationship
      between time and genetic divergence. It appears that a gene ancestral to modern
      TLRs 1 and 6 duplicated approximately 130 million years ago, only shortly before
      the speciation event that led to humans and mice. Though it is not represented in
      mice, TLR10 split from the TLR[1/6] precursor about 300 million years ago. The
      origins of other TLRs are more ancient, dating to the origins of vertebrate life,
      and some present-day vertebrate species appear to have many more TLRs than
      others. Moreover, the patterns of TLR expression are quite variable at the level
      of tissues, even among closely related species. A given TLR in species that are
      related by descent from a common ancestor may acquire different duties within
      each descendant line, so that some microbial inducers are avidly recognized in
      one species but not in others; likewise the intensity and the antomic location of
      an innate immune response may vary considerably. In this review, we discuss the
      computational methods used to analyze divergence of the TIR, and the conclusions
      that may be safely drawn.

PMID- 12467242
TI  - Plant disease resistance: commonality and novelty in multicellular innate
      immunity.
AB  - Pathogen avirulence genes encode for effector molecules that play a crucial role
      in the process of pathogen colonization of plant tissue. Successful host defense
      requires rapid and efficient detection of the pathogen avirulence factors. In the
      last few years, much progress has been made in delineating the plant molecular
      sentinels that participate in pathogen identification. Because this ability is
      genetic information that is 'hard-wired' into the genome, it is called 'innate
      immunity' and it draws its origins from a phylogenetically ancient form of
      immunity common to plants and animals. Conservation is shown in many of the
      functional molecular motifs of innate genes such as the Toll/interleukin 1
      receptor domains, nucleotide binding domains and structures that contain leucine
      rich repeats. Novel plant molecular surveillance domains also include pathogen
      pattern recognition by coiled-coil domains and specialized kinases. The rapid
      evolution of plant innate immunity genes is readily detected in their sequence
      polymorphism, by their massive amplification and appearance in the genome in a
      clustered organization. By comparative biology of highly diverged innate immunity
      systems we can enhance our appreciation of the truly basic forces that have
      shaped its evolution in mutlicellular organisms.

PMID- 12467243
TI  - Signal transduction pathways activated by the IL-1 receptor/toll-like receptor
      superfamily.
AB  - Toll-like receptors (TLRs) are an important point of first contact between host
      and microbe, and once activated generate signals which culminate in the induction
      of genes important for host defence. TLRs respond to different microbial
      products, and the signalling pathways activated are very similar to that
      generated by the pro-inflammatory cytokine interleukin-1 (IL-1). This is because
      the Type I IL-1 receptor and TLRs are highly homologous in their cytosolic
      portions, possessing a Toll/IL-1 receptor (TIR) domain. Signals triggered include
      the important transcription factor NF-kappa B and two MAP kinases, p38 and Jun N
      terminal kinase. Receptor-proximal proteins involved include the adapter MyD88,
      IRAK, IRAK-2, Tollip, TRAF6 and TAK-1. These latter two proteins need to be
      ubiquitinated in order to be active. Differences between signals generated by
      TLRs are emerging, with TLR-4 signalling requiring an additional adapter termed
      MyD88-adapter-like (Mal), which may regulate the expression of genes specific for
      the response required to eliminate infection by Gram-negative bacteria. Future
      studies on TLR signalling may reveal hitherto unsuspected specificities in the
      innate immune response to infection.

PMID- 12467244
TI  - Toll receptors in Drosophila: a family of molecules regulating development and
      immunity.
AB  - In recent years, Toll-like receptors (TLRs) have emerged as key receptors which
      detect microbes and initiate an inflammatory response. The Toll receptor was
      originally identified and characterized 14 years ago for its role in the
      embryonic development of the fruit-fly Drosophila melanogaster. Subsequently, it
      was also shown to be an essential component of the signaling pathway mediating
      the anti-fungal host defense in this model organism. New factors involved in the
      activation of the Toll receptor or in intracytoplasmic signaling during the
      immune response in Drosophila have recently been identified. The existence of
      significant functional differences between mammalian TLRs and Drosophila Toll
      receptors is also becoming apparent.

PMID- 12467245
TI  - Toll-like receptors and their ligands.
AB  - The Toll-like receptors (TLRs) are key molecules involved in the recognition of
      pathogens by the innate immune system. This family of germ line-encoded receptors
      has evolved to recognize conserved features of microbes. Currently, 10 TLR family
      members have been identified in mammals. The number of ligands for these
      receptors continues to grow, and it seems clear that multiple ligands exist for
      each receptor. Whether engagement of different TLRs leads to differences in gene
      expression and thereby differences in the immune response remains to be seen.
      However, recent work has demonstrated that activation of TLRs is required for
      initiation of only certain adaptive immune responses.

PMID- 12467246
TI  - Toll-like receptor-5 and the innate immune response to bacterial flagellin.
AB  - The innate immune system identifies the presence of infection by detecting
      structures that are unique to microbes and that are not expressed in the host.
      The bacterial flagellum (Latin, a whip) confers motility, on a wide range of
      bacterial species. Vertebrates, plants, and invertebrates all have evolved
      flagellar recognition systems that are activated by flagellin, the major
      component of the bacterial flagellar filament. In mammals, flagellin is
      recognized by Toll-like receptor-5 and activates defense responses both
      systemically and at epithelial surfaces. Here, we review the role for Toll-like
      receptor-5 in mediating the mammalian innate immune response to flagellin, and
      how this provides for defense against infections caused by many different species
      of flagellated bacteria.

PMID- 12467247
TI  - TLR4 as the mammalian endotoxin sensor.
AB  - For more than a century, the ability to sense endotoxin (later known also as
      lipopolysaccharide; LPS) stood as the archetypal innate immune response: even
      before the phrase 'innate immunity' became popular. Yet the mechanism by which
      LPS initiated a signal remained unknown. The problem was solved in 1998 by
      positional cloning, which revealed that Toll-like receptor (TLR) 4, one of ten
      mammalian paralogues with homology to the Drosophila protein Toll, is the central
      component of the LPS receptor. During the 3 years that followed, gene knockout
      work supported the view that the TLRs perceive a number of indispensable
      molecular structures shared by diverse representatives of the microbial world.
      The highly specific LPS-sensing function of TLR4 is remarkable for its prevalence
      in Mammalia, which to the present time is the only class of the phylum Chordata
      known to have a gene encoding TLR4, and known to display exquisite sensitivity to
      LPS. The fact that LPS signals are elicited through a single biochemical pathway
      has raised important pharmacotherapeutic opportunities as well.

PMID- 12467248
TI  - TLR2: cellular sensor for microbial and endogenous molecular patterns.
AB  - Toll-like receptor (TLR) 2 is a member of the vertebrate protein family of TLRs
      that has been studied in substantial detail over the last years. The
      extracellular domain of the type I receptor molecule TLR2 contains 18 to 20
      leucine rich repeat (LRR) and LRR like motives. The intracellular domain of TLR2
      contains a Toll/IL-1 receptor/resistance protein typical TIR domain. After the
      first implication of TLR4 in immunity thereinafter followed by the discovery of
      the lipopolysaccharide signal transducer function of TLR4, TLR2 was the first of
      ten mammalian TLRs proven to be directly involved in recognition of pathogen
      associated molecular patterns (PAMPs). Among the TLR2 specific agonists are
      microbial products representing broad groups of species such as Gram-positive and
      Gram-negative bacteria, as well as mycobacteria, spirochetes, and mycoplasm. PAMP
      induced phagosomal localization of TLR2 and TLR2 dependent apoptosis have been
      shown. Complex formation with other molecules involved in pattern recognition
      such as CD14, MD2, TLR1, and TLR6 has been implicated for TLR2. Surprisingly even
      proteinaceous host material such as heat shock protein (HSP) 60 has been
      demonstrated to activate cells through TLR2. Thus, TLR2 may be a sensor and
      inductor of specific defense processes, including oxidative stress and cellular
      necrosis initially spurred by microbial compounds. Here we summarize the current
      knowledge on the structure and function of TLR2, which is far from being
      complete. Detailed understanding of the biology of TLR2 will probably contribute
      to the characterization of a number of infectious diseases and potentially help
      in the development of novel intervention strategies.

PMID- 12467249
TI  - Bacterial CpG-DNA licenses TLR9.
AB  - The family of Toll-like receptors (TLRs) plays an important role in the innate
      immune response to pathogens. TLRs sense pathogen associated molecular patterns
      (PAMP) and lead to the stimulation of immune cells. In man, so far ten members
      (TLR1-10) have been reported. This review focuses on TLR9 which is an essential
      component for the recognition of bacterial CpG-DNA. Expression of TLR9 and
      structural consideration as well as direct ligand interaction of TLR9 and CpG-DNA
      are discussed.

PMID- 12467250
TI  - MyD88 as a bottle neck in Toll/IL-1 signaling.
AB  - Myeloid differentiation factor 88 (MyD88) is an adaptor molecule composed of an N
      terminal death domain and a C-terminal Toll/interleukin (IL)-1R homology domain.
      Ligand binding to Toll-like receptor (TLR)/IL-1R family members results in the
      association of MyD88 to the cytoplasmic tail of receptors; this then initiates
      the signaling cascade that leads to the activation of nuclear factor-kappa B and
      mitogen-activated protein kinases. Analysis of MyD88-deficient mice revealed its
      essential role in TLR/IL-1R signaling as well as in both the innate and the
      adaptive immune response.

PMID- 12467251
TI  - Heat shock proteins as ligands of toll-like receptors.
AB  - Toll-like receptors (TLRs) have been described as sensors for pathogen-associated
      molecular patterns crucial for the initiation of an innate immune response. These
      mechanisms were developed long before the adaptive immune system evolved. The
      latest additions to the growing list of TLR ligands are heat shock proteins
      (HSPs). Interestingly, not only bacterial but also mammalian HSPs interact with
      TLRs demonstrating that the exclusive association of TLRs with microbial ligands
      is obsolete. Human HSP60 and Gp96 are the first examples of non-pathogen derived
      ligands of TLRs. More importantly, Gp96 provides the first example of how the
      innate and adaptive immune system can be stimulated simultaneously by the same
      molecule which is released under physiological conditions from necrotic cells.
      Understanding the mechanisms of innate immune system interaction with HSPs will
      make it possible to rationally modulate immune responses, either towards immunity
      or towards tolerance.

PMID- 12467252
TI  - Social roles, context and evolution in the origins of depression.
AB  - This paper reviews the author's research on the social origins of depression
      begun in the early 1970s. It emphasizes the importance of taking account of the
      context and meaning of proximal causal factors by the use of investigator-based
      ratings using intensive interviews and the need to extend research to cover a
      whole lifetime. The implications of the research program that has involved some
      twenty inquiries in a variety of cultural settings is discussed in terms of the
      importance of both a comparative and an evolutionary perspective concerning
      meaning that bring together the biology involved in an evolutionary perspective
      emphasizing a common human nature with one that takes account of cultural and
      individual differences. In short an approach that take seriously a
      biopsychosocial perspective.

PMID- 12467253
TI  - Negotiating case decisions in substance abuse managed care.
AB  - In substance abuse managed care, the number of treatment sessions that a provider
      can deliver is constrained by the policies and procedures of the specialized
      managed care organizations (MCOs) that typically administer the substance abuse
      portions of healthcare plans. Managed care organizations commonly are alleged to
      control treatment providers through rules, but they also might rely on a
      particular patterned authorization of discretion, whereby they determine when and
      how frequently to respond to providers' appeals of rule-based decisions. The
      current paper uses data from a national random sample of managed care contracts
      between MCOs and substance abuse providers to test the hypotheses that (1)
      managed care organizations' "logics" about the types of provider discretion to
      allow affect the rate to which they concede to appeals, and (2) the rate of
      conceding to appeals, in turn, affects the providers' duration of substance abuse
      treatment. Results from generalized linear estimation models support the
      hypotheses and suggest that many MCOs pattern discretion to balance strict rules
      with concern about the quality or cost of care. The results more generally
      suggest that MCOs use discretion in planned ways, and thus that the patterns of
      control are more complex and sophisticated than commonly described in the
      literatures on managed care, transaction cost economics, or other perspectives.

PMID- 12467254
TI  - Is doctor-patient race concordance associated with greater satisfaction with
      care?
AB  - We examined a national sample of African American, white, Hispanic, and Asian
      American respondents to test the hypothesis that doctor-patient race concordance
      is predictive of patient satisfaction. Our analysis examined racial/ethnic
      differences in patient satisfaction among patients in multiple combinations of
      doctor-patient race/ethnicity pairs. Additionally, we outline the determinants of
      doctor-patient race concordance. The analysis used the 1994 Commonwealth Fund
      Minority Health Survey to construct a series of multivariate models. We found
      that for respondents in each race/ethnic group, patients who had a choice in the
      selection of their physician were more likely to be race concordant. Whites were
      more likely to be race concordant with their physician compared to African
      American, Hispanic, and Asian American respondents. Among each race/ethnic group,
      respondents who were race concordant reported greater satisfaction with their
      physician compared with respondents who were not race concordant. These findings
      suggest support for the continuation of efforts to increase the number of
      minority physicians, while placing greater emphasis on improving the ability of
      physicians to interact with patients who are not of their own race.

PMID- 12467255
TI  - Stability of retrospective reports in depression: traumatic events, past
      depressive episodes, and parental psychopathology.
AB  - Research findings based on the retrospective reports of depressed individuals
      have long been held suspect because of possible negative reporting biases
      associated with depression. In the present study we assess the stability of
      retrospective reports of past traumatic events, past depressive episodes,
      parental depression, and parental substance abuse in a sample of 234 adults whose
      depression status changed over two assessments conducted one year apart.
      Depression status was found to affect reporting of number of past depressive
      episodes and past traumatic events, but not reporting of parental
      psychopathology. Implications of these findings are discussed for research that
      relies on the retrospective self-reports of depressed participants.

PMID- 12467256
TI  - Academic and health-related trajectories in adolescence: the intersection of
      gender and athletics.
AB  - This study takes a life course approach to adolescent academic and health-related
      behavior. Researchers have often studied academic achievement and substance use
      as unrelated, static, and de-contextualized phenomena. Applying latent growth
      curve modeling to a sample of 2,651 high school freshmen and sophomores in
      California and Wisconsin (1987-1990), this study treats achievement and substance
      use as dynamic trajectories, inter-related to each other, and influenced by
      proximate and structural contexts. In general, achievement is high at the start
      of high school and then declines. This downward trend is driven by male non
      athletes. Substance use is initially low and then increases, with boys driving
      this increase. Finally, academic and health-related trajectories are most related
      among athletes, who experience long-term academic consequences from risky health
      related behavior. Overall, gender-athletic status can serve as either protective
      or risk factor, depending on the behavior and the temporal perspective.

PMID- 12467257
TI  - Like mother, like daughter? Female genital cutting in Minia, Egypt.
AB  - Evidence that 97 percent of ever-married Egyptian women were circumcised in 1995
      fueled interest to understand the levels, determinants, and consequences of this
      practice. Qualitative data suggest that ideologies of femininity, pressure to
      conform to behaviors characterizing womanhood, and constraints to other
      opportunities perpetuate women's support for female genital cutting in Minia,
      Egypt. While the practice remains prevalent in Minia, age-specific probabilities
      of genital cutting are lower among daughters than mothers and among younger than
      older daughters. A mother's education is negatively associated with, and her
      circumcision status positively associated with, her intent and decision to
      circumcise a daughter. Increasing reliance on doctors to perform the procedure is
      positively associated with urban residence and father's education, indicating a
      need to understand local meanings of modernity. Overall, increasing girls' access
      to higher education may contribute to further declines in female genital cutting
      in this setting.

PMID- 12467258
TI  - Individual and contextual risks of death among race and ethnic groups in the
      United States.
AB  - An emerging area of social science research focuses on individual-level and
      contextual-level determinants of black-white adult mortality differentials in the
      United States. However, no research on adult mortality differentials has
      distinguished multiple Hispanic subgroups and explored the role of nativity at
      both the individual and contextual levels for small geographic areas. Using the
      1986-1997 National Health Interview Survey-National Death Index linked file, we
      examine the effects of individual and contextual factors on black-white and
      multiple Hispanic subgroups (Mexican Americans, Puerto Ricans, and "other"
      Hispanic) differentials in adult mortality. In addition, we use a new, innovative
      geographic area--the very small area--as our contextual unit of analysis. We find
      that excess mortality risks for all race-ethnic groups considered are associated
      with not only individual characteristics, but also neighborhood characteristics.
      In addition, percent foreign born in a neighborhood is protective of Hispanic
      subgroup mortality for Puerto Rican, Mexican American, and "other" Hispanic
      adults in the 45-64 age category. These findings indicate a need for future
      research to examine more throughly the pathways through which neighborhood
      factors affect multiple Hispanic subgroup mortality and the role of nativity as a
      protective factor for older adult Hispanic mortality.

PMID- 12467259
TI  - Auditing and reporting for HIPAA compliance. Accounting principles help
      healthcare providers shoulder the burden of proof.

PMID- 12467260
TI  - Safe and secure. With HIPAA deadlines looming and a prolific number of security
      choices on the horizon, healthcare organizations face a challenging future.

PMID- 12467261
TI  - Landscape in flux. CIOs' priorities change as they manage enterprises primed for
      tech and service users armed with a list of IT requirements.

PMID- 12467262
TI  - The impact of clinical reminders and alerts on health screenings. The VA
      Pittsburgh Healthcare System achieves notable results by enhancing an automated
      clinical reminder system within its CPR--and has the data to prove it.

PMID- 12467263
TI  - Managing multiple services with multiple modules. Ambulatory surgery center
      maximizes its use of an automated product suite.

PMID- 12467264
TI  - What works: Ready, set, grow. A local practice implements electronic medical
      record (EMR) technology, triples patient volume and reduces per patient costs by
      more than 10 percent.

PMID- 12467265
TI  - Managed care and CRM. CRM has long-term potential to transform payers'
      relationships with brokers and employers, providers and members.

PMID- 12467266
TI  - Security/authentication HotList.

PMID- 12467267
TI  - Uterine fibroid embolization fares well against hysterectomy, study says.

PMID- 12467268
TI  - Stop overstocking blood for neurosurgery, study says.

PMID- 12467269
TI  - Migraine sufferers are not seeking nor receiving guideline-based care.

PMID- 12467270
TI  - Guidelines outline strategies to reduce post-operative nausea and vomiting.

PMID- 12467271
TI  - The Great War, the Russian Civil War, and the invention of big science.
AB  - The revolutionary transformation in Russian science toward the Soviet model of
      research started even before the revolution of 1917. It was triggered by the
      crisis of World War I, in response to which Russian academics proposed radical
      changes in the goals and infrastructure of the country's scientific effort. Their
      drafts envisioned the recognition of science as a profession separate from
      teaching, the creation of research institutes, and the turn toward practical,
      applied research linked to the military and industrial needs of the nation. The
      political revolution and especially the Bolshevik government that shared or
      appropriated many of the same views on science, helped these reforms materialize
      during the subsequent Civil War. By 1921, the foundation of a novel system of
      research and development became established, which in its most essential
      characteristics was similar to the U. S. later phenomenon known as "big science."

PMID- 12467272
TI  - Beyond species: Il'ya Ivanov and his experiments on cross-breeding humans and
      anthropoid apes.
AB  - The possibility of crossing humans with other anthropoid species has been
      discussed in fiction as well as in scientific literature during the twentieth
      century. Professor Il'ya Ivanov's attempt to achieve this was critical for the
      beginning of organized primate research in the Soviet Union, and remains one of
      the most interesting and controversial experiments that was ever done on non
      human primates. The possibility of removing the boundary that separates humans
      from other animal species, apes in particular, is loaded with important political
      meaning and violates cultural and ethical taboos. The history of Ivanov's
      scientific experiment thus helps to reveal some of the twentieth-century's
      important cultural conventions and hidden assumptions about human nature,
      species, and social hierarchy.

PMID- 12467273
TI  - Love-hate for man-machine metaphors in Soviet physiology: from Pavlov to
      "physiological cybernetics".
AB  - This article reinterprets the debate between orthodox followers of the Pavlovian
      reflex theory and Soviet "cybernetic physiologists" in the 1950s and 60s as a
      clash of opposing man-machine metaphors. While both sides accused each other of
      "mechanistic," reductionist methodology, they did not see anything "mechanistic"
      about their own central metaphors: the telephone switchboard metaphor for nervous
      activity (the Pavlovians), and the analogies between the human brain and a
      computer (the cyberneticians). I argue that the scientific utility of machine
      analogies was closely intertwined with their philosophical and political meanings
      and that new interpretations of these metaphors emerged as a result of political
      conflicts and a realignment of forces within the scientific community and in
      society at large. I suggest that the constant travel of man-machine analogies,
      back and forth between physiology and technology has blurred the traditional
      categories of the "mechanistic" and the "organic" in Soviet neurophysiology, as
      perhaps in the history of physiology in general.

PMID- 12467274
TI  - Current world literature: neurology.

PMID- 12467275
TI  - Current world literature: allergy, immunology and related disorders.

PMID- 12467276
TI  - Current world literature: genetics.

PMID- 12467277
TI  - Current world literature: psychiatry.

PMID- 12467278
TI  - Whipple's disease: a malady defined by medical progress in the twentieth century.

PMID- 12467279
TI  - The Royal College of Surgeons 19th-century textbook of paediatrics and its
      authors Evanson and Maunsell.
AB  - Richard T. Evanson, Professor of Medicine in the RCSI and Henry Maunsell,
      Professor of Obstetrics, jointly published a textbook of paediatrics which went
      through five editions between 1836 and 1847. The textbook was based on their
      practical experience in the treatment of children in the Institution of the
      Diseases, founded in 1821. This was probably the first Children's Hospital in
      these islands. The textbook reviews neonatal care, normal development, and the
      diagnosis and treatment of childhood illnesses. It was well received at home and
      abroad and it was a major contribution to contemporary literature.

PMID- 12467280
TI  - The genesis of the Faculty of Occupational Medicine.

PMID- 12467281
TI  - Methimazole-induced hepatotoxicity.
AB  - OBJECTIVE: To present the case of a patient with Graves' hyperthyroidism in whom
      treatment with methimazole led to severe cholestasis. METHODS: A detailed case
      report and an overview of previously published cases of methimazole- and
      carbimazole-induced hepatotoxicity, found in a MEDLINE search with use of
      methimazole, carbimazole, thionamides and antithyroid agents as subject headings,
      are provided. RESULTS: In a 36-year-old woman with severe hyperthyroidism,
      treatment with methimazole (20 mg twice daily) was initiated. Nineteen days
      later, pruritus, scleral icterus, dark urine, and abdominal discomfort prompted
      discontinuation of the therapy. Laboratory investigations and abdominal
      ultrasonography showed findings consistent with a cholestatic reaction to
      methimazole. Recovery was slow but complete. Of the 30 previously published cases
      of hepatotoxicity related to treatment with methimazole or carbimazole in which
      the nature of the hepatic injury was described, 19 were also cholestatic.
      CONCLUSION: Physicians should be aware that thionamide drugs can be associated
      with hepatotoxicity. Analysis of the known cases suggests that older age of the
      patient and higher dose of the drug are risk factors for cholestatic injury.

PMID- 12467282
TI  - 2002 Founders Award. Kenneth L. Mossman.

PMID- 12467283
TI  - 2002 Founders Award. Charles E. Roessler.

PMID- 12467284
TI  - 2002 Elda E. Anderson Award. Richard R. Brey.

PMID- 12467285
TI  - 2002 Distinguished Scientific Achievement Award. Raymond A. Guilamette.

PMID- 12467286
TI  - 2002 Outstanding Science Teacher Award. Bobette Doerrie.

PMID- 12467287
TI  - 2002 Outstanding Science Teacher Award. Paul S. Lombardi.

PMID- 12467288
TI  - 2002 Robley D. Evans Commemorative Medal. Kenneth W. Skrable.

PMID- 12467289
TI  - 2002 William B. McAdams Outstanding Service Award. Paul L. Ziemer.

PMID- 12467290
TI  - 2002 National Registry of Radiation Protection Technologists Arthur F. Humm Jr.
      Memorial Award. Gary Kephart.

PMID- 12467291
TI  - Interaction of radiation and smoking in lung cancer induction among workers at
      the Mayak nuclear enterprise.
AB  - For radiation-related cancer risk evaluation, it is important to assess not only
      influences of individual risk factors but also their interactive effects (e.g.,
      additive, multiplicative, etc.). Multivariate analysis methods adapted for
      interactive effects allow such assessments. We have used a multivariate analysis
      approach to investigate the pair-wise interactions of the previously identified
      three main etiological factors for lung cancer induction in Russian workers of
      the Mayak Production Association (PA) nuclear enterprise. These three factors are
      as follows: (1) body burden of inhaled plutonium-239 (239Pu), an influence on
      absorbed alpha-radiation dose; (2) cumulative, absorbed external gamma-radiation
      dose to the lung; and (3) level of cigarette smoking as indicated by a smoking
      index (SI). The SI represents the cigarettes smoked per day times years smoking.
      The Mayak PA workers were exposed by inhalation to both soluble and insoluble
      forms of 239Pu. Based on a cohort of 4,390 persons (77% male), we conducted a
      nested, case-control study of lung cancer induction using 486 matched cases and
      controls. Each case was matched to two controls. Matching was based on five
      factors: sex, year of birth, year work began, profession, and workplace. Three
      levels of smoking were considered: low (SI = 1 to 499), used as a reference
      level; middle (SI = 500 to 900); and high (SI = 901 to 2,000). For lung cancer
      induction, a supra-multiplicative effect was demonstrated for high external gamma
      ray doses (> 2.0 Gy) plus high 239Pu intakes (body burden >2.3 kBq). This
      observation is consistent with the hypothesis of curvilinear dose-response
      relationships for lung cancer induction by high- and low-LET radiations. The
      interaction between radiation (external gamma rays or 239Pu body burden) and
      cigarette smoke was found to depend on the smoking level. For the middle level of
      smoking in combination with gamma radiation (> 2.0 Gy) or 239Pu body burden (>
      2.3 kBq), results were consistent with additive effects. However, for the high
      level of smoking in combination with gamma radiation (> 2.0 Gy) or 239Pu body
      burden (> 2.3 kBq), results were consistent with the occurrence of multiplicative
      effects. These results indicate that low-dose risk estimates for radiation
      induced lung cancer derived without adjusting for the influence of cigarette
      smoking could be greatly overestimated. Further, such systematic error may
      considerably distort the shape of the risk vs. dose curve and could possibly
      obscure the presence of a dose threshold for radiation-induced lung cancer.

PMID- 12467292
TI  - Assessment of patient effective radiation dose and associated radiogenic risk
      from extracorporeal shock-wave lithotripsy.
AB  - The aim of the present study was to calculate patient effective dose and
      associated radiogenic risk from fluoroscopy guided extracorporeal shock-wave
      lithotripsy procedures. Fluoroscopy required during extracorporeal shock-wave
      lithotripsy was classified in two types identified by beam orientation: antero
      posterior and 30 degrees anterior-oblique projected exposures. Duration of each
      exposure was monitored in 124 patients undergoing extracorporeal shock-wave
      lithotripsy treatment for ureteral stones. The dose from a kidney-ureter-bladder
      radiograph and the dose per min of fluoroscopy along antero-posterior and
      anterior-oblique projections were measured at 13 organs/tissues using an
      anthropomorphic phantom and thermoluminescence dosimetry. A radio-opaque object
      was placed in the phantom to simulate an ureteral stone at the proximal and
      distal ureter. The total effective dose in male and female patients with proximal
      ureteral stones was 1.71 mSv and 1.82 mSv, respectively. The corresponding values
      for male and female patients with distal ureteral stones was 0.76 mSv and 1.62
      mSv, respectively. In the United States, the theoretical sex-averaged radiogenic
      excess of fatal cancers was estimated to be 140 per million and 85 per million of
      patients treated for proximal and distal ureteral stone, respectively. The
      average radiogenic risk for genetic defect associated to treatments of proximal
      and distal ureteral stones was found to be 2.5 and 24.4 per million of births,
      respectively. The radiation risk from a typical fluoroscopy guided extracorporeal
      shock-wave lithotripsy treatment of ureteral stones is low. Presented data may be
      used to determine patient effective dose from extracorporeal shock-wave
      lithotripsy procedures performed in any laboratory.

PMID- 12467293
TI  - Statistical analysis of historical occupational dose records at a large medical
      center.
AB  - Routine monitoring of occupational radiation exposure is done primarily to
      demonstrate compliance with dose limits. Statistical analysis of past and present
      dose records provides a useful tool in the management of institutional radiation
      safety programs. In this study, a statistical analysis of annual dose records
      from 1985-1999 from a large tertiary care medical center with a cyclotron and
      radiopharmaceutical production facility is performed. A total of 6,089 annual
      dose records, categorized into ten occupational groups, were included in the
      analysis. Dose distribution is skewed, with 85% of workers receiving an annual
      dose of less than 1.0 mSv, while 1.3% have doses > or =10 mSv. The mean annual
      dose of all monitored workers during this 15-y period ranged from 0.5 to 1.2 mSv.
      Large variation in the mean annual dose exists among the different occupational
      groups. Four occupational groups were identified as relatively highly exposed,
      namely cyclotron and radiopharmaceutical production, cardiac catheterization,
      nuclear medicine, and diagnostic radiology. These four occupational groups also
      showed different trends in the mean annual dose. A correlation study showed that
      total annual collective dose has no linear association with the number of
      monitored workers, the number of measurably exposed workers, or the number of
      workers with annual dose between 0.1 to <10 mSv. Moderate correlation (r = 0.64)
      was observed between the annual collective dose and the collective dose of
      workers with an annual dose between 0.1 to <10 mSv. A strong and significant
      correlation (r = 0.95) exists between the total annual collective dose and both
      the number of workers with annual dose of > or =10 mSv and the corresponding
      collective dose due to these highly exposed workers. Although the fraction of
      these highly exposed workers is small (about 1%), they have a significant impact
      on the total collective dose and their contribution can be as high as 50%.
      Workers with annual dose of > or =10 mSv tend to concentrate in a few identified
      occupational groups and not across all occupational groupings. The cyclotron and
      radiopharmaceutical production department is of particular concern due to its
      high individual dose levels and increasing mean annual dose trend for the last 5
      y. Radiochemists and cyclotron engineers tend to receive an annual dose exceeding
      the dose limit. A plot of the collective dose of highly exposed workers vs. the
      total collective dose shows that if a dose constraint of 10 mSv is imposed on
      highly exposed occupational groups, the total collective dose is expected to be
      about 200 person-mSv.

PMID- 12467294
TI  - Estimation of the effective dose when protective aprons are used in medical
      procedures: a theoretical evaluation of several methods.
AB  - The use of the personal dose equivalent Hp(10), as measured by one or more
      dosimeters, in estimating the effective dose equivalent H(E) and the effective
      dose E was examined for situations in which a protective apron is worn by the
      monitored person during medical procedures. The photon energy range considered
      was between 0.03-1.0 MeV. Several methods recommended in the technical literature
      for this purpose were assessed and their ability to provide reasonable estimates
      for H(E) and E were compared. The assessments were theoretical and used Monte
      Carlo transport methods and an anthropomorphic phantom to calculate H(E), E, and
      Hp(10). The results showed that all of the recommended methods, using either one
      or more dosimeters, were applicable to this situation but that most gave good
      results only within limited photon energy ranges, outside of which they either
      considerably over-or under-estimated the doses. Some provided good estimates over
      the entire energy range considered.

PMID- 12467295
TI  - Spatial distribution of indoor aerosol deposition under accidental release
      conditions.
AB  - Indoor aerosol dispersion and particle deposition was investigated using a series
      of puff releases of nonspecific activatable tracers simulating an accidental
      source. Initial particle size distribution included the respirable range, with
      most of the particles between 0.5 to 5.0 microm. Tracers were released in a
      nuclear laboratory/work environment and were collected via passive collector
      foils to obtain the spatial distribution of deposition. The observed distribution
      characteristics did not always correspond to the measured air flow patterns, and
      they showed a non-negligible dependence on aerosol dynamics such as
      thermophoretic effects. The collected data represent integrated deposition flux,
      which can serve for validation of aerosol dynamics models that aim to predict the
      deposition fluence of particles and may also be used for planning surface
      contamination surveys following accidental releases.

PMID- 12467296
TI  - Influence of dust loading on the alpha-particle energy resolution of continuous
      air monitors for thin deposits of radioactive aerosols.
AB  - Alpha-particle continuous air monitors must sometimes be operated in dusty
      environments where significant dust loading of the filter can be anticipated. It
      is important to understand how this dust loading affects the response of the
      continuous air monitors. Not only must a filter be changed if there is a
      reduction in airflow, but a change may be necessary if the energy resolution
      deteriorates and the continuous air monitor loses sensitivity and specificity for
      the radioactive aerosols of interest. A series of experiments were conducted to
      investigate alpha-particle energy resolution of continuous air monitor filters,
      particularly under dust loading conditions. Aerosol particles of various sizes
      were tagged with radon decay products to serve as surrogates for radioactive
      aerosols of interest such as plutonium or uranium. While the size of radioactive
      aerosols, filter type, and dust type affected the energy resolution, the
      thickness of an underlying (nonradioactive) dust layer did not show significant
      effect for the materials studied and a loading range of 0.01-10 mg x cm(-2). Our
      results indicate that it is possible for continuous air monitors to detect the
      release of radioactive aerosols with little deterioration in energy resolution
      under conditions of significant dust loading provided that the deposited layer of
      radioactive aerosols remains thin (< or = 0.1 mg x cm(-2)).

PMID- 12467297
TI  - Atmospheric aerosol measurements of 238U and 232Th at Fernald, Ohio, and
      implications on inhalation dose calculations.
AB  - Measurements of the aerosol size distribution of 238U and 232Th at the U.S.
      Department of Energy's Fernald Environmental Management Project site were made to
      improve the inhalation dose calculations to off-site individuals. For
      approximately 1 y an 8-stage cascade impactor was co-located with a high volume
      sampler and operated at the Fernald Environmental Management Project site to
      collect aerosol samples. During most of the year, the site was dominated by giant
      particles with more than 70% of the mass of 238U above 15 microm. The seasonal
      average of the activity median aerodynamic diameter, based on the impactor
      samples, which excluded particles >15 microm, for both uranium and thorium was
      approximately 6.5 microm. These numbers reflect the activities at the site and
      the domination of the resuspension processes. During most sampling periods the
      size distribution was bimodal. Thorium concentrations were comparable to the
      uranium concentrations during the late spring and summer period and decreased to
      approximately 25% of the 238U concentration in the late summer. Fernald
      Environmental Management Project is required to calculate the maximum allowable
      dose from airborne emissions, excluding radon, to meet NESHAP compliance. These
      calculations assume an AMAD of 1 microm. We found that if you combine size
      distribution information with the latest ICRP 66 lung model you reduce the
      estimated dose by a factor of 7. Inclusion of the size distribution of
      radionuclides at any sampling site would substantially improve the dose estimates
      to the population.

PMID- 12467298
TI  - Radon exposure at drinking water supply plants in Slovenia.
AB  - Radon was measured at ten drinking water supply plants in Slovenia, in rooms
      attended by workers. Concentrations ranged from 40 to 2600 Bq x m(-3) resulting
      in annual effective doses of the personnel, calculated according to the ICRP 65
      methodology, of below 0.5 mSv at 6 places, and of 0.6-3.0 mSv at the others. In
      addition, at each plant water was analyzed for 222Rn and 226Ra and ranges of 0.5
      33 kBq x m(-3) and 5-34 Bq x m(-3), respectively, were obtained.

PMID- 12467299
TI  - Radiation exposure from diagnostic imaging: agreement between self-report and
      medical records.
AB  - Data on diagnostic imaging procedures from a highly structured interview were
      compared to medical records in a case-control study of radiography and acute
      myelogenous leukemia. Three hundred and twenty-eight cases and 315 controls (78%
      of participants) had medical records available from an average of 71% of
      providers. Proxies were used for 49% of cases because of rapid fatality. Mean
      agreement (number of procedures in medical records subtracted from number in
      interview) showed similar levels of overreporting in cases [0.6; 95% confidence
      interval (CI): 0.0, 1.1] and controls (0.7; CI: 0.2, 1.3) with few procedures (<=
      10). Most participants with more procedures underreported exposure, and
      underreporting increased with increasing exposure, especially among cases [mean
      (CI) agreement = -2.1 (-4.3, 0.0) for 11-20 procedures, -6.4 (-13.6, 0.7) for >20
      procedures] and case proxies. High-dose, fluoroscopic, and non-routine procedures
      were self-reported more accurately than low-dose, non-fluoroscopic, and routine
      procedures, respectively (p < 0.01 for each comparison), and tended to be
      underreported. Case-control differences in agreement were non-significant for
      these categories of procedures. We conclude that diagnostic imaging procedures of
      most interest to the AML-radiography hypothesis are self-reported accurately but
      that underreporting does occur and might lead to attenuated risk estimates.

PMID- 12467300
TI  - Matrix models of compartmental systems--a physical interpretation of the
      eigenvectors of compartmental systems.

PMID- 12467301
TI  - Thrombin as a survival factor for cancer cells: thrombin activation in malignant
      effusions in vivo and inhibition of idarubicin-induced cell death in vitro.
AB  - OBJECTIVES: The aim of the experiments shown here, is to demonstrate exemplarily
      that thrombin can be a survival factor for malignant cells. METHODS: Activation
      of the coagulation system has been examined in patients with acute myeloid
      leukemia (AML) and non-Hodgkin lymphoma (NHL) before and after chemotherapy as
      well as in malignant effusions of heavily pretreated patients with solid tumors.
      Thrombin receptor expression (PAR-I) has been examined on HL-60 cells; the effect
      ofthrombin on the proliferation of the cells and inhibition of apoptosis
      induction by idarubicin has been shown. RESULTS: Using fibrinopeptide A as an
      indirect parameter for thrombin activation, we found elevated levels in patients
      with AML and NHL before and a significant 2-fold increase after chemotherapy (p <
      0.02 for the AML group; p < 0.0006 for the NHL group). Apparently, this does not
      only affect patients with hematological diseases, but also with solid tumors. In
      order to find out if the tumor cells directly activate thrombin, we examined
      malignant effusions of patients with different solid tumors. Comparing
      prothrombin fragment 1 + 2 in ascites and pleural effusions with the patients'
      serum levels, we found it significantly increased in all cases (mean of 1.96 +/-
      0.5 nmol/l in the serum vs. 12.1 +/- 3.6 nmol/l in effusions; p < 0.001). The
      majority of patients presented elevated serum levels. Additionally, we incubated
      HL-60 cells (human promyelocytic leukemia) with thrombin prior to treatment with
      idarubicin. Expression of thrombin receptor (PAR-1) could be verified by FACS
      analysis using a monoclonal antibody. HL-60 cells responded with increased
      proliferation to thrombin exposure with concentrations between 0.3 and 3 U/ml.
      This effect could be abolished by the addition of hirudin, demonstrating thrombin
      specificity. In these concentrations, thrombin was able to abrogate the induction
      of apoptosis by idarubicin completely (p < 0.005). CONCLUSIONS: Here we give
      evidence for the role of thrombin as a resistance factor for tumor cells towards
      chemotherapy. In the light of the fact that thrombin is regularly activated in
      cancer patients, these findings indicate that thrombin is a clinically relevant
      cellular resistance factor. A number of pre-clinical and clinical studies imply
      that inhibition of the coagulation system, e.g. by low-molecular weight heparins
      or warfarin, increases the effect of chemotherapy.

PMID- 12467302
TI  - NFkappaB-dependent chemoresistance in solid tumors.
AB  - The Rel/NFkappaB family of transcription factors is involved in multiple cellular
      processes, including inflammation, cell cycle regulation, apoptosis and
      oncogenesis. Constitutive activation of NFkappaB has been described in a great
      number of solid tumors and this activation appears to support cancer cell
      survival and to reduce the sensitivity against chemotherapeutic drugs.
      Additionally, some of these drugs induce this transcription factor themselves and
      through this mechanism lower their cytotoxic potential. Inhibition of NFkappaB by
      various means has been shown to enhance the sensitivity to antineoplastic- or
      radiation-induced apoptosis in vitro and in vivo. Furthermore, suppression of
      NFkappaB results in attenuation of cancer cachexia and metastasis in some mouse
      tumor models. Studies are underway to further delineate the role of NFkappaB in
      cancer cell survival, growth and resistance to standard chemotherapy and
      radiation regimens. Moreover, the effects of novel therapeutic agents which
      specifically target NFkappaB proteins are currently being assessed in
      experimental models of cancer cell growth both in vitro and in vivo. In this
      review, we discuss the possible involvement of NFkappaB in the chemoresistance of
      various solid tumors and potential future treatment strategies based on NFkappaB
      inhibition.

PMID- 12467303
TI  - 4-1 BB ligand--just another costimulating molecule?
AB  - Initially, scientific interest in the 4-1BB/4-1BB Ligand system focused on the
      role of the 4-1BB (CD137) receptor in the costimulation of T cells. More
      recently, evidence is accumulating that 4-1BBL is more than "just" the ligand for
      a costimulatory molecule. In this review we discuss the functional properties of
      4-1BB Ligand such as its preference for CD8 positive T cells and the differences
      to costimulation via the B7/CD28 system. Furthermore, the available data
      regarding its ability to transduce signals bidirectionally, i.e. also back into
      the ligand bearing cell, its release as a soluble form following shedding from
      the cell surface, and its role in the interaction of tumor cells with the immune
      system are reviewed.

PMID- 12467304
TI  - DNA repair in resistance to alkylating anticancer drugs.
AB  - The major critical target of alkylating antineoplastic drugs belonging to the
      group of methylating and chloroethylating agents is DNA. DNA alkylation lesions
      can be repaired by the action of alkyltransferase (MGMT) and base excision repair
      enzymes. The major cell killing and apoptotic alkylation lesions are O6
      methylguanine (O6MeG) and O6-chloroethylguanine. O6MeG causes mispairing with
      thymine which is erroneously processed by mismatch repair (MMR), leading to
      secondary lesions that potently trigger the mitochondrial apoptotic pathway.
      Apoptosis induced by O6MeG is a late cellular response that requires cell
      proliferation to occur. Data are available indicating that DNA double-strand
      breaks are actively involved as the ultimate trigger of apoptosis. O6MeG and O6
      chloroethylguanine are repaired by the specific action of MGMT thus counteracting
      the killing effects of the lesions. The expression of MGMT is highly variable and
      is often increased in tumors compared to normal tissue. Determination of MGMT
      activity in various tumors showed low expression in brain, pancreas and skin and
      high expression in testicle, breast, colorectal, lung and ovarian tumors.
      Distribution profiles of MGMT revealed non-random distribution indicating the
      existence of subpopulations exhibiting low and high activity. Since MGMT is one
      of the most important factors determining drug resistance to alkylation,
      strategies have been developed to inhibit MGMT in tumors with the aid of MGMT
      inhibitors and overexpression of MGMT in healthy, non-target tissue (e.g. blood
      stem cells) by transferring a mutated form of MGMT inaccessible to inhibition.
      Targeting MGMT inhibitors to tumors may further enhance the antineoplastic
      efficiency of alkylating agents. The role of base excision repair, Fos and p53 in
      drug resistance to alkylation is also discussed.

PMID- 12467305
TI  - Cytoprotective features of selenazofurin in hematopoietic cells.
AB  - OBJECTIVES: Antineoplastic activity of tiazofurin (Tz) and selenazofurin (Se)
      depends on their conversion to substances which are analogs of NAD. NAD performs
      pleiotropic and essential cellular functions, both as a cofactor in oxidation
      reduction reactions and as a substrate for poly- and mono-ADP-ribosylation
      reactions. The therapeutic potential of modulating intracellular NAD levels and
      activity of NAD-dependent enzymes by concomitant administration of conventional
      anticancer agents merits further research. Our aim was to investigate the
      cytotoxic effects of Tz and Se in hematopoietic cells and to test their ability
      to potentiate the effects of DNA strand-disrupting agents. MATERIAL: THP-1, a
      cell line, derived from human acute monoblastic leukemia, was used. CLL
      lymphocytes were obtained from 8 patients with CLL. METHODS: The WST-l test was
      used to detect the function of NAD(P)-dependent dehydrogenases after exposure of
      THP-1 cells to Tz or Se. Cytotoxicity of Tz, Se, MNNG and chlorambucil was
      assessed using the membrane permeability assay (PI test). RESULTS: THP-1 cells
      were sensitive to cytotoxic effects of Tz and Se, with IC50 values of 2.5 x 10(
      5) M for Tz and 2 x 10(-6) M for Se, as determined with the WST-1 test; 10 microM
      Se induced cell membrane disruption in more than 20% of THP-1 cells 48 hours
      after commencement of treatment, whereas the same concentration of Tz failed to
      increase membrane permeability. Pretreatment of THP-1 cells with 0.5 - 1.5 microM
      Se had no effect on the time course of cell death, induced by treatment with the
      DNA-damaging agent 1-methyl-3-nitro-1 - nitrosoguanidinium (MNNG) for 36 hours.
      However, when incubation of THP-1 cells with MNNG was prolonged (72 hours)
      without changing the incubation medium, pretreatment with Se had the following
      effects: the relative number of cells that died spontaneously decreased, and the
      cytotoxicity of MNNG was diminished. This effect was also demonstrated ex vivo in
      6 of 8 cases of CLL, treated with MNNG and chlorambucil. CONCLUSIONS: Contrary to
      other investigations, we here demonstrate that preincubation with Se may
      partially protect cells from cell death induced by the alkylating agents MNNG and
      chlorambucil in the THP-1 cell line and in CLL lymphocytes presumably by
      affecting spontaneous cell death.

PMID- 12467306
TI  - New insights into the clinical pharmacokinetics of trofosfamide.
AB  - OBJECTIVE: This study focuses on the pharmacokinetics of trofosfamide (TRO) and
      metabolites after oral administration of TRO. METHODS: Twelve patients with solid
      tumors and non-Hodgkin lymphomas were treated with 450 mg TRO orally for 7 days.
      TRO and the stable metabolites ifosfamide (IFO), cyclophosphamide (CYC), 2- and 3
      dechloroethylifosfamide (2-DCE, 3-DCE) were determined by GC and the sum of the 4
      OH-metabolites was measured by HPLC. RESULTS: A fast metabolism of TRO with a
      half-life of about 1 h was observed. IFO was the main stable metabolite, whereas
      CYC was only detected in minor quantities. The peak levels and the AUC of the 4
      OH-metabolites were 9.5 and 4.3 times higher than observed after an equimolar IFO
      dose. Only 6% of the administered dose was recovered in urine within 24 hours as
      stable metabolites. TRO was under limit of detection. CONCLUSIONS: Our results
      confirm that dechloroethylation of TRO to IFO is a major metabolic pathway.
      Additionally, we found considerable 4-hydroxylation not shown previously. With
      respect to the low levels of IFO and CYC observed, the sum of 4-OH-metabolites
      cannot be explained by hydroxylation of these metabolites only. Hence, we assume
      a direct 4-hydroxylation of TRO occurring to a high extent. Bioavailability of
      TRO could not be calculated directly, because TRO is only available as an oral
      formulation. The bioavailability of oral IFO, however, is reported to be almost
      100%. Therefore, after normalization of the dose, a bioavailability of 32% for
      IFO after oral TRO could be calculated. Thus, in contrast to previous reports,
      direct 4-hydroxylation of TRO seems to be the main metabolic pathway.

PMID- 12467307
TI  - Radiofrequency ablation of a stereotactically localized nonpalpable breast
      carcinoma.
AB  - A nonpalpable breast lesion was detected in a 71-year-old woman who had returned
      for her annual mammogram. Stereotactic core needle biopsy revealed an
      infiltrating ductal carcinoma. The patient agreed to stereotactic localization
      and radiofrequency ablation of the lesion followed after 4 weeks by open surgical
      biopsy. The breast lesion was localized and the radiofrequency ablation performed
      under local anesthesia in the outpatient/office setting. The lesion was ablated
      for a total of 20 minutes at a sustained mean temperature of 75 degrees C. After
      a 30-second cooldown the peripheral temperature of the four peripheral
      thermocouples ranged from 58 degrees C to 70 degrees C. A surgical clip was
      placed at the site of the ablated lesion. The postprocedure course was uneventful
      and the patient proceeded to open biopsy 4 weeks later. The open biopsy specimen,
      a left segmental mastectomy, underwent specimen radiography, which confirmed the
      surgical clip in the center of the lesion. There was extensive central necrosis
      and hemorrhage surrounded by fat necrosis. There was no definite viable residual
      tumor and the margins were clear. This is the first case in a clinical protocol
      designed to determine the efficacy of stereotactic localization and
      radiofrequency ablation of nonpalpable breast lesions. Additional ablations will
      be required to define the procedure but the results from this initial patient
      suggest that this is a promising minimally invasive curative approach for
      nonpalpable breast lesions.

PMID- 12467308
TI  - The presenting chest roentgenogram in acute type A aortic dissection: a
      multidisciplinary study.
AB  - Acute type A aortic dissection requires early diagnosis and prompt surgical
      intervention. It is not entirely clear whether patients with this form of
      dissection have clear-cut chest roentgenogram (CXR) patterns or whether the CXR
      can guide the physician in directing further workup for acute aortic dissection.
      The purpose of this study is to evaluate the impact of the initial CXR in
      arousing suspicion for acute type A aortic dissection. Twelve physicians from
      four specialties (emergency medicine, radiology, cardiology, and cardiothoracic
      surgery) evaluated the presenting CXR of ten patients with acute type A aortic
      dissection and the CXRs of ten normal individuals in a blinded manner. They were
      asked whether the CXRs were normal or abnormal (part A) and what the findings
      were and then were asked whether the CXRs were suspicious for acute aortic
      dissection (part B) and what the findings were. In part A, of the normal CXRs 81
      of 120 (68%) readings were recorded as normal. Of the dissection CXRs 112 of 120
      (93%) readings were recorded as abnormal (P < 0.001). In part B, the physicians
      were asked specifically about suspicion for aortic dissection. Of the normal CXRs
      101 of 120 (84%) readings were listed as not suspicious for dissection (i.e., 16%
      of the normal CXRs were listed as supsicious for dissection). Of the dissection
      CXRs 88 of 120 (73%) readings were recorded as suspicious for dissection (p <
      0.001). The most frequent findings on a dissection CXR when physicians were
      specifically asked about dissection included widened mediastinum in 46 of 120
      (38%) followed by not suspicious for dissection in 32 of 120 (27%). Among the
      physician specialties the only statistically significant finding was that the
      cardiology group was the most likely group to find an abnormality in a "normal"
      CXR. This data indicates that the presenting CXR is neither sensitive nor
      specific for acute type A dissection. In a patient with a suspicious history or
      physical examination, however, a CXR showing mediastinal widening or other aortic
      abnormalities should increase the suspicion for dissection and warrant further
      workup. Furthermore in a patient with a clinical suspicion a normal CXR reading
      should not delay echocardiography to rule out type A dissection.

PMID- 12467309
TI  - Blunt injury to the external iliac artery: a case report.
AB  - Blunt vascular trauma is rare as compared with penetrating vascular trauma. The
      incidence of iliac artery injury has been reported as low as 0.4 per cent of
      total arterial trauma. Iliac artery injury in blunt trauma is rare because of its
      anatomic location and protection by the pelvis. This article presents a case of
      external iliac artery injury secondary to blunt trauma. A deceleration-type
      mechanism is suggested that results in the production of an intimal flap and
      later vessel thrombosis. We discuss the clinical details of presentation and
      angiographic diagnosis as well as treatment options.

PMID- 12467310
TI  - Angiographic selective methylene blue staining of an occult small-bowel
      arteriovenous malformation.
AB  - This case report details a technique to intraoperatively define a segment of
      small bowel containing a bleeding arteriovenous malformation allowing definitive
      surgery. A patient with an arteriovenous malformation of the small intestine
      underwent angiographic localization using a highly selective microcatheter and
      intraoperative methylene blue dye allowing a specific segment of intestine to be
      resected. Angiographic identification and intraoperative location of small
      intestine arteriovenous malformations can allow the surgeon to more accurately
      define the affected segment allowing the surgery to be specific and successful.

PMID- 12467311
TI  - Abdominal compartment syndrome in the surgical intensive care unit.
AB  - The abdominal compartment syndrome (ACS) is a clinical entity that develops after
      sustained and uncontrolled intra-abdominal hypertension. ACS has been
      demonstrated to affect multiple organ systems including the cardiovascular,
      respiratory, gastrointestinal, genitourinary, and neurologic systems. To date
      most descriptions of ACS are found in the trauma literature, but the development
      of ACS in the general surgical population is being increasingly observed. In this
      study the development of ACS in a nontrauma surgical population is described and
      examined. The records of 18 surgical intensive care unit patients with documented
      ACS were reviewed retrospectively. Data acquired included demographics, urine
      output in mL/hour, cardiac index in L/m2/min: systemic vascular resistance index
      in mm Hg/L/m2/min: and pulmonary artery occlusion pressure, peak inspiratory
      pressure, partial pressure of oxygen in arterial blood, pH, partial pressure of
      carbon dioxide, and intra-abdominal pressure (all in mm Hg). When they were
      available values were obtained before and after decompression. Data are presented
      as mean +/- standard deviation and are analyzed by Student's t-test; significance
      was accepted to correspond to a P value <0.05. Nineteen episodes of ACS were
      identified in 18 patients. The average age was 69.2 years, and the observed
      mortality of the group was 61.1 per cent (11 of 18). Diagnoses included abdominal
      aortic aneurysm (eight), postoperative laparotomy (six), pancreatitis (three),
      and cerebral aneurysm (one). Of the parameters examined urine output, peak
      inspiratory pressure, and cardiac index demonstrated a significant change before
      and after decompression. The average intra-abdominal pressure was 43.4 mm Hg.
      Five of 18 patients (two with abdominal aortic aneurysm, two with postoperative
      laparotomy, and one with pancreatitis) were found to have necrotic bowel on
      decompressive laparotomy. The development of ACS is described in a surgical
      intensive care unit. ACS is the end result of uncontrolled intra-abdominal
      hypertension and results in systemic derangements. Surgical decompression of ACS
      significantly reduces peak inspiratory pressure while increasing urine output and
      cardiac index. The observed association between ACS and ischemic bowel may result
      from decreased mucosal perfusion as a direct result of abdominal hypertension. In
      our patient population ACS resulted in a 61.1 per cent mortality.

PMID- 12467312
TI  - The benefit of using two techniques for sentinel lymph node mapping in breast
      cancer.
AB  - Sentinel lymph node (SLN) mapping has revolutionized the way we stage breast
      cancer. A blue dye technique (BD) and the use of a radiotracer with the
      assistance of a gamma-detecting probe (GDP) have been used for the identification
      of the sentinel nodes. Some groups have suggested that only one technique is
      necessary. The reported false negative rates have been 0 to 12 per cent and
      success rates as low as 65 per cent. We have prospectively evaluated these
      techniques and have used both for the identification of the SLN. Ten surgeons
      participated in this study. From April 1998 through May 1999, 58 patients
      underwent SLN mapping followed by an axillary lymph node dissection. After the
      injection of 0.3 to 1.96 mCi of filtered sulfur colloid diluted to 4 mL all
      patients had preoperative lymphoscintigraphy. Five minutes before surgery 3 to 5
      mL of isosulfan blue was injected around the tumor or tumor bed. Even though
      preoperative lymphoscintigraphy identified an SLN in 35 patients (63%) successful
      intraoperative detection of an SLN was possible using both techniques in 53
      patients (91%). The SLN was detected by the BD and the GDP in 37 (65%) and 45
      (80%) respectively. Nineteen patients (33%) were positive for metastatic disease
      in the axilla. Twenty-two (19%) of 113 SLNs removed were positive for disease.
      All cases of metastatic disease in the axilla were detected by the mapping
      technique. False negative rate was 0 per cent. In 11 patients the only positive
      node was the sentinel node (58%). Furthermore six (32%) patients were upstaged by
      the use of immunostains for cytokeratin. Twenty-two positive SLNs were detected
      in the 19 patients. The positive lymph node was identified only by BD in four
      patients (21%), only by GDP in six patients (31%), and by both techniques in nine
      patients (47%). We conclude that if only one technique had been used the false
      negative rate could have been as high as 32 per cent. Both techniques must be
      used to obtain a low false negative rate and high yield in the identification of
      the SLN.

PMID- 12467313
TI  - Infection in penetrating abdominal trauma: risk factors and preventive
      antibiotics.
AB  - Infection remains the greatest risk for victims of penetrating abdominal injury
      with major infections occurring in 10 to 15 per cent. Attributable mortality is
      approximately 30 per cent of those who develop major abdominal infections. In
      addition to this morbidity infection adds approximately $43,000.00 of hospital
      charges per infected patients. This article addresses two significant areas: risk
      factors and antibiotic utilization. The most important risk factor is the
      presence of hollow viscus injury; colonic wounding carries the highest incidence
      of infection relative to intra-abdominal organs injured. Pancreatic and liver
      injuries significantly increase infection risk when combined with hollow viscus
      wounds. The degree of injury as measured by the volume of hemorrhage and the
      presence of shock as well as the anatomic degree of injury likewise correlates
      with the incidence of septic morbidity. Antibiotic utilization is addressed by
      the three issues of antibiotic agents of choice, duration of administration, and
      optimal dosing. Regimens of choice should include anaerobic coverage. Twenty-four
      hours of antibiotic administration is satisfactory with currently available
      agents. Evidence-based medicine analyses from the Eastern Association for the
      Surgery of Trauma have addressed those two issues. There are few data on optimal
      dosing. Increased volumes of distribution and rates of excretion have been
      demonstrated in trauma patients. This would suggest that higher-than-normal doses
      should be used. Laboratory studies would support such an approach. However,
      significant clinical research is desirable to address issues of concentration
      dependent bacterial killing and time-dependent killing. Those pharmacodynamic
      considerations are variable among antibiotic classes.

PMID- 12467314
TI  - Surgical management of esophageal perforation: role of esophageal conservation in
      delayed perforation.
AB  - Definitive repair of esophageal perforation is considered the preferred treatment
      for patients presenting early (<24 hours). However, the optimal management of
      delayed presentation (>24 hours) has not been well defined. This study examined
      the management of esophageal perforation and compared the outcomes of early
      versus delayed presentation. Records of patients admitted with the diagnosis of
      esophageal perforation were reviewed. Contrast studies were used to confirm the
      diagnosis in all cases. Patient demographics and outcome were analyzed to
      determine differences between early and delayed presentation. A total of 22 cases
      of esophageal perforation were identified (eight early vs 14 delayed
      presentations). Operative interventions included primary repair (four),
      reinforced repair (14) either with intercostal muscle or pleural flap, and a
      complete esophageal resection (one). Debridement and drainage without repair were
      done in two patients and a proximal intramural tear was treated with antibiotics
      and observation. Two patients died during hospitalization. All surviving patients
      had near-normal restoration of esophageal function. Follow-up at 3 years has
      shown minimal gastrointestinal problems. One patient required repeat esophageal
      dilatations and two patients underwent antireflux therapy. Esophageal repair
      should be considered in all cases of nonmalignant esophageal perforation and
      should not be influenced by the time of presentation.

PMID- 12467315
TI  - Venous claudication in a child with thrombophilia.
AB  - Deep venous thrombosis (DVT) rarely occurs in active children. Its presence
      usually suggests an inherited or acquired hypercoagulable state. Occasionally
      mechanical obstruction may be the inciting factor in this process. Initial
      management usually consists of sequential heparin and warfarin anticoagulation.
      We present the management of DVT in an adolescent girl with elevated levels of C
      reactive protein and lupus anticoagulant. Venous claudication and severe lower
      extremity swelling on ambulation complicated her course. After more than 2 weeks
      of conservative therapy with anticoagulation thrombolytic therapy was instituted.
      This was terminated early because of mild hematuria. However, follow-up duplex
      scan at 2 years has shown complete resolution of the iliofemoral thrombosis.
      Spontaneous DVT in children differ from that in adults in that an underlying
      etiology can usually be uncovered. These differences are explored.

PMID- 12467316
TI  - Valid informed consent: a process, not a signature.
AB  - Surgeons have dutifully used "consent forms" for most of the last century. But
      only in the last two decades have we begun to understand the difference between a
      patient's legalistically signed form and the meaningful process of communicating
      the reasons for considering surgical or other invasive intervention. Furthermore,
      we must be reasonably assured that the patient is legally competent, understands
      the situation and alternatives, and is not coerced (by family or medical
      professionals) in the decision-making. To accomplish this, time-consuming patient
      education and negotiation are necessary. To limit this process to a brief
      agreement that the procedure should be done and the patient is willing (as
      evidenced by a signature) is to return to paternalism. Little evidence suggests
      that such signing is valid. Of more importance, patients want and are owed a
      clear understanding of what is probably ahead including risks and preventive
      measures to limit complications. This article analyzes the components of
      "consent," suggests methods to ensure the validity of the agreement, and proposes
      that an educated patient benefits greatly by an appropriate process.

PMID- 12467317
TI  - Type B aortic dissection with rupture of the left common iliac artery: a case
      report.
AB  - Type B aortic dissection involves the appearance of a false lumen distal to the
      left subclavian artery and extending distally into the descending thoracic aorta
      and into the abdominal aorta. Complications of the dissection include rupture of
      the thoracic aorta, leg ischemia, visceral ischemia, and renal failure. A 37-year
      old man presented with complaints of sudden onset of chest pain, left leg pain,
      and numbness. Examination revealed no femoral, popliteal, or distal pulses with
      decreased sensory and motor function on the left lower extremity. A CT scan
      revealed an aortic dissection at the proximal descending aorta extending into the
      iliac arteries with a left retroperitoneal hematoma at the iliac bifurcation. An
      MRI confirmed the dissection distal to the left subclavian artery into the iliac
      artery with a distal occlusion. Exploration revealed rupture of the left iliac
      artery dissection with arterial occlusion and a contained hematoma. The common
      iliac artery was ligated and an 8-mm Dacron bypass graft from the right common
      femoral artery to the left femoral artery was performed. Type B aortic dissection
      can present as rupture of the common iliac artery. Revascularization of the
      extremity with a femoral-femoral crossover graft is the recommended procedure in
      the absence of visceral ischemia. The surgeon should have a keen suspicion of
      this rare complication and its management.

PMID- 12467318
TI  - Giant retroperitoneal sarcoma: a case report and review of the management of
      retroperitoneal sarcomas.
AB  - A 42-year-old man presented with lower abdominal pain and a vague abdominal mass.
      He underwent resection of a well-differentiated liposarcoma arising from his
      retroperitoneum measuring 50 cm and weighing 11.7 kg (25.8 lb). This is the
      second largest retroperitoneal soft-tissue sarcoma (RSTS) that has been reported.
      Over the last 15 years 1123 patients with RSTS in 25 series have been reported
      with a mean tumor size of 15.7 cm. RSTS represents 0.10 to 0.15 per cent of all
      malignancies but 45 per cent of all retroperitoneal tumors. Diagnosis and
      treatment of RSTS can be extremely challenging for a general surgeon. Symptoms
      are nonspecific and may occur only after the tumor is very large. Abdominal
      discomfort is the presenting complaint in 60 to 70 per cent of patients and
      palpable mass in 70 to 80 per cent. Treatment of RSTS remains surgical. Multiple
      trials of chemotherapy and radiation therapy show no survival benefit. The only
      successful treatment of this tumor is complete excision; 51.4 per cent of tumors
      can be completely excised, and 50.2 per cent of these excisions include adjacent
      organs. Long-term prognosis without complete excision is grim with average 5- and
      10-year survival rates of 16.7 and 8.0 per cent. With aggressive surgical therapy
      survival is increased to 58.0 and 39.6 per cent.

PMID- 12467319
TI  - Conservatism and new technology: the impact on abdominal aortic aneurysm repair.
AB  - The last decade has represented a time of fundamental change in the treatment of
      abdominal aortic aneurysms (AAAs). Potentially, vascular surgeons will either
      acquire catheter-based skills or relinquish the care for many patients with
      infrarenal AAA. We investigated AAA referral patterns and method of AAA repair
      after the establishment of an endovascular AAA program at our institution. We
      conducted a retrospective review of elective AAA repairs after the initiation of
      an endovascular AAA program in April 1994. Six vascular surgeons performed all
      procedures with a clear distinction between the surgeons (n=3) who performed
      traditional AAA repair only and those (n=3) who managed AAAs by means of either
      endovascular or traditional treatment. From April 1994 through December 2000, 740
      elective AAA repairs were performed. During this time the mean number of AAA
      repairs has been 106/year ranging from 75 to 155/year. More notable however is
      the steady increase in the percentage of endovascular AAA repairs from 6 per cent
      of all AAA repairs in 1994 to 61 per cent in 2000. During this time traditional
      surgeons have experienced a plateau in total AAA repairs performed per year with
      their number of open repairs decreasing by 36 per cent. At the same time
      endovascular surgeons have seen a progressive rise in total AAA cases including
      an increase of 200 per cent in open repairs and of 1367 per cent in endovascular
      repairs. Our vascular surgeons who repair AAA utilizing both endovascular and
      open techniques have experienced an increase in aneurysm referrals since the
      advent of an endovascular AAA program. Those who have not adopted endovascular
      skills have seen a decline in their aneurysm practice. The larger question about
      whether or not to embrace new technology before the availability of long-term
      follow-up remains unanswered.

PMID- 12467320
TI  - Stercoral perforation of the sigmoid colon: report of a rare case and its
      possible association with nonsteroidal anti-inflammatory drugs.
AB  - Stercoral perforation of the colon is a rare phenomenon with fewer than 90 cases
      reported in the literature to date. The pathogenesis of stercoral ulceration is
      thought to result from ischemic pressure necrosis of the bowel wall caused by a
      stercoraceous mass. Stercoral perforation in more than 90 per cent of cases
      involves the sigmoid or rectosigmoid colon with associated fecal mass causing
      localized mucosal ulceration and bowel wall thinning due to localized pressure
      effect. We report the case of a 45-year-old woman who presented with a 12-hour
      history of epigastric pain. Significant comorbidities included systemic lupus
      erythematosus, sarcoidosis, hypertension, and previous history of congestive
      heart failure. The patient was also on prednisone and a nonsteroidal anti
      inflammatory drug for joint pains. On physical examination the patient had signs
      of generalized peritonitis. Chest X-ray showed significant free air under the
      diaphragm. Emergency laparotomy revealed localized perforation over the
      antimesenteric border of the sigmoid colon with associated stercoral mass at the
      site of perforation. A segmental resection of the sigmoid colon with end
      colostomy (Hartmann's procedure) was performed. The patient made an uneventful
      recovery. Stercoral perforation is often a consequence of chronic constipation;
      however, there are other predisposing factors as the condition is rare compared
      with the frequency of severe constipation. One of the hypotheses includes the
      association of nonsteroidal anti-inflammatory drugs (NSAIDs) with stercoral
      perforation of the colon. Our case report lends support to this association with
      NSAID use; thus there need to be greater awareness and caution when using NSAIDs
      in chronically constipated patients.

PMID- 12467321
TI  - Ultrasound is not a useful screening tool for acute acalculous cholecystitis in
      critically ill trauma patients.
AB  - Acute acalculous cholecystitis remains a diagnostic challenge in critically ill
      trauma patients. Laboratory studies are nonspecific and associated injuries or
      mental status changes may mask clinical signs and symptoms. We conducted a
      retrospective study to assess the utility of ultrasound in the diagnosis of acute
      acalculous cholecystitis. We hypothesized that ultrasound is inadequate as a
      screening tool for acute acalculous cholecystitis. The abdominal ultrasounds of
      all patients undergoing evaluation for acute acalculous cholecystitis in a 40
      month period at our Level I trauma center were reviewed. Thickened gallbladder
      wall, pericholecystic fluid and emphysematous gallbladder were considered
      positive sonographic criteria. Sludge, cholelithiasis, and hydrops were
      considered suggestive. Patients who did not undergo cholecystectomy had their
      gallbladders evaluated either during subsequent laparotomy or at autopsy or they
      were discharged from the hospital without need for intervention. Sixty-two
      patients were included. Twenty-one patients underwent cholecystectomy for
      presumed acute acalculous cholecystitis. The data revealed a sensitivity of 30
      per cent (6/20) and a specificity of 93 per cent (39/42) for ultrasound
      evaluation. Twenty patients had subsequent hepatobiliary scans [hepato
      iminodiacetic acid (HIDA)] with a sensitivity of 100 per cent (12/12) and
      specificity of 88 per cent (7/8). Our data do not support ultrasound as a
      reliable routine screening tool for acute acalculous cholecystitis. Despite its
      convenience as a bedside procedure ultrasound has insufficient sensitivity to
      justify its use and a more sensitive diagnostic tool should be used.

PMID- 12467322
TI  - Preshunt and postshunt portal vein pressures and portal vein-to-inferior vena
      cava pressure gradients do not predict outcome following partial portal
      decompression.
AB  - This study was undertaken to determine whether preshunt, postshunt, or changes in
      portal vein (PV) pressures or portal vein-to-inferior vena cava (PV-IVC) pressure
      gradients determine outcome following partial portal decompression attained
      through small-diameter prosthetic H-graft portacaval shunt (HGPCS). Seventy-seven
      adults underwent HGPCS (Child's class A 10%, B 56%, and C 34%) and were
      prospectively evaluated per protocol. PV pressures and PV-IVC pressure gradients
      decreased significantly in all patients with shunting (P < 0.001). Eight (10%)
      patients died within 30 days of shunting (Child's class B 50% and C 50%); seven
      of these deaths were due to liver failure. Preshunt, postshunt, and changes in PV
      pressures or PV-IVC pressure gradients with shunting were not different among
      eight perioperative deaths and survivors. At a mean follow-up of 3 years 24 (35%)
      additional patients died. Of late deaths 62 per cent were due to liver failure
      (Child's class B 40% and C 60%). Again preshunt, postshunt, or changes in PV
      pressures and PV-IVC pressure gradients with shunting did not predict who would
      die of late liver failure. We conclude that the small-diameter HGPCS effectively
      provides partial portal decompression. Preshunt or postshunt PV pressures or PV
      IVC pressure gradients or changes in pressures with shunting do not determine
      outcome following HGPCS. Long-tern outcome is influenced by the severity of
      cirrhosis before shunting and by the self-destructive behaviors typical of
      patients with alcoholic cirrhosis.

PMID- 12467323
TI  - Morbidity and mortality of short-bowel syndrome in infants with abdominal wall
      defects.
AB  - Total parenteral nutrition (TPN) has made survival beyond infancy possible for
      many infants who have sustained small intestinal loss as a result of
      gastroschisis or omphalocele. The length and quality of life in these patients
      have often been limited by the development of late sequelae secondary both to the
      protracted use of TPN and the long-term complications of a shortened gut. This
      study was undertaken to determine what factors influence the morbidity and
      mortality of short-bowel syndrome (SBS) due to gastroschisis or omphalocele. A
      retrospective chart review of 850 infants who received TPN from January 1977
      through December 1999 was carried out. All infants were treated at one academic
      medical center; those who had received > or =3 months of TPN were further
      segregated and their diagnosis, surgical procedures, length of bowel, ability to
      wean from TPN, follow-up weight and height, and developmental progress were
      recorded. Seventeen children were identified with SBS and either gastroschisis or
      omphalocele. Tight primary or secondary closure of the abdominal wall was
      believed to be a major cause of bowel necrosis and SBS in at least ten of the 17
      patients. Overall survival was 76 per cent (13/17); survival was correlated with
      length of remaining bowel and was 86 per cent in patients having more than 15 cm
      of small bowel remaining but only 33 per cent in patients with less than 15 cm of
      small bowel remaining (P = 0.05). A longer length of residual small bowel
      resulted in a significantly shorter duration of TPN with a mean duration of 1.0
      year for survivors having >38 cm and 10.0 years for survivors with <38 cm of
      bowel remaining (P = 0.03). Hepatic dysfunction with progressive failure
      resulting from TPN was related to death in three of the four nonsurvivors. The
      presence or absence of an ileocecal valve appeared unrelated both to the success
      of TPN weaning and to the length of time on TPN (P > 0.2). Eight of the 13
      survivors have no ileocecal valve; five have undergone >50 per cent colonic
      resection. Nine of the survivors have adapted to enteral feedings (mean 36 +/- 60
      months) during which time weaning from TPN occurred. The mean age of survivors is
      7.9 +/- 5.1 years. Near-normal weights (defined as exceeding the fifth percentile
      for weight) were achieved for 92 per cent of the patients (12/13) with 46 per
      cent of the patients (6/13) exceeding the 50th percentile. Near-normal heights
      (exceeding the fifth percentile) were achieved for 77 per cent of the patients
      (10/13) with 15 per cent of the patients (2/13) exceeding the 50th percentile.
      Quality of life was measured on the basis of return to public school: nine of ten
      school-age survivors attend school and eight are normal without signs of
      developmental delay. Tight abdominal closure of gastroschisis or omphalocele may
      cause bowel necrosis and SBS. TPN has improved the long-term survival and quality
      of life in infants with SBS.

PMID- 12467324
TI  - Routine chest radiograph is not indicated after open tracheostomy: a multicenter
      perspective.
AB  - Obtaining a chest radiograph (CXR) after open tracheostomy has been standard
      practice for many surgeons. We hypothesized that routine CXR after uncomplicated
      open tracheostomy is unnecessary. A prospective multicenter protocol was carried
      out on adult surgical patients undergoing uncomplicated tracheostomy. CXR was not
      routinely ordered in the immediate postoperative period but was obtained only for
      clinical indications. Preoperative and subsequent postoperative CXRs were
      reviewed for evidence of complications. Twenty-two surgeons at four institutions
      performed 151 tracheostomies. Posttracheostomy CXR was not diagnostic in four
      patients with potential tracheostomy-related complications (i.e., tachypnea,
      tachycardia, desaturation, and elevated peak airway pressure). In the 147
      patients without clinical indications for CXR subsequent CXR revealed no
      significant new findings. In this era of cost containment the need for CXR after
      tracheostomy must be questioned. Routine CXR is not indicated or cost effective
      after uncomplicated open tracheostomy in adults.

PMID- 12467325
TI  - Laparoscopically assisted hemicolectomy for Crohn's disease: are we still getting
      better?
AB  - The most common indications for laparoscopic surgery in Crohn's disease include
      ileocolic resection and right hemicolectomy. The aim of this study was to compare
      the results of right hemicolectomy in an early phase versus a later phase.
      Between August 1992 and October 1998 all patients who underwent laparoscopic
      surgery for ileocolic resection and right hemicolectomy were divided into
      chronological groups: Group I = August 1992 to January 1996 and Group II =
      February 1996 to October 1998. Statistical analysis was performed using the Mann
      Whitney test, Student t test, or Fisher's exact test. We identified 41 patients;
      16 patients [eight females and eight males with an average age of 37.1 (range 20
      59) years] were in Group I and 25 [16 females and nine males with an average age
      of 41.9 (range 15-74) years] were in Group II [P = not significant (NS)]. Overall
      there were five (12%) intraoperative complications reported: two (12%) in Group I
      and three (12%) in Group II (P = NS). Mean operative time was 149 (range 90-260)
      minutes in Group I versus 158 (range 100-285) minutes in Group II (P = NS). Mean
      length of hospital stay was 7.4 (range 4-18) days in Group I and 6.6 (range 3-20)
      days in Group II (P = NS). Four patients (25%) in Group I and seven (28%) in
      Group II had their procedures converted to laparotomy (P = NS). In Group I four
      (25%) patients had surgery-related postoperative complications, one of which was
      wound related. One patient has an anastomotic leak whereas two had prolonged
      postoperative ileus. In Group II six (24%) patients had surgery-related
      complications, two of which were wound related, three were cases of prolonged
      postoperative ileus, and one was an anastomotic leak (P = NS between Groups I and
      II). Perhaps as a result of the relative technical ease of right-sided resections
      or the nature of the disease the expected decrease in morbidity and conversion
      rate over time could not be shown.

PMID- 12467326
TI  - A validation trial of subdermal injection compared with intraparenchymal
      injection for sentinel lymph node biopsy in breast cancer.
AB  - Sentinel lymph node (SLN) biopsy is increasingly being used as an accurate and
      less morbid surrogate for axillary dissection. However, a standardized technique
      in the biopsy of SLNs is not used. Some authors propose subdermal injection to be
      as accurate as peritumoral intraparenchymal injection (IPI). Our objective is to
      determine whether the SLNs identified by subdermal injection truly represent SLNs
      and match those found with IPI. Specific end points of the study were 1)
      successful localization of the SLN by the IPI of isosulfan blue or the
      radiocolloid intradermal injection, 2) successful uptake of radiocolloid and
      isosulfan blue on individual SLN, and 3) determination of the frequency with
      which the radiocolloid injection detected the "gold standard" blue SLN. SLNs were
      found in 71 of 73 cases (success rate = 97%). Blue SLNs were identified in 64
      patients (88%). SLNs in 61 patients (84%) were radioactive. A total of 112 SLNs
      were identified in 71 patients (1.6 nodes/patient). Seventy-six of 87 SLNs found
      with IPI were also radioactive (concordance of 87%). All SLNs harboring
      metastatic cancer (16 patients) were found by both techniques, being both blue
      and radioactive. Our results support the concept of shared lymphatic pathways in
      the breast with a high degree of communication between the subdermal lymphatics
      and the intraparenchymal lymphatics. The success in identification of the SLN is
      made simpler and improved by the addition of subdermal radiocolloid injection.

PMID- 12467327
TI  - Percutaneous dilatational tracheostomy is as safe as open tracheostomy.
AB  - Although percutaneous dilatational tracheostomy (PDT) has been advocated as an
      alternative to open tracheostomy (OT) its relative safety has been questioned
      repeatedly. This study prospectively compared the safety and complications of PDT
      and OT. Ninety-four patients underwent PDT and 252 patients underwent OT at this
      institution from December 1998 through April 2000 with the choice of procedure
      left to the operator. OT was performed in the operating room whereas PDT was
      performed in intensive care units (ICUs). PDT was performed by surgeons and
      medical intensivists under a strict institutional policy and procedure governing
      patient selection and conduct of the procedure. Complications were defined as
      bleeding, loss of airway, hypotension, hypoxia, tracheostomy tube malposition,
      subcutaneous emphysema, infection, and conversion of PDT to OT. All patients
      survived the operation. PDT and OT had similar complication rates: 2.1 per cent
      for PDT versus 2.8 per cent for OT (P = not significant). Postoperative bleeding,
      which was the most frequent complication, occurred in one PDT patient and four OT
      patients. One PDT patient required conversion to OT as a result of extensive
      tracheal fibrosis. Subcutaneous emphysema, soft-tissue infection, and a
      malpositioned tracheostomy tube were the remaining complications in the OT
      patients. We conclude that the complication rates of PDT and OT are comparable.
      The choice of PDT or OT should be dictated by the surgeon's training and
      experience, the patient's condition, neck anatomy, and stability for transfer to
      the operating room.

PMID- 12467328
TI  - Benign anatomical mistakes: the correct anatomical term for the recurrent
      laryngeal nerve.
AB  - The term recurrent laryngeal nerve has been adopted by Nomina Anatomica (1989)
      and Terminologia Anatomica (1998) to describe this vagus branch from its origin,
      its turn dorsally around the subclavian artery and the aortic arch, and its
      cranial pathway until it reaches its terminal organs in the neck. However, there
      is still much confusion, and either the terms inferior and recurrent laryngeal
      nerve are used interchangeably or inferior laryngeal nerve is considered the
      terminal branch of the recurrent laryngeal nerve. We hereby feel that it is
      necessary to reassess the term and we propose the term inferior laryngeal nerve
      for the entire nerve under consideration, from its origin from the vagus nerve to
      its destinations, including tracheal, esophageal, and pharyngeal branches. If the
      term superior laryngeal nerve is a given, standard and accepted term in the
      anatomical terminology, then logically the term inferior laryngeal nerve should
      also be accepted, as opposed to it. Of course the upward travel of the inferior
      laryngeal nerve is "recurrent". When nonrecurrence is encountered together with
      an arteria lusoria, a retroesophageal right subclavian artery or a right aortic
      arch, we consider that the term nonrecurrent inferior laryngeal nerve should be
      used to describe the deviation from the normal.

PMID- 12467329
TI  - The origins of blood transfusion: early history.

PMID- 12467330
TI  - Re: Laparoscopic repair of inguinal hernias with higher risk for recurrence:
      independent assessment of results from 121 repairs.

PMID- 12467332
TI  - Vitamin D and topical therapy.
AB  - A sequential therapy regimen involving an initial clearing phase of daily
      applications of calcipotriene 0.005% ointment and halobetasol 0.05% ointment for
      2 weeks, followed by halobetasol applied twice daily on weekends and
      calcipotriene applied twice daily on weekdays, has been shown to be effective in
      the management of chronic plaque psoriasis. As a clearing regimen, the combined
      use of halobetasol and calcipotriene for 2 weeks was superior to monotherapy with
      either agent. Subsequently, the use of halobetasol on weekends and calcipotriene
      on weekdays allowed 76% of patients to stay in remission for up to 6 months,
      compared with 40% of patients who applied halobetasol on weekends only and
      placebo on weekdays. Calcipotriene can be inactivated when mixed with some
      topical preparations; however, halobetasol propionate 0.05% ointment and cream
      have been shown to be compatible with calcipotriene for up to 2 weeks. The
      compatibility of calcipotriene and halobetasol permits the use of these agents
      together.

PMID- 12467333
TI  - Vitamin D and UVB radiation therapy.
AB  - Several studies have examined the combination of calcipotriene and UVB radiation
      in the treatment of psoriasis. Most show greater clearing with the combination
      than with monotherapy with either treatment. Data from one study found that
      calcipotriene had a UVB-sparing effect when combined with broadband UVB
      phototherapy, resulting in fewer UVB exposures and a lower cumulative dose. This
      finding suggests that patients treated with calcipotriene may be able to achieve
      lesion clearing with less frequent UVB radiation treatments than those not
      treated with calcipotriene. The combination of calcipotriene and UVB radiation
      does not alter the tolerability or safety of therapy. Calcipotriene may be
      applied at any time up to 2 hours before or immediately after UVB radiation.

PMID- 12467334
TI  - Vitamin D and psoralen plus UVA radiation.
AB  - Psoralen plus UVA (PUVA) light is a very effective and widely used monotherapy
      for psoriasis. However, it is associated with cumulative long-term risks,
      including premature cutaneous aging and skin cancers. Several studies have shown
      that the addition of calcipotriene ointment to PUVA radiation has a UVA-sparing
      effect, clearing psoriatic lesions sooner with lower cumulative doses of UVA
      radiation compared with doses of PUVA radiation alone. A recently completed
      multicenter study in Spain demonstrated that the use of calcipotriene cream plus
      PUVA radiation was also safe and effective for the treatment of plaque psoriasis,
      achieving results that were similar to those obtained with calcipotriene ointment
      plus PUVA radiation. Because creams are cosmetically more acceptable and less
      likely to stain, patients may prefer calcipotriene cream formulations. When used
      in conjunction with PUVA radiation, calcipotriene should be applied after the UVA
      radiation treatment because standard doses of UVA radiation have been shown to
      inactivate calcipotriene.

PMID- 12467335
TI  - Vitamin D and systemic therapy.
AB  - The most frequently used systemic treatments for severe psoriasis are
      methotrexate (MTX), oral retinoids, and cyclosporine; however, all of these
      agents are associated with dose-related toxicities that limit their use. The
      safety and efficacy of topical calcipotriene for the treatment of psoriasis have
      been demonstrated in numerous clinical studies. The rationale for using
      calcipotriene in combination with systemic therapies is based on their different
      modes of action and nonoverlapping side effects. Three controlled clinical trials
      have demonstrated that the addition of calcipotriene ointment to systemic
      antipsoriatic treatment with MTX, acitretin, and cyclosporine increases the
      therapeutic efficacy compared with systemic therapy alone and minimizes side
      effects by either reducing the dosage or duration of treatment.

PMID- 12467336
TI  - Vitamin D and scalp psoriasis.
AB  - Calcipotriene has been shown to be safe and effective for the treatment of
      psoriasis. For scalp psoriasis, the safety advantage of this nonsteroid agent is
      as important as its efficacy. Even though monotherapy with calcipotriene solution
      may not always be efficacious for severe scalp psoriasis, many patients are
      managed effectively with a sequential therapy regimen consisting of 3 phases. In
      phase 1 (clearing), patients apply clobetasol solution or gel in the morning and
      calcipotriene solution in the evening daily for 2 weeks. After the scalp
      psoriasis improves, clobetasol is reduced to weekends and calcipotriene solution
      is applied on weekdays (phase 2, transitional). Phase 3 is maintenance on
      calcipotriene solution alone to prevent recurrence. For patients with
      recalcitrant scalp psoriasis-where only a clobetasol-strength, superpotent
      topical corticosteroid is effective-a flip-flop therapy regimen has been proposed
      that allows for the safe, prolonged use of clobetasol solution by limiting its
      treatment to twice a day for 2-week periods with the use of calcipotriene
      solution twice a day for a minimum of 2 weeks during the corticosteroid-free in
      between periods.

PMID- 12467337
TI  - A pilot twin study of psychological measures of attention deficit hyperactivity
      disorder.
AB  - There has been much interest in the genetics of attention deficit hyperactivity
      disorder and molecular genetic studies are now underway. The success of genetic
      studies will depend on how well the phenotype is defined. Twin studies using
      parent and teacher rated questionnaires or interviews all appear to yield highly
      heritable measures. Nevertheless, there is evidence to suggest that parent
      measures are subject to rater bias. Consequently there has been much interest in
      obtaining more objective measures of related traits such as attention span and
      impulsiveness using, computerised neuropsychological tasks. However there have
      been few twin studies examining the genetic contribution to these
      neuropsychological measures. The present study aims to investigate whether
      performance on the Matching Familiar Figures Test (MFFT) and Continuous
      Performance Task (CPT) is genetically influenced in childhood. 20 monozygotic
      (MZ) and 20 dizygotic (DZ) twin pairs were randomly selected from the Greater
      Manchester Twin Register. Preliminary data suggest that MZ twins perform more
      similarly than DZ twins on the MFFT, but not the CPT. Future work needs to
      examine whether other neuropsychological measures commonly used in research on
      ADHD are genetically influenced using larger twin samples.

PMID- 12467338
TI  - Chromosomal fragility in a behavioral disorder.
AB  - Numerous studies have shown there is consistent evidence implicating genetic
      factors in the etiology of autism. In some cases chromosomal abnormalities have
      been identified. One type of these abnormalities is gaps and breaks nonrandomly
      located in chromosomes, denominated fragile sites (FS). We cytogenetically
      analyzed a group of autistic individuals and a normal population, and we examined
      the FS found in both samples with the aim of (1) comparing their FS expression,
      (2) ascertaining whether any FS could be associated with our autistic sample, and
      (3) examining if there are differences between individual and pooled-data
      analyses. Different statistical methods were used to analyse the FS of pooled and
      individual data. Our results show that there are statistically significant
      differences in the spontaneous expression of breakages between patients and
      controls, with a minimal sex difference. Using the method for pooled data, eight
      autosomal FS have preferential expression in patients and five patients were
      found to be positive at FS Xq27.3. With the method per-individual analysis, four
      FS emerged as specific in our autistic sample. Inferences of FS from pooled data
      were different from those of individual data. The findings suggest that although
      analysis of pooled data is necessitated by the problem of sparse data, analysis
      of single individuals is essential to know the significance of FS in autism.

PMID- 12467339
TI  - Overexpression of a CREB repressor isoform enhances the female sexual receptivity
      in Drosophila.
AB  - The cAMP responsive transcriptional factor, CREB, is highly conserved among
      animal species, and its activity affects their behavior. In Drosophila
      melanogaster, one of alternatively spliced products of the CREB gene, dCREB2-a,
      is a transcriptional activator, while another isoform, dCREB2-b, is a repressor
      of dCREB2-a. Here, we demonstrate that overexpression of dCREB2-b in virgin
      females enhances their sexual receptivity. We studied the role of dCREB2 in
      female mating behavior using two transgenic lines, hs-dCREB2-a and hs-dCREB2-b,
      which overexpress respective products with heat-shock treatment. Wild-type males
      started their courtship behavior and mated more quickly with heat-shocked hs
      dCREB2-b females than with non-heat-shocked hs-dCREB2-b females. Overexpression
      of dCREB2-a in females affected neither their courtship behavior nor mating
      frequency. The effects of overexpressed dCREB2-b were not due to elevated
      locomotor activities of heat-shocked females nor due to more vigorous courtship
      behavior of paired wild-type males. CREB might be involved in female sexual
      behavior of animals.

PMID- 12467340
TI  - QTL analysis of a red junglefowl x White Leghorn intercross reveals trade-off in
      resource allocation between behavior and production traits.
AB  - Behaviors with high energetic costs may decrease in frequency in domestic animals
      as a response to selection for increased production. The aim of this study was to
      quantify production traits, foraging behavior, and social motivation in F2
      progeny from a White Leghorn x red junglefowl intercross (n = 751-1046) and to
      perform QTL analyses on the behavioral traits. A foraging-social maze was used
      for behavioral testing, which consisted of four identical arms and a central box.
      In two arms there was ad libitum access to the birds' usual food, and in the
      other two there was novel food (sunflower seeds) mixed with cat litter. In one
      arm with each of the two food sources, social stimuli were simulated by the
      presence of a mirror. Each bird could therefore feed on novel or well known food
      either alone or in the perceived company of a conspecific. Egg production, sexual
      maturity (females), food intake, and growth were measured individually, and
      residual food intake and metabolic body weight were estimated using standard
      methods. A genome scan using 104 microsatellite markers was carried out to
      identify QTLs affecting behavioral traits. Phenotypic growth rates at different
      ages showed weak associations in both sexes. Sexual maturity and egg weight were
      not strongly correlated to growth, indicating that these traits are not
      genetically linked. Time spent in each arm and in the central part of the maze
      was analyzed using principal component analyses. Four principal components (PC)
      were extracted, each reflecting a pattern of behavior in the maze. Females with
      early onset of sexual maturity scored higher on the PC1 reflecting preference for
      free food without social stimuli, and females with higher egg production scored
      higher on the PC2 reflecting exploration. Males with an overall higher growth
      rate and higher residual food intake scored higher on the PC3, which possibly
      reflected fear of the test situation, and tended to score higher on the PC4
      reflecting low contrafreeloading. Significant QTLs were found for PC1 and PC4
      scores on chromosomes 27 and 7, respectively. The location of the QTLs coincided
      with known QTLs for growth rate and body weight. The results suggest a trade-off
      between energy-demanding behavior and high production and that some of this may
      be caused by genetic linkage or pleiotropic gene effects.

PMID- 12467341
TI  - Food intake, water intake, and drinking spout side preference of 28 mouse
      strains.
AB  - Male mice from 28 inbred strains (129P3/J, A/J, AKR/J, BALB/cByJ, BUB/BnJ,
      C3H/HeJ, C57BL/6J, C57L/J, CAST/Ei, CBA/J, CE/J, DBA/2J, FVB/NJ, I/LnJ, KK/H1J,
      LP/J, NOD/LtJ, NZB/B1NJ, P/J, PL/J, RBF/DnJ, RF/J, RIIIS/J, SEA/GnJ, SJL/J, SM/J,
      SPRET/Ei, and SWR/J) were fed chow and had access to two water bottles. Body
      weight, food intake, water intake, and drinking spout side preference were
      measured. There were large strain differences in all the measures collected, with
      at least a two-fold difference between strains with the lowest and the highest
      trait values. Estimates of heritability ranged from 0.36 (spout side preference)
      to 0.87 (body weight). Body weight, food intake, and water intake were
      interrelated among the strains, although substantial strain variation in food and
      water intakes independent from body weight was present. The strain differences
      described here provide useful information for designing mutagenesis screens and
      choosing strains for genetic mapping studies.

PMID- 12467342
TI  - Voluntary consumption of NaCl, KCl, CaCl2, and NH4Cl solutions by 28 mouse
      strains.
AB  - Male mice from 28 inbred strains (129P3/J, A/J, AKR/J, BALB/cByJ, BUB/BnJ,
      C3H/HeJ, C57BL/6J, C57L/J, CAST/Ei, CBA/J, CE/J, DBA/2J, FVB/NJ, I/LnJ, KK/H1J,
      LP/J, NOD/LtJ, NZB/B1NJ, P/J, PL/J, RBF/DnJ, RF/J, RIIIS/J, SEA/GnJ, SJL/J, SM/J,
      SPRET/Ei, and SWR/J) were tested with NaCl (75-450 mM), KCl (30-300 mM), CaCl2 (3
      100 mM), and NH4Cl (10-300 mM) solutions using two-bottle preference tests with
      water as the second choice. For each mineral, there was a wide range of strain
      variation in solution intakes and preferences. This variation had a substantial
      genetic component as assessed using heritability estimates. In most cases, the
      strain means were continuously distributed; however, strains with deviating high
      or low intakes or preferences were also observed. The associations among the
      responses to different minerals were only modest, suggesting distinct genetic
      controls of sodium, potassium, calcium, and ammonium consumption. These results
      provide a valuable resource for investigators who wish to identify genes involved
      in the regulation of mineral consumption and balance.

PMID- 12467343
TI  - Professionalism and boundaries.

PMID- 12467344
TI  - Boundaries in the doctor-patient relationship.
AB  - Boundaries in the doctor-patient relationship is an important concept to help
      health professionals navigate the complex and sometimes difficult experience
      between patient and doctor where intimacy and power must be balanced in the
      direction of benefiting patients. This paper reviews the concept of boundary
      violations and boundary crossings in the doctor-patient relationship, cautions
      about certain kinds of boundary dilemmas involving dual relationships, gift
      giving practices, physical contact with patients, and self-disclosure. The paper
      closes with some recommendations for preventing boundary violations.

PMID- 12467345
TI  - Relationships, not boundaries.
AB  - The authors find it more useful to pay attention to relationships than to
      boundaries. By focusing attention on bounded, individual psychological issues,
      the metaphor of boundaries can distract helping professionals from thinking about
      inequities of power. It oversimplifies a complex issue, inviting us to ignore
      discourses around gender, race, class, culture, and the like that support
      injustice, abuse, and exploitation. Making boundaries a central metaphor for
      ethical practice can keep us from critically examining the effects of distance,
      withdrawal, and non-participation. The authors describe how it is possible to
      examine the practical, moral, and ethical effects of our participation in
      relationships by focusing on just relationships rather than on boundaries. They
      give illustrations and clinical examples of relationally-focused ethical
      practices that derive from a narrative approach to therapy.

PMID- 12467346
TI  - The painter and the cameraman: boundaries in clinical relationships.
AB  - The issue of boundaries in clinician-patient encounters is considered through
      narrative analysis of four clinical stories in which boundaries crossings are a
      self-conscious topic. One story is by a physician as patient, two are by
      physicians, and one is by a palliative care nurse. The stories are discussed
      using Walter Benjamin's distinction between the painter, who maintains distance
      and sees the whole, and the cameraman, who uses technology to penetrate realities
      and then reassembles fragments. The essay argues that distance and closeness are
      ethical issues that constitute the possibility of clinical encounters but the
      encounter also changes the clinician's sense of boundaries. The relevant ethics
      of boundary decisions in most clinical encounters are not procedural ethics but
      an ethics of self-creation: in orienting to boundaries as doctors do, they create
      themselves in their relations to others.

PMID- 12467347
TI  - Traversing boundaries: clinical ethics, moral experience, and the withdrawal of
      life supports.
AB  - While many have suggested that to withdraw medical interventions is ethically
      equivalent to withholding them, the moral complexity of actually withdrawing life
      supportive interventions from a patient cannot be ignored. Utilizing interplay
      between expository and narrative styles, and drawing upon our experiences with
      patients, families, nurses, and physicians when life supports have been
      withdrawn, we explore the changeable character of "boundaries" in end-of-life
      situations. We consider ways in which boundaries imply differences--for example,
      between cognition and performance--and how the encounter with boundaries can
      generate altered meanings important for understanding decisions and actions in
      these contexts. We conclude that the reliance on mere roles to support the moral
      weight of withdrawing medical interventions is inadequate. Roles that lead us to
      such moments are exceeded by the responsibility encountered in such moments. And
      here, we suggest, is the momentous character of withdrawal: it presents the grave
      astonishment, the trembling awe, in the "not-being-there" of the other in death.

PMID- 12467348
TI  - The nature of illness experience: a course on boundaries.
AB  - With the Accreditation Council for Graduate Medical Education's designation of
      "professionalism" as one of six core competencies in residency medical education,
      some educators of residents and medical students believe that the concept of
      professional role is too restrictive and narrow for grappling with the complex
      dynamics of professional-patient relationships. The ethical quandaries of
      abortion and physician assisted suicide illustrate how individual personal values
      cannot be ignored in the dynamic relationship between health care professional
      and patient. This article describes a medical school course where students are
      paired with "patient mentors." Within the dynamic and intimate relationship that
      unfolds over several months, students explore the "experience of boundaries," and
      are invited to use this experience to consider their evolving professional
      identity.

PMID- 12467349
TI  - Introduction and expression of foreign genes in cultured mouse embryonic gonads
      by electroporation.
AB  - To analyse the functions of genes that are expressed and potentially involved in
      the development of embryonic gonad cells, a method was developed by which foreign
      genes can be introduced and expressed in cultured mouse genital ridges. Genital
      ridges from mouse embryos at 12.5 days post coitus (dpc) were injected with
      plasmid DNA of a green fluorescence protein (GFP) gene construct and then placed
      between small electrodes. Rectangular pulses were charged to electroporate DNA
      into the cells. The treated genital ridges were cultured on a membrane of a
      culture insert, and GFP gene expression was observed under a fluorescence
      microscope. Green fluorescence protein expression in the genital ridges was found
      as early as 1 h after electroporation. Thereafter, the expression gradually
      increased, peaked after 1 day, and then decreased. A significant number of cells
      were, however, still positive for fluorescence even after 2 weeks in the culture,
      in which both gonads and germ cells had continued to develop. The GFP gene was
      expressed in 1-2% of cells in each genital ridge in a DNA concentration-dependent
      manner. In addition, we confirmed that an electroporated red fluorescent protein
      (DsRed) gene construct was expressed in GFP-expressing primordial germ cells in
      genital ridges of Oct-4/GFP transgenic embryos, although the DNA was mainly found
      in somatic cells in genital ridges. Finally, an expression vector containing the
      internal ribosome entry site-green fluorescent protein (IRES-GFP) gene was
      constructed. An inserted lacZ gene showed similar expression pattern to that of
      GFP Using this vector, we can easily monitor the expression of an inserted gene
      of interest by GFP expression. Therefore, this experimental system could be
      useful for quick assays of gene function in genital ridges.

PMID- 12467350
TI  - Storage of cane toad (Bufo marinus) sperm for 6 days at 0 degrees C with
      subsequent cryopreservation.
AB  - We investigated the recovery of motility of cane toad (Bufo marinus) sperm after
      storage for 6 days at 0 degree C (on ice) and after subsequent cryopreservation.
      Sperm suspensions were prepared from testes macerated in either simplified
      amphibian Ringer (SAR) or 10% (w/v) sucrose diluents, with 15% or 20% (v/v)
      glycerol or Me2SO as cryoprotectants, and were stored for 6 days. Alternatively,
      suspensions were prepared in either SAR or 10% (w/v) sucrose diluent and stored
      for 6 days, after which some of these suspensions were kept in diluents alone or,
      alternatively, had 15% or 20% (v/v) glycerol or Me2SO added. All treatments
      (suspensions) were then cryopreserved. Sperm motility was measured at Day 1 and
      Day 6 (before and after cryopreservation). A substantial and variable proportion
      (range 0%-40%) of sperm was immotile in suspensions immediately after preparation
      from testes macerates. Sperm stored in either SAR or 10% (w/v) sucrose diluent
      maintained approximately 75% motility for 6 days, but few sperm survived
      cryopreservation. After storage and cryopreservation, recovery of motility was
      substantially higher with Me2SO than in glycerol. However, both cryoprotectants
      exhibited toxicity at high concentrations. Glycerol was more toxic than Me2SO in
      10% (w/v) sucrose than in SAR diluent, both before and after cryopreservation.
      The addition of some cryoprotectants to suspensions before storage gave greater
      recovery both before and after cryopreservation. After cryopreservation, the
      highest rate of sperm recovery was in suspensions with 10% (w/v) sucrose and 15%
      (v/v) Me2SO added prior to storage (mean (+/-SEM) 46 +/- 7% relative to initial;
      39 +/- 6% absolute). Sperm were also stored for 6 days at 0 degrees C in
      suspensions or testes (with suspensions then prepared from testes) and
      cryopreserved. Sperm maintained higher recovery and membrane integrity both
      before and after cryopreservation when stored in suspensions rather than in
      testes.

PMID- 12467351
TI  - In vitro production of pig embryos: a point of view.
AB  - Porcine embryos have become raw materials for different programmes of
      reproductive biotechnology and the in vitro production of embryos has some
      advantages over in vivo production in gene transfer programmes and for
      xenotransplantation. Despite this promising future, several problems limit the
      success of the in vitro production (IVP) of viable porcine embryos. Porcine IVP
      has not been fully developed because of several problems associated with
      different techniques, such as incomplete final maturation status after in vitro
      maturation, a high incidence of polyspermy after in vitro fertilization and a low
      development rate and poor quality of blastocysts at the end of culture. The
      results could be improved with studies comparing in vivo and in vitro conditions,
      standardization of techniques for sperm processing, testing new additives in the
      culture media and developing intracytoplasmic sperm injection procedures. The
      first objective of the present article is to summarize the main studies published
      on the subject. Second, we provide a guide for researchers starting work on the
      IVP of pig embryos, making special mention of first papers and the most recent
      achievements for each of the different techniques. Third, we provide suggestions
      for future experiments designed to improve the results of each technique.

PMID- 12467352
TI  - Persistence of pregnant mare serum gonadotrophin in plasma of Japanese quail
      (Coturnix coturnix japonica).
AB  - Pregnant mare serum gonadotrophin (PMSG) is currently being used to develop a
      hormone regime that will stimulate reproductive development in Japanese quail
      (Coturnix coturnix japonica). In this study, the persistence of PMSG in quail
      plasma was examined after a single injection of the hormone (500 IU). Plasma
      concentrations of PMSG increased to a peak 12 h after injection and declined to
      approximately 50% of peak concentrations 24 h after injection. Pregnant mare
      serum gonadotrophin concentrations declined gradually thereafter and had not
      returned to basal levels by 96 h after injection. Cloacal diameter, and ovarian
      and oviducal mass, had increased significantly by 96 h after injection. The
      persistence of PMSG in quail plasma has implications for the use of the hormone
      in future regimes stimulating reproductive activity in birds.

PMID- 12467353
TI  - Effect of protein supplementation on development to the hatching and hatched
      blastocyst stages of cat IVF embryos.
AB  - The effects of protein supplementation in culture medium on development to the
      hatching and hatched blastocyst stages of cat in vitro-fertilized embryos were
      investigated. In the first experiment, presumptive zygotes derived from in vitro
      maturation and in vitro fertilization (IVF) were cultured in modified Earle's
      balanced salt solution (MK-1) supplemented with 0.4% bovine serum albumin (BSA)
      or 5% fetal bovine serum (FBS) for 9 days. There were no significant differences
      between the BSA and FBS groups with respect to the proportion of cleavage and
      development to the morula and blastocyst stages of zygotes. However, the presence
      of FBS in the medium enhanced development to the hatching blastocyst stage of
      zygotes compared with the BSA group (31.4% v. 7.8%). Moreover, 2.9% of zygotes
      cultured with FBS developed to the hatched blastocyst stage. The mean cell number
      of blastocysts derived from zygotes cultured with FBS was significantly higher
      (P<0.01) than that from zygotes cultured with BSA (136.6 v.101.5). In the second
      experiment, embryos at the morula orblastocyst stage, which were produced by
      culturing in MK-1 supplemented with 0.4% BSA after IVF, were subsequently
      cultured in MK-1 with 0.4% BSA or 5% FBS. Significantly more morulae developed to
      the blastocyst (P<0.05) and hatching blastocyst stages (P<0.01) in the FBS group
      than in the BSA group (71.5% and 53.6% v. 44.9% and 6.0%, respectively). Although
      none of the morulae cultured with BSA developed to the hatched blastocyst stage,
      11.5% of morulae cultured with FBS developed to the hatched blastocyst stage.
      Moreover, the proportion of development to the hatching blastocyst stage of
      blastocysts was significantly higher (P<0.01) in the FBS group than in the BSA
      group (68.7% v. 9.8%). None of the blastocysts cultured with BSA developed to the
      hatched blastocyst stage, whereas 7.3% of blastocysts cultured with FBS developed
      to the hatched blastocyst stage. The results of the present study indicate that
      supplementation with FBS at different stages of early embryo development promotes
      development to the hatching and hatched blastocyst stages of cat IVF embryos.

PMID- 12467354
TI  - Apoptosis of endometrial cells in the bitch.
AB  - The relationship between apoptosis of endometrial cells in the bitch, and the
      occurrence of degeneration of the endometrial luminal epithelium and regression
      of the endometrial glandular epithelium was determined. Mature bitches (n = 12)
      were ovariectomized and treated with hormones to simulate uterine changes that
      occur during the oestrous cycle. All bitches were treated with oestradiol
      benzoate (0.6-4.8 microg x kg(-1), i. m., twice per day) for 11-12 days then with
      progestagen (megestrol acetate, 2 mg x kg(-1), p. o., once per day) for 35-37
      days. Bitches were treated daily for a further 3 weeks with megestrol acetate at
      dose rates of 0.5 mg x kg(-1) (decreased-dose group (n = 3)), 2 mg x kg(-1)
      (standard-dose group (n = 3)), or 3 (1 wk), 4 (1 wk) and 5 (1 wk) mg x kg(-1)
      (increased-dose group (n = 3)), or received no treatment (withdrawal-dose group
      (n = 3)). These bitches were necropsied at the end of the treatment period. A
      further 10, ovary-intact, bitches were necropsied when in oestrus (n = 1),
      dioestrus (n = 5), and at 3 weeks (n = 1) and 9 weeks (n = 3) of anoestrus.
      Degeneration of the luminal epithelium was observed in all bitches except those
      in oestrus, at 9 weeks of anoestrus and one in dioestrus. Apoptosis was observed
      in the glandular epithelial cells, stromal cells and endothelial cells of blood
      capillaries in all bitches except those at oestrous and at 9 weeks of anoestrous.
      High average apoptotic indices were detected in the basal glandular epithelium of
      the dioestrous, decreased-dose, standard-dose and increased-dose groups, whereas
      low apoptotic indices were detected at 3 weeks of anoestrous and in the
      withdrawal-dose groups. These results indicate that degeneration of cells of the
      glandular epithelium, but not of the luminal epithelium, was due to apoptosis of
      these cells.

PMID- 12467355
TI  - Boar semen controlled-delivery system: morphological investigation and in vitro
      fertilization test.
AB  - A technology for encapsulation of swine semen in barium alginate and protamine
      alginate has recently been proposed for the controlled release of the
      spermatozoa, thus reducing the number of instrumental inseminations required.
      Controlled-release capsules containing swine spermatozoa were prepared by adding
      saturated BaCl2 solution to ejaculate and dropping the resulting suspension into
      a sodium alginate solution, leading to the formation of barium alginate capsules.
      A second type of capsule was obtained by cross-linking the barium alginate with
      protamine sulfate. Two types of membrane were thus obtained: barium alginate gel
      and a protamine cross-linked alginate membrane. Morphological (scanning electron
      microscopy and transmission electron microscopy), functional (motility, membrane
      integrity and in vitro fertilization test) and technological (capsule structure
      and weight) approaches were used to characterize the encapsulated spermatozoa and
      the controlled-delivery system. No differences in terms of morphological and
      functional characteristics (acrosome integrity and spermatozoa motility) between
      free and encapsulated semen were found. The technological process did not
      compromise in vitro fertilization potency of the spermatazoa, although seasonal
      variability was found. The capsule weight was related to either the pH of the
      semen or the season. This study represents the starting point for the development
      of further investigations into the storage and release kinetics of cells from the
      capsules and for the development of an in vivo fertilization protocol.

PMID- 12467356
TI  - Folliculogenesis in buffalo (Bubalus bubalis): a review.
AB  - The urgent need for improving the reproductive performance of buffalo
      necessitates a better understanding of the mechanisms controlling ovarian
      follicular growth and development. Attention needs to be focused on improving
      superovulation responses and conception rates, and reducing the variability in
      ovulation rate and embryo loss. Application of ultrasonic imaging has revealed
      that follicular turnover during an unstimulated oestrous cycle occurs in waves,
      with each wave involving synchronous development of a group of follicles, one
      dominant and several subordinate follicles. There is a predominance of two waves
      with the first wave beginning around Day 0 (day of ovulation) and the second wave
      around Day 9 or 10. Primary reasons for a lower superovulation response in
      buffalo compared with that in cattle is a lower number of primordial and antral
      follicles, a slower shift from small to large follicles during superovulation, a
      higher incidence of deep atresia and inability of several large follicles to
      ovulate, especially when superovulation is induced by equine chorionic
      gonadotrophin treatment. There is near complete lack of information in Bubalus
      bubalis on the factors controlling the selection of the dominant follicle, the
      period of functional dominance and the effects of environmental factors, such as
      climate and nutrition, on follicular dynamics.

PMID- 12467357
TI  - Production of a biologically active recombinant marsupial growth factor using the
      methylotrophic yeast Pichia pastoris.
AB  - The cytokine stem cell factor (SCF) and its interaction with its receptor c-kit
      plays an important role in the development of germ cells in eutherians. To
      investigate the putative roles of the SCF/c-kit system in marsupials, recombinant
      Australian brushtail possum (Trichosurus vulpecula) SCF was purified after
      secretion by the methylotrophic yeast Pichia pastoris. The purification procedure
      utilized Ni2+ affinity chromatography with a poly-histidine tag engineered onto
      the C-terminus of the recombinant SCE The recombinant possum SCF had a molecular
      weight of 48 kDa, as determined by sodium dodecyl sulphate-polyacrylamide gel
      electrophoresis, and was biologically active with respect to its ability to
      maintain and induce proliferation of marsupial primordial germ cells in vitro.
      Furthermore, the recombinant possum SCF stimulated proliferation of the cell line
      TF1 and this bioactivity could be inhibited using an antibody directed against
      recombinant mouse SCF. This source of biologically active marsupial SCF may prove
      useful in future studies of marsupial development.

PMID- 12467358
TI  - Low maternal nutrition during pregnancy reduces the number of Sertoli cells in
      the newborn lamb.
AB  - The nutritional status of females during pregnancy can play a critical role in
      the postnatal growth and development of the offspring, often leading to permanent
      changes ('fetal programming'). The Sertoli cells are a strong candidate for fetal
      programming of future performance because the number of Sertoli cells is highly
      correlated with adult testicular size and the maximum rate of sperm production.
      For Merino ewes, we imposed different levels of metabolizable energy (ME) intake
      (LowME: 70% of requirements for maintenance of ewe body mass and normal growth of
      conceptus (n = 13); HighME: 110% of those requirements (n = 12)) from Week 10 of
      pregnancy until parturition and then tested for effects on testicular histology
      in newborn males. Pregnant ewes were weighed weekly and lambs were weighed at
      birth and 2 days later. Blood was sampled at the same times. LowME ewes did not
      gain weight, whereas HighME ewes gained 17% over their pretreatment weight.
      Birthweights were higher in HighME lambs than in LowME lambs. Paired testes
      tended to be heavier in the HighME group than in the LowME group (P=0.08). The
      diameter of the testicular cords did not differ. The absolute volume of
      testicular cords (0.36 +/- 0.02 v. 0.30 +/- 0.02 mL for HighME v. LowME,
      respectively; P=0.03) and the number of Sertoli cells (43.0 +/- 2.5 v. 34.5 +/-
      2.0 x 10(8) for HighME v. LowME, respectively; P=0.018) per testis were both
      greater in the HighME than in the LowME group. Plasma follicle-stimulating
      hormone concentrations were not significantly affected at birth or 2 days later.
      We conclude that undernutrition during pregnancy can reduce testicular
      development in the newborn. Depending on the ability of the Sertoli cell
      population to recover between birth and puberty, this may limit the ultimate
      number of Sertoli cells and, hence, the future capacity for sperm production and
      fertility.

PMID- 12467359
TI  - Effect of 2,4-dinitrophenol on the energy metabolism of cattle embryos produced
      by in vitro fertilization and culture.
AB  - In cattle embryos, the proportion of ATP produced by glycolysis increases
      following the major activation of the embryonic genome, and development to the
      blastocyst stage is improved in the presence of 10 microM 2,4-dinitrophenol
      (DNP), an uncoupler of oxidative phosphorylation, from Day 5 to Day 7 of culture.
      In Experiment 1 of the present study, culture of cattle embryos in the presence
      of 10 microM DNP from Day 5 to Day 7 stimulated development to the blastocyst
      stage, but had no significant effects on oxygen, pyruvate or glucose uptake, or
      on lactate production. In Experiment 2, culture of cattle embryos in the presence
      of 10 microM DNP from Day 5 to Day 7, stimulated the metabolism of [2
      14C]pyruvate (a measure of Krebs cycle activity) on all of Days 5, 6 and 7, and
      stimulated metabolism of [5-3H]glucose (a measure of glycolysis) on Day 7 only.
      The results show that 10 microM DNP stimulates oxidative and glycolytic
      metabolism in Day-5 to Day-7 cattle embryos, but this does not fully explain the
      observed increase in developmental competence. We propose that partial inhibition
      or uncoupling of oxidative phosphorylation may reduce the level of intracellular
      reactive oxygen species production, thereby facilitating development.

PMID- 12467360
TI  - Expression of anti-Mullerian hormone mRNA during gonadal and follicular
      development in the brushtail possum (Trichosurus vulpecula).
AB  - The ontogeny of anti-Mullerian hormone (AMH) gene expression in the brushtail
      possum during formation of the ovary and growth of follicles was examined using
      in situ hybridization. For comparative purposes, the expression pattern of AMH
      was also examined in the developing testis. In the female, AMH mRNA was observed
      in the ovary of 50% (3/6) of pouch young collected around the time of sexual
      differentiation of the gonad (Days 1-5): the signal was predominately localized
      to the inner-cortical and outer-medullary region of the ovary. Thereafter, AMH
      mRNA was not observed in the developing ovary until Days 78-113 of postnatal life
      when follicles first formed at the cortical-medullary boundary. At this time, AMH
      mRNA was observed in the cuboidal granulosa cells of some early growing (i.e.
      transitional) follicles and in the granulosa cells of primary follicles.
      Thereafter, AMH mRNA was present in granulosa cells at all subsequent stages of
      follicular growth (i.e. primary through antral), but not in preovulatory
      follicles. In all cases, once follicles had formed, AMH mRNA was limited to the
      granulosa cells and was not observed in the surface epithelium, stromal cells,
      oocytes, theca, corpus luteum, medullary cords, rete or interstitial glands. In
      the possum testis, Sertoli cells strongly expressed AMH around the time of sexual
      differentiation of the gonad, but expression decreased to very low levels in
      adults, suggesting that AMH plays a similar role in brushtail possums to that
      observed in other mammalian species. In conclusion, localization of mRNA for AMH
      exclusively to granulosa cells of growing follicles in the brushtail possum is
      consistent with a central role for this hormone in control of granulosa cell
      function in marsupials. In addition, expression of AMH in the developing ovary
      around the time of morphological sexual differentiation raises intriguing
      questions regarding the possible role of AMH at this time.

PMID- 12467361
TI  - Short-term effects of different thermal conditions during uteroplacental
      ischaemia on fetal growth of Sprague-Dawley rats.
AB  - The purpose of the present study was to investigate the short-term effect of
      various body temperatures on fetal growth during uteroplacental ischaemia. Under
      mild hyperthermia (n = 6), normothermia (n = 6) and hypothermia (n = 6), a 30-min
      period of ischaemia was induced in Sprague-Dawley rat dams by clamping the
      uterine arteries of one uterine horn at 17 days of gestation, leaving the other
      horn undisturbed. Three days later, the bodyweight of the pups, and the weights
      of the brains, livers and placentas were compared using the Mann-Whitney U-test.
      Fetal bodyweight, organ and placental weights were significantly reduced in the
      uterine horns subjected to ischaemia under the conditions of mild hyperthermia
      and normothermia (P<0.05), but not with mild hypothermia, compared with the
      weights in undisturbed uterine horns. It was concluded that both mild
      hyperthermia and normothermia during ischaemia retard the growth of late
      gestation rat pups, in contrast to the sparing effect of mild hypothermia.

PMID- 12467362
TI  - Semen collection from mice: electroejaculation.
AB  - The effects of device type (electrostimulator, function generator or computer
      generated waveforms), waveform (square, triangle or sine wave), probe type (ring
      or strip) and anaesthetic compound (ketamine/xylazine combination or
      pentobarbitone sodium) were investigated on electroejaculation (EEJ) responses of
      C57B1 x CBA and C57Bl/6J mice. Ejaculates were analysed for total sperm count and
      motility variables using computer-assisted sperm analyses. Automated computer
      generated waveforms delivered through a sound card were more effective and
      reproducible compared with waveforms generated by function generator and
      electrostimulator. Sine waves and triangle waves were found to be more effective
      in producing ejaculate than square waves. As an anaesthetic, pentobarbitone
      sodium tended to outperform ketamine/xylazine across waveforms and strains. Strip
      probes failed to produce any ejaculate regardless of the device or waveform
      employed. Sperm obtained by EEJ exhibited poor motility and C5B1/6J mice had
      lower motility variables than C57BI x CBA mice.

PMID- 12467363
TI  - Simultaneous detection of viability and sex of bovine spermatozoa.
AB  - The viability and sex of bovine spermatozoa were simultaneously evaluated. After
      viability and acrosome staining with trypan blue/Giemsa, only live spermatozoa
      became decondensed by a modified papain-dithiothreitol method. Owing to this
      specific effect, live sperm heads were easily distinguished by their enlarged
      size and dark violet colour from small, light blue dead sperm heads. In the same
      sperm sample, X- and Y-chromosome-bearing sperm were distinguished by their
      fluorescent signal, using fluorescence in situ hybridization (FISH) with an XY
      paint set and 4,6-diamino-2-phenylindole counterstaining. The combined staining
      provides a method for morphological and viability evaluation before FISH and
      permits identification of the proportions of X- and Y-chromosome-containing live
      spermatozoa in a semen sample. However, only 25% of the undecondensed dead sperm
      express signals allowing detection of the sex of the chromosome. The method may
      be an effective tool in evaluating sex-oriented semen samples.

PMID- 12467364
TI  - Susceptibility of reproduction in female pigs to impairment by stress and the
      role of the hypothalamo-pituitary-adrenal axis.
AB  - Although it is generally considered that stress can impair reproduction, we
      suggest that the impact of acute or repeated acute stress or acute or repeated
      acute elevations of cortisol are of little consequence in female pigs, even if
      these occur during the series of endocrine events that induce oestrus and
      ovulation. It is important to understand the impact of acute stress on
      reproduction because, in the intensive production of livestock, animals are often
      subjected to short-term challenges. There seems little doubt that reproduction in
      a proportion of female pigs is susceptible to impairment by severe and prolonged
      stress or the sustained elevation of cortisol but only when this continues for a
      substantial period. In female pigs, where reproduction is susceptible to
      impairment by severe prolonged stress, it is possible that the mediators of this
      suppression are cortisol, corticotrophin-releasing factor and vasopressin but, in
      pigs, there is evidence to suggest that adrenocorticotrophic hormone is not
      involved. Other substances secreted during stress may be involved but these are
      not considered in this review. It is possible that the mediators of stress act at
      any level of the hypothalamo-pituitary-ovarian axis. Although a variety of
      experimental manipulations have provided potential mediators and mechanisms for
      the stress-induced suppression of reproduction, these experimental manipulations
      rarely represented physiological circumstances so it is not clear if such
      mechanisms would be important in a physiological context. The precise mediators
      and mechanisms by which hormones released during stress may inhibit reproductive
      processes during severe prolonged stress are yet to be determined.

PMID- 12467365
TI  - Translations of the International Outcome inventory for Hearing Aids (IOI-HA).

PMID- 12467366
TI  - Extending the IOI to significant others and to non-hearing-aid-based
      interventions.
AB  - Two extensions of the International Outcome Inventory for Hearing Aids are
      described: the first is designed for the significant other (SO) (IOI-HA-SO), and
      the second for alternative interventions for hearing difficulties (IOI-AI). A
      feature of the IOI-HA-SO is that several items are modified to inquire about
      effects of the partner's hearing loss on the SO. The IOI-AI is designed to cover
      effects of use of listening aids other than personally worn hearing aids, use of
      hearing tactics, and aural surgery.

PMID- 12467367
TI  - The International Outcome Inventory for Hearing Aids (IOI-HA): psychometric
      properties of the English version.
AB  - The International Outcome Inventory for Hearing Aids (IOI-HA) is a seven-item
      questionnaire designed to be generally applicable in evaluating the effectiveness
      of hearing aid treatments. The inventory was developed to facilitate cooperation
      among researchers and program evaluators in diverse settings. It is brief and
      general enough to be appended to other outcome measures that might be planned in
      a particular application, and will provide directly comparable data across
      otherwise incompatible projects. For this plan to be successful, it is essential
      to generate psychometrically equivalent translations in the languages in which
      hearing aid research and treatment assessments are performed. This article
      reports the psychometric properties of the inventory for the original English
      version. The items are reasonably internally consistent, providing adequate
      statistical support for summing the scores to generate a total outcome score.
      However, for maximum internal consistency, it would be desirable to generate two
      scores for the inventory.

PMID- 12467368
TI  - International Outcome Inventory for Hearing Aids (IOI-HA): results from The
      Netherlands.
AB  - This paper presents data on the Dutch translation of the International Outcome
      Inventory for Hearing Aids (IOI-HA). The inventory was used as an additional
      postal tool in a nationwide study on the benefits of bilateral hearing aid
      fitting. Responses of 505 hearing aid users were analysed. Descriptive statistics
      and inter-item correlations are reported. Factor analysis resulted in the
      extraction of two factors. Cronbach's alpha coefficients and corrected item total
      correlations showed high internal consistency of the scales. Significant
      correlations were found between IOI Factor 2 and the Hearing Handicap and
      Disability Inventory and subscales of the Amsterdam Inventory for Hearing
      Disability and Handicap.

PMID- 12467369
TI  - The International Outcome Inventory for Hearing Aids (IOI-HA) and its
      relationship to the Client-oriented Scale of Improvement (COSI).
AB  - The International Outcome Inventory-Hearing Aids (IOI-HA) was administered to 161
      consecutive patients who had been fitted with hearing aids just prior to their
      being discharged from the clinic. Most also completed the Client-oriented Scale
      of Improvement (COSI). Very few questions (<2%) were not completed. Analyses
      indicated two subscales of IOI-HA, one of which could be defined as a 'benefit'
      subscale and the other a 'residual problems' subscale. Both elements of COSI
      correlated with the 'benefit' subscale, but only the 'residual' measure of COSI
      related to the 'residual problems' subscale. There were no consistent
      relationships between the IOI-HA and a range of demographic factors.

PMID- 12467370
TI  - Directivity of different hearing aid microphone locations.
AB  - In this study, we present a new method to derive a single-number measure of the
      directivity of hearing aids. The method is an extension of the conventional
      directivity index (DI), and is called overall directivity index (ODI). The
      directivities of five different hearing aid styles were compared with that of the
      open ear. The behind-the-ear (BTE) style showed the lowest directionality
      compared to the other hearing aid styles and the open ear. There were only minor
      differences in directivity between any of the four different hearing aid styles
      placed in the ear and of the open ear canal. The conventional measure of DI is
      less suitable for hearing aids, because it ignores sound coming from other than
      the frontal direction. To quantify directionality of a hearing aid in a real-life
      situation, we suggest the single-number ODI, weighted with the articulation index
      and related to a listening segment of 0-30 degrees. An application of the data is
      shown for a BTE with a directional microphone.

PMID- 12467371
TI  - Unilateral sensorineural hearing impairment in childhood: analysis of 31
      consecutive cases.
AB  - This report presents the selected variables of a consecutive series of 1-10-year
      old children with unilateral sensorineural hearing impairment (USNHI; defined as
      four-frequency pure-tone audiometry (PTA) 0.5, 1, 2, 4 kHz > or = 30 dB HL):
      severity, presumptive aetiologies, age at ascertainment, hearing aid acceptance,
      non-verbal intelligence, time of occurrence of first words and two-word
      utterances, size of vocabulary, and linguistic achievements. During a 4-year
      period in a defined geographical area of Germany (Lower Saxony), 31 children were
      carefully audiologically and psychologically examined at the Department of
      Phoniatrics/Pedaudiology, University of Gottingen. All children were fitted
      unilaterally with a hearing aid. The HI was mild in 3%, moderate in 23%, severe
      in 29% and profound in 45% of the cases. The hearing defect was congenital in
      23%, postnatally acquired in 16%, and of unknown onset in 61% of the cases. The
      affected side was the right in 17 cases, and the left in 14. The mean age at
      ascertainment was 65.5 months (SD 25.5; median 70). According to parental
      judgement, nearly 81% of the children had accepted their hearing aid (based on
      the daily/weekly time for which the child was using the hearing aid). On average,
      the children scored in the normal range in standardized non-verbal intelligence
      tests. They were delayed in using two-word phrases (on average for 5 months), but
      not in using their first words. However, children with USNHI experienced no more
      difficulty on standardized linguistic tasks than normally hearing subjects of the
      same age and gender.

PMID- 12467372
TI  - Otoacoustic emissions in the general adult population of Nord-Trondelag, Norway:
      I. Distributions by age, gender, and ear side.
AB  - Transient evoked otoacoustic emissions (TEOAEs) and distortion-product
      otoacoustic emissions (DPOAEs) are described as a function of age, gender and ear
      side in an unscreened adult population of 6415 subjects comprising a subsample of
      the 51975 subjects from the Nord-Trondelag Hearing Loss Study. While most
      descriptions of OAEs are from samples selected based on hearing threshold, the
      present sample is from a less selected general population. The OAEs were recorded
      as a part of the programme of a general health screening. The large sample size
      provided accurate estimations of mean values. TEOAEs were analysed at 1, 2 and 4
      kHz. DPOAEs were measured with f2 frequencies of 2, 3, 4, 6, and 8 kHz. Signs of
      bimodality were seen in the OAE density distributions of the > or = 45-year age
      group. The OAEs declined as a function of age, with the steepest gradient between
      30 and 65 years. OAEs were generally higher in females than in males and in right
      ears than in left ears. Controlling for pure-tone thresholds reduced some of the
      effects of age, gender and ear side.

PMID- 12467373
TI  - Otoacoustic emissions in the general adult population of Nord-Trondelag, Norway:
      II. Effects of noise, head injuries, and ear infections.
AB  - Otoacoustic emissions (OAEs) have been suggested as a sensitive measure of
      cochlear function with the potential for preclinical detection of damage. The
      present work assesses the risk for decreased OAEs associated with occupational
      and leisure noise, head injuries and recurrent ear infections. The predictive
      power of the environmental factors on different OAE values is compared with the
      prediction of conventional pure-tone hearing thresholds (PTTs). The analyses are
      based on data from 5072 adult subjects comprising a subsample of the 51975
      subjects from the Nord-Trondelag Hearing Loss Study. The subjects participated in
      a general health screening, including an examination of pure-tone audiometry,
      transient OAEs and distortion-product OAEs, and completed a questionnaire
      regarding history of noise exposure and ear disease. The predictions of OAEs and
      PTTs were analysed using regression analysis for various sex and age groups (20
      44 years, 45-64 years, > or = 65 years). The fraction of the variance explained
      by exposure was generally moderate (0-4%, varying with age, sex, and type of
      measurement). Males showed moderate effects of work noise, impulse noise and ear
      infection, while ear infection was the only significant predictor in females.
      There were no effects of music noise and head injuries. The effect of exposure on
      OAEs that remained after controlling for PTTs was small and similar to the effect
      of exposure on PTTs that remained after controlling for OAEs.

PMID- 12467374
TI  - The role of neurotrophins in neurotransmitter release.
AB  - The neurotrophins (NTs) have recently been shown to elicit pronounced effects on
      quantal neurotransmitter release at both central and peripheral nervous system
      synapses. Due to their activity-dependent release, as well as the subcellular
      localization of both protein and receptor, NTs are ideally suited to modify the
      strength of neuronal connections by "fine-tuning" synaptic activity through
      direct actions at presynaptic terminals. Here, using BDNF as a prototypical
      example, the authors provide an update of recent evidence demonstrating that NTs
      enhance quantal neurotransmitter release at synapses through presynaptic
      mechanisms. The authors further propose that a potential target for NT actions at
      presynaptic terminals is the mechanism by which terminals retrieve synaptic
      vesicles after exocytosis. Depending on the temporal demands placed on synapses
      during high-frequency synaptic transmission, synapses may use two alternative
      modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or
      a faster rapid retrieval at the active zone, referred to as "kiss-and-run." By
      modulating Ca2+ microdomains associated with voltage-gated Ca2+ channels at
      active zones, NTs may elicit a switch from the slow to the fast mode of
      endocytosis of vesicles at presynaptic terminals during high-frequency synaptic
      transmission, allowing more reliable information transfer and neuronal signaling
      in the central nervous system.

PMID- 12467375
TI  - Na+ signals at central synapses.
AB  - A basic characteristic of animal cells is the maintenance of a steep inwardly
      directed electrochemical gradient for sodium ions. In vertebrate neurons, this
      Na+ gradient energizes intracellular ion regulation and enables influx of Na+
      during action potentials and excitatory postsynaptic currents. Several studies
      suggested that Na+ ions could also play a role in activity-dependent synaptic
      plasticity. This review focuses on recent studies that demonstrated the presence
      of substantial intracellular Na+ transients during action potential firing or
      excitatory synaptic transmission in postsynaptic dendrites and dendritic spines.
      The large amplitudes of these activity-induced Na+ transients suggest that this
      signal will significantly alter electrical and biochemical properties of spines
      and dendrites and might influence the properties of synaptic transmission.

PMID- 12467376
TI  - Neurobiology of lysophosphatidic acid signaling.
AB  - Lysophosphatidic acid (LPA), a growth factor-like lysophospholipid, induces
      diverse cellular responses. The identification of the first LPA receptor gene,
      through studies of neuroproliferative regions within the embryonic cerebral
      cortex, has led to the classification of a family of at least eight
      lysophospholipid receptors with diverse roles in organismal development and
      function. A growing body of literature has identified roles for LPA signaling
      under physiological and pathological conditions, particularly within the
      developing nervous system. Here the authors review features of the LPA receptor
      family and cellular responses of nervous system-derived cells, and discuss
      developmental and pathological roles for LPA signaling in the nervous system.

PMID- 12467377
TI  - Metabotropic glutamate receptors: electrical and chemical signaling properties.
AB  - Over the last two decades, glutamate has been established as the main excitatory
      neurotransmitter in the mammalian brain. Glutamate released from synapses
      activates ion channel-forming receptors at postsynaptic cells and consequently
      mediates fast postsynaptic potentials. These receptors are termed ionotropic
      glutamate receptors (iGluRs). The subsequent discovery of metabotropic glutamate
      receptors (mGluRs) revealed that glutamate can also mediate slow synaptic
      potentials, modulate ion channels, and directly couple to GTP binding proteins.
      In contrast to the iGluRs, the mGluRs possess seven transmembrane domains and a
      large intracellular C-terminus that involves interactions with a variety of other
      intracellular signaling systems. Eight functionally distinct mGluR subtypes are
      known to be localized to specific neuron types at presynaptic and/or postsynaptic
      membranes. Their physiological functions involve the generation of slow
      excitatory and inhibitory synaptic potentials, modulation of synaptic
      transmission, synaptic integration, and plasticity. The classical role of
      glutamate as a fast excitatory synaptic transmitter was largely extended by
      mGluRs acting as a neuromodulator and even as an activator of inhibitory
      mechanisms at certain synapses.

PMID- 12467378
TI  - GABA and glutamate in the human brain.
AB  - Cortical excitability reflects a balance between excitation and inhibition.
      Glutamate is the main excitatory and GABA the main inhibitory neurotransmitter in
      the mammalian cortex. Changes in glutamate and GABA metabolism may play important
      roles in the control of cortical excitability. Glutamate is the metabolic
      precursor of GABA, which can be recycled through the tricarboxylic acid cycle to
      synthesize glutamate. GABA synthesis is unique among neurotransmitters, having
      two separate isoforms of the rate-controlling enzyme, glutamic acid
      decarboxylase. The need for two separate genes on two chromosomes to control GABA
      synthesis is unexplained. Two metabolites of GABA are present in uniquely high
      concentrations in the human brain. Homocarnosine and pyrrolidinone have a major
      impact on GABA metabolism in the human brain. Both of these GABA metabolites have
      anticonvulsant properties and can have a major impact on cortical excitability.

PMID- 12467379
TI  - Forced limb-use and recovery following brain injury.
AB  - Animals subjected to exercise display significant alterations in brain function
      and neurochemistry, reflecting the innate plasticity of the adult brain to
      environmental challenges. Following injury, the brain is sensitive to
      reorganization and regeneration, and thus may be primed for influence by external
      behavioral demand such as increased use of an injured forelimb. The focus of this
      review is on the effects of altered use of the impaired forelimb in unilateral
      rodent models of brain injury. Both the benefits of increased use and the
      detrimental effects of decreased use following injury will be discussed.

PMID- 12467380
TI  - Matrix metalloproteinases and neuroinflammation in multiple sclerosis.
AB  - Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral
      proteases that are important in normal development, angiogenesis, wound repair,
      and a wide range of pathological processes. Growing evidence supports a key role
      of the MMPs in many neuroinflammatory conditions, including meningitis,
      encephalitis, brain tumors, cerebral ischemia, Guillain-Barre, and multiple
      sclerosis (MS). The MMPs attack the basal lamina macromolecules that line the
      blood vessels, opening the blood-brain barrier (BBB). They contribute to the
      remodeling of the blood vessels that causes hyalinosis and gliosis, and they
      attack myelin. During the acute inflammatory phase of MS, they are involved in
      the injury to the blood vessels and may be important in the disruption of the
      myelin sheath and axons. Normally under tight regulation, excessive proteolytic
      activity is detected in the blood and cerebrospinal fluid in patients with acute
      MS. Because they are induced in immunologic and nonimmunologic forms of
      demyelination, they act as a final common pathway to exert a "bystander" effect.
      Agents that block the action of the MMPs have been shown to reduce the damage to
      the BBB and lead to symptomatic improvement in several animal models of
      neuroinflammatory diseases, including experimental allergic encephalomyelitis.
      Such agents may eventually be useful in the control of excessive proteolysis that
      contributes to the pathology of MS and other neuroinflammatory conditions.

PMID- 12467381
TI  - Light-induced geometric isomerization of 1,2-diphenylcyclopropanes included
      within Y zeolites: role of cation-guest binding.
AB  - Through a systematic study of several diphenylcyclopropane derivatives, we have
      inferred that the cations present within a zeolite control the excited-state
      chemistry of these systems. In the parent 1,2-diphenylcylopropane, the cation
      binds to the two phenyl rings in a sandwich-type arrangement, and such a mode of
      binding prevents cis-to-trans isomerization. Once an ester or amide group is
      introduced into the system (derivatives of 2beta,3beta-diphenylcyclopropane
      1alpha-carboxylic acid), the cation binds to the carbonyl group present in these
      chromophores and such a binding has no influence on the cis-trans isomerization
      process. Cation-reactant structures computed at density functional theory level
      have been very valuable in rationalizing the observed photochemical behavior of
      diphenylcyclopropane derivatives included in zeolites. While the parent system,
      1,2-diphenylcylopropane, has been extensively investigated in the context of
      chiral induction in solution, owing to its failure to isomerize from cis to
      trans, the same could not be investigated in zeolites. However, esters of
      2beta,3beta-diphenylcyclopropane-1alpha-carboxylic acid could be studied within
      zeolites in the context of chiral induction. Chiral induction as high 20% ee and
      55% de has been obtained with selected systems. These numbers, although low, are
      much higher than what has been obtained in solution with the same system or with
      the parent system by other investigators (maximum approximately 10% ee).

PMID- 12467382
TI  - Novel examples of three-dimensional aromaticity: 1,3-dehydro-silaadamantane
      dications. A theoretical (DFT, GIAO NMR, NICS) study.
AB  - A DFT study of the hitherto elusive 1,3-dehydro-silaadamantane dications 2(2+)
      5(2+) has been carried out. Computed nucleus independent chemical shift (NICS)
      values are strongly indicative of three-dimensional heteroaromaticity in the
      resulting caged dications (via 2-electron, 4-center homoconjugation). In the
      optimized structures, silicon is pyramidalized. Although charge calculations (NPA
      and MKS) indicate significant positive charge build-up at silicon(s), the (29)Si
      GIAO NMR chemical shifts are unusually shielded. The latter finding agrees with
      the recent DFT calculations on 7-silanobornadien-7-ylium monocation 10(+),
      suggesting that silicon shielding is a consequence of unusual bonding and
      homoconjugation in the dications. Both NICS values and silicon shielding decrease
      in going from 2(2+) to 5(2+). Natural bond orbital (NBO) analysis was utilized to
      shed light on the origin of the three-dimensional heteroaromaticity in these
      dications.

PMID- 12467383
TI  - Total synthesis and biological evaluation of Amaryllidaceae alkaloids:
      narciclasine, ent-7-deoxypancratistatin, regioisomer of 7-deoxypancratistatin,
      10b-epi-deoxypancratistatin, and truncated derivatives.
AB  - Biocatalytic approaches have yielded efficient total syntheses of the major
      Amaryllidaceae alkaloids, all based on the key enzymatic dioxygenation of
      suitable aromatic precursors. This paper discusses the logic of general synthetic
      design for lycoricidine, narciclasine, pancratistatin, and 7-deoxypancratistatin.
      Experimental details are provided for the recently accomplished syntheses of
      narciclasine, ent-7-deoxypancratistatin, and 10b-epi-deoxypancratistatin via a
      new and selective opening of a cyclic sulfate over aziridines followed by aza
      Payne rearrangement. The structural core of 7-deoxypancratistatin has also been
      degraded to a series of intermediates in which the amino inositol unit is cleaved
      and deoxygenated in a homologous fashion. These truncated derivatives and the
      compounds from the synthesis of the unnatural derivatives have been tested
      against six important human cancer cell lines in an effort to further develop the
      understanding of the mode of action for the most active congener in this group,
      pancratistatin. The results of the biological activity testing as well as
      experimental, spectral, and analytical data are provided in this manuscript for
      all relevant compounds.

PMID- 12467384
TI  - Connective synthesis of polysubstituted tetrahydropyrans by a novel and
      stereocontrolled metallo-ene/Intramolecular Sakurai Cyclization sequence.
AB  - A novel methodology based upon the allylmetalation step followed by an
      Intramolecular Sakurai Cyclization (IMSC) provides an efficient access to a
      variety of tetrahydropyran derivatives. This new strategy nicely complements our
      initial protocol that embodied a tandem ene reaction/IMSC sequence. Both mono-
      and dihydroxy-tetrahydropyrans could be easily assembled with complete
      stereocontrol at the various chiral centers.

PMID- 12467385
TI  - Tandem enantioselective conjugate addition--cyclopropanation. Application to
      natural products synthesis.
AB  - A tandem asymmetric conjugate addition-cyclopropanation was developed, in which a
      cyclic or linear enone was converted to a TMS-protected 3-substituted
      cyclopropanol in an efficient one-pot reaction. These compounds were then
      selectively cleaved to yield alpha-methyl-beta-alkyl ketones, alpha-methylene
      enones, or chain extended gamma-alkyl-enones. This methodology was applied to the
      formal total synthesis of (-)-(S,S)-clavukerin A and (+)-(R,S)-isoclavukerin.

PMID- 12467386
TI  - Thionin-sensitized intrazeolite photooxygenation of trisubstituted alkenes:
      substituent effects on the regioselectivity as probed through isotopic labeling.
AB  - The regioselectivity for the intrazeolite photooxygenation of several
      trisubstituted alkenes with geminal dimethyl groups was examined. The length of
      the alkyl chain at the lone position was varied, and as end groups, the phenyl or
      the cyclohexyl functionalities were chosen. The general trend for all alkenes is
      a significant increase of the reactivity at the twin position compared to the
      photooxygenation in solution. For the cyclohexyl-substituted alkenes, it was
      found that the regioselectivity is nearly independent of the alkyl chain length.
      However, for the phenyl-substituted alkenes, the ene reactivity of the allylic
      methylene hydrogen atoms at the lone position and the twix/twin regioselectivity
      depend significantly on the distance of the phenyl group from the double bond.
      These trends are discussed in terms of cation-pi interactions and conformational
      effects. Intramolecular and intermolecular isotope effects in the intrazeolite
      photooxygenation of deuterium-labeled alkenes suggest that a perepoxide-type
      intermediate is formed in the rate-determining step. Type I photooxygenation that
      involves reaction of the radical cations of the alkenes with superoxide ion are
      unlikely.

PMID- 12467387
TI  - N-tert-Butoxy-1-aminopyrenyl Radicals. Isolation, Electronic Structure, and
      Magnetic Characterization.
AB  - N-tert-Butoxy-2,7-di-tert-butyl-1-pyrenylaminyl (4), N-tert-butoxy-2-tert-butyl-1
      pyrenylaminyl (5), and N-tert-butoxy-7-tert-butyl-1-pyrenylaminyl (6) free
      radicals were generated by the reaction of the lithium amides of the
      corresponding 1-aminopyrenes with tert-butyl peroxybenzoate in THF at -78 degrees
      C. Although 6 could not be isolated due to the gradual decomposition in solution,
      4 and 5 were quite persistent and could be isolated as monomeric radical
      crystals. The X-ray crystallographic analyses for the isolated free radicals were
      successfully carried out, indicating that the N and O atoms are almost coplanar
      with the pyrene ring. The ESR spectra of 4 and 5 were very complex due to the
      presence of many magnetically unequivalent protons. Therefore, the proton
      hyperfine coupling (hfc) constants were determined by (1)H ENDOR/TRIPLE resonance
      spectroscopy. To assign the hfc constants for the pyrene ring protons, a
      partially deuterated radical, 4-d(4), was prepared and the ENDOR and ESR spectra
      were measured. To discuss the spin density distribution for 4 and 5 ab initio
      molecular orbital calculations were performed by the DFT UBecke 3LYP method,
      using the STO 6-31G basis set. Magnetic susceptibility measurements were carried
      out for 4 and 5 with a SQUID magnetometer. For 4 a weak antiferromagnetic
      interaction was observed, and for 5 a very strong antiferromagnetic interaction
      was observed. The antiferromagnetic interactions were explained by their crystal
      structures.

PMID- 12467388
TI  - Synthesis of tetrahydrocannabinols based on an indirect 1,4-addition strategy.
AB  - The synthetic procedure presented for the preparation of the title compounds
      requires 1,4-addition of bulky cuprates to cyclohexenones and subsequent reaction
      with electrophiles. However, the enolates generated by BF(3).OEt(2)-assistance
      suffer from lack of nucleophilicity. To circumvent this problem, we developed an
      indirect method consisting of the following three steps: (1) iodination of the
      cyclohexenones at the alpha position; (2) BF(3).OEt(2)-assisted 1,4-addition of
      cuprates (Ar(2)Cu(CN)Li(2), Ar = aryl) followed by quenching the enolates with
      water; (3) reaction of the alpha-iodo-beta-aryl-cylohexanones thus formed with
      EtMgBr to generate magnesium enolates. The enolates thus generated in this way
      showed a high reactivity toward ClP(O)(OEt)(2) to furnish enol phosphates. The
      aforementioned procedure was also applied to a synthesis of optically active
      Delta(9)-tetrahydrocannabinol. In addition, a naphthalene analogue of the latter
      compound was also synthesized in a similar way.

PMID- 12467389
TI  - Chelation-controlled reduction: stereoselective formation of syn-1,3-diols and
      synthesis of compactin and mevinolin lactone.
AB  - Chelation-controlled reduction of chiral beta-alkoxy ketones containing a
      competing beta'-oxygen functionality has been investigated. Various syn-1,3-diols
      were prepared conveniently by reduction of beta-alkoxy ketones with LiI/LiAlH(4)
      (syn:anti selectivity up to >99:1). The corresponding beta-alkoxy ketones were
      derived from nitro-aldol reactions of chiral alkoxy aldehydes with a series of
      nitro compounds. This methodology is utilized in a short and efficient synthesis
      of the delta-lactone moiety of the HMG-CoA reductase inhibitors compactin and
      mevinolin.

PMID- 12467390
TI  - Synthesis of novel nocathiacin-class antibiotics. Condensation of glycolaldehyde
      with primary amides and tandem reductive amination of amadori-rearranged 2
      oxoethyl intermediates.
AB  - Nocathiacin I (1) and nocathiacin IV (2) are novel indole-containing thiazolyl
      peptide antibiotics, which exhibit potent activity against key Gram-positive
      bacterial pathogens, including multi drug-resistant Staphylococcus aureus,
      Streptococcus pneumoniae, and Enterococcus faecium. New nocathiacins 7-12 were
      prepared from 2 by a condensation with glycolaldehyde followed by tandem
      reductive amination of the 2-oxoethyl intermediate 4. The latter was formed via
      Amadori rearrangement from initial 2-hydroxyethylideneamide 3. This
      transformation readily tolerates the complex architecture of nocathiacins and
      allows selective incorporation of water solubilizing groups to the primary amide
      in 2 without protecting group manipulation.

PMID- 12467391
TI  - The beta-fluorine effect. Electronic versus steric effects in radical
      deoxygenations of fluorine-containing pentofuranose nucleosides.
AB  - Stereoselective pyramidalization of free radicals by a vicinal fluorine
      substituent, the beta-fluorine effect, was invoked to rationalize a 77:23
      anti/syn ratio of 2-deuterio-1-fluorocyclopentanes obtained by radical reduction
      of trans-2-fluoro-1-bromocyclopentane with tributyltin deuteride (Dolbier, W. R.,
      Jr.; Bartberger, M. D. J. Org. Chem. 1995, 60, 4984-4985). We have evaluated
      analogous reductions of the four possible stereoisomers of some adenine 2'(3')
      fluoro-3'(2')-O-phenoxythiocarbonyl nucleoside derivatives. In all cases, the
      steric effect of adenine on the beta face directs deuterium transfer from the
      stannane to C2'(C3') on the alpha face of the furanose ring. However, the beta
      fluorine effect enhances ratios of deuterium transfer anti to the vicinal
      fluorine substituent.

PMID- 12467392
TI  - Dimethyldihydropyrene-dehydrobenzoannulene hybrids: studies in aromaticity and
      photoisomerization.
AB  - The synthesis and study of dehydrobenzoannulene (DBA)-dimethyldihydropyrene (DDP)
      hybrids as models for the investigation of aromaticity in weakly diatropic
      systems is reported. Three new monofused DBA-DDP hybrids have been synthesized,
      and their NMR spectra are discussed with regard to quantifying the aromaticity
      remaining in multibenzene-fused DBAs. Nucleus-independent chemical shifts,
      determined at a series of locations for each compound, bond lengths, and (1)H and
      (13)C NMR chemical shifts were calculated and used to probe the aromaticity of
      these hybrids. Systems where more than one annulene/DBA is fused to the DDP core
      have also been obtained, and their potential use in photoinduced isomerization
      applications is discussed.

PMID- 12467393
TI  - Diatropicity of 3,4,7,8,9,10,13,14-octadehydro[14]annulenes: a combined
      experimental and theoretical investigation.
AB  - The synthesis and study of a series of octadehydro[14]annulenes is described. The
      aromaticity of these annulenes was investigated through examination of
      experimental data from arene-fused systems as well as calculated nucleus
      independent chemical shifts (NICS) and bond lengths. Benzene ring fusion to the
      parent system results in a stepwise loss in aromaticity as the number of fused
      rings is increased from one to two to three. This decrease in annulenic ring
      current is manifested in the alkene proton chemical shifts (0-2 benzenes) as well
      as the NICS (0-3 benzenes). Comparison of isomeric thiophene-fused annulenes
      shows further evidence of ring current competition as these allow for observation
      of intermittent degrees of delocalization throughout the annulenic core. A
      consistent relationship between the magnitude of the NICS values and the degree
      of benzannelation is also observed.

PMID- 12467394
TI  - Solid-phase synthesis of amine-bridged cyclic enkephalin analogues via on-resin
      cyclization utilizing the Fukuyama-Mitsunobu reaction.
AB  - An efficient solid-phase synthetic route is described for the preparation of 13
      membered amine-bridged cyclic enkephalin analogues (ABEs) 1a and 1c-1j (Figure 1)
      resulting from a sulfonamide-containing peptide whose backbone is bound to a
      resin. The Fukuyama-Mitsunobu reaction of the 2-nitrobenzenesulfonyl-protected
      amine bound to the solid support with protected aminoethanol in the presence of
      triphenylphosphine and diisopropyl azodicarboxylate (DIAD) is utilized to prepare
      a resin-bound sulfonamide-protected secondary amine. After peptide cyclization,
      this protected amine functionality becomes the "amine bridge" of the target
      molecule. In addition, the reagent DIAD was found to be a superior reagent
      compared to diethyl azodicarboxylate (DEAD) in the solid-phase Fukuyama-Mitsunobu
      reaction.

PMID- 12467395
TI  - Synthesis and characterization of photolabile o-nitrobenzyl derivatives of urea.
AB  - We present here the synthesis and characterization of four photolabile
      derivatives of urea in which alpha-substituted 2-nitrobenzyl groups are
      covalently attached to the urea nitrogen. These derivatives photolyze readily in
      aqueous solution to release free urea. The alpha-substituents of the 2
      nitrobenzyl group strongly influence the rate of the photolysis reaction measured
      with transient absorption spectroscopy. Rates of photolysis at pH 7.5 and room
      temperature (approximately 22 degrees C) for N-(2-nitrobenzyl)urea, N-(alpha
      methyl-2-nitrobenzyl)urea, N-(alpha-carboxymethyl-2-nitrobenzyl)urea, and N
      (alpha-carboxy-2-nitrobenzyl)urea are, respectively, 1.7 x 10(4), 8.5 x 10(4),
      4.0 x 10(4), and 1.1 x 10(5) s(-)(1). The quantum yields determined by
      measurement of free urea following irradiation by a single laser pulse at 308 nm
      were 0.81 for N-(2-nitrobenzyl)urea, 0.64 for N-(alpha-methyl-2-nitrobenzyl)urea,
      and 0.56 for N-(alpha-carboxy-2-nitrobenzyl)urea. The caged N-(alpha-carboxy-2
      nitrobenzyl)urea is not a substrate of the enzyme urease, while the
      photolytically released urea is. Also, neither this caged urea nor its photolytic
      side products inhibit hydrolysis of free urea by urease. Thus, the alpha-carboxy
      2-nitrobenzyl derivative of urea is suitable for mechanistic investigations of
      the enzyme urease.

PMID- 12467396
TI  - Dual binding mode of methylmethanetriacetic Acid to tripodal amidopyridine
      receptors.
AB  - A series of tripodal amidopyridine receptors capable of selective recognition of
      methylmethanetriacetic acid (MMTA) in organic solvents is described.
      Intramolecular hydrogen-bonding groups, built into some of the receptors, were
      designed as preorganization devices. Binding was studied by NMR titration,
      variable temperature NMR experiments, 2D-NMR, isothermal titration calorimetry,
      and single-crystal X-ray crystallography. The results reveal that a balancing act
      between inter- and intramolecular hydrogen-bonding interactions in the complexes
      governs both the dynamics and the geometry of binding. Receptor 1b (without
      intramolecular hydrogen-bonding groups) features a simple symmetric MMTA binding
      geometry with optimal enthalpic interactions. In sharp contrast, receptor 1a
      (with intramolecular hydrogen-bonding groups) reveals a temperature-dependent
      dual binding mode where MMTA can bind in two completely different geometries. The
      two solution binding geometries of 1a.MMTA were unraveled by NMR experiments and
      correlated to the X-ray structures.

PMID- 12467397
TI  - Synthesis of dihydrodiol metabolites implicated in the mechanism of
      carcinogenesis of phenanthro[4,3-b][1]benzothiophene and phenanthro[3,4
      b][1]benzothiophene, the polycyclic sulfur heterocycles with a "Fjord" structure.
AB  - Dihydrodiols, which are potential proximate carcinogens of phenanthro[4,3
      b][1]benzothiophene (3) and phenanthro[3,4-b][1]benzothiophene (4) and possess a
      "fjord" structure, were synthesized. The dihydrodiols synthesized were trans-3,4
      dihydroxy-3,4-dihydrophenanthro[4,3-b][1]benzothiophene (5) and trans-3,4
      dihydroxy-3,4-dihydrophenanthro[3,4-b][1]benzothiophene (6). The precursors to
      the dihydrodiols 5 and 6 were 3-methoxyphenanthro[4,3-b][1]benzothiophene (11)
      and 3-methoxyphenanthro[3,4-b][1]benzothiophene (16). Compound 11 was obtained
      via Suzuki cross-coupling reaction of easily accessible starting materials.
      However, this synthetic strategy utilizing Suzuki reaction for the preparation of
      16 was comparatively less productive than that described previously due to time
      consuming synthesis of the starting material(s), and extremely poor yield
      associated with cyclization of the epoxide 15 to 16. The methoxy derivatives 11
      and 16 were converted to the corresponding dihydrodiols 5 and 6 by a sequence
      involving demethylation, oxidation, and reduction. The trans-stereochemistry of
      the dihydrodiols was established by (1)H NMR, which indicated a large coupling
      constant between vicinal carbinol protons. The UV spectra of the dihydrodiols 5
      and 6 are presented.

PMID- 12467398
TI  - Synthesis of helix 69 of Escherichia coli 23S rRNA containing its natural
      modified nucleosides, m(3)Psi and Psi.
AB  - The synthesis of 3-methylpseudouridine (m(3)Psi) phosphoramidite, 5'-O
      [benzhydryloxybis(trimethylsilyloxy)silyl]-2'-O-[bis(2-acetoxyethoxy)methyl]-3
      methylpseudouridine-3'-(methyl-N,N-diisopropyl)phosphoramidite, is reported.
      Selective pivaloyloxymethyl protection of the Psi N1 followed by methylation at
      N3 was used to generate the naturally occurring pseudouridine analogue. The
      m(3)Psi phosphoramidite was used in combination with pseudouridine (Psi) and
      standard base phosphoramidites to synthesize a 19-nucleotide RNA representing
      helix 69 of Escherichia coli 23S ribosomal RNA (rRNA) (residues 1906-1924),
      containing a single m(3)Psi at position 1915 and two Psi's at positions 1911 and
      1917. Our synthesis of the fully modified helix 69 RNA demonstrates the ability
      to make milligram quantities of RNA that can be used for further high-resolution
      structure studies. Site-selective introduction of the methyl group at the N3
      position of pseudouridine at position 1915 causes a slight increase in the
      thermodynamic stability of the RNA hairpin relative to pseudouridine; RNAs
      containing either uridine or 3-methyluridine at position 1915 have similar
      stability. One-dimensional imino proton NMR and circular dichroism spectra of the
      modified RNAs reveal that the methyl group does not cause any substantial changes
      in the RNA hairpin structure.

PMID- 12467399
TI  - Nucleophilicity in ionic liquids. 2.(1) Cation effects on halide nucleophilicity
      in a series of bis(trifluoromethylsulfonyl)imide ionic liquids.
AB  - In this work, the nucleophilicities of chloride, bromide, and iodide have been
      determined in the ionic liquids [bmim][N(Tf)(2)], [bm(2)im][N(Tf)(2)], and
      [bmpy][N(Tf)(2)] (where bmim = 1-butyl-3-methylimidazolium, bm(2)im = 1-butyl-2,3
      dimethylimidazolium, bmpy = 1-butyl-1-methylpyrrolidinium, and N(Tf)(2) =
      bis(trifluoromethylsulfonyl)imide). It was found that in the [bmim](+) ionic
      liquid, chloride was the least nucleophilic halide, but that changing the cation
      of the ionic liquid affected the relative nucleophilicities of the halides. The
      activation parameters DeltaH(), DeltaS(), and DeltaG() have been estimated for
      the reaction of chloride in each ionic liquid, and compared to a similar reaction
      in dichloromethane, where these parameters were found for reaction by both the
      free ion and the ion pair.

PMID- 12467401
TI  - Conformational studies of N(3)-substituted [1,3,4]-oxadiazinan-2-ones.
AB  - Pseudoephedrine-based [1,3,4]-oxadiazinan-2-ones acylated at the N(3)-position
      with either acetyl (2a), propionyl (2b), or phenylacetyl (2c) substituents are
      known to undergo conformational changes that are observable by (13)C NMR
      spectroscopy. The conformational properties of new [1,3,4]-oxadiazinan-2-one
      derivatives 2d-k are examined by X-ray crystallography and variable-temperature
      (13)C NMR spectroscopy and further evaluated by semiempirical AM1 calculations.
      The collected data reveal that the conformational changes of the overall ring
      system are dependent upon the stereoelectronic factors of the N(3)-substituent.

PMID- 12467400
TI  - Synthesis and antituberculosis activity of C-phosphonate analogues of
      decaprenolphosphoarabinose, a key intermediate in the biosynthesis of
      mycobacterial arabinogalactan and lipoarabinomannan.
AB  - The cell wall complex in mycobacteria, including the human pathogen Mycobacterium
      tuberculosis, is comprised in large part of two polysaccharides that contain a
      significant number of arabinofuranose residues. Both polysaccharides are
      assembled by a family of arabinosyltransferases that use
      decaprenolphosphoarabinose (3) as the donor species. In this paper, we describe
      the synthesis of a panel of C-phosphonate analogues of 3, which were designed to
      inhibit these arabinosyltransferases and thus block the biosynthesis of
      mycobacterial cell wall polysaccharides. A number of routes were explored for the
      preparation of the targets. The successful approach involved the synthesis of a
      protected C-phosphonate allyl ester 16, which was then coupled to an alkene via
      an olefin cross metathesis reaction. Subsequent reduction of the alkene with
      diimide and deprotection afforded the targets. Screening of these compounds in
      vitro against Mycobacterium tuberculosis revealed that one of the compounds, 15f,
      possessed antituberculosis activity, with an MIC value of 3.13 microg/mL.

PMID- 12467402
TI  - Solvent-free, microwave-assisted synthesis of thiophene oligomers via Suzuki
      coupling.
AB  - The purpose of this study was to obtain a rapid, efficient, and environmentally
      friendly methodology for the synthesis of highly pure thiophene oligomers. The
      solvent-free, microwave-assisted coupling of thienyl boronic acids and esters
      with thienyl bromides, using aluminum oxide as the solid support, allowed us to
      rapidly check the reaction trends on changing times, temperature, catalyst, and
      base and easily optimize the experimental conditions to obtain the targeted
      product in fair amounts. This procedure offers a novel, general, and very rapid
      route to the preparation of soluble thiophene oligomers. Thus, for example,
      quaterthiophene was obtained in 6 min by reaction of 2-bromo-2,2'-bithiophene
      with bis(pinacolato)diboron (isolated yield 65%), whereas quinquethiophene was
      obtained in 11 min by reaction of dibromoterthiophene with thienylboronic acid
      (isolated yield 74%). The synthesis of new chiral 2,2'-bithiophenes is reported.
      The detailed analysis of the byproducts of some reactions allowed us to elucidate
      a few aspects of reaction mechanisms. While the use of microwaves proved to be
      very convenient for the coupling between conventional thienyl moieties, the same
      was not true for the coupling of thienyl rings to thienyl-S,S-dioxide moieties.
      Indeed, in this case, the targeted product was obtained in low yields because of
      the competitive, accelerated, Diels-Alder reaction that affords a variety of
      condensation products.

PMID- 12467403
TI  - Sheet structure of an L,D-dipeptide aggregate: inclusion compounds of (S)
      phenylglycyl-(R)-phenylglycine with amides.
AB  - A simple dipeptide, (S)-phenylglycyl-(R)-phenylglycine (S,R-1), formed inclusion
      compounds with a small amide such as formamide, acetamide, N,N-dimethylformamide
      (DMF), or N,N-dimethylacetamide. By single-crystal X-ray analysis, the inclusion
      compounds were shown to have a wavy layer structure. The molecules of S,R-1 are
      arranged in parallel via ionic pairing of the carboxyl and amino groups to
      construct the wavy layers. The guest molecules were accommodated in a channel
      cavity between the layers by means of hydrogen bonding with (+)NH(3) of S,R-1.
      The cavity is surrounded by the phenyl groups of S,R-1 that conformationally
      rotate so as to make the cavity size fit the guest amide.

PMID- 12467404
TI  - Rapid one-pot synthesis of riboflavin isotopomers.
AB  - Flavocoenzymes labeled with stable isotopes are important reagents for the study
      of flavoproteins using isotope-sensitive methods such as NMR, ENDOR, infrared,
      and Raman spectroscopy. We describe highly versatile one-pot methods for the
      preparation of riboflavin isotopomers labeled with (13)C in every desired
      position of the xylene moiety. The starting materials are commercially available
      (13)C-labeled glucose samples, which are converted into riboflavin using enzymes
      of the oxidative pentose phosphate pathway in combination with recombinant
      enzymes of the riboflavin biosynthetic pathway. The overall reaction comprises
      six enzyme-catalyzed reaction steps for the synthesis of the vitamin and two
      auxiliary enzymes for in situ recycling of cofactors. The overall yields of
      riboflavin based on isotope-labeled glucose are 35-50%.

PMID- 12467405
TI  - Highly stereoselective three-component reactions of phenylselenomagnesium
      bromide, acetylenic sulfones, and saturated aldehydes/ketones or alpha,beta
      unsaturated enals or enones.
AB  - beta-Phenylseleno-alpha-tolylsulfonyl-substituted alkenes were synthesized via
      the three-component conjugate-nucleophilic addition of acetylenic sulfones,
      phenylselenomagnesium bromide, and carbonyl compounds, such as aldehydes,
      aliphatic ketones, or alpha,beta-unsaturated enals or enones. The reaction is
      highly regio- and stereoselective with moderate to good yields. Functionalized
      allylic alcohols were obtained in the case of aldehydes and aliphatic ketones. In
      the case of alpha,beta-unsaturated enones, functionalized allylic alcohols or
      functionalized gamma,delta-unsaturated ketones were obtained, depending on the
      structures of the ketones.

PMID- 12467406
TI  - Highly regioselective construction of spirocycles via phosphine-catalyzed [3 + 2]
      cycloaddition.
AB  - A direct entry to spirocycles with low to moderate regioselectivity was achieved
      by triphenylphosphine-catalyzed [3 + 2]-cycloaddition of active exo
      methylenecycles (1) and ethyl 2,3-butadienoate (2). The regioselectivity of the
      reaction was greatly improved by using the bulky tert-butyl ester of the 2,3
      butadienoate (5). The regioselectivity of the reaction was further enhanced by
      using the tert-butyl 2-butynoate as the substrate. This protocol provided an
      efficient entry to the skeleton of spirocarbocycles, especially
      spiro[4.n]alkanes.

PMID- 12467407
TI  - Radical-induced formation of some siloles and diazasiloles.
AB  - The Bu(3)Sn radical-induced reaction of o-iodobenzylvinylsilanes and o
      iodoallylsilanes leads to cyclic products in yields of 40-60%. These
      regioselective cyclizations occur with high preference for a 5-exo and a 7-endo
      mode with a 6-exo mode being absent. An example for ring closure via a 7-exo mode
      is described.

PMID- 12467408
TI  - Kinetics and mechanism of the aminolysis of methyl 4-nitrophenyl, methyl 2,4
      dinitrophenyl, and phenyl 2,4-dinitrophenyl carbonates.
AB  - The reactions of methyl 4-nitrophenyl carbonate (MNPC) with a series of secondary
      alicyclic amines (SAA) and quinuclidines (QUIN), methyl 2,4-dinitrophenyl
      carbonate (MDNPC) with QUIN and 1-(2-hydroxyethyl)piperazinium ion (HPA), and
      phenyl 2,4-dinitrophenyl carbonate (PDNPC) with SAA are subjected to a kinetic
      investigation in aqueous solution, at 25.0 degrees C and an ionic strength of 0.2
      M. By following spectrophotometrically the nucleofuge release (330-400 nm) under
      amine excess, pseudo-first-order rate coefficients (k(obsd)) are obtained. Plots
      of k(obsd) vs [amine] at constant pH are linear, with the slope (k(N)) being pH
      independent. The Bronsted-type plot (log k(N) vs amine pK(a)) for the reactions
      of SAA with MNPC is biphasic with slopes beta(1) = 0.3 (high pK(a) region) and
      beta(2) = 1.0 (low pK(a) region) and a curvature center at pK(a)(0) = 9.3. This
      plot is consistent with a stepwise mechanism through a zwitterionic tetrahedral
      intermediate (T(+/-)) and a change in the rate-determining step with SAA
      basicity. The Bronsted plot for the quinuclidinolysis of MNPC is linear with
      slope beta(N) = 0.86, in line with a stepwise process where breakdown of T(+/-)
      to products is rate limiting. A previous work on the reactions of SAA with MDNPC
      was revised by including the reaction of HPA. The Bronsted plots for the
      reactions of QUIN and SAA with MDNPC and SAA with PDNPC are linear with slopes
      beta = 0.51, 0.48, and 0.39, respectively, consistent with concerted mechanisms.
      Since quinuclidines are better leaving groups from T(+/-) than isobasic SAA,
      yielding a less stable T(+/-), it seems doubtful that the quinuclidinolysis of
      PDNPC is stepwise, as reported.

PMID- 12467409
TI  - Alkylation of the inverted porphyrin nickel(II) complex by dihalogenalkanes:
      formation of monomeric and dimeric derivatives.
AB  - An efficient and simple method of modification of "inverted" porphyrin is
      provided by reactions of 5,10,15,20-tetraaryl-2-aza-21
      carbaporphyrinatonickel(II) 2 with dihalogenalkanes under basic conditions. The
      substituents are bound to the internal carbon or external nitrogen of the
      inverted pyrrole depending on dihalogenalkane and basic catalyst. The monomeric 2
      or 21-ethoxymethyl-substituted species are formed in the reaction of 2 with
      dihalomethanes and sodium ethoxide or ethanol in the presence of K(2)CO(3). A
      novel, dimeric 21,21'-ethylene-linked derivative 11 is obtained from 2 and
      ethylene bromide in dichloromethane in the presence of potassium carbonate end
      ethanol, while application of potassium tert-butoxide promotes formation of N
      bromoethyl-substituted monomer 12. Reaction of 2 with propylene bromide in the
      presence of proton scavenger efficiently leads to the 21-allyl-substituted
      monomer 14 that is a product of the HBr elimination from a transient 21
      bromopropyl-substituted species. The new compounds have been identified and
      characterized by means of mass spectrometry and optical and NMR spectroscopies. A
      single-crystal X-ray analysis performed for 12 allows discussion of structural
      parameters concerning the macrocycle and coordination core. Formation of
      deprotonated species [2](-), which is proposed as a key intermediate in the
      alkylation reaction, has been observed spectroscopically. Chirality of the N
      substituted derivatives induced by protonation of the internal carbon is observed
      by NMR at low temperatures.

PMID- 12467410
TI  - Diastereoselective aldolization of alpha-aminonitriles. Diastereoselective
      synthesis of beta-amino alcohols and beta,gamma-diamino alcohols.
AB  - Aldolization performed by addition of lithiated N-benzyl-N-tert
      butylaminoacetonitrile to aldehydes provides diastereomerically pure anti-beta
      hydroxy-alpha-aminonitriles. They are transformed into syn,anti-protected
      beta,gamma-diamino alcohols by a two-step procedure, involving addition of a
      Grignard reagent and reduction. The cleavage of the N-tert-butyl group is
      achieved by a simple acidic treatment. The application of this methodology to
      chiral, nonracemic aldehydes is studied. Starting from D
      isopropylideneglyceraldehyde, an anti, anti, syn, anti-(2R,3S,4S,5R,6R)
      diaminotriol is prepared in acceptable yield and with a good level of
      diastereoselectivity.

PMID- 12467411
TI  - Addition of organocerium reagents to morpholine amides: synthesis of important
      pheromone components of Achaea janata.
AB  - Readily preparable morpholine amides hitch in good yields with organocerium
      reagents to produce ketones. Even in the presence of substrates and reagents with
      high steric hindrance, the organometallic compounds prepared from dry cerium(III)
      chloride and organomagnesium or organolithium compounds at -78 degrees C add
      cleanly to morpholine amides. The low cost of starting materials makes this new
      scheme of synthesis very interesting for the preparation of biologically
      important pheromones.

PMID- 12467412
TI  - Superacidic activation of 1- and 3-isoquinolinols and their electrophilic
      reactions.
AB  - Isomeric 1- and 3-isoquinolinols (11 and 12) when activated in CF(3)SO(3)H-SbF(5)
      acid system undergo selective ionic hydrogenation with cyclohexane to give
      5,6,7,8-tetrahydro-1(2H)- and 5,6,7,8-tetrahydro-3(2H)-isoquinolinones (22 and
      27). Under the influence of aluminum chloride similar products were also obtained
      along with 3,4-dihydro-1(2H)- and 1,4-dihydro-3(2H)-isoquinolinones (23 and 28),
      respectively. Compounds 11 and 12 also condense with benzene in the presence of
      aluminum halides, under mild conditions, to give 3,4-dihydro-3-phenyl-1(2H)- and
      1,4-dihydro-1-phenyl-3(2H)-isoquinolinones (24 and 29), respectively. Prolonged
      reaction time or catalysis under strongly acidic HBr-AlBr(3) provides an
      alternative reaction pathway to yield 5,6-dihydro-6,8-diphenyl-1(2H)- and 5,6,7,8
      tetrahydro-6,8-diphenyl-3(2H)-isoquinolinones (25 and 30), respectively. Products
      24 and 29 were also found to revert back to 11 and 12 in the presence of aluminum
      halides in o-dichlorobenzene. The mechanism of these intriguing reactions, which
      involves superelectrophilic dicationic intermediates, is discussed.

PMID- 12467413
TI  - Diastereoselective synthesis of 2-aminoalkyl-3-sulfonyl-1,3-oxazolidines on solid
      support.
AB  - Herein we report our investigation on the oxidation of solid-support-bound amino
      alcohols to their corresponding aldehydes. These aldehydes were converted into
      diastereomerically pure (>10:1) 2,4-cis-2-aminoalkyl-3-sulfonyl-1,3-oxazolidines
      using optically pure 1,2-amino alcohols. The relative configuration was
      determined using the nuclear Overhauser effect (NOE). The synthesized
      oxazolidines, which were obtained in high purities, represent a new, diverse
      scaffold for the solid-phase synthesis of libraries directed toward a
      pharmacological target.

PMID- 12467414
TI  - A new short synthesis of 3-substituted 5-amino-1-(chloromethyl)-1,2-dihydro-3H
      benzo[e]indoles (amino-CBIs).
AB  - A new short synthesis of 3-substituted 5-amino-1-(chloromethyl)-1,2-dihydro-3H
      benzo[e]indoles from Martius Yellow is disclosed. The key steps of the synthesis
      were three efficient regioselective reactions (iodination, 5-exo-trig aryl
      radical-alkene cyclization and carboxylation).

PMID- 12467415
TI  - The synthesis of azapeptidomimetic beta-lactam molecules as potential protease
      inhibitors.
AB  - Synthetic methods for the construction of a novel peptidomimetic structure are
      reported. The structure incorporates a beta-lactam and an azapeptide in a peptide
      backbone with the intention of generating rationally designed substrate-based
      protease inhibitors. The beta-lactam is formed by subjecting serine or threonine
      azapeptides to Mitsunobu reaction conditions. Importantly, the azapeptidomimetic
      beta-lactam structure permits extended binding inhibition and the synthetic
      methods to create tetrapeptidomimetic structures are described.

PMID- 12467416
TI  - Equatorial contra axial polar substituents. The relation of a chemical reaction
      to stereochemical substituent constants.
AB  - The established rates of glycoside hydrolysis reactions were analyzed using free
      energy relationship plots based on substituent constants that depend on whether
      the substituent is axial or equatorial. In all cases good correlations were found
      when assuming either that the transition state had a charged ring-oxygen atom or
      that it had a charged anomeric carbon atom. The spontaneous hydrolysis of 2,4
      dinitrophenyl beta-glycopyranosides and the acidic hydrolysis of methyl beta-D
      glycopyranosides were found to give a good correlation, when 100% charge at the
      ring-oxygen in the transition state of these reactions is assumed. The acidic
      hydrolysis of methyl alpha-glycopyranosides was found to give good correlations
      regardless of whether 100% charge at the ring-oxygen or 100% charge at the
      anomeric carbon was assumed. The findings clearly demonstrate how crucial the
      stereochemistry of even remote polar substituents is for their electronic effect
      on chemical reaction.

PMID- 12467417
TI  - Acylation through Ketene Intermediates.
AB  - Carboxylic acids possessing a strong electron-withdrawing group in the alpha
      position undergo facile dehydration upon reaction with carbodiimides to form the
      corresponding substituted ketenes that can react in situ with alcohols providing
      esters in a high yield. The ketene formed by the treatment of ethyl 2
      methylmalonate with DCC was trapped in situ by a [4+2] cycloaddition with a
      second DCC molecule. The chemoselectivity of the acylation through the ketene
      intermediates was found to be substantially different from that of conventional
      acylation reagents showing a very low sensitivity toward the steric bulk of
      alcohols. A comparison of the sensitivity of the acylation to the steric bulk of
      alcohols supports the presence of a pseudopericyclic pathway for the nucleophilic
      addition of alcohols to ketenes derived from ethyl malonic and
      diethylphosphonoacetic acid.

PMID- 12467418
TI  - Effect of ring strain on the thiolate-disulfide exchange. A computational study.
AB  - B3LYP/aug-cc-pVDZ and MP2/6-31+G calculations of the reactions of HS(-) with
      small cyclic disulfides (dithiirane, 1,2-dithietane, 1,2-dithiolane, and 1,2
      dithiane) were performed to determine the reaction mechanism. For the five- and
      six-membered rings, the reaction proceeds via the addition-elimination pathway,
      consistent with acyclic analogues. The smaller, more strained three- and four
      membered rings react by the S(N)2 mechanism. Addition of the nucleophile cannot
      be accommodated by the small rings without concomitant ring cleavage.

PMID- 12467419
TI  - Cross-coupling reactions of phenylmagnesium halides with fluoroazines and
      fluorodiazines.
AB  - The first nickel-catalyzed cross-coupling reactions between fluoroarenes and aryl
      organometallics using commercially available ligands are described. The nickel
      catalyzed cross-coupling reactions between aryl Grignard reagents and
      fluoroazines and -diazines occurred in THF at room temperature using commercially
      available 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, or
      1,1'-bis(diphenylphosphino)ferrocene as ligand. Various fluoro substrates such as
      pyridines, diazines (pyrazine, pyridazine), benzodiazines (quinoxaline), and
      quinolines were successfully involved in the reaction with phenylmagnesium
      halides (phenylmagnesium chloride, 2-methoxyphenylmagnesium bromide, and 4
      methoxyphenylmagnesium bromide). The conditions used also allowed the cross
      coupling of 4-fluorotoluene with arylmagnesium reagents.

PMID- 12467420
TI  - Kinetics and mechanism of the pyridinolysis of aryl furan-2-carbodithioates in
      acetonitrile.
AB  - Kinetic studies on the pyridinolysis of aryl furan-2-carbodithioates 1 are
      carried out at 60.0 degrees C in acetonitrile. The biphasic rate dependence on
      the pyridine basicity with a breakpoint at pK(a) degrees = 5.2 is interpreted to
      indicate a change of the rate-limiting step from breakdown (beta(X) = 0.7-0.8) to
      formation (beta(X) = 0.2) of the tetrahedral intermediate, T(+/-), at the
      breakpoint as the basicity of the pyridine nucleophile is increased. Observation
      of the breakpoint is possible with pyridines since the expulsion rate of the
      pyridine (k(-)(a)) from T(+/-) is sufficiently low, with the low k(-)(a)/k(b)
      ratio leading to a low breakpoint, pK(a) degrees. The clear-cut change in the
      cross-interaction constants, rho(XZ), from a positive (rho(XZ) = +0.86) to a
      small negative (rho(XZ) = -0.11) value at the breakpoint supports the mechanistic
      change proposed. The magnitudes of rho(Z) and activation parameters are also
      consistent with the proposed mechanism.

PMID- 12467421
TI  - Effect of amine nature on reaction mechanism: aminolyses of o-4-nitrophenyl
      thionobenzoate with primary and secondary amines.
AB  - Pseudo-first-order rate constants (k(obs)) have been measured
      spectrophotometrically for reactions of O-4-nitrophenyl thionobenzoate (2) with a
      series of primary and acyclic secondary amines. The plots of k(obs) vs amine
      concentration are linear for the reaction of 2 with primary amines. The slope of
      the Bronsted-type plot for the reaction of 2 with primary amines decreases from
      0.77 to 0.17 as the amine basicity increases, indicating that the reaction
      proceeds through a zwitterionic addition intermediate in which the rate
      determining step changes from the breakdown of the intermediate to the reaction
      products to the formation of the intermediate as the amine basicity increases. On
      the other hand, for reactions with all the acyclic secondary amines studied, the
      plot of k(obs) vs amine concentration exhibits an upward curvature, suggesting
      that the reaction proceeds through two intermediates, e.g., a zwitterionic
      addition intermediate and an anionic intermediate. The microscopic rate constants
      (k(1), k(-)(1), k(2), and k(3) where available) have been determined for the
      reactions of 2 with all the primary and secondary amines studied. The k(1) value
      is larger for the reaction with the primary amine than for the reaction with the
      isobasic acyclic secondary amines, while the k(-)(1) value is much larger for the
      latter reaction than for the former reaction. The k(3) value for the reaction
      with secondary amine is independent of the amine basicity. The small k(2)/k(-)(1)
      ratio is proposed to be responsible for the deprotonation process observed in
      aminolyses of carbonyl or thiocarbonyl derivatives.

PMID- 12467422
TI  - Chemoenzymatic dynamic kinetic resolution of beta-halo alcohols. An efficient
      route to chiral epoxides.
AB  - Enzymatic resolution of beta-chloro alcohols in combination with ruthenium
      catalyzed alcohol isomerization led to a successful dynamic kinetic resolution
      (conversion up to 99% and ee up to 97%). The efficiency of the DKR is
      dramatically reduced when beta-bromo alcohols are used. The presence of the bromo
      substituent causes decomposition of the ruthenium catalysts, which triggers the
      progressive deactivation of the enzyme. The synthetic utility of this procedure
      has been illustrated by the practical synthesis of different chiral epoxides.

PMID- 12467423
TI  - Solid-state photodimerization of steroid enones.
AB  - Androst-4-ene-3,17-dione (1) and 17alpha-methyltestosterone (2) are dimerized in
      the solid-state by UV radiation. These substances were selected by a search in
      the CSD among the steroid enones presenting in the crystalline state an
      intermolecular short contact between a hydrogen alpha to a carbonyl group and the
      oxygen of an enone system. Dimerization occurs by transfer of the hydrogen to the
      oxygen and connection between the two involved carbons. Androst-4-ene-3,17-dione
      (1) affords dimer 3 and trimer 4, both formed by connection of the C-16 of a
      molecule with the C-3 of a near one. Irradiation of 17alpha-methyltestosterone
      (2) gives the isomeric trienones 5 and 6. These compounds are reasonably formed
      by dehydration of unisolated intermediate products 7 and/or 8 obtained by
      coupling of two molecules through a linkage between the C-2 and the C-3' carbons.
      The formation mechanisms of the photoproducts are satisfactory explained on the
      basis of the molecular arrangement of the monomers in the crystal state. Modeling
      of the dimeric molecules was done using molecular mechanics calculations. A
      single-crystal X-ray of the dimer of androst-4-ene-3,17-dione confirms the
      structural interpretation of spectral data. The conformer found in the solid
      state agrees well with the results of molecular mechanics calculations.

PMID- 12467424
TI  - Equilibrium acidities and homolytic bond dissociation energies of acidic C-H
      bonds in alpha-arylacetophenones and related compounds.
AB  - The equilibrium acidities (pK(AH)s) and the oxidation potentials of the congugate
      anions [E(ox)(A(-))s] were determined in dimethyl sulfoxide (DMSO) for eight
      ketones of the structure GCOCH(3) and 20 of the structure RCOCH(2)G, (where R =
      alkyl, phenyl and G = alkyl, aryl). The homolytic bond dissociation energies
      (BDEs) for the acidic C-H bonds of the ketones were estimated using the equation
      BDE(AH) = 1.37pK(AH) + 23.1E(ox)(A(-)) + 73.3. While the equilibrium acidities of
      GCOCH(3) were found to be dependent on the remote substituent G, the BDE values
      for the C-H bonds remained essentially invariant (93.5 +/- 0.5 kcal/mol). A
      linear correlation between pK(AH) values and [E(ox)(A(-))s] was found for the
      ketones. For RCOCH(2)G ketones, both pK(AH) and BDE values for the adjacent C-H
      bonds are sensitive to the nature of the substituent G. However, the steric bulk
      of the aryl group tends to exert a leveling effect on BDEs. The BDE of alpha-9
      anthracenylacetophenone is higher than that of alpha-2-anthracenylacetophenone by
      3 kcal/mol, reflecting significant steric inhibition of resonance in the 9
      substituted system. A range of 80.7-84.4 kcal/mol is observed for RCOCH(2)G
      ketones. The results are discussed in terms of solvation, steric, and resonance
      effects. Ab initio density functional theory (DFT) calculations are employed to
      illustrate the effect of steric interactions on radical and anion geometries. The
      DFT results parallel the trends in the experimental BDEs of alpha
      arylacetophenones.

PMID- 12467425
TI  - Carbene and nitrene rearrangements: a theoretical study of cyclic allenes and
      carbenes, carbodiimides, and azirines.
AB  - B3LYP/6-31G(d) calculations of structures, energies, and infrared spectra of
      several rearrangement products of (hetero)aromatic nitrenes and carbenes are
      reported. 3-Isoquinolylnitrene 36 ring closes to the azirine 37 prior to ring
      expansion to the potentially stable but unobserved seven-membered-ring
      carbodiimide 38 and diazacycloheptatrienylidene C(s)()-39S. A new, stable
      cycloheptatrienylidene, C(s)()-19S, is located on the naphthylcarbene energy
      surface. 4-Quinolylnitrene undergoes reaction via the azirine 50 in solution, but
      ring expansion to the stable seven-membered-ring ketenimine 47 under Ar matrix
      photolysis conditions. There is excellent agreement between calculated infrared
      spectra of 1,5-diazacyclohepta-1,2,4,6-tetraene 54 (obtained by photolysis of 4
      pyridyl azide), 1-azacyclohepta-1,2,4,6-tetraene 5, 1-azacyclohepta-1,3,5,6
      tetraene 55, and 1-azacyclohepta-1,3,4,6-tetraene 56 and the available
      experimental data.

PMID- 12467426
TI  - Access to the naphthylcarbene rearrangement manifold via isomeric
      benzodiazocycloheptatrienes.
AB  - Irradiation (lambda = 670 or >613 nm) of 4,5-benzodiazocycloheptatriene (15),
      matrix isolated in argon at 10 K, produces primarily 2,3-benzobicyclo[4.1.0]hepta
      2,4,6-triene (9) accompanied by small amounts of triplet 4,5
      benzocycloheptatrienylidene (2) and 2-naphthylcarbene (10). A reversible
      photoequilibrium is established in which 9 is converted to 10 at lambda = 290 nm
      and then regenerated at lambda = 360 nm. Similarly, matrix-isolated 2,3
      benzodiazocycloheptatriene (16) produces 4,5-benzobicyclo[4.1.0]hepta-2,4,6
      triene (11) at lambda = 670 or >613 nm, but without detection of 2,3
      benzocycloheptatrienylidene (4). Irradiation of 11 at lambda = 290 nm induces
      ring opening to triplet 1-naphthylcarbene (12), which, in turn, cyclizes back to
      11 at lambda = 342 or >497 nm. The diazo compounds and photoproducts are
      characterized by IR, UV/visible, and ESR spectroscopy, where appropriate, and by
      comparison of the experimental and B3LYP/6-31G calculated IR spectra for each
      species. Alternate rearrangement products such as allenes 6, 7, and 8 are not
      detected in the photolysis of either diazo compound.

PMID- 12467427
TI  - Origins and predictions of stereoselective antibody catalysis: theoretical
      analysis of Diels-Alder catalysis by 39A11 and its germ-line antibody.
AB  - The binding of enantiomeric haptens and transition states by the Schultz Diels
      Alderase antibody 39A11 and its germ-line antibody were studied theoretically.
      The mechanisms by which one hapten and one transition state stereoisomer is
      recognized selectively are explored with docking simulations and quantum
      mechanical models. Transition states of the relevant Diels-Alder reaction were
      located with density functional theory. A prediction is made that the
      stereoselectivity of 39A11 will be achieved by two strategically placed hydrogen
      bonds and pi-stacking interactions of the maleimide with a binding-site
      tryptophan, arranged so as to coordinate one enantiomeric transition state.
      Binding of other ligands by antibody 39A11 and the germ-line antibody has also
      been investigated. The polyspecific nature of 39A11 and its germ-line precursor
      was found to originate from the general ability of the binding pockets to achieve
      hydrophobic binding of small organic substrates. Comparison of the highly
      homologous progesterone and Diels-Alderase antibodies (DB3, 1E9, and 39A11)
      highlights the fact that differences of several key residues in the binding
      pockets are sufficient to confer selectivity for different antigens.

PMID- 12467429
TI  - 2-Pyridinethiol/2-pyridinethione tautomeric equilibrium. A comparative
      experimental and computational study.
AB  - The gas phase and solvent dependent preference of the tautomerization between 2
      pyridinethiol (2SH) and 2-pyridinethione (2S) has been assessed using variable
      temperature Fourier transform infrared (FTIR) experiments, as well as ab initio
      and density functional theory computations. No spectroscopic evidence (nu(S)(
      )(H) stretch) for 2SH was observed in toluene, C(6)D(6), heptane, or methylene
      chloride solutions. Although, C(s)() 2SH is 2.61 kcal/mol more stable than C(s)()
      2S (CCSD(T)/cc-pVTZ//B3LYP/6-311+G(3df,2p)+ZPE), cyclohexane solvent-field
      relative energies (IPCM-MP2/6-311+G(3df,2p)) favor 2S by 1.96 kcal/mol. This is
      in accord with the FTIR observations and in quantitative agreement with the -2.6
      kcal/mol solution (toluene or C(6)D(6)) calorimetric enthalpy for the 2S/2SH
      tautomerization favoring the thione. As the intramolecular transition state for
      the 2S, 2SH tautomerization (2TS) lies 25 (CBS-Q) to 30 kcal/mol (CCSD/cc-pVTZ)
      higher in energy than either tautomer, tautomerization probably occurs in the
      hydrogen bonded dimer. The B3LYP/6-311+G(3df,2p) optimized C(2) 2SH dimer is
      10.23 kcal/mol + ZPE higher in energy than the C(2)(h)() 2S dimer and is only
      2.95 kcal/mol + ZPE lower in energy than the C(2) 2TS dimer transition state.
      Dimerization equilibrium measurements (FTIR, C(6)D(6)) over the temperature range
      22-63 degrees C agree: K(eq)(298) = 165 +/- 40 M(-)(1), DeltaH = -7.0 +/- 0.7
      kcal/mol, and DeltaS = -13.4 +/- 3.0 cal/(mol deg). The difference between
      experimental and B3LYP/6-311+G(3df,2p) [-34.62 cal/(mol deg)] entropy changes is
      due to solvent effects. The B3LYP/6-311+G(3df,2p) nucleus independent chemical
      shifts (NICS) are -8.8 and -3.5 ppm 1 A above the 2SH and 2S ring centers,
      respectively, and the thiol is aromatic. Although the thione is not aromatic, it
      is stabilized by the thioamide resonance. In solvent, the large 2S dipole, 2-3
      times greater than 2SH, favors the thione tautomer and, in conclusion, 2S is
      thermodynamically more stable than 2SH in solution.

PMID- 12467428
TI  - Activation of leinamycin by thiols: a theoretical study.
AB  - Reaction of thiols with the 1,2-dithiolan-3-one 1-oxide heterocycle found in
      leinamycin (1) results in the conversion of this antitumor antibiotic to a DNA
      alkylating episulfonium ion (5). While the products formed in this reaction have
      been rationalized by a mechanism involving initial attack of thiol on the central
      sulfenyl sulfur (S2') of the 1,2-dithiolan-3-one 1-oxide ring, the carbonyl
      carbon (C3') and the sulfinyl sulfur (S1') of this heterocycle are also expected
      to be electrophilic. Therefore, it is important to consider whether nucleophilic
      attack of thiol at these sites might contribute either to destruction of the
      antibiotic or conversion to its episulfonium ion form. To address this question,
      we have used computational methods to examine the attack of methyl thiolate on
      each of the three electrophilic centers in a simple analogue of the 1,2-dithiolan
      3-one 1-oxide heterocycle found in leinamycin. Calculations were performed at the
      MP2/6-311+G(3df,p)//B3LYP/6-31G level of theory with inclusion of solvent
      effects. The results indicate that the most reasonable mechanism for thiol
      mediated activation of leinamycin involves initial attack of thiolate at the S2'
      position of the antibiotic's 1,2-dithiolan-3-one 1-oxide heterocycle, followed by
      conversion to the 1,2-oxathiolan-5-one intermediate (3).

PMID- 12467430
TI  - Low-temperature synthesis of tetraalkylureas from secondary amines and carbon
      dioxide.
AB  - The reaction of dialkylamines with CO(2) giving tetraalkylureas can be performed
      at 60 degrees C. The reaction requires CCl(4), is weakly promoted by DMAN or
      PPh(3), and is not promoted by a Pd catalyst. A two-step procedure, in which
      dialkylammonium dialkylcarbamate is produced in situ and then reacted with CCl(4)
      and free dialkylamine, gave greater yields of urea than a simple single-stage
      procedure.

PMID- 12467431
TI  - Thieno[3,4-b]pyrazines: synthesis, structure, and reactivity.
AB  - A general synthetic route has been developed for the efficient preparation of 2,3
      disubstituted thieno[3,4-b]pyrazines. These methods eliminate problems in the
      preparation of the precursor 3,4-diaminothiophene and utilize alpha-diones
      prepared through the reaction of the appropriate organocuprates with oxalyl
      chloride. This combination allows the convenient preparation of thieno[3,4
      b]pyrazine and its 2,3-disubstituted analogues (where substituent = methyl,
      hexyl, octyl, decyl, dodecyl, and phenyl) in high yield. Characterization of the
      structure and reactivity of this class of compounds is also described, including
      the results of structural, electrochemical, and pK(a) studies.

PMID- 12467432
TI  - Synthesis of C-carbamoyl-1,2,3-triazoles by microwave-induced 1,3-dipolar
      cycloaddition of organic azides to acetylenic amides.
AB  - 1,3-Dipolar cycloaddition of organic azides 1, 2, or 3 to acetylenic amides 4 or
      5 under solvent-free microwave irradiation produced the corresponding N
      substituted C-carbamoyl-1,2,3-triazoles 7a-12a in good to excellent yields. Under
      similar reaction conditions, 1,3-dipolar cycloaddition of diazide 6 and
      acetylenic amide 4 gave the azido-triazole 13a.

PMID- 12467433
TI  - Rapid defunctionalization of carbonyl group to methylene with
      polymethylhydrosiloxane-B(C(6)F(5))(3).
AB  - The polymethylhydrosiloxane-B(C(6)F(5))(3) combination is found to be a versatile
      carbonyl defunctionalization system under mild and rapid conditions. For the
      first time, B(C(6)F(5))(3) has been used as a nonconventional Lewis acid catalyst
      to activate PMHS. Aromatic and aliphatic carbonyl compounds were effectively
      reduced to give the corresponding alkanes in high yields.

PMID- 12467434
TI  - First enantioselective synthesis of vinyl oxiranes from aldehydes and ylides
      generated from allyl halides and chiral sulfides.
AB  - Asymmetric allylidenation of aldehydes with sulfur ylides is possible with proper
      substitution of the initial sulfide, to avoid the [2,3] sigmatropic rearrangement
      of the unsaturated ylides. One-pot reaction of (2R,5R)-dimethylthiolane with
      allyl halides, aldehydes, and sodium hydroxide in tert-butyl alcohol affords
      vinyl oxiranes in good yields. Enantiomeric excesses up to 90% and trans
      selectivities have been achieved with methallyl-type halides.

PMID- 12467435
TI  - Use of 9-methylfluorene as an indicator in the titration of common group IA and
      group IIA organometallic reagents.
AB  - 9-Methylfluorene was tested as an indicator in the titration of commonly used
      organometallic reagents. This indicator is readily prepared in three steps from
      fluorenone. In THF solution the deprotonated indicator is red and exhibits a
      sharp endpoint. The highly basic reagents sec-butyllithium and tert-butyllithium
      can be titrated in ether solution, where the color of the deprotonated indicator
      is yellow.

PMID- 12467436
TI  - A CASPT2 and CASSCF approach to the cycloaddition of ketene and imine: a new
      mechanistic scheme of the Staudinger reaction.
AB  - We report a new theoretical study of the mechanism of the parent Staudinger
      reaction between ketene and formaldimine. This mechanism, in contrast with
      previously reported computational studies, involves the formation of two
      different intermediates, gauche and trans, which can be interconnected on the
      potential energy surface depending upon reaction conditions. This novel
      CASPT2/CASSCF mechanistic scheme may be considered a new starting point to
      rationalize stereochemical outcome and solvent effects in these reactions.

PMID- 12467437
TI  - Simple and efficient chemoselective mild deprotection of acetals and ketals using
      cerium(III) triflate.
AB  - A new and chemoselective method for the cleavage of alkyl and cyclic acetals and
      ketals at room temperature in wet nitromethane by using catalytic cerium(III)
      trifluoromethane sulfonate is presented. The high yields, the observed
      selectivity, the very gentle reaction conditions, and the almost neutral pH make
      this procedure particularly attractive for multistep synthesis.

PMID- 12467438
TI  - An efficient route to pentasubstituted acylferrocenes.
AB  - A number of pentasubstituted acylferrocenes were selectively prepared from
      ferrous chloride, sodium acylcyclopentadienides, and the corresponding
      pentasubstituted lithium cyclopentadienides in good yields. The selectivity is
      governed by the different steric and electronic properties of the
      acylcyclopentadienides vs the pentasubstituted cyclopentadienides.

PMID- 12467439
TI  - Glycosyl trifluoroacetimidates. 2. Synthesis of dioscin and xiebai saponin I.
AB  - Two trisaccharide steroidal saponins, dioscin (1) and Xiebai saponin I (2) with
      various bioactivities, were efficiently synthesized using the newly developed
      glycosyl N-phenyl trifluoroacetimidates (10-13) as glycosylation donors. Thus,
      dioscin was synthesized in five steps and a 33% overall yield from diosgenin and
      glycosyl trifluoroacetimidates (10 and 11). Xiebai saponin I was synthesized in
      eight steps and a 32% overall yield from laxogenin and glycosyl
      trifluoroacetimidates (10, 12, and 13), whereupon, the rare steroid laxogenin was
      prepared from diosgenin in four steps and an overall 69% yield. All the
      glycosylation reactions involved in the present syntheses demonstrated that
      glycosyl trifluoroacetimidates were successful donors comparable to the
      corresponding glycosyl trichloroacetimidates.

PMID- 12467440
TI  - Substrate mimetics-specific peptide ligases: studies on the synthetic utility of
      a zymogen and zymogen-like enzymes.
AB  - Although proteases are capable of synthesizing peptide bonds, they are not
      proficient at peptide fragment ligation. Further manipulations are needed to
      shift the native enzyme activity from the cleavage to the synthesis of peptides.
      This account reports on the synthetic potential of nonactivatable trypsinogen and
      zymogen-like enzymes designed to minimize proteolytic side reactions during
      peptide synthesis.

PMID- 12467441
TI  - Synthesis of new tren-based tris-macrocycles. Anion cluster assembling inside the
      cavity generated by a bowl-shaped receptor.
AB  - The synthesis of three new tris-macrocycles, containing three [12]aneN(4) (L1),
      [12]aneN(3)O (L2), or [14]aneN(4) (L3) moieties appended to a tren unit, is
      reported. The crystal structure of the [(Na(ClO(4))(6)) subset
      L1(2)H(13)]Na(6)Cl(2)(ClO(4))(12) compound shows the anionic cluster
      [Na(ClO(4))(6)](5)(-) assembled inside the cavity defined by two bowl-shaped
      polyammonium receptors, held by multiple charge-charge and hydrogen bond
      interactions.

PMID- 12467442
TI  - An efficient procedure for the preparation of (E)-alpha-alkylidenecycloalkanones
      mediated by a CeCl(3) x 7H(2)O-NaI system. Novel methodology for the synthesis of
      (S)-(-)-pulegone.
AB  - 2-Alkylidenecycloalkanones are powerful synthons used as the key intermediates in
      many important syntheses. Because of their potential, a general method of
      preparation from readily available starting materials, under very mild
      conditions, was considered to be worthwhile. Cerium(III) chloride heptahydrate in
      combination with sodium iodide in refluxing acetonitrile promotes a regio- and
      stereoselective beta-elimination reaction to (E)-2-alkylidenecycloalkanones in 2
      (1-hydroxyalkyl)cycloalkanones. The synthetic value of the present procedure is
      demonstrated by the synthesis of monoterpene (S)-(-)-pulegone (8) in its
      optically active form.

PMID- 12467443
TI  - Preservation of chitinolytic Pantoae agglomerans in a viable form by cellular
      dried alginate-based carriers.
AB  - Improved viability of Gram-negative bacteria during freeze-dehydration, storage,
      and soil inoculation is of crucial importance to their efficient application. The
      chitinolytic Pantoae (Enterobacter) agglomerans strain IC1270, a potential
      biocontrol agent of soil-borne plant-pathogenic fungi, was used as a model
      organism to study the efficacy of freeze-dried alginate-based beads
      (macrocapsules) as possible carriers for immobilized Gram-negative bacterial
      cells. These macrocapsules were produced by freeze-dehydration of alginate gel
      spherical beads, in which different amounts of bacteria, glycerol, and colloidal
      chitin were entrapped. Subsequent drying produced different unexpected
      structures, pore-size distributions, and changes in the outer and inner
      appearance of the resultant dried cellular solid. With increasing glycerol
      content, the proportion of larger pores increased. These structures can be
      related to changes in the slow-release properties of the dried beads. The amount
      of glycerol in the beads differed from that in the alginate solution as a result
      of leakage during the beads' preparation and dehydration. Entrapping 10(9) cells
      per bead produced from alginate solution containing 30% glycerol and 1% chitin
      resulted in improved (in comparison to other studies) survival prospects (95%)
      during freeze-drying. Moreover, immobilization of the bacterium sharply improved
      its survival in nonsterile irrigated and dry soils compared to bacteria in a
      water suspension. The results suggest that optimized conservation of Gram
      negative bacteria in dry glycerol-containing alginate-based cellular solids is
      not only possible but applicable for a variety of uses.

PMID- 12467444
TI  - Modulation of phosphoenolpyruvate synthase expression increases shikimate pathway
      product yields in E. coli.
AB  - Product yields in microbial synthesis are ultimately limited by the mechanism
      utilized for glucose transport. Altered expression of phosphoenolpyruvate
      synthase was examined as a method for circumventing these limits. Escherichia
      coli KL3/pJY1.216A was cultured under fed-batch fermentor conditions where
      glucose was the only source of carbon for the formation of microbial biomass and
      the synthesis of product 3-dehydroshikimic acid. Shikimate pathway byproducts 3
      deoxy-D-arabino-heptulosonic acid, 3-dehydroquinic acid, and gallic acid were
      also generated. An optimal expression level of phosphoenolpyruvate synthase was
      identified, which did not correspond to the highest expression levels of this
      enzyme, where the total yield of 3-dehydroshikimic acid and shikimate pathway
      byproducts synthesized from glucose was 51% (mol/mol). For comparison, the
      theoretical maximum yield is 43% (mol/mol) for synthesis of 3-dehydroshikimic
      acid and shikimate pathway byproducts from glucose in lieu of amplified
      expression of phosphoenolpyruvate synthase.

PMID- 12467445
TI  - Alterations in Taxol production in plant cell culture via manipulation of the
      phenylalanine ammonia lyase pathway.
AB  - One approach to increasing secondary metabolite production in plant cell culture
      is to manipulate metabolic pathways to utilize more resources toward production
      of one desired compound or class of compounds, such as diverting carbon flux from
      competing secondary pathways. Since phenylalanine provides both the
      phenylisoserine side chain and the benzoyl moiety at C-2 of Taxol, we speculated
      that blockage of the phenylpropanoid pathway might divert phenylalanine into
      Taxol biosynthesis. We used specific enzyme inhibitors to target the first enzyme
      in the phenylpropanoid pathway, phenylalanine ammonia lyase (PAL), the critical
      control point for conversion of L-phenylalanine to trans-cinnamic acid. Cinnamic
      acid acted quickly in reducing PAL activity by 40-50%, without affecting total
      protein levels, but it generally inhibited the taxane pathway, reducing Taxol by
      90% of control levels. Of the taxanes produced, 13-acetyl-9-dihydro-baccatin III
      and 9-dihydrobaccatin III doubled as a percentage of total taxanes in C93AD and
      CO93P cells treated with 0.20 and 0.25 mM cinnamic acid, when all other taxanes
      were lowered. The PAL inhibitor alpha-aminooxyacetic acid (AOA) almost entirely
      shut down Taxol production at both 0.5 and 1.5 mM, whereas L-alpha-aminooxy-beta
      phenylpropionic acid (AOPP) had the opposite effect, slightly enhancing Taxol
      production at 1 microM but having no effect at 10 microM. The discrepancy in the
      effectiveness of AOA and AOPP and the lack of effect with addition of
      phenylalanine or benzoic acid derivatives further indicates that the impact of
      cinnamic acid on Taxol is related not to its effect on PAL but rather to a
      specific effect on the taxane pathway. On the basis of these results, a less
      direct route for inhibiting the phenylpropanoid pathway may be required to avoid
      unwanted side effects and potentially enhance Taxol production.

PMID- 12467446
TI  - Metabolic control analysis of eucaryotic pyruvate dehydrogenase multienzyme
      complex.
AB  - Metabolic control analysis (MCA) of pyruvate dehydrogenase multienzyme (PDH)
      complex of eucaryotic cells has been carried out using both in vitro and in vivo
      mechanistic models. Flux control coefficients (FCC) for the sensitivity of
      pyruvate decarboxylation rate to activities of various PDH complex reactions are
      determined. FCCs are shown to be strong functions of both pyruvate levels and
      various components of PDH complex. With the in vitro model, FCCs are shown to be
      sensitive to only the E1 component of the PDH complex at low pyruvate
      concentrations. At high pyruvate concentrations, the control is shared by all of
      the components, with E1 having a negative influence while the other three
      components, E2, X, and K, exert a positive control over the pyruvate
      decarboxylation rate. An unusual behavior of deactivation of the E1 component
      leading to higher net PDH activity is shown to be linked to the combined effect
      of protein X acylation and E1 deactivation. The steady-state analysis of the in
      vivo model reveals multiple steady state behavior of pyruvate metabolism with two
      stable and one unstable steady-states branches. FCCs also display multiplicity,
      showing completely different control distribution exerted by pyruvate and PDH
      components on three branches. At low pyruvate concentrations, pyruvate supply
      dominates the decarboxylation rate and PDH components do not exert any
      significant control. Reverse control distribution is observed at high pyruvate
      concentration. The effect of dilution due to cell growth on pyruvate metabolism
      is investigated in detail. While pyruvate dilution effects are shown to be
      negligible under all conditions, significant PDH complex dilution effects are
      observed under certain conditions. Comparison of in vitro and in vivo models
      shows that PDH components exert different degrees of control outside and inside
      the cells. At high pyruvate levels, PDH components are shown to exert a higher
      degree of control when reactions are taking place inside the cells as compared to
      the in vitro situation.

PMID- 12467447
TI  - Evaluation of factors promoting astaxanthin production by a unicellular green
      alga, Haematococcus pluvialis, with fractional factorial design.
AB  - Factors affecting the astaxanthin production by a unicellular green alga,
      Haematococcus pluvialis UTEX 16, were evaluated with sequential fractional
      factorial design. To simulate an actual production mode, a two-stage process was
      adapted for astaxanthin production: the alga was first cultivated under
      vegetative growth conditions, and then astaxanthin production was induced by
      applying various induction methods. A high dose of irradiation was most effective
      for the production of astaxanthin both in weight (mg/g) and in cellular (pg/cell)
      contents. A combination of nitrogen deficiency and acetate addition also
      significantly increased the astaxanthin content of cells on a dry weight basis.
      Meanwhile, the acetate addition alone increased only the cellular content of
      astaxanthin. Although the addition of ferrous ion alone had a negative effect on
      the weight content of astaxanthin, simultaneous addition of ferrous ion and
      acetate was effective for increasing the cellular content of astaxanthin.

PMID- 12467448
TI  - Enhanced stress tolerance in Escherichia coli and Nicotiana tabacum expressing a
      betaine aldehyde dehydrogenase/choline dehydrogenase fusion protein.
AB  - In Escherichia coli the osmoprotective compound glycine betaine is produced from
      choline by two enzymes; choline dehydrogenase (CDH) oxidizes choline to betaine
      aldehyde and then further on to glycine betaine, while betaine aldehyde
      dehydrogenase (BADH) facilitates the conversion of betaine aldehyde to glycine
      betaine. To evaluate the importance of BADH, a BADH/CDH fusion enzyme was
      constructed and expressed in E. coli and in Nicotiana tabacum. The fusion enzyme
      displayed both enzyme activities, and a coupled reaction could be measured. The
      enzyme was characterized regarding molecular weight and the dependence of the
      enzyme activities on environmental factors (salt, pH, and poly(ethylene glycol)
      addition). At high choline concentrations, E. coli cells expressing BADH/CDH were
      able to grow to higher final densities and to accumulate more glycine betaine
      than cells expressing CDH only. The intracellular glycine betaine levels were
      almost 5-fold higher for BADH/CDH when product concentration was related to CDH
      activity. Also, after culturing the cells at high NaCl concentrations, more
      glycine betaine was accumulated. On medium containing 20 mM choline, transgenic
      tobacco plants expressing BADH/CDH grew considerably faster than vector
      transformed control plants.

PMID- 12467449
TI  - Characterization of an inducible promoter system in Catharanthus roseus hairy
      roots.
AB  - Transgenic hairy root cultures of Catharanthus roseus were established with a
      glucocorticoid-inducible promoter controlling the expression of green fluorescent
      protein (GFP), and GFP expression was characterized. The inducible system shows a
      tightly controlled, reversible, and dosage-dependent response to the
      glucocorticoid dexamethasone in C. roseus hairy roots. Full induction was noted
      after 12-18 h in the mature regions of the root tips and after 6 h in the
      meristem tissue. Upon removal of the inducing agent, GFP expression declined to
      undetectable levels in the mature tissues after 24 h and in the meristem after 48
      h. Although no dosage-dependent response was noted in the meristem region, such a
      response was apparent in the mature region of the tip and verified by
      quantitative GFP analysis. The inducible promoter system allowed quantitative
      control of GFP expression between 0.01 and 10 microM dexamethasone with
      saturation occurring at higher levels. Using GFP as a model system allowed
      demonstration of the ability to control temporal and quantitative gene expression
      with the glucocorticoid-inducible promoter in transgenic C. roseus hairy roots.

PMID- 12467450
TI  - Facile and statistical optimization of transfection conditions for secretion of
      foreign proteins from insect Drosophila S2 cells using green fluorescent protein
      reporter.
AB  - Insect Drosophila melanogaster S2 cells were developed as a plasmid-based and
      therefore nonlytic expression system for functional foreign proteins.
      Transfection is an important step to introduce foreign target DNA into cells and
      should be properly optimized to obtain maximum production yield. Single factor
      search (SFS) methodology is still generally used to determine optimal condition
      in a biological system. Although this method is relatively simple to perform, it
      has many disadvantages such as not considering interactions between several
      factors and not covering the entire region of the solution pool. Therefore, we
      approached this optimization problem statistically with response surface (RSM)
      and evolutionary operation (EVOP) methodologies and compared the transfection
      efficiencies with the traditional SFS method. We employed secreted green
      fluorescent protein (GFP) as a reporter for determination of optimal transfection
      condition and secreted human erythropoietin (hEPO) as a confirming foreign model
      protein. Consequently, we arrived at the best optimal transient transfection
      condition (1 microg of plasmid DNA, 5 microg of lipofectin, 2 x 10(6) cells of
      initial cell number, and 18 h of transfection duration time) through a systematic
      access in a series of SFS, RSM, and EVOP. The secreted hEPO yield using optimal
      transient transfection condition by EVOP methodology was enhanced by about 1.8
      fold compared to that of traditional SFS. This optimized transient transfection
      condition can be used as a basis for optimal stable transfections. A linear
      relationship between secreted GFP fluorescence intensity and secreted hEPO
      concentration indicated that facile and noninvasive determination of optimal
      transfection conditions for expression and secretion of foreign proteins in S2
      cell cultures was made possible by simple measurement of GFP fluorescence.

PMID- 12467451
TI  - Secretion of cellobiase is mediated via vacuoles in Termitomyces clypeatus.
AB  - The majority of cellobiase activity in Termitomyces clypeatus was localized in
      vacuolar fractions of the fungus under secretory and nonsecretory conditions of
      growth. Activities of marker proteins for subcellular organelles, e.g., vacuoles,
      cytosol, ER, and mitochondria, in mycelial extracts from the secreting conditions
      increased by approximately 20, 12, 5, and 2.5 times, respectively, as compared to
      those obtained from mycelium grown in nonsecreting conditions. The average size
      and concentration of vacuoles visualized by electron microscopy were also
      increased in secreting conditions in the fungus. The specific activity of
      cellobiase in vacuoles isolated in Ficoll-sucrose gradient, as obtained from
      mycelial growth in secretory medium, was more than 40 times higher in comparison
      to that found from nonsecretory medium. The results indicated that subcellular
      localization of cellobiase in vacuoles is regulated by the cellular signaling
      prevailing in the fungus. Mycelial extraction of intracellular proteins by hand
      grinding and by bead-beater from cells frozen in the presence or absence of
      liquid nitrogen was also compared. Maximum recovery of intracellular protein was
      obtained with the bead-beater under aerobic conditions in the absence of
      nitrogen. Highest recovery of vacuoles up to 85% was obtained by single-step
      ultracentrifugation of the mycelial extract of the fungus in Ficoll-sucrose
      gradient. The method appeared to be useful for separation of other subcellular
      organelles in filamentous fungi.

PMID- 12467452
TI  - Complete conversion of D,L-5-monosubstituted hydantoins with a low velocity of
      chemical racemization into D-amino acids using whole cells of recombinant
      Escherichia coli.
AB  - A reaction system was developed for the production of D-amino acids from D,L-5
      monosubstituted hydantoins with a very slow rate of spontaneous racemization. For
      this purpose the D-hydantoinase and D-carbamoylase from Agrobacterium radiobacter
      NRRL B11291 were cloned in separate plasmids and expressed in Escherichia coli.
      The third enzyme, hydantoin racemase, was cloned from Agrobacterium tumefaciens
      C58. The hydantoin racemase amino acid sequence was significantly similar to
      those previously described. A reaction system consisting of recombinant
      Escherichia coli whole cell biocatalysts containing separately expressed D
      hydantoinase, D-carbamoylase, and hydantoin recemase showed high substrate
      specificity and was effective toward both aliphatic and aromatic D,L-5
      monosubstituted hydantoins. After optimizing reaction conditions (pH 8 and 50
      degrees C), 100% conversion of D,L-5-(2-methylthioethyl)-hydantoin (15 mM) into D
      methionine was obtained in 30 min.

PMID- 12467453
TI  - Continuous desulfurization of dibenzothiophene with Rhodococcusrhodochrous IGTS8
      (ATCC 53968).
AB  - Desulfurization of a model fuel system consisting of hexadecane and
      dibenzothiophene (DBT) by Rhodococcus rhodochrous IGTS8 was demonstrated in a 2-L
      continuous stirred tank reactor (CSTR). The reactor was operated in a
      semicontinuous and continuous mode with and without recycling of the model fuel.
      A constant volumetric desulfurization activity A(t), (in mg HBP L(-1) h(-1)) was
      maintained in the reactor with a feeding strategy of fresh cell suspension based
      on a first-order decay of the biocatalyst. Maximum desulfurization rates, as
      measured by specific desulfurization activity, of 1.9 mg HBP/g DCW h were
      attained. Rates of biocatalyst decay were on the order of 0.072 h(-1).
      Theoretical predictions of a respiratory quotient (RQ) associated with this
      biotransformation reaction agree well with experimental data from off-gas
      analysis. In addition, the ratio of the specific desulfurization activity a(t),
      (in mg HBP/g DCW h) of recycled and fresh biocatalyst was determined and
      evaluated.

PMID- 12467454
TI  - Integrated process for the enzymatic synthesis of the octapeptide PhAcCCK-8.
AB  - A process for the enzymatic synthesis of PhAcCCK-8 is presented. The CCK-8
      (CCK(26-33)) peptide fragment is the minimum sequence with biological activity of
      the cholecystokinin hormone. A synthetic convergent strategy has been developed
      starting from amino acid derivatives as raw materials, employing proteases as
      biocatalysts for each peptide coupling. The enzymes have been immobilized by
      deposition onto solid supports in order to be employed in organic media at low
      water activity. N-terminal protecting groups such as PhAc, which can be
      introduced and removed enzymatically, have been employed. The synthesis process
      has been set up at preparative level with focus in the integration of reaction
      and separation steps with an overall yield of 15%.

PMID- 12467455
TI  - Reversible immobilization of invertase on Sepabeads coated with
      polyethyleneimine: optimization of the biocatalyst's stability.
AB  - Invertase from S. cerevisiae has been immobilized by ionic adsorption on
      Sepabeads fully coated with PEI. The enzyme was strongly adsorbed on the support
      (no desorption of the invertase was found under conditions in which all of the
      enzyme was released from conventional anionic exchanger supports (e.g., DEAE
      agarose)). Nevertheless, the enzyme could still be desorbed after its
      inactivation, and new fresh enzyme could be adsorbed on the supports without
      detrimental effects on enzyme loading. This is a multimeric enzyme, its minimal
      oligomerization active state being the dimer, but under certain conditions of pH
      and concentration it may give larger multimers. Very interestingly, results
      suggested that the adsorption of the enzyme on this large and flexible polymeric
      bed was able to freeze some of the different oligomeric structures of the enzyme.
      Thus, we have found that the enzyme immobilized at certain pH values (pH 8.5) and
      high enzyme concentration, in which the main enzyme structure is the tetramer,
      was more stable than immobilized preparations produced in conditions under which
      oligomerization was not favorable (dimers at low enzyme concentration) or it was
      too high (e.g., hexamers-octamers at low pH value). The optimal enzyme
      preparation remained fully active after a 15-day incubation at 50 degrees C and
      pH 4.5 (conditions of standard industrial use) and presented an optimal
      temperature approximately 5 degrees C higher than that of soluble enzyme.

PMID- 12467456
TI  - Optimization of Allium sativum solvent extraction for the inhibition of in vitro
      growth of Helicobacter pylori.
AB  - Helicobacter pylori (Hp) is the bacterium responsible for serious gastric
      diseases such as ulcers and cancer. The work described here involved the study of
      the inhibitory power of Allium sativum extracts against the in vitro growth of Hp
      (Hp ivg). We used purple garlic of the "Las Pedroneras" variety for this study.
      The effects of two different extraction methods (Soxhlet, stirred tank extractor)
      and four solvents with different characteristics (water, acetone, ethanol, and
      hexane) were investigated in terms of the efficiency of the extraction process.
      Satisfactory results were obtained in most cases in the activity tests,
      indicating that different extracts gave rise to good inhibitory activity against
      Hp ivg. The extracts that showed the highest bacteriostatic activities were
      selected to evaluate the influence of the most important operation variables on
      the extraction yield: stirring speed, operation time, garlic conditioning, and
      garlic storage time. The best results were obtained using ethanol and acetone as
      solvents in a stirred tank. The inhibitory powers of these extracts were compared
      to those shown by some commercial antibiotics used in the medical treatment of Hp
      infections. The results of this study show that garlic extracts produce levels of
      inhibition similar to those of the commercial materials. These extracts were also
      tested against other common bacteria, and equally satisfactory results were
      obtained. The research described here represents an important starting point in
      the fight against and/or prevention of peptic ulcers, as well as other
      pathologies associated with Hp infections such us gastric cancer. The extracted
      material can be used by direct application and involves a simple and economical
      extraction procedure that avoids isolation or purification techniques.

PMID- 12467457
TI  - Effect of long-term cobalt deprivation on methanol degradation in a methanogenic
      granular sludge bioreactor.
AB  - The effect of the trace metal cobalt on the conversion of methanol in an upflow
      anaerobic sludge bed (UASB) reactor was investigated by studying the effect of
      cobalt deprivation from the influent on the reactor efficiency and the sludge
      characteristics. A UASB reactor (30 degrees C; pH 7) was operated for 261 days at
      a 12-h hydraulic retention time (HRT). The loading rate was increased stepwise
      from 2.6 g chemical oxygen demand (COD) x L reactor(-1) x d(-1) to 7.8 g COD x L
      reactor(-1) x d(-1). Cobalt deprivation had a strong impact on the methanogenic
      activity of the sludge. In batch tests, the methanogenic activity of the sludge
      with methanol as the substrate increased 5.3 (day 28) and 2.1 (day 257) times by
      addition of 840 nM of cobalt. The sludge had an apparent K(m) for cobalt of 948
      nM after 28 days of operation and 442 nM at the end of the run. Cobalt
      deprivation during 54 days of operation led to a methanol conversion efficiency
      of only 55%. Continuous addition of cobalt (330 nM) for 33 days improved the
      methanol removal efficiency to 100%. In this period of cobalt dosing, the cobalt
      concentration in the sludge increased 2.7 times up to 32 microg x g TSS(-1). Upon
      omission of the cobalt addition, cobalt washed-out at a stable rate of 0.1 microg
      x g VSS(-1) x d(-1). At the end of the run, the cobalt concentration of the
      sludge was similar to that of the seed sludge.

PMID- 12467458
TI  - Stabilization and improvement of catalytic activity of a low molar mass
      cellobiase by cellobiase-sucrase aggregation in the culture filtrate of
      Termitomyces clypeatus.
AB  - The extracellular cellobiase (EC 3.2.1.21) of Termitomyces clypeatus separated in
      two protein fractions when culture filtrate or ammonium sulfate precipitated
      proteins were chromatographed on BioGel P-200 column. During purification of
      cellobiase (CBS) from the lower molar mass (LMM) protein fraction, the enzyme
      behaved like a low molecular weight multimeric protein. The purified enzyme gave
      a single 56 kDa band in SDS-PAGE but ladderlike bands (14, 28, 42, and 56 kDa) on
      denaturation by reducing-SDS and urea. The protein, however, dissociated on
      dilution and protomeric (14 kDa) and multimeric forms (28 and 60 kDa) were eluted
      separately during HPGPLC. Specific activity of CBS gradually decreased as the
      molar mass of the enzyme was lowered in different eluted peaks. Protein present
      in all CBS pool fractions had the same amino acid composition and all displayed
      the same, single protein peak in reverse-phase HPLC and 56 kDa band in SDS-PAGE.
      Thus, T. clypeatus CBS was a multimeric 14 kDa protein that was optimally active
      as a tetramer. CBS purified from the higher molar mass fraction (HMM) as a SDS
      PAGE homogeneous 110-kDa protein did not dissociate on dilution or by SDS-urea.
      The purified protein was a protein aggregate as CBS consistently contained 20 +/-
      5% sucrase (SUC) Units in the preparation. The aggregate resolved during reverse
      phase chromatography on a C(4) column, and an additional protein peak other than
      CBS was detected. The aggregated CBS had a higher temperature optimum and was
      more stable toward thermal and chemical denaturations than SUC-free CBS. Increase
      of stability and catalytic activity of CBS by aggregation with SUC was much
      higher than those by the multimerization of CBS itself. All of these observations
      for the first time suggested that the heterologous protein-protein aggregation,
      observed for a long time for fungal enzymes, might have a significant role in
      modulating physicochemical properties of the extracellular enzyme.

PMID- 12467459
TI  - Kinetics of the alkaline phosphatase catalyzed hydrolysis of disodium p
      nitrophenyl phosphate in frozen model systems.
AB  - The alkaline phosphatase catalyzed hydrolysis of disodium-p-nitrophenyl phosphate
      was studied in four model systems comprising sucrose, maltodextrin,
      carboxymethylcellulose (CMC), and CMC-lactose in a temperature range of -28 to 20
      degrees C. In the maltodextrin and CMC-lactose model systems, the reaction rate
      decreased to a very low value as the glass transition temperature was approached.
      In the CMC and CMC-lactose systems with low initial solute concentration, as a
      consequence of freeze-concentration, a rate maximum around the initial freezing
      temperature was observed. The Arrhenius equation described the temperature
      dependence of the reaction rate both in the liquid and the glassy states in all
      systems studied, while a slightly curved Arrhenius plot was observed in the
      "rubbery" state of the CMC and CMC-lactose systems. The WLF equation with system
      dependent coefficients described the kinetics in the rubbery state of all the
      model systems except sucrose, excluding the short temperature range where
      reaction rate enhancement with decreasing temperature was observed.

PMID- 12467460
TI  - Mature experimental constructed wetlands treating urban water receiving high
      metal loads.
AB  - The aim was to assess over 2 years the treatment efficiencies of vertical-flow
      wetland filters containing macrophytes and granular media of different adsorption
      capacities. Different concentrations of lead and copper sulfate (constant for 1
      year each) were added to urban beck inflow water in order to simulate pretreated
      (pH adjustment assumed) mine wastewater. After 1 year of operation, the inflow
      concentrations for lead and copper were increased from 1.30 to 2.98 and from 0.98
      to 1.93 mg/L, respectively. However, the metal mass load rates (mg/m(2)/d) were
      increased by a factor of approximately 4.9 for lead and 4.3 for copper. No
      breakthrough of metals was recorded. Lead and copper accumulated in the biomass
      of the litter zone and rhizomes of the macrophytes. Furthermore, microbiological
      activity decreased during the second year of operation. Bioindicators such as
      ciliated protozoa and zooplankton decreased sharply in numbers but diatoms
      increased. In conclusion, the use of macrophytes and adsorption media did not
      significantly enhance the filtration of lead and copper. Particulate lead is
      removed by filtration processes including straining. Furthermore, some expensive
      and time-consuming water quality variables can be predicted with less expensive
      ones such as temperature in order to reduce sampling costs.

PMID- 12467461
TI  - Nonlinear dynamics of eucaryotic pyruvate dehydrogenase multienzyme complex:
      decarboxylation rate, oscillations, and multiplicity.
AB  - Pyruvate conversion to acetyl-CoA by the pyruvate dehydrogenase (PDH) multienzyme
      complex is known as a key node in affecting the metabolic fluxes of animal cell
      culture. However, its possible role in causing possible nonlinear dynamic
      behavior such as oscillations and multiplicity of animal cells has received
      little attention. In this work, the kinetic and dynamic behavior of PDH of
      eucaryotic cells has been analyzed by using both in vitro and simplified in vivo
      models. With the in vitro model the overall reaction rate (nu(1)) of PDH is shown
      to be a nonlinear function of pyruvate concentration, leading to oscillations
      under certain conditions. All enzyme components affect nu(1) and the nonlinearity
      of PDH significantly, the protein X and the core enzyme dihydrolipoamide
      acyltransferase (E2) being mostly predominant. By considering the synthesis rates
      of pyruvate and PDH components the in vitro model is expanded to emulate in vivo
      conditions. Analysis using the in vivo model reveals another interesting kinetic
      feature of the PDH system, namely, multiple steady states. Depending on the
      pyruvate and enzyme levels or the operation mode, either a steady state with high
      pyruvate decarboxylation rate or a steady state with significantly lower
      decarboxylation rate can be achieved under otherwise identical conditions. In
      general, the more efficient steady state is associated with a lower pyruvate
      concentration. A possible time delay in the substrate supply and enzyme synthesis
      can also affect the steady state to be achieved and leads to oscillations under
      certain conditions. Overall, the predictions of multiplicity for the PDH system
      agree qualitatively well with recent experimental observations in animal cell
      cultures. The model analysis gives some hints for improving pyruvate metabolism
      in animal cell culture.

PMID- 12467462
TI  - Rhamnolipid biosurfactant production by strains of Pseudomonas aeruginosa using
      low-cost raw materials.
AB  - This study was aimed at the development of economical methods for higher yields
      of biosurfactant by suggesting the use of low-cost raw materials. Two oil
      degrading strains, Pseudomonas aeruginosa GS9-119 and DS10-129, were used to
      optimize a substrate for maximum rhamnolipid production. Among the two strains,
      the latter produced maxima of 4.31, 2.98, and 1.77 g/L rhamnolipid biosurfactant
      using soybean oil, safflower oil, and glycerol, respectively. The yield of
      biosurfactant steadily increased even after the bacterial cultures reached the
      stationary phase of growth. Characterization of rhamnolipids using mass
      spectrometry revealed the presence of dirhamnolipids (Rha-Rha-C(10)-C(10)).
      Emulsification activity of the rhamnolipid biosurfactant produced by P.
      aeruginosa DS10-129 was greater than 70% using all the hydrocarbons tested,
      including xylene, benzene, hexane, crude oil, kerosene, gasoline, and diesel. P.
      aeruginosa GS9-119 emulsified only hexane and kerosene to that level.

PMID- 12467463
TI  - Continuous production of high-content fructooligosaccharides by a complex cell
      system.
AB  - A complex biocatalyst system with a bioreactor equipped with a microfiltration
      (MF) module was employed to produce high-content fructooligosaccharides (FOS) in
      a continuous process initiated by a batch process. The system used mycelia of
      Aspergillus japonicus CCRC 93007 or Aureobasidium pullulans ATCC 9348 with beta
      fructofuranosidase activity and Gluconobacter oxydans ATCC 23771 with glucose
      dehydrogenase activity. Calcium carbonate slurry was used to control pH to 5.5,
      and gluconic acid in the reaction mixture was precipitated as calcium gluconate.
      Sucrose solution with an optimum concentration of 30% (w/v) was employed as feed
      for the complex cell system, and high-content FOS was discharged continuously
      from a MF module. The complex cell system was run at 30 degrees C with an
      aeration rate of 5 vvm and produced more than 80% FOS with the remainder being 5
      7% glucose and 8-10% sucrose on a dry weight basis, plus a small amount of
      calcium gluconate. The system worked for a 7-day continuous production process
      with a dilution rate of 0.04 h(-1), and the volumetric productivity for total FOS
      was more than 160 g L(-1) h(-1).

PMID- 12467464
TI  - Application of fungi as biocatalysts for the reduction of diethyl 1
      oxoalkylphosphonates in anhydrous hexane.
AB  - Five different species of microorganisms, namely, Rhodotorula rubra, Rhodotorula
      glutinis, Cladosporium sp., Verticillium sp., and baker's yeast, turned out to be
      useful biocatalysts for enantioselective reduction of a variety of diethyl 1
      oxoalkylphosphonates. To suppress substrate decomposition, bioreductions were
      carried out under anhydrous conditions, using lyophilized cells immobilized on
      Celite R 630. The influence of reaction conditions such as biotransformation time
      and chemical additives on the yield of the reaction is discussed.

PMID- 12467465
TI  - On-line purification of monoclonal antibodies using an integrated stirred-tank
      reactor/expanded-bed adsorption system.
AB  - While expanded-bed adsorption (EBA) units have been used to recover proteins from
      whole cell cultures, the development of a more efficient, on-line process could
      streamline the traditional multistep process. This study implements a bench-scale
      on-line purification system in which whole cell cultures are loaded directly into
      a chromatography column to capture a monoclonal antibody (mAb) in a single step.
      The on-line purification system used here integrates a stirred-tank reactor (STR)
      and an EBA unit into a new hybrid (STR-EBA) system. To conduct this work, first,
      column and buffer conditions were optimized to capture immunoglobulin G from a
      hybridoma cell culture. A high cell removal (>95%) was achieved in part by
      removing the top flow distributor and mesh. Then, the 95% extent of removal was
      sustained for four successive cycles, each using PBS. With 20 mM phosphate
      buffer, however, the removal decreased from 95% to 75% stepwise. Next, the
      operational constraints of the EBA system were determined for the hybridoma cell
      culture, focusing on the effects of cell viability and density on cell removal.
      This study shows that the cell removal was not significantly different in the
      range of 80% to 0% viability. Cell density was also varied between 1 x 10(6) and
      1 x 10(8) cells/mL. From 0.1 to 6 x 10(7) cells/mL, cell retention in the column
      was less than 5% and product recovery remained high, approximately 95%. After
      characterizing the working conditions of the EBA system, on-line purification was
      performed. With 1.1 L of culture containing 3 x 10(6) cells/mL and 100 mg/L of
      IgG, repeated-batch cultures were implemented. Half of the culture volume (550
      mL) was directly sent to the EBA system every day, for 11 days, and the same
      amount of fresh medium was fed into the STR. During on-line purification,
      productivity was 58 mg of IgG/cycle (day) and purity was greater than 95%. Simple
      batch culture alone produced 17 mg of IgG/day. This result suggests that the on
      line STR-EBA system can achieve higher and faster production compared with STR
      batch and off-line EBA purification. Overall, the STR-EBA system with repeated
      batch mode was an effective and flexible system for bench-scale mAb production.

PMID- 12467466
TI  - Aqueous extraction of beta-glucuronidase from transgenic canola: kinetics and
      microstructure.
AB  - Aqueous extraction kinetics of recombinant beta-glucuronidase (rGUS) from
      transgenic canola (Brassica napus) was investigated in terms of the particle size
      and microstructural characteristics resulting from canola seed processing. The
      canola had been transformed to express recombinant GUS intracellulary in the
      seed, and electron microscopy showed that the cells are distributed among (1)
      disrupted cells in a thin layer at or adjacent to the particle surface, (2)
      disrupted cells within the interior, and (3) intact cells within the interior. A
      simple compartmental model containing two extractable pools and a third
      nonextractable pool fitted the batch extraction results very well. Comparing the
      rate constants from the model to estimates of expected transport rates from the
      observed cell fractions showed that the two extractable pools roughly correspond
      to the two disrupted cell fractions. Both flaking, causing more extensive cell
      wall damage throughout the seed, and grinding, increasing the total surface area,
      increase the size of the first pool and, therefore, the extraction yield. Mass
      transfer from the same type of pool from two types of processed seed behaved
      similarly. GUS extraction from the first extractable pool is 10-20 times faster
      (<1 min) than from the second extractable pool.

PMID- 12467467
TI  - True and apparent temperature dependence of protein adsorption equilibrium in
      reversed-phase HPLC.
AB  - The adsorption behavior of bovine insulin on a C(8)-bonded silica stationary
      phase was investigated at different column pressures and temperatures in
      isocratic reversed-phase HPLC. Changes in the molar volume of insulin (deltaV(m))
      upon adsorption were derived from the pressure dependence of the isothermal
      retention factor (k'). The values of deltaV(m) were found to be practically
      independent of the temperature between 25 and 50 degrees C at -96 mL/mol and to
      increase with increasing temperature, up to -108 mL/mol reached at 50 degrees C.
      This trend was confirmed by two separate series of measurements of the thermal
      dependence of ln(k'). In the first series the average column pressure was kept
      constant. The second series involved measurements of ln(k') under constant mobile
      phase flow rate, the average column pressure varying with the temperature. In
      both cases, a parabolic shape relationship was observed between ln(k') and the
      temperature, but the values obtained for ln k' were higher in the first than in
      the second case. The relative difference in ln(k'), caused by the change in
      pressure drop induced by the temperature, is equivalent to a systematic error in
      the estimate of the Gibbs free energy of 12%. Thus, a substantial error is made
      in the estimates of the enthalpy and entropy of adsorption when neglecting the
      pressure effects associated with the change in the molar volume of insulin. This
      work proves that the average column pressure must be kept constant during
      thermodynamic measurements of protein adsorption constants, especially in RPLC
      and HIC. Our results show also that there is a critical temperature, T(c)
      approximately equals 53 degrees C, at which ln(k') is maximum and the insulin
      adsorption process changes from an exothermic to an endothermic one. This
      temperature determines also the transition point in the molecular mechanism of
      insulin adsorption that involves successive unfolding of the protein chain.

PMID- 12467468
TI  - Adsorption of cadmium ion and gallium ion to immobilized metallothionein fusion
      protein.
AB  - A fusion protein made from maltose binding protein (pmal) and human
      metallothionein (MT) was expressed using E. coli. The purified recombinant
      protein (pmal-MT) was immobilized on Chitopearl resin, and characteristics of
      pmal-MT for metal binding were evaluated. As expected from the tertiary structure
      of metallothionein, the pmal-MT ligand adsorbed 12.1 cadmium molecules per one
      molecule of the ligand at pH 5.2. The pmal-MT ligand also bound 26.6 gallium
      molecules per one molecule of the ligand at pH 6.5. Neither cadmium ion nor
      gallium ion bound to a control protein bovine serum albumin (BSA). Adsorption
      isotherms for both ions were correlated by Langmuir-type equations. Two types of
      binding sites have been elucidated on the basis of HSAB (hard and soft acid and
      base) theory. It was suggested that gallium ion specifically binds to amino acid
      residues containing oxygen and nitrogen atoms, while cadmium ion binds to
      specific binding sites formed by multiple cysteine residues. The pmal-MT ligand
      bound these metals in the concentration range of 0.2-1.0 mM, and the bound metal
      ions could be eluted under relatively mild conditions (pH 2.0). The pmal-MT
      Chitopearl resin was stable and could be used repeatedly without loss of binding
      activity. Thus, this new ligand would be useful for recovery of toxic heavy
      metals and/or valuable metal ions from various aqueous solutions.

PMID- 12467469
TI  - Continuous separation of multicomponent protein mixtures by annular displacement
      chromatography.
AB  - Displacement chromatography is a predominantly nonlinear mode of chromatography,
      which has certain advantages over the elution mode for preparative
      bioseparations. Whereas continuous production (and separation) processes have
      their theoretical benefits in this context, protein displacement chromatography
      has up to now only been performed in the batch mode. In this contribution, we
      demonstrate that the principle of continuous annular chromatography can be
      adapted to displacement chromatography. Separations of up to three standard
      proteins (two whey proteins, soybean trypsin inhibitor) were developed and
      optimized using a small (4 x 250 mm) batch column. These separations were
      subsequently transferred directly to the continuous system (500-mL column).
      Separations of similar quality in terms of final product purity and recovery
      yield were obtained using the continuous system.

PMID- 12467470
TI  - Standing wave design and experimental validation of a tandem simulated moving bed
      process for insulin purification.
AB  - A tandem simulated moving bed (SMB) process for insulin purification has been
      proposed and validated experimentally. The mixture to be separated consists of
      insulin, high molecular weight proteins, and zinc chloride. A systematic approach
      based on the standing wave design, rate model simulations, and experiments was
      used to develop this multicomponent separation process. The standing wave design
      was applied to specify the SMB operating conditions of a lab-scale unit with 10
      columns. The design was validated with rate model simulations prior to
      experiments. The experimental results show 99.9% purity and 99% yield, which
      closely agree with the model predictions and the standing wave design targets.
      The agreement proves that the standing wave design can ensure high purity and
      high yield for the tandem SMB process. Compared to a conventional batch SEC
      process, the tandem SMB has 10% higher yield, 400% higher throughput, and 72%
      lower eluant consumption. In contrast, a design that ignores the effects of mass
      transfer and nonideal flow cannot meet the purity requirement and gives less than
      96% yield.

PMID- 12467471
TI  - Microcarrier culture of lepidopteran cell lines: implications for growth and
      recombinant protein production.
AB  - Several microcarrier systems were screened with Sf-9 and High-Five cell lines as
      to their ability to support cell growth and recombinant (beta-galactosidase)
      protein production. Growth of both cell lines on compact microcarriers, such as
      Cytodex-1 and glass beads, was minimal, as cells detached easily from the
      microcarrier surface and grew as single cells in the medium. Cell growth was also
      problematic on Cytopore-1 and -2 porous microcarriers. Cells remained attached
      for several days inside the microcarrier pores, but no cell division and
      proliferation were observed. On the contrary, insect cells grew well in the
      interior of Fibra-Cel disks mainly as aggregates at points of fiber intersection,
      reaching final (plateau) densities of about 4 x 10(6) (Sf-9) and 2.7 x 10(6)
      (High-Five) cells mL(-1) (8 x 10(6) and 5.5 x 10(6) cells per cm(2) of projected
      disk area, respectively). Their growth was described well by the logistic
      equation, which takes into account possible inhibition effects. Beta
      Galactosidase (beta-gal) production of Sf-9 cells on Fibra-Cel disks (infected at
      3.3 x 10(6) cells mL(-1)) was prolonged (192 h), and specific protein production
      was similar to that of high-density free cell infection. Cultispher-S
      microcarriers were found to be a very efficient system for the growth of High
      Five cells, whereas no growth of Sf-9 cells took place for the same system.
      Concentrations of about 9 x 10(6) cells mL(-1) were reached within 120 h, with
      cell growth in both microcarriers and aggregates, appearance of cellular bridges
      between microcarriers and aggregates, and eventual formation of macroaggregates
      incorporating several microcarriers. Specific protein productions after beta-gal
      baculovirus infection at increasing cell concentrations were almost constant,
      thus leading to elevated volumetric protein production: final beta-gal titers of
      946, 1728, and 1484 U mL(-1) were obtained for infection densities of 3.4, 7.2,
      and 8.9 x 10(6) cells mL(-1), respectively.

PMID- 12467472
TI  - Genetic programming assisted stochastic optimization strategies for optimization
      of glucose to gluconic acid fermentation.
AB  - This article presents two hybrid strategies for the modeling and optimization of
      the glucose to gluconic acid batch bioprocess. In the hybrid approaches, first a
      novel artificial intelligence formalism, namely, genetic programming (GP), is
      used to develop a process model solely from the historic process input-output
      data. In the next step, the input space of the GP-based model, representing
      process operating conditions, is optimized using two stochastic optimization (SO)
      formalisms, viz., genetic algorithms (GAs) and simultaneous perturbation
      stochastic approximation (SPSA). These SO formalisms possess certain unique
      advantages over the commonly used gradient-based optimization techniques. The
      principal advantage of the GP-GA and GP-SPSA hybrid techniques is that process
      modeling and optimization can be performed exclusively from the process input
      output data without invoking the detailed knowledge of the process phenomenology.
      The GP-GA and GP-SPSA techniques have been employed for modeling and optimization
      of the glucose to gluconic acid bioprocess, and the optimized process operating
      conditions obtained thereby have been compared with those obtained using two
      other hybrid modeling-optimization paradigms integrating artificial neural
      networks (ANNs) and GA/SPSA formalisms. Finally, the overall optimized operating
      conditions given by the GP-GA method, when verified experimentally resulted in a
      significant improvement in the gluconic acid yield. The hybrid strategies
      presented here are generic in nature and can be employed for modeling and
      optimization of a wide variety of batch and continuous bioprocesses.

PMID- 12467473
TI  - Identification of critical batch operating parameters in fed-batch recombinant E.
      coli fermentations using decision tree analysis.
AB  - To develop a useful fermentation process model, it is first necessary to identify
      which batch operating parameters are critical in determining the process outcome.
      To identify critical processing inputs in large databases, we have explored the
      use of Decision Tree Analysis with the decision metrics of Gain (i.e., Shannon
      Entropy changes), Gain Ratio, and a multiple hypergeometric distribution. The
      usefulness of this approach lies in its ability to treat "categorical" variables,
      which are typical of archived fermentation databases, as well as "continuous"
      variables. In this work, we demonstrate the use of Decision Tree Analysis for the
      problem of optimizing recombinant green fluorescent protein production in E.
      coli. A database of 85 fermentations was generated to examine the effect of 15
      process input parameters on final biomass yield, maximum recombinant protein
      concentration, and productivity. The use of Decision Tree Analysis led to a
      considerable reduction in the fermentation database through the identification of
      the significant as well as insignificant inputs. However, different decision
      metrics selected different inputs and different numbers of inputs to classify the
      data for each output.

PMID- 12467474
TI  - A lab-built respirometer for plant and animal cell culture.
AB  - A very simple off-line respirometer was developed to measure oxygen consumption
      rates of low respiring and shear-sensitive cell suspensions. The respirometer is
      composed of a 10 mL glass syringe in which the plunger was substituted with a
      polarographic dissolved oxygen probe. Mechanical agitation is provided by means
      of a magnetic stirring bar inside the measuring chamber and a stir plate placed
      below the respirometer. Abiotic oxygen fluxes occurring in the measurement
      chamber such as oxygen diffusion and probe oxygen consumption were investigated.
      The apparent oxygen uptake rate was then corrected for abiotic oxygen fluxes,
      leading to accurate measurements of respiration rates ranging from 0.5 to 25.0 mM
      x h(-1). Additionally, the effect of the stirring bar shape and of the test
      length on the integrity of plant (Eschschzoltzia californica) and animal (NS0)
      cells was evaluated. Animal cells showed a higher resistance to mechanical
      stirring inside the respirometer compared to plant cells (0% of broken cells and
      78.1% respectively for a polygonal stirring bar and a 15 min test). For plant
      cells, cell damage inside the measurement chamber was reduced by optimizing the
      stirring bar shape and reducing the test length to 5 min or less. This very
      simple design was shown to provide reliable and low-cost quantification of the
      oxygen uptake rate of plant and animal cells and can be use even for more
      demanding measurements such as oxygen affinity studies.

PMID- 12467475
TI  - On-line determination of biomass in a microalga bioreactor using a novel
      computerized flow injection analysis system.
AB  - A flow injection analysis (FIA) device has been developed, which is able to assay
      successfully for biomass in a microalga bioreactor. The device is fully
      computerized and is operated via diluting small aliquots of the culture followed
      by measuring optical density (OD); this figure is then accurately correlated with
      biomass, in terms of both cell number and ash-free dry weight, during the entire
      culture time. Furthermore, the device is not expensive, is highly versatile, and
      is easy to operate owing to specifically developed, user-friendly software. The
      growth rate and biomass productivity of Pavlova lutheri, cultivated under batch
      and semicontinuous modes, were monitored as experimental testing model.

PMID- 12467476
TI  - Design of methanol Feed control in Pichia pastoris fermentations based upon a
      growth model.
AB  - The methylotrophic yeast Pichia pastoris is an effective system for recombinant
      protein productions that utilizes methanol as an inducer, and also as carbon and
      energy source for a Mut(+) (methanol utilization plus) strain. Pichia
      fermentation is conducted in a fed-batch mode to obtain a high cell density for a
      high productivity. An accurate methanol control is required in the methanol fed
      batch phase (induction phase) in the fermentation. A simple "on-off" control
      strategy is inadequate for precise control of methanol concentrations in the
      fermentor. In this paper we employed a PID (proportional, integral and
      derivative) control system for the methanol concentration control and designed
      the PID controller settings on the basis of a Pichia growth model. The closed
      loop system was built with four components: PID controller, methanol feed pump,
      fermentation process, and methanol sensor. First, modeling and transfer functions
      for all components were derived, followed by frequency response analysis, a
      powerful method for calculating the optimal PID parameters K(c) (controller
      gain), tau(I) (controller integral time constant), and tau(D) (controller
      derivative time constant). Bode stability criteria were used to develop the
      stability diagram for evaluating the designed settings during the entire methanol
      fed-batch phase. Fermentations were conducted using four Pichia strains, each
      expressing a different protein, to verify the control performance with optimal
      PID settings. The results showed that the methanol concentration matched the set
      point very well with only small overshoot when the set point was switched, which
      indicated that a very good control performance was achieved. The method developed
      in this paper is robust and can serve as a framework for the design of other PID
      feedback control systems in biological processes.

PMID- 12467477
TI  - Carbon mass balance evaluation of cellulase production on soluble and insoluble
      substrates.
AB  - A methodology is described and applied for performing carbon mass balances across
      cellulase enzyme production processes using both soluble sugar and insoluble
      cellulose substrates. The fungus Trichoderma reesei was grown on either glucose,
      lactose, or cellulose in aerobic batch mode, and the evolution of the main
      carbonaceous components (cell mass, cellulose, soluble protein, adsorbed protein,
      sugars, and carbon dioxide) was followed. A variety of analytical techniques were
      utilized to measure these components, including (i) gravimetric analysis, (ii)
      near-infrared spectroscopy, (iii) bicinchoninic acid based soluble protein
      measurement, (iv) gas mass spectrometry and flow rate, (v) CHNS/O elemental
      analyses, and (vi) high-performance liquid chromatography. The combined set of
      measurements allowed carbon mass balances across the cellulase production process
      to be assessed to determine the consistency of the underlying kinetic data.
      Results demonstrate the capability to determine the levels and distribution of
      all major carbonaceous components during the cellulase production process on both
      soluble and insoluble substrates. Average carbon mass balance closures were near
      100% during early stages (<72 h) of the cultivations using glucose, lactose, or
      cellulose as the substrates, but carbon mass closures trended high later in the
      cultivation. Analysis of carbon allocation results suggests that an error in the
      gas mass flow rate measurement was the primary cause for carbon mass balance
      closures to exceed 110% late in the process.

PMID- 12467478
TI  - On-line monitoring of adhesion and proliferation of cultured hepatoma cells using
      optical waveguide lightmode spectroscopy (OWLS).
AB  - Monitoring of cell adhesion, cell spreading, and cell proliferation opens
      attractive perspectives in the on-line control of monolayer cell cultures in
      toxicity tests, in bioreactors as used for the serial production of skin grafts,
      or in extracorporeal liver devices. In this study the hepatoma Hep G2 cell
      adhesion and proliferation was monitored using an integrated optical method,
      optical waveguide lightmode spectroscopy (OWLS). This method is based upon
      refractive index measurements within a 100-nm thin layer above a Si(Ti)O(2)
      surface on which the cells were cultured and exposed to cytotoxic and cytostatic
      agents. The OWLS signal was proportional to cell density during the spreading
      period (4 h), and in long-term experiments (46 h) the OWLS signal correlated on a
      logarithmic scale with cell density. After administration of the protein
      synthesis inhibitor cycloheximide (4 microg/mL) to fully spread hepatoma cells,
      cell growth was arrested and change of the OWLS signal became noticeable within 6
      h after drug administration. For exposure to increasing concentrations of the
      anticancer drug cyclophosphamide (2.5-20 mM) a concentration-dependent reduction
      of the OWLS signal was found. For cycloheximide and cyclophospamide the OWLS
      signal was also confirmed by cell viability measurements using the neutral red
      assay, the thiazolylblue tetrazoliumbromide assay, total protein measurements,
      and cell morphology. It was demonstrated that the OWLS signal detects minor
      changes in cell adhesion, which serve as indicators of metabolic state and growth
      behavior. OWLS is thus a quantitative tool to characterize impaired cell growth
      mediated by culture medium, by extracellular matrix, or after exposure to a
      toxin.

PMID- 12467479
TI  - Design of the pH profile for asymmetric bioreduction of ethyl 4-chloro-3
      oxobutyrate on the basis of a data-driven method.
AB  - The goal of this paper was to design the optimal time-varying operating pH
      profile in the asymmetric reduction of ethyl 4-chloro-3-oxobutyrate by baker's
      yeast. Ethyl (S)-4-chloro-3-hydroxybutyrate was produced to reach two important
      quality indices: reaction yield and product optical purity. The method integrated
      an orthogonal function approximation and an orthogonal array. The technique used
      a set of orthonormal functions as the basis for representing the possible
      profile. The optimal profile could be obtained if the orthogonal coefficients
      were properly adjusted. The orthogonal array was used to design and analyze the
      effect of each orthogonal coefficient in order to reach the optimal objective
      (quality) function. The performance based on the proposed strategy was
      significantly improved by over 10% compared with the traditional fixed pH or
      uncontrolled pH values during the reaction. The proposed method can be applied to
      the required dynamic profile in the bioreactor process to effectively improve the
      product quality, given good design directions and the advantage of the
      traditional statistical approach.

PMID- 12467480
TI  - Electronic speckle pattern interferometry: a tool for determining diffusion and
      partition coefficients for proteins in gels.
AB  - The aim of this study was to demonstrate electronic speckle pattern
      interferometry (ESPI) as a powerful tool in determining diffusion coefficients
      and partition coefficients for proteins in gels. ESPI employs a CCD camera
      instead of a holographic plate as in conventional holographic interferometry.
      This gives the advantage of being able to choose the reference state freely. If a
      hologram at the reference state is taken and compared to a hologram during the
      diffusion process, an interferometric picture can be generated that describes the
      refraction index gradients and thus the concentration gradients in the gel as
      well as in the liquid. MATLAB is then used to fit Fick's law to the experimental
      data to obtain the diffusion coefficients in gel and liquid. The partition
      coefficient is obtained from the same experiment from the flux condition at the
      interface between gel and liquid. This makes the comparison between the different
      diffusants more reliable than when the measurements are performed in separate
      experiments. The diffusion and partitioning coefficients of lysozyme, BSA, and
      IgG in 4% agarose gel at pH 5.6 and in 0.1 M NaCl have been determined. In the
      gel the diffusion coefficients were 11.2 +/- 1.6, 4.8 +/- 0.6, and 3.0 +/- 0.3
      m(2)/s for lysozyme, BSA, and IgG, respectively. The partition coefficients were
      determined to be 0.65 +/- 0.04, 0.44 +/- 0.06, and 0.51 +/- 0.04 for lysozyme,
      BSA, and IgG, respectively. The current study shows that ESPI is easy to use and
      gives diffusion coefficients and partition coefficients for proteins with
      sufficient accuracy from the same experiment.

PMID- 12467481
TI  - Comparison of techniques for monitoring antibody fragment production in E. coli
      fermentation cultures.
AB  - The use of an optical biosensor for monitoring antibody fragment accumulation
      following induction in a batch fermentation of recombinant E. coli is compared to
      the more traditional method of ELISA quantification. Using the biosensor,
      concentration data can be obtained within minutes of sample addition to the
      device, compared to an average assay time of 3-4 h for the ELISA. We describe two
      biosensor assays developed as an alternative to ELISA and compare them with ELISA
      in the ability to provide quantitative product accumulation profiles during
      fermentation. Discrepancies in titers recorded by the assays are explained by a
      combination of differences in product variants detected by each assay and
      interference from sample contaminants. Method of sample preparation is also shown
      to be important if accurate concentration data is required. Both biosensor assays
      are shown to be capable of providing product accumulation profiles comparable to
      those obtained by ELISA. The use of a rapid extraction technique would allow such
      data to be obtained during process operation, enabling improved fermentation
      control and more rapid process development.

PMID- 12467482
TI  - Laminar-flow-based separations at the microscale.
AB  - The natural separation maintained by microfluidic flows is employed as the basis
      of a particle/cell sorting device. This method of separating particulate
      suspensions exploits the inherent laminar nature of microscale fluid dynamics and
      incorporates applied fields and image cytometry to enable sorting based upon any
      visually identifiable difference between colloid-sized cells or particles. This
      technique may be used to easily isolate, separate, sort, or enrich virtually any
      suspension of microscale biological or colloidal particles within a microfluidic
      system. The entire footprint of the device described here is less than 0.01
      mm(2), allowing it to be readily incorporated within highly integrated micro
      total analysis systems (microTAS).

PMID- 12467483
TI  - Renaturation and interaction of ribonuclease A with AOT surfactant in reverse
      micelles.
AB  - This study extended works on effects of solute on the percolation of reverse
      micelles to the effects of interactions between protein and surfactants on
      protein refolding by reverse micelles. The changes in percolation behavior were
      identified and attributed to the position of solutes in the core aqueous phase
      and the interaction between the solute and the surfactants. The percolation
      behavior of reverse micelles with solutes was related to protein renaturation and
      the reverse micelle. This study aims to highlight the involvement of the
      interface and the interaction of the protein with the surfactant during protein
      refolding. Ribonuclease A and AOT reverse micelles together constitute a model
      system considered here. The systemic parameters of the reverse micelle, water
      content (W(o)) and pH value, were applied to modify the interaction between the
      denatured protein molecules and the surfactant interface. The interactions and
      the locations of the protein molecules were determined from changes in
      percolation temperature measured by conductivity. The percolation and protein
      activity show that a stronger interaction of the protein molecules with
      surfactant corresponds to superior recovery of protein activity. The
      investigation concludes that the refolding of protein by reverse micelles is not
      only facilitated by the isolation of reverse micelles but also by the interaction
      due to the interface of the reverse micelle.

PMID- 12467484
TI  - Strawberry pectin methylesterase (PME): purification, characterization, thermal
      and high-pressure inactivation.
AB  - Pectin methylesterase (PME) was extracted from strawberries (Fragaria ananassa,
      cv Elsanta) and purified by affinity chromatography on a CNBr-Sepharose 4B-PME
      inhibitor column. A single protein and PME activity peak was obtained. A
      biochemical characterization in terms of molecular mass, pI, and kinetic
      parameters of strawberry PME was performed. In a second step, the thermal and
      high-pressure stability of the enzyme was studied. Isothermal and combined
      isothermal-isobaric inactivation of purified strawberry PME could be described by
      a fractional-conversion model. Purified strawberry PME is much more stable toward
      high-pressure treatments in comparison to those from oranges and bananas.

PMID- 12467485
TI  - Enhancement of enzyme activity in supercritical carbon dioxide via changes in
      acid-base conditions.
AB  - Enzyme performance is often impaired in supercritical carbon dioxide. We were
      able to enhance enzyme activity in this medium via changes in acid-base
      conditions by using ion-exchange materials (solid H(+)/Na(+) buffer pairs and a
      zeolite), which were selected on the basis of the response of an organosoluble
      acid-base indicator. The concentration of ion-exchange materials had an important
      effect on the catalytic activity of subtilisin Carlsberg cross-linked enzyme
      crystals (CLECs), and this was related to the protonation and hydration states of
      the enzyme. The buffer Na(2)CO(3)/NaHCO(3) gave the highest enhancement in enzyme
      activity (by a factor of 54), probably as a result of its high basicity and
      capacity to counteract the deleterious effect of carbonic acid to a greater
      extent than the other materials tested.

PMID- 12467486
TI  - Operational stability of high initial activity protease catalysts in organic
      solvents.
AB  - The first studies on the operational stability of cross-linked enzyme crystals
      (CLECs) in organic media are described. Although these catalysts display high
      initial specific activity, they inactivate rapidly, losing more than 50% of the
      initial activity within the first 4 h under continuous flow. Furthermore, the
      inactivation is not reversible when returned to an aqueous medium. The same rapid
      inactivation occurs with adsorbed protease preparations that show similar high
      initial specific activity (propanol-rinsed enzyme preparations (PREPs) of
      subtilisin and alpha-chymotrypsin).

PMID- 12467487
TI  - Strain improvement to enhance the production of recombinant penicillin acylase in
      high-cell-density Escherichia coli cultures.
AB  - Using fed-batch operation for high-cell-density cultivation, efforts are
      frequently made for optimization of culture parameters, particularly feeding
      strategy. The current study also emphasized the importance of selecting strains
      for the production of recombinant proteins in high-cell-density cultures. With
      Escherichia coli penicillin acylase (PAC) as a target protein, the host/vector
      system of MDdeltaP7 harboring pTrcKnPAC2902 and pKS12 was designed for
      optimization of fed-batch cultivation for recombinant protein production. The
      host, MDdeltaP7, potentially had a high translational and periplasmic processing
      efficiency for pac expression. On the other hand, the vector, pTrcKnPAC2902, was
      genetically constructed for pac overexpression. Coexistence of the other vector,
      pKS12, significantly enhanced PAC production by improving cell physiology and
      reducing the amount of inclusion body formation upon pac overexpression. An
      extremely high volumetric PAC activity at 37,500 U/L was obtained with the use of
      the developed host/vector system under optimum fed-batch culture conditions.

PMID- 12467488
TI  - High initial activity but low storage stability observed for several preparations
      of subtilisin Carslberg suspended in organic solvents.
AB  - Colyophilization with methyl-beta-cyclodextrin activates subtilisin Carlsberg by
      more than 200-fold in organic solvents, though this is a short-lived effect.
      About 93% of the enzyme's high initial activity observed in THF (at 45 degrees C)
      decreases exponentially with a t(1/2) of 1.8 h, until it reaches a residual
      activity (of 7%) that remains constant throughout the 4 days duration of the
      experiment. A further study of this enzyme reveals a general trend: the initial
      activities of the lyophilized powder and the cross-linked enzyme crystals are
      also greatly reduced upon incubation in this solvent, although these preparations
      retain 50% of their activity after about 20 h of incubation. All of the
      preparations studied retained some residual activity (which persisted throughout
      the duration of the experiments) after the initial exponential decay. The data
      here presented suggest that the mode of enzyme preparation is an important issue
      to consider when planning lengthy reactions.

PMID- 12467489
TI  - Safety of sumatriptan in pregnancy: a review of the data so far.
AB  - The high prevalence of migraine in women during their reproductive years means
      that new drug treatments for migraine, such as the serotonin 5-HT(1B/1D) receptor
      agonists (the 'triptans'), are likely to be widely used by women of childbearing
      potential. Scrutiny of these agents in an effort to detect any signal of
      teratogenicity is thus important. A systematic review of the medical literature
      was conducted to identify information regarding the safety of sumatriptan during
      pregnancy. This agent was chosen to be investigated because it has been available
      for the longest and is the most widely used of the triptan class. Information was
      obtained regarding the impact of migraine on pregnancy outcome, and data on
      sumatriptan use in pregnancy were obtained from animal studies, preclinical drug
      trials, postmarketing surveillance efforts, prospective pregnancy registries,
      national birth registries and teratogen information services. Synthesis of
      information from these sources is sufficient to rule out a large increase in
      birth defects from sumatriptan use during pregnancy and is reassuring for cases
      where inadvertent exposure to sumatriptan during pregnancy has occurred. However,
      current information is not sufficient to rule out small increases in the risk for
      birth defects. For this reason, caution should be exercised in making a positive
      recommendation for the use of sumatriptan during pregnancy.

PMID- 12467490
TI  - Bipolar depression: management options.
AB  - Bipolar depression is the predominant abnormal mood state in bipolar disorder.
      However, despite the key pertinence of this phase of the condition, the focus of
      research and indeed of clinical interest in the management of bipolar disorder
      has been mainly on mania. Bipolar depression has been largely neglected, and
      early studies often failed to distinguish depression due to major unipolar
      depression from that due to bipolar disorder. Consequently, many treatments used
      in the management of major depression have been adopted for use in bipolar
      depression without any robust evidence of efficacy. The selective serotonin
      reuptake inhibitors (SSRIs), bupropion, tricyclic antidepressants and monoamine
      oxidase inhibitors are all effective antidepressants in the management of bipolar
      depression. They are all associated with a small risk of antidepressant-induced
      mood instability. The mood stabilisers lithium, carbamazepine and valproate
      semisodium (divalproex sodium) all appear to have modest acute antidepressant
      properties. Among these, lithium is supported by the strongest data, but the use
      of lithium in the treatment of bipolar depression as a monotherapeutic agent is
      limited by its slow onset of action. Recently, there has been a growing body of
      evidence suggesting that lamotrigine may have particular effectiveness in both
      the acute and prophylactic management of bipolar depression. Clinical management
      of bipolar depression involves various combinations of antidepressants and mood
      stabilisers and is partly determined by the context in which the depressive
      episode occurs. In general, 'de novo' and 'breakthrough' (where the patient is
      already receiving medication) bipolar depression may be successfully managed by
      initiating mood stabiliser monotherapy, to which an antidepressant or second mood
      stabiliser may be added at a later date, if necessary. Breakthrough episodes of
      bipolar depression occurring in patients receiving combination therapy (two mood
      stabilisers or a mood stabiliser plus an antidepressant) require either switching
      of ongoing medications or further augmentation. If this fails, then novel
      strategies or ECT should be considered. Bipolar depression is a disabling illness
      and the predominant mood state for the vast majority of those with bipolar
      disorder. It therefore warrants prompt management once suitably diagnosed,
      especially as it is associated with a considerable risk of suicide and in the
      majority of instances is eminently treatable.

PMID- 12467491
TI  - The role of insulin resistance in the pathogenesis of Alzheimer's disease:
      implications for treatment.
AB  - An emerging body of evidence suggests that an increased prevalence of insulin
      abnormalities and insulin resistance in Alzheimer's disease may contribute to the
      disease pathophysiology and clinical symptoms. It has long been known that
      insulin is essential for energy metabolism in the periphery. In the past 2
      decades, convergent findings have begun to demonstrate that insulin also plays a
      role in energy metabolism and other aspects of CNS function. Investigators
      reported 20 years ago that insulin and insulin receptors were densely but
      selectively expressed in the brain, including the medial temporal regions that
      support the formation of memory. It has recently been demonstrated that insulin
      sensitive glucose transporters are localised to the same regions supporting
      memory and that insulin plays a role in memory functions. Collectively, these
      findings suggest that insulin may contribute to normal cognitive functioning and
      that insulin abnormalities may exacerbate cognitive impairments, such as those
      associated with Alzheimer's disease. Insulin may also play a role in regulating
      the amyloid precursor protein and its derivative beta-amyloid (Abeta), which is
      associated with senile plaques, a neuropathological hallmark of Alzheimer's
      disease. It has been proposed that insulin can accelerate the intracellular
      trafficking of Abeta and interfere with its degradation. These findings are
      consistent with the notion that insulin abnormalities may potentially influence
      levels of Abeta in the brains of patients with Alzheimer's disease. The increased
      occurrence of insulin resistance in Alzheimer's disease and the numerous
      mechanisms through which insulin may affect clinical and pathological aspects of
      the disease suggest that improving insulin effectiveness may have therapeutic
      benefit for patients with Alzheimer's disease. The thiazolidinedione
      rosiglitazone has been shown to have a potent insulin-sensitising action that
      appears to be mediated through the peroxisome proliferator-activated receptor
      gamma (PPAR-gamma). PPAR-gamma agonists, such as rosiglitazone, also have anti
      inflammatory effects that may be of therapeutic benefit in patients with
      Alzheimer's disease. This review presents evidence suggesting that insulin
      resistance plays a role in the pathophysiology and clinical symptoms of
      Alzheimer's disease. Based on this evidence, we propose that treatment of insulin
      resistance may reduce the risk or retard the development of Alzheimer's disease.

PMID- 12467492
TI  - Oxidative mechanisms and tardive dyskinesia.
AB  - Tardive dyskinesia has been and continues to be a significant problem associated
      with long-term antipsychotic use, but its pathophysiology remains unclear. In the
      last 10 years, preclinical studies of the administration of antipsychotics to
      animals, as well as clinical studies of oxidative processes in patients given
      antipsychotic medications, with and without tardive dyskinesia, have continued to
      support the possibility that neurotoxic free radical production may be an
      important consequence of antipsychotic treatment, and that such production may
      relate to the development of dyskinetic phenomena. In line with this hypothesis,
      evidence has accumulated for the efficacy of antioxidants, primarily vitamin E
      (alpha-tocopherol), in the treatment and prevention of tardive dyskinesia. Early
      studies suggested a modest effect of vitamin E treatment on existing tardive
      dyskinesia, but later studies did not demonstrate a significant effect. Because
      evidence has continued to accumulate for increased oxidative damage from
      antipsychotic medications, but less so for the effectiveness of vitamin E,
      especially in cases of long-standing tardive dyskinesia, alternative antioxidant
      approaches to the condition may be warranted. These approaches may include the
      use of antioxidants as a preventive measure for tardive dyskinesia or the use of
      other antioxidants or neuroprotective drugs, such as melatonin, for established
      tardive dyskinesia.

PMID- 12467494
TI  - Mitochondrial threshold effects.
AB  - The study of mitochondrial diseases has revealed dramatic variability in the
      phenotypic presentation of mitochondrial genetic defects. To attempt to
      understand this variability, different authors have studied energy metabolism in
      transmitochondrial cell lines carrying different proportions of various
      pathogenic mutations in their mitochondrial DNA. The same kinds of experiments
      have been performed on isolated mitochondria and on tissue biopsies taken from
      patients with mitochondrial diseases. The results have shown that, in most cases,
      phenotypic manifestation of the genetic defect occurs only when a threshold level
      is exceeded, and this phenomenon has been named the 'phenotypic threshold
      effect'. Subsequently, several authors showed that it was possible to inhibit
      considerably the activity of a respiratory chain complex, up to a critical value,
      without affecting the rate of mitochondrial respiration or ATP synthesis. This
      phenomenon was called the 'biochemical threshold effect'. More recently,
      quantitative analysis of the effects of various mutations in mitochondrial DNA on
      the rate of mitochondrial protein synthesis has revealed the existence of a
      'translational threshold effect'. In this review these different mitochondrial
      threshold effects are discussed, along with their molecular bases and the roles
      that they play in the presentation of mitochondrial diseases.

PMID- 12467495
TI  - Effect of polyvalencies of glycotopes on the binding of a lectin from the edible
      mushroom, Agaricus bisporus.
AB  - Agaricus bisporus agglutinin (ABA) isolated from edible mushroom has a potent
      anti-proliferative effect on malignant colon cells with considerable therapeutic
      potential as an anti-neoplastic agent. Since previous studies on the structural
      requirement for binding were limited to molecular or submolecular levels of
      Galbeta1-3GalNAc (T; Thomsen-Friedenreich disaccharide glycotope; where Gal
      represents D-galactopyranose and GalNAc represents 2-acetamido-2-deoxy-D
      galactopyranose) and its derivatives, the binding properties of ABA were further
      investigated using our collection of glycans by enzyme-linked lectinosorbent
      assay and lectin-glycan inhibition assay. The results indicate that polyvalent
      Galbeta1-related glycotopes, GalNAcalpha1-Ser/Thr (Tn), and their cryptoforms,
      are the most potent factor for ABA binding. They were up to 5.5x10(5) and
      4.7x10(6) times more active than monomeric T and GalNAc respectively. The
      affinity of ABA for ligands can be ranked as: multivalent T (alpha) (Galbeta1
      3GalNAcalpha1-), Tn and I / II (Galbeta1-3GlcNac/Galbeta1-4GlcNAc, where GlcNAc
      represents 2-acetamido-2-deoxy-D-glucopyranose)>>>>monomeric T (alpha) and Tn > I
      >>GalNAc>>> II, L (Galbeta1-4Glc, where Glc represents D-glucopyranose) and Gal
      (inactive). These specific binding features of ABA establish the importance of
      affinity enhancement by high-density polyvalent (versus multiantennary I / II)
      glycotopes and facilitate our understanding of the lectin receptor recognition
      events relevant to its biological activities.

PMID- 12467496
TI  - Analyses of temporal regulatory elements of the prosaposin gene in transgenic
      mice.
AB  - The expression of prosaposin is temporally and spatially regulated at
      transcriptional and post-translational levels. Transgenic mice with various 5'
      flanking deletions of the prosaposin promoter fused to luciferase (LUC) reporters
      were used to define its temporal regulatory region. LUC expression in the
      transgenic mice carrying constructs with 234 bp (234LUC), 310 bp (310LUC) or 2400
      bp (2400LUC) of the 5'-flanking region was analysed in the central nervous system
      and eye throughout development. For 310LUC and 2400LUC, low-level LUC activity
      was maintained until embryonal day 18 in brain, eye and spinal cord. The peak
      level of LUC activity was at birth, with return to a plateau (1/3 of peak)
      throughout adulthood. Deletion of the region that included the retinoic acid
      receptor-related orphan receptor (ROR alpha)-binding site and sequence-specific
      transcription factor (Sp1) cluster sites (44-310 bp) suppressed the peak of
      activity. By comparison, the peak level for 234LUC was shifted 2 weeks into
      neonatal life in the brain, but not in the eye, and no peak of activity was
      observed in the spinal cord. The endogenous prosaposin mRNA in eye, spinal cord
      and cerebellum had low-level expression before birth and continued to increase
      into adulthood. In cerebrum, the endogenous mRNA showed similar expression
      profile to constructs 310LUC, 2400LUC and 234LUC, with the peak expression at 1
      week and a decreased level in adult. In the brain of the newborn, 2400LUC was
      highly expressed in the trigeminal ganglion and brain stem regions when compared
      with the generalized expression pattern for endogenous prosaposin mRNA. These
      results suggest that the modifiers (ROR alpha- and Sp1-binding sites) residing
      within 310 bp of the 5'-flanking region mediate developmental regulation in the
      central nervous system and eye. Additional regulatory elements outside the 5'
      region of the 2400 bp promoter fragment appear to be essential for the
      physiological control of the prosaposin locus.

PMID- 12467497
TI  - Biochemical and genetic characterization of a novel enzyme of pentitol
      metabolism: D-arabitol-phosphate dehydrogenase.
AB  - An enzyme with a specificity that has not been described previously, D-arabitol
      phosphate dehydrogenase (APDH), has been purified from cell lysate of
      Enterococcus avium. SDS/PAGE indicated that the enzyme had a molecular mass of
      41+/-2 kDa, whereas a molecular mass of 160+/-5 kDa was observed under non
      denaturing conditions, implying that the APDH may exist as a tetramer with
      identical subunits. Purified APDH was found to have a narrow substrate
      specificity, converting only D-arabitol 1-phosphate and D-arabitol 5-phosphate
      into xylulose 5-phosphate and ribulose 5-phosphate, respectively, in the
      oxidative reaction. Both NAD(+) and NADP(+) were accepted as cofactors. Based on
      the partial protein sequences, the APDH gene was cloned. Homology comparisons
      place APDH within the medium-range dehydrogenase family. Unlike most members of
      this family, APDH requires Mn(2+) but no Zn(2+) for enzymic activity. The DNA
      sequence surrounding the gene suggests that it belongs to an operon that also
      contains several components of phosphotransferase system. Both biochemical
      evidence and protein sequence homology comparisons indicate that similar enzymes
      are widespread among the Gram-positive bacteria. Their apparent biological role
      is to participate in arabitol catabolism via the 'arabitol phosphate route',
      similar to the ribitol and xylitol catabolic routes described previously.

PMID- 12467498
TI  - New liquid aerosol generation devices: systems that force pressurized liquids
      through nozzles.
AB  - Over the past few decades, aerosol delivery devices have been relatively
      inefficient, wasteful, and difficult for patients to use. These drawbacks have
      been tolerated because the drugs available for inhalation have wide therapeutic
      margins and steep dose-response curves at low doses. Recently several forces have
      converged to drive innovation in the aerosol device industry: the ban on
      chlorofluorocarbon propellants in metered-dose inhalers, the need for more user
      friendly devices, and the invention of expensive inhalable therapies for topical
      and systemic lung delivery. Numerous devices are in development to improve the
      efficiency, ease of use, and reproducibility of aerosol delivery to the lung,
      including systems that force liquid through a nozzle to form the aerosol cloud.
      The Respimat is a novel, compact, propellant-free, multi-dose inhaler that
      employs a spring to push drug solution through a nozzle, which generates a slow
      moving aerosol. Deposition studies show that the Respimat can deliver 39-44% of a
      dose to the lungs. Clinical asthma and chronic obstructive pulmonary disease
      trials with bronchodilators show that the Respimat is 2-8 times as effective as a
      metered-dose inhaler. Respimat has been tested with bronchodilators and inhaled
      corticosteroids. The AERx device uses sophisticated electronics to deliver
      aerosol from a single-dose blister, using an integral, disposable nozzle array.
      The electronics control dose expression and titration, timing of aerosol
      generation with the breath, and provide feedback for proper inhalation technique.
      Lung deposition ranges from 50 to 80% of the loaded dose, with remarkable
      reproducibility. AERx has been tested with a variety of drugs, for both topical
      and systemic delivery, including rhDNase (dornase alfa), insulin, and opioids.
      These novel devices face competition from other technologies as well as financial
      and regulatory hurdles, but they both offer a marked improvement in the
      efficiency of pulmonary drug delivery.

PMID- 12467499
TI  - Nebulizers that use a vibrating mesh or plate with multiple apertures to generate
      aerosol.
AB  - Several electronic nebulizer devices that use a vibrating mesh or plate with
      multiple apertures to generate a fine-particle, low-velocity aerosol have been
      marketed or will shortly become available for clinical use. These devices have a
      high efficiency of delivering aerosol to the lung, such that the nominal dose of
      drugs to be administered could be substantially reduced. Moreover, the volume of
      drug solution left in these new devices when the nebulization has ceased is
      negligible, so there is potential to improve the cost-effectiveness of
      administering expensive medications. Because these devices nebulize at a faster
      rate than conventional jet or ultrasonic nebulizers, the duration of each
      treatment could be shortened. These devices efficiently nebulize solutions and
      suspensions; they have been successfully used for aerosolizing insulin, other
      proteins and peptides, and fragments of DNA. They could be employed for a wide
      variety of clinical applications, including the delivery of aerosols for systemic
      therapy and gene transfer. These devices have overcome many of the limitations
      associated with conventional jet and ultrasonic nebulizers, and they offer the
      versatility to modify the aerosol characteristics according to the clinical
      application for which they are employed. With these devices clinicians will be
      able to precisely control drug delivery to the respiratory tract.

PMID- 12467500
TI  - The electrospray and its application to targeted drug inhalation.
AB  - This review explains the fundamentals of electrostatic spray (electrospray)
      atomization, with emphasis on operation in the so called cone-jet mode, which
      produces droplets with a very narrow size distribution. Since the control of
      droplet size is key to maximizing distal lung deposition, the electrospray should
      be well-suited to targeted drug inhalation. Electrospray droplets are a few
      micrometers in diameter, but they originate from a much larger nozzle, which
      allows nebulization of suspensions without clogging. Also discussed are: the
      physical principles of the break-up of the liquid ligament; droplet dispersion by
      Coulombic forces; and the most important scaling law linking the droplet size to
      liquid flow rate and liquid physical properties. The effects of the most critical
      of those properties may result in some restrictions on drug formulation. Droplets
      produced by electrospray are electrically charged, so to prevent electrostatic
      image forces from causing upper respiratory tract deposition. The charge is
      neutralized by generating a corona discharge of opposite polarity. Briefly
      discussed are the main differences between the laboratory systems (with which the
      electrospray has been quantitatively characterized during research in the past 10
      years) and commercial electrospray inhalers under development at BattellePharma.
      Some remarkable miniaturization has incorporated liquid pump, power supply,
      breath activation, and dose counter into a palm-size portable device. The maximum
      flow rates dispersed from these devices are in the range of 8-16 microL/s, which
      makes them suitable for practical drug inhalation therapy. Fabrication is
      economically competitive with inexpensive nebulizers. Dramatic improvements in
      respirable dose efficiency (up to 78% by comparison with commercial metered-dose
      inhalers and dry powder inhalers) should ensure the commercialization of this
      promising technology for targeted drug inhalation.

PMID- 12467501
TI  - Smart nebulizers.
AB  - Physicians are familiar with conventional nebulizers, which deliver aerosols in a
      relatively uncontrolled manner. As aerosol medications evolve beyond
      bronchodilators, the need for control of dose variability, the possibility of
      overdose, and the need for efficient delivery have provoked the industry to
      redesign aerosol delivery systems. The need to target aerosol delivery to
      specific lung regions has focused efforts to coordinate aerosol delivery with
      defined breathing maneuvers. This review summarizes the major factors affecting
      aerosol deposition, discusses how those factors are guiding new designs for
      aerosol delivery systems, and describes some examples of the improved precision
      and efficiency of those systems.

PMID- 12467502
TI  - Standardization issues: in vitro assessment of nebulizer performance.
AB  - The delivery of nebulized drugs is poorly controlled and the choice of the most
      appropriate delivery device is poorly understood, particularly because of off
      license prescriptions and a lack of evidence-based medicine. Standardized in
      vitro methods for measuring nebulizer performance have been adopted in Europe, by
      the 2001 publication of a European Standard, prEN13544-1. These standardized
      methods were subsequently incorporated within the European Respiratory Society
      nebulizer guidelines, which will provide clinicians with useful information to
      improve nebulizer therapies. Standards for measuring nebulizer performance should
      be considered in North America and elsewhere. Careful consideration should be
      given to either adopting the methods embodied in the European Standard or
      developing the basis for developing that standard further through the
      International Standards Organization. Either way, confusion among clinicians
      would be reduced and nebulizer safety and aerosol delivery efficiency increased
      by standardizing in vitro methods of nebulizer performance assessment.

PMID- 12467503
TI  - The future of nebulization.
AB  - Currently available nebulizers are inefficient, bulky, noisy, and take longer to
      use than other inhalation devices. Use of nebulizers is increasingly confined to
      patients who cannot use other devices or who require therapies not available in
      another form. In the future, nebulizers will be smaller and more efficient.
      "Smart" nebulizers that can monitor patient use and provide feedback to the
      patient and the caregiver will be developed. Critical study will be needed to
      determine whether these innovations improve patient compliance with therapy.
      Nebulizers will also be refined for delivering complex molecules for both
      pulmonary and systemic disease. One example is in the use of gene therapy, in
      which issues such as the best gene vector are unresolved. Nebulizing these
      complex molecules without damaging them may be difficult, and nebulizers of the
      future will have to be more efficient to avoid wasting expensive drugs. For the
      delivery of widely used, less expensive medications, such as some
      bronchodilators, these innovations will not be cost-effective, so cheaper, less
      efficient nebulizers will continue to be used.

PMID- 12467504
TI  - Liquid nebulization: emerging technologies conference summary.
AB  - Most physicians and respiratory therapists are knowledgeable of the use of
      aerosolized drugs, but many are less familiar with the performance
      characteristics of the nebulizer. In fact, the general opinion is that the
      performance of the nebulizer is relatively unimportant. However, there is
      accumulating evidence that the nebulizer itself does make a difference. The
      decision to replace a good performing nebulizer with a poor performing nebulizer
      may decrease the delivered dose in half or more. Although this is less important
      for routine bronchodilator therapy, it may make a big difference with newer
      aerosolized drugs. Increasingly, the Food and Drug Administration is approving
      drugs to be used with a specific nebulizer brand and new nebulizer designs are
      becoming available for use with these drugs. There are several reasons why I
      think this conference was important. First, new aerosol drug formulations are
      becoming available and these will require better performing nebulizers. Second,
      we as clinicians need to be knowledgeable of the newer generations of nebulizers
      so that we can make informed purchase decisions. Third, and perhaps most
      important, we must gain an increased appreciation for aerosol therapy as a
      science. The proceedings of this conference do much to synthesize the current
      state-of-the art related to new nebulizer systems. This provides, in a complete
      and cogent manner, the scientific basis for which clinicians can improve their
      knowledge of the new generation of nebulizers.

PMID- 12467506
TI  - Attachment-related psychodynamics.
AB  - Because there has been relatively little communication and cross-fertilization
      between the two major lines of research on adult attachment, one based on coded
      narrative assessments of defensive processes, the other on simple self-reports of
      'attachment style' in close relationships, we here explain and review recent work
      based on a combination of self-report and other kinds of method, including
      behavioral observations and unconscious priming techniques. The review indicates
      that considerable progress has been made in testing central hypotheses derived
      from attachment theory and in exploring unconscious, psychodynamic processes
      related to affect-regulation and attachment-system activation. The combination of
      self-report assessment of attachment style and experimental manipulation of other
      theoretically pertinent variables allows researchers to test causal hypotheses.
      We present a model of normative and individual-difference processes related to
      attachment and identify areas in which further research is needed and likely to
      be successful. One long-range goal is to create a more complete theory of
      personality built on attachment theory and other object relations theories.

PMID- 12467507
TI  - The dynamics of measuring attachment.

PMID- 12467508
TI  - Developmental origins of attachment styles.

PMID- 12467509
TI  - Assessing adult attachment: empirical sophistication and conceptual bases.

PMID- 12467510
TI  - Attachment style measurement: a clinical and epidemiological perspective.

PMID- 12467511
TI  - Building bridges.

PMID- 12467512
TI  - Attachment-related dynamics: what can we learn from self-reports of avoidance and
      anxiety?

PMID- 12467513
TI  - Attachment-related psychodynamics: another shake to the kaleidoscope.

PMID- 12467514
TI  - Measurement of adult attachment: the place of self-report and interview
      methodologies.

PMID- 12467515
TI  - Building bridges between social, developmental and clinical psychology.

PMID- 12467516
TI  - Fearful-avoidance, disorganization, and multiple working models: some directions
      for future theory and research.

PMID- 12467517
TI  - Bowlby's secure base theory and the social/personality psychology of attachment
      styles: work(s) in progress.

PMID- 12467518
TI  - Dialogue on adult attachment: diversity and integration.

PMID- 12467519
TI  - Cyclooxygenase-2 inhibitors: promise or peril?
AB  - The discovery of two isoforms of the cyclooxygenase enzyme, COX-1 and COX-2, and
      the development of COX-2-specific inhibitors as anti-inflammatories and
      analgesics have offered great promise that the therapeutic benefits of NSAIDs
      could be optimized through inhibition of COX-2, while minimizing their adverse
      side effect profile associated with inhibition of COX-1. While COX-2 specific
      inhibitors have proven to be efficacious in a variety of inflammatory conditions,
      exposure of large numbers of patients to these drugs in postmarketing studies
      have uncovered potential safety concerns that raise questions about the
      benefit/risk ratio of COX-2-specific NSAIDs compared to conventional NSAIDs. This
      article reviews the efficacy and safety profiles of COX-2-specific inhibitors,
      comparing them with conventional NSDAIDs.

PMID- 12467520
TI  - Annexin 1 localisation in tissue eosinophils as detected by electron microscopy.
AB  - BACKGROUND: Human and rodent leukocytes express high levels of the glucocorticoid
      inducible protein annexin 1 (ANXA1) (previously referred to as lipocortin 1).
      Neutrophils and monocytes have abundant ANXA1 levels. AIM: We have investigated,
      for the first time, ANXA1 ultrastructural expression in rat eosinophils and
      compared it with that of extravasated neutrophils. The effect of inflammation
      (carrageenin peritonitis) was also monitored. METHODS: Electron microscopy was
      used to define the sub-cellular localisation of ANXA1 in rat eosinophils and
      neutrophils extravasated in the mesenteric tissue. A pair of antibodies raised
      against the ANXA1 N-terminus (i.e. able to recognise intact ANXA1, termed LCPS1)
      or the whole protein (termed LCS3) was used to perform the ultrastructural
      analysis. RESULTS: The majority of ANXA1 was localised in the eosinophil cytosol
      (approximately 60%) and nucleus (30-40%), whereas a small percentage was found on
      the plasma membrane (< 10%). Within the cytosol, the protein was equally
      distributed in the matrix and in the granules, including those containing the
      typical crystalloid. The two anti-ANXA1 antibodies gave similar results, with the
      exception that LCPS1 gave a lower degree of immunoreactivity in the plasma
      membrane. Inflammation (i.e. carrageenin injection) produced a modest increase in
      eosinophil-associated ANXA1 reactivity (significant only in the cytoplasm
      compartment). Extravasated neutrophils, used for comparative purposes, displayed
      a much higher degree of immunoreactivity for the protein. CONCLUSION: We describe
      for the first time ANXA1 distribution in rat eosinophil by ultrastructural
      analysis, and report a different protein mobilisation from extravasated
      neutrophils, at least in this acute model of peritonitis.

PMID- 12467521
TI  - Induced sputum is a reproducible method to assess airway inflammation in asthma.
AB  - To evaluate the reproducibility of induced sputum analysis, and to estimate the
      sample size required to obtained reliable results, sputum was induced by
      hypertonic saline inhalation in 29 asthmatic subjects on two different days. The
      whole sample method was used for analysis, and inflammatory cells were counted on
      cytospin slides. Reproducibility, expressed by intra-class correlation
      coefficients, was good for macrophages (+0.80), neutrophils (+0.85), and
      eosinophils (+0.87), but not for lymphocytes (+0.15). Detectable differences were
      5.5% for macrophages, 0.6% for lymphocytes, 5.2% for neutrophils, and 3.0% for
      eosinophils. We conclude that analysis of induced sputum is a reproducible method
      to study airway inflammation in asthma. Sample sizes greater than ours give
      little improvement in the detectable difference of eosinophil percentages.

PMID- 12467522
TI  - Effects of methotrexate upon inflammatory parameters induced by carrageenan in
      the mouse model of pleurisy.
AB  - BACKGROUND: The model of pleurisy induced by carrageenan exhibits a biphasic
      response (4 and 48 h) and permits the quantification of exudate, cell migration
      and certain enzymes such as myeloperoxidase (MPO) and adenosine-deaminase (ADA)
      that are markers of activated leukocytes. AIMS: The present study evaluates
      whether there exists, in the pleurisy model, a significant inhibition of ADA and
      MPO enzymes, leukocyte kinetics and other markers of inflammation [nitric oxide
      (NO) levels, exudation] caused by methotrexate treatment by the intraperitoneal
      (i.p.) route. METHODS: The pleurisy was induced by carrageenan (1%) in mice, and
      the parameters were analyzed 4 and 48 h after. RESULTS: After the induction of
      inflammation (4 h), methotrexate (20 mg/kg, i.p., 24 h before pleurisy induction)
      inhibited the leukocyte infiltration (p < 0.05), NO levels and MPO activity (p <
      0.01), but not ADA activity and fluid leakage (p > 0.05). Regarding the second
      phase of pleurisy (48 h), methotrexate (40 mg/kg, i.p., 0.5 h before pleurisy
      induction) inhibited the leukocyte infiltration (p < 0.05), fluid leakage, NO
      levels (p < 0.01), and ADA and MPO activity (p < 0.05). CONCLUSIONS: These
      findings support the evidence that the acute administration of methotrexate has
      an important systemic anti-inflammatory activity in the studied inflammatory
      model. This effect was due to a significant inhibition on both neutrophil and
      mononuclear cells, being less marked in relation to exudation 48 h after. In
      relation to the enzymes studied and to NO levels, the findings support the
      evidence that methotrexate inhibits both enzymes (MPO and ADA) from leukocytes at
      the site of injury, thus reflecting the activation of both neutrophils and
      lymphocytes, respectively. Furthermore, the inhibiting effect on NO in both
      phases of pleurisy induced by carrageenan (4 and 48 h) indicates that
      methotrexate acts on constitutive and/or inducible NO synthases by means of
      different cells of the pleural cavity.

PMID- 12467523
TI  - Cellular and cytokine immunoregulation in patients with chronic obstructive
      pulmonary disease and bronchial asthma.
AB  - BACKGROUND: Different forms of chronic airway inflammation may involve diverse
      pathogenic elements. In general, deficient defence response is a feature of
      chronic obstructive pulmonary disease (COPD), whereas distorted immunoregulatory
      mechanisms lead to development of asthmatic symptoms. In addition to diverse
      effector mechanisms, the cellular and humoral elements participating in the
      development of immune response may appear to be different in COPD and bronchial
      asthma (BA) patients. AIMS: To evaluate the immunoregulatory properties of T
      cells and monocytes in cultures of peripheral blood mononuclear cells (PBMC) and
      to determine the chosen cytokine profiles in COPD and BA patients. METHODS: The
      microcultures of PBMC from COPD and BA patients were assessed for the T-cell
      response to mitogens, saturation of interleukin (IL)-2 receptors, T-cell
      suppressive activity and monokine influence on lymphocyte proliferation.
      Concomitantly, the cytokine (IL-1beta, interleukin-1 receptor antagonist, tumour
      necrosis factor-alpha, IL-4, IL-6, IL-8) concentrations were determined in the
      serum, the broncho-alveolar lavage fluid and in the culture supernatants.
      RESULTS: The T-lymphocyte reactions (response to phytohaemagglutinin, IL-2
      receptor saturation, suppressive activity) were lower in BA patients than in COPD
      patients. Reversely, the immunogenic activity of monocytes (IL-1beta versus IL
      1ra production) was higher in BA patients than in COPD patients. The highest
      values of cytokine concentrations were found in the culture supernatants. The
      concentrations of tumour necrosis factor-alpha, IL-4, IL-6 and IL-8 were
      significantly higher and the concentration of IL-1ra was lower in BA patients
      than in COPD patients. CONCLUSION: The assessments of cellular immunoregulatory
      properties and cytokine profiles in the cultures of blood mononuclear cells may
      prove helpful for diagnostic and therapeutic discrimination between BA and COPD
      patients.

PMID- 12467524
TI  - Differential expression and upregulation of interleukin-1alpha, interleukin-1beta
      and interleukin-6 by freshly isolated human small intestinal epithelial cells.
AB  - BACKGROUND: Small intestinal epithelial cells (SIEC) may contribute to local
      immune regulation. AIM: To examine production of interleukin (IL)-1alpha, IL
      1beta and IL-6 by freshly isolated human SIEC. METHODS: IL-1alpha and IL-1beta
      mRNA in epithelial layers (EL) prepared from small intestine and in intestinal
      epithelial cell (EC) lines were examined by reverse transcription-polymerase
      chain reaction. IL-1alpha, IL-1beta and IL-6 protein expression by SIEC was
      examined by flow cytometry before and after activation with lipopolysaccharide
      and epithelial growth factor. RESULTS: IL-1alpha and IL-1beta mRNA was detected
      in EL and EC lines. Background expression of IL-1alpha and IL-1beta protein by
      SIEC was observed, which did not increase even following activation. IL-6 protein
      was expressed by SIEC, in a proportion that increased in two out of three samples
      following activation. CONCLUSIONS: IL-6 expression and the presence of IL-1alpha
      and IL-1beta mRNA suggest a role for SIEC in the regulation of local
      inflammation.

PMID- 12467525
TI  - N-Acetylcysteine enhances the action of anti-inflammatory drugs as suppressors of
      prostaglandin production in monocytes.
AB  - The anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAIDs) is
      associated with inhibition of cyclooxygenase (COX), the rate-limiting enzyme
      responsible for the synthesis of prostaglandins. Since oxygen free radicals can
      act as second cellular messengers, especially to modulate the metabolism of
      arachidonic acid and the prostaglandin tract, it seems plausible that
      antioxidants might affect the production of prostaglandin by activated cells.
      This research is focused on the effect of the antioxidant N-acetylcysteine (NAC)
      on the inhibition of prostaglandin E(2) formation in activated monocytes by
      specific and non-specific COX inhibitors. We found that lipopolysaccharide
      induced prostaglandin E(2) formation was significantly reduced by rofecoxib and
      by diclofenac, two NSAIDs. Addition of NAC to each of these drugs enhanced the
      effect of the NSAIDs. These results suggest that one might expect either a
      potentiation of the anti-inflammatory effect of COX inhibitors by their
      simultaneous administration with NAC, or obtaining the same anti-inflammatory at
      lower drug levels.

PMID- 12467526
TI  - Effect of soluble interleukin-6 receptor alpha and interleukin-6 secreted by
      polymorphonuclear leukocytes on tumor necrosis factor-alpha expression and its
      production by peripheral blood mononuclear cells.
AB  - BACKGROUND: It has recently been shown that soluble interleukin-6 receptor (sIL
      6R) alone or complexed with interleukin (IL)-6, besides their regulatory role in
      a wide variety of both normal and abnormal biologic reactions mediated by IL-6,
      could be an effective stimulator of the cell function. AIMS: The key question of
      the present study is whether the sIL-6Ralpha or sIL-6R with IL-6 released by
      polymorphonuclear leukocytes (PMN) can influence cytokine secretion such as tumor
      necrosis factor-alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMC),
      which together with PMN develop the inflammatory and immune response of a host.
      METHODS: Cells were isolated from heparinized whole blood of healthy persons. The
      PMN were cultured for 1 h at 37 degrees C in 5% CO(2). After incubation, the
      culture supernatant of PMN was removed and was added to PBMC. The PBMC were
      cultured for 1 h at 37 degrees C in the same conditions. In the culture
      supernatants and lysates of PMN, we examined the concentrations of sIL-6R by
      enzyme-linked immunosorbent assay (ELISA). TNF-alpha was measured at both protein
      and mRNA levels. Protein levels were determined by ELISA. To examine TNF-alpha
      mRNA expression, we isolated mRNA from PBMC after culture, using TRIZOL Reagent.
      The quantity of mRNA TNF-alpha was determined by the Quantikine mRNA assay.
      RESULTS AND CONCLUSION: The results obtained revealed that sIL-6R with IL-6
      secreted by PMN may play a regulatory role in the immune response by modulating
      the TNF-alpha expression and its production by PBMC. This may have a significant
      influence on an early phase of the inflammation and other reactions mediated by
      TNF-alpha.

PMID- 12467527
TI  - Expression of a splice variant of the platelet-activating factor receptor
      transcript 2 in various human cancer cell lines.
AB  - Platelet-activating factor receptor (PAF-R) transcripts were analysed by reverse
      transcriptase-polymerase chain reaction in five human cancer cell lines derived
      from the breast (BT20, SKBR3 and T47D cells), the pancreas (Miapaca cells) and
      the bladder (5,637 cells) in order to confirm the existence of a splice variant
      of the PAF-R transcript 2. After cloning and sequencing, we confirmed its
      existence in all cell lines. It consisted of the PAF-R transcript 2 lengthening
      with 82 nucleotides from the 3' end of exon 1 of the PAF-R gene. The role of this
      elongated form of the tissue-type PAF-R transcript in cell physiology remains to
      be elucidated.

PMID- 12467528
TI  - [The influence of different nutritional support routes on the intestinal mucosal
      epithelial cell cycle in burned rats].
AB  - OBJECTIVE: To explore the influence of different nutritional support routes on
      the intestinal mucosal epithelial cell cycle in burned rats. METHODS: Sixty-six
      Wistar rats inflicted with 30% TBSA III degree burns on the back were employed as
      the model and were randomly divided into enteral feeding group (EF) and
      intravenously parenteral nutrition group (PN). Equal volume of nutritional
      support fluid containing predetermined equal amount of calories and nitrogen was
      applied via feeding or intravenously infusion through external jugular vein. The
      indices were observed on 6, 12, 24, 48 and 72 postburn hours (PBHs) with the
      reference to those in 6 normal rats. The intestinal epithelial cell cycle in
      jejunal and ileal mucous membrane was analyzed by flow cytometry. Western
      blotting method was employed in the examination of the expression of cyclin D1, E
      and that of cyclin dependent kinase (CDK)2 and CDK4. RESULTS: (1) lntestinal
      mucosal epithelial G0/G1 ratio in jejunum in EF group was significantly lower
      than that in PN group at 72 PBHs (P < 0.05). While the ratio in ileum in EF was
      obviously higher than that in PN groups at 6, 12, 48 and 72 PBHs (P < 0.05). (2)
      The cell percentage of S phase in EF group was evidently higher than that in PN
      group (P < 0.05 - 0.01) at 48 and 72 PBHs. (3) Intestinal mucosal cyclin D1
      expression increased significantly in EF group at 24 PBHs and in PN group at 48
      PBHs (P < 0.05) and which in EF group was obviously higher than that in PN group
      at 72 PBHs (P < 0.05). (4) The expression of the intestinal mucosal cyclin E in
      EF group at 72 PBHs was evidently higher than the control value and that in PN
      group (P < 0.05). (5) The expression of CDK2 exhibited no obvious difference
      among PN,EF and control group (P < 0.05). The CDK4 expression in EF group
      increased obviously at 72 PBHs (P < 0.05). CONCLUSION: Early postburn enteral
      feeding was beneficial to the progression of intestinal mucosal epithelial cell
      cycle and to the repairing and renovation of injured intestinal mucosal membrane.
      Cyclin and CDK might be important in the modulation of the intestinal mucosal
      epithelial cell cycle.

PMID- 12467529
TI  - [The influence of recombinant human growth hormone on the apoptosis and
      intestinal mucosal structure in severely scalded rats].
AB  - OBJECTIVE: To explore the influence of recombinant human growth hormone (rhGH) on
      the apoptosis and intestinal mucosal structure in severely scalded rats. METHODS:
      Thirty male Wistar rats were randomly divided into three groups, i.e. control,
      scalding and rhGH groups. The rats in scalding and rhGH groups were inflicted
      with 25% TBSA III degree scalding on the back and immediately followed by
      intraperitoneal injection of dexamethasone (80 mg/kg). The scalded rats were
      administered with normal saline and rhGH (1.33 IU.kg(-1).d(-1)) since 2 postburn
      hours (PBHs), respectively in the last two groups. The changes of the apoptosis
      rate, the intestinal mucosal proliferative index (PI) and epithelial
      ultrastructure and the intestinal mucosal pathomorphology of the distal end of
      ileal mucosal tissue were observed on 30 and 96 PBHs. RESULTS: The intestinal
      mucosa morphology and epithelia in scalding group were severely injured but were
      significantly ameliorated by rhGH to near those in control group. The PI in rhGH
      and scalding groups at 30 PBHs was evidently higher that that in control group (P
      < 0.05 - 0.01). But the PI exhibited no obvious difference between scalding and
      rhGH groups. While the PI in rhGH group at 96 PBHs was obviously higher than that
      in both scalding and control groups (P < 0.01). The intestinal mucosal epithelial
      apoptotic rate in scalding group was significantly higher than that in control
      group (P < 0.01), while that in rhGH group was evidently lower than that in
      scalding and control groups (P < 0.05 - 0.01). CONCLUSION: rhGH could promote
      postburn intestinal mucosa epithelial proliferation in slow - action manner and
      inhibit intestinal mucosal epithelial apoptosis with rapid and obvious effects.
      As a result, the intestinal mucosal epithelial injury could be ameliorated by
      rhGH by means of its inhibiting roles and the normal morphological structure of
      intestinal mucosa was maintained ad hoc.

PMID- 12467530
TI  - [Changes of the mRNA expression and the intestinal mucosal cyclooxygenase
      activity in scalded rats].
AB  - OBJECTIVE: To investigate the changes of the mRNA expression and the intestinal
      mucosal cyclooxygenase (COXs) activity in scalded rats. METHODS: Wistar rats
      inflicted with 30% TBSA III degree scalding were employed as the model. The
      changes of COX-1, COX-2 activities were determined by substrate fluorescence
      analysis and the mRNA expressions of COX-1 and COX-2 by RT-PCR. RESULTS: The mRNA
      expressions and the activities of COX-2 in rat intestinal mucosa increased
      obviously after injury. But those of COX-1 exhibited lower range of change.
      CONCLUSION: The pathological mechanism of rat intestinal mucosa injury after
      scalding might be closely related to the COXs participation by different styles
      between the two enzymes.

PMID- 12467531
TI  - [The protective effects of small dose of dopamine on the intestinal mucosa of
      scalded rats in shock stage].
AB  - OBJECTIVE: To investigate the protective effects of small dose of dopamine on the
      intestinal mucosa of scalded rats in shock stage. METHODS: Wistar rats inflicted
      by 30% TBSA of III degree scalding were employed as the model. The rats were pre
      placed with cardiac catheter before and were resuscitated intravenously after
      injury. The scalded rats were treated by routine (control) and small dose of
      dopamine (3 micro g.kg(-1).min(-1)), respectively. The changes of rat serum
      levels of diamine oxidase (DAO), malondialdehyde (MDA) and lactic acid (LA) were
      observed after treatment. And the pathomorphological changes of the intestine
      were scored. RESULTS: The general condition of the rats with dopamine treatment
      in shock stage was better than that in control group. The rat serum levels of
      MDA, LA and DAO decreased obviously, especially during 3 to 12 postburn hours
      (PBHs) after treatment by small dose of dopamine. The pathomorphological scoring
      of ileum in dopamine treating group was better than that in control. CONCLUSION:
      The intestinal mucosa of severely scalded rats in shock stage could be well
      protected by small dose of dopamine.

PMID- 12467532
TI  - [A preliminary study of the postburn intestinal biological barrier injury in
      severely burned rats].
AB  - OBJECTIVE: To investigate the postburn change in the intestinal biological
      barrier in severely burned rats. METHODS: Wistar rats inflicted by 30% TBSA III
      degree scalding on the back were employed as the model. The samples were
      harvested at 24, 48, 72 and 96 postburn hours (PBHs), respectively with the
      employment of microorganism analysis, biochemical and radio-immune methods for
      the study. The membranous flora in cecum, the mucin and sIgA in intestinal
      content, the intestinal endotoxin and bacterial translocation rate and
      quantification analysis and the endotoxin content in cava vein were observed.
      RESULTS: The total intestinal membranous flora amount decreased, especially and
      obviously did the anaerobic bacteria such as bifidobacteria. But aerobic ones
      increased. In addition, The fungus and enterobacteria exhibited rapid overgrowth.
      This lead to evident imbalance between anaerobic and aerobic bacteria and to the
      destruction of intestinal biological barrier and the decrease of colonization
      resistance. As a result, the intestinal bacterial translocation rate increased
      markedly. The endotoxin content in the cava and intestinal containing increased,
      while the mucin and sIgA contents decreased. CONCLUSION: Intestinal biological
      barrier could be severely damaged after major burn, which might be one of the
      causes of postburn intestinal infection.

PMID- 12467533
TI  - [Study on the mechanism of hepatocytic insulin signal transduction defects in
      severely scalded rats].
AB  - OBJECTIVE: To investigate the mechanism of hepatocytic insulin signal
      transduction defects in severely scalded rats, so as to clarify the molecular
      basis of postburn insulin resistance. METHODS: Wistar rats inflicted by 30% III
      degree scalding on the back were employed as the model. The rat hepatocytic
      insulin receptor was partially purified by wheat-germ agglutinin (WGA)-sepharose
      4B affinity chromatography. The change of receptor tyrosine protein kinase (TPK)
      activity, the receptor beta-subunit autophosphorylation and the hepatocytic
      insulin receptor binding behavior of scalded rats during early stage of scalding
      were observed by means of insulin receptor binding test, sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE) autoradiography of phosphorylation
      of insulin receptor and phosphorylation of exogenous substrate. RESULTS: There
      exhibited no evident changes of hepatocytic insulin receptor maximal binding
      capacity and affinity at 3 postburn days (PBDs) in scalded rats. The
      autophosphorylation capacity of the receptor beta-subunit decreased
      significantly. And the receptor TPK activity decreased obviously and its reaction
      to insulin stimulation decreased markedly. CONCLUSION: The defects of the insulin
      receptor signal transduction in hepatocyte leading to the post-receptor defects
      of insulin biological effects might be molecular mechanism of postburn insulin
      resistance.

PMID- 12467534
TI  - [A preliminary exploration of fluid resuscitation during the shock stage of mass
      burn patients].
AB  - OBJECTIVE: To explore the effects of fluid resuscitation during the shock stage
      of mass burn patients. METHODS: Eleven major burn patients out of 25 were rescued
      at spot and were resuscitated. The treatment results were analyzed and concluded.
      RESULTS: The eleven patients were all cured by smoothly living through the shock
      stage. CONCLUSION: The approaching of medical personnel to the site might be the
      guarantee of correct and timely fluid resuscitation during shock stage, which
      could be effective on the prevention of burn shock development.

PMID- 12467535
TI  - [Clinical significance of the change of serum CK-MM in electrical injured
      patients].
AB  - OBJECTIVE: To evaluate the diagnostic value of the changes in serum CK and its
      isozymes in the muscular infection and necrosis in electrical injured patients.
      METHODS: Seventeen patients were divided into A and B groups according to the
      causes, i.e. electrical injury as A and electrical arc flame burn as B groups.
      Obvious muscle necrosis was identified in A but not in B groups. The serum CK-MM
      concentration was determined after injury, before and after the operations.
      Simultaneously, the blood and urine routine, the hepatic and renal function and
      wound bacterial counting were determined and compared with those in 20 healthy
      people. RESULTS: 1. The serum CK-MM in A group increased evidently after injury
      and 1 day after wound debridement to the 6 times that in normal control. The
      enzyme decreased to normal at 3 post-operative days in 15 cases and remained at
      relative high level in 2 cases due to the wound infection and lowered down to
      normal level after wound re-debridement. 2. The serum CK-MM in B group increased
      slightly before and after skin grafting. CONCLUSION: CK-MM could be employed as
      the index for the infection and necrosis of the muscle in electrical injured
      patients due to its high specificity and sensitivity.

PMID- 12467536
TI  - [The effects of recombinant human growth hormone on the metabolism of branch
      chain amino acid in severely burned patients].
AB  - OBJECTIVE: To explore the effects of recombinant human growth hormone (rhGH) when
      applied postoperatively on the metabolism of branch chain amino acid in severely
      burned patients. METHODS: Fifty burn patients, aged 12 - 50 years and inflicted
      by more than 30% TBSA with 10% or more of III degree burn and admitted from the
      January of 1999 to the January of 2001 were enrolled in the study. The patients
      were randomly divided into rhGH treating (rhGH group) and control groups.
      Escharectomy was performed within 3 postburn day (PBDs). rhGH (0.3 IU/kg) was
      injected percutaneously every evening for ten days since the 1st postoperative
      day (POD). The changes of the plasma levels of GH and branch chain amino acid and
      the urine level of 3-methyl histidine (3-MH) were observed in the morning in the
      patients from the two groups. RESULTS: The plasma GH level before operation
      decreased obviously in two groups of patients when comparing with normal value (P
      < 0.05). The plasma GH level in rhGH group was evidently higher than that in
      control group since the 3rd POD (P < 0.05). There was significant increase of the
      output amount of urine 3-MH in all patients, but which was obviously higher in
      control group than that in rhGH group (P < 0.05). The plasma levels of branch
      chain amino acid in burn patients before and one day after operation were lower
      than normal levels. The plasma levels of valine, isoleucine and leucine increased
      to peak values at POD 3 in rhGH group and at POD 7 in control group and decreased
      thereafter. The plasma branch chain amino acid level in rhGH group was evidently
      lower than that in control group since POD 7 (P < 0.05). The plasma GH level in
      rhGH group was negatively and significantly correlated with the urine output
      amount of 3-MH (P < 0.01). CONCLUSION: Postoperative application of rhGH in major
      burn patients might be beneficial to the protein synthesis from amino acids by
      skeletal muscles and to the decrease of muscle protein degrading rate.

PMID- 12467537
TI  - [An experimental study on the cograft of auto-microskin and allo-dermal matrix].
AB  - OBJECTIVE: To explore the promoting effects of cograft of auto-microskin and allo
      dermal matrix on burn wound healing. METHODS: Forty-six patches of full skin loss
      wounds were made in the backs of 6 small white swines. Auto-microskin and meshed
      acellular allo-dermal matrix were simultaneously prepared. The 46 wounds were
      averagely divided into test (T) and control (C) groups. The wounds in T group
      were covered with auto-microskin and allo-dermal matrix (1:4) and split-thick
      allo-porcine skin. While the wounds in C group were grafted with autoskin and
      allo-dermal matrix. RESULTS: The skin survival rate exhibited no difference
      between C and T groups (P > 0.05). There was similar histological exhibition in
      the two groups after skin grafting. The structure of collagen fibres appeared
      integrated, clear with regular arrangement and steady diameter at 8 - 20 post
      operative weeks. Simultaneously, it was revealed by histological examination that
      normal vascular structure could be identified in the grafted skin and that
      inflammatory reaction ameliorated gradually and that epithelium combined well
      with dermis. It was also found that the epidermal papillar across the basement
      membrane fixed well to allo-dermis. The skin appeared smooth, elastic and
      functioned well at 5 months after skin grafting. CONCLUSION: The grafted skin
      survived well after the cograft of auto-microskin and allo-dermal matrix, which
      might be ideal covering material for the major deep burn wound healing.

PMID- 12467538
TI  - [Histological observation of the effects of tangential excision within twenty
      four postburn hours on the progressive injury of the progression of deep partial
      thickness burn wound].
AB  - OBJECTIVE: To evaluate the effects of early tangential excision on the prevention
      of the progression of deep partial thickness burn wound. METHODS: Twelve burn
      patients with deep partial thickness burn wound were enrolled and received
      tangential excision of the burn wound within 24 postburn hours (PBHs). The
      histological samples were harvested from the wound before and 5 - 7 postoperative
      days (PODs) after the operation and the wound without operation 5 - 7 postburn
      days (PBDs). The samples were observed by means of HE staining, Masson's staining
      and the labelling of Vimentin antigen positive cells by immunohistological skill.
      RESULTS: The inflammatory reaction of the burn wound without operation aggravated
      progressively along with that of disease and the tissue necrosis area enlarged.
      And the residual skin appendages disappeared due to the enhanced inflammatory
      reaction. The brown area expanded and light green area shrinked by Masson's
      staining. The Vimentin antigen positive cell count decreased significantly. But
      in the burn wound being performed tangential excision within 24 PBHs, focal
      inflammatory reaction exhibited evident ligher than that in burn wound without
      operation. Moreover, there appeared fresh granulation formation and partial
      epithelial coverage with no enlarged necrotic tissue area in the operated wound
      when compared with that in non-operated wound (P < 0.05). Furthermore, the light
      green area exhibited no obvious shrinking by Masson's staining and the Vimentin
      antigen positive cell count was much more in the operation area than that in non
      operative area (P < 0.05). CONCLUSION: It might be beneficial to the host to
      perform tangential excision within 24 PBHs, which could remove burn wound
      necrotic tissue in time and hamper the progression of tissue degenerative injury.
      The healing process of deep partial thickness burn wound was therefore
      accelerated.

PMID- 12467539
TI  - [An experimental study of the changes of rat hepatocytic glycolysis during
      hypoxia].
AB  - OBJECTIVE: To investigate the effects of hypoxia on the glycolysis in cultured
      rat hepatocytes. METHODS: Mixed gas with different concentrations of O(2), CO(2)
      and N(2) was prepared for the in vitro culture of normal rat hepatocytes. The
      cell strains were set to be A, B, C groups, which were observed at 1, 2, 4, 8 and
      16 hours after hypoxia with normal hepatocytes as the control. Biochemical
      methods were employed to determine the activities of the key enzymes during
      hepatocytic glycolysis such as hexokinase (HK), phosphofructokinase (PFK),
      pyruvate kinase (PK), lactate dehydrogenase (LDH) and the change of the content
      of lactic acid (LA) in the culture fluid. RESULTS: (1) The LDH activity of the
      rat hepatocytes increased significantly at all the time points of hypoxia in A
      and B groups when compared with that in control group (P < 0.05), while the
      activity increased obviously in C group since 2 hours after hypoxia (P < 0.05).
      (2) The HK activity of the cells in A group increased significantly at 1, 2, 4
      and 16 hours after hypoxia and that in B and C groups increased obviously at 1
      hour when compared with control group (P < 0.05). While the cellular PFK activity
      in A group increased markedly at 1 and 4 hours after hypoxia and that in B and C
      groups increased evidently at 4 hours after hypoxia (P < 0.05). The cellular PK
      activity in all the three groups increased at all the hypoxic time points (P <
      0.05). (3) The cellular LA content in A and B groups began to increase since 2
      hours and that in C group did so since 4 hours after hypoxia and increased along
      with the time lapse (P < 0.05). CONCLUSION: hypoxia might initiate glycolysis.

PMID- 12467540
TI  - [Impact of invasive pneumococcal infection in children].

PMID- 12467541
TI  - [Prognostic value of the pediatric index of mortality (PIM) score and lactate
      values in critically-ill children].
AB  - OBJECTIVE: To analyze and compare the prognostic value of the pediatric index of
      mortality (PIM) score and lactate values on admission to a pediatric intensive
      care unit (PICU). PATIENTS AND METHODS: We performed a prospective study of 500
      consecutive children: 237 girls (47.4 %) and 263 boys (52.6 %) with a mean age of
      51.5 59.7 (range: 3 days-18 years) admitted to our PICU. PIM scores and blood
      lactate concentrations were determined on admission. The predictive ability of
      PIM and lactate concentrations in relation to mortality and length of stay in the
      PICU were analyzed. RESULTS: Thirty-six patients (7.2 %) died. According to the
      PIM score, the mean probability of death in children who died was 23.6 % 28.9,
      which was significantly higher than that in surviving children (3.4 % 7.3; p <
      0.001). The area under the ROC curve for PIM was 0.81 0.03 (95 % CI: 0.74-0.89).
      Lactate level in nonsurvivors was 4.9 % 3.5 mmol/L, which was significantly
      higher than that in survivors (1.9 % 1.5 mmol/L; p < 0.001). The area under the
      ROC curve for blood lactate was 0.76 0.04 (95 % CI: 0.67-0.85). No statistically
      significant differences were found between either ROC curves. In survivors, a
      significant relationship was found between PIM score and length of stay in the
      PICU while in nonsurvivors an inverse relationship was found between blood
      lactate concentrations and length of stay. CONCLUSIONS: Both PIM score and blood
      lactate concentrations on admission to the PICU have a moderate prognostic value
      in critically-ill children. The prognostic value of the PIM score is greater than
      that of blood lactate concentration but is more difficult to obtain, whereas
      blood lactate determination is fast and easy.

PMID- 12467542
TI  - [Epidemiology of invasive pneumococcal disease in children in Gipuzkoa (Spain)
      from 1981 to 2001].
AB  - OBJECTIVES: To assess the epidemiological characteristics of invasive
      pneumococcal disease (IPD) in children in Gipuzkoa (Spain) as well as the
      serotype distribution among these episodes and to analyze the potential impact of
      new conjugate vaccines. METHODS: We performed a retrospective study of cases of
      IPD in the pediatric population (< 15 years) between 1981 and 2001. Patients were
      included if blood, cerebrospinal, joint or peritoneal fluid isolates were culture
      positive for Streptococcus pneumoniae. RESULTS: One hundred twenty-nine episodes
      (30 meningitis, 39 bacteremic pneumonia, 7 peritonitis, 1 arthritis and 52
      bacteremia without focus) were identified. The incidence of IPD in children
      increased throughout the study period and from 1999-2001 was 12.6 cases per
      100,000/ year in children aged < 15 years, 34.5 in those < 5 years, 48.4 in those
      < 2 years and 40.8 in infants < 2 months. The incidence of pneumococcal
      meningitis was similar throughout the study period (1981-2001): 1.3 in children
      aged < 15 years, 3.5 in those < 5 years, 8.1 in those < 2 years and 10.2 in
      infants < 2 months. From 1989 to 2001 mortality was 1 % (1/98 cases). The
      pneumococcal serotypes and serogroups present in the 7-valent vaccine accounted
      for 60.5 % and 70.9 % of the cases (9-valent vaccine: 70.2 % and 80.6 %; 11
      valent vaccine: 76.6 % and 87.2 %). From 1999-2001, penicillin resistance was
      35.4 % and erythromycin resistance was 38.7 %. CONCLUSIONS: The incidence of IPD
      in children in Gipuzkoa has increased in the last few years, with rates similar
      to those in other European countries. Continued surveillance is required to
      assess the impact of the new conjugate vaccines on this infection.

PMID- 12467543
TI  - [Bacteremic pneumococcal pneumonia].
AB  - BACKGROUND: Streptococcus pneumonia is the most common bacterial cause of
      community-acquired pneumonia in children. The reference standard for etiological
      diagnosis is isolation of S. pneumoniae from blood Since the advent of conjugate
      vaccines, disease caused by this organism can now be prevented. Many studies have
      been performed of the global incidence of invasive pneumococcal infections and of
      pneumococcal meningitis but few studies investigated bacteremic pneumococcal
      pneumonia and its complications in children. OBJECTIVES: To determine the
      incidence, patient characteristics, clinical signs, laboratory data, percentage
      and days of hospitalization, response to antibiotic treatment, antibiotic
      resistance, complications and causal serogroups of bacteremic pneumococcal
      pneumonia in our environment in order to estimate requirements for systematic
      vaccination programs. MATERIAL AND METHODS: From January 1990 to May 2001, data
      on all pediatric cases of invasive pneumococcal infections diagnosed in our
      hospital were collected. Several characteristics of patients with bacteremic
      pneumococcal pneumonia were analyzed. Bacteremic pneumococcal pneumonia was
      diagnosed in patients with positive blood or pleural fluid cultures for S.
      pneumoniae and radiographically evident pulmonary infiltrate. The incidence of
      both types of pneumonia were determined according to population census data. All
      S. pneumonia strains were sent to the Pneumococci Reference Laboratory of the
      Instituto Carlos III in Madrid for serotyping. We estimated the serotype coverage
      of the pneumococcal 7-valent conjugate vaccine according to the serotypes
      included in this vaccine and their distribution. RESULTS: Forty cases of
      bacteremic pneumococcal pneumonia were diagnosed, yielding an incidence of 17,10
      and 5 cases per 10(5) children aged less than 2, 4 and 15 years old respectively.
      The mean age was 50 months and 43% were aged less than 4 years. Peaks occurred in
      January, March, April and May. A total of 77.5% of the patients were admitted to
      hospital and the mean length of stay was 9.2 days. The mean duration of fever was
      2 days and was 4.2 days in patients with pleural empyema. All patients presented
      fever and its mean duration before admission was 4 days. Fifty-eight percent of
      the patients had cough. Thirty-nine percent appeared generally unwell, vomiting
      was present in 47% and abdominal pain in 28%. Respiratory auscultation detected
      rales in 30% of the patients, hypophonesis in 28% and polypnea or dyspnea in 35%.
      Most patients showed alveolar bilateral infiltrations and 20% had pleural
      empyema. Seventy-eight percent had WBC counts > 15,000 and 93% showed
      neutrophilia of > 60%. Erythrocyte sedimentation rate and C-reactive protein were
      elevated in 77% and 85% of the patients, respectively. Overall, 40% of the
      isolates showed intermediate susceptibility to penicillin and 5% were resistant.
      Eighteen percent showed intermediate susceptibility to cefotaxime and 18% were
      resistant to erythromycin. Thirty-four strains were resistant to erythromycin.
      Thirty-four strains were serogroups and in children < or = 59 months, 34% of the
      serogroups were included in the pneumococcal 7-valent pneumococcal conjugate
      vaccine. CONCLUSION: The significant morbidity of bacteremic pneumococcal
      pneumonia and the implicated serogroups supports the use of the new heptavalent
      vaccine in the pediatric age group.

PMID- 12467544
TI  - [Drug utilization and recommended conditions for use in children].
AB  - BACKGROUND: Studies carried out in other countries show that drugs are used in
      children outside the approved conditions, in a context in which investigation,
      information and authorization of medications in the pediatric population are
      scarce. OBJECTIVES: To evaluate the conditions of drug use recommended in
      children and variability in sources of drug information. METHODS: We performed a
      descriptive, retrospective study. Data on medication consumption in 1997 were
      obtained from a pediatric university hospital. Information on conditions of drug
      use in children was analyzed using a Spanish catalog of medications. This
      information was compared with that of a North American catalog for international
      reference. RESULTS: Most of the drugs used were of unrestricted (43; 47 %) or
      restricted (26; 28 %) pediatric use, but drugs that are not recommended (8; 9 %)
      or those with unspecified conditions of use in children were also used (15; 16
      %). Approximately 12 % of the drugs were not identified in the North American
      catalog; of the remaining drugs, 60 % were of unrestricted pediatric use, 35 % of
      restricted use and 5 % were not recommended. CONCLUSIONS: A substantial
      proportion of drugs administered to hospitalized children are not recommended or
      their possible use in this population is not specified. It is worth encouraging
      research, having sources of information that help to make decisions, especially
      in conditions that have not been approved, and adapting regulatory attitudes, as
      far as possible, to the evidence and therapeutic needs.

PMID- 12467545
TI  - [Changes in antibiotics prescription in primary care].
AB  - BACKGROUND: Bacterial resistance to antimicrobial drugs constitutes a
      considerable problem in clinical practice. Overprescribing of these drugs
      contributes to bacterial resistance and current literature shows a growing
      interest in the rationalization of antibiotic use. OBJECTIVES: To observe the
      appropriateness of antibiotic prescriptions to children in an outpatient primary
      care setting, before and after a critical analysis of prescribing habits was
      performed. PATIENTS AND METHODS: Children aged 0-4 years attending the outpatient
      pediatric clinic were surveyed in two different periods: 1997 and 2000. The
      number of visits, infectious and respiratory diseases observed, and courses of
      antibiotics prescribed was determined. RESULTS: A total of 456 children, 2,339
      diseases, and 829 antibiotic prescriptions were included. Several differences
      were observed between the two periods: the number of antibiotic courses
      administered to each child in one year averaged 2.3 in the first period and 1.5
      in the second (p < 0.001). The number of processes receiving antibiotic
      prescription decreased from 38.8 % to 31.7 % (p < 0.001). The appropriateness of
      the decision to treat increased from 85.1 % to 93.3 % (p < 0.001), and the
      appropriateness of the antibiotic prescribed increased from 56.3 % to 78.7 % (p <
      0.001). The most frequently diagnosed infectious diseases were common cold,
      tonsillopharyngitis, otitis and bronchitis. The most frequently prescribed
      antibiotic drugs were amoxicillin, amoxicillin-clavulanate and V penicillin.
      CONCLUSIONS: Physicians' knowledge of their own antibiotics prescription profiles
      with subsequent critical comparative analysis with current literature on the
      subject can help to modify prescribing habits.

PMID- 12467546
TI  - [Acute mastoiditis: an increasing entity].
AB  - BACKGROUND: Mastoiditis used to be the most common complication of acute otitis
      media. However, once antibiotics became widely available, it was rarely reported.
      Recently, this complication has become more frequent. OBJECTIVES: To determine
      the frequency of acute mastoiditis in our center in the last few years and to
      analyze the clinical and bacteriologic characteristics of the patients with this
      diagnosis. METHODS: Retrospective analysis of all patients admitted to our
      hospital with a diagnosis of acute mastoiditis from 1994-2001. RESULTS: One
      hundred patients were diagnosed with acute mastoiditis during the study period.
      The mean age was 2 years and 10 months (range: 2 months-13 years) and the median
      age was 15 months. The mean number of episodes was 12.5 cases of acute
      mastoiditis per year, but 52 % of the cases occurred from 1999-2001. Culture of
      middle ear effusions was performed in 47 patients, revealing Streptococcus
      pneumoniae in 17, Haemophilus influenzae in 3, and other pathogens in 10
      children. Cultures were sterile in 17 patients. Three children did not respond to
      medical therapy and required mastoidectomy. CONCLUSIONS: In the last few years,
      the incidence of acute mastoiditis in our population has increased considerably.
      This complication is more common in children aged less than 2 years.

PMID- 12467547
TI  - [Childhood headache. A diagnostic approach].
AB  - Headaches are common during childhood and become more frequent in adolescence.
      The rational, cost-effective evaluation of children with headache begins with a
      careful history. The first step is to identify the temporal pattern of the
      headache -acute, acute-recurrent, chronic-progressive, chronic-nonprogressive, or
      mixed. The next step is a physical and neurologic examination. Neuroimaging is
      not routinely warranted in the evaluation of childhood headache and should be
      reserved for use in children with acute or chronic-progressive patters of
      abnormalities in neurologic examination. Pediatric migraine differs from adult
      migraine. Recent studies indicate the need to revise diagnostic criteria for
      pediatric migraine, which would allow its real prevalence in this age group to be
      determined. The sensitivity and specificity of the International Headache Society
      (IHS) criteria for childhood migraine would be increased if the minimum duration
      of migraine were reduced and if a diagnosis of migraine were allowed when severe
      headache is associated with nausea, even though the criteria of location,
      quality, and aggravation by physical activity are not fulfilled. There are no
      differences in the fulfillment of the IHS criteria for migraine and tension-type
      headache between children and adolescents. Independent of age, the intensity of
      headache and the presence or absence of nausea are the most important features
      for differentiating the two major types of idiopathic headache.Migraines,
      migraine variants, tension headache and other types of headache often present for
      the first time during childhood and require close follow-up by the pediatrician.
      Investigation into this disorder is still developing.

PMID- 12467548
TI  - [Balloon valvoplasty for critical aortic valve stenosis in neonates].
AB  - OBJECTIVES: To evaluate the immediate results obtained with balloon aortic
      valvuloplasty in neonates and long-term echocardiographic outcome as well as to
      identify variables predictive for outcome. To identify the degree of agreement
      between hemodynamic and echocardiographic study. PATIENTS AND METHODS: We
      analyzed the results obtained in 26 procedures performed in 18 boys and 8 girls
      (2.25:1), aged 2 to 49 days (16.1 12.9 days). All procedures were performed in
      the Pediatric Cardiology Unit of Ramon y Cajal Hospital in Madrid between June
      1989 and June 2001. Follow-up was from 0 to 144 months (39.5 39.7 months).
      RESULTS: The immediate effects observed through echocardiographic study were a
      significant decrease in the maximum Doppler gradient (from 77.8 to 32.4 mm Hg; p
      < 0.0001) and in the medium Doppler gradient (from 41.7 to 18.5 mm Hg; p < 0.05).
      Hemodynamic studies showed a significant decrease in left ventricular systolic
      pressure (from 119.8 to 82.8 mm Hg; p < 0.0001) and an increase in aortic
      systolic pressure (from 56.8 to 66.6 mm Hg; p < 0.007). The hemodynamic peak
      gradient decreased from 63.1 to 17.7 mm Hg; p < 0.0001. In 23 % of the patients,
      aortic insufficiency significantly increased. Echocardiographic follow-up showed
      a significant increase in the telediastolic size of the left ventricle and a
      decrease in the maximum and medium Doppler gradient. The procedure showed initial
      success in 68.7 % and analysis of survival free of valvular surgery was 65.8 % at
      45 months. Proportional risk analysis revealed that the post-valvuloplasty
      gradient was a predictive factor for future valvular surgery.

PMID- 12467549
TI  - [Cutaneous colonization by Malassezia spp. in neonates].
AB  - BACKGROUND: Malassezia spp. is a lipophilic yeast considered to be a normal
      component of the human skin flora. It has been associated with sepsis in patients
      receiving intravenous infusion of lipid emulsions through central venous
      catheters (CVC). Current evidence indicates a high rate of skin colonization in
      healthy adults, in contrast with the low rate of colonization in prepubertal
      children. Of note is the high prevalence of colonized infants in the neonatal
      intensive care unit (NICU). METHODS: We performed a prospective open
      observational study of colonization in all infants admitted to the NICU during a
      nine-month period (October 1997-June 1998). Length of stay in the unit,
      birthweight and the use of CVC for parenteral fat infusion were evaluated.
      RESULTS: Seventy-seven neonates were included in the study. The mean length of
      stay in the NICU was 24 days. A total of 63.6 % weighed less than 2,500 g at
      birth and 72 % were given parenteral nutrition supplemented with fat emulsion
      through a CVC. The overall rate of colonization in the unit was 41.5 and 75 % of
      the patients became colonized within the first two weeks of admission.
      CONCLUSIONS: These data emphasize the need for preventive measures to reduce the
      transmission of these yeasts in the NICU and to prevent the occurrence of
      neonatal sepsis due to Malassezia spp. in immunologically immature infants.

PMID- 12467550
TI  - [Comparison of the epidemiological characteristics of neural tube defects
      classified according to failure of the different points of closure].
AB  - OBJECTIVES: To study the epidemiological characteristics of neural tube defects
      (NTD) classified according to the theory of multi-site closure of the neural tube
      and to correlate several factors with the failure of different closure sites.
      MATERIAL AND METHODS: We used the data from the Spanish Collaborative Study of
      Congenital Malformations (ECEMC), collected from April 1976 to April 1995. During
      this time, 757 NTD of non-syndromic origin were diagnosed. These were classified
      into groups according to the failure of the point of closure and a range of
      variables were analyzed by comparing the different groups of NTD with each other.
      RESULTS AND CONCLUSIONS: Among non-syndromic NTD, 2.11 % recurred in siblings.
      However, the real recurrence rate in our population is 2.63 %, which corresponds
      with the recurrence rate observed before 1986. From this year the recurrence rate
      was modified by the legal possibility of abortion after prenatal diagnosis. The
      infants with NTD classified according to multi-site closure failure of neural
      tube differed in weight, mortality, maternal use of valproic acid, and maternal
      diabetes mellitus. While valproic acid is more specific to failure of closure
      sites 1 and 1 5, maternal diabetes mellitus preferentially affects failure of
      closure site 4. Closure site 4 is clearly genetically determined: it is
      frequently observed in genetic syndromes, predominantly affects females and is
      associated with a higher rate of maternal abortions and higher recurrence.
      Moreover, it is frequently observed in infants with multiple congenital anomalies
      and is associated with a higher rate of malformations among relatives.

PMID- 12467551
TI  - [Practice guidelines in gastroenterology (VIII). Upper gastrointestinal
      hemorrhage and lower gastrointestinal hemorrhage. Spanish Society of
      Gastroenterology, Hepatology and Pediatric Nutrition].

PMID- 12467552
TI  - [External ventricular assist devices as circulatory support in patients with
      dilated cardiomyopathy].
AB  - Ventricular assist devices have demonstrated their utility in patients with
      intractable cardiac failure, both as support until complete myocardial recovery
      and as a bridge to transplantation. Specific pediatric pneumatic paracorporeal
      systems can be applied even in infants. Long-term survival has been reported
      although experience is limited. We report the case of an 8-year-old boy with
      dilated cardiomyopathy awaiting cardiac transplantation. The patient developed
      profound cardiogenic shock with multiorgan failure while being evaluated for
      heart transplantation. He was given biventricular assistance with the MEDOS-HIA
      system (MEDOS-Helmholtz Institute). Maximum stroke volume ventricles of 25 and 22
      ml were used, achieving a cardiac output of 2.2 l/min in both ventricles. The
      patient was supported with ventricular assistance for 9 days, but multiple organ
      failed to improve and transplantation became impossible. Progressive loss of
      peripheral circulatory resistance unresponsive to treatment developed and
      ventricular assistance was discontinued. The previous severe shock and advanced
      and progressive multiorgan failure could be responsible for the poor outcome of
      our patient despite maintenance of adequate cardiac output. Nevertheless, the use
      of ventricular assist devices is a real therapeutic alternative in children with
      severe cardiogenic shock, allowing them to recover completely or undergo heart
      transplantation. Patient selection, the choice of a system of appropriate size,
      and early implantation seem to be the cornerstones for obtaining good results.

PMID- 12467553
TI  - [Langerhans' cell histiocytosis: various manifestations with the same
      histopathologic base].
AB  - Langerhans' cell histiocytosis (LCH), previously known as histiocytosis X, is a
      rare disease. It is characterized by the accumulation and proliferation of
      histiocytes, eosinophils and Langerhans' cells with Birbeck granules detected by
      electron microscopy. It involves single organs or systems or can present as a
      multisystem disease. The clinical presentation may vary widely, ranging from
      benign self-limiting types with spontaneous regression to slowly-progressive
      malignant disease. We report five cases of LCH with the same histopathologic
      basis but different outcome.

PMID- 12467554
TI  - [Postgraduate training: analysis and proposals].

PMID- 12467555
TI  - [beta-hCG-induced precocious puberty?].

PMID- 12467556
TI  - [Antenatal diagnosis and isotopic studies in urethral ectopia].

PMID- 12467558
TI  - [Dextromethorphan poisoning].

PMID- 12467559
TI  - [Exogenous surfactant. A rescue treatment in a neonate with varicella complicated
      with pneumonia].

PMID- 12467560
TI  - [Myocardial stunning].

PMID- 12467561
TI  - [Renal angiomyolipoma: a case with a difficult diagnosis].

PMID- 12467562
TI  - [Congenital hyperferritinemia and cataract syndrome].

PMID- 12467564
TI  - [Recurrent hematuria].

PMID- 12467565
TI  - Kurt Wuthrich and NMR of biological macromolecules.
AB  - Nuclear magnetic resonance (NMR) spectroscopy is the only experimental technique
      that can determine the structures and dynamics of biological macromolecules and
      their complexes in solution and with atomic resolution. The award of the 2002
      Nobel Prize in Chemistry to Kurt Wuthrich of the Swiss Federal Institute of
      Technology and The Scripps Research Institute honors his pioneering efforts in
      developing and applying this technique. Wuthrich shared the prize with John B.
      Fenn and Koichi Tanaka, who were recognized for the development of ionization
      methods for the analysis of proteins using mass spectrometry.

PMID- 12467566
TI  - RORalpha: an orphan nuclear receptor on a high-cholesterol diet.
AB  - A high-resolution X-ray crystal structure of the retinoic acid receptor-related
      orphan receptor (RORalpha; NR1F1), which reveals a molecule of cholesterol within
      the ligand binding pocket, is a breakthrough in functional analysis of this
      orphan nuclear receptor.

PMID- 12467567
TI  - Smads "freeze" when they ski.
AB  - The transforming growth factor-beta (TGF-beta) signal is manifest through
      activated heteromeric Smad complex-mediated transcriptional modulation of target
      genes that translates into diverse, context-specific biologic effects, such as
      the potent TGF-beta-initiated cytostatic program. The TGF-beta pathway is
      effectively antagonized through the direct binding and subsequent repression of
      activated Smad heteromeric complexes by the Ski family of proto-oncoproteins.

PMID- 12467568
TI  - Application of NMR in structural proteomics: screening for proteins amenable to
      structural analysis.
AB  - In the time of structural proteomics when protein structures are targeted on a
      genome-wide scale, the detection of "well-behaved" proteins that would yield good
      quality NMR spectra or X-ray images is the key to high-throughput structure
      determination. Already, simple one-dimensional proton NMR spectra provide enough
      information for assessing the folding properties of proteins. Heteronuclear two
      dimensional spectra are routinely used for screenings that reveal structural, as
      well as binding, properties of proteins. NMR can thus provide important
      information for optimizing conditions for protein constructs that are amenable to
      structural studies.

PMID- 12467569
TI  - Crystal structure of a SEA variant in complex with MHC class II reveals the
      ability of SEA to crosslink MHC molecules.
AB  - Although the biological properties of staphylococcal enterotoxin A (SEA) have
      been well characterized, structural insights into the interaction between SEA and
      major histocompatibilty complex (MHC) class II have only been obtained by
      modeling. Here, the crystal structure of the D227A variant of SEA in complex with
      human MHC class II has been determined by X-ray crystallography. SEA(D227A)
      exclusively binds with its N-terminal domain to the alpha chain of HLA-DR1. The
      ability of one SEA molecule to crosslink two MHC molecules was modeled. It shows
      that this SEA molecule cannot interact with the T cell receptor (TCR) while a
      second SEA molecule interacts with MHC. Because of its relatively low toxicity,
      the D227A variant of SEA is used in tumor therapy.

PMID- 12467570
TI  - Atomic resolution structure of Moloney murine leukemia virus matrix protein and
      its relationship to other retroviral matrix proteins.
AB  - Matrix proteins associated with the viral membrane are important in the formation
      of the viral particle and in virus maturation. The 1.0 A crystal structure of the
      ecotropic Gammaretrovirus Moloney murine leukemia virus (M-MuLV) matrix protein
      reveals the conserved topology of other retroviral matrix proteins, despite
      undetectable sequence similarity. The N terminus (normally myristylated) is
      exposed and adjacent to a basic surface patch, features likely to contribute to
      membrane binding. The four proteins in the asymmetric unit make varied contacts.
      The M-MuLV matrix structure is intermediate, between those of the lentiviruses
      and other retroviruses. The protein fold appears to be maintained, in part, by
      the conservation of side chain packing, which may provide a useful tool for
      searching for weak distant similarities in proteins.

PMID- 12467571
TI  - Structure of the monomeric isocitrate dehydrogenase: evidence of a protein
      monomerization by a domain duplication.
AB  - NADP(+)-dependent isocitrate dehydrogenase is a member of the beta
      decarboxylating dehydrogenase family and catalyzes the oxidative decarboxylation
      reaction from 2R,3S-isocitrate to yield 2-oxoglutarate and CO(2) in the Krebs
      cycle. Although most prokaryotic NADP(+)-dependent isocitrate dehydrogenases
      (IDHs) are homodimeric enzymes, the monomeric IDH with a molecular weight of 80
      100 kDa has been found in a few species of bacteria. The 1.95 A crystal structure
      of the monomeric IDH revealed that it consists of two distinct domains, and its
      folding topology is related to the dimeric IDH. The structure of the large domain
      repeats a motif observed in the dimeric IDH. Such a fusional structure by domain
      duplication enables a single polypeptide chain to form a structure at the
      catalytic site that is homologous to the dimeric IDH, the catalytic site of which
      is located at the interface of two identical subunits.

PMID- 12467572
TI  - Domain arrangement of Der, a switch protein containing two GTPase domains.
AB  - The EngA subfamily of essential bacterial GTPases has a unique domain structure
      consisting of two adjacent GTPase domains (GD1 and GD2) and a C-terminal domain.
      The structure of Thermotoga maritima Der bound to GDP determined at 1.9 A
      resolution reveals a novel domain arrangement in which the GTPase domains pack at
      either side of the C-terminal domain. Unexpectedly, the C-terminal domain
      resembles a KH domain, missing the distinctive RNA recognition elements.
      Conserved motifs of the nucleotide binding site of GD1 are integral parts of the
      GD1-KH domain interface, suggesting the interactions between these two domains
      are directly influenced by the GTP/GDP cycling of the protein. In contrast, the
      GD2-KH domain interface is distal to the GDP binding site of GD2.

PMID- 12467573
TI  - Structures of the cancer-related Aurora-A, FAK, and EphA2 protein kinases from
      nanovolume crystallography.
AB  - Protein kinases are important drug targets in human cancers, inflammation, and
      metabolic diseases. This report presents the structures of kinase domains for
      three cancer-associated protein kinases: ephrin receptor A2 (EphA2), focal
      adhesion kinase (FAK), and Aurora-A. The expression profiles of EphA2, FAK, and
      Aurora-A in carcinomas suggest that inhibitors of these kinases may have inherent
      potential as therapeutic agents. The structures were determined from crystals
      grown in nanovolume droplets, which produced high-resolution diffraction data at
      1.7, 1.9, and 2.3 A for FAK, Aurora-A, and EphA2, respectively. The FAK and
      Aurora-A structures are the first determined within two unique subfamilies of
      human kinases, and all three structures provide new insights into kinase
      regulation and the design of selective inhibitors.

PMID- 12467574
TI  - Large conformational changes in the catalytic cycle of glutathione synthase.
AB  - Glutathione synthase catalyzes the final ATP-dependent step in glutathione
      biosynthesis, the formation of glutathione from gamma-glutamylcysteine and
      glycine. We have determined structures of yeast glutathione synthase in two
      forms: unbound (2.3 A resolution) and bound to its substrate gamma
      glutamylcysteine, the ATP analog AMP-PNP, and two magnesium ions (1.8 A
      resolution). These structures reveal that upon substrate binding, large domain
      motions convert the enzyme from an open unliganded form to a closed conformation
      in which protein domains completely surround the substrate in the active site.

PMID- 12467575
TI  - The crystal structure of the hexadeca-heme cytochrome Hmc and a structural model
      of its complex with cytochrome c(3).
AB  - Sulfate-reducing bacteria contain a variety of multi-heme c-type cytochromes. The
      cytochrome of highest molecular weight (Hmc) contains 16 heme groups and is part
      of a transmembrane complex involved in the sulfate respiration pathway. We
      present the 2.42 A resolution crystal structure of the Desulfovibrio vulgaris
      Hildenborough cytochrome Hmc and a structural model of the complex with its
      physiological electron transfer partner, cytochrome c(3), obtained by NMR
      restrained soft-docking calculations. The Hmc is composed of three domains, which
      exist independently in different sulfate-reducing species, namely cytochrome
      c(3), cytochrome c(7), and Hcc. The complex involves the last heme at the C
      terminal region of the V-shaped Hmc and heme 4 of cytochrome c(3), and represents
      an example for specific cytochrome-cytochrome interaction.

PMID- 12467576
TI  - Crystal structure of SANOS, a bacterial nitric oxide synthase oxygenase protein
      from Staphylococcus aureus.
AB  - Prokaryotic genes related to the oxygenase domain of mammalian nitric oxide
      synthases (NOSs) have recently been identified. Although they catalyze the same
      reaction as the eukaryotic NOS oxygenase domain, their biological function(s) are
      unknown. In order to explore rationally the biochemistry and evolution of the
      prokaryotic NOS family, we have determined the crystal structure of SANOS, from
      methicillin-resistant Staphylococcus aureus (MRSA), to 2.4 A. Haem and S
      ethylisothiourea (SEITU) are bound at the SANOS active site, while the
      intersubunit site, occupied by the redox cofactor tetrahydrobiopterin (H(4)B) in
      mammalian NOSs, has NAD(+) bound in SANOS. In common with all bacterial NOSs,
      SANOS lacks the N-terminal extension responsible for stable dimerization in
      mammalian isoforms, but has alternative interactions to promote dimer formation.

PMID- 12467577
TI  - X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data
      that cholesterol or a cholesterol derivative is the natural ligand of RORalpha.
AB  - The retinoic acid-related orphan receptor alpha (RORalpha) is an orphan member of
      the subfamily 1 of nuclear hormone receptors. No X-ray structure of RORalpha has
      been described so far, and no ligand has been identified. We describe the first
      crystal structure of the ligand binding domain (LBD) of RORalpha, at 1.63 A
      resolution. This structure revealed a ligand present in the ligand binding pocket
      (LBP), which was identified by X-ray crystallography as cholest-5-en-3beta-ol
      (cholesterol). Moreover, RORalpha transcriptional activity could be modulated by
      changes in intracellular cholesterol level or mutation of residues involved in
      cholesterol binding. These findings suggest that RORalpha could play a key role
      in the regulation of cholesterol homeostasis and thus represents an important
      drug target in cholesterol-related diseases.

PMID- 12467578
TI  - Mapping of the interaction interface of DNA polymerase beta with XRCC1.
AB  - Residues of DNA polymerase beta (beta-Pol) that interact with the DNA repair
      protein XRCC1 have been determined by NMR chemical shift mapping (CSM) and
      mutagenesis. 15N/(13)C/(2)H/(1)H,(13)C-methyl(Leu,Ile,Val)-labeled beta-Pol palm
      thumb domain was used for assignments of the 1H, 15N, and 13C resonances used for
      CSM of the palm-thumb on forming the 40 kDa complex with the XRCC1 N-terminal
      domain (NTD). Large chemical shift changes were observed in the thumb on
      complexation. 15N relaxation data indicate reduction in high-frequency motion for
      a thumb loop and three palm turn/loops, which showed concomitant chemical shift
      changes on complexation. A deltaV303-V306 deletion and an L301R/V303R/V306R
      triple mutation abolished complex formation due to loss in hydrophobicity. In an
      updated model, the thumb-loop of beta-Pol contacts an edge/face region of the
      beta sheet of the XRCC1 NTD, while the beta-Pol palm weakly contacts the alpha2
      helix.

PMID- 12467579
TI  - Crystal structures of C4 form maize and quaternary complex of E. coli
      phosphoenolpyruvate carboxylases.
AB  - Phosphoenolpyruvate carboxylase (PEPC) catalyzes the first step in the fixation
      of atmospheric CO(2) during C(4) photosynthesis. The crystal structure of C(4)
      form maize PEPC (ZmPEPC), the first structure of the plant PEPCs, has been
      determined at 3.0 A resolution. The structure includes a sulfate ion at the
      plausible binding site of an allosteric activator, glucose 6-phosphate. The
      crystal structure of E. coli PEPC (EcPEPC) complexed with Mn(2+),
      phosphoenolpyruvate analog (3,3-dichloro-2-dihydroxyphosphinoylmethyl-2
      propenoate), and an allosteric inhibitor, aspartate, has also been determined at
      2.35 A resolution. Dynamic movements were found in the ZmPEPC structure, compared
      with the EcPEPC structure, around two loops near the active site. On the basis of
      these molecular structures, the mechanisms for the carboxylation reaction and for
      the allosteric regulation of PEPC are proposed.

PMID- 12467580
TI  - Multiple mechanisms for contrast adaptation in the retina.
AB  - The retina adapts to average light intensity but also to the range of light
      intensities (contrast). A study by Baccus and Meister, in this issue of Neuron,
      identifies three ways that ganglion cells and interneurons adapt to high
      contrast: shorten integration time, reduce gain, and depolarize. Only the
      depolarization decays, over tens of seconds.

PMID- 12467581
TI  - Orientation tuning--a crooked path to the straight and narrow.
AB  - Neurons in visual cortex are selective for the orientation of a visual stimulus,
      while the receptive fields of their thalamic input are circular. Cortical
      orientation selectivity arises from the organization of both thalamic input and
      local cortical circuits. In this issue of Neuron, Schummers and colleagues
      provide evidence that the local circuit mechanisms contributing to orientation
      selectivity differ depending on the local organization of the orientation map.

PMID- 12467582
TI  - A hidden sensory function for motor cortex.
AB  - Sensory perception has traditionally been attributed to the activation of sensory
      cortices. However, by inducing an illusory perception of movement, Naito and
      colleagues show in this issue of Neuron that the illusory perception of movement
      is related to activation of primary motor cortex.

PMID- 12467583
TI  - Junctional signaling microdomains: bridging the gap between the neuronal cell
      surface and Ca2+ stores.
AB  - Growing evidence suggests that plasma membranes are locally differentiated into
      microdomains that are important interaction sites for organization of signaling
      molecules. These signaling microdomains create local conditions that enhance
      molecular interactions, excluding others, thereby ensuring speed, spatial
      localization, and specificity of signal transduction. With the special emphasis
      on InsP(3) and Ca(2+) signaling pathways, we will discuss here the evolving
      concept of signaling microdomains that provide a key framework for understanding
      the differential regulation of many cellular target proteins.

PMID- 12467584
TI  - View from the top: hierarchies and reverse hierarchies in the visual system.
AB  - We propose that explicit vision advances in reverse hierarchical direction, as
      shown for perceptual learning. Processing along the feedforward hierarchy of
      areas, leading to increasingly complex representations, is automatic and
      implicit, while conscious perception begins at the hierarchy's top, gradually
      returning downward as needed. Thus, our initial conscious percept--vision at a
      glance--matches a high-level, generalized, categorical scene interpretation,
      identifying "forest before trees." For later vision with scrutiny, reverse
      hierarchy routines focus attention to specific, active, low-level units,
      incorporating into conscious perception detailed information available there.
      Reverse Hierarchy Theory dissociates between early explicit perception and
      implicit low-level vision, explaining a variety of phenomena. Feature search "pop
      out" is attributed to high areas, where large receptive fields underlie spread
      attention detecting categorical differences. Search for conjunctions or fine
      discriminations depends on reentry to low-level specific receptive fields using
      serial focused attention, consistent with recently reported primary visual cortex
      effects.

PMID- 12467585
TI  - Transgenically encoded protein photoinactivation (FlAsH-FALI): acute inactivation
      of synaptotagmin I.
AB  - We demonstrate a noninvasive technique for protein photoinactivation using a
      transgenically encoded tag. A tetracysteine motif that binds the membrane
      permeable fluorescein derivative 4',5'-bis(1,3,2-dithioarsolan-2-yl)fluorescein
      (FlAsH) was engineered into synaptotagmin I (Syt I4C). Neuronally expressed Syt
      I4C rescues the syt I null mutation, can be visualized after FlAsH labeling, and
      is normally distributed at the Drosophila neuromuscular synapse. Illumination of
      FlAsH bound Syt I4C at 488 nm decreases evoked release in seconds demonstrating
      efficient fluorophore-assisted light inactivation (FlAsH-FALI) of Syt I. The
      inactivation of Syt I is proportional to the duration of illumination and follows
      first-order kinetics. In addition, Syt I FlAsH-FALI is specific and does not
      impair Syt I-independent vesicle fusion. We demonstrate that Syt I is required
      for a post-docking step during vesicle fusion but does not function to stabilize
      the docked vesicle state.

PMID- 12467586
TI  - Nuclear retention of MBP mRNAs in the quaking viable mice.
AB  - Quaking viable (qk(v)) mice fail to properly compact myelin in their central
      nervous systems. Although the defect in the qk(v) mice involves a mutation
      affecting the expression of the alternatively spliced qk gene products, their
      roles in myelination are unknown. We show that the QKI RNA binding proteins
      regulate the nuclear export of MBP mRNAs. Disruption of the QKI nucleocytoplasmic
      equilibrium in oligodendrocytes results in nuclear and perikaryal retention of
      the MBP mRNAs and lack of export to cytoplasmic processes, as it occurs in qk(v)
      mice. MBP mRNA export defect leads to a reduction in the MBP levels and their
      improper cellular targeting to the periphery. Our findings suggest that QKI
      participates in myelination by regulating the mRNA export of key protein
      components.

PMID- 12467587
TI  - Bifocal is a downstream target of the Ste20-like serine/threonine kinase
      misshapen in regulating photoreceptor growth cone targeting in Drosophila.
AB  - Misshapen (Msn) has been proposed to shut down Drosophila photoreceptor (R cell)
      growth cone motility in response to targeting signals linked by the SH2/SH3
      adaptor protein Dock. Here, we show that Bifocal (Bif), a putative cytoskeletal
      regulator, is a component of the Msn pathway for regulating R cell growth cone
      targeting. bif displays strong genetic interaction with msn. Phenotypic analysis
      indicates a specific role for Bif to terminate R1-R6 growth cones. Biochemical
      studies show that Msn associates directly with Bif and phosphorylates Bif in
      vitro. Cell culture studies demonstrate that Msn interacts with Bif to regulate F
      actin structure and filopodium formation. We propose that Bif functions
      downstream of Msn to reorganize actin cytoskeleton in decelerating R cell growth
      cone motility at the target region.

PMID- 12467588
TI  - Gamma protocadherins are required for survival of spinal interneurons.
AB  - The murine genome contains approximately 70 protocadherin (Pcdh) genes. Many are
      expressed in the nervous system, suggesting that Pcdhs may specify neuronal
      connectivity. Here, we analyze the 22 contiguous genes of the Pcdh-gamma cluster.
      Individual neurons express subsets of Pcdh-gamma genes. Pcdh-gamma proteins are
      present in most neurons and associated with, but not confined to, synapses. Early
      steps in neuronal migration, axon outgrowth, and synapse formation proceed in
      mutant mice lacking all 22 Pcdh-gamma genes. At late embryonic stages, however,
      dramatic neurodegeneration leads to neonatal death. In mutant spinal cord, many
      interneurons are lost, but sensory and motor neurons are relatively spared. In
      cultures from mutant spinal cord, neurons differentiate and form synapses but
      then die. Thus, Pcdh-gamma genes are dispensable for at least some aspects of
      connectivity but required for survival of specific neuronal types.

PMID- 12467589
TI  - Adenosine: a neuron-glial transmitter promoting myelination in the CNS in
      response to action potentials.
AB  - Neuronal activity influences myelination of the brain, but the molecular
      mechanisms involved are largely unknown. Here, we report that oligodendrocyte
      progenitor cells (OPCs) express functional adenosine receptors, which are
      activated in response to action potential firing. Adenosine acts as a potent
      neuron-glial transmitter to inhibit OPC proliferation, stimulate differentiation,
      and promote the formation of myelin. This neuron-glial signal provides a
      molecular mechanism for promoting oligodendrocyte development and myelination in
      response to impulse activity and may help resolve controversy on the opposite
      effects of impulse activity on myelination in the central and peripheral nervous
      systems.

PMID- 12467590
TI  - Visual experience before eye-opening and the development of the retinogeniculate
      pathway.
AB  - Visual experience before eye-opening is not usually thought to have any
      developmental significance. Here we show that naturalistic visual stimuli
      presented through unopened eyelids robustly activate neurons in the ferret dorsal
      lateral geniculate nucleus. Further, dark-rearing prior to natural eye-opening
      has striking effects upon geniculate physiology. Receptive field maps after dark
      rearing show increased convergence of On- and Off-center responses, and neurons
      frequently respond to both bright and dark phases of drifting gratings. There is
      also increased selectivity for the orientation of the gratings. These
      abnormalities of On-Off segregation can be explained by the finding that the
      responses of immature On and Off cells to naturalistic stimuli are strongly
      anticorrelated.

PMID- 12467591
TI  - Subunit stoichiometry of the CNG channel of rod photoreceptors.
AB  - Cyclic nucleotide-gated (CNG) channels play a central role in the conversion of
      sensory stimuli into electrical signals. CNG channels form heterooligomeric
      complexes built of A and B subunits. Here, we study the subunit stoichiometry of
      the native rod CNG channel by chemical crosslinking. The apparent molecular
      weight (M(w)) of each crosslink product was determined by SDS-PAGE, and its
      composition was analyzed by Western blotting using antibodies specific for the A1
      or B1 subunit. The number of crosslink products and their M(w) as well as the
      immunological identification of A1 and B1 subunits in the crosslink products led
      us to conclude that the native rod CNG channel is a tetramer composed of three A1
      and one B1 subunit. This is an example of violation of symmetry in tetrameric
      channels.

PMID- 12467592
TI  - Rod cyclic nucleotide-gated channels have a stoichiometry of three CNGA1 subunits
      and one CNGB1 subunit.
AB  - Phototransduction relies on the precise balance of speed and sensitivity to
      achieve optimal performance. The cyclic nucleotide-gated (CNG) ion channels, with
      their Ca(2+) permeability, high sensitivity to changes in cytosolic cGMP, rapid
      gating kinetics, and Ca(2+)-calmodulin modulation, are beautifully optimized for
      their role in light detection. Many of these specializations come about from the
      heteromeric composition of the native channel, comprised of CNGA1 and CNGB1
      subunits. However, the stoichiometry and arrangement of these subunits is
      unknown. Here we have used an approach based on fluorescence resonance energy
      transfer (FRET) to determine the composition of the intact functional channel in
      the surface membrane. We find, surprisingly, that the channel contains three
      CNGA1 subunits and only one CNGB1 subunit. These results have implications for
      CNG channel function in particular and assembly of membrane proteins in general.

PMID- 12467593
TI  - Synaptotagmin I functions as a calcium sensor to synchronize neurotransmitter
      release.
AB  - To characterize Ca(2+)-mediated synaptic vesicle fusion, we analyzed Drosophila
      synaptotagmin I mutants deficient in specific interactions mediated by its two
      Ca(2+) binding C2 domains. In the absence of synaptotagmin I, synchronous release
      is abolished and a kinetically distinct delayed asynchronous release pathway is
      uncovered. Synapses containing only the C2A domain of synaptotagmin partially
      recover synchronous fusion, but have an abolished Ca(2+) cooperativity. Mutants
      that disrupt Ca(2+) sensing by the C2B domain have synchronous release with
      normal Ca(2+) cooperativity, but with reduced release probability. Our data
      suggest the Ca(2+) cooperativity of neurotransmitter release is likely mediated
      through synaptotagmin-SNARE interactions, while phospholipid binding and
      oligomerization trigger rapid fusion with increased release probability. These
      results indicate that synaptotagmin is the major Ca(2+) sensor for evoked release
      and functions to trigger synchronous fusion in response to Ca(2+), while
      suppressing asynchronous release.

PMID- 12467594
TI  - Fast and slow contrast adaptation in retinal circuitry.
AB  - The visual system adapts to the magnitude of intensity fluctuations, and this
      process begins in the retina. Following the switch from a low-contrast
      environment to one of high contrast, ganglion cell sensitivity declines in two
      distinct phases: a fast change occurs in <0.1 s, and a slow decrease over
      approximately 10 s. To examine where these modulations arise, we recorded
      intracellularly from every major cell type in the salamander retina. Certain
      bipolar and amacrine cells, and all ganglion cells, adapted to contrast.
      Generally, these neurons showed both fast and slow adaptation. Fast effects of a
      contrast increase included accelerated kinetics, decreased sensitivity, and a
      depolarization of the baseline membrane potential. Slow adaptation did not affect
      kinetics, but produced a gradual hyperpolarization. This hyperpolarization can
      account for slow adaptation in the spiking output of ganglion cells.

PMID- 12467595
TI  - Novel protein kinase A-dependent long-term depression of excitatory synapses.
AB  - Dopamine neurons of the ventral tegmental area (VTA) are critically involved in
      processing novel and rewarding information, and mediate the addictive properties
      of many drugs of abuse. Excitatory synapses on these neurons, like those in other
      brain regions, exhibit long-term depression (LTD). Amphetamine or dopamine block
      LTD at VTA synapses, indicating that both pathological and local physiological
      stimuli regulate LTD. Here we show that in common with other forms of LTD, VTA
      LTD results from a selective decrease in AMPA receptor function accompanied by a
      decrease in cell surface AMPA receptors. However, unlike the case for any
      previously described form of LTD, activation of cyclic AMP-dependent protein
      kinase (PKA) is necessary and sufficient to trigger LTD at synapses on VTA
      dopamine neurons.

PMID- 12467596
TI  - Decoding of polymodal sensory stimuli by postsynaptic glutamate receptors in C.
      elegans.
AB  - The C. elegans polymodal ASH sensory neurons detect mechanical, osmotic, and
      chemical stimuli and release glutamate to signal avoidance responses. To
      investigate the mechanisms of this polymodal signaling, we have characterized the
      role of postsynaptic glutamate receptors in mediating the response to these
      distinct stimuli. By studying the behavioral and electrophysiological properties
      of worms defective for non-NMDA (GLR-1 and GLR-2) and NMDA (NMR-1) receptor
      subunits, we show that while the osmotic avoidance response requires both NMDA
      and non-NMDA receptors, the response to mechanical stimuli only requires non-NMDA
      receptors. Furthermore, analysis of the EGL-3 proprotein convertase provides
      additional evidence that polymodal signaling in C. elegans occurs via the
      differential activation of postsynaptic glutamate receptor subtypes.

PMID- 12467597
TI  - Dynamic modification of cortical orientation tuning mediated by recurrent
      connections.
AB  - Receptive field properties of visual cortical neurons depend on the
      spatiotemporal context within which the stimuli are presented. We have examined
      the temporal context dependence of cortical orientation tuning using dynamic
      visual stimuli with rapidly changing orientations. We found that tuning to the
      orientation of the test stimulus depended on a briefly presented preceding
      stimulus, with the preferred orientation shifting away from the preceding
      orientation. Analyses of the spatial-phase dependence of the shift showed that
      the effect cannot be explained by purely feedforward mechanisms, but can be
      accounted for by activity-dependent changes in the recurrent interactions between
      different orientation columns. Thus, short-term plasticity of the intracortical
      circuit can mediate dynamic modification of orientation tuning, which may be
      important for efficient visual coding.

PMID- 12467598
TI  - Probabilistic decision making by slow reverberation in cortical circuits.
AB  - Recent physiological studies of alert primates have revealed cortical neural
      correlates of key steps in a perceptual decision-making process. To elucidate
      synaptic mechanisms of decision making, I investigated a biophysically realistic
      cortical network model for a visual discrimination experiment. In the model, slow
      recurrent excitation and feedback inhibition produce attractor dynamics that
      amplify the difference between conflicting inputs and generates a binary choice.
      The model is shown to account for salient characteristics of the observed
      decision-correlated neural activity, as well as the animal's psychometric
      function and reaction times. These results suggest that recurrent excitation
      mediated by NMDA receptors provides a candidate cellular mechanism for the slow
      time integration of sensory stimuli and the formation of categorical choices in a
      decision-making neocortical network.

PMID- 12467599
TI  - Synaptic integration by V1 neurons depends on location within the orientation
      map.
AB  - Neurons in the primary visual cortex (V1) are organized into an orientation map
      consisting of orientation domains arranged radially around "pinwheel centers" at
      which the representations of all orientations converge. We have combined optical
      imaging of intrinsic signals with intracellular recordings to estimate the
      subthreshold inputs and spike outputs of neurons located near pinwheel centers or
      in orientation domains. We find that neurons near pinwheel centers have
      subthreshold responses to all stimulus orientations but spike responses to only a
      narrow range of orientations. Across the map, the selectivity of inputs covaries
      with the selectivity of orientations in the local cortical network, while the
      selectivity of spike outputs does not. Thus, the input-output transformation
      performed by V1 neurons is powerfully influenced by the local structure of the
      orientation map.

PMID- 12467600
TI  - I feel my hand moving: a new role of the primary motor cortex in somatic
      perception of limb movement.
AB  - The primary motor cortex (MI) is regarded as the site for motor control.
      Occasional reports that MI neurons react to sensory stimuli have either been
      ignored or attributed to guidance of voluntary movements. Here, we show that MI
      activation is necessary for the somatic perception of movement of our limbs. We
      made use of an illusion: when the wrist tendon of one hand is vibrated, it is
      perceived as the hand moving. If the vibrated hand has skin contact with the
      other hand, it is perceived as both hands bending. Using fMRI and TMS, we show
      that the activation in MI controlling the nonvibrated hand is compulsory for the
      somatic perception of the hand movement. This novel function of MI contrasts with
      its traditional role as the executive locus of voluntary limb movement.

PMID- 12467602
TI  - The 2nd Unicompartmental Arthritis Meeting.

PMID- 12467601
TI  - International arthroplasty symposium incorporating the Charnley era meeting.
      Total knee arthroplasty section 27th and 28th June, 2000 Wrightington Hospital,
      Wigan, UK.

PMID- 12467603
TI  - The World Congress of Orthopaedic Sports Trauma, Gold Coast, Queensland.

PMID- 12467604
TI  - Gothenburg, Sweden: 3rd symposium of the International Cartilage Repair Society.

PMID- 12467607
TI  - Caged RNase: photoactivation of the enzyme from perfect off-state by site
      specific incorporation of 2-nitrobenzyl moiety.
AB  - Photo-triggered activation of semisynthetic Ribonuclease S' from a perfect off
      state was successfully carried out by incorporation of photo-labile caged moiety
      into a proximity to the active site.

PMID- 12467606
TI  - Antiviral activity of cyclopentenyl nucleosides against orthopox viruses
      (Smallpox, monkeypox and cowpox).
AB  - An improved method for the synthesis of enantiomerically pure D-cyclopentenyl
      nucleosides has been accomplished and their antiviral activity against orthopox
      viruses have been evaluated. The key intermediate, L-cyclopent-2-enone 13 was
      prepared from D-ribose using a ring closing metathesis reaction in eight steps.
      Among the synthesized nucleosides, the adenine 2 (Neplanocin A), cytosine 14, and
      5-F-cytosine 15 analogues exhibited potent anti-orthopox virus activity,
      including smallpox virus.

PMID- 12467608
TI  - Synthesis and antifungal activity of 2,5-disubstituted-6-arylamino-4,7
      benzimidazolediones.
AB  - 2,5-Disubstituted-6-arylamino-4,7-benzimidazolediones were synthesized and tested
      for in vitro antifungal activity against pathogenic fungi. Among them, 6
      arylamino-5-chloro-2-(2-pyridyl)-4,7-benzimidazolediones exhibited potent
      antifungal activity against Candida species and Aspergillus niger.

PMID- 12467609
TI  - True interaction mode of porcine pancreatic elastase with FR136706, a potent
      peptidyl inhibitor.
AB  - The crystal structure of porcine pancreatic elastase (PPE) complexed with a
      potent peptidyl inhibitor, FR136706, was solved at 2.2A resolution. FR136706 fits
      snugly into the extended active site pocket. The benzene moiety of FR136706
      induced dramatic movement of the side chain moiety of Arg217 and both moieties
      formed a pi-pi interaction, which has never been found previously in structures
      of PPE complexed with inhibitors. This novel interaction mode may lead to design
      of new types of inhibitors.

PMID- 12467610
TI  - Identification of a stable chymase inhibitor using a pharmacophore-Based database
      search.
AB  - In general, serine protease chymase inhibitors readily decompose in plasma. We
      previously found that thiazolidine-2,4-dione and thiadiazole derivatives are also
      unstable. Using a pharmacophore-based database search, we identified a
      benzo[b]thiophen-2-sulfonamide derivative as a stable chymase inhibitor. Finding
      a lead compound with adequate activity and stability by a pharmacophore-based
      approach is more efficient than modifying an unstable compound to reduce its
      instability without simultaneously decreasing its inhibitory activity. Our
      pharmacophore model of chymase inhibitors suggests that the two hydrophobic
      interactions in the S1 and S1' regions and the two H-bonding interactions between
      them play important roles in chymase inhibitors.

PMID- 12467611
TI  - Siphonols A-E: novel nitric oxide inhibitors from Orthosiphon stamineus of
      Indonesia.
AB  - From the methanolic extract of Orthosiphon stamineus, four novel highly
      oxygenated isopimarane-type diterpenes named siphonols A-D (1-4) and a novel
      biogenetically interesting norisopimarane-type diterpene named siphonol E (5)
      were isolated. The new compounds 1-3 and 5 showed more potent inhibitory effects
      on the nitric oxide (NO) production in lipopolysaccharide (LPS)-activated
      macrophage-like J774.1 cells than a positive control N(G)-monomethyl-L-arginine
      (L-NMMA). Siphonols A-E (1-5) represent the first examples of isopimaranes
      oxygenated at C-20.

PMID- 12467612
TI  - Synthesis and gamma-secretase activity of APP substrate-based hydroxyethylene
      dipeptide isosteres.
AB  - Two new APP substrate-based hydroxyethylene isosteres (AT and VI) were prepared
      and their dipeptide conjugates shown not to inhibit the gamma-secretase-mediated
      formation of either Abeta1-40 or Abeta1-42. The FG isostere and a des-hydroxy
      hydroxyethylene isostere also gave inactive compounds. Conversely, a number of
      compounds containing the intact substrate-unrelated Phe-Phe (FF) hydroxyethylene
      isostere were shown to be potent inhibitors (ED(50)=14-732 nM). These results
      show that the factors governing the substrate-based design of gamma-secretase
      inhibitors are more complicated than first thought.

PMID- 12467613
TI  - Homologues and isomers of noladin ether, a putative novel endocannabinoid:
      interaction with rat cannabinoid CB(1) receptors.
AB  - Two regioisomers and 13 analogues of the putative endocannabinoid noladin ether
      (2-arachidonyl glyceryl ether, 2-AGE, 1) were synthesized and tested for their
      interaction with CB(1) receptors in rat brain membranes. The results showed that
      a C-20 tetra-unsaturated moiety is necessary for high affinity, and that a series
      of alkyl glyceryl ethers of potential occurrence in brain tissues have less
      affinity than 2-AGE for CB(1) receptors.

PMID- 12467614
TI  - Comparison of library screening techniques used in the development of dsDNA
      ligands.
AB  - The gel retardation and FID (fluorescent intercalator displacement) techniques
      have been compared for the selection of dsDNA binding ligands out of library
      mixtures. The selection procedure involves the synthesis and screening of
      unnatural oligopeptide libraries based on an iterative deconvolution procedure.
      Both methods yield comparable selection results and binding constants for the
      selected compounds, meaning that they can be considered as complementary in the
      discovery process of new antigene compounds. Furthermore, a quinazolin-2,4-dione
      amino acid has been identified as possessing interesting properties for
      interaction with dsDNA.

PMID- 12467615
TI  - Structural chemistry and In vitro antitubercular activity of acetylpyridine
      benzoyl hydrazone and its copper complex against Mycobacterium smegmatis.
AB  - Acetylpyridine benzoyl hydrazone (APBH) 1 and its copper complex
      [[(APBH)CuCl](2)].(EtOH) 2 were structurally characterized by elemental analysis,
      magnetic measurements, spectroscopy, electrochemistry and single crystal X-ray
      diffraction studies. The ligand assumes Z-isomeric form and planar geometry in
      solid state, coordinating through pyridyl nitrogen, azomethine nitrogen and the
      carbonyl oxygen of the benzoyl group. The copper complex is dimeric and has a
      distorted octahedral geometry in which the two copper atoms are bridged by two
      chloride atoms. Antimycobacterial screening of ligand and its copper compound
      against Mycobacterium smegmatis shows clear enhancement in the antitubercular
      activity upon copper complexation.

PMID- 12467616
TI  - Identification of novel muscarinic M(3) selective antagonists with a
      conformationally restricted Hyp-Pro spacer.
AB  - The identification of potent and selective muscarinic M(3) antagonists that are
      based on the recently discovered triphenylpropioamide derivative, 1, and have a
      unique amino acid spacer group is described. The introduction of a hydroxyproline
      proline group to the spacer site and the use of a propyl or cyclopropylmethyl
      group as the piperidine N-substituent led to the discovery of the novel M(3)
      selective antagonists [8c, 8g; K(i)<2 nM (M(3)), M(1)/M(3)>700-fold,
      M(2)/M(3)>180-fold], which have a more rigid structure than 1.

PMID- 12467617
TI  - New tetrahydrobenzindoles as potent and selective 5-HT(7) antagonists with
      increased In vitro metabolic stability.
AB  - Chemical modifications of compound 1 (DR4004), a potent, selective antagonist of
      the 5-HT(7) receptor, were conducted with the aim of improving its metabolic
      stability. Halogenation of putative sites of oxidative metabolism afforded
      compounds 7-10, which retained high affinity and selectivity for the 5-HT(7)
      receptor, and showed increased in vitro metabolic stability. Compound 10 (DR4485)
      showed oral bioavailability, and should be a useful tool for evaluating the
      therapeutic potential of 5-HT(7) antagonists.

PMID- 12467618
TI  - Synthetic study on the unique dimeric arylpiperazine: access to the minor
      contaminant of aripiprazole.
AB  - The dimeric derivative of aripiprazole was synthesized via the two notable
      synthetic technologies as a key step: (1) efficient aldehyde bis-arylation by
      Bi(OTf)(3) and (2) facile Wynberg amination at room temperature. The synthesis
      has established the structural identity with the minor contaminant sometimes
      present in Aripiprazole.

PMID- 12467619
TI  - Rational approaches towards reversible inhibition of type B monoamine oxidase.
      Design and evaluation of a novel 5H-Indeno[1,2-c]pyridazin-5-one derivative.
AB  - The stereoelectronic properties of several potent reversible monoamine oxidase B
      (MAO-B) inhibitors were studied with a view to develop a pharmacophore model for
      reversible MAO-B inhibition. This study suggested that important specific H-bond
      and hydrophobic interactions are required for potent and selective MAO-B
      inhibition. These requirements were applied in the design and synthesis of a
      novel reversible and selective MAO-B inhibitor, 3-methyl-8-(4,4,4-trifluoro
      butoxy)indeno[1,2-c]pyridazin-5-one, that is ca. 7000 times more selective as an
      inhibitor for MAO-B than for MAO-A, with K(i(MAO-B)) in the low nanomolar range.

PMID- 12467620
TI  - Synthesis and antimalarial activity of 2-methoxyprop-2-yl peroxides derivatives.
AB  - 2-Methoxyprop-2-yl peroxides were synthesized and evaluated in vitro against
      Plasmodium falciparum. These acyclic artemisinin-related peroxides revealed
      moderate to good activity but were devoid of alkylating property towards the
      synthetic model of heme Mn(II)-TPP.

PMID- 12467621
TI  - Hepatoprotective pyrrole derivatives of Lycium chinense fruits.
AB  - As a part of our search for hepatoprotective compounds from Lycium chinense
      fruits, three new pyrrole derivatives (1-3) were isolated. These compounds and a
      related synthetic methylated compound (4) were evaluated for their biological
      activity and structure-activity relationship, and compounds 1 and 2 showed
      hepatoprotective effects comparable to silybin at the concentration of 0.1 microM
      (64.4 and 65.8%, respectively).

PMID- 12467622
TI  - Fluorescent bioprobes for visualization of puromycin-sensitive aminopeptidase in
      living cells.
AB  - Non-peptide, small-molecular, non-competitive inhibitors of puromycin-sensitive
      aminopeptidase (PSA), that is, 3-(2,6-diethylphenyl)-2,4(1H,3H)-quinazolinedione
      (PAQ-22, 3) and its 1N-methyl analogue (MPAQ-22 4), were structurally modified to
      afford fluorescent bioprobes, ANTAQ (5) and DAMPAQ-22 (6). The cellular
      localization of PSA could be visualized by the use of these fluorescent
      bioprobes.

PMID- 12467623
TI  - Design and synthesis of novel benzofurans as a new class of antifungal agents
      targeting fungal N-myristoyltransferase. Part 3.
AB  - A new series of acid-stable antifungal agents having strong inhibitory activity
      against Candida albicans N-myristoyltransferase (CaNmt) has been developed
      starting from acid-unstable benzofuranylmethyl aryl ether 2. The inhibitor design
      is based on X-ray crystallographic analysis of a CaNmt complex with aryl ether 3.
      Among the new inhibitors, pyridine derivative 8b and benzimidazole derivative 8k
      showed clear antifungal activity in a murine systemic candidiasis model.

PMID- 12467624
TI  - Design and synthesis of pseudo-symmetric HIV protease inhibitors containing a
      novel hydroxymethylcarbonyl (HMC)-hydrazide isostere.
AB  - Pseudo-symmetric HIV-1 protease inhibitors containing a novel HMC-hydrazide
      isostere as the transition-state mimic were designed and synthesized. Most of the
      synthetic compounds with varied structures at the P and P' sites around this core
      unit showed potent inhibitory activity against HIV-1 protease with nanomolar K(i)
      values.

PMID- 12467625
TI  - N,N-disubstituted piperazines: synthesis and affinities at alpha4beta2(*) and
      alpha7(*) neuronal nicotinic acetylcholine receptors.
AB  - A series of N,N-disubstituted piperazines were prepared and evaluated for binding
      to alpha4beta2(*) and alpha7(*) neuronal nicotinic acetylcholine receptors using
      rat striatum and whole brain membrane preparations, respectively. This series of
      compounds exhibited selectivity for alpha4beta2(*) nAChRs and did not interact
      with the alpha7(*) nAChRs subtype. The most potent analogues were compounds 8b
      and 8f (K(i)=32 microM). Thus, linking together a pyridine pi-system and a cyclic
      amine moiety via a piperazine ring affords compounds with low affinity, but good
      selectivity for alpha4beta2(*) nicotinic receptors.

PMID- 12467626
TI  - Structure-activity and crystallographic analysis of benzophenone derivatives-the
      potential anticancer agents.
AB  - Compounds 1-5, structurally related to combretastatin A-4 showed excellent
      cytotoxic activities against a panel of human cancer cell lines including multi
      drug resistant cell lines. The X-ray three-dimensional structural analysis shows
      that proton donor in B ring may be required for cytotoxic activity, with
      intermolecular hydrogen bonding playing an important role.

PMID- 12467627
TI  - Design of novel N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)
      guanidines as thymidine phosphorylase inhibitors, and flexible docking to a
      homology model.
AB  - A novel class of thymidine phosphorylase (TP) inhibitors has been designed based
      on analogy to the enzyme substrate as well as known inhibitors. Flexible docking
      studies, using a homology model of human TP, of the designed N-(2,4-dioxo-1,2,3,4
      tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as well as their synthetic
      precursors provide insight into the observed experimental trends in binding
      affinity.

PMID- 12467628
TI  - Development of an orexin-2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin
      B.
AB  - Investigation of L-alanine and D-amino acid replacement of orexin-B revealed that
      three L-leucine residues at the positions of 11, 14, and 15 in orexin-B were
      important to show selectivity for the orexin-2 receptor (OX(2)) over the orexin-1
      receptor (OX(1)). L-Alanine substitution at position 11 and D-leucine
      substitution at positions 14 and 15 maintained the potency of orexin-B to
      mobilize [Ca(2+)](i) in CHO cells expressing the OX(2), while their potency for
      the OX(1) was significantly reduced. In combined substitutions, we identified
      that [Ala(11), D-Leu(15)]orexin-B showed a 400-fold selectivity for the OX(2)
      (EC(50)=0.13nM) over OX(1) (EC(50)=52nM). [Ala(11), D-Leu(15)]orexin-B is a
      beneficial tool for addressing the functional roles of the OX(2).

PMID- 12467629
TI  - Design, synthesis, and biological evaluation of angiogenesis inhibitors: aromatic
      enone and dienone analogues of curcumin.
AB  - The quest to find new antitumor compounds is an ongoing research endeavor in many
      laboratories around the world. The use of small-molecule angiogenesis inhibitors
      promises to be a potentially effective method for cancer treatment and possible
      prevention. Many antiangiogenic compounds are in various stages of laboratory
      evaluations and clinical trials. Curcumin is a natural product that has exhibited
      potent antiangiogenic properties. Based on a simple pharmacophore model, using
      standard drug design concepts, aromatic enone and aromatic dienone analogues of
      curcumin were prepared and/or obtained commercially. These compounds were
      screened for antiangiogenic properties via an in vitro SVR assay and were found
      to inhibit cell proliferation.

PMID- 12467630
TI  - 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the
      arylpropylpiperidine side chains.
AB  - The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted
      pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as
      well as replacement of the benzylic methylene with sulfones, gem
      difluoromethylenes and alcohols in an effort to balance the antiviral potency
      with reasonable pharmacokinetics.

PMID- 12467631
TI  - Imidazo[4,5-b]pyridines as corticotropin releasing factor receptor ligands.
AB  - A series of high affinity CRF receptor ligands with an imidazo[4,5-b]pyridine
      core is described. Individual analogues were synthesized and tested in a rat CRF
      receptor binding assay. The best compounds were further tested in the dog N-in-1
      pharmacokinetic model to assess plasma levels at 1mg/kg (po) and in the rat
      situational anxiety model to assess anxiolytic efficacy at 3mg/kg (po). The
      structure-activity relationships for good receptor binding affinity are described
      herein.

PMID- 12467632
TI  - Imidazo[4,5-c]pyridines as corticotropin releasing factor receptor ligands.
AB  - A series of high affinity CRF receptor ligands with an imidazo[4,5-c]pyridine
      core is described. Individual analogues were synthesized and tested in vitro in
      rat brain receptors to determine binding affinity. The best compound was further
      tested in the dog N-in-1 pharmacokinetic model to assess oral bioavailability at
      1 mg/kg po.

PMID- 12467633
TI  - Structure-activity relationship of linear peptide Bu-His-DPhe-Arg-Trp-Gly-NH(2)
      at the human melanocortin-1 and -4 receptors: histidine substitution.
AB  - Systematic substitution of His(6) residue using non-selective hMC4R pentapeptide
      agonist (Bu-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2)) as the template led to
      the identification of Bu-Atc(6)(2-aminotetraline-2-carboxylic acid)-DPhe(7)
      Arg(8)-Trp(9)-Gly(10)-NH(2) which showed moderate selectivity towards hMC4R over
      hMC1R. Further SAR studies resulted in the discovery of Penta-5-BrAtc(6)-DPhe(7)
      Arg(8)-Trp(9)-Gly(10)-NH(2) and Penta-5-Me(2)NAtc(6)-DPhe(7)-Arg(8)-Trp(9)
      Gly(10)-NH(2) which are potent hMC4R agonists and are inactive in hMC1R, hMC3R
      and hMC5R agonist assays.

PMID- 12467634
TI  - 3-Acylamino-azetidin-2-one as a novel class of cysteine proteases inhibitors.
AB  - A new class of inhibitors for cysteine proteases cathepsin B, L, K and S is
      described. These inhibitors are based on the beta-lactam ring designed to
      interact with the nucleophilic thiol of the cysteine in the active site of
      cysteine proteases. Some 3-acylamino-azetidin-2-one derivatives showed very
      potent inhibition activities for cathepsins L, K and S at the nanomolar or
      subnanomolar IC(50) values.

PMID- 12467635
TI  - Studies on the synthesis and anti-Osteoporosis of estrogen-GHRPs linkers.
AB  - The linkers of estrogen-GHRPs were prepared by the combination of estradiol,
      estrone, TyrGlyGlyPheLeuOH, and TyrGlyGlyPheLeuOH. Their anti-osteoporosis effect
      was evaluated by analyzing the data, for instance the weight of the body, femur,
      femur ash, the content of calcium and phosphor in the femur, the content of
      calcium and ALP activity in the serum, obtained from the corresponding bioassay
      in vivo. The results indicated that the anti-osteoporosis potency for estradiol,
      estrone, TyrGlyGlyPheLeuOH and TyrGlyGlyPheLeuNH(2) may be totally enhanced each
      other via the corresponding linkers.

PMID- 12467636
TI  - Nodulisporic acid side-chain modifications: access to the 2", 3", 4", and 6"
      registers.
AB  - Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic
      acid (NsA) side chain are disclosed. A mild one-carbon,
      Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde
      permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded
      the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin
      isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA
      permitted a one-carbon homologation to the 6" register. These efforts identified
      new analogues with significant flea activity and illustrated the biological
      significance of unsaturation at the 1",2" register.

PMID- 12467638
TI  - Structure of the skin barrier and its modulation by vesicular formulations.
AB  - The natural function of the skin is to protect the body from unwanted influences
      from the environment. The main barrier of the skin is located in the outermost
      layer of the skin, the stratum corneum. Since the lipids regions in the stratum
      corneum form the only continuous structure, substances applied onto the skin
      always have to pass these regions. For this reason the organization in the lipid
      domains is considered to be very important for the skin barrier function. Due to
      the exceptional stratum corneum lipid composition, with long chain ceramides,
      free fatty acids and cholesterol as main lipid classes, the lipid phase behavior
      is different from that of other biological membranes. In stratum corneum
      crystalline phases are predominantly present, but most probably a subpopulation
      of lipids forms a liquid phase. Both the crystalline nature and the presence of a
      13 nm lamellar phase are considered to be crucial for the skin barrier function.
      Since it is impossible to selectively extract individual lipid classes from the
      stratum corneum, the lipid organization has been studied in vitro using isolated
      lipid mixtures. These studies revealed that mixtures prepared with isolated
      stratum corneum lipids mimic to a high extent stratum corneum lipid phase
      behavior. This indicates that proteins do not play an important role in the
      stratum corneum lipid phase behavior. Furthermore, it was noticed that mixtures
      prepared only with ceramides and cholesterol already form the 13 nm lamellar
      phase. In the presence of free fatty acids the lattice density of the structure
      increases. In stratum corneum the ceramide fraction consists of various ceramide
      subclasses and the formation of the 13 nm lamellar phase is also affected by the
      ceramide composition. Particularly the presence of ceramide 1 is crucial. Based
      on these findings a molecular model has recently been proposed for the
      organization of the 13 nm lamellar phase, referred to as "the sandwich model", in
      which crystalline and liquid domains coexist. The major problem for topical drug
      delivery is the low diffusion rate of drugs across the stratum corneum.
      Therefore, several methods have been assessed to increase the permeation rate of
      drugs temporarily and locally. One of the approaches is the application of drugs
      in formulations containing vesicles. In order to unravel the mechanisms involved
      in increasing the drug transport across the skin, information on the effect of
      vesicles on drug permeation rate, the permeation pathway and perturbations of the
      skin ultrastructure is of importance. In the second part of this paper the
      possible interactions between vesicles and skin are described, focusing on
      differences between the effects of gel-state vesicles, liquid-state vesicles and
      elastic vesicles.

PMID- 12467639
TI  - Squalene epoxidase as hypocholesterolemic drug target revisited.
AB  - Therapeutic success of statins has distinctly established inhibition of de novo
      hepatic cholesterol synthesis as an effective approach to lower plasma LDL
      cholesterol, the major risk factor for atherosclerosis and coronary heart
      disease. Statins inhibit HMG CoA reductase, a rate limiting enzyme which
      catalyses conversion of HMG CoA to mevalonic acid. However, in this process
      statins also inhibit the synthesis of several non-sterols e.g. dolichols and
      ubiquinone, which are implicated in side effects observed with statins. This
      prompted many major pharmaceutical companies in 1990s to target selective
      cholesterol synthesis beyond farnesyl pyrophosphate. The enzymes squalene
      synthetase, squalene epoxidase and oxidosqualene cyclase were identified as
      potential targets. Though inhibitors of these enzymes have been developed, till
      date no compound has been reported to have entered clinical trials. We evaluated
      the literature to understand merits and demerits of pursuing squalene epoxidase
      as a target for hypocholesterolemic drug development. Squalene epoxidase
      catalyses the conversion of squalene to 2,3-oxidosqualene. Although it has been
      extensively exploited for antifungal drug development, it has received little
      attention as a target for hypocholesterolemic drug design. This enzyme though
      recognized in the early 1970s was cloned 25 years later. This enzyme is an
      attractive step for pharmacotherapeutic intervention as it is the secondary rate
      limiting enzyme and blocking cholesterol synthesis at this step may result in
      accumulation of only squalene which is known to be stable and non toxic.
      Synthesis of several potent, orally bioavailable inhibitors of squalene epoxidase
      has been reported from Yamonuchi, Pierre Fabre and Banyu pharmaceuticals.
      Preclinical studies with these inhibitors have clearly demonstrated the potential
      of squalene epoxidase inhibitors as hypocholesterolemic agents.
      Hypochloesterolemic therapy is intended for prolonged duration and safety is an
      important determinant in clinical success. Lack of clinical trials, despite
      demonstrated preclinical efficacy by oral route, prompted us to evaluate safety
      concerns with squalene epoxidase inhibitors. In dogs, NB-598, a potent
      competitive squalene epoxidase inhibitor has been reported to exhibit signs of
      dermatitis like toxicity which has been attributed by some reviewers to
      accumulation of squalene in skin cells. Tellurium, a non-competitive inhibitor of
      squalene epoxidase has been associated with neuropathy in weanling rats. On the
      other hand, increased plasma levels of squalene in animals and humans (such as
      occurring subsequent to dietary olive oil or squalene administration) are safe
      and associated with beneficial effect such as chemoprevention and
      hypocholesterolemic activity. In our view, high circulating levels of squalene
      epoxidase inhibitor may be responsible for dermatitis and neuropathy. Competitive
      inhibition and pharmacokinetic profile minimizing circulating plasma levels (e.g.
      by hepatic sequestration and high first pass metabolism) could be important
      determinants in circumventing safety concerns of squalene epoxidase inhibitors.
      Recently, cholesterol-lowering effect of green tea has been attributed to potent
      squalene epoxidase inhibition, which can be consumed in much higher doses without
      toxicological effect. These facts strengthen optimism for developing clinically
      safe squalene epoxidase inhibitors. Put in perspective squalene epoxidase appears
      to be undervalued target which merits attention for development of better
      hypocholesterolemic drugs.

PMID- 12467640
TI  - Biosynthesis and secretion of plant cuticular wax.
AB  - The cuticle covers the aerial portions of land plants. It consists of amorphous
      intracuticular wax embedded in cutin polymer, and epicuticular wax crystalloids
      that coat the outer plant surface and impart a whitish appearance. Cuticular wax
      is mainly composed of long-chain aliphatic compounds derived from very long chain
      fatty acids. Wax biosynthesis begins with fatty acid synthesis in the plastid.
      Here we focus on fatty acid elongation (FAE) to very long chains (C24-C34), and
      the subsequent processing of these elongated products into alkanes, secondary
      alcohols, ketones, primary alcohols and wax esters. The identity of the gene
      products involved in these processes is starting to emerge. Other areas of this
      field remain enigmatic. For example, it is not known how the hydrophobic wax
      components are moved intracellularly, how they are exported out of the cell, or
      translocated through the hydrophilic cell wall. Two hypotheses are presented for
      intracellular wax transport: direct transfer of lipids from the endoplasmic
      reticulum to the plasma membrane, and Golgi mediated exocytosis. The potential
      roles of ABC transporters and non-specific lipid transfer proteins in wax export
      are also discussed. Biochemical-genetic and genomic approaches in Arabidopsis
      thaliana promise to be particularly useful in identifying and characterizing gene
      products involved in wax biosynthesis, secretion and function. The current review
      will, therefore, focus on Arabidopsis as a model for studying these processes.

PMID- 12467641
TI  - The airway goblet cell.
AB  - The two principal features of airway goblet cells are rapid secretion of mucin
      onto the airway surface and increase in number (hyperplasia) with chronic inhaled
      'insult'. The first is associated with homeostasis, the latter with
      pathophysiology. Myristoylated alanine-rich C kinase (MARCKS) is a key molecule
      regulating mucin exocytosis, a process also involving cooperative interaction
      between protein kinase (PK) C and PKG. The epidermal growth factor (EGF) cascade
      and calcium activated chloride channels (CLCA) are key signalling molecules
      involved in development of goblet cell hyperplasia, with Bcl-2, an inhibitor of
      apoptosis, involved in maintenance of hyperplasia. Goblet cell hyperplasia and
      associated mucus hypersecretion is a pathophysiological feature of asthma and
      chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies to
      prevent or reverse goblet cell hyperplasia include inhibitors of EGF receptor
      tyrosine kinase and CLCA, of which viable pharmaceutical molecules are now
      available for clinical trial in hypersecretory conditions of the airways.

PMID- 12467642
TI  - Pathological aspects of apoptosis in severe sepsis and shock?
AB  - Today, despite the application of contemporary operative/pharmacological
      approaches in the treatment of the critically ill trauma/surgery patient, we are
      still faced with a high incidence of patients who develop sepsis and subsequent
      multiple organ failure. This review attempts to summarize data gathered over the
      last few years, from both experimental and patient settings, that not only
      documents the presence of apoptosis, but begins to define its contribution to the
      pathology of sepsis and shock, which in turn precipitate organ injury/damage.

PMID- 12467643
TI  - The tail lysozyme complex of bacteriophage T4.
AB  - The tail baseplate of bacteriophage T4 contains a structurally essential, three
      domain protein encoded by gene 5 in which the middle domain possesses lysozyme
      activity. The gene 5 product (gp5) undergoes post-translational cleavage,
      allowing the resultant N-terminal domain (gp5*) to assemble into the baseplate as
      a trimer. The lysozyme activity of the undissociated cleaved gp5 is inhibited
      until infection has been initiated, when the C-terminal portion of the molecule
      is detached and the rest of the molecule dissociates into monomers. The 3D
      structure of the undissociated cleaved gp5, complexed with gp27 (another
      component of the baseplate), shows that it is a cell-puncturing device that
      functions to penetrate the outer cell membrane and to locally dissolve the
      periplasmic cell wall.

PMID- 12467644
TI  - Triplex-forming oligonucleotides as modulators of gene expression.
AB  - Triplex-forming oligonucleotides (TFOs) have gained prominence in the recent
      years because of their potential applications in antigene therapy. In particular
      they have been used as (i) inducers of site-specific mutations, (ii) reagents
      that selectively and specifically cleave target DNA, and (iii) as modulators of
      gene expression. In this mini-review, we have made an attempt to highlight the
      characteristics of these TFOs and the effects of various modifications in the
      phosphate backbone as well as in the purine and pyrimidine moieties, which
      contribute to the stability and efficiency of triplex formation. Studies to
      explore the mechanism of down-regulation of transcription of various genes
      suggest that at least some TFOs exert their effect by inhibiting binding of
      specific transcription factors to their cognate cis-acting elements. Recent
      reports indicate the presence of these potential triplex-forming DNA structures
      in the genomes of prokaryotes and eukaryotes that may play a major role in target
      site selection and chromosome segregation as well as in the cause of heritable
      diseases. Finally, some potential problems in the development of these TFOs as
      antigene therapeutic agents have also been discussed.

PMID- 12467645
TI  - Sense oligonucleotide competition for gene promoter binding and activation.
AB  - Considerable evidence has ensued on the importance of growth factors during
      regeneration both for cell replication and for stimulation of reparative cells to
      synthesize and secrete extracellular matrix components. During the healing
      process if the growth factor concentration is too high because of over
      expression, abnormal wound healing and tissue fibrosis will occur. The growth
      factor concentration at the wound site may be controlled by gene therapy and the
      titration of gene dosage. However, if there is a narrow window between the
      beneficial effects and adverse effects of gene therapy, oligonucleotide
      approaches may be used concurrently with gene therapy to control growth factor
      concentration(s) at the wound site. Antisense oligos offer a method to control
      the concentration of growth factors at the level of translation. A novel method
      using sense oligos to the proalpha1 (I) collagen gene to inhibit gene
      transcription and collagen synthesis has recently been reported. The exogenous
      modified oligodeoxynucleotide competes with the cis-element (i.e. the
      transforming growth factor-beta (TGF-beta) element) in the distal 5'-flanking
      region of the proalpha1 (I) collagen gene for the trans-acting factor (i.e. the
      TGF-beta activator protein complex), thereby down regulating promoter activity of
      the proalpha1 (I) collagen gene and inhibiting type I collagen synthesis. The
      oligonucleotide approaches, both antisense and sense therapies, may be used to
      regulate over-expression of growth factors and thereby either eliminate or lessen
      the potential adverse effects of gene therapy.

PMID- 12467646
TI  - Actin, microtubules and focal adhesion dynamics during cell migration.
AB  - Cell migration is a complex cellular behavior that results from the coordinated
      changes in the actin cytoskeleton and the controlled formation and dispersal of
      cell-substrate adhesion sites. While the actin cytoskeleton provides the driving
      force at the cell front, the microtubule network assumes a regulatory function in
      coordinating rear retraction. The polarity within migrating cells is further
      highlighted by the stationary behavior of focal adhesions in the front and their
      sliding in trailing ends. We discuss here the cross-talk of the actin
      cytoskeleton with the microtubule network and the potential mechanisms that
      control the differential behavior of focal adhesions sites during cell migration.

PMID- 12467647
TI  - Sucrose feeding effects inhibition of gamma-glutamyltranspeptidase in the liver
      of the rat: possible mediation by thyroid hormone.
AB  - The effect of sucrose on Fischer 344 rat liver gamma-glutamyltranspeptidase
      (gammaGT) was studied: in adults fed sucrose for 3 weeks; and rats exposed to
      sucrose from the 18th day of gestation to the 40th day after birth. Rats fed
      regular rodent chow served as controls. Sucrose caused mild lipemia; and in the
      liver an increase in size and fat build-up without damage. In adult sucrose-fed
      rats, compared to controls, plasma glucose levels were increased: 1.12-, 1.40-
      and 1.13-fold after 24, 48h and 3 week consumption of sucrose, respectively.
      Insulin levels were unaltered for the first week of sucrose consumption but
      increased from control levels: 16% at 1 week, and 2.0-fold at 3 weeks. The T3
      levels were comparable to control levels 24h after the sucrose was started and
      were increased: 1.22-, 1.13- and 1.12-fold at 48h, 1 and 3 weeks, respectively.
      The T4 levels were comparable at all time points between sucrose-fed and control
      rats. Liver gammaGT activity exhibited a steady decrease from control levels:
      after 24, 48h, 1 and 3 weeks of sucrose feeding the decrease was 5, 8, 21 and
      37%, respectively in homogenates; and 10, 17, 24 and 41%, respectively in plasma
      membranes. Perinatal sucrose exposure effected in 40-day-old rats, compared
      controls: a 1.09-fold increase in plasma glucose; no change in plasma insulin; an
      increase of 1.15- and 1.39-fold in plasma levels of total and free T3,
      respectively; a decrease of 20 and 14% in plasma levels of total and free T4,
      respectively. gammaGT activity was decreased in liver plasma membranes isolated
      from sucrose-exposed rats relative to those of control: 80% in the male; 82% in
      the female. Relative specific activities of gammaGT were the same in both males:
      15.4 and 16.1 in control and sucrose-exposed male rats, respectively; and
      females: 14.1 and 15.4 in control and sucrose-exposed female rats, respectively.
      gammaGT was 2-fold higher in the livers of female relative to male rats in
      sucrose-exposed and control groups. Kidney gammaGT activities were the same in
      control and sucrose-exposed rats. The involvement of T3 in the sucrose-induced
      decrease in liver gammaGT is discussed.

PMID- 12467648
TI  - Musarmins: three single-chain ribosome-inactivating protein isoforms from bulbs
      of Muscari armeniacum L. and Miller.
AB  - Three new ribosome-inactivating protein (RIP; EC 3.2.2.22) isoforms that we have
      named musarmins (MUs) 1, 2 and 3 have been isolated from the bulbs of Muscari
      armeniacum L. and Miller by ion-exchange chromatography and gel filtration.
      Analysis by electrophoresis revealed that they are single-chain proteins and mass
      spectrometry analysis afforded Mr values of 28,708, 30,003 and 27,626 for MUs 1,
      2 and 3, respectively. Musarmins strongly inhibited protein synthesis carried out
      by mammalian ribosomes, with IC50 values in the 0.14-0.24nM range but not that
      carried out by plant cell-free systems or HeLa cells. MUs promote the single
      depurination of rabbit reticulocyte 28S rRNA. cDNA cloning of genes coding for
      musarmins revealed that they contain open reading frames of 298, 294 and 295
      aminoacids for MU1, MU2 and MU3, respectively. Mature MU1, MU2 and MU3 contain
      277, 273 and 273 aminoacids, respectively suggesting post-translational C
      terminal processing. An untranslated mRNA coding for an ORF very similar to that
      of MU3 was detected in leaves. Each of the four MU genes contains an intron. In
      contrast to other RIPs, MUs are present only in bulbs and are not induced in
      leaves either by senescence, or by treatment of leaves with H2O2 or salicylic
      acid, or by growth in darkness. Therefore, these proteins could play a non-vital
      role in plants; for instance, as anti-pathogens and protective agents only in
      some stages of the plant life cycle (237).

PMID- 12467649
TI  - Development of a ponasterone A-inducible gene expression system for application
      in cultured skeletal muscle cells.
AB  - The goal of this study was to develop an inducible gene expression system to
      assess functions of specific proteins in differentiated cultured skeletal muscle.
      We utilized and modified the ecdysone inducible system because others have used
      this system to express exogenous genes in vitro and in transgenic animals. A
      limitation of the commercially-available ecdysone system is its constitutive
      expression in all tissues. Hence, its application in vivo would result in
      expression of a cloned gene in undifferentiated and differentiated tissues. To
      target its expression to muscle, we removed the constitutively-active CMV
      promoter of pVgRXR and replaced it with a skeletal muscle alpha-actin promoter so
      that the regulatory features of the system would be expressed in differentiated
      muscle cells. We transfected our newly designed expression system into L8 muscle
      myoblasts and established stable cell lines via antibiotic selection. We
      determined that reporter gene activity was induced by ponasterone A in myotubes,
      a differentiated muscle phenotype, but not in myoblasts (undifferentiated cells).
      This proved the validity of the concept of an inducible muscle-specific
      expression system. We then determined that beta-galactosidase expression was
      dependent upon the dose of ponasterone A and duration of exposure to inducer.
      This creates potential to regulate both the level of expression and duration of
      expression of a cloned gene in differentiated muscle.

PMID- 12467650
TI  - Human neutrophils isolated from peripheral blood contain Ku protein but not DNA
      dependent protein kinase.
AB  - Ku protein, a heterodimer of 70kDa (Ku70) and 86kDa (Ku86) polypeptides, is
      involved in non-homologous DNA end-joining (NHEJ) of DNA double-strand break
      repair and V(D)J recombination in combination with the catalytic component of DNA
      dependent protein kinase (p470). Although Ku protein is known to be ubiquitously
      present in eukaryotic cells, it was previously reported to be absent in mature
      neutrophils. Using a mixture of protease inhibitors in the isolation procedure of
      neutrophils from human peripheral blood, we were able to detect Ku in the
      neutrophils by immunoblot and flow-cytometric analyses. Transcripts of Ku70 and
      Ku86 genes were also detected by the reverse transcriptase-polymerase chain
      reaction (RT-PCR), and Ku protein was shown to be localized in the nucleus of
      neutrophils as a heterodimer. Like poly(ADP-ribose) polymerase-1, neither mRNA
      nor protein of p470 was detected in the neutrophils. These results suggest that
      Ku is involved independently of p470 in DNA metabolism and signal transduction.

PMID- 12467651
TI  - Finding regulatory sequences.
AB  - DNA regulatory sequences control gene expression by forming DNA-protein complex
      with specific DNA binding protein. A major task of studies of gene regulation is
      to identify DNA regulatory sequences in genome-wide. Especially with the rapid
      pace of genome project, the function of DNA regulatory sequences becomes one of
      the focuses in functional genome era. Several approaches for screening and
      characterizing DNA regulatory sequences emerged one by one, from initial low
      throughput methods to high-throughput strategies. Even though at present
      bioinformatics tools facilitate the process of screening regulatory fragments,
      the most reliable results will come from experimental test. This article
      highlights some experimental methods for the identification of regulatory
      sequences. A brief review of the history and procedures for selection methods are
      provided. Tendency as well as limitation and extension of these methods are also
      presented.

PMID- 12467652
TI  - Blood leptin homeostasis: sex-associated differences in circulating leptin levels
      in rats are independent of tissue leptin expression.
AB  - Circulating leptin levels are higher in women than in men. The aim of the study
      has been to determine in rats the putative existence of sex-associated
      differences in leptin expression in different adipose tissue depots (gonadal,
      retroperitoneal, mesenteric and inguinal white adipose tissue and interscapular
      brown adipose tissue) and the relationship with circulating leptin levels. Adult
      male and female Wistar rats acclimated to 22 degrees C or to 28 degrees C were
      used. Leptin mRNA expression was assessed by northern blot and serum leptin
      levels by enzyme-linked immunosorbent assay (ELISA). Contrary to what happens in
      humans, we report here that male rats acclimated to standard animal house
      conditions (22 degrees C) have a higher leptin concentration in blood than female
      rats. This situation cannot be explained by a greater size of the fat depots in
      males, because the adiposity index is similar in both genders, but are rather
      associated to higher leptin specific mRNA expression by the white adipose tissue.
      Around thermoneutral conditions (28 degrees C), sex related differences in leptin
      mRNA expression disappear, but the gender difference in circulating leptin levels
      remains. In addition, leptin mRNA expression is higher in both genders in
      thermoneutral conditions but this is not reflected in changes in the circulating
      leptin levels. In conclusion, this study shows that rat circulating leptin levels
      are finely regulated, and not exclusively dependent on leptin mRNA expression,
      but other mechanisms are also involved, possibly regarding leptin rate of
      degradation.

PMID- 12467655
TI  - Calcinosis--calcinogenic plants.
AB  - The calcinogenic plants are among the most noxious plants to animals in the
      world. The pathological and biochemical effects of calcinogenic plants in cattle,
      sheep, goats, pigs, horses, buffalo and laboratory animals have been determined.
      The chemical nature of the toxic agents and the precise mechanism by with the
      calcinogenic plants induces calcinosis have been defined. Most of the active
      principle present as steroidal glycoside is hydrolyzed in intestine, rumen and
      other tissues or by the bacterial flora releasing the steroidal fragment, in most
      cases 1,25(OH)(2)D(3). The excess of vitamin D stimulates CaBP synthesis and
      calcium and phosphate absorption, producing hypercalcemia and/or
      hyperphosphatemia. The excessively absorbed mineral cannot be physiologically
      accommodated, and the deposition in soft tissues results in calcinosis. The
      different means of treatment of calcinosis and control of calcinogenic plants are
      discussed with regards to their effectiveness. A number of potential uses of
      calcinogenic plants have been suggested but none has been exploited on a large
      scale. The understanding of the mechanisms involved with calcinosis contributed
      enormously to the compression of vitamin D mechanism. Research methods were
      developed and improved but a lot is to be done in this fascinating subject.

PMID- 12467656
TI  - Intra-tissue distribution of tetrodotoxin in two marine puffers Takifugu
      vermicularis and Chelonodon patoca.
AB  - Micro distribution pattern of tetrodotoxin (TTX) in several tissues of marine
      puffers Takifugu vermicularis and Chelonodon patoca was investigated by means of
      monoclonal antibody-based immunoenzymatic technique under light microscope. In
      the investigation TTX was visualized at glands in the skin of T. vermicularis,
      while in C. patoca TTX was detected in succiform cells of the skin section.
      Similarly, in the ovary section of T. vermicularis TTX was recognized at late
      peri nucleolus stage, yolk granule stage-I, and yolk granule stage-II of oocytes.
      The oocytes of late peri nucleolus stage and yolk granule stage-I showed TTX
      antigen at their nucleus and yolk vesicles, while in yolk granule stage-II TTX
      was visualized at yolk granules and yolk vesicles. In the ovary of C. patoca TTX
      was detected in the connective tissues and in the nucleus of some perinucleolar
      oocytes. In the liver and muscle of C. patoca TTX was found to be distributed in
      parenchymal hepatocytes and muscle fiber, respectively. This study, however,
      reveals that intra-tissue distribution of TTX varies in respect of species.

PMID- 12467657
TI  - Snakebite envenomation in Costa Rica: a revision of incidence in the decade 1990
      2000.
AB  - We reviewed snakebite records from the Costa Rican health system from the year
      1990-2000. During this decade, a total of 5550 snakebite cases occurred in the
      country. While the average number of snakebites per year was relatively constant
      at 504 cases, the annual incidence per 100,000 people decreased. This reduction
      is mainly due to high population growth in Costa Rica, which increased 35% during
      the study period. The most affected population lives in rural areas characterized
      by high precipitation, and mainly includes young agricultural workers. The
      lancehead Bothrops asper is considered the most important species affecting
      humans.

PMID- 12467658
TI  - Effects of the venom of a Mygalomorph spider (Lasiodora sp.) on the isolated rat
      heart.
AB  - We studied the effect of the venom of the Brazilian spider, Lasiodora sp.
      (Mygalomorphae, Theraphosidae), on force generation and electrical activity in
      the isolated rat heart. Previous work showed that this venom is excitotoxic to
      excitable cells due to Na(+) channel gating modifier activity [Toxicon 39 (2001)
      991]. In the isolated heart, the venom (10-100 microg bolus administration)
      caused a dose-dependent bradycardia, with transient cardiac arrest and rhythm
      disturbances. The electrocardiogram showed that the reduction of heart rate was
      due to sinus bradycardia, sinus arrest and partial or complete A-V block. All of
      the effects were reversible upon washout of the venom. The effect of the venom
      was potentiated by the anticholinesterase neostigmine (3.3 microM), suppressed by
      the muscarinic acetylcholine receptor antagonist atropine (1.4 microM), and
      inhibited by the vesicular acetylcholine transporter inhibitor (-)-vesamicol (10
      microM). Tetrodotoxin (200 nM) did not inhibit the effect of the venom. Together,
      these data suggest that this Lasiodora venom evokes vesicular release of
      acetylcholine from parasympathetic nerve terminals by activating tetrodotoxin
      resistant Na(+) channels.

PMID- 12467659
TI  - Ultrastructural patterns of secretory activity in poison cutaneous glands of
      larval and juvenile Dendrobates auratus (Amphibia, Anura).
AB  - A transmission electron-microscope study has been performed on larval and
      juvenile skin of the Central American arrow-frog Dendrobates auratus to
      investigate early secretory processes and maturational changes in the serous
      (poison) glands. Poison biosynthesis involves the endoplasmic reticulum (both
      smooth and rough types), as well as Golgi stacks which release early serous
      product as secretory vesicles (or pre-granules). These vesicles contain fine
      grained material, along with single electron-opaque bodies, spheroidal in shape,
      that accompany the grained product throughout its post-Gogian, maturational
      change. The first steps of this process involve condensation and lead to the
      formation of secretory granules with a glomerular-like substructure, resulting
      from a thick, random aggregation of rods (secretory granule subunits). Advanced
      maturational activity causes the loss of peculiar granule substructure: the dense
      bodies split into fragments, whereas the thick glomerular arrangement becomes
      looser, until the secretory product changes into a dispersed material. This
      ultrastructural study revealed biosynthesis and maturation processes in close
      sequence, suggesting the poison of D. auratus contains proteins and/or peptides
      as well as lipophilic compounds. Molecules of both these classes are known to
      perform several roles relevant to survival strategies in extant anurans.
      Furthermore, the ephemeral granules with a glomerular-like substructure detected
      in tadpoles and froglets exhibit the complex patterns of mature poisons in adult
      specimens of other anurans: Hylidae and related families. This agrees with
      current trends in the taxonomy of these advanced frogs and underlines the
      pertinence of an ontogenetic approach in investigating anuran phylogenesis.

PMID- 12467660
TI  - Microcystin-LR induces oxidative DNA damage in human hepatoma cell line HepG2.
AB  - Microcystins are naturally occurring hepatotoxins produced by strains of
      Microcystis aeruginosa. They are involved in promoting primary liver tumours and
      a previous study showed that they might also be tumour initiators. In this study
      we demonstrate that microcystin-LR (MCLR) at doses that were not cytotoxic (0.01
      1 microg/ml), induced dose and time dependent DNA strand breaks in human hepatoma
      cell line HepG2. These DNA strand breaks were transient, reaching a maximum level
      after 4h of exposure and declining with further exposure. In the presence of the
      DNA repair inhibitors cytosine arabinoside (AraC) and hydroxyurea (HU), together
      with MCLR, DNA strand breaks accumulated after prolonged exposure. These results
      suggest that DNA strand breaks are intermediates, produced during the cellular
      repair of MCLR induced DNA damage. Digestion of DNA with purified, oxidative DNA
      damage specific enyzmes, endonuclease III (Endo III) and formamidopyrimidine-DNA
      glycosylase (Fpg) markedly increased DNA strand breaks in MCLR treated cells,
      providing evidence that a substantial portion of the MCLR induced DNA strand
      breaks originate from excision of oxidative DNA adducts. A hydroxyl radical
      scavenger (DMSO) significantly reduced MCLR induced DNA damage. From these
      results we conclude that MCLR induces formation of reactive oxygen species that
      cause DNA damage, and that MCLR may act as an initiator of liver cancer.

PMID- 12467661
TI  - Increased plasma levels of IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha in patients
      moderately or severely envenomed by Tityus serrulatus scorpion sting.
AB  - Scorpion envenomation is a common medical problem in many countries and an
      important cause of morbidity and mortality, especially among children. The plasma
      levels of pro-inflammatory (IL-1beta, IL-6, IL-8 and TNF-alpha) and anti
      inflammatory (IL-10) cytokines were measured in individuals stung by Tityus
      serrulatus (Ts) scorpions. According to clinical manifestations patients were
      classified, as defined by the Brazilian Ministry of Health, as having mild (n=15,
      mean age=42.2 years), moderate (n=8, mean age=26 years) or severe (n=4, mean
      age=14 years) envenomation. Blood samples were taken immediately (T1) and 6h (T2)
      after admission to the hospital. Eighteen age-matched healthy volunteers were
      used as control. TNF-alpha, IL-1beta, IL-6 and IL-8 levels were significantly
      increased in moderate and severe cases and the levels of these cytokines were
      positively correlated with the severity of envenomation, as evaluated by clinical
      profile and plasma venom concentration. IL-10 levels were increased in severe and
      moderate cases and reduced in mild cases. The results reported in the present
      study suggest that the physiopathological manifestation of Ts envenomation may be
      mediated, at least in part, by cytokines, and that the early treatment after
      scorpion sting with drugs that inhibit cytokine production, such as
      glucocorticoids, may have a potential beneficial effect, ameliorating the
      severity of the clinical manifestations observed, particularly in severe and
      moderate cases.

PMID- 12467662
TI  - The impact of a low dose, low volume, multi-site immunization on the production
      of therapeutic antivenoms in Thailand.
AB  - Therapeutic antivenom against snakes was first produced by Albert Calmette in
      1894. Since then antivenoms have saved the life of countless snakebite victims.
      However, there are still many problems associated with antivenom production, for
      example variable percentage of responder horses, low neutralizing potency of
      antivenom, the large amount of snake venom needed for immunization and the
      difficulties encountered in producing potent polyvalent antivenoms. These
      problems have led to shortage and high cost of antivenom and, in some cases,
      failure of treatment. In 1997, a new immunization protocol for antivenom
      production was reported. It involves the injection of venom at low dose (approx.
      2mg/horse) emulsified in Complete Freund's adjuvant in low volume (0.1-0.2
      ml/site) in a total of 10 sites around the neck area of the horse. This
      immunization protocol has minimized the local reaction at the injection site thus
      allowing the use of the potent oil adjuvant. This, together with the increase in
      total surface area of the droplets, allow a more effective immune response to
      take place, e.g. enhancing the migration and activation of more antigen
      presenting cells and lymphocytes. The low dose, low volume multi-site
      immunization has resulted in dramatic improvements on the antivenom production in
      terms of amount of venom used for immunization, the time required to reach
      hyperimmune stage, the percent of responder horses and the potency of the
      antivenom. Furthermore, this protocol has made it possible to produce potent
      truly polyvalent antivenoms against several elapid and viperid snakes. This
      immunization protocol has alleviated various problems associated with antivenom
      production and has implications for immunization in general.

PMID- 12467663
TI  - Effects of sodium dodecyl sulfate on the conformation and hemolytic activity of
      St I and St II, two isotoxins purified from Stichodactyla helianthus.
AB  - The effect of sodium dodecyl sulfate (SDS) upon the conformation and hemolytic
      activity of St I and St II strongly depends on its concentration. At relatively
      low surfactant concentrations (ca. 0.5-5mM range) the surfactant leads to the
      formation of aggregates, as suggested by the turbidity observed even at
      relatively low (micromolar range) protein concentrations. In this surfactant
      range, the proteins show an increase in intrinsic fluorescence intensity and
      reduced quenching by acrylamide, with an almost total loss of its hemolytic
      activity. At higher surfactant concentrations the protein adducts disaggregates.
      This produces a decrease in fluorescence intensity, increase in quenching
      efficiency by acrylamide, loss of the native tertiary conformation (as reported
      by the near UV-CD spectra), and increase in alpha-helix content (as evidenced by
      the far UV-CD spectra). However, and in spite of these substantial changes, the
      toxins partially recover their hemolytic activity. The reasons for this
      recovering of the activity at high surfactant concentrations is discussed.

PMID- 12467664
TI  - Biological and immunochemical characterization of Micrurus altirostris venom and
      serum neutralization of its toxic activities.
AB  - Micrurus altirostris venom from Rio Grande do Sul State, Brazil, was
      characterized by its biological activities, immunochemical properties and
      electrophoretic pattern. The results showed a high edematogenic activity, whose
      peak was observed after 30min of venom injection, as well as a high indirect
      hemolytic activity. This venom was myotoxic, as shown by a peak of CK release at
      6h after injection, and also by the appearance of muscular lesions characterized
      by necrosis, loss of striated muscle fibers, and the presence of vacuolization,
      edema and inflammatory infiltrate. This venom showed minimum proteolytic activity
      and no hemorrhagic, dermonecrotic or coagulant activities. Nonetheless, M.
      altirostris venom presented high lethal activity. Electrophoretic patterns of
      Micrurus frontalis and M. altirostris venoms showed different protein bands. Anti
      elapidic serum could recognize M. frontalis (homologous) and M. altirostris
      (heterologous) venoms by Western blotting, and both venoms presented similar
      titers when assayed by ELISA. The results observed on neutralization tests showed
      that the anti-elapidic serum produced by Instituto Butantan neutralized myotoxic
      and hemolytic activities. However, this antivenom could not neutralize the lethal
      activity of M. altirostris venom. Thus, these data suggest that M. altirostris
      venom presents different biological, enzymatic and immunological characteristics
      from other Micrurus venoms, and some activities are not neutralized by the
      commercial anti-elapidic serum produced in Brazil.

PMID- 12467665
TI  - Purification and characterization of an anticoagulant phospholipase A(2) from
      Indian monocled cobra (Naja kaouthia) venom.
AB  - An anticoagulant, non-toxic phospholipase A(2) was isolated from the venom of
      Indian monocled cobra (Naja kaouthia) by a combination of ion-exchange
      chromatography on CM-Sephadex C-50 and gel filtration on Sephadex G-50. This
      purified protein named NK-PLA(2)-I, had a subunit molecular mass of 13.6 kDa and
      migrated as a dimer under non-reduced condition in SDS-PAGE. NK-PLA(2)-I was a
      highly thermostable protein requiring basic pH optima for its catalytic activity
      and showed preferential hydrolysis of phosphotidylcholine. This protein exhibited
      higher anticoagulant, indirect hemolysis, liver and heart tissue damaging
      activity but exerted less toxicity, direct hemolysis, edema and lung tissue
      damaging activity as compared to whole venom. Treatment of NK-PLA(2)-I with rho
      BPB, TPCK, PMSF, antivenom and heating had almost equal effect on PLA(2), and
      other pharmacological properties except in vitro tissue damaging activity.
      Current investigation provides a fairly good indication that NK-PLA(2)-I induces
      various pharmacological effects by mechanisms, which are either dependent or
      independent of its catalytic activity.

PMID- 12467666
TI  - Micronucleus induction in mussels exposed to okadaic acid.
AB  - Some toxins present in the marine environment are capable of inducing
      mutagenicity and/or carcinogenicity. Among these toxins, okadaic acid (OA) is
      gaining considerable interest since it induces DNA based modifications at low
      concentrations and accumulates in filter-feeding marine animals, including those
      used for human consumption. This study aims to evaluate the genotoxicity of OA in
      the haemocytes of the mussel Perna perna, using the micronucleus assay. Fifty
      four mussels were separated into three groups of 18 animals. One group received
      0.3 microg of OA diluted in 10 microl of ethanol and ultrapure water while the
      other groups were considered as controls and were exposed to a solvent plus
      seawater mixture. A significantly higher frequency of micronuclei was observed in
      haemocytes from the OA-exposed group. There were no statistical differences
      between the two control groups.

PMID- 12467667
TI  - Bothrops lanceolatus (Fer de lance) venom stimulates leukocyte migration into the
      peritoneal cavity of mice.
AB  - The ability of Bothrops lanceolatus venom to induce neutrophil migration into the
      peritoneal cavity of mice was investigated. Intraperitoneal injection of venom
      caused dose- and time-dependent neutrophil migration, which peaked with 750 ng of
      venom/cavity 4h after venom injection. The neutrophil migration was significantly
      reduced by pretreatment with dexamethasone (0.5 mg/kg, s.c.), an indirect
      inhibitor of phospholipase A(2) (PLA(2)), and AA861 (0.01 mg/kg, s.c.), a 5
      lipoxygenase inhibitor, but in contrast, was not modified by pretreatment with
      indomethacin (2 mg/kg, s.c.), an inhibitor of the cyclooxygenase pathway,
      meloxicam (5 mg/kg, s.c.), an inhibitor of the cyclooxygenase-2 pathway, or the
      PAF inhibitor WEB2086 (40 mg/kg, s.c.). Dexamethasone and AA861 also inhibited
      the neutrophil migration by 60% when administered immediately after venom
      injection, and the coadministration of these two drugs caused a 75% reduction in
      migration. BLV-induced neutrophil migration was not due to contamination by
      endotoxin since polymyxin B-treated venom retained its activity. Heating the
      venom (97 degrees C, 2 min) reduced the PLA(2) activity by 64% and this was
      accompanied by a corresponding reduction (68%) in neutrophil migration. These
      results suggest that arachidonate-derived lipoxygenase metabolites (possibly
      leukotriene B(4)) are involved in the chemotaxis observed. Macrophages may be an
      important source of these metabolites since the migratory response to venom was
      potentiated in mice pretreated with thioglycollate, but reduced when the
      peritoneal cavity was washed with sterile saline.

PMID- 12467668
TI  - Three polymorphic genes encoding a depressant toxin from the Egyptian scorpion
      Leiurus quinquestriatus quinquestriatus.
AB  - Four clones encoding the insect depressant toxin LqqIT2 have been isolated from
      the Egyptian scorpion Leiurus quinquestriatus quinquestriatus using RT-PCR. The
      four clones have been sequenced and their deduced amino acid sequences have been
      compared with the original amino acid sequence determined from the purified
      LqqIT2 protein and polymorphisms have been shown. This study succeeded in
      isolating more than one copy of the LqqIT2 gene, although only one amino acid
      sequence has been identified from the purified LqqIT2 toxin.

PMID- 12467669
TI  - Characterisation of the genes encoding Aa1 isoforms from the scorpion Androctonus
      australis.
AB  - Aa1 is a toxin purified from the venom of the North African scorpion Androctonus
      australis. It blocks fast K(+) currents in cerebellar granular cells [Biochim.
      Biophys. Acta 1468 (2000) 203]. Two full-length cDNAs (about 250 bp) encoding the
      precursors of putative Aa1 isoforms (AaTX1 and AaTX2) were amplified by PCR from
      a venom gland cDNA library of A. australis. The deduced precursors were composed
      of 59 amino acid residues including a signal peptide of 22 residues and a mature
      toxin of 37 residues. The peptides display 94% sequence identity with Aa1. Intron
      exon organisation of the gene corresponding to the AaTX1 cDNAs was also depicted.

PMID- 12467670
TI  - The case for eradication.

PMID- 12467671
TI  - South Africa receives cash boost to tackle AIDS.

PMID- 12467672
TI  - HIV drugs destined for Africa end up in Europe.

PMID- 12467673
TI  - Immune system stimulator shows promise against tuberculosis.

PMID- 12467674
TI  - Access denied to essential medicines in developing world.

PMID- 12467675
TI  - Research ethics fund for developing countries.

PMID- 12467680
TI  - Most US hospitals avoid reuse of single-use devices.

PMID- 12467681
TI  - Vegetarian option for biotech drugs could cut BSE risk.

PMID- 12467683
TI  - Piercing the cartilage and not the lobes leads to ear infections.

PMID- 12467686
TI  - Q fever--a forgotten disease?

PMID- 12467687
TI  - Role of proinflammatory and anti-inflammatory cytokines in the immune response to
      Plasmodium falciparum malaria.

PMID- 12467688
TI  - Pathogenesis and pathophysiology of pneumococcal meningitis.
AB  - Until the introduction of antibiotics in the 1930s and 1940s, acute bacterial
      meningitis was fatal in most cases. Since then it has become curable with a
      variable mortality and morbidity rate for individual pathogens and patients.
      Neuropathological and clinical studies have shown that a fatal outcome of the
      disease is often due to central nervous system (CNS) complications including
      cerebrovascular involvement, brain oedema formation, and hydrocephalus resulting
      in increased intracranial pressure and seizure activity. During recent years,
      experimental studies with animal models have substantially increased our
      knowledge of the interactions of bacterial pathogens with mammalian cells and
      their entry into the CNS, and the complex pathophysiological mechanisms of brain
      dysfunction during acute bacterial meningitis. There is now a substantial body of
      evidence that cytokines, chemokines, proteolytic enzymes, and oxidants are
      involved in the inflammatory cascade that leads to tissue destruction in
      bacterial meningitis. Genetic targeting and/or pharmacological blockade of these
      pathways was beneficial in experimental bacterial meningitis. Apart from
      dexamethasone, these treatment strategies hold major promise for the adjunctive
      therapy of acute bacterial meningitis in clinical practice.

PMID- 12467689
TI  - Malaria vaccines: where are we and where are we going?
AB  - Malaria is still killing over one million people each year and its incidence is
      increasing. The need for an effective vaccine is greater than ever. A major
      difficulty with vaccine research is that the malaria parasite presents thousands
      of antigens to the human immune system that vary throughout its life cycle.
      Identifying those that may prove to be vaccine targets is complicated and time
      consuming. Most vaccines are targeted at individual stages of the malaria life
      cycle, although it is likely that only the development of a multistage vaccine
      will offer complete protection to both visitors to, and residents of, a malaria
      endemic area. With the development of a successful vaccine other issues such as
      cost, distribution, education, and compliance will have to be addressed. This
      review describes some of the current vaccine candidates for immunising against
      malaria.

PMID- 12467690
TI  - Pertussis of adults and infants.
AB  - Bordetella pertussis continues to circulate even in populations where a high
      vaccine coverage of infants and children is achieved. Cases in adolescents and
      adults are reported with increasing frequency in many countries. Adults are a
      reservoir for infections in very young infants, in whom pertussis may be severe
      and life-threatening. The salient clinical feature of pertussis in adolescents
      and adults is prolonged coughing, and recognising that pertussis does occur in
      these age groups is the most important step in its diagnosis. A laboratory
      diagnosis can be made by bordetella-PCR from nasopharyngeal swabs or secretions
      and by detection of antibodies, mainly to pertussis toxin; laboratory diagnosis
      is, however, not well standardised. Vaccination of adolescents and adults is now
      possible with acellular pertussis vaccines, which are well tolerated,
      immunogenic, and effective. Adolescent boosters and the vaccination of health
      care workers are already included in vaccination calendars in some countries.
      Vaccine-recommending bodies and national health-care organisations must have
      locally relevant information on the transmission of pertussis from adults to
      infants to be able to make decisions on the advisability, feasibility, and
      priority for booster immunisation against pertussis.

PMID- 12467691
TI  - A young rash on old shoulders--scarlet fever in an adult male.

PMID- 12467692
TI  - Neurocysticercosis: an update.
AB  - Taeniosis and cysticercosis, diseases caused by the parasitic tapeworm Taenia
      solium, are distributed worldwide where pigs are eaten and sanitation is poor,
      and also in the more developed countries as a result of increasing migration.
      Neurocysticercosis is the commonest parasitic disease of the human nervous
      system. Immunological assays detect positivity for human cysticercosis in 8-12%
      of people in some endemic regions, which indicates the presence of antibodies
      against the parasite but not necessarily active or central-nervous-system
      infection. The only reliable tool for diagnosis of neurocysticercosis is imaging
      by CT or MRI. The presence of viable cysts with a mural nodule, associated with
      degenerative cysts and calcifications, is typical. Classification of
      neurocysticercosis into active, transitional, and inactive forms gives a good
      clinical-imaging correlation and facilitates medical and surgical treatment. The
      main clinical manifestations of neurocysticercosis are seizures, headache, and
      focal neurological deficits, and it can have such sequelae as epilepsy,
      hydrocephalus, and dementia. Treatment should be individually fitted for each
      patient, with antiepileptic drugs, analgesics, corticosteroids, or a combination
      of these. Anthelmintic drugs (praziquantel and albendazole) are used routinely,
      but so far no controlled clinical trial has established specific indications or
      definitive doses of treatment. Parenchymal forms of neurocysticercosis have a
      good prognosis in terms of clinical remission. The most effective approach to
      taeniosis and cysticercosis is prevention, which should be a primary public
      health focus for less developed countries.

PMID- 12467693
TI  - Chronicle of an outbreak foretold: meningococcal meningitis W135 in Burkina Faso.
AB  - Burkina Faso lies within the African meningitis belt. Until recently, serogroup A
      of Neisseria meningitidis was the most common cause of epidemic meningitis in
      Burkina Faso. However, during the epidemic that started in January 2002, W135 was
      the predominant serogroup of meningococcus. Vaccine against the W135 serogroup is
      expensive and in short supply. Strategies to react to a future African epidemic
      of W135 meningococcal meningitis with a sufficient and affordable supply of
      vaccine must be put into place now.

PMID- 12467694
TI  - Enterococcus avium splenic abscess: a rare bird.

PMID- 12467696
TI  - Baruch Blumberg--hepatitis B and beyond. Interviewed by Pam Das.

PMID- 12467699
TI  - Alive but non-infectious.

PMID- 12467702
TI  - Enoyl-CoA hydratase. reaction, mechanism, and inhibition.
AB  - Enoyl-CoA hydratase (ECH) catalyzes the second step in the physiologically
      important beta-oxidation pathway of fatty acid metabolism. This enzyme
      facilitates the syn-addition of a water molecule across the double bond of a
      trans-2-enoyl-CoA thioester, resulting in the formation of a beta-hydroxyacyl-CoA
      thioester. The catalytic mechanism of this proficient enzyme has been studied in
      great depth through a combination of kinetic, spectroscopic, and structural
      techniques, and is proposed to occur via the formation of a single transition
      state. Sequence alignment and mutagenesis studies have implicated the key
      residues important for catalysis: Gly-141, Glu-144, and Glu-164 (rat liver ECH
      numbering). The two catalytic glutamic acid residues are believed to act in
      concert to activate a water molecule, while Gly-141 is proposed to be involved in
      substrate activation. Recently, two potent inhibitors of ECH have been reported
      in the literature, which result in the irreversible inactivation of the enzyme
      via covalent adduct formation. This review summarizes studies on the structure,
      mechanism, and inhibition of ECH.

PMID- 12467703
TI  - Crystal structures of reversible ketone-Based inhibitors of the cysteine protease
      cruzain.
AB  - The crystal structures of two hydroxymethyl ketone inhibitors complexed to the
      cysteine protease cruzain have been determined at 1.1 and 1.2 A resolution,
      respectively. These high resolution crystal structures provide the first
      structures of non-covalent inhibitors bound to cruzain. A series of compounds
      were prepared and tested based upon the structures providing further insight into
      the key binding interactions.

PMID- 12467704
TI  - N-(trifluoromethyl)benzyl substituted N-normetazocines and N-norketobemidones.
AB  - To further investigate the unusual profile of N-benzyl substituted opioids, N
      trifluoromethylbenzyl normetazocines and norketobemidones were prepared. The
      introduction of trifluoromethyl substituents on the benzyl group of the (-)
      metazocines reduced affinity at all three receptors, with the greatest loss at
      kappa receptors. Surprisingly, some of the (+)-normetazocines actually possessed
      higher affinity than the corresponding (-)-isomers. In the ketobemidone series,
      the effects were different-the 4-trifluoromethyl substituted ketobemidone
      actually possessed 3-fold higher mu affinity than the unsubstituted parent to
      give a ligand with good mu affinity. In functional in vitro assays, this compound
      was a weak antagonists, but in apparent contradiction it was inactive in in vivo
      assays.

PMID- 12467705
TI  - Synthesis and antibacterial activity of 5-substituted oxazolidinones.
AB  - A series of 5-substituted oxazolidinones with varying substitution at the 5
      position of the oxazolidinone ring were synthesized and their in vitro
      antibacterial activity was evaluated. The compounds demonstrated potent to weak
      antibacterial activity. A novel compound (PH-027) demonstrated potent
      antibacterial activity, which is comparable to or better than those of linezolid
      and vancomycin against antibiotic-susceptible standard and clinically isolated
      resistant strains of gram-positive bacteria. Although the presence of the C-5
      acetamidomethyl functionality at the C-5 position of the oxazolidinones has been
      widely claimed and reported as a structural requirement for optimal antimicrobial
      activity in the oxazolidinone class of compounds, our results from this work
      identified the C-5 triazole substitution as a new structural alternative for
      potent antibacterial activity in the oxazolidinone class.

PMID- 12467706
TI  - Structure-based mutagenesis approaches toward expanding the substrate specificity
      of D-2-deoxyribose-5-phosphate aldolase.
AB  - 2-Deoxyribose-5-phosphate aldolase (DERA, EC 4.1.2.4) catalyzes the reversible
      aldol reaction between acetaldehyde and D-glyceraldehyde-3-phosphate to generate
      D-2-deoxyribose-5-phosphate. It is unique among the aldolases as it catalyzes the
      reversible asymmetric aldol addition reaction of two aldehydes. In order to
      expand the substrate scope and stereoselectivity of DERA, structure-based
      substrate design as well as site-specific mutation has been investigated. Using
      the 1.05 A crystal structure of DERA in complex with its natural substrate as a
      guide, five site-directed mutants were designed in order to improve its activity
      with the unnatural nonphosphorylated substrate, D-2-deoxyribose. Of these, the
      S238D variant exhibited a 2.5-fold improvement over the wild-type enzyme in the
      retroaldol reaction of 2-deoxyribose. Interestingly, this S238D mutant enzyme was
      shown to accept 3-azidopropinaldehyde as a substrate in a sequential asymmetric
      aldol reaction to form a deoxy-azidoethyl pyranose, which is a precursor to the
      corresponding lactone and the cholesterol-lowering agent Lipitor. This
      azidoaldehyde is not a substrate for the wild-type enzyme. Another structure
      based design of new nonphosphorylated substrates was focused on the aldol
      reaction with inversion in enantioselectivity using the wild type or the S238D
      variant as the catalyst and 2-methyl-substituted aldehydes as substrates. An
      example was demonstrated in the asymmetric synthesis of a deoxypyranose as a new
      effective synthon for the total synthesis of epothilones. In addition, to
      facilitate the discovery of new enzymatic reactions, the engineered E. coli
      strain SELECT (Deltaace, adhC, DE3) was developed to be used in the future for
      selection of DERA variants with novel nonphosphorylated acceptor specificity.

PMID- 12467707
TI  - GFP-linked zinc finger protein sp1. fluorescence study and implication for N
      terminal zinc finger 1 as hinge finger.
AB  - The N-terminal zinc finger (zf) of Sp1 is referred to as the 'hinge finger',
      which connects the C-terminal DNA binding domain with the N-terminal activation
      domain. In this study, we investigated how a green fluorescent protein (GFP)
      linked to the N-terminal zinc finger is located spatially. The fluorescence
      resonance energy transfer technique and steady-state fluorescence anisotropy
      measurements indicate the results as follows: (1) In the binding to GC-box DNA,
      the geometry of the GFP domain of the GFP-linked Sp1 zinc finger is similar to
      that of the Ala-556-->Arg mutant. (2) The GFP-linked Sp1 zinc finger is folded
      more compactly in the absence of DNA (hydrodynamic volume V=78.2 nm(3)) and
      consequently alters the conformation at the GFP domain more extensively
      (DeltaV=43.6 nm(3)) upon DNA binding than the Ala-556-->Arg mutant (99.5, 14.8
      nm(3), respectively). These results implicate that the N-terminal 'hinge finger'
      moderates various interactions of the adjacent N-terminal regulation domain with
      other transcriptional factors as well as DNA binding and is essential for the
      function of Sp1 and/or Sp/XKLF family members.

PMID- 12467708
TI  - Synthesis of new 2,4-Diaminopyrido[2,3-d]pyrimidine and 2,4-Diaminopyrrolo[2,3
      d]pyrimidine inhibitors of Pneumocystis carinii, Toxoplasma gondii, and
      Mycobacterium avium dihydrofolate reductase.
AB  - A concise new route allowing easy access to five previously unreported 2,4
      diamino-6-(substituted benzyl)pyrido[2,3-d]pyrimidines (2a-e) was developed,
      involving condensation of 2,4-dipivaloylamino-5-bromopyrido[2,3-d]pyrimidine (6)
      with an organozinc halide in the presence of a catalytic amount of [1,1'
      bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH(2)Cl(2), followed by
      removal of the pivaloyl groups with base. Also prepared via a scheme based on the
      Taylor ring expansion/ring annulation synthesis were three heretofore undescribed
      2,4-diamino-5-(substituted benzyl)-7H-pyrrolo[2,3-d]pyrimidines (3b-c). Standard
      spectrophotometric assays were used to compare the ability of 2a-e and 3b-c to
      inhibit dihydrofolate reductase (DHFR) from Pneumocystis carinii, Toxoplasma
      gondii, and Mycobacterium avium, three examples of opportunistic pathogens to
      which AIDS patients are highly vulnerable because of their immunocompromised
      state. For comparison, 13 previously untested 2,4-diamino-6-(substituted
      benzyl)quinazolines (17a-m) were also evaluated as inhibitors of these enzymes,
      as well as the enzyme from rat liver. None of the quinazolines or
      pyridopyrimidines tested was more potent against the P. carinii enzyme than the
      structurally related reference compound piritrexim (1), and none showed
      selectivity for the P. carinii enzyme over the rat enzyme. One of the
      pyridopyrimidines (2c) showed 10-fold selectivity for T. gondii versus rat DHFR,
      and two of them (2b, 2c) showed selectivity for the M. avium enzyme. However,
      this gain in species selectivity was achieved at the cost of decreased in
      potency, as has been noted with many other lipophilic DHFR inhibitors.

PMID- 12467709
TI  - 19F NMR studies of tryptophan/serum albumin binding.
AB  - 19F NMR provides direct measures of the Trp binding avidity of 'fatty acid free'
      bovine serum albumin when D- and L-6-fluorotryptophan are used as the probes.
      Both a high and low affinity binding site are present. The addition of octanoate
      either displaces the ligand from both sites or greatly decreases the affinity
      such that little binding occurs at 2 mM levels. In the case of L-6
      fluorotryptophan separate signals are observed for the high and low affinity
      binding sites and titrations with competing ligands can be used to establish the
      relative affinities of ligands at the high affinity site. Binding at this site
      appears to be hydrophobic and shape specific with L-Phe being a very poor ligand
      (K(D)[L-Phe]/K(D)[L-Trp]=800) while both GHKalphaNal and GHKW displace L-6
      fluorotryptophan from this site. In tripeptides of the general formula GHK[
      epsilon NH(CH(2))(n)(CO)W], affinity increases with tether length and binding at
      the low affinity site is restored. This NMR assay appears well-suited for the
      discovery of selective binding agents in this and other biorecognition phenomena.

PMID- 12467710
TI  - Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B
      receptors.
AB  - We have recently reported the discovery of numerous new compounds that are
      selective inhibitors of all of the subtypes of the adenosine receptor family via
      a pharmacophore database searching and screening strategy. During the course of
      this work we made the unexpected discovery of a potent A(2B) receptor antagonist,
      4-methyl-7-methoxyquinazolyl-2-(2'-amino-4'-imidazolinone) (38, CMB 6446), which
      showed selectivity for this receptor and functioned as an antagonist, with a
      binding K(i) value of 112 nM. We explored the effects of both substituent- and
      ring-structural variations on the receptor affinity in this series of
      derivatives, which were found to be mostly non-selective adenosine receptor
      ligands with K(i) values in the micromolar range. Since no enhancement of A(2B)
      receptor affinity of 38 was achieved, the previously reported pharmacophore-based
      searching strategy yielded the most potent and selective structurally-related hit
      in the database originally searched.

PMID- 12467711
TI  - Solid-phase synthesis of diamine and polyamine amino acid derivatives as HIV-1
      tat-TAR binding inhibitors.
AB  - A series of diamine and polyamine derivatives, either free amines or salts (HCl
      or TFA), of aspartic and glutamic acid were prepared in excellent yields using
      Rink Amide solid-phase synthesis. The asparagine and glutamine derivatives were
      all evaluated for their ability to inhibit Tat-TAR binding using a FIGS cellular
      assay, with the polyamine derivatives exhibiting the most promising binding
      activity.

PMID- 12467712
TI  - Three-dimensional pharmacophore hypotheses of octopamine/tyramine agonists which
      inhibit [1-14C]acetate incorporation in Plodia interpunctella.
AB  - Three-dimensional pharmacophore hypotheses were built from a set of 36 octopamine
      (OA)/tyramine (TA) agonists responsible for the inhibition of sex-pheromone
      production in Plodia interpunctella. Among the ten chemical-featured models
      generated by a program Catalyst/Hypo, hypotheses including hydrogen-bond acceptor
      (HBA), hydrogen-bond acceptor aliphatic (HBAl), hydrophobic (Hp), hydrophobic
      aromatic (HpAr) and hydrophobic aliphatic (HpAl) features were considered to be
      important and predictive in evaluating OA/TA agonists. Active agonists mapped
      well onto all the features of the hypothesis such as HBA, HBAl, Hp, HpAr and HpAl
      features. On the other hand, inactive compounds were shown to be poorly capable
      of achieving an energetically favorable conformation shared by the active
      molecules in order to fit the 3-D chemical-feature pharmacophore models. Those
      hypotheses are considered to be used in designing new leads for hopefully more
      active compounds. Further research on the comparison of models from the agonists
      may help elucidate the mechanisms of OA/TA receptor-ligand interactions.

PMID- 12467713
TI  - Structure-activity relationship studies on chalcone derivatives. the potent
      inhibition of chemical mediators release.
AB  - Some chalcones exert potent anti-inflammatory activities. 2',5'-Dialkoxychalcones
      and 2',5'-dihydroxy-4-chloro-dihydrochalcone inhibited nitric oxide (NO)
      production in lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-activated N9
      microglial cells and in LPS-activated RAW 264.7 macrophage-like cells have been
      demonstrated in our previous reports. These compounds also suppressed the
      inducible NO synthase (iNOS) expression and cyclooxygenase-2 (COX-2) activity in
      RAW 264.7 cells. In an effort to continually develop potent anti-inflammatory
      agent, a series of chalcones were prepared by Claisen-Schmidt condensation of
      appropriate acetophenones with appropriate aromatic aldehyde and then evaluated
      their inhibitory effects on the activation of mast cells, neutrophils,
      macrophages, and microglial cells. Most of the 2',5'-dihydroxychaclone
      derivatives exhibited potent inhibitory effects on the release of beta
      glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu
      Phe (fMLP)/cytochalasin B (CB). Some chalcones showed potent inhibitory effects
      on superoxide anion generation in rat neutrophils in response to fMLP/CB.
      Compounds 1 and 5 exhibited potent inhibitory effects on NO production in
      macrophages and microglial cells. Compound 11 showed inhibitory effect on NO
      production and iNOS protein expression in RAW 264.7 cells. The present results
      demonstrated that most of the 2',5'-dihydroxychaclones have anti-inflammatory
      effects. The potent inhibitory effect of 2',5'-dihydroxy-dihydrochaclones on NO
      production in LPS-activated macrophage, probably through the suppression of iNOS
      protein expression, is proposed to be useful for the relief of septic shock.

PMID- 12467714
TI  - N-, alpha-, and beta-Substituted 3-Aminopropionic acids: design, syntheses and
      antiseizure activities.
AB  - A treatment for epilepsy is proposed based on analogues of 3-aminopropionic acid
      (beta-alanine), a putative neurotransmitter in the central nervous system (CNS).
      A model three point pharmacophore was proposed based on modelling data obtained
      from the study of antagonists for both the glial gamma-aminobutyric acid (GABA)
      uptake site and the glycine co-agonist site of N-methyl-D-aspartate (NMDA)
      receptor. Three series of 3-aminopropionic acids containing, N-, alpha-, and beta
      substituents, were designed and synthesized to probe the position and the size of
      a lipophilic binding pocket within the proposed pharmacophore. These analogues
      were tested in vivo for both their antiseizure activities and their neurologic
      toxicities. Among the fourteen novel 3-aminopropionic acids synthesized, eight
      were found to have promising antiseizure activity. This study shows that
      substitution on the N-terminus confers the greatest antiseizure activity,
      particularly against pilocarpine-induced seizures.

PMID- 12467715
TI  - Coumarin, chromone, and 4(3H)-pyrimidinone novel bicyclic and tricyclic
      derivatives as antiplatelet agents: synthesis, biological evaluation, and
      comparative molecular field analysis.
AB  - As a further part of our chemical and biological studies in this field, we
      describe the multistep preparations of the properly substituted 2-(1
      piperazinyl)chromone 1b, 4-(1-piperazinyl)coumarins 5c-h, their linear benzo
      fused analogues 4a,b and 8a,b, bicyclic (15e-g) and tricyclic (15h,i) fused
      derivatives of 6-(1-piperazinyl)pyrimidin-4(3H)-one, and of the 4H-pyrido[1,2
      a]pyrimidine derivatives 9b,c. The in vitro evaluation of their inhibitory
      properties towards human platelet aggregation induced in platelet-rich plasma by
      ADP, collagen, or the Ca (2+)ionophore A23187 showed the high activity of
      compounds 5d-g and 15f,g,i, among which the coumarins 5g and 5d proved to be, in
      that order, the most effective in vitro antiplatelet agents until now synthesized
      by us. Thus, in order to consider also the 4-aminocoumarin structural class, we
      developed a new statistically significant 3-D QSAR model, more general than the
      one previously obtained, through a further CoMFA study based on the antiplatelet
      activity data and molecular steric and electrostatic potentials of both the
      previously studied and herein described compounds.

PMID- 12467716
TI  - Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of
      farnesyl protein transferase.
AB  - SCH 66336 is a trihalo tricyclic compound that is currently undergoing Phase II
      clinical trials for the treatment of solid tumors. Modifications of SCH 66336 by
      incorporating such groups as amides, acids, esters, ureas and lactams off the
      first or the distal piperidine (from the tricycle) provided potent FPT inhibitors
      some of which exhibited good cellular activity. A number of these compounds
      incorporate properties that might improve pharmacokinetic stability of these
      inhibitors by virtue of their increased solubility or by their change in log P.

PMID- 12467717
TI  - Non-classical antifolates, 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines
      and 2,4-Diamino-6(5H)-oxopyrimidines, synthesis and antitumor studies.
AB  - A series of non-classical antifolates, namely 5-(N-phenylpyrrolidin-3-yl)-2,4,6
      triaminopyrimidines (25a-i) and 2,4-diamino-(N-phenylpyrrolidin-3-yl)-6(5H)
      oxopyrimidines (26a,b,c,f,h,i) was synthesized and evaluated for their in vitro
      cytotoxicity. Reacting aniline derivatives with 1,4-dibromo-2-butanol gave 1
      phenyl-3-pyrrolidinols (19a--i), which were oxidized to pyrrolidin-3-ones (20a
      i). The Knoevenagel reaction of 20a-i with malononitrile or ethyl cyanoacetate
      gave 3-(dicyanomethylene)- (21a-i) and 3-[cyano(ethoxycarbonyl)methylene]
      pyrrolidines (22a,b,c,f,h,i), respectively, which were subsequently reduced to
      the corresponding 3-(dicyano)methyl- or 3
      [cyano(ethoxycarbonyl)methyl)]pyrrolidines (23a-i and 24a,b,c,f,h,i,
      respectively). Condensation of either 23a-i or 24a,b,c,f,h,i with guanidine
      afforded the target compounds. The cytotoxicity of these compounds was evaluated
      based on their ability to inhibit various human tumors (human colon
      adenocarcinoma COLO 205, lung carcinoma H23 and its adriamycin resistant cell
      line H23/0.3, T-cell leukemia MOLT-4, promyelocytic leukemia HL-60, and T-cell
      acute lymphocytic leukemia CCRF-CEM) cell growth in culture. These studies
      revealed that the 2,4,6-triaminopyrimidine derivatives were more cytotoxic than
      the 2,4-diamino-6(5H)-oxopyrimidine counter parts, in which the latter was
      inactive in all testing systems. The 2,4,6-triaminopyrimidine derivatives bearing
      halogen substituent on the phenyl ring (25f,h,i) were cytotoxic in all cultured
      leukemia cell growth. Among these compounds, 5-(4-fluoro and 4-chlorophenyl)
      2,4,6-triaminopyrimidines (25e and 25h, respectively) were more potent than
      methotrexate (MTX) in inhibiting of H23/0.3 cell growth. These compounds inhibit
      the folate metabolic pathways as indicated by tritium release from [5
      3H]deoxyuridine in MTX sensitive human fibrosarcoma HT-1080 cells. Dihydrofolate
      reductase is the major target for 25f,h,i, as shown by leucovorin (LV) rescue of
      MTX cytotoxicity.

PMID- 12467718
TI  - Carbohydrate-centered maleimide cluster as a new type of templates for
      multivalent peptide assembling. synthesis of multivalent HIV-1 gp41 peptides.
AB  - This paper describes a facile synthesis of carbohydrate-centered maleimide
      clusters and their application as a new type of templates for multivalent peptide
      assembling. Simultaneous introduction of multiple maleimide functionalities onto
      a carbohydrate core was achieved through the reaction of carbohydrate-based
      polyamines with methoxycarbonylmaleimide or with the N-hydroxylsuccinimide ester
      of 6-maleimidohexanoic acid. The clustered maleimides placed on the carbohydrate
      core allow rapid and highly chemoselective ligation with multiple copies of
      cysteine-containing peptides under virtually neutral conditions at room
      temperature. This mild and highly efficient ligation method is extremely valuable
      for synthesizing large and complex multivalent peptides that may not be easily
      obtained by conventional ligation methods. The usefulness of the maleimide
      clusters as a new type of templates for multivalent peptide synthesis was
      exemplified by the synthesis of two tetravalent gp41 peptides incorporating the
      sequence of the potent HIV inhibitor, T20. The synthetic multivalent gp41
      peptides are useful as novel immunogens to raise specific antibodies for HIV
      studies. They are also useful probes for studying HIV membrane fusion mechanisms.

PMID- 12467719
TI  - Image registration via level-set motion: applications to atlas-based
      segmentation.
AB  - Image registration is an often encountered problem in various fields including
      medical imaging, computer vision and image processing. Numerous algorithms for
      registering image data have been reported in these areas. In this paper, we
      present a novel curve evolution approach expressed in a level-set framework to
      achieve image intensity morphing and a simple non-linear PDE for the
      corresponding coordinate registration. The key features of the intensity morphing
      model are that (a) it is very fast and (b) existence and uniqueness of the
      solution for the evolution model are established in a Sobolev space as opposed to
      using viscosity methods. The salient features of the coordinate registration
      model are its simplicity and computational efficiency. The intensity morph is
      easily achieved via evolving level-sets of one image into the level-sets of the
      other. To explicitly estimate the coordinate transformation between the images,
      we derive a non-linear PDE-based motion model which can be solved very
      efficiently. We demonstrate the performance of our algorithm on a variety of
      images including synthetic and real data. As an application of the PDE-based
      motion model, atlas based segmentation of hippocampal shape from several MR brain
      scans is depicted. In each of these experiments, automated hippocampal shape
      recovery results are validated via manual "expert" segmentations.

PMID- 12467720
TI  - Segmentation of carpal bones from CT images using skeletally coupled deformable
      models.
AB  - The in vivo investigation of joint kinematics in normal and injured wrist
      requires the segmentation of carpal bones from 3D (CT) images, and their
      registration over time. The non-uniformity of bone tissue, ranging from dense
      cortical bone to textured spongy bone, the irregular shape of closely packed
      carpal bones, small inter-bone spaces compared to the resolution of CT images,
      along with the presence of blood vessels, and the inherent blurring of CT imaging
      render the segmentation of carpal bones a challenging task. We review the
      performance of statistical classification, deformable models (active contours),
      region growing, region competition, and morphological operations for this
      application. We then propose a model which combines several of these approaches
      in a unified framework. Specifically, our approach is to use a curve evolution
      implementation of region growing from initialized seeds, where growth is
      modulated by a skeletally-mediated competition between neighboring regions. The
      inter-seed skeleton, which we interpret as the predicted boundary of collision
      between two regions, is used to couple the growth of seeds and to mediate long
      range competition between them. The implementation requires subpixel
      representations of each growing region as well as the inter-region skeleton. This
      method combines the advantages of active contour models, region growing, and both
      local and global region competition methods. We demonstrate the effectiveness of
      this approach for our application where many of the difficulties presented above
      are overcome as illustrated by synthetic and real examples. Since this
      segmentation method does not rely on domain-specific knowledge, it should be
      applicable to a range of other medical imaging segmentation tasks.

PMID- 12467721
TI  - Irregularity index: a new border irregularity measure for cutaneous melanocytic
      lesions.
AB  - One of the important clinical features that differentiates benign melanocytic
      nevi from malignant melanomas is the irregularity of the lesion border. There are
      two types of border irregularities: texture irregularities, the small variations
      along the border, and structure irregularities, the global indentations and
      protrusions. Texture irregularities are subject to noise, whereas structure
      irregularities may suggest excessive cell growth or regression of a melanoma. We
      have designed a new algorithm for measuring the structure irregularities in the
      border. Our algorithm first locates all the local and global indentations and
      protrusions and organizes them in a hierarchical structure. Then an area-based
      index, called the irregularity index, is computed for each indentation and
      protrusion along the border. From the individual irregularity indices, two
      important new measures, the most significant irregularity index and the overall
      irregularity index are derived. These two new indices provide a measure of the
      degree of irregularity along the lesion border. A double-blinded test was
      performed to examine the effectiveness of these two new indices. Fourteen
      experienced dermatologists were asked to evaluate the borders of 40 pigmented
      lesions. The clinical evaluation result was then compared with the two new
      indices and other published shape measurements. The user study showed that both
      of the new indices vastly outperformed the other shape descriptors. Moreover, our
      algorithm captured the knowledge of expert dermatologists in analysing malignancy
      of a lesion based on its shape alone, indicating that the new measures may be
      useful for diagnosing melanomas.

PMID- 12467722
TI  - Recovering the X-ray projection geometry for three-dimensional tomographic
      reconstruction with additional sensors: attached camera versus external
      navigation system.
AB  - Three-dimensional tomographic reconstruction using intra-operative mobile C-arms
      could provide physicians with new and exciting tools for image-guided surgery.
      Recovery of the projection geometry of mobile X-ray systems is a crucial step for
      such reconstruction procedures. Recent work on medical imaging describes the use
      of optical or electro-magnetic sensor systems in order to navigate surgical
      instruments. These systems can also be used for the estimation of C-arm motion,
      and therefore for the recovery of the projection geometry of the X-ray C-arm. In
      this case, the mathematical problem that needs to be solved is equivalent to the
      hand-eye calibration well studied by both the computer vision and robotics
      community. We first study the recovery of the motion and projection geometry
      using five different hand-eye calibration methods proposed in the literature. The
      optical navigation system POLARIS from Northern Digital Inc. was used in our
      experiments. The results of the estimated motion and projection geometry using
      the five hand-eye calibration methods are compared with the same results obtained
      using an off-the-shelf CCD camera attached to the mobile C-arm. The experimental
      results include three-dimensional tomographic reconstruction results using our
      mobile C-arm. We show that even though the motion of the C-arm is more precisely
      recovered using the navigation system, the projection geometry is better
      estimated using the attached CCD camera.

PMID- 12467723
TI  - Reconstruction and web distribution of measurable arterial models.
AB  - In this paper a novel framework for the segmentation, 3D reconstruction and web
      distribution of vessel structures specifically tailored to the assessment of
      abdominal aortic aneurysms for endovascular surgery planning is presented.
      Deformable models are used for segmentation, while VRML97 and ECMA scripting are
      used to obtain models that are not only viewable from any VRML97 enabled browser,
      but that also allow users to perform, directly from standard web browsers, guided
      measurements of geometrical parameters, relevant to surgical planning.

PMID- 12467724
TI  - Detection and segmentation of drusen deposits on human retina: potential in the
      diagnosis of age-related macular degeneration.
AB  - Assessment of the risk for the development of age-related macular degeneration
      requires reliable detection and quantitative mapping of retinal abnormalities
      that are considered as precursors of the disease. Typical signs for the latter
      are the so-called drusen that appear as abnormal white-yellow deposits on the
      retina. Segmentation of these features using conventional image analysis methods
      is quite complicated mainly due to the non-uniform illumination and the
      variability of the pigmentation of the background tissue. This paper presents a
      novel segmentation algorithm for the automatic detection and mapping of drusen in
      retina images acquired with the aid of a digital Fundus camera. We employ a
      modified adaptive histogram equalization, namely the multilevel histogram
      equalization (MLE) scheme, for enhancing local intensity structures. For the
      detection of drusen in retina images, we develop a novel segmentation technique,
      the histogram-based adaptive local thresholding (HALT), which extracts the useful
      information from an image without being affected by the presence of other
      structures. We provide experimental results from the application of our technique
      to real images, where certain abnormalities (drusen) have slightly different
      characteristics from the background. The performance of the algorithm is
      established through statistical analysis of the results. This analysis indicates
      that the proposed drusen detector gives reliable detection accuracy in both
      position and mass size.

PMID- 12467726
TI  - Merosin-deficient congenital muscular dystrophy with mental retardation and
      cerebellar cysts, unlinked to the LAMA2, FCMD, MEB and CMD1B loci, in three
      Tunisian patients.
AB  - We report three Tunisian patients affected by congenital muscular dystrophy with
      mental retardation and cerebellar cysts on cranial magnetic resonance imaging.
      The clinical features were characterized by hypotonia at birth, joint
      contractures associated with severe psychomotor retardation, absence of speech,
      inability to walk in three patients, but calf hypertrophy was noted only in two
      patients. Brain magnetic resonance imaging showed several cerebellar cysts and
      vermis hypoplasia in all of the patients. Abnormality of the white matter was
      present in two patients. The pattern of gyration was normal in all cases. Serum
      creatine kinase was elevated in all three cases and their muscle biopsy showed
      dystrophic changes compatible with congenital muscular dystrophy. The
      immunohistochemical analysis of the skeletal muscle revealed partial merosin
      deficiency, more pronounced for the N-terminal antibody. Linkage analysis
      excluded congenital muscular dystrophy loci on chromosomes 6q22, 9q31, 1p32 and
      1q42. These patients constituted a particular form of congenital muscular
      dystrophy with a combination of severe motor delay, mental retardation, partial
      merosin deficiency and cerebellar cysts. Two patients showed white matter
      abnormalities on magnetic resonance imaging and hypertrophy of the calves. These
      cases, in addition to those reported previously, confirmed the large phenotypic
      variability in the group of secondary merosin deficiency congenital muscular
      dystrophy.

PMID- 12467727
TI  - Two dystrophin proteins and transcripts in a mild dystrophinopathic patient.
AB  - Two muscle dystrophin transcripts and proteins were detected in a 17-year-old boy
      with a persistently elevated serum creatine kinase level. A decreased amount of
      full-length dystrophin and a 360 kDa polypeptide lacking the COOH-terminus were
      detectable in the patient's muscle biopsy; accordingly, transcript analysis
      revealed the expression of a wild type messenger RNA together with a shorter
      frameshifted one. No genomic DNA mutation was found and the presence of a somatic
      mosaicism was excluded. This dystrophinopathy may be caused by a novel dystrophin
      gene transcriptional defect, namely aberrant intraexonic splicing.

PMID- 12467728
TI  - The dystrophin lymphocyte promoter revisited: 4.5-megabase intron, or artifact?
AB  - The human dystrophin gene has seven generally recognised promoters and one, the
      so-called lymphocyte promoter, whose status remains uncertain. We re-evaluated
      this promoter in the light of recently available human and mouse genome
      sequences, and attempted to compare its activity in lymphocytes with that of the
      muscle promoter. We find that the lymphocyte promoter lies immediately adjacent
      to the chronic granulomatous disease gene, CYBB, approximately 4.5 megabases
      upstream of dystrophin exon 2. This makes the supposed lymphocyte dystrophin
      primary transcript 7 megabases in size, with an expected transcription time in
      excess of 2 days. We also find that lymphocyte promoter use in peripheral blood
      lymphocytes is negligible compared to that of the muscle promoter in the same
      tissue. Together with the presence in the intron of a sense-strand multi-exon
      gene, and lack of conserved linkage in the mouse, we propose that the lymphocyte
      promoter is not a biologically significant part of the dystrophin gene.

PMID- 12467729
TI  - Relocalization of neuronal nitric oxide synthase (nNOS) as a marker for complete
      restoration of the dystrophin associated protein complex in skeletal muscle.
AB  - A lack of effective treatments for Duchenne muscular dystrophy, a fatal X-linked
      myopathy, has focused attention on the possibility of gene therapy. The aim of
      the gene therapy approach is the restoration of the dystrophin associated complex
      of proteins, one member of which is neuronal nitric oxide synthase, an important
      enzyme in signal transduction. Transgenic mdx mice and plasmid gene transfer of
      both human and murine recombinant dystrophins was used to assess whether nNOS
      could be restored to the sarcolemma following dystrophin gene transfer at a
      variety of levels of expression. Murine revertant fibres and human patients with
      different dystrophin deletions were used to assess the relationship between exon
      deletion and loss of neuronal nitric oxide synthase localization to the
      sarcolemma. We demonstrate that the domain encoded by exons 45-48 is required for
      localization of neuronal nitric oxide synthase to the sarcolemma. On the basis of
      these observations we suggest that neuronal nitric oxide synthase is a useful
      marker for complete restoration of the dystrophin associated complex and should
      be used as one of the criteria for selecting the recombinant molecule to be used
      for gene therapy in Duchenne muscular dystrophy.

PMID- 12467730
TI  - Down-regulation of an ankyrin repeat-containing protein, V-1, during skeletal
      muscle differentiation and its re-expression in the regenerative process of
      muscular dystrophy.
AB  - Using Western blot analysis and immunohistochemical methods, we examined the
      expression of V-1, a member of the ankyrin repeat-containing protein family,
      during differentiation and regeneration of skeletal muscle. The expression of V-1
      was high in cultured myoblasts and decreased during their differentiation into
      myotubes, while high expression was maintained when muscle differentiation was
      inhibited by treatment with basic fibroblast growth factor. Down-regulation of V
      1 also occurred during in vivo muscle differentiation from embryonic to postnatal
      stages, reaching an undetectable level in mature skeletal muscle. In contrast,
      strong V-1 immunoreactivity was detected again in myoblasts and regenerating
      muscle fibers with a small diameter, which were observed in Duchenne muscular
      dystrophy and its animal model, mdx mouse. Thus, it seems that V-1 is a good
      marker for early stage of muscle regeneration and changes of its expression
      suggest that V-1 plays a role in prenatal muscle differentiation and postnatal
      muscle regeneration.

PMID- 12467731
TI  - Syncoilin accumulation in two patients with desmin-related myopathy.
AB  - We have recently shown that syncoilin interacts with desmin in skeletal muscle
      and has a role in attaching and organising desmin filaments to the Z-lines. We
      have analysed patients with desmin accumulation and have found that syncoilin is
      both upregulated at the sarcolemma and aggregates with desmin indicating the
      presence of two distinct protein populations. Additional dystrophin-associated
      protein complex components also accumulate. The striking finding was that alpha
      dystrobrevin-1 and neuronal nitric oxide synthase (nNOS) are almost completely
      lost from the membrane of these patients indicating that the myopathy may result
      from both the abnormal accumulation of proteins and an increase in ischaemic
      injury due to the loss of nNOS. We speculate that the loss of alpha-dystrobrevin
      from the membrane, and subsequent loss of nNOS, is due to the alpha-dystrobrevin
      syncoilin-desmin interaction.

PMID- 12467732
TI  - Effect of acid maltase deficiency on the endosomal/lysosomal system and glucose
      transporter 4.
AB  - Membrane bound glycogen storage in muscle is characteristic for the lysosomal
      storage disorder acid maltase (acid alpha-glucosidase) deficiency while in
      phosphofructokinase and phosphorylase deficiency, glycogen is stored free in the
      cytoplasm. Using immunohistochemistry, we examined whether acid maltase
      deficiency had an effect on early endosomes, recycling endosomes and trans-Golgi
      network, vesicle systems linked to lysosomes. Vacuolated glycogen containing
      fibres stained intensely for the lysosomal marker lysosomal-membrane-protein-1
      within fibres and at the sarcolemma. There was a similar increase in
      immunoreactivity for markers of early endosomes (rab5), recycling endosomes
      (transferrin receptor) and the trans-Golgi network. In acid maltase deficiency,
      but not in normal muscle or other glycogenoses, staining for the insulin
      responsive glucose transporter 4 was markedly increased and partially co
      localised with all vesicular markers. Our results suggest an effect of acid
      maltase deficiency extending to various vesicle systems linked to lysosomes. The
      enzyme defect may also affect the homoeostasis of receptors cycling through these
      organelles such as glucose transporter 4.

PMID- 12467733
TI  - Early and severe presentation of X-linked myotubular myopathy in a girl with
      skewed X-inactivation.
AB  - X-linked myotubular myopathy is a severe congenital myopathy in males, caused by
      mutations in the myotubularin (MTM1) gene on chromosome Xq28. In heterozygous
      carriers of MTM1 mutations, clinical symptoms are usually absent or only mild. We
      report a 6-year-old girl presenting at birth with marked hypotonia and associated
      feeding and respiratory difficulties. A muscle biopsy performed at 5 months
      suggested a diagnosis of myotubular myopathy. On examination at 6 years she had
      marked facial weakness with bilateral ptosis and external ophthalmoplegia, severe
      axial and proximal weakness and a mild scoliosis. Muscle magnetic resonance
      imaging showed a distinctive pattern of muscle involvement. Molecular genetic
      investigation of the MTM1 gene identified a heterozygous mutation in exon 12. X
      inactivation studies in lymphocytes showed an extremely skewed pattern (97:3).
      This case emphasizes that investigation of the MTM1 gene and X-inactivation
      studies are indicated in isolated females with histopathological and clinical
      findings suggestive of myotubular myopathy.

PMID- 12467734
TI  - The phenotypic manifestations of autosomal recessive axonal Charcot-Marie-Tooth
      due to a mutation in Lamin A/C gene.
AB  - Charcot-Marie-Tooth disease constitutes a genetically heterogeneous group of
      hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot
      Marie-Tooth is designated type 2. Six loci for autosomal dominant and three for
      recessive Charcot-Marie-Tooth type 2 have been reported so far. In this study we
      report the phenotype of autosomal recessive axonal Charcot-Marie-Tooth type 2 due
      to a recently-described mutation (c.892C>T-p.R298C) in a gene encoding Lamin A/C
      nuclear envelope proteins and the first gene in which a mutation leads to
      autosomal recessive Charcot-Marie-Tooth type 2. We have explored eight patients
      from four Algerian families. The onset is usually in the second decade and the
      course is rapid, involving upper limbs and proximal muscles, leading to a severe
      condition in less than 4 years. Many different mutations in Lamin A/C have been
      identified as causing variable phenotypes, such as limb girdle muscular dystrophy
      type 1B, autosomal dominant and recessive Emery-Dreyfuss muscular dystrophy,
      dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type
      familial partial lipodystrophy should prompt us to fully investigate the skeletal
      and cardiac muscles in patients affected with autosomal recessive Charcot-Marie
      Tooth type 2 carrying a mutation in LMNA.

PMID- 12467735
TI  - Hepatitis C virus infection and myositis: a virus localization study.
AB  - We report a case of myositis associated with chronic hepatitis C virus infection.
      Muscle biopsy and immunohistochemistry showed perifascicular atrophy, few
      necrotic and regenerating fibres, scarce perivascular infiltrates, deposits of
      immunoglobulin G, C3, fibrinogen and MAC in muscle vessel walls, and non-uniform
      expression of major histocompatibility complex-I antigens among muscle fibres.
      Hepatitis C virus NS3 antigen and hepatitis C virus RNA were detected in
      infiltrating cells but not within muscle fibres or endothelial cells. Our
      findings suggest that humoral-mediated immune mechanisms, not directly related to
      hepatitis C virus infection of muscle structures, may sustain the local
      inflammatory reaction in this patient.

PMID- 12467736
TI  - Report of the 95th European Neuromuscular Centre (ENMC) sponsored international
      workshop cognitive impairment in neuromuscular disorders, Naarden, The
      Netherlands, 13-15 July 2001.

PMID- 12467737
TI  - The 105th ENMC sponsored workshop: pathogenesis in the non-sarcoglycan limb
      girdle muscular dystrophies, Naarden, April 12-14, 2002.

PMID- 12467738
TI  - What is Davidenkov's scapuloperoneal amyotrophy: is it a myopathic entity or a
      neurogenic syndrome? What was Davidenkov's opinion concerning this knotty
      problem?

PMID- 12467745
TI  - An evaluation of leukaemia inhibitory factor as a potential therapeutic agent in
      the treatment of muscle disease.
AB  - The exogenous delivery of growth factors and cytokines is a potential therapeutic
      strategy to alleviate the degenerative effects of primary inherited myopathies
      such as Duchenne muscular dystrophy. The mdx mouse diaphragm is a model for
      examining the progressive degeneration of dystrophic muscle. We have delivered
      leukaemia inhibitory factor to the mdx diaphragm using slow release alginate
      gels. Previous studies have reported an improvement in the histology of mdx
      diaphragms after delivery of leukaemia inhibitory factor in a similar manner, but
      little attention has been paid to the mechanism by which leukaemia inhibitory
      factor acts. We have used autoradiography to examine cell proliferation, Evans
      Blue Dye to examine myofibre damage, and morphometric analysis to examine
      histology in leukaemia-inhibitory-factor-treated diaphragms and compared them
      with untreated mdx and normal C57Bl10/ScSn diaphragms. Autoradiography showed
      that although myoblast proliferation was significantly increased in leukaemia
      inhibitory factor-treated mdx diaphragms, leukaemia inhibitory factor did not
      reduce myofibre damage and no histological improvement was observed. The data
      presented here, while demonstrating a role for leukaemia inhibitory factor in
      myoblast proliferation, do not support a strong and consistent benefit of
      leukaemia inhibitory factor on dystrophic muscle in vivo as a means of
      alleviating the effects of chronic dystrophic muscle degeneration.

PMID- 12467746
TI  - High dose weekly oral prednisone improves strength in boys with Duchenne muscular
      dystrophy.
AB  - Daily prednisone improves strength in boys with Duchenne muscular dystrophy, but
      side effects are almost universal. We used a different dosing regimen of
      prednisone to determine if benefit to boys with Duchenne muscular dystrophy might
      be maintained with fewer side effects. Twice weekly oral prednisone was given
      each Friday and Saturday (5mg/kg/dose). This total dose is twice as high as the
      daily low dosage prednisone regimen (0.75 mg/kg/day). Twenty boys (8.0+/-1.2
      years) were treated. Historical control groups included 18 untreated boys (6.1+/
      1.6 years) and four boys (7.3+/-0.6 years) treated with daily prednisone.
      Strength (using a hand-held manometer and grip meter) and timed functional
      testing were measured. There was an improvement in upper extremity strength for
      95% of boys (n=20) at 6 months using quantitative strength testing. Improvement
      in lower extremity strength occurred in all boys with antigravity quadriceps
      strength (17/17). The improvement (P=0.001 for proximal upper extremities;
      P=0.002 for grip; and P<0.0001 for proximal lower extremities) was significant
      compared to untreated boys. Sixteen boys were treated continuously for more than
      12 months (22+/-1.5 months). Of these, 15 remained significantly stronger than
      prior to treatment and 8/16 showed additional gains in strength after six months
      of treatment. Six boys were on the weekly prednisolone 2 years or longer without
      interruption. All six had upper and lower extremity strength at follow-up that
      was as good or better than at baseline. Functional testing improved in boys less
      than 8 years without contractures. Three boys without antigravity quadriceps
      strength at the start of treatment lost the ability to walk unassisted within 6
      months. Eight other boys lost the ability to ambulate unassisted between 12 and
      24 months of treatment. In each, progressive contractures developed. Linear
      growth was maintained in all boys on weekly treatment. Obesity rates did not
      differ from untreated boys. Twice weekly prednisone improved strength over 6-12
      months in the majority of boys, but did not slow contracture development.
      Sustained benefit beyond 12 months is possible with fewer side effects compared
      to daily prednisone.

PMID- 12467747
TI  - Survival in Duchenne muscular dystrophy: improvements in life expectancy since
      1967 and the impact of home nocturnal ventilation.
AB  - We reviewed the notes of 197 patients with Duchenne muscular dystrophy whose
      treatment was managed at the Newcastle muscle centre from 1967 to 2002, to
      determine whether survival has improved over the decades and whether the impact
      of nocturnal ventilation altered the pattern of survival. Patients were grouped
      according to the decade of death and whether or not they were ventilated. Kaplan
      Meier survival analyses showed significant decade on decade improvement in
      survival. Mean age of death in the 1960s was 14.4 years, whereas for those
      ventilated since 1990 it was 25.3 years. Cardiomyopathy significantly shortened
      life expectancy from 19 years to a mean age of 16.9 years. Better coordinated
      care probably improved the chances of survival to 25 years from 0% in the 1960s
      to 4% in the 1970s and 12% in the 1980s, but the impact of nocturnal ventilation
      has further improved this chance to 53% for those ventilated since 1990.

PMID- 12467748
TI  - The spectrum of pathology in central core disease.
AB  - Central core disease is a congenital myopathy with muscle weakness defined
      pathologically by the presence of extensive areas in muscle fibres that are
      devoid of oxidative enzyme activity. The gene responsible has been shown to be
      the ryanodine receptor 1 on chromosome 19q13 and mutations have now been
      identified in several patients. Some cases with the morphological defect remain
      molecularly undefined, particularly those studied before molecular studies were
      available. We have studied three families with congenital onset, each with a
      dominantly inherited mutation in a C-terminal exon of the ryanodine receptor 1.
      They illustrate the spectrum of pathology that can be observed in patients with
      the myopathic features of central core disease. We show that extensive fibrosis
      and fat may be present, type 1 fibre uniformity may occur in the absence of
      cores; cores may be central or peripheral, single or multiple; and that an
      appearance of multiple focal minicores might cause a diagnostic pathological
      dilemma. In addition, we show the value of immunocytochemistry in identifying
      cores, in particular the use of antibodies to desmin and gamma-filamin.

PMID- 12467749
TI  - Genotype-phenotype correlations in X-linked myotubular myopathy.
AB  - X-linked myotubular myopathy is a severe congenital myopathy that presents in the
      neonatal period with profound hypotonia and an inability to establish spontaneous
      respiration. Usually death occurs in infancy from respiratory failure. However,
      there is phenotypic variability; a number of affected boys have achieved
      respiratory independence and become ambulatory. Disease-causing mutations have
      been identified throughout the MTM1 gene on Xq28. MTM1 encodes the protein
      myotubularin, which is expressed ubiquitously. The main objectives of this study
      were to establish whether the nature or site of the mutation in the MTM1 gene
      could predict severity of the disease and to investigate whether early intensive
      clinical intervention facilitated survival until spontaneous improvement
      occurred. An association was demonstrated between the presence of a non
      truncating mutation of the MTM1 gene and the mild phenotype. However, many non
      truncating mutations were also seen in association with the severe phenotype and
      these were not confined to recognized functional domains of the protein. This
      suggests that the use of mutation analysis to predict prognosis in the early
      period following diagnosis is limited. Unexpectedly, over 50 patients surviving
      for more than 1 year were identified in this study. Further information obtained
      on 40 of these cases revealed that 50% were receiving 24-h ventilatory support,
      while 27% were ventilated at night only. The high survival rate for this disorder
      therefore reflects intensive medical intervention without which the majority of
      these boys would not survive.

PMID- 12467750
TI  - De novo missense mutation in a constitutively expressed exon of the slow alpha
      tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline
      myopathy.
AB  - We describe an atypical case of nemaline myopathy with an unusual distribution of
      muscle weakness who presented at 14 years of age with kyphoscoliosis. In this
      patient, we demonstrate heterozygosity for a de novo CGT-CAT (Arg167His) mutation
      in a constitutively expressed exon (exon 5) of slow alpha-tropomyosin (TPM3).
      This is the first mutation identified in a constitutively expressed exon of TPM3
      in a nemaline myopathy patient, but is similar to recently described mutations in
      beta-tropomyosin (TPM2) associated with nemaline myopathy and mutations in fast
      alpha-tropomyosin (TPM1) which cause hypertrophic cardiomyopathy.

PMID- 12467751
TI  - Skeletal muscle of mice with a mutation in slow alpha-tropomyosin is weaker at
      lower lengths.
AB  - Skeletal muscle function was measured in anaesthetised transgenic mice having a
      mutation in the TPM3 gene (slow alpha-tropomyosin), a similar mutation as found
      in some patients with nemaline myopathy, and was compared with control muscles.
      Measurements of isometric and dynamic muscle performance were done with
      electrical nerve stimulation at physiological temperatures. No muscle weakness
      was found in the transgenic muscles when performance was measured at muscle
      optimum length. This was true not only with full activation but also at lower
      activation levels, indicating that calcium sensitivity was not affected at this
      length. Also, fatigability was not affected in these conditions. However,
      isometric force of the muscles with the mutation in TPM3 was lower at lengths
      below optimum, with more impairment at decreasing length. As the muscles are
      active over a large range of different muscle lengths during daily activities,
      this finding may explain, at least in part, the muscle weakness experienced by
      patients with nemaline myopathy.

PMID- 12467752
TI  - Frequent low penetrance mutations in the Lamin A/C gene, causing Emery Dreifuss
      muscular dystrophy.
AB  - Emery Dreifuss muscular dystrophy is a genetically heterogeneous disorder
      characterized by the clinical triad of early onset contractures, progressive
      muscular wasting and weakness with humeroperoneal distribution and cardiac
      conduction defects. Mutations in the Lamin A/C (LMNA) gene are responsible for
      the autosomal dominant and the autosomal recessive forms. Familiar and sporadic
      patients carrying mutations in the LMNA gene show high variability in the
      clinical symptomatology and age of onset. In this report, we describe four
      families harboring missense mutations in the LMNA gene and we show that the
      effect of mutations ranges from silent to fully penetrant. We suggest that
      incomplete penetrance of dominant mutations in the LMNA gene is a common feature
      and we emphasize the significance of mutational analysis in relatives of sporadic
      cases of laminopathies, as asymptomatic carriers face high risk of sudden cardiac
      death.

PMID- 12467753
TI  - Limb-girdle myasthenia: clinical, electrophysiological and morphological features
      in familial and autoimmune cases.
AB  - Limb-girdle myasthenia is an uncommon disease and includes familial and
      autoimmune forms. Patients present proximal muscle weakness and wasting, and
      sometimes fatigability, without cranial nerve involvement and fluctuations. We
      observed, during a 15-year period, nine subjects with limb-girdle myasthenia, (24
      55 years; 8 males, 1 female) who constituted 3.2% of 281 myasthenic patients
      attending our department. All had previously received a diagnosis different from
      myasthenia. Diagnosis of limb-girdle myasthenia was established by clinical,
      muscle biopsy and electrophysiological assessment including repetitive nerve
      stimulation and single fiber electromyography. Five patients had the familial
      form with tubular aggregates in skeletal muscle; four patients had the autoimmune
      form. Patients with the familial form had a good response to acetylcholinesterase
      inhibitors, and the patients with the autoimmune form responded to immunotherapy.
      Our findings reinforce the opportunity to suspect limb-girdle myasthenia in
      unclassifiable proximal myopathies and to differentiate familial from autoimmune
      cases, especially for therapeutic implications.

PMID- 12467754
TI  - Workshop: management of adults and children with feeding difficulties secondary
      to chronic muscle disease, 22nd March 2002, Sheffield, UK.

PMID- 12467755
TI  - Report on the muscular dystrophy campaign workshop: exercise in neuromuscular
      diseases Newcastle, January 2002.

PMID- 12467756
TI  - Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th
      ENMC international workshop, 23-24 November 2001, Naarden, The Netherlands.

PMID- 12467760
TI  - Apparent lack of trans-dominant negative effects of various vif mutants on the
      replication of HIV-1.
AB  - The vif gene of human immunodeficiency virus type 1 (HIV-1) is essential for
      virus growth in non-permissive cells such as H9. To elucidate the mechanism of
      action of the Vif protein, vif mutants, which show trans-dominant negative
      effects on the replication of HIV-1, would be useful tools. In this study, a new
      assay system to identify the mutants of this category was established. For this
      new system, various reporter clones carrying both mutant and authentic vif
      sequences were generated. By determining the growth ability of the viruses
      derived from the reporter constructs, the potential negative effect of the mutant
      vif sequence was readily and sensitively monitored. Ten vif mutant sequences
      tested were found not to exert the trans-dominant negative effect on the
      replication of HIV-1.

PMID- 12467761
TI  - Reactivity of serum samples from patients with a flavivirus infection measured by
      immunofluorescence assay and ELISA.
AB  - Flavivirus infections are a significant public health problem, since several
      members of the Flaviviridae family are highly pathogenic to humans. Accurate
      diagnosis and differentiation of the infecting virus is important, especially in
      areas where many flaviviruses are circulating. In this study we evaluated a newly
      developed commercially available immunofluorescence assay (IFA) (INDX, Baltimore,
      MD, USA) for the detection of IgM and IgG antibodies against dengue virus, yellow
      fever virus, Japanese encephalitis virus and West Nile virus. IFA was compared
      with standard diagnostic enzyme immunoassays (EIAs) specific for the detection of
      IgM and IgG antibodies against these viruses. Forty-seven serum samples from
      patients with a defined flavivirus infection were tested. As controls, serum
      samples from individuals with antibodies against tick-borne encephalitis virus
      and hepatitis C virus as well as healthy individuals were included. The results
      obtained from this study indicate that IFA showed a significantly better
      discrimination for flavivirus specific IgM antibodies than did the standard IgM
      specific EIAs (the overall cross-reactivity varied between 4 and 10% by IFA and
      30-44% by EIA for the respective viruses). In contrast, the detection of
      flavivirus specific IgG antibodies showed high cross-reactions in both IFA and
      EIAs (overall cross-reactivity 16-71 and 62-84%, respectively). This study
      clearly stated the complexity of flavivirus diagnosis, showing that one cannot
      rely on one assay or search for one virus only. The flavivirus IFA is a useful
      tool for the identification of flavivirus infections during the acute stage of
      disease. In particular, IFA can be an important diagnostic tool for testing
      samples from travellers who have been accidentally exposed to these viruses.

PMID- 12467763
TI  - Global epidemiology and burden of hepatitis C.
AB  - Despite rapid progress in our knowledge of hepatitis C virology and pathogenesis,
      little is known about the current and future burden of this infection throughout
      the world. Prevalence and population-based studies have suggested that
      complications of the liver disease associated with chronic hepatitis C infection
      may potentially require substantial health care resources and generate very high
      costs for medical systems in the United States, Europe and worldwide. Careful
      understanding and assessment of hepatitis C health and economic burdens are
      likely to guide better programs for the management of infected individuals and
      the prevention of complications.

PMID- 12467764
TI  - Current and future hepatitis C virus diagnostic testing: problems and
      advancements.
AB  - Serological antibody assays used in hepatitis C virus diagnosis have improved in
      sensitivity and specificity. However, detection of active viremia or monitoring
      levels of virus during or after patient treatment is most commonly undertaken
      using nucleic acid-based technologies. Advancements in diagnostic technologies
      and implications for managing patients with hepatitis C in various clinical
      settings are discussed.

PMID- 12467765
TI  - Advances in therapy for hepatitis C infection.
AB  - The first approved therapy for chronic hepatitis C virus (HCV) infection was
      recombinant interferon. Subsequently, controlled studies demonstrated that the
      combination of interferon-alpha and ribavirin leads to significantly higher
      virologic sustained responses in patients with chronic hepatitis C. A novel
      modification of the interferon molecule resulted in the formulation of pegylated
      interferons, which have a longer half-life than standard interferon. Two recent
      trials have established the superiority of pegylated interferons compared with
      interferon-alpha in inducing sustained virologic responses in patients with
      chronic HCV infection, with or without cirrhosis. Presumably, pegylated
      interferons will replace standard interferon in treating HCV infection. Phase 3
      trials of pegylated interferons in combination with ribavirin are currently under
      way. Noninterferon-based therapies for the treatment of HCV infection are also in
      the developmental and experimental phases. Our aims in this review are to present
      the currently available therapeutic options for HCV infection and the evidence
      supporting their use in typical patients with chronic hepatitis C or in patients
      with special circumstances. We also briefly review novel therapeutic approaches,
      including noninterferon-based therapies.

PMID- 12467766
TI  - Hepatitis C in the setting of HIV co-infection.
AB  - Hepatitis C virus (HCV) co-infection is common among HIV-infected individuals and
      can lead to increased morbidity and mortality in this population. HIV adversely
      impacts the natural history of HCV disease with higher rates of liver disease
      progression but the effect of HCV on the natural history of HIV is disputed.
      Additionally, presence of HCV may decrease tolerability of highly active
      antiretroviral regimens for HIV treatment due to a potential increase in
      hepatotoxicity. Currently there is limited information available regarding HCV
      therapy in the setting of HIV co-infection but the HCV virologic response to
      interferon regimens appears to be similar to those individuals with HCV infection
      alone. However, additional information is required to assess the efficacy and
      safety of HCV therapy including possible interaction of HCV and HIV anti-viral
      medications in these co-infected individuals.

PMID- 12467767
TI  - Hepatitis C in the liver transplant recipient: current understanding and
      treatment.
AB  - Hepatitis C virus (HCV)-related liver disease is the leading indication for
      orthotopic liver transplantation worldwide. Recurrent HCV infection as defined by
      viremia after transplantation is nearly universal, with histologic evidence of
      recurrent hepatitis present in the majority. Although short-term survival appears
      to be similar to that in other causes of liver failure, it has recently been
      demonstrated that approximately 20-30% of HCV-positive patients develop allograft
      cirrhosis by 5 years. Therefore, it is possible to define disease outcomes within
      a relatively short period of follow-up. Identification of patients who are likely
      to develop progressive HCV-related allograft injury is important to optimize
      results of current antiviral therapy.

PMID- 12467768
TI  - Neutrophil elastase-mediated killing of bacteria: lessons from targeted
      mutagenesis.
AB  - Engineering of mice deficient in neutrophil elastase (NE) has allowed us to
      demonstrate the role of this protease in host defense against bacteria and to
      begin to understand its killing mechanism. Strategies to inhibit NE because of
      its involvement in tissue-destructive diseases should be reconsidered, while
      preserving its beneficial properties.

PMID- 12467769
TI  - Interactions between malaria and HIV infection-an emerging public health problem?
AB  - Recent evidence demonstrates interactions between malaria and HIV infection. HIV
      infected people are more likely to experience clinical malaria, and acute malaria
      can up-regulate HIV replication, leading to higher plasma viral loads. This is
      most serious in pregnant women, where HIV infection increases the risk of
      placental malaria, leading to increased infant morbidity and mortality.

PMID- 12467770
TI  - Anaerobic infections in children.
AB  - Anaerobic bacteria can cause a variety of endogenous infections in children.
      Because of their fastidious nature, they are difficult to isolate from infectious
      sites, and are often overlooked. Anaerobic infections can occur in all body
      sites, including the central nervous system, oral cavity, head and neck, chest,
      abdomen, pelvis, skin, and soft tissues. They colonize the newborn after delivery
      and have been recovered from several types of neonatal infections. These include
      cellulitis of the site of fetal monitoring, neonatal aspiration pneumonia,
      bacteremia, conjunctivitis, omphalitis, and infant botulism. The lack of adequate
      therapy may lead to clinical failures. Their isolation requires appropriate
      methods of collection, transportation and cultivation of specimens. Treatment is
      complicated by their slow growth, their polymicrobial nature and their growing
      resistance to antimicrobials. Antimicrobial therapy is often the only form of
      therapy required, whereas in others it is an important adjunct to a surgical
      approach. Because anaerobes are generally recovered mixed with aerobic organisms,
      the choice of antimicrobial agents should provide coverage of both types of
      pathogens.

PMID- 12467772
TI  - Clinical virology in real time.
AB  - The ability to detect nucleic acids has had and still has a major impact on
      diagnostics in clinical virology. Both quantitative and qualitative techniques,
      whether signal or target amplification based systems, are currently used
      routinely in most if not all virology laboratories. Technological improvements,
      from automated sample isolation to real time amplification technology, have given
      the ability to develop and introduce systems for most viruses of clinical
      interest, and to obtain clinical relevant information needed for optimal
      antiviral treatment options. Both polymerase chain reaction (PCR) and nucleic
      acid sequence-based amplification (NASBA) can currently be used together with
      real time detection to generate results in a short turn-around time and to
      determine whether variants relevant for antiviral resistance are present. These
      new technologies enable the introduction of an individual patient disease
      management concept. Within our clinical setting, we have introduced this e.g. for
      quantitative detection of Epstein-Barr Virus (EBV) in T-dell depleted allogeneic
      stem cell transplant patients. This enabled us to develop models for pre-emptive
      anti B-cell immunotherapy for EBV reactivation, thereby effectively reducing not
      the incidence of EBV-lymphoproliferative disease but the virus related mortality.
      Furthermore, additional clinically relevant viruses can now easily be detected
      simultaneously. It also becomes more feasible to introduce molecular testing for
      those viruses that can easily be detected using classical virological methods,
      like culture techniques or antigen detection. Prospective studies are needed to
      evaluate the clinical importance of the additional positive samples detected. It
      should however be made clear that a complete exchange of technologies is unlikely
      to occur, and that some complementary technologies should stay operational
      enabling the discovery of new viruses. The implementation of these molecular
      diagnostic technologies furthermore warrants the use and introduction of
      standardized materials as well as participation in international quality control
      programs. Finally, the use of an internal control throughout the whole procedure
      not only ensures the accuracy of the results generated, but also is necessary to
      enable precise quantification of these results and to determine detection
      thresholds more accurately. Since so many targets do have clinical implications,
      laboratories might prefer to use universal internal controls before the in-house
      developed assays should be introduced in clinical virology.

PMID- 12467773
TI  - Quality control in nucleic acid testing--where do we stand?
AB  - Quality control has been playing an increasingly important role in the
      implementation of nucleic acid amplification techniques (NATs) for clinical
      diagnosis since the introduction of these methods in the early 1990s. Initial
      multicenter studies involving hepatitis B virus (HBV), hepatitis C virus (HCV),
      Mycobacterium tuberculosis, and human immunodeficiency virus type 1 (HIV-1)
      revealed serious problems in specificity (false-positive rates of ca. 40%) and
      sensitivity, large variations in quantitative results, and a plethora of units
      (largely not comparable between assays). The problem areas identified included
      the need for standardized reagents and common units, contamination control
      mechanisms, inhibition control mechanisms, genotype-independent detection and
      quantitation, facilitated nucleic acid isolation procedures, clinically relevant
      dynamic ranges, and internal run controls. Progress made in each of these areas
      will be discussed. In addition to the above-mentioned problem areas, the value of
      external quality control of existing and evolving NATs was recognized. To this
      end, the European Union Quality Control Concerted Action for Nucleic Acid
      Amplification in Diagnostic Virology was established in May 1998. During its
      three-and-a-half years of existence, a total of 14 proficiency panels containing
      8-13 well-characterized, simulated clinical samples of various viral loads and
      genotypes were prepared for herpesviruses (herpes simplex virus, human
      cytomegalovirus), blood-borne viruses (HBV, HCV, HIV-1), enteroviruses, and
      Chlamydia trachomatis, distributed to up to 20 different countries, and tested by
      up to 97 different laboratories. The results show dramatic improvement in
      specificity (false-positive rates <3% for most panels), presumably due to a
      generally greater expertise of participating laboratories, more frequent use of
      enzymatic or mechanical contamination control mechanisms, and increased
      utilization of standardized reagents (commercial kits). However, considerable
      problems with sensitivity remain (false-negative rates up to 50%), reflecting the
      high detection limits of some commercial viral load kits still on the market as
      well as inadequate standardization of quantitation controls between assay
      systems. In conclusion, although considerable progress has been made, quality
      control of NATs in clinical diagnosis remains an ongoing challenge.

PMID- 12467774
TI  - Highly sensitive hepatitis C virus RNA detection methods: molecular backgrounds
      and clinical significance.
AB  - After treatment of chronic hepatitis C virus (HCV), infection with interferon
      alpha+/-ribavirin in a considerable proportion of patients with a virologic end
      of-treatment response (ETR), a relapse during follow-up is observed. The
      biological background of relapse is unknown. Either antiviral therapy leads to a
      complete replication arrest and latent virions survive until the end-of-treatment
      or replication is not completely suppressed. For the latter hypothesis, residual
      HCV RNA should be detectable dependent on the sensitivity of the HCV RNA assay.
      In patients from different studies, serum or plasma samples from the end-of
      treatment were investigated for the presence of HCV RNA with a standard
      polymerase chain reaction (PCR)-based assay and retested for comparison with a
      new highly sensitive transcription-mediated amplification (TMA)-based assay.
      Generally, in patients with virologic non-response or sustained virologic
      response (SR), no differences were observed between PCR- and TMA-based assays. In
      patients with relapse after standard interferon-alpha therapy with or without
      ribavirin, HCV RNA was detected in 33-36% of end-of-treatment samples previously
      negative by PCR-based assays. The lower rate of HCV RNA detected by TMA (7%) in
      end-of-treatment samples from patients after treatment with pegylated interferon
      alpha 2a is most likely explained by the longer half-life of pegylated interferon
      alpha in comparison with standard interferon-alpha. HCV RNA is detectable at the
      end-of-treatment by TMA in 7-36% of patients who were HCV RNA negative by reverse
      transcriptase (RT)-PCR-based methods. These PCR-negative/TMA-positive patients
      have to be considered as non-responders (NR) with a very low HCV RNA viral load.
      Future studies will show whether these patients benefit from prolonged antiviral
      therapy.

PMID- 12467775
TI  - Hepatitis C viral dynamics: basic concept and clinical significance.
AB  - Viral dynamics is a concept analyzing the time course of treatment-induced
      changes in blood virion concentration (kinetics) to derive conclusions of where,
      when and how in the living organism virions are produced or eliminated.
      Originally applied to human immunodeficiency virus type 1 and hepatitis B virus,
      it has elucidated mechanisms of antiviral therapy in hepatitis C virus infection
      as well. This review summarizes key aspects of mathematical modeling as well as
      important clinical applications, namely induction therapy and prediction of
      virologic response to treatment. Furthermore, limitations of currently available
      quantitative assays will be discussed.

PMID- 12467776
TI  - Molecular genotyping of hepatitis B virus.
AB  - The development of new therapeutic agents against hepatitis B virus (HBV) and the
      predictable emergence of resistant mutants have highlighted the need to provide
      new molecular assays for optimal therapeutic management. Similarly, other
      variants and genotypes of HBV have now been identified that appear to have
      distinct clinical and pathological importance. This paper outlines the current
      clinical importance of HBV on a global scale, reviews the current generation of
      molecular genotyping assays and discusses the prospects for new assays in the
      near future.

PMID- 12467777
TI  - A simple approach to the generation of heterologous competitive internal controls
      for real-time PCR assays on the LightCycler.
AB  - BACKGROUND: The real-time PCR technology allows convenient detection and
      quantification of virus derived DNA. This approach is used in many PCR based
      assays in clinical laboratories. Detection and quantification of virus derived
      DNA is usually performed against external controls or external standards. Thus,
      adequacy within a clinical sample is not monitored for. This can be achieved
      using internal controls that are co-amplified with the specific target within the
      same reaction vessel. OBJECTIVES: We describe a convenient way to prepare
      heterologous internal controls as competitors for real-time PCR based assays.
      STUDY DESIGN: The internal controls were devised as competitors in real-time PCR,
      e.g. LightCycler-PCR. The bacterial neomycin phosphotransferase gene (neo) was
      used as source for heterologous DNA. Within the neo gene a box was chosen
      containing sequences for four differently spaced forward primers, one reverse
      primer, and a pair of neo specific hybridization probes. Pairs of primers were
      constructed to compose of virus-specific primer sequences and neo box specific
      primer sequences. Using those composite primers in conventional preparative PCR
      four types of internal controls were amplified from the neo box and subsequently
      cloned. RESULTS: A panel of the four differently sized internal controls was
      generated and tested by LightCycler PCR using their virus-specific primers. All
      four different PCR products were detected with the single pair of neo specific
      FRET-hybridization probes. CONCLUSION: The presented approach to generate
      competitive internal controls for use in LightCycler PCR assays proved convenient
      und rapid. The obtained internal controls match most PCR product sizes used in
      clinical routine molecular assays and will assist to discriminate true from false
      negative results.

PMID- 12467778
TI  - Results of the 2001 AcroMetrix HIV-1 resistance proficiency program.
AB  - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) drug resistance mutation
      testing has become a useful tool in assessing antiretroviral treatment and
      managing patient care. As these complex molecular genotyping procedures move into
      routine use in clinical laboratories, the need arises for quality control
      procedures that will ensure that drug resistance associated mutations are
      accurately identified. OBJECTIVES: The AcroMetrix HIV-1 Resistance Proficiency
      Program was designed to assess proficiency in the identification of HIV-1 drug
      resistance mutations using molecular genotyping methods. This study describes
      results obtained from a variety of laboratories participating in the 2001
      proficiency program. STUDY DESIGN: The 2001 program included three challenges,
      each comprised of five blind-labeled panel members containing mutations in the
      reverse transcriptase (RT) and/or protease (PR) genes. Challenge HIV-R01 was
      distributed to 19 laboratories in May 2001, challenge HIV-R02 was shipped to 25
      participants in August 2001, and challenge HIV-R03 was distributed to 31
      laboratories in November 2001. RESULTS AND CONCLUSION: Participants correctly
      identified 74% of the total number of mutations and 82% of the panel members
      (i.e. all appropriate mutations detected in each panel member) in HIV-R01, 88% of
      the mutations and 91% of the panel members in HIV-R02, and 75% of the mutations
      and 52% of the panel members in HIV-R03. The AcroMetrix HIV-1 Resistance
      Proficiency Program, along with AcroMetrix's Internet-based reporting system
      (http://www.labqc.org), provides a useful tool for assessing operator proficiency
      within individual laboratories, and for comparing HIV-1 resistance testing
      proficiency among laboratories and technology platforms worldwide.

PMID- 12467779
TI  - Evaluation of the LiPA HIV-1 RT assay version 1: comparison of sequence and
      hybridization based genotyping systems.
AB  - BACKGROUND: Specific mutations in the reverse transcriptase (RT) gene of HIV-1
      are associated with reduced activity of nucleoside inhibitors used in the
      antiretroviral treatment of infected patients. The appearance of these mutations
      may result in therapy failure. Therefore, HIV-1 genotyping is an important tool
      for monitoring antiretroviral therapy. At present different assay systems are
      used to obtain information about the changes in the viral genome. OBJECTIVE: The
      aim of this study was to evaluate the LiPA HIV-1 RT assay version 1 for
      monitoring drug resistance mutations in comparison to full-length sequencing.
      STUDY DESIGN: Two hundred and forty-four samples were analyzed using the LiPA HIV
      1 RT assay version 1 and were compared with full RT gene sequences obtained by in
      house sequencing. RESULTS: In 129/244 (52.9%) samples full concordance between
      both systems was found, in 86/244 (35.2%) samples at least one position was not
      detected by the LiPA assay, in 19/244 (7.8%) samples the results were
      contradictory, and in 10/244 (4.1%) contradictory as well as absent signals from
      the LiPA assay were found. Analyzing total codons, missing signals were observed
      at 137 codons, mainly found at positions 41 (40/137) and 215 (41/137). The 32
      contradictions between LiPA and sequencing were equally distributed across all
      codons except for position 184 with only one case. The main reason for missing
      signals is the heterogeneity of the HIV genome, which could not be fully covered
      by the LiPA probes, e.g. unusual mutations or polymorphisms in the vicinity of
      the relevant positions. The same is the case for some contradictions, although
      most of them are not evident (19/32 positions). CONCLUSIONS: We analyzed a
      patient population with partly multiple therapy failures. The LiPA HIV-1 RT assay
      version 1 gives a high degree of samples with at least one missing signal (39.4%)
      in our cohort and this is not acceptable for a diagnostic tool. However, the LiPA
      assay might work better in untreated patients and could, therefore, still be used
      for screening.

PMID- 12467780
TI  - Serological and molecular response on combined antiviral treatment in children
      with chronic hepatitis B after pediatric malignancy.
AB  - BACKGROUND: Chronic hepatitis B is a serious long-term problem for children
      surviving malignancy. The annual rate of spontaneous clearance of hepatitis B e
      antigen (HBeAg) is only 3% in these patients, and the response to monotherapy
      with interferon (IFN)-alpha is also low. OBJECTIVE: To monitor the serological
      and molecular response on combined antiviral treatment in children with chronic
      hepatitis B after pediatric malignancy. STUDY DESIGN: Twelve patients with a
      history of childhood malignancy and chronic hepatitis B were treated with
      prednisone for 4 weeks (0.6 mg/kg body weight per day orally for 3 weeks followed
      by 0.3 mg/kg body weight per day for 1 week) followed by IFN-alpha-2a (5
      megaunits/m(2) body surface area, three times a week, subcutaneously) at least
      for 1 year. After 1 year of IFN-alpha monotherapy, treatment was discontinued in
      patients with HBeAg seroconversion as well as patients without HBeAg
      seroconversion and a decrease of serum hepatitis B virus (HBV) DNA level less
      than 0.5 logs of the basal level. Patients who had a decrease of the serum HBV
      DNA of more than 0.5 logs of the basal level underwent treatment continuation
      with IFN-alpha combined with famciclovir (FAM) (20 mg/kg body weight per day
      orally) for another year. RESULTS: After 1 year of IFN-alpha monotherapy, a
      decrease of the serum HBV DNA level to less than 0.5 logs was found in eight of
      12 patients. Two of them additionally developed HBeAg seroconversion after 3 and
      12 months. The remaining six patients received antiviral treatment with IFN-alpha
      combined with FAM for another year. Two of them showed HBeAg seroconversion after
      21 and 24 months from study entry. HBeAg seroconversion was only observed in
      patients who had a decrease of serum HBV DNA to levels below 1 x 10(6) copies/ml.
      Treatment-induced toxicity was moderate and reversible in all patients.
      CONCLUSION: Combination treatment of chronic hepatitis B with prednisone, IFN
      alpha, and FAM seems to be a safe and effective treatment option for children
      surviving pediatric malignancy.

PMID- 12467781
TI  - Human cytomegalovirus load in various body fluids of congenitally infected
      newborns.
AB  - BACKGROUND: Congenital human cytomegalovirus (hCMV) infection is the most common
      intrauterine viral disease in western countries. Little is known about hCMV virus
      load in various body fluids of congenitally infected children. OBJECTIVES: To
      determine virus load in various body fluids. To assess the impact of hCMV virus
      load to predict the outcome of congenitally infected newborns and efficacy of
      antiviral therapy. STUDY DESIGN: Cord vein blood, urine, and cerebrospinal fluid
      (CSF) of congenitally hCMV-infected children were investigated and hCMV load was
      determined by quantitative polymerase chain reaction (PCR). Fourteen of 30
      children had clinical symptoms and/or pathological laboratory results and 16 had
      none of them at birth. Ganciclovir was given to 21 children (10 of them with
      symptoms, 11 of them without symptoms). Viral load before and after therapy was
      measured. RESULTS: There was a significant difference between median virus load
      in cord vein blood (2.3 x 10(3) copies per ml) and in urine (4.2 x 10(5) copies
      per ml; P<0.001) at diagnosis of congenital hCMV infection. At that time, no
      significant difference of virus load was found between the various groups
      (symptomatic vs. asymptomatic; with therapy vs. without therapy), neither in
      serum nor in urine. Comparing median virus load in urine before (3.0 x 10(5)
      copies per ml) and after therapy (2.0 x 10(3) copies per ml), a significant
      decrease was observed (P<0.001). Virus load in CSF was always found to be less
      than 400 copies per ml, and only those children with symptoms showed a positive
      result. CONCLUSION: At birth, virus load in urine seems to be superior to that in
      cord vein blood to reflect the situation in the organs precisely. As predicting
      factor for the risk of developing symptoms, only hCMV detection in the CSF
      appears to be promising. The significant decrease of virus load in children with
      therapy may reflect the efficacy of therapy. Studies including a greater number
      of children are needed.

PMID- 12467782
TI  - Hybrid Capture II HPV Test detects at least 15 human papillomavirus genotypes not
      included in its current high-risk probe cocktail.
AB  - BACKGROUND: Hybrid Capture II HPV Test (HCII) (Digene Corporation, Gaithersburg,
      MD) is a signal amplified hybridization microplate-based assay designated to
      detect 18 human papillomavirus (HPV) genotypes using two probe cocktails, for
      high-risk HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68 and
      low-risk HPV genotypes 6, 11, 42, 43 and 44. At present, HCII is the only
      commercially available HPV assay with sufficient scientific data to support its
      performance in the clinical setting. OBJECTIVES: To determine the specificity and
      accuracy of HCII high-risk probe cocktail for detection of 13 HPV genotypes
      included in the high-risk probe cocktail. STUDY DESIGN: Cervical samples obtained
      from 325 women recognized as HPV positive using the HCII high-risk probe cocktail
      were included in the study. HPV genotypes were determined by restriction fragment
      analysis of PGMY09/PGMY11 polymerase chain reaction (PCR) products using seven
      restriction endonucleases. RESULTS: A 450 bp fragment of HPV L1 gene was
      successfully amplified from 312 out of 325 samples. Of the 312 PCR-positive
      samples, 280 samples were associated with the expected high-risk HPV genotypes
      and 32 samples with the HPV genotypes not included in the HCII high-risk probe
      cocktail. Thus, HPV53 was detected in 8 samples, HPV66 in 4 samples, HPV54 in 3
      samples, HPV6, HPV26, HPV70 each in 2 samples, and HPV11, HPV40, HPV42, HPV61,
      HPV73, HPV81, MM4, IS39, CP6108 each in 1 sample. In 2 samples, we were not able
      to determine the HPV genotype. CONCLUSIONS: Our study shows that HCII high-risk
      probe cocktail detects at least 15 HPV genotypes not included in the current HCII
      high-risk probe cocktail. The potential impact of HCII high-risk probe cocktail
      cross-reactivity with phylogenetically related and unrelated HPV genotypes,
      including genotypes currently considered to be low-risk HPVs, remains to be
      determined.

PMID- 12467783
TI  - Hepatitis B virus activity in patients with anti-hepatitis C virus antibody
      positivity and hepatitis B antigen positivity.
AB  - BACKGROUND: Co-infection with hepatitis B virus (HBV) and HCV seems to be
      relatively frequent. There might be a mutual influence on replication activity of
      HBV and HCV. OBJECTIVES: To determine the HBV activity in patients with serum HCV
      RNA and HBsAg positivity and in those with confirmed anti-HCV antibody and HBsAg
      positivity but serum HCV RNA negativity. STUDY DESIGN: A total of 1,200 anti-HCV
      antibody positive samples were investigated. Samples of HCV RNA and HBsAg
      positive patients were compared with those of confirmed anti-HCV and HBsAg
      positive but serum HCV RNA negative patients. HBV activity was tested with the
      quantitative Cobas Amplicor HBV Monitor Test (Roche Diagnostic Systems,
      Pleasanton, CA). RESULTS: Of all studied patients with chronic hepatitis C (serum
      HCV RNA positivity) only 1.0% were found to be HBsAg positive. In contrast, of
      all patients with confirmed anti-HCV positivity but serum HCV RNA negativity,
      11.9% tested HBsAg positive. The median of HBV DNA levels of patients with serum
      HCV RNA positivity and HBeAg seroconversion (4.0 x 10(2) HBV DNA copies per ml)
      was found to be slightly lower than that of patients with serum HCV RNA
      negativity and HBeAg seroconversion (2.5 x 10(3) HBV DNA copies per ml; P>0.05).
      The median of HBV DNA levels of patients with serum HCV RNA positivity but
      without HBeAg seroconversion (1.1 x 10(4) HBV DNA copies per ml) was found to be
      significantly lower than that of patients with serum HCV RNA negativity but
      without HBeAg seroconversion (2.6 x 10(7) HBV DNA copies per ml; P<0.05).
      CONCLUSION: A mutual effect on HBV and HCV replication could be observed. The
      molecular assay for quantification of serum HBV DNA was found to be useful for
      the routine diagnostic laboratory.

PMID- 12467784
TI  - Evaluation of the Cobas AmpliPrep/Cobas Amplicor HIV-1 Monitor Ultrasensitive
      Test: comparison with the Cobas Amplicor HIV-1 Monitor test (manual specimen
      preparation).
AB  - In this preliminary study, we evaluated the performance of the Cobas
      AmpliPrep/Cobas Amplicor HIV-1 Monitor Ultrasensitive Test (CAP; Roche Molecular
      Systems, Branchburg, NJ) for automated specimen preparation and quantitative
      detection of human immunodeficiency virus type 1 (HIV-1) RNA and compared it to
      the Cobas Amplicor HIV-1 Monitor Ultrasensitive Test (MCA; Roche), which includes
      a manual sample preparation protocol. A dilution panel of a patient sample was
      prepared. Additionally, 584 EDTA plasma samples were collected from HIV-1
      infected patients. Reproducibility was estimated with six assay runs using the
      dilution panel. The inter-assay coefficient of variation ranged from 39.4 to
      48.4% (CAP assay) and from 34.3 to 45.6% (MCA assay), whereas the intra-assay
      coefficient of variation ranged from 6.2 to 58.0% (CAP assay) and from 4.4 to
      57.3% (MCA assay). Comparison of CAP assay results with the HIV-1 copy number of
      the dilution panel determined by the MCA assay resulted in a good agreement,
      although the CAP results were found to be slightly lower. A significant
      correlation between both test systems was found when clinical samples were
      analyzed. The mean viral load of 152 samples, which were within the linear range
      of both tests, was 3.70 log(10) HIV-1 copies/ml by the CAP assay compared to 3.73
      by the MCA assay. In conclusion, we could demonstrate that the new Cobas
      AmpliPrep/Cobas Amplicor HIV Monitor Ultrasensitive Test is reproducible and
      sensitive. In comparison to the assay with manual extraction, no significant
      difference in HIV-1 RNA copy numbers was observed.

PMID- 12467785
TI  - Clinical utility of molecular detection of human papillomavirus in cervical
      samples by hybrid capture technology.
AB  - High-risk human papillomaviruses (HPVs) are the primary risk factor for
      developing cervical carcinoma. Hybrid capture II HPV Test (HCII) is a
      standardized test for molecular detection of HPV DNA in cervical swabs. The aim
      of the study was to evaluate the clinical utility of the HCII when used in
      combination with conventional cytology in a group of 171 women who were followed
      up with both, cytology and molecular testing for 3 years. At the end of the
      study, only women positive for high-risk HPV at baseline had retained or worsened
      cervical intraepithelial neoplasia (CIN). In most women who were negative for
      high-risk HPV, CIN had resolved within 3 years. These results are in concordance
      with earlier studies reporting the highly negative predictive value of high-risk
      HPV testing. Both cytology and high-risk HPV testing provide significant clinical
      information on the current cervical status of a woman. They should be used in
      combination for primary screening of CIN, which will provide a more selective and
      cost-effective follow-up.

PMID- 12467787
TI  - An open, component-based information infrastructure for integrated health
      information networks.
AB  - A fundamental requirement for achieving continuity of care is the seamless
      sharing of multimedia clinical information. Different technological approaches
      can be adopted for enabling the communication and sharing of health record
      segments. In the context of the emerging global information society, the creation
      of and access to the integrated electronic health record (I-EHR) of a citizen has
      been assigned high priority in many countries. This requirement is complementary
      to an overall requirement for the creation of a health information infrastructure
      (HII) to support the provision of a variety of health telematics and e-health
      services. In developing a regional or national HII, the components or building
      blocks that make up the overall information system ought to be defined and an
      appropriate component architecture specified. This paper discusses current
      international priorities and trends in developing the HII. It presents
      technological challenges and alternative approaches towards the creation of an I
      EHR, being the aggregation of health data created during all interactions of an
      individual with the healthcare system. It also presents results from an ongoing
      Research and Development (R&D) effort towards the implementation of the HII in
      HYGEIAnet, the regional health information network of Crete, Greece, using a
      component-based software engineering approach. Critical design decisions and
      related trade-offs, involved in the process of component specification and
      development, are also discussed and the current state of development of an I-EHR
      service is presented. Finally, Human Computer Interaction (HCI) and security
      issues, which are important for the deployment and use of any I-EHR service, are
      considered.

PMID- 12467788
TI  - XML-based application interface services--a method to enhance integrability of
      disease specific systems.
AB  - Disease specific systems usually offer excellent functionality for the management
      of the covered diseases. But the restriction to a certain disease often hampers
      their wide spread use since they are not optimised for clinical workflow. The
      Giessener Tumordokumentationssystem (GTDS) is a disease specific system that is
      not only designed for the use in tumour registries but also to support clinical
      care. In order to integrate it into hospital information systems, we implemented
      standard communication interfaces. However, interfaces are not satisfactory since
      they do not consider aspects of the normal workflow of a clinical user.
      Therefore, we developed a strategy that should ease the access to the system in
      the environment of existing systems. From the technical point of view, XML with
      its capabilities to represent even complex data in a rather simple way helped to
      implement this strategy. We use XML to communicate with API-like services and
      created a WWW environment to demonstrate the access to these services. Since HTML
      based access itself is a means to integrate systems, we intend to expand this
      environment to an appropriate region based means to improve the communication
      with registries. Another application using the services is the transfer of data
      between two registries with common patients.

PMID- 12467789
TI  - A methodology for incorporating web technologies into a computer-based patient
      record, with contributions from cognitive science.
AB  - Cognitive science is a rich source of insight for creative use of new Web
      technologies by medical informatics workers. I outline a project to Web-enable an
      existing computer-based patient record (CPR) in the context of ideas from
      philosophy, linguistics, artificial intelligence, and cognitive psychology. Web
      prototypes play an important role (a) because Web technology lends itself to
      rapid prototype development, and (b) because prototypes help team members bridge
      among disparate medical, computing, and business ontologies. Six Web-enabled CPR
      prototypes were created and ranked. User scenarios were generated using a user
      communication matrix. Resulting prototypes were compared according to the degree
      to which they satisfied medical, computing, and business constraints. In a
      different organization, or at different time, candidate prototypes and their
      ranking might have been different. However, prototype generation and comparison
      are fundamentally influenced by factors usefully understood in a cognitive
      science framework.

PMID- 12467790
TI  - Combining diagnosis and treatment using ASBRU.
AB  - Traditionally, diagnosis and treatment have been seen as two distinct tasks.
      Consequently, most approaches to computer supported health care focus on one of
      the two-mostly on diagnosis or rather on the interpretation of measurements which
      is much better understood and formalised. However, in practice diagnosis and
      treatment overlap and influence each other in many ways. Combinations range from
      repeatedly going through the diagnosis-treatment loop over a period of time to
      permanent monitoring of the patients' health condition as it is done in intensive
      care units. In this article we describe how to model these combinations using the
      clinical protocol-representation language ASBRU. It implements treatment steps in
      a hierarchy of skeletal, time-oriented plans. Diagnosis can either be described
      in a declarative way in the conditions, under which treatment steps are taken or
      it can be modelled explicitly as plans of their own right. We demonstrate our
      approach using examples taken from the American Association of Paediatricians'
      guideline for the treatment of hyperbilirubinemia in the new-born.

PMID- 12467791
TI  - Representation primitives, process models and patient data in computer
      interpretable clinical practice guidelines: a literature review of guideline
      representation models.
AB  - Representation of clinical practice guidelines in a computer-interpretable format
      is a critical issue for guideline development, implementation, and evaluation. We
      studied 11 types of guideline representation models that can be used to encode
      guidelines in computer-interpretable formats. We have consistently found in all
      reviewed models that primitives for representation of actions and decisions are
      necessary components of a guideline representation model. Patient states and
      execution states are important concepts that closely relate to each other.
      Scheduling constraints on representation primitives can be modeled as sequences,
      concurrences, alternatives, and loops in a guideline's application process.
      Nesting of guidelines provides multiple views to a guideline with different
      granularities. Integration of guidelines with electronic medical records can be
      facilitated by the introduction of a formal model for patient data. Data
      collection, decision, patient state, and intervention constitute four basic types
      of primitives in a guideline's logic flow. Decisions clarify our understanding on
      a patient's clinical state, while interventions lead to the change from one
      patient state to another.

PMID- 12467792
TI  - An evaluation of the usefulness of two terminology models for integrating nursing
      diagnosis concepts into SNOMED Clinical Terms.
AB  - OBJECTIVES: We evaluated the usefulness of two models for integrating nursing
      diagnosis concepts into SNOMED Clinical Terms (CT). METHODS: First, we dissected
      nursing diagnosis term phrases from two source terminologies (North American
      Nursing Diagnosis Association Taxonomy 1 (NANDA) and Omaha System) into the
      semantic categories of the European Committee for Standardization (CEN)
      categorical structure and ISO reference terminology model (RTM). Second, we
      critically analyzed the similarities between the semantic links in the CEN and
      ISO models and the semantic links used to formally define diagnostic concepts in
      SNOMED CT. RESULTS: Our findings demonstrated that focus, bearer/subject of
      information, and judgment were present in 100% of the NANDA and Omaha term
      phrases. The Omaha term phrases contained no additional descriptors beyond those
      considered mandatory in the CEN and ISO models. The comparison among the semantic
      links showed that SNOMED CT currently contains all but one of the semantic links
      needed to model the two source terminologies for integration. In conclusion, our
      findings support the potential utility of the CEN and ISO models for integrating
      nursing diagnostic concepts into SNOMED CT.

PMID- 12467793
TI  - Supporting decisions in medical applications: the knowledge management
      perspective.
AB  - In the medical domain, different knowledge types are typically available.
      Operative knowledge, collected during every day practice, and reporting expert's
      skills, is stored in the hospital information system (HIS). On the other hand,
      well-assessed, formalised medical knowledge is reported in textbooks and clinical
      guidelines. We claim that all this heterogeneous information should be secured
      and distributed, and made available to physicians in the right form, at the right
      time, in order to support decision making: in our view, therefore, a decision
      support system cannot be conceived as an independent tool, able to substitute the
      human expert on demand, but should be integrated with the knowledge management
      (KM) task. From the methodological viewpoint, case based reasoning (CBR) has
      proved to be a very well suited reasoning paradigm for managing knowledge of the
      operative type. On the other hand, rule based reasoning (RBR) is historically one
      of the most successful approaches to deal with formalised knowledge. To take
      advantage of all the available knowledge types, we propose a multi modal
      reasoning (MMR) methodology, that integrates CBR and RBR, for supporting context
      detection, information retrieval and decision support. Our methodology has been
      successfully tested on an application in the field of diabetic patients
      management.

PMID- 12467794
TI  - Data quality probes-exploiting and improving the quality of electronic patient
      record data and patient care.
AB  - Increasing reliance is being placed on electronic medical records to support
      clinical care and achieve improved quality standards. In order for clinical
      information systems (CIS) to deliver excellence the data within it needs to be
      complete, consistent and accurate. This capture of data is critical but forms
      only part of the procedure in delivering quality health care during the clinician
      patient encounter. A number of processes are involved in this encounter, each of
      which has to be performed flawlessly to deliver a perfect outcome. This paper
      outlines a method of assessing the quality of these processes involved in
      healthcare provision and data quality within a CIS. It proposes the principle of
      Data Quality Probes (DQP) to assess the performance of the whole encounter
      system. The main feature of this is the generation of a query which clinical
      knowledge predicts should not retrieve any cases in a system performing
      flawlessly. Any cases retrieved (which fail the DQP) indicate an error in either
      data quality or clinical judgment. This approach is applied practically within
      the paradigm of a UK family practice testing the hypothesis that a series DQPs
      can provide a valuable method for monitoring both the data accuracy of a CIS and
      the provision of quality patient care.

PMID- 12467795
TI  - Home care delivery through the mobile telecommunications platform: the Citizen
      Health System (CHS) perspective.
AB  - Health delivery practices are shifting towards home care. The reasons are the
      better possibilities for managing chronic care, controlling health delivery
      costs, increasing quality of life and quality of health services and the distinct
      possibility of predicting and thus avoiding serious complications. For the above
      goals to become routine, new telemedicine and information technology (IT)
      solutions need to be implemented and integrated in the health delivery scene, and
      these solutions need to be assessed through evidence-based medicine in order to
      provide solid proof for their usefulness. Thus, the concept of contact or call
      centers has emerged as a new and viable reality in the field of IT for health and
      telemedicine. In this paper we describe a generic contact center that was
      designed in the context of an EU funded IST for health project with acronym
      Citizen Health System (CHS). Since the generic contact center is composed by a
      number of modules, we shall concentrate in the modules dealing with the
      communication between the patient and the contact center using mobile
      telecommunications solutions, which can act as link between the internet and the
      classical computer telephony communication means. We further elaborate on the
      development tools of such solutions, the interface problems we face, and on the
      means to convey information from and to the patient in an efficient and medically
      acceptable way. This application proves the usefulness of wireless technology in
      providing health care services all around the clock and everywhere the citizen is
      located, it proves the necessity for restructuring the medical knowledge for
      education delivery to the patient, and it shows the virtue of interactivity by
      means of using the limited, yet useful browsing capabilities of the wireless
      application protocol (WAP) technology.

PMID- 12467796
TI  - The patient clinical information system (PatCIS): technical solutions for and
      experience with giving patients access to their electronic medical records.
AB  - As health records evolve into electronic form, increasing demand is being made to
      provide patients with access to them. We sought to study the character and impact
      of such access to determine how patients use such records, what cognitive effects
      it has on them, and how it affects their relationship with their health care
      providers. We created the Patient Clinical Information System (PatCIS) to
      interface with the clinical data repository at New York Presbyterian Hospital
      (NYPH) to allow patients to add to and review their medical data. We also
      provided educational resources and automated advice programs. We provided access
      to the system to thirteen subjects over a 36-month period and reviewed their
      activities in the system's usage log. We also collected data via questionnaire
      and telephone interview. We collected data for a total of 223 patient months. We
      found that patients varied in their use of the system, from once a month or less
      to one or more times per day. All patients primarily used the system to review
      laboratory results. Both they and their physicians believed that use of the
      system enhanced the patients' understanding of their conditions and improved
      their communication with their physicians. There were no adverse events
      encountered during the study.

PMID- 12467797
TI  - Requirements and prototyping of a home health care application based on emerging
      JAVA technology.
AB  - IT support for home health care is an expanding area within health care IT
      development. Home health care differs from other in- or outpatient care delivery
      forms in a number of ways, and thus, the introduction of home health care
      applications must be based on a rigorous analysis of necessary requirements to
      secure safe and reliable health care. This article reports early experiences from
      the development of a home health care application based on emerging JAVA
      technologies. A prototype application for the follow-up of diabetes patients is
      presented and discussed in relation to a list of general requirements on home
      health care applications.

PMID- 12467798
TI  - Visualization methods for data analysis and planning in medical applications.
AB  - Time plays an important role in medicine, both the past and the future. The
      medical history of a patient represents the past, which needs to be understood by
      the physician to make the right decisions. The past contains two different kinds
      of information: measured data (such as blood pressure) and incidents (such as
      seizures). Planning therapies, on the other hand, requires looking into the
      future to a certain extent. Visual representations exist for both the past and
      the future, and they are very useful for getting a better understanding of data
      or a plan. This paper surveys visualization techniques for both data analysis and
      planning, and compares them based on a number of criteria.

PMID- 12467799
TI  - Haptic reproduction and interactive visualization of a beating heart for
      cardiovascular surgery simulation.
AB  - This paper aims to achieve haptic reproduction and real-time visualization of a
      beating heart for cardiac surgery simulation. Unlike most forgoing approaches,
      the authors focus on time series datasets and propose a new framework for
      interactive simulation of active tissues. The framework handles both detection
      and response of collisions between a manipulator and a beating virtual heart.
      Physics-based force feedback of autonomous cardiac motion is also produced based
      on a stress-pressure model, which is adapted to elastic objects filled with
      fluid. Time series datasets of an adult man were applied to an integrated
      simulation system with a force feedback device. The system displays multi
      dimensional representation of a beating heart and provides a basic training
      environment for surgical palpation. Finally, results of measurement and medical
      assessment confirm the achieved quality and performance of the presented
      framework.

PMID- 12467800
TI  - Using the critical incident technique to define a minimal data set for
      requirements elicitation in public health.
AB  - The introduction of computer-based information systems (ISs) in public health
      provides enhanced possibilities for service improvements and hence also for
      improvement of the population's health. Not least, new communication systems can
      help in the socialization and integration process needed between the different
      professions and geographical regions. Therefore, development of ISs that truly
      support public health practices require that technical, cognitive, and social
      issues be taken into consideration. A notable problem is to capture 'voices' of
      all potential users, i.e., the viewpoints of different public health
      practitioners. Failing to capture these voices will result in inefficient or even
      useless systems. The aim of this study is to develop a minimal data set for
      capturing users' voices on problems experienced by public health professionals in
      their daily work and opinions about how these problems can be solved. The issues
      of concern thus captured can be used both as the basis for formulating the
      requirements of ISs for public health professionals and to create an
      understanding of the use context. Further, the data can help in directing the
      design to the features most important for the users.

PMID- 12467801
TI  - Guideline and quality indicators for development, purchase and use of controlled
      health vocabularies.
AB  - Developers and purchasers of controlled health terminologies require valid
      mechanisms for comparing terminological systems. By Controlled Health
      Vocabularies, we refer to terminologies and terminological systems designed to
      represent clinical data at a granularity consistent with the practice of today's
      healthcare delivery. Comprehensive criterion for the evaluation of such systems
      historically have been lacking and the known criteria are inconsistently applied.
      Although there are many papers which describe specific desirable features of a
      controlled health vocabulary, to date there is not a consistent guide for
      evaluators of terminologies to reference, which will help them compare
      implementations of terminological systems on an equal footing [Methods Inf. Med.
      37 (1998) 394, J. Am. Med. Inform. Assoc. 5 (1998) 503]. This guideline serves to
      fill the gap between academic enumeration of desirable terminological
      characteristics and the practical implementation or rigorous evaluations which
      will yield comparable data regarding the quality of one or more controlled health
      vocabularies.

PMID- 12467802
TI  - Leveraging XML-based electronic medical records to extract experiential clinical
      knowledge. An automated approach to generate cases for medical case-based
      reasoning systems.
AB  - Case-based reasoning (CBR)-driven medical diagnostic systems demand a critical
      mass of up-to-date diagnostic-quality cases that depict the problem-solving
      methodology of medical experts. In practical terms, procurement of CBR-compliant
      cases is quite challenging, as this requires medical experts to map their
      experiential knowledge to an unfamiliar computational formalism. In this paper,
      we propose a novel medical knowledge acquisition approach that leverages
      routinely generated electronic medical records (EMRs) as an alternate source for
      CBR-compliant cases. We present a methodology to autonomously transform XML-based
      EMR to specialized CBR-compliant cases for CBR-driven medical diagnostic systems.
      Our multi-stage methodology features: (a) collection of heterogeneous EMR from
      Internet-accessible EMR repositories via intelligent agents, (b) automated
      transformation of both the structure and content of generic EMR to specialized
      CBR-compliant cases, and (c) inductive estimation of the weight of each case
      defining attribute. The computational implementation of our methodology is
      presented as case acquisition and transcription info-structure (CATI).

PMID- 12467803
TI  - Statistical analysis of the nursing minimum data set for The Netherlands.
AB  - The purpose of this overview is to examine and illustrate the feasible options
      for the statistical analysis of nursing minimum data sets (NMDSs). After
      explaining the need for these data collections, examples from different countries
      are discussed and examples of the methods used for statistical analysis are
      summarized. Distinct purposes for information uses and for the presentation of
      information requires different approaches for data collection and statistical
      analysis. The feasible options for the nursing minimum data set for the
      Netherlands (NMDSN) have been described to illustrate the different methods
      available. Six studies are discussed, illustrating their goals, data collection
      methods, data analysis, and results. These studies include visualizing nursing
      care by means of frequencies of nursing diagnoses and interventions, RIDIT
      (relative to an identified distribution) analysis, fingerprints, and graphs from
      multidimensional scaling techniques. In addition, using data sets for workload
      measurement and testing of instruments is presented. The overview ends with
      general recommendations for data collection and analysis of NMDSs.

PMID- 12467804
TI  - Adaptive user interface customization through browsing knowledge capitalization.
AB  - Hypermedia data browsing is a mean for improving information access. However, the
      overload and the heterogeneity of medical information, as well as the multitude
      of possible navigational paths, turn the consultation of data into a difficult
      task. We present in this paper a solution for the development of adaptive user
      interfaces in a hypermedia data browsing environment. It is based on the
      capitalization of the users knowledge in the decision-making process, expressed
      in terms of navigational paths and of data presentation modes that are customized
      to the user's preferences and practice. This capitalization offers the user a way
      to automatically store and reuse the experience accumulated in browsing through
      patient records. We illustrate our approach with the implementation of HEMA, a
      clinical workstation prototype that we have specialized for the cardiology
      domain.

PMID- 12467805
TI  - European Association for Cardio-Thoracic Surgery: carrying the torch.

PMID- 12467806
TI  - Early and long term outcome of the arterial switch operation for transposition of
      the great arteries: predictors and functional evaluation.
AB  - OBJECTIVES: The aims of this report were to study the early and late outcome in
      terms of mortality, freedom from reoperation, predictors for late pulmonary
      stenosis (PAS) and insufficiency of the neo-aortic valve (AVI) in patients with
      transposition of the great arteries (TGA) undergoing arterial switch operation
      (ASO). MATERIALS AND METHODS: Between January 1990 and December 2001, 134
      patients with TGA underwent ASO. The patients were divided in Group I (n=88)-TGA
      with intact ventricular septum and Group II (n=46)-TGA with ventricular septal
      defect (VSD). The pulmonary artery was reconstructed employing the direct
      anastomosis technique (PT-I) in 21 (15.7%) patients, the double-patch technique
      (PT-II) in 41 (30.6%), single pantaloon patch (partial circumference) (PT-III) in
      46 (34%) and single pantaloon patch (total circumference) (PT-IV) in 35 (26%)
      patients. The mean follow-up was 3.4+/-1.3 years. RESULTS: The hospital mortality
      was 17 (12.7%) patients. The mortality in Group I was significantly lower than
      Group II (P=0.002). The overall actuarial survival at 1, 3 and 5 years follow-up
      resulted to be 98, 93, and 91.5%, resulting to be significantly higher in Group I
      (P=0.032). The multivariate analysis revealed the complex TGA (P=0.007), VSD
      (P=0.032), coronary anomalies (P=0.004), aortic coarctation or hypoplastic aortic
      arch (P=0.021), left ventricular outflow tract obstruction (LVOTO) or moderate
      PAS (P=0.041) as strong predictors for poor free-reoperation cumulative survival.
      A strong inverse correlation was found between the mean trans-pulmonary gradient
      at follow-up and the age at the operation (r=-0.41, P<0.0001). The univariate
      analysis revealed the PT-I technique (P=0.002), prior moderate PAS (P=0.0001),
      and age <1 month (P=0.018) as strong predictors for moderate-to-severe PAS. The
      neo-AVI incidence was significantly higher in Group II (P=0.011). Predictors for
      neo-AVI were male sex (P=0.003), preoperative neo-AV Z-score >1 (P<0.001), prior
      or concomitant operation for aortic coarctation or hypoplastic aortic arch
      (P=0.001), LV retraining (P=0.003). CONCLUSION: ASO remains the procedure of
      choice for the treatment of various forms of TGA with acceptable early and later
      outcome in terms of overall survival and free reoperation. Strong predictors for
      poor overall free-reoperation survival are complex TGA, VSD, coronary anomalies,
      aortic coarctation and LVOTO or moderate PAS. The pulmonary artery reconstruction
      using a single 'pantaloon patch' seems to offer less residual stenosis. Patients
      with a VSD and a significant mismatch between the neo-aortic root and distal
      aorta are at a higher risk for developing postoperative neo-AVI.

PMID- 12467807
TI  - Simultaneous repair of pectus excavatum and congenital heart disease over the
      past 30 years.
AB  - OBJECTIVE: Pectus excavatum may be present in patient requiring operations for
      cardiac defects. The study was undertaken in order to assess our simultaneous
      repairs of pectus excavatum and congenital heart disease over past 30 years.
      METHODS: Between 1970 and 2000, 12 patients underwent simultaneous repair of
      pectus excavatum and congenital heart disease. Six of 12 patients had ventricular
      septal defects as cardiac malformations (subgroup A). Operative technique, after
      the intracardiac procedure using cardiopulmonary bypass, consists of total
      subperichondrial resection of deformed costal cartilages, transection of deformed
      portion of the sternum in 2-3 points, and fixation of the sternum in elevated
      position using two Kirschner wires and a bridge external traction. Postoperative
      catheterization was performed in five of 12 patients (subgroup B). We evaluated
      the operative data, the improvement of pectus deformity and right ventricular
      performance retrospectively. The operative data in subgroup A were compared with
      those in recent random patients with ventricular septal defects only or with
      pectus excavatum only (control groups). RESULTS: There was no operative death and
      non-serious complications were seen in nine patients (atelectasis in six,
      superficial wound infection in two, chylothorax in one). Pectus deformities
      improved with the drop of vertebral index postoperatively. The mean total
      operative time and postoperative drainage in subgroup A were 128.4% and 123.7%,
      respectively of those in the ventricular septal defect control group. The mean
      perioperative bleeding in subgroup A was more than the sum of those in control
      groups. Right ventricular end-diastolic (RVEDVI), end-systolic (RVESVI), stroke
      (RVSVI) volume indices and ejection fraction (RVEF) in subgroup B tended to
      increase after surgery. In particular, there were significant increases of RVEDVI
      (35%, P<0.05) and RVSVI (77%, P<0.01). CONCLUSION: Simultaneous cardiac and
      pectus repairs were performed successfully without serious complications.
      Moreover, simultaneous repair resulted in an improvement of right ventricular
      performance with significant increases of RVEDVI and RVSVI.

PMID- 12467808
TI  - Thyroid hormones levels in infants during and after cardiopulmonary bypass with
      ultrafiltration.
AB  - OBJECTIVE: The aim of this study was to find out if infants after cardiopulmonary
      bypass develop non-thyroidal illness and if illness severity after
      cardiopulmonary bypass depends on hormone concentration in ultrafiltrate.
      METHODS: Thyroid hormone status was assessed in 20 infants with congenital heart
      defects undergoing cardiac surgery (age range 7 days-11 months). Blood samples
      were collected preoperatively, during cardiopulmonary bypass, after
      cardiopulmonary bypass, and also postoperatively in 1, 2, 3, and 8 day after
      cardiac surgery. Plasma thyrotropin, thyroxine, free thyroxine, triiodothyronine,
      free triiodothyronine and reverse triiodothyronine were measured in blood samples
      and also in ultrafiltrate. RESULTS: All patients had reduction in serum
      thyrotropin, thyroxine, free thyroxine, triiodothyronine, free triiodothyronine,
      and elevation of reverse triiodothyronine after cardiac surgery. In all patients
      we performed ultrafiltration. Patients were divided in to two groups. (with and
      without prolonged recovery). In the group of patients with prolonged recovery we
      noticed significantly higher amount of triiodothyronine per kilogram body weight.
      One of these patients died. The average level of total thyroxine decreased from
      the level 126 nmol/l before bypass to the minimal level 73 nmol/l after bypass,
      free thyroxine from the level 18 pmol/l before bypass to the minimal level 12
      pmol/l after bypass. The average level of total triiodothyronine decreased from
      the level 1.54 nmol/l before bypass to the minimal level 0.42 nmol/l after
      bypass, free triiodothyronine from the level 6.12 pmol/l before bypass to the
      minimal level 3.21 pmol/l after bypass. The average level of TSH decreased from
      the level 4.31 mU/l before bypass to the level 0.64 mU/l after bypass. The
      average level of reverse-triiodothyronine increase from the level 0.83 nmol/l
      before bypass to the maximal level 1.94 nmol/l after bypass. CONCLUSIONS: We
      conclude that non-thyroidal illness occurs in all infants after cardiopulmonary
      bypass. The amount of free triiodothyronine that is filtrated during
      cardiopulmonary bypass may influence postoperative recovery.

PMID- 12467809
TI  - Hybrid approaches to complex congenital cardiac surgery.
AB  - OBJECTIVES: A hybrid operation is a joint procedure involving the interventional
      cardiologist and the cardiac surgeon concomitantly to optimise surgical
      management. The aim of our study was to demonstrate the conceptual development
      and the feasibility of a hybrid approach to complex congenital cardiac surgery.
      METHODS: Descriptive study of two different indications for concomitant
      intervention by the cardiologist and the cardiac surgeon. Seven patients with
      complex congenital heart defects requiring high risk operative interventions were
      included in the study. The indications were: (1) intraoperative stenting of a
      pulmonary artery stenosis with concomitant additional surgical procedures (n=4).
      (2) Balloon occlusion of Blalock-Taussig shunts or major aorto-pulmonary
      collateral artery to control pulmonary blood flow during surgical repair (n=3).
      RESULTS: All patients had successful hybrid procedures. There were no important
      complications related to the temporal proximity of the interventional procedure
      and cardiac surgery, the latter being significantly facilitated by the former.
      CONCLUSIONS: Intraoperative stenting of pulmonary artery stenosis with additional
      surgical repair and balloon occlusion on cardiopulmonary bypass can be performed
      safely and may be complementary in patients with complex lesions by providing a
      better result in combination than either alone can offer.

PMID- 12467810
TI  - Endoluminal stent graft repair for acute and chronic type B aortic dissection and
      atherosclerotic aneurysm of the thoracic aorta: an interdisciplinary task.
AB  - OBJECTIVE: Endoluminal thoracic aortic stenting is a new therapeutic tool in
      reducing the operative trauma of the patient. However, the inherent risks of
      aortic stent grafting are perivascular leakage, stent dislocation, blunt rupture
      of the aorta, side branch occlusion and neurological sequelae. To reduce these
      risks, in our institution all stent implantations were performed in close
      collaboration with our fellow cardiologists under biplane X-ray control supported
      by simultaneous intravascular and transoesophageal ultrasound imaging. METHODS:
      Between August 1999 and August 2001, endovascular stent graft repair was
      performed in 34 patients (27 male, seven female) with a mean age of 68.6+/-7
      years (range 58-84). Indication for treatment was an acute Type B aortic
      dissection in six patients (18%), a symptomatic chronic Type B dissection in 12
      patients (35%), a true aneurysm of the descending aorta in seven patients (21%)
      and an atherosclerotic contained rupture of the descending aorta in nine (26%)
      patients. Out of six acute type B dissections three patients (8.8%) and one
      patient (2.9%) out of the chronic dissection group were in severe haemorrhagic
      shock, ventilated and required high-dose adrenergic support. The others (30
      patients, 88.3%) remained symptomatic despite maximum medical treatment. In a
      special case a combined surgical and endoluminal stent graft repair was
      performed. Individually manufactured Talent, Medtronic AVE (33), and Gore (1)
      stents were used. Follow-up examination was performed 1 week after implantation
      and repeated every 3 months (mean follow-up 8 months, range 1-24). RESULTS: In
      all patients the aneurysm or the entry of the dissection could be excluded. The
      observed hospital mortality was 2.9% (one patient). No perivascular leakage, no
      stent dislocation, no neurological deficit or perfusion impairment was observed.
      All patients except four were extubated immediately after the procedure and
      discharged from hospital on postoperative day 2-3. The late procedure-related
      mortality was 5.8% (two patients) resulting in an overall mortality of 8.8%
      (three patients). CONCLUSION: Stent graft repair is a safe and feasible treatment
      option for selected patients, especially in emergency situations, if the aortic
      lesions can be clearly identified and localized. The use of biplane X-ray control
      combined with simultaneous intravascular and transoesophageal ultrasound imaging
      in an interdisciplinary approach enables a more precise targeting of the stent
      landing zone, resulting in low morbidity and mortality rates.

PMID- 12467811
TI  - A new outside stent--does it prevent vein graft intimal proliferation?
AB  - OBJECTIVE: The saphenous vein subjected to arterial pressure stretches to its
      elastic limits and constitutes intimal hyperplasia. Sheathing of the vein graft
      with pressure-resistant tubing might prolong vein graft patency. METHODS: Twenty
      one sheep received radial vein grafts or hybrid grafts composed of radial vein,
      collagen fibrin glue and highly flexible torlen/dacron mesh tubing transplanted
      into the carotid artery position. Veins were examined with the use of light and
      electron microscopy. Proliferating cell antigen (Ki-67) stains served as markers
      of proliferation. RESULTS: The mean wall thickness of both intimal and medial
      layers was evaluated. The mean intimal wall thickness was 19+/-11 microm in
      hybrid grafts vs. 24+/-7 microm in unsheathed grafts (P<0.001); 22+/-6 vs. 26+/
      10 microm (P<0.001); 23+/-8 vs. 52+/-15 microm (P<0.001); 37+/-21 vs. 90+/-31
      microm (P<0.001); 57+/-31 vs. 104+/-28 microm (P<0.001); 58+/-21 vs. 133+/-32
      microm (P<0.001); and 72+/-22 vs. 244+/-100 microm (P<0.001) after respectively 5
      days, 9 days, 4 weeks, 6 weeks, 8 weeks, 10 weeks and 12 weeks from implantation.
      Electronic microscope examination of hybrid grafts revealed a smooth endothelial
      layer with intact nuclei and an intima composed of layers of collagen and muscle
      fibers. In unsheathed grafts endothelial edema and nuclear destruction were
      observed. CONCLUSIONS: The external vein graft support with mesh tubing reduces
      intimal and medial layer thickening and cell proliferation in composite vein
      grafts transplanted in the arterial position.

PMID- 12467812
TI  - Improved early results after heart valve surgery over the last decade.
AB  - OBJECTIVES: This study was undertaken to investigate time trends in early
      mortality, morbidity and clinical characteristics of patients undergoing heart
      valve surgery over the last decade. METHODS: A regional, prospectively collected,
      study comprising all patients (2,327) undergoing valve surgery in a defined
      geographical area from January 1990 to December 1999 was conducted. Data were
      collected from 1,746 patients submitted to aortic valve replacement (AVR), 432 to
      mitral valve replacement (MVR), 78 to double valve replacement (DVR) and 71 to
      mitral valve repairs. Logistic regression was used to identify risk factors for
      early mortality. Time trends of early mortality, morbidity and clinical
      characteristics were analysed. RESULTS: The total early mortality rate was 5.9%;
      for AVR it was 4.8%, MVR 9%, DVR 14% and mitral valve repair 1.4%. The risk
      factor profiles for early mortality were similar in all groups of valve
      interventions, with shock, age over 70 years and advanced NYHA class as the
      strongest risk factors. There was a decrease in early mortality over the period
      which remained after correction for risk factors. The proportion of patients over
      70 years of age and of patients with diabetes increased, whereas other risk
      factors were not altered during the study period. CONCLUSION: It is confirmed
      that early risks for death after heart valve surgery have decreased. This
      improvement was consistent after adjustment for risk factors.

PMID- 12467813
TI  - Eleven years' experience with the Biocor stentless aortic bioprosthesis: clinical
      and hemodynamic follow-up with long-term relative survival rate.
AB  - OBJECTIVE: The long-term durability and hemodynamics of stentless valves are
      largely unknown. Our aim was to prospectively investigate long-term hemodynamic
      function and clinical outcome after aortic valve replacement with the Biocor
      stentless aortic bioprosthesis. PATIENTS AND METHODS: Between October 1990 and
      November 2000 we inserted the Biocor stentless aortic valve in 112 patients
      (male/female: 38:74) with a mean age of 78.5 years (median 79.3, range 60-88).
      The predominant diagnosis was aortic stenosis in 86% of the patients. Concomitant
      coronary artery bypass surgery was performed in 31% of the patients. Average
      prosthetic valve size was 23.3+/-1.6 mm. All patients were followed in a
      prospective study with a mean follow-up of 66+/-33 months. The follow-up was 100%
      complete with a closing interval from October 1 to December 31, 2001. The
      observed actuarial survival of patients was compared to expected survival for an
      age- and gender-matched comparison population as calculated from Swedish life
      tables by Statistics Sweden. Relative survival rates were calculated annually for
      the patient population. RESULTS: Early mortality was 7% (8/112). Late mortality
      was 38% (43/112). Actuarial survival at 5 and 9 years was 74+/-5% and 38+/-7%,
      respectively. Observed survival among patients was not different from the
      expected survival for the comparison population and calculation of relative
      survival rates indicates a 'normalized' survival pattern for the patient
      population. At 5 and 9 years the actuarial freedom from valve-related death was
      94+/-3% and 86+/-6%; from cardiac death, 82+/-4% and 57+/-8%; from valve
      reoperation, 96+/-2% and 87+/-6%; from structural valve degeneration, 96+/-2% and
      87+/-6%; from thromboembolism, 89+/-4% and 71+/-9%; and from endocarditis, 96+/
      2% and 90+/-5%. At 9 years the transvalvular mean pressure difference for all
      valves was 7.3+/-1.3 mmHg (range 6-10 mmHg) measured with Doppler
      echocardiography. Aortic regurgitation progressed slowly over time in a few
      patients and necessitated reoperation in two patients. CONCLUSION: The Biocor
      stentless bioprosthesis has an excellent hemodynamic function and confers a good
      long-term outcome. This patient population could be regarded as 'cured' from
      valve disease since the observed survival did not differ from the expected
      survival for an age- and gender-matched Swedish comparison population, a
      conclusion that is also supported by a constant relative survival after the first
      postoperative year. However, despite excellent long-term hemodynamics, patients
      with stentless bioprostheses need to be evaluated with echocardiography at
      regular intervals to discover the rare cases of progressive aortic regurgitation.

PMID- 12467814
TI  - Multivariate analysis of risk factors for hospital mortality in valvular
      reoperations for prosthetic valve dysfunction.
AB  - OBJECTIVES: The purpose of the study was to analyze risk factors for hospital
      mortality in patients undergoing valvular reoperations for prosthetic valve
      dysfunction. METHODS: We performed a prospective analysis of 146 patients who
      underwent valvular reoperations for prosthetic valve dysfunction between July
      1995 and June 1999 at the Heart Institute of the University of Sao Paulo Medical
      School. Multivariate statistical analysis with logistic regression was used to
      analyze preoperative and intraoperative variables to determine risk factors for
      hospital mortality. RESULTS: The overall hospital mortality was 10.9% (16
      patients). Univariate analysis showed that the following variables were
      associated with higher mortality rates: advanced New York Heart Association
      (NYHA) functional class, increased creatinine level, prolonged extracorporeal
      circulation time and treatment of annular abscess. Logistic multivariate analysis
      identified advanced NYHA functional class and a creatinine level higher than 1.5
      mg/dl as independent predictors of hospital mortality. CONCLUSIONS: Advanced NYHA
      functional class and higher creatinine levels were independent predictors of
      hospital mortality in patients submitted for valvular reoperations for prosthetic
      valve dysfunction.

PMID- 12467815
TI  - Evolution of case-mix in heart surgery: from mortality risk to complication risk.
AB  - During the last two decades despite an increase of the average preoperative
      mortality risk of patients referred to heart surgery a decrease of hospital
      mortality has been observed in many surgical institutions. The ratio between the
      increase of risk and the decrease of mortality could be defined as the 'risk
      paradox' for coronary surgery. Meanwhile an increase of the incidence of
      postoperative complications is leading to a longer stay in intensive care that
      involves a remarkable cost increase per single hospitalisation and a
      disproportionally long-term use of reanimation beds in those patients who survive
      the operation but have comorbidities complicating the postoperative course. This
      progressive change of the epidemiology of patients undergoing heart surgery is
      coupled with a progressive increase of costs. In the present review a comparison
      of stratification models developed to predict hospital mortality with those
      developed to predict prolonged stay in intensive care is discussed. Such
      predictions are not obviously aimed at deciding whether to operate a patient or
      not, but can be looked in managing high risk patients, e.g. by a daily monitoring
      and revision of their prognosis and relevant therapeutic choices, as well as in
      discussing with their relatives about whether to continue or not implacable
      treatments. After identifying the models, it is desirable that they are spread
      into professional Societies in order to sensitise field operators' awareness on
      the issue of proper intervention indications and on the opportunity of
      identifying those patients for whom an intervention is not to be advised and to
      whom propose medical or intervention treatments.

PMID- 12467816
TI  - Vacuum-assisted suction drainage versus conventional treatment in the management
      of poststernotomy osteomyelitis.
AB  - OBJECTIVE: The purpose of our study was to compare vacuum-assisted suction
      drainage (VASD) to conventional wound management, in the treatment of
      poststernotomy osteomyelitis (SOM). METHODS: We included a total of 42 patients
      that developed poststernotomy osteomyelitis and required open wound management,
      between 1998 and 2000, in this study. Twenty of these patients were treated by
      VASD and the other 22 by conventional wound management. The patients were well
      comparable with regards to age, presenting postoperative day, infecting organism
      and risk factors for osteomyelitis. This was a retrospective study. RESULTS: The
      patients treated by VASD had a significantly reduced treatment duration (mean
      17.2+/-5.8 vs. 22.9+/-10.8 days, P=0.009) and total hospital stay (mean 27.2+/
      6.5 vs. 33.0+/-11.0 days, P=0.03). Perioperative mortality was similar, with one
      early death in each group. CONCLUSION: We conclude from our experience in the
      treatment of 42 patients with poststernotomy osteomyelitis that VASD shortened
      wound healing and hospital stay and thus proved to be an excellent alternative to
      conventional open management of these wounds.

PMID- 12467817
TI  - Prediction of atrial fibrillation after coronary artery bypass grafting by
      measuring atrial peptide levels and preoperative atrial dimensions.
AB  - OBJECTIVE: We prospectively tested the hypothesis that atrial enlargement and
      increased level of atrial natriuretic peptide, N-terminal atrial natriuretic
      peptide and brain natriuretic peptide would predict atrial fibrillation after
      coronary artery bypass grafting. METHODS: Eighty-eight elective coronary artery
      bypass grafting patients had preoperative echocardiographic assessment. The level
      of atrial natriuretic peptide, N-terminal atrial natriuretic peptide and brain
      natriuretic peptide were measured preoperatively. Patients were ECG- monitored
      during the whole hospital stay. RESULTS: Thirty one (35.2%) patients had
      postoperative atrial fibrillation. In univariate analysis increased age
      (P=0.003), enlargement of left and right atria (P=0.002 and P=0.004,
      respectively) and increased level of preoperative atrial natriuretic peptide and
      N-terminal atrial natriuretic peptide (P=0.016 and P=0.03, respectively) were
      associated with postoperative atrial fibrillation. There was correlation between
      the age and level of N-terminal atrial natriuretic peptide (r=0.45 and P<0.001).
      In multivariate analysis only age and the left atrial enlargement were
      independent predictors of postoperative atrial fibrillation (P=0.02 and P=0.01).
      CONCLUSION: Left atrial enlargement was independent predictor for postoperative
      atrial fibrillation. However, atrial peptides were associated with age and did
      not independently predict postoperative atrial fibrillation. In addition, the
      wide variation of the peptide levels renders the implementation of this measure
      in clinical practice superfluous.

PMID- 12467818
TI  - The role of Na+/H+ exchange in the efficacy of multidose hypothermic cardioplegia
      in immature rabbit hearts.
AB  - OBJECTIVES: Recent studies have demonstrated that the use of a Na(+)/H(+)
      exchange inhibitor as an additive can enhance the cardioprotective efficacy of
      cardioplegia in the adult heart under both normothermic and hypothermic
      conditions. However, few references are available as to the cardioprotective
      effect of acidic cardioplegia or Na(+)/H(+) exchange inhibitors in the neonatal
      heart, particularly under hypothermic conditions. METHODS AND RESULTS: In
      isolated working hearts from rabbits aged 7-10 days, function was assessed prior
      to 10 h of ischemia (20 degrees C) and again after 35 min of reperfusion. All
      hearts received a pre-ischemic infusion (10 ml) of cardioplegic solution (20
      degrees C) at pH 7.8, followed by nine subsequent infusions (5 ml every 1 h) of
      cardioplegic solution (20 degrees C) at pH 6.6, 7.0, 7.4, 7.8 (control) or 8.2
      (n=8/group). When the pH was increased to 8.2, post-ischemic recovery of cardiac
      output was reduced and cumulative creatine kinase (CK) leakage during
      cardioplegic infusions was increased. In contrast, when the pH of the
      cardioplegic solution was lowered to 6.6, the post-ischemic recovery of cardiac
      output was maintained and CK leakage was reduced. Next, the effects of 5-(N,N
      dimethyl)amiloride (DMA), an inhibitor of Na(+)/H(+) exchange, were investigated.
      The inclusion of DMA in the pH 8.2 solution improved the post-ischemic recovery
      of cardiac output from 12.6+/-4.1% to 52.0+/-3.0% (P<0.0001) and reduced
      cumulative CK leakage during cardioplegic infusions from 38.0+/-4.0 to 26.1+/-3.7
      IU/45 ml/g dry weight (P=0.044). In contrast, the inclusion of DMA in the pH 6.6
      solution provided no added benefit. (Data are expressed as the mean+/-SEM.)
      CONCLUSIONS: These results suggest that the lesser efficacy of multidose
      hypothermic cardioplegia in the neonatal rabbit heart may depend on the pH of the
      cardioplegic solution and is likely to arise, at least in part, from activation
      of the Na(+)/H(+) exchanger.

PMID- 12467819
TI  - Non-depolarizing cardioplegia activates Ca2+-ATPase in sarcoplasmic reticulum
      after reperfusion.
AB  - OBJECTIVES: Depolarizing cardioplegia is the most common method for myocardial
      preservation in cardiac operations. However, depolarizing cardioplegia causes
      depolarization of the membrane potential by extracellular hyperkalemia, resulting
      in depletion of energy stores and calcium overload. This study examined the
      hypothesis that non-depolarizing cardioplegia would provide superior protection
      compared with depolarizing cardioplegia. METHODS: In an isolated rat heart
      Langendorff model, hearts were perfused for 10 min with St. Thomas' Hospital
      cardioplegic solution (Group I: n=20), St. Thomas' Hospital cardioplegic
      solution+Lidocaine 1 mM (Group II: n=20) or non-depolarizing cardioplegia (Group
      III: n=20). The hearts then were subjected to 60 min of normothermic global
      ischemia, after which they were perfused with Krebs-Henseleit buffer at 37
      degrees C for 30 min. The percent recovery of functional data, myocardial cyclic
      AMP contents, and myocardial cyclic GMP contents were recorded at each time point
      (base, after the administration of cardioplegia, after global ischemia, and after
      30 min of reperfusion). Ca(2+)-ATPase in sarcoplasmic reticulum was measured at
      pre-ischemia and 30 min of reperfusion. RESULTS: The percent recovery of
      developed pressure and +/-dp/dt were significantly higher in Group III than in
      other groups. Myocardial cyclic AMP and GMP contents were elevated after
      reperfusion in all groups. However, in Group III, myocardial cyclic AMP contents
      after 30 min of reperfusion were significantly higher than in other groups (Group
      III: 14.7+/-1.6 vs. Group I: 8.7+/-1.0, Group II: 8.3+/-0.2 pmol/mg dry weight,
      P=0.05) but not cGMP. The sarcoplasmic reticulum Ca(2+)-ATPase activities at 30
      min of reperfusion significantly increased in Group III compared with Groups II
      and I (Group III: 70.3+/-3.6 vs. Group I: 46.8+/-3.4, Group II: 53.9+/-6.1
      micromol Pi/mg per h, P=0.025 and P=0.030). CONCLUSIONS: Non-depolarizing
      cardioplegia induced the activity of Ca(2+)-ATPase in sarcoplasmic reticulum
      after reperfusion. The activity would be increased by the cyclic AMP pathway.
      These findings suggested that non-depolarizing cardioplegia prevented calcium
      overload after reperfusion, especially decreased cytosolic calcium during the
      diastolic phase.

PMID- 12467820
TI  - Comparison of protein with DNA therapy for chronic myocardial ischemia using
      fibroblast growth factor-2.
AB  - OBJECTIVE: Treatment of coronary disease by growth factors has become an
      increasingly used strategy for otherwise untreatable patients and is subject to a
      number of clinical studies. The aim is to stimulate the development of a
      sufficient collateral circulation and hereby to rescue cardiac function. The
      objective of our study was to compare the effectiveness of fibroblast growth
      factor-2 (FGF-2) as protein and as naked plasmid DNA in a porcine model of
      chronic myocardial ischemia. MATERIALS AND METHODS: A severe stenosis of the left
      anterior descending artery (LAD) artery was created in healthy pigs. After 1
      week, perfusion and regional and global contractility was assessed at baseline at
      rest and under stress. Afterwards, recombinant FGF-2 (n=6) or naked plasmid DNA
      encoding FGF-2 (n=7) was intramyocardially injected into the LAD territory.
      Control animals were left untreated (n=5). After 3 months, the animals were re
      examined and underwent immunohistologic analysis. One animal received an Enhanced
      Green Fluorescent Protein plasmid. RESULTS: Plasmid-dependent protein synthesis
      was present in cardiomyocytes. FGF-2 protein as well as plasmid injections
      resulted in an increased number of capillaries and of arterioles compared with
      untreated ischemia. The improvement of the regional myocardial blood flow by FGF
      2 plasmid therapy at rest might however indicate the effectiveness of the DNA
      application for the induction of a collateral circulation. A benefit from FGF-2
      plasmid therapy was revealed with regard to regional contractility. Systemic
      hemodynamics were partially improved following plasFGF-2 treatment. CONCLUSIONS:
      In this porcine model of chronic myocardial ischemia, intramyocardial injection
      of FGF-2 plasmid was more effective than of FGF-2 protein in improving regional
      perfusion and contractility compared to untreated ischemia.

PMID- 12467821
TI  - Bridge to transplantation with the DeBakey VAD axial pump: a single center
      report.
AB  - AIMS: To report our experience with a left ventricular assist device axial pump
      as a bridge to transplantation: the DeBakey Ventricular Assist Device (VAD).
      METHODS: From February 1999 to February 2002, nine patients (among which eight
      males), with a mean age of 47 years, all in NYHA functional class IV, were
      proposed for a bridge to transplantation with the DeBakey VAD. Five patients had
      primary dilated cardiomyopathy, four had ischemic cardiomyopathy. All the
      patients had inotropic support prior to the intervention (dobutamine with a mean
      dose of 12 mcg/kg per min), six had an intra-aortic counterpulsation, four
      presented ventricular rhythm disorders. Interventions were performed through
      sternotomy alone (no need for an abdominal pocket) under extra-corporeal
      circulation on beating heart (except in one patient suffering from an apical
      thrombosis for which cardioplegic arrest was performed) as followed: implantation
      of the apical inflow cannula, tunneling of the percutaneous cable, implantation
      of the outflow graft under aortic side clamping, starting of the DeBakey VAD
      during CPB weaning-off. RESULTS: Mean support duration was 81+/-62 days (16-224
      days). Eight reoperations were required (three for bleeding or cardiac tamponade,
      one for haemoperitoneum, one for aortic bifurcation thrombectomy, one for right
      ventricular assist device implantation, two for iterative replacements of the
      DeBakey VAD). A significant hemolysis was observed in two patients. No device
      infection or dysfunction were observed. Secondary recovery of a pulsed flow was
      observed either clinically or by Echo-Doppler in six patients. Five patients were
      transplanted, four died prior to transplantation (three from multi-organ failure
      on post-operative day 35, 16 and 50, respectively, and the last patient was found
      disconnected at day 109). CONCLUSIONS: The DeBakey VAD is at the origin of
      renewed interest for continuous flow assist devices. Still under evaluation, the
      advantages of miniaturization and facility of implantation of this new device
      seem to be promising.

PMID- 12467822
TI  - Cardiac myxomas: 24 years of experience in 49 patients.
AB  - OBJECTIVES: In this single-center study we reviewed our experience with a
      significant number of cardiac myxoma cases occurring over the past two decades.
      PATIENTS AND METHODS: Cardiac myxomas represented 86% of all surgically treated
      cardiac tumors at our center. Specifically, there were 49 consecutive patients,
      each with at least one myxoma. A detailed clinical, immunological, and
      echocardiographic long-term examination of 37 patients revealed one recurrent
      myxoma. RESULTS: Most myxomas originated from the left atrium (87.7%), but also
      much less frequently from the mitral valve (6.1%), from the right atrium (4.1%),
      and from the left and right atria (2.0%). The myxomas produced a prolapse into
      the left ventricle in 40.8% of the patients, mitral stenosis in 10.2%, and
      threatened left ventricular outflow tract obstruction in 2.0%. Multiple myxomas
      were found in 20.4% of the patients. Cardiac signs appeared in 93.9% of the
      patients. Preoperative embolic events had occurred in 26.5%. Immunologic
      alterations were present in 87.5%. For resection, a bilateral atriotomy was used.
      An additional aortotomy was needed to expose one mitral valve myxoma.
      Postoperatively, 81.1% of the patients remained without cardiac symptoms. The
      early mortality rate was 2.0% and the late mortality rate was 6.1%. Long-term
      prognosis was excellent with an actuarial survival rate of 0.74. Specific
      immunologic alterations were found in 71.4% of the patients. The actuarial
      freedom from reoperation of the myxoma was 0.96. The rate of reoperations was low
      with 2.0% after 24 years. CONCLUSIONS: Myxomas were usually detected and operated
      on in symptomatic patients. A high index of suspicion seems important for early
      diagnosis. Immunologic findings may play an additional role in confirming the
      diagnosis and the recurrence of a myxoma. Immediate surgical treatment was
      indicated because of the high risk of embolization or of sudden cardiac death.
      Also, a familial genesis must be excluded in myxoma patients.

PMID- 12467823
TI  - Video-assisted thymectomy for myasthenia gravis: an update of a single
      institution experience.
AB  - OBJECTIVE: Video-assisted thymectomy was introduced in 1992 as a minimally
      invasive alternative for the treatment of myasthenia gravis. As experience with
      this technique is limited and follow-up short, we present this expanded and
      updated experience for purposes of validation of the technique. METHODS: Thirty
      eight video-assisted thymectomies for myasthenia gravis were performed in our
      institution between March 1992 and March 2002. Two patients were lost to follow
      up. We analyzed clinical results of 36 patients (14 males and 22 females) with a
      mean age of 41.2 years. Preoperative clinical staging was assessed by the newly
      recommended Myasthenia Gravis Foundation of America Clinical Classification.
      Clinical status at follow-up was assessed by the Myasthenia Gravis Foundation of
      America Postintervention Status classification. RESULTS: There was no
      perioperative mortality or long-term morbidity. One of 38 (2.6%) patients
      required conversion to limited thoracotomy for bleeding. The mean length of
      hospital stay was 1.64 days (range 0-8 days) with a median stay of 1 day. The
      mean length of follow-up is 53.24 months (range 4-126 months). Overall clinical
      improvement at follow-up was observed in 30 of 36 (83.0%) patients, with five of
      36 (14.0%) patients in complete stable remission. CONCLUSIONS: Video-assisted
      thymectomy for myasthenia gravis provides acceptable clinical long-term results
      by a minimally invasive approach comparable to standard surgical approaches to
      the disease. The presented data is reported in accordance with the new guidelines
      by Myasthenia Gravis Foundation of America Task Force for valid comparison with
      future studies.

PMID- 12467824
TI  - Surgical treatment of post-traumatic tracheobronchial injuries: 14-year
      experience.
AB  - OBJECTIVE: Tracheobronchial injuries have different clinical pictures and high
      mortality unless aggressive treatment is used. We reviewed our surgical
      experience. METHODS: The records of 32 patients from 1988 to 2002 were reviewed.
      Mean age was 22.3 years (range: 4-53). Three patients were female. Prominent
      symptoms were dyspnea, subcutaneous air and pneumothorax in chest X-rays.
      Associated injuries were seen in 22 patients (68.7%): most frequently in the lung
      parenchyma (11 patients) and esophagus (seven patients). Bronchoscopic detection
      of a rupture of the trachea or bronchus was the main indication for surgery.
      RESULTS: Nineteen injuries (59%) were penetrating and 13 blunt (41%). The most
      common presenting sign of airway disruption was subcutaneous emphysema (25%) and
      stridor (22%). Of the 32 patients, 22 underwent bronchoscopic examination.
      Bronchography was used in three patients admitted during the late period.
      Surgical morbidity was 19.3%. Seven patients died (21.8%), of whom six had been
      operated on. In operations performed during the first 2 h of trauma, no mortality
      occurred. There were associated injuries in 100% of patients that died and in 60%
      of those that survived. The proportion (100 vs. 24%) and duration (2.8 vs. 11.6
      days) of ventilatory support were lower in patients that survived than in those
      that died. Mean injury severity score of patients that died was 34.7+/-8.8 while
      it was 24.3+/-8.6 in those that survived. Tracheal stenosis developed in three
      patients (9.3%). CONCLUSION: In civilian life, tracheobronchial injuries occur
      relatively rarely. Early diagnosis and operative intervention save lives.
      Associated injury is an important mortality factor.

PMID- 12467825
TI  - Giant bullous emphysema resection by VATS. Analysis of laser and stapler
      techniques.
AB  - OBJECTIVE: Advances in video-assisted thoracic surgical (VATS) technique led the
      authors to reconsider the treatment and thoracoscopic management of patients with
      giant bullous emphysema (GBE). METHODS: From January 1993 to December 2001 we
      treated 40 patients with unilateral GBE: 24 males and 16 females, mean age 51+/-1
      years. Thirty patients presented respiratory insufficiency, seven patients a
      spontaneous pneumothorax and three patients a bullae infection. Excision was
      performed by using Nd:YAG laser in five patients (12.5%) and stapling device in
      35 patients (87.5%). Among the last 35, in 20 patients a partial pleurectomy
      stripping up to the 5th intercostal space was associated. In 15 patients this
      technique was modified through the systematic application of
      polytetrafluoroethylene (PTFE) to reinforce stitches. RESULTS: We experienced one
      conversion to open thoracotomy owing to haemorrhaging, in one patient who
      underwent a partial pleurectomy stripping. In the stapler resection patients,
      with PTFE application, the mean duration of air leaks, for type 1 bullae of
      Wakabayashi was 2.2+/-1.8 days and, for type 4, 5.9+/-1.4 days; the mean length
      of hospital stay was 6.1+/-0.5 days. CONCLUSIONS: The resection in VATS of giant
      bullous emphysema by stapling device associated to reinforcement in PTFE reduces
      duration of air leaks and hospitalisation and improves pulmonary function.

PMID- 12467826
TI  - Peripheral small-sized (2 cm or less) non-small cell lung cancer with mediastinal
      lymph node metastasis; clinicopathologic features and patterns of nodal spread.
AB  - OBJECTIVE: The diagnosis of small-sized (2 cm or less) non-small cell lung cancer
      (NSCLC) has increased with the development of computed tomography (CT), whereas
      unexpected extensive multiple-level mediastinal involvement has been occasionally
      detected in this small-sized lung cancer. To establish the optimal surgical
      strategy, we retrospectively analyzed the clinicopathologic features, efficacy of
      preoperative investigations and lobe specific patterns of nodal spread in small
      sized NSCLC with mediastinal involvement. METHODS: Among 1,550 resected lung
      cancer cases between 1981 and 2000, 267 (17.2%) had peripheral small-sized NSCLC.
      Of these, 29 patients (10.8%) with mediastinal lymph node involvement who
      underwent pulmonary resection and systematic nodal dissection were reviewed.
      RESULTS: Among 29 patients, 27 patients (93.1%) were adenocarcinoma, and 51.7%
      (15/29) showed no lymph node enlargement on CT (cN0). Surgical pathology revealed
      multiple-level mediastinal involvement in 65.5% (19/29) of all patients and 60.0%
      (9/15) of cN0 patients. All of right upper lobe tumors (n=11) showed multiple
      level involvement. Thallium-201 single photon emission computed tomography (201Tl
      SPECT) was positive for increased focal uptake in the mediastinum in 72.7% (8/11)
      of patients. CONCLUSIONS: The vast majority of cases were adenocarcinoma, and two
      thirds of them showed multiple-level mediastinal involvement, even in cN0
      patients. We thus recommend to perform systematic nodal dissection or meticulous
      sampling for accurate intrathoracic staging, especially for right upper lobe
      tumor. 201Tl-SPECT appears to be more sensitive preoperative investigation for
      mediastinal metastasis compared with CT scan.

PMID- 12467828
TI  - Giant pulmonary hamartoma.

PMID- 12467827
TI  - Comparison of clinical and surgical-pathologic staging of the patients with non
      small cell lung carcinoma.
AB  - OBJECTIVE: Clinical staging of non-small cell lung cancer helps to determine the
      extent of disease and separate patients with potentially resectable disease from
      those that are unresectable. Since, clinical staging is based on radiologic and
      bronchoscopic findings, overstaging or understaging may occur comparing to the
      final surgical-pathologic evaluation. We aimed to analyze preoperative and
      postoperative stagings in order to evaluate stage migrations and our surgical
      strategy for marginally resectable patients. METHODS: We did a retrospective
      analysis of 180 patients with non-small cell lung cancer who underwent
      resectional surgery between 1994 and 2000. In all patients, a thoracic
      computerized tomography and bronchoscopy were performed to define clinical
      staging (cTNM). RESULTS: In 86 patients (47.7%) clinical and surgical-pathologic
      staging concurred. When comparing T subsets alone, correct staging, overstaging
      and understaging occurred in 133 (73.9%), 28 (15.5%), 47 (26.1%) patients,
      respectively. Only 13 of 21 patients (61.9%) who were thought to have T4 tumor
      preoperatively were found to have pT4. Also six patients with cT2 and five
      patients with cT3 were subsequently found to have T4 disease according to
      pathology. Clinical staging overestimated the nodal staging in 35 patients
      (19.4%), while underestimated the lymph node involvement in 45 patients (25%).
      CONCLUSION: Construction of cTNM stage remains a crude evaluation, preoperative
      mediastinoscopy in every patient must be performed. Preoperative limited T4
      disease is not to deny surgery to patients since a considerable number of
      patients with cT4 are to be understaged following surgery.

PMID- 12467829
TI  - Purulent pneumopericarditis due to ulcer of the retrosternal stomach roll after
      esophagectomy.

PMID- 12467830
TI  - Giant leiomyoma of the esophagus.
AB  - Leiomyoma is the most common benign tumour found in the esophagus but it is,
      however, a rare neoplasm; in fact of all esophageal tumours, benign tumours
      account for fewer than 10%, of which 4% are leiomyomas. Leiomyomas should be
      removed when diagnosed, even if asymptomatic, because malignancy cannot otherwise
      be excluded and symptoms are likely to develop if treatment is delayed or
      omitted. Enucleation of esophageal leiomyoma is a safe and effective procedure.
      We report a case of symptomatic giant anular leiomyoma of the distal esophagus,
      compressing the trachea and the descending aorta, resected after right
      thoracotomy.

PMID- 12467831
TI  - Late splenic metastasis after curative resection for oesophageal carcinoma.
AB  - The spleen is an unusual site of distant metastasis from solid tumours. While
      contiguous involvement of the spleen may occur in tumours arising from the
      stomach, pancreas or colon; the spleen as the seat of distant metastasis is a
      rare occurrence. We report herewith one such instance of metastatic involvement
      of the spleen in an operated case of carcinoma oesophagus.

PMID- 12467832
TI  - Gastrointestinal stromal tumor of the posterior mediastinum.
AB  - Gastrointestinal stromal tumor (GIST) is a rare, but potentially aggressive
      tumor. We present an asymptomatic 64-year-old man with an incidental 9-cm GIST
      that arose in the posterior mediastinum. Wide surgical excision was performed
      with rotation of an intercostal muscle flap to buttress a surgically created
      esophageal wall defect. The patient is now free of disease 26 months
      postoperative. This tumor is defined by the carcinogenic over-expression of KIT
      protein, a tyrosine kinase receptor. Accurate diagnosis of gastrointestinal
      stromal tumor is imperative, as specific medical therapy is now available for
      potential control of recurrent or metastatic disease.

PMID- 12467833
TI  - Intrathoracic desmoid tumor with invasion of the great vessels.
AB  - A desmoid tumor of the mediastinum was diagnosed and treated in a 35-year-old
      white male who presented with a right supraclavicular mass. He was treated with
      resection, which involved several vascular structures, requiring multiple
      vascular reconstructions followed by post-operative radiotherapy. The authors
      concluded that, when located in the mediastinum, the invasive character of such
      tumors and its tendency to recur may pose a considerable surgical challenge,
      requiring careful pre-operative planning and long term post-operative follow -up.
      The role of radiation therapy is limited to the control of local recurrences.

PMID- 12467834
TI  - Sleeve resection of the right main bronchus for postlobectomy broncho-pleural
      fistula.
AB  - In this case report we present a novel treatment for bronchial fistula after
      lobectomy. The patient had right upper lobectomy for T1 N0 M0 peripheral
      adenocarcinoma and he had been reexplored 4 days later for massive air leak in
      another chest surgery department. After the reoperation the bronchial fistula
      persisted and the patient was admitted to our department. Nineteen days after the
      reoperation, bronchoscopy confirmed that the bronchial stump was totally opened.
      A sleeve resection to the right main broncus including the fistulous stump of
      right upper lobe was performed.

PMID- 12467835
TI  - Lipomatous hypertrophy of the interatrial septum and upper right atrial inflow
      obstruction.
AB  - Lipomatous hypertrophy of the heart is a benign rare abnormality characterized by
      large fatty tissue deposits in the interatrial septum. An increased incidence of
      atrial arrhythmias is described in these patients, significant blood flow
      obstruction however is not the rule. We report a case of lipomatous hypertrophy
      of the interatrial septum, detected by transeosophageal echocardiography (TEE).
      The tumour mass protruded into the right atrium and the superior caval vein
      (SCV), thus causing upper right atrial inflow obstruction. Partial resection of
      the tumour and pericardial patch-reconstruction of the SCV were performed in
      combination with coronary artery bypass grafting due to coronary artery disease
      (CAD). The diagnostic and therapeutic management is discussed and a review of the
      literature performed.

PMID- 12467836
TI  - Aortic valve replacement for a patient with warm-reactive autoimmune hemolytic
      anemia.
AB  - We treated a 68-year-old woman with warm-reactive type of autoimmune hemolytic
      anemia (AIHA) who underwent aortic valve replacement. In consideration of the
      different hemolytic mechanisms between cardiopulmonary bypass and warm-reactive
      AIHA, conventional surgical procedures could be performed after the
      discontinuation of steroid therapy.

PMID- 12467837
TI  - Vacuum-assisted closure in the paediatric patient with post-cardiotomy
      mediastinitis.
AB  - Mediastinitis has a high mortality and is a major cause for concern in the
      neonatal cardiac surgical population. Vacuum-Assisted Closure (V.A.C.) is a newly
      established technique for expediting healing in the management of wounds
      resistant to established treatments; this includes the treatment of post
      cardiotomy mediastinitis in the adult cardiac surgical patient. We describe the
      previously unreported use of the V.A.C. device for the successful treatment of
      post-cardiotomy mediastinitis in an infant. The device also improved the
      mechanics of respiration. We discuss potential risks and benefits of V.A.C. and
      suggest guidelines for its use.

PMID- 12467838
TI  - Possible close relationship between non-occlusive mesenteric ischemia and
      cholesterol crystal embolism after cardiovascular surgery.
AB  - A senile patient developed fatal intestinal necrosis right after uneventful
      cardiovascular operation using usual cardiopulmonary bypass. Cholesterol crystal
      embolism (CCE) was demonstrated histologically, but angiograms were typical of
      non-occlusive mesenteric ischemia (NOMI). Very severe vasoconstriction occurred
      not only in the superior mesenteric artery but also in other splanchnic arteries.
      The clinical course strongly suggested that NOMI resulted from CCE and that some
      humoral factors were released and played very important roles in this case.

PMID- 12467839
TI  - Composite graft using the gastroepiploic artery, regarding the study design.

PMID- 12467841
TI  - Non-uniform aortic medial degenerative changes associated with aortic valve
      disease.

PMID- 12467843
TI  - Resection of Kommerell's diverticulum and left subclavian artery transfer does
      not always relieve symptoms.

PMID- 12467844
TI  - Second primary cancers occurring in patients with early stage non-small-cell lung
      cancer treated with radiation therapy alone.

PMID- 12467847
TI  - Surgical treatment of complex cardiac anomalies: the 'one and one half ventricle
      repair'.
AB  - OBJECTIVE: One and one half ventricle repair is a surgical option for congenital
      cardiac anomalies characterised by right ventricle (RV) hypoplasia and/or
      dysplasia. METHODS: From March 1994 to March 2001, eight patients (mean age 9.1
      years, range 7 months to 35 years) with hypoplastic and/or dysplastic RV
      underwent correction of their intracardiac anomaly in association with a BCPS
      (one and one half ventricle repair). Preoperative diagnoses included: Ebstein's
      anomaly of tricuspid valve (TV) in two, inlet ventricular septal defect (VSD) in
      association with straddling/overriding TV in two patients, pulmonary atresia
      intact ventricular septum in one, tertralogy of Fallot in association with
      complete atrioventricular canal defect in one, truncus arteriosus in one and
      heterotaxy syndrome with VSD and anomalous systemic venous return in one. Four
      patients underwent previous surgery which included: main pulmonary artery (MPA)
      banding in two patients, pulmonary valvotomy, central shunt and right ventricular
      outflow tract reconstruction in one, pulmonary artery separation from truncus
      arteriosus and modified Blalock-Taussig shunt in one, and MPA closure in one. Two
      patients underwent a bidirectional cavo-pulmonary shunt before the one and a one
      half ventricle repair. Associated cardiac lesions were treated simultaneously.
      RESULTS: There were no hospital deaths. All the patients were discharged home in
      good clinical conditions. There were no late deaths or reoperations. At mean
      follow-up of 29.8 months (range 8 months to 7.3 years) all the patients are alive
      and in good general conditions. MPA percutaneous balloon dilation was performed
      in two patients at 33 and 4 months, respectively, both after MPA reconstruction
      (which was previously ligated) and dilation of the left pulmonary artery branch
      in one patient, repeated twice at 10 and 14 months from repair, for a hypoplastic
      left pulmonary artery after truncus arteriosus repair. CONCLUSIONS: Surgical
      treatment of congenital cardiac anomalies in the presence of a hypoplastic and or
      a dysplastic RV by means of one and one half ventricle repair has the advantage
      of reducing the surgical risk for biventricular repair, and compared to the
      Fontan circulation, it maintains a low right atrium pressure, a pulsatile
      pulmonary blood flow and improves the systemic oxygen saturation. Short and
      medium-term results are promising. Longer follow-up is needed, to prove the
      efficacy of such a repair, in the long term.

PMID- 12467848
TI  - The carotid artery as a noninvasive window for cardiovascular risk in apparently
      healthy individuals.
AB  - Cardiovascular diseases are the leading cause of death and disability in
      industrialized countries. Because the etiologies are related to alteration of
      arterial wall properties, the noninvasive evaluation could help the
      presymptomatic diagnosis and potentially the prevention of future events.
      Ultrasound (US) is currently the only modality to image the arterial wall in real
      time with sufficient resolution to allow for observation of its morphological,
      hemodynamic and elastic properties. Increased wall thickness and atheromatous
      plaques of carotid arteries are associated with cardiovascular risk factors and
      diseases. Also, carotid Doppler waveforms and wall elasticity may have
      associations with arterial health. Although evaluation of these arterial
      properties are currently limited to the research laboratories, most of such
      properties can be evaluated in the standard setting of carotid ultrasonography.
      This article reviews "potential" utilities of carotid US evaluation for
      cardiovascular risk assessment in apparently healthy individuals.

PMID- 12467849
TI  - Carotid artery intima-media thickness and plaque score for the risk assessment of
      stroke subtypes.
AB  - As measures for the severity of carotid atherosclerosis, we compared common
      carotid artery (CCA) intima-media thickness (IMT) and plaque score (PS) for risk
      assessment of respective stroke subtypes. The subjects comprised 792 nonstroke
      and 311 stroke patients, including 72 with atherothrombotic infarction (AI), 113
      with lacunar infarction (LI), 54 with cardioembolic infarction and 29 with
      cerebral hemorrhage. IMT was bilaterally measured on CCA far walls, and averaged.
      PS was obtained by summing up the maximum thickness of all plaques in bilateral
      carotid arteries. Both IMT and PS were greater in AI and LI patients than in
      nonstroke patients (all p < 0.05), but similar between other subtype and
      nonstroke patients. By receiver operating characteristic (ROC) curve analyses,
      both measures discriminated the likelihood for AI and LI (all p < 0.05), but not
      for other subtypes. When discriminating AI, ROC area defined by PS (0.80) was
      greater than that defined by IMT (0.68) (p < 0.05). Thus, although both CCA IMT
      and PS appear to help for risk assessment of AI and LI, risk of AI may be more
      effectively assessed by PS.

PMID- 12467850
TI  - Aortic pulse waveforms for evaluating cardiac performance in the human fetus.
AB  - Pulse waveforms of the fetal descending aorta were obtained using an echo
      tracking system to clarify the gestational age-related changes and the usefulness
      for detecting cardiac dysfunction. Peak systolic (PSD) and end diastolic diameter
      (EDD), pulse amplitude (Amp) and Amp:EDD ratio, calculated from the pulse
      waveforms, were adopted for analysis. In 196 normal fetuses after 20 weeks, the
      PSD, EDD and Amp increased, and Amp:EDD ratio decreased linearly with advancing
      gestation. The 19 fetuses with suspected cardiac dysfunction were divided into
      healthy and altered cardiac function subgroups, according to the values of
      fractional shortening and preload index. Of these, 7 fetuses with cardiac
      dysfunction had significantly higher incidence of low Amp (p < 0.01) and Amp:EDD
      ratio (p < 0.001) than remaining 12 fetuses with normal cardiac function. The
      pulse waveform analysis in the fetal descending aorta proved useful for detecting
      fetal cardiac dysfunction in utero.

PMID- 12467851
TI  - Estimation of the Doppler ultrasound maximal umbilical waveform envelope: I.
      Estimation method.
AB  - We developed a parametric method of estimating the Doppler ultrasound (US)
      umbilical maximal flow waveform envelope that is robust to varying levels of
      signal-to-noise ratio (SNR). The method differs from previously proposed
      estimation algorithms in that it does not incorporate preliminary removal or
      reduction of noise; thus, avoiding potential resulting biases. Instead, we relied
      on a multiple time series interpretation that facilitates a regression approach.
      The maximal waveform shape was assumed to take the form of a periodic series of
      gamma functions with a hidden baseline that is typically not reached on the
      downward diastolic phase before the flow increases to the systolic peak. The
      waveform shape is fitted via optimisation of the cross correlation of the Doppler
      signal and a periodic reference function locating the cardiac cycles within the
      blood flow image. Starting values for the iterative optimisation process were
      obtained using nonstandard least squares regression. Assessments of the fit of
      the model to waveform data were carried out through visual inspection. In 7 of
      327 images analysed (2.1%), there appeared to be some discrepancy between the
      waveform shape and the gamma waveform envelope, such as variations in systolic or
      diastolic flows. Modification of the estimation procedure to incorporate blood
      flow cycles of slightly different lengths and use of other functional forms may
      improve the fit for waveforms for which the gamma fit is poor. The method has
      been developed with special reference to umbilical blood flow images, but it can
      be used directly to model blood flow in other low-resistance vessels or adapted
      for other vessels with different shape characteristics.

PMID- 12467852
TI  - Estimation of the Doppler ultrasound umbilical maximal waveform envelope: II.
      Prediction of fetal distress.
AB  - Blood flow variables obtained via Doppler ultrasound (US) waveform estimation
      have been investigated for prediction of fetal distress. The umbilical flow was
      assessed using a number of waveform summary statistics in addition to the
      currently used resistance indices. We examined the relationship between umbilical
      artery waveform patterns and intrauterine growth restriction, preterm delivery
      and hypertensive disorders. To enhance prediction, we defined waveform skewness
      profiles based on pivotal points of the umbilical waveform that appeared to be
      related to the incidence of preterm delivery and that facilitated construction of
      IUGR prediction models. The data comprised 204 unselected pregnancies with the
      umbilical artery images recorded at 18 pregnancy weeks. The sample was divided
      into 114 pregnancies used to estimate model parameters and 90 pregnancies to
      validate the model. Logistic prediction models for detection of abnormal velocity
      waveforms associated with intrauterine growth restriction were derived, based on
      the waveform information. The estimated model sensitivity and specificity on the
      training data were 74% and 84%, respectively. Validation of the model on
      independent data yielded a sensitivity of 57% and specificity of 84%. The
      logistic IUGR prediction model appears to have significant predictive ability and
      potential for clinical use, even at this early gestational age. Our data suggest
      that prediction of IUGR at 18 pregnancy weeks can be much improved when the
      waveform shape is captured with a number of summary statistics in addition to
      resistance indices.

PMID- 12467853
TI  - Online automated detection of cerebral embolic signals from a variety of embolic
      sources.
AB  - A major limitation of embolic signal (ES) detection by transcranial Doppler
      ultrasound is the lack of a reliable automated system. The performance of an
      automated system needs to be evaluated for different embolic sources on
      consecutively acquired typical data. We evaluated a new online frequency
      filtering approach in a total of 565 h of data containing 925 ES from four groups
      of patients: post carotid endarterectomy (postCEA), symptomatic carotid stenosis
      (SCS), asymptomatic carotid stenosis (ACS) and atrial fibrillation (AF). The
      following sensitivities and specificities were achieved: postCEA = sensitivity
      95.8%, specificity 88.2%; SCS = sensitivity 98.4%, specificity 88.6%; ACS =
      sensitivity 85.7%, specificity 13.0%; AF = sensitivity 54.8%, specificity 7.0%.
      This online automated system performed similarly to the human expert in the
      postCEA and SCS groups, but less well in patients with AF and ACS. The low ratio
      of ES to normal data in patients with ACS may have contributed to the lower
      specificity; further evaluation with a higher number of ES is required.
      Refinement of the algorithm is required to improve its sensitivity for AF data.

PMID- 12467854
TI  - Skeletal status in survivors of childhood acute lymphoblastic leukemia assessed
      by quantitative ultrasound: a pilot cross-sectional study.
AB  - Intensive treatment in acute lymphoblastic leukemia (ALL) with the use of
      multimodality therapies, including radiotherapy, corticosteroids and cytotoxic
      agents, may lead to disturbances in bone metabolism. The aim of this study was to
      determine the degree of possible changes in bone status in survivors of ALL. The
      studied population consisted of 54 subjects aged 13.0 +/- 3.3 years (31 girls and
      23 boys). The mean age at diagnosis was 5.5 +/- 3.5 years, age at the completion
      of therapy was 8.4 +/- 3.5 years, and the period of follow-up was 4.6 +/- 3.4
      years. Patients were divided into three subgroups (low-, moderate- and high-risk)
      according to the presence of risk factors of ALL and compared with 1020 healthy
      subjects (508 girls and 512 boys). Patients and controls did not differ
      significantly in regard to age, height, or weight. Bone status was assessed by
      quantitative ultrasound (US) at right (dominant) hand phalanges using DBM Sonic
      1200 (IGEA, Carpi, Italy) that measures amplitude-dependent speed of sound (Ad
      SoS, m/s). Root mean square (RMS)_CV% was 0.43%. Mean Ad-SoS values were 2018 +/-
      73 m/s in patients and 2003 +/- 80 m/s in controls and did not differ
      significantly. Ad-SoS tended to be lower in moderate- and high-risk patients, but
      differences were not significant. Ad-SoS correlated significantly with age in
      patients (r value ranged from 0.63 to 0.77, p < 0.01) and controls (r value
      ranged from 0.79 to 0.84, p < 0.0001). In multiple forward regression analysis,
      the following equation was obtained: Ad-SoS (m/s) = 1878 (m/s) + 11.4 x age at
      the study (y) + 4.0 x period after therapy completion (y) - 9.5 x duration of the
      therapy (y). It can be concluded that bone status assessed by quantitative US at
      the hand phalanges in survivors of acute lymphoblastic leukemia 4.6 years after
      completion of the therapy is not affected in comparison to healthy controls.

PMID- 12467855
TI  - In vivo performance of a matrix-based quantitative ultrasound imaging device
      dedicated to calcaneus investigation.
AB  - We developed a prototype of an ultrasound (US) bone matrix densitometer, the BEAM
      scanner, in the context of a European Space Agency research program. This device,
      which is a contact imaging device, was designed to overcome the limitations of
      immersion devices in space. Broadband US attenuation (BUA) and speed of sound
      (SOS) parameters were calculated from the radiofrequency (RF) signal. The
      principle aim of this study was to evaluate in vivo performance in direct
      comparison with a currently available device (UBIS 3000, DMS, France). The short
      term precision of the BEAM scanner for BUA was estimated at 2.8%, whereas it was
      2.3% with UBIS 3000. The short-term precision for SOS was 0.3%, and this was the
      same as the coefficient of variation (CV) of the UBIS 3000. CVs of 3.4% and 0.6%
      for midterm precision were found for BUA and SOS, respectively, and UBIS 3000
      scores were 3% and 0.4%, respectively. This preliminary study demonstrates the
      high performance of the BEAM scanner and its new concept offers a wide range of
      improvements and new applications.

PMID- 12467856
TI  - Classification of breast masses in ultrasonic B-mode images using a compounding
      technique in the Nakagami distribution domain.
AB  - Classification of masses in ultrasonic B-mode images of the breast tissue using
      "normalized" parameters of the Nakagami distribution was recently investigated.
      The technique, however, did not yield performances that were comparable to those
      of an experienced radiologist, and utilized only a single image for tissue
      characterization. Because radiologists commonly use two to four images of a mass
      for characterization, a similar procedure is developed here. A simple summation
      of the normalized Nakagami parameters from two different images of a mass is
      utilized for classification as benign or malignant. The performance of the
      normalized Nakagami parameters before and after the summation has been carried
      out through a receiver operating characteristic (ROC) study. The bootstrap
      procedure has been utilized to compute the mean and SD of the ROC area, A(z),
      obtained for each parameter. It has been observed that combining normalized
      Nakagami parameters from two images of the mass may help to improve
      classification performance over that from utilizing the parameters of just a
      single image. The performance of this automated parameter-based approach appears
      to match that of a trained radiologist.

PMID- 12467857
TI  - Diagnosis of breast tumors with sonographic texture analysis using wavelet
      transform and neural networks.
AB  - To increase the ability of ultrasonographic technology for the differential
      diagnosis of solid breast tumors, we describe a novel computer-aided diagnosis
      (CADx) system using neural networks for classification of breast tumors. Tumor
      regions and surrounding tissues are segmented from the physician-located region
      of-interest (ROI) images by applying our proposed segmentation algorithm.
      Cooperating with the segmentation algorithm, three feasible features, including
      variance contrast, autocorrelation contrast and distribution distortion of
      wavelet coefficients, were extracted from the ROI images for further
      classification. A multilayered perceptron (MLP) neural network trained using
      error back-propagation algorithm with momentum was then used for the differential
      diagnosis of breast tumors on sonograms. In the experiment, 242 cases (including
      benign breast tumors from 161 patients and carcinomas from 82 patients) were
      sampled with k-fold cross-validation (k = 10) to evaluate the performance. The
      receiver operating characteristic (ROC) area index for the proposed CADx system
      is 0.9396 +/- 0.0183, the sensitivity is 98.77%, the specificity is 81.37%, the
      positive predictive value is 72.73% and the negative predictive value is 99.24%.
      Experimental results showed that our diagnosis model performed very well for
      breast tumor diagnosis.

PMID- 12467858
TI  - Ultrasound properties of human prostate tissue during heating.
AB  - Changes in the ultrasound (US) properties of tissue during heating affect the
      delivery of US thermal therapy and may provide a basis for US image monitoring of
      thermal therapy. The US attenuation coefficient and backscatter power of fresh
      human prostate tissue were measured as the tissue was heated. Samples of human
      prostate were obtained directly from autopsies and heated rapidly to final
      temperatures of 45 degrees C, 50 degrees C, 55 degrees C, 60 degrees C and 65
      degrees C. A 5.0-MHz transducer was scanned in a raster pattern over the tissue
      and radiofrequency (RF) data were collected at 36 uncorrelated positions. Both
      attenuation and backscatter were measured over the frequency range 3.5 to 7.0 MHz
      at each min of a 30-min heating. Little change was observed in attenuation or
      backscatter at 55 degrees C or less. The attenuation coefficient and backscatter
      power increased by factors of 1.25 and 5, respectively, during the 60 degrees C
      heating. During the 65 degrees C heating, the same properties showed increases by
      factors of 2.7 and 9.

PMID- 12467859
TI  - Fundamental limitations of noninvasive temperature imaging by means of ultrasound
      echo strain estimation.
AB  - Ultrasonic estimation of temperature-induced echo strain has been suggested as a
      means of predicting the location of thermal lesions formed by focused ultrasound
      (US) surgery before treatment. Preliminary investigations of this technique have
      produced optimistic results because they were carried out with rubber phantoms
      and used room temperature, rather than body temperature, as the baseline. The
      objective of the present study was to determine, through modelling, the likely
      feasibility of using ultrasonic temperature imaging to detect and localise the
      focal region of the heating beam for a medium with a realistic temperature
      dependence of sound speed subjected to a realistic temperature rise. We
      determined the minimum ultrasonic signal-to-noise ratio (SNR) required to
      visualise the heated region for liver of varying fat content. Due to the small
      (0.5%) change in sound speed at the focus, the threshold SNR for normal liver
      (low fat content) was found to be at least 20 dB. This implies that temperature
      imaging in this tissue type will only be feasible if the effects of electronic
      noise can be minimised and if other sources of noise, such as cardiac-induced
      motion, do not substantially reduce the visibility of the focal region. For liver
      of intermediate fat content, the heated region could not be visualised even when
      the echo data were noise-free. Tissues with a very high fat content are likely to
      represent the most favourable conditions for ultrasonic temperature imaging.

PMID- 12467860
TI  - Low-intensity pulsed ultrasound accelerates the regeneration of the sciatic nerve
      after neurotomy in rats.
AB  - The biophysical qualities of pulsed ultrasound (US) led us to appraise its effect
      on the regeneration of a peripheral nerve. In this study, our intention was to
      evaluate the effects of pulsed US on the axotomy of the sciatic nerve in rats.
      The proximal stump of the nerve was stimulated on 12 consecutive days with pulsed
      US and the effects of the sonication were evaluated through morphological and
      morphometric techniques. Our findings suggest that sonication leads to a rapid
      regeneration of the nerve after axotomisation. These affirmations are based on
      the counting of different types of fibre components in mixed nerves and the
      morphological recovery of the same in comparison with nerves of animals submitted
      to sham operation.

PMID- 12467861
TI  - Lithotripter shock waves with cavitation nucleation agents produce tumor growth
      reduction and gene transfer in vivo.
AB  - Cavitation nucleation agents (CNA) can greatly enhance DNA transfer and cell
      killing for therapeutically useful applications of nonthermal bioeffects of
      ultrasound (US). Renal carcinoma (RENCA) tumor cells were implanted and grown to
      about 400 microL tumor volumes on the hind legs of syngeneic Balb/c mice. Before
      treatment, mice were anesthetized, the tumor region was shaved and depilated, and
      a DNA plasmid coding for marker proteins was injected into the tumor. Two sets of
      tests were completed: the first set involved measurement of tumor growth for 4
      days and use of a beta-galactosidase marker plasmid for localization of
      transfection, and the second set involved 2 days of growth and use of a
      luciferase marker plasmid for assessing overall protein expression. Either
      saline, Optison US contrast agent, a vaporizing perfluoropentane droplet
      suspension (SDS) or air bubble was also injected intratumorally at 10% of tumor
      volume as a CNA. In some tests, droplets or contrast agent were injected IV.
      Shock waves (SW) were generated from a spark-gap lithotripter at 7.4 MPa peak
      negative pressure amplitude. For sham exposure, tumor volume increased by a
      factor of 3.6 in 4 days. With 500-SW treatment, all the CNA reduced 4-day tumor
      growth about the same amount (to factors of 1.2 to 1.9). Marker gene expression
      was generally localized to the region around the needle injection path. All the
      agents, except saline, produced statistically significant increases of 11.8- to
      14.6-fold in luciferase expression after 2 days, relative to sham exposure. IV
      injection of Optison or droplet nucleation agents before SW treatment reduced
      tumor growth to factors of 1.0 and 0.7, but did not increase transfection. These
      results demonstrate the efficacy of CNA in vivo and should lead to improved
      strategies for simultaneous SW tumor ablation and cancer gene therapy.

PMID- 12467862
TI  - Spontaneous homogeneous nucleation, inertial cavitation and the safety of
      diagnostic ultrasound.
AB  - Gas bubbles of sufficient size to serve as cavitation nuclei may form
      spontaneously in tissue in regions of very low interfacial tension. In the
      absence of an acoustic wave or other mechanical stress, such nuclei will quickly
      dissolve and disappear from the medium. Under the influence of an acoustic wave,
      however, these microbubbles may grow to many times their initial size and then
      collapse violently, a process known as inertial cavitation. In this work, the in
      vivo energetics and dynamics of the nucleation-cavitation process were modeled by
      treating tissue as a homogeneous fluid. The assumption of a viscosity of 10(-3)
      Pa s (i.e., that of water) resulted in the lowest acoustic rarefactional pressure
      threshold for nucleation-cavitation events, approximately 4.0 MPa, which was
      essentially frequency-independent over the range 1 to 15 MHz. The rarefactional
      pressure threshold for a viscosity of 5 x 10(-3) Pa s (that of blood) also was
      approximately 4.0 MPa at 1 MHz, but the threshold for this higher viscosity
      increased nearly linearly with frequency above approximately 5 MHz, never being
      more than approximately 0.2 MPa below the equivalent derated peak rarefactional
      pressure calculated assuming MI = 1.9, the current USFDA guideline.

PMID- 12467863
TI  - On the origin of respiratory artifacts in BOLD-EPI of the human brain.
AB  - BOLD-based functional MRI (fMRI) can be used to explicitly measure hemodynamic
      aspects and functions of human neuro-physiology. As fMRI measures changes in
      regional cerebral blood flow and volume as well as blood oxygenation, rather than
      neuronal brain activity directly, other processes that may change the above
      parameters have to be examined closely to assess sensitivity and specificity of
      fMRI results. Physiological processes that can cause artifacts include cardiac
      action, breathing and vasomotion. Although there has been substantial research on
      physiological artifacts and appropriate compensation methods, controversy still
      remains on the mechanisms that cause the fMRI signal fluctuations. Respiratory
      correlated fluctuations may either be induced by changes of the magnetic field
      homogeneity due to moving organs, intra-thoracic pressure differences,
      respiration-dependent vasodilation or oxygenation differences. The aim of this
      study was to characterize the impact of different breathing patterns by varying
      respiration frequency and/or tidal volume on EPI time courses of the resting
      human brain. The amount of respiration-related oscillations during three
      respiration patterns was quantified, and statistically significant differences
      were obtained in white matter only: p < 0.03 between 6 vs. 12 ml/kg body weight
      end tidal volume at a respiration frequency of 15/min, p < 0.03 between 12 vs. 6
      ml/kg body weight and 15 vs. 10 respiration cycles/min. There was no significant
      difference between 15 vs. 10 respiration cycles/min at an end tidal volume of 6
      ml/kg body weight (p = 0.917). In addition, the respiration-affected brain
      regions were very similar with EPI readout in the a-p and l-r direction. Based on
      our results and published literature we hypothesize that venous oxygenation
      oscillations due to changing intra-thoracic pressure represent a major factor for
      respiration-related signal fluctuations and increase significantly with
      increasing end tidal volume in white matter only.

PMID- 12467864
TI  - Magnetic resonance imaging with lateralized arterial spin labeling.
AB  - We report the development of a new MRI technique which allows spins from right
      sided arteries to be labeled separately from spins from left-sided arteries. This
      method uses two spatially-selective adiabatic inversion pulses to alternate the
      labeling of the right carotid and vertebral artery separate from the left carotid
      and vertebral artery. Normal volunteers were scanned on a clinical 1.5 T system
      and the resultant brain images correlated with the T2 anatomic images. Arterial
      anatomy was depicted using the new sequence and corresponded to the labeling
      scheme employed by the sequence. It was demonstrated that spatially selective
      inversion pulses permit the encoding of the spins within specific vascular
      origins and the observation of their run-off territory.

PMID- 12467865
TI  - Quantitative MR renography using a calibrated internal signal (ERETIC).
AB  - To measure MR renograms, cortical and medullary kidney signal intensity evolution
      is followed after contrast agent injection. To obtain an accurate quantitative
      signal measurement, the use of a reference signal is necessary to correct the
      potential MRI system variations in time. The ERETIC method (Electronic Reference
      To access In vivo Concentrations) provides an electronic reference signal. It is
      synthesized as an amplitude modulated RF pulse applied during the acquisition.
      The ERETIC method was as precise as the external tube reference method but
      presents major advantages like its free adjustability (shape, location and
      magnitude) to the characteristics of the organ studied as well as its not taking
      room inside the magnet. Even though ERETIC showed a very good intrinsic
      stability, systems' variations still affect its signal in the same way as real
      NMR signals are affected. This method can be easily implemented on any imaging
      system with two RF channels.

PMID- 12467866
TI  - An automated method for volumetric quantification of magnetization transfer of
      the brain.
AB  - Cerebral white matter damages can be detected and characterized using
      magnetization transfer (MT) imaging. In this study a fully automated method of
      measuring and analyzing the MT of the whole human brain is presented and
      assessed. A 3D-FLASH sequence with off-resonance RF pulse was optimized for fast,
      volumetric MT measurements. The postprocessing software developed for this
      purpose includes a SPM99-based segmentation algorithm, a visualization tool, and
      a histogram-based MT parameter analysis. The reproducibility of the method was
      tested with phantom measures and in studies on nine healthy volunteers. Small
      variances (0-1.6%) and therefore, a high reproducibility of MT parameter
      measurements were found in vitro, slightly higher variances in volunteer
      investigations (0.7-4.0%). With our technique, we expect to be able to better
      recognize and follow up the progression of white matter diseases. Due to the high
      reproducibility, this volumetric approach is specifically suitable for
      longitudinal MT studies.

PMID- 12467867
TI  - 3-D echo planar (1)HMRS imaging in MS: metabolite comparison from supratentorial
      vs. central brain.
AB  - To determine if metabolite ratios as measured by 3-dimensional echo planar
      spectroscopy imaging (3D-EPSI) from central brain regions of interest (ROI)
      centered at the corpus callosum reflect imaging metrics of large volumes of
      supratentorial brain (STB) from patients with multiple sclerosis. METHODS: 48 MS
      patients with relapsing-remitting, secondary progressive, and primary progressive
      disease underwent a 3D-EPSI sequence covering large volumes of STB. Metabolite
      ratios were first estimated from all voxels within a STB mask using a linear
      regression of N-acetylaspartate (NAA) over Creatine (Cr), NAA over choline (Cho)
      and Cho over Cr. Secondly, spectroscopic voxels from a central brain (CB) ROI
      centered at the corpus callosum were selected within the STB. Ratios were
      compared using Bland-Altman regression analysis and Spearman's correlation
      coefficients between STB versus central brain. Ratios from studied ROIs were
      correlated with the EDSS and compared to normal controls. RESULTS: Very strong
      correlations ranging from 0.884 and 0.938 (p < 0.0001) were found for all
      metabolite ratios between STB versus central brain. NAA/Cr ratios were similarly
      and negatively correlated with the EDSS across all ROIs, trends ranging from 
      0.257 to -0.314 (p < 0.1). NAA/Cr from all MS patients was similarly decreased
      compared to controls across all ROIs (p < 0.01). CONCLUSION: Metabolite ratios
      from a central brain ROI were statistically equivalent and highly correlated with
      ratios from the STB. The study of NAA/Cr using (1)HMRS from a central brain ROI
      centered at the corpus callosum seems to be representative of brainwide axonal
      changes in patients with MS.

PMID- 12467868
TI  - Measuring magnetic fields generated by DC currents in receive-only coils.
AB  - DC decoupling currents applied to receive-only coils during radiofrequency
      transmission can create stray magnetic fields capable of changing the resonant
      frequency of nearby nuclei. It is difficult to measure these fields with
      conventional field-mapping techniques because the fields are not present when the
      signal is acquired. The stray fields can be measured empirically with cardiac
      tags.

PMID- 12467869
TI  - Renal malacoplakia: demonstration by MR imaging.
AB  - We report herein a case of histologically verified bilateral renal malacoplakia.
      MRI features were distinctive and include multiple nodules 1-2 cm in diameter
      that were low in signal on T1, T2 and early and late post gadolinium images with
      intervening fibrous stroma. Demonstration of renal malacoplakia on MR images may
      obviate the need for major surgery and rapidly direct patients to appropriate
      antimicrobial therapy for treatment.

PMID- 12467870
TI  - MR angiography of left-sided cervical aortic arch with aneurysm formation.

PMID- 12467871
TI  - Proton MR spectroscopy of cerebellitis.
AB  - Single voxel proton MR spectroscopy ((1)H-MRS) of the vermis was obtained in two
      patients with cerebellitis. In the acute phase (1)H-MRS revealed low N-acetyl
      aspartate (NAA)/creatine (Cr) and NAA/choline (Cho) and normal Cho/Cr ratios.
      Decrease of the concentration of NAA was confirmed by quantitative analysis in
      one patient. The NAA/Cr and NAA/Cho ratios and NAA concentration were increased
      in (1)H-MRS examinations obtained 10 and 24 months after the acute episode. (1)H
      MRS demonstrates reversible metabolite changes in cerebellitis.

PMID- 12467872
TI  - In vivo multiple spin echoes imaging of trabecular bone on a clinical 1.5 T MR
      scanner.
AB  - In vivo multiple spin echoes (MSE) images of bone marrow in trabecular bone were
      obtained for the first time on a clinical 1.5 T scanner. Despite of a reduced
      sensitivity of the MSE trabecular bone images with respect to the cerebral matter
      ones, it is possible to observe some features in the MSE trabecular bone images
      that may be useful in the diagnosis of osteopenic states. Two different CRAZED
      type MSE imaging sequences based on spin-echo and EPI imaging modalities were
      applied in phantom and in vivo. Preliminary experimental results indicate that
      EPI imaging readout seems to conceal the MSE contrast correlated with pore
      dimension in porous media. However it is still possible to detect anisotropy
      effects related to the bone structure in MSE-EPI images. Some strategies are
      suggested to optimize the quality of MSE trabecular bone images.

PMID- 12467873
TI  - Epithelioid hemangioendothelioma of the liver. MR imaging findings.
AB  - We report the MR appearance of epithelioid hemangioendothelioma (EHE) in a 51
      year old man, who presented with a 14-month history of fatigue and anemia to his
      physician. The tumor showed massive replacement of the liver and had an unusual
      appearance of multiple high fluid content focal lesions with diminished
      vascularity.

PMID- 12467875
TI  - Postnatal changes in the overall postsynaptic currents evoked in CA1 pyramidal
      neurons of the rat hippocampus.
AB  - Evoked fast postsynaptic currents (fPSCs) during the postnatal development of
      rats (postnatal day 6-70, P6-P70) were systematically examined in hippocampal CA1
      pyramidal neurons using whole-cell recordings with biocytin-filled electrodes.
      Focal stimulation of the stratum radiatum in the CA1 region elicited fPSCs in 80%
      of the neurons P6-7, 90% of P9-10, and 100% of > or =P11. In neurons P6-7, the
      fPSCs were exclusively inward and had multiple (on average 5.6) peaks. The fPSCs
      increased in amplitude with the growth of dendritic arborization, but decreased
      in the number of peaks. A distinct outward fPSC following the inward fPSC emerged
      in neurons > or =P11 and was abolished by bicuculline (50 microM). Bicuculline
      increased the amplitude and duration of the initial inward fPSC (fEPSC) in all
      age groups and characteristically recruited the polysynaptic second component of
      fEPSCs in neurons P11-P21. No spontaneous periodic inward current was detected in
      any age group after blocking GABAA receptors. The coapplication of DL-2-amino-5
      phosphonopentanoic acid (AP5, 100 microM) with bicuculline did not eliminate the
      polysynaptic second component, but the second component was only elicited in
      slices in which the CA3 region was kept intact. Moreover, the bicuculline- and
      AP5-resistant second component was due to the burst activity of CA3 pyramidal
      neurons, which were excited through excitatory recurrents of the Schaffer
      collaterals. Plausible physiological functions of the generation of the second
      component in vivo were discussed.

PMID- 12467876
TI  - Proteases involved in long-term potentiation.
AB  - Much attention has been paid to proteases involved in long-term potentiation
      (LTP). Calpains, Ca-dependent cysteine proteases, have first been demonstrated to
      be the mediator of LTP by the proteolytic cleavage of fodrin, which allows
      glutamate receptors located deep in the postsynaptic membrane to move to the
      surface. It is now generally considered that calpain activation is necessary for
      LTP formation in the cleavage of substrates such as protein kinase Czeta, NMDA
      receptors, and the glutamate receptor-interacting protein. Recent studies have
      shown that serine proteases such as tissue-type plasminogen activator (tPA),
      thrombin, and neuropsin are involved in LTP. tPA contributes to LTP by both
      receptor-mediated activation of cAMP-dependent protein kinase and the cleavage of
      NMDA receptors. Thrombin induces a proteolytic activation of PAR-1, resulting in
      activation of protein kinase C, which reduces the voltage-dependent Mg2+ blockade
      of NMDA receptor-channels. On the other hand, neuropsin may act as a regulatory
      molecule in LTP via its proteolytic degradation of extracellular matrix protein
      such as fibronectin. In addition to such neuronal proteases, proteases secreted
      from microglia such as tPA may also contribute to LTP. The enzymatic activity of
      each protease is strictly regulated by endogenous inhibitors and other factors in
      the brain. Once activated, proteases can irreversibly cleave peptide bonds. After
      cleavage, some substrates are inactivated and others are activated to gain new
      functions. Therefore, the issue to identify substrates for each protease is very
      important to understand the molecular basis of LTP.

PMID- 12467877
TI  - The presynaptic modulation of glutamate release and the membrane dysfunction
      induced by in vitro ischemia in rat hippocampal CA1 neurons.
AB  - Superfusion with an oxygen and glucose deprived medium (in vitro ischemia) of rat
      hippocampal CA1 pyramidal neurons in tissue slices produced a rapid
      depolarization within 5 min and thereafter showed no functional recovery
      (irreversible membrane dysfunction), even if oxygen and glucose were
      reintroduced. We previously suggested that such a rapid depolarization is
      triggered by the accumulation of extracellular glutamate (Glu). As a result, we
      examined the effects of either the activation or inhibition of presynaptic
      receptors, which modulate Glu release from the nerve terminal, on the potential
      change produced by in vitro ischemia. The adenosine A1 receptor antagonist, 8
      cyclopenthyl theophylline, A2a receptor antagonist, ZM241385, and A2b receptor
      antagonist, alloxazine, did not significantly alter either the latency or the
      maximal slope of the rapid depolarization. In addition, the GABAB receptor
      antagonist, 2-hydroxysaclofen, or the metabotropic Glu receptor type 4
      antagonist, alpha-methylserine-O-phosphate, did not change either the latency or
      the maximal slope. The adenosine A(1) receptor agonist, 2-chloro-N6
      cyclopentyladenosine, A2a receptor agonist, CGS2168, or A2b receptor agonist, 5'
      (N-ethylcarboxamido)-adenosine, did not affect these parameters either. None of
      these drugs restored the membrane potential to the pre-exposure level after the
      reintroduction of oxygen and glucose. Simultaneous intracellular recordings from
      CA1 and CA3 pyramidal neurons in the same slices revealed the membrane of the CA3
      neurons to be hyperpolarized when a rapid depolarization occurred in the CA1
      neurons. These results suggest that presynaptic Glu release does not accelerate
      during the generation of the rapid depolarization induced by in vitro ischemia.

PMID- 12467878
TI  - Role of presynaptic 5-HT1A and 5-HT3 receptors in modulation of synaptic GABA
      transmission in dissociated rat basolateral amygdala neurons.
AB  - Serotonin (5-HT) is considered to play a significant role in anxiety-related
      behaviors in animals through actions on the amygdaloid complex. To evaluate this
      role from the point of neurotransmitter release regulation, nystatin-perforated
      patch recording was employed on mechanically dissociated basolateral amygdala
      neurons containing functional synaptic boutons. GABAAergic miniature inhibitory
      postsynaptic currents (mIPSCs) were pharmacologically separated. In subsets of
      neurons, 8-OH-DPAT (1 microM), a specific 5-HT1A agonist, continuously inhibited
      mIPSC frequency without effects on mIPSC amplitude. By comparison, mCPBG (1
      microM), a specific 5-HT3 agonist, transiently facilitated mIPSC frequency
      without effects on mIPSC amplitude. Together these results suggest the
      presynaptic existence of both 5-HT receptor subtypes. In these neurons,
      application of 8-OH-DPAT and its subsequent removal still suppressed mCPBG
      induced responses on mIPSCs. This suppression was not caused by a reduction of
      presynaptic 5-HT3 receptor affinities to mCPBG and was completely eliminated by
      pretreatment with N-ethylmaleimide, a pertussis toxin sensitive GTP-binding
      protein inhibitor. In the neurons exhibiting presynaptic modulation with mCPBG
      but not 8-OH-DPAT, such suppression by exposure to 8-OH-DPAT was not observed. In
      conclusion, activation of presynaptic 5-HT1A receptors inhibited mIPSC frequency
      and at the same time suppressed, via a G-protein-mediated mechanism, the
      transient facilitation of mIPSC frequency produced by activation of presynaptic 5
      HT3 receptors.

PMID- 12467879
TI  - Corticospinal transmission to motoneurons in cervical spinal cord slices from
      adult rats.
AB  - Cervical spinal cord slices were prepared from adult rats. Intracellular
      recordings from motoneurons revealed that electrical stimulation of the
      ventralmost part of the dorsal funiculus (which contains primarily descending
      corticospinal axons) elicited EPSPs in 75% of the neurons. The latencies of these
      EPSPs tended to be shorter than those elicited by dorsal horn gray matter
      stimulation. Pairs of subthreshold dorsal funiculus stimuli were able to elicit
      action potentials in motoneurons. These data are consistent with previous
      morphological and electrophysiological studies indicating that cervical
      motoneurons receive both mono-and polysynaptic corticospinal inputs. In addition,
      motoneurons were markedly depolarized by iontophoretic application of AMPA or KA
      (7 out of 7 neurons), but only weakly depolarized by NMDA (1 out of 6 neurons).
      CNQX (but not AP-5) blocked EPSPs elicited by dorsal funiculus stimulation. Thus,
      corticospinal transmission to motoneurons is mediated primarily by non-NMDA
      glutamate receptors.

PMID- 12467880
TI  - Involvement of reduced acetylcholine release in Delta9-tetrahydrocannabinol
      induced impairment of spatial memory in the 8-arm radial maze.
AB  - To clarify the mechanism by which Delta9-tetrahydrocannabinol, a major
      psychoactive component of marijuana, impairs spatial memory in the 8-arm radial
      maze in rats via the cholinergic system, we used two acetylcholinesterase
      inhibitors, physostigmine and tetrahydroaminoacridine. Moreover, we examined the
      effect of Delta9-tetrahydrocannabinol on acetylcholine release in the frontal
      cortex and dorsal and ventral hippocampus using in vivo microdialysis.
      Physostigmine (0.01-0.05 mg/kg, i.p.) and tetrahydroaminoacridine (1-5 mg/kg,
      p.o.) improved the impairment of spatial memory induced by Delta9
      tetrahydrocannabinol (6 mg/kg, i.p.) in the 8-arm radial maze. Delta9
      tetrahydrocannabinol (6 mg/kg, i.p.) produced a significant decrease in
      acetylcholine release in the dorsal hippocampus as assessed by microdialysis.
      Moreover, tetrahydroaminoacridine at a dose of 1 mg/kg, which improved the
      impairment of spatial memory, reversed the decrease in acetylcholine release
      induced by Delta9-tetrahydrocannabinol in the dorsal hippocampus during 60-120
      min after the Delta9-tetrahydrocannabinol injection. These findings suggest that
      inhibition of the cholinergic pathway by reduced acetylcholine release is one of
      the means by which Delta9-tetrahydrocannabinol impairs spatial memory in the 8
      arm radial maze.

PMID- 12467882
TI  - Receptor subtype specific activation of the rat gastric vagal afferent fibers to
      serotonin.
AB  - Systemic administration (i.v.) of serotonin (5-HT) evoked a transient vagal
      afferent nerve discharge, bradycardia, and hypotension in the rat. The half
      effective dose of 5-HT for nerve discharge was 13 micro g/kg. The time- and dose
      dependent kinetics of the nerve discharge rate were similar to the change of
      heart rate. The afferent neuronal discharge was mimicked by a selective 5-HT3
      receptor agonist, 1-phenylbiguanide hydrochloride (PBA), and inhibited by a
      selective 5-HT3 antagonist, granisetron. The 5-HT(3/4) agonist, cisapride
      partially activated the vagus nerve, but the 5-HT4 agonist, RS6733 had no effect
      on the vagal afferent activity. Intra-gastric perfusion of lidocaine, moreover,
      abolished the 5-HT-induced vagal activation. These results indicate that the 5-HT
      transmission signal in the gastric mucosa inputs to the brain stem via 5-HT3
      receptor-mediated vagal nerve afferent.

PMID- 12467881
TI  - Roles of histamine in regulation of arousal and cognition: functional
      neuroimaging of histamine H1 receptors in human brain.
AB  - Brain histamine is involved in a wide range of physiological functions such as
      regulation of the sleep-wake cycle, arousal, cognition, and memory mainly through
      interactions with histamine H1 receptors (H1Rs). Neurons producing histamine,
      histaminergic neurons, are exclusively located in the posterior hypothalamus and
      transmit histamine to almost all regions of the brain. Histamine H1 antagonists,
      or antihistamines, often prescribed for treatment of allergic disorders,
      sometimes induce sleepiness and cognitive deficits. It is understood that the
      mechanism of such CNS side effects is that antihistamine blocks H1Rs in the
      brain. The purpose of the present study was to compare the CNS side effects of
      different antihistamines. Subjective sleepiness was measured using the Stanford
      Sleepiness Scale (SSS) and psychomotor performance was examined by a
      tachistoscope testing system in healthy, young, Japanese volunteers (16 males, 20
      28 yrs.) before and after oral administration of antihistamines such as
      fexofenadine (FEX) and cetirizine (CET). Additionally, H1R occupancy by
      antihistamines was examined by PET with 11C-doxepin in 8 volunteers. The results
      of SSS and psychomotor tests demonstrated that FEX tended to be less sedative
      than CET though the difference was not statistically significant. PET
      measurements revealed that no H1Rs in the cerebral cortex were occupied by FEX
      while about 30% of H1Rs were occupied by CET. In summary, it was confirmed that
      histamine and H1Rs are involved in maintaining arousal and cognition in humans,
      and that the severity of clinical symptoms is correlated to the amount of
      antihistamine that penetrated into the brain.

PMID- 12467883
TI  - Subchronic treatment with cyclosporin A decreases the binding properties of the
      GABAA receptor in ovariectomized rats.
AB  - In this study, we investigated the effect of cyclosporin A on the binding
      properties of the GABAA receptor in the hippocampus, known to be responsible for
      the induction of seizures, to clarify the mechanism of cyclosporin A-inhibited
      GABA neurotransmission in ovariectomized rats, as a climacterium model. The
      effects of single and subchronic treatments with cyclosporin A were examined on
      [3H]muscimol binding to hippocampal synaptosomal membranes in sham,
      ovariectomized, and estradiol/ovariectomized rats. A single treatment with
      cyclosporin A (40 mg/kg, i.p.) failed to change [3H]muscimol binding in the 3
      groups, when compared with each corresponding vehicle-treated group. Subchronic
      treatment with cyclosporin A (40 mg/kg, i.p., once a day for 5 days)
      significantly decreased the amount of [3H]muscimol binding in ovariectomized
      rats. However, this inhibitory effect was not observed in sham or
      estradiol/ovariectomized rats. These results demonstrated that the binding
      activity of the GABAA receptor was decreased in ovariectomized rats after
      subchronic cyclosporin A treatment. This study supports the hypothesis that
      ovariectomy elevates the susceptibility to cyclosporin A-induced convulsions by
      accelerating the inhibitory actions of cyclosporin A on GABA neurotransmission in
      the hippocampus.

PMID- 12467885
TI  - Molecules interacting with PRIP-2, a novel Ins(1,4,5)P3 binding protein type 2:
      Comparison with PRIP-1.
AB  - A family of phospholipase C-related, catalytically inactive proteins (designated
      PRIP) have been identified as a group of novel inositol 1,4,5-trisphosphate
      binding proteins with a domain organization similar to phospholipase C-delta but
      lacking the enzymatic activity. The PRIP family consists of at least two types of
      proteins (PRIP-1 and PRIP-2 subfamilies). In the present study, we examined the
      tissue distribution of PRIP-2, its expression in rat brain at the mRNA level, and
      the characteristics of its binding to inositol compounds, protein phosphatase 1,
      and gamma-amino butyric acid receptor associated protein. We also compared these
      characteristics with those of PRIP-1. Northern blot analysis and reverse
      transcription polymerase chain reaction showed that PRIP-1 was present mainly in
      the brain, whereas PRIP-2 was expressed ubiquitously. In situ hybridization
      studies using rat brain revealed that the mRNA for both PRIP-1 and PRIP-2 was
      similarly expressed; it was detected in the granular cell and Purkinje cell
      layers in the cerebellum, and in the hippocampal pyramidal cells, dentate granule
      cells, and pyramidal and/or granule cells of the cerebral cortex in the cerebrum.
      PRIP-2 bound inositol 1,4,5-trisphosphate and its parent lipid,
      phosphatidylinositol 4,5-bisphosphate, with a similar affinity, while PRIP-1
      preferentially bound the former ligand by about 10-fold. PRIP-1 and PRIP-2
      interacted with protein phosphatase 1 and gamma-amino butyric acid receptor
      associated protein in a similar manner. These results indicate that, similar to
      PRIP-1, PRIP-2 may be involved in both inositol 1,4,5-trisphosphate-mediated and
      gamma-amino butyric acid-related signaling.

PMID- 12467884
TI  - Spatial and temporal aspects of Ca2+ signaling mediated by P2Y receptors in
      cultured rat hippocampal astrocytes.
AB  - ATP produces a variety of Ca2+ responses in astrocytes. To address the complex
      spatio-temporal Ca2+ signals, we analyzed the ATP-evoked increase in
      intracellular Ca2+ concentration ([Ca2+]i) in cultured rat hippocampal astrocytes
      using fura-2 or fluo-3 based Ca2+ imaging techniques. ATP at less than 10 nM
      produced elementary Ca2+ release event "puffs" in a manner independent of
      extracellular Ca2+. Stimulation with higher ATP concentrations (3 or 10 micro M)
      resulted in global Ca2+ responses such as intercellular Ca2+ wave. These Ca2+
      responses were mainly mediated by metabotropic P2Y receptors. ATP acting on both
      P2Y1 and P2Y2 receptors produced a transient Ca2+ release by inositol 1,4,5
      trisphosphate (InsP3). When cells were stimulated with ATP much longer, the
      transient [Ca2+]i elevation was followed by sustained Ca2+ entry from the
      extracellular space. This sustained rise in [Ca2+]i was inhibited by Zn2+ (<10
      micro M), an inhibitor of capacitative Ca2+ entry (CCE). CCE induced by
      cyclopiazonic acid or thapsigargin and Ca2+ entry evoked by ATP share the same
      pharmacological profile in astrocytes. Taken together, the hierarchical Ca2+
      responses to ATP were observed in hippocampal astrocytes, i.e., puffs, global
      Ca2+ release by InsP3, and CCE in response to depletion of InsP3-sensitive Ca2+
      stores. It should be noted that these Ca2+ signals and their modulation by Zn2+
      could occur in the hippocampus in situ since both ATP and Zn2+ are rich in the
      hippocampus and could be released by excitatory stimulation.

PMID- 12467886
TI  - Phosphatidylinositol and PI-4-monophosphate recover amyloid beta protein-induced
      inhibition of Cl- -ATPase activity.
AB  - The neuronal Cl- -ATPase/pump is a candidate for an outwardly directed active Cl-
      transport system, which requires phosphatidylinositol-4-monophosphate (PI4P) for
      its optimal activity. We previously reported that low concentrations (1-10 nM) of
      amyloid beta proteins (Abetas, Abeta1-42, Abeta25-35), the neurotoxic peptides in
      Alzheimer's disease, reduced Cl- -ATPase activity in cultured rat hippocampal
      neurons without any changes in the activities of Na+/K+-ATPase or anion
      insensitive Mg(2+)-ATPase, and decreased PI, PIP, and PIP2 levels in neuronal
      plasma membranes (Journal of Neurochemistry 2001, 78, 569-579). In this study, we
      examined the effects of exogenously applied PI and PI4P on the Abeta25-35-induced
      changes in Cl- -ATPase activity, the intracellular concentration of Cl- ([Cl-
      ]i), and glutamate neurotoxicity using primary cultured rat hippocampal neurons.
      The Abeta decreased Cl- -ATPase activity to 47% of control and increased [Cl- ]i
      in hippocampal pyramidal cell-like neurons to a level 3 times higher than the
      control. The addition of PI (50-750 nM) or PI4P (50-150 nM) dose-dependently
      blocked the inhibitory effects of Abeta on Cl- -ATPase activity. High doses of PI
      (750 nM) and PI4P (100-150 nM) reduced Na+/K+-ATPase activity to 41% and 35% of
      control, respectively, but this inhibition was attenuated by the co-application
      of phosphatidylserine (PS, 1 micro M). PI or PI4P (75 nM each) reversed the Abeta
      induced increase in [Cl-]i. In the Abeta-exposed culture, stimulation by
      glutamate (10 micro M, 10 min) resulted in an increase in DNA fragmentation and
      decreases in cell viability. Addition of PI or PI4P prevented the Abeta-induced
      aggravation of glutamate neurotoxicity. Thus, PI and PI4P were demonstrated to
      prevent Abeta-induced decreases in Cl- -ATPase activity and increases in neuronal
      [Cl- ]i in parallel with the attenuation of Abeta-induced aggravation of
      glutamate neurotoxicity.

PMID- 12467887
TI  - Exocytosis mechanism as a new targeting site for mechanisms of action of
      antiepileptic drugs.
AB  - Carbamazepine (CBZ) and zonisamide (ZNS) are effective antiepileptic drugs (AEDs)
      for the treatment of epilepsy and mood disorder. One of the mechanisms of action
      of CBZ and ZNS is inactivation of voltage-gated Na+ channel (VGSC). However, the
      major mechanism(s) of action of these AEDs is not clear yet. We have been
      exploring novel targeting mechanisms for the antiepileptic actions of CBZ and ZNS
      during the past ten years. In this report, we describe our hypothesis regarding
      the new targeting mechanisms for the antiepileptic action of AEDs. We determined
      an interaction between these AEDs and inhibitors of both voltage-sensitive Ca2+
      channels (VSCCs) and soluble N-ethylmaleimide-sensitive factor attachment protein
      receptor (SNARE) on neurotransmitter exocytosis using microdialysis. Perfusion
      with therapeutic concentrations of CBZ and ZNS increased basal neurotransmitter
      release. This stimulatory action was predominantly inhibited by inhibitors of N
      type VSCC and syntaxin. CBZ and ZNS increased Ca2+-evoked release, an action
      selectively inhibited by inhibitors of N-type VSCC and syntaxin. CBZ and ZNS
      reduced K+-evoked release, an action predominantly inhibited by inhibitors of P
      type VSCCs and synaptobrevin. These actions of CBZ and ZNS on neurotransmitter
      exocytosis could be observed under the condition of inhibition of VGSC using
      perfusion with tetrodotoxin. Our findings enhance our understanding of the
      mechanisms of action of CBZ and ZNS as AEDs, which possibly reduce P-type
      VSCCs/synaptobrevin-related exocytosis mechanisms during the depolarization
      stage, and simultaneously enhance N-type VSCCs/syntaxin-related exocytosis
      mechanisms at the resting stage.

PMID- 12467888
TI  - Modification of ATP-sensitive K+ channels by proteolysis in smooth muscle cells
      from pig urethra.
AB  - Patch-clamp experiments have been performed to investigate the effects of
      endoproteases (such as trypsin, carboxypeptidase B) on both membrane currents and
      unitary currents in isolated smooth muscle cells from pig proximal urethra
      (conventional whole-cell configuration, cell-attached configuration, and inside
      out patches). Application of either trypsin (1 mg/mL) or carboxypeptidase B (0.1
      mg/mL) to the intracellular surface of the excised membrane patches stimulated
      the activity of a 2.1 pA K+ channel (in symmetrical 140 mM K+ conditions) at a
      holding potential of -50 mV. The trypsin-induced K+ channels in inside-out
      configuration exhibited the same amplitude and similar channel opening kinetics
      to the levcromakalim-induced ATP-sensitive K+ channel (i.e. K ATP channel) in
      cell-attached patches of the same membrane; however, the sensitivity of the
      channels to glibenclamide was greatly reduced after the trypsin-treatment. The
      activity of the trypsin-induced K+ channel was reversibly inhibited by
      cibenzoline in an inside-out configuration (Ki = 5 microM). It is concluded that
      trypsin and carboxypeptidase B reactivate the channel with an intact pore
      activity but the different pharmacological properties of the channels may reflect
      some change in the conformation in channel proteins after proteolysis.

PMID- 12467889
TI  - Contribution of nifedipine-insensitive voltage-dependent Ca2+ channel to diameter
      regulation in rabbit mesenteric artery.
AB  - We investigated a possible role of nifedipine-insensitive high voltage-activated
      (NI-HVA) Ca2+ channels in arterial diameter regulation in the semi-terminal
      branches of rabbit mesenteric artery (RMA). From these branches, NI-HVA Ca2+
      currents showing almost identical properties to those previously identified in a
      similar region of guinea-pig [Circulation Research 1999;85:596-605] were recorded
      with whole-cell patch clamp recording. With video-microscopic measurement, the
      diameter of RMA segments perfused intraluminally at a constant rate (2-6 mL/h;
      269 +/- 9 micro m, n = 27) decreased by 50-60% by raising the external K+
      concentration ([K+]o) to 75 mM, a substantial part of which remained after
      addition of 1-10 micro M nifedipine (44 +/- 5% of initial diameter, n = 27). This
      nifedipine-insensitive diameter decrease (NI-DD) appeared to consist of initial
      transient and subsequent tonic phases (this separation was, however, not always
      clear), was resistant to tetrodotoxin, and was completely abolished in Ca2+-free
      or 100 micro M Cd2+-containing bath solutions. The magnitude of NI-DD increased
      depending on [K+]o with a threshold concentration of 20-40 mM. Raising the
      external Ca2+ concentration dose-dependently increased the magnitude of NI-DD,
      the extent being more prominent in the late tonic phase. Combined application of
      caffeine (10 mM) with ryanodine (3 micro M) produced a large transient NI-DD,
      which strongly attenuated the NI-DD evoked by a subsequent elevation in [K+]o.
      Using the fura-2 spectrofluorimetric Ca2+ imaging technique, a nifedipine
      insensitive [Ca2+]i increase showing similar [K+]o-dependence and Cd2+
      sensitivity to NI-DD was observed. These properties of NI-DD accord with those of
      NI-HVA Ca2+ channels, thus suggesting their contribution to small arterial
      diameter regulation in RMA.

PMID- 12467890
TI  - Upregulation of CRH gene expression and downregulation of arginine vasopressin
      gene expression in the hypothalamus of bilateral nephrectomized rats.
AB  - The expression of the corticotropin-releasing hormone (CRH) gene and the arginine
      vasopressin (AVP) gene in the hypothalamus examined in bilateral nephrectomized
      rats by in situ hybridization histochemistry. The expression of the CRH gene was
      significantly increased in the parvocellular part of the paraventricular nucleus
      (PVN) 12 and 20 h after bilateral nephrectomy in comparison with that after sham
      operation. The plasma concentration of adrenocorticotropic hormone (ACTH) in
      nephrectomized rats was significantly higher than that in sham operated rats 20 h
      after surgery. In contrast, the expression of the AVP gene in both the
      parvocellular and magnocellular parts of the PVN and throughout the supraoptic
      nucleus (SON) was significantly decreased 20 h after bilateral nephrectomy in
      comparison with that after sham operation. These results suggest that nephrectomy
      induced upregulation of the CRH gene with elevation of plasma ACTH may be due to
      the activation of the hypothalamo-pituitary adrenal (HPA) axis.

PMID- 12467891
TI  - Functional implications of Ca2+ mobilizing properties for nitric oxide production
      in aortic endothelium.
AB  - We have investigated the relationship between Ca2+ mobilization and the cellular
      production of nitric oxide (NO) by using fura-2 and diaminofluorescein-2 (DAF-2),
      an NO-sensitive dye, in bovine aortic endothelial cells (BAEC). High
      concentrations of ATP (100 microM) or thapsigargin (1 micro M) depleted
      intracellular Ca2+ store sites with a single Ca2+ transient, and induced an
      increase in DAF-2 fluorescence even in Ca2+-free solution, thereby indicating
      that store depletion leads to NO production. The same level of increase in DAF-2
      fluorescence was elicited by low concentrations of ATP (1 micro M), which induced
      Ca2+ oscillations but did not deplete store sites, only in the presence of
      extracellular Ca2+. Furthermore, inhibition of ATP (1 micro M)-induced Ca2+ entry
      with La3+ suppressed DAF-2 fluorescence. ATP (0.3 micro M), applied in Ca2+-free,
      Mn2+-containing solution induced Mn2+ entry-coupled fura-2 quenching, repeating
      shortly after each oscillation peak. These results indicate that NO is produced
      preferentially by entered Ca2+, and that Ca2+ oscillations, which are induced by
      low levels of stimulation, play a significant role in NO production by strongly
      modulating Ca2+ entry.

PMID- 12467892
TI  - Hyperexcitability and changes in activities of Ca2+/calmodulin-dependent kinase
      II and mitogen-activated protein kinase in the hippocampus of rats exposed to 1
      bromopropane.
AB  - Chronic inhalation of 1-bromopropane (1-BP), a substitute of ozone-depleting
      chlorofluorocarbons, has been suspected of having central neurotoxicity (Clinical
      Neurology and Neurosurgery 101 (1999) 199; Journal of Occupational Health 44
      (2002) 1) for humans. In animal experiments, 1-BP inhalation (1500 ppm) caused
      hyperexcitability in the CA1 and the dentate gyrus (DG) [Journal of Occupational
      Health 42 (2000) 149, Journal of Occupational Health 44 (2002) 156]. We studied
      whether the hyperexcitability is associated with changes of Ca2+/calmodulin
      dependent kinase II (CaMKII), mitogen-activated protein kinase (MAPK), and
      protein kinase C (PKC). Male Wistar rats were exposed to 1-BP for 6 hours in a
      day in an exposure chamber with a concentration of 700 ppm for 8 weeks. After the
      inhalation, paired-pulse ratios of field excitatory postsynaptic potentials and
      population spikes (PSs) were analyzed in the CA1 and DG of hippocampal slices.
      Control rats were then given fresh air in the inhalation chamber.
      Semiquantitative immunoblotting analyses of protein kinases using antibodies
      against active and conventional protein kinases were done using the whole
      hippocampus. A paired-pulse ratio of PS was increased at the 5 ms interpulse
      interval in the CA1 and at the 10-20 ms interpulse intervals in the DG. The
      amount of active MAPK and total amount of CaMKIIalpha and beta were significantly
      increased by 28, 29, and 46% compared to control, respectively, without any
      change in PKC activity. In contrast, the amount of active CaMKIIbeta was
      decreased to 78%. These results suggest that modifications of intracellular
      signaling cascades are associated with hyperexcitability that occurred in the
      hippocampal formation of rats exposed to the chronic inhalation of 1-BP.

PMID- 12467893
TI  - The role of contextual cues on counterirritation in the development process of
      analgesic tolerance to morphine.
AB  - Tolerance to morphine analgesia was determined by daily exposing rats either to
      the same box or different boxes during repeated administration of formalin (2.5%,
      0.4 mL/body, sc) and morphine (5 mg/kg, sc). The analgesic effect was determined
      daily for four consecutive days by exposing rats to either the same box or
      different boxes, and the process of tolerance development was assessed by a hot
      plate test (52.5 degrees C). The rats were divided into four groups: one group
      received formalin and morphine in the same context (Group FM-Same), one group in
      the different context (Group FM-Diff), one group received saline and morphine in
      the same context (Group SM-Same), two groups received formalin in the same or
      different contexts (Groups FS-Same or FS-Diff), and one group received saline in
      the same context (Group SS-Same). The response latency of Group SM-Same was
      decreased from Day 2 to a level similar to that of Group SS-Same on Day 4, while
      that of FM-Same decreased more slowly. The latency of Group FM-Diff maintained
      the level of Day 2 until Day 4, being significantly longer than that of FM-Same.
      In the Extinction Phase, all rats received formalin and saline injections in the
      same box they had been exposed to on Day 1. On the first day, hyperalgesia was
      evident in Group SM-Same alone. In the Re-test Phase, the rats underwent a second
      morphine injection, and showed recovery from tolerance. These results indicate
      that formalin-induced chronic stress pain reduces tolerance development to
      morphine, and the mutual influence of pain, counterirritation, between formalin
      and hot-plate, facilitates the effect of contextual cues by inhibiting an
      associative learning.

PMID- 12467894
TI  - Early decrease of survival factors and DNA repair enzyme in spinal motor neurons
      of presymptomatic transgenic mice that express a mutant SOD1 gene.
AB  - The primary pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS) have
      been elusive. Some of the mechanisms would be implicated in an imbalance between
      death and survival factors, and impairment of DNA repair possibly caused by
      oxidative stress. Phosphatidylinositol 3-kinase (PI3-K) and its downstream
      effector, Akt/protein kinase B (PKB), have been shown to play a pivotal role in
      neuronal survival against apoptosis supported by neurotrophic factors. To
      elucidate the mechanisms of motor neuron death in ALS, we examined the expression
      of PI3-K, Akt, and the DNA repair enzyme redox factor-1 (Ref-1) protein in the
      spinal cord of transgenic mice with an ALS-linked mutant Cu/Zn superoxide
      dismutase (SOD1) gene, a valuable model for human ALS. Immunoblotting and
      immunocytochemical analyses showed that most spinal motor neurons lost
      immunoreactivity for PI3-K, Akt, and Ref-1 in the presymptomatic stage that
      preceded a significant loss of neurons. These results suggest that an early
      decrease of survival signal proteins and a DNA repair enzyme in the spinal motor
      neurons may account for the mutant SOD1-mediated motor neuron death in this
      animal model of ALS.

PMID- 12467895
TI  - Cyclosporine A-increased nitric oxide production in the rat dorsal hippocampus
      mediates convulsions.
AB  - To test whether nitric oxide (NO) participates in cyclosporine A (CsA)-induced
      neurotoxicity including convulsions, we examined the effect of an NO synthase
      inhibitor on convulsions induced by combined treatment with CsA and bicuculline
      in mice and the effect of CsA on NO production in the dorsal hippocampus using an
      in vivo microdialysis method in rats. CsA (200 mg/kg, i.p.) significantly
      increased the intensity of convulsions induced by an intracerebroventricular
      injection of bicuculline (25 pmol) in mice. This facilitation was blocked by N
      omega -nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, but not
      by N omega -nitro-D-arginine methyl ester (D-NAME), an inactive form of L-NAME
      (10 mg/kg, i.p.). CsA (20-50 mg/kg, i.p.) dose-dependently increased NO 2 -
      levels in dialysates obtained with microdialysis in the rat dorsal hippocampus.
      This enhanced NO 2 - formation was blocked by L-NAME but not by D-NAME (50 mg/kg,
      i.p.). These findings suggest that CsA stimulates NO production and induces
      convulsions as a result of an interaction between NO and the gamma-aminobutyric
      acid (GABA) system in the hippocampus.

PMID- 12467896
TI  - Lactate utilization as an energy substrate in ischemic preconditioned rat brain
      slices.
AB  - We examined the utilization of lactate as an energy substrate in ischemic
      preconditioned slices obtained from the rat brain left hemisphere, of which the
      contralateral middle cerebral artery was occluded 48 h before the slice
      preparation. The levels of high-energy phosphates in the brain slices were
      measured using 31P NMR with a time resolution of 4 min at 25 degrees C. When
      iodoacetic acid-pretreated brain slices were further treated with fluorocitrate,
      a glial toxin, for 2 h (neuron-rich slices), the recovery of the phosphocreatine
      (PCr) level in artificial cerebrospinal fluid (ACSF) containing lactate after
      high-K+ stimulation was completely abolished in intact slices, whereas the PCr
      level in ischemic preconditioned slices well recovered in otherwise similar
      conditions. These results indicated that neurons, when preconditioned with
      ischemia, acquire the ability to utilize lactate as an energy substrate. In
      parallel experiments, we recorded population excitatory postsynaptic potentials
      and spikes from granule cells in hippocampal slices. Population spikes of intact
      slices in ACSF containing lactate were completely abolished in 30 min, but those
      of the ischemic preconditioned slices were maintained well over 50%. These
      results show that ischemic preconditioning may induce certain systematic changes
      in neurons, such as the expression of lactate transporters and/or the activation
      of lactate dehydrogenase.

PMID- 12467897
TI  - Regulation of brain cell environment on neuronal protection: role of TNFalpha in
      glia cells.
AB  - Bacterial endotoxin lipopolysaccharide (LPS) treatment of neuron-rich cells and
      glia-rich cells exhibited significant cell damage 12 hr after incubation,
      although no severe or significant cell damage induced by LPS appeared in neuron
      glia co-cultured cells. Moreover, severe and significant time-dependent cell
      damage was induced by a larger dose treatment (10 mM) of glutamate (Glu), and
      this damage was seen in neuron-rich cells, neuron-glia co-cultured cells, and
      glia-rich cells. Examining extracellular tumor necrosis factor alpha (TNFalpha)
      induced by either LPS or Glu treatment, the levels of extracellular TNFalpha
      induced by LPS were significantly higher than those induced by Glu. These
      significant increases of TNFalpha were measured within 2 hr after LPS treatment
      in neuron-glia co-cultured cells and glia-rich cells, although no significant
      changes were detected in the neuron-rich cells. With Glu treatment, a significant
      increase in TNFalpha levels was detected after 6 hr of Glu treatment only in glia
      rich cells. Our results indicate that cerebral TNFalpha is mainly produced in
      glia cells and that its production is dependently regulated by each stimulant. In
      addition, the production of TNFalpha is not directly related to the trigger of
      cell injury.

PMID- 12467898
TI  - The dawn of a new era for stroke treatment.
AB  - Due to two developments that have taken place within the past few years, the
      treatment for stroke is about to change immensely. First, it has become possible
      to significantly inhibit the spread of hypoperfusive tissue damage by initiating
      antioxidant therapy within 24 hours of a stroke. As a result of this new therapy,
      many physicians now feel that the prognosis for stroke patients has improved
      considerably. Second, elucidation of the brain function of post-stroke
      rehabilitation has made headway as advanced functional brain imaging techniques
      have provided reliable data, thereby substantiating new rationales.

PMID- 12467899
TI  - Melatonin reduces cerebral edema formation caused by transient forebrain ischemia
      in rats.
AB  - Reduction of cerebral edema, an early symptom of ischemia, is one of the most
      important remedies for reducing subsequent chronic neural damage in stroke.
      Melatonin, a metabolite of tryptophan released from the pineal gland, has been
      found to be effective against neurotoxicity in vitro. The present study was aimed
      to demonstrate the effectiveness of melatonin in vivo in reducing ischemia
      induced edema using magnetic resonance imaging (MRI). Rats were subjected to
      middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was
      administered twice (6.0 mg/kg, p.o.): just prior to 1 h MCA occlusion and 1 day
      after the surgery. T2-weighted multislice spin-echo images were acquired 1 day
      after the surgery. Increases in T2-weighted signals in ischemic sites of the
      brain were clearly observed after MCA occlusion. The signal increase was found
      mainly in the striatum and in the cerebral cortex in saline-treated control rats.
      In the melatonin-treated group, the total volume of cerebral edema was reduced by
      45.3% compared to control group (P < 0.01). The protective effect of melatonin
      against cerebral edema was more clearly observed in the cerebral cortex (reduced
      by 56.1%, P < 0.01), while the reduction of edema volume in the striatum was weak
      (reduced by 23.0%). The present MRI study clearly demonstrated that melatonin is
      effective in reducing edema formation in ischemic animals in vivo, especially in
      the cerebral cortex. Melatonin may be highly useful in preventing cortical
      dysfunctions such as motor, sensory, memory, and psychological impairments.

PMID- 12467900
TI  - Restricted clinical efficacy of cyclosporin A on rat transient middle cerebral
      artery occlusion.
AB  - The immunosuppressant cyclosporin A (CsA) has been shown to have neuroprotective
      action. The inhibition of both calcineurin activation and mitochondrial
      permeability transition pore (mtPTP) opening are considered the primary
      neuroprotective mechanisms of CsA. Here we have evaluated the effect of CsA on
      significantly reducing infarct size induced by transient middle cerebral artery
      occlusion (MCAO) in rats, and examined variable therapeutic applications for
      brain infarction. Experimental rats were divided into 12 groups according to: CsA
      administration time (immediately after occlusion or immediately after
      reperfusion); dosage (between 10 and 50 mg/kg); route (i.v. or i.p.); and with or
      without needle insertion, which hypothetically disrupts the blood brain barrier
      (BBB). Neuroprotective effects of CsA were hardly noticeable when administered
      immediately after occlusion or by i.v. injection. By needle insertion, CsA
      administration significantly reduced infarct size, although vehicle treatment
      also reduced infarct size compared with nontreatment animals, i.e. no needle
      insertion. These results suggest that needle insertion allows endogenous
      neuroprotective substances to pass into the brain. Furthermore, single dosages
      over 30 mg/kg CsA were excessive and negated potential neuroprotective effects.
      However, two i.p. administrations of 20 mg/kg CsA immediately and 24 hrs after
      reperfusion significantly ameliorated the infarct size compared to the vehicle
      treated group. We conclude that CsA exhibits significant neuroprotective
      activity, although its therapeutic application for stroke may be limited by very
      strict and precise management requirements.

PMID- 12467901
TI  - Neuroprotective effect and brain receptor binding of taltirelin, a novel
      thyrotropin-releasing hormone (TRH) analogue, in transient forebrain ischemia of
      C57BL/6J mice.
AB  - Thyrotropin-releasing hormone (TRH) and some of its stable analogues have been
      shown to improve neurologic dysfunctions such as brain trauma in both animals and
      humans. Our previous study revealed that taltirelin, a novel orally active TRH
      analogue, binds to rat brain TRH receptors in vivo. The present study was
      undertaken to investigate whether taltirelin has neuroprotective effects in
      transient brain ischemia of C57BL/6J mice induced by bilateral carotid artery
      occlusion (2VO). Neuronal cell density in the hippocampal CA1 region of C57BL/6J
      mice was significantly (39.9%) decreased 1 week after 2VO-reperfusion, compared
      to the case of the sham group, and this reduction of hippocampal neuronal density
      was significantly suppressed by an intravenous (i.v.) injection of taltirelin
      (0.3 mg/kg). The i.v. injection of taltirelin at this dosage produced a
      significant increase in the dissociation constant (Kd) of specific [3H]MeTRH
      binding in sham and 2VO-reperfusion groups (33.6 and 51.4%, respectively)
      compared with the vehicle-treated group. These results indicate that the
      intravenously injected taltirelin bound to TRH receptors in the ischemic brain.
      There was little difference in the brain-to-plasma concentration ratio (Kp) of
      [14C]sucrose between the sham and 2VO groups of C57BL/6J mice, indicating that
      the tight junction of the blood-brain barrier may be intact in the ischemic
      brain. In conclusion, the study has shown that taltirelin may have a significant
      neuroprotective effect on the ischemic brain.

PMID- 12467902
TI  - Repeated cerebral ischemia induced hippocampal cell death and impairments of
      spatial cognition in the rat.
AB  - We developed a method of causing strong ischemic insult only in vulnerable nerve
      cells, such as hippocampal cells, without causing hemiplegia or difficulty in
      moving, by repeating cerebral ischemia for a brief time with a short interval
      periods. The rats subjected to 10 min of cerebral ischemia exhibited no
      impairment of spatial cognition at the test trial 7 days after final reperfusion.
      However, when the 10 min ischemia was repeated twice with a 1 hr interval, the
      rats exhibited a significant decrease in number of correct choices and increase
      in number of errors. Three times of repeated cerebral ischemia also induced a
      significant decrease in the number of correct choices and increase in the number
      of errors, but there were some rats showing motor difficulty. Cell death was
      typically observed in the CA1 layer of the hippocampus of rats subjected twice to
      10 min of cerebral ischemia. Hippocampal and cortical acetylcholine (ACh) release
      weas transiently increased during the first and second 10 minutes of ischemia and
      normalized immediately after recirculation; thereafter, ACh release from these
      areas gradually decreased and showed a significantly low level at 7 days after
      recirculation. These results suggest that the repeated cerebral ischemia-induced
      impairment of spatial memory may be due to the dysfunction of hippocampal and
      cortical ACh systems and hippocampal cell death. The repeated cerebral ischemia
      model which produces cell death and ACh dysfunction in the hippocampus is thought
      to be useful for evaluating new drugs for the treatment of cerebrovascular
      dementia.

PMID- 12467903
TI  - Involvement of bcl-family expression in the spatial memory impairment induced by
      repeated ischemia.
AB  - In the present study, we examined the effects of repeated ischemia (10 min x 2, 1
      hr interval) on spatial memory in rats in an 8-arm radial maze test compared with
      single ischemia (10 min x 1). Repeated ischemia produced more severe impairment
      of spatial memory and stronger TUNEL-positive immunoreactivity in the hippocampal
      CA1 region than single ischemia at 7 days after reperfusion. Moreover, repeated
      ischemia altered bcl-family expression, which is related to apoptosis, while this
      was not affected by single ischemia. These results suggest that spatial memory
      impairment at 7 days after repeated ischemia may be related to apoptosis in
      hippocampal CA1 cells.

PMID- 12467904
TI  - Complex cytokine regulation of tissue fibrosis.
AB  - Tissue fibrosis, a serious and even deadly complication of chronic inflammation
      and environmental exposures, is regulated by a host of factors including
      interactions with the extracellular matrix, surface of inflammatory cells,
      hormones, and an extremely complex and redundant network of profibrotic
      cytokines. The nature of mechanisms by which cytokines regulate fibrosis is dual 
      indirect, through attraction of inflammatory cells, and direct, through binding
      to specific receptors on fibroblasts and stimulating proliferation, collagen
      production and secretion of autocrine factors. This review focuses on
      systematizing the direct effects of cytokines on fibroblasts. Understanding of
      the complexity of the cytokine-driven mechanisms of fibrosis is important for
      identification of potential molecular targets for future pharmacological
      interventions in prevention and treatment of tissue fibrosis.

PMID- 12467905
TI  - A comparative study on the anti-inflammatory, antinociceptive and antipyretic
      effects of isoquinoline alkaloids from the roots of Turkish Berberis species.
AB  - Roots and barks of various Berberis species are used as folk remedy for the
      treatment of various inflammatory diseases such as lumbago, rheumatism and to
      reduce fever. Six isoquinoline alkaloids namely berberine, berbamine, palmatine,
      oxyacanthine, magnoflorine, and columbamine were isolated as the main components
      of alkaloidal fraction from the roots of Turkish Berberis species and effects
      were studied using various in vivo models in mice. All alkaloids inhibited
      inflammations in varying degrees, among them berberine, berbamine and palmatine
      were shown to possess significant and dose-dependent inhibitory activity against
      serotonin-induced hind paw oedema both on oral and topical applications and
      acetic acid-induced increase in vascular permeability on oral administration.
      Moreover, these three alkaloids were also shown to possess dose-dependent
      antinociceptive activity, which assessed by using the model based on the
      inhibition of p-benzoquinone-induced writhing movements as well as antipyretic
      activity on FCA-induced increased rectal temperature on subacute administration.
      However, all alkaloids induced gastric lesions in varying degrees.

PMID- 12467906
TI  - Fruit-juice concentrate of Asian plum inhibits growth signals of vascular smooth
      muscle cells induced by angiotensin II.
AB  - Bainiku-ekisu, the fruit-juice concentrate of the Oriental plum (Prunus mume) has
      recently been shown to improve human blood fluidity. We have shown that
      angiotensin II (AngII) stimulates growth of vascular smooth muscle cells (VSMCs)
      through epidermal growth factor (EGF) receptor transactivation that involves
      reactive oxygen species (ROS) production. To better understanding the possible
      cardiovascular protective effect of Bainiku-ekisu, we have studied whether
      Bainiku-ekisu inhibits AngII-induced growth promoting signals in VSMCs. Bainiku
      ekisu markedly inhibited AngII-induced EGF receptor transactivation. H(2)O(2)
      induced EGF receptor transactivation was also inhibited by Bainiku-ekisu. Thus,
      Bainiku-ekisu markedly inhibited AngII-induced extracellular signal-regulated
      kinase (ERK) activation. However, EGF-induced ERK activation was not affected by
      Bainiku-ekisu. AngII stimulated leucine uptake in VSMCs that was significantly
      inhibited by Bainiku-ekisu. Also, Bainiku-ekisu possesses a potent antioxidant
      activity. Since the activation of EGF receptor, ERK and the production of ROS
      play central roles in mediating AngII-induced vascular remodeling, these data
      suggest that Bainiku-ekisu could exert a powerful cardiovascular protective
      effect with regard to cardiovascular diseases.

PMID- 12467907
TI  - Correlation between methotrexate-induced intestinal damage and decrease in
      polyamine content.
AB  - A synthetic analog of prostaglandin E(1), OP-1206 [17S, 20-dimethyl-trans
      Delta(2)-prostaglandin E(1)] protects the small intestine from the methotrexate
      (MTX)-induced damage. The purpose of this study is to evaluate the protective
      effect of OP-1206 on the methotrexate-induced small intestinal damage in rats
      from the biochemical point of view. MTX (15 mg/kg body weight) was orally
      administered to rats once daily for 5 days. OP-1206 (0.5 microg/kg body weight)
      was orally administered to rats twice a day for 5 days, and on the 6th day
      biochemical components in the jejunal mucosa of the treated rats were determined.
      The contents of DNA, RNA, proteins and polyamines (spermine and spermidine) in
      the jejunal mucosa of rats were markedly decreased by the MTX treatment. The
      coadministration of OP-1206 with MTX prevented such decreases caused by the MTX
      treatment. The MTX treatment decreased the incorporation of 3H-thymidine into DNA
      in the jejunal mucosa, while the coadministration of OP-1206 with MTX prevented
      it. These results indicated that OP-1206 could protect the intestinal mucosa
      against the biochemical effects of MTX through a trophic action on intestinal
      villi. Further, it should be noted that polyamines may possibly play an important
      role of modulation action on intestinal mucosa.

PMID- 12467908
TI  - Circumvention of multidrug resistance and reduction of cardiotoxicity of
      doxorubicin in vivo by coupling it with low density lipoprotein.
AB  - Doxorubicin (Dox) was coupled into human low density lipoprotein (LDL) to form a
      complex LDL-Dox. In in vitro studies, the accumulation of LDL-Dox in human
      resistant hepatoma (R-HepG2) cells was found to be higher than that of free Dox
      in the cells, resulting in an increase of the cytotoxic effect on the cells.
      Moreover, in in vivo studies, under the same dosage of drugs (1 mg/kg), the anti
      proliferative effect on the tumor cells of LDL-Dox in nude mice bearing R-HepG2
      cells was higher than that of free Dox as evidenced by the larger reduction in
      tumor volumes and tumor weights in LDL-Dox treated group. Histological studies
      showed that LDL-Dox treatment did not cause any heart damage when compared with
      the control group. In contrast, Dox treatment caused disruption and vacuolization
      of myocardial filament. Plasma lactate dehydrogenase activity and plasma creatine
      kinase activity in nude mice bearing R-HepG2 cells were found to be elevated in
      the Dox-treated group but remained unchanged in LDL-Dox-treated group. The
      present studies indicate that when Dox is coupled with LDL, the multidrug
      resistance can be circumvented and the cardiotoxicity can be reduced.

PMID- 12467909
TI  - Fasting stress exacerbates classical conditioned histamine release in guinea
      pigs.
AB  - To clarify the contribution of stress to classical conditioning-associated
      asthmatic responses, the effect of fasting stress on conditioned histamine
      release was investigated in a guinea pig model of asthma. The animals were
      randomly divided into 2 groups for Experiment 1 and 2, and received a
      conditioning procedure in which ovalbumin (OA) as an unconditioned stimulus (US)
      and dimethylsulfide (DMS, sulfur smelling) as a conditioned stimulus (CS) were
      simultaneously inhaled after fasting for 16 h. Then, one group was given food as
      a reward for respiratory distress, and the other group was denied it for more
      than 3 h, while being placed in front of the feeding group. After this procedure
      was repeated 5 times, the plasma histamine levels in response to the CS were
      measured in half of each group in Experiment 1, and the respiratory resistance
      (Rrs) was assessed similarly in the other half of each group in Experiment 2. The
      same experiments were again performed after exchanging assignments of feeding
      group or fasting group in both experiments. The control groups in both
      experiments received the CS and the US 10 times separately in a random order
      under 16 h fasting conditions and were provided food after the exposures. After
      these pseudo-conditioning presentations, the plasma histamine levels or the Rrs
      in response to the CS were measured. In Experiment 1, the plasma histamine levels
      in the fasting stress group after the first conditioning sessions were
      significantly higher than those of the other groups. This difference was not
      observed when the groups were exchanged. In Experiment 2, the fasting stress
      group showed higher values in the Rrs compared to the other groups, irrespective
      of the first or second conditionings; however, they were not significant. The
      present study indicates that fasting stress after the conditioning procedures
      exacerbates the following conditioned histamine release, although the stress
      effect on bronchoconstriction was not confirmed.

PMID- 12467911
TI  - Effect of Amorphophallus Konjac oligosaccharides on STZ-induced diabetes model of
      isolated islets.
AB  - Three oligosaccharide fractions from the root of Amorphophallus Konjac, which was
      reported with hypoglycemic effects on diabetes subjects, were isolated and
      studied using the STZ-treated diabetes model. Among them, one fraction named as
      KOS-A, was found with nitric oxide (NO(*)) free radical regulation effect, while
      the other two were not. At concentrations less than 1.5 mM, KOS-A positively
      decreased STZ-induced NO(*) level of islets, but normal NO(*) release for non-STZ
      treated islets was not affected within the range. At 15 mM, KOS-A played a
      contrary role and increased NO(*) level for islets both with and without STZ
      treatment. Islets insulin secretion changed corresponding to NO(*) level in the
      assay. Increased insulin secretion appeared parallel to the decrease of NO(*),
      and normal insulin release was not affected by KOS-A less than 1.5 mM. Structure
      determination of KOS-A shows that it is a tetrasaccharide with Mw of 666 Da and
      reductive end of alpha-D-mannose. These results indicate that low dosage of KOS
      A, with its function on attenuating STZ-induced NO(*) level, doesn't alter normal
      NO(*) and insulin secretion pathways of isolated islets. The NO(*) attenuation
      function of KOS-A on the diabetes model is mainly resulted from environmental
      free radical scavenging by the oligosaccharide. Present results also imply the
      mechanism of clinical Amorphophallus Konjac hypoglycemic function maybe related
      with free radical attenuation and lower risks of islets damage from NO(*)
      radical.

PMID- 12467910
TI  - Effects of Chan Su, a traditional Chinese medicine, on the calcium transients of
      isolated cardiomyocytes: cardiotoxicity due to more than Na, K-ATPase blocking.
AB  - Extracts of Chan Su, a traditional Chinese medication used as a topical
      anesthetic and cardiac medication, were incubated with cardiomyocytes that had
      been loaded with a calcium specific fluorescent probe. Calcium transients were
      measured by real-time fluorescence spectrophotometry following treatment. The
      transients were rapidly abolished following addition of a moderate concentration
      of the extract (400 ng/ml), resulting in high levels of intracellular calcium,
      while the lower amount (40 ng/ml) blocked the sodium-potassium adenosine
      triphosphatase. Treatments with ouabain and nifedipine were also made, either
      prior to, or after the addition of the Chan Su, in an attempt to better delineate
      the site(s) of action. The moderate concentration of Chan Su (400 ng/ml) extract
      caused the myocytes to cease beating within seconds of addition, even in
      experiments when saturating concentrations of nifedipine or ouabain had been
      previously added to the cells. As expected bufalin, the active component of Chan
      Su has similar effects. Our findings indicate that this compound is extremely
      cardiotoxic, even in small dose and acts rapidly to alter intracellular calcium
      stores in cardiomyocytes and possibly acts at sites other than the Na(+)+K(+)
      ATPase, either directly, or indirectly via changes in calcium concentrations.

PMID- 12467912
TI  - Naltrexone potentiates both amnestic and anxiolytic effects of chlordiazepoxide
      in mice.
AB  - Studies have suggested that opioid antagonists potentiate the anxiolytic effect
      but not the amnestic action of chlordiazepoxide (CDZ). We investigated the
      effects of naltrexone (NAL) on the anxiolytic and amnestic effects of CDZ in mice
      tested in the plus-maze discriminative avoidance task (DAT). Mice are conditioned
      to choose between two enclosed arms (one of which aversive) while avoiding the
      two open arms of the apparatus. This task measures memory (time spent in the
      aversive vs. time in the non-aversive enclosed arms) and anxiety (time spent in
      the open arms). Mice treated with saline (SAL) or 5 mg/kg NAL, and SAL or 2.5
      mg/kg CDZ were submitted to DAT training. The test was performed 24 h later,
      without aversive stimuli. In the training, NAL + CDZ group showed higher percent
      time spent in the open arms than all the other groups. In the test, NAL + CDZ
      (but not SAL + CDZ) group showed higher percent time spent in the aversive
      enclosed arm than SAL + SAL and NAL + SAL groups. The data suggest that NAL
      potentiates the small decreases in anxiety and retention induced by a
      subeffective dose of CDZ.

PMID- 12467913
TI  - Mechanism of the antiulcerogenic effect of Ganoderma lucidum polysaccharides on
      indomethacin-induced lesions in the rat.
AB  - Many cytokines, in particular tumor necrosis factor (TNF)-alpha have been known
      to play an important role in the pathogenesis of gastric mucosal lesions caused
      by various factors such as drugs and Helicobacter pylori infection. Our previous
      studies have shown that the polysaccharide fractions isolated from the fruiting
      bodies of Ganoderma lucidum (GLPS) prevented indomethacin- and acetic acid
      induced gastric mucosal lesions in the rat. However, the mechanisms remain
      unclear. This study aimed to investigate whether GLPS had a direct mucosal
      healing effect in the indomethacin-treated rat, and to explore the possible
      mechanisms by determining the gastric mucosal mRNA and protein levels of TNF
      alpha and ornithine decarboxylase (ODC) activity. In addition, the effects of
      GLPS on the cellular proliferation, ODC and c-Myc protein expression and mucus
      synthesis in the rat gastric cell culture (RGM-1) were examined. The present
      study demonstrated that GLPS at 250 and 500 mg/kg by intragastric input caused
      ulcer-healing effect in the rat; this was accompanied with a significant
      suppression of TNF-alpha gene expression, but with an increased ODC activity. In
      RGM-1 cells, GLPS at 0.05, 0.25 and 1.0 mg/ml significantly enhanced
      [3H]thymidine incorporation and ODC activity in a concentration-dependent manner.
      However, these effects were abrogated by the addition of the ODC inhibitor, DL
      alpha-difluoromethyl-ornithine (DFMO). GLPS at 0.25-1.0 mg/ml also increased
      mucus synthesis, as indicated by the increased D-[6-3H]glucosamine incorporation
      in RGM-1 cells. Furthermore, GLPS at 0.05-1.0 mg/ml increased the c-Myc protein
      expression. These findings indicated that GLPS produced a mucosal healing effect
      in the rat model, perhaps due partly to the suppression of TNF-alpha and
      induction of c-myc and ODC gene.

PMID- 12467914
TI  - Application of LC-NMR for the study of the volatile metabolite of MK-0869, a
      substance P receptor antagonist.
AB  - LC-NMR was applied to identify the polar volatile metabolite of MK-0869. MK-0869,
      a morpholine-based compound containing a triazolone ring, is a very potent NK(1)
      receptor antagonist. Currently, it is in development as an anti-emesis agent in
      chemotherapy treatments. The primary metabolites of MK-0869, M1 and M2, are non
      polar and lack the triazolone ring. Incubation of [14C]M1 with liver microsomes
      from male rats produced a very polar and volatile metabolite, M3. Analysis was
      not possible by LC-MS or by conventional NMR because of poor ionization, small
      molecular weight and volatility, leaving chemical derivatization and LC-NMR as
      alternative methods. Reduction of M3 with NaBH(4) resulted in a derivative that
      had the same retention time as p-fluorophenylethylene glycol on HPLC. A small
      aliquot of the solution containing M3 was passed through the LC of the LC-NMR
      system, which was connected on-line with a radioactivity detector. The
      simultaneous UV and radioactivity chromatograms thus identified the
      chromatographic UV peak that was associated with the metabolite. Analysis was
      carried out by stop-flow on another portion of this fraction. From the chemical
      derivatization and the analysis by LC-NMR, M3 is shown to be p-fluoro-alpha
      hydroxyacetophenone. Further studies using LC-NMR showed that M3 could be
      generated from both M1 and M2 in NADPH-dependant reactions catalyzed by
      microsomes containing recombinant human CYP2C19, CYP1A2 or CYP3A4.

PMID- 12467915
TI  - A double antibody radioimmunoassay for the determination of XV459, the active
      hydrolysis metabolite of roxifiban, in human plasma.
AB  - A radioimmunoassay (RIA) was developed for the determination of XV459, the active
      hydrolysis metabolite of the oral prodrug roxifiban (DMP 754), in human plasma.
      XV459 is a potent antagonist of the glycoprotein IIb/IIIa receptor. The method
      utilizes a competitive double antibody format employing an 125I-labeled XV459
      analogue tracer which competes with XV459 for antibody binding sites and a second
      antibody precipitation step to separate antibody bound analyte from free analyte.
      The method has a validated lower quantification limit of 0.35 ng/ml (0.81 nM)
      using 12.5 microl of plasma and with dilution can accommodate clinical plasma
      samples ranging up to 48.0 ng/ml (110.7 nM). Cross-validation to an existing
      quantitative liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS)
      method showed good correlation (r(2)=0.98). The RIA has been successfully used to
      assay over 10000 clinical samples with sensitivity and specificity comparable to
      the LC-MS/MS method, but with faster turn around time and at greatly reduced
      costs.

PMID- 12467916
TI  - Assessment of trace aluminium content in parenteral solutions by combined cloud
      point preconcentration-flow injection inductively coupled plasma optical emission
      spectrometry.
AB  - A micelle-mediated phase separation without added chelating agents to
      preconcentrate trace levels of aluminium in parenteral solutions as a prior step
      to its determination by flow injection inductively coupled plasma optical
      emission spectrometry has been developed. The enrichment step is based on the
      cloud point extraction of aluminium with the non-ionic surfactant
      polyethyleneglycolmono-p-nonylphenylether (PONPE 7.5). The chemical variables
      affecting the sensitivity of the extractive-spectrometric procedure were studied
      in detail. After optimization, a preconcentration factor of 200 and a %E higher
      than 99.9 were achieved. The detection limit (DL) value of aluminium for the
      preconcentration of 50 ml of parenteral solution was 0.25 microgl(-1). The
      calibration graph using the preconcentration system for aluminium was linear with
      a correlation coefficient of 0.9997 at levels near the DLs up to at least 200
      microgl(-1). The developed hyphenated assay, which thoroughly satisfies the
      typical requirements for pharmaceutical control processes, is appropriate to
      monitor the aluminium concentration in parenteral nutrition.

PMID- 12467917
TI  - High-throughput inhibition screening of major human cytochrome P450 enzymes using
      an in vitro cocktail and liquid chromatography-tandem mass spectrometry.
AB  - A method has been developed for the high-throughput inhibition screening of the
      major human cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and
      CYP3A4) using an in vitro substrate cocktail and liquid chromatography-tandem
      mass spectrometry (LC-MS-MS). A cocktail consisting of the selective substrates
      phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), bufuralol
      (CYP2D6), and midazolam (CYP3A4) was incubated with human liver microsomes. The
      metabolic reactions were terminated with methanol containing dextrorphan as an
      internal standard. Following centrifugation, the supernatant was analyzed by LC
      MS-MS employing a fast gradient. The concentrations of the substrate metabolites
      paracetamol, 4-hydroxytolbutamide, 5-hydroxyomeprazole, 1'-hydroxybufuralol, and
      1'-hydroxymidazolam-in each sample were determined by LC-MS-MS in a single assay.
      The method was validated by incubating known CYP inhibitors (furafylline, CYP1A2;
      sulfaphenazole, CYP2C9; s-mephenytoin, CYP2C19; quinidine, CYP2D6; and
      troleandomycin, CYP3A4) with the individual substrates they were known to inhibit
      and with the substrate cocktail. IC50s (microM) determined using the substrate
      cocktail were in good agreement with those obtained with individual substrates
      (furafylline, 2.9 vs. 2.0; sulfaphenazole, 0.75 vs. 0.72; s-mephenytoin, 170 vs.
      180; quinidine, 0.17 vs. 0.24; troleandomycin, 2.6 vs. 3.2) and with previously
      reported values in the literature.

PMID- 12467918
TI  - A SPME-GC procedure for monitoring peppermint flavor in tablets.
AB  - A method was developed using solid-phase microextraction (SPME) and gas
      chromatography to monitor the peppermint flavor loss in a taste-masked tablet
      formulation. This was accomplished by headspace sampling of two major components
      of peppermint: menthone and menthol. It was found that the excipients from the
      tablet produced an important matrix effect and that standard addition analysis
      was necessary for improved accuracy of the determination. The method was shown to
      be specific and precise. Furthermore, the method produced acceptable results with
      adequate quantitation limits to determine peppermint flavors in taste-masked
      tablets. The optimized extraction procedure was successfully used to monitor the
      stability of peppermint flavor in an oral solid formulation. The accelerated
      stability studies of the tablet showed that the menthone and menthol was lost in
      an exponential manner and levels off after several days of heat exposure.

PMID- 12467919
TI  - Analysis of isoaspartate in a recombinant monoclonal antibody and its charge
      isoforms.
AB  - Monoclonal antibody (mAb) therapy applications have been growing rapidly in
      recent years. Like other proteins, therapeutic mAbs can under go various
      enzymatic and non-enzymatic reactions that can affect their structural integrity
      and stability. Among the degradation reactions, isoaspartate (isoAsp) formation
      is one of the major sources of charge heterogeneity of mAbs. This paper reports
      the detection and quantification of isoAsp in a recombinant mAb and its charge
      isoforms resolved by cation exchange high performance liquid chromatography. The
      assay utilizes the enzyme protein isoaspartyl methyltransferase in conjunction
      with strong cation exchange separation and UV detection (at 260 nm) of S-adenosyl
      L-homocysteine, which is produced stoichiometrically in the enzymatic reaction.
      The mAb is found to contain an average 0.2 mol of isoAsp per mol of protein,
      however, various charge isoforms were found to contain different levels of
      isoAsp. The most acidic isoforms contain approximately 0.7 mol of isoAsp per mol
      of protein, and no isoAsp is detected in the most basic isoform. It appears that
      the majority of isoAsp in the mAb is formed as a result of asparagine
      deamidation.

PMID- 12467920
TI  - 2D-IR correlation analysis of deteriorative process of traditional Chinese
      medicine 'Qing Kai Ling' injection.
AB  - The traditional Chinese medicine 'Qing Kai Ling' injection after deterioration is
      distinguished from the original formulation using Fourier-transform infrared
      spectroscopy (FTIR) and two-dimensional correlation infrared spectroscopy (2D
      IR). The IR spectra of the injections before and after deterioration are so
      similar, that it is very difficult to distinguish them by using the conventional
      approach. However, the higher spectral resolution and more structural information
      provided by 2D-IR analysis makes the identification possible. According to the
      results of 2D correlation analysis, the band at 1611 cm(-1) in IR spectra, in
      fact, consists of the overlap of three bands at 1572, 1667 and 1729 cm(-1), which
      are assigned to the alkaloids (heterocyclic compounds), flavone derivatives, and
      carbonyl compounds in the injection, respectively. Interestingly, the autopeak at
      1667 cm(-1) disappears in synchronous spectrum of the deteriorated 'Qing Kai
      Ling' injection. It is suggested that the deterioration of the injection in air
      at room temperature be due to the oxidation of the flavone compounds mainly. As
      all intensities of the correlation peaks involved with the band in 1059 cm(-1)
      decrease greatly, it is assigned to the thermal decomposition of the glucoside
      components. Hence, it can conclude that the oxidation of the flavone compounds
      and the decomposition of the glucoside components are some of the main causes
      concerning to the deterioration of 'Qing Kai Ling' injection at ambient
      temperature. Thus, the 2D-correlation analysis provides a powerful method for the
      quality control of the traditional Chinese medicine injection.

PMID- 12467921
TI  - Flow injection determination of isoniazid using N-bromosuccinimide- and N
      chlorosuccinimide-luminol chemiluminescence systems.
AB  - A chemiluminescent method for the determination of isoniazid is described. Method
      is based on the chemiluminescence (CL) generated during the oxidation of luminol
      by N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS) in alkaline medium. It
      was found that the isoniazid could greatly enhance this CL intensity when present
      in the luminol solution. Based on this observation, a new flow-injection CL
      method for the determination of isoniazid is proposed in this paper. The
      detection limits were 4 and 3 ng ml(-1) isoniazid for the NBS- and NCS-luminol CL
      systems, respectively. The relative CL intensity was linear with the isoniazid
      concentration in the range of 8-600 and 600-5000 ng ml(-1) for the NBS-luminol CL
      system, and 6-200 and 200-2000 ng ml(-1) for the NCS-luminol CL system. The
      results obtained for the assay of pharmaceutical preparations compared well with
      those obtained by the official method and demonstrated good accuracy and
      precision.

PMID- 12467922
TI  - Determination of hydrochlorothiazide and rutin in Chinese herb medicines and
      human urine by capillary zone electrophoresis with amperometric detection.
AB  - In this paper, capillary zone electrophoresis with amperometric detection (CZE
      AD) was firstly applied to the simultaneous determination of rutin (RT) and
      hydrochlorothiazide (HCT) in compound Chinese herb medicines and human urine
      samples. The two analytes could be perfectly analyzed within 12 min and showed
      significant current responses at carbon electrode under the optimum conditions.
      It was found that the linear range of HCT was from 2.0 x 10(-6) to 1.0 x 10(-4)
      mol l(-1) and that of RT was from 1.0 x 10(-6) to 1.0 x 10(-4) mol l(-1). Their
      sensitivity was determined by linear regression and calculated as 7.02 x 10(4)
      and 2.17 x 10(5) nA l mol(-1), respectively, and their detection limits were 5.0
      x 10(-7) and 2.0 x 10(-7) mol l(-1), respectively (S/N=3). Above results
      demonstrated that this method was of high sensitivity, good repeatability, high
      selectivity and could be used in metabolic kinetics studies of medicines.
      Satisfactory results were obtained when this method was used to simultaneously
      analyze the amounts of RT and HCT in one general compound Chinese herb medicine
      Zhen Ju jiang Ya Pian and human urine samples.

PMID- 12467923
TI  - Microcalorimetric studies to determine the enthalpy of solution of diclofenac
      sodium, paracetamol and their binary mixtures at 310.15 K.
AB  - A sensitive and selective microcalorimetric technique has been used to determine
      the enthalpy of solution of diclofenac sodium (DS), paracetamol (PC) and their
      binary mixtures over a wide range of composition in the pH range 4-12. The
      systems showed endothermic behavior. The molar enthalpies of solutions of DS vary
      between 42.26+/-0.16 and 50.48+/-0.03 kJ mol(-1) at pH 4-9 and for PC from
      24.28+/-0.05 to 36.03+/-0.01 kJ mol(-1) at pH 5-12. The excess molar enthalpy of
      their mixtures has also been determined. The values of excess molar enthalpy of
      solutions are negative and very low in magnitude indicating no specific
      interaction between DS and PC in solution.

PMID- 12467924
TI  - Investigation of salicylaldehyde-5-sulfonate as a precolumn derivatizing agent
      for the determination of n-alkane diamines, lysine, diaminopimelic acid, and
      isoniazid by capillary zone electrophoresis.
AB  - Reactions of primary amines with salicylaldehyde-5-sulfonate (SAS) lead to the
      formation of stable Schiff bases at weakly alkaline pH and at moderate
      temperature in an ethanol-rich aqueous solution. Some alkane diamines were
      converted to salicylaldimine with SAS, and the products were resolved and
      detected by capillary zone electrophoresis (CZE). The reactivity of SAS was
      applied also to the derivatization of amino acids. Optimal conditions for the
      analysis of lysine in the presence of diaminopimelic acid, the metabolite of
      lysine, were investigated. Addition of Na(2)SO(4) into the migrating solution
      enhanced the stacking effect, and led to increase in the detection limits.
      Another advantage of the use of SAS is its ability to form stable water-soluble
      metal chelate as Schiff base ligands. For practical analysis, the copper chelate
      of the Schiff base of isoniazid, which is known as the most active antibacterial
      used in the treatment of pulmonary tuberculoses, was investigated, and the
      detection limit of isoniazid was improved in the magnitude of 11 times compared
      with the one of free isoniazid.

PMID- 12467925
TI  - Quantification of hyaluronic acid fragments in pharmaceutical formulations using
      LC-ESI-MS.
AB  - Three different hyaluronic acid fragment preparations (HAF) derived from
      hyaluronic acid (HA) by hyaluronate lyase digestion have been investigated. The
      amount of these fragment mixtures in pharmaceutical formulations was determined
      by liquid chromatography-electrospray tandem mass spectrometry (LC/MS/MS). HAF
      analysis was performed in less than 8 min using a Nucleosil 100-7 C2 column.
      Based on the assumption that the mass distribution is kept constant, which is
      confirmed by the calibration results, quantification can be carried out relating
      to the most intense fragments. For that purpose, the ratios of the peak areas of
      product ions of m/z=378 (tetramer, hexamer, octamer) to the peak area of m/z=83
      ([2xmaltose-H(+)], internal standard) were calculated. Calibration was done for
      each HAF and good linearity from 5 to 80 microg/ml has been shown. To evaluate
      the molecular weight distribution of the fragment preparations used in this
      approach MALDI-TOF, mass spectra have been collected.

PMID- 12467926
TI  - Development of generic continuous-flow enzyme immunoassay system for analysis of
      aminoglycosides in serum.
AB  - A simple generic continuous-flow enzyme immunoassay (CFEIA) for analysis of
      aminoglycosides in serum has been successfully developed. The developed assay
      employed a specific monoclonal antibody and beta-galactosidase (beta-GAL) enzyme
      as label. The assay involves an off-line competitive binding reaction between the
      analyte and free labelled analyte for the binding sites of the antibody. After
      equilibrium is reached, the sample was injected into the flow system. The bound
      antibody complexes with the analyte and the labelled analyte were trapped in a
      protein G column, while the unbound free labelled analyte was eluted and detected
      colorimetrically down-stream, after reaction with chlorophenolic red-beta-D
      galactopyranoside as a substrate for the beta-GAL enzyme. The concentration of
      the analyte in a sample was quantified by its ability to inhibit the binding of
      the analyte-enzyme conjugate to the antibody, and the signal was directly
      proportional to the concentration of the analyte in the original sample. The
      optimum conditions for the developed CFEIA were investigated and applied to the
      analysis of tobramycin, as a representative example of the aminoglycosides, in
      serum samples. The detection limit of the assay was 0.06 microgml(-1). The assay
      showed good precision; the coefficients of variation were 2.49-4.33 and 3.30
      6.82% for intra- and inter-assay precision, respectively. Serum matrix
      constituents and the endogenous compounds did not interfere with the assay.
      Analytical recovery of spiked tobramycin, in the concentration range between 0.5
      and 8.0 microgml(-1), was 101.55+/-3.14. The assay results correlated well with
      those obtained by high-performance liquid chromatography (r=0.991). All the
      obtained results strongly demonstrate that the developed CFEIA is a suitable
      method for a rapid and reliable analysis of aminoglycosides in serum.

PMID- 12467927
TI  - Determination of progesterone in commercial formulations and in non conventional
      micellar systems.
AB  - Progesterone was determined in commercial pharmaceutical formulations and
      experimental micellar systems by means of two analytical methods based on liquid
      chromatography and derivative spectrophotometry. The chromatographic analysis,
      with ultraviolet detection at 245 nm, was carried out on a C8 column using a
      mobile phase composed of 2-propanol and a pH 2.5, 30 mM phosphate buffer.
      Derivative spectrophotometry (DS) used the difference between the values of the
      first derivative at 227.2 and 253.6 nm. Both methods require only a simple
      extraction procedure of progesterone from the formulations before analysis. The
      high-performance liquid chromatography (HPLC) procedure allows for the
      quantitative determination of progesterone in all pharmaceutical formulations
      tested (oily and alcoholic injectable solutions, gel preparations and soft
      capsules) and also of the newly-developed polymeric micellar system. On the
      contrary, the derivative spectrophotometric method is not suitable for the
      pharmaceutical formulation containing estradiol and for the new micellar systems.
      The results obtained with the two methods are in good agreement and always
      satisfactory in terms of precision and accuracy.

PMID- 12467928
TI  - The metabolism of 2-trifluormethylaniline and its acetanilide in the rat by 19F
      NMR monitored enzyme hydrolysis and 1H/19F HPLC-NMR spectroscopy.
AB  - The urinary excretion profile and identity of the metabolites of 2
      trifluoromethyl aniline (2-TFMA) and 2-trifluoromethyl acetanilide (2-TFMAc),
      following i.p. administration to the rat at 50 mg kg(-1), were determined using a
      combination of 19F NMR monitored enzyme hydrolysis, SPEC-MS and 19F/1H HPLC-NMR.
      A total recovery of approximately 96.4% of the dose was excreted into the urine
      as seven metabolites. The major routes of metabolism were N-conjugation
      (glucuronidation), and ring-hydroxylation followed by sulphation (and to a lesser
      extent glucuronidation). The major metabolites excreted into the urine for both
      compounds were a labile N-conjugated metabolite (a postulated N-glucuronide) and
      a sulphated ring-hydroxylated metabolite (a postulated 4-amino-5
      trifluoromethylphenyl sulphate) following dosing of 2-TFMA. These accounted for
      approximately 53.0 and 31.5% of the dose, respectively. This study identifies
      problems on sample component instability in the preparation and analysis
      procedures.

PMID- 12467929
TI  - Rapid determination of lidocaine solutions with non-column chromatographic diode
      array UV spectroscopy and multivariate calibration.
AB  - A new method for the rapid determination of pharmaceutical solutions is proposed.
      A conventional HPLC system with a Diode Array Detector (DAD) was used with no
      chromatographic column connected. As eluent, purified water (Milli Q) was used.
      The pump and autosampler of the HPLC system were mainly utilised as an automatic
      and convenient way of introducing the sample into the DAD. The method was tested
      on the local anaesthetic compound lidocaine. The UV spectrum (245-290 nm) from
      the samples analysed in the detector was used for multivariate calibration for
      the determination of lidocaine solutions. The content was determined with PLS
      regression. The effect on the predictive ability of three factors: flow, data
      collection rate and rise time as well as two ways of exporting a representative
      UV spectrum from the DAD file collected was investigated by means of an
      experimental design comprising 11 experiments. For each experiment, 14 solutions
      containing a known content of lidocaine were analysed (0.02-0.2 mg ml(-1)). From
      these 14 samples two calibration sets and two test sets were made and as the
      response in the experimental design the Root Mean Square Error of Prediction
      (RMSEP) values from the predictions of the two test sets were used. When the
      factor setting giving the lowest RMSEP was found, this setting was used when
      analysing a new calibration set of 12 lidocaine samples (0.1-0.2 mg ml(-1)). This
      calibration model was validated by two external test sets, A and B, analysed on
      separate occasions for the evaluation of repeatability (test set A) and
      determination over time (test set B). For comparison, the reference method,
      liquid chromatography, was also used for analysis of the ten samples in test set
      B. This comparison of the two methods was done twice on different occasions. The
      results show that in respect of accuracy, precision and repeatability the new
      method is comparable to the reference method. The main advantages compared with
      liquid chromatography are the much shorter time of analysis (<30 s) as well as
      the automatic and simple analytical procedure and the low consumption of organic
      solvents.

PMID- 12467930
TI  - Capillary electrophoretic separation of drug enantiomers in human serum.
AB  - Enantiomers of various solutes including several basic drugs and alpha-amino
      acids were analyzed by capillary electrophoresis in diluted human serum, and
      chloroquine and tryptophan were found to be well enantioseparated. In order to
      specify the protein responsible for enantioseparation, these drug enantiomers
      were analyzed in the presence of various serum protein fractions. The results
      indicated that albumin fraction caused enantioseparation but the alpha and beta 
      globulin mixed fraction, the gamma-globulin fraction and the alpha(1)-acid
      glycoprotein fraction did not exhibit any enantioseparation. The association
      constants between these drugs and albumin were roughly estimated based on our
      method. Approximate values were 1.50 x 10(3) and 1.85 x 10(3) M(-1) for
      chloroquine enantiomers, and 1.51 x 10(4) and 2.45 x 10(4) M(-1) for tryptophan
      enantiomers. The difference of the association constant values between the
      enantiomers was found to be 19% for chloroquine and 38% for tryptophan, when
      calculated based on the slower moving enantiomers.

PMID- 12467931
TI  - A chromatographic method for rapid and simultaneous analysis of codeine
      phosphate, ephedrine HCl and chlorpheniramine maleate in cough-cold syrup
      formulation.
AB  - The present paper describes a simple, accurate and precise reversed phase HPLC
      method for rapid and simultaneous quantification of codeine phosphate, ephedrine
      HCl and chlorpheniramine maleate in a cough-cold syrup formulation. Separations
      were carried out on a Zorbax XDB C8 column (150 x 4.6 mm ID), 5 microm particle
      size. A gradient elution system was developed using varying percentages of two
      mobile phases: methanol-glacial acetic acid-triethylamine (980:15:6 v/v) and
      water-glacial acetic acid-triethylamine (980:15:6 v/v). The elution of the
      analytes was achieved in less than 7 min with a flow rate of 1.5 ml/min.
      Detection was by UV absorbance at a wavelength of 254 nm. Quantification of the
      components in actual syrup formulations was calculated against the responses of
      freshly prepared external standard solutions. The method was validated and met
      all analysis requirements of quality assurance and quality control recommended by
      FDA of the USA.

PMID- 12467932
TI  - Identification and quantitation of antineoplastic compounds in chemotherapeutic
      infusion bags by use of HPTLC: application to the vinca-alkaloids.
AB  - An instrumental quantitative high-performance thin-layer chromatographic (HPTLC)
      method has been developed for the determination of vinca-alkaloids
      (antineoplastic compounds) in chemotherapeutic infusion bags prepared in a
      hospital pharmacy. The method uses automated band application onto silica gel
      plates containing a fluorescent indicator and scanning densitometry of
      fluorescence-quenched zones of samples and standards. Samples were analyzed to
      check the content of the active substance against the label declaration of the
      preparation. The four compounds were separated using the following solvent system
      CH(2)Cl(2)-CH(3)OH (93:7, v/v). Vincristine (VCR) and vinorelbine (NVB) were
      assessed in the same run whilst vinblastine (VLB) and vindesine (VDS) were
      analyzed in a second run. HPTLC allows the identification and the quantitation of
      more than 20 samples in the same chromatographic run. The analysis of the samples
      requires 30 min compared with more than 2 h using a typical HPLC method.
      Moreover, there is no need for a conditioning step, as with HPLC, and each
      analysis by HPTLC is less expensive.

PMID- 12467933
TI  - Simultaneous determination of arylpropionic acidic non-steroidal anti
      inflammatory drugs in pharmaceutical formulations and human plasma by HPLC with
      UV detection.
AB  - A simple and sensitive high-performance liquid chromatography-UV detection method
      was developed for the simultaneous determination of non-steroidal anti
      inflammatory drugs (NSAIDs) having an arylpropionic acid moiety in pharmaceutical
      formulations and human plasma. Isocratic separation was employed on ODS column
      (250 x 4.6 mm i.d., 5 microm) at ambient temperature. The mobile phase consisted
      of acetonitrile, phosphate buffer (pH 3.5; 50 mM), methanol and tetrahydrofuran.
      The NSAIDs in the eluent were monitored under a wavelength-programme to provide
      their maximum absorbance. Mefenamic acid was used as an internal standard. Drugs
      were found to be 96.8-101.9% of their label claim in pharmaceutical formulations.
      One hundred microliters of human plasma samples were pretreated with a simple
      liquid-liquid extraction using ethyl acetate. The detection limits of compounds
      studied at a signal-to-noise ratio of 3 were 11.5-75 ng/ml in human plasma
      samples. The proposed method is simple, selective and could be applicable for
      routine analysis of arylpropionic acidic NSAIDs in pharmaceutical as well as in
      human plasma samples.

PMID- 12467935
TI  - The rationale for combination therapy.
AB  - The use of combination lipid-altering therapy for dyslipidemia is becoming
      increasingly important for effective management of patients with coronary heart
      disease (CHD). In accordance with the Adult Treatment Panel III guidelines, the
      primary target of therapy is lowering low-density lipoprotein (LDL) cholesterol.
      Studies have demonstrated the benefit of LDL cholesterol reduction in decreasing
      CHD event rates and all-cause mortality. However, low high-density lipoprotein
      (HDL) cholesterol remains a significant predictor of CHD events. In addition,
      lipid-lowering therapy targeting aberrant lipoprotein subclass and triglyceride
      levels afford additional benefit for patients with mixed dyslipidemias.
      Aggressive lipid-altering therapy often requires the use of combination therapy
      involving statins in conjunction with niacin, fibric-acid derivatives, or bile
      acid resins or intestinal inhibitors of active cholesterol transport. This
      article reviews the rationale for the use of combination therapy in the treatment
      of dyslipidemia, highlighting management strategies.

PMID- 12467936
TI  - Combination therapy for elevated low-density lipoprotein cholesterol: the key to
      coronary artery disease risk reduction.
AB  - Lowering elevated low-density lipoprotein (LDL) cholesterol is a key management
      principle in reducing the risk of coronary artery disease (CAD). An aggressive
      approach to CAD risk reduction requires multiple therapeutic strategies, as no
      single approach is likely to succeed independently. The use of combination
      therapy for elevated LDL cholesterol is effective for CAD risk reduction. In
      fact, the majority of patients with CAD are unlikely to achieve their treatment
      goals with monotherapy. This article reviews the use of combination therapy for
      the management of elevated LDL cholesterol, highlighting important therapy
      considerations.

PMID- 12467937
TI  - Combination therapy for combined dyslipidemia.
AB  - Patients with combined dyslipidemia are at high risk for coronary artery disease
      and often require combination drug therapy to achieve lipid levels recommended by
      the US National Cholesterol Education Program's third Adult Treatment Panel (ATP
      III). In addition to recommendations for low-density lipoprotein (LDL)
      cholesterol and triglyceride levels, ATP III established non-high-density
      lipoprotein (HDL) cholesterol goals for individuals with triglycerides >or=2.26
      mmol/L (>or=200 mg/dL). It also introduced certain criteria for the diagnosis of
      the metabolic syndrome, a clustering of risk factors (abdominal obesity, elevated
      triglycerides, low HDL cholesterol, elevated blood pressure, impaired fasting
      glucose) that increases cardiovascular risk and is common in patients with
      combined dyslipidemia. Statin monotherapy has been shown to benefit these
      patients, and additional benefit may be obtained by combination therapy that
      provides greater reductions in both LDL cholesterol and triglycerides as well as
      greater increases in HDL cholesterol. However, combining a statin with either
      niacin or a fibrate may increase the risk for myopathy and therefore requires
      careful monitoring and evaluation of the risk-benefit ratio for each patient.
      Moreover, combination therapy may be associated with increased drug costs and
      decreased patient compliance. Recently developed agents that may improve the
      effectiveness of combination therapy include ezetimibe-a cholesterol absorption
      inhibitor-and a formulation that combines extended-release niacin and lovastatin
      in a single pill. Clinical trials are needed to determine the optimal treatment
      in patients with combined dyslipidemia.

PMID- 12467938
TI  - Existing and investigational combination drug therapy for high-density
      lipoprotein cholesterol.
AB  - For the past 3 to 4 decades, clinical outcomes trials have shown that drugs that
      favorably alter serum lipid levels reduce the risk of coronary artery disease
      (CAD) events. However, despite these successes, the reduction in serum low
      density lipoprotein (LDL) cholesterol levels with monotherapy lipid-altering
      drugs does not "cure" CAD to the same degree that antibiotics "cure" many
      infections, nor do they "prevent" CAD in the same way that childhood
      immunizations "prevent" the onset of such conditions as measles, mumps, and
      rubella. Clinical outcome trials of monotherapy lipid-altering drugs have
      demonstrated a reduction in the relative risk of CAD in only a minority of
      patients. Thus, although safe and very effective in lowering serum LDL
      cholesterol levels, drugs that predominantly lower cholesterol do not "cure"
      atherosclerotic disease, nor have they been shown to "prevent" most CAD events in
      numerous clinical outcome trials. The reason for the suboptimal CAD outcomes
      benefits of monotherapy lipid-altering drugs is likely because atherosclerosis is
      a complex pathologic process with many important risk factors involved in the
      initiation and progression of atherosclerotic lesions and involved in the onset
      of the CAD event itself. An elevated serum LDL cholesterol level is an important
      CAD risk factor, but it is not the only lipid risk factor. A decreased serum high
      density lipoprotein (HDL) cholesterol level is another important risk factor for
      CAD. Combination therapy through existing drugs (or possibly, in the future,
      through investigational lipid-altering drugs) may not only improve LDL
      cholesterol but also improve serum HDL cholesterol levels. This more global,
      multidimensional approach to lipid-altering drug treatment may provide the best
      chance to prevent CAD.

PMID- 12467939
TI  - Use of combination therapy for dyslipidemia: a lipid clinic approach.
AB  - Combination drug therapy has been used in the management of dyslipidemia by lipid
      clinics since the early 1980s. The explosion of statin use in the early and mid
      1990s has caused a shift to monotherapy for dyslipidemia. However, the use of
      combination therapy has reemerged as a treatment option for patients who have
      elevated triglyceride and low-density lipoprotein (LDL) cholesterol levels as
      more attention is now focused on non-high-density lipoprotein cholesterol. This
      article discusses the use of combination therapy in a lipid clinic based on
      experiences from a multisite clinical practice of >48 physicians and 80,000
      patients. Approaches to LDL lowering for complex dyslipidemias and management
      strategies for specific lipid-lowering therapies are provided.

PMID- 12467940
TI  - Combination therapy for dyslipidemia: safety and regulatory considerations.
AB  - The use of combination therapy is an effective way to manage dyslipidemia in
      patients with coronary artery disease (CAD). However, combination therapy is not
      a frequently used strategy in the treatment of CAD. Aggressive lipid-altering
      therapy often requires the use of combination therapy involving statins in
      conjunction with niacin, fibric-acid derivatives, ezetimibe, or bile acid resins.
      Yet, safety concerns regarding the combination of statins with other lipid
      altering drugs and patient acceptance of combination therapy have influenced its
      application in the treatment of CAD. This article discusses several safety and
      regulatory considerations for the use of combination therapy for dyslipidemia.

PMID- 12467941
TI  - Dexamethasone-induced effects on lymphocyte distribution and expression of
      adhesion molecules in treatment-resistant depression.
AB  - Alterations in immune function are associated with major depression and have been
      related to changes in endocrine function. We investigated whether alterations in
      immune function were associated with altered basal hypothalamic-pituitary-adrenal
      (HPA) function (salivary cortisol) and lymphocyte sensitivity to dexamethasone
      (DEX) intake (1 mg PO). The latter was explored by comparing the impact of DEX
      induced changes on peripheral lymphocyte redistribution and expression of
      adhesion molecules (beta2 integrins and L-selectin). The study included 36
      inpatients with treatment-resistant major depression (unipolar subtype) and 31
      matched healthy controls. The dexamethasone suppression test (DST) was carried
      out and used to classify 10 patients as HPA axis non-suppressors. The latter
      presented significantly higher post-DEX salivary cortisol levels than DST
      suppressors, 82.0 vs. 8.9 nM l(-1) h(-1). No differences in basal salivary
      cortisol levels were found between patients and controls. Changes in cell
      redistribution (CD4(+), CD8(+), CD19(+), CD56(+) and HLADR(+) cells) after DEX
      administration were more prominent in controls than in patients, but the effects
      of DEX varied dependent on whether patients exhibited DEX-induced suppression of
      cortisol secretion. Glucocorticoid-induced suppression of adhesion molecule
      expression was also generally less marked in patients than controls. Our data
      indicate that alterations in immune function and steroid regulation associated
      with depression are not related to elevated basal levels of cortisol and further
      suggest that lymphocyte steroid resistance is associated with drug-resistant
      depression.

PMID- 12467942
TI  - Nocturnal cortisol and melatonin secretion in primary insomnia.
AB  - The present study investigated evening and nocturnal serum cortisol and melatonin
      concentrations in patients with primary insomnia to test if this clinical
      condition is accompanied by an increase of cortisol secretion and a simultaneous
      decrease of nocturnal melatonin production. Ten drug-free patients (4 males, 6
      females) with primary insomnia (mean age+/-S.D.: 39.2+/-9.1 years) and 10 age-
      and gender-matched healthy controls participated in the study. All subjects spent
      three consecutive nights in the sleep laboratory with polysomnography.
      Measurement of cortisol and melatonin (from 19:00 h to 09:00 h) was performed
      prior to and during the last laboratory night. Contrary to expectation, cortisol
      secretion did not differ between healthy controls and insomniac patients. On the
      other hand, nocturnal melatonin production was significantly diminished in
      insomniac patients. Polysomnographically determined sleep patterns, in contrast
      to subjective ratings of sleep, demonstrated only minor alterations of sleep in
      the insomniac group. The lack of increased cortisol secretion in the patients
      with primary insomnia indicates that results from studies on the biological
      consequences of experimental sleep loss in healthy subjects cannot be applied to
      primary insomnia in general, especially if there are only minor objective sleep
      alterations. In spite of the negligible objective sleep disturbances in the
      present sample, nocturnal melatonin production was reduced, which tentatively
      suggests a role for this hormone in primary insomniacs. The pathophysiological
      significance of this finding is, however, still a matter of debate.

PMID- 12467943
TI  - Neuroendocrine response to meta-chlorophenylpiperazine and ipsapirone in relation
      to anxiety and aggression.
AB  - The aim of this study was to establish the association of trait anxiety and anger
      with hormonal responses to acute challenges with two different 5-HT agonists in a
      mixed group of patients with depressed mood. Fifteen patients and 16 normal
      controls received single oral doses of 0.5 mg/kg meta-chlorophenylpiperazine
      (MCPP), a 5-HT(2C) agonist, and 10 mg of ipsapirone, a 5-HT(1A) agonist,
      according to a double-blind, placebo-controlled, cross-over design. Dutch-adapted
      versions of the Spielberger Trait-Anxiety Inventory and the Spielberger Trait
      Anger Scale administered assessed at study entry. Hormonal responses, expressed
      as drug-placebo differences, to MCPP and ipsapirone (changes in cortisol, ACTH
      and prolactin) were measured. Blood levels of MCPP and ipsapirone were also
      measured. MCPP and ipsapirone elevated cortisol, ACTH and prolactin. In the
      patient group, there was a significant correlation between trait anxiety and the
      cortisol response to MCPP. No significant correlations between the ACTH and
      prolactin responses to MCPP and levels of anxiety/anger were observed in the
      patients. No significant correlations could be established between levels of
      anxiety/anger and hormonal responses to ipsapirone. This study provided evidence
      for an association between measures of anxiety/aggression and the hormonal
      response to MCPP. Thus, in subjects with depressed mood, high levels of anxiety
      suggest a higher probability of 5-HT(2C) disturbances.

PMID- 12467944
TI  - D-fenfluramine-evoked serotonergic responses in olanzapine-treated schizophrenic
      patients.
AB  - Antagonist activity at the 5-HT(2) receptor may contribute to the therapeutic
      efficacy of atypical antipsychotics in schizophrenia. This neuroendocrine study
      examined the in vivo functional serotonergic (5-HT) activity of the atypical
      antipsychotic olanzapine. We examined central 5-HT(2) responses by measuring the
      serum prolactin (PRL) over 5 h in response to 30 mg of D-fenfluramine (DFEN) in
      two groups of male schizophrenic patients. Blunted PRL responses to DFEN indicate
      functional 5-HT(2) receptor antagonism. Seven patients treated with olanzapine at
      a mean (S.D.) dose of 13.1 (4.6) for a mean of 28 weeks were compared with a
      matched group of eight patients who had received no antipsychotic treatment for
      at least 2 weeks. Baseline PRL levels did not differ significantly in the two
      patient groups and were within the normal range. The olanzapine-treated patients
      showed a significantly lower maximal DFEN-evoked PRL response and a significantly
      lower group x time overall PRL release compared with the untreated patient group.
      We have previously demonstrated a similar degree of functional in vivo 5-HT(2)
      antagonism with the atypical antipsychotic clozapine. This study thus suggests
      that this activity may not contribute to the unique clinical efficacy of
      clozapine.

PMID- 12467945
TI  - Eye movement disturbances in schizophrenia and a polymorphism of catechol-O
      methyltransferase gene.
AB  - Previous studies suggested an association between the catechol-O
      methyltransferase (COMT) Val/Met polymorphism and the performance on
      neuropsychological tests, measuring prefrontal function in schizophrenia. The aim
      of this study was to examine the relationship between this polymorphism and
      performance on oculomotoric tests in schizophrenic patients. The intensity of eye
      movement disturbances on fixation and smooth pursuit tests and the Val/Met
      polymorphism of COMT gene were studied in 117 schizophrenic patients (74 male and
      43 female). In male schizophrenic patients, the mean intensity of both kinds of
      eye movement disturbances was lower in subjects who had the Met/Met genotype,
      with significant difference compared to other genotypes. Also, a significantly
      higher frequency of the Met allele and the Met/Met genotype was found in male
      schizophrenic patients exhibiting a lower intensity of smooth pursuit
      disturbances, and a trend in this direction was observed for the intensity of
      fixation disturbances. No such relationship was found in female schizophrenic
      patients. The results obtained suggest that, in male schizophrenic patients the
      Met allele of the COMT Val/Met polymorphism may have an alleviating effect on eye
      movement disturbances. They also point to possible gender differences as to the
      role of COMT in brain function in schizophrenia.

PMID- 12467946
TI  - Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2)
      with schizophrenia.
AB  - The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved
      in glutamatergic transmission as candidates for schizophrenia-susceptibility
      genes. The GluR6 kainate receptor gene GRIK2 is located on chromosome 6q16.3-q21,
      a schizophrenia susceptibility region, as suggested by multiple linkage studies.
      We examined 15 SNPs evenly distributed in the entire GRIK2 region (>700 kb) in
      Japanese patients with schizophrenia (n=100) and controls (n=100). Neither
      genotype nor allele frequency showed a significant association with the disorder.
      We constructed 2-SNP haplotypes from the 15 SNPs. Although we observed three long
      linkage disequilibrium blocks (>150 kb) within the GRIK2 region, none of the
      pairwise haplotypes showed a significant association with the disorder.
      Therefore, we conclude that GRIK2 does not play a major role in the pathogenesis
      of schizophrenia in the Japanese population.

PMID- 12467947
TI  - Changes in cognitive functioning following comprehensive treatment for first
      episode patients with schizophrenia spectrum disorders.
AB  - The course of cognitive functioning over a 1-year period was examined among a
      community cohort of individuals presenting with first episode schizophrenia
      spectrum psychosis. Data were obtained for 83 outpatients at entry to an early
      intervention program and 12 months later on the National Adult Reading Test,
      Wechsler Adult Intelligence Scales-Third Edition, Wechsler Memory Scales-Third
      Edition, Paced Auditory Serial Addition Task, Wisconsin Card Sorting Test, Stroop
      Colour and Word Test, Trail Making Test, Continuous Performance Task and
      Thurstone Word Fluency Test. Paired sample t-tests indicated significant and
      positive changes in verbal and non-verbal intelligence, auditory and visual
      memory, working memory and some aspects of executive functioning. Processing
      speed also improved though remained an area of relative weakness for this sample.
      Findings indicated generally average performance at both assessment periods.
      Neither gender nor duration of untreated psychosis were related to the degree of
      change in cognitive functioning for this sample. The implications of these
      findings and the impact of early intervention with this population are discussed.

PMID- 12467948
TI  - Correlation between clinical syndromes and neuropsychological tasks in
      unmedicated patients with recent onset schizophrenia.
AB  - The aim of this study is to circumscribe the cognitive deficits according to
      schizophrenic syndromes in a population of sub-acute untreated patients. We have
      studied the cross-sectional correlation between cognitive deficits and
      schizophrenic symptoms, in a group of 24 untreated patients (including 17
      neuroleptic-naive patients) with recent onset of the disease. A task of
      alertness, a working memory (WM) test (including two levels of difficulty) and an
      abbreviated version of the Wisconsin Card Sorting Test (WCST) were selected. WM
      deficits and poor performance on the WCST were highly correlated with
      disorganized symptoms, modestly with the positive syndrome and not with the
      negative syndrome. Thus, disorganized symptoms, more than any other, appear to be
      related to the impairment of executive function and WM in recent onset
      unmedicated patients with schizophrenia.

PMID- 12467949
TI  - Schizophrenia and memory impairment: evidence for a neurocognitive subtype.
AB  - Evidence is presented that verbal memory impairment distinguishes a subgroup of
      patients with schizophrenia who also differ in symptom profile and illness
      adjustment. On the basis of the California Verbal Learning Test (CVLT), a sample
      of patients was partitioned into memory-impaired (n=16) and memory-unimpaired
      groups (n=16). Groups were matched for age, sex, IQ, and anti-psychotic
      medication. These groups were then compared using the Brief Psychiatric Rating
      Scale (BPRS) and the Sickness Impact Profile (SIP). Results indicate that memory
      impaired schizophrenia patients experience significantly more positive symptoms
      and a poorer quality of life than their memory-unimpaired counterparts. This
      finding supports the idea that neurocognitive measures are a valuable way of
      organizing the heterogeneous disease states of schizophrenia.

PMID- 12467950
TI  - Schizophrenia Quality of Life Scale: validation of the Japanese version.
AB  - This study was performed to test the validity and value of the Schizophrenia
      Quality of Life Scale as an assessment tool in a Japanese-language version
      (JSQLS). The subjects for the present study were 55 inpatients with a diagnosis
      of schizophrenia as defined by DSM-IV. The JSQLS was administered together with
      two other self-report measures, the Medical Outcomes Study 36-item short-form
      health survey questionnaire (SF-36) and the WHO QOL-26, to assess validity.
      Psychotic symptoms and extrapyramidal symptoms were assessed using the BPRS and
      the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), respectively. All the
      scales (psychosocial, motivation/energy and symptoms/side effects) showed good
      internal consistency reliability (Cronbach's alpha=0.93, 0.73 and 0.80,
      respectively). The correlations of items with their scale total revealed that
      almost all items were significantly correlated with their own scale score. There
      were associations with relevant SF-36, WHO QOL-26, and DIEPSS scores. From the
      results of the testing of the reliability and validity of the JSQLS, it is
      concluded that the JSQLS is a simple and reliable scale.

PMID- 12467951
TI  - Auditory masking experiments in schizophrenia.
AB  - Twelve schizophrenic subjects with acoustic hallucinations in their case
      histories were compared with 12 healthy reference subjects and eight subjects
      with panic disorder in a test of three auditory masking tasks, simultaneous
      masking (SM), forward masking (FM) and backward masking (BM). The schizophrenic
      subjects showed no differences from reference subjects on SM but had higher
      thresholds for the two other conditions (FM and BM). Schizophrenics with very
      increased thresholds (n=6) had a significantly higher need for residential
      treatment. Thresholds for SM and BM were not, as for reference subjects, related
      to age for schizophrenics. No statistically significant differences regarding any
      masking experiments were found between the panic disorder subjects and the
      reference subjects. Simultaneous masking, reflecting functions of the basilar
      membrane and those of elementary brainstem processing, showed no signs of
      dysfunction in schizophrenic subjects. Schizophrenics showed aberrations in FM
      and BM, possibly influenced by more central (cortical) processes.

PMID- 12467952
TI  - Time series models of symptoms in schizophrenia.
AB  - The symptom courses of 84 schizophrenia patients (mean age: 24.4 years; mean
      previous admissions: 1.3; 64% males) of a community-based acute ward were
      examined to identify dynamic patterns of symptoms and to investigate the relation
      between these patterns and treatment outcome. The symptoms were monitored by
      systematic daily staff ratings using a scale composed of three factors:
      psychoticity, excitement, and withdrawal. Patients showed moderate to high
      symptomatic improvement documented by effect size measures. Each of the 84
      symptom trajectories was analyzed by time series methods using vector
      autoregression (VAR) that models the day-to-day interrelations between symptom
      factors. Multiple and stepwise regression analyses were then performed on the
      basis of the VAR models. Two VAR parameters were found to be associated
      significantly with favorable outcome in this exploratory study: 'withdrawal
      preceding a reduction of psychoticity' as well as 'excitement preceding an
      increase of withdrawal'. The findings were interpreted as generating hypotheses
      about how patients cope with psychotic episodes.

PMID- 12467953
TI  - Relationship between major depression and heart rate variability. Clinical
      consequences and implications for antidepressive treatment.
AB  - A high sympathetic and/or a low cardiovagal activity in patients with major
      depression (MD) may contribute to the higher cardiac morbidity and mortality of
      MD patients. Standardized tests of heart rate variability (HRV) allow a
      quantitative estimation of autonomic nervous system function. However, previous
      studies on the relationship between HRV and MD have revealed conflicting results.
      Our study compared time and frequency domain HRV indices (5-min resting study,
      deep breathing test, Valsalva test) between 32 patients with MD (DSM-III-R) and
      64 non-depressed controls. The severity of depressive symptoms was assessed by
      the Hamilton Depression Scale (HAM-D); patients were divided into subgroups with
      moderate (M-HAM-D<25) or severe depressive symptoms (S-HAM-D>or=25). After
      controlling for age, gender and smoking, S-HAM-D patients showed a higher heart
      rate and a significantly lower modulation of cardiovagal activity compared to
      controls. Although some of the HRV indices of the M-HAM-D group did not differ
      significantly from controls, they were in the expected direction. There was a
      significantly negative correlation between the HAM-D scores and the vagal HRV
      indices, suggesting a direct association between the severity of depressive
      symptoms and the modulation of cardiovagal activity. Clinical consequences
      arising from these findings and possible implications for treatment are
      discussed.

PMID- 12467954
TI  - Effects of season and climate on the first manic episode of bipolar affective
      disorder in Korea.
AB  - The purpose of this study was to determine if a seasonal pattern existed for the
      first manic episodes in Korea. The first manic episodes out of 152 bipolar
      disorder patients were investigated, in subjects who were admitted in two
      hospitals in Seoul between 1996 and 1999. Correlations between the monthly
      climate variables and the first monthly manic episodes indicated that the first
      manic episodes peaked in 25 cases during March. The mean monthly hours of
      sunshine and sunlight radiation correlated significantly with manic episodes.
      Separating the patients into two groups, namely, with and without major
      depressive episode, only the occurrence of manic episodes with major depressive
      episode was significantly correlated with mean monthly hours of sunshine.
      Separating the subjects by gender, the monthly first manic episodes was
      significantly correlated with the intensity of sunlight radiation in female
      patients only. These findings suggested that increasing the duration and
      intensity of sunlight could facilitate breakdown into the manic episodes.

PMID- 12467955
TI  - Facial affect perception in alcoholics.
AB  - Satisfactory interpersonal interaction involves understanding others' facial
      expressions. Alcoholic individuals often have severe interpersonal difficulties
      that may relate to poor and distorted perception of facial expressions. The
      importance of attention direction has been highlighted by the finding, in recent
      primate studies, of neurons responsible for the detection of attention direction.
      Studies on humans suggest that expression perception is modulated by attention
      direction (whether the expression is directed towards or away from the observer).
      Here, for the first time, the relationship between attention direction and
      perception of expression (anger, sadness, happiness and disgust) in alcoholic and
      control subjects is investigated. We used animated facial stimuli depicting
      different emotions to give measures of recognition accuracy and of perceptual
      sensitivity. Our study demonstrated that alcoholics made more errors than control
      subjects in recognising expressions generally and had a tendency to mis-label sad
      expressions directed towards them as being hostile (angry/disgusted). When asked
      to select the point when they started to see the expression, alcoholics,
      especially female alcoholics, chose higher expression intensities. This study
      highlights the importance of investigating the modulating effects of attention
      direction when studying the perception of expressions and provides an indication
      of how alcoholics' inappropriate social reactions may be triggered.

PMID- 12467956
TI  - Hedonic response to sucrose solutions and the fear of weight gain in patients
      with eating disorders.
AB  - Previous research has shown that patients with bulimia nervosa (B), anorexia
      nervosa, restricting type, or restrictive-anorectic (RA), and anorexia nervosa,
      binge eating, purging type, or anorectic-bulimic (AB) exhibit a reduced hedonic
      response to sucrose compared with control subjects. We hypothesized that this
      response could be linked to an excessive fear of weight gain rather than a
      decreased ability to experience pleasure. We therefore compared the hedonic
      responses to sucrose solutions in B, RA and AB women (n=20/group) in two
      different conditions: sucrose solution swallowed vs. sucrose solution spit. Under
      double-blind conditions and according to a Latin square design, patients received
      sucrose in solution (0, 5, 10, 20, and 40%) and rated each concentration for
      pleasantness on a nine-point scale. The two test conditions were randomly
      administered. The threshold concentration of sweet taste perception was also
      assessed, and the subjects filled out Chapman's Social and Physical Anhedonia
      Scale. The hedonic response to sucrose adjusted for the sweet taste perception
      threshold was significantly lower in the 'swallow' than in the 'spit' condition.
      There was a significant effect of sucrose concentrations as well as a significant
      condition by concentration interaction. When 'fear to swallow' sucrose solution
      responses were included as a covariate, the significant difference between the
      conditions of 'swallow' or 'spit' disappeared, but there was a significant
      concentration by condition by fear to swallow interaction and an almost
      significant covariate effect. When 'Drive for Thinness' on the Eating Disorder
      Inventory was included as a covariate, similar results were obtained. Social
      Anhedonia but not Physical Anhedonia correlated positively with 'Drive for
      Thinness' and 'fear of swallowing sucrose solutions', and correlated inversely
      with maximal hedonic response to the 'swallow' condition. 'We conclude that the
      hedonic responses to sucrose in patients with eating disorders are decreased when
      solutions are swallowed. This may reflect excessive fear of gaining weight rather
      than decreased ability to experience pleasure'.

PMID- 12467957
TI  - Central and peripheral chemoreflexes in panic disorder.
AB  - Klein (Arch Gen Psychiatry, 50, 1993, 306-317) has suggested that panic disorder
      patients have a false suffocation alarm that may be associated with a lowered
      threshold for carbon dioxide detection. We compared the thresholds and
      sensitivities of the central and peripheral chemoreflexes between panic disorder
      patients and age- and sex-matched healthy volunteers to test this aspect of the
      hypothesis. We used a modified version of Read's rebreathing technique in 11
      panic disorder patients and 10 healthy volunteers to examine the peripheral and
      central chemoreflex characteristics in these two populations. Subjects were
      examined during three rebreathing tests: training, hyperoxic (central chemoreflex
      alone) and hypoxic (combined central and peripheral chemoreflex). Panic symptoms
      were retrospectively assessed between groups using a DSM-IV derived Panic Symptom
      Scale. Comparisons of panic disorder patients with agoraphobia and healthy
      volunteers showed no significant differences in sensitivities or thresholds.
      Klein's hypothesis is not supported by these data. If a false suffocation alarm
      exists, its triggering may not be implemented within the respiratory
      chemoreflexes.

PMID- 12467958
TI  - Suicidality, impulsivity and aggression--is there a link to 5HIAA concentration
      in the cerebrospinal fluid?
AB  - In biological suicide research, low cerebrospinal fluid-5-hydroxyindolacetic acid
      (CSF-5HIAA) concentrations have been associated with suicidality, aggression and
      impulsivity. However, it frequently appears that the interpretation of existing
      study results is flawed. The analysis of various published findings suggests that
      contaminating factors like impulsivity or depressive symptoms in suicide
      attempters are often not taken into consideration at the time of suicide. The
      seemingly 'robust' association of low CSF-5HIAA concentration with 'suicidality'
      and 'aggression' is in fact rather weak. Reported associations of subgroups of
      suicidal behavior (e.g. violent suicide attempts) with low CSF-5HIAA
      concentrations are likely to represent somewhat premature translations of
      findings from studies that have flaws in methodology. Furthermore, the perception
      of 'suicidal behavior' as autoaggressive behavior or inwardly directed aggression
      in the view of the authors may not be useful in biological suicide research. The
      construct of aggressivity is insufficiently defined, resulting in difficulties to
      interpret empirical data. Some evidence exists, however, that reduced CSF-5HIAA
      concentrations might be related to certain depressive symptoms and changes in
      impulsivity. More carefully designed studies are required to overcome the
      existing methodological shortcomings.

PMID- 12467960
TI  - Overview of Epstein-Barr virus-associated diseases in Japan.
AB  - Epstein-Barr virus (EBV) associated diseases and studies performed in Japan are
      reviewed. Infectious mononucleosis is a common disease in Japanese infants.
      Chronic and severe EBV-infections include severe chronic active EBV-infection
      (SCAEBV), EBV-associated hemophagocytic syndrome, and mosquito allergy with
      granular lymphocyte proliferative disorder (GLPD). Autoimmune lymphoproliferative
      syndrome (ALPS), a disease caused by a defect in the Fas-Fas ligand pathway of
      cell-death, may develop into lymphoproliferative disease after early exposure to
      EBV. More than ten cases of X-linked lymphoproliferative syndrome (XLP) were
      discovered in Japanese children, and the frequency of post-transplant
      lymphoproliferative disorder (PTLD) increased after the number of patients
      receiving organ transplantation increased. Recently, an association of EBV with
      gastric carcinoma and hepatocellular carcinoma has been suggested. EBV-infected
      cells, such as B-cells, T-cells, NK-cells, and epithelial cells in EBV-associated
      diseases have also been clarified.

PMID- 12467961
TI  - Immunological aspects of Epstein-Barr virus infection.
AB  - Epstein-Barr virus (EBV) is a member of ubiquitous gamma herpes viruses, which
      primarily induces acute infectious mononucleosis (IM) or subclinical infection in
      susceptible subjects. The host reactions account for the clinical manifestation
      of IM. This virus also contributes to the development of lymphoid or epithelial
      malignancies. The outgrowth of EBV-infected B-cells is first controlled by
      interferon (IFN)-gamma and natural killer (NK) cells, and later by EBV-specific
      cytotoxic T-lymphocytes (CTL). To overcome the host responses and establish the
      persistent infection, EBV conducts the protean strategies of immune evasion.
      Several EBV genes modulate apoptotic signals and cytokine balances to persist B
      cell infection without insulting the host. Uncontrolled lymphoproliferation
      occurs as EBV(+) B-cell lymphoproliferative disease (LPD)/lymphoma in AIDS,
      posttransplant, or primary immunodeficiency diseases (PID). On the other hand,
      EBV(+) T/NK cells are involved in EBV-associated hemophagocytic
      lymphohistiocytosis (EBV-HLH) or chronic active EBV infection (CAEBV) in children
      having no underlying immunodeficiencies, and at times lead to the clonal
      evolution of T/NK-cell LPD/lymphomas. Recent advance in molecular techniques has
      enabled us to analyze the clonality of EBV-infected lymphocytes and to quantify
      the gene expression of EBV and cytokines. Dominant autocrine loop of T helper
      (Th) 2 and Th1 may exert in EBV(+) B-LPD and T-LPD, respectively. Intensive
      studies on the immunological interface between effector components and EBV(+)
      target cells will provide more information on clarifying the pathogenesis of EBV
      associated lymphoid malignancies, as well as on exploiting the therapeutic and
      preventive strategies for the formidable EBV-associated disease in childhood.

PMID- 12467962
TI  - Genetic background as a possible determinant of clinical and biological features
      of Epstein-Barr virus infection--a hypothetical view.
AB  - Epstein-Barr virus (EBV) is involved in various clinical disorders and many of
      the disease entities are lymphoid and epithelial malignancies. The exact
      mechanisms that determine the exact form of EBV-related disorder are not clear at
      present. Many of the clinical manifestations of these diseases are based on the
      biological characteristics of the target cells for EBV infection and the
      expression and function of EBV gene, which also perturb host immune functions. In
      this monograph, I propose a hypothesis regarding the mechanism involved in
      shaping the manifestation of EBV infection that genomic instability of EBV
      infected cells and how a defective immune surveillance system against such cells
      plays a critical role in determining the clinical manifestation of EBV infection.
      Using EBV-infected B-cells from patients and carriers with ataxia telangiectasia
      as an example of EBV infection, I present and discuss evidence in support of the
      proposed hypothesis.

PMID- 12467963
TI  - Diagnosis of Epstein-Barr virus-associated diseases.
AB  - Epstein-Barr virus (EBV) is a common DNA virus distributed worldwide. Usually the
      initial infection involves the upper respiratory tract without any problems and
      almost the entire population more than 25 years old test positive for anti-EBV
      antibodies. However, EBV often causes not only acute lytic infection but also
      chronic active infection with B cells and even T cells. In addition the EBV
      genome has been detected in tumors of hematopoietic or epithelial cell origin
      such as Burkitt's lymphomas, Hodgkin's disease, NK/T cell lymphomas,
      nasopharyngeal carcinomas (NPCs) and gastric adenocarcinomas. It is clearly
      important to make a correct diagnosis for EBV associated diseases and monitor the
      EBV load in individual patients for an appropriate therapy. In this paper recent
      advances in serological, immunological and molecular approaches for detection of
      EBV associated disease are described.

PMID- 12467964
TI  - Biological aspects of Epstein-Barr virus (EBV)-infected lymphocytes in chronic
      active EBV infection and associated malignancies.
AB  - Most primary Epstein-Barr virus (EBV) infections are clinically inapparent, but
      occasionally EBV infection can cause acute infectious mononucleosis. EBV has been
      linked to a variety of hematologic and non-hematologic malignancies. Chronic
      active EBV (CAEBV) infection designates a recently identified EBV-associated
      syndrome characterized by a variety of serious hematological disorders, including
      malignant lymphoma. EBV was found to infect circulating T- and/or NK-cells in
      patients with CAEBV infection. These EBV-infected T- and/or NK-cells express EBNA
      1, LMP-1, and LMP-2A, a type II form of EBV latency, which is also observed in
      nasopharyngeal carcinoma (NPC), Hodgkin's disease (HD), and peripheral T-cell
      lymphoma. CAEBV infections may thus represent a subset of EBV-associated T-
      and/or NK-cell lymphoproliferative disorders.

PMID- 12467965
TI  - Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus
      associated T/NK-cell lymphoproliferative disease.
AB  - Epstein-Barr virus (EBV) is implicated in a variety of human diseases, some of
      which have fatal outcomes. Some EBV related diseases are considered to be
      candidates for the treatment of hematopoietic stem cell transplantation (HSCT). X
      linked lymphoproliferative (XLP) syndrome is one of the representative diseases
      in which more than half of affected males die of infectious mononucleosis (IM)
      within a few weeks of primary infection, whereas the minority who survive have an
      increased risk of acquired hypogammaglobulinemia and lymphoma. Patients with XLP
      usually die by the age 40. Similarly, the majority of patients with chronic
      active EBV infection develop hemophagocytic syndrome, organ failure,
      opportunistic infection, and/or lymphoma and die within 5-10 years from onset.
      Recently, HSCT has provided successful outcomes in these patients. In this
      review, progress in the new therapeutic strategy is summarized, focusing on EBV
      associated T/NK-cell lymphoproliferative disease (LPD), which is one of the
      heterogeneous EBV-associated disorder.

PMID- 12467966
TI  - Clinical features and treatment strategies of Epstein-Barr virus-associated
      hemophagocytic lymphohistiocytosis.
AB  - Epstein-Barr virus (EBV) is the major triggering factor producing hemophagocytic
      syndrome or hemophagocytic lymphohistiocytosis (HLH). In this review, diagnostic
      problems, clinical and histopathological features, and treatment strategies of
      EBV-HLH have been described. In patients with EBV-HLH, the EBV-infected T cells
      or natural killer (NK) cells are mostly mono- or oligo-clonally proliferating,
      where hypercytokinemia plays a major role and causes hemophagocytosis, cellular
      damage and dysfunction of various organs. Although the majority of EBV-HLH cases
      develop in apparently immunocompetent children and adolescents, it also occurs in
      association with infectious mononucleosis, chronic active EBV infection, familial
      HLH, X-linked lymphoproliferative disease, lymphoproliferative disease like
      peripheral T-cell lymphoma and NK cell leukemia. In terms of treatment, special
      therapeutic measures are required to control the cytokine storm generated by EBV
      and to suppress proliferating EBV-genome-containing cells, because the clinical
      courses are often fulminant and result in a poor outcome.

PMID- 12467967
TI  - Overview and problematic standpoints of severe chronic active Epstein-Barr virus
      infection syndrome.
AB  - Epstein-Barr virus (EBV) is an ubiquitous human herpesvirus. Its infection is
      generally subclinical. However, in certain circumstances, EBV causes infectious
      mononucleosis (IM) and lymphoproliferative disorders (LPD) in immunologically
      compromised individuals. Furthermore, EBV infection is etiologically linked to
      human malignancies such as Burkitt's lymphoma (BL), nasopharyngeal carcinoma
      (NPC) and miscellaneous malignant diseases because of the presence of viral
      genome in their tumor tissues. Since the late 1970s, a chronic undefined illness
      possibly associated with EBV infection, named such as severe chronic active EBV
      infection syndrome (SCAEBV), has been of interest due to its unique
      manifestations that often result in a poor prognosis. This review is an overview
      of SCAEBV with respect to its; history, diagnosis, pathogenesis, therapeutic
      approaches, and ideas on how to further recognize this enigmatic disease.

PMID- 12467968
TI  - Cell type specific infection of Epstein-Barr virus (EBV) in EBV-associated
      hemophagocytic lymphohistiocytosis and chronic active EBV infection.
AB  - While Epstein-Barr virus (EBV) tropism in B cells and nasopharygeal epithelial
      cells in the normal host has been demonstrated, recently the role of its
      infection into non-B cell populations has been suggested to play a pivotal role
      in the pathogenesis of several EBV-related hematological as well as non
      hematological diseases. Ectopic EBV infection in T cells or natural killer (NK)
      cells has been reported in EBV-associated hematological diseases, such as acute
      fulminant EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and chronic
      active EBV infection (CAEBV). Recent advances in the analysis of EBV infection in
      lymphocyte subpopulations have clarified the differential virus-cell interaction
      within these EBV-related disorders. EBV infection was predominantly found in
      CD8(+) T-cells from EBV-HLH, and in CD4(+) T-cells or NK cells from CAEBV, while
      the majority of EBV infected cells were found in B cells from acute infectious
      mononucleosis (IM). Different virus-cell interactions between acute EBV-HLH and
      CAEBV have indicated different pathogenic mechanisms against EBV infection
      between the two EBV-associated diseases, accounting for the difference in
      clinical manifestations between the two diseases.

PMID- 12467969
TI  - Rapamycin insensitivity in Schistosoma mansoni is not due to FKBP12
      functionality.
AB  - Rapamycin (RAPA) is a well-known immunosuppressant, the action of which is
      mediated by the immunophilin FKBP12. Upon RAPA binding, FKBP12 forms ternary
      complexes with phosphatidyl inositol related kinases known as the target of RAPA
      (TOR), which can lead to a mitotic block at the G1-S phase transition. Such an
      antiproliferative effect makes RAPA an attractive anticancer, antifungal or
      antiparasitic compound. In this study, we found the helminth parasite Schistosoma
      mansoni to be insensitive to the drug. In order to elucidate the mechanism
      underlying RAPA resistance, the S. mansoni drug receptor FKBP12 (SmFKBP12) was
      cloned for functional analysis. Western blot experiments showed that the protein
      is constitutively expressed in all life cycle stages and in both male and female
      parasites. The Escherichia coli-synthesised recombinant protein possessed
      enzymatic activity, which was inhibitable by RAPA. Moreover, SmFKBP12 was able to
      complement mutant Saccharomyces cerevisiae cells lacking FKBP12 in their RAPA
      sensitivity phenotype, leading us to conclude that SmFKBP12 is expressed in yeast
      in a functional form and capable of interacting with the drug and yeast TOR
      kinase. Even though the wild type SmFKBP12 appeared to restore a large part of
      RAPA sensitivity, a mutation of Asp(89)-Lys(90) to Pro(89)-Gly(90) in the
      schistosome protein was found to be more effective and restored drug sensitivity
      to the same level as the endogenous yeast protein. Despite ternary complex
      formation, our results suggest that additional unknown factors other than a
      functional drug receptor are implicated in drug resistance mechanisms.

PMID- 12467970
TI  - Trypanosoma brucei MRE11 is non-essential but influences growth, homologous
      recombination and DNA double-strand break repair.
AB  - MRE11 is a conserved multi-functional protein that is important for maintaining
      genomic integrity in yeast and mammalian cells. By database searching, we
      identified a full-length candidate MRE11 on Trypanosoma brucei chromosome II. We
      subsequently cloned and sequenced the corresponding gene from the Lister 427
      strain. MRE11 is a single copy gene that encodes an 83 kDa protein of 763 amino
      acids. GFP-MRE11 and Ty1-MRE11 fusion proteins localized to the nucleus of
      bloodstream and procyclic T. brucei. Interestingly, Ty1-MRE11 associated, to some
      extent, with telomeres of procyclic but not bloodstream forms. This association
      appears cell-cycle dependent, with the highest co-localization in G1 cells. We
      were able to generate an MRE11 null mutant in bloodstream forms, indicating that
      it is non-essential. However, the null mutant was impaired in homologous
      recombination, as evidenced by the reduced integration efficiency of transfected
      DNA. A conditional null mutant, containing a tetracycline-inducible ectopic Ty1
      MRE11, exhibited reduced growth and plating efficiency and increased sensitivity
      to DNA double-strand breaks, induced by methyl methanesulphonate or ionizing
      radiation, in the absence of tetracycline.

PMID- 12467971
TI  - Physiological and morphological evidences for the presence acidocalcisomes in
      Trypanosoma evansi: single cell fluorescence and 31P NMR studies.
AB  - A new Ca(2+) intracellular store, the acidocalcisome, has been reported in
      trypanosomatids. It has been characterized physiologically as a Ca(2+) store
      sensitive to nigericin. The Ca(2+)/H(+)-ATPase is the system responsible for
      Ca(2+) accumulation, which depends on a pH gradient formed by ATP- and PPi
      dependent proton pumps. In this work we present physiological and morphological
      evidences for the presence of acidocalcisomes in Trypanosoma evansi. The
      parasites were purified and loaded with the fluorescent dye Fura 2-AM in order to
      detect the intracellular changes of Ca(2+) levels in individual cells. The
      simultaneous incubation of T. evansi cells with ionomycin and nigericin led to
      large release of Ca(2+) (ca. 200 nM) from intracellular stores, which was not
      observed with either agent alone. On the other hand, no enhancement of the
      nigericin-induced Ca(2+) release was observed in the presence of oligomycin.
      Additionally, the pretreatment with bafilomycin decreases the nigericin-induced
      Ca(2+) release. These results confirm the presence of an intracellular non
      mitochondrial acidic Ca(2+) storage compartment. These results suggest that H(+)
      ATPase is involved in the process of Ca(2+) accumulation into the
      acidocalcisomes. Furthermore, the cells loaded with acridine orange exhibited
      abundant fluorescent vacuoles, which were sensitive to nigericin or bafilomycin
      A(1). Electronic transmission microscopy observations demonstrated the presence
      of electron dense particles in the parasites. High levels of inorganic
      pyrophosphate and triphosphate were detected in perchloric acid extracts of T.
      evansi by high resolution 31P NMR. Taken together, these results present the
      first evidence for the presence of acidocalcisomes in T. evansi.

PMID- 12467972
TI  - Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and
      Leishmania mexicana.
AB  - Trypanosoma cruzi and Leishmania parasites have a strict requirement for specific
      endogenous sterols (ergosterol and analogs) for survival and growth and cannot
      use the abundant supply of cholesterol present in their mammalian hosts. Squalene
      synthase (SQS, E.C. 2.5.1.21) catalyzes the first committed step in sterol
      biosynthesis and is currently under intense study as a possible target for
      cholesterol-lowering agents in humans, but it has not been investigated as a
      target for anti-parasitic chemotherapy. SQS is a membrane-bound enzyme in both T.
      cruzi epimastigotes and Leishmania mexicana promastigotes with a dual subcellular
      localization, being almost evenly distributed between glycosomes and
      mitochondrial/microsomal vesicles. Kinetic studies showed that the parasite
      enzymes display normal Michaelis-Menten kinetics and the values of the kinetic
      constants are comparable to those of the mammalian enzyme. We synthesized and
      purified 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH), a potent and specific
      inhibitor of mammalian SQS and found that it is also a powerful non-competitive
      inhibitor of T. cruzi and L. mexicana SQS, with K(i)'s in the range of 12-62 nM.
      BPQ-OH induced a dose-dependent reduction of proliferation the extracellular
      stages of these parasites with minimal growth inhibitory concentrations (MIC) of
      10-30 microM. Growth inhibition and cell lysis induced by BPQ-OH in both
      parasites was associated with complete depletion of endogenous squalene and
      sterols, consistent with a blockade of de novo sterol synthesis at the level of
      SQS. BPQ-OH was able to eradicate intracellular T. cruzi amastigotes from Vero
      cells cultured at 37 degrees C, with a MIC of 30 microM with no deleterious
      effects on host cells. Taken together, these results support the notion that SQS
      inhibitors could be developed as selective anti-trypanosomatid agents.

PMID- 12467973
TI  - Y-box binding protein from Schistosoma mansoni: interaction with DNA and RNA.
AB  - A Schistosoma mansoni homologue of the human Y-box binding protein (SMYB1), as
      well as truncated proteins containing its N-terminal Cold Shock Domain (CSD) or
      its C-terminal domain (TAIL) were cloned into the p-MAL-c2 expression vector and
      produced in Escherichia coli. In order to characterize the interactions of these
      proteins to an inverted CCAAT motif present in a number of gene promoters, their
      binding to DNA was measured by Electrophoretic Mobility Shift Assays. SMYB1 bound
      to single- and double-stranded DNA containing the CCAAT motif and could bind also
      to RNA. The truncated CSD and TAIL domain proteins bound to dsDNA and RNA, but
      exhibited distinct binding patterns. Protein-DNA interaction was also
      investigated in vivo, using the Yeast One-Hybrid System. The plasmid constructs
      were GSTTRI, a DNA fragment composed of three copies of the CCAAT motif of the S.
      mansoni glutathione S-transferase gene promoter and four oligonucleotides
      spanning different regions of the S. mansoni p14 gene promoter. None of the yeast
      clones transformed with the above plasmids was able to grow in selective medium
      or to activate the transcription of the HIS3 reporter gene, suggesting that SMYB1
      could not interact with these promoters in vivo.

PMID- 12467974
TI  - Abundant larval transcript-1 and -2 genes from Brugia malayi: diversity of
      genomic environments but conservation of 5' promoter sequences functional in
      Caenorhabditis elegans.
AB  - The genomic organisation of two abundant larval transcript (alt) genes from the
      filarial nematode Brugia malayi has been defined. The products of these genes are
      78% identical in amino acid sequence, and are highly expressed in a stage
      specific manner by mosquito-borne infective larvae. alt-1 is present as two near
      identical copies organised in an inverted repeat of approximately 7.6 kb,
      occupying a total of 16 kb of the genome. alt-2 is a single-copy gene at a
      different locus to alt-1. The two alt-1 genes (alt-1.1 and -1.2) are 99.7%
      identical in coding sequence and 99.5% in intronic sequences. Both alt-1 and -2
      contain 3 introns, and the third intron of alt-2 exhibits a size polymorphism
      evident in different individual parasites from the laboratory-maintained strain.
      Genomic sequence up- and down-stream from alt-1.1/1.2 (26 and 6 kb, respectively)
      and alt-2 (6 and 4 kb, respectively) show that neither gene is in a multiple
      array or an operon. Most notably, the neighbouring genes of alt-1 and -2 show no
      similarity to each other, or to the genes flanking the distant alt homologue in
      Caenorhabditis elegans. Despite this diversity in flanking genes, the 5' UTR
      tracts extending some 800 bp upstream of each B. malayi alt gene show a high
      degree of similarity (overall 59% identity with tracts of 77-86% identity).
      Surmising that this region may contain conserved promoter elements, constructs
      containing the B. malayi alt 5' UTR with or without coding sequence were made
      fused to beta-galactosidase reporter protein. These constructs were injected into
      the syncytical gonad of C. elegans and progeny stained for beta-gal expression.
      Our results show relatively strong expression in the gut cells of C. elegans for
      both alt-1 and -2 constructs, commencing in larval worms and continuing into
      adulthood. Moreover, expression was enhanced when constructs contained segments
      of alt-1 coding and intronic sequence in addition to the 5' UTR. We conclude that
      the high level of alt transcription in filarial L3s is not due to expression from
      a multi-copy gene family but to a set of strong promoter elements shared between
      the two alt genes.

PMID- 12467975
TI  - Characterization of a recombinant immunodiagnostic antigen (NIE) from
      Strongyloides stercoralis L3-stage larvae.
AB  - Due to the process of internal autoinfection, even chronic asymptomatic
      infections with Strongyloides stercoralis have the potential to become severe
      disseminated disease with fatal outcome. Intermittent and scanty larval excretion
      makes parasitologic diagnosis difficult. Serodiagnosis is helpful, but antigen
      preparation from infective larvae requires access to patients or immunosuppressed
      experimental animals. For these reasons, attention has turned to recombinant
      antigens for immunodiagnosis. A 31-kDa candidate antigen (NIE) derived from an L3
      cDNA library is described in this report. Multiple alignment of the deduced amino
      acid sequence of NIE showed approximately 12-18% identity with various other
      organisms, including 17.9% of Asp1 of Ancylostoma caninum, 12.6% of Hemonchus
      contortus, and 17.6% of insect venom allergen 5 of yellow jacket. By ELISA,
      antibodies to the purified recombinant NIE antigen were demonstrated in 87.5% of
      48 sera from strongyloides-infected patients and in only 6.5% of sera from
      presumed normal controls. Immunoreactivity of purified NIE antigen with parasite
      specific IgE from sera of strongyloides-infected patients indicated its potential
      use as an immediate sensitivity skin test antigen. This application of the NIE
      antigen was supported by its capacity to trigger release of histamine upon in
      vitro exposure to blood from strongyloides-infected patients and its failure to
      produce histamine release from blood of normal controls.

PMID- 12467976
TI  - A study of genetic diversity in the gene encoding the circumsporozoite protein
      (CSP) of Plasmodium falciparum from different transmission areas--XVI. Asembo Bay
      Cohort Project.
AB  - We have investigated the genetic diversity of the gene encoding the CS protein. A
      total of 75 complete and 96 partial sequences are studied. We find high levels of
      genetic polymorphisms as evidenced by 50 and 24 alleles at the Th2R and Th3R
      epitopes, respectively. Overall, we find that African isolates are more
      polymorphic as compared with parasites from other geographic regions. We conclude
      that the uneven geographic polymorphism may have an adverse impact on the
      effectiveness of vaccines based on this antigen alone. We find extensive
      polymorphism in the repeat allotypes, or RATs. In order to explore how the
      protein structure may impose restrictions in the number of repeats, we have
      simulated the stability of the structure of the tandem repeat region. Our
      analysis suggests that the protein structure may play an important role in the
      observed polymorphism in the number of CS repeats in Plasmodium falciparum. We
      explored the linkage and recombination events among the polymorphic sites. We
      found that putative recombination events overlap with linked sites. We discuss
      how this pattern is explained by the action of positive natural selection, where
      the recombination events detected are convergent mutations. We conclude that it
      is inappropriate to use linkage-recombination patterns on genes under positive
      selection for assessing the structure of parasite populations.

PMID- 12467977
TI  - The Trypanosoma cruzi membrane glycoprotein AGC10 inhibits human lymphocyte
      activation by a mechanism preceding translation of both, interleukin-2 and its
      high-affinity receptor subunits.
AB  - Like living Trypanosoma cruzi, its AGC10 membrane glycoprotein inhibits
      interleukin-2 (IL-2) secretion and membrane expression of CD25, CD122, and CD132
      (the components of the high-affinity IL-2 receptor) by activated human
      lymphocytes. Since these molecules are required for effective lymphocyte
      division, we explored the molecular mechanism underlying these alterations. In
      the presence of AGC10 the cytoplasmic levels of IL-2 protein of CD4(+) and CD8(+)
      blood lymphocytes stimulated with phorbol myristate acetate (PMA) plus ionomycin
      were markedly reduced. AGC10 also decreased the intracellular levels of CD25,
      CD122, and CD132 in CD4(+) and CD8(+) cells stimulated with the T-cell mitogen
      phytohemagglutinin (PHA). These results indicated that the AGC10-induced
      alterations preceded IL-2 secretion and transport of IL-2 receptor components to
      the cell membrane. Supporting this view were the substantially diminished levels
      of IL-2, CD25, CD122, and CD132 mRNA found in AGC10-containing cultures of PHA
      activated lymphocytes. These decreases were not due to increased mRNA
      instability. Thus, the rates of decay for each of these mRNA species were
      comparable in the presence or absence of AGC10, suggesting a mechanism involving
      transcription inhibition. AGC10 targeted an early lymphocyte activation event
      since inhibition of lymphoproliferation subsided when AGC10 was added to cultures
      at or after 20 h post-activation. AGC10 also caused large reductions in the mRNA
      levels of cyclin D2 and cdk4, both critical for progression through G1. These
      results show for the first time that AGC10-induced inhibition of
      lymphoproliferation entails curtailed biosynthesis of IL-2 and, IL-2 receptor
      molecules, and suggest that the effect involves inhibition of gene transcription.

PMID- 12467978
TI  - Characterization and comparative functional analysis in yeast of a Schistosoma
      mansoni Rho1 GTPase gene.
AB  - Low-molecular weight GTP-binding proteins (LMWGPs) of the Ras superfamily are
      believed to play a role in Schistosoma mansoni female development and egg
      production. Here we describe the characterization of a novel S. mansoni gene
      (SMRHO1), highly homologous to Rho-type LMWGPs from several other organisms and
      encoding a polypeptide with 193 amino acids and an estimated molecular mass of
      21.8 kDa. SMRHO1 complemented a Saccharomyces cerevisiae rho1 null mutant strain
      even in restrictive temperature and calcium concentration, in contrast with the
      human RHOA GTPase that was not able to provide complementation in such
      conditions. Comparison of the amino acid sequence of the alpha3-helix loop7
      regions of the two proteins allowed the identification of the proline 96 and
      threonine 100 amino acid residues of human RHOA as the most probable determinants
      of the complementation differences. We generated SMRHO1 mutants (smrho1(E97P),
      smrho1(L101T) and smrho1(E97P,) L101T) by site directed mutagenesis and
      reproduced the conditional lethality phenotype at high temperature, providing
      strong evidence that the related amino acid positions (Gln(101) and Ile(105)) in
      the Rho1 GTPase are indeed important for regulation of the cell wall synthesis
      performed by this protein in yeast. The observation that specific amino acid
      positions seem to be important for the different functions performed by the Rho
      GTPases leads to the idea that SMRHO1 might be a useful target in the development
      of new anti-schistosomiasis drugs, although it does share high sequence homology
      with the human RhoA GTPase.

PMID- 12467979
TI  - A putative novel nuclear-encoded subunit of the cytochrome c oxidase complex in
      trypanosomatids.
AB  - A relatively large nuclear-encoded polypeptide, designated trCOIV, is found in
      the cytochrome c oxidase (CO) complex of trypanosomatids. In order to determine
      if this polypeptide represents a bona fide subunit of the complex, we have
      characterized the cDNA and the gene for this polypeptide in Leishmania
      tarentolae. Its nuclear gene has no sequence similarity to mammalian COIV. The
      trCOIV preprotein has a long mitochondrial targeting sequence of 31 residues. The
      mature polypeptide cofractionates with kinetoplast-mitochondria and its
      preferential mitochondrial localization was confirmed by immunofluorescence and
      immunoelectron microscopy. Based on the hydropathy plot analysis, the protein
      lacks pronounced transmembrane domains and likely occupies a peripheral position
      within the CO complex. The corresponding genes are also present in the sequenced
      portions of the Trypanosoma cruzi, Trypanosoma brucei and Leishmania major
      genomes, and the same polypeptide is found in cytochrome oxidase isolated from
      procyclic T. brucei and promastigote Leishmania mexicana amazonensis. However,
      the trCOIV gene, the mRNA and the polypeptide could not be detected in a
      respiration-deficient trypanosomatid Phytomonas serpens.

PMID- 12467980
TI  - Choline transport in Leishmania major promastigotes and its inhibition by choline
      and phosphocholine analogs.
AB  - Phosphatidylcholine is the most abundant phospholipid in the membranes of the
      human parasite Leishmania. The metabolic pathways leading to its biosynthesis are
      likely to play a critical role in parasite development and survival and may offer
      a good target for antileishmanial chemotherapy. Phosphatidylcholine synthesis via
      the CDP-choline pathway requires transport of the choline precursor from the
      host. Here, we report the first characterization of choline transport in this
      parasite, which is carrier-mediated and exhibits Michaelis-Menten kinetics with
      an apparent K(m) value of 2.5 microM for choline. This process is Na(+)
      independent and requires an intact proton gradient to be fully functional.
      Choline transport into Leishmania is highly specific for choline and is inhibited
      by the choline carrier inhibitor hemicholinium-3, the channel blocker quinacrine,
      the antimalarial aminoquinolines quinine and quinidine, the antileishmanial
      phosphocholine analogs, miltefosine and edelfosine, and by choline analogs, most
      of which have antimalarial activities. Most importantly, choline analogs kill the
      promastigote form of the parasite in vitro in the low micromolar range. These
      results set the stage for the use of choline analogs in antileishmanial
      chemotherapy and shed new lights on the mechanism of action of the leishmanicidal
      phosphocholine analogs.

PMID- 12467981
TI  - Role of dihydrolipoyl dehydrogenase (E3) and a novel E3-binding protein in the
      NADH sensitivity of the pyruvate dehydrogenase complex from anaerobic
      mitochondria of the parasitic nematode, Ascaris suum.
AB  - The pyruvate dehydrogenase complex (PDC) plays changing roles during the aerobic
      anaerobic transition in the life cycle of the parasitic nematode, Ascaris suum.
      However, the dihydrolipoyl dehydrogenase (E3) subunit appears to be identical in
      all stages, despite the fact that the PDC is less sensitive to NADH inhibition in
      anaerobic muscle. Therefore, we have cloned cDNAs encoding E3 and a novel
      anaerobic-specific E3-binding protein (E3BP) that lacks the terminal lipoyl
      domain found in E3BPs from yeast and mammals, and functionally expressed E3 and
      E3 mutants designed to have decreased dimer stability on the assumption that the
      binding of E3 to an anaerobic-specific E3BP might stabilize the E3 dimer
      interface and decrease E3 sensitivity to NADH inhibition. As predicted, the
      mutants exhibited decreased thermal stability, increased sensitivity to NADH and
      the binding of E3(Y18F) to the E3-depleted core of the pig heart PDC increased E3
      activity and decreased E3 sensitivity to NADH inhibition. However, although the
      free A. suum E3 was less sensitive to NADH inhibition than the pig heart E3, both
      E3s were significantly more sensitive to NADH inhibition when assayed with
      dihydrolipoamide than their corresponding PDCs assayed with pyruvate. More
      importantly, the binding of rE3 to its core complex had little effect on its
      apparent K(m) for NAD(+), K(i) for NADH inhibition, or the NADH/NAD(+) ratio
      yielding 50% inhibition. These data suggest that although binding to the core
      stabilizes the E3 dimer interface, it does not play a significant role in
      reducing the sensitivity of the A. suum PDC to NADH inhibition during
      anaerobiosis.

PMID- 12467982
TI  - Characterization of a Leishmania mexicana mutant defective in synthesis of free
      and protein-linked GPI glycolipids.
AB  - The cell surface of the promastigote stage of the protozoan parasite, Leishmania
      mexicana is coated by a number of glycosylphosphatidylinositol (GPI)-anchored
      proteins, a GPI-anchored lipophosphoglycan (LPG) and an abundant class of free
      GPIs, termed glycoinositolphospholipids (GIPLs). We have developed a new screen
      for isolating L. mexicana mutants that are defective in GPI biosynthesis,
      involving concanavalin A selection of a parental strain with a modified surface
      coat. One mutant was isolated that lacked the major GIPL species and mature GPI
      protein anchor precursors, but synthesized normal levels of LPG anchor
      precursors. Based on analysis of apolar GIPLs that accumulate in this mutant and
      in vivo and in vitro synthesized GPIs, this mutant was found to have a defect in
      the addition of an alpha1-6 linked mannose to the common precursor, Man(1)GlcN
      PI. The apolar GIPLs were transported to the cell surface with the same kinetics
      as mature GIPLs. However, non-anchored isoforms of the major GPI-anchored
      protein, gp63, were either slowly secreted (with a t(1/2) of 2 h) or retained
      within the endoplasmic reticulum, respectively. These findings suggest that
      common enzymes are involved in the synthesis of GIPLs and protein anchors and
      have implications for understanding how the biosynthesis of the major surface
      components of these parasites is regulated.

PMID- 12467983
TI  - Evidence for intragenic recombination in Plasmodium falciparum: identification of
      a novel allele family in block 2 of merozoite surface protein-1: Asembo Bay Area
      Cohort Project XIV.
AB  - We have investigated intragenic recombination in Block 2 of the merozoite surface
      protein-1 (MSP-1), where three allele-specific families: K1, Mad20, and RO33 were
      previously known. Using parasites from western Kenya, we have found a fourth
      Block 2 allele type, which is a recombinant between Mad20 and RO33 alleles. These
      recombinant alleles, which we have termed MR, contain sequence from the 5' region
      of Mad20 and the 3' region of RO33. The results of this study provide new data on
      the complexity of the MSP-1 antigen gene, which is a candidate vaccine antigen,
      and further support the importance of intragenic recombination in generating
      genetic variability in Plasmodium falciparum parasites in nature.

PMID- 12467984
TI  - Monoclonal antibodies raised in Btk(xid) mice reveal new antigenic relationships
      and molecular interactions among gp53 and other Trichinella glycoproteins.
AB  - Tyvelose-bearing glycoproteins or Trichinella spiralis Group 1 antigens (TSL-1
      antigens) are thought to be key molecules in the immunobiology of Trichinella. In
      the present study, we investigated the binding characteristics of several mAbs
      produced in Btk(xid) immunodeficient mice that recognise gp53 and some other
      minor glycoproteins of this parasite. The data obtained reveal the existence of
      an O-glycan/peptide epitope (recognised by mAb US8) common to all TSL-1
      glycoproteins, as well as a specific interaction between the TSL-1 antigen gp53
      and other unknown Trichinella glycoproteins in the 35-40 kDa range (these latter
      react with mAbs US8 and US9, but not with mAb US5). Some of the epitopes
      recognised by our mAbs are differentially expressed in Trichinella species: the
      epitope recognised by mAb US5 on gp53 (another O-glycan/peptide epitope) is
      present only in T. spiralis, whereas those recognised by mAbs US8 and US9
      (peptide epitopes) are present in encapsulated Trichinella species. The data
      obtained also reveal that gp53 is synthesised and glycosylated in beta
      stichocytes only. The possible relevance of these findings is discussed.

PMID- 12467985
TI  - Polymorphism among alleles of the 6-phosphogluconate dehydrogenase gene from
      Leishmania major and Leishmania tropica.

PMID- 12467986
TI  - Unprocessed Toxoplasma ROP1 is effectively targeted and secreted into the nascent
      parasitophorous vacuole.

PMID- 12467987
TI  - A novel potential surface protein in Trichomonas vaginalis contains a leucine
      rich repeat shared by micro-organisms from all three domains of life.

PMID- 12467988
TI  - Expression and genome-wide distribution of the gene family encoding a 90 kDa
      surface glycoprotein of metacyclic trypomastigotes of Trypanosoma cruzi.

PMID- 12467989
TI  - Silencing of the thioredoxin gene in Trypanosoma brucei brucei.

PMID- 12467990
TI  - Targeting of a tetracycline-inducible expression system to the transcriptionally
      silent minichromosomes of Trypanosoma brucei.

PMID- 12467991
TI  - New directions in research on pain and ethnicity: a comment on Riley, Wade,
      Myers, Sheffield, Pappas, and Price (2002).

PMID- 12467992
TI  - Opioid-induced abnormal pain sensitivity: implications in clinical opioid
      therapy.

PMID- 12467993
TI  - Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic
      acid in a model of bone cancer pain.
AB  - Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female
      rats produced tumour growth within the bone associated with a reduction in bone
      mineral density (BMD) and bone mineral content (BMC), severe radiological signs
      of bone destruction, together with the development of behavioural mechanical
      allodynia and hyperalgesia. Histological and radiological examination showed that
      chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.),
      for 19 days significantly inhibited tumour proliferation and preserved the
      cortical and trabecular bone structure. In addition, BMD and BMC were preserved
      and a dramatic reduction of tartrate resistant acid phosphatase-positive
      polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic
      treatment with zoledronic acid but not the significantly less effective
      bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex,
      attenuated mechanical allodynia and hyperalgesia in the affected hind paw.
      Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic
      peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or
      clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia
      in the neuropathic and inflammatory pain models. We conclude that zoledronic
      acid, in addition to, or independent from, its anti-metastatic and bone
      preserving therapeutic effects, is an anti-nociceptive agent in a rat model of
      metastatic cancer pain. This unique property of zoledronic acid amongst the
      bisphosphonate class of compounds could make this drug a preferred choice for the
      treatment of painful bone metastases in the clinic.

PMID- 12467994
TI  - Interference due to pain following spinal cord injury: important predictors and
      impact on quality of life.
AB  - Two studies were designed to examine important predictors of pain following
      spinal cord injury (SCI), and the impact of pain on self-reported quality of life
      (QOL). Pain was defined as "interference in day-to-day activities secondary to
      pain". In order to determine risk factors associated with the development of pain
      interference, Study 1 examined the predictive validity of multiple demographic,
      medical, and QOL variables at year 1 post-SCI to self-reported pain interference
      2 years post-injury. Results showed that middle age (30-59-year-olds), lower self
      reported mental health, and pain interference at 1 year post-SCI were the most
      important unique predictors of pain interference 2 years post-SCI. In Study 2,
      participants were separated into four groups; (1) those pain-free at years 1 and
      2, (2) those pain-free at year 1 and in pain at year 2, (3) those in pain at year
      1 and pain-free at year 2, and (4) those in pain at years 1 and 2. Results showed
      that only those experiencing a change in pain interference status reported a
      change in QOL. More specifically, those developing pain interference (group 2)
      from year 1 to year 2 reported decreased life satisfaction, physical health, and
      mental health, whereas, those with resolving pain interference from year 1 to
      year 2 reported an increase in these same domains. Unexpectedly, change in pain
      interference status was unrelated to change in self-reported handicap.
      Implications and future directions are discussed.

PMID- 12467995
TI  - Dynorphin-independent spinal cannabinoid antinociception.
AB  - Spinal antinociception produced by delta 9-tetrahydro-cannabinol (Delta(9)-THC)
      and other cannabinoid agonists has been suggested to be mediated by the release
      of dynorphin acting at the kappa opioid receptor. Alternatively, as cannabinoid
      receptors are distributed appropriately in the pain transmission pathway,
      cannabinoid agonists might act directly at the spinal level to inhibit
      nociception, without requiring dynorphin release. Here, these possibilities were
      explored using mice with a deletion of the gene encoding prodynorphin.
      Antinociceptive dose-response curves were constructed for spinal Delta(9)-THC and
      WIN 55,212-2 in prodynorphin knock-out mice and in wild-type littermates. WIN
      55,212-2 and Delta(9)-THC were equipotent in the wild-type and prodynorphin knock
      out mice. Spinal pretreatment with a kappa opioid receptor antagonist, nor
      binaltorphimine (nor-BNI), did not alter the dose-response curves for either WIN
      55,212-2 or Delta(9)-THC in prodynorphin knock-out and wild-type mice. However,
      the same dose of nor-BNI used blocked U50,488H-induced antinociception in both
      wild-type and prodynorphin knock-out mice, confirming kappa opioid receptor
      activity. Pretreatment with SR141716A, a cannabinoid receptor antagonist blocked
      the antinociceptive actions of both WIN 55,212-2 and Delta(9)-THC. These data
      support the conclusion that antinociception produced by spinal cannabinoids are
      likely to be mediated directly through activation of cannabinoid receptors
      without the requirement for dynorphin release or activation of kappa opioid
      receptors.

PMID- 12467996
TI  - Employment and litigation: improved by work, assisted by verdict.
AB  - Previous research exploring the relationship between litigation status and the
      symptoms of the plaintiff has been inconsistent and limited by methodological
      difficulties. This longitudinal study addressed many of the methodological
      shortcomings of previous research and examined the relationship between
      litigation status, employment, depression, pain and disability over the duration
      of the compensation process. Two hundred chronic back pain participants were
      selected from patients who attended an initial assessment interview at a pain
      centre. According to their litigation and employment status these patients were
      divided into four groups, namely a non-litigating non-working group, a non
      litigating working group, a litigating non-working group and a litigating working
      group. All participants completed three questionnaires, one at intake, one at a
      minimum of 2 years later (for litigants during the litigation process), with the
      final questionnaire completed at a minimum of 15 months thereafter (for litigants
      after they had settled their claim). Questionnaires contained measures of pain
      (Visual Analogue Scale, Short Form McGill Pain Questionnaire), depression (Zung
      Self-Rating Depression Scale), and disability (Oswestry Disability
      Questionnaire). Overall participants who were working scored lower on all the
      measures than did participants who were not working. On the other hand
      participants who were litigating scored higher on all the measures than did
      participants who were not litigating. There was a significant time effect on all
      measures but this was qualified on some measures by the interactions of time with
      litigation status and work status. The present research further demonstrated that
      both litigation and employment were significant factors influencing recovery from
      injury.

PMID- 12467997
TI  - Reactivity to superficial and deep stimuli in patients with chronic
      musculoskeletal pain.
AB  - In this study, we evaluated pain sensitivity in patients with fibromyalgia or
      other types of chronic, diffuse musculoskeletal pain to establish whether
      fibromyalgia represents the end of a continuum of dysfunction in the nociceptive
      system. One hundred and forty five patients and 22 healthy subjects (HS)
      completed an epidemiological questionnaire to provide information about fatigue,
      stiffness, sleep, the intensity of pain (VAS 0-100) and its extent both at onset
      and at present. Algometry was performed at all American College of Rheumatology
      (ACR) tender points and at ten control points. Patients were divided into five
      main groups: fibromyalgia (FS) patients, secondary-concomitant fibromyalgia
      (SCFS) patients, patients with widespread pain (WP) but not reaching the ACR
      criterion of 11 tender points, patients with diffuse multiregional pain (MP) not
      reaching the ACR criteria (widespread pain, tender point counts), and patients
      with multiregional pain associated with at least 11 tender points (MPTE). von
      Frey monofilaments were used to assess superficial punctate pressure pain
      thresholds. Heat and cold pain thresholds were determined with a thermal
      stimulator. Ischemic pain was assessed by the cold pressure test and the
      submaximal effort tourniquet test. The scores for stiffness and present pain
      intensity gradually increased concomitantly with the increase in tender point
      count and pain extent. The pressure pain thresholds for positive tender and
      positive control points were significantly lower in the SCFS, FS and MPTE groups
      than in HS, MP and WP groups, the latter three groups displaying similar values.
      In all groups, there were no differences in pain thresholds between positive
      tender and positive control points. The heat pain threshold and the pain
      threshold in the cold pressure test were lower in the FS and SCFS groups than in
      HS. The cold pressure tolerance was lower in patients with widespread pain than
      in HS. In the von Frey test, all patient groups except MP had similar values,
      which were significantly lower than in HS. Finally, all patient groups displayed
      lower tourniquet tolerance than HS. In each psychophysical test, patients with
      widespread pain and patients with multiregional pain showed similar thresholds;
      however, the thresholds in the MP or MPTE groups differed from those in the FS
      and SCFS groups. In the FS group, pain thresholds and pain tolerance did not
      differ according to the presence of ongoing pain at the stimulated site and were
      not correlated to ongoing pain. The results indicate that dysfunction in the
      nociceptive system is already present in patients with multiregional pain with a
      low tender point count; it becomes more and more severe as the positive tender
      point count and pain extent increase and it is maximal in fibromyalgia patients.

PMID- 12467998
TI  - The contribution of pain, reported sleep quality, and depressive symptoms to
      fatigue in fibromyalgia.
AB  - The major objective of this research was to evaluate the predictors of fatigue in
      patients with fibromyalgia (FM), using cross-sectional and daily assessment
      methodologies. In the cross-sectional phase of the research involving a sample of
      105 FM patients, greater depression and lower sleep quality were concurrently
      associated with higher fatigue. While pain was correlated with fatigue, it did
      not independently contribute to fatigue in the regression equation. For a subset
      of patients from the cross-sectional sample (n=63) who participated in a week of
      prospective daily assessment of their pain, sleep quality, and fatigue, multiple
      regression analysis of aggregated (averaged) daily scores revealed that previous
      day's pain and sleep quality predicted next day's fatigue. Depression from the
      cross-sectional phase was not related to aggregated daily fatigue scores. A path
      analytic framework was tested with disaggregated (removing between subjects
      variability) data in which pain was predicted to contribute to lower sleep
      quality which, in turn, was predicted to lead to greater fatigue. The results
      revealed that poor sleep quality fully accounted for the positive relationship
      between pain and fatigue, thus substantiating the mediational role of sleep
      quality. The findings are indicative of a dysfunctional, cyclical pattern of
      heightened pain and non-restful sleep underlying the experience of fatigue in FM.

PMID- 12467999
TI  - Temporo-spatial analysis of cortical activation by phasic innocuous and noxious
      cold stimuli--a magnetoencephalographic study.
AB  - Clinical findings and recent non-invasive functional imaging studies pinpoint the
      insular cortex as the crucial brain area involved in cold sensation. By contrast,
      the role of primary (SI) and secondary (SII) somatosensory cortices in central
      processing of cold is controversial. So far, temporal activation patterns of
      cortical areas involved in cold processing have not been examined. Using
      magnetoencephalography, we studied, in seven healthy subjects, the temporo
      spatial dynamics of brain processes evoked by innocuous and noxious cold
      stimulation as compared to tactile stimuli. For this purpose, a newly designed
      and magnetically silent cold-stimulator was employed. In separate runs, cold and
      painful cold stimuli were delivered to the dorsum of the right hand. Tactile
      afferents were stimulated by pneumatic tactile stimulation.Following innocuous
      cold stimulation (DeltaT=5+/-0.3 degrees C in 50+/-2ms), magnetic source imaging
      revealed an exclusive activation of the contra- and ipsilateral posterior insular
      cortex. The mean peak latencies were 194.3+/-38.1 and 241.0+/-31.7ms for the
      response in the ipsi- and contralateral insular cortex, respectively. Based on
      the measurement of onset latencies, the estimated conduction velocity of
      peripheral nerve fibres mediating cold fell in the range of Adelta-fibres (7.4+/
      0.8 m/s). Noxious cold stimulation (DeltaT=35+/-5 degrees C in 70+/-12ms)
      initially activated the contra- and ipsilateral insular cortices in the same
      latency ranges as innocuous cold stimuli. Additionally, we found an activation of
      the contra- and ipsilateral SII areas (peak latencies 304+/-22.7 and 310.1+/
      19.4ms, respectively) and a variable activation of the cingulate cortex. Notably,
      neither cold- nor painful cold stimulation produced an activation of SI. By
      contrast, the evoked cortical responses following tactile stimulation could be
      located to the contralateral SI cortex and bilateral SII. In conclusion, this
      study strongly corroborates the posterior insular cortex as the primary
      somatosensory area for cortical processing of cold sensation. Furthermore, it
      supports the role of SII and the cingulate cortex in mediating freeze-pain.
      Therefore, these results suggest different processing of cold, freeze-pain and
      touch in the human brain.

PMID- 12468000
TI  - Racial/ethnic differences in the experience of chronic pain.
AB  - The purpose of this study was to examine racial/ethnic-related differences in a
      four-stage model of the processing of chronic pain. The subjects were 1557
      chronic pain patients (White=1084, African American=473) evaluated at a pain
      management clinic at a large southeastern university medical center. Using an
      analysis of covariance controlling for pain duration and education, African
      American patients reported significantly higher levels of pain unpleasantness,
      emotional response to pain, and pain behavior, but not pain intensity than
      Whites. Differences were largest for the unpleasantness and emotion measures,
      particularly depression and fear. The groups differed by approximately 1.0 visual
      analogue scale unit, a magnitude that may be clinically significant.
      Racial/ethnic differences in the linear relationship between stages were also
      tested using structural equation modeling and LISREL-8. The results indicate
      differences in linear associations between pain measures with African Americans
      showing a stronger link between emotions and pain behavior than Whites.

PMID- 12468001
TI  - Lumbar spinal cord stimulation for cervical-originated central pain: a case
      report.
AB  - This case presents a patient with neuropathic pain in a lower extremity, which
      appeared subsequent to the removal of a C1 meningioma and which was successfully
      treated by lower thoracic spinal cord stimulation.

PMID- 12468002
TI  - An efficient method for studying short-term plasticity with random impulse train
      stimuli.
AB  - In this article, we introduce an efficient method that models quantitatively
      nonlinear dynamics associated with short-term plasticity (STP) in biological
      neural systems. It is based on the Voterra-Wiener modeling approach adapted for
      special stimulus/response datasets. The stimuli are random impulse trains (RITs)
      of fixed amplitude and Poisson distributed, variable interimpulse intervals. The
      class of stimuli, we use can be viewed as a hybrid between the paired impulse
      approach (variable interimpulse interval between two input impulses) and the
      fixed frequency approach (impulses repeated at fixed intervals, varying in
      frequency from one stimulus dataset to the next). The responses are sequences of
      population spike amplitudes of variable size and are assumed to be
      contemporaneous with the corresponding impulses in the RITs they are evoked by.
      The nonlinear dynamics of the mechanisms underlying STP are captured by kernels
      used to create compact STP models with predictive capabilities. Compared to
      similar methods in the literature, the method presented in this article provides
      a comprehensive model of STP with considerable improvement in prediction accuracy
      and requires shorter experimental data collection time.

PMID- 12468003
TI  - The sliding window correlation procedure for detecting hidden correlations:
      existence of behavioral subgroups illustrated with aged rats.
AB  - We developed the sliding window correlation procedure in order to examine
      populations for possible heterogeneity in the ways two variables are related with
      each other. This procedure involves computing correlation coefficients (R) for
      overlapping successive segments of the covariate scores. The distribution of
      resulting Rs reveals fluctuations in the degree and direction of R over the
      sample of ranked scores. This procedure is applied to behavioral data of aged
      rats, which were rank-ordered according to water maze performance, and correlated
      with open field exploration and conflict behavior in a light/dark chamber.
      Results revealed correlation coefficients of varying magnitudes and opposing
      directions for different segments of the population, which were obscured by
      overall correlation analysis. E.g. for the superior learners, the Rs were highest
      between maze learning ability, increased open field exploration and reduced
      anxiety in the conflict test, whereas for the intermediate learners the Rs were
      highest for maze learning ability related with reduced exploration and increased
      anxiety. Thus, the sliding window correlation distribution can be applied in
      conjunction with overall correlation analysis to provide information about the
      potential presence and locations of subgroups within a population, especially if
      overall correlation analysis does not yield significant results.

PMID- 12468004
TI  - NEUROFIT: software for fitting Hodgkin-Huxley models to voltage-clamp data.
AB  - I introduce publicly available software for accurate fitting of Hodgkin-Huxley
      models to voltage-clamp data. I describe the model and non-linear fitting
      procedure employed by the software and compare its results with the usual method
      of fitting such models using potassium A-current data from a pyloric dilator cell
      of the lobster Panulirus interruptus and sodium current data from an electrocyte
      cell of the electric fish Sternopygus macrurus. The set of parameter values for
      the model determined by this software yield current traces that are substantially
      closer to the observed data than those determined from the usual fitting method.
      This improvement is due to the fact that the software fits all of the parameters
      simultaneously utilizing all of the data rather than fitting steady-state and
      time constant parameters disjointly using peak currents and portions of the
      rising and falling phases. I analyze the convergence properties of the software's
      fitting algorithm using simulated data showing that accurate parameter values are
      obtained for most of the parameters using any reasonable initial values. The
      software also incorporates a linear pre-estimation procedure to help in
      determining reasonable initial values for the full non-linear algorithm. I
      illustrate and discuss some of the inadequacies of voltage-clamp data.

PMID- 12468005
TI  - Specific interference with gene expression and gene function mediated by long
      dsRNA in neural cells.
AB  - Double-stranded (ds) RNA-induced sequence-specific interference with gene
      expression, RNA interference (RNAi), has been extensively used in invertebrates,
      allowing for efficient and high-throughput gene silencing and gene function
      analysis. In vertebrates, however, use of RNAi to study gene function has been
      limited due to non-specific effects induced by double-stranded RNA (dsRNA)
      dependent protein kinase and interferon activation. dsRNA-induced specific
      inhibition of vertebrate gene expression has only been shown in embryonic and non
      differentiated mammalian cells. In this report, we demonstrate dsRNA-induced
      specific interference of gene expression and gene function in partially as well
      as fully differentiated mouse neuroblastoma cells. Specific silencing was
      observed in the expression of an integrated transgene coding for green
      fluorescent protein and a variety of endogenous genes. Moreover, we show that
      RNAi-mediated inhibition of poly (ADP-ribose) polymerase (PARP) expression
      induced cellular resistance to oxygen-glucose deprivation, consistent with the
      role of PARP in ischemia-induced brain damage. Our results indicate that RNAi can
      be used as a powerful tool to study gene function in neural cells.

PMID- 12468006
TI  - Odorant responses of Xenopus laevis tadpole olfactory neurons: a comparison
      between preparations.
AB  - We used a slice preparation of the olfactory epithelium of Xenopus laevis
      tadpoles to record odorant responses of olfactory receptor neurons (ORNs) and
      compared these to odorant responses recorded in isolated ORNs. The maximum
      recording time in the slice was considerably longer than in isolated ORNs, which
      is essential when many odorants are to be tested. No odorant-induced responses
      could be obtained from isolated ORNs recorded in the on-cell mode, while
      recordings in the slice (on-cell and whole-cell) as well as previously reported
      perforated-patch recordings in isolated ORNs of the same species () were
      successful, though qualitatively different. In the slice preparation, amino acids
      as well as an extract from Spirulina algae always induced excitatory responses,
      while, in a previous study on isolated ORNs, responses were either excitatory or
      inhibitory. The results of this study show that ORNs obtained using different
      preparation techniques can give markedly different responses upon the application
      of odorants. Our experiments indicate that the slice preparation combined with
      the on-cell configuration of the patch-clamp technique is the method of choice
      for testing many odorants on individual ORNs.

PMID- 12468007
TI  - Use of "reference series" to realign histological serial sections for three
      dimensional reconstructions of the positions of cellular events in the developing
      brain.
AB  - The present study demonstrates how, predominantly by external fiducials,
      histological serial sections used to reconstruct patterns of individually marked
      cellular events in large organs or whole embryos can be realigned with the help
      of "reference series". Resin-embedded embryos were cut at 1 microm and
      consecutive sections were alternately placed on two sets of slides. For
      cytological diagnosis and acquisition of embryonic contours, stained sections of
      the first series, termed "working series", were scanned with the x 100 objective
      using "Huge Image", a recently established image acquisition system. For
      acquisition of the contours of the resin block, adjacent unstained sections of
      the second series, termed "reference series", were scanned with the x 5
      objective. Thereafter, "hybrid sections" were created which combined vectorized
      embryonic contours and cellular events taken from the working series with
      vectorized block contours taken from the reference series. For realignment,
      consecutive "hybrid sections" were matched by best-fit of the block contours.
      Stacks of realigned "hybrid sections" were shaped like truncated pyramids and,
      thus, reflected repeated "trimming" of the resin block during the sectioning
      procedure. Among 266 "hybrid sections" at intervals of 8 microm, needed to
      reconstruct the brain of a 15-day-old embryo of Tupaia belangeri (Scandentia),
      internal fiducials were required five times for realigning a total of six
      adjacent truncated pyramids. Application of this method provided realistic
      reconstructions of the positions of apoptotic cells in the entire developing
      brain without the need of secondary introduction of external fiducials.

PMID- 12468008
TI  - Determination and quantification of pharmacological, physiological, or behavioral
      manipulations on ensembles of simultaneously recorded neurons in functionally
      related neural circuits.
AB  - The present report describes methods for evaluating the impact of physiological,
      pharmacological or behavioral manipulations on simultaneously recorded single
      neurons within a functional sensory network of the awake, freely moving rat.
      Surgical techniques were developed to implant a subcutaneous electrode at the
      base of a single facial whisker (mystacial vibrissae) so that uniform electrical
      stimuli could be routinely delivered to a discrete region of the whisker pad in
      the awake and freely moving animal. Multi-channel extracellular recording was
      used to monitor the spike train activity from ensembles of single neurons in
      whisker-related regions of the thalamus and neocortex. Algorithms were developed
      to verify the stability of individual cell recordings during extended
      experimental sessions. Additional analysis procedures and criteria were
      established for identifying and evaluating the treatment-specific changes in
      single neuron discharge patterns that are likely to occur under these
      experimental conditions. Finally, analyses for evaluating the impact of
      experimental manipulations on sensory representations distributed over
      populations of neurons are discussed. The development of these techniques has
      provided us with the means to investigate the influence of systemically
      administered drugs or broadly projecting monoamine pathways on single neurons and
      local circuits within primary sensory networks of the awake or anesthetized
      mammalian brain.

PMID- 12468009
TI  - Assessment of locus and extent of neurotoxic lesions in monkeys using
      neuroimaging techniques: a replication.
AB  - In a recent study, [Hippocampus 11 (2001) 361] demonstrated that in vivo
      neuroimaging techniques could be used to accurately quantify the extent of
      neuronal damage after ibotenic acid injections in non-human primates. The present
      study was undertaken to replicate these findings and to further estimate whether
      the concentration of ibotenic acid used (10-15 mg/ml) to produce the neuronal
      loss did not affect the fibers coursing within or around the targeted brain area.
      Magnetic resonance (MR) images (T1-weighted and FLAIR) were acquired in three
      monkeys before and after they received neurotoxic lesions of the hippocampal
      formation. The postsurgical FLAIR images were taken 7-10 days after surgery to
      visualize the hyperintense signals produced by increased edema at the injection
      sites. One year post-surgically, T1-weighted images were acquired and compared
      with T1-weighted images obtained pre-surgery to estimate reduction in hippocampal
      volume resulting from neuronal loss. Estimated neuronal loss was then compared
      with actual cell loss found during histological evaluation of brain tissue. Both
      neuroimaging techniques accurately estimated the extent of hippocampal damage and
      damage to surrounding structures. In addition, the concentration of ibotenic acid
      (10 mg/ml) used in the present study did not appear to have significantly damaged
      or de-myelinated fibers coursing through or around the hippocampal formation.
      Together with the previous results of [Hippocampus 11 (2001) 361], the present
      data strongly demonstrate that in vivo neuroimaging techniques provide powerful
      tools to estimate reliably and rapidly the extent and localization of brain
      lesions in non-human primates.

PMID- 12468010
TI  - Modified herpes simplex virus delivery of enhanced GFP into the central nervous
      system.
AB  - Controlled expression of proteins is a key experimental approach to a deeper
      understanding of the molecular basis of neuronal function. Here we evaluate the
      HSV-1 (herpes simplex virus) amplicon vector for gene delivery into the brains of
      living rats. We demonstrate that HSV-1 amplicon vectors expressing enhanced green
      fluorescent protein (EGFP) can reliably infect neurons after it is injected into
      cortex, striatum and thalamus in rats, producing sufficient numbers of infected
      neurons for electrophysiological experiments in acute brain slices. Expression of
      EGFP delivered by the HSV-1 amplicon was detected for up to 5 weeks post
      infection. We detected no changes in the morphology or the electrophysiological
      properties of thalamic, striatal or cortical neurons within a period of at least
      2 weeks after HSV-1 amplicon injection. We conclude that the HSV-1 amplicon is a
      valuable tool for gene delivery in the rat central nervous system.

PMID- 12468012
TI  - Blood-brain barrier, brain metabolism and cerebral blood flow.
AB  - For optimal function of the brain with its meticulous operations, an adequate and
      constant micro environment seems to be a prerequisite. This is secured by the
      blood-brain barrier which is impermeable to hydrophilic substances, with notable
      exceptions such as glucose, which cross the barrier by a mechanism of facilitated
      diffusion. A constant micro environment is further secured by the blood flow
      which is balanced to the metabolic demand of the cerebral tissue and which also
      contributes to the maintenance of a constant pH. During activation, blood flow
      and glucose consumption increase more than oxygen consumption in activated areas
      of the brain. The flow increase forms the physiological basis for measurement and
      mapping of functional activation using positron emission tomography and the
      changes in the metabolic pattern which has been called uncoupling of flow and
      oxygen metabolism is the basis for such measurements using functional magnetic
      resonance imaging.

PMID- 12468013
TI  - The role of in vivo molecular imaging with PET and SPECT in the elucidation of
      psychiatric drug action and new drug development.
AB  - This paper reviews the contribution of human PET and SPECT neuroreceptor
      occupancy studies to the understanding of drug action in psychiatric illness, and
      how they can aid the development of new drugs. All effective antipsychotics show
      significant D(2) receptor occupancy. However, at least for atypical
      antipsychotics, there is no clear relationship between occupancy and clinical
      response. The mechanisms underlying antipsychotic efficacy, and the minimal
      effective D(2) occupancy, remain to be elucidated, particularly for drugs with
      modest or transient occupancy. The low liability of some atypical antipsychotics
      for extrapyramidal side effects does not appear to be explained by their 5-HT(2A)
      antagonism, and the muscarinic receptor occupancy of some drugs may be partly
      explanatory. Previous reports of apparent 'limbic selectivity' of atypical
      antipsychotics may be in error, and may be due to technical differences in
      radiotracers. For SSRIs, high occupancies at the serotonin transporter (SERT) are
      achieved at therapeutic doses, although the minimum SERT occupancy required for
      therapeutic response remains undefined. Previous attempts to augment the
      antidepressant effect of SSRIs by pindolol have generally used daily doses which
      result in inadequate 5-HT(1A) receptor occupancy. For benzodiazepines, clinical
      doses would appear to leave a wide margin of unoccupied receptors. For
      methylphenidate and cocaine, typical doses occupy more than 50% of dopamine
      transporters, and their profiles are extremely similar. In therapeutic drug
      development, these techniques may be used to assess receptor occupancy profiles,
      likely drug dosages and dosing intervals which cannot be reliably assessed in
      humans by other methods.

PMID- 12468014
TI  - Radioligand studies: imaging and quantitative analysis.
AB  - Radioligand studies enable visualisation and measurement of molecular pathways
      and pharmacokinetic processes. Using positron emission tomography, accurate
      measurements of the time course of radioligand uptake and clearance can be
      obtained. A tracer kinetic model is needed to derive physiological or
      pharmacokinetic parameters from these tissue time-activity curves. In addition,
      an input function that indicates delivery to the tissue is required. Usually this
      will be the arterial plasma curve. For receptor studies, where binding potential
      is the parameter of interest, it might also be possible to avoid arterial
      sampling provided a tissue can be defined that is devoid of receptors.

PMID- 12468015
TI  - Functional MRI experiments: acquisition, analysis and interpretation of data.
AB  - Functional MRI is widely used to address basic and clinical neuroscience
      questions. In the key domains of fMRI experiments, i.e. acquisition, processing
      and analysis, and interpretation of data, developments are ongoing. The main
      issues are sensitivity for changes in fMRI signal that are associated with brain
      function, and the design of tasks with which brain functions are invoked. In this
      paper we address these issues, in terms of strengths, weaknesses and future
      developments. Acquisition of data is commonly achieved with techniques that
      measure blood oxygen level-dependent (BOLD) signal changes. Although the
      mechanisms that affect BOLD signal are complex and not well understood, fMRI
      yields results that agree with known functional topography. Sensitivity for task
      related brain activity is expected to benefit from technological advances in
      acquisition, i.e. SENSE or parallel imaging, and higher field scanners (3 T).
      Data analysis is geared towards modelling sources of signal variation, i.e.
      reducing noise in the data time-series, and the cerebrovascular response to task
      related changes in neuronal activity. Analytical algorithms such as connectivity
      and component analysis contribute to the extraction of meaningful information
      from fMRI datasets. The choice of tasks, and consequently of the statistical
      evaluation procedures, is best guided by the specific questions that are
      formulated a priori. The future is expected to bring more sophisticated
      questions, and tasks that allow for accurate modelling of involved brain
      functions. An example of a hypothesis-driven experiment is presented, where we
      investigated whether practise of a working memory task caused a shift in the
      neuronal representation of working memory or not.

PMID- 12468016
TI  - Functional anatomical correlates of antidepressant drug treatment assessed using
      PET measures of regional glucose metabolism.
AB  - Neurophysiological studies of major depression performed using PET imaging have
      shown abnormalities of regional cerebral blood flow (CBF) and glucose metabolism
      in multiple prefrontal cortical and limbic structures that have been more
      generally implicated in emotional processing. The current study investigated the
      effects of antidepressant drug treatment in these regions using PET measures of
      glucose metabolism. Subjects with primary MDD (n=27) were imaged while
      unmedicated and depressed, and, of these, 20 were rescanned following chronic
      antidepressant drug treatment. Regional metabolism was compared between
      unmedicated depressives and controls and between the pre- and post-treatment
      conditions in regions-of-interest (ROI) where metabolism or flow had previously
      been shown to be abnormal in unmedicated depressives. At baseline, the mean
      metabolism was increased in the left and right lateral orbital
      cortex/ventrolateral prefrontal cortex (PFC), left amygdala, and posterior
      cingulate cortex, and decreased in the subgenual ACC and dorsal medial/dorsal
      anterolateral PFC in the unmedicated depressives relative to controls, consistent
      with the results of previous studies. Following treatment, metabolism
      significantly decreased in the left amygdala and left subgenual ACC, and
      corresponding changes in the orbital and posterior cingulate cortices approached
      significance. The metabolic reduction in the amygdala and right subgenual ACC
      appeared largely limited to those subjects who both responded to treatment and
      remained well at 6 months follow-up, in whom the reduction in amygdala metabolism
      tightly correlated with the reduction in HDRS scores. The magnitude of the
      treatment-associated, metabolic change in the amygdala also correlated positively
      with the change in the stressed plasma cortisol levels measured during scanning.
      These data converge with those from other PET studies to indicate that primary
      MDD is associated with abnormal metabolism in limbic and paralimbic structures of
      the mesiotemporal and prefrontal cortices. Chronic antidepressant drug treatment
      reduces metabolism in the amygdala and ventral ACC in subjects showing a
      persistent, positive treatment response. In contrast, the persistence of the
      abnormal metabolic deficits in the dorsomedial/dorsal anterolateral PFC in MDD
      during treatment may conceivably relate to the histopathological changes reported
      in these regions in post mortem studies of MDD.

PMID- 12468017
TI  - Small animal PET.
AB  - Positron emission tomography (PET) has well-established strengths which are
      commonly exploited in human clinical research. Not least of these are its dynamic
      and quantitative capabilities. The recent growth in small animal PET, spurred on
      by technological developments and an interest in the application of imaging to
      the field of genomics in mice, has seen impressive improvements in image spatial
      resolution. The availability of commercial small animal PET scanners has meant a
      broadening of the user base away from PET development environments and into
      experimental laboratories. This paper will review these developments and assess
      the impact on overall data quality.

PMID- 12468018
TI  - Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in
      humans: results from imaging studies.
AB  - Methylphenidate is the most commonly prescribed drug for the treatment of ADHD.
      We have used positron emission tomography to assess the role that
      methylphenidate's effects in brain dopamine have on its therapeutic and
      reinforcing effects. We have documented that in the human brain therapeutic doses
      of methylphenidate block more than 50% of the dopamine transporters and
      significantly enhance extracellular DA, an effect that appears to be modulated by
      the rate of DA release. Thus, we postulate that methylphenidate's therapeutic
      effects are in part due to amplification of DA signals, that variability in
      responses is in part due to differences in DA tone and that methylphenidate's
      effects are context dependent. Methylphenidate-induced increases in DA are also
      associated with its reinforcing effects but only when this occurs rapidly, as
      with intravenous administration. Moreover, abuse of methylphenidate is
      constrained by its long half-life, which we postulate limits the frequency at
      which it can be administered.

PMID- 12468019
TI  - Receptor binding and drug modulation in anxiety.
AB  - Anxiety is an emotion that allows an individual to prepare for, or respond to,
      changes in the environment. For many people, however, this emotion is expressed
      inappropriately and impairs their lives causing considerable distress and
      disability. These disorders cause a great deal of personal distress, result in
      reduced life expectancy and, in the UK alone, have an estimated cost of
      approximately pound 5 billion per year. Despite a great deal of research, an
      adequate account of the mechanisms that underlie these human disorders is still
      lacking. An understanding of the brain substrates underlying these disorders is
      likely to provide such adequate explanations, but one of the principal challenges
      facing the investigators has been the reciprocal mapping of pre-clinical and
      clinical knowledge. Altogether, the last 10 years have seen a consolidation of
      imaging techniques. These are now mature in many areas and are likely to provide
      fundamental contributions in our understanding of human psychopharmacology.

PMID- 12468020
TI  - Disease process and drug treatments in Parkinson's disease.

PMID- 12468021
TI  - In vivo imaging of neuroinflammation.
AB  - We briefly outline the rationale for employing positron emission tomography
      (PET), using the ligand [11C](R)-PK11195, the binding site for which is highly
      expressed by activated microglia, in order (a) to detect in vivo
      neuroinflammatory changes occurring in a variety of brain diseases and at
      different disease stages and (b) to monitor the progression of neuroinflammation
      as a generic in vivo marker of 'disease activity'. The use of [11C](R)-PK11195
      PET is described as a systematic attempt at measuring the emerging phenomenology
      of tissue pathology itself-as opposed to measuring, for example, the loss of
      neuronal function or structure-and as a proof of principle for the clinical
      utility of imaging glial cells in vivo.

PMID- 12468022
TI  - Architectonics of the human cerebral cortex and transmitter receptor
      fingerprints: reconciling functional neuroanatomy and neurochemistry.
AB  - The density of transmitter receptors varies between different locations in the
      human cerebral cortex. We hypothesized that this variation may reflect the cyto-
      and myeloarchitectonical as well as the functional organisation of the cortex. We
      compared data from different imaging modalities (postmortem studies: cyto- and
      myeloarchitecture, quantitative in vitro receptor autoradiography; in vivo
      studies: PET receptor neuroimaging) in order to test our hypothesis. The regional
      and laminar distribution of the densities of numerous receptor types representing
      all classical transmitter systems as well as the adenosine system are visualized
      and measured in different cortical areas. The receptor distribution patterns
      segregate motor, primary sensory, unimodal sensory, multimodal association and
      other functionally identified cortical areas from each other. Areas of similar
      function show similar receptor fingerprints and differ from those with other
      properties. Thus, receptor distribution patterns reflect an organisational
      structure strictly correlated with the architectonics and functions of the human
      cerebral cortex.

PMID- 12468023
TI  - Synaptic and cellular events: the last frontier?
AB  - The use of functional magnetic resonance imaging (fMRI) to follow random or
      serial sequences of neural activity is explored and illustrated with examples
      that include auditory hallucinations and a short-term memory paradigm. Despite
      the availability of ultra-high-speed fMRI sequences, the inherent latency of the
      haemodynamic response limits the time resolution of fMRI studies. To access finer
      time-scales, it can be combined with electromagnetic techniques (MEG or EEG).
      Functional magnetic resonance spectroscopy (MRS) studies, in which infusion of [1
      (13)C]glucose enables rates of the tricarboxylic acid cycle to be determined,
      demonstrates substantial (50%) increases in this flux on visual activation. Not
      only does this provide a quantitative estimate of the energy cost of brain
      activation, it also shows that the extra glucose is consumed essentially
      oxidatively. In the same studies, measurements of the rate of glutamine
      synthesis, enable the rate of recycling of neurotransmitter glutamate to be
      estimated.

PMID- 12468024
TI  - Neurons of the superior nucleus of the medial habenula and ependymal cells
      express IL-18 in rat CNS.
AB  - The habenular-interpeduncular pathway is involved in the modulation of several
      functions including neuroendocrine and stress responses. Interleukin-18 (IL-18)
      is a pro-inflammatory cytokine predominantly studied as a modulator of immune
      functions and also produced in the adrenal cortex following activation of the
      hypothalamic-pituitary-adrenal axis. In the central nervous system, IL-18 was
      demonstrated to induce sleep and to influence long-term potentiation and was
      proposed to mediate local inflammatory reactions. The present study investigated
      the localization of IL-18 and its expression following either acute or chronic
      restraint stress in the brain of adult male Wistar rats. Using
      immunocytochemistry and in situ hybridization we report the unprecedented
      localization of IL-18 in the neurons of the superior part of the medial habenula
      (MHbS), their projections to the interpenducular nucleus and its expression in
      the ependymal cells surrounding the third and the lateral ventricles. In
      addition, acute (2 h) or chronic (6 h/day for 3 weeks) restraint stress induced a
      strong elevation of IL-18 immunostaining in the MHbS but not in ependymal cells.
      The present data suggest that IL-18 may participate in the modulation of stress
      responses in the MHbS. They also suggest that ependymal cells may be the source
      of IL-18 previously reported in the cerebrospinal fluid (CSF). The role of IL-18
      in the ependyma and the CSF remains to be elucidated.

PMID- 12468025
TI  - Protective effects of timolol against the neuronal damage induced by glutamate
      and ischemia in the rat retina.
AB  - The purpose of this study was to determine whether timolol, an ocular hypotensive
      drug, has retinal neuroprotective effects in experimental in vitro and in vivo
      models. For in vitro studies, we used retinal neuron cultures from rat embryos
      and purified retinal ganglion cells (RGCs) from newborn rats. In the former,
      neurotoxicity was induced using 1 mM glutamate and cell viability was assessed.
      In RGCs, neurotoxicity was induced using 25 microM glutamate for 3 days and cell
      viability was assessed. For the in vivo study, we used a rat model of retinal
      ischemic injury induced by elevating intraocular pressure (IOP) by raising the
      hydrostatic pressure. The retinal damage was evaluated by counting the number of
      cells in the ganglion cell layer (GCL) and by examining the a- and b-waves in the
      electroretinogram (ERG). For the intraocular distribution study, 0.5% [3H]timolol
      was topically applied to rat eyes, and these were enucleated after various
      intervals and divided into parts. Each part was combusted and the radioactivity
      measured. Timolol (0.1 and 1 microM) markedly reduced the glutamate-induced
      neuronal cells in retinal neuron cultures and in RGCs. After ischemic
      reperfusion, both the number of cells in the GCL and a- and b-waves in the ERG
      decreased; however, topically applied 0.5% timolol reduced these effects.
      Topically applied 0.5% timolol was detected at a concentration of approximately 1
      microg/g wet tissue in retina-choroid at 30 min after its application. In
      conclusion, timolol was effective against retinal neuron damage both in vitro and
      in vivo. Furthermore, topically applied timolol reached the retina-choroid. These
      findings suggest that timolol has a direct neuroprotective effect against retinal
      damage.

PMID- 12468026
TI  - Adaptation of monoaminergic responses to phencyclidine in nucleus accumbens and
      prefrontal cortex following repeated treatment with fluoxetine or imipramine.
AB  - The adaptive neuronal changes that follow chronic administration of
      antidepressant drugs are thought to underlie clinical improvement in patient
      populations. Recent evidence suggests that alterations specific to N-methyl-D
      aspartate (NMDA) receptors may be a final common pathway to antidepressant
      action. To investigate this possibility, we sought to establish the effects of
      chronic fluoxetine or imipramine treatment on the monoamine stimulating effect of
      the non-competitive NMDA antagonist phencyclidine. Male, Sprague-Dawley rats
      (n=9/group) were treated with saline (1 ml/kg, i.p.), imipramine (10 mg/kg, i.p.)
      or fluoxetine (10 mg/kg, i.p.) once daily for 14 consecutive days. After a 7-day
      drug-free period, animals given an acute challenge of either saline or
      phencyclidine (5 mg/kg, i.p.). One hour later, animals were killed, brains were
      removed, and the prefrontal cortex, striatum, and nucleus accumbens were
      dissected. Samples were assayed for the monoamines and their primary metabolites
      by HPLC. Repeated treatment with fluoxetine or imipramine did not alter baseline
      dopamine or serotonin turnover. Acute phencyclidine treatment increased
      prefrontal cortex and nucleus accumbens dopamine turnover in saline-treated
      animals (P<0.01); however, the effect in the nucleus accumbens was prevented in
      animals pretreated with imipramine or fluoxetine. Acute phencyclidine challenge
      also increased serotonin turnover in prefrontal cortex of saline- or imipramine
      pretreated rats (P<0.01), though this effect was attenuated in animals pretreated
      with fluoxetine. Overall, the data suggest that repeated antidepressant treatment
      alters monoamine turnover in specific brain regions in response to blockade of
      NMDA receptors. The data highlight the importance of adaptive responses to NMDA
      receptors resulting from chronic antidepressant treatment.

PMID- 12468027
TI  - Prolonged reversal of morphine tolerance with no reversal of dependence by
      protein kinase C inhibitors.
AB  - The phosphatidylinositol (PI) cascade plays a pivotal role in mediating
      behavioral tolerance to the antinociceptive effects of morphine. Earlier we
      reported that antinociceptive tolerance was completely reversed 30 min after the
      administration of inhibitors of each step in the PI cascade. The aim of this
      study was to determine whether injection of a single dose of protein kinase C
      (PKC) inhibitor would elicit a prolonged reversal of morphine tolerance for up to
      24 h. Three days after implantation of placebo- or 75-mg morphine pellets, mice
      received intracerebroventricular (i.c.v.) injections of vehicle or PKC inhibitor
      drug. Morphine challenge doses were then administered 4, 8 and 24 h later to test
      for tolerance reversal. In non-tolerant mice, Go-7874 and sangivamycin had no
      effect on the potency of morphine. However, Go-7874 and sangivamycin
      significantly reversed morphine tolerance at 4, 8 and 24 h. In addition, the role
      of PKC in morphine physical dependence was determined. Go-7874 and sangivamycin
      by themselves did not precipitate spontaneous morphine withdrawal. Therefore,
      experiments were conducted to determine whether the PKC inhibitors would block
      naloxone-precipitated withdrawal. However, neither a 30-min nor a 24-h
      pretreatment with Go-7874 or sangivamycin blocked naloxone withdrawal. Our
      results along with other publications indicate that PKC is a pivotal kinase
      essential for maintaining animals in an opioid tolerant state. Finally, the use
      of persistent PKC inhibitors that lasted for 24 h demonstrated that the neuronal
      systems in these animals did not adapt by increasing the activity of other
      protein kinase cascades to re-establish morphine tolerance.

PMID- 12468028
TI  - Anticonvulsant valproate reduces seizure-susceptibility in mutant Drosophila.
AB  - Despite the frequency of seizure disorders in the human population, the genetic
      basis for these defects remains largely unclear. Currently, only a fraction of
      the epilepsies can be linked conclusively to a genetic determinant. In addition,
      a significant number of epileptics do not respond to the current anticonvulsant
      therapies. We have turned to Drosophila as a model to address these problems and
      have identified genetic mutants that are more sensitive to seizures, bang
      sensitive (BS) mutants, such as slamdance (sda), bangsenseless (bss) and easily
      shocked (eas), as well as mutants that are resistant to seizures, such as
      paralytic, maleless(napts), shaking-B(2) and Shaker. Here, we have developed a
      new method for evaluating compounds with anticonvulsant activity. The methodology
      uses Drosophila BS mutants to assay the ability of compounds to suppress the
      seizure susceptible phenotype normally seen in the BS mutants. To test the
      effectiveness of this method, two BS mutant strains were administered the
      anticonvulsant valproate and in both cases the drug was able to suppress
      seizures. The Drosophila system provides a potentially powerful way of developing
      and testing new drugs with anticonvulsant properties.

PMID- 12468029
TI  - Activation of the neuroprotective ERK signaling pathway by fructose-1,6
      bisphosphate during hypoxia involves intracellular Ca2+ and phospholipase C.
AB  - The mechanism of the neuroprotective action of the glycolytic pathway
      intermediate fructose-1,6-bisphosphate (FBP) may involve activation of a
      phospholipase-C (PLC) dependent MAP kinase signaling pathway. In this study, we
      determined whether FBP's capacity to decrease delayed cell death in hippocampal
      slice cultures is dependent on PLC signaling or activation of the intracellular
      Ca(2+)-MEK/ERK neuroprotective signaling cascade. FBP (3.5 mM) reduced delayed
      death from oxygen/glucose deprivation in CA1, CA3 and dentate neurons in slice
      cultures. The phospholipase-C inhibitor U73122 and the MEK1/2 inhibitor U0126
      prevented this protection. In hippocampal and cortical neurons, FBP increased
      phospho-ERK1/2 (p42/44) immunostaining during hypoxic, but not normoxic
      conditions. Increased phospho-ERK immunostaining was dependent on PLC and also on
      MEK 1/2, an upstream regulator of ERK. Further, we found that FBP enhancement of
      phospho-ERK immunostaining depended on [Ca(2+)](i): PLC inhibition and the IP(3)
      receptor blocker xestospongin C prevented FBP from increasing [Ca(2+)](i) and
      increasing phospho-ERK levels. However, while FBP-induced increases in
      [Ca(2+)](i) were blocked by xestospongin and a PLC inhibitor, [Ca(2+)](i)
      increases induced by the neuroprotective growth factor BDNF were not prevented.
      We conclude that during hypoxia FBP initiates a series of neuroprotective signals
      which include PLC activation, small increases in [Ca(2+)](i), and increased
      activity of the MEK/ERK signaling pathway.

PMID- 12468030
TI  - Parvalbumin neuron circuits and microglia in three dopamine-poor cortical regions
      remain sensitive to amphetamine exposure in the absence of hyperthermia, seizure
      and stroke.
AB  - The dopamine-releasing and depleting substance amphetamine (AMPH) can make
      cortical neurons susceptible to damage, and the prevention of hyperthermia,
      seizures and stroke is thought to block these effects. Here we report a 2-day
      AMPH treatment paradigm which affected only interneurons in three cortical
      regions with average or below-average dopamine input. AMPH (six escalating
      doses/day ranging from 5 to 30 mg/kg for 2 days) was given at 17-18 degrees C
      ambient temperature (T) to adult male rats. During the 2-day AMPH treatment, peak
      body T stayed below 38.9 degrees C in 40% of the AMPH treated rats. In 60% of the
      rats, deliberate cooling suppressed (<39.5 degrees C) or minimized (<40.0 degrees
      C) hyperthermia. Escalation of stereotypes to seizure-like behaviors was rare and
      post-mortem morphological signs of stroke were absent. Neurons labeled with the
      anionic, neurodegeneration-marker dye Fluoro-Jade (F-J) were seen 1 day after
      dosing, peaked 3 days later, but were barely detectable 14 days after dosing.
      Only nonpyramidal neurons in layer IV of the somatosensory barrel cortex and in
      layer II of the piriform cortex and posterolateral cortical amygdaloid nucleus
      were labeled with Fluoro-Jade. Isolectin B-labeled activated microglia were only
      detected in their neighborhood. F-J labeled neurons were extremely rare in
      cortical regions rich in dopamine (e.g. cingulate cortex), and were absent in
      cortical regions with no dopamine (e.g. visual cortex). Parvalbumin was seen in
      some Fluoro-Jade-labeled neurons and parvalbumin immunostaining in local axon
      plexuses intensified. This AMPH paradigm affected fewer cortical regions, and
      caused smaller reduction in striatal tyrosine hydroxylase (TH) immunoreactivity
      than previous 1-day AMPH regimens generating seizures or severe (above 40 degrees
      C) hyperthermia. Correlation between peak or mean body T and the extent of
      neurodegeneration or microgliosis was below statistical significance.
      Astrogliosis (elevated levels of the astroglia-marker, glial fibrillary acidic
      protein (GFAP)) was detected in many brain regions. In the striatum and midbrain,
      F-J labeled neurons and activated microglia were absent, but astrogliosis,
      decreased TH immunolabel, and swollen TH fibers were detected. In sum, after this
      AMPH treatment, cortical pyramidal neurons were spared, but astrogliosis was
      brain-wide and some interneurons and microglia in three cortical regions with
      average or below-average dopamine input remained sensitive to AMPH exposure.

PMID- 12468031
TI  - Transplantation of neural stem cells in a rat model of stroke: assessment of
      short-term graft survival and acute host immunological response.
AB  - The use of progenitors and stem cells for neural grafting is promising, as these
      not only have the potential to be maintained in vitro until use, but may also
      prove less likely to evoke an immunogenic response in the host, when compared to
      primary (fetal) grafts. We investigated whether the short-term survival of a
      grafted conditionally immortalised murine neuroepithelial stem cell line (MHP36)
      (2 weeks post-implantation, 4 weeks post-ischaemia) is influenced by: (i)
      immunosuppression (cyclosporin A (CSA) vs. no CSA), (ii) the local (intact vs.
      lesioned hemisphere), or (iii) global (lesioned vs. sham) brain environment.
      MHP36 cells were transplanted ipsi- and contralateral to the lesion in rats with
      middle cerebral artery occlusion (MCAo) or sham controls. Animals were either
      administered CSA or received no immunosuppressive treatment. A proliferation
      assay of lymphocytes dissociated from cervical lymph nodes, grading of the
      survival of the grafted cells, and histological evaluation of the immune response
      revealed no significant difference between animals treated with or without CSA.
      There was no difference in survival or immunological response to cells grafted
      ipsi- or contralateral to the lesion. Although a local upregulation of
      immunological markers (MHC class I, MHC class II, CD45, CD11b) was detected
      around the injection site and the ischaemic lesion, these were not specifically
      upregulated in response to transplanted cells. These results provide evidence for
      the low immunogenic properties of MHP36 cells during the initial period following
      implantation, known to be associated with an acute host immune response and
      ensuing graft rejection.

PMID- 12468032
TI  - Coordinate expression of survival p-ERK and proapoptotic cytochrome c signals in
      rat brain neurons after transient MCAO.
AB  - In order to determine possible coordinate expression of major survival and
      proapoptotic signals, immunofluorescent analyses for phosphorylated ERK (p-ERK)
      and cytochrome c were carried out after 90 min of transient middle cerebral
      artery occlusion (MCAO) in rats. Strong induction of p-ERK was primarily
      expressed in the ischemic penumbra, while that of cytosolic cytochrome c signal
      was strongly induced in the ischemic core from 3 min to 3 h of reperfusion. The
      double-stained cells with strong p-ERK/weak cytochrome c became most apparent at
      3 min primarily expressed in the ischemic penumbra, whereas the cells with weak p
      ERK/strong cytochrome c were predominantly found in the ischemic core at 3 h. The
      proportion of double positive cells among the total number of single positive
      cells decreased in the ischemic core, and increased in the ischemic penumbra.
      These findings suggest that the coordinate expression of p-ERK and cytochrome c
      is fundamentally involved in cell survival or death at the early stage of
      reperfusion, and that they could play roles in different temporal and spatial
      profiles.

PMID- 12468033
TI  - Differential induction of interleukin-1beta and tumour necrosis factor-alpha may
      account for specific patterns of leukocyte recruitment in the brain.
AB  - In peripheral tissue, IL-1beta has been shown to induce TNFalpha expression and
      vice versa, resulting in mixed neutrophil and mononuclear cell recruitment to the
      site of injury. This has led to the concept of crosstalk in peripheral cytokine
      signalling pathways. In the brain parenchyma, however, restricted patterns of
      leukocyte recruitment following the focal injection of pro-inflammatory agents
      into the brain are observed. This study investigates the expression of the
      principal pro-inflammatory cytokines--IL-1beta and TNFalpha--in the brain after
      IL-1beta, TNFalpha, NMDA or endotoxin injection into the brain parenchyma of
      rats. Each of these agents gives rise to a distinct pattern of acute leukocyte
      recruitment at 24 h. We found that IL-1beta induces de novo synthesis of
      additional IL-1beta but not TNFalpha, as determined by RT-PCR and ELISA, and
      TNFalpha does not induce either itself or IL-1beta. Injection of NMDA results in
      IL-1beta, but not TNFalpha up-regulation. Injection of IL-1beta or NMDA is
      associated with neutrophil recruitment whereas injection of TNFalpha is
      associated with mononuclear cell recruitment. Following injection of endotoxin,
      both TNFalpha and IL-1beta levels are elevated and neutrophils and mononuclear
      cells are recruited to the brain. These data suggest that the signalling pathways
      that are present in the periphery are modified in the brain and that differential
      induction of TNFalpha and IL-1beta may have a role in the atypical pattern of
      leukocyte recruitment observed in the brain.

PMID- 12468034
TI  - Secretion of apolipoprotein E by brain glia requires protein prenylation and is
      suppressed by statins.
AB  - Apolipoprotein E (ApoE) genotype modulates the risk of Alzheimer's disease. ApoE
      has been shown essential for amyloid beta-peptide fibrillogenesis and deposition,
      a defining pathological feature of this disease. Because astrocytes and microglia
      represent the major source of extracellular apoE in brain, we investigated apoE
      secretion by glia. We determined that protein prenylation is required for apoE
      release from a continuous microglial cell line, primary mixed glia, and from
      organotypic hippocampal cultures. Using selective protein prenylation inhibitors,
      apoE secretion was found to require protein geranylgeranylation. This prenylation
      involved a protein critical to apoE secretion, not apoE proper. ApoE secretion
      could also be suppressed by inhibiting synthesis of mevalonate, the precursor to
      both types of protein prenylation, using hydroxyl-3-methylglutaryl coenzyme A
      reductase inhibitors (statins). Recent reports have described the beneficial
      effects of statins on the risk of dementia. Our finding that protein
      geranylgeranylation is required for apoE secretion in the brain parenchyma
      provides another contributing mechanism to explain the effective properties of
      statins against the development of dementia. In this model, statin-mediated
      inhibition of mevalonate synthesis, an essential reaction in forming
      geranylgeranyl lipid, would lower extracellular levels of parenchymal apoE.
      Because apoE has been found necessary for plaque development in transgenic models
      of Alzheimer's disease, suppressing apoE secretion by statins could reduce
      plaques and, in turn, improve cognitive function.

PMID- 12468035
TI  - Neuronal and inducible nitric oxide synthase immunoreactivity following serotonin
      depletion.
AB  - Serotonin (5HT) modulates the development and plasticity of its innervation areas
      in the central nervous system (CNS). Astrocytic 5HT(1A) receptors are involved in
      the plastic phenomena by releasing the astroglial-derived neurotrophic factor S
      100beta. Several facts have demonstrated that nitric oxide (NO) and the nitric
      oxide synthase enzyme (NOS) may also be involved in this neuroglial interaction:
      (i) NO, S-100beta and 5HT are involved in CNS plasticity; (ii) micromolar S
      100beta concentration stimulates inducible-NOS (iNOS) expression; (iii) neuronal
      NOS (nNOS) immunoreactive neurons are functionally and morphologically related to
      the serotoninergic neurons; (iv) monoamines level, including 5HT, can be
      modulated by NO release. We have already shown that 5HT depletion increases
      astroglial S-100beta immunoreactivity, induces neuronal cytoskeletal alterations
      and produces an astroglial reaction, while once 5HT level is recovered, a
      sprouting phenomenon occurs [Brain Res. 883 (2000) 1-14]. To further characterize
      the relationship among nNOS, iNOS and 5HT we have analyzed nNOS and iNOS
      expression in the CNS after 5HT depletion induced by parachlorophenylalanine
      (PCPA) treatment. Studies were performed immediately after ending the PCPA
      treatment and during a recovery period of 35 days. Areas densely innervated by
      5HT fibers were studied by means of nNOS and iNOS immunoreactivity as well as
      NADPH diaphorase (NADPHd) staining. All parameters were quantified by computer
      assisted image analysis. Increased nNOS immunoreactivity in striatum and
      hippocampus as well as increased NADPHd reactivity in the striatum, hippocampus
      and parietal cortex were found after PCPA treatment. The iNOS immunoreactivity in
      the corpus callosum increased 14 and 35 days after the end of PCPA treatment.
      These findings showed that nNOS immunoreactivity and NADPHd activity increased
      immediately after 5HT depletion evidencing a close functional interaction between
      nitrergic and serotoninergic systems. However, iNOS immunoreactivity increased
      when 5HT levels were normalized, which could indicate one of the biological
      responses to S-100beta release.

PMID- 12468036
TI  - Serotonin immunoreactivity in the retinal projecting isthmo-optic nucleus and
      evidence of brainstem raphe connections in the pigeon.
AB  - Serotonin (5-HT) immunoreactive (-ir) profiles within the isthmo-optic nucleus
      (ION) of the centrifugal visual system (CVS) were studied in the pigeon using
      light microscopic immunohistofluorescent and electron microscopic
      immunocytochemical pre-embedding techniques. The brainstem origin of the 5-HT
      input upon the ION was determined by combining 5-HT immunohistofluorescence
      (FITC) and retrograde transneuronal tracing after intraocular injection of
      Rhodamine beta-isothiocyanate. The light microscopic results showed that 5-HT
      endings were mainly localised within the neuropillar zones of the ventral ION.
      The 5-HT-ir cell bodies, belonging to a lateral extension of the dorsal raphe
      system, were observed within the same region as the centrifugal ectopic neurons
      (EN) underlying the ION and some displayed dendritic processes which penetrated
      the nucleus. Double-labeled neurons, representing 5-HT-ir afferents to the ION,
      were identified only within the n. linearis caudalis region of the ventral raphe.
      The electron microscopic results confirmed the presence of 5-HT-ir dendritic
      processes within the ventral part of the nucleus and showed that they were
      contacted by axon terminals belonging to intrinsic interneurons. The functional
      organisation of the ION and the possible contribution of serotonergic raphe
      afferents and efferents are discussed in relation to present hypotheses linking
      the avian CVS to mechanisms of visual attention.

PMID- 12468037
TI  - Effects of adrenalectomy on AGRP, POMC, NPY and CART gene expression in the basal
      hypothalamus of fed and fasted rats.
AB  - Glucocorticoids regulate body energy balance through both peripheral and central
      mechanisms. In order to understand the central mechanisms that mediate these
      effects of glucocorticoids we studied the effects of adrenalectomy (ADX) and food
      deprivation on the expression of four neuropeptide genes (measured by S1 nuclease
      protection assay) in the medial basal hypothalamus (MBH), which are known to
      regulate energy balance: pro-opiomelanocortin (POMC), agouti-related peptide
      (AGRP), neuropeptide Y (NPY), and cocaine and amphetamine regulated transcript
      (CART). Adult male rats were ADX or sham operated (SHAM), and studied 1-2 weeks
      later. In the first study effects of ADX and corticosterone replacement on POMC
      and AGRP expression were determined. ADX decreased POMC and AGRP gene expression
      in the MBH by 27 and 38%, respectively, compared to SHAM rats. Corticosterone
      treatment increased the expression of POMC by 87% and AGRP by 45% in ADX rats.
      The second study was designed to determine if glucocorticoids are necessary for
      the fasting induced changes in POMC, AGRP, NPY and CART in the MBH. ADX caused a
      20-30% decrease in the expression of all four neuropeptide genes in the MBH. As
      expected, fasting suppressed POMC and CART expression and increased AGRP and NPY
      expression. The fasting-induced increases in AGRP and NPY persisted after ADX but
      no further significant decreases in POMC or CART were noted after fasting in ADX
      rats. Plasma leptin and insulin declined significantly after ADX and increased
      with corticosterone replacement; both leptin and insulin declined further in
      fasted, ADX animals. In conclusion, ADX decreases both anorexigenic, POMC and
      CART, and orexigenic, AGRP and NPY, neuropeptide gene expression in the MBH. AGRP
      and NPY decrease after ADX despite the fall in plasma leptin and insulin
      concentrations which in other situations would increase these neuropeptides.
      Furthermore, glucocorticoids are not required for fasting-induced upregulation of
      AGRP and NPY expression.

PMID- 12468038
TI  - The role of sex hormones on formalin-induced nociceptive responses.
AB  - Many chronic pain conditions are more frequent in women than in men. This
      observation suggests that there is a potential role of sex hormones on pain
      perception. In the present study, we measured nociceptive responses to the
      formalin test in normal and gonadectomized male and female rats. The nociceptive
      responses to formalin injection were divided in four phases: acute (phase I),
      interphase and late phases (phases II and III). Four groups of rats were tested:
      (a) males (n = 15), (b) females (n = 16), (c) ovariectomized females (OVX) (n =
      15) and (d) castrated males (CAST) (n = 15). Females presented significantly more
      nociceptive responses than males during phase I, interphase and phase II (P <
      0.01). They also presented significantly more nociceptive responses than OVX
      females during the interphase (P < 0.05). CAST males presented significantly more
      nociceptive responses during the phases I (P < 0.01), II (P < 0.01) and III (P <
      0.05) than the male rats. Finally, the responses of CAST males and OVX females
      were virtually identical, suggesting that the differences recorded between males
      and females in the formalin test were related to an activational effect of the
      sex hormones rather than an organizational effect. In conclusion, these results
      permit the support of the role of sex hormones on the modulation of pain
      perception. Interestingly, male and female sex hormones seem to act specifically
      on the different phases of the formalin test, suggesting some specific roles for
      sex hormones in different pain conditions.

PMID- 12468039
TI  - Dissociation of human thalamic and cortical SEP gating as revealed by
      intrathalamic recordings under muscle relaxation.
AB  - 'Gating' refers to a reduction of cortical somatosensory evoked potentials (SEP)
      under multiple simultaneous afferent inputs. This study used the opportunity for
      intrathalamic recordings in patients with movement disorders to clarify to what
      extent cortical SEP gating is preceded by thalamic gating. Recordings were
      performed in 10 patients, narcotised by intravenous propofol when receiving
      implantation of a therapeutic deep brain stimulator system. SEP were elicited by
      an 8.1-Hz median nerve stimulation at twice motor threshold and were recorded
      simultaneously from both intrathalamic and scalp electrodes before and after the
      application of the depolarising muscle blocker succinylcholine which eliminated
      both the background muscular tone and the repetitive muscle twitches caused by
      the median nerve stimulation. Peripheral compound action potentials recorded at
      the upper arm remained unchanged after complete muscle relaxation, proving a
      continuously effective nerve stimulation. In contrast, the primary cortical SEP
      component (N20) was significantly increased under succinylcholine (+17%). This
      cortical release from gating was not paralleled, however, by an increased
      thalamic response; rather, the primary thalamic response (P16) showed a slight (
      9%) but highly significant amplitude reduction. As the recordings were performed
      in narcotised patients, any potentially variable attentional bias on part of the
      subjects can be excluded as confounding factor when comparing the two
      experimental conditions with vs. without reafferent somatosensory inflow. Thus,
      given the high signal-to-noise ratio of intrathalamically recorded SEP, the
      present study shows a distinct thalamo-cortical dissociation with the primary
      somatosensory cortex representing the predominant level exhibiting SEP gating.

PMID- 12468040
TI  - TGF-beta1 increases tyrosine hydroxylase expression by a mechanism blocked by BMP
      2 in human neuroblastoma SH-SY5Y cells.
AB  - Human neuroblastoma SH-SY5Y cells were used to study the effects of transforming
      growth factor beta1 (TGF-beta1) and bone morphogenetic protein 2 (BMP-2) on
      neuronal differentiation and acquisition of a catecholaminergic phenotype. SH
      SY5Y cells express the intracellular factors activated through the receptors of
      the TGFbeta superfamily members, Smad1 and Smad4, as in basal conditions or after
      differentiation with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or retinoic acid
      (RA). TGF-beta1 and BMP-2 induce differentiation in SH-SY5Y cells by different
      pathways: the effect of TGF-beta1 is potentiated by TPA and the effect of BMP-2
      is blocked by RA. Cell differentiation due to TGF-beta1 treatment is accompanied
      by an increase in tyrosine hydroxylase (TH) expression, more pronounced in the
      presence of TPA or RA and counteracted by BMP-2. BMP-2 and RA both induce
      noncatecholaminergic cell differentiation, and together they may induce choline
      acetyltransferase expression in serum-cultured cells. In conclusion, our results
      suggest that TGF-beta1 and BMP-2 may contribute, in opposite ways, to regulation
      of the neuronal catecholaminergic phenotype.

PMID- 12468041
TI  - Differential effects of the 5-HT2 receptor antagonist on the anti-immobility
      effects of noradrenaline and serotonin reuptake inhibitors in the forced swimming
      test.
AB  - The effects of the 5-HT(2) receptor antagonist, LY 53857 on the effects of
      noradrenaline and serotonin reuptake inhibitors were investigated using the
      forced swimming test. LY 53857 enhanced anti-immobility effects of clomipramine
      and maprotiline, which can inhibit reuptake of noradrenaline. However, LY 53857
      did not affect the immobility time of mice treated with the selective serotonin
      reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine. These results suggest
      that antagonism of the 5-HT(2) receptor leads to potentiation of the
      antidepressant effects of noradrenaline reuptake inhibitors but not SSRIs and
      that LY 53857 may modify the activity of noradrenergic neurons.

PMID- 12468042
TI  - Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe
      transient focal cerebral ischemia in rats.
AB  - Oxidative stress, inducible nitric oxide synthase (iNOS) and neutrophils all
      contribute to post-ischemic brain damage. This study has determined the time
      courses of these three phenomena after ischemia in parallel with histological and
      functional outcomes. Ischemia was produced in rats by occluding the left middle
      cerebral artery and both common carotid arteries for 20 min. Regional cerebral
      blood flow (rCBF) rapidly decreased to 20% of its preischemic value during
      occlusion and stabilized at 60% following reperfusion. The striatal infarction
      was maximal 15 h after reperfusion (50+/-3 mm(3)), whereas the cortical
      infarction reached its maximum at 48 h (183+/-10 mm(3)). This drastic decrease in
      rCBF followed by incomplete reperfusion and massive infarction is, thus,
      extremely severe. The cortical infarction was strongly correlated with the
      neurologic deficit and loss of body weight. Oxidative stress, evaluated by the
      decrease in glutathione concentrations, appeared in the striatum at 6 h after
      reperfusion and in the cortex at 15 h. Calcium-independent NOS activity,
      considered as inducible NOS activity, was significantly enhanced at 24 h in the
      striatum and at 48 h in the cortex. Myeloperoxidase activity, a marker of
      neutrophil infiltration, was significantly increased at 48 h in both the striatum
      and cortex. These time courses show that the delayed iNOS activity and neutrophil
      infiltration that occur after the maturation of infarction in severe ischemia may
      not contribute to ischemic brain damage. By contrast, early oxidative stress may
      well be implicated in cerebral injury.

PMID- 12468043
TI  - Cholinergic modulation of basal and amphetamine-induced dopamine release in rat
      medial prefrontal cortex and nucleus accumbens.
AB  - Behavioral evidence suggests that muscarinic/cholinergic inhibition of brain
      dopaminergic activity may be a useful principle for developing novel
      antipsychotic drugs (APDs). Thus, oxotremorine, a muscarinic agonist, attenuates
      amphetamine-induced locomotor activity in rodents, an effect also produced by a
      wide variety of proven APDs, whereas scopolamine, a muscarinic antagonist, has
      the opposite effect. Since atypical APDs such as clozapine, olanzapine,
      risperidone, ziprasidone and quetiapine, increase brain acetylcholine as well as
      dopamine (DA) release in a region-specific manner, their effects on cholinergic
      and dopaminergic neurotransmission may also contribute to various actions of
      these drugs. Oxotremorine (0.5-1.5 mg/kg) dose-dependently and preferentially
      increased DA release in rat medial prefrontal cortex (mPFC), compared to the
      nucleus accumbens (NAC). However, S-(-)-scopolamine (0.5-1.5 mg/kg) produced
      similar increases in DA release in the mPFC, but the effect was much less than
      that of oxotremorine. Whereas a dose of S-(-)-scopolamine of 0.5 mg/kg comparably
      increased DA release in the mPFC and NAC, 1.5 mg/kg had no effect on DA release
      in the NAC. Oxotremorine-M (0.5 mg/kg), a M(1/4)-preferring agonist, also
      increased DA release in the mPFC, but not the NAC, an effect completely abolished
      by telenzepine (3 mg/kg), a M(1/4)-preferring antagonist, which by itself had no
      effect on DA release in either region. Oxotremorine (0.5, but not 1.5, mg/kg)
      attenuated amphetamine (1 mg/kg)-induced DA release in the NAC, whereas S-(-)
      scopolamine did not. Oxotremorine (1.5 mg/kg) and S-(-)-scopolamine (0.5 mg/kg)
      modestly but significantly potentiated amphetamine (1 mg/kg)-induced DA release
      in the mPFC. These results suggest that stimulation of muscarinic receptors, in
      particular M(1/4), as indicated by the effect of oxotremorine-M and telenzepine,
      may preferentially increase cortical DA release and inhibit amphetamine-induced
      DA release in the NAC.

PMID- 12468044
TI  - Striatal 6-hydroxydopamine induces apoptosis of nigral neurons in the adult rat.
AB  - The massive dopaminergic neuronal loss that occurs in Parkinson's disease shows
      features of apoptosis. In the current study we have characterised the neuronal
      death in an animal model of Parkinson's disease. 6-Hydroxydopamine infused in the
      striatum of adult rats induced progressive loss of dopamine neurons, identified
      as tyrosine hydroxylase immunoreactive profiles, in the ipsilateral substantia
      nigra starting at day 5 post-lesion (32%). Silver staining revealed the presence
      of apoptotic profiles with neuronal morphology in the substantia nigra
      ipsilateral to the intrastriatal 6-hydroxydopamine injection. These apoptotic
      nuclei were first observed at day 6 post-lesion, peaked between days 7 and 10 and
      then abruptly declined. The apoptotic morphology of 6-hydroxydopamine-induced
      neuronal death was confirmed by electron microscopic studies. These data show
      that intrastriatal 6-hydroxydopamine-induced dopaminergic neuronal death in the
      adult rat is apoptotic and supports the use of this lesion protocol as an animal
      model of Parkinson's disease.

PMID- 12468045
TI  - Failure of delayed and prolonged hypothermia to favorably affect hemorrhagic
      stroke in rats.
AB  - Prolonged hypothermia reduces global and focal cerebral ischemic injury in
      rodents even when delayed for hours. However, it is not known whether hypothermia
      can reduce injury following intracerebral hemorrhage (ICH). Accordingly, we
      studied striatal injury and concomitant motor deficits after 2 days of
      hypothermia, induced 1 h after creation of an ICH by infusion of bacterial
      collagenase. Rats were first trained to retrieve food pellets in the Montoya
      staircase task. They were then implanted with core temperature telemetry probes
      and later subjected to normothermic ICH or sham operation (vehicle injection).
      Half self-regulated temperature after surgery; others were cooled to 33 degrees C
      (24 h) and then 35 degrees C (24 h). Hypothermia did not affect behavioral scores
      of sham animals (89.8% of baseline in staircase test) or histology. Untreated
      (normothermic) ICH rats lost 23.1 mm(3) of tissue at a 1-month survival, which
      significantly impaired food pellet retrieval (66.0% retrieval) with the
      contralateral limb (tested on days 21-25). Contrary to our hypothesis,
      hypothermia failed to lessen either the reaching impairment (62.8%) or the lesion
      (22.2 mm(3)). While other hemorrhagic insults or complications may be improved
      with hypothermia, our data suggest that it will not salvage tissue that is
      quickly lost after ICH. We also assessed walking across a horizontal ladder and
      spontaneous paw usage in a cylinder test at 1-4 weeks after ICH, but neither test
      was sufficiently sensitive to this mild insult. This indicates that skilled
      reaching is more severely disrupted than spontaneous paw usage or walking after a
      striatal hemorrhage.

PMID- 12468046
TI  - Effects of prolactin-releasing peptide microinjection into the ventrolateral
      medulla on arterial pressure and sympathetic activity in rats.
AB  - Prolactin-releasing peptide (PrRP), originally isolated from the hypothalamus, is
      highly localized in the cardiovascular regions of the medulla, and
      intracerebroventricular administration of PrRP causes a pressor response. In the
      present study we investigated the cardiovascular effects of PrRP applied to
      functionally different areas of the ventrolateral medulla (VLM), and to the
      nucleus tractus solitarius (NTS) and the area postrema (AP). In urethane
      anesthetized rats, microinjection of PrRP into the pressor area of the most
      caudal VLM, recognized as the caudal pressor area in the rat, elicited dose
      dependent increases in mean arterial pressure, heart rate, and renal sympathetic
      nerve activity. In the same injection area, neither thyrotropin-releasing
      hormone, corticotropin-releasing hormone nor angiotensin II affected these
      baseline cardiovascular variables. On the other hand, microinjection of PrRP into
      more rostral parts of the VLM, i.e. the depressor area of the caudal VLM and the
      pressor area of the rostral VLM, as well as the NTS and the AP, had no effect on
      these cardiovascular variables. Immunohistochemical analysis in the medulla
      revealed that the cardiovascularly PrRP-responsive region contained PrRP
      immunoreactive cell bodies and nerve fibers. These results suggest that the most
      caudal VLM is an action site of PrRP to induce a pressor response, which is
      mediated, at least partly, by the increase in sympathetic outflow.

PMID- 12468047
TI  - Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1
      40).
AB  - Progressive neuronal loss and cognitive decline in Alzheimer's disease (AD) might
      be aggravated by beta-amyloid-enhanced excitotoxicity. Memantine is an
      uncompetitive NMDA receptor antagonist under clinical development for the
      treatment of AD. Memantine has neuroprotective actions in several in vitro and in
      vivo models. In the present study, we determined whether memantine protected
      against beta-amyloid induced neurotoxicity and learning impairment in rats.
      Twenty Sprague-Dawley rats received vehicle or vehicle plus memantine (steady
      state plasma concentrations of 2.34+/-0.23 microM, n=10) s.c. by osmotic pump for
      9 days. After 2 days of treatment, 2 microl of water containing beta-amyloid 1-40
      [Abeta(1-40)] were injected into the hippocampal fissure. On the ninth day of
      treatment, animals were sacrificed, and morphological and immunohistochemical
      techniques were used to determine the extent of neuronal degeneration and
      astrocytic and microglial activation in the hippocampus. Psychomotor activity and
      spatial discrimination were tested on the eighth day of treatment. Abeta(1-40),
      but not water, injections into hippocampus led to neuronal loss in the CA1
      subfield, evidence of widespread apoptosis, and astrocytic and microglial
      activation and hypertrophy. Memantine treated animals had significant reductions
      in the amount of neuronal degeneration, pyknotic nuclei, and GFAP immunostaining
      as compared with vehicle treated animals. These data suggest that memantine, at
      therapeutically relevant concentrations, can protect against neuronal
      degeneration induced by beta-amyloid.

PMID- 12468049
TI  - Can a healthy endothelium influence the cardiovascular effects of hormone
      replacement therapy?
AB  - Emerging clinical and observational evidences suggest that estrogen confers
      physiologic benefits that are receptor mediated and depend on the integrity and
      functional status of the endothelium within the coronary vasculature. In
      postmenopausal women, estrogen replacement therapy (ERT) and hormone replacement
      therapy (HRT) regimens can enhance the lipoprotein panel; blunt the expression of
      numerous cytokines, chemokines, and other proinflammatory mediators of
      endothelial injury and vascular smooth muscle cell proliferation; up-regulate
      endothelial nitric oxide synthase activity and nitric oxide production; and
      augment fibrinolysis potential and vasodilator capacity (diminish arterial
      resistance). Advancing age and atherosclerotic injury to the vessel wall tend to
      deplete estrogen receptors, compromise endothelial function, promote thrombus
      formation, and thus potentially diminish the efficacy of ERT and HRT. Therefore,
      optimizing the clinical benefits of these regimens in postmenopausal women
      depends largely on promoting a healthy endothelium through life-style
      modifications that diminish coronary risk.

PMID- 12468048
TI  - Suppression by zinc of transient OFF responses of carp amacrine cells to red
      light is mediated by GABA(A) receptors.
AB  - Modulation by Zn(2+) of ON and OFF responses of transient amacrine cells driven
      by red- and green-sensitive cones was investigated in isolated, superfused carp
      retina, using intracellular recording techniques. Zn(2+) selectively abolished
      the OFF response to red flash of the transient amacrine cells. This Zn(2+) effect
      was mimicked by GABA application and was blocked by bicuculline, indicating the
      involvement of GABA(A) receptors. Such differential modulation was observable
      neither in bipolar cells nor in sustained OFF amacrine cells. It is suggested
      that the Zn(2+) effect reported here might be due to a direct action of Zn(2+) on
      GABA(A) receptors of the transient amacrine cells.

PMID- 12468050
TI  - Circadian heart rate and blood pressure variability considered for research and
      patient care.
AB  - OBJECTIVES: To review mechanisms of circadian variations in heart rate
      variability (HRV) and blood pressure variability (BPV) and mortality and
      morbidity due to cardiovascular diseases (CVD). METHODS: Results from 7-day/24-h
      HRV and BPV are interpreted by gender and age-specified reference values in the
      context of a Medline search. RESULTS: Abnormal HRV and BPV measured around the
      clock for 7 days provides information on the risk of subsequent morbid events in
      subjects without obvious heart disease and without abnormality outside the
      conventional (in the sense of chronobiologically unquantified) physiological
      range. Meditation, beta-blockers, ACE inhibitors, n-3 fatty acids and estrogens
      may have a beneficial influence on HRV, but there is no definitive outcome
      validated therapy. Low HRV has been associated with a risk of arrhythmias and
      arrhythmic death, unstable angina, myocardial infarction, progression of heart
      failure and atherosclerosis. BPV may be characterized by treatable circadian
      hyper-amplitude-tension (CHAT), which can be transient '24-h CHAT' or '7-day
      CHAT', MESOR-hypertension and/or an unusually-timed (odd) circadian acrophase
      (ecphasia), all associated with an increased risk of stroke, stroke death,
      myocardial infarction, and kidney disease. CONCLUSIONS: Precise insight into the
      patho-physiology in time of HRV and BPV is needed with development of a consensus
      on best measures of HRV for clinical purposes and to determine when a 7-day
      record interpreted chronobiologically suffices and when it does not, for
      detection within as well as outside the conventional normal range, for diagnostic
      clinical practice and to direct therapy of risk greater than that associated with
      hypertension, smoking or any other risk factor.

PMID- 12468052
TI  - Natural history and predictors of moderate mitral regurgitation following balloon
      mitral valvuloplasty using Inoue balloon.
AB  - BACKGROUND: We studied the predictors and natural history of moderate mitral
      regurgitation following valvuloplasty using Inoue balloon since it has not been
      well documented in a large series. METHODS: Balloon mitral valvuloplasty was
      performed in 590 consecutive patients with severe mitral stenosis with mitral
      regurgitation of mild or lesser grade. Echocardiography and haemodynamics of
      patients who developed moderate mitral regurgitation were compared with those who
      did not. They were followed-up. Factors that predicted the development of
      moderate regurgitation were studied. RESULTS: 21 patients (3.5%) developed
      moderate regurgitation (identified by auscultation, haemodynamics, angiography
      and colour flow mapping). They were managed conservatively. At 3 months,
      regurgitation decreased in severity to mild grade in 12 patients. At 1 year, it
      was trivial in 5, mild in 11 and remained moderate in 5. There was progressive
      symptomatic improvement. No clinical, echocardiographic, hemodynamic or
      procedural variables could predict the development of moderate mitral
      regurgitation. CONCLUSIONS: Patients with moderate regurgitation after mitral
      valvuloplasty show gradual improvement in regurgitation and symptoms. There were
      no factors-clinical, echocardiographic, hemodynamic or procedural-that predicted
      the occurrence of moderate MR after BMV.

PMID- 12468053
TI  - Normal limits of the electrocardiogram in Chinese subjects.
AB  - BACKGROUND: Accurate normal limits of the electrocardiogram (ECG) are the basis
      on which diagnostic criteria are developed. The ECG, however, is subject to age-
      and sex-variations and may also be racially determined. Studies into normal ECG
      limits for the Chinese, comprising one fifth of the world population, are few and
      have their limitations. We have undertaken to establish normal limits of the ECG
      from a large sample of healthy Chinese subjects. METHODS: Standard simultaneous
      12-lead ECGs from 5360 apparently healthy Chinese subjects (3614 men and 1746
      women, ages ranging from 18 to 84 years) were collected with a modern digital
      recorder and processed with a well-validated ECG computer program. The medians,
      lower limits (2nd percentile) and upper limits (98th percentile) of various ECG
      measurements were calculated and age and sex differences examined. RESULTS:
      Significant age trends were present in, for example, P-wave duration, QTc
      interval, and frontal QRS axis, with concomitant changes of R amplitudes in the
      extremity leads. Sex differences existed for heart rate, interval durations, the
      Sokolow and Cornell indices, and QRS and ST-T amplitudes in different leads.
      Notably, left-precordial R-wave amplitudes in women increased with age; the
      Sokolow index showed a clearer age trend for men than for women, the reverse
      being true for the Cornell index. Some of these findings are at odds with
      established diagnostic ECG criteria. CONCLUSIONS: Normal ECG limits of Chinese
      subjects show marked age and sex differences. This merits the definition and use
      of age- and sex-specific ECG criteria for a Chinese population.

PMID- 12468054
TI  - The association of lower testosterone level with coronary artery disease in
      postmenopausal women.
AB  - OBJECTIVE: Testosterone (T) is assumed to be a risk factor for coronary artery
      disease (CAD). However, recent studies have demonstrated a beneficial effect of T
      on myocardial ischaemia in men with CAD. To assess the potential role of T in CAD
      in postmenopausal women we investigated the association between T level and CAD
      and relationship between T and other CAD metabolic risk factors. RESULTS: Within
      the 12-month study period, 108 consecutive, postmenopausal women (age 62+/-7
      years) referred for diagnostic coronary angiography were prospectively included
      in the study. In all patients serum level of T, sex hormone-binding globulin
      (SHBG), total cholesterol (T-chol), LDL-chol, HDL-chol, triglycerides (TG),
      apolipoproteins A(1) and B (apo A(1), apo B), lipoprotein a [Lp(a)], and C
      reactive protein were measured. Testosterone free index (TFI) was calculated as
      Tx100/SHBG. CAD was documented in 51 (47%) patients (CAD+). Women with CAD had
      decreased T level and lower TFI (T: 0.99+/-0.4 vs. 1.41+/-0.7 nmol/l, P=0.005;
      TFI: 3.2+/-1.4 vs. 4.2+/-2.2, P=0.04, CAD+ vs. CAD-, respectively). No difference
      in SHBG was found between the two groups. In 16 women (six CAD+, 10 CAD-) who
      were on hormonal replacement therapy (HRT+) we observed significantly elevated T
      level and TFI (T: 1.62+/-0.5 vs. 1.15+/-0.7 nmol/l; TFI: 5.0+/-2.2 vs. 3.5+/-1.8,
      HRT+ vs. HRT-, respectively, P<0.05). When these women were excluded from the
      analysis, T level remained decreased in CAD+ group (0.96+/-0.4 vs. 1.22+/-0.5
      nmol/l, CAD+ vs. CAD- respectively, P<0.02). CAD+ group had an unfavourable
      profile of metabolic CAD risk factors as evidenced by elevated T-chol, LDL-chol,
      Lp(a), apoB, and decreased apoA(1) (P<0.05 vs. CAD- in all comparisons). Neither
      T nor TFI correlated with CAD metabolic risk factors (r<0.2, P>0.1 for all
      correlations), apart from an inverse correlation between T and Lp(a) (r=-0.24,
      P=0.04). CONCLUSION: In postmenopausal women decreased T level is associated with
      CAD independently of the other CAD metabolic risk factors. Hormonal replacement
      therapy tends to increase T level which may further support the beneficial role
      of HRT in postmenopausal women.

PMID- 12468055
TI  - Prolonged ST segment depression after stress testing: does it really identify
      more severe disease?
AB  - BACKGROUND: It is generally perceived that the persistence of ST segment
      depression for more than 5 min after treadmill exercise testing (ETT) signifies a
      strongly positive test and predicts more severe ischemia and coronary artery
      disease. AIM: The aim of this study was to determine if prolonged ST segment
      changes (>5 min) after ETT identifies patients with more severe ischemia and thus
      severe coronary artery disease. METHODS: Twenty five patients (19 males, mean age
      58+/-10 years) with >1 mm ST segment depression and recovery time <or=5 min
      (group 1) and 25 patients (20 males, mean age 62+/-10 years) with >1 mm ST
      segment depression and recovery time >5 min (group 2) undergoing ETT and single
      photon emission computed tomography were prospectively enrolled. Summed stress
      and difference scores, stress and reversible extent % of perfusion abnormalities,
      and lung heart ratio was calculated. RESULTS: There was no significant difference
      in the mean summed stress score (9+/-9 versus 13+/-10, P=0.13), summed difference
      score (4+/-3 versus 6+/-5, P=0.13), stress extent % (14+/-16 versus 19+/-13,
      P=0.13), extent of reversibility % (7+/-9 versus 7+/-7, P=0.93), or lung heart
      ratio (0.48+/-0.07 versus 0.46+/-0.07, P=0.50) between the two groups. There was
      no significant difference in the incidence of severe ischemia (summed difference
      score >13) in the 2 groups (24% versus 40%, P=0.36). CONCLUSION: We conclude that
      utilizing the commonly used cutoff for prolonged ST segment depression: >5 min in
      recovery, does not identify patients with more severe ischemia or coronary artery
      disease and, therefore, at increased risk. Thus, it appears unnecessary to give
      special consideration to these patients by way of prolonged monitoring in
      recovery, or a more aggressive non-invasive ischemia imaging approach after the
      ETT.

PMID- 12468056
TI  - Experience of cardiac rehabilitation after coronary artery surgery: effects on
      health and risk factors.
AB  - OBJECTIVE: Cardiac rehabilitation (CR) programs are provided to support the
      recovery process following acute myocardial infarction and coronary artery bypass
      grafting (CABG). Attendance varies. We related attendance following CABG to
      severity of cardiac symptoms, general health status (Short Form-36) and
      prevalence of modifiable coronary artery disease (CAD) risk factors. METHODS: 209
      patients due to undergo CABG were recruited and assessed preoperatively as well
      as at a mean of 16.4 months postoperatively. General health status was measured
      using the Short Form-36 questionnaire. Severity of cardiac symptoms was assessed
      on a visual analogue scale. Modifiable coronary artery disease risk factors
      (smoking, body mass index, hypertension and elevated cholesterol) and social
      deprivation index were noted. RESULTS: There were ten early and three late
      deaths. Thirteen patients withdrew consent for investigation, therefore 183 were
      fully studied. Of these 65.0% completed a CR programme and 24.6% did not attend
      any programme; 10.4% partially completed (less than 50% of time) and were
      excluded from analysis. Nonattenders were more likely to be smokers (P=0.002),
      diabetic (P=0.028) and were more from socially deprived geographical areas
      (P=0.013), but the proportion of patients with BMI>25, BP>140/90 or cholesterol
      >5.0 mmol l(-1) were the same. There were no differences in age, preoperative
      NYHA score, number of grafts, angina recurrence (46 vs. 38%, P=0.35) or
      breathlessness (62 vs. 69%, P=0.40) between attenders and nonattenders. The
      severity scores of angina (2.7 vs. 3.2, P=0.286) and breathlessness (3.5 vs. 3.6;
      P=0.79) were no different. However, four of the eight health domains measured
      showed significantly better values for attenders than nonattenders; namely:
      general health (60 vs. 46%, P=0.001), physical function (64 vs. 51% P=0.01), role
      limitation physical (48 vs. 29%; P=0.02) and social function 74 vs. 62%, P=0.04).
      CONCLUSIONS: This is the first report using SF 36 to evaluate benefits from
      attending CR. Higher general health scores (SF-36) were associated with
      attendance at CR although CAD risk factors and cardiac symptoms were not improved
      but this may be due to the long interval between assessments.

PMID- 12468057
TI  - Prognostic significance of heart rate variability in dilated cardiomyopathy.
AB  - BACKGROUND: Identifying high-risk individuals among patients with nonischemic
      dilated cardiomyopathy (DCM) is a major and unsolved task of clinical cardiology.
      We aimed to determine prognostic significance of heart rate variability (HRV) for
      predicting cardiac events in DCM patients with markedly depressed left
      ventricular function. METHODS: In 69 DCM patients in sinus rhythm, with normal
      coronary angiography and mean ejection fraction 32 (11%) cardiac events defined
      as cardiac death or heart transplantation during a mean 20-month follow-up were
      related to baseline time-domain HRV parameters calculated from 24-h digital
      Holter monitoring. RESULTS: There were 18 (26%) cardiac events (10 deaths and 8
      heart transplantations). In multivariate Cox analysis, standard deviation of
      normal-to-normal intervals (SDNN) (hazard ratio: 1.35; 95% confidence interval
      1.11-1.63; P=0.002) and ejection fraction (hazard ratio: 4.21; confidence
      interval 1.64-10.78; P=0.003) were significant and independent predictors of
      cardiac events. One-year event-free survival was significantly lower in patients
      with SDNN<80 ms compared to those with SDNN>or=80 ms (35% vs. 89%, respectively;
      P<0.00005). Low SDNN was identifying high-risk patients among those with both
      depressed and relatively preserved left ventricular function. CONCLUSIONS:
      Broadly available time-domain HRV analysis adds independent prognostic
      information improving risk stratification of DCM patients and therefore it should
      be incorporated in routine clinical evaluation to determine patients' priority
      for heart transplantation.

PMID- 12468058
TI  - Interleukin-6 and tumor necrosis factor-alpha levels increase in response to
      maximal exercise in patients with chronic heart failure.
AB  - Chronic heart failure (CHF) is characterized by the activation of neurohormones
      and cytokines. Strenuous exercise causes activation of both systems but the
      effect of acute bouts of exercise on cytokines is not known in patients with CHF.
      This study determined whether maximal exercise induces activation of cytokines in
      CHF. Plasma interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, epinephrine,
      norepinephrine, and atrial and brain natriuretic peptides (ANP and BNP) were
      determined before and after symptom-limited cardiopulmonary exercise testing in
      80 patients with CHF (LVEF=38+/-1%, peak VO(2)=18.8+/-0.5 ml/min/kg) and age
      matched 33 controls. Resting IL-6 (Controls vs. CHF: 1.3+/-0.2 vs. 2.5+/-0.3
      pg/ml, P<0.001) and TNF-alpha (2.7+/-0.2 vs. 3.8+/-0.2 pg/ml, P<0.01) were
      elevated in CHF. LogIL-6 and logTNF-alpha were positively correlated (r=0.34 and
      r=0.35, respectively) with logplasma norepinephrine, and were negatively
      correlated (r=-0.39 and r=-0.32, respectively) with peak VO(2). Maximal exercise
      increased IL-6 and TNF-alpha both in controls and CHF (all P<0.01). Changes in IL
      6 (DeltaIL-6) correlated with Deltaepinephrine (r=0.63, P<0.0001) and
      Deltanorepinephrine (r=0.57, P=0.0006) in controls, but not in CHF. DeltaTNF
      alpha correlated with DeltaANP (r=0.28, P=0.01) only in CHF. In summary, cytokine
      activation at rest was associated with high plasma norepinephrine and exercise
      intolerance. Maximal exercise caused increases in IL-6 and TNF-alpha
      concentrations. Sympathetic activation seems to be important for the IL-6
      increase during exercise in controls. In CHF, changes in ANP during exercise were
      associated with the exercise-induced increase in TNF-alpha, but still unknown
      mechanisms are involved for the cytokine activation during exercise.

PMID- 12468059
TI  - Restenosis after intracoronary stent placement: can apolipoprotein(a)
      polymorphism play a role?
AB  - BACKGROUND: The relationship between lipoprotein(a) and restenosis after
      intracoronary stent implantation has been analysed by two specific studies, but
      the role of apoliprotein(a) polymorphism was not considered. The aim of the
      present prospective study was to evaluate whether lipoprotein(a) levels and
      apolipoprotein(a) phenotypes are predictors of restenosis after elective stent
      implantation in patients with de novo lesions of coronary arteries. METHODS: We
      recruited 182 patients with a new lesion successfully treated with elective
      placement of one or two Palmaz-Schatz stents. Follow-up angiography was scheduled
      at 6 months or earlier if clinically indicated. Nine patients were lost to the
      follow up. Among 173 patients enrolled, restenosis was present in 52 (30.0%) and
      absent in 121 (70.0%). RESULTS: Lipoprotein(a) levels were higher in the
      restenosis than in the nonrestenosis group (29.5+/-17.2 versus 27.4+/-20.2
      mg/dl), even if the difference did not attain statistical significance (P=0.067).
      The restenosis group had a percentage of subjects with at least one
      apolipoprotein(a) isoform of low molecular weight significantly greater than the
      nonrestenosis group (82.7 versus 66.9%; P=0.035). A multiple logistic regression
      analysis showed that multiple stenting (RR: 4.01; CI 95%: 1.65-13.91; P=0.004),
      presence of diabetes (RR: 3.96; CI 95%: 1.67-9.37; P=0.002) and presence of
      multivessel disease (RR: 2.71; CI 95%: 1.19-6.16; P=0.017) were predictors of
      restenosis after stent placement. Lipoprotein(a) and apolipoprotein(a)
      polymorphism did not enter the model as predictive variables. CONCLUSIONS: Our
      study confirms that multiple stenting, diabetes and multivessel disease are
      powerful predictors of restenosis after intracoronary stent implantation. On the
      contrary, lipoprotein(a) and apolipoprotein(a) polymorphism do not appear to be
      reliable markers of restenosis in patients with stent implantation.

PMID- 12468060
TI  - Electrocardiographic artifact mimicking acute myocardial infarction.

PMID- 12468061
TI  - Hemoptysis as an unusual manifestation of right atrial myxoma.
AB  - Atrial myxoma is the most frequent tumor of the heart, though right-side
      locations and initial clinical manifestation in the form of hemoptysis are
      infrequent. We describe the case of a young woman with right atrial myxoma
      diagnosed by transthoracic echocardiography and presenting hemoptysis as the most
      important manifestation. The symptomatology disappeared after surgical removal of
      the lesion.

PMID- 12468062
TI  - Acute pulmonary hypertensive crisis after TAPVC repair treated with atrial
      septectomy with inflow occlusion. Total anomalous pulmonary venous connection.
AB  - Acute pulmonary hypertensive crisis is a fatal complication after obstructive
      TAPVC repair. An atrial septectomy or enlargement of a small ASD could be a
      lifesaving procedure in order to maintain cardiac output in severe cases. This
      procedure can be accomplished with inflow occlusion in patients with critical
      condition.

PMID- 12468063
TI  - Pancarditis as initial presentation of systemic lupus erythematosus.
AB  - Systemic lupus erythematosus (SLE) is a multisystem disorder with cardiac
      involvement in about 50% of cases, yet clinically significant lesions are less
      common. SLE with pancarditis at initial presentation has so far not been
      reported. We present a rare case of SLE with culture negative endocarditis,
      reversible left ventricular (LV) dysfunction and mild pericardial effusion.
      Treatment with steroids showed improvement in cardiac contractile function and
      mitral valve vegetations disappeared over 3 months. In a case of pancarditis with
      culture negative endocarditis, SLE as a possibility must be explored. After
      excluding infective endocarditis, a short trial of high dose corticosteroids
      effects overall improvement in carditis of SLE.

PMID- 12468064
TI  - Storms of ventricular tachyarrhythmias associated with primary
      hyperparathyroidism in a patient with dilated cardiomyopathy.

PMID- 12468065
TI  - Computational morphology of the lung and its virtual imaging.
AB  - The author proposes an entirely new approach called 'virtual imaging' of an organ
      based on 'computational morphology'. Computational morphology describes
      mathematically design as principles of an organ structure to generate the organ
      model via computer, which can be called virtual organ. Virtual imaging simulates
      image data using the virtual organ. The virtual organ is divided into cubic
      voxels, and the CT value or other intensity value for each voxel is calculated
      according to the tissue properties within the voxel. The validity of the model is
      examined by comparing virtual images with clinical images. Computational image
      analysis methods can be developed based on validated models. In this paper,
      computational anatomy of the lung and its virtual X-ray imaging are introduced.

PMID- 12468066
TI  - MR imaging of lung cancer.
AB  - Since publication of the Radiologic Diagnostic Oncology Group Report in 1991, the
      clinical application of pulmonary magnetic resonance (MR) imaging to patients
      with lung cancer has been limited. Computed tomography has been much more widely
      available for staging of lung cancer in clinical situations. Currently,
      ventilation and perfusion scintigraphy is the only modality that demonstrates
      pulmonary function while 2-[fluorine-18]-fluoro-2-deoxy-D-glucose positron
      emission tomography is the only modality that reveals biological glucose
      metabolism of lung cancer. However, recent advancements in MR imaging have made
      it possible to evaluate morphological and functional information in lung cancer
      patients more accurately and quantitatively. Pulmonary MR imaging may hold
      significant potential to substitute for nuclear medicine examinations. In this
      review, we describe recent advances in MR imaging of lung cancer, focusing on (1)
      characterization of solitary pulmonary nodules; (2) differentiation from
      secondary change; evaluation of (3) medastinal invasion, (4) chest wall invasion,
      (5) lymph node metastasis, and (6) distant metastasis; and (7) pulmonary
      functional imaging. We believe that further basic studies, as well as clinical
      applications of newer MR techniques, will play an important role in the
      management of patients with lung cancer.

PMID- 12468067
TI  - Chest radiographic evaluation of diffuse infiltrative lung disease: review of a
      dying art.
AB  - The chest radiographic evaluation of interstitial lung diseases is among the most
      difficult tasks in radiology. The following article reviews one system of pattern
      recognition used in the differential diagnosis of interstitial lung disease. The
      patterns reviewed include three reticular patterns: The Peripheral Reticular
      pattern, the Cystic pattern and the Linear pattern and two other patterns: the
      Nodular pattern and the ground-glass pattern. The majority of interstitial lung
      diseases may be classified into one of these patterns, which allows for improved
      differential diagnosis.

PMID- 12468068
TI  - Computerized detection of pulmonary nodules by single-exposure dual-energy
      computed radiography of the chest (part 1).
AB  - OBJECTIVE: To clarify the usefulness of computerized detection of pulmonary
      nodules (PNs) in single-exposure dual-energy subtraction computed radiography
      (CR) images of the chest. METHODS AND MATERIAL: Our scheme uses bone-subtracted
      CR (BS-CR) images, and consists of a contrast-adaptive filter for detection of
      the candidates for PNs and a vessel-enhancing filter for elimination of vessel
      opacities in the candidates for PNs. For the evaluation, 12 clinical cases with
      multiple PNs were used, and four radiologists participated in this study.
      RESULTS: The detectability of our computer-aided diagnosis (CAD) was compared
      with detectabilities of radiologists. The mean true-positive (TP) number of four
      radiologists was 1.60+/-1.03, and that of the CAD was 1.83+/-1.34. There was no
      significant difference in the nodule detectabilities between the radiologists and
      CAD (P=0.18). However, the false-positive (FP) rate of the CAD was 9.42+/-2.54
      per image, whereas the mean FP rate of the radiologists was 1.40+/-0.64 per
      image. CONCLUSION: Computerized detection of PNs is considered to be useful in
      the determination of radiological diagnoses. However, reducing the number of FP
      findings remains an important problem to be solved.

PMID- 12468069
TI  - Detection of simulated pulmonary nodules by single-exposure dual-energy computed
      radiography of the chest: effect of a computer-aided diagnosis system (Part 2).
AB  - OBJECTIVE: To evaluate the performance of the computer-aided diagnosis (CAD)
      scheme on the detection of pulmonary nodules (PNs) in single-exposure dual-energy
      subtraction computed radiography (CR) images of the chest, and to evaluate the
      effect of this CAD scheme on radiologists' detectibilaties. METHODS AND MATERIAL:
      We compared the detectability by the CAD scheme with the detectability by 12
      observers by using conventional CR (C-CR) and bone-subtracted CR (BS-CR) images
      of 25 chest phantoms with a low-contrast nylon nodule. RESULTS: Both in the CAD
      scheme and for the observers, the detectability of BS-CR images was superior to
      that of C-CR images (P<0.005). The detection performance of the CAD scheme was
      equal to that of the observers. The nodules detected by the CAD did not
      necessarily coincide with those by the observers. Thus, if observers can use the
      results of the CAD system as a 'second opinion', their detectabilities increase.
      CONCLUSION: The CAD system for detection of PNs in the single-exposure dual
      energy subtraction method is promising for improving radiologists'
      detectabilities of PNs.

PMID- 12468070
TI  - MR-pathologic correlation of lung specimens.
AB  - The aim of this study was to assess the feasibility of a new MR-pathologic
      correlation method utilizing a high-resolution MR technique with a 3-inch surface
      coil and elimination of susceptibility by replacing air in the pulmonary alveoli
      of lung specimens with water. Inflated cadaver lung specimens of various lung
      disorders were imaged using a conventional spin echo (SE) sequence in a clinical
      1.5 T MR scanner. The MR images were correlated with pathologic specimens. In six
      out of seven specimens, MR revealed detailed images corresponding to pathological
      changes. MR may provide a non-invasive and non-destructive method for examining
      lung specimens and for image-pathologic correlation.

PMID- 12468071
TI  - Differentiation of metastatic versus non-metastatic mediastinal lymph nodes in
      patients with non-small cell lung cancer using respiratory-triggered short
      inversion time inversion recovery (STIR) turbo spin-echo MR imaging.
AB  - OBJECTIVES: To differentiate between metastatic and non-metastatic lymph nodes in
      patients with non-small cell lung cancer using respiratory-triggered short
      inversion time inversion recovery (STIR) turbo spin-echo (SE) MR imaging. METHODS
      AND PATIENTS: One hundred and forty mediastinal lymph nodes were detected in 25
      patients with non-small cell lung cancer who underwent respiratory-triggered STIR
      turbo SE imaging. Ratios of signal intensity of lymph nodes to 0.9% saline
      phantoms (lymph node-saline ratio) were compared by Student's t-test using the
      pathological diagnosis as the gold standard. The threshold value of the lymph
      node-saline ratio was determined for a positive test, and tested for its
      capability to provide a differential diagnosis. RESULTS: One hundred and forty
      lymph nodes were diagnosed and classified into two groups: metastatic lymph node
      (n=21) and non-metastatic lymph node (n=119). The mean lymph node-saline ratio in
      the non-metastatic lymph node group (0.42+/-0.01; mean+/-standard error) was
      significantly lower than that of the metastatic lymph node group (0.77+/-0.02,
      P<0.0001). When 0.6 was adapted as the threshold for a positive test,
      sensitivity, specificity, and accuracy for differentiating metastatic lymph node
      from non-metastatic lymph node per lymph nodes were 100, 96, and 96%, and
      sensitivity, specificity, and accuracy for differentiating metastatic lymph node
      from non-metastatic lymph node per patients were 100, 75, and 88%, respectively.
      CONCLUSIONS: Both metastatic and non-metastatic lymph nodes in patients with non
      small cell lung cancer were well differentiated using respiratory-triggered STIR
      turbo SE imaging.

PMID- 12468072
TI  - Extrapleural hematoma as an unexpected finding on a follow-up chest X-ray after
      coronary surgery.
AB  - We present two cases of an extrapleural hematoma, on a follow-up chest X-ray
      after coronary artery bypass surgery using an internal mammary artery (IMA). In
      both cases, the finding was disclosed on a routine chest film obtained 1 month
      post-operatively, in a patient who was either asymptomatic or had nonspecific
      symptoms. Follow-up chest films showed spontaneous resolution in both patients.
      We emphasize the recognition and significance of such a self-limited post
      operative radiological finding.

PMID- 12468073
TI  - Involvement of the thyroid and the salivary glands in childhood non-Hodgkin's
      lymphomas at initial diagnosis.
AB  - OBJECTIVE: The clinical spectrum of childhood non-Hodgkin's lymphoma (NHL) is
      different from that in adults, with frequent extranodal involvement. We searched
      the incidence and radiological appearance of the secondary involvement of the
      thyroid and salivary glands by ultrasonography (US) to assess its importance for
      staging of the disease. MATERIALS AND METHODS: We examined the thyroid, parotid
      and submandibulary glands of 43 children with NHL, age ranging between 9 months
      and 17 years, by US. RESULTS: According to US findings, involvement of the
      parotid gland was very common as detected in 18 of the cases with NHL (41%). It
      was the most common organ involved in lymphoma. Lymphomatous infiltration of the
      thyroid gland, with bilateral multiple focal lesions, was detected in two
      patients and proved by fine needle aspiration biopsy in all cases (5%). Salivary
      gland and thyroid involvement changed staging in three (6%) of the patients,
      however, the treatment plan was unchanged. CONCLUSIONS: This study shows that
      anatomic sites, known to be very rarely involved at the initial presentation of
      the disease is actually more commonly involved in childhood NHL. However, it does
      not cause any significant change in the treatment planning or in the survival.

PMID- 12468074
TI  - Sclerosing adenosis: mammographic and ultrasonographic findings with clinical and
      histopathological correlation.
AB  - OBJECTIVE: To evaluate the mammographic and ultrasonographic findings of
      sclerosing adenosis, a relatively uncommon entity which may sometimes mimic
      carcinoma. MATERIALS AND METHODS: A retrospective review of the records of 33,700
      women, who have undergone mammographic examination at our institution between
      January 1985 and July 2001 revealed 43 histopathologically proven sclerosing
      adenosis. The history, physical examination, mammographic and ultrasonographic
      findings were analyzed in all patients. In 30 patients, the nonpalpable lesions
      were preoperatively localized by the needle-hookwire system under the guidance of
      mammography (n=22) or ultrasonography (US) (n=8). Radiological features were
      correlated with histopathological findings. RESULTS: The age of the patients
      varied between 32 and 55 years (mean, 43.7 years). Only two patients had a family
      history of breast cancer. In six patients, the presenting complaint was
      mastalgia. A palpable mass was present in 13 cases. The mammographic findings
      were; microcalcifications in 24 (55.8%) (clustered in 22, diffuse in two), mass
      in five (11.6%), asymmetric focal density in three (6.9%), and focal
      architectural distortion in three (6.9%) patients. Four of the masses were
      irregularly contoured, while one was well-circumscribed. On US, focal acoustic
      shadowing without a mass configuration was noted in the three patients who showed
      asymmetrical focal density on mammography. In eight patients, who showed normal
      mammograms, a solid mass was detected on US. Two masses had discrete well
      circumscribed oval or lobulated contours, while six showed microlobulation and
      irregularity. In one case, the irregularly contoured mass had marked posterior
      acoustic shadowing. Two of the three patients, who had focal architectural
      distortion on mammograms, had an irregularly contoured solid mass, while the
      third presented as focal acoustic shadowing without a mass configuration.
      CONCLUSION: Sclerosing adenosis mostly presents as a nonpalpable lesion with
      different mammographic and sonographic appearances. The most common finding is
      microcalcifications on mammograms. Awareness of the possible imaging features
      will enable us to consider sclerosing adenosis in the differential diagnosis. The
      radiological features may sometimes mimic malignancy, so histopathologic
      examination is mandatory for definite diagnosis.

PMID- 12468079
TI  - Natural selection and neutral theory. Proceedings of the 5th Anton Dohrn
      Workshop. Naples, Italy. October 24-27, 2001.

PMID- 12468080
TI  - The dawn of gene isolation.
AB  - Ever since it became clear through the work of Watson and Crick that the gene is
      a stretch of double stranded helical DNA and is understandable in chemical terms,
      biochemists have striven to get their hands on isolated genes. The isolation of
      the ribosomal genes of Xenopus laevis in 1966 provided a first instance where a
      purified DNA of known function could be investigated, long before the advent of
      gene cloning technologies. The second instance was the purification of the Lac
      operon from Escherichia coli. Later, but still before the gene cloning days the
      5S RNA genes of X. laevis and the histone genes of the sea urchin Psammechinus
      miliaris were isolated by physico-chemical methods, but their isolation marked
      the end of an era. By 1975, gene cloning technology was well established and the
      isolation of genes quickly became an everyday occurrence.

PMID- 12468081
TI  - Specificity in DNA recognition by phage integrases.
AB  - The lambda-related (lambdoid) coliphages are related to one another by frequent
      natural recombination and maintain a high level of functional polymorphism for
      several activities of the phages. Arguments are presented that the polymorphism
      of the integration module results from selection (presumably frequency-dependent)
      for new (not improved) specificities of site recognition. Analysis of phages
      lambda and HK022 by Weisberg and collaborators previously showed that changes in
      five noncontiguous amino acids could switch site recognition specificity. Phage
      21 and defective element e14, which integrate at the same site, differ in
      recognition specificity for both core and arm sites. In vitro assays of e14 and
      21 insertion and excision confirm this conclusion. Inhibition by ds arm site
      oligonucleotides defines the sequence specificity more precisely.

PMID- 12468082
TI  - Genetic polymorphism at two linked loci, Sod and Est-6, in Drosophila
      melanogaster.
AB  - We have examined the patterns of polymorphism at two linked loci, Sod and Est-6,
      separated by nearly 1000 kb on the left arm of chromosome 3 of Drosophila
      melanogaster. The evidence suggests that natural selection has been involved in
      shaping the polymorphisms. At the Sod locus, a fairly strong (s>0.01) selective
      sweep, started >or=2600 years ago, increased the frequency of a rare haplotype,
      F(A), to about 50% frequency in populations of Europe, Asia, and the Americas.
      More recently, an F(A) allele mutated to an S allele, which has increased to
      frequencies 5-15% in populations of Europe, Asia and North America. All S alleles
      are identical (or very nearly) in sequence and differ by one nucleotide
      substitution (which accounts for the F-->S electrophoretic difference) from F(A)
      alleles. At the Est-6 locus, the evidence indicates both directional and
      balancing selection impacting separately the promoter and the coding regions of
      the gene, with linkage disequilibrium occurring within each region. Some linkage
      disequilibrium also exists between the two genes.

PMID- 12468083
TI  - Natural selection at linked sites in humans.
AB  - Theoretical and empirical work indicates that patterns of neutral polymorphism
      can be affected by linked, selected mutations. Under background selection,
      deleterious mutations removed from a population by purifying selection cause a
      reduction in linked neutral diversity. Under genetic hitchhiking, the rise in
      frequency and fixation of beneficial mutations also reduces the level of linked
      neutral polymorphism. Here we review the evidence that levels of neutral
      polymorphism in humans are affected by selection at linked sites. We then discuss
      four approaches for distinguishing between background selection and genetic
      hitchhiking based on (i) the relationship between polymorphism level and
      recombination rate for neutral loci with high mutation rates, (ii) relative
      levels of variation on the X chromosome and the autosomes, (iii) the frequency
      distribution of neutral polymorphisms, and (iv) population-specific patterns of
      genetic variation. Although the evidence for selection at linked sites in humans
      is clear, current methods and data do not allow us to clearly assess the relative
      importance of background selection and genetic hitchhiking in humans. These
      results contrast with those obtained for Drosophila, where the signals of
      positive selection are stronger.

PMID- 12468084
TI  - An algorithm for detecting directional and non-directional positive selection,
      neutrality and negative selection in protein coding DNA sequences.
AB  - Positive selection or adaptive evolution is thought to be responsible, at least
      some of the time, for the rapid accumulation of advantageous changes in protein
      coding genes. The origin of new enzymatic functions, erection of barriers to
      heterospecific fertilization, and evasion of host response by pathogens, among
      other things, are thought to be instances of adaptive evolution. Detecting
      positive selection in protein-coding genes is fraught with difficulties.
      Saturation for sequence change, codon usage bias, ephemeral selection events and
      differential selective pressures on amino acids all contribute to the problem. A
      number of solutions have been proposed with varying degrees of success, however
      they suffer from limitations of not being accurate enough or being prohibitively
      computationally intensive. We have developed a character-based method of
      identifying lineages that undergo positive selection. In our method we assess the
      possibility that for each internal branch of a phylogenetic tree an event
      occurred that subsequently gave rise to a greater number of replacement
      substitutions than might be expected. We classify these replacement substitutions
      into two categories - whether they subsequently became invariable or changed
      again in at least one descendent lineage. The former situation indicates that the
      new character state is under strong selection to preserve its new identity
      (directional selection), while the latter situation indicates that there is a
      persistent pressure to change identity (non-directional selection). The method is
      fast and accurate, easy to implement, sensitive to short-lived selection events
      and robust with respect to sampling density and proportion of sites under the
      influence of positive selection.

PMID- 12468085
TI  - Can mutation or fixation biases explain the allele frequency distribution of
      human single nucleotide polymorphisms (SNPs)?
AB  - One of the most abiding controversies in evolutionary biology concerns the role
      of neutral processes in molecular evolution. A main focus of the debate has been
      the evolution of isochores, the strong and systematic variation of base
      composition in mammalian genomes. One set of hypotheses argue that regions of
      similar GC are owing to localised mutational biases coupled with neutral
      evolution. The alternatives point to either selection or biased gene conversion
      as mechanisms to preferentially remove A or T bases, favouring G and C instead.
      Using a novel method, we compare models including such fixation biases to models
      based on mutation bias alone, under the assumption that non-coding, non
      repetitive human DNA is at compositional equilibrium. While failing to fully
      explain the allele frequency distributions of recent single nucleotide
      polymorphism data, we show that the data are best fitted if the mutation bias is
      assumed to be constant across the genome, while fixation bias varies with GC
      content. We also attempt to estimate the strength of fixation bias, which
      increases linearly with increasing GC. Our approximation suggests that this force
      exists within the necessary parameter range: it is not so weak as to be drowned
      by random drift, but not so strong as to lead to exclusive use of G and C alone.
      Together these results demonstrate that mutation bias fails to explain the
      evolution of isochores, and suggest that either selection or biased gene
      conversion are involved.

PMID- 12468086
TI  - Playing chicken (Gallus gallus): methodological inconsistencies of molecular
      divergence date estimates due to secondary calibration points.
AB  - For any given taxonomic divergence event, one may find in the literature a wide
      range of time estimates. Many factors contribute to the variation in molecular
      date estimates for the same evolutionary event. High on the list is the choice of
      calibration points for converting genetic distances into evolutionary rates and,
      subsequently, into dates of divergence. In this study, we investigate one
      critical source of error in estimating divergence times, i.e. the use of
      secondary calibration points, which are divergence time estimates that have been
      derived from one molecular dataset on the basis of a primary external calibration
      point, and which are used again independently of the original external
      calibration point on a second dataset. Unless particular care is exercised, this
      practice leads to internal inconsistencies, and the inferred dates of divergence
      are by necessity unreliable. We present a consistency test for assessing the
      reliability of divergence time estimates based on secondary calibration points.
      As a case study, we examine recent estimates of divergence times among phyla and
      kingdoms based on multiple nuclear protein-coding genes, and show that they fail
      the consistency test.

PMID- 12468087
TI  - Structure, function and DNA composition of Saccharomyces cerevisiae chromatin
      loops.
AB  - Recent localization of cohesin association regions along the yeast chromatin
      fibre suggests that compositional variability of DNA in yeast is related to the
      function and organization of the chromosomal loops. The bases of the loops, where
      the chromatin fibre is attached to the chromosomal axis, are AT-rich, bind
      cohesin, and are flanked by genes transcribed convergently. The hotspots of
      meiotic recombination are mainly found in the GC-rich parts of the loops,
      'external' with respect to the chromosomal axis, frequently in the vicinity of
      the promoters of divergently transcribed genes. There are two possible reasons
      why the regions of the hotspots of recombination were enriched in GC content
      during evolution. One is a biased repair of recombination intermediates, and the
      second is a selective advantage due to an increased chromatin accessibility,
      which may have the carriers of GC-enriched alleles over the carriers of AT-rich
      alleles.

PMID- 12468088
TI  - Molecular evolution of color vision in vertebrates.
AB  - Visual systems of vertebrates exhibit a striking level of diversity, reflecting
      their adaptive responses to various color environments. The photosensitive
      molecules, visual pigments, can be synthesized in vitro and their absorption
      spectra can be determined. Comparing the amino acid sequences and absorption
      spectra of various visual pigments, we can identify amino acid changes that have
      modified the absorption spectra of visual pigments. These hypotheses can then be
      tested using the in vitro assay. This approach has been a powerful tool in
      elucidating not only the molecular bases of color vision, but the processes of
      adaptive evolution at the molecular level.

PMID- 12468089
TI  - Comprehensive sequence analysis of translation termination sites in various
      eukaryotes.
AB  - Recent investigations into the translation termination sites of various organisms
      have revealed that not only stop codons but also sequences around stop codons
      have an effect on translation termination. To investigate the relationship
      between these sequence patterns and translation as well as its termination
      efficiency, we analysed the correlation between strength of consensus and
      translation efficiency, as predicted according to Codon Adaptation Index (CAI)
      value. We used RIKEN full-length mouse cDNA sequences and ten other eukaryotic
      UniGene datasets from NCBI for the analyses. First, we conducted sequence profile
      analyses following translation termination sites. We found base G and A at
      position +1 as a strong consensus for mouse cDNA. A similar consensus was found
      for other mammals, such as Homo sapiens, Rattus norvegicus and Bos taurus.
      However, some plants had different consensus sequences. We then analysed the
      correlation between the strength of consensus at each position and the codon
      biases of whole coding regions, using information content and CAI value. The
      results showed that in mouse cDNA, CAI value had a positive correlation with
      information content at positions +1. We also found that, for positions with
      strong consensus, the strength of the consensus is likely to have a positive
      correlation with CAI value in some other eukaryotes. Along with these
      observations, biological insights into the relationship between gene expression
      level, codon biases and consensus sequence around stop codons will be discussed.

PMID- 12468090
TI  - On biased distribution of introns in various eukaryotes.
AB  - We conducted comprehensive analyses on intron positions in the Mus musculus
      genome by comparing genomic sequences in the GenBank database and cDNA sequences
      in the mouse cDNA library recently developed by Riken Genomic Sciences Center.
      Our results confirm that introns have a tendency to be located toward the 5' end
      of the gene. The same type of analysis was conducted in the coding region of
      seven eukaryotes (Saccharomyces cerevisiae, Plasmodium falciparum, Caenorhabditis
      elegans, Drosophila melanogaster, M. musculus, Homo sapiens, Arabidopsis
      thaliana). Introns in genes with a single intron have a locational bias toward
      the 5' end in all species except A. thaliana. We also measured the distance from
      the start codon to the position of the intron, and found that single introns
      prefer the location immediately after the start codon in S. cerevisiae and P.
      falciparum. We discuss three possible explanations for these findings: (1) they
      are the consequence of intron loss by reverse-transcriptase; (2) they are
      necessary to accommodate the function; and (3) they are concerned with the
      mechanism of pre-mRNA splicing.

PMID- 12468091
TI  - A simple and species-independent coding measure.
AB  - We present a coding measure which is based on the statistical properties of the
      stop codons, and that is able to estimate accurately the variation of coding
      content along an anonymous sequence. As the stop codons play the same role in all
      the genomes (with very few exceptions) the measure turns out to be species
      independent. We show results both for prokaryotic and for eukaryotic genomes,
      indicating, first, the accuracy of the measure, and, second, that better
      prediction is achieved if the measure is applied on homogeneous, isochore-like
      sequences than if it is applied following the standard moving window approach.
      Finally, we discuss on some of the possible applications of the measure.

PMID- 12468092
TI  - Study of statistical correlations in DNA sequences.
AB  - Here we present a study of statistical correlations among different positions in
      DNA sequences and their implications by directly using the autocorrelation
      function. Such an analysis is possible now because of the availability of large
      sequences or even complete genomes of many organisms. After describing the way in
      which the autocorrelation function can be applied to DNA-sequence analysis, we
      show that long-range correlations, implying scale independence, appear in several
      bacterial genomes as well as in long human chromosome contigs. The source for
      such correlations in bacteria, which may extend up to 60 kb in Bacillus subtilis,
      may be related to massive lateral transfer of compositionally biased genes from
      other genomes. In the human genome, correlations extend for more than five
      decades and may be related to the evolution of the 'neogenome', a modern
      evolutionary acquisition composed by GC-rich isochores displaying long-range
      correlations and scale invariance.

PMID- 12468093
TI  - Isochore chromosome maps of the human genome.
AB  - The human genome is a mosaic of isochores, which are long DNA segments (z.Gt;300
      kbp) relatively homogeneous in G+C. Human isochores were first identified by
      density-gradient ultracentrifugation of bulk DNA, and differ in important
      features, e.g. genes are found predominantly in the GC-richest isochores. Here,
      we use a reliable segmentation method to partition the longest contigs in the
      human genome draft sequence into long homogeneous genome regions (LHGRs), thereby
      revealing the isochore structure of the human genome. The advantages of the
      isochore maps presented here are: (1) sequence heterogeneities at different
      scales are shown in the same plot; (2) pair-wise compositional differences
      between adjacent regions are all statistically significant; (3) isochore
      boundaries are accurately defined to single base pair resolution; and (4) both
      gradual and abrupt isochore boundaries are simultaneously revealed. Taking
      advantage of the wide sample of genome sequence analyzed, we investigate the
      correspondence between LHGRs and true human isochores revealed through DNA
      centrifugation. LHGRs show many of the typical isochore features, mainly size
      distribution, G+C range, and proportions of the isochore classes. The relative
      density of genes, Alu and long interspersed nuclear element repeats and the
      different types of single nucleotide polymorphisms on LHGRs also coincide with
      expectations in true isochores. Potential applications of isochore maps range
      from the improvement of gene-finding algorithms to the prediction of linkage
      disequilibrium levels in association studies between marker genes and complex
      traits. The coordinates for the LHGRs identified in all the contigs longer than 2
      Mb in the human genome sequence are available at the online resource on isochore
      mapping: http://bioinfo2.ugr.es/isochores.

PMID- 12468094
TI  - Are isochore sequences homogeneous?
AB  - Three statistical/mathematical analyses are carried out on isochore sequences:
      spectral analysis, analysis of variance, and segmentation analysis. Spectral
      analysis shows that there are GC content fluctuations at different length scales
      in isochore sequences. The analysis of variance shows that the null hypothesis
      (the mean value of a group of GC contents remains the same along the sequence)
      may or may not be rejected for an isochore sequence, depending on the subwindow
      sizes at which GC contents are sampled, and the window size within which group
      members are defined. The segmentation analysis shows that there are stronger
      indications of GC content changes at isochore borders than within an isochore.
      These analyses support the notion of isochore sequences, but reject the
      assumption that isochore sequences are homogeneous at the base level. An isochore
      sequence may pass a homogeneity test when GC content fluctuations at smaller
      length scales are ignored or averaged out.

PMID- 12468095
TI  - Wide intra-genomic G+C heterogeneity in human and chicken is mainly due to strand
      symmetric directional mutation pressures: dGTP-oxidation and symmetric cytosine
      deamination hypotheses.
AB  - The intra-strand Parity Rule 2 of DNA (PR2) states that A=T and G=C within each
      strands. Useful corollaries of PR2 are G/(G+C)=A/(A+T)=0.5, G/(G+A)=C/(C+T)=G+C,
      G/(G+T)=C/(C+A)=G+C. Here. A, T, G, and C represent relative contents of the four
      nucleotide residues in a specific strand of DNA, so that A+T+G+C=1. Thus,
      deviations from the PR2 is a sign of strand-specific (or asymmetric) mutation
      and/or selection pressures. The present study delineates the symmetric and
      asymmetric effects of mutations on the intra-genomic heterogeneity of the G+C
      content in the human genome. The results of this study on the human genome are:
      (1) When both two- and four-codon amino acids were combined, only slight
      departures from the PR2 were observed in the total ranges of G+C content of the
      third-codon position. Thus, the G+C heterogeneity is likely to be caused by
      symmetric mutagenesis between the two strands. (2) The above result makes the
      deamination of cytosine due to double-strand breathing of DNA [Mol. Biol. Evol.
      17 (2000) 1371] and/or incorporation of the oxidized guanine (8-oxo-guanine)
      opposite adenine during DNA replication (dGTP-oxidation hypothesis) as the most
      likely candidates for the major cause of the diversities of the G+C content. (3)
      Patterns of amino acid-specific PR2-biases detected by plotting PR2 corollaries
      against the G+C content of third codon position revealed that eight four-codon
      amino acids can be divided into three types by the second codon letter: (a) C(2)
      type (Ala, Pro, Ser4, and Thr), (b) G(2)-type (Arg4 and Gly), and (c) T(2)-type
      (Leu4 and Val). (4) Most of the asymmetric plot patterns of the above three
      classes in PR2 biases can be explained by C(2)-->T(2) deamination of C(2)pG(3) of
      C(2)-type to T(2)pG(3) (T(2)-type) in both human and chicken. This explains the
      existence of some preferred codons in human and chicken. However, these biases
      (asymmetric) hardly contribute to the overall G+C content diversity of the third
      codon position.

PMID- 12468096
TI  - Expression patterns and gene distribution in the human genome.
AB  - Genes are non-uniformly distributed in the human genome, reaching the highest
      concentration in GC-rich isochores. This is one of the fundamental aspects of the
      human genome organization (Gene 241/259 (2000a,b) 3/31, for a review). In the
      present paper the gene distribution was analyzed in relationship to the gene
      expression pattern and levels. In this study evidence is produced showing: (i)
      that a biased gene distribution towards GC-rich isochores applies to both tissue
      specific and housekeeping genes; and (ii) that genes localized in GC-rich
      isochores have high transcriptional levels. Since gene density and
      transcriptional levels are correlated with each other and both are correlated
      with the GC content of the isochores, the biased gene distribution in the human
      genome presumably is the result of selection at the gene expression levels.

PMID- 12468097
TI  - Isochores, GC3 and mutation biases in the human genome.
AB  - In this work we re-examined the hypothesis that the variation in GC content in
      the human genome is due to different regional mutational biases. For this purpose
      we inferred the mutational pattern by using mutation databases that are available
      for many genes associated with human genetic diseases. The assumption of this
      approach is that such mutations reflect the actual frequency distribution of
      mutations as they arise in the population. Four classes of genes, classified
      according to their GC(3) level, were included in this study: GC(3)-poor genes
      (GC(3)<45%), genes with intermediate GC(3) content (45%<GC(3)<60%), GC(3)-rich
      genes (60%<GC(3)<75%) and very GC(3)-rich genes (GC(3)>75%). Our results show
      that most genes are under AT mutational biases, with very little variation
      compared to the expectations of neutral GC level. It is noteworthy that the
      mutational patterns in the GC(3)-rich genes do not appear to account for their
      GC(3)-richness. Instead, GC(3)-rich and very GC(3)-rich genes exhibit patterns of
      mutations that yield expectations of neutral GC(3) content that are much lower
      than their actual GC(3).

PMID- 12468098
TI  - Localization of the gene-richest and the gene-poorest isochores in the interphase
      nuclei of mammals and birds.
AB  - At a resolution of 850 bands, human chromosomes comprise two subsets of bands,
      the GC-richest H3(+) and the GC-poorest L1(+) bands, accounting for about 17 and
      26%, respectively, of all bands. The former are a subset of the R bands and the
      latter are a subset of the G bands. These bands showed the highest and the lowest
      gene densities, respectively, as well as a number of other distinct features.
      Here we report that human and chicken interphase nuclei are characterized by the
      following features. (1) The gene-richest/GC-richest chromosomal regions are
      predominantly distributed in internal locations, whereas the gene-poorest/GC
      poorest DNA regions are close to the nuclear envelope. (2) The interphase
      chromosomes seem to be characterized by a polar arrangement, because the gene
      richest/GC-richest bands and the gene-poorest/GC-poorest bands are predominantly
      located in the distal and proximal regions, respectively, of chromosomes, and
      because interphase chromosomes are extremely long. While this polar arrangement
      is evident in the larger chromosomes, it is not displayed by the chicken
      microchromosomes and by some small human chromosomes, namely by chromosomes that
      are almost only composed by GC-rich or by GC-poor DNA. (3) The gene-richest
      chromosomal regions display a much more spread-out conformation compared to the
      gene-poorest regions in human nuclei. This finding has interesting implications
      for the formation of GC-rich isochores of warm-blooded vertebrates.

PMID- 12468099
TI  - The base composition of the genes is correlated with the secondary structures of
      the encoded proteins.
AB  - The analysis of a non-redundant set of human proteins, for which both the
      crystallographic structures and the corresponding gene sequences are available,
      show that bases at third codon position are non-uniformly distributed along the
      coding sequences. Significant compositional differences are found by comparing
      the gene regions corresponding to the different secondary structures of the
      proteins. Inter-and intra-structure differences were most pronounced in the GC
      richest genes. These results are not compatible with any proposed hypotheses
      based on a neutral process of formation/maintenance of the high GC(3) levels of
      the genes localized in the GC-richest isochores of the human genome.

PMID- 12468101
TI  - Molecular strategies in Metazoan genomic evolution.
AB  - During the evolution of Metazoa, the mitochondrial genome has remained
      practically unchanged as indicated by its small size and constant gene content in
      each lineage, although several evolutionary processes have taken place. In
      contrast, the nuclear genome of Metazoa has undergone dramatic changes, as is
      demonstrated by some entire genomes completely sequenced so far. The expansion of
      gene families and the appearance of new functions and new regulatory circuits are
      among the most prominent features. Here, we report a description of the evolution
      of the p53 gene family as an example of expansion of both genetic complexity and
      gene expression of the nuclear genome.

PMID- 12468100
TI  - Length distribution of long interspersed nucleotide elements (LINEs) and
      processed pseudogenes of human endogenous retroviruses: implications for
      retrotransposition and pseudogene detection.
AB  - Deciphering the human genome includes reliable identification and structural
      characterization of individual retrotransposon elements. The most active group of
      autonomous transposable elements, the long interspersed nuclear elements (LINE),
      transpose themselves as well as other RNAs, including those of human endogenous
      retroviruses (HERV). During this transposition, however, the LINE-encoded reverse
      transcriptase (RT) often abortively dissociates from the RNA template, leaving a
      prematurely terminated, 5' truncated copy. We have analyzed the length
      distributions of LINEs and of processed pseudogenes derived from HERV-W. As
      expected, we have found that the majority of 5' truncated LINEs and HERV-W
      processed pseudogenes show a prevalence of very short elements terminated close
      to the 3' end. On the other hand, the number of complete elements is far above
      the expectation. The characteristic distribution in both cases indicates two
      important conclusions: (i) dissociation of LINE RT from the template cannot be
      fully explained by low processivity of RT modelled as a stochastic, Poisson-type
      process. (ii) Currently cited numbers of pseudogenes within the human genome are
      underestimated, since a large percentage of pseudogenes are terminated in the 3'
      untranslated region and remain undetectable in translated homology searches of
      protein databases against the human genome.

PMID- 12468102
TI  - Periodicity in prokaryotic and eukaryotic genomes identified by power spectrum
      analysis.
AB  - We used a power spectrum method to identify periodic patterns in nucleotide
      sequence, and characterized nucleotide sequences that confer periodicities to
      prokaryotic and eukaryotic genomes and genomes. A 10-bp periodicity was prevalent
      in hyperthermophilic bacteria and archaebacteria, and an 11-bp periodicity was
      prevalent in eubacteria. The 10-bp periodicity was also prevalent in the
      eukaryotes such as the worm Caenorhabditis elegans. Additionally, in the worm
      genome, a 68-bp periodicity in chromosome I, a 59-bp periodicity in chromosome
      II, and a 94-bp periodicity in chromosome III were found. In human chromosomes 21
      and 22, approximately 167- or 84-bp periodicity was detected along the entire
      length of these chromosomes. Because the 167-bp is identical to the length of DNA
      that forms two complete helical turns in nucleosome organization, we speculated
      that the respective sequences may correspond to arrays of a special compact form
      of nucleosomes clustered in specific regions of the human chromosomes. This
      periodic element contained a high frequency of TGG. TGG-rich sequences are known
      to form a specific subset of folded DNA structures, and therefore, the sequences
      might have potential to form specific higher order structures related to the
      clustered occurrence of a specific form of the speculated nucleosomes.

PMID- 12468103
TI  - Presenilins in the heart: presenilin-2 expression is increased by low glucose and
      by hypoxia in cardiac cells.
AB  - Cardiac cells are subjected to hypoxia in many cardiovascular diseases. We
      studied a broad spectrum of genes using a macroarrays-based method to analyze RNA
      of rat cardiac fetal cell line H9c2 after 4 h of hypoxic conditions in the
      incubator-1% oxygen concentration, as compared to normoxic conditions (21%
      oxygen). The cDNAs were prepared from total RNAs using Atlas Rat 1.2 Array
      (Clontech Laboratories) and hybridized to the membrane containing 1176 rat cDNAs
      and 9 housekeeping control cDNAs. Genes expression was analyzed using AtlasImage
      1.01 software. We found over 45 genes up-regulated in a range of 1.5-2.9 times
      and 9 genes down-regulated to a range of 0.4-0.7 times, under hypoxia versus
      normoxia. Presenilin-2 (PS2) was detected in the cultured heart cells. RT-PCR
      confirmed the presence of PS2 in the heart of adult rats. Using quantitative real
      time RT-PCR, we further studied the expression of presenilin-2 mRNA under
      conditions of low oxygen supply and glucose starvation. Glucose deprivation
      itself caused significant up-regulation of the presenilin-2 (to 160%) and with
      low oxygen increased presenilin-2 level to over 200% of the control. Presenilin-2
      has previously been associated with intercellular signaling in the central
      nervous system, in Alzheimer's disease. The finding of presenilin-2 in the heart
      and the responsiveness to low glucose and hypoxia suggests that PS2 may be
      regulated by conditions of ischemia, a condition which both the heart and brain
      may experience.

PMID- 12468104
TI  - Expression and distribution of pituitary adenylate cyclase-activating peptide in
      human prostate and prostate cancer tissues.
AB  - The presence, expression and distribution of pituitary adenylate cyclase
      activating peptide (PACAP) in human prostate cancer and healthy tissue were
      investigated by means of biochemical and morphological procedures. Reverse
      transcription-polymerase chain reaction (RT-PCR) analysis demonstrated the
      presence of its precursor encoding mRNA in both normal and pathological
      conditions (amplification products with 577 or 226 bp were identified).
      Immunochemistry using an appropriate antibody served to detect in both classes of
      tissues a 19.9-kDa product corresponding to the PACAP preproprotein and another
      protein of 14.6 kDa that may represent a product partially processed by
      convertases. However, a 5-kDa band characteristic of PACAP-38 peptide was not
      observed. Immunohistochemistry on tissue sections indicated the location of PACAP
      in the epithelial layer of prostate glands (and in some scarce leucocytes) but
      not in the stroma, either in normal or carcinomatous tissues. No clear
      differences could be established when comparing samples from patients with
      different tumor Gleason grades. These results are the first demonstration of the
      localization of PACAP or its precursors and its mRNA in the human prostate gland
      and their presence during the progression of prostate carcinoma.

PMID- 12468105
TI  - Inhibitory effect of galanin on dopamine-induced enhanced vasopressin secretion
      in rat neurohypophyseal tissue cultures.
AB  - The effect of galanin (GAL) on vasopressin (VP) secretion was studied in 13-14
      day cultures of isolated rat neurohypophyseal (NH) tissue. The VP content of the
      supernatant was determined by radioimmunoassay (RIA) after a 1- or 2-h
      incubation. A significantly decreased content of VP was detected following the
      administration of 10(-6)-10(-9) M doses of GAL. Dopamine (DA) and the DA-active
      drugs apomorphine (APM) and Pro-Lys-Gly (PLG) (10(-6) M in each medium) increased
      the VP level of NH tissue cultures. This VP concentration elevation could be
      blocked by the administration of GAL together with DA, APM or PLG. The DA
      blocking effect of GAL was prevented by previous treatment with the GAL receptor
      antagonist galantid (M15). The results indicate that VP release is directly
      influenced by the GAL-ergic system. The GAL-ergic control of VP secretion from NH
      tissue in rats can occur independently of the hypothalamus, at the level of the
      posterior pituitary.

PMID- 12468106
TI  - The predominant role of brain angiotensinogen and angiotensin in environmentally
      induced hypertension.
AB  - Rats exposed chronically to a cold environment (5 degrees C/4 degrees F) develop
      hypertension. This cold-induced hypertension (CIH) is a non-genetic, non
      pharmacological, non-surgical model of environmentally induced hypertension in
      rats. The renin-angiotensin system (RAS) appears to play a role in both
      initiating and/or maintaining the high blood pressure in CIH. The goal of the
      present study was to evaluate the role of central and peripheral circulating RAS
      components, angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and
      angiotensin (Ang) II, in CIH. Seventy-two Sprague-Dawley adult male rats were
      used. Thirty-six rats were kept in cold room at 5 degrees C while the other 36
      were at 24 degrees C as controls for 5 weeks. Systolic blood pressure (SBP) was
      recorded by tail cuff. The SBP was increased in rats exposed to cold within 1
      week, and this increase was significant for the next 2-5 weeks of the cold
      exposure (p<0.01). Three subgroups of the cold-treated and control rats (n=12)
      were sacrificed at 1, 3 and 5 weeks. The brain and liver were removed and plasma
      was saved. The AGT mRNA significantly increased in the hypothalamus and liver in
      cold-treated rats from the first week of exposure to cold, and was maintained
      throughout the time of exposure to cold (n=4, p<0.01). The AGT protein levels in
      the brain, liver and plasma did not differ significantly between cold-treated and
      control rats (p>0.05, n=4). The hypothalamic Ang II levels were significantly
      increased, whereas plasma Ang II levels significantly decreased, in the rats of 5
      weeks of cold exposure (n=8, p<0.05). Plasma ACE significantly increased in the
      rats of 1 week of cold exposure (p<0.05, n=12). The results show differential
      regulation of RAS components, AGT, ACE and Ang II, between brain and periphery in
      cold-exposed rats. We conclude that the exposure to low temperature initially
      increases plasma RAS but with continuous exposure to cold, the brain RAS
      maintains the hypertension, probably by sustained sympathetic activation, which
      would provide increased metabolism but also vasoconstriction leading to
      hypertension.

PMID- 12468107
TI  - Plasma levels and cardiovascular gene expression of urotensin-II in human heart
      failure.
AB  - The peptide urotensin-II (U-II) has been described as most potent vasoconstrictor
      identified so far, but plasma values in humans and its role in cardiovascular
      pathophysiology are unknown. We investigated circulating urotensin-II and its
      potential role in human congestive heart failure (CHF). We enrolled control
      individuals (n=13; cardiac index [CI], 3.5+/-0.1 l/min/m2; pulmonary wedge
      pressure [PCWP], 10+/-1 mm Hg), patients with moderate (n=10; CI, 2.9+/-0.3
      l/min/m2; PCWP, 14+/-2 mm Hg) and severe CHF (n=11; CI, 1.8+/-0.2 l/min/m2; PCWP,
      33+/-2 mm Hg). Plasma levels of urotensin-II differed neither between controls,
      patients with moderate and severe CHF nor between different sites of measurement
      (pulmonary artery, left ventricle, coronary sinus, antecubital vein) within the
      single groups. Hemodynamic improvement by vasodilator therapy in severe CHF (CI,
      +78+/-3%; PCWP, -55+/-3%) did not affect circulating U-II over 24 h.
      Preprourotensin-II mRNA expression in right atria, left ventricles, mammary
      arteries and saphenous veins did not differ between controls with normal heart
      function and patients with end-stage CHF. In conclusion, urotensin-II plasma
      levels and its myocardial and vascular gene expression are unchanged in human
      CHF. Circulating urotensin-II does not respond to acute hemodynamic improvement.
      These findings suggest that urotensin-II does not play a major role in human CHF.

PMID- 12468108
TI  - The effects of duodenal peptides on glucagon-like peptide-1 secretion from the
      ileum. A duodeno--ileal loop?
AB  - Secretion of the gut hormone glucagon-like peptide-1 (GLP-1) is stimulated by
      meal ingestion. The response is rapid, suggesting a stimulatory pathway elicited
      from the upper gastrointestinal area. In pigs, we have been unable to demonstrate
      a neural stimulatory pathway, but GLP-1 secretion is regulated by local
      somatostatin secretion. In search for an endocrine pathway, we studied the effect
      of a range of concentrations of cholecystokinin octapeptide (26-33) (CCK 8),
      gastric inhibitory peptide 1-42 (GIP), secretin, motilin, calcitonin gene-related
      peptide (CGRP), and the modified amino acid, 5-hydroxytryptamine (serotonin, 5
      HT) on GLP-1 and somatostatin release from isolated perfused segments of porcine
      ileum.GLP-1 secretion was stimulated by 1 nM CCK 8 and 10 nM GIP, but suppressed
      by 1 nM motilin and 1 microM 5-HT. Secretin and CGRP had no effect. Somatostatin
      secretion was stimulated by CCK 8 at 1 and 10 nM, by GIP at 1 and 10 nM and by 10
      nM CGRP. Secretin, 5-HT and motilin had no effect on somatostatin secretion. We
      conclude that CCK 8 and GIP 1-42 stimulated GLP-1 secretion, but only in
      concentrations greatly exceeding normal postprandial concentrations. Thus, we
      find it unlikely that endocrine agents from the duodenum regulate GLP-1 secretion
      in pigs.

PMID- 12468109
TI  - Cardiac function in neuropeptide Y Y4 receptor-knockout mice.
AB  - Autonomic control of cardiovascular function in neuropeptide Y (NPY) Y4 receptor
      knockout mice was investigated using pancreatic polypeptide (PP), NPY and
      specific agonists and antagonists for other NPY receptors well characterised in
      cardiovascular function. Y4 receptor-knockout mice, anaesthetised with sodium
      pentobarbitone, displayed slower heart rate, indicated by a higher pulse interval
      and lower blood pressure compared to control mice. After vagus nerves were cut
      heart rate increased but was still significantly slower than in control mice. PP
      had no effect on blood pressure or cardiac vagal activity in either group of
      mice, which was consistent with earlier studies in other species. Injection of
      NPY evoked an increase in blood pressure but the response was significantly
      reduced in Y4 receptor-knockout mice compared to the controls. The reduction in
      pressor activity was not Y1 mediated as the selective Y1 antagonist, BIBP 3226,
      was effective in blocking NPY pressor activity in knockout mice. In addition,
      cardiac vagal inhibitory activity evoked by low doses of NPY was also reduced
      when compared to control responses. As N-acetyl [Leu(28, 31)] NPY 24-36 inhibited
      vagal activity dose dependently in both groups of mice with no difference in
      response at any dose, it is unlikely that this effect also is receptor mediated.
      We propose that the reduced vasoconstrictor and vagal inhibitory activity evoked
      by NPY in Y4 receptor-knockout mice is due to a lack of adrenergic tone bought
      about by a proposed reduction in sympathetic activity, possibly resulting from
      altered NPY activity secondarily affecting adrenergic transmission. We conclude
      that Y4 receptor deletion disrupts autonomic balance within the cardiovascular
      system.

PMID- 12468110
TI  - Persistent decreased plasma cholecystokinin levels in celiac patients under
      gluten-free diet: respective roles of histological changes and nutrient
      hydrolysis.
AB  - Celiac disease is associated with impaired cholecystokinin (CCK) release. The
      mechanism by which CCK release is impaired is poorly understood and seems to be
      related to the mucosal atrophy or to decreased stimulation due to reduced
      intraduodenal nutrient hydrolysis. The aims of our study were to evaluate basal
      and postprandial CCK in celiac patients presenting with distinctive types of
      mucosal lesions (normal, infiltrative and atrophic), and to study the role of
      protein hydrolysis on CCK release. Plasma CCK was measured in 20 celiac patients
      (normal mucosa: n=6; infiltrative type: n=6; atrophic type=8) and 9 controls,
      before and after ingestion of a polymeric or a semi-elemental meal. Significant
      decreases in basal CCK plasma (B 0.6 [95% CI, 0.3-1.3] pmol/l; p<0.003) and
      postprandial CCK area under curve (AUC 34 [19-61] pmol/l x 120 min, p<0.0001)
      were observed in patients with an atrophic mucosa compared with treated patients
      (B 1.6 [1.0-2.4] pmol/l, AUC 267 [172-414] pmol/l x 120 min) or healthy
      volunteers (B 1.0 [0.7-1.4] pmol/l, AUC 186 [131-264] pmol/l x 120 min). A
      significant defective CCK release was also observed in patients with an
      infiltrative type: B 0.4 [0.2-0.7] pmol/l and AUC 56 [31-101] pmol/l x 120 min;
      p<0.0001. Administration of a semi-elemental diet did not correct the defective
      CCK release. In conclusion, the decreased CCK levels observed in celiac patients
      are not strictly related to the mucosal atrophy but rather to the lymphocytic
      infiltrate. Administration of a predigested meal did not correct the impaired CCK
      release. Some inhibitory mechanism could be involved in the CCK cell dysfunction
      observed in celiac patients presenting with lesser degrees of disease activity.

PMID- 12468111
TI  - The neuropeptide secretoneurin stimulates adhesion of human monocytes to arterial
      and venous endothelial cells in vitro.
AB  - Monocytes appear to play a central role in inflammatory processes like
      atherogenesis or lung inflammation both as the progenitors of foam cells and as a
      potential source of factors mediating further inflammatory processes. However,
      signals mediating the influx of monocytes into the inflammatory focus remain
      partly unknown. Secretoneurin (SN) is a more recently characterised 33-amino acid
      neuropeptide that is co-released from afferent nerve endings together with
      substance P (SP) and calcitonin gene-related peptide (CGRP). Furthermore, SN has
      been shown to affect human fibroblast, endothelial, smooth muscle, eosinophil and
      monocyte functions in vitro. An activity of SN on monocyte adhesion to the
      vascular wall has not yet been reported. The aim of this study was to investigate
      whether the adhesion properties of human monocytes (U937 and Mono Mac-6) to
      endothelial cells could be influenced by SN. In an in vitro model of the vascular
      wall, incubation of arterial (rat aortic endothelial cells) and venous
      endothelial cells (immortalised human umbilical vein endothelial line: EA.hy 926)
      with SN resulted in a time- and concentration-dependent increase in monocyte
      adhesion with a maximal effect seen after 4-6 h at a concentration of 10(-8) M
      SN. Increased monocyte adhesion seems not to be tissue-specific as SN-induced
      adhesion was observed on both arterial and venous endothelial cells. A specific
      antibody preparation against SN completely abolished increased monocyte adhesion
      toward SN-stimulated endothelium. Since adhesion was enhanced to a similar degree
      and with similar time kinetics as responses evoked by interleukin-1 (IL-1, 1
      ng/ml) or lipopolysaccharide (LPS, 100 ng/ml), involvement of identical adhesion
      molecules can be suggested. Our observations provide substantial evidence that in
      inflammatory processes, SN might play a role in recruitment of monocytes to
      inflamed tissue.

PMID- 12468112
TI  - Localization of mu-opioid receptor 1A on sensory nerve fibers in human skin.
AB  - Opioid peptides are endogenous neuromodulators that play a major role in the
      nociceptive pathway by interacting with opioid receptors. So far, four opioid
      receptors (micro-, delta-, kappa-, orphan-receptor) have been cloned with a wide
      distribution in the central and peripheral nervous system. In the present study,
      we give first evidence for the presence of the micro-opioid receptor (MOR)
      isoform 1A in nerve fibers of human skin. Immunohistochemical analysis revealed
      MOR immunoreactivity to be present in dermal and epidermal nerve fibers. Double
      immunofluorescence staining revealed that MOR is present on calcitonin gene
      related protein (CGRP)-positive sensory nerve fibers, while autonomic nerves of
      blood vessels, hair follicles, or skin glands were negative. In diseased skin
      such as psoriasis vulgaris, atopic dermatitis, and prurigo nodularis,
      distribution of MOR 1A immunoreactivity was similar to that of normal skin. These
      findings expand our knowledge about a direct regulatory role of cutaneous opioid
      receptors in the skin. Thus, peripheral cutaneous opioid receptors may be
      involved in the transmission of pain and pruritus, respectively. This is
      supported by previous observation that opioid receptor antagonists may
      significantly diminish experimentally evoked histamine-induced itch of the skin.
      Together, our findings contribute to the understanding of the high antipruritic
      potency of opioid receptor antagonists in various skin and systemic diseases.

PMID- 12468113
TI  - Growth hormone-releasing hormone facilitates hypoglycemia-induced release of
      cortisol.
AB  - Early sleep in humans is characterized by a distinct suppression of pituitary
      adrenal activity coinciding with enhanced activity of the somatotropic axis.
      Here, we tested in awake humans the hypothesis of an inhibiting influence of
      hypothalamic growth hormone-releasing hormone (GHRH) on pituitary-adrenal
      activity. For this purpose, pituitary-adrenal activity was stimulated in 10 men
      through a standard insulin-hypoglycemia-test (IHT) and in another 10 men through
      combined administration of CRH/vasopressin. Stimulation was performed in each man
      on three conditions following pretreatment with Placebo and GHRH administered
      intravenously (50 microg) or intranasally (300 microg) 1 h before. GH, ACTH and
      cortisol as well as blood pressure and heart rate were measured repeatedly.
      Contrary to expectations, pretreatment with GHRH did not suppress but enhanced
      secretion of cortisol upon insulin-induced hypoglycemia regardless of the route
      of GHRH pretreatment (p<0.05). In contrast, GHRH did not facilitate cortisol
      release after stimulation with CRH/vasopressin. Changes in ACTH remained
      inconsistent. Plasma levels of GH increased significantly after i.v. GHRH
      application, but remained unchanged after the intranasal administration. Blood
      pressure and heart rate were not influenced by the treatments. Results indicate
      facilitating effects of GHRH mediated at a suprapituitary (i.e. hypothalamic)
      level as suggested by restriction of the effect to the hypoglycemia-induced
      cortisol release with no effects after pituitary stimulation with
      CRH/vasopressin.

PMID- 12468114
TI  - The use of 'arms-length' organizations for health system change in Ontario,
      Canada: some observations by insiders.
AB  - During the past decade, there has been substantial health system reform in the
      United States, United Kingdom, New Zealand, and many other countries. For the
      most part, Canada has not pursued 'big bang' health system change but rather a
      variety of strategies to achieve incremental change. In this paper, we present
      the ways in which three arms-length organizations have been used by government to
      effect incremental system change in Ontario during the past several years. We
      observe that, (1) the influence of politics and political interference can be
      reduced through an arms-length organization; (2) an arms-length organization with
      the power to make decisions entails more political risk for government and
      encounters more scrutiny and criticism by providers and the media than an
      organization with the power to recommend only; (3) an arms-length organization
      with a limited lifespan faces more delaying tactics by adversely affected parties
      than an organization without a limited lifespan; (4) an arms-length organization
      with perceived influence may attract causes that are not related to its mandate;
      (5) the importance and difficulty of communicating complex information about
      system change to a wide variety of audiences cannot be overstated; (6) system
      change informed by the use of expert opinion encounters less provider resistance
      and may result in better decisions; and (7) the reputation of the Chair and the
      perceived competence and experience of the CEO are critical success factors in
      the success of an arms-length organization.

PMID- 12468115
TI  - The economic impact of malaria in Africa: a critical review of the evidence.
AB  - Information on the economic burden of malaria in Africa is needed to target
      interventions efficiently and equitably, and to justify investment in research
      and control. A standard method of estimation has been to sum the direct costs of
      expenditure on prevention and treatment, and the indirect costs of productive
      labour time lost. This paper discusses the many problems in using such data to
      reflect the burden to society or the potential benefits from control. Studies
      have generally focussed on febrile illness, overestimating the burden of
      uncomplicated malaria, but underestimating the costs of severe illness, other
      debilitating manifestations, and mortality. Many use weak data to calculate
      indirect costs, which fail to account for seasonal variations, the difference
      between the average and marginal product of labour, and the ways households and
      firms 'cope' in response to illness episodes. Perhaps most importantly, the costs
      of coping mechanisms in response to the risk of disease are excluded, although
      they may significantly affect productive strategies and economic growth. Future
      work should be rooted in a sound understanding of the health burden of malaria
      and the organisation of economic activities, and address the impact on the
      productive environment, and epidemiological and socio-economic geographical
      variation.

PMID- 12468116
TI  - The reliability and validity of willingness to pay surveys for reproductive
      health pricing decisions in developing countries.
AB  - This paper examines the reliability, theoretical and predictive validity of
      willingness to pay (WTP) surveys for setting prices for reproductive health
      services in developing countries. Four country applications were conducted; the
      surveys used similar elicitation methods (a series of three closed-ended
      questions to cover the range of target prices, followed by a single open ended
      question to elicit maximum WTP) and samples of current or potential users of
      family planning, gynecology, and prenatal care services. In all four
      applications, respondents were able to understand WTP questions and responded
      with high levels of internal consistency. Evidence supporting theoretical
      validity was also found in all surveys. Higher income and more highly motivated
      users had higher WTP than lower income and less motivated users. Predictive
      validity was assessed in one study. Services utilization predicted by a WTP
      survey was compared with actual post-price increase utilization. Adding WTP to
      information already possessed by program managers resulted in a threefold
      increase in ability to predict utilization change as a result of a price
      increase, and in nearly half of cases predicted percent change in utilization was
      within 10% of observed change. WTP surveys when used for reproductive services
      price setting appear reliable and valid, and improve a program manager's ability
      to predict client responses to price changes.

PMID- 12468117
TI  - Establishing a standard for patient-completed instrument adaptations in Eastern
      Europe: experience with the Nottingham Health Profile in Hungary.
AB  - The widely used generic patient-completed measures of health status were
      developed in the USA or the UK. Few Eastern European versions of these measures
      have been produced and these have used questionable translation methodologies.
      Clinical trials now commonly include patients from Eastern Europe and require the
      use of patient-completed instruments. The absence of such instruments led to the
      development of a Hungarian version of the Nottingham Health Profile (NHP). The
      adaptation process employed (translation, field-testing and psychometric
      assessment) also served as a test of whether the standardised rigorous
      methodology used for adapting the NHP could be applied in Eastern Europe. Few
      problems were found in producing a conceptually equivalent Hungarian NHP that was
      acceptable to interviewees. Reliability and internal consistency of the Hungarian
      NHP were comparable to other language versions. The measure also correlated as
      expected with perceived physical disability, general health, disease severity and
      rating of day. This successful adaptation confirms the value of the methodology
      applied. The Hungarian NHP will be invaluable as an outcome measure in both
      clinical and health economic trials and (in the absence of a generic quality of
      life instrument) as a comparator instrument for the validation of future
      Hungarian adaptations of disease-specific quality of life instruments.

PMID- 12468119
TI  - Financial and organisational reforms in the health sector; implications for the
      financing and management of mental health care services.
AB  - Since 1980 many developed countries have planned and implemented health sector
      reforms of different scales and ambitions. Norway has been no exception, and the
      main political aspirations have been to increase efficiency and improve consumer
      choice and responsiveness. The major financial reform was the introduction of an
      activity based financing based on diagnostic related groups (DRG). Other central
      reforms include legislative rights for patients to choose hospital of their own
      choice, and the handing over of the responsibility of hospital based care form
      the county to the state. For some of these reforms mental health care is not
      included. The aim of the study is to appraise with examples from different
      countries whether it is feasible include metal health care into the reforms and
      whether the reforms in general are conducive for mental health care policy goals.
      The problems are elaborated and discussed at the level of technically and
      politically feasibility and the costs involved.

PMID- 12468118
TI  - Is publicly funded health care really distributed according to need? The example
      of cardiac rehabilitation in the UK.
AB  - OBJECTIVES: To demonstrate the importance of measuring both the horizontal and
      vertical components of equity in order to examine whether patients are receiving
      the health care that they need. METHODS:  DESIGN: A theoretical demonstration
      followed by analysis of a prospectively collected national random sample of acute
      cardiac admissions to 94 hospitals in the UK. PATIENTS: One thousand and sixty
      four patients under 70 years old. ANALYSIS: The association between use of
      cardiac rehabilitation and gender (after adjusting for clinical need) was
      measured using multivariable analysis with effect modification. RESULTS:
      Hypertensive males were nearly twice as likely to undergo rehabilitation compared
      with hypertensive females (OR 1.76, 95%CI 1.03-3.02). Hyertensive patients were
      less likely to undergo rehabilitation than normotensive patients (OR 0.67, 95% CI
      0.50-0.89) but this treatment difference did not apply in the same way to both
      men and women. Hypertensive women were half as likely to undergo rehabilitation
      compared with normotensive women (OR 0.48, 95% CI 0.30-0.78), whereas
      hypertensive men were as likely as normotensive men to receive rehabilitation (OR
      1.00. 95%CI 0.63-1.60). CONCLUSIONS: Horizontal inequity was demonstrated because
      male and female hypertensive patients with equal needs were not treated equally.
      There was also vertical inequity because although patients with hypertension were
      treated differently to normotensive patients, this treatment difference was not
      the same for men and women.

PMID- 12468120
TI  - A model for costs of stroke services.
AB  - In industrialised countries, stroke is one of the most common causes of death and
      handicap, and the costs for stroke services are high. However, rational planning
      of stroke services and estimation of the costs of their provision are complex,
      even when generic pathways for stroke diagnosis and treatment are well
      understood. The reason is the chronic nature of cerebro-vascular disease and the
      cumulative effect of disabling brain injury. In this paper we describe
      development of a computer model for estimating the costs of stroke services,
      intended for use by planners and purchasers of stroke care services. The model
      operates by incrementing patients' experience of stroke events and their outcomes
      in annual steps, and is calibrated using Swedish data. We demonstrate the cost
      consequences by simulating three different policy changes. The model facilitates
      comparisons between stroke prevention, treatment and rehabilitation, and we
      conclude that by combining the three policy options it is possible to reduce the
      costs for stroke services markedly.

PMID- 12468121
TI  - Selective referrals in a 'hub and spoke' institutional setting: the case of
      coronary angioplasty procedures.
AB  - We analyse the highly-regulated cardiovascular sector of the health service in
      the Italian region of Emilia Romagna: this sector is characterised by strict
      regulatory control and a great emphasis on co-ordination and co-operation between
      public and private producers. These features have been even more marked since
      2000, due to the adoption of the 'hub and spoke' organisational model, whereby a
      close relationship of selective referral from the network of satellite cardiology
      units (spokes) to the six Cardiac Surgical Centres (hubs) has been developed, so
      as to concentrate high risk procedures in highly specialised units. We focus on
      coronary angioplasty procedures (PTCA) and examine relations among centres before
      and after the official introduction of this hierarchical system completed the
      regionalisation of cardiovascular services. Secondly, since earlier regional
      efforts to reconfigure cardiovascular care by sending referrals to a few major
      centres may already have produced a high level of co-ordination among units, we
      investigate what happens to the volume-effect advantage across hospital
      categories with regard to the likelihood of adverse results for PTCA. We used
      descriptive statistics and logistic regression models to assess the existence of
      selective referrals and the concentration of clinical complexity in more
      specialised centres. Figures were taken from a regional administrative database
      based on hospital discharge abstracts (SDO) for the period 1998-2000.

PMID- 12468122
TI  - Generic number systems and haplotype analysis.
AB  - Three simple and elegant algorithms involving binary and mixed-radix numbers are
      presented as C subroutines and applied to gene-counting procedure. The first, a
      multikey radix-sorting subroutine, is used to tally individuals with similar
      genetic marker information. The second, a subroutine for N-ary number addition,
      is used to enumerate all possible phases of a heterozygote. The third, a mixed
      radix number subroutine, is used to generate all haplotypes and indexing single
      array of haplotype frequencies. Examples exposing these algorithms are also
      given. The sorting algorithm entails broad application while the N-ary and mixed
      radix number algorithms are very efficient for generic looping. Implementation of
      gene-counting using these algorithms avoids use of multilocus genotype identifier
      and improves its portability to other analysis.

PMID- 12468123
TI  - Finding subtle motifs with variable gaps in unaligned DNA sequences.
AB  - Biologists have determined that the control and regulation of gene expression is
      primarily determined by relatively short sequences in the region surrounding a
      gene. These sequences vary in length, position, redundancy, orientation, and
      bases. Finding these short sequences is a fundamental problem in molecular
      biology with important applications. Though there exist many different approaches
      to signal (i.e. short sequence) finding, some new study shows that this problem
      still leaves plenty of room for improvement. In 2000, Pevzner and Sze proposed
      the Challenge Problem of motif detection. They reported that most current motif
      finding algorithms are incapable of detecting the target motifs in their
      Challenge Problem. In this paper, we show that using an iterative-restart design,
      our new algorithm can correctly find the target motifs. Furthermore, taking into
      account the fact that some transcription factors form a dimer or even more
      complex structures, and transcription process can sometimes involve multiple
      factors with variable spacers in between, we extend the original problem to an
      even more challenging one by addressing the issue of combinatorial signals with
      gaps of variable lengths. To demonstrate the effectiveness of our algorithm, we
      tested it on a series of the new challenge problem as well as real regulons, and
      compared it with some current representative motif-finding algorithms.

PMID- 12468124
TI  - Assessment of average, population and individual bioequivalence in two- and four
      period crossover studies.
AB  - The aim of bioequivalence studies is to assess the equivalence of two
      pharmaceutical formulations of the same active drug substance. Currently three
      types of bioequivalence are distinguished: average, population and individual
      bioequivalence. Average and population bioequivalence can be assessed in two
      period (non-replicated) crossover studies, whereas individual bioequivalence
      requires three- or four-period replicated studies, with a preference for four
      period studies. The PC-program BIOEQV80 is presented for the statistical analysis
      of average and population bioequivalence from two-period crossover studies. The
      program BIOEQ2X2 is presented for the statistical analysis of all three types of
      bioequivalence from four-period replicated crossover studies. The statistical
      aspects of population and individual bioequivalence are based on a recent
      Guidance issued by the US Food and Drug Administration.

PMID- 12468125
TI  - Image analysis system for assessment of immunohistochemically stained
      proliferative marker (MIB-1) in oesophageal squamous cell carcinoma.
AB  - The prognosis of oesophageal cancer patients is related to the portion of MIB-1
      positively stained tumour nuclei. In this study, an image analysis system was
      developed based on LEICA Image Processing and Analysis System to reduce the
      subjective, tedious and inaccurate manual counting of nuclei staining.
      Representative oesophageal cancer tissues were collected and immunohistochemical
      preparations of MIB-1 were made. The MIB-1 positive nuclei in these tumours were
      assessed by quantitative counting, semi-quantitative counting, and three computer
      assessment methods using LEICA QWIN PRO. Our results showed that computer
      assessment methods were reliable and consistent. The procedure using the system
      could be accomplished within 15 min. Overlapped or missed counting of nuclei by
      the observer were eliminated. The image analysis system can really assist experts
      in obtaining reliable data for the prognosis of oesophageal cancer patients
      quickly.

PMID- 12468126
TI  - TRAP: Tandem Repeat Assembly Program produces improved shotgun assemblies of
      repetitive sequences.
AB  - The software commonly used for assembly of shotgun sequence data has several
      limitations. One such limitation becomes obvious when repetitive sequences are
      encountered. Shotgun assembly is a difficult task, even for non-repetitive
      regions, but the use of quality assessments of the data and efficient matching
      algorithms have made it possible to assemble most sequences efficiently. In the
      case of highly repetitive sequences, however, these algorithms fail to
      distinguish between sequencing errors and single base differences in regions
      containing nearly identical repeats. None of the currently available fragment
      assembly programs are able to correctly assemble highly similar repetitive data,
      and we, therefore, present a novel shotgun assembly program, Tandem Repeat
      Assembly Program (TRAP). The main feature of this program is the ability to
      separate long repetitive regions from each other by distinguishing single base
      substitutions as well as insertions/deletions from sequencing errors. This is
      accomplished by using a novel multiple-alignment based analysis method. Since
      repeats are a common complication in most sequencing projects, this software
      should be of use for the whole sequencing community.

PMID- 12468127
TI  - Labview virtual instruments for calcium buffer calculations.
AB  - Labview VIs based upon the calculator programs of Fabiato and Fabiato (J.
      Physiol. Paris 75 (1979) 463) are presented. The VIs comprise the necessary
      computations for the accurate preparation of multiple-metal buffers, for the back
      calculation of buffer composition given known free metal concentrations and
      stability constants used, for the determination of free concentrations from a
      given buffer composition, and for the determination of apparent stability
      constants from absolute constants. As implemented, the VIs can concurrently
      account for up to three divalent metals, two monovalent metals and four ligands
      thereof, and the modular design of the VIs facilitates further extension of their
      capacity. As Labview VIs are inherently graphical, these VIs may serve as useful
      templates for those wishing to adapt this software to other platforms.

PMID- 12468128
TI  - A data model for managing drug therapy within a patient data management system
      for intensive care units.
AB  - The major intent of this article was to describe the design principles of the
      drug-therapy documentation module of the Patient Data Management System (PDMS)
      ICUData, in routine use at the intensive care unit (ICU) of the Department of
      Anesthesiology and Intensive Care Medicine at the University Hospital of Giessen,
      Germany, since February 1999. The new drug management system has been in routine
      use since March 2000. Until 8 January 2001, 1140 patients have been documented
      using this approach. It could be demonstrated that it was possible to transform
      the formerly unstructured text-based documentation into a detailed and structured
      model. The mediated benefit resulted in the automatic calculation of fluid
      balance. Further, detailed statistical analyses of therapeutic behavior in drug
      administration are now possible.

PMID- 12468129
TI  - The computer simulation of wear behavior appearing in total hip prosthesis.
AB  - Computer algorithms are proposed for the estimation of wear appearing in
      artificial hip joints using finite element analysis based on the modified
      Archard's wear law, contact features and an analogue wear process. A pin-on-disk
      plate experiment is reconstructed to assess the efficiency and validity of the
      algorithms proposed here. Through the successful verification of wear depth and
      volume loss of the pin-on-disk plate as well as the artificial hip joint, the
      current algorithms provide significant agreement with experiments, clinical
      measurements and numerical calculations and are shown to be both valid and
      feasible. Further investigation into the effect of femoral heads with various
      sizes suggests that the larger femoral head may induce larger wear volume but
      gives a smaller wear depth and that wear depth and volume loss are apparently
      nonlinearly related to the femoral head diameter. It is shown that the current
      algorithms are useful and helpful in understanding wear behavior for alternative
      or new designs of artificial hip joints and even for other analogous structures.

PMID- 12468130
TI  - Andropause and quality of life: findings from patient focus groups and clinical
      experts.
AB  - OBJECTIVES: To develop a condition-specific quality of life (QoL) questionnaire
      to assess the symptoms of the decline in testosterone that occurs as men age,
      otherwise known as the andropause. METHODS: Two focus groups of patients with low
      testosterone levels and an expert panel of physicians in the treatment of male
      testosterone deficiency. RESULTS: The patient focus groups confirmed that men are
      unlikely to realise they have low testosterone levels until this is diagnosed and
      that they are unlikely to share their experiences with peers. Both patients and
      physicians considered decreased energy levels and impaired sexual performance had
      the greatest adverse impact on well-being. Patients generally felt that
      testosterone replacement therapy led to improved energy levels and, to a lesser
      extent, improved libido and erectile function. Evaluation of the responses
      resulted in the identification of seven key domains (energy, emotional, social,
      social emotional, mental functioning, physical functioning and sexual
      functioning) that should be considered when assessing the impact of andropause on
      QoL. CONCLUSIONS: Understanding the impact of low testosterone levels on QoL is
      critical to diagnosis and effective treatment. The use of an andropause-specific
      QoL questionnaire will facilitate quantification of patient experiences and may
      thus improve subsequent therapy.

PMID- 12468131
TI  - Difference in the effects of body composition on bone mineral density between pre
      and postmenopausal women.
AB  - OBJECTIVE: This study was to investigate whether the effect of lean and fat mass
      component on bone mineral density (BMD) differs between pre- and postmenopausal
      women. MATERIALS AND METHODS: Subjects were 360 pre- and 193 postmenopausal
      Japanese women with right side dominance. Age, height, and years since menopause
      (YSM, in postmenopausal women) were recorded. Body fat and lean body mass were
      measured by whole body scanning with dual-energy X-ray absorptiometry (DEXA). BMD
      of the vertical axis (L2-4 of the lumbar spine, pelvis, bilateral legs, and total
      body) and horizontal axis (arms) were also measured by DEXA. RESULTS: In
      premenopausal women, lean body mass was independently correlated with BMD of the
      left arm (partial correlation coefficient = 0.417), right arm (0.430), L2-4
      (0.285), pelvis (0.276), left leg (0.403), right leg (0.412), and total body
      (0.377) (P < 0.001). However, body fat mass was not correlated with several BMD
      sites except for pelvis BMD (0.187, P < 0.01). In postmenopausal women, body fat
      mass was independently correlated with BMD of the left arm (0.248, P < 0.01), L2
      4 (0.188, P < 0.05), pelvis (0.263, P < 0.01), left leg (0.228, P < 0.01), right
      leg (0.319, P < 0.001), and total body (0.188, P < 0.01)). However, lean body
      mass was correlated with BMD in only three segmental regions including left arm
      (0.175), right arm (0.217), and left leg (0.210; P < 0.05). CONCLUSION: Lean body
      mass is a significant determinant of BMD in premenopausal women, while body fat
      mass is a significant determinant in postmenopausal women.

PMID- 12468132
TI  - Hyperparathyroidism in elderly osteopenic women.
AB  - Raised levels of parathyroid hormones (PTH) predispose to osteoporotic fracture
      particularly in the elderly. The true prevalence of primary or secondary
      hyperparathyroidism is unknown, as PTH evaluation is not performed as a screening
      test in the elderly. We report raised PTH levels in 27 of 190 (14.2%) community
      living fully mobile postmenopausal women with densitometrically established
      osteopenia, consuming an average of 645 (+/-191) mg of calcium per day. Twenty
      five of the 27 women with raised PTH were normocalcaemic, hypercalcaemia been
      found only in two. Serum 25 hydroxy vitamin D levels were all within the normal
      range (above 22 nmol/l). Women with a raised PTH were significantly older and
      their serum 25 hydroxy vitamin D levels were significantly lower than those women
      with normal PTH values. These data suggest that in community leaving healthy
      postmenopausal women, normocalcaemic hyperparathyroidism, in the presence of what
      are still considered normal vitamin D levels, may be common. This may suggests
      that widespread supplementation with calcium and vitamin D may be required in
      postmenopausal women for PTH suppression and preservation of bone mass.

PMID- 12468133
TI  - Hysteroscopic findings in postmenopausal abnormal uterine bleeding: a comparison
      between HRT users and non-users.
AB  - OBJECTIVES: The aim of our study was to investigate hysteroscopic findings in a
      sample of 410 menopausal women (hormonal replacement therapy, HRT users n = 219
      and HRT non-users n = 191) and to evaluate the relationship between the presence
      of intrauterine disease, the use of HRT and the presence of AUB. METHODS: Two
      hundred and nineteen women on HRT underwent standard office hysteroscopy by means
      of the Hamou hysteroscope (in 94 cases for abnormal uterine bleeding (AUB) and in
      125 cases for periodic endometrium monitoring). One hundred and ninety-one women
      who had never received HRT were submitted to office hysteroscopy (154 for AUB and
      37 for other reasons). RESULTS: Intrauterine diseases are more frequent in
      patients who do not use HRT (P = 0.02). Endometrial polyps is a frequent disease
      present in 30% of the sample (23.7% of HRT users and 30.8% of HRT non-users).
      Myomas were present in 8.7% of all patients examined (6.8% of HRT users and 11%
      of HRT non-users). Irregular bleeding in menopause is often associated with
      endouterine abnormalities: in symptomatic patients the frequency of endouterine
      diseases was 41% while in asymptomatic patients was 28% (P = 0.003). In patients
      taking HRT (n = 219) endouterine disease is demonstrated in 37% with AUB and in
      26% without AUB (P = 0.07). CONCLUSION: Benign intrauterine diseases (endometrial
      polyps and submucous myomas) are more frequent in postmenopausal women who do not
      use HRT. In patients taking HRT irregular bleeding is associated with
      intrauterine diseases; however, the absence of AUB does not exclude the presence
      of endometrial polyps or myomas.

PMID- 12468134
TI  - Evaluation of irritation and sensitisation of two 50 microg/day oestrogen
      patches.
AB  - OBJECTIVES: To comparatively assess the irritation and sensitisation of the
      Estradot transdermal oestrogen patch, in healthy postmenopausal women, using the
      Menorest transdermal oestrogen patch, as a comparator. METHODS: In an open-label,
      single-centre, randomised, active-treatment, within-patient controlled study, 208
      healthy postmenopausal women, age range 40-70 years, received and completed
      simultaneous treatment with a 5 cm(2) (50 microg/day) oestradiol patch (Estradot)
      and a 14.5 cm(2) (50 microg/day) oestradiol patch (Menorest). The treatment was
      given for 72 h, then 96 h, for eight successive applications during an induction
      phase, and for 72 h during a challenge phase. There was a 14-day resting period
      between phases. Skin irritation (measured by erythema on a scale of 0-4), topical
      sensitisation, patch adherence and local skin reaction, were assessed and
      recorded immediately before or after removal of each patch, as appropriate.
      RESULTS: Most patients experienced a significant difference in irritation with
      Menorest than with Estradot (P < 0.0001) at the end of the induction phase. Patch
      loss was also significantly higher for Menorest as compared to Estradot (P =
      0.0253) at the end of the induction phase. Most incidences of erythema were
      classified as slight (score of 1), and there was no significant difference in the
      percentage of topical sensitisation, or in the incidence of local skin reactions
      between Estradot and Menorest. Patch loss was low for both systems. CONCLUSIONS:
      Estradot demonstrates reduced skin irritation, superior adhesion and a lower rate
      of patch loss compared to Menorest.

PMID- 12468135
TI  - Bleeding patterns in peri and postmenopausal women taking a continuous combined
      regimen of estradiol with norethisterone acetate or a conventional sequential
      regimen of conjugated equine estrogens with medrogestone.
AB  - OBJECTIVES: The aim of this study was to compare the incidence of women
      presenting irregular bleeding episodes following 9 months of treatment with a low
      dose continuous combined hormone replacement therapy consisting of estradiol
      (E(2)) and norethisterone acetate (NETA) versus a sequential hormone replacement
      therapy consisting of conjugated equine estrogens (CEE) and medrogestone (MG).
      Secondary aims were to establish the relationship between menopausal age and the
      occurrence of irregular bleeding for both therapies and to assess the efficacy of
      both therapies in alleviating menopausal symptoms. METHODS: This was a stratified
      and randomised, open label study conducted with late peri and postmenopausal
      women at 35 sites in Austria and Germany. A total of 446 women were randomly
      allocated into two cohorts based on time since last bleeding and then stratified
      to either a low dose continuous combined therapy consisting of 1 mg E(2) and 0.5
      mg NETA for 28 days or a sequential therapy consisting of 0.625 mg CEE for 28
      days and 5 mg MG for the final 14 days. Bleeding and menopausal complaints were
      continuously assessed. Treatments were administered for 9 lunar months. RESULTS:
      The incidence rate of women presenting irregular bleeding episodes including
      spotting during cycle 9 was 12.2% with 1mgE(2)/0.5mgNETA and 25.8% with
      0.625mgCEE/5mgMG (P = 0.0014). In the group of postmenopausal women (time since
      last bleeding > or = 12 months) the incidence of irregular bleeding during cycle
      9 was 11.0% for 1mgE(2)/0.5mgNETA and 25.0% for 0.625mgCEE/5mgMG). In the group
      of late perimenopausal women (time since last bleeding 6-11 months) the incidence
      of irregular bleeding was similar for both treatments at cycle 3, but markedly
      less in patients with 1mgE(2)/0.5mgNETA at cycle 6 and 9, being significantly
      different compared to patients with 0.625mgCEE/5mgMG at cycle 6 (P < 0.05). The
      cumulative rate of amenorrhea (no bleeding or spotting) achieved with
      1mgE(2)/0.5mgNETA was 89% for the postmenopausal women and 83.7% for the late
      perimenopausal women. Both treatments relieved menopausal complaints equally
      effective. CONCLUSIONS: Regarding the occurrence of irregular bleeding, the low
      dose continuous combined therapy was superior to the sequential therapy
      (0.625mgCEE/5mgMG). The low dose continuous combined E(2)/NETA regimen is also
      suitable for late perimenopausal women since more than 80% of the women had no
      bleeding or spotting after 9 months of treatment.

PMID- 12468136
TI  - Oral dexketoprofen for pain treatment during diagnostic hysteroscopy in
      postmenopausal women.
AB  - OBJECTIVE: To assess the efficacy of dexketoprofen (DEX) in reducing pain at
      different stages of the hysteroscopic procedure in comparison with local
      anaesthesia in menopausal women. METHODS: Menopausal patients affected by uterine
      bleeding submitted to diagnostic hysteroscopy, were randomised to receive either
      25 mg DEX tablet (n = 148) or intracervical injection of 5 ml mepivacaine 2% (n =
      150). Pain suffered during the procedure itself and 30, 60, 120 min after, was
      scored on the 11 point Visual Analogic Scale, recorded and analysed. RESULTS: No
      statistical difference were noted during the procedure itself in both groups of
      treatment. Patients treated with DEX has significantly less postoperative pain.
      CONCLUSIONS: DEX is not superior to mepivacaine in reducing the discomfort of the
      procedure but does significantly reduce postoperative pain.

PMID- 12468137
TI  - Consensus on medical treatment of non-small cell lung cancer.

PMID- 12468138
TI  - Molecular approaches to lung cancer evaluation.
AB  - The stagnation of therapeutic results in lung cancer over the last decade(s) is a
      matter of great concern, also due to the constantly increasing incidence of the
      disease. Among the reasons for this failing therapeutic progress is the lack of
      understanding of the molecular mechanisms underlying the disease. Presently
      molecular biology techniques contribute to the deciphering of these mechanisms.
      This review article gives an overview of the actual situation. The genetic
      changes leading to malignancy are successively considered at the DNA, RNA and
      protein levels. Alterations at the DNA level represent the bulk of the available
      data, being related to p53 mutations, alterations in the beta-tubulin gene,
      microsatellite alterations, methods for identifying individual and isolated
      aberrant cells, identification of epigenetic mechanisms such as methylation of
      the promoter region of tumor suppressor genes; alterations in pre-neoplastic
      lesions are also evoked. In all cases, the techniques are described and results
      presented. RNA based methods are critically considered, and the yeast functional
      assay described. Protein based methods are also considered. The use of cDNA
      microarrays opens new perspectives and brings the simultaneous identification of
      numerous DNA alterations at a grip, with hopefully significant improvements in
      treatment results and increased efficiency for early detection and prevention.

PMID- 12468139
TI  - Chemotherapy in NSCLC: historical review.
AB  - The use of chemotherapy in patients with advanced NSCLC has been under
      investigation for several years. It has evolved from administration in the
      palliative care setting to integration into combined-modality curative therapy
      settings in patients with locoregionally-advanced disease. Following the largest
      meta-analysis in 1995 it was suggested that platinum-based chemotherapy was
      effective in treating patients with advanced disease. The absolute improvement in
      survival was 10% at 1 year and an increased median survival of 1.5 months. Since
      this analysis, platinum-based chemotherapy is considered the gold standard of
      treatment in this disease.

PMID- 12468140
TI  - Consensus development conference on the medical treatment of non-small cell lung
      cancer: treatment of the early stages.
AB  - Surgery remains the mainstay of treatment for early non-small cell lung cancer
      (NSCLC) but more than 80% of recurrences occur within 2 years from radical
      surgery. The pattern of recurrence may differ by histology with more local
      recurrences seen for patients with squamous cell carcinoma and more distant
      metastases seen in patients with adenocarcinoma. A number of studies demonstrate
      that dissemination of cancer cells at levels much below those detected by any
      current available imaging techniques, including PET scanning also, affect
      prognosis of patients with clinical early-stage NSCLC. The current clinical
      evidence does not recommend adjuvant chemotherapy and/or radiotherapy in
      completely resected stage I-II-IIIA for N1. There are few randomised trials
      available for analysis of neo-adjuvant chemotherapy involving patients with
      resectable stage III disease; overall these trials suggest that induction
      chemotherapy (with or without radiation) improves survival, particularly in those
      patients who undergo significant downstaging. Heterogeneous study populations
      limit the ability to define the optimal patient population who would most benefit
      from this approach. There is no conclusive evidence that neo-adjuvant
      chemotherapy in early NSCLC is associated with an increased post surgical
      morbility and mortality. Additional trials are needed. More recently neo-adjuvant
      chemotherapy has been tested in resectable stage I-II NSCLC and proved to be
      feasible and better tolerated than adjuvant chemotherapy. Several randomised
      trials are currently ongoing. In the next future the role of targeted biological
      therapies as agents acting on minimal residual disease should be explored.

PMID- 12468141
TI  - Neo-adjuvant chemotherapy in early stages of non-small cell lung cancer.

PMID- 12468142
TI  - Comments on treatment strategy for locally advanced non-small cell lung cancer.
AB  - In spite of significant improvement in local and in systemic treatment, long-term
      survival of patients with locally advanced non-small cell lung cancer (NSCLC)
      remains disappointing. The main reason may be our reluctance to explore the
      optimal ways of combining new modalities of irradiation with the new drugs. A
      survey of on-going clinical trials points to weak scientific collaboration
      between radiotherapists and medical oncologists. A comparison of different
      treatment strategies reveals that only the best local treatment combined with the
      best systemic treatment can lead to a clinically meaningful improvement in long
      term survival. Curing a higher percentage of patients is the first step in our
      attempts to combat therapeutic nihilism.

PMID- 12468143
TI  - Consensus conference on medical treatment of non-small cell lung cancer: adjuvant
      treatment.
AB  - The 5-year survival rate for patients with non-small cell lung cancer (NSCLC) who
      undergo complete surgical resection is only 40-69%, depending on the stage. It is
      well known that distant metastatic disease is the dominant site of recurrence in
      such patients and this observation served as the basis for trials of
      postoperative systemic therapy. The earliest trials of adjuvant chemotherapy,
      which consisted of single alkylating agents, did not achieve this goal or, even
      worse, showed a detrimental effect on survival. The introduction of more active
      drugs, such as cisplatin and vinca alkaloids, made it possible to obtain more
      promising results in terms of delayed recurrence of the disease. A recent meta
      analysis of all randomized trials with accrual from January 1965 to December 1991
      showed that the absolute risk of death was reduced by 3% at 2 years and by 5% at
      5 years for patients who were treated with postoperative cisplatin-containing
      regimens compared with patients who were treated with surgery alone. Although the
      results of this meta-analysis suggest that postoperative cisplatin chemotherapy
      regimens may result in a slight survival improvement, adjuvant chemotherapy in
      NSCLC cannot be considered a standard therapy, and it is important that large,
      carefully conducted, randomized trials are performed in this group of patients.
      Four such randomized trials are being conducted in Europe. One of them, the ALPI
      trial, recently completed its accrual with 1200 patients. The IALT, ANITA, and
      MRC trials are still ongoing. The results of such trials are eagerly awaited and
      it is hoped that, once the value of postoperative chemotherapy is well
      ascertained, future developments can further improve results of combined
      treatment. In such direction, the recently reported results of PORT meta-analysis
      evaluating the role of radiation therapy are of great contribution in selecting a
      suitable population for future studies. In fact, only patients with pN2 disease
      seem to have a beneficial effect in terms of survival, especially if they have a
      good performance status, while radiotherapy is not justified in N0-1 patients.
      The optimal integration of chemotherapy and radiation therapy when both therapies
      are indicated represents another goal for future research.

PMID- 12468144
TI  - Combined chemotherapy and radiotherapy in inoperable non-small cell lung cancer.
AB  - Despite its low efficacy, radiotherapy has traditionally been considered the
      mainstay of treatment in inoperable stage III NSCLC. One of the attempts to
      improve the outcome is combining radiation with chemotherapy. This strategy is
      expected to increase the cure rate not only by improved locoregional tumor
      control but also by elimination of micrometastases outside the radiotherapy
      field. Chemotherapy and radiation may be applied in sequence or concurrently. The
      results of randomized studies testing these two strategies have been
      inconsistent, however a series of recent trials and the metaanalysis demonstrated
      a survival benefit of chemoradiation over radiotherapy alone. Recently,
      concurrent chemotherapy and radiation was found to be superior to sequential
      application but toxicity of the former is higher. The value of new agents
      (taxanes, vinorelbine, gemcitabine and topoisomerase inhibitors) in combined
      modality therapy of NSCLC seems to be promising, but warrants further clinical
      evaluation.

PMID- 12468145
TI  - Chemotherapy for advanced non-small cell lung cancer (NSCLC).

PMID- 12468146
TI  - Combined platinum containing treatment in NSCLC.

PMID- 12468147
TI  - Two- versus three-drug combinations in the chemotherapy of advanced non-small
      cell lung cancer.
AB  - Palliative chemotherapy with three-drug combinations might result in higher
      efficacy but also enhanced toxicity when compared with two-drug combinations.
      Italian trials suggested the superiority of cisplatin/gemcitabine/vinorelbine and
      cisplatin/gemcitabine/paclitaxel over corresponding two-drug combinations.
      However, a Spanish trial failed to demonstrate an advantage of
      cisplatin/gemcitabine/vinorelbine over cisplatin/gemcitabine and another
      multicenter phase III trial did not find differences in response rates and
      survival between cisplatin/vinorelbine/ifosfamide and cisplatin/vinorelbine. Thus
      three-drug combinations have not convincingly been demonstrated to be superior to
      two-drug combinations and should not be considered as standard protocols in
      advanced NSCLC.

PMID- 12468148
TI  - Combination chemotherapy without cisplatin in the treatment of advanced non-small
      cell lung cancer.
AB  - Cisplatin-based combinations are standard regimens in the treatment of advanced
      non-small cell lung cancer. Survival improvement has been achieved using this
      therapy. However, the high toxicity induced by cisplatin-based doublets urges the
      research of alternate treatments. Newest cytotoxic compounds yield a better
      efficacy-toxicity ratio. Platinum-free doublet regimens based on new drugs are
      expected to offer the patient an improved survival without decreasing his quality
      of life. Treatment-allocated time and period with high grade toxicity could be
      considered as wasted from the patient point of view. QUALY methods based on time
      without symptoms and toxicity allow the accurate evaluation of this end-point.
      This brief state-of-the-art deals with methodological statements highlighted by
      the first publications of randomized studies comparing non-platinum-based
      doublets with either single-drug chemotherapy or standard cisplatin-based
      doublets.

PMID- 12468149
TI  - Second-line chemotherapy in relapsing or refractory patients with non-small cell
      lung cancer.
AB  - PURPOSE: A comprehensive review of the literature on the efficacy of antitumor
      agents either alone or in combination as second-line chemotherapy in advanced non
      small cell lung cancer (NSCLC) cancer was undertaken. RESULTS: An increasing
      number of patients with advanced NSCLC who progress or fail to respond to front
      line chemotherapy are young and in good performance status, requiring further
      treatment. Since advanced NSCLC is an incurable and fatal disease, the aims of
      second-line chemotherapy should be the palliation of the symptoms and, probably,
      the improvement of survival. Docetaxel, gemcitabine, irinotecan and paclitaxel
      have shown a promising activity as second-line treatment in patients with NSCLC,
      and several phase II studies of regimens associating either these drugs or these
      drugs with CDDP and ifosfamide have shown objective responses ranging from 15 to
      25% and a median survival ranging from 4 to 8 months. Two randomized trials have
      clearly demonstrated that single agent docetaxel in the second line setting
      confers a survival benefit and an improvement of both the quality of life and the
      control of tumor-related symptoms establishing, thus, the role of docetaxel as
      standard treatment for relapsing or refractory patients with NSCLC. CONCLUSIONS:
      Increasing evidence from both phase II and III studies seems to indicate that
      second-line chemotherapy may confer a survival benefit in a selected group of
      patients with advanced NSCLC.

PMID- 12468150
TI  - Chemotherapy of non-small cell lung cancer in the elderly.
AB  - Around one-third of all patients with non-small cell lung cancer (NSCLC) are over
      the age of 70. Elderly patients tolerate chemotherapy poorly because of impaired
      organ function and co-morbidities. For this reason, these patients are often not
      considered eligible for aggressive cisplatin-based chemotherapy. A
      multidimensional geriatric evaluation is important to plan appropriate
      treatments. At present, there are no indications for adjuvant and neoadjuvant
      chemotherapy. Combined chemo-radiotherapy in locally advanced disease increases
      toxicity and seems determine no survival advantage as compared to radiation
      therapy alone. In advanced disease, single agent vinorelbine proves to be active
      and well-tolerated, and compared to best supportive care, improves survival and
      perhaps quality of life. Gemcitabine is active and well tolerated as well.
      Taxanes are in advanced phase of evaluation. A phase III randomized trial showed
      that polychemotherapy with gemcitabine + vinorelbine does not improve any outcome
      as compared to single agent chemotherapy with vinorelbine or gemcitabine. In
      clinical practice, single agent chemotherapy should remain the standard
      treatment. The choice of the drug should be based on the toxicity profile of each
      drug and type of co-morbid conditions. In the near future, new therapeutic
      strategies and biological agents could improve present results.

PMID- 12468151
TI  - The role of chemotherapy (CT) and supportive care (SC) in advanced non-small cell
      lung cancer (NSCLC).

PMID- 12468152
TI  - Anemia and lung cancer.

PMID- 12468153
TI  - Role of supportive care in the treatment of NSCLC: supportive care for
      myelotoxicity.
AB  - Chemotherapy-associated myelosuppression is a major limitation of anticancer
      therapy in both local advanced and metastatic NSCLC. In the past, primary
      prophylactic use of hematopoietic growth factors was administered in these
      patients to reduce the incidence of febrile neutropenia, to avoid dose reduction
      and dose delay, and to improve patient quality of life. However, so far, for
      myeloid growth factors significance is missing that response to treatment can be
      improved in terms of better outcome. Therefore, the routine use of primary for
      secondary prophylactic CSF in patients with stage III or IV NSCLC is discouraged.
      This is due to the fact that there is no evidence that intensified chemotherapy
      schedules improve patients' prognosis. The application of CSF may be considered
      (but not given routinely) in patients with pre-existing neutropenia due to
      diseases or (extensive) prior chemotherapy, poor performance status, previous
      radiotherapy of areas with large amounts of bone marrow reserve or a history of
      recurrent febrile neutropenia while receiving earlier therapy. However, none of
      these indications has ever been proven in randomised clinical trial. In contrast,
      locally advanced NSCLC is a potentially curable disease. Future schedules may
      combine increased dose intensity of chemotherapy with sequential or simultaneous
      radiotherapy, where the primary or secondary use of myeloid growth factors may be
      justified. Chemotherapy-associated thrombopenia: So far, no thrombopoietic
      factors are available for clinical use.

PMID- 12468154
TI  - Future developments in the treatment of lung cancer.
AB  - Lung cancer is the most frequent cause of cancer deaths in the western world.
      Despite some improvements in treatment results, especially by the use of combined
      treatment modalities, the overall prognosis is still very poor, and less than 15%
      of the patients survive 5-year after primary diagnosis. Through rapid
      developments in biotechnology and increased knowledge about important signaling
      pathways leading to cell proliferation, apoptosis, angiogenesis and metastases,
      new treatment possibilities with specific targeted therapies have emerged for
      chemoprevention and treatment of lung cancer. Together with developments of new
      technology available for early diagnosis new paradigms for management of lung
      cancer are under development with great promises for improvement of the overall
      prognosis.

PMID- 12468156
TI  - "What's in a name? That which we call a rose, by any other name.".

PMID- 12468157
TI  - Hormone replacement therapy regimens and breast cancer risk(1).
AB  - Hormone replacement therapy (HRT) has increased in the United States over the
      past 2 decades in response to reports of long-term health benefits. A
      relationship between HRT and breast cancer risk has been observed in a number of
      epidemiological studies. In 2002, the Women's Health Initiative Randomized
      Controlled Trial reported an association between continuous combined HRT and
      breast cancer risk. The objective of this study was to examine the association
      between breast cancer risk and HRT according to regimen and duration and recency
      of use.A multicenter, population-based, case-control study was conducted in five
      United States metropolitan areas from 1994 to 1998. Analyzed were data from 3823
      postmenopausal white and black women (1870 cases and 1953 controls) aged 35-64
      years. Odds ratios (ORs) were calculated as estimates of breast cancer risk using
      standard, unconditional, multivariable logistic regression analysis. Potential
      confounders were included in the final model if they altered ORs by 10% or more.
      Two-sided P values for trend were computed from the likelihood ratio statistic.
      Continuous combined HRT was associated with increased breast cancer risk among
      current users of 5 or more years (1.54; 95% confidence interval 1.10, 2.17).
      Additionally, a statistically significant trend indicating increasing breast
      cancer risk with longer duration of continuous combined HRT was observed among
      current users (P =.01). There were no positive associations between breast cancer
      risk and other HRT regimens. Our data suggest a positive association between
      continuous combined HRT and breast cancer risk among current, longer term users.
      Progestin administered in an uninterrupted regimen may be a contributing factor.
      Risk dissipates once use is discontinued.

PMID- 12468158
TI  - Local relapse in patients treated for squamous cell vulvar carcinoma: incidence
      and prognostic value.
AB  - To evaluate the risk factors for local relapse in vulvar cancer patients and its
      impact on survival as a function of its different patterns, which include local
      recurrences at the primary tumor site, recurrences remote from the primary tumor,
      and skin bridge recurrences. Between January 1978 and June 1999, 215 patients
      were treated for vulvar squamous cell carcinoma. The median follow-up was 38
      months. To evaluate the role of local relapse in survival, a Cox regression
      multivariable analysis was performed using local relapse as a time-dependent
      covariate. The local relapse-free survival rate was 78.6% (+/- 7.1%) at 5 years.
      Multivariable analyses showed that the local relapse was increased by the factors
      margin status and depth of invasion. Pathologic nodal status, tumor size, margin
      status, and depth of invasion were predictors of cancer-related death in the Cox
      multivariable model with fixed covariates. The contribution of local relapse for
      disease-specific survival at the site of the primary tumor (relative risk [RR]
      6.35; 95% confidence interval [CI] 2.07, 15.76) or skin bridge recurrence (RR
      6.48; 95% CI 2.54, 16.49) was highly significant, whereas the contribution of
      local relapse at the other sites was not (RR 2.29; 95% CI 0.53, 9.91). In this
      model, margin status was not significant. The risk of cancer-related death after
      local relapse was 58.4% (+/- 18.3%) at 1 year and 70.9% (+/- 17.6%) at 3
      years.Local relapses at the site of the primary tumor or skin bridge recurrences
      are strong predictors for cancer-related death, but not local relapse at a
      distant site.

PMID- 12468159
TI  - Combined second-trimester biochemical and ultrasound screening for Down syndrome.
AB  - OBJECTIVE: To evaluate the efficacy of a Down syndrome screening protocol that
      combines second-trimester maternal serum analytes and the continuous ultrasound
      measures of nuchal fold thickness and proximal long bone length. METHODS:
      Ultrasound measurements of nuchal fold, femur length, and humerus length were
      reviewed for 72 second-trimester Down syndrome and 7063 unaffected fetuses.
      Derived statistical variables for these parameters were entered into a
      multivariable Gaussian model together with the statistical variables used in the
      "quad" test (maternal serum alpha-fetoprotein, unconjugated estriol, human
      chorionic gonadotropin, and inhibin A). Maternal age-specific sensitivities,
      false-positive rates, and positive predictive values were generated together with
      receiver operating characteristic curves. Overall efficacy of ultrasound
      screening alone, the quad test, and the combination of the ultrasound and quad
      test were compared using a 1:270 second-trimester risk cutoff applied to 1999 US
      births. RESULTS: Using ultrasound, a sensitivity of 79.9% and false-positive rate
      of 6.7% may be achieved (positive predictive value: 1 in 42). The quad test has a
      sensitivity of 81.5% and false-positive rate of 6.9% (positive predictive value:
      1 in 42). The combination of the quad test with nuchal fold and long bone
      measurements may achieve 90% sensitivity and a 3.1% false-positive rate (positive
      predictive value: 1 in 18). CONCLUSION: Combining second-trimester serum testing
      and fetal biometry is a feasible approach to Down syndrome screening, compatible
      with current obstetric practice. This modality is substantially more effective
      than either serum screening or ultrasound alone. Efficacy may be comparable to
      that reported for combined first- and second-trimester (integrated) screening.

PMID- 12468160
TI  - Episiotomy use in the United States, 1979-1997.
AB  - OBJECTIVE: To describe episiotomy usage at vaginal delivery in the United States
      from 1979-1997. METHODS: We used the National Hospital Discharge Survey, a
      federal database of a national sample of inpatient hospitals. Data from 1979 to
      1997 were analyzed using International Classification of Diseases, Ninth
      Revision, Clinical Modification codes for diagnoses and procedures. Rates per
      1000 women were calculated using the 1990 census population for women aged 15-44
      years. We calculated the number of episiotomies per 100 vaginal deliveries. Rates
      and percentages were compared using the score test for linear trend. RESULTS: The
      number of episiotomies ranged from a high of 2,015,000 in 1981 to a low of
      1,128,000 in 1997. The age-adjusted annual rate for episiotomy with vaginal
      deliveries varied from 32.7 in 1979 to 18.7 in 1997 per 1000 women aged 15-44
      years. The percentage of episiotomy with vaginal deliveries ranged from 65.3% in
      1979 to 38.6% in 1997 (P <.001). Episiotomy with operative deliveries decreased
      over time (87.0% to 70.8%, P <.001), as did episiotomy with spontaneous
      deliveries (60.1% to 32.8%, P <.001). Women undergoing episiotomy were slightly
      younger (mean +/- standard deviation, 25.7 +/- 5.5 years) than women without
      episiotomy (26.2 +/- 5.7 years, P <.001). Black women (39%) were less likely to
      receive episiotomy than white women (60%, P <.001). More women with private
      insurance (62%) had episiotomy performed than women with government insurance
      (43%, P <.001). CONCLUSION: Although episiotomy use has decreased over time, the
      most recent rate of 39 per 100 vaginal deliveries remains higher than evidence
      based recommendations for optimal patient care.

PMID- 12468161
TI  - Fetal deaths in the United States. Influence of high-risk conditions and
      implications for management.
AB  - OBJECTIVE: To estimate the effect of specific maternal-fetal high-risk conditions
      on the risk and timing of fetal death. METHODS: This study examined 10,614,679
      non-anomalous singleton pregnancies delivering at or beyond 24 weeks' gestation,
      derived from the U.S. linked birth/infant death data sets, 1995-1997. Fetal death
      rates for pregnancies at low risk were compared with pregnancies complicated by
      chronic hypertension, gestational hypertensive disorders, diabetes, small for
      gestational age infants, and abruption. Adjusted relative risks as well as
      population-attributable risks for fetal death were derived by gestational age for
      each high-risk condition compared with low-risk pregnancies. RESULTS: The fetal
      death rate for low-risk pregnancies was 1.6 per 1000 births. Adjusted relative
      risk for fetal death was 9.2 (95% confidence interval [CI] 8.8, 9.7) for
      abruption, 7.0 (95% CI 6.8, 7.2) for small for gestational age infants, 1.4 (95%
      CI 1.3, 1.5) for gestational hypertensive disorders, 2.7 (95% CI 2.4, 3.0) for
      chronic hypertension, and 2.5 (95% CI 2.3, 2.7) for diabetes. Fetal death rates
      were lowest between 38 and 41 weeks. The fetal death rate (per 1000 births) for
      these high-risk conditions was 61.4, 9.6, 3.5, 7.6, and 3.9, respectively. Almost
      two thirds of fetal deaths were attributable to the pregnancy complications
      examined. CONCLUSION: High-risk conditions in pregnancy are associated with an
      increased risk for fetal death, particularly in the third trimester. Delivery
      should be considered at 38 weeks, but no later than 41 weeks, for these
      pregnancies.

PMID- 12468162
TI  - Clinical evaluation of a "hand pump" vacuum delivery device.
AB  - OBJECTIVE: To evaluate the clinical performance of a hand-held vacuum delivery
      system. METHODS: Between December 1999 and September 2000, a prospective audit
      was undertaken of all vacuum deliveries performed at Derby City General Hospital.
      RESULTS: In this period, 3296 deliveries occurred, of which 317 (9.6%) were by
      vacuum. Of these, data were collected on 300 (94.6%), 78 deliveries with the hand
      held vacuum and 222 with standard vacuum. There were no differences in the
      demographic profiles, indication, gestational age at delivery, or birth weights
      between the two groups (P >.05 in all instances). In all types of delivery,
      nonrotational and rotational, the hand-held vacuum performed comparably to its
      contemporaries with no increase in delivery "failures" being noted. There were no
      differences in the extent or frequency of maternal injuries between the
      instruments, and other than transient scalp abrasions, there were no significant
      fetal injuries. CONCLUSION: The hand-held vacuum delivery system is a
      functionally effective addition to the practitioners' "armory," providing an
      alternative to the standard metal and silastic cups.

PMID- 12468163
TI  - The recurrence risk of adverse outcome in the second pregnancy in women with
      rheumatic disease1.
AB  - OBJECTIVE: To study recurrence risks of adverse pregnancy outcome in the second
      pregnancy in women with rheumatic disease. METHODS: In a national population
      based cohort study, women with rheumatic disease recorded from 1967 to 1995 in
      the Medical Birth Registry of Norway were compared with mothers without such
      diagnoses with regard to recurrence risks of adverse pregnancy outcomes in the
      second pregnancy. The odds ratios (ORs) of all outcomes were adjusted for
      maternal age, those of cesarean delivery for time period, and those of
      preeclampsia for interpregnancy interval. RESULTS: Women with rheumatic disease
      an dadverse pregnancy outcome in the first pregnancy had a statistically
      significant higher recurrence risk of the same event in the second pregnancy than
      women without rheumatic disease (preeclampsia: OR 2.22; 95% confidence interval
      [CI] 1.18, 4.19) (cesarean delivery: OR 1.52; 95% CI 1.05, 2.21) (preterm birth:
      OR 1.86; 95% CI 1.12, 3.11). In women with rheumatic disease diagnosed between
      the first and second births, a significantly increased recurrence risk of low
      birth weight occurred. Women with rheumatic disease also had a higher occurrence
      of markers for placental dysfunction (preeclampsia, preterm birth, or small for
      gestational age) in the second birth after any of these outcomes in the first
      birth (OR 1.35; 95% CI 1.02, 1.78) (35.1% versus 29.2%). CONCLUSION: The
      recurrence risk of an adverse outcome in the second pregnancy is increased in any
      woman, but was even higher in women with a rheumatic disease. These patients
      should be counseled accordingly, be closely monitored during pregnancy, and have
      access to appropriate subspecialists.

PMID- 12468164
TI  - The resistance index in the fetal middle cerebral artery by gestational age and
      ventricle size in a normal population.
AB  - OBJECTIVE: To study the association between fetal middle cerebral artery flow and
      the lateral cerebral ventricular width throughout gestation. METHODS: The study
      is a prospective cohort evaluation of 430 singleton male and female fetuses
      between 20 and 40 weeks' normal gestation. Abdominal ultrasonography and Doppler
      measurements were performed to measure the fetal atrial ventricular size and
      resistance index (RI) of the middle cerebral artery. RESULTS: The mean (+/-
      standard deviation) ventricular width was 6.2 +/- 1.2 mm. The modification in the
      RI of the middle cerebral artery throughout gestation showed a biphasic mode,
      increasing gradually to a peak at 30 weeks' gestation and decreasing
      progressively thereafter. No significant correlation was found between the middle
      cerebral artery flow and the lateral cerebral ventricular width (r =.11). In
      addition to the 430 cases studied, three cases of mild ventriculomegaly and three
      cases of hydrocephalus were evaluated. The RI of the middle cerebral artery was
      within the normal range in all six of these cases. CONCLUSION: Fetal middle
      cerebral artery blood flow is not affected by the width of the lateral
      ventricles, even in enlarged ventricles.

PMID- 12468165
TI  - Menopausal symptoms in older women and the effects of treatment with hormone
      therapy.
AB  - OBJECTIVE: In some women, hot flashes and other symptoms attributed to menopause
      persist for many years after the cessation of menses. The frequency and severity
      of such symptoms and response to hormone therapy in older women have not been
      well documented. METHODS: We used data from the Heart and Estrogen/Progestin
      Replacement Study, a blinded, clinical trial among 2763 women with documented
      coronary disease and a uterus who were randomized to receive either conjugated
      estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg in one tablet or
      placebo. Participants were queried at baseline and annually regarding menopausal
      symptoms. Breast symptoms were self-reported, and uterine bleeding was recorded
      on a daily diary. RESULTS: Symptoms associated with menopause were relatively
      common among Heart and Estrogen/Progestin Replacement Study participants, whose
      average age was 67 years and who averaged 18 years since menopause. At baseline,
      16% of women reported frequent hot flashes, 26% vaginal dryness, 10% genital
      irritation, 55% trouble sleeping, and 53% early awakening. Women assigned to
      hormone therapy reported less frequent hot flashes, vaginal dryness, and trouble
      sleeping compared with women assigned to placebo, but more frequent vaginal
      discharge, genital irritation, uterine bleeding, and breast symptoms. The
      reporting of breast symptoms among women in the hormone group decreased from 40%
      at 1 year to 13% by the 4th year. Uterine bleeding was reported by 31% and
      spotting by an additional 33% of women in the hormone group during the 1st year
      of treatment; by the 4th year, these proportions had fallen to 11% and 20%,
      respectively. CONCLUSION: Symptoms typically attributed to menopause are common
      in elderly women. Postmenopausal hormone therapy reduces hot flashes, trouble
      sleeping, and vaginal dryness, but at standard doses in elderly women is
      associated with vaginal discharge, genital irritation, uterine bleeding, and
      breast symptoms.

PMID- 12468166
TI  - Efficacy of intermittent, luteal phase sertraline treatment of premenstrual
      dysphoric disorder.
AB  - OBJECTIVE: Premenstrual dysphoric disorder is a menstrually related disorder that
      intermittently causes disabling emotional, behavioral, and physical symptoms. The
      goal of the current study was to evaluate the efficacy and tolerability of
      sertraline for premenstrual dysphoric disorder when treatment was limited to the
      luteal phase. METHODS: Two hundred eighty-one women who met Diagnostic and
      Statistical Manual of Mental Disorders (4th edition) criteria for premenstrual
      dysphoric disorder and who completed two prospective screening cycles and one
      single-blind placebo cycle were randomized to three cycles of double-blind,
      luteal phase treatment with either a placebo or sertraline in a flexible daily
      dose of 50-100 mg. Outcome measures included the Daily Record of Severity of
      Problems and the Clinical Global Impression Severity and Improvement scales.
      RESULTS: Luteal phase treatment with sertraline was significantly superior to the
      placebo, as demonstrated by end- point analysis of Clinical Global Impression
      Improvement scale scores (sertraline, 2.3 +/- 1.1, versus placebo, 2.7 +/- 1.1; P
      <.001), and cycle 3 Daily Record of Severity of Problems change scores
      (sertraline, 27.6 +/- 26.8, versus placebo, 17.6 +/- 23.3; P <.002). A
      significant difference was also noted in responder rates in favor of sertraline
      (50%) versus placebo (26%, P <.001) by cycle 1 (with responder defined as a
      Clinical Global Impression Improvement scale score of 1 or 2). Quality of life
      and functioning outcomes were also significantly improved. Intermittent luteal
      administration of sertraline was well tolerated, with only approximately 8% of
      patients on sertraline and less than 1% on placebo discontinuing because of
      adverse events. CONCLUSION: Sertraline was significantly more effective than a
      placebo and was well tolerated as a treatment for premenstrual dysphoric disorder
      when administered intermittently during the luteal phase of the menstrual cycle.

PMID- 12468167
TI  - Urinary incontinence predictors and life impact in ethnically diverse
      perimenopausal women.
AB  - OBJECTIVE: To document prevalence of mild, moderate, and severe urinary
      incontinence among ethnically diverse perimenopausal women, identify risk
      factors, and assess the effect of severity on women's daily lives using treatment
      seeking, bother, and nighttime voiding as indicators. METHODS: Baseline data from
      the longitudinal cohort of the Study of Women's Health Across the Nation, a
      prospective, multiethnic, multisite study of the natural history of menopausal
      transition was used (n = 3302). Interview and self-completed questionnaires
      assessed most variables of interest. Body mass index and diabetes mellitus were
      measured clinically. Incontinence severity was derived by multiplying frequency
      by volume leaked. Risk factors and effect on treatment seeking, bother, and
      nighttime voiding were assessed by the construction of multiple logistic
      regression models for each ethnic group and the total population. RESULTS: Mean
      age was 46.4 years. Incontinence prevalence was 57%, with nearly 15% categorized
      as moderate and 10% as severe. Biologic factors constituted the most important
      risk for severity, specifically perimenopausal compared with premenepausal status
      (odds ratio [OR] 1.35), body mass index (OR 1.04), diabetes mellitus (OR 1.55),
      and current smoking (OR 1.38). Nonwhite groups had lower risk, but the
      relationship of ethnicity is complex. Severity was associated with likelihood of
      discussing with a health care provider, with bothersomeness, and with likelihood
      of nighttime voiding. CONCLUSION: Large numbers of perimenopausal women
      experience urinary incontinence with 25% wearing protection or changing
      undergarments on several days per week. Mutable factors predicting severity
      included body mass index and current smoking.

PMID- 12468168
TI  - Randomized trial of lidocaine ointment versus placebo for the treatment of
      postpartum perineal pain.
AB  - OBJECTIVE: To estimate the efficacy of lidocaine ointment in relieving pain after
      a vaginal delivery with an episiotomy or perineal laceration. METHODS: In a
      randomized, double-blind, placebo-controlled trial, 200 women received lidocaine
      ointment (n = 108) or a placebo (n = 92). Pain relief was assessed by the amount
      of ointment used (weight of jar before use - weight of jar after use), total
      number of pain pills used, and a pain questionnaire. The sample size was
      calculated using a beta of.2 and an alpha of.05 with an expected reduction of
      other pain medications from an average use of six pills to four pills for the
      population. RESULTS: There was no significant difference in the amount of
      lidocaine versus placebo used for postpartum day 1 (5.1 g versus 4.0 g,
      respectively [P =.13]) or day 2 (3.7 g versus 2.6 g, respectively [P =.18]).
      Patients receiving lidocaine instead of the placebo showed no significant
      difference in the total amount of postpartum pain medications (6.3 versus 6.8
      tablets, respectively [P =.53]), subjective pain parameters (P =.36), or
      satisfaction from ointment (P =.99). Patients with an episiotomy used more pain
      medications than those with a laceration (7.9 versus 5.6 tablets, respectively [P
      =.003]). Those with minor versus major lacerations required fewer pain pills (6.1
      versus 10.8 tablets, respectively [P <.001]) and used less ointment (4.3 g versus
      7.9 g, respectively [P =.02]) on the first postpartum day. CONCLUSION: Topical
      application of 5% lidocaine ointment was not effective in relieving episiotomy or
      perineal laceration pain.

PMID- 12468169
TI  - Relationship between maternal methadone dosage and neonatal withdrawal.
AB  - OBJECTIVE: To determine whether maternal methadone dosage affects duration and
      degree of neonatal narcotic withdrawal. METHODS: This was a retrospective cohort
      study of pregnant women with opioid addiction who delivered live-born singletons
      between April 1990 and April 2001. Inpatient detoxification or outpatient
      methadone maintenance therapy was offered. Women who had a positive drug screen
      or whose neonate tested positive for opioids were considered to be supplementing.
      We evaluated indices of neonatal withdrawal according to the maximum daily
      methadone dosage in the last week of pregnancy. RESULTS: Seventy women with
      opioid addiction were followed. Median methadone dosage was 20 mg (range 0-150
      mg), and 32 infants (46%) were treated for narcotic withdrawal. Among women who
      received less than 20 mg per day, 20-39 mg per day, and at least 40 mg per day of
      methadone, treatment for withdrawal occurred in 12%, 44%, and 90% of infants,
      respectively (P < 0.02). Methadone dosage was also correlated with both duration
      of neonatal hospitalization and neonatal abstinence score (r(s) =.70 and.73
      respectively, both P <.001). Neonates were more likely to experience withdrawal
      if their mothers were supplementing with heroin, 68% versus 35% (P =.01).
      Regardless of supplementation, there was a significant relationship between
      methadone dosage and neonatal withdrawal (P <.05). CONCLUSION: Maternal methadone
      dosage was associated with duration of neonatal hospitalization, neonatal
      abstinence score, and treatment for withdrawal. Heroin supplementation did not
      alter this dose-response relationship. In selected pregnancies, lowering the
      maternal methadone dosage was associated with both decreased incidence and
      severity of neonatal withdrawal.

PMID- 12468170
TI  - Preterm premature rupture of membranes. Nutritional and socioeconomic factors.
AB  - OBJECTIVE: To estimate if there were dietary or socioeconomic factors associated
      with preterm premature rupture of membranes (PROM). METHODS: In this case-control
      study, women with preterm PROM (n = 46) were compared with healthy pregnant women
      matched for gestational age and vitamin supplementation. Measurements included
      fasting homocysteine, red blood cell folate, albumin, creatinine, and complete
      blood count. Dietary intake was determined by a food frequency questionnaire.
      Socioeconomic and demographic factors were recorded. RESULTS: There were no
      differences between fasting homocysteine, red blood cell folate, and vitamin
      B(12) levels and dietary intake between patients and controls. There was lower
      hemoglobin in women with preterm PROM compared with the controls (P <.001). There
      was a three-fold increased odds of having a total family income of less than
      $25,000 (Canadian) (odds ratio 3.1, 95% confidence interval 1.6, 6) in women with
      preterm PROM. CONCLUSION: Preterm PROM is associated with low maternal hemoglobin
      and low socioeconomic status. There was no association with nutritional intake.
      The lower hemoglobin level may be a marker for subclinical infection.

PMID- 12468171
TI  - Validation of the Quintero staging system for twin-twin transfusion syndrome.
AB  - OBJECTIVE: To validate an established staging system for twin-twin transfusion
      syndrome. METHODS: Prospective observational study in a tertiary referral fetal
      medicine center of 52 consecutive cases of twin-twin transfusion syndrome. Each
      pregnancy was assessed longitudinally for a variety of prognostic factors
      including fetal biometry, amniotic fluid volume, arterial and venous Doppler
      sonogram abnormalities, and the presence of hydrops. Data were used to determine
      stage at diagnosis and first treatment, and worst stage throughout pregnancy.
      Perinatal outcome was assessed by stage. Management comprised serial
      amnioreduction, septostomy, selective reduction, or delivery, alone or in
      combination. RESULTS: Median gestation at presentation and first treatment were
      both 21 weeks (range 14-34 and 15-34), and at delivery it was 29 weeks (range 16
      40). Sixty-three percent of pregnancies (33 of 52) were at least stage III at
      presentation. Forty-five percent of pregnancies (22 of 49) progressed to a more
      advanced stage. Overall survival was 47% (47 of 100), with no difference between
      donor and recipient fetuses (40% [20 of 50] versus 54% [27 of 50] [chi(2) P
      =.5]). Survival rates were 58% (15 of 26), 60% (six of ten), 42% (20 of 48), 43%
      (six of 14), and 0% (none of two) for stages I-V, respectively, with no
      significant influence of stage at presentation on survival. Survival was poorer
      where stage increased, versus decreased (27% [12 of 44] versus 94% [17 of 18]
      chi(2) P <.001). Kaplan-Meier survival curves indicated that staging at
      presentation identified pregnancies at greater risk of earlier rather than later
      gestational perinatal loss. CONCLUSION: The Quintero staging system did not
      distinguish good from bad outcome at presentation, and thus should be used with
      caution in guiding initial management of twin-twin transfusion syndrome. However,
      prognosis was influenced by a change in stage, and pregnancies progressing to
      higher stage disease were at increased risk of earlier perinatal loss. Staging
      may thus be more useful in monitoring disease progression.

PMID- 12468172
TI  - Increased plasma adenosine concentrations and the severity of preeclampsia.
AB  - OBJECTIVE: To investigate the relationship between changes in plasma adenosine
      and the severity of preeclampsia, and norepinephrine and tumor necrosis factor
      alpha concentrations. METHODS: Plasma concentrations of adenosine,
      norepinephrine, and tumor necrosis factor-alpha relating to the pathogenesis of
      preeclampsia were measured in women with mild (n = 21) and severe (n = 21)
      preeclampsia and normal pregnancies (n = 21), matched for age, gestational age,
      and parity, in the third trimester of pregnancy. We then evaluated the
      relationships among plasma adenosine, norepinephrine, tumor necrosis factor-alpha
      concentrations, and the severity of preeclampsia. RESULTS: Mean plasma adenosine,
      norepinephrine, and tumor necrosis factor-alpha concentrations were significantly
      higher in women with mild and severe preeclampsia than in normal control subjects
      (P <.05). In women with preeclampsia, plasma adenosine concentrations increased
      according to the severity of preeclampsia (0.60 +/- 0.03 micromol/L and 0.72 +/-
      0.03 micromol/L, respectively, versus 0.41 +/- 0.03 micromol/L for normal
      subjects), which correlated with increases of norepinephrine and tumor necrosis
      factor-alpha concentrations (r =.58, P <.05; r =.49, P <.05, respectively). In
      preeclampsia, norepinephrine concentration also correlated with maternal blood
      pressure (r =.50, P <.05). CONCLUSION: Adenosine is an established suppressor of
      the effects of norepinephrine and tumor necrosis factor-alpha. The increased
      plasma concentrations of adenosine in preeclampsia might serve to counteract
      further progression of the complication.

PMID- 12468173
TI  - Hysterectomy for the massive leiomyomatous uterus.
AB  - OBJECTIVE: To determine if the complication rate of abdominal hysterectomy is
      increased in women with greatly enlarged myomatous uteri. METHODS: Three groups
      of women undergoing abdominal hysterectomy were analyzed according to uterine
      size: group 1, 208 women with uteri less than 500 g; group 2, 63 women with
      uterine weights of 500-999 g; and group 3, 47 women with leiomyomata whose uteri
      weighed at least 1000 g. Logistic regression was used to compare the groups on
      the risks of having at least one major complication. Adjusted comparisons on
      other surgical outcomes were performed using a logistic model (for qualitative
      variables) or a general linear model (for quantitative variables). RESULTS: The
      risk of experiencing at least one perioperative complication, including blood
      loss over 500 mL, perioperative blood transfusion, major organ injury,
      therapeutic antibiotic use, and hospital readmission, increased significantly
      with uterine weight (P =.006). Group 3 women were at greater risk of having at
      least one of these complications than either group 1 or group 2 women, with
      adjusted odds ratios of 3.42 (95% confidence interval [CI] 1.62, 7.25) and 2.64
      (95% CI 1.14, 6.13), respectively. Estimated blood loss with surgery also
      increased with increasing uterine weight (P <.001). Mean estimated blood losses
      for the study groups were 555.8 +/- 386.5 mL (group 3), 464.3 +/- 285.2 mL (group
      2), and 387.6 +/- 281.4 mL (group 1) (P =.032). CONCLUSION: The complication rate
      from hysterectomy increases with increasing uterine weight, due mainly to an
      increased blood loss associated with surgery for larger uteri.

PMID- 12468174
TI  - A stiff bristled, spiral-shaped ectocervical brush: a device for transepithelial
      tissue biopsy.
AB  - OBJECTIVE: To compare a new spiral-shaped tissue-sampling brush with a standard
      cervical punch biopsy. METHODS: Before large loop excision of the transformation
      zone, women with cervical intraepithelial neoplasia underwent a transepithelial
      brush biopsy of a portion of a colposcopically identified lesion, followed by a
      punch biopsy of the remaining portion. Brush biopsy samples were processed using
      liquid-based cytology and cell block techniques. Diagnoses were made using a
      consensus of three pathologists. Brush biopsy samples without basal cells were
      considered inadequate. The histological diagnosis was compared with the brush
      biopsy and punch biopsy samples. Patient-reported pain and physician-reported
      bleeding for punch and brush biopsies were compared. RESULTS: Fifty-two women
      were enrolled in the study; 47 successfully completed the study protocol. Eight
      brush biopsy specimens were inadequate. Thirty-nine women showed abnormal
      pathology (human papillomavirus/cervical intraepithelial neoplasia I or worse) on
      large loop excision of the transformation zone, and 32 women had high-grade (or
      worse) lesions. The punch biopsy correlated with high-grade disease in 53.1% of
      these women. The brush biopsy result correlated with high-grade disease in 79.3%
      of these women using a cell block technique and 76.7% using liquid cytology.
      There was significantly less pain (P <.001) and significantly less bleeding (P
      <.001) with the brush biopsy. CONCLUSION: When an adequate sample is collected,
      spiral brush biopsy is as good as a standard punch biopsy for detecting cervical
      pathology, with substantially less pain and bleeding. User training and
      guidelines for sampling are needed to assure that an adequate sample is
      collected.

PMID- 12468175
TI  - The factor V leiden mutation and the risk of venous thromboembolism in
      gynecologic oncology patients1.
AB  - OBJECTIVE: To measure the strength of the association between the factor V Leiden
      mutation and venous thromboembolism in gynecologic oncology patients. METHODS: We
      conducted a case-control study of gynecologic cancer patients in a referral
      center who were group matched for demographics, tumor type, and treatment. The
      prevalence of the factor V Leiden mutation was determined in both cases and
      controls, and an odds ratio was calculated. The factor V Leiden mutation was
      detected using polymerase chain reaction amplification and nucleic acid
      restriction digest of deoxyribonucleic acid extracted from leukocytes. RESULTS:
      Seventy-five patients were enrolled in the study. Seventy-four samples were
      available for analysis. There were no differences between the cases and controls
      with respect to age, race, body mass index, smoking, cancer type, high stage (III
      or IV) of cancer, or treatment modality. The odds ratio for having the factor V
      Leiden mutation in patients with venous thromboembolism was 0.3 (95% confidence
      interval 0.1, 1.7). CONCLUSION: This study suggests that the factor V Leiden
      mutation is not associated with an increased risk of venous thromboembolism in
      gynecologic oncology patients. This contrasts with other studies showing a strong
      association between the factor V Leiden mutation and venous thromboembolism in
      cases of previously unexplained venous thromboembolism, and venous
      thromboembolism associated with other hypercoagulable states, such as pregnancy
      and oral contraceptive use. The risk of venous thromboembolism due to cancer
      outweighs the contribution of the factor V Leiden mutation.

PMID- 12468177
TI  - Thomas Eakins' Agnew Clinic. a study of medicine through art.
AB  - In 1889, Thomas Eakins was commissioned to paint a portrait of Dr. David Hayes
      Agnew to commemorate his exemplary career as a physician and teacher at The
      University of Pennsylvania. What was originally proposed as a three-quarters
      portrait of the retiring professor quickly became an enormous painting depicting
      an operating theater with Dr. Agnew assuming his role as both surgeon and
      educator. When comparing this piece with an earlier Eakins' painting, The Gross
      Clinic, one can trace the rapid evolution of surgical techniques that accompanied
      medicine's advancement in the late 19th century. Eakins obviously embraced this
      progress, but was the public ready to do so too?

PMID- 12468176
TI  - E-cadherin expression in endometrioid, papillary serous, and clear cell carcinoma
      of the endometrium.
AB  - OBJECTIVE: To compare the frequency and pattern of E-cadherin expression in
      endometrioid, papillary serous, and clear cell carcinomas of the endometrium.
      METHODS: E-cadherin expression was examined in 76 endometrial carcinomas by
      immunohistochemistry using a monoclonal antibody to E-cadherin and was correlated
      with poor prognostic indicators such as depth of myometrial invasion, lymph node
      status, and intraperitoneal spread. The frequency of expression was compared
      between endometrioid, papillary serous, and clear cell carcinomas by the Fisher
      exact test. Logistic regression was used to examine the simultaneous effect of
      histological type and tumor grade on E-cadherin expression. RESULTS: Sixty-three
      endometrioid, nine papillary serous, two clear cell, and two carcinomas of mixed
      histology were examined. E-cadherin negative tumors were more likely to be poorly
      differentiated (P <.01), have cervical extension (P =.02), have positive
      peritoneal cytology (P <.01), and have adnexal spread (P =.01) when compared with
      E-cadherin positive tumors. Papillary serous and clear cell carcinomas were
      significantly less likely to express E-cadherin than endometrioid carcinoma (38%
      versus 95%, P <.001). Tumor grade and histological type were identified as
      significant predictors of E-cadherin expression in univariable analysis; however,
      only histological type remained significant in multivariable analysis (P =.01).
      When grade was controlled, endometrioid carcinoma remained 23 times more likely
      to express E-cadherin than papillary serous and clear cell carcinomas.
      CONCLUSION: Papillary serous and clear cell carcinomas are significantly less
      likely to express E-cadherin than endometrioid tumors. This difference may
      account for the more aggressive behavior of papillary serous and clear cell
      carcinomas.

PMID- 12468178
TI  - Systematic review of randomized controlled trials of misoprostol to prevent
      postpartum hemorrhage.
AB  - OBJECTIVE: To assess the effects of prophylactic misoprostol use in the third
      stage of labor compared with injectable uterotonics or placebo or no treatment.
      DATA SOURCES: The Cochrane Pregnancy and Childbirth Group trials register; the
      Cochrane Library, including databases such as the database of systematic reviews
      and the Cochrane Controlled Trials Register; and MEDLINE were searched.
      Researchers in the field were also contacted. The date of the latest search was
      March 1, 2002. METHODS OF STUDY SELECTION: Randomized trials comparing
      misoprostol with injectable oxytocin or oxytocin-ergot preparations to prevent
      postpartum hemorrhage or placebo/no treatment as active management of the third
      stage of labor were eligible for inclusion. Eligibility and trial quality were
      assessed following selected criteria. Data were extracted and analyzed using
      RevMan software. TABULATION, INTEGRATION, AND RESULTS: Sixteen randomized trials
      with a total of 28,138 women were considered. Data were available for 27,498
      women. Oral misoprostol (600 microg) is less effective than injectable
      uterotonics in reducing blood loss at least 1000 mL (relative risk [RR] 1.36, 95%
      confidence interval [CI] 1.17, 1.58) and increases the use of additional
      uterotonics. Shivering and pyrexia (temperature greater than 38C) are the main
      side effects of misoprostol and are dose related. Compared with injectable
      uterotonics, the RR of "any shivering" with misoprostol (600 microg) is 3.27 (95%
      CI 3.01, 3.56) and pyrexia is 6.96 (95% CI 5.65, 8.57). The RR of blood loss of
      500 mL or more is 1.11 (95% CI 0.87, 1.43) and the RR of use of additional
      uterotonics is 1.80 (1.13, 2.85) in the three trials (1441 women) comparing
      rectal misoprostol (400 microg) with injectable uterotonics. CONCLUSION:
      Injectable oxytocin or oxytocin-ergot preparations are more effective than
      misoprostol as part of the active management of the third stage of labor.

PMID- 12468179
TI  - Cerclage and cervical insufficiency: an evidence-based analysis.
AB  - Since the cervical cerclage was introduced to clinical practice 50 years ago, the
      efficacy of the operation has not been established by evidence-based standards
      for many indications. Serious flaws in the methods employed to study the safety
      and efficacy of cerclage have led to confusion and misuse of the operation,
      although some investigators maintain that current standards make randomized
      clinical trials of this traditional surgery unethical. At present, five
      randomized clinical trials have offered significant information about elective
      cerclages performed for historical indications, and the expected neonatal
      survival rate with properly selected elective cerclages is around 87%.
      Transvaginal ultrasound studies have revealed new paradigms regarding normal
      cervical function in pregnancy and further understanding about the significance
      and predictive value of cervical changes at gestational ages between 20-37 weeks.
      Only two randomized clinical trials have been conducted regarding cerclage in
      women with decreasing cervical length or with cervical funneling. One of these
      two failed to demonstrate any resulting improvement in neonatal survival, and the
      other was too small to be conclusive. To date, no randomized clinical trials have
      been conducted to demonstrate the efficacy or safety of emergency cerclages
      performed for advanced cervical dilatation. The many retrospective case series
      regarding emergency cerclage have failed to provide an evidence-based solution to
      the management of this problem. Before this traditional surgery continues
      extensive use in clinical practice, it should be assessed rigorously with
      randomized clinical trials of sufficient statistical power and external validity
      to establish the appropriate indications for the operation. In addition, a more
      thorough understanding of cervical function and molecular biology is essential.

PMID- 12468180
TI  - Fitsari 'dan Duniya. An African (Hausa) praise song about vesicovaginal fistulas.
AB  - The vesicovaginal fistula from prolonged obstructed labor is a condition that is
      no longer seen in the affluent, industrialized world, yet it continues to exist
      in epidemic proportions in sub-Saharan Africa, where several million women are
      estimated to suffer from this condition. The unremitting urinary incontinence
      that is produced by a fistula causes these women to become social outcasts. The
      problem is particularly acute in Nigeria, where the Federal Ministry of Women's
      Affairs estimates that there may be as many as 800,000 unrepaired fistula cases.
      Because of the social stigma attached to their condition, fistula victims have
      often been subjected to major psychosocial trauma. Finding ways to help such
      patients reintegrate into social networks is an important part of their
      treatment. When fistula patients meet one another, they realize that they are not
      alone in their suffering. This article describes the use of a "praise song" by a
      group of Nigerian fistula patients as a vehicle for building group identity as
      part of a "sisterhood of suffering." A transcription and translation of a Hausa
      praise song about vesicovaginal fistulas is presented, along with a commentary on
      the text that sheds new light on a problem that is unfamiliar to most Western
      obstetrician-gynecologists.

PMID- 12468181
TI  - Timing intercourse to achieve pregnancy: current evidence.
AB  - Physicians who counsel women for preconception concerns are in an excellent
      position to give advice to couples regarding the optimal timing of intercourse to
      achieve pregnancy. The currently available evidence suggests that methods that
      prospectively identify the window of fertility are likely to be more effective
      for optimally timing intercourse than calendar calculations or basal body
      temperature. There are several promising methods with good scientific bases to
      identify the fertile window prospectively. These include fertility charting of
      vaginal discharge and a commercially available fertility monitor. These methods
      identify the occurrence of ovulation clinically and also identify a longer window
      of fertility than urinary luteinizing hormone kits. Prospectively identifying the
      full window of fertility may lead to higher rates of conception. Proper
      information given early in the course of trying to achieve pregnancy is likely to
      reduce time to conception for many couples, and also to reduce unnecessary
      intervention and cost.

PMID- 12468182
TI  - Is there a sea change ahead for obstetrics and gynecology?
AB  - A number of beneficial sociocultural reforms have occurred throughout our
      society, including a new work/family balance. This change, and a number of
      others, are challenging the dynamic balance within our specialty. We must
      advocate for appropriate social, political, and economic interventions that will
      realistically mesh with the health care needs of our nation, while preserving
      that which is best about the culture of American medicine.

PMID- 12468183
TI  - Perspectives on the Women's Health Initiative trial of hormone replacement
      therapy.
AB  - The premature termination of one comparison in the Women's Health Initiative
      primary prevention trial due to stopping rules being reached necessitates a
      reconsideration of hormone replacement therapy (HRT). This part of the Women's
      Health Initiative trial, however, examined only one popular HRT regimen
      (conjugated equine estrogen [0.625 mg] and medroxyprogesterone acetate [2.5 mg]
      daily) in asymptomatic postmenopausal women. To help clinicians understand this
      large, complex trial, we describe several pervasive biases in earlier
      observational studies, review the principal findings of the trial, summarize
      recent systematic reviews, and offer clinical suggestions for HRT. Observational
      studies of HRT have found consistent, powerful protection against heart disease;
      this now appears due to consistent, powerful selection biases. These biases have
      the same net effect: Women using HRT in observational studies were healthier than
      those not using it. The Women's Health Initiative trial found that the overall
      risk-benefit ratio tipped against using HRT for prevention. Cardiovascular
      disease and breast cancer were increased among users, whereas colorectal cancer
      and osteoporotic fractures were reduced. Whether these findings relate to women
      with menopausal symptoms and to different HRT regimens is unknown. Hormone
      replacement therapy remains the best treatment for menopausal symptoms. Although
      estrogen has proven benefit for osteoporosis prevention, alternatives include
      raloxifene, alendronate, and risedronate. For women needing HRT, use of a low
      dose, with reassessments at least annually, appears prudent. Heart disease
      prevention strategies of proven value include exercise, weight control, blood
      pressure and lipid control, and avoidance of smoking. Hormone replacement therapy
      should not be used for this purpose.

PMID- 12468184
TI  - Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of
      treatment.

PMID- 12468187
TI  - Smallpox vaccine and pregnancy.

PMID- 12468189
TI  - Uterine necrosis after uterine artery embolization for leiomyoma.

PMID- 12468190
TI  - Chronic hypertension in pregnancy.

PMID- 12468192
TI  - What's a smart woman like you doing at home?

PMID- 12468193
TI  - Secondary cytoreduction surgery for recurrent epithelial ovarian cancer.

PMID- 12468195
TI  - ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician
      Gynecologists: number 41, December 2002.
AB  - Polycystic ovary syndrome (PCOS) is a condition of unexplained hyperandrogenic
      chronic anovulation that most likely represents a heterogenous disorder. Its
      etiology remains unknown, and treatment is largely symptom based and empirical.
      Recent findings suggest PCOS has substantial metabolic sequelae, including risk
      of diabetes and possibly cardiovascular disease, and that primary treatment
      should focus on metabolic sequelae. The purpose of this document is to examine
      the best available evidence on the diagnosis and clinical management of PCOS.

PMID- 12468196
TI  - ACOG Committee Opinion: number 279, December 2002. Prevention of early-onset
      group B streptococcal disease in newborns.
AB  - During the past two decades, group B streptococci (GBS), or Streptococcus
      agalactiae, has emerged as an important cause of perinatal morbidity and
      mortality. Intrapartum administration of antibiotics to the woman (during labor
      or after rupture of membranes, but before delivery) has been demonstrated to
      reduce early-onset neonatal GBS disease. In 1996, the federal Centers for Disease
      Control and Prevention (CDC), the American College of Obstetricians and
      Gynecologists, and the American Academy of Pediatrics recommended that obstetric
      providers adopt either a culture-based or a risk-based approach for the
      prevention of early-onset GBS. A recent multistate retrospective cohort study of
      live births in 1998 and 1999 of residents from eight areas of the Active
      Bacterial Core Surveillance/Emerging Infections Program network suggests that the
      culture-based approach is superior to the risk-based approach. The Committee on
      Obstetric Practice supports the new CDC recommendations that obstetric providers
      adopt a culture-based strategy for the prevention of early-onset GBS disease in
      the newborn. It is important to acknowledge that complete implementation of this
      complex strategy will not eliminate all cases of early-onset GBS.

PMID- 12468197
TI  - ACOG Committee Opinion: number 280, December 2002. The role of the generalist
      obstetrician-gynecologist in the early detection of ovarian cancer.
AB  - The purpose of this Committee Opinion is to define the role of the generalist
      obstetrician-gynecologist in the early detection of ovarian cancer. Currently, it
      appears that the best way to detect early ovarian cancer is for both the patient
      and her clinician to have a high index of suspicion of the diagnosis in the
      symptomatic woman. In evaluating symptoms, physicians should perform a physical
      examination, including a pelvic examination. In premenopausal women with
      symptoms, a CA 125 measurement has not been shown to be useful in most
      circumstances. In postmenopausal women with a pelvic mass, a CA 125 measurement
      may be helpful in predicting a higher likelihood of a malignant tumor than a
      benign tumor, which may be useful in making consultation or referral decisions or
      both. A woman with a suspicious or persistent complex adnexal mass requires
      surgical evaluation by a physician trained to appropriately stage and debulk
      ovarian cancer. Data suggest that currently available screening tests do not
      appear to be beneficial for screening low-risk, asymptomatic women. An annual
      gynecologic examination with an annual pelvic examination is recommended for
      preventive health care.

PMID- 12468198
TI  - ACOG Committee Opinion: number 281, December 2002. Rubella vaccination.
AB  - The incidence of rubella decreased from 0.45 per 100,000 in 1990 to 0.1 per
      100,000 in 1999. Although there is a nationwide shortage of rubella vaccine,
      women who are rubella susceptible during pregnancy should receive MMR (measles
      mumps-rubella) vaccination postpartum. In October 2001, the federal Centers for
      Disease Control and Prevention changed the recommendations concerning the
      pregnancy interval after receiving rubella vaccine. This interval has been
      reduced from 3 months to 1 month.

PMID- 12468199
TI  - Apoptosis in leukocytes induced by UVA in the presence of 8-methoxypsoralen,
      chlorpromazine or 4,6,4'-trimethylangelicin.
AB  - Although 8-methoxypsoralen (8-MOP) has been successfully used in extracorporeal
      photochemotherapy (ECP) of several T cell-mediated diseases, the exact mechanism
      of the drug therapeutic action has not been established. We have studied in vitro
      apoptotic activity of 8-MOP, and for comparison of 4,6,4'-trimethylangelicin
      (TMA) and chlorpromazine (CPZ) as alternative photosensitizers for potential use
      in photopheresis. However, while 8-MOP and CPZ are known for their immune
      suppressive activity, TMA does not exhibit such an activity in an animal model
      for ECP. Apoptosis and necrosis were measured in both Jurkat cells and primary
      rat leukocytes under conditions comparable to those used in the animal model to
      suppress contact hypersensitivity (CHS). Cells were irradiated with UVA (200
      kJ/m(2)) after treatment with 8-MOP, CPZ or TMA (300 ng/ml). Flow cytometric
      analysis (annexin-V-FLUOS/propidium iodide) and fluorescence microscopy
      examinations, using acridine orange/propidium iodide, indicated that the number
      of cells undergoing apoptosis or necrosis increased significantly after 24 h
      following treatment. Similar results were observed irrespective of the cell type
      and photosensitizer used. The results of the present study, combined with
      previous observations with the animal model for ECP, suggest that apoptosis is
      not likely to be a critical step in the cascade of events leading to
      immunosuppression.

PMID- 12468200
TI  - Investigation of photobleaching of hypocrellin B in non-polar organic solvent and
      in liposome suspension.
AB  - Hypocrellin B (HB) is a natural pigment with a promising application in the
      photodynamic therapy (PDT) for anticancer treatment. The photobleaching of HB in
      non-polar organic solvents and in liposomes in aqueous solution were investigated
      by the measurements of absorption spectra, quenching experiments and
      determination of photoproducts. Control experiments indicated that the
      sensitizer, oxygen and light were all essential for the photobleaching of HB,
      which suggested that it was mainly self-sensitized photooxidation. The
      illumination of HB with visible light in aerobic non-polar solvent generated
      singlet oxygen efficiently [Phi(1O(2))=0.76] which then attacked the sensitizer
      HB with formation of an endoperoxide product. The endoperoxide of HB was unstable
      at room temperature and underwent predominantly loss of singlet oxygen with
      regeneration of parent HB. The singlet oxygen released from the endoperoxide of
      HB was detected with chemical trapping experiments. When HB was embedded in EPC
      liposomes, no endoperoxide product and no singlet oxygen release from the
      photobleaching process of HB were detected. The quenching experiments indicated
      that the singlet oxygen mechanism (type II) played an important role in the non
      polar solvent and the free radical mechanism (type I) was predominant in
      liposomal aqueous solution for the photobleaching of HB.

PMID- 12468201
TI  - Epidermal reconstructs: a new tool to study topical and systemic photoprotective
      molecules.
AB  - In this study, we compared the effects of sunscreens and antioxidants on
      reconstructed epidermis made with or without melanocytes 24 h after UVB, UVA or
      UVA+B irradiation. For this purpose, we studied sunburn cells and cyclobutane
      pyrimidine dimer formation, protein and lipid oxidation, catalase and superoxide
      dismutase activities and vitamin E levels. Topical sunscreens protected against
      direct cell death and thymine dimer formation whereas their protective effect
      against protein and lipid oxidation and antioxidant depletion was less marked
      partly due to the difficulty of spreading the cream. Antioxidant molecules
      protected against direct cell death and protein oxidation but not against thymine
      dimer formation. Since topical sunscreens and systemic antioxidant protected the
      skin differently, we speculate that their association might protect more
      efficiently against UV-induced damage. This model is relevant to study systemic
      molecules but is less practical, due to the technical limitations of studying
      topical molecules.

PMID- 12468202
TI  - Estimation of energy of the upper electron-excited states of the bacterial
      bioluminescent emitter.
AB  - The hypothesis of activity of the upper electron-excited states of the bacterial
      bioluminescent emitter was verified using dye molecules as foreign energy
      acceptors. Six compounds were selected having fluorescent state energies ranging
      from 25,700 to 32,000 cm(-1) (anthracene, pyrene, 1.4-bis(5-phenyloxasol-2
      yl)benzene (POPOP), p-bis(o-methylstyryl)benzene (MSB), 2-methoxy-naphtalene, p
      terphenyl), exceeding that of the bioluminescent emitter (22,000 cm(-1)). Their
      absorption spectra do not overlap with the bioluminescence spectrum; the trivial
      light absorption and the intermolecular resonance S-S energy transfer were
      excluded. Bacterial bioluminescent spectra of the coupled enzyme system NADH:FMN
      oxidoreductase-luciferase in the presence of MSB were presented as an example.
      The weak sensitized fluorescence of MSB was registered. The results obtained have
      confirmed the activity of the energetic precursor in the bacterial
      bioluminescence. Its energy can be located in the interval of 26,000-27,000 cm(
      1).

PMID- 12468203
TI  - Erythrocyte response to near-infrared radiation.
AB  - The effects of NIR (near-infrared radiation 700-2,000 nm) on bovine erythrocytes
      in plasma was studied as a continuation of earlier studies. Cell shape was
      observed and the changes of ratio of hemolysis and electrokinetic potential
      measured as a function of irradiation time. After 10 min of irradiation, the
      shape of erythrocyte cells was mainly echinocytic. When these cells were
      incubated at 311 K for 24 h they regained their initial shape, but fresh
      erythrocytes that were irradiated for 30 min and aged in vitro did not. These
      phenomena are due to: (1) the absorption of NIR excitation by hemoglobin; the
      primary photochemical process being the photo-dissociation of oxyhemoglobin to
      deoxyhemoglobin. Resulting shape and ratio of hemolysis, structural changes and
      oxidative stress follow higher deoxyhemoglobin concentration. (2) The absorption
      of the NIR excitation by proteins, water and lipids. After NIR absorption the
      membrane surface dehydrates, leading to enhanced protonation and dissociation of
      hydrogen-bonded complexes. This in turn leads to a change in electrokinetic
      potential.

PMID- 12468204
TI  - Anti-tumor effect of Merocyanine 540-mediated photochemotherapy combined with
      Edelfosine: potential implications for the ex vivo purging of hematopoietic stem
      cell grafts from breast cancer patients.
AB  - High-dose chemotherapy combined with autologous stem cell support has improved
      response rates in high-risk and metastatic breast cancer, but has failed to
      improve long-term survival. Breast cancer has a tendency to metastasize to the
      bone marrow, and live tumor cells are known to circulate in the peripheral blood
      of breast cancer patients. Sensitive immunohistochemical, culture-based, and
      reverse transcriptase polymerase chain reaction (RT-PCR)-based methods have shown
      that about 50% of histologically normal stem cell grafts from breast cancer
      patients are contaminated with occult tumor cells, which may cause or contribute
      to tumor recurrences. Merocyanine 540 (MC540)-mediated photodynamic therapy (PDT)
      inactivates a wide range of leukemia and lymphoma cells and is well tolerated by
      normal hematopoietic stem and progenitor cells. Unfortunately, most solid tumor
      cells (including breast cancer cells) are only moderately sensitive or refractory
      to MC540-PDT. We report here that if MC540-PDT is followed by a 1-h incubation
      with the alkyl-lysophospholipid, Edelfosine (ET-18-OCH(3)), the depletion of
      murine and human breast cancer cells is greatly enhanced whereas the recovery of
      normal hematopoietic stem and progenitor cells is only minimally degraded. When
      used under conditions that reduce CD34-positive human bone marrow cells only 5.1
      fold, and murine and human granulocyte/macrophage progenitors 6.8- and 3-fold,
      respectively, combination purging with MC540-PDT and Edelfosine depletes murine
      (Mm5MT) and human (MDA-MB-435S) breast cancer cells >17,000- and >125,000-fold,
      respectively. These data suggest that combination purging with MC540-PDT and
      Edelfosine may offer a simple, safe and effective method for the ex vivo purging
      of autologous stem cell grafts from breast cancer patients.

PMID- 12468205
TI  - Ultraviolet radiation has no effect on respiratory oxygen consumption or enhanced
      post-illumination respiration in three species of microalgae.
AB  - A 30-min exposure to UV-B radiation (1.1 Wm(-2), unweighted) from a xenon arc
      lamp caused pronounced inhibition (33-78%) of net photosynthetic oxygen
      production in three species of microalgae, Phaeodactylum tricornutum Bohlin,
      Dunaliella tertiolecta Butcher and Wolozynskia sp., however, no statistical
      differences (t-test, alpha=0.05) in dark-respiration rates were found between the
      control group and the UV-treated group, for any of the species tested. These
      results indicate: (i) that the respiratory processes responsible for oxygen
      consumption do not sustain any appreciable impairment registered in the first
      half-hour after ultraviolet radiation (UVR) exposure; and (ii) any change in
      respiration that may occur in response to increased repair demands is not
      detected in this period. Dark-respiration rates were observed to be significantly
      higher in all species tested (17-29%; t-test, alpha=0.05) following illumination
      with photosynthetically active radiation, compared to dark-respiration before
      illumination. This increase, interpreted as enhanced post-illumination
      respiration (EPIR), was observed in all three species. The magnitude of this
      increase was not affected by prior exposure to UVR.

PMID- 12468206
TI  - Kinetic study of delta-Ala induced porphyrins in mice using photoacoustic and
      fluorescence spectroscopies.
AB  - The production of delta-aminolevulinic acid (ALA)-induced porphyrins in mice skin
      and blood was studied by photoacoustic and fluorescence spectroscopies. Mice were
      intraperitoneally administered with 30 mg/kg of ALA. The abdominal skin was
      subsequently excised at specific times within an 8-h interval and its absorption
      spectrum obtained by photoacoustics. The highest porphyrins concentration in
      skin, determined from the optical absorption of the Soret band at 410 nm, was
      found to occur nearly 2 h after ALA administration, but a first peak was also
      observed at approximately 15 min. Our hypothesis that the first peak represents
      the porphyrins content in blood vessels within the skin, whereas the second peak
      corresponds to porphyrins production in skin tissue, was confirmed by analysing
      the evolution of protoporphyrin IX content in plasma extracted intracardiacally.
      By finally applying phase resolved photoacoustic spectroscopy, we were able to
      evaluate the mean depth at which porphyrins are generated.

PMID- 12468207
TI  - Synthesis, dark toxicity and induction of in vitro DNA photodamage by a tetra(4
      nido-carboranylphenyl)porphyrin.
AB  - The total synthesis of tetra(4-carboranylphenyl)porphyrins 4 and 6 and their
      zinc(II) complexes 5 and 7 are described. These compounds were characterized by
      analytical and spectroscopic methods and, in the case of 5, by X-ray
      crystallography. The water-soluble nido-carboranylporphyrins 6 and 7 were found
      to have low dark toxicity towards V79 hamster lung fibroblast cells, using a
      clonogenic assay (50% colony survival, CS(50)>300 microM). Upon light activation
      nido-carboranylporphyrin 6 effectively induced DNA damage in vitro. Two different
      methods were used to assess the extent of DNA damage: the super-coiled to nicked
      DNA and the alkaline Comet assay using human leukemia K562 cells. Significant PDT
      induced DNA damage was observed for porphyrin 6 using both assays, compared to
      light-only and porphyrin-only experiments. It is concluded that this type of nido
      carboranylporphyrin is a promising sensitizer for both the boron neutron capture
      therapy and the photodynamic therapy of tumors.

PMID- 12468208
TI  - Protection against UVB irradiation by natural filters extracted from lichens.
AB  - Natural substances extracted from lichens and boldo tree were tested in vivo and
      in vitro as possible UV-light filters. The protection factors were compared with
      that found for the references: Nivea sun Spray LSF 5, octylmethoxycinnamate (OMC)
      and 4-tert.-butyl-4'-methoxy dibenzoylmethane (BM-DBM). The stability of the
      single compounds was studied through UV-Vis spectroscopy. Usnic acid resulted to
      be the best UVB filter, with an in vivo protection factor similar to Nivea sun
      Spray LSF 5. Most of the single compounds studied in vitro resulted to have
      higher or similar filtering power than octylmethoxycinnamate. The protection
      factors as well as the good UV-light absorption of their photo-products suggest
      that these natural substances may be useful as new filters in sun-screen
      preparations.

PMID- 12468209
TI  - Site-directed photochemical disruption of the actin cytoskeleton by actin-binding
      Rose Bengal-conjugates.
AB  - The in situ light-induced, non-enzymatic digestion of cytoskeletal actin by a
      xanthene dye conjugated to heavy meromyosin, anti-actin antibodies and/or anti
      myosin antibodies is reported. The dye Rose Bengal was conjugated to either anti
      actin antibodies, anti-myosin antibodies or heavy meromyosin. Under our
      experimental conditions, visible light induced the non-enzymatic breakdown of
      cytoskeletal actin when mammalian tissue culture cells were probed either with
      Rose Bengal-conjugated anti-actin and/or anti-myosin antibodies. Similar results
      were obtained when tissue culture cells were probed with Rose Bengal-conjugated
      heavy meromyosin before irradiation with visible light. The in situ photochemical
      reaction depended on the presence of actin-binding Rose Bengal-conjugates.

PMID- 12468210
TI  - Hyperpigmentation induced by topical 5-aminolaevulinic acid plus visible light.
AB  - Photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) is an alternative
      tool for the treatment of superficial non-melanoma skin cancers. Recently ALA-PDT
      has been employed with encouraging results also for warts, condylomata and
      psoriasis. In this study the effects of topical ALA plus irradiation with visible
      light on intact human skin have been evaluated. Five skin areas (A, B, C, D, and
      E) on the inner upper part of the arms of five healthy volunteers (skin types III
      and IV) were treated with (A) ALA 20% in base cream without irradiation, (B) only
      the vehicle (base cream) without ALA, (C, D and E) ALA cream at the
      concentrations of 5, 10 and 20%, respectively; all treatments were applied with
      an occlusive dressing. Four hours after ALA or vehicle application areas B, C, D
      and E were irradiated with a fixed dose of 40 J/cm(2). ALA penetration through
      the intact skin was evaluated by in vivo fluorescence determination. The effects
      on healthy skin were evaluated by clinical and chromometric examinations, light
      microscopy, immunohistochemistry and electron microscopy. RESULTS: (1) in vivo
      fluorescence demonstrated that ALA is able to penetrate through the intact skin,
      when applied with occlusive dressing and induces a classical fluorescence peak
      due to Protoporphyrin IX (PpIX) formation, which is the active photosensitiser.
      (2) Skin areas receiving ALA plus irradiation showed erythema and swelling just
      after the irradiative session and hyperpigmentation 48-72 h later. (3)
      Colourimetric data confirmed significant skin colour changes: values a*
      (representing the erythematous changes) increased only on the skin areas where
      ALA+irradiation were applied and during the 48 h after irradiation, thereafter a*
      began to decrease; values L* (pigmentation) increased during the 2 weeks
      following treatment. (4) Histopathological, immunohistochemical (S100, HMB-45)
      and electron microscopic findings showed an absolute increment of the number of
      melanocytes, which appeared clearly activated. In conclusion the application of
      ALA cream followed by irradiation is able to induce a pigmentation response in
      healthy human skin, at least in skin types III and IV. This melanocytic
      activation could have a potential for the treatment of skin disorders
      characterised by hypopigmentation.

PMID- 12468211
TI  - Two-photon excitation studies of hypocrellins for photodynamic therapy.
AB  - The photophysical and photochemical properties of hypocrellins (HA and HB) are
      examined with two-photon excitations at 800 nm using femtosecond pulses from a
      Ti:sapphire laser. The two-photon excited fluorescence spectra of HA and HB are
      very similar to those obtained by one-photon excitation, which may indicate that
      the two-photon induced photodynamic processes of hypocrellins are similar to one
      photon induced photodynamic processes. The two-photon excitation cross sections
      of HA and HB are measured at 800 nm as about 34.8 x 10(-50) cm(4) s/photon and
      21.3 x 10(-50) cm(4) s/photon, respectively. The large two-photon cross sections
      of both HA and HB, suggest that the hypocrellins can be potential two-photon
      phototherapeutic agents. As an example for two-photon photodynamic therapy of
      hypocrellins, we also further examine the cell-damaging effects of HA upon two
      photon illumination. Our preliminary results of cell viability test indicate
      hypocrellins can effectively damage the Hela cells under two-photon illumination.

PMID- 12468213
TI  - Studies on alginate-chitosan microcapsules and renal arterial embolization in
      rabbits.
AB  - Spherical and well-dispersed alginate-chitosan microcapsules, with a mean
      diameter of 77.28+/-0.93 microm (n=3), were prepared by the emulsification
      gelation method. Adriamycin hydrochloride (ADM) was used as a model drug to
      investigate the drug loading capacity and release characteristics of the
      microcapsules. The drug/carrier ratio and chitosan concentration influenced the
      encapsulation efficiency of adriamycin. The adriamycin release from microcapsules
      was obviously different in 0.1 mol/l HCl from that in phosphate-buffered saline
      (PBS, pH 7.4). The drug was completely and rapidly released in 0.1 mol/l HCl,
      while it showed a sustained release after a burst release in PBS. The increase in
      chitosan concentration had no effect on adriamycin release in PBS. Using
      sulforhodamin B (SRB)-staining survival assay, the inhibition of adriamycin
      alginate-chitosan microcapsules (ADM-ACM) to different cancer cell lines (human
      BGC-823 cells, Bel-7402 cells and Hela cells) in vitro was determined. The
      inhibitory rate of ADM-ACM suspension to the three cell lines significantly
      outran that of ADM solution, no matter at high or low concentration. The effects
      of blank alginate-chitosan microcapsules (BACM) on renal arterial embolization
      were examined with transcatheter arterial embolization in rabbits. The angiogram
      and histopathological results indicated the blank microcapsules had excellent
      short- and long-term effects on renal arterial embolization.

PMID- 12468214
TI  - Design of controlled-release solid dosage forms of alginate and chitosan using
      microwave.
AB  - The influence of microwave irradiation on the drug release properties of
      alginate, alginate-chitosan and chitosan beads was investigated. The beads were
      prepared with the highest possible concentration of polymer by an extrusion
      method. Sulphathiazole was selected as a model drug. The beads were subjected to
      microwave irradiation at various combinations of irradiation power and time. The
      profiles of drug dissolution, drug content, drug stability, drug polymorphism,
      drug-polymer interaction, polymer crosslinkage and complexation were determined
      by dissolution testing, drug content assay, differential scanning calorimetry
      (DSC) and fourier transform infra-red spectroscopy (FTIR). The chemical stability
      of the drug entrapped in the beads was unaffected by the microwave irradiation.
      However, the drug in the chitosan beads underwent polymorphic changes.
      Polymorphic changes were prevented by means of drug-alginate interaction in
      alginate and alginate-chitosan beads. Changes in the polymorphic state of drug
      were found to have insignificant effect on the drug release profiles of chitosan
      beads. The release-retarding property of alginate and alginate-chitosan beads was
      significantly enhanced by subjecting the beads to microwave irradiation.
      Positively charged calcium ions and chitosan are known to interact with
      negatively charged alginate. DSC and FTIR analyses indicated that the reduction
      in rate and extent of drug released from the treated beads was primarily due to
      additional formation of non-ionic bonds, involving alginate crosslinkage and
      alginate-chitosan complexation. The results showed that microwave technology can
      be employed in the design of solid dosage forms for controlled-release
      application without the use of noxious chemical agents.

PMID- 12468215
TI  - Investigation of the factors influencing the release rates of cyclosporin A
      loaded micro- and nanoparticles prepared by high-pressure homogenizer.
AB  - An oil-in-water solvent evaporation method was used to prepare cyclosporin A
      (CyA)-loaded particles varying in size (nanoparticles, 'small-sized'
      microparticles, 'large-sized' microparticles), polymer compositions [poly(D,L
      lactide-co-glycolic acid) (PLGA) 50/50, PLGA 85/15, poly(D,L-lactic acid) (PLA)]
      and additive fatty acid ester (ethyl myristate; EM). The particles were
      characterized for drug loading and entrapment efficiency by high-performance
      liquid chromatography, particle size by dynamic light scattering and surface
      morphology by scanning electron microscopy (SEM). In vitro release kinetics were
      studied using a modified dialysis method. The results showed drug loadings
      ranging from 6.48 to 9.01% with high encapsulation efficiency (71.2-98.9%). SEM
      studies showed discrete and spherical particles with smooth surfaces, whereas
      rather gross surface defects resulted from the incorporation of EM as an
      additive. The release profiles of various formulations approximated zero-order
      release kinetics in the first 3 weeks with a negligible initial burst. In
      general, the smaller the particle size and the higher the glycolic acid content
      in the copolymer, the faster the release of CyA. The effect of EM on the release
      profile appeared to be rather complex since an increased release rate was
      observed from EM containing PLGA 50/50 particles, whereas the incorporation of EM
      into the PLGA 85/15 and PLA particles led to a decreased release rate. Further
      investigation needs to be performed to elucidate the reason why EM influences the
      CyA release differently depending on the particle size and polymer type.

PMID- 12468216
TI  - Study of release kinetics of small and high molecular weight substances dispersed
      into spray-dried ethylcellulose microspheres.
AB  - Spray-dried ethylcellulose microspheres were used as matrices for the
      encapsulation of a fungal lactase and/or small paramagnetic probes (Tempol or
      Tempo). Their dissolution in water was studied. Kinetics fitted with the model Q
      = kt(n) of Korsemeyer et al. [Int. J. Pharm. 15 (1983) 25] exhibited a non
      Fickian diffusion. The calculated diffusional exponent (n) values were near 0.26
      whatever the encapsulated probes. The release rates (k) were only slightly
      different for paramagnetic probes and lactase. This result indicated that the
      probes' release mechanisms are not diffusion controlled. Other factors such as
      matrix porosity and probe solubility in the matrix and in water could influence
      the probes' release rate.

PMID- 12468217
TI  - Controlled release of an osteogenic peptide from injectable biodegradable
      polymeric composites.
AB  - Poly(D,L-lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) blend
      microparticles loaded with the osteogenic peptide TP508 were added to a mixture
      of poly(propylene fumarate) (PPF), poly(propylene fumarate)-diacrylate (PPF-DA),
      and sodium chloride (NaCl) for the fabrication of PPF composite scaffolds that
      could allow for tissue ingrowth as well as for the controlled release of TP508
      when implanted in an orthopedic defect site. In this study, PPF composites were
      fabricated and the in vitro release kinetics of TP508 were determined. TP508
      loading within the PLGA/PEG microparticles, PEG content within the PLGA/PEG
      microparticles, the microparticle content of the PPF composite polymer component,
      and the leachable porogen initial mass percent of the PPF composites were varied
      according to a fractional factorial design and the effect of each variable on the
      release kinetics was determined for up to 28 days. Each composite formulation
      released TP508 with a unique release profile. The initial release (release
      through day 1) of the PLGA/PEG microparticles was reduced upon inclusion in the
      PPF composite formulations. Day 1 normalized cumulative mass release from PPF
      composites ranged from 0.14+/-0.01 to 0.41+/-0.01, whereas the release from
      PLGA/PEG microparticles ranged from 0.31+/-0.02 to 0.58+/-0.01. After 28 days,
      PPF composites released 53+/-4% to 86+/-2% of the entrapped peptide resulting in
      cumulative mass releases ranging from 0.14+/-0.01 microg TP508/mm(3) scaffold to
      2.46+/-0.05 microg TP508/mm(3) scaffold. The results presented here demonstrate
      that PPF composites can be used for the controlled release of TP508 and that
      alterations in the composite's composition can lead to modulation of the TP508
      release kinetics. These composites can be used to explore the effects varied
      release kinetics and dosages on the formation of bone in vivo.

PMID- 12468218
TI  - Effects of material hydrophobicity on physical properties of polymeric
      microspheres formed by double emulsion process.
AB  - Human serum albumin (HSA) was encapsulated as a model protein in microspheres of
      biodegradable and biocompatible polymers by the water-in-oil-in-water (w/o/w)
      emulsion solvent extraction/evaporation (double emulsion) technique for purpose
      of controlled release. To improve the properties and control the rate of drug
      release of the delivery vehicle, materials with different hydrophobicity from
      that of their conventional counterparts, such as poly(lactide-co-ethylene glycol)
      (PELA) in place of poly(lactide-co-glycolide) (PLGA) as the polymer matrix, ethyl
      acetate/acetone in place of dichloride methane (DCM) as the (co)solvent and d
      alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) as the
      additive, were used to prepare the microspheres. It has been found that PELA
      microspheres, compared with PLGA ones, were slightly smaller in size if prepared
      at identical emulsification strength. They had more porous surface and internal
      structure, higher encapsulation efficiency (EE) and more rapid in vitro release
      rate. Furthermore, the physical properties of the microspheres were also affected
      by the presence of solvents and additives and their properties. Our results
      suggest that these materials could have interesting potential applications in
      preparation of polymeric microspheres for controlled protein release.

PMID- 12468219
TI  - Development of an in vitro drug release assay that accurately predicts in vivo
      drug retention for liposome-based delivery systems.
AB  - The therapeutic activity of numerous drugs can be dramatically improved by
      liposomal encapsulation. However, this requires that liposomes retain their
      encapsulated drugs following systemic administration. Often, in vitro drug
      release assays do not accurately predict the liposomal drug retention properties
      observed in vivo. We postulate that this discrepancy is due to the large membrane
      pool present in blood cells and tissues, into which drugs can distribute after in
      vivo administration. Herein we describe an in vitro drug release assay that more
      accurately predicts in vivo drug release from liposomes following systemic
      administration. Drug-encapsulated large unilamellar vesicles (LUVs) approximately
      100 nm in diameter were incubated with a 100-fold excess of multilamellar
      vesicles (MLVs) containing 300 mM sucrose, which served as 'acceptors' for drug
      release and transfer from 'donor' LUVs. Following incubation at 37 degrees C, the
      donor and acceptor populations were separated with greater than 90% efficiency by
      centrifugation at 1600xg for 10 min. The amount of drug in the MLV pellet
      reflects the degree of drug leakage from the donor liposomes. Drug release
      profiles using this in vitro assay were compared to those obtained using dialysis
      based assays and in vivo results following systemic administration to mice. Our
      results indicate that this release assay is a better predictor of in vivo drug
      transfer than dialysis-based systems. We also demonstrate its utility in
      measuring exchange of lipophilic components.

PMID- 12468220
TI  - Distribution and quantification of polyethylenimine oligodeoxynucleotide
      complexes in human skin after iontophoretic delivery using confocal scanning
      laser microscopy.
AB  - Iontophoresis may be a potentially useful technique for the delivery of
      oligonucleotides into the skin. To enhance intracellular uptake during
      iontophoresis, we investigated the dermal delivery of oligodeoxynucleotides (ODN)
      as a polyelectrolyte complex with polyethylenimine (PEI). Perpendicular cross
      sectioning was performed to visualize and quantify the penetration properties of
      double labeled PEI/ODN complexes across full thickness human skin. Due to the net
      positive charge of the complexes, anodal iontophoresis was expected to enhance
      skin delivery by electrorepulsion compared to passive diffusion. Confocal laser
      scanning microscopy demonstrated that non-complexed ODN could penetrate the skin
      after 1 h of cathodal iontophoresis but not by passive diffusion or anodal
      iontophoresis. However, extensive degradation occurred as documented by a
      dramatic decrease of fluorescence intensity within viable skin tissue after 10 h.
      Anodal iontophoresis of the complexes led to a deep penetration of both the TAMRA
      labeled ODN and the Oregon Green-labeled PEI. A constant increase in fluorescence
      indicated a protective effect of the polymer against nuclease degradation. Co
      localization of red and green fluorescence was noted within numerous nuclei of
      epidermal keratinocytes. In contrast, passive diffusion of the complexes did not
      lead to successful uptake into keratinocytes and was limited to the stratum
      corneum. Complexation of ODN by PEI, therefore, seems to be a promising method to
      enhance both the transport of charged complexes into the skin and to facilitate
      intracellular uptake, which may potentially be useful for the local treatment of
      skin diseases using ODN.

PMID- 12468221
TI  - Translocation through the nuclear pore complex.

PMID- 12468222
TI  - A closer look at the cholesterol sensor.

PMID- 12468223
TI  - MARVEL: a conserved domain involved in membrane apposition events.

PMID- 12468229
TI  - TSE agent strains and PrP: reconciling structure and function.
AB  - The molecular structures of the infectious agents that cause transmissible
      spongiform encephalopathy (TSE) diseases are still not known despite the current
      wide acceptance of the prion hypothesis as the basis for their resolution. Here,
      data supporting and challenging the prion hypothesis in relation to both the
      biochemical and biological properties of TSE infectious agents are discussed. The
      need for the independent transmission of TSE agent-specific genetic information
      is described and the requirements for the molecule to carry this information are
      proposed. Such a molecule is likely to be a small nucleic acid encoding
      information to determine the diversity of the pathogenesis of TSE agents.

PMID- 12468230
TI  - p53 latency--out of the blind alley.

PMID- 12468231
TI  - Multisite phosphorylation provides sophisticated regulation of transcription
      factors.
AB  - Reversible phosphorylation is a prevalent mechanism by which the activity of
      eukaryotic transcription factors is regulated rapidly in response to changes in
      the cellular environment. Accumulated evidence has expanded the concept of
      phosphorylation to a process that provides dynamic and precise tuning of the
      transactivating potential of a factor, rather than being a static on/off switch.
      In the case of transcription factors such as heat shock factor 1 (HSF1), p53 and
      nuclear factor of activated T cells (NFAT), multisite phosphorylation enables
      several effects to operate within a single factor, thereby functioning as a key
      to signal integration. Studies on these transcription factors illustrate recent
      progress in solving the dynamic nature of transcriptional regulation by multisite
      phosphorylation.

PMID- 12468232
TI  - The chaperonin folding machine.

PMID- 12468233
TI  - The third dimension for protein interactions and complexes.

PMID- 12468234
TI  - Biochemistry, the early years at Liverpool.

PMID- 12468237
TI  - Liver regeneration with reference to stem cells.

PMID- 12468238
TI  - Hepatic progenitor cells in human liver diseases.
AB  - The canals of Hering and bile ductules in human liver contain hepatic progenitor
      cells that can differentiate towards the biliary and hepatocytic lineage.
      Proliferation and differentiation of hepatic progenitor cells is referred to as
      'activation' and this process occurs to a variable degree in almost all human
      liver diseases. Several studies indicate that hepatic progenitor cell activation
      in diseased liver is regulated by neural and neuroendocrine factors such as the
      vagal innervation. Analogous to oval cells in animal liver, there is evidence
      that human hepatic progenitor cells may be able to give rise to hepatocellular
      carcinoma and other liver tumors.

PMID- 12468239
TI  - Progenitor cells of the biliary epithelial cell lineage.
AB  - Stem-like cells have been identified in liver that are able to differentiate in
      vivo and in culture to biliary epithelial cells (BEC), hepatocytes and oval
      cells. The growth factors/cytokines and signal pathways required for the
      differentiation processes are beginning to be evaluated. There is increasing
      evidence to suggest that these stem-like cells may originate from both the bone
      marrow population or from a precursor remnant from liver embryogenesis, as they
      share many of the same markers (CD34, c-kit, CD45). Most recently, it has been
      shown that a population of progenitor cells can copurify with mesenchymal bone
      marrow cells and differentiate under specific culture conditions to form both
      hepatic epithelial and also endothelial cells. The interaction of haemopoietic
      and mesenchymal stem cells needs further evaluation. The close association of
      ductular reactive cells and neovessels in end-stage cholestatic liver diseases
      and the relation to Jagged/Notch signalling pathway may be important in the
      regulation of stem cells to form both biliary epithelial and endothelial cells.

PMID- 12468240
TI  - Hepatic oval 'stem' cell in liver regeneration.
AB  - Hepatic oval cell activation, proliferation, and differentiation has been
      observed under certain physiological conditions, mainly when the proliferation of
      existing hepatocytes has been inhibited followed by severe hepatic injury.
      Hepatic oval cells display a distinct phenotype and have been shown to be a
      bipotential progenitor of two types of epithelial cells found in the liver,
      hepatocytes and bile ductular cells. Bone marrow stem cells have recently been
      shown to be a potential source of the hepatic oval cells and that reconstitution
      of an injured liver from a purified stem cell population is possible. The focus
      of this review is on the studies involving the activation, proliferation, and
      differentiation of these hepatic oval cells and the role that they play in
      regeneration of the damaged liver. In order to present the potentiality of the
      hepatic oval cell, an experimental model that involves the inhibition of normal
      hepatic growth and division as well as severe hepatic injury via chemical or
      surgical means has been employed. In this model, an as yet undetermined signal or
      perhaps the lack of regenerative capability in the hepatocytes activates the
      hepatic oval cell compartment. However, other than understanding a potential
      origin of these cells and some of the markers that characterize them, it still
      remains unclear as to how these cells migrate ('home') into the damaged areas and
      how they begin their differentiation into mature and functioning hepatic cells.

PMID- 12468241
TI  - Bone marrow to liver: the blood of Prometheus.
AB  - The existence of hepatic stem or progenitor cells has been controversial for
      decades, though it was presumed that if such cells existed, they would lie within
      the liver. There is now consensus, however, that not only do facultative hepatic
      stem cells exist within the liver, but also that cells from extra-hepatic sites,
      in particular the bone marrow, can contribute to hepatocyte and cholangiocyte
      regeneration. Despite confidence that engraftment of marrow cells in the liver
      occurs, the mechanistic details of this process remain poorly understood.
      Moreover, the physiological importance and therapeutic utility of this phenomenon
      remains controversial.

PMID- 12468242
TI  - Cellular origin of hepatocellular carcinomas.
AB  - There are four levels of cells in the hepatic lineage which may respond to
      different carcinogenic regimens: (1) the mature hepatocyte, which responds to
      diethylnitrosamine (DEN) hepatocarcinogenesis. (2) The bile duct progenitor
      cells, which give rise to cholangiocellular carcinomas when the furan model is
      used or when hamsters infected with liver flukes (Clornorchis sinensis) are
      exposed to dimethylnitrosamine. (3) The ductular 'bipolar' progenitor cell which
      gives rise to hepatocellular carcinomas (HCC) in several N-2-acetylaminofluorene
      (N-2-AAF) based regimens, and (4) the periductular stem cell, which is the cell
      of origin of HCC induced by the choline deficiency models of
      hepatocarcinogenesis. Extrahepatic (bone marrow) origin of the periductular stem
      cells is supported by recent data showing that hepatocytes may express genetic
      markers of donor hematopoietic cells after bone marrow transplantation.

PMID- 12468243
TI  - The role of non-parenchymal cells in liver growth.
AB  - The main non-parenchymal cells of the liver, Kupffer cells, sinusoidal
      endothelial cells and stellate cells, participate in liver growth with respect to
      both their own proliferation, and effects on hepatocyte proliferation. In the
      well-characterised paradigm of 70% partial hepatectomy, they undergo DNA
      synthesis and cell division 20-24h later than the hepatocyte population. They
      exert both positive and negative influences on hepatocyte proliferation,
      including provision of an extracellular matrix-bound reservoir of hepatocyte
      growth factor that is activated after damage; priming of hepatocytes for DNA
      synthesis through rapid generation of TNF-alpha and IL-6; and generation of
      factors at later time points that curb hepatocyte DNA synthesis (IL-1, TGF-beta)
      and initiate reconstruction and reformation of matrix proteins.

PMID- 12468244
TI  - Principles of hepatocyte repopulation.
AB  - Hepatocyte transplantation (HTx) is technically feasible and can be clinically
      beneficial. Current research focuses on optimizing parameters which relate to the
      outcome of HTx, including site of transplantation, cell number and, most notably,
      the preferred cell type to be transplanted (differentiated adult vs. fetal
      hepatocytes vs. putative progenitor or precursor cells). However, the single
      major impediment towards the clinical effectiveness of HTx is the limited
      expansion of donor cells in the recipient liver. To this end, a relative growth
      advantage must be present or is to be imposed on transplanted hepatocytes versus
      resident cells. Possible strategies are presented and discussed.

PMID- 12468245
TI  - Therapeutic potential of hepatocyte transplantation.
AB  - Liver repopulation with transplanted cells offers unique opportunities for
      treating a variety of diseases and for studies of fundamental mechanisms in cell
      biology. Our understanding of the basis of liver repopulation has come from
      studies of transplanted cells in animal models. A variety of studies established
      that transplanted hepatocytes as well as stem/progenitor cells survive, engraft,
      and function in the liver. Transplanted cells survive life-long, although cells
      do not proliferate in the normal liver. On the other hand, the liver is
      repopulated extensively when diseases or other injuries afflict native
      hepatocytes but spare transplanted cells. The identification of ways to
      repopulate the liver with transplanted cells has greatly reinvigorated the field
      of liver cell therapy. The confluence of insights in stem/progenitor cells,
      transplantation immunology, cryobiology, and liver repopulation in specific
      models of human diseases indicates that the field of liver cell therapy will
      begin to reap the promised fruit in the near future.

PMID- 12468246
TI  - Improving the next generation of bioartificial liver devices.
AB  - Several extracorporeal bioartificial liver (BAL) devices are currently being
      evaluated as an alternative or adjunct therapy for liver disease. While these
      hybrid systems show promise, in order to become a clinical reality, BAL devices
      must clearly demonstrate efficacy in improving patient outcomes. Here, we present
      aspects of BAL devices that could benefit from fundamental advances in cell and
      developmental biology. In particular, we examine the development of human
      hepatocyte cell lines, strategies to stabilize the hepatocyte phenotype in vitro,
      and emphasize the importance of the cellular microenvironment in bioreactor
      design. Consideration of these key components of BAL systems will greatly improve
      next generation devices.

PMID- 12468247
TI  - Identification and propagation of liver stem cells.
AB  - Although the liver has been known for its enormous regenerative capacity, little
      is known about the mechanisms responsible for such regeneration.To provide
      evidence for the existence of liver stem cell, using FACS and single cell-based
      assays, cells with multi-lineage differentiation potential and self-renewal
      capability have been prospectively identified. These cells could be clonally
      propagated in culture where they continuously produced hepatocytes and
      cholangiocytes as descendants while maintaining primitive stem cells. When the
      cells clonally expanded in vitro were transplanted into mouse, they
      morphologically and functionally differentiated into hepatocytes and
      cholangiocytes. Furthermore, these cells differentiated into pancreatic acinar
      cells or intestinal epithelial cells upon transplantation into pancreas or
      duodenal wall. Manipulation of self-renewing liver stem cells may provide new
      insight into therapies for diseases of the digestive system.

PMID- 12468248
TI  - Progress in human hepatocytes: isolation, culture & cryopreservation.
AB  - The quality of the hepatocytes used for clinical cell transplantation is very
      important, and depends to a large extent on the nature of the tissue used for
      isolation. The collagenase perfusion technique to isolate hepatocytes from animal
      livers has been further developed for isolation of human hepatocytes. As the
      donor organ pool is a scarce resource, marginal livers unsuitable for
      transplantation and segments from reduced grafts remain the main source of tissue
      for cell isolation. Use of livers from non-heart beating donors and foetal livers
      may further increase the tissue pool. With the limited supply of available
      tissue, improvements in the cryopreservation protocols are required to maintain
      cell viability on thawing and establish hepatocyte banks.

PMID- 12468249
TI  - Vertebrate development: a view from the zebrafish.

PMID- 12468250
TI  - Zebrafish gastrulation movements: bridging cell and developmental biology.
AB  - During vertebrate gastrulation, large cellular rearrangements lead to the
      formation of the three germ layers, ectoderm, mesoderm and endoderm. Zebrafish
      offer many genetic and experimental advantages for studying vertebrate
      gastrulation movements. For instance, several mutants, including silberblick,
      knypek and trilobite, exhibit defects in morphogenesis during gastrulation. The
      identification of the genes mutated in these lines together with the analysis of
      the mutant phenotypes has provided new insights into the molecular and cellular
      mechanisms that underlie vertebrate gastrulation movements.

PMID- 12468251
TI  - Catching a wave: the oscillator and wavefront that create the zebrafish somite.
AB  - Segmentation of the paraxial mesoderm is governed by an oscillator mechanism that
      creates a dynamic prepattern within the caudal presomitic mesoderm. The
      oscillator is comprised of genetic circuit involving the Notch signaling pathway
      and its target genes her1 and her7. The stabilization of the oscillating
      prepattern is antagonized by a gradient of Fgf signaling which is highest in the
      caudal presomitic mesoderm. Once the level of Fgf signaling declines in the
      rostral presomitic mesoderm, a wavefront mediated by the transcription factor
      fss/tbx24, stabilizes the prepattern and leads to the segmental expression of a
      number of genes which then establish segment polarity and initiate morphological
      somite formation.

PMID- 12468252
TI  - Primordial germ cell development in zebrafish.
AB  - In sexually reproducing organisms, primordial germ cells (PGCs) give rise to
      gametes that are responsible for the development of a new organism in the next
      generation. These cells follow a characteristic developmental path that is
      manifested in specialized regulation of basic cell functions and behavior making
      them an attractive system for studying cell fate specification, differentiation
      and migration. This review summarizes studies aimed at understanding the
      development of this cell population in zebrafish and compares these results with
      those obtained in other model organisms.

PMID- 12468253
TI  - Making the connection: retinal axon guidance in the zebrafish.
AB  - Genetic screens in zebrafish have identified a large number of mutations that
      affect neural connectivity in the developing visual system. These mutants define
      genes essential for accurate retinal axon guidance in the eye and brain and the
      characterization of these mutants is helping to define the cellular and molecular
      mechanisms that guide axons in the vertebrate embryo. The combination of
      zebrafish genetic and embryological approaches promises to greatly increase our
      understanding of how multiple guidance mechanisms establish the complex neural
      interconnectivity of the vertebrate brain.

PMID- 12468254
TI  - Cardiac development in zebrafish: coordination of form and function.
AB  - Organogenesis is a dynamic process involving multiple phases of pattern formation
      and morphogenesis. For example, heart formation involves the specification and
      differentiation of cardiac precursors, the integration of precursors into a tube,
      and the remodeling of the embryonic tube to create a fully functional organ.
      Recently, the zebrafish has emerged as a powerful model organism for the analysis
      of cardiac development. In particular, zebrafish mutations have revealed specific
      genetic requirements for cardiac fate determination, migration, fusion, tube
      assembly, looping, and remodeling. These processes ensure proper cardiac
      function; likewise, cardiac function may influence aspects of cardiac
      morphogenesis.

PMID- 12468255
TI  - Plumbing the mysteries of vascular development using the zebrafish.
AB  - The zebrafish has recently emerged as an advantageous model organism for studying
      how the stereotypic and evolutionarily conserved network of vertebrate blood
      vessels arises during development. The ability to screen for vascular-specific
      mutants and to image and experimentally manipulate blood vessels throughout
      living embryos has already yielded new insights into the anatomy of the early
      vasculature, the dynamics of growing blood vessels, the specification of early
      vascular progenitors, and arterial-venous differentiation of blood vessels.

PMID- 12468256
TI  - Effect of NO synthase inhibition on cardiovascular and pulmonary dysfunction in a
      porcine short-term model of endotoxic shock.
AB  - In a porcine model of endotoxic shock, we evaluated the circulatory and
      respiratory effects of NO synthase (NOS) blockade. Twenty anaesthetised pigs were
      divided into three groups and studied for 240 min after induction of endotoxic
      shock with lipopolysaccharides of Escherichia coli (LPS). After 180 min of
      endotoxic shock, one group (n = 6) received aminoguanidine, another group (n = 6)
      received N(G)-nitro-L -arginine methyl ester (L -NAME) and a third group (n = 8)
      received only LPS. A sham group (n = 3) was also studied. LPS decreased systemic
      arterial pressure and cardiac output (CO) and increased mean pulmonary arterial
      pressure (MPAP), pulmonary vascular resistance (PVR) and heart rate. Significant
      changes were also observed in compliance (-18.4%) and resistance (+33.6%) of the
      respiratory system. Aminoguanidine did not modify LPS-dependent effects, while,
      after L -NAME, a significant increase in MPAP, PVR and SVR and a decrease in CO
      were observed. In conclusion, aminoguanidine does not play a significant
      cardiocirculatory and pulmonary role in the short-term dysfunction of endotoxic
      shock, while L -NAME has a detrimental effect on haemodynamics, suggesting a
      protective role of constitutive NO production at vascular level during the early
      stages of endotoxaemia.

PMID- 12468257
TI  - Role of renal PGE2 in the adaptation from foetal to extrauterine life in term and
      preterm infants.
AB  - Urinary PGE(2) concentrations were assayed using a new EIA method, in 16 preterm
      and 18 term neonates at birth and 3 days later, since there is evidence that
      PGE(2) in urine are likely to reflect their renal generation and then could be
      correlated with kidney maturation or renal problems. PGE(2) concentrations were
      not different at birth (1.50+/-1.12 vs 1.56+/-1.94 ng/day), while resulted
      significantly higher in preterms, compared to terms, three days after birth
      (2.22+/-1.23 vs 1.39+/-0.79 ng/day). This increase in daily PGE(2) excretion
      observed only in preterm neonates could be due to an increased renal biosynthesis
      as a mechanism of compensatory response to prevent further decrements in renal
      plasma flow, since prostanoids play an important role in protecting the immature
      kidney from high levels of angiotensin II. Otherwise, the passive reabsorption of
      PGE(2) along the distal nephron could be altered because of kidney immaturity.
      The measurement of PGE(2) in urine of neonates, particularly prematures, could be
      useful to provide a better understanding of the homeostatic function of the
      kidney in the phase of adaptation to extra-uterine life.

PMID- 12468258
TI  - Cyclooxygenase-pathway participates in the regulation of regional cerebral blood
      flow in response to neuronal activation under normo- and hypercapnia.
AB  - The present study was designed to investigate whether cyclooxygenase products are
      involved in the regulation of the regional cerebral blood flow, evoked by
      somatosensory activation (evoked rCBF) under normo- and hypercapnia. Indomethacin
      (IMC) was used as cyclooxygenase inhibitor. It was applied intravenously (i.v.,
      10 mg/kg/h) in two experimental protocols-before hypercapnia (i) and after
      hypercapnia (ii). Somatosensory activation was induced by electrical hind paw
      stimulation (5 Hz frequency, 5 s duration, 1.5 mA). The evoked rCBF-response was
      measured in alpha -chloralose anesthetized rats using laser-Doppler flowmetry.
      IMC abolished completely the effect of hypercapnia on the baseline level of CBF.
      The drug reduced significantly evoked rCBF-response also. The inhibitory effect
      of IMC on evoked rCBF-response is better expressed under normocapnia
      (approximately 70%) than that under hypercapnia (approximately 40%). After IMC
      application, the normalized evoked rCBF curves peaked earlier as compared to that
      before its application (P<0.05), although the rise time of 0.5 s was nearly
      constant regardless of stimulus frequency. In conclusion, the results suggest a
      participation of IMC-sensitive and cyclooxygenase-dependent mechanisms in the
      regulation of evoked rCBF, induced by somatosensory stimulation.

PMID- 12468259
TI  - Maternal and umbilical fatty acid status in relation to maternal diet.
AB  - The aim of this study was to describe the dietary fat intake during pregnancy and
      to study the relationship between the intake of polyunsaturated fatty acids
      (PUFAs) and the fatty acid composition of maternal and umbilical plasma
      phospholipids (PLs) and cholesterol esters (CEs) at delivery. In addition, the
      contribution of food groups to the intake of total fat and fatty acids in the
      diet was quantified.Maternal and umbilical blood samples were collected at
      delivery from 30 healthy pregnant women. The women completed a food frequency
      questionnaire during the first and third trimesters. The total fat intake during
      pregnancy is 85 (SD 24) g/day. The mean intake of saturated fatty acids (SFAs) is
      33.4 g/day, of monounsaturated fatty acids (MUFAs) 28.6 g/day and of PUFA 15.2
      g/day. Major sources of fat, MUFA and PUFA are fats, oils and sauces. Major
      sources of SFA are meat and poultry followed by cheese and eggs. Meat and poultry
      contribute the most to the intake of 20:4n-6 whereas fish is the major source of
      20:5n-3 (EPA) and 22:6n-3 (docosahexaenoic acid (DHA)) in the diet. Linoleic
      acid, EPA and DHA (w%) in PL of maternal plasma are positively related to the
      intake of these fatty acids during pregnancy. No association is found between the
      maternal intake of the two parent essential fatty acids (18:2n-6 and 18:3n-3) and
      their fraction in umbilical PL or CE. EPA and the sum of n-6 fatty acids (w%) in
      umbilical plasma PL are positively correlated with the dietary intake of these
      fatty acids.

PMID- 12468260
TI  - Characterization and identification of cytochrome P450 metabolites of arachidonic
      acid released by human peritoneal macrophages obtained from the pouch of Douglas.
AB  - Cytochrome P450 metabolism of arachidonic acid (AA) was investigated in human
      peritoneal macrophages which play a central role in chronic pelvic diseases in
      women (for example in endometriosis). The formation of eicosanoids other than
      prostaglandins (PGs) by these cells is still unknown. In non-activated
      macrophages obtained from women in the reproductive age, the main [(3)H]-AA
      metabolites coeluted with epoxyeicosatrienoic acids, dihydroxyeicosatrienoic
      acids (DHETs) and hydroxyeicosatetraenoic acids (HETEs) in reverse-phase HPLC.
      After zymosan activation a shift to PGs pathway was observed. Treatment with low
      doses of 2,3,7,8-tetrachlorodibenzo- p -dioxin increased the formation of a
      metabolite coeluting with 5,6-DHET. By gas chromatography/mass spectrometry 5,6
      DHET (after beta-naphthoflavone induction), and 14,15-DHET as well as 11,12-DHET
      (after AA stimulation) were identified as major epoxygenase metabolites,
      respectively. The enantioselective formation of 12(S)-HETE was demonstrated by
      chiral-phase HPLC. Our findings demonstrate that non-activated peritoneal
      macrophages produce substantial amounts of bioactive cytochrome P450 metabolites
      of AA.

PMID- 12468261
TI  - Induction of thromboxane A2 synthesizing enzymes in DMSO-induced granulocytic
      differentiation of HL-60 cells.
AB  - Human leukemia (HL)-60 cells were differentiated by several agents, and
      prostaglandins (PGs) and thromboxane (TX) synthesizing activity increased in
      response to the differentiation of the cells. We examined the expression of
      messenger RNA (mRNA) for TX-synthesizing enzymes, cyclooxygenase (COX)-1, COX-2
      and TXA(2) synthase, in dimethyl sulfoxide (DMSO)-differentiated HL-60 cells by
      reverse transcriptase polymerase chain reaction (RT-PCR), and A23187-stimulated
      TXB(2) production, a stable metabolite of TXA(2), by radioimmunoassay (RIA).
      A23187-stimulated TXB(2) production, and mRNA abundance for COX-2, were not
      detected in non-treated HL-60 cells. TXA(2) synthase mRNA were barely detected in
      non-treated HL-60 cells. DMSO-induced HL-60 cells gained induction of TXB(2)
      synthesis and mRNA for COX-2 and TXA(2) synthase during granulocytic
      differentiation. COX-1 mRNA was constitutively expressed. A23187-stimulated
      TXB(2) production in DMSO-treated cells was inhibited by NS-398, a specific COX-2
      inhibitor. These results demonstrated that TXB(2) production in granulocytic HL
      60 cells was regulated at both the enzyme level of COX-2 and TXA(2) synthase.

PMID- 12468262
TI  - Interleukin-1beta in the functional and structural luteolysis. Relationship with
      the nitric oxide system.
AB  - The aim of the present report was to investigate the in vitro effect of
      interleukin-1beta(IL-1beta) on corpus luteum (CL) function and some aspects of
      this mechanism involved. Ovarian rat dispersates from mid-luteal phase were
      exposed to different doses of IL-1beta (1, 10, 20 ng/ml). Meanwhile 1, 10 and 20
      ng/ml of IL-1beta decreased progesterone (P4) production, only the highest doses
      of IL-1beta increased prostaglandin F2alpha (PGF2alpha) levels. To investigate
      the possible relationship between PGs production and P4 synthesis, we incubated
      together IL-1beta (20 ng/ml) and indomethacin (0.1 mM) a potent inhibitor of
      cyclooxygenase pathway. We found that P4 inhibition induced by IL-1beta was
      completely prevented by addition of indomethacin. On the other hand, when ovarian
      rat tissue were exposed at 20 ng/ml of IL-1beta (doses that affected both
      PGF2alpha and P4 production) the nitric oxide synthase (NOS) activity was
      augmented. Moreover, IL-1beta effects on PGF2alpha and P4 levels were impaired
      when a NOS inhibitor N(W)-nitro- L -arginine methyl ester (L-NAME, 600 microM)
      was added to the incubation media. These data demonstrate that: (i) at the tested
      doses (1-20 ng/ml), IL-1beta is involved in CL function through the diminution of
      P4 production of whole ovarian dispersate culture; (ii) at the highest doses
      assayed (20 ng/ml) IL-1beta increased PGF2alpha production; (iii) at these doses,
      IL-1beta decreased P4 production by means of a cyclooxygenase pathway and (iv)
      the NO system would be a key intermediary second messenger in the IL-1beta
      actions.

PMID- 12468263
TI  - Transient experimental anemia in cholesterol-fed rabbits induces systemic
      overexpression of the reticulocyte-type 15-lipoxygenase and protects from aortic
      lipid deposition.
AB  - Oxidative modification of low-density lipoprotein has been implicated in
      atherogenesis and the lipid peroxidizing enzyme 12/15-lipoxygenase (12/15-LOX)
      was suggested to be involved. For this study, we induced a strong and long
      lasting systemic overexpression of the 15-LOX, in female New Zealand White
      rabbits by transient experimental anemia. After the hematopoietic parameters had
      returned to normal, these animals and age-matched controls were fed a lipid-rich
      Western-type diet for 10 weeks. Analyzing the lipid deposition in the aortic
      wall, we found that the 15-LOX overexpressing rabbits deposited significantly
      (P<0.01) less cholesteryl linoleate in the thoracic aorta than the corresponding
      controls. Similar results were obtained when free cholesterol and cholesteryl
      oleate were quantified. However, in the aortic arch where lipid deposition was
      much more severe a similar trend was observed, but the effects were not
      significant any more. Comparative determination (lipoxygenase overexpressing vs.
      control animals) of various plasma parameters as well as histological inspections
      of major organs did not reveal any indications for major organ malfunction. These
      data suggest that transient experimental anemia, which is accompanied by a long
      lasting overexpression of the reticulocyte-type 15-LOX protects cholesterol-fed
      rabbits from lipid deposition in the aortic wall.

PMID- 12468264
TI  - The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the
      generation of platelet-activating factor and leukotriene B4 in hypoxic-ischemic
      brain in young mice.
AB  - Platelet-activating factor (PAF), leukotriene B(4) (LTB(4)) and other cytokines
      have been indicated to be responsible for the neuronal damage in hypoxic-ischemic
      brain. Diets in omega-3 (n-3) fatty acids appear to have an antiinflammatory
      effect, which is thought to be due to decrease in active prostaglandins and
      leukotrienes production after incorporation of these fatty acids into cell
      membrane phospholipids. We investigated the effect of dietary supplementation
      with n-3 fatty acids on endogenous PAF and LTB(4) biosynthesis in hypoxic
      ischemic brain of young mice. Young mice were randomly divided into four groups:
      Group 1 mice were fed standard chow (n-3 polyunsaturated fatty acids free); Group
      2 and Group 3 mice were given standard diet supplemented with 10% by weight of
      fish oil, as source of n-3 polyunsaturated fatty acids, for 3 and 6 weeks,
      respectively. Group 4 mice served as control. We injured the right cerebral
      hemisphere of young mice by ligating the right common carotid artery and exposing
      the mice to 8% oxygen for 60 min. Approximately 10-fold increase in PAF
      concentration was determined in hypoxic-ischemic brain tissue of Group 1 mice.
      Tissue concentration of PAF showed a profound decline in Group 3 mice compared to
      Groups 1 and 2 (P<0.01, P<0.05, respectively). LTB(4) was also significantly
      elevated in the brain of Group 1 mice when compared to the brain of control mice
      (P<0.001). A striking decline was observed in the concentration of LTB(4) in both
      Group 2 and Group 3 mice compared to Group 1 mice (P<0.05, P<0.01, respectively).
      The present study shows that n-3 fatty-acid-enriched diet inhibits endogenous PAF
      and LTB(4) generation in hypoxic-ischemic brain tissue; however it demonstrates
      that 6 weeks of dietary supplementation with n-3 fatty acids results in a
      significant decrease in tissue level of PAF in the brain.

PMID- 12468265
TI  - Suppression of cyclooxygenase-2 and inducible nitric oxide synthase expression by
      conjugated linoleic acid in murine macrophages.
AB  - Activated macrophages express inducible isoforms of cyclooxygenase (COX-2) and
      nitric oxide synthase (iNOS), and produce excessive amounts of prostaglandin E(2)
      (PGE(2)) and nitric oxide (NO) which play key roles in cancer pathogenesis.
      Conjugated linoleic acid (CLA) is an anticarcinogen while arachidonic acid (AA)
      may be a procarcinogen by increased PGE(2) production. This study examined the
      effects of CLA and AA on PGE(2) and NO synthesis in endotoxin-activated
      macrophages. RAW264.7 macrophages were incubated in medium containing no added
      lipid (control), 30 microM AA (AA medium), or 30 microM CLA (CLA medium) for 24 h
      followed by activation with bacterial endotoxin lipopolysaccharide (LPS; 100
      ng/ml) for 9 h. CLA significantly depressed PGE(2) and NO production by 78%
      (P=0.003) and 57% (P=0.0001) respectively. Northern blot analysis of COX-2 and
      iNOS showed significant 33% (P=0.01) and 51% (P=0.04) decreases, respectively,
      paralleling those seen for PGE(2) and NO production. In contrast, AA
      significantly increased PGE(2) synthesis by 62% (P=0.02) and also suppressed NO
      production and iNOS expression in the same manner as observed for CLA. These
      results suggest that the anticarcinogenic effect of CLA in endotoxin-activated
      macrophages may be related to its ability to decrease both PGE(2) and NO
      synthesis by suppressing transcription of COX-2 and iNOS.

PMID- 12468266
TI  - Effects of endothelin-1 (ET-1) and thrombin antagonism on cardiovascular and
      respiratory dysfunctions during endotoxic shock in pig.
AB  - We evaluated the endothelin-1 (ET-1) and thrombin involvement in cardiovascular
      and respiratory dysfunction during endotoxic shock in 18 anaesthetized,
      mechanically ventilated pigs, divided into three groups. Group 1 was pre-treated
      only with lipopolysaccharide (LPS), group 2 was treated with lepirudin, a
      thrombin inhibitor, group 3 was pre-treated with bosentan, a dual inhibitor of ET
      1 receptors. Results show that LPS caused systemic hypotension, pulmonary
      biphasic hypertension, increase in lung resistances (R(L)) and decrease in
      compliance (C(L)). Lepirudin partially reduced the LPS-dependent pulmonary
      hypertension, without affecting the changes in C(L) and R(L). On the contrary,
      bosentan completely abolished the pulmonary hypertension and the changes inC(L)
      and R(L), and worsened the LPS-dependent systemic hypotension. Our results show
      that ET-1 is largely responsible for pulmonary derangement due to endotoxic
      shock; at bronchial level, the ET-1 release seems due only to LPS, while, at
      pulmonary vascular level, it results also from LPS-dependent thrombin activation.

PMID- 12468267
TI  - Nuclear receptor agonists stimulate release of arachidonic acid from rat liver
      cells.
AB  - Release of arachidonic acid (AA) from rat liver cells is stimulated after a 6 h
      incubation with compounds that are members of the nuclear receptor superfamily,
      including vitamin D(3), clofibrate, 22(R) OH cholesterol, farnesol, progesterone,
      testosterone, 17beta-estradiol, hydrocortisone, 3,3'5 triiodothyronine, juvenile
      hormone III, WY14643, L -thyroxine, the tyrosine analog of thiazolidinediones,
      GW7845, tamoxifen, hydroxytamoxifen, 17alpha-estradiol and D -thyroxine.
      Squaline, lanosterol, cholesterol and the 17beta-estradiol antagonist, ICI
      182,780, do not stimulate. ICI-182,780 inhibits the release stimulated by 17beta
      estradiol, vitamin D(3), 22(R) OH cholesterol, celecoxib or indomethacin.
      Actinomycin D abolishes the release stimulated by 15-deoxy-delta(12,14) PGJ(2),
      but is less effective at inhibiting the release stimulated by all of the agonists
      listed above as well as the release stimulated by 9-cis retinoic acid, all trans 
      retinoic acid, the thiazidinedione, ciglitazone and the non-steroidal anti
      inflammatory drugs, indomethacin and celecoxib. Based on the effects of the
      17beta-estradiol antagonist, ICI-182,780, the release of AA appears to be a
      membrane effect and may not be mediated by the classical estrogen receptors. From
      the results obtained with actinomycin D, some stimulations may require
      transcription.

PMID- 12468268
TI  - Inhibition of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by
      cyclooxygenase inhibitors and chemopreventive agents.
AB  - 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD(+)-dependent
      oxidation of 15(S)-hydroxyl group of prostaglandins and has been considered a key
      enzyme involved in biological inactivation of prostaglandins. This enzyme is
      markedly induced by androgens in hormone-sensitive human prostate cancer cells
      (Tong M., Tai H. H. Biochem Biophys Res Commun 2000; 276: 77-81) and may be
      involved in tumorigenesis. Inhibition of this enzyme may be of value in
      anticancer therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit
      cyclooxygenases (COXs) have been shown to be chemopreventive in epidemiological
      and animal-model studies. However, chemoprevention by these drugs may not be
      directly related to their inhibition of COXs. Other targets may be also involved
      in their chemopreventive activity. We have examined a variety of NSAIDs including
      COX-2 selective inhibitors, peroxisome proliferator-activated receptor (PPAR)
      gamma agonists and phytophenolic compounds which have been shown to be
      chemopreventive for their effect on 15-PGDH. It was found that most of these
      compounds were potent inhibitors of 15-PGDH. Among these compounds, ciglitazone
      appeared to be the most powerful inhibitor (IC(50)=2.7 microM). Inhibition by
      ciglitazone was non-competitive with respect to NAD(+) and uncompetitive with
      respect to PGE(2).

PMID- 12468269
TI  - Comparison of PGE2, prostacyclin and leptin release by human adipocytes versus
      explants of adipose tissue in primary culture.
AB  - The present studies were designed to investigate the sites of PGE(2),
      prostacyclin and leptin formation in human adipose tissue. Most of the PGE(2) and
      prostacyclin formation by adipose tissue explants from obese humans after 48 h in
      primary culture was due to blood vessels and other tissues not digested by
      collagenase. However, there was appreciable PGE(2) formation by adipocytes over a
      48 h incubation and leptin formation was only seen in adipocytes. An increase in
      COX-2 immunoreactive protein was also seen after incubation of isolated human
      adipocytes for 48 h. The release of PGE(2) by adipocytes incubated for 48 h was
      about 4% that by intact adipose tissue explants while the release of prostacyclin
      was about 1.5% that by tissue. However, in a different experimental design where
      PGE(2) formation was measured over 2 h in the presence of 20 microM arachidonic
      acid the formation of PGE(2) by adipocytes after 48 h prior incubation in primary
      culture was 38% of that by tissue explants. Dexamethasone enhanced leptin release
      by adipocytes while inhibiting PGE(2) release and COX-2 up-regulation. The
      mechanisms involved in up-regulation of COX-2 activity during primary culture of
      adipocytes and the inhibition of this by dexamethasone do not appear to involve
      p38 MAPK or p42-44 MAPK. Interleukin I(beta) further enhanced PGE(2) formation by
      adipocytes but did not affect leptin formation. In conclusion, these data
      indicate that leptin release is exclusively a function of adipocytes while
      prostanoids are made by both adipocytes and the other cells present in human
      adipose tissue

PMID- 12468270
TI  - The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory
      and antithrombotic agent.
AB  - The effect of an aqueous extract of ginger (Zingiber officinale) on serum
      cholesterol and triglyceride levels as well as platelet thromboxane-B(2) and
      prostaglandin-E(2) production was examined. A raw aqueous extract of ginger was
      administered daily for a period of 4 weeks, either orally or intraperitoneally
      (IP) to rats. Fasting blood serum was investigated for thromboxane-B(2),
      prostaglandin-E(2), cholesterol and triglycerides. A low dose of ginger (50
      mg/kg) administered either orally or IP did not produce any significant reduction
      in the serum thromboxane-B(2) levels when compared to saline-treated animals.
      However, ginger administered orally caused significant changes in the serum
      PGE(2) at this dose. High doses of ginger (500 mg/kg) were significantly
      effective in lowering serum PGE(2) when given either orally or IP. However,
      TXB(2) levels were significantly lower in rats given 500 mg/kg ginger orally but
      not IP. A significant reduction in serum cholesterol was observed when a higher
      dose of ginger (500 mg/kg) was administered. At a low dose of ginger (50 mg/kg),
      a significant reduction in the serum cholesterol was observed only when ginger
      was administered IP. No significant changes in serum triglyceride levels were
      observed upon administration of either the low or high dose of ginger. These
      results suggest that ginger could be used as an cholesterol-lowering,
      antithrombotic and anti-inflammatory agent.

PMID- 12468271
TI  - Newborn screening: rationale for a comprehensive, fully integrated public health
      system.
AB  - Newborn screening has existed for approximately four decades. During that period
      of time, newborn screening has evolved conceptually from a laboratory test for a
      single disorder, phenylketonuria (PKU), to a multi-part public health system
      involving education, screening, diagnostic follow-up, treatment/management, and
      system evaluation. At a time when newborn screening is recognized as a model for
      predictive medicine, it also faces critical challenges that will determine its
      future credibility and viability. In order to understand these challenges, it is
      helpful to review briefly the history of newborn screening.

PMID- 12468272
TI  - Identification of the PPARA locus on chromosome 22q13.3 as a modifier gene in
      familial combined hyperlipidemia.
AB  - Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder that
      is present in 10% of patients with premature coronary artery disease (CAD). It
      was the objective of the present study to evaluate the possible involvement of
      the PPARA locus in the pathophysiology of FCHL. Mutation detection analyses of
      the six coding PPARA exons resulted in the identification of four novel variants,
      [C/T] intron 3, S234G, [G/A] intron 5, and [C/A] 3(') UTR in three FCHL probands,
      whereas no novel variants were identified in spouses. In a case-control study,
      markers D22S275 and D22S928 were shown not to be associated with FCHL. However,
      D22S928, mapped within 1Mb of the PPARA gene, was shown to have a modifying
      effect on plasma apoCIII concentrations (P=0.011) and the combined hyperlipidemic
      FCHL phenotype (P=0.038). In addition two PPARA polymorphisms in intron 2 and 7
      were studied, but these were not associated with FCHL. The frequency of the L162V
      variant was less in FCHL probands (1.98%) compared to that in spouses (4.84%).
      These results clearly demonstrate the genetically complex nature of FCHL and
      identify the PPARA gene as a modifier of the FCHL phenotype.

PMID- 12468273
TI  - Variable clinical presentation of lysosomal beta-mannosidosis in patients with
      null mutations.
AB  - Beta-mannosidosis is an autosomal recessive lysosomal storage disease resulting
      from a deficiency of the lysosomal enzyme beta-mannosidase. The clinical
      manifestations of this disease in reported human cases are very heterogeneous
      ranging from relatively mild to moderately severe. This is in contrast with the
      severe prenatal onset seen in ruminant beta-mannosidosis. In humans, mental
      retardation, hearing loss, frequent infections, and behavioral problems are
      relatively common. Dysmorphology and skeletal involvement such as those seen in
      ruminants are unusual. The purpose of this study is to determine the range of
      clinical expression in human beta-mannosidosis resulting from null mutations. We
      determined that the beta-mannosidase gene consists of 17 exons. Intron-based PCR
      primers were designed and used to amplify each of the exons in genomic DNA
      isolated from patient fibroblasts. We identified two patients with null
      mutations. Results of the analysis showed that one patient was heterozygous for
      nonsense mutations G334T (E83X) in exon 2 and C1363T (Q426X) in exon 10,
      resulting in truncation of the deduced peptide sequence from 879 to 82 and 425
      amino acids, respectively. The second patient was homozygous for a deletion
      mutation in exon 11 (1541delAT). This deletion causes a reading frame shift and
      26 out of frame amino acids before a stop codon occurs in exon 12, resulting in
      truncation of the deduced peptide sequence from 879 to 510 amino acids. Because
      disease presentation in these patients with null mutations is very variable,
      ranging from mild to severe, we conclude that beta-mannosidosis in humans may
      indeed be milder than typical of other lysosomal storage disorders.

PMID- 12468274
TI  - A new gene, EVC2, is mutated in Ellis-van Creveld syndrome.
AB  - Ellis-van Creveld syndrome (EvC; MIM 225500) is an autosomal recessive
      chondrodysplastic dwarfism. Thus far, the identified mutations in the EVC gene
      located on chromosome 4p16 have only accounted for illness in a small proportion
      of affected individuals. In this report we describe a novel gene, EVC2, that is
      mutated in an Ashkenazi individual with EvC syndrome. Our findings demonstrate
      for the first time that the heterogeneity observed in this disorder is not solely
      the result of mutations in a single gene.

PMID- 12468275
TI  - Metabolism of 13C galactose by lymphoblasts from patients with galactosemia
      determined by NMR spectroscopy.
AB  - In order to assess the pathways by which galactose is metabolized by galactose-1
      phosphate uridyltransferase (GALT) deficient cells, lymphoblasts from 10
      galactosemic patients with defined genotypes (six Q188R homozygotes, two S153L
      homozygotes, and two with homozygous deletions) were incubated with 1mM 1- or 2
      13C galactose for 2.5 and 5 h. The 13C-labeled metabolites were identified and
      quantified using nuclear magnetic resonance and the results were compared to that
      obtained with cells from eight normal individuals. Cells from galactosemic
      patients formed two to three times the galactose-1-phosphate (Gal-1P) in normal
      cells, no difference being observed between the various genotypes. Galactitol
      formation was not significantly different from normal cells. No labeled
      galactonate was detected. Cells with the Q188R and S135L mutations formed both
      labeled uridine diphosphogalactose (UDPgal) and uridine diphosphoglucose
      (UDPglu), but to a lesser extent than normals, whereas cells with the GALT
      deletion did not. The pattern of 13C enrichment of the ribose carbons of
      adenosine monophosphate upon incubation of the normal cells with 1-13C galactose
      paralleled that found for incubations with 1-13C glucose, which is consistent
      with galactose disposition through the Leloir pathway to glucose and its
      subsequent metabolism to ribose. Cells with the GALT deletion formed no
      detectable labeled ribose, whereas cells from a patient homozygous for Q188R
      mutation formed labeled ribose in a pattern similar to normal albeit with lower
      enrichment. The results suggest that there is residual GALT activity and function
      of the Leloir pathway in the presence of the Q188R as well as S135L mutation.

PMID- 12468276
TI  - High frequency of tetrahydrobiopterin-responsiveness among
      hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002.
AB  - Tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia (HPA) is a recently
      described variant of phenylalanine hydroxylase deficiency. In contrast to
      patients with classical phenylketonuria, these patients respond to BH(4) loading
      tests (20mg/kg) with decrease of plasma phenylalanine levels 4 and 8 h after
      administration and they can be treated with BH(4) monotherapy. We retrospectively
      evaluated 1,919 loading tests from 33 different countries performed in our
      laboratory between 1988 and 2002 of which 278 loading tests were performed with
      6R-BH(4), which is about 33% more active than the formerly used 6R,S-BH(4). The
      loading tests were performed between the ages of one week and 4.6 years, using
      2.6-30.0 mg 6R,S- or 6R-BH(4)/kg. Plasma phenylalanine levels before the test
      ranged from 121 to 4,705 micromol/L. We calculated the phenylalanine
      "hydroxylation rate" 4 and 8 h after BH(4) administration and plotted the slope
      of the hydroxylation rate against the phenylalanine levels at time 0. The slope
      was greater than 3.75 in 65, 74, 33, 17, 0, and 10% of patients with basal
      phenylalanine levels of 120-400, 400-800, 800-1,200, 1,200-1,600, 1,600-2,200,
      and >2,200 micromol/L, respectively, when loaded with 20 mg 6R-BH(4)/kg
      (p>0.0001). This is 5-20 times higher compared with tests using 6R,S-BH(4) or
      lower doses of BH(4). More than 70% of patients with mild HPA (<800 micromol/L)
      are found to be BH(4) responders. Therapy with BH(4) (approximately 10mg/kg/day)
      was initiated in several patients instead of a low-phenylalanine diet, resulting
      in much better treatment compliance. Our data further demonstrate that BH(4)
      loading tests can only distinguish between BH(4) responders and non-responders.
      To differentiate between BH(4) and phenylalanine hydroxylase deficiencies
      additional tests are essential.

PMID- 12468277
TI  - A novel nonsense mutation in the ligand binding domain of the vitamin D receptor
      causes hereditary 1,25-dihydroxyvitamin D-resistant rickets.
AB  - Hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR) is a genetic
      disorder most often caused by mutations in the vitamin D receptor (VDR). In this
      report, we present our findings on a young girl who 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 also had total body
      alopecia. Fibroblasts from the patient were cultured for analysis of the VDR
      structure and function. In [3H]1,25(OH)(2)D(3) binding assays, no significant
      specific binding to the VDR was observed in cytosols from the patient's
      fibroblasts. The patient's fibroblast were also totally resistant to high doses
      of 1,25(OH)(2)D(3) as demonstrated by their failure to induce expression of the
      24-hydroxylase gene, a marker of 1,25(OH)(2)D(3) activity. DNA sequence analysis
      of the VDR gene uncovered a unique C to T mutation in exon 8. The mutation
      changed the codon for glutamine to a premature stop codon at amino acid 317
      (Q317X). Restriction enzyme analysis showed that the patient was homozygous for
      the mutation. Both parents were heterozygous for the mutant allele. In
      conclusion, we have identified a novel mutation in the VDR, Q317X, as the
      molecular defect in a patient with HVDRR. The Q317X mutation deletes 110 amino
      acids of the ligand-binding domain of the VDR and results in the loss of
      [3H]1,25(OH)(2)D(3) binding and target gene transactivation.

PMID- 12468278
TI  - Mutation analysis of the G4.5 gene in patients with isolated left ventricular
      noncompaction.
AB  - Mutations in the gene G4.5, originally associated with Barth syndrome, have been
      reported to result in a wide spectrum of severe infantile X-linked
      cardiomyopathies. The purpose of this study was to investigate patients with
      isolated left ventricular noncompaction (LVNC) for disease-causing mutations in
      G4.5. In 27 patients including 10 families with isolated LVNC, mutation analysis
      of G4.5 was performed using single-strand DNA conformation polymorphism (SSCP)
      analysis and DNA sequencing. A novel splice acceptor site mutation of intron 8 of
      G4.5 was identified in a family with severe infantile X-linked LVNC without the
      usual findings of Barth syndrome. This mutation results in deletion of exon 9
      from the mRNA, and is predicted to significantly disrupt the protein product.
      Genotype-phenotype correlation of G4.5 mutations in all 38 cases reported in the
      literature to date revealed that there was no correlation between location or
      type of mutation and either cardiac phenotype or disease severity. We suggest
      that males presenting with cardiomyopathy, particularly during infancy, even in
      the absence of the typical signs of Barth syndrome, should be evaluated for
      mutations in G4.5.

PMID- 12468279
TI  - Creatine depletion in a new case with AGAT deficiency: clinical and genetic study
      in a large pedigree.
AB  - Arginine:glycine amidinotransferase (AGAT, EC 2.1.4.1) deficiency is a recently
      recognized autosomal recessive inborn error of creatine biosynthesis,
      characterized by mental retardation and severe language impairment. We
      extensively investigated a third 5-year-old patient with AGAT deficiency,
      discovered in the pedigree of the same Italian family as the two index cases. At
      the age of 2 years he presented with psychomotor and language delay, and autistic
      like behavior. Brain MRI was normal, but brain 1H-MRS disclosed brain creatine
      depletion, which almost completely normalized following creatine monohydrate
      supplementation. A remarkable clinical improvement paralleled the restoration of
      brain creatine concentration. AGAT and GAMT (guanidinoacetate:methyltransferase)
      genes were analyzed in the proband and in 26 relatives, including the two cousins
      with AGAT deficiency. Sequencing of the proband's AGAT gene disclosed the same
      homozygous mutation at nt position 9093 converting a tryptophan (TGG) to a stop
      codon (TAG) at residue 149 (W149X), as already described in the two previously
      reported cases. The proband's parents and 10 additional subjects of the pedigree
      were carriers for this mutation. AGAT deficiency was further confirmed by
      undetectable AGAT activity in the patient's lymphoblasts. Mutation analysis of
      the GAMT gene revealed a sequence variation in exon 6 (T209M), not in the
      proband, but in 15 additional subjects from the pedigree. The silent nature of
      this sequence variation is supported by its homozygosity in one AGAT deficient
      cousin and in one asymptomatic adult, both with normal GAMT activity.

PMID- 12468280
TI  - Modeling of pain using artificial neural networks.
AB  - In dealing with human nervous system, the sensation of pain is as sophisticated
      as other physiological phenomena. To obtain an acceptable model of the pain,
      physiology of the pain has been analysed in the present paper. Pain mechanisms
      are explained in block diagram representation form. Because of the nonlinear
      interactions existing among different sections in the diagram, artificial neural
      networks (ANNs) have been exploited. The basic patterns associated with chronic
      and acute pain have been collected and then used to obtain proper features for
      training the neural networks. Both static and dynamic representations of the ANNs
      were used in this regard. The trained networks then were employed to predict
      response of the body when it is exposed to special excitations. These excitations
      have not been used in the training phase and their behavior is interesting from
      the physiological view. Some of these predictions can be inferred from clinical
      experimentations. However, more clinical tests have to be accomplished for some
      of the predictions.

PMID- 12468281
TI  - Heterogeneous perfusion is a consequence of uniform shear stress in optimized
      arterial tree models.
AB  - Using optimized computer models of arterial trees we demonstrate that flow
      heterogeneity is a necessary consequence of a uniform shear stress distribution.
      Model trees are generated and optimized under different modes of boundary
      conditions. In one mode flow is delivered to the tissue as homogeneously as
      possible. Although this primary goal can be achieved, resulting shear stresses
      between blood and the vessel walls show very large spread. In a second mode,
      models are optimized under the condition of uniform shear stress in all segments
      which in turn renders flow distribution heterogeneous. Both homogeneous perfusion
      and uniform shear stress are desirable goals in real arterial trees but each of
      these goals can only be approached at the expense of the other. While the present
      paper refers only to optimized models, we assume that this dual relation between
      the heterogeneities in flow and shear stress may represent a more general
      principle of vascular systems.

PMID- 12468282
TI  - Defining and measuring trophic role similarity in food webs using regular
      equivalence.
AB  - We present a graph theoretic model of analysing food web structure called regular
      equivalence. Regular equivalence is a method for partitioning the species in a
      food web into "isotrophic classes" that play the same structural roles, even if
      they are not directly consuming the same prey or if they do not share the same
      predators. We contrast regular equivalence models, in which two species are
      members of the same trophic group if they have trophic links to the same set of
      other trophic groups, with structural equivalence models, in which species are
      equivalent if they are connected to the exact same other species. Here, the
      regular equivalence approach is applied to two published food webs: (1) a
      topological web (Malaysian pitcher plant insect food web) and (2) a carbon-flow
      web (St. Marks, Florida seagrass ecosystem food web). Regular equivalence
      produced a more satisfactory set of classes than did the structural approach,
      grouping basal taxa with other basal taxa and not with top predators. Regular
      equivalence models provide a way to mathematically formalize trophic position,
      trophic group and trophic niche. These models are part of a family of models that
      includes structural models used extensively by ecologists now. Regular
      equivalence models uncover similarities in trophic roles at a higher level of
      organization than do the structural models. The approach outlined is useful for
      measuring the trophic roles of species in food web models, measuring similarity
      in trophic relations of two or more species, comparing food webs over time and
      across geographic regions, and aggregating taxa into trophic groups that reduce
      the complexity of ecosystem feeding relations without obscuring network
      relationships. In addition, we hope the approach will prove useful in predicting
      the outcome of predator-prey interactions in experimental studies.

PMID- 12468283
TI  - Evolution was chemically constrained.
AB  - The objective of this paper is to present a systems view of the major features of
      biological evolution based upon changes in internal chemistry and uses of
      cellular space, both of which it will be stated were dependent on the changing
      chemical environment. The account concerns the major developments from
      prokaryotes to eukaryotes, to multi-cellular organisms, to animals with nervous
      systems and a brain, and finally to human beings and their uses of chemical
      elements in space outside themselves. It will be stated that the changes were in
      an inevitable progression, and were not just due to blind chance, so that "random
      searching" by a coded system to give species had a fixed overall route. The
      chemical sequence is from a reducing to an ever-increasingly oxidizing
      environment, while organisms retained reduced chemicals. The process was
      furthered recently by human beings who have also increased the range of reduced
      products trapped on Earth in novel forms. All the developments are brought about
      from the nature of the chemicals which organisms accumulate using the environment
      and its changes. The relationship to the manner in which particular species (gene
      sequences) were coincidentally changed, the molecular view of evolution, is left
      for additional examination. There is a further issue in that the changes of the
      chemistry of the environment developed largely at equilibrium due to the
      relatively fast reactions there of the available inorganic chemicals. Inside
      cells, some of these same chemicals also came to equilibrium within compounds.
      All such equilibria reduced the variance (degrees of freedom) of the total
      environmental/biological system and its possible development. However, the more
      sophisticated organic chemistry, almost totally inside cells until humans
      evolved, is kinetically controlled and limited by the demands of cellular
      reduction necessary to produce essential chemicals and by the availability of
      certain elements and energy. Hence the variability of reductive cellular organic
      chemistry and its limitations in cells have to be considered separately. While as
      a whole they drive the oxidation of the environment, they also allow speciation
      within the major changes of organisms. Human beings have introduced recently new,
      virtually irreversible, inorganic and organic chemistry in the environment, much
      of it new modes of irreversible storage of reduced chemicals, and this is, we
      state, the last possible step of chemical evolution. We must attempt to evaluate
      its effect on organisms generally. It must be clear that all the changes and the
      original life forms are dependent upon energy as well as material capture and
      flow. We shall have to consider in which forms energy was available over the
      period of evolution, how it was usefully transformed, and the ways in which its
      sources changed.

PMID- 12468284
TI  - Reputation and the evolution of conflict.
AB  - The outcomes of conflicts in many human societies generate reputation effects
      that influence the nature of later conflicts. Those willing to escalate over even
      trivial offenses are considered honorable whereas those who do not are considered
      dishonorable (Nisbett & Cohen, 1996). Here I extend Maynard Smith's hawk-dove
      model of animal conflict to explore the logic of a strategy which uses reputation
      about its opponents to regulate its behavior. I show that a reputation-based
      strategy does well when (1) the value of the resource is large relative to the
      cost of losing a fight, (2) communities are stable, and (3) reputations are well
      known but subject to some amount of error. Reputation-based strategies may thus
      result in greater willingness to fight, but less fighting at equilibrium,
      depending upon the nature of the contests and the local socioecology.
      Additionally, this strategy is robust in the presence of poor knowledge about
      reputation.

PMID- 12468285
TI  - Asymmetric random walk in a reaction intermediate of homologous recombination.
AB  - At an intermediate step of the homologous recombination between two double
      stranded DNA molecules, a point (often called Holliday structure) connecting two
      strands coming from two recombining partners migrates along the homologous
      region. Assuming random walk of a connecting point, we previously explained the
      dependence of recombination frequency on the homology length observed in vivo. In
      this model, the random walk was assumed to be symmetric in that the forward
      transition rate equals the backward one. According to observations in vitro,
      however, catalysed migration appears unidirectional. Taking into account possible
      asymmetry, we thus reformulate our random walk model to reexamine the
      observations in vivo. We also derive some theoretical results to analyse dynamic
      processes observed in vitro.

PMID- 12468286
TI  - Development of a mathematical method for classifying and comparing tree
      architecture using parameters from a topological model of a trifurcating
      botanical tree.
AB  - This paper describes a model for the topological mapping of trifurcating
      botanical trees. The model was based on a system of modular units that
      represented the interconnectivity of shoot meristems (terminal segments) and
      internodes (internal segments) within whole plant canopies, organized with
      increasing centrifugal ordering. The model was capable of describing the dynamics
      of plant growth as expressed by changes in topological parameters over time.
      Preliminary calculations for experimental trees indicated that the model
      represents growth in a biologically sound manner. Methods are described for the
      calculation of the architecture parameters size, size-complexity, structural
      complexity, and tree asymmetry index (TAI). Parameter calculations were based on
      the mathematical principles developed for the classification of bifurcating
      dendrite trees, and were designed to both extract structural information, and to
      enable statistical comparison between trees of different size. Parameters were
      mathematically adjusted for trifurcation, and appeared to be able to represent
      quantitatively the architectural properties of tree structures. In addition to
      the calculation of the TAI for trifurcating trees, new methods were developed to
      enable comparisons to be made of the architectural complexity of trifurcating
      trees of differing size. These were based on the principle of the pair-wise
      comparison of the mean centrifugal order number (MCON) with respect to segments
      against highest order number. We argue and illustrate that this principle can be
      more informative than that of pair-wise comparison of the MCON against tree
      degree (topological size). Further improvements to this method were made by
      examining branching points (vertices) rather than segments (links) to calculate
      the MCON.

PMID- 12468287
TI  - The driving force for life's emergence: kinetic and thermodynamic considerations.
AB  - The principles that govern the emergence of life from non-life remain a subject
      of intense debate. The evolutionary paradigm built up over the last 50 years,
      that argues that the evolutionary driving force is the Second Law of
      Thermodynamics, continues to be promoted by some, while severely criticized by
      others. If the thermodynamic drive toward ever-increasing entropy is not what
      drives the evolutionary process, then what does? In this paper, we analyse this
      long-standing question by building on Eigen's "replication first" model for
      life's emergence, and propose an alternative theoretical framework for
      understanding life's evolutionary driving force. Its essence is that life is a
      kinetic phenomenon that derives from the kinetic consequences of autocatalysis
      operating on specific biopolymeric systems, and this is demonstrably true at all
      stages of life's evolution--from primal to advanced life forms. Life's unique
      characteristics--its complexity, energy-gathering metabolic systems, teleonomic
      character, as well as its abundance and diversity, derive directly from the
      proposition that from a chemical perspective the replication reaction is an
      extreme expression of kinetic control, one in which thermodynamic requirements
      have evolved to play a supporting, rather than a directing, role. The analysis
      leads us to propose a new sub-division within chemistry--replicative chemistry. A
      striking consequence of this kinetic approach is that Darwin's principle of
      natural selection: that living things replicate, and therefore evolve, may be
      phrased more generally: that certain replicating things can evolve, and may
      therefore become living. This more general formulation appears to provide a
      simple conceptual link between animate and inanimate matter.

PMID- 12468288
TI  - Discrete and continuous mathematical models of DNA branch migration.
AB  - DNA junctions, known as Holliday junctions, are intermediates in genetic
      recombination between DNAs. In this structure, two double-stranded DNA helices
      with similar sequence are joined at a branch point. The branch point can move
      along these helices when strands with the same sequence are exchanged. Such
      branch migration is modeled as a random walk. First, we model this process
      discretely, such that the motion of the branch is represented as transfer between
      discrete compartments. This is useful in analysing the results of DNA branch
      migration on junction comprised of synthetic oligonucleotides. The limit in which
      larger numbers of smaller steps go to continuous motion of the branch is also
      considered. We show that the behavior of the continuous system is very similar to
      that of the discrete system when there are more than just a few compartments.
      Thus, even branch migration on oligonucleotides can be viewed as a continuous
      process. One consequence of this is that a step size must be assumed when
      determining rate constants of branch migration. We compare migration where
      forward and backward movements of the branch are equally probable to biased
      migration where one direction is favored over the other. In the latter case
      larger differences between the discrete and continuous cases are predicted, but
      the differences are still small relative to the experimental error associated
      with experiments to measure branch migration in oligonucleotides.

PMID- 12468289
TI  - Relationship between number of muscles, behavioral repertoire size, and
      encephalization in mammals.
AB  - Behavior for mammals is built out of multiple muscles acting in a coordinated
      fashion. Prima facie, there are three principal ways to increase an animal's
      behavioral repertoire size. The first is to, for each new behavior type, create a
      set of new muscle types (e.g. triceps, sartorius, etc.) with new functions
      specifically devoted to the implementation of that behavior type. If this were
      the case, then although each behavior is built out of many muscles, behavior is
      not built in a combinatorial fashion out of muscles. The second is similar to the
      first in that new behavior types are implemented via new muscle types, but,
      instead, muscles are used in a combinatorial fashion, so that it is the
      combination of the new muscle type with existing muscle types that makes the new
      behavior type possible. This is analogous to the addition of new words in a
      language. The third way behavioral complexity may be scaled up is to increase the
      complexity of behavioral expressions themselves (rather than increasing the
      number of muscles types), namely by having more muscles involved in an average
      behavior. This is analogous to uttering longer sentences in a language. My main
      task in this paper is to examine which of these ways underlies the increase of
      behavioral complexity among mammals. Behavioral repertoire sizes from the
      ethology literature were accumulated for mammals from two dozen species across
      eight orders, and the number of muscle types was estimated from atlases of
      anatomy across eight mammalian orders. The manner in which behavioral complexity
      actually increases among mammals appears to favor the second possibility
      mentioned above: greater behavioral complexity is achieved primarily by
      increasing the number of muscle types, and by using muscles in a combinatorial
      fashion. The theoretical framework I describe allows us to interpret the manner
      in which the number of muscle types scales with behavioral repertoire size, and I
      conclude that the number of degrees of freedom in the construction of behavioral
      expressions is on the order of three, which is probably due to neurobiological
      limitations in forming behaviors. The ontogeny of behavior in rat is also
      discussed within this framework. Finally, I show that there is a strong positive
      relationship between behavioral repertoire size and encephalization among
      mammals.

PMID- 12468290
TI  - Carving the cognitive niche: optimal learning strategies in homogeneous and
      heterogeneous environments.
AB  - A model learning system is constructed, in which an organism samples behaviors
      from a behavioral repertoire in response to a stimulus and selects the behavior
      with the highest payoff. The stimulus and most rewarding behavior may be kept in
      the organism's long-term memory and reused if the stimulus is encountered again.
      The value of the memory depends on the reliability of the stimulus, that is, how
      the corresponding payoffs of behaviors change over time. We describe how the
      inclusion of memory can increase the optimal sampling size in environments with
      some stimulus reliability. In addition to using memory to guide behavior, our
      organism may use information in its memory to choose the stimulus to which it
      reacts. This choice is influenced by both the organism's memory state and how
      many stimuli the organism can observe (its sensory capability). The number of
      sampled behaviors, memory length, and sensory capability are the variables that
      define the learning strategy. When all stimuli have the same reliability, there
      appears to be only a single optimal learning strategy. However, when there is
      heterogeneity in stimulus reliability, multiple locally optimal strategies may
      exist.

PMID- 12468291
TI  - Shape anisotropy of lipid molecules and voids.
AB  - Biological polymers, viz., proteins, membranes and micelles exhibit structural
      discontinuities in terms of spaces unfilled by the polymeric phase, termed voids.
      These voids exhibit dynamics and lead to interesting properties which are
      experimentally demonstrable. In the specific case of phospholipid membranes,
      numerical simulations on a two-dimensional model system showed that voids are
      induced primarily due to the shape anisotropy in binary mixtures of interacting
      disks. The results offer a minimal description required to explain the unusually
      large permeation seen in liposomes made up of specific lipid mixtures (Mathai &
      Sitaramam, 1994). The results are of wider interest, voids being ubiquitous in
      biopolymers.

PMID- 12468292
TI  - Intracellular accumulation and mechanism of action of doxorubicin in a spatio
      temporal tumor model.
AB  - A spatio-temporal model of tumor response to sequestered, intracellular
      doxorubicin is presented and simulated. An important feature of the model is the
      characterization of different mechanisms by which doxorubicin initiates the cell
      death cascade. The model predicts that the long-term response of the tumor to
      repeated rounds of therapy is very sensitive to changes in the threshold level of
      doxorubicin required to initiate apoptosis at the maximum rate. In fact,
      perturbations of this parameter mediate the difference between effective tumor
      regression and minimal growth delays. The model is also used to investigate which
      parameters are most influential in rendering the tumor drug resistant.
      Sensitivity analysis shows that decreasing cellular permeability, as opposed to
      decreasing sequestration rate or increasing cellular efflux, is the most
      effective way for tumor cells to overcome the growth control afforded by
      successive rounds of treatment.

PMID- 12468293
TI  - Optimal conservation effort for a population in a stochastic environment.
AB  - We study the optimal conservation effort for a population in a fluctuating
      environment. The survivorship of a population is affected by unpredictable
      environmental fluctuation (noise) and can be improved by conservation effort
      accompanied by a cost. The optimal effort level is the one that minimizes the
      total cost, defined as the weighted sum of the population extinction risk and the
      economic cost of conservation effort. The optimal effort depends on the variance
      and the probability distribution of the noise, the relative importance of the
      population's survival vs. the economic cost, the effectiveness of conservation
      effort, and the time scope over which we optimize. The analysis of dynamic
      programming illustrates that the choice of extinction risk function greatly
      affects the optimal effort level. The conservation effort level that is the best
      solution of a multiple-year optimization may be higher than that for the
      corresponding single-year optimization, if the population is relatively safe.
      However, the conservation level for the multiple-year optimization becomes lower
      than for the single-year optimization if the population is endangered. In a
      similar manner, the optimal conservation effort level for the problem with a
      short time scope is either higher or lower than that for the problem with a long
      time scope, depending on the extinction risk of the population. Next, for each
      parameter of the model, we define five different sensitivities of extinction
      probability or of the total cost. We then study the mean increase in the total
      cost caused by the uncertainty of parameters. To achieve the best conservation
      result, we need to invest the limited research effort to the parameter with the
      largest effect to the optimal effort level, rather than to those with large
      impacts on the extinction probability or on the total cost. The recommended
      policy should depend critically on the choice of the criterion to optimize, which
      shows the importance of theoretical study of the relationship in performing
      proper decision making in conservation practice.

PMID- 12468294
TI  - A model for protein-DNA interaction dynamics.
AB  - We map a simplified version of the protein-DNA interaction problem into an Ising
      model in a random magnetic field. The model includes a "head" which moves along
      the chain while interacting with the underlying spins. The head moves by using
      the statistical fluctuations of base openings. A Monte Carlo (MC) simulation of
      this model reveals the possibility of biased diffusion in one direction, followed
      by sequence identification and binding. The model provides some insight into the
      mechanisms used by some repressor proteins to diffuse and bind to specific DNA
      binding sites.

PMID- 12468295
TI  - A minimum on the mean number of steps taken in adaptive walks.
AB  - I consider the adaptation of a DNA sequence when mutant fitnesses are drawn
      randomly from a probability distribution. I focus on "gradient" adaptation in
      which the population jumps to the best mutant sequence available at each
      substitution. Given a random starting point, I derive the distribution of the
      number of substitutions that occur during adaptive walks to a locally optimal
      sequence. I show that the mean walk length is a constant:L = e-1, where e
      approximately 2.72. I argue that this result represents a limit on what is
      possible under any form of adaptation. No adaptive algorithm on any fitness
      landscape can arrive at a local optimum in fewer than a mean of L = e-1 steps
      when starting from a random sequence. Put differently, evolution must try out at
      least e wild-type sequences during an average bout of adaptation.

PMID- 12468296
TI  - A finite element analysis for the prediction of load-induced fluid flow and
      mechanochemical transduction in bone.
AB  - Interstitial fluid flow through the lacunocanalicular cavities of mechanically
      loaded bone provides the biophysical basis for a number of postulates regarding
      mechanotransduction in bone. Recently, the existence of load-induced fluid flow
      and its influence on molecular transport through bone has been confirmed using
      tracer methods to visualize fluid flow induced by in vivo four-point-bending of
      rat tibiae. In this paper, we present a theoretical two-stage approach for the
      calculation of load-induced flow fields and for the evaluation of their influence
      on molecular transport in bone loaded in four-point bending, analogous to the
      aforementioned experimental model. In the first stage, the fluid velocities are
      calculated using a three-dimensional, poroelastic finite element model. In the
      second stage, mass transport analysis, this calculated fluid flow serves as a
      forced convection flow and its contribution to the total transport potential is
      determined. Based on this combined approach, the overall tracer concentration in
      the loaded bone is significantly higher than that in the unloaded bone.
      Furthermore, augmentation of mass transport through convective flow is more
      pronounced in the tension band of the tissue, as compared to the compression
      band. In general, augmentation of tracer concentration via convective mechanisms
      is most pronounced in areas corresponding to lowest fluid velocities, which is
      indicative of fluid flow direction and areas of increased "dwell time" or
      accumulation during the loading cycle. This theoretical model, in combination
      with the corresponding experimental model, provides unique insight into the role
      of mechanical loads in modulating local flow distributions and concentration
      gradients within bone tissue.

PMID- 12468297
TI  - The role of dimerization in noise reduction of simple genetic networks.
AB  - Fluctuations are an intrinsic property of genetic networks due to the small
      number of interacting molecules. We study the role of dimerization reactions in
      controlling these fluctuations in a simple genetic circuit with negative
      feedback. We compare two different pathways. In the dimeric pathway the proteins
      to be regulated form dimers in solution that afterward bind to an operator site
      and inhibit transcription. In the monomeric pathway monomers bind to the operator
      site and then recruit another monomer to form a dimer directly on the DNA. We
      find that while both pathways implement the same negative feedback mechanism, the
      protein number fluctuations in the dimeric pathway are drastically reduced
      compared to the monomeric pathway. This difference in the ability to reduce
      fluctuations may be of importance in the design of genetic networks.

PMID- 12468298
TI  - T1-relaxation of 129Xe on metal single crystal surfaces-multilayer experiments on
      iridium and monolayer considerations.
AB  - The surface of a typical laboratory single crystal has about 10(15) surface atoms
      or adsorption sites, respectively, and is thus far out of reach for conventional
      NMR experiments using thermal polarization. It should however be in reach for NMR
      of adsorbed laser polarized (hyperpolarized) 129Xe, which is produced by spin
      transfer from optically pumped rubidium. With multilayer experiments of xenon
      adsorbed on an iridium surface we do not only demonstrate that monolayer
      sensitivity has been obtained, we also show that such surface experiments can be
      performed under ultra high vacuum conditions with the crystal being mounted in a
      typical surface analysis chamber on a manipulator with far-reaching sample
      heating and cooling abilities. With only four spectra summed up we present an NMR
      signal from at most 4x10(14) atoms of 129Xe, four layers of naturally abundant
      xenon, respectively. The fact that no monolayer signal has been measured so far
      is explained by a fast Korringa relaxation due to the Fermi contact interaction
      of the 129Xe nuclei with the electrons of the metal substrate. T(1)-relaxation
      times in the order of several ms have been calculated using all electron density
      functional theory for several metal substrates.

PMID- 12468299
TI  - PFG NMR measurements of flow through porous media: effects of spatial
      correlations of the magnetic field and the velocity field.
AB  - Used for a long time for diffusion studies, PFG NMR techniques are now widely
      used to study flow through porous media. We discuss here the effects of the
      magnetic field inhomogeneities and the finite gradient pulse duration in this
      case. We propose a statistical model based on spatial correlations of the
      magnetic field and velocity field and as far as we can, we draw practical
      conclusions on the PFG NMR measurements conditions.

PMID- 12468300
TI  - Double-quantum solid-state NMR of 13C spin pairs coupled to 14N.
AB  - We examine the double-quantum magic angle spinning NMR spectra of pairs of 13C
      nuclei coupled to one or more 14N nuclei. The experimental spectra of 13C(2)
      glycine and glycyl-[13C(2)]-glycyl-glycine are used to demonstrate the
      sensitivity of the spectra to the orientation of 14N quadrupole interaction
      tensors and to the molecular torsional angles.

PMID- 12468301
TI  - Spectrally resolved velocity exchange spectroscopy of two-phase flow.
AB  - The Velocity EXchange SpectroscopY (VEXSY) technique, which provides a means to
      correlate macroscopic molecular displacements measured during two intervals
      separated by a variable mixing period, has been applied for the first time to a
      system of two-phase flow. The chemical shift difference between water and methyl
      protons has been exploited to simultaneously determine the probability of
      displacements, or propagator, of both components in a water/silicone oil mixture
      flowing through a glass bead pack. The joint two-time probability densities as
      well as the conditional probabilities of velocities show a clearly distinct
      dispersion behaviour of both fluids which is a consequence of the different
      wetting properties of the fluids with respect to the glass surface of the bead
      pack.

PMID- 12468302
TI  - Implementation of conditional phase-shift gate for quantum information processing
      by NMR, using transition-selective pulses.
AB  - Experimental realization of quantum information processing in the field of
      nuclear magnetic resonance (NMR) has been well established. Implementation of
      conditional phase-shift gate has been a significant step, which has lead to
      realization of important algorithms such as Grover's search algorithm and quantum
      Fourier transform. This gate has so far been implemented in NMR by using coupling
      evolution method. We demonstrate here the implementation of the conditional phase
      shift gate using transition selective pulses. As an application of the gate, we
      demonstrate Grover's search algorithm and quantum Fourier transform by
      simulations and experiments using transition selective pulses.

PMID- 12468303
TI  - Temperature accuracy and temperature gradients in solution-state NMR
      spectrometers.
AB  - In solution-state NMR spectrometers, there is a systematic deviation between the
      temperature of the sample and the temperature reported by the spectrometer. In
      addition, temperature gradients are often present in the sample. The size of both
      the temperature deviations and the temperature gradients depends on several
      factors, including the temperature, the flow rate of the heating/cooling gas, and
      the amount of radiofrequency heating.

PMID- 12468304
TI  - Spin interaction filter in solid-state NMR Imaging.
AB  - In the tilted rotating frame (TRF), the transverse relaxation time T(2rho)
      depends strongly on the orientation of TRF with respect to the usual rotating
      frame. In the spin space, the relative orientation of the two reference frames
      modifies the contribution of various spin interactions to T(2rho) relaxation.
      Since the orientation of the frames and, to some extent, the role of the spin
      Hamiltonians in TRF are controllable experimentally, the T(2rho) relaxation can
      be made sensitive to molecular mechanisms related to the selected spin
      interaction. In this paper, the realization of a contrast Hamiltonian-dependent
      in solid-state NMR Imaging is proved. The solid-state imaging approach is based
      on the magic angle in the rotating frame. Some results on simple solid polymers
      are presented.

PMID- 12468305
TI  - Gradient echo imaging of flowing hyperpolarized nuclei: theory and phantom
      studies on 129Xe dissolved in ethanol.
AB  - The influence of flip angle and flow velocity on the signal intensity achieved
      when imaging a hyperpolarized substance with a spoiled gradient echo sequence was
      investigated. The study was performed both theoretically and experimentally using
      hyperpolarized xenon dissolved in ethanol. Analytical expressions regarding the
      optimal flip angle with respect to signal and the corresponding signal level are
      presented and comparisons with thermally polarized substances are made. Both
      experimentally and theoretically, the optimal flip angle was found to increase
      with increasing flow velocity. Numerical calculations showed that the velocity
      dependence of the signal differs between the cases of hyperpolarized and
      thermally polarized substances.

PMID- 12468306
TI  - A simple scheme for the design of solvent-suppression pulses.
AB  - Excitation sculpting was first introduced as a way to efficiently suppress
      solvent signals. It requires a pulse sequence that acts as a null pulse at the
      solvent-resonance frequency and as an inversion pulse everywhere else. In this
      article, it is shown that such a goal can be achieved starting with "top-hat"
      inversion shaped pulses such as I-BURP-2 or gaussian cascade G3. The result is a
      Globally Antisymmetric Selective Pulse, or GASP. Numerical optimization was used
      to extend the performance of such pulses. Multifrequency signal suppression was
      shown to be possible through application of successive excitation sculpting
      modules.

PMID- 12468307
TI  - Capture and manipulation of magnetically aligned Pf1 with an aqueous polymer gel.
AB  - The magnetic alignment of the Pseudomonas bacteriophage Pf1 is captured
      indefinitely in a gel of the aqueous triblock copolymer Pluronic F-127. In
      addition to preserving high-resolution liquids NMR spectra for dissolved solutes,
      the gel prevents the reorientation of the phage allowing mechanical manipulation
      of the angle between the axis of the phage alignment and the static magnetic
      field. The residual 2H quadrupolar couplings for several solutes dissolved in
      this material as a function of the angle Theta between the non-spinning sample
      tube and the static magnetic field are consistent with the value of
      P(2)(cosTheta)=(3cos(2)Theta-1)/2. The variable-angle correlation spectrum for
      these solutes is shown to separate residual quadrupolar effects from isotropic
      chemical shifts. Finally, the compatibility of Pluronic F-127 with NMR studies of
      aqueous biological macromolecules is demonstrated in a measurement of residual
      dipolar couplings in an 15N-labeled nucleic acid.

PMID- 12468308
TI  - A new contrast parameter for visualization of the cross-link density in rubber
      based on the dipolar-correlation effect.
AB  - A new parameter for NMR mapping is suggested on the basis of the mean squared
      dipolar fluctuation (MSDF). The MSDF characterizes the relaxation mechanism due
      to ultra-slow dipolar fluctuations in liquids subject to local anisotropy of
      molecular motions. These fluctuations can be monitored on the time scale
      exceeding a few microseconds. In rubber materials, the MSDF is a function of the
      density of chemical cross-links strongly affecting (anisotropic) mesh chain
      fluctuations. Experimentally, the MSDF is determined from the attenuation curves
      of the quotient of the amplitudes of the stimulated and the primary echoes
      produced by the three 90 degrees radio-frequency pulse sequence. In order to
      evaluate the MSDF maps, the latter sequence was combined with the standard scheme
      of the magnetic field gradients providing a spatial resolution. The pixel values
      of the MSDF are "visualized" using grey shades related to the equidistant
      intervals covering the whole range of the measured values. The MSDF maps are
      demonstrated for the two composite samples. The first sample consists of a water
      filled tube in the middle part surrounded by high molecular mass polyisoprene
      (PI) in the outer part. The relaxation weighted spin density image of this sample
      is dominated by a water signal with PI producing a much weaker intensity. The
      MSDF map, on the contrary, enhances the relative intensity of the outer, PI, part
      while scaling the middle, water, part down to the level of noise. The second
      sample consists of the four rubber pieces with different cross-link density. This
      sample thus models an inhomogeneous rubber object. The MSDF map produces clear
      contrast for the relevant regions. The advantages of employing this kind of NMR
      mapping for a characterization of materials are discussed.

PMID- 12468309
TI  - The evaluation of different MAS techniques at low spinning rates in aqueous
      samples and in the presence of magnetic susceptibility gradients.
AB  - It was recently demonstrated that the nuclear magnetic resonance (NMR) linewidths
      for stationary biological samples are dictated mainly by magnetic susceptibility
      gradients, and that phase-altered spinning sideband (PASS) and phase-corrected
      magic angle turning (PHORMAT) solid-state NMR techniques employing slow and ultra
      slow magic angle spinning (MAS) frequencies can be used to overcome the static
      susceptibility broadening to yield high-resolution, spinning sideband (SSB)-free
      1H NMR spectra [Magn. Reson. Med. 46 (2001) 213; 47 (2002) 829]. An additional
      concern is that molecular diffusion in the presence of the susceptibility
      gradients may limit the minimum useful MAS frequency by broadening the lines and
      reducing SSB suppression at low spinning frequencies. In this article the
      performance of PASS, PHORMAT, total sideband suppression (TOSS), and standard MAS
      techniques were evaluated as a function of spinning frequency. To this end,
      300MHz (7.05T) 1H NMR spectra were acquired via PASS, TOSS, PHORMAT, and standard
      MAS NMR techniques for a 230-microm-diameter spherical glass bead pack saturated
      with water. The resulting strong magnetic susceptibility gradients result in a
      static linewidth of about 3.7kHz that is larger than observed for a natural
      biological sample, constituting a worst-case scenario for examination of
      susceptibility broadening effects. RESULTS: (I) TOSS produces a distorted
      centerband and fails in suppressing the SSBs at a spinning rate below
      approximately 1kHz. (II) Standard MAS requires spinning speeds above a few
      hundred Hz to separate the centerband from the SSBs. (III) PASS produces nearly
      SSB-free spectra at spinning speeds as low as 30Hz, and is only limited by T(2)
      induced signal losses. (IV) With PHORMAT, a SSB-free isotropic projection is
      obtained at any spinning rate, even at an ultra-slow spinning rate as slow as
      1Hz. (V) It is found empirically that the width of the isotropic peak is
      proportional to F(-x), where F is the spinning frequency, and x=2 for MAS, 0.84
      for PASS, and 0.5 for PHORMAT.

PMID- 12468310
TI  - Double-blind evaluation of two commercial hypoallergenic diets in cats with
      adverse food reactions.
AB  - The aim of this study was to evaluate two commercially available selected-protein
      source diets as maintenance diets in cats with dermatological manifestations of
      adverse food reactions. Twenty cats with a confirmed adverse food reaction were
      tested in a double-blind manner. An adverse food reaction was diagnosed when,
      after recovery with a home-cooked elimination diet, the signs relapsed after a
      challenge with their previous dietary components, and re-disappeared on a second
      elimination diet period. Hereafter the cats were blind and randomly challenged
      with two commercial hypoallergenic diets. Relapse of the clinical signs was seen
      in eight cats (40%) on a lamb and rice diet and in 13 cats (65%) on a chicken and
      rice diet (P>0.05). Neither one of the commercial diets was as effective in
      controlling the skin problems as the home-cooked elimination diet. The study
      confirms that commercial hypoallergenic diets are adequate for maintenance.

PMID- 12468311
TI  - Feline relapsing polychondritis: two cases and a review of the literature.
AB  - Only 11 reports of cats with relapsing polychondritis (RPC) were found in the
      literature. We describe two additional cases and provide a review of the
      literature. Predominantly young to middle aged cats are affected (range 1.5 to
      14.5 years, median 3 years). There is no sex predilection for feline RPC. In all
      cats with feline RPC, the ears were affected. The findings in one of our cases
      and one case in the literature raise the question if other organs such as the
      joints, the eyes or the heart may be involved in feline RPC. The histological
      lesions observed in biopsy samples of the ears were similar in all cats.
      Glucocorticoids were not effective in the treatment of RPC. Dapsone appeared to
      result in some clinical improvement but side effects were observed in one of four
      cats. Some cats improved without treatment.

PMID- 12468312
TI  - Feline inflammatory polyps: historical, clinical, and PCR findings for feline
      calici virus and feline herpes virus-1 in 28 cases.
AB  - Inflammatory polyps are associated with significant aural or nasopharyngeal
      disease in cats. It has been proposed that chronic viral infection may induce the
      masses. Ventral bulla osteotomy (VBO) is usually recommended for definitive
      therapy but removal of masses from the nasopharynx or external ear canal by
      traction/avulsion is also used. A retrospective study of 28 cats with
      inflammatory polyps was conducted to correlate recurrence with mode of therapy.
      Tissues from 41 polyps were assayed for feline calicivirus and feline herpesvirus
      1 by RT-PCR and PCR, respectively. Of the 14 cats initially treated by
      traction/avulsion, recurrence was detected in five of nine cats with radiographic
      evidence of bulla disease but none of the cats with normal bullae.
      Traction/avulsion is a reasonable treatment for inflammatory polyps if the bullae
      are radiographically normal. Failure to detect feline calicivirus and feline
      herpesvirus-1 suggests that tissue persistence of these viruses is not associated
      with the development of inflammatory polyps.

PMID- 12468313
TI  - Laparoscopic cryptorchidectomy in a cat.
AB  - Several techniques for castration of cryptorchid cats have been described. In
      this case report, the use of laparoscopy for castration of a bilateral
      cryptorchid cat (with testes located in the abdomen) is described. Three trocars
      were inserted into the abdominal cavity, the testicles were easily identified
      adjacent to the urinary bladder. Haemostasis of the gubernaculum testis and
      spermatic cord was achieved with bipolar cauterisation. The testicles were easily
      removed in approximately 20 min. To the authors' knowledge this is the first
      report of the use of laparoscopy for the treatment of cryptorchidism in cats.

PMID- 12468314
TI  - Anal sac adenocarcinoma in a Siamese cat.
AB  - A 12-year-old male neutered Siamese cat presented with a history of inappetance
      and lethargy and an enlarged left anal sac. The anal sac was surgically excised
      and histopathology confirmed the diagnosis of anal sac adenocarcinoma. Perianal
      tumours are rare in the cat and anal sac adenocarcinoma has not been previously
      reported. This is in contrast to the dog where anal sac adenocarcinoma is a well
      recognised albeit uncommon tumour.

PMID- 12468315
TI  - Presumed localized tetanus in two cats.
AB  - In this report two cases of localised tetanus in two young (<1 year) intact male
      and outdoor DSH cats, which had been missing, are described. Clinical examination
      revealed severe muscular spasms on the right (case 1) or both thoracic limbs
      (case 2). In the latter cat, wrinkling of the forehead and mild trismus were also
      seen. The routine diagnostic workup (CBC, survey radiographs of the spine, CSF
      analysis) did not reveal any abnormalities in both cats. EMG testing on the
      affected muscles in the second animal showed persistent spontaneous motor unit
      potentials, strongly indicating tetanus. The treatment, that was symptomatic
      (diazepam, metronidazole) and supportive (physical therapy, assist feeding and
      intravenous fluid therapy) resulted in the progressive improvement of limb
      rigidity and the restoration of motor dysfunction in a period of 5- (case 1) and
      2- (case 2) month duration.

PMID- 12468316
TI  - Diagnosis, treatment, and long-term follow-up of bilateral, upper urinary tract
      infection (UTI) in a cat.
AB  - A case of bilateral, upper urinary tract infection caused by haemolytic E coli in
      a female Birman cat is presented. Ultrasonographic examination of the kidneys
      documented changes in size, outline, echogenicity and architecture. Ultrasound
      guided fine needle aspiration of fluid from the renal pelvis was used to make the
      diagnosis. Fluid was submitted for culture and sensitivity and based on the
      results, antimicrobial therapy was initiated. The treatment was monitored over a
      406-day follow-up period. Despite extensive treatment with specific antibiotics
      and supportive therapy, recurrence of urinary tract infection occurred.

PMID- 12468317
TI  - What is your diagnosis? Localised tetanus in a cat.

PMID- 12468319
TI  - Lymph-vascular space invasion in endometrial adenocarcinoma: confusion,
      confessions, and conclusions.

PMID- 12468320
TI  - Should the presence of lymphvascular space involvement be used to assign patients
      to adjuvant therapy following hysterectomy for unstaged endometrial cancer?
AB  - Objective. Thegoal of this study was to determine the influence of LVSI
      (lymphvascular space involvement) on the risk of lymph node metastases from
      endometrial cancer.Methods. All patients with surgically staged endometrial
      cancer from 1998 to 2000 were identified from divisional databases. The influence
      of LVSI on the risk for nodal metastases was determined after controlling for
      tumor grade and depth of invasion, and comparisons were made with the chi(2) or
      Fisher's exact tests. Multivariable analysis was performed using a logistic
      regression model.Results. We identified 366 patients who fit the study criteria.
      Pathologically, 92/366 (25%) tumors had LVSI, and 46 patients (13%) had evidence
      of pelvic lymph node metastases. Cancers with LVSI were significantly more likely
      to have nodal disease (35/92 versus 11/274, P < 0.001). When controlled for tumor
      grade, the presence of LVSI led to an increased incidence of pelvic node
      metastases (P < 0.001 for all grades). When stratified by depth of invasion in
      thirds, the presence of LVSI led to a significantly increased chance of pelvic
      lymph node metastases (P < 0.05 for each strata). When tumor grade and depth of
      invasion were evaluated together, LVSI led to a significantly increased risk of
      pelvic node metastases in patients with deeply invasive tumors. In a
      multivariable analysis, LVSI led to a significantly increased risk for pelvic
      lymph node metastases (P < 0.05).Conclusion. LVSI leads to an independent and
      significantly increased risk for pelvic lymph node metastases. As such, the
      presence of LVSI may indicate the need for lymphadenectomy or adjuvant therapy
      for potential regional lymph node metastases in patients with unstaged
      endometrial cancer.

PMID- 12468321
TI  - A phase II trial of topotecan in patients with advanced, persistent, or recurrent
      endometrial carcinoma: a gynecologic oncology group study.
AB  - OBJECTIVE: To estimate the antitumor activity of topotecan in women with
      advanced, persistent, or recurrent endometrial carcinoma previously treated with
      chemotherapy, and to determine the nature and degree of toxicity of topotecan in
      this cohort of patients. MATERIALS AND METHODS: Eligible patients were those who
      had failed one prior chemotherapy regimen. Topotecan 0.5 to 1.5 mg/m(2) was
      administered iv daily for 5 days, every 3 weeks, until progression of disease or
      adverse affects prohibited further therapy. RESULTS: Of 29 patients entered, 28
      were evaluable for toxicity and 22 were evaluable for response. Patient
      characteristics included a median age of 65, with 41% having prior radiation and
      14% having prior hormonal therapy. Nine patients (41%) had a performance status
      (PS) of 0, 11 (50%) had a PS of 1, and 2 (9%) had a PS of 2. Patients received
      from 2 to 11 (with a median of 4) courses of treatment. The most frequently
      observed grade 4 toxicities were neutropenia seen in 17 (61%) patients,
      leukopenia in 11 (39%), and thrombocytopenia in 7 (25%). Two deaths were
      considered potentially related to treatment. There was one (4.5%) complete and
      one (4.5%) partial response; 12 (55%) patients maintained stable disease and
      eight (36%) experienced increasing tumor. CONCLUSION: Topotecan at this dose and
      schedule does not appear to have major activity in patients with advanced or
      recurrent endometrial carcinoma previously treated with chemotherapy.

PMID- 12468322
TI  - Lysophosphatidic acid induces focal adhesion assembly through Rho/Rho-associated
      kinase pathway in human ovarian cancer cells.
AB  - OBJECTIVE: The level of lysophosphatidic acid (LPA) is elevated in patients with
      ovarian cancer, and LPA has been reported to have a pivotal role in cancer
      dissemination. In the current study, the effect of LPA on the motility of ovarian
      cancer cells was investigated. METHODS: We analyzed the effects of LPA on the
      migration activity, the focal adhesion formation, and the tyrosine
      phosphorylation of focal adhesion proteins in human ovarian cancer cell lines
      Caov-3 and OVCAR-3. Inhibitors of the small GTPase Rho, one of its downstream
      effectors (Rho-associated kinase (ROCK)), myosin light chain kinase (MLCK), and
      myosin light chain (MLC) phosphatase were used to examine the mechanism of LPA
      induced cellular effects. RESULTS: LPA enhanced the migration of ovarian cancer
      cells and facilitated their invasion. Rho and ROCK played essential roles in the
      migratory process, as evidenced by the inhibition of migration and focal adhesion
      formation of cancer cells by Clostridium botulinum C3 exoenzyme (C3), an
      inhibitor of Rho, or Y-27632, an inhibitor of ROCK. LPA also evoked the formation
      of focal adhesions and tyrosine phosphorylation of focal adhesion kinase and
      paxillin, all of which were inhibited by C3 or Y-27632. CONCLUSION: These results
      suggest that LPA induced the migration of ovarian cancer cells, at least in part,
      through accelerated formation of focal adhesions mediated by Rho/ROCK-induced
      actomyosin contractility. This study may provide the basis for new therapies to
      control the metastasis of ovarian cancer.

PMID- 12468323
TI  - Outcomes in surgery for ovarian cancer.
AB  - OBJECTIVE: Theobjective was to determine the relationship among hospital volume
      of ovarian cancer surgery,academic status of institution, surgical specialty, and
      outcomes of care (30-day postoperative mortality, reoperation rate, and overall
      survival). METHODS: This population-based cohort study included all newly
      diagnosed ovarian cancer patients treated from 1992 to 1998 in Ontario, Canada.
      Hospitalization and surgical billing databases were used. Logistic regression was
      used to evaluate the importance of hospital type, hospital volume, surgical
      specialty, and surgeon volume of ovarian cancer operations on postoperative
      mortality, reoperation rates, and survival. RESULTS: Ovarian cancer surgery was
      performed on 3815 women between April 1992 and March 1998. When adjusted for age,
      comorbidity, acuity of the operation, and metastatic disease, no factors
      influenced postoperative mortality. The adjusted relative risk for reoperation
      within 3 months of the initial surgery showed that patients were less likely to
      have a repeat operation if the initial operation was done in a high- or
      intermediate-volume hospital (RR 0.24 95% CI 0.12-0.48, RR 0.29 95% CI 0.20-0.42,
      respectively), a hospital with a gynecologic oncologist (RR 0.29 95% CI 0.15
      0.56), by a gynecologic oncologist (RR 0.04 95% CI 0.01-0.12) or gynecologist (RR
      0.37 95% CI 0.21-0.66), or by a high-volume surgeon (RR 0.09 95% CI 0.03-0.23).
      The adjusted survival was improved if the initial surgery was done by a
      gynecologic oncologist (HR 0.70 95% CI 0.57-0.85) or gynecologist (HR 0.65 95% CI
      0.53-0.79). CONCLUSIONS: There is a relationship between hospital volume and
      reoperation rate. Institution type only influenced reoperation rate.
      Statistically significant associations were found between surgical specialty and
      all three outcome variables. The volume of surgery performed by an individual
      surgeon only influenced reoperation rate. Our results are preliminary but support
      the need for further studies examining factors such as stage.

PMID- 12468324
TI  - Human papillomavirus type 16 E6 and E7 gene variations in Indian cervical cancer.
AB  - OBJECTIVES: Human papillomavirus type 16 is a causative factor for development of
      cervical cancer. The E6 and E7 genes of HPV 16 are critical to the process of
      immortalization and transformation of host cells. Recent reports suggest that
      variants of these two genes may contribute to the risk of malignant progression
      of cancer in the uterine cervix. However, no data exist on sequence variations of
      HPV 16 E6 and E7 genes that may exist in India. Therefore, we examined intratype
      variations in the E6 and E7 viral genes in DNA isolated from HPV 16-positive
      cervical scrapes and biopsies. METHODS: The open reading frames of the E6 and E7
      genes were amplified by PCR and then directly sequenced by the fluorescent dye
      dideoxy termination method.Results. In addition to the prototype E6 gene
      sequence, five sets of mutations of the E6 gene were identified. The European
      prototype (350T) was detected in 9.1% of the study group while the European
      variant (350G) was seen in 28% of patients. The remaining variants (a combination
      of the 350G mutation with 335T, 145T, or 419G) were significantly associated with
      cases compared to controls. The 350G + 145T variant was found at much higher
      incidence in cases in younger women, suggesting that this variant may be
      associated with aggressive tumor behavior. Interestingly the 350G + 419G
      combination was found only in controls. There was no significant association
      between the four genotypes of E7 and any stage of tumor progression or age.
      CONCLUSIONS: The results indicate that specific mutations in the E6 gene are
      found in young Indian women with high-grade squamous intraepithelial lesions and
      invasive cancer, suggesting that these mutations represent more oncogenically
      active HPV 16. Whether this increased oncogenecity is due to differences in p53
      inactivation, ineffective keratinocyte differentiation, and/or altered response
      to the immune system by these oncogenic E6 mutants remains to be clarified.

PMID- 12468325
TI  - Surgical stage I endometrial cancer: predictors of distant failure and death.
AB  - OBJECTIVES: The objective was to analyze the effect of various histopathologic
      characteristics on prognosis in surgical stage I (node-negative) endometrial
      carcinoma. METHODS: During a 10-year period, 229 patients with stage I epithelial
      (all subtypes) endometrial cancer had hysterectomy and node dissection. Mean
      number of nodes harvested was 16.2 pelvic and 5.7 paraaortic. Median follow-up
      was 83 months. Sixty-seven patients (29%) received adjuvant radiotherapy.
      RESULTS: Five-year disease-related survival (DRS) was 95%, and 5-year relapse
      free survival (RFS) 91%. We observed 7 (3%) isolated vaginal recurrences, 14 (6%)
      distant failures, and 1 (0.4%) simultaneous recurrence at both regional (pelvic
      sidewall) and distant sites. Only 1 of 7 patients (14%) with vaginal failure died
      of the disease (median follow-up of censored patients after failure was 110
      months), compared with 10 of the 15 patients (67%) with distant failure. By
      univariate analysis, myometrial invasion (MI) >or= 66%, nonendometrioid
      histology, lymphovascular invasion, absence of associated hyperplasia, and tumor
      diameter >2 cm were significant predictors of poor prognosis with distant failure
      (P <or= 0.05). Cox regression analysis identified MI >or= 66% as the only
      independent predictor of DRS (P < 0.001, relative risk [RR] = 12.44), RFS (P <
      0.001, RR = 8.67), and distant failure (P < 0.001, RR = 24.89). Only 2% of
      patients with MI < 66% had distant failure and died of the disease at 5 years,
      compared with a 29% 5-year distant failure rate and a 22% 5-year death rate among
      patients with MI >or= 66%. CONCLUSION: Stage I (negative nodes) endometrial
      cancer patients with MI >or= 66% are at significant risk for distant failure and
      death and should be considered candidates for new randomized trials of adjuvant
      systemic therapy.

PMID- 12468326
TI  - Intraoperative measurements to determine the extent of radical hysterectomy.
AB  - HYPOTHESES: The extent of radical hysterectomy can be objectively measured and
      the measured extent of resection will correlate with morbidity. STUDY DESIGN:
      Observational. The extent of radical hysterectomy was determined by measurement
      of overall length and excised portions of the uterosacral and cardinal ligaments.
      Analysis of morbidity was performed on 120 patients. Univariate analysis was
      accomplished with correlation, t test, and chi(2) statistical methods, and
      regression models were used for multivariate analysis. RESULT: In precisely
      defined terms, the patients in this study underwent modified radical
      hysterectomy. The extent of the resection had an independent relationship to
      blood loss, operative time, and duration of postoperative bladder drainage. The
      extent of resection was also directly related to persistent bladder and rectal
      dysfunction. CONCLUSIONS: This method for objectively measuring the extent of a
      radical hysterectomy is feasible. The extent of the procedure correlates with
      morbidity.

PMID- 12468327
TI  - Surgical resection of pulmonary and extrapulmonary recurrences of uterine
      leiomyosarcoma.
AB  - OBJECTIVE: The objective was to determine long-term survival and predictors of
      outcome in a retrospective cohort of patients who underwent surgical resection of
      recurrent uterine leiomyosarcoma (LMS). METHODS: Between January 1991 and March
      2001, 41 patients who underwent surgical resection for recurrent uterine
      leiomyosarcoma were identified. The records of these patients were reviewed and
      abstracted data included patient age, date of initial diagnosis, tumor histology
      and grade, residual tumor after all operations, the use of adjuvant therapy,
      dates and sites of all recurrences, and disease status at last follow-up.
      Survival was determined from the time of first recurrence to last follow-up.
      Survival curves were estimated using the Kaplan-Meier method and P values were
      generated using the likelihood ratio test from the Cox proportional hazards model
      and chi(2) analysis. RESULTS: Forty-one patients with recurrent uterine LMS (17
      local pelvic, 18 distant, 6 both) underwent surgical resection at time of first
      recurrence. A thoracic procedure alone was performed in 13 cases. Information on
      residual disease was available for 37 patients. The disease-specific 2-year
      survival for all 41 patients was 71.2% (95% CI: 58.1, 87.3). In univariate
      analysis, time to first recurrence and optimal resection were significantly
      associated with longer overall survival. CONCLUSION: Optimal surgical resection
      for recurrent uterine leiomyosarcoma may provide an opportunity for long-term
      survival in a select patient population. Time to first recurrence and optimal
      surgical resection were predictors of improved outcome in this study.

PMID- 12468328
TI  - Fractal tumor growth of ovarian cancer: sonographic evaluation.
AB  - OBJECTIVE: The objective of this study was to determine whether sonographically
      depicted ovarian tumor growth is fractal, and the mean fractal dimension differs
      according to stages of the disease and histologic types. METHODS: The fractal
      dimensions of outlines of sonographically depicted solid components in 160
      ovarian tumors were measured using a box-counting method. RESULTS: The mean
      fractal dimensions of the surface of intracystic solid components in serous,
      mucinous, endometrioid, and clear cell adenocarcinoma were 1.259, 1.243, 1.238,
      and 1.182, respectively. These values were significantly greater than the
      topological dimension of a line (=1). The value was significantly higher in stage
      I or II (1.381) than stage III or IV (1.205) in serous carcinoma (P = 0.02), but
      not significantly different in clear cell carcinoma (1.187 and 1.172,
      respectively). In stage I or II, the value of serous carcinoma (1.381) was
      significantly higher than that of clear cell carcinoma (1.187) (P = 0.03). The
      value of mucinous cystadenoma of low malignant potential was 1.337, which was
      also significantly greater than 1. The mean fractal dimensions of outlines of
      solid tumors in cases with dysgerminoma and thecoma-fibroma were 1.036 and 1.023,
      respectively. These values were not significantly different from 1. CONCLUSION:
      This study shows that the surface of solid components in cystic epithelial
      ovarian cancers has a fractal structure, and the mean fractal dimension may
      differ according to stages of the disease and histologic types. Fractal geometry,
      a vocabulary of irregular shapes, can be useful for describing the pathological
      architecture of ovarian tumors and for yielding insights into the mechanisms of
      tumor growth.

PMID- 12468329
TI  - Case of PSTT treated with chemotherapy followed by open uterine tumor resection
      to preserve fertility.
AB  - BACKGROUND: Placental site trophoblastic tumor (PSTT) is a rare variant of
      gestational trophoblastic malignancy, usually seen in young women with a 20%
      fatality rate. The hysterectomy is general for PSTT, but hysterectomy is
      undesirable for patients who wish to remain fertile. Recent advancement of
      chemotherapy and tumor detection and assessment technologies should allow removal
      of tumor from the uterus by conservative surgery, without losing fertility,
      although very few cases have been reported to date. This report describes a young
      PSTT patient treated by combination chemotherapy and open uterine surgery, which
      resulted in an early restoration of the menstrual cycle and apparent preservation
      of fertility. CASE: A 26-year-old secundigravida primipara woman presented with a
      case of PSTT which was diagnosed 4 months after a spontaneous abortion. The tumor
      was confined to the uterus. Two courses of EMA/CO chemotherapy resulted in a
      remarkable reduction of the tumor mass, but low levels of serum beta-hCG
      persisted. After precise evaluation of the residual tumor by MRI and
      hysteroscopy, the anterior wall of the uterus was opened to resect the tumor in
      the posterior myometrium. An argon beam coagulator was used to evaporate the
      myometrium tissue surrounding the lesion. One week later, the patient had normal
      menstruation. MRI taken 2 weeks after the operation detected no tumor in the
      uterus nor uterine deformation. Serum beta-hCG was reduced below the level of
      detection. CONCLUSIONS: Open uterine resection of PSTT tumor following
      appropriate chemotherapy could achieve long-term remission and save fertility of
      young patients who wish to avoid hysterectomy for future pregnancy.

PMID- 12468330
TI  - Primary non-Hodgkin's lymphoma in Bartholin's gland.
AB  - BACKGROUND: Non-Hodgkin's lymphoma (NHL) may involve the lower female genital
      tract, most often as a manifestation of systemic disease and rarely as a
      primarily localisation. CASE: A 73-year-old woman, HIV-negative, presented with a
      5-month history of a mass in the left Bartholin's gland. The performed biopsy was
      reported to be a poorly differentiated carcinoma. Therefore, the patient
      underwent a vulvectomy with superficial groin node dissection. Unexpectedly, the
      definitive histological diagnosis showed that the tumor was an extranodal diffuse
      large B-cell non-Hodgkin lymphoma. CONCLUSION: This is the first report of a NHL
      located in the Bartholin's gland. Primary NHLs involving the external genitalia
      are rare and often inaccurately diagnosed. A greater awareness of this entity
      among clinicians and pathologists could uncover more cases.

PMID- 12468331
TI  - Scalp metastasis in carcinoma of the uterine cervix--a rare entity.
AB  - BACKGROUND: Distant metastasis in carcinoma of uterine cervix is a rare
      manifestation and bone metastasis is uncommon. CASE: A 60-year-old woman treated
      by radical radiotherapy for moderately differentiated cervical carcinoma FIGO
      stage IIIB presented 4 months later with swelling over right side of the scalp.
      Fine needle aspiration cytology from swelling showed poorly differentiated
      metastatic carcinoma. X-ray of the skull was suggestive of osteolytic metastasis
      of calvaria. CONCLUSION: Bone metastasis in cervical carcinoma is a late
      manifestation of advanced malignancy and heralds poor prognosis. Scalp metastasis
      is a very rarely reported phenomenon.

PMID- 12468332
TI  - Liposomal doxorubicin for treatment of metastatic chemorefractory vulvar
      adenocarcinoma.
AB  - BACKGROUND: Primaryadenocarcinoma of the vulva is a rare entity, and for widely
      metastatic vulvar adenocarcinoma, no effective treatment has been established.
      CASE: A 65-year-old woman was diagnosed with regionally advanced vulvar
      adenocarcinoma, with bulky involvement of bilateral groin lymph nodes, and
      associated extramammary Paget's disease. Initial therapy consisted of multiagent
      chemotherapy and vulvar and groin irradiation, followed by radical vulvectomy
      with groin and pelvic lymph node dissection. She subsequently developed widely
      metastatic disease including brain, pulmonary, hepatic, osseus, and subcutaneous
      lesions. Treatment with liposomal doxorubicin (Doxil) resulted in dramatic
      regression of metastatic lesions and marked improvement in quality-of-life. She
      remains clinically well, greater than 1 year since initiating Doxil treatment for
      widely metastatic vulvar adenocarcinoma, and has surpassed 5 years of survival
      since her initial diagnosis. CONCLUSIONS: We report the first case of Doxil used
      for the treatment of metastatic chemorefractory vulvar adenocarcinoma. We
      observed that Doxil was a well-tolerated and effective agent for this gynecologic
      malignancy, and warrants further investigation.

PMID- 12468333
TI  - Small intestinal volvulus following laparotomy for endometrial clear cell
      carcinoma in a woman with a past history of total gastrectomy and Roux-en-Y
      anastomosis for gastric carcinoma.
AB  - BACKGROUND: Small intestinal volvulus is a rare complication following Roux-en-Y
      anastomosis. CASE REPORT: A 63-year-old woman was diagnosed with small intestinal
      volvulus following laparotomy for clear cell carcinoma of the endometrium. Her
      past medical history included a total gastrectomy and antecolic Roux-en-Y
      anastomosis for Duke's B gastric carcinoma. Operative findings were of
      transmesenteric herniation of the ileum through the Roux-en-Y small intestinal
      mesenteric window, with metastatic deposits fixing the hernia at its base to
      create a volvulus. The proximal transverse colon was very dilated and thin due to
      partial obstruction by the volvulus. Her treatment involved adhesiolysis and
      unraveling of the small intestinal volvulus. CONCLUSIONS: This is the first case
      report of a small intestinal volvulus following a Roux-en-Y anastomosis involving
      a metastatic gynacological malignancy.

PMID- 12468334
TI  - PET-CT localizes previously undetectable metastatic lesions in recurrent
      fallopian tube carcinoma.
AB  - BACKGROUND: Fallopian tube carcinoma is a rare malignancy that commonly recurs
      after initial surgical resection. New combined instrumentation with co-registered
      PET and CT is a new technique that combines functional and anatomic imaging to
      detect metastatic disease that may be difficult to detect with either modality
      alone. CASE: We present two cases of suspected fallopian tube carcinoma
      recurrence demonstrating the unique potential of combined PET-CT using 18F-fluoro
      2-deoxyglucose (FDG). These cases demonstrate the unique capability to detect and
      localize metastatic disease when serum CA-125, laparoscopy, and CT scan alone
      were unable to detect recurrence. CONCLUSION: PET-CT with FDG may prove to be a
      sensitive and accurate method for detection of metastatic disease and may
      influence the clinical management of recurrent fallopian tube carcinoma.

PMID- 12468335
TI  - Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian
      cancer treated with fertility-sparing therapy.
AB  - OBJECTIVES: The purpose of this study was to determine the recurrence rate,
      survival, and pregnancy outcome in patients with Stage IA and Stage IC invasive
      epithelial ovarian cancer treated with unilateral adnexectomy. METHODS: A multi
      institutional retrospective investigation was undertaken to identify patients
      with Stage IA and IC epithelial ovarian cancer who were treated with fertility
      sparing surgery. All patients with ovarian tumors of borderline malignancy were
      excluded. Long-term follow-up was obtained through tumor registries and telephone
      interviews. The time and sites of tumor recurrence, patient survival, and
      pregnancy outcomes were recorded for every patient. RESULTS: Fifty two patients
      with Stage I epithelial ovarian cancer treated from 1965 to 2000 at 8
      participating institutions were identified. Forty-two patients had Stage IA
      disease, and 10 had Stage IC cancers. Cell type was distributed as follows:
      mucinous, 25; serous, 10; endometrioid, 10; clear cell, 5; and mixed, 2.
      Histologic differentiation was as follows: grade 1, 38; grade 2, 9; and grade 3,
      5. Twenty patients received adjuvant chemotherapy (mean 6 courses, range 3-12
      courses). Patients received the following chemotherapeutic agents:
      cisplatin/taxol or carboplatin/taxol, 11; melphalan, 5; cisplatin and
      cyclophosphamide, 3; and single-agent cisplatin, 1. Eight patients had second
      look laparotomies and all were negative. Duration of follow-up ranged from 6 to
      426 months (median 68 months). Five patients developed tumor recurrence 8-78
      months after initial surgery. Sites of recurrence were as follows: contralateral
      ovary, 3; peritoneum, 1; and lung, 1. Nine patients underwent subsequent
      hysterectomy and contralateral oophorectomy for benign disease. At present, 50
      patients are alive without evidence of disease and 2 have died of disease 13 and
      97 months after initial treatment. The estimated survival was 98% at 5 years and
      93% at 10 years.Twenty-four patients attempted pregnancy and 17 (71%) conceived.
      These 17 patients had 26 term deliveries (no congenital anomalies noted) and 5
      spontaneous abortions. CONCLUSION: The long-term survival of patients with Stage
      IA and IC epithelial ovarian cancer treated with unilateral adnexectomy is
      excellent. Fertility-sparing surgery should be considered as a treatment option
      in women with Stage I epithelial ovarian cancer who desire further childbearing.

PMID- 12468336
TI  - Association between in vitro platinum resistance in the EDR assay and clinical
      outcomes for ovarian cancer patients.
AB  - OBJECTIVE: The initial clinical response to platinum is a major determinant of
      outcome for patients with ovarian cancer. This retrospective study was undertaken
      to correlate the response and survival of newly diagnosed advanced ovarian cancer
      patients who received platinum-based therapy with in vitro drug response to
      cisplatin or carboplatin measured as percentage cell inhibition (PCI) in the in
      vitro Extreme Drug Resistance (EDR) assay. METHODS: Outcomes for newly diagnosed
      ovarian cancer patients with tumor specimens submitted in a serial fashion for
      the EDR assay were studied. EDR assay results for cisplatin and carboplatin were
      correlated with clinical outcome for 79 evaluable chemotherapy nai;ve cases who
      presented with advanced (stages IIC, III, and IV) ovarian cancer. Stage IV and
      suboptimally debulked stage IIIc accounted for 16 cases, while 63 cases were
      optimally debulked Stage III/IIc. All patients were treated with platinum-based
      combination chemotherapy at a single institution. In vitro results for patient
      tumors were classified as low drug resistance (PCI > median), intermediate drug
      resistance [PCI between the median and 1 standard deviation (SD) below the
      median], or extreme drug resistance (PCI more than 1 SD below the median). For
      the purpose of this analysis, in vitro EDR to either cisplatin or carboplatin was
      considered to represent extreme resistance to platinum (EDRP), while the absence
      of EDR to either cisplatin or carboplatin was considered to represent low
      resistance to platinum (LDRP). Patients demonstrating relative in vitro
      resistance to paclitaxel and non-cross-resistance to cyclophosphamide and/or
      doxorubicin received cyclophosphamide plus platinum (CP); cyclophosphamide,
      doxorubicin, and platinum (CAP); or platinum alone in place of paclitaxel plus
      platinum (TP). Progression-free survival (PFS) and overall survival (OS) were
      correlated with EDR assay results. RESULTS: Median PFS was 6 months for the 17
      cases exhibiting EDRP, compared to 24 months for the 62 cases exhibiting LDRP in
      vitro [relative risk (RR) 3.78, confidence intervals (CI) 1.82-7.83], adjusted
      for stage, debulking status, in vitro response to 3-OH-cyclophosphamide, and
      histological grade. Estimated overall 5-year survival was 19% for patients with
      tumors showing EDRP, compared to 68% for patients with tumors showing LDRP (RR
      2.32, CI 1.06-5.07). Patients treated with CP (n = 20) showed no significant
      difference in OS compared to patients treated with TP (n = 54), CAP (n = 4), or
      cisplatin (n = 1) alone. In vitro platinum response remained an independent
      predictor of PFS and OS in multivariate analyses adjusted for CP versus TP, CAP,
      or platinum administration, and adjusted for debulking status. Median PFS for all
      79 patients was 22 months, with an estimated 5-year survival of 57%. CONCLUSIONS:
      Patients with tumors demonstrating in vitro EDR to platinum were at significantly
      increased risk for progression and death when treated with standard platinum
      based regimens. Such patients may therefore benefit from entry onto trials with
      novel agents or combinations.

PMID- 12468337
TI  - Correlation of p53 immunostaining in primary and residual ovarian cancer at the
      time of positive second-look laparotomy and its prognostic role: a Southwest
      Oncology Group ancillary study.
AB  - OBJECTIVE: The objective of this study was to verify the correlation between p53
      immunostaining at initial diagnosis and at positive reassessment after completing
      platinum-based chemotherapy and to assess prognostic differences between patients
      whose tumors display positive immunostaining versus those that have negative
      immunostaining at such reassessment. METHODS: This study made use of samples from
      patients entered into a prospective randomized study of the Southwest Oncology
      Group (SWOG 8835) that treated patients with minimal residual disease at second
      look laparotomy with either intraperitoneal (ip) mitoxantrone or
      fluorodeoxyuridine (FUDR). Unstained slides from tumor obtained at the initial
      diagnosis and at reassessment were retrospectively requested from individual
      institutions. The degree of nuclear staining was determined using the anti-p53
      mouse monoclonal antibody Pab1801 and previously published techniques, with a
      cutoff of 10% or more staining of tumor cell nuclei for a positive result. Cox
      model regression analysis was performed for overall survival and progression-free
      survival, with p53 status, ip treatment, and baseline CA125 as independent
      variables. RESULTS: p53 determination was feasible in 22 patients both at
      diagnosis and at the second-look samples; 9 additional patients had only either
      sample available. Since concordance between the 10 negative and 12 positive
      immunostained samples was 100%, all 31 patients were considered in the Cox model.
      The death hazard ratio of p53-positive versus p53-negative patients was 4.18 (two
      sided P value of 0.006). CONCLUSION: p53 immunostaining at second-look laparotomy
      correlates with the immunostaining at diagnosis. In this series confined to
      patients with minimal residual disease after initial therapy subjected to second
      line intraperitoneal treatment, it appears to identify a poor prognostic
      (positive) subset for survival.

PMID- 12468338
TI  - Procollagen-derived biomarkers in malignant ascites of ovarian cancer.
      Independent prognosticators for progression-free interval and survival.
AB  - OBJECTIVE: Matrix formation is a hallmark of solid tumor biology. Circulating
      antigens of structural matrix proteins should reflect this fact, yet are subject
      to systemic variables. We propose that if measured regionally, in a cancer
      induced extravascular fluid pool such as malignant ascites of ovarian cancer, the
      same antigens retain their conceptual advantage as surrogate markers for tumor
      biology. METHODS: In malignant ascites obtained at staging laparatomy of 35 women
      with ovarian cancer, the protein-normalized levels of the C-terminal propeptide
      of procollagen type I (pnPICP) and the N-terminal propeptide of procollagen type
      III (pnPIIINP) were determined. Using univariate and multivariate analysis, we
      examined these parameters, their (pnPIIINP/pnPICP) quotient, and clinical
      criteria (FIGO stage, age, residual tumor, histology, and tumor grade) for impact
      on progression-free interval and survival. RESULTS: The absolute level of
      pnPIIINP was the single most powerful independent factor impacting on survival,
      its P value being distinctly below (P = 0.0005 vs 0.003) and its risk ratio
      distinctly above (15 vs 2.5) residual tumor after debulking surgery. The relative
      level of pnPIIINP, i.e. (pnPIIINP / pnPICP), impacted on the likelihood of
      recurrence even more than residual tumor. By Kaplan-Meier analysis, cutoff values
      for the absolute or relative pnPIIINP level significantly discriminated patients
      with shortened survival or progression-free interval, respectively. CONCLUSIONS:
      Since malignant ovarian epithelium itself forms collagen type III, and since
      collagen type III is a solid-phase regulator of angiogenesis, we propose that
      ascitic pnPIIINP is a fluid-phase indicator for angiogenic activity in ovarian
      cancer and thus represents a tumor virulence index.

PMID- 12468339
TI  - Cytokeratin 20 as a biomarker of gestational trophoblastic disease: diagnostic
      and prognostic significance.
AB  - OBJECTIVES: This study was designed to examine whether cytokeratin 20 (CK20) is
      expressed in molar pregnancies and may therefore be used in the diagnosis of
      gestational trophoblastic disease (GTD). The potential of CK20 expression in
      predicting the evolution and the prognosis of the different subtypes of GTD was
      also assessed. METHODS: A total of 48 samples were studied for CK20 expression by
      RT-PCR methodology. Among these, 24 samples were obtained by curettage of the
      uterine cavity of patients diagnosed with hydatidiform mole (14 complete moles
      and 10 partial moles), 4 samples were obtained from choriocarcinoma cell lines (2
      JAR and 2 JEG), and 20 samples were of normal trophoblast (control group)
      obtained from patients that underwent elective termination of pregnancy. RESULTS:
      Expression of CK20 was identified in all the samples of complete mole (CM), all
      choriocarcinoma cell lines, and 50% of the patients with partial mole (PM). None
      of the preparations of normal trophoblastic tissue from the control group
      expressed the CK20. A significant difference (P < 0.00001) was found in CK20
      expression between samples of patients with GTD and control samples. Comparison
      between CK20 expression in CMs and PMs revealed a significantly more frequent
      expression of CK20 in CMs (P = 0.006). More than 50% of the patients with PMs
      that were positive for CK20 had an invasive evolution. CONCLUSIONS: In our
      opinion, CK20 may assist in distinguishing between molar and normal trophoblastic
      tissue and may be considered a marker of GTD. In cases in which pathological
      classification of different subtypes of GTD is in doubt, CK20-positive expression
      is suggestive for a CM whereas CK20-negative is more indicative for PM.

PMID- 12468340
TI  - Vaginal reconstruction at the time of pelvic exenteration: a surgical and
      psychosexual analysis of techniques.
AB  - OBJECTIVES: Vaginal reconstruction following pelvic exenteration is an important
      aspect of the physical and psychological rehabilitation of women after radical
      surgery for pelvic malignancies. The choice of techniques is vast, and proper
      patient and surgical selection is important for obtaining satisfactory functional
      and aesthetic results. The objective of this retrospective study is to review
      different techniques for vaginal reconstruction and report the complications and
      patient satisfaction associated with the different procedures. METHODS: Between
      January 1988 and April 2001, 104 pelvic exenterations were performed by the
      division of gynecologic oncology at the University of Miami, School of Medicine.
      Twenty-five (24%) patients underwent vulvo-vaginal reconstruction at the time of
      the exenteration. A retrospective chart review of the 25 patients was performed,
      and 9 patients were available and contacted for an interview. RESULTS: Twenty
      four (96%) patients had received prior definitive radiation therapy. Overall,
      there were 9 complications (6 major and 3 minor) attributed to vaginal
      reconstruction, accounting for 36% perioperative morbidity. Seven of the nine
      (78%) patients interviewed reported successful vaginal intercourse at some point
      after their operation. All 5 surviving patients in the myocutaneous flap group
      were very satisfied with their sexual function and were sexually active at the
      time of their interview. CONCLUSIONS: Vaginal reconstruction at the time of
      pelvic exenteration is an important topic that should be discussed with the
      patient during the preoperative visit. Although the myocutaneous flaps are
      associated with longer operative times, they appear to be the preferred type due
      to decreased postoperative fistulae and better patient satisfaction.

PMID- 12468341
TI  - Laparoscopic staging compared with imaging techniques in the staging of advanced
      cervical cancer.
AB  - OBJECTIVE: We evaluated the evidence of laparoscopy for decision regarding
      treatment options in advanced cervical cancer patients. METHODS: One hundred nine
      consecutive patients with cervical cancer FIGO stage Ib2 and higher underwent
      laparoscopic staging of the extent of disease. Laparoscopic and histopathologic
      evaluation of tumor involvement of the paraaortic and pelvic lymph nodes, wall of
      the bladder, and rectal pillar was compared with preoperative findings of MRI
      and/or CT. RESULTS: Paraaortic lymphadenectomy was performed in 101 (92.7%)
      patients and 21 (19.3%) patients had positive paraaortic lymph nodes. Pelvic
      lymphadenectomy was performed in 75 (68.8%) patients and 20 (26.7%) patients had
      positive pelvic lymph nodes. In 11 patients (11.5%) infiltration of the bladder
      and in 6 patients (6.25%) infiltration of the rectal pillar or cul-de-sac was
      found. Intraoperative complications associated with laparoscopic staging occurred
      in 3.7% of patients. The negative predictive value for the evaluation of
      paraaortic or pelvic lymph nodes, the bladder wall, rectal pillar, and cul-de-sac
      ranged from 73% (CT for pelvic lymph nodes) to 96% (MRI for bladder wall). Lack
      of information about the extent of disease was adjusted on the basis of
      laparoscopic findings in 24 (22%) patients and improved treatment plans.
      CONCLUSION: Laparoscopic staging of patients with advanced cervical cancer is
      accurate, associated with low morbidity, and helps to adjust treatment according
      to extent of disease.

PMID- 12468342
TI  - Pathologic findings in prophylactic oophorectomy specimens in high-risk women.
AB  - OBJECTIVE: To ascertain the frequency of significant pathologic alterations in
      prophylactic oophorectomy specimens in high-risk women referred to a tertiary
      care center. METHODS: Surgical cases for prophylactic oophorectomy referred to a
      gynecologic oncology clinic from November 1996 to January 2001 were reviewed.
      Serial sections of entirely submitted tubes and ovaries were procured and
      reviewed by a pathologist with expertise in gynecologic malignancies. All
      patients had undergone genetic counseling and either underwent mutational
      analysis of BRCA1 and BRCA2 genes or had family history suggestive for ovarian
      and breast cancer susceptibility. RESULTS: Thirty women with either a documented
      deleterious BRCA1 or BRCA2 mutation or a suggestive family history underwent
      prophylactic oophorectomy during the study period. Seventy-three percent of women
      had undergone genetic testing. Of those, 63.5% harbored a BRCA1 mutation, 13.5%
      were BRCA2 carriers, and the remaining 23% tested negative. Five of the 30 women
      (17%) were found to have clinically occult malignancy. Four of the five were
      diagnosed only on histologic review. A single patient had grossly apparent
      primary peritoneal carcinoma at the time of laparoscopy. Three patients were
      found to have primary fallopian tube malignancy, two with in situ papillary
      serous carcinoma, and one with early invasive disease. Each of the fallopian tube
      neoplasms measured less than 1 cm. The final patient was diagnosed with an
      ovarian adenofibroma with a focus of low malignant potential neoplasm and clear
      cell features. Three of the five were known BRCA1 mutation carriers, one had a
      documented BRCA2 mutation, and one has not yet been tested. CONCLUSIONS: The high
      rate of occult malignancy detected in this series suggests that this finding in
      women at heightened risk for ovarian cancer is relatively common. Further,
      clinically occult tumors were not limited to ovarian origin, and the majority of
      cases harbored malignant foci less than 1 cm in greatest dimension that were not
      recognized at the time of surgery. These findings support the recommendations
      that in this high-risk population (1) the fallopian tubes and ovaries should be
      submitted entirely and be evaluated by a pathologist with expertise in
      gynecologic malignancies in serial sections; (2) laparoscopy and laparotomy are
      the surgical modalities of choice to allow inspection of the peritoneal surfaces
      at time of prophylactic oophorectomy and collect fluid for cytologic evaluation;
      (3) despite the rarity of fallopian tube carcinoma in the general population,
      BRCA1 and BRCA2 mutation carriers may be at increased risk for tubal cancers.

PMID- 12468343
TI  - A pilot study of ovarian cancer chemoprevention using medroxyprogesterone acetate
      in an avian model of spontaneous ovarian carcinogenesis.
AB  - OBJECTIVE: Our previous studies have documented the feasibility of using the
      laying hen, Gallus domesticus, as a model of spontaneous ovarian carcinogenesis.
      This study was performed to determine the ability of medroxyprogesterone acetate
      (Depo-Provera) to reduce the frequency of spontaneously developing reproductive
      tract adenocarcinoma in the avian model. METHOD: Four hundred 3-year-old hens
      were in a two-arm trial designed to determine the frequency of epithelial
      reproductive tract adenocarcinomas. Animals were designated to receive three
      injections of 100 mg Depo-Provera versus no injection over a 16-month period.
      Both groups were subjected to two induced molts 12 months apart. Egg counts were
      obtained and decreased egg production was documented in the treated hens due to
      Depo-Provera. At the end of 16 months surviving animals were sacrificed and the
      frequency of reproductive tract adenocarcinoma was determined histologicically.
      RESULTS: Histologic information was obtained from the 293 hens that completed the
      full prescribed course of study. At the time of necropsy, multiple hens had
      evidence of carcinomatosis and massive ascites consistent with metastatic
      reproductive tract adenocarcinomas. Of the tissues examined from the informative
      cases gathered at the time of sacrifice, there was evidence of a reduction of
      reproductive tract adenocarcinoma observed in the Depo-Provera group (45/127-35%)
      when compared to the control group (69/166-42%). A risk reduction of 15% is
      observed in the treatment group (risk ratio 0.85: 95% confidence interval 0.63
      1.15). CONCLUSION: The high rate of reproductive tract adenocarcinoma observed in
      this study supports the avian hen as a valid model of spontaneous ovarian
      carcinogenesis in which to test chemoprevention strategies and provides a unique
      opportunity for investigating the pathogenesis of ovarian carcinoma. The current
      histologic findings are consistent with the theory that a reduction of ovulatory
      events may prevent the development of ovarian adenocarcinoma.

PMID- 12468344
TI  - Laparoscopic photodynamic diagnosis of ovarian cancer using 5-aminolevulinic acid
      in a rat model.
AB  - OBJECTIVE: The objective of this study was to determine the efficacy and
      sensitivity of laparoscopic photodynamic diagnosis to detect 5-aminolevulinic
      acid (ALA)-induced fluorescent tumors in an animal model. METHODS: Cancer cells
      were injected into the peritoneum of rats to induce peritoneal carcinomatosis.
      After 3-4 weeks, ALA was administered to establish fluorescence in tumor nodules.
      All intraperitoneal surfaces were inspected using fluorescence and white light
      laparoscopy. Suspicious lesions were then biopsied in vivo under either
      fluorescence or white light laparoscopic guidance. Fluorescence intensities of
      the cancerous lesions compared to normal tissues were determined. A pathologist
      blinded to our clinical impression analyzed all biopsied specimens. We compared
      the sensitivity of fluorescence and white light laparoscopic-guided detection of
      cancerous lesions and determined the clinical utility of fluorescent photodynamic
      diagnosis in detecting metastatic ovarian cancer. RESULTS: Forty-three biopsies
      were performed in vivo under laparoscopic fluorescent guidance and 42 biopsies
      were taken using white light in various regions of the peritoneal surface from
      nine rats. Ten biopsies were also removed from nonfluorescent regions as nontumor
      controls. Cancerous lesions showed significantly higher fluorescent intensity
      compared to noncancerous lesions. Cancerous lesions that were difficult to
      differentiate from normal surrounding tissue under white light conditions were
      clearly detected by ALA-induced fluorescence. The average size of these
      metastatic lesions biopsied under fluorescent light was 1.0 mm (range: 0.3-2.5)
      compared to 1.5 mm (range: 0.5-2.9) with white light illumination (P < 0.05).
      CONCLUSIONS: Fluorescent laparoscopic detection of micrometastatic ovarian cancer
      using ALA is significantly more sensitive than white-light laparoscopy in
      detecting smaller cancerous lesions in an ovarian cancer rat model. Human trials
      are indicated.

PMID- 12468345
TI  - Gestational trophoblastic tumors in Norway, 1968-1997: patient characteristics,
      treatment, and prognosis.
AB  - OBJECTIVES: The aim of this study was to give an overview of the Norwegian
      population of gestational trophoblastic tumors (GTT), diagnosed during 1968-1997
      and treated with chemotherapy at the Norwegian Radium Hospital (NRH), with regard
      to patient characteristics, treatment, and prognosis. METHODS: The cases were
      grouped according to a modified version of the WHO scoring system. Staging was
      performed retrospectively according to the systems adopted by FIGO. Survival
      estimates were calculated by the method described by Kaplan and Meier. Cox
      regression models were used to find the best classification system with regard to
      prognosis (disease-free survival). RESULTS: A total of 141 cases, 106 invasive
      moles (IM) and 35 choriocarcinomas (CC), were diagnosed in Norway and treated
      with chemotherapy at the NRH in the period 1968-1997. Altogether, 56% of the
      patients were assigned to the low-risk category, 20% to the medium-risk category,
      and 15% to the high-risk category. Most cases were classified into the clinical
      stages I (69%) and III (23%). The overall 5-year survival rate was 96%. A more
      favorable prognosis was seen in patients diagnosed in the 1980s and 1990s
      compared with those diagnosed in the 1970s (P = 0.04). Five patients had
      progressive disease and died from the disease. Nine patients relapsed. The
      prognosis (disease-free survival) was more favorable for IM compared with CC (P <
      0.01). The FIGO classification system seemed to be a better predictor of disease
      free survival than the WHO scoring system. CONCLUSIONS: This study showed that
      the prognosis of patients with GTT improved in the 1980s and 1990s in Norway, and
      that the FIGO system might be the best predictor of disease-free survival.

PMID- 12468346
TI  - Ascites as a predictor of ovarian malignancy.
AB  - OBJECTIVE: To determine the utility of ascites as a predictor of ovarian
      malignancy and define its relationship with the histologic type of ovarian tumor
      (benign, borderline, or malignant) and stage of disease. METHODS: This
      retrospective cohort study analyzed the clinical and pathological finding of 125
      patients from two institutions treated for a pelvic mass. Preoperative data to
      include: physical examination, imaging studies (USD, CT, or MRI), and operative
      reports were reviewed for evidence of ascites. This was correlated with final
      pathologic findings and stage of disease. Collected data were summarized with
      descriptive statistics. Further statistical analysis was performed using
      Pearson's chi(2), cross tabulation, and the Median Test. Data were analyzed with
      SPSS 6.1 for Windows. RESULTS: One-hundred twenty-five patients were evaluable
      for this study. The ovarian pathologic findings were as follows: 57 benign (45%),
      12 borderline (10%), and 56 malignant (45%). Fifty-three patients (42%) had frank
      ascites at laparotomy. Seventy-two patients (58%) had no ascites. All patients
      with ascites diagnosed preoperatively (n = 41) on physical examination or imaging
      studies were confirmed intraoperatively. Absence of ascites was correctly
      diagnosed preoperatively in 72/84 patients (86%). Of the 57 benign tumors, only 5
      patients (9%) had small amounts of peritoneal effusion. Of the 12 borderline
      tumors, 7 patients (58%) had ascites. Of the 56 malignant tumors, 41 (73%) had
      ascites. Using presence or absence of ascites on clinical assessment as the
      predictor variable and benign or malignant (borderline and invasive
      histopathology) tumors as the outcome variable, the positive predictive value
      (PPV) of ascites to detect ovarian malignancy was 95% and the negative predictive
      value (NPV) was 64%. When borderline tumors were excluded, the PPV and NPV of
      ascites to detect malignant invasive tumors were 95 and 73%, respectively.
      Furthermore, a progressive relationship between stage of ovarian malignancy and
      percentage of cases with ascites was identified. Ovarian malignancies in the
      early stages (I and II) produced ascites only in 17% of the cases. In advanced
      stages (III and IV), 89% produced ascites. In addition, for stage I and II
      disease, all patients possessed <0.5 liters of ascites at surgery, whereas the
      majority of patients (66%) with stage III and IV disease had >0.5 liters.
      CONCLUSIONS: Our findings indicate the presence of ascites on preoperative
      physical examination or imaging study is highly predictive of ovarian malignancy
      in women with a pelvic mass. The absence of ascites may not always predict benign
      disease since nearly half of borderline tumors and 83% of early stage malignant
      ovarian tumors do not produce ascites. A progressive relationship between stage
      of malignancy and incidence as well as volume of ascites was also observed.

PMID- 12468347
TI  - Correlation between expression of EGFR and the prognosis of patients with
      cervical carcinoma.
AB  - OBJECTIVE: Overexpression of epidermal growth factor receptor (EGFR) gene has
      been detected in a large number of human tumors, in most of which the association
      between overexpression of EGFR and poor prognosis of the disease has been
      reported. However, the prognostic role of EGFR oncoprotein in cervical carcinoma
      remains controversial. The current study aimed to determine the prognostic value
      of EGFR in patients with cervical cancer. METHODS: We measured EGFR oncoprotein
      with an enzyme-linked immunosorbent assay (ELISA). Results were correlated to
      clinical data. RESULTS: The presence of measurable levels of EGFR in the tumor
      was found in all of the explored tumors. The levels varied widely from 31 to 2874
      fmol/mg protein with a median at 582 fmol/mg protein, and Q1, Q2, and Q3
      quartiles were 156, 562, and 1047, respectively. Overexpression of EGFR was
      associated with an impaired prognosis with respect to disease-free interval (P =
      0.03) and overall survival (P = 0.04). Multivariate analysis revealed that tumor
      EGFR provided prognostic information with respect to disease-free interval (P =
      0.002) and overall survival (P = 0.005) independently of the two established
      prognosticators, FIGO stage and lesion size. CONCLUSION: Our results are
      consistent with the concept that EGFR confers prognostic information in addition
      to that provided by the established clinicopathologic parameters of FIGO stage
      and lesion size.

PMID- 12468348
TI  - Contribution of whole-body 18FDG PET imaging in the management of cervical
      cancer.
AB  - OBJECTIVE: The objective of this study was to assess the contribution of
      [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)FDG PET)
      imaging in the management of cervical cancer. METHODS: Fully corrected whole-body
      PET was performed in 60 patients (pts) with proven cervical cancer. In
      pretreatment staging, 22 pts underwent PET in addition to routine protocol
      including International Federation of Obstetrics and Gynecology (FIGO) staging
      and pelvic magnetic resonance imaging (MRI). Eighteen of them had pelvic
      lymphadenectomy. After treatment, PET was performed in 38 pts routinely followed
      up by clinical and radiological examinations. Results of PET and routine
      protocols were compared to final diagnoses, including histological findings in 31
      pts and clinical outcomes in the other cases. Median follow-up time was 12 +/-
      7.3 months. RESULTS: In all but 2 patients (FIGO stage IA), both PET and MRI
      detected the primary tumor. In 6 pts, MRI alone noted loco-regional tumor spread
      but PET localized 9 unsuspected extrapelvic nodal sites (6 para-aortic, 2
      mediastinal, and 1 supra-clavicular). However, PET missed 8 microscopic pelvic
      nodal metastases. In 18% of the patients, PET staging significantly influenced
      the treatment choices. In follow-up, PET accurately diagnosed a recurrent disease
      in 13 pts with falsely negative or equivocal conventional imaging (CI). Ten
      patients with a negative PET were still in complete remission after a minimal
      follow-up time of 12 months. Overall, the agreement of PET with final diagnosis
      was significantly better than that of routine protocol (P < 0.05). CONCLUSIONS:
      Whole-body (18)FDG PET appears useful in the management of cervical cancer, in
      particular for staging extrapelvic metastases or optimally detecting a
      recurrence. MRI is better indicated for evaluating the loco-regional status of
      the disease.

PMID- 12468349
TI  - Weekly carboplatin and docetaxel for locally advanced primary and recurrent
      cervical cancer: a phase I study.
AB  - OBJECTIVE: The aim of this study was to determine the dose-limiting toxicities
      (DLTs) and maximum tolerated doses (MTDs) of a docetaxel-carboplatin regimen in
      patients with locally advanced cervical cancer (LACC) or recurrent cervical
      cancer. The regimen was administered weekly, with a maximum of 12 courses.
      PATIENTS AND METHODS: Twenty patients were treated with with a total of 145
      cycles of weekly carboplatin and docetaxel. The starting dose of docetaxel was 25
      mg/m(2) with increments of 5 mg/m(2) until a final dose of 35 mg/m(2) was
      reached. Dose-escalation of docetaxel was followed by carboplatin at AUC 2, AUC
      2.5, and AUC 3, respectively. Defined dose-limiting toxicities were WHO grade (G)
      3 hematotoxicity, G4 mucositis, and G2 neurotoxicity. The response status of the
      patients was assessed using the common ECOG response criteria. RESULTS: Two of
      four patients developed a DLT at dose level 4. Nonhematological toxicity was
      generally mild, except for ubiquitous complete alopecia. The MTD was reached at
      docetaxel 35 mg/m(2) and carboplatin AUC 2 mg/mL.min. The overall response rate
      was 65% in the entire group of evaluable patients and 77% in patients with
      primary LACC, with two cases of pathological complete response. CONCLUSION: This
      dose-dense regimen was well-tolerated and could be administered on an outpatient
      basis.

PMID- 12468350
TI  - Detection of human papillomavirus DNA in malignant lesions from Chinese women
      with carcinomas of the upper genital tract.
AB  - OBJECTIVE: The aim of this study was to determine the prevalence of high-risk
      oncogenic human papillomaviruses (HPVs) in malignant lesions from Hong Kong
      Chinese women with carcinomas of the upper genital tract. METHODS: The presence
      of high-risk HPVs in 55 cases of endometrial adenocarcinomas and 60 cases of
      primary epithelial ovarian cancers was detected by polymerase chain reaction
      (PCR) using consensus primers complementary to late 1 (L1) gene of the genital
      HPVs. Amplified PCR products were verified and typed by Southern blot analysis
      using (32)P-labeled DNA probes prepared from cloned HPV-16 and -18 plasmids. To
      confirm the presence of high-risk HPV types in the tumor tissues, PCR
      amplification using HPV type 16- and 18-specific primers for part of the E6 gene
      were also carried out. RESULTS: While HPV-18 was not detected, HPV-16 DNA
      sequences were identified in 5 (9.1%) of the 55 studied endometrial carcinoma
      samples. Of the 5 HPV-16-positive cases, there were 4 stage I, and 1 stage II
      endometrial cancer. In addition, 6 (10%) of the 60 epithelial ovarian carcinomas
      were positive for high-risk HPVs, which included 5 cases with HPV-16 and 1 case
      with HPV-18. Clinical staging revealed that 5 of the 6 HPV-positive cases were
      stage I and the remaining case was stage III ovarian cancer. Histology of the 6
      HPV-positive cases showed that there were 1 case of clear-cell adenocarcinoma, 1
      case of mucinous cystadenocarcinoma, and 4 cases of mucinous tumor of borderline
      malignancy. No other HPV types were detected. CONCLUSION: High-risk HPV was
      detected in approximately 10% of the tumor samples from women with upper genital
      tract carcinomas. As compared to the high positive rate of HPV infections in
      cervical cancer, it appears that HPV infection plays a relatively minor role in
      the pathogenesis of endometrial and ovarian carcinomas.

PMID- 12468351
TI  - Stage IIIC endometrioid corpus cancer includes distinct subgroups.
AB  - OBJECTIVE: Because stage IIIC corpus cancer is a heterogeneous substage, the
      outcomes of patients with stage IIIC disease were assessed according to the
      extent of extrauterine disease. METHODS: From 1984 through 1993, 51 patients with
      surgical stage IIIC corpus cancer were treated at our institution; 5 patients had
      tumors with nonendometrioid histologic features and were excluded from the
      analyses. Of the 46 patients with endometrioid carcinoma, 22 had lymph nodes as
      the only site of extrauterine disease (stage IIIC(0)) and 24 also had peritoneal
      cytologic, uterine serosal, adnexal, or vaginal involvement or a combination of
      these (stage IIIC(ab)). The mean number of lymph nodes removed was 18 pelvic and
      8 aortic nodes. Median follow-up for surviving patients was 84 months. RESULTS:
      Patients with stage IIIC(0) cancer had a 5-year cause-specific survival (CSS) of
      72% and a 5-year recurrence-free survival (RFS) of 68%, and those with stage
      IIIC(ab) had a CSS of 33% and an RFS of 25% (P < 0.01). Of the 22 patients with
      stage IIIC(0) endometrioid cancer, 21 had adjuvant radiotherapy (1 also received
      chemotherapy) and 1 was not treated. Relapse occurred in 7 (32%) patients, with
      only 1 having an initial failure component outside the node-bearing areas (lung).
      Of the 24 patients with stage IIIC(ab) cancer, 16 received adjuvant radiotherapy
      (1 had concomitant chemotherapy), 2 had chemotherapy, 4 had hormonal therapy, and
      2 were not treated. We observed 16 recurrences (67%). Of the 14 patients with
      known initial sites of failure, 9 had an extranodal failure component.
      CONCLUSION: Assessment of CSS, RFS, and sites of relapse suggests that FIGO
      surgical stage IIIC endometrioid corpus cancer includes two distinct and readily
      separable subgroups: (1) stage IIIC(0), nodal involvement only, and (2) stage
      IIIC(ab), nodal plus cytologic, uterine serosal, adnexal, or vaginal involvement,
      or a combination of these. Our results also suggest that different treatment
      strategies are needed for these subgroups.

PMID- 12468352
TI  - Patient preferences regarding side effects of chemotherapy for ovarian cancer: do
      they change over time?
AB  - OBJECTIVE: The goals of this study were to: (1) systematically evaluate patient
      preferences regarding side effects of high-dose chemotherapy with stem cell
      support for treatment of advanced ovarian cancer; and (2) assess whether
      patients' preferences changed over time. METHODS: Forty patients with stage III
      or IV disease were enrolled in this study. Patients' preferences regarding 12
      health states (side effects) were assessed using visual analogue scale (VAS) and
      time trade-off (TTO) methods during mobilization chemotherapy (T(1)) and 6-7
      weeks later after high-dose chemotherapy and stem cell transplant (T(2)). Each
      assessment involved a 45-min interview conducted at the patient's bedside.
      RESULTS: The three most preferred health states were no evidence of disease
      (NED), a chemotherapy with few or no side effects, and alopecia, while the least
      preferred health states were chemotherapy with multiple severe side effects,
      hepatotoxicity, and nausea and vomiting. These results were observed at both T(1)
      and T(2) using both preference assessment methods. Pancytopenia scores
      significantly increased from T(1) to T(2) using the VAS method (P < 0.05), but
      decreased using the TTO method. CONCLUSIONS: Chemotherapy-experienced women with
      ovarian cancer have consistent preferences for the best and worst health states
      associated with the side effects of chemotherapy. Patients are more averse to
      nausea and vomiting than many other symptoms. Women's perceptions of pancytopenia
      may be dependent upon the number of prior cycles of chemotherapy and site of care
      for anemia, thrombocytopenia, and febrile neutropenia.

PMID- 12468353
TI  - Endocervical curettage at conization to predict residual cervical adenocarcinoma
      in situ.
AB  - OBJECTIVE: To determine if performing an endocervical curettage (ECC) at the time
      of conization is a useful diagnostic tool for predicting residual cervical
      adenocarcinoma in situ (AIS) among women who might wish to preserve their
      fertility. METHODS: All patients diagnosed with AIS from 1995 to 2000 at four
      institutions were identified. Data were retrospectively extracted from clinical
      records. Women included in the statistical analysis were (1) younger than 40
      years, (2) had an ECC performed at the time of the initial cone biopsy, (3) had a
      clearly demarcated surgical margin pathologically, and (4) underwent a second
      surgical procedure. RESULTS: Twenty-nine (24%) of 123 AIS patients met criteria
      for inclusion. The median age was 33 years (range, 17 to 39) and 13 (46%) were
      nulliparous. Initial surgery was a cold-knife conization (n = 17) or loop
      electrosurgical excision procedure (n = 12). Twelve (41%) ECCs and 15 (52%) cone
      margins were histologically positive. Sixteen patients underwent a repeat
      conization; 13 underwent hysterectomy. Thirteen (45%) patients had residual AIS
      at the time of their second surgical procedure. ECC had a superior positive
      predictive value (100% vs 47%; P < 0.01) and negative predictive value (94% vs
      57%; P = 0.01) compared to cone margin in predicting residual AIS. None of the
      women undergoing fertility-sparing surgery developed recurrent AIS or
      adenocarcinoma. CONCLUSION: ECC performed at the time of conization may be a
      useful tool for predicting residual AIS in women considering fertility
      preservation.

PMID- 12468354
TI  - Craniotomy for central nervous system metastases in epithelial ovarian carcinoma.
AB  - BACKGROUND: Although central nervous system (CNS) metastases from epithelial
      ovarian carcinoma are rare, recent studies indicate that the incidence may be
      increasing. Numerous series have reported various modalities for treatment with
      median survivals of 3 to 5 months, but the role of craniotomy has not been
      specifically addressed. METHODS: We conducted a retrospective review of all
      patients who underwent craniotomy between 1989 and 2001 for pathologically
      confirmed recurrent epithelial ovarian cancer metastatic to the CNS. RESULTS: We
      identified 14 patients who had a mean age at diagnosis of 59.3 years (range, 45
      to 70). Distribution by stage and grade was as follows: Stage I, 0; II, 1; III,
      12; and IV, 1; and grade 1,0; 2,4; and 3,10. Histologic distribution was as
      follows: papillary serous, 9; endometrioid, 2; mixed papillary serous and
      endometrioid, 1; carcinosarcoma, 1; and poorly differentiated adenocarcinoma, 1.
      Six patients had optimal primary cytoreduction, while 7 had suboptimal primary
      cytoreduction. All patients received initial platinum-based chemotherapy. Ten of
      14 patients underwent second-look evaluation, and in 8 patients the findings were
      negative. The median time from initial diagnosis of ovarian carcinoma to CNS
      relapse was 3.5 years (range, 1.3 to 8.2). In 7 patients (50%), the CNS
      recurrence was the first site of relapse. Eight patients (57%) had extracranial
      disease at the time of craniotomy. Distribution of CNS lesions were as follows:
      supratentorial, 12; and cerebellar, 2. The mean operative time for craniotomy was
      178 min (range, 70 to 305). The average blood loss was 125 mL (range, 20 to 250).
      The only major operative complications were deep vein thromboses that developed
      in two patients. No patient developed a neurologic deficit as a result of
      craniotomy. One patient died of progressive disease 37 days after surgery.
      Postoperative treatment included whole-brain radiation in 11 patients,
      chemotherapy in 4, and hormonal therapy in 4. Four patients (29%) had a CNS
      relapse after craniotomy. The median survival of patients after craniotomy was 18
      months, and the 1- and 2-year survival rates were 66% (95% confidence interval
      (CI): 43-100) and 39% (95% CI: 17-90), respectively. CONCLUSIONS: Despite optimal
      cytoreduction, platinum-based chemotherapy, and negative second-look surgical
      assessment, patients with ovarian cancer can fail distantly with CNS metastases.
      Craniotomy with adjuvant radiation therapy can provide control of brain
      metastases in the majority of these patients and may result in improved survival
      over radiation therapy alone in selected patients.

PMID- 12468355
TI  - Major hepatectomy at interval debulking for stage IV ovarian carcinoma: a case
      report.
AB  - BACKGROUND: Previous studies have reported the results of hepatic resection for
      metastatic ovarian cancer at the time of primary cytoreductive surgery and at the
      time of recurrence. CASE: We present the first case of major hepatic resection
      performed at the time of interval cytoreduction for metastatic ovarian carcinoma.
      CONCLUSION: Interval debulking with hepatic resection may be a promising approach
      for patients left with bulky parenchymal liver metastasis after primary
      cytoreductive surgery.

PMID- 12468356
TI  - Strumal carcinoid tumor of the ovary: a case exhibiting severe constipation
      associated with PYY.
AB  - BACKGROUND: Primary carcinoid tumor of the ovary is uncommon and represents less
      than 0.1% of ovarian malignancy. Recently, it was reported that the strumal
      carcinoid tumor may be complicated by severe constipation as one symptom of the
      carcinoid syndrome. CASE: A 50-year-old nulliparous woman complained of
      persisting constipation and abdominal distention with pelvic mass, raising the
      possibility of ovarian tumor. The sugically resected tumor was diagnosed as
      strumal carcinoid tumor. Her long-lasting severe constipation completely
      disappeared after tumor removal but recurred with recurrent hepatic disease. The
      tumor cells were positive for PYY, a peptide hormone that has a strong inhibitory
      effect on intestinal motility, by immunohistochemical stain. CONCLUSION: Our case
      provides the more convincing information to indicate that PYY protein, produced
      by ovarian tumor cells in the trabecular carcinoid component, may be associated
      with severe constipation.

PMID- 12468357
TI  - Successful management of metastatic placental site trophoblastic tumor with
      multiple pulmonary resections.
AB  - INTRODUCTION: Placental site trophoblastic tumor (PSTT) is an uncommon variant of
      gestational trophoblastic disease. Most of these tumors are confined to the
      uterus and treated with a simple hysterectomy. However, 30% of these patients
      will present with metastatic disease. These patients are typically treated with a
      hysterectomy followed by adjuvant multiagent chemotherapy. Unfortunately, PSTT is
      relatively resistant to chemotherapy when compared to other forms of gestational
      trophoblastic disease. Consequently, these patients have a poor prognosis. CASE:
      We present a case report of a 26-year-old female with multiple metastatic lesions
      to the lungs unresponsive to chemotherapy who was managed with multiple pulmonary
      resections. She has remained clinically free of disease at 28 months of follow
      up. CONCLUSION: A patient with metastatic PSTT was successfully managed with
      radical surgical resection of chemotherapy-resistant sites.

PMID- 12468358
TI  - Syndrome of inappropriate secretion of antidiuretic hormone induced by
      intraarterial cisplatin chemotherapy.
AB  - BACKGROUND: Syndrome of inappropriate secretion of antidiuretic hormone induced
      by intraarterial cisplatin therapy is a previously unreported complication. CASE:
      A 63-year-old woman with stage Ib2 squamous cell carcinoma of the cervix was
      treated with intraarterial cisplatin infusion in a neoadjuvant setting. Four days
      following the second course of chemotherapy, she became drowsy with severe
      fatigue and decreased mental awareness. Blood tests showed sodium of 110 mEq/L.
      Urine and plasma osmolarities were 308 and 240 mOsm/kg, respectively, confirming
      the diagnosis of a syndrome of inappropriate secretion of antidiuretic hormone
      induced by intra-arterial cisplatin infusion. CONCLUSION: The potential for
      development of clinically significant hyponatremia early in the course of
      cisplatin therapy with any infusion routes emphasizes the need to closely monitor
      patients.

PMID- 12468359
TI  - Serous adenocarcinoma of the inguinal region arising from endometriosis followed
      by a successful pregnancy.
AB  - BACKGROUND: Inguinal serous carcinoma arising from endometriosis is an unusual
      cancer. It is uncertain how patients with these tumors should be managed,
      especially those patients who desire future fertility. CASE: We present a 34-year
      old woman with a right groin mass with cyclical pain. Resection of this mass
      revealed complex atypical hyperplasia, well-differentiated endometrioid
      adenocarcinoma, and serous carcinoma within a focus of endometriosis. The patient
      desired to maintain her fertility and was treated conservatively. She is
      currently 3 years free of disease after diagnosis. She also had one successful
      pregnancy. CONCLUSION: This is a rare case of carcinoma arising from
      endometriosis. The long-term prognosis for this patient remains unclear and the
      patient will require long-term follow-up.

PMID- 12468360
TI  - Skin relapse from cervical cancer.
AB  - BACKGROUND: Cutaneous lymphangitis carcinomatosis from cervical carcinoma is a
      very rare form of tumor metastatization; only anecdotal cases are reported in the
      literature. Most of the patients with skin relapse experienced metastasis as a
      single or multiple nodules. CASE: A case of cutaneous lymphangitis carcinomatosis
      mimicking contact dermatitis was diagnosed at our institution in a patient
      affected by cervical carcinoma stage IIB. Palliative chemotherapy with paclitaxel
      was started and the patient experienced complete clinical response. The
      hypothetical mechanism of spread and the unusual manifestation of relapse are
      described. CONCLUSION: In a woman with a history of cervical cancer, a diffuse
      pruritic skin eruption should alert the clinician to the possibility of cutaneous
      carcinomatous lymphangitis. If a lymphangitis carcinomatosis is diagnosed,
      systemic intravenous chemotherapy should be considered.

PMID- 12468361
TI  - Why do ovarian cancer patients not consult a gynecologic oncologist?

PMID- 12468363
TI  - Nutritional care in hospitals.

PMID- 12468364
TI  - Colonic anti-inflammatory mechanisms of conjugated linoleic acid.
AB  - Conjugated linoleic acid (CLA) is a mixture of positional (e.g. 7,9; 9,11; 10,12;
      11,13) and geometric (cis or trans) isomers of octadecadienoic acid. This
      compound was first shown to prevent mammary carcinogenesis in murine models.
      Later investigations uncovered a number of additional health benefits, including
      decreasing atherosclerosis and inflammation while enhancing immune function. The
      mechanisms of action underlying these biological properties are not clearly
      understood. The aim of this review is to highlight recent advances in CLA
      research related to experimental inflammatory bowel disease. In addition, two
      possible mechanisms of action (i.e. endoplasmic and nuclear) were discussed in
      detail in the context of enteric inflammatory disorders. Conjugated linoleic acid
      was first implicated in down-regulating the generation of inducible eicosanoids
      (i.e. PGE(2) and LTB(4)) involved in early micro-inflammatory events
      (endoplasmic). More recently, CLA has been shown to modulate the expression of
      genes regulated by peroxisome proliferator-activated receptors (PPARs; nuclear).
      In pigs, prolonged dietary CLA treatment stimulated the expression of PPAR-gamma
      in the muscle. Thus, evidence supporting both mechanistic theories of CLA acting
      through eicosanoid synthesis and PPAR activity is available. The further
      understanding of the anti-inflammatory mechanisms of action of CLA may yield
      novel nutritional therapies for enteric inflammation.

PMID- 12468365
TI  - Incidence of nutritional risk and causes of inadequate nutritional care in
      hospitals.
AB  - BACKGROUND AND AIMS: Many patients in hospitals are undernourished and
      nutritional care is inadequate in most hospitals. The aim of this investigation
      was to gain insight into how this situation could be improved. METHODS: Seven
      hundred and fifty randomly selected patients were screened at admission in three
      hospitals and surveyed during their entire hospitalization. Each time a patient
      was not treated according to a clearly defined nutritional standard, the nurse
      responsible for the patient was interviewed about possible reasons according to
      preformed questionnaires. RESULTS: The investigators found that 22% of the
      patients were nutritionally at-risk, and that only 25% of these patients received
      an adequate amount of energy and protein. The departments had only screened for
      nutritional problems in 60% of the cases. Only 47% of the patients, who the
      departments judged to be at-risk patients, had a nutrition plan worked out, and
      only about 30% of the at-risk patients were monitored by the departments by
      recording of dietary intake and/or body weight. The main causes for inadequate
      nutritional care were lack of instructions to deal with these problems, and lack
      of basic knowledge with respect to dietary requirements and practical aspects of
      the hospital's food provision. Patient-related aspects and the system of food
      provision also contributed, but only to a small degree. CONCLUSIONS: These
      findings form the basis of the strategy to improve nutritional care in these
      hospitals.

PMID- 12468366
TI  - Effect of early intrajejunal nutrition on pancreatic pathological features and
      gut barrier function in dogs with acute pancreatitis.
AB  - BACKGROUND: In patients with major trauma and burns, total enteral nutrition
      (TEN) significantly decreases the acute phase response and incidence of septic
      complications when compared with total parenteral nutrition (TPN). Traditionally,
      it was believed that early intrajejunal nutrition (EIN) in severe acute
      pancreatitis (SAP) may exacerbate the clinical pathological features, lead to
      recurrence of symptoms and delay complications. OBJECTIVE: To compare the effect
      of EIN vs TPN on the pancreatic pathological features and gut barrier function in
      dogs with acute pancreatitis (AP). METHODS: Fifteen dogs (surviving over 7 days,
      the death rate being 32%, 7/22) were divided into parenteral nutrition (PN) group
      (n=7) and EIN group (n=8). SAP model was induced by injecting 1 ml/kg of combined
      solution of 2.5% sodium taurocholate and 8000-10000 BAEE units trypsin/ml into
      the pancreas via the pancreatic duct. Nutrients were delivered to the EIN group
      by catheter via a jejunostomy feeding 24 h postoperatively. The two groups were
      isocaloric and isonitrogenous. Systemic blood samples were obtained before and 1,
      4, 7 d following AP, and cultured by aerobic as well as anaerobic bacterial
      growth. Systemic plasma and portal vein endotoxin levels were quantified by the
      chromogenic limulus amebocyte lysate (LAL) technique. Portal vein blood and
      specimens of tissue from mesenteriolum and mesocolon lymph nodes, lung, pulmonary
      portal lymph nodes and pancreas were adopted before the experiment was finished.
      Aliquots of the homogenata were cultured as blood mentioned above. Serum glucose,
      calcium, amylase and lysosomal enzymes were determined. All dogs were injected
      with 50 microCi (125)I-BSA 4 h at the 7th day before being sacrificed. The (125)I
      BSA indexes of the pancreas/muscle and pancreas/blood were measured, and
      pancreatitic pathological scores (PPSs) of the different partial pancreas were
      observed. The content of mucosa protein, DNA and the villi, the thickness of
      mucosa and the whole bowel wall of the ileum and transverse colon were measured.
      RESULTS: The study showed that serum glucose in the PN group was higher than in
      the EIN group after SAP 3 d; the levels of systemic plasma endotoxin and the
      magnitude of bacterial translocation to the portal and systemic blood and distant
      organ reduced significantly in the EIN group P<0.01. There were no differences
      between the two groups in the data of serum calcium, amylase and lysosomal
      enzymes, P>0.05; the (125)I-BSA index of pancreas/muscle and pancreas/blood, and
      PPS of the head, body, tail and total pancreas did not reach significant
      difference between the two groups, P>0.05. The contents of protein and DNA, the
      height of villi, the thickness of mucosa and the whole bowel wall of the ileum
      and transverse colon in the EIN group were higher than that in the PN group,P
      <0.01. CONCLUSION: Our results suggested that EIN was safe and effective to be
      adopted by intrajejunal delivery of nutrients in SAP dogs, did not make SAP
      clinical pathological features deteriorate, and decreased the occurrence rate of
      endotoxin and gut bacterial translocation.

PMID- 12468367
TI  - Central venous catheter complications in 447 patients on home parenteral
      nutrition: an analysis of over 100.000 catheter days.
AB  - RATIONALE: The purpose of this study is to report the frequency of central venous
      catheter (CVC) complications and to analyze the potential risk factors for
      complications requiring CVC removal in home parenteral nutrition (HPN) patients.
      METHODS: A questionnaire developed by the ESPEN HAN WORKING GROUP was distributed
      to 12 European centers to investigate the complications occurring during the
      period between January 1995 and December 2000 when HPN patients used their first
      CVC. The questionnaire collected informations related to the Home Parenteral
      Nutrition technique and the underlying disease. Factors affecting the time of CVC
      removal were jointly investigated using Cox's multivariable regression models.
      RESULTS: The study was performed on 447 patients for a total of 110869 CVC-days.
      Complications occurred in about 1/4 of patients, approximately half were
      infections and about half required Central Venous Catheter removal. The Cox
      analysis showed that using the CVC 7 times/week and implanted ports were
      associated with a hazard ratio of 3 and 2.8, respectively. A reduced risk of
      removal (of about 40%) was associated with using CVC also for non-nutritional
      purposes (P = 0.0016). CONCLUSIONS: Within the limits of this retrospective
      investigation, the type of CVC, the type of administration of HPN and the type of
      training are important factors associated with occurrence of complications or
      with CVC removal. However, in our opinion, proper care of the CVC, of preparation
      and administration of the nutritive admixture seem to be paramount for a safe
      management of HPN.

PMID- 12468368
TI  - Protective effects of recombinant growth hormone on intestinal mucosa in rats
      receiving abdominal radiotherapy.
AB  - BACKGROUND AND AIMS: Radiation injury to the gut induces nutrient losses that
      compromise the body ability to adequately fight infection, heal wounds and
      recover from illness. Recombinant growth hormone (rhGH), is known to enhance
      anabolism, therefore, we tested the hypothesis that rhGH preserves whole body
      growth and trophism of the jejunum and ileum of irradiated rats. METHODS: After
      acclimatization period, the rats were divided in three groups: (1). control rats
      (C), (2). rats irradiated with a single dose of 10 Gy (group A); (3). rats
      irradiated with a single dose of 5 Gy (Group B); after irradiation, rats were
      given subcutaneously (sc) saline or 0.25 or 0.50 mg rhGH/kg BW/d for the
      following 6 days. Body weight changes were recorded during this time. On day 6
      post-radiation, rats were killed and small intestine mucosa dry and wet weights
      were measured, as well as mucosa protein content. RESULTS: Group A rats lost body
      weight during the 6-day post-radiation period, regardless of rhGH treatment and
      dosage. rhGH was effective in preventing weight loss and normalizing growth in
      group B rats (saline 23.1+/-11.1, vs. controls P<0.05; rhGH: 35.0+/-10.0 g BW/d,
      vs. controls P = ns). Trophic effect of rhGH was observed on mucosa weight and
      mucosa protein content in rats irradiated with 5 Gy, but not in those receiving
      10 Gy. CONCLUSION: rhGH seems to normalize growth and mucosa protein content in
      irradiated rats. However, rhGH beneficial effects were observed only in rats
      receiving the lower dose of radiation.

PMID- 12468369
TI  - Comparison of the Cosmed K4 b(2) and the Deltatrac II metabolic cart in measuring
      resting energy expenditure in adults.
AB  - BACKGROUND AND AIMS: The objective of the study was to compare data obtained from
      the Cosmed K4 b(2) and the Deltatrac II metabolic cart for the purpose of
      determining the validity of the Cosmed K4 b(2) in measuring resting energy
      expenditure. METHODS: Nine adult subjects (four male, five female) were measured.
      Resting energy expenditure was measured in consecutive sessions using the Cosmed
      K4 b(2), the Deltatrac II metabolic cart separately and the Cosmed K4 b(2) and
      Deltatrac II metabolic cart simultaneously, performed in random order. Resting
      energy expenditure (REE) data from both devices were then compared with values
      obtained from predictive equations. RESULTS: Bland and Altman analysis revealed a
      mean bias for the four variables, REE, respiratory quotient (RQ), V CO(2), V O(2)
      between data obtained from Cosmed K4 b(2) and Deltatrac II metabolic cart of
      268+/-702 kcal/day, -0.0+/-0.2, 26.4+/-118.2 and 51.6+/-126.5 ml/min,
      respectively. Corresponding limits of agreement for the same four variables were
      all large. Also, Bland and Altman analysis revealed a larger mean bias between
      predicted REE and measured REE using Cosmed K4 b(2) data (-194+/-603 kcal/day)
      than using Deltatrac metabolic cart data (73+/-197 kcal/day). CONCLUSIONS:
      Variability between the two devices was very high and a degree of measurement
      error was detected. Data from the Cosmed K4 b(2) provided variable results on
      comparison with predicted values, thus, would seem an invalid device for
      measuring adults.

PMID- 12468370
TI  - Lack of adaptation to severe malnutrition in elderly patients.
AB  - BACKGROUND & AIMS: Sarcopenia is a common feature in the healthy elderly.
      However, little is known on age-related modifications of body composition in
      malnourished patients. The aims of this cross-sectional study were to evaluate
      the effects of aging per se on body composition and resting energy expenditure
      (REE) in malnourished patients. METHODS: Ninety-seven non-stressed patients
      referred for chronic malnutrition (C-reactive protein <5 mg/l) were separated
      into two groups: middle-aged (26 female, 19 male, 48+/-15 yr), and elderly (26
      female, 26 male, 79+/-6 yr). Body composition was assessed by bioelectrical
      impedance analysis and REE by indirect calorimetry. RESULTS: In middle-aged
      patients, body composition remained stable between moderate (body-mass index
      [BMI; in kg/m(2)] 16-18.5) and severe (BMI < 16) malnutrition, with similar
      values of fat-free mass (FFM), body cell mass (BCM) and fat mass (FM) as
      percentages of body weight, whereas in elderly patients malnutrition occurred at
      the expense of FFM and BCM, with unchanged FM absolute values. REE/FFM values
      remained stable in middle-aged patients at every stage of malnutrition, whereas
      they increased in elderly patients along with their degree of malnutrition. In
      multivariate analysis, both body composition and REE/FFM were influenced by sex,
      age, BMI and mid-arm circumference. CONCLUSION: Compared to younger patients,
      weight loss in the elderly leads to cachexia, with a preferential loss of FFM and
      BCM that may participate in the more severe outcomes observed in these patients.
      They also show elevated REE/FFM values that induce higher energy needs.

PMID- 12468371
TI  - Longitudinal pattern of glutamine/glutamate balance across the leg in long-stay
      intensive care unit patients.
AB  - BACKGROUND & AIMS: Progressive muscle wasting is a characteristic feature of
      patients treated at the intensive care unit (ICU). As a consequence, endogenous
      glutamine production by skeletal muscle may be compromised. We investigated the
      time pattern of the glutamine and glutamate net balance across the leg in long
      stay ICU patients. METHODS: Critically ill patients with multiple organ failure
      that were expected to stay in the ICU for more than 3 days were included in a
      longitudinal study. Possible changes in amino acid net balance over the leg
      muscle were investigated overtime. The patients (n=20) were studied descriptively
      every third or fourth day, on a total of 2-7 occasions. MAIN RESULTS: The
      glutamine net release from leg muscles did not change significantly during the
      initial 2 weeks of ICU stay and was not related to the plasma concentration of
      glutamine. The net uptake of glutamate across the leg muscles was unaltered
      during this time period, but it was found to correlate statistically with both
      the arterial glutamate concentration and the glutamine net release. A continuous
      net release of phenylalanine indicated a progressive net loss of muscle protein
      in these patients. CONCLUSION: The net release of glutamine from skeletal muscle
      does not decrease in stabilized critically ill patients with multiple organ
      failure over the initial 2 weeks of ICU stay, despite progressive muscle wasting.

PMID- 12468372
TI  - Refeeding syndrome with enteral nutrition in children: a case report, literature
      review and clinical guidelines.
AB  - Refeeding syndrome is a potentially fatal complication of the nutritional
      management of severely malnourished patients. The syndrome almost always develops
      during the early stages of refeeding. It can be associated with a severe
      derangement in electrolyte and fluid balance, and result in significant morbidity
      and mortality. It is most often reported in adults receiving total parenteral
      nutrition (TPN), although refeeding with enteral feeds can also precipitate this
      syndrome. We report what we believe to be the first case of refeeding syndrome in
      an adolescent with newly diagnosed Crohn's disease. This developed within a few
      days of starting exclusive polymeric enteral nutrition. A systematic literature
      review revealed 27 children who developed refeeding syndrome after oral/enteral
      feeding. Of these, nine died as a direct result of complications of this
      syndrome. We discuss the implications of this syndrome on clinical practice and
      propose evidence-based guidelines for its management.

PMID- 12468373
TI  - Use of the refractometer as a tool to monitor dietary formula concentration in
      gastric juice.
AB  - BACKGROUND AND AIMS: Critically ill patients do not always tolerate nasogastric
      tube feeding. Gastric residual volumes are widely used to evaluate feeding
      tolerance, but controversy exists about what constitutes the residual volume
      (diet formula or digestive juice). In this paper, we describe the use of the
      refractometer as a tool to monitor dietary formula concentration in gastric juice
      and evaluate gastric juice refractometry as a possible clinical application.
      METHODS: Brix value (an index of the total solutes in solution) readings for
      polymeric diet at pH 1, 4, 7 and 8, and at 4 degrees C, 25 degrees C and 37
      degrees C, and in fasting gastric juice were determined with a refractometer.
      RESULTS: We found that distilled water, minerals, and vitamins had low Brix
      values of 0+/-0, 1.2+/-0.1, and 0.4+/-0.1, respectively. On the other hand,
      because carbohydrate (17 g/100 ml), protein (5.3 g/100 ml), fat (4.1 g/100 ml),
      and full-strength polymeric diet had high concentrations of dissolved nutrients,
      they also had high Brix values (12.1+/-0.6, 6.5+/-0.1, 6.0+/-0.1, and 23.5+/-0.1,
      respectively). The Brix values of polymeric diet had a linear additive
      relationship with the diet formula concentration at various pHs, temperatures,
      and in the gastric juice. CONCLUSION: Brix value measurement can be used to
      monitor stomach dietary formula concentration. Such information can be obtained
      at the bedside and used to evaluate feeding-intolerant patients receiving enteral
      feeding.

PMID- 12468374
TI  - A novel synbiotic therapy dramatically improved the intestinal function of a
      pediatric patient with laryngotracheo-esophageal cleft (LTEC) in the intensive
      care unit.
AB  - To demonstrate the beneficial effects of synbiotic therapy (combined use of
      probiotics and prebiotics) in critically ill patients, we designed a new protocol
      for such therapy. Three agents were used as synbiotics: Bifidobacterium breve,
      Lactobacillus casei, and galactooligosaccharides. More than 1 x 10(9) of
      probiotic bacteria were contained in each 1.0 g pack. We administered 3.0 g per
      day of each agent to the patient.A critically ill 9-month-old girl with
      laryngotracho-esophageal cleft (type IV) was treated by our new synbiotic
      therapy. Abundant amounts of synbiotic bacteria were detected in the feces which
      suggests that these administered bacteria affected intestinal function in situ.
      Bowel movements resumed soon after the commencement of synbiotic therapy and
      considerable amounts of short chain fatty acids were detected in the feces.
      Growth of the patient was satisfactory under this treatment. Our new synbiotic
      therapy had a beneficial effect to improve intestinal function. We recommend
      synbiotic therapy for critically ill patients in intensive care units as an
      important immunonutritional therapy.

PMID- 12468375
TI  - The solution was the problem.
AB  - There are increasing numbers of adults living in the community who require
      enteral tube feeding. While there is significant evidence of the importance of
      this treatment, there are side effects which can cause difficulties for patients,
      their carer tabers and health professionals. Gastrointestinal complications are
      the most common side effects with feed formula being cited as the main culprit,
      often without investigating other potential causes. Many patients requiring
      aggressive nutrition support also require concurrent drug therapy to manage
      underlying disease. Drugs are often given via tubes in liquid form. These elixirs
      often contain large quantities of sorbitol, which will increase the osmolar
      concentration. There is a lack of awareness from primary health-care
      professionals about the difficulties that can arise when giving medications to
      patients receiving enteral feeding which may affect patient care and the
      nutritional outcomes.

PMID- 12468376
TI  - Bak Foong Pills stimulate anion secretion across normal and cystic fibrosis
      pancreatic duct epithelia.
AB  - The present study examined the effect of Bak Foong Pills (BFP), an over-the
      counter traditional Chinese medicine (China registration no. Z980035), on anion
      secretion and the underlying signaling pathways in normal and cystic fibrosis
      pancreatic duct cell lines, CAPAN-1 and CFPAC-1, respectively, using the short
      circuit current technique. Apical addition of BFP ethanol extract (600 microg/ml)
      induced a fast transient I(SC) peak that was followed by a slower but more
      sustained increase in I(SC) in CAPAN-1 cells. However, the response to BFP in
      CFPAC-1 was predominantly the first transient peak. Apical addition of DIDS (200
      microM) inhibited the first peak by more than 60% in both cell lines without
      significantly affecting the second I(SC) rise. More than 85% of the BFP-induced
      first transient in both cell lines was inhibited when extra and intracellular
      Ca(2+) was chelated or emptied by pre-treatment with BAPTA (100 microM) and
      thapsigargin (10 microM), respectively. Acute addition of PMA (1 microM), a PKC
      activator, blocked more than 95% of the BFP-induced first peak in both cell
      lines, consistent with previously reported PKC modulation of Ca(2+)-dependent
      pancreatic anion secretion. The BFP-induced second I(SC) rise in CAPAN-1 could be
      inhibited by 73.6% and 71.13% by pretreatment of the cells with MDL-12330A (20
      microM), an adenylate cyclase inhibitor and Rp-cAMP (200 microM), a cyclic AMP
      antagonist, respectively. However, less than 25% of the I(SC) was inhibited by
      combined treatment with BAPTA and thapsigargin. The second rise was also
      completely blocked by DPC (2mM) or Glibenclamide (1mM). The results indicate that
      BFP ethanol extract stimulates pancreatic duct anion secretion in normal and CF
      cells via different signaling pathways involving both Ca(2+) and cAMP.

PMID- 12468377
TI  - Telomerase-dependent reactivation of DNA synthesis in macrophages implies
      alteration of telomeres.
AB  - In previous work we demonstrated that various types of cultured cells with a
      limited life span could not reactivate DNA synthesis in the nuclei of mouse
      peritoneal macrophages in heterokaryons. We now investigate the role of
      telomerase in the process of the macrophage nucleus reactivation in heterokaryons
      with immortal telomerase-positive 3T3 Swiss mouse fibroblasts and human
      fibroblasts with introduced hTERT gene. We report that introduction of the hTERT
      gene into human diploid fibroblasts results in emergence of telomerase activity
      in these cells and the ability to induce the reactivation of DNA synthesis in the
      macrophage nuclei in heterokaryons. Inhibition of telomerase activity in
      heterokaryons by reverse transcriptase inhibitors (azidothymidine and guanosine
      polyphosphonate analogues) and by a 2'-O-methyl-RNA oligonucleotide anti-sense to
      the template region of telomerase RNA, block reactivation of DNA synthesis in
      macrophage nuclei without inhibiting DNA synthesis in the nuclei of fibroblasts.
      Our results suggest alterations (shortening or damage) in the macrophage telomere
      structure. As far as we know, heterokaryons with macrophages are the first
      cellular model for rapid investigation of the effects of telomerase inhibitors.

PMID- 12468378
TI  - Paracrine action of transforming growth factor-alpha in rectal crypt epithelium
      of humans.
AB  - Colon and rectal mucosal crypt epithelium is a rapidly renewing cell population,
      where cell proliferation is normally balanced by cell loss. This report concerns
      the putative paracrine action of transforming growth factor alpha(TGF-alpha) in
      this homeostatic process. Immunohistochemical staining for proliferating cell
      nuclear antigen (PCNA) and TGF-alpha was performed on biopsy specimens of rectal
      mucosa taken from consenting patients. The height of the proliferative
      compartment in mid-axially sectioned crypts in each individual was determined
      from the distribution of PCNA stained cells. The number of TGF-alpha stained
      cells that exhibited intense positive staining in a continuous column from the
      mouth down the side of the crypt was also scored in each individual patient.
      There was a significant positive correlation (P=0.05,n =22 patients) between the
      height of the proliferative compartment and the number of cells staining for TGF
      alpha. Non-cellular TGF-alpha reactivity was also observed in the lamina propria
      adjacent to the TGF-alpha reactive epithelial cells, indicating secretion of TGF
      alpha by these epithelial cells. These findings suggest that TGF-alpha is
      released from epithelial cells in the upper compartment of the crypt into the
      adjacent lamina propria and then diffuses to the epithelial cells in the lower
      part of the crypt, resulting in expansion of the proliferative compartment.

PMID- 12468379
TI  - Modification of oscillatory behaviour of protein tyrosine kinase and phosphatase
      during all-trans retinoic acid-induced differentiation of leukaemic cells.
AB  - Granulocytic maturation of human acute promyelocytic leukaemic (HL-60) cells was
      induced using all-trans retinoic acid (ATRA). Time-dependent changes in the
      enzyme activities of protein tyrosine phosphatase (PTP) and protein tyrosine
      kinase (PTK), and the total extractable protein content were monitored in
      proliferating and differentiating cells. The existence of periodicity was
      demonstrated clearly in both PTP and PTK enzyme activities and in the amount of
      protein extracted from the cells. Following ATRA treatment, differentiation
      induced changes in rhythmic characteristics such as period and amplitude were
      evident. A noticeable effect was that of ATRA on the enzyme activity of PTP, for
      which four distinct patterns of oscillatory behaviour were identified. This study
      examines these changes, in an attempt to gain insight into the role which
      biochemical oscillators may play in the regulation of molecular control
      mechanisms.

PMID- 12468380
TI  - The significance of alpha 5 beta 1 integrin dependent and independent actin
      cytoskelton organization in cell transformation and survival.
AB  - Cell-matrix and cell-cell interactions are important physiological determinants
      of cell growth, survival and transformation. Cell adhesion to the extra cellular
      matrix (ECM) via integrins also crucially influences the organization of the
      cytoskeleton. It triggers a cascade of intracellular biochemical events, which
      regulate cell viability and growth. We have studied the relationship between cell
      attachment to the substratum and cytoskeletal organization and cell survival and
      transformation. Our results demonstrate that in the absence of attachment to the
      substratum, adhesion-dependent fibroblasts exhibit rapid loss of viability.
      However, a small percentage of cells survive even after remaining non-adherent
      for 16h. The adherent and non-adherent cells differ from one another both
      morphologically and physiologically. The latter show a loss of alpha5beta1
      integrin expression on their surface and bind non-specifically to the substratum
      and ECM, thereby activating certain pathways more efficiently than adherent
      cells. We have also shown that non-adherent cells grow faster and have worse
      cytoskeletal organization after attachment to the substratum, and do not form
      focal adhesions or actin stress fibres. Hence, our data suggests that rat
      fibroblasts in prolonged suspension exhibit some properties that are comparable
      to cells undergoing transformation, by adapting integrin-dependent or independent
      signalling pathways for their survival.

PMID- 12468382
TI  - Effects of transforming growth factor-beta 1 and fibronectin on SPARC expression
      in cultures of human periodontal ligament cells.
AB  - Transforming growth factor-beta(1) (TGF-beta(1)) increases synthesis of secreted
      protein, acidic and rich in cysteine (SPARC), as well as fibronectin (FN) and
      type I collagen. However, little is known about the regulatory mechanism of SPARC
      expression. We examined the effect of FN on SPARC expression by TGF-beta(1) in
      cultures of human periodontal ligament cells (HPL cells). TGF-beta(1) increased
      the SPARC and SPARC mRNA levels in HPL cells. Extracellular matrix (ECM) produced
      by HPL cells in the presence of TGF-beta(1) also increased the SPARC levels.
      Contents of FN and type I collagen in the ECM were increased by TGF-beta(1). HPL
      cells cultured on FN-coated plates secreted more SPARC than those on non-coated
      plates. However, type I collagen had little effect on SPARC levels. The addition
      of anti-alpha5 antibody to the cultures abolished the increase in SPARC mRNA
      expression by TGF-beta(1). This study demonstrated that FN may be partly involved
      in the increase in SPARC expression by TGF-beta(1) in HPL cells.

PMID- 12468381
TI  - Exogenous activin increases the proportion of insulin cells in the developing
      chick pancreas in culture.
AB  - As activin is believed to be a key signalling factor during early pancreatic
      development, its influence on the proliferation and/or determination of insulin
      cells in the developing chick dorsal pancreatic bud was investigated. Dorsal
      pancreatic buds of 5-day-old chick embryos were explanted on to Matrigel and
      cultured in serum-free medium (Ham's F12.ITS), to which 1 or 10ng/ml activin was
      added. After 7 days in culture, the explants were processed for
      immunocytochemistry and the insulin-positive cells were scored and expressed as a
      proportion of the sum of insulin and glucagon cells. When compared to the control
      cultures (Hams F12.ITS alone), activin treatment resulted in respective increases
      in the proportion of insulin cells of 1.6 and 1.9 fold. It is suggested that
      activin treatment favours differentiation of the insulin cell pathway relative to
      glucagon cells.

PMID- 12468383
TI  - Actin-related protein (Arp2) inserts into artificial lipid membranes.
AB  - Arp2 is localized in the cytoplasm of eukaryotic cells where it controls actin
      dynamics. Computer analyses have suggested one possible lipid binding site,
      residues 185-202 of the primary amino acid sequence on Arp2, that could allow for
      membrane attachment/insertion. We expressed this region as a fusion protein with
      schistosomal glutathione S-transferase (GST) and investigated the interaction of
      this fragment with mixtures of dioleoylphosphatidylserine (DOPS) and
      dioleoylphosphatidylglycerol (DOPG) phospholipids in reconstituted lipid bilayers
      using differential scanning calorimetry (DSC). Calorimetric measurements showed
      that as the fusion protein increased, the main chain transition enthalpy
      decreased and the chain-melting temperature shifted, which is indicative of
      partial protein insertion into the hydrophobic region of the lipid membrane. This
      was confirmed using the Langmuir Blodgett technique (film balance) on lipid
      monolayers. The dissociation constant (K(d)) determined by the temperature jump
      method was approximately 1.1 microM.

PMID- 12468385
TI  - Mechanistics of amoeboid locomotion: signal to forces.
AB  - Dictyostelium serves as an ideal model system for studying the molecular and
      structural properties of the actomyosin and microtubule systems. This organism
      also has been the vehicle on which the gene-targeting technique was pioneered.
      Dictyostelium also represents a small number of organisms whose chemotactic
      ligand-receptor mechanism has been well characterized. This article reviews
      recent advances in studies of the actin-based cytoskeletal system in
      Dictyostelium, focusing on the mechanistic aspects of the amoeboid motion.
      Special emphasis is placed on the recently identified cell-substrate-anchoring
      structures 'eupodia', and the measurement of single-cell migration forces. The
      recent advances in signal transduction cascade is also discussed with relevance
      to the mechanistics in amoeboid locomotion.

PMID- 12468386
TI  - Calcium pump phosphoenzyme from young and old human red cells.
AB  - An increase in intracellular Ca(2+) occurs during ageing of human erythrocytes in
      vivo. The aged cells show a reduced capacity for active Ca(2+) extrusion. Such a
      defect may arise from pump proteolysis, due to calpain activation by the raised
      intracellular Ca(2+). To test this possibility, Ca(2+) pump phosphorylation by
      [gamma-(32)P]ATP was studied on percoll-separated young and old human
      erythrocytes. After phosphorylation for 30 s with Ca(2+), the amount of
      phosphoenzyme produced by the young cell membranes was 50% that of the old cells.
      With Ca(2+) plus La(3+), in contrast, the phosphoenzyme level was nearly the same
      in both preparations. After a prolonged phosphorylation period (50-90 s), the
      phosphoenzyme reached almost identical equilibrium levels in both membrane
      preparations. On the other hand, a single Ca(2+)-dependent radioactive band of
      about 150 kDa was apparent in both preparations after acidic electrophoresis.
      Likewise, Western blotting using 5F10 monoclonal antibody also detected a single
      band of similar molecular weight. These results demonstrate that there is no
      alteration in either molecular mass or number of active Ca(2+) pump units during
      cell ageing, thus indicating that the reduced Ca(2+) pumping activity of aged
      cells does not arise from pump proteolysis.

PMID- 12468387
TI  - Cell adhesion during the migratory slug stage of Dictyostelium discoideum.
AB  - Prespore-specific Antigen (PsA) is selectively expressed on the surface of
      prespore cells at the multicellular migratory slug stage of Dictyostelium
      discoideum development. It is a developmentally regulated glycoprotein that is
      anchored to the cell membrane through a glycosyl phosphatidylinositol (GPI)
      anchor. We present the results of an in vitro immunological investigation of the
      hypothesis that PsA functions as a cell adhesion molecule (CAM), and of a ligand
      binding assay indicating that PsA has cell membrane binding partner(s). This is
      the first evidence to implicate a direct role for a putative CAM in cell-cell
      adhesion during the multicellular migratory slug stage of D. discoideum
      development. Cell-cell adhesion assays were carried out in the presence or
      absence of the monoclonal antibody (mAb) MUD1 that has a single antigenic
      determinant: a peptide epitope on PsA. These assays showed specific inhibition of
      cell-cell adhesion by MUD1. Further, it was found that a purified recombinant
      form of PsA (rPsA), can neutralize the inhibitory effect of MUD1; the inhibitory
      effect on cell-cell adhesion is primarily due to the blocking of PsA by the mAb.
      The resistance of aggregates to dissociation in the presence of 10 mM EDTA
      (ethylenediamintetraacetic acid) indicates that PsA mediates EDTA-stable cell
      cell contacts, and that PsA-mediated cell adhesion is likely to be independent of
      divalent cations such as Ca(2+) or Mg(2+).

PMID- 12468388
TI  - Pharmacological characteristics of novel putative purinoceptors in vascular
      endothelium.
AB  - Using an isolated rat aorta with intact endothelium, a functional bioassay system
      was created as follows: pre-contract the isolated rat aorta with intact
      endothelium in the presence of 0.62 micromol/l of norepinephrine, and then add
      acetylcholine to obtain maximal endothelium-dependent relaxation. In the addition
      of low concentration of adenosine, a P(1) agonist or ATP, a P(2) agonist to this
      system, the rat aorta smooth muscle contraction was observed. This observation
      could not be explained in terms of the classic P(1) and P(2) receptor properties,
      suggesting that there may be a novel subtype of purinoceptors in the endothelium
      of the rat aorta. The P(1) and P(2) agonists-induced rat aorta smooth muscle
      contraction could be blocked by the pretreatments of the bioassay system with a G
      protein (Gi/o) inhibitor, PTX, and EDNO synthesis inhibitor, L-NAME and
      cyclooxygenase inhibitor, indomethacine. The data strongly support that this
      novel purinoceptor may couple with PTX-sensitive G protein, Gi or Go, and the
      novel purinoceptor-mediated rat aorta smooth muscle contraction is dependent on
      the endogenous nitric oxide and prostaglandin synthesis. In an additional
      observation, pathophysiological conditions, such as hypertension, altered the
      characteristics of the novel receptor. Hypertension caused the novel receptor
      insensitive to adensone and uncoupling to PTX-sensitive G-proteins and lost of
      ability to initiate the receptor-mediated prostaglandin synthesis. All together,
      the novel putative endothelial purinoceptor may play an important role in the
      control of vascular tone in physiological or pathophysiological statues.

PMID- 12468389
TI  - Expression and regulation of SPARC, fibronectin, and collagen IV by dexamethasone
      in lens epithelial cells.
AB  - Cataract formation is a deleterious side effect of some hormone therapies, thus,
      it is important to understand how hormones regulate lens basement structure and
      function. We have examined the effects of dexamethasone (DEX) on the regulation
      of Secreted Protein Acidic and Rich in Cysteines (SPARC), fibronectin (FN), and
      collagen IV (CN IV). To radiolabel newly synthesized proteins, cultured
      monolayers of bovine anterior lens capsule epithelial (ALCE) cells were pulsed
      with [(3)H] proline. To identify proteins, an immunofluorescent technique,
      immunoprecipitation with specific antibodies, and electrophoretic separation on
      sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) were used.
      DEX increased production of total proteins, whereas it specifically decreased
      synthesis of FN and CN IV. A decrease in FN and CN IV synthesis by DEX in ALCE
      cells may decrease adhesion of lens epithelium to the basement membrane (BM),
      which may in turn cause pathogenesis. Messenger RNAs were identified by Northern
      blot analyses using specific DNA probes. Treatment of lens epithelial cells with
      DEX causes a 100-150% up-regulation of SPARC mRNA in a concentration-dependent
      fashion. The increase in the expression of FN mRNA by DEX was in a dose-response
      fashion and varied from 50-600%. A 24-hour treatment with DEX (10(-6)M) increased
      CN IV mRNA levels to 386% over baseline levels. Thus showing a differential
      upregulation by DEX of mRNAs of SPARC, FN, and CN IV. Results of nuclear run-on
      transcription assays indicate that regulation of RNAs by DEX may occur, in part,
      at the transcriptional level. The aberrant expression of lens basement membrane
      proteins by DEX may contribute to abnormal lens cell function and ultimately to
      anterior subcapsular cataract.

PMID- 12468390
TI  - Localization of pan-cadherin immunoreactivity in adult rat tissues.
AB  - Cadherins, being responsible for selective cell recognition and normal tissue
      integrity in adults, regulate morphogenesis in a variety of organs during
      development. In this study, anti-rat pan-cadherin antibody, specific to all
      subgroups of the cadherin family, was used to map the distribution of the pan
      cadherin immunoreactivity in adult rat organs. Pan-cadherin immunoreactivity
      positive tissues were: secretory cells of the adenohypophysis, autonomic nerve,
      corneal epithelium, oesophageal nerve plexus, stomach and pyloric glandular
      cells, epithelium of the ileum and its nerve plexus, alveolar cells of the lung,
      proximal convoluted tubules of the kidney, islet cells of Langerhans, and the
      acinar cells of the exocrine pancreas. For the first time, positive pan-cadherin
      immunoreactivity was demonstrated in the epithelial cells of the corpus ciliaris
      and in the nerve plexus of corpus cavernosum of the penis. In conclusion, our
      results suggest that cells in many tissues and organs of the adult rat synthesize
      cadherins.

PMID- 12468391
TI  - Regulation of leukotriene synthesis by arachidonic acid in human
      polymorphonuclear leukocyte adhesive interactions is dependent on the presence of
      albumin.
AB  - We have previously demonstrated that the pretreatment of polymorphonuclear
      leukocytes (PMNs) with the chemotherapeutic drug, Suramin, increases both cell
      attachment and inhibits calcium ionophore A23187-stimulated leukotriene (LT)
      synthesis. Here, we examined the effects of extracellular arachidonic acid (AA)
      and albumin on attachment and LT synthesis in the interaction of PMNs with both
      collagen-coated surfaces and human umbilical vein endothelial cell (HUVEC)
      monolayers. Suramin decreased the release of radiolabelled AA and 5-lipoxygenase
      metabolites by [(14)C-AA]-prelabelled PMNs stimulated with A23187, with and
      without human serum albumin (HSA) in the culture medium. Addition of 1 microM AA
      together with calcium ionophore stimulated the release of endogenous AA to the
      same level as control and Suramin-pretreated cells, but attachment was unaffected
      and LT synthesis was still inhibited with Suramin treatment. Using 24 microM AA,
      regulation of LT synthesis was dependent on the presence of HSA in the medium.
      Without HSA, 24 microM AA induced detachment of PMNs and increased LT synthesis
      in Suramin-treated cells above the control level. In the presence of HSA, 24
      microM AA did not influence PMN attachment or abolish Suramin-induced inhibition
      of LT synthesis. These results suggest that tight attachment of PMNs to a solid
      surface leads to decreased LT synthesis during subsequent stimulation of the
      cells by A23187 in the presence or absence of exogenous substrate.

PMID- 12468392
TI  - A simple non-enzymatic method for the isolation of high yields of functional rat
      hepatocytes.
AB  - A method for isolation of rat hepatocytes using liver perfusion by
      ethylenediamine tetra-acetic acid (EDTA)-containing sucrose solution and
      mechanical tissue disaggregation by controlled vibration (MVD) is described. The
      yields of hepatocytes produced by this method were similar to those obtained
      using collagenase perfusion. The cells had well preserved membrane integrity as
      judged by the trypan blue staining test (91 +/- 4%), ATP contents, rates of
      endogenous respiration and enzyme leakage that indicated they were functional
      cells. There was little evidence of expression of latent damage when the cells
      were stored either at 37 degrees C (by pre-incubation) or at 4 degrees C. This
      method can be used to isolate high yields of functional cells from rat liver if
      the collagenase perfusion technique is not available.

PMID- 12468394
TI  - A comparison of sentence- and discourse-level semantic processing: an ERP study.
AB  - Eighteen subjects listened to sentences ending with semantically congruent or
      incongruent words. Each congruent sentence was embedded at the end of a short
      story so that the final word was semantically acceptable at the sentence level
      but incongruent in terms of discourse context. The same stories were also
      presented with congruent endings. Auditory ERPs elicited by the final words in
      these sentences and stories were compared. Both sentence- and discourse-level
      semantic integration were associated with N400 and Late Positive Component (LPC)
      effects in addition to a new component, P550. Local and global semantic
      processing, although evoking the same components, were characterized by
      differential effects on ERP amplitudes according to the amount of text integrated
      and its congruence. These results indicate similar cognitive processes of context
      build up, underlying sentence- and discourse-semantic processing.

PMID- 12468395
TI  - The lateralized stroop: a meta-analysis and its implications for models of
      semantic processing.
AB  - The prevailing theory in the literature concerning the lateralization of Stroop
      effects involves a speed of processing account (see ). Because the left
      hemisphere (LH) demonstrates an overall advantage relative to the right
      hemisphere (RH) on most verbal tasks, interference effects are hypothesized to be
      greater in the LH than in the RH. Inspection of the data, however, reveals that
      many studies find no difference in magnitude of Stroop interference between the
      hemispheres. Given findings within the lateralized semantic priming literature,
      this is not surprising. A meta-analysis on a subset of lateralized Stroop
      experiments was conducted to determine whether or not the LH produces
      significantly more interference than the RH in this paradigm. Based on a number
      of exclusionary criteria, a total of 19 different studies were included,
      representing a potential 26 effect size estimates of differential interference.
      The effect size representing interference using congruent conditions as the
      baseline (d+=.06) reveals that there is no significant difference between the
      hemispheres in magnitude of the Stroop interference effect. The LH interference
      effect was d+=.73, which is significant. Likewise, the RH interference effect,
      d+=.67, was significant. In summary, while there was no significant difference
      between the hemispheres, each hemisphere, when examined independently, did
      exhibit significant within hemisphere interference effects. These findings are
      presented in light of the lateralized semantic priming literature.

PMID- 12468396
TI  - Variability in the anatomy of the planum temporale and posterior ascending ramus:
      do right- and left handers differ?
AB  - The anatomy of the planum temporale (PT) and posterior ascending ramus (PAR) was
      studied in vivo in 67 healthy right- and left-handed adults using MRI-based
      morphometry. The left PT was significantly larger than the right, and there was a
      weakly significant effect of the right PAR larger than the left. A leftward PT
      asymmetry was found in 72%, and a rightward PAR asymmetry was found in 64% of the
      sample. The "typical" configuration of a larger left PT and larger right PAR co
      occurred in 56% of the subjects studied, which was only slightly more often than
      predicted by chance. Eight of 67 subjects had "reversed" PT and PAR asymmetries,
      with consistent left and mixed handers over-represented in this group. Right PAR
      size was the only variable that predicted writing hand, and left PT size was the
      only measure that differed by sex. The left PT was expanded relative to the left
      PAR in 93% of the sample, suggesting that this configuration may be
      developmentally regulated and may be a critical substrate for the development of
      language. These findings demonstrate that important relationships exist between
      hand preference, and the anatomy of posterior cortical language areas.

PMID- 12468397
TI  - Crossed aphasia: an analysis of the symptoms, their frequency, and a comparison
      with left-hemisphere aphasia symptomatology.
AB  - This study presents a thorough analysis of published crossed aphasia (CA) cases,
      including for the first time the cases published in Japanese. The frequency of
      specific symptoms was determined, and symptomatology differences based on gender,
      familial sinistrality, and CA subtype were investigated. Results suggested that
      the CA population is comparable to the left-hemisphere patient population.
      However, male were significantly more likely than female CA subjects to show a
      positive history of familial sinistrality. Typical right-hemisphere (i.e.,
      nonlanguage-dominant) symptoms were frequent but rarely carefully reported or
      assessed. Results are compared with previous CA reviews and left-hemisphere
      aphasia. Suggestions for a more systematic assessment of the CA symptomatology
      are presented.

PMID- 12468399
TI  - Antibody-based therapy of non-Hodgkin's lymphoma.
AB  - Monoclonal antibodies (mAb) have dramatically advanced our ability to treat non
      Hodgkin's lymphoma (NHL), and there has been a virtual explosion of clinical data
      regarding their use. Rituximab is a humanized anti-CD20 mAb and has significant
      single agent activity in follicular lymphoma, and to a lesser extent in mantle
      cell and diffuse large B-cell lymphoma (DLCL). Rituximab appears to have
      synergistic activity with cytotoxic chemotherapy and the combination has recently
      demonstrated improved rates of complete remission (CR) and overall survival in
      older patients with DLCL. Alemtuzumab (Campath-1H) is a humanized mAb targeting
      CD52 and has recently been approved in the USA for the treatment of fludarabine
      refractory B-cell chronic lymphocytic leukaemia. Impressive activity has also
      been demonstrated in T-cell prolymphocytic leukaemia and mycosis fungoides. The
      radioconjugated anti-CD20 mAbs ibritumomab tiuxetan and I131-tositumomab also
      have impressive clinical activity in low-grade B-cell NHL, and the former has
      demonstrated superior CR rates to rituximab. Myelosuppression is more significant
      however, and their place in the treatment algorithm remains to be clearly
      defined. Other immunotoxins (e.g. BL22) and mAb against alternate targets (e.g.
      epratuzumab, humanized anti-CD22) are in development.

PMID- 12468398
TI  - Pre- and post-treatment evaluation of non-Hodgkin's lymphoma.
AB  - Once the diagnosis of a non-Hodgkin's lymphoma (NHL) has been established three
      critical steps in patient management must follow. The first is the pre-treatment
      evaluation and staging to identify prognostic factors (the subject of another
      chapter in this volume), impending problems, such as ureteral obstruction, spinal
      cord compression, biliary or vena caval obstruction. This assessment directs the
      best therapeutic approach, and also provides a baseline against which to assess
      response. The second step is the treatment itself. Third, conscientious follow-up
      after completion of therapy to monitor for disease recurrence as well as for long
      term sequelae of therapy. A careful history and physical examination are the most
      important components of patient evaluation. Whereas some evaluation procedures
      have become standard practice (e.g. chest radiographs, CT scans, gallium scan,
      blood chemistry and assessment of hepatic and renal function), the role of other
      studies is still being defined (e.g. PET scan). The increased use of systemic
      therapies has somewhat reduced the requirement for precise staging to determine
      treatment strategies, but will become more critical to identify early patients
      with resistant disease and those with minimal residual disease following
      treatment so that novel therapies can be introduced at that point.

PMID- 12468400
TI  - High-dose treatment with autologous haemopoietic progenitor cell support for
      large B-cell, follicular and mantle-cell lymphoma.
AB  - The purpose of this chapter is to review the available information on the use of
      high-dose treatment (HDT) in large B-cell, follicular and mantle-cell lymphoma.
      The last 10 years have seen a dramatic increase in the number of patients
      receiving high-dose treatment with autologous haemopoietic progenitor cell
      support for non-Hodgkin's lymphoma. In patients with recurrent large B-cell
      lymphoma, HDT is now accepted as the 'standard of care', provided responsiveness
      to conventional chemotherapy at the time of recurrence has been demonstrated. In
      contrast, the situation in newly diagnosed patients is far from clear. Several
      phase III studies have been conducted, comparing conventional chemotherapy with
      either: the same treatment followed by HDT or an abbreviated number of cycles of
      conventional therapy followed by HDT. The results hitherto have not conclusively
      shown an advantage for HDT. In mantle-cell and follicular lymphoma, HDT should
      still be regarded as experimental. Current studies are evaluating the use of anti
      CD20, given either as part of the treatment prior to HDT or as maintenance
      therapy. In view of the propensity for both of these illnesses to involve the
      bone marrow, a number of studies have addressed the question of in vitro
      treatment of the stem cell product. The advent of PCR analysis has made it
      possible to evaluate the significance of 'molecular remission'. In follicular
      lymphoma, there is a correlation between freedom from recurrence and persistent
      PCR negativity for bcl-2 rearrangement-containing cells in follow-up bone marrow
      samples.

PMID- 12468401
TI  - Allogeneic haemopoietic stem cell transplantation for non-Hodgkin's lymphoma.
AB  - This chapter outlines the rationale for allogeneic haemopoietic stem cell
      transplantation in non-Hodgkin's lymphoma and pertinent results from published
      studies. Trials comparing allogeneic with autologous transplantation are
      discussed, as are disease-specific results for low-grade (including transformed),
      mantle cell and high-grade (Burkitt's and lymphoblastic) subtypes of the disease.
      Allogeneic transplantation for non-Hodgkin's lymphoma in the paediatric
      population, the use of unrelated donors, allografting after failed autologous or
      allogeneic transplantation, the graft-versus-lymphoma effect, the use of donor
      leukocyte infusions and non-myeloablative allografts are considered.

PMID- 12468402
TI  - Non-Hodgkin's lymphoma: the evolving role of purine analogues.
AB  - Indolent non-Hodgkin's lymphoma is the commonest form of lymphoma in the USA and
      Europe, with a long natural history with multiple responses and relapses.
      Indolent lymphomas include follicular lymphomas (the more frequent subtype),
      immunocytoma, and small lymphocytic lymphomas according to the Revised European
      American Lymphoma classification. The tendency has been to use simple oral
      medication until patients have more advanced aggressive disease but new agents
      such as the purine analogues have led to re-evaluation of this approach. The
      newer purine analogues -- fludarabine, 2-chlorodeoxyadenosine (cladribine) and
      deoxycoformycin (pentostatin) -- are a group of potently lymphotoxic
      antimetabolite molecules. Their activity in the indolent non-Hodgkin's lymphomas,
      in particular in the follicular subtype, may be due to their unique ability as
      antimetabolites to inhibit resting as well as dividing cells. Within the last
      decade they have moved from salvage therapy to front-line studies. Further
      insight into the mechanism of action of the purine analogues will to lead to
      further advances in this group of diseases.

PMID- 12468403
TI  - The management of lymphoma in the immunosuppressed patient.
AB  - Two forms of acquired immunodeficiency have dominated the last quarter of the
      twentieth century and are responsible for the majority of lymphomas in the
      immunosuppressed: post-transplantation lymphoproliferative disorders (PTLD) and
      AIDS-related lymphomas (ARL). The central role of Epstein-Barr virus in PTLD has
      led to novel treatment strategies designed to enhance immunity to this virus both
      as prevention and therapy. This is achieved by reducing iatrogenic
      immunosuppression and adoptive immunotherapy with allogeneic cytotoxic T
      lymphocytes. Improved immune function in HIV seropositive patients treated with
      highly active antiretroviral therapy appears to be reducing the relative risk of
      AIDS-related lymphoma. However, ARL will remain a frequent diagnosis with the
      rapidly rising incidence of HIV throughout the world. The clinical management
      requires expertise in both the lymphoma chemotherapy and the treatment of HIV,
      including antiretroviral therapy and opportunistic infection management. Modest
      improvements in survival have been achieved recently for ARL.

PMID- 12468404
TI  - Treatment of extranodal lymphomas.
AB  - At least one-quarter of the non-Hodgkin's lymphomas arise primarily at extranodal
      sites. The rising incidence of non-Hodgkin's lymphomas, observed over recent
      decades, have mainly affected the primary extranodal entities. Survival rates
      vary among the specific sites of primary extranodal lymphomas. This is due partly
      to differences in natural history, related mainly to the histological type but
      also to differences in management strategy which are related to organ-specific
      problems. Few controlled studies facilitate therapeutic decisions in this
      setting. This chapter represents a general overview of the available data.

PMID- 12468405
TI  - Molecular remission and non-Hodgkin's lymphoma.
AB  - Non-Hodgkin's lymphomas are highly sensitive to treatment and complete clinical
      responses are often achieved. However, disease recurrence is common and is caused
      by the persistence of malignant lymphoma cells at a level below the limits of
      detection by conventional assessment such as clinical examination, bone marrow
      morphology and CT scans. This minimal residual disease can be detected using
      molecular techniques such as the polymerase chain reaction (PCR), and treatments
      capable of eliminating minimal residual disease are described as producing
      molecular remission. Molecular assessment is now commonly used as a measure of
      outcome in clinical trials of novel therapies for the treatment of lymphoma. The
      evidence for using molecular remission as a surrogate marker of clinical response
      in this setting is reviewed and the significance of minimal residual disease in
      determining prognosis and planning treatment strategies is addressed.

PMID- 12468406
TI  - Chronic lymphocytic leukaemia: a model for investigating potential new targets
      for the therapy of indolent lymphomas.
AB  - We address two key issues whose investigation may help to define new prognostic
      parameters and new potential targets for therapeutic intervention. First, which
      are the conceptual implications of the cellular origin of indolent lymphomas?
      Second, how may deciphering the biology of chronic lymphocytic leukaemia (CLL)
      lead to the development of new modalities of treatment? The latter issue is
      articulated in the following three key questions. (1) Which are the molecular
      pathways through which the microenvironment exerts its influence on the malignant
      clone? (2) What are the relationships between proliferation and defective
      apoptosis? (3)Is there any evidence of a role for antigenic stimulation?

PMID- 12468407
TI  - Non-Hodgkin's lymphomas: clinical governance issues.
AB  - Every patient in every part of the world has the right to expect the best
      possible quality of care from health care providers. Non-Hodgkin's lymphomas
      (NHL) are an extremely heterogeneous group of conditions which require important
      decisions to be taken at many points along the treatment pathway. To get this
      right every time requires that high-quality standards are instituted and adhered
      to, so that the best possible outcome is achieved. In the past this has not
      always been the case because of the failure of clinicians sometimes to adhere to
      an optimal management plan. In 1995, the UK government commissioned an inquiry
      into the running of cancer services in the United Kingdom, which culminated in a
      series of recommendations to improve them. Subsequently, these recommendations
      were implemented as objectives of the NHS Cancer Plan which is the framework by
      which the UK government wishes to improve cancer services. Concurrently another
      general concept has emerged which is designed to ensure that the highest quality
      standards may be achieved for all patients across the whole National Health
      Service (NHS). This concept, termed 'clinical governance', brings together a
      corporate responsibility of all health care workers to deliver high quality
      standards, in the hope that this will translate into better long-term survival of
      patients with malignant disease. This chapter focuses on the issues surrounding
      clinical governance and how the principles of this concept relate to non
      Hodgkin's lymphomas.

PMID- 12468409
TI  - Obesity: epidemiology and possible prevention.
AB  - Obesity can be defined as the excessive accumulation of fat in adipose tissue, to
      the extent that health may be impaired. The most widely used measures of total
      and abdominal adiposity are the body mass index and waist circumference. Obesity
      is now a global public health problem, with about 315 million people world-wide
      estimated to fall into the WHO-defined obesity categories with a body mass index
      (BMI) of 30 or above. The primary causes of the rapid global rise in obesity
      rates lie in the profound environmental and societal changes now affecting large
      parts of the world and creating societies in which physical activity is low and
      the availability of high-fat, energy-dense foods has increased. Strategies aimed
      at preventing weight gain and obesity have not been successful to date but are
      likely to be more cost effective, and to have a greater positive impact on long
      term control of body weight than treating obesity once it has developed.

PMID- 12468410
TI  - The emerging pattern of the genetic contribution to human obesity.
AB  - It has been a little more than 5 years since the publication of the first genome
      scans focused on obesity-related phenotypes in humans. While the number of scans
      reported has grown steadily during this time, the results from many of these
      studies have been modest at best. However, there are a handful of studies that
      have now reported highly significant findings, and even more important perhaps is
      the fact that several of these findings have now been replicated as well.
      Currently there is strong statistical support for approximately half a dozen
      quantitative trait loci (QTLs) influencing obesity-related phenotypes across a
      number of populations and ethnic groups. While some of these signals localize
      near genes that might have been considered a priori as candidate genes for
      obesity, several others offer evidence for previously unsuspected genes. As a
      result, there is an intriguing pattern of genetic contribution to obesity that
      has begun to emerge and which promises to greatly increase our understanding of
      the relationship between obesity and other chronic diseases such as coronary
      heart disease and type 2 diabetes.

PMID- 12468411
TI  - Hypothalamic regulation of energy homeostasis.
AB  - The co-ordinated regulation of food intake and energy expenditure takes place in
      the hypothalamic regions of the brain. Current understanding of the systems
      involved in this regulation suggests that, in the hypothalamus, there are two
      major groups of neuropeptides involved in orexigenic and anorexic processes. The
      orexigenic neuropeptides are neuropeptide Y (NPY) and agouti-related peptide
      (AgRP) and the anorexic neuropeptides are alpha-melanocyte-stimulating hormone
      (alpha-MSH) and cocaine and amphetamine-related transcript (CART). Theneurons
      expressing these neuropeptides interact with each other and with signals from the
      periphery (such as leptin, insulin, ghrelin and glucocorticoids) to regulate
      feeding behaviour, energy expenditure and various endocrine axes. Although direct
      evidence is limited, there are examples of genetic obesity in humans which
      suggest that the balance between orexigenic and anorexic pathways in the
      hypothalamus is also pivotally important in the maintenance of energy homeostasis
      in humans.

PMID- 12468412
TI  - Adipose tissue as an endocrine organ.
AB  - Adipose tissue is a highly active endocrine organ secreting a range of soluble
      products with both local and distant actions. These hormones have important roles
      in metabolism, reproduction, cardiovascular function and immunity. It is now
      evident that adipose endocrine function directly influences other organ systems,
      including the brain, liver and skeletal muscle. The endocrine function of adipose
      tissue is significantly regulated by nutritional status, and both are
      inextricably linked to the energy storage role of adipose tissue. This chapter
      highlights the endocrinology of adipose tissue by concentrating on functional
      aspects of the secreted products. The data of particular relevance to humans are
      highlighted, and areas in need of future research are suggested.

PMID- 12468413
TI  - Peripheral metabolic actions of leptin.
AB  - The adipocyte-derived hormone, leptin, regulates food intake and systemic fuel
      metabolism; ob /ob mice, which lack functional leptin, exhibit an obesity
      syndrome that is similar to morbid obesity in humans. Leptin receptors are
      expressed most abundantly in the brain but are also present in several peripheral
      tissues. The role of leptin in controlling energy homeostasis has thus far
      focused on brain receptors and neuroendocrine pathways that regulate feeding
      behaviour and sympathetic nervous system activity. This chapter focuses on
      mounting evidence that leptin's effects on energy balance are also mediated by
      direct peripheral actions on key metabolic organs such as skeletal muscle, liver,
      pancreas and adipose tissue. Strong evidence indicates that peripheral leptin
      receptors regulate cellular lipid balance, favouring beta-oxidation over
      triacylglycerol storage. There are data to indicate that peripheral leptin also
      modulates glucose metabolism and insulin action; however, its precise role in
      controlling gluco-regulatory pathways remains uncertain and requires further
      investigation.

PMID- 12468414
TI  - Substrate oxidation, obesity and exercise training.
AB  - Regular physical exercise is of the utmost importance in the treatment of obesity
      because exercise is one of the factors determining long-term weight maintenance
      in weight reduction programmes and because exercise has been associated with a
      reduced risk for developing type 2 diabetes mellitus and cardiovascular disease.
      Obesity is associated with an impaired utilization of fat as a fuel during post
      absorptive conditions, during beta-adrenergic stimulation and possibly during
      exercise, although the latter data are controversial. One of the underlying
      mechanisms for the positive effect of exercise training in obesity may be related
      to its effects on fat utilization because exercise training has been shown to
      increase basal fat oxidation and exercise fat oxidation in lean volunteers. Data
      on the effect of aerobic exercise training on exercise fat oxidation are
      controversial, whereas the available data indicate that exercise training may not
      be able to increase resting fat oxidation or 24-hour fat oxidation in obese
      subjects. Because disturbed muscle fat oxidation may be a primary event in the
      aetiology of obesity it is of the utmost importance to obtain more information on
      how and whether exercise training may be able to compensate for these
      impairments.

PMID- 12468415
TI  - Non-exercise activity thermogenesis (NEAT).
AB  - Non-exercise activity thermogenesis (NEAT) is the energy expended for everything
      we do that is not sleeping, eating or sports-like exercise. It ranges from the
      energy expended walking to work, typing, performing yard work, undertaking
      agricultural tasks and fidgeting. Even trivial physical activities increase
      metabolic rate substantially and it is the cumulative impact of a multitude of
      exothermic actions that culminate in an individual's daily NEAT. It is,
      therefore, not surprising that NEAT explains a vast majority of an individual's
      non-resting energy needs. Epidemiological studies highlight the importance of
      culture in promoting and quashing NEAT. Agricultural and manual workers have high
      NEAT, whereas wealth and industrialization appear to decrease NEAT. Physiological
      studies demonstrate, intriguingly, that NEAT is modulated with changes in energy
      balance; NEAT increases with overfeeding and decreases with underfeeding. Thus,
      NEAT could be a critical component in how we maintain our body weight and/or
      develop obesity or lose weight. The mechanism that regulates NEAT is unknown.
      However, hypothalamic factors have been identified that specifically and directly
      increase NEAT in animals. By understanding how NEAT is regulated we may come to
      appreciate that spontaneous physical activity is not spontaneous at all but
      carefully programmed.

PMID- 12468416
TI  - Obesity and liver disease.
AB  - Non-alcoholic steatohepatitis (NASH) is a disease of emerging identity and
      importance. It is frequently associated with obesity, especially visceral fat,
      and is intimately related to fatty liver and markers of the insulin resistance
      syndrome. Both the prevalence and the severity of liver steatosis are related to
      body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridaemia
      and impaired glucose tolerance or type 2 diabetes. The identification of obese
      patients who may progress from steatosis to NASH and from NASH to
      fibrosis/cirrhosis is an important clinical challenge. Substantial weight loss is
      accompanied by a marked attenuation of insulin resistance and related metabolic
      syndrome and, concomitantly, by a remarkable regression of liver steatosis in
      most patients, although increased inflammation may be detected in some subjects.
      Thus, NASH may be considered as another disease of affluence, as is the insulin
      resistance syndrome, and perhaps being part of it, especially in obese patients.

PMID- 12468417
TI  - Pharmacotherapy of obesity.
AB  - The growing recognition of the health risks of obesity coupled with the
      difficulties in treating it successfully by lifestyle modification predicates a
      need for effective drug treatment. The history of drug treatment in the second
      half of the 20th century is, however, one of disappointment and concern over drug
      toxicity. However, the advances in our understanding of the mechanism of weight
      control, together with improved ways of evaluating anti-obesity drugs, has
      resulted in two effective compounds, sibutramine and orlistat, becoming available
      for clinical use. Sibutramine has actions on both energy intake and expenditure
      and had been shown to enhance weight loss and weight maintenance achieved by
      diet, in simple obesity as well as when accompanied by complications of diabetes
      or hypertension. About 50-80% of patients can achieve a >5% loss, significantly
      more than if patients receive the same lifestyle intervention with placebo.
      Orlistat, which acts peripherally to block the absorption of dietary fat, has had
      similar results in clinical trials; a recent study (XENDOS) has just reported
      results which show that the enhanced, albeit modest, weight loss achieved with
      orlistat delays the development of diabetes over a 4-year period. A number of
      other compounds are expected to complete or enter clinical trials over the next
      decade. There is considerable optimism that we will soon have the pharmacological
      tools needed to make the treatment of obesity feasible.

PMID- 12468419
TI  - A finite element analysis methodology for representing the articular cartilage
      functional structure.
AB  - Recognising that the unique biomechanical properties of articular cartilage are a
      consequence of its structure, this paper describes a finite element methodology
      which explicitly represents this structure using a modified overlay element
      model. The validity of this novel concept was then tested by using it to predict
      the axial curling forces generated by cartilage matrices subjected to saline
      solutions of known molality and concentration in a novel experimental protocol.
      Our results show that the finite element modelling methodology accurately
      represents the intrinsic biomechanical state of the cartilage matrix and can be
      used to predict its transient load-carriage behaviour. We conclude that this
      ability to represent the intrinsic swollen condition of a given cartilage matrix
      offers a viable avenue for numerical analysis of degenerate articular cartilage
      and also those matrices affected by disease.

PMID- 12468420
TI  - Virtual power based algorithm for decoupling large motions from infinitesimal
      strains: application to shoulder joint biomechanics.
AB  - New trends of numerical models of human joints require more and more computation
      of both large amplitude joint motions and fine bone stress distribution.
      Together, these problems are difficult to solve and very CPU time consuming. The
      goal of this study is to develop a new method to diminish the calculation time
      for this kind of problems which include calculation of large amplitude motions
      and infinitesimal strains. Based on the Principle of Virtual Power, the present
      method decouples the problem into two parts. First, rigid body motion is
      calculated. The bone micro-deformations are then calculated in a second part by
      using the results of rigid body motions as boundary conditions. A finite element
      model of the shoulder was used to test this decoupling technique. The model was
      designed to determine the influence of humeral head shape on stress distribution
      in the scapula for different physiological motions of the joint. Two versions of
      the model were developed: a first version completely deformable and a second
      version based on the developed decoupling method. It was shown that biomechanical
      variables, as mean pressure and von Mises stress, calculated with the two
      versions were sensibly the same. On the other hand, CPU time needed for
      calculating with the new decoupled technique was more than 6 times less than with
      the completely deformable model.

PMID- 12468421
TI  - Multigrid block preconditioning for a coupled system of partial differential
      equations modeling the electrical activity in the heart.
AB  - The electrical activity of the heart may be modeled with a system of partial
      differential equations (PDEs) known as the bidomain model. Computer simulations
      based on these equations may become a helpful tool to understand the relationship
      between changes in the electrical field and various heart diseases. Because of
      the rapid variations in the electrical field, sufficiently accurate simulations
      require a fine-scale discretization of the equations. For realistic geometries
      this leads to a large number of grid points and consequently large linear systems
      to be solved for each time step. In this paper, we present a fully coupled
      discretization of the bidomain model, leading to a block structured linear
      system. We take advantage of the block structure to construct an efficient
      preconditioner for the linear system, by combining multigrid with an operator
      splitting technique.

PMID- 12468422
TI  - Feature-based, automated segmentation of cerebral infarct patterns using T2- and
      diffusion-weighted imaging.
AB  - Diffusion-weighted imaging enables the diagnosis of cerebral ischemias very
      early, thus supporting therapies such as thrombolysis. However, morphology and
      tissue-characterizing parameters (e.g. relaxation times or water diffusion) may
      vary strongly in ischemic regions, indicating different underlying pathologic
      processes. As the determination of the parameters by a supervised segmentation is
      very time consuming, we evaluated whether different infarct patterns may be
      segmented by an automated, multidimensional feature-based method using a unified
      segmentation procedure. Ischemias were classified into 5 characteristic patterns.
      For each class, a 3D histogram based on T(2)- and diffusion-weighted images as
      well as calculated apparent diffusion coefficients (ADC) was generated from a
      representative data set. Healthy and pathologic tissue classes were segmented in
      the histogram as separate, local density maxima with freely shaped borders.
      Segmentation control parameters were optimized in a 3-step procedure. The method
      was evaluated using synthetic images as well as results of a supervised
      segmentation. For the analysis of cerebral ischemias, the optimal control
      parameter set led to sensitivities and specificities between 1.0 and 0.9.

PMID- 12468423
TI  - A digital model for the venous junctions.
AB  - The venous network in the lower limbs is composed of a considerable number of
      confluent junctions. Each of these singularities introduces some blood flow
      disturbances. Each physiological junction is unique, in terms of its geometry as
      well as the blood flow rate. In order to account for this great variability, we
      developed a numerical model based on the use of the N3S code (a software package
      for solving Navier-Stokes equations). To test the validity of the model, one of
      the numerical simulations is compared with the data obtained in the corresponding
      experimental configuration. The velocity measurements were carried out with an
      ultrasonic pulsed Doppler velocimeter. We also measured pressure differences
      using differential sensors. The numerical computations were then used to obtain
      the values of the flow variables at any point, with various geometrical and flow
      configurations. As far as the velocity field is concerned, a very marked three
      dimensional pattern with swirls was observed. The pressure evolution was also
      strongly disturbed, with a non-linear decrease. All these data indicate that
      confluence effects cannot be neglected when evaluating pressure decreases. With a
      tool of this kind, it is possible to accurately predict the disturbances
      associated with any geometrical configuration or any flow rate.

PMID- 12468424
TI  - Duodenal nonheme iron content correlates with iron stores in mice, but the
      relationship is altered by Hfe gene knock-out.
AB  - Hereditary hemochromatosis is a common iron-loading disorder found in populations
      of European descent. It has been proposed that mutations causing loss of function
      of HFE gene result in reduced iron incorporation into immature duodenal crypt
      cells. These cells then overexpress genes for iron absorption, leading to
      inappropriate cellular iron balance, a persistent iron deficiency of the duodenal
      mucosa, and increased iron absorption. The objective was to measure duodenal iron
      content in Hfe knock-out mice to test whether the mutation causes a persistent
      decrease in enterocyte iron concentration. In both normal and Hfe knock-out mice,
      duodenal nonheme iron content was found to correlate with liver iron stores (P
      <.001, r = 0.643 and 0.551, respectively), and this effect did not depend on
      dietary iron levels. However, duodenal iron content was reduced in Hfe knock-out
      mice for any given content of liver iron stores (P <.001).

PMID- 12468425
TI  - Therapeutic LMP1 polyepitope vaccine for EBV-associated Hodgkin disease and
      nasopharyngeal carcinoma.
AB  - Development of an epitope-based vaccination strategy designed to enhance Epstein
      Barr virus (EBV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) is increasingly
      being considered as a preferred approach for the treatment of EBV-associated
      relapsed Hodgkin disease (HD) and nasopharyngeal carcinoma (NPC). EBV-encoded
      latent membrane proteins, LMP1 and LMP2, are the only target antigens available
      for therapeutic augmentation of CTL responses in patients with HD and NPC. Here,
      we describe preclinical studies using a recombinant poxvirus vaccine that encodes
      a polyepitope protein comprising 6 HLA A2-restricted epitopes derived from LMP1.
      Human cells infected with this recombinant polyepitope construct were efficiently
      recognized by LMP1-specific CTL lines from HLA A2 healthy individuals.
      Furthermore, immunization of HLA A2/K(b) mice with this polyepitope vaccine
      consistently generated strong LMP1-specific CTL responses to 5 of the 6 epitopes,
      which were readily detected by both ex vivo and in vitro assays. More important,
      this polyepitope vaccine successfully reversed the outgrowth of LMP1-expressing
      tumors in HLA A2/K(b) mice. These studies provide an important platform for the
      development of an LMP-based polyepitope vaccine as an immunotherapeutic tool for
      the treatment of EBV-associated HD and NPC.

PMID- 12468426
TI  - B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease
      progression.
AB  - The ligation of programmed death-ligand 1 (B7-H1) to T cells results in the
      preferential production of interleukin 10 (IL-10). We investigated if B7-H1 would
      be up-regulated in HIV infection, a disease characterized by increased IL-10
      production, by measuring B7-H1, B7-1 (CD80), and B7-2 (CD86) expression and mRNA
      in 36 HIV-infected patients and in 22 healthy controls (HCs). Results showed that
      (1) B7-H1 expression and mRNA are augmented in cells of HIV patients; (2)
      increased IL-10 production in these patients is largely induced by B7-H1
      expressing CD14(+) cells; (3) an inverse correlation is detected between B7-H1
      expression and CD4 counts, whereas the up-regulation of B7-H1 is directly
      associated with HIV plasma viremia; (4) antiviral therapy results in the parallel
      down modulation of IL-10 production and B7-H1 expression/synthesis; and (5) B7
      H1/CD80 and B7-H1/CD86 mRNA ratios are increased in peripheral blood mononuclear
      cells (PBMCs) of HIV patients compared with HCs. B7-H1 synthesis and expression
      are up-regulated in HIV infection, and the degree of dysregulation correlates
      with the severity of disease. Aberrant antigen presentation by antigen-presenting
      cells (APCs) that exhibit increased B7-H1 expression and IL-10 production in HIV
      infection could be responsible for T-lymphocyte unresponsiveness and loss of
      protective immunity. B7-H1 is a surrogate marker potentially involved in AIDS
      disease progression.

PMID- 12468427
TI  - Detection, isolation, and stimulation of quiescent primitive leukemic progenitor
      cells from patients with acute myeloid leukemia (AML).
AB  - Although many acute myeloid leukemia (AML) colony-forming cells (CFCs) and long
      term culture-initiating cells (LTC-ICs) directly isolated from patients are
      actively cycling, quiescent progenitors are present in most samples. In the
      current study, (3)H-thymidine ((3)H-Tdr) suicide assays demonstrated that most
      NOD/SCID mouse leukemia-initiating cells (NOD/SL-ICs) are quiescent in 6 of 7 AML
      samples. AML cells in G(0), G(1), and S/G(2)+M were isolated from 4 of these
      samples using Hoechst 33342/pyroninY staining and cell sorting. The progenitor
      content of each subpopulation was consistent with the (3)H-Tdr suicide results,
      with NOD/SL-ICs found almost exclusively among G(0) cells while the cycling
      status of AML CFCs and LTC-ICs was more heterogeneous. Interestingly, after 72
      hours in serum-free culture with or without Steel factor (SF), Flt-3 ligand (FL),
      and interleukin-3 (IL-3), most G(0) AML cells entered active cell cycle
      (percentage of AML cells remaining in G(0) at 72 hours, 1.2% to 37%, and 0% to
      7.6% in cultures without and with growth factors [GFs], respectively) while G(0)
      cells from normal lineage-depleted bone marrow remained quiescent in the absence
      of GF. All 4 AML samples showed evidence of autocrine production of 2 or more of
      SF, FL, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In
      addition, 3 of 4 samples contained an internal tandem duplication of the FLT3
      gene. In summary, quiescent leukemic cells, including NOD/SL-ICs, are present in
      most AML patients. Their spontaneous entry into active cell cycle in short-term
      culture might be explained by the deregulated GF signaling present in many AMLs.

PMID- 12468428
TI  - A novel I-branching beta-1,6-N-acetylglucosaminyltransferase involved in human
      blood group I antigen expression.
AB  - The human blood group i and I antigens are determined by linear and branched poly
      N-acetyllactosamine structures, respectively. In erythrocytes, the fetal i
      antigen is converted to the adult I antigen by I-branching beta-1,6-N
      acetylglucosaminyltransferase (IGnT) during development. Dysfunction of the I
      branching enzyme may result in the adult i phenotype in erythrocytes. However,
      the I gene responsible for blood group I antigen has not been fully confirmed. We
      report here a novel human I-branching enzyme, designated IGnT3. The genes for
      IGnT1 (reported in 1993), IGnT2 (also presented in this study), and IGnT3 consist
      of 3 exons and share the second and third exons. Bone marrow cells preferentially
      expressed IGnT3 transcript. During erythroid differentiation using CD34(+) cells,
      IGnT3 was markedly up-regulated with concomitant decrease in IGnT1/2. Moreover,
      reticulocytes expressed the IGnT3 transcript, but IGnT1/2 was below detectable
      levels. By molecular genetic analyses of an adult i pedigree, individuals with
      the adult i phenotype were revealed to have heterozygous alleles with mutations
      in exon 2 (1006G>A; Gly336Arg) and exon 3 (1049G>A; Gly350Glu), respectively, of
      the IGnT3 gene. Chinese hamster ovary (CHO) cells transfected with each mutated
      IGnT3 cDNA failed to express I antigen. These findings indicate that the
      expression of the blood group I antigen in erythrocytes is determined by a novel
      IGnT3, not by IGnT1 or IGnT2.

PMID- 12468429
TI  - Shear stress inhibits adhesion molecule expression in vascular endothelial cells
      induced by coculture with smooth muscle cells.
AB  - Vascular endothelial cells (ECs), which exist in close proximity to vascular
      smooth muscle cells (SMCs), are constantly subjected to blood flow-induced shear
      stress. Although the effect of shear stress on endothelial biology has been
      extensively studied, the influence of SMCs on endothelial response to shear
      stress remains largely unexplored. We examined the potential role of SMCs in
      regulating the shear stress-induced gene expression in ECs, using a parallel
      plate coculture flow system in which these 2 types of cells were separated by a
      porous membrane. In this coculture system, SMCs tended to orient perpendicularly
      to the flow direction, whereas the ECs were elongated and aligned with the flow
      direction. Under static conditions, coculture with SMCs induced EC gene
      expression of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion
      molecule-1 (VCAM-1), and E-selectin, while attenuating EC gene expression of
      endothelial nitric oxide synthase (eNOS). Shear stress significantly inhibited
      SMC-induced adhesion molecule gene expression. These EC responses under static
      and shear conditions were not observed in the absence of close communication
      between ECs and SMCs, and they were also not observed when ECs were cocultured
      with fibroblasts instead of SMCs. Our findings indicate that under static
      conditions, coculture with SMCs induces ICAM-1, VCAM-1, and E-selectin gene
      expression in ECs. These coculture effects are inhibited by shear stress and
      require specific interaction between ECs and SMCs in close contact.

PMID- 12468430
TI  - PECAM-1-dependent neutrophil transmigration is independent of monolayer PECAM-1
      signaling or localization.
AB  - Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), a tyrosine
      phosphoprotein highly expressed on endothelial cells and leukocytes, is an
      important component in the regulation of neutrophil transendothelial migration.
      Engagement of endothelial PECAM-1 activates tyrosine phosphorylation events and
      evokes prolonged calcium transients, while homophilic engagement of neutrophil
      PECAM-1 activates leukocyte beta-integrins. Although PECAM-1 modulates
      polymorphoneutrophil transmigration via homophilic PECAM-1-PECAM-1 interaction,
      the mechanisms underlying endothelial PECAM-1 function are unknown. Proposed
      mechanisms include (1) formation of a haptotactic gradient that "guides"
      neutrophils to the cell-cell border, (2) service as a "passive ligand" for
      neutrophil PECAM-1, ultimately mediating activation of neutrophil beta integrins,
      (3) regulation of endothelial calcium influx, and (4) mediation of SH2 protein
      association, and/or (5) catenin and non-SH2 protein interaction. Utilizing PECAM
      1-null "model" endothelial cells (REN cells), we developed a neutrophil
      transmigration system to study PECAM-1 mutations that specifically disrupt PECAM
      1-dependent signaling and/or PECAM-1 cell localization. We report that
      interleukin-1 beta (IL-1 beta) elicits PECAM-1-dependent transmigration that
      requires homophilic PECAM-PECAM-1 engagement, but not heterophilic neutrophil
      PECAM-1 interactions, and is intercellular adhesion molecule-1 dependent.
      Conversely, whereas IL-8 and leukotriene-B(4)-mediated transmigration is PECAM-1
      independent, PECAM-1 and IL-8-dependent transmigration represent separable and
      additive components of cytokine-induced transmigration. Surprisingly, neither
      monolayer PECAM-1-regulated calcium signaling, cell border localization, nor the
      PECAM-1 cytoplasmic domain was required for monolayer PECAM-1 regulation of
      neutrophil transmigration. We conclude that monolayer (endothelial cell) PECAM-1
      functions as a passive homophilic ligand for neutrophil PECAM-1, which after
      engagement leads to neutrophil signal transduction, integrin activation, and
      ultimately transmigration in a stimulus-specific manner.

PMID- 12468431
TI  - Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating
      factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells.
AB  - Granulocyte colony-stimulating factor (G-CSF) is the major regulator of
      neutrophil production. Studies in cell lines have established that conserved
      tyrosines Tyr704, Tyr729, Tyr744, Tyr764 within the cytoplasmic domain of G-CSF
      receptor (G-CSF-R) contribute significantly to G-CSF-induced proliferation,
      differentiation, and cell survival. However, it is unclear whether these
      tyrosines are equally important under more physiologic conditions. Here, we
      investigated how individual G-CSF-R tyrosines affect G-CSF responses of primary
      myeloid progenitors. We generated G-CSF-R-deficient mice and transduced their
      bone marrow cells with tyrosine "null" mutant (m0), single tyrosine "add-back"
      mutants, or wild-type (WT) receptors. G-CSF-induced responses were determined in
      primary colony assays, serial replatings, and suspension cultures. We show that
      removal of all tyrosines had no major influence on primary colony growth.
      However, adding back Tyr764 strongly enhanced proliferative responses, which was
      reverted by inhibition of ERK activity. Tyr729, which we found to be associated
      with the suppressor of cytokine signaling, SOCS3, had a negative effect on colony
      formation. After repetitive replatings, the clonogenic capacities of cells
      expressing m0 gradually dropped compared with WT. The presence of Tyr729, but
      also Tyr704 and Tyr744, both involved in activation of signal transducer and
      activator of transcription 3 (STAT3), further reduced replating efficiencies.
      Conversely, Tyr764 greatly elevated the clonogenic abilities of myeloid
      progenitors, resulting in a more than 10(4)-fold increase of colony-forming cells
      over m0 after the fifth replating. These findings suggest that tyrosines in the
      cytoplasmic domain of G-CSF-R, although dispensable for G-CSF-induced colony
      growth, recruit signaling mechanisms that regulate the maintenance and outgrowth
      of myeloid progenitor cells.

PMID- 12468432
TI  - Hematopoietic capacity of connexin43 wild-type and knock-out fetal liver cells
      not different on wild-type stroma.
AB  - In 1995 and 1997 we proposed that gap junctions between stromal and hematopoietic
      cells formed by connexin43 (Cx43) determine hematopoiesis. If this were the case,
      are the critical gap junctions in this regard those between hematopoietic and
      stromal cells, or those between stromal cells alone? To test the first
      possibility, we compared hematopoietic repopulating capacity between fetal liver
      hematopoietic cells expressing the different mouse Cx43 genotypes, wild type
      (WT), hemizygous, or knock-out (KO) on WT host mice stroma. We deleted host
      glucose phosphate isomerase 1(a) (Gpi-1(a)) stems and then raced identifiable
      Cx43 WT host fetal liver against congenic donor Cx43 WT, hemizygous, or KO cells
      in sets, comparing their capacity to form 5 end cells. Hematopoietic capacity did
      not differ between the Cx43 WT and KO genotypes. The role of Cx43 gap junctions
      in hematopoiesis remains uncertain.

PMID- 12468433
TI  - Suppression of myeloid transcription factors and induction of STAT response genes
      by AML-specific Flt3 mutations.
AB  - The receptor tyrosine kinase Flt3 is expressed and functionally important in
      early myeloid progenitor cells and in the majority of acute myeloid leukemia
      (AML) blasts. Internal tandem duplications (ITDs) in the juxtamembrane domain of
      the receptor occur in 25% of AML cases. Previously, we have shown that these
      mutations activate the receptor and induce leukemic transformation. In this
      study, we performed genome-wide parallel expression analyses of 32Dcl3 cells
      stably transfected with either wild-type or 3 different ITD isoforms of Flt3.
      Comparison of microarray expression analyses revealed that 767 of 6586 genes
      differed in expression between FLT3-WT- and FLT3-ITD-expressing cell lines. The
      target genes of mutationally activated Flt3 resembled more closely those of the
      interleukin 3 (IL-3) receptor than those of ligand-activated Flt3. The serine
      threonine kinase Pim-2 was up-regulated on the mRNA and the protein level in Flt3
      ITD-expressing cells. Further experiments indicated that Pim-2 function was
      important for clonal growth of 32D cells. Several genes repressed by the
      mutations were found to be involved in myeloid gene regulation. Pu.1 and
      C/EBPalpha, both induced by ligand-activation of wild-type Flt3, were suppressed
      in their expression and function by the Flt3 mutations. In conclusion, internal
      tandem duplication mutations of Flt3 activate transcriptional programs that
      partially mimic IL-3 activity. Interestingly, other parts of the transcriptional
      program involve novel, IL-3-independent pathways that antagonize differentiation
      inducing effects of wild-type Flt3. The identification of the transcriptional
      program induced by ITD mutations should ease the development of specific
      therapies.

PMID- 12468434
TI  - Role of the WT1 tumor suppressor in murine hematopoiesis.
AB  - The WT1 tumor-suppressor gene is expressed by many forms of acute myeloid
      leukemia. Inhibition of this expression can lead to the differentiation and
      reduced growth of leukemia cells and cell lines, suggesting that WT1 participates
      in regulating the proliferation of leukemic cells. However, the role of WT1 in
      normal hematopoiesis is not well understood. To investigate this question, we
      have used murine cells in which the WT1 gene has been inactivated by homologous
      recombination. We have found that cells lacking WT1 show deficits in
      hematopoietic stem cell function. Embryonic stem cells lacking WT1, although
      contributing efficiently to other organ systems, make only a minimal contribution
      to the hematopoietic system in chimeras, indicating that hematopoietic stem cells
      lacking WT1 compete poorly with healthy stem cells. In addition, fetal liver
      cells lacking WT1 have an approximately 75% reduction in erythroid blast-forming
      unit (BFU-E), erythroid colony-forming unit (CFU-E), and colony-forming unit
      granulocyte macrophage-erythroid-megakaryocyte (CFU-GEMM). However,
      transplantation of fetal liver hematopoietic cells lacking WT1 will repopulate
      the hematopoietic system of an irradiated adult recipient in the absence of
      competition. We conclude that the absence of WT1 in hematopoietic cells leads to
      functional defects in growth potential that may be of consequence to leukemic
      cells that have alterations in the expression of WT1.

PMID- 12468435
TI  - Short-term injection of antiapoptotic cytokine combinations soon after lethal
      gamma -irradiation promotes survival.
AB  - Recovery from radiation-induced (RI) myelosuppression depends on hematopoietic
      stem and progenitor cell survival and the active proliferation/differentiation
      process, which requires early cytokine support. Single cytokine or late-acting
      growth factor therapy has proved to be inefficient in ensuring reconstitution
      after severe RI damage. This work was aimed at evaluating the in vivo survival
      effect of combinations of early-acting cytokines whose antiapoptotic activity has
      been demonstrated in vitro: stem cell factor (SCF [S]), FMS-like tyrosine kinase
      3 ligand (FLT-3 ligand [F]), thrombopoietin (TPO [T]), interleukin-3 (IL-3 [3]),
      and stromal derived factor-1 (SDF-1). B6D2F1 mice underwent total body
      irradiation at 8 Gy cesium Cs 137 gamma radiation (ie, lethal dose 90% at 30
      days) and were treated soon after irradiation, at 2 hours and at 24 hours, with
      recombinant murine cytokines, each given intraperitoneally at 50 microg/kg per
      injection. All treatments induced 30-day survival rates significantly higher than
      control (survival rate, 8.3%). 4F (SFT3) and 5F (4F + SDF-1) were the most
      efficient combinations (81.2% and 87.5%, respectively), which was better than 3F
      (SFT, 50%), TPO alone (58.3%), and SDF-1 alone (29.2%) and also better than 4F
      given at 10 microg/kg per injection (4F10, 45.8%) or as a 50 microg/kg single
      injection at 2 hours (4Fs, 62.5%). Despite delayed death occurring mainly from
      day 150 on and possible long-term hematopoiesis impairment, half the 30-day
      protective effects of 4F and 5F were preserved at 300 days. Our results show that
      short- and long-term survival after irradiation depends on appropriate multiple
      cytokine combinations and at optimal concentrations. The proposal is made that an
      emergency cytokine regimen could be applied to nuclear accident victims as part
      of longer cytokine treatment, cell therapy, or both.

PMID- 12468436
TI  - Quantitative real-time RT-PCR analysis of PML-RAR alpha mRNA in acute
      promyelocytic leukemia: assessment of prognostic significance in adult patients
      from intergroup protocol 0129.
AB  - The potential prognostic value of quantitative real-time reverse transcription
      polymerase chain reaction (RT-PCR [qrtPCR]) measurements of PML-RAR alpha mRNA in
      acute promyelocytic leukemia was retrospectively assessed before treatment and at
      3 posttreatment intervals in 123 patients on intergroup protocol 0129. The
      primary measure was the PML-RAR alpha(GAPDH) normalized quotient (NQ), that is,
      PML-RAR alpha mRNA copies divided by glyceraldehyde-3'-phosphate dehydrogenase
      (GAPDH) mRNA copies. Only samples with more than 2.5 x 10(5) copies of the
      housekeeping gene GAPDH mRNA (detection sensitivity exceeding 10(4)) were
      considered NQ evaluable. With RNA from low-density selected cells, paired
      peripheral blood (PB) and bone marrow samples (n = 140) had comparable NQs (P
      <.001). Before treatment, high NQ was associated with short-form PML-RAR alpha (P
      <.001), but not with white blood cell count or clinical outcome. Following
      treatment, NQ was lower in all-trans retinoic acid-induced complete remission
      (CR) than chemotherapy-induced CR (P =.018) and at first test after consolidation
      chemotherapy (P =.037). After consolidation chemotherapy, patients with NQ
      exceeding 10(-5) had 4.1-fold increased relapse risk (P =.008); however, 73% of
      patients who experienced relapse had NQ lower than 10(-5). In the follow-up
      period (FUP), any NQ exceeding 10(-5) and 10(-6) had 17.5-fold and 7.6-fold
      increased relapse risk, respectively (P <.001), while no gradation of relapse
      risk (approximately 18%) could be identified at NQ lower than 10(-6), including
      NQ(-). These results indicate that qrtPCR monitoring of PML-RAR alpha NQ can
      identify patients at high risk of relapse and suggest that clinically practical
      PB NQ monitoring at more frequent FUP intervals may improve predictive accuracy
      for relapse or continuing CR in patients with persistent, fluctuating minimal
      residual disease levels.

PMID- 12468437
TI  - Pathogenic molds (including Aspergillus species) in hospital water distribution
      systems: a 3-year prospective study and clinical implications for patients with
      hematologic malignancies.
AB  - The incidence of mold infections in patients with hematologic malignancies
      continues to increase despite the widespread use of air filtration systems,
      suggesting the presence of other hospital sources for these molds. Water sources
      are known to harbor pathogenic molds. We examined samples from water, water
      surfaces, air, and other environment sources from a bone marrow transplantation
      unit with optimal air precautions. Molds (Aspergillus species, others) were
      recovered in 70% of 398 water samples, in 22% of 1311 swabs from plumbing
      structures and environmental surfaces, and in 83% of 274 indoor air samples.
      Microscopic examination of the water plumbing lines revealed hyphal forms
      compatible with molds. Four findings suggest that indoor airborne molds were
      aerosolized from the water: (1) higher mean airborne concentrations of molds in
      bathrooms (16.1 colony-forming units [CFU]/m(3)) than in patient rooms (7
      CFU/m(3)) and hallways (8.6 CFU/m(3); P =.00005); (2) a strong type and rank
      correlation between molds isolated from hospital water and those recovered from
      indoor hospital; (3) lack of seasonal correlation between the airborne mold
      concentration in outdoor and indoor air; and (4) molecular relatedness between a
      clinical strain and a water-related strain (previously reported). Hospital water
      distribution systems may serve as a potential indoor reservoir of Aspergillus and
      other molds leading to aerosolization of fungal spores and potential exposure for
      patients.

PMID- 12468438
TI  - CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia
      patients with poor-risk karyotype associated with NRAS mutation, but not
      associated with FLT3 internal tandem duplication.
AB  - The etiology of acute myeloid leukemia (AML) is largely unknown. Biologic and
      epidemiologic data implicate exogenous toxicants, including cytotoxic drugs,
      benzene, radiation, and cigarette smoking. Allelic variation in genes encoding
      enzymes such as NADP(H) quinone oxidoreductase (NQO1) and glutathione S
      transferase T1 (GSTT1) that metabolize environmental toxicants predispose to
      subtypes of AML, including therapy-related AML. We assayed NRAS oncogene mutation
      and FLT3 internal tandem duplication in 447 AML patients with an abnormal
      karyotype treated in Medical Research Council (MRC) AML clinical trials.
      Functional allelic variant frequencies in genes encoding carcinogen-metabolizing
      enzymes GSTT1, GSTM1, CYP1A1, CYP2D6, CYP2C19, SULT1A1, and NQO1 were previously
      determined for this cohort. FLT3 internal tandem duplication (ITD) frequency was
      17%, and NRAS mutation 12% for the entire cohort. The 2 mutations were found
      together in only 4 patients. No association was found between enzyme allelic
      variant frequencies and the presence of FLT3 ITD for the entire cohort or within
      cytogenetic subgroups. CYP1A1*2B (Val) high-inducibility variant allele was
      overrepresented in patients with NRAS mutation compared with no mutation, for (1)
      the entire AML cohort (n = 8/53 vs 26/371; odds ratio [OR] = 2.36; 95% confidence
      interval [CI] 1.01-5.53) and (2) the poor-risk karyotype group (n = 6/14 vs 4/89;
      OR = 15.94; 95% CI 3.71-68.52) comprising patients with partial/complete deletion
      of chromosome 5 or 7, or abnormalities of chromosome 3. The CYP1A1*2B allele may
      predispose to the development of these subgroups of AML by augmented phase 1
      metabolism to highly reactive intermediates of CYP1A1 substrates, including
      polycyclic aromatic hydrocarbons, or by generation of oxidative stress as a
      metabolic by-product.

PMID- 12468439
TI  - Vascular component of airway remodeling in asthma is reduced by high dose of
      fluticasone.
AB  - We conducted a randomized, double-blind, parallel-group study to assess the
      effect of 6 weeks treatment with low-dose (100 microg twice a day) or high-dose
      (500 microg twice a day) inhaled fluticasone propionate (FP) on the vascular
      component of airway remodeling in 30 patients with mild to moderate asthma. We
      also studied the effect on the inflammatory cells and the basement membrane
      thickness, and we compared findings from bronchial biopsies taken in patients
      with asthma with those in eight control subjects. Bronchial responsiveness to
      methacholine and asthma symptom score were measured before and after treatments.
      Eight patients in the low-dose FP group and eight patients in high-dose FP group
      completed the study. At baseline, patients with asthma showed an increase in the
      number of vessels and in vascular area as compared with control subjects. In the
      subjects with asthma, number of vessels correlated with vascular area (p < 0.01)
      and with number of mast cells (p < 0.01). Bronchial responsiveness to
      methacholine, asthma symptom score, and inflammatory cells decreased
      significantly after both low- and high-dose FP (p < 0.05). However, the number of
      vessels, the vascular area, and the basement membrane thickness decreased only
      after high-dose FP (p < 0.05). In conclusion, this study shows that in patients
      with mild to moderate asthma, high dose of inhaled FP given over 6 weeks can
      significantly affect airway remodeling by reducing both submucosal vascularity
      and basement membrane thickness.

PMID- 12468440
TI  - Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl
      transpeptidase-deficient mice.
AB  - To investigate repair mechanisms in bleomycin-induced pulmonary fibrosis, we used
      mice deficient in gamma-glutamyl transpeptidase (GGT-/-), a key enzyme in
      glutathione (GSH) and cysteine metabolism. Seventy-two hours after bleomycin
      (0.03 U/g), GGT-/- mice displayed a different inflammatory response to wild-type
      mice as judged by a near absence of neutrophils in lung tissue and
      bronchoalveolar lavage and a less pronounced rise in matrix metalloproteinase-9.
      Inflammation in GGT-/- mice consisted mainly of lymphocytes and macrophages. At 1
      month, lungs from bleomycin-treated GGT-/- mice exhibited minimal areas of
      fibrosis compared with wild-type mice(light microscopy fibrosis index: 510 +/-
      756 versus 1975 +/- 817, p < 0.01). Lung collagen content revealed a significant
      increase in bleomycin-treated wild-type (15.1 +/- 3.8 versus 8.5 +/- 0.7 microg
      hydroxy(OH)-proline/mg dry weight, p < 0.01) but not in GGT-/- (10.4 +/- 1.7
      versus 8.8 +/- 0.8). Control lungs from GGT-/- showed a significant reduction of
      cysteine (0.03 +/- 0.005 versus 0.055 +/- 0.001, p < 0.02) and GSH levels (1.24
      +/- 0.055 versus 1.79 +/- 0.065, p < 0.002). These values decreased after 72
      hours of bleomycin in both GGT-/- and wild-type but reached their respective
      control values after 1 month. Supplementation with N-acetyl cysteine partially
      ameliorated the effects of GGT deficiency. These findings suggest that increased
      neutrophils and matrix metalloproteinase-9 during the early inflammatory response
      and adequate thiol reserves are key elements in the fibrotic response after
      bleomycin-induced pulmonary injury.

PMID- 12468442
TI  - Pressor response to chemoreflex activation before and after microinjection of
      glycine into the NTS of awake rats.
AB  - Microinjection of glycine into the rostral (bilateral) and caudal (midline)
      commissural nucleus of the solitary tract (NTS) using three guide cannulas
      implanted in the direction of these sites produced an increase in mean arterial
      pressure (MAP) and abolished the pressor response to chemoreflex activation
      [potassium cyanide (n = 7)]. Strychnine, a glycine receptor antagonist,
      attenuated the increase in MAP, and in this new experimental condition (n = 5)
      the pressor response to chemoreflex activation was not altered. Considering that
      the effect of glycine on the attenuation of the pressor response to chemoreflex
      activation could be secondary to the increase in baseline MAP, in a third group
      of rats (n = 5) sodium nitroprusside infusion (intravenous) after microinjections
      of glycine into the NTS normalizes MAP. In this case, the pressor response to
      chemoreflex activation was similar to the control. These data show that glycine
      when microinjected bilaterally into the lateral commissural NTS as well as into
      the medial commissural NTS plays no major inhibitory role in the processing of
      the neurotransmission of the sympathoexcitatory component of the chemoreflex.

PMID- 12468443
TI  - Maturation depresses mouse cerebrovascular tone through endothelium-dependent
      mechanisms.
AB  - In light of previous observations that the range of arterial pressures over which
      cerebral blood flow is autoregulated differs dramatically in neonates and adults,
      the present experiments explored the hypothesis that pressure-induced intrinsic
      arterial tone is regulated differently in neonatal and adult cerebral arteries.
      In cannulated and pressurized endothelium-intact mouse cerebral arteries <150
      microm in diameter, active intrinsic tone was evident at intraluminal pressures
      as low as 10 mmHg in neonatal arteries, but only at pressures of 60 mmHg or
      greater in adult arteries. Administration of 10 microM indomethacin produced no
      significant effect on tone at any pressure in either neonatal or adult arteries,
      but subsequent addition of 100 microroarginine methyl ester (NAME) significantly
      vasoconstricted both neonatal and adult arteries at all pressures. Conversely,
      administration of 100 microE alone significantly vasoconstricted adult arteries
      only, and subsequent addition of 10 microomethacin produced a significant
      additional vasoconstriction in adult arteries only, indicating an important
      interaction between the nitric oxide synthase and cyclooxygenase pathways, at
      least in adult arteries. In the presence of both indomethacin and NAME, intrinsic
      tone was significantly greater in neonatal than adult arteries, but when the
      endothelium was removed, tone was similar in neonatal and adult arteries at all
      pressures. Together, these results suggest that pressure-induced myogenic tone is
      regulated similarly in neonatal and adult mouse cerebral arteries but that the
      contribution of endothelial vasoactive factors to intrinsic tone is highly age
      dependent.

PMID- 12468444
TI  - Peptides that regulate food intake: separable mechanisms for dorsal hindbrain
      CART peptide to inhibit gastric emptying and food intake.
AB  - We investigated whether dorsal hindbrain and/or peripheral cocaine- and
      amphetamine-regulated transcript peptide (CARTp) acts to suppress gastric
      emptying of a caloric stimulus. Furthermore, effects of dorsal hindbrain CARTp on
      sucrose consumption and licking microstructure was studied, as well as the
      possible contribution of corticotropin-releasing factor (CRF) receptors to
      mediate effects of CARTp downstream on emptying and sucrose intake. Rats bearing
      gastric fistulas received intragastric infusions (1.0 ml/min) of 12 ml 12.5%
      glucose. Gastric samples were withdrawn immediately after the intragastric
      infusion to reflect emptying during gastric fill. CARTp injected in the fourth
      ventricle intracerebroventricularly (0.5 and 1.0 microg) suppressed gastric
      emptying. CARTp reduced sucrose intake at similar doses and altered a variety of
      lick microstructure variables (no. of licks, bursts, clusters, licks/burst,
      licks/clusters, interlick interval, first meal size, and first meal duration).
      Pretreatment with the CRF antagonist alpha-helical CRF-(9-41) blocked the effect
      of 1.0 microg CARTp on gastric emptying but not on sucrose consumed or on any of
      the licking microstructure parameters. These data demonstrate differential
      mediation of the feeding and gastric inhibitory effects of CARTp and suggest that
      CARTp-induced inhibition of gastric emptying does not contribute to this
      peptide's ability to inhibit food intake.

PMID- 12468445
TI  - Combating diabetes.

PMID- 12468446
TI  - New weapons to combat an ancient disease: treating diabetes.

PMID- 12468447
TI  - Protein tyrosine nitration and peroxynitrite: reply.

PMID- 12468448
TI  - Transgenic plants expressing antibodies: a model for phytoremediation.
AB  - The feasibility of using antibody expressing transgenic plants either to
      neutralize bioactive molecules in the rhizosphere, or to accumulate and
      concentrate the molecules in leaves has been demonstrated in a model system
      consisting of hydroponic Nicotiana plant cultures expressing a murine monoclonal
      IgG1. Two transgenic plant types were used; in the first, functional antibody was
      rhizosecreted and shown to bind with antigen in the surrounding medium to form an
      immune complex. In the second, a transmembrane sequence retained monoclonal
      antibody in the plants, on the plasma membrane. Antigen added to the nutrient
      medium around the roots of mIgG plants was transported within 24 h to the topmost
      leaves of the plant where it was sequestered as an immune complex by binding to
      antibody on the cell membrane. Concentration of immune complex in the leaf tissue
      remained constant over a 72 h period after removal of antigen from nutrient
      medium. Free antigen was not detected in the leaves of wild-type plants. The two
      strategies of rhizosecretion-mediated binding and sequestration in leaf tissue
      could potentially be used in the phytoremediation of any pollutant for which it
      is possible to generate a monoclonal antibody.

PMID- 12468449
TI  - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation
      suppresses ischemic induction of Egr-1 and its inflammatory gene targets.
AB  - The peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor whose
      activation regulates metabolism and inflammation. Recent data indicate that the
      zinc finger transcription factor early growth response gene-1 (Egr-1) acts as a
      master switch for the inflammatory response in ischemic vessels. Experiments
      tested the hypothesis that activation of endogenous PPAR-gamma inhibits induction
      of Egr-1. Egr-1 is rapidly induced in murine lungs after ischemia-reperfusion, as
      well as in alveolar mononuclear phagocytes deprived of oxygen as an ischemic
      model. In vitro, the natural PPAR-gamma ligand (15-deoxy-Delta12,14-prostaglandin
      J2) and a PPAR-gamma activator (troglitazone), but not a PPAR-alpha activator
      (bezafibrate), strikingly diminished Egr-1 mRNA and protein expression and
      nuclear DNA binding activity corresponding to Egr-1. In vivo, treatment with
      troglitazone before ischemia prevented induction of Egr-1 and its target genes
      such as interleukin-1beta, monocyte chemotactic protein-1, and macrophage
      inflammatory protein-2. As a consequence of PPAR-gamma activation, pulmonary
      leukostasis was decreased and oxygenation and overall survival were improved.
      Activation of PPAR-gamma suppresses activation of Egr-1 and its inflammatory gene
      targets and provides potent protection against ischemic pulmonary injury. These
      data reveal a new mechanism whereby PPAR-gamma activation may decrease tissue
      inflammation in response to an ischemic insult.

PMID- 12468450
TI  - Behavioral conditioning of immunosuppression is possible in humans.
AB  - Behavioral conditioned immunosuppression has been described in rodents as the
      most impressive demonstration of brain-to-immune system interaction. To analyze
      whether behavioral conditioned immunosuppression is possible in humans, healthy
      subjects in this double-blind, placebo-controlled study were conditioned in four
      sessions over 3 consecutive days, receiving the immunosuppressive drug
      cyclosporin A as an unconditioned stimulus paired with a distinctively flavored
      drink (conditioned stimulus) each 12 h. In the next week, re-exposure to the
      conditioned stimulus (drink), but now paired with placebo capsules, induced a
      suppression of immune functions as analyzed by the IL-2 and IFN-gamma mRNA
      expression, intracellular production, and in vitro release of IL-2 and IFN-gamma,
      as well as lymphocyte proliferation. These data demonstrate for the first time
      that immunosuppression can be behaviorally conditioned in humans.

PMID- 12468451
TI  - Activation-regulated expression and chemotactic function of sphingosine 1
      phosphate receptors in mouse splenic T cells.
AB  - Sphingosine 1-phosphate (S1P) from platelets and macrophages stimulates migration
      and enhances survival of T cells. Mouse spleen CD4 and CD8 T cells are shown to
      express predominantly S1P1 (Edg-1) and S1P4 (Edg-6) G-protein-coupled receptors
      with only minimal representation of S1P2, S1P3, and S1P5. At and below plasma
      concentrations of healthy mammals (1 nM-1 microM), S1P evokes trans-Matrigel
      chemotaxis of mouse CD4 and CD8 T cells and recruits T cells into subcutaneous
      air pouches. T cell receptor-mediated activation of CD4 T cells suppresses
      expression of S1P1 and S1P4 receptors and eliminates their chemotactic responses
      to S1P. The immunoregulator FTY720, a structural homologue of S1P, lacks T cell
      chemotactic activity and competitively inhibits T cell chemotactic responses to
      S1P in vitro and in vivo. S1P may be a distinctive contributor to compartmental
      immunity by attracting naive and memory T cells preferentially over activated
      effector T cells.

PMID- 12468452
TI  - Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional
      coactivator PGC-1.
AB  - Endurance exercise induces increases in mitochondria and the GLUT4 isoform of the
      glucose transporter in muscle. Although little is known about the mechanisms
      underlying these adaptations, new information has accumulated regarding how
      mitochondrial biogenesis and GLUT4 expression are regulated. This includes the
      findings that the transcriptional coactivator PGC-1 promotes mitochondrial
      biogenesis and that NRF-1 and NRF-2 act as transcriptional activators of genes
      encoding mitochondrial enzymes. We tested the hypothesis that increases in PGC-1,
      NRF-1, and NRF-2 are involved in the initial adaptive response of muscle to
      exercise. Five daily bouts of swimming induced increases in mitochondrial enzymes
      and GLUT4 in skeletal muscle in rats. One exercise bout resulted in approximately
      twofold increases in full-length muscle PGC-1 mRNA and PGC-1 protein, which were
      evident 18 h after exercise. A smaller form of PGC-1 increased after exercise.
      The exercise induced increases in muscle NRF-1 and NRF-2 that were evident 12 to
      18 h after one exercise bout. These findings suggest that increases in PGC-1, NRF
      1, and NRF-2 represent key regulatory components of the stimulation of
      mitochondrial biogenesis by exercise and that PGC-1 mediates the coordinated
      increases in GLUT4 and mitochondria.

PMID- 12468453
TI  - Analysis of ecstasy (MDMA)-induced transcriptional responses in the rat cortex.
AB  - 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular drug of abuse.
      MDMA is pharmacologically classified as an entactogen because of its affinities
      to classical hallucinogens and stimulants. Oral ingestion of a single dose of the
      drug is associated with euphoria, elevated self-confidence, and heightened
      sensory awareness in humans. Evidence for neurotoxicity in the human serotonin (5
      HT) system has been provided. In rats, a single injection of MDMA induces
      hyperthermia and formation of reactive oxygen species. These effects may cause
      MDMA-associated, long-term 5-HT depletion, with the cortex being quite sensitive
      to the biochemical effects of MDMA. It has been suggested that these MDMA effects
      may be associated with molecular changes in this brain region. To test these
      ideas, we have made use of the cDNA array analysis, which can provide a more
      global view of the molecular changes secondary to MDMA injections. Our results
      show that the genes regulated by MDMA encode proteins that belong to signaling
      pathways, transcription regulators, or xenobiotic metabolism. Our observations
      indicate that cortical cells respond to the acute administration of MDMA by
      modulating transcription of several genes that might lead to long-term changes in
      the brain.

PMID- 12468454
TI  - Base excision repair capacity in mitochondria and nuclei: tissue-specific
      variations.
AB  - Base excision repair is the main pathway for repair of oxidative base lesions in
      DNA. Mammalian cells must maintain genomic stability in their nuclear and
      mitochondrial genomes, which have different degrees of vulnerability to DNA
      damage. This study quantifies DNA glycosylase activity in mitochondria and
      nucleus from C57/BL 6 mouse tissues including brain, liver, heart, muscle,
      kidney, and testis. The activities of oxoguanine DNA glycosylase (OGG1), uracil
      DNA glycosylase, and endonuclease III homologue 1 (NTH1) were measured using
      oligonucleotide substrates with DNA lesions specific for each glycosylase.
      Mitochondrial content was normalized to citrate synthase activity and
      mitochondrial function was assessed by measuring cytochrome c oxidase (COX)
      activity. In nuclear and mitochondrial extracts, the highest DNA glycosylase
      activities were in testis. Brain and heart, tissues with the highest oxidative
      load, did not have higher levels of OGG1 or NTH1 activity than muscle or kidney,
      which are more glycolytic tissues. In general, mitochondrial extracts have lower
      DNA glycosylase activity than nuclear extracts. There was no correlation between
      glycosylase activities in the mitochondrial extracts and COX activity, suggesting
      that DNA repair enzymes may be regulated by a mechanism different from this
      mitochondrial enzyme.

PMID- 12468455
TI  - Vascular PG-M/versican variants promote platelet adhesion at low shear rates and
      cooperate with collagens to induce aggregation.
AB  - We have identified a novel von Willebrand factor/fibrinogen/selectin-independent,
      platelet adhesion-promoting function of vascular PG-M/versicans that may be
      relevant in normal venous thrombosis and critical in atherosclerotic conditions.
      A purification scheme was devised to obtain vascular versicans, which by
      biochemical, immunochemical, and ultrastructural means were asserted to be 1)
      composed primarily of isoforms V1 and V2; 2) free of contaminants; 3) prevalently
      substituted with chondroitin-4-sulfate and dermatan sulfate (DS) chains; and 4)
      capable of binding hyaluronan to form link protein-stabilized ternary complexes.
      Real-time analysis of human platelet perfused under diverse shear forces showed
      that they largely failed to bind to several vascular and nonvascular
      proteoglycans (PGs). In contrast, they bound in a dose- and shear rate-dependent
      manner to vascular versicans, exhibiting a unique attachment-detachment kinetics
      and establishing a firm substrate tethering characterized with no significant
      aggregation. Digestion of these PGs with lyases and competition experiments with
      purified glycosaminoglycans revealed that platelet adhesion to vascular versicans
      was primarily mediated by their DS chains. Incorporation of the versicans into
      fibrillar collagen substrates augmented their adhesive activity and strongly
      promoted platelet aggregation at low and high shear rates. Affinity
      chromatography of platelet surfaces on DS columns identified a 120-140 kDa
      polypeptide complex that behaved as a specific vascular versican binding membrane
      ligand in solid-phase binding assays. These findings indicate that selective
      versican variants of the subendothelium may serve as ancillary
      GPIbalpha/integrin/selectin-independent platelet ligands in healthy and diseased
      vascular beds and may be directly responsible for the platelet accruing after
      rupture of atherosclerotic plaques.

PMID- 12468456
TI  - Regulation of the membrane estrogen receptor-alpha: role of cell density, serum,
      cell passage number, and estradiol.
AB  - We used modified immunocytochemical conditions to quantify a membrane form of
      estrogen receptor-alpha (mERalpha) in a rat pituitary tumor cell line,
      GH3/B6/F10. We studied the regulation of mERalpha vs. levels of intracellular
      ERalpha (iERalpha) using our 96-well plate immunoassay. The anti-ERalpha antibody
      C542 was used to label the ERalpha (via conjugated alkaline phosphatase) in fixed
      permeabilized (for iERalpha) vs. nonpermeabilized cells (for mERalpha).
      Expression of mERalpha was highest at low cell densities (<1000 cells/well) and
      decreased significantly at densities where cellular processes touched, whereas
      the more abundant iERalpha increased with increasing cell density over the same
      range. Serum starvation for 48 h caused increases in mERalpha, whereas iERalpha
      levels showed no significant changes. A large decline in mERalpha and iERalpha
      levels with cell passage number was observed. Minutes after nM 17beta-estradiol
      (E2) treatment, a portion of the cells rounded up and detached from the culture
      plate, whereas nM cholesterol had no such effect. Although E2 treatment did not
      change mERalpha levels, the antigen was reorganized from a fine particulate to
      aggregation into asymmetric large granules of staining. That common culturing
      conditions favor down-regulation of mERalpha may explain the relatively few
      reports of this protein in other experimental systems.

PMID- 12468457
TI  - Antibiotics for acute purulent rhinitis.

PMID- 12468458
TI  - Sensory stimulation in dementia.

PMID- 12468459
TI  - A clinical trials register for Europe.

PMID- 12468460
TI  - Drug eluting coronary stents.

PMID- 12468461
TI  - People with schizophrenia must have a say in their treatment.

PMID- 12468463
TI  - Smaller families aid economic growth, says UN report.

PMID- 12468467
TI  - Woman who had attended euthanasia workshop kills herself.

PMID- 12468471
TI  - Private doctors must improve their treatment of tuberculosis, says WHO.

PMID- 12468472
TI  - UK government approves heroin use on prescription.

PMID- 12468474
TI  - Paediatricians did not have duty of care to patient's mother.

PMID- 12468475
TI  - Health department to improve investigation of waiting list fiddles.

PMID- 12468478
TI  - Effectiveness of appropriately trained nurses in preoperative assessment:
      randomised controlled equivalence/non-inferiority trial.
AB  - OBJECTIVE: To determine whether preoperative assessments carried out by
      appropriately trained nurses are inferior in quality to those carried out by
      preregistration house officers. DESIGN: Randomised controlled equivalence/non
      inferiority trial. SETTING: Four NHS hospitals in three trusts. Three of the four
      were teaching hospitals. PARTICIPANTS: All patients attending for assessment
      before general anaesthesia for general, vascular, urological, or breast surgery
      between April 1998 and March 1999. INTERVENTION: Assessment by one of three
      appropriately trained nurses or by one of several preregistration house officers.
      MAIN OUTCOME MEASURES: History taken, physical examination, and investigations
      ordered. Measures evaluated by a specialist registrar in anaesthetics and placed
      in four categories: correct, overassessment, underassessment not affecting
      management, and underassessment possibly affecting management (primary outcome).
      RESULTS: 1907 patients were randomised, and 1874 completed the study; 926 were
      assessed by house officers and 948 by nurses. Overall 121/948 (13%) assessments
      carried out by nurses were judged to have possibly affected management compared
      with 138/926 (15%) of those performed by house officers. Nurses were judged to be
      non-inferior to house officers in assessment, although there was variation among
      them in terms of the quality of history taking. The house officers ordered
      considerably more unnecessary tests than the nurses (218/926 (24%) v 129/948
      (14%). CONCLUSIONS: There is no reason to inhibit the development of nurse led
      preoperative assessment provided that the nurses involved receive adequate
      training. However, house officers will continue to require experience in
      preoperative assessment.

PMID- 12468479
TI  - Withholding the artificial administration of fluids and food from elderly
      patients with dementia: ethnographic study.
AB  - OBJECTIVE: To clarify the practice of withholding the artificial administration
      of fluids and food from elderly patients with dementia in nursing homes. DESIGN:
      Qualitative, ethnographic study in two phases. SETTING: 10 wards in two nursing
      homes in the Netherlands. PARTICIPANTS: 35 patients with dementia, eight doctors,
      43 nurses, and 32 families. RESULTS: The clinical course of dementia was
      considered normal and was rarely reason to begin the artificial administration of
      fluids and food in advanced disease. Fluids and food seemed to be given mainly
      when there was an acute illness or a condition that needed medical treatment and
      which required hydration to be effective. The medical condition of the patient,
      the wishes of the family, and the interpretations of the patients' quality of
      life by their care providers were considered more important than living wills and
      policy agreements. CONCLUSIONS: Doctors' decisions about withholding the
      artificial administration of fluids and food from elderly patients with dementia
      are influenced more by the clinical course of the illness, the presumed quality
      of life of the patient, and the patient's medical condition than they are by
      advanced planning of care. In an attempt to understand the wishes of the patient
      doctors try to create the broadest possible basis for the decision making process
      and its outcome, mainly by involving the family.

PMID- 12468480
TI  - Informing participants of allocation to placebo at trial closure: postal survey.
AB  - OBJECTIVES: To assess whether and how investigators of placebo controlled
      randomised trials inform participants of their treatment allocation at trial
      closure and to assess barriers to feedback. DESIGN: Postal survey with a
      semistructured questionnaire. PARTICIPANTS: All investigators who published a
      placebo controlled randomised trial in 2000 in five leading medical journals, and
      a random sample of 120 trials listed in the national research register database.
      MAIN OUTCOME MEASURES: Number of investigators who informed participants of their
      treatment allocation at trial closure, methods for delivering the information,
      and barriers to unmasking treatment. RESULTS: 45% of investigators informed
      either all or most participants of their treatment allocation, and 55% did not
      inform any participant or only informed those who asked. The main reasons for not
      informing participants were that the investigators never considered this option
      (40%) or to avoid biasing results at study follow up (24%). CONCLUSION: Further
      research is required to examine sensitive ways to communicate treatment
      information to trial participants.

PMID- 12468481
TI  - Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of
      United Kingdom mortality data.

PMID- 12468482
TI  - Leflunomide can potentiate the anticoagulant effect of warfarin.

PMID- 12468483
TI  - Association between bacterial vaginosis or chlamydial infection and miscarriage
      before 16 weeks' gestation: prospective community based cohort study.
AB  - OBJECTIVES: To assess whether bacterial vaginosis or chlamydial infection before
      10 weeks' gestation is associated with miscarriage before 16 weeks. DESIGN:
      Prospective cohort study. SETTING: 32 general practices and five family planning
      clinics in south London. PARTICIPANTS: 1216 pregnant women, mean age 31,
      presenting before 10 weeks' gestation. MAIN OUTCOME MEASURE: Prevalence of
      miscarriage before 16 weeks' gestation. RESULTS: 121 of 1214 women (10.0%, 95%
      confidence interval 8.3% to 11.7%) miscarried before 16 weeks. 174 of 1201 women
      (14.5%, 12.5% to 16.5%) had bacterial vaginosis. Compared with women who were
      negative for bacterial vaginosis those who were positive had a relative risk of
      miscarriage before 16 weeks' gestation of 1.2 (0.7 to 1.9). Bacterial vaginosis
      was, however, associated with miscarriage in the second trimester at 13-15 weeks
      (3.5, 1.2 to 10.3). Only 29 women (2.4%, 1.5% to 3.3%) had chlamydial infection,
      of whom one miscarried (0.32, 0.04 to 2.30). CONCLUSION: Bacterial vaginosis is
      not strongly predictive of early miscarriage but may be a predictor after 13
      weeks' gestation. The prevalence of Chlamydia was too low to assess the risk, but
      it is unlikely to be a major risk factor in pregnant women.

PMID- 12468484
TI  - Food allergy.

PMID- 12468485
TI  - Do short courses in evidence based medicine improve knowledge and skills?
      Validation of Berlin questionnaire and before and after study of courses in
      evidence based medicine.
AB  - OBJECTIVE: To develop and validate an instrument for measuring knowledge and
      skills in evidence based medicine and to investigate whether short courses in
      evidence based medicine lead to a meaningful increase in knowledge and skills.
      DESIGN: Development and validation of an assessment instrument and before and
      after study. SETTING: Various postgraduate short courses in evidence based
      medicine in Germany. PARTICIPANTS: The instrument was validated with experts in
      evidence based medicine, postgraduate doctors, and medical students. The effect
      of courses was assessed by postgraduate doctors from medical and surgical
      backgrounds. INTERVENTION: Intensive 3 day courses in evidence based medicine
      delivered through tutor facilitated small groups. MAIN OUTCOME MEASURE: Increase
      in knowledge and skills. RESULTS: The questionnaire distinguished reliably
      between groups with different expertise in evidence based medicine. Experts
      attained a threefold higher average score than students. Postgraduates who had
      not attended a course performed better than students but significantly worse than
      experts. Knowledge and skills in evidence based medicine increased after the
      course by 57% (mean score before course 6.3 (SD 2.9) v 9.9 (SD 2.8), P<0.001). No
      difference was found among experts or students in absence of an intervention.
      CONCLUSIONS: The instrument reliably assessed knowledge and skills in evidence
      based medicine. An intensive 3 day course in evidence based medicine led to a
      significant increase in knowledge and skills.

PMID- 12468486
TI  - Withdrawing life support and resolution of conflict with families.

PMID- 12468487
TI  - Misleading electrocardiographic results in patient with hyperkalaemia and
      diabetic ketoacidosis.

PMID- 12468488
TI  - Antithrombotic therapy in acute coronary syndromes.

PMID- 12468489
TI  - Values and leadership.

PMID- 12468490
TI  - Interview with Gro Brundtland by Gavin Yamey.

PMID- 12468491
TI  - Copying letters to patients. Concerns of clinicians and patients need to be
      addressed first.

PMID- 12468492
TI  - Comparison of different measures of blood pressure. Use sphygmomanometers more,
      not less.

PMID- 12468493
TI  - Pleasing some of the people none of the time.

PMID- 12468494
TI  - Retaining nurses in the NHS. Extent of shortage will be known only when nurses
      spend all their time nursing.

PMID- 12468495
TI  - Thrombolysis for acute ischaemic stroke. Trial participants need to be informed
      of uncertainty principle.

PMID- 12468496
TI  - When medical students go off the rails. Lack of continuity from admission to
      postgraduate career is a problem.

PMID- 12468497
TI  - CONSORT statement requires closer examination.

PMID- 12468500
TI  - Cognitive intelligence.

PMID- 12468499
TI  - Medical leadership.

PMID- 12468501
TI  - The current crisis in GP recruitment.

PMID- 12468505
TI  - Fine-needle aspiration cytology of the sentinel lymph node in head and neck
      cancer.
AB  - In squamous cell carcinoma of the head and neck, staging of the neck cannot rule
      out occult metastatic disease. An improved staging is necessary to avoid elective
      neck dissection in patients staged as N0. The study was performed to determine
      the feasibility of the detection of occult metastatic disease by ultrasound
      guided fine-needle aspiration cytology (USgFNAC) of sentinel lymph nodes (SLN).
      METHODS: Sixteen consecutive patients diagnosed with oral, oropharyngeal, or
      dermal squamous cell carcinoma who had been staged as N0 underwent
      lymphoscintigraphy in double tracer technique to localize SLNs. A USgFNAC was
      performed on SLNs before elective neck dissection. The results of USgFNAC were
      compared with pathohistologic findings, which were regarded as the gold standard.
      RESULTS: Seven of 16 patients were upstaged to N+ after histopathologic
      examination of the neck dissection specimen. In only 1 of these patients was
      metastatic disease detected by USgFNAC of the SLN. CONCLUSION: The combination of
      lymphoscintigraphy and USgFNAC of the SLN improves preselection of N+ patients
      and, thus, the staging procedures. However, based on present results this method
      does not seem reliable in deciding whether an elective neck dissection can be
      avoided. A biopsy of the SLN with close histopathologic work-up seems to be
      mandatory for the detection of occult metastatic disease, because the merely
      incidental aspiration of micrometastatic material within normal-sized lymph nodes
      results in a high number of false-negative results by USgFNAC.

PMID- 12468506
TI  - Deposition of cigar smoke particles in the lung: evaluation with ventilation scan
      using (99m)Tc-labeled sulfur colloid particles.
AB  - This study examined the degree to which cigar smokers inhale when they smoke
      cigars. A second objective was to assess the level of association between self
      reported inhalation and observable cigar particle deposition in the lung. We
      hypothesized that cigar smokers with a history of cigarette smoking would show a
      greater amount of smoke deposition than would cigar smokers with no history of
      cigarette smoking. We conjectured that self-reported cigar smoke inhalation would
      be a reliable predictor of observable smoke particle deposition in the lung.
      METHODS: Twenty-four male cigar smokers were recruited to participate in the
      study. Twelve of the participants were current or past regular cigarette smokers,
      and the remaining 12 participants had no history of cigarette smoking. The
      volunteers completed an anonymous questionnaire commenting on the frequency of
      their current cigarette and cigar use as well as the degree to which they inhale
      when they smoke cigars. Volunteers smoked a cigar through a holder that permitted
      cigar smoke to mix with a radioaerosol of (99m)Tc-labeled sulfur colloid
      particles. The total radioactivity administered to each volunteer was 100 MBq.
      Lung ventilation scanning was subsequently performed. RESULTS: Total lung counts
      showed that volunteers inhaled the cigar smoke to varying degrees, although 100%
      of nonsmokers and 58% of smokers in the study reported that they never or rarely
      inhaled when they smoked cigars. With respect to total lung counts, smokers as a
      group inhaled less than their nonsmoking counterparts; however, this difference
      reflected a trend in the data and did not reach statistical significance.
      CONCLUSION: Contrary to the widely held belief that cigar smokers do not inhale
      when they smoke cigars, we concluded that cigar smoke is inhaled regardless of
      self-reported inhalation and smoking history.

PMID- 12468507
TI  - Distribution of ventilation/perfusion ratios in pulmonary embolism: an adjunct to
      the interpretation of ventilation/perfusion lung scans.
AB  - Diagnosis of pulmonary embolism (PE) by visual interpretation of
      ventilation/perfusion (V/Q) scans is limited by the high percentages of patients
      classified in the intermediate- and low-probability categories. This study
      proposes a quantitative analysis of the distribution of V/Q ratios to better
      identify patients with PE. METHODS: We studied 99 consecutive patients who
      underwent dual-isotope (81m)Kr/(99m)Tc-macroaggregate V/Q scanning and arterial
      blood gas analysis within 48 h. The 8-view V/Q scans were visually analyzed by 2
      observers according to the revised criteria of the Prospective Investigation of
      Pulmonary Embolism Diagnosis (PIOPED) (normal scan or low, intermediate, or high
      probability of PE). Quantitative analysis of the posterior-view distribution
      histogram of V/Q ratios was performed using dedicated software. Briefly, regions
      of interest were drawn around the lungs on the matched V/Q images, smooth
      filtering was applied, normalized regional V/Q ratios were calculated within each
      pixel, and a distribution histogram was built. RESULTS: Patients with normal
      scans (n = 16) had a predominance of V/Q ratios (63.3% +/- 13.0%) between 0.8 and
      1.2. They had only 9.8% +/- 5.8% of ratios > 1.2, and the remaining 26.9% +/-
      7.5% of ratios were <0.8. By contrast, patients with PE (n = 34) were
      characterized by a significant increase (15.5 +/- 10.0%, P = 0.04) in high V/Q
      ratios (>1.2) and a significant increase (34.5% +/- 8.2%, P = 0.003) in low V/Q
      ratios (<0.8). Interestingly, a similar pattern was found in patients with a high
      PIOPED probability of PE, 21.3% +/- 11.0% and 37.5% +/- 9.2%, respectively.
      Within the nondiagnostic group (intermediate- + low-probability scans, n = 58),
      17 patients were finally diagnosed with PE. Analysis of the distribution
      histogram in this group allowed the identification of 5 patients with PE
      (specificity, 78%). CONCLUSION: A quantitative approach to lung scan
      interpretation, based on the distribution histogram of V/Q ratios, may be helpful
      for categorizing patients with suspected PE.

PMID- 12468508
TI  - Comparison of fatty meal and intravenous cholecystokinin infusion for gallbladder
      ejection fraction.
AB  - Gallbladder ejection fraction (GBEF) measured with a fatty meal (half-and-half
      milk) was compared with that measured with 2 equal sequential intravenous
      infusions of cholecystokinin (CCK-8) in a paired study of healthy subjects.
      METHODS: GBEF was measured by (99m)Tc-hepatic iminodiacetic acid
      cholescintigraphy in 13 healthy subjects. Each subject received 2 sequential
      doses of CCK-8 (3 ng/kg/min for 10 min) on day 1, followed by, on day 2, a 240-mL
      (8 oz) fatty meal (half-and-half milk) per 70 kg of body weight. RESULTS: The
      mean +/- SD GBEF of 53.6% +/- 20.2% with fatty meal was significantly lower than
      the mean of 75.8% +/- 16.3% (P < 0.01) with the first dose of CCK-8 and 71.3% +/-
      17.4% (P < 0.05) with the second dose. Fatty meal GBEF varied widely, from 23.5%
      to 91.8%. Percentile rankings of the fatty meal GBEF were determined as the
      preferred methodology for reporting results. Latent and ejection periods were
      significantly longer with fatty meal than with either dose of CCK-8. CONCLUSION:
      GBEF measured with fatty meal can serve as an alternative method to intravenous
      injection of CCK-8 when the hormone is no longer available for clinical use. The
      measurement of GBEF with fatty meal requires careful attention to the details of
      the meal and the measurement time sequence.

PMID- 12468509
TI  - The mean transit time and functional image in asialoglycoprotein receptor
      scintigraphy: a novel modality for evaluating the regional dynamic function of
      hepatocytes.
AB  - In this study, we attempted to evaluate the regional dynamic function of
      hepatocytes by introducing unique parameters in (99m)Tc
      diethylenetriaminepentaacetic acid-galactosyl-human serum albumin (99m)Tc-GSA)
      scintigraphy. (99m)Tc-GSA scintigraphy provides valuable information for the
      receptor population density. However, the conventional indices are the results of
      the analyses of 2 fixed points and, as a result, it is not possible to accurately
      estimate the regional dynamic function. METHODS: We performed (99m)Tc-GSA
      scintigraphy 100 times on a total of 54 pediatric patients. The average age at
      examination was 7.4 +/- 5.8 y. Ninety-one of the 100 scintigraphy cases were
      available for this study. We converted the time-activity curve for the liver of
      (99m)Tc-GSA to a horizontal mirror image curve, and, on the basis of the height
      over-area method, calculated the mean transit time (MTT) in each pixel and
      depicted the functional image as unique parameters, which were thus compared with
      the conventional indices. For these parameters, we used the time-activity curve
      for only the liver. RESULTS: The whole liver MTT showed a significant correlation
      with both the clearance (y = 590.3x + 10.3; r = 0.51; P < 0.0001) and the
      receptor (y = -1,836.2x + 2,038.8; r = -0.66; P < 0.0001) indices. On the basis
      of the MTT in each pixel, we could depict the functional image of the liver. In
      actual clinical situations, the functional image was quite useful for making a
      visual evaluation of the dynamic distribution of (99m)Tc-GSA. The functional
      image indicated that, even at an extremely early stage of biliary atresia, the
      hepatic functional reserve might be exacerbated earlier in the right lobe than in
      the left lobe. CONCLUSION: The MTT and the functional image enable us to
      elucidate the regional dynamic function of hepatocytes both quantitatively and
      visually. In addition, this diagnostic modality can be used at virtually all
      medical institutions using a modified analytic program already in public use.

PMID- 12468510
TI  - Usefulness of brain SPECT to evaluate brain tolerance and hemodynamic changes
      during temporary balloon occlusion test and after permanent carotid occlusion.
AB  - The purpose of this study was to evaluate the usefulness of SPECT during
      temporary carotid balloon occlusion testing and to evaluate the changes in
      regional cerebral blood flow (CBF) and regional cerebral perfusion reserve (CPR)
      after permanent carotid occlusion. METHODS: Temporary balloon occlusion testing
      was performed on 40 patients (24 head and neck tumors, 16 aneurysms). During the
      balloon occlusion (total time, 30 min), (99m)Tc-ethylcysteinate dimer (ECD) was
      injected intravenously about 5 min before balloon deflation, followed by SPECT
      data acquisition. SPECT images were visually evaluated, and the severity of
      hypoperfusion on the occluded side was classified using 4 grades (normal, mild,
      moderate, and severe). The count ratio of the occluded side to the contralateral
      side (L/N ratio) was also analyzed. In 7 patients who subsequently underwent
      permanent carotid occlusion, CBF and CPR were quantitatively assessed using
      (133)Xe inhalation dynamic SPECT at rest and after acetazolamide (ACZ)
      enhancement (CPR was defined as the percentage increase in CBF after ACZ), and
      the patients were followed up periodically. RESULTS: SPECT after temporary
      occlusion showed moderate or severe hypoperfusion in 12 patients, whereas
      neurologic deterioration was observed in only 4 patients. The L/N ratios were
      0.96 +/- 0.03 in normal perfusion (13 patients), 0.93 +/- 0.03 in mild
      hypoperfusion (15 patients), 0.83 +/- 0.03 in moderate hypoperfusion (10
      patients) and 0.66 +/- 0.09 in severe hypoperfusion (2 patients) (P < 0.0001). In
      the 7 patients who underwent permanent carotid occlusion, CPR decreased after
      surgery (35% +/- 7% vs. 7% +/- 14%, P < 0.05), even though the resting CBF did
      not change (54 +/- 8 mL/100 g/min vs. 52 +/- 6 mL/100 g/min, not statistically
      significant). The steal phenomenon (rCPR < 0%) was observed in 3 patients, 1 of
      whom experienced transient hemiparesis when blood pressure dropped soon after
      surgery. On follow-up, the decreased CPR gradually improved and no infarction
      developed. CONCLUSION: SPECT is useful to detect cerebral hypoperfusion during
      carotid occlusion. Assessment of CPR is recommended to predict the potential risk
      of postsurgical complications and to follow up patients after permanent carotid
      occlusion.

PMID- 12468511
TI  - Effects of methylphenidate discontinuation on cerebral blood flow in prepubescent
      boys with attention deficit hyperactivity disorder.
AB  - Methylphenidate (MPH) is an effective symptomatic treatment of attention deficit
      hyperactivity disorder (ADHD), but the mechanisms of its therapeutic action have
      not been fully elucidated. To address this issue, we assessed the effects of
      discontinuation of chronic MPH treatment on regional cerebral blood flow (rCBF)
      in ADHD patients. METHODS: Twenty-two prepubescent boys with ADHD (age range, 8.2
      11.5 y) and 7 healthy volunteers were studied with SPECT on and off MPH. Their
      rCBF data were automatically normalized to whole-brain counts and coregistered
      with standard anatomic space. rCBF changes were evaluated with statistical
      parametric mapping based on voxel-by-voxel ANOVA. RESULTS: When the subjects were
      not taking MPH, rCBF was higher in the motor, premotor, and the anterior
      cingulate cortices (Brodmann's areas 4, 6, and 32). CONCLUSION: Brief
      discontinuation of MPH treatment is associated with increased motor and anterior
      cingulate cortical activity. Our findings suggest that MPH treatment modulates
      motor and anterior cingulate cortical activity directly or indirectly.
      Alternatively, our findings may be related to MPH withdrawal. These data provide
      novel information on the potential mechanisms of the therapeutic action of MPH.
      Furthermore, they are clinically relevant to the commonly occurring brief
      interruptions in MPH treatment.

PMID- 12468512
TI  - Proceed, with caution: SPECT cerebral blood flow studies of children and
      adolescents with attention deficit hyperactivity disorder.

PMID- 12468513
TI  - Dobutamine stress myocardial perfusion imaging in coronary artery disease.
AB  - The accurate noninvasive diagnosis and functional evaluation of coronary artery
      disease is an important step in selecting the appropriate management strategy.
      Dobutamine stress myocardial perfusion imaging is an alternative to exercise in
      patients with limited exercise capacity. In many centers, the test is performed
      on patients who have a contraindication for vasodilator stress testing. Recent
      studies have shown hyperemia induced by the standard dobutamine-atropine stress
      test is not less than hyperemia induced by dipyridamole. The feasibility of the
      test is 90% and is often higher in patients without beta-blocker therapy. The
      safety of the test has been well studied and was also demonstrated in specific
      patients groups, such as patients with left ventricular dysfunction, the elderly,
      and heart transplant recipients. The diagnostic accuracy has been demonstrated in
      patients with and without myocardial infarction and in specific groups such as
      those with hypertension, left ventricular hypertrophy, and heart transplant
      recipients and after revascularization. The technique has a high sensitivity for
      prediction of functional recovery in patients with myocardial dysfunction
      referred for revascularization. The presence and severity of myocardial perfusion
      abnormalities assessed by this method are powerful predictors of cardiac events,
      incremental to clinical data. This article describes the methodology, safety,
      feasibility, diagnostic accuracy, and prognostic value of dobutamine stress
      myocardial perfusion imaging in patients with known or suspected coronary artery
      disease, with additional considerations for the application of the test in
      specific patient groups.

PMID- 12468514
TI  - Sigma receptor scintigraphy with N-[2-(1'-piperidinyl)ethyl]-3-(123)I-iodo-4
      methoxybenzamide of patients with suspected primary breast cancer: first clinical
      results.
AB  - The aim of this study was to investigate the potential of a new iodobenzamide, N
      [2-(1'-piperidinyl)ethyl]-3-(123)I-iodo-4-methoxybenzamide (P-(123)I-MBA), to
      visualize primary breast tumor in humans in vivo. Tumor accumulation of
      benzamides is based on a preferential binding to sigma receptors that are
      overexpressed on breast cancer cells. METHODS: P-(123)I-MBA (148-185 MBq) was
      administered to 12 patients with a mammographically suspicious breast mass. Two
      hours after administration, whole-body and spot images of the healthy and the
      diseased breast were obtained. RESULTS: A focal increased tracer accumulation was
      observed in 8 of 10 patients with histologically confirmed breast cancer (mean
      tumor-to-background ratio, 2.04). No uptake was seen in a case of lymphatic
      adenitis. CONCLUSION: This preliminary patient study shows that P-(123)I-MBA
      accumulates in most breast tumors in vivo. Future work should focus on the
      relationship between P-(123)I-MBA uptake and the proliferative activity of cells
      to anticipate use of this technique as a tool to noninvasively assess the degree
      of tumor proliferation.

PMID- 12468515
TI  - Preclinical comparison of (111)In-labeled DTPA- or DOTA-bombesin analogs for
      receptor-targeted scintigraphy and radionuclide therapy.
AB  - The 14-amino-acid peptide bombesin (BN) has a high affinity for the gastrin
      releasing peptide (GRP) receptor that is expressed by a variety of tumors.
      Recently, high densities of GRP receptors were identified by in vitro receptor
      autoradiography in human prostate and breast carcinomas using [(125)I-Tyr(4)]BN
      as radioligand. Radiometal-labeled diethylenetriaminepentaacetic acid (DTPA)-BN
      derivatives are potentially useful radioligands for receptor-targeted
      scintigraphy and radiotherapy of GRP receptor-expressing tumors. METHODS: [DTPA
      Pro(1),Tyr(4)]BN (A), [DOTA-Pro(1),Tyr(4)]BN (B), [DTPA-epsilon-Lys(3),Tyr(4)]BN
      (C), and [DOTA-epsilon-Lys(3),Tyr(4)]BN (D) (where DOTA is dodecanetetraacetic
      acid) were synthesized and studied for competition with binding of [(125)I
      Tyr(4)]BN to the GRP receptor. The (111)In-labeled BN analogs were studied in
      vitro for binding and internalization by GRP receptor-expressing CA20948 and
      AR42J pancreatic tumor cells as well as in vivo for tissue distribution in rats.
      Specific tissue binding was tested by coinjection of 0.1 mg [Tyr(4)]BN. RESULTS:
      All BN analogs competitively inhibited the binding of [(125)I-Tyr(4)]BN to the
      GRP receptor with 50% inhibitory concentration values in the range of 2-9 nmol/L.
      All (111)In-labeled analogs showed high and specific time- and temperature
      dependent binding and internalization by CA20948 and AR42J cells. In in vivo
      studies, high and specific binding was found in GRP receptor-positive tissues
      such as pancreas (0.90, 1.2, 0.54, and 0.79 percentage injected dose per gram for
      A-D, respectively). In a rat model, the AR42J tumor could clearly be visualized
      by scintigraphy using [(111)In-DTPA-Pro(1),Tyr(4)]BN as the radioligand. Although
      [(111)In-DOTA-Pro(1),Tyr(4)]BN showed the highest uptake of radioactivity in GRP
      receptor-positive tissues as well as higher target-to-blood ratios, [(111)In-DTPA
      Pro(1),Tyr(4)]BN was easier to handle and is more practical to use. Therefore, we
      decided to start phase I studies with this DTPA-conjugated radioligand.
      CONCLUSION: [(111)In-DTPA-Pro(1),Tyr(4)]BN is a promising radioligand for
      scintigraphy of GRP receptor-expressing tumors. We are currently performing a
      phase I study on patients with invasive prostate carcinoma.

PMID- 12468516
TI  - A dosimetry model for the small intestine incorporating intestinal wall activity
      and cross-doses.
AB  - Current internal radiation dosimetry models for the small intestine, and for most
      walled organs, lack the ability to account for the activity uptake in the
      intestinal wall. In existing models the cross-dose from nearby loops of the small
      intestine is not taken into consideration. The aim of this investigation was to
      develop a general model for calculating the absorbed dose to the radiation
      sensitive cells in the small intestinal mucosa from radionuclides located in the
      small intestinal wall or contents. METHODS: A model was developed for calculation
      of the self-dose and cross-dose from activity in the intestinal wall or contents.
      The small intestine was modeled as a cylinder with 2 different wall thicknesses
      and with an infinite length. Calculations were performed for various mucus
      thicknesses. S values were calculated using the EGS4 Monte Carlo simulation
      package with the PRESTA algorithm and the simulation results were integrated over
      the depth of the radiosensitive cells. The cross-organ dose was calculated by
      summing the dose contributions from other intestinal segments. Calculations of S
      values for self-dose and cross-dose were made for monoenergetic electrons, 0.050
      10 MeV, and for the radionuclides (99m)Tc, (111)In, (131)I, (67)Ga, (90)Y, and
      (211)At. RESULTS: The self-dose S value from activity located in the small
      intestinal wall is considerably greater than the S values for self-dose from the
      contents and the cross-dose from wall and contents except for high electron
      energies. For all radionuclides investigated and for electrons 0.10-0.20 MeV and
      8-10 MeV in energy, the cross-dose from activity in the contents is higher than
      the self-dose from the contents. The mucus thickness affects the S value when the
      activity is located in the contents. CONCLUSION: A dosimetric model for the small
      intestine was developed that takes into consideration the localization of the
      radiopharmaceutical in the intestinal wall or in the contents. It also calculates
      the contribution from self-dose and cross-dose. With this model, more accurate
      calculations of absorbed dose to radiation-sensitive cells in the intestine are
      possible.

PMID- 12468517
TI  - Model-based versus patient-specific dosimetry: blurring the lines.

PMID- 12468518
TI  - Volumetric analysis of 18F-FDG PET in glioblastoma multiforme: prognostic
      information and possible role in definition of target volumes in radiation dose
      escalation.
AB  - The use of (18)F-FDG PET for brain tumors has been shown to be accurate in
      identifying areas of active disease. Radiation dose escalation in the treatment
      of glioblastoma multiforme (GBM) may lead to improved disease control. On the
      basis of these premises, we initiated a pilot study to investigate the use of
      (18)F-FDG PET for the guidance of radiation dose escalation in the treatment of
      GBM. METHODS: Patients were considered eligible to participate in the study if
      they had a diagnosis of GBM, were at least 18 y old, and had a score of at least
      60 on the Karnofsky Scale. Patients were treated with standard conformal
      fractionated radiotherapy (1.8 Gy per fraction, to 59.4 Gy), with volumes defined
      by MRI. At a dose of 45-50.4 Gy, patients underwent (18)F-FDG PET for boost
      target delineation. Final noncoplanar fields (3-4) were designed to treat the
      volume of abnormal (18)F-FDG uptake plus a 0.5-cm margin for an additional 20 Gy
      (2 Gy per fraction), to a total dose of 79.4 Gy. If no abnormal (18)F-FDG uptake
      was observed, treatment was stopped after the conventional course of 59.4 Gy.
      Age, Karnofsky score, MRI-based volumes, and (18)F-FDG PET volume were analyzed
      as prognostic variables for time to tumor progression (TTP) and overall survival.
      (18)F-FDG PET volumes and MRI-based volumes were compared to assess concordance.
      RESULTS: For the 27 patients who could be evaluated, median actuarial TTP was 43
      wk, and median actuarial survival was 70 wk. On univariate analysis, (18)F-FDG
      PET, T1-weighted MRI gadolinium enhancement (excluding nonenhancing resection
      cavity), and T2-weighted MRI volumes were significantly predictive of TTP. On
      multivariate analysis, only (18)F-FDG PET volume retained significance for
      predicting TTP. Similar results were obtained on analysis of these variables as
      prognostic factors for survival. When (18)F-FDG PET-based volumes were compared
      with MRI-based volumes, a difference of at least 25% was detected in all
      patients, with all but 2 having smaller (18)F-FDG PET volumes. Of patients in
      whom (18)F-FDG uptake was initially present but treatment subsequently failed,
      83% demonstrated the first tumor progression within the region of abnormal (18)F
      FDG uptake. CONCLUSION: In comparison with MRI, (18)F-FDG PET defined unique
      volumes for radiation dose escalation in the treatment of GBM. (18)F-FDG PET
      volumes were predictive of survival and time to tumor progression in the
      treatment of patients with GBM.

PMID- 12468519
TI  - 18F-Fluoroerythronitroimidazole radiation dosimetry in cancer studies.
AB  - 18F-Fluoroerythronitromidazole (FETNIM) is a new promising PET tracer for imaging
      tumor hypoxia. Accurate radiation dosimetry is important for estimating absorbed
      radiation doses to patients and for calculating the allowable injected dose.
      METHODS: Radiation absorbed doses were estimated from PET scans obtained on
      cancer patients on the basis of the MIRD procedure. Dynamic acquisition data was
      obtained from the thorax, abdomen, and head and neck regions. The tracer was
      injected intravenously and mean injected activity was 366 MBq (range, 288-385
      MBq). Arterial blood was continuously assayed over dynamic PET imaging. The
      bladder wall dose was evaluated from the voided urine activity measurements.
      RESULTS: The effective dose to a 70-kg adult was 0.015 or 0.019 mSv/MBq,
      calculated on 2- or 4-h voiding intervals, respectively. The critical organ
      proved to be the urinary bladder wall, with a highest absorbed dose of 0.062 or
      0.127 mGy/MBq depending on the voiding schedule as described above. Absorbed
      doses in all other organs were at least 5-fold smaller than the bladder wall
      doses. CONCLUSION: With an injected activity of 370 MBq (18)F-FETNIM, the
      radiation doses are generally comparable with those of other related radionuclide
      imaging procedures. Specifically, in comparison with (18)F-fluoromisonidazole,
      the absorbed doses of (18)F-FETNIM are equal. However, special attention should
      be given to adequate hydration and voiding to limit the relatively high exposure
      of the critical organ, bladder wall, to (18)F-FETNIM.

PMID- 12468520
TI  - The inhibitory effect of (111)In-DTPA(0)-octreotide on intrahepatic tumor growth
      after partial hepatectomy.
AB  - The aim of this animal study was to evaluate whether peptide receptor
      radionuclide therapy with (111)In-diethylenetriaminepentaacetic acid (DTPA)(0)
      octreotide was able to reduce tumor growth even under tumor growth-stimulating
      conditions induced by partial hepatectomy (PHx). METHODS: Rats underwent 70% PHx
      or sham operation. The development of hepatic metastases was determined 21 d
      after direct injection of somatostatin receptor (SS-R)-positive or SS-R-negative
      tumor cells into the portal vein. Groups of 8 or 9 animals that underwent PHx or
      sham operation were treated with octreotide 50 micro g/kg subcutaneously twice
      daily or with 370 MBq (111)In-DTPA(0)-octreotide intravenously on days 1 and 8.
      Both treatments were compared with control treatment. Forty non-tumor-bearing
      rats were used to determine the influence of (111)In-DTPA(0)-octreotide therapy
      on liver regeneration after PHx. RESULTS: PHx induced an increase in tumor growth
      in all experiments (P < 0.01). Octreotide treatment did not influence tumor
      growth after PHx or sham operation. (111)In-DTPA(0)-octreotide could effectively
      reduce tumor growth in the liver of SS-R-positive tumors also under conditions of
      increased tumor growth as generated by PHx (P < 0.01). (111)In-DTPA(0)-octreotide
      was also effective on SS-R-negative tumors after PHx (P = 0.01) but not after
      sham operation. Furthermore, (111)In-DTPA(0)-octreotide therapy did not influence
      liver regeneration or liver function after PHx. CONCLUSION: Peptide receptor
      radionuclide therapy with (111)In-DTPA(0)-octreotide is effective in SS-R
      positive tumors. During liver regeneration, the growth of SS-R-negative tumors is
      also reduced. This effect is not induced by impairment of liver regeneration or
      liver function. Radionuclide therapy could therefore be a promising treatment
      modality for patients with symptomatic liver metastases of neuroendocrine tumors
      in combination with liver resection.

PMID- 12468521
TI  - Rat studies comparing 11C-FMAU, 18F-FLT, and 76Br-BFU as proliferation markers.
AB  - We analyzed and compared 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-[methyl
      (11)C]thymine ((11)C-FMAU), 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) and 1
      (2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-[(76)Br]bromouracil ((76)Br-BFU)
      with respect to tissue uptake, DNA incorporation, and excretion modulation in
      rats. The goal of the investigation was to evaluate the efficiency of the 3
      nucleoside tracers as potential tracers for measuring proliferation. METHODS:
      Sprague-Dawley rats were divided into 3 groups and administered 5 MBq (11)C-FMAU,
      1 MBq (18)F-FLT, or 2 MBq (76)Br-BFU. For each tracer, a subgroup was also
      administered 6 mg/kg cimetidine. The rats in the (11)C-FMAU group were killed at
      5, 20, 40, 60, and 80 min after injection; the rats in the (18)F-FLT group were
      killed at 80 min and 2 and 4 h; and the rats in the (76)Br-BFU group were killed
      at 5, 20, 40, and 80 min and 2, 4, 6, and 24 h. Samples of blood, liver, kidney,
      spleen, and intestine were taken, and the radioactivity was measured. DNA
      separation was made in the samples of spleen, and the radioactivity in the DNA
      fraction was measured. RESULTS: Maximal uptake of radioactivity was seen in the
      spleen and intestine, organs with active DNA synthesis. The highest relative
      radioactivity uptake was at 60 min in the (11)C-FMAU groups and at 4 h in the
      (18)F-FLT group. In the (76)Br-BFU group, the uptake increased gradually during
      the observation period, and uptake of radioactivity increased markedly in rats
      receiving cimetidine. Cimetidine did not affect radioactivity uptake in the (11)C
      FMAU or (18)F-FLT groups. The fraction of radioactivity in DNA was 78% in spleen
      at 60 min in the (11)C-FMAU group, 80% at 60 min and 97% at 4 h in the (76)Br-BFU
      group. The DNA-incorporation was only 2% in the (18)F-FLT group. CONCLUSION:
      (76)Br-BFU predominantly incorporates into DNA and has great potential as a PET
      tracer for the assessment of proliferation in vivo. (11)C-FMAU also may have
      potential as a proliferation marker, but the observation time is limited. (18)F
      FLT does not incorporate into DNA and is therefore not a direct marker of
      proliferation.

PMID- 12468522
TI  - A novel DOTA-alpha-melanocyte-stimulating hormone analog for metastatic melanoma
      diagnosis.
AB  - Scintigraphic imaging of metastatic melanoma lesions requires highly tumor
      specific radiolabeled compounds. Because both melanotic and amelanotic melanomas
      overexpress receptors for alpha-melanocyte-stimulating hormone (alpha-MSH;
      receptor name: melanocortin type 1 receptor, or MC1R), radiolabeled alpha-MSH
      analogs are potential candidates for melanoma diagnosis. The aim of this study
      was to develop a melanoma-selective radiolabeled alpha-MSH analog suitable for
      melanoma diagnosis. METHODS: The very potent alpha-MSH analog [Nle(4), D-Phe(7)]
      alpha-MSH (NDP-MSH) and a newly designed alpha-MSH octapeptide analog,
      [betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (MSH(oct)), were
      conjugated to the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10
      tetraacetic acid (DOTA) to enable radiometal incorporation. The resulting DOTA
      conjugates were evaluated in vitro for their MC1R-binding affinity and
      melanogenic activity in isolated mouse B16F1 cells and in vivo for their
      biodistribution in mouse models of primary and metastatic melanoma after labeling
      with (111)In. RESULTS: DOTA-MSH(oct) was shown to bind with high affinity
      (inhibitory concentration of 50% [IC(50)] = 9.21 nmol/L) to the MC1R, although
      with lower potency than does DOTA-NDP-MSH (IC(50) = 0.25 nmol/L). In B16F1
      melanoma-bearing mice, both (111)In-DOTA-NDP-MSH and (111)In-DOTA-MSH(oct)
      exhibited high MC1R-mediated uptake by melanoma, which differed by a factor of
      only 1.5 at 4 h after injection. The main route of excretion for both
      radioconjugates was the kidneys, whereby (111)In-DOTA-MSH(oct) led to somewhat
      higher kidney values than did (111)In-DOTA-NDP-MSH. In contrast, the latter was
      much more poorly cleared from other nonmalignant tissues, including bone, the
      most radiosensitive organ. Therefore, (111)In-DOTA-MSH(oct) displayed higher
      uptake ratios of tumor to nontarget tissue (e.g., tumor-to-bone ratio 4 h after
      injection was 4.9 for (111)In-DOTA-NDP-MSH and 53.9 for (111)In-DOTA-MSH(oct)).
      Lung and liver melanoma metastases could easily be visualized on tissue section
      autoradiographs after injection of (111)In-DOTA-MSH(oct). Radio-reversed-phase
      high-performance liquid chromatography analysis of urine samples revealed that
      most (111)In-DOTA-MSH(oct) is excreted intact 4 h after injection, indicating
      good in vivo stability. CONCLUSION: (111)In-DOTA-MSH(oct) exhibits more favorable
      overall performance than does (111)In-DOTA-NDP-MSH in murine models of primary
      and metastatic melanoma, making it a promising melanoma imaging agent.

PMID- 12468523
TI  - Synthesis and initial evaluation of 17-(11)C-heptadecanoic acid for measurement
      of myocardial fatty acid metabolism.
AB  - Fatty acid oxidation defects are being increasingly identified as causes of
      abnormal heart function and sudden death in children. Children with medium-chain
      acyl-coenzyme A (acyl-CoA) dehydrogenase defects can metabolize fatty acids
      labeled in the carboxylic acid end of the compound. Accordingly, our goal was to
      label a long-chain fatty acid in the omega-position and evaluate its myocardial
      kinetics. METHODS: Heptadecanoic acid, a 17-carbon fatty acid, was labeled in the
      C-17 position with (11)C by the general process of coupling (11)C-methyliodide to
      t-butyl-15-hexadecanoate. Yield was approximately 5%-10% end-of-bombardment.
      Subsequently, evaluation studies were performed on isolated perfused rat hearts
      and in intact, anesthetized dogs. The myocardial uptake and efflux of 17-(11)C
      heptadecanoic acid were compared with those of 1-(11)C-palmitate. RESULTS: With
      the exception of delayed efflux of tracer reflecting the temporal delay for beta
      oxidation, the washout of 17-(11)C-heptadecanoic acid from the heart mirrored
      that of 1-(11)C-palmitate in isolated rat hearts and in intact dogs with PET.
      CONCLUSION: 17-(11)C-Heptadecanoic acid may be a useful tracer for the
      identification of defects in fatty acid metabolism in subjects with medium- and
      short-chain fatty acid oxidation defects.

PMID- 12468524
TI  - Correction of partial-volume effect for PET striatal imaging: fast implementation
      and study of robustness.
AB  - PET imaging of D(2) receptors or (18)F-L-dopa metabolism are reference protocols
      to follow and study neurodegenerative diseases, but the accuracy of striatal PET
      imaging is limited by the partial-volume effect (PVE). For such studies, the
      geometric transfer matrix (GTM) method has been proposed to correct the regional
      mean values for PVE and is now widely used. METHODS: The GTM method models the
      geometric interactions induced by the PET system between the anatomic regions in
      which PVE correction is performed. This implies estimation of the corresponding
      regional spread function (RSF). The literature describes 2 implementations for
      the RSF calculation; they differ in the way the point spread function (PSF) of
      the imaging system is modeled, but no comparison or discussion has been given.
      The first and reference implementation uses an accurate intrinsic detector PSF
      that is applied in the sinogram space. The second uses a global PSF that is
      applied in the image space. In this work, we compared the 2 GTM implementations
      for 3-dimensional (3D) PET striatal imaging using Monte Carlo simulations and a
      phantom study. We studied the robustness of the GTM correction with respect to
      residual registration errors between PET and anatomy and with respect to residual
      segmentation errors. RESULTS: Despite the differences in RSF calculation and
      computation cost between the 2 implementations, similar recovery results were
      obtained (between 95% and 100%). The study of robustness of the GTM correction
      yielded 2 results. A realistic residual misregistration between the anatomic and
      PET images did not modify the algorithm accuracy but decreased its precision.
      Conversely, a realistic residual missegmentation of the anatomic regions
      submitted to GTM correction decreased the correction accuracy. CONCLUSION: A
      simple but efficient implementation in the image space of the GTM method yields
      accurate PVE correction in striatal regions in studies with 3D PET and enables
      clinical use. The method is less sensitive to residual misregistration errors
      between PET and anatomy than to residual missegmentation of the anatomy. Special
      care should be taken with segmentation of the regions to correct for PVE.

PMID- 12468525
TI  - Fractal analysis of cerebral blood flow distribution in Alzheimer's disease.

PMID- 12468526
TI  - An alternative to kinevac.

PMID- 12468527
TI  - Clinical impact of (18)F-FDG PET in thyroid carcinoma patients with elevated
      thyroglobulin levels and negative (131)I scanning results after therapy.

PMID- 12468528
TI  - Crystal structures of the BtuF periplasmic-binding protein for vitamin B12
      suggest a functionally important reduction in protein mobility upon ligand
      binding.
AB  - BtuF is the periplasmic binding protein (PBP) for the vitamin B12 transporter
      BtuCD, a member of the ATP-binding cassette (ABC) transporter superfamily of
      transmembrane pumps. We have determined crystal structures of Escherichia coli
      BtuF in the apo state at 3.0 A resolution and with vitamin B12 bound at 2.0 A
      resolution. The structure of BtuF is similar to that of the FhuD and TroA PBPs
      and is composed of two alpha/beta domains linked by a rigid alpha-helix. B12 is
      bound in the "base-on" or vitamin conformation in a wide acidic cleft located
      between these domains. The C-terminal domain shares structural homology to a B12
      binding domain found in a variety of enzymes. The same surface of this domain
      interacts with opposite surfaces of B12 when comparing ligand-bound structures of
      BtuF and the homologous enzymes, a change that is probably caused by the
      obstruction of the face that typically interacts with this domain by the base-on
      conformation of vitamin B12 bound to BtuF. There is no apparent pseudo-symmetry
      in the surface properties of the BtuF domains flanking its B12 binding site even
      though the presumed transport site in the previously reported crystal structure
      of BtuCD is located in an intersubunit interface with 2-fold symmetry. Unwinding
      of an alpha-helix in the C-terminal domain of BtuF appears to be part of
      conformational change involving a general increase in the mobility of this domain
      in the apo structure compared with the B12-bound structure. As this helix is
      located on the surface likely to interact with BtuC, unwinding of the helix upon
      binding to BtuC could play a role in triggering release of B12 into the transport
      cavity. Furthermore, the high mobility of this domain in free BtuF could provide
      an entropic driving force for the subsequent release of BtuF required to complete
      the transport cycle.

PMID- 12468529
TI  - Specific inhibition of AQP1 water channels in isolated rat intrahepatic bile duct
      units by small interfering RNAs.
AB  - Cholangiocytes express water channels (i.e. aquaporins (AQPs)), proteins that are
      increasingly recognized as important in water transport by biliary epithelia.
      However, direct functional studies demonstrating AQP-mediated water transport in
      cholangiocytes are limited, in part because of the lack of specific AQP
      inhibitors. To address this issue, we designed, synthesized, and utilized small
      interfering RNAs (siRNAs) selective for AQP1 and investigated their effectiveness
      in altering AQP1-mediated water transport in intrahepatic bile duct units (IBDUs)
      isolated from rat liver. Twenty-four hours after transfection of IBDUs with
      siRNAs targeting two different regions of the AQP1 transcript, both AQP1 mRNA and
      protein expression were inhibited by 76.6-92.0 and 57.9-79.4%, respectively.
      siRNAs containing the same percent of base pairs as the AQP1-siRNAs but in random
      sequence (i.e. scrambled siRNAs) had no effect. Suppression of AQP1 expression in
      cholangiocytes resulted in a decrease in water transport by IBDUs in response to
      both an inward osmotic gradient (200 mosm) or a secretory agonist (forskolin),
      the osmotic water permeability coefficient (P(f)) decreasing up to 58.8% and net
      water secretion (J(v)) decreasing up to 87%. A strong correlation between AQP1
      protein expression and water transport in IBDUs transfected with AQP1-siRNAs was
      consistent with the decrease in water transport by IBDUs resulting from AQP1 gene
      silencing by AQP1-siRNAs. This study is the first to demonstrate the feasibility
      of utilizing siRNAs to specifically reduce the expression of AQPs in epithelial
      cells and provides direct evidence of the contribution of AQP1 to water transport
      by biliary epithelia.

PMID- 12468530
TI  - Tip60 acetyltransferase activity is controlled by phosphorylation.
AB  - Here we show that the phosphorylation of histone acetyltransferase Tip60, a
      target of human immunodeficiency virus, type 1-encoded transactivator Tat, plays
      a crucial role in the control of its catalytic activity. Baculovirus-based
      expression and purification of Tip60 combined with mass spectrometry allowed the
      identification of serines 86 and 90 as two major sites of phosphorylation in
      vivo. The phosphorylation of Tip60 was found to modulate its histone
      acetyltransferase activity. One of the identified phosphorylated serines, Ser-90,
      was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylated
      in vitro by the cyclin B/Cdc2 complex. Accordingly, the phosphorylation of Tip60
      was enhanced after drug-induced arrest of cells in G(2)/M. This G(2)/M-dependent
      phosphorylation of Tip60 was abolished by treating cells with a specific
      inhibitor of the cyclin-dependent kinase, roscovitin. All together, these results
      strongly suggest a G(2)/M-dependent control of Tip60 activity.

PMID- 12468531
TI  - Hepatocyte growth factor induces GATA-4 phosphorylation and cell survival in
      cardiac muscle cells.
AB  - Hepatocyte growth factor (HGF) is released in response to myocardial infarction
      and may play a role in regulating cardiac remodeling. Recently, HGF was found to
      inhibit the apoptosis of cardiac muscle cells. Because GATA-4 can induce cell
      survival, the effects of HGF on GATA-4 activity were investigated. Treatment of
      HL-1 cells or primary adult rat cardiac myocytes with HGF, at concentrations that
      can be detected in the human serum after myocardial infarction, rapidly enhances
      GATA-4 DNA-binding activity. The enhanced DNA-binding activity is associated with
      the phosphorylation of GATA-4. HGF-induced phosphorylation and activation of GATA
      4 is abolished by MEK inhibitors or the mutation of the ERK phosphorylation site
      (S105A), suggesting that HGF activates GATA-4 via MEK-ERK pathway-dependent
      phosphorylation. HGF enhances the expression of anti-apoptotic Bcl-x(L), and this
      is blocked by dominant negative mutants of MEK or GATA-4. Forced expression of
      wild-type GATA-4, but not the GATA-4 mutant (S105A) increases the expression of
      Bcl-x(L). Furthermore, expression of the GATA-4 mutant (S105A) suppresses HGF
      mediated protection of cells against daunorubicin-induced apoptosis. These
      results demonstrate that HGF protects cardiac muscle cells against apoptosis via
      a signaling pathway involving MEK/ERK-dependent phosphorylation of GATA-4.

PMID- 12468532
TI  - The small heat-shock protein alpha B-crystallin promotes FBX4-dependent
      ubiquitination.
AB  - AlphaB-crystallin is a small heat-shock protein in which three serine residues
      (positions 19, 45, and 59) can be phosphorylated under various conditions. We
      describe here the interaction of alphaB-crystallin with FBX4, an F-box-containing
      protein that is a component of the ubiquitin-protein isopeptide ligase SCF
      (SKP1/CUL1/F-box). The interaction with FBX4 was enhanced by mimicking
      phosphorylation of alphaB-crystallin at both Ser-19 and Ser-45 (S19D/S45D), but
      not at other combinations. Ser-19 and Ser-45 are preferentially phosphorylated
      during the mitotic phase of the cell cycle. Also alphaB-crystallin R120G, a
      mutant found to co-segregate with a desmin-related myopathy, displayed increased
      interaction with FBX4. Both alphaB-crystallin S19D/S45D and R120G specifically
      translocated FBX4 to the detergent-insoluble fraction and stimulated the
      ubiquitination of one or a few yet unknown proteins. These findings implicate the
      involvement of alphaB-crystallin in the ubiquitin/proteasome pathway in a
      phosphorylation- and cell cycle-dependent manner and may provide new insights
      into the alphaB-crystallin-induced aggregation in desmin-related myopathy.

PMID- 12468533
TI  - Essential role of the transcription factor Ets-2 in Xenopus early development.
AB  - The fibroblast growth factor (FGF)/MAPK pathway plays an important role in early
      Xenopus developmental processes, including mesoderm patterning. The activation of
      the MAPK pathway leads to induction of Xenopus Brachyury (Xbra), which regulates
      the transcription of downstream mesoderm-specific genes in mesoderm patterning.
      However, the link between the FGF/MAPK pathway and the induction of Xbra has not
      been fully understood. Here we present evidence suggesting that Ets-2 is involved
      in the induction of Xbra and thus in the development of posterior mesoderm during
      early embryonic development. Overexpression of Ets-2 caused posteriorized embryos
      and led to the induction of mesoderm in ectodermal explants. Expression of a
      dominant-negative form of Ets-2 or injection of antisense morpholino
      oligonucleotides against Ets-2 inhibited the formation of the trunk and tail
      structures. Overexpression of Ets-2 resulted in the induction of Xbra, and
      expression of the dominant-negative Ets-2 inhibited FGF- or constitutively active
      MEK-induced Xbra expression. Moreover, overexpression of Ets-2 up-regulated the
      transcription from Xbra promoter reporter gene constructs. Ets-2 bound to the
      Xbra promoter region in vitro. These results taken together indicate that Xenopus
      Ets-2 plays an essential role in mesoderm patterning, lying between the FGF/MAPK
      pathway and the Xbra transcription.

PMID- 12468534
TI  - The regulation of subtilisin-cleaved actin by tropomyosin/troponin.
AB  - Vertebrate striated muscle contraction is regulated in a Ca(2+)-dependent fashion
      by tropomyosin (Tm) and troponin (Tn). This regulation involves shifts in the
      position of Tm and Tn on actin filaments and may include conformational changes
      in actin that are then communicated to myosin subfragment 1 (S1). To determine
      whether subdomain 2 of actin plays a role in this regulation, the DNase-I loop 38
      52 of this subdomain was cleaved by subtilisin between residues Met(47) and
      Gly(48). Despite impaired unregulated function, the potentiation and regulation
      of cleaved actin movement in the in vitro motility assay was not significantly
      different from that of uncleaved actin. Stopped-flow measurements of ADP release
      from regulated and unregulated cleaved acto-S1 showed a marked increase in ADP
      release from acto-S1 in the presence of the regulatory complex. The enhancement
      of the actin affinity for S1 in the presence of regulatory proteins was greater
      for uncleaved than for cleaved F-actin. Finally, both cleaved and uncleaved
      actins protect myosin loop 1 from papain cleavage equally well. Our results
      suggest that the potentiation of actin function in the in vitro motility assay by
      regulatory proteins stems from changes in cross-bridge cycle kinetics. In
      addition, the unimpaired calcium-sensitive regulation of cleaved actin indicates
      that subdomain 2 conformation does not play an essential role in the regulation
      process.

PMID- 12468535
TI  - Negative regulation of ERK and Elk by protein kinase B modulates c-Fos
      transcription.
AB  - In this study, we have identified novel regulatory steps involved in the cross
      talk between protein kinase B (PKB) and MAPK signaling pathways. We found that
      PKB down-regulates the Ras-Raf-MEK-ERK pathway by reducing the activity of ERK,
      which leads to inactivation of the transcription factor Elk1. In addition, PKB is
      able to reduce protein levels of Elk1. Both events lead to suppression of serum
      response element (SRE)-dependent transcription and a consequent decrease in the
      transcription of SRE-containing genes, such as c-fos. Because activation of the
      Ras/MAPK cascade is reported to increase c-fos transcription before apoptosis,
      our results are consistent with a specific role for PKB in promoting cell
      survival. Decrease in c-Fos protein levels in glioblastoma cells with
      constitutively active PKB provides further support for our observations.
      Therefore, our findings delineate a novel mechanism regulating immediate-early
      transcription, which may be involved in the initial steps in PKB-induced
      oncogenic transformation.

PMID- 12468536
TI  - Cell surface tumor endothelium marker 8 cytoplasmic tail-independent anthrax
      toxin binding, proteolytic processing, oligomer formation, and internalization.
AB  - The interaction of anthrax toxin protective antigen (PA) and target cells was
      assessed, and the importance of the cytosolic domain of tumor endothelium marker
      8 (TEM8) in its function as a cellular receptor for PA was evaluated. PA binding
      and proteolytic processing on the Chinese hamster ovary cell surface occurred
      rapidly, with both processes nearly reaching steady state in 5 min. Remarkably,
      the resulting PA63 fragment was present on the cell surface only as an oligomer,
      and furthermore, the oligomer was the only PA species internalized, suggesting
      that oligomerization of PA63 triggers receptor-mediated endocytosis. Following
      internalization, the PA63 oligomer was rapidly and irreversibly transformed to an
      SDS/heat-resistant form, in a process requiring an acidic compartment. This
      conformational change was functionally correlated with membrane insertion,
      channel formation, and translocation of lethal factor into the cytosol. To
      explore the role of the TEM8 cytosolic tail, a series of truncated TEM8 mutants
      was transfected into a PA receptor-deficient Chinese hamster ovary cell line.
      Interestingly, all of the cytosolic tail truncated TEM8 mutants functioned as PA
      receptors, as determined by PA binding, processing, oligomer formation, and
      translocation of an lethal factor fusion toxin into the cytosol. Moreover, cells
      transfected with a TEM8 construct truncated before the predicted transmembrane
      domain failed to bind PA, demonstrating that residues 321-343 are needed for cell
      surface anchoring. Further evidence that the cytosolic domain plays no essential
      role in anthrax toxin action was obtained by showing that TEM8 anchored by a
      glycosylphosphatidylinositol tail also functioned as a PA receptor.

PMID- 12468537
TI  - Reactions of deoxy-, oxy-, and methemoglobin with nitrogen monoxide. Mechanistic
      studies of the S-nitrosothiol formation under different mixing conditions.
AB  - The reaction between hemoglobin (Hb) and NO* has been investigated thoroughly in
      recent years, but its mechanism is still a matter of substantial controversy. We
      have carried out a systematic study of the influence of the following factors on
      the yield of S-nitrosohemoglobin (SNO-Hb) generated from the reaction of NO* with
      oxy-, deoxy-, and metHb: 1) the volumetric ratio of the protein and the NO*
      solutions; 2) the rate of addition of the NO* solution to the protein solution;
      3) the amount of NO* added; and 4) the concentration of the phosphate buffer. Our
      results suggest that the highest SNO-Hb yields are mostly obtained by very slow
      addition of substoichiometric amounts of NO* from a diluted solution. Possible
      pathways of SNO-Hb formation from the reaction of NO* with oxy-, deoxy-, and
      metHb are described. Our data strongly suggest that, because of mixing artifacts,
      care should be taken to use results from in vitro experiments to draw conclusion
      on the mechanism of the reaction in vivo.

PMID- 12468538
TI  - Heat shock factor 1 contains two functional domains that mediate transcriptional
      repression of the c-fos and c-fms genes.
AB  - Heat shock factor 1 (HSF1), in addition to its pivotal role as a regulator of the
      heat shock response, functions as a versatile gene repressor. We have
      investigated the structural domains involved in gene repression using mutational
      analysis of the hsf1 gene. Our studies indicate that HSF1 contains two adjacent
      sequences located within the N-terminal half of the protein that mediate the
      repression of c-fos and c-fms. One region (NF) appears to be involved in
      quenching transcriptional activation factors on target promoters and binds to the
      basic zipper transcription factor NF-IL6 required for activation of c-fms and IL
      1beta. The NF domain encompasses the leucine zipper 1 and 2 sequences as well as
      the linker domain between the DNA binding and leucine zipper regions. The
      function of this domain in gene repression is highly specific for HSF1, and the
      homologous region from conserved family member HSF2 does not restore repressive
      function in HSF2/HSF1 chimeras. In addition, HSF2 is not capable of binding to NF
      IL6. The NF domain, although necessary for repression, is not sufficient, and a
      second region (REP) occupying a portion of the regulatory domain is required for
      repression. Neither domain functions independently, and both are required for
      repression. Furthermore, we constructed dominant inhibitors of c-fos repression
      by HSF1, which also blocked the repression of c-fms and IL-1beta, suggesting a
      shared mechanism for repression of these genes by HSF1. Our studies suggest a
      complex mechanism for gene repression by HSF1 involving the binding to and
      quenching of activating factors on target promoters. Mapping the structural
      domains involved in this process should permit further characterization of
      molecular mechanisms that mediate repression.

PMID- 12468539
TI  - A specific bacterial aminoacylase cleaves odorant precursors secreted in the
      human axilla.
AB  - Human axillary odor is known to be formed upon the action of Corynebacteria sp.
      on odorless axilla secretions. The known axilla odor determinant 3-methyl-2
      hexenoic acid was identified in hydrolyzed axilla secretions along with a
      chemically related compound, 3-hydroxy-3-methylhexanoic acid. The natural
      precursors of both these acids were purified from non-hydrolyzed axilla
      secretions. From liquid chromatography/mass spectrometry analysis, it appeared
      that the acids are covalently linked to a glutamine residue in fresh axilla
      secretions, and the corresponding conjugates were synthesized for confirmation.
      Bacterial isolates obtained from the human axilla and belonging to the
      Corynebacteria were found to release the acids from these odorless precursors in
      vitro. A Zn(2+)-dependent aminoacylase mediating this cleavage was purified from
      Corynebacterium striatum Ax20, and the corresponding gene agaA was cloned and
      heterologously expressed in Escherichia coli. The enzyme is highly specific for
      the glutamine residue but has a low specificity for the acyl part of the
      substrate. agaA is closely related to many genes coding for enzymes involved in
      the cleavage of N-terminal acyl and aryl substituents from amino acids. This is
      the first report of the structure elucidation of precursors for human body
      odorants and the isolation of the bacterial enzyme involved in their cleavage.

PMID- 12468540
TI  - The role of C-terminal tyrosine phosphorylation in the regulation of SHP-1
      explored via expressed protein ligation.
AB  - The protein-tyrosine phosphatase SHP-1 plays a variety of roles in the "negative"
      regulation of cell signaling. The molecular basis for the regulation of SHP-1 is
      incompletely understood. Whereas SHP-1 has previously been shown to be
      phosphorylated on two tail tyrosine residues (Tyr(536) and Tyr(564)) by several
      protein-tyrosine kinases, the effects of these phosphorylation events have been
      difficult to address because of the intrinsic instability of the linkages within
      a protein-tyrosine phosphatase. Using expressed protein ligation, we have
      generated semisynthetic SHP-1 proteins containing phosphotyrosine mimetics at the
      Tyr(536) and Tyr(564) sites. Two phosphonate analogues were installed,
      phosphonomethylenephenylalanine (Pmp) and difluorophosphonomethylenephenylalanine
      (F(2)Pmp). Incorporation of Pmp at the 536 site led to 4-fold stimulation of the
      SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to
      no effect. Incorporation of F(2)Pmp at the 536 site led to 8-fold stimulation of
      the SHP-1 tyrosine phosphatase activity and 1.6-fold at the 564 site. A
      combination of size exclusion chromatography, phosphotyrosine peptide stimulation
      studies, and site-directed mutagenesis led to the structural model in which
      tyrosine phosphorylation at the 536 site engages the N-Src homology 2 domain in
      an intramolecular fashion relieving basal inhibition. In contrast, tyrosine
      phosphorylation at the 564 site has the potential to engage the C-Src homology 2
      domain intramolecularly, which can modestly and indirectly influence catalytic
      activity. The finding that phosphonate modification at each of the 536 and 564
      sites can promote interaction with the Grb2 adaptor protein indicates that the
      intramolecular interactions fostered by post-translational modifications of
      tyrosine are not energetically strong and susceptible to intermolecular
      competition.

PMID- 12468541
TI  - Revisiting monomeric HIV-1 protease. Characterization and redesign for improved
      properties.
AB  - Interactions between the C-terminal interface residues (96-99) of the mature HIV
      1 protease were shown to be essential for dimerization, whereas the N-terminal
      residues () and Arg(87) contribute to dimer stability (Ishima, R., Ghirlando, R.,
      Tozser, J., Gronenborn, A. M., Torchia, D. A., and Louis, J. M. (2001) J. Biol.
      Chem. 276, 49110-49116). Here we show that the intramonomer interaction between
      the side chains of Asp(29) and Arg(87) influences dimerization significantly more
      than the intermonomer interaction between Asp(29) and Arg(8'). Several mutants,
      including T26A, destablize the dimer, exhibit a monomer fold, and are prone to
      aggregation. To alleviate this undesirable property, we designed proteins in
      which the N- and C-terminal regions can be linked intramolecularly by disulfide
      bonds. In particular, cysteine residues were introduced at positions 2 and 97 or
      98. A procedure for the efficient preparation of intrachain-linked polypeptides
      is presented, and it is demonstrated that the Q2C/L97C variant exhibits a native
      like single subunit fold. It is anticipated that monomeric proteases of this kind
      will aid in the discovery of novel inhibitors aimed at binding to the monomer at
      the dimerization interface. This extends the target area of current inhibitors,
      all of which bind across the active site formed by both subunits in the active
      dimer.

PMID- 12468542
TI  - 14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2
      (TSC2) tumor suppressor gene product, tuberin.
AB  - TSC2, or tuberin, is the product of the tuberous sclerosis tumor suppressor gene
      TSC2 and acts downstream of the phosphatidylinositol 3-kinase-Akt signaling
      pathway to negatively regulate cellular growth. One mechanism underlying its
      function is to assemble into a heterodimer with the TSC1 gene product TSC1, or
      hamartin, resulting in a reduction in phosphorylation, and hence activation, of
      the ribosomal subunit S6 kinase (S6K). We identified a novel interaction between
      TSC2 and 14-3-3beta. We found that 14-3-3beta does not interfere with TSC1-TSC2
      binding and can form a ternary complex with these two proteins. Association
      between 14-3-3beta and TSC2 requires phosphorylation of TSC2 at a unique residue
      that is not a known Akt phosphorylation site. The overexpression of 14-3-3beta
      compromises the ability of the TSC1-TSC2 complex to reduce S6K phosphorylation.
      The antagonistic activity of 14-3-3beta toward TSC is dependent on the 14-3-3beta
      TSC2 interaction, since a mutant of TSC2 that is not recognized by 14-3-3beta is
      refractory to 14-3-3beta. We suggest that 14-3-3 proteins interact with the TSC1
      TSC2 complex and negatively regulate the function of the TSC proteins.

PMID- 12468544
TI  - The Coxsackievirus and adenovirus receptor (CAR) forms a complex with the PDZ
      domain-containing protein ligand-of-numb protein-X (LNX).
AB  - The Coxsackievirus and adenovirus receptor (CAR) functions as a virus receptor,
      but its primary biological function is unknown. A yeast two-hybrid screen was
      used to identify Ligand-of-Numb protein-X (LNX) as a binding partner to the
      intracellular tail of CAR. LNX harbors several protein-protein interacting
      domains, including four PDZ domains, and was previously shown to bind to and
      regulate the expression level of the cell-fate determinant Numb. CAR was able to
      bind LNX both in vivo and in vitro. Efficient binding to LNX required not only
      the consensus PDZ domain binding motif in the C terminus of CAR but also upstream
      sequences. The CAR binding region in LNX was mapped to the second PDZ domain. CAR
      and LNX were also shown to colocalize in vivo in mammalian cells. We speculate
      that CAR and LNX are part of a larger protein complex that might have important
      functions at discrete subcellular localizations in the cell.

PMID- 12468543
TI  - Leptomycin B, an inhibitor of the nuclear export receptor CRM1, inhibits COX-2
      expression.
AB  - Cyclooxygenase (COX)-2, the inducible prostaglandin synthase, is overexpressed in
      cancer and chronic inflammatory diseases. Post-transcriptional regulation of COX
      2 mRNA is important in controlling the expression of the COX-2 gene. Here, we
      report that leptomycin B (LMB), a specific inhibitor of the nuclear export factor
      CRM1 potently inhibits the stabilization of COX-2 mRNA in MDA-MB-231 human
      mammary cancer cells. However, COX-2 promoter-driven reporter gene expression is
      not inhibited by LMB, suggesting that LMB acts at the post-transcriptional level.
      Subcellular fractionation experiments indicate that LMB inhibited the time
      dependent export of COX-2 mRNA into the membrane-bound polysomal compartment at
      the endoplasmic reticulum. LMB suppressed COX-2 expression by interleukin-1beta
      in HT-29 human colon cancer cells and in human umbilical vein endothelial cells
      but had no effect on COX-2 expression induced by Escherichia coli
      lipopolysaccharide in monocytic THP-1 cells. These data suggest that the nuclear
      export of COX-2 mRNA may be rate-liming in a cell-specific manner. LMB may be
      useful to control COX-2 expression in various human diseases in which COX-2 plays
      a pathogenetic role.

PMID- 12468545
TI  - Catalase protects HepG2 cells from apoptosis induced by DNA-damaging agents by
      accelerating the degradation of p53.
AB  - Oxidants such as H(2)O(2) play a role in the toxicity of certain DNA-damaging
      agents, a process that often involves the tumor suppressor p53. H(2)O(2) is
      rapidly degraded by catalase, which protects cells against oxidant injury. To
      study the effect of catalase on apoptosis induced by DNA-damaging agents, HepG2
      cells were infected with adenovirus containing the cDNA of catalase (Ad-Cat).
      Forty-eight hours after infection, catalase protein and activity was increased 7
      10-fold compared with control cells infected with Ad-LacZ. After treatment with
      Vp16 or mitomycin C, control cells underwent apoptosis in a p53-dependent manner;
      however, overexpression of catalase inhibited this apoptosis. Basal levels as
      well as Vp16- or mitomycin C-stimulated levels of p53 and p21 protein were
      decreased in the catalase-overexpressing cells as compared with control cells;
      however, p53 mRNA levels were not decreased by catalase. There was no difference
      in p53 protein synthesis between catalase-overexpressing cells and control cells.
      However, pulse-chase experiments indicated that p53 protein degradation was
      enhanced in the catalase-overexpressing cells. Proteasome inhibitors but not
      calpeptin prevented the catalase-mediated decrease of p53 content. Whereas Vp16
      increased, catalase overexpression decreased the phosphorylation of p53. The
      protein phosphatase inhibitor okadaic acid did not prevent the catalase-mediated
      down-regulation of p53 or phosphorylated p53. These results demonstrate that
      catalase protects HepG2 cells from apoptosis induced by DNA-damaging agents in
      association with decreasing p53 phosphorylation; the latter may lead to an
      acceleration in the degradation of p53 protein by the proteasome complex. This
      suggests that the level of catalase may play a critical role in cell-induced
      resistance to the effects of anti-cancer drugs which up-regulate p53.

PMID- 12468546
TI  - Functional interactions within yeast mediator and evidence of differential
      subunit modifications.
AB  - It is possible to recruit RNA polymerase II to a target promoter and, thus,
      activate transcription by fusing Mediator subunits to a DNA binding domain. To
      investigate functional interactions within Mediator, we have tested such fusions
      of the lexA DNA binding domain to Med1, Med2, Gal11, Srb7, and Srb10 in wild
      type, med1, med2, gal11, sin4, srb8, srb10, and srb11 strains. We found that lexA
      Med2 and lexA-Gal11 are strong activators that are independent of all Mediator
      subunits tested. lexA-Srb10 is a weak activator that depends on Srb8 and Srb11.
      lexA-Med1 and lexA-Srb7 are both cryptic activators that become active in the
      absence of Srb8, Srb10, Srb11, or Sin4. An unexpected finding was that lexA-VP16
      differs from Gal4-VP16 in that it is independent of the activator binding
      Mediator module. Both lexA-Med1 and lexA-Srb7 are stably associated with Med4 and
      Med8, which suggests that they are incorporated into Mediator. Med4 and Med8
      exist in two mobility forms that differ in their association with lexA-Med1 and
      lexA-Srb7. Within purified Mediator, Med4 is present as a phosphorylated lower
      mobility form. Taken together, these results suggest that assembly of Mediator is
      a multistep process that involves conversion of both Med4 and Med8 to their low
      mobility forms.

PMID- 12468547
TI  - Chemokine-cytokine cross-talk. The ELR+ CXC chemokine LIX (CXCL5) amplifies a
      proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B
      pathway.
AB  - It is well established that cytokines can induce the production of chemokines,
      but the role of chemokines in the regulation of cytokine expression has not been
      fully investigated. Exposure of rat cardiac-derived endothelial cells (CDEC) to
      lipopolysaccharide-induced CXC chemokine (LIX), and to a lesser extent to KC and
      MIP-2, activated NF-kappaB and induced kappaB-driven promoter activity. LIX did
      not activate Oct-1. LIX-induced interleukin-1beta and tumor necrosis factor-alpha
      promoter activity, and up-regulated mRNA expression. Increased transcription and
      mRNA stability both contributed to cytokine expression. LIX-mediated cytokine
      gene transcription was inhibited by interleukin-10. Transient overexpression of
      kinase-deficient NF-kappaB-inducing kinase (NIK) and IkappaB kinase (IKK), and
      dominant negative IkappaB significantly inhibited LIX-mediated NF-kappaB
      activation in rat CDEC. Inhibition of G(i) protein-coupled signal transduction,
      poly(ADP-ribose) polymerase, phosphatidylinositol 3-kinase, and the 26 S
      proteasome significantly inhibited LIX-mediated NF-kappaB activation and cytokine
      gene transcription. Blocking CXCR2 attenuated LIX-mediated kappaB activation and
      kappaB-driven promoter activity in rat CDEC that express both CXCR1 and -2, and
      abrogated its activation in mouse CDEC that express only CXCR2. These results
      indicate that LIX activates NF-kappaB and induces kappaB-responsive
      proinflammatory cytokines via either CXCR1 or CXCR2, and involved
      phosphatidylinositol 3-kinase, NIK, IKK, and IkappaB. Thus, in addition to
      attracting and activating neutrophils, the ELR(+) CXC chemokines amplify the
      inflammatory cascade, stimulating local production of cytokines that have
      negative inotropic and proapoptotic effects.

PMID- 12468548
TI  - Synthesis and characterization of the first potent inhibitor of yapsin 1.
      Implications for the study of yapsin-like enzymes.
AB  - The potent peptidic inhibitor, Y1, of the basic residue-specific yeast aspartyl
      protease, yapsin 1, was synthesized and characterized. The inhibitor was based on
      the peptide sequence of a cholecystokinin(13-33) analog that yapsin 1 cleaved
      with an efficiency of 5.2 x 10(5) m(-1) s(-1) (Olsen, V., Guruprasad, K., Cawley,
      N. X., Chen, H. C., Blundell, T. L., and Loh, Y. P. (1998) Biochemistry 37, 2768
      2777). The apparent K(i) of Y1 for the inhibition of yapsin 1 was determined to
      be 64.5 nm, and the mechanism is competitive. Y2 was also developed as an analog
      of Y1 for coupling to agarose beads. The resulting inhibitor-coupled agarose
      beads were successfully used to purify yapsin 1 to apparent homogeneity from
      conditioned medium of a yeast expression system. Utilization of this new reagent
      greatly facilitates the purification of yapsin 1 and should also enable the
      identification of new yapsin-like enzymes from mammalian and nonmammalian
      sources. In this regard, Y1 also efficiently inhibited Sap9p, a secreted aspartyl
      protease from the human pathogen, Candida albicans, which has specificity for
      basic residues similar to yapsin 1 and might provide the basis for the prevention
      or control of its virulence. A single-step purification of Sap9p from conditioned
      medium was also accomplished with the inhibitor column. N-terminal amino acid
      sequence analysis yielded two sequences indicating that Sap9p is composed of two
      subunits, designated here as alpha and beta, similar to yapsin 1.

PMID- 12468549
TI  - Co-repressor release but not ligand binding is a prerequisite for transcription
      activation by human retinoid acid receptor alpha ligand-binding domain.
AB  - Nuclear hormone receptors coordinately regulate the activity of genetic networks
      through the recruitment of transcriptional co-regulators, including co-repressors
      and co-activators. Allosteric modulation of the ligand-binding domain by hormonal
      activators shifts the co-factor binding preference by defined structural changes
      in overlapping docking sites. We report here that mutations at conserved residues
      within the docking motif of the retinoic acid receptor alpha cause defects in
      dimerization, co-regulator association, and transcriptional regulation.
      Furthermore, although a minimal co-repressor receptor interaction domain is
      sufficient for receptor binding, flanking sequences appear to stabilize this
      interaction without interfering with ligand sensitivity. However, ligand
      sensitivity is changed by the K262A mutation, which requires much higher
      concentrations of all-trans-retinoic acid to promote co-repressor dissociation.
      Consequently, K262A functions as a dominant-negative mutant at low concentrations
      of all-trans-retinoic acid. As a result, transcriptional activation is
      mechanistically linked to co-repressor release.

PMID- 12468550
TI  - New insights into the tPA-annexin A2 interaction. Is annexin A2 CYS8 the sole
      requirement for this association?
AB  - Annexin A2 has been described as an important receptor for tissue-type
      plasminogen activator in endothelium and other cell types. Interaction between
      tissue-type plasminogen activator and its cellular receptor is critical for many
      of the functions of this protease. The annexin A2 motif that mediates tissue
      plasminogen activator interaction has been assigned to the hexapeptide LCKLSL in
      the amino-terminal domain of the protein, and it has been proposed that Cys(8) of
      this sequence is essential for tPA binding. In an attempt to identify other amino
      acids critical for tPA-annexin A2 interaction, we have analyzed a set of peptides
      containing several modifications of the original hexapeptide, including glycine
      scans, alanine scans, d-amino acid scans, conservative mutations, cysteine
      blocking, and enantiomer and retroenantiomer sequences. Using a non-radioactive
      competitive binding assay, we have found that all cysteine-containing peptides,
      independently of their sequence, compete the interaction between tPA and annexin
      A2. Cysteine-containing peptides also inhibit tPA binding to the surface of
      cultured human umbilical vein endothelial cells (HUVEC). Mass spectrometry
      demonstrates that the peptides bind through a disulfide bond to a cysteine
      residue of annexin A2, the same mechanism that has been suggested for the
      inhibition mediated by homocysteine. These data call for a revision of the role
      of the LCKLSL sequence as the sole annexin A2 structural region required to bind
      tPA and indicate that further studies are necessary to better define the annexin
      A2-tPA interaction.

PMID- 12468551
TI  - Peroxisome proliferator-activated receptor gamma and transforming growth factor
      beta pathways inhibit intestinal epithelial cell growth by regulating levels of
      TSC-22.
AB  - Peroxisome proliferator-activated receptor gamma (PPARgamma) and transforming
      growth factor-beta (TGF-beta) are key regulators of epithelial cell biology.
      However, the molecular mechanisms by which either pathway induces growth
      inhibition and differentiation are incompletely understood. We have identified
      transforming growth factor-simulated clone-22 (TSC-22) as a target gene of both
      pathways in intestinal epithelial cells. TSC-22 is member of a family of leucine
      zipper containing transcription factors with repressor activity. Although little
      is known regarding its function in mammals, the Drosophila homolog of TSC-22,
      bunched, plays an essential role in fly development. The ability of PPARgamma to
      induce TSC-22 was not dependent on an intact TGF-beta1 signaling pathway and was
      specific for the gamma isoform. Localization studies revealed that TSC-22 mRNA is
      enriched in the postmitotic epithelial compartment of the normal human colon.
      Cells transfected with wild-type TSC-22 exhibited reduced growth rates and
      increased levels of p21 compared with vector-transfected cells. Furthermore,
      transfection with a dominant negative TSC-22 in which both repressor domains were
      deleted was able to reverse the p21 induction and growth inhibition caused by
      activation of either the PPARgamma or TGF-beta pathways. These results place TSC
      22 as an important downstream component of PPARgamma and TGF-beta signaling
      during intestinal epithelial cell differentiation.

PMID- 12468552
TI  - Functional expression of a fusion-dimeric MoFe protein of nitrogenase in
      Azotobacter vinelandii.
AB  - The MoFe protein component of the complex metalloenzyme nitrogenase is an
      alpha2beta2 tetramer encoded by the nifD and the nifK genes. In nitrogen fixing
      organisms, the alpha and beta subunits are translated as separate polypeptides
      and then assembled into tetrameric MoFe protein complex that includes two types
      of metal centers, the P cluster and the FeMo cofactor. In Azotobacter vinelandii,
      the NifEN complex, the site for biosynthesis of the FeMo cofactor, is an
      alpha2beta2 tetramer that is structurally similar to the MoFe protein and encoded
      as two separate polypeptides by the nifE and the nifN genes. In Anabaena
      variabilis it was shown that a NifE-N fusion protein encoded by translationally
      fused nifE and nifN genes can support biological nitrogen fixation. The
      structural similarity between the MoFe protein and the NifEN complex prompted us
      to test whether the MoFe protein could also be functional when synthesized as a
      single protein encoded by nifD-K translational fusion. Here we report that the
      NifD-K fusion protein encoded by nifD-K translational fusion in A. vinelandii is
      a large protein (as determined by Western blot analysis) and is capable of
      supporting biological nitrogen fixation. These results imply that the MoFe
      protein is flexible in that it can accommodate major structural changes and
      remain functional.

PMID- 12468553
TI  - Identification of residues critical for regulation of protein stability and the
      transactivation function of the hypoxia-inducible factor-1alpha by the von Hippel
      Lindau tumor suppressor gene product.
AB  - Under normoxic conditions the hypoxia-inducible factor-1alpha (HIF-1alpha)
      protein is targeted for degradation by the von Hippel-Lindau (pVHL) tumor
      suppressor protein acting as an E3 ubiquitin ligase. Binding of pVHL to HIF
      1alpha is dependent on hydroxylation of specific proline residues by O(2)
      dependent prolyl 4-hydroxylases. Upon exposure to hypoxia the hydroxylase
      activity is inhibited, resulting in stabilization of HIF-1alpha protein levels
      and activation of transcription of target genes. One of the two critical proline
      residues, Pro(563) in mouse HIF-1alpha, is located within a bifunctional domain,
      the N-terminal transactivation domain (N-TAD), which mediates both pVHL-dependent
      degradation at normoxia and transcriptional activation at hypoxia. Here we have
      identified two N-TAD residues, Tyr(564) and Ile(565), which, in addition to
      Pro(563), were critical for pVHL-mediated degradation at normoxia. We have also
      identified D568A/D569A/D570A, F571A, and L573A as mutations of the N-TAD that
      abrogated binding to pVHL both in vitro and in vivo, and constitutively
      stabilized N-TAD against degradation. Moreover, the mutations Y564G, L556A/L558A,
      and F571A/L573A drastically reduced the transactivation function of either the
      isolated N-TAD or full-length HIF-1alpha in hypoxic cells. Interestingly, the
      P563A mutant exhibited a constitutively active and potent transactivation
      function that was enhanced by functional interaction with the transcriptional
      coactivator protein CREB-binding protein. In conclusion, we have identified by
      mutation analysis several residues that are critical for either one or both of
      the interdigitated and conditionally regulated degradation and transactivation
      functions of the N-TAD of HIF-1alpha.

PMID- 12468554
TI  - Post-transcriptional regulation of acetylcholinesterase mRNAs in nerve growth
      factor-treated PC12 cells by the RNA-binding protein HuD.
AB  - Expression of acetylcholinesterase (AChE) is greatly enhanced during neuronal
      differentiation, but the nature of the molecular mechanisms remains to be fully
      defined. In this study, we observed that nerve growth factor treatment of PC12
      cells leads to a progressive increase in the expression of AChE transcripts,
      reaching approximately 3.5-fold by 72 h. Given that the AChE 3'-untranslated
      region (UTR) contains an AU-rich element, we focused on the potential role of the
      RNA-binding protein HuD in mediating the increase in AChE mRNA seen in
      differentiating neurons. Using PC12 cells engineered to stably express HuD or an
      antisense to HuD, our studies indicate that HuD can regulate the abundance of
      AChE transcripts in neuronal cells. Furthermore, transfection of a reporter
      construct containing the AChE 3'-UTR showed that this 3'-UTR can increase
      expression of the reporter gene product in cells expressing HuD but not in cells
      expressing the antisense. RNA gel shifts and Northwestern blots revealed an
      increase in the binding of several protein complexes in differentiated neurons.
      Immunoprecipitation experiments demonstrated that HuD can bind directly AChE
      transcripts. These results show the importance of post-transcriptional mechanisms
      in regulating AChE expression in differentiating neurons and implicate HuD as a
      key trans-acting factor in these events.

PMID- 12468555
TI  - Toxoplasma gondii Rab6 mediates a retrograde pathway for sorting of
      constitutively secreted proteins to the Golgi complex.
AB  - Toxoplasma gondii relies on protein secretion from specialized organelles for
      invasion of host cells and establishment of a parasitophorous vacuole. We
      identify T. gondii Rab6 as a regulator of protein transport between post-Golgi
      dense granule organelles and the Golgi. Toxoplasma Rab6 was localized to
      cisternal rims of the late Golgi and trans-Golgi network, associated transport
      vesicles, and microdomains of dense granule and endosomal membranes.
      Overexpression of wild-type Rab6 or GTP-activated Rab6(Q70L) rerouted soluble
      dense granule secretory proteins to the Golgi and endoplasmic reticulum and
      augmented the effect of brefeldin A on Golgi resorption to the endoplasmic
      reticulum. Parasites expressing a nucleotide-free (Rab6(N124I)) or a GDP-bound
      (Rab6(T25N)) mutant accumulated dense granule proteins in the Golgi and
      associated transport vesicles and displayed reduced secretion of GRA4 and a delay
      in glycosylation of GRA2. Activated Rab6 on Golgi membranes colocalized with
      centrin during mitosis, and parasite clones expressing Rab6 mutants displayed a
      partial shift in cytokinesis from endodyogeny (formation of two daughter cells)
      to endopolygeny (multiple daughter cells). We propose that Toxoplasma Rab6
      regulates retrograde transport from post-Golgi secretory granules to the parasite
      Golgi.

PMID- 12468556
TI  - Treatment of cardiovascular and renal risk factors in the diabetic hypertensive.

PMID- 12468557
TI  - Blood pressure effects of vitamin C: what's the key question?

PMID- 12468558
TI  - Hypertension staging through ambulatory blood pressure monitoring.

PMID- 12468559
TI  - Masked hypertension.

PMID- 12468560
TI  - Lack of long-term effect of vitamin C supplementation on blood pressure.
AB  - In a double-blinded randomized controlled trial, we investigated the long-term
      effect of vitamin C supplementation on blood pressure. A total of 439 Japanese
      subjects with atrophic gastritis initially participated in the trial using
      vitamin C and beta-carotene to prevent gastric cancer. Before and on early
      termination of beta-carotene supplementation, 134 subjects dropped out of this
      trial, whereas 120 and 124 subjects took the vitamin C supplement daily at either
      50 mg or 500 mg, respectively, for 5 years. Before supplementation, neither
      systolic nor diastolic blood pressure was significantly related with the serum
      vitamin C concentration. This relationship was unchanged after adjustment for
      age, body mass index, and alcohol intake or after stratification by gender. After
      5 years, systolic blood pressure significantly increased in groups, regardless of
      vitamin C dose, compared with baseline. Systolic blood pressure in the high-dose
      group (500 mg daily) increased from 125.4 to 131.7 mm Hg (5.88 mm Hg increase;
      95% confidence interval [CI], 3.11 to 8.65). This value was similar with that of
      the low-dose group (5.73 mm Hg increase; 95% CI, 2.62 to 8.83) and of the dropout
      group (4.52 mm Hg increase; 95% CI, 1.26 to 7.77). There was no difference in
      change of diastolic blood pressure among the 3 groups. In conclusion, we observed
      no reduction in blood pressure with long-term moderate doses (500 mg/day) of
      vitamin C supplementation in a high-risk population for stomach cancer and
      stroke.

PMID- 12468561
TI  - Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes.
AB  - Experimental evidence suggests that acute parenteral administration of high-dose
      ascorbic acid has beneficial vascular effects in type 2 diabetes. We studied the
      hemodynamic effects of chronic oral supplementation in this condition. Thirty
      patients, 45 to 70 years of age, with type 2 diabetes, were randomly assigned in
      a double-blind manner to receive 500 mg ascorbic acid daily by mouth or placebo.
      Patients were studied at baseline and after 4 weeks of assigned treatment. The
      central aortic augmentation index (AgIx) and the time to wave reflection (Tr)
      were derived from radial artery pulse wave analysis data. AgIx and Tr were used
      as measures of systemic arterial stiffness and aortic stiffness, respectively.
      Ascorbic acid decreased brachial systolic blood pressure from 142.1+/-12.6 (SD)
      to 132.3+/-12.1 mm Hg (difference [95% CI] 9.9 [4.7, 15.0]; P<0.01), brachial
      diastolic pressure from 83.9+/-4.8 to 79.5+/-6.0 mm Hg (4.4 [1.8, 7.0]; P<0.01),
      and AgIx from 26.8+/-5.5% to 22.5+/-6.8% (4.3 [1.5, 7.1]; P<0.01). Tr increased
      from 137.1+/-12.6 to 143.4+/-9.2 ms (-6.3 [-10.1, -2.5]; P<0.01). Placebo had no
      hemodynamic effects, and this difference between treatments was significant
      (P<0.01 for blood pressure and Tr, P=0.03 for AgIx). We have therefore shown that
      after 1 month, oral ascorbic acid lowered arterial blood pressure and improved
      arterial stiffness in patients with type 2 diabetes. As strict control of blood
      pressure reduces cardiovascular risk in diabetes, ascorbic acid supplementation
      may potentially be a useful and inexpensive adjunctive therapy. Larger and longer
      studies now need to be performed.

PMID- 12468562
TI  - Serum antioxidant vitamins and blood pressure in the United States population.
AB  - Serum vitamin C has been inversely associated with blood pressure in several
      epidemiologic studies, but little is known about effect of other antioxidant
      vitamins. We examined the relation between serum vitamins A, C, and E, alpha
      carotene, and beta-carotene levels and blood pressure among 15 317 men and women
      > or =20 years of age who participated in the Third National Health and Nutrition
      Examination Survey. Blood pressure was characterized as the average of 6
      measurements obtained over 2 visits by trained observers and hypertension was
      defined as blood pressure > or =140/90 mm Hg and/or taking antihypertensive
      medications. In multivariate models, a 1 SD difference in vitamin A (16.2
      microg/dL) and vitamin E (20.4 microg/dL) was associated with a 43% (OR, 1.43;
      95% CI, 1.34 to 1.53) and 18% (OR, 1.18; 95% CI, 1.09 to 1.27) higher odds of
      hypertension, respectively. A 1 SD difference in alpha-carotene (0.47 micro g/dL)
      and beta-carotene (496 microg/dL) was associated with a 16% (OR, 0.84; 95% CI,
      0.76 to 0.94) and 11% (OR, 0.89; 95% CI, 0.82 to 0.97) lower odds of
      hypertension, respectively. In addition, serum vitamins A and E were positively
      and significantly associated with both systolic and diastolic blood pressure,
      whereas alpha-carotene and beta-carotene were inversely and significantly
      associated with systolic and vitamin C associated with diastolic blood pressure
      in multivariate linear regression analyses. These findings indicate that
      antioxidant vitamins may be important in the underlying cause and prevention of
      hypertension. Further studies in this important area are warranted.

PMID- 12468563
TI  - Classification of blood pressure levels by ambulatory blood pressure in
      hypertension.
AB  - Whereas clinic blood pressure (CBP) above normality is divided into stages, no
      corresponding classifications are available for 24-hour ambulatory blood pressure
      (ABP). We conducted a study (1) to define stages of hypertension by ABP
      corresponding to CBP stages and (2) to evaluate if these stages have prognostic
      impact similar to CBP stages. Seven hundred thirty-six hypertensive patients were
      included. Mean systolic blood pressure was 149+/-15.2/87+/-8.6 mm Hg for CBP and
      135+/-13/79+/-9.7 mm Hg for ABP. The mean bias between both methods was -13.3 mm
      Hg (95% CI, -14.3 to -12.2; 1.96xSD limits of agreement, 15.7 to -42.3) and -7.3
      mm Hg (95% CI, -7.9 to -6.6; 1.96xSD limits of agreement, 9.8 to -24.3) for
      systolic and diastolic blood pressure (P>0.0001 for both), respectively.
      Classification of hypertension by ABP revealed lower cutoff values for the
      different stages of hypertension compared with the corresponding cutoff values
      for CBP (CBP versus ABP: 140/90 versus 132/81 mm Hg; 160/100 versus 140/88 mm Hg;
      180/110 versus 148/94 mm Hg, P<0.001). Overall, 82 (11.1%) patients had nonfatal
      clinical cardiovascular events and 9 (1.2%) patients died of a cardiovascular
      cause during follow-up. The distribution of cardiovascular events was
      significantly associated with increasing ABP value (P<0.006). Staging of
      hypertension by ABP may facilitate the use of this method in daily clinical
      practice, as ABP can now be used not only to confirm the diagnosis of
      hypertension but also to assess the severity and prognosis of hypertensive
      disease.

PMID- 12468564
TI  - Ablation of NK1 receptors in rat nucleus tractus solitarii blocks baroreflexes.
AB  - The neuropeptide substance P (SP) is found in vagal afferent nerves within the
      nucleus tractus solitarii, where it is released on stimulation of arterial
      baroreflexes. The neurokinin-1 receptors at which SP may act have been identified
      in the nucleus tractus solitarii, but there remains uncertainty if the neurons at
      which SP acts are critical to baroreflex transmission. By using SP conjugated
      with the toxin saporin, which kills the neurons at which SP may act, we sought to
      test the hypothesis that neurons expressing the neurokinin-1 receptor are
      critical to baroreflex transmission in the nucleus tractus solitarii. One and 2
      weeks after injection of the toxin into the rat nucleus tractus solitarii,
      immunoreactivity for the neurokinin-1 receptor was lost. When the toxin had been
      injected bilaterally, the baroreflex gain was significantly reduced. Therefore,
      neurons that express SP receptors play a critical role in mediating baroreflexes
      through the nucleus tractus solitarii of rat.

PMID- 12468565
TI  - Augmented diurnal variations of the cardiac renin-angiotensin system in
      hypertensive rats.
AB  - There are several controversies concerning the enhanced gene expression of
      cardiac renin-angiotensin system components in spontaneously hypertensive rats
      (SHR) compared with their normotensive control Wistar-Kyoto (WKY) rats. We
      hypothesized that these discrepancies arise from circadian fluctuations in gene
      expression. We examined the circadian mRNA expression of renin, angiotensinogen,
      ACE, and angiotensin type 1a (AT1a) and type 2 (AT2) receptors in the hearts of
      SHR and WKY rats by real-time quantitative reverse transcription-polymerase chain
      reaction. The cardiac mRNA expression of the renin-angiotensin system components
      showed circadian oscillations in both SHR and WKY rats. The amplitudes of these
      circadian fluctuations were greater in the SHR than in the WKY rats. The mRNA
      levels of the renin-angiotensin system components were also increased in the SHR
      compared with the WKY rats at many time points (especially during the dark
      phase). However, the levels of ACE, AT1a receptor, and AT2 receptor mRNA in the
      SHR and WKY rats were almost the same during the late light phase. In contrast to
      mRNA expression, ACE activity was similar both at the time of maximum and minimum
      mRNA expression. The AT1 receptor antagonist candesartan upregulated AT1a
      receptor mRNA and downregulated ACE mRNA at specific time points only in the SHR
      group. Our findings of differential diurnal expression of cardiac renin
      angiotensin system genes in SHR and WKY rats appear to explain the discrepancies
      between prior studies. However, the physiological relevance of the differential
      circadian mRNA expression of the renin-angiotensin system components remains to
      be elucidated.

PMID- 12468566
TI  - Angiotensin II and oxidative stress in Dahl Salt-sensitive rat with heart
      failure.
AB  - Reactive oxygen species have an important pathogenic role in organ damage. We
      investigated the role of oxidative stress via nicotinamide adenine dinucleotide
      phosphate (NAD[P]H) oxidase in the kidney of the Dahl salt-sensitive (DS) rats
      with heart failure (DSHF). Eleven-week-old DS rats fed an 8%-NaCl diet received
      either vehicle or imidapril (1 mg/kg per day) for 7 weeks. The renal expression
      of the NAD(P)H oxidase p47phox and endothelial NO synthase were evaluated. In
      DSHF rats, associated with increased renal angiotensin II, mRNA and protein
      expression of NAD(P)H oxidase p47phox were enhanced with an increase in renal
      lipid peroxidation production (0.33+/-0.03 versus 0.22+/-0.01 nmol/mg protein,
      P<0.05) and urinary excretion of hydrogen peroxide (26.9+/-6.6 versus 9.5+/-2.1
      U/mg creatinine, P<0.01) compared with levels in Dahl salt-resistant rats. The
      endothelial NO synthase expression was decreased in the kidney. Treatment with
      imidapril reduced renal angiotensin II and NAD(P)H oxidase expression and the
      oxidative products (kidney lipid peroxidation product: 0.16+/-0.02, P<0.001;
      urinary hydrogen peroxide: 3.1+/-0.2, P<0.01 versus DSHF rats). Imidapril
      significantly decreased albuminuria and reduced glomerulosclerosis without
      changes in the blood pressure. In conclusion, DSHF rats showed increased
      oxidative stress in the kidney via NAD(P)H oxidase. Blockade of local angiotensin
      II with subpressor dose of imidapril inhibited NAD(P)H oxidase and prevented
      renal damage.

PMID- 12468567
TI  - Endothelin-converting enzyme inhibition ameliorates angiotensin II-induced
      cardiac damage.
AB  - We tested the hypothesis that endothelin-converting enzyme (ECE) inhibition
      ameliorates end-organ damage in rats harboring both human renin and human
      angiotensinogen genes (dTGR). Hypertension develops in the animals, and they die
      by age 7 weeks of heart and kidney failure. Three groups were studied: dTGR
      (n=12) receiving vehicle, dTGR receiving ECE inhibitor (RO0687629; 30 mg/kg by
      gavage; n=10), and Sprague-Dawley control rats (SD; n=10) receiving vehicle, all
      after week 4, with euthanasia at week 7. Systolic blood pressure was not reduced
      by ECE inhibitor compared with dTGR (205+/-6 versus 206+/-6 mm Hg at week 7,
      respectively). In contrast, ECE inhibitor treatment significantly reduced
      mortality rate to 20% (2 of 10), whereas untreated dTGR had a 52% mortality rate
      (7 of 12). ECE inhibitor treatment ameliorated cardiac damage and reduced left
      ventricular ECE activity below SD levels. Echocardiography at week 7 showed
      reduced cardiac hypertrophy (4.8+/-0.2 versus 5.7+/-0.2 mg/g, P<0.01) and
      increased left ventricular cavity diameter (5.5+/-0.3 versus 3.1+/-0.1 mm,
      P<0.001) and filling volume (0.42+/-0.04 versus 0.16+/-0.06 mL, P<0.05) after ECE
      inhibitor compared with untreated dTGR. ECE inhibitor treatment also reduced
      cardiac fibrosis, tissue factor expression, left ventricular basic fibroblast
      growth factor mRNA levels, and immunostaining in the vessel wall, independent of
      high blood pressure. In contrast, the ECE inhibitor treatment showed no
      renoprotective effect. These data are the first to show that ECE inhibition
      reduces angiotensin II-induced cardiac damage.

PMID- 12468568
TI  - AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the
      endothelium.
AB  - Recently, we demonstrated that the heptapeptide angiotensin-(1-7) (Ang-[1-7])
      exhibits a favorable kinetic of nitric oxide (NO) release accompanied by
      extremely low superoxide (O2-) production. In this report we describe AVE 0991, a
      novel nonpeptide compound that evoked effects similar to Ang-(1-7) on the
      endothelium. AVE 0991 and unlabeled Ang-(1-7) competed for high-affinity binding
      of [125I]-Ang-(1-7) to bovine aortic endothelial cell membranes with IC50 values
      of 21+/-35 and 220+/-280 nmol/L, respectively. Stimulated NO and O2- release from
      bovine aortic endothelial cells was directly and simultaneously measured on the
      cell surface by selective electrochemical nanosensors. Peak concentrations of NO
      and O2- release by AVE 0991 and Ang-(1-7) (both 10 micromol/L) were not
      significantly different (NO: 295+/-20 and 270+/-25 nmol/L; O2-: 18+/-2 and 20+/-4
      nmol/L). However, the released amount of bioactive NO was approximately 5 times
      higher for AVE 0991 in comparison to Ang-(1-7). The selective Ang-(1-7)
      antagonist [D-Ala(7)]-Ang-(1-7) inhibited the AVE 0991-induced NO and O2-
      production by approximately 50%. A similar inhibition level was observed for the
      Ang II AT1 receptor antagonist EXP 3174. In contrast, the Ang II AT2 receptor
      antagonist PD 123,177 inhibited the AVE 0991-stimulated NO production by
      approximately 90% but without any inhibitory effect on O2- production. Both NO
      and O2- production were inhibited by NO synthase inhibition ( approximately 70%)
      and by bradykinin B2 receptor blockade (approximately 80%). AVE 0991 efficiently
      mimics the effects of Ang-(1-7) on the endothelium, most probably through
      stimulation of a specific, endothelial Ang-(1-7)-sensitive binding site causing
      kinin-mediated activation of endothelial NO synthase.

PMID- 12468569
TI  - Effect of AT2 receptor on expression of AT1 and TGF-beta receptors in VSMCs from
      SHR.
AB  - We recently reported that overexpression of the angiotensin II type 2 (AT2)
      receptor downregulates the AT1a receptor through the bradykinin/NO pathway in a
      ligand-independent manner in vascular smooth muscle cells (VSMCs). In the present
      study, we investigated the effect of AT2 receptor overexpression on the
      expression of the AT1a receptor and transforming growth factor-beta (TGF-beta)
      receptor subtypes in VSMCs from spontaneously hypertensive rats (SHR) and Wistar
      Kyoto rats (WKY). Transfection of the AT2 receptor gene downregulated expression
      of the AT1a receptor in VSMCs from WKY, but did not affect expression of the AT1a
      receptor in VSMCs from SHR. Transfection of the AT2 receptor abolished DNA
      synthesis in response to angiotensin II in VSMCs from WKY; in VSMCs from SHR,
      basal DNA synthesis was suppressed, but DNA synthesis in response to Ang II was
      not altered. The NO substrate L-arginine augmented downregulation of the AT1a
      receptor in VSMCs from WKY, whereas it did not affect expression of the AT1a
      receptor in VSMCs from SHR. In response to AT2 receptor transfection, expression
      of TGF-beta type I receptor mRNA was suppressed significantly in VSMCs from WKY,
      whereas expression of TGF-beta type I receptor was not altered in VSMCs from SHR.
      These results suggest that the AT2 receptor downregulates AT1a and TGF-beta type
      I receptors in normal VSMCs, but not in SHR-derived VSMCs. The lack of
      downregulation of the AT1a receptor may contribute, in part, to the exaggerated
      growth of VSMCs from SHR.

PMID- 12468570
TI  - ACE inhibition versus angiotensin type 1 receptor antagonism: differential
      effects on PAI-1 over time.
AB  - ACE inhibition reduces plasminogen activator inhibitor-1 (PAI-1), a risk factor
      for myocardial infarction, whereas the effect of angiotensin receptor antagonism
      on PAI-1 is uncertain. The present study compares the time course of effects of
      ACE inhibition and angiotensin type 1 (AT1) receptor antagonism on morning plasma
      PAI-1 antigen. Blood pressure and endocrine, metabolic, and fibrinolytic
      variables were measured in 20 insulin-resistant (defined by fasting glucose >8.3
      mmol/L, body mass index >28 kg/m2, or fasting serum triglyceride > or =2.8
      mmol/L) hypertensive subjects (mean age, 47.9+/-2.1 years) (1) before and after 1
      week of hydrochlorothiazide 12.5 mg/d, and (2) before and 1, 3, 4, and 6 weeks
      after addition of ramipril (escalated to 10 mg/d) or losartan (escalated to 100
      mg/d). Hydrochlorothiazide decreased systolic (P=0.011) and diastolic (P=0.019)
      pressure. Ramipril (from 133.6+/-5.1/94.5+/-2.4 to 127.0+/-3.1/91.4+/-3.3 mm Hg)
      or losartan (from 137.0+/-3.9/93.1+/-2.9 to 123.7+/-2.6/86.4+/-2.1 mm Hg) further
      reduced systolic (P=0.009) and diastolic (P=0.037) pressure. The pressure effects
      of the 2 drugs were similar. Hydrochlorothiazide increased plasma PAI-1 (P=0.013)
      but not tissue-type plasminogen activator (tPA) (P=0.431) antigen. Addition of
      either ramipril or losartan significantly decreased plasma PAI-1 antigen
      (P=0.046). However, the effect of losartan on PAI-1 antigen was not sustained
      throughout the 6-week treatment period, such that there was a significant
      drugxtime interaction (P=0.043). tPA antigen decreased during either ramipril or
      losartan (P=0.032), but tPA activity decreased only during losartan (P=0.018).
      Short-term interruption of the renin-angiotensin-aldosterone system by either ACE
      inhibition or AT1 receptor antagonism decreases PAI-1 antigen, but the duration
      of this effect is greater for ACE inhibition than for AT1 receptor antagonism.

PMID- 12468572
TI  - Angiotensin II-induced insulin resistance is associated with enhanced insulin
      signaling.
AB  - Angiotensin II (AII) is involved in the pathogenesis of both hypertension and
      insulin resistance, though few studies have examined the relationship between the
      two. We therefore investigated the effects of chronic AII infusion on blood
      pressure and insulin sensitivity in rats fed a normal (0.3% NaCl) or high-salt
      (8% NaCl) diet. AII infusion for 12 days significantly elevated blood pressure
      and significant insulin resistance, assessed by a hyperinsulinemic-euglycemic
      clamp study and glucose uptake into isolated muscle and adipocytes. High-salt
      loading exacerbated the effects of AII infusion significantly. Despite the
      insulin resistance, insulin-induced tyrosine phosphorylation of the insulin
      receptor and insulin receptor substrates, activation of phosphatidylinositol (PI)
      3-kinase, and phosphorylation of Akt were all enhanced by AII infusion.
      Subsequently, to investigate whether oxidative stress induced by AII contributes
      to insulin resistance, the membrane-permeable superoxide dismutase mimetic,
      tempol, was administered to AII-infused rats. Chronic AII infusion induced an
      accumulated plasma cholesterylester hydroperoxide levels, indicating the
      increased oxidative stress, whereas the treatment with tempol normalized plasma
      cholesterylester hydroperoxide levels in AII-infused rats. In addition, the
      treatment with tempol normalized insulin resistance in AII-infused rats, shown as
      a decreased glucose infusion rate in the hyperinsulinemic euglycemic clamp study
      and a decreased insulin-induced glucose uptake into isolated skeletal muscle, as
      well as enhanced insulin-induced PI 3-kinase activation to those in the control
      rats. These results strongly suggest that AII-induced insulin resistance cannot
      be attributed to impairment of early insulin-signaling steps and that increased
      oxidative stress, possibly through impaired insulin signaling located downstream
      from PI 3-kinase activation, is involved in AII-induced insulin resistance.

PMID- 12468571
TI  - PPARalpha activator effects on Ang II-induced vascular oxidative stress and
      inflammation.
AB  - Docosahexaenoic acid (DHA), a peroxisome proliferator-activated receptor-alpha
      (PPARalpha) activator, reduces blood pressure (BP) in some hypertensive models by
      unclear mechanisms. We tested the hypothesis that DHA would prevent BP elevation
      and improve vascular dysfunction in angiotensin (Ang) II-infused rats by
      modulating of NADPH oxidase activity and inflammation in vascular wall. Sprague
      Dawley rats received Ang II (120 ng/kg per minute SC) with or without DHA (2.5 mL
      of oil containing 40% DHA/d PO) for 7 days. Systolic BP (mm Hg), elevated in Ang
      II-infused rats (172+/-3) versus controls (108+/-2, P<0.01), was reduced by DHA
      (112+/-4). In mesenteric small arteries studied in a pressurized myograph,
      media/lumen ratio was increased (P<0.05) and acetylcholine-induced relaxation
      impaired in Ang II-infused rats (P<0.05); both were normalized by DHA. In blood
      vessels of Ang II-infused rats, NADPH oxidase activity measured by
      chemiluminescence and expression of adhesion molecules intercellular adhesion
      molecule and vascular cell adhesion molecule-1 were significantly increased.
      These changes were abrogated by DHA. PPARalpha activator DHA attenuated the
      development of hypertension, corrected structural abnormalities, and improved
      endothelial dysfunction induced by Ang II. These effects are associated with
      decreased oxidative stress and inflammation in the vascular wall.

PMID- 12468573
TI  - Rosiglitazone treatment restores renal dopamine receptor function in obese Zucker
      rats.
AB  - Earlier we have reported a defective dopamine D1-like receptor function, which
      was accompanied by a decrease in D1 receptor numbers and the inability of
      dopamine to inhibit Na,K-ATPase and Na,H-exchanger in proximal tubules of
      hyperinsulinemic obese Zucker rats. The present study was designed to test the
      hypothesis that the defect in dopamine receptor function is a result of
      hyperinsulinemia in obese rats. We designed experiments to study D1 receptor
      function in obese Zucker rats treated with rosiglitazone, as it lowers plasma
      insulin by improving insulin sensitivity. A group of untreated lean and obese
      rats served as controls. Rosiglitazone treatment (10 mg/kg orally, 4 weeks)
      caused significant decreases in plasma insulin, blood glucose, and blood pressure
      while causing an increase in renal sodium excretion compared with untreated obese
      rats. In the isolated proximal tubules obtained from untreated lean rats,
      dopamine caused concentration-dependent inhibition of the Na,K-ATPase activity,
      but this inhibitory effect was absent in untreated obese rats. In rosiglitazone
      treated obese rats, the inhibitory effect of dopamine on Na,K-ATPase was
      significantly restored. This was accompanied by a complete restoration of D1
      receptor numbers in proximal tubular membranes of treated obese rats. In another
      set of experiments, treatment of primary proximal tubule epithelial cells in
      culture medium with insulin caused a significant decrease in the D1 receptor
      abundance, suggesting a direct role of insulin on D1 receptor regulation. We
      conclude that hyperinsulinemia causes downregulation of D1 receptor function and
      lowering of plasma insulin levels leads to restoration of renal D1 receptor
      function.

PMID- 12468574
TI  - Insulin resistance but not inflammation is associated with gestational
      hypertension.
AB  - Hypertensive disorders of pregnancy, including gestational hypertension and
      preeclampsia, are leading causes of pregnancy-associated morbidity. Although
      insulin resistance and inflammation contribute to preeclampsia, prospective data
      regarding mechanisms of gestational hypertension are sparse. We conducted a
      prospective, nested case-control study to test the hypotheses that insulin
      resistance, marked by reduced sex hormone-binding globulin (SHBG) levels, and
      inflammation, marked by increased C-reactive protein levels, are similarly
      associated with gestational hypertension. We measured first-trimester C-reactive
      protein and SHBG levels in 51 women who subsequently developed gestational
      hypertension and 102 randomly selected normotensive pregnant controls. Compared
      with controls, first-trimester SHBG levels were significantly reduced among women
      who later developed gestational hypertension (176+/-73 versus 203+/-79 nmol/L;
      P=0.03), but there was no difference in C-reactive protein levels. There was
      statistically significant interaction among nulliparity, first-trimester SHBG
      levels, and risk of gestational hypertension, such that increasing SHBG levels
      were associated with significantly reduced risk of gestational hypertension among
      nulliparous women (odds ratio, 0.64 per 50-nmol/L increase; 95% confidence
      interval, 0.46, 0.90; P<0.01) but not among multiparous women. This association
      remained significant after adjusting for potential confounders (odds ratio, 0.55;
      95% confidence interval, 0.31, 0.98; P=0.04). We conclude that insulin
      resistance, but not inflammation, is an independent risk factor for gestational
      hypertension among nulliparous women. Furthermore, important mechanistic
      differences exist in the pathogenesis of gestational hypertension comparing
      nulliparous and multiparous women.

PMID- 12468575
TI  - Hyperaldosteronism among black and white subjects with resistant hypertension.
AB  - Recent reports suggesting that the prevalence of primary hyperaldosteronism may
      be higher than historically thought have relied on an elevated plasma aldosterone
      concentration/plasma renin activity ratio to either diagnose or identify subjects
      at high risk of having primary hyperaldosteronism and have not included
      suppression testing of all evaluated subjects. In this prospective study of 88
      consecutive patients referred to a university clinic for resistant hypertension,
      we determined the 24-hour urinary aldosterone excretion during high dietary salt
      ingestion, baseline plasma renin activity, and plasma aldosterone in all
      subjects. Primary hyperaldosteronism was confirmed if plasma renin activity was
      <1.0 ng/mL per hour and urinary aldosterone was >12 microg/24-hour during high
      urinary sodium excretion (>200 mEq/24-hour). Eighteen subjects (20%) were
      confirmed to have primary hyperaldosteronism. The prevalence of
      hyperaldosteronism was similar in black and white subjects. Of the 14 subjects
      with confirmed hyperaldosteronism who have been treated with spironolactone, all
      have manifested a significant reduction in blood pressure. In this population, an
      elevated plasma aldosterone/plasma renin activity ratio (>20) had a sensitivity
      of 89% and a specificity of 71% with a corresponding positive predictive value of
      44% and a negative predictive value of 96%. These data provide strong evidence
      that hyperaldosteronism is a common cause of resistant hypertension in black and
      white subjects. The accuracy of these results is strengthened by having done
      suppression testing of all evaluated subjects.

PMID- 12468576
TI  - Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism.
AB  - Primary aldosteronism is a specifically treatable and potentially curable form of
      secondary hypertension. The aldosterone/plasma renin activity ratio (ARR) is
      routinely used as a screening test. Antihypertensive therapy can interfere with
      the interpretation of this parameter, but a correct washout period can be
      potentially harmful. We have investigated the effects of therapy with atenolol,
      amlodipine, doxazosin, fosinopril, and irbesartan on the ARR in a group of 230
      patients with suspected primary aldosteronism. The percent change from control of
      ARR in patients taking amlodipine was -17%+/-32; atenolol, 62%+/-82; doxazosin, 
      5%+/-26; fosinopril, -30%+/-24; and irbesartan, -43%+/-27. The ARR change induced
      by atenolol was significantly higher compared with that induced by all other
      drugs (P<0.0001), and the ARR change induced by irbesartan was significantly
      lower than that induced by doxazosin (P<0.0001). One of 55 patients from the
      group taking amlodipine (1.8%) and 4/17 of the patients taking irbesartan (23.5%)
      gave a false-negative ARR (<50). None of the patients of the groups taking
      fosinopril, doxazosin, and atenolol displayed a false-negative ARR. Doxazosin and
      fosinopril can be used in hypertensive patients who need to undergo aldosterone
      and PRA measurement for the diagnosis of primary aldosteronism; amlodipine gave a
      very small percentage of false-negative diagnoses. beta-Blockers also do not
      interfere with the diagnosis of primary aldosteronism, but they can be
      responsible for an increased rate of false-positive ARRs. The high rate of false
      negative diagnoses in patients undergoing irbesartan treatment requires
      confirmation in a higher number of patients.

PMID- 12468577
TI  - Racial difference in the activity of the amiloride-sensitive epithelial sodium
      channel.
AB  - Compared with whites, blacks appear to retain additional sodium that suppresses
      secretion of renin and aldosterone. The epithelial sodium channel (ENaC) is an
      aldosterone-regulated site for sodium reabsorption. ENaC activity could be higher
      in blacks, contributing to sodium retention or, alternatively, lower because of
      reduced stimulation by aldosterone. To examine the level of ENaC activity in
      blacks relative to whites, blood pressure (BP) responses to amiloride (5 mg/d),
      an inhibitor of ENaC, were measured in 20 black and 25 white normotensive young
      people. After 1 week, systolic BP decreased by 3.0+/-9.2 (SD) and diastolic by
      2.8+/-8.3 mm Hg in the whites, whereas systolic BP increased by 2.5+/-7.1 and
      diastolic by 3.8+/-8.0 mm Hg in the blacks; the racial difference in the BP
      response was significant for both systolic (P=0.034) and diastolic BP (P=0.010).
      As ENaC activity increases, renal secretion of potassium increases
      proportionately, and in a larger sample of subjects, the urinary potassium
      excretion rate was lower in the blacks (n=301) than in the whites (n=461): 3.2+/
      0.1 versus 3.8+/-0.1 mmol/mmol creatinine (P=0.0001). The concentration of serum
      potassium was higher in the blacks (n=81) than in the whites (n=167): 4.36+/-0.05
      versus 4.21+/-0.03 (P=0.012). In summary, a favorable BP response to amiloride in
      the whites as well as the evidence for greater retention of potassium in the
      blacks is consistent with blacks having less ENaC activity than whites. We
      suggest that increased sodium retention in blacks occurring at other nephron
      sites suppresses aldosterone secretion and in turn ENaC function.

PMID- 12468578
TI  - Effects of doxazosin and propranolol on A2A adenosine receptors in essential
      hypertension.
AB  - A2A adenosine receptors inhibit neutrophil adhesion and superoxide anion
      generation. The aim of the present study was to evaluate the effect of
      antihypertensive treatment with doxazosin or propranolol on the binding and
      functional parameters of A2A adenosine receptors of lymphocytes and neutrophils
      in essential hypertensive patients. Two groups of previously untreated, essential
      hypertensive patients were studied. The mean affinity (K(d)) and density (B(max))
      of adenosine receptors, by the A2A selective radioligand [3H]-ZM-241385 binding
      assays, and EC50, by cAMP assays, were obtained first on no medication and a
      second time after treatment for up to 13 weeks with doxazosin (13 patients) or
      propranolol (8 patients). A third group of 15 healthy normotensive volunteers
      matched by age, sex, and body mass index was used as a control. Binding and
      functional parameters of the A2A adenosine receptors were significantly higher in
      the 2 hypertensive groups than in controls (P always <0.0001), both in lymphocyte
      and neutrophil membranes. After treatment with propranolol, the binding
      parameters did not change significantly, whereas after treatment with doxazosin,
      K(d), B(max), and EC50 values returned to control levels. In never-treated
      essential hypertensive patients, lower affinity, higher density, and impaired
      function of A2A adenosine receptors are present. The binding and functional
      parameters of A2A adenosine receptors appear to be normalized after treatment
      with doxazosin but not with propranolol.

PMID- 12468579
TI  - Reactivity as a predictor of subsequent blood pressure: racial differences in the
      Coronary Artery Risk Development in Young Adults (CARDIA) Study.
AB  - This study investigated the association between cardiovascular reactivity and
      subsequent ambulatory blood pressure in 316 black and white men and women in the
      Coronary Artery Risk Development in Young Adults (CARDIA) Study. Cardiovascular
      laboratory reactivity was examined in subjects 20 to 33 years old, and ambulatory
      blood pressure and heart rate were measured 3 years later. Average ambulatory
      pressure during a 24-hour period was regressed separately on stress reactivity
      and standard covariate risk factors in each race/gender subgroup. Blacks had
      higher blood pressure and heart rates than whites, men had higher blood pressure
      than women, and women had higher heart rates than men. After controlling for age,
      baseline systolic pressure, familial history of hypertension, smoking, alcohol
      consumption, body mass index, and exercise, systolic blood pressure reactivity to
      star tracing and cold pressor stress were significantly associated with systolic
      ambulatory pressure in black men and women 3 years later (partial r=0.24 to
      0.37). Heart rate reactivity to video challenge and star tracing were also
      significantly predictive of subsequent ambulatory heart rate in blacks. Diastolic
      star tracing reactivity was significantly associated with subsequent ambulatory
      blood pressure in black women (r=0.23), and diastolic reactivity to video and
      star tracing were significantly predictive of ambulatory diastolic pressure in
      white men (r=0.39). We conclude that hyperresponsivity to stress may be a risk
      factor for subsequent blood pressure elevation in blacks and may be one pathway
      leading to the higher prevalence of hypertension in blacks than in whites.

PMID- 12468580
TI  - Prevalence, awareness, treatment, and control of hypertension in china.
AB  - The objective of this study was to estimate the prevalence and distribution of
      hypertension and to determine the status of hypertension awareness, treatment,
      and control in the general adult population in China. The International
      Collaborative Study of Cardiovascular Disease in ASIA (InterASIA), conducted in
      2000-2001, used a multistage cluster sampling method to select a nationally
      representative sample. A total of 15 540 adults, age 35 to 74 years, were
      examined. Three blood pressure measurements were obtained by trained observers by
      use of a standardized mercury sphygmomanometer after a 5-minute sitting rest.
      Information on history of hypertension and use of antihypertensive medications
      was obtained by use of a standard questionnaire. Hypertension was defined as a
      mean systolic blood pressure > or =140 mm Hg, diastolic blood pressure > or =90
      mm Hg, and/or use of antihypertensive medications. Overall, 27.2% of the Chinese
      adult population age 35 to 74 years, representing 129 824 000 persons, had
      hypertension. The age-specific prevalence of hypertension was 17.4%, 28.2%,
      40.7%, and 47.3% in men and 10.7%, 26.8%, 38.9%, and 50.2% in women age 35 to 44
      years, 45 to 54 years, 55 to 64 years, and 65 to 74 years, respectively. Among
      hypertensive patients, only 44.7% were aware of their high blood pressure, 28.2%
      were taking antihypertensive medication, and 8.1% achieved blood pressure control
      (<140/90 mm Hg). Our results indicate that hypertension is highly prevalent in
      China. The percentages of those with hypertension who are aware, treated, and
      controlled are unacceptably low. These results underscore the urgent need to
      develop national strategies to improve prevention, detection, and treatment of
      hypertension in China.

PMID- 12468581
TI  - Loss of chromosome 16 from renal epithelial cells in humans.
AB  - This work explores the notion that low-frequency, acquired aneuploidy may play a
      role in complex genetic traits such as essential hypertension. To this end, renal
      epithelial cells in urinary sediments and in renal cysts were examined by
      fluorescent in situ hybridization with DNA probes specific for the
      heterochromatic and centromere regions of chromosomes 16 and 1. Chromosome 16 was
      probed because it harbors variant genes causing monogenic hypertension. These
      genes have also been investigated for their role in essential hypertension.
      Chromosome 1 was also probed as an internal control. Higher proportions of renal
      epithelial cells in the urinary sediments showed monosomy of chromosome 16 than
      monosomy of chromosome 1 (P<0.001). We also observed in epithelial cells of renal
      cysts a preponderance of monosomy for chromosome 16 over monosomy for chromosome
      1 (P<0.024). Low-frequency loss of heterozygosity that results from acquired
      monosomy of chromosome 16 and perhaps other chromosomes may contribute to
      expression of complex genetic traits such as essential hypertension, in which the
      diverse phenotypic manifestations are poorly understood.

PMID- 12468582
TI  - Blunted tubuloglomerular feedback by absence of angiotensin type 1A receptor
      involves neuronal NOS.
AB  - To define the role of angiotensin type 1A (AT1A) receptor in modulating
      tubuloglomerular feedback signals and to determine its relationship to neuronal
      NO synthase (nNOS), the diameter of the afferent arterioles of wild-type and AT1A
      receptor-deficient mice was measured by the blood-perfused juxtamedullary nephron
      technique. The afferent arteriolar diameter of wild-type and AT1A receptor
      deficient mice averaged 16.7+/-0.6 (n=9) and 16.8+/-0.7 micro m (n=9),
      respectively. In the wild-type mice, addition of 10 micro mol/L acetazolamide to
      the blood perfusate exerted a biphasic afferent arteriolar constriction, with the
      initial response and sustained response averaging 47.2+/-3.8% and 33.9+/-3.3%,
      respectively. In AT1A receptor-deficient mice, the initial response and sustained
      response averaged 51.6+/-3.6% and 9.5+/-1.3%, respectively, and the sustained
      response was significantly attenuated compared with that of wild-type mice.
      Inhibition of nNOS with 10 micro mol/L S-methyl-L-thiocitrulline significantly
      decreased the afferent arteriolar diameter of AT1A receptor-deficient mice, from
      15.1+/-1.2 to 5.0+/-0.3 micro m (n=7), and the decrease was significantly greater
      than that observed in wild-type mice (from 15.9+/-1.2 to 10.6+/-1.3 micro m;
      n=8). During nNOS inhibition, the initial and sustained afferent arteriolar
      constrictor responses to acetazolamide in wild-type mice averaged 54.4+/-6.4% and
      44.8+/-11.3%; respectively, and were similar to those in AT1A receptor-deficient
      mice (53.2+/-6.4% and 59.5+/-4.4%, respectively). These results suggest that AT1A
      receptors enhance tubuloglomerular feedback-mediated afferent arteriolar
      constriction, at least in part, through reducing the counteracting modulation by
      nNOS.

PMID- 12468583
TI  - Increase in Cx45 gap junction channels in cerebral smooth muscle cells from SHR.
AB  - We recently reported the novel finding of expression and function of connexin45
      (Cx45) in cerebrovascular smooth muscle cells. We examined the hypothesis that
      Cx45 is altered in hypertension. Immunoblots for Cx45 showed a significant
      increase in Cx45 in cerebral arteries from adult spontaneously hypertensive rats
      (SHR) compared with adult Wistar-Kyoto (WKY) rats, with no difference in aorta or
      femoral artery. Patch-clamp of cerebral smooth muscle cells pairs from SHR versus
      WKY showed a significantly steeper voltage dependence of deactivation and partial
      block of junctional currents by quinine and by a peptide that interferes with
      docking of Cx45, consistent with dominance of functional Cx45 channels in SHR. We
      examined potential roles of blood pressure versus angiotensin in elevated Cx45 in
      SHR by measuring Cx45 protein in 4 groups: (1) long-term administration in Wistar
      rats of the nitric oxide synthase inhibitor L-NAME; (2) long-term administration
      in SHR of the ACE inhibitor captopril; (3) long-term administration in Wistar
      rats of angiotensin; and (4) exposure of basilar artery segments in organ culture
      to angiotensin. Blood pressure was significantly elevated in groups 1 and 3 and
      was normal in group 2. In groups 1, 2, and 4, there was no significant change in
      Cx45 protein. In group 3, there was a modest but insignificant increase in Cx45
      protein but no change in voltage dependence of deactivation of junctional
      currents. Overall, our data show increased Cx45 in SHR that is unlikely to be due
      to either elevated blood pressure or to angiotensin. Relative dominance of Cx45
      over Cx43 in cerebral vessels may predispose SHR to ischemic stroke.

PMID- 12468586
TI  - Arterial pulse wave velocity and heart rate.

PMID- 12468584
TI  - Cyclooxygenase-2 inhibition attenuates lipopolysaccharide-induced cardiovascular
      failure.
AB  - The present study aimed to determine the relevance of cyclooxygenase-2 (COX-2)
      derived prostanoids for the adverse effects of lipopolysaccharides (LPSs) on
      cardiovascular function. For this goal, male Sprague-Dawley rats received a
      single intravenous dose of LPS (10 mg/kg) and were treated with different
      cyclooxygenase inhibitors. Injection of LPS caused a marked decrease of systolic
      arterial pressure, from 128 to 79 mm Hg, and a concomitant increase of heart
      rate, from 380 to 530 minutes(-1). Both the decrease of systemic arterial
      pressure and the increase of heart rate induced by LPS were almost absent if the
      animals also received the COX-2 blocker rofecoxib (20 mg/kg), regardless whether
      the drug was given 1 hour before or 1 hour after LPS. Although plasma and organ
      levels of prostanoids were lowered by rofecoxib, the characteristic LPS-induced
      increases of NO synthase II and COX-2 gene expression, as well as of plasma and
      tissue nitrate/nitrite concentrations, were not affected by rofecoxib. Although
      rofecoxib treatment did also not change LPS-induced tissue cytokine
      concentrations, it markedly improved LPS-induced liver damage, as indicated by
      the decrease of transaminases. Moreover, the overall well-being of the LPS
      injected animals improved on concomitant treatment with the COX-2 inhibitor.
      Taken together, our data suggest that COX-2-derived prostanoids are major
      mediators for the detrimental effects of LPS on cardiovascular and organ
      function.

PMID- 12468587
TI  - Central aortic pressure influences pulse wave velocity.

PMID- 12468588
TI  - Endothelin Antagonism and Insulin's Vascular Effects.

PMID- 12468589
TI  - Howerde E. Sauberlich, 1919-2001.

PMID- 12468590
TI  - (n-3) Fatty acids and infectious disease resistance.
AB  - The current view of the manner in which (n-3) polyunsaturated fatty acids (PUFA)
      affect the immune system is centered on their ability to alter cytokine
      production and secondarily to diminish eicosanoid biosynthesis. The purpose of
      this article is to review the evidence that (n-3) PUFA affect host infectious
      disease resistance. Although there have been a few human clinical trials
      involving (n-3) PUFA and human infectious disease, the data are equivocal and the
      study designs confounded by the simultaneous inclusion of other immunonutrients
      (i.e., arginine and nucleotides) with the (n-3) PUFA. Thus, this review focuses
      on animal feeding trials that include an in vivo challenge of the host with a
      live infectious agent. Host survival and pathogen clearance are the most common
      end points measured in these studies. The data suggest that (n-3) PUFA can both
      improve and impair host resistance to a number of pathogens. However, the data
      are still quite limited in breadth and depth. For those pathogens for which data
      exist, the number of published studies in general does not exceed two or three.
      Emphasis is placed on defining important microbiological and immunological
      differences in various host-pathogen interactions that might help explain the
      incongruity in the findings published to date. The authors believe that direct
      examination of (n-3) PUFA on human infectious disease resistance is warranted.

PMID- 12468591
TI  - The clinical importance of the metabolite equol-a clue to the effectiveness of
      soy and its isoflavones.
AB  - Equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman] is a nonsteroidal estrogen of the
      isoflavone class. It is exclusively a product of intestinal bacterial metabolism
      of dietary isoflavones and it possesses estrogenic activity, having affinity for
      both estrogen receptors, ERalpha and ERbeta. Equol is superior to all other
      isoflavones in its antioxidant activity. It is the end product of the
      biotransformation of the phytoestrogen daidzein, one of the two main isoflavones
      found in abundance in soybeans and most soy foods. Once formed, it is relatively
      stable; however, equol is not produced in all healthy adults in response to
      dietary challenge with soy or daidzein. Several recent dietary intervention
      studies examining the health effects of soy isoflavones allude to the potential
      importance of equol by establishing that maximal clinical responses to soy
      protein diets are observed in people who are good "equol-producers." It is now
      apparent that there are two distinct subpopulations of people and that "bacterio
      typing" individuals for their ability to make equol may hold the clue to the
      effectiveness of soy protein diets in the treatment or prevention of hormone
      dependent conditions. In reviewing the history of equol, its biological
      properties, factors influencing its formation and clinical data, we propose a new
      paradigm. The clinical effectiveness of soy protein in cardiovascular, bone and
      menopausal health may be a function of the ability to biotransform soy
      isoflavones to the more potent estrogenic isoflavone, equol. The failure to
      distinguish those subjects who are "equol-producers" from "nonequol producers" in
      previous clinical studies could plausibly explain the variance in reported data
      on the health benefits of soy.

PMID- 12468592
TI  - Dietary soy and soy isoflavones have gender-specific effects on plasma lipids and
      isoflavones in golden Syrian f(1)b hybrid hamsters.
AB  - The specific components of soy responsible for its beneficial effects on plasma
      lipids are unknown. Golden Syrian F(1)B Hybrid hamsters (75 male, 74 female) were
      evaluated for the effect of dietary soy and soy isoflavones on plasma lipids.
      They were fed the following diets for 16 wk: casein/lactalbumin (C/L), soy
      protein with isoflavones [Soy(+)], soy protein with isoflavones removed [Soy(-)],
      Soy(-) plus isoflavone extract (IF), and C/L + IF. At necropsy, plasma total
      cholesterol, HDL cholesterol (HDLC), LDL + VLDL cholesterol (LDL + VLDLC),
      isoflavones, and uterine and accessory gland weights were measured. Male hamsters
      fed the three soy-containing diets had lower LDL + VLDLC concentrations than
      those fed the two C/L diets (P < 0.01), and those fed Soy(-) + IF did not differ
      from those fed Soy(+). In females, diet did not affect plasma LDL + VLDLC
      concentration. Females fed Soy(+) or Soy(-) had higher HDLC (P < 0.05) than those
      fed C/L. HDLC was not affected by diet in males. Due to higher equol production
      (P < 0.01), males had greater plasma isoflavone concentrations (P < 0.01) than
      females. There was a positive association between plasma total isoflavones and
      LDL + VLDLC (r = 0.65, P < 0.05) in females. These data suggest gender
      differences in plasma lipid and isoflavone responses to soy- based diets in
      Syrian F(1)B Hybrid hamsters, which offer an opportunity to explore effects of
      sex hormones on isoflavone metabolism and the effects of isoflavones on lipid
      metabolism.

PMID- 12468593
TI  - Grape seed and grape skin extracts elicit a greater antiplatelet effect when used
      in combination than when used individually in dogs and humans.
AB  - Grape products, rich in polyphenolics, inhibit platelet aggregation (PA), a risk
      factor for coronary artery disease. We postulated that combining extracts of
      grape seed (GSD) and grape skin (GSK), primary sources of grape polyphenolics,
      individually shown to inhibit PA, might enhance their individual antiplatelet
      effects. This hypothesis was examined in vitro (human platelets) and ex vivo (dog
      platelets) by studying the effects of the extracts on collagen-induced whole
      blood PA. In vitro, threshold concentration of only GSD, individually incubated
      with blood, significantly inhibited PA; PA was inhibited by 12.7 +/- 3.5% (P < or
      = 0.01). No significant changes in Pa were observed with threshold concentrations
      of GSK, used individually. In two dose combinations, GSD and GSK inhibited PA
      40.5 +/- 10.1% (P < or = 0.005) and 96.5 +/- 3.1% (P < or = 0.001). In the ex
      vivo study, seven dogs were fed threshold doses of GSD or GSK individually, in
      combination or in combination with a proprietary enzyme blend (EB; thought to
      enhance bioavailability) for 8 d. PA was measured before and after each
      treatment. PA measurements were also repeated 24 h after the final dose of GSD +
      GSK + EB. Feeding the extracts individually did not affect PA, whereas feeding
      them in combination inhibited PA by 31.9 +/- 7.1% (P < or = 0.05). Feeding EB in
      addition to GSD + GSK inhibited PA by 56.2 +/- 8.1% (P < or = 0.005); 24 h later,
      PA was still inhibited by 31.5 +/- 10.5% (P < or = 0.05), suggesting a residual
      antiplatelet effect from the administration of the final dose. The results
      suggest that the components of GSD and GSK, when present in combination as in red
      wine, grape juice or in a commercial preparation containing both extracts,
      exhibit a greater antiplatelet effect than when present individually.

PMID- 12468594
TI  - Dietary chicory inulin increases whole-body bone mineral density in growing male
      rats.
AB  - Chicory inulin is a natural linear fructan that is not digested in the upper part
      of the gastrointestinal tract but is fermented in the cecocolon. It enhances
      calcium absorption in rats and improves femur and tibia mineral contents in
      gastrectomized or ovariectomized rats. We studied the effect of inulin (0, 5 and
      10 g/100 g diet) on whole-body bone mineral content (WBBMC), whole-body bone area
      (WBBA) and whole-body bone mineral density (WBBMD) in live, growing male rats fed
      diets containing 0.2, 0.5 or 1 g Ca/100 g. Three experiments, each corresponding
      to one of the different dietary Ca concentrations, were performed using male
      Wistar rats (n = 108; 4 wk old). WBBMC was measured by dual-energy X-ray
      absorptiometry every 4 wk up to wk 22. Inulin increased WBBMC (P < 0.05) and
      WBBMD (P < 0.001) significantly but not WBBA at all ages and all dietary calcium
      concentrations. This is the first report to demonstrate that chicory inulin not
      only increases calcium absorption but also increases mineral parameters in whole
      body bones.

PMID- 12468595
TI  - Occupancy of glycoprotein IIb/IIIa by B-6 vitamers inhibits human platelet
      aggregation.
AB  - Vitamin B-6 inhibits platelet aggregation. However, the effect of the occupancy
      of GPIIb/IIIa, a major receptor responsible for aggregation on platelet
      membranes, by B-6 vitamers on platelet aggregation is unknown. This study was
      carried out to quantify GPIIb/IIIa occupancy in platelets treated with B-6
      vitamers [pyridoxal-5-phosphate (PLP); pyridoxal (PL); pyridoxine (PN);
      pyridoxamine (PM)], using a monoclonal antibody-based assay, by flow cytometry.
      Antibody binding was compared with inhibition of platelet aggregation. PLP, PL,
      PN and PM occupied GPIIb/IIIa with dissociation constants of 1.83 +/- 1.15, 19.43
      +/- 7.86, 3.63 +/- 1.67 and 10.89 +/- 2.93 mmol/L, respectively. Occupancy of
      GPIIb/IIIa by the four B-6 vitamers was negatively correlated with platelet
      aggregation (r = -0.90 to -0.94, P < 0.001). The concentrations of the four B-6
      vitamers that inhibited maximal platelet aggregation were in the order of PLP <
      PN <PM < PL, the same order in which they occupied > or =80% of the GPII/IIIa
      receptor. Platelet aggregation was inhibited by B-6 vitamers via the occupancy of
      GPIIb/IIIa with the potency of PLP > PN > PM > PL.

PMID- 12468596
TI  - Iron deficiency and marginal vitamin A deficiency affect growth, hematological
      indices and the regulation of iron metabolism genes in rats.
AB  - Iron deficiency and marginal vitamin A (VA) deficiency frequently coexist and
      affect billions of people, mostly children and women, worldwide. The effects of
      these micronutrient deficiencies alone and in combination on hematologic,
      biochemical and molecular indices of iron and VA status were investigated in a 2
      x 2 randomized blocked study conducted in growing male Sprague-Dawley rats. From
      3-8 wk of age, rats were fed one of four purified diets that were either adequate
      or restricted in iron (Fe) and adequate or marginal in VA: (+)Fe(+)VA, 20.3 and
      0.367 micro g/g, respectively, denoted control diet; (-)Fe(+)VA, 3.34 and 0.405
      micro g/g; (+)FeVA(m), 22.2 and 0.051 micro g/g; or (-)FeVA(m), 3.03 and 0.055
      micro g/g. Weight-matched rats fed adequate micronutrients were included to
      control for possible confounding effects of Fe deficiency on growth and feed
      efficiency. Iron restriction reduced (P < 0.05) weight gain, feed efficiency,
      blood hemoglobin and hematocrit. Plasma and liver iron and plasma transferrin
      saturation were reduced by approximately 50%, whereas liver transferrin mRNA and
      protein and transferrin receptor mRNA were elevated, as was liver ferritin light
      chain protein and light-chain mRNA. Liver heavy-chain ferritin mRNA, hemopexin,
      ceruloplasmin and cellular retinol-binding protein mRNA were not affected by iron
      or VA restriction. Although marginal VA deficiency did not exacerbate indices of
      poor iron status during iron deficiency, iron deficiency was associated with
      lower plasma retinol and elevated liver VA concentrations. These results are
      consistent with an impaired mobilization of liver retinol during iron deficiency
      as well as multiple alterations in iron metabolism.

PMID- 12468597
TI  - Feedback regulation of beta,beta-carotene 15,15'-monooxygenase by retinoic acid
      in rats and chickens.
AB  - beta,beta-Carotene 15,15'-monooxygenase (formerly termed beta,beta-carotene
      15,15'-dioxygenase, EC 1.13.11.21) catalyzes the conversion of provitamin A
      carotenoids to retinal in vertebrate tissues. In the present study, we
      investigated whether preformed vitamin A or beta-carotene and its direct
      metabolites can regulate the enzyme activity in vivo. We found dose-dependent
      decreases in intestinal beta,beta-carotene monooxygenase activity after oral
      administration to rats of retinyl acetate (up to -79%), beta-carotene (up to 
      79%), apo-8'-carotenal (up to -56%), all-trans retinoic acid (up to -88%), and 9
      cis retinoic acid (up to -67%). Liver beta,beta-carotene 15,15'-monooxygenase
      (betaCMOOX) activity was not affected. Apo-12'carotenal and the retinoic acid
      receptor (RAR) alpha antagonist Ro 41-5253 significantly increased the intestinal
      enzyme activity by 55 and 94%, respectively. When beta-carotene was administered
      to rats pretreated with the two cytochrome P(450) (CYP) inducers, pentobarbital
      and naphthoflavone, the intestinal betaCMOOX activity increased by 39%. In a
      transcriptional study in chickens, treatment with retinoic acid resulted in low
      expression of the intestinal betaCMOOX. Our data suggest that retinoids and
      carotenoids might regulate betaCMOOX expression by a transcriptional feedback
      mechanism via interaction with members of the RAR family.

PMID- 12468599
TI  - Dietary protein quantity and quality affect rat hepatic gene expression.
AB  - To gain a comprehensive understanding of the molecular mechanisms underlying the
      effects of dietary protein on alternations in physiologic and pathologic status,
      the GeneChip microarray system was used to investigate the consequences of two
      different states of protein malnutrition on gene expression in rat liver.
      Expressions of 281 genes were increased or decreased by twofold or more by
      treatment with a protein-free diet for 1 wk compared with control rats fed a
      casein diet. Similarly, 111 genes were affected in rats fed a wheat gluten diet
      compared with those fed the casein diet. Although some of the genes identified
      were known to respond to protein nutrition, a majority were newly identified as
      responders to protein nutritional status. Interesting findings included the
      drastic changes in the levels of genes for Id (inhibitor of DNA binding)
      proteins, which are involved in the regulation of multiple genes, and of a set of
      genes in the pathway of cholesterol biosynthesis and disposal. This study
      represents a step toward a more global understanding of gene expression changes
      in states of protein malnutrition.

PMID- 12468598
TI  - Gene expression profiles of genistein-treated PC3 prostate cancer cells.
AB  - Our previous studies have shown that genistein inhibits the growth of PC3
      prostate cancer cells and induces apoptosis by inhibiting nuclear factor kappaB
      (NF-kappaB) and Akt signaling pathways. To better understand the precise
      molecular mechanism(s) by which genistein exerts its effects on PC3 cells, we
      utilized cDNA microarray to interrogate 12,558 known genes to determine the gene
      expression profiles altered by genistein treatment. We found a total of 832 genes
      that showed a greater than twofold change after genistein treatment from two
      independent experiments with a high degree of concordance. Among these genes, 774
      genes were down-regulated and 58 genes were up-regulated with genistein
      treatment. Cluster analysis showed nine different types of expression
      alternations. These genes were also subjected to cluster analysis according to
      their biological functions. We found that genistein regulated the expression of
      genes that are critically involved in the regulation of cell growth, cell cycle,
      apoptosis, cell signaling transduction, angiogenesis, tumor cell invasion and
      metastasis. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was
      used to confirm the results of cDNA microarray, and the results of RT-PCR were
      consistent with the microarray data. We conclude that genistein affected the
      expression of a large number of genes that are related to the control of cell
      survival and physiologic behaviors. The gene expression profiles provide
      comprehensive molecular mechanism(s) by which genistein exerts its pleiotropic
      effects on cancer cells. Genistein-induced regulation of these genes may be
      further exploited for devising chemopreventive and/or therapeutic strategies for
      prostate cancer.

PMID- 12468600
TI  - Diallyl disulfide increases rat h-ferritin, L-ferritin and transferrin receptor
      genes in vitro in hepatic cells and in vivo in liver.
AB  - Of the oil-soluble organosulfur compounds derived from garlic, diallyl disulfide
      (DADS) is one of the most abundant. We examined the effect of DADS on gene
      expression in rat liver. By suppressive subtractive hybridization, we identified
      the heavy (H)-ferritin gene as a DADS-stimulated gene in the rat liver epithelial
      (REL) cells. DADS stimulation of H- and L (light)-ferritin mRNA was analyzed in
      REL cells and in rat liver. Incubation of the REL cells in 10 micro mol/L DADS
      for 4 h increased H-ferritin 1.9 +/- 0.2-fold, n = 3) and light(L)-ferritin mRNA
      1.5 +/- 0.2-fold, n = 3). Stimulation did not occur in the presence of an
      inhibitor of transcription, actinomycin D. Stimulation of ferritin at the RNA and
      protein levels was also found in rats administered a DADS-enriched oil solution
      intragastrically. There was a 3 +/- 1.1-fold increase in H- and 3 +/- 0.14-fold
      increase for L-ferritin mRNA 24 h after the end of the infusion in the presence
      of DADS, (n = 3). The expression of the transferrin receptor, an iron
      transporter, was also enhanced by DADS in rat liver. In conclusion, our data
      suggest that DADS could modify iron homeostasis through the modulation of
      ferritin and transferrin receptor gene expression.

PMID- 12468601
TI  - Butter differs from olive oil and sunflower oil in its effects on postprandial
      lipemia and triacylglycerol-rich lipoproteins after single mixed meals in healthy
      young men.
AB  - Accumulation of postprandial triacylglycerol-rich lipoproteins is generated by
      assimilation of ingested dietary fat and has been increasingly related to
      atherogenic risk. Nevertheless, the influence of different kinds of dietary fatty
      acids on postprandial lipid metabolism is not well established, except for (n-3)
      polyunsaturated long-chain fatty acids. Our goal was to evaluate the effects of
      test meals containing a common edible fat source of saturated (butter),
      monounsaturated (olive oil) or (n-6) polyunsaturated (sunflower oil) fatty acids
      on postprandial lipid and triacylglycerol-rich lipoprotein responses. After a 12
      h fast, 10 healthy young men ingested mixed meals containing 0 g (control) or 40
      g fat, provided as butter, olive oil or sunflower oil in a random order. Fasting
      and postmeal blood samples were collected for 7 h. The no-fat test meal did not
      elicit any change over baseline except for plasma phospholipids, insulin and
      nonesterified fatty acids. Conversely, the three fat-containing meals elicited
      bell-shaped postprandial changes (P < 0.05) in serum triacylglycerols, free and
      esterified cholesterol, and nonesterified fatty acids. The butter meal induced a
      lower postprandial rise of triacylglycerols in serum and chylomicrons
      (incremental AUC, mmol.h/L: 0.72) than the two unsaturated oils (olive oil: 1.6,
      sunflower oil: 1.8), which did not differ. Circulating chylomicrons were smaller
      after the butter meal than after the two vegetable oil meals. The in vitro
      susceptibility of circulating chylomicrons to hydrolysis by postheparin plasma
      was higher after sunflower oil than after butter or olive oil. We conclude that
      butter results in lower postprandial lipemia and chylomicron accumulation in the
      circulation of young men than olive or sunflower oils after consumption of a
      single mixed meal.

PMID- 12468602
TI  - A spread enriched with plant sterol-esters lowers blood cholesterol and
      lipoproteins without affecting vitamins A and E in normal and
      hypercholesterolemic Japanese men and women.
AB  - The objective of the study was to investigate whether different initial baseline
      cholesterol levels modulate the efficacy of a spread enriched with plant sterol
      esters (PS) in lowering blood cholesterol in a Japanese population consuming
      their usual diet. Healthy adults with a mean age of 45 y and mean plasma total
      cholesterol (TC) level of 6.5 mmol/L were recruited to participate in a double
      blind trial comprised of a run-in period of 1 wk, followed by two intervention
      periods of 3 wks in a 2 x 2 crossover design and a post-trial follow-up of 3 wk.
      Volunteers consumed two spreads, one enriched with PS (12 g/100 g plant sterols)
      and a control spread not fortified with PS. Recommended spread intake was 15 g/d.
      Effects on plasma lipids, lipoproteins, beta-carotene and vitamins A and E were
      assessed. Plasma TC and LDL cholesterol (LDL-C) concentrations were 5.8 and 9.1%
      lower, respectively, when subjects consumed the PS spread than when they consumed
      the control spread (P < 0.001). Subjects were divided into two groups [normal and
      mildly cholesterolemic (TC <5.7 mmol/L) and hypercholesterolemic (TC >/= 5.7
      mmol/L)]. Reductions (P < 0.001) in TC and LDL-C due to treatment in the former
      group were 4.9 and 7.9%, respectively. In the hypercholesterolemic group, the
      reductions (P < 0.001) were 7.1 and 10.6%, respectively. The decreases did not
      differ between normal/mildly cholesterolemic and hypercholesterolemic subjects.
      Plasma apolipoprotein B (apoB) and remnant-like particle (RLP) cholesterol (RLP
      C) concentrations were lower when subjects consumed the PS spread (44.3 g/L) than
      the control spread (49.7 g/L). Plasma beta-carotene concentration was lower (P <
      0.001) in subjects consuming the PS spread than in the control. Changes in plasma
      vitamins A and E levels did not differ after intake of the PS and control
      spreads. In conclusion, consumption of a PS-enriched spread effectively lowered
      plasma TC, LDL-C, apoB and RLP-C regardless of baseline plasma TC at an intake of
      1.8 g/d of plant sterols.

PMID- 12468603
TI  - Oral fat exposure increases the first phase triacylglycerol concentration due to
      release of stored lipid in humans.
AB  - Oral exposure to dietary fat (through modified sham feeding, which entails
      mastication and expectoration of foods) augments the postprandial triacylglycerol
      (TAG) concentration, in part, though augmented lipid absorption. This study was
      designed to characterize early events in this process. At 2200 h, 25 healthy
      adults (13 men, 12 women) consumed 80 g of almonds (high oleic acid content) and
      fasted until approximately 0700 h. After placement of a catheter in a hand vein
      and 4 blood draws at 10-min intervals, 50 1-g safflower oil (high linoleic acid
      content) capsules were consumed. After another blood draw, modified sham feeding
      was initiated with a cracker only or cracker with cream cheese in random order
      with 1 wk between trials. Oral exposures occurred at 5-min intervals for 60 min
      then at 15-min intervals from min 60 to 120. Additional blood draws occurred at
      2, 4, 6, 8, 10, 12, 14, 30, 60, 120, 240, 360 and 480 min. Oral stimulation,
      especially by fat, prompted the rapid (mean approximately 23 min) release of
      lipid stored from the previous meal (almonds) in all participants. This resulted
      in multimodal postprandial triacylglycerol (TAG) peaks generally occurring at 0
      30 min, 60-120 min and 240-480 min after loading and initiation of oral
      stimulation. TAG magnitudes during these times were correlated (r = 0.40-0.89, P
      < 0.001-P = 0.053). It is proposed that the sensory-enhanced release of lipid
      from the residual pool initiates an early TAG rise, which augments the peak
      attributable to absorption of meal lipid; this in turn supplements a later peak
      associated with release of endogenously synthesized TAG because lipid from all
      three sources competed for a common clearance mechanism. If substantiated,
      additional understanding of the behavioral factors (e.g., eating patterns) that
      initiate this cascade will be warranted.

PMID- 12468604
TI  - Cocoa products decrease low density lipoprotein oxidative susceptibility but do
      not affect biomarkers of inflammation in humans.
AB  - Flavonoids and related polyphenolics with antioxidant and anti-inflammatory
      activities may play a role in the prevention of cardiovascular disease by
      decreasing oxidative stress and inflammation. We wished to determine the effects
      of cocoa extract supplementation on markers of oxidative stress and inflammation.
      Healthy subjects (n = 25) were studied at baseline, after cocoa supplementation
      (36.9 g of dark chocolate bar and 30.95 g of cocoa powder drink) for 6 wk and
      after a 6-wk washout period. Fasting blood and early morning urine were collected
      at the three time points. Two indices of flavonoid intake, total phenols and
      oxygen radical absorbance capacity of plasma, were measured after an overnight
      fast. Neither was affected by supplementation. Measures of oxidative stress
      included copper-catalyzed LDL oxidation kinetics and urinary F(2) isoprostanes.
      LDL oxidizability was lower after chocolate supplementation as evidenced by a
      longer lag time (P < 0.05) of conjugated diene formation (101.0 +/- 20.7 min)
      compared with baseline (91.3 +/- 18.0 min) and washout (96.4 +/- 7.5 min) phases.
      There was no effect of chocolate on urinary F(2) isoprostane levels or on markers
      of inflammation including the whole-blood cytokines, interleukin-1 beta,
      interleukin-6 and tumor necrosis factor-alpha, high sensitivity C-reactive
      protein and P-selectin. In conclusion, cocoa products supplementation in humans
      affects LDL oxidizability, but not urinary F(2) isoprostanes or markers of
      inflammation.

PMID- 12468605
TI  - Esterification does not impair lutein bioavailability in humans.
AB  - Age-related macular degeneration (ARMD) is inversely associated with the
      accumulation of lutein + zeaxanthin in the macula, but higher lutein intakes are
      inconsistently related to reduced risk of ARMD in epidemiologic studies.
      Resolution of efficacy awaits clinical trials designed with knowledge of lutein
      supplement pharmacokinetics. Lutein bioavailability was determined for lutein
      diester and unesterified lutein formulations as they might be incorporated into
      dietary supplements. Healthy subjects (n = 18) consumed a single dose of each
      formulation (either 0.5 or 0.67 micro mol lutein/kg body, 10 and 8 subjects,
      respectively) in random order, and the appearance of free lutein + zeaxanthin was
      measured in serum from 0 to 408 h. Areas under the serum concentration x time
      curves (AUC), as a measure of bioavailability, were independent of gender, body
      mass index and lutein dose. The lutein diester formulation was 61.6% more
      bioavailable than the unesterified lutein formulation with higher mean AUC,
      maximum serum concentration and ascending slope (P < 0.05). The AUC was greater
      in 14 of 18 subjects when they consumed the lutein diester formulation.
      Comparison with data from previous studies suggested that dissolution was a
      greater limitation to bioavailability than lutein ester hydrolysis because an oil
      solubilized unesterified lutein preparation, given at 0.5 micro mol/kg body,
      resulted in greater mean peak concentrations and AUC compared with either the
      unesterified or lutein diester formulations used in our study. In conclusion, the
      lutein diester formulation poses no impediment to lutein bioavailability at the
      doses tested, but formulation dissolution is an important factor in lutein
      bioavailability and should be evaluated before a supplement and dose are selected
      for use in clinical trials.

PMID- 12468606
TI  - Growth retardation is associated with changes in the stress response system and
      behavior in school-aged jamaican children.
AB  - In the developing world, 39% of children <5 y old are short for their age
      (stunted, defined as height-for-age less than -2 SD of National Center for Health
      Statistics references), and many have poor levels of mental development along
      with behavioral problems. We showed previously that 8- to 10-y-old children from
      a longitudinal cohort who experienced early childhood stunting had altered
      hypothalamic-pituitary-adrenocortical (HPA) and sympathetic-adrenomedullary (SAM)
      system activity. We repeated the study with 31 newly recruited, stunted Jamaican
      school children (less than -2.0 SD height-for-age) and nonstunted controls (n =
      31, more than -1.0 SD height-for-age) matched for sex, age and school. All
      children were tested in a 1.5-h session, including psychological and physiologic
      stressors, in which their behaviors, salivary cortisol concentrations and heart
      rates were measured. In addition, we measured urinary catecholamine (epinephrine,
      norepinephrine, dopamine) concentrations, which were not reported for the
      children in the longitudinal cohort. After controlling for covariates that
      differed between groups (child intelligence quotient, body mass index and birth
      weight), stunted children had faster resting heart rates while lying and sitting
      (P < 0.05) and also during psychological testing (P < 0.05), as well as higher
      concentrations of urinary epinephrine (P < 0.05) and norepinephrine (P < 0.05),
      compared with nonstunted children. In addition, the stunted children were less
      happy (P < 0.01), more inhibited (P < 0.01) and more frustrated (P < 0.05) during
      the psychological tests than nonstunted children. These results suggest that
      growth retardation is associated with alterations in stress-sensitive systems,
      particularly the SAM system, and that this connection may contribute to the poor
      levels of development observed in stunted children.

PMID- 12468607
TI  - The diagnostic criteria for iron deficiency in infants should be reevaluated.
AB  - Diagnostic criteria for iron deficiency (ID) and iron deficiency anemia (IDA) in
      infants are poorly defined. Our aim was to establish appropriate cut-off values
      for hemoglobin (Hb), plasma ferritin, erythrocyte mean cell volume (MCV), zinc
      protoporphyrin (ZPP) and soluble transferrin receptors (TfR) in infancy.
      Exclusively breast-fed infants (n = 263) in Honduras and Sweden were randomly
      assigned to receive iron supplementation or placebo, and blood samples were
      obtained at 4, 6 and 9 mo of age. Reference ranges were determined using three
      different approaches for defining iron-replete infants. The usefulness of several
      variables for predicting the Hb response to iron was evaluated. We found the
      following 2 SD cut-off values in iron-replete infants: Hb <105 g/L at 4-6 mo and
      <100 g/L at 9 mo; ZPP >75 micro mol/mol heme at 4-6 mo and >90 micro mol/mol heme
      at 9 mo; ferritin <20 micro g/L at 4 mo, <9 micro g/L at 6 mo and <5 micro g/L at
      9 mo; and TfR >11 mg/L at 4-9 mo. The Hb response to iron was not a useful
      definition of IDA at 4 mo of age. Hb, MCV and ZPP at 6 mo as well as growth
      variables predicted the Hb response at 6-9 mo, but ferritin and TfR at 6 mo did
      not. We conclude that there is need for a reevaluation of the definitions of ID
      and IDA in infants.

PMID- 12468608
TI  - Determination of a cut-off value for the molar ratio of retinol-binding protein
      to transthyretin (RBP:TTR) in Bangladeshi patients with low hepatic vitamin A
      stores.
AB  - The purpose of this study was to determine a cut-off value of the molar ratio of
      retinol-binding protein to transthyretin (RBP:TTR) to indicate marginal vitamin A
      (VA) deficiency. Plasma RBP and TTR were measured by radial immunodiffusion in
      two groups of patients, i.e., surgical patients with known hepatic VA stores, and
      a cohort of children residing in a malaria-endemic area of Papua New Guinea who
      had received placebo or 210 micro mol of VA every 3 mo for 9 mo. A RBP:TTR ratio
      < or =0.36 selectively detected five of seven patients (71% sensitivity) with
      hepatic VA stores < or =69.9 nmol/g of tissue (i.e., < or =20 micro g/g),
      indicative of marginal VA deficiency. Using this cut-off value, 28% (n = 245) of
      children from Papua New Guinea had marginal VA deficiency before supplementation.
      After 7 mo, a low ratio persisted in 29% (n = 92) of placebo-treated children but
      in only 11% (n = 83) of those receiving VA supplements (chi(2), P < 0.01). At the
      end of the study, 13 mo after initiation or 4 mo after the last dose of VA, the
      percentage of children with a low ratio was still lower (chi(2), P < 0.02) in the
      VA group, 42.5% (n = 113) than in the placebo group, 58.6% (n = 118). These
      results demonstrate that a cut-off value < or =0.36 is indicative of marginal VA
      deficiency and can be used as an indirect method of VA assessment.

PMID- 12468609
TI  - A randomized, 4-month mango and fat supplementation trial improved vitamin A
      status among young Gambian children.
AB  - Supplementation with carotene-rich fruits may be an effective and sustainable
      approach to prevent vitamin A deficiency. To test the effectiveness of mango
      supplementation, 176 Gambian children, aged 2 to 7 y, were randomly assigned to
      one of four treatments: 75 g of dried mango containing approximately 150 micro g
      retinol activity equivalents with (MF) or without (M) 5 g of fat, 5 d/wk for 4 mo
      or 60,000 micro g of vitamin A (A) or placebo (P) capsule at baseline. After 4
      mo, plasma beta-carotene was greater in both the M (P < 0.05) and MF (P = 0.07)
      groups compared with the P group. After controlling for baseline plasma retinol,
      elevated acute phase proteins and age, plasma retinol concentrations in the A and
      MF, but not M, groups were higher than in the P group at the end of the study (P
      < 0.01). Increases in retinol concentrations, however, were small in both groups.
      These results support the use of dietary supplementation with dried mangoes and a
      source of fat as one of several concurrent strategies that can be used to help
      maintain vitamin A status of children in developing countries where there is a
      severe seasonal shortage of carotenoid-rich foods.

PMID- 12468610
TI  - Vitamin a supplementation of vitamin a deficient measles patients lowers the risk
      of measles-related pneumonia in zambian children.
AB  - This is an a posteriori analysis of previously published data to assess whether
      improving vitamin A (VA) status resolves measles-related pneumonia (MP).
      Nonhospitalized acute measles patients (2 d of rash onset) had their VA status
      determined based on the molar ratio of retinol-binding protein to transthyretin
      (RBP/TTR). Using a cutoff value of </=0.36, indicative of marginal VA deficiency,
      82 children were diagnosed as marginally VA deficient and 114 were diagnosed as
      VA sufficient. At baseline, marginally VA-deficient patients had significantly
      lower serum retinol and higher serum C-reactive protein concentrations than VA
      sufficient children. At the 2-wk follow-up visit, serum retinol and the RBP/TTR
      ratio were significantly greater in marginally VA-deficient measles patients
      receiving VA supplements than in those receiving placebo; whereas in VA
      sufficient measles patients, retinol increased in those receiving VA supplements
      or placebo. Concomitantly the odds ratio of unresolved pneumonia in marginally VA
      deficient measles patients receiving VA supplements compared with those receiving
      placebo was 0.20 (95% confidence interval, 0.05-0.71). In conclusion, VA
      supplements during measles infection improved VA status of VA-deficient children
      and helped resolve MP, demonstrating the importance of determining VA status when
      assessing the efficacy of VA supplements.

PMID- 12468611
TI  - Dietary fiber-rich barley products beneficially affect the intestinal tract of
      rats.
AB  - The objective of this study was to investigate the effects of barley-rich diets
      in the intestinal tract of rats. Four test groups (A-D) of 10 young male Wistar
      rats were fed diets containing 50 g/100 g barley extrudates (A, B and D) or
      mixtures (C) for 6 wk; the control diet contained no barley. The barley
      containing supplements in the test diets were: A = cultivar "HiAmi"; B = "HiAmi"
      and "Prowashonupana" (50:50); C = "Prowashonupana" and Novelose (50:50); D =
      "Prowashonupana" and amylose from maize (60:40). These supplements contained 7-12
      g/100 g beta-glucan and 7-24 g/100 g resistant starch. Additionally, 5 g
      microcrystalline cellulose/100 g was present in all diets. Carbohydrate
      utilization (indirect calorimetry) was lower (P < 0.05) in rats fed the barley
      containing diets C or D than in the controls. In the test groups, the following
      differences from the controls were found: greater food intake in the last 2 wk (P
      < 0.05); increased weight gain in wk 6 (P < 0.05); greater mass of the ceca
      (groups B-D; P < 0.05) and colons (P < 0.001) as well as masses of cecal (groups
      C and D; P < 0.01) and colon contents (P < 0.001); greater concentrations of
      resistant starch in cecal and most of the colon contents (P < 0.05); and more
      beta-glucan in the small intestine, cecum and colon (P < 0.05). The numbers of
      coliforms and Bacteroides were lower than in the controls in groups B-D and those
      of Lactobacillus were greater in all test groups (P < 0.05). Short-chain fatty
      acids (SCFA) were higher in the cecal contents of the test groups (> or = 800
      micro mol/g DM; P < 0.001) compared with the controls ( approximately 200 micro
      mol/g DM). Similarly, SCFA were higher in colon and feces of the test groups. The
      concentrations of excreted bile acids increased up to 30% during the feeding
      period. The proportions of secondary bile acids were lower and the amounts of
      neutral sterols (P < 0.001) were greater in feces of rats fed the barley
      containing diets for 6 wk than in the controls. Diets containing more soluble
      macromolecular dietary fibers such as beta-glucans affected the excretion of bile
      acids and neutral sterols the most, whereas the fermentation of dietary fiber,
      including resistant starch, influenced the steroids in feces. These results
      suggest that dietary fiber-rich barley-containing diets have beneficial
      physiologic effects.

PMID- 12468612
TI  - Dietary arginine slightly and variably affects tissue polyamine levels in male
      swiss albino mice.
AB  - Many key metabolic and physiologic functions involve arginine and arginine
      derived metabolites. Requirements for arginine, a "conditionally essential" amino
      acid for most mammalian species, are met in variable proportions by dietary
      intake and endogenous synthesis, the latter being sufficient to fulfill arginine
      needs in adult humans and mice under nonpathologic conditions. However, dietary
      arginine restriction causes orotic aciduria and abnormal function of the urea
      cycle. Furthermore, the importance of dietary arginine in the maintenance of
      homeostasis of arginine-derived metabolites in the body has not yet been analyzed
      in detail. We therefore examined whether the deprivation or supplementation of
      dietary arginine affects tissue and circulating levels of arginine-derived
      polyamines. We pair-fed male Swiss albino mice (30 g) for 15 or 30 d synthetic
      diets containing 0, 1.12 or 2.24 g/100 g L-arginine. Tissue and blood levels of
      the main free polyamines, putrescine, spermidine and spermine, were measured by
      HPLC. In general, neither the deprivation nor the supplementation of arginine
      dramatically affected the levels of any of the polyamines analyzed. Variations
      were organ, time and polyamine specific, and most differences were in the levels
      of putrescine at 15 d and of spermidine at 30 d. Thus, in contrast to effects on
      urea cycle function, dietary arginine does not appear to be essential for the
      maintenance of the homeostasis of free polyamine levels in adult mice,
      emphasizing the importance of endogenous arginine synthesis in preserving the
      polyamine body pool.

PMID- 12468613
TI  - Fructooligosaccharides and Lactobacillus acidophilus modify gut microbial
      populations, total tract nutrient digestibilities and fecal protein catabolite
      concentrations in healthy adult dogs.
AB  - The objective of this research was to determine whether fructooligosaccharides
      (FOS) and (or) Lactobacillus acidophilus (LAC) affected concentrations of gut
      microbial populations, fermentative end products and nutrient digestibilities in
      healthy adult dogs. Two experiments were performed using 40 adult dogs (20
      dogs/experiment). Dogs in each experiment were randomly assigned to one of 4
      treatments. Twice daily, treatments were given orally via gelatin capsules: 1) 2
      g sucrose + 80 mg cellulose; 2) 2 g FOS + 80 mg cellulose; 3) 2 g sucrose + 1 x
      10(9) colony forming units (cfu) LAC; or 4) 2 g FOS + 1 x 10(9) cfu LAC. Data
      were analyzed by the General Linear Models procedure of SAS. In Experiment 1, FOS
      resulted in lower (P = 0.08) Clostridium perfringens and greater fecal butyrate
      (P = 0.06) and lactate (P < 0.05) concentrations. In Experiment 2, FOS
      supplementation increased (P < 0.05) bifidobacteria, increased lactobacilli (P =
      0.08), increased fecal lactate (P = 0.06) and butyrate (P < 0.05), and decreased
      (P < 0.05) fecal ammonia, isobutyrate, isovalerate and total branched-chain fatty
      acid concentrations. Dogs fed LAC had the highest fecal concentrations of
      hydrogen sulfide and methanethiol in Experiment 1 and dimethyl sulfide in
      Experiment 2, whereas dogs fed FOS had the lowest concentrations of these
      compounds. Overall, FOS appeared to enhance indices of gut health by positively
      altering gut microbial ecology and fecal protein catabolites, whereas LAC was
      more effective when fed in combination with FOS rather than fed alone.

PMID- 12468614
TI  - Insufficient dietary vitamin e increases the concentration of 7beta
      hydroxycholesterol in tissues of rats fed salmon oil.
AB  - This study was conducted to determine the interaction between the type of dietary
      fat (coconut oil or salmon oil) and the vitamin E concentration of the diet [10,
      20, 40 or 240 mg alpha-tocopherol equivalents (alpha-toc)/kg] in relation to the
      concentration of 7beta-hydroxycholesterol (7beta-OH) in liver, plasma, LDL and
      erythrocytes of rats. In the rats whose diet contained salmon oil, the
      concentration of 7beta-OH was dependent on the dietary vitamin E concentration.
      Rats whose diet contained 10 mg alpha-toc/kg had significantly higher
      concentrations of 7beta-OH in all samples studied than those whose diet contained
      20, 40 or 240 mg alpha-toc/kg. Increasing the dietary vitamin E concentration
      from 40 to 240 mg alpha-toc/kg did not reduce the concentration of 7beta-OH in
      any samples. In the rats whose diet contained coconut oil, the concentration of
      7beta-OH was independent of the dietary vitamin E concentration in all samples.
      The study shows that insufficient vitamin E in the diet increases the formation
      of 7beta-OH in rats fed salmon oil, whereas a dietary vitamin E supply in excess
      of the requirement does not lower 7beta-OH concentrations compared with an
      adequate vitamin E supply.

PMID- 12468615
TI  - Retinoic acid enhances the T helper 2 cell development that is essential for
      robust antibody responses through its action on antigen-presenting cells.
AB  - Previously we reported that vitamin A-deficient (-A) mice had a profound
      reduction in T helper 2 (Th2) cells, accounting for their depressed T-dependent
      antibody responses. Providing vitamin A or its active metabolites reversed this
      defect. The current experiments utilized splenocytes from T cell receptor
      transgenic mice to investigate how all-trans retinoic acid (atRA) augments Th2
      development. These cells were stimulated in vitro in the presence or absence of
      atRA, with or without exogenous cytokines driving Th1 or Th2 development. Without
      exogenous cytokines, atRA addition significantly inhibited the interferon (IFN)
      gamma response but did not alter the interleukin (IL)-4 response. With Th1
      polarizing cytokines, atRA enhanced the IFN-gamma response, with no effect on the
      IL-4 response. Most importantly, with the Th2 polarizing cytokine IL-4, atRA
      significantly increased the IL-4 secretion (fivefold) and also increased the Th2
      cell frequency twofold. The striking Th2 enhancement was also observed when only
      antigen-presenting cells were treated with atRA before stimulation of untreated
      CD4(+) transgenic T cells, but not vice versa. Thus, atRA maximized Th2 cell
      development in an IL-4-dependent manner, through an effect on antigen-presenting
      cell function.

PMID- 12468616
TI  - Dietary fish oil increases tumor necrosis factor secretion but decreases
      interleukin-10 secretion by murine peritoneal macrophages.
AB  - Dietary fish oil has immunomodulatory effects that are mediated in part by its
      effects on cytokines. Secretion of the inflammatory and the anti-inflammatory
      cytokines tumor necrosis factor (TNF) and interleukin (IL)-10 by murine resident
      peritoneal macrophages was monitored after ex vivo stimulation with
      lipopolysaccharide. Macrophages were obtained from mice fed a corn oil diet
      containing 200 g/kg corn oil or a fish oil diet containing 180 g/kg fish oil and
      20 g/kg corn oil. Dietary fish oil increased secretion of the proinflammatory
      cytokine, TNF, but decreased secretion of the anti-inflammatory cytokine, IL-10.
      The cytokines appeared in the medium after 1.5 h and peaked at 6-12 h.
      Neutralizing antibodies against TNF and IL-10 had little effect on secretion of
      the other cytokine, indicating that the effects of fish oil on TNF and IL-10
      secretion by these cells are independent of one another. Furthermore, although
      inhibiting prostaglandin production enhanced TNF secretion by macrophages from
      mice fed the corn oil diet, it did not affect IL-10 secretion by macrophages in
      this group. Blocking leukotriene B(4) production also did not affect IL-10
      secretion in macrophages from mice fed a nonpurified diet. These results
      demonstrate that fish oil has an overall pro-inflammatory effect given its
      effects on secretion of both inflammatory and anti-inflammatory cytokines by
      resident peritoneal macrophages.

PMID- 12468617
TI  - Dietary L-lysine deficiency increases stress-induced anxiety and fecal excretion
      in rats.
AB  - Little is known about the psychobehavioral consequences of a dietary deficiency
      of the amino acid, L-lysine. This report demonstrates that a 4-d long L-lysine
      deficiency in rats interfered with the normal circadian release of the
      neurotransmitter serotonin, but not dopamine, measured by in vivo microdialysis
      in the central nucleus of the amygdala. L-Lysine deficiency was induced by
      feeding rats a L-lysine-deficient diet. Controls were pair-fed a L-lysine
      sufficient diet. Footshock stress-induced anxiety, measured in an elevated plus
      maze paradigm, and wrap-restraint stress-stimulated fecal excretion were
      significantly greater in the L-lysine-deficient rats than in the controls. We
      conclude that a severe deficiency of dietary L-lysine enhances serotonin release
      in the amygdala, with subsequent changes in psychobehavioral responses to stress.

PMID- 12468618
TI  - HIV-1 viral load and elevated serum alpha(1)-antichymotrypsin are independent
      predictors of body composition in pregnant Zimbabwean women.
AB  - Human immunodeficiency virus (HIV) infection affects body composition, but their
      relationship has not been studied in pregnant women. We conducted a cross
      sectional study among 1669 women receiving antenatal care between 22 and 35 wk of
      gestation in Harare, Zimbabwe. The role of HIV-1 status and viral load, malaria
      and elevated serum alpha(1)-antichymotrypsin (ACT, an acute phase protein) in
      weight, body mass index (BMI), arm circumference (AC), triceps skinfold thickness
      (TSF), and arm muscle (AMA) and fat (AFA) area were assessed using multiple
      linear regression analysis. The mean (range) age was 24.4 (14-45) y and
      gestational age 29 (22-35) wk. HIV infection was present in 31.5% of the women,
      malaria parasitemia in 0.4% and 11.4% had serum ACT >0.4 g/L. There was no
      difference in any anthropometric variable between HIV-infected and uninfected
      women. However, women with viral loads (genome equivalents/mL) between 4 and 5
      and >5 log(10) had 1.1 [95% confidence interval (CI): -0.3, 2.3] and 2.5 (95% CI:
      0.1, 5.1) kg lower weights compared with uninfected women; this was explained by
      losses of both AFA and AMA. Malaria parasitemia was associated with 6 cm(2) (95%
      CI: 0.4; 11.8) or 25% lower AMA. Elevated serum ACT was a negative predictor of
      all anthropometric variables, i.e., levels between 0.3 and 0.4, 0.4 and 0.5 and
      >0.5 g/L were associated with 1, 2 and 6 kg lower mean body weights,
      respectively. Despite the limitations of a cross-sectional design, we conclude
      that arm fat and muscle areas, reflecting body fat and lean body mass, seem to be
      unaffected in the majority of HIV-infected pregnant women, but decline with
      increasing viral loads. The effects of viral load are not explained by elevated
      serum ACT, which is a strong independent predictor of all anthropometric
      variables.

PMID- 12468619
TI  - Lycopene inhibits proliferation and enhances gap-junction communication of KB-1
      human oral tumor cells.
AB  - Cell-cell interaction via gap junctions is considered to be a key factor in
      tissue homeostasis, and its alteration is associated with the neoplastic
      phenotype. Experimental and epidemiologic data suggest that carotenoids,
      particularly lycopene and beta-carotene, can reduce the risk of certain cancers.
      The aim of this study was to assess whether lycopene and beta-carotene interfere
      at some stage with the carcinogenic processes in human cancer cells derived from
      the oral cavity. KB-1 cells, originating from a human oral cavity tumor, were
      incubated with different concentrations of lycopene or beta-carotene delivered
      via the cell culture media from stock solutions in tetrahydrofuran. Lycopene
      strongly and dose dependently inhibited proliferation of KB-1 human oral tumor
      cells. beta-Carotene was a far less effective growth inhibitor. Lycopene (3 and 7
      micro mol/L) significantly upregulated both the transcription (P < 0.005) and the
      expression (P < 0.05) of connexin 43, a key protein in the formation of gap
      junctional communication. beta-Carotene (3 micro mol/L) tended to upregulate
      connexin 43 expression (P = 0.07) and significantly affected transcription of
      connexin 43 at 7 micro mol/L (P < 0.05). Gap-junctional communication measured by
      scrape-loading dye transfer and electron microscopy showed that lycopene enhanced
      gap-junctional communication between the cancer cells, whereas beta-carotene was
      less effective in this regard. The pattern of cellular uptake and incorporation
      into cancer KB-1 cells differed significantly between the carotenoids. beta
      Carotene was avidly and rapidly incorporated into KB-1 cells, whereas lycopene
      uptake into the cells took place after longer incubation periods and only at the
      highest concentrations. The results of the present study further support the
      hypothesis that carotenoids in general, and lycopene in particular, may be
      effective anticarcinogenic agents in oral carcinogenesis.

PMID- 12468620
TI  - Whole blood collected on filter paper provides a minimally invasive method for
      assessing human transferrin receptor level.
AB  - Iron deficiency is the most common micronutrient deficiency worldwide, and
      transferrin receptor (TfR) level has been identified as an important measure of
      iron status that is not confounded by inflammation. However, logistical
      constraints associated with sample collection and processing have limited efforts
      to measure TfR, particularly at the community level. Standardized filter paper
      provides a relatively convenient and minimally invasive means for collecting and
      transporting samples of whole blood from simple finger pricks, and we present
      results of our validation of an improved method for quantifying TfR in dried
      blood spots. The method is based on commercially available reagents and uses
      capillary blood that is applied directly from the finger to filter paper,
      eliminating the need for premeasurement at the collection site. The blood spot
      TfR assay is precise and reliable, agrees well with plasma TfR, and can be
      performed at any facility with a microplate reader and basic laboratory
      equipment. Concentrations of TfR remain stable for at least 4 wk when blood spots
      are stored at room temperature, but begin to deteriorate after 3 d of exposure to
      higher temperatures. The advantages and disadvantages of the blood spot TfR
      method are discussed, as well as its potential contribution to future field-based
      studies of iron deficiency.

PMID- 12468621
TI  - A cost constraint alone has adverse effects on food selection and nutrient
      density: an analysis of human diets by linear programming.
AB  - Economic constraints may contribute to the unhealthy food choices observed among
      low socioeconomic groups in industrialized countries. The objective of the
      present study was to predict the food choices a rational individual would make to
      reduce his or her food budget, while retaining a diet as close as possible to the
      average population diet. Isoenergetic diets were modeled by linear programming.
      To ensure these diets were consistent with habitual food consumption patterns,
      departure from the average French diet was minimized and constraints that limited
      portion size and the amount of energy from food groups were introduced into the
      models. A cost constraint was introduced and progressively strengthened to assess
      the effect of cost on the selection of foods by the program. Strengthening the
      cost constraint reduced the proportion of energy contributed by fruits and
      vegetables, meat and dairy products and increased the proportion from cereals,
      sweets and added fats, a pattern similar to that observed among low socioeconomic
      groups. This decreased the nutritional quality of modeled diets, notably the
      lowest cost linear programming diets had lower vitamin C and beta-carotene
      densities than the mean French adult diet (i.e., <25% and 10% of the mean
      density, respectively). These results indicate that a simple cost constraint can
      decrease the nutrient densities of diets and influence food selection in ways
      that reproduce the food intake patterns observed among low socioeconomic groups.
      They suggest that economic measures will be needed to effectively improve the
      nutritional quality of diets consumed by these populations.

PMID- 12468622
TI  - Functional foods: benefits, concerns and challenges-a position paper from the
      american council on science and health.
AB  - Functional foods can be considered to be those whole, fortified, enriched or
      enhanced foods that provide health benefits beyond the provision of essential
      nutrients (e.g., vitamins and minerals), when they are consumed at efficacious
      levels as part of a varied diet on a regular basis. Linking the consumption of
      functional foods or food ingredients with health claims should be based on sound
      scientific evidence, with the "gold standard" being replicated, randomized,
      placebo-controlled, intervention trials in human subjects. However, not all foods
      on the market today that are claimed to be functional foods are supported by
      enough solid data to merit such claims. This review categorizes a variety of
      functional foods according to the type of evidence supporting their
      functionality, the strength of that evidence and the recommended intakes.
      Functional foods represent one of the most intensively investigated and widely
      promoted areas in the food and nutrition sciences today. However, it must be
      emphasized that these foods and ingredients are not magic bullets or panaceas for
      poor health habits. Diet is only one aspect of a comprehensive approach to good
      health.

PMID- 12468623
TI  - Nutrition monitoring: summary of a statement from an american society for
      nutritional sciences working group.

PMID- 12468624
TI  - Kidney and bladder stones in rodents fed purified diets.

PMID- 12468625
TI  - Diet, growth factors and cancer: introduction to the symposium proceedings.

PMID- 12468626
TI  - Insulin-like growth factor-I and estrogen interactions in breast cancer.
AB  - There is increasing evidence that estradiol and insulin-like growth factor-I (IGF
      I) act through a complex cross-talk mechanism to stimulate the proliferation of
      normal mammary epithelium to increase the risk of breast cancer. The emerging
      model of cross-talk suggests that estradiol regulates the expression of IGF-I and
      the IGF receptor I. The subsequent binding of IGF-I to its receptor initiates an
      intracellular signal transduction pathway that activates transcription factors,
      including the estrogen receptor. Recent studies show that the effects of IGF-I on
      estrogen receptor activity are mediated in part by the protein kinase A and
      phosphatidylinositol-3-kinase/Akt pathways.

PMID- 12468627
TI  - Low-calcemic vitamin D analogs (deltanoids) for human cancer prevention.
AB  - A short summary is provided of leading chemopreventive analogs of vitamin D3.

PMID- 12468628
TI  - Short chain fatty acids and colon cancer.
AB  - The development of intestinal cancer involves complex genetic and epigenetic
      alterations in the intestinal mucosa. The principal signaling pathway responsible
      for the initiation of tumor formation, the APC-beta-catenin-TCF4 pathway,
      regulates both cell proliferation and colonic cell differentiation, but many
      other intrinsic and extrinsic signals also modulate these cell maturation
      pathways. The challenge is to understand how signaling and cell maturation are
      also modulated by nutritional agents. Through gene expression profiling, we have
      gained insight into the mechanisms by which short chain fatty acids regulate
      these pathways and the differences in response of gene programs, and of the
      specific regulation of the c-myc gene, to physiological regulators of intestinal
      cell maturation, such as butyrate, compared with pharmacological regulators such
      as the nonsteroidal antiinflammatory drug sulindac. Moreover, we used a
      combination of gene expression profiling of the response of cells in culture to
      sulindac and the response of the human mucosa in subjects treated with sulindac
      for 1 month, coupled with a mouse genetic model approach, to identify the cyclin
      dependent kinase inhibitor p21(WAF1/Cip1) as an important suppressor of Apc
      initiated intestinal tumor formation and a necessary component for tumor
      inhibition by sulindac. Finally, the mucous barrier, secreted by intestinal
      goblet cells, is the interface between the luminal contents and the intestinal
      mucosa. We generated a mouse genetic model with a targeted inactivation of the
      Muc2 gene that encodes the major intestinal mucin. These mice have no
      recognizable goblet cells due to the failure of cells to synthesize and store
      mucin. This leads to perturbations in intestinal crypt architecture, increased
      cellular proliferation and rates of cell migration, decreased apoptosis and
      development of adenomas and adenocarcinomas in the small and large intestine and
      the rectum.

PMID- 12468629
TI  - Retinoic acid receptors and cancer.
AB  - Retinoids have been shown to inhibit the growth of many human tumor cells.
      Although the exact molecular mechanism of retinoid-mediated growth suppression
      remains known, the importance of the retinoic acid receptors (RARs) and retinoid
      X receptors (RXRs) has been in established a number of tumor cell models. We
      wanted to determine if modulation of RAR/RXR function would alter the retinoid
      sensitivity of oral squamous carcinoma cells (SCCs). Growth of SCCs was
      significantly suppressed by treatment with either all-trans retinoic acid (RA) or
      the synthetic, conformationally restricted RAR-gamma-selective retinoids SR 11254
      and SR 11389. In contrast, stable oral SCC clones that constitutively
      overexpressed the mouse dominant negative mutant, RAR-beta (R269Q), were shown to
      exhibit reduced RAR/RXR transcriptional transactivation function and reduced
      sensitivity to growth inhibition by RA, SR 11254 and SR 11389. Likewise, the RAR
      gamma antagonist SR 11253 was found to block the ability of SR 11254 and SR 11389
      to inhibit SCC growth. These results indicate that modulation of RAR function
      through the use of either an RAR-gamma-selective antagonist or a pan-RAR dominant
      negative mutant significantly alters the growth inhibitory response of oral SCCs
      to retinoids.

PMID- 12468630
TI  - DNA methylation and diet in cancer.
AB  - The studies reviewed here investigate the association between folate status and
      DNA methylation in cancer tissues. We evaluated tissue vitamin levels and global
      DNA methylation, a biomarker of neoplasia, in normal lung and lung cancer
      tissues. Lung squamous cell carcinoma tissues exhibited global DNA
      hypomethylation, with decreased folate and vitamin B-12 concentrations, and
      increased vitamin C concentrations, relative to matched uninvolved control
      tissues. Breast cancer tissues also had globally hypomethylated DNA and decreased
      vitamin B-12 and vitamin C levels, but folate concentrations were elevated in
      breast cancer tissues. Global DNA methylation status in buccal mucosal cells may
      reflect global methylation status in lung tissues, because there was a
      significant association between global DNA methylation in buccal mucosal cells
      and malignant tissues of the lung, but not between methylation in peripheral
      leukocytes and lung tissues. We found that global DNA hypomethylation, as
      assessed by a radiolabeled 5-methylcytosine technique, was associated with
      susceptibility for development of lung cancer, which is involved in the
      progression of the disease. DNA methylation was also associated with the
      development of squamous cell carcinomas in whites but not in blacks. Overall,
      these studies suggest that global DNA methylation patterns may vary depending on
      the type of cancer, that tissue vitamin levels are associated with global DNA
      methylation status and that ethnicity should be considered in studies of DNA
      methylation.

PMID- 12468631
TI  - Antioxidant regulation of protein kinase C in cancer prevention.
AB  - Besides scavenging free radicals, antioxidants inhibit signaling enzymes such as
      protein kinase C (PKC) that play a crucial role in tumor promotion. By having
      different oxidation susceptible regions, PKC can respond to both oxidant tumor
      promoters and cancer-preventive antioxidants to elicit opposite cellular
      responses. Oxidant tumor promoters activate PKC by reacting with zinc-thiolates
      present within the regulatory domain. In contrast, the oxidized forms of some
      cancer-preventive agents, such as polyphenolics (ellagic acid, 4-hydroxytamoxifen
      and curcumin) and selenocompounds, can inactivate PKC by oxidizing the vicinal
      thiols present within the catalytic domain. This brings an efficient
      counteractive mechanism to block the signal transduction induced by tumor
      promoters at the first step itself. Because prostate cancer prevention clinical
      trials in large human population are under way, we have focused more on
      understanding the cancer-preventive mechanism of selenium. Methylselenol, the
      postulated cancer-preventive metabolite, has no direct effect on PKC activity.
      However, methylseleninic acid, locally generated by the reaction of membrane
      methylselenol with PKC-bound tumor-promoting fatty acid hydroperoxides,
      selectively inactivates PKC. This mechanism clarifies how the volatile
      methylselenol that is present in a low concentration induces the inactivation of
      PKC selectively in the promoting precancer cells. Selenoprotein thioredoxin
      reductase reverses selenium-induced inactivation of PKC, suggesting that
      selenoproteins may serve as a safeguard against the toxicity induced by
      selenometabolites. Moreover, this also explains how a resistance to selenium
      develops in advanced malignant cells. The redox-mediated inactivation of PKC may,
      at least in part, be responsible for the antioxidant-induced inhibition of tumor
      promotion and cell growth, as well as for the induction of cell death.

PMID- 12468632
TI  - Causes of adult weight gain.

PMID- 12468633
TI  - The role of physical activity in prevention and treatment of body weight gain in
      adults.
AB  - Overweight and obesity are increasing in prevalence, and this has resulted in a
      significant public health burden. Therefore, it is important to identify
      interventions that prevent weight gain and prevent weight regain after weight
      loss. Energy expended in physical activity has the potential to affect energy
      balance, and this can potentially affect body weight regulation. There is some
      evidence that physical activity can minimize weight gain, and it appears that
      needs to be moderate to vigorous in intensity to significantly affect body
      weight. Moreover, it appears that improvements in fitness are associated with
      reductions in risk of weight gain. Physical activity also is associated with
      improved maintenance of weight loss. Although it appears that interventions
      targeting physical activity are necessary to affect weight gain and improve long
      term weight loss, the impact of these interventions on other components of energy
      balance should be examined. In addition, although minimal public health
      recommendations can significantly affect health outcomes, additional research is
      needed to identify the optimal dose of physical activity to prevent weight gain
      and improve long-term weight loss.

PMID- 12468634
TI  - Biobehavioral influences on energy intake and adult weight gain.
AB  - U.S. adults are now gaining more weight and becoming obese at an earlier age than
      in previous years. The specific causes of adult weight gain are unknown, but may
      be attributed to a combination of factors leading to positive energy balance.
      U.S. food supply data indicate that Americans have had a gradual increase in
      energy intake since 1970, and that per capita energy intake was 1.42 MJ/d (340
      kcal/d) higher in 1994 than that in 1984. In contrast, self-reported physical
      activity remained constant between 1990 and 1998. Taken together, these data
      indicate that the increasing trend in U.S. adult weight gain is primarily
      attributable to overconsumption of energy. Epidemiological and experimental
      studies in animals and humans provide strong evidence that biobehavioral factors
      such as dietary variety, liquid (vs. solid) energy, portion size, palatability
      (taste), snacking patterns, restaurant and other away-from-home food, and dietary
      restraint and disinhibition influence hunger, satiety and/or voluntary energy
      intake. When these eating behaviors are consistently experienced either
      separately or in combination over the long term, they are likely to facilitate
      overeating. We provide a brief overview of the evidence to date for the role of
      these biobehavioral factors in contributing to excess energy intake and increases
      in body weight over time.

PMID- 12468637
TI  - Expression and regulation of endothelin-1 and its receptors in human penile
      smooth muscle cells.
AB  - We report for the first time that penile smooth muscle cells (SMC) not only
      respond to, but also synthesize, endothelin-1 (ET-1), one of the main regulators
      of SMC activity. Immunohistochemical studies indicated that, beside endothelial
      cells (EC), SMC of the human adult and fetal penis also express ET-1 and its
      converting enzyme, ECE-1. Accordingly, cultures of adult penile stromal cells
      express these genes. We also prepared and characterized penile SMC from human
      fetuses. These cells express SMC specific markers such as alpha smooth muscle
      actin and phosphodiesterase type 5A3 along with hallmarks of androgen-dependent
      cells (androgen receptor and 5alpha reductase type 2). Human fetal penile SMC
      (hfPSMC) are immunopositive for ET-1 and release ET-1. ET-1 expression in hfPSMC
      was strongly increased by several factors such as transforming growth factor
      beta1 (TGF-beta1), interleukin-1alpha (IL-1alpha), ET-1 itself and prolonged (24
      h) hypoxia. This latter condition not only affected ET-1 expression but also
      responsiveness. While at normal oxygen tension, hfPSMC responded to ET-1 with a
      decreased proliferation mediated by the endothelin-A receptors and TGF-beta1;
      however, during hypoxia, ET-1 stimulated cell growth. Accordingly, prolonged
      hypoxia up-regulated endothelin-B receptor mRNA expression. In conclusion, our
      results indicate that in penile tissues SMC produce ET-1 and that such production
      is modulated by factors involved in penile physiology and tissue remodelling. In
      addition, the hfPSMC we have characterized might be a useful model for studying
      biochemical aspects of the human erectile process in vitro.

PMID- 12468638
TI  - Seminal plasma activates cyclooxygenase-2 and prostaglandin E2 receptor
      expression and signalling in cervical adenocarcinoma cells.
AB  - Enhanced cyclooxygenase (COX) expression and prostaglandin E2 (PGE2) synthesis
      are regarded as promoters of neoplastic cell proliferation and angiogenesis.
      Expression of COX-2 and synthesis of PGE2 are up-regulated in cervical
      carcinomas. In sexually active women, growth and invasiveness of neoplastic
      cervical epithelial cells may be also under the direct influence of PGE2 present
      in seminal plasma. The aims of this study were to investigate the effect of
      seminal plasma and PGE2 on the expression of COX-2 and expression and signalling
      of the PGE2 receptor subtypes (EP1-EP4) in HeLa (cervical adenocarcinoma) cells.
      Treatment of HeLa cells with seminal plasma or PGE2 resulted in up-regulation of
      COX-2 expression (P < 0.05). In addition, seminal plasma induced the mRNA
      expression of EP1, EP2 and EP4 receptors, whilst PGE2 treatment of HeLa cells
      induced the expression of the EP4 receptor (P < 0.05). This was coincident with a
      rapid accumulation of adenosine 3',5'-cyclic monophosphate (cAMP) in HeLa cells
      stimulated with seminal plasma or PGE2, which was greater in seminal plasma
      stimulated cells compared with PGE2 stimulated cells (P < 0.05). Subsequently, we
      investigated whether the effect of seminal plasma on cAMP signalling in HeLa
      cells was mediated via the cAMP-linked EP2/EP4 receptors. Stimulation of HeLa
      cells with seminal plasma or PGE2 resulted in an augmented cAMP accumulation in
      cells transfected with the EP2 or EP4 receptor cDNA compared with control
      transfected cells (P < 0.05). These data suggest that, in sexually active women,
      seminal plasma may play a role in modulating neoplastic cell function and
      cervical tumorigenesis.

PMID- 12468639
TI  - Effects of GnRH analogues, 'add-back' steroid therapy, antiestrogen and
      antiprogestins on leiomyoma and myometrial smooth muscle cell growth and
      transforming growth factor-beta expression.
AB  - The objective of this study was to elucidate the biological significance of GnRH
      and antiprogestins and antiestrogen in leiomyoma and their interactions with
      ovarian steroid 'add-back' therapy. Leiomyoma and myometrial smooth muscle cells
      (LSMC and MSMC) were isolated and exposed to GnRH agonist (leuprolide acetate,
      LA), 17beta-estradiol (E2), medroxyprogesterone acetate (MPA), GnRH antagonist
      (Antide), estrogen antagonist, ICI182780 (Fulvestrant) and progesterone
      antagonists RU486 (Mifepristone) and ZK98299 (Onapristone) and combinations
      thereof. The rate of DNA synthesis, cell proliferation and transforming growth
      factor-beta (TGF-beta) expression were then determined. In both cell types, we
      found that in a dose-dependent manner, LA inhibited, whereas E2, MPA and the
      combination of E2 + MPA stimulated, the rate of DNA synthesis in these cells.
      Antide reversed the inhibitory effect of LA, while LA partly inhibited the
      stimulatory effect of the steroids. In addition, RU486, ICI182780 and ZK98299 at
      0.1 micro mol/l or higher doses inhibited the rate of DNA synthesis and partly
      reversed the effects of E2 and/or MPA. We also found that LSMC expressed elevated
      levels of TGF-beta1 compared with MSMC. In both cell types, the effects of LA,
      E2, MPA, RU, ZK and ICI and combinations thereof on TGF-beta1 production were
      reflective of their effects on DNA synthesis. In line with this, TGF-beta1 was
      found to stimulate DNA synthesis and the E2-, TGF-beta1- or E2 + TGF-beta1
      induced DNA synthesis was found to be inhibited by TGF-beta1 neutralizing
      antibodies and/or LA. In conclusion, the results provide further evidence that
      GnRH agonist- and RU486-induced leiomyoma regression is mediated in part through
      an interactive mechanism that results in altered cell growth and suppression of
      TGF-beta production.

PMID- 12468640
TI  - High xylosyltransferase activities in human follicular fluid and cultured
      granulosa-lutein cells.
AB  - Follicular fluid proteoglycans play an important role in human oocyte maturation,
      including the development of a fluid-filled compartment and maintenance of the
      hypocoagulative state of the follicular fluid. Human xylosyltransferase (EC
      2.4.2.26, XT) is the key enzyme in the biosynthesis of glycosaminoglycan chains
      in proteoglycans and is secreted into body fluids together with large
      proteoglycans. We investigated the XT activities in human follicular fluid and
      granulosa-lutein cells from women undergoing IVF procedures. The mean XT activity
      was determined as 17.7 mU/l, which is 20-fold higher than in serum and the
      highest XT activity ever found in body fluids. Cultured human granulosa-lutein
      cells secreted large amounts of XT (14.52 micro U/10(6) cells), indicating that
      these cells are the main source of this enzyme in human follicular fluid. The XT
      from human follicular fluid was found to be associated with large chondroitin
      sulphate-containing proteoglycans. Furthermore, heparin was shown to bind
      strongly to the follicular fluid XT and to inhibit its enzyme activity. These
      findings indicate that XT may play a role in maintaining the haemostatic
      potential of the follicular fluid.

PMID- 12468641
TI  - Isolation, characterization and expression of the human Factor In the Germline
      alpha (FIGLA) gene in ovarian follicles and oocytes.
AB  - The Factor In the Germline alpha (FIGalpha) transcription factor regulates
      expression of the zona pellucida proteins ZP1, ZP2 and ZP3 and is essential for
      folliculogenesis in the mouse. Using the published mouse Figla sequence, BLAST
      searches identified a human chromosome 2 BAC clone with high sequence identity.
      Using PCR primers derived from this clone, amplicons derived from ovarian
      follicles and mature oocytes revealed 100% identity with the appropriate human
      BAC clone, the expected homology with the mouse Figla gene sequence, and homology
      on translation with the FIGalpha protein identified in the Japanese rice fish,
      medaka (Oryzias latipes). PCR expression profiling of this transcript revealed
      FIGLA mRNA expression in cDNA derived from ovarian follicles (5/5 samples from
      the primordial through to the secondary stage) mature oocytes (6/9 samples), and
      less frequently in preimplantation embryos (2/7 samples). Subsequent BLAST
      searches revealed the predicted full length coding sequence of the human FIGalpha
      protein which demonstrates 68 and 25% similarity overall to mouse and medaka
      proteins respectively, with 96 and 57% identity respectively within the basic
      helix-loop-helix region. This confirms our identification of the human homologue
      for this gene which maps to chromosome 2p12. Further work is required to
      understand its role in normal human oocyte development and the potential
      involvement in human infertility.

PMID- 12468642
TI  - Endometrial interleukin-6 in vitro is not regulated directly by female steroid
      hormones, but by pro-inflammatory cytokines and hypoxia.
AB  - Endometrial interleukin-6 (IL-6) mRNA has been reported to be suppressed in the
      mid-secretory phase in patients with recurrent early spontaneous abortions. This
      prompted our study concerning the regulation of endometrial IL-6 in cell culture
      models of endometrial epithelial and stromal cells. Steroid-dependent secretion
      of IL-6 was analysed by 17beta-estradiol (10(-8) mol/l) or progesterone (10(-6)
      mol/l) treatment and withdrawal (n = 8). Regulation by pro-inflammatory cytokines
      was studied in co-cultures of endometrial cells with human blood peripheral
      mononuclear cells (PBMC; n = 5) and by stimulation with IL-1beta, IL-6 and tumour
      necrosis factor alpha (TNFalpha), secreted by PBMCs at high concentrations.
      Regulation by hypoxia was assessed by culture of endometrial cells in 2% oxygen
      for 6 and 24 h (n = 5). IL-6 mRNA and protein levels were analysed by RT-PCR and
      enzyme-linked immunosorbent assays respectively. Endometrial IL-6 was not
      directly affected by 17beta-estradiol and/or progesterone. Co-culturing
      endometrial cells with PBMCs led to an increase of stromal but not epithelial IL
      6 mRNA levels. In stromal cells, IL-6 secretion increased 2-10-fold if stimulated
      with 10 ng/ml recombinant IL-1beta or TNFalpha (P < 0.05). Hypoxia stimulated IL
      6 secretion in epithelial cells up to 2-fold and in stromal cells up to 48-fold
      (P < 0.05). In conclusion, IL-6 expression in stromal and epithelial cells in
      vitro is regulated differently by pro-inflammatory cytokines and hypoxia. These
      results suggest a tight and specific network of control for this important
      cytokine within different endometrial compartments.

PMID- 12468643
TI  - Distinct mechanisms regulate cyclooxygenase-1 and -2 in peritoneal macrophages of
      women with and without endometriosis.
AB  - Prostaglandin (PG) E2 has been shown to stimulate steroidogenesis in ectopic
      endometriotic stromal cells and may be involved in the development of
      endometriosis since this disorder is highly estrogen dependent. The biosynthesis
      of PGE2 is controlled by the rate-limiting enzyme termed cyclooxygenase (COX).
      The objective of the current study was to investigate the expression of COX in
      peritoneal macrophages isolated from women with and without endometriosis, and to
      explore the effects of pro-inflammatory agents on COX expression in peritoneal
      macrophages. Using quantitative RT-PCR and Western blot analyses, we found that
      expression of COX-2 was markedly increased (P < 0.05) in peritoneal macrophages
      isolated from women with early or severe endometriosis, whereas expression of COX
      1 was elevated only in the severe stage (P < 0.05). On the contrary,
      monocytes/macrophages purified from peripheral blood of patients with
      endometriosis had minimal or undetectable levels of COX-2, and this was not
      different from disease-free women. Treatment with interleukin-1beta, tumour
      necrosis factor-alpha or PGE2 caused a significant increase in COX-2 (P < 0.05)
      but not COX-1 expression in peritoneal macrophages isolated from disease-free
      women. In contrast, these agents had no substantial effect on COX-1 and COX-2
      expression in peritoneal macrophages from women with endometriosis. In summary,
      expression of COX in peritoneal macrophages was associated with the severity of
      endometriosis. Elevated expression of both COX-1 and COX-2 in peritoneal
      macrophages may contribute to the increased peritoneal fluid PGE2 concentrations
      and may thus play an important role in the development of endometriosis.

PMID- 12468644
TI  - Altered expression of genes involved in the production and degradation of
      endometrial extracellular matrix in patients with unexplained infertility and
      recurrent miscarriages.
AB  - During the secretory phase of the menstrual cycle, the composition of
      extracellular matrix (ECM) in endometrium changes to favour implantation. In the
      present study, we have analysed whether some cases of unexplained infertility and
      recurrent abortions could be explained by abnormal production or turnover of
      endometrial ECM. Comparison of mRNA levels of a panel of collagens, matrix
      metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and
      cathepsins in the samples revealed higher levels of type I collagen, MMP-2 and
      cathepsin H and decreased levels of TIMP-3 mRNA in mid-secretory endometrium of
      patients with unexplained infertility and/or recurrent miscarriages when compared
      with normal mid-secretory endometrium. Furthermore, changes were also seen in the
      levels of type I collagen and TIMP-3 mRNA between the proliferative and mid
      secretory phases of normal endometrium. The results suggest an altered ECM
      turnover in the endometrium of patients with fertility disorders prior to
      implantation.

PMID- 12468645
TI  - Expression and subcellular distribution of the active form of c-Src tyrosine
      kinase in differentiating human endometrial stromal cells.
AB  - Decidual growth factors and locally produced cytokines are thought to activate
      specific phosphorylation signalling pathway(s), thereby eliciting a variety of
      decidual functions. We have previously reported the activation of c-Src tyrosine
      kinase during ovarian steroid-induced decidualization of cultured human
      endometrial stromal cells. As chicken c-Src is known to be activated upon
      dephosphorylation of tyrosine 527 (Y527, corresponding to Y530 in human), we here
      employed a monoclonal antibody, clone 28, directed against the active form of
      human c-Src whose Y530 is dephosphorylated, and investigated whether c-Src became
      dephosphorylated at Y530 and thereby activated during decidualization. We found
      that the active form of c-Src was up-regulated and demonstrated increased kinase
      activity during in-vitro decidualization. Immunohistochemistry revealed that
      decidual cells in early pregnancy decidua were intensely stained with clone 28
      when compared with the stromal cells in the non-pregnant endometrium. Moreover,
      the active form of c-Src translocated from a perinuclear region to the cytoplasm
      upon decidualization. Thus, the Y530 dephosphorylation, kinase activation, and
      subcellular translocation of c-Src may be intracellular signalling events
      associated with decidualization in vivo as well as in vitro.

PMID- 12468646
TI  - Enhanced expression of the immunoregulator, p43-placental isoferritin, in Down's
      syndrome placentae and fetal kidneys.
AB  - Human placental isoferritin is composed of a 43 kDa subunit and ferritin light
      chains. It acts as an immunosuppressive cytokine in normal gestation and in some
      malignant conditions. We investigated p43-placental isoferritin expression at the
      maternal fetal tissue interface and in fetal kidneys in Down's syndrome (DS)
      compared with normal control samples. Following termination of mid-gestation
      pregnancies placental and fetal kidney tissue samples were collected.
      Immunohistochemical analysis of the specimens was performed using a monoclonal
      antibody generated against human p43-placental isoferritin protein (CM-H-9 mAb).
      Expression of p43-placental isoferritin was detected in Hofbauer cells and in the
      syncytial layer of placental tissue. Significantly higher numbers of positive
      Hofbauer cells were detected in DS placentae at 17 weeks gestation compared with
      the controls. The number of immunopositive Hofbauer cells decreased in DS
      placentae at 20 weeks gestation, 3 weeks later than in controls. In kidneys of
      fetuses at 17 weeks gestation, p43-placental isoferritin immunoreactivity was
      confined to the proximal tubules of the nephrons. DS kidneys had higher staining
      intensities compared with similar gestational age controls. Enhanced expression
      of p43-placental isoferritin was observed in DS placentae and fetal kidneys. This
      may explain the increased p43-placental isoferritin levels in the maternal serum
      of DS gestations.

PMID- 12468647
TI  - Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice.
AB  - p57Kip2, a potent inhibitor of several cyclin/cyclin dependent kinase complexes
      (CDK ), is a paternally imprinted gene in both humans and mice, and here we show
      that pregnant mice which are heterozygous for p57Kip2 deficiency display symptoms
      similar to preeclampsia. p57-/+ (heterozygotes for p57Kip2 ) female mice that
      were mated with p57-/+ males showed hypertension, proteinuria, thrombocytopenia,
      decreased anti-thrombin III activity, and increased endothelin levels during late
      pregnancy. In their kidneys, endotheliosis of glomeruli were recognized along
      with fibrinoid or hyalinoid deposits. These characteristics were also observed in
      pregnant p57-/+ females that were mated with wild type males, but not in pregnant
      wild type females mated with p57-/+ males or wild type males. The pregnant p57-/+
      mice had conceptuses both with and without p57Kip2 expression. The conceptuses
      without p57Kip2 expression showed trophoblastic hyperplasia, which mimics the
      hallmark proliferation of intermediate trophoblasts in clinical preeclampsia. It
      is suggested that the preeclampsia-like symptoms of the pregnant p57-/+ mice
      might have been induced by the conceptus(es) without p57Kip2 expression. In
      addition, pregnant p57-/+ mice might serve as a new animal model for preeclampsia
      characterized by trophoblastic hyperplasia.

PMID- 12468648
TI  - Preimplantation genetic diagnosis for beta-thalassaemia using sequencing of
      single cell PCR products to detect mutations and polymorphic loci.
AB  - In order to carry out preimplantation genetic diagnosis (PGD) for beta
      thalassaemia, we have applied direct sequencing of single cell PCR products to
      detect mutations and polymorphic loci within the beta-globin gene. Conventional
      duplex PCR was used to amplify two regions of the beta-globin gene with an
      amplification efficiency of 79% for blastomeres. Sequencing data were obtained
      for 100% of amplified products, with 12% having confirmed allele drop-out (ADO).
      A double ADO event was observed at least twice, confirming the real risk of such
      an event during PGD. In one couple, the presence of a polymorphism linked to the
      female partner's mutation enabled us to eliminate the risk of misdiagnosis due to
      double ADO without having to amplify both mutations within the same PCR product.
      We present here the data from eight clinical PGD cycles for three couples
      resulting in a singleton pregnancy and a twin pregnancy with all babies confirmed
      to be free from beta-thalassaemia (major).

PMID- 12468649
TI  - Can sex selection be ethically tolerated?

PMID- 12468650
TI  - Reproductive tourism as moral pluralism in motion.
AB  - Reproductive tourism is the travelling by candidate service recipients from one
      institution, jurisdiction, or country where treatment is not available to another
      institution, jurisdiction, or country where they can obtain the kind of medically
      assisted reproduction they desire. The more widespread this phenomenon, the
      louder the call for international measures to stop these movements. Three
      possible solutions are discussed: internal moral pluralism, coerced conformity,
      and international harmonisation. The position is defended that allowing
      reproductive tourism is a form of tolerance that prevents the frontal clash
      between the majority who imposes its view and the minority who claim to have a
      moral right to some medical service. Reproductive tourism is moral pluralism
      realised by moving across legal borders. As such, this pragmatic solution
      presupposes legal diversity.

PMID- 12468651
TI  - Palliative care research: trading ethics for an evidence base.
AB  - Good medical practice requires evidence of effectiveness to address deficits in
      care, strive for further improvements, and justly apportion finite resources.
      Nevertheless, the potential of palliative care is still held back by a paucity of
      good evidence. These circumstances are largely attributable to perceived ethical
      challenges that allegedly distinguish dying patients as a special client class.
      In addition, practical limitations compromise the quality of evidence that can be
      obtained from empirical research on terminally ill subjects. This critique aims
      to appraise the need for focused research, in order to develop clinical and
      policy decisions that will guide health care professionals in their care of dying
      patients. Weighted against this need are tenets that value the practical and
      ethical challenges of palliative care research as unique and insurmountable. The
      review concludes that, provided investigators compassionately apply ethical
      principles to their work, there is no justification for not endeavouring to
      improve the quality of palliative care through research.

PMID- 12468652
TI  - Withholding life prolonging treatment, and self deception.
AB  - OBJECTIVES: To compare non-treatment decision making by general practitioners and
      geriatricians in response to vignettes. To see whether the doctors' decisions
      were informed by ethical or legal reasoning. DESIGN: Qualitative study in which
      consultant geriatricians and general practitioners (GPs) randomly selected from a
      list of local practitioners were interviewed. The doctors were asked whether
      patients described in five vignettes should be admitted to hospital for further
      care, and to give supporting reasons. They were asked with whom they would
      consult, who they believed ought to make such decisions, and whether the
      relatives' preferences would influence their decision making. MAIN MEASURES: To
      analyse the factors influencing the doctors' decisions not to admit otherwise
      terminally ill patients to hospital for life prolonging treatment. RESULTS:
      Seventeen GPs and 18 geriatricians completed the interview. All vignettes
      produced strong concordance in decision making between both groups. Ten per cent
      of the doctors would provide life prolonging treatment to patients with severe
      brain damage. Most would admit a surgical patient regardless of age or
      disability. Medical reasons were largely used to explain decision making. The
      wishes of relatives were influential and resource considerations were not. There
      was variability regarding decision making responsibility. CONCLUSIONS: Little
      attempt was made to link decision making with ethical or legal concepts and there
      may have been non-recognition, or denial, of the ethical consequences of failure
      to admit. The process of decision making may involve deception. This may be
      conscious, because of the illegality of euthanasia, or unconscious (self
      deception), because of deepseated medical and societal reluctance to accept that
      intentionally withholding life prolonging treatment may equate with intentionally
      causing death.

PMID- 12468653
TI  - Medical authority and nursing integrity.
AB  - This paper explores the respective legitimacy or illegitimacy of medical
      authority over nursing work. The analysis makes use of Joseph Raz's ideas
      concerning the nature of authority. Various scenarios are considered which lend
      themselves to differing interpretations, and the conclusion reached is that
      acting in accordance with legitimate medical authority enhances rather than
      compromises the nurse's professional integrity. Difficulties, however, may lie in
      disentangling legitimate from illegitimate attempts to control nursing work.

PMID- 12468654
TI  - The ethics of prophylactic antibiotics for neurosurgical procedures.
AB  - The prophylactic use of antibiotics has become a routine procedure in many areas
      of medicine. In neurosurgery, however, there is considerable debate over their
      use in the prevention of postoperative infection. We pose several ethical
      questions about antibiotic prophylaxis in a neurosurgical setting. These
      questions are discussed under the following categories: responsible usage of
      antibiotics; the ethical dilemmas of controlled, antibiotic clinical trials, and
      some problems inherent in not using prophylactic antibiotics.

PMID- 12468655
TI  - Evaluation of do not resuscitate orders (DNR) in a Swiss community hospital.
AB  - OBJECTIVE: To evaluate the effect of an intervention on the understanding and use
      of DNR orders by physicians; to assess the impact of understanding the importance
      of involving competent patients in DNR decisions. DESIGN: Prospective clinical
      interventional study. SETTING: Internal medicine department (70 beds) of the
      hospital of La Chaux-de-Fonds, Switzerland. PARTICIPANTS: Nine junior physicians
      in postgraduate training. INTERVENTION: Information on the ethics of DNR and
      implementation of new DNR orders. MEASUREMENTS AND MAIN RESULTS: Accurate
      understanding, interpretation, and use of DNR orders, especially with respect to
      the patients' involvement in the decision were measured. Junior doctors writing
      DNR orders had an extremely poor understanding of what DNR orders mean. The
      correct understanding of the definition of a DNR order increased from 31 to 93%
      (p<0.01) after the intervention and the patients' involvement went from 17% to
      48% (p<0.01). Physicians estimated that 75% of their DNR patients were mentally
      competent at the time of the decision. CONCLUSION: An intervention aimed at
      explaining the ethical principles and the definition of DNR orders improves
      understanding of them, and their implementation, as well as patient
      participation. Specific efforts are needed to increase the involvement of
      mentally competent patients in the decision.

PMID- 12468656
TI  - Undignifying institutions.
AB  - Declarations of the importance of dignity in health care are commonplace in codes
      of practice and other mission statements, yet these documents never clarify
      dignity's meaning. Their vague aspirations are compared to comments from staff
      and patients about opportunities for and barriers against the promotion of
      dignity in elderly care institutions. These suggest that while nurses and health
      care assistants have an intuitive understanding of dignity, they either do not or
      cannot always bring it about in practice. Thus, despite stated intentions to
      promote dignity, it appears that the circumstances of at least some elderly care
      institutions cause patients to experience avoidable indignities. Such
      institutions are "undignifying institutions" because they fail to acknowledge
      dignity's basic components, focus excessively on quantifiable priorities, and
      have insufficient resources available to assure consistently dignifying care. As
      a partial solution, we argue that health workers should be taught to understand
      and specify the components of dignity, which will better prepare them to
      challenge undignifying practices and to recognise opportunities for dignity
      promotion.

PMID- 12468657
TI  - Consent to open label extension studies: some ethical issues.
AB  - A frequent feature of pharmaceutical research is the open label extension study,
      in which patients participating in double blind placebo controlled trials of new
      medications are invited, on completion of the initial trial, to take the study
      drug for some further period. Patients are openly given the active substance at
      this stage, regardless of their assignment in the initial trial. Investigators
      are typically reluctant to unblind the patients' assignment at the point of entry
      into the open label phase, on the grounds that this may introduce ascertainment
      bias in the main study. It is argued that patients invited to participate in open
      label extension studies cannot give a proper consent to such research unless they
      know to which arm of the main trial they were recruited. It is further argued
      that to recruit certain groups of patients from placebo controlled trials into
      open label extension studies may also be unethical for clinical reasons.

PMID- 12468658
TI  - Clinical issues on consent: some philosophical concerns.
AB  - On occasions, laws on consent are subject to modification, largely on account of
      being subject to common law rather than statute-for example, in the UK. Guideline
      publications such as the UK Department of Health Reference Guide to Consent for
      Examination or Treatment are intended to provide information for clinicians on
      when and how to apply current laws in everyday clinical situations. While the
      extent to which guidelines influence clinician behaviour depends on how much they
      are read and followed, what is also relevant, and sometimes omitted from
      consideration, is discussion about underlying philosophical concepts. This paper
      analyses philosophical weaknesses relating to English laws on consent, the main
      focus of attention being applied ethics and the rights of adults with incapacity.
      It draws comparisons between the US and the UK, and advocates changes in English
      law in order to help rectify weaknesses in patient protection. Discussion
      includes references to Scottish law, and the use of advance directives, and it
      voices concerns about over-reliance on "best interests" determinations. The
      problem is partly one of logical analysis, and what can happen is that best
      interests determinations fail to show proper respect for adults lacking the
      capacity to consent to examination or treatment on their own behalf. This is
      fundamentally a matter of rights, and requires further investigation and
      appropriate legal remedies in order to respond to ethical deficiencies in English
      law as it now stands.

PMID- 12468659
TI  - Tobacco, taxation, and fairness.
AB  - The author defends himself against an attack by Smith and Bopp on his views on
      smoking and taxation. The theory that, on the grounds of equity and/or fairness,
      smokers should pay via taxation on tobacco for the health care costs of treating
      smoking-related medical conditions is discussed and shown to be defective. It is
      argued that the fundamental mistake that Smith and Bopp make is to confuse and
      conflate the separate issues of whether particular taxes are fair and whether
      they are justifiable. The conclusion is reached that an excise duty on tobacco is
      a good tax. It is a non-fair or even an unfair tax but it is justified on grounds
      other than fairness.

PMID- 12468663
TI  - The model state emergency health powers act.

PMID- 12468664
TI  - Improving city health: how can we tell?

PMID- 12468666
TI  - The World Cities Project: rationale, organization, and design for comparison of
      megacity health systems.
AB  - This article provides an overview of the World Cities Project (WCP), our
      rationale for it, our framework for comparative analysis, and an overview of
      current studies in progress. The WCP uses New York, London, Paris, and Tokyo as a
      laboratory in which to study urban health, particularly the evolution and current
      organization of public health infrastructure, as well as the health status and
      quality of life in these cities. Comparing world cities in wealthier nations is
      important because of (1) global trends in urbanization, emerging health risks,
      and population aging; (2) the dominant influence of these cities on "megacities"
      of developing nations; and (3) the existence of data and scholarship about these
      world cities, which provides a foundation for comparing their health systems and
      health. We argue that, in contrast to nation-states, world cities provide
      opportunities for more refined comparisons and cross-national learning. To
      provide a framework for WCP, we define an urban core for each city and examine
      the similarities and differences among them. Our current studies shed light on
      inequalities in health care use and health status, the importance of
      neighborhoods in protecting population health, and quality of life in diverse
      urban communities.

PMID- 12468667
TI  - Uncovering the historic environmental hazards of urban brownfields.
AB  - In Baltimore, over 1,000 vacant industrial sites persist across its urban
      landscape, yet little is known about the potential environmental health risks
      that may undermine future cleanup and redevelopment activities and the health of
      those in communities near these sites. This study examined the characteristics of
      urban brownfield properties in southeast Baltimore, Maryland, and screened sites
      for their potential environmental hazards. In addition, demographic and health
      data were evaluated to profile the social and health status of those in
      brownfield communities. The results show that brownfields in southeast Baltimore
      represent a range of historic operations, including metal smelting, oil refining,
      warehousing, and transportation, as well as paints, plastics, and metals
      manufacturing. The screening method identified a range of substances associated
      with these properties, including heavy metals, chlorinated hydrocarbons, and
      polycyclic aromatic hydrocarbons, all of which are suspected or recognized
      toxicants, and many of which are persistent in the environment. Spatially, these
      sites are concentrated in white, working class neighborhoods in which poverty
      levels exceed and educational attainment lags behind state and national averages.
      Moreover, these sites are concentrated in communities in which excess mortality
      rates due to respiratory disease, cancer, and heart disease exist when compared
      to the city, state, and national averages. This investigation demonstrated the
      usefulness of historic archives, real estate records, regulatory files, and
      national hazard-tracking systems based on standard industrial classification
      (SIC) to screen brownfield properties for their hazard potential. This analysis
      provides the foundation for further site monitoring and testing, cleanup and
      redevelopment priority setting, risk management strategies, and neighborhood
      planning, and it illustrates the need for increased health surveillance and
      disease prevention strategies in affected communities.

PMID- 12468668
TI  - Print media coverage of risk-risk tradeoffs associated with West Nile
      encephalitis and pesticide spraying.
AB  - When mosquito-borne West Nile virus emerged in the United States in 1999 and
      triggered pesticide spraying, society was faced with a controversy over an
      important risk-risk tradeoff-the risks of pesticide exposure versus those of West
      Nile encephalitis. Effective public communication about risk-risk tradeoffs is
      important because it can assist individuals and society in investing resources
      optimally. This study examined how effectively major North American print media
      in the year 2000 provided information on this risk-risk tradeoff. My colleagues
      and I found that the print media were generally ineffective in providing precise
      information about pesticide risks and in comparing risks of pesticide exposure
      with those of West Nile encephalitis. The media were also ineffective in
      mentioning the efficacy of pesticide spraying or comparing the economic costs of
      pesticide spraying with those of West Nile encephalitis. We suggest that greater
      effort in collecting and reporting precise risk information, fostering more
      active relationships between journalists and scientists/public health
      professionals, and recognizing biases resulting from preconceptions can help
      improve reporting by the print media and public health agencies on risk-risk
      tradeoffs associated with emerging insect-borne infectious diseases. These
      efforts could help improve public health by improving decision making related to
      the control of insect-borne diseases.

PMID- 12468669
TI  - Childhood lead poisoning from paint chips: a continuing problem.
AB  - Although lead poisoning (plumbism) has been recognized for centuries, lead
      exposures still occur frequently today because of its varied uses and persistence
      in the environment. Despite the awareness of the adverse effects of lead on
      adults, childhood plumbism was first reported only about a century ago. Young
      children are one of the most vulnerable groups to the adverse effects of lead
      because of their rapidly developing central nervous systems. Federal regulations
      in the 1970s have been successfully implemented to decrease the amount of
      environmental lead by decreasing the content of lead in gasoline and indoor
      paint. However, almost 30 years after these laws were passed, inner-city housing
      with leaded paint still exists. We describe three children living in New York
      City who developed plumbism from the ingestion of leaded paint chips.

PMID- 12468670
TI  - Is home renovation or repair a risk factor for exposure to lead among children
      residing in New York City?
AB  - Children can be lead poisoned when leaded paint is disturbed during home
      renovation or repair. We conducted a case-control study to assess the association
      between elevated blood lead levels (BLLs) in children younger than 5 years of age
      and renovation or repair of homes built before 1950 in New York City. In 1998, we
      interviewed parents of 106 case children (BLLs >/= 10 micro g/dL) and 159 control
      children (BLLs </= 5 micro g/dL) living in selected New York City neighborhoods.
      We then used logistic regression methods to estimate odds ratios (ORs) for
      elevated BLLs among children living in housing that had undergone various
      renovations or repairs in the 6 months before the blood lead test, and we
      adjusted for age and test month. Case children were only slightly more likely
      than control children to live in a house that had undergone any renovation (OR =
      1.2, 95% confidence interval [95% CI] = 0.7, 2.1). Case children were more likely
      to (1) live in housing that had interior surfaces prepared for painting,
      especially by hand sanding (OR = 3.5, 95% CI = 1.1, 10.9; population attributable
      risk [PAR%] = 10.4%, 95% CI = 0.5%, 19.3%); and (2) have work-created dust
      throughout their housing unit (OR = 6.3, 95% CI = 1.2, 32.3; PAR% = 6.8%, 95% CI
      = 0.0%, 13.1%). The risk for excess lead exposure is increased by home renovation
      or repair work involving interior paint preparation or reported dispersal of dust
      beyond the work area. The proportion of cases related to this exposure is high
      enough to merit preventive measures.

PMID- 12468671
TI  - Incidence of violence against HIV-infected and uninfected women: findings from
      the HIV Epidemiology Research (HER) study.
AB  - The effect of human immunodeficiency virus (HIV) infection on the incidence of
      violence against women was addressed in a prospective cohort of HIV-infected and
      uninfected women. Participants were enrolled between 1993 and 1995 in four US
      cities and followed up semiannually through 1998. Among 1,087 women with a total
      accrual of 2,988 person-years (PY) of follow-up, there were 185 reports of abuse
      (incidence rate = 6.19 per 100 PY). The rate of abuse among HIV-infected women
      with a CD4+ count less than 350 cells/ micro L was lower than that among HIV
      infected women with more CD4+ cells/ micro L or among uninfected women (4.87,
      6.92, and 6.44 per 100 PY, respectively). In multivariate analysis, being
      separated or divorced, having a history of abuse in adulthood, using marijuana,
      using crack, and having multiple sex partners were each significantly associated
      with an elevated abuse rate; being older was inversely associated with abuse.
      Among HIV-infected women, those with fewer CD4+ cells/ micro L continued to show
      a decreased abuse rate (hazard ratio = 0.55, 95% CI = 0.36, 0.82) after
      adjustment for these factors. It is important to complement existing and future
      HIV prevention and intervention strategies with efforts to reduce violence
      against women.

PMID- 12468672
TI  - HIV risk profile and prostitution among female street youths.
AB  - The objective of this study was to compare human immunodeficiency virus (HIV)
      risk factors among female street youths involved in prostitution and those with
      no history of prostitution. Youths aged 14 to 25 years were recruited into the
      Montreal Street Youth Cohort. Semiannually, youths completed an interviewer
      administered questionnaire. Statistical analyses comparing characteristics and
      HIV risk factors for girls involved in prostitution and those never involved were
      carried out using parametric and nonparametric methods. Of the girls, 88 (27%)
      reported involvement in prostitution, and 177 girls reported no history of
      prostitution at the baseline interview. Girls involved in prostitution were two
      times and five times more likely to have reported bingeing on alcohol and on
      drugs, respectively. A history of injection drug use was four times more likely
      to have been reported by girls involved in prostitution. Further, these girls
      were 2.5 times more likely to have reported injected cocaine as their drug of
      choice. Girls involved in prostitution were younger the first time they had
      consensual sex and were twice as likely to have reported anal sex. Consistent
      condom use for anal, vaginal, and oral sex was low for all girls. Girls involved
      in prostitution reported more risky sexual partners. In conclusion, girls
      involved in prostitution may be at increased risk of HIV infection due to their
      injection drug use and risky sexual behaviors. Unique intervention strategies are
      necessary for reducing HIV infection among female street youths involved in
      prostitution.

PMID- 12468673
TI  - Longitudinal influence of perceptions of peer and parental factors on African
      American adolescent risk involvement.
AB  - To explore the long-term contributions of perceived peer and parental influences
      on adolescent risk and protective behaviors (sexual involvement, condom use, and
      drug use), we assessed self-reported behaviors and perceptions of peer risk
      involvement and parental supervision and communication among 383 low-income,
      urban African Americans aged 9 to 15 years at baseline over a 4-year period.
      Baseline perceptions of peer sexual involvement were significantly associated
      with youth sexual behavior at baseline and were predictive of sexual involvement
      through all 4 years of follow-up. Perceived parental monitoring was inversely
      correlated with sexual involvement through 3 years of follow-up. Perceptions of
      peer condom use were associated with increased levels of condom use at baseline
      and through 6 months of follow-up. Positive parental communication was correlated
      with increased condom use. Drug use was higher among youths who perceived peers
      or family members to be using drugs and was inversely correlated with increased
      parental monitoring and supervision. Stepwise regression revealed peer and
      parental influences for all three behaviors. Perceptions of both peer and
      parental behaviors influence long-term risk and protective behaviors of
      adolescents. Therefore, parents should be included in adolescent risk-reduction
      intervention efforts. Inclusion of friends and/or changing youth perceptions of
      peer involvement may also be effective intervention strategies.

PMID- 12468674
TI  - The "ecstasy" hangover: hyponatremia due to 3,4-methylenedioxymethamphetamine.
AB  - 3,4-Methylenedioxymethamphetamine (MDMA, or "ecstasy") has gained an undeserved
      reputation as a "safe" drug among its users. However, hyperthermia,
      rhabdomyolysis, hepatotoxicity, disseminated intravascular coagulation, long-term
      serotonergic neurotoxicity, and death are all associated with MDMA use.
      Hyponatremia is also reported, and its manifestations are frequently delayed
      several hours after the drug is ingested. The etiology of this hyponatremia is
      unclear; both the syndrome of inappropriate antidiuretic hormone release (SIADH)
      and free-water intoxication are advanced as explanations. We describe a 19-year
      old female who presented to the emergency department with altered mental status 1
      day after using MDMA. Her initial serum sodium was 121 mmol/L, and computerized
      tomography (CT) of her head demonstrated cerebral edema. She was treated with
      hypertonic saline and fluid restriction, and her serum sodium increased to 132
      mmol/L over the next 24 hours. She regained consciousness completely within 48
      hours of presentation and recovered uneventfully. MDMA toxicity, particularly the
      pathophysiology and treatment of MDMA-induced hyponatremia, are discussed.

PMID- 12468675
TI  - Effects of increasing syringe availability on syringe-exchange use and HIV risk:
      Connecticut, 1990-2001.
AB  - Syringe-exchange programs (SEPs) in Connecticut operate with caps on the number
      of syringes exchanged per visit. We investigated the effects of legislation
      increasing the cap on drug injectors' access to clean syringes through the SEPs
      in New Haven and Hartford. The mixed design of this study included longitudinal
      and cross-sectional data from individuals and ecological data from program
      operations. Five parameters-syringe return rate, syringes per visit to the SEP,
      syringe reuse rate, syringe human immunodeficiency virus (HIV) prevalence, and
      syringe sharing-were monitored through syringe tracking and testing of SEP
      syringes and by interviewing injectors. Two increases in the cap-from 5 to 10 and
      then from 10 to 30-had little effect on the five parameters that measured
      injectors' access to clean syringes. In contrast, access to clean syringes
      increased when the New Haven SEP first began operations, when syringes first
      became available at pharmacies in Hartford, and when the agency running the
      Hartford SEP changed. Legislation providing piecemeal increases in the cap may
      not, by themselves, be sufficient to increase injectors' access to clean syringes
      and decrease the risk of human immunodeficiency virus transmission in this
      population.

PMID- 12468676
TI  - Beliefs about methadone in an inner-city methadone clinic.
AB  - Despite being considered both the most effective treatment for heroin addiction
      and an essential tool in the prevention of human immunodeficiency virus (HIV),
      methadone maintenance (MM) is often held in low esteem by heroin addicts-even
      those in MM treatment. This survey examined current beliefs and attitudes about
      MM of patients at an inner-city clinic, and the personal experience and attitudes
      of these patients with this treatment. Consenting patients in a methadone clinic
      serving a poor population with high rates of human immunodeficiency virus
      infection were queried about their attitudes toward and beliefs about methadone
      using a 16-item questionnaire. Over 2 days, 315 questionnaires were completed
      (acceptance rate 40%), totaling 32% of the 1,000 clinic patients. Nearly 80%
      believed that methadone had a positive effect on his or her life, but 80% were
      certain or unsure as to whether methadone is bad for one's health, and a similar
      percentage (80%) believed that discontinuing methadone was an important goal.
      Patients continue to have strongly negative attitudes toward and beliefs about
      methadone despite their acknowledgement that methadone has been very positive for
      them as individuals. As a result, many patients leave MM treatment prematurely,
      and there are usually unfilled slots in MM programs in New York City, even while
      continued need exists (e.g., less than 25% of the heroin addicts in the city are
      in treatment). The restrictive nature of many MM programs may account for these
      attitudes and beliefs.

PMID- 12468677
TI  - Case-reporting of acute hepatitis B and C among injection drug users.
AB  - Although public health surveillance system data are widely used to describe the
      epidemiology of communicable disease, occurrence of hepatitis B and C virus (HBV
      and HCV, respectively) infections may be misrepresented by under-reporting in
      injection drug users (IDUs). This study was carried out to examine the
      relationship between HBV and HCV incidence and case-reporting of hepatitis B and
      C in Seattle IDUs. Names of participants in a Seattle IDU cohort study who
      acquired HBV or HCV infection over a 12-month follow-up period were compared to a
      database of persons with acute hepatitis B and C reported to the health
      department surveillance unit over the same period. Of 2,208 IDUs enrolled in the
      cohort who completed a follow-up visit, 63/759 acquired HBV infection, 53/317
      acquired HCV infection, and 3 subjects acquired both HBV and HCV. Of 113 cohort
      subjects who acquired HBV or HCV, only 2 (1.5%) cases were reported; both had
      acute hepatitis B. The upper 95% confidence limit for case-reporting of hepatitis
      C in the cohort was 5.7%, and for hepatitis B, it was 7.5%. In this study,
      reporting of acute hepatitis in IDUs was extremely low, raising questions
      regarding the use of community surveillance data to estimate underlying incidence
      in that population group.

PMID- 12468678
TI  - Health care utilization among drug-using and non-drug-using women.
AB  - This article explores patterns of health care utilization among urban female
      illegal drug users and nonusers. Interviews were conducted between August 1997
      and August 2000 in Atlanta, Georgia, among current drug-using and nonusing women
      aged 18 to 71 years (n = 235). Women were recruited using outreach and targeted
      sampling. Data were examined with multivariate and bivariate methods. Compared to
      nonusers, the most frequent users were significantly more likely to fail to seek
      needed health care (adjusted odds ratio [aOR] = 3.31, 95% confidence interval
      [CI] = 1.18, 9.29) and to use a hospital emergency room as their primary source
      for care (aOR = 6.04, 95% CI = 1.97, 18.56). Multivariate results also suggest
      that age, self-rated health, alcohol use, insurance coverage, financial strain,
      and the presence of minor children are associated with health service
      utilization. Future health policy and research among similar populations must
      continue to address individual and sociodemographic factors that influence
      service utilization and seek to incorporate preventive care for vulnerable
      populations within emergency room settings.

PMID- 12468679
TI  - The evolving role and care management approaches of safety-net Medicaid managed
      care plans.
AB  - This article provides new empirical data about the viability and the care
      management activities of Medicaid managed-care plans sponsored by provider
      organizations that serve Medicaid and other low-income populations. Using survey
      and case study methods, we studied these "safety-net" health plans in 1998 and
      2000. Although the number of safety-net plans declined over this period, the
      surviving plans were larger and enjoying greater financial success than the plans
      we surveyed in 1998. We also found that, based on a partnership with providers,
      safety-net plans are moving toward more sophisticated efforts to manage the care
      of their enrollees. Our study suggests that, with supportive state policies,
      safety-net plans are capable of remaining viable. Contracting with safety-net
      plans may not be an efficient mechanism for enabling Medicaid recipients to
      "enter the mainstream of American health care," but it may provide states with an
      effective way to manage and coordinate the care of Medicaid recipients, while
      helping to maintain the health care safety-net for the uninsured.

PMID- 12468684
TI  - Improving the quality of health services in developing countries: lessons for the
      West.

PMID- 12468680
TI  - Improving the process through which health plans and providers exchange
      performance-related mammography data.
AB  - The ability of health plans to bring about quality improvement is limited by the
      fact that physician networks are highly differentiated, with physician groups
      participating in many plans and plans contracting with many physician groups. The
      primary purpose of our study was to investigate the problems in the current
      system of quality monitoring by managed-care organizations (MCOs) at a large
      integrated health care delivery system (Montefiore Medical Center) and to develop
      ways of addressing these problems through collaboration among MCOs. The project
      began by mapping the current system for collecting, reporting, and using
      performance data to improve performance, using breast cancer screening as an
      example. We found that neither health plans nor providers were satisfied with the
      current system. From the perspective of the health plans, the current quality
      monitoring was costly and, more important, was not yielding appreciable increases
      in screening rates. From the providers' perspective, multiple health plan
      requests for chart pulls and other data collection activities cost them
      substantial amounts of time and money and generated multiple mailings of
      educational materials and reports, but rarely supplied meaningful information
      about their performance. From the perspective of the hospital, the current
      procedure of reporting from MCO to provider or center bypassed the institution's
      own quality monitoring and management structure and thus limited the
      institution's ability to assist in quality improvement. This study clearly showed
      the importance of collaboration among plans at a given provider site.
      Specifically, it pointed to the need for provider-oriented reporting of data,
      rather than plan-oriented reporting, to give physicians numbers that they
      believe. It also showed the need to engage the institution's own quality
      management system to assist in bringing about improvements.

PMID- 12468685
TI  - From patients to politicians: a cognitive engineering view of patient safety.

PMID- 12468686
TI  - Writing for quality and safety in health care: it may be easier than you think.

PMID- 12468687
TI  - Capturing what matters to patients when they evaluate their hospital care.

PMID- 12468688
TI  - Optimizing quality collaboratives.

PMID- 12468689
TI  - Progress of unit based quality improvement: an evaluation of a support strategy.
AB  - OBJECTIVE: To evaluate a strategy for supporting nurses to work with quality
      improvement (QI). DESIGN: Post-intervention evaluation. Study participants and
      intervention: 240 nurses participated in a uniformly designed 4 day basic
      training course in applying a model for QI. Of these, 156 nurses from over 50
      healthcare institutions constituted the generic education (GE) group while 84
      nurses from 42 neonatal units took part in a project to develop national
      guidelines, constituting the targeted intervention (TI) group. METHOD: Postal
      questionnaire 4 years after the training courses. RESULTS: The response rate was
      80% in the TI group and 64% in the GE group. Nurses in the TI group had a
      significantly higher rate in completing all phases of the QI cycle (p=0.0002).
      With no differences between the groups, 39% of all nurses were still involved in
      QI work 4 years after the training courses. Three factors were significantly
      related to nurses continuing their involvement in QI projects: remaining employed
      on the same unit (OR 11.3), taking courses in nursing science (OR 4.1), and
      maintenance of the same QI model (OR 3.1). Reported motives for remaining active
      in QI work were the enhancement of knowledge, influence over clinical practice,
      and development as a nurse. Reasons for discontinuation were organisational
      restructuring, a lack of facilitation and knowledge, and change of workplace.
      CONCLUSIONS: Participation in a national guideline project, including a common
      focus for improvement, facilitation and opportunities for networking, seems to
      have enhanced the ability to carry out the process of QI, but not to sustain the
      QI work over a longer period.

PMID- 12468690
TI  - Comparison of patients' and general practitioners' evaluations of general
      practice care.
AB  - OBJECTIVES: To compare patients' and general practitioners' (GPs') evaluations of
      the quality of general practice care. DESIGN: Written surveys among patients and
      GPs. SETTING: General practice in the Netherlands. SUBJECTS: 1772 patients (from
      45 GPs) and a random sample of 315 GPs. MAIN OUTCOME MEASURES: Patients' and GPs'
      evaluations of 23 aspects of general practice care and GPs' perceptions of
      patients' evaluations using a 5 point scale. RESULTS: The response rate was 88%
      in the patient sample and 63% in the GP sample. The patients' ratings of care
      were significantly more positive (mean 4.0) than those of the GPs (mean 3.7) as
      well as GPs' perceptions of patients' evaluations (mean 3.5) (p<0.001). The
      overall rank order correlations between the patients' evaluations, GPs'
      evaluations, and GPs' perceptions of the patients' evaluations were 0.75 or
      higher (p<0.001). Patients and practitioners gave the most positive evaluations
      of specific aspects of the doctor-patient relationship ("keeping patients'
      records and data confidential", "listening to patients", and "making patients
      feel they had enough time during consultations") and aspects of the organisation
      of care ("provide quick service for urgent health problems" and "helpfulness of
      the staff (other than the doctor)"). The aspects of care evaluated least
      positively by patients as well as by GPs were other organisational aspects
      ("preparing patients for what to expect from specialist or hospital care" and
      "getting through to practice on the telephone"). CONCLUSIONS: GPs and patients
      have to some extent a shared perspective on general practice care. However, GPs
      were more critical about the quality of care than patients and they
      underestimated how positive patients were about the care they provide.
      Furthermore, specific aspects of care were evaluated differently, so surveys and
      other consultations with patients are necessary to integrate their perspective
      into quality improvement activities.

PMID- 12468691
TI  - Development of explicit criteria for cholecystectomy.
AB  - OBJECTIVE: Consensus development techniques were used in the late 1980s to create
      explicit criteria for the appropriateness of cholecystectomy. New diagnostic and
      treatment techniques have been developed in the last decade, so an updated
      appropriateness of indications tool was developed for cholecystectomy in patients
      with non-malignant diseases. The validity and reliability of panel results using
      this tool were tested. METHODS: Criteria were developed using a modified Delphi
      panel judgement process. The level of agreement between the panelists (six
      gastroenterologists and six surgeons) was analysed and the ratings were compared
      with those of a second different panel using weighted kappa statistics. RESULTS:
      The results of the main panel were presented as a decision tree. Of the 210
      scenarios evaluated by the main panel in the second round, 51% were found
      appropriate, 26% uncertain, and 23% inappropriate. Agreement was achieved in 54%
      of the scenarios and disagreement in 3%. Although the gastroenterologists tended
      to score fewer scenarios as appropriate, as a group they did not differ from the
      surgeons. Comparison of the ratings of the main panel with those of a second
      panel resulted in a weighted kappa statistic of 0.75. CONCLUSIONS: The parameters
      tested showed acceptable validity and reliability results for an evaluation tool.
      These results support the use of this algorithm as a screening tool for assessing
      the appropriateness of cholecystectomy.

PMID- 12468692
TI  - Patient and nurse assessment of quality of care in postoperative pain management.
AB  - OBJECTIVE: To describe and compare patient and nurse assessments of the quality
      of care in postoperative pain management, to investigate differences between
      subgroups of patients, and to compare patient assessments in different
      departments. DESIGN: Patient and nurse questionnaires. SETTING: Five surgical
      wards in general surgery, orthopaedics, and gynaecology in a central county
      hospital in Sweden. SAMPLE: Two hundred and nine inpatients and 64 registered
      nurses. The response rates were 96% for the patients and 99% for the nurses;
      there were 196 paired patient-nurse assessments. METHOD: The Strategic and
      Clinical Quality Indicators in Postoperative Pain Management patient
      questionnaire was used which comprises 14 items in four subscales (communication,
      action, trust, and environment). The items were scored on a 5 point scale with
      higher values indicating a higher quality of care. Five complementary questions
      on levels of pain intensity and overall satisfaction with pain relief were scored
      on an 11 point scale. Twelve of the 14 items in the patient questionnaire and two
      of the complementary questions were adjusted for use in the nurse questionnaire.
      RESULTS: The patients' mean (SD) score on the total scale (scale range 14-70) was
      58.6 (8.9) and the nurses' mean (SD) score (scale range 12-60) was 48.1 (6.2).
      The percentage of patients who scored 1 or 2 for an individual item
      (disagreement) ranged from 0.5% to 52.0%, while for nurses the percentage ranged
      from 0.0% to 34.8%. Forty two patients (24%) reported more pain than they
      expected; these patients assessed the quality of care lower. There were
      differences between patient and nurse assessments concerning the environment
      subscale, the question on overall satisfaction, and patients' experience of worst
      possible pain intensity. CONCLUSION: The results provided valuable baseline data
      and identified important areas for quality improvement in postoperative pain
      management.

PMID- 12468693
TI  - Patients' experiences and satisfaction with health care: results of a
      questionnaire study of specific aspects of care.
AB  - OBJECTIVE: To determine what aspects of healthcare provision are most likely to
      influence satisfaction with care and willingness to recommend hospital services
      to others and, secondly, to explore the extent to which satisfaction is a
      meaningful indicator of patient experience of healthcare services. DESIGN: Postal
      survey of a sample of patients who underwent a period of inpatient care. Patients
      were asked to evaluate their overall experience of this episode of care and to
      complete the Picker Inpatient Survey questionnaire on specific aspects of their
      care. SAMPLE: Patients aged 18 and over presenting at five hospitals within one
      NHS trust in Scotland. METHOD: 3592 questionnaires were mailed to patients' homes
      within 1 month of discharge from hospital during a 12 month period. Two reminders
      were sent to non-responders; 2249 (65%) questionnaires were returned. RESULTS:
      Almost 90% of respondents indicated that they were satisfied with their period of
      inpatient care. Age and overall self-assessed health were only weakly associated
      with satisfaction. A multiple linear regression indicated that the major
      determinants of patient satisfaction were physical comfort, emotional support,
      and respect for patient preferences. However, many patients who reported their
      satisfaction with the care they received also indicated problems with their
      inpatient care as measured on the Picker Inpatient Survey; 55% of respondents who
      rated their inpatient episode as "excellent" indicated problems on 10% of the
      issues measured on the Picker questionnaire. DISCUSSION: The evidence suggests
      that patient satisfaction scores present a limited and optimistic picture.
      Detailed questions about specific aspects of patients' experiences are likely to
      be more useful for monitoring the performance of various hospital departments and
      wards and could point to ways in which delivery of health care could be improved.

PMID- 12468694
TI  - Prescribing errors in hospital inpatients: their incidence and clinical
      significance.
AB  - BACKGROUND: It has been estimated that 1-2% of US inpatients are harmed by
      medication errors, the majority of which are errors in prescribing. The UK
      Department of Health has recommended that serious errors in the use of prescribed
      drugs should be reduced by 40% by 2005; however, little is known about the
      current incidence of prescribing errors in the UK. This pilot study sought to
      investigate their incidence in one UK hospital. METHODS: Pharmacists
      prospectively recorded details of all prescribing errors identified in non
      obstetric inpatients during a 4 week period. The number of medication orders
      written was estimated from a 1 in 5 sample of inpatients. Potential clinical
      significance was assessed by a pharmacist and a clinical pharmacologist. RESULTS:
      About 36200 medication orders were written during the study period, and a
      prescribing error was identified in 1.5% (95% confidence interval (CI) 1.4 to
      1.6). A potentially serious error occurred in 0.4% (95% CI 0.3 to 0.5). Most of
      the errors (54%) were associated with choice of dose. Error rates were
      significantly different for different stages of patient stay (p<0.0001) with a
      higher error rate for medication orders written during the inpatient stay than
      for those written on admission or discharge. While the majority of all errors
      (61%) originated in medication order writing, most serious errors (58%)
      originated in the prescribing decision. CONCLUSIONS: There were about 135
      prescribing errors identified each week, of which 34 were potentially serious.
      Knowing where and when errors are most likely to occur will be helpful in
      designing initiatives to reduce them. The methods developed could be used to
      evaluate such initiatives.

PMID- 12468695
TI  - Quality collaboratives: lessons from research.
AB  - Quality improvement collaboratives are increasingly being used in many countries
      to achieve rapid improvements in health care. However, there is little
      independent evidence that they are more cost effective than other methods, and
      little knowledge about how they could be made more effective. A number of
      systematic evaluations are being performed by researchers in North America, the
      UK, and Sweden. This paper presents the shared ideas from two meetings of these
      researchers. The evidence to date is that some collaboratives have stimulated
      improvements in patient care and organisational performance, but there are
      significant differences between collaboratives and teams. The researchers agreed
      on the possible reasons why some were less successful than others, and identified
      10 challenges which organisers and teams need to address to achieve improvement.
      In the absence of more conclusive evidence, these guidelines are likely to be
      useful for collaborative organisers, teams and their managers and may also
      contribute to further research into collaboratives and the spread of innovations
      in health care.

PMID- 12468696
TI  - Human factors engineering and patient safety.
AB  - The case study and analyses presented here illustrate the crucial role of human
      factors engineering (HFE) in patient safety. HFE is a framework for efficient and
      constructive thinking which includes methods and tools to help healthcare teams
      perform patient safety analyses, such as root cause analyses. The literature on
      HFE over several decades contains theories and applied studies to help to solve
      difficult patient safety problems and design issues. A case study is presented
      which illustrates the vulnerabilities of human factors design in a transport
      monitor. The subsequent analysis highlights how to move beyond the more obvious
      contributing factors like training to design problems and the establishment of
      informal norms. General advice is offered to address these issues and design
      issues specific to this case are discussed.

PMID- 12468697
TI  - Lessons learned from non-medical industries: the tragedy of the USS Greeneville.
AB  - In February 200l the nuclear powered submarine USS Greeneville collided with the
      Japanese fishing trawler Ehime Maru, killing nine passengers. A series of small
      failures and hurried actions escalated into tragedy. This incident provides
      lessons learned that can be used by healthcare organizations to improve patient
      safety. Expertise, training, equipment, and procedures appeared to be adequate
      protection, yet the presence of multiple defences obscured their faulty
      functioning, just as they often do in medical settings. A number of other
      problems occurred aboard Greeneville which we also see in health care. The
      problem was the total breakdown of communication. The Greeneville team also
      failed to move from a rigid hierarchical structure to a more flexible adaptive
      structure. Communication often breaks down in healthcare settings, which are
      organized to maximize status and hierarchical differences, thus often impeding
      information flow needed to make decisions. Redundancy failed aboard Greeneville
      as it often does in medicine. Finally, the Captain of the Greeneville established
      an artificially hurried situation. Time constrained situations happen all the
      time in health care. We recommend strategies to mitigate the development of these
      kinds of processes.

PMID- 12468699
TI  - My adventures as a hospital patient.

PMID- 12468698
TI  - Research methods used in developing and applying quality indicators in primary
      care.
AB  - Quality indicators have been developed throughout Europe primarily for use in
      hospitals, but also increasingly for primary care. Both development and
      application are important but there has been less research on the application of
      indicators. Three issues are important when developing or applying indicators:
      (1). which stakeholder perspective(s) are the indicators intended to reflect;
      (2). what aspects of health care are being measured; and (3). what evidence is
      available? The information required to develop quality indicators can be derived
      using systematic or non-systematic methods. Non-systematic methods such as case
      studies play an important role but they do not tap in to available evidence.
      Systematic methods can be based directly on scientific evidence by combining
      available evidence with expert opinion, or they can be based on clinical
      guidelines. While it may never be possible to produce an error free measure of
      quality, measures should adhere, as far as possible, to some fundamental a priori
      characteristics (acceptability, feasibility, reliability, sensitivity to change,
      and validity). Adherence to these characteristics will help maximise the
      effectiveness of quality indicators in quality improvement strategies. It is also
      necessary to consider what the results of applying indicators tell us about
      quality of care.

PMID- 12468703
TI  - The problem with rational approaches to reforming the NHS.
AB  - Several papers with a common theme published between May and August 2002 are
      drawn together to present a research-informed critique of economic logic present
      within recent NHS reform. They attempt to persuade the reader that excessive
      faith in predictive systems of thought that are underpinned by theories of
      rational behaviour is misplaced within the NHS. They suggest rational economic
      theory makes some problematic assumptions about human and individual behaviour.
      The problem is that there are many modes of thought at work within the NHS, and
      not all of these cogs are turned by economic rationality. Increasingly, over the
      last 10 years or so, economic concepts have become more and more prominent in the
      NHS. Their influence has gone beyond finance becoming a dominant issue. In
      addition to budgets, contracts and cost itemisation, theoretical relationships of
      supply and demand are now called upon to change professional behaviour. A new
      framework for the NHS has been built which is developing market forces. The
      papers provide some insight into whether the systems set in place to produce a
      patient-centred service do so in a meaningful way. The first paper examines an
      emerging primary care group (PCG). Now part of primary care trusts, PCGs were a
      lynchpin of new economic relationships in the new NHS. Community based, in theory
      PCGs take decisions made about healthcare resources closer to the patient for
      whom they are a proxy demander and shaper of services. To what extent do PCGs
      fulfil this role? The first paper is based on data collected during an in-depth 2
      year observation study to test the applicability of health economics to
      healthcare organisations. It examines the early experience of commissioning
      services for coronary heart disease (CHD).

PMID- 12468702
TI  - Inhaler devices for the treatment of asthma and chronic obstructive airways
      disease (COPD).
AB  - The research evidence on the effectiveness of inhaler devices for the treatment
      of asthma and chronic obstructive pulmonary disease published in a recent issue
      of Effective Health Care is reviewed.

PMID- 12468704
TI  - John Williamson and the terrifying results of the medical practice information
      demonstration project.

PMID- 12468705
TI  - Funnel plots for institutional comparison.

PMID- 12468706
TI  - Hospital success rate: a multidimensional indicator of prognosis.

PMID- 12468707
TI  - Cleveland Health Quality Choice was a failure, not a martyr.

PMID- 12468708
TI  - Resuscitation trolleys: human factors engineering.

PMID- 12468709
TI  - Sequence relationships in the legume lectin fold and other jelly rolls.
AB  - Distant sequence relationships in proteins containing the beta jelly-roll fold
      were investigated using sensitive sequence comparison methods, including PSI
      BLAST and Hidden Markov Models. A relationship was identified between the rmlC
      like and phosphomannose isomerase SCOP (version 1.53) superfamilies, which were
      merged in the most recent SCOP release. No other distant sequence relationships
      linking jelly roll superfamilies were found.

PMID- 12468710
TI  - Affinity chromatography system for parallel purification of recombinant protein
      samples.
AB  - In protein engineering, the tasks of generating and testing a large number of
      variants of a molecule and of optimizing expression conditions for one distinct
      molecule create the need for purification methods that can handle a large number
      of samples simultaneously. We describe the development and some application
      results of a simple affinity chromatography system that can be used for the
      parallel purification of 24 protein samples, yielding sufficient quantities for
      biochemical and functional analysis. Advantages of this system over existing
      systems are as follows. Compared with commercially available complete
      chromatography systems, the costs of this system are minimal. In comparison with
      vacuum systems with various outlets, and with batch purification systems where
      centrifugation is necessary, this system allows gentler processing of the
      samples. This could be important for proteins that are easily damaged.

PMID- 12468711
TI  - Protein design is NP-hard.
AB  - Biologists working in the area of computational protein design have never doubted
      the seriousness of the algorithmic challenges that face them in attempting in
      silico sequence selection. It turns out that in the language of the computer
      science community, this discrete optimization problem is NP-hard. The purpose of
      this paper is to explain the context of this observation, to provide a simple
      illustrative proof and to discuss the implications for future progress on
      algorithms for computational protein design.

PMID- 12468712
TI  - A conformational analysis of Walker motif A [GXXXXGKT (S)] in nucleotide-binding
      and other proteins.
AB  - The sequence GXXXXGKT/S, popularly known as Walker motif A, is widely believed to
      be the site for binding nucleotides in many proteins. Examination of the crystal
      structures in the Protein Data Bank showed that about half of the examples having
      these sequences do not bind or use nucleotides. Data analyses showed 92 different
      Walker sequences of the variable quartet (XXXX). Ramachandran angles in this
      segment revealed conformational similarity in the group of 45 proteins, known to
      bind or utilize nucleotides. The conformations of this segment in other proteins
      differ widely and it is not known whether they play any role in their functions.
      A flip of a peptide unit at different locations, with little change in the
      backbone conformation was noted in nine pairs of these proteins having same
      Walker sequence. An examination of the immediate neighborhood of the Walker
      sequence indicates that this region is preceded by a beta-strand and followed by
      an alpha-helix, resulting in the motif beta-W-alpha, an invariant feature amongst
      nucleotide-binding proteins.

PMID- 12468713
TI  - Asymmetric conductivity of engineered porins.
AB  - Positively charged peptide segments of 16 and 18 residues were inserted at a
      periplasmic turn of the porin from Rhodobacter blasticus in order to form an
      electric field-dependent plug. The X-ray diffraction analysis of a mutant
      confirmed that the structure of the porin had remained intact and that the insert
      was mobile. Incorporation experiments of single molecules into lipid bilayers
      showed that the distribution of electric conduction increments depended on the
      field polarity. The observed distributions are explained if the porin molecules
      enter the bilayer preferentially with their periplasmic surface first.
      Furthermore, the conduction of membrane-incorporated porin mutants changed
      reproducibly on field reversal showing asymmetries of reverse similar 15%, while
      the wild-type remained constant. This asymmetry is most likely caused by the
      electric field pressing the charged insert onto the pore eyelet in one field
      direction and removing it from the eyelet in the other. The results encourage
      attempts to improve the inserts in order to eventually reach diode
      characteristics.

PMID- 12468714
TI  - Robustness of hen lysozyme monitored by random mutations.
AB  - We investigated the robustness of hen lysozyme by using random mutant libraries.
      Six random mutant libraries containing 1, 1.5, 2, 3, 5 and 14 amino acid
      mutations per hen lysozyme were systematically constructed by varying the
      concentrations of Mg(2+) and Mn(2+) on polymerase chain reaction. The mutated
      genes from the six libraries were cloned to a yeast expression vector and a total
      of 4000 clones were screened on the basis of lysis activity and ELISA employing
      monoclonal antibody that recognized only lysozyme with native conformation. About
      80% of the clones with an average of two amino acid mutations retained active
      structure. Almost all clones with an average of five mutations lost active
      structure. On the other hand, 80% of the clones with an average of two amino acid
      mutations retained both gross conformation and active structure and 24% of the
      clones with an average of 14 amino acid mutations retained gross conformation.
      These results show that gross conformation is robust against mutations and so is
      active structure to a lesser extent.

PMID- 12468715
TI  - Mutation of charged residues in the TR3 death domain does not perturb interaction
      with TRADD.
AB  - Members of the death receptor family play a prominent role in developmental and
      pathological neuronal cell death. The death signal is transduced via interaction
      between the death domain of the receptor and an intracellular adapter, TRADD. We
      performed alanine-scanning mutagenesis of specific charged residues in the TR3
      death domain to determine whether they play a crucial role in TR3-TR3 and TR3
      TRADD interaction. Mutation of charged residues in the second and third helices
      of the TR3 death domain failed to perturb self-interaction or interaction with
      TRADD. These data suggest that despite some similarity between the death domains
      of TR3 and TNFR1 the nature of the interaction with TRADD differs from that
      reported for TNFR1.

PMID- 12468716
TI  - Metal-dependent stabilization of an active HMG protein.
AB  - Using a cloned single domain of the high mobility group protein 1 (HMGB1), we
      evaluated the effect of introducing metal binding site(s) on protein stability
      and function. An HMG domain is a conserved sequence of approximately 80 amino
      acids rich in basic, aromatic and proline residues that is active in binding DNA
      in a sequence- or structure-specific manner. The design strategy focuses on
      anchoring selected regions of the protein, specifically loops and turns in the
      molecule, using His-metal ligands. Changes in secondary structure,
      thermostability and DNA binding properties of a series of such mutants were
      evaluated. The two most stable mutant constructs contain three surface histidine
      replacements (two metal binding sites) in the regions encompassing both turns of
      the molecule. On ligation with the divalent nickel cation, the stability of these
      two triple histidine mutants (I38H/N51H/D55H and G39H/N51H/D55H) increases by 1.3
      and 1.6 kcal/mol, respectively, relative to the wild-type protein, although the
      creation of binding sites per se destabilizes the protein. The DNA-binding
      properties of the modified proteins are not impaired by the introduction of the
      metal binding motifs. These results indicate that it is feasible to stabilize
      protein tertiary structure using appropriate placement of surface His-metal bonds
      without loss of function.

PMID- 12468717
TI  - Design of a monomeric human glutathione transferase GSTP1, a structurally stable
      but catalytically inactive protein.
AB  - By the introduction of 10 site-specific mutations in the dimer interface of human
      glutathione transferase P1-1 (GSTP1-1), a stable monomeric protein variant,
      GSTP1, was obtained. The monomer had lost the catalytic activity but retained the
      affinity for a number of electrophilic compounds normally serving as substrates
      for GSTP1-1. Fluorescence and circular dichroism spectra of the monomer and wild
      type proteins were similar, indicating that there are no large structural
      differences between the subunits of the respective proteins. The GSTs have
      potential as targets for in vitro evolution and redesign with the aim of
      developing proteins with novel properties. To this end, a monomeric GST variant
      may have distinct advantages.

PMID- 12468718
TI  - Engineering streptococcal protein G for increased alkaline stability.
AB  - Most protein-based affinity chromatography media are very sensitive towards
      alkaline treatment, which is a preferred method for regeneration and removal of
      contaminants from the purification devices in industrial applications. In a
      previous study, we concluded that a simple and straightforward strategy
      consisting of replacing asparagine residues could improve the stability towards
      alkaline conditions. In this study, we have shown the potential of this rationale
      by stabilizing an IgG-binding domain of streptococcal protein G, i.e. the C2
      domain. In order to analyze the contribution of the different amino acids to the
      alkaline sensitivity of the domain we used a single point mutation strategy.
      Amino acids known to be susceptible towards high pH, asparagine and glutamine,
      were substituted for less-alkali-susceptible residues. In addition, aspartic acid
      residues were mutated to evaluate if the stability could be further increased.
      The stability of the different C2 variants was subsequently analyzed by exposing
      them to NaOH. The obtained results reveal that the most sensitive amino acid
      towards alkaline conditions in the structure of C2 is Asn36. The double mutant,
      C2(N7,36A), was found to be the most stable mutant constructed. In addition to
      the increased alkaline stability and also very important for potential use as an
      affinity ligand, this mutated variant also retains the secondary structure, as
      well as the affinity to the Fc fragment of IgG.

PMID- 12468719
TI  - Construction of block-shuffled libraries of DNA for evolutionary protein
      engineering: Y-ligation-based block shuffling.
AB  - Evolutionary protein engineering is now proceeding to a new stage in which novel
      technologies, besides the conventional point mutations, to generate a library of
      proteins, are required. In this context, a novel method for shuffling and
      rearranging DNA blocks (leading to protein libraries) is reported. A cycle of
      processes for producing combinatorial diversity was devised and designated Y
      ligation-based block shuffling (YLBS). Methodological refinement was made by
      applying it to the shuffling of module-sized and amino acid-sized blocks. Running
      three cycles of YLBS with module-sized GFP blocks resulted in a high diversity of
      an eight-block shuffled library. Partial shuffling of the central four blocks of
      GFP was performed to obtain in-effect shuffled protein, resulting in an intact
      arrangement. Shuffling of amino acid monomer-sized blocks by YLBS was also
      performed and a diversity of more than 10(10) shuffled molecules was attained.
      The deletion problems encountered during these experiments were shown to be
      solved by additional measures which tame type IIS restriction enzymes. The
      frequency of appearance of each block was skewed but was within a permissible
      range. Therefore, YLBS is the first general method for generating a huge
      diversity of shuffled proteins, recombining domains, exons and modules with ease.

PMID- 12468721
TI  - Demeter: on seeds and goddesses.

PMID- 12468722
TI  - A high-throughput Arabidopsis reverse genetics system.
AB  - A collection of Arabidopsis lines with T-DNA insertions in known sites was
      generated to increase the efficiency of functional genomics. A high-throughput
      modified thermal asymmetric interlaced (TAIL)-PCR protocol was developed and used
      to amplify DNA fragments flanking the T-DNA left borders from approximately
      100000 transformed lines. A total of 85108 TAIL-PCR products from 52964 T-DNA
      lines were sequenced and compared with the Arabidopsis genome to determine the
      positions of T-DNAs in each line. Predicted T-DNA insertion sites, when mapped,
      showed a bias against predicted coding sequences. Predicted insertion mutations
      in genes of interest can be identified using Arabidopsis Gene Index name searches
      or by BLAST (Basic Local Alignment Search Tool) search. Insertions can be
      confirmed by simple PCR assays on individual lines. Predicted insertions were
      confirmed in 257 of 340 lines tested (76%). This resource has been named SAIL
      (Syngenta Arabidopsis Insertion Library) and is available to the scientific
      community at www.tmri.org.

PMID- 12468723
TI  - Host DNA replication is induced by geminivirus infection of differentiated plant
      cells.
AB  - The geminivirus Tomato golden mosaic virus (TGMV) replicates in differentiated
      plant cells using host DNA synthesis machinery. We used 5-bromo-2-deoxyuridine
      (BrdU) incorporation to examine DNA synthesis directly in infected Nicotiana
      benthamiana plants to determine if viral reprogramming of host replication
      controls had an impact on host DNA replication. Immunoblot analysis revealed that
      up to 17-fold more BrdU was incorporated into chromosomal DNA of TGMV-infected
      versus mock-infected, similarly treated healthy leaves. Colocalization studies of
      viral DNA and BrdU demonstrated that BrdU incorporation was specific to infected
      cells and was associated with both host and viral DNA. TGMV and host DNA
      synthesis were inhibited differentially by aphidicolin but were equally sensitive
      to hydroxyurea. Short BrdU labeling times resulted in some infected cells showing
      punctate foci associated with host DNA. Longer periods showed BrdU label
      uniformly throughout host DNA, some of which showed condensed chromatin, only in
      infected nuclei. By contrast, BrdU associated with viral DNA was centralized and
      showed uniform, compartmentalized labeling. Our results demonstrate that
      chromosomal DNA is replicated in TGMV-infected cells.

PMID- 12468725
TI  - Regulation of axis determinacy by the Arabidopsis PINHEAD gene.
AB  - Plants produce proximal-distal growth axes with two types of growth potential:
      they can be indeterminate, in which case growth continues indefinitely, or they
      can be determinate, in which case growth is limited to the production of a single
      organ or a discrete set of organs. The indeterminate shoot axes of Arabidopsis
      pinhead/zwille mutants frequently are transformed to a determinate state. PINHEAD
      (PNH) is expressed in the central domain of the developing plant: the provascular
      tissue, the shoot apical meristem, and the adaxial (upper) sides of lateral organ
      primordia. Here, we show that ectopic expression of PNH on the abaxial (lower)
      sides of lateral organs results in upward curling of leaf blades. This phenotype
      correlates with a loss of cell number coordination between the two surfaces of
      the blade, indicating that ectopic PNH can cause changes in cell division rates.
      More strikingly, moving PNH expression from the central to the peripheral domain
      of the embryo causes transformation of the determinate cotyledon axis to an
      indeterminate state. We propose that growth axes are specified as determinate
      versus indeterminate in a PNH-mediated step. Our results add to a growing body of
      evidence that radial positional information is important in meristem formation.
      These results also indicate that genes regulating cell division and axis
      determinacy are likely to be among PNH targets.

PMID- 12468724
TI  - OSM1/SYP61: a syntaxin protein in Arabidopsis controls abscisic acid-mediated and
      non-abscisic acid-mediated responses to abiotic stress.
AB  - To identify the genetic loci that control salt tolerance in higher plants, a
      large-scale screen was conducted with a bialaphos marker-based T-DNA insertional
      collection of Arabidopsis ecotype C24 mutants. One line, osm1 (for osmotic stress
      sensitive mutant), exhibited increased sensitivity to both ionic (NaCl) and
      nonionic (mannitol) osmotic stress in a root-bending assay. The osm1 mutant
      displayed a more branched root pattern with or without stress and was
      hypersensitive to inhibition by Na(+), K(+), and Li(+) but not Cs(+). Plants of
      the osm1 mutant also were more prone to wilting when grown with limited soil
      moisture compared with wild-type plants. The stomata of osm1 plants were
      insensitive to both ABA-induced closing and inhibition of opening compared with
      wild-type plants. The T-DNA insertion appeared in the first exon of an open
      reading frame on chromosome 1 (F3M18.7, which is the same as AtSYP61). This
      insertion mutation cosegregated closely with the osm1 phenotype and was the only
      functional T-DNA in the mutant genome. Expression of the OSM1 gene was disrupted
      in mutant plants, and abnormal transcripts accumulated. Gene complementation with
      the native gene from the wild-type genome completely restored the mutant
      phenotype to the wild type. Analysis of the deduced amino acid sequence of the
      affected gene revealed that OSM1 is related most closely to mammalian syntaxins 6
      and 10, which are members of the SNARE superfamily of proteins required for
      vesicular/target membrane fusions. Expression of the OSM1 promoter::beta
      glucuronidase gene in transformants indicated that OSM1 is expressed in all
      tissues except hypocotyls and young leaves and is hyperexpressed in epidermal
      guard cells. Together, our results demonstrate important roles of OSM1/SYP61 in
      osmotic stress tolerance and in the ABA regulation of stomatal responses.

PMID- 12468726
TI  - A phytochrome-associated protein phosphatase 2A modulates light signals in
      flowering time control in Arabidopsis.
AB  - Reversible protein phosphorylation, which is catalyzed by functionally coupled
      protein kinases and protein phosphatases, is a major signaling mechanism in
      eukaryotic cellular functions. The red and far-red light-absorbing phytochrome
      photoreceptors are light-regulated Ser/Thr-specific protein kinases that regulate
      diverse photomorphogenic processes in plants. Here, we demonstrate that the
      phytochromes functionally interact with the catalytic subunit of a Ser/Thr
      specific protein phosphatase 2A designated FyPP. The interactions were influenced
      by phosphorylation status and spectral conformation of the phytochromes.
      Recombinant FyPP efficiently dephosphorylated oat phytochrome A in the presence
      of Fe(2+) or Zn(2+) in a spectral form-dependent manner. FyPP was expressed
      predominantly in floral organs. Transgenic Arabidopsis plants with overexpressed
      or suppressed FyPP levels exhibited delayed or accelerated flowering,
      respectively, indicating that FyPP modulates phytochrome-mediated light signals
      in the timing of flowering. Accordingly, expression patterns of the clock genes
      in the long-day flowering pathway were altered greatly. These results indicate
      that a self-regulatory phytochrome kinase-phosphatase coupling is a key signaling
      component in the photoperiodic control of flowering.

PMID- 12468727
TI  - Arabidopsis E2Fc functions in cell division and is degraded by the ubiquitin
      SCF(AtSKP2) pathway in response to light.
AB  - Selective ubiquitin-mediated proteolysis through the cell cycle controls the
      availability, and therefore the activity, of several cell proliferation proteins.
      E2F transcription factors play distinct roles in both proliferating and
      differentiated cells by regulating gene expression. Here, we report that
      Arabidopsis AtE2Fc is regulated by a balance between gene expression and
      ubiquitin-proteasome proteolysis. AtE2Fc degradation implicates the function of
      the E3 ubiquitin-ligase Skp1, Cullin, F-box (SCF(AtSKP2)) complex and seems to be
      dependent on cyclin-dependent kinase phosphorylation. In addition, we found that
      AtE2Fc degradation is triggered by light stimulation of dark-grown seedlings.
      Interestingly, the auxin response mutant axr1-12, in which RUB1 modification of
      the SCF component CUL1 is impaired, shows increased AtE2Fc protein levels,
      suggesting a dysfunction in the control of AtE2Fc stability. Likewise,
      overexpression of a stable form of the AtE2Fc protein negatively affects cell
      division and increases cell size. These effects are mediated, at least in part,
      by downregulating the cell cycle gene AtCDC6. The negative role of AtE2Fc in gene
      expression is further supported by the fact that AtE2Fc interacts with plant
      retinoblastoma-related protein, suggesting that AtE2Fc might form part of a
      repressor complex. We propose that AtE2Fc might play a role in cell division and
      during the transition from skotomorphogenesis to photomorphogenesis.

PMID- 12468728
TI  - Xyloglucan endotransglycosylases have a function during the formation of
      secondary cell walls of vascular tissues.
AB  - Xyloglucan transglycosylases (XETs) have been implicated in many aspects of cell
      wall biosynthesis, but their function in vascular tissues, in general, and in the
      formation of secondary walls, in particular, is less well understood. Using an in
      situ XET activity assay in poplar stems, we have demonstrated XET activity in
      xylem and phloem fibers at the stage of secondary wall formation.
      Immunolocalization of fucosylated xylogucan with CCRC-M1 antibodies showed that
      levels of this species increased at the border between the primary and secondary
      wall layers at the time of secondary wall deposition. Furthermore, one of the
      most abundant XET isoforms in secondary vascular tissues (PttXET16A) was cloned
      and immunolocalized to fibers at the stage of secondary wall formation. Together,
      these data strongly suggest that XET has a previously unreported role in
      restructuring primary walls at the time when secondary wall layers are deposited,
      probably creating and reinforcing the connections between the primary and
      secondary wall layers. We also observed that xylogucan is incorporated at a high
      level in the inner layer of nacreous walls of mature sieve tube elements.

PMID- 12468729
TI  - Arabidopsis OST1 protein kinase mediates the regulation of stomatal aperture by
      abscisic acid and acts upstream of reactive oxygen species production.
AB  - During drought, the plant hormone abscisic acid (ABA) triggers stomatal closure,
      thus reducing water loss. Using infrared thermography, we isolated two allelic
      Arabidopsis mutants (ost1-1 and ost1-2) impaired in the ability to limit their
      transpiration upon drought. These recessive ost1 mutations disrupted ABA
      induction of stomatal closure as well as ABA inhibition of light-induced stomatal
      opening. By contrast, the ost1 mutations did not affect stomatal regulation by
      light or CO(2), suggesting that OST1 is involved specifically in ABA signaling.
      The OST1 gene was isolated by positional cloning and was found to be expressed in
      stomatal guard cells and vascular tissue. In-gel assays indicated that OST1 is an
      ABA-activated protein kinase related to the Vicia faba ABA-activated protein
      kinase (AAPK). Reactive oxygen species (ROS) were shown recently to be an
      essential intermediate in guard cell ABA signaling. ABA-induced ROS production
      was disrupted in ost1 guard cells, whereas applied H(2)O(2) or calcium elicited
      the same degree of stomatal closure in ost1 as in the wild type. These results
      suggest that OST1 acts in the interval between ABA perception and ROS production.
      The relative positions of ost1 and the other ABA-insensitive mutations in the ABA
      signaling network (abi1-1, abi2-1, and gca2) are discussed.

PMID- 12468730
TI  - A kinesin-like protein is essential for oriented deposition of cellulose
      microfibrils and cell wall strength.
AB  - Cortical microtubules have long been hypothesized to regulate the oriented
      deposition of cellulose microfibrils. However, the molecular mechanisms of how
      microtubules direct the orientation of cellulose microfibril deposition are not
      known. We have used fibers in the inflorescence stems of Arabidopsis to study
      secondary wall deposition and cell wall strength and found a fragile fiber (fra1)
      mutant with a dramatic reduction in the mechanical strength of fibers. The fra1
      mutation did not cause any defects in cell wall composition, secondary wall
      thickening, or cortical microtubule organization in fiber cells. An apparent
      alteration was found in the orientation of cellulose microfibrils in fra1 fiber
      walls, indicating that the reduced mechanical strength of fra1 fibers probably
      was attributable to altered cellulose microfibril deposition. The FRA1 gene was
      cloned and found to encode a kinesin-like protein with an N-terminal microtubule
      binding motor domain. The FRA1 protein was shown to be concentrated around the
      periphery of the cytoplasm but absent in the nucleus. Based on these findings, we
      propose that the FRA1 kinesin-like protein is involved in the microtubule control
      of cellulose microfibril order.

PMID- 12468731
TI  - Empty pericarp2 encodes a negative regulator of the heat shock response and is
      required for maize embryogenesis.
AB  - The heat shock response (HSR) is an evolutionarily conserved
      molecular/biochemical reaction to thermal stress that is essential to the
      survival of eukaryotic organisms. Recessive Mutator transposon mutations at the
      maize empty pericarp2 (emp2) locus led to dramatically increased expression of
      heat shock genes, retarded embryo development, and early-stage abortion of
      embryogenesis. The developmental timing of emp2 mutant embryo lethality was
      correlated with the initial competence of maize kernels to invoke the HSR.
      Cloning and sequence analyses revealed that the emp2 gene encoded a predicted
      protein with high similarity to HEAT SHOCK BINDING PROTEIN1, which was first
      described in animals as a negative regulator of the HSR. emp2 is a loss-of
      function mutation of an HSR-negative regulator in plants. Despite the recessive
      emp2 phenotype, steady state levels of emp2 transcripts were abundant in mutant
      kernels, and the predicted coding region was unaffected. These expression data
      suggest that emp2 transcription is feedback regulated, whereas S1 nuclease
      mapping suggests that emp2 mutant transcripts are 5' truncated and
      nontranslatable. In support of this model, immunoblot assays revealed that EMP2
      protein did not accumulate in mutant kernels. These data support a model whereby
      an unattenuated HSR results in the early abortion of emp2 mutant embryos.
      Furthermore, the developmental retardation of emp2 mutant kernels before the HSR
      suggests an additional role for EMP2 during embryo development distinct from the
      HSR.

PMID- 12468732
TI  - Gibberellins are required for seed development and pollen tube growth in
      Arabidopsis.
AB  - Gibberellins (GAs) are tetracyclic diterpenoids that are essential endogenous
      regulators of plant growth and development. GA levels within the plant are
      regulated by a homeostatic mechanism that includes changes in the expression of a
      family of GA-inactivating enzymes known as GA 2-oxidases. Ectopic expression of a
      pea GA 2-oxidase2 cDNA caused seed abortion in Arabidopsis, extending and
      confirming previous observations obtained with GA-deficient mutants of pea,
      suggesting that GAs have an essential role in seed development. A new
      physiological role for GAs in pollen tube growth in vivo also has been
      identified. The growth of pollen tubes carrying the 35S:2ox2 transgene was
      reduced relative to that of nontransgenic pollen, and this phenotype could be
      reversed partially by GA application in vitro or by combining with spy-5, a
      mutation that increases GA response. Treatment of wild-type pollen tubes with an
      inhibitor of GA biosynthesis in vitro also suggested that GAs are required for
      normal pollen tube growth. These results extend the known physiological roles of
      GAs in Arabidopsis development and suggest that GAs are required for normal
      pollen tube growth, a physiological role for GAs that has not been established
      previously.

PMID- 12468737
TI  - ZEN1 is a key enzyme in the degradation of nuclear DNA during programmed cell
      death of tracheary elements.
AB  - Tracheary elements (TEs) have a unique cell death program in which the rapid
      collapse of the vacuole triggers the beginning of nuclear degradation. Although
      various nucleases are known to function in nuclear DNA degradation in animal
      apoptosis, it is unclear what hydrolase is involved in nuclear degradation in
      plants. In this study, we demonstrated that an S1-type nuclease, Zinnia
      endonuclease 1 (ZEN1), functions directly in nuclear DNA degradation during
      programmed cell death (PCD) of TEs. In-gel DNase assay demonstrated the presence
      of a 24-kD Ca(2+)/Mg(2+)-dependent nuclease and a 40-kD Zn(2+)-dependent nuclease
      as well as ZEN1 in 60-h-cultured cells that included differentiating TEs. Such
      cell extracts possessed the ability to degrade the nuclear DNA isolated from
      Zinnia elegans cells in the presence of Zn(2+), and its activity was suppressed
      by an anti-ZEN1 antibody, indicating that ZEN1 is a central DNase responsible for
      nuclear DNA degradation. The introduction of the antisense ZEN1 gene into Zinnia
      cells cultured for 40 h specifically suppressed the degradation of nuclear DNA in
      TEs undergoing PCD but did not affect vacuole collapse. Based on these results, a
      common mechanism between animal and plant PCD is discussed.

PMID- 12468733
TI  - A gain-of-function mutation in an Arabidopsis Toll Interleukin1 receptor
      nucleotide binding site-leucine-rich repeat type R gene triggers defense
      responses and results in enhanced disease resistance.
AB  - In a screen for suppressors of npr1-5-based salicylic acid (SA) insensitivity, we
      isolated a semidominant gain-of-function mutation, designated ssi4, that confers
      constitutive expression of several PR (pathogenesis-related) genes, induces SA
      accumulation, triggers programmed cell death, and enhances resistance to
      bacterial and oomycete pathogens. Through map-based cloning, ssi4 was identified
      and found to encode a putative protein belonging to the TIR-NBS-LRR (Toll
      Interleukin1 Receptor-Nucleotide Binding Site-Leu-Rich Repeat) class of R
      (resistance) proteins. Comparison between ssi4 and the corresponding wild-type
      sequence revealed a single amino acid substitution in the NBS. Epistasis analysis
      indicated that SA and EDS1 are required for ssi4-induced PR-1 expression and
      enhanced disease resistance; they also are required for the increased
      accumulation of SSI4 and EDS1 transcripts detected in the ssi4 mutant. Although
      high levels of ssi4 transcripts correlate with the appearance of the mutant
      phenotype, overexpression of the wild-type SSI4 gene failed to induce stunting,
      spontaneous lesion formation, or increased PR-1 expression associated with the
      ssi4 mutation. Thus, the ssi4 phenotype does not appear to be caused by
      overexpression of this R gene; rather, we propose that the NBS substitution
      generates a constitutively activated R protein. Furthermore, because SA treatment
      induced the expression of SSI4 and the closely related TIR-NBS-LRR genes RPP1 and
      RPS4 but had little effect on the expression of the coiled-coil NBS-LRR genes
      RPM1 and RPS2, we suggest that SA not only functions as a critical signal for
      downstream resistance events but also upregulates the expression of certain R
      genes.

PMID- 12468736
TI  - Gibberellin-mediated proteasome-dependent degradation of the barley DELLA protein
      SLN1 repressor.
AB  - DELLA proteins are nuclear repressors of plant gibberellin (GA) responses. Here,
      we investigate the properties of SLN1, a DELLA protein from barley that is
      destabilized by GA treatment. Using specific inhibitors of proteasome function,
      we show that proteasome-mediated protein degradation is necessary for GA-mediated
      destabilization of SLN1. We also show that GA responses, such as the aleurone
      alpha-amylase response and seedling leaf extension growth, require proteasome
      dependent GA-mediated SLN1 destabilization. In further experiments with protein
      kinase and protein phosphatase inhibitors, we identify two additional signaling
      steps that are necessary for GA response and for GA-mediated destabilization of
      SLN1. Thus, GA signaling involves protein phosphorylation and dephosphorylation
      steps and promotes the derepression of GA responses via proteasome-dependent
      destabilization of DELLA repressors.

PMID- 12468735
TI  - Abscisic acid-induced transcription is mediated by phosphorylation of an abscisic
      acid response element binding factor, TRAB1.
AB  - The rice basic domain/Leu zipper factor TRAB1 binds to abscisic acid (ABA)
      response elements and mediates ABA signals to activate transcription. We show
      that TRAB1 is phosphorylated rapidly in an in vivo labeling experiment and by
      phosphatase-sensitive mobility shifts on SDS-polyacrylamide gels. We had shown
      previously that a chimeric promoter containing GAL4 binding sites became ABA
      inducible when a GAL4 binding domain-TRAB1 fusion protein was present. This
      expression system allowed us to assay the ABA response function of TRAB1. Using
      this system, we show that Ser-102 of TRAB1 is critical for this function. Because
      no ABA-induced mobility shift was observed when Ser-102 was replaced by Ala, we
      suggest that this Ser residue is phosphorylated in response to ABA. Cell
      fractionation experiments, as well as fluorescence microscopy observations of
      transiently expressed green fluorescent protein-TRAB1 fusion protein, indicated
      that TRAB1 was localized in the nucleus independently of ABA. Our results suggest
      that the terminal or nearly terminal event of the primary ABA signal transduction
      pathway is the phosphorylation in the nucleus of preexisting TRAB1.

PMID- 12468738
TI  - Structural analysis of the maize rp1 complex reveals numerous sites and
      unexpected mechanisms of local rearrangement.
AB  - Rp1 is a complex disease resistance locus in maize that is exceptional in both
      allelic variability and meiotic instability. Genomic sequence analysis of three
      maize BACs from the Rp1 region of the B73 inbred line revealed 4 Rp1 homologs and
      18 other gene-homologous sequences, of which at least 16 are truncated. Thirteen
      of the truncated genes are found in three clusters, suggesting that they arose
      from multiple illegitimate break repairs at the same sites or from complex
      repairs of each of these sites with multiple unlinked DNA templates. A 43-kb
      region that contains an Rp1 homolog, six truncated genes, and three Opie
      retrotransposons was found to be duplicated in this region. This duplication is
      relatively recent, occurring after the insertion of the three Opie elements. The
      breakpoints of the duplication are outside of any genes or identified repeat
      sequence, suggesting a duplication mechanism that did not involve unequal
      recombination. A physical map and partial sequencing of the Rp1 complex indicate
      the presence of 15 Rp1 homologs in regions of approximately 250 and 300 kb in the
      B73 inbred line. Comparison of fully sequenced Rp1-homologous sequences in the
      region demonstrates a history of unequal recombination and diversifying selection
      within the Leu-rich repeat 2 region, resulting in chimeric gene structures.

PMID- 12468734
TI  - Cloning the tomato curl3 gene highlights the putative dual role of the leucine
      rich repeat receptor kinase tBRI1/SR160 in plant steroid hormone and peptide
      hormone signaling.
AB  - Brassinosteroids (BRs) are plant steroid hormones that are essential for normal
      plant development. To gain better understanding of the conservation of BR
      signaling, the partially BR-insensitive tomato mutant altered brassinolide
      sensitivity1 (abs1) was identified and found to be a weak allele at the curl3
      (cu3) locus. BR content is increased in both of these mutants and is associated
      with increased expression of DWARF: The tomato homolog of the Arabidopsis
      Brassinosteroid Insensitive1 Leu-rich repeat (LRR) receptor-like kinase, named
      tBri1, was isolated using degenerate primers. Sequence analysis of tBRI1 in the
      mutants cu3 and abs1 revealed that cu3 is a nonsense mutant and that abs1 is a
      missense mutant. A comparison of BRI1 homolog sequences highlights conserved
      features of BRI1 sequences, with the LRRs in close proximity to the island domain
      showing more conservation than N-terminal LRRs. The most homologous sequences
      were found in the kinase and transmembrane regions. tBRI1 (SR160) also has been
      isolated as the putative receptor for systemin, a plant peptide hormone. This
      finding suggests a possible dual role for tBRI1 in steroid hormone and peptide
      hormone signaling.

PMID- 12468740
TI  - Regulation of root hair initiation and expansin gene expression in Arabidopsis.
AB  - The expression of two Arabidopsis expansin genes (AtEXP7 and AtEXP18) is tightly
      linked to root hair initiation; thus, the regulation of these genes was studied
      to elucidate how developmental, hormonal, and environmental factors orchestrate
      root hair formation. Exogenous ethylene and auxin, as well as separation of the
      root from the medium, stimulated root hair formation and the expression of these
      expansin genes. The effects of exogenous auxin and root separation on root hair
      formation required the ethylene signaling pathway. By contrast, blocking the
      endogenous ethylene pathway, either by genetic mutations or by a chemical
      inhibitor, did not affect normal root hair formation and expansin gene
      expression. These results indicate that the normal developmental pathway for root
      hair formation (i.e., not induced by external stimuli) is independent of the
      ethylene pathway. Promoter analyses of the expansin genes show that the same
      promoter elements that determine cell specificity also determine inducibility by
      ethylene, auxin, and root separation. Our study suggests that two distinctive
      signaling pathways, one developmental and the other environmental/hormonal,
      converge to modulate the initiation of the root hair and the expression of its
      specific expansin gene set.

PMID- 12468739
TI  - Two E2F elements regulate the proliferating cell nuclear antigen promoter
      differently during leaf development.
AB  - E2F transcription factors regulate genes expressed at the G1/S boundary of the
      cell division cycle in higher eukaryotes. Although animal E2F proteins and their
      target promoters have been studied extensively, little is known about how these
      factors regulate plant promoters. An earlier study identified two E2F consensus
      binding sites in the promoter of a Nicotiana benthamiana gene encoding
      proliferating cell nuclear antigen (PCNA) and showed that the proximal element
      (E2F2) is required for the full repression of PCNA expression in mature leaves.
      In this study, we examined the distal element (E2F1) and how it interacts with
      the E2F2 site to regulate the PCNA promoter. Gel shift assays using plant nuclear
      extracts or purified Arabidopsis E2F and DP proteins showed that different
      complexes bind to the two E2F sites. Mutation of the E2F1 site or both sites
      differentially altered PCNA promoter function in transgenic plants. As reported
      previously for the E2F2 mutation, the E2F1 and E2F1+2 mutations partially
      relieved the repression of the PCNA promoter in mature leaves. In young tissues,
      the E2F1 mutation resulted in a threefold reduction in PCNA promoter activity,
      whereas the E2F1+2 mutation had no detectable effect. The activity of E2F1+2
      mutants was indistinguishable from that of E2F2 mutants. These results
      demonstrate that both E2F elements contribute to the repression of the PCNA
      promoter in mature leaves, whereas the E2F1 site counters the repression activity
      of the E2F2 element in young leaves.

PMID- 12468741
TI  - A peptide chain release factor 2 affects the stability of UGA-containing
      transcripts in Arabidopsis chloroplasts.
AB  - Positional cloning of the hcf109 (high chlorophyll fluorescence) mutation in
      Arabidopsis has identified a nucleus-encoded, plastid-localized release factor 2
      like protein, AtprfB, indicating that the processes of translational termination
      in chloroplasts resemble those of eubacteria. Control of atprfB expression by
      light and tissues is connected to chloroplast development. A point mutation at
      the last nucleotide of the second intron causes a new splice site farther
      downstream, resulting in a deletion of seven amino acid residues in the N
      terminal region of the Hcf109 protein. The mutation causes decreased stability of
      UGA-containing mRNAs. Our data suggest that transcripts with UGA stop codons are
      terminated exclusively by AtprfB in chloroplasts and that AtprfB is involved in
      the regulation of both mRNA stability and protein synthesis. Furthermore,
      sequence data reveal a +1 frameshift at an internal in-frame TGA stop codon in
      the progenitor prfB gene of cyanobacteria. The expression pattern and functions
      of atprfB could reflect evolutionary driving forces toward the conservation of
      TGA stop codons exclusively in plastid genomes of land plants.

PMID- 12468742
TI  - Differential expression of alternative oxidase genes in maize mitochondrial
      mutants.
AB  - We have examined the expression of three alternative oxidase (aox) genes in two
      types of maize mitochondrial mutants. Nonchromosomal stripe (NCS) mutants carry
      mitochondrial DNA deletions that affect subunits of respiratory complexes and
      show constitutively defective growth. Cytoplasmic male-sterile (CMS) mutants have
      mitochondrial DNA rearrangements, but they are impaired for mitochondrial
      function only during anther development. In contrast to normal plants, which have
      very low levels of AOX, NCS mutants exhibit high expression of aox genes in all
      nonphotosynthetic tissues tested. The expression pattern is specific for each
      type of mitochondrial lesion: the NADH dehydrogenase-defective NCS2 mutant has
      high expression of aox2, whereas the cytochrome oxidase-defective NCS6 mutant
      predominantly expresses aox3. Similarly, aox2 and aox3 can be induced
      differentially in normal maize seedlings by specific inhibitors of these two
      respiratory complexes. Translation-defective NCS4 plants show induction of both
      aox2 and aox3. AOX2 and AOX3 proteins differ in their ability to be regulated by
      reversible dimerization. CMS mutants show relatively high levels of aox2 mRNAs in
      young tassels but none in ear shoots. Significant expression of aox1 is detected
      only in NCS and CMS tassels. The induction pattern of maize aox genes could serve
      as a selective marker for diverse mitochondrial defects.

PMID- 12468743
TI  - Quantification of health effects of exposure to air pollution.

PMID- 12468744
TI  - Mortality among US and UK veterans of the Persian Gulf War: a review.
AB  - Mortality data on Gulf War veterans was reviewed as a means of evaluating the
      long term consequences of the war. Studies were located from searches of Medline,
      Proceedings of the Conference on Federally Sponsored Gulf War Veterans' Illnesses
      Research, Proceedings of the American Public Health Association Annual Meetings,
      Annual Reports to Congress, and personal contacts with knowledgeable
      investigators. Data on study design, methods, and results were obtained from
      published studies of both US and UK veterans who served in the Persian Gulf. The
      methodology and results of studies are summarised and evaluated. Additional
      research recommendations based on reviewed studies are presented. It is concluded
      that in both US and UK studies, mortality from external causes was higher, while
      mortality from all illnesses was lower among Gulf War veterans in comparison to
      those of non-Gulf War veterans. Increased mortality from external causes is
      consistent with patterns of postwar mortality observed in veterans of previous
      wars. Further follow up of Gulf War veterans and their controls is warranted for
      evaluating the mortality risk from diseases with longer latency periods.

PMID- 12468745
TI  - Definition and assessment of specific occupational demands concerning lifting,
      pushing, and pulling based on a systematic literature search.
AB  - AIMS: (1) To find a universal strategy for the identification of specific demands
      of a job or task, focusing on occupations in which there may be an increased risk
      for health complaints owing to these specific demands. (2) To select reliable and
      valid tests concerning lifting, pushing, and pulling, which consider the relation
      between occupational work demands and the assessment of the maximally acceptable
      load on an individual level. METHODS: Literature search was performed using
      Medline (1988 to May 2001), Embase (1966 to May 2001), and NIOSHTIC (1971-98).
      RESULTS: No universal strategy was found for the definition of specific
      occupational demands. Therefore a "three step strategy" was formulated for
      defining specific occupational demands in a job or a task in order to prevent
      health complaints on an individual level. Many tests were found in the literature
      concerning lifting, but only a few concerning pushing and pulling. None of the
      tests concerning pushing, pulling, or lifting considered the relation between
      work demands and the assessment of the maximally acceptable load on an individual
      level. Furthermore, none of the tests met the criteria of reliability and
      prognostic value for musculoskeletal complaints completely. Only for the
      prognostic value of relative strength capacity tests concerning pushing pulling
      and lifting, did there appear to be limited proof for the development of
      musculoskeletal complaints. CONCLUSIONS: In general, for the prevention of work
      related health complaints, it can be suggested that more attention should be paid
      to: (1) the definition of specific occupational demands; (2) the assessment of
      specific occupational demands; and (3) the quality of tests for specific
      occupational demands.

PMID- 12468746
TI  - Cost-benefit and cost-effectiveness analysis of a disability prevention model for
      back pain management: a six year follow up study.
AB  - AIMS: To test the long term cost-benefit and cost-effectiveness of the Sherbrooke
      model of management of subacute occupational back pain, combining an occupational
      and a clinical rehabilitation intervention. METHODS: A randomised trial design
      with four arms was used: standard care, occupational arm, clinical arm, and
      Sherbrooke model arm (combined occupational and clinical interventions). From the
      Quebec WCB perspective, a cost-benefit (amount of consequence of disease costs
      saved) and cost-effectiveness analysis (amount of dollars spent for each saved
      day on full benefits) were calculated for each experimental arm of the study,
      compared to standard care. RESULTS: At the mean follow up of 6.4 years, all
      experimental study arms showed a trend towards cost benefit and cost
      effectiveness. These results were owing to a small number of very costly cases.
      The largest number of days saved from benefits was in the Sherbrooke model arm.
      CONCLUSIONS: A fully integrated disability prevention model for occupational back
      pain appeared to be cost beneficial for the workers' compensation board and to
      save more days on benefits than usual care or partial interventions. A limited
      number of cases were responsible for most of the long term disability costs, in
      accordance with occupational back pain epidemiology. However, further studies
      with larger samples will be necessary to confirm these results.

PMID- 12468747
TI  - Cross sectional study on lung function of coke oven workers: a lung function
      surveillance system from 1978 to 1990.
AB  - AIMS: To determine the association between lung function of coke oven workers and
      exposure to coke oven emissions. METHODS: Lung function data and detailed work
      histories for workers in recovery coke ovens of a steelworks were extracted from
      a lung function surveillance system. Multiple regressions were employed to
      determine significant predictors for lung function indices. The first sets of
      lung function tests for 613 new starters were pooled to assess the selection
      bias. The last sets of lung function tests for 834 subjects with one or more year
      of coke oven history were pooled to assess determinants of lung function.
      RESULTS: Selection bias associated with the recruitment process was not observed
      among the exposure groups. For subjects with a history of one or more years of
      coke oven work, each year of working in the most exposed "operation" position was
      associated with reductions in FEV(1) of around 9 ml (p = 0.006, 95% CI: 3 ml to
      16 ml) and in FVC of around 12 ml (p = 0.002, 95% CI: 4 ml to 19 ml). Negative
      effects of smoking on lung function were also observed. CONCLUSIONS: Exposure to
      coke oven emissions was found to be associated with lower FEV(1) and FVC. Effects
      of work exposure on lung function are similar to those found in other studies.

PMID- 12468749
TI  - Relation between colour vision loss and occupational styrene exposure level.
AB  - AIMS: To investigate the relation between colour vision loss and the exposure
      level of styrene. Exposure level included the current exposure concentration,
      past cumulative exposure, and the maximum exposure level in the past. METHODS:
      Colour vision was examined by the Lanthony desaturated panel D-15 test for 76
      subjects exposed to styrene in a fibreglass reinforced plastics boat plant (as an
      exposed group) and 102 non-exposed subjects (as a control group). The current
      exposure level was expressed by the concentration of atmospheric styrene and end
      shift urinary mandelic acid (MA) and phenylglyoxylic acid (PGA) levels. The
      individual cumulative exposure index (CEI) was calculated, based on the exposure
      frequency and urinary MA concentrations measured for the past eight years.
      RESULTS: The Colour Confusion Index (CCI) of the exposed group showed a
      significant difference from the age matched controls. However, only a slight
      significant relation was found between CCI and the concentration of urinary MA
      plus PGA. In this study, the exposed group was further divided into two subgroups
      (as sub-MA+PGA groups) by the median of urinary MA plus PGA of each subject. The
      dividing line between the subgroups was 0.24 g/g creatinine, which was equivalent
      to an atmospheric concentration of styrene of about 10 ppm. The CCI values of
      both the sub-MA+PGA groups were significantly higher than that of the control
      group. The relation between CCI value and the maximum exposure concentration in
      the past eight years was examined. It was found that the CCI values of the group
      with the maximum exposure concentration of styrene over 50 ppm were significantly
      higher than that of the other groups. CONCLUSIONS: Exposure to styrene would
      impair colour vision even if the exposure concentration was lower than 10 ppm.
      Furthermore, if the maximum concentration of styrene exposure transiently
      exceeded 50 ppm in the past, the styrene related damage might remain. Thus, the
      safe limit of exposure to styrene and the relation between exposure to styrene
      and the degree of damage to ocular structure, retina, optic nerve, and brain need
      to be re-examined.

PMID- 12468750
TI  - Respiratory symptoms and diseases among workers in the soft tissue producing
      industry.
AB  - AIMS: To correlate the prevalence of respiratory tract symptoms and diseases with
      dust and fibre exposure in the soft tissue industry in Germany. METHODS: Ambient
      monitoring was performed for inhalable, respirable dust and fibres in seven soft
      tissue producing factories. In 441 workers (72 controls, 90 moderate, 279 high
      exposure) a standardised questionnaire on respiratory symptoms, diseases,
      occupational history, and smoking habits was used. Crude differences in the
      prevalence of respiratory symptoms and diseases were assessed. Logistic
      regression analysis was used to determine the relation between the respiratory
      symptoms/diseases and the cumulative dust and fibre exposure, respectively, while
      adjusting for age, gender, smoking habits, and factory. The effects of exposure
      intensity and duration were differentiated by categorising dust/fibre
      concentrations and years of exposure separately and setting up logistic
      regression models. RESULTS: The mean concentrations for inhalable, respirable,
      and fibrous dusts were 10.3 mg/m(3), 0.22 mg/m(3), and 415,000 fibres/m(3).
      Adjusted odds ratios (OR) with relation to cumulative dust exposure intensity
      were significantly raised for blocked nose (18.2), mucosal irritation (6.5), dry
      nose (8.9), cough (3.5), phlegm (7.5), exercise induced dyspnoea (2.6),
      hoarseness (11.3), and sneezing attacks (7.9) (ORs for highest exposure
      categories). Cumulative dust or fibre exposure had no significant effects on the
      prevalence of respiratory diseases. For all symptoms with significantly raised
      ORs, combined effects of intensity and duration of exposure were found.
      CONCLUSIONS: Because of the high prevalence of respiratory symptoms a reduction
      of dust exposures is recommended. Chronic exposure effects could not be found in
      this study, however, a healthy worker effect has to be considered.

PMID- 12468752
TI  - Passive smoking and its impact on employers and employees in Hong Kong.
AB  - AIMS: To estimate the prevalence of passive smoking at work in the whole
      workforce in Hong Kong (population 6.8 million), the characteristics of the
      passive smokers, any extra use of health care among passive smokers, and who pays
      for that health care. METHODS: A random sample of 14,325 households was contacted
      by telephone; 6,186 responding adults who worked full time were asked about their
      employment, their most recent use of health care and the cost of that care, their
      medical benefits, and their exposure to secondhand smoke in the workplace. After
      weighting the sample for sex, age, household size, and income, 4,739 subjects
      were included in the analysis. RESULTS: Of 1,961 full time workers who did not
      smoke, 47.5% were exposed to secondhand smoke in the workplace compared with only
      26% exposed at home. Exposure at work was associated with being younger, male,
      married, less educated, and having a lower income. Those exposed at work were 37%
      more likely to report having visited a doctor for a respiratory illness in the
      previous 14 days. Employers were paying 28% of the cost of these visits, the
      government paid 8%, and the individuals paid 63%. If extrapolated to the 3
      million workers in the Hong Kong population, employers would pay just over US$9
      million per year, while the affected workers would pay around US$20 million.
      CONCLUSION: As well as the costs of active smoking, the cost of extra health care
      utilisation associated with passive smoking is an additional cost being paid by
      those employers who have not established smoke free workplaces and by their
      employees.

PMID- 12468751
TI  - Self perceived work related stress and the relation with salivary IgA and
      lysozyme among emergency department nurses.
AB  - AIMS: To assess and compare the self perceived work related stress among
      emergency department (ED) and general ward (GW) nurses, and to investigate its
      relation with salivary IgA and lysozyme. METHODS: One hundred and thirty two of
      208 (63.5%) registered female ED and GW nurses participated in the study. A
      modified mental health professional stress scale (PSS) was used to measure self
      perceived stress. ELISA methods were used to determine the salivary IgA and
      lysozyme levels. RESULTS: On PSS, ED nurses had higher scores (mean 1.51) than GW
      nurses (1.30). The scores of PSS subscales such as organisational structure and
      processes (OS), lack of resources (RES), and conflict with other professionals
      (COF) were higher in ED than in GW nurses. ED nurses had lower secretion rates of
      IgA (geometric mean (GM) 49.1 micro g/min) and lysozyme (GM 20.0 micro g/min)
      than GW nurses (68.2 micro g/min, 30.5 micro g/min). Significant correlations
      were observed between PSS and log IgA and lysozyme secretion rates. OS, RES, and
      COF were correlated with log IgA and lysozyme levels. CONCLUSION: ED nurses, who
      reported a higher level of professional stress, showed significantly lower
      secretion rates of salivary IgA and lysozyme compared to GW nurses. Salivary IgA
      and lysozyme were inversely correlated with self perceived work related stress.
      As these salivary biomarkers are reflective of the mucosal immunity, results
      support the inverse relation between stress and mucosal immunity.

PMID- 12468753
TI  - Influence of years engaged in agriculture and number of pregnancies and
      deliveries on mortality of inhabitants of the Jinzu River basin area, Japan.
AB  - BACKGROUND: The occurrence of itai-itai disease is thought to be affected by such
      factors as pregnancy, lactation, hormonal disorders, aging, and calcium
      deficiency. AIMS: To study the influence of years engaged in agriculture and
      number of pregnancies and deliveries on the mortality of inhabitants of the Jinzu
      River basin area, which has been an endemic region for itai-itai disease.
      METHODS: From 6,667 participants (3,181 men, 3,486 women; participation rate
      93.4%) in the 1967 health survey, 3,639 subjects (1,591 men, 2,048 women) whose
      years engaged in agriculture were established, and 2,559 women/2,410 women with a
      known number of pregnancies/deliveries were selected as the target population.
      These data were confirmed on the basis of self reported replies confirmed
      afterwards by interview. The survival survey was conducted for 6,127 days from 1
      August 1967 to 10 May 1984. Subjects were divided according to three water
      systems: the Jinzu River, non-Jinzu River, and mixed water system; the influence
      on mortality of the years engaged in agriculture and the number of
      pregnancies/deliveries was analysed using a Cox's proportional hazards model
      according to the water systems. RESULTS: The mean years engaged in agriculture
      and mean number of pregnancies/deliveries were not different among the three
      water systems. Cox's hazard ratios of these parameters to mortality were not
      statistically significant in the any of the water systems. CONCLUSIONS: Neither
      the years engaged in agriculture nor the number of pregnancies/deliveries
      influenced mortality in subjects living not only in the non-Jinzu River basin but
      also in the Jinzu River basin using a Cox's proportional hazards model.

PMID- 12468754
TI  - Long term medical conditions: career prospects.

PMID- 12468756
TI  - Sex ratio at birth in Masjid-i-Sulaiman (Khozestan province, Iran).

PMID- 12468757
TI  - Episodes of environmental poisoning worldwide.

PMID- 12468759
TI  - Inflammation, blood pressure, and stroke: an opportunity to target primary
      prevention?

PMID- 12468760
TI  - Worsening in ischemic stroke patients: supplementary activation of cerebral
      hemodynamic with EC/IC bypass.

PMID- 12468761
TI  - Progressive stroke, lacunae, and systemic blood pressure.

PMID- 12468762
TI  - CT or MRI for imaging patients with acute stroke: visualization of "tissue at
      risk"?

PMID- 12468763
TI  - Spreading and synchronous depressions of cortical activity in acutely injured
      human brain.
AB  - BACKGROUND AND PURPOSE: Cortical spreading depression (CSD) has been much studied
      experimentally but never demonstrated unequivocally in human neocortex by direct
      electrophysiological recording. A similar phenomenon, peri-infarct
      depolarization, occurs in experimental models of stroke and causes the infarct to
      enlarge. Our current understanding of the mechanisms of deterioration in the days
      after major traumatic or ischemic brain injury in humans has not yielded any
      effective, novel drug treatment. This study sought clear evidence for the
      occurrence and propagation of CSD in the injured human brain. METHODS: In 14
      patients undergoing neurosurgery after head injury or intracranial hemorrhage, we
      placed electrocorticographic (ECoG) electrodes near foci of damaged cortical
      tissue. RESULTS: Transient episodes of depressed ECoG activity that propagated
      across the cortex at rates in the range of 0.6 to 5.0 mm/min were observed in 5
      patients; this rate of propagation is characteristic of CSD. We also observed, in
      8 of the 14 patients, transient depressions of ECoG amplitude that appeared
      essentially simultaneous in all recording channels, without clear evidence of
      spread. CONCLUSIONS: These results indicate that CSD or similar events occur in
      the injured human brain and are more frequent than previously suggested. On the
      basis of these observations, we suggest that the related phenomenon, peri-infarct
      depolarization, is indeed likely to occur in boundary zones in the ischemic human
      cerebral cortex.

PMID- 12468764
TI  - Long-term effects of inflammation-sensitive plasma proteins and systolic blood
      pressure on incidence of stroke.
AB  - BACKGROUND AND PURPOSE: The present study investigated the relationships between
      inflammation-sensitive plasma proteins (ISPs) and systolic blood pressure (SBP),
      as well as the joint long-term effects of ISP and SBP on incidence of stroke.
      METHODS: BP and 5 ISPs (fibrinogen, alpha1-antitrypsin, haptoglobin,
      ceruloplasmin, orosomucoid) were assessed in 6071 healthy men 28 to 61 years of
      age. All-cause mortality and incidence of stroke were monitored over a mean
      follow-up of 18.7 years in men defined by SBP (<120, 120 to 139, >/=140 mm Hg)
      and ISP (0 to 1 or 2 to 5 ISPs in the top quartile). RESULTS: SBP and diastolic
      BP were significantly and positively associated with the number of ISPs in the
      top quartile. As expected, elevated SBP was associated with an increased
      incidence of stroke. Among men with SBP >/=140 mm Hg, there were, however,
      significant differences between those with high and low ISP levels. After risk
      factor adjustment, men with SBP >/=140 mm Hg and high ISP levels had a relative
      risk of stroke of 4.3 (95% CI, 2.3 to 7.8) compared with men with SBP <120 mm Hg
      and low ISP levels. In the absence of high ISP levels, the risk associated with
      SBP >/=140 was 2.5 (95% CI,1.4 to 4.6). Men with high ISP levels had a
      significantly increased risk of stroke also after exclusion of the events from
      the first 10 years of follow-up. CONCLUSIONS: High ISP levels are associated with
      elevated BP. These proteins are associated with an increased risk of stroke among
      men with high BP and provide information on stroke risk even after many years of
      follow-up.

PMID- 12468765
TI  - C-reactive protein predicts progression of atherosclerosis measured at various
      sites in the arterial tree: the Rotterdam Study.
AB  - Background and Purpose- C-reactive protein (CRP) predicts myocardial infarction
      and stroke. Its role as a predictor of the progression of subclinical
      atherosclerosis is not yet known. We investigated whether CRP predicts
      progression of atherosclerosis measured at various sites in the arterial tree.
      METHODS: CRP levels were measured in a random sample of 773 subjects >/=55 years
      of age who were participating in the Rotterdam Study. Subclinical atherosclerosis
      was assessed at various sites at 2 points in time, with a mean duration between
      measurements of 6.5 years. RESULTS: After adjustment for age, sex, and smoking
      habits, odds ratios (ORs) associated with CRP levels in the highest compared with
      the lowest quartile were increased for progression of carotid (OR, 1.9; 95% CI,
      1.1 to 3.3), aortic (OR, 1.7; 95% CI, 1.0 to 3.0), iliac (OR, 2.0; 95% CI, 1.2 to
      3.3), and lower extremity (OR, 1.9; 95% CI, 1.0 to 3.7) atherosclerosis. The OR
      for generalized progression of atherosclerosis as indicated by a composite
      progression score was 4.5 (95% CI, 2.3 to 8.5). Except for aortic
      atherosclerosis, these estimates hardly changed after additional adjustment for
      multiple cardiovascular risk factors. In addition, ORs for progression of
      atherosclerosis associated with high CRP levels were as high as those associated
      with the traditional cardiovascular risk factors high cholesterol, hypertension,
      and smoking. Geometric mean levels of CRP increased with the total number of
      sites showing progression of atherosclerosis (P=0.002 for trend). CONCLUSIONS:
      CRP predicts progression of atherosclerosis measured at various sites in the
      arterial tree.

PMID- 12468766
TI  - Chlamydia pneumoniae in carotid artery atherosclerosis: a comparison of its
      presence in atherosclerotic plaque, healthy vessels, and circulating leukocytes
      from the same individuals.
AB  - BACKGROUND AND PURPOSE: There is growing clinical and experimental evidence that
      infections with Chlamydia pneumoniae might contribute to the development and
      progression of atherosclerosis. However, studies detecting the pathogen in
      atherosclerotic lesions examined either only atherosclerotic vessels or control
      vessels without atherosclerosis obtained from a different group of individuals.
      We analyzed atherosclerotic plaques of the carotid artery, samples of apparently
      healthy greater saphenous veins, and circulating leukocytes from the same
      individual patients for the presence of C pneumoniae. METHODS: From each of 46
      patients undergoing carotid endarterectomy for symptomatic carotid artery
      stenosis, these samples were analyzed by nested polymerase chain reaction for C
      pneumoniae-specific DNA. Furthermore, we determined IgA and IgG titers specific
      for the pathogen and plasma levels of C-reactive protein in these patients.
      RESULTS: C pneumoniae DNA was detected in 86.9% of the leukocytes and in 82.6% of
      the atherosclerotic plaques but in only 6.5% of the saphenous veins. In 85% of
      patients who also had leukocytes positive for C pneumoniae, the atherosclerotic
      plaques were positive and the saphenous veins were negative. The presence of C
      pneumoniae-specific DNA in leukocytes significantly coincided with the presence
      of the respective DNA in the plaques of the carotid arteries (P=0.0002). No
      association between the presence of C pneumoniae and specific IgA or IgG levels
      was seen. C-reactive protein levels were significantly higher in patients with
      chlamydia-positive atherosclerotic plaques and with positive leukocytes than in
      patients with negative plaques of the carotid arteries or negative leukocytes,
      respectively (P<0.01, P<0.05). CONCLUSIONS: Our observation of >80% incidence of
      C pneumoniae in atherosclerotic plaques of the carotid artery does not prove
      causality between an infection with the pathogen and the development of
      atherosclerosis. It must be emphasized, however, that >90% of apparently healthy
      saphenous veins were negative for C pneumoniae. Given the structural and
      functional differences between veins and arteries, careful interpretation of our
      results regarding a possible causative role of C pneumoniae seems warranted.

PMID- 12468770
TI  - Isolated and borderline isolated systolic hypertension relative to long-term risk
      and type of stroke: a 20-year follow-up of the national health and nutrition
      survey.
AB  - BACKGROUND AND PURPOSE: Although the short-term risks of stroke and types of
      stroke associated with isolated systolic hypertension (ISH) and borderline
      isolated systolic hypertension (BISH) have been described, the long-term effects
      of these hypertensive conditions, particularly in younger individuals, are
      unclear. We performed this study to evaluate the long-term risks of stroke, type
      of stroke, and predictors of stroke associated with ISH and BISH and how this
      risk compares with that for persons with diastolic hypertension and normotension.
      METHODS: We used the 20-year follow-up data for 12 344 adults aged 25 to 74 years
      who participated in the First National Health and Nutrition Examination Survey
      Follow-Up Study to determine the aforementioned risks. Blood pressure (BP)
      measurements of the participants were obtained during baseline evaluation. ISH
      was defined as systolic BP >/=160 mm Hg and diastolic BP <90 mm Hg. BISH was
      defined as systolic BP between 140 and 159 mm Hg and diastolic BP <90 mm Hg.
      Diastolic hypertension was defined as a diastolic BP >/=90 mm Hg. Normotension
      was defined as systolic BP <140 mm Hg and diastolic BP <90 mm Hg. Incidence of
      stroke overall and incidence of ischemic stroke and intracerebral hemorrhage were
      determined from a review of hospital records and death certificates. Relative
      risk (RR) of stroke and stroke type in association with each hypertensive
      category was determined by Cox proportional hazards analysis after adjustment for
      potential confounding variables. RESULTS: Among the 12 344 participants,
      hypertension was categorized as ISH (n=493), BISH (n=1241), and diastolic
      hypertension (n=3954). Normotension was observed in 6656 persons. After
      adjustment for differences in age, sex, education, serum cholesterol level, body
      mass index, diabetes mellitus, and cigarette smoking, a significantly higher RR
      for all strokes was observed in participants with ISH (RR, 2.7; 95% CI, 2.0 to
      3.4) and BISH (RR, 1.4; 95% CI, 1.1 to 1.8) than those with normotension. The
      risk was significantly higher for ischemic stroke or intracerebral hemorrhage in
      persons with ISH and BISH. Among the 1734 persons with either ISH or BISH, the
      risk of stroke was independently associated with older age, diabetes mellitus,
      and systolic BP >/=180 mm Hg. CONCLUSIONS: Increased risks for stroke, ischemic
      stroke, and intracerebral hemorrhage were observed in patients with BISH, similar
      to those associated with ISH and diastolic hypertension. Future clinical trials
      are required to evaluate the effect of antihypertensive treatment in younger
      patients with BISH and ISH.

PMID- 12468768
TI  - Addressing the heterogeneity of the ischemic stroke phenotype in human genetics
      research.
AB  - BACKGROUND AND PURPOSE: Many investigators have approached ischemic stroke as a
      complex phenotype by dividing the ischemic stroke population into distinct
      subtypes. The purpose of this study was to review systematically the methods used
      to subtype ischemic stroke in recent genetic studies. METHODS: The MEDLINE
      database was searched for articles pertaining to research on the genetics of
      human ischemic stroke published from January 2000 through January 2002. Abstracts
      and full-length reports were then sequentially screened to select articles
      pertaining to original case-control or cohort studies. RESULTS: The initial
      search yielded 153 publications. Of 41 relevant articles, ischemic stroke was
      subtyped in 25 (61%). The most common standard subtyping system was the
      Cerebrovascular Classification of Diseases III system (9 articles). Of the
      subtyping systems used, 3 had previously published interrater reliability. The
      subtyping system was reported to have been prespecified in 1 study. Four articles
      reported using central adjudication. Two articles reported that the person doing
      the subtyping was blinded to genotype, and 2 reported that the person doing the
      genotyping was blinded to the patient's subtype status. CONCLUSIONS: When
      investigators subtyped ischemic stroke, they typically used either nonstandard
      classification systems or systems of undetermined reliability. Important
      methodological issues, including blinding and prespecification of the
      classification system, were rarely reported. Advances in methodology and
      scientific reporting standards would foster identification of subtype-specific
      genetic risk factors.

PMID- 12468769
TI  - Genetic basis of variation in carotid artery plaque in the San Antonio Family
      Heart Study.
AB  - BACKGROUND AND PURPOSE: In contrast to the commonly used quantitative marker of
      subclinical atherosclerosis, namely intima-media thickness, we investigated the
      extent to which the presence or absence of carotid artery plaque (CAP) was under
      genetic control. METHODS: The study population consisted of 750 individuals
      distributed across 29 randomly ascertained extended Mexican American pedigrees
      who participated in the second examination cycle of the San Antonio Family Heart
      Study. Extracranial focal CAP was identified by B-mode ultrasound bilaterally in
      the internal carotid artery or the carotid bulb. Using a variance decomposition
      approach implemented in the SOLAR computer program, we performed genetic analysis
      on the discrete trait CAP (ie, liability to disease) using a threshold model.
      Covariates considered in the analysis included age, sex, diabetes, current
      smoking status, lipid levels, and markers of hypertension and obesity. RESULTS:
      Fifty-one of 461 women and fifty-seven of 289 men with a mean age of 42.1 years
      had evidence of a plaque in the right and/or left carotid artery. The age- and
      sex-adjusted heritability (h(2)+/-SE) for CAP was significant (h(2)=0.28+/-0.15,
      P=0.01). Furthermore, after adjustment for additional covariates that contributed
      significantly to the model (P<0.05; diabetes, hypertension, body mass index,
      waist circumference, and smoking status), heritability remained significant
      (h(2)=0.23+/-0.15, P=0.03). CONCLUSIONS: Our data indicate that after established
      cardiovascular risk factors are controlled for, the variation of the discrete
      trait CAP is under appreciable additive genetic influences.

PMID- 12468767
TI  - Cryptogenic stroke in relation to genetic variation in clotting factors and other
      genetic polymorphisms among young men and women.
AB  - BACKGROUND AND PURPOSE: The purpose of the present study was to compare the
      prevalences of genetic polymorphisms in persons with cryptogenic stroke with
      those among stroke patients with evidence of large-artery occlusive disease or an
      unequivocal cardioembolic source (noncryptogenic stroke). METHODS: We compared
      the prevalences of genetic polymorphisms thought to be related to thrombi
      formation in young stroke patients with evidence of large-artery occlusive
      disease or an unequivocal cardioembolic source (noncryptogenic stroke; controls;
      n=79) with those in young stroke patients without such sources (cryptogenic
      stroke; cases; n=67). Common variations in the genes encoding factor V,
      prothrombin, angiotensin I-converting enzyme, 5,10-methylenetetrahydrofolate
      reductase, endothelial cell nitric oxide synthase, tissue plasminogen activator,
      plasminogen activator inhibitor-1, and fibrinogen were evaluated. We also
      compared the allele prevalence of these genes among all stroke patients with
      those among a large pool of historical controls assayed for these genes. RESULTS:
      None of these genetic polymorphisms was statistically significantly related to
      cryptogenic stroke. With respect to a comparison of all ischemic stroke with
      historical controls, only the prevalence of tissue plasminogen activator D allele
      among stroke subjects was statistically significantly higher than that of the
      historical controls (P=0.0014). CONCLUSIONS: These findings generally do not
      support the hypothesis that genes associated with a prothrombotic state are risk
      factors among a subgroup of young people with stroke of undetermined cause.
      Except for the D tissue plasminogen activator allele, the findings also indicated
      that these genetic factors are unrelated, or only weakly related, to all ischemic
      stroke.

PMID- 12468771
TI  - Stroke in the young in the northern Manhattan stroke study.
AB  - BACKGROUND AND PURPOSE: Stroke and stroke subtype incidence in young black and
      Hispanic populations have not been well studied. The purpose of this study was to
      determine stroke incidence rates in these populations and to compare rates among
      various race-ethnic, sex, and age groups. METHODS: A population-based incidence
      study identified all cases of first stroke in Northern Manhattan from 1993 to
      1997. Stroke and stroke subtype incidence rates were calculated for younger (20
      to 44 years of age) and older (>/=45 years of age) adults. The relative risk (RR)
      of stroke in blacks and Hispanics compared with whites was calculated. Stroke
      subtypes, infarct subtypes, and case fatality rates were compared in the young
      and old and in different race-ethnic groups and sexes. RESULTS: Over 4 years, 74
      cases of first stroke in young patients were discovered (47% women, 12% black,
      80% Hispanic, 8% white). The stroke incidence rates (cases per 100 000 persons
      per year) in the young were 23 overall, 10 for infarct, 7 for intracerebral
      hemorrhage (ICH), and 6 for subarachnoid hemorrhage. The RR of stroke in the
      young was greatest for blacks (2.4; 95% CI, 0.8 to 6.7) and Hispanics (2.5; 95%
      CI, 1.1 to 5.8) compared with whites. ICH was more frequent in men with a RR of
      3.7 (95% CI, 1.4 to 10.1). Case fatality rates at 30 days were higher in blacks
      (38%) and Hispanics (16%) compared with whites (0%). CONCLUSIONS: Young blacks
      and Hispanics have greater stroke incidences than young whites.

PMID- 12468772
TI  - A population-based study of brain arteriovenous malformation: long-term treatment
      outcomes.
AB  - BACKGROUND AND PURPOSE: By undertaking long-term follow-up of a functionally
      isolated population study group, we sought to achieve a true picture of intrinsic
      brain arteriovenous malformation (BAVM). We sought to assess the validity of
      earlier population-based series and to determine the effects of newer treatment
      methods on the overall morbidity and mortality of BAVM. METHODS: We excluded
      other intracranial vascular pathologies by defining criteria. By retrospective
      and prospective study, 240 patients with BAVM were followed for a mean of 10.11
      years from first diagnosis. RESULTS: Death rates were as follows: all causes,
      12.9%; all BAVM related, 8.75%; BAVM related during conservative management,
      24.6%; and BAVM related during active management, 3.9% (P=0.031). Mean diagnosis
      to-death interval was 10.6 years. Oxford neurological disability scale grades of
      209 survivors (July 2001) were as follows: grades 0 to 2, 74.1%; grade 3, 17.2%;
      and grades 4 to 5, 9.5%. Death rates were higher for patients who had bled or
      suffered nonhemorrhagic neurological deficit at original presentation. Incidence
      of first-ever hemorrhage in untreated patients was as follows: 0 to 9 years, 4.6%
      (P=0.0035); 30 to 39 years, 21% (P=0.02); and 60 to 69 years, 40.0% (P=0.045).
      The first bleed was fatal in 4.6%. CONCLUSIONS: We find no evidence of a
      substantial undiagnosed reservoir of nonsymptomatic BAVM. All BAVM are
      potentially hazardous. The great majority of BAVM patients become symptomatic
      during the patient's lifetime, and the majority will bleed. The risk of first
      hemorrhage is lifelong and rises with age. Compared with earlier population-based
      series, our low overall patient mortality is predominantly due to higher
      proportions of active treatment in the 1980s and 1990s.

PMID- 12468773
TI  - Shortening the NIH Stroke scale for use in the prehospital setting.
AB  - BACKGROUND AND PURPOSE: Prehospital stroke scales should identify stroke patients
      and measure stroke severity. The goal of this study was to identify a subset of
      the 15 items in the National Institutes of Health Stroke Scale (NIHSS-15) that
      measures stroke severity and predicts outcomes. METHODS: Using 2 distinct data
      sets from acute stroke clinical trials, we derived and validated shortened
      versions of the NIHSS (sNIHSS). Stepwise logistic regression and bootstrap
      techniques were used in selection of NIHSS-15 items. Areas under the receiver
      operator characteristic curve (C statistics) were used to compare predictive
      performance of logistic models incorporating differing versions of the NIHSS.
      RESULTS: The derivation analyses suggested the 8 NIHSS-15 items that were most
      predictive of "good outcome" 3 months after stroke, in order of decreasing
      importance: right leg item, left leg, gaze, visual fields, language, level of
      consciousness, facial palsy, and dysarthria. The sNIHSS-8 comprises all 8 and the
      sNIHSS-5, the first 5. In the validation models, C statistics were NIHSS-15=0.80,
      sNIHSS-8=0.77, and sNIHSS-5=0.76. Statistical comparisons suggested that the
      NIHSS-15 had better predictive performance than the sNIHSS-8 or the sNIHSS-5; the
      absolute difference in C statistics was small. There was no significant
      difference between the sNIHSS-8 and the sNIHSS-5. CONCLUSIONS: Much of the
      predictive performance of the full NIHSS-15 was retained with a shortened scale,
      the sNIHSS-5. Shortening the NIHSS-15 will facilitate its use during prehospital
      evaluations. The sNIHSS severity information may be useful to triage acute stroke
      patients in communities and to provide a baseline stroke severity for prehospital
      acute stroke trials.

PMID- 12468774
TI  - Sudden deafness and anterior inferior cerebellar artery infarction.
AB  - BACKGROUND AND PURPOSE: Acute ischemic stroke in the distribution of the anterior
      inferior cerebellar artery (AICA) is known to be associated with vertigo,
      nystagmus, facial weakness, and gait ataxia. Few reports have carefully examined
      the deafness associated with the AICA infarction. Furthermore, previous
      neurological reports have not emphasized the inner ear as a localization of
      sudden deafness. The aim of this study was to investigate the incidence of
      deafness associated with the AICA infarction and the sites predominantly involved
      in deafness. METHODS: Over 2 years, we prospectively identified 12 consecutive
      patients with unilateral AICA infarction diagnosed by brain MRI. Pure-tone
      audiogram, speech discrimination testing, stapedial reflex testing, and auditory
      brainstem response were performed to localize the site of lesion in the auditory
      pathways. Electronystagmography was also performed to evaluate the function of
      the vestibular system. RESULTS: The most common affected site on brain MRI was
      the middle cerebellar peduncle (n=11). Four patients had vertigo and/or acute
      auditory symptoms such as hearing loss or tinnitus as an isolated manifestation
      from 1 day to 2 months before infarction. Audiological testings confirmed
      sensorineural hearing loss in 11 patients (92%), predominantly cochlear in 6
      patients, retrocochlear in 1 patient, and combined on the affected side cochlear
      and retrocochlear in 4 patients. Electronystagmography demonstrated no response
      to caloric stimulation in 10 patients (83%). CONCLUSIONS: In our series, sudden
      deafness was an important sign for the diagnosis of AICA infarction. Audiological
      examinations suggest that sudden deafness in AICA infarction is usually due to
      dysfunction of the cochlea resulting from ischemia to the inner ear.

PMID- 12468776
TI  - MOSAIC: Multimodal Stroke Assessment Using Computed Tomography: novel diagnostic
      approach for the prediction of infarction size and clinical outcome.
AB  - BACKGROUND AND PURPOSE: With new CT technologies, including CT angiography (CTA),
      perfusion CT (PCT), and multidetector row technique, this method has regained
      interest for use in acute stroke assessment. We have developed a score system
      based on Multimodal Stroke Assessment Using CT (MOSAIC), which was evaluated in
      this prospective study. METHODS: Forty-four acute stroke patients (mean age, 63.8
      years) were enrolled within a mean of 3.0+/-1.9 hours after symptom onset. The
      MOSAIC score (0 to 8 points) was generated by results of the 3 sequential CT
      investigations: (1) presence and amount of early signs of infarction on
      noncontrast CT (NCCT; 0 to 2 points), (2) stenosis (>50%) or occlusion of the
      distal internal carotid or middle cerebral artery on CTA (0 to 2 points), and (3)
      presence and amount of reduced cerebral blood flow on 2 adjacent PCT slices (0 to
      4 points). The predictive value of the MOSAIC score was compared with each single
      CT component with respect to the final size of infarction and the clinical
      outcome 3 months after stroke by use of the modified Rankin Scale (mRS) and the
      Barthel Index (BI). RESULTS: Among the CT components, PCT showed the best
      correlation to infarction size (r=0.75) and clinical outcome (r=0.60 to 0.62)
      compared with NCCT (r=0.43 to 0.58) and CTA (r=0.47 to 0.71). The MOSAIC score
      showed consistently higher correlation factors (r=0.67 to 0.78) and higher
      predictive values (0.73 to 1.0) than all single CT components with respect to
      outcome measures. A MOSAIC score <4 predicted independence with 89% to 96%
      likelihood (mRS </=2, BI >/=90); a MOSAIC score <5 predicted fair outcome with
      96% to 100% likelihood (mRS </=3, BI >/=60). CONCLUSIONS: The MOSAIC score based
      on multidetector row CT technology is superior to NCCT, CTA, and PCT in
      predicting infarction size and clinical outcome in hyperacute stroke.

PMID- 12468775
TI  - AMPA antagonist ZK200775 in patients with acute ischemic stroke: possible glial
      cell toxicity detected by monitoring of S-100B serum levels.
AB  - BACKGROUND AND PURPOSE: S-100B and neuron-specific enolase (NSE) serum
      concentrations can be used as peripheral markers of glial cell and neuronal
      damage, respectively. We investigated these markers in a clinical trial with the
      alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist ZK200775
      in acute ischemic stroke patients. METHODS: In a multicenter, double-blind,
      randomized, placebo-controlled phase 2 trial, 61 ischemic stroke patients were
      treated with either placebo or active drug in a dose-finding design. Twenty-five
      patients received placebo, 12 patients received a total dose of 262.5 mg in 48
      hours (dose group 1), and 13 patients received a total dose of 525 mg in 48 hours
      (dose group 2). Eleven patients received a total dose of 105 mg over a period of
      6 hours (dose group 3; reduction of total dose and infusion time because of
      adverse events in group 2). Serum concentrations of S-100B and NSE were analyzed
      with the use of a monoclonal sandwich immunoluminometric assay. Neurological
      outcome was assessed with the National Institutes of Health Stroke Scale (NIHSS).
      RESULTS: In group 2 there was a significant transient worsening in the mean NIHSS
      score 48 hours after the start of treatment. The mean increase was 11 points.
      This was due to reduction of consciousness (stupor and coma) in 8 of 13 patients.
      Neurological deterioration in group 2 was associated with a higher increase of S
      100B concentrations, but not of NSE concentrations, than in the placebo group.
      The trial was stopped prematurely for safety reasons. CONCLUSIONS: The AMPA
      antagonist ZK200775 transiently worsened the neurological condition in patients
      with acute ischemic stroke. Our results suggest that in addition to neuronal
      dysfunction, glial cell toxicity may have occurred. It may be useful to introduce
      monitoring of serum markers of brain damage in phase 2 trials with glutamate
      receptor antagonists.

PMID- 12468777
TI  - Visual rating scales for age-related white matter changes (leukoaraiosis): can
      the heterogeneity be reduced?
AB  - BACKGROUND AND PURPOSE: It has been hypothesized that the use of different visual
      rating scales partly explains the discordant results of studies investigating
      risk factors and clinical correlates of age-related cerebral white matter changes
      (leukoaraiosis). We aimed to compare 6 widely used rating scales for
      leukoaraiosis and to calculate conversion coefficients of the score of 1 scale in
      the score of a second scale. METHODS: Two trained raters evaluated 80 pairs of CT
      and MRI scans using 2 CT and 4 MRI rating scales for white matter changes.
      Correlations among the scales were evaluated and regression lines were
      constructed with each of the CT and MRI scale scores as variables. RESULTS: A
      high correlation was observed in all the paired comparisons of the 6 scales
      (Spearman's rho ranging from 0.85 to 0.96, P<0.0001). Using regression analysis,
      we determined numeric parameters to transform the score of 1 scale to the
      corresponding score for each of the remaining scales and relative confidence
      intervals. The predictive values of these conversions expressed as R(2) ranged
      from 0.75 to 0.92. CONCLUSIONS: The present findings support the view that a good
      correlation exists among the considered visual rating scales for white matter
      changes. With the limitation that conversion parameters are calculated by
      applying a linear regression to partly nonlinear scales, their use allows
      comparison of the results of previous studies that used different scales and to
      pool data from past and ongoing clinical trials.

PMID- 12468778
TI  - Contrast-enhanced magnetic resonance angiography of carotid arteries: utility in
      routine clinical practice.
AB  - BACKGROUND AND PURPOSE: Contrast-enhanced magnetic resonance angiography (CEMRA)
      is among the newer noninvasive tests used for the evaluation of patients with
      carotid artery disease. Evidence supporting its utility in routine clinical
      practice is lacking. METHODS: The results of CEMRA were compared with those of
      catheter angiography in 50 consecutive patients being evaluated for carotid
      endarterectomy (CEA) at a community hospital. Using indications for CEA based on
      published guidelines, we determined the rate of misclassification for surgery,
      sensitivity, specificity, and positive and negative predictive values. In
      addition, the interrater agreement (kappa score) of CEMRA was compared with that
      of catheter angiography in the studied population and with interpretations
      provided by 2 blinded radiologists. RESULTS: Compared with catheter angiography,
      24% (95% CI, 12% to 36%) of patients would have been misclassified for CEA on the
      basis of CEMRA results alone. CEMRA was associated with sensitivity of 92%,
      specificity of 62%, positive predictive value of 78%, and negative predictive
      value of 89%. When both CEMRA and duplex Doppler ultrasound were performed and
      the results were concordant, the misclassification rate decreased to 17% (95% CI,
      2% to 32%). kappa scores were similar for CEMRA and catheter angiography (0.72
      and 0.75, respectively). CONCLUSIONS: CEMRA was found to be highly sensitive for
      detection of surgically amenable carotid stenosis. kappa scores for the
      interpretation of CEMRA and catheter angiography were similar. However,
      clinicians should be cautious when using CEMRA alone for surgical decision making
      in CEA candidates because a significant number of patients may be misclassified.
      The rate of misclassification is reduced when the results of CEMRA and duplex
      Doppler ultrasound are concordant.

PMID- 12468779
TI  - Multiparametric MRI ISODATA ischemic lesion analysis: correlation with the
      clinical neurological deficit and single-parameter MRI techniques.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to show that the computer
      segmentation algorithm Iterative Self-Organizing Data Analysis Technique
      (ISODATA), which integrates multiple MRI parameters (diffusion-weighted imaging
      [DWI], T2-weighted imaging [T2WI], and T1-weighted imaging [T1WI]) into a single
      composite image, is capable of defining the ischemic lesion in a time-independent
      manner equally as well as the MRI techniques considered the best for each phase
      after stroke onset (ie, perfusion weighted imaging [PWI] and DWI for the acute
      phase and T2WI for the outcome phase). METHODS: We measured MRI parameters of
      PWI, DWI, T2WI, and T1WI from patients at the acute phase (<30 hours) and DWI,
      T2WI, and T1WI at the outcome phase (3 months) of ischemic stroke. The clinical
      neurological deficit was graded with the National Institutes of Health Stroke
      Scale (NIHSS). We compared the ISODATA lesion size with the PWI, DWI, and T2WI
      lesion sizes measured within the same slice at each phase. The lesion sizes were
      also correlated with NIHSS score of each phase. RESULTS: We included 11 patients;
      9 (82%) were women, and 7 (64%) were black. The mean+/-SD age was 65.5+/-9.3
      years (range, 45 to 82 years). The median NIHSS score was 15 (minimum, 4;
      maximum, 24)at the acute phase and 3 (minimum, 0; maximum, 22) at the outcome
      phase. The median time interval from stroke symptom onset to the acute MRI study
      was 10 hours (range, 6 to 29 hours), and the mean time interval to the outcome
      study was 93+/-11 days (range, 72 to 106 days). In the acute phase, the ISODATA
      lesion size had high correlation with the PWI lesion size (r=0.95; 95% CI, 0.89
      to 0.98; P<0.0001), DWI lesion size (r=0.83; 95% CI, 0.66 to 0.92; P<0.0001), and
      T2WI lesion size (r=0.67; 95% CI, 0.39 to 0.84; P=0.008) and moderate correlation
      with NIHSS score (r=0.59; 95% CI, 0.02 to 0.88; P=0.06). In the outcome phase,
      the ISODATA lesion size had high correlation with the T2WI lesion size (r=0.97;
      95% CI, 0.94 to 0.99; P<0.0001) and NIHSS score (r=0.78; 95% CI, 0.34 to 0.94;
      P=0.004). CONCLUSIONS: The integrated ISODATA method can identify and
      characterize the ischemic lesion independently of time elapsed since stroke
      onset. The ISODATA lesion size highly correlates with the PWI and DWI lesion size
      in the acute phase and with the T2WI lesion size in the outcome phase of ischemic
      stroke, as well as with the clinical neurological status of the patient.

PMID- 12468781
TI  - Oral citicoline in acute ischemic stroke: an individual patient data pooling
      analysis of clinical trials.
AB  - BACKGROUND AND PURPOSE: No single neuroprotective agent has been shown to
      influence outcome after acute stroke. Citicoline has been studied worldwide in
      many clinical trials with positive findings, but only 1 trial has obtained
      significant results in the primary efficacy variables. Our objective was to
      evaluate the effects of oral citicoline in patients with acute ischemic stroke by
      a data pooling analysis of clinical trials. The primary efficacy end point chosen
      was the common evaluation of recovery, combining National Institutes of Health
      Stroke Scale </=1, modified Rankin Scale score </=1, and Barthel Index >/=95 at 3
      months using the generalized estimating equations analysis. METHODS: A systematic
      search of all prospective, randomized, placebo-controlled, double-blind clinical
      trials with oral citicoline (MEDLINE, Cochrane, and Ferrer Group bibliographic
      databases) was undertaken. Individual patient data were extracted from each study
      and pooled in a single data file. The main inclusion criteria included compatible
      neuroimaging with ischemic stroke, National Institutes of Health Stroke Scale
      >/=8, and prior modified Rankin Scale score </=1. Four clinical trials using
      various doses of oral citicoline (500, 1000, and 2000 mg) were identified.
      RESULTS: Of 1652 randomized patients, 1372 fulfilled the inclusion criteria (583
      received placebo, 789 received citicoline). Recovery at 3 months was 25.2% in
      citicoline-treated patients and 20.2% in placebo-treated patients (odds ratio
      [OR], 1.33; 95% CI, 1.10 to 1.62; P=0.0034). The dose showing the largest
      difference with placebo was 2000 mg, with 27.9% of patients achieving recovery
      (OR, 1.38; 95% CI, 1.10 to 1.72; P=0.0043). The overall safety of citicoline was
      similar to placebo. CONCLUSIONS: Treatment with oral citicoline within the first
      24 hours after onset in patients with moderate to severe stroke increases the
      probability of complete recovery at 3 months.

PMID- 12468780
TI  - Low concentration of serum total cholesterol is associated with multifocal signal
      loss lesions on gradient-echo magnetic resonance imaging: analysis of risk
      factors for multifocal signal loss lesions.
AB  - BACKGROUND AND PURPOSE: Multifocal signal loss lesions (MSLLs) on T2*-weighted
      gradient-echo (GE) MRI are believed to be microbleeds histopathologically.
      Previous epidemiological studies suggested that low serum cholesterol is
      associated with the increased risk of intracerebral hemorrhage. We investigated
      risk factors of MSLLs and the relationship between lipid profiles and MSLLs on GE
      MRI. METHODS: We included consecutively 172 patients who underwent brain MRI.
      MSLLs on GE-MRI were counted by 2 neurologists separately and graded by
      consensus. The concentrations of lipid profiles were categorized as quartiles,
      and the MSLLs were graded as absent (total count, 0), mild (1 to 2), moderate (3
      to 10), and severe (>10). RESULTS: The mean concentrations of total cholesterol
      and low-density lipoprotein cholesterol were significantly lower in patients with
      a severe degree of MSLLs than in those without MSLL (P<0.05). By multivariate
      analysis, MSLLs were significantly correlated with hypertension (odds ratio [OR],
      3.42; 95% CI, 1.17 to 9.97), leukoaraiosis (OR, 4.62; 95% CI, 2.87 to 7.41), the
      lowest quartile of serum total cholesterol (<4.27 mmol/L; OR, 10.91; 95% CI, 3.98
      to 25.57), and the highest quartile of high-density lipoprotein (>1.47 mmol/L;
      OR, 3.5; 95% CI, 1.45 to 8.29). CONCLUSIONS: Our results suggest that both the
      lipid profile levels and the severity of hypertension may be closely associated
      with MSLLs on GE-MRI.

PMID- 12468783
TI  - Analysis of the safety and efficacy of intra-arterial thrombolytic therapy in
      ischemic stroke.
AB  - BACKGROUND AND PURPOSE: Intra-arterial thrombolytic therapy (IAT) may be a
      treatment option for patients with ischemic stroke. We analyzed the safety and
      efficacy of IAT on the basis of published data. METHODS: We searched computerized
      databases for studies using IAT in >/=10 patients with ischemic stroke. Some
      studies had control patients for comparison. Data were collected on age, stroke
      territory, time to treatment, medication, site of arterial occlusion and
      recanalization on angiogram, outcomes, and symptomatic intracranial hemorrhage
      (SICH). RESULTS: The analysis included 27 studies with 852 patients who received
      IAT and 100 control subjects. There were more favorable outcomes in the IAT than
      in the control group (41.5% versus 23%, P=0.002), with a lower mortality rate for
      IAT (IAT, 27.2%; control group, 40%, P=0.004). The IAT group had an odds ratio of
      2.4 (95% CI, 1.45 to 3.85) for favorable outcome. SICH was more frequent in the
      IAT group compared with the control group (9.5% versus 3%, P=0.046). The subgroup
      of patients receiving a combination of intravenous thrombolytic therapy and IAT
      had more favorable outcomes than the IAT alone subgroup, but this trend did not
      reach statistical significance (53.6% versus 41.5%, P=0.1). Among the patients
      treated with IAT, those who had supratentorial strokes were more likely to have
      favorable outcomes than those with infratentorial strokes (42.2% versus 25.6%;
      P=0.001; odds ratio, 2.0; 95% CI, 1.33 to 3.0). CONCLUSIONS: IAT for ischemic
      stroke appears efficacious but carries an increased risk of SICH. Further
      prospective studies are needed to prove the safety and efficacy of IAT in stroke.

PMID- 12468782
TI  - Prospective, randomized, double-blind trial investigating the effect of
      doxycycline on matrix metalloproteinase expression within atherosclerotic carotid
      plaques.
AB  - BACKGROUND AND PURPOSE: Elevated levels of matrix metalloproteinases (MMPs),
      particularly MMP-1 and MMP-9, have been implicated in plaque rupture. It has been
      suggested that inhibition of MMPs may stabilize vulnerable atherosclerotic
      plaques and improve clinical outcome. The aim of the study was to investigate the
      ability of doxycycline, a nonspecific MMP inhibitor, to reduce MMP concentration
      in carotid atheroma. METHODS: The study design was a prospective, double-blind
      randomized trial. One hundred patients requiring carotid endarterectomy were
      randomized to receive 200 mg/d doxycycline or placebo for 2 to 8 weeks before
      surgery. During endarterectomy, carotid plaques were retrieved. The
      concentrations of MMPs and doxycycline were determined in the atherosclerotic
      tissue by enzyme-linked immunosorbent assay and high-performance liquid
      chromatography, respectively. Clinical events were recorded, as was the rate of
      preoperative embolization (transcranial Doppler). RESULTS: Analysis of
      endarterectomized specimens demonstrated a mean doxycycline concentration of 6.0
      micro g/g wet weight in treated patients. Administration of doxycycline
      significantly reduced the concentration of MMP-1 in carotid plaques from a mean
      of 14.8 to 10.3 ng/100g wet weight (P=0.038). This difference was due to
      decreased MMP-1 transcript (P<0.001). There was no difference in any other MMP
      (MMP-2, -3, or -9) or tissue inhibitor of matrix metalloproteinases-1 or -2.
      CONCLUSIONS: Doxycycline penetrated atherosclerotic plaques with acceptable
      tissue levels. This resulted in a reduction in MMP-1 concentration because of
      decreased expression.

PMID- 12468784
TI  - Direct percutaneous transluminal angioplasty for acute middle cerebral artery
      trunk occlusion: an alternative option to intra-arterial thrombolysis.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the safety and
      efficacy of direct percutaneous transluminal angioplasty (PTA) for patients with
      acute middle cerebral artery (MCA) trunk occlusion. METHODS: Over the past 9
      years, a total of 70 patients with acute MCA trunk occlusion were treated with
      intra-arterial reperfusion therapy. In the last 5 years, 34 patients were treated
      with direct PTA, and subsequent thrombolytic therapy was added if necessary for
      distal embolization. The other 36 patients, mainly in the first 4 years, were
      treated with thrombolytic therapy alone and were used as controls. Pretherapeutic
      neurological status was evaluated with National Institutes of Health Stroke Scale
      scores. The modified Rankin Scale (mRS) was used to assess clinical outcome at 90
      days. RESULTS: There were no significant differences in pretherapeutic National
      Institutes of Health Stroke Scale score and duration of ischemia between the 2
      groups. The rate of partial or complete recanalization in the PTA group was
      91.2%, whereas that in the thrombolysis-alone group was 63.9% (P<0.01). The
      incidence of large parenchymal hematoma with neurological deterioration in the
      PTA group was 2.9%, while that in the thrombolysis-alone group was 19.4%
      (P=0.03). Although direct PTA did not improve the rate of favorable outcome (mRS
      score 0 or 1; 41.7% for the thrombolysis-alone group versus 52.9% for the PTA
      group; P=0.48), outcome in terms of independence (mRS score 0, 1, 2) was
      significantly better in the PTA group (73.5%) than in the thrombolysis-alone
      group (50.0%; P=0.04). CONCLUSIONS: Although definitive conclusions on the
      comparative merits of these 2 therapies cannot be drawn because of an open trial,
      direct PTA may be an effective alternative option to intra-arterial thrombolysis
      for acute MCA trunk occlusion.

PMID- 12468785
TI  - Long-term outcome after angioplasty for symptomatic extracranial carotid stenosis
      in poor surgical candidates.
AB  - BACKGROUND AND PURPOSE: The optimal treatment of patients with symptomatic
      carotid stenosis who are poor surgical candidates is uncertain. The purposes of
      this study were to report the long-term outcome after angioplasty in a series of
      these patients and to compare these data with historical control data from the
      North American Symptomatic Carotid Endarterectomy Trial (NASCET). METHODS: We
      identified 42 consecutive patients with >70% carotid stenosis and ipsilateral
      ischemic symptoms within 120 days of treatment with angioplasty. All were
      considered poor surgical candidates by experienced surgeons. Baseline
      epidemiological stroke risk factors were obtained from review of medical records.
      Follow-up was from clinic records and by telephone. RESULTS: Baseline
      epidemiological stroke risk factors were similar to those of medically treated
      NASCET patients. Angioplasty patients tended to have higher degrees of stenosis
      (45% with >90% stenosis versus 24% in NASCET) and more frequent contralateral
      stenosis or occlusion (30% versus 9%) than NASCET patients. Three patients
      suffered procedural strokes; 2 of the 3 made nearly complete recoveries. One
      additional patient suffered a central retinal occlusion 48 hours after
      angioplasty. No ipsilateral strokes occurred during the mean follow-up period of
      1.7 years. Three patients were lost to follow-up. The cumulative risk of stroke
      was 9.5% (4 of 42) compared with 26% at 2 years for medically treated patients in
      NASCET. CONCLUSIONS: These pilot data suggest a beneficial effect of angioplasty
      for patients with high-grade symptomatic carotid stenosis who are not good
      surgical candidates.

PMID- 12468786
TI  - A pilot study of event-related functional magnetic resonance imaging of monitored
      wrist movements in patients with partial recovery.
AB  - BACKGROUND AND PURPOSE: Previous functional imaging studies of motor recovery
      after stroke have investigated cerebral activation during periods of repetitive,
      often complex, movement. This article reports the use of an event-related
      approach to study activation associated with isolated simple movements (wrist
      extension). This allows investigation of the pattern of the motor response and
      corresponding brain activation on a trial-by-trial basis. Patients with partial
      recovery can be assessed, and allowance can be made for abnormalities in the
      shape of hemodynamic responses. METHODS: Functional MRI at 3 T was performed
      during a series of isolated, near-isometric wrist extension movements. A visual
      tracking procedure was used to elicit forces of 10% and 20% of maximum voluntary
      contraction. Force output from both wrists was monitored continuously. A voxel
      wise procedure was used to fit the optimum hemodynamic response functions in each
      case. RESULTS: Three chronic stage patients with partial recovery were
      successfully scanned and compared with 8 healthy controls. The patients showed
      well-lateralized motor responses but inaccurate control of force. During movement
      of the paretic wrist, we observed excessive activation of the ipsilateral primary
      motor cortex and increased relative activation of the supplementary motor area
      compared with movement of the nonparetic side. In the primary motor area,
      hemodynamic responses peaked more quickly on the ipsilateral side in 2 patients
      for movements of the paretic hand, whereas controls showed the opposite trend.
      CONCLUSIONS: An event-related approach can be used to study the relationship
      between motor responses and cerebral activation in patients with partial
      recovery. These preliminary findings suggest that excessive activation in
      ipsilateral motor cortex and secondary motor areas remains evident under these
      tightly controlled conditions and cannot be ascribed to mirror movements or
      abnormalities in the timing of the blood oxygen level-dependent (BOLD) response.
      However, close monitoring of motor responses also makes evident continuing
      impairment in motor skill, which makes comparison with activation in normal
      controls difficult.

PMID- 12468787
TI  - Brief comprehensive quality of life assessment after stroke: the assessment of
      quality of life instrument in the north East melbourne stroke incidence study
      (NEMESIS).
AB  - BACKGROUND AND PURPOSE: Generic utility health-related quality of life
      instruments are useful in assessing stroke outcome because they facilitate a
      broader description of the disease and outcomes, allow comparisons between
      diseases, and can be used in cost-benefit analysis. The aim of this study was to
      validate the Assessment of Quality of Life (AQoL) instrument in a stroke
      population. METHODS: Ninety-three patients recruited from the community-based
      North East Melbourne Stroke Incidence Study between July 13, 1996, and April 30,
      1997, were interviewed 3 months after stroke. Validity of the AQoL was assessed
      by examining associations between the AQoL and comparator instruments: the
      Medical Outcomes Short-Form Health Survey (SF-36); London Handicap Scale; Barthel
      Index; National Institutes of Health Stroke Scale; and Irritability, Depression,
      Anxiety scale. Sensitivity of the AQoL was assessed by comparing AQoL scores from
      groups of patients categorized by severity of impairment and disability and with
      total anterior circulation syndrome (TACS) versus non-TACS. Predictive validity
      was assessed by examining the association between 3-month AQoL scores and
      outcomes of death or institutionalization 12 months after stroke. RESULTS:
      Overall AQoL utility scores and individual dimension scores were most highly
      correlated with relevant scales on the comparator instruments. AQoL scores
      clearly differentiated between patients in categories of severity of impairment
      and disability and between patients with TACS and non-TACS. AQoL scores at 3
      months after stroke predicted death and institutionalization at 12 months.
      CONCLUSIONS: The AQoL demonstrated strong psychometric properties and appears to
      be a valid and sensitive measure of health-related QoL after stroke.

PMID- 12468788
TI  - Treadmill training with partial body weight support and an electromechanical gait
      trainer for restoration of gait in subacute stroke patients: a randomized
      crossover study.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to compare treadmill and
      electromechanical gait trainer therapy in subacute, nonambulatory stroke
      survivors. The gait trainer was designed to provide nonambulatory subjects the
      repetitive practice of a gait-like movement without overexerting therapists.
      METHODS: This was a randomized, controlled study with a crossover design
      following an A-B-A versus a B-A-B pattern. A consisted of 2 weeks of gait trainer
      therapy, and B consisted of 2 weeks of treadmill therapy. Thirty nonambulatory
      hemiparetic patients, 4 to 12 weeks after stroke, were randomly assigned to 1 of
      the 2 groups receiving locomotor therapy every workday for 15 to 20 minutes for 6
      weeks. Weekly gait ability (functional ambulation category [FAC]), gait velocity,
      and the required physical assistance during both kinds of locomotor therapy were
      the primary outcome measures, and other motor functions (Rivermead motor
      assessment score) and ankle spasticity (modified Ashworth score) were the
      secondary outcome measures. Follow-up occurred 6 months later. RESULTS: The
      groups did not differ at study onset with respect to the clinical characteristics
      and effector variables. During treatment, the FAC, gait velocity, and Rivermead
      scores improved in both groups, and ankle spasticity did not change. Median FAC
      level was 4 (3 to 4) in group A compared with 3 (2 to 3) in group B at the end of
      treatment (P=0.018), but the difference at 6-month follow up was not significant.
      The therapeutic effort was less on the gait trainer, with 1 instead of 2
      therapists assisting the patient at study onset. All but seven patients preferred
      the gait trainer. CONCLUSIONS: The newly developed gait trainer was at least as
      effective as treadmill therapy with partial body weight support while requiring
      less input from the therapist. Further studies are warranted.

PMID- 12468789
TI  - Monitoring disease progression in CADASIL with diffusion magnetic resonance
      imaging: a study with whole brain histogram analysis.
AB  - BACKGROUND AND PURPOSE: In cerebral autosomal dominant arteriopathy with
      subcortical infarcts and leukoencephalopathy (CADASIL), a large increase in water
      diffusion has been found both inside and outside the cerebral lesions as detected
      on conventional MRI. The aim of the present study was to assess the sensitivity
      of diffusion tensor imaging for monitoring the progression of cerebral tissue
      damage during the course of CADASIL. METHODS: With the use of diffusion tensor
      imaging, whole brain trace of the diffusion tensor [Trace(D)] histograms were
      obtained in 22 CADASIL patients and 12 age-matched controls at baseline, in 14
      patients after a mean delay of 21 months, and in 5 controls after a mean delay of
      29 months. Parameters derived from these histograms (mean value, peak height, and
      peak location) were analyzed at baseline and during the follow-up. RESULTS: At
      baseline, all the histogram parameters differed between patients and controls and
      were found to be significantly correlated with both the Mini-Mental State
      Examination score and Rankin Scale score in the patient group. The follow-up
      study showed a decrease in the peak height associated with an increase in the
      mean value of whole brain Trace(D) histograms in the 14 CADASIL patients scanned
      twice. The diffusion changes appeared larger in the patients whose Rankin score
      increased during the study period. CONCLUSIONS: These results suggest that the
      measurement of water diffusion over time is a sensitive marker for the
      progression of tissue damage in the brain. Thus, quantitative diffusion MRI can
      be used to monitor disease progression in CADASIL and possibly in other types of
      small-vessel brain disorders.

PMID- 12468790
TI  - Diffusion- and perfusion-weighted magnetic resonance imaging of the brain before
      and after coronary artery bypass grafting surgery.
AB  - BACKGROUND AND PURPOSE: Coronary artery bypass grafting (CABG) is a frequently
      performed surgical procedure that can be associated with neurological
      complications. Some studies have demonstrated that new focal brain lesions,
      detected by MRI, can develop after CABG. Furthermore, it has been suggested that
      the presence of such new lesions is associated with a decline in neurocognitive
      test scores. Advanced MRI techniques, including diffusion- (DWI) and perfusion
      weighted imaging (PWI), offer important diagnostic advantages over conventional
      imaging in the assessment of patients undergoing CABG. We sought to determine
      whether focal PWI and DWI abnormalities could occur after CABG, particularly in
      patients without any measurable neurological deterioration. METHODS: Thirteen
      patients prospectively underwent MRI with DWI and PWI before and after CABG. A
      battery of neurocognitive tests was administered before and after surgery.
      Demographic, clinical, and radiographic characteristics of the patients were
      collected and compared. RESULTS: Four patients developed new DWI defects after
      CABG. The lesions were small, rounded, and multiple (3 of 4 patients). One of
      these patients was diagnosed with stroke on clinical grounds. The patients with
      new lesions had a larger neurocognitive decline than their counterparts with
      stable MRI. Other clinical characteristics of patients with new DWI lesions,
      including stroke risk factors, were similar to those of patients without MRI
      changes. No focal perfusion abnormalities were observed on preoperative or
      postoperative scans. CONCLUSIONS: Postoperative DWI abnormalities can occur after
      CABG, even in patients without overt neurological defects. The PWI scans remained
      unchanged. Larger prospective studies are required to determine whether the new
      lesions are clearly associated with neurocognitive decline or with specific
      perioperative stroke risk factors.

PMID- 12468791
TI  - Carotid plaque area: a tool for targeting and evaluating vascular preventive
      therapy.
AB  - BACKGROUND AND PURPOSE: Carotid plaque area measured by ultrasound (cross
      sectional area of longitudinal views of all plaques seen) was studied as a way of
      identifying patients at increased risk of stroke, myocardial infarction, and
      vascular death. METHODS: Patients from an atherosclerosis prevention clinic were
      followed up annually for up to 5 years (mean, 2.5+/-1.3 years) with baseline and
      follow-up measurements recorded. Plaque area progression (or regression) was
      defined as an increase (or decrease) of >/=0.05 cm(2) from baseline. RESULTS:
      Carotid plaque areas from 1686 patients were categorized into 4 quartile ranges:
      0.00 to 0.11 cm(2) (n=422), 0.12 to 0.45 cm(2) (n=424), 0.46 to 1.18 cm(2)
      (n=421), and 1.19 to 6.73 cm(2) (n=419). The combined 5-year risk of stroke,
      myocardial infarction, and vascular death increased by quartile of plaque area:
      5.6%, 10.7%, 13.9%, and 19.5%, respectively (P<0.001) after adjustment for all
      baseline patient characteristics. A total of 1085 patients had >/=1 annual
      carotid plaque area measurements: 685 (63.1%) had carotid plaque progression, 306
      (28.2%) had plaque regression, and 176 (16.2%) had no change in carotid plaque
      area over the period of follow-up. The 5-year adjusted risk of combined outcome
      was 9.4%, 7.6%, and 15.7% for patients with carotid plaque area regression, no
      change, and progression, respectively (P=0.003). CONCLUSIONS: Carotid plaque area
      and progression of plaque identified high-risk patients. Plaque measurement may
      be useful for targeting preventive therapy and evaluating new treatments and
      response to therapy and may improve cost-effectiveness of secondary preventive
      treatment.

PMID- 12468792
TI  - Association of obesity and central fat distribution with carotid artery wall
      thickening in middle-aged women.
AB  - BACKGROUND AND PURPOSE: The association between obesity and atherosclerotic
      disease is controversial. In the present analysis, we evaluated whether common
      carotid intima-media thickness (IMT) and area, 2 markers of preclinical
      atherosclerosis, were increased in obese subjects. METHODS: More than 5000 middle
      aged women (n=5062; age, 30 to 69 years) living in the area of Naples, Southern
      Italy, were recruited for a prospective, currently ongoing study on the etiology
      of cardiovascular disease and cancer in the female population (the Progetto ATENA
      study). A subsample of 310 participants underwent high-resolution B-mode
      ultrasound examination, and the IMTs, intima-media areas, and lumen diameters of
      common carotid arteries were measured with a semiautomated computerized program.
      Subjects were divided into 3 groups on the basis of the recently published
      obesity guidelines for body mass index (BMI), a marker of general obesity, and
      tertiles of waist-to-hip ratio (WHR), a marker of regional obesity. RESULTS:
      Women with a BMI >/=30 kg/m(2) showed higher systolic and diastolic blood
      pressures, triglycerides, and fasting glucose and insulin, as well as lower high
      density lipoprotein concentrations, than subjects with lower BMI. A gradual
      increase in common carotid IMT and intima-media area was observed when lean women
      (0.94+/-0.01 mm and 19.8+/-0.5 mm(2), respectively) were compared with overweight
      (0.98+/-0.01 mm and 21.0+/-0.4 mm(2)) and obese (1.02+/-0.02 mm and 22.6+/-0.8
      mm(2), P<0.005 for linear trend) individuals. Similarly, women in the highest
      tertile of WHR (>0.85) had adverse risk factor profiles and thicker carotid
      intima-media complex than those in the first 2 tertiles (P<0.01 and P<0.05 for
      IMT and intima-media area, respectively). In multivariate analyses, BMI and WHR
      were significant predictors of carotid wall thickness, independently of other
      traditional and nontraditional cardiovascular risk factors (age, blood pressure,
      lipid abnormalities, fasting insulin). CONCLUSIONS: The present results indicate
      a graded and independent association between general and abdominal obesity
      reflected by high BMI and WHR-and carotid artery wall thickening in a population
      of middle-aged women.

PMID- 12468793
TI  - Association between behavior-dependent cardiovascular risk factors and
      asymptomatic carotid atherosclerosis in a general population.
AB  - BACKGROUND AND PURPOSE: Physical inactivity and unfavorable dietary and lifestyle
      patterns are related to cardiovascular disease and premature death. Their
      relationship to atherosclerosis of the carotid arteries and subsequent stroke is
      unclear. The objective of this study was to investigate the association between
      those behavioral cardiovascular risk factors and asymptomatic atherosclerosis of
      the carotid arteries in a population of former East Germany. METHODS: The Study
      of Health in Pomerania (SHIP) is a cross-sectional survey in northeast Germany.
      In 1632 individuals aged 45 to 70 years, high-resolution B-mode ultrasound was
      used to assess the mean intima-media thickness of the right and left common
      carotid arteries. Carotid plaques and stenosis were recorded. Physical activity,
      dietary patterns, and cardiovascular risk factors were assessed in interviews
      with the use of standardized scales. Physically active participants with optimal
      dietary patterns were classified in the optimal lifestyle group, and those
      inactive with unfavorable diet were classified in the unfavorable group. RESULTS:
      After adjustment for sex and age, significant decreasing trends were found for
      both intima-media thickness and severe asymptomatic atherosclerosis from
      unfavorable to optimal lifestyle patterns in never smokers but not in smokers.
      Regression analysis revealed an increased risk of severe asymptomatic
      atherosclerosis in subjects with an unfavorable lifestyle pattern compared with
      those with an optimal pattern (odds ratio 2.68; 95% CI, 1.13 to 6.37), following
      a significant linear trend. CONCLUSIONS: Physical activity and optimal diet are
      associated with reduced risk of early atherosclerosis in subjects who never
      smoked, while no benefit of an otherwise optimal lifestyle is observed in
      smokers.

PMID- 12468794
TI  - Carotid endarterectomy and race: do clinical indications and patient preferences
      account for differences?
AB  - BACKGROUND AND PURPOSE: Carotid endarterectomy (CE) has been proved to reduce the
      risk of stroke for certain patients, but black patients are less likely than
      whites to receive CE. The purpose of this work was to determine the importance of
      clinical indications and patient preferences in predicting the use of carotid
      angiography and CE in a racially stratified sample of patients. METHODS: Between
      1997 and 1999, 708 patients with at least 1 carotid artery containing a >/=50%
      stenosis were enrolled (617 whites, 91 blacks) from 5 Veteran Affairs Medical
      Centers. Patient interviews were conducted at the time of the index carotid
      ultrasound, and each patient was followed up for 6 months to determine clinical
      events and receipt of carotid angiography or CE. RESULTS: Black and white
      patients were similar in terms of age, sex, education level, and social support.
      More black than white patients received ultrasound for a completed stroke (36%
      versus 13%), and fewer black patients were classified as asymptomatic (56% versus
      70%) or as having had a TIA (8% versus 17%; P<0.001). Health-related quality of
      life scores, trust in physician, and medical comorbidity scores were similar for
      black and white patients. Black patients expressed higher aversion to CE than
      white patients (31% versus 15% in the highest aversion quartile for blacks and
      whites, respectively; P=0.01). During follow-up, 20% of white patients and 14% of
      black patients received CE (P=0.19). In adjusted analyses, only patient clinical
      status as it relates to the indication for CE and site were associated with
      receipt of CE. CONCLUSIONS: Contrary to prior research, patient's race was not
      associated with receipt of invasive carotid imaging or CE for older male
      veterans. These findings persist after controlling for patient preferences,
      comorbid illness, and quality of life. For patients enrolled in an equal-access
      health care system, clinical status was the primary determinant of the receipt of
      CE.

PMID- 12468795
TI  - To what extent should quality of care decisions be based on health outcomes data?
      Application to carotid endarterectomy.
AB  - BACKGROUND AND PURPOSE: Most quality improvement methods implicitly assume that
      facilities with high complication rates are likely to have substandard processes
      of care, a stable characteristic that, in the absence of intervention, will
      persist over time. We assessed the extent to which this holds true for carotid
      endarterectomy. METHODS: Using data from the Department of Veterans Affairs
      National Surgical Quality Improvement Project, we classified facilities on the
      basis of 30-day complications of carotid endarterectomy (stroke, myocardial
      infarction, death) during 1994 to 1995 (period 1, n=3389) and then compared these
      groups of facilities for complication rates during 1996 to 1997 (period 2,
      n=4453). RESULTS: Despite wide variation in facility-specific complication rates,
      the correlation between rates in periods 1 and 2 was low (Spearman correlation
      coefficient, 0.04; P=0.01) Facility-specific rates did not show greater
      correlation when we examined only facilities with higher volumes patients in
      different clinical categories (asymptomatic, transient ischemic attack, stroke).
      Comorbid illness profiles were similar between the 2 time periods. CONCLUSIONS:
      Most of the facility-specific differences in complication rates in period 1 were
      not maintained into period 2. Many apparent quality improvement problems may not
      be as large as they first appear, especially when based on few complications per
      facility. The inability, in practice, to estimate complication rates at a high
      degree of precision is a fundamental difficulty for clinical policy making
      regarding procedures with complication rates such as carotid endarterectomy.

PMID- 12468796
TI  - Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral
      vasospasm resulting from subarachnoid hemorrhage.
AB  - BACKGROUND AND PURPOSE: Endothelial nitric oxide synthase (eNOS) activity is
      decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS
      activity. We hypothesized that simvastatin would increase eNOS protein and
      ameliorate SAH-induced cerebral vasospasm. METHODS: Mice were treated with
      subcutaneous simvastatin or vehicle for 14 days and then subjected to
      endovascular perforation of the right anterior cerebral artery or sham surgery.
      Three days later, neurological deficits were scored (5 to 27; 27=normal), and
      middle cerebral artery diameter and eNOS protein were measured. The study was
      repeated, but simvastatin treatment was started after SAH or sham surgery.
      RESULTS: In SAH mice, simvastatin pretreatment increased middle cerebral artery
      diameter (SAH-simvastatin=74+/-22 micro m, SAH-vehicle=52+/-18 micro m, P=0.03;
      sham-simvastatin=102+/-8 micro m, sham-vehicle=105+/-6 micro m). Pretreatment
      reduced neurological deficits (SAH-simvastatin=25+/-2, SAH-vehicle=20+/-2,
      P=0.005; sham-simvastatin and sham-vehicle=27+/-0). Simvastatin pretreatment also
      increased eNOS protein. Simvastatin posttreatment caused a modest increase in
      middle cerebral artery diameter in SAH mice (SAH-simvastatin=56+/-12 micro m, SAH
      vehicle=45+/-4 micro m, P=0.03; sham-simvastatin=92+/-13 micro m, sham
      vehicle=99+/-10 micro m) and reduced neurological deficits (SAH-simvastatin=21+/
      1, SAH-vehicle=19+/-2, P=0.009). Simvastatin posttreatment did not significantly
      increase eNOS protein. CONCLUSIONS: Simvastatin treatment before or after SAH
      attenuated cerebral vasospasm and neurological deficits in mice. The mechanism
      may be attributable in part to eNOS upregulation.

PMID- 12468797
TI  - Cerebral capillary endothelial cell mitogenesis and morphogenesis induced by
      astrocytic epoxyeicosatrienoic Acid.
AB  - Background and Purpose- Epoxyeicosatrienoic acids (EETs) are products of
      cytochrome P450 epoxygenation of arachidonic acid. We have previously
      demonstrated that astrocyte-conditioned medium induced mitogenesis in brain
      capillary endothelial cells. The goals of the present studies are to further
      define the mechanism through which this can occur and to confirm that EETs are
      derived from astrocytes, through which astrocytic activity can regulate cerebral
      angiogenesis in response to neuronal activation. METHODS: Astrocytes and cerebral
      capillary endothelial cells in primary cultures were cocultured to examine the
      interaction of the 2 cell types. We used multiple immunohistochemical techniques
      to characterize the multicellular nature of the capillaries, which is not simply
      an artifact related to the culture conditions. The mitogenic effect of EETs was
      determined by (3)H-thymidine incorporation and cell proliferation assay.
      Endothelial tube formation was examined in vitro and in vivo with the use of a
      reconstituted basement membrane (Matrigel) assay. RESULTS: In cocultures of
      astrocytes and capillary endothelium, we observed morphological changes in both
      cell types such that each assumed certain physiological characteristics, ie,
      endothelial networks and astrocytes with "footlike" projections as well as
      intermittent gap junctions forming within the endothelial cells. EETs from
      astrocytes as well as synthetic EETs promoted mitogenesis of endothelial cells, a
      process sensitive to inhibition of tyrosine kinase with genistein. Treatments
      with exogenous EETs were sufficient for endothelial cells to differentiate into
      capillary-like structures in culture as well as in vivo in a Matrigel matrix.
      CONCLUSIONS: The 2 major conclusions from these data are that astrocytes may play
      an important role in regulating angiogenesis in the brain and that cytochrome
      P450-derived EETs from astrocytes are mitogenic and angiogenic.

PMID- 12468798
TI  - Endothelin-1-induced vasospasms of spiral modiolar artery are mediated by rho
      kinase-induced Ca(2+) sensitization of contractile apparatus and reversed by
      calcitonin gene-related Peptide.
AB  - BACKGROUND AND PURPOSE: Vasospasms of the spiral modiolar artery may cause an
      ischemic stroke of the inner ear that manifests itself by a sudden hearing loss.
      Previously we have shown that endothelin-1 (ET-1) induces vasospasms of the
      spiral modiolar artery. Here we tested the hypotheses that ET-1-induced
      vasospasms are (1) reversible by ET(A) receptor antagonists; (2) mediated by a
      Ca(2+) sensitization of the contractile apparatus via a Rho-kinase-induced
      inhibition of myosin light chain phosphatase; and (3) reversible by the
      vasodilator calcitonin gene-related peptide (CGRP). METHODS: The Ca(2+)
      sensitivity of the contractile apparatus was evaluated by correlation between the
      smooth muscle cell Ca(2+) concentration and the vascular diameter, which were
      measured by microfluorometry with the fluorescent dye fluo-4 and videomicroscopy,
      respectively. RESULTS: ET-1-induced vasospasms were prevented but not reversed by
      the ET(A) receptor antagonists BQ-123 and BMS-182874. The Ca(2+) sensitivity of
      the contractile apparatus was increased by ET-1 and by inhibition of myosin light
      chain phosphatase with calyculin A and was decreased by CGRP. ET-1-induced
      vasospasms and Ca(2+) sensitization were prevented and reversed by the Rho-kinase
      antagonist Y-27632 and by CGRP. CONCLUSIONS: ET-1 induces vasospasms of the
      spiral modiolar artery via ET(A) receptor-mediated activation of Rho-kinase,
      inhibition of myosin light chain phosphatase, and an increase in Ca(2+)
      sensitivity, which is reversed by CGRP. The observation that vasospasms were
      reversed by Y-27632 but not by BQ-123 or BMS-182874 suggests that Rho-kinase,
      rather than the ET(A) receptor, is the most promising pharmacological target for
      the treatment of ET-1-induced vasospasms, ischemic strokes, and sudden hearing
      loss.

PMID- 12468799
TI  - Altered calcium dynamics do not account for attenuation of endothelium-derived
      hyperpolarizing factor-mediated dilations in the female middle cerebral artery.
AB  - BACKGROUND AND PURPOSE: The contribution of endothelium-derived hyperpolarizing
      factor (EDHF) to ATP-mediated dilations is significantly attenuated in the rat
      middle cerebral artery of intact and estrogen-treated ovariectomized (OVX)
      females compared with males and vehicle-treated OVX females. Since an increase in
      endothelial calcium appears to be a critical prerequisite in the EDHF response,
      we tested the hypothesis that endothelial cell intracellular calcium
      ([Ca(2+)](i)) fails to reach sufficient levels to elicit robust EDHF-mediated
      dilations in females and that this effect is mediated by estrogen. METHODS:
      Vascular diameter and [Ca(2+)](i) were measured concomitantly in perfused middle
      cerebral artery segments with the use of videomicroscopy and fura 2 fluorescence,
      respectively. RESULTS: In the presence of N(G)-nitro-L-arginine methyl ester and
      indomethacin, the dilation to 10(-5) mol/L ATP was significantly reduced (P<0.05)
      in intact females (42+/-8%; n=6) and estrogen-treated OVX females (25+/-6%; n=9)
      compared with intact males (89+/-5%; n=6) and vehicle-treated OVX females (92+/
      2%; n=7). Contrary to our initial hypothesis, endothelial cell [Ca(2+)](i)
      increased to comparable levels in intact females (461+/-116 nmol/L), estrogen
      treated OVX females (417+/-50 nmol/L), intact males (421+/-77 nmol/L), and
      vehicle-treated OVX females (530+/-92 nmol/L). In response to luminal ATP (10(-5)
      mol/L), smooth muscle cell [Ca(2+)](i) decreased to a greater degree in males
      (37+/-4%; n=8) compared with females (21+/-5%; n=7) and in vehicle-treated OVX
      females (18+/-7%; n=7) compared with estrogen-treated OVX females (3+/-5%; n=9).
      CONCLUSIONS: Our data suggest that loss of a factor coupling EDHF to reduction of
      ionized smooth muscle cell [Ca(2+)](i) accounts for the attenuated EDHF-mediated
      dilations in the female middle cerebral artery.

PMID- 12468800
TI  - Endogenous dopamine amplifies ischemic long-term potentiation via D1 receptors.
AB  - BACKGROUND AND PURPOSE: Several observations indicate that, during energy
      deprivation, endogenous dopamine may become neurotoxic. Accordingly, the nucleus
      striatum is a preferential site of silent infarcts in humans, and experimental
      ischemia caused by homolateral carotid occlusion selectively damages this
      dopamine-enriched brain area. In an attempt to clarify how dopamine takes part in
      ischemia-induced neuronal damage, we performed in vitro electrophysiological
      recordings from neurons of the nucleus striatum. METHODS: Intracellular
      recordings with sharp microelectrodes were performed from corticostriatal slices.
      Slices were obtained from both rats and wild-type and dopamine D1 receptor
      lacking mice. In some experiments, the striatum was unilaterally denervated by
      injecting the dopamine-specific neurotoxin 6-hydroxydopamine in the homolateral
      substantia nigra. Dopamine agonists and antagonists, as well as drugs targeting
      the intracellular cascade coupled to dopamine receptor stimulation, were applied
      at known concentrations. RESULTS: Manipulation of the dopamine system failed to
      affect the membrane depolarization of striatal neurons exposed to combined oxygen
      and glucose deprivation of short duration, but it reduced the amplitude of
      postischemic long-term potentiation (LTP) expressed at corticostriatal synapses.
      In particular, pharmacological blockade or genetic inactivation of
      D1/cAMP/protein kinase A pathway prevented the long-term increase of the
      excitatory postsynaptic potential (EPSP) amplitude caused by a transient ischemic
      episode, while it failed to prevent the increase of the EPSP half-decay coupled
      to ischemic LTP. CONCLUSIONS: The present data suggest that endogenous dopamine,
      via D1 receptors, selectively facilitates the expression of ischemic LTP on the
      AMPA-mediated component of the EPSPs, while it does not alter the expression of
      this form of synaptic plasticity on the N-methyl-D-aspartate-mediated component
      of corticostriatal synaptic potentials. Understanding the cellular and molecular
      mechanisms of ischemia-triggered excitotoxicity offers hope for the development
      of specific treatments able to interfere with this pathological process.

PMID- 12468801
TI  - Dynamic changes in cerebral blood flow and angiogenesis after transient focal
      cerebral ischemia in rats. Evaluation with serial magnetic resonance imaging.
AB  - BACKGROUND AND PURPOSE: Angiogenesis occurs after cerebral ischemia, but the
      relationship between angiogenesis and cerebral hemodynamic change is unknown. The
      aim of the present study was to investigate the relationship between ischemia
      induced angiogenesis and hemodynamics in a well-defined 3-vessel occlusion model
      of the rat by using diffusion- (DWI), perfusion-, and T2-weighted MRI (T2WI).
      METHODS: Rats were subjected to 60 minutes of transient middle cerebral artery
      occlusion or sham operation. DWI and T2WI were used to characterize the extent of
      the ischemic lesion from 4.5 hours to 14 days after reperfusion. A flow-sensitive
      alternating inversion recovery method and dynamic susceptibility contrast MRI
      were used to evaluate the temporal changes in relative cerebral blood flow (CBF)
      and cerebral blood volume (CBV), respectively. Rats were randomly selected and
      killed at each time point for investigation of vascular density and for
      hematoxylin-eosin staining. RESULTS: Ischemic lesions developed in the
      ipsilateral cortex, as demonstrated by DWI and T2WI. CBF was significantly
      increased in the ipsilateral cortex, especially in the cortical outer layer from
      day 1 to day 14, and peaked on day 7 (P<0.05), while CBV was significantly
      increased on day 7 (P<0.01). The vascular density on the ipsilateral brain
      surface was gradually increased from day 1 to day 5, peaked on day 7, and then
      decreased on day 14. Histology study showed pannecrosis in the cortex from day 1
      to day 5 and partial liquefaction of the necrotic tissues on days 7 and 14.
      CONCLUSIONS: A delayed increase in both CBF and CBV is documented in the
      ipsilateral cortex after transient focal brain ischemia, and such an increase may
      be associated with angiogenesis.

PMID- 12468802
TI  - Altered vascular function in fetal programming of hypertension.
AB  - BACKGROUND AND PURPOSE: Reduced endothelium-dependent vasorelaxation partly due
      to loss of nitric oxide (NO) bioavailability occurs in most cases of chronic
      hypertension. Intrauterine nutritional deprivation has been associated with
      increased risk for hypertension and stroke, associated with relaxant dysfunction
      and decreased vascular compliance, but the underlying mechanisms are not known.
      The present studies were undertaken to investigate whether endothelial
      dysfunction associated with altered NO-dependent vasodilatation pathways is also
      observed in a model of in utero programming of hypertension. METHODS: Pregnant
      Wistar rats were fed a normal (18%), low (9%), or very low (6%) protein
      isocaloric diet during gestation. Vasomotor response of resistance cerebral
      microvessels (<50 micro m) was studied in adult offspring of dams fed the 18% and
      9% protein diets by a video imaging technique. Endothelial NOS (eNOS), soluble
      guanylate cyclase (sGC), and K(Ca) channel expression were measured by Western
      blot. NO synthase (NOS) activity was measured enzymatically as well as in situ by
      NADPH diaphorase staining. RESULTS: Litter size and survival to adulthood were
      not affected by the diets. Birth weights of offspring of dams fed the 6% diet
      were markedly lower than those of dams fed the 9% diet, which were marginally
      lower than those of controls. Systolic blood pressures of adult offspring of
      mothers in the 6% and 9% groups were comparably greater (156+/-2 and 155+/-1 mm
      Hg, respectively) than that of control offspring (137+/-1 mm Hg); we therefore
      focused on the 9% and 18% groups. Cerebral microvessel constriction to
      thromboxane A(2) mimetic and dilation to carba-prostaglandin I(2) did not differ
      between diet groups. In contrast, vasorelaxation to the NO-dependent agents
      substance P and acetylcholine was diminished by 50% in low protein-exposed
      offspring, but eNOS expression and activity were similar between the 2 diet
      groups. Vasorelaxant response to the NO donor sodium nitroprusside was also
      decreased and was associated with reduced (by 50% to 65%) cGMP levels and sGC
      expression. cGMP analogues caused comparable vasorelaxation in the 2 groups.
      Expression of K(Ca) (another important mediator of NO action) and relaxation to
      the K(Ca) opener NS1619 were unchanged by antenatal diet. CONCLUSIONS: Maternal
      protein deprivation, which leads to hypertension in the offspring, is associated
      with diminished NO-dependent relaxation of major organ (cerebral)
      microvasculature, which seems to be largely attributed to decreased sGC
      expression and cGMP levels. The study provides an additional explanation for
      abnormal vasorelaxation in nutrient-deprived subjects in utero.

PMID- 12468803
TI  - Thrombolytic treatment of clot embolism in rat: comparison of intra-arterial and
      intravenous application of recombinant tissue plasminogen activator.
AB  - BACKGROUND AND PURPOSE: We sought to test the hypothesis that intra-arterial
      recombinant tissue plasminogen activator (rtPA) treatment of thromboembolic
      stroke is more efficient than intravenous application. METHODS: Rats were
      embolized by intracarotid injection of autologous fibrin-rich blood clots. One
      hour later rtPA (10 mg/kg) was infused either intravenously (n=8) or intra
      arterially (n=8). Control rats (n=8) received intra-arterial infusion of saline.
      Treatment was monitored by MR perfusion-weighted imaging and apparent diffusion
      coefficient (ADC) imaging, and outcome was evaluated by comparing incidence of
      hemorrhages and lesion volumes of ATP and pH. RESULTS: Clot embolism led to a
      decline of perfusion-weighted imaging signal intensity in the middle cerebral
      artery territory to <40% of control. Both intra-arterial and intravenous
      treatment significantly improved blood flow in cerebral cortex but not in caudate
      putamen. In untreated animals, ATP and pH lesion volumes were 510.3+/-94.5 and
      438.6+/-39.2 mm(3) at 7 hours after clot embolism, respectively. Both intravenous
      and intra-arterial rtPA treatment produced hemorrhagic complications but reduced
      ATP lesion size to 296.2+/-136.1 and 370.3+/-103.7 mm(3) and reduced pH lesion
      size to 263.3+/-114.6 and 303.3+/-103.0 mm(3), respectively (P<0.05 for untreated
      versus treated rats; no difference between intravenous and intra-arterial
      treatment). ADC imaging revealed that lesion reduction was due to inhibition of
      infarct growth but not to reversal of primary injury. CONCLUSIONS: This study
      documents reduction of injury by rtPA treatment but does not reveal a difference
      between intra-arterial and intravenous application. Our data do not support an
      advantage of intra-arterial thrombolysis.

PMID- 12468804
TI  - Different mechanisms of secondary neuronal damage in thalamic nuclei after focal
      cerebral ischemia in rats.
AB  - BACKGROUND AND PURPOSE: After focal cerebral ischemia, depending on its
      localization and extent, secondary neuronal damage may occur that is remote from
      the initial lesion. In this study differences in secondary damage of the
      ventroposterior thalamic nucleus (VPN) and the reticular thalamic nucleus (RTN)
      were investigated with the use of different ischemia models. METHODS: Transient
      middle cerebral artery occlusion (MCAO) leads to cortical infarction, including
      parts of the basal ganglia such as the globus pallidus, and to widespread edema.
      Photothrombotic ischemia generates pure cortical infarcts sparing the basal
      ganglia and with only minor edema. Neuronal degeneration was quantified within
      the ipsilateral RTN and VPN 14 days after ischemia. Glial reactions were studied
      with the use of immunohistochemistry. RESULTS: MCAO resulted in delayed neuronal
      cell loss of the ipsilateral VPN and RTN. Glial activation occurred in both
      nuclei beginning after 24 hours. Photothrombotic ischemia resulted in delayed
      neuronal cell loss only within the VPN. Even 2 weeks after photothrombotic
      ischemia, glial activation could only be seen within the VPN. CONCLUSIONS: Pure
      cortical infarcts after photothrombotic ischemia, without major edema and without
      effects on the globus pallidus of the basal ganglia, only lead to secondary VPN
      damage that is possibly due to retrograde degeneration. MCAO, which results in
      infarction of cortex and globus pallidus and which causes widespread edema, leads
      to secondary damage in the VPN and RTN. Thus, additional RTN damage may be due to
      loss of protective GABAergic input from the globus pallidus to the RTN or due to
      the extensive edema. Retrograde degeneration is not possible because the RTN, in
      contrast to the VPN, has no efferents to the cortex.

PMID- 12468805
TI  - Delayed argatroban treatment reduces edema in a rat model of intracerebral
      hemorrhage.
AB  - BACKGROUND AND PURPOSE: Studies indicate that thrombin plays an important role in
      intracerebral hemorrhage (ICH)-induced edema formation. Although thrombin is
      produced as the blood clots, it may be bound to fibrin and only gradually
      released from the clot. The time window for administration of a thrombin
      inhibitor to reduce ICH-induced edema is unknown. Whether this time window
      extends beyond the period when a thrombin inhibitor might exacerbate rebleeding
      is also unknown. METHODS: This study examines (1) whether argatroban, an
      inhibitor of both free and fibrin-bound thrombin, can reduce edema formation
      after intracerebral infusion of 100 micro L of blood in the rat; (2) the
      therapeutic time window for argatroban; and (3) whether argatroban promotes
      rebleeding in a model in which ICH was induced by intracerebral injection of
      collagenase. RESULTS: Intracerebral infusion of blood caused a marked increase in
      perihematomal water content. Intracerebral injection of argatroban 3 hours after
      ICH caused a significant reduction in edema measured at 48 hours (80.9+/-1.0%
      versus 82.6+/-0.8%; P<0.01). The systemic administration of high-dose argatroban
      (0.9 mg/h) starting 6 hours after ICH also significantly reduced edema (80.3+/
      1.1% versus 82.0+/-1.3% in vehicle controls; P<0.05). There was no protection
      when the onset of argatroban administration was delayed to 24 hours after ICH or
      if a lower dose of argatroban (0.3 mg/h) was used. Argatroban did not increase
      collagenase-induced hematoma volume when given into the clot after 3 hours or
      given systemically at 6 hours. CONCLUSIONS: Our data suggest that argatroban may
      be an effective therapy for ICH-induced edema.

PMID- 12468806
TI  - Selective blockade of endothelin-B receptors exacerbates ischemic brain damage in
      the rat.
AB  - BACKGROUND AND PURPOSE: Endothelins act through 2 receptors, namely, ET(A) and
      ET(B). In the cerebral circulation, ET(A) mediates marked and prolonged
      vasoconstriction, and its blockade increases cerebral blood flow (CBF) and
      reduces ischemic brain damage. However, the role of ET(B) receptors remains
      unclear. In this study we examined, in rats, the kinetics of expression of ET(B)
      and the effects of ET(B) blockade on changes in CBF and brain damage after focal
      cerebral ischemia and N-methyl-D-aspartate (NMDA)-induced excitotoxic injury.
      METHODS: Rats were subjected to transient (60 minutes) focal cerebral ischemia or
      cortical injection of NMDA. The selective ET(B) antagonist BQ-788 was injected
      intracerebroventricularly 30 minutes before and 30 minutes after the onset of
      ischemia. Cortical perfusion was monitored by laser-Doppler flowmetry. The volume
      of infarction or NMDA-induced cortical lesion was assessed at 24 hours after the
      insult. The reverse transcription-polymerase chain reaction technique was used to
      assess ET(B) expression. RESULTS: Cerebral ischemia failed to alter the
      expression of ET(B) mRNA in both acute and chronic stages. Administration of BQ
      788 resulted in an increase in infarction volume (178%; P<0.05) accompanied by a
      decrease in residual CBF (-26.7% versus control; P<0.01). In these animals we
      found a positive correlation between the volume of infarction and the severity of
      the decrease in CBF. NMDA-induced cortical lesions were not affected by the
      administration of BQ-788. CONCLUSIONS: Our results suggest that the ET(B)
      antagonist BQ-788 induces deleterious effects that are mediated by the reduction
      of residual blood flow after ischemia and argue that the optimal therapeutic
      strategy in stroke would be to target the use of selective ET(A) antagonists and
      not mixed ET(A)/ET(B) antagonists.

PMID- 12468807
TI  - Cerebral autoregulation under moderate hypothermia in patients with acute stroke.
AB  - BACKGROUND AND PURPOSE: We undertook this study to examine the integrity of
      cerebral autoregulation in patients with acute ischemic stroke treated with
      moderate hypothermia (33 degrees C). METHODS: Fourteen patients, aged 58+/-11
      years, with an acute anterior circulation infarction and National Institutes of
      Health Stroke Scale score >15 were evaluated. Patients received catecholamines
      (norepinephrine) via continuous intravenous infusion and were mechanically
      ventilated. Alpha-stat was used for pH maintenance. Arterial pressure (AP) and
      intracranial pressure (ICP) were invasively monitored. Flow velocity in the
      middle cerebral artery (MCA) supplying the unaffected hemisphere was continuously
      monitored. Instantaneous maximum flow velocity (V(max) MCA), ICP, and AP were
      simultaneously recorded in real time. Mean values of V(max) MCA (V(mean) MCA) and
      AP (MAP) were calculated over 1 minute. Static cerebral autoregulation (sCA) was
      calculated as sCA=(%DeltaCVR/%DeltaMAP)x100% (where %DeltaCVR is an estimate of
      percent change in cerebrovascular resistance). An sCA value of 0% indicates
      absent autoregulation, and a value of 100% indicates perfect autoregulation.
      Autoregulation is considered impaired when sCA values are <40%. MAP changes were
      produced by increasing the rate of the norepinephrine infusion. Six patients were
      examined under both normothermic and hypothermic conditions, while 8 were
      examined only under hypothermia. RESULTS: The induced MAP increase was 22+/-7 mm
      Hg (minimum 13, maximum 40 mm Hg). Mean sCA was 64+/-16% (minimum 40%, maximum
      100%). No effect of moderate hypothermia on sCA or V(mean) MCA was evident in any
      of the 6 serially examined patients. Normocapnia was observed in all cases.
      CONCLUSIONS: sCA appears intact under moderate hypothermia with the use of alpha
      stat for pH maintenance.

PMID- 12468808
TI  - Amitriptyline in the prophylaxis of central poststroke pain. Preliminary results
      of 39 patients in a placebo-controlled, long-term study.
AB  - BACKGROUND AND PURPOSE: We performed a double-blind, placebo-controlled study to
      investigate the effectiveness of amitriptyline for the prophylactic treatment of
      patients with acute thalamic stroke in preventing central poststroke pain.
      METHODS: Subject received, in a randomized sequence, either amitriptyline
      titrated from 10 to 75 mg in extended-release form or placebo over a therapy
      period of 365 days. We documented the time when pain developed; the intensity,
      type, site, and distribution of pain; and the presence/absence and type of
      allodynia. RESULTS: Thirty-nine patients (23 women and 16 men; age range, 36 to
      68 years) with central poststroke pain participated. The placebo group showed a
      pain rate of 21% within 1 year after the diagnosis of thalamic stroke compared
      with 17% in the group under prophylactic treatment with amitriptyline. Average
      (SE) time to pain was 318 (23) days for patients in the placebo group and 324
      (24) days for patients in the amitriptyline group. CONCLUSIONS: With the achieved
      sample sizes of this study and a pain rate of approximately 21% in the placebo
      group, any near-perfect pain protection would have been detected. Near-perfect
      pain protection, in this context, refers to pain in <2.4% of the recruited
      patients treated with amitriptyline or in approximately 89% of placebo-treated
      patients. Larger studies are recommended to test the hypothesis that prophylactic
      amitriptyline reduces but does not completely prevent central poststroke pain.

PMID- 12468809
TI  - Effects of nonpeptide V(1) vasopressin receptor antagonist SR-49059 on infarction
      volume and recovery of function in a focal embolic stroke model.
AB  - BACKGROUND AND PURPOSE: Cerebral edema develops very early after the onset of
      focal cerebral ischemia and may be a major factor in early disability after an
      acute ischemic stroke. There have been very limited studies on the usefulness of
      antiedemic agents as neuroprotective agents in the setting of focal cerebral
      ischemia. We tested the neuroprotective effects of a new potent nonpeptide
      vasopressin receptor V(1) antagonist, SR-49059, in a focal embolic stroke model
      in rats. METHODS: Focal ischemic injury was induced by embolizing a preformed
      clot into the middle cerebral artery (MCA). Infarction volume was measured at 48
      hours after the MCA occlusion. Neurological deficits, ischemic brain edema,
      seizure activity, and mortality and hemorrhage rates were also documented.
      RESULTS: Treatment with SR-49059 (2 mg/kg), initiated immediately after MCA
      occlusion, significantly reduced infarction volume (P<0.05) measured at 48 hours
      after the arterial occlusion. In animals in which the treatment was delayed for 1
      hour after MCA occlusion, infarction volume was also reduced significantly
      (P<0.05). Infarction volume in the rats that received the drug at 3 or 6 hours
      after MCA occlusion was not different from that in the vehicle-treated group.
      Treatment with SR-49059, when started early after the arterial occlusion, also
      reduced neurological deficits and ischemic brain edema. Injection of drug at a
      higher dose (30 mg/kg) also reduced infarction volume and improved functional
      recovery but was not superior to the lower dose (2 mg/kg) when the drug was
      administrated at 1 hour after MCA occlusion. CONCLUSIONS: Our data show that the
      selective vasopressin receptor antagonist SR-49059 is a potent neuroprotective
      agent when used early after onset of arterial occlusion in an embolic focal
      ischemia model in rats. Further studies are needed in stroke models to better
      understand its neuroprotective properties when used alone or in combination with
      thrombolysis.

PMID- 12468812
TI  - Unmasking the anti-inflammatory cytokine response in rheumatoid synovitis.

PMID- 12468813
TI  - Evidence from clinical trials and long-term observational studies that disease
      modifying anti-rheumatic drugs slow radiographic progression in rheumatoid
      arthritis: updating a 1983 review.
AB  - Earlier reports, including a comprehensive 1983 review, had indicated that
      slowing of radiographic progression was relatively unusual in treatment of
      rheumatoid arthritis (RA) using traditional disease modifying anti-rheumatic
      drugs. However, in recent years, slowing of radiographic progression has been
      documented in a number of clinical trials, as well as long-term observational
      studies, with use of (in alphabetical order) adalimumab, anakinra,
      corticosteroids, cyclophosphamide, cyclosporin, etanercept, gold salts,
      infliximab, leflunomide, methotrexate and sulphasalazine. At this time, disease
      modification is a realistic goal in the clinical care of patients with RA.
      Documentation of improved long-term outcomes requires long-term observational
      data over 5-20 yr to supplement data from randomized controlled clinical trials
      over 6-24 months.

PMID- 12468814
TI  - Clinical and serological associations of ribosomal P autoantibodies in systemic
      lupus erythematosus: prospective evaluation in a large cohort of Italian
      patients.
AB  - OBJECTIVE: To verify the association of ribosomal anti-P antibodies (anti-P), as
      detected by a sensitive ELISA, with serological findings and clinical
      manifestations, including neuropsychiatric involvement evaluated according to the
      American College of Rheumatology (ACR) nomenclature, in a large cohort of
      patients with systemic lupus erythematosus (SLE). METHODS: Anti-P were evaluated
      in the serum of 149 consecutive Italian SLE patients by an ELISA using a multiple
      antigen peptide carrying four copies of a common P0, P1 and P2 epitope. A
      complete laboratory evaluation and clinical examination were performed in each
      patient. In addition, all patients underwent an accurate neuropsychiatric and
      neuropsychological assessment performed by trained specialists according to the
      1999 ACR suggestions. RESULTS: Serum anti-P were detected in 18/149 patients
      (12.1%). The anti-P prevalence was similar (11.7%) when the analysis was
      performed in a larger series of sera including 82 additional SLE patients, who
      were not included in the clinical study. The age of anti-P-positive patients at
      disease onset was less than 33 yr and, in comparison with the anti-P-negative
      patients, these patients showed more active disease activity and a higher
      prevalence of photosensitivity and malar and discoid rash. A strong association
      between IgG anticardiolipin antibodies and anti-P was also found. However, anti-P
      were associated with neither neuropsychiatric syndromes nor cognitive impairment.
      CONCLUSION: This study does not seem to confirm the described association of anti
      P with SLE neuropsychiatric manifestations. However, it supports the anti-P
      association with different skin manifestations as well as the presence of
      anticardiolipin in a subset of patients with SLE characterized by early disease
      onset.

PMID- 12468815
TI  - The rheumatoid arthritis patient in the clinic: comparing more than 1,300
      consecutive DMARD courses.
AB  - BACKGROUND: Therapy of rheumatoid arthritis (RA) is typically characterized by
      the sequential use of disease-modifying anti-rheumatic drugs (DMARDs). This study
      aimed to reveal treatment patterns with traditional DMARDs and their changes
      during the two decades before the recent introduction of new DMARDs. METHODS: A
      total of 593 RA patients were followed from their first presentation to our
      clinic throughout the course of their disease; 222 patients received their first
      DMARD therapy while under our care. More than 2,300 patient years of therapy were
      analysed for the efficacy [using C-reactive protein (CRP) and erythrocyte
      sedimentation rate (ESR) as surrogates] and duration of drug therapy of
      consecutive DMARDs. RESULTS: Before 1985, 65-90% of initial DMARDs were gold
      compounds, but their use decreased continuously thereafter. Antimalarial (AM)
      drugs were important initial DMARDs in new patients at all times, whereas
      sulphasalazine (SSZ) and methotrexate (MTX) gained increasing significance after
      1985 (the first DMARD was MTX in up to 29% of new patients). Penicillamine (DPA),
      azathioprine (AZP), cyclosporin (CyA) and combination therapies were not usually
      employed initially, but were reserved for the later course of the disease.
      Gender, age and rheumatoid factor were not different between patients receiving
      different DMARDs. The baseline acute-phase response was higher in patients
      treated with MTX (mean CRP 3.5 mg/dl) than in those treated with SSZ (CRP 2.4
      mg/dl; P < 0.05) or AM (CRP 2.1 mg/dl; P < 0.05), suggesting that MTX was used
      preferentially in patients with high disease activity. On the other hand, once AM
      or SSZ had been discontinued, MTX was the most common subsequent DMARD (in 31 and
      56% respectively). Comparison of first DMARDs with subsequent ones revealed that
      first DMARDs were more effective: the acute-phase response decreased most
      prominently during first therapies (CRP reduction was 1.28 mg/dl during first
      courses and 0.35 mg/dl during fourth or later courses; P < 0.01); and retention
      rates were significantly longer for first compared with subsequent therapies
      (median of 24.5 months for first and 18.6 months for fourth or subsequent
      therapies; P < 0.001). CONCLUSION: MTX was the most commonly employed DMARD
      therapy for RA and was used increasingly as first therapy in newly diagnosed RA.
      Patients with high disease activity were given MTX therapy more often than other
      DMARDs, while those with low activity were more likely to receive SSZ or AM, and
      MTX on failure of these drugs. First DMARDs in new patients were retained longer
      than subsequent DMARDs, apparently because they are more effective.

PMID- 12468816
TI  - Increased level of HLA-B27 expression in ankylosing spondylitis patients compared
      with healthy HLA-B27-positive subjects: a possible further susceptibility factor
      for the development of disease.
AB  - OBJECTIVE: In B27 transgenic rats, susceptibility to the development of a
      spondyloarthropathy-like disease has been shown to correlate with the level of
      B27 transgene expression on lymphoid cells. The aim of this work was to study HLA
      B27 molecule expression in peripheral blood mononuclear cells (PBMCs) from
      patients with ankylosing spondylitis (AS) and from normal controls (NC). METHODS:
      Twenty B27(+) AS patients and 16 B27(+) NC were studied. HLA-B27 whole molecules
      and free heavy chains (HCs) and total HLA class I molecules were evaluated at the
      surface of PBMCs by immunofluorescence and flow cytometry. B27 subtypes were
      defined with the PCR-SSP (polymerase chain reaction-sequence-specific primer)
      technique. Cellular activation was evaluated by the expression of CD69, CD25
      molecules and interferon gamma (IFN-gamma) production. RESULTS: B27 expression
      was 55,536.3+/-18,961.0 MESF (molecules of equivalent soluble fluorochromes)
      units in AS and 25,936.0+/-12,117.5 MESF in NC (P=0.00009), total HLA class I
      expression was 448,840.2+/-136,293.8 MESF in AS and 533,494.4+/-232,931.1 MESF in
      NC (not significant), HC expression was 10,593.4+/-6,396.1 MESF in AS and
      14,843.0+/-7,544.2 MESF in NC (not significant). The higher B27 expression in the
      SA group was not due to higher cell activation as it was not correlated with CD69
      and CD25 expression in PBMCs or with the level of IFN-gamma. HLA-B27 expression
      did not correlate with indexes of disease status [Bath Ankylosing Spondylitis
      Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index
      (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI)]. CONCLUSIONS: We
      found greater expression of HLA-B27 molecules in patients with AS than in healthy
      subjects. This phenomenon was not accompanied by general up-regulation of HLA
      class I molecules or by greater expression of classical T-cell activation
      markers. On this basis we propose that the higher expression of the HLA-B27
      molecules is a further predisposing factor for the development of AS.

PMID- 12468817
TI  - Generic measures of health-related quality of life in ankylosing spondylitis:
      reliability, validity and responsiveness.
AB  - OBJECTIVE: To assess the acceptability and measurement properties of two generic
      measures of health-related quality of life (HRQL): the EuroQol and the Short Form
      12-item Health Survey Questionnaire (SF-12) in ankylosing spondylitis (AS).
      METHODS: Instruments were administered by means of a self-completed questionnaire
      to AS patients recruited from across the United Kingdom. Instruments were
      assessed for data quality and scaling assumptions. Test-retest reliability was
      assessed in those patients reporting no change in general health at 2 weeks. The
      convergent validity of both instruments was assessed and scores were correlated
      with responses to health transition questions. Responsiveness was assessed for
      patients reporting change in health at 6 months. RESULTS: The instruments had
      high completion rates. Although slightly skewed towards better levels of health,
      scores covered the available range for both sections of the EuroQol [EQ-5D and EQ
      visual analogue scale (EQ-VAS)]. Score distributions approximated normality for
      the SF-12. Test-retest reliability estimates support the use of both instruments
      in group evaluation and the SF-12 Physical Component Summary score (PCS) in
      individual evaluation (>0.90). Correlations between instruments were in the
      hypothesized direction and were of a moderate level. The EQ-VAS had the strongest
      linear relationship, with responses to both specific and general health
      transition questions (P<0.01). The EQ-VAS and SF-12 PCS were the most responsive
      instruments. The EQ-5D was the least responsive instrument. CONCLUSION: The
      instruments have undergone a comprehensive comparative evaluation to assess the
      measurement properties required for patient-assessed measures of health outcome
      in AS. Adequate levels of acceptability, reliability and validity were found for
      both instruments. Although evidence supporting instrument responsiveness was
      strong for the EQ-VAS and SF-12 PCS, it was very weak for the EQ-5D and SF-12
      Mental Component Summary Scale (MCS). The EQ-VAS and SF-12 PCS can both be
      recommended for use in group evaluation, and the SF-12 PCS is recommended in
      routine practice or research. However, the lower reliability of the SF-12 MCS and
      the limited ability of both the EQ-5D and SF-12 MCS to detect change in health
      may restrict these roles.

PMID- 12468818
TI  - Balance impairments in individuals with symptomatic knee osteoarthritis: a
      comparison with matched controls using clinical tests.
AB  - OBJECTIVES: To compare balance in individuals with symptomatic knee
      osteoarthritis (OA) and in age-, gender- and body-mass-matched controls using
      simple clinical measures. METHODS: Thirty-three people with OA and 33 controls
      participated. Static postural sway [antero-posterior (AP), lateral and total] was
      measured using a swaymeter on two different surfaces and under two visual
      conditions. Dynamic standing balance was assessed using the 'step test'. RESULTS:
      Both groups displayed similar postural sway on most variables measured.
      Significantly greater sway was noted in the OA group on a firm surface in both
      lateral (eyes open) and AP directions (eyes closed), as well as total sway (eyes
      closed) (P < 0.05). Poorer dynamic standing balance was observed in the OA group
      as evidenced by the step test (P < 0.0001). CONCLUSIONS: Balance deficits can be
      identified in the osteoarthritic population using simple, inexpensive measures.
      However, the clinical relevance of the small deficits identified remains unknown
      and warrants further investigation.

PMID- 12468820
TI  - The use of the Internet as a resource for health information among patients
      attending a rheumatology clinic.
AB  - OBJECTIVES: To determine the proportion of patients attending a rheumatology
      clinic who have access to a computer with Internet capabilities, to establish how
      often they search for health information, and how difficult or useful they find
      this resource. METHODS: We performed a questionnaire-based study of consecutive
      patients attending a rheumatology clinic in two city teaching hospitals over a 1
      week period. Patients were asked if they owned or had access to a computer with
      Internet capabilities, and if they had searched for information on shopping,
      holidays, entertainment or health information. Further questions were then
      directed at the nature of the health information, how useful it was and how easy
      the patient found it to access the details. Patient demographic data were
      obtained by case record review. RESULTS: One hundred and forty patients were
      approached; 138 completed questionnaires were collected. One hundred and one
      respondents (73%) were female. Median patient age was 58 yr (range 18-84). One
      hundred and seven (78%) had rheumatoid arthritis, with median disease duration of
      8 yr (range 6 months to 49 yr). Sixty (43%) had access to the Internet, mostly at
      home, and used it most frequently for holiday information. Thirty-seven (27% of
      all respondents) reported that they had searched for medical information on a
      median of 2 (range 1-10) occasions in the previous 12 months. Of these, 83%
      perceived the information as useful, 54% discovered something they had not
      previously known and 31% reported it was easier than asking their doctor or
      nurse. Patients searched on-line for information on their arthritis (83%), drug
      treatment (54%), alternative therapies (31%), diet and arthritis (46%) and
      patient organizations (11%). No patients recalled being advised to search for
      information by their doctor or nurse. Patients who searched for medical
      information were younger (median age 48 vs 62 yr; P<0.001), more likely to be
      employed (32 vs 16%) and more likely to be married or in a stable relationship
      (84 vs 66%); there were no differences in sex distribution, diagnosis, disease
      duration or social deprivation. CONCLUSIONS: One in four patients attending our
      rheumatology clinic had searched the Internet for medical information in the last
      12 months. Almost one-third found it easier than asking their health-care
      professional. Further studies are required to explore the wider application of
      this resource and to determine the validity and reliability of the information
      obtained.

PMID- 12468819
TI  - Comparison of the faecal microflora of patients with ankylosing spondylitis and
      controls using molecular methods of analysis.
AB  - OBJECTIVES: To determine whether differences within the complex intestinal
      microflora can be demonstrated between patients with ankylosing spondylitis (AS)
      and healthy individuals. METHODS: The composition of the faecal microflora of 15
      ankylosing spondylitis patients and 15 matched controls was determined using a
      variety of nucleic acid-based methods, including denaturing gradient gel
      electrophoresis (DGGE). Concentrations of serum antibodies reactive with
      intestinal bacteria were determined. T-cell proliferation responses to autologous
      intestinal bacteria were determined using a bioluminescent assay. RESULTS: DGGE
      demonstrated a unique and stable bacterial community in the faeces of each
      individual. No specific differences in colonization profiles were discernible
      between patients and controls. Analysis of individual bacterial groups using
      nucleic acid-based methods showed no differences in faecal colonization with
      Klebsiella pneumoniae or Bacteroides vulgatus. A significantly higher proportion
      of faecal samples from AS patients were found to contain sulphate-reducing
      bacteria compared with samples from controls (P=0.0004). Three out of five
      patients showed elevated T-cell proliferation responses to Bacteroides species
      cultured from their own faeces. The concentrations of serum immunoglobulin A
      (IgA) and IgM antibodies reactive with klebsiella or bacteroides cells were lower
      in the patient group relative to the controls. CONCLUSIONS: By using DGGE, we
      have demonstrated the complexity and individuality of the human intestinal
      microflora and shown that this is a confounding factor in determining the
      possible significance of individual organisms in the pathogenesis of
      spondyloarthritis. Nevertheless, we demonstrated a higher prevalence of sulphate
      reducing bacteria in the faeces of patients with AS. These organisms have been
      implicated in the pathogenesis of inflammatory bowel disease. We also detected a
      possible loss of immunological tolerance to autologous Bacteroides isolates in
      patients with AS.

PMID- 12468821
TI  - Three-dimensional kinematics at the ankle joint complex in rheumatoid arthritis
      patients with painful valgus deformity of the rearfoot.
AB  - OBJECTIVE: To evaluate the three-dimensional (3D) kinematics of the ankle joint
      complex (AJC) in rheumatoid arthritis (RA) patients with painful valgus deformity
      of the rearfoot. METHODS: Fifty patients with RA underwent gait analysis using
      electromagnetic tracking techniques to measure 3D kinematics at the AJC under
      barefoot and shod walking conditions. Three axial rotations
      (dorsiflexion/plantarflexion, inversion/eversion and internal/external rotation)
      were measured during the gait cycle, and the angular positions at key gait
      events, range of motion and the motion: time integral were measured. Descriptive
      and analytical comparisons were made with normative data derived from a sex- and
      age-matched population (n=45). RESULTS: AJC dysfunction in RA was characterized
      by excessive eversion motion (within an eversion range) and no inversion motion
      through the neutral joint position for the subtalar component of the joint
      complex, in both barefoot and shod walking conditions. Motion was coupled such
      that internal rotation of the leg relative to the rearfoot was greater than
      normal. AJC motion was different for all rotations between barefoot and shod
      conditions, but in both situations there were statistically significant between
      group differences in the motion:time integral for inversion/eversion (barefoot,
      P<0.0001; shod, P<0.0001) and external/internal rotation (barefoot, P<0.0001;
      shod, P<0.0001). There were no statistically significant differences between RA
      and normative data for dorsiflexion/plantarflexion motion under barefoot (P=0.16)
      and shod (P=0.50) walking conditions. CONCLUSION: Painful valgus deformity of the
      rearfoot is associated with changes in the 3D kinematics affecting eversion at
      the AJC and internal rotation of the leg, both when walking barefoot and in
      shoes.

PMID- 12468823
TI  - Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in
      ankylosing spondylitis.
AB  - OBJECTIVE: Since ulcerative colitis and Crohn's disease, which are associated
      with ankylosing spondylitis (AS), have been found to be variably associated with
      the IL-1B and the IL-1RN genes encoding interleukin-1beta (IL-1beta) and the
      interleukin-1 receptor antagonist (IL-1ra), we have investigated whether these
      polymorphisms in IL-1B and IL-1RN are also involved in AS. METHODS: DNA was
      isolated from peripheral blood of 106 patients with AS and 104 healthy controls.
      All patients and controls were Dutch Caucasians. Bi-allelic polymorphisms at
      positions +3,953 and -511 in the IL-1B gene, and a penta-allelic polymorphism in
      intron 2 of the IL-1RN gene were studied by polymerase chain reaction-based
      methods. RESULTS: Allele IL-1RN*2 was significantly increased in AS (odds
      ratio=1.60; 95% confidence interval=1.20-2.80; P=0.031) compared with healthy
      controls, and independent from the polymorphism in loci IL-1B-511 and IL
      1B+3,953. No significant associations were found between AS and the IL-1B-511 or
      IL-1B+3,953 polymorphisms. CONCLUSION: Similar to other chronic inflammatory
      diseases, AS is associated with the IL-1RN*2 allele. Further studies are
      necessary to determine the biological significance of these findings in relation
      to susceptibility or severity of the disease.

PMID- 12468822
TI  - Increased expression of nerve growth factor (NGF) and high affinity NGF receptor
      (p140 TrkA) in human osteoarthritic chondrocytes.
AB  - OBJECTIVE: We aimed to investigate the expression of nerve growth factor (NGF)
      and high affinity NGF receptor (p140 TrkA) on chondrocytes from human healthy and
      osteoarthritic cartilage. METHODS: We recruited 12 patients with osteoarthritis
      (OA) undergoing surgical knee replacement. Articular cartilage was split into two
      zones showing macroscopically and histologically the lowest (MIN) and highest
      (MAX) degree of osteoarthritic damage. Additional specimens of cartilage were
      obtained from three healthy donors. Chondrocytes were isolated by enzymatic
      digestion and freshly processed for NGF protein, Trk A detection and mRNA
      extraction. NGF-beta mRNA was determined by a reverse transcriptase-polymerase
      chain reaction (RT-PCR). NGF-beta and TrkA expression was evaluated by
      immunofluorescence and flow cytometry analysis. RESULTS: NGF-beta-specific mRNA
      was detected in normal and osteoarthritic chondrocytes. NGF-beta protein levels
      were low in normal chondrocytes, increased in MIN osteoarthritic cartilage and
      further enhanced in MAX osteoarthritic cartilage. Likewise, TrkA was scarcely
      expressed on normal chondrocytes and progressively increased on osteoarthritic
      chondrocytes based on the extent of anatomic damage. CONCLUSIONS: This is the
      first study showing that human chondrocytes synthesize NFG-beta and express on
      their surface the high affinity NGFR (p140 TrkA). Of note, NGF-beta and TrkA were
      upregulated in osteoarthritic chondrocytes suggesting a role of NGF in the
      pathophysiology of OA. We can speculate that NGF, like other growth factors,
      stimulates chondrocyte metabolism in the osteoarthritic process.

PMID- 12468824
TI  - Higher specialist training in rheumatology.

PMID- 12468826
TI  - Long-term follow-up of 246 adults with juvenile idiopathic arthritis: education
      and employment.
AB  - OBJECTIVE: To examine the levels of education and employment in adults with
      juvenile idiopathic arthritis (JIA) compared with their siblings and national
      figures. PATIENTS AND METHODS: Two hundred and forty-six adults identified with
      long-standing JIA had an average disease duration of 28.3 yr. Educational
      achievements and employment status were recorded and comparative data obtained
      from siblings and the National Office for Statistics, UK. The effects, incidence
      and nature of discrimination in the workplace were also explored. RESULTS: Across
      all levels of education the study group achieved significantly better results
      than both the national average and their siblings. In contrast, the rate of
      unemployment in the patient group was more than twice that in the national
      population. The percentage of patients who had encountered discrimination in the
      workplace was 25.1.

PMID- 12468825
TI  - Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional
      outcome.
AB  - OBJECTIVE: To examine the clinical and functional outcome of adults with juvenile
      idiopathic arthritis (JIA) using the recent World Health
      Organization/International League Against Rheumatism (ILAR) classification.
      PATIENTS AND METHODS: Two hundred and fifty-nine adults with long-standing JIA
      (average disease duration 28.3 yr) were eligible for the study; 246 (95%)
      attended for an interview, clinical examination and notes review and 231 (89.2%)
      returned a comprehensive functional and psychosocial self-assessment
      questionnaire. RESULTS: Of all patients, 43.3% had active arthritis clinically
      and 54.4% on laboratory measures (C-reactive protein). Clinical inflammation was
      less common in systemic-onset JIA. The percentage of all patients with severe
      disability (Health Assessment Questionnaire score >1.5) was 42.9. Uveitis
      occurred frequently in the oligoarticular-onset and enthesitis-related subsets.
      Over 30% of the extended oligoarticular group with uveitis developed glaucoma
      compared with none of the enthesitis group. CONCLUSIONS: Adults with JIA often
      have significant levels of disability, often related to continuing active disease
      over prolonged periods. There is a clear need for good transition from paediatric
      to high-quality adult rheumatology care.

PMID- 12468827
TI  - Long-term follow-up of 246 adults with juvenile idiopathic arthritis: social
      function, relationships and sexual activity.
AB  - OBJECTIVE: To examine social function, relationships and sexual activity in
      adults with juvenile idiopathic arthritis (JIA). PATIENTS AND METHODS: Two
      hundred and forty-six adults identified with long-standing JIA had an average
      disease duration of 28.3 yr. Specific information was sought on marital status,
      offspring, age at first sexual encounter, and problems related to disease in
      sexual activity and pregnancy. RESULTS: Fewer patients (42.8%) were in stable
      relationships than their siblings (55.3%). The percentage of patients with
      children was 27.5. Twenty-three per cent of all known pregnancies ended in
      miscarriage. Of the women who had had a Caesarean, 78.9% had either reduced hip
      mobility or short stature. JIA had a detrimental effect on body image in 50.7% of
      patients but relationships were affected in only 28.2%. The percentage of
      patients who were sexually active or had had previous sexual experience was 83.3;
      58.3% of these had disease-related sexual problems. CONCLUSIONS: A significant
      proportion of individuals are sexually active before transfer to adult
      rheumatology care at the age of 18 yr. This highlights the need to introduce
      sexual counselling in adolescent clinics. The high incidence of psychological
      sexual problems may benefit from appropriate counselling and training.

PMID- 12468828
TI  - Long-term follow-up of 246 adults with juvenile idiopathic arthritis: predictive
      factors for mood and pain.
AB  - OBJECTIVE: To examine the predictive factors for anxiety, depression and pain in
      adults with juvenile idiopathic arthritis (JIA). PATIENTS AND METHODS: Two
      hundred and forty-six adults identified with long-standing JIA had an average
      disease duration of 28.3 yr. Candidate factors potentially predictive for pain,
      anxiety and depression were assessed by multiple regression analysis. RESULTS: Of
      the patients, 31.6% were anxious, 5.2% were depressed, and 21.1% had previously
      suffered from depression. The percentage of the variance accounted for by other
      variables was 78.8 for anxiety variance and 54.5 for depression, but there was
      little influence from physical disease-related factors. Severe pain, measured on
      a visual analogue scale, occurred in 32.9% of patients, and 22.8% had poor
      perceived control over their pain. Function, coping strategies, pain self
      efficacy, inflammation and previous depression could predict 39.6% of the
      variance in pain. CONCLUSIONS: Comparing adults with children, disease activity
      and control over pain remain predictors of pain but become less important than
      disability and coping strategies.

PMID- 12468829
TI  - Anti-tumour necrosis factor therapy associated with cutaneous vasculitis.

PMID- 12468830
TI  - Allergic vasculitis associated with celecoxib.

PMID- 12468831
TI  - Cervical discitis in a patient with an oesophageal stent for carcinoma.

PMID- 12468832
TI  - A fresh look at polymyalgia rheumatica.

PMID- 12468833
TI  - Validation of an Indian version of the Health Assessment Questionnaire in
      patients with rheumatoid arthritis.

PMID- 12468836
TI  - Natural history of lumbar disc hernia with radicular leg pain: Spontaneous MRI
      changes of the herniated mass and correlation with clinical outcome.
AB  - A prospective sequential MRI study was done to investigate the morphologic
      changes of the lumbar disc hernia (LDH). We also studied the relationship between
      the MRI changes and the type of LDH and the clinical outcome. MRI was performed
      every 3 months from the onset for a maximum of 24 months in 42 patients with
      radicular leg pain and symptoms definitely diagnosed as caused by LDH. The size
      of the herniated mass was determined by the ratio of the anteroposterior diameter
      of the spinal canal to the maximum diameter of the LDH mass on T2-weighted axial
      images. The clinical outcome was evaluated as excellent, good, or poor depending
      on leg pain and physical findings. The JOA (Japanese Orthopaedic Association)
      score for LDH was also used to assess the outcome. Thirty-seven (88%) of the 42
      patients showed >50% reduction of the hernia on MRI 3-12 months after onset, and
      the morphologic changes of the herniated mass were well correlated with the
      clinical outcome.

PMID- 12468837
TI  - Experimental study of multiple level compression of the spinal cord in the rat.
AB  - A rat model study was performed to evaluate the effects of compression of the
      thoracic spinal cord. Dorsal screw compression of the thoracic spinal cord up to
      50% canal diameter was created at T5 (Group A), T5 and T11 (Group B), and T5 and
      T8 (Group C). Clinical grading (Tarlov criteria), sensory evoked and motor evoked
      potentials, horse raddish peroxidase neural transport, and microangiography were
      studied. Single level compression had little effect. For double compression,
      there were marked detrimental effects both clinically and electrophysiologically,
      especially when the compression was close together. Neutral transport was
      affected in all groups, but the difference was not significant between them.

PMID- 12468838
TI  - Osteoporosis: A possible aetiological factor in the development of Scheuermann's
      disease.
AB  - The aim of this study was to test the hypothesis that spinal osteoporosis is an
      aetiological factor in the development of Scheuermann's disease in adolescents.
      Clinical and radiological data was collected on 12 individuals with Scheuermann's
      disease (SD). Lumbar spine bone mineral density (L2-4) was measured using dual
      energy X-ray absorptiometry. Age and sex-matched adolescents were used as
      controls. The number of standard deviations from the mean of age and sex-matched
      controls were calculated. In regards to results, SD patients demonstrated high
      bone densities of between 1 and 1.5 standard deviations above the mean of age
      matched controls. These results suggest that osteoporosis is not an aetiological
      factor in Scheuermann's disease and that bone density measurements may indeed be
      higher than aged-matched controls in the general population.

PMID- 12468839
TI  - The use of arm span as a predictor of height: A study of South Indian women.
AB  - This study was undertaken to find out the relationship between various body
      parameters to identify the measurement that correlates most closely to stature.
      Sitting height, standing height, arm span and leg lengths of 505 healthy women
      between the ages of 20 and 29 were measured. The relationship between the
      parameters was determined by computing correlation coefficients and 95%
      confidence intervals. The correlation between sitting height, arm span and leg
      length were poor (r=0.56 and 0.29 respectively), while the correlation of arm
      span and leg length with standing height were good (r=0.82 and 0.84
      respectively). These estimations can be of use in quantifying the age related
      loss in stature and in identifying individuals with disproportionate growth
      abnormalities and skeletal dysplasias. It can also be useful to find out the
      alterations in the height of an individual that may occur due to progressive
      deformities of the spine. The adequacy of the correction of spinal deformities
      may also be facilitated by computing the ratio of arm span to standing height.

PMID- 12468840
TI  - Chemical eluates from ultra-high molecular weight polyethylene and fibroblast
      proliferation.
AB  - Although polyethylene wear particles have been implicated in osteolysis and
      implant loosening, this study is the first to test whether chemical eluates
      extracted from ultra-high molecular weight polyethylene (UHMWPE) could also be
      involved in this process. Eluates were prepared from UHMWPE bar stock and
      examined for their effects on (3)H-thymidine incorporation by human foreskin
      fibroblasts grown in 96-well culture plates. Low concentrations of eluates
      stimulated (3)H-thymidine uptake; whereas, high concentrations inhibited uptake
      in a dose-dependent manner. Maximum inhibition of proliferation for eluates (87+/
      0.03% inhibition, n = 45 paired wells) was greater than that observed for
      particles (54+/-0.07% inhibition, n = 45 paired wells). Ethylene oxide
      sterilization of UHMWPE reduced (3)H-thymidine uptake at low eluate
      concentrations relative to sterilization by gamma-irradiation. It was concluded
      that leachable eluates from UHMWPE implantse contribute to the osteolytic process
      at the bone-implant interface.

PMID- 12468841
TI  - Sports related fractures: A review of 113 cases.
AB  - To establish a profile of fractures related to sporting activities, to determine
      the extent to which these injuries resulted in morbidity, and to find suitable
      target areas for injury prevention, a one-year study was undertaken at Seremban
      Hospital, Negeri Sembilan, Malaysia, from July 15, 1998 to July 14, 1999. All
      patients presenting to the Department of Orthopaedic & Traumatology with
      fractures sustained during sporting activities were enrolled. Fractures related
      to sporting activities are increasing and an entity to be recognized despite the
      good function outcome of the treatment. Suitable target areas for injury
      prevention were found to be football (for males), netball (for females), the
      second decade of life and competitive sporting events.

PMID- 12468842
TI  - Foot and ankle injuries occurring in inflatable rescue boats (IRB) during surf
      lifesaving activities.
AB  - Inflatable Rescue Boats (IRBs) are utilised by the Surf Life Saving Association
      (SLSA) in Australia to perform rescue operations and in regional competitions
      between surf clubs. These activities have resulted in a number of serious foot
      and ankle injuries which reflect the high impact of this activity in heavy and
      unpredictable surf. We have retrospectively reviewed 12 significant injuries
      relating to IRB usage presented to our regional hospital emergency department
      over a 3-year period. These include 6 Lisfranc fracture dislocations of the
      midfoot, 4 ankle fracture variants, one tibial shaft fracture, and one traumatic
      rupture of the peroneal retinaculum leading to peroneal tendon dislocation.
      Analysis of IRB footstraps in current usage shows they are directly related to
      the patterns of injury seen. We have recommended modifications to footstraps and
      handgrips currently in use with the aim of minimising or preventing these
      injuries.

PMID- 12468843
TI  - Bilateral total knee arthroplasty: One mobile-bearing and one fixed-bearing.
AB  - We compared the early results of mobile-bearing knee prosthesis with fixed
      bearing knee prosthesis in 16 patients who had one-stage, sequential, bilateral
      replacements. In each patient, a Low Contact Stress (LCS, Depuy) rotating
      platform prosthesis was inserted in one side, and an Anatomic Modular Knee (AMK,
      Depuy) posterior-stabilised prosthesis was inserted in the other side. The same
      surgical routines were adopted for both sides in each patient. There were
      significant improvements in the Knee Society knee score and functional score, as
      well as the Oxford Knee score after both mobile-bearing and fixed-bearing knee
      replacements (p<0.001). However, we could not find any significant difference
      between the clinical results of the two prostheses. The authors early experience
      with the mobile-bearing total knee prosthesis was as favourable as the medium
      term experience of the fixed-bearing total knee prosthesis in this prospective,
      match-pair study.

PMID- 12468844
TI  - Infection of the inguinal region treated by musculocutaneous flaps.
AB  - This study documented the treatment of the inguinal dead space with chronic
      infection using musculocutaneous flaps. The average age of the patients (5 males
      and 2 females) was 50.0 years. Six cases of reconstruction after malignant tumor
      resection and one case after total hip arthoroplasty were treated. Six rectus
      abdominis flaps and 2 vastus lateralis flaps were used. Previous radiation
      therapy had been performed on five patients. The duration of chronic infection
      averaged 2.3 months, excluding a 4- year long case. All flaps survived and the
      average follow-up period was 2.8 years. Five cases had no relapse of the
      infection but two cases relapsed 18 months and 2 years respectively after the
      surgery. These two did not have tumor prostheses removed prior to the surgery.

PMID- 12468845
TI  - Unusual presentation of shoulder joint tuberculosis: A case report.
AB  - Tuberculosis of the shoulder joint is uncommon. In adults the classical dry type
      of shoulder tuberculosis (caries sicca) has been described, while the fulminating
      variety has not been reported. We treated a case of fulminating variety of
      tuberculosis of the shoulder joint with anti-tubercular therapy and a shoulder
      immobilizer sling. At 18 months of follow up, the patient was disease free and
      had a good functional range of motion.

PMID- 12468846
TI  - Pachydermoperiostosis: Three case reports.
AB  - Three patients with pachydermoperiostosis are reported. All patients presented
      with moderate pain and swelling in multiple joints unresponsive to treatment,
      characteristic facial features which were marked in two cases, clubbing of nails
      and enlargement of distal parts of the extremities. One patient had
      spondylolisthesis of L5-S1 vertebrae, an association not previously described in
      this syndrome. The natural history of the disease is reviewed and the
      differential diagnosis is discussed.

PMID- 12468847
TI  - Trapezius interposition of a distal third clavicular fracture in a child: A case
      report.
AB  - We report an 11-year-old child with fracture of the distal clavicle who was
      denied conservative treatment because the medial end of the clavicle was anchored
      into the trapezius muscle fiber by an extreme posterior displacement. Surgical
      reduction was indicated.

PMID- 12468848
TI  - Massive prepatellar bursitis in post-polio residual paralysis: A case report.
AB  - We report a case of post-polio residual paralysis, an eighteen-year old girl who
      was ambulatory on all four limbs and presented to us with a massive pre-patellar
      bursitis on her left knee.

PMID- 12468849
TI  - High cervical lipoma: A case report and review with classification.
AB  - We experienced a 51 year-old female with high cervical lipoma who complained of
      neck pain and hypoaesthesia on her right lower extremity. She underwent surgery
      for removal of the tumour, but she was found unconscious after the surgery and
      then died after 19 days.

PMID- 12468850
TI  - Review article: Paediatric bone and joint infection.
AB  - Paediatric musculoskeletal infection remains an important cause of morbidity.
      Methicillin sensitive Staphylococcus aureus is still the most common organism
      although the incidence of methicillin resistant S. aureus in the community is
      rising. Osteomyelitis and septic arthritis due to Haemophilus influenzae is
      decreasing in incidence secondary to immunisation and in some units has been
      replaced by infections with the gram negative bacillus, Kingella kingae. Recent
      prospective studies indicate that uncomplicated osteomyelitis can be treated by
      three to four weeks of antibiotics. However, there is still a small group of
      children who will have overwhelming disseminated infection. These children
      require aggressive surgical and medical intervention. Two recent reports have
      identified an increased incidence of septic arthritis in children who have
      hemophilia and are HIV positive.

PMID- 12468852
TI  - Editorial.

PMID- 12468851
TI  - Review Article: Polyethylene wear and osteolysis in total hip arthroplasty.
AB  - Polyethylene wear has been accepted as a major cause of osteolysis in total hip
      arthroplasty. Submicron particles, which are secondary to abrasive wear, migrate
      into the effective joint space and stimulate a foreign-body response resulting in
      bone loss which is mainly mediated by macrophages. Diagnosis depends on serial
      radiographic evaluation and frequent follow-up. Polyethylene wear and osteolysis
      can be prevented by reducing the wear such as using a small femoral head,
      adaptive polyethylene thickness, suitable surgical techniques, non-polyethylene
      articulation, etc. The presence of cement or circumferential coatings may also
      retard the distal migration of particles. Medicines such as NSAIDs and
      bisphosphonate appear to inhibit the progress of osteolysis. As far as treatment,
      revision surgery is able to reconstruct the joint by replacing partial or total
      prosthesis and repair the defect by bone grafting according to intraoperative
      assessment.

PMID- 12468853
TI  - Bacterial load in tissues and its predictive value for infection in open
      fractures.
AB  - The role of quantitative bacteriology is considered controversial for the
      prediction of infection in open fractures. A study was done in 20 patients with
      open fractures. Post debridement pieces of skin, muscle and periosteal tissue
      were obtained for quantitative bacterial counts. Among a total of 50 samples from
      all of the tissues, 29 showed positive bacterial counts (16 of 20 skin, 11 of 20
      muscle and 2 of 10 periosteum samples). By quantitative estimation, the bacterial
      load was >10(5) per gram in 10 skin and 3 muscle tissue samples. Infection
      developed in 9 of the 20 cases within one month, and eight of these patients had
      contamination of >10(5) per gram in 8 of the skin but only 3 muscle samples. It
      was concluded that with tissue specific bacterial load estimation, prediction of
      subsequent infection can be made if skin tissue contains >10(5) per gram, or if
      muscle tissue carries any level of bacterial presence.

PMID- 12468854
TI  - Intramedullary pin fixation in clavicular fractures: A study comparing the use of
      small and large pins.
AB  - The S-shaped clavicle poses a problem for intramedullary pin fixation. Stability
      of fracture fixation is closely related to the length of intramedullary pin
      engagement. This study was carried out to determine the engagement length of
      intramedullary pins into clavicular fractures using a small and a large pin.
      Seven pairs of fresh cadaveric clavicles were prepared and arranged into Group 1
      and Group 2 for paired study. A mid-third clavicular fracture was created at the
      junction of the two curves of the clavicle. In Group 1, a 3.2 mm diameter
      threaded Steinman pin was introduced into the medullary canal of the clavicle by
      retrograde technique and the medial fragment of the fracture was drilled until
      the pin perforated the bone cortex. In Group 2, a 4 mm diameter threaded Steinman
      pin was used in the same manner. The results showed that Group 1 had an average
      engagement of pin into the clavicle of 9.11 cm with a ratio to total length of
      the clavicle of 0.59. In Group 2, the average engagement length into the clavicle
      was 7.17 cm with a ratio of 0.47. The difference was significant, with the
      smaller pin providing better fixation. The pins in both groups perforated the
      lateral fragment at the posterosuperior aspect and the medial fragment at the
      anterior aspect of the clavicle. The angle that the pin made with the long axis
      of the clavicle in Group 1 was 22.43 degrees and in Group 2, 26.57 degrees.
      Although the 3.2 mm diameter pin was more aligned to the long axis of the
      clavicle than the 4 mm diameter pin, the difference was not significant.

PMID- 12468855
TI  - Medial approach for operative treatment of the widely displaced supracondylar
      fractures of the humerus in childre.
AB  - Twenty-seven widely displaced supracondylar fractures of the humerus in children
      were treated by open reduction and cross K-wire fixation by the medial approach
      over a 30-month period. The mean follow-up was 14 months, average age 8 years and
      the mean delay in presentation 49 hours. Medial approach provided an excellent
      view of the medial bone pathology via an internervous plane and enabled an
      anatomical reduction in all cases. Cross K-wire fixation obviated the need to
      immobilize the elbow at 90 degrees or more flexion. No postoperative
      neurovascular complication was noted. Most patients regained full range of motion
      within 6 weeks of pin removal and no change in the carrying angle was noted.
      Delayed presentation, repeated manipulations and massage were responsible for
      loss of motion. Superficial pin tract infection was noted in 5 patients and
      resolved with dressings and antibiotics. No deep infection occurred. Medial
      approach for open reduction and internal fixation of the widely-displaced
      supracondylar fracture of the humerus is safe and straightforward, ensuring
      anatomical reduction and excellent function.

PMID- 12468856
TI  - Clinical study of surgical treatment of carpal tunnel syndrome: Open versus
      endoscopic technique.
AB  - Twenty-six patients (30 hands) who underwent endoscopic carpal tunnel release
      were physically examined and asked to complete questionnaires on their symptoms,
      functional limitations and satisfaction. Their mean grip strength improved
      considerably from 17.5 kg before the operation to 31.3 kg at the final follow-up.
      Symptoms at the final follow-up were hypesthesia in 9 hands, muscle atrophy in
      10, positive Tinel sign in 3, and positive Phalen sign in 1. The mean symptom
      severity score improved from 3.01 before the operation to 1.44 at the final
      follow-up and the mean functional status score improved from 3.20 to 1.54. The
      average times to return to activities of daily living and work were 7.3 days and
      18.4 days respectively. Twenty-two of the 26 patients (85%) were satisfied. There
      was no injury to neurovascular structures. Arterial injuries were prevented by
      marking the superficial palmar arch and ulnar artery with a Doppler ultrasonic
      hemodrometer before surgery.

PMID- 12468857
TI  - Clinical results of the new cervico-thoracic orthosis 'Neck-Chest brace'
AB  - The efficacy of a new cervico-thoracic Neck-Chest brace (N-C brace) prepared for
      post- operative patients of cervical canal expansive laminoplasty was assessed.
      The orthosis is light in weight (300 g) and easy to fit. The effect of the
      orthosis to restrict the neck motion was studied in 10 normal young males by
      using lateral view radiographs in extension and flexion positions. The average
      range of the neck motion for the N-C brace was 24.4% of the values obtained
      without the orthosis. The restriction of the motion was significantly better than
      that without orthosis. Then, the clinical efficacy of the N-C brace was assessed
      in 40 patients of cervical spondylotic myelopathy who underwent expansive
      laminoplasty. Alignment changes of the postoperative cervical spine was found
      only in 10% of the patients who had a straight and kyphotic curvature pattern in
      the cervical spine before operation. The cervical alignments in the other 90% of
      patients were not changed post-operatively. These data clearly demonstrated that
      the N-C brace effectively controls the neck motion and is recommended for
      patients who have a lordotic curvature pattern in the cervical spine to prevent
      the post-surgical changes in the alignment after expansive laminoplasty.

PMID- 12468858
TI  - Patterns of presentation of congenital scoliosis.
AB  - In analysing and investigating 66 consecutive cases of congenital scoliosis, we
      aimed to evaluate the clinical pattern of presentation, identify the underlying
      vertebral anomaly causing the deformity, and determine the frequency of
      associated intraspinal anomalies, cardiovascular anomalies and genito-urinary
      anomalies. Associated general anomalies were seen in 44% of the cases. The
      commonest pattern of deformity was a right-sided thoracolumbar curve.
      Hemivertebra was the most common vertebral anomaly (45%). Occult intraspinal
      anomalies were seen in 15% of cases, diastematomyelia being the commonest
      anomaly. Genitourinary anomalies and cardiovascular abnormalities were
      encountered in 6% and 15% of patients respectively. As decision making in the
      treatment of congenital scoliosis depends on the natural history of progression
      of the deformity and associated intra and extra spinal anomalies, identification
      of all associated anomalies is essential.

PMID- 12468859
TI  - Strenuous walking exercise and spontaneous fracture of the femoral neck in the
      elderly.
AB  - Spontaneous fractures of the hip which developed after strenuous walking exercise
      in 8 elderly people are reported. All patients had Singh hip index 4 or below at
      the time of initial examination and walked from 8,000 to 10,000 steps per day.
      This presentation aims to arouse the attention of physicians, recreational sports
      coaches, and elderly people to the deleterious effects of strenuous walking
      exercise on bone, and it looks for an optimal level of walking exercise according
      to the elderly patient"s bone quality. Walking exercise should be stopped
      immediately if pain in the hip develops and continues without relief for several
      days or more. The optimal walking frequency per day should be prescribed on the
      basis of the Singh index or T-score of BMD. If the BMD is 1/3 to 1/2 of normal,
      walking frequency should be adjusted to 1/3 to 1/2 of those of the normal adult
      with good bone quality.

PMID- 12468860
TI  - Cementless total hip arthroplasty using the omnifit system: An 8.2 year follow-up
      study of 166 hips.
AB  - One hundred and sixty-six cementless primary total hip arthroplasties were
      performed in 133 patients with porous coated Omnifit prosthesis. The average age
      was 49.7 years. The mean follow-up period was 8.2 years with a minimum of 5
      years. Good to excellent clinical results were achieved in 93% of patients. The
      overall revision rate was 5.4%. Radiographically, bone ingrowth occurred in all
      unrevised cups, and in 95% of unrevised stems. Osteolytic lesions appeared at an
      average of 3.8 years postoperatively. Femoral and pelvic osteolysis were seen in
      21% and 4% of the surviving hips respectively. All femoral osteolytic lesions
      were found in the proximal Gruen zones 1 and 7. The mean annual polyethylene wear
      rate was 0.15 mm. Approximately one-third of the hips were observed to have
      excessive wear. Our experience with cementless Omnifit total hip prosthesis is
      encouraging. Of significant concern is the high incidence of excessive
      polyethylene wear and osteolysis.

PMID- 12468861
TI  - Prevention of heterotopic bone formation in high risk patients post-total hip
      arthroplasty.
AB  - A retrospective study was carried out to evaluate prophylaxis for heterotopic
      ossification (HO) about the hip joint post total hip arthroplasty (THA). Between
      1990 and 1996, 20 patients with known risk for developing HO were treated
      prophylactically to prevent this complication. Patients at risk were divided into
      3 groups based on risk factors for HO formation (previous ipsilateral hip HO
      formation, previous contralateral hip HO formation and bilateral hypertrophic
      osteoarthritis) Single fraction radiotherapy of 600, 700 or 800 cGy was
      administered postoperatively to all patients. The aim was to irradiate all
      patients within 72 hours of THA. 12 (60%) patients received in addition a short
      course of postoperative indomethacin for less than 13 days. Patients in this
      study were investigated for the following treatment variables: relative risk for
      forming HO, radiotherapy doses administered, time delays between surgery and
      irradiation, combined radiotherapy and indomethacin treatment versus radiotherapy
      alone, and surgical approach used for THA. Heterotopic ossification in patients
      was measured radiographically by use of the Brooker grading sytem, and was
      assessed clinically by use of the Harris Hip Score (HHS). A significant
      difference was found between relative risk groups (p = 0.02). Patients with
      previous HO formation in the ipsilateral hip joint were at greater risk of
      developing HO than those with previous contralateral HO formation. Moreover both
      of these groups were at greater risk than those with advanced bilateral
      hypertrophic osteoarthritis. Other variables studied showed differences that were
      not significant due to small sample numbers. This study, though limited by sample
      number, addresses questions regarding effective radiotherapy dosage, time delays
      acceptable before irradiation postoperatively, usefulness of short course
      postoperative indomethacin, and preferred operative approaches to minimise HO.

PMID- 12468862
TI  - Anterior cruciate ligament reconstruction using the double bundle method.
AB  - Clinical results of our reconstruction technique for anterior cruciate ligament
      using the double bundle, i.e., the combination of bone-tendon-bone (BTB) from the
      patellar tendon and semitendinosus tendon (ST), were evaluated. BTB was fixed in
      the tunnels produced on the isometric points on the tibia and femur, and ST, on
      the tibial tunnel through the same route as BTB. Throughout the observation
      period, no patients developed pain, limited range of motion, and/or instability
      of the operated knee. All patients were able to return to previous sports
      activities within 12 months. No apparent changes occurred on the reconstructed
      ligament. In 4 of 14 patients, knee stability was quantitatively examined, and a
      good result was obtained. The double bundle was found to be a useful method for
      patients who require physiologically more durable reconstruction.

PMID- 12468863
TI  - Persistent back pain in adults: Four case reports.
AB  - The author describes 4 cases of thoracic back pain. All 4 had significant night
      pain, and 3 of the 4 presented with an upper motor neuron lesion of the lower
      limbs subsequestly diagnosed as a primary vertebral tumor. All lesions were well
      demonstrated on CT examination and were proved to be chordoma, lymphoma, solitary
      plasmacytoma or aneurysmal bone cyst. Awareness of primary thoracic tumours is
      important, as early recognition may prevent irreversible damage to the cord.

PMID- 12468864
TI  - Adult-onset intradural spinal teratoma in the lumbar spine: A case report.
AB  - Intradural spinal teratoma is a very rare tumour that can be associated with
      dysraphic defects. We report a case of adult-onset intradural spinal teratoma in
      the lumbar spine. The patient was a 54-year-old female who had chief complaints
      of a gait disturbance. X-rays showed an enlargement of the interpedicular
      distance at L3/L4 and spina bifida distal to L4. MRI showed a spindle-shaped
      tumour between L2 and L5. We performed laminotomy using an ultrasonic surgical
      knife. Pathological diagnosis of the resected tumour was matured teratoma. The
      diagnosis of matured teratoma was made because the tumour had no epithelium and a
      layered structure including prostate tissue, matured fat, cartilage and sweat
      gland.

PMID- 12468865
TI  - Multiple joint replacement in chronically neglected polyarthritic patients: Two
      case reports.
AB  - Multiple joint replacement is a viable option for rehabilitation of young
      polyarthritic patients with unsalvageable joints. Young polyarthritic patients in
      this part of the world suffer from chronic neglect because of ignorance, apathy
      and low socio-economic status. During the period of chronic neglect, these
      patients acquire extreme deformities of various joints either due to active
      disease (ankylosing spondylitis, rheumatoid arthritis) or irreversible changes in
      the joint configuration like ankylosis and soft-tissue contracture. Associated
      spine and thoracic cage affection create problems for anaesthesia and peri
      operative positioning. We report 2 cases of multiple joint replacements for young
      polyarthritic patients who were bedridden for 6 to 11 years. Surgeries were
      performed in a phased manner and after extensive rehabilitation both patients
      were able to walk unaided. Various problems and difficulties encountered have
      been addressed so as to serve as a guide to surgeons who may have to deal with
      such unusual situations of chronic neglect. We also report a modified exposure
      technique without trochanteric osteotomy for total hip replacement, which is
      valuable in extreme external rotation ankylosis.

PMID- 12468866
TI  - Review article: Reconstructive surgery following resection of primary and
      secondary tumours of the hip.

PMID- 12468867
TI  - Management of Osteomyelitis.

PMID- 12468868
TI  - Chronic triangular fibrocartilage complex tears with distal radioulna joint
      instability: A new method of triangular fibrocartilage complex reconstruction.
AB  - From September 1996 to September 1997, 27 adult patients were diagnosed with
      chronic triangular fibrocartilage complex (TFCC) tears with distal radioulna
      joint (DRUJ) instability in our clinic. They all received the procedure of TFCC
      reconstruction with partial extensor carpi ulnaris (ECU) tendon combined with or
      without ulnar shortening. There were 26 males and one female in the study with a
      mean age of 22.4 years. The follow-up period ranged from 22 to 28 months with a
      mean of 26.2 months. 24 patients who had positive or zero ulnar variance received
      the procedure of ulnar shortening. Three patients who had minus ulnar variance
      only received TFCC reconstruction. After the operation, the DRUJ was fixed by a
      2.0 mm K-wire for 4 weeks. All patients underwent a rehabilitation program and
      they were reexamined at our outpatient department (OPD). The results were graded
      according to the Mayo Modified Wrist Score. Five of the 27 patients rated their
      wrists 'excellent', 18 rated 'good', and 4 rated 'fair. Overall, a total of 23
      patients (85%) rated satisfactorily and returned to work or sport activities. In
      the 4 patients rated 'fair', mild pain at work and/or exercise, and mildly
      limited supination were found; however their grip strength was improved at least
      by 65% compared to the opposite hand. Therefore, as suggested by this study, TFCC
      reconstruction with partial ECU tendon combined with the ulnar shortening
      procedure is an alternative method for chronic TFCC tears with DRUJ instability.

PMID- 12468869
TI  - Locally made instruments for endoscopic carpal tunnel release.
AB  - Endoscopic carpal tunnel release (ECTR) was introduced into Thailand when this
      technique became widely accepted. However, the technique was limited to only a
      few institutions because of the training required and the very high cost of the
      instruments. Because of the economic crisis in Thailand, most hospitals in the
      public health ministry had no budget to invest in new instruments. However, new
      technology cannot be ignored so the authors modified some unused instruments in
      conjunction with an arthroscope in order to perform ECTR. A 5 cm by 4 mm slot was
      made at the mid-portion of an old unused 5 mm arthroscopic sheath. One end of
      this sheath was reshaped to fit the meniscectomy hook blade. A 4.5 mm Steinmann
      pin was reshaped to be the obturator of the arthroscopic sheath. ECTR was
      performed with this instrument in conjunction with an arthroscope (modified from
      Chow's 2-portals technique). The transverse carpal ligament was clearly viewed
      and identified, and the transverse carpal ligament was completely divided by the
      menisectomy hook blade. The operation time was 10 to 20 minutes. 30 patients
      received ECTR with this set of instruments, and they were completely relieved
      from the symptoms and returned to work early without any complications. The
      advantages of this instrument are that it is very cheap, it has a low learning
      curve, and it is safe and effective.

PMID- 12468870
TI  - Unusual arterial injury following a fracture of the forearm bones: A case report.
AB  - The author describes a case of a 10-year-old boy with fracture of both forearm
      bones and a concomitant partial rupture of the ulnar artery. The damage to the
      ulnar artery was repaired at the time of fasciotomy with a good functional
      outcome.

PMID- 12468871
TI  - Body height correction in scoliosis patients for pulmonary function test.
AB  - We studied standing anteroposterior roentgenograms from 140 scoliosis patients
      and obtained a correction equation for body height by Cobb angle. This equation
      is applicable to patients with a double curve or special curve pattern as well as
      patients with a single curve. The repeatability of the method examined with this
      equation was higher than that with the previous correction method for body height
      by Cobb angle, and the difference between the corrected values and the measured
      values was small. Therefore, this method is considered to be more reliable.

PMID- 12468872
TI  - Periprosthetic fracture of the femur after hip arthroplasty: The clinical outcome
      using cortical strut allografts.
AB  - Between 1993 and 1998, 15 patients with periprosthetic fractures of the femur
      after hip arthroplasty were treated using deep-frozen cortical strut allografts
      as an adjunct support after internal fixation or revision arthroplasty. According
      to the Vancouver classification system, there were 7 type B1, 2 type B2, 4 type
      B3 and 2 type C fractures. Seven patients had severe osteopenia, 10 patients had
      bone defects between 2 to 7 cm and 2 were associated with infection. Nine
      patients had internal fixation of the fracture using a compression plate, and 6
      had revision arthroplasty using a long-stemmed femoral prosthesis. The average
      length of the allograft was 13.9 cm. At an average follow-up of 31 months, all
      the patients had a satisfactory functional result except one who had a leg length
      discrepancy of 4 cm due to multiple operations. There were no non-unions,
      malunions or infections. The fractures healed between 10 to 24 weeks (average,
      15.6 weeks). In conclusion, a cortical strut allograft associated with internal
      fixation can be an effective method of treating periprosthetic fractures of the
      femur after hip arthroplasty.

PMID- 12468873
TI  - Evaluation of Letournel and Judet classification of acetabular fracture with
      plain radiographs and three-dimensional computerized tomographic scan.
AB  - Letournal and Judet classification of acetabular fracture is widely used. The
      classification is based on the identification of fracture lines on plain
      radiographs. Three-dimensional CT scan was claimed to give a better view of the
      fracture line. Our study showed that intraobserver reproducibility and
      interobserver reliability were almost the same when classification was done by
      using plain radiographs and 3D-CT scan. And 3D-CT scan did not increase either
      the interobserver reliability or the intraobserver reproducibility in classifying
      the fracture.

PMID- 12468874
TI  - Epidural steroid injection for sciatica: An analysis of 526 consecutive cases
      with measurements and the whistle test.
AB  - The effects of epidural injections of triamcinolone acetonide and bupivacaine in
      the treatment of sciatica were analyzed in a retrospective series of 526
      consecutive cases with measurements. A new test (the whistle test) is described.
      There is a paucity of measureable parameters in reports on the subject in the
      literature, and many are not specific or symptom-oriented to sciatica. The
      procedure was performed by the same operator and reviewed one week post
      operatively with measurements. 491 patients (93.35%) achieved excellent to good
      pain relief, backed by appropriate increases of straight-leg-raise measurements.
      But 17 patients (3.46%) of this group required surgery later. It is concluded
      that epidural steroid injection is a simple, cost-effective and minimally
      invasive treatment for sciatica, especially in the acute. It also serves as a
      method for crisis intervention and as a prognosticator.

PMID- 12468875
TI  - A revised protocol for more clearly classifying a nonunion.
AB  - Classifying a nonunion solely on the extent of callus formation on a radiograph
      is insufficient. We have conducted a study with a revised protocol to classify a
      nonunion more clearly, which uses both radiographic observation and fixation
      stability. 47 consecutive femoral shaft nonunions were studied using this
      protocol and 42 nonunions were followed up for at least one year after discovery
      (range, 1-3 years). 40 nonunions healed after treatment with a union rate of
      95.2% (40/42) and a union period of 4.7 plus or minus 0.9 months. The 2 cases of
      failure were due to implant failure and both healed after reoperation. We
      recommend this revised protocol as a pretreatment assessment for all nonunions
      because of its integrity and effectiveness.

PMID- 12468876
TI  - Meniscal tearing after ACL reconstruction.
AB  - The knees of 72 patients with unilateral anterior-cruciate- ligament (ACL) injury
      were analyzed before ACL reconstruction as well as by follow-up arthroscopy on
      the day of staple removal. At ACL reconstruction 31 lateral menisci and 40 medial
      menisci were found to be normal. 28 lateral menisci and 24 medial menisci were
      treated surgically, while 13 lateral menisci and 8 medial menisci with small or
      incomplete meniscal tearing were not treated. At follow-up arthroscopy there were
      3 new cases of lateral meniscal tearing and 3 new cases of medial meniscal
      tearing in the groups diagnosed as normal prior to surgery. Two of the 13 cases
      with small or incomplete lateral meniscal tearing required resection, 8 healed
      and the other 3 demonstrated no progressive change. Four of the 8 cases with
      small or incomplete medial meniscal tears healed, 3 exhibited no progressive
      change and one required surgical treatment. There was no correlation between
      meniscal tearing and knee instability as indicated by a positive Lachman test or
      a positive pivot shift sign. The results of the present study indicate that ACL
      reconstruction prevents progressive changes in meniscal tears and will prevent
      secondary osteoarthritis, and that some small tears of the lateral meniscus
      require no surgical treatment.

PMID- 12468877
TI  - Exposure in difficult total knee arthroplasty using coronal tibial tubercle
      osteotomy.
AB  - Exposure in a total knee arthroplasty can be challenging regardless of whether it
      is a difficult primary or a revision. Various techniques both proximal and distal
      to the patella have been described and implemented to gain exposure and improve
      knee flexion. When patella eversion is not possible due to previous surgery or
      severe preoperative knee flexion contracture, a coronal tibial tubercle osteotomy
      may be utilized. We present successful results utilizing the coronal tibial
      tubercle osteotomy procedure. The technique involved in this series is based on
      that described by Whiteside. It involves the development of a long lateral
      musculoperiosteal flap incorporating the tibial tubercle and anterior tibia, and
      leaving the proximal tibial cortex intact. This is extended along the tibia
      distally for 10 cm. It finishes by gradually osteotomising the anterior surface
      of the tibial crest. The tubercle is reattached with wires at the end of the
      procedure. This technique minimizes complications that have been associated with
      the tibial tubercle osteotomy. The 10 knees in 9 patients, who had total knee
      arthroplasty with a coronal tibial tubercle osteotomy, were reviewed pre and
      postoperatively. All knees were assessed using the Hospital for Special Surgery
      knee score (HSS). The scores averaged 43.6 preoperatively (range, 29 57) and 79.2
      postoperatively (range, 67 90), and the mean range of motion was 59.5 degrees
      preoperatively and 78.0 degrees postoperatively. There were no cases of extension
      lag. Fixed flexion deformity was present in 3 cases postoperatively. Average time
      to union at the proximal and distal ends of the osteotomy was 8 and 24 weeks
      respectively. There was no evidence of nonunion and no other significant
      complications occurred.

PMID- 12468878
TI  - Correction of complex lower limb deformities by the Ilizarov technique: An audit
      of complications.
AB  - This is an audit of complications resulting from correction of complex lower limb
      deformities by the Ilizarov technique. 33 patients (40 bone segments) were
      reviewed and divided into 4 groups according to the type of surgery carried out:
      limb lengthening and/or correction of deformity, bone or joint stabilisation,
      treatment of nonunion or bone defect, angular and/ or rotation correction. Most
      minor complications were fixator specific. Pin tract infections were almost
      universal but responded well to oral antibiotics and rarely resulted in
      osteomyelitis. Major complications were procedure specific and more common in
      those patients who underwent leg lengthening, treatment for nonunion and bone
      transport. There was also a high incidence of nerve injury as a result of acute
      angular deformity correction. Despite the high complication rate the Ilizarov
      technique remains an effective tool for complex lower limb reconstruction
      surgery.

PMID- 12468879
TI  - Predictive value of magnetic resonance imaging in avascular necrosis following
      talar fractures.
AB  - Ischemic bone necrosis following talar fractures is a problematic complication
      and its early diagnosis is important. Patients with Hawkins Type II and III talar
      fractures received internal fixation using titanium alloy screws, and
      chronological bone changes were observed with Magnetic Resonance Imaging (MRI).
      With the Type II patient, Hawkins' sign was radiographically confirmed 2 months
      after the surgery. Furthermore, there were no changes of MR images for 2 years
      and a good clinical outcome was obtained. However, in the Type III patient,
      Hawkins' sign was negative and MRI revealed a low signal-intensity band on the
      talus 2 months after the surgery and then necrosis was radiographically
      confirmed; pain appeared 10 months later. These 2 cases suggest that MRI is a
      useful means for detecting bone necrosis with talar fractures in the early post
      operative period.

PMID- 12468880
TI  - In vitro study of immune tolerance induced by CTLA4-Ig in bone transplantation:
      The effect on cell proliferation stimulated by lymphocytes and bone supernatant.
AB  - To clarify the effect of CTLA4-lg on immune rejection of bone grafts, we observed
      the effect of CTLA4-lg on lymphocyte proliferation of BALB/C mice stimulated by
      lymphocytes and bone supernatant of C57BL/6 mice. The splenic lymphocytes and
      bone supernatant of C57BL/6 mice, as the stimulator cells and stimulator
      antigens, were cultured in vitro with the splenic lymphocyte of BALB/C mice. At
      the same time, CTLA4-lg at a dose of 5,10 or 20 &mgr;g/ml and L6 (as control) at
      20 &mgr;g/ml were added. Six days later, the incorporation of 3 H-TdR was
      determined. Results indicated that CTLA4-Ig at a dose of 5, 10 or 20 &mgr;g/ml
      significantly inhibited the cell proliferation stimulated by lymphocytes and bone
      supernatant of C57BL/6 mice. The effect was non-cytotoxic. L6 showed no
      significant inhibition of cell proliferation. CTLA4-Ig can efficiently block the
      proliferation of alloresponsive T cell stimulated by lymphocytes and bone
      supernatant of C57BL/6 mice. This study provides a basis for further study of
      CTLA4-induced immune tolerance of bone grafts.

PMID- 12468881
TI  - Retrodental synovial cyst which disappeared after posterior C1-C2 fusion: A case
      report.
AB  - Synovial cysts of the cervical spine are extremely rare. We describe an 8-year
      old boy with atlantoaxial subluxation and hypoplasia of the dens. Magnetic
      resonance imaging showed a round lesion, posterior to the odontoid process. This
      mass was characterized by a low signal intensity on T1-weighted images, and high
      signal intensity on T2-weighted images. The retrodental synovial cyst disappeared
      after posterior atlantoaxial arthrodesis.

PMID- 12468883
TI  - Bilateral septic arthritis of the hips associated with radiotherapy to the
      pelvis: A case report.

PMID- 12468882
TI  - Chondrosarcoma of the thoracic spine in an 8-year-old child with 12 years follow
      up: A case report.

PMID- 12468884
TI  - Review article: Treatment of Achilles tendon ruptures.

PMID- 12468885
TI  - The New Logo and the Future Direction of the Journal.

PMID- 12468886
TI  - Inflammation and infection in clinical stroke.
AB  - Stroke has enormous clinical, social, and economic implications, and demands a
      significant effort from both basic and clinical science in the search for
      successful therapies. Atherosclerosis, the pathologic process underlying most
      coronary artery disease and the majority of ischemic stroke in humans, is an
      inflammatory process. Complex interactions occur between the classic risk factors
      for atherosclerosis and its clinical consequences. These interactions appear to
      involve inflammatory mechanisms both in the periphery and in the CNS. Central
      nervous system inflammation is important in the pathophysiologic processes
      occurring after the onset of cerebral ischemia in ischemic stroke, subarachnoid
      hemorrhage, and head injury. In addition, inflammation in the CNS or in the
      periphery may be a risk factor for the initial development of cerebral ischemia.
      Peripheral infection and inflammatory processes are likely to be important in
      this respect. Thus, it appears that inflammation may be important both before, in
      predisposing to a stroke, and afterwards, where it is important in the mechanisms
      of cerebral injury and repair. Inflammation is mediated by both molecular
      components, including cytokines, and cellular components, such as leukocytes and
      microglia, many of which possess pro- and/or antiinflammatory properties, with
      harmful or beneficial effects. Classic acute-phase reactants and body temperature
      are also modified in stroke, and may be useful in the prediction of events,
      outcome, and as therapeutic targets. New imaging techniques are important
      clinically because they facilitate dynamic evaluation of tissue damage in
      relation to outcome. Inflammatory conditions such as giant cell arteritis and
      systemic lupus erythematosus predispose to stroke, as do a range of acute and
      chronic infections, principally respiratory. Diverse mechanisms have been
      proposed to account for inflammation and infection-associated stroke, ranging
      from classic risk factors to disturbances of the immune and coagulation systems.
      Considerable opportunities therefore exist for the development of novel
      therapies. It seems likely that drugs currently used in the treatment of stroke,
      such as aspirin, statins, and modulators of the renin-angiotensin-aldosterone
      system, act at least partly via antiinflammatory mechanisms. Newer approaches
      have included antimicrobial and antileukocyte strategies. One of the most
      promising avenues may be the use of cytokine antagonism, for example, interleukin
      1 receptor antagonist.

PMID- 12468887
TI  - Protein histidine phosphatase: a novel enzyme with potency for neuronal
      signaling.
AB  - The importance of reversible phosphorylation for neuronal signaling and cell
      survival is well recognized. Knowledge in vertebrates, however, is so far limited
      to O-phosphates from serine, threonine, and tyrosine. The authors describe an
      enzyme acting on N-phosphates. It is the first protein histidine phosphatase
      identified in vertebrates. This histidine phosphatase is ubiquitously expressed
      in mammalian tissues including brain. Characterization and sequencing showed a
      yet unknown protein with no similarity to other phosphatases. In Caenorhabditis
      elegans, the homolog of this histidine phosphatase was exclusively expressed in
      neurons, suggesting a distinct role of reversible histidine phosphorylation in
      neuronal functions.

PMID- 12468888
TI  - Positron emission tomography compartmental models: a basis pursuit strategy for
      kinetic modeling.
AB  - A kinetic modeling approach for the quantification of in vivo tracer studies with
      dynamic positron emission tomography (PET) is presented. The approach is based on
      a general compartmental description of the tracer's fate in vivo and determines a
      parsimonious model consistent with the measured data. The technique involves the
      determination of a sparse selection of kinetic basis functions from an
      overcomplete dictionary using the method of basis pursuit denoising. This enables
      the characterization of the systems impulse response function from which values
      of the systems macro parameters can be estimated. These parameter estimates can
      be obtained from a region of interest analysis or as parametric images from a
      voxel-based analysis. In addition, model order estimates are returned that
      correspond to the number of compartments in the estimated compartmental model.
      Validation studies evaluate the methods performance against two preexisting data
      led techniques, namely, graphical analysis and spectral analysis. Application of
      this technique to measured PET data is demonstrated using [11C]diprenorphine
      (opiate receptor) and [11C]WAY-100635 (5-HT1A receptor). Although the method is
      presented in the context of PET neuroreceptor binding studies, it has general
      applicability to the quantification of PET/SPECT radiotracer studies in
      neurology, oncology, and cardiology.

PMID- 12468889
TI  - Noise reduction in the simplified reference tissue model for neuroreceptor
      functional imaging.
AB  - The Simplified Reference Tissue Model (SRTM) produces functional images of
      receptor binding parameters using an input function derived from a reference
      region and assuming a model with one tissue compartment. Three parameters are
      estimated: binding potential (BP), relative delivery (R1), and the reference
      region clearance constant k'2. Since k'2 should not vary across brain pixels, the
      authors developed a two-step method (SRTM2) using a global value of k'2. Whole
      brain simulations were performed using human input functions and rate constants
      for [18F]FCWAY, [11C]flumazenil, and [11C]raclopride, and parameter SD and bias
      were determined for SRTM and SRTM2. The global mean of k'2 was slightly biased
      (2% to 6%), but the median was unbiased (<1%) and was used as the global value.
      Binding potential noise reductions with SRTM2 were 4% to 14%, 20% to 53%, and 10%
      to 30% for [18F]FCWAY, [11C]flumazenil, and [11C]raclopride, respectively, with
      larger reductions for shorter scans. R1 noise reduction was larger than that of
      BP. Simulations were also performed to assess bias when the reference and/or
      tissue regions followed a two-tissue compartment model. Owing to the constrained
      k'2, SRTM2 showed somewhat larger biases due to violations of the one-compartment
      model assumption. These studies demonstrate that SRTM2 should be a useful method
      to improve the quality of neuroreceptor functional images.

PMID- 12468890
TI  - Brain incorporation of [11C]arachidonic acid in young healthy humans measured
      with positron emission tomography.
AB  - Arachidonic acid (AA) is an important second messenger involved in signal
      transduction mediated by phospholipase A2. The goal of this study was to
      establish an in vivo quantitative method to examine the role of AA in this
      signaling process in the human brain. A simple irreversible uptake model was
      derived from rat studies and modified for positron emission tomography (PET) to
      quantify the incorporation rate K* of [11C]AA into brain. Dynamic 60-minute three
      dimensional scans and arterial input functions were acquired in 8 young healthy
      adults studied at rest. Brain radioactivity was corrected for uptake of the
      metabolite [11C]CO2. K* and cerebral blood volume (Vb) were estimated pixel-by
      pixel and were calculated in regions of interest. K* equaled 5.6+/-1.2 and 2.6+/
      0.5 microL x min(-1) x mL(-1) in gray and white matter, respectively. K* and Vb
      values were found to be unchanged with data analysis periods from 20 to 60
      minutes. Thus, PET can be used to obtain quantitative images of the incorporation
      rate K* of [11C]AA in the human brain. As brain incorporation of labeled AA has
      been shown in awake rats to be increased by pharmacological activation associated
      with phospholipase A2-signaling, PET and [11C]AA may be useful to measure signal
      transduction in the human brain.

PMID- 12468891
TI  - Widespread and long-lasting alterations in GABA(A)-receptor subtypes after focal
      cortical infarcts in rats: mediation by NMDA-dependent processes.
AB  - Impairment of inhibitory neurotransmission has been reported to occur in
      widespread, structurally intact brain regions after focal ischemic stroke. These
      long-lasting alterations contribute to the functional deficit and influence long
      term recovery. Inhibitory neurotransmission is primarily mediated by gamma
      aminobutyric acid (GABA)A receptors assembled of five subunits that allow a
      variety of adaptive changes. In this study, the regional distribution of five
      major GABA(A)-receptor subunits (alpha1, alpha2, alpha3, alpha5, and gamma2) was
      analyzed immunohistochemically 1, 7, and 30 days after photochemically induced
      cortical infarcts. When compared with sham-operated controls, a general and
      regionally differential reduction in immunostaining was found within the cortex,
      hippocampus, and thalamus of both hemispheres for almost all subunits. Within
      ipsilateral and contralateral neocortical areas, a specific pattern of changes
      with a differential decrease of subunits alpha1, alpha2, alpha5, and gamma2 and a
      significant upregulation of subunit alpha3 was observed in the contralateral
      cortex homotopic to the infarct. This dysregulation was most prominent at day 7
      and still present at day 30. Interestingly, a single application of the
      noncompetitive N-methyl-D-aspartate-receptor antagonist MK-801 during lesion
      induction completely blocked these bihemispheric alterations. Cortical spreading
      depressions induced by topical application of KCl do not change GABA(A)-receptor
      subunit expression. As alterations in subtype distribution crucially influence
      inhibitory function, ischemia-induced modifications in GABA(A)-receptor subtype
      expression may be of relevance for functional recovery after stroke.

PMID- 12468892
TI  - High glycogen levels in brains of rats with minimal environmental stimuli:
      implications for metabolic contributions of working astrocytes.
AB  - The concentration of glycogen, the major brain energy reserve localized mainly in
      astrocytes, is generally reported as about 2 or 3 micromol/g, but sometimes as
      high as 3.9 to 8 micromol/g, in normal rat brain. The authors found high but very
      different glycogen levels in two recent studies in which glycogen was determined
      by the routine amyloglucosidase procedure in 0.03N HCl digests either of frozen
      powders (4.8 to 6 micromol/g) or of ethanol-insoluble fractions (8 to 12
      micromol/g). To evaluate the basis for these discrepant results, glycogen was
      assayed in parallel extracts of the same samples. Glycogen levels in ethanol
      extracts were twice those in 0.03N HCl digests, suggesting incomplete enzyme
      inactivation even with very careful thawing. The very high glycogen levels were
      biologically active and responsive to physiologic and pharmacological challenge.
      Glycogen levels fell after brief sensory stimulation, and metabolic labeling
      indicated its turnover under resting conditions. About 95% of the glycogen was
      degraded under in vitro ischemic conditions, and its "carbon equivalents"
      recovered mainly as glc, glc-P, and lactate. Resting glycogen stores were reduced
      by about 50% by chronic inhibition of nitric oxide synthase. Because
      neurotransmitters are known to stimulate glycogenolysis, stress or sensory
      activation due to animal handling and tissue-sampling procedures may stimulate
      glycogenolysis during an experiment, and glycogen lability during tissue sampling
      and extraction can further reduce glycogen levels. The very high glycogen levels
      in normal rat brain suggest an unrecognized role for astrocytic energy metabolism
      during brain activation.

PMID- 12468893
TI  - Generalized sensory stimulation of conscious rats increases labeling of oxidative
      pathways of glucose metabolism when the brain glucose-oxygen uptake ratio rises.
AB  - Interpretation of functional metabolic brain images requires understanding of
      metabolic shifts in working brain. Because the disproportionately higher uptake
      of glucose compared with oxygen ("aerobic glycolysis") during sensory stimulation
      is not fully explained by changes in levels of lactate or glycogen, metabolic
      labeling by [6-14C]glucose was used to evaluate utilization of glucose during
      brief brain activation. Increased labeling of tricarboxylic acid cycle-derived
      amino acids, mainly glutamate but also gamma-aminobutyric acid, reflects a rise
      in oxidative metabolism during aerobic glycolysis. The size of the glutamate,
      lactate, alanine, and aspartate pools changed during stimulation. Brain lactate
      was derived from blood-borne glucose and its specific activity was twice that of
      alanine, revealing pyruvate compartmentation. Glycogen labeling doubled during
      recovery compared with rest and activation; only 4% to 8% of the total 14C was
      recovered in lactate plus glycogen. Restoration of glycogen levels was slow, and
      diversion of glucose from oxidative pathways to restore its level could cause a
      prolonged reduction of the global O2/glucose uptake ratio. The rise in the brain
      glucose-oxygen uptake ratio during activation does not simply reflect an upward
      shift of glycolysis under aerobic conditions; instead, it involves altered fluxes
      into various (oxidative and biosynthetic) pathways with different time courses.

PMID- 12468894
TI  - Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal
      dementia, and hippocampal sclerosis in the State of Florida Brain Bank.
AB  - Alzheimer disease (AD) is the most common dementing illness in the elderly, but
      there is equivocal evidence regarding the frequency of other disorders such as
      Lewy body disease (LBD), vascular dementia (VaD), frontotemporal dementia (FTD),
      and hippocampal sclerosis (HS). This ambiguity may be related to factors such as
      the age and gender of subjects with dementia. Therefore, the objective of this
      study was to calculate the relative frequencies of AD, LBD, VaD, FTD, and HS
      among 382 subjects with dementia from the State of Florida Brain Bank and to
      study the effect of age and gender on these frequencies. AD was the most frequent
      pathologic finding (77%), followed by LBD (26%), VaD (18%), HS (13%), and FTD
      (5%). Mixed pathology was common: Concomitant AD was present in 66% of LBD
      patients, 77% of VaD patients, and 66% of HS patients. The relative frequency of
      VaD increased with age, whereas the relative frequencies of FTD and LBD declined
      with age. Males were overrepresented among those with LBD, whereas females were
      overrepresented among AD subjects with onset age over 70 years. These estimates
      of the a priori probabilities of dementing disorders have implications for
      clinicians and researchers.

PMID- 12468895
TI  - The carrot and the stick: benefits and barriers in getting a diagnosis.
AB  - The goals of this study were to identify the benefits and barriers perceived by
      family caregivers of persons who have been through a diagnostic assessment for
      dementia symptoms and to determine which caregivers experience more benefits and
      barriers associated with assessments. A survey was mailed to caregivers involved
      in the decision to seek a diagnostic assessment for a family member at a
      University of Kentucky memory disorders clinic. A total of 528 family caregivers
      (response rate 71.7%) returned a 4-page survey designed to elicit benefits,
      barriers, and demographic information. Respondents delayed the diagnostic
      assessment for an average of 22.4 months after noticing symptoms. Perceived
      benefits involved confirmation of a medical condition, access to treatment, and
      help preparing for the caregiving role. Barriers were both emotional and
      pragmatic in nature. Respondents who were younger, visited the rural assessment
      clinic, and had less education experienced more barriers. All groups reported
      receiving the same number of benefits from the assessment. By incorporating these
      benefits and barriers, interventions can be designed to increase the likelihood
      of early diagnostic assessments.

PMID- 12468896
TI  - Dementing disorders in the elderly: evolution of disease severity over 7 years.
AB  - The goal of this study was to describe the evolution of dementia severity in a
      very old dementia population. We investigated a representative group of demented
      subjects gathered from a population-based study (n = 223). Changes in cognition,
      functioning, and performance on global scales were followed over a period of 7
      years. At baseline, 19% of the demented subjects were found to be severely
      impaired according to the Clinical Dementia Rating scale, 41% according to the
      Mini-Mental State Examination score, and 31% according to Katz activities of
      daily living scale. After 7 years these proportions were 78%, 93%, and 68%,
      respectively. The probability of surviving 3 years, 5 years, and 7 years after
      baseline examination was 48%, 28%, and 15%, respectively. Over a 7-year follow-up
      period, subjects suffering from questionable-mild dementia had a mean survival of
      3.9 years (95% confidence interval 3.3-4.5), whereas subjects with severe
      dementia survived on average 2.9 years (95% confidence interval 2.5-3.2). Male
      gender, lower education, and poor cognitive and functional status were associated
      with shorter survival in milder cases, whereas the only factors that predicted
      shorter survival in more severe cases were older age and poor functional status.
      Long-term survivors in dementia are not rare, and as the absolute number of
      demented people is increasing, expanding our knowledge of these persons is of
      high public health importance.

PMID- 12468897
TI  - Frontal hypometabolism does not explain inhibitory dysfunction in Alzheimer
      disease.
AB  - A series of tasks assessing inhibitory processes was administered to patients
      with Alzheimer disease and control subjects. Two groups of patients with
      Alzheimer disease were examined: patients with hypometabolism restricted to the
      posterior (temporal and parietal) cerebral areas and patients with hypometabolism
      in both posterior and anterior (frontal) cerebral areas. The performances of the
      patients with Alzheimer disease were inferior to those of control subjects on all
      inhibitory tasks, but the two groups of patients obtained similar scores. These
      data indicate that frontal lobe hypometabolism is not necessary to produce
      inhibitory impairment in Alzheimer disease. Consequently, inhibitory dysfunction
      could be the consequence of a (partial) disconnection process between posterior
      and anterior cerebral areas.

PMID- 12468898
TI  - Prognostic factors for functional independence in older adults with mild
      dementia: results from the canadian study of health and aging.
AB  - We investigated the prevalence of and prognostic factors for functional
      independence in personal activities of daily living in a population-based sample
      of 90 seniors with mild dementia from the Canadian Study of Health and Aging.
      Personal activities of daily living were assessed from the report of proxy
      respondents at baseline and at the 5-year follow-up (or retrospectively if death
      had occurred). Sixteen (17.8% of the total group of 90) subjects maintained their
      personal activities of daily living independence over the full 5-year period or
      up to 3 months before death (15.1% if the four subjects reclassified as not
      demented at the second wave are excluded). An age of 75-84 years (vs. those 65-74
      years of age and 85+ years of age; odds ratio 12.9, 95% confidence interval 2.7,
      112.7), the absence of gait-balance-movement problems (odds ratio 5.2, 95%
      confidence interval 1.3, 25.8), the presence of extrapyramidal signs (odds ratio
      9.5), and fewer years of formal education (odds ratio 3.6) were favorable
      prognostic factors in our multivariate modeling. An absence of sensory problems
      was a statistically significant favorable prognostic factor in bivariate
      analysis. Prior studies on the time required for patients with dementia to
      progress to functional milestones used clinic-based samples. Our findings, which
      have potential public health implications, need to be confirmed and expanded
      upon.

PMID- 12468899
TI  - Impaired awareness, behavior disturbance, and caregiver burden in Alzheimer
      disease.
AB  - Caregiver burden, the stress experienced as a result of caregiving, is determined
      by many factors. This study examined the contributions of the patient's awareness
      of memory deficit and behavioral disturbance to caregiver burden in Alzheimer
      disease. Participants were 41 patients with Alzheimer disease and their
      caregivers. Dementia severity, functional impairment, awareness of memory
      deficit, and behavioral disturbance were measured and examined in relation to
      caregiver burden. Positive correlations were found between caregiver burden and
      both impaired awareness of memory deficit and behavioral disturbance. Regression
      analyses demonstrated that both impaired patient awareness of memory deficit and
      behavioral disturbance contributed to caregiver burden over and above dementia
      severity and functional impairment. However, when both were entered together into
      regression equations, only behavioral disturbance contributed to caregiver
      burden. Of the problem behaviors, measures of disinhibition contributed most to
      caregiver burden. These data further our understanding of the multiple
      contributors to caregiver burden. We conclude that both patient awareness of
      memory deficit and behavioral disturbance impact caregiver burden, with
      behavioral disturbance making the greater contribution.

PMID- 12468900
TI  - On disentangling states versus traits: demonstration of a new technique using the
      Alzheimer's disease assessment scale.
AB  - Part of the challenge in research on degenerative neurologic disease relates to
      distinguishing those measurements that essentially describe patient
      characteristics stable across the course of illness (traits) from those that vary
      systematically within subjects (states), particularly those specifically related
      to stage or duration of illness. A components-of-variance approach was used to
      examine the state versus trait aspects of the Alzheimer's Disease Assessment
      Scale (ADAS) Cognitive and Noncognitive subscales, a clinical instrument
      frequently used in research on Alzheimer disease. Subjects were 190 patients with
      probable AD followed longitudinally. Stage of illness was indexed by mental
      status scores. Analysis of variance was used to partition total variance into
      that associated with subjects (trait), stages (state: stage), subjects x stages
      (state: other), and error. ADAS Cognitive scores were strongly related to stage
      of illness (83% of true variance). ADAS Noncognitive scores were modestly related
      to stage (approximately 21% of true variance) and moderately related to state:
      other (47%). We discuss how state-trait analyses can be helpful in focusing
      attention on those areas of assessment most likely to accomplish specific
      objectives.

PMID- 12468901
TI  - Therapeutic psychosocial intervention for elderly subjects with very mild
      Alzheimer disease in a community: the tajiri project.
AB  - Elderly subjects with mild memory impairment but not apparent dementia are the
      focus of early intervention trials. To examine the effects of structural
      psychosocial intervention for elderly subjects with very mild Alzheimer disease,
      i.e., Clinical Dementia Rating 0.5. The design is a prospective study. The
      experimental group (14 Clinical Dementia Rating 0.5 subjects) and the control
      group (11 Clinical Dementia Rating 0.5 subjects) were studied. Subjects with
      cerebrovascular disease as shown by magnetic resonance imaging were excluded. The
      experimental group participated in activities in a day-care-like setting once a
      week over a period of 6 months, whereas the control group did not. Each group was
      reevaluated after approximately 9 months. The effects of intervention were
      evaluated by cognitive tests, affective scales, a global clinical measure, an
      observation scale in the sessions, and a projective test. The experimental group
      showed a significant improvement on the word fluency test, whereas the control
      group showed a significant decline on the Mini-Mental State Examination, the
      digit span, and the Trail Making-A test. The experimental group revealed
      significantly higher levels on the Mini-Mental State Examination and the digit
      span compared with the control group after the 6-month intervention. A
      significant improvement was found for the global clinical measure, the
      observation scale, and the projective test in the experimental group after the
      intervention. After controlling the potential confounders (age, educational
      level, baseline cognitive, and affective status) in a multiple regression
      analysis, the same results were found. We considered that psychosocial
      intervention had beneficial effects for subjects with very mild Alzheimer
      disease.

PMID- 12468902
TI  - Recommended and reported use of communication strategies in Alzheimer caregiving.
AB  - Individuals with Alzheimer disease experience cognitive and behavioral
      impairments that affect their ability to communicate. In an effort to compensate
      for these declines, a number of communication strategies have been recommended in
      the literature for Alzheimer disease caregivers. These include recommendations
      for caregivers to modify their language behavior and/or the context of
      communication. The purpose of this study was to (1) review the Alzheimer disease
      caregiving literature and identify communication strategies commonly recommended
      for family caregivers and (2) determine how often caregivers report using these
      strategies and how effective they feel each is in facilitating communication. A
      review of the literature identified 10 recurring communication strategies. A
      questionnaire was constructed that asked caregivers to report on the use and
      efficacy of these 10 strategies. Twenty family (spouse) caregivers of persons
      diagnosed with Alzheimer disease completed the questionnaire. The results show
      that caregivers perceived using the 10 strategies, although the strategies
      appearing most frequently in the literature were not necessarily the ones used
      most often by caregivers. A positive correlation was observed between caregivers'
      perceived use of strategies and their effectiveness. Use and efficacy of a
      strategy did not significantly vary as a function of dementia severity or the
      gender of the caregiver. The findings provide evidence that caregivers are aware
      of their communication behavior and modify it in ways that they think improve
      communication with their spouse.

PMID- 12468903
TI  - Recruitment rates in gerontological research: the situation for drug trials in
      dementia may be worse than previously reported.
AB  - Recruitment issues pose a major problem in dementia research. This paper aims to
      clarify issues involved in the recruitment of individuals suffering from dementia
      for research studies. Five studies conducted by the same research team are
      analyzed in terms of their recruitment procedures and the obstacles encountered
      with recruitment. Recruitment rates varied from about 80% to 1%. Rates increased
      according to perceptions of risk, perceptions of benefits, and exclusion
      criteria. Pharmacologic studies had much lower recruitment rates than
      nonpharmacologic studies. Investigators need to limit exclusion criteria as much
      as possible. The extremely low recruitment rates of pharmacologic studies in
      frail persons with dementia may render the results irrelevant for that
      population. Similarly, the major differences in procedures between pharmacologic
      and nonpharmacologic studies may invalidate comparisons of results among such
      studies. More attention needs to be given to a systematic reporting of
      recruitment rates.

PMID- 12468904
TI  - Recruitment for drug studies in dementia.

PMID- 12468905
TI  - Comments from the Editor-in-Chief.

PMID- 12468906
TI  - Search for improved therapy of sickle cell anemia.

PMID- 12468907
TI  - Treatment: the most important prognostic variable.

PMID- 12468908
TI  - Hepatic venoocclusive disease in blood and bone marrow transplantation in
      children: incidence, risk factors, and outcome.

PMID- 12468909
TI  - A prospective double-blind randomized trial of urokinase flushes to prevent
      bacteremia resulting from luminal colonization of subcutaneous central venous
      catheters.
AB  - PURPOSE: This study was undertaken to determine if central venous catheter (CVC)
      related infection in children with cancer could be prevented by monthly flushing
      of the catheter with urokinase. PATIENTS AND METHODS: Between August 1994 and
      July 1998, 103 patients with cancer were randomized at the time of subcutaneous
      CVC placement to receive monthly flushing of their catheters with either 5000 IU
      of urokinase-heparin or heparin alone. Patients subsequently had blood cultures
      taken from their CVCs during an episode of fever. RESULTS: Seventy-four of the
      103 patients (72%) enrolled in the study received at least 6 catheter flushes: 40
      with urokinase-heparin and 34 with heparin. The median number of flushes was 9.5
      in the urokinase-heparin group and 10.2 in the heparin-only group (P = 0.62).
      There were 5 positive blood cultures in the urokinase-heparin group and seven in
      patients receiving heparin alone (P = 0.27). Staphylococcus epidermidis was
      isolated from the blood of 3 patients receiving urokinase-heparin and 6 in those
      receiving heparin alone (P = 0.17). CONCLUSION: Prophylactic monthly catheter
      flushes with 5000 IU urokinase did not significantly decrease the number of
      documented bacteremic events in children with cancer who have CVCs.

PMID- 12468910
TI  - Continuous infusion of ceftazidime in the empiric treatment of febrile
      neutropenic children with cancer.
AB  - PURPOSE: Infection remains one of the most important complications in cancer
      therapy. The choice of antibiotics and the method of administration can affect
      results. Beta-lactam antibiotics can be administered by several short injections
      per day or by continuous infusion. The latter modality may provide superior
      pharmacokinetics. PATIENTS AND METHODS: The authors studied the pharmacokinetics
      of ceftazidime in children treated for malignancy and in febrile aplasia after
      chemotherapy. They received a continuous infusion of ceftazidime (200 mg/kg/day)
      after a loading dose (65 mg/kg/day) administered with amikacin (25 mg/kg/day) and
      vancomycin (50 mg/kg/day). RESULTS Twenty-three pharmacokinetic studies were
      performed. Mean ceftazidime serum levels were 31.1 +/- 11.9, 31.2 +/- 10, 32.4 +/
      11.6, 33 +/- 11.6, and 30.4 +/- 12.1 mg/L at 25, 27, 30, 36, and 43 hours,
      respectively. Treatment was tolerated well. There were no toxic or infectious
      deaths. CONCLUSIONS: Ceftazidime's time-dependent pharmacokinetics shows the
      advantage of continuous infusion. This study confirmed the feasibility and safety
      of this administration schedule in the empiric treatment of febrile neutropenic
      children with cancer.

PMID- 12468911
TI  - The neutropenic diet: what's the evidence?
AB  - Despite improved survival of children with cancer, opportunistic infections
      remain a significant cause of morbidity and mortality in this population. Several
      interventions have been tried to decrease the incidence of infection by reducing
      patients' exposure to bacteria during neutropenia. The neutropenic diet is one
      such intervention that was intended to limit the introduction of bacteria into
      the host's gastrointestinal tract. The only studies evaluating this diet have
      used this strategy in combination with multiple other interventions, and the
      independent effect of this diet remains unknown. More research about the
      neutropenic diet is needed to establish its effectiveness in clinical practice.

PMID- 12468912
TI  - Treatment of infantile fibrosarcoma with chemotherapy and surgery: results from
      the Dana-Farber Cancer Institute and Children's Hospital, Boston.
AB  - PURPOSE: To retrospectively evaluate the treatment and outcome of patients
      diagnosed with infantile fibrosarcoma at the Dana-Farber Cancer Institute and
      Children's Hospital, Boston. PATIENTS AND METHODS: Between 1982 and 1998, a total
      of 11 infants were diagnosed pathologically with infantile fibrosarcoma. A
      retrospective chart review was conducted to determine the extent of surgical
      therapy and chemotherapy required for a favorable clinical outcome. Cytogenetic
      findings were reviewed and archived tumor specimens were analyzed, when
      available, for the presence of the TEL/TRKC fusion gene. RESULTS: Three patients
      had primary surgical resection with negative pathologic margins and have been
      lost to follow-up. Two patients received chemotherapy only after limited biopsy
      or subtotal resection and are alive with no evidence of disease 8 and 18 years
      from diagnosis. Four patients had limited biopsies followed by chemotherapy with
      delayed resection. One of these four patients had negative margins and received
      no further chemotherapy. The other three of these patients had positive
      microscopic margins; two of them received postoperative chemotherapy while the
      third did not. All four are currently alive with no evidence of disease. Two
      patients had progressive disease within 7 and 10 months of diagnosis while on
      chemotherapy after subtotal resections. One of these two patients is dead of
      disease; the other is alive after palliative radiotherapy. Seven patients had
      archived or frozen tissue available for molecular analysis. All seven had
      evidence of TEL gene rearrangement; six exhibited the TEL/TRKC fusion. Six
      patients had characteristic trisomies previously reported to be associated with
      infantile fibrosarcoma. CONCLUSIONS: Previously reported series of treatment
      outcomes in infantile fibrosarcoma have been limited to very few patients due to
      the rare occurrence of this tumor. In our experience, initial chemotherapy
      combined with surgery has been successful for most cases. When disease
      progression occurred, it was within one year of diagnosis. There was no
      development of distant metastases in the patients with progressive disease. The
      role of additional chemotherapy for microscopic margins after local control is
      not clear. We found a high incidence of the TEL/TRKC fusion gene, confirming its
      utility in diagnosis. We propose a uniform approach to treatment to gather
      clinical and biologic information about this rare and curable disease.

PMID- 12468913
TI  - Expression of cell cycle-related gene products in Langerhans cell histiocytosis.
AB  - BACKGROUND The pathogenesis of Langerhans cell histiocytosis (LCH), a disease
      characterized by an abnormal accumulation of the dendritic Langerhans cells, is
      still unknown. Based on the monoclonality of the CD1a+ cell and reports of
      familial clustering, it is hypothesized that a genetic alteration at a cellular
      level may be causative. This genetic change may have an effect on the cellular
      mechanisms controlling proliferation and apoptosis. MATERIALS AND METHODS LCH
      lesions were studied for the expression of Ki-67, present in the nucleus of
      proliferating cells. Furthermore, the expression of cell cycle-related gene
      products TGF-beta receptor I and II, MDM2, p53, p21, p16, Rb, and Bcl2 were
      studied. The TGF-betaR genes play a role in tumor suppression, whereas Bcl2
      inhibits apoptosis. The remaining genes are part of either the p53-p21 and/or p16
      Rb pathways, which induce cell cycle arrest or apoptosis in response to DNA
      damage. RESULTS In 30 biopsies the diagnosis of LCH could be confirmed on the
      basis of CD1a positivity (27 bone and 3 skin). All cases showed scattered nuclear
      positive staining for the proliferation marker Ki-67. In more than 90% (n >/=27)
      of these cases, expression of TGFbeta receptor I and II, MDM2, p53, p21, p16, Rb,
      and Bcl2 was detected in lesional LCH cells. The overexpression was in general
      heterogeneous, ranging from limited focal staining of scattered cells within the
      lesion to strong diffuse staining. CONCLUSIONS These findings suggest that the
      cellular mechanisms that sense and respond to DNA-damage, namely the p53-p21
      pathway and the p16-Rb pathway, are activated. The expression of Ki-67 indicates
      that the cells in LCH are proliferating. The observed overexpression of Bcl2 may
      play a role in the activation of p53 and p16 and/or the arrest of apoptosis.

PMID- 12468914
TI  - p53 expression in biopsies from children with Langerhans cell histiocytosis.
AB  - PURPOSE: Langerhans cell histiocytosis (LCH) is a rare pediatric and adult
      disease causing skin rashes, osteolytic bone lesions, tumorous growth in various
      organs, and in some patients, organ dysfunction. The cause of the disease is
      obscure, and it is not yet understood why some patients develop single-system
      lesions only without relapse, whereas others develop fatal multiorgan disease.
      The expression of p53 tumor suppressor gene product detected
      immunohistochemically can be used as a guideline to alterations in DNA repair
      control and apoptosis. The authors have chosen to analyze p53 expression in
      biopsies from children with LCH and correlate it with clinical manifestation and
      outcome in a broad range of organs. PATIENTS AND METHODS: The study was performed
      on 50 specimens from 32 children (19 boys and 13 girls), median age 3 1/4 years,
      range 5 months to 12 1/3 years with a definite diagnosis of LCH based on CD1a
      positivity. The slides were stained with p53 antibody and semiquantitatively
      evaluated using a grading system from 1 to 5 as an estimate for 0% to 20%, 20% to
      40%, 40% to 60%, 60% to 80%, and 80% to 100% p53-positive for pathologic
      Langerhans cells (pLC), respectively. RESULTS: The p53 protein was expressed in
      various degrees in pLC in all lesions. The degree of p53 expression could not be
      correlated to either clinical manifestation or outcome. CONCLUSIONS: An increased
      expression of p53 in pLC indicates an altered DNA repair control with or without
      abnormal control of apoptosis.

PMID- 12468915
TI  - Induction of fetal hemoglobin synthesis in children with sickle cell anemia on
      low-dose oral sodium phenylbutyrate therapy.
AB  - This study was designed to determine if low doses of oral sodium phenylbutyrate
      (SPB) induce hemoglobin F (HbF) synthesis in children with hemoglobin SS (HbSS).
      We treated 8 children with HbSS over a period of 5-30 weeks. The initial dose
      (1.0 g/d) was increased weekly (by 1.0 g/d) until F-reticulocytes doubled. All
      patients showed an increase in F-reticulocytes (P = 0.002) that was dose
      dependent (P = 0.001). Three of 5 patients who continued oral SPB for more than
      10 weeks had substantial increases in HbF. We conclude that lower dose SPB is
      effective in inducing HbF synthesis in some children with HbSS. Further trials
      are warranted to determine the optimal treatment regimen.

PMID- 12468916
TI  - Soluble P-selectin, interleukin 6, and thrombopoietin levels in children with
      acute and chronic idiopathic thrombocytopenic purpura and their relationship with
      mega-dose methylprednisolone therapy: a pilot study.
AB  - We observed less severe symptoms in patients with chronic idiopathic
      thrombocytopenic purpura (ITP) than in patients with acute ITP with similar
      platelet counts. Thrombopoietin (TPO), soluble P-selectin, soluble P-selectin per
      platelet, and interleukin 6 (IL-6) were evaluated in children with ITP before
      treatment in 16 acute and 22 chronic cases and after treatment in 10 acute and
      chronic cases who received mega-dose methylprednisolone. The levels of IL-6,
      soluble P-selectin, soluble P-selectin per platelet, and platelet count were
      similar in acute and chronic ITP (P > 0.05) but TPO in acute ITP was higher than
      that of the patients with chronic ITP (P < 0.05). The posttreatment IL-6 and TPO
      declined (P < 0.05), but soluble P-selectin and platelet count increased (P <
      0.05). Posttreatment soluble P-selectin per platelet levels were higher than the
      normal values (P < 0.05). These results suggest that IL-6, soluble P-selectin,
      and soluble P-selectin per platelet are not responsible for the milder symptoms
      in chronic than in acute ITP. Mega-dose methylprednisolone seems to keep the
      soluble P-selectin levels elevated.

PMID- 12468917
TI  - Hepatic venoocclusive disease in blood and bone marrow transplantation in
      children and young adults: incidence, risk factors, and outcome in a cohort of
      241 patients.
AB  - PURPOSE: To describe recent characteristics of incidence, risk factors,
      treatment, and outcome of venoocclusive disease (VOD) in children and young
      adults undergoing blood and bone marrow transplantation (BMT). METHODS: All
      children and young adults (n = 241) undergoing first myeloablative transplant at
      the UCSF Pediatric BMT unit between 1992 and 2000 were included. Retrospective
      chart review was done. Descriptive statistics and univariate and multivariate
      analyses of risk factors are presented. RESULTS: Venoocclusive disease developed
      in 65 patients (27%); it was severe in 13/65 patients (20%). Matched unrelated
      donor transplantation, advanced-stage malignancies, and transplantation in the
      recent period (1998-2000) were identified as significant risk factors for VOD in
      univariate and multivariate analyses. Heparin prophylaxis did not decrease the
      incidence of VOD. Venoocclusive disease was diagnosed at a median day 8 after
      BMT. Five of 13 patients with severe VOD (38%) survived for more than 1 year
      after BMT, even after renal and respiratory failure and high total bilirubin
      levels up to 35 mg/dL. Nine of the 13 patients received fibrinolytic treatment
      with tissue plasminogen activator, anti-thrombin 3, or defibrotide. The survival
      rate at day 100 after BMT for children with VOD was 77%; it was 94% for those
      without VOD. CONCLUSIONS: The persistently high incidence of VOD, its significant
      impact on posttransplant survival, and the demonstration of recovery from even
      severe VOD underscore the importance of early diagnosis and initiation of
      specific therapy. The use of Bearman's model of prediction of severity of VOD and
      the application of fibrinolytic drugs when adequate are highly recommended.

PMID- 12468918
TI  - Novel therapeutic approaches in the treatment of children with hepatoblastoma.
AB  - Hepatoblastoma is the most common liver tumor diagnosed in children. Children
      with persistently unresectable disease, metastatic disease at presentation,
      recurrent disease, or slowly declining alpha-fetoprotein levels are at high risk
      for recurrence, exhibit an extremely poor prognosis, and are in desperate need of
      novel therapeutic agents and strategies. Four high-risk patients were treated.
      One patient with a local recurrence was treated with irinotecan followed by
      orthotopic liver transplant. Three patients were treated with tandem high-dose
      chemotherapy (HDT) with autologous stem cell rescue (two with primary metastatic
      disease and one with recurrent disease). All three of the patients treated with
      HDT had relapse (two of them subsequently received irinotecan); the remaining
      patient underwent surgical resection of a solitary recurrent pulmonary
      metastasis. Irinotecan demonstrated significant antitumor effects in all three
      treated patients and was well tolerated. None of the three patients treated with
      HDT remained disease-free, although the patient who underwent surgical resection
      of a solitary recurrent pulmonary metastasis remains disease-free 6 years from
      diagnosis. Further exploration of the use of irinotecan is warranted in high-risk
      patients with hepatoblastoma.

PMID- 12468919
TI  - Acute myelogenous leukemia and glycogen storage disease 1b.
AB  - Glycogen storage disease 1b (GSD 1b) is caused by a deficiency of glucose-6
      phosphate translocase and the intracellular accumulation of glycogen. The disease
      presents with failure to thrive, hepatomegaly, hypoglycemia, lactic acidosis, as
      well as neutropenia causing increased susceptibility to pyogenic infections. We
      present a case of a young woman with GSD 1b who developed acute myelogenous
      leukemia while on long-term granulocyte colony-stimulating factor therapy. The
      presence of two rare diseases in a single patient raises suspicion that GSD 1b
      and acute myelogenous leukemia are linked. Surveillance for acute myelogenous
      leukemia should become part of the long-term follow-up for GSD 1b.

PMID- 12468920
TI  - Helicobacter pylori-associated large gastric ulcer during treatment for childhood
      leukemia.
AB  - During treatment of acute lymphoblastic leukemia, serious gastrointestinal
      complications rarely occur in children. Helicobacter pylori is not known as a
      pathogen causing peptic ulcer in children with leukemia who are receiving
      chemotherapy. We describe a 14-year-old girl with acute lymphoblastic leukemia in
      whom, during the most aggressive part of treatment, a large, life-threatening H.
      pylori-associated gastric ulcer developed. H. pylori infection played a role in
      the origin of the ulcer, as confirmed by the clinical resolution after its
      specific treatment. This case points to a possible role for H. pylori as a
      pathogen in children with leukemia who have either evident or occult
      gastrointestinal bleeding.

PMID- 12468921
TI  - Transient abnormal myelopoiesis in Noonan syndrome.
AB  - An infant affected by Noonan syndrome and presenting with abnormal hemopoiesis is
      described. Cytogenetic analysis, molecular studies, and in vitro culture assays
      ruled out myelodysplasia or other hematologic malignancies but were consistent
      with transient abnormal myelopoiesis. At present, 3 years and 10 months after
      diagnosis, the patient shows a normal hematologic picture. Supportive treatment
      in such patients, unless refractory cytopenias or overt leukemia develops, is
      emphasized.

PMID- 12468922
TI  - Pseudotumor cerebri in two adolescents with acquired aplastic anemia.
AB  - A 13-year-old boy and a 16-year-old girl both presented with headaches and nausea
      after they were diagnosed with severe acquired aplastic anemia. Both patients had
      symptoms and signs consistent with the clinical syndrome of pseudotumor cerebri
      including headaches, nausea, papilledema, and elevated intracranial pressure.
      Both patients were treated with therapeutic lumbar puncture and acetazolamide,
      which relieved their symptoms. Acetazolamide dosage was given while the patients
      underwent an immunosuppressive regimen. We hypothesize that the pseudotumor
      cerebri in these two pediatric patients was the result of an increased production
      of cerebrospinal fluid in response to anemia and that the removal of fluid and
      treatment with acetazolamide appear to be helpful in such cases.

PMID- 12468923
TI  - Recombinant plasminogen activator therapy for cerebral vein thrombosis in a child
      carrier of prothrombin gene mutation.
AB  - Venous thrombosis of transverse and sigmoid sinuses was diagnosed in a 3-year-old
      child who is a carrier of the G20210A prothrombin gene mutation. Recombinant
      tissue plasminogen activator (rt-PA) treatment was started 9 days following the
      onset of neurologic signs. Nine days of rt-PA therapy completely dissolved the
      thrombus. This case provides further evidence that rt-PA is useful and safe in
      children with thrombosis.

PMID- 12468925
TI  - Use of hydroxyurea and recombinant erythropoietin in management of homozygous
      beta0 thalassemia.
AB  - This report describes the sustained response of an Iranian girl with homozygous
      beta(0) thalassemia (IVS-II-1G-->A) to hydroxyurea (HU) and recombinant
      erythropoietin (rEPO). Since the start of this regimen 7 years ago, she has been
      transfusion-independent and her hemoglobin is maintained between 9.5-11.0 gm/dL.
      She is maintaining consistent growth around the 10th percentile for age and
      enjoys a good quality of life. She has not had any therapy-related adverse
      effects. This experience suggests that therapy with HU and rEPO may be useful
      long-term in some patients with beta thalassemia.

PMID- 12468924
TI  - Autoimmune thyroiditis after bone marrow transplantation in a boy with Wiskott
      Aldrich syndrome.
AB  - We report a boy with Wiskott-Aldrich syndrome (WAS) who developed autoimmune
      thyroiditis 19 months after allogenic bone marrow transplantation (BMT). Possible
      causes of his autoimmune illness were 1) transference of autoimmune cells from
      the donor, which was ruled out because of the absence of autoimmune illness in
      his healthy HLA-identical brother (donor); 2) persistent mixed chimerism after
      BMT ruled out by post-BMT molecular analysis of the proband's peripheral
      lymphocytes; and 3) patient's predisposition to autoimmune disease secondary to
      an dysregulated immune system because of WAS and his HLA haplotype. This case
      brings previously unreported findings to the spectrum of WAS.

PMID- 12468926
TI  - Fetus in fetu: unexpected cause of an abdominal mass.

PMID- 12468927
TI  - Giant actin inclusions in hematopoietic cells: a variant of Brandalise syndrome?

PMID- 12468929
TI  - Mutant elastase in pathogenesis of cyclic and severe congenital neutropenia.
AB  - Severe neutropenia is characterized by maturation arrest of myeloid cells at the
      promyelocyte stage of hematopoiesis. We reported that accelerated apoptosis of
      bone marrow myeloid progenitor cells was observed in both cyclic (CN) and severe
      congenital neutropenia (SCN). Short and long-term cultures of bone marrow CD34+
      cells revealed reduced production of multipotent progenitors in SCN. In contrast,
      production of these cells was slightly elevated in CN compared with CD34+ cells
      from healthy volunteers. Production of myeloid-committed progenitor cells was
      significantly reduced in both CN and SCN. FACS analysis of CD34+ cells revealed G
      /G cell cycle arrest in SCN but not in CN.(0) (1) All CN patients and more than
      90% of SCN patients have mutation in the neutrophil elastase (NE) gene. Molecular
      modeling of NE tertiary structure indicates that mutations observed in SCN are
      primarily located around the glycosylation sites, whereas CN mutations affect
      predominantly the active site. Transient expression of CN- or SCN-specific mutant
      NE cDNA results in impaired survival of human myeloid progenitor cells compared
      with control cells transfected with intact NE cDNA. We hypothesize that abnormal
      processing and subcellular localization of mutant NE might predetermine the
      etiology of cyclic or severe congenital neutropenia.

PMID- 12468930
TI  - Retroviral-mediated gene transfer and nonmyeloablative conditioning: studies in a
      murine X-linked chronic granulomatous disease model.
AB  - Our laboratory has reported the correction of neutrophil NADPH oxidase function
      by retroviral-mediated gene transfer (RMGT) in murine X-linked chronic
      granulomatous disease (X-CGD). Few studies, however, have used nonmyeloablative
      conditioning in conjunction with RMGT. Promising methods of decreased intensity
      conditioning include low dose irradiation and antimetabolite conditioning.
      Preliminary studies using syngeneic mice transplanted with fresh marrow cells
      indicate that high levels of donor cell chimerism can be achieved with low-dose
      radiation or 5-fluorouracil-based conditioning regimens. Early data from
      experiments in which low-dose radiation-conditioned X-CGD recipients were
      transplanted with retrovirus-transduced X-CGD marrow cells show that gene
      corrected neutrophils can be detected by NBT assay for NADPH oxidase activity
      reconstitution 4 months posttransplant, although these levels are much lower than
      the 50%-70% gene-corrected cell detected in lethally irradiated recipients.
      Transplantation of retrovirus-transduced marrow cells into 5-fluorouracil
      conditioned hosts is also being explored.

PMID- 12468931
TI  - RAC2 GTPase deficiency and myeloid cell dysfunction in human and mouse.
AB  - Rho GTPases including Rho, Rac, and Cdc42 act as intracellular molecular switches
      to control cellular responses such as actin cytoskeleton rearrangement, gene
      transcription, cell growth, and possibly transformation. Their roles have been
      increasingly implicated in activation of signaling processes in leukocytes
      including integrin-mediated signal transduction and growth factor-induced cell
      survival and proliferation pathways. In particular, functional disruption of
      Rac2, a hematopoietic-specific Rho GTPase, causes severe myeloid cell dysfunction
      in both mouse and man. Rac2-deficient mice and a human patient with a D57N Rac2
      mutant share a phenotype of leukocytosis with defective neutrophil chemotaxis and
      superoxide production in response to some, but not all, agonists. Our studies
      also suggested that the phenotypic abnormalities associated with D57N may involve
      not only neutrophil cellular functions, but also abnormal cell survival in other
      hematopoietic cells. Together, these data demonstrate a critical and unique role
      for Rac2 in normal neutrophil function and define a new genetic immunodeficiency
      syndrome in humans.

PMID- 12468938
TI  - What your patient needs to know about prostate cancer.

PMID- 12468939
TI  - Warm for Christmas.

PMID- 12468940
TI  - Targeting cellulitis.

PMID- 12468941
TI  - Your state board of nursing: friend or foe?

PMID- 12468942
TI  - Getting to the heart of nursing.

PMID- 12468943
TI  - Easier than getting blood from a bone.

PMID- 12468944
TI  - Don't get uptight about ring removal.

PMID- 12468945
TI  - Caring for an alcohol-dependent patient.

PMID- 12468946
TI  - Spinal cord injury.

PMID- 12468947
TI  - Is the gastric epithelial barrier regulated by cadherin recruitment?
AB  - While still highly controversial, regulation of junctional structure remains an
      important feature in many physiological/pathological conditions. Mizuno et al.
      here report a mechanism in stomach epithelia where additional copies of cadherins
      appear to be recruited to the cell surface, apparently to maintain the solute
      barrier. This phenomenon may represent an important novel mechanism which
      epithelia may use to enhance barrier.

PMID- 12468948
TI  - Protective actions of rat gastric epithelial E-cadherin expression against
      epithelial barrier dysfunctions induced by chemical hypoxia-reoxygenation in
      vitro.
AB  - BACKGROUND AND AIM: E-cadherin expressed on gastric epithelium is reported to
      form adherence junctions and stabilize barrier functions. While hypoxia
      reoxygenation is well known to cause gastric mucosal injury during reoxygenation,
      gastric E-cadherin actions against this stress remain unclear. In this study,
      using the oxygen depleting agent thioglycolic acid we examined whether E-cadherin
      expressed on rat cultured gastric epithelial cells has protective actions against
      epithelial barrier dysfunction induced by chemical hypoxia-reoxygenation.
      METHODS: Chemical hypoxia was induced by incubating cells with 5 mm thioglycolic
      acid in glucose free medium for 60 min. Cells were then reoxygenated for 240 min
      by changing to normal medium. The expression of E-cadherin on the cell surface
      was measured with an enzyme immunoassay, and epithelial permeability was
      determined by the diffusion rate of FITC-dextran through the cell layer. RESULTS:
      E-cadherin expression increased during the 60 min hypoxic period, accompanied by
      activation of protein kinase C, protein kinase G and protein kinase A. The
      increased expression significantly diminished, but was considerably higher than
      the control values during reoxygenation for 180 min, which was partially due to
      generation of reactive oxygen species but not to activation of protein kinase.
      Conversely, epithelial permeability was stabilized during hypoxia, but increased
      only for 30 min of reoxygenation, probably due to generation of reactive oxygen
      species. Epithelial permeability during hypoxia was elevated by a combination of
      all the protein kinase inhibitors. CONCLUSION: An increase in the expression of E
      cadherin during hypoxia through the activation of the kinases is likely to
      stabilize epithelial barrier functions. The reactive oxygen species generated
      during 30 min reoxygenation increased the molecular expression of E-cadherin less
      than during hypoxic stress. The transient break in the barrier functions caused
      by reactive oxygen species during reoxygenation appears to overcome the reactive
      oxygen species mediated cytoprotective action increasing E-cadherin expression.

PMID- 12468949
TI  - Helicobacter pylori cagA genotype and density of colonization in relation to
      gastric inflammation in children.
AB  - OBJECTIVE: To assess the relationship between density determined by quantitative
      culture, status, and gastric histology in children. METHODS: Children with
      clinical symptoms indicating pathology in the upper gastrointestinal tract were
      referred for endoscopy. From each child blood was taken for serology, and antral
      biopsies were obtained for quantitative culture of and histology. Histological
      assessment was performed according to the updated Sydney System. The status of
      cultured was determined by polymerase chain reaction (PCR) and serum IgG response
      to CagA by western blotting. RESULTS: Adequate antral biopsies were obtained from
      41 children with positive cultures. CagA IgG antibodies were found in 27 patients
      (66%), 25 of whom were also positive by the PCR. Two children infected with +
      strains as determined by the PCR were CagA seronegative. Infection with + strains
      was associated with significantly higher activity of inflammation and denser
      bacterial colonization in the antrum compared to negative strains. No correlation
      was observed between the density of colonization and chronic antral inflammation.
      CONCLUSIONS: This study shows that infection of children with + strains of is
      associated with enhanced activity of antral inflammation and higher density of
      colonization. There is a good correlation between serum western blot and
      bacterial PCR positivity in determining status and a positive relationship
      between histology and quantitative culture in assessing density in paediatric
      patients.

PMID- 12468950
TI  - Levofloxacin based regimens for the eradication of Helicobacter pylori.
AB  - BACKGROUND: A 7 day treatment scheme based on
      rabeprazole/levofloxacin/amoxycillin or tinidazole achieved an eradication rate
      over 90%. However, the combination of drugs and duration of treatment for the
      correct use of levofloxacin in the eradication of are still unclear. OBJECTIVE:
      To compare the efficacy and tolerability of rabeprazole/levofloxacin based dual
      therapies given for 5, 7 or 10 days with rabeprazole/levofloxacin/amoxycillin
      triple therapy for 7 days. METHODS: One hundred and sixty patients with infection
      documented by the C-urea breath test and histology were included in this
      prospective, open label study. Subjects were randomized in four groups: (1)
      levofloxacin (500 mg o.d.), amoxycillin (1 g b.d.) and rabeprazole (20 mg o.d.)
      for 7 days; (2) levofloxacin (500 mg o.d.) and rabeprazole (20 mg o.d.) for 5
      days; (3) levofloxacin (500 mg o.d.) and rabeprazole (20 mg o.d.) for 7 days; and
      (4) levofloxacin (500 mg o.d.) and rabeprazole (20 mg o.d.) for 10 days. Six
      weeks after the end of therapy status was checked by using the C-urea breath
      test. RESULTS: All patients completed the therapeutic regimens. The eradication
      rate was not significantly modified by treatment duration in the dual therapy
      schemes (5 days: 20/40, 50%; 7 days: 28/40, 70%; 10 days: 26/40, 65%). The
      eradication rate of the 1 week levofloxacin based triple therapy was
      significantly higher than that observed using any dual therapies (36/40). No
      major adverse effects were observed. CONCLUSIONS: A rabeprazole/levofloxacin dual
      eradication regimen is simple and well tolerated but does not achieve an
      acceptable eradication rate when compared to a 1 week
      rabeprazole/levofloxacin/amoxycillin triple therapy. The eradication rate did not
      increase with a longer regimen.

PMID- 12468951
TI  - Correlation between erosive oesophageal and gastro-duodenal diseases. the
      influence of aspirin, simple analgesics, and Helicobacter pylori.
AB  - OBJECTIVE: Previous erosive oesophagitis studies have excluded patients with
      peptic ulcers or taking aspirin, and conflicting results have been reported
      concerning the influence of. We aimed to study the possible correlation between
      erosive oesophageal and gastro-duodenal diseases in patients with or without
      erosive oesophagitis who are taking low-dose aspirin, or simple analgesics, or
      those infected with. METHODS: Endoscopic oesophageal and gastro-duodenal lesions
      were graded in 287 patients with reflux oesophagitis, median age 57 years,
      including 168 with oesophageal erosions, 131 infected with, 45 patients taking
      aspirin 75 mg daily, and 65 patients taking simple analgesics containing
      paracetamol/codeine. RESULTS: The grades of oesophageal erosions correlated
      positively with the duodenal scores (r = 0.15; P = 0.01) in the study group as a
      whole (n = 287), and in patients (n = 131) with (r = 0.169; P = 0.05). Eighty of
      168 patients with erosive oesophagitis had (48%), compared with 51 of 119
      patients (43%) with non-erosive oesophageal disease (P = 0.47). Oesophageal
      scores were highest in the aspirin group (P = 0.04; Kruskal-Wallis test), with
      grades > or =3 being found in 36% of patients on aspirin, 22% on simple
      analgesics, and in 18% of other patients. CONCLUSIONS: The degree of oesophageal
      damage correlates positively with that in the duodenal mucosa, although the
      overall prevalence of erosive oesophagitis is not influenced by. Also, patients
      taking aspirin have a greater degree of oesophageal damage. These indicate the
      presence of a common process mediating both oesophageal and duodenal diseases in
      at least some patients with these disorders.

PMID- 12468952
TI  - Early increase of lower oesophageal sphincter pressure after band ligation of
      oesophageal varices in cirrhotics: an intriguing phenomenon.
AB  - AIM: We conducted a prospective, randomized comparison of endoscopic variceal
      ligation, sclerotherapy and metoclopramide injection in order to evaluate their
      early effect on lower oesophageal sphincter pressure. METHODS: Twenty-six
      patients with established cirrhosis and an episode of variceal bleeding
      controlled by one session of endoscopic therapy were randomized to undergo an
      oesophageal manometry. The patients' lower oesophageal sphincter pressure was
      evaluated, prior to and immediately after a single session of ligation (n = 10),
      a single session of sclerotherapy (n = 8) or a bolus injection of 20 mg
      metoclopramide hydrochloride (n = 8). RESULTS: Ligation produced a higher early
      increase in lower oesophageal sphincter pressure (from 12.3 +/- 2.3 to 27.8 +/-
      3.0 mmHg) as compared with sclerotherapy (from 13.6 +/- 2.5 to 22.4 +/- 4.5 mmHg)
      or metoclopramide injection (from 14.6 +/- 3.2 to 22.5 +/- 2.9 mmHg); (P =
      0.0001). CONCLUSION: Our data indicate that ligation of oesophageal varices
      produces an early increase in lower oesophageal sphincter pressure in cirrhotic
      patients.

PMID- 12468953
TI  - Irritable bowel syndrome in Germany. A cost of illness study.
AB  - OBJECTIVES: When asked, between 10% and 15% of people in the Western world report
      symptoms compatible with irritable bowel syndrome, and around 5% seek medical
      advice for these complaints. This should incur considerable costs. The present
      study was designed to give a cost estimate for the treatment of patients with
      irritable bowel syndrome paid for by German statutory health insurance. METHODS:
      Fifty doctors working in private practice were randomly selected to each carry
      out personal interviews on four irritable bowel syndrome patients chosen from
      their own records (total 200 patients). Using a structured questionnaire,
      information regarding diagnostic procedures, drugs and other therapies,
      hospitalization and days off work were obtained from the case records. To
      calculate the total direct costs of the illness, all single cost elements such as
      physician services, medication and hospitalization were included. RESULTS: The
      number of office visits was nine per patient per year; nearly one-third of
      employed patients missed work for irritable bowel syndrome, and one out of 15
      patients was hospitalized for this condition. Several technical procedures were
      ordered, mostly laboratory tests. Nearly all patients had at least one drug
      prescription for irritable bowel syndrome during the year of the survey, with a
      mean of 3.5 prescriptions per patient. The largest pharmacological groups were
      antispasmodics (29.2%) and prokinetics (8.9%). Total direct costs for one
      irritable bowel syndrome patient per year amounted to 1548 DEM (791.48 [OV0556]),
      comprising roughly 25% for physician visits and tests, 50% for drugs and 25% for
      hospitalization. Including indirect costs for sick leave, total costs were 1946
      DEM (994.97 [OV0556]) per patient per year. CONCLUSIONS: The costs incurred by
      irritable bowel syndrome are considerable.

PMID- 12468954
TI  - Extended analysis of a double-blind, placebo-controlled, 15-week study with
      otilonium bromide in irritable bowel syndrome.
AB  - BACKGROUND/OBJECTIVE: In order to follow the most recent developments and
      recommendations in trial methodology for drug evaluation in patients with
      irritable bowel syndrome, we performed an extended analysis of a large clinical
      trial from a previously published study of otilonium bromide, using an assessment
      that integrates the key symptoms of irritable bowel syndrome. MATERIALS AND
      METHODS: A large-scale clinical trial with a double-blind, placebo-controlled,
      parallel-group study design was conducted in 378 patients, treated for 15 weeks
      with the recommended standard dose of 40 mg otilonium bromide or placebo three
      times daily. The study was based on the collection of 12 single efficacy
      endpoints. The new efficacy assessment was based on the data reported by the
      patients. Rather than demonstrating score differences between the treatment
      groups of the study, we carried out an assessment that integrates the most
      frequent symptoms reported (pain frequency and intensity, presence of meteorism
      and distension) by the patient. RESULTS: The rate of response to treatment within
      2-4 months (the primary efficacy outcome measure) was significantly higher in the
      otilonium bromide group (36.9%) than in the placebo group (22.5%; P = 0.007). In
      each month of treatment, the rate of monthly response was higher in the otilonium
      bromide group as compared to the placebo group (P < 0.05). The total monthly and
      weekly responses to the single endpoints (intensity and frequency of pain and
      discomfort, meteorism/abdominal distension, severity of diarrhoea or constipation
      and mucus in the stool) were significantly more frequent in the group treated
      with otilonium bromide than in the placebo-treated group, with differences
      ranging from 10% to 20%. The subgroup analysis of the intestinal habits endpoint
      indicates that patients with diarrhoea have an additional benefit. CONCLUSION:
      The present re-evaluation of a previously published study confirms that otilonium
      bromide is more effective than placebo for the treatment of irritable bowel
      syndrome, being very efficient in relieving pain and discomfort.

PMID- 12468955
TI  - Morphometric quantification of normal submucous plexus in the distal rectum of
      adult healthy volunteers.
AB  - OBJECTIVE: Inadequate morphometric characterization of the normal adult submucous
      plexus has precluded the diagnosis of colonic dysganglionoses associated with
      constipation, such as intestinal neuronal dysplasia type B (IND B). The internal
      submucous plexus (Meissner plexus) was morphometrically quantified in adult
      healthy volunteers. DESIGN: Open, prospective morphometric study in balanced
      groups of female and male volunteers. PARTICIPANTS: Thirty-seven adult healthy
      male and female volunteers with normal bowel function and no history of
      gastrointestinal disease. METHODS: Four jumbo rectal biopsies (3-5 mm3) were
      taken 5 and 10 cm above the pectinate line. Two expert gastrointestinal
      pathologists assessed biopsy sections after specific nerve cell staining for
      lactic dehydrogenase, nitric oxide synthase and acetylcholinesterase, mainly for
      characteristics of ganglia and nerve cells in the submucous plexus. RESULTS: No
      healthy individual demonstrated over 20% of submucosal ganglia as giant ganglia
      or more than four giant ganglia per 30 sections (the morphometric criteria for
      IND B). Single submucosal nerve cells and ganglion numbers halved between 10 and
      5 cm above the pectinate line, but there were no age or gender differences. The
      biological variability of nerve cell and ganglion density in the submucous plexus
      was large. CONCLUSIONS: Healthy adults show less than 20% of submucosal ganglia
      as giant ganglia and no more than four giant ganglia per 30 rectal biopsy
      sections. There is therefore no overlap with the histomorphological criteria of
      IND B. These data therefore support the specificity of the previously defined
      criteria for IND B in adults.

PMID- 12468956
TI  - Smoking cessation would substantially reduce the future incidence of pancreatic
      cancer in the European Union.
AB  - OBJECTIVE: Since pancreatic cancer is one of the most rapidly fatal cancers,
      prevention is of paramount importance to reduce the future burden of this
      disease. We studied the impact of ceasing smoking on the future incidence of
      pancreatic cancer in the European Union (EU). METHODS: We developed a computer
      simulation model, Markov multi-state type, using country-specific published data
      on population sizes, smoking behaviour, pancreatic cancer incidence and total
      mortality rates, corresponding relative risks for ex- and current smokers, and
      estimated probabilities of starting and ceasing smoking (transition rates), with
      which we refined previously reported preliminary results. We simulated a scenario
      based on theoretically maximal smoking reduction, a more feasible scenario based
      on the World Health Organization's 'Health for All' target in which smoking
      prevalence is reduced to 20% in 2015, and scenarios based on reductions in
      smoking prevalence in 20 steps of 5% (from 0% to 100% reduction) in 2015.
      Simulations were based on changes in transition rates for smoking behaviour. We
      estimated the absolute and relative reduction of pancreatic cancer patients in
      the EU, for each scenario compared to a reference scenario in which the current
      transition rates remained unchanged, for the period 1994-2015. RESULTS:
      Theoretically, if all smokers would quit instantly, the estimated number of new
      pancreatic cancer patients up to 2015 in the EU could be reduced by 15% (around
      150 000 patients). The more feasible scenario would lead to a reduction of almost
      29 500 male and 9500 female patients. These results corresponded to a reduction
      in smoking prevalence with around 45% and 30% among men and women, respectively,
      in each EU country. CONCLUSION: Giving up smoking would substantially reduce the
      future incidence of pancreatic cancer. This emphasizes the importance of
      prevention in the reduction of the future pancreatic cancer burden.

PMID- 12468957
TI  - The prevalence of coeliac disease in rheumatoid arthritis.
AB  - OBJECTIVE: To determine the prevalence of coeliac disease in rheumatoid
      arthritis. METHODS: One hundred and sixty patients with seropositive rheumatoid
      arthritis were tested for the endomysial antibody. Those found positive were
      studied further with endoscopic small bowel biopsy. RESULTS: Only one patient was
      found to have coeliac disease, and that had already been diagnosed. Thus the
      prevalence of previously undiagnosed coeliac disease in rheumatoid arthritis is 0
      (95% CI 0-0.24%) and the overall prevalence of coeliac disease is 0.63% (95% CI
      0.1-3.5%). These prevalences are not significantly different from the reported
      prevalences of coeliac disease in the general population. CONCLUSIONS: This study
      does not support an association between coeliac disease and seropositive
      rheumatoid arthritis or the screening of such patients for coeliac disease.

PMID- 12468958
TI  - Gut delivery of budesonide, a locally active corticosteroid, from plain and
      controlled-release capsules.
AB  - OBJECTIVE: To compare the pharmacokinetics and site of uptake of budesonide from
      a controlled-release formulation and a deuterium-labelled standard formulation
      given before and after a meal. METHODS: Six healthy volunteers were randomized
      into an open, crossover study. They received 4.5 mg controlled-release budesonide
      (mixed with In pellets to trace gastrointestinal transit) and 4.8 mg 2H8
      budesonide simultaneously at each of two visits: one visit before a standardized
      breakfast and the other after breakfast. Plasma concentrations of budesonide were
      followed over 24 h. The transit of the (111)In pellets through the
      gastrointestinal tract was followed for 36 h. Data on the site of absorption were
      calculated from transit times and absorption curves. RESULTS: The time to peak
      plasma concentration was significantly increased with controlled-release
      budesonide when compared with the deuterium-labelled standard formulation (before
      breakfast, 4.5 h vs 1.8 h; after breakfast, 5.2 h vs 2.9 h). When given after
      breakfast, the controlled-release formulation was associated with a mean
      residence time 1.6 h longer than that seen with the standard formulation.
      However, the areas under the plasma concentration curves were similar with the
      two formulations, regardless of when the treatments were given (before breakfast,
      18.0 +/- 3.8 nmol/l vs 18.0 +/- 6.0 nmol/l; after breakfast, 16.9 +/- 7.0 nmol/l
      vs 18.5 +/- 9.0 nmol/l). Over 60% of the total budesonide absorbed from
      controlled-release capsules was delivered and absorbed in the ileum and colon.
      The corresponding proportion for the standard formulation was approximately 33%.
      CONCLUSIONS: Controlled-release budesonide effectively delivers most of the
      budesonide dose to the ileum and colon, the regions that are most often affected
      by inflammatory bowel disease. In addition, the time of food intake has little
      effect on the site of absorption or the bioavailability of the controlled-release
      formulation. Delivery to the colon and ileum was independent of whether the drug
      was given before or after breakfast.

PMID- 12468959
TI  - Renal failure in cirrhotic patients: role of terlipressin in clinical approach to
      hepatorenal syndrome type 2.
AB  - OBJECTIVES: Renal failure secondary to hepatorenal syndrome or to organic renal
      disease occurs frequently in cirrhotic patients with portal hypertension. The
      present prospective study investigates the usefulness of terlipressin in both the
      diagnostic and the therapeutic approach to cirrhotics with renal failure.
      PATIENTS AND METHODS: Sixteen patients were studied: 11 with hepatorenal syndrome
      type 2 (group 1) and five with organic renal disease (group 2). All received
      terlipressin (1 mg/4 h intravenously) for 7 days. Subsequently, 12 patients (nine
      from group 1 and three from group 2) underwent a transjugular intrahepatic
      portosystemic shunt. RESULTS: Terlipressin significantly improved renal function
      (serum creatinine, 1.8 +/- 0.8 versus 2.4 +/- 0.9 mg/dl; blood creatinine
      clearance, 53 +/- 8 versus 21.3 +/- 8.7 ml/min; P < 0.05) in group 1 [8/11
      patients (73%) versus 1/5 (20%) of group 2; P < 0.05]. The only patient in group
      2 who responded to terlipressin had a mixed renal dysfunction. Renal function
      improved significantly after transjugular portosystemic shunt in all patients who
      responded to terlipressin. CONCLUSIONS: Terlipressin administration significantly
      improves renal function in cirrhotic patients with hepatorenal syndrome type 2
      but not in organic kidney failure. By providing the critical information that a
      patient's kidney function is (or is not) reversible, a trial with terlipressin
      may be useful when selecting cirrhotic patients with renal failure as candidates
      for a transjugular intrahepatic portosystemic shunt or liver transplantation.

PMID- 12468961
TI  - Re-treatment with interferon-beta of patients with chronic hepatitis C virus
      infection.
AB  - OBJECTIVE: To evaluate the efficacy of interferon-beta (IFN-beta) in the re
      treatment of patients with chronic hepatitis C who did not respond to IFN-alpha
      monotherapy. PATIENTS AND METHODS: Thirty patients (24 men and six women; mean
      age, 41 +/- 13 (SD) years; range, 23-62 years), with chronic hepatitis C that was
      non-responsive to a standard course of IFN-alpha therapy, were re-treated with
      recombinant human IFN-beta-1a. All patients received IFN-beta, 12 MIU
      subcutaneously, three times weekly for 3 months, after which time patients'
      responses were evaluated. Responders (normal alanine aminotransferase, and
      negative for serum hepatitis C virus RNA) continued to receive IFN-beta, 12 MIU,
      for a further 3 months. Non-responders had their dose increased to 18 MIU for the
      remaining 3 months of treatment. After 6 months of treatment, therapy was stopped
      and patients were followed-up for a further 6 months. RESULTS: Overall, six (20%)
      of the 30 patients exhibited a response at the end of treatment. One patient
      (3.3%) maintained a sustained virological response at the end of post-treatment
      follow-up. CONCLUSIONS: Treatment with recombinant IFN-beta, at doses of up to 18
      MIU for 6 months, is safe and well tolerated. However, the results of the trial
      do not support the use of IFN-beta monotherapy in patients with chronic hepatitis
      C that is resistant to IFN-alpha.

PMID- 12468960
TI  - The influence of sulindac on patients with primary biliary cirrhosis that
      responds incompletely to ursodeoxycholic acid: a pilot study.
AB  - OBJECTIVES: In 30% of patients with primary biliary cirrhosis (PBC)
      ursodeoxycholic acid (UDCA) causes full biochemical normalization, while 70% are
      incomplete responders. The only differences between the two groups are the
      significantly higher cholestasis indices in the incomplete responders. In these
      patients we investigated whether the strongly choleretic sulindac together with
      UDCA is superior to UDCA monotherapy. DESIGN AND METHODS: Twenty-three patients
      with PBC incompletely responding to UDCA monotherapy were entered in the open
      label study for 12 months. Eleven patients (stage II, seven; III, two; and IV,
      two) received UDCA (10-15 mg/kg/day) plus sulindac (100-300 mg/day) (Group I).
      Twelve patients (stage I, six; II, four; III, one; and IV, one) were treated with
      UDCA alone (Group II). Liver biochemistry, analysis of antimitochondrial,
      antinuclear, smooth muscle, and liver-kidney-microsomal antibodies,
      ultrasonography and gastroscopy were done in regular intervals. RESULTS: In Group
      I all liver indices, IgG, IgM and IgA significantly improved although
      pretreatment data and stages of the disease tended to be higher than in Group II.
      In five patients of Group I liver histology improved slightly. Sulindac was well
      tolerated. The biochemical indices did not further improve on UDCA monotherapy.
      CONCLUSIONS: Sulindac in combination with UDCA further improves liver
      biochemistries in patients with PBC who responded incompletely to UDCA alone.

PMID- 12468962
TI  - Acquired inhibitors to coagulation factors in patients with gastrointestinal
      diseases.
AB  - OBJECTIVES: To study the frequency and specificity of acquired coagulation
      inhibitors in inflammatory and malignant gastrointestinal diseases. METHODS: In a
      10-year period, 511 patients from the island of Crete in Greece were studied, 302
      with ulcerative colitis, 112 with Crohn's disease, 82 with gastrointestinal
      carcinoma and 15 with gastrointestinal lymphoma. Prothrombin time and activated
      partial thromboplastin time were measured by routine methods. When prothrombin
      time and/or activated partial thromboplastin time were found to be prolonged,
      mixture experiments with 25%, 50% and 75% pooled normal human plasma were
      performed. If clotting times were inadequately corrected, the presence of an
      acquired inhibitor against a coagulation factor was suggested. Specific
      coagulation factor assays were then performed with deficient plasmas. RESULTS:
      Fifteen patients acquired inhibitors to the following coagulation factors within
      the 10-year observation period: factor IX (four patients); factor X (three
      patients); factor XII (three patients); factor VIII (two patients); factor XI
      (two patients); and factor V (one patient). The activity of the above factors
      varied from < 1% to 10%. Five patients with ulcerative colitis, six with Crohn's
      disease, two with gastrointestinal lymphoma and two with gastrointestinal
      carcinoma developed an inhibitor. Only one patient with factor VIII inhibitor
      presented with severe bleeding and was treated with recombinant human activated
      factor VII, while the others had no complications. Remission was obtained in all
      patients after immunosuppressive therapy, chemotherapy or tumour resection.
      CONCLUSION: An increased incidence of coagulation factor inhibitors was found in
      patients with gastrointestinal inflammatory and malignant diseases compared to
      the healthy population. In addition, an increased incidence of these inhibitors
      was also found in the common population of Crete compared to that found in other
      areas.

PMID- 12468963
TI  - Intestinal Wegener's granulomatosis in a patient with severe alpha-1-antitrypsin
      deficiency resulting from a unique combination of two deficiency alleles (PiZ and
      PiMProcida).
AB  - Alpha-1-antitripsyn neutralizes the tissue damaging effects of proteases. Alpha-1
      antitripsyn deficiency manifests with necrotizing vasculitis. Wegener's
      granulomatosis is a systemic necrotizing vasculitis that uncommonly affects the
      gut. The molecular genetics of patients with Wegener's granulomatosis of the
      gastrointestinal tract have never been characterized. A 63-year-old man with
      emphysema was admitted with a fever of unknown origin. Initially, this fever was
      linked to ileocolic Crohn's disease and later attributed to antineutrophil
      cytoplasm antibody-positive systemic vasculitis. Genetic analysis revealed that
      the alpha-1-antitripsyn deficiency was due to a previously unreported compound
      heterozygosity for two mutations (PiZ and PiMProcida). Our findings appear to
      support the concept that severe alpha-1-antitripsyn deficiency is implicated in
      the pathogenesis of the Crohn's disease-like milder intestinal manifestations
      belonging to the spectrum of Wegener's granulomatosis.

PMID- 12468965
TI  - Caroli's disease - a report of two siblings.
AB  - A 26-year-old man had suffered from several episodes of right upper-quadrant pain
      for 6 months. Abdominal ultrasonography showed multiple saccular dilatations of
      the intrahepatic biliary tract, with hepatolithiasis at the bilateral hepatic
      lobe. Abdominal computed tomography also revealed saccularly dilated intrahepatic
      ducts with hepatolithiasis. Communication between saccular dilatations of the
      intrahepatic biliary tract and normal bile ducts was demonstrated by endoscopic
      retrograde cholangiopancreatography. Choledochal cyst type V (Caroli's disease)
      was diagnosed. The patient's 29-year-old sister was also diagnosed with Caroli's
      disease based on abdominal sonography. An ultrasonography survey was carried out
      on the family. Reports of Caroli's disease occurring in two siblings are rare in
      the literature.

PMID- 12468964
TI  - Disseminated cytomegalovirus infection in Crohn's disease following anti-tumour
      necrosis factor therapy.
AB  - This case report describes a 63-year-old woman with a 15-year history of Crohn's
      disease. After a severe relapse with colitis she was treated with
      immunosuppressive agents, including an increased dosage of corticosteroids,
      azathioprine and a single dose of infliximab (anti-tumour necrosis factor-alpha).
      This led to a brief improvement, which was followed by worsening diarrhoea, fever
      and skin lesions. Biopsies from upper and lower endoscopies and from an
      ulcerative skin lesion revealed cytomegalovirus vasculitis in all the tissues
      removed. The patient improved slowly by withdrawal of the immunosuppressives and
      with anti-viral therapy. Whenever patients with inflammatory bowel disease
      deteriorate rapidly, cytomegalovirus infection should be ruled out before the
      immunosuppressive therapy is fortified.

PMID- 12468966
TI  - A case of primary non-Hodgkin's lymphoma of the transverse colon presenting as
      inflammatory bowel disease.
AB  - Primary colonic lymphoma (PCL) is uncommon. We report such a case in a 76-year
      old man who presented with diarrhoea and a barium enema that suggested a
      diagnosis of inflammatory bowel disease (IBD). However, subsequent endoscopy
      confirmed the diagnosis of PCL. PCL is a rare entity and can be misdiagnosed as
      IBD because of the symptoms and radiological findings. The correct diagnosis is
      important, since the management of these two conditions is entirely different.

PMID- 12468967
TI  - The accuracy of pedicle screw placement in the thoracic spine using the "Funnel
      Technique": part 1. A cadaveric study.
AB  - A cadaveric study using the "funnel technique" to probe thoracic pedicles was
      conducted. The results (location, level, and perforation rate) of three spine
      surgeons of varying experience were compared. The objectives were to evaluate the
      reliability and accuracy of the funnel technique for the placement of thoracic
      pedicle screws and to describe the technique. Nine fresh cadavers (216 thoracic
      pedicles) were used for pedicle screw placement using the funnel technique. The
      study was conducted by three spine surgeons with a significantly different level
      of experience in thoracic pedicle screw placement (72 thoracic pedicles each).
      Critical and noncritical perforations were recorded. The perforation rate was 6%
      (13 of 216 pedicles). Of this, only 0.4% (1 of 216) was a critical perforation (a
      contact with T8 nerve root). The junior spine surgeon who had no previous
      experience with thoracic pedicle screw placement had a 12.5% (9 of 72)
      perforation rate, the surgeon very familiar with the technique had a 5.5% (4 of
      72) perforation rate, and the senior author who originated this technique had a
      1.4% (1 of 70) perforation rate. All perforations made by the junior spine
      surgeon occurred in his first 24 pedicles; none occurred in his last 48 pedicles.
      The reliability of the funnel technique in placement of thoracic pedicle screws
      was proven in our cadaveric study. It provided even an entry-level surgeon with a
      safe way to identify and place thoracic pedicle screws. The funnel technique is a
      simple, safe, and cost-effective alternative to any other currently recommended
      techniques for pedicle screw placement.

PMID- 12468968
TI  - Thoracic pedicle screw instrumentation using the "Funnel Technique": part 2.
      Clinical experience.
AB  - This study is a retrospective review of the clinical results of patients treated
      with thoracic pedicle screws using the "funnel technique." The objective is to
      report the clinical results of patients treated with thoracic pedicle screws
      using the funnel technique for screw placement. A total of 115 patients treated
      with the use of at least one thoracic pedicle screw were retrospectively
      identified. All patients were treated at a single medical center, under the
      senior author's supervision. Twenty-five different residents were responsible for
      placing 50-60% of these screws, and five different fellows and the senior author
      placed the remainder. The accuracy of screw placement and the complications
      related to the use of thoracic pedicle screws were analyzed by assessing
      intraoperative and postoperative charts and radiographs. There were 115 patients
      (age range 9-82 years) with the average follow-up period of 17 months. The total
      number of screws used was 348; the screw diameter ranged from 4.0 to 7.75 mm.
      There were no vascular or pulmonary complications. There was no iatrogenic
      neurologic injury, except for one patient who developed a transient anterior
      thigh numbness from intraoperative positioning. In fracture patients, 35% (10 of
      28) had documented neurologic improvement postoperatively. There were no
      obviously misplaced pedicle screws on detailed review of intraoperative and
      postoperative radiographs. No screws had to be electively removed for
      complications related to misplacement. There were four broken screws, one broken
      rod, two loose screws, and three connector disengagements. Two patients had deep
      infections and four patients had pseudarthrosis requiring additional surgery. The
      clinical results proved that thoracic pedicle screws can be safely placed with
      the funnel technique.

PMID- 12468969
TI  - Surgical preference in anterior cervical discectomy: a national survey of
      Canadian spine surgeons.

PMID- 12468970
TI  - Effects of surgical treatment for cervical spondylotic myelopathy in patients >
      or = 70 years of age: a retrospective comparative study.
AB  - The objective of this study was to compare efficacy of cervical surgery for
      myelopathy in patients > or = 70 and < or = 60 years of age. Forty patients > or
      = 70 years and 50 patients < or = 60 years of age with MRI and CT proven
      myelopathy were neurologically assessed using the JOA score. Three operative
      procedures were performed: anterior spinal fusion, laminoplasty, and laminectomy.
      Postoperatively, patients exhibited comparable outcomes irrespective of age or
      operative procedure performed. The only exception was the increase in
      postoperative neurologic complications noted for the older individuals with
      greater comorbidities.

PMID- 12468972
TI  - A retrospective view of seven specifically selected cases of patients with
      osteoporotic compression fractures and concomitant radiculopathy.

PMID- 12468971
TI  - Treatment of lower lumbar radiculopathy caused by osteoporotic compression
      fracture: the role of vertebroplasty.
AB  - The authors used vertebroplasty for the treatment of severe lower lumbar
      radicular pain caused by osteoporotic compression fracture. Patients presented
      with severe radiating leg pain rather than lower back pain from recent
      osteoporotic compression fracture of lower lumbar vertebra. Radiologic findings
      showed osteoporotic compression fracture combined with preexisting stenosis of
      the intervertebral foramen resulting in root compression. After injection of
      polymethylmethacrylate into the compressed vertebral body through the pedicle of
      the symptomatic side, all seven patients experienced dramatic pain relief that
      lasted throughout the mean follow-up duration of 9.1 months. They conclude that
      vertebroplasty may be an effective way of relieving radicular pain caused by
      osteoporotic compression fracture combined with foraminal stenosis.

PMID- 12468973
TI  - Lumbar disc herniation regression after successful epidural steroid injection.
AB  - In some lumbar disc herniation patients, noninvasive measures fail, necessitating
      more aggressive treatment, such as epidural steroid injections or surgery. This
      study sought to determine whether improvement in patients who receive epidural
      steroid injections is related to regression of herniated nucleus pulposus or
      whether such patients' symptoms decrease because of the steroid effect in the
      presence of continued herniated nucleus pulposus. Two nonoperatively treated
      patient cohorts were followed who had follow-up MRI. Specifically, 38 other
      patients who improved without invasive treatment within 6 weeks after the onset
      of their symptoms were compared with 20 patients who improved with epidural
      steroid injections. Results found that both groups had similar initial and follow
      up herniated nucleus pulposus size and outcomes. The epidural steroid injection
      group had fewer sequestered or extruded herniations that resorbed, and most were
      of lower hydration. In conclusion, epidural steroid injections do not alter
      ultimate herniated nucleus pulposus regression. Patients in whom the disc
      herniation has less hydration may have prolonged symptoms, but many improve with
      epidural steroid injections.

PMID- 12468974
TI  - The biomechanical effects of multilevel posterior foraminotomy and foraminotomy
      with double-door laminoplasty.
AB  - The aim of this study is to evaluate the biomechanical effects of multilevel
      foraminotomy and foraminotomy with double-door laminoplasty compared with
      foraminotomy with laminectomy. Using fresh human cadaveric specimens (C2-T1),
      sequential injuries were created in the following order: intact, bilateral
      foraminotomies (C3-C4, C4-C5, C5-C6), laminoplasty (C3-C6) using hydroxyapatite
      spacer, removal of the spacers, and laminectomy. Changes in the rotations of each
      vertebra in each injury status were measured in six loading modes: flexion,
      extension, right and left lateral bending, and right and left axial rotation.
      Foraminotomy alone and following laminoplasty showed no significant differences
      in motion compared with intact except in axial rotation. After removal of the
      spacers and following laminectomy, the motion increased significantly in flexion
      and axial rotation. The ranges of initial slack showed similar trends when
      compared with the results at maximum load. Clinical implications of these
      observations are presented.

PMID- 12468975
TI  - Protocol and results of a day-surgical program for the removal of lumbar pedicle
      screw implants.
AB  - The removal of potentially painful lumbar pedicle screw implants is a recognized
      procedure not yet extensively reported in the literature. The extensive
      dissection required to accomplish it is such that this operation is generally
      done on an inpatient basis. A defined protocol of pre-, intra-, and postoperative
      care was instituted in the senior author's practice in 1995, with the goal of
      accomplishing these operations on a day-surgical basis. We report the results of
      70 such procedures performed in the calendar years 1995-1999 with attention to
      the efficacy of the protocol in facilitating ambulatory care. The protocol is
      safe and effective.

PMID- 12468976
TI  - Improvement of preoperative foot drop after lumbar surgery.
AB  - Foot drop is a common and debilitating finding in patients with lumbar spinal
      disorders. Recovery of function after surgical treatment of the underlying
      disorder is not well documented in the literature. The purpose of this
      retrospective study was to analyze the prognosis of preoperative foot drop after
      lumbar surgery in 55 patients with foot drop and herniated nucleus pulposus
      and/or lumbar spinal stenosis. Preoperative dorsiflexion motor strength improved
      measurably in 98%, and 71% had full recovery of strength. All patients had
      associated neurologic findings and 71% experienced complete resolution. No
      statistically significant relationship was found between the extent of recovery
      and age, diagnosis (herniated nucleus pulposus lumbar spinal stenosis), duration
      of symptoms, or severity of preoperative weakness. In our series, the prognosis
      of preoperative foot drop and associated neurologic deficits treated by lumbar
      spine surgery was excellent.

PMID- 12468977
TI  - Modeling of the naked facet sign in the lumbar spine.
AB  - The study design is a computer visualization model that simulated flexion
      deformities about the lumbar spine for evaluation of the naked facet sign (NFS).
      The objectives were to ascertain the angles of rotation required for NFS to occur
      in the lumbar spine with various centers of rotation about the vertebral body and
      to assess whether NFS correlates with unstable flexion-distraction injuries in
      the lumbar spine. The presence of the NFS on axial computed tomography (CT)
      images occurs when the inferior articulating facet of the cephalad vertebra is
      not paired with an adjacent superior articulating facet of the caudal vertebra.
      This sign, when evidenced in the lumbar spine, is suggestive of significant
      injury secondary to a flexion-distraction force. A previous study using a
      computer-generated spine model challenged the utility of the NFS in the
      thoracolumbar spine. The NFS may prove to be more diagnostic of an unstable
      injury in the lumbar spine because of its normal lordotic resting position. A
      commercial spine computer visualization model was used to simulate various
      degrees of flexion injury in the lumbar spine. Lumbar functional spinal units
      (FSU) L2-L5 were each examined separately. The model simulated two CT scan slices
      (each 2 mm thick), which were created parallel to the inferior endplate of the
      cephalad vertebra of each FSU. The cephalad vertebra was rotated in 0.5 degrees
      increments until NFS was produced. The appearance of NFS required >/=11 degrees
      kyphotic angulation in more than two thirds of simulated centers of rotation
      about the lumbar vertebral bodies. The NFS was produced between a range of 8-24.5
      degrees. For rotations about a point located 3 cm anterior to the vertebral body
      (to simulate seat-belt-type flexion-distraction injuries), the minimum angle
      required for NFS was 7.5 degrees. Our data correlate well with previously
      published results from in vitro and cadaveric studies. As opposed to the
      thoracolumbar spine, which normally rests in a neutral position, the lumbar spine
      normally rests in a lordotic position. Therefore, NFS in the lumbar spine may be
      more suggestive of an unstable injury and would warrant closer examination of the
      patient and additional radiographic studies.

PMID- 12468978
TI  - Upper sympathetic trunk lesion after video-assisted fracture stabilization of the
      thoracic spine: a case report.
AB  - This case report draws attention to the upper sympathetic trunk lesion as a
      complication of video-assisted thoracic spine surgery. A 39-year-old man
      developed an upper sympathetic trunk lesion after right-sided thoracoscopic
      fracture stabilization of T5 and T6. Dizziness and reduced perspiration persisted
      at the most recent follow-up 8 months after surgery. This rare complication can
      be overlooked and remain undiagnosed. Diagnosis is based on clinical symptoms and
      neurologic examination. There are no treatment options. Symptoms can be
      bothersome for the patient and may persist. In the upper thoracic spine, the
      course of the sympathetic trunk lies in close proximity of the vertebral bodies;
      thus, care must be taken to avoid it when resecting the posterior parts of the
      vertebral body.

PMID- 12468979
TI  - Effectiveness of radical resections in malignant dumbbell tumors of the thoracic
      spine: review of three cases.
AB  - We report postoperative evolution and prognosis after radical resection of three
      dumbbell-shaped neurogenic tumors. It was a malignant schwannoma in all cases.
      Patients were observed from 8 to 27 months postoperatively. All tumors were
      completely excised, with histologically controlled extratumoral resection limits.
      The surgical technique used is the one developed by the authors for extended
      Pancoast Tobias resections. The patients had been operated on previously with
      possible local contamination, and the previous surgical wound needed to be
      excised with the tumor The patients died 8, 12, and 27 months postoperatively.
      This short series of three malignant dumbbell tumors dramatically shows that
      prognosis is undoubtedly more related to inadequate previous resection and to the
      tumor malignancy than to the surgical technique itself. The authors consider that
      the combined anteroposterior approach is the most efficient technique with
      minimum complications, even in major multilevel resections. Indications for such
      extended surgery include the inability to use adjuvant therapy and impending
      neurologic deficit.

PMID- 12468980
TI  - Esophageal perforation after fracture of the cervical spine: case report and
      review of the literature.
AB  - We present a posttraumatic esophageal tear that occurred in a 55-year old patient
      after a truck accident. He sustained a two-level injury with a type II odontoid
      fracture and a unilateral fracture of the left superior articular process of C6
      with an incomplete quadriplegia at C5. Both lesions were treated nonoperatively.
      The tear was attributed to the stretching of the esophagus over anterior
      degenerative spurs at the level of the lesion (C5-C6) during hyperextension. The
      diagnosis of the esophageal perforation was delayed for 6 days. The treatment
      consisted of surgical debridement, volume expansion, antibiotic therapy,
      hyperbaric oxygenation, assisted ventilation, and esophageal exclusion. A
      complete review of the literature was performed.

PMID- 12468981
TI  - Analysis of the spastic gait caused by cervical compression myelopathy.
AB  - We evaluated the spastic gait of patients with cervical myelopathy with a three
      dimensional gait analysis system. Fifteen patients with cervical myelopathy (S
      group) were investigated. The results obtained were compared with those of normal
      volunteers (N group). The S group exhibited significant reduction of gait
      velocity and step length (p < 0.01). In the knee flexion-extension curve, two
      peaks were observed in the N group. In the S1 group (symptomatic period <1 year),
      the anterior peak was not smooth, whereas in the S2 group (symptomatic period >1
      year), no peak was observed. The pelvis tilted to the side of the standing leg in
      the N group. However, in the S1 group, this tilting was much less pronounced, and
      in some patients tilting toward the nonsupporting leg was observed. In the S2
      group, the pelvis again tilting toward the supporting side was observed.

PMID- 12468982
TI  - Filling of a sacral bone defect from a perineurial cyst by cementation.
AB  - In this study we present a case of Tarlov's cyst that is treated operatively. The
      operation involved partial excision and oversewing of the cyst wall with
      connection to the dural sac and methylmethacrylate filling of the sacral bone
      defect that is formed by the cyst to prevent cyst recurrence. In symptomatic
      cases Tarlov's cyst can be treated operatively with a favorable outcome.

PMID- 12468983
TI  - Pyogenic lumbar facet joint arthritis with intradural extension: a case report.
AB  - There have been 40 previously reported cases of lumbar facet joint pyogenic
      infection. These have been well characterized earlier. Intradural pyogenic
      extension has never been reported from a facet joint origin. This case
      demonstrates an elderly diabetic man with acute onset of nontraumatic back pain
      with no other source of infectious pathology. Surgical exploration identified a
      purulent left L4-L5 facet joint with epidural and intradural extension. Minimal
      spinal fluid leak was present. Wound cultures were positive for Group B beta Full
      resolution occurred with appropriate intravenous vancomycin antibiotic therapy.

PMID- 12468984
TI  - Intrathoracic giant meningocele developing hydrothorax: a case report.
AB  - A 67-year-old woman with neurofibromatosis type 1 presented with progressive
      dyspnea. Radiologic evaluation and magnetic resonance imaging revealed
      progression of a giant meningocele associated with hydrothorax. Laminoplasty with
      incision of the meningocele and dural plasty was performed, although nerve
      rootlets were killed. Microsurgical incision of the neck of the meningocele is a
      favorable operation even in large meningoceles such as the present case.

PMID- 12468985
TI  - Intracranial subdural hematoma after resection of a thoracic spinal cord tumor.
AB  - Intracranial subdural hematoma associated with intracranial hypotension is a rare
      complication of dural puncture and other procedures on the dura. This report
      describes the case of a 25-year-old man who developed intracranial subdural
      hematoma after resection of a thoracic spinal cord tumor. Intracranial subdural
      hematoma could result in severe and permanent neurologic deficit if it remains
      unrecognized. Severe and prolonged postdural puncture headache should be regarded
      as a warning sign of an intracranial subdural hematoma, and in those patients
      early investigation is recommended.

PMID- 12468986
TI  - A giant herniated disc following intradiscal electrothermal therapy.
AB  - The introduction of intradiscal electrothermal therapy for the management of
      discogenic back pain has been met with intense interest over the past few years.
      During this time there have been several noncontrolled studies published on the
      procedure, most of which have shown excellent outcomes but few, if any,
      complications. The authors describe a 29-year-old, 152-kg active duty male
      soldier who underwent two-level intradiscal electrothermal therapy for L4-L5 and
      L5-S1 discogenic pain. Before the procedure, the patient had a small L5-S1
      contained herniation, with no signs of radiculitis. Postprocedure, the patient
      developed radicular symptoms and was noted on MRI to have a large L5-S1 disc
      herniation effacing the left S1 nerve root. Follow-up discography revealed a
      negative discogram at L4-L5. The patient proceeded to undergo a single-level
      lumbar fusion, which resulted in nearly complete relief of his radicular and
      axial low back pain. Two years post-surgery, he is off all narcotic medications
      and continues to work full-time as a soldier. This case illustrates both the
      potential benefits and complications that may be associated with intradiscal
      electrothermal therapy.

PMID- 12468988
TI  - Colonic perforation complicating posteroanterior fusion using fibular strut
      autograft for a high-grade spondylolisthesis.
AB  - Posteroanterior fusion using a fibular strut autograft has been advocated for the
      surgical treatment of high-grade lumbosacral spondylolisthesis. We report here
      the treatment of a 14-year-old girl using an S2-L5 fibular autograft, which
      resulted in the postoperative complication of a sigmoid colon perforation.
      Techniques for recognizing, treating, and avoiding this complication are
      presented.

PMID- 12468987
TI  - Paraparesis in a black man brought on by ossification of the ligamentum flavum:
      case report and review of the literature.
AB  - We present the second case of paraparesis secondary to ossification of the
      ligamentum flavum at the midthoracic region in a black man. Ossification of the
      ligamentum flavum is frequently described in the Japanese population where the
      presentation is often in the lower thoracic region. The patient is a 37-year-old
      black man who, over the 6 months before admission, noticed progressive
      paraparesis. CT myelogram revealed severe thoracic stenosis by an ossified
      ligamentum flavum from T4 to T7 with most severe involvement at the T5, T6, and
      T7 levels. The patient underwent multilevel laminectomies and medial
      facetectomies from T4 to T7. Over the past decade, ossification of the ligamentum
      flavum has been reported with increasing frequency in non-Asian patients. This is
      the third case report in a black man. In addition, ossification of the ligamentum
      flavum in this particular location is rarely reported. The increased use of
      advanced neuroimaging techniques in the evaluation of "back pain" may reveal that
      the prevalence of this condition is higher than expected in non-Asian
      populations. Improvement in neurologic symptoms secondary to decompressive
      laminectomies will depend on the degree and duration of spinal cord compression.

PMID- 12468989
TI  - Defect in the articular process of the lumbar facet.
AB  - Bone defect in the lumbar articular facet is rarely noted, and only a few reports
      on its clinical course have been presented. We report on seven cases with lumbar
      inferior facet defect whose symptoms were mimicking spondylolysis. We have found
      three types of the defect shape on radiographs: linear, blunt, and irregular.
      There were five cases with linear type, one with blunt, and one with irregular.
      All patients had persistent low back pain, especially when doing physical
      activity or sports, but no one had history of major trauma or accident. Injection
      of a small amount of anesthetic temporarily alleviated the low back pain. The low
      back pain in six patients was controlled with conservative treatments, such as
      bracing or medication; bone union was especially gained in one case. However, a
      volleyball player's pain could not be controlled conservatively, and removal of
      the bone fragment was performed. It is considered that facet defect is not as
      rare as presumed, and more attention should be paid to it as a source of low back
      pain.

PMID- 12468991
TI  - Mechanisms and state of the art of transcranial magnetic stimulation.
AB  - In 1985, Barker et al. built a transcranial magnetic stimulation (TMS) device
      with enough power to stimulate dorsal roots in the spine. They quickly realized
      that this machine could likely also noninvasively stimulate the superficial
      cortex in humans. They waited a while before using their device over a human
      head, fearing that the TMS pulse might magnetically "erase the hard-drive" of the
      human brain. Almost 10 years later, in 1994, an editorial in this journal
      concerned whether TMS might evolve into a potential antidepressant treatment. In
      the intervening years, there has been an explosion of basic and clinical research
      with and about TMS. Studies are now uncovering the mechanisms by which TMS
      affects the brain. It does not "erase the hard-drive" of the brain, and it has
      many demonstrated research and clinical uses. This article reviews the major
      recent advances with this interesting noninvasive technique for stimulating the
      brain, critically reviewing the data on whether TMS has anticonvulsant effects or
      modulates cortical-limbic loops.

PMID- 12468992
TI  - Update on magnetic seizure therapy: a novel form of convulsive therapy.
AB  - Magnetic seizure therapy (MST) refers to the use of transcranial magnetic
      stimulation to induce a seizure for therapeutic purposes. MST is under
      investigation as a means of improving the safety profile of electroconvulsive
      therapy (ECT). Although both MST and ECT induce seizures through electrical
      stimulation of the brain, the electric field induced by MST is more focal and
      limited than that induced by ECT. Because magnetic fields pass through tissue
      unimpeded, there is greater control over the site and extent of stimulation with
      MST than can be achieved with ECT. This enhanced control represents a means of
      focusing the treatment on target cortical structures thought to be essential to
      antidepressant response and of reducing spread to medial temporal regions
      implicated in the cognitive side effects of ECT. MST is currently at an early
      stage of development. This article reviews the experience with MST in animal
      models and initial human investigations. Preliminary results have demonstrated
      the feasibility of performing MST in the clinical setting, and there are
      suggestions that MST may have advantages over ECT in terms of subjective side
      effects and some measures of acute cognitive functioning. The antidepressant
      efficacy of MST is not yet known, but studies designed to address that critical
      issue are underway. As with all attempts to refine convulsive therapy techniques
      (such as modifications in stimulation parameter configurations and electrode
      placement), the ultimate clinical value of MST will need to be established
      through controlled clinical trials.

PMID- 12468993
TI  - Mechanisms and state of the art of vagus nerve stimulation.
AB  - Vagus nerve stimulation (VNS) is an established treatment of medically refractory
      partial-onset seizures. Recent data from an open-label multicenter pilot study
      also suggest a potential clinical usefulness in the acute and maintenance
      treatment of drug-resistant depressive disorder. Despite the fact that surgery is
      needed to implant the stimulating device, the option of long-term use largely
      devoid of severe side effects would give this treatment modality a privileged
      place in the management of drug-resistant depression. However, definite
      therapeutic effects of clinical significance remain to be confirmed in large,
      placebo-controlled trials. Besides the potential clinical usefulness, VNS can be
      used as a research tool in epilepsy patients implanted for clinical reasons,
      allowing neurophysiologic investigations of the parasympathetic system and its
      interactions with other parts of the central nervous system.

PMID- 12468994
TI  - Update on deep brain stimulation.
AB  - Deep brain stimulation (DBS) is an established therapy for movement disorders and
      an investigational treatment in other neurologic conditions and in
      neuropsychiatry. DBS can target with precision neuroanatomical targets deep
      within the brain that are proposed, on the basis of increasing evidence from
      functional neuroimaging and other methods, to be centrally involved in the
      pathophysiology of some neuropsychiatric illnesses. DBS is nonablative, offering
      the advantages of reversibility and adjustability. In theory, this characteristic
      might permit therapeutic effectiveness to be enhanced or side effects to be
      minimized. Although its mechanisms of action are unknown, several possible
      effects have been proposed to underlie the therapeutic effects of DBS in movement
      disorders, and potentially in other conditions as well. This issue is the subject
      of very active investigation in a number of clinical and preclinical
      laboratories. DBS may offer a degree of hope for patients with intractable
      neuropsychiatric illness. Research intended to realize this potential will
      require a very considerable commitment of resources, energy, and time across
      disciplines including psychiatry, neurosurgery, neurology, neuropsychology, and
      bioethics. Investigations in this area should proceed cautiously.

PMID- 12468995
TI  - Effect of stimulus intensity and number of treatments on ECS-related seizure
      duration and retrograde amnesia in rats.
AB  - BACKGROUND: Animal models are frequently used to generate and test hypotheses
      about amnesia resulting from electroconvulsive therapy (ECT). Although many
      predictors of ECT-induced amnesia are known, their relative effects have been
      inadequately researched in the context of the animal models. OBJECTIVE: We sought
      to determine the relative retrograde amnestic effects of electroconvulsive shock
      (ECS) stimulus intensity (dose) and number on strong memories in rats. We also
      sought to identify dose-dependent ceiling amnestic effects, if any. METHODS:
      Adult rats (n = 144) were overtrained in a passive avoidance task using a step
      down apparatus. The rats were then randomized in a factorial design to receive
      one, two, or three once-daily bilateral ECS at 0-mC (sham ECS), 30-mC, 60-mC, 120
      mC, or 180-mC doses. Recall of the pre-ECS training was assessed 1 day after the
      last ECS. RESULTS: Retrograde amnesia was observed only in rats that received 3
      ECS; dose-dependent amnestic effects did not emerge. Higher stimulus intensity
      was associated with a small (13%) but significant increase in motor seizure
      duration, but only at the first ECS; stimulus intensity did not influence the
      attenuation of seizure duration across repeated occasions of ECS. CONCLUSION:
      With bilateral ECS, the number of ECSs administered is a more important variable
      than the ECS dose in weakening a strong, recently acquired, noxious memory; this
      finding may have important clinical implications. Higher stimulus intensity
      marginally increases motor seizure duration at the first ECS but does not
      influence the decrease in seizure duration across repeated ECSs.

PMID- 12468996
TI  - United Kingdom national survey of the views of geriatric psychiatrists on the
      administration of electroconvulsive therapy to patients with fractures.
AB  - Traditionally, psychiatrists have been cautious in administering
      electroconvulsive therapy (ECT) to patients with recent fractures. Drawing on the
      collective experience of geriatric psychiatrists in the United Kingdom may allow
      a better understanding of the use of ECT in fractures. The opinions of UK
      consultant geriatric psychiatrists on the use of ECT in the presence of recent
      fracture were acquired by a detailed questionnaire survey. Questionnaires were
      sent to 551 geriatric psychiatrists, and 306 (56%) usable responses were
      received. Twelve percent of geriatric psychiatrists had used ECT in fractures,
      and 55% would be prepared to administer ECT in the presence of fractures. They
      would seek specialist advice from anesthetists and orthopedic surgeons before,
      during, and after the administration of ECT. Geriatric psychiatrists generally
      did not seek advice from specialist ECT consultants. The researchers concluded
      that geriatric psychiatrists are prepared to administer ECT in the presence of
      fractures after seeking specialist advice from anesthetists and orthopedic
      surgeons.

PMID- 12468997
TI  - Patients' and their relatives' knowledge of, experience with, attitude toward,
      and satisfaction with electroconvulsive therapy in Hong Kong, China.
AB  - Although electroconvulsive therapy (ECT) is a safe and efficacious treatment,
      there is a widespread negative view of ECT in public and professional circles.
      There are no data on Chinese patients' knowledge of, experience with, attitude
      toward, and level of satisfaction with ECT in Hong Kong. The aims of this study
      were to examine patients' experience of ECT, and patients' and their relatives'
      knowledge of, attitude toward, and level of satisfaction with ECT. To this
      effect, a prospective cross-sectional survey was conducted, involving 96 patients
      and their 87 relatives. The study showed that the majority of patients believed
      they had not received adequate information about ECT. The most commonly reported
      side effect was memory impairment. Patients and relatives had only limited
      knowledge of ECT, yet the majority of them were satisfied with the treatment and,
      having found it beneficial, maintained a positive attitude toward its use. The
      researchers concluded that Hong Kong Chinese patients and their relatives
      accepted ECT as a treatment. The way information is provided to patients and
      relatives when obtaining consent for ECT needs improvement.

PMID- 12468998
TI  - Clinical approach to agitation after electroconvulsive therapy: a case report and
      literature review.
AB  - Agitation is a neurologic complication that may occur after electroconvulsive
      therapy (ECT). Severe agitation after ECT has been associated with multiple
      factors, both anesthetic and psychiatric. This case report describes severe
      postictal agitation after ECT in a patient with bipolar affective disorder. The
      clinical management of this challenging presentation is discussed, including both
      the anesthetic and psychiatric approaches.

PMID- 12468999
TI  - ECT use delayed in the presence of comorbid mental retardation: a review of
      clinical and ethical issues.
AB  - The objective is to develop a clinically and ethically supportive literature for
      the use of electroconvulsive therapy (ECT) in patients with mental retardation
      who are concurrently experiencing a significant psychiatric illness. A review of
      both the clinical and ethical literature using traditional, manual library
      methods and the Medline and Psychlit databases was undertaken. In addition, a
      record of all patients who had undergone ECT at our facility between 1995 and
      2000 was examined for patients with comorbid mental retardation. We found that
      the use of ECT for people who have both a psychiatric illness and comorbid mental
      retardation was significantly delayed. However, a rapid response to index,
      continuation, and maintenance ECT was also noted. Further, this response occurred
      with routine ECT administered irrespective of age, gender, diagnosis, stimulus
      parameters, electrode placement, or number of treatments. In addition, the
      successful use of right-sided unilateral ECT at six times the initial seizure
      threshold was reported in a patient who had previously responded to bilateral
      ECT. A cogent ethical justification was developed with the use of the rule of
      double effect. We concluded that for patients who have mental retardation and who
      subsequently develop a psychiatric illness, ECT is delayed and left as a
      treatment of last choice. Although the literature is sparse and uncontrolled, a
      cogent clinical and ethical justification may help negotiate these and other
      delays.

PMID- 12469000
TI  - Worsening of motor function and mood in a patient with Parkinson's disease after
      pharmacologic challenge with oral rivastigmine.
AB  - Patients with Parkinson's disease (PD) can experience cognitive impairment. There
      are currently no medications indicated for the treatment of cognitive impairment
      in PD. Clinicians are faced with the dilemma as to whether or not to treat
      patients with PD with the acetylcholinesterase inhibitors that are currently
      approved for use in Alzheimer's disease (AD) and that have shown promise in
      clinical trials of Dementia with Lewy bodies (DLB). Although these medications
      may help cognition, there is a theoretical concern that by increasing
      acetylcholine relative to dopamine, they might worsen motor function. We report
      the case of a patient with PD and cognitive impairment who developed a marked
      worsening of motor function, mood, and anxiety in the setting of a pharmacologic
      challenge study using a 3-mg oral dose of the acetylcholinesterase inhibitor,
      rivastigmine. We believe that the mechanism of the motor and perhaps psychiatric
      worsening was increased central cholinergic tone. We conclude that further
      studies should be done to evaluate the efficacy and tolerability of these agents
      in this illness but that caution should be exercised when using
      acetylcholinesterase inhibitors in patients with PD.

PMID- 12469001
TI  - Tetrabenazine treatment for Huntington's disease-associated chorea.
AB  - Tetrabenazine (TBZ), a monoamine depleter and dopamine receptor blocker, is used
      to treat a variety of hyperkinetic movement disorders. The objective was to study
      the efficacy and tolerability of TBZ for chorea associated with Huntington's
      disease (HD). Nineteen patients (12 female), mean age 56.3 +/- 12.4 years (range
      37-76 years) diagnosed with HD were prospectively evaluated at initial and follow
      up visits using a modified Abnormal Involuntary Movement Scale (AIMS). Patients
      were videotaped, and the randomized videotapes were rated with the motor subset
      of the AIMS by two investigators who were blinded to treatment assignment.
      Eighteen patients completed and were rated after 5.9 +/- 3.3 months (range 2-11)
      at a final mean TBZ dose of 62.5 +/- 37.4 mg/day (range 25-150). The blinded
      videotaped motor scores showed that 15 were better on TBZ, 2 were better before
      TBZ, and 1 was unchanged (p < 0.001, Wilcoxon signed rank test). The mean score
      improved from 16.2 +/- 4.8 to 12.8 +/- 4.4. Adverse events included akathisia,
      insomnia, constipation, depression, drooling, and subjective weakness. All 18 of
      these patients have continued to take TBZ since completion of the study. TBZ was
      well tolerated and resulted in a significant improvement in modified AIMS scores
      in HD patients. These results support the use of TBZ for chorea in patients with
      HD.

PMID- 12469002
TI  - Quetiapine and essential tremor.
AB  - The safety and tolerability of quetiapine (up to 75 mg/day) as monotherapy on
      essential tremor were investigated in an open-label study in 10 patients. Five
      men and 5 women, with a mean age of 66.3 years, affected by essential tremor
      participated in the trial. They were treated with increasing doses of quetiapine
      to 75 mg/day over a 6-week period. Side effects included a paradoxical
      psychiatric reaction in one and anger in another, and in both cases quetiapine
      was discontinued. In two other patients, somnolence led to dose reduction. There
      were no pre- versus post-treatment differences, but 3 out of 10 patients
      benefited (improvement >20%). Although the study was not powered to assess
      efficacy, quetiapine seems to be a safe drug for the treatment of essential
      tremor.

PMID- 12469003
TI  - Sequential changes in the plasma concentration of risperidone following
      intentional overdose.
AB  - Risperidone (RIS) is a novel antipsychotic agent whose pharmacokinetics have yet
      to be fully determined. In particular, little is known about RIS following an
      overdose. We report the pharmacokinetics following ingestion of a high dose of
      RIS by serially measuring the plasma concentration in two patients. These
      patients were admitted in a comatose state following an intentional overdose of
      RIS; all patients survived. In the first patient, 14 mg of RIS had been ingested
      2 hr before the first blood sample was obtained. The second patient ingested an
      estimated 90 mg of RIS. Seven time-points were determined. The maximum
      concentration of unaltered RIS was 325 ng/mL and that of the principal metabolite
      (9-hydroxy-risperidone: 9-OH RIS) was 139 ng/mL. By plotting the time
      concentration curve for the active fraction (RIS plus 9-OH-RIS) in the first and
      second patients, the half-life of RIS following overdose was determined and was
      approximately 12.7 hr and 17.8 hr, respectively. These values are similar to the
      half-life of RIS in healthy individuals ingesting a therapeutic dose. Two
      patients did not developed parkinsonism nor dystonia, and were discharged without
      sequelae.

PMID- 12469004
TI  - Sensorimotor polyneuropathy after a three-month oral acitretin therapy.
AB  - We report a patient with chronic plaque psoriasis who developed clinical and
      electrophysiologic features of polyneuropathy affecting motor and sensory fibers
      in upper and lower extremities after three months of treatment with oral
      acitretin. Drug withdrawal resulted in a complete clinical recovery and
      normalization of all electrophysiologic abnormalities within two months.

PMID- 12469005
TI  - Donepezil for the treatment of behavioral symptoms in patients with Alzheimer's
      disease.
AB  - Behavioral and psychologic symptoms of dementia (BPSD) are common manifestations
      in mid- and late-stage Alzheimer's disease (AD). Traditional treatments for BPSD
      are neuroleptics and sedatives, which are not devoid of serious adverse effects.
      A number of studies show beneficial effects in the treatment of BPSD with
      acetylcholinesterase inhibitors (AChEI). The present study aimed to evaluate the
      effect of donepezil (using the generic drug Memorit) as monotherapy for AD
      patients suffering from BPSD. Twenty-eight consecutive patients followed at the
      Memory Outpatient Clinic and Psychogeriatric Department of the Abarbanel Mental
      Health Center were treated with donepezil for 6 months. Starting dose was 5 mg
      daily during the first 4 weeks and continuation with 10 mg daily thereafter.
      Treatment effects were evaluated using the Mini Mental State Examination (MMSE),
      the Neuro-Psychiatric Inventory (NPI), and the Clinical Global Impression of
      Change Scale (CGIC) caregiver version. Twenty-four of 28 patients completed the
      study. Of these, five patients needed additional rescue neuroleptic treatment due
      to incomplete response. The mean dose of donepezil was 9.10 mg/day (median 10
      mg/day). The overall NPI improved significantly from 33.4 to 21.2 (p = 0.008).
      The mean CGIC at study's end was 3.0 (mild improvement). The cognitive scores did
      not change significantly. When compared to the patients who completed the study,
      patients who discontinued had higher mean scores on the irritability and
      agitation subscales of the NPI, they were older, and they had longer disease
      duration and lower MMSE mean scores. Three adverse events were recorded: one
      syncope causing a toe phalanx fracture and gastrointestinal complaints that
      resolved over time in two additional patients. Acetylcholinesterase inhibitors
      should be considered for the treatment of BPSD before neuroleptic treatment is
      instituted in AD patients with low levels of irritability and agitation.

PMID- 12469006
TI  - Evaluation of the hospital anxiety and depression scale in patients with
      Parkinson's disease.
AB  - The purpose of this study was to evaluate the psychometric properties of the
      Hospital Anxiety and Depression Scale (HADS) in patients with Parkinson's disease
      (PD) and to assess the prevalence of symptoms of anxiety and depression in this
      population. The HADS was sent to 205 patients with PD, together with three
      quality-of-life (QoL) instruments, i.e. the Parkinson's Disease Questionnaire
      (PDQ-39), the EQ-5D, and a visual analogue scale (VAS). Hospital Anxiety and
      Depression Scale scores were also compared with Hoehn-Yahr (H&Y) scores. Eighty
      six percent of the patients returned the questionnaires. The quality of the data
      was good. Cronbach alpha for the HADS was 0.88. Test-retest reliability over 2
      weeks was 0.84 for the sum score of the HADS (intraclass correlation coefficient)
      and ranged from 0.42-0.76 for individual items (weighted kappa). Factor analysis
      revealed two factors, accounting for 51.9% of the variance. One factor
      represented anxiety, the other depression. Correlations with PDQ-39, EQ-5D, VAS,
      and H&Y were 0.72, -0.59, -0.59, and 0.32, respectively (p values < 0.001).
      Depression scores accounted for 52% of the variance in QoL, whereas disease
      severity explained 24%. Using the cut-off values proposed by the developers
      indicated that possible and probable anxiety were present in 29.4% and 19.8% of
      the patients, respectively. Percentages for possible and probable depression were
      21.5 and 16.9. The psychometric performance of the HADS in patients with PD is
      satisfactory. In addition, almost 50% of the patients displayed symptoms of
      anxiety, whereas nearly 40% showed signs of depression.

PMID- 12469007
TI  - Neuropsychiatric effects of guanfacine in children with mild tourette syndrome: a
      pilot study.
AB  - The objective of this study was to evaluate the neuropsychiatric effects of the
      alpha-2a adrenergic agonist guanfacine in children with Tourette syndrome (TS).
      Twenty-four children with TS participated in a 4-week, double-blind, placebo
      controlled study of guanfacine. Tic severity, neuropsychologic functioning, and
      parent ratings of behavior were evaluated pre- and post-treatment. The sample had
      mild tic severity and subtle neuropsychologic dysfunction pretreatment. Post
      treatment, patients receiving guanfacine were rated by parents as significantly
      improved (compared to placebo) on one measure of executive function (parent-rated
      metacognition). Improvement on tic severity, performance-based neuropsychologic
      measures, and all other parent ratings were not significantly better than
      placebo. At a moderate dose and short-term treatment duration, guanfacine did not
      provide significant neuropsychiatric benefits in this group of children with mild
      TS.

PMID- 12469008
TI  - [Gadolinium chelating agents for arteriography and CT x-ray].

PMID- 12469009
TI  - [Imaging of skull base tumors in adults].
AB  - The skull base is divided into three parts: anterior, central and posterior.
      Numerous foramina are located in the skull base and transmit important
      neurovascular structures. Numerous types of tumor can be observed at the skull
      base. They are classified as anterior, central and posterior skull base tumors.
      They are also divided into three groups according to their origin: tumors arising
      from the skull base itself, intracranial tumors and extracranial tumors invading
      the skull base. Imaging is very important for diagnosis, treatment and follow-up
      of patients with skull base tumors. Magnetic resonance imaging is the most useful
      modality as it visualizes the lesion on different planes and permits the planning
      of therapy. Computed tomography depicts the osseous lesions more precisely and
      may be necessary before surgery. Catheter angiography is now in most cases
      replaced by magnetic resonance angiography. Interventional neuroradiology is
      necessary if the lesion is highly vascularized or if a vessel is encased in the
      tumor.

PMID- 12469010
TI  - [Physiological basis of functional MRI].
AB  - Afferent neurotransmission of a given neuronal group and its subsequent dendritic
      activity are followed by a transient hemodynamic response such as an increase of
      the local blood flow and of the intravascular level of oxygen. This neurovascular
      regulation involves neurons, astrocytes, interneurons and various transmitter
      substances. The resulting changes in the magnetic susceptibility is then detected
      by the MRI machine which can specifically localize regional brain activity. Blood
      oxygenation level dependent contrast reflects afferent inputs and their post
      synaptic (dendritic) processing, rather than the output from the concerned
      cerebral zone (spiking). In other words, this contrast depends on local
      informational treatment of an active zone without implying any effective
      influence upon its targets.

PMID- 12469011
TI  - [CT dacryography without selective lacrimal duct catheterization: review of 39
      patients].
AB  - OBJECTIVES: Dacryographies and CT dacryographies are usually performed after
      catheterization of a lacrimal canaliculus. We evaluated the quality of
      opacification on CT scan after simple instillation of contrast medium, without
      any catheterization. PATIENTS AND METHODS: 39 patients (78 nasolacrimal ducts)
      were examined for lacrimal pathways obstruction by CT scan after instillation of
      diluted contrast medium. Additional CT scan imaging was performed after
      catheterization when the first study did not provide adequate opacification.
      RESULTS: CT dacryography after instillation is a well tolerated technique. In our
      study, it allowed detection of all pathologic lacrimal ducts; 7 normal lacrimal
      pathways (after catheterization) were not opacified after instillation (false
      positives). The sensitivity of the method was 100%, its specificity 84%.
      CONCLUSION: CT dacryography after instillation is a physiologic, simple and
      sensitive method to evaluate lacrimal obstruction. We propose it as a first step,
      catheterization being used only in the absence of opacification after
      instillation.

PMID- 12469012
TI  - [CT and MRI aspects of 28 patients with cerebral radiation necrosis irradiated
      for ORL tumors: correlation with the radiation technique].
AB  - PURPOSE: To describe and correlate with radiation therapy the occurrence of
      cerebral radiation necrosis in patients irradiated for nasopharyngeal or
      ethmoidal tumor. Materials and Methods. From 1986 to 1998, 1 201 patients, 981
      with nasopharyngeal tumors, and 220 with ethmoidal tumors were treated by
      radiotherapy. Twenty eight developed cerebral necrosis. MRI were performed in all
      patients and CT in 18 patients. Diagnosis was considered at imaging, and
      confirmed by follow-up. RESULTS: The incidence of cerebral radionecrosis was
      2.33%. The time interval between treatment and necrosis ranged from 2 months to 9
      years. CT showed edema and/or focal enhancement in all cases except for 4
      patients with normal CT examinations. MRI showed edema and/or abnormal focal
      punctate or gyriform enhancement in all patients. Lesions were localized in the
      temporal lobe (n=18), frontal lobe (n=9), pons (n=3) and optic nerve (n=2). The
      doses related to the areas of necrosis ranged from 13 to 135Gy. In 2 cases
      necrosis was situated at the boundaries of the radiation field. Imaging follow-up
      showed complete (n=3) or incomplete remission (n=1), lesion progression (n=11),
      cerebral atrophy (n=5) and stability (n=7). CONCLUSION: MRI is useful to diagnose
      cerebral necrosis. New technologies may reduce the incidence of this
      complication.

PMID- 12469013
TI  - [Gadolinium in arteriography and interventional radiology: 39 patients].
AB  - OBJECTIVE: To report the experience of using various Gadolinium chelates as
      contrast media in digital subtraction angiography in patients with relative or
      absolute contraindications for iodinated contrast agents. MATERIAL: and Methods.
      Forty-two arteriograms were performed in 39 consecutive patients using Gadolinium
      chelates (gadoteridol, gadodiamide, and gadopentetate dimeglumine). The
      vasculature of the brain, of the upper and lower limbs and the renal arteries
      were examined. Among these 39 patients, 17 were treated by various endovascular
      procedures. RESULTS: In 40 examinations out of 42, the angiographic result was
      satisfactory, allowing either a diagnostic evaluation or an endovascular
      therapeutic procedure. Clinical tolerance was excellent. In one case of renal
      failure that was reported after angiography, the patient had received both iodine
      and gadolinum-based contrast agents. CONCLUSION: Gadolinium appears to be an
      interesting alternative for arteriography in patients with absolute or relative
      contraindication to iodinated contrast agents, and also seems to demonstrate
      efficacy during endovascular therapeutic procedures.

PMID- 12469014
TI  - [Pheochromocytomas and CT: can size predict malignancy?].
AB  - OBJECTIVES: The purpose of this study was to determine clinical and imaging
      findings associated with malignancy in pheochromocytomas. MATERIAL: and methods.
      A multicentric retrospective CT study including 50 lesions (23 benign and 27
      malignant histologically proven pheochromocytomas) was conducted. The diagnosis
      of malignancy was based on histological criteria (capsular rupture, local
      invasion), on synchronous metastases or on the occurrence of locoregional
      recurrences or metastases during the outcome. The analysis was based on clinical
      data (age, sex, secretion of the lesion and hypertension) and on radiological
      criteria (largest diameter of the tumor, side, homogeneity, regularity and
      sharpness of contours). RESULTS: A statistical difference was found between the
      median largest diameter, the regularity and sharpness of contours benign and
      malignant lesions (p<0.0001); other clinical and radiological criteria being non
      significantly different. A largest diameter greater than 45 mm enabled to suggest
      malignancy with a sensitivity of 100% and a specificity of 69%. CONCLUSION: A
      diameter larger than 50mm, presence of a locoregional invasion and of metastases
      are strong arguments favouring.

PMID- 12469015
TI  - [Portal pulmonary venous anastomosis and portal hypertension].
AB  - The authors report two cases of portopulmonary anastomosis to show the value of
      multidetector CT with MPR MIP reformations in the diagnosis of portopulmonary
      venous anastomosis. This diagnosis has consequences in the treatement of
      hypoxemia in patients with chronic liver disease and embolization of bleeding
      esophageal varices in these patients.

PMID- 12469016
TI  - [Imaging of a foreign body in the submandibular space].
AB  - Foreign bodies in the oral cavity are infrequent in children. In spite of a
      negative clinical exploration, US and CT showed the suction cup of a rubber
      tipped dart in the left submandibular space of a 3 year-old child. Surgery could
      be guided by these investigations.

PMID- 12469017
TI  - [Massive hemoperitoneum from rupture of an intra-peritoneal varix].
AB  - Rupture of an intra-abdominal varix in a patient with portal hypertension is a
      rare but severe cause of massive hemoperitoneum. The authors report the case of a
      patient with alcoholic cirrhosis that presented to the emergency department with
      hypovolemic shock. Imaging showed massive hemoperitoneum, severe portal
      hypertension and suggested the diagnosis of spontaneous rupture of an intra
      abdominal varix, confirmed at laparotomy.

PMID- 12469018
TI  - [Primary extensive hydatidosis of the thigh: unusual radiological aspects].
AB  - Soft tissue involvement by hydatid disease remains unusual (5%) even in endemic
      areas. Patients typically present late because disease progression is slow and
      often asymptomatic. The authors report the unusual imaging appearance in a 59
      year old woman with a one year history of progressive diffuse painless swelling
      of the left thigh. Ultrasonography showed multiple anechoic and hypoechoic cystic
      lesions, some of which containing serpentine echogenic structures consistent with
      partly calcified membranes. CT and MRI confirmed a diagnosis of hydatid disease
      and were helpful to demonstrate the relationship between cysts and adjacent
      structures. Surgical management was performed early because of fistulization to
      the skin.

PMID- 12469019
TI  - [Quiz? Subacute osteomyelitis with articular involvement].

PMID- 12469021
TI  - [Image display devices(2)--CRT monitor].

PMID- 12469023
TI  - [Actual CT inspection(1): a setup of a scanning parameter].

PMID- 12469022
TI  - [Thoracic molecular imaging].

PMID- 12469024
TI  - [Nationwide survey of image quality and glandular tissue dose in digital
      mammography].

PMID- 12469025
TI  - [Digital sampling limitation on the dental radiograph].

PMID- 12469026
TI  - [A few remarks on a historical study (II) of Japanese Society of Radiological
      Technology].

PMID- 12469027
TI  - [Application possibility of terahertz-wave source to imaging].

PMID- 12469028
TI  - [The information of image diagnosis contributes to the IVR management: The
      treatment choice for hepatocellular carcinoma].

PMID- 12469029
TI  - [Evaluation of flat-panel detector for general radiography systems].

PMID- 12469030
TI  - [Apparatus engineering of X ray CT equipment (3): Development of helical scan].

PMID- 12469031
TI  - [Basic examination of in-plane spatial resolution in multi-slice CT].
AB  - In computed tomography(single-slice spiral CT, conventional CT), in-plane(x-y
      plane) spatial resolution is consistently identified as depending on the detector
      density of the in-plane(x-y plane). However, we considered that the in-plane(x-y
      plane) spatial resolution of multi-slice CT (MSCT) was influenced by an error in
      the detector's sensitivity to the Z-axis and by the frequency of use of direct
      row data and complementary row data when the image of spiral pitches(SP) was
      reconstructed. Our goal in this experiment was to analyze the relationship of the
      in-plane(x-y plane)spatial resolution of an asymmetric-type detector in MSCT to
      SP, tube current, and rotation time. By employing a tungsten wire phantom of 0.2
      mm in diameter, we examined modulation transfer functions(MTF) by point-spread
      functions(PSF) of CT-images. Next, using the mean-square-root bandwidth theory,
      we analyzed the MTF of wire phantoms. The analysis of in-plane(x-y plane) spatial
      resolution revealed that various tube currents had no effect on the value of the
      mean-square-root bandwidth. However, rotation time and high spiral pitch did have
      an effect on mean-square-root bandwidth. Considering the results mentioned above,
      spiral pitch(z-axis reconstruction algorithm) had a slight effect on in-plane(x-y
      plane) spatial resolution of asymmetric-type detectors in MSCT. Accordingly, we
      proposed a new general view of VDDz(view/mm) in MSCT that considered view data
      density on the Z-axis according to spiral pitch(mm/rotation), rotation
      time(view/rotation), and slice collimation.

PMID- 12469032
TI  - [Characteristics of a new non-invasive x-ray output analyzer].
AB  - The X-ray systems study group used the Victoreen NERO mAx model 8000, a new non
      invasive X-ray output analyzer, to measure the tube voltage, tube voltage
      waveform, tube current, and irradiation time for conditions corresponding to
      general radiography and mammography. The measurement results were then compared
      with those obtained using a conventional invasive measuring instrument. The peak
      values of the tube voltage measured by the NERO mAx and the invasive measuring
      instrument were compared. The NERO mAx had a good measurement error range of -1.2
      to +0.9 kV. For tube current measurement by the NERO mAx, the maximum error for
      general radiography conditions was +11 mA and that for mammography conditions was
      +6 mA. For irradiation time measurement, the value for general radiography
      conditions was slightly greater and the value for mammography conditions was
      slightly less than the corresponding values obtained by the invasive measuring
      instrument. If radiation quality is changed during measurement of the
      characteristics, measurement values change. Since the NERO mAx incorporates two
      types of X-ray detectors, it shows good measurement reproducibility. The NERO mAx
      has been shown to have suitable characteristics for use as a measuring instrument
      for constancy tests. In the future, constancy tests should be used to
      quantitatively control the factors determining clinical image quality.

PMID- 12469033
TI  - [Modulation transfer function measurements on magnetic resonance imaging: use of
      the edge spread function].
AB  - A convenient, accurate method to measure the modulation transfer function (MTF)
      of magnetic resonance(MR) images is discussed. To avoid any distortion of the
      edge spread function(ESF) which is inadvertently produced by the magnitude
      operator, the MTF was calculated from the ESF obtained from the salad-oil/water
      interface. Our MTF findings closely correlated with the MTF findings as
      calculated by an alternate method (Steckner et al.). Our method was only adapted
      to some specific sequences and some specific encoding directions, however, MTF
      was successfully obtained by the magnitude operator without any errors. In our
      method, the production and arrangement of phantoms were also easier to control.
      Our new method is therefore considered to be useful for evaluating the resolution
      property of MR images from various institutions.

PMID- 12469034
TI  - [Absorbed dose in CT: comparison by CT dose index].
AB  - Few reports have discussed the absorbed dose on CT units with increased scanning
      capacity even with the current widespread adoption of multi-slice CT units. To
      compare and investigate the dose indexes among CT units, we measured the absorbed
      dose on CT units operating in Nagano Prefecture Japan. The measurements showed
      proportionality between phantom absorbed dose and the exposured mAs values in
      conventional scanning operation. Further, the measurements showed that the
      absorbed dose in the center of the phantom differed by about 2.1-fold between the
      highest and lowest levels on individual CT units. Within a single company, multi
      slice CT units of the same company gave absorbed doses of about 1.3 to 1.5 times
      those of conventional single-slice CT units under the same exposured conditions
      of conventional scanning. When the scanning pitch was reduced in helical
      scanning, the absorbed dose at the center of the phantom increased.

PMID- 12469035
TI  - [Evaluation of routine examinations using automatic scan technique optimization
      for X-CT].
AB  - Auto mA is a function that automatically controls tube current so as to stabilize
      image quality. To determine the applicability of this function to routine
      inspection work, an evaluation was carried out by two doctors in the department
      of radiology and five technicians in the department of diagnostic radiology using
      home-made phantoms and phantoms for low contrast resolution determination. The
      phantom experiment provided an almost constant level of SD values in each Auto mA
      mode tested, independent of scanning type, slice thickness, and phantom shape. In
      addition, nearly stable low contrast resolution was attained independent of
      phantom shape, e.g., circle and ellipse. The results suggest that stable image
      quality is available in the clinical stage for individual patients and regions,
      independent of the size and shape of targets. As for the evaluation of clinical
      images, the image quality requested by clinical operations at our hospital was
      attained even in the low dose mode that provides the lowest dose level. In
      addition, for variations in tube current values for photographing in individual
      regions, both sustained image uniformity and exposure reduction were found to be
      satisfactory in comparison with constant tube current.

PMID- 12469036
TI  - [Dosimetry with phantom for total body irradiation(TBI)].
AB  - Total body irradiation(TBI) is being used as a method of preparation for bone
      marrow transplantation(BMT). In TBI, the dose calculation is based on dosimetry
      using a phantom. We measured the basic dose with a phantom using a 10 MV X-rays.
      We confirmed the accuracy of the dose calculation performed in our facilities and
      investigated a method of more accurate dosimetry. We measured the variation in
      dose according to the size of the phantom and the depth using a tough water
      phantom, and examined the difference in TMR according to SCD, field size, and
      size of the phantom. Consequently, the dose has been changed regardless of the
      size of the phantom at larger than 80 x 30 x 30 cm(3), and it is about 1% larger
      than 30 x 30 x 30 cm(3). Also TMR has changed according to various conditions,
      including the size of the phantom, field size, and SCD. Therefore, it was found
      that dosimetry using the 30 x 30 x 30 cm(3) phantom leads to underestimation in
      dose calculation, and there is no difference in dose between the field size of
      151.5 x 160 cm(2) and 151.5 x 80 cm(2). It is also necessary to consider the
      effect of the vertical size of the phantom.

PMID- 12469037
TI  - [Examination of patient factors and contrast medium factors that exert influence
      on contrast enhancement].
AB  - PURPOSE: To determine the relationship between patient factors and contrast
      medium factors, both of which influence contrast enhancement. Our goal was to
      achieve improved standardization and reproducibility of enhancement based on the
      findings of this study. METHODS: Enhancement units(EU) and the contrast
      enhancement index(CE index) were calculated in the areas of the hepatic
      parenchyma and abdominal aorta in 370 subjects who underwent our hepatic dynamic
      study. We analyzed the obtained values in terms of differences in age, sex, body
      weight, iodine volume per body weight, and volume and concentration of contrast
      medium. RESULTS: Changes in EU values were dependent on total iodine volume and
      body weight, showing a positive correlation with iodine volume per body weight.
      When assessed in terms of fixed total volume, the values were found to show a
      negative correlation with body weight. The obtained CE index values were closely
      distributed on a fixed iodine volume per weight, with slight variations that were
      related to sex, body weight, and age. Particularly, in the analysis of changes in
      enhancement levels according to age, a notable increase in contrast enhancement
      in inverse relationship with decline in glomerular filtration rate(GFR) with
      aging was observed.

PMID- 12469038
TI  - The contribution of plaque and arterial remodeling to de novo atherosclerotic
      luminal narrowing in the femoral artery.
AB  - BACKGROUND: Atherosclerotic luminal narrowing is caused by plaque growth and
      arterial remodeling. In peripheral arteries, a role for constrictive remodeling
      in luminal narrowing has been recognized, but the impact on lumen decrease has
      not yet been assessed. We studied to what extent arterial remodeling and plaque
      formation contribute to luminal narrowing in the superficial femoral artery.
      METHODS: Elderly subjects (n = 79) were studied. Post mortem, pressure-fixed
      femoral arteries (n = 125) were dissected and divided into 0.5-cm segments (n =
      3266). In each cross section, we measured lumen area, plaque area, and the area
      encompassed by the internal elastic lamina (IEL area). For each artery, the cross
      section with the least amount of plaque was considered the reference segment. In
      cross sections with a decrease in lumen area compared with the reference, we
      determined the contributions of both plaque increase and IEL area change.
      RESULTS: A decrease in lumen area was found in 2193 cross sections. In cross
      sections with >50% lumen stenosis, plaque increase (accompanied by IEL area
      increase) fully explained lumen decrease in 80 of 280 cross sections (29%). In
      the remaining 200 of 280 cross sections (71%), both plaque increase and IEL area
      decrease contributed to lumen stenosis. In 57 of 280 cross sections (20%), IEL
      area decrease was the major determinant of lumen decrease, dominating over plaque
      increase. In 143 of 280 cross sections (51%), plaque increase was the major
      determinant, dominating over IEL area decrease. CONCLUSION: The results of this
      post mortem study suggest that in a substantial part (20%) of severely stenotic
      lesions in the femoral artery, constrictive remodeling, not plaque size, is the
      major determinant of lumen decrease. Further serial studies are needed to confirm
      these results.

PMID- 12469039
TI  - Regeneration.

PMID- 12469040
TI  - Contemporary results of juxtarenal aneurysm repair.
AB  - OBJECTIVE: The increasing use of aortic endografts predictably will add to the
      complexity of open abdominal aortic aneurysm (AAA) repair and, therefore, the
      proportion of surgically treated infrarenal AAAs that are juxtarenal in location
      (JRA) will grow. This study reviews a single-center experience with JRAs.
      METHODS: Between June 1994 and December 2000, 138 patients underwent elective
      repair of a JRA, comprising 16.1% of 859 consecutive asymptomatic and intact
      symptomatic nonruptured infrarenal AAAs repaired over the same period. All
      patients with JRA needed proximal suprarenal clamping (SRC) or supravisceral
      (SVC) clamping. Patient demographics, selected risk factors, and operative
      details were recorded. Univariate analyses of selected risk factors for an
      adverse perioperative event were assessed, and multivariate analyses were
      performed with linear and logistic regression with backwards selection. RESULTS:
      SRC was used in 95 patients (69%), and 43 patients (31%) underwent SVC. The
      mortality rate was 5.1% (7/138) for JRA repair, and 2.8% (20/720) for infrarenal
      AAA repair (P =.03). The mortality rate was significantly greater for those
      patients who received SVC compared with SRC (11.6% versus 2.1%; P =.02).
      Multivariate analysis identified SVC position as the only independent predictor
      of mortality (odds ratio [OR], 6.1; 95% CI, 1.1 to 32.9; P =.035). Transient
      renal insufficiency occurred in 39 patients (28.3%), but only eight patients
      (5.8%) needed dialysis. Patients who had SVC had a significantly greater rate of
      renal insufficiency than those who received SRC (41.9% versus 22.1%; P =.02).
      Multivariate analysis showed SVC position (OR, 3.3; 95% CI, 1.4 to 7.8; P =.008),
      diabetes (OR, 3.7; 95% CI, 1.1 to 12.9; P =.04), and preoperative renal
      insufficiency (OR, 5.8; 95% CI, 2.2 to 15.4; P <.001) were independent predictors
      of postoperative renal insufficiency. Renal ischemia during proximal clamping
      cannot alone explain renal complications because clamp time was shorter in
      patients with SVC (24.9 +/- 2.4 minutes versus 32.2 +/- 1.5 minutes; P =.009).
      CONCLUSION: JRA repair can be accomplished with a low mortality rate, but a more
      proximal clamp position may adversely affect outcome in these patients.
      Postoperative renal insufficiency is related to diabetes, preoperative renal
      insufficiency, and SVC position. These results suggest SRC is safer than SVC for
      proximal aortic clamp control of JRAs. Although clamp level must be tailored to
      patient anatomy, outcome may be improved if the clamp level can be kept distal to
      the superior mesenteric artery origin.

PMID- 12469041
TI  - Life expectancy after endovascular versus open abdominal aortic aneurysm repair:
      results of a decision analysis model on the basis of data from EUROSTAR.
AB  - BACKGROUND/OBJECTIVES: Although endovascular abdominal aortic aneurysm (AAA)
      repair (ENDO) has decreased operative morbidity risks compared with open AAA
      repair (OPEN), risks of rupture and reintervention are higher after ENDO. We used
      decision analysis to examine the effect of these competing risks on quality
      adjusted life expectancy (QALE) after ENDO and OPEN. METHODS: We used a Markov
      decision-analysis model to simulate hypothetic cohorts of patients undergoing
      ENDO or OPEN. Patients moved through a multistate transition model according to
      probabilities derived from the literature, the EUROSTAR database (for ENDO) and
      Medicare claims data (for OPEN). Our primary outcome measure was QALE after
      surgery. We used sensitivity analysis to determine which factors most influenced
      this outcome. RESULTS: In the base-case analysis of 70-year-old men, life
      expectancy after ENDO was 7.09 quality-adjusted life years compared with 7.03
      quality-adjusted life years for OPEN, a difference of 3 weeks. Sensitivity
      analysis showed that at less than age 64 years, OPEN results in greater QALE.
      However, the difference in QALE was small (<3 months) across the entire range of
      ages studied (60 to 85 years). The optimal strategy was sensitive to changes in
      ENDO and OPEN operative mortality rate, rupture rate after ENDO, late conversion
      to OPEN rate, ENDO revision rate, and OPEN reoperation rate. However, the
      difference between OPEN and ENDO strategies was small across the plausible range
      of most of these variables. CONCLUSION: For most patients who are candidates for
      AAA repair, ENDO and OPEN result in similar QALE. Decision analysis suggests that
      OPEN may be preferred for younger patients with low operative risk and ENDO may
      be preferred for older patients with higher operative risk. However, given the
      similarity in overall outcome, patient preference should be weighed heavily in
      decision making.

PMID- 12469042
TI  - Stent graft repair in the aortic arch and descending thoracic aorta: a 4-year
      experience.
AB  - BACKGROUND: Thoracic aortic aneurysms (TAAs) and type B aortic dissections (ADs)
      are relatively frequent, serious conditions that are often managed nonoperatively
      because of perceived poor outcome of standard surgical reconstruction. Recently
      developed stent graft techniques represent a more attractive, less invasive
      option. We sought to determine the technical feasibility and safety of
      endovascular repair in the thoracic aorta with a retrospective review of our
      experience with such an approach. METHODS: Forty-seven patients received thoracic
      stent graft implants during the 4-year period ending March 31, 2002. All patients
      signed an Institutional Review Board-approved informed consent. Thirty-one
      patients had TAAs, and 16 had ADs. Device design and implant strategy were on the
      basis of evaluation of morphology with angiography and computed tomographic scan.
      The procedures were done with fluoroscopic guidance, with local anesthesia in
      five cases, spinal anesthesia in 19 cases, and general anesthesia in 23 cases.
      Endovascular access was achieved with femoral cutdown in 41 cases and a temporary
      iliac conduit in six cases. A Talent patient-specific device, with 4-mm to 6-mm
      oversize, was used in all. Proximal endograft attachment was in the descending
      thoracic aorta in 16 cases, parasubclavian in 21 cases, and the suprasubclavian
      aorta in 10 cases. Eight patients had adjunctive cervical reconstruction to
      transpose or revascularize the left subclavian or left common carotid arteries,
      enabling more proximal endograft attachment in the aortic arch. RESULTS: Access
      failure occurred in one patient (2.1%). One patient (2.1%) died within 30 days of
      access-related iliac artery rupture. Another death occurred at 60 days from a
      ruptured thoracoabdominal aneurysm with type I endoleak. No instances of
      paraplegia, stroke, or surgical conversion were seen. Five patients (TAA) were
      found to have endoleak on 30-day computed tomographic scan. Repair of type I
      endoleak was undertaken in three cases at 1, 4, and 6 months. Eight patients
      (17%) had adverse events within the first 30 days. Length of follow-up ranged
      from 1 to 44 months, with a mean of 18 months. Two patients were lost to follow
      up, and one withdrew from the study. Four additional mortalities were observed,
      none related to the endograft or aortic pathology. CONCLUSION: Stent graft repair
      of TAA and AD is feasible and can be achieved with technical success and
      relatively low rates of perioperative morbidity and mortality. The Talent
      customized design proved versatile in various morphologies. More information is
      needed on indications, clinical efficacy, and long-term results.

PMID- 12469043
TI  - Multicenter trial of the PowerLink bifurcated system for endovascular aortic
      aneurysm repair.
AB  - PURPOSE: The purpose of this study was to assess the results of abdominal aortic
      aneurysm repair with the PowerLink bifurcated endovascular graft (Endologix, Inc,
      Irvine, Calif). METHOD: Twelve centers used the PowerLink bifurcated system for
      elective endovascular aneurysm repair in 118 patients recruited during a 16-month
      interval and followed for a 25-month interval (mean follow-up, 16 months) as part
      of a pivotal US Food and Drug Administration trial. Stent grafts were oversized
      by 10% to 20% relative to computed tomographic scan-based diameter measurements.
      All repairs were performed in the operating room through one surgically exposed
      femoral artery and a contralateral 9F sheath percutaneously placed. Results were
      assessed with contrast-enhanced computed tomography and plain abdominal
      radiography at 1, 6, and 12 months after surgery. RESULTS: Three failed
      insertions and one late conversion for endoleak remediation occurred, resulting
      in four conversions (3.3%) to open surgery. Of the failed insertions, two were
      from a faulty delivery system design, which was corrected. No failures occurred
      after the modification. One perioperative death (0.8%) occurred that was not
      device related. Eight late deaths were from unrelated causes, and one was from
      complications after reoperation for treatment of an endoleak. Endoleaks were
      noted in 19 patients (16%) at the time of the endograft procedure: 12 resolved
      spontaneously, four resolved with secondary interventions (three type I, one type
      II), and three underwent observation, yielding a 30-day endoleak rate of 5.9%.
      Two graft limb thromboses (0.8%) were seen. One graft migration (0.8%) was of no
      clinical significance. No ruptures or wire fractures were found. The mean
      aneurysm diameter was reduced from 51 mm (preoperative) to 45 mm (12 months; P
      <.0001). CONCLUSION: The PowerLink system appears to be safe and effectively
      protects patients from abdominal aortic aneurysm rupture over the short to medium
      term. The low endoleak rate is superior to that reported for other devices. The
      graft and stent materials have thus far been free from failure and fatigue. The
      sutureless stent and endoskeleton design confer a number of unique advantages and
      challenges. Careful follow-up over the longer term is necessary to assure the
      durability of these results.

PMID- 12469044
TI  - Internal iliac occlusion without coil embolization during endovascular abdominal
      aortic aneurysm repair.
AB  - PURPOSE: When abdominal aortic aneurysms and common iliac artery (CIA) aneurysms
      undergo concomitant endovascular repair, endograft limb extension into the
      external iliac artery is often necessary. Usually, the internal iliac artery
      (IIA) is coil embolized in such a case to prevent endoleak. It has been our
      practice to coil embolize the IIA only in cases where there is not adequate stent
      graft seal in the CIA immediately proximal to the IIA origin (effectively sealing
      the entire IIA origin). In this study, we evaluated the outcomes of this
      approach. METHODS: We retrospectively reviewed 204 consecutive endovascular
      abdominal aortic aneurysm repairs at Dartmouth-Hitchcock Medical Center from 1996
      to 2001. Computed tomographic angiography with three-dimensional reconstruction
      was the primary preoperative imaging modality, and the decision to cover the IIA
      without concomitant coil embolization was based before surgery on the presence of
      adequate graft oversizing (> or =10% to 15%) in the most distal 5 mm of CIA and
      15 mm of proximal external iliac artery, respectively. RESULTS: The IIA was
      occluded 33 times in 31 patients. In 22 cases (67%), the IIA was covered without
      coil embolization (COVER group). The remaining 11 patients (33%) with inadequate
      graft oversizing in the CIA underwent IIA coil embolization (COIL group). The
      follow-up periods for the COVER and COIL groups were 19 +/- 2 months and 10 +/- 3
      months, respectively. All operations in both groups were technically successful
      without evidence of endoleak at completion angiography. No endoleaks, graft
      migrations, or aneurysm enlargements were associated with the covered or coiled
      IIAs during the follow-up period. No clinical sequelae were seen in the COVER
      group, with the exception of buttock claudication in six patients (27%) that
      resolved completely in five patients. In the COIL group, five patients (45%) had
      buttock claudication. In addition, one case of buttock necrosis and one case of
      ischemic neuropathy occurred in the COIL group. CONCLUSION: Covering the IIA
      without coiling effectively excluded the CIA aneurysm in every case and was
      associated with a low incidence rate of complications compared with coil
      embolization. With detailed preoperative imaging and patient selection, IIA coil
      embolization may not be necessary in as many as two thirds of patients who need
      IIA occlusion.

PMID- 12469045
TI  - The distribution of carotid endarterectomy procedures among surgeons and
      hospitals in New York state: is regionalization of specialized vascular care
      occurring?
AB  - INTRODUCTION: In a published analysis of all carotid endarterectomies (CEAs)
      performed in New York state from 1990 to 1995, perioperative mortality rate was
      inversely correlated with surgeon and hospital CEA volume, was significantly
      higher when CEAs were performed by surgeons who performed less than five CEAs
      annually, and was significantly lower in hospitals where surgeons performed more
      than 100 CEAs annually. The purpose of this study was to determine whether this
      information has influenced practice patterns in New York state. METHODS: The
      database of the Center for Medical Consumers was queried to determine the volume
      distribution among surgeons and hospitals of all CEAs performed in New York state
      in 1999 and 2000. RESULTS: During 1999, 695 surgeons in 169 hospitals performed
      9458 CEAs (mean, 13.6 per surgeon). Three hundred fifty-three surgeons (51%)
      performed less than five CEAs, and 180 (26%) performed only one CEA during the
      year. Only 41 surgeons (6%) performed more than 50 CEAs. Likewise, in only 28 of
      the hospitals (17%) were more than 100 CEAs performed during 1999, whereas in 73
      of the hospitals (43%) 20 or less CEAs were carried out during the year. During
      2000, 684 surgeons performed 8196 CEAs in 165 hospitals. Three hundred fifty
      three (52%) performed less than five CEAs, and 229 (33%) performed only one CEA
      during the year. Only 33 surgeons (5%) performed more than 50 CEAs during 2000.
      In only 26 hospitals (16%) were more than 100 CEAs performed during 2000, whereas
      in 71 hospitals (43%) 20 or less CEAs were carried out. CONCLUSION: It appears
      that published compelling evidence that operator and institutional volume
      influence outcome has not influenced referral patterns or led to a
      regionalization of CEA care in New York state. Robust educational programs
      directed to patients and referring physicians appear indicated.

PMID- 12469046
TI  - The utility of color duplex ultrasonography in the diagnosis of temporal
      arteritis.
AB  - PURPOSE: Temporal arteritis (TA) is frequently diagnosed with nonspecific
      clinical characteristics, followed by a temporal artery biopsy to confirm the
      presence of vasculitis. Consequently, numerous screening surgical biopsies are
      performed with a high negative-biopsy rate. A prospective study was performed
      evaluating color duplex ultrasound scan (CDU) as the preferred method for the
      diagnosis of vasculitis in the evaluation of suspected TA. METHODS: Thirty-two
      patients with suspected TA on the basis of clinical criteria were evaluated with
      CDU before a temporal artery biopsy. The presence of a hypoechoic "halo,"
      suggesting edema of the inflamed vessel, and inflammatory stenoses were noted.
      Histologic examinations of standard temporal artery biopsies then were performed,
      and the results were compared with the CDU findings. In addition, a metaanalysis
      was performed to identify articles related to the use of ultrasound scan in the
      detection of TA. RESULTS: All patients completed a bilateral CDU examination of
      the temporal arteries, and in 75% of patients biopsied, no evidence of vasculitis
      was found at histologic examination. When CDU examined for halo alone as the
      determinant for disease, the sensitivity, specificity, positive predictive value
      (PPV), and negative predictive value (NPV), compared with histologic confirmation
      of TA, were 85.7%, 92.0%, 75.0%, and 95.8%, respectively. With the criteria for a
      halo sign present, an inflammatory stenosis present, or both present on CDU, the
      sensitivity, specificity, positive predictive value, and NPV were 100%, 80.0%,
      58.3%, and 100%, respectively. CONCLUSION: CDU is a superior noninvasive method
      of determining the presence of vasculitis when compared with routine surgical
      biopsy. Examination of the temporal artery with CDU can effectively predict which
      patient will need surgical biopsy. The utility of CDU in the diagnosis of TA is
      maintained by a high sensitivity in detecting patients with the disease and also
      by a high NPV that can eliminate patients who would not benefit from biopsy.

PMID- 12469048
TI  - Is the nihilistic approach to surgical reduction of superficial and perforator
      vein incompetence for venous ulcer justified?
AB  - OBJECTIVE: Twenty-five years ago, the senior author showed a 55% postoperative
      ulcer recurrence rate after open perforator ligation. Those data contributed to a
      nihilistic attitude toward incompetent perforating veins. Conversely, since the
      introduction of subfascial endoscopic perforator surgery (SEPS), we have
      undertaken ablation of superficial and perforator reflux as initial treatment in
      patients with ulcers (C6) or healed ulcers (C5). This report outlines our long
      term results. METHODS: Between December 1994 and November 1999, SEPS was
      performed on 51 limbs in 45 patients with C5/C6 disease. Sixteen limbs underwent
      SEPS alone, and 35 had additional surgery on the greater saphenous vein (GSV),
      the lesser saphenous vein, or the tributary varicies. Data were collected
      according to the reporting standards in venous disease. Preoperative duplex scan
      of deep, superficial, and perforating veins was performed. Data were analyzed
      with Kaplan-Meier method, Mantel-Cox log-rank test, or t test. RESULTS: Of the 51
      limbs that underwent SEPS, the GSV was stripped in 28. Twenty-nine were C6, and
      22 were C5. Etiology was primary (Ep) in 25 limbs and secondary (Es) in 26 limbs.
      All limbs had duplex scan evidence of perforator incompetence (Ap), and deep
      insufficiency (A(D)) was seen in 39 cases (76%). Reflux predominated (P(R)). The
      clinical follow-up period was 0 to 82 months (median, 38 months). Venous
      disability scores improved from 9.8 before surgery to 4.2 at last follow-up (P
      <.05). Kaplan-Meier analysis showed 74% healing at 6 months. The presence of an
      ulcer more than 2 cm in diameter, secondary etiology, and SEPS without
      concomitant GSV stripping were associated (P <.05) with delayed healing. Among
      patients in whom ulcers healed or who were seen with healed ulcers, the 5-year
      ulcer recurrence rate was 13%. Lesser saphenous vein reflux was the only factor
      that correlated with increased ulcer recurrence. Deep system reflux as measured
      with duplex scan valve closure times did not correlate with the rate of ulcer
      healing or recurrence. CONCLUSION: Nihilism has no place in the management of
      venous disease in the 21st century. An aggressive approach to superficial and
      perforating vein reflux in this cohort of patients with C5 and C6 disease
      resulted in rapid ulcer healing and low 5-year recurrence rates. Prior saphenous
      vein stripping, large ulcers, and secondary etiology were associated with delayed
      healing. A less aggressive posture toward lesser saphenous vein reflux
      contributed to a higher recurrence rate in this subgroup of patients. These risk
      factors are useful in counseling patients as to their expected postoperative
      course; however, no combination of factors should a priori preclude surgical
      intervention in this group of patients.

PMID- 12469047
TI  - Spontaneous recanalization of arterial occlusions: an unusual mechanism for
      symptomatic improvement.
AB  - OBJECTIVE: Patients with infrainguinal occlusive disease may experience
      spontaneous symptomatic improvement. This is generally thought to be from
      augmented collateral circulation. This study reports another mechanism. METHODS:
      Over a 20-year period, 4123 patients underwent lower extremity arteriography for
      limb ischemia. For a variety of reasons, 451 patients had repeat arteriography.
      RESULTS: Five patients were identified as having conclusive arteriographic
      evidence of spontaneous recanalization of occluded arterial segments without
      having undergone any surgical or thrombolytic interventions. Repeat contrast
      arteriography was performed on these patients for failing grafts (n = 2) or
      contralateral lower extremity ischemia (n = 3). Three other patients had magnetic
      resonance arteriographic or duplex arteriographic evidence of spontaneous
      arterial recanalization. Spontaneous recanalizaton occurred in ileofemoral (n =
      2), superficial femoral (n = 2), popliteal (n = 3), and peroneal (n = 1) arterial
      segments. The average time interval of occlusion to recanalization was 21 weeks
      (2 weeks to 2 years). Two of the eight patients had failed revascularization
      procedures before spontaneous recanalization. All eight patients had restoration
      of pulses distal to the recanalized segments and significant symptomatic
      improvement as defined with the Society for Vascular Surgery/American Association
      for Vascular Surgery categories for limb ischemia. CONCLUSION: Spontaneous
      recanalization of arterial segments can occur and must be considered when
      evaluating other proposed treatments of critical limb ischemia, including
      cilostazol, lytic agents, and angiogenic agents, such as vascular endothelial
      growth factor. Although its true incidence is unknown, this represents another
      mechanism for spontaneous symptomatic improvement without treatment in patients
      with severe limb ischemia.

PMID- 12469049
TI  - Initial experience with cerebral protection devices to prevent embolization
      during carotid artery stenting.
AB  - OBJECTIVE: Carotid artery stenting (CAS) for treatment of carotid stenosis has
      not received wide acceptance because of the availability of carotid
      endarterectomy (CEA) with its excellent results and because of the risk of
      embolic stroke associated with CAS. The feasibility and efficacy of cerebral
      protection devices that may prevent such embolic complications have yet to be
      shown. We report our initial results with CAS performed with cerebral protection.
      METHODS: For a period of 28 months, 31 patients with carotid artery stenosis,
      most of whom were considered at high risk for CEA (87%), underwent treatment with
      CAS in conjunction with either the PercuSurge GuardWire (n = 19; Medtronic,
      Minneapolis, Minn), the Cordis Angioguard filter (n = 7; Cordis, Warren, NJ), or
      the ArteriA Parodi Anti-embolization catheter (n = 4; ArteriA, San Francisco,
      Calif) with US Food and Drug Administration-approved investigational device
      exemptions. Factors that made CEA high risk included restenosis after CEA (n =
      6), hostile neck (n = 6), high or low lesions (n = 4), and severe comorbid
      medical conditions (n = 11). Preoperative neurologic symptoms were present in
      58%, and the mean stenosis was 85% +/- 12%. Data were prospectively recorded and
      analyzed on an intent-to-treat basis. Neurologic evaluation was performed before
      and after CAS by a protocol neurologist. RESULTS: CAS was performed with local
      anesthesia with the Wallstent (n = 23; Boston Scientific Corp, Natick, Mass) or
      the PRECISE carotid stent (n = 7; Cordis) in conjunction with one of the
      protection devices in an operating room with a mobile C-arm. Each patient
      received dual antiplatelet therapy before surgery. The overall technical success
      rate was 97% (30/31). In one patient, the lesion could not be crossed with a
      guidewire because of a severely stenosed and tortuous lesion. This patient was
      not a candidate for CEA and was treated conservatively. In the remaining 30
      cases, CAS had a good angiographic result (residual stenosis, <10%). All patients
      tolerated the protection device well, and no intraprocedural neurologic
      complications occurred. Macroscopic embolic particles were recovered from each
      case. One patient (3%) with a severely tortuous vessel had a major stroke
      immediately after CAS, and no deaths occurred. The combined 30 day stroke/death
      rate was 3%. During a mean follow-up period of 17 months, one subacute occlusion
      of the stent occurred but did not result in a stroke. Three other patients had
      duplex scan-proven in-stent restenosis, and two underwent treatment with repeat
      percutaneous transluminal angioplasty with a good result. No patient had a stroke
      during the follow-up period. CONCLUSION: CAS with cerebral protection devices can
      be performed safely with a high technical success rate. Although many patients
      who underwent treatment with CAS were at high risk, the neurologic complication
      rate was low and CAS appears to be an acceptable treatment option for select
      patients at high risk for CEA. Tight lesions and tortuous anatomy may make the
      use of distal protection devices difficult. Further study is warranted.

PMID- 12469050
TI  - Surgical treatment of nonaneurysmal aortic arch lesions in patients with systemic
      embolization.
AB  - PURPOSE: Atherosclerotic lesions of the aortic arch are potential sources of
      arterial embolism. Here we investigate whether surgery, with the necessary
      circulatory supports, can be proposed as a good option for treatment of this
      problem. Study of these lesions on a national scale in France has made possible
      the assessment for future indications of techniques and results of the surgical
      management of aortic arch lesions, which retrospectively proved to be embolic.
      METHODS: Thirty-eight patients, (19 men and 19 women) underwent surgery between
      1976 and 1996 in 17 French cardiovascular surgical centers. The average age at
      the time of surgery was 49 +/- 12 years (range, 31 to 82 years). Atherosclerotic
      lesions were detected with transesophagial echocardiography (n = 19), angiography
      of the aortic arch (n = 16), computed tomography (n = 9), and magnetic resonance
      imaging (n = 10). Surgery consisted of thrombectomy and endarterectomy (n = 22),
      aortic resection and graft replacement (n = 10), and patch aortoplasty (n = 5;
      one thrombus disappeared spontaneously before surgery was performed). RESULTS:
      The average postoperative period was 30 months (range, 3 to 82 months). Contact
      was lost with four patients after a follow-up period of 12 months. On pathologic
      specimens obtained at surgery, an atherosclerotic plaque was found in 73% of the
      cases (n = 28). In 15% of the cases, the aorta appeared normal (n = 6) and four
      other types of lesion were identified: angiosarcoma (n = 1), ectasia at the
      insertion of the remains of the ductus arteriosus (n = 1), rupture of tunica
      intima (n = 1), and a fibroblastic plaque (n = 1). A thrombus was identified in
      26 cases, attached to the arterial wall in 18 cases. When transesophagial
      echocardiographic results showed mobile lesions (n = 22), histopathologic
      examination of specimens allowed the detection of a thrombus in 18 cases and an
      atherosclerotic plaque with a mobile projection in four cases. The postoperative
      mortality rate was 2.6%. The morbidity rate (28.9%; n = 11) was related to
      neurologic complications (n = 6), vascular complications (n = 4), and infection
      (n = 1). Four cases (12%) were reoperated. CONCLUSION: Nonaneurysmal aortic arch
      lesions are a frequent and still underestimated source of stroke and peripheral
      embolization. Surgery with circulatory support can be recommended in good
      operative candidates with recurrent critical events despite medical management
      and with high embolic potential (young patients with no calcified plaques).

PMID- 12469051
TI  - Can screening for genetic markers improve peripheral artery bypass patency?
AB  - OBJECTIVE: Three genetic mutations have been associated with an increased risk of
      thromboembolic events: factor V Leiden R506Q, prothrombin G20210A, and
      methylenetetrahydrofolate reductase C677T (MTHFR) mutations. The aim of this
      study was to determine the effect of these mutations on patency of peripheral
      bypass procedures and preoperative and postoperative thromboembolic events.
      METHODS: Two hundred forty-four randomly selected volunteers participating in the
      Veterans Affairs Cooperative Study #362 were tested for factor V Leiden,
      prothrombin, or MTHFR mutations with polymerase chain reaction. Patients enrolled
      in the study were randomized to receive aspirin therapy or aspirin and warfarin
      therapy after a peripheral bypass procedure. The frequencies of preoperative and
      postoperative thromboembolic events and primary patency (PP), assisted primary
      patency (APP), and secondary patency (SP) rates were compared among carriers of
      the various mutations. RESULTS: Fourteen patients (5.7%) were heterozygous for
      the factor V Leiden mutation, seven (2.9%) were heterozygous for the prothrombin
      mutation, and 108 (44.6%) were heterozygous and 15 (6.2%) homozygous for the
      MTHFR mutation. After surgery, patients homozygous for the MTHFR gene mutation
      had increased graft thrombosis, compared with patients who were heterozygous
      (33.3% versus 11.1%; P =.01), and lower PP, APP and SP rates (P <.05).
      Furthermore, patients heterozygous for the MTHFR mutation had fewer graft
      thromboses (11.1% versus 24.4%; P =.01), fewer below-knee amputations (0.9%
      versus 7.6%; P =.02), and higher PP, APP, and SP rates (PP, 79.6%; APP, 88.9%;
      SP, 90.7%; P <.05) compared with wild-type control subjects (PP, 63%; APP, 75.6%;
      SP, 76.5%; P <.05). CONCLUSION: Patients with either factor V Leiden or
      prothrombin mutations were not at an increased risk for postoperative graft
      occlusion or thromboembolic events. Patients heterozygous for MTHFR mutation had
      a lower risk of graft thrombosis and higher graft patency rates compared with
      both homozygous and wild-type control subjects. Patients homozygous for the MTHFR
      mutation had lower graft patency rates compared with patients who were
      heterozygous, and a trend was seen toward lower patency rates compared with wild
      type control subjects. Therefore, screening for the MTHFR gene mutation before
      surgery may identify patients at an increased risk of graft thrombosis.

PMID- 12469052
TI  - Initial experiences in endovenous treatment of saphenous vein reflux.
AB  - INTRODUCTION: The most common site of venous reflux is the long saphenous vein
      (LSV). The preferred treatment for reflux in the LSV is surgical stripping of the
      LSV. However, the complications of surgical stripping are well documented and
      undesirable. The constant search for treatment options with less morbidity, which
      are also cosmetically more acceptable, has resulted in the endovenous treatment
      for primary varicose veins, developed by VNUS Medical Technologies, Inc
      (Sunnyvale, Calif). We hereby present our first treatment experiences and propose
      refinements to the procedure. METHODS: Two types of heat-generating endovenous
      catheters were used to treat incompetence of the LSV with a diameter of up to 12
      mm. The procedure was performed on a blood-empty limb. RESULTS: Twenty-six limbs,
      in 26 patients, were treated, and the follow-up period was 1 year. The mean
      preoperative CEAP score was 4, and the postoperative score was 1.26, which was
      statistically significantly less (P <.0001, with Wilcoxon nonparametric matched
      pair test). Five patients had postoperative paresthesia of the saphenous nerve,
      and one patient had a burn from the procedure. The overall complication rate was
      23%. All complications occurred in the first half of the studied population (P
      =.015, with Fisher exact test), indicating the learning curve effect. In one
      patient (3.8%), was total recanalization of the treated segment occurred, one
      patient (3.8%) could not be treated at all (technical failure), and one patient
      (3.8%) had partial recanalization of the LSV. Eight patients (30.8%) had closure
      of the entire LSV but with persisting reflux in the saphenofemoral junction
      (SFJ). Two patients had a competent SFJ with occlusion of the LSV. In 13 patients
      (50%), closure of both the LSV and the SFJ was seen. The LSV was successfully
      occluded in 88% of the patients. CONCLUSION: The endovenous catheter should not
      be used more than 5 to 10 cm below the knee to prevent saphenous nerve damage.
      Performance of the procedure with bloodlessness is preferable. A result of 88% of
      successfully treated LSV segments indicates a promising alternative for surgical
      stripping of the LSV.

PMID- 12469053
TI  - A quantitative approach to lower extremity vein repair.
AB  - OBJECTIVE: We prospectively investigated the patency of venous repair in a
      quantitative fashion with measurement of vein blood flow velocities after lower
      extremity injuries caused by either military or civilian trauma. MATERIAL AND
      METHODS: During a 10-year study period (March 1990 to December 2000), surgical
      intervention was performed after lower extremity vascular injuries in 130
      patients. Most of these patients were men (n = 125), with a mean age of 23 +/- 5
      years (range, 17 to 44 years). One hundred ten direct venous injuries were
      identified in 97 patients, involving the common femoral vein in seven, the deep
      femoral vein in three, the superficial femoral vein in nine, the popliteal vein
      in 46, and the posterior tibial (n = 21), anterior tibial (n = 17), or peroneal
      veins (n = 7) in 45. Popliteal vein thrombosis without apparent venous injury was
      found in seven patients. Bone fractures (n = 45), nerve injuries (n = 27), or
      extensive tissue loss (n = 7) often were associated with vascular injuries.
      Duplex color ultrasonography was used to evaluate patency and to measure blood
      flow velocity in repaired veins during the early postoperative period and at the
      time of late follow-up examinations. RESULTS: Significant differences were seen
      in venous blood flow velocities between severe (extremity diameter more than
      twice normal) and moderate (diameter 1.5 to 2 times normal) reperfusion injuries.
      The mean flow velocity in repaired popliteal veins was 15 +/- 2 cm/s with severe
      reperfusion injuries compared with 8.4 +/- 1.1 cm/s with moderate reperfusion
      injuries (P <.0001). Flow velocities were lower than 5 cm/s in repaired
      infrapopliteal veins, and most of these veins occluded on the first postoperative
      day. Amputations were necessary in 11 patients, all of whom had both tibial
      fractures and extensive tissue loss. Sodium warfarin therapy was routinely
      administrated before hospital discharge. The mean follow-up period was 6.2 years
      (range, 1.3 to 10 years). Repaired common femoral and superficial femoral veins
      had relatively high patency rates (100% and 89% at 1 year, 100% and 78% at 6
      years, respectively), whereas the patency rates for repaired popliteal veins were
      disappointing (86% at 1 year, 60% at 6 years). All seven popliteal veins that
      required thrombectomy in the absence of direct injuries remained patent, however.
      Patch angioplasty had the highest 6-year patency rate (75%) in comparison with
      all other techniques that were used for venous injuries (lateral repair, 58%; end
      to-end anastomosis, 43%; saphenous vein graft interposition, 36%). CONCLUSION:
      Venous repair has a high patency rate at the femoral and popliteal levels, but
      the patency rate for infrapopliteal venous repair is extremely poor because of
      low flow velocities. Therefore, we conclude that repair of infrapopliteal venous
      injuries is unnecessary.

PMID- 12469054
TI  - Regional hyperthermic fibrinolytic perfusion after unsuccessful venous
      thrombectomy of extensive deep venous thrombosis.
AB  - OBJECTIVE: Because of the dose-dependent increase in bleeding complications, the
      intraoperative administration of fibrinolytic agents is limited. This limitation
      impairs the efficacy of fibrinolytic therapy because low-dose fibrinolysis often
      fails in the treatment of complex deep venous thrombosis (DVT). The aim of this
      study was to investigate the efficacy and safety of intraoperative high-dose
      fibrinolytic therapy for extended DVT, which was performed with the regional
      hyperthermic fibrinolytic perfusion (RHFP) technique. METHODS: From January 1993
      to June 2001, in 53 patients with extended DVT, unsuccessful venous thrombectomy
      (recanalization, <50%) was followed by RHFP with 0.5 mg/kg of body weight of
      recombinant tissue plasminogen activator. The extent of thrombosis was documented
      before, during (after the surgical thrombectomy), and after (between
      postoperative days 2 and 5) surgery with phlebography and was quantified with the
      Marder score. Intraoperative and postoperative complications were recorded
      prospectively. RESULTS: After RHFP, a recanalization was achieved in 64 of 146
      venous segments (43.8%) that were still occluded despite thrombectomy. Eighty-two
      segments (56.2%) remained occluded. Compared with the preoperative phlebography,
      32 patients (60.3%) had a successful recanalization (>50%). Eleven patients
      (20.8%) showed minimal and 10 patients (18.9%) no recanalization. No lethal
      complications occurred. One patient (1.9%) had pulmonary embolism develop, and
      two patients (3.8%) had bleeding complications develop. CONCLUSION: With the
      intraoperative use of hyperthermia-assisted high-dose fibrinolysis, improvement
      of the results of mechanical thrombectomy of extended DVT was possible. The RHFP
      protected against systemic side effects of the fibrinolysis and show a high
      safety of application.

PMID- 12469056
TI  - Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during
      ischemia reperfusion.
AB  - OBJECTIVE: Ischemia-reperfusion injury is a pathologic event characterized by
      tissue damage. It is mediated by tumor necrosis factor (TNF) and other cytokines
      that activate complement and proteases and stimulate fibrinolysis, degranulation
      of white blood cells, and free radical production. We recently reported that
      vagus nerve stimulation (VNS) suppresses endotoxin-induced cytokine synthesis
      through alpha bungarotoxin-sensitive cholinergic receptors. VNS protects against
      endotoxin-induced shock by inhibiting hepatic and cardiac synthesis of TNF. Here,
      the effects of VNS on suppression of ischemia-reperfusion injury and cytokine
      release were studied in a rat model of aortic occlusion. METHODS: Adult male
      Lewis rats were subjected to laparotomy and suprarenal aortic clamping for 15
      minutes followed by reperfusion. Blood pressure, heart rate, and respiratory rate
      were recorded every 3 minutes for 90 minutes. Exposed cervical vagus nerves in
      the experimental group were stimulated for 5 minutes before and after aortic
      occlusion, with constant voltage (1 V, 2 ms, 5 Hz); sham-operated animals
      received no stimulation. TNF levels in serum and organs were measured with enzyme
      linked immunosorbent assay ELISA (BioSource International, Camarillo, Calif).
      Data analysis was performed with the Student t test. RESULTS: Control animals had
      shock develop (mean, 59% decrease in blood pressure) whereas blood pressure in
      the stimulated animals did not decrease (control versus stimulated animals, P
      <.05). VNS significantly inhibited TNF levels in serum (7 +/- 1 ng/mL versus 45
      +/- 6 ng/mL; P =.0008), heart (21 +/- 11 ng/g protein versus 85 +/- 15 ng/g
      protein; P =.01), and liver (16 +/- 2 ng/g protein versus 42 +/- 12 ng/g protein;
      P =.02). CONCLUSION: VNS significantly attenuates TNF synthesis and shock during
      reperfusion injury in a standard model of aortic occlusion. Clinical evaluation
      of VNS for this condition may be warranted.

PMID- 12469055
TI  - Preoperative and intraoperative evaluation of diameter-reflux relationship of
      calf perforating veins in patients with primary varicose vein.
AB  - OBJECTIVE: Interruption of incompetent perforating veins (PVs) is important for
      varicose vein surgery. The purpose of this study was to evaluate the preoperative
      and intraoperative diameter-reflux relationship of PVs and to evaluate the
      accuracy of preoperative duplex scanning in patients with varicose vein. METHODS:
      Patients with primary varicose veins were retrospectively investigated. Diameters
      and reflux of PVs were evaluated before surgery with color flow duplex ultrasound
      scan (US). During operation, the incompetent PVs were defined as those that
      showed an outward spurt of blood flow from the stump of the PVs. The sensitivity
      and specificity of US in the detection of reflux of PVs were calculated.
      Competent versus incompetent vein diameters were compared with the Student t test
      and one-way analysis of variance. RESULTS: Three hundred twenty-four calf PVs
      were detected in 304 legs of 175 patients with varicose vein. Diameters of
      competent and incompetent PVs confirmed with intraoperative finding averaged 2.67
      +/- 1.10 mm (n = 28) and 3.28 +/- 1.01 mm (n = 58), respectively, at the upper
      calf (P =.012), 2.85 +/- 0.85 mm (n = 53) and 3.68 +/- 0.94 mm (n = 137),
      respectively, at the lower calf (p <.001), and 2.67 +/- 0.99 mm (n = 14) and 3.27
      +/- 0.66 mm (n = 22), respectively, at the posterior calf (P =.036). The overall
      sensitivity of detection of reflux with US was 87.7%, and the specificity was
      75.3%. Diameters of true-incompetent PVs and false-incompetent PVs were 3.59 +/-
      0.94 mm (n = 199) and 3.31 +/- 0.84 mm (n = 24), respectively (P =.157).
      Diameters of true-competent PVs and false-competent PVs were 2.61 +/- 0.91 mm (n
      = 73) and 2.89 +/- 0.82 mm (n = 28), respectively (P =.158). CONCLUSION: Although
      the diameter of incompetent PVs was larger than that of competent PVs in both US
      and intraoperative findings, diameter measurement alone can not completely
      distinguish competent and incompetent PVs. The sensitivity and specificity of
      reflux obtained with US showed that the accuracy of preoperative duplex scanning
      to evaluate PV competency was not sufficient.

PMID- 12469057
TI  - Ingrowth of aorta vascular cells into basic fibroblast growth factor-impregnated
      vascular prosthesis material: a porcine and human in vitro study on blood vessel
      prosthesis healing.
AB  - OBJECTIVE: One of the most life-threatening vascular diseases is rupture of an
      abdominal aneurysm. The conventional treatment is based on surgical
      reconstruction. An alternative treatment is endovascular aneurysm repair (EVAR).
      Despite many advantages, one of the problems of EVAR is endoleakage from
      deficient healing between the aortic neck and the fabric of the endograft. We
      hypothesize that better healing, achieved with induction of vascular cell
      ingrowth into the graft material, would lead to better graft healing. METHODS:
      Both pig aorta and human normal and aneurysmal aortic wall were used for organ
      cultures. Various growth factors were evaluated for the potential to induce
      intimal hyperplasia (ie, platelet-derived growth factor, vascular endothelial
      growth factor, and basic fibroblast growth factor [bFGF]). After the most potent
      growth factor had been selected, a vascular prosthetic material (Dacron fabric)
      impregnated with collagen and heparin was incubated with this growth factor.
      Impregnated pieces of Dacron were fixated on top of the aortic organ cultures for
      study of ingrowth of the neointima formation into the graft material. RESULTS:
      bFGF was the most potent growth factor to induce neointima in aortic organ
      cultures. The pieces of impregnated Dacron had a release of 5 ng/24 h of bFGF for
      a period of at least 28 days. With fixation on top of the aortic organ cultures,
      the impregnated Dacron was capable of inducing neointima formation and ingrowth
      of the neointima into the graft material after 28 days. CONCLUSION: We showed
      that a Dacron prosthesis impregnated with collagen, heparin, and bFGF is capable
      of inducing graft healing in our in vitro model, the aortic organ cultures of pig
      and human aortas. These results suggest that the problem of endoleakage with EVAR
      may be solved with a perfect proximal healing between the aortic wall and the
      prosthesis.

PMID- 12469058
TI  - Flow-induced neointimal regression in baboon polytetrafluoroethylene grafts is
      associated with decreased cell proliferation and increased apoptosis.
AB  - OBJECTIVE: We have previously shown that baboon grafts subjected to elevated
      shear stress exhibit an increase in luminal area through atrophy of the
      neointimal layer. This study was designed to investigate the smooth muscle cell
      (SMC) growth kinetics during early regression and evaluate the influence of
      nitric oxide (NO) in the regulation of this process. METHODS: Sixteen baboons
      underwent bilateral polytetrafluorethylene aortoiliac graft placement. After
      development of a neointima over an 8-week period, blood flow through one graft
      was increased with placement of a downstream arteriovenous fistula. Grafts were
      harvested at 4 (n = 6), 7 (n = 5), and 14 (n = 5) days and assessed for
      neointimal cross-sectional area, SMC proliferation and apoptosis, and macrophage
      infiltration. High-flow grafts were compared with contralateral normal-flow
      controls. Eleven baboons underwent an identical experimental preparation to
      evaluate the effect of NO inhibition. Eight weeks after graft implantation, the
      animals were treated with an initial bolus (100 mg/kg) followed by continuous
      infusion (60 mg/kg/d) of either N(G)-nitro-L-arginine methyl ester (L-NAME; n =
      6) or the inactive stereoisomer N(G)-nitro-D-arginine methyl ester (n = 5).
      Grafts were harvested at 7 days and evaluated with the experimental endpoints
      detailed previously. RESULTS: Distal fistula placement resulted in a 3.8-fold
      increase in mean centerline velocity and wall shear stress. Grafts harvested
      during the initial 14 days after flow manipulation showed a progressive reduction
      in neointimal cross-sectional area. This change was associated with a decrease in
      subendothelial SMC proliferation and an increase in neointimal SMC apoptosis, the
      latter being in the region adjacent to the graft. Animals treated with L-NAME
      showed a 20% reduction in platelet cyclic guanosine monophosphate and a 17%
      reduction in serum nitrate/nitrite concentrations. Despite this inhibition of NO
      production, no effect on the flow-dependent changes in neointimal area, cell
      proliferation, or apoptosis was observed in the L-NAME-treated baboons.
      CONCLUSION: The local hemodynamic environment within healing prosthetic grafts
      modulates neointimal SMC proliferation and apoptosis. An increase in graft flow
      leads to atrophy of the neointima.

PMID- 12469059
TI  - Pararenal vena cava leiomyosarcoma versus leiomyomatosis: difficult diagnosis.
AB  - Inferior vena cava (IVC) leiomyosarcoma is a rare cancer treated with wide
      surgical resection. IVC leiomyomatosis is a benign tumor treated with open caval
      excision. A patient with an IVC tumor with iliocaval thrombosis was treated with
      thrombolysis and iliac stents. The patient was sent 1 year later to our
      institution with an IVC mass. Transvenous biopsy was consistent with
      leiomyomatosis. At surgery, the lesion was adherent, resected and the IVC
      reconstructed. Pathologic evaluation documented well-differentiated
      leiomyosarcoma not leiomyomatosis. Thorough evaluation of iliocaval thrombosis is
      recommended before endovascular management. Diagnostic modalities may be
      inadequate to differentiate leiomyosarcoma from leiomyomatosis.

PMID- 12469060
TI  - Stent graft repair of visceral artery aneurysms.
AB  - Endovascular techniques with coil embolization have been used in certain visceral
      aneurysm cases, often resulting in sacrifice of the involved visceral vessel and
      end-organ thrombosis. We describe two cases in which stent grafts were used to
      treat these aneurysms, allowing preservation of visceral artery and end-organ
      flow while completely excluding the aneurysm. Case 1 was a 50-year-old morbidly
      obese woman with a history of multiple abdominal operations for renal cell
      carcinoma who was found to have a large splenic artery aneurysm. A 12-mm x 50-mm
      Wallgraft endoprosthesis (Boston Scientific, Watertown, Mass) was placed across
      the aneurysm from a femoral approach. The aneurysm was completely excluded, and
      splenic artery flow was preserved. A subsequent computed tomographic scan showed
      complete aneurysm exclusion and preserved flow to the spleen. Case 2 was a 73
      year-old man with hypertension with back pain who was found with computed
      tomographic scan to have an 8-cm hepatic artery aneurysm. Arteriography showed a
      large saccular aneurysm arising from the mid portion of the common hepatic
      artery. Two 5-mm x 26-mm Jostent stent grafts (Jomed, Alpharetta, Ga) were placed
      across the aneurysm neck, completely excluding the aneurysm and preserving
      hepatic artery flow. The patient became pain free, and subsequent duplex
      ultrasound scan showed a thrombosed aneurysm with normal hepatic artery flow.
      Stent graft techniques show early promise as a safe and effective treatment of
      visceral artery aneurysms in selected patients at high risk. Endografts, unlike
      coil embolization, exclude the aneurysm and preserve end organ perfusion.
      Determining the durability of this type of therapy will require further study.

PMID- 12469061
TI  - Distal inferior mesenteric veins to renal vein shunt for treatment of bleeding
      anorectal varices: case report and review of literature.
AB  - Isolated intractable bleeding from anorectal varices is a rare complication of
      portal hypertension. We report a case of a patient with cirrhosis and hepatofugal
      flow who had severe lower gastrointestinal bleeding from anorectal varices. This
      is the first case report of construction of a distal inferior mesenteric vein
      shunt to left renal vein as a selective shunt for treatment of bleeding anorectal
      varices in a patient with hepatofugal flow. The patient is a 39-year-old white
      man with a medical history significant for alcohol abuse who was seen with bright
      red blood per rectum requiring 10 units of packed red blood cells over the course
      of a year. The work-up revealed anorectal varices with no other colonic lesions.
      The patient underwent construction of a distal inferior mesenteric vein to left
      renal vein shunt.

PMID- 12469063
TI  - Regarding "Laparoscopic remodeling of abdominal aortic aneurysms after
      endovascular exclusion: a technical description".

PMID- 12469062
TI  - Laparoscopic remodeling of abdominal aortic aneurysms after endovascular
      exclusion: a technical description.
AB  - We report our experience with a novel combined laparoscopic-endovascular
      procedure to treat endoleaks and graft migration. The operative procedure
      consisted of the following steps: laparoscopic exposure of the aorta, clipping of
      lumbar arteries and of the inferior mesenteric artery, incision of the sac of the
      aneurysm without clamping the aorta, and removal of thrombus material.
      Laparoscopic sutures were placed externally to attach the endograft to the aortic
      neck. Laparoscopy was performed a mean interval of 20.2 months after endovascular
      abdominal aortic aneurysm repair in four cases and immediately after endovascular
      abdominal aortic aneurysm exclusion in eight consecutive patients. We have yet to
      prove whether this combined approach is superior to a purely endovascular
      technique.

PMID- 12469064
TI  - Regarding "Surgical treatment of nonaneurysmal aortic arch lesions in patients
      with systemic embolizations".

PMID- 12469065
TI  - Guidelines for hospital privileges in vascular surgery: an update by an ad hoc
      committee of the American Association for Vascular Surgery and the Society for
      Vascular Surgery.

PMID- 12469066
TI  - Pharmacologic therapy for peripheral arterial disease and claudication.
AB  - Peripheral arterial disease (PAD) is a common manifestation of systemic
      atherosclerosis that is associated with a high risk of cardiovascular mortality
      and significant limitation in function because of limb ischemia. Patients with
      PAD should be considered to have significant coronary and cerebral arterial
      disease that requires aggressive risk factor management, including the
      prescription of antiplatelet drugs, to lower the subsequent risk of myocardial
      infarction, stroke, and death. In the population with PAD, level 1 and level 2
      evidence supports the use of statin drugs for lipid management, angiotensin
      converting enzyme-1 inhibitors for blood pressure control, and aspirin or
      clopidogrel as antiplatelet agents. Once this is accomplished, the severity of
      limb symptoms should be assessed, and a structured exercise program or the
      selected use of drugs such as cilostazol to treat claudication should be
      prescribed. In patients primarily considered for surgical treatment, antiplatelet
      and anticoagulant drug therapy can be used as a means of promoting graft patency,
      and beta-adrenergic blockers can be used as a means of reducing the perioperative
      risks associated with vascular surgery.

PMID- 12469067
TI  - Update on perioperative evaluation and management of cardiac disease in vascular
      surgery patients.

PMID- 12469068
TI  - Nonmonetary conflicts of interest.

PMID- 12469069
TI  - Is there an increased risk for DVT with the VNUS closure procedure?

PMID- 12469070
TI  - Regarding "The effect of long saphenous vein stripping on quality of life".

PMID- 12469071
TI  - New Year's resolutions.

PMID- 12469072
TI  - Duplex-guided thrombin injection for the treatment of iatrogenic pseudoaneurysms.
AB  - This study compares duplex-guided thrombin injection (DGTI) with duplex-guided
      compression (DGC) for the treatment of iatrogenic pseudoaneurysms. A
      nonrandomized prospective study, approved by the institutional review board, was
      performed to evaluate the success rate in DGTI versus DGC (with the use of
      historical data) in patients who arrive at the vascular surgery service for the
      treatment of iatrogenic pseudoaneurysm as identified by ultrasound examination.
      DGTI has been shown to have major advantages over DGC, such as improved patient
      and operator acceptance, shorter pseudoaneurysm thrombosis times, broader patient
      applications, and higher success rate.

PMID- 12469073
TI  - Effects of leg and body position on transcutaneous oxygen measurements in healthy
      subjects and subjects with peripheral artery disease after lower-extremity
      arterial revascularization: a pilot study.
AB  - Transcutaneous oxygen (TcPO(2)) measurements provide a noninvasive, objective
      determination of the oxygen level at the skin surface. This offers a means of
      estimating the underlying circulation and tissue oxygenation. The purpose of the
      pilot study was to measure the TcPO(2) value of the lower extremity of healthy
      men and women and of patients with peripheral arterial disease (PAD) in 4
      different body and leg positions 24 hours after peripheral vascular surgery
      reconstruction. The specific aim was to determine if lower-extremity TcPO(2)
      measurements were affected by changes in extremity position in these subject
      populations. A convenience sample of 4 healthy health care professionals and 4
      patients who had peripheral vascular reconstruction surgery 24 hours before the
      measurements were studied. Subjects were studied in 4 different leg and body
      positions: supine with legs extended, sitting with legs dependent, a 5 degrees
      head-up reverse Trendelenburg, and supine with legs elevated 10 in. The
      Radiometer TCM30 TcPO(2) monitor was used to carry out these measures. Findings
      revealed a statistically significant difference in TcPO(2) measurements between
      the 2 groups, with the healthy subjects having a significantly higher TcPO(2)
      measurement in all extremity positions compared with the revascularized subjects
      with PAD (P =.02-.05). Significant changes were noted in both the foot
      temperature (P =.03) and TcPO(2) measurements with extremity positions within the
      healthy subject group (P =.001). The foot and leg TcPO(2) measurements affect
      from leg and body position did not reach significance (P =.09) in the subjects
      with PAD. No change in foot temperature with extremity positioning (P =.42) was
      noted in the subjects with PAD. This pilot study provides a base in which
      additional research will be performed with TcPO(2) measurements in both the
      healthy and revascularized person.

PMID- 12469074
TI  - Preparing and presenting a research poster.

PMID- 12469075
TI  - The Nursing Research Committee: the James A. Haley Veterans' Hospital.
AB  - Nursing research has been a part of the culture at the James A. Haley Veterans'
      Hospital for many years. A Nursing Research Committee (NRC) has been an integral
      part of this success. The emphasis remains on involving the staff nurse in
      nursing research. By defining clear-cut goals and objectives, leadership of the
      NRC reaps substantial professional results.

PMID- 12469076
TI  - Neer Award 2001: nonrecoverable strain fields of the anteroinferior glenohumeral
      capsule under subluxation.
AB  - Although tears of the glenohumeral capsule have been observed in anteroinferior
      instability, prefailure, nonrecoverable deformation is suspected but has not been
      shown to exist after shoulder subluxation. The inferior glenohumeral ligament in
      the anteroinferior capsule (AIC) is a primary stabilizer in anteroinferior
      instability. The aim of this study was to examine the nonrecoverable strain field
      of the AIC due to shoulder subluxation. Nonrecoverable strains were calculated
      between a nominal strain state and a postsubluxed state. AIC marker coordinates
      were reconstructed from stereoradiographs, and strains were calculated from these
      coordinates. Nonrecoverable strain was shown to develop, varying from 3% to 7%
      through a range of joint subluxation. High strain tended to occur on the glenoid
      side of the AIC. Interestingly, strains were generally not oriented along major
      ligamentous bands. This is the first study to quantify planar nonrecoverable
      strain fields in the glenohumeral joint capsule.

PMID- 12469077
TI  - Patients' expectations of shoulder surgery.
AB  - Patients' preoperative expectations of shoulder surgery affect both the decision
      to proceed with surgery and how patients assess outcomes of surgery. Our goals
      were to identify patients' expectations of shoulder surgery, to develop and test
      a patient-derived shoulder surgery expectations survey, and to determine the
      prevalence of major expectations by diagnosis. An initial sample of 409 patients
      (mean age, 51 +/- 17 years; 58% men) with diverse shoulder diagnoses were asked
      open-ended questions preoperatively about their expectations of shoulder surgery.
      Their responses were grouped into 38 categories including the following: pain
      relief, increasing range of motion, improving the ability to wash and dress,
      returning to sports, improving the ability to interact and care for others, and
      for the shoulder to be back to the way it was before shoulder symptoms started.
      Expectations varied by demographic characteristics, diagnosis, and functional
      status measured by the L'Insalata Shoulder Rating Questionnaire and the Short
      Form 36. The most frequently cited categories were then assembled into closed
      format questions to form a draft survey. A second sample of 100 patients with
      diverse shoulder diagnoses completed the draft survey on 2 separate occasions to
      establish test-retest reliability. Items retained to form the final survey were
      frequently cited, represented clinically relevant or potentially unrealistic
      expectations, and had concordance levels of 0.40 to 0.83 measured by the kappa
      statistic (71% had kappa >or= 0.60). The final 17-item Hospital for Special
      Surgery Shoulder Surgery Expectations Survey requires less than 5 minutes to
      complete. This patient-derived, self-administered survey has several possible
      uses in daily clinical practice, such as providing a way to learn about the
      patient's perspectives, providing the orthopaedist with a template to guide a
      formal discussion about realistic and unrealistic goals, and providing a
      prospective record that can be used jointly by the orthopaedist and patient
      postoperatively to assess the outcome of surgery.

PMID- 12469078
TI  - Qualitative clinical evaluation of scapular dysfunction: a reliability study.
AB  - The purpose of this study was to determine the intrarater and interrater
      reliability of a clinical evaluation system for scapular dysfunction. No commonly
      accepted terminology presently exists for describing the abnormal dynamic
      scapular movement patterns that are commonly associated with shoulder injury. A
      method of observation was devised for clinical evaluation of scapular
      dysfunction. Blinded evaluators (2 physicians and 2 physical therapists) were
      familiarized with the evaluation method of scapular movement patterns before
      viewing a videotape of 26 subjects with and without scapular dysfunction. Each
      evaluator was asked to categorize the predominant scapular movement pattern
      observed during bilateral humeral scaption and abduction motions. Reliability was
      assessed by a kappa coefficient. Intertester reliability (kappa = 0.4) was found
      to be slightly lower than intratester reliability (kappa = 0.5). These results
      indicate that, with refinement, this qualitative evaluation method may allow
      clinicians to standardize the categorization of dynamic scapular dysfunction
      patterns.

PMID- 12469079
TI  - Radiographic study of the anatomic relationships of the greater tuberosity.
AB  - Accurate reproduction of the anatomic relationship is important in nonconstrained
      prosthetic arthroplasty. However, the geometry of the glenohumeral joint for
      prosthetic components has not been established. In this study, we evaluated the
      relationship between the position of the greater tuberosity and various geometric
      measurements in the glenohumeral joint. Radiographs of 519 shoulders without
      osseous lesions were reviewed. There were 296 male and 223 female patients, with
      a mean age of 49.7 years. Four parameters were measured on true anteroposterior
      radiographs, including the distance between the humeral head-greater tuberosity
      junctional point and the top of the humeral head, as well as the neck shaft
      angle. There were significant differences in all parameters between males and
      females. The distance between the humeral head-greater tuberosity junctional
      point and the top of the humeral head significantly correlated with the neck
      shaft angle in both males (P <.01, r = 0.468) and females (P <.01, r = 0.639). If
      the neck shaft angle of the replacement is smaller than the anatomic neck shaft
      angle of the patient, the placement of the humeral head component with the same
      distance between the humeral head-greater tuberosity junctional point and the top
      of the humeral head as that before surgery might not reproduce the anatomic
      glenohumeral joint. We conclude that determining the distance between the humeral
      head-greater tuberosity junctional point and the top of the humeral head and its
      relationship to the neck shaft angle is important for the prevention of
      postoperative subacromial impingement.

PMID- 12469080
TI  - Intratendinous strain fields of the supraspinatus tendon: effect of a surgically
      created articular-surface rotator cuff tear.
AB  - Articular-surface partial-thickness rotator cuff tears play a significant role in
      shoulder pathology, but the role of the articular-surface tissue is poorly
      understood. This investigation assessed the effect of an articular-surface
      partial-thickness rotator cuff tear on intratendinous strain fields. A magnetic
      resonance imaging-based technique quantified intratendinous strains in healthy
      cadaveric shoulders at 15 degrees, 30 degrees, 45 degrees, and 60 degrees of
      glenohumeral abduction. A second set of magnetic resonance images was acquired
      after an articular-surface partial-thickness tear was created arthroscopically.
      Measures of strain were grouped into 3 tendon regions. A 3-factor analysis of
      variance assessed the effects of joint position, tendon region, and tendon tear.
      Intratendinous strains were influenced significantly by joint position, but few
      differences existed between tendon regions. The articular-surface partial
      thickness tear increased intratendinous strain for all joint positions except 15
      degrees. The results lend insight into the mechanical behavior of the normal and
      pathologic rotator cuff.

PMID- 12469082
TI  - Acromial shapes and extension of rotator cuff tears: magnetic resonance imaging
      evaluation.
AB  - Magnetic resonance imaging makes it possible to inspect the status of the rotator
      cuff and the shape of the acromion. To clarify the relationship between acromial
      shapes and rotator cuff tears, we evaluated magnetic resonance images obtained in
      192 shoulders. We classified the acromial shapes into 3 types: type I (flat),
      type II (curved), and type III (hooked). Among a group of 91 shoulders with
      rotator cuff tears, 33 (36.3%) were type I, 22 (24.2%) type II, and 36 (39.6%)
      type III. The size of rotator cuff tears in type III acromions was significantly
      larger than in type I or II acromions. Comparison of the incidence of each
      acromial shape between groups of specimens with and without rotator cuff tears
      revealed no significant differences. We suggest that whereas acromial shapes have
      a bearing on the extent of rotator cuff tears, the correlation between rotator
      cuff tears and a type III acromion is not as strong as has been suggested in the
      literature.

PMID- 12469081
TI  - Expression of neuropeptides and cytokines at the extensor carpi radialis brevis
      muscle origin.
AB  - To reveal whether neuropeptides and cytokines affect the pathogenesis of tennis
      elbow, expressions of substance P, calcitonin gene-related peptide, interleukin 1
      alpha, and transforming growth factor beta1 at the origin of the extensor carpi
      radialis brevis muscle were investigated in patients with tennis elbow (n = 10).
      Innervation in the origin was determined with use of the protein gene product
      9.5. Substance P-like immunoreactivity and calcitonin gene-related peptide-like
      immunoreactivity were observed in the nerve fibers around small vessels without
      apparent infiltration of inflammatory cells. Cells showing positive interleukin 1
      alpha or transforming growth factor beta1 immunoreactivity were noted in small
      vessels and the dense collagen meshwork in 5 of 10 cases. The results suggested
      that these neuropeptides and cytokines might promote inflammation and stimulate
      proliferation and matrix synthesis of fibroblasts, contributing to the pathology
      of tennis elbow.

PMID- 12469083
TI  - The effects of shoulder plyometric training on proprioception and selected muscle
      performance characteristics.
AB  - The purpose of this study was to determine the effect of plyometric training of
      the shoulder internal rotators on proprioception, kinesthesia, and selected
      muscle performance characteristics in female swimmers. Twenty-four female
      division I swimmers were evaluated before and after a 6-week plyometric training
      program. Proprioception and kinesthesia were assessed for internal and external
      rotation at 0 degrees, 75 degrees, and 90% of the subject's maximum external
      rotation. The Biodex II was used to assess strength characteristics at 60 degrees
      /s, 240 degrees /s, and 450 degrees /s. Plyometric training sessions (2
      times/week) involved 3 sets of 15 repetitions with a trampoline, weighted balls,
      and elastic tubing. A 2-way analysis of variance revealed significant improvement
      (P <.05) in proprioception at 0 degrees moving into external rotation, as well as
      75 degrees and 90% moving into both internal and external rotation. Kinesthesia
      demonstrated significant improvement for all test conditions after plyometric
      training. Significant gains in selected muscle performance characteristics
      included time to peak torque (60 degrees /s and 240 degrees /s), amortization
      time (450 degrees /s), and torque decrement (240 degrees /s). This study suggests
      that plyometric activities may facilitate neural adaptations that enhance
      proprioception, kinesthesia, and muscle performance characteristics. Significant
      neuromuscular benefits may be attained if they are implemented earlier into
      shoulder rehabilitation programs.

PMID- 12469084
TI  - American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form,
      patient self-report section: reliability, validity, and responsiveness.
AB  - The purpose of this study was to examine the psychometric properties of the
      American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form
      (ASES), patient self-report section. Patients with shoulder dysfunction (n = 63)
      completed the ASES, The University of Pennsylvania Shoulder Score, and the Short
      Form-36 during the initial evaluation, 24 to 72 hours after the initial visit,
      and after 3 to 4 weeks of physical therapy. The test-retest reliability
      (intraclass correlation coefficient[1-way random-effects], 0.84; 95% CI lower
      limit, 0.75) and internal consistency (Cronbach alpha, 0.86) values were
      acceptable. The standard error of the measure was 6.7 ASES points (90% CI, 11.0).
      Construct and discriminant validity was demonstrated. Responsiveness was
      demonstrated with a standardized response mean of 1.5 and an effect size of 1.4.
      The minimal detectable change was 9.7 ASES points (90% CI, 16), and the minimal
      clinically important difference was 6.4 ASES points. The results indicate that
      the ASES is a reliable, valid, and responsive outcome tool.

PMID- 12469085
TI  - Magnetic resonance imaging analysis of the subacromial space in the impingement
      sign positions.
AB  - External shoulder impingement is commonly diagnosed by passively moving the
      shoulder into various positions of elevation and internal rotation in order to
      perform impingement sign maneuvers. There is a lack of agreement among clinicians
      regarding the positions of the anatomic structures in the subacromial space when
      these maneuvers are performed. The purpose of this study was to use magnetic
      resonance imaging to identify and measure the changes in anatomic structures in
      the subacromial space as the arm was moved from complete rest to 160 degrees of
      forward flexion during the Neer and Hawkins impingement sign maneuvers. Ten
      subjects with normal shoulders (mean age, 32 years) were studied. The
      acromiohumeral interval was smallest with the arm at the side (mean, 6.4 mm) and
      progressively increased as the arm was elevated from 90 degrees to 160 degrees
      (mean, 7.7-14.2 mm). In no instance was the rotator cuff found to be in contact
      with the anterior acromion. The rotator cuff insertion appeared to be in closest
      proximity to the anteroinferior acromion, not at full elevation (Neer sign
      position), but at 90 degrees of flexion (Hawkins sign position). Our data suggest
      that a clinically positive Hawkins sign is consistent with external shoulder
      impingement. Clinical suspicion that mechanisms other than impingement may be
      involved, particularly if the Neer impingement sign is also positive, is
      nonetheless advised.

PMID- 12469086
TI  - Clinical evaluation and treatment of spinoglenoid notch ganglion cysts.
AB  - Spinoglenoid notch cysts were identified by magnetic resonance imaging in 73
      patients. Posterosuperior labral tears were identified in 65 patients who had
      spinoglenoid notch cysts. Patient follow-up was available on 88% of patients at a
      mean of 20.5 months after treatment. There were 52 men and 11 women, with a mean
      age of 39 years (range, 19-76 years). All patients reported shoulder pain.
      Infraspinatus atrophy occurred in 25 patients, weakness with external rotation in
      43, and posterior shoulder tenderness in 30. Nineteen patients underwent
      nonoperative management of the cyst (group I). Eleven underwent attempted needle
      aspiration of the cyst (group II). Six had isolated arthroscopic treatment of a
      labral defect with no cyst excision (group III). Twenty-seven were treated with
      surgical cyst excision with the cyst and superior labral tear fixed
      arthroscopically or with an open approach in various combinations (group IV). Of
      the patients, 53% were satisfied in group I, 64% in group II, 67% in group III,
      and 97% in group IV.

PMID- 12469087
TI  - Infection after mini-open rotator cuff repair.
AB  - A consecutive case series from 2 institutions of patients with postoperative
      wound infections after mini-open rotator cuff repair was reviewed. Between 1991
      and 2000, 360 patients underwent mini-open rotator cuff repair after arthroscopic
      subacromial decompression. Seven patients had postoperative infection develop
      (1.9%). All patients were men, with a mean age of 55 years (range, 40-64 years).
      Treatment included serial irrigation and debridement, long-term intravenous
      antibiotics, and revision rotator cuff repair. Mean follow-up after definitive
      treatment was 32 months (range, 12-57 months). Propionibacter acnes was present
      in 6 of 7 patients (86%) with infections. The initial rotator cuff repair was
      disrupted in 4 shoulders and intact in 3. A revision rotator cuff repair was
      performed at the final irrigation and debridement in all 4 shoulders. Results
      were 100% satisfactory. The mean American Shoulder and Elbow Surgeons pain score
      improved from 7 (range, 6-9) preoperatively to 1 (range, 0-2). The mean final
      score was 95. Because these infections were noted to occur only in
      arthroscopically assisted rotator cuff repairs, a second preparation and draping
      were introduced as routine protocol. No postoperative infections have occurred in
      the ensuing 200 mini-open rotator cuff repairs.

PMID- 12469088
TI  - Operative management of the frozen shoulder in patients with diabetes.
AB  - Forty-three patients with diabetes (47 shoulders) who had a manipulation under
      anesthesia only (24 shoulders), a manipulation under anesthesia followed by an
      arthroscopy (12 shoulders), or an arthroscopic release (11 shoulders) for a
      frozen shoulder were followed-up for a mean period of 35 months. The mean
      Constant score improved from 20.3 to 63.7 points (P <.001). The mean improvement
      in forward flexion was 71.7 degrees, in abduction 78.5 degrees, in external
      rotation with the arm at the side 36.3 degrees, and in internal rotation from the
      buttock to the first lumbar vertebra (P <.001 for all). When gentle manipulation
      with the patient under anesthesia was possible, the outcome was satisfactory in
      13 of 15 shoulders (86.7%) in patients with non-insulin-dependent diabetes and in
      17 of 21 shoulders (81%) in patients with insulin-dependent diabetes (P >.5).
      Insulin-dependent patients with diabetes were more likely to require an
      arthroscopic release than patients with non-insulin-dependent diabetes (P <.05).
      Most of our patients obtained their maximum relief of pain and functional
      recovery within 3 months of surgery. We recommend manipulation under anesthesia
      for the resistant frozen shoulder in patients with diabetes. Arthroscopic release
      is required when mobilization under anesthesia is not possible.

PMID- 12469089
TI  - Fit of current glenoid component designs: an anatomic cadaver study.
AB  - The glenoids of 412 scapula specimens were templated with the use of 6 currently
      available glenoid systems to determine the goodness of fit for the various
      designs. When a fitting criterion of a mismatch of less than 2 mm between the
      template and the actual glenoid periphery for 8 radial locations was used, the
      various designs fit from 0% to 48% of the glenoids. Because glenoid component
      fixation longevity can depend on the degree of osseous support, these results
      indicate that glenoid component design and sizing can be improved.

PMID- 12469090
TI  - Iliotibial band reconstruction for treatment of glenohumeral instability
      associated with irreparable capsular deficiency.
AB  - The surgical management of patients with recurrent anterior instability after
      failed surgery can be complicated by the loss of capsular tissue and, in some
      cases, irreparable tears of the subscapularis tendon. We describe a new surgical
      technique for reconstruction of the capsular ligaments using the iliotibial band
      (ITB) to reconstruct deficient capsular tissues, and we report the results of 7
      patients. All patients had prior surgery, with a mean of 2.2 procedures, and
      recurrent instability as the primary indication for their index and revision
      surgeries. After ITB reconstruction, the patients demonstrated significant
      improvement in their American Shoulder and Elbow Surgeons (ASES) score (P
      =.0004), and no patient had any persistent symptoms of instability. Physiologic
      range of motion and function were maintained. We would recommend our method of
      ITB reconstruction for patients with instability and capsular deficiency after
      failed surgery and believe that this procedure has advantages over those
      previously described. Capsular deficiency and persistent instability after prior
      surgery can occur after prior open or arthroscopic surgery. Capsular deficiency
      has been described after thermal capsulorrhaphy and is thought to represent
      excessive thermal injury and tissue necrosis. After open capsulorrhaphy, capsular
      deficiency can be associated with subscapularis tendon deficiency.(4,6-8,12,13)
      Capsular deficiency occurring after either open or arthroscopic surgery presents
      a difficult surgical challenge. The purpose of this case series is to evaluate
      our experience in the surgical management of recurrent glenohumeral instability
      after surgery initially performed for treatment of glenohumeral instability that
      failed and is associated with irreparable tears of the subscapularis and capsular
      deficiency. The primary objectives of this study are to describe the surgical
      technique for capsular reconstruction with ITB and to report the clinical results
      in 7 patients.

PMID- 12469091
TI  - Arthroscopic treatment of post-traumatic elbow contracture.
AB  - The purpose of this study was to evaluate range of motion and patient-reported
      outcome after complete arthroscopic release of post-traumatic elbow contracture.
      Fourteen consecutive patients who underwent elbow arthroscopy and capsular
      release were reviewed retrospectively at a minimum follow-up of 1 year. Pain and
      range of motion were measured. Patient outcome was assessed with the American
      Shoulder and Elbow Surgeons Elbow Assessment Form. Mean self-reported
      satisfaction on a visual analog scale was 8.4 out of 10. Only 6 patients
      continued to have pain, with a mean maximum pain score of 4.6 out of 10. Flexion
      increased from a mean of 117.5 degrees to 133 degrees, and extension improved
      from a mean of 35.4 degrees to 9.3 degrees. In those patients with a preoperative
      arc of motion less than 100 degrees (10 patients), the mean arc of motion
      improved from 69 degrees to 119 degrees. All patients had improved function after
      the procedure, with a mean self-reported functional ability score of 28.3 out of
      30. There were no neurovascular complications. The improvement in range of motion
      and functional outcome compares favorably with open-release procedures. Combined
      with the potential benefits of improved joint visualization and low surgical
      morbidity, arthroscopic release of post-traumatic elbow contracture appears to be
      a reasonable alternative to open techniques.

PMID- 12469092
TI  - Osteochondritis dissecans of the humeral head in an amateur boxer.

PMID- 12469094
TI  - Reimplantation of a glenoid component after component removal and allograft bone
      grafting: a report of 3 cases.

PMID- 12469093
TI  - Reconstruction of chronic distal biceps tendon rupture with use of fascia lata
      combined with a ligament augmentation device: a report of 3 cases.

PMID- 12469095
TI  - Traumatic latissimus dorsi tendon rupture.

PMID- 12469097
TI  - [New Ideas in the Treatment of Chronic Cardiac Failure. Inotropic Stimulation of
      the Heart in the Era of ECA Inhibitors and beta-adrenoblockers]

PMID- 12469098
TI  - [Statins as Anti-Inflammatory Agents]
AB  - Statins modify cellular composition of atherosclerotic plaques decreasing their
      inflammatory elements capable to produce plaque destabilizing metalloproteinases
      and prothrombotic tissue factor. In humans long term administration of these
      drugs leads to decrease of levels of markers of inflammation notably of C
      reactive protein. Possible mechanisms of anti-inflammatory action of statins
      include activation of peroxisome proliferator activated receptor alpha. Indirect
      evidence exists from studies with clinical end points that statins are effective
      in patients with elevated initial level of C-reactive protein (CARE) and that
      this phenomenon occurs irrespective of the initial LDL CH level (AFCAPS) and its
      changes during statin therapy. Thus administration of statins apparently is an
      intervention capable to selectively modify the harmful components of inflammation
      in the arteries and to create new avenue for the management of patients with
      cardiovascular disease who do not have hypercholesterolemia (R.Ross).

PMID- 12469096
TI  - Metastatic carcinoma to the acromion in a patient after total shoulder
      arthroplasty: a case report and review of the literature.

PMID- 12469099
TI  - [Results of 6-Month Follow-up of Patients With Non-ST-Elevation Acute Coronary
      Syndrome Treated With Enoxaparin. Data of Multicenter Study in Russia]
AB  - Two hundred eighty four patients aged 30-85 (mean 62-/+10.2) years hospitalized
      because of prolonged attack of rest angina were included into open noncomparative
      study of enoxaparin tolerability. In addition to conventional aspirin the
      patients received enoxaparin (1 mg or 100 anti-Xa U/kg subcutaneously) every 12
      hours for 2-8 days. Events registered during follow-up for 6 months were deaths,
      nonfatal myocardial infarctions, attacks of angina with new ischemic ECG changes
      during initial hospitalization, and anginal attacks causing repeat
      hospitalization. Total number of patients with these events during first 15 days
      was 11.3% (including 1 death and 3 nonfatal myocardial infarctions). After 6
      months number of events almost doubled and reached 20.6%. Most pronounced was
      increase in numbers of deaths and nonfatal infarctions (up to 11 and 10 events,
      respectively). During period of follow-up most of patients continued to take
      aspirin and beta blockers, while myocardial revascularization was performed in 6
      patients, and use of statins was negligible. Among 32 parameters (demographic
      data, medical history, characteristics of index exacerbation of coronary artery
      disease and therapy) included into multifactorial analysis only actual decisions
      of physicians (prolongation of treatment with enoxaparin, the use of calcium
      antagonists) were independent predictors of angina recurrence. Apparently these
      decisions better reflected real severity of patients clinical condition then
      ihobjectiveln parameters registered by investigators.

PMID- 12469100
TI  - [Possibilities of Surface ECG Mapping in Diagnosis of Ischemic Heart Disease in
      Patients With Aortic Stenosis]
AB  - Method of surface ECG mapping and graded bicycle exercise test were used for
      noninvasive detection of coronary artery involvement in 24 patients with aortic
      stenosis. The actual presence of coronary artery disease was verified by coronary
      angiography. Isointegral ST-segment maps were constructed and analyzed. Stepwise
      discriminant analysis revealed parameters of maps most significant for diagnosis
      of ischemic heart disease. Two discriminant equations based on these parameters
      allowed to detect noninvasively coronary artery involvement in patients with
      aortic stenosis.

PMID- 12469101
TI  - [Dynamics of Heart Rate Variability, Parameters of 24-Hour Blood Pressure
      Monitoring and Lipid Peroxidation in Very High Risk Patients With Hypertension
      During Treatment With Lacidipin]

PMID- 12469102
TI  - [Morpho-Functional Changes of Thoracic Aorta in Atherosclerosis: Multiplane
      Transesophageal Ultrasound Study]
AB  - AIM: To elucidate possibilities of multiplane transesophageal ultrasound for
      assessment of localization and structure of atherosclerotic plaques in the
      thoracic aorta as well as relationship between changes of elastic-tonic
      properties, processes of aortic wall remodeling, stage of aortic atheromatosis,
      and coronary atherosclerosis. MATERIAL: Patients with chronic ischemic heart
      disease and atherosclerosis of thoracic aorta (n=120), healthy volunteers (n=11,
      all men, mean age 51-/+8 years). METHODS: Multiplane transesophageal ultrasound
      with subsequent calculation of parameters of elasticity and stiffness. The
      classification of C. Pitsavos et al. (1997) was used for grading aortic
      atheromatosis. RESULTS. Atherosclerotic plaques were found in 109 patients (91%)
      and 69 patients (58%) had pronounced (stage 3-5) atheromatosis of thoracic aorta.
      The plaques were most frequently (87%) localized in descending aorta. Calcinated
      hyperdense plaques, soft plaques with low density, soft plaques with
      heterogeneous density prevailed in ascending aorta, aortic arch, and descending
      aorta, respectively. Sensitivity and specificity of thoracic atherosclerosis as
      predictor of atherosclerotic lesions in coronary vessels were 90 and 65%,
      respectively. Pronounced diffuse atherosclerosis of thoracic aorta decreased its
      elastic-tonic properties as evidenced by significant lowering of parameters of
      elasticity and increase of stiffness index. This process was associated with
      remodeling of thoracic aorta (progressive passive dilatation, thickening of its
      wall and lowering of amplitude of systolic excursion). Atheromatosis stage
      correlated inversely with systolic excursion and parameters of elasticity and
      directly with stiffness index, intima-media thickness, systolic and diastolic
      diameters of the aorta. There was also a direct correlation between stage of
      aortic atheromatosis and age and total score of coronary artery involvement.
      CONCLUSION: Multiplane transesophageal echocardiography is a highly informative
      noninvasive method of assessment of morpho-functional changes of thoracic aorta
      caused by atherosclerosis.

PMID- 12469103
TI  - [Multicenter Study of Efficacy and Safety of a Preparation of Lovastatin in
      Patients With Ischemic Heart Disease and Mild or Moderate Hypercholesterolemia]
AB  - Ninety patients with ischemic heart disease and mild or moderate
      hypercholesterolemia were included in a multicenter study of efficacy and safety
      of a preparation of lovastatin (Holetar, KRKA). After 6 weeks of a diet period 46
      patients remained on diet and in 44 patients lovastatin was added to diet for 12
      weeks. All patients received 20 mg/day for 6 weeks. If after 6 weeks on
      lovastatin target level of low density lipoprotein cholesterol (LDL CH, 3.0
      mmol/l) was not achieved the dose was doubled. Target LDL CH level was achieved
      in 47% and 58% of patients by the end of 6 and 12 weeks, respectively. The 20 mg
      dose lowered levels of LDLCH by 27% and of triglycerides by 10%. The drug was
      well tolerated.

PMID- 12469104
TI  - [Immediate and Remote Results of Endovascular Recanalization of Chronic Coronary
      Artery Occlusions]
AB  - We compared early and long-term follow-up results of balloon angioplasty and
      stenting of chronic coronary occlusions. The initial success rate was 75% (82 of
      109 patients). Proportion of patients free of angina was 57 and 69% after
      successful balloon angioplasty and stenting, respectively. Stenting of coronary
      occlusions yielded better immediate angiographic results than did balloon
      angioplasty: residual stenosis and minimal diameter of artery after stenting were
      13.5-12.4% and 2.7-0.2 mm, respectively; those after balloon angioplasty were
      23.2-15.6% and 2.3-0.2 mm, p<0,05, respectively. Four-year clinical outcome was
      better in stenting than in angioplasty group: free of angina were 52 and 22% of
      patients in stenting and angioplasty group, respectively (p<0,05). There was no
      difference at follow-up between two groups in the rate of myocardial infarction,
      death, repeat revascularization. Repeat coronary angiography was performed after
      38-24 months in 44% of patients. The rate of 'late' restenosis was 32% in
      stenting and 73% in balloon angioplasty group (p<0,05); mean stenosis and minimal
      diameter of artery after stenting were 43.5-12.4% and 1.7-0.6 mm, respectively;
      those after balloon angioplasty were 67.5-15.6% and 0.72+0.5 mm, respectively
      (p<0,05).

PMID- 12469105
TI  - [Left Ventricular Diastolic Function Before and After Coronary Artery Bypass
      Surgery in Patients Without History of Myocardial Infarction]

PMID- 12469106
TI  - [Calcium 2+ Response of Lymphocytes to Standard Test-Substances in Patients With
      Ischemic Heart Disease and Heart Failure]
AB  - Changes of [Ca 2+]i were studied in peripheral blood lymphocytes of patients with
      ischemic heart disease and heart failure. Basal [Ca 2+]i and its changes under
      action of mitogenes (PHA, Con A; 10 mcg/ml), butylhydroxyquinone (BHQ; 9-14 mcM)
      and arachidonic acid (3-10 mc/M) were measured. Patients with heart failure had
      pronounced changes of kinetics and amplitude of Ca 2+ response of lymphocytes to
      mitogenes, significantly higher amplitudes of responses to BHQ (in patients with
      stage IIB and III heart failure), as well as additional increment of [Ca 2+]i in
      response to rachidonic acid during action of optimal concentrations of BHQ. This
      data allowed to propose presence of supplementary inositol triphosphate
      insensitive calcium depots in cells of patients with heart failure. Furthermore
      it was possible to assume lowering of sensitivity of Ca 2+ ATP-ase of plasmatic
      membranes to its natural regulators.

PMID- 12469107
TI  - [Orthostatic Insufficiency. Clinical and Hemodynamic Characteristics of Patients
      With Disturbances of Blood Pressure Regulation]

PMID- 12469108
TI  - [Efficacy of Behavioral Rehabilitation Programs in Patients With Myocardial
      Infarction. Dependence on the Type of Coronary Behavior]

PMID- 12469109
TI  - [Advances in Diagnostics and Management of Chronic Heart Failure (recommendations
      of the European Cardiology Society 2001)]

PMID- 12469110
TI  - [Biochemical Markers of Myocardial Necrosis. Part 2. Value of Biomarkers in
      Patients With Non-ST-Elevation Acute Coronary Syndrome]

PMID- 12469111
TI  - [The Use of Hormonal Replacement Therapy in Patients With Type II Diabetes]

PMID- 12469112
TI  - [Subacute Infectious Endocarditis in an AIDS-Infected Patient]

PMID- 12469113
TI  - Structure and regulation of the cAMP-binding domains of Epac2.
AB  - Cyclic adenosine monophosphate (cAMP) is a universal second messenger that, in
      eukaryotes, was believed to act only on cAMP-dependent protein kinase A (PKA) and
      cyclic nucleotide-regulated ion channels. Recently, guanine nucleotide exchange
      factors specific for the small GTP-binding proteins Rap1 and Rap2 (Epacs) were
      described, which are also activated directly by cAMP. Here, we have determined
      the three-dimensional structure of the regulatory domain of Epac2, which consists
      of two cyclic nucleotide monophosphate (cNMP)-binding domains and one DEP
      (Dishevelled, Egl, Pleckstrin) domain. This is the first structure of a cNMP
      binding domain in the absence of ligand, and comparison with previous structures,
      sequence alignment and biochemical experiments allow us to delineate a mechanism
      for cyclic nucleotide-mediated conformational change and activation that is most
      likely conserved for all cNMP-regulated proteins. We identify a hinge region that
      couples cAMP binding to a conformational change of the C-terminal regions.
      Mutations in the hinge of Epac can uncouple cAMP binding from its exchange
      activity.

PMID- 12469114
TI  - Angiopoietins have distinct modular domains essential for receptor binding,
      dimerization and superclustering.
AB  - Angiopoietins are a recently discovered family of angiogenic factors that
      interact with the endothelial receptor tyrosine kinase Tie2, either as agonists
      (angiopoietin-1) or as context-dependent agonists/antagonists (angiopoietin-2).
      Here we show that angiopoietin-1 has a modular structure unlike any previously
      characterized growth factor. This modular structure consists of a receptor
      binding domain, a dimerization motif and a superclustering motif that forms
      variable-sized multimers. Genetic engineering of precise multimers of the
      receptor-binding domain of angiopoietin-1, using surrogate multimerization
      motifs, reveals that tetramers are the minimal size required for activating
      endothelial Tie2 receptors. In contrast, engineered dimers can antagonize
      endothelial Tie2 receptors. Surprisingly, angiopoietin-2 has a modular structure
      and multimerization state similar to that of angiopoietin-1, and its antagonist
      activity seems to be a subtle property encoded in its receptor-binding domain.

PMID- 12469115
TI  - Plasmodium falciparum erythrocyte invasion through glycophorin C and selection
      for Gerbich negativity in human populations.
AB  - Geographic overlap between malaria and the occurrence of mutant hemoglobin and
      erythrocyte surface proteins has indicated that polymorphisms in human genes have
      been selected by severe malaria. Deletion of exon 3 in the glycophorin C gene
      (called GYPCDeltaex3 here) has been found in Melanesians; this alteration changes
      the serologic phenotype of the Gerbich (Ge) blood group system, resulting in Ge
      negativity. The GYPCDeltaex3 allele reaches a high frequency (46.5%) in coastal
      areas of Papua New Guinea where malaria is hyperendemic. The Plasmodium
      falciparum erythrocyte-binding antigen 140 (EBA140, also known as BAEBL) binds
      with high affinity to the surface of human erythrocytes. Here we show that the
      receptor for EBA140 is glycophorin C (GYPC) and that this interaction mediates a
      principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not
      bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells
      using this invasion pathway. This provides compelling evidence that Ge negativity
      has arisen in Melanesian populations through natural selection by severe malaria.

PMID- 12469116
TI  - TCRs with high affinity for foreign pMHC show self-reactivity.
AB  - T cells with high-affinity T cell receptors (TCRs) for a foreign peptide-major
      histocompatibility complex (pMHC) appear to be negatively selected, even though
      they have never seen the foreign antigen. To examine how this process operates,
      we used in vitro yeast display to isolate high-affinity TCRs from the T cell
      clone 2C. The TCRs showed fast on-rates, which were consistent with reduced CDR
      (complementarity determining region) flexibility, and cross-reactivity with other
      cognate pMHCs. T cell hybridomas transfected with a high-affinity TCR were
      stimulated by endogenous self-pMHC, which suggested that T cells bearing the TCR
      would be negatively selected. The immune system appears to maintain a repertoire
      of flexible, low-affinity TCRs at the expense of more effective high-affinity
      TCRs.

PMID- 12469117
TI  - Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70
      interactions.
AB  - It has been proposed that HIV-1, in addition to directly infecting and killing
      CD4+ T cells, causes T cell dysfunction and T cell loss by chronic immune
      activation. We analyzed the effects of chronic immune activation in mice that
      constitutively expressed CD70, the ligand for the tumor necrosis factor receptor
      family member CD27, on B cells. CD70 transgenic (CD70 Tg) mice showed a
      progressive conversion of naive T cells into effector-memory cells, which
      culminated in the depletion of naive T cells from lymph nodes and spleen. T cell
      changes depended on continuous CD27-CD70 interactions and T cell antigen receptor
      stimulation. Despite this hyperactive immune system, CD70 Tg mice died aged 6-8
      months from Pneumocystis carinii infection, a hallmark of T cell
      immunodeficiency. Thus, persistent delivery of costimulatory signals via CD27
      CD70 interactions, as may occur during chronic active viral infections, can
      exhaust the T cell pool and is sufficient to induce lethal immunodeficiency.

PMID- 12469118
TI  - A small molecule Abl kinase inhibitor induces differentiation of Abelson virus
      transformed pre-B cell lines.
AB  - Abelson murine leukemia virus-transformed cell lines have provided a critical
      model system for studying the regulation of B cell development. However,
      transformation by v-Abl blocks B cell development, resulting in the arrest of
      these transformants in an early pre-B cell-like state. We report here that
      treatment of Abelson virus-transformed pre-B cell lines with the small molecule
      Abl kinase inhibitor (STI571) results in their differentiation to a late pre-B
      cell-like state characterized by induction of immunoglobulin (Ig) light chain
      gene rearrangement. DNA microarray analyses enabled us to identify two genes
      inhibited by v-Abl that encode the Igk 3' enhancer-binding transcription factors
      Spi-B and IRF-4. We show that enforced expression of these two factors is
      sufficient to induce germline Igk transcription in Abelson-transformed pro-B cell
      lines. This suggests a key role for these factors, and perhaps for c-Abl itself,
      in the regulated activation of Ig light chain gene rearrangement.

PMID- 12469119
TI  - IL-28, IL-29 and their class II cytokine receptor IL-28R.
AB  - Cytokines play a critical role in modulating the innate and adaptive immune
      systems. Here, we have identified from the human genomic sequence a family of
      three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are
      distantly related to type I interferons (IFNs) and the IL-10 family. We found
      that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed
      antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric
      class II cytokine receptor that consisted of IL-10 receptor beta (IL-10Rbeta) and
      an orphan class II receptor chain, designated IL-28Ralpha. This newly described
      cytokine family may serve as an alternative to type I IFNs in providing immunity
      to viral infection.

PMID- 12469120
TI  - Mutant antimicrobial peptide hepcidin is associated with severe juvenile
      hemochromatosis.
AB  - Animal models indicate that the antimicrobial peptide hepcidin (HAMP; OMIM
      606464) is probably a key regulator of iron absorption in mammals. Here we report
      the identification of two mutations (93delG and 166C-->T) in HAMP on 19q13 in two
      families with a new type of juvenile hemochromatosis.

PMID- 12469122
TI  - A molecular signature of metastasis in primary solid tumors.
AB  - Metastasis is the principal event leading to death in individuals with cancer,
      yet its molecular basis is poorly understood. To explore the molecular
      differences between human primary tumors and metastases, we compared the gene
      expression profiles of adenocarcinoma metastases of multiple tumor types to
      unmatched primary adenocarcinomas. We found a gene-expression signature that
      distinguished primary from metastatic adenocarcinomas. More notably, we found
      that a subset of primary tumors resembled metastatic tumors with respect to this
      gene-expression signature. We confirmed this finding by applying the expression
      signature to data on 279 primary solid tumors of diverse types. We found that
      solid tumors carrying the gene-expression signature were most likely to be
      associated with metastasis and poor clinical outcome (P < 0.03). These results
      suggest that the metastatic potential of human tumors is encoded in the bulk of a
      primary tumor, thus challenging the notion that metastases arise from rare cells
      within a primary tumor that have the ability to metastasize.

PMID- 12469121
TI  - Nf1 has an essential role in endothelial cells.
AB  - Neurofibromatosis type 1 (NF1) or von Recklinghausen neurofibromatosis is a
      genetic disorder that occurs in 1 of 4000 births and is characterized by benign
      and malignant tumors. Cardiovascular defects also contribute to NF1, though the
      pathogenesis is still unclear. Deficiency in neurofibromin (encoded by Nf1) in
      mice results in mid-embryonic lethality owing to cardiac abnormalities previously
      thought to be secondary to cardiac neural-crest defects. Using tissue-specific
      gene inactivation, we show that endothelial-specific inactivation of Nf1
      recapitulates key aspects of the complete null phenotype, including multiple
      cardiovascular abnormalities involving the endocardial cushions and myocardium.
      This phenotype is associated with an elevated level of ras signaling in Nf1(-/-)
      endothelial cells and greater nuclear localization of the transcription factor
      Nfatc1. Inactivation of Nf1 in the neural crest does not cause cardiac defects
      but results in tumors of neural-crest origin resembling those seen in humans with
      NF1. These results establish a new and essential role for Nf1 in endothelial
      cells and confirm the requirement for neurofibromin in the neural crest.

PMID- 12469123
TI  - Identifying distinct classes of bladder carcinoma using microarrays.
AB  - Bladder cancer is a common malignant disease characterized by frequent
      recurrences. The stage of disease at diagnosis and the presence of surrounding
      carcinoma in situ are important in determining the disease course of an affected
      individual. Despite considerable effort, no accepted immunohistological or
      molecular markers have been identified to define clinically relevant subsets of
      bladder cancer. Here we report the identification of clinically relevant
      subclasses of bladder carcinoma using expression microarray analysis of 40 well
      characterized bladder tumors. Hierarchical cluster analysis identified three
      major stages, Ta, T1 and T2-4, with the Ta tumors further classified into
      subgroups. We built a 32-gene molecular classifier using a cross-validation
      approach that was able to classify benign and muscle-invasive tumors with close
      correlation to pathological staging in an independent test set of 68 tumors. The
      classifier provided new predictive information on disease progression in Ta
      tumors compared with conventional staging (P < 0.005). To delineate non-recurring
      Ta tumors from frequently recurring Ta tumors, we analyzed expression patterns in
      31 tumors by applying a supervised learning classification methodology, which
      classified 75% of the samples correctly (P < 0.006). Furthermore, gene expression
      profiles characterizing each stage and subtype identified their biological
      properties, producing new potential targets for therapy.

PMID- 12469124
TI  - Our small relative.

PMID- 12469125
TI  - Zinc finger protein too few controls the development of monoaminergic neurons.
AB  - The mechanism controlling the development of dopaminergic (DA) and serotonergic
      (5HT) neurons in vertebrates is not well understood. Here we characterized a
      zebrafish mutant--too few (tof)--that develops hindbrain 5HT and noradrenergic
      neurons, but does not develop hypothalamic DA and 5HT neurons. tof encodes a
      forebrain-specific zinc finger transcription repressor that is homologous to the
      mammalian Fezl (forebrain embryonic zinc finger-like protein). Mosaic and co
      staining analyses showed that fezl was not expressed in DA or 5HT neurons and
      instead controlled development of these neurons non-cell-autonomously. Both the
      eh1-related repressor motif and the second zinc finger domain were necessary for
      tof function. Our results indicate that tof/fezl is a key component in regulating
      the development of monoaminergic neurons in the vertebrate brain.

PMID- 12469126
TI  - Neuron-to-astrocyte signaling is central to the dynamic control of brain
      microcirculation.
AB  - The cellular mechanisms underlying functional hyperemia--the coupling of neuronal
      activation to cerebral blood vessel responses--are not yet known. Here we show in
      rat cortical slices that the dilation of arterioles triggered by neuronal
      activity is dependent on glutamate-mediated [Ca(2+)](i) oscillations in
      astrocytes. Inhibition of these Ca(2+) responses resulted in the impairment of
      activity-dependent vasodilation, whereas selective activation--by patch pipette-
      of single astrocytes that were in contact with arterioles triggered vessel
      relaxation. We also found that a cyclooxygenase product is centrally involved in
      this astrocyte-mediated control of arterioles. In vivo blockade of glutamate
      mediated [Ca(2+)](i) elevations in astrocytes reduced the blood flow increase in
      the somatosensory cortex during contralateral forepaw stimulation. Taken
      together, our findings show that neuron-to-astrocyte signaling is a key mechanism
      in functional hyperemia.

PMID- 12469127
TI  - Neural regions essential for writing verbs.
AB  - Functional imaging data collected during cognitive tasks show which brain regions
      are active during those tasks, but do not necessarily indicate which regions are
      essential for those tasks. Here, in a study of two cases of selectively impaired
      written naming of verbs after focal brain ischemia, we combined imaging and
      behavioral testing to unambiguously identify brain regions that are crucial for a
      specific cognitive process. We used magnetic resonance perfusion imaging to show
      that the selective impairment in each case was due to hypoperfusion (low blood
      flow) in left posterior inferior frontal gyrus (PIFG) and precentral gyrus (PrG);
      the impairment was immediately reversed when blood flow was restored to these
      regions, indicating that parts of the left frontal lobe are crucial for
      representing and processing verbs.

PMID- 12469128
TI  - Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in
      vivo.
AB  - Neural stem cells exist in the developing and adult nervous systems of all
      mammals, but the basic mechanisms that control their behavior are not yet well
      understood. Here, we investigated the role of Sonic hedgehog (Shh), a factor
      vital for neural development, in regulating adult hippocampal neural stem cells.
      We found high expression of the Shh receptor Patched in both the adult rat
      hippocampus and neural progenitor cells isolated from this region. In addition,
      Shh elicited a strong, dose-dependent proliferative response in progenitors in
      vitro. Furthermore, adeno-associated viral vector delivery of shh cDNA to the
      hippocampus elicited a 3.3-fold increase in cell proliferation. Finally, the
      pharmacological inhibitor of Shh signaling cyclopamine reduced hippocampal neural
      progenitor proliferation in vivo. This work identifies Shh as a regulator of
      adult hippocampal neural stem cells.

PMID- 12469129
TI  - Seeing the action: neuropsychological evidence for action-based effects on object
      selection.
AB  - Previous studies have shown that selection for perceptual report is often limited
      to one object at a time, with elements being selected together if they belong to
      part of the same perceptual group. Here we used the neuropsychological phenomenon
      of extinction in human patients with parietal lesions to show that selection is
      influenced also by action relations between objects. Performance was better for
      objects that were positioned spatially so that they could be used together,
      relative to objects that were positioned inappropriately for their combined use.
      The action relation was critical, as performance for pictures did not improve if
      the items were only verbally associated. We found the opposite result with words.
      Effects of action relations emerged even on trials where only one object could be
      reported, showing implicit coding of 'action' units for selection. The effects of
      verbal associations may instead reflect priming between lexical entries.

PMID- 12469130
TI  - A developmental switch in the signaling cascades for LTP induction.
AB  - Long-term potentiation (LTP) is thought to be critically involved not only in
      learning and memory, but also during the activity-dependent developmental phases
      of neural circuit formation and refinement. Whether the mechanisms underlying LTP
      change during this phase of postnatal development, however, is unknown. We report
      here that, unlike LTP in the more mature CA1 region of the hippocampus, LTP in
      neonatal rodent hippocampus (<9 postnatal days, <P9) requires cyclic AMP
      dependent protein kinase A (PKA) but not Ca(2+)/calmodulin-dependent protein
      kinase II (CaMKII).

PMID- 12469131
TI  - Stereoscopic depth processing in the visual cortex: a coarse-to-fine mechanism.
AB  - For binocular animals viewing a three-dimensional scene, the left and right eyes
      receive slightly different information, and the brain uses this 'binocular
      disparity' to interpret stereoscopic depth. An important theoretical conjecture
      in this mechanism is that coarse processing precedes and constrains finely
      detailed processing. We present three types of neurophysiological data from the
      cat's visual cortex that are consistent with a temporal coarse-to-fine tuning of
      disparity information. First, the disparity tuning of cortical cells generally
      sharpened during the time course of response. Second, cells responsive to large
      and small spatial scale had relatively shorter and longer temporal latencies,
      respectively. Third, cross-correlation analysis between simultaneously recorded
      pairs of cortical cells showed that connections between disparity-tuned neurons
      were generally stronger for coarse-to-fine processing than for fine-to-coarse
      processing. These results are consistent with theoretical and behavioral studies
      and suggest that rapid, coarse percepts are refined over time in stereoscopic
      depth perception.

PMID- 12469132
TI  - Prefrontal interactions reflect future task operations.
AB  - When task instructions are given, the human brain establishes a task set before
      the task is actually performed. By introducing a delay between the instruction
      and the task, we have identified the neural correlates of task sets using
      functional magnetic resonance imaging (fMRI). Subjects were instructed to
      remember a sequence of positions or letters, either in the order presented or in
      the reverse order. Spatial or verbal processing areas were active during the
      delay, depending on whether positions or letters were to be remembered, whereas
      the anterior region of the prefrontal cortex (PFC) was active regardless of the
      domain of the items. Furthermore, the nature of the interaction between the
      anterior PFC and the domain-specific posterior prefrontal areas (superior frontal
      sulcus and left inferior frontal gyrus) depended on whether the items were to be
      remembered in the forward or backward order. Thus we have identified inter
      regional interactions that reflect preparation for task performance.

PMID- 12469133
TI  - A general method for the covalent labeling of fusion proteins with small
      molecules in vivo.
AB  - Characterizing the movement, interactions, and chemical microenvironment of a
      protein inside the living cell is crucial to a detailed understanding of its
      function. Most strategies aimed at realizing this objective are based on
      genetically fusing the protein of interest to a reporter protein that monitors
      changes in the environment of the coupled protein. Examples include fusions with
      fluorescent proteins, the yeast two-hybrid system, and split ubiquitin. However,
      these techniques have various limitations, and considerable effort is being
      devoted to specific labeling of proteins in vivo with small synthetic molecules
      capable of probing and modulating their function. These approaches are currently
      based on the noncovalent binding of a small molecule to a protein, the formation
      of stable complexes between biarsenical compounds and peptides containing
      cysteines, or the use of biotin acceptor domains. Here we describe a general
      method for the covalent labeling of fusion proteins in vivo that complements
      existing methods for noncovalent labeling of proteins and that may open up new
      ways of studying proteins in living cells.

PMID- 12469134
TI  - Overexpression of a plasma membrane Na+/H+ antiporter gene improves salt
      tolerance in Arabidopsis thaliana.
AB  - High concentrations of Na+ in saline soils inhibit plant growth and reduce
      agricultural productivity. We report here that CaMV 35S promoter driven
      overexpression of the Arabidopsis thaliana SOS1 gene, which encodes a plasma
      membrane Na+/H+ antiporter, improves plant salt tolerance in A. thaliana.
      Transgenic plants showed substantial upregulation of SOS1 transcript levels upon
      NaCl treatment, suggesting post-transcriptional control of SOS1 transcript
      accumulation. In response to NaCl treatment, transgenic plants overexpressing
      SOS1 accumulated less Na+ in the xylem transpirational stream and in the shoot.
      Undifferentiated callus cultures regenerated from the transgenic plants were also
      more tolerant of salt stress, which was correlated with reduced Na+ content in
      the transgenic cells. These results show that improved salt tolerance could be
      achieved by limiting Na+ accumulation in plant cells.

PMID- 12469135
TI  - Gastrointestinal malignant non Hodgkin's B cell lymphomas in the immunocompetent
      patient (Review).
AB  - The gastrointestinal tract is the most common site for extranodal non Hodgkin's
      lymphomas with B cell lymphomas being the most commonly encountered. The clinical
      symptoms and endoscopic findings are non-specific, however, the first obtained
      biopsy establishes the diagnosis in more than three quarters of the patients.
      Recognizing early lesions and differentiating lymphomas from hyperplastic
      reactive lesions may be difficult, but essential. As the classification of these
      lesions has been the subject of much controversy in the past, we reviewed the
      literature and summarized the distinct recognizable entities. We high-lighted
      recent advances in understanding clinical and histological findings in these
      lesions with adjunct immunohistochemistry and cytogenetics.

PMID- 12469136
TI  - The angiogenic switch of human colon cancer occurs simultaneous to initiation of
      invasion.
AB  - We previously reported that vessel count, vascular endothelial growth factor
      (VEGF) and platelet derived endothelial cell growth factor (PD-ECGF) expression
      are associated with metastasis formation in human colon cancer. This study was
      done to determine a stage of colon cancer progression where induction of these
      factors occurred (i.e. the angiogenic switch). We examined vessel count, VEGF,
      and matrix metalloproteinase (MMP)-7 expression in cancer cells and PD-ECGF
      expression in infiltrating cells in 25 adenomas, 35 mucosal cancers (Tis), 29
      submucosal invasive cancers (T1) and 33 muscularis propria invasive cancers (T2)
      by immunostaining. The intensity of staining of VEGF and MMP-7 was evaluated
      blindly at the invasive edge and was confirmed by image analysis. Intensity of
      staining for these factors was graded on a scale of 0 to 3+, with 0 representing
      no detectable stain and 3+ representing the strongest stain. Intensites of PD
      ECGF-positive infiltrating cells were similar on a scale 0 to 3+, as previous
      studies from our laboratory have demonstrated that PD-ECGF is expressed primarily
      in tumor infiltrating cells. The vessel density was 12.7+/-2.2 (SE) in adenoma,
      11.8+/-1.7 in Tis, 35.0+/-6.5 in T1, and 35.2+/-5.3 in T2. There were significant
      differences in vessel densities between Tis and T1 (p<0.001). The intensities of
      VEGF expression were 0.6+/-0.1, 0.9+/-0.2, 1.7+/-0.3, and 1.8+/-0.3 for adenoma,
      Tis, T1 and T2, respectively, with significant differences between in Tis and T1
      (p<0.001). There were also significant differences in the intensities of the
      expression of MMP-7 and PD-ECGF between Tis and T1. These results suggest that
      angiogenic switch may occur between Tis and T1, i.e. simultaneous to initiation
      of invasion, in the early development of colon cancer.

PMID- 12469137
TI  - Comparison of automated cellular imaging system and manual microscopy for
      immunohistochemically stained cryostat sections of lung cancer specimens applying
      p53, ki-67 and p120.
AB  - Seventy-one frozen lung tissue specimens from 52 patients suffering from non
      small cell lung cancer (NSCLC) were analysed in this study. Cryostat sections
      were stained with monoclonal antibodies against p53, ki-67 and p120, all of which
      are of prognostic value in NSCLC. Slides were evaluated by standard manual
      microscopy (MM) and using a new Automated Cellular Imaging System (ACIS). The
      results obtained with ACIS correlated significantly with MM examination
      (p<0.001). However, ACIS showed a higher sensitivity, especially for specimens
      with a low infiltration volume. In 15 (6.8%) MM negative cases singular positive
      cells were identified with ACIS. In cases with a high infiltration volume
      subjective (MM) quantitation tended to overestimate the number of infiltrating
      cells. ACIS guaranteed a high reproducibility of data. We conclude that ACIS
      assisted analysis is a valid means of investigating the p53, ki-67 and p120
      antibody expression in cryostat sections of lung cancer specimens. ACIS can
      complement conventional manual microscopy due to its higher accuracy, sensitivity
      and better reproducibility of data.

PMID- 12469138
TI  - Differential roles of alterations of p53, p16, and SMAD4 expression in the
      progression of intraductal papillary-mucinous tumors of the pancreas.
AB  - Intraductal papillary-mucinous tumors (IPMTs) of the pancreas are characterized
      by dilated pancreatic ducts and ductules that are lined by tall columnar mucin
      producing neoplastic epithelial cells. IPMTs have been suggested to be distinct
      neoplasms with a less aggressive phenotype than that of conventional ductal
      adenocarcinomas of the pancreas. Molecular mechanisms underlying tumorigenesis of
      IPMTs are beginning to be characterized. Allelic losses have frequently been
      detected at 9p, 17p, and 18q, suggesting that inactivation of tumor suppressor
      genes at these loci play a role in tumorigenesis of IPMTs. Using
      immunohistochemistry, we analyzed 38 IPMTs, including 9 hyperplasia, 16 adenoma,
      and 13 carcinoma tissues, for expression of p53, Ki-67, p16, and SMAD4. Nuclear
      p53 expression was observed in 5 (38%) of 13 carcinoma tissues but not in
      hyperplasia or adenoma tissues. Partial loss of p16 expression was observed in 9
      (56%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively.
      Partial loss of p16 expression was observed even in adenomas with mild atypia.
      Partial loss of SMAD4 expression was observed in 6 (38%) and 12 (92%) of the 16
      adenoma and 13 carcinoma tissues, respectively. The SMAD4 negative index was
      significantly higher in invasive carcinomas than in non-invasive carcinomas. Our
      results suggest that loss of p16 is an early event and p53 alteration is a late
      event during the progression of IPMTs. SMAD4 inactivation appears to be an early
      event but also involved in invasive tumor growth. Our results suggest that these
      alterations accumulate during the progression of IPMTs, reflecting results of
      analysis of allelic losses that showed a stepwise accumulation of genetic changes
      during progression.

PMID- 12469139
TI  - MnSOD expression within tumor cells is closely related to mode of invasion in
      human gastric cancer.
AB  - Manganese superoxide dismutase (MnSOD) plays an important role in protecting
      cells from injury due to oxidative stress. We used immunohistochemical techniques
      to evaluate the expression of MnSOD in specimens obtained from 61 patients with
      gastric cancer. Immunostaining for MnSOD in tumor cells was compared to that of
      corresponding normal epithelial tissue. Staining for MnSOD was restricted to the
      cytoplasm of cells, and overexpression was observed more frequently among the
      normal mucosa than among tumor cells. Either absent or less intense MnSOD
      staining was observed in the cells of 44 (72.1%) tumors compared to that of the
      normal mucosa (group A). MnSOD staining of equal or greater intensity than that
      observed in the normal mucosa was observed in 17 (27.9%) tumors (group B). There
      was no association of MnSOD expression with metastatic behavior and prognosis,
      however decreased MnSOD expression in tumor cells (group A) was correlated with a
      greater probability of infiltrative type or undifferentiated type
      adenocarcinomas. Multivariate analysis found that gross appearance (mode of
      invasion) of the tumor was a significant factor related to MnSOD expression
      (p<0.05). These findings suggested that variations in MnSOD expression among
      different types of tumors might occur secondary to cell differentiation and/or
      proliferation.

PMID- 12469140
TI  - Spindle-cell ameloblastic carcinoma: A case report with immunohistochemical,
      ultrastructural, and comparative genomic hybridization analyses.
AB  - Spindle-cell ameloblastic carcinoma is a classification proposed for a group of
      rare odontogenic carcinomas with sarcomatoid components and is distinguished from
      odontogenic carcinosarcoma. We report a case of spindle-cell ameloblastic
      carcinoma of the right mandible that occurred in a 67-year-old Japanese man.
      Growth of the tumor was destructive, there was extensive lung metastasis, and the
      outcome was unfavorable. Ultrastructural and immunohistochemical examination
      showed the spindle-cell component of the tumor to be epithelial in character. A
      gain of 5q with amplification of 5q13 was detected in the tumor by comparative
      genomic hybridization.

PMID- 12469141
TI  - Loss of heterozygosity on chromosome 16p and 18q in anaplastic thyroid carcinoma.
AB  - The aim of this study was to clarify the genetic alterations in anaplastic
      transformation of the thyroid cancer. A total of 17 thyroid cancers including 7
      anaplastic and 10 papillary cancers were analyzed for loss of heterozygosity
      (LOH) on chromosome 16p and 18q. All the samples from anaplastic cancer showed
      LOH at one or more loci out of ten markers on 16p, and only two showed one LOH at
      two loci out of five markers on 18q. No LOH was found on either 16p or 18q in
      papillary cancers. D16S423, D16S418 and D16s406 on 16p13.3 were the most
      frequently deleted loci in anaplastic cancers, and the region around these may
      harbor the putative tumor suppressor gene related to anaplastic transformation of
      thyroid cancer.

PMID- 12469142
TI  - Significance of immunohistochemical expression of manganese superoxide dismutase
      as a marker of malignant potential in colorectal carcinoma.
AB  - Manganese superoxide dismutase (MnSOD) is an important superoxide anion scavenger
      located in mitochondria and protects cells from the damage caused by reactive
      oxygen species. The oxygen balance has been reported to be related to the
      occurrence and invasiveness of malignant tumors. The aim of the current study was
      to elucidate the clinicopathological significance of immunohistochemical MnSOD
      expression in colorectal carcinoma. Consecutive 186 primary colorectal carcinomas
      which had been resected from 1987 to 1999 were examined for MnSOD expression by
      means of an immunohistochemical investigation. Sixty nine carcinomas (37.1%) had
      a positive response to MnSOD. The proportion of lymph node metastasis in MnSOD
      positive carcinomas (49.3%, 34 out of 69) was significantly higher than that in
      MnSOD negative carcinomas (26.5%, 31 out of 117; p=0.002). The proportion of
      patients classified to Dukes' stage A, B, C, and D in MnSOD positive carcinomas
      was 10.1, 33.3, 40.7, and 15.9%, respectively, and those were 23.1, 49.5, 24.8,
      and 2.6%, respectively in MnSOD negative carcinomas (p=0.0001). The survival rate
      in patients with MnSOD positive carcinomas was significantly worse than that in
      patients with MnSOD negative carcinomas (p=0.01). Multivariate analysis
      demonstrated that Dukes' stage of tumors was found to be a factor independently
      associated with prognosis of the patients. Our results showed that
      immunohistochemical expression of MnSOD can give auxiliary clinical information
      for malignant potential of colorectal carcinoma.

PMID- 12469143
TI  - Expression of survivin and matrix metalloproteinases in adenocarcinoma and
      squamous cell carcinoma of the uterine cervix.
AB  - Cervical cancer can be classified into two histological types: squamous cell
      carcinoma (SCA) and adenocarcinoma (ACA). Reportedly ACA has poorer prognoses,
      metastasizes more easily to lymph nodes, and is more resistant to radiotherapy
      than SCA. To clarify the cause of characteristic differences between these
      histological types, we examined the expressions of apoptosis inhibiting and tumor
      invasion related factors in both histological types. We reviewed the 34 cases of
      cervical cancer (17 ACA, 17 SCA) that had surgery as their initial treatment at
      Osaka City University Medical School Hospital between 1996 and 2001. The
      differences of survivin, and matrix metalloproteinase (MMP-2, and MMP-7)
      expressions between both histological types were immunohistochemically assayed,
      and the correlation between the expression of each protein and
      clinicopathological characteristics was analyzed. Survivin was expressed
      significantly stronger in ACA cases (p=0.035). The number of patients who
      expressed MMP-2 and MMP-7 simultaneously was significantly higher in SCA cases
      (p=0.039). MMP-2 and MMP-7 had tendencies to be expressed stronger in SCA
      (p=0.057 and p=0.084, respectively). These results suggest that the differences
      of the expression of survivin (an apoptosis inhibiting factor), MMP-2, and MMP-7
      (tumor-invasion related factors) between ACA and SCA were causes of the
      characteristic differences between the two histological types.

PMID- 12469144
TI  - Differential expression patterns of hyaluronan receptors CD44 and RHAMM in
      transitional cell carcinomas of urinary bladder.
AB  - Recurrence due to invasive growth is the major risk factor of transitional cell
      carcinoma (TCC) of urinary bladder. The interactions of hyaluronic acid (HA) and
      its receptors, CD44 and RHAMM, on cancer cells can promote invasion and
      metastasis but parallel study on these two genes in TCCs has not been available.
      The current work is aimed to address this issue by frozen tissue array-based
      immunocytochemical staining and Western blot hybridization. The results revealed
      that 19 out of 28 non-cancerous mucosa (68%) expressed CD44, in which 9 (33%)
      harbored variant exon 6 (v6). CD44 and v6 were both 5/11 (46%) in papillary, non
      invasive carcinomas (pTa) and 6/14 (43%) in the tumors remained in sub-epithelial
      layer (pT1), while 5/29 (17%) and 3/29 (10%) in pT2-4 invasive tumors. RHAMM
      expression was uncommon in non-cancerous mucosa (5/28) but became frequent in pTa
      (9/11), pT1 (12/14) and pT2-4 (24/29) tumors. RHAMM proteins were labeled
      intracellularly and showed more than one isoforms. Our data further confirm the
      promising prognostic value of CD44 for TCC patients and demonstrate, for the
      first time, the correlation between RHAMM expression and malignant transformation
      of urothelial cells.

PMID- 12469145
TI  - Fas-related apoptosis in gastric adenocarcinoma.
AB  - The aims of this study were to determine whether human gastric adenocarcinomas
      express FasL or Fas, whether FasL expression is associated with increased
      apoptotic induction, especially, tumor-infiltrating lymphocyte (TIL) and whether
      apoptotic induction is associated with the tumor stage and histologic type. Early
      gastric carcinoma (EGC) (n=38) and advanced gastric carcinoma (AGC) (n=61) cases
      were analyzed in patients who received gastric resection from 1997 to 1998. There
      were 38 diffuse type and 61 intestinal type cases. Immunohistochemical staining
      for Fas, FasL and CD45, TACS trade mark in situ apoptosis detection kit, and
      double staining with the observation under a confocal scanning laser microscope
      were employed. FasL was localized to neoplastic cells in 23 cases (61%) of EGC
      group and 40 cases (66%) of AGC group. The extent of FasL expression was
      variable, with both FasL-positive and -negative neoplastic regions occurring
      within tumors. TILs were detected by CD45, and apoptosis of TILs as detected by
      co-expression of CD45 and TACS on serial histologic sections. TILs adjacent to
      FasL expressing tumor regions were decreased in number and TILs adjacent to FasL
      negative tumor regions were increased in number; apoptotic induction of TIL
      showed the opposite pattern (p<0.05). Fas was expressed homogeneously throughout
      the tumor masses independent of the tumor stage. Fas expression in 39 cases (64%)
      was intestinal type and in 26 cases (68%), diffuse type. Labeling indices for
      tumoral apoptosis in EGC and AGC were 6.72% and 7.13%, respectively. Co
      expression of FasL and Fas, which occurrs over large areas of the tumors, did not
      result in an enhanced rate of tumor cell apoptosis. In addition, tumor stage and
      other prognostic factors were not associated with Fas and FasL expressions,
      number of TIL and apoptotic induction. A statistically significant reduction of
      TILs concomitant with significantly increased TIL apoptosis adjacent to FasL
      expressing regions of gastric adenocarcinomas were demonstrated. This finding
      suggests Fas-mediated apoptotic depletion of TIL in response to FasL expression
      in stomach cancers, and provides evidence to support the Fas counterattack theory
      as a mechanism of immune escape in gastric cancer. Furthermore, gastric carcinoma
      cells of the intestinal and the diffuse type did not differ in their expression
      of the Fas-apoptotic system.

PMID- 12469146
TI  - Multicenter phase II study of fractionated bimonthly oxaliplatin with leucovorin
      and 5-fluorouracil in patients with metastatic colorectal cancer, pre-treated
      with chemotherapy.
AB  - In vitro and in vivo studies have shown that oxaliplatin (L-OHP), 5-fluorouracil
      (5-FU) and leucovorin (L) have a synergistic activity on metastatic colorectal
      cancer (MCC). In order to better exploit the synergism of action between the
      three drugs, L-OHP was administered over 2 days, together with 5-FU-L, in a
      cohort of patients with MCC that had been pre-treated with chemotherapy. Forty
      six patients were entered into the trial. All had been pre-treated with
      chemotherapy for metastatic disease: 14 with the 'de Gramont' regimen alone, and
      32 with the same regimen combined with irinotecan (CPT-11). The outpatient
      treatment consisted of L-OHP 50 mg/m(2), followed immediately by the 'de Gramont'
      regimen. All drugs were administered on days 1 and 2, every 14 days. Median
      patient age was 65 years (range: 46-78), male/female ratio was 29/17. All 46
      patients were evaluated for response and toxicity. We observed 1 complete
      response (2.2%) and 14 partial responses (30.4%), giving an overall response rate
      of 32.6% (95% CI: 19.5-48.06%); 22 patients had stable disease (47.8%) and 9
      patients progressed (19.6%). After a median follow-up of 13 months, median time
      to progression was 6.4 months (range: 3.1-31.2+), while overall median survival
      was 12.2 months (range: 3.7-31.2+). Toxicity was manageable: grade 3 or 4
      neutropenia was observed in 33% of patients, while only 6% of patients had grade
      1-2 neurotoxicity. The fractionated bimonthly schedule of L-OHP plus 5-FU-L,
      showed activity, with an acceptable toxicity profile, both in patients with MCC
      pre-treated with the 'de Gramont' regimen alone, or with this regimen associated
      with CPT-11.

PMID- 12469147
TI  - Thermoradiotherapy combined with p53 gene therapy of human salivary gland
      adenocarcinoma cell line.
AB  - We report on thermoradiotherapy combined with p53 gene therapy in the human
      salivary gland adenocarcinoma cell line HSG. HSG cells were successfully infected
      at a rate of 62.3% with MOIs of 20 of either AxCAip53 or AxCAiLacZ. The AxCAiLacZ
      did not inhibit the survival of the HSG cells. The survival fractions of AxCAip53
      infected HSG cells were lower than those of the AxCAiLacZ-infected HSG cells, but
      there was no significant difference (p=0.30). AxCAip53 decreased the survival
      rates of thermotherapy (43 degrees C; p=0.084 and 44 degrees C; p=0.18),
      radiotherapy (6 Gy; p=0.20) and thermoradiotherapy (6 Gy plus 43 degrees C;
      p=0.24 and 6 Gy plus 44 degrees C; p=0.96), but there were no significant
      differences. In comparing the survival rates of thermoradiotherapy with those of
      thermotherapy and radiotherapy, thermoradiotherapy, regardless of the combination
      with p53 gene therapy, demonstrated actual survival rates lower than theoretical
      survival rates based on survival rates of thermotherapy multiplied by survival
      rates of radiotherapy. This result indicates that thermoradiotherapy is effective
      in the treatment of HSG cells. Thermoradiotherapy combined with p53 gene therapy
      was the most effective therapy among the combinations of therapies demonstrating
      that thermoradiotherapy combined with p53 gene therapy may be a useful tool in
      the treatment of HSG cells.

PMID- 12469148
TI  - Prognostic factors in patients with squamous oesophageal cancer associated with
      solitary lymph node metastasis after oesophagectomy and extended lymphadenectomy.
AB  - It is not fully understood whether oesophageal cancer, associated with solitary
      lymph node metastasis, is still a local disease or already a systemic one. Among
      283 patients with squamous oesophageal cancer who underwent oesophagectomy and 3
      field lymphadenectomy, 37 patients had single metastasized nodes.
      Clinicopathologic factors, following Japanese Guideline for the Clinical and
      Pathological studies on Carcinoma of the Esophagus, related to survival and pre
      operative predictability of nodal involvement was studied. Five-year survival was
      48%. Initial pattern of recurrence was mostly haematogenous. Among the factors
      related to survival, grade of lymph node metastasis (pN1 vs. pN2, pN3, p=0.006)
      was more closely related than depth of invasion (pT1, pT2 vs. pT3, pT4, p=0.037).
      Five-year survival was 71.7% for pN1 patients, whereas it was 22% for pN2 or pN3
      patients. Of the metastasized nodes 65% were <10 mm, and 27% was <5 mm in the
      maximum diameter. Oesophageal cancer is still a local disease in half of the
      patients with a solitary metastasized node. For these patients, dissection along
      the recurrent laryngeal nerve is necessary to retrieve the node possibly
      metastasized.

PMID- 12469149
TI  - Causes of death and pattern of recurrence after esophagectomy and extended
      lymphadenectomy for squamous cell carcinoma of the thoracic esophagus.
AB  - Improved understanding of how esophageal cancer behaves following curative
      resection, including knowledge of other causes of death, is essential for
      informed decision making. The medical records of 246 consecutive patients with
      squamous cell carcinoma of the thoracic esophagus who had undergone esophagectomy
      and lymphadenectomy of the neck, chest, and abdomen that was deemed
      macroscopically curative, were reviewed. Patients who had had other malignancies
      or anticancer treatment were excluded. Median follow-up period was 1289 days
      (minimum, 730 days). The initial patterns of recurrence were classified as
      intramediastinal, hematogenous, or lymphatic. Forty-two patients died of a cause
      other than recurrence. The in-hospital death rate was 3.6%, and 19 patients died
      of pulmonary disease. Sixteen patients developed a second primary, most of which
      were in the upper aerodigestive tract; five of those patients died. Ninety-eight
      patients developed recurrence. Depth of invasion and number of nodal metastases
      predicted recurrence. The pattern of recurrence was intra-mediastinal, lymphatic,
      and hematogenous in 11, 21, and 67 patients, respectively. The patients with
      lymphatic recurrence survived longer than the patients with either of the other
      types of recurrences. Eighty-three percent of recurrences presented within 24
      months. The time-to-recurrence correlated with survival after recurrence. The
      disease recurred earlier in patients with advanced stage than unadvanced disease
      at the time of esophagectomy. The time-to-recurrence, and anticancer therapy
      after the recurrence related to the survival. Meticulous care must be taken to
      detect hematogenous recurrence as early as possible so that adjuvant therapy may
      be started. Maintaining a good performance status permits the use of aggressive
      therapy should there be a recurrence. Pulmonary physiotherapy and treatment of
      metachronous primary tumors may improve overall survival.

PMID- 12469150
TI  - Vascular endothelial growth factor activating matrix metalloproteinase in ascitic
      fluid during peritoneal dissemination of ovarian cancer.
AB  - The role of vascular endothelial growth factor (VEGF) during peritoneal
      dissemination of ovarian carcinoma and the association with tumor microvessel
      density (MVD) and matrix metalloproteinase (MMP) activity was investigated. To
      this end, MVD, tumor tissue and ascitic fluid levels of VEGF, and MMP activity of
      ascitic fluid were examined in patients with ovarian cancer and benign ovarian
      tumor. The effect of ascites on cell growth, cell invasion activity and
      angiogenesis was investigated in vitro. Ascitic fluid and tumor tissue samples
      were obtained from 15 patients with benign ovarian tumor and 24 patients with
      ovarian carcinoma. Tissue extract and ascitic fluid levels of VEGF were measured
      using enzyme immunoassay. Tumor microvessels were detected immunohistochemically.
      MMP activity was measured by gelatin zymography. For the in vitro experiment, the
      SKOV-3 human ovarian carcinoma cell line was utilized. Cell growth was examined
      using MTT-assay, cell invasion activity was measured by Matrigel in vitro
      invasion assay, and neovascularization was assessed using an angiogenesis kit.
      VEGF levels in tissue extract and ascitic fluid, MVD, expression of active form
      MMP-2 in ascitic fluid and ascites volume were higher in ovarian cancer patients
      than in benign ovarian tumor patients. In addition, these were elevated in stage
      III and IV diseases compared to stage I and II diseases in ovarian cancer
      patients. MVD and expression of active form MMP-2 in ascitic fluid were closely
      correlated with VEGF level in tissue extracts, and MVD and ascites volume were
      closely correlated with VEGF level in ascitic fluid. Cell invasive activity and
      angiogenesis activity increased when cells were exposed to ascites. These
      increases were apparent when exposed to ascites obtained from ovarian cancer
      patients and were related to VEGF concentrations of ascitic fluid and expression
      of active form MMP-2 in ascitic fluid. The increased VEGF secreted from tumor
      cells is suggested to enhance tumor growth through angiogenesis, to produce
      ascites and to elevate ascitic VEGF concentrations and expression of active form
      MMP-2. The progression of peritoneal involvement may be induced by elevated VEGF
      and expression of active form MMP-2, followed by increased VEGF in the primary
      tumor. Control of VEGF in the primary tumor may become an effective strategy
      against peritoneal dissemination of ovarian carcinoma.

PMID- 12469151
TI  - Tamoxifen-induced non-alcoholic steatohepatitis in patients with breast cancer:
      determination of a suitable biopsy site for diagnosis.
AB  - We have evaluated the distribution of fatty infiltration in the liver for
      determination of a suitable biopsy site for diagnosis of tamoxifen-induced non
      alcoholic steatohepatitis (NASH) in patients with breast cancer. Thirty-eight
      consecutive breast cancer patients undergoing tamoxifen treatment were analyzed
      by CT to identify hepatic steatosis (HS) via calculation of the liver/spleen CT
      ratio in Couinaud's 8 areas. We defined hepatic fatty infiltration as a
      liver/spleen ratio of less than 0.9. The extent and distribution of the fatty
      infiltration was assessed using the liver/spleen ratio of the patients who had
      the lowest CT ratio below 0.9 in the 8 areas. Thirteen (34.2%) of the 38 patients
      had hepatic fatty infiltration. The liver/spleen ratios of each area differed
      significantly in all patients (p<0.0001). The CT ratio of these 13 patients was
      significantly lower in the right lobe than the left lobe (p<0.0001), although the
      ratios did not differ significantly among the 4 areas of the right lobe (p=0.52).
      Needle biopsy for diagnosis of NASH should be performed at the right lobe, which
      contains significantly more infiltrated fat than the left lobe in the liver.

PMID- 12469152
TI  - Induction chemotherapy followed by radiotherapy in the treatment of anal cancer.
AB  - This study was conducted to investigate the efficacy of the induction
      chemotherapy followed by radiotherapy in anal cancer. Twenty-three patients
      diagnosed with anal cancer between March 1991 and February 1999 were treated with
      induction chemotherapy with 5-fluorouracil based regimens followed by external
      beam radiation. After a median follow-up of 78 months, the overall survival and
      the disease-free survival at 5 years was 71.3 and 67.5%, respectively. The
      colostomy-free survival at 5 years was 91%, as the inguinal lymph nodes were the
      most frequent site of relapse. Serious side effects did not occur and late
      complications did not develop either. Induction chemotherapy followed by
      radiotherapy in patients with anal cancer is effective in terms of its response
      and preserving the anal sphincter without serious acute and late complications.

PMID- 12469153
TI  - Detection of occult tumor cells in peripheral blood from patients with small cell
      lung cancer by promoter methylation and silencing of the retinoic acid receptor
      beta.
AB  - In order to investigate the possibility of detecting occult tumor cells of small
      cell lung cancer (SCLC), we used the methylation-specific PCR assay to detect
      methylation of retinoic acid receptor-beta (RARbeta) in peripheral mononuclear
      cells (PMNC). The methylation-specific PCR assay can detect one tumor cell per
      10(3) normal cells. Seventy-two patients participated in this study. They
      received an initial full-dose of combination chemotherapy for SCLC between
      October 1995 and June 2000. The patients were classified according to the
      clinical stage of their tumors as limited disease (LD) in 31 patients and
      extensive disease (ED) in 41. PMNC were obtained before each patient underwent
      chemotherapy. We detected RARbeta methylation in PMNC from 42 of the 72 SCLC
      patients (58.3%). Nineteen of 31 patients with LD-SCLC (61.3%) and 23 of 41
      patients with ED-SCLC (56.1%) were positive for RARbeta methylation. The overall
      survival for patients who were positive and negative for RARbeta methylation was
      not significantly different in both the LD- and ED-SCLC groups (log-rank test,
      p=0.13 and p=0.38, respectively); however, 2-year survival was significantly
      greater in the RARbeta methylation-positive LD-SCLC patients (chi(2) test,
      p=0.044). In conclusion, occult tumor cells can be detected in the peripheral
      blood of patients with SCLC using methylation of RARbeta, and long-term survival
      appears to be better in LD-SCLC patients with occult tumor cells in their blood.

PMID- 12469154
TI  - Differential effects of two fluorouracil administration regimens for colorectal
      cancer.
AB  - Mechanisms of anti-tumor action of 5-fluorouracil (5-FU) are presumed to inhibit
      DNA synthesis and RNA function, and the balance of these mechanisms is presumed
      to depend on the modalities of administration. On the other hand, variability of
      5-FU sensitivity of the tumors is also presumed to depend on the enzymes of 5-FU
      metabolism (e.g. dihydropyrimidine dehydrogenase; DPD, rate limiting enzyme of
      catabolism) and action target (e.g. thymidylate synthase; TS). We studied the
      effects of modalities of administration and enzyme activities related to
      metabolism and target of 5-FU on the mechanism of anti-tumor action in patients
      with colorectal cancer. Thirty-eight patients who were diagnosed at stage II to
      IV preoperatively were enrolled. Patients were randomly assigned to receive 24-h
      protracted IV infusion of 5-FU at 320 mg/m(2)/day for 5 days (CIV group: 18
      patients) or 10-min bolus IV infusion of 5-FU at the same dosage for 5 days (BIV
      group: 20 patients) administered from the 5th preoperative day. Specimens from
      the tumor and non-tumor regions were obtained by operation. F-RNA (fraudulent
      RNA, or 5-FU in RNA) concentration, an indicator for action of 5-FU to RNA, and
      the enzyme activities of DPD and TS, an indicator for action of 5-FU to DNA, in
      the collected specimens were measured by GC-MS or RI-HPLC. F-RNA concentration
      (ng/mg-RNA) in the tumor and non-tumor region in the CIV group was 100.58+/-16.88
      and 50.11+/-6.03, respectively, with a significant difference between them
      (P<0.05), and in the tumor and non-tumor region in the BIV group was 195.32+/
      16.26 and 121.05+/-10.62, respectively, with a significant difference between
      them (P<0.01). F-RNA concentration in the tumor and non-tumor regions in the BIV
      group was significantly higher than those in the CIV group (P<0.05). DPD activity
      and TS activity were not significantly different between the CIV and the BIV
      groups in the tumor and non-tumor region, respectively. F-RNA concentration was
      negatively correlated to DPD activity (r=-0.540, P<0.05) in the tumor region in
      the CIV group. F-RNA was not correlated to DPD activity in the non-tumor region
      in the CIV group or in the tumor and non-tumor region in the BIV group. F-RNA was
      not correlated to TS activity in the tumor or non-tumor region of the two groups.
      DPD activity was not correlated to TS activity in the tumor or non-tumor region
      of the two groups. BIV inhibited RNA function more potently than CIV and this was
      not dependent on TS or DPD activity. As for the inhibition of DNA synthesis,
      other indicators should be considered further.

PMID- 12469155
TI  - Measurement of serum thymidine phosphorylase levels by highly sensitive enzyme
      linked immunosorbent assay in gastric cancer.
AB  - Thymidine phosphorylase (TP) is an enzyme that converts 5'-DFUR to 5-FU and also
      acts as an angiogenic factor. Measurement of serum TP levels has recently become
      possible by highly sensitive enzyme-linked immunosorbent assay (ELISA). We
      examined 38 patients with gastric adenocarcinoma to measure serum TP levels by
      highly sensitive ELISA method and tissue TP levels by conventional ELISA. In
      addition, immunohistochemical staining of normal and cancer tissues was also
      performed. Serum TP levels in patients with stages III and IV and inoperable or
      recurrent cancer were significantly higher than those in healthy controls. A high
      correlation was found between serum TP levels and tumor TP levels (r=0.65,
      p<0.0001). Moreover, serum TP levels were about 1/2500 of tumor TP levels. Tissue
      TP values in tumor were significantly higher than those in normal tissue. On the
      other hand, no significant differences among the cancer stages were found in
      either serum or tumor tissue. In conclusion, we demonstrate that serum TP levels
      strongly reflect tumor TP levels, and it may predict clinicopathological factors,
      prognosis, or sensitivity of anti-cancer drugs.

PMID- 12469156
TI  - Prognostic value of Bcl-2 in invasive breast cancer receiving chemotherapy and
      endocrine therapy.
AB  - Apoptosis induced by anticancer agents is a mechanism of treatment activity,
      overexpression of antiapoptotic genes could produce drug resistant tumors. We
      have demonstrated that the susceptibility of Bcl-2-negative tumors to a series of
      anticancer drugs was significantly higher than that of Bcl-2-positive tumors. The
      purpose of this study was to examine if negative Bcl-2 expression has treatment
      benefit in breast cancer patients received chemotherapy and endocrine treatment.
      A cohort of 147 Japanese women with invasive ductal carcinoma was studied. All
      the patients received postoperative adjuvant therapy consisting of combination
      chemotherapy with cyclophosphamide, epirubicin, and fluorouracil, and tamoxifen
      therapy. The expression of Bcl-2, estrogen receptor (ER) and MIB-1 was evaluated
      in breast cancer surgical specimens. Bcl-2 immunostaining was inversely
      correlated with increasing histologic grade (p=0.0095) and MIB-1 (p=0.0128).
      Furthermore, a positive correlation between Bcl-2 and ER was observed (p<0.0001).
      Unexpectedly, survival curves determined by the Kaplan-Meier method and
      univariate analysis demonstrated that Bcl-2-positivity was associated with
      favorable prognosis (p=0.0430). Cox proportional hazard model demonstrated that
      positive Bcl-2 expression still has favorable survival (p=0.0242) after
      consideration of other prognostic factors. Our results imply that Bcl-2 is a
      significant favorable prognostic factor for breast cancer with chemotherapy and
      endocrine therapy.

PMID- 12469157
TI  - Clinical usefulness of macrophage colony-stimulating factor for ovarian cancers:
      Long-term prognosis after five years.
AB  - We performed a randomized double blind study between 1992 and 1995 in which 214
      patients with FIGO stage I to III ovarian cancers received administration of
      10(6) units (low dose group) or 8x10(6) units (high dose group) of macrophage
      colony-stimulating factor (M-CSF) after cyclophosphamide/adriamycin/cisplatin
      (CAP) therapy. The period required to finish a set of intensive chemotherapy,
      which was the primary endpoint, was significantly shortened (p=0.0004), and the
      incidence of febrile neutropenia significantly decreased (p=0.04). In this study,
      we followed the patients for a prolonged period. The patients were divided into
      two groups: patients with complete tumor excision and those with incomplete
      excision, then the relapse rate and survival rate 5 years after initiation of the
      clinical study were compared. The relapse rate tended to be lower in the high
      dose group than in the low dose group in patients with no residual tumor
      (p=0.0750). However, there was no difference in the relapse rate between the two
      dose groups in patients with residual tumor. Although there were no significant
      differences in the survival rate between the high and low dose groups in patients
      with or without residual tumor, the survival rate in mucinous adenocarcinoma
      patients with no residual tumor was 64.3% in the low dose group (n=14) and 92.3%
      in the high dose group (n=14), showing a significantly higher rate (p=0.0436),
      and the survival rate tended to be higher in the high dose group in patients with
      serous adenocarcinoma (p=0.0786). Furthermore, in patients aged 40 years or
      younger with no residual tumor, the survival rates were 73.9 and 100% in the low
      and high dose groups, respectively, showing a significantly higher rate in the
      high dose group (p=0.0310). Our results suggest that administration of M-CSF can
      improve the long-term prognosis of ovarian cancer patients with no residual
      tumor, but further prospective randomized trials with a primary endpoint of
      relapse-preventing effect are needed.

PMID- 12469158
TI  - Risk of thyroid cancer and high prevalence of hepatitis C virus.
AB  - Some studies report an increased risk of autoimmune thyroid disease in hepatitis
      C and B as well as in interferon therapy. Recently a new link between HCV and
      papillary thyroid cancer has been published. The mechanism responsible for the
      oncogenetic role of HCV is not well understood, but it involves immunity system
      and autoimmunity disorders. We designed a case-control study on HCV exposure. To
      assess the positivity to HCV ELISA test and polymerize chain reaction technique
      (PCR) were used. For statistical analysis an odds ratio and corresponding 95%
      confidence intervals were computed using unconditional multiple-logistic
      regression models. Our findings show a statistically significant association
      between HCV and papillary thyroid cancer (OR = 3.3, 95% CI 1.5-7.4, p=0.003),
      overall in female gender (OR = 3.3, 95% CI 1.2-8.7, p=0.01) and in the > or =50
      years age category the risk for thyroid cancer was confirmed by the OR = 3.2 (95%
      CI 1.3-7.9, p=0.01). Based on our study there is an association between HCV and
      thyroid cancer and it is more readily detectable in countries with a high
      prevalence of HCV.

PMID- 12469159
TI  - Expression of cyclin D1 but not of cyclin E is an indicator of poor prognosis in
      small adenocarcinomas of the lung.
AB  - We investigated the significance of cyclin D1 and cyclin E expression in resected
      tumors on the survival of patients with small adenocarcinomas of the lung.
      Seventy-two patients with resected tumors <2 cm in diameter and of pathological
      stage I were entered into the study. There were 29 males and 43 females, with a
      median age of 64 years (range 26-83 years). The patients underwent curative
      surgical resection for lung cancer between July 1992 and November 1999. The
      resected tumors were subjected to immunostaining for cyclin D1 and cyclin E
      expression. Twenty-six patients had tumors with >20% cyclin D1-positive cells,
      but only 1 patient had a tumor with >20% cyclin E-positive cells. When the
      survival of 72 patients was compared in relation to their oncogene expression,
      the overall survival of patients with positive expression of cyclin D1 was
      significantly worse than that of individuals whose tumors had negative expression
      of the gene (log-rank test p=0.0049). Increased expression of cyclin D1 but not
      of cyclin E is an indicator of poor prognosis in patients with small
      adenocarcinomas of the lung.

PMID- 12469160
TI  - Cyclin D1 expression and patient outcome after tamoxifen therapy in estrogen
      receptor positive metastatic breast cancer.
AB  - Cyclin D1 expression is closely related with ER status in breast cancer. We
      executed this study to evaluate whether therapeutic response to tamoxifen varies
      with levels of cyclin D1 expression in 66 ER positive breast cancer patients
      having solitary bone metastasis. Treatment response to tamoxifen and correlation
      between cyclin D1 expression and biologic data of the patients were analyzed.
      Cyclin D1 expression was detected in 46 patients (69.7%) and significantly
      reduced in poorly differentiated cancer (p=0.023). Patients with cyclin D1
      expressing tumors showed better response to tamoxifen but the difference was not
      statistically significant. Cyclin D1 expression was associated with
      differentiation of the breast cancer but not useful in discriminating a good
      responder to tamoxifen treatment.

PMID- 12469161
TI  - Feasibility and therapeutic efficacy of weekly 1-h low-dose paclitaxel infusion
      for relapsed breast cancer.
AB  - The therapeutic efficacy of weekly paclitaxel infusion for relapsed breast cancer
      patients is not known. We assessed safety, feasibility, and therapeutic efficacy
      in a pilot study of weekly 1-h low-dose paclitaxel infusion for relapsed breast
      cancer in an outpatient clinic. Eighteen patients with relapsed breast cancer who
      had received prior chemotherapy regimens, including anthracyclines, mitomycin,
      and 5-fluorouracil beyond a second line of treatment were enrolled into the
      study. The dose of paclitaxel was between 40 mg/m(2) and 80 mg/m(2) per week in a
      1-h infusion, and a treatment cycle was 4 weeks until there was no evidence of
      progressive disease. When a dose of 80 mg/m(2) was administered, the treatment
      cycle was weekly infusion three times with a 1-week interval per 4-week cycle.
      The mean treatment period was 5.5 months and the maximal length of administration
      was 8 months. The overall response rate was 44.4%, including 2 cases of complete
      response and 6 cases of partial response. Tumor response was observed in 3 of 7
      cases of lung metastases (42.8%), 6 of 12 cases of soft tissue metastases
      (50.0%), and 1 of 3 cases of liver metastases (33.3%), whereas 8 cases with bone
      metastases did not respond. The mean time to response was 1.8 months and the mean
      response duration was 4.3 months. The dose between 31.5 mg/m(2)/wk and 79.7
      mg/m(2)/wk was not associated with tumor response. Toxicities associated with
      weekly 1-h low-dose paclitaxel infusion were tolerable, and most were less than
      grade 2, including alopecia (100%), neutropenia (88.8%), flushing (66.6%), face
      edema (61.1%), numbness (55.5%), and myalgia (38.8%). There was 1 case of grade 3
      neutropenia. Weekly 1-h low-dose paclitaxel might be a therapeutically effective,
      safe infusion and feasible as a salvage chemotherapy for relapsed breast cancer
      patients following failure of prior chemotherapy.

PMID- 12469162
TI  - Effect of oral contraceptive on ovarian function in young females undergoing
      neoadjuvant chemotherapy treatment for osteosarcoma.
AB  - We compared the residual ovarian function and the fertility of two groups of
      female patients treated at different times at the authors' institution by
      neoadjuvant chemotherapy for localized osteosarcoma of the extremities. From 1997
      to 2000, one group of 31 females received neoadjuvant treatment according to the
      IOR 6 protocol, which included high-dose ifosfamide, high-dose methotrexate,
      adryamycin, and cis-platinum. In this group of patients an oral contraceptive
      (OC) was given in an attempt to prevent post-chemotherapy ovarian failure.
      Another group of 90 patients was treated between 1974 to 1995 with the same
      antiblastic drugs according to similar protocols (IOR 1-IOR 5). These patients
      did not receive OC or other treatment to protect ovarian function. There were no
      significant differences between the two groups of patients. Early chemotherapy
      induced menopause occurred in 3 out of 19 postpubertal patients who received the
      OC and in 3 out of 71 postpubertal patients in the control group. In the OC group
      there were 2 cases of thrombophlebitis. No delay in menarche was seen in
      prepubertal patients. From statistical evaluation we underline that age and
      alkylant doses are the most important predictive factors for early menopause and
      that oral contraceptives during chemotherapy do not protect ovarian function in
      patients receiving high-dose alkylant based chemotherapy.

PMID- 12469163
TI  - Combination therapy with interferon alpha and beta to chronic hepatitis C.
AB  - To increase the sustained response (SR) rate in chronic hepatitis C (CHC), we
      tried a combination therapy with interferon (IFN) alpha and beta. Fifty patients
      were grouped into 4 groups: group 1H (n=9), HCV serotype 1 and high HCV-RNA titer
      (over 6 log copies/ml); group 1L (n=11), HCV serotype 1 and low HCV-RNA titer
      (less than 6 log copies/ml); group 2H (n=23), HCV serotype 2 and high HCV-RNA
      titer; group 2L (n=7), HCV serotype 2 and low HCV-RNA titer. They were given a
      total dose of 768 MIU which included natural IFN beta (6 MIU) once daily for 28
      consecutive days and then natural IFNalpha (10 MIU) three times a week for 20
      weeks. Forty-nine patients with CHC receiving IFN alpha at total dose of 480 MIU
      served as single therapy group. In combination group, SR rate was achieved in
      62%, 44% in 1H, 45% in 1L, 70% in 2H, and 86% in 2L, respectively. In single
      group, SR rate was achieved in 45, 14, 58, 60, and 82%, respectively. There was
      no significant difference for SR rate between combination group and single group.
      However, in patients with HCV-RNA titer between 6-7 log copies/ml of 1H group, SR
      rate in combination group (67%, 4/6) was significantly higher than that of single
      group (18%, 3/17) (p<0.05). These data suggest the usefulness of combination
      therapy with IFN alpha and beta in CHC with serotype 1 having moderately high HCV
      RNA titer.

PMID- 12469164
TI  - Amifostine as chemoprotectant in metastatic breast cancer patients treated with
      doxorubicin.
AB  - Amifostine has shown to selectively protect normal tissues against cytotoxic and
      mutagenic effects of several anti-neoplastic drugs, such as alkylating agents,
      organoplatinum compounds, anthracyclines, taxanes, and ionising radiation. This
      cytoprotection is broad-spectrum and selective, without loss of therapeutic
      efficacy. In this study we have treated 31 patients affected with inoperable or
      metastatic breast cancer, not previously submitted to chemotherapy for advanced
      disease, with amifostine 910 mg/m(2) followed by doxorubicin 75 mg/m(2). The
      overall response rate was 52% with a median response duration of 13 months (range
      6-53+) and a median overall survival of 21 months (range 3-59+). With regard to
      toxicity, 14 patients (45%) experienced transient g4 neutropenia which was
      febrile only in one case (3%). Grade 3-4 thrombocytopenia was not recorded.
      Nausea and vomiting occurred in 14% of cycles. Grade 3 mucositis was observed in
      only 1 patient, whereas 2 patients (6%) developed an asymptomatic drop of left
      ventricular ejection fraction (LVEF) >10% below basal value. In conclusion, this
      study suggests that amifostine can reduce doxorubicin related toxicity, thus
      improving the patients' quality of life and the efficacy/toxicity ratio of this
      drug.

PMID- 12469165
TI  - P16 hypermethylation contributes to the characterization of gene inactivation
      profiles in primary gastric cancer.
AB  - The objective of this study was to investigate the contribution of p16
      inactivation in gastric cancer and to compare it with p53. A cohort of 34 primary
      GCs were analyzed for p16 mutations and transcriptional silencing of the gene due
      to hypermethylation of the promoter. SSCP analysis and direct sequencing of exons
      1 and 2 of the p16 gene were performed to detect any structural alterations. The
      methylation specific PCR (MSP) assay was applied to reveal hypermethylation of
      the 'CpG' island in the regulatory region using specific primer pairs for
      methylated and unmethylated nucleotides after a chemical reaction converting
      cytosines into uracile when unmethylated. SSCP and direct sequencing analysis did
      not detect any p16 mutations. The MSP assay showed 4 MSP(+) variants (11.8%).
      Three MSP(+) were stage III-IV disease and 1 MSP(+) was detected in an early
      stage disease (IB). All MSP(+) were diffuse type adenocarcinomas. The MSP(+)
      samples were different from previously reported samples harboring p53 mutations
      in the same cohort. These data increase the number of gastric cancers showing
      alterations of either p53 or p16 to 29.4% (10/34). Functional inactivation by
      hypermethylation of the p16 locus and p53 mutations could play a significant,
      complementary role in the pathogenesis of sporadic gastric cancer.

PMID- 12469166
TI  - Types of human papillomavirus revealed in cervical adenocarcinomas after DNA
      sequencing.
AB  - In a collection of 173 cervical adenocarcinomas, the prevalence of HPV in
      relation to the age of women and the distribution of the various oncogenic types
      of HPV were evaluated. The tumour material was analysed by PCR of the HPV L1 gene
      followed by direct DNA sequencing and/or the polymerase chain reaction and single
      strand conformation polymorphism (PCR-SSCP) technique for the identification and
      typing of HPV. In 68% (117/173) of the adenocarcinomas, HPV was present. A
      significant correlation was observed between the prevalence of HPV and age: in
      women younger than 40 years, HPV was present in 88%, whereas in women 60 years
      and older, it was found in only 39% (p<0.001). Among the HPV-positive tumours,
      type 18 predominated (52%) followed by type 16 (35%) and type 45 (7.7%) while
      other oncogenic types of HPV (31 and 59) were rarely found. HPV 16 was relatively
      more frequent in older women but this observation was not significant (p=0.06).
      HPV-typing by PCR and direct DNA sequence analysis is more specific than analysis
      by PCR-SSCP, especially among the less frequently occurring types of HPV. Our
      results further show that the prevalence of HPV in women with cervical
      adenocarcinomas is age-related and that the most frequently occurring types of
      HPV are 18, followed by 16 and 45. We have concluded that the oncogenic role of
      HPV in cervical squamous carcinomas and adenocarcinomas is, in some respects,
      discrepant.

PMID- 12469167
TI  - Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity
      in sarcoma cells.
AB  - More than 80% of patients with extremity sarcoma ultimately develop metastases to
      pulmonary sites. Doxorubicin alone or in combination with other chemotherapeutic
      agents may result in partial or complete tumor response for sarcoma pulmonary
      metastases. Regardless of the response, there has been no proven survival benefit
      from cytotoxic chemotherapy in the treatment of localized or metastatic soft
      tissue sarcoma. Insulin-like growth factor-I receptor (IGF-I-R) activation may
      contribute to resistance to chemotherapy in mesenchymal neoplasia. IGF-I-R
      activation by its ligand decreases in vitro cytotoxic response of sarcoma to
      doxorubicin, the most active agent against soft tissue sarcoma in adults.
      Furthermore, IGF-I-R is frequently overexpressed in soft tissue sarcoma and may
      predict poor response to traditional chemotherapy. The effect of doxorubicin on a
      human soft tissue sarcoma cell derived from a dedifferentiated lung metastasis
      was evaluated using titrated doxorubicin doses with and without exogenous IGF-I
      (100 ng/ml). Western blot analysis was performed to evaluate levels of
      phosphorylated IGF-I-R under control and experimental conditions. In vitro
      proliferation assays were performed. Nuclear activation through IGF-I receptor
      mediated pathways prior to exposing sarcoma cells to doxorubicin altered the
      pattern of response to doxorubicin with enhanced mitogenesis (>2-fold) and
      blunted doxorubicin cytotoxicity (>10% change in IC50). These data suggest that
      activation of IGF-I receptor in sarcoma cells is a potential mechanism for tumor
      resistance to doxorubicin. Inhibition of IGF-I receptor activation represents a
      novel approach to enhance the degree and duration of response to traditional
      chemotherapy against soft tissue sarcoma.

PMID- 12469168
TI  - A phase I trial of weekly docetaxel and cisplatinum combined to concurrent
      hyperfractionated radiotherapy for non-small cell lung cancer and squamous cell
      carcinoma of head and neck.
AB  - We conducted a phase I study to evaluate the activity and tolerability of
      concurrent docetaxel and cisplatinum radiosensitization with hyperfractionated
      irradiation, in patients with advanced non-small cell lung cancer (NSCLC) and
      squamous cell carcinoma of the head and neck (SCCHN). Nine patients (5 stage
      III(A) and 4 III(B)) with NSCLC, and 15 with SCCHN (10 stage III and 5 IV) were
      treated with a b.i.d. hyperfractionated (HF) radiotherapy schedule. The
      normalized total dose for alpha/beta ratio = 10 Gy was 69.6 Gy for NSCLC and 80.5
      Gy for SCCHN patients. The standard dose of cisplatin (10 mg/m(2)) was given
      combined to docetaxel on a weekly basis. The docetaxel starting dose level was 10
      mg/m(2)/week and was escalated by 3 mg/m(2) increments in cohorts of 8 patients
      (5 SCCHN and 3 NSCLC). DLT (grade 3 malaise) was observed in 4 out of 8 patients
      treated at the 16 mg/m(2)/week docetaxel dose level. The 13 mg/m(2)/week
      docetaxel dose level was defined as the MTD causing grade 3 mucositis in 4 out of
      8 patients. In total 4 (17%) patients developed grade 3 neutropenia. G-CSF
      support was given in 1/8, 4/8, and 5/8 patients treated at the 10, 13 and 16
      mg/m(2) docetaxel dose levels respectively. Fatigue was the most common adverse
      event (5/24: 21%) and was responsible for more than 1 week treatment delay in 4
      out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. Nine (3
      NSCLC and 6 SCCHN patients: 37.5%) had treatment delay of 1 week, while 7 (3
      NSCLC and 4 SCCHN: 29%) had delays of 2 weeks for combined chemoradiation
      sequelae. Acute hypersensitivity reactions occurred in 3 (12.5%) patients, and
      grade 3 mucositis in 2/8, 5/8 and 6/8 patients, treated at 10, 13 and 16
      mg/m(2)/week docetaxel dose levels respectively. The overall response rate was
      79% (CI = 63-96%) with 33% and 53% CRs for NSCLC and SCCHN patients respectively.
      There were 3 deaths among 9 NSCLC and 4 among 15 SCCHN patients. Local and/or
      distant disease recurrences were shown in 4 NSCLC and in 6 SCCHN patients; 5
      NSCLC and 9 SCCHN patients are alive with no evidence of tumor progression at 8.5
      months mean follow-up time. Radiosensitization with docetaxel and cisplatin given
      concurrently with HF (b.i.d.) radiotherapy on a weekly basis is a promising
      approach and the recommended dose for further phase II studies is 10 mg/m(2)/week
      for both drugs. The antitumor activity shown was significant in both types of
      tumors. The incorporation of docetaxel in chemoradiotherapy regimens for future
      treatment of squamous cell carcinoma of the lung and head and neck, merits
      evaluation in phase II and III trials.

PMID- 12469169
TI  - Phase II clinical trial of local use of GM-CSF for prevention and treatment of
      chemotherapy- and concomitant chemoradiotherapy-induced severe oral mucositis in
      advanced head and neck cancer patients: an evaluation of effectiveness, safety
      and costs.
AB  - In the present open non-randomized phase II study we looked for effectiveness,
      safety, tolerability and costs of locally applied GM-CSF in preventing or
      treating mucositis in patients receiving chemotherapy or chemoradiotherapy for
      head and neck cancer. In addition to clinical mucositis scoring system, the
      effects of treatment with GM-CSF were evaluated by its impact on patient quality
      of life and by laboratory immunological assays such as serum proinflammatory
      cytokines, IL-2 and leptin. The trial was designed to assess the effectiveness of
      local GM-CSF treatment in two different settings: i) prophylaxis of mucositis;
      ii) treatment of mucositis. Prophylaxis was chosen for chemoradiotherapy
      treatments of high mucosatoxic potential, while curative treatment was reserved
      for chemotherapy or chemoradiotherapy treatments of lesser potential of inducing
      mucositis. From January 1998 to December 2001, 68 patients entered the study. The
      great majority of patients of both groups had head and neck cancer, were stage
      IV, PS ECOG 0-1, were habitual smokers and were treated with chemotherapy and
      concomitant (or sequential) chemoradiotherapy. Forty-six patients were included
      in the 'prophylactic' setting and 22 patients in the 'curative' setting. The main
      findings of our study are: only 50% of patients included in the 'prophylactic'
      setting developed mucositis; the duration of oral mucositis from appearance until
      complete remission was significantly shorter in the 'prophylactic' than in the
      'curative' setting; the mean grade of oral mucositis at baseline, on day 3 of
      therapy and on day 6 of therapy was significantly lower in the 'prophylactic'
      than in the 'curative' setting; 24 (55.82%) patients in the 'prophylactic'
      setting had grade 3/4 oral mucositis at baseline compared to 25 (80.60%) patients
      in the 'curative' setting (p=0.048). Thirteen (30.23%) patients in the
      'prophylactic' setting had grade 3/4 oral mucositis on day 3 of therapy compared
      to 19 (61.29%) patients in the 'curative' setting (p=0.015); 'prophylactic'
      setting was able to shorten grade 3/4 oral mucositis to grade 0/1 more
      effectively than the 'curative' one on day 6 of therapy (p=0.05). The present
      clinical trial is to date by far the largest study assessing the effectiveness of
      topical GM-CSF and it is the first study comparing the efficacy of topical GM-CSF
      in the 'prophylactic' setting, i.e., with the aim to prevent the
      chemoradiotherapy-induced oral mucositis, with that in the 'curative' treatment,
      i.e., the therapy for established oral mucositis. The topical application of GM
      CSF was demonstrated to be effective for oral mucositis induced by chemotherapy
      and chemoradiotherapy regimens. Moreover, the 'prophylactic' setting was
      demonstrated to be more effective than the 'curative' one.

PMID- 12469170
TI  - Characteristics of normal stromal components and their correlation with cancer
      occurrence in human prostate.
AB  - Prostate cancer is one of the most common age-related malignancies. The
      occurrence frequency of prostate cancer is very different according to prostate
      zones. The prostate stroma is an important element in growth and differentiation
      of the normal prostate and also has a close relationship to the occurrence of
      benign prostatic hypertrophy and cancer. We examined 14 cases of normal prostate
      tissues obtained at autopsy and 11 cases of prostate cancer tissues at radical
      prostatectomy specimens with cancers for clarifying the characteristics of
      stromal components in the normal prostate and the correlation between the stroma
      and the occurrence of prostate cancers. Stromal cells, such as smooth muscle
      cells, myofibroblasts and fibroblasts were identified by immunohistochemistry
      (IHC). Connective tissue fibers were detected by Elastica van Gieson and also IHC
      stain. Quantitative analysis of the smooth muscle tissue and connective tissue
      fibers were performed using a computer image analyzer system. In the normal
      prostate, stromal components varied in each zone. Every zone of the prostate
      contained smooth muscle cells, myofibroblasts, fibroblasts and collagen fibers.
      Elastic fibers were clearly visible in the transition zone. Smooth muscle cells
      were the main stromal component but less numerous in the frequent occurrence zone
      (peripheral zone) of prostate cancer (p<0.05). Myofibroblasts and fibroblasts
      were found either in normal or cancer tissues, although a few in number. The
      increase of collagen fibers accompanied decrease of smooth muscle cells as
      prostate cancer grade increased (p<0.05). The characteristics of stromal
      components and their amounts in the normal prostate appear to correlate with a
      distinct predilection for cancer occurrence in the peripheral zone and a weak
      stromal reaction in prostate cancers.

PMID- 12469171
TI  - Diagnostic significance of platelet count and other blood analyses in patients
      with lung cancer.
AB  - The objective of this study was to evaluate the clinical value of an elevated
      platelet count and other routine laboratory tests for predicting malignancy in
      patients with radiologically suspected lung cancer. Platelet count, haemoglobin,
      total leukocyte count, erythrocyte sedimentation rate (ESR) and serum lactate
      dehydrogenase (LDH) were analysed in 126 prospectively admitted patients with
      suspected lung cancer. The patients were divided by pathologic diagnosis into
      those with benign disorders (n=65) and with malignancies (n=61). Patients with
      lung cancer were staged (TNM) and the tumours were classified according to
      histological types (WHO). Thrombocytosis (platelet count >400x10(9)/l) was
      present in 8% (5/65) of patients with benign disease and in 57% (35/61) of
      patients with malignant disease (p<0.00001). The prevalence of thrombocytosis in
      patients with primary lung cancer was 53% (27/51). Elevated platelet count was
      more common in advanced disease (stage III and IV). No difference was observed
      between histological types. The sensitivity of thrombocytosis for predicting
      malignancy was 0.57 and the specificity 0.92. When elevated platelet counts, LDH
      and ESR were combined, a sensitivity of 0.71 and a specificity of 1.00 was
      achieved. The positive and negative predictive values were 1.00 and 0.89,
      respectively. Elevated platelet count is frequently observed in patients with
      lung cancer. When test results of platelet count and other routine blood analyses
      are combined, a high sensitivity and specificity for predicting malignancy can be
      achieved. These tests are clinically useful in the evaluation of patients with
      radiologically suspected lung cancer.

PMID- 12469172
TI  - Detection of CK19, CK20 and EGFR mRNAs in peripheral blood of carcinoma patients:
      correlation with clinical stage of disease.
AB  - Expression of genes such as cytokeratin 19 (CK19), cytokeratin 20 (CK20) and
      epidermal growth factor receptor (EGFR) has been investigated at mRNA level in
      peripheral blood of carcinoma patients to detect the presence of circulating
      tumor cells (CTC). We performed this study because recent literature emphasizes
      that the importance of CK19, 20 and EGFR mRNAs in CTC as prognostic factors
      remains unclear especially for breast, head and neck and colon cancer patients.
      Reverse transcriptase polymerase chain reaction (RT-PCR) followed by Southern
      blot hybridization was performed in blood samples from 47 subjects (12
      colorectal, 15 head and neck and 20 breast carcinoma patients), as well as in 35
      healthy donors. The CK19 expression was found in 36/47 patients (9 colorectal, 9
      head and neck and 18 breast cancer), two patients (one affected by colorectal and
      one by head and neck cancer) were positive for CK20 whereas EGFR was found
      expressed in 9 patients (3 colorectal, 5 head and neck and one breast cancer).
      Seven of 35 and 4/35 healthy donors displayed positivity for the expression of
      CK19 and CK20 genes respectively, whereas no EGFR mRNA was found in this group.
      The correlation of the detection of CTC in peripheral blood with progression of
      the disease in a follow-up period of 40 months did not show any prognostic value
      to the presence of mRNAs of these biomarkers in blood. We believe that research
      should be addressed, at least for breast cancer, to the identification of occult
      metastases in sentinel lymph nodes, such as recently performed in melanoma
      patients.

PMID- 12469173
TI  - Limitations of tissue microarrays in the evaluation of focal alterations of bcl-2
      and p53 in whole mount derived prostate tissues.
AB  - Several investigators have reported the correlation of p53 and bcl-2
      immunoreactivity with post operative prostate specific antigen (PSA) recurrence.
      Focal and or clustered expression is typical for these biomarkers. The purpose of
      this study was to compare the effectiveness of tissue microarrays to detect p53
      and bcl-2 overexpression and their prognostic significance. Tissue microarrays
      (TMA) of 99 patients with mean follow-up of 61 months contained 760 samples from
      241 carcinomas, 431 benign glands, and 88 foci of prostatic intraepithelial
      neoplasia (PIN). Overexpression of p53 was seen in 43.3% of 97 patients, whereas
      bcl-2 overexpression was noted in 23.7% of 97 patients using TMA technology,
      compared to 66.0% and 26.9%, respectively in the corresponding radical
      prostatectomy samples. The tissue microarray technology is a powerful tool to
      study the multifocal and heterogeneous nature of prostate cancer. However, the
      prognostic value of p53 and bcl-2 could not be confirmed using this technology in
      contrast to radical prostatectomy sections. The TMA technique is probably more
      informative and reliable in evaluating the prognostic value of homogeneously
      expressed biomarkers.

PMID- 12469174
TI  - Transcriptional profiling of circulating tumor cells: quantification and cancer
      progression (Review).
AB  - Circulating tumor cells in peripheral blood have been demonstrated to reflect the
      biological characteristics of tumors including the potential for metastasis
      development and tumor recurrence. A number of mRNA markers may feasibly enable
      the detection of circulating tumor cells from virtually all patients with
      different cancer types. Of clinical relevance, quantification of circulating
      tumor cell mRNAs in cancer patients may prove valuable for monitoring disease
      progression and patients' response to treatment, and assessing the risk for
      metastasis or recurrence. With prognostic implications, the quantities of mRNA
      markers in blood could indicate the stage of cancer progression and the need for
      more intensive therapeutic intervention to better the outcome of cancer patients.

PMID- 12469175
TI  - Management of renal angiomyolipoma in patients with tuberous sclerosis complex.
AB  - Renal angiomyolipomas are common in patients with tuberous sclerosis complex
      (TSC), and the risk of severe haemorrhage from these angiomyolipomas can become
      substantial. This case illustrates a potentially life-threatening condition due
      to the development of a large aneurysm within an angiomyolipoma, which was
      discovered within 14 months of her screening renal ultrasound scan. Renal
      arterial embolisation and renal sparing surgery resulted in good recovery. Clear
      guidelines for the screening, surveillance, and treatment of angiomyolipomas in
      patients with TSC are required. This includes the appropriate frequency of
      surveillance for patients in different age groups and at different stages of
      angiomyolipoma development, based on a growing knowledge of the natural history
      of this condition, since growth of renal angiomyolipomas can be rapid and
      asymptomatic. Computed tomography or magnetic resonance imaging may be required
      to demonstrate complications in large lesions, as three ultrasound examinations
      in this patient failed to detect the large aneurysm which had developed.
      Angiogenesis inhibitors could potentially play a role in preventing the
      development of angiomyolipomas, which could improve the prognosis for patients
      with TSC and therefore warrants investigation through phase II/III clinical
      trials.

PMID- 12469176
TI  - Prognostic significance of cell proliferation in human neuroblastoma: comparison
      with other prognostic factors.
AB  - Peripheral neuroblastic tumors (PNT), are heterogeneous neoplasms that include
      neuroblastoma (NB), ganglioneuroblastoma (GNB) and ganglioneuroma (GN) and
      present great biological heterogeneity. There are few reports analyzing PCNA and
      Ki-67 expression in PNT; however, controversy exists concerning the specificity
      of PCNA as a real proliferative marker. The objective of our study was to
      determine which of these cellular proliferation markers is more specific on
      cellular cycle and could contribute with more information on the cell cycle. We
      found that PCNA was expressed in NB unfavourable cases, with MYCN amplification
      and high mitosis-karyorrhexis-index (MKI). Whereas, Ki-67 showed statistical
      significance regarding cases unfavourable with intermediate and high MKI,
      aneuploid and stages 3 and 4. Survival showed that patients with tumor not
      expressing Ki-67 (MIB1) lived longer than those without PCNA (88.93 vs 74.05%).
      We conclude that Ki-67 expression permits reliable detection of the cellular
      proliferation neuroblastoma fraction and provides useful prognostic information
      when associated with other biological factors.

PMID- 12469177
TI  - Auto-immune neutropenia occurring in association with malignant melanoma.
AB  - Neutropenia is frequently observed in the practice of oncology, usually resulting
      from the use of cytotoxic drugs. Less frequently, neutropenia is due to
      infiltration of the bone marrow by malignant disease. Both of these usually cause
      some depletion of all haematopoietic linages. True isolated neutropenia is, in
      contrast, a less frequent phenomenon. We report a case of auto-immune neutropenia
      occurring in a patient with metastatic melanoma, and discuss the differential
      diagnosis and implications for patient management.

PMID- 12469178
TI  - Enkephalin degradating enzymes in pheochromocytoma patients.
AB  - Adrenal gland as a major source of enkephalins on the periphery can be affected
      by a rare adrenal gland tumor, adrenal pheochromocytoma. It has been demonstrated
      that this tumor might be associated with altered concentration of enkephalin-like
      peptides. The effect of these peptides can be either prolonged or abbreviated by
      two neutrophil membrane bound enzymes; aminopeptidase N (APN) and neutral
      endopeptidase (NEP). We assumed that altered enkephalin level in pheochromocytoma
      patients (but not in patients with non-functional adenomas or tumors of different
      origin) might result in differently regulated APN and/or NEP activity. We
      measured APN and NEP activity on surface of neutrophils, level of lipid
      peroxidation (LPO) in plasma and enkephalin concentration in plasma in patients
      with pheochromocytomas, non-functional adenomas, malignant renal tumors and
      healthy controls. Catheholamines and vanyllmandelic acid (VMA) were measured in
      24-h urine of pheochromocytoma patients. NEP and APN activity on neutrophils from
      all pheochromocytoma patients was significantly increased as compared with
      healthy controls, non-functional adenomas and malignant renal tumors. In all
      pheochromocytoma patients NEP activity was reduced almost to the control level
      after surgery. At the same time APN activity was in some patients up- and in
      others down-regulated. In comparison, elevated levels of cateholamines and VMA
      were found after multiple determinations in 6 out of 10 pheochromocytoma
      patients. Although preliminary, this study has shown specifically and
      consistently up-regulated NEP activity on neutrophils from pheochromocytoma
      patients, and uniformly decreased NEP activity in these patients after
      adrenalectomy.

PMID- 12469179
TI  - Chemoprevention of prostate cancer by diet-derived antioxidant agents and
      hormonal manipulation (Review).
AB  - Cancer of the prostate is the most commonly diagnosed solid malignancy and the
      second leading cause of cancer-related death in men living in developed
      countries. With an ageing population, the number of men living with early stages
      of prostate cancer is expected to increase. There is an increasing need to
      prevent the onset of cancer or delay the progression of carcinogenesis in this
      organ. Chemoprevention is the administration of pharmacological agents to
      prevent, delay or reverse carcinogenesis. An example is the reversal of high
      grade intraepithelial neoplasia by hormonal manipulation using anti-oestrogens in
      breast carcinogenesis or anti-androgens in prostate carcinogenesis.
      Epidemiological data showing ethnic and geographic variations in the incidence
      of, and mortality from, prostate cancer have suggested that the consumption of
      certain dietary factors, particularly anti-oxidants, may be protective. These
      factors include the vitamins D and E, soy, lycopene and selenium. The
      administration of 5-alpha reductase inhibitors to patients with benign prostatic
      hyperplasia may also constitute a potentially chemopreventive intervention. The
      efficacy of chemopreventive agents needs to be investigated in randomised,
      placebo-controlled trials in suitable cohorts of high-risk individuals. In
      parallel, reliable assays of potential biomarkers of the efficacy of intervention
      need to be developed and validated rigorously.

PMID- 12469180
TI  - Molecular signaling in death receptor and mitochondrial pathways of apoptosis
      (Review).
AB  - In recent years major progress has been made in understanding the molecular steps
      of death receptor and mitochondrial pathway of apoptosis. Mechanisms of NF-kappaB
      mediated survival (anti-apoptotic) signal have been delineated. A novel anti
      apoptotic mechanism of FLIP in the recruitment of RIP and TRAF-1 and TRAF-2 to
      activate ERK and NF-kappaB has been defined. These are some of the recent
      discoveries in death receptor and mitochondrial pathways of apoptosis that have
      been reviewed in this article.

PMID- 12469181
TI  - Cellular signaling pathways affect the function of ribonucleotide reductase mRNA
      binding proteins: mRNA stabilization, drug resistance, and malignancy (Review).
AB  - Ribonucleotide reductase is an enzyme that is essential for DNA synthesis and
      repair. It is composed of 2 dimeric proteins called R1 and R2 that are both
      necessary for enzymatic activity that reduces ribonucleotides to
      deoxyribonucleotides. This is the rate-limiting reaction that provides a supply
      of precursors for DNA synthesis therefore it is essential for cell proliferation.
      The importance of understanding the complex regulation of ribonucleotide
      reductase is emphasized by observations that mechanisms controlling its
      expression and activity may be altered during malignant cell proliferation which
      leads to drug resistance, making it a useful target to develop chemotherapeutic
      compounds in the treatment of cancer. Expression studies with the R1 and R2 genes
      have provided evidence for a direct role for the components of ribonucleotide
      reductase in determining malignant potential. Ribonucleotide reductase is
      regulated by transcriptional activation of gene expression and post
      transcriptional mechanisms that alter mRNA message stability. Post
      transcriptional regulation of mRNA turnover plays an important role in modulating
      mRNA steady state levels and therefore directly influences gene expression. The
      3'-untranslated region (UTR) of R1 and R2 messages contain sequences that are
      important in regulating gene expression through changes in message stability.
      Studies have found that mRNA message stability is mediated by growth factors,
      cytokines and tumor promoters. Several studies have elucidated signal
      transduction pathways of tumor promoters, TGF-beta and oxidation/reduction
      agents. This report reviews how knowledge of these signaling pathways is
      revealing new insights into how ribonucleotide reductase mRNA binding proteins
      are important in regulating cellular proliferation, drug resistance and
      malignancy.

PMID- 12469182
TI  - Constitutive expression of cytotoxic proteases and down-regulation of protease
      inhibitors in LGL leukemia.
AB  - Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder often
      associated with rheumatoid arthritis. The etiology of LGL leukemia is not known.
      In order to better understand the pathogenesis of LGL leukemia, we analyzed
      differential gene expression using microarray technology. We found that
      approximately 80 genes were up-regulated and 12 genes were down-regulated when
      compared to normal peripheral blood mononuclear cells (PBMC). In the present
      study, we were interested in a group of genes involved in cytotoxic function. The
      up-regulated genes involved in cytotoxic function were serine proteinases
      (granzymes A, B, H and K) cysteine proteinases [cathepsin C, cathepsin W
      (lymphopain)], calpain small subunit and caspase-8. In addition, a pore-forming
      protein perforin, was also up-regulated. Northern blot analysis and RNase
      protection assays (RPA) confirmed that these genes were over-expressed in the
      majority of samples from LGL leukemia patients. Of interest, proteolytic
      inhibitors such as cystatin C, A, alpha-1 antitrypsin and metalloproteinase
      inhibitors were down-regulated in leukemic LGL when compared to normal peripheral
      blood mononuclear cells. Importantly, the pattern of gene expression in leukemic
      LGL resembles that seen in activated cytotoxic T cells (CTL).

PMID- 12469183
TI  - Combined deficiency of hMLH1, hMSH2, hMSH3 and hMSH6 is an independent prognostic
      factor in colorectal cancer.
AB  - We examined biological and clinicopathological significance of individual and
      combined hMLH1, hMSH2, hMSH3 and hMSH6 expression with immunohistochemistry in
      301 unselected colorectal cancers. Weak hMLH1 expression was correlated to
      microsatellite instability (P=0.04), negative p53 expression (P=0.005) and
      mucinous carcinomas (P=0.02). Weak hMSH2 expression was related to negative ras
      (P<0.001) and p53 expression (P=0.005), and better survival (P=0.03). hMSH2,
      hMSH3 and hMSH6, as well as hMLH1, hMSH2, hMSH3 and hMSH6, were combined into a
      'functional' and a 'less-functional' group, respectively. Both 'less-functional'
      groups were/tended to be associated with microsatellite instability, negative ras
      and p53 expression, and better survival. In summary, hMLH1 and hMSH2 were more
      important when investigated individually, and the combined groups were more
      related to the mutator pathway, suggesting that combined deficiencies of the
      proteins are more efficiently involved in the mutator pathway. Our result from
      weak versus strong staining may suggest that the intensity of staining should be
      considered in future studies on mismatch repair proteins.

PMID- 12469184
TI  - Role of p53 in G2/M cell cycle arrest and apoptosis in response to gamma
      irradiation in ovarian carcinoma cell lines.
AB  - We investigated the cell cycle and apoptotic response to irradiation in 4 human
      ovarian carcinoma cell lines, i.e., PA-1, Caov-3, SK-OV-3, and ES-2. Cell lines
      were also analysed for their p53 and Bax expression to address the relationship
      with cell cycle and apoptotic response. Apoptosis was examined by flow cytometric
      measurement of annexin V binding and by determination of cytoplasmic histone
      associated DNA fragments with a photometric enzyme immunoassay. Cell cycle
      analyses were performed on the basis of flow cytometry. p53 and Bax protein
      expression was examined by immunocytochemistry in untreated cells and after
      irradiation. p53 cDNA sequencing and a functional yeast-based assay (FASAY) were
      performed to determine the p53 mutational status. All cell lines exhibited a dose
      dependent G2/M arrest. No arrest in G1 was seen. A strong correlation was found
      between the G2/M arrest and the induction of apoptosis. PA-1, the only cell line
      found to express wild-type p53, showed the highest susceptibility to accumulate
      in G2/M and the strongest apoptotic response after irradiation. In this cell line
      irradiation resulted in an unequivocal accumulation of p53 protein and in an
      increased expression of Bax protein. Caov-3, lacking wild-type p53, showed
      upregulation of Bax expression after irradiation. Caov-3 proved to be relative
      sensitive to apoptosis compared to SK-OV-3 and ES-2. These two cell lines were
      found to be p53 mutated in sequence analysis and irradiation had no effect on the
      expression of p53. No change in Bax expression was seen in ES-2, while SK-OV-3
      exhibited decreased Bax protein levels after irradiation. Our data suggest that
      the G2/M arrest is an important component of the pathway leading from irradiation
      induced DNA damage to apoptosis in the examined cell lines. The G2/M arrest and
      associated apoptosis found in the examined cell lines does not necessarily
      require wild-type p53, although wild-type p53 and possibly Bax may contribute to
      a maximum response to irradiation. Two independent mechanisms, p53-dependent and
      p53-independent, are suggested in the examined cell lines.

PMID- 12469185
TI  - Expression of the anti-apoptotic gene survivin in myelodysplastic syndrome.
AB  - Survivin is a member of the inhibitor of apoptosis protein (IAPs) family and
      considered to play a pivotal role in oncogenesis. We present the first report of
      survivin expression profile in myelodysplastic syndrome (MDS). Expression of
      survivin messenger RNA was evaluated by semi-quantitative reverse transcriptase
      polymerase chain reaction (RT-PCR) in patients with MDS and acute myeloid
      leukemia (AML). Eleven out of 12 patients with refractory anemia (RA) (91.6%),
      and all 3 patients with refractory anemia with excess blasts in transformation
      (RAEBt) (100%), were positive for survivin expression with the majority of cases
      showing abundant levels of the survivin transcript. On the other hand, expression
      of survivin was undetectable in the 4 patients with chronic myelomonocytic
      leukemia (CMMoL). The level and frequency of survivin expression in patients with
      refractory anemia were compared to those in patients with AML. Out of 12 patients
      with de novo AML, 5 patients (41.7%) showed detectable levels of survivin
      expression. Abundant survivin expression in RA was also confirmed by
      immunohistochemistry. In contrast, survivin was almost absent in two cases with
      aplastic anemia. We propose that high levels of survivin expression can serve as
      a reliable diagnostic marker of RA in MDS.

PMID- 12469186
TI  - Genetic pathways of 'de novo' colorectal carcinomas with reference to fetal-type
      glycogen phosphorylase positive foci.
AB  - 'De novo' carcinogenesis has been advocated besides 'adenoma carcinoma sequence'
      as another dominant pathway leading to the colorectal carcinoma. Our previous
      study demonstrated that brain (fetal)-type glycogen phosphorylase (BGP) positive
      foci in the transitional mucosa (BGP foci) have frequent p53 mutations and that
      the distribution of BGP foci has a close relationship with the location of 'de
      novo' carcinoma. The aims of the present study were to investigate further
      genetic alterations in the BGP foci and to clarify the mechanism of 'de novo'
      carcinogenesis. Twenty-eight colorectal carcinomas with invasion into submucosa
      or superficial muscularis propria without any adenoma component expressing
      immunoreactive p53 protein were selected from 168 resected specimens.
      Investigations of the p53, K-ras and APC mutations was performed in the BGP foci,
      BGP negative colorectal mucosa and 'de novo' carcinoma using PCR-SSCP and DNA
      squencing. In all 28 cases, immunoreactive BGP was positive in the carcinomas and
      the BGP foci were observed sporadically in the mucosa adjacent to the carcinoma.
      No K-ras mutation was observed in either carcinoma or BGP foci in any of the
      cases. Mutations of p53 and APC were 14 (50.0%) and 9 (32.1%) in 'de novo'
      carcinomas, and 11 (39.3%) and 1 (3.6%) in BGP foci, respectively. Both p53 and
      APC mutations were detected in 8 and 1, p53 mutation alone in 6 and 10, APC
      mutation alone in 1 and 0 out of 28 carcinomas and BGP positive foci,
      respectively. These results suggest that the BGP foci may play a very important
      role in the 'de novo' colorectal carcinogenesis from the frequent genetic
      alterations of p53, and that there may be two major pathways, i.e., the p53-APC
      pathway and the p53 alone pathway, from the chain of genetic alterations between
      BGP foci and 'de novo' carcinoma.

PMID- 12469187
TI  - Clinical significance of the expression of activin A in esophageal carcinoma.
AB  - Activin A is a member of the transforming growth factor beta (TGF-beta)
      superfamily and is a strong differentiation factor of embryonic stem (ES) cells.
      It is unknown whether activin A has any correlation with carcinoma cell
      differentiation. We investigated the expression of activin-betaA (Act-betaA)
      which is a subunit of activin A, its receptor type I and IIb (ActRI, ActRIIb) and
      its inhibitor, inhibin-alpha (Inh-alpha), which is a subunit of inhibin A in
      esophageal carcinoma by reverse transcription polymerase chain reaction (RT-PCR)
      method. Act-betaA was overexpressed in carcinoma tissues significantly (p=0.030).
      On the other hand, Inh-alpha, ActRI and ActRIIb were neither overexpressed, nor
      suppressed. In immunohistochemistry and in situ hybridization analysis, Act-betaA
      expression was mainly derived from carcinoma cells. The mRNA expression of Act
      betaA was not associated with carcinoma cell differentiation but lymph node
      metastasis (n0, 1, 2 vs. n3, 4; p=0.013) and clinical stage (I, II, III vs. IV;
      p=0.026). Moreover, patients with high mRNA expression of Act-betaA had a
      tendency to show poor prognosis compared to those with low mRNA expression
      (p=0.064). The finding indicated that activin A expression might not be
      associated with carcinoma cell differentiation but tumor aggressiveness such as
      lymph node metastasis in esophageal carcinoma.

PMID- 12469188
TI  - Restoration of p53 gene function in 12-O-tetradecanoylphorbor 13-acetate
      resistant human leukemia K562/TPA cells.
AB  - The human leukemia K562 cell line does not express wild-type p53 protein. Due to
      the loss of one p53 allele and an insertion mutation in exon 5 of the other
      allele resulting in a frameshift mutation, K562 cells express a truncated p53
      protein of 148 amino acids. A human leukemia phorbol ester-resistant subline,
      K562/TPA, is cross-resistant to some anticancer agents. A remarkable difference
      in cell cycle progression at G1/S phase was observed in the synchronised K562/TPA
      cells as compared with K562 cells. Southern blot and DNA sequence analysis
      revealed no mutation in exon 5 of the p53 gene in K562/TPA cells. p21Cip1
      expression was also restored in K562/TPA cells confirming that the reversal of
      this p53 gene mutation restored wild-type p53 function in these cells. This is a
      unique report describing reversal of p53 gene mutation by drugs. This was
      associated with the expression of wild-type p53 mRNA and protein in K562/TPA
      cells. The K562/TPA cell line may provide a very useful tool for the
      investigation of the relationship between p53 status and chemosensitization.

PMID- 12469189
TI  - Angiostatin inhibits extracellular HIV-Tat-induced inflammatory angiogenesis.
AB  - The HIV-Tat protein can be released extracellularly where it is able to recruit
      leukocytes and induce angiogenesis. These activities are mediated by the direct
      interaction of Tat with VEGFR2 on endothelial cells and chemokine receptors on
      leukocytes. We have recently shown that angiostatin, an anti-angiogenic peptide
      fragment of plasminogen, is able to inhibit the recruitment of neutrophils
      induced by bacterial fMLP and alpha chemokines both in vitro and in vivo. In vivo
      this was associated with an inhibition of the angiogenic response by angiostatin.
      These observations suggested that angiostatin could be a suitable inhibitor of
      Tat-induced angiogenesis, as it acts on both endothelial and neutrophil at the
      same time. In vitro, chemotaxis assays demonstrated that angiostatin inhibited
      Tat-induced chemotaxis of neutrophils with an inverse bell shaped profile. In
      vivo the injection of matrigel plugs containing Tat or its chemokine-like peptide
      (CysL24-51) caused the infiltration of neutrophils and a strong angiogenic
      response. Angiostatin completely blocked this inflammatory response, inhibiting
      the recruitment of inflammatory and endothelial cells inside the implant. Taken
      together, these results indicate that angiostatin can act as an inhibitor of both
      endothelial and neutrophil recruitment. As these cell types are also the targets
      of extracellularly released Tat, angiostatin could be used to contrast Tat
      associated vasculopathies.

PMID- 12469190
TI  - A matrix metalloproteinase 2 cleavable melittin/avidin conjugate specifically
      targets tumor cells in vitro and in vivo.
AB  - Extracellular matrix breakdown as well as increased expression in cancer cells
      and tumor microvascular endothelial cells make matrix metalloproteinase 2 (MMP2)
      an attractive target for cancer treatment. By taking advantage of MMP2's
      properties, an MMP2 cleavable melittin/avidin conjugate was designed. Melittin
      alone is extremely toxic to cells and induces immediate cell lysis, but becomes
      inactive when coupled with avidin. The incorporation of the MMP2 target sequence
      into the peptide was used as a means for targeting tumor cells. In vitro, the
      melittin/avidin conjugate showed strong cytolytic activity against cancer cells
      with high MMP2 activity; DU 145 prostate cancer cells and SK-OV-3 ovarian cancer
      cells. The conjugate exhibited very little cytolytic activity against normal L
      cells that displayed low MMP2 activity. These data demonstrate the MMP2
      specificity of the melittin/avidin conjugate. In vivo, the size of tumors
      injected with the melittin/avidin conjugate was significantly smaller as compared
      to untreated tumors. Therefore, due to its tumor targeting capabilities as well
      as its cytolytic properties in vitro and in vivo, the melittin/avidin conjugate
      displays the potential for use in cancer therapy.

PMID- 12469191
TI  - Expression of cyclooxygenase-2 and its relationship to p53 accumulation in
      ovarian adenocarcinomas.
AB  - To investigate cyclooxygenase-2 (COX-2) expression and its relationship to p53
      accumulation in ovarian adenocarcinomas, COX-2 and p53 protein expressions were
      examined by immunohistochemistry in 86 ovarian adenocarcinomas and six normal
      ovaries. In addition, COX-2 mRNA expression level was examined by semi
      quantitative PCR in 36 ovarian adenocarcinomas. Neither COX-2 expression nor p53
      accumulation were detected in normal ovarian surface epithelium or germinal
      inclusion cyst epithelial cells. In contrast, COX-2 protein expression was
      detected in 31.4% of adenocarcinomas, and p53 protein accumulation was found in
      30.2% of adenocarcinomas. A significantly higher COX-2 expression rate was
      observed in endometrioid adenocarcinomas than in either mucinous (p=0.019) or
      clear cell (p=0.021) adenocarcinomas, and a significantly higher p53 accumulation
      rate was observed in serous adenocarcinomas compared to clear cell
      adenocarcinomas (p=0.015). p53 accumulation correlated with advanced clinical
      stage (stage I vs. stage II/III/IV: p=0.007), whereas no correlation was found
      between COX-2 expression and clinical stage. There was a significant positive
      correlation between COX-2 expression and p53 accumulation status (p=0.003). Log
      rank testing showed that p53 accumulation was significantly correlated with poor
      patient survival (p=0.004), whereas no correlation was found between COX-2
      expression and survival. COX-2 mRNA expression was detected in 72.2% of ovarian
      adenocarcinomas, and a significant correlation between COX-2 mRNA expression
      status and immunoreactivity (p=0.023) was observed. These results suggest that
      COX-2 expression might play an important role in ovarian cancer development and
      that COX-2 expression in ovarian adenocarcinomas is frequently associated with
      p53 protein accumulation. COX-2 overexpression in ovarian cancer cells might
      partly be caused by dysfunctional p53.

PMID- 12469192
TI  - In vitro inhibition of growth and induction of apoptosis in cancer cell lines by
      thymoquinone.
AB  - Thymoquinone (TQ) is likely responsible for the chemotherapeutic effects of N.
      sativa extract; however, the cellular mechanisms remain ill-defined. TQ-induced
      cytotoxicity was investigated using canine osteosarcoma (COS31), its cisplatin
      resistant variant (COS31/rCDDP), human breast adenocarcinoma (MCF7), human
      ovarian adenocarcinoma (BG-1) and Madin-Darby canine (MDCK) cell lines. TQ
      induced cytotoxicity was determined using a proliferation assay (MTT assay) and
      apoptosis assays. Effects of TQ on the cell cycle were determined using flow
      cytometry. COS31/rCDDP resistant cells were the most sensitive cell line to TQ
      and MDCK cells were the least sensitive. TQ (25 micro M) induced apoptosis of
      COS31 cells 6 h after treatment and decreased the number of COS31 cells in S
      phase and increased cells in G1-phase, indicating cell cycle arrest at G1. These
      results suggest that TQ kills cancer cells by a process that involves apoptosis
      and cell cycle arrest. Non-cancerous cells are relatively resistant to TQ.

PMID- 12469193
TI  - Apoptosis, proliferation, and hormone receptors in endometrial carcinoma: results
      depending on methods of analysis.
AB  - Apoptosis and proliferation were studied in 29 endometrial adenocarcinomas of the
      endometrioid type and characterized by the immunohisto-chemical pattern of
      estrogen receptor (ER) alpha and progesterone receptor (PR) expression.
      Intratumoral heterogeneous distribution of both ER and PR as well as of the
      proliferation marker Ki-67 was studied and quantified. Both density and
      heterogeneity of the two steroid receptors and Ki-67 varied, depending on the
      histological malignancy grade (grades 1-3, or G1-3); interestingly, however, the
      apoptotic index (Ai) was in the same range for all grades. Receptor staining was
      evaluated by three different methods: i) counting the percentage of stained cells
      (staining index), according to stereological principles; ii) the mixed method, a
      combination of the staining index results and ranking staining intensity; and
      iii) a superficial and rapid visual scoring. The three methods gave equal
      results. Apoptotic cells and bodies were generally scattered in the endometrial
      carcinoma but more frequently observed adjacent to necrotic foci. Bcl-2, known as
      anti-apoptotic factor, showed no correlation to apoptotic index, Ki-67
      expression, ER, or PR. Overexpression of p53 was seen in two tumors of grade 3.
      In a detailed study of intra-tumoral microfoci performed on consecutively taken
      tissue sections, a higher staining index of both ER and PR was found in the areas
      of maximal proliferation compared with the areas of minimal proliferation in
      tumors of grades 1-2, but not in G3 tumors. Other covariations were also found
      when non-specified areas were studied. The Ki-67 index was both higher and more
      heterogeneous in G2-3 tumors than in G1 tumors. Our results indicate that there
      is an increasing discrepancy between cell death and cell proliferation with
      progressing tumor grade, which may contribute to the differences in tumor
      aggressivity.

PMID- 12469194
TI  - Determination of the in vivo effects of prednisone on Bcl-2 family protein
      expression in childhood acute lymphoblastic leukemia.
AB  - Glucocorticoid resistance is often associated with treatment failure in children
      with acute lymphoblastic leukaemia (ALL) but the underlying molecular mechanisms
      are still unclear. In 30 consecutive children with ALL treated with prednisone we
      determined changes in the expression of Bcl-2, Bax and Bcl-xl proteins in
      leukemic lymphoblasts and related these to clinical features and rate of
      prednisone-induced apoptosis. The apoptotic index increased after prednisone
      therapy in 24 of the 30 patients. At diagnosis, we detected expression of Bcl-2
      and Bcl-xl protein in 28 samples, while Bax expression protein was detected in 21
      of the 30 patients. Prednisone treatment induced a decrease in Bcl-2 and Bcl-xl
      levels in 17 and 16 of the 28 patients, respectively, while Bax protein increased
      in 14 of the 21 patients. Twenty of the 30 patients studied were considered to be
      good prednisone responders, whereas 10 were poor responders. We observed a
      statistically significant decrease only for Bcl-xl protein expression in T
      phenotype ALL, in the poor responder group and in patients with >20000/mm(3)
      white cell count (WBC) at diagnosis. These data suggest a role of Bcl-xl in the
      mechanisms of protection of leukemic cells from apoptosis induced by
      glucocorticoids (GCs).

PMID- 12469195
TI  - Engagement of PI-3-kinase mediated protein kinase C zeta activation in protecting
      Friend cells from ionizing radiation-induced apoptosis.
AB  - Murine erythroleukemia cells (Friend) respond to ionizing radiation with the
      activation and nuclear translocation of p85alpha subunit of phosphatidylinositol
      3-kinase (PI-3-kinase) which mediates the downstream activation and nuclear
      translocation of atypical Protein kinase C zeta (PKC zeta). This event occurs
      mainly upon high dose of ionizing radiation (15 Gy) and is concomitant to an
      increase in BrdU incorporation, which probably accounts for a predominant repair
      DNA synthesis. Following treatment with wortmannin, a relatively specific
      inhibitor of PI-3-kinase, both an increased number of apoptotic cells and the
      inhibition of protein kinase C zeta translocation were detected. Altogether the
      evidence suggests a potential role of the PI-3-kinase/PKC zeta pathway in
      protecting Friend cells from ionizing radiation-induced apoptosis offering PKC
      zeta for consideration as possible target of pharmacological treatments.

PMID- 12469196
TI  - Protein kinase C-alpha activation by phorbol ester induces secretion of
      gelatinase B/MMP-9 through ERK 1/2 pathway in capillary endothelial cells.
AB  - In the present study, phorbol 12-myristate 13-acetate (PMA) was found to increase
      secretion of matrix metalloproteinase (MMP)-9 and in vitro invasion in bovine
      capillary endothelial (BCE) cells, which were blocked by specific inhibitors of
      protein kinase C (PKC). To elucidate molecular mechanisms involved, we studied
      the effect of PMA on the activation of mitogen activated protein kinases (MAPKs),
      and found that PMA activated extracellular signal-regulated kinase (ERK)1/2 and
      PD98059, a specific inhibitor of MAPK kinase, significantly reduced PMA-induced
      MMP-9 secretion as well as in vitro invasion of BCE cells. Treatment of safingol,
      a specific PKC-alpha inhibitor, and introduction of antisense PKC-alpha into
      these cells reduced the secretion of MMP-9 and activation of ERK1/2 by PMA.
      Furthermore, we employed adenoviral PKC-alpha and found that weak PMA stimulation
      (5 ng/ml) enhanced ERK1/2 activation and MMP-9 secretion in these cells.
      Therefore, we strongly suggest that PKC-alpha, partly at least, have a crucial
      role in MMP-9 secretion and invasion of BCE cells which are mediated via ERK1/2
      signaling pathway.

PMID- 12469197
TI  - Preliminary analysis of azoxymethane induced colon tumors in inbred mice commonly
      used as transgenic/knockout progenitors.
AB  - Azoxymethane (AOM) is a colon carcinogen that is used to study the pathogenesis
      of sporadic colorectal cancer. We have evaluated differential susceptibility to
      AOM in inbred mice used as progenitors of recombinant/transgenic lines. In
      experiment 1, male FVB/N, 129/SvJ, C57Bl/6J mice were treated i.p. with 10 mg/kg
      AOM once per week for 4 weeks and sacrificed after 20 weeks. Only AOM-treated
      FVB/N mice developed tumors (3.6 tumors/mouse) in distal colon. In experiment 2,
      A/J, AKR/J, Balb/CJ mice were treated with AOM for 6 weeks and sacrificed after
      24 weeks. AOM-treated A/J and Balb/CJ mice developed 9.2 and 1 tumor/mouse,
      respectively. Despite these differences, tumors had similar morphology regardless
      of strain. Immunohistochemistry with beta-catenin resulted in marked nuclear and
      cytoplasmic staining of tumor cells in FVB/N. However, fainter and heterogeneous
      beta-catenin staining was observed in A/J tumors, suggesting distinct pathways of
      tumorigenesis in different strains. Irrespective of cytological features of
      malignancy, tumor cells rarely breached the muscularis mucosa and showed no
      evidence of distant metastasis. Lack of invasiveness and metastasis in even the
      most sensitive strains provides a model system for studying the potential role of
      'metastasis genes' in imparting a malignant phenotype.

PMID- 12469199
TI  - Quercetin regulates growth of Ishikawa cells through the suppression of EGF and
      cyclin D1.
AB  - Quercetin and other polyphenols have anti-carcinogenic and anti-tumorigenic
      activity in various organs, however, studies of this activity are lacking in
      endometrial cancer. We hypothesize that quercetin has anti-proliferative activity
      and the mechanisms of quercetin action may be through modulation of cell cycle
      and cell growth regulatory genes. To test this hypothesis, we treated endometrial
      cancer cells (Ishikawa cell line) with quercetin, and cell proliferation,
      expression of growth signal genes (EGF, VEGF, and TGF-alpha), cell cycle genes
      (p53, p21, p73, and cyclin D1), and apoptosis-related genes (bcl-2 and bax) were
      analyzed. Results of these experiments demonstrate that after a 7-day exposure to
      1, 10 and 100 micro M of quercetin, growth of Ishikawa cells was inhibited by 3,
      51 and 87%, respectively. The gene and protein expression data suggest that
      quercetin treatment (100 micro M) significantly decreased EGF and cyclin D1,
      whereas VEGF was up-regulated in Ishiwaka cell lines. Other genes such as TGF
      alpha, p53, p21, p73, bcl-2 and bax were not significantly changed with quercetin
      treatment in Ishiwaka cell lines. The present study suggests that quercetin can
      suppress proliferation of Ishikawa cells through down-regulation of EGF and
      cyclin D1.

PMID- 12469198
TI  - N-phenethyl-2-phenylacetamide isolated from Xenorhabdus nematophilus induces
      apoptosis through caspase activation and calpain-mediated Bax cleavage in U937
      cells.
AB  - The present study was designed to assess the mechanism of N-phenethyl-2
      phenylacetamide (NPPA), one of three new compounds isolated from Xenorhabdus
      nematophilus, on the induction of apoptosis in U937 cells. NPPA displayed strong
      inhibitory effects on cell proliferation and viability of U937 cells and induced
      apoptosis. Investigation of the mechanism of NPPA-induced apoptosis revealed that
      treatment with NPPA produced morphological features of apoptosis and DNA
      fragmentation. This was associated with caspase-3 activation and cleavage of
      poly(ADP-ribose) polymerase. U937 cells treated with NPPA demonstrated cytochrome
      c accumulation in the cytosol during apoptosis induction. Pretreatment of cells
      with the pan-caspase inhibitor (z-VAD-fmk) prevented NPPA-induced apoptosis.
      These results suggested that NPPA induces apoptosis through cytochrome c
      dependent caspase-3 activation in U937 cells. In late stage of apoptosis, 18 kDa
      fragment of Bax was generated with the down-regulation of the expressions of XIAP
      following NPPA treatment, suggesting that the modulation of Bax and XIAP proteins
      plays some roles in NPPA-mediated apoptosis. Pretreatments of z-VAD-fmk and the
      calpain inhibitor, calpeptin, inhibited Bax cleavage. Pretreatment of z-VAD-fmk
      restored the expression level of XIAP, but pretreatment of calpeptin did not.
      These results suggest that the elevated caspase activities cleave XIAP in this
      experiment. And Bcl-2 over-expression attenuates NPPA-induced apoptosis by
      inhibiting caspase-3 activation, and subsequently inhibits calpain autolysis and
      Bax cleavage. These results suggested that Bax cleavage is mediated by calpain,
      and calpain activation may be caspase-dependent. Taken together, the apoptotic
      effects of NPPA may be related, in part to the caspase-3 activation, the down
      regulation of XIAP, and Bax cleavage mediated by caspase-dependent calpain
      activation.

PMID- 12469200
TI  - Expression of angiogenic factors including VEGFs and the effects of hypoxia and
      thalidomide on human myeloma cells.
AB  - Angiogenic factors are major causes of tumor progression in hematological
      malignancies, particularly multiple myeloma, as well as solid tumors. The
      introduction of thalidomide as an anti-angiogenic agent in myeloma treatment has
      demonstrated the importance of angiogenic factors in the progression of myeloma.
      However, the direct effects of angiogenic factors, particularly VEGFs, hypoxia,
      and thalidomide, on myeloma cells are not been documented. In this study, we
      demonstrate increased expression and production levels of VEGF in myeloma
      compared to non-myelomatous hematological lines, resistance to hypoxia and
      enhancement of VEGF-A production by hypoxia in myeloma, and direct growth
      inhibition of myeloma cells due to apoptosis and G1 arrest caused by TNFalpha
      upregulation induced by thalidomide. These findings may encourage the clinical
      use of anti-angiogenic agents for their cytostatic effects and the prevention of
      progression.

PMID- 12469201
TI  - Profiling of gene expression associated with hepatolithiasis by complementary DNA
      expression array.
AB  - By use of cDNA expression array method, we compared the expression profiles of
      genes in hepatolithiasis tissues with those of paired normal tissues. Expression
      of 1176 cancer related genes that include 33 tumor suppressor genes, 100 proto
      oncogenes and 37 DNA damage repair genes were examined in this study. We found
      that expression of tumor suppressor genes and proto-oncogenes was systemically
      activated in hepatholithiasis tissues, suggesting that expression of genes
      controlling cell growth becomes unstable in liver lobe of hepatolithiasis. In
      contrast, expression of DNA damage repair genes were not activated but rather
      remained unchanged in hepatholithiasis tissues, suggesting that repair process is
      not strongly activated but rather impaired in hepatholithiasis tissues.

PMID- 12469202
TI  - Bcl-2 in cancer and normal tissue cells as a prediction marker of response to 5
      fluorouracil.
AB  - Bcl-2 in cancer cells was shown to be a potent indicator of 5-FU efficacy, but
      the protein in normal tissue cells appeared not to be a marker of 5-FU toxicity
      probably due to the functional alteration of Bcl-2 associated with cell
      senescence. Transfection analysis of Bcl-2-S and Bcl-2-AS into A549 lung cancer
      cells revealed that Bcl-2 suppressed cell death induced by 5-FU, and the gene
      expression level of Bcl-2 was closely correlated with the IC50 for 5-FU in 21
      fresh human gastric tumor specimens. Such correlation could not be observed in a
      neonatal human foreskin fibroblast strain, MJ90 (HCA2), and 21 human normal
      tissues adjacent to tumors. Transfection analysis of Bcl-2-S and Bcl-2-AS into
      MJ90 cells showed that Bcl-2 correlated with the resistance to 5-FU in the
      transfectants at PDL60 as in A549 cells, but increased Bcl-2 in the PDL72
      senescent transfectant did not cause an increase of the resistance to 5-FU. Cell
      aging was observed in MJ90 cells and Bcl-2 in the cells was found to decrease
      with the cell senescence. The senescent cells, however, were more resistant to 5
      FU than the younger PDL60 cells having proliferation activity.

PMID- 12469203
TI  - Simian virus 40 and malignant mesothelioma (Review).
AB  - Simian virus 40 (SV40) was recognized as a contaminant of early poliovirus
      vaccines that were provided to millions of individuals in Europe and in the USA
      between 1955 and 1963. SV40, a DNA virus of the family of papovaviridae, was
      proven to be oncogenic in rodents and able to transform human and animal cells in
      vitro. In 1993 SV40 was accidentally discovered to produce mesotheliomas in
      hamsters when it was injected in visceral cavities. Afterwards, SV40 DNA
      sequences were detected with significative frequency in human pleural
      mesotheliomas by using polymerase chain reaction (PCR) and then SV40 DNA
      oncogenicity was associated with its large T antigen (Tag). This finding was
      confirmed by many laboratories, while a few research groups failed to replicate
      these data and argued that the SV40 DNA detection might be a PCR contamination
      artefact. In this review the dispute is examined in the light of recent
      experiments performed to identify molecular and cellular aspects of
      carcinogenicity and/or co-carcinogenicity of SV40 in human mesothelioma.

PMID- 12469204
TI  - Rap1 activity is elevated in malignant astrocytomas independent of tuberous
      sclerosis complex-2 gene expression.
AB  - Increased small GTPase protein mitogenic signaling is common in tumors. We have
      previously demonstrated that sporadic astrocytomas exhibit high levels of
      activated Ras important for tumor growth. Individuals with tuberous sclerosis
      complex (TSC) develop astrocytoma-like tumors resulting from mutations in the
      TSC2 protein, tuberin, which is hypothesized to function as a Rap1 GTPase
      activating protein (GAP). Since we have previously reported that high-grade
      astrocytomas frequently exhibit loss of tuberin expression or increased Rap1
      levels, we sought to determine whether there is a correlation between decreased
      tuberin Rap1-GAP function or Rap1 overexpression and tumor Rap1 activity. In this
      study, we compared levels of Rap1-GTP, Rap1 and tuberin levels in normal brain
      tissue and 24 grade II-IV astrocytoma specimens. Whereas Rap1 overexpression was
      observed in astrocytomas of all malignancy grades, tuberin loss was seen most
      frequently in the higher-grade astrocytomas. In the grade IV glioblastoma
      multiforme tumors, Rap1 activity was 2-3-fold higher than in lower grade or non
      neoplastic brain. However, there was no correlation between tuberin expression or
      Rap1 overexpression and the levels of Rap1 activity in the tumors studied,
      suggesting that the increased Rap1 activation is not the direct result of reduced
      tuberin Rap1-GAP function or elevated Rap1 protein expression.

PMID- 12469205
TI  - Effect of gemcitabine and cis-platinum combinations on ribonucleotide and
      deoxyribonucleotide pools in ovarian cancer cell lines.
AB  - Gemcitabine (dFdC) and cisplatin (CDDP) act synergistically by an increase in
      platinum-DNA adduct formation. Since ribonucleotide (NTP) and deoxyribonucleotide
      (dNTP) levels are essential for DNA-synthesis and repair of DNA damage, we
      investigated whether disturbances might account for differences in effects
      between sensitive and resistant cell lines. The human ovarian cancer cell line
      A2780, its CDDP-resistant variant ADDP and its dFdC-resistant variant AG6000 were
      exposed for 24 h to dFdC or CDDP alone, or a combination causing moderate to
      strong growth inhibition. In AG6000 cells UTP levels were 2-fold lower and in
      ADDP cells almost 2-fold higher than in A2780 cells. Levels of dTTP, dATP and
      dCTP were 2-5-fold lower in the resistant cell lines. Drug treatment affected NTP
      and dNTP levels most pronounced in A2780 cells. dFdC alone, at 1.5 nM to 1 micro
      M increased ATP, GTP and CTP pools 1.2 to 2.0-fold, while 10 micro M dFdC
      increased UTP 2.5-fold. Combination of dFdC and CDDP increased all NTP levels at
      low dFdC and CDDP concentrations more than 1.2-fold, but at 20 micro M CDDP only
      CTP increased 2.4-fold. Only 1.5 nM dFdC increased all dNTP pools more than 1.6
      fold, but at 0.1 and 1 micro M dFdC, dATP and dGTP decreased down to 10-fold,
      while dTTP increased 3-5-fold. CDDP and the combination increased all dNTP pools
      over 1.4 and 1.9-fold, respectively. In AG6000 cells dFdC and CDDP hardly
      affected the NTP and dNTP status, except at the high concentrations, which
      decreased ATP, GTP and UTP levels 1.2-1.8-fold. Both CDDP alone and the
      combination increased dTTP, dCTP and dATP pools up to 1.6-fold. In ADDP cells NTP
      and most dNTP levels were hardly affected, except dGTP levels which decreased to
      non-detectable levels. In conclusion, both dFdC and CDDP induce concentration and
      combination dependent changes in NTP and dNTP pools.

PMID- 12469206
TI  - Expression and regulation of WNT1 in human cancer: up-regulation of WNT1 by beta
      estradiol in MCF-7 cells.
AB  - WNT family of secreted-type glycoproteins play key roles in carcinogenesis and
      embryogenesis. We have cloned and characterized human WNT2B/WNT13, WNT3, WNT3A,
      WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14 and WNT14B/WNT15
      using bioinformatics and cDNA-PCR, and also reported frequent up-regulation of
      WNT2 in primary gastric cancer. Here, expression and regulation of WNT1 in human
      cancer were investigated using cDNA-PCR. WNT1 mRNA was relatively highly
      expressed in OKAJIMA cells (gastric cancer) and BxPC-3 cells (pancreatic cancer).
      Expression of WNT1 mRNA was up-regulated in 5 out of 10 cases of primary gastric
      cancer. Effects of beta-estradiol on expression of human WNT1 in MCF-7 cells
      (breast cancer) was next investigated, because mouse Wnt-1 induces mammary
      carcinogenesis even in estrogen receptor alpha (ERalpha) knockout mice.
      Expression of WNT1 mRNA was significantly up-regulated by beta-estradiol in MCF-7
      cells. WNT1 was found to be one of estrogen target genes in human MCF-7 cells,
      which in part explains Wnt1-induced mammary carcinogenesis in ERalpha knockout
      mice.

PMID- 12469207
TI  - Determination of RNA expression for cholecystokinin/gastrin receptors (CCKA, CCKB
      and CCKC) in human tumors of the central and peripheral nervous system.
AB  - Gastrin (G17) belongs to the cholecystokinin (CCK) peptide family widely
      distributed in the brain, and we were the first to show that it significantly
      modulates the growth and migration features of tumor astyrocytes. Conflictual
      data have been published as to whether CCKA, CCKB and CCKC receptors are, or are
      not, present in tumors of the central and peripheral nervous system (CPNS) in
      general, and in gliomas in particular. In the present study we employed
      polymerase chain reaction (PCR) on a series of 29 CNPS tumors, including 20
      gliomas (17 astrocytic and 3 oligodendroglial tumors), 4 schwannomas and 5
      meningiomas to investigate whether RNAs were present or absent in the case of
      these CCKA, CCKB and CCKC receptors. The presence of the three CCK receptor
      subtypes was also assayed on three experimental models, i.e. the U373 human
      glioma, the C6 rat glioma and the 9L rat gliosarcoma. The data show that 9/20
      (45%) of the gliomas exhibited RNAs for the CCKB receptor as did the C6 rat
      glioma, 13/20 (65%) RNAs for the CCKC receptor as did the U373 human glioma and
      the 9L rat gliosarcoma. Of the 20 gliomas, 17 (85%) expressed RNAs for either the
      CCKB or the CCKC receptor (or both), a feature which was also observed in the
      experimental models. One schwannoma and one meningioma exhibited RNAs for the
      CCKB receptor, while 4/4 schwannomas and 4/5 meningiomas showed RNAs for the CCKC
      receptor. None of the gliomas, schwannomas or meningiomas exhibited RNAs for the
      CCKA receptor, which were found in the 9L rat gliosarcoma model only. These data
      emphasize that 85% of the gliomas under study and 86% (25/29) of the tumors of
      the central and peripheral nervous system exhibited CCKB and/or CCKC receptors.
      This therefore suggests an important role for gastrin in the biological
      development of these tumors.

PMID- 12469208
TI  - Risk estimation of radiation-induced thyroid cancer from treatment of brain
      tumors in adults and children.
AB  - The purpose of this study was to estimate the risk of thyroid cancer induction
      attributable to brain radiation therapy in adult and pediatric patients. An
      anthropomorphic phantom was used to simulate treatment of brain tumors with two
      lateral opposed fields. Thyroid dose was measured using thermoluminescent
      dosimeters. Phantom measurements were performed for all possible field sizes that
      may be applied during brain radiotherapy in adults and children. The dependence
      of the thyroid dose on the distance from the irradiation field and on the
      presence of beam modifiers in the primary beam was investigated. All phantom
      exposures were generated with a 6 MV photon beam. Thyroid dose was found to vary
      from 9.6 to 89.4 cGy and from 8.0 to 194.0 cGy depending upon the field size used
      and the thyroid location in respect to the field edge for adults and children
      respectively. The excess relative risk of thyroid cancer induction for exposed
      children was estimated to be 0.6-14.9. The corresponding excess relative risk for
      adults was 0.1-1.1. The introduction of lead blocks or wedges into the primary
      beam may result in a considerable increase of the risk of thyroid cancer due to
      the increase of the thyroid dose. This study shows that brain radiotherapy during
      childhood may be associated with an increased risk of secondary thyroid cancer
      while the risk in adult patients is much smaller.

PMID- 12469209
TI  - Activation of HTLV-I long terminal repeat by apoptosis inducing agents: mechanism
      and implications for HTLV-I pathogenicity (review).
AB  - HTLV-I is the etiological agent of adult T-cell leukemia (ATL), tropical spastic
      paraparesis/HTLV-I associated myelopathy (TSP/HAM) and certain other clinical
      disorders. After infection in human the virus enters into a latent state, in
      which very low viral gene expression can be detected. On the other hand several
      major characteristics of ATL and TSP/HAM indicate that their genesis requires
      activation of the dormant virus. TSP/HAM is characterized by high virus
      expression, which accounts for most of its immunopathological manifestations,
      whereas the process leading to ATL is believed to be initiated by the viral Tax
      protein, implying that it requires, at least, a temporary activation of the
      latent virus. Data from our and other laboratories suggest that this activation
      may likely be induced by environmental or/and intrinsic apoptosis-inducing
      factors. Moreover, we have demonstrated a mechanistic linkage between the
      activation of the viral promoter and the early stage of the apoptotic cascade.
      However, we have also shown that Tax rescues virus-expressing T-cells from
      apoptotic death. This suggests that Tax protein, emerging after activation of the
      latent virus, can rescue the host cells of the activated virus from the ultimate
      apoptotic death. Since the development of both TSP/HAM and ATL seems to depend on
      the viral Tax protein, we describe a possible system for anti Tax gene-therapy
      approach based on a negative transdominant mutant Tax gene.

PMID- 12469210
TI  - Cardiomyopathy: molecular and immunological aspects (review).
AB  - Idiopathic cardiomyopathy is reviewed from molecular standpoint. About a half of
      all patients with hypertrophic cardiomyopathy show intra-familial occurrence. In
      familial hypertrophic cardiomyopathy, nine gene abnormalities have been
      discovered in the sarcomere, i.e. the genes of beta cardiac myosin heavy chain,
      cardiac troponin T, alpha-tropomyosin, cardiac myosin binding protein-C,
      essential or regulatory myosin light chain, cardac troponin I, alpha-cardiac
      actin, and titin. Sudden death can occur in patients with familial-type
      hypertrophic cardiomyopathy with abnormalities of the cardiac troponin T or
      troponin I gene, even if hypertrophy is not marked. Some cases of familial
      dilated cardiomyopathy show gene abnormalities for cytoskeletal components such
      as desmin and laminin A/C. Mutations of the delta-sarcoglycan gene have also been
      discovered in familial or sporadic dilated cardiomyopathy. Mutations in
      mitochondrial genes have been observed in both hypertrophic and dilated
      cardiomyopathy. It is postulated that chronic viral myocarditis may sometimes
      lead to dilated cardiomyopathy, and hepatitis C virus is also thought to be an
      etiological factor. Immunological abnormalities have also been reported, such as
      autoantibodies against myosin, beta-receptors, ADP/ATP carrier proteins.

PMID- 12469211
TI  - Expression of RANKL and OPG mRNA in periodontal disease: possible involvement in
      bone destruction.
AB  - Periodontitis is a complex, multifactorial process affected by bacterial plaque
      components and host defense mechanisms. Inflammation of the periodontitium may
      lead the destruction of the underlying ligament and alveolar bone. Receptor
      activator of NF-kappaB ligand (RANKL), a novel TNF receptor-related protein is an
      important factor for osteoclast differentiation and activation. Given osteolysis
      by osteoclast has been demonstrated in periodontitis, we hypothesized that RANKL
      expression may be associated with bone destruction in periodontitis. We used semi
      quantitative RT-PCR to compare the gene expression of RANKL and osteoprogerin
      (OPG), a decoy receptor of RANKL, between moderate and advanced periodontitis,
      and healthy subjects. The level of RANKL mRNA was highest in advanced
      periodontitis. In contrast, the level of OPG mRNA in both advanced and moderate
      periodontitis was lower than that in the healthy group. It appears that the ratio
      of RANKL to OPG mRNA in periodontitis has increased. To determine the
      localization of RANKL gene transcripts in gingival tissue at the cellular level,
      in situ hybridization was performed using digoxigenin-labeled specific
      riboprobes. RANKL mRNA was expressed in inflammatory cells, mainly lymphocyte and
      macrophages. In addition, proliferating epithelium in the vicinity of
      inflammatory cells expressed high levels of RANKL mRNA. In short, our data
      suggest that up regulation of RANKL mRNA in both inflammatory cells and
      epithelium may be associated with the activation of osteoclastic bone destruction
      in periodontitis.

PMID- 12469213
TI  - Radiation-induced oxidative DNA damage, 8-oxoguanine, in human peripheral T
      cells.
AB  - The mechanism leading to the high level of radiosensitivity of T lymphocytes has
      not yet been fully described. In our previous study, we demonstrated that human
      peripheral T lymphocytes revealed early apoptotic changes (annexin V-positive)
      and late apoptotic changes (propidium iodide-positive), at 13 and 24 h after
      irradiation of 5 Gy, respectively. Changes in mitochondrial membrane potential
      were observed at 10 h after irradiation of 5 Gy. Subsequently, mitochondrial
      cytochrome c release was confirmed. In order to elucidate the mechanism which
      occurs prior to the mitochondrial membrane potential changes, we examined in the
      present study the radiation dose and the timing of oxidative DNA damage induced
      in human peripheral T lymphocytes following 10 MV X-ray irradiation. As a result,
      the production of 8-oxoguanine, i.e., the product of oxidative DNA damage, was
      clearly identified starting at 10, 6, and 3 h, after 2, 5, and 20 Gy of
      irradiation, respectively. Therefore, we concluded that it remains necessary to
      evaluate the extent of radiation-induced oxidative DNA damage. Furthermore, it is
      important to analyze superoxide radical production and scavenging in terms of the
      variety of radiosensitivities found among various types of normal tissue cells
      and neoplastic cells.

PMID- 12469212
TI  - Protodioscin isolated from fenugreek (Trigonella foenumgraecum L.) induces cell
      death and morphological change indicative of apoptosis in leukemic cell line H
      60, but not in gastric cancer cell line KATO III.
AB  - Protodioscin (PD) was purified from fenugreek (Trigonella foenumgraecum L.) and
      identified by Mass, and 1H- and 13C-NMR. The effects of PD on cell viability in
      human leukemia HL-60 and human stomach cancer KATO III cells were investigated.
      PD displayed strong growth inhibitory effect against HL-60 cells, but weak growth
      inhibitory effect on KATO III cells. Morphological change showing apoptotic
      bodies was observed in the HL-60 cells treated with PD, but not in KATO III cells
      treated with PD. Flow cytometric analysis showed that the hypodiploid nuclei of
      HL-60 cells were increased to 75.2, 96.3, and 100% after a 3-day treatment with
      2.5, 5, and 10 microM PD, respectively. The fragmentation by PD of DNA to
      oligonucleosomal-sized fragments, that is a characteristic of apoptosis, was
      observed to be both concentration- and time-dependent in the HL-60 cells. These
      findings suggest that growth inhibition by PD of HL-60 cells results from the
      induction of apoptosis by this compound in HL-60 cells.

PMID- 12469214
TI  - Vascular endothelial growth factor-C expression in human gallbladder cancer and
      its relationship to lymph node metastasis.
AB  - Lymph node metastasis is a major prognostic factor in human cancer. Vascular
      endothelial growth factor C (VEGF-C) is a lymphangiogenic polypeptide that has
      been implicated in several human solid tumors. However, the clinical significance
      of VEGF-C has remained unknown in gallbladder carcinoma. Paraffin-embedded tumor
      specimens of 52 surgically resected gallbladder cancers were
      immunohistochemically stained for VEGF-C, VEGF, and CD34. The correlations among
      VEGF-C expression, VEGF expression, microvessel density (MVD), clinicopathologic
      features, and clinical outcomes were statistically analyzed. Thirty-three (63%)
      of the 52 gallbladder cancers were highly positive for VEGF-C protein by
      immunohistochemistry. VEGF-C expression was significantly correlated with
      lymphatic vessel involvement, lymph node metastasis, and worse outcomes after
      operation (p<0.001, p<0.001, p<0.001, respectively), but not with MVD. By the Cox
      regression model, lymphatic vessel involvement emerged as an independent
      prognostic parameter. These results suggest that VEGF-C may play a role in tumor
      progression via lymphangiogenesis and lymph node metastasis in human gallbladder
      cancer.

PMID- 12469215
TI  - Lipopolysaccharides from different bacterial sources elicit disparate cytokine
      responses in whole blood assays.
AB  - The stimulatory effects of different purified lipopolysaccharide (LPS)
      preparations from E. coli, S. typhosa, P. aeruginosa, and K. pneumoniae on
      cytokine and chemokine production were measured in whole blood assays by ELISA.
      Incubation of 0.5 ml whole blood with 10 ng/ml E. coli and S. typhosa resulted in
      a time-dependent production of TNF-alpha, IL-1beta, IFN-gamma, IL-10 and MCP-1.
      K. pneumoniae, however, showed preferential effects on IL-1beta, IL-10 and MCP-1
      production with less potent effects on TNF-alpha and IFN-gamma. LPS derived from
      P. aeruginosa showed a similar potency to other LPS preparations on MCP-1
      production, yet completely failed to elicit the production of other cytokines. To
      further investigate potencies of the different LPS preparations, mediator
      production was determined following stimulation with agonist concentrations of
      0.1 ng and 1000 ng per ml over a 24 h time period. Dose-response curves were
      obtained with LPS derived from E. coli, S. typhosa and K. pneumoniae on all
      mediators apart from IL-1beta and MCP-1. Most strikingly though, was the ability
      of LPS derived from P. aeruginosa to selectively elicit a significant dose
      response effect on MCP-1 production, despite its very weak stimulatory effects on
      all other cytokines. These data imply that the bacterial origin of different LPS
      preparations can exhibit disparate effects on inflammatory mediator production.
      Furthermore, the potent, selective dose-response effect of P. aeruginosa LPS on
      MCP-1 production could help to explain the preponderance of a relentless
      inflammatory cellular infiltrate in diseases such as cystic fibrosis (CF).

PMID- 12469216
TI  - The kinesin superfamily protein Rab6KIFL is not involved in the pathophysiology
      of Charcot-Marie-Tooth disease type 4C.
AB  - Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive peripheral
      neuropathy reported in several Algerian families. The gene locus of this disease
      has been narrowed to 5q31-33. Recently, a missense mutation in the gene for the
      kinesin superfamily KIF1B was reported as the cause of Charcot Marie Tooth
      disease type 2A (CMT2A). We suspected that Rab6KIFL, one of the kinesin
      superfamily proteins, might be involved in the pathophysiology of CMT4C, because
      Rab6KIFL gene is located in 5q31. The coding regions of the Rab6KIFL gene of
      genomic DNA derived from one Algerian family with CMT4C were analyzed by direct
      sequencing. No mutation in Rab6KIFL gene was found in this family. Further
      investigation is necessary to identify the causative gene for CMT4C.

PMID- 12469217
TI  - Analysis of the epidermal growth factor receptor promoter: the effect of nuclear
      factor-kappaB.
AB  - The epidermal growth factor receptor gene is highly regulated and responsive to
      extracellular stimuli that control cell growth. We have identified five putative
      nuclear factor-kappaB (NF-kappaB) binding sites within the epidermal growth
      factor receptor (EGFR) promoter region by sequence analysis. We have analyzed the
      potential role of NF-kappaB family members in the regulation of the EGFR
      transcription. Electrophoretic mobility shift analysis demonstrated that the p50
      and p49, subunit proteins of the NF-kappaB, bound to the EGFR promoter at four
      out of five of these sites. However, it was found that NF-kappaB could not
      transactivate the EGFR by cotransfection experiments with each NF-kappaB subunit,
      using p50, p65 and c-Rel and an EGFR promoter luciferase reporter. Treatment of
      cells with tumor necrosis factor (TNF)-alpha, which could degrade the I-kappaB
      and then result in translocation of NF-kappaB to nucleus, did not enhance EGFR
      promoter reporter gene transcription. Also, TNF-alpha did not induce EGFR
      expression at the protein level. These results indicate that even though purified
      NF-kappaB can bind to the putative sites, there is no evidence that NF-kappaB
      transactivates the EGFR promoter region.

PMID- 12469218
TI  - CYP2E1 overexpression up-regulates both non-specific delta-aminolevulinate
      synthase and heme oxygenase-1 in the human hepatoma cell line HLE/2E1.
AB  - Cytochrome P450 (CYP) is known to turn over rapidly both in vivo in the liver,
      and in vitro in cultured hepatoma cells expressing CYP. We examined changes in
      heme metabolism by analyzing gene expression of the non-specific delta
      aminolevulinate synthase (ALAS-N), and heme oxygenase-1 (HO-1), the rate limiting
      enzyme in heme synthesis and catabolism, respectively, in the human hepatoma cell
      line HLE/2E1, in which CYP2E1 was overexpressed by transfection of its expression
      vector. Both ALAS-N mRNA and HO-1 mRNA levels were found to be markedly up
      regulated in HLE/2E1 cells as compared with those in non-transfected cells (HLE),
      or in mock-transfected cells (HLE/MOCK). Treatment of HLE/2E1 cells with
      succinylacetone (SA), a potent inhibitor of delta-aminolevulinate dehydratase and
      thereby heme synthesis, resulted in a further increase in ALAS-N mRNA but a
      decrease in HO-1 mRNA levels. In contrast, treatment of cells with heme, as heme
      arginate, to SA-pretreated HLE/2E1 cells restored both mRNA levels to the
      untreated control level. These findings suggest that the overexpression of CYP2E1
      results in the up-regulation of ALAS-N in order to meet with an increased demand
      for heme synthesis for CYP2E1 formation, while it also results in the up
      regulation of HO-1 presumably by enzyme induction by free heme released from
      CYP2E1, which then results in the elimination of toxic excess free heme and
      ultimately restores the physiologic milieu.

PMID- 12469219
TI  - Uncommon cytidine-homopolymer dimorphism in 5'-UTR of the human otoferlin gene.
AB  - Human otoferlin, homologous to the Caenorhabditis elegans spermatogenesis factor
      FER-1 that was shown to be involved in membrane vesicle fusion, belongs to a
      group of membrane-anchored cytosolic proteins and is found expressed in brain,
      cochlear inner hair cells and vestibular type I sensory cells. Nonsense and
      missense mutations of OTOF lead to an autosomal recessive deafness phenotype
      (DFNB9). We describe here an unusual C-homopolymer dimorphism at position -136 of
      5'-UTR of the OTOF short splice form. Although at first identified within a
      family with a hereditary component of hearing deficiency this C3/C5 dimorphism is
      found frequently in European populations (0.4 for C3, 0.6 for C5) and does not
      segregate with the deafness phenotype. The polymorphic site may become useful for
      studying the origin of different OTOF mutations within various populations, for
      assessing recombination events within large pedigrees as well as founder effects
      and for association studies in further deafness phenotypes.

PMID- 12469220
TI  - Mutation analysis of K-ras and beta-catenin genes related to O6-methylguanin-DNA
      methyltransferase and mismatch repair protein status in human gallbladder
      carcinoma.
AB  - O6-methylguanin-DNA methyltransferase (MGMT) is a DNA repair enzyme that
      transfers methyl groups from O6-methylguanine to itself. Alkylation of DNA at the
      O6 position of guanine is the first step by alkylating agents in inducing DNA
      mutations in an organism. When MGMT and the mismatch repair (MMR) system are
      impaired, O6-methylguanine mispairs with thymine during DNA replication,
      resulting in a G:C right curved arrow A:T transitional mutation in DNA. We
      obtained cancer lesions by manual micro-dissection (MMD) from 26 paraffin
      embedded formalin-fixed gallbladder carcinoma and Laser Capture Micro-dissection
      (LCM) method from 10 fresh frozen specimens. Mutation analysis was performed on
      the micro-dissected samples for K-ras and beta-catenin genes. At codon 12 of the
      K-ras gene, the MMD and LCM methods detected mutations in 3 (11.5%) and 1 (10%)
      case, respectively. In exon 3 of beta-catenin gene, only 1 (3.8%) case revealed a
      mutation in MMD cancer foci. Two cases without MGMT or MMR expression revealed a
      G right curved arrow A transition mutation in the K-ras gene. The findings
      suggested that negative MGMT and MMR status contributed to a G:C right curved
      arrow A:T transitional mutation in the K-ras gene. However, K-ras and beta
      catenin mutations were actually rare in GB carcinoma. Other gene mutations
      frequently occurring in gallbladder carcinoma might be affected by this negative
      MGMT and MMR status.

PMID- 12469221
TI  - MEN 2A families: from hot spots to hot regions.
AB  - The aim of this study was to look for common ancestors among MEN 2A Portuguese
      families presenting with the same germ-line mutation of the RET proto-oncogene.
      To address this question from a genetic point of view, we performed haplotype
      analysis in six out of nine, apparently separate, MEN 2A families using four
      polymorphic markers. Three families carrying the C634R mutation and presenting
      the same phenotype shared the same haplotype surrounding the MEN 2A mutation.
      Moreover, these families were originally from the same geographic region although
      settled at different places along the country. Altogether, data suggested a
      common ancestral MEN 2A chromosome for three families. Since MEN 2A is a rare
      inherited cancer syndrome, identification of common ancestors may draw attention
      for specific geographic regions from where other affected families may arise at a
      higher chance and, therefore, termed 'hot regions'.

PMID- 12469222
TI  - Renin mRNA expression and renal dysfunction in tacrolimus-induced acute
      nephrotoxicity.
AB  - Tacrolimus is a superior immunosuppressive agent and has markedly improved the
      short-term outcome of renal allografts. Despite the beneficial effects of
      maintaining immunotolerance in organ transplant recipients, it has well
      characterized side effects on renal hemodynamics in the early phase. The
      mechanism of tacrolimus-induced acute nephrotoxicity is still unclear. The
      purpose of this study was to elucidate the role of renin-angiotensin system (RAS)
      in tacrolimus-induced acute nephrotoxicity. We examined the renal mRNA levels of
      renin in order to elucidate the relationship between plasma renin activity (PRA)
      and tacrolimus-induced renal dysfunction. Daily administration of tacrolimus (4
      mg/kg/day) for 2 weeks in spontaneously hypertensive rats (SHR) significantly
      increased BUN and plasma creatinine (P-Cr) level, while endogenous creatinine
      clearance (Ccr) significantly decreased in tacrolimus treated rats. Regarding
      tubular function data, fractional excretion of Na (FENa) and fractional excretion
      of K were higher in the tacrolimus treated group. Renin mRNA levels in the renal
      cortex in tacrolimus treated rats significantly increased when compared to the
      vehicle-treated rats. Ccr level was inversely proportional to PRA, with a high
      correlation coeffecient. The rise in PRA significantly correlated with increase
      in FENa by liner regression. Therefore, the results indicate that RAS is involved
      in the tacrolimus-induced acute nephrotoxicity.

PMID- 12469223
TI  - Clinical significance of CEA-mRNA expression in peritoneal lavage fluid from
      patients with gastric cancer.
AB  - Peritoneal dissemination is one of the most common modes of gastric cancer
      recurrence even after curative resection. Cytological examination of peritoneal
      lavage fluid is useful for detection of free cancer cells in the peritoneal
      cavity. However, some patients with negative cytological findings have peritoneal
      metastases of their gastric cancer. The purpose of the present study was to
      investigate the incidence and clinical significance of metastases harbored in the
      peritoneal cavity of patients with gastric carcinoma. Peritoneal lavage fluid was
      collected from the left subphrenic or Douglas cavities of 136 gastric cancer
      patients without macroscopic peritoneal metastases and 31 patients with benign
      disease. Peritoneal lavage fluid was examined by both conventional cytological
      examination (Papanicolaou and Giemsa staining), and carcinoembryonic antigen
      (CEA)-specific reverse transcription-polymerase chain reaction (RT-PCR). Among
      136 gastric cancer patients, 5 patients (3.6%) were positive for free cancer
      cells by cytological examination and 30 (22.1%) were positive by RT-PCR. A
      difference in positivity between the left subphrenic and Douglas cavity was found
      in 18 patients by RT-PCR. The frequency of RT-PCR results increased according to
      lymph node metastases, lymphatic invasion, depth of tumor invasion and stage
      grouping. The incidence of peritoneal recurrence was significantly higher in
      patients with positivity than those with negativity by RT-PCR (p<0.0001). Among
      cytologically negative patients, survival was significantly shorter in patients
      with positive than in those with negative CEA-mRNA expression (p<0.0001). The
      technique of RT-PCR was more sensitive than cytological examination in the
      detection of cancer cells and prediction of peritoneal recurrence. Adjuvant
      therapy may be advisable for the gastric cancer patients with positive findings
      of peritoneal lavage by RT-PCR.

PMID- 12469224
TI  - The relationship among the polymorphisms of SULT1A1, 1A2 and different types of
      cancers in Taiwanese.
AB  - Sulfotransferase (SULT) enzymes play an important role in the detoxification,
      metabolism and bioactivation of numerous xenobiotics, many dietary and
      environmental mutagens, drugs, neurotransmitters and hormones. The genes for
      SULT1A1 and SULT1A2 contain common genetic polymorphisms that are associated with
      individual variations in the level of enzyme activities as well as variations of
      biochemical and physical properties. We developed a PCR-RFLP method to analyze
      the frequencies of SULT1A1 and SULT1A2 alleles among cancerous patients and
      normal controls in Taiwan. The results showed that SULT1A1*1 and SULT1A2*1 were
      in positive linkage disequilibrium. Neither SULT1A1*3 nor SULT1A2*3 were found in
      this study. The frequencies of SULT1A1*2 and SULT1A2*2 for hepatic, colon, lung,
      oral, gastric, renal and cervical cancerous patients were 3.95, 5.56, 4.92, 3.84,
      2.70, 7.41 and 4.50%, respectively. No statistical significance was found for
      these cancer patients after comparison with normal controls (4.0%) for the
      allelic frequencies of SULT1A1*2 and SULT1A2*2.

PMID- 12469225
TI  - Effect of IL-1beta, TNF-alpha and IL-4 on complement regulatory protein mRNA
      expression in human articular chondrocytes.
AB  - Most of the cells possess complement regulatory proteins (CRPs) that protect them
      against complement-mediated damage. In our previous work we revealed that human
      articular chondrocytes express CPRs. Moreover, increase of CRPs expression after
      treatment of chondrocytes with proinflammatory cytokines IL-1beta and TNF-alpha
      has been demonstrated by ELISA technique. Chondroprotective cytokine IL-4
      stimulated expression of CD46 only. In this work RT-PCR technique was used to
      evaluate the expression of mRNA of cell surface CPRs in cultured isolated
      articular human chondrocytes after treatment with IL-1beta, TNF-alpha and IL-4.
      Chondrocytes stimulated with IL-1beta and TNF-alpha showed augmented levels of
      CD46, CD55 and CD59 mRNA. Treatment with IL-4, however, increased only the level
      of CD46 mRNA. These results confirm and extend our previous observations. CD35
      mRNA was not found. Expression of complement regulatory proteins on chondrocytes
      and its upregulation by cytokines stimulating matrix degradation could be
      important for the protection of these cells against complement-mediated lysis,
      which might be caused by immunocomplexes deposited in articular cartilage in
      inflammatory joint diseases.

PMID- 12469226
TI  - Cholesteryl esters in human malignant neoplasms.
AB  - Cholesteryl esters (CholE) were detected in human malignant neoplasms by means of
      in vitro nuclear magnetic resonance spectroscopy. Spectroscopic analysis of the
      total lipid extracts obtained from cerebral tumors revealed appreciable amount of
      esterified cholesterol in high grade gliomas such as glioblastomas and anaplastic
      oligodendrogliomas, characterized by prominent neovascularity. The finding that
      no CholE were detected in the healthy brain and in low grade and benign tumors
      supports a possible correlation between this class of lipids and histological
      vascular proliferation. Compared with high grade gliomas, renal cell carcinomas
      show higher levels of CholE, absent in the healthy renal parenchyma and in benign
      oncocytomas. In nefro-carcinomas, cytoplasmic lipid inclusions and prominent
      vascularization contribute to the increased levels of CholE present mainly as
      oleate. CholE are discussed as potential biochemical markers of cancer and as a
      target for new therapeutic strategies.

PMID- 12469227
TI  - Analysis of intestinal HLA-DR bound peptides and dysregulated immune responses to
      enteric flora in the pathogenesis of inflammatory bowel disease.
AB  - Isolation of antigenic peptides from the MHC-groove has contributed to the
      understanding of T cell responses. However, these MHC-associated peptides have
      been isolated from various murine and human cell lines. The specific antigen
      responsible for the pathogenesis of inflammatory bowel disease is unknown. We
      examined antigenic peptides bound to the class II major histocompatibility
      complex (MHC) groove in human intestine by ion-trap tandem mass spectrometry
      equipped with online reverse-phase high performance liquid chromatography. We
      detected 55 parent proteins from 4 controls, 9 patients with ulcerative colitis,
      and 9 patients with Crohn's disease. The calculated molecular masses (m/z) of
      these peptides ranged from 874.4 to 2727.4, representing 10-26 amino acid
      residues. Fifty-one of these 55 parent proteins were exogenous proteins.
      Escherichia coli-, Saccharomyces cerevisiae-, and Caenorhabditis elegans-derived
      peptides were found frequently in patients with inflammatory bowel disease. The
      present results suggest that in vivo antigen processing by antigen-presenting
      cells and T lymphocytes in human intestine participate with exogenous antigen
      presentation. Increased immune responses against E. coli, S. cerevisiae and C.
      elegans found in patients with inflammatory bowel may participate as dysregulated
      immune responses to enteric flora in the pathogenesis of inflammatory bowel
      disease.

PMID- 12469228
TI  - Pharmacodynamics, insulinotropic action and hypoglycemic effect of nateglinide
      and glibenclamide in normal and diabetic rats.
AB  - Control and streptozotocin-induced diabetic rats, as well as GK rats, received a
      single oral administration of either nateglinide (50 microg/g body wt.) or
      glibenclamide (1.0 microg/g body wt.). The plasma D-glucose and insulin
      concentrations, as well as the content of plasma, liver and pancreas in either
      nateglinide or glibenclamide were measured 60 min or 24 hours after the
      administration of these antidiabetic agents. At the 60th min, the plasma, hepatic
      and pancreatic content of nateglinide largely exceeded that of glibenclamide. At
      the 24th hour, however, the plasma concentration, as well as liver and pancreas
      content, of nateglinide became negligible, whilst that of glibenclamide exceeded
      the values recorded at the 60th min. A comparable pattern characterized the
      insulinotropic action and hypoglycemic effect of these two antidiabetic agents.
      This study thus emphasizes the vastly different pharmacodynamics of nateglinide
      and glibenclamide in both control and diabetic rats.

PMID- 12469229
TI  - Identification and characterization of human Inscuteable gene in silico.
AB  - Neuroblast undergoes asymmetrical cell division to produce the neuroblast itself
      and ganglion mother cell along the apical-basal axis. Inscuteable (Insc) and
      Partner of Inscuteable (Pins) are translocated to the apical cell cortex during
      asymmetrical cell division of Drosophila neuroblast. Insc is implicated in the
      apical-basal orientation of mitotic spindle and the basal localization of
      Prospero (Pros) and Numb. Here, we identified and characterized human Inscuteable
      (INSC) gene using bioinformatics. Human INSC gene, consisting of at least 13
      exons, was located within human genome draft sequence AC090744.5 (around
      nucleotide position 150581-16936 in reverse orientation). Human INSC gene,
      closely linked to CALCB gene with an interval of about 30 kb, was assigned to
      human chromosome 11p15.2-p15.1. Amino-acid sequence of human INSC polypeptide
      (579 aa) was determined based on exon sequences of human INSC gene. C. elegans
      hypothetical protein F43E2.3 (NP_495539), homologous to human INSC, was
      designated C. elegans Insc. Central INSC homologous (ISH) domain and C-terminal
      PDZ-binding motif were evolutionary conserved among INSC proteins. The former
      part of ISH domain is implicated in Pros localization, while function of the
      latter part of ISH domain and C-terminal PDZ-binding motif remain to be
      elucidated. Human INSC mRNA was expressed in eye, kidney, fetal cochlea,
      parathyroid tumor, chondrosarcoma, epidermoid carcinoma, and skin tumor. Because
      LGN/Pins, PARD3/Par-3Bazooka, PARD6A/Par-6 and PRKCZ/aPKC genes implicated in
      asymmetrical cell division are evolutionarily and functionally conserved, human
      INSC protein might be implicated in asymmetrical cell division of human neural
      stem cells and other stem cells.

PMID- 12469230
TI  - Frequent microsatellite alterations in a predominantly younger age of onset
      breast cancer population.
AB  - Microsatellite instability (MSI) and loss of heterozygosity (LOH) was
      investigated in paired tumour and normal tissue DNA from 108 predominantly
      premenopausal breast cancer patients (under age 45 years at presentation) for 25
      simple repeat loci interspersed across 11 chromosomes. MSI was observed at a
      single locus in 69 (64%) patients; 41 of these had instability at more than one
      site. Greatest frequency of MSI was at loci D2S1356 (33%), D2S2739 (22%), D3S1766
      (21%) and D13S796 (20%). LOH was seen at a single site in 55% of patients and at
      two or more sites in 27 patients with greatest frequency at D2S1356 (33%), D2S443
      (19%) and D17S1299 (18%). Both mutations were found in the same patient but at
      different loci. Clearly, choice of loci is a determining factor in assessing
      genomic instability. The relatively high frequency of MSI may also reflect
      peculiarities of this younger patient population. Occurrence of MSI or LOH was
      unrelated to clinical stage, nodal status, tumour size or grade or steroid
      receptor status. It was independent of mutations detected in exons 5-9 of the p53
      gene. There was no significant association with survival. The lack of such
      correlations reflects a random disabling mechanism that may equally affect genes
      promoting cell death as well as growth.

PMID- 12469231
TI  - Arylamine N-acetyltransferase 2 polymorphism in the ethnic populations of South
      India.
AB  - The human N-acetylation polymorphism is a genetic trait phenotypically reflected
      by differences in N-acetyltransferase (NAT) activity with therapeutic agents
      (rapid and slow acetylation). Acetylation polymorphism arises from the allelic
      variations in human arylamine N-acetyltransferase 2 gene (NAT2), which results in
      the production of NAT2 proteins with variable enzyme activity or stability.
      Certain NAT2 traits may contribute to the occurrence of adverse drug effects and
      act as susceptibility factors for certain malignancies such as bladder or lung
      cancer. We report the results of NAT2 genotyping of ethnic communities in South
      India. One hundred and sixty-six unrelated individuals belonging to eight
      Dravidian ethnic communities of South India, with typical Dravidian features,
      were genotyped for their acetylation status. Slow acetylators were found to be
      predominant in these populations, with a frequency of 74%. The allele 6A was
      found in the highest frequency, while 5B/6A was the most frequent genotype. A
      novel deletion at 859 site was observed in one of these communities; this
      heterozygous deletion was linked to a homozygous mutation at 481 site. The
      predominance of slow acetylator genotypes in our study populations conforms to
      the results in most other Asian populations, where approximately 60% of the
      individuals have been genotyped as slow acetylators. Sex specificity for
      acetylator status in our study varied from population to population.

PMID- 12469232
TI  - Extensive posttreatment ganglioneuromatous differentiation of rhabdomyosarcoma:
      malignant ectomesenchymoma in an infant.

PMID- 12469233
TI  - Real-time polymerase chain reaction as an aid for the detection of SYT-SSX1 and
      SYT-SSX2 transcripts in fresh and archival pediatric synovial sarcoma specimens:
      report of 25 cases from St. Jude Children's Research Hospital.
AB  - Synovial sarcoma is the most common nonrhabdomyosarcomatous soft tissue sarcoma
      in children and adolescents and is characterized by a reciprocal t(X;18)(p11;q11)
      which results in the fusion of the SYT gene on chromosome 18q11 to either of two
      closely related genes, SSX1 (Xp11.23) or SSX2 (Xp11.21). Detection of this
      translocation or its resultant gene fusion by molecular methods is helpful in the
      pathologic diagnosis of synovial sarcoma, especially in poorly differentiated
      tumors. This study was designed to evaluate the utility of a real-time reverse
      transcriptase-polymerase chain reaction (RT-PCR) assay to detect and distinguish
      SYT-SSX1 and SYT-SSX2 fusions in fresh and archival specimens of synovial sarcoma
      in pediatric patients seen at St. Jude Children's Research Hospital. In addition,
      the clinicopathologic features of the tumors with SYT-SSX1 vs. SYT-SSX2 fusions
      were compared. The 25 patients studied had a median age of 13 years 9 months
      (range 5 to 19 years). Estimates of survival and event-free survival at 5 years
      were 78.7 +/- 10.5% and 56.2 +/- 13.2%, respectively. Seventeen (68%) tumors were
      monophasic, eight (32%) were biphasic. Seven tumors contained poorly
      differentiated areas. Positive results for either SYT-SSX1 or SYT-SSX2 were
      obtained in 21/25 (84%) cases. Three cases did not have a detectable gene fusion
      and one had no amplifiable RNA. SYT-SSX1 transcripts were found in 18/24 (75%) of
      the tumors while SYT-SSX2 transcripts were identified in 3/24 (12.5%). All of the
      poorly differentiated tumors and seven out of eight tumors from patients who
      developed lung metastases had an SYT-SSX1 fusion transcript. Real-time PCR is
      useful in detecting and distinguishing SYT-SSX1 from SYT-SSX2 gene fusions in
      synovial sarcoma. Valuable aspects of this methodology are the applicability to
      both frozen and formalin-fixed samples, decreased labor costs, and the rapidity
      of results. In addition, distinguishing SYT-SSX1 from SYT-SSX2 fusions with these
      methods allow for prospective collection of information that may clarify issues
      of prognostic relevance.

PMID- 12469234
TI  - Histopathological diagnosis of partial and complete hydatidiform mole in the
      first trimester of pregnancy.
AB  - The diagnosis of molar pregnancy is a continuing diagnostic problem for many
      practicing histopathologists who are required to examine specimens of products of
      conception, particularly since changes in gynecological management in recent
      years have resulted in uterine evacuation at earlier gestations. The aim of this
      review is to provide practical, up-to-date, diagnostically useful information
      regarding the histological diagnosis of molar disease in early pregnancy.
      Pathophysiological issues relevant to molar pregnancies, such as genetic
      abnormalities, will be briefly summarized, but nonhistopathological aspects of
      molar disease will not be covered in detail in this review.

PMID- 12469235
TI  - A little bit of everything: molecular genetics of congenital hyperinsulinism.

PMID- 12469236
TI  - Renal cell carcinoma with t(X;17): singular pediatric neoplasm with specific
      phenotype/genotype features.
AB  - Renal cell carcinomas in children are extremely rare and are usually associated
      with specific chromosomal rearrangements, different from those seen in adult
      patients. We present the case of a 9-year-old girl with a renal cell carcinoma
      with t(X;17) diagnosed at our institution. We also review the pertinent
      literature, with an emphasis on the genetic and molecular aspects associated with
      this rare neoplasm.

PMID- 12469237
TI  - Psychiatric genetics: the case of single gene disorders.
AB  - Quantitative and molecular genetics have made important developments in the last
      three decades. There is increasing evidence of the role of heredity in the field
      of neuropsychiatric disorders in children. So far, only a few pathways between
      genes and behaviour have been unravelled. Quantitative genetics puts polygenic
      inheritance models forward. Molecular genetic research based on these models
      seems promising, but until now has provided only a limited explanation for the
      variance in the studied neuropsychiatric disorders. In these models the
      complexity of the expression of a single gene grows exponentially with the number
      of genes involved. Consequently, research on the gene-phenotype relationships and
      phenotypical variability in such models is extremely complex.The candidate gene
      approach, in which the gene-phenotype pathway of a single gene is studied, is
      more manageable, and in our opinion essential in understanding multiple gene
      models. We discuss recent findings in the field and their relevance for
      neuropsychiatric phenotypes. Single gene defects will only explain a part of the
      range of neuropsychiatric disorders in children, but the evidence that this
      approach can generate may help to clarify neuropsychiatric phenotypes. The
      discovery of single gene disorders in subgroups of subjects with a
      neuropsychiatric phenotype may result in new perspectives for their treatment.

PMID- 12469238
TI  - Repetitive behaviors in autistic disorder.
AB  - INTRODUCTION: Repetitive behaviors are common in autistic disorder, as in other
      developmental disabilities. Behaviors as diverse as stereotypies, cognitive
      inflexibility, and a need for sameness are grouped together under DSM IV
      classification, even though they are diverse in phenomenology, underlying neural
      circuitry, and possible clinical significance. In order to better define
      repetitive behaviors, we studied the relationship between such behaviors and
      chronological age, developmental level, estimated IQ, presumed mood state,
      severity of illness, as well as behavior reactivity to environmental stimuli, in
      a group of 121 consecutive autistic children, aged 2-4 and 7-11 years. RESULTS:
      Younger autistic children displayed more motor and sensory repetitive behaviors.
      Older children had more complex behaviors. Children with higher IQ scores,
      likewise, demonstrated more complex repetitive behaviors. Most motor behaviors
      and self injury showed features of reactivity. CONCLUSIONS: Certain "repetitive"
      activities may not represent core features of autistic disorder and may be
      equivalent to normal motor and cognitive behaviors, as seen during typical
      development.

PMID- 12469239
TI  - Evaluation of neuromotor deficits in children with autism and children with a
      specific speech and language disorder.
AB  - Several studies have described problems in motor functions in children with
      autism and children with a specific speech and language disorder. The purpose of
      this study was to identify neuromotor deficits in these neurodevelopmentally
      impaired children. A standardised neurological examination was performed in 11
      children with childhood autism, 11 children with an expressive language disorder,
      11 children with a receptive language disorder and 11 control children. The
      children were matched for age and non-verbal IQ, not for gender. All children had
      a non-verbal IQ above 85. The neurological examination procedure allowed for a
      qualitative and quantitative assessment of five specific neurological subsystems:
      fine and gross motor functions, balance, coordination and oral motor functions.
      The high-functioning children with autism and the children with a specific
      language disorder (expressive or receptive) had more motor problems than the
      control children on most neurological subsystems. There were few statistically
      significant differences between the three groups of developmentally impaired
      children. The frequent co-occurrence of verbal and non-verbal, in particular
      neuromotor, deficits in developmentally impaired children put an additional
      burden on the development of these children and should be diagnosed as early as
      possible.

PMID- 12469240
TI  - Predictors of depression at eighteen. A 7-year follow-up study in a Spanish
      nonclinical population.
AB  - This study prospectively examined predicting factors and depressive antecedents
      of depression in early adulthood and determined differences by sex. 199
      adolescents aged 11-12 from the general community were followed up annually for 4
      years and reassessed at 18 years of age. Sociodemographic data, depressive
      symptomatology, anxiety level, personality dimensions, self-esteem, academic
      aptitude and pubertal development were reported throughout this period and tested
      as possible risk variables of depression. At 18, depression was diagnosed using
      ICD-10 criteria. Of the cases of major depression (MDD) at eighteen, 30% had been
      diagnosed as MDD between 12 and 14 years of age. Of the cases of MDD at eighteen,
      80% had had depressive symptomatology between the ages of 11 and 14. Subclinical
      scores in the Children's Depression Inventory (CDI) were early indicators of long
      term risk. Gender differences were found in the risk pattern; depressive symptoms
      were more significant in girls than in boys. In boys, early anxious
      symptomatology was a significant predictor. This study reports cross-cultural
      data that support a continuity of depression from adolescence to young adulthood.

PMID- 12469241
TI  - Uncomplicated Gilles de la Tourette syndrome and probable Ganser syndrome. A case
      report and review of the literature.
AB  - Gilles de la Tourette syndrome (GTS) is a genetic neuropsychiatric disorder,
      which is more common than previously thought. Ganser syndrome is an uncommon
      disorder, particularly in children. We present the first report of a young girl
      aged 7 who was diagnosed independently as having both GTS and Ganser syndrome and
      who was otherwise well and remained well and improved at follow-up 8 years later.
      This highlights how the clinicians must always be vigilant when atypical
      behaviours begin, especially when one diagnosis has already been given. There may
      well be treatment implications.

PMID- 12469242
TI  - A report on the Society of American Gastrointestinal Endoscopic Surgeons (SAGES)
      Outcomes Initiative: what have we learned and what is its potential?
AB  - INTRODUCTION: The Society of American Gastrointestinal Endoscopic Surgeons
      (SAGES) Outcomes Initiative established a national database in 1999. The goal was
      to provide a vehicle whereby surgeons could accumulate meaningful data about
      their surgical activity and procedure outcomes. METHODS: Through a secure
      Internet site, participants entered core data at the time of operation on all
      patients undergoing any laparoscopic or open procedure. Procedure-specific data
      was accumulated for cholecystectomy, inguinal hernia, and fundoplication. A
      second data set was collected at the time of follow-up evaluation. Individual
      data and a summary of national data were available through the Web site for
      contemporaneous review. RESULTS: Between May 1999 and December 2001, 4,100 cases
      were entered by 73 surgeons, including data for 1070 cholecystectomies, 1,070
      antireflux procedures, and 300 hernias. The remaining cases encompassed all other
      procedures. Perioperative and follow-up data showed many interesting findings.
      For example, 30% of cholecystectomies were first-assisted by a nonphysician. The
      rate of conversion from laparoscopic cholecystectomy to open surgery was 3%. In
      the gastroesophageal reflex disease (GERD) report on fundoplications, 21% of the
      patients had a previous fundoplication. This report contains a summary of the
      data collected during this period in the national database. CONCLUSIONS: The
      SAGES Outcomes Initiative allows surgeons to be involved in data collection about
      their practice. It provides data on the general practice of surgery, which are
      more useful for setting benchmarks than published data from the surgical elite.

PMID- 12469243
TI  - Laparoscopic repair of large incisional hernias.
AB  - BACKGROUND: Traditional approaches to incisional hernias (IH)--particularly in
      cases with large fascial defects--are plagued by a significant recurrence rate as
      well as frequent wound infections. The laparoscopic repair of incisional hernias
      was designed to offer a minimally invasive and tension-free technique that yields
      less morbidity and fewer recurrences than the standard open repair. Several years
      ago, we adopted the laparoscopic technique in our department and set out to
      appraise its touted advantages. METHODS: During the years 1997-2000, 103 patients
      underwent laparoscopic IH repair with implanted Dual Gore-tex mesh. Forty percent
      of them were obese, and 41% had undergone more than one previous attempt at
      conventional repair. All patients were discharged home within 24-72 hs. RESULTS:
      In three patients, the operation was converted to open surgery due to severe
      adhesions and technical difficulties. In two cases, inadvertent enterotomies were
      repaired laparoscopically, and since there was no major spillage, the repair was
      continued as planned, with no adverse consequences. Twelve patients underwent
      additional laparoscopic procedures at the initial operation. Two graft infections
      and four recurrences were observed during the 1-49 month follow-up period.
      CONCLUSIONS: Laparoscopic IH repair is technically feasible and safe in patients
      with large fascial defects as well as in obese patients. This operation decreases
      postoperative pain, hastens the recovery period, and reduces postoperative
      morbidity and recurrence.

PMID- 12469244
TI  - State of the art in gastrointestinal surgery 100 years ago: Operations in the
      gastrointestinal tract in general (chapter XII) and Resection of bowel carcinoma
      (chapter XIV) from the Textbook of Special Surgery (1897) by Eduard Albert (1841
      1900).

PMID- 12469245
TI  - Influence of drying-rewetting frequency on soil bacterial community structure.
AB  - Soil drying and rewetting represents a common physiological stress for the
      microbial communities residing in surface soils. A drying-rewetting cycle may
      induce lysis in a significant proportion of the microbial biomass and, for a
      number of reasons, may directly or indirectly influence microbial community
      composition. Few studies have explicitly examined the role of drying-rewetting
      frequency in shaping soil microbial community structure. In this experiment, we
      manipulated soil water stress in the laboratory by exposing two different soil
      types to 0, 1, 2, 4, 6, 9, or 15 drying-rewetting cycles over a 2-month period.
      The two soils used for the experiment were both collected from the Sedgwick Ranch
      Natural Reserve in Santa Ynez, CA, one from an annual grassland, the other from
      underneath an oak canopy. The average soil moisture content over the course of
      the incubation was the same for all samples, compensating for the number of
      drying-rewetting cycles. At the end of the 2-month incubation we extracted DNA
      from soil samples and characterized the soil bacterial communities using the
      terminal restriction fragment length polymorphism (T-RFLP) method. We found that
      drying-rewetting regimes can influence bacterial community composition in oak but
      not in grass soils. The two soils have inherently different bacterial
      communities; only the bacteria residing in the oak soil, which are less
      frequently exposed to moisture stress in their natural environment, were
      significantly affected by drying-rewetting cycles. The community indices of
      taxonomic diversity and richness were relatively insensitive to drying-rewetting
      frequency. We hypothesize that drying-rewetting induced shifts in bacterial
      community composition may partly explain the changes in C mineralization rates
      that are commonly observed following exposure to numerous drying-rewetting
      cycles. Microbial community composition may influence soil processes,
      particularly in soils exposed to a significant level of environmental stress.

PMID- 12469246
TI  - Inability to find consistent bacterial biocontrol agents of Pythium
      aphanidermatum in cucumber using screens based on ecophysiological traits.
AB  - A collection of 821 rhizobacteria from cucumber, originating from different root
      locations and stages of plant development, was screened for potential biocontrol
      agents of Pythium aphanidermatum (Edson) Fitzp. The screening procedure exploited
      carbon source utilization profiles and growth rates of bacteria as indicators of
      a partial niche overlap with the pathogen. The bacteria were tested for growth on
      nine carbon sources (glucose, fucose, sucrose, maltose, asparagine, alanine,
      galacturonic acid, succinic acid, and linoleic acid), most of which are reported
      to be used by the zoospores of P. aphanidermatum in the infection process. The
      isolates were classified as fast- or slow-growing, depending on their growth rate
      in 1/10 strength TSB. By nonhierarchical cluster analysis, 20 clusters were
      generated of bacteria with similar profiles of carbon source utilization.
      Redundancy analysis showed that the type of root sample explained 47% of the
      variance found in the relative abundance of bacteria from the clusters. Bacteria
      from clusters using none or few of the carbon sources, e.g., maltose and linoleic
      acid, with many slow-growing isolates, showed a preference for plants in the
      vegetative or generative stage, or for old root regions (root base). Bacteria
      from clusters with fast-growing isolates, using many carbon sources, were
      relatively abundant in the seedling stage. A selection of 127 bacteria from the
      different clusters was tested for disease suppressive capabilities in bioassays
      on young cucumber plants in nutrient solution, inoculated with zoospores of P.
      aphanidermatum. Nine of these bacteria produced biosurfactants, and 27 showed
      antibiosis against mycelial growth in plate assays. For 31 isolates, significant
      positive effects on plant biomass were shown, as analyzed with a general linear
      regression model. For most isolates, these effects occurred only in one of two
      replicate assays and no reductions in the degree of root and crown rot were
      found. Of the isolates that used many of the tested carbon sources, only four had
      positive effects on plant biomass. The majority of the isolates that positively
      affected plant biomass used few to moderate numbers of carbon sources and did not
      produce antibiotics or biosurfactants. In conclusion, competition for the tested
      carbon sources with the zoospores did not play a decisive role in disease
      suppression, and no clear relation was found between ecophysiological traits and
      disease suppression. Only isolate 3.1T8, isolated from root tips in the
      generative stage of plant growth, significantly increased plant biomass and
      suppressed root and crown rot symptoms in five out of six bioassays. The isolate
      produced an antifungal substance in plate assays and showed biosurfactant
      production in several (cucumber-derived) media.

PMID- 12469247
TI  - Bacterial growth efficiency in the tropical estuarine and coastal waters of Goa,
      southwest coast of India.
AB  - Bacterial growth efficiency (BGE) is an index of organic carbon passing through
      bacteria in an aquatic system. BGE values of natural bacterioplankton assemblages
      were measured in tropical estuarine and adjacent coastal waters in Goa along the
      southwest coast of India. The BGE values for estuarine and coastal waters were 18
      (+/-7.84%) and 11 (+/-4.19%), respectively. BGE in these waters were at the lower
      end of what is usually found in productive systems. This may be due to the high
      respiration rates. Further, it was observed that grazers also influenced BGE. As
      BGE was positively correlated with bacterial productivity, the observed variation
      in BGE was attributed to bacterial productivity. BGE was inversely related to C:N
      ratio, indicating a close coupling between the nature of the substrates and BGE.
      Being system-dependent, the variations in BGE at the two locations were dynamic
      and were regulated by the quality of the substrates. Therefore, a constant value
      for BGE would lead to error in carbon budgets in these waters.

PMID- 12469248
TI  - Rodent model for investigating the effects of estrogen on bone and muscle
      relationship during growth.
AB  - It has been reported that in humans from about 11-12 years of age, bone mass
      begins to increase faster in girls than in boys with the same muscle mass, and by
      14-15 years of age, bone mass per unit mass of muscle was found to be
      significantly higher in girls than in boys. Because around 15 years is the
      beginning of reproductive age in women, it was suggested that estrogen was
      involved in the higher bone mass in women during puberty. The present study was
      undertaken to determine if bone mass per unit muscle mass is higher in female
      than in male Sprague Dawley (SD) rats during growth, as has been reported in
      humans during growth and consequently, whether these SD rats are suitable for
      studying the musculoskeletal effects of estrogen, as may occur in humans during
      growth. L-4 vertebra of female and male SD rats aged 1-6 months were studied
      using peripheral quantitative computed tomography (pQCT). Muscle cross-sectional
      area was measured as a surrogate for muscle mass and bone mineral content (BMC)
      was measured as a surrogate for bone mass. From 1 to 6 months of age, total BMC,
      cortical BMC, and cancellous BMC increased faster in females than in males with
      similar muscle area, and at 3 and 6 months of age, the above vertebral indices of
      bone mass were significantly higher in female than in male rats. Since one of the
      main differences between female and male rats is the level of serum estrogen, the
      higher bone mass per unit muscle area seen at the L-4 vertebra in these female SD
      rats is similar to what has been reported in humans during puberty when serum
      estrogen level is high in females. The findings from this study indicate that
      female and male SD rats aged 1-6 months can be used as appropriate model for
      studying the effects of serum estrogen on the skeletal response of voluntary
      muscle forces, as has been reported in humans during growth.

PMID- 12469249
TI  - The integrin alpha(v)beta(3) and CD44 regulate the actions of osteopontin on
      osteoclast motility.
AB  - In the studies reported here we demonstrate that osteopontin is secreted from the
      basolateral surfaces of osteoclasts where it binds to the avb3-integrin,
      suggesting that it may be an autocrine factor. Osteopontin stimulation of
      osteoclasts produced changes in cell shape by causing disruption of peripheral
      podosome structures and formation of actin filaments at the leading edge of the
      migrating osteoclasts. The latter was part of the assumption of a motile
      phenotype prior to cells reforming peripheral ring type podosome containing clear
      zones. It is well established in our laboratory as well as in others that
      osteopontin stimulated osteoclast motility and bone resorption. The effect of
      osteopontin was mimicked by RGD containing peptides and blocked by a avb3
      antibody, demonstrating that signals generated by integrin ligation contributed
      to the actions of osteopontin. In addition, the migratory effects of osteopontin
      on osteoclasts were also mediated through CD44 receptors since blocking
      antibodies to CD44 blocked stimulation of motility. Our data strongly suggest
      that osteopontin is an osteoclast autocrine motility factor binding to avb3 and
      CD44 during stimulation of osteoclast migration.

PMID- 12469250
TI  - Ultrastructural changes accompanying the mechanical deformation of bone tissue: a
      Raman imaging study.
AB  - Raman spectroscopy and imaging are known to be valuable tools for the analysis of
      bone, the determination of protein secondary structure, and the study of the
      composition of crystalline materials. We have utilized all of these attributes to
      examine how mechanical loading and the resulting deformation affects bone
      ultrastructure, addressing the hypothesis that bone spectra are altered, in both
      the organic and inorganic regions, in response to mechanical loading/deformation.
      Using a cylindrical indenter, we have permanently deformed bovine cortical bone
      specimens and investigated the ultrastructure in and around the deformed areas
      using hyperspectral Raman imaging coupled with multivariate analysis techniques.
      Indent morphology was further examined using scanning electron microscopy. Raman
      images taken at the edge of the indents show increases in the low-frequency
      component of the amide III band and high-frequency component of the amide I band.
      These changes are indicative of the rupture of collagen crosslinks due to shear
      forces exerted by the indenter passing through the bone. However, within the
      indent itself no evidence was seen of crosslink rupture, indicating that only
      compression of the organic matrix takes place in this region. We also present
      evidence of what is possibly a pressure-induced structural transformation
      occurring in the bone mineral within the indents, as indicated by the appearance
      of additional mineral factors in Raman image data from indented areas. These
      results give new insight into the mechanisms and causes of bone failure at the
      ultrastructural level.

PMID- 12469252
TI  - The importance of ethical guidelines in medicine today.

PMID- 12469251
TI  - Modulation of cytosolic calcium levels in osteoblast-like osteosarcoma cells by
      olpadronate and its amino-derivative IG-9402.
AB  - The molecular mechanisms as well as the structure/activity relationships involved
      in the antiresorptive actions of bisphosphonates on bone cells are still not
      clear. Replacement of the R1-hydroxyl by an NH2 group in olpadronate (OPD)
      abolishes its antiresorptive activity. We show here that in the rat osteosarcoma
      derived osteoblast-like ROS 17/2.8 cell line, OPD and IG-9402 (NH2-OPD; [3-(N,N
      dimethylamine)-1-aminopropylidene bisphosphonate]), similar to 1,25(OH)2-vitamin
      D3, rapidly modulate cytosolic calcium levels ([Ca2+]i). As for the steroid
      hormone, the osteosarcoma cell Ca2+i response to OPD was rapid (30 sec) and
      sustained (>5 min), exhibiting a biphasic profile. The response to IG-9402 was
      also fast but smaller than that of OPD and 1,25(OH)2D3, and rapidly declined to
      levels near basal. The effect of these bisphosphonates on [Ca2+]i was dose
      dependent, being maximal at 10(-8) M and was not observed in non-bone cellular
      systems, e.g., skeletal muscle and breast cells. Pretreatment of the ROS 17/2.8
      cells with the Ca2+ channel blockers nifedipine and verapamil markedly reduced
      (>70%) the influx phase of the response to OPD and almost completely inhibited
      that of IG-9402, indicating the participation of voltage-dependent Ca2+ channels
      in the action of both compounds. Moreover, preincubation with the phospholipase C
      inhibitors U73122 and neomycin or depletion of inner stores with thapsigargin
      completely blocked the response to either olpadronate or its amino-derivative.
      Both OPD and IG-9402 significantly increased osteocalcin release into the culture
      medium of osteosarcoma cells. The results support the involvement of the Ca2+
      signaling pathway as part of the mechanism by which bisphosphonates induce bone
      cellular responses.

PMID- 12469253
TI  - Is induction of fetal diuresis with intraamniotic furosemide effective for the
      removal of intestinal waste products from amniotic fluid?
AB  - AIM: In gastroschisis, contact with amniotic fluid (AF) causes intestinal damage.
      Intraamniotic meconium has been shown to be responsible for the intestinal
      damage, and intestinal damage has been shown to correlate with intraamniotic
      meconium concentrations. Intraamniotic meconium below a threshold level does not
      cause intestinal damage. Intraamniotic meconium concentrations can be lowered by
      AF exchange. Can induction of foetal diuresis by an intraamniotic injection of
      furosemide be used as an alternative method for the same purpose? METHOD:
      Pregnant rabbits on the 23rd - 25th gestational days (normal gestation time: 31 -
      33 days) were divided into two groups, the control group and the furosemide
      group. Initial AF samples were taken, then either 5 mg/kg furosemide or a placebo
      was injected into the amniotic cavity. Final AF samples were obtained 6 hours
      later. AF urea nitrogen, creatinine, amylase, alkaline phosphatase and bilirubin
      levels were determined. RESULTS: There was no significant difference between the
      initial and final levels of AF urea nitrogen, creatinine, bilirubin, amylase, and
      alkaline phosphatase in the control group, while the final AF urea nitrogen and
      creatinine levels of the furosemide group were not significantly different from
      the initial levels (p > 0.05). Final AF bilirubin, amylase and alkaline
      phosphatase levels of the furosemide group were significantly decreased compared
      with initial levels (p < 0.01). CONCLUSION: Induction of foetal diuresis with
      intraamniotic furosemide is effective for the removal of intestinal waste
      products from amniotic fluid.

PMID- 12469254
TI  - The first experience with non-operative treatment of hypersplenism in children
      with portal hypertension.
AB  - The register of Latvian children with portal hypertension (PH) includes 34
      patients from 2 to 16 years old. In 26 children the PH is caused by a prehepatic
      obstruction. The most widespread symptoms of PH are variceal bleeding and
      hypersplenism. The traditional management of hypersplenism has been splenectomy.
      We have used partial splenic embolization (PSE) as an alternative to splenectomy.
      From 1998 to 2000 we carried out PSE in 8 patients with PH. A percutaneous
      femoral artery approach to the splenic artery was used to deliver microspheres
      with a diameter of 0.3 mm into the spleen, minimizing blood circulation to the
      organ by 60 - 70 %. In 7 patients symptoms of hypersplenism disappeared and blood
      tests returned to normal status. In one patient we carried out PSE twice. In one
      case PSE was not successful and the patient underwent partial resection.
      Abdominal pain and subfebrility were observed on average 2 weeks after PSE. In 7
      patients the 4 - 20 months follow-up period demonstrated the efficiency of the
      non-operative hypersplenism management method. We conclude that PSE is the method
      of choice to treat hypersplenism.

PMID- 12469255
TI  - In hydronephrosis less than 10 % kidney function is not an indication for
      nephrectomy in children.
AB  - PURPOSE: To reduce the incidence of nephrectomy or hydronephrosis in children.
      MATERIALS AND METHODS: From September 1998 to October 2000, we treated 58
      patients with hydronephrosis; their ages ranged from 35 days to 11 years (mean
      age 4 years 7 months). All patients were subjected to a DTPA renogram with split
      function. In 12 patients (study group), kidney function was less than 10 % (range
      0 - 10 %). Initially, nephrostomy was carried out in all 12 patients followed by
      Anderson-Hyne's pyeloplasty after 4 - 6 weeks. Postoperatively renal USG, urine
      r/m/e & c/s (routine and microscopic examination and culture and sensitivity
      test), blood urea, serum creatinine were assessed and DMSA scan and DTPA renogram
      with split functions were carried out in all patients. RESULTS: In the study
      group, all 12 patients showed improvement of renal function (more than 10 %)
      after nephrostomy and in all of them pyeloplasty was subsequently carried out
      within 4 - 6 weeks. There were no significant pre-, peri- or postoperative
      complications. CONCLUSIONS: Contrary to common practice we do not recommend
      nephrectomy for hydronephrotic kidneys which show < 10 % of renal function on
      renogram. The renal functional status improves significantly after a preliminary
      nephrostomy, thus avoiding the need for a straightforward nephrectomy in children
      along with all the possible long-term effects of a single kidney.

PMID- 12469256
TI  - Hormonal analysis in post-pubertal patients with posterior urethral valves.
AB  - AIMS: Infertility in patients with posterior urethral valves (PUV) is known but
      the exact incidence and etiology is still speculative; it may be partly due to
      dysfunction of genital organs. The aim of this study is to analyse the hormonal
      profile of post-pubertal patients with PUV. MATERIALS AND METHODS: All post
      pubertal patients with posterior urethral valves (age > 16 years) visiting the
      follow-up urology clinic of our department from 1985 to December 1999 were
      contacted and requested to participate in the study; 9 patients agreed and form
      the study group. The medical records were reviewed. Physical examination included
      examination of the genitalia and secondary sexual characteristics. Blood samples
      were taken for estimation of lutenizing hormone (LH), follicle-stimulating
      hormone (FSH), prolactin and testosterone. RESULTS: Ages ranged from 16 - 21
      years (mean age = 17.5 years). Physical examination was normal for the entire
      study group except for 2 patients; one patient had hypertension and the other had
      unilateral undescended testis at the time of initial presentation. Secondary
      sexual characteristics were normal in all patients. At the time of the study, one
      patient had chronic renal failure; in the others the renal function tests were
      normal. LH and testosterone were normal in all patients including the patient
      with unilateral undescended testis, and one patient had marginally elevated FSH.
      Hyperprolactinemia was noted in 5 of 9 patients. CONCLUSION: In the present
      study, hyperprolactinemia was seen in 62 % (5 of 9) patients. Hyperprolactinemia
      is known to cause slow ejaculation and can have an impact on the subsequent
      fertility status of these patients. The bearing of these findings on subsequent
      sexual and fertility functions of PUV patients requires further investigation.

PMID- 12469257
TI  - The sex hormone receptors in the bladder in childhood - I: preliminary report in
      male subjects.
AB  - The sex hormone receptors (oestrogen, androgen, progesterone) in the bladder were
      demonstrated in clinical studies by various authors in adult patients. But the
      presence of these receptors in childhood had not been investigated. The aim of
      this study was to assess the presence of sex hormone receptors in the bladder of
      male subjects in childhood. The study included 20 bladder biopsies from a total
      of 15 children. Biopsies were taken during open surgery and/or cystoscopic
      procedures for various indications from the bladder dome, trigonum and in the
      region of the bladder neck. All biopsies were routinely fixed and processed for
      histopathological assessment and investigated immunohistochemically to determine
      the sex hormone receptors in the bladder. The sex hormone receptors were
      demonstrated with different densities and locations. In particular, sex hormone
      receptors were found very frequently in biopsies taken from the bladder neck.
      Overall receptor positivity in the specimens was 90 % for progesterone, 65 % for
      androgen and 25 % for oestrogen. There was no receptor expression in the deeper
      tissues of the bladder wall. This preliminary study demonstrated: 1. Sex hormone
      receptors are present in children; 2. There was a female sex hormone
      (progesterone, oestrogen) receptor expression in male subjects; 3. The receptors
      are mainly localised at the bladder neck and in transitional epithelium of the
      bladder wall. We think that the sex hormone receptor map may be useful in the
      evaluation of lower urinary tract and specially bladder neck disorders in
      childhood in the future.

PMID- 12469258
TI  - Treatment of neuropathic urinary and faecal incontinence.
AB  - The author presents 14 children after meningomyelocoele repair with faecal and
      urinary incontinence, aged from 6 to 17 years who have undergone the MACE
      procedure. MACE with synchronous Mitrofanoff continent stoma creation was
      performed in one child with severe stenosis of the urethra. MACE with
      simultaneous bladder augmentation was used in 10 patients. 5 of them underwent
      colocystoplasty, 3 had ileocystoplasty and 2 ureterocystoplasty. Of these 10
      children, three have additionally undergone the Mitrofanoff procedure. Patients'
      follow-up ranged from six months to two years. Three children had trouble with
      the MACE stoma because of its stenosis. One of them required revision of the
      stoma. All patients became clean and dry, and this operation improved not only
      their quality of life, but also their independence.

PMID- 12469259
TI  - Ultrasound examination of paediatric testicles after laparoscopic laser
      dissection of internal testicular vessels in cryptorchism.
AB  - PURPOSE: To evaluate the growth of testicles, their sonographic structure and the
      recovery of testicular perfusion through collateral vessels after preliminary
      laparoscopic laser dissection (PLLD) of the internal spermatic artery in
      cryptorchism. MATERIALS AND METHODS: The postoperative position, the volume
      increase, the structural and vascular abnormalities and the incidence of
      epididymal abnormalities were evaluated with ultrasound in 32 children (mean age:
      6.5 +/- 1.34 years) after PLLD. The intratesticular blood flow and the flow-in
      anastomoses from the deferential and cremasteric arteries were assessed using
      colour and power Doppler US (7.5 MHz transducer). RESULTS: All testicles were
      permanently positioned in the scrotum and showed growth after surgical treatment.
      None of the testes showed sonographic signs of atrophy. There were no clear
      differences in intratesticular perfusion compared to the non-operated testis. A
      collateral blood flow in the deferential artery was found in 44 cases by colour
      and/or power Doppler US. A perfusion to the lower testicular pole was detected in
      29 cases by power Doppler. Intraoperatively, 12 epididymal inversions were
      eliminated so that an elongated epididymis was sonographically visualised in
      three testes. CONCLUSION: Ultrasound can be used for the postoperative control of
      the testicular structure and the volume increase as well as detection of the flow
      in anastomoses. The collateral blood supply after PLLD was sufficient for
      subsequent growth of testicles in all cases.

PMID- 12469260
TI  - Ectopic thymic tissue as a rare and confusing entity.
AB  - A 16-year-old girl with intrathyroidal ectopic thymic tissue, which was diagnosed
      incidentally after surgery for thyroid nodule, is reported to emphasise the
      possible clinical and surgical presentations of this rare entity.

PMID- 12469261
TI  - Mucinous cystadenoma: a rare abdominal mass in childhood.
AB  - Ovarian masses are uncommon in children. Only 10 - 17 % of them are epithelial
      tumours. Mucinous cystadenoma in children is a benign cystic ovarian neoplasm,
      and it is met very rarely in the medical literature. We present a 13-year-old
      girl with a giant ovarian mucinous cystadenoma.

PMID- 12469262
TI  - Intraabdominal desmoplastic small round cell tumour: report of two cases in
      paediatric patients.
AB  - Intraabdominal Desmoplastic Small Round Cell Tumour (IDSRCT) is a very rare
      neoplasia with a unique immunoprofile. Children and young adults are most
      commonly affected. We report two cases with IDSRCT in children who initially
      presented with ascites, pain and abdominal mass. Complete surgical excision was
      possible only in one patient. Although both patients underwent multiagent
      chemotherapy, they had a relapse of the disease. One patient died two years after
      diagnosis. The tumour has a very poor prognosis. Survival is correlated to the
      radical resection of the tumour combined with intense chemotherapy and
      radiotherapy.

PMID- 12469263
TI  - Congenital solitary intestinal fibromatosis.
AB  - Neonatal intestinal obstruction due to a tumour is rare. We report a six-day-old
      male neonate who presented with abdominal distension and vomiting. Laparotomy
      revealed colonic obstruction caused by a stenosing fibrotic lesion in the
      proximal transverse colon. Histopathological examination of the resected specimen
      confirmed fibromatosis. We believe this represents the third reported case of
      solitary colonic fibromatosis. The literature on neonatal intestinal fibromatosis
      is reviewed.

PMID- 12469264
TI  - A nephron-sparing surgical procedure for Fraley's syndrome. A case report.
AB  - A 14.5-year-old girl with Fraley's syndrome, which caused left flank pain and
      massive haematuria with anaemia underwent left renal surgery. The infundibulum
      for the left upper calyx group was entrapped between the lower segmental renal
      artery and one branch of the renal vein. Despite other known surgical procedures,
      the surgeon explored the area around the entrapped infundibulum and resected the
      vein. Impression of the infundibulum disappeared, the dilatation of the upper
      calyces diminished, the pain was immediately relieved, and the haematuria
      stopped. In the two-year follow-up period the patient remained healthy, without
      haematuria or a subjective feeling of illness. The surgical treatment performed
      was successful, and it is also one of the most nephron-sparing procedures
      available.

PMID- 12469265
TI  - Tubo-ovarian abscess after colonic vaginoplasty for high cloacal anomaly in a 13
      year-old girl.
AB  - Recently a few articles have been published concerning the long-term follow-up of
      vaginoplasty of cloaca. However, no postoperative evaluation has been fully
      described and, in particular, the late complications are still unknown. We report
      a case of tuboovarian abscess after colonic vaginoplasty for high cloacal anomaly
      in a 13-year-old girl. She required a left salpingo-oophorectomy and
      postoperatively showed regular menstruation. Therefore we stress that tubo
      ovarian abscess is one of the important late complications after colonic
      vaginoplasty for high cloacal anomaly.

PMID- 12469266
TI  - Embolization of hepatic hemangiomas in infants.
AB  - A small number of cavernous liver hemangiomas in infants cause serious symptoms,
      requiring active treatment. We report two newborns with giant liver hemangiomas,
      treated by intra-arterial embolization. The babies presented at 2 - 8 days after
      birth with tachypnoea and cardiac dilation. A giant liver hemangioma located in
      the right liver lobe in one infant and in the left liver lobe in the other was
      found at ultrasonography and computed tomography. Dilated liver veins indicated
      abnormal shunting of the blood through the hemangiomas. Because of progress of
      symptoms superselective embolization of the arteries feeding the hemangiomas and
      arising from the celiac trunk was performed with a mixture of Lipoidol and
      Histoacryl. A decrease of tachypnoea and of heart volume was noted after
      embolization. In one infant surgery was necessary due to gastrointestinal
      bleeding. The intra-arterial embolization is a valuable method for the treatment
      of newborns with symptomatic cavernous liver hemangiomas.

PMID- 12469267
TI  - Laparoscopic treatment of varicoceles in children.

PMID- 12469268
TI  - Laparoscopic-assisted appendectomy in children: the two-trocar technique.

PMID- 12469270
TI  - In honour of Professor Emeritus Dr. Paul Schweizer.

PMID- 12469271
TI  - [The value of natriuretic peptides NT-pro-BNP and BNP for the assessment of left
      ventricular volume and function. A prospective study of 150 patients].
AB  - BACKGROUND AND OBJECTIVE: An early detection of patients with left-ventricular
      (LV) dysfunction is essential for effective treatment of congestive heart
      failure. The B-type natriuretic peptide (BNP) was described as a strong
      diagnostic parameter of LV-dysfunction. Aim of this study was to compare the
      diagnostic value of BNP and the aminoterminal part of pro-BNP (NT-pro-BNP) within
      an heterogenous patient population. SUBJECTS AND METHODS: NT-pro-BNP and BNP were
      measured in 150 hospitalized cardiologic patients (age-median 64 years, 109 male
      versus 41 female). The values were correlated with clinical and haemodynamic
      parameters of the invasively determined LV-function. RESULTS: Patients with
      pathologic haemodynamic values of the LV-function had significantly higher NT-pro
      BNP and BNP levels than patients with normal haemodynamic parameters. In our
      study population a severe systolic LV-dysfunction (ejectionfraction EF<40 %)
      could be detected with a sensitivity and specifity of 100 % and 64 % by NT-pro
      BNP and 100 % and 45 % by BNP. Sensitivity and specifity for the detection of any
      systolic dysfunction (EF<60 %) and of a systolic or diastolic dysfunction,
      respectively, were 94 %, 37 % and 88 %, 41 % for NT-pro-BNP (94 %, 40 % and 84 %,
      44 % for BNP). The corresponding negative predictive values were 100 %, 96 % and
      71 % for NT-pro-BNP and 100 %, 96 % and 68 % for BNP. CONCLUSION: NT-pro-BNP and
      BNP were highly sensitive diagnostic parameters with a very good negative
      predictive value for LV-dysfunction. Because of the uncomplicated measurement,
      they could be used effectively to rule out LV-dysfunction in cardiovascular high
      risk patients by general practitioners.

PMID- 12469272
TI  - [The paradox of TSH elevation in Sheehan's syndrome].
AB  - HISTORY AND CLINICAL FINDINGS: A 59-year-old woman was examined because of weight
      gain, increasing fatigue and secondary amenorrhoea, which occurred after a
      complicated delivery at age 18. The finding of an increased TSH concentration was
      initially considered as primary hypothyroidism and substitution therapy was
      commenced. Because of the concomitant secondary amenorrhoea the patient was
      referred for additional endocrinological investigations. INVESTIGATIONS:
      Biochemical analysis confirmed the increase in TSH concentrations, and revealed a
      gonadotropin deficiency, a decrease in IGF-I concentration and a free urinary
      cortisol concentration at the lower end of the normal range. Dynamic testing of
      pituitary function (insulin tolerance test) confirmed a severe growth hormone
      deficiency and partial secondary adrenal insufficiency. An MRI study of the
      pituitary showed an empty sella with some remaining pituitary tissue at the
      bottom of the sella. DIAGNOSIS, TREATMENT AND CLINICAL COURSE: The laboratory
      findings of pituitary insufficiency with an empty sella on MRI scan suggested
      Sheehan's syndrome despite an increase in thyrotropin level. Pituitary
      replacement therapy was started with hydrocortone, combined estrogens and
      progesterone in addition to levothyroxin, which considerably improved clinical
      symptoms. CONCLUSION: A history of secondary amenorrhoea after a complicated
      delivery including significant bleeding or septic complications suggest Sheehan's
      syndrome, which can result in partial or complete panhypopituitarism. In such
      circumstances the pituitary hormone levels are usually reduced. TSH
      concentrations, however, may be increased.

PMID- 12469273
TI  - [Chronic myeloid leukemia--case report].

PMID- 12469274
TI  - [Chronic myeloid leukemia--pathophysiology and diagnosis].

PMID- 12469275
TI  - [Chronic myeloid leukemia--treatment].

PMID- 12469278
TI  - [Structure and function of blood-tissue barriers].
AB  - SUMMARY: Pharmacologic effects caused by systemic administration of drugs in some
      organs are prevented by poor transport of the often large or hydrophilic
      molecules to the parenchyme. The exclusion of macromolecules from the tissue is
      called blood-tissue barrier. Common examples for barriers are the blood-brain,
      the blood-placenta-, the blood-retina-, the blood-testis- and the blood- thymus
      barrier. The barriers have a well defined anatomic substrate: for the blood-brain
      , the inner blood- retina and the blood-thymus-barrier it is the endothelium, for
      the blood-placenta-, the outer blood-retina-, the blood-testis- and the blood
      thymus-barrier these are epithelial cells in the vicinity of the capillary.
      Epithelia with barrier-function typically have dense intercellular junctions and
      few pinocytotic vesicles. They express many transporters for the selective
      transport and for the exchange of molecules. One group of transporters is
      responsible for the multi-drug resistance. Inflammations and tumors are the most
      common causes for disturbances of the blood-tissue-barriers. Strategies available
      for drug delivery to tissues with barriers include the opening of the barrier and
      the modification of the drug. The opening of the permeability can be achieved by
      the co-application of the respective drug with mediators as bradykinin or
      hyperosmolar concentrations of mannitol. Modifications of the drug include
      lipidization of the molecule, enclosure into liposomes and coupling to substances
      that are actively taken up by the cells. The pharmaceutical treatment of organs
      with blood-tissue barriers requires both an efficacious drug and an special
      application strategy.

PMID- 12469279
TI  - [Can an estrogen substitution modify the emotional state of a premenopausal
      woman?].

PMID- 12469280
TI  - [Does treatment with piracetam in stroke patients with aphasia make sense?].

PMID- 12469281
TI  - [Lectin compared to mistletoe use: experimental therapy form with preclinically
      verified risk potential].

PMID- 12469282
TI  - [Phlogiston - feuerluft - oxygene: from the discovery of oxygen to its medical
      application].

PMID- 12469283
TI  - [The centennial of oxygen-therapy (1902 - 2002)--reassessing its history. Part I:
      "The long way of oxygen"--from its discovery to its implementation as a rational
      therapy in anaesthesia and emergency-medicine].
AB  - This historical survey in two parts analyses the history of inhalative oxygen
      therapy and its interactions with the history of anaesthesiology. For this
      purpose, we will start with illustrating "the long way of oxygen" from its first
      isolation by Carl Wilhelm Scheele (1772) and Joseph Priestley (1774) to its
      breakthrough for therapeutic application in the 20th century. We will show that
      the two main factors delaying the successful implementation of a truly rational
      oxygen therapy were of technical nature: The complicated and costly production of
      the gas and insufficient means to apply it continuously and with reliable and
      sufficient dosages to the patients. Both problems could not be satisfactorily
      solved until 1902. From this year on, however, the "Linde Process" allowed cheap
      mass-production of oxygen. Simultaneously, various inventions of modern pressure
      gas technology allowed to solve the application problems. Here, a special
      significance is to be awarded to pressure reducing valves. These were first
      introduced into medical technology by Draeger Inc. (Lubeck/Germany) on a
      significant scale, proving particularly successful in anaesthesia and rescue
      devices (e. g. in the "Roth-Draeger Anaesthesia Apparatus" [1902]). Critically
      discussing earlier research on the history of oxygen therapy, we therefore
      propose a historical reassessment, accepting the year 1902 as the internationally
      decisive "turning point" towards the development of modern oxygen therapy.

PMID- 12469284
TI  - [Thio- and oxybarbiturates inhibit peristalsis in the Guinea-pig ileum in vitro].
AB  - INTRODUCTION: Inhibition of gastrointestinal motility by drugs used for
      anaesthesia or sedation in critically ill patients in the ICU is a major problem
      leading to various complications. Thus this study examines whether the thio- and
      oxybarbiturates thiopentone and pentobarbitone exert an inhibitory effect on
      intestinal peristalsis. METHODS: Peristalsis in isolated segments of the guinea
      pig small intestine was elicited by distension of the gut wall through a rise of
      intraluminal pressure and recorded via the intraluminal pressure changes
      associated with the aborally moving peristaltic contractions. Thiopentone and
      pentobarbitone (0.1 - 300 microM)-induced inhibition of peristalsis was reflected
      by an increase of the peristaltic pressure threshold (PPT). RESULTS: Thiopentone
      (EC50 = 19,8 microM) and pentobarbitone (EC50 = 99.7 micro M) concentration
      dependently increased the PPT. While the vehicle (saline) and 0.1 - 10 micro M
      thiopentone and pentobarbitone were without any effect on the PPT, 100 micro M
      caused a significant increase in PPT, and complete abolition of peristalsis
      occurred after 300 micro M thiopentone or pentobarbitone in all segments tested.
      Inhibition was reversed by changing the bath solution. CONCLUSIONS: Thio- and
      oxybarbiturates inhibit intestinal peristalsis in the guinea-pig ileum. It is
      assumed that thiopentone and pentobarbitone affect propulsive peristalsis also in
      the human small intestine.

PMID- 12469285
TI  - [A comparison of the Proseal laryngeal mask to the standard laryngeal mask on
      anesthesized, non-relaxed patients].
AB  - It was our goal to compare the Proseal-laryngeal mask airway (PLMA) with the
      classical laryngeal mask airway (LMA) in a german multicenter trial. Handling of
      the instruments and application criteria were to be tested. 7 anaesthesia
      departments were able to take part in this study. 280 patients could be
      investigated after approval of the ethics committee of the medical faculty of the
      university of Goettingen. 145 patients received the PLMA and 135 the LMA. The
      surgical interventions were small to moderate procedures with a duration of at
      least 20 minutes in the sections general surgery, trauma/orthopedic surgery,
      urology, vascular surgery, gynecology, ENT-surgery and ophthalmology. There was
      equivalence of the two instruments PLMA and LMA concerning duration and ease of
      insertion, endoscopic position check, observations on emergence, potential for
      injury and some postoperative complaints. This equivalence could be confirmed
      statistically. Laryngospasm was observed in three, Bronchospasm in two patients
      with the PLMA, in no one with the LMA. In one case of laryngospasm and another of
      bronchospasm a mechanism of supraglottic laryngeal stenosis has been involved
      which may occur in rare instances with the PLMA. This mechanism is due to the
      double cuff of the PLMA with the instruments proximity to the laryngeal inlet.
      The seal pressure in both groups differs significantly (p = 0.001). The mean
      value for the seal pressure was 29,3 +/- 0,21 mbar for the PLMA and 20,9 +/- 0,21
      mbar for the LMA. In the PLMA the gastric tube could be positioned with the first
      attempt in 118 patients, with the second attempt in 17 cases. In 10 patients the
      gastric tube could not be placed. Contrary to the LMA the tip of the PLMA cuff
      may be bent in some cases with loss of airway safety and positioning of the
      gastric tube. The symptoms sore throat and painful swallowing on the first
      postoperative day were more frequent with LMA application. These differences
      could be confirmed statistically (sore throat p = 0.01, painful swallowing p =
      0.04). They may be explained by the more rigid LMA compared to the PLMA and by
      the fact that the LMA in this study was older than the PLMA, loosing plasticizer.
      The drainage tube within the PLMA offers safety from aspiration in patients with
      no primary aspiration risk, additional reassurance for a correct position and a
      better stability of the airway. Our data may support a wider indication range for
      the PLMA compared with the LMA. The PLMA may be applied in laparoscopies and
      lower abdominal surgical interventions. Careful clinical observation will show,
      if the minimal invasiveness of the PLMA offers an advantage for these patients.
      The PLMA should not be applied in patients with increased aspiration risk.

PMID- 12469286
TI  - Impact of reservoir hematocrit and processing parameters on the quality of
      processed blood product.

PMID- 12469287
TI  - [Leucocyte activation through intra operative blood salvage].

PMID- 12469288
TI  - [Intraoperative blood salvage with irradiation of blood in cancer surgery --
      answers to current queries].

PMID- 12469289
TI  - [Autotransfusion in special procedure and diseases].

PMID- 12469290
TI  - [Haemostasis with haemodilution -- a quantitative mathematical model of
      thrombocytes and fibrinogen in haemodilution].

PMID- 12469291
TI  - [Identical transfusion trigger in autologous and homologous blood packs?].

PMID- 12469292
TI  - [Compensation mechanisms of perioperative anemia].

PMID- 12469293
TI  - [Tolerance of perioperative anemia].

PMID- 12469294
TI  - [Aseptic central venous catheter exchange with a guide wire].
AB  - Central venous catheters are exchanged in cases of malfunction, suspected
      infections, or when another catheter type is required. It can be replaced by new
      venipuncture or using a guide wire. The guide wire technique should be used with
      a defective catheter or when the catheter type is to be changed. It is
      contraindicated at exit site infections or proven or suspected catheter
      infections. Due to possible cross contamination of new by old catheter material
      meticulous aseptic technique is required. A detailed description of the process
      of catheter exchange using a guide wire with special regard to the aseptic
      technique is given.

PMID- 12469295
TI  - Isolation and characterization of a Gram-positive polyphosphate-accumulating
      bacterium.
AB  - A Gram-positive polyphosphate-accumulating bacterium was isolated from phosphate
      removal activated sludge using pyruvate-supplemented agar plates. The isolate was
      oval or coccobacilli (0.4-0.7 x 0.5-1.0 mm) that occurred singly, in pairs or
      irregular clumps. Polyphosphate granules in the cells were observed by toluidine
      blue staining. The pure culture of the isolate rapidly took up phosphate (9.2 mg
      P/g-dry weight) in the 3-h aerobic incubation without organic substrates, after
      anaerobic incubation with organic substrates containing casamino acids. When
      acetate was the sole carbon source in the anaerobic incubation, the isolate did
      not remove phosphate. These physiological features of the isolate were similar to
      those of Microlunatus phosphovorus. However, unlike M. phosphovorus the P-removal
      ability of the isolate was relatively low and was not accelerated by repeating
      the anaerobic/aerobic incubation cycles. Phylogenetic analysis and comparison of
      several characteristics showed that the isolate was identified as Tetrasphaera
      elongata which was recently proposed as a new polyphosphate-accumulating species
      isolated from activated sludge. As the isolate contained menaquinone (MK)-8(H(4))
      as the predominant isoprenoid ubiquinone, it may be significantly responsible for
      phosphate removal, because MK-8(H(4)) has reportedly been found in fairly high
      proportions in many phosphate-removing activated sludges.

PMID- 12469296
TI  - Cloning, nucleotide sequencing, and expression of the beta-galactosidase-encoding
      gene (lacA) from Aspergillus oryzae.
AB  - lacA coding for beta-galactosidase (beta-gal) was cloned from the genomic DNA of
      Aspergillus oryzae RIB40. There were 9 exons in lacA and the coding region of
      3,015 bp encoded a protein of 1,005 aa with a deduced molecular mass of 109,898.
      A. oryzae lacA was highly homologous to fungal beta-gals, with the highest aa
      identity of 70.7% to A. niger lacA, and also showed significant identity to acid
      beta-gals belonging to family 35 glycosyl hydrolases. Approximately 10 copies of
      lacA under control of A. oryzae glaA promoter were integrated into the chromosome
      of A. oryzae M-2-3. The recombinant strain expressed more than 700-fold of the
      beta-gal activity as compared to the wild type strain under induction by maltose.

PMID- 12469297
TI  - Succinate accumulation in pig large intestine during antibiotic-associated
      diarrhea and the constitution of succinate-producing flora.
AB  - Succinate was the major organic acid detected in the hindgut content of pigs
      suffering from antibiotic-associated diarrhea. Antibiotic-associated diarrhea was
      induced by an oral dose of polymyxin B sulfate (3,000,000 units/day) or an
      intramuscular injection of enrofloxacin (0.6 g enrofloxacin/day). In the large
      intestine of enrofloxacin-treated pigs, Gram-negative facultative anaerobic rods
      phylogenetically related to Escherichia coli and Gram-positive facultative
      anaerobic non-spore-forming rods phylogenetically related to Lactobacilli were
      isolated as succinate producers. Succinate-producing Lactobacilli were only
      isolated as the succinate producer in polymyxin B sulfate-treated pigs. In
      contrast to antibiotic-associated diarrhea pigs, bacteria belonging to
      Bacteroidaceae, Fusobacteria, and Enterobacteriaceae were detected as succinate
      producers in a non-treated pig. In antibiotic-associated diarrhea conditions,
      antibiotic-resistant Enterobacteria, E. coli in particular, and Lactobacilli may
      contribute to an abnormal succinate accumulation and may affect water absorption
      in the hindgut that relates to an expression of antibiotic-associated diarrhea.

PMID- 12469298
TI  - Phylogenetic structure of the genera Flexibacter, Flexithrix, and Microscilla
      deduced from 16S rRNA sequence analysis.
AB  - The 16S rDNA sequences of 40 strains of 17 species in the genus Flexibacter, 5
      strains of 4 species in the genus Microscilla, and 1 strain of Flexithrix
      dorotheae, including all type strains of approved and validated species in these
      genera, were determined to reveal their phylogenetic relationships. The 16S rRNA
      sequence analysis demonstrated the extreme heterogeneity of the genera
      Flexibacter and Microscilla. The strains examined diverged into 24 distinct lines
      of descent (1 group included both flexibacteria and flexithrix, and 1 group
      included both flexibacteria and microscilla) that were remote from each other at
      the genus level or higher. Flexibacter strains were scattered across the
      cytophaga-flavobacteria-bacteroides phylum and divided into 20 phylogenetic
      groups, and the genus Microscilla was separated into 5 groups. Flexibacter
      flexilis, the type species of the genus Flexibacter, and Microscilla marina, the
      type species of the genus Microscilla, were isolated from other organisms in
      their respective genera. This means that each genus should be restricted to only
      the type species. Flexithrix dorotheae, the type species of the genus Flexithrix,
      clustered with Flexibacter aggregans. The heterogeneity was found not only within
      genera but also within species. Flexibacter aggregans, Flexibacter aurantiacus,
      Flexibacter flexilis, Flexibacter roseolus, Flexibacter tractuosus, and
      "Microscilla sericea" each contained phylogenetically distant strains. The
      taxonomic concept of the genera Flexibacter, Flexithrix, and Microscilla should
      be reorganized in accordance with the natural relationships revealed in this
      study.

PMID- 12469299
TI  - Isolation of Arthrobacter strains on the basis of their cystite formation.

PMID- 12469300
TI  - Comparison of 16S rRNA, ammonia monooxygenase subunit A and hydroxylamine
      oxidoreductase gene, in chemolithotrophic ammonia-oxidizing bacteria.

PMID- 12469301
TI  - Covalently linked polyamines in the cell wall peptidoglycan of Selenomonas,
      Anaeromusa, Dendrosporobacter, Acidaminococcus and Anaerovibrio belonging to the
      Sporomusa subbranch.

PMID- 12469303
TI  - DNA base composition of planktonic species of Anabaena (Cyanobacteria) and its
      taxonomic value.
AB  - Fifty axenic strains of planktonic Anabaena, including 24 strains of the straight
      form and 26 strains of the coiled form, were examined for their DNA base
      composition (GC content). The taxonomic value of their GC content at species
      level was evaluated by comparing their morphological, physiological and
      biochemical properties. The DNA base composition determined for all fifty strains
      ranged from 35.9 to 56.4 mol% GC. The straight-form strains were in the range of
      35.9-56.4 mol% GC, while coiled forms were in the range of 38.1-50.3 mol% GC. In
      general, strains assigned to the same species showed similar DNA base
      composition. However, of three strains of A. affinis Lemmermann that were
      separated into two categories, two had 40.6-40.9 mol% GC, and the third strain
      45.6 mol% GC. It is noteworthy that the DNA base composition of the newly
      established species A. eucompacta Li et Watanabe was 45.5 mol% GC, which differed
      from 39.5 mol% GC of the morphologically close species, A. compacta (Nygarrd)
      Hickel.

PMID- 12469302
TI  - Rapid cell death in Xanthomonas campestris pv. glycines.
AB  - Xanthomonas campestris pv. glycines strain AM2 (XcgAM2), the etiological agent of
      bacterial pustule disease of soybean, exhibited post-exponential rapid cell death
      (RCD) in LB medium. X. campestris pv. malvacearum NCIM 2310 and X. campestris
      NCIM 2961 also displayed RCD, though less pronouncedly than XcgAM2. RCD was not
      observed in Pseudomonas syringae pv. glycines, or Escherichia coli DH5alpha.
      Incubation of the post-exponential LB-grown XcgAM2 cultures at 4 degrees C
      arrested the RCD. RCD was also inhibited by the addition of starch during the
      exponential phase of LB-growing XcgAM2. Protease negative mutants of XcgAM2 were
      found to be devoid of RCD behavior observed in the wild type XcgAM2. While
      undergoing RCD, the organism was found to transform to spherical membrane bodies.
      The presence of membrane bodies was confirmed by using a membrane specific
      fluorescent label, 1,6-diphenyl 1,3,5-hexatriene (DPH), and also by visualizing
      these structures under microscope. The membrane bodies of XcgAM2 were found to
      contain DNA, which was devoid of the indigenous plasmids of the organism. The
      membrane bodies were found to bind annexin V indicative of the externalization of
      membrane phosphatidyl serine. Nicking of DNA in XcgAM2 cultures undergoing RCD in
      LB medium was also detected using a TUNEL assay. The RCD in XcgAM2 appeared to
      have features similar to the programmed cell death in eukaryotes.

PMID- 12469304
TI  - Effects of fructooligosaccharide on conversion of L-tryptophan to skatole and
      indole by mixed populations of pig fecal bacteria.
AB  - An in vitro study was conducted to examine the effects of fructooligosaccharide
      (FOS) at levels of 0.5, 1.0, and 1.5% on conversion of L-tryptophan to skatole
      and indole by a mixed bacterial population from the large intestines of pigs.
      Microbial suspensions were anaerobically incubated at 38 degrees C for 24 h.
      Samples were periodically removed for determination of pH and indole compounds.
      After 24 h incubation, microbial populations in each culture media were analyzed.
      Addition of 0.5, 1.0, and 1.5% FOS to the slurries with L-tryptophan
      significantly decreased the skatole concentration, the peak value of indole-3
      acetic acid and the medium pH. The viable counts of Bifidobacterium were
      significantly higher as compared with the control. Addition of 1.0 and 1.5% FOS
      significantly decreased the rate of tryptophan degradation and the relative rate
      of skatole production. The relative rate of indole production was significantly
      increased. The viable counts of Clostridium and Escherichia coli were
      significantly reduced. The total viable counts of anaerobes were significantly
      increased. These results suggest that the reduced concentration of skatole
      observed in the presence of FOS may be caused by the decreased tryptophan
      degradation due to the increased need for amino acids in the synthesis of
      bacterial cellular protein, and by shifting microbial metabolism of tryptophan
      toward indole production at the expense of skatole, which might result from the
      changed microbial ecosystem and pH. Our observations open the possibility of
      inhibiting microbial production of skatole and decreasing the skatole
      concentration in backfat by feeding pigs diets containing FOS, but it remains to
      be demonstrated in vivo.

PMID- 12469305
TI  - The effect of sodium acetate on the growth yield, the production of L- and D
      lactic acid, and the activity of some enzymes of the glycolytic pathway of
      Lactobacillus sakei NRIC 1071(T) and Lactobacillus plantarum NRIC 1067(T).
AB  - The effect of sodium acetate was studied on the change of the growth yield, the
      production of L- and D-lactic acid, and the activity of lactate dehydrogenases
      (LDHs; L-lactate dehydrogenase [EC 1.1.1.27, L-LDH] plus D-lactate dehydrogenase
      [EC 1.1.1.28, D-LDH]), fructose-1, 6-bisphosphate aldolase [EC 4.1.2.13, FBP
      aldolase], and phosphofructokinase [EC 2.7.1.11, PFK] of Lactobacillus sakei NRIC
      1071(T) and Lactobacillus plantarum NRIC 1067(T). The growth yield of L. sakei
      NRIC 1071(T) was increased 1.6 times in the presence of sodium acetate compared
      with its absence. The activity of LDHs in L. sakei NRIC 1071(T) and L. plantarum
      NRIC 1067(T) was retained longer under the addition of sodium acetate in the
      reaction mixture. As a result, these strains produced much more lactic acid in
      the presence of sodium acetate compared with its absence. Furthermore, the
      activity of L-LDH in L. sakei NRIC 1071(T) cultivated in the presence of sodium
      acetate increased three times or more compared with the activity of the cells
      cultivated in its absence. Consequently, the type of stereoisomers of lactic acid
      produced by L. sakei shifted from the DL-type to the L-type because the ratio of
      L-lactic acid to D-lactic acid produced became larger with the addition of sodium
      acetate to culture media. This phenomenon was not observed in L. plantarum NRIC
      1067(T). Further, the participation of lactate racemase is discussed from the
      viewpoint of the production of D-lactic acid by L. sakei.

PMID- 12469306
TI  - Inhibition of hepatitis B virus assembly with synthetic peptides derived from the
      viral surface and core antigens.
AB  - The long surface antigen (L-HBsAg) of hepatitis B virus (HBV) plays a central
      role in the production of infectious virions. During HBV morphogenesis, both the
      PreS and S domains of L-HBsAg form docking sites for the viral nucleocapsids.
      Thus, a compound that disrupts the interaction between the L-HBsAg and
      nucleocapsids could serve as a therapeutic agent against the virus based upon
      inhibition of morphogenesis. Synthetic peptides correspond to the binding sites
      in L-HBsAg inhibited the association of L-HBsAg with core antigen (HBcAg). A
      synthetic peptide carrying the epitope for a monoclonal antibody to the PreS1
      domain competed weakly with L-HBsAg for HBcAg, but peptides corresponding to a
      linear sequence at the tip of the nucleocapsid spike did not, showing that the
      competing peptide does not resemble the tip of the spike.

PMID- 12469307
TI  - Haliangium ochraceum gen. nov., sp. nov. and Haliangium tepidum sp. nov.: novel
      moderately halophilic myxobacteria isolated from coastal saline environments.
AB  - Phenotypic and phylogenetic studies were performed on two myxobacterial strains,
      SMP-2 and SMP-10, isolated from coastal regions. The two strains are
      morphologically similar, in that both produce yellow fruiting bodies, comprising
      several sessile sporangioles in dense packs. They are differentiated from known
      terrestrial myxobacteria on the basis of salt requirements (2-3% NaCl) and the
      presence of anteiso-branched fatty acids. Comparative 16S rRNA gene sequencing
      studies revealed that SMP-2 and SMP-10 are genetically related, and constitute a
      new cluster within the myxobacteria group, together with the Polyangium
      vitellinum Pl vt1 strain as the closest neighbor. The sequence similarity between
      the two strains is 95.6%. Based on phenotypic and phylogenetic evidence, it is
      proposed that these two strains be assigned to a new genus, Haliangium gen. nov.,
      with SMP-2 designated as Haliangium ochraceum sp. nov. (= JCM 11303(T) = DSM
      14365(T)), and SMP-10 as Haliangium tepidum sp. nov. (= JCM 11304(T)= DSM
      14436(T)).

PMID- 12469308
TI  - Characterization of the toluene-sensitive mutants of Pseudomonas putida
      KT2442TOL.

PMID- 12469309
TI  - Phylogenetic position of Mixia osmundae inferred from 28S rDNA comparison.

PMID- 12469310
TI  - Ameliorative role of nitric oxide on H2O2 toxicity to a chlorophycean alga
      Scenedesmus obliquus.
AB  - A concentration-dependent toxicity of hydrogen peroxide (H(2)O(2)) was observed
      on growth yield, chlorophyll a content and chlorophyll fluorescence
      characteristics of the green microalga Scenedesmus obliquus under laboratory
      batch culture conditions. The addition of sodium nitroprusside, a nitric oxide
      (NO) donor, in combination with H(2)O(2) prevented chlorophyll losses, and the
      inhibition level of growth yield, maximum quantum yield of photosystem II (PSII)
      and the light-adapted quantum yield of PSII were significantly reduced. The
      antioxidant compounds, penicillamine and thiourea also reduced the damage caused
      by H(2)O(2) exposure. The protective actions of sodium nitroprusside were,
      however, arrested in cultures where sodium nitroprusside was supplemented in
      combination with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3
      oxide (c-PTIO), a specific scavenger of NO. The NO(3)(-)-grown Scenedesmus
      depicted less sensitivity to H(2)O(2) toxicity with respect to the quantum yields
      of PSII as compared to its NH(4)(1)-grown counterpart. The role of NO in
      providing protection against H(2)O(2) toxicity to the processes under study was
      discussed.

PMID- 12469311
TI  - Evolutionary relationships within Aspergillus section Flavi based on sequences of
      the intergenic transcribed spacer regions and the 5.8S rRNA gene.
AB  - Sequences of the intergenic transcribed spacer regions and the 5.8S rRNA gene
      (455 nucleotides) of type strains or representative isolates of 23 species and
      subspecies either currently assigned to Aspergillus subgenus Circumdati section
      Flavi or other closely related sections, were analyzed. Parsimony analysis of
      sequence data indicated that species of Aspergillus section Flavi form distinct
      clades. The three main clades identified based on sequence data could also be
      distinguished based on colony color, and their ubiquinone systems. The 'A.
      flavus' clade includes species characterized with Q-10(H(2)) as their main
      ubiquinone, conidial colors in shades of green, and dark sclerotia. The 'A.
      tamarii' clade involves species with ubiquinone system Q-10(H(2)), and conidia in
      shades of olive to brown, while the 'A. alliaceus' clade consists of species with
      Q-10 ubiquinone system, and conidia in shades of ocher. The synnematous species
      A. coremiiformis was found to be closely related to species in the 'A. tamarii'
      clade. A. thomii and A. terricola var. americana were found to be related to the
      'A. flavus' clade in spite of producing brownish colonies. Three species, A.
      nomius, A. avenaceus, and A. leporis were found to form separate lineages not
      closely related to any of the main clades identified. It is suggested that A.
      clavatoflavus and A. zonatus be excluded from Aspergillus section Flavi.
      Phylogenetic analysis of partial 26S rRNA gene sequences (564 nucleotides)
      supported our findings.

PMID- 12469312
TI  - Dioszegia zsoltii sp. nov., a new ballistoconidium-forming yeast species with two
      varieties.
AB  - As a result of conventional characterization of yeasts isolated from various
      plant leaves collected in Yunnan, China, six ballistoconidium-forming strains
      with orange-colored colonies were grouped together. Molecular phylogenetic
      analysis based on 18S rDNA sequencing showed that two representative strains of
      this group of yeasts, CH 2.068 and CH 2.497, were closely related to the species
      in the genus Dioszegia and had signature sequences typical of this genus.
      However, the six strains from Yunnan differed from the described Dioszegia
      species remarkably (14.5-17.7% nucleotide divergences) in the ITS (internal
      transcribed spacer) region sequences, which indicated that they represent a
      distinct species. Furthermore, among the six strains studied, the ITS region
      sequence comparison allowed the recognition of two subgroups represented by CH
      2.068 and CH 2.497, which differ from each other in three bases in the ITS 2
      region. DNA-DNA relatedness revealed that the two subgroups represent two
      varieties of a new species in the genus Dioszegia, for which Dioszegia zsoltii
      sp. nov. var. zsoltii and Dioszegia zsoltii var. yunnanensis var. nov. are
      proposed.

PMID- 12469313
TI  - Purification and characterization of a novel chitinase from Burkholderia cepacia
      strain KH2 isolated from the bed log of Lentinus edodes, Shiitake mushroom.
AB  - One of the chitinases secreted in the culture filtrate of a gram-negative
      bacteria, Burkholderia cepacia strain KH2, which was isolated from the bed log of
      Lentinus edodes, Shiitake mushrooms, was purified by DEAE Sepharose CL-6B
      chromatography, followed by Sephacryl S-100 HR gel filtration. The purified
      enzyme was homogenous, determined by sodium dodecyl sulfate polyacrylamide gel
      electrophoresis (SDS-PAGE), with an estimated molecular weight of 34,000 and an
      isoelectric point (pI) of 5.9. The enzyme was stable at pH values of 4.0-6.0, and
      at temperatures up to 50 degrees C; the optimum pH and temperature were 4.5 and
      50 degrees C, respectively. The enzyme exhibited higher activities toward
      chitosan 7B, a 62% deacetylated chitosan, than toward the highly deacetylated
      chitosan substrates. The enzyme was observed to drastically hydrolyze partially
      deacetylated chitin substrates, with the subsequent formation of N
      acetylchitooligosaccharides [(GlcNAc) (n), n=2-7]. Separation and quantification
      of the hydrolysis products of (GlcNAc) (n), n52-6, by HPLC showed the splitting
      into (GlcNAc)(n), n=3-6. Activity toward N-acetylchitobiose was not detected.
      Oligomers with a higher number of units than the starting substrate were also
      detected, which indicate transglycosylation activity.

PMID- 12469314
TI  - Analysis of the differences in microbial community structures between suspended
      and sessile microorganisms in rivers based on quinone profile.
AB  - In this study, a quinone profiling method was applied to clarify the differences
      in community structure between suspended and sessile microorganisms in rivers.
      The compositions of microbial quinone of 6 sites for 4 rivers were analyzed.
      Ubiquinone (UQ)-8, UQ-10, menaquinone (MK)-7, and plastoquinone (PQ)-9 were
      observed in all samples of suspended and sessile microorganisms for the sites
      investigated. The dominant quinone species in suspended microorganisms was
      ubiquinone, and that in sessile microorganism was photosynthetic quinones (namely
      PQ-9 and vitamin K1). This indicated that aerobic bacteria were abundant in the
      suspended microorganisms, and photosynthetic microorganisms such as micro-algae
      and cyanobacteria dominated in the sessile microorganisms. The quinone
      concentration in the river waters tested, which reflects the concentration of
      suspended microorganisms, ranged from 0.045 to 1.813 nmol/L. The microbial
      diversities of suspended and sessile microorganisms calculated based on the
      composition of all quinones were in the range from 3.4 to 7.5, which was lower
      than those for activated sludge and soils. Moreover, the diversity of
      heterotrophic bacteria for sessile microorganisms in the rivers was higher than
      that for the suspended microorganisms.

PMID- 12469315
TI  - Polyphasic approaches to the identification of predominant polyphosphate
      accumulating organisms in a laboratory-scale anaerobic/aerobic activated sludge
      system.
AB  - By combination of denaturing gradient gel electrophoresis of PCR-amplified 16S
      rDNA (PCR-DGGE), quinone profiling, and 16S rRNA-targeted fluorescence in situ
      hybridization (FISH), a polyphosphate-accumulating organism (PAO) responsible for
      phosphate (P)-removal was identified in activated sludge with high P-removal
      ability from a laboratory-scale anaerobic/aerobic continuous flow reactor. The
      DNA fragment from the most dense band on the DGGE gel was closely related to that
      of 'Candidatus Accumulibacter phosphatis' (beta-Proteobacteria). Quinone
      profiling also suggested the predominance of beta-Proteobacteria. FISH with a
      specific oligonucleotide probe designed for the sequence showed that the targeted
      bacterium was dominant in the activated sludge, and the accumulation and
      consumption of polyphosphate were observed by dual staining with 4',6-diamidino-2
      phenylindole. The bacterium was concluded to be the responsible PAO in the
      reactor. However, when the P-removal ability per cell slightly decreased, the
      dominance of the PAO greatly diminished in the activated sludge. Such sludge
      might be dominated by other types of PAOs.

PMID- 12469316
TI  - A phylogenetic study of ubiquinone-7 species of the genus Candida based on 18S
      ribosomal DNA sequence divergence.
AB  - To clarify phylogenetic relationships among ubiquinone 7 (Q7)-forming species of
      the genus Candida, we analyzed the nearly complete sequences of 18S ribosomal RNA
      genes (18S rDNAs) from fifty strains (including 46 type strains) of Candida
      species, and from 8 type strains of species/varieties of the genera Issatchenkia,
      Pichia and Saturnispora. Q7-forming Candida species were divided into three major
      groups (Group I, II, and III) and were phylogenetically distant from a group that
      includes the type species of the genus Candida. Group I included four clusters
      with basal branches that were weakly supported. The first cluster comprised C.
      vartiovaarae, C. maritima, C. utilis, C. freyschussii, C. odintsovae, C. melinii,
      C. quercuum, Williopsis saturnus var. saturnus, and W. mucosa. The second cluster
      comprised C. norvegica, C. montana, C. stellimalicola, C. solani, C. berthetii,
      and C. dendrica. Williopsis pratensis, W. californica, Pichia opuntiae and 2
      related species, P. amethionina (two varieties), and P. caribaea were also
      included in this cluster. The third cluster comprised C. pelliculosa (anamorph of
      P. anomala), C. nitrativorans, and C. silvicultrix. The fourth cluster comprised
      C. wickerhamii and C. peltata, which were placed in the P. holstii - C. ernobii
      clade with Q8-containing species. Group II comprised C. pignaliae, C. nemodendra,
      C. methanolovescens, C. maris, C. sonorensis, C. pini, C. llanquihuensis, C.
      cariosilignicola, C. ovalis, C. succiphila (including its two synonyms), C.
      methanosorbosa, C. nitratophila, C. nanaspora, C. boidinii (including its two
      synonyms), W. salicorniae, and P. methanolica. Group III was composed of four
      clusters with strong bootstrap support. The first cluster comprised C. valida
      (anamorph of P. membranifaciens), C. ethanolica, C. pseudolambica, C. citrea, C.
      inconspicua, C. norvegensis, C. rugopelliculosa, and C. lambica. Three species
      and two varieties of the genus Issatchenkia were also included in this cluster.
      The second cluster comprised C. diversa, C. silvae, 4 Saturnispora species, and
      P. besseyi. The third comprised C. sorboxylosa, and the fourth comprised C. vini.
      Based on this 18S rDNA sequence analysis, it is evident that Q7-forming Candida
      species and the genera Pichia and Williopsis are polyphyletic. The genus
      Issatchenkia is suggested to be congeneric with the genus Pichia. The genus
      Saturnispora is phylogenetically definable.

PMID- 12469317
TI  - Symbiotic root nodule bacteria isolated from yam bean (Pachyrhizus erosus).
AB  - A total of 25 isolates from root nodules of yam bean (Pachyrhizus erosus L.
      Urban), a tuber-producing leguminous plant, were characterized. All isolates
      formed effective nodules mainly on lateral roots while edible tubers were
      developed on the taproot. The root nodules formed were identified as the typical
      determinate type. By an analysis of the partial sequences of the 16S rRNA gene
      (approximately 300 bp) of 10 strains which were selected randomly, the isolated
      root nodule bacteria of yam bean were classified into two different genera,
      Rhizobium and Bradyrhizobium. Two strains, YB2 (Bradyrhizobium group) and YB4
      (Rhizobium group) were selected and used for further analyses. The generation
      time of each strain was shown to be 22.5 h for strain YB2 and 0.8 h for strain
      YB4, respectively. Differences between strains YB2 and YB4 were also reflected in
      the bacteroid state in the symbiosome. Symbiosome in nodule cells for the strain
      YB4 contained one bacteroid cell in a peribacteroid membrane, whereas a
      symbiosome for strain YB2 contained several bacteroid cells.

PMID- 12469318
TI  - Effects of ozone treatment on cell growth and ultrastructural changes in
      bacteria.
AB  - Ozone appeared to inhibit growth and caused the death of gram negative and gram
      positive tested bacteria: Escherichia coli, Salmonella sp., Staphylococcus aureus
      and Bacillus subtilis. Bacterial cultures at 10(3), 10(4), 10(5), 10(6), and
      10(7) cfu/ml dilution were exposed to 0.167/mg/min/L of ozone at different time
      intervals (0, 5, 10, 15, 30, 60, 90, 120, and 150 min). Cell viability was
      observed in all types of tested bacteria at 10(3), 10(4), 10(3) cfu/ml within 30
      min after ozone exposure. However, cell inactivation was not significantly
      observed at concentrations of 10(6), 10(7) cfu/ml even after an exposure of 150
      min. Ultrastructural changes of treated bacteria showed deformation, rough damage
      and surface destruction revealed by scanning electron microscopy. Some bacterial
      cells showed collapsed and shrunken patterns within 60 min and severe rupture and
      cellular lysis after 90 min of ozone treatment. This study supports the proposed
      mechanism of the bacteria inactivation by ozone that caused cell membrane
      destruction and finally lysis reaction. Thus, the precaution of using ozone as a
      biocide should be used to address appropriate concentrations of bacterial
      contamination in water.

PMID- 12469319
TI  - Lactic acid bacteria isolated from soy sauce mash in Thailand.
AB  - Fourteen sphere-shaped and 30 rod-shaped lactic acid bacteria were isolated from
      soy sauce mash of two factories in Thailand. These strains were separated into
      two groups, Group A and Group B, by cell shape and DNA-DNA similarity. Group A
      contained 14 tetrad-forming strains, and these strains were identified as
      Tetragenococcus halophilus by DNA similarity. Group B contained 30 rod-shaped
      bacteria, and they were further divided into four Subgroups, B1, B2, B3, and B4,
      and three ungrouped strains by phenotypic characteristics and DNA similarity.
      Subgroup B1 contained 16 strains, and these strains were identified as
      Lactobacillus acidipiscis by DNA similarity. Subgroup B2 included two strains,
      and the strains were identified as Lactobacillus farciminis by DNA similarity.
      Subgroup B3 contained five strains. The strains had meso-diaminopimelic acid in
      the cell wall, and were identified as Lactobacillus pentosus by DNA similarity.
      The strains tested produced DL-lactic acid from D-glucose. Subgroup B4 contained
      four strains. The strains had meso-diaminopimelic acid in the cell wall, and they
      were identified as Lactobacillus plantarum by DNA similarity. Two ungrouped
      strains were homofermentative, and one was heterofermentative. They showed a low
      degree of DNA similarity with the type strains tested, and were left unnamed. The
      distribution of lactic acid bacteria in soy sauce mash in Thailand is discussed.

PMID- 12469320
TI  - Phylogenetic characterization of microbial mats and streamers from a Japanese
      alkaline hot spring with a thermal gradient.
AB  - Dense microbial mats and streamers of various colors developed in an alkaline-hot
      spring water at 48-76 degrees C and ~0.077 mm sulfide in Nakabusa, Japan. The
      microbial community structures with a thermal gradient were compared by
      denaturing gradient gel electrophoresis (DGGE) analysis of the PCR-amplified 16S
      ribosomal RNA gene fragments. The sequence analysis revealed that a predominant
      cyanobacterial DGGE band phylogenetically related to Synechococcus elongatus was
      detected only from green mats at 48 degrees C. Four DGGE bands were detected
      commonly from green mats at 48 degrees C, orange mats at 58 degrees C and brown
      mats at 60 degrees C. The sequence analysis revealed that these were
      phylogenetically related to Chloroflexaceae group, Rhodothermus group, a
      candidate division OP10, and an unclassified bacterium. On the other hand,
      Aquificae-, Thermodesulfobacteria-, Thermus group-, and Crenarchaeota-like
      sequences were detected as a predominant component of DGGE profiling from the
      streamers only at temperatures over 66 degrees C, but no phototrophic bacterial
      bands were detected. Thus, the microbial community structure above 60 degrees C
      was drastically different from that at the lower temperatures. After the addition
      of hydrogen into in vitro gray streamers with in situ spring water, sulfide
      production markedly occurred in the presence of ambient sulfate at 66 degrees C.
      This result suggests that in situ sulfide is partly produced by
      Thermodesulfobacteria-like sulfate-reducing bacteria in the streamers.

PMID- 12469321
TI  - A promoter activity in Saccharomyces cerevisiae of the 3'-noncoding region of the
      basidiomycetous mushroom gene.
AB  - The 3'-noncoding region of the priB gene derived from the basidiomycete Lentinus
      edodes was found to contain one GC box-like sequence, two CAAT boxes, two TATA
      box-like sequences and two pyrimidine-rich stretches (CT-motifs). It also
      contained a 16-bp sequence similar to the consensus sequence for PRIB protein
      binding and a short (61 bp) intron. Single-strand-specific S1 nuclease analysis
      of plasmid pBR322 DNA containing the 3'-noncoding region propagated in
      Escherichia coli revealed that this region forms an unusual, extended open
      structure within/around the downstream pyrimidine/purine (CT/AG)-biased sequence.
      To examine the promoter activity of the priB 3'-noncoding region in Saccharomyces
      cerevisiae, in which an autonomously replicating plasmid vector is available, we
      constructed two plasmids, YEp3'NCR-lacZ and YEp3'UTR-lacZ. The former contains
      the priB 3'-noncoding region and the reporter E. coli beta-galactosidase gene
      while the latter contains the priB 3'-noncoding region lacking the intron and the
      reporter gene. The yeast transformants obtained through introductions of these
      plasmids showed beta-galactosidase activity and the activity conferred by
      YEp3'NCR-lacZ was about 50% of that conferred by YEp3'UTR-lacZ. The primer
      extension analysis showed that transcription of the reporter gene on both
      plasmids starts at three alternative sites all of which are located within the
      downstream CT-motif, suggesting a role for the unusual structure of the CT/AG
      biased sequence in the initiation of transcription.

PMID- 12469322
TI  - A unique feature of Bacillus thuringiensis H-serotype flora in soils of a
      volcanic island of Japan.

PMID- 12469323
TI  - Survival of freeze-dried Lactobacillus acidophilus immobilized in kappa
      carrageenan gel.

PMID- 12469324
TI  - A 122.5-kilobase deletion of the P gene underlies the high prevalence of
      oculocutaneous albinism type 2 in the Navajo population.
AB  - Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder. There are
      four known types of OCA: OCA1-OCA4. The clinical manifestations of all types of
      OCA include skin and hair hypopigmentation and visual impairment. Although there
      are a few documented observations of high frequency of albinism among Native
      Americans, including the Hopi, Zuni, Kuna, Jemez, Laguna, San Juan, and Navajo,
      no causative molecular defect has been previously reported. In the present study,
      we show that albinism in one Native American population, the Navajo, is caused by
      a LINE-mediated 122.5-kilobase deletion of the P gene, thus demonstrating that
      albinism in this population is OCA2. This deletion appears to be Navajo specific,
      because this allele was not detected in 34 other individuals with albinism who
      listed other Native American origins, nor has it been reported in any other
      ethnic group. The molecular characterization of this deletion allele allowed us
      to design a three-primer polymerase chain reaction system to estimate the carrier
      frequency in the Navajo population by screening 134 unrelated normally pigmented
      Navajos. The carrier frequency was found to be approximately 4.5%. The estimated
      prevalence of OCA2 in Navajos is between approximately 1 per 1,500 and 1 per
      2,000. We further estimate that this mutation originated 400-1,000 years ago from
      a single founder.

PMID- 12469325
TI  - The proto-oncogene BCL-6 in normal and malignant B cell development.
AB  - BCL-6 is an important regulator of the immune system. It is required for GC
      formation and T cell dependent antibody responses. Mice deficient in BCL-6 fail
      to form GC and mount reduced levels of T cell-dependent antibody responses. BCL-6
      (-/-) mice, in addition, develop a massive inflammatory response in many organs
      characterized by eosinophilic infiltration and hyper-IgE production, a typical
      Th2 hyperimmune response. This suggests a negative role of BCL-6 in Th2 pathway.
      The BCL-6 gene encodes a POZ/zinc finger transcription repressor highly expressed
      in GC B cells, but not in pre-GC B cells or in more differentiated memory or
      plasma cells. By functioning as a potent transcriptional repressor of various
      target genes, BCL-6 modulates IL-4, BCR, and CD40L signals for normal B cell
      development. In B cell lymphomas, structural alterations of the BCL-6 promoter
      region, including chromosome translocation and somatic hypermutation, represent
      the most frequent genetic lesions associated with non-Hodgkin lymphoma,
      especially of diffuse large cell lymphoma, a malignancy often derived from
      germinal centre (GC) B cells. This suggests that deregulated expression of BCL-6
      may contribute to lymphomagenesis.

PMID- 12469326
TI  - Hypermethylation of gene promoters in hematological neoplasia.
AB  - Cancer cells are associated with global hypomethylation but with focal
      hypermethylation of specific gene promoters organized as CpG island. DNA
      methyltransferases, DNMT1 and 3 (3a and 3b), have been implicated in mediating
      maintenance and de novo methylation. Hypermethylation of gene promoters results
      in the inactivation of the corresponding genes, by preclusion of the formation of
      the transcription complex, due to the recruitment of MBP, MeCPs and histone
      deacetylase. This results in the deacetylation of histone and thus a compact
      chromatin complex unfavourable for the initiation of transcription. This
      methylation-associated gene silencing has been demonstrated in various genes
      including tumour suppressor genes (p15, p16, p73, VHL). Therefore, gene promoter
      hypermethylation collaborates with other mechanisms of gene inactivation such as
      deletion and intragenic mutations to fulfil Knudson's hypothesis.
      Hypermethylation may serve as a molecular disease marker for the detection of
      minimal residual disease. Emerging evidence suggests a possible prognostic value
      of gene promoter hypermethylation. Moreover, gene hypermethylation may also serve
      as a target for therapeutic invention by hypomethylating agents.

PMID- 12469327
TI  - Characteristics and survival of patients with non-Hodgkin's lymphoma with and
      without acquired immunodeficiency syndrome.
AB  - Our objective was to determine the characteristics and survival of patients with
      non-Hodgkin's lymphoma (NHL) with and without acquired immunodeficiency syndrome
      (AIDS). A cancer registry and AIDS registry linkage for San Diego County was
      performed in October 1998 as part of a national multicentre study. We performed
      Kaplan-Meier analysis to compare survival in NHL patients with and without AIDS,
      after matching for age, sex, and race/ethnicity. We performed logistic regression
      to determine which patient and tumour characteristics were significantly
      associated with 1-year survival. Of the 4361 cases of NHL, 324 (7%) had AIDS and
      4037 (93%) were not known to have AIDS. Patients with AIDS were more likely to
      have extranodal, high-grade, and disseminated NHL diagnosed by non-histologic
      means and were less likely to have received chemotherapy. Patients with AIDS and
      NHL who survived at least 1 year had less advanced disease stage and received
      chemotherapy. The median survival in patients with AIDS was 4 months (95%
      confidence interval (CI): 4-5) and 95 months (95% CI: 58-157) in patients without
      AIDS (P<0.001). Although these patients with AIDS-related NHL were unlikely to
      survive, the highly active antiretroviral agents currently used may improve
      outcomes in future patients.

PMID- 12469328
TI  - Investigation of the high partition of YM992, a novel antidepressant, in rat
      brain - in vitro and in vivo evidence for the high binding in brain and the high
      permeability at the BBB.
AB  - Brain extracellular fluid (ECF) concentration of YM992, a novel antidepressant,
      was determined using brain microdialysis to investigate the high partition of
      this drug to the brain after systemic administration to rats. Plasma,
      cerebrospinal fluid (CSF), ECF and brain concentrations were determined at the
      steady-state after intravenous infusion to rats. The concentration ratio of brain
      to plasma at the total concentration base was 71.3, while those of ECF to plasma
      and CSF to plasma at the free concentration base were comparable. The
      distribution volume in brain was 375 ml/g brain and in vitro binding of YM992 to
      rat brain was 98.1-98.5%, suggesting a high binding in the brain. The carotid
      artery injection study showed that the brain uptake index of YM992 was 141%,
      furthermore, the uptake clearance into brain after i.v. dosing to rats was 0.6
      ml/min/g brain, indicating a high permeability at the blood-brain barrier (BBB).
      These findings suggest that the high partition of YM992 to rat brain is
      attributed to its high level of binding in the brain as well as its high
      permeability at the BBB.

PMID- 12469329
TI  - Effect of zolpidem on human cytochrome P450 activity, and on transport mediated
      by P-glycoprotein.
AB  - The influence of high concentrations of zolpidem (100 microM, corresponding to
      approximately 200 times maximum therapeutic concentrations) on the activity of
      six human Cytochrome P450 (CYP) enzymes was evaluated in a model system using
      human liver microsomes. Zolpidem produced negligible or weak inhibition of human
      CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. Transport of rhodamine 123, presumed to be
      mediated mainly by the energy-dependent efflux transport protein P-glycoprotein,
      was studied in a cell culture system using a human intestinal cell line. High
      concentrations of zolpidem (100 microM), exceeding the usual therapeutic range by
      more than 100-fold, produced only modest impairment of rhodamine 123 transport.
      The findings indicate that zolpidem is very unlikely to cause clinical drug
      interactions attributable to impairment of CYP activity or P-gp mediated
      transport.

PMID- 12469330
TI  - Effect of concomitant colestipol hydrochloride administration on the
      bioavailability of diltiazem from immediate- and sustained-release formulations.
AB  - Effects of concomitant colestipol administration on plasma concentrations of
      diltiazem and desacetyldiltiazem from immediate-release (IR) and sustained
      release (SR) formulations were assessed in two studies. In the first study, 12
      subjects received 120-mg diltiazem hydrochloride (diltiazem) SR capsules or 120
      mg diltiazem IR tablets administered alone and in combination with colestipol
      hydrochloride (colestipol). Following concomitant administration of SR diltiazem
      with colestipol, AUC(0-infinity ) and C(max), respectively, were 22 and 36% less,
      and were 27 and 33% lower for IR diltiazem. In the second study, subjects
      received 120-mg diltiazem SR capsules at staggered times, without colestipol, 1 h
      prior to or 4 h following multiple doses of colestipol. A 17% decrease in AUC(0
      infinity ) was observed when diltiazem was taken 1 h before colestipol was given,
      and a 22% decrease when diltiazem was taken 4 h after colestipol, relative to
      diltiazem SR alone. C(max) values were similarly decreased. Results from these
      two studies show that colestipol can cause a significant decrease in diltiazem
      absorption from both IR and SR dosage forms. Staggering the administration of
      colestipol and diltiazem SR did not blunt this effect, indicating that
      concomitant administration of diltiazem and colestipol should be used with
      caution, and that the efficacy of diltiazem should be monitored to assure
      adequate dosing.

PMID- 12469331
TI  - Dose dependent pharmacokinetics of albendazole in human.
AB  - Pharmacokinetics of albendazole sulphoxide (ABZ-SO) in three different single
      oral doses of albendazole (ABZ) (400, 800 and 1200 mg) was studied in 10 healthy
      human volunteers in a double blind three-way crossover design. The serum levels
      of albendazole main metabolite, albendazole sulphoxide (ABZ-SO), were analysed by
      a modified high-pressure liquid chromatography method. (ABZ is not detectable in
      biological fluids itself.)For ABZ-SO, there was no significant difference in the
      biological half life, normalized serum peak concentration (C(max-ABZ
      SO)/Dose(ABZ)), time to reach peak concentration (T(max)) and mean residence time
      (MRT), whereas apparent clearance (Cl(p)/F), apparent distribution volume
      (V(d)/F), normalized area under the serum concentration-time curve (AUC(ABZ
      SO)/Dose(ABZ)) and normalized area under the first moment curve (AUMC(ABZ
      SO)/Dose(ABZ)) of albendazole main metabolite (ABZ-SO) were statistically
      different at different doses of the parent drug, resulting in substantially lower
      serum concentration and thereafter AUC(ABZ-SO)/Dose(ABZ) and AUMC(ABZ
      SO)/Dose(ABZ) in higher doses. These observations indicate dose dependent
      pharmacokinetics of albendazole (observed for ABZ-SO), which were explained on
      the basis of a change in fraction of dose absorbed (F) as a result of slow and
      incomplete dissolution of the main drug in the GI tract.

PMID- 12469333
TI  - Design of proteome-based studies in combination with serology for the
      identification of biomarkers and novel targets.
AB  - Recently proteome analysis has rapidly developed in the post-genome era and is
      now widely accepted as a complementary technology to genetic profiling. The
      improvement in the technology of both two-dimensional electrophoresis (2-DE)
      analysis as well as protein identification has made proteomics a valuable and
      powerful tool to study human diseases. A combination of conventional proteome
      analysis with serology has been developed as a promising experimental approach
      for the discovery of serological markers in different malignancies. However, the
      design of proteome-based studies has to be carefully performed since there are a
      number of critical needs for systematic and reproducible proteome analysis. In
      particular, the selection of tissue and its preparation represent an important
      step in proteome analysis. Besides the preparation of protein samples, the 2-DE
      and protein identification is a further critical issue. So far proteome-based
      technologies have been successfully used in tumor immunnology for the
      identification of tumor-specific autoantigens. Similarly, this technology has
      been employed for the detection of virulence factors, antigens and vaccine
      candidates in infectious diseases, as well as for the identification of
      diagnostic and prognostic markers, suggesting that proteome-based analysis is a
      promising tool for the identification of prognostic, diagnostic markers as well
      as for novel therapeutic targets which could be used for treatment of diseases.
      The integration of proteome-based approaches with data from genomic or genetic
      profiling will lead to a better understanding of different diseases, which will
      then contribute to the direct translation of the research findings into clinical
      practice.

PMID- 12469334
TI  - Sample prefractionation with Sephadex isoelectric focusing prior to narrow pH
      range two-dimensional gels.
AB  - Due to their heterogeneity and huge differences in abundance, the detection and
      identification of all proteins expressed in eukaryotic cells and tissues is a
      major challenge in proteome analysis. Currently the most promising approaches are
      sample prefractionation procedures prior to narrow pH range two-dimensional gel
      electrophoresis (IPG-Dalt) to reduce the complexity of the sample and to enrich
      for low abundance proteins. We recently developed a simple, cheap and rapid
      sample prefractionation procedure based on flat-bed isoelectric focusing (IEF) in
      granulated gels. Complex sample mixtures are prefractionated in Sephadex gels
      containing urea, zwitterionic detergents, dithiothreitol and carrier ampholytes.
      After IEF, up to ten gel fractions alongside the pH gradient are removed with a
      spatula and directly applied onto the surface of the corresponding narrow pH
      range immobilized pH gradient (IPG) strips as first dimension of two-dimensional
      (2-D) gel electrophoresis. The major advantages of this technology are the highly
      efficient electrophoretic transfer of the prefractionated proteins from the
      Sephadex IEF fraction into the IPG strip without any sample dilution, and the
      full compatibility with subsequent IPG-IEF, since the prefactionated samples are
      not eluted, concentrated or desalted, nor does the amount of the carrier
      ampholytes in the Sephadex fraction interfere with subsequent IPG-IEF.
      Prefractionation allows loading of higher protein amounts within the separation
      range applied to 2-D gels and facilitates the detection of less abundant
      proteins. Also, this system is highly flexibile, since it allows small scale and
      large scale runs, and separation of different samples at the same time. In the
      current study, this technology has been successfully applied for prefractionation
      of mouse liver proteins prior to narrow pH range IPG-Dalt.

PMID- 12469335
TI  - Application of proteomics for fast identification of species-specific peptides
      from marine species.
AB  - In this work, a novel approach based on proteomics is applied for the analysis of
      the three European marine mussel species: Mytilus edulis (ME), Mytilus
      galloprovincialis (MG) and Mytilus trossulus (MT), which are of interest in
      biotechnology and food industry. The proteomes of these species are poorly
      described in databases, are difficult to diagnose, and have a controversial
      taxonomy, To characterise species-specific peptides, we compared 51 matrix
      assisted laser desorption/ioization-time of flight peptide mass maps generated
      from 6 random selected prominent spots derived from the two-dimensional
      electrophoresis analysis of foot protein extracts from several individuals. Minor
      species-specific differences in the peptide maps were detected in only one of the
      spots, corresponding to tropomyosin. Two peptides were unique to ME and MG
      individuals, whereas another peptide was present only in MT individuals. The
      sequence of these peptides was characterised by, nanoelectrospray ionization-ion
      trap (nanoESI-IT) tandem mass spectrometry (MS/MS) analysis followed by database
      searching and de novo sequence interpretation. We detected a single T to D amino
      acid substitution in MT tropomyosin. Unambiguous and highly-specific species
      identification was then demonstrated by analysing peptide extracts from
      tropomyosin spots by micro high-performande liquid chromatography (microHPL) ESI
      IT mass spectrometry using the selected ion monitoring configuration, focused on
      these peptides, in continuous MS/MS operation. Our results suggest that
      proteomics may be successfully applied for the identification of species whose
      proteome is not present in databases.

PMID- 12469336
TI  - Sugar-coated microarrays: a novel slide surface for the high-throughput analysis
      of glycans.
AB  - The development of DNA and protein microarrays represents a significant advance
      in transcriptomics and proteomics research. Such arrays allow the high
      throughput, parallel analysis of protein occurrence and interactions and gene
      expression. However, this advance has not been matched by equivalent technology
      for analysis of glycomes. One reason for this is that compared to proteins, it is
      difficult to reliably immobilise populations of chemically and structurally
      diverse glycans. We describe the development of a new microarray slide surface to
      which diverse glycan structures can be directly immobilised without prior
      derivatisation of the slide surface or any modification of the arrayed samples.
      The slides can be used to produce comprehensive microarrays of carbohydrates,
      glycoproteins and proteoglycans using isolated samples or cell extracts. Using
      standard microarray equipment, a series of carbohydrate microarrays were
      generated and probed with a panel of monoclonal antibodies with specificities for
      glycan epitopes. The arrays were highly reproducible, stable, and could be stored
      dry for several months. Glycans play central roles in development,
      carcinogenesis, cell adhesion, and immunity and are increasingly the subject of
      therapeutic approaches. We anticipate that the development of carbohydrate
      microarrays will be important for the high-throughput analysis of glycans and
      their molecular interactions.

PMID- 12469337
TI  - In situ alkylation with acrylamide for identification of cysteinyl residues in
      proteins during one- and two-dimensional sodium dodecyl sulphate-polyacrylamide
      gel electrophoresis.
AB  - Cysteinyl residues in proteins were alkylated with acrylamide during sodium
      dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) to yield a
      thioether derivative, cys-S-beta-propionamide (PAM cys). The process was termed
      in situ alkylation with acrylamide. Using this method, the recovery of PAM-cys
      peptides from bovine serum albumin (BSA) was 88.6% at 10 picomol in one
      dimensional (1-D) SDS-PAGE and 97.1% at 50 picomol in two-dimensional (2-D) SDS
      PAGE. The coverage of tryptic peptide of BSA in 1-D and 2-D SDS-PAGE was 83.7%
      and 81.1%, respectively. The advantages of in situ alkylation with acrylamide
      were the following: (i) cysteinyl peptides were effectively derived in a single
      PAM cys and then proteins were precisely identified using databases; (ii) marked
      reduction of salts compared with post alkylation, e.g., using carboxymethylamide
      (CAM), resulting in higher signal intensity and wider coverage of cysteinyl
      peptides from PAM cys, compared with those of CAM derivatives, in mass
      spectrometry peptide mapping; and (iii) shorter duration by excluding the
      processes of post alkylation and desalting before peptide mapping.

PMID- 12469338
TI  - Fluorescence two-dimensional difference gel electrophoresis and mass spectrometry
      based proteomic analysis of Escherichia coli.
AB  - Separation and relative quantitation of complex protein mixtures remain two of
      the most challenging aspects of proteomics. Here an advanced technique called
      fluorescence difference 2-D gel electrophoresis technology (2D-DIGE) has been
      applied to a model system study of the Escherichia coli proteome after benzoic
      acid treatment. The molecular weight and charge matched cyanine dyes enable pre
      electrophoretic labelling of control and treated samples which are then mixed and
      run in the same gel. Pooled control and treated samples labelled with Cy trade
      mark 3 were used as an internal standard for both Cy5 labelled control and
      treated E. coli samples. Together with DeCyder trade mark imaging analysis
      software, more accurate quantitative analysis than conventional two-dimensional
      polyacrylamide gel electrophoresis was achieved. Using matrix-assisted laser
      desorption/ionization-time of flight and quadrupole-time of flight mass
      spectrometry a total of 179 differentially expressed protein spots were
      identified. These included enzymes, stress related and substrate (e.g. amino
      acids, maltose, ribose and TRP repressor) binding proteins. Of the spots
      analysed, 77% contained only one protein species per spot, hence the change in
      protein expression measured was solely attributed to the identified protein. Many
      membrane proteins and protein isoforms were identified indicating both adequate
      solubilization of E. coli samples and potential post-translational modification.
      The results indicate that the regulatory mechanisms following benzoic acid
      treatment of E. coli are far more complicated than hitherto expected.

PMID- 12469339
TI  - Atomic force microscopy detection of molecular complexes in multiprotein P450cam
      containing monooxygenase system.
AB  - The application of atomic force microscopy (AFM) technique in proteomic research,
      identification and visualization of individual molecules and molecular complexes
      within the P450cam containing monooxygenase system was demonstrated. The method
      distinguishes between the binary protein complexes and appropriate monomeric
      proteins and, also, between the binary and ternary complexes. The AFM images of
      the components of a cytochrome P450cam containing monooxygenase system -
      cytochrome P450cam (P450cam), putidaredoxin (Pd) and putidaredoxin reductase
      (PdR) - were obtained on a mica support. The molecules of P450cam, Pd and PdR
      were found to have typical heights of 2.6 +/- 0.3 nm, 2.0 +/- 0.3 and 2.8 +/- 0.3
      nm, respectively. The measured heights of the binary Pd/PdR and P450cam/PdR
      complexes were 4.9 +/- 0.3 nm and 5.1 +/- 0.3 nm, respectively. The binary
      P450cam/Pd complexes were found to have a typical height of about (3.9 / 5.7 nm)
      and the ternary PdR/Pd/P450cam complexes, a typical height of about 9.1 +/- 0.3
      nm.

PMID- 12469340
TI  - Subproteomics: identification of plasma membrane proteins from the yeast
      Saccharomyces cerevisiae.
AB  - As a consequence of their poor solubility during isoelectric focusing, integral
      membrane proteins are generally absent from two-dimensional gel proteome maps. In
      order to analyze the yeast plasma membrane proteome, a plasma membrane
      purification protocol was optimized in order to reduce contaminating membranes
      and cytosolic proteins. Specifically, the new fractionation scheme largely
      depleted the plasma membrane fraction of cytosolic proteins by deoxycholate
      stripping and ribosomal proteins by sucrose gradient flotation. The plasma
      membrane complement was resolved by two-dimensional electrophoresis using the
      cationic detergent cetyl trimethyl ammonium bromide in the first, and sodium
      dodecyl sulfate in the second dimension, and fifty spots were identified by
      matrix-assisted laser desorption/ionization-time of flight mass spectometry. In
      spite of the presence of still contaminating ribosomal proteins, major proteins
      corresponded to known plasma membrane residents, the ABC transporters Pdr5p and
      Snq2p, the P-type H(+)-ATPase Pma1p, the glucose transporter Hxt7p, the seven
      transmembrane-span Mrh1p, the low affinity Fe(++) transporter Fet4p, the twelve
      span Ptr2p, and the plasma membrane anchored casein kinase Yck2p. The four
      transmembrane-span proteins Sur7p and Nce102p were also present in the isolated
      plasma membranes, as well as the unknown protein Ygr266wp that probably contains
      a single transmembrane span. Thus, combining subcellular fractionation with
      adapted two-dimensional electrophoresis resulted in the identification of
      intrinsic plasma membrane proteins.

PMID- 12469341
TI  - Interaction and domain networks of yeast.
AB  - Data of currently available protein-protein interaction sets and protein domain
      sets of yeast are used to set up protein and domain interaction and domain
      sequence networks. All of them are far from being random or regular networks. In
      fact, they turn out to be sparse and locally well clustered indicating so-called
      scale-free and partially small-world topology. These subtle topologies display
      considerable indirect properties which are measured with a newly introduced
      transitivity coefficient. Fairly small sets of highly connected proteins and
      domains shape the topologies of the underlying networks, emphasizing a kind of
      backbone the nets are based on. The biological nature of these particular nodes
      is further investigated. Since highly connected proteins and domains accumulated
      a significant higher number of links by their important involvement in certain
      cellular aspects, their mutational effect on the cell is considered by a
      perturbation analysis. In comparison to domains of yeast, what factors force
      domains to accumulate links to other domains in protein sequences of higher
      eukaryotes are investigated.

PMID- 12469342
TI  - Differential proteomic analysis of Bacillus subtilis nitrate respiration and
      fermentation in defined medium.
AB  - A comparative investigation of protein expression by two-dimensional gel
      electrophoresis was conducted between Bacillus subtilis cultures grown in defined
      medium under aerobic, anaerobic nitrate respiration, or fermentation conditions.
      Defined medium specific for either nitrate respiration or fermentation allowed
      distinction between proteins induced by each individual growth process. Our
      differential protein profiling analysis between aerobic and anaerobic conditions
      showed that anaerobic fermentation induced at least 44 proteins and nitrate
      respiration induced at least 19 proteins compared to aerobic controls. Certain
      proteins were specifically induced during nitrate respiration or fermentation,
      while others were induced by both anaerobic processes. Eleven proteins induced by
      nitrate respiration and/or fermentation were identified by peptide mass matching
      using matrix-assisted laser desorption/ionization-time of flight mass
      spectrometry. Proteins encoded by feuA, hmp, and ytkD were induced by nitrate
      respiration. Proteins encoded by pyrR, sucD, trpC, and ywjH were induced by
      fermentation. Proteins encoded by acuB, pdhC, ydjL, and yvyD were induced by
      nitrate respiration and fermentation. This proteomic analysis has provided a more
      complete characterization of B. subtilis anaerobic growth and increased our
      understanding of its metabolic pathways of nitrate respiration and fermentation.

PMID- 12469343
TI  - Proteomic study of the soluble proteins from the unicellular cyanobacterium
      Synechocystis sp. PCC6803 using automated matrix-assisted laser
      desorption/ionization-time of flight peptide mass fingerprinting.
AB  - The unicellular cyanobacteria Synechocystis sp. (PCC6803) has become a model
      organism for a range of biochemical and molecular biology studies aimed at
      investigating environmental stress responses. In this study the soluble proteins
      of Synechocystis were analysed using narrow pH range (pH 4.5-5.5) zoom gels,
      automated matrix-assisted laser desorption/ionization mass spectrometry
      acquisition, spectral processing and database searching. The work sets the
      foundation for investigations of proteomic changes following stress treatment.
      One hundred and ninety-two protein spots were analysed and 105 proteins
      identified, of these 37 were novel proteins not previously seen on two
      dimensional gels. Proteins involved in amino acid biosynthesis, energy metabolism
      and protein modification were identified using this fully automated procedure
      demonstrating that automated acquisition and processing will be a useful tool for
      proteomic analyses on this organism.

PMID- 12469344
TI  - Targeting of tumor associated antigens in renal cell carcinoma using proteome
      based analysis and their clinical significance.
AB  - The suitability of proteome-based strategies for the targeting of tumor
      associated markers along with further analysis regarding their clinical
      significance were investigated in human renal cell carcinoma (RCC). The
      immunogenic protein expression profile of normal kidney and RCC cell lines was
      studied by proteome analysis combined with immunoblotting using sera from healthy
      donors and RCC patients, also termed PROTEOMEX. Employing this approach, a series
      of proteins reactive with either RCC patient sera and/or reactive with control
      sera were identified by microanalysis of tryptic peptides. Some of these
      candidate antigens represent members of the cytoskeletal family, such as
      cytokeratins, in particular cytokeratin 8, cytoskeletal tropomyosin, F-actin
      capping protein, gamma-actin, stathmin, tubulin-alpha, tubulin-beta and vimentin.
      The expression pattern and clinical significance of three of these antigens,
      namely cytokeratin 8, stathmin and vimentin, were further analyzed in a large
      series of surgically removed RCC lesions of distinct subtypes. A heterogeneous
      expression pattern of cytokeratin 8, stathmin and vimentin was demonstrated in
      the different RCC subtypes. All epithelial cells of the autologous normal kidney
      showed a strong cytokeratin 8 staining pattern, whereas they totally lack
      vimentin expression. Stathmin was expressed in 10% of tubule cells. In
      conclusion, PROTEOMEX could be employed for the identification of tumor
      associated antigens of the cytoskeleton which are differentially expressed in RCC
      of distinct subtypes as well as in normal renal epithelium.

PMID- 12469345
TI  - Manifold decreased protein levels of matrin 3, reduced motor protein HMP and
      hlark in fetal Down's syndrome brain.
AB  - Down's syndrome (DS) is the most frequent genetic cause of mental retardation and
      although known for more than a hundred years, the underlying pathomechanisms for
      the phenotype and abnormal brain functions remain elusive. Performing protein
      hunting in fetal Down's syndrome (trisomy 21) brain we detected aberrant
      expression of several proteins. Fetal brain cortex from controls and Down's
      syndrome at the early second trimester of gestation was used for expressional
      analysis. Two-dimensional electrophoresis with subsequent in-gel digestion of
      spots and matrix-assisted laser desorption/ionization spectroscopical
      identification followed by quantification of spots with specific software was
      applied. The nuclear matrix protein matrin 3, cytoskeletal motor protein HMP, and
      the circadian clock protein hlark were significantly decreased in fetal DS brain.
      C8ORF2 protein was reduced but did not reach statistical significance. Prox1 and
      predicted protein Dj149A16.6 were comparable between groups. Reduction of brain
      proteins may represent or cause deficient cytoskeletal structure, transcription
      machinery and exocytosis, functions already known to be deteriorated in DS brain.
      Some of the described proteins were only predicted and we here show the existence
      of the corresponding proteins in fetal human brain.

PMID- 12469348
TI  - L-histidine decarboxylase as a probe in studies on histamine.
AB  - Because the Falck-Hillarp formaldehyde fluorescence method, which was superbly
      applied to identify catecholaminergic and serotonergic neurons, is not applicable
      to histamine, the first author (T.W.) developed an antibody to L-histidine
      decarboxylase (HDC) for identification of the histaminergic neuron system in the
      brain. The anti-HDC antibody was of great use for mapping the location and
      distribution of this histaminergic neuron system. (S)-alpha
      fluoromethylhistidine, a specific and potent irreversible inhibitor of HDC, was
      also very useful in studies on functions of the neuron system. The activity of
      HDC is increased by various agents, treatments, and physiological conditions. We
      found new compounds that increased HDC activity (i.e., tetradecanoylphobol
      acetate (TPA), other tumor promoters, and staphylococcal enterotoxin A); and
      using mast cell-deficient mutant (W/W(v)) mice, we obtained evidence that this
      increase occurred in macrophages. To further characterize the mechanism of
      increases in HDC activity, the second author (H.O.) cloned human HDC cDNA and a
      human HDC gene. In studies on the regulation mechanism of the HDC gene, which is
      expressed only in limited types of cells such as mast cells, enterochromaffin
      like cells in the stomach, cells in the tuberomammillary nucleus of the brain,
      and macrophages, CpG islands in the promoter region of the HDC gene were found to
      be demethylated in cells expressing the gene, whereas they are methylated in
      other cells that do not express the HDC gene. In collaboration with many other
      researchers, we developed HDC knockout mice. The resulting research is producing
      a lot of interesting findings in our laboratory as well as in others. In summary,
      HDC has been and will be useful in studies on functions of histamine.

PMID- 12469349
TI  - Organic synthesis in a changing world.
AB  - This article is based on a lecture presented to the Chemical Society of Japan at
      Wasada University on March 27, 2002, by Professor Steven V. Ley. The lecture,
      "Organic Synthesis in a Changing World," was a comprehensive account of the
      ongoing research efforts of professor Ley's group in the development and
      application of solid-supported reagents and scavengers for use in organic
      synthesis.

PMID- 12469350
TI  - Macrotetrolide biosynthesis: a novel type II polyketide synthase.
AB  - Polyketide biosynthesis is catalyzed by polyketide synthase (PKS) and three types
      of bacterial PKS are known to date. Feeding experiments with isotope-labeled
      precursors established the polyketide origin of the macrotetrolides, but the
      labeling pattern cannot be rationalized according to the established PKS
      paradigm. Genetic analysis of the macrotetrolide biosynthesis unveiled an
      unprecedented organization for a polyketide gene cluster that features five genes
      encoding discrete ketoacyl synthase (KS) and four genes encoding discrete
      ketoreductase (KR) but lacking an acyl carrier protein (ACP). Macrotetrolide
      biosynthesis is proposed to involve a novel type II PKS that acts directly on
      acyl CoA substrates, functions noniteratively, and catalyzes both C-C and C-O
      bond formation. These findings demonstrate once again Nature's versatility in
      making complex molecules and suggests new strategies for PKS engineering to
      further expand the scope and diversity of polyketide library. They also should
      serve as an inspiration in searching for PKS with novel chemistry for
      combinatorial biosynthesis.

PMID- 12469351
TI  - High-sensitivity analyses of metabolites in biological samples by capillary
      electrophoresis using dynamic pH junction-sweeping.
AB  - Emerging fields of biochemical research, such as metabolomics, present challenges
      to current separation technologies because of the large number of metabolites
      present in a cell and their often low (submicromolar) concentration. Although
      capillary electrophoresis (CE) holds great promise as the method of choice for
      high-resolution separations of biological samples, it suffers from poor
      concentration sensitivity, especially with the use of UV detection. In CE,
      sweeping and dynamic pH junction represent two complementary on-line focusing
      techniques that have been used for sensitivity enhancement of hydrophobic and
      weakly acidic analytes, respectively. However, the application of either the
      sweeping or dynamic pH junction technique alone might, in some cases, be less
      effective for the analysis of certain sample mixtures. Recent work in the
      development of a hyphenated dynamic pH junction-sweeping technique is presented
      as an effective on-line method of preconcentration suitable for both hydrophilic
      (anionic) and hydrophobic (neutral) analytes. Sensitive analyses of flavin
      metabolites by CE with laser-induced fluorescence (LIF) detection is demonstrated
      in various biological matrixes, including cell extracts of Bacillus subtilis,
      pooled human plasma, as well as heat-deproteinized flavoenzymes. Enhanced analyte
      band narrowing and improved sensitivity is achieved for flavins using dynamic pH
      junction-sweeping compared to either sweeping or dynamic pH junction alone. This
      results in over a 1200-fold improvement in sensitivity relative to conventional
      injection methods, giving a limit of detection (LOD, defined as S/N = 3) of about
      4.0 x 10(-12) M. Strategies for sensitive and more comprehensive analyses of
      other cell metabolites, including nucleotides, coenzymes, and steroids, are also
      discussed when using on-line focusing techniques in conjunction with multiplexed
      CE and UV detection.

PMID- 12469352
TI  - A case study in conformation design: learning by doing.
AB  - Efforts are described to design simple, fully flexible but conformationally
      preorganised omega-hydroxy-nonanoic acids that could serve as the conformation
      controlling unit in analogues of the potent protein-kinase C activator
      aplysiatoxin. Such analogues are macrodilactones incorporating the designed omega
      hydroxy-nonanoic acid and 3,4-dihydroxy-pentanoic acid, which contains the
      pharmacophoric groups. The design process (replacement of CH(2) groups by an
      oxygen atom, annelation of a six-membered ring and placement of alkyl
      substituents) of the omega-hydroxy-nonanoic acids was monitored by force-field
      calculations. In the end of this process simple analogues of aplysiatoxin are
      proposed in which the proper disposition of the pharmacophoric groups is secured
      by a conformationally flexible but preorganised template structure as part of the
      macrodilactone ring.

PMID- 12469353
TI  - Specific GABA(A) agonists and partial agonists.
AB  - The GABA(A) receptor system is implicated in a number of neurological and
      psychiatric diseases, making GABA(A) receptor ligands interesting as potential
      therapeutic agents. Only a few different classes of structures are currently
      known as ligands for the GABA recognition site on the hetero-pentameric GABA(A)
      receptor complex, reflecting the very strict structural requirements for GABA(A)
      receptor recognition and activation. Within the series of compounds showing
      agonist activity at the GABA(A) receptor site that have been developed, most of
      the ligands are structurally derived from the GABA(A) agonists muscimol, THIP, or
      isoguvacine, which we developed in the initial stages of the project. Using
      recombinant GABA(A) receptors, functional selectivity was demonstrated for a
      number of compounds, including THIP, showing highly subunit-dependent potency and
      maximal response. In light of the interest in partial GABA(A) receptor agonists
      as potential therapeutics, structure-activity studies of a number of analogs of 4
      PIOL, a low-efficacy partial GABA(A) agonist derived from THIP, have been
      performed. In this connection, a series of GABA(A) ligands has been developed
      that exhibit pharmacological profiles from moderately potent low-efficacy partial
      GABA(A) agonist activity to potent and selective antagonist effects. Very little
      information is available on direct-acting GABA(A) receptor agonists in clinical
      studies. However, the results of clinical studies on the effect of the partial
      GABA(A) agonist THIP on human sleep patterns show that the functional
      consequences of a direct-acting agonist are different from those seen after the
      administration of GABA(A) receptor modulators, such as benzodiazepines and
      barbiturates.

PMID- 12469354
TI  - Selective transformations of organic compounds by imidozirconocene complexes.
AB  - Imidozirconocene complexes (Cp(2)Zr=NR(THF)) possess a rich reaction chemistry,
      in contrast to many imido complexes of later transition metals. The synthesis and
      structural characteristics of these compounds are briefly described, along with a
      qualitative molecular orbital description of the metallocene-imido interaction.
      Imidozirconocene complexes react at the Zr=N linkage with a variety of X-H bonds,
      and undergo overall [2 + 2] cycloaddition reactions with a wide range of
      unsaturated organic and organometallic compounds. Results of studies detailing
      the scope and mechanism of these reactions are presented herein, along with
      applications to catalytic hydroamination, imine metathesis, and asymmetric
      transformations.

PMID- 12469355
TI  - In situ scanning tunneling microscopy of oxide-supported metal clusters:
      nucleation, growth, and thermal evolution of individual particles.
AB  - An experimental approach was developed for imaging the nucleation and growth of
      individual oxide-supported nanoparticles and their subsequent in situ chemical
      and thermal treatments by scanning tunneling microscopy (STM). The potential of
      the method is demonstrated for Au nanoparticles supported on a reduced TiO(2)
      substrate where a cluster-by-cluster comparison is made of the morphological
      evolution and stability of nanoparticles during their nucleation and thermal
      annealing. Using this methodology the details of the nucleation and growth
      kinetics can be directly observed.

PMID- 12469357
TI  - Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide
      1.
AB  - GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response
      to meal ingestion and normally functions in the so-called ileal brake, that is,
      inhibition of upper gastrointestinal motility and secretion when nutrients are
      present in the distal small intestine. It also induces satiety and promotes
      tissue deposition of ingested glucose by stimulating insulin secretion. Thus, it
      is an essential incretin hormone. In addition, the hormone has been demonstrated
      to promote insulin biosynthesis and insulin gene expression and to have trophic
      effects on the beta cells. The trophic effects include proliferation of existing
      beta cells, maturation of new cells from duct progenitor cells and inhibition of
      apoptosis. Furthermore, glucagon secretion is inhibited. Because of these
      effects, the hormone effectively improves metabolism in patients with type 2
      diabetes mellitus. Thus, continuous subcutaneous administration of the peptide
      for six weeks in patients with rather advanced disease greatly improved glucose
      profiles and lowered body weight, haemoglobin A(1C), and free fatty acids (FFA).
      In addition, insulin sensitivity doubled and insulin responses to glucose were
      greatly improved. There were no side effects. Continuous administration is
      necessary because of rapid degradation by the enzyme dipeptidyl peptidase-IV.
      Alternative approaches include the use of analogues that are resistant to the
      actions of the enzyme, as well as inhibitors of the enzyme. Both approaches have
      shown remarkable efficacy in both experimental and clinical studies. The GLP-1
      based therapy of type 2 diabetes, therefore, represents a new and attractive
      alternative.

PMID- 12469358
TI  - Glucose-responsive insulin-producing cells from stem cells.
AB  - Recent success with immunosuppression following islet cell transplantation offers
      hope that a cell transplantation treatment for type 1 (juvenile) diabetes may be
      possible if sufficient quantities of safe and effective cells can be produced.
      For the treatment of type 1 diabetes, the two therapeutically essential functions
      are the ability to monitor blood glucose levels and the production of
      corresponding and sufficient levels of mature insulin to maintain glycemic
      control. Stem cells can replicate themselves and produce cells that take on more
      specialized functions. If a source of stem cells capable of yielding glucose
      responsive insulin-producing (GRIP) cells can be identified, then transplantation
      based treatment for type 1 diabetes may become widely available. Currently, stem
      cells from embryonic and adult sources are being investigated for their ability
      to proliferate and differentiate into cells with GRIP function. Human embryonic
      pluripotent stem cells, commonly referred to as embryonic stem (ES) cells and
      embryonic germ (EG) cells, have received significant attention owing to their
      broad capacity to differentiate and ability to proliferate well in culture. Their
      application to diabetes research is of particular promise, as it has been
      demonstrated that mouse ES cells are capable of producing cells able to normalize
      glucose levels of diabetic mice, and human ES cells can differentiate into cells
      capable of insulin production. Cells with GRIP function have also been derived
      from stem cells residing in adult organisms, here referred to as endogenous stem
      cell sources. Independent of source, stem cells capable of producing cells with
      GRIP function may provide a widely available cell transplantation treatment for
      type 1 diabetes.

PMID- 12469359
TI  - Glucose-stimulated signaling pathways in biphasic insulin secretion.
AB  - Glucose-stimulated biphasic insulin secretion involves at least two signaling
      pathways, the KATP channel-dependent and KATP channel-independent pathways,
      respectively. In the former, enhanced glucose metabolism increases the cellular
      adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio, closes KATP
      channels and depolarizes the cell. Activation of voltage-dependent Ca(2+)
      channels increases Ca(2+) entry and [Ca(2+)]i and stimulates insulin release. The
      KATP channel-independent pathways augment the response to increased [Ca(2+)]i by
      mechanisms that are currently unknown. However, they affect different pools of
      insulin-containing granules in a highly coordinated manner. The beta-cell granule
      pools can be minimally described as reserve, morphologically docked, readily and
      immediately releasable. Activation of the KATP channel-dependent pathway results
      in exocytosis of an immediately releasable pool that is responsible for the first
      phase of glucose-stimulated insulin release. Following glucose metabolism, the
      rate-limiting step for the first phase lies in the rate of signal transduction
      between sensing the rise in [Ca(2+)]i and exocytosis of the immediately
      releasable granules. The immediately releasable pool of granules can be enlarged
      by previous exposure to glucose (by time-dependent potentiation, TDP), and by
      second messengers such as cyclic adenosine monophosphate (cyclic AMP) and
      diacylglycerol (DAG). The second phase of glucose-stimulated insulin secretion is
      due mainly to the KATP channel-independent pathways acting in synergy with the
      KATP channel-dependent pathway. The rate-limiting step here is the conversion of
      readily releasable granules to the state of immediate releasability, following
      which, in an activated cell they will undergo exocytosis. In the rat and human
      beta-cell the KATP channel-independent pathways induce a time-dependent increase
      in the rate of this step that results in the typical rising second-phase
      response. In the mouse beta-cell the rate appears not to be changed much by
      glucose. Potential intermediates involved in controlling the rate-limiting step
      include increases in cytosolic long-chain acyl-CoA levels, adenosine triphosphate
      (ATP) and guanosine triphosphate (GTP), DAG binding proteins, including some
      isoforms of protein kinase (PKC), and protein acyl transferases. Agonists that
      can change the rate-limiting steps for both phases of insulin release include
      those like glucagon-like peptide 1 (GLP-1) that raise cyclic AMP levels and those
      like acetylcholine that act via DAG.

PMID- 12469360
TI  - Normal renal function 8 to 13 years after cyclosporin A therapy in 285 diabetic
      patients.
AB  - BACKGROUND: Cyclosporin A (CyA) may induce acute nephrotoxicity. The question has
      been raised of the possible long-term unfavorable course of CyA-induced lesions.
      Advantage was taken of a large cohort of diabetic patients treated for several
      months using moderate CyA dosage to evaluate the long-term evolution of renal
      function in such patients. METHODS: Two hundred and eighty five recently
      diagnosed type 1 diabetic patients having received CyA for a mean of 19.9 months
      were monitored for 13 years, in parallel with 100 similar patients treated with
      insulin alone. RESULTS: In the CyA-treated group, a transient increase in
      creatininemia levels occurred during the first 18 months of treatment associated
      with a transient increase in renal vascular resistance. Both effects disappeared
      later on: creatininemia levels then remained normal. Inulin and p-aminohippurate
      (PAH) clearances remained normal throughout follow-up. Neither permanent renal
      failure nor progressive deterioration of renal function occurred in either group
      or in individual patients. A 10 to 12% increase in inulin and PAH clearance was
      elicited by IV amino acid infusion at 7 to 10 years, a finding consistent with a
      normal renal functional reserve. Patients with moderate kidney lesions on biopsy
      at 1 year had normal and stable clearance values at 7 to 13 years. The prevalence
      of arterial hypertension and retinopathy was lower in the CyA-treated group than
      in the control group, possibly because of the tighter metabolic control obtained
      in the CyA group. CONCLUSION: These results suggest that low-dose CyA treatment
      combined with thorough monitoring does not result in long-term renal dysfunction.

PMID- 12469361
TI  - Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral
      neuropathy.
AB  - BACKGROUND: Recent studies indicate that impaired glucose tolerance (IGT) in man
      is a causative factor in idiopathic sensory neuropathy, and that insulinopenia
      may contribute substantially to the severity of diabetic peripheral neuropathy.
      The effect of sustained IGT and progressive insulinopenia in the absence of overt
      hyperglycemia on peripheral nerve abnormalities was examined in the Goto-Kakizaki
      (GK)-rat. METHODS: Two and eighteen-month-old GK rats with decreased glucose
      tolerance and overt insulinopenia, respectively, were examined with respect to
      nerve function, structure, morphometry and molecular integrity, and were compared
      to age-matched control rats. RESULTS: Both 2-(p < 0.001) and 18-month-old (p <
      0.001) GK rats showed reduced body weight. Blood glucose levels following glucose
      tolerance tests were elevated in both the 2-month and the 18-month-old GK rats.
      Fasting plasma insulin levels in the 2-month GK rats were increased threefold (p
      < 0.05) but decreased by 71% (p < 0.001) in the 18-month GK rats. The two-month
      GK rats showed a normal nerve conduction velocity, whereas in the 18-month GK
      rats it was reduced to 76% (p < 0.001) of control values. No morphometric
      abnormalities were found in the 2-month GK rats, whereas the 18-month GK rats
      showed loss of small myelinated fibers (p < 0.001), atrophy and loss of
      unmyelinated axons (p < 0.05) and an increased (p < 0.01) frequency of
      regenerating fibers. In the older GK rats, both mRNA and protein expression of
      nerve growth factor (NGF) in the sciatic nerve were significantly reduced (p <
      0.001 and p < 0.05), and NGFR TrkA (high affinity NGF receptor) and NGFRp75 (low
      affinity NGF-receptor) protein expression was reduced in dorsal root ganglia
      (DRG) (both p < 0.05). These changes were accompanied by significantly reduced
      protein expressions of substance P (SP) and calcitonin gene-related protein
      (CGRP) in DRG's (both p < 0.001) as well as a 40% (p < 0.001) decrease in SP and
      a 62% (p < 0.001) decrease in CGRP-positive DRG neurons. In the sciatic nerve, SP
      and CGRP protein expression was decreased by 71% (p < 0.01) and 79% (p < 0.01),
      respectively. CONCLUSION: IGT combined with hyperinsulinemia for 2 months have no
      detectable effect on peripheral nerve function or structure. In contrast, IGT and
      subsequent insulinopenia result in a functional and structural neuropathy
      associated with impaired NGF support and neuropeptide synthesis. We suggest that
      these abnormalities are mainly due to insulinopenia rather than hyperglycemia.

PMID- 12469362
TI  - Effects of nateglinide and glibenclamide on postprandial lipid and glucose
      metabolism in type 2 diabetes.
AB  - BACKGROUND: Postprandial hyperlipemia and small, dense LDL particles are features
      of dyslipidemia in type 2 diabetes. The purpose of this study was (1) to
      determine whether the oral insulinotropic drugs, nateglinide and glibenclamide,
      can overcome the defect of insulin action to suppress the hepatic VLDL release
      after a meal and decrease the postprandial lipemia and (2) to evaluate the acute
      effect of postprandial hypertriglyceridemia on LDL particle size in subjects with
      type 2 diabetes. METHODS: Forty-three subjects with type 2 diabetes and mean
      baseline HbA(1c) 7.6% (95% CI 7.3 to 7.9) were treated with nateglinide 120 mg
      three times daily or glibenclamide 5 mg once or twice daily for 12 weeks in a
      double-blind randomised trial. Insulin, glucose, and lipoprotein responses to a
      mixed fat-rich meal were determined for 8 h postprandially at baseline and at 12
      weeks on-trial. RESULTS: Nateglinide and glibenclamide significantly augmented
      the maximal response in serum insulin at 60 min postprandially compared with the
      response without the drug [additional increase 25.0 mU/l (95% CI 11.2-38.8) p =
      0.001 and 12.5 mU/l (95% CI 4.6-20.3) p = 0.003, respectively] and reduced
      hyperglycemia. Neither drug affected fasting or postprandial lipid or lipoprotein
      levels. LDL size did not significantly change in the 8-h postprandial period.
      CONCLUSIONS: Although nateglinide and glibenclamide increase postprandial insulin
      secretion and attenuate hyperglycemia, they do not alleviate postprandial lipemia
      in subjects with type 2 diabetes and good glycemic control. Although small LDL
      particle size is associated with chronic hypertriglyceridemia, LDL size does not
      change during acute postprandial hypertriglyceridemia.

PMID- 12469363
TI  - Current literature in diabetes.

PMID- 12469365
TI  - Influence of ionic inorganic solutes on self-assembly and polymerization
      processes related to early forms of life: implications for a prebiotic aqueous
      medium.
AB  - A commonly accepted view is that life began in a marine environment, which would
      imply the presence of inorganic ions such as Na+, Cl-, Mg2+, Ca2+, and Fe2+. We
      have investigated two processes relevant to the origin of life--membrane self
      assembly and RNA polymerization--and established that both are adversely affected
      by ionic solute concentrations much lower than those of contemporary oceans. In
      particular, monocarboxylic acid vesicles, which are plausible models of primitive
      membrane systems, are completely disrupted by low concentrations of divalent
      cations, such as magnesium and calcium, and by high sodium chloride
      concentrations as well. Similarly, a nonenzymatic, nontemplated polymerization of
      activated RNA monomers in ice/eutectic phases (in a solution of low initial ionic
      strength) yields oligomers with > 80% of the original monomers incorporated, but
      polymerization in initially higher ionic strength aqueous solutions is markedly
      inhibited. These observations suggest that cellular life may not have begun in a
      marine environment because the abundance of ionic inorganic solutes would have
      significantly inhibited the chemical and physical processes that lead to self
      assembly of more complex molecular systems.

PMID- 12469366
TI  - Remote sensing of planetary properties and biosignatures on extrasolar
      terrestrial planets.
AB  - The major goals of NASA's Terrestrial Planet Finder (TPF) and the European Space
      Agency's Darwin missions are to detect terrestrial-sized extrasolar planets
      directly and to seek spectroscopic evidence of habitable conditions and life.
      Here we recommend wavelength ranges and spectral features for these missions. We
      assess known spectroscopic molecular band features of Earth, Venus, and Mars in
      the context of putative extrasolar analogs. The preferred wavelength ranges are 7
      25 microns in the mid-IR and 0.5 to approximately 1.1 microns in the visible to
      near-IR. Detection of O2 or its photolytic product O3 merits highest priority.
      Liquid H2O is not a bioindicator, but it is considered essential to life.
      Substantial CO2 indicates an atmosphere and oxidation state typical of a
      terrestrial planet. Abundant CH4 might require a biological source, yet abundant
      CH4 also can arise from a crust and upper mantle more reduced than that of Earth.
      The range of characteristics of extrasolar rocky planets might far exceed that of
      the Solar System. Planetary size and mass are very important indicators of
      habitability and can be estimated in the mid-IR and potentially also in the
      visible to near-IR. Additional spectroscopic features merit study, for example,
      features created by other biosignature compounds in the atmosphere or on the
      surface and features due to Rayleigh scattering. In summary, we find that both
      the mid-IR and the visible to near-IR wavelength ranges offer valuable
      information regarding biosignatures and planetary properties; therefore both
      merit serious scientific consideration for TPF and Darwin.

PMID- 12469367
TI  - On the existence and stability of liquid water on the surface of mars today.
AB  - The recent discovery of high concentrations of hydrogen just below the surface of
      Mars' polar regions by Mars Odyssey has enlivened the debate about past or
      present life on Mars. The prevailing assumption prior to the discovery was that
      the liquid water essential for its existence is absent. That assumption was based
      largely on the calculation of heat and mass transfer coefficients or theoretical
      climate models. This research uses an experimental approach to determine the
      feasibility of liquid water under martian conditions, setting the stage for a
      more empirical approach to the question of life on Mars. Experiments were
      conducted in three parts: Liquid water's existence was confirmed by droplets
      observed under martian conditions in part 1; the evolution of frost melting on
      the surface of various rocks under martian conditions was observed in part 2; and
      the evaporation rate of water in Petri dishes under Mars-like conditions was
      determined and compared with the theoretical predictions of various investigators
      in part 3. The results led to the conclusion that liquid water can be stable for
      extended periods of time on the martian surface under present-day conditions.

PMID- 12469368
TI  - Reassessing the possibility of life on venus: proposal for an astrobiology
      mission.
AB  - With their similar size, chemical composition, and distance from the Sun, Venus
      and Earth may have shared a similar early history. Though surface conditions on
      Venus are now too extreme for life as we know it, it likely had abundant water
      and favorable conditions for life when the Sun was fainter early in the Solar
      System. Given the persistence of life under stabilizing selection in static
      environments, it is possible that life could exist in restricted environmental
      niches, where it may have retreated after conditions on the surface became
      untenable. High-pressure subsurface habitats with water in the supercritical
      liquid state could be a potential refugium, as could be the zone of dense cloud
      cover where thermoacidophilic life might have retreated. Technology based on the
      Stardust Mission to collect comet particles could readily be adapted for a pass
      through the appropriate cloud layer for sample collection and return to Earth.

PMID- 12469369
TI  - Rock surfaces as life indicators: new ways to demonstrate life and traces of
      former life.
AB  - Life and its former traces can only be detected from space when they are abundant
      and exposed to the planetary atmosphere at the moment of investigation by
      orbiters. Exposed rock surfaces present a multifractal labyrinth of niches for
      microbial life. Based upon our studies of highly stress-resistant microcolonial
      fungi of stone monument and desert rock surfaces, we propose that microbial
      biofilms that develop and become preserved on rock surfaces can be identified
      remotely by the following characteristics: (1) the existence of spectroscopically
      identifiable compounds that display unique adsorption, diffraction, and
      reflection patterns characteristic of biogenerated organic compounds (e.g.,
      chlorophylls, carotenes, melanins, and possibly mycosporines), (2) demonstrably
      biogenic geomorphological features (e.g., biopitting, biochipping, and
      bioexfoliation), and (3) biominerals produced in association with biofilms that
      occupy rock surfaces (e.g., oxalates, forsterite, and special types of
      carbonates, sulfides, and silicates). Such traces or biosignatures of former life
      could provide macroscopically visible morphotypes and chemically identifiable
      products uniquely indicative of life.

PMID- 12469370
TI  - An online astrobiology course for teachers.
AB  - A continuing challenge for scientists is to keep K-12 teachers informed about new
      scientific developments. Over the past few years, this challenge has increased as
      new research findings have come from the field of astrobiology. In addition to
      trying to keep abreast of these new discoveries, K-12 teachers must also face the
      demands of the content and pedagogical goals imposed by state and national
      science education standards. Furthermore, many teachers lack the scientific
      content knowledge or training in current teaching methods to create their own
      activities or to implement appropriately new teaching materials designed to meet
      the standards. There is a clear need for special courses designed to increase the
      scientific knowledge of K-12 science teachers. In response to this need, the
      authors developed a suite of innovative, classroom-ready lessons for grades 5-12
      that emphasize an active engagement instructional strategy and focus on the
      recent discoveries in the field of astrobiology. They further created a graduate
      level, Internet-based distance-learning course for teachers to help them become
      familiar with these astrobiology concepts and to gain firsthand experience with
      the National Science Education Standards-based instructional strategies.

PMID- 12469373
TI  - The purpose of a code of ethics and code of conduct for nursing students.

PMID- 12469374
TI  - The evolution of the ANA Code of Ethics.

PMID- 12469375
TI  - Educational choices and career mapping.

PMID- 12469376
TI  - [Family practice--a clinical discipline between theory and practice].

PMID- 12469377
TI  - [Renal cancer--a new clearing report].

PMID- 12469378
TI  - [To strengthen patient's own power and to counteract oppressive forces:
      Empowerment in a medical perspective].
AB  - The aim of this article is to describe the empowerment concept in a medical
      perspective. The concept originated as a reaction to the oppression of groups and
      individuals in the USA. Later it was introduced in relation to health promotion.
      Empowerment implies counteracting oppression of groups and individuals, and being
      conscious of different positions of power. The concept can be used to describe a
      goal and a process, as well as a strategy. It implies both the mobilisation of
      the patient's own power, as well as counteracting oppressive forces. It is
      concluded that empowerment is particularly important for the most disempowered
      patients (for instance people who have been given a psychiatric label).
      Empowerment in the health services is a relevant strategy to achieve fundamental
      changes in the control and influence of powerless groups, and thereby reduce
      inequality in health.

PMID- 12469379
TI  - [The patient-oriented perspective, the clinician and the postmodernism-patient].

PMID- 12469380
TI  - [Potentially marginalized 20-44-years-olds in general practice. Who are they? The
      results of a questionnaire screening].
AB  - INTRODUCTION: The study presents the results of a questionnaire screening of 20
      44-year-old patients as introduction to a preventive intervention study in
      general practice. The purpose was to identify those with most problems or lack of
      resources and unhealthy lifestyle. MATERIAL AND METHODS: In a cross-sectional
      study of the 20-44-year-old patients at 27 general practitioners, 2056 completed
      a questionnaire about resources, lifestyle, and family situation. The 30% with
      seven or more problems out of 33 possible (n = 625) were offered randomisation
      with a view to intervention. The answers are described and analysed comparing the
      two groups by OR and logistic regression. RESULTS: The four most important
      answers to find persons with more than seven problems were in women: difficulties
      in finding solutions, lack of security, not good self rated health, and
      difficulties in handling children. In men the most important answers were: lack
      of security, no confidant in the family, feeling extremely stressed, and lack of
      exercise. A little more than two thirds of the persons with many problems could
      be found among those with problems in two out of the four questions. DISCUSSION:
      Important characteristics among the 30% with most problems or lack of resources
      were low self-esteem, personal strain, and lack of security. These uncovered
      basic needs are considered essential barriers to health promoting self-care
      behaviour. By focusing on this, general practice might contribute to bridge the
      gap between the healthy and unhealthy.

PMID- 12469381
TI  - [Illness perception in general practice--in relation to patients with
      somatization disorder].
AB  - In this paper different perceptions of disease and illness in general practice
      and possible implications of these perceptions for the GP's clinical work are
      described and discussed. The focus is on patients with medically unexplained
      symptoms and on the question whether the illness perception of the GP to some
      extent can explain the often inappropriate treatment of these patients.

PMID- 12469382
TI  - [What is the patient's view of risks?].

PMID- 12469383
TI  - [General practitioners' perception of disease risks and benefit of prevention].
AB  - INTRODUCTION: Uncertainty and risk are central issues in relation to health and
      health care services. Healthy individuals do not necessarily fall ill, despite
      the presence of risk factors. Doctors, health service administrators, and
      patients are more inclined to choose interventions against risk factors, when
      information about the effects is presented in terms of relative risk reductions
      rather than absolute risk reductions. The aim of the study was to gain better
      insight into how general practitioners (GPs) perceive risk of disease, and
      whether this perception depends on the risk reduction being presented in absolute
      or relative terms. MATERIAL AND METHODS: Questionnaires with clinical episodes
      were sent to 1500 Danish GPs. The GPs were randomised into four groups of 375,
      all of whom received the same case history with information about risk reduction
      achieved through medical treatment phrased in terms of either relative risk
      reduction, absolute risk reduction, number needed to treat, or all of the
      aforementioned terms of risk reduction. The GPs were asked whether they would
      recommend medical treatment as primary prevention, knowing the case history and
      expected risk reduction. RESULTS: The GPs' attitude towards recommending medical
      treatment depended on the phrasing of risk reductions. Of the doctors who
      received all information on risk reductions, 72% would definitely or probably
      recommend medication, whereas 91% would recommend medication if only information
      about relative risk reduction was given, and 63% would recommend medication if
      information was given in terms of absolute risk reduction or number needed to
      treat. DISCUSSION: To advise patients rationally, knowledge of the patients'
      preferences, as well as consideration of all available measures of risk
      reductions, is needed.

PMID- 12469384
TI  - [Cardiovascular risk factors. Different evaluations by physicians and patients].
AB  - INTRODUCTION: General practitioners have an important role in the prevention of
      cardiovascular disorders, and it is a precondition for motivating patients to
      preventive issues that doctors are aware of the prevalent risk factors. The aim
      of the study was to analyse agreement between patients' and general
      practitioners' (GPs) perception of risk factors and overall risk of ischemic
      heart diseases (IHD). MATERIAL AND METHODS: The data consisted of records from an
      audit in May 1999. The GPs (n = 26) registered all enquiries from patients with
      IHD (n = 252) and a sample of healthy individuals (n = 1239). Both doctors and
      patients were asked to register the occurrence of cardiovascular risk factors
      (smoking, weight, stress, family history) and they were asked to evaluate the
      state of health and to estimate the overall risk of IHD. The agreement was
      evaluated by Kappa statistics. RESULTS: The level of agreement between GPs and
      patients varied from 70 to 97 per cent. Disagreement was observed most often for
      patients with IHD and patients listed with elderly GPs. (> 50 years).
      Disagreement was predominantly caused by a lower detection rate of the risk
      factors by the GPs. The patients' perception of overall risk of IHD was badly
      correlated to doctors' perception. Generally, patients perceived the overall risk
      of IHD lower than their doctors, and in more than half of the patients with a
      perception of low risk the GP estimated the risk as high. DISCUSSION: Patients
      and GPs have different perceptions of the risk of IHD. This may be due to the
      fact that GPs do not have all the information about their patients' lifestyle. It
      may also be due to different perception of the importance of specific risk
      factors and different reference frames for risk perception. GPs have an important
      role in communicating cardio-preventive issues and the meaning of risk factors.
      Interventions should be considered to improve risk communication in general
      practice.

PMID- 12469385
TI  - [Patients' evaluations as quality measurements in general practice].
AB  - Patients' evaluations have several functions as quality measurements: A general
      judgement of the quality of the health care system and a direct assessment of
      defined aspects of service and care. In this article the concept of patient
      satisfaction and the application of patients' evaluations on quality improvement
      in the health care system is discussed. Despite many attempts to formulate an
      explanatory theory about the matter, a useful theoretical basis for the concept
      of satisfaction is still missing. This does not imply the exclusion of patients'
      evaluation of the health system, and it is discussed why and in which areas of
      quality improvement patients should be involved and how their evaluations should
      be interpreted. Studies including patients' evaluations are referred to and
      discussed.

PMID- 12469386
TI  - [The APO method--a popular form of quality development in general practice].

PMID- 12469387
TI  - [Quality development in general practice using diagnostic classification
      "Expanded Danish ICPC" in the computerized medical records].

PMID- 12469389
TI  - [New biostatistical methods in general practice research. A literature review].

PMID- 12469388
TI  - [Models for continuing education in general practice focusing on functional
      disorders].

PMID- 12469390
TI  - [Mupirocin in the prevention of surgical wound infection caused by Staphylococcus
      aureus].

PMID- 12469391
TI  - [Resuscitation and footnotes].

PMID- 12469392
TI  - [The National Patient Registry--clinical databases--not an either or but both
      and].

PMID- 12469393
TI  - [The National Patient Registry as a clinical quality database].

PMID- 12469394
TI  - [Quality assurance and clinical databases].

PMID- 12469395
TI  - [Celebra and the CLASS trial--a scandal!].

PMID- 12469396
TI  - [Hypersensitivity to shellfish].

PMID- 12469397
TI  - [Is influenza vaccination required?].

PMID- 12469398
TI  - Cumulative probability of decompression sickness.

PMID- 12469399
TI  - The pentylenetetrazole allosteric component of the GABAA receptor plasticity.

PMID- 12469400
TI  - Carcinostatic, protective, and adaptive activities of tris-(2
      hydroxyethyl)ammonium salts of arylheteroacetic acids.

PMID- 12469401
TI  - Frequency tuning of the auditory system of acoustically active noctuids
      (noctuidae, lepidoptera).

PMID- 12469402
TI  - Specific features of EEG and cognitive disorders after exposure to radiation.

PMID- 12469403
TI  - Effect of arginine-vasopressin on Amoeba proteus: specific features of signal
      transmission.

PMID- 12469404
TI  - Mathematical model of the evolution of locomotion in tetrapods.

PMID- 12469405
TI  - Critical periods of the dopaminergic system formation in rat brain.

PMID- 12469406
TI  - Metabolic disturbances in the gray matter of the human brain in autoimmune
      demyelinating disease of the nervous system and their contribution to the
      symptomatology of the disease.

PMID- 12469407
TI  - Increasing the cold resistance of the rat isolated heart and restoring its
      contractility without warming after cold-induced cardiac arrest.

PMID- 12469408
TI  - Central mechanisms that control respiration in the pond snail Lymnaea stagnalis:
      is the VD4 neuron involved in respiratory rhythm generation?

PMID- 12469409
TI  - Evaluation of the heterogeneity and specificity of promising antitumoral
      preparations by means of high-order derivative spectroscopy.

PMID- 12469410
TI  - The distribution pattern of galactose-specific lectin receptors in sensory
      ganglia of mature white rats.

PMID- 12469411
TI  - Endocytosis of exopolysaccharides of the potato ring rot causal agent by host
      plant cells.

PMID- 12469412
TI  - Plants as possible reservoirs of bacteria pathogenic for humans and animals.

PMID- 12469413
TI  - Life-cycle adaptation of hydroids of the family Corynidae and the subfamily
      Obeliinae to habitat conditions.

PMID- 12469414
TI  - Effects of synthetic auxin (2,4-D) on the level of indolyl-3-acetic acid in
      cultivars and supernodulating mutants of pea (Pisum sativum L.).

PMID- 12469415
TI  - The role of glacial epochs in the formation of chromosomal polymorphism in the
      common shrew Sorex araneus L. (Insectivora, Mammalia).

PMID- 12469416
TI  - The intestine of phoronids has epitheliomuscular cells.

PMID- 12469417
TI  - Polyaxial cleavage in sponges (Porifera): a new pattern of metazoan cleavage.

PMID- 12469418
TI  - A new early cretaceous mammal from western Siberia.

PMID- 12469419
TI  - Characteristics of a pluripotent population at early stages of embryonic stem
      cell differentiation in culture.

PMID- 12469421
TI  - Battlefield use of depleted uranium and the health of veterans.
AB  - Depleted uranium munitions have been used in recent military operations in both
      the Gulf and the Balkans and there have been concerns that exposure to depleted
      uranium may be a cause of 'Gulf War Syndrome' and cancer clusters. We recount the
      properties of depleted uranium, its military uses and the situations in which
      personnel may be exposed. Following a review of scientific literature, the health
      effects of depleted and natural uranium exposure are described and the major
      outcomes of research into Gulf Veterans' Illnesses are summarised. We conclude
      that, although there is the potential for uranium exposures to cause renal damage
      or lung cancer, the risk of harm following depleted uranium exposure in military
      settings seems to be low. We advise on the management of casualties exposed to
      depleted uranium and suggest control measures that may be appropriate to protect
      personnel who provide casualty care.

PMID- 12469420
TI  - Selective analysis of a glucose-xylose binary mixture using microbial sensors.

PMID- 12469423
TI  - Sports and training injuries in British soldiers: the Colchester Garrison Sports
      Injury and Rehabilitation Centre.
AB  - OBJECTIVES: To record and analyse the injuries and conditions requiring referral
      to the Colchester Garrison Sports Injury and Rehabilitation Centre over a three
      year period, with special reference to type and site of injury, aetiology, and
      outcome. METHODS: An ongoing prospective study in which data on the diagnosis,
      cause of injury, and treatment of all patients referred to the Centre was coded
      and stored on a database. A total of seventeen variables were recorded. SUBJECTS:
      All patients were trained, serving soldiers in the British Army referred via
      their General Practitioner to the Sports Injury and Rehabilitation Centre.
      RESULTS: A total of 3921 referrals were made over the three-year period. The most
      common specific condition seen was low back pain (22.2%) followed by sprain of
      the ankle (15.1%). Lower limb conditions, both overuse and traumatic, accounted
      for over half (55.8%) of all referrals. Military training was the most common
      cause of all conditions (35.2%) followed by organised or personal sport (28.5%).
      In addition to medical treatment and physiotherapy, 30% of patients required
      formal rehabilitation. CONCLUSIONS: This is the first full review of the data
      collected by the Sports Injury and Rehabilitation Centre. It defines the injury
      patterns for trained soldiers rather than military recruits. Low back pain is
      identified as a major cause of morbidity in this population. The review serves as
      a benchmark in the planning of injury prevention strategies and the establishment
      of future rehabilitation services.

PMID- 12469422
TI  - The medical and surgical management of chronic anal fissure.
AB  - Major advances in our understanding of the mechanisms involved in chronic anal
      fissure have allowed the introduction of many new medical therapies for this
      condition. The literature about current treatment modalities licensed for anal
      fissure and those novel therapies still under evaluation has been reviewed. These
      new treatments are examined in the context of traditional surgical management of
      the disease and a future treatment algorithm suggested.

PMID- 12469424
TI  - Dressings for burn injury in a military conflict--change of practice based on
      current evidence.

PMID- 12469425
TI  - Aeromedical evacuation following abdominal surgery.

PMID- 12469426
TI  - Musculoskeletal injuries in female soldiers: analysis of cause and type of
      injury.
AB  - OBJECTIVES: To record and analyse those injuries and conditions requiring
      referral to a military sports injury and rehabilitation centre over a three year
      period, with special reference to gender, type and site of injury, and the cause
      of the injury. METHODS: A prospective study in which data on the gender,
      diagnosis, and cause of injury, of all patients referred to the Colchester
      Garrison Sports Injury and Rehabilitation Centre was recorded. All subjects were
      trained, serving soldiers in the British Army referred via their General
      Practitioner. RESULTS: Low back pain (OR 2.71, p < 0.0001) and injuries to the
      hip, thigh and lower leg (OR 2.33, p < 0.0001) were more frequent in female
      soldiers. Military training (OR 4.62, p < 0.0001), work (OR 2.53, p < 0.0001),
      recreation (OR 2.39, p < 0.0001), and pre-existing conditions (OR 4.2, p <
      0.0001) were the causes most commonly cited by female rather than male soldiers.
      There was no statistical gender difference for sport related or road traffic
      accident injuries. CONCLUSIONS: Female soldiers are more likely to sustain an
      injury than their male counterparts. Specific injuries account for the majority
      of this difference. Military training, work, and recreation are more likely to be
      the cause of injury in the female soldier. Conditions existing prior to military
      service were also more common. There was no gender difference in the injuries
      caused by sport or road traffic accidents. These results may act as a basis for
      targeted intervention in order to reduce inequality without reducing overall
      training standards.

PMID- 12469427
TI  - Bullet markers--a simple technique to assist in the evaluation of penetrating
      trauma.
AB  - Radio-opaque markers in penetrating trauma are useful in both the clinical
      evaluation of the injuries and in the permanent record of the location of the
      wounds. The use of an unfolded paperclip taped over the wound as a marker is
      recommended as a valuable adjunct in the radiological evaluation of penetrating
      trauma.

PMID- 12469428
TI  - An audit of Territorial Army Medical Grades on presentation for mobilisation and
      full time reserve service at RTMC Chilwell.
AB  - An audit was carried out on a cohort of Territorial Army (TA) personnel passing
      through RTMC in order to assess the quality of their previous medical assessments
      compared to that undertaken at the time of their mobilisation. The results
      confirmed the high downgrading rate (18%) amongst TA personnel compared to
      previous studies that identified grading error rates of 6-6.5% amongst Regular
      Army personnel. Errors in the entry medical assessments for TA personnel were
      also identified in nearly half (44%) of records examined. Possible solutions are
      identified through improved education of examining medical officers and by
      increasing the pre-deployment time available to obtain specialist referrals. A
      case is also made for having improved access to previous medical information,
      both to improve the quality of the pre-deployment medical screening and to ensure
      appropriate continuity of care for deployed TA personnel.

PMID- 12469429
TI  - Acute atraumatic bilateral compartment syndrome in the leg.

PMID- 12469430
TI  - Injuries of the sterno-clavicular joint in backpackers.
AB  - Anterior sterno-clavicular dislocation, or fracture dislocation, as a result of
      carrying a backpack has not previously been described. We describe two cases, and
      reflect on the factors that may have led to the injuries, noting that the current
      PLCE (personal load carrying equipment) may also increase the risk of this
      condition. The condition is one that carries a grading of U8 (unfit for service),
      and is one that Medical Officers should be aware of, as it has serious
      implications for a continuing military career.

PMID- 12469431
TI  - Battlefield advanced trauma life support.

PMID- 12469432
TI  - Immediate assessment and management of acute medical emergencies.
AB  - The pre-hospital management of acute medical emergencies can be difficult.
      Critically ill patients must be evaluated quickly and accurately to ensure that
      immediately life-threatening problems are identified and treated. Figure 1 and
      Box 2 provide a structured method for rapid assessment in the pre-hospital phase.
      Although the majority of medically unwell patients will not require an aggressive
      resuscitation phase during the primary survey, the use of the structured approach
      in all patients will ensure that 'time critical' pre-hospital medical emergencies
      are identified. This approach also emphasizes that once immediately correctable
      problems have been treated, the priority is transfer the patient to the nearest
      resuscitation facility.

PMID- 12469433
TI  - Self assessment exercises in sports and exercise medicine.

PMID- 12469434
TI  - Army physiotherapy.

PMID- 12469435
TI  - Nikolai Ivanovich Pirogov (1810-1881).

PMID- 12469436
TI  - Spinal injuries on deployment--added factors.

PMID- 12469438
TI  - Surgical saddlery.

PMID- 12469437
TI  - The evolution of casualty evacuation in the British Army in the 20th century
      (Part 2)--1918 to 1945.
AB  - This is the second in a series of papers that examine the evolution of the
      military casualty evacuation chain during the 20th century. The Spanish Civil War
      demonstrated to the world the revolutionary tactic of 'Blitzkrieg' developed by
      the Germans. This and the experience of the British Expeditionary Force in 1940
      emphasised the need for mobility in forward medical units. The campaign in the
      Western Desert led to the creation of a number of new units such as the Field
      Surgical Unit and the Field Transfusion Unit which were introduced across the
      British Army as a result of the findings of the Hartgill Committee. The aeroplane
      transformed the evacuation chain from CCSs to base hospitals and beyond.

PMID- 12469439
TI  - The job and the calling.

PMID- 12469440
TI  - Listening and breaking down the walls.

PMID- 12469441
TI  - Malaria and the femme fatale: sex and death in French colonial Africa.

PMID- 12469442
TI  - Literature and obstetrics: reading maternal posture in Jacques Ferron's "Little
      William".

PMID- 12469443
TI  - Exposing the "nerves of language": Virginia Woolf, Charles Mauron, and the
      affinity between aesthetics and illness.

PMID- 12469444
TI  - Metamorphosis: defending the human.

PMID- 12469445
TI  - Keats, professional medicine, and the two Hyperions.

PMID- 12469446
TI  - CMS proposes new system of records.

PMID- 12469447
TI  - Developing a central business office.

PMID- 12469448
TI  - Acoustic phenotypes for speech-genetics studies: toward an acoustic marker for
      residual /s/ distortions.
AB  - Findings in a prior study series indicate that acoustic markers may have the
      requisite sensitivity and specificity to discriminate speakers with histories of
      several types of speech disorders, one of which is posited to be genetically
      inherited. The present study in this series compares acoustic data from three
      groups of adolescent speakers. Group 1 speakers had residual dentalized /s/
      distortions in conversational speech and histories of significant age
      inappropriate deletion and substitution errors. Group 2 speakers also had
      residual dentalized /s/ distortions in conversational speech, but their speech
      histories were limited to dentalized distortions of /s/ and other
      fricatives/affricates. Group 3 speakers had typical speech on assessment and no
      histories of speech errors. Owing to the limited number of perceptually
      dentalized /s/ tokens produced by Groups 1 and 2 speakers in a phrase-level
      speech task, acoustic analyses were completed on /s/ tokens transcribed as
      correct for speakers in all groups. Moments analyses of /s/ spectra in three
      words with /s/-initial clusters yielded statistically significant differences and
      consistent trends for mean spectral frequency and spectral variance for Group 1
      compared with Group 2 speakers. These findings for perceptually normal /s/ tokens
      are interpreted as additional support for the potential of acoustic markers to
      discriminate speakers' speech-error histories. The discussion considers possible
      developmental and normalization correlates of the acoustic findings for speakers
      with each of the two types of speech-error histories studied in this paper.

PMID- 12469449
TI  - Acoustic phonetics in a clinical setting: a case study of /r/-distortion therapy
      with surgical intervention.
AB  - Acoustic measures are used to document the speech of a 6-year-old child with
      persistent /r/-distortion through several treatment interventions. The child
      originally presented a complex of speech disorders and was treated by a speech
      language pathologist using phonological process techniques. The procedures
      successfully corrected most of his speech problems, although /r/ remained
      severely distorted. The primary acoustic manifestation of this distortion was a
      high third formant. Surgical correction of a banded lingual frenulum, along with
      adenoton-sillectomy indicated for sleep apnea, is shown to have had a small
      effect in lowering the third formant. A dramatic change was seen on
      reintroduction of therapy, when an extreme drop in third formant frequencies for
      /r/ was observed. The acoustic data are interpreted using speaker-internal
      controls derived from a dialect-appropriate adult model.

PMID- 12469450
TI  - Feature development in Cantonese.
AB  - The phonetic inventories of 122 typically developing Cantonese-speaking children,
      aged from 0;10 to 4;7, were examined in terms of feature distinctions. The
      applicability of Dinnsen. Chin, Elbert and Powell's implicational feature
      hierarchy to these data was investigated. Results show that modifications to the
      hierarchy are necessary for the Cantonese phonetic system. A revised hierarchy
      for Cantonese is proposed. Differences between this proposal and the original
      work are discussed. The implicational nature of the proposed hierarchy was also
      tested on longitudinal data from ten children (aged from 0;10 to 3;5 at the
      beginning of the study) over a 1 year period. The proposed hierarchy successfully
      predicted the route of sound change of these inventories. Implications for
      further research on feature development are discussed.

PMID- 12469451
TI  - Coarticulation patterns in children with developmental apraxia of speech.
AB  - The aim of this study was to enhance our insight into the underlying deficit in
      developmental apraxia of speech (DAS). In particular, the involvement of planning
      and/or programming of speech movements in context was tested by analysing
      coarticulatory cohesion. For this purpose, second formant frequency measurements
      were conducted in repetitions of nonsense utterances ([[symbol: see text]] C =
      /s,x,b,d/; V = /i.a.u/), and compared across nine children with DAS, six normally
      speaking (NS) children and six adult women. The results showed both intra- and
      intersyllabic anticipatory coarticulation in NS children and adult women, in
      which the intersyllabic coarticulation was stronger in NS children than in adult
      women. The children with DAS showed more variability as compared to NS children,
      made, on average, less distinction between the vowels, and showed individually
      idiosyncratic coarticulation patterns. These results are discussed in the light
      of a delay as well as a deviance of speech development in children with DAS.

PMID- 12469452
TI  - Long-term results of Heller myotomy without an antireflux procedure in achalasic
      patients.
AB  - Both open and laparoscopic myotomies have been used in the treatment of
      achalasia. Postoperative gastro-oesophageal reflux is among the commonly reported
      side effects of myotomy. The addition of an antireflux procedure to the standard
      surgical approach has given rise to controversy. The objective of our study was
      to determine whether or not an antireflux procedure should be used in addition to
      Heller myotomy. Over the period from 1980 to 1990, 94 patients (mean age: 47.9
      years) with achalasia underwent Heller myotomy calibrated by intraoperative
      oesophageal manometry without fundoplication. In 1999-2000, all patients filled
      in a clinical questionnaire: all underwent radiographic oesophageal imaging,
      oesophageal manometry, ambulatory 24-h oesophageal pH monitoring, and
      oesophagogastroduodenoscopy, when necessary. Ten healthy age-matched subjects
      were compared in the manometric and radiological studies. Myotomy improved the
      clinical profiles and instrumental data results in all patients. Gastro
      oesophageal reflux was present in 10 patients (10.6%); none of these 10 subjects
      presented oesophagitis. Heller open myotomy yields good long-term results.
      Intraoperative manometric calibration reduces the side effects of myotomy, such
      as gastro-oesophageal reflux. The addition of fundoplication is not justified in
      all patients.

PMID- 12469453
TI  - [Esophagectomy for carcinoma: impact of age on clinical results and survival].
AB  - Advances in perioperative management have allowed more and more elderly patients
      to undergo major surgery with postoperative morbidity and mortality rates similar
      to those of younger individuals. The aim of this study was to evaluate the impact
      of age on the clinical outcome and long-term survival of patients with
      oesophageal cancer undergoing oesophagectomy. Eight hundred and seventy-five
      patients with oesophageal carcinoma were divided into two groups: A (n = 393)
      aged > or = 65 years, and B (n = 482) aged < 65 years. One hundred and forty-nine
      (38%) patients in group A underwent surgery compared to 263 (55%) in group B (P <
      0.01). Postoperative mortality and the prevalence of anastomotic leak and
      respiratory complications were similar in both groups. There was, however, a
      higher prevalence of cardiovascular complications in group A (13% versus 3%, P <
      0.01). Five-year survival was about 35% in both groups. In conclusion, advanced
      age should not be considered a contra-indication to oesophagectomy for carcinoma,
      since the long-term survival of elderly patients undergoing resection is similar
      to that of younger ones.

PMID- 12469454
TI  - [Impact of endoscopic surveillance of Barrett's esophagus on survival of patients
      with esophageal adenocarcinoma].
AB  - In an attempt to reduce mortality from oesophageal adenocarcinoma, it has been
      recommended to enroll patients with Barrett's oesophagus in endoscopic
      surveillance programs in order to detect malignant degeneration at an early and
      possibly curable stage. The aim of this study was to assess the impact of
      endoscopic biopsy surveillance on the outcome of Barrett's adenocarcinoma. From
      November 1992 to December 2000, 328 patients with histologically proven
      oesophageal adenocarcinoma were referred to our department. One hundred of these
      patients had Barrett's adenocarcinoma. In 12 (12%) patients, cancer was
      discovered during endoscopic surveillance for Barrett's metaplasia. The
      prevalence of gastro-oesophatgeal reflux disease in the Barrett's group was 38.8%
      versus 8.1% (P < 0.01) of non-Barrett's patients. In the surveyed group, there
      were 9 (75%) early stage tumours (Tis-1N0), versus 10 (11.4%, P < 0.01) in the
      non-surveyed patients. Three out of five surveyed patients operated on for high
      grade dysplasia proved to have invasive carcinoma in the oesophagectomy specimen.
      All surveyed patients were alive after a median follow-up period of 50 months;
      the median survival in the non-surveyed group was 24 +/- 3 months (P < 0.01).
      Endoscopic surveillance of Barrett's oesophagus allows early detection of
      malignant degeneration and better long-term survival than in non-surveyed
      patients.

PMID- 12469455
TI  - What preoperative assessment is necessary for insulinomas? Calculating the degree
      of waste: analysis of 29 cases.
AB  - In patients affected with insulinomas the preoperative work-up is debated. The
      success rate of various localisation procedures seems considerably inferior in
      respect to intraoperative results. Aim of the study is to evaluate our personal
      experience with this dichotomy. Twenty nine patients with definitive diagnoses of
      primary hyperinsulinemia from 1985 until June of 2001 were selected. Sensitivity,
      diagnostic accuracy, positive predictive value and cost of ultrasound (US) (29
      pts.), computerised tomography (CT) (29 pts.), magnetic resonance imaging (MRI)
      (16 pts.), selective angiography (18 pts) and intraoperative ultrasound (IOUS)
      (18 pts.) in the localisation of neoplasm were evaluated. The presence of
      neoplasm was verified at operation or at autopsy in 27 cases (93%). The
      sensitivity of US, CT, MRI and selective angiography was 52%, 44%, 57% and 82%,
      respectively, with a cost of non-diagnostic studies equal to 422 [symbol: see
      text]/patient with a comprehensive waste equal to 43.7% of resources utilised.
      The sensitivity of IOUS and visualisation or physical exam by the surgeon was
      100%, 46% and 96%, respectively. In 2 cases where there was a recurrence of
      symptoms after surgery, the histological exam of the operative specimen did not
      have evidence of insulinoma tissue. Surgery with the help of IOUS, preceded by
      only one pre-op diagnostic imaging technique represents the best approach for
      establishing the diagnosis of and treating insulinomas.

PMID- 12469456
TI  - [Drug-induced acute pancreatitis: a personal contribution].
AB  - Drugs are commonly considered a rare cause of acute pancreatitis but there are an
      increasing number of reports of numerous medications that seem to be involved in
      the pathogenesis of acute pancreatitis with different degrees of causative
      relationship to the disease (definite--probable--possible). The number of drugs
      that have been associated to date with acute pancreatitis exceeds 260. The
      authors report here on their personal series of four cases of drug-induced acute
      pancreatitis (warfarin, lysinopril/hydrochlorothiazide,
      lamivudine/stavudine/indinavir, valproic acid), focusing on a number of
      epidemiological and clinical aspects.

PMID- 12469457
TI  - [Influence of enteral nutrition on cytokine response in resective liver surgery].
AB  - Postoperative infectious complications are nowadays a major problem in liver
      surgery. Better surgical outcomes with a consequent reduction in treatment and
      hospitalisation costs are a primary objective. The aim of this prospective,
      randomised study was to evaluate the cytokine response during and after portal
      clamping in patients undergoing liver resection and continuously fed with enteral
      nutrition as compared to patients receiving parenteral nutritional support. Forty
      patients with liver tumours were divided into two groups of 20 on the basis of
      the presence or absence of chronic liver disease. Furthermore, the latter group
      of 20 were randomised to two subgroups A and B of 10 patients on the basis of the
      different perioperative nutrition modalities. Group A patients were fed by so
      called uninterrupted enteral nutrition, which means without interruption from the
      day before surgery with a nutritional solution delivered via a nasojejunal tube.
      The patients in group B were submitted to hepatic resection with parenteral
      nutritional support. Liver resection had to consist in resection of at least 30%
      of the parenchyma in non-cirrhotic patients or in segmental resection in
      cirrhotic ones. Ten milliliter blood samples were harvested before operation, and
      10, 30 and 60 min after declamping and at 24 h. Interleukin 6 and a-tumour
      necrosis factor values were detected in blood samples. The values of C reactive
      protein and of prealbumin were recorded at 72 h postoperatively. We also
      evaluated postoperative complications, resumption of bowel movements, oral intake
      of nourishment, and patient discharge. Values in blood samples in the two groups
      showed a statistically significant difference in interleukin 6 values only after
      24 h (10 min: group A 121 +/- 25.3, group B 156 +/- 31.4; after 24 h: group A
      31.5 +/- 12, group B 105.1 +/- 24.1), while the a-tumour necrosis factor assay
      showed no significant difference between the two groups. However, there was an
      appreciably longer hospital stay (group A 10.9 +/- 3.1 days (range: 7-21 days),
      group B 13.2 +/- 2.7 days (range: 8-19 days) (P < 0.02) and a quicker resumption
      of bowel movements in group A. The data available show that uninterrupted enteral
      nutrition produces a modulation of the cytokine response following portal
      clamping. A lower cytokine activation cascade reduces the impact of the action of
      cytokines on the hepatic parenchyma with consequent enhancement of the hepatic
      Kupffer cell component. These factors thus substantially reduce the length of the
      patient's hospital stay and consequently the cost of medical care.

PMID- 12469458
TI  - Selection criteria for non-surgical treatment of liver injury in adult
      polytraumatized patients.
AB  - Conservative treatment of hepatic trauma is currently implemented in 80-90% of
      cases with a success rate of 92.5% and is mainly based on the haemodynamic status
      of the patients. We conducted a retrospective study of 71 patients with hepatic
      trauma from January 1993 to April 2001 and reviewed our experience with surgical
      and conservative treatment, also considering associated extrahepatic lesions.
      Fifty-three (74.6%) patients with liver trauma underwent celiotomy and 18 (25.3%)
      were treated conservatively. Haemodynamic instability was the most common
      indication for surgery (34 patients). Eighteen (52.9%) patients required an
      extrahepatic surgical procedure. Nineteen (35.8%) patients were haemodynamically
      stable and the indications for surgery in these cases were penetrating trauma in
      6, large haemoperitoneum in 12, and diaphragmatic rupture in 1. The overall
      mortality in the operated group was 15%, but the liver-related mortality rate was
      7.5%. The success rate for conservative management was 88.8%, with mortality 0%
      and morbidity 11%. The patients managed conservatively had grades of injury (I
      III) similar to the haemodynamically stable operated patients (94.4% vs 94.7%),
      whereas the haemoperitoneum was larger in the operated group (63.1% vs 11.1%).
      Non-operative management is the preferred treatment option in haemodynamically
      stable patients with limited haemoperitoneum, regardless of the grade of the
      hepatic lesion, and without severe intra-abdominal injuries.

PMID- 12469459
TI  - Preoperative evaluation of primary hyperparathyroidism: role of diagnostic
      imaging.
AB  - This study analyses the diagnostic value of preoperative diagnostic imaging
      examinations in the identification and location of pathological parathyroid
      glands. We examined 77 patients with primary hyperparathyroidism using
      ultrasonography of the neck and Tc99m-MIBI scintigraphy for preoperative
      assessment purposes. All patients underwent surgical treatment. We compared the
      diagnostic imaging results with those furnished by histological examinations.
      TC99m-MIBI scintigraphy revealed the presence of a pathological parathyroid gland
      in 74/77 cases (96.1%) compared with 75/77 cases (97.4%) diagnosed by
      ultrasonography. The two examinations combined detected pathological glands in
      100% of cases. The location of the pathological gland was correct in 57 cases
      (74.0%) at scintigraphy and in 56 cases (72.7%) at ultrasonography. In one case
      (1.3%) persistent hyperparathyroidism was demonstrated. There were no cases of
      relapse. In this study preoperative evaluation by ultrasonography and
      scintigraphy displayed great sensitivity in identifying and locating pathological
      parathyroid glands. Surgical neck exploration is still the gold standard in the
      correct location of pathological parathyroid glands measuring less than 5 mm.

PMID- 12469460
TI  - [Complications of total thyroidectomy: incidence, prevention and treatment].
AB  - The range of indications for total thyroidectomy in the treatment of thyroid
      disease is steadily increasing, but any attempt to assess its real efficacy
      necessarily calls for a knowledge of the incidence of complications, amongst
      other things in order to provide the patient with complete information regarding
      the operation before obtaining his or her consent. Retrospective and
      observational analysis of 14,934 thyroidectomies performed in 42 Endocrine
      Surgery Units in Italy has made it possible to compare total thyroidectomy (TT)
      versus subtotal thyroidectomy with a bilateral remnant (ST-BR), subtotal
      thyroidectomy with a unilateral remnant (ST-UR) and total lobectomy-isthmectomy
      (TLI). The correlation between the number of total thyroidectomies and each of
      the other surgical procedures and the number of complications occurring with each
      of them was also assessed in order to quantify the effective risk of
      complications by determining the Odds Ratios on the basis of univariate analysis
      of the variables considered. The cases reviewed consisted of 9,599 TT (64%),
      3,130 TLI (21%), 1,448 ST-UR (22%) and 757 ST-BR (5%); 13,023 (87%) cases were
      suffering from benign disease and 1,911 (13%) from malignancies. Recurrent
      laryngeal nerve injuries were present in 4.3% of the TT cases with 2.4% transient
      and 1.3% definitive (as against 3% in ST-BR and 2% in ST-UR with 1.4% and 1.1%
      transient, and 1% and 0.6% definitive, respectively; and 1.4% transient and 0.6%
      definitive in TLI). Hypocalcaemia after TT was transient in 14% and definitive in
      2.2% (as against transient rates of 5% in ST-BR and ST-UR and 0.4 in TLI; and
      definitive hypocalcaemia in 0.6%, 0.8% and 0.07%, respectively). Haemorrhage
      occurred in 1.6% of TT cases (as against 2.1%, 0.5% and 0.4% in ST-BR, ST-UR and
      TLI, respectively). The Odds Ratios showed that TT presented a 16% higher
      complication rate than ST-UR which was assigned a value of 1, a 3% higher rate
      than ST-BR and a 5% lower rate than TLI. This greater incidence of complications
      with TT is attributable mainly to the greater incidence of transient
      hypoglycaemia and to a lesser extent to the slightly higher incidence of
      definitive hypoglycaemia, whereas the incidences of recurrent laryngeal nerve
      injuries were very similar in TT and ST-BR. Haemorrhagic complications were more
      frequent in ST-BR than in TT. Bearing in mind that TT is the absolute indication
      in the more demanding thyroid diseases (tumours, retrosternal goitre, Basedow's
      disease, recurrences) and in view of its fairly low complication rate, we believe
      that TT is a safe, reliable procedure, provided it is performed in a technically
      scrupulous manner. ST-BR is a technique which should be abandoned owing to the
      fact that its complication rate is comparable to that of TT and to the
      recurrences it may give rise to. ST-UR may be indicated if the surgeon is not
      sure of safeguarding the anatomical integrity of the recurrent nerve on one side.

PMID- 12469461
TI  - Malignant thyroid nodules: comparison between color Doppler diagnosis and
      histological examination of surgical samples.
AB  - The aim of this study was to verify the reliability of the differential diagnosis
      between benign and malignant thyroid nodules on the basis of vascularization. The
      study was conducted on 108 patients with a scintigraphically "cold" thyroid
      nodule, including 54 carcinomas and 54 benign nodules. All patients underwent
      total thyroidectomy. Diagnosis based on histological examination of the surgical
      specimen was compared with ultrasonographic diagnosis obtained according to a
      personal classification proposed by the authors. Vascular ultrasonographic
      investigation produced 10 false positives, 6 false negatives and 92 correct
      diagnoses, with 88.8% sensitivity, 81.5% specificity, an 82.7% positive
      predictive value and an 88% negative predictive value. It can thus be used
      effectively to identify the larger nodules, while it is unable to provide any
      indication as to their histological type. Ultrasound vascular thyroid study is a
      non-invasive and low-cost method and is very reliable in the differential
      diagnosis of cold thyroid nodules. The best ultrasonographic modality is power
      Doppler. Ultrasound contrast media increase vascular definition but, due to their
      higher cost and the longhier duration of the examination, they should only be
      used in the case of small nodules.

PMID- 12469462
TI  - [Anterior resection in rectal cancer: the role of lymphadenectomy. Comparison of
      2 surgical experiences].
AB  - Of great interest today is the debate regarding the benefits and limitations of
      extended lymphadenectomy in rectal cancer, particularly with regard to patient
      survival. In the present report we review the experience of two different
      surgical departments: a total of 458 patients with rectal cancer were operated on
      in the 1st Surgical Department of S. Martino Hospital, Genoa, and in the 1st
      Surgical Department of Galliera Hospital, Genoa over the period from 1980 to
      1989. Anterior rectal resection was performed in 137 rectal tumours at the S.
      Martino Hospital and in 146 at the Galliera Hospital. The mean follow-up was 48
      months (range: 24-120 months). In the first group of patients, ligation at the
      origin of the mesenteric vessels (with subsequent peri-aortic lymphadenectomy)
      (D2-D3) was performed, while in the second group the mesenteric vessel ligation
      was done at the level of the origin of the left colic vessels (D1). There were no
      complementary therapies (radio or chemotherapy) either before or after surgery,
      because these were only introduced later. The data obtained from analysis of the
      long-term survival curves showed that there were no statistical differences
      between the two surgical experiences. The execution of extended lymphadenectomy
      would not appear to afford any additional benefit in terms of the survival of
      patients with rectal cancer. The well-matched starting conditions in the two
      groups allowed effective comparison between the two experiences and evaluation of
      the "pure" surgical aspect.

PMID- 12469463
TI  - [Impact of the sentinel lymph node in the staging of colorectal carcinoma].
AB  - In view of the very good results obtained by lymphatic mapping and sentinel node
      biopsy in the staging of patients with melanoma or breast cancer, we investigated
      the feasibility of intraoperative regional lymphatic mapping in patients with
      primary colorectal carcinoma. The aim of this study was to determine whether
      lymphatic mapping and sentinel node assessment can identify aberrant drainage
      patterns or make for better staging of the neoplasm in those cases with no or
      only minimal lymphatic neoplastic involvement. Sixteen consecutive patients with
      primary colorectal cancer (stage T2-T3) but without macroscopic involvement of
      the lymphatic system underwent intraoperative lymphatic mapping by injecting 1
      1.5 ml of isosulfan blue dye. The identified and resected sentinel nodes were
      examined using conventional haematoxylin-eosin staining and cytokeratin
      immunohistochemistry. Sentinel node identification was successful in 15 out of 16
      cases (93.8%). In 11 cases (73.3%) sentinel node status correctly predicted the
      final staging. The false-negative rate was 26.7%. Immunohistochemical analysis
      revealed the presence of micrometastasis in one case (6.7%), which was
      consequently upstaged. In cases of colorectal cancer lymphatic mapping is an
      easy, perfectly feasible technique. However, in our experience, it would not
      appear to significantly improve the accuracy of the histopathological staging of
      colorectal carcinoma.

PMID- 12469464
TI  - Surgical treatment of hydatid disease of the liver. An experience from outside
      the endemic area.
AB  - Hydatid disease is quite rare in European countries outside the endemic areas. It
      occurs most frequently in the liver and lungs. Surgery remains the main treatment
      modality for hydatid disease of the liver. There is still considerable debate as
      to whether the best approach is conservative surgery or radical surgery in which
      the cyst is totally removed including the pericyst by total pericystectomy or
      partial hepatectomy. We report the results of our 15-year experience with this
      type of surgery. A series of 35 consecutive patients operated on for hydatid
      disease of the liver from January 1985 to December 2000 was analysed (18 women
      and 17 men with a mean age of 47.7 years). The most common complaints were pain
      (59%), hepatomegaly and intra-abdominal masses (37%). The cysts were single in 23
      patients and multiple in 12, and were found in the right lobe in 21 cases (59%),
      in the left lobe in 9 cases (26%), and in both lobes in 5 (15%). In one patient
      (2.8%), concomitant extrahepatic (splenic) disease was present. The diameter of
      the cysts ranged from 3.5 to 20 cm (mean value: 9.5 cm). Patients were subdivided
      according to the kind of surgery (radical versus conservative) and period of
      operation (group 1: 1985-1992; group 2: 1993-2000). With the increase in surgical
      skills and the advent of new techniques, radical surgery (12 cystoperistectomies,
      3 left lobectomies and 3 segmentectomies) came to be performed more frequently
      than conservative surgery in the second period (18/20 in group 2 versus in 7/15
      group 1) with low complication rates, a 3.7% mortality rate and similar operative
      time (175 min versus 145 min) and hospital stay (16.8 days versus 19.2 days) as
      compared to the conservative approach. The policy of applying radical surgery
      whenever feasible can be implemented with acceptable morbidity and near zero
      mortality. Radical surgery, however, needs to be applied judiciously, and there
      is still an important role for conservative surgery.

PMID- 12469465
TI  - [Adenomyomatosis of the gallbladder. Personal experience and analysis of the
      literature].
AB  - Gallbladder adenomyomatosis is a pathological condition due to parietal
      thickening and intramural diverticulosis. Though it has always been considered a
      hyperplastic benign disease, the possibility of malignant transformation is
      currently admitted. Through an analysis of their personal experience and of the
      relevant literature, the authors draw attention to anatomical and clinical
      features, diagnostic interpretations and up-to-date trends in the therapy of this
      condition. Over the period from 1990 to 2001, 13 patients with adenomyomatosis of
      the gallbladder were observed, amounting to 4% of all cholecystectomies performed
      over the same period. According to the extent of the disease three forms have
      been identified: diffuse (26%), segmental (26%) and localized (48%). The clinical
      presentation appears to be mainly conditioned by the frequent association with
      gallstones (84%), and for this reason ultrasonographic features were commonly
      interpreted as being signs of chronic inflammation or suspected neoplasia, though
      retrospective ultrasound evaluation revealed pathognomonic signs of gallbladder
      adenomyomatosis. Indications to surgery were therefore mainly based upon the
      presence of stones and chronic inflammation. Cholecystectomy is currently also
      indicated in symptomatic cases of non-lithiasic gallbladder adenomyomatosis,
      whereas there appears to be no such clear-cut rule for the treatment of
      asymptomatic cases. Nevertheless, prophylactic laparoscopic cholecystectomy may
      be justified considering the evolution, the uncertain nature of the disease and
      the difficult differential diagnosis versus malignant lesions.

PMID- 12469466
TI  - [Laparoscopic versus mini-cholecystectomy: analysis of hospital costs and social
      costs in a prospective randomized study].
AB  - The aim of the study was to calculate the hospital and social costs in relation
      to efficacy of clinical outcome, hospital stay and time off work in two groups of
      patients randomly treated with laparoscopic or mini-cholecystectomy. One hundred
      and eighty-one patients with simple, symptomatic gallstone disease were included
      in the study; of these, 9 cases were excluded because of conversion to
      conventional cholecystectomy. Eighty-six cases underwent laparoscopic
      cholecystectomy and 86 mini-cholecystectomy. Operative time (median time: 35
      minutes) and hospital stay (median stay: 3 days) were the same for both surgical
      procedures. The median time off work was 10 days for laparoscopic cholecystectomy
      and 20 days for mini-cholecystectomy (P = 0.007). Hospital expenses showed a
      saving of 820.48 euros for each patient undergoing mini-cholecystectomy. Since
      laparoscopic cholecystectomy is associated with a shorter period off work, it
      seems to be cheaper with a daily saving of 164.96 and 146.51 Euros per patient,
      according to cost/effectiveness and cost/utility analyses, respectively.
      Consequently, although laparoscopic cholecystectomy shows a better outcome in
      terms of socioeconomic aspects and patient compliance, in an attempt to
      rationalize hospital expenditure, we would advocate mini-cholecystectomy for
      those patients who do not need to return to work early.

PMID- 12469467
TI  - [Diverticular disease: complications and treatment].
AB  - This study reports on 10 years of experience in observing diverticular disease.
      The study considers 77 patients, 41 males and 36 females, aged from 50 to 88
      years (mean age: 70 years), observed from January 1991 to December 2001. Sixty
      two patients were admitted from the Accident and Emergency Unit and 15 were
      elected patients. Five patients underwent emergency surgery, while 72 received
      only antibiotic therapy. The overall mortality rate was 0. The morbidity rate was
      22% in those patients undergoing emergency surgery. In only one of the elected
      patients was wound suppuration detected. Diverticular disease, in most cases, is
      treated by antibiotic therapy alone, but in 30% of cases surgery is necessary.
      Colon resection and immediate anastomosis are the first choice operation also in
      the emergency setting, provided local conditions (inflammation, septic
      contamination) make anastomosis safe. In patients with major peritoneal
      contamination, Hartman's operation and subsequent recanalization after 6 months
      are to be preferred.

PMID- 12469468
TI  - [Extrauterine endometriosis: what interest for the general surgeon? Presentation
      of 3 clinical cases and review of the literature].
AB  - Extragonadal endometriosis is rarely diagnosed preoperatively for the variety of
      its localizations. Presentations to general surgeons may be atypical and pose
      diagnostic difficulty, mimicking other acute diseases. We report three cases
      treated with surgical operation. Case 1: a 28-year-old woman admitted for bowel
      obstruction due to coecal endometriosis, with appendix mucocele, peritoneal
      pseudomyxoma and ovarian endometrioma. The patient underwent right colectomy and
      right adnexectomy in the emergency setting. Case 2: a 31-year-old woman with
      endometriosis of the distal extraperitoneal portion of the round ligament
      presenting as an irreducible inguinal hernia. An operation was performed: the
      round ligament and a polycystic structure encompassing it were completely
      excised. Case 3: a 41-year-old woman, with umbilical endometriosis diagnosed by
      her gynaecologist, was admitted to our department for excision. Surgical
      treatment of extragonadal endometriosis is adequate. However, postoperative
      follow-up is mandatory and hormonal suppressive therapy may be indicated by the
      gynaecologist.

PMID- 12469470
TI  - [Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC): a
      double cancer in the non-cirrhotic liver].
AB  - The authors report a case of a large tumour, located in the right hepatic lateral
      segments, (size: 15 cm), consisting of a hepatocellular carcinoma (size: 10 cm)
      and an intrahepatic cholangiocarcinoma (size: 5 cm). The mass was detected by
      ultrasonography during an examination for abdominal pain in an 80-year-old
      female. After tumour biopsy and histological examination, hepatic resection was
      performed. The postoperative course was uneventful and the patient was discharged
      6 days after surgery. The rarity of this double cancer is stressed.

PMID- 12469469
TI  - [Stromal tumors of the rectum: a case report and review of the literature].
AB  - This paper describes a case of epithelioid leiomyosarcoma of the rectum in a
      patient admitted for constipation and rectal bleeding. After an initial biopsy
      diagnosis of leiomyoma, a local excision was performed, showing the malignant
      nature of the tumour. Consequently, the patient underwent an abdomino-perineal
      amputation, adjuvant radiation (50 Gy) and a 24-month follow-up, which revealed
      no signs of local or distant recurrence. Sarcomas of the rectum are rare and
      therefore poorly documented neoplasms. They belong to the wider group of
      gastrointestinal stromal tumours, which are classified in 4 histological types:
      (i) smooth muscle, (ii) neural, (iii) mixed and (iv) undifferentiated. Since they
      grow within the intestinal wall, the symptoms are usually few or late, leading to
      delays in diagnosis. The diagnostic and staging protocol of stromal tumours of
      the rectum includes CT and MRI. The treatment is primarily surgical, where
      possible, and should guarantee complete clearance of the tumour, which often
      requires an aggressive approach. Non-curative resection, high tumour grade and
      size > 10 cm, are considered unfavourable prognostic factors. Further trials are
      needed to establish the exact role of adjuvant therapy. Though it prolongs the
      disease-free interval, there is no clear evidence that it influences the overall
      survival.

PMID- 12469471
TI  - [Intestinal duplication in the adult. A case report of colonic duplication and a
      review of the literature].
AB  - Alimentary tract duplications are uncommon congenital anomalies that are usually
      present during the first decade of life. However, a smaller number of cases may
      remain unsuspected until adulthood. They are most common in the ileum but can
      occur anywhere along the alimentary tract. Duplications may be cystic or tubular
      in appearance and characteristically arise from the mesenteric aspect of the
      intestine. Abdominal pain, nausea and/or vomiting, palpable mass, weight loss,
      and bleeding are the most common symptoms. This paper reports the case of a 24
      year-old male with a cystic duplication of the ascending colon not correctly
      diagnosed prior to operation. When faced with such an abdominal cystic lesion,
      differential diagnoses versus duplication cyst, mesenteric cyst, choledochal
      cyst, giant diverticulum, and cystic tumour of the pancreas should be considered.
      Ultrasound and computerized tomography are good tools for diagnosis and for
      delineating the relationship between the cyst and peripheral structures. Surgery
      provides treatment and allows a final pathological diagnosis. Removal of the cyst
      could be considered satisfactory but resection of the duplication and the
      adjacent bowel is recommended because of the possibility of malignant
      degeneration and the risk of gastrointestinal ulceration and haemorrhage due to
      ectopic gastric mucosa.

PMID- 12469472
TI  - [Paget-Schroetter disease: clinical and therapeutic considerations].
AB  - A case of subclavian-axillary vein thrombosis prompted us to review the recent
      literature on the subject. Paget-Shroetter disease is an uncommon disease, which
      is still associated with high early and late morbidity rates and the prevention
      of which requires early diagnosis and treatment. The importance of trauma (in the
      form of physical strain) in determining the symptoms of the disease is
      universally accepted. We observed subclavian-axillary vein thrombosis in a young
      22-year-old athlete who complained of unexpected onset of pain in the left
      armpit, spreading to the arm and to the shoulder on the same side, functional
      impotence of the upper arm and swelling of the hand and forearm, and engorgement
      of the vessels in the arm, shoulder and clavipectoral region, which in the course
      of time developed the characteristics of a collateral circulation. The patient
      underwent phlebography which documented lack of opacification of the axillo
      subclavian axis and showed the presence of a collateral circulation with dilation
      of the vein of the shoulder and arm. We first attempted to dissolve the thrombus
      by locoregional infusion of urochinase and later started anticoagulative therapy
      with an intravenous infusion of heparin (10,000 IU/h after a bolus of 500 units).
      Because of the poor result of thrombolysis and anticoagulative therapy and the
      progressive worsening of the disease, the patient underwent surgery to restore
      the continuity of the venous axis. The surgical procedure was performed through a
      skin incision along the upper edge of the collar-bone. This was dissected and the
      two stumps were well separated to allow a clear view of the subclavian vein.
      Phlebotomy, thrombectomy and reconstruction of the venous axis with an expanded
      polytetrafluoroethylene patch were performed. The postoperative course was
      uneventful and the patient underwent phlebography again on postoperative day 8,
      which demonstrated complete patency of the subclavian vein, and was discharged on
      postoperative day 20 on oral anticoagulative therapy.

PMID- 12469473
TI  - [Italian Society of Surgery. II Consensus Conference. Acute pancreatitis.
      Bologna, 30 October 2001].

PMID- 12469474
TI  - [The method of the sentinel lymph node].

PMID- 12469475
TI  - Birth spacing. Three to five saves lives.
AB  - Couples who space their births 3 to 5 years apart increase their children's
      chances of survival, and mothers are more likely to survive, too, according to
      new research. Many women want to space births longer than they currently do.
      Programs can do more to help them achieve the birth intervals they want.

PMID- 12469476
TI  - [Principles of and indications for metabolic irradiation].

PMID- 12469477
TI  - [Care of urinary diversions].

PMID- 12469478
TI  - [Hemospermia].

PMID- 12469479
TI  - [Competence of the disciplinary Order of Physicians].

PMID- 12469480
TI  - [Medications and sexuality].

PMID- 12469481
TI  - Air leaks and the pleural space.

PMID- 12469482
TI  - Predictors of alveolar air leaks.
AB  - Persistent air leaks are caused by the failure of the postoperative lung to
      achieve a configuration that is physiologically amenable to healing. The raw
      pulmonary surface caused by the dissection of the fissure often is separated from
      the pleura, and the air leak fails to close. Additionally, higher air flow
      thorough an alveolar-pleural fistula seems to keep the fistula open. Other
      factors that interfere with wound healing, such as steroid use, diabetes, or
      malnutrition, can result in persistence of the leak. A thoracic surgeon can
      minimize the incidence of air leak through meticulous surgical technique and can
      identify patients in whom the balance of risks (Table 1) and benefits warrant
      operative intervention based on an understanding of the underlying
      pathophysiology.

PMID- 12469484
TI  - Chest tube management after pulmonary resection.
AB  - This article has provided a detailed description of the entire decision-making
      process of chest tube management. Although these protocols were derived from
      prospective randomized trials, further studies are needed.

PMID- 12469483
TI  - Intraoperative techniques to prevent air leaks.
AB  - Persistent air leaks prolong chest tube duration and hospital stay after lung
      surgery. Air leaks also may lead to life-threatening empyemas. Preventing
      postoperative air leaks and BPFs is the best treatment for air-leak
      complications. Meticulous closure of parenchymal, pleural, and bronchial defects
      is the mainstay of air-leak control. The reinforcement of parenchymal suture and
      staple lines, pleural apposition, and well-vascularized tissue-flap coverage of
      bronchial suture and staple lines further reduce the incidence of prolonged air
      leaks and BPFs.

PMID- 12469485
TI  - Persistent air-leak following pulmonary resection.
AB  - Air leaks are an unavoidable complication of pulmonary resection. The definition
      of a persistent air leak is arbitrary and may even be irrelevant in solving the
      problem. Persistent air leaks are more common in patients with severe COPD, and
      preoperative interventions are ineffective in reducing their prevalence.
      Meticulous surgical technique and care in handling and resection of the pulmonary
      parenchyma are essential in preventing persistent air leaks. Buttressing
      parenchymal staple lines and creating a pleural tent or pneumoperitoneum should
      be reserved for patients at risk for persistent air leaks. The use of currently
      available sealants is ineffective for the treatment of this complication. To stop
      persistent air leaks, early cessation of suction and placing chest tubes to an
      underwater seal is more effective than continuous suction. The management of
      persistent air leaks may require provocative chest tube clamping and permissive
      chest tube removal or patient discharge from the hospital with a chest tube and a
      Heimlich valve.

PMID- 12469486
TI  - Special article: a brief history of pneumonectomy. 1999.
AB  - The ineluctable conclusion to be drawn from this article is that thoracic surgery
      could not develop without endotracheal ventilation. What is astounding is that
      this technique, known since the 16th century and perfected in the late 19th
      century, was ignored and in fact rejected by surgeons [4]. The negative effect
      that Sauerbruch had on the development of thoracic anesthesia was well stated by
      Comroe: "An impressive piece of hardware, backed by a highly prestigious
      designer, can hold back progress for decades" [49]. Before the formation of the
      AATS, there was no forum for the discussion of methods for solving the problems
      of pulmonary resection and anesthesia. Experience gained in the animal laboratory
      was largely ignored and not applied to pneumonectomy in humans. Ligation of the
      pulmonary artery does not initiate the clinical course of massive pulmonary
      embolism. In the absence of infection, concern about the postpneumonectomy space
      is groundless. Preresection phrenic nerve crush and pneumothorax are unnecessary,
      as are attempts to stabilize the postpneumonectomy mediastinum by adjusting
      intrapleural pressure or by thoracoplasty. It behooves thoracic surgeons to heed
      Comroe's comment: "Finally, what are we, with our infinite wisdom and magnificent
      technical advances, doing today that will appear primitive, curious or even
      stupid 50 years from now?"

PMID- 12469487
TI  - Control of the pleural space after pneumonectomy.
AB  - The authors believe that most patients who undergo pneumonectomy do not require
      drainage of the postpneumonectomy space. Needle or catheter aspiration is simple
      and usually adequate. In cases in which significant bleeding, rapid pleural fluid
      accumulation, or contamination is expected, however, drainage of the space is
      recommended. If drainage is used, the tube probably should be connected to a
      balanced drainage system to ensure proper physiologic positioning of the
      mediastinum during the critical immediate postoperative period.

PMID- 12469488
TI  - Management of empyema after lung resections (pneumonectomy/lobectomy).
AB  - Empyemas that complicate lung resection are an uncommon but morbid and too-often
      deadly sequela, particularly after pneumonectomy. Knowledge of the conditions
      that place patients at high risk for this complication and of the well
      established principles of bronchial stump closure are crucial to preventing
      empyemas. One should be familiar with the various options of stump reinforcement
      and should use them aggressively, particularly in high-risk situations. Prompt
      recognition of this complication demands immediate intervention and drainage of
      the empyema space to minimize the risks of aspiration to the remaining lung. The
      principles that guide the management of these empyemas are those established by
      Clagett and Geraci 40 years ago [37]. Modern variations of these guidelines have
      allowed improved results and a more timely recovery and should be considered in
      low-risk patients.

PMID- 12469489
TI  - Special article: physiologic consequences of pneumonectomy. Consequences on the
      esophageal function. 1999.
AB  - Pneumonectomy is associated with gross anatomic and physiologic changes of the
      esophagus. So far, only a few studies have examined the influences of anatomic
      changes of the esophagus and the resulting physiologic consequences. When
      pneumonectomy is performed without pulmonary replacement, the esophagus is
      displaced to the side of pneumonectomy and posteriorly. Indentation of the
      esophagus by the trachea, bronchus, or aortic arch and dilatation at various
      levels are present. After pneumonectomy, the peak amplitude of esophageal
      peristaltic contractions is reduced. This feature is more pronounced in patients
      who are more than 60 years old and in patients who had their pneumonectomy
      performed more than 6 years ago. Injury of the vagal nerves, local ischemia,
      scarring of the esophagus and mediastinum after surgery, and disturbance of the
      autonomic nervous systems are the major reasons leading to esophageal dysmotility
      and delayed gastric emptying. Despite the severe morphologic and physiologic
      changes of the esophagus observed after pneumonectomy, few patients complain of
      gastrointestinal symptoms after pneumonectomy. Esophageal functional
      abnormalities may be present in patients with lung cancers before pneumonectomy
      because of a close anatomic relationship between the esophageal vagal nerve
      supply and the pulmonary hilum, making the vagal nerves susceptible to
      disturbances by the tumors or by involved hilar or mediastinal lymph nodes. After
      pneumonectomy, esophageal dysmotility is exaggerated. After recipient
      pneumonectomy for thoracic organ transplantation, esophageal dysmotility and
      delayed gastric emptying are common, but their relationship to gastroesophageal
      reflux, chronic aspiration, or subsequent development of bronchiectasis and
      obliterative bronchiolitis is controversial. To reduce the incidence of
      esophageal dysmotility after pneumonectomy, every effort should be made during
      surgery to prevent direct injury of the esophagus or the vagal nerves. A
      prospective study involving a larger patient population is needed to precisely
      define the problem and its management.

PMID- 12469490
TI  - Postoperative chylothorax.
AB  - Chylothorax is an unusual complication of surgical procedures within the chest.
      Early recognition is important so that appropriate conservative measures can be
      applied. Operative intervention after a short course of supportive therapy will
      control most chyle fistulas. Methods of diagnosis in the postoperative setting
      and literature supporting various treatment options are the focus of this
      article.

PMID- 12469491
TI  - Role of Eloesser flap and thoracoplasty in the third millennium.
AB  - In the modern era of thoracic surgery, few indications remain for thoracoplasty.
      Indeed, many surgeons believe that the resulting deformity outweighs the
      usefulness of collapse therapy. Rather than trying to obliterate chronic spaces,
      these surgeons advocate myoplasty techniques to fill the space. Unfortunately,
      these techniques are not minor procedures and two to three operations are often
      necessary to solve the problem. This is the reason why thoracoplasty remains the
      best option in selected patients. In some cases, it should be a first-line
      procedure rather than as a last resort when everything else has failed. In their
      discussion of the article by Horrigan and Snow [31], Pairolero and Trastek [44]
      summarized well the current attitudes toward these different concepts: "Although
      management of the chronically infected pleural space has changed over the years,
      the goals of therapy remain the same to conserve the patient's life with a healed
      chest wall without evidence of infection. Determination of which techniques are
      necessary to achieve these goals must be tailored to the individual patients."

PMID- 12469492
TI  - Sample collection and preparation in cytology: increasing diagnostic yield.
AB  - Cytology is a valuable diagnostic tool for examining many types of lesions. The
      diagnostic yield of cytology is dependent on optimal sample collection and smear
      preparation. This article outlines the basic techniques for collection of samples
      via fine-needle biopsy, imprints, scrapings, and swabs. Tips are given on how to
      avoid some of the most common problems that lead to nondiagnostic samples.

PMID- 12469493
TI  - Recognition of basic cell types and criteria of malignancy.
AB  - In-house examination of cytologic preparations can yield timely information and
      be done with minimal equipment. This article describes the features that allow
      for recognition of the basic cell types encountered on cytologic smears. General
      cellular features suggestive of malignancy are covered as well as some common
      potential pitfalls in their application. These basic concepts can be applied to
      samples from each of the specific anatomic locations covered in subsequent
      articles in this issue.

PMID- 12469494
TI  - Cytology of subcutaneous glandular tissues.
AB  - This article deals with the cytologic appearance of various glandular tissues
      located in the subcutaneous tissues. Normal cytologic features are described. In
      addition, inflammatory, infectious, neoplastic, and hyperplastic changes are
      discussed. Most of these features are depicted in the 60+ photomicrographs that
      are distributed throughout the article. Many of the changes are similar in the
      glands, and it is usually possible to differentiate the gland of origin based on
      cytologic appearances. Subcutaneous neoplasms that are not associated with a
      subcutaneous gland, and lymph node cytology are not covered in this article but
      are addressed elsewhere.

PMID- 12469495
TI  - Liver cytology.
AB  - Physical examination, clinical laboratory testing, and medical imaging are
      effective in establishing the presence of liver disease; however, they
      infrequently establish a definitive diagnosis. Morphologic evaluation of liver
      tissue is generally accepted as a valuable diagnostic tool in establishing a
      diagnosis in liver disease. Clinicians have several options for obtaining
      specimens for morphologic evaluation, including surgically obtained wedge
      biopsies, percutaneous core biopsies, and fine-needle aspiration specimens.
      Surgical and core biopsy procedures require anesthesia or sedation and have a
      substantial risk of bleeding complications. Fine-needle aspiration usually does
      not require sedation and is rarely associated with hemorrhage; thus, it is
      frequently chosen for animals that are poor anesthetic risks or have
      coagulopathies. Diseases like malignant lymphoma, hepatic lipidosis, and
      suppurative hepatitis are readily diagnosed cytologically, whereas hepatocellular
      adenomas, hyperplastic nodules, fibrosis, and chronic inflammation are more
      difficult to identify cytologically.

PMID- 12469496
TI  - Cytology of the pancreas.
AB  - Pancreatic fine-needle biopsy and cytologic evaluation is an important diagnostic
      tool that is not commonly used in veterinary medicine. This article discusses how
      to obtain and interpret pancreatic fine-needle biopsies. Normal pancreatic
      cytology, along with the potential diagnostic pitfalls, is also outlined. The
      cytologic features of pancreatic inflammation, hyperplasia, and neoplasia are
      discussed and illustrated.

PMID- 12469497
TI  - Cytology of bone marrow.
AB  - Cytologic examination of bone marrow aspirates can provide a wealth of diagnostic
      information. Practitioners should not hesitate to perform bone marrow aspirates
      when indicated. This article is designed to assist the practitioner in the
      evaluation of bone marrow aspiration biopsies. The indications for marrow
      evaluation, methods of sample collection, sample preparation, and cytologic
      examination of bone marrow are discussed. Cases are provided to demonstrate
      accurate interpretation of bone marrow aspirates.

PMID- 12469498
TI  - Symmetric structures and equifinality of evolution outcomes in simple neural
      network models.

PMID- 12469499
TI  - Molecular modeling of the closed forms of the kainate-binding domains of kainate
      receptors and qualitative analysis of the structure-activity relationships for
      some agonists.

PMID- 12469500
TI  - Air carbon dioxide prevents proteins from being developed by silver staining in
      polyacrylamide gel.

PMID- 12469501
TI  - Blood coagulation dynamics under the conditions of Hageman factor deficiency: a
      mathematical model.

PMID- 12469502
TI  - Comparative analysis of the ligand-binding sites of the metabotropic glutamate
      receptors mGluR1-mGluR8.

PMID- 12469503
TI  - The use of polycondensed hemoglobin as the basis of a blood substitute capable of
      transporting oxygen.

PMID- 12469504
TI  - Ca(2+)-activator of the luminescence system of the earthworms Henlea sp.,
      (Annelida: Clitellata: Oligochaeta: Enchytraeidae).

PMID- 12469505
TI  - Conformational aspects of the interaction of various cholinesterases with
      polymethylene-bis(trimethylammonium) derivatives.

PMID- 12469506
TI  - A new pair of donor-acceptor markers for immunoassay: a porphyrin-cyanine dye.
      Energy transfer in solutions and Langmuir films.

PMID- 12469507
TI  - Molecular modeling the human A1 adenosine receptor and study of the mechanisms of
      its selective ligand binding.

PMID- 12469508
TI  - Low rate of induced nitric oxide synthesis in immunocompetent organs is
      characteristic of hereditary immune deficiency in mice.

PMID- 12469509
TI  - Exopolyphosphatase of the halotolerant bacterium Brevibacterium sp. strain VKM Ac
      2118 grown at normal and enhanced salinity.

PMID- 12469510
TI  - The time course of the photosynthetic activity in the forming transport domains
      of the Chara corallina plasmalemma.

PMID- 12469511
TI  - Comparative analysis of protein kinases that phosphorylate tobacco mosaic virus
      movement protein in vitro.

PMID- 12469512
TI  - Short double-stranded RNA suppresses multiple drug resistance gene expression in
      tumor cells.

PMID- 12469513
TI  - Methylation, copy number, and activity of ribosomal genes do not change after
      telomerization of human fibroblasts.

PMID- 12469514
TI  - [Herpetic meningo-encephalitis].
AB  - Herpes simplex encephalitis is characterized by a very poor prognosis. HSV1 and
      HSV2 are the two viruses responsible for this neurological infection. The gold
      standard assay for the diagnosis is PCR on CSF. However, one should not wait for
      the result of this assay to initiate an antiviral treatment, using i.v.
      aciclovir.

PMID- 12469515
TI  - [Clinical management of genital herpes: what can be done in pregnancy?].
AB  - Neonatal herpes infection is the major complication of genital herpes even if it
      occurs in less than 1/10,000 births. A great number of recent studies illustrates
      the natural history of genital herpes. The importance of viral transmission by
      asymptomatic shedding is now well established. The widespread use of viral
      diagnosis strategies is the prerequisite to efficient genital herpes prevention
      in order to eradicate viral mother-to-child transmission. This starts with the
      detection of at-risk situations such as primary infection in late pregnancy. Once
      the at-risk situation is known there should be concern about the adaptation of
      treatment strategies including antiviral therapy. The following work proposes
      different strategies facing each at-risk situation in order to discuss the
      efficiency of new diagnostic and treatment tools.

PMID- 12469516
TI  - [Antiretroviral drugs for the treatment and prevention of herpes infections in
      the year 2000].
AB  - Major developments in the two last decades have improved the diagnosis and the
      treatment of Herpes Simplex Virus infection. Aciclovir was the first effective
      antiherpetic drug available. Afterwards other drugs have been developed either
      with a better bioavailability or with an activity against aciclovir-resistant
      strains. Although there is at present no effective vaccine or drug capable of
      eradicating established infection, these antiviral drugs are able to shorten the
      course and decrease severity of symptomatic episodes in both normal and
      immunocompromised patients. Moreover in patients with frequently recurrent herpes
      a suppressive therapy will suppress episodes or decrease their frequency. The
      ongoing therapeutic research, beside the development of new drugs inhibiting
      viral replication, concerns the strengthening of specific immune response which
      should lead to the development of effective therapeutic and preventive vaccines.

PMID- 12469517
TI  - [What's new in vaccines against herpes simplex infections?].
AB  - Herpes simplex viruses (HSV) can cause a variety of infections, including genital
      herpes. Despite effective antiviral therapy HSV infections remain a public health
      problem. Vaccines offer the possibility for controlling the spread and limiting
      HSV disease, two strategies for herpes vaccination: prophylactic immunization or
      therapeutic immunization. The article discusses the results of different studies,
      in particular, concerning recombinant vaccines, DISC vaccines and DNA vaccines.

PMID- 12469518
TI  - [Genital herpes and quality of life].
AB  - Genital herpes is a frequent chronic, sexually-transmitted disease among adults.
      Besides its physical consequences that largely depend on the frequency and
      intensity of recurrences, genital herpes frequently induces a psychological
      morbidity. This paper discusses the instruments of measure that can be used in
      the evaluation of health-related quality of life among infected patients and
      states the results of a French study that confirmed the substantial psychological
      morbidity caused by genital herpes.

PMID- 12469520
TI  - Elastin, past, present and future.

PMID- 12469519
TI  - [Epidemiology of human herpes virus 8 (HHV-8) or the herpes virus associated with
      Kaposi's sarcoma (KSHV)].
AB  - Human herpesvirus 8 (HHV-8), also called Kaposi's sarcoma-associated herpesvirus
      (KSHV), is not a ubiquitous virus. In countries with a low viral seroprevalence
      (< 5% in adult general population) as the USA, Northern Europe and Asia, the
      infection concerns essentially homosexual men. In this latter population, the
      viral transmission seems to occur during sex. In endemic countries (HHV-8
      seroprevalence between 10-70% in the adult general population) as in the
      Mediterranean basin (Italy, Greece), and Africa (East and Central Africa), men,
      women and children are infected. In these countries, HHV-8 seroprevalence
      increases with age and often reaches adult rates before the end of puberty. Viral
      transmission, in general endemic populations, seems to occur from mother to child
      and between sibs whereas heterosexual transmission appears to concern essentially
      groups at risk for sexual transmitted diseases. Saliva is a major reservoir of
      HHV-8.

PMID- 12469521
TI  - [An efficient department of radiology is a key to good diagnosis of venous
      thrombosis. However indications for insertion of vena cava filters are not yet
      certain].

PMID- 12469522
TI  - [Ask the patient about snoring and daytime sleepiness. Connection between sleep
      apnea syndrome and heart disease--metabolic disorders].

PMID- 12469523
TI  - [Vena cava filters in complicated venous thromboembolism. Ten years' experiences
      at Malmo University Hospital].
AB  - All 74 patients treated with vena cava filter insertion during 1991-2000 at Malmo
      University Hospital were reviewed. Thirty-nine patients (53%) died during follow
      up. Indications for permanent filter insertion (n = 63, age 25-89 years, 35 men)
      were contraindication for or side effects of anticoagulant treatment, or
      pulmonary embolism during anticoagulant treatment. Temporary vena cava filters (n
      = 11, age 19-85 years, three men) were inserted during surgery or thrombolysis.
      No complications occurred during temporary filter insertion. During 33 (1-120)
      months of follow-up of patients with permanent vena cava filters 37 patients
      (59%) died, thrombosis of the inferior vena cava occurred in 14 patients (22%),
      and recurrent pulmonary embolism in five patients (8%). Vena cava filter
      insertion should be considered as an alternative treatment in a selected group of
      patients with contraindications to or insufficient effect of anticoagulant
      treatment.

PMID- 12469524
TI  - [A nation-wide survey: striking differences in the diagnostic procedures relating
      to thrombosis].
AB  - A questionnaire revealed that nearly 40 000 examinations of clinically suspected
      deep venous thrombosis (DVT) were performed in Sweden in 2001, with a slight
      predominance of phlebographies. In about two thirds of all cases the deep muscle
      veins of the calf were included in the interpretation when phlebography was
      performed, but in less than one fifth when Doppler sonography (CDU) was used. In
      more than half of the cases a negative CDU was not followed by phlebograghy. On
      the other hand, the combination of CDU and phlebography was routinely used in
      nearly two thirds of all ambiguous cases. The interpretation of nonfiling of
      contrast medium in vein segments on phlebography varied from DVT to no DVT. Most
      of the phlebographies were performed with digital X-ray technique.

PMID- 12469525
TI  - [Sleep apnea a risk factor of cardiovascular disease].
AB  - Obstructive sleep apnea (OSA) affects almost one fifth of the male and 10% of the
      female middle-aged population. Only one fifth of subjects with more or less
      severe disorder of breathing report simultaneous daytime sleepiness. There is
      growing research evidence for an independent association between OSA and
      cardiovascular disease (CVD). The suggestion that this link is not only
      correlative but also causative is strongly supported by a series of recent
      clinical and epidemiological studies. The association between OSA and
      traditionally recognized cardiovascular risk factors suggests that OSA may
      provide an additive and synergistic risk in cases with co-existing obesity,
      insulin resistance, diabetes and/or dyslipidaemia. These recent insights advocate
      better awareness of OSA and potentially also a wider use of screening-tools for
      early identification and treatment of sleep related breathing disorders.
      Moreover, current research within the fields of obesity and cardiovascular
      prevention needs to identify OSA as a study confounder. Continuous intense
      research into pathophysiological mechanisms and therapeutic possibilities of CVD
      related to OSA appears to be an important and potentially rewarding area of
      disease prevention.

PMID- 12469526
TI  - [Many paths converge in arthritis. Awareness of risk factors and illness
      mechanisms increase steadily].
AB  - Osteoarthritis does not deserve the term "degenerative joint disease", the course
      of the disease is characterized by dynamic changes in both synthesis and
      degradation of cartilage and other joint tissues. At the end stage all tissues of
      the joint are involved, not only the cartilage. In the early phases of the
      disease, changes in cartilage metabolism can be detected through assay of
      biomarkers in joint fluid, blood or urine. These changes evolve into macroscopic
      changes of fibrillation and loss of cartilage. Concomitantly, changes occur in
      other joint tissues and bone. The more advanced stages of change, as loss of
      joint space and osteophytes, may be detected by radiological examination.
      Osteoarthritis is a complex disease where genetic variations in several loci
      appear to interact with environmental factors to initiate and drive disease
      progression towards several different phenotypes. These may be recognized in
      different joint patterns, predominant inflammation or lack of inflammation,
      predominant loss of joint space or osteophytosis, etc. Increased occupational
      joint load, joint injuries and obesity are well recognized risk factors for
      osteoarthritis.

PMID- 12469527
TI  - [Physical activity can influence the course of early arthritis. Both strength
      training and aerobic exercise provide pain relief and functional improvement].
AB  - There is no causal treatment for osteoarthritis. Instead treatment is aimed at
      decreasing pain and improving function. The base of osteoarthritis treatment is
      education and exercise. Exercise, both aerobic exercise and muscular strength
      training, have positive effects on pain and function. The minimum recommendations
      of exercise are equivalent to the recommendations of physical activity to obtain
      or maintain a good general health. Acupuncture is a safe and effective treatment
      for osteoarthritis pain. However, function is not automatically improved when
      pain is relieved.

PMID- 12469528
TI  - [Multidisciplinary course in emergency medicine gives residents greater
      confidence].
AB  - Lack of courses in emergency medicine for doctors under training is currently a
      problem in Sweden. Only 10 percent will have these courses early under their
      internship. The University hospital in Malmoe has therefore decided to create a
      course for doctors under training and to offer it early in their education. The
      curriculum is based on a problem-based learning concept using a modified case
      methodology that has been used since the 1920's at Harvard Business school in
      Boston. The course integrates doctors from different specialties with experienced
      nurses from the emergency ward. The five day course comprises; three theoretical
      days where cases from the emergency room are discussed with the case methodology,
      followed by two days of practical training. Our results from 100 participants
      over a period of two years is very encouraging, over 85 percent of the
      participants were very satisfied with the course. The multidisciplinary
      discussion about different cases was much appreciated. Our experience of this
      problem-based learning concept is very good, since it promotes deep rather than
      surface learning and promotes an in-depth collaboration between disciplines.

PMID- 12469529
TI  - [Insignificant connection between breast feeding and adult intellectual
      development].

PMID- 12469530
TI  - [The first open heart surgery--a cool story. Winter sleep of marmosets inspired
      the breakthrough].

PMID- 12469531
TI  - [A new model for general practice Spur-inspection within the frame of pilot
      projects].

PMID- 12469532
TI  - [Measurement of bone density in the heel--nothing for clinical osteoporosis
      care].

PMID- 12469533
TI  - [Psychological aspects of ill-health in working life].

PMID- 12469534
TI  - [External and unbiased quality assurance of scientific manuscripts].

PMID- 12469535
TI  - [What is evidence-based care?].

PMID- 12469536
TI  - [Dubious article on circumcision].

PMID- 12469537
TI  - [Why are not old people allowed to die?].

PMID- 12469538
TI  - [All this sick leave--I didn't know that it was life].

PMID- 12469539
TI  - The social injustice of the HIV/AIDS epidemic.

PMID- 12469540
TI  - Aerobic exercise training fails to lower hypertriglyceridemia levels in persons
      with advanced HIV-1 infection.
AB  - The purpose of this study was to determine whether blood lipid and lipoprotein
      concentrations varied in 5 men with advanced HIV-1 infection after 12 months of
      aerobic exercise training. Prior to exercise, the mean baseline cholesterol and
      high-density lipoprotein cholesterol (HDL-C) serum concentration were each lower,
      and mean baseline triglyceride concentration was higher compared to a healthy
      population norm. Consistent exercise training for 12 months failed to
      significantly (p > .05) alter cholesterol or HDL-C. Triglyceride concentration
      was significantly (p < .05) elevated above baseline (63 mg/dL) regardless of
      exercise compliance. The results suggest that long-term exercise training cannot
      correct lipid profile abnormality, particularly hypertriglyceridemia, common to
      individuals with advanced HIV-1 infection.

PMID- 12469541
TI  - Gender-specific profiles of self-reported adolescent HIV risk behaviors.
AB  - The purposes of this study were to (a) identify behaviors that put adolescents at
      risk for HIV infection by retrospectively comparing a cohort of HIV positive and
      negative young adults and (b) determine gender-specific high-risk profiles. HIV
      positive (n = 61) and HIV-negative (n = 124) individuals from two midwestern
      cities completed a survey tool prepared by the investigators examining six areas
      of behavior and activity identified in the literature as high risk. Alcohol use,
      drug use, and gang-related behaviors were not associated with HIV status in these
      young adults. Early, frequent, and unprotected sex with large numbers of partners
      were the predictive risk factors for HIV-seropositive status. Gender profiles,
      however, differed. Whereas the female profile suggested that early and
      unprotected sex were the only reliable predictors, HIV-positive male subjects had
      larger numbers of partners, engaged in more risky sexual behaviors, were more
      likely to have experienced sexual abuse before and during adolescence, and were
      more likely to have used cocaine during their adolescence. Conclusions include
      the confirmation of a resurgence of HIV among young males having sex with males
      and confirmation of females as the largest growing group of HIV-positive young
      adults.

PMID- 12469542
TI  - Profiles of rural nurses' use of personal protective equipment: a cluster
      analysis.
AB  - This study examined the relationship between profiles of rural registered nurses'
      levels of compliance with the use of personal protective equipment and HIV
      related attitudes. Survey data were collected from 395 practicing registered
      nurses in nine rural counties in New York and Pennsylvania. Cluster analysis
      grouped respondents according to their use of protective equipment by patient HIV
      status. Seven profiles were identified from the resulting 13 clusters. Profiles
      were named according to the characteristics of the protective equipment usage
      that were most evident in each profile. Usage levels included minimal users,
      appropriate users, anticipatory users, glove users, discriminate users, maximal
      users, and optimal users. Of these, three were classified as compliant, one as
      undercompliant, and three as overcompliant. Selective compliance (changing usage
      in response to patients' HIV status) was characteristic of five profiles.
      Knowledge that patients were HIV-positive accounted for overcompliance and
      selective compliance and was related to nurses' HIV attitudes. Undercompliance
      was related to care of patients who were HIV-negative or unknown. Rural nurses'
      use of personal protective equipment is not homogenous but discrete and
      idiosyncratic. This analysis expands current knowledge and redefines nursing
      practice of standard precautions.

PMID- 12469543
TI  - Influence of abuse on condom negotiation among Mexican-American women involved in
      abusive relationships.
AB  - This study explored cultural and gender perspectives of abuse on condom
      negotiation behaviors for AIDS prevention among Mexican-American women in abusive
      intimate relationships. A convenience sample of 20 abused women participated in
      the study. Data were collected through a demographic questionnaire and audiotaped
      responses to a semistructured interview guide. Content analysis using QSR NUDIST
      was used to analyze the verbatim transcriptions of all participant interviews.
      The predominant category, "He always got his way," was developed in response to
      the content of the verbatim transcriptions. The category was further expanded to
      include the self-descriptive subcategories of "He beat me," "He made me feel
      bad," and "He forced me." Through content analysis, a relationship between abuse
      by male sexual partners and condom negotiation for AIDS prevention was
      identified. Trustworthiness of the data collection and analysis was established
      through methods suggested by Lincoln and Guba.

PMID- 12469545
TI  - HIV/AIDS health policy: considering the influential climates.

PMID- 12469544
TI  - Results of a pilot intervention trial to improve antiretroviral adherence among
      HIV-positive patients.
AB  - A small pilot trial of a multicomponent (behavioral strategies, simplified
      patient information, and social support) and multidisciplinary (cognitive
      behavioral therapy and nursing) medication adherence intervention was conducted
      for HIV-infected adults prescribed antiretrovirals. Patients (N = 33) were
      randomly assigned to the intervention condition or standard care. Compared to the
      control group, patients in the intervention condition had significantly higher
      self-efficacy to communicate with clinic staff (p = .04) and to continue
      treatment (p = .04), were significantly more likely to be using behavioral and
      cognitive strategies (p = .01 and p = .04), reported significantly higher life
      satisfaction (p = .03), reported significantly increased feelings of social
      support (p = .04), and showed a trend toward an increase in taking their
      medications on schedule (p = .06). The intervention, however, did not appear to
      affect health-related anxiety or to significantly improve adherence to dose.
      Implications for future intervention planning are discussed.

PMID- 12469546
TI  - The terrorism of caring.

PMID- 12469548
TI  - Putting the question 'which is best?' to the test.

PMID- 12469547
TI  - A comparative study reveals that a regimen containing sustiva provides an
      effective alternative to protease inhibitor-based therapy.

PMID- 12469549
TI  - [Colic surgery in the horse: a retrospective study of 272 patients].
AB  - In the period from January 1995 until December 2000, 272 horses underwent a
      laparotomy for gastrointestinal disorders. The results of these surgeries were
      evaluated. From these 272 patients 176 (= 65%) were discharged in good health
      from the hospital. When the patients that were euthanized immediately after the
      start of the surgery, because of a fatal deterioration, were not taken into
      account, the short time survival rate was 77%. Strangulated small and large
      intestinal obstructions (48%) had a lower short time survival rate than non
      strangulated obstructions (87%). Fatal postoperative complications occurred in
      18% of the patients in which the surgery was completed. Postoperative shock was
      the most common cause. Non-fatal complications were found in 16% of the patients
      which survived surgery. The major non-fatal complications were incisional hernia
      and thrombophlebitis of the jugular vein. From the patients that survived the
      surgery 81% returned to their former level of performance. Early referral may
      decrease the percentage of fatal complications and improve the prognoses of
      surgery.

PMID- 12469550
TI  - [Veterinarian hits aggressive cat off the examining table].

PMID- 12469551
TI  - [Bovine spongiform encephalitis: the importance of one European ruling].

PMID- 12469552
TI  - [Reaction to the opinion of zoo veterinarians about legal home remedies].

PMID- 12469553
TI  - [Discussion about caring for sick seals in progress. Cuddle to death or shoot
      them?].

PMID- 12469554
TI  - [Predecessors: veterinarians from earlier times (49). Alexandre Francois Liautard
      (1835-1918)].

PMID- 12469555
TI  - [Integrity of the veterinarian: a look inside].

PMID- 12469556
TI  - [Detection of bacterial contamination in platelet concentrates: perspectives].
AB  - Bacterial contamination of blood components represents today the highest
      infectious risk of blood transfusion, the risk is particularly high when it
      affects platelet concentrates. In France the prevention methods developed over
      the past six years (donor selection, phlebotomy site preparation, first 30 ml
      diversion, systematic leuko-reduction...) aimed at limiting the introduction of
      bacteria in blood and bacterial proliferation. Several methods have been tested
      for the detection of bacterial contamination in platelet concentrates but none
      have been generalised. Difficulties were met, due to the necessity of 1)
      detecting only the platelet concentrates presenting a real infectious risk, when
      the presence of bacteria is observed in 2.2% (2-4%) of donated blood and 2)
      guaranteeing the availability of platelet concentrates. New methods have been
      developed which seem able to bring responses to these difficulties. Several
      processes are being (or will be) assessed, including automated blood culture,
      bacterial genomic detection with or without amplification, flow cytometric
      methods. In parallel, an indirect method able to detect the presence of bacteria,
      based on oxygen consumption, will also be evaluated. One (or several) of these
      processes should allow, in the short-term, to detect platelet concentrates
      presenting an infectious risk. In the future, the interest of bio-chips for
      bacterial detection in biological fluids must be investigated.

PMID- 12469557
TI  - [Validity of pretransfusion bedside agglutination tests for pretransfusional
      control].
AB  - The incidence rate of ABO hazards of transfusion remains high in France. In this
      country, bedside pretransfusion controls include an agglutination test for red
      cells only, although its validity has scarcely been assessed in the practice. 847
      nurses from 9 public hospitals and private clinics in a French region
      participated in a study aimed at measuring the sensitivity and specificity of
      pretransfusion bedside agglutination tests within hospital wards. Sensitivity was
      found to be 93.9% +/- 3%. Nondetection of mismatching was increased by two risk
      factors only: having worked more than 4 years in the same ward, and not having
      been trained to use this test. The sensitivity of this test might still be
      improved. This test is found sensitive enough to be kept. Nevertheless, if used
      alone, it is not a safe protection against recipient's mismatch. Authors
      recommend both to improve agglutination test sensitivity and to link it strongly
      to the bedside checking of both transfusion information and the recipient's
      identity.

PMID- 12469558
TI  - [Transfusional record and blood grouping methods: essential factors of
      transfusion safety].
AB  - The clinical and biological control of the whole transfusion process is a major
      preoccupation for everyone dealing with blood transfusion. Specially when the
      patient is a female recipient or belongs to a group with a high prevalence of
      alloimmunisation. This case report points out the outstanding importance of the
      immune compatibility, which must be strongly maintained to prevent any harmful
      consequences. The transfusional record transmission and a simple and sensitive
      blood grouping test are essential to increase transfusion safety.

PMID- 12469559
TI  - [Flow cytometry in immunohematology].
AB  - Flow cytometry is an objective, sensitive and quantitative technique which allows
      rapid and simultaneous analysis of several parameters on a great number of cells.
      Hence, flow cytometry is particularly suitable for the analysis of complex cell
      populations, rare events and quantitative studies. In immunohematology, flow
      cytometry is a very powerful approach to the study of mixed red cell populations
      (hematopoietic chimerism, transfusion or bone marrow transplantation), the
      detection of low frequency cell populations (reticulocytes, fetomaternal
      hemorrhage) and the quantitative analysis of red blood cell antigens.

PMID- 12469560
TI  - [Is it possible to organize into a hierarchy blood donation contraindications?].
AB  - Because it symbolizes henceforth the sanitary risk and fears which are linked to
      it, the blood transfusion must master the potential or real risks associated to
      its practice. The analysis of these risks leads to confirm the initial selection
      phase of candidates for blood donation as an always original stage of the blood
      transfusion safety towards the identified infectious risks, but also mainly
      towards the emergent or modelled risks. The evaluation of the current system of
      prevention leads to consider two potential dangers: the ineffectiveness of the
      selection because of the lack of meaning given to this stage, and the donors'
      disaffection caused by badly accepted or badly justified deferrals. The deficit
      of meaning can be due to an insufficient information of the population as for the
      policy of collective prevention of transfusion-transmitted infectious diseases.
      It can be worsened by the construction of the pre-donation interview which can
      appear as a succession of questions without visible links. This paper suggests
      risk analysis to blood transfusion, and a reflection to improve this important
      stage of blood product safety approach represent by the selection of candidates
      to a blood donation.

PMID- 12469561
TI  - The future of acute (general) medicine?

PMID- 12469562
TI  - Creutzfeldt-Jakob Disease.

PMID- 12469563
TI  - Changes in patterns of acute medical receiving in Scotland 1996 to 2001.
AB  - The purpose of this study was to review changes in working practises of
      physicians and hospitals from 1996 to 2001 in the light of rising medical
      admissions and published reports into the organisation of acute admissions.
      Information was gathered by direct discussion with the appropriate lead doctor
      for each hospitals acute service in February 2001. The results were compared with
      a previously published study, which recorded the situation as of October 1996.
      The hospitals which were studied were the twenty seven Scottish hospitals which
      admit more than 3000 acute medical patients each year. There has been a 25%
      increase in number of consultants carrying out receiving duties. Nearly all
      hospitals now have an acute admission unit. Four hospitals have appointed acute
      care physicians. Triage of appropriate patients to more specialised ward based
      care has increased. There has been a rise in geriatricians involvement in acute
      receiving from four to fifteen hospitals. New developments include early
      discharge for chronic obstructive airway disease, outpatient management of venous
      thrombosis, discharge planning and streamlining investigation of chest pain. Two
      hospitals have specific alcohol support services. There continues to be progress
      and changes within medical and geriatric services over the last five years
      stimulated by the continuing rise in number of medical admissions.

PMID- 12469564
TI  - Audit of a change in otolaryngology discharge letters using the Scottish
      Intercollegiate Guidelines Network (SIGN) recommendations.
AB  - Hospital and general practitioners should establish good communications so that
      continuity of care can be maintained when patients are discharged from hospital.
      A discharge letter was routinely prepared utilizing the standardized morbidity
      registration forms by the house surgeon for delivery to the patients general
      practitioner. The authors developed a new discharge letter, which was sent under
      separate cover to the general practitioner. The two discharge letters were
      assessed utilising data fields recommended by the Scottish Intercollegiate
      Guidelines Network (SIGN). A total of 162 consecutive paediatric patient
      discharges were identified. The mean number of items present in the existing and
      the new discharge letters were 13.7 + 1.8 and 12.2 + 3 respectively. The new
      discharge letter met the SIGN guidelines more closely than the existing discharge
      letter.

PMID- 12469565
TI  - Three years experience of adults admitted to hospital in north-east Scotland with
      E. coli O157.
AB  - To describe the epidemiology, clinical features, treatment and outcomes of adults
      with E. coli O157 infection presenting to Aberdeen Royal Infirmary over a three
      year period. METHODS: A retrospective casenote review. RESULTS: Thirty-two
      confirmed cases of E. coli O157 infection were admitted between 1997 and 2000.
      The median age was 58 years (range 16-93). Ten patients (31%) were from the city
      of Aberdeen and 22 (69%) from surrounding rural areas. Twenty-seven patients
      (85%) presented between May and October. The source of infection was unknown or
      unconfirmed in all cases. Bloody diarrhoea was present in 30 (94%). Leucocytosis
      was present in 18 (63%) but only four patients (13%) had a fever. Six of the 32
      patients (19%) developed Haemolytic-Uraemic Syndrome (HUS) of whom 2 died. Ten
      patients received antibiotics of whom two developed HUS. Twenty-seven of the 32
      (85%) had made a full recovery by time of discharge, three (9%) had impaired
      renal function and two (6%) died in hospital. CONCLUSION: E. coli O157 infection
      tends to occur sporadically in rural areas in North East Scotland. It is not
      usually associated with fever. Infection occurs more commonly in the summer and
      autumn. HUS complicates infection in almost one fifth of patients.

PMID- 12469566
TI  - Hyponatraemia in hip fracture patients.
AB  - We performed a retrospective review of hyponatraemia in patients with hip
      fractures, before and after surgery. All patients admitted with fractures of the
      neck of femur who had a surgical intervention to deal with the fracture were
      included. Results were determined using two definitions for hyponatraemia. The
      incidence of pre-operative and post-operative hyponatraemia were both 2.8% if
      hyponatraemia was defined as [Na] < 130 mmol/l. No cases of hyponatraemia were
      found pre-operatively when hyponatraemia was defined as [Na] < 125 mmol/l. Using
      this definition the post operative incidence of hyponatraemia was 0.93%. The
      incidence of hyponatraemia in this group of patients is small. However the
      potentially severe affects of hyponatraemia warrant close monitoring of these
      patients and the establishment of methods to prevent this problem from occurring.

PMID- 12469567
TI  - The medical faculty, University of Glasgow evolution of clinical teaching in the
      late 19th and early 20th centuries.

PMID- 12469568
TI  - Interview with Greg Van Pelt, FACHE, vice president and chief executive,
      Providence Health System, Washington Region, Seattle. Interview by Kyle L
      Grazier.

PMID- 12469569
TI  - Healthcare reform: one coalition's efforts at effecting change.

PMID- 12469570
TI  - The inclusive, diverse workplace: we are not there yet.

PMID- 12469571
TI  - Sustaining the edge: factors influencing strategy selection in academic health
      centers.
AB  - Competition within the acute care sector as well as increased penetration by
      managed care organizations has influenced the structure and role of academic
      health centers during the past decade. The market factors confronting academic
      health centers are not dissimilar from conditions that confront other
      organizations competing in mature industries characterized by declining
      profitability and intense rivalry for market share. When confronted with intense
      competition or adverse external events, organizations in other industries have
      responded to potential threats by forming alliances, developing joint ventures,
      or merging with another firm to maintain their competitive advantage. Although
      mergers and acquisitions dominated the strategic landscape in the healthcare
      industry during the past decade, recent evidence suggests that other types of
      strategic ventures may offer similar economic and contracting benefits to member
      organizations. Academic health centers have traditionally been involved in
      network relationships with multiple partners via their shared technology,
      collaborative research, and joint educational endeavors. These quasi
      organizational relationships appear to have provided a framework for strategic
      decisions and allowed executives of academic health centers to select strategies
      that were competitive yet closely aligned with their organizational mission. The
      analysis of factors that influenced strategy selection by executives of academic
      health centers suggests a deliberate and methodical approach to achieving market
      share objectives, expanding managed care contracts, and developing physician
      networks.

PMID- 12469572
TI  - Community health center-led networks: cooperating to compete.
AB  - The primary mission of community health centers (CHCs) is to provide primary and
      preventive healthcare for the underserved and vulnerable populations, including
      the uninsured, underinsured, and Medicaid beneficiaries. Economic and regulatory
      challenges have placed these safety net providers in a precarious position,
      forcing some to respond using cooperative strategies. This article focuses on
      seven CHC-led networks, delineating their integrative efforts in the core areas
      of managed care, clinical, administrative, information, and finance. Interviews
      with key representatives from each network highlight the networks'
      accomplishments and the critical success factors and outcomes of their
      integrative efforts. Several underlying themes emerged from this study that are
      consistent with findings of previous studies conducted in other organizational
      settings. Specifically participants in CHC-led networks cite the following
      factors as contributors to success: reciprocity, communication, trust, and long
      standing relationships among key individuals. This is the first study to provide
      a rich depiction of CHC network activities.

PMID- 12469573
TI  - Healthcare managers' roles, competencies, and outputs in organizational
      performance improvement.
AB  - Healthcare CEOs recognize that managers are under increasing pressure to work
      smarter and more efficiently with fewer available resources. Jobs in the
      healthcare industry are in a constant state of change, requiring a workforce that
      is not only prepared to adjust quickly to the changing environment but to
      simultaneously maintain or improve overall organizational performance.
      Traditionally, trainers were viewed as the people with the primary responsibility
      for improving organizational performance. Today some CEOs believe healthcare
      managers should own that responsibility, and other CEOs believe the
      responsibility should be shared among healthcare managers and trainers. This
      shift in how accountability is viewed poses at least two important questions. Are
      managers aware of the various roles they need to enact to achieve successful
      organizational performance improvement? Do managers possess the competencies
      associated with those roles? The seven most contemporary trainer roles, now
      referred to as workplace learning and performance roles, are examined in this
      article to help managers increase their knowledge of the roles, competencies, and
      outputs expected of them. Based on findings of a study conducted to examine CEO's
      perceptions of managers' roles in the performance improvement process, this
      article provides theoretical backgrounds, includes verbatim study comments, and
      offers practical recommendations or tips for managers.

PMID- 12469574
TI  - Eliminating night hours for a community's sole urgent care clinic.

PMID- 12469575
TI  - Survey of postgraduate fellows. Conducted by the American College of Healthcare
      Executives, Division of Research and Development, June 2003.

PMID- 12469576
TI  - [Osteoarthritis is frequent, very frequent. What can we do?].

PMID- 12469577
TI  - [Correctly used thrombolysis is effective in the treatment of stroke. Sweden co
      ordinates the EU's follow up of safety and quality].

PMID- 12469578
TI  - [New discoveries are against statin treatment of acute coronary disease. But the
      assessment of therapeutic effects based on observational studies is difficult].

PMID- 12469579
TI  - [Early thrombolysis indicated in threatened cerebral infarction. A study of 60
      patients treated at Akademiska sjukhuset in Uppsala].
AB  - Results of the routine use of tissue plasminogen activator (tPA) within 3 hours
      of an acute ischemic stroke have been reported from the United States, Canada and
      Germany. Published reports from other countries and from centers using tPA within
      a wider timeframe are limited. 60 patients in a Swedish University Hospital were
      treated with i.v. tPA within 6 hours of onset of acute ischemic stroke symptoms.
      Two patients suffered more extensive parenchymal intracerebral hemorrhages, of
      which one required surgery and one died. At 3 months, 47% were independent, 35%
      dependent and 18% deceased. Due to the relatively low number of patients in this
      series, data should be cautiously interpreted, but the results are comparable to
      those of large randomized controlled trials and published phase 4 studies. The
      risk of tPA treatment after 3-6 hours does not seem to be significantly increased
      as compared to treatment within 3 hours.

PMID- 12469580
TI  - [Hip and knee osteoarthritis. Conventional X-ray best and cheapest diagnostic
      method].
AB  - Osteoarthritis is a multifactorial disease affecting cartilage and subchondral
      bone. Conventional radiographs are inexpensive and readily available. The hip
      joint should be examined in weight-bearing with an anteroposterior and a right
      and left anterior oblique view, rotating the patient 55 degrees in each oblique
      view. Radiographically established osteoarthritis of the hip is present when the
      joint space width is less than 3 mm or less than the width in the contralateral
      hip joint. The femorotibial joint should be examined in a posteroanterior view in
      weight-bearing and in semiflexion with the central X-ray beam tangential to the
      medial tibial plateau and with the medial aspect of the foot parallel to the
      beam. A diagnosis of osteoarthritis of the femorotibial joint is established with
      the presence of osteophytes at the medial or lateral aspect of the joint. Joint
      space narrowing with a joint width less than 3 mm is a sign of severe disease.
      The femoropatellar joint should be examined in skyline view in standing with the
      X-ray beam parallel to the articular aspect of the patella. A diagnosis of
      osteoarthritis of the femoropatellar joint is established with a joint space
      width less than 5 mm. Conventional radiographs of the hip and knee joints are
      believed to remain the primary examination for detecting signs of degenerative
      disease in these joints, although MRI is a superior technique for revealing even
      small areas of degenerative changes.

PMID- 12469581
TI  - [Clinical criteria best foundation for diagnosis of mild to moderate arthritis.
      Symptoms, not radiological results, dictate choice of treatment].
AB  - No generally accepted definition of osteoarthritis exists. Traditionally, the
      diagnosis is obtained by radiographic examination but different definitions are
      used for different purposes. Since no causal treatment exists, treatment is
      aiming at reducing symptoms and improving function. The correlation between
      radiographic features of osteoarthritis and symptoms is poor. Thus, it is
      recommended that in the early and moderate stages the diagnosis osteoarthritis be
      obtained through clinical examination. Radiographs should be obtained when other
      serious pathologies are suspected or when operative procedures are being
      discussed.

PMID- 12469582
TI  - [A promising start for quality indicator work within vascular surgery?].

PMID- 12469583
TI  - [Nocturia and nocturnal polyuria in the elderly. Treatment essential for
      increasing patients' quality of life and decreasing the risk of injury].
AB  - Nocturia, i.e. nocturnal voiding episodes, is a symptom which can occur at all
      ages, but there is an age-related increase in both men and women. Both health and
      quality of life are deteriorated by nocturia. Sleep is disturbed, with daytime
      sleepiness and reduced well-being as consequences. The risk of fall injuries is
      increased among elderly persons who need to get up several times at night for
      toilet visits. Nocturia is associated with an increase in nocturnal urine output,
      and an increased number of nocturnal voids indicates a shift of urine output from
      the daytime to the night. One of the aims of the treatment of nocturia is
      therefore to normalise the circadian rhythm of diuresis.

PMID- 12469584
TI  - [Time to revise guidelines concerning anticoagulants in atrial fibrillation].

PMID- 12469585
TI  - [Physical activity reduces blood pressure].

PMID- 12469586
TI  - [It's possible to increase the response rate to postal questionnaires].

PMID- 12469587
TI  - [The survey of Danish biobanks suggests a "drop-out" registry].

PMID- 12469588
TI  - [Stanley Burns--the man who collects historical medical failures].

PMID- 12469589
TI  - [Advice to the Scientific Committee: There is only one way to distribute basic
      research grants].

PMID- 12469590
TI  - [Symposium as a tool for scientific training all the way through the education].

PMID- 12469591
TI  - [Evidence-based management of appendicitis--more research required].

PMID- 12469592
TI  - [Insinuating and provocative about circumcision].

PMID- 12469593
TI  - [Capacity of health services and physicians].

PMID- 12469594
TI  - [Sick leave and structure renewal].

PMID- 12469595
TI  - [Am I as a physician always obliged to intervene?].

PMID- 12469596
TI  - Statistics of the concentration of tropospheric bioaerosol.

PMID- 12469597
TI  - Effect of ions on cholinesterase catalysis of substrates with regard for their
      unproductive binding.

PMID- 12469598
TI  - Sterilization of mail by means of an electron beam accelerator.

PMID- 12469599
TI  - The luminescence system of soil enchytraeids, Henlea sp., (Annelida: Clitellata:
      Oligochaeta: Enchytraeidae).

PMID- 12469600
TI  - Spatial organization of intracellular organelles of stretch receptor neurons as
      an indicator of their different functional states.

PMID- 12469601
TI  - Individual differences in the structure of choice motivation in humans.

PMID- 12469602
TI  - Sex-related differences in the cell cycle parameters of the ventricular zone in
      the developing preoptic area of rat embryos.

PMID- 12469603
TI  - The use of trecresanum to stimulate antibody formation in offspring of
      experimental animals during the embryonic period.

PMID- 12469604
TI  - Stimulation of liver regeneration after atrophy in cirrhotic rats.

PMID- 12469605
TI  - Protein composition of circulating immune complexes in patients with periodic
      disease complicated or not complicated by renal amyloidosis.

PMID- 12469606
TI  - Effects of orthovanadate and genistein on the plasma membrane Cl(-)-ATPase
      sensitive to GABA-ergic ligands in the bream (Abramis brama L.) brain.

PMID- 12469607
TI  - Task-related striatal neurons shared by various stages of monkey behavior.

PMID- 12469608
TI  - Asymmetry of structural changes in the rabbit hippocampus during "animal
      hypnosis".

PMID- 12469609
TI  - The effect of the serotonergic receptor antagonist mianserine on the activity of
      Na, K-ATPase from rat cerebral cortex membranes.

PMID- 12469611
TI  - Local histopathological changes of amniote skin caused by a feeding tick (Acari;
      Ixodinae).

PMID- 12469610
TI  - The effect of chemical sympathectomy on the conducting system of the white rat
      vagus nerve.

PMID- 12469612
TI  - Feeding of the symbiotic polychaete Gastrolepidia clavigera (Polynoidae) and its
      interactions with its hosts.

PMID- 12469613
TI  - Scotch pine adaptation to climate changes.

PMID- 12469614
TI  - The phenomenon of endoparasitism at early stages of fish development.

PMID- 12469615
TI  - Peroxidase in the interactions between pea plants and Rhizobium.

PMID- 12469617
TI  - Natural radioresistance as a criterion of species (as exemplified by large taxa
      of the order rodentia).

PMID- 12469616
TI  - Association of the CCR2 chemokine receptor gene polymorphism with myocardial
      infarction.

PMID- 12469618
TI  - Identification of a new type of ecological hazard of chemicals: inhibition of
      processes of ecological remediation.

PMID- 12469619
TI  - The bony skull of the Siberian Salamander Salamandrella keyserlingi (Amphibia:
      Urodela: Hynobiidae) and the role of thyroid hormones in its development.

PMID- 12469620
TI  - [Obesity--an epidemic of the XXI century].

PMID- 12469621
TI  - [Metabolic syndrome].

PMID- 12469622
TI  - [Interconnection between insulin resistance and lipid metabolism disorders in
      obese patients].
AB  - AIM: Investigation of blood lipid spectrum, level of free fatty acids (FFA),
      glucose, insulin in blood and insulin resistance in obese patients depending on
      the type of obesity and effects on them of biguanides derivatives. MATERIAL AND
      METHODS: Routine blood biochemical examination was made in 59 obese patients. 34
      of them had trunk obesity (TO) and 25--gluteofemoral obesity (GFO). 18 patients
      with TO received gliformine treatment in a day dose 1.5 g for 3 months. RESULTS:
      More pronounced metabolic disturbances indicated by the presence of insulin
      resistance, compensatory hyperinsulinemia, high levels of FFA associated with
      impaired glucose tolerance and dislipidemia, high rate of arterial hypertension
      were observed in patients with TO. Correlations were found between lipid
      metabolism disturbances and insulin resistance. Gliformin treatment resulted in
      loss of weight, decline of insulin resistance and hyperinsulinemia, improvement
      of carbohydrate metabolism, lipid blood spectrum, lowering of blood pressure.
      CONCLUSION: Biguanide derivatives are a perspective group of drugs for treatment
      of the diseases running with insulin resistance.

PMID- 12469623
TI  - [Clinico-immunologic subtypes of type I diabetes mellitus].
AB  - AIM: To study clinico-immunological characteristics of diabetes mellitus type I.
      MATERIAL AND METHODS: Clinical examination was made of 333 patients with diabetes
      mellitus type I with manifestation of carbohydrate metabolism impairment and
      intoxication syndrome because of diabetic ketoacidosis (group 1) and without it
      (group 2). Compared to donors (n = 68), T-cell, B-cell and monocytic components
      of immune system were studied in patients with uncomplicated DM type 1 in both
      groups (28 and 15 patients, respectively). RESULTS: Patients with different
      subtypes of the disease differ by the course and rate of progression, defects in
      T-cell and monocyte components of immunity. CONCLUSION: Type 1 diabetes mellitus
      is a heterogenous pathology with subtype 1 (rapidly progressive) and subtype 2
      (slowly progressive).

PMID- 12469624
TI  - [Lipid metabolism and functional status of the kidney in hypothyroid patients
      depending on the phase of disease].
AB  - AIM: To evaluate renal function in correlation with lipid metabolism parameters
      in patients with primary hypothyroidism (HT) in compensation and decompensation.
      MATERIAL AND METHODS: 45 HT patients' examination included study of blood
      creatinine, urea, cholesterol, triglycerides, high and low density lipoproteins,
      urinary microalbumin, thyroid hormones and thyrotropin, beta 2-microglobulin
      levels, glomerular filtration rate (GFR), renal functional reserve (RFR). Also,
      Zimnitsky test and ultrasound investigation of the kidneys were made. RESULTS: It
      was found that renal dysfunction in decompensated HT is characterized by normal
      renal concentration function, high intraglomerular pressure (low GFR and RFR),
      high concentration of beta 2-microglobulin in blood. Severe HT runs with negative
      correlation between GFR and total blood cholesterol, LDL. Albuminuria and low RFR
      in decompensated HT and marked hyperlipidemia suggest development of
      glomerulopathy related to abnormal physicochemical processes in glomerular
      endothelium. CONCLUSION: Patients with decompensated HT have apparant glomerular
      dysfunction and disturbances in lipid metabolism. Hyperlipidemia in HT is a
      factor of renal damage.

PMID- 12469625
TI  - [Hypothalamic syndrome with dexamethasone-dependent hyperaldosteronism and
      disrupted arginine-vasopressin secretion].

PMID- 12469626
TI  - [Polymorphic locus D6S392 near the Mn-dependent superoxide dismutase gene is
      associated with diabetes mellitus in the Moscow population].
AB  - AIM: Distribution of alleles of tetranucleotide microsatellite D6S392 located
      nearby the gene of Mn-dependent superoxide dismutase (SOD2) was studied in
      healthy donors (n = 143), patients with insulin-dependent (n = 166) and insulin
      independent (n = 101) diabetes mellitus (IDDM and IIDM). MATERIALS AND METHODS:
      Alleles of the polymorphic locus D6S392 were amplified using polymerase chain
      reaction (PCR) on the basis of genome DNA isolated from the venous blood of the
      examinees. PCR products were analysed with gel-electrophoresis in polyacrylamide
      gel. Significance of differences of allele and genotypes distribution in the
      population control and patients were assessed with Fisher's criterion and
      Bonferroni's corrections. RESULTS: Locus D6S392 contains 31 allele from 210 to
      330 pn in length and 37 to 67 tandem repeats. Compared to controls, IDDM patients
      had less frequent incidence of low molecular allele 41 and 42 as well as allele
      62. CONCLUSION: Polymorphic locus D6S392 is closely associated with development
      of DM in Moscow population. This may indicate possible participation of the gene
      SOD2 in development of this pathology.

PMID- 12469627
TI  - [Associative analysis of the connection between mutation C1167T in the catalase
      gene and polymorphic marker D6S392 nearby the Mn-dependent superoxide dismutase
      gene with diabetic microangiopathies].
AB  - AIM: To study allele polymorphism of two variable regions [C1167T substitution in
      the catalase (CAT) gene D6S392 microsatellite near the Mn-dependent superoxide
      dismutase (SOD2) gene] was studied in insulin-dependent diabetic (IDDM) patients
      with (n = 36) or without (n = 56) diabetic nephropathy, and with (n = 30) or
      without (n = 44) diabetic retinopathy. MATERIAL AND METHODS: Both polymorphic
      regions were amplified using polymerase chain reaction (PCR). PCR products were
      separated using polyacrylamide (D6S366) or agarose (C1167T) gel electrophoresis.
      In a case of C1167, PCR-amplified products were digested with BstXI restriction
      endonuclease before electrophoresis. A significance of the difference between
      allele distributions in complicated and uncomplicated IDDM patients was estimated
      using the exact Fisher's test. RESULTS: No significant difference was observed in
      allele and genotype frequencies in complicated and uncomplicated IDDM subjects.
      CONCLUSION: C1167 polymorphism in the CAT gene and D6S366 near the SOD2 gene are
      not associated with the development of diabetic nephropathy and diabetic
      retinopathy in IDDM.

PMID- 12469628
TI  - [Clinico-genetic aspects of the hypotensive response and regression of left
      ventricular hypertrophy in arterial hypertension patients].
AB  - AIM: To study clinicogenetic determinants of left ventricular hypertrophy (LVH)
      regress in 52-week antihypertensive therapy to achieve the target arterial
      pressure (AP) < 140/90 mm Hg. MATERIAL AND METHODS: I/D-polymorphism of
      angiotensin converting enzyme gene, T174M-polymorphism of angiotensinogen gene,
      A1166C-polymorphism of angiotensin II ATI-receptor gene (ATII), 4a/b-polymorphism
      of endothelial NO-synthetase gene (eNOS) were determined in 64 patients (24
      males, 40 females, mean age 54 +/- 1.1 years) with arterial hypertension (AH) and
      LVH. Echocardiography, laboratory tests, clinical measurements of blood pressure
      (BP) and 24-h AP monitoring were made after 4 weeks of placebo and 52 weeks of
      treatment. RESULTS: Baseline values of LV myocardium mass index (LVMMI)
      correlated significantly with mean 24 hour and night systolic arterial pressure;
      24-h, day and night pulse pressure (PP). In patients with regress of LVH the
      degree of LVMMI reduction significantly correlated with lowering of day and night
      PP, baseline level of neutrophils, uric acid and creatinine 52 weeks after
      treatment. Groups made by polymorphism, did not significantly differ by initial
      LVMMI, frequency of achievement of target AP. In patients with genotypes ID/II
      and aa, the level of achieved diastolic arterial pressure was significantly lower
      than in other groups. Resistant LVH was seen in 42.2% patients. Frequency of AP
      normalization was higher in the group of patients with LVH regress (48.6% vs
      25.9%; p < 0.05). Resistant LVH occurred more frequently in patients with
      genotype DD (64.0 vs 28.2% in patients with II/ID, p < 0.05) and in patients with
      genotype 4ab (62.9 vs 30.4% in patients with genotype aa and 21.4%--with genotype
      bb; p < 0.05 in both cases). In patients with resistant LVH frequency of DD
      genotype increased (59.3 vs 24.3% in patients with regress of LVH; p < 0.01),
      genotype AA (74.5 vs 48.6%; p < 0.01) and genotype ab (63.0 vs 27.0%, p < 0.01).
      CONCLUSION: Regress of LVH in AH patients depends on dynamics and complex
      interactions of some hemodynamic, laboratory and genetic parameters.

PMID- 12469629
TI  - [Use of conjugated allergen-polymer vaccines (pollen allergens of new generation)
      for allergen-specific immunotherapy].
AB  - AIM: To assess effectiveness of new pollen allergotropins for allergen-specific
      immunotherapy (ASI). MATERIAL AND METHODS: The allergotropins were produced
      basing on conjugation of pollen allergoids (timothy, birch, mugwort pollen) and
      polyelectrolite (polyoxidonium) with immunomodulating properties. Pollen
      allergotropins (timpol, berpol) were designed to treat pollenosis caused by
      sensitization to timothy and birch pollen. Pollen allergotropins were studied in
      ASI given to 140 patients with pollenosis and 10 patients with bronchial asthma.
      RESULTS: In the group of pollenosis patients with hypersensitivity to birch
      pollen the response to berpol was excellent in 55% patients (the disease symptoms
      disappeared, antihistamine drugs intake was stopped), good--in 33%, satisfactory-
      in 12%. Timpol produced a marked response in all the patients treated for
      hypersensitivity to timothy pollen. CONCLUSION: Pollen allergotropins have a high
      therapeutic effect under low risk of provoking reactions of anaphylactic type in
      patients on ASI.

PMID- 12469630
TI  - [Catalytic autoantibodies and their future in practical medicine].

PMID- 12469631
TI  - [Beta2-adrenergic receptors in immunomodulation: current status and future
      directions].

PMID- 12469632
TI  - [Nerve regulation of cardiac rhythm in rheumatoid arthritis and multiple
      sclerosis patients].
AB  - AIM: To study nervous regulation of cardiac rhythm (CR) in patients with
      rheumatoid arthritis (RA) and multiple sclerosis (MS). MATERIAL AND METHODS:
      Nervous regulation of cardiac rhythm was studied in 57 patients with RA and MS vs
      40 healthy subjects. RESULTS: It was found that nervous regulation of CR in RA
      and MS patients at rest is characterized by imbalance of functions of the
      autonomic nervous system with enhancement of ergotropic effects in patients with
      RA and deficiency of trophotropic impacts in growing ergotropic component in
      patients with MS. Stress tests led to dysfunction of CR central regulation with
      disturbed activity of the subcortical nervous centers (SNC) and autonomic
      maintenance of the processes, were characterized in emotional stress by
      insufficient activity of SNC and enhancement of parasympathetic effects in RA
      patients, hyperactivation of SNC with intensification of sympathetic impacts in
      MS patients manifesting in destabilizing effect of the sympathetic nervous system
      in both groups of patients. CONCLUSION: The findings should be taken into
      consideration when vegetotropic drugs are used in the treatment of RA and MS
      patients.

PMID- 12469633
TI  - [Renal and uterine hemodynamics in pregnancy with chronic glomerulonephritis of
      the hypertonic type].
AB  - AIM: To study gestational changes in renal and uterine hemodynamics and their
      relation to systemic and intracardiac hemodynamics in pregnant hypertensive women
      with chronic glomerulonephritis (CGN). MATERIAL AND METHODS: Echocardiography,
      ultrasonic dopplerography of renal and uterine arteries were made in 16 pregnant
      women with CGN and AH syndrome in trimester II-III and 1-3 months after the
      delivery. Hemodynamic indices in pregnancy were compared to those after the
      delivery which were considered baseline. RESULTS: In CGN pregnant women with AH
      syndrome resistance of renal arteries did not change in pregnancy and were
      similar postpartum. With advancing pregnancy, the resistance of the uterine
      arteries diminished. The indices of the resistance in the main trunk of the renal
      artery correlated with volumetric cardiohemodynamic indices, heart rate and total
      peripheral resistance in segmental interlobular arteries. No significant
      correlation were found between uterine, systemic and cardiac hemodynamics though
      it existed between renal and uterine blood flow. CONCLUSION: Pregnancy does not
      affect vascular resistance of renal arteries in CGN pregnant women with AH
      syndrome, but contrary to pregnancy with essential hypertension in that with CGN
      and AH syndrome renal circulation responds to changes in systemic hemodynamics
      and volumetric indices of cardiohemodynamics. These findigns may reflect
      disturbances in autoregulation of renal circulation and additional effects on
      pregnancy outcome in women with CGN and AH syndrome.

PMID- 12469634
TI  - [Chronic liver diseases in pregnancy].

PMID- 12469635
TI  - [Arterial hypertension and metabolic disorders in the postmenopausal period].

PMID- 12469636
TI  - [Monitoring arterial hypertension in workers in professions exposed to vibration
      hazards (results of a 15-year study)].
AB  - AIM: To follow up for 15 years prevalence of arterial hypertension (AH) in
      workers exposed to vibration, to study AH course and possible correction in long
      term vibration exposure. MATERIAL AND METHODS: The survey covered 1232 males aged
      25-59 years exposed to vibration at their working places for 1 to 30 years (test
      group) and 1163 males matched for age but not exposed to vibration (control
      group). Active primary and secondary prevention of AH and annual population
      control for 10 years were performed in the test group. The control group was
      followed up outpatiently without active intervention. Final screening was
      conducted 5 years after completion of the program of AH prophylaxis. RESULTS:
      Among workers exposed to vibration AH prevalence was similar to that in the
      controls and tended to reduction in the process of preventive treatment. However,
      after the end of prophylactic measures AH incidence rate returned to the baseline
      level. In workers at risk of vibration aftereffects conversion of normal arterial
      pressure to hypertension was observed more frequently than in unexposed patients.
      This requires active prophylactic intervention. CONCLUSION: Long-term exposure to
      moderate and high frequency vibration is an AH risk factor. Incidence rate of AH
      increases with longer exposure to vibration. Compared to controls, aged workers
      exposed to vibration have AH much more frequently.

PMID- 12469637
TI  - [Diagnostic and prognostic value of quantitative monitoring of prostate specific
      antigen in blood serum and urine from patients with prostate cancer after radical
      prostatectomy].
AB  - AIM: To study values of prostate-specific antigen (PSA) in the blood serum and
      urine before and after massage of the prostatic bed in patients with prostatic
      cancer (PC) after radical prostatectomy. MATERIAL AND METHODS: Changes in serum
      and urine PSA concentrations were followed up in 17 patients with PC (T2-3N0M0)
      14 months (4-24 mon) after radical prostatectomy. Control examinations were made
      once a month. MRT or CT and osteoscintigraphy were made in suspected recurrence
      and/or metastases of PC. RESULTS: There were no changes in PSA consentrations in
      the serum and urine before and after the massage of prostatic bed in 10 of 17
      patients. In 3 patients PSA concentrations in blood and serum increased after the
      massage, in one of them blood levels of PSA after the massage went up 5 months
      after PSA increase in the urine. In 4 of 17 patients urine PSA levels increased
      after the massage, the blood levels remaining the same. CONCLUSION: Follow-up
      measurements of blood and urinary levels in PC patients after radical
      prostatectomy before and following massage of the prostatic bed allow detection
      of prostatic PSA-positive cells which were not removed at surgery. We suggest
      that these cells may be the basis of recurrent disease.

PMID- 12469638
TI  - [Modern approaches to treating locally-advanced and disseminated prostate
      cancer].

PMID- 12469640
TI  - [Change in central hemodynamics in lymphoma patients].
AB  - AIM: To elucidate features of hemodynamics in patients with lymphoma and
      hemodynamic effects of polychemotherapy. MATERIAL AND METHODS: Parameters of
      central hemodynamics were studied echocardiographycally in 42 patients with
      lymphoma. RESULTS: In a definite rise in the levels of tumor progression markers,
      changes in the immunity, impaired hemopoiesis there was rearrangement of
      hemodynamics (development of tachycardia, trend to excentric remodeling of the
      left ventricle). The above changes in hemodynamics enhanced in conduction of
      polychemotherapy. CONCLUSION: To avoid cardiotoxicity of polychemotherapy,
      lymphoma patients should receive cardioprotectors.

PMID- 12469639
TI  - [Features of BCG-therapy in treating patients with superficial bladder cancer].
AB  - AIM: To specify features of BCG-therapy which may predict effectiveness of the
      treatment and optimize the treatment regimen. MATERIAL AND METHODS: Intravesical
      immunotherapy with imuron (a 6-week course) was conducted in 62 patients with
      superficial cancer of the urinary bladder who had undergone surgical treatment
      and were prognostically poor. 51 patients of group 1 received maintenance therapy
      as 3 weekly instillations each 3 months for the first year followed by once in 6
      months. 11 patients of group 2 received single monthly instillations. All the
      patients registered their complaints, measured body temperature with fixation of
      maximal value. The diagnosis of the recurrence was made with control cystoscopy
      carried out each 3 months in the first postoperative year and later once in 6
      months. RESULTS: Recurrent tumors were observed in 25 (49%) and 7 (63.6%)
      patients of groups 1 and 2, respectively. Side effects (high body temperature,
      dysuria and macrohematuria) were reported in group 1 during basic treatment. Side
      effects occurred also in maintenance. They were more pronounced than in group 2.
      CONCLUSION: Intravesical BCG-therapy causes cystitis considered a normal reaction
      to treatment. Fever indicates an inflammatory reaction which is rather a positive
      sign of immune reaction and may serve a prognostic factor.

PMID- 12469641
TI  - [A new approach to raising the efficiency of drug therapy for erectile
      dysfunction].
AB  - AIM: To try combined treatment of erectile dysfunction with viagra and
      alprostadil in case of failure of their monotherapy; to compare effectiveness of
      viagra in dynamics of treatment, in various doses and dose adjustment. MATERIAL
      AND METHODS: 82 patients with ED of different genesis received a course of
      intracavernous injections of alprostadil followed by a course of viagra; 25
      patients received combined treatment with alprostadil and viagra. Each course
      lasted for 3 months. Viagra efficiency was also assessed in long-term use (12
      months) and different initial doses (50 or 100 mg). RESULTS: Monotherapy with
      alprostadil or viagra was effective in 73.2 and 75.6% patients, respectively.
      Their combination was more beneficial--88.0%. When used for a long time, viagra
      lost efficiency in psychogenic ED by 17.7%, in organic ED--by 16.9%. In an
      initial viagra dose 50 mg efficiency reached 70.3%, 100 mg--80.0%. CONCLUSION:
      Combined treatment of ED is a method of choice in monotherapy failure and in
      severe ED. Lowering of viagra efficiency in long-term administration may be
      explained by disappearance of placebo effect.

PMID- 12469642
TI  - [Sexual dysfunction in patients with cardiovascular diseases].

PMID- 12469643
TI  - [Pharmacoeconomic aspects of treating osteoporosis].

PMID- 12469644
TI  - [Features of daily rhythm of arterial pressure in patients with primary arterial
      hypertension and neurogenic syncope conditions].
AB  - AIM: A comparative analysis of parameters of systemic BP in patients with primary
      arterial hypotension (PAH) and in patients with neurogenic syncopes (NS) in the
      cycle sleep-awake. MATERIALS AND METHODS: Blood pressure was investigated in 20
      patients with PAH aged 16-44 years and 18 patients with NS aged 16-49 years. 24-h
      ambulatory monitoring of BP was made on the monitor ABPM-02/M (Meditech,
      Hungary). RESULTS: Rhythm indices of BP in NS patients corresponded to age normal
      criteria. 24-h arrhythmia of BP in PAH patients manifests with excessive drop of
      diastolic BP in sleep (55% patients were overdippers). PAH and NS patients differ
      maximally by hypotonic load in sleep: 1.0 +/- 0.7% in NS vs 15.4 +/- 3.2% in PAH.
      Hypotonia episodes in awake PAH patients were registered at each 4th-5th
      measurement of BP, in NS patients--at each 11th-13th. Heart rate in awake PAH
      patients is higher than in healthy subjects. CONCLUSION: Hypotonic load in sleep
      carries the highest differentially-diagnostic importance. This makes more
      perspective examinations of such patients in the cycle sleep-awake. The changes
      observed in PAH patients evidence for activation of cerebral sympathico-adrenal
      systems participating in baroreflex regulation.

PMID- 12469645
TI  - Under the microscope. Will "sound science" weaken the endangered species act?

PMID- 12469646
TI  - Immunology. Subduing suppressors.

PMID- 12469647
TI  - Anthropology. Parched turf battle.

PMID- 12469648
TI  - By the numbers. Deinstitutionalization.

PMID- 12469650
TI  - The brightest explosions. In the universe.

PMID- 12469649
TI  - Scientific American 50.

PMID- 12469652
TI  - On thin ice?

PMID- 12469651
TI  - The enigma of Huntington's disease.

PMID- 12469654
TI  - Order in Pollock's chaos.

PMID- 12469653
TI  - Food for thought. Dietary change was a driving force in human evolution.

PMID- 12469655
TI  - Getting real. What's next in computer displays? Depth and shadows.

PMID- 12469656
TI  - What's your HIPAA ETA?

PMID- 12469657
TI  - Make clinical research top priority.

PMID- 12469658
TI  - Accreditation: the first layer of the quality floor.
AB  - Employers find data valuable, but still seek other measures. In this article,
      experts assess the uneasy relationship between the business community, healthcare
      organizations, and accreditation.

PMID- 12469659
TI  - Sizing up HEDIS: experts take system's measure.
AB  - NCQA's performance measurement system is well established in the industry. But is
      it really addressing the questions that matter? In this article, industry experts
      discuss how HEDIS has made its mark.

PMID- 12469660
TI  - Taking a second look at Joint Commission standards.

PMID- 12469661
TI  - A cancer program's seal of approval.
AB  - Like hospitals and other healthcare organizations, cancer programs are also
      eligible for accreditation. Here's an overview of how the process works, and how
      HIM professionals can contribute.

PMID- 12469662
TI  - A closer look at all-patient refined DRGs.

PMID- 12469664
TI  - A provider's eye-view of PDAs. Interview by Hill Burrington-Brown.

PMID- 12469663
TI  - Inpatient rehabilitation PPS presents new challenges, opportunities.

PMID- 12469665
TI  - Here comes rehab PPS!

PMID- 12469666
TI  - Another look at LOINC (Logical Observation and Identifier Codes).

PMID- 12469667
TI  - Practice brief. Understanding the minimum necessary standard.

PMID- 12469668
TI  - CPT changes for 2002.

PMID- 12469670
TI  - The power of cancer data. Interview by Jane Jeffries.

PMID- 12469669
TI  - Anthrax: what every coder should know.

PMID- 12469671
TI  - What's in a name? Are you merely a family practitioner?

PMID- 12469672
TI  - Payment for care plan oversight.

PMID- 12469673
TI  - The cost of translation.

PMID- 12469674
TI  - Another ounce of prevention. Slowly but surely, Medicare coverage of preventive
      services has grown. Here's an update.

PMID- 12469675
TI  - The HIPAA privacy rule: answers to frequently asked questions.

PMID- 12469676
TI  - Serving up the feedback sandwich.

PMID- 12469677
TI  - How to help your low-income patients get prescription drugs.

PMID- 12469678
TI  - "Oh, by the way...": agenda setting in office visits.

PMID- 12469679
TI  - A primer on employment contracts.

PMID- 12469680
TI  - How to cope if you feel attracted to a patient.

PMID- 12469681
TI  - Bioterrorism talk.

PMID- 12469683
TI  - Pelvic floor muscle training for urinary incontinence in women.

PMID- 12469682
TI  - Damaging effect of detonation diamonds on human white and red blood cells in
      vitro.

PMID- 12469684
TI  - Potent inhibition of human immunodeficiency virus type 1 replication by an
      intracellular anti-Rev single-chain antibody.

PMID- 12469685
TI  - Lamotrigine and rash: scratching beneath the surface.

PMID- 12469686
TI  - Topiramate produced weight loss following olanzapine-induced weight gain in
      schizophrenia.

PMID- 12469687
TI  - High frequency of residual depressive symptoms in bipolar II disorder: the need
      for a better treatment.

PMID- 12469688
TI  - Quetiapine augmentation of sertraline in obsessive-compulsive disorder.

PMID- 12469689
TI  - EMDR for women who experience traumatic events.

PMID- 12469690
TI  - High degree of tolerability for monotherapy with high doses of quetiapine: a case
      report.

PMID- 12469691
TI  - Hypokalemia with venlafaxine.

PMID- 12469692
TI  - Intranasal estradiol: new formulation. Intranasal oestrogen delivery system: just
      a gimmick.
AB  - (1) Many oral and transdermal (patch and gel) estradiol preparations are already
      available for controlling menopausal symptoms due to oestrogen deficiency. (2)
      Marketing authorization has now been granted in Europe for an intranasal delivery
      system, which produces a high, brief plasma estradiol peak. (3) According to two
      clinical trials, the symptomatic effects of 300 micrograms of estradiol daily by
      the intranasal route is similar to that of 50 micrograms /day transdermally
      (unblinded trial) and 2 mg/day orally (double-blind trial). (4) The most frequent
      side effects are intranasal reactions (in approximately 50% of patients), breast
      pain (30-40% of patients), and metrorrhagia (approximately 7% of cycles). (5) The
      long-term consequences of such high plasma estradiol peaks, including the risk of
      breast cancer, are unknown. (6) Intranasal estradiol is not reimbursed in France,
      unlike other oestrogen preparations for use in menopausal women. (7) In practice,
      oral and transdermal delivery systems, with which we have lengthy experience, are
      adequate for relieving menopausal symptoms. The intranasal route offers no proven
      advantage, and its long-term risks are unknown.

PMID- 12469693
TI  - Sirolimus: new preparation. No tangible advance in renal transplantation.
AB  - (1) Sirolimus, an immunosuppressant, is chemically related to tacrolimus but has
      a different mechanism of action. (2) In a double-blind trial in patients also
      treated with ciclosporin and a steroid, sirolimus was more effective than
      azathioprine at preventing acute rejection during the first three months, but
      caused more adverse effects (especially renal). (3) An unblinded trial compared
      ciclosporin + steroid + sirolimus with steroid + sirolimus for maintenance
      treatment. Ciclosporin was withdrawn gradually from the steroid + sirolimus
      group. Side effects from ciclosporin were therefore reduced (mainly
      nephrotoxicity and arterial hypertension), but rates of acute rejection,
      hepatotoxicity, and thrombocytopenia went up. (4) Sirolimus has numerous adverse
      effects, including hyperlipidemia, thrombocytopenia, hepatic disorders and
      opportunistic infections. The adverse effects of long term treatment are unknown.
      Sirolimus is metabolised by the cytochrome P450 isoenzyme CYP3A4, so may induce
      drug interactions. (5) In practice, sirolimus offers no advantage over existing
      immunosuppressive treatments for people with renal transplants.

PMID- 12469694
TI  - Moxifloxacin: new preparation. A me-too with more cardiac risks.
AB  - (1) Moxifloxacin is the fourth fluoroquinolone to be licensed in France with
      indications covering ENT and respiratory tract infections. (2) In community
      acquired pneumonia, acute bacterial sinusitis and acute exacerbations of chronic
      bronchitis, moxifloxacin seems no more effective than other fluoroquinolones
      available in France (with which it has not been compared) or the other
      antibiotics with which it has been compared. (3) Moxifloxacin has the usual
      adverse effects of fluoroquinolones, but carries a greater risk of QT
      prolongation than ciprofloxacin, levofloxacin and ofloxacin.

PMID- 12469695
TI  - Rosiglitazone and pioglitazone: new preparations. Two new oral antidiabetics both
      poorly assessed.
AB  - (1) Treatment of type 2 (non insulin-dependent) diabetes is based on lifestyle
      measures and management of cardiovascular risk. (2) The reference first-line drug
      therapy for type 2 diabetes, when drug therapy is needed, is single-agent
      treatment with metformin (a biguanide) for overweight patients, or with
      glibenclamide (a glucose-lowering sulphonylurea) for other patients. (3) If
      monotherapy fails to control blood glucose levels adequately, most clinical
      guidelines then recommend a combination of metformin with a glucose-lowering
      sulphonylurea, although the few available comparative clinical data raise the
      possibility of excess mortality with this treatment. (4) Rosiglitazone and
      pioglitazone (glitazones that reduce insulin resistance) have been authorized in
      the European Union for combination with a glucose-lowering sulphonylurea (for
      patients in whom metformin is ineffective or poorly tolerated) or with metformin
      (for obese patients). (5) None of the available trials of rosiglitazone and
      pioglitazone include data on mortality or morbidity. (6) There are fewer data on
      pioglitazone than on rosiglitazone. (7) According to short-term comparative
      trials, rosiglitazone and pioglitazone are more effective than placebo on blood
      glucose levels. Combinations of rosiglitazone or pioglitazone with metformin or
      with glucose-lowering sulphonylureas have not been compared with the metformin +
      glucose-lowering sulphonylurea combination or with insulin. (8) Rosiglitazone and
      pioglitazone frequently cause weight gain. (9) Pioglitazone has a slightly
      favourable effect on lipid profiles, unlike rosiglitazone, which increases LDL
      cholesterol levels. (10) The main side effect of rosiglitazone and pioglitazone
      is sodium and water retention, which can provoke oedema, anaemia (by
      haemodilution), and even heart failure. Rosiglitazone and pioglitazone are also
      hepatotoxic. (11) Combining rosiglitazone with insulin is contraindicated, owing
      to the increased risk of heart failure. The same applies to pioglitazone. (12) In
      practice, neither rosiglitazone nor pioglitazone has a place in the management of
      type 2 diabetes, except in the context of strictly controlled long-term
      comparative clinical trials.

PMID- 12469696
TI  - Tobramycin for nebulisation: new formulation. A high price for a small
      improvement in formulation.
AB  - (1) In patients with cystic fibrosis, chronic bronchial infection with
      Pseudomonas aeruginosa is a major factor in the development of chronic
      respiratory failure and premature death. (2) Over the last two decades, such
      patients have commonly received long-term treatment with antibiotic aerosols
      (mainly tobramycin or colistin, in off-licence uses). (3) Tobramycin solution for
      nebulisation is the first antibiotic preparation to be licensed in the EU for
      this indication. (4) Comparative evaluation of antibiotic aerosol therapy for
      chronic bronchial infections due to P. aeruginosa includes two large trials of
      nebulised tobramycin. (5) A combined analysis of these two placebo-controlled
      trials, both lasting 20 weeks, showed that tobramycin aerosol delayed the
      deterioration of respiratory function and reduced the number of hospitalisations.
      However, an increase in P. aeruginosa resistance to tobramycin was reported. (6)
      The file on tobramycin includes no precise criteria for stopping treatment, and
      no data on the long-term impact of the observed increase in bacterial resistance.
      (7) The main adverse effects of tobramycin aerosol are tinnitus and voice
      changes. Deafness has also been reported. (8) The available assessment file does
      not show whether the risk-benefit ratio of tobramycin aerosol differs from that
      of other nebulised antibiotics used (off-licence) in this setting. However,
      tobramycin is the best-assessed nebulised antibiotic for this indication. (9) In
      practice, tobramycin solution for nebulisation may be considered the reference
      long-term treatment for chronic pulmonary infections due to P. aeruginosa in
      patients with cystic fibrosis. Assessment should continue, however, especially
      regarding the possible impact on mortality and the selection of resistant
      strains.

PMID- 12469697
TI  - [Physiopathology and management of diseases of children--voice disorders].

PMID- 12469699
TI  - [Intractable deep-seated mycoses:  The probrems and solutions].

PMID- 12469698
TI  - After Bristol: putting patients at the centre.

PMID- 12469700
TI  - Public sector risk management: a specific model.
AB  - Risk management programs for state mental health authorities are generally
      limited in scope and reactive in nature. Recent changes in how mental health care
      is provided render it necessary to redirect the risk management focus from its
      present institutional basis to a statewide, network-based paradigm that is
      integrated across public and private inpatient and community programs alike.
      These changes include treating an increasing number of individuals in less-secure
      settings and contracting for an increasing number of public mental health
      services with private providers. The model proposed here is closely linked to the
      Quality Management Process.

PMID- 12469701
TI  - The effectiveness of the assertive community treatment model.
AB  - This study sought to determine the benefits of an assertive community treatment
      model (ACT) versus a continuing day-treatment program (CDTP) for the treatment of
      chronic mentally ill patients. The study utilized a quasi-experimental design
      with a matched-groups comparison of outcomes achieved by patients in two
      community mental health centers in the South Bronx area of New York City. The
      study assessed outcomes regarding hospital readmissions, quality of life, and
      housing and vocational rehabilitation. The sample size was 60, with 30 subjects
      in each group. Due to the small size and baseline differences between groups,
      nonparametric tests were the primary statistical analyses.

PMID- 12469702
TI  - Successful program maintenance when federal demonstration dollars stop: the
      ACCESS program for homeless mentally ill persons.
AB  - A major issue that has long dogged federal human services demonstration programs
      is the perception that when federal dollars end, the programs end-regardless of
      any proven successes. Access to Community Care and Effective Services and
      Supports (ACCESS) was a 5-year federal demonstration project to foster
      partnerships between service providers for homeless people with serious mental
      illness and co-occurring substance abuse disorders; and to identify effective,
      replicable systems integration strategies. After federal funding ended, research
      teams visited the ACCESS sites to determine which project elements remained and
      which strategies were used by the sites to continue ACCESS. This article
      describes ACCESS services and systems integration activities retained by the
      sites, new funding streams, and strategies used to obtain continued funding.

PMID- 12469703
TI  - Using benchmarking research to locate agency best practices for African American
      clients.
AB  - Using a collective case study design with benchmarking features, research
      reported here sought to locate differences in agency practices between public
      mental health agencies in which African American clients were doing comparatively
      better on specific proxy outcomes related to community tenure, and agencies with
      less success on those same variables. A panel of experts from the Ohio Department
      of Mental Health matched four agencies on per capita spending, percentage of
      African American clients, and urban-intensive setting. The panel also
      differentiated agencies on the basis of racial group comparisons for a number of
      proxy variables related to successful community tenure. Two agencies had a record
      of success with this client group (benchmark agencies); and two were less
      successful based on the selected criteria (comparison agencies). Findings
      indicated that when service elements explicitly related to culture were similar
      across study sites, the characteristics that did appear to make a difference were
      aspects of organizational culture. Implications for administration practice and
      further research are discussed.

PMID- 12469704
TI  - Provider assessments of the Massachusetts Behavioral Health Program: year 7.

PMID- 12469705
TI  - The psychology of aggression: a critique of correctional approaches to treating
      violent behavior.

PMID- 12469706
TI  - A review of combination regimens for osteoporosis--prevention and treatment.
AB  - Two long-used interventions for reducing the morbidity and mortality associated
      with osteoporosis are postmenopausal hormone replacement therapy (HRT) and
      treatment with antiresorptive agents. Postmenopausal HRT works through prevention
      of osteoporosis, whereas antiresorptive agents, such as the bisphosphonates,
      reverse low bone mass. Because of their different mechanisms, it has been thought
      that combining the two therapies would yield additive improvements in bone
      mineral density (BMD) and in fracture risk reduction. Results from several recent
      clinical trials in postmenopausal women with low bone mass support this idea,
      demonstrating clinically relevant additive improvements in BMD after treatment
      with HRT (or a selective estrogen receptor modulator) plus a bisphosphonate. Data
      regarding fracture rates after HRT and bisphosphonate combination therapy are
      unavailable, however. A newer osteoporosis treatment is subcutaneously injected
      parathyroid hormone (PTH). Treatment with PTH stimulates new bone formation, and
      recent studies have shown that PTH monotherapy reduces fracture rates. Initial
      data from studies of HRT and PTH combination therapy have shown impressive gains
      in BMD, but fracture rate data have not been published. Use of HRT for
      osteoporosis, either alone or in combination with a bisphosphonate or PTH, has
      become problematic since the recent report of a small number of serious adverse
      effects associated with HRT in the Women's Health Initiative.

PMID- 12469707
TI  - Optimizing the dose of hormone replacement therapy.
AB  - Over the last 5 years we have seen the evolution of several new products and
      several new regimens for estrogen replacement in menopause. Before this time, the
      decision surrounding hormone replacement therapy (HRT) mainly focused on whether
      to take estrogen or not, and if the addition of a progestogen was required.
      However, with new paradigms we now have several options for HRT, with various
      doses of estrogen ranging from very low doses of oral estrogen (0.3 mg conjugated
      equine estrogen [CEE], 0.25 mg 17beta-estradiol), transdermal patches which
      deliver a minimum of 20 microg of 17beta-estradiol per day, or intranasal methods
      which deliver 100-400 microg of 17beta-estradiol, to the more commonly prescribed
      doses of 0.625 mg of CEE or 0.5 mg 17beta-estradiol. The decision to add a
      progestogen to the regimen of replacement therapy is well accepted, particularly
      in a woman who has an intact uterus; however, now the controversy has focused on
      which progestogen least attenuates the lipid benefits received from the estrogen
      replacement therapy. Estrogen treatment in the postmenopausal woman has several
      proven benefits. For the woman who has vasomotor symptoms or complaints related
      to urogenital atrophy, there is little controversy regarding its use. However, a
      continuing controversial area is that of long-term prevention of osteoporosis and
      cardiovascular disease. It is in these areas that the decision on the dose and
      the addition of a progestin to hormone replacement therapy is under review.

PMID- 12469708
TI  - Systematic review of data concerning etiopathology of ovarian hyperstimulation
      syndrome.
AB  - The ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of
      ovarian stimulation occurring during the luteal phase or early pregnancy. It has
      been observed over the last 60 years, since gonadotropins were first used to
      induce ovulation. The prevalence varies, according to study, from 0.5% to 5%. The
      pathogenesis of OHSS is, apparently, complex. It involves a vasoactive mediator,
      secreted by the ovaries (in overabundance) after artificial stimulation.
      Estradiol, which is a marker of ovarian response, is not the mediator. The
      candidate mediators reviewed are prolactin and prostaglandins; the ovarian
      prorenin-renin-angiotensin system; cytokines (including allergy-cytokines
      histamine as a system); VEGF; angiogenin; the Kinin-Kallikrein system; VCAM and
      ICAM; selectins; von Willebrand factor; and endothelin. The main conclusion is
      that OHSS is the result of disturbance of the basically inflammation-like normal
      ovulation process, and has as its main feature capillary leakage and transmission
      of mediators to other compartments.

PMID- 12469709
TI  - Effects of temperature on sperm motion characteristics and reactive oxygen
      species.
AB  - OBJECTIVE: To evaluate the effect of temperature on sperm motility, sperm motion
      characteristics, and production of reactive oxygen species (ROS) in semen.
      METHODS: We collected semen samples from 12 infertile patients and 12 healthy
      donors and divided each sample into four aliquots just after liquefaction. One
      aliquot was analyzed immediately after liquefaction and the remaining three were
      analyzed after one hour of incubation at 4 degrees C, 25 degrees C, and 37
      degrees C. Sperm motility and motion characteristics were measured by computer
      assisted sperm analysis (CASA). Levels of ROS were determined in washed sperm
      suspensions using a chemiluminescence assay and results were expressed as x10(6)
      counted photons per minute (cpm)/20 million sperm/mL. RESULTS: Motility,
      curvilinear velocity, straight-line velocity, average path velocity, and
      amplitude of lateral head displacement decreased significantly from baseline
      values in both the patients and donors after incubation at 4 degrees C.
      Percentage motility was highest and ROS levels were lowest in the samples that
      were incubated at 37 degrees C. CONCLUSION: Based on our results, we suggest that
      semen samples be stored at 37 degrees C after collection and during
      transportation and processing.

PMID- 12469710
TI  - Bone mineral density and grip strength in postmenopausal Turkish women with
      osteoporosis: site specific or systemic?
AB  - OBJECTIVE: To assess the relationship of grip strength to site-specific bone
      mineral density of the metacarpal bone and also axial bone mineral density. The
      bone mineral density of the lumbar spine, femoral neck and the nondominant hand
      were measured by DEXA. SUBJECTS: A total of 187 postmenopausal women were
      included in the study. Of the patients, 102 were osteoporotic, and 85 were not
      osteoporotic and served as control subjects. METHODS: Grip strength of the
      nondominant hand was measured by hand-held dynamometer. Skinfold thickness of the
      nondominant hand was measured by a caliper (Holstain). Biochemical markers of
      bone turnover and other osteoporosis-related variables were also measured.
      RESULTS: There was a statistically significant difference between groups
      regarding bone mineral density of the lumbar, femoral (neck) and hand regions and
      the grip strength (P < .05). Hand bone mineral density (BMD) was found to be
      correlated with bone mineral density of the lumbar and femoral (neck) regions in
      osteoporotic patients. Grip strength was correlated positively with the BMD of
      the nondominant hand. Grip strength was correlated negatively with age and years
      since menopause. Grip strength was also correlated positively with femoral neck
      BMD. CONCLUSION: The study provides support for a site-specific and also systemic
      relationship between muscle and bone. Grip strength is also a predictor of hand
      bone mineral density.

PMID- 12469711
TI  - Observations on the suitability of the aethalometer for vehicular and workplace
      monitoring.
AB  - A field study was undertaken to evaluate the suitability of the aethalometer, an
      instrument capable of performing near-real-time measurement of low-level (10
      1,000 ng/m3) airborne combustion products, for vehicular and workplace
      monitoring. Several technical limitations were identified: (1) there was no ready
      means for external calibration of optical measurements; (2) airflow rates were
      unstable; (3) effective range of concentrations was limited; and (4) the
      aethalometer demonstrated sensitivity to movement and vibration. Unless
      addressed, these limitations will restrict future uses of the aethalometer for
      vehicular and workplace monitoring.

PMID- 12469712
TI  - Levels and composition of atmospheric particulates (PM10) in a mining-industrial
      site in the city of Lavrion, Greece.
AB  - The present work focuses on the characterization of air quality and the
      identification of pollutant origin at a former mining site in the city of
      Lavrion, Greece. A historical metallurgy complex is reused for establishing the
      Lavrion Technology and Cultural Park (LTCP). A serious problem with this is the
      severe soil contamination that resulted from intensive mining and metallurgical
      activities that has taken place in the greater area for the past 3,000 years.
      Among other consequences, surface-polluted depositions, rich in heavy and toxic
      metals, are loose and easily wind-eroded, resulting in transportation of
      particulate matter (PM) in the surrounding atmosphere. On the other hand, there
      are a number of industries relatively close to the site that are potential
      sources of PM air pollution. The current study deals with the collection and
      analysis of PM10 samples with respect to their concentration in heavy metals,
      such as Pb, Cd, Cu, Fe, Zn, Mn, Cr, and Ni. Though not a heavy metal, As also is
      included. Furthermore, the source of these elements is verified using statistical
      correlation and by calculating enrichment factors (EFs), considering that some
      substances are certainly of contaminated soil origin. Results show that PM10 and
      element concentrations are relatively low during winter but significantly
      increase during summer. Fe, Pb, Zn, Mn, and Cu may be considered of contaminated
      soil origin, while As, Ni, Cd, and Cr are very much enriched with respect to
      contaminated soil, indicating another possible source attributed to the adjacent
      industrial plants.

PMID- 12469713
TI  - Decomposition of SF6 in an RF plasma environment.
AB  - Sulfur hexafluoride (SFd)-contained gas is a common pollutant emitted during the
      etching process used in the semiconductor industry. This study demonstrated the
      application of radio-frequency (RF) plasma in the decomposition of SF6. The
      decomposition fraction of SF6 [etaSF6 (C(in)-C(out))/C(in) x 100%] and the mole
      fraction profile of the products were investigated as functions of input power
      and feed O2/SF6 ratio in an SiO2 reactor. The species detected in both SF6/Ar and
      SF6/O2/ Ar RF plasmas were SiF4, SO2, Fe2, SO2F2, SOF2, SOF4, S2F10, S2OF10,
      S2O2F10, and SF4. The results revealed that at 40 W, etaSF6 exceeded 99%, and the
      reaction products were almost all converted into stable compounds such as SiF4,
      SO2, and F2 with or without the addition of oxygen. Sulfur oxyfluorides such as
      SO2F2, SOF2, SOF4, S2OF10, and S2O2F10 were produced only below 40 W. The results
      of this work can be used to design a plasma/chemical system for online use in a
      series of a manufacturing process to treat SF6-containing exhaust gases.

PMID- 12469714
TI  - Pore structure effects on Ca-based sorbent sulfation capacity at medium
      temperatures: activated carbon as sorbent/catalyst support.
AB  - The reaction between three different Ca-based sorbents and SO2 were studied in a
      medium temperature range (473-773 K). The largest SO2 capture was found with
      Ca(OH)2 at 773 K, 126.31 mg SO2 x g Ca(OH)2(-1), and the influence of SO2
      concentration on the sorbent utilization was observed. Investigations of the
      internal porous structure of Ca-based sorbents showed that the initial reaction
      rate was controlled by the surface area, and once the sulfated products were
      produced, pore structure dominated. To increase the surface area of Ca-based
      sorbents available to interact with and retain SO2, one kind of CaO/ activated
      carbon (AC) sorbent/catalyst was prepared to study the effect of AC on the
      dispersion of Ca-based materials. The results indicated that the Ca-based
      material dispersed on high-surface-area AC had more capacities for SO2 than
      unsupported Ca-based sorbents. The initial reaction rates of the reaction between
      SO2 and Ca-based sorbents and the prepared CaO/AC sorbents/catalysts were
      measured. Results showed that the reaction rate apparently increased with the
      presence of AC. It was concluded that CaO/AC was the active material in the
      desulfurization reaction. AC acting as the support can play a role to supply O2
      to increase the affinity to SO2. Moreover, when AC is acting as a support, the
      surface oxygen functional group formed on the surface of AC can serve as a new
      site for SO2 adsorption.

PMID- 12469715
TI  - 1-Butanol removal from a contaminated airstream under continuous and diurnal
      loading conditions.
AB  - A polysulfone microporous membrane module was investigated for control of 1
      butanol-contaminated gas streams. A diurnal loading condition, using two
      different butanol concentrations, was used to simulate start-up and stop
      conditions associated with shift work. The membrane module was also used to
      remove 1-butanol from air under continuous loading conditions in a bioreactor.
      The reactors were seeded with a mixed bacterial consortium capable of butanol
      biodegradation. Biokinetic parameters for butanol utilization were determined for
      the culture to be a maximum specific utilization rate (k) equal to 4.3 d(-1) and
      a half saturation constant (Ks) equal to 8.9 mg L(-1). A biofilter running only
      with diurnal loading conditions giving a "40-hr work-week" had an average 1
      butanol removal rate of 29% (111 ppm, 74 gm(-3) hr(-1)) from a 350-ppm influent
      at the end of an 8-hr operational day. End-of-day removal varied between 4 and
      67% during the operational period. With continuous steady-state operation
      followed by placement on a diurnal loading schedule and influent butanol
      concentrations increased to 700 ppm, butanol removal averaged 38% (269 ppm, 145
      gm-3 hr(-1)). Under continuous loading, steady-state conditions, 1-butanol
      removal from the airstream was greater than 99% (200 ppm, 73 gm-3 hr(-1)). These
      results suggest that the bioreactor can be operated on a diurnal schedule or 40
      hr week operational schedule without any decline in performance.

PMID- 12469716
TI  - Survey of waste comminglers' VOC exposures.
AB  - Twelve U.S. universities performing hazardous waste solvent commingling
      operations were surveyed for waste handler exposures to 45 U.S. Environmental
      Protection Agency (EPA)-designated volatile organic compounds (VOCs). Personal
      exposures (n = 33) and area concentrations (n = 30) were determined using gas
      chromatography/ mass spectrometry (GC/MS) analysis of passively collected
      samples. Air monitoring data were used to determine the veracity of laboratory
      generated reports of waste container contents. Participants completed a
      questionnaire concerning the use of personal protective equipment, ventilation,
      and other appropriate safety equipment for their specific commingling operation.
      Follow-up telephone interviews were conducted to elucidate safeguards in place.
      Results showed that personal exposures exceeded area concentrations in 70% of
      operations. For the contaminant concentrations reported, 17% of personal samples
      exceeded Occupational Safety & Health Administration (OSHA) time-weighted average
      or ceiling limit values. Methylene chloride was a frequently seen airborne
      contaminant not listed on drum inventory sheets. When airborne constituents were
      compared with container content tags, 44% of the chemicals detected in air were
      omitted from the waste tags. This study concluded that the most frequently
      necessary safeguard is respiratory protection, preferably a supplied-air-type.
      The use of local exhaust ventilation systems rather than dilution or natural
      systems and facility operation in a totally explosion-safe manner are also
      recommended.

PMID- 12469717
TI  - Evaluation of the potential of laser-induced breakdown spectroscopy for detection
      of trace element in liquid.
AB  - The analytical figure of merit of the potential of laser-induced breakdown
      spectroscopy (LIBS) has been evaluated for detection of trace element in liquid.
      LIBS data of Mg, Cr, Mn, and Re were studied. Various optical geometries, which
      produce the laser spark in and at the liquid sample, were tested. The calibration
      curves for Mg, Cr, Mn, and Re were obtained at the optimized experimental
      conditions with bulk liquid and in liquid jet. It was found that measurements
      using a liquid jet provide better detection limits than bulk liquid measurements.
      The limits of detection (LOD) of Mg, Cr, Mn, and Re in the present liquid jet
      measurement are found to be 0.1, 0.4, 0.7, and 8 ppm, respectively. The LOD of Mg
      using Mg 279.55 nm was compared with the values found in other liquid work.

PMID- 12469718
TI  - Hg reactions in the presence of chlorine species: homogeneous gas phase and
      heterogeneous gas-solid phase.
AB  - The kinetics of Hg chlorination (with HCl) was studied using a flow reactor
      system with an online Hg analyzer, and speciation sampling using a set of
      impingers. Kinetic parameters, such as reaction order (alpha), overall rate
      constant (k'), and activation energy (Ea), were estimated based on the simple
      overall reaction pathway. The reaction order with respect to C(Hg), k', and Ea
      were found to be 1.55, 5.07 x 10(-2) exp(-1939.68/T) [(microg/m3)(-055)(s)(-1)].
      and 16.13 [kJ/ mol], respectively. The effect of chlorine species (HCl, CH2Cl2)
      on the in situ Hg capture method previously developed (28) was also investigated.
      The efficiency of capture of Hg by this in situ method was higher than 98% in the
      presence of chlorine species. Furthermore, under certain conditions, the presence
      of chlorine enhanced the removal of elemental Hg by additional gas-phase
      oxidation.

PMID- 12469719
TI  - An evaluation of the UAM-V predicted concentrations of carbon monoxide and
      reactive nitrogen compounds over the eastern United States during summer 1995.
AB  - While there is a clear need to evaluate a photochemical model's ability in
      predicting not only the concentrations of O3, but also precursors and other trace
      species, many previous studies have focused only on the assessment of During the
      1995 summer season, in addition to the routine monitoring of criteria pollutants,
      several research-oriented monitoring campaigns were conducted over the eastern
      United States, providing an extensive database of reactive nitrogen compounds,
      CO, and speciated hydrocarbon data. In this study, we examine the ability of a
      photochemical modeling system, RAMS/ UAM-V, to reproduce the measured
      concentrations of CO, NO2, and NOy over the region during the summer of 1995. The
      results demonstrate that there is agreement between modeled and measured seasonal
      average concentrations of NO2, both at the routine and research monitors. The
      same is true for NOy, but to a lesser degree. However, the model is found to
      significantly underpredict CO for the routine monitors in comparison to the
      research monitors.

PMID- 12469720
TI  - Evaluation of OC/EC speciation by thermal manganese dioxide oxidation and the
      IMPROVE method.
AB  - Ambient particulate samples are routinely analyzed for organic and elemental
      carbon (OC/EC) using either thermal manganese dioxide oxidation (TMO) or thermal
      volatilization-pyrolysis correction methods, such as the Interagency Monitoring
      of PROtected Visual Environments (IMPROVE) method with correction by reflectance,
      or a variation of the National Institute of Occupational Safety and Health
      (NIOSH) Method 5040 using thermal optical transmittance (TOT). With TMO, EC is
      modeled after the oxidation properties of submicron graphite and needle coke by
      MnO2, and is the fraction of total carbon (TC) that is not oxidized at >525
      degrees C. In thermal volatilization methods, EC is the fraction of TC that
      accounts for the light extinction properties of the sample at the start of
      analysis. Chow et al. (2001) compared IMPROVE and NIOSH methods implemented on
      the same instrument using 60 samples of various types and found that NIOSH EC was
      lower than IMPROVE. This study compares total, organic, and elemental carbon
      measurements from the TMO and IMPROVE thermal optical reflectance (TOR) methods
      using a sample set consisting of 60 IMPROVE nonurban, 16 Korean urban, 10 Hong
      Kong urban, and 14 synthetic carbon black samples.

PMID- 12469721
TI  - Electrostatic precipitation of ultrafine particles enhanced by simultaneous
      diffusional deposition on wire screens.
AB  - A laboratory-scale electrostatic precipitator has been designed and constructed
      in which the grounded collector plate has been substituted by a set of wire
      screens placed perpendicularly to the gas flow. Particles are deposited onto the
      screens by two mechanisms--electrostatic deposition and diffusional deposition-
      which act simultaneously. On the one hand, electrostatic deposition is effective
      for relatively large particles, but it is quite ineffective for the smallest ones
      because their charging probability in the corona field is too low. On the other
      hand, the diffusional collection efficiency of particles on fibers is high for
      small particles but low for the larger ones. Therefore, the simultaneous
      diffusional-electrostatic precipitation may become a useful technique for
      efficient filtration of particles below 0.1 microm. A preliminary experimental
      evaluation of this filtering device has shown that submicrometer particles with
      diameters down to a few nanometers can be collected with number efficiencies
      greater than 99%.

PMID- 12469722
TI  - In praise of simplicity.

PMID- 12469723
TI  - Mexican Americans' explanatory model of type 2 diabetes.
AB  - The purpose of this study was to develop a culturally specific explanatory model
      (EM) of diabetes mellitus from the perspective of Mexican Americans living along
      the United States-Mexican bonier Kleinman's concept of EMs of illness was used as
      the theoretical orientation, and the grounded theory method was used to sample,
      collect, and analyze data. The Mexican Americans in this study described their
      perceptions of type 2 diabetes using the following constructs: causes, symptom,
      treatment, and social significance. Each of the components of Mexican Americans'
      EM contained elements of both the folk and the biomedical perspective. Susto (a
      fright or scare) was perceived to be the primary cause of diabetes, although
      participants also incorporated biomedical causes. Treatment included the use of
      both herbal and biomedical modalities. The use of herbal remedies was not well
      understood by the participants despite the fact that some used herbal therapies
      to control their diabetes.

PMID- 12469724
TI  - Perceived benefits and barriers to physical activity among older Latina women.
AB  - Evidence of the benefits of physical activity in the health of aging women
      continues to grow but questions remain about the factors that influence these
      women's ability to engage in this behavior. The authors used a qualitative design
      to describe the social and culture-specific perceived benefits and barriers to
      physical activity among 143 Latina women, ages 40 to 79. Content analysis of
      these women's responses revealed that perceived benefits (health promotion,
      physical fitness, improved roles) and barriers (time constraints of women's
      roles, personal health, internal and external factors) function as competing
      elements that may explain physical inactivity. Health care providers should
      emphasize overcoming barriers and promote perceived benefits as clinical
      interventions that may pose the greatest potential to increase physical activity
      among aging Latina women. This emphasis holds promise as a feasible and effective
      primary care intervention for achieving increased physical-activity-related
      health benefits.

PMID- 12469725
TI  - Where and to what extent is prevention of low birth weight possible?
AB  - Law birth weight (LBW), due to shortened gestation and/or inadequate fetal
      growth. is the major determinant of infant mortality and morbidity. Despite
      improvements in infant mortality, them has been no reduction in LBW rates. The
      authors examined the relationship between 33 maternal characteristics and the
      increased risks of preterm (PT) delivery or small-for-gestational-age (SGA)
      births in 76,444 Alberta women 1994-1997. PT was associated with preexisting
      medical conditions, obstetrical history, and pregnancy complications. Modifiable
      factors such as advanced maternal age contributed only 11% to the overall PT
      risk. SGA births were associated with several modifiable factors, including low
      prepregnancy weight, maternal age, smoking, drinking, and drug dependency. These
      contributed to 29% and 31% of PTand term SGA births. Smoking remains an important
      target for intervention, having contributed to 8% of PT births and about 24% of
      SGA births. SGA appears to be more amenable to prevention than PT delivery.

PMID- 12469726
TI  - Work context, personal control, and burnout amongst nurses.
AB  - While situational factors such as high workloads have been found to be predictive
      of burnout, not all people in the same work context develop burnout. This
      suggests that individual factors are implicated in susceptibility to burnout. We
      investigated the relationships between care type (acute/chronic), neuroticism,
      control (primary/secondary), and symptoms of burnout (exhaustion, cynicism, and
      reduced professional efficacy) amongst 21 chronic came nurses and 83 acute care
      nurses working in a public hospital in regional Australia. Similar levels of
      burnout symptomatology and neuroticism were found in each group of nurses, and
      neuroticism was found to be associated with exhaustion, cynicism, and reduced
      professional efficacy in the total sample of nurses. Our prediction that primary
      control would protect against burnout symptoms in acute care nurses was supported
      only for professional efficacy, and the prediction that secondary control would
      protect against burnout in chronic care nurses was not supported.

PMID- 12469727
TI  - Barriers and facilitators in nursing home intervention research.
AB  - Conducting intervention research in nursing home (NH) settings is particularly
      challenging because of the advanced age and frailty of the participants and the
      characteristics of the setting itself. The purpose of this project was to better
      understand the barriers and facilitators to the research process in NHs. Three
      primary data sources were used: investigator field notes, guided interviews with
      the research team and NH staff members, and research assistant (RA) e-mail
      communications. Data were analyzed using qualitative content and matrix analytic
      techniques. Barriers to the research process were largely congruent with
      previously identified NH staff characteristics, such as lack of communication
      between NH staff and the research team ineffective nursing leadership, decreased
      staff-to-resident ratios, and high turnover of NH staff. Research facilitators
      emerged in two overlapping areas, intraresearch team issues such as the
      flexibility and compatibility of the RAs, effective NH staff-to-research team
      communication, and the presence of an effective nurse leader in the NH.

PMID- 12469728
TI  - Statistical variation of aberration structure and image quality in a normal
      population of healthy eyes.
AB  - A Shack-Hartmann aberrometer was used to measure the monochromatic aberration
      structure along the primary line of sight of 200 cyclopleged, normal, healthy
      eyes from 100 individuals. Sphero-cylindrical refractive errors were corrected
      with ophthalmic spectacle lenses based on the results of a subjective refraction
      performed immediately prior to experimentation. Zernike expansions of the
      experimental wave-front aberration functions were used to determine aberration
      coefficients for a series of pupil diameters. The residual Zernike coefficients
      for defocus were not zero but varied systematically with pupil diameter and with
      the Zernike coefficient for spherical aberration in a way that maximizes visual
      acuity. We infer from these results that subjective best focus occurs when the
      area of the central, aberration-free region of the pupil is maximized. We found
      that the population averages of Zernike coefficients were nearly zero for all of
      the higher-order modes except spherical aberration. This result indicates that a
      hypothetical average eye representing the central tendency of the population is
      nearly free of aberrations, suggesting the possible influence of an
      emmetropization process or evolutionary pressure. However, for any individual eye
      the aberration coefficients were rarely zero for any Zernike mode. To first
      approximation, wave-front error fell exponentially with Zernike order and
      increased linearly with pupil area. On average, the total wave-front variance
      produced by higher-order aberrations was less than the wave-front variance of
      residual defocus and astigmatism. For example, the average amount of higher-order
      aberrations present for a 7.5-mm pupil was equivalent to the wave-front error
      produced by less than 1/4 diopter (D) of defocus. The largest pupil for which an
      eye may be considered diffraction-limited was 1.22 mm on average. Correlation of
      aberrations from the left and right eyes indicated the presence of significant
      bilateral symmetry. No evidence was found of a universal anatomical feature
      responsible for third-order optical aberrations. Using the Marechal criterion, we
      conclude that correction of the 12 largest principal components, or 14 largest
      Zernike modes, would be required to achieve diffraction-limited performance on
      average for a 6-mm pupil. Different methods of computing population averages
      provided upper and lower limits to the mean optical transfer function and mean
      point-spread function for our population of eyes.

PMID- 12469729
TI  - Preneural limitations on letter identification in central and peripheral vision.
AB  - We created a sequential ideal-observer model that could address the question, How
      much of letter identification performance and its change with eccentricity can be
      accounted for by preneural factors? The ideal-observer model takes into account
      preneural factors including the stimulus rendering properties of a CRT display,
      the optical imaging quality of the eye, and photon capture and sampling
      characteristics of the cones. We validated the formulation of the model by
      comparing its performance on simple psychophysical tasks with that of previous
      sequential ideal-observer models. The model was used to study properties of the
      image rendering of letters. For example, the model's identification of high
      resolution letters (i.e., many pixels per letter), but not low-resolution
      letters, is largely immune to changes in pixel width. We compared human and ideal
      observer letter-identification acuity for the lowercase alphabet at 0 degrees, 5
      degrees, and 20 retinal eccentricity. Acuity of the ideal observer for high
      contrast letters is approximately seven times better than that of the human
      observers at 0 degrees. Acuity decreased with eccentricity more rapidly for human
      observers than for the ideal observer such that the thresholds differed by a
      factor of 50 at 20 degrees. A decrease in stimulus duration from 100 to 33 ms
      resulted in no decrease in relative threshold size between the human and ideal
      observers at all eccentricities, indicating that humans effectively integrate
      stimulus information over this range. Decreasing contrast from 75% to 25%,
      however, reduced the difference in acuities twofold at all eccentricities between
      humans and the ideal-observer model, consistent with the presence a compressive
      nonlinearity only in the human observers. The gap between human and ideal acuity
      in central vision means that there are substantial limitations in human letter
      recognition beyond the stage of photoreceptor sampling. The increasing
      performance gap between human and ideal-observer performance with eccentricity
      implicates an increasing role of neural limitations with eccentricity in limiting
      human letter identification.

PMID- 12469730
TI  - Peripheral refractive errors in myopic, emmetropic, and hyperopic young subjects.
AB  - To gain more insight into the relationship between foveal and peripheral
      refractive errors in humans, spheres, cylinders, and their axes were binocularly
      measured across the visual field in myopic, emmetropic, and hyperopic groups of
      young subjects. Both automated infrared photorefraction (the "PowerRefractor";
      www. plusoptix.de) and a double-pass technique were used because the
      PowerRefractor provided extensive data from the central 44 deg of the visual
      field in a very convenient and fast way. Two-dimensional maps for the average
      cross cylinders and spherical equivalents, as well as for the axes of the power
      meridians of the cylinders, were created. A small amount of lower-field myopia
      was detected with a significant vertical gradient in spherical equivalents. In
      the central visual field there was little difference among the three refractive
      groups. The established double-pass technique provided complementary data also
      from the far periphery. At 45 deg eccentricity the double-pass technique revealed
      relatively more hyperopic spherical equivalents in myopic subjects than in
      emmetropic subjects [+/-2.73 +/- 2.85 D relative to the fovea, p < 0.01 (+/-
      standard deviation)] and more myopic spherical equivalents in hyperopic subjects
      (-3.84 +/- 2.86 D relative to the fovea, p < 0.01). Owing to the pronounced
      peripheral astigmatism, spherical equivalents (refractions with respect to the
      plane of the circle of least confusion) became myopic relative to the fovea in
      all three groups. The finding of general peripheral myopia was unexpected. Its
      possible roles in foveal refractive development are discussed.

PMID- 12469731
TI  - Estimating the scene illumination chromaticity by using a neural network.
AB  - A neural network can learn color constancy, defined here as the ability to
      estimate the chromaticity of a scene's overall illumination. We describe a
      multilayer neural network that is able to recover the illumination chromaticity
      given only an image of the scene. The network is previously trained by being
      presented with a set of images of scenes and the chromaticities of the
      corresponding scene illuminants. Experiments with real images show that the
      network performs better than previous color constancy methods. In particular, the
      performance is better for images with a relatively small number of distinct
      colors. The method has application to machine vision problems such as object
      recognition, where illumination-independent color descriptors are required, and
      in digital photography, where uncontrolled scene illumination can create an
      unwanted color cast in a photograph.

PMID- 12469732
TI  - Focusing analysis of the pinhole photon sieve: individual far-field model.
AB  - Recently, a new class of diffractive optical element called a photon sieve, which
      consists of a great number of pinholes, was developed for the focusing and
      imaging of soft x rays. In terms of the closed-form formula for the far field of
      individual pinholes and the linear superposition principle, we present a simple
      yet accurate analytical model for the focusing of the pinhole photon sieve. This
      model is applicable to arbitrary paraxial illumination with arbitrary complex
      amplitude distribution at the photon sieve plane. We check the validity range of
      this model by comparing it with the exact Fresnel diffraction integral. Some
      special problems, such as the individual quasi-far-field correction for very
      large pinholes and the related phase shift induced by this correction, are also
      discussed.

PMID- 12469733
TI  - Experimental characterization of subwavelength diffraction gratings by an inverse
      scattering neural method.
AB  - Characterization of gratings with small period-to-wavelength ratios is difficult
      to perform but is very helpful in improving the fabrication process. We
      experimentally tested an inverse-scattering method using a neural network on
      silicon etched gratings. We also characterized the gratings by using two popular
      microscopic methods. The validity of each method was determined by comparing
      measured diffracted intensities with calculated ones obtained from measured
      profiles. An estimation of accuracy and repeatability was deduced from a scan
      along a grating sample. This method was thus well validated for nondestructive
      and noninvasive measurements under experimental conditions that were close
      conditions of actual usage. This method is easy to implement and requires the
      measurement of only a few diffracted intensities.

PMID- 12469734
TI  - Multiplexed computer-generated holograms with irregular-shaped polygonal
      apertures and discrete phase levels.
AB  - We propose a novel type of multiplexed computer-generated hologram (MCGH) with
      irregular-shaped polygonal apertures and discrete phase levels. Each elementary
      cell forming the new MCGH is divided into a central aperture and several
      peripheral apertures. The new MCGH allows us to exploit the huge space-bandwidth
      product provided by standard lithography technologies. With use of the Abbe
      transform, the Fraunhofer diffraction patterns from the polygonal apertures and,
      therefore, the layout coefficients can be computed with simple algebraic
      expressions. Several symmetries related to the polygonal apertures also
      facilitate the layout-coefficient computation. In the novel iterative subhologram
      design algorithm (ISDA), we consider all subholograms equally and apply the image
      plane constraint to the total reconstructed image, which is the coherent addition
      of the subimages from the subholograms. We designed MCGHs with several billions
      of pixels per period, which cannot be achieved with the classical iterative
      Fourier transform algorithm, because of the prohibitive computational cost and
      memory limitation. MCGHs with irregular polygonal apertures and discrete phases,
      which were designed by the ISDA, reconstruct a desired image of large size with
      high diffraction efficiencies and low reconstruction errors.

PMID- 12469735
TI  - Arbitrary spot location diffractive beam-splitting elements.
AB  - Diffractive beam-splitting elements are typically designed for replicating beams
      on positions belonging to an equidistant grid in the spatial spectrum. The
      parameter of the output grid follows directly from the period of the beam
      splitter transmission through the grating equation. Our objective is to develop
      design strategies allowing a more accurate positioning of the replicated beams.
      Issues occurring when the output grid parameter is decreased below the output
      beam width are discussed and shown to be avoidable. Furthermore, a design
      algorithm is introduced, which permits an arbitrary positioning of the replicated
      beams. This algorithm is constructed for high computational efficiency by
      utilizing fast Fourier transform operations in the major part of its iterations.

PMID- 12469736
TI  - Convergence properties of a quadratic approach to the inverse-scattering problem.
AB  - The local-minima question that arises in the framework of a quadratic approach to
      inverse-scattering problems is investigated. In particular, a sufficient
      condition for the absence of local minima is given, and some guidelines to ensure
      the reliability of the algorithm are outlined for the case of data not belonging
      to the range of the relevant quadratic operator. This is relevant also when an
      iterated solution procedure based on a quadratic approximation of the
      electromagnetic scattering at each step is considered.

PMID- 12469737
TI  - Electromagnetic field calculations for an irregularly shaped, near-spheroidal
      particle with arbitrary illumination.
AB  - A spheroidal coordinate separation-of-variables solution has been developed for
      the determination of the internal, near-surface, and far-scattered
      electromagnetic fields for irregularly shaped elongated (prolatelike) and
      irregularly shaped flattened (oblatelike) particles with arbitrary monochromatic
      illumination. Calculated results are presented, for both plane-wave and focused
      Gaussian-beam illumination, which demonstrate the effects of particle geometry on
      the internal, near-surface, and far-scattered-field distributions.

PMID- 12469738
TI  - Hamiltonian orbit structure of the set of paraxial optical systems.
AB  - In the paraxial regime of three-dimensional optics, two evolution Hamiltonians
      are equivalent when one can be transformed to the other modulo scale by
      similarity through an optical system. To determine the equivalence sets of
      paraxial optical Hamiltonians one requires the orbit analysis of the algebra
      sp(4, R) of 4 x 4 real Hamiltonian matrices. Our strategy uses instead the
      isomorphic algebra so(3, 2) of 5 x 5 matrices with metric (+1, +1, +1, -1, -1) to
      find four orbit regions (strata), six isolated orbits at their boundaries, and
      six degenerate orbits at their common point. We thus resolve the degeneracies of
      the eigenvalue classification.

PMID- 12469739
TI  - Minimum length of a single-mode fiber spatial filter.
AB  - Using the concept of leaky modes, we derive the minimum length of a single-mode
      fiber required to act as a spatial-mode filter of given quality. The degree of
      filter action is defined by the ratio of power carried by the fundamental mode to
      that carried by the leaky modes.

PMID- 12469740
TI  - Polaritons in hollow cylinders in the presence of a dc magnetic field.
AB  - We study the effects of a dc external magnetic field on the polaritons
      propagating in hollow dielectric cylinders, taking into account the retardation
      effects. In solving Maxwell's equations we show that only the TM modes can
      propagate in these systems, and we obtain the dispersion relation of the confined
      surface-polariton modes. The effects of geometric parameters and the external
      magnetic field on the propagation of surface-polariton modes are also analyzed
      and show significant influence on the behavior of the modes. Numerical results
      are presented for the dispersion relation of surface polaritons with GaAs as the
      optically active medium.

PMID- 12469741
TI  - Bidirectional reflectance distribution function of specular surfaces with
      hemispherical pits.
AB  - We derive the bidirectional reflectance distribution function for a class of
      opaque surfaces that are rough on a macroscale and smooth on a microscale. We
      model this type of surface as a distribution of spherical mirrors. Since our
      study concerns geometrical optics, it is only the aperture of the concavities
      that is relevant, not the dimension. The three-dimensional problem is effectively
      transformed into a much simpler two-dimensional one involving the possibly
      infinitely many reflections in a spherical mirror. We find that these types of
      surface show very strong backscattering when the pits are deep but forward
      scattering when the pits are shallow. Such surfaces also show spectral effects as
      a result of multiple reflections and polarization effects that are due to the
      orientation of the effective surface. Both this model and the locally diffuse
      thoroughly pitted surface model [Int. J. Comput. Vision 31, 129 (1999)] are
      superior to other models in that they allow for an exact treatment for physically
      realizable surface geometries.

PMID- 12469742
TI  - Conditions for correction of linear and quadratic field-dependent aberrations in
      plane-symmetric optical systems.
AB  - The Abbe sine condition and the recently developed pupil astigmatism conditions
      provide a powerful set of relationships for describing imaging systems that are
      free from aberrations that have linear and quadratic dependence on field, to all
      orders in the pupil. We have proved both of these conditions and applied them to
      axisymmetric imaging systems. We now extend our approach to plane-symmetric
      systems. Still using Hamilton's characteristic functions, we derive the general
      sine conditions and the pupil astigmatism conditions that describe plane
      symmetric systems that are free of all aberrations with linear and quadratic
      field dependence.

PMID- 12469743
TI  - Analysis of a hybrid micro/macro-optical method for distortion removal in free
      space optical interconnections.
AB  - Eikonal analyses are applied to a hybrid micro/macro-optical shuffle
      interconnection approach that minimizes distortion in a multichip smart-pixel
      shuffle interconnection system. The optical system uses off-axis imaging elements
      to link clusters of dense arrays of vertical-cavity surface-emitting laser
      (VCSEL) sources to matching clusters within arrays of detectors. A critical
      requirement for such a system is that the images of the two-dimensional arrays of
      the VCSELs must be registered on their associated detector arrays with a
      precision of the order of 10 microm across the entire multichip array. The hybrid
      approach exploits the typical narrow-beam cone angles of VCSELs by use of beam
      deflecting micro-optics to create a distortion-canceling symmetry about a central
      aperture in the optical system for each VCSEL-detector link. The second- and
      third-order aberrations of the plane-symmetric system created by the global off
      axis imaging system are analyzed. The results prove that the hybrid concept
      cancels distortion and minimizes the spot size at the detector array plane.

PMID- 12469744
TI  - Light collimation, imaging, and concentration at the thermodynamic limit.
AB  - A new type of optical instrument, the curved hologram, is introduced that allows
      us the unique opportunity to independently control its spatial phase function and
      its shape (whereas in reflecting or refracting optical elements the shape
      uniquely determines the spatial phase function). We show how proper design of the
      hologram shape (using a simple analytic procedure) yields perfect uniform
      collimation and also collimation and concentration of diffuse (monochromatic)
      light at the thermodynamic limit of brightness conservation. The results of our
      experimental demonstration as well as those of our numerical ray-tracing
      simulations verify our design.

PMID- 12469745
TI  - Passband-shifting filters through postgrowth modification of filter optical
      thickness.
AB  - We describe a postgrowth method to produce passband filters with different center
      wavelengths from a single growth run by irreversibly changing the refractive
      index of a layer or a series of layers within the filter. This leads to a new
      type of filter, the passband-shifting filter, whose center wavelength can be
      irreversibly shifted from lambda0 to lambda0 - deltalambda after the filter has
      been grown. The passband shift can be controlled exactly by proper design of the
      multilayer. We present the theory behind passband-shifting-filter design along
      with transfer-matrix simulations and preliminary experimental results for a two
      cavity filter, using lateral oxidation of AlxGa1-x As-based materials to effect
      the passband shift.

PMID- 12469746
TI  - Analysis of spectroscopic measurements of leaf water content at terahertz
      frequencies using linear transforms.
AB  - We provide a unified framework for a range of linear transforms that can be used
      for the analysis of terahertz spectroscopic data, with particular emphasis on
      their application to the measurement of leaf water content. The use of linear
      transforms for filtering, regression, and classification is discussed. For
      illustration, a classification problem involving leaves at three stages of
      drought and a prediction problem involving simulated spectra are presented.
      Issues resulting from scaling the data set are discussed. Using Lagrange
      multipliers, we arrive at the transform that yields the maximum separation
      between the spectra and show that this optimal transform is equivalent to
      computing the Euclidean distance between the samples. The optimal linear
      transform is compared with the average for all the spectra as well as with the
      Karhunen-Loeve transform to discriminate a wet leaf from a dry leaf. We show that
      taking several principal components into account is equivalent to defining new
      axes in which data are to be analyzed. The procedure shows that the coefficients
      of the Karhunen-Loeve transform are well suited to the process of classification
      of spectra. This is in line with expectations, as these coefficients are built
      from the statistical properties of the data set analyzed.

PMID- 12469747
TI  - Phenomenon of spectral switches as a new effect in singular optics with
      polychromatic light.
AB  - It is shown that the recently discovered phenomenon of so-called spectral
      switches has a natural interpretation in the framework of singular optics with
      polychromatic light and that it should be regarded as being primarily a
      manifestation of diffraction-induced spectral changes rather than correlation
      induced spectral changes as was suggested in the original papers [the first one
      appearing in Opt. Commun. 162, 57 (1999)] reporting this effect.

PMID- 12469748
TI  - On the extinction of radiation by a homogeneous but spatially correlated random
      medium: comment.
AB  - Some extinction laws for radiation transmitted through inhomogeneous random media
      were discussed by Kostinski [J. Opt. Soc. Am. A 18, 1929 (2001)] by means of a
      complicated use of concepts of statistical theory of fluids. We show that these
      extinction laws are readily obtained in terms of classical probability theory.
      The validity of exponential extinction laws for large observation distances (as
      compared with the size of inhomogeneities of a medium) is proven and emphasized.
      It is shown that Kostinski's results turn out to be applicable to small
      observation distances only, for which the concept of extinction law is hardly
      applicable.

PMID- 12469749
TI  - Coverage of carious roots by a subepithelial connective tissue graft.
AB  - PURPOSE: To assess whether coverage of an untreated or restored carious root
      lesion with a subepithelial connective tissue graft would provide a predictable,
      esthetically acceptable result and prevent further caries progression. MATERIALS
      AND METHODS: Twenty-seven teeth from 13 patients with root caries and gingival
      recessions of 3.4 +/- 0.2 mm (mean +/- SEM) were treated with subepithelial
      connective tissue grafts. Eighteen teeth had untreated caries, and the other nine
      had composite or glass-ionomer restorations. The carious dentin and the plastic
      restorations were removed prior to the surgical procedure. The exposed roots were
      thoroughly planed and covered by a subepithelial connective graft with no further
      root treatment or conditioning. The teeth were examined periodically from 1-6
      years post-treatment for retention of root surface coverage and presence of
      carious lesions. RESULTS: The mean root coverage recession left after the
      treatment was 0.3 +/- 0.1 mm, with coverage of 92.4 +/- 2.4%. Significant
      differences (P< 0.05) were found between the coverage of roots with carious
      lesions that had not been restored and those that had restorations removed.
      However, since the number of teeth with restorations was limited, further study
      is required to confirm this difference. In 18 cases, complete coverage of the
      recession was achieved. The results were stable, and no further recessions or
      recurrent caries were detected.

PMID- 12469750
TI  - Fluoride, hydrogen ion and HEMA release from light-cured GIC restoratives.
AB  - PURPOSE: To quantitatively measure the amount of fluoride, hydroxy ion and
      hydroxyethyl methacrylate (HEMA) released from various light-cured restorative
      materials. MATERIALS AND METHODS: Three resin-modified glass-ionomer cements
      (RMGI): Photac-Fil Aplicap, Vitremer, and Fuji II LC and two polyacid-modified
      resin-based composites (compomer): Dyract and Variglass VLC were used in this
      study. Disc-shaped specimens were made as per manufacturer's recommendations and
      the surfaces were polished with a 600 grit abrasive paper. Immediately after
      setting, each disc was immersed into 10 ml of distilled water at 37 degrees C and
      the eluates were collected after 8- or 24-hour immersion. The concentration of
      HEMA in the eluate was determined by high performance liquid chromatography. In
      addition, the concentration of fluoride ion and pH were measured by the
      respective ion selective electrode. RESULTS: The RMGIs released the greater
      amount of fluoride and smaller amounts of HEMA compared to the compomers at both
      the 8- and 24-hour eluates. Although there were no significant differences in pH
      of the 8-hour eluates among the restoratives, the pHs of the RMGI were
      significantly higher than those of the compomers for the 24-hour eluates.

PMID- 12469751
TI  - Effect of accelerated restorative techniques on the microleakage of Class II
      composites.
AB  - PURPOSE: To assess the marginal seal of Class II resin-based composite
      restorations cured by a high intensity halogen light or a plasma arc light.
      MATERIALS AND METHODS: Class II cavities were prepared in extracted molar teeth
      with cervical margins located apical to the cemento-enamel junction. Cavities
      were restored with a posterior resin-based composite (Tetric Ceram) using either
      a two-increment or a bulk placement and cure restorative technique after
      application of bonding agent (Excite). Test parameters included light unit
      type/curing mode, application of flowable composite and restorative technique.
      After thermocycling, the teeth were immersed in basic fuchsin dye. Sectioned
      restorations were examined under a stereomicroscope (x 25) and extent of
      microleakage (mm) was recorded using an image analysis system. Data was analyzed
      by non-parametric statistical tests. RESULTS: No leakage was observed at the
      occlusal enamel margin of a nyrestoration. Median gingival leakage values for the
      different test groups ranged from 0.02-2.51 mm. Light unit type had a highly
      significant effect on leakage (P=0.0002). The highest leakage scores were
      recorded with the plasma arc light used in standard curing mode and the lowest
      with the halogen light in turbo-boost mode.

PMID- 12469752
TI  - Effect of multiple application of a dentin adhesive on contraction gap width of a
      resin-based composite.
AB  - PURPOSE: To test the efficacy of the multiple application of a total-etch dentin
      adhesive was investigated by measuring (1) the contraction gap width of a light
      activated resin-based composite in a cylindrical dentin cavity and (2) the early
      tensile bond strength to a flat dentin surface with the Single Bond Dental
      Adhesive System. MATERIALS AND METHODS: Contraction gap width was measured in a
      cylindrical dentin cavity (3 mm x 1.5 mm) treated with a single coat or double
      coats of the Single Bond adhesive and restored with Silux Plus or Z-100. As
      control, the cavity was treated with an experimental dentin bonding system
      consisting of EDTA, 35% GM and Clearfil Photo Bond. Early tensile bond strengths
      of Silux Plus or Z-100 were measured on the flat dentin surface treated with the
      three bonding procedures as in the contraction gap study within 10 min. after
      final cure. RESULTS: The contraction gap of Silux Plus and Z-100 was prevented
      with the double coats of the Single Bond adhesive, whereas the contraction gap of
      Z-100 was not prevented with the single coat of the Single Bond and the
      experimental system. When the film thickness of the Single Bond system was less
      than 2 microm, the gap could not be prevented. The tensile bond strengths of
      Silux Plus and Z-100 to flat dentin mediated with the three bonding procedures
      were not significantly different (P>0.05).

PMID- 12469753
TI  - Microleakage of four simplified adhesive systems under thermal and mechanical
      stresses.
AB  - PURPOSE: To evaluate microleakage at the dentin margins of Class II resin-based
      composite restorations using four simplified adhesive systems: Etch & Prime 3.0,
      Prime & Bond NT, Clearfil Liner Bond 2V and Clearfil SE Bond, upon thermal and
      mechanical stresses. MATERIALS AND METHODS: Forty slot preparations (5mm x 3mm x
      1.5mm) were cut in sound human molars with gingival margins below the
      cement/enamel junction. All adhesive systems were applied strictly according to
      manufacturers' instructions. Cavities were restored using Clearfil AP-X composite
      resin. After finishing and polishing, teeth were submitted to thermal (x700, 5-55
      degrees C, 60-second dwell time) and consecutively mechanical cycling (100,000
      cycle; 8 Kgf load). Specimens were coated with nail polish, immersed in silver
      nitrate for 2 hours and sectioned longitudinally with a diamond disc. The extent
      of leakage was ranked using a 0-4 scale. RESULTS: Statistical analysis was
      performed using Kruskal-Wallis test. Minimal leakage occurred with Clearfil SE
      Bond. There was a statistically significant difference (P<0.01) between this
      system and Clearfil Liner Bond 2V, although the latter also showed low values of
      dye penetration. No statistically significant difference was found between Etch &
      Prime 3.0 and Prime & Bond NT. Both showed statistically greater leakage than the
      two other systems (P<0.01).

PMID- 12469754
TI  - Effect of application time of APF and NaF gels on microhardness and fluoride
      uptake of in vitro enamel caries.
AB  - PURPOSE: To evaluate the effect of time of fluoride application gel, acidulated
      or neutral, on in vitro enamel resistance to demineralization and fluoride
      uptake. MATERIALS AND METHODS: One hundred and ninety-two human enamel blocks
      were used in this study and 144 were treated with fluoride gel, acidulated or
      neutral, for 1 or 4 minutes. Ninety-six blocks treated with fluoride and 24
      control blocks were submitted to a high cariogenic challenge. After the pH
      cycling, enamel demineralization was assessed by surface and cross-sectional
      microhardness. Fluoride in the enamel blocks was also determined after removing
      an enamel layer by etching acid. RESULTS: Acidulated fluoride gel formed more
      fluoride in enamel than neutral gel (P<0.05), and it was also more efficient in
      reducing the demineralization of the enamel blocks submitted to a cariogenic
      challenge than the neutral one (P<0.05). It was found that the time of
      application was significant in terms of fluoride uptake, but it did not render
      the enamel more resistant to demineralization.

PMID- 12469755
TI  - Microleakage of adhesively bonded cervical amalgam restorations.
AB  - PURPOSE: To evaluate dye penetration in adhesively bonded cervical amalgam
      restorations. MATERIALS AND METHODS: The specimens were randomly divided into
      four groups and the adhesives Prime & Bond 2.1, Prime & Bond 2.1 Dual Cure,
      Scotchbond Multi Purpose Plus and Amalgambond Plus were tested. After being
      restored and polished, the teeth were thermocycled 1,000 times at temperatures
      varying between 5 degrees C +/- 2 degrees C and 55 degrees C +/- 2 degrees C.
      Statistical analysis was carried out using the Kruskal-Wallis test and multiple
      comparisons. RESULTS: Scotchbond Multi-Purpose Plus demonstrated lower levels of
      microleakage in enamel and dentin. The dual adhesives were more effective than
      the "one bottle" adhesive.

PMID- 12469756
TI  - Microtensile bond strength of thermally stressed composite-dentin bonds mediated
      by one-bottle adhesives.
AB  - PURPOSE: To evaluate the effects of thermally stressing composite-dentin bonds in
      teeth subjected to a modified microtensile bond test that allowed application of
      two bonding agents side-by-side to the same tooth. MATERIALS AND METHODS:
      Extracted human molars with a slot dissecting the occlusal dentin surface were
      conditioned and primed on one side with Prime & Bond NT (PBNT) and Prime One
      Mirage (P-One) on the other side. The composite was light-cured onto the surface.
      Approximately 0.5 mm thick dumbbell-shaped tensile specimens were tested after 24
      hour water storage or after thermocycling 2400 times at 5 and 55 degrees C.
      Interfacial morphologies were evaluated by scanning electron microscopy (SEM).
      RESULTS: Mean tensile bond strengths (TBS +/- standard deviation) were (36 +/- 24
      MPa and 31 +/- 16 MPa) for PBNT, and (51 +/- 25 MPa and 40 +/- 18 MPa) for P-One
      without and with thermocycling, respectively. 97% of all tested specimens failed
      adhesively. Differences between the bonding systems and the therrmal treatments
      were significant (two-way ANOVA, P < 0.05). Regression analysis showed regional
      correlation between mean TBS of each bonding agent when grouped by the teeth from
      which they were obtained (r = 0.66, P = 0.002). SEM revealed that both bonding
      agents effectively wetted the conditioned dentin producing a typical hybrid
      layer, surface-textured resin tags with multiple lateral branches.

PMID- 12469757
TI  - Relationship of dentin shear bond strengths to different laboratory test designs.
AB  - PURPOSE: To compare 6 shear bond test procedures using 2 primers by evaluating
      differences in strength and fracture surfaces. MATERIALS AND METHODS: Part I - a
      2(3)-factorial design evaluated the effects of (1) 2 primer systems, (2) the
      dentin moisture level, and (3) the application technique defining the bond area.
      The outcome of Part I then led to choosing for Part II one primer system,
      applying the primer the entire surface with moist dentin as the substrate while
      comparing 6 shear test designs: (1) knife-edged chisel-on-iris; (2) similar to 1
      with support added to the tooth; (3) chisel on composite plug; (4) similar to 3
      with support added; (5) wire loop on composite plug; (6) modified Watanabe
      assembly. RESULTS: In Part I mean shear bond strengths (SBS) ranged from 14-36
      MPa. SBS was highest for either primer when it was applied to moist dentin over
      the entire dentin surface. Each of the factors, moisture level, primer system and
      application technique significantly affected SBS (3-way ANOVA, P<0.05). The
      effects from each primer system on SBS depended on the surface moisture or the
      application technique, indicating significant interactions. In Part II, mean SBS
      ranged from 18-32 MPa with Groups 1 and 2 having significantly higher bond
      strengths than the others (P<0.05).

PMID- 12469758
TI  - The effect of six polishing systems on the surface roughness of two packable
      resin-based composites.
AB  - PURPOSE: To evaluate the surface roughness of two packable composites after
      finishing and polishing with six different systems. MATERIALS AND METHODS:
      Solitaire and Alert composite samples were prepared and polished with Poli I and
      Poli II aluminum oxide pastes, Ultralap diamond paste, Enhance finishing points,
      Politip rubber polishers, fine and extra fine diamond burs, and 30-blade tungsten
      carbide burs according to the manufacturers' instructions. The polished surfaces
      were then evaluated with a profilometer and a scanning electron microscope.
      RESULTS: Solitaire composite resin presented the smoothest surfaces when polished
      with Poli I and II aluminum oxide pastes, Ultralap diamond paste, Politip
      finishing points and 30-blade tungsten carbide burs. The smoothest surfaces for
      Alert composite were evident with the 30-blade tungsten carbide burs.

PMID- 12469759
TI  - Can modern restorative procedures and materials reliably seal cavities? In vitro
      investigations. Part 1.
AB  - Secondary caries, marginal discoloration and marginal gap/fracture account for a
      significant majority of clinical diagnoses of restoration failure and reason for
      restoration replacement. These failures occur at the interface between the
      restoration and the cavity preparation. It is an underlying belief, or at least
      an underlying assumption of the dental profession, that improving the seal
      between a restorative material and tooth structure will reduce the frequency of
      such occurrences, which will in turn lead to enhanced restoration longevity. This
      paper reviews the current status of in vitro literature regarding the ability of
      modern restorative materials and techniques to reliably seal cavity preparations.
      In addition, methodology for accomplishing in vitro research is reviewed for the
      purpose of elucidating trends, areas of interest and controversial topics.

PMID- 12469760
TI  - Perioral umbilicated papules.

PMID- 12469761
TI  - Some perspective on black-white cancer statistics.

PMID- 12469762
TI  - Cancer statistics for African Americans.
AB  - The American Cancer Society provides estimates on the number of new cancer cases
      and deaths, and compiles health statistics on African Americans in a biennial
      publication, Cancer Facts and Figures for African Americans. The compiled
      statistics include cancer incidence, mortality, survival, and lifestyle behaviors
      using the most recent data on incidence and survival from the National Cancer
      Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program,
      mortality data from the National Center for Health Statistics (NCHS), and
      behavioral information from the Behavior Risk Factor Surveillance System (BRFSS),
      Youth Risk Behavior Surveillance System (YRBSS), and National Health Interview
      Survey (NHIS). It is estimated that 132,700 new cases of cancer and 63,100 deaths
      will occur among African Americans in the year 2003. Although African Americans
      have experienced higher incidence and mortality rates of cancer than whites for
      many years, incidence rates have declined by 2.7 percent per year in African
      American males since 1992, while stabilizing in African-American females. During
      the same period, death rates declined by 2.1 percent and 0.4 percent per year
      among African-American males and females, respectively. The decrease in both
      incidence and death rates from cancer among African-American males was the
      largest of any racial or ethnic group. Nonetheless, African Americans still carry
      the highest cancer burden among US racial and ethnic groups. Most cancers
      detectable by screening are diagnosed at a later stage and survival rates are
      lower within each stage of disease in African Americans than in whites. The
      extent to which these disparities reflect unequal access to health care versus
      other factors is an active area of research.

PMID- 12469763
TI  - American Cancer Society guideline for the early detection of cervical neoplasia
      and cancer.
AB  - An update to the American Cancer Society (ACS) guideline regarding screening for
      the early detection of cervical neoplasia and cancer, based on recommendations
      from a formal review and recent workshop, is presented. The new screening
      recommendations address when to begin screening, when screening may be
      discontinued, whether to screen women who have had a hysterectomy, appropriate
      screening intervals, and new screening technologies, including liquid-based
      cytology and HPV DNA testing.

PMID- 12469764
TI  - The difficult problem of acute myeloid leukemia in the older adult.
AB  - Acute myeloid leukemia (AML) in older adults is a biologically and clinically
      distinct entity. Based on analysis of cytogenetic and molecular data, it is known
      that leukemic cells in older patients are intrinsically resistant to standard
      chemotherapy. Due to comorbid disease and impaired bone marrow stem cell reserve,
      older adults tolerate myelosuppressive chemotherapy poorly, with a treatment
      related mortality rate of 25 percent. About 35 percent of adults under age 40 are
      cured, but the complete remission rate (likelihood of temporary disease
      eradication) is 45 percent in those over age 60, considerably lower than the 75%
      rate among younger patients, and the possibility of long-term disease free
      survival is 20 percent in those achieving remission or less than 10 percent
      overall. Standard allogeneic bone marrow transplantation is too dangerous to be
      considered as a means to eradicate minimal residual disease after remission is
      obtained and myelointensive chemotherapy is not a beneficial post-remission
      strategy in this age cohort. These disappointing results call for more effective
      and less toxic therapeutic options. Advances in our understanding of the
      pathophysiology of AML and promising early clinical data suggest that the era of
      truly targeted therapy in this difficult disease may soon be a reality.

PMID- 12469765
TI  - Patient pages. Early detection of cervical cancer.

PMID- 12469767
TI  - Temporal variations of natural and anthropogenic radionuclides in sea otter skull
      tissue in the North Pacific Ocean.
AB  - Marine mammals being among the top predators in the food web tend to accumulate
      organic and inorganic contaminants from the environment. The body burden of
      contaminants in these species could reflect their foods and thus contaminant
      levels could serve as proxies on the changes of ecosystem. A pilot study was
      carried out to investigate the possibility of radionuclide leakage at Amchitka
      using a suite of sea otter (Enhydra lutris) skulls collected near Amchitka
      nuclear test-sites before (1950s) and after the testing (1990s), and at Adak,
      another Aleutian Island, about 300 km from Amchitka, where the potential impact
      of radionuclide leakage from Amchitka is expected to be negligible. In addition,
      the naturally occurring and anthropogenic radionuclide content on the sea otter
      skull was also utilized to investigate if there was any significant ecosystem
      changes in the environment. Concentration of 210Pb in sea otter bones collected
      during the 1950s was significantly higher than those collected in the 1990s. We
      propose that among the various factors that could cause this higher enrichment in
      210Pb, changes in the sea otter prey is the most likely one. Comparison of the
      137Cs, 90Sr, 239,240Pu concentrations appear not to be significantly higher in
      sea otter skulls collected in 1990s from Amchitka where the underground tests in
      1965-71 than those from Adak, although significant differences were detected
      among different groups collected at various times.

PMID- 12469766
TI  - National action plan for childhood cancer: report of the national summit meetings
      on childhood cancer.

PMID- 12469768
TI  - The effects of exposure of 60Co on the oxidant/antioxidant status among radiation
      victims.
AB  - This retrospective study has been performed with radiation victims who were
      accidentally exposed to a 60Co source and its release into the environment. The
      aim of the study was to assess the effects of elevated radiation exposures on
      plasma level, on erythrocyte thio barbituric acid reactive substance (TBARS)
      level and on erythrocyte glutathione (GSH) levels. Patients were treated in
      different hospitals with different symptoms such as nausea, vomiting, dizziness,
      along with severe anemia in some patients. Blood samples were collected 3-5 days
      following the radiation accident. Increases in plasma (6.25 +/- 0.90 nmol ml(-1))
      and erythrocyte TBARS levels (330.5 +/- 30.5 micromol gHb(-1)) were found in
      comparison to a healthy group (3.72 +/- 0.68 nmol ml(-1) and 150.7 +/- 20.5
      micromol gHb(-1), respectively) at a significant level (p<0.001). Erythrocyte GSH
      levels (5.2 +/- 0.30 micromol gHb(-1)) were found to be decreased among the
      victims (healthy group: 10.2 +/- 0.7 micromol gHb(-1)) at the same significance
      level (p<0.001). These observations confirm a significant change induced by
      radiation in the oxidant/antioxidant status among the victims. It is suggested
      here that antioxidant supplementation therapy might be effective in preventing
      the harmful effects of 60Co radiation among radiation victims.

PMID- 12469769
TI  - Accumulation of 137Cs by fungal mycelium in forest ecosystems of Ukraine.
AB  - During 1996-1998, 16 fruit bodies of different species and 204 soil samples down
      to 10 cm in the close vicinity of the fruit body sites were collected in a
      coniferous forest in the Ovruch region of Ukraine. The soil samples were sliced
      into 1 or 2 cm layers and the fungal mycelium was prepared from each of the
      layers. The 137Cs activity concentration was determined in both soil and
      mycelium. The mean weight of fungal mycelium was 13.8 mg g(-1) of soil in the
      upper 4 cm and 7.3 mg g(-1) when measured for the upper 10 cm. At the sites of
      Paxillus involutus and Sarcodon imbricatus, the mycelium was rather homogeneously
      distributed in the upper 10 cm and at sites of Xerocomus subtomentosus and
      Cantharellus cibarius, the mycelium was distributed mostly in the upper layers.
      The highest 137Cs activity concentrations were found in the upper layers of the
      soil profile. The 137Cs activity concentrations were usually higher in the fruit
      bodies compared with the mycelium, with ratios ranging from 0.1 to 66 and a mean
      of 9.9. The percentage of the total inventory of 137Cs in the soil found in the
      fungal mycelium ranged from 0.1 to 50%, with a mean value of 15%.

PMID- 12469770
TI  - Variations of the ambient dose equivalent rate in the ground level air.
AB  - The ambient dose equivalent rate is caused by ionizing radiation of radionuclides
      in the atmosphere and on the ground surface as well as by cosmic radiation.
      Seasonal and diurnal variations of the ambient dose equivalent rate (ADER) in the
      ground level air are influenced by the concentration of 222Rn daughters. The
      222Rn concentration in the ground level atmosphere, in turn, depends on the rate
      of the 222Rn exhalation from soil and turbulent air mixing. Its diurnal and
      seasonal variations depend on meteorological conditions. The aim of this study is
      to estimate the influence of variations of the rate of the 222Rn exhalation from
      soil and its concentrations in the ground level air on variations of ADER in the
      ground level air, as well as the dependence of these parameters on meteorological
      conditions. The 222Rn diffusion coefficient and its exhalation rate in
      undisturbed loamy soil have been determined. The 222Rn concentration in the soil
      air and its concentration in the ground level air correlate inversely
      (correlation coefficient is r = -0.62). The main factors determining the 222Rn
      exhalation from soil are: the soil temperature (r = 0.64), the difference in
      temperature of soil and air (r = 0.57), and the precipitation amount (r = 0.50).
      The intensity of gamma radiation in the ground level air is mostly related to the
      222Rn concentration in the air (r = 0.62), while the effect of the exhalation
      rate from soil is relatively low (r = 0.36). It has been shown that ADER due to
      222Rn progeny causes only 7-16% of the total ADER and influences its variation.
      The comparison of variations of ADER due to 222Rn progeny and the total ADER
      during several years shows that these parameters correlate positively.

PMID- 12469771
TI  - Tin mining and processing in Nigeria: cause for concern?
AB  - The range and means of measured dose rates and activity concentrations of 40K,
      natural U and Th in environmental samples of a Nigerian tin mine and its tailing
      sites are presented. The measured concentration levels of eU and eTh in tailing
      samples and the measured dose rates were found to be elevated with values up to
      approximately 100 times above background levels of control soils. For the purpose
      of protection of workers and the public it is therefore advisable that these
      sites should be properly monitored, controlled and potential remediation
      strategies be considered in order to avoid any radiological impact to the
      population.

PMID- 12469772
TI  - Model reconstruction of 90Sr concentrations in fish from 16 Ural lakes
      contaminated by the Kyshtym accident of 1957.
AB  - The paper outlines the results of the ECOMOD model application to simulate 90Sr
      dynamics in fish dwelling in Southern Ural lakes and contaminated as a result of
      the Kyshtym accident. The detailed reconstruction of 90Sr behavior in fish for
      the 40-year period (1957-1997) was made for the most contaminated lakes (Uruskul
      and Berdenish). The adapted ECOMOD model was applied for the other 14 Ural lakes
      to explain the peculiarities in 90Sr accumulation by fish in lakes with different
      concentrations of Ca2+ ions in lake water.

PMID- 12469773
TI  - Release of cadmium in the Danube estuary: contribution of physical and chemical
      processes as determined by an experimental approach.
AB  - The behavior of dissolved cadmium (Cd) in the Danube estuary was investigated
      through field sampling and mixing experiments using Danube River water and Black
      Sea water. The experiments were performed by mixing these two end-member waters
      in various proportions, with the addition of stable or radioactive Cd to the
      freshwater Danube end-member prior to the mixing. The release of Cd that resulted
      in maximum concentrations under field conditions was well simulated by mixing
      experiments. The experimental results were modeled assuming that the release of
      Cd was the sum of the contribution of physical effects resulting from dilution
      effects and the contribution of chemical effects resulting from dissolved Cd
      complex formation (and isotopic exchange when concerned). In the absence of
      dissolved Cd-complexing ligands, the release of Cd due to the dilution of the
      particulate phase during mixing could explain part of the maximum concentrations
      observed in field conditions. Kinetic effects were established by comparing the
      theoretical and measured contribution of chemical effects resulting from
      dissolved Cd-complex formation. The non-equilibrium state observed during the
      mixing experiment suggested the presence of particulate labile Cd that was not
      easily mobilized. All these features supported the hypothesis that Cd released in
      estuaries is controlled both by the dilution of the particulate phase and by
      kinetic competitive complexation between particulate ligands (covering a large
      spectrum of nature and strength) and dissolved ligands.

PMID- 12469774
TI  - Evaluating prey capture by larval mummichogs (Fundulus heteroclitus) as a
      potential biomarker for contaminants.
AB  - We evaluated larval prey capture as a "behavioral biomarker" of contamination by
      examining feeding behavior of larval mummichogs (Fundulus heteroclitus) from many
      different sites, including a severely contaminated "Superfund" site, moderately
      contaminated sites, and reference areas. Prey capture ability was related to
      sediment contaminant levels. The levels of contaminants at a site were highly
      correlated with each other, so that the impact of individual contaminants was
      confounded. The number of captures of brine shrimp by mummichog larvae from all
      sites was highly variable, but significant negative correlations of prey capture
      were seen with mercury, lead, zinc, cadmium, and PCBs. As observed previously
      with adults, polyaromatic hydrocarbons (PAHs) did not appear to impair prey
      capture ability. The only site in which prey capture rates of 8-day old larvae
      were severely affected was the most highly contaminated Superfund site, Berry's
      Creek, NJ. This implies that larval prey capture is not as sensitive a behavioral
      biomarker for contamination as adult behavior studied previously.

PMID- 12469775
TI  - Biological targets of neurotoxic pesticides analysed by alteration of
      developmental events in the Mediterranean sea urchin, Paracentrotus lividus.
AB  - Biological effects of neurotoxic insecticides widely used for agricultural
      purposes were studied using the early development of the Mediterranean sea urchin
      Paracentrotus lividus as a model. These compounds, dispersed as aerosols or
      powders in agricultural regions near to the coast, may affect the health of
      organisms in the marine environment. The biological effects of Basudin (an
      organophosphate compound containing 20% Diazinon), Diazinon (Dzn, a
      thionophosphate), Carbaryl and Pirimicarb (carbamates) on the early phases of sea
      urchin development were thus investigated. Morphological, biochemical,
      histochemical and immuno histochemical analyses were performed both during embryo
      and larval development. For the morphological effects on fertilisation and first
      cleavages, the effective concentration of insecticides was found to be 10(-4) M,
      while for further stages concentrations between 10(-5) and 10(-7) M were
      effective: 10(-3) M of any of these insecticides totally arrested development.
      During embryonic development, the treatment with organophosphates slowed the rate
      of early mitotic cycles down, affected nuclear and cytoskeletal status as well as
      DNA synthesis. From the gastrulation stage onwards, the main effects were exerted
      on the rate of primary mesenchyme cells migration, larval size, perioral arm
      length, and acetylcholinesterase activity distribution, thus deregulating the
      cholinergic system, which modulates cell-to-cell communication mediated by the
      signal molecule acetylcholine.

PMID- 12469776
TI  - Manganese accumulation by the antennule of the Norway lobster Nephrops norvegicus
      (L.) as a biomarker of hypoxic events.
AB  - In laboratory tests, manganese accumulation by the appendages of the sediment
      burrowing Norway lobster. Nephrops norvegicus (L.) (including the lateral
      antennules) was approximately three times greater [600 microg Mn g(-1) (dry
      weight) after 5 days in 20 mg Mn l(-1)] than that by the carapace. The
      accumulation was linearly dose-dependent (10-40 mg Mn l(-1)) and duration
      dependent (2-30 days). and showed no decrease after 3 weeks in undosed seawater.
      A high manganese uptakc to the lateral antennules during hypoxia in the field was
      verified from the SE Kattegat, Sweden. These results indicate that accumulation
      of Mn on the mobile appendages of the Norway lobster fulfils most of the criteria
      for a biomarker of exposure to hypoxia. Using these measurements in conjunction
      with Mn concentrations in the internal tissues, it may be possible to resolve
      both the timing and the extent of the Mn exposure and the underlying hypoxic
      event.

PMID- 12469777
TI  - Contaminant exposure and effects in Baltic ringed and grey seals as assessed by
      biomarkers.
AB  - The Baltic Sea ecosystem has suffered from a heavy pollutant load for more than
      three decades. Persistent organic pollutants (POPs) and heavy metals have been of
      most concern due to their persistence and toxic properties. Ringed seals (Phoca
      hispida baltica) and grey seals (Halichoerus grypus) living in the Baltic Sea
      have been suffering from pathological impairments, including reproductive
      disturbances, which have resulted in a depressed reproductive capacity. We
      investigated several biochemical parameters as potential biomarkers for exposure
      to and effects of the contaminant load in the Baltic seals. Seals from less
      polluted areas were used as reference material in terms of the pollution load. In
      both Baltic seal populations, the levels of some biochemical parameters diverged
      from those in the reference seals, and some of these showed a clear correlation
      with the individual contaminant load. Of the potential bioindicators, we propose
      cytochrome P4501A activity and vitamin E levels, in blubber or plasma, as
      exposure biomarkers for polychlorinated biphenyls (PCBs) and
      dichlorodiphenyltrichloroethane (DDT) in both species. The arylhydrocarbon
      receptor-mediated chemical-activated luciferase gene expression (CALUX) response
      reflects the whole PCB and DDT burden in ringed seals. Retinyl palmitate (vitamin
      A) levels showed a negative correlation with the individual POP load, and is
      proposed as potential effect biomarkers for the depletion of the vitamin A
      stores. As the nutritional levels of both vitamin A and E have an impact on the
      vitamin levels in the seals, more information on the dietary vitamin levels is
      needed before any conclusions can be drawn. As the relationship between
      biochemical parameters and contaminants varied between the two species, species
      specific characteristics has to be considered when monitoring the health status
      and possible toxic effects of the contaminant load in ringed and grey seals.

PMID- 12469778
TI  - Tipping the scales: biologic therapy 2002.

PMID- 12469779
TI  - Cutaneous dental sinus tract, a common misdiagnosis: a case report and review of
      the literature.
AB  - Cutaneous sinus tracts of dental origin are often initially misdiagnosed and
      inappropriately treated because of their uncommon occurrence and the absence of
      symptoms in approximately half the individuals affected. Patients are often
      referred with a recurrent or chronic cyst, a furuncle, or an ulcer on the face or
      neck. Correct diagnosis is based on a high index of suspicion and on radiologic
      evidence of a periapical root infection. Appropriate treatment results in
      predictable and rapid healing of these lesions. We present a case report of this
      common misdiagnosis and a review of the literature with regard to diagnosis and
      treatment.

PMID- 12469780
TI  - A status report on the medical management of rosacea: focus on topical therapies.

PMID- 12469781
TI  - Add sucralfate to list of aphthous ulcer treatments.

PMID- 12469782
TI  - A case of bullous pemphigoid limited to psoriatic plaques.
AB  - Psoriasis occurs with increased incidence in patients with bullous pemphigoid
      (BP). In this article, we describe the seventh reported English literature case
      in which the bullous lesions were limited to psoriatic plaques, and we discuss
      the pathophysiologic mechanisms that might explain this phenomenon. Treatment
      with acitretin quickly cleared both psoriatic and bullous lesions, suggesting a
      direct link between the psoriatic inflammatory process and the evolution of
      bullous lesions.

PMID- 12469783
TI  - The FDA guidelines for the treatment of psoriasis using cyclosporine A: are they
      adequate?
AB  - I present a review of the current US Food and Drug Administration (FDA)
      guidelines for using cyclosporine A (CSA) to treat psoriasis, with particular
      emphasis on the period for which CSA may be administered. My concern is that,
      without violating the guidelines, CSA could be given for a prolonged period with
      only very brief time-outs. I also review the risks for renal toxicity,
      malignancy, and other side effects from prolonged administration.

PMID- 12469784
TI  - Metastatic breast cancer to 4 eyelids: a clinicopathologic report.
AB  - A 47-year-old woman presented complaining of progressive, painless swelling of
      all 4 eyelids for 6 weeks. Her medical history was significant for breast cancer
      14 months prior. Examination results showed a diffuse, firm thickening of all 4
      eyelids with mild erythema of the overlying skin. Orbital computer tomography
      revealed extensive preseptal infiltration of soft tissue of all 4 eyelids, which
      enhanced with contrast. Results of a bilateral biopsy of the upper eyelids
      demonstrated extensive infiltration of the orbicularis muscle. Histologic
      features were consistent with metastatic breast cancer. Results of both the
      primary breast cancer biopsy taken 14 months previously and the eyelid biopsies
      were the same histologic type. Presentation of metastatic breast cancer to the
      eyelids is rare, but a recurrence must be considered in any patient with a
      history of breast cancer, despite the length of tumor-free survival. Bilateral
      involvement should not exclude metastases from diagnostic consideration, but
      rather, the diagnosis requires a high degree of clinical suspicion and
      recognition of the various cutaneous forms.

PMID- 12469785
TI  - The stability of tretinoin in tretinoin gel microsphere 0.1%.
AB  - Topical tretinoin is highly effective and widely used in the treatment of acne
      vulgaris. In studies to determine the degree of tretinoin photo degradation
      (isomerization), 2 tretinoin formulations, tretinoin gel microsphere 0.1% and
      tretinoin gel 0.025%, alone or in combination with erythromycin-benzoyl peroxide
      topical gel, were exposed to fluorescent light, incandescent light, or darkness
      for up to 24 hours. Results of the investigations revealed that after 24 hours of
      exposure to fluorescent light, 98% of the initial tretinoin in the tretinoin gel
      microsphere 0.1% formulation remained unchanged. When tretinoin gel microsphere
      0.1% was combined with erythromycin-benzoyl peroxide topical gel and exposed to
      fluorescent light, 99% and 87% of the tretinoin was recovered after 4 and 24
      hours, respectively, indicating only a limited amount of degradation. In
      contrast, exposure of tretinoin gel 0.025% to 24 hours of fluorescent light
      resulted in up to 69% tretinoin degradation and up to 89% degradation when the
      gel was combined with the erythromycin-benzoyl peroxide topical gel. The data
      suggest that the tretinoin gel microsphere 0.1% formulation offers marked
      protection against tretinoin photo degradation, even in the presence of a strong
      oxidizing agent such as benzoyl peroxide.

PMID- 12469786
TI  - Intraoperative consultation: an historical perspective.

PMID- 12469787
TI  - Intraoperative consultation for nervous system lesions.
AB  - The pathologist responsible for nervous system intraoperative consultations must
      know basics of the clinical history, details of the location and imaging
      characteristics of the lesion, and must be familiar with known clinicopathologic
      entities. Although cytologic and frozen section techniques have not changed
      significantly in the past 15 years, significant advancements in neuroimaging have
      greatly improved the ability to generate an accurate preoperative differential
      diagnosis. Such information can greatly aid the pathologist during intraoperative
      consultation. This review concerns the intraoperative cytologic and frozen
      section findings of the major clinicopathologic entities encountered in surgical
      neuropathology. While neoplastic processes of the central nervous system will be
      emphasized, important non-neoplastic conditions that mimic brain tumors will also
      be covered. A basic clinicopathologic approach to successful neurosurgical intra
      operative consultation is provided.

PMID- 12469788
TI  - Evaluation of surgical margins in anatomic pathology: technical, conceptual, and
      clinical considerations.
AB  - Virtually all anatomic pathologists are involved in the assessment of tissue
      margins in surgical procedures that are performed for malignant diseases. The
      natural tendency to view this process as uncomplicated has, in recent years, been
      countered by a body of literature on the biological milieu of the marginal zone.
      Moreover, empirical clinical information has shown that "negative" and "positive"
      marginal status has an imperfect correlation with risk of recurrent disease in
      several organ systems and in reference to various tumor types. Problems also
      remain regarding the optimal techniques for pathologic sampling of margins; the
      possible roles, if any, of adjuvant (eg, immunohistologic and "molecular")
      procedures for margin evaluation, and reporting motifs for selected surgical
      resections. This review considers conceptual data now available on surgical
      margins, provides a working approach to the generic assessment of marginal
      surfaces, and presents organ- and tumor- specific information pertaining to this
      area of practice.

PMID- 12469789
TI  - Intraoperative assessment of thyroid and parathyroid lesions.
AB  - The value of intraoperative frozen section analysis of thyroid nodules and of
      parathyroid lesions continues to change as new and ancillary techniques (both
      preopearative and intraoperative) become widely used, eg, fine needle aspiration,
      new radiologic scan techniques, rapid hormone assays. This articles reviews the
      use of frozen section diagnosis in the evaluation of thyroid and parathyroid
      lesions, presents the current literature and the author's experiences, and
      proposes a practical approach to these cases.

PMID- 12469790
TI  - Intraoperative and on-site cytopathology consultation: utilization, limitations,
      and value.
AB  - The intraoperative and on-site cytopathology can be successfully performed with a
      number of smear preparations. Specimen concentration technique is the preferred
      method. The Romanowsky stain such as Diff Quik used in our laboratory is
      economical, convenient, reproducible, and quick. This can be at times combined
      with Ultrafast pap or other rapid stains, which provide good nuclear details.
      Such evaluations are most valuable in the staging of epithelial tumors and
      primary diagnosis of a number of central nervous system lesions. On-site and
      intraoperative diagnoses help triage the specimens for additional studies. This
      reduces the turn around time and makes the procedure cost-effective and
      beneficial to the patient. An awareness of the "normal" adjacent structures and
      familiarity with the cytomorphology of the specimens in comparison to the
      exfoliative specimens is critical in developing a cytopathology service with high
      degree of sensitivity and specificity.

PMID- 12469791
TI  - Intraoperative consultation in gynecologic pathology.
AB  - Intraoperative consultation is widely used in gynecologic surgical practice to
      make intraoperative diagnosis, primarily to aid the surgeon to plan the extent of
      surgery. This article reviews the indications, performance and interpretation,
      accuracy and diagnostic pitfalls in the three major areas of gynecologic
      malignancies where intraoperative consultations are most frequently requested:
      ovarian masses, endometrial carcinoma and carcinoma of the cervix. For ovarian
      masses intraoperative consultation is usually requested either for histologic
      confirmation of malignant or borderline primary ovarian tumors before proceeding
      with radical surgery, or to rule out malignancy at the time of surgery for
      presumed benign disease. The diagnosis of endometrial carcinoma is usually made
      preoperatively before definitive surgical treatment. Thus, intraoperative
      consultation is most often used to identify the subgroup of patients with
      features of high risk disease who have an increased risk of metastases and who
      will benefit from formal surgical staging. In cases of carcinoma of the cervix
      frozen section is most commonly used to estimate the extent of spread of known
      invasive carcinoma at the time of radical surgery. Despite its restrictions,
      frozen section diagnosis is an important and reliable tool in the clinical
      management of patients with ovarian, endometrial and cervical tumors. The
      specificity of the method in experienced hands is high, the sensitivity is
      sufficient. The diagnosis of borderline ovarian tumors may be troublesome
      however, mainly due to their heterogeneity in appearance, especially in the case
      of large tumors of mucinous histologic type. It is important for pathologists to
      have a clear idea of the role and limitations of frozen section diagnosis in
      gynecological surgery in order to play a meaningful and optimal role in the
      management of the gynecologic oncology patient.

PMID- 12469792
TI  - Frozen sections in hematopathology.
AB  - The diagnostic complexity of lymphoproliferative disorders has increased
      tremendously within the last decade as evidenced by the recently published World
      Health Organization (WHO) classification of hematological malignancies. Diagnosis
      of these malignancies now often requires confirmation by ancillary studies, such
      as immunohistochemistry, flow cytometry, cytogenetics, and/or molecular studies.
      In fact, in some cases, these ancillary studies are diagnostic rather than simply
      confirmatory; furthermore, results from these studies may play a direct role in
      selecting patient therapy. Importantly, this comprehensive approach to the
      diagnosis of hematological disorders starts at the time of receipt of fresh
      tissue in the anatomic pathology laboratory. Appropriate handling and triaging of
      this fresh tissue, which includes recognizing grossly abnormal areas,
      interpreting the frozen section, and deciding to send portions of the specimen to
      ancillary laboratories, is pivotal to the optimal diagnosis, prognostication, and
      ultimate management of the patient.

PMID- 12469793
TI  - Sentinel lymph node evaluation for tumor metastasis.
AB  - The sentinel lymph node biopsy procedure for evaluation of metastatic tumor has
      become a common procedure for breast carcinoma and malignant melanoma. There is
      little standardization in the histopathologic management of these specimens. The
      history, technical details, and histopathologic work-up for sentinel lymph node
      biopsy are reviewed. Particular attention is paid to the intraoperative
      consultation and a protocol for optimal histopathologic management is presented.

PMID- 12469794
TI  - Treatment of Crohn's disease--the new era.

PMID- 12469795
TI  - Pancreatic cancer--a major health problem requiring centralization and multi
      disciplinary team-work for improved results.

PMID- 12469796
TI  - Oxidative stress, vitamin A and vitamin E behaviour in patients submitted to
      conservative surgery for complicated Crohn's disease.
AB  - AIMS: To assess whether plasma peroxidation and plasma levels of antioxidant
      compounds are correlated with clinical and biochemical activity in complicated
      Crohn's disease patients, and to evaluate whether the relief of obstructive
      complication by conservative surgery has any effect on the oxidative stress.
      PATIENTS AND METHODS: From May 1998 to May 2000, 20 Crohn's disease patients were
      studied. Basal peroxidative state (basal thiobarbituric acid reactive
      substances), peroxidative state after stimulation with copper sulfate (stimulated
      thiobarbituric acid reactive substances], lag time of plasma peroxidation
      susceptibility, plasma levels of vitamin E and A, C reactive protein, erythrocyte
      sedimentation rate and Crohn's disease activity index, were determined, before
      surgery, then 2 months and 1 year after surgery. A group of 134 healthy
      volunteers were used as controls. All patients were treated by conservative
      surgical procedures (i.e., strictureplasty and/or minimal resections). Student t
      test for paired and unpaired data and Spearman R correlation coefficient were
      calculated. RESULTS: Peroxidative plasma levels, as well as inflammatory indices,
      are significantly reduced 2 months and 1 year after surgery (p < 0.005), but
      basal levels of peroxidation and antioxidant scavengers seem to be disregulated
      in Crohn's disease patients compared to those in controls (p < 0.005). A
      correlation was found between basal thiobarbituric acid reactive substances, lag
      time and erythrocyte sedimentation rate (R:0.51; p < 0.05. R:0.56; p < 0.05) and
      C reactive protein (R:0. 6; p < 0.005. R:0. 65; p < 0.005). CONCLUSIONS: An
      imbalance between pro- and antioxidant mechanisms, due to chronic gut
      inflammation, is present in complicated Crohn's disease, and an excess of lipid
      peroxidation is probably an important pathogenetic factor Conservative surgery
      can reduce the oxidative stress avoiding repeated or extended resections that
      could lead to intestinal malabsorption and short bowel syndrome.

PMID- 12469797
TI  - Effect of acute cigarette smoking, alone or with alcohol, on gastric barrier
      function in healthy volunteers.
AB  - BACKGROUND: Smoking is a risk factor for gastroduodenal ulcer and gastric
      adenocarcinoma. However, the pathophysiological mechanisms induced by acute
      cigarette smoking in the human gastric mucosa are poorly understood. AIM: To
      evaluate the effect of acute cigarette smoking, alone or with alcohol, on the
      gastric permeability to sucrose, a specific marker of mucosal damage in the
      stomach. SUBJECTS AND METHODS: Twenty healthy volunteers (8 smokers/12 non
      smokers) were studied. Each fasted subject ingested 500 ml of a 20% sucrose
      solution and the amount of sucrose excreted in a 5-hour urine collection was
      measured by gas chromatography Four sucrose permeability tests were carried out:
      1. basal, 2. while smoking 5 cigarettes, 3. after drinking 50 ml of a 40 degrees
      alcoholic beverage, 4. a combination of 2+3. RESULTS: Sucrose excretion increased
      after alcohol ingestion (40.5 +/- 6.0 mg vs 143.1 +/- 28.9 mg, p = 0.002), but
      was not modified by acute cigarette smoking (34.4 +/- 5.9 mg). When alcohol and
      cigarettes were simultaneously consumed, the increase in alcohol-induced sucrose
      excretion was significantly reduced (73.1 +/- 16.6 mg, p = 0.03). Basal sucrose
      excretion was similar in smokers and non-smokers. However, in acute cigarette
      smoking, a decrease in sucrose excretion was observed in smokers (p = 0.02) but
      not in non-smokers. CONCLUSIONS: These results indicate that acute cigarette
      smoking may tighten the gastric mucosa in habitual smokers and this is associated
      with a smaller increase of gastric permeability induced by alcohol.

PMID- 12469798
TI  - Remodelling of zero-stress state of small intestine in streptozotocin-induced
      diabetic rats. Effect of gliclazide.
AB  - BACKGROUND: Biomechanical properties in terms of residual strains in diabetic
      small intestine have not been studied. Furthermore, no data have been reported on
      affect of gliclazide on gastrointestinal complications of diabetes. AIMS: To
      determine remodelling of zero-stress state of small intestine in streptozotocin
      induced diabetic rats and effect of gliclazide treatment. MATERIALS:
      Morphological properties and residual strains were studied in duodenum, jejunum
      and ileum obtained from diabetic rats, gliclazide-treated diabetic rats and
      normal rats (n = 8 each group). METHODS: Diabetes was induced by single
      intraperitoneal injection of 65 mg/kg streptozotocin. Gliclazide (10 mg kg(-1)
      day(-1) was injected directly into stomach lumen by intragastric gavage twice
      daily. Experimental period was 35 days. To approach no-load state; intestinal
      segments were surgically excised and cut transversely into short ring-shaped
      segments. Each ring was cut radially to obtain geometry of zero-stress state.
      Circumferential length, the wall thickness and opening angle were measured from
      digital images of each specimen and residual strains were computed. RESULTS:
      Blood glucose level of diabetic group (approximately 20 mmol/l) was consistently
      higher than that in normal group (approximately 4 mmol/l) after induction of
      diabetes (p < 0.001). Gliclazide lowered average blood glucose level to between
      10 and 15 mmol/l (p < 0.001). Plasma insulin levels of both diabetic groups
      (average between 10 and 15 pmol/l) were significantly lower than those in normal
      group (average approximately 18 pmol/l, p < 0.05). Wet weight per unit length and
      wall thickness of duodenum, jejunum and ileum were significantly higher in
      Diabetes group than those in Normal group (p < 0.05). Opening angle and absolute
      value of residual strain were significantly smaller in duodenum and larger in
      jejunum and ileum in Diabetes group than in Normal group (p < 0.001). Gliclazide
      treatment partly restored these changes (p < 0.05). CONCLUSIONS: Diabetes induced
      morphometric and biomechanical remodelling in intestine. Gliclazide partly
      restored these changes.

PMID- 12469799
TI  - Vascular reserve in the lower limbs of cirrhotic patients: a duplex Doppler
      ultrasound study.
AB  - AIM: To evaluate femoral artery impedance at rest and during reactive hyperaemia.
      PATIENTS: Study population comprised 11 cirrhotic patients without ascites, 10
      with ascites and 16 age- and sex-matched healthy subjects. METHODS:
      Echocardiographic assessment of systemic haemodynamics; duplex Doppler ultrasound
      measurement of femoral artery pulsatility index and vascular reserve [pulsatility
      index rest/pulsatility index hyperaemia). RESULTS: Cirrhotic patients had
      elevated cardiac index and low systemic vascular resistance. Pulsatility index
      (right femoral artery) was not statistically different either at rest or after
      reactive hyperaemia (controls: rest 10.6 +/- 0.4, hyperaemia 2.6 +/- 0.2;
      compensated cirrhosis: rest 10.1 +/- 0.8, hyperaemia 3.4 +/- 0.4; ascitic
      cirrhosis: rest 11.4 +/- 1.6, hyperaemia 2.9 +/- 0.4. Vascular reserve was 4.38
      +/- 0.35 in controls, 3.33 +/- 0.39 in compensated and 4.70 +/- 0.89 in ascitic
      cirrhosis (p = not significant). No correlation was found between systemic
      haemodynamic parameters and either pulsatility index or vascular reserve.
      CONCLUSIONS: The lower limb vascular reserve is preserved in cirrhosis.

PMID- 12469800
TI  - Epidemiology of pancreatic cancer in Northeastern Italy: incidence, resectability
      rate, hospital stay, costs and survival (1990-1992).
AB  - BACKGROUND: The incidence of pancreatic cancer and relative hospital stay and
      costs are not well known. AIMS: To define the incidence, hospital stay and cost
      of pancreatic cancer in a well-defined area of Italy. PATIENTS AND METHODS: Each
      new case of pancreatic cancer diagnosed between 1990 and 1992 among 669,703
      inhabitants in the Veneto Region of Northern Italy was recorded and followed
      until death or for 5 years after diagnosis. Four types of hospital stay were
      defined. Type 1: undiagnosed pancreatic cancer; type 2: first diagnosis of
      pancreatic cancer, treatment excluded; type 3: main treatment; and type 4: follow
      up and disease-related complications. Data were analysed for hospital stay
      related procedures, costs and survival. RESULTS: Pancreatic cancer was diagnosed
      in 253 patients (12.6/100,000 per year), 43 patients (17.7%) underwent surgical
      resection, and 93 (36.8%) palliative surgery. The mean duration of type 3
      hospital stay was similar for resection, palliative and exploratory surgery. The
      estimated hospital cost was significantly higher for surgical resection, almost
      the same for palliative and exploratory surgery, and only slightly lower for
      medical treatment. Each patient spent a mean of 57.7 days in the hospital. The
      hospital mortality rate was 4.6% for surgical resection, 22.1% for palliative
      surgery, and 18.7% for exploratory laparotomy. Overall, the 1-, 2-, 3- and 5-year
      survival rates were 20.9%, 5.1%, 2.9% and 1.2%, respectively. CONCLUSIONS:
      Pancreatic cancer is an expensive, almost incurable disease. Integrated
      treatments in specialized Centres should reduce the mortality rate and costs.

PMID- 12469801
TI  - Multislice spiral computed tomography in diagnosis and staging of pancreatic
      carcinoma: preliminary experience.
AB  - BACKGROUND: Computed tomography has become the modality of choice for
      preoperative evaluation of patients with suspected pancreatic carcinoma, although
      some limitations are well known. AIMS: To evaluate use of multislice spiral
      computed tomography in preoperative assessment of patients with suspected
      pancreatic carcinoma using volume-rendering as image reconstruction algorithm.
      PATIENTS: A total of 27 patients with suspected pancreatic carcinoma underwent
      multislice spiral computed tomography examination. METHODS: All studies were
      performed on a multislice computed tomography scanner with the following
      parameters: slice collimation, 1 mm; slice thickness, 1.25 mm; reconstruction
      interval, 1 mm; scan time, 22-25 sec; mAs, 165. Scans were acquired with a
      biphasic technique with a 30-sec (pancreatic phase) and a 70-sec (portal venous
      phase) delay time after start of contrast material injection. Diagnostic
      confirmation was obtained with surgical exploration, percutaneous biopsy, or with
      a combination of follow-up imaging studies. RESULTS: Multislice spiral computed
      tomography yielded correct diagnosis of pancreatic carcinoma in 20 cases
      (sensitivity, 95%; specificity, 100%). Positive predictive values for
      resectability and unresectability were 80% and 93.3%, respectively. Three
      dimensional volume-rendered images improved diagnostic confidence in the
      depiction of major vascular structures. Two cases of anomalous origin of hepatic
      artery were also identified with volume-rendered images. CONCLUSIONS: Multislice
      technology improves accuracy of spiral computed tomography for diagnosis and
      staging of pancreatic carcinoma.

PMID- 12469802
TI  - Spiral computed tomography assessment of resectability of pancreatic ductal
      adenocarcinoma: analysis of results.
AB  - BACKGROUND: Despite more recent technical advances, single detector spiral
      computed tomography is still the most widely used imaging technique for the
      detection and staging of pancreatic adenocarcinoma. Many reports have recently
      focused on single detector spiral computed tomography imaging findings indicative
      of unresectability AIM: To evaluate the ability of single detector spiral
      computed tomography in the pre-operative staging of ductal adenocarcinoma of the
      pancreas in selecting surgically resectable versus unresectable cases,
      considering different parameters (vascular and local infiltration, liver
      metastases, lymphadenopathy, and peritoneal carcinomatosis). PATIENTS AND
      METHODS: A total of 100 patients diagnosed with ductal adenocarcinoma of the
      pancreas, pathologically verified, and examined with single detector spiral
      computed tomography were considered. Of these, 63 underwent surgery; 37 were
      excluded (imaging evidence of unresectability in biopsy-proven adenocarcinomas).
      Single detector spiral computed tomography studies, performed at the time of
      surgery, were retrospectively reviewed by two radiologists. The final results
      were reached by consensus, without being aware of the operation. All prospective
      clinical readings were also considered, and tabulated. RESULTS: In the patients
      undergoing surgery, 44 proved to be unresectable and 19 resectable. Considering
      the above-mentioned parameters, the prospective assessment of resectability
      demonstrated a rather low sensitivity (68%), with high specificity (95%).
      Accordingly, a high positive predictive value (97%) was achieved, while the
      negative predictive value was 56%. After the retrospective evaluation, the value
      of sensitivity increased (84%) to the expense of the specificity (84%). Moreover,
      a positive predictive value of 92.5%, and a negative predictive value of 69.5%
      were obtained. CONCLUSIONS: The demonstration of many signs of unresectability of
      pancreatic ductal adenocarcinoma reported in the literature yields a better
      sensitivity in the diagnosis, but unfortunately, is associated with an inevitable
      reduction in specificity.

PMID- 12469803
TI  - Hepatocellular carcinoma with an unusual medullary-like histology and signs of
      regression ("medullary-like hepatocellular carcinoma").
AB  - The case of a variant of hepatocellular carcinoma is described, which, based on
      its unique histology, we propose to term, medullary-like hepatocellular
      carcinoma. It developed in a 56-year-old male patient with liver cirrhosis, and
      consisted of large, amphophilic cells with a solid growth pattern. The tumour was
      densely infiltrated with lymphocytes and plasma cells. Lymphocytes formed a
      mixture of B and T cells, and plasma cells were polytypic. In addition, numerous
      S-100 protein-reactive stellate cells were observed at the tumour border, where
      marked apoptosis of hepatocellular carcinoma cells was evident. In areas of dense
      lymphoplasmacytic infiltration, part of the tumour cells had lost their
      intercellular connections and their beta-catenin reactivity. Some tumour cells
      expressed FasL, but not Fas. The tumour exhibited several foci of regression,
      showing small remnants of damaged tumour cells within dense infiltrations. The
      patient is alive without evidence of disease 25 months after resection. Medullary
      like hepatocellular carcinoma is a lesion which mimics several features known for
      other medullary carcinomas, including a marked immune response which may be
      responsible for partial regression of this tumour.

PMID- 12469804
TI  - Fluorescence endoscopy and photodynamic therapy.
AB  - Fluorescence endoscopy is a new technique which allows a better detection of non
      visible malignant or premalignant lesions or, those which are difficult to
      detect. Exogenously applied sensitisers accumulate selectively in malignant
      lesions and induce fluorescence after illumination with light of adequate
      wavelength. However, also endogenous fluorophores, different located in malignant
      or benign lesions, induce a different autofluorescence in these lesions. Tissue
      fluorescence can be detected by optical sampling of the mucosa using fluorescence
      spectroscopy or by generating real time fluorescence images with specialised
      camera systems. Compared to point fluorescence spectroscopy the latter technique
      enables the screening of large surface areas of mucosa. Meanwhile, fluorescence
      endoscopy is a widely used technique in urology employing 5-aminolaevulinic acid
      sensitisation. In gastroenterology, this technique seems promising for the
      detection of early cancers or dysplasia in patients with Barrett's oesophagus or
      ulcerative colitis. Using different sensitisers, photodynamic therapy seems to be
      a promising option for patients with advanced oesophageal cancer and in the
      palliative treatment of non-resectable bile duct cancer, furthermore for patients
      with early gastric cancer and dysplasia in Barrett's oesophagus. Probably, by
      laser light fractionation or a combination of different sensitisers, an enhanced
      effect can be expected.

PMID- 12469805
TI  - Festschrift in honor of Professor Hans-Wolfgang Spiess on the occasion of his
      60th birthday.

PMID- 12469806
TI  - Investigations of low-amplitude radio frequency pulses at and away from rotary
      resonance conditions for I = 5/2 nuclei.
AB  - Additional experimental evidence of rotary resonance effects for multiple-quantum
      coherence conversion in a spin-5/2 system is presented. Two-dimensional plots of
      the relative efficiency of MQ excitation and conversion are given as a function
      of radio frequency (rf) amplitude and pulse width. Data are presented for the
      excitation of five-quantum coherence (5QC), as well as for 5QC to three-quantum
      coherence (3QC) conversion, 5QC to IQC (the central transition coherence)
      conversion, and 3QC to IQC conversion. A two-fold increase in the signal-to-noise
      ratio is achieved by substituting low amplitude rf pulses in place of hard rf
      pulses for 5QC excitation and 5QC to 3QC conversion in a mixed multiple-quantum
      magic angle spinning (MAS) (MMQMAS) experiment. The anisotropic line shape for
      the low-amplitude rf pulse version of the MMQMAS experiment was observed to be
      distorted from the MAS line shape. The cause and implications of the distortion
      are discussed.

PMID- 12469807
TI  - High-sensitivity multinuclear NMR spectroscopy of a smectite clay and of clay
      intercalated polymer.
AB  - The nuclear magnetic resonance (NMR) properties of a smectite clay low in
      paramagnetic ions, and NMR experiments to detect organic material near the
      silicate surfaces with high sensitivity, have been explored by 1H, 29Si, and 13C
      NMR. In oven-dried hectorite clay, 1H NMR reveals a sharp signal at 0.35 ppm that
      narrows significantly with spinning speed. It is assigned to the "inner" OH
      protons of the silicate layers. In fluorohectorite, where the OH groups are
      replaced by fluorines, no such 1H peak is observed. The assignment is further
      confirmed by the efficient cross-polarization observed in two-dimensional (2D) 1H
      29Si HETCOR spectra, and by 29Si-detected REDOR experiments with 1H-dephasing in
      the 29Si dipolar field, which yield a 1H-29Si distance of 2.9 + 0.4 A. In these
      1H-29Si experiments, the sensitivity of the 29Si signal is enhanced at least
      fivefold by refocusing the decay resulting from the inhomogeneous broadening of
      the single 29Si peak, stretching the 29Si signal out over 80 ms. The small 1H
      linewidth of this signal at spinning frequencies exceeding 4 kHz is attributed to
      the large proton-proton distances in the clay. The upfield isotropic chemical
      shift of the OH groups is explained by their inaccessibility to hydrogen-bonding
      partners, as a result of their location in hexagonal "cavities" of the clay
      structure. The well-resolved, easily selectable OH-proton signal and the high
      sensitivity 29Si detection open excellent perspectives for NMR studies of
      composites of clays with organic molecules. Two-dimensional 1H-29Si and 1H-1H
      chemical-shift correlation experiments enable efficient detection of the 1H
      spectrum of organic segments near the clay surface. Combined with 1H spin
      diffusion, the organic segments at up to several nanometers from the clay
      surfaces can be probed. A 2D 1H-13C correlation experiment yields the 13C
      spectrum of the organic species near the clay surfaces. A mobility gradient of
      intercalated poly(ethylene oxide), PEO, segments is proven in 1H-3Si WISE
      experiments with spin diffusion.

PMID- 12469808
TI  - A study of a moleculartweezer host-guest system by a combination of quantum
      chemical calculations and solid-state NMR experiments.
AB  - A study of a host-guest system consisting of a naphthalene-spaced tweezer with a
      1,4 dicyanobenzene guest molecule is presented. The complex is investigated using
      a combination of quantum-chemical calculations and solid-state NMR experiments.
      The advantages of such an approach are illustrated. The focus is on the
      calculation of (1) 1H NMR and (2) 13C NMR chemical shifts for model fragments of
      the solid-state structure, (3) the analysis of host-guest interactions important
      for molecular recognition, and (4) the investigation of the process of a guest
      molecule rotation. For modeling the solid-state structure, up to three host-guest
      units are considered and the convergence with respect to the size of the solid
      state fragment is investigated.

PMID- 12469810
TI  - 19F/29Si rotational-echo double-resonance and heteronuclear spin counting under
      fast magic-angle spinning in fluoride-containing octadecasil.
AB  - 19F/29Si rotational-echo double-resonance (REDOR) and theta-REDOR NMR techniques
      have been applied under fast magic-angle spinning to a powder sample of fluoride
      containing octadecasil. Efficient dipolar recoupling was observed and the effect
      of finite pulse lengths was found to be negligible using standard radiofrequency
      field strengths. Moreover, the determined internuclear distance of the 19F-29Si
      spin pairs formed by the silicons in the D4R units (T-1 site) and the fluoride
      anions is in very good agreement with previous REDOR and Hartmann-Hahn cross
      polarization measurements. Numerical simulation of the REDOR dephasing curves at
      both the T-1 and T-2 sites considering all fluoride anions in the infinite solid
      lattice clearly confirm the X-ray crystal structure of octadecasil. Heteronuclear
      spin-counting theta-REDOR experiments are found to be very useful to obtain
      direct insight into the local network of dipolar interactions. Indeed, while 19F
      29Si pair-like behavior is confirmed at the T-1 site, multiple dipolar
      interactions are clearly evidenced at the T-2 site.

PMID- 12469809
TI  - REDOR-based heteronuclear dipolar correlation experiments in multi-spin systems:
      rotor-encoding, directing, and multiple distance and angle determination.
AB  - We review a variety of recently developed 1H-X heteronuclear recoupling
      techniques, which rely only on the homonuclear decoupling efficiency of very-fast
      magic-angle spinning. All these techniques, which are based on the simple
      rotational-echo, double-resonance (REDOR) approach for heteronuclear recoupling,
      are presented in a common context. Advantages and possibilities with respect to
      the complementary application of conventionally X and 1H-inversely detected
      variants are discussed in relation to the separability and analysis of multiple
      couplings. We present an improved and more sensitive approach to the
      determination of 1H-X dipolar couplings by spinning-sideband analysis, termed
      REREDOR, which is applicable to XHn groups in rigid and mobile systems and bears
      some similarity to more elaborate separated local-field methods. The estimation
      of medium-range 1H-X distances by analyzing signal intensities in two-dimensional
      REDOR correlation spectra in a model-free way is also discussed. More
      specifically, we demonstrate the possibility of combined distance and angle
      determination in H-X-H or X-H-X three-spin systems by asymmetric recoupling
      schemes and spinning-sideband analysis. Finally, an 1H-X correlation experiment
      is introduced which accomplishes high sensitivity by inverse (1H) detection and
      is therefore applicable to samples with 15N in natural abundance.

PMID- 12469811
TI  - Quantification of composition and domain sizes of industrial
      poly(phthalamide)/poly(dimethylsiloxane) block copolymers using different 1H
      solid state NMR methods.
AB  - We have applied several 1H solid state NMR techniques to obtain structural
      information on industrial silicone copolymers as thermoplastic elastomers that
      proved difficult to be analysed by conventional techniques. Static measurements
      were applied to achieve the separation between mobile and rigid parts. To get
      structural information fast magic angle spinning at 25 kHz in combination with a
      high field of 700 MHz was used. 1H spin diffusion was applied to determine the
      domain sizes of the micro phase-separated polymer components.

PMID- 12469812
TI  - Partitioning of main and side-chain units between different phases: a solid-state
      13C NMR inversion-recovery cross-polarization study on a homogeneous, metallocene
      based, ethylene-1-octene copolymer.
AB  - 13C NMR inversion-recovery cross-polarization experiments are used to study the
      phase structure and partitioning of main and side-chain groups in a homogeneous,
      metallocene-based, ethylene-1-octene copolymer. The results provide strong
      evidence for a three-phase model, i.e. a rigid, (imperfect) crystalline phase,
      which is mainly composed of long sequences of methylene carbon atoms of the main
      chain, a semi-rigid, amorphous interphase (also denoted as 'rigid amorphous'),
      which is enriched by chain segments bearing methylene and methine carbon atoms of
      the main chain, and a soft fraction of the amorphous phase (also denoted as
      'mobile amorphous'), which is largely composed of side chains and short methylene
      sequences of the main chain.

PMID- 12469813
TI  - Structure and ionic interactions of organic-inorganic composite polymer
      electrolytes studied by solid-state NMR and Raman spectroscopy.
AB  - Solid-state NMR studies of composite polymer electrolytes are reported. The
      materials consist of polyethylene oxide and an organic inorganic composite,
      together with a lithium salt, and are candidates for electrolytes in solid-state
      lithium ion batteries. Silicon and aluminum MAS and multiple quantum MAS are used
      to characterize the network character of the organic-inorganic composite, and
      spin diffusion measurements are used to determine the nanostructure of the
      polymer/composite blending. Multiple quantum spin counting is used to measure the
      ion aggregation. The NMR results are supported by Raman spectra, calorimetry, and
      impedance spectroscopy. From these experiments it is concluded that the composite
      suppresses polymer crystallization without suppressing its local mobility, and
      also suppresses the tendency for the ions to aggregate. This polymer composite
      thus appears very promising for application in lithium ion batteries.

PMID- 12469814
TI  - Solid-state NMR spectroscopy under periodic modulation by fast magic-angle sample
      spinning and pulses: a review.
AB  - Fast magic-angle spinning (MAS) holds promise for new approaches to pulsed high
      resolution NMR in solids where homogeneous interactions dominate. Prerequisite
      for developing new pulse methods is the understanding of signal encoding by spin
      interactions under MAS conditions and of interferences between MAS and pulses.
      This review discusses corresponding strategies and techniques in a coherent way
      with particular concentration on homonuclear decoupling techniques for line
      narrowing in solids.

PMID- 12469815
TI  - Determination of molecular orientational order in cold-stretched poly(p-phenylene
      vinylene) thin films by DECODER 13C NMR.
AB  - The properties of poly(p-phenylene vinylene) (PPV) films depend on the degree of
      orientational order present in the films. Recently, Dermaut et al. reported a
      novel cold-stretching technique (Macromolecules 33, 5634-5637 (2000)) in which
      chain alignment can be introduced into PPV precursor films by uniaxially
      stretching them prior to the thermal elimination reaction that forms PPV. The two
      dimensional direction exchange with correlation for orientation-distribution
      evaluation and reconstruction (DECODER) 13C NMR technique was applied to both
      unstretched PPV films and PPV films that were uniaxially cold stretched to a draw
      ratio lambda = l/l0 = 5. The unstretched films were found to be moderately
      ordered, comprised of a component present at 80% with a Gaussian distribution of
      60 degrees fwhm, while the remaining 20% is isotropically distributed. A
      distribution of 9 degrees +/- 3 degrees fwhm was measured by NMR in good
      agreement with IR dichroism measurements for the uniaxially cold-stretched films,
      establishing that a high degree of orientational order can be introduced by cold
      stretching PPV films.

PMID- 12469816
TI  - Measurement of orientation distributions using chemical shift amplification.
AB  - A new three-dimensional magic angle spinning (MAS) experiment is proposed, based
      on a combination of the two-dimensional rotor-synchronized MAS experiment of
      Spiess and co-workers and a new chemical shift anisotropy amplification method.
      The new experiment is demonstrated on a macroscopically ordered sample of ultra
      high molecular weight poly(ethylene).

PMID- 12469817
TI  - In situ deuteron NMR investigations of sheared liquid crystalline polymers.
AB  - The flow behavior of nematic liquid crystalline polysiloxanes of the side-chain
      type is studied by in situ 2H NMR spectroscopy on samples under shear in a cone
      and-plate cell. The director orientation as a function of applied shear rate is
      determined from the quadrupole splitting of the spectra. The data analysis yields
      the two Leslie viscosity coefficients alpha2 and alpha3 and the flow-alignment
      parameter lambda = -(alpha3 + alpha2)/(alpha3 - alpha2). The values of lambda
      were determined for several homopolymers with only one type of side chain and
      random copolymers containing two different side chains. The results show that the
      flow behavior is related to the phase structure of the polymers, which varies
      with their composition. Only polymers with large amounts of smectic clusters in
      the nematic state show the tumbling instability (absolute value(lambda) < 1);
      other polymers are flow aligning (absolute value(lambda) > or = 1). For some
      polymers, a transition from tumbling at low temperature to flow aligning at high
      temperatures was observed.

PMID- 12469818
TI  - Segmental anisotropy in strained elastomers detected with a portable NMR scanner.
AB  - Single-side NMR is particularly suitable for measurements of segmental anisotropy
      induced in elastomers by uniaxial forces or local strain. Proton transverse
      nuclear magnetic relaxation was investigated with the NMR-MOUSE by recording the
      Hahn-echo decay in cross-linked natural rubber bands. This provided information
      on the dependence of the Hahn-echo decay on the angle between the direction of
      the uniaxial stretching force and the axis Z defined direction perpendicular to
      the magnet pole faces of the NMR-scanner. The anisotropy effect on the Hahn-echo
      decay is correlated with the extension ratio, and it is more evident in the
      liquid-like regime of the decay. A weaker segmental anisotropy is detected by 1H
      solid- and Hahn-echo decays recorded by multi-pulse sequences. A qualitative
      understanding of the angular dependence is obtained by an analytical theory of
      the Hahn-echo decay adapted to the case of stretched elastomers and to strongly
      inhomogeneous magnetic fields. Using angular-dependent 1H residual second van
      Vleck moments and correlation times reported previously [P.T. Callaghan and E.T.
      Samulski, Macromolecules 30, 113 (1997)] from stretched natural rubber bands the
      segmental anisotropy measured in inhomogeneous magnetic fields by the Hahn-echo
      decay was numerically simulated. As an example of a macroscopic distribution of
      local segmental anisotropy, 1H Hahn-echo decays were measured by the NMR-MOUSE
      sensor in a stretched cross-linked natural rubber plate with a circular cut in
      the center.

PMID- 12469819
TI  - Two-dimensional 109Ag NMR and random-walk simulation studies of silver dynamics
      in glassy silver ion conductors.
AB  - By applying one- and two-dimensional 109Ag NMR, we demonstrate that silver
      diffusion in silver iodide/silver phosphate glasses is governed by a very broad,
      continuous distribution of correlation times G(lg tau). As a consequence, over a
      wide temperature range, the 109Ag NMR spectra can be described by a weighted
      superposition of a Gaussian and a Lorentzian where these line-shape components
      result from the slow and the fast silver ions in G(lg tau), respectively. For the
      109Ag NMR two-time correlation functions F2(t), measured as a stimulated echo, a
      very stretched decay to F2SS(t(m)) = 0 is observed. When fitting to a Kohlrausch
      function, exp[-(t/tau)beta], a stretching parameter beta approximately = 0.2 is
      found. The temperature dependence of the mean correlation time of silver dynamics
      is described by an Arrhenius law where the activation energy is consistent with
      the one reported for the dc conductivity sigma(dc). In addition, it is shown that
      the effect of complex dynamical processes on NMR multi-time correlation functions
      can easily be calculated when performing random-walk simulations for schematic
      models such as the random-barrier model and the random-energy model. Based on
      these models it is possible to simulate various NMR observables and the mean
      square displacement, thus revealing the information content of multi-dimensional
      NMR experiments on solid ion conductors.

PMID- 12469820
TI  - Deuterium NMR and ab initio studies of strongly hydrogen-bonded molecules.
AB  - Two newly synthesized alkylated cyanomalonaldehyde derivatives possess very short
      intramolecular hydrogen bonds, which are studied by deuterium NMR. Both the
      dimethyl and di-tert-butyl derivatives have small deuterium quadrupole coupling
      constants and large asymmetry parameters. In addition, the di-tert-butyl
      compound, which has one of the shortest O D...O hydrogen bonds yet measured, has
      a quadrupole coupling which anomalously increases with temperature. The
      significance of these phenomena is explored using a theoretical model which
      employs vibrationally averaged ab initio electric field gradient tensors
      calculated with large basis sets and electron correlation via the
      multiconfigurational self-consistent field method.

PMID- 12469821
TI  - Deuteron NMR study of the diverse mobility of the ammonium ions in the ordered
      phase of (ND4)2PtCl4.
AB  - A detailed description of the diverse mobility of the ND4+ ions in the low
      temperature ordered phase of (ND4)2PtCl4 is developed on the basis of single
      crystal deuteron NMR spectra and site-selective T1 measurements. The ordered
      phase of (ND4)2PtCl4 consists of two kinds of domains in which the orientation of
      the ND4+ tetrahedra differs by a 90 degrees rotation about an axis which
      otherwise is a two-fold symmetry axis of the tetrahedra. Inside the domains, the
      ND4+ ions do not reorient at low temperatures. The domains are separated by
      domain walls which contain, according to the deuteron NMR spectra, about 10% of
      all ND4+ ions. These ions are highly mobile even at 10 K. On rising the
      temperature, the thickness of the domain walls increases, that is, the ions in
      more and more layers become mobile. Moreover, we provide evidence for
      fluctuations of the locations of the domain walls. The central resonance of the
      domain-wall ions shows a complicated structure below 36 K. On the basis of a
      tunnelling hypothesis we make an attempt to account for this structure. There are
      indications that the tunnelling process is incoherent.

PMID- 12469822
TI  - NMR studies of restricted diffusion in lyotropic systems.
AB  - Tortuosity, 1/alpha, and surface-to-volume ratio, S/V, were determined in aqueous
      solutions of decylammonium, dodecylammonium and tetradecylammonium chlorides of
      various concentrations by measuring the apparent diffusion coefficient of water,
      D(app)(delta). This was found to be much smaller than in the bulk state. Such
      restricted diffusion is interpreted in terms of the Mitra model, where D(delta)
      depends on diffusion time and is controlled primarily by S/V. The samples exhibit
      lamellar (L), hexagonal (H) and isotropic (I) liquid crystalline phases. We
      observed changes in S/V upon phase transition. In the lamellar and hexagonal
      phases, the system is ordered, resulting in relatively small S/V ratios, compared
      to the micellar-isotropic phase. We did not observe a dependence on the diffusion
      time, delta, in the isotropic phase, because the duration of the experiment was
      not sufficiently short to observe the change from D(app)(delta) to D(eff). We
      observed the effective diffusion coefficient of water, which directly probes the
      tortuosity of the system. The S/V ratios were obtained by fitting the Mitra
      model, using known values of the bulk water diffusion coefficients, and the
      assumption that D(app) --> D0 for delta --> 0. S/V is correlated with the type of
      structure, increasing on transition to the isotropic phase and decreasing on
      transition to other phases. The change in tortuosity is small, but slightly
      larger for the isotropic phase.

PMID- 12469823
TI  - Sorption isotherm measurements by NMR.
AB  - An experimental setup is described for the automated recording of sorption
      isotherms by NMR experiments at precisely defined levels of relative humidity
      (RH). Implementation is demonstrated for a cotton fabric; Bloch decays. T1 and
      T2* relaxation times were measured at predefined steps of increasing and
      decreasing relative humidities (RHs) so that a complete isotherm of NMR
      properties was obtained. Bloch decays were analyzed by fitting to relaxation
      functions consisting or a slow- and a fast-relaxing component. The fraction of
      slow-relaxing component was greater than the fraction of sorbed moisture
      determined from gravimetric sorption data. The excess slow-relaxing component was
      attributed to plasticized segments of the formerly rigid cellulose matrix. T1 and
      T2* sorption isotherms exhibit hysteresis similar to gravimetric sorption
      isotherms. However, correlating RH to moisture content (MC) reveals that both
      relaxation constants depend only on MC, and not on the history of moisture
      exposure.

PMID- 12469824
TI  - Soil quality in New Zealand: policy and the science response.
AB  - Soil depletion and degradation have been increasingly recognized as important
      environmental issues in many parts of the world. Over the last decade a number of
      political and legislative measures have been introduced to encourage and enforce
      sustainable soil management in New Zealand. Application of the new legislation
      has highlighted gaps in our knowledge of soil quality and a lack of scientific
      methods to assess and monitor soil quality. This paper describes the legislative
      measures and outlines the sdentific response to the needs of regulatory agencies
      responsible for maintaining environmental quality. The research recommended a set
      of indicators to assess soil quality. Each soil quality attribute has an
      associated "target range" defining the acceptable value for the attribute. The
      paper also discusses the communication of results to end-users, including the
      development of a computerized assessment tool. The legislative measures and
      scientific response have fostered a closer relationship between the policy and
      science communities, leading to more well-focused research, but greater
      collaboration is still required.

PMID- 12469825
TI  - Design and performance of a dynaniic gas flux chamber.
AB  - Chambers are commonly used to measure the emission of many trace gases and
      chemicals from soil. An aerodynamic (flow through) chamber was designed and
      fabricated to accurately measure the surface flux of trace gases. Flow through
      the chamber was controlled with a small vacuum at the outlet. Due to the design
      using fans, a partition plate, and aerodynamic ends, air is forced to sweep
      parallel and uniform over the entire soil surface. A fraction of the air flowing
      inside the chamber is sampled in the outlet. The air velocity inside the chamber
      is controlled by fan speed and outlet suction flow rate. The chamber design
      resulted in a uniform distribution of air velocity at the soil surface. Steady
      state flux was attained within 5 min when the outlet air suction rate was 20
      L/min or higher. For expected flux rates, the presence of the chamber did not
      affect the measured fluxes at outlet suction rates of around 20 L/min, except
      that the chamber caused some cooling of the surface in field experiments.
      Sensitive measurements of the pressure deficit across the soil layer in
      conjunction with measured fluxes in the source box and chamber outlet show that
      the outflow rate must be controlled carefully to minimize errors in the flux
      measurements. Both over- and underestimation of the fluxes are possible if the
      outlet flow rate is not controlled carefully. For this design, the chamber
      accurately measured steady flux at outlet air suction rates of approximately 20
      L/min when the pressure deficit within the chamber with respect to the ambient
      atmosphere ranged between 0.46 and 0.79 Pa.

PMID- 12469826
TI  - Hydrogen sulfide effects on ammonia removal by a biofilter seeded with earthworm
      casts.
AB  - Ammonia (NH3) removal efficencies were evaluated when hydrogen sulfide (H2S) and
      NH3 in binary mixture gases were supplied to a ceramic biofilter seeded with
      earthworm (Lumbricus terrestris) casts. The effect of inlet H2S concentration and
      space velocity (SV) on the removal of NH3 was investigated after the acclimation
      of the biofilter with NH3 gas. When NH3 was singly supplied to the biofilter, NH3
      removal was maintained at almost 100% until inlet NH3 concentration was increased
      up to 600 microL L(-1) and SV up to 330 h(-1), at which the elimination capacity
      of NH3 was 148 g N m(-3) h(-1). When H2S was supplied simultaneously, however,
      the accumulation of toxic sulfide ions showed dual effects on NH3 removal
      efficiencies. First, no effects were observed at inlet H2S loading below 60 g S
      m(-3) h(-1); however, inhibition by H2S at higher loading was observed above 60 g
      S m(-3) h(-1). The point at which loading achieved a maximum of more than 99% NH3
      removal efficiency was 139 g N m(-3) h(-1), when inlet H2S concentration was held
      under 100 microL L(-1), but it dropped to 76 and 30 g N m(-3) h(-1) when the
      inlet H2S concentration increased to 220 and 460 microL L(-1), respectively. The
      critical points of inlet H2S loading that guaranteed over 99% NH3 removal were
      determined as 100, 100, 60, and 40 g S m(-3) h(-1) at inlet NH3 concentrations of
      100, 200, 400, and 600 microL L(-1), respectively. Inlet NH3 loading had synergic
      effects of increasing the inhibition of inlet H2S loading on the NH3 removability
      of the biofilter.

PMID- 12469827
TI  - Application technique and slurry co-fermentation effects on ammonia, nitrous
      oxide, and methane emissions after spreading: I. Ammonia volatilization.
AB  - Ammonia emissions after spreading animal manure contribute a major share to N
      losses from agriculture. There is an increasing interest in anaerobic co
      digestion of liquid manure with organic additives. This fermentation results in a
      change of physical and chemical parameters of the slurry. Among these are an
      increased pH and ammonium content, implying a higher risk of NH3 losses from
      fermentation products. To compare different application techniques and the effect
      of fermentation on NH3 volatilization, we used the standard comparison method and
      tested it for reliability. This method seems to be perfectly suited for
      experiments with a large number of treatments and replicates if prerequisites
      concerning the experimental layout are considered. We tested four different
      application techniques on arable and grassland sites. The more the substrate was
      incorporated into the soil or applied near the soil surface on the grassland
      site, the less NH3 was lost. Injection of the substrate reduced losses to less
      than 10% of applied NH4+ on both sites, whereas losses after splash plate
      application amounted to more than 30%. Trail shoe application on grassland
      performed as well as injection. Harrowing on arable land also reduced emissions
      efficiently, if harrowing occurred within the first 2 h after application.
      Emissions from trail hose-applied co-fermentation product were not greater than
      from unfermented slurry. Better infiltration of the less viscous substrate seemed
      to have compensated for the increased loss potential.

PMID- 12469828
TI  - Application technique and slurry co-fermentation effects on ammonia, nitrous
      oxide, and methane emissions after spreading: II. Greenhouse gas emissions.
AB  - The aim of this study was to investigate the effect of different application
      techniques on greenhouse gas emission from co-fermented slurry. Ammonia (NH3),
      nitrous oxide (N2O), and methane (CH4) emissions were measured in two field
      experiments with four different application techniques on arable and grassland
      sites. To gather information about fermentation effects, unfermented slurry was
      also tested, but with trail hose application only. Co-fermented slurry was
      applied in April at a rate of 30 m3 ha(-1). Measurements were made every 4 h on
      the first day after application and were continued for 6 wk with gradually
      decreasing sampling frequency. Methane emissions were <150 g C ha(-1) from co
      fermentation products and seemed to result from dissolved CH4. Only in the
      grassland experiment were emissions from unfermented slurry significantly higher,
      with wetter weather conditions probably promoting CH4 production. Nitrous oxide
      emission was significantly increased by injection on arable and grassland sites
      two- and threefold, respectively. Ammonia emissions were smallest after injection
      or trail shoe application and are discussed in the preceding paper. We evaluated
      the climatic relevance of the measured gas emissions from the different
      application techniques based on the comparison of CO2 equivalents. It was evident
      that NH3 emission reduction, which can be achieved by injection, is at least
      compensated by increased N2O emissions. Our results indicate that on arable land,
      trail hose application with immediate shallow incorporation, and on grassland,
      trail shoe application, bear the smallest risks of high greenhouse gas emissions
      when fertilizing with co-fermented slurry.

PMID- 12469829
TI  - Irrigation of broccoli and canola with boron- and selenium-laden effluent.
AB  - Selenium (Se), boron (B), and salinity contamination of agricultural drainage
      water is potentially hazardous for water reuse strategies in central California.
      To demonstrate the feasibility of using plants to extract Se from drainage water,
      Se accumulation was determined in canola (Brassica napus L.) and broccoli
      (Brassica oleracea L.) irrigated with drainage effluent in the San Joaquin
      Valley, California. In the 2-yr field study, both crops were irrigated with a
      typical drainage water containing Se (150 microg L(-1)), B (5 mg L(-1)), and a
      sulfate dominated salinity (EC of 7 dS m(-1)). Total dry matter yields were at
      least 11 Mg ha(-1) for both canola and broccoli, and plant tissue Se
      concentrations did not exceed 7 mg kg(-1) DM for either crop. Based on the amount
      of soluble Se applied to crops with drainage water and the estimated amount of
      soluble Se remaining in soil to a depth of 90 cm at harvest, both canola and
      broccoli accumulated at least 40% of the estimated soluble Se lost from the soil
      for both years. Applied Se not accounted for in plant tissue or as soluble Se in
      the soil was presumably lost by biological volatilization. This study suggests
      that irrigating two high value crops such as canola and broccoli with Se-laden
      effluent helps manage Se-laden effluent requiring treatment, and also produces
      economically viable Se-enriched crops. Future research should focus on managing
      residual salt and B in the soil for sustaining long time water reuse strategies.

PMID- 12469830
TI  - Transport and degradation of toluene and o-xylene in an unsaturated soil with
      dipping sedimentary layers.
AB  - A lysimeter trench was established at the Gardermoen delta (50 km north of Oslo,
      Norway) to study the flow of water and transport and degradation of aromatic jet
      fuel components (toluene and o-xylene) in the undisturbed unsaturated zone. Site
      investigations with ground-penetrating radar revealed the presence of dipping
      sedimentary layers within the foreset unit. This study has shown that the foreset
      bed of the Gardermoen delta structure provided a preferential flow path for the
      transport of the solute plumes, but did not have dramatic effects on the
      degradation potential under the current conditions. The degradation potential for
      toluene and o-xylene in the unsaturated zone at Gardermoen was very high and
      almost all of the injected hydrocarbons were biodegraded before reaching the
      saturated zone. However, the horizontal displacement of the plume showed that
      knowledge about sedimentary structures in the unsaturated zone is important for a
      sufficient monitoring of contaminant transport and for remediation purposes.
      Carbon dioxide and O2 were measured in situ simultaneously with extraction of
      water samples, and indicated aerobic biodegradation of toluene and o-xylene.
      Overall, first-order degradation coefficients were calculated to be in the range
      of 0.19 to 0.21 d(-1) and 0.10 to 0.11 d(-1) for toluene and o-xylene,
      respectively.

PMID- 12469831
TI  - Biodegradation during contaminant transport in porous media: V. The influence of
      growth and cell elution on microbial distribution.
AB  - This study investigated the interaction between microbial growth and cell
      elution, and their influence on resultant microbial distribution between the
      aqueous and solid phases during solute transport in a sandy, low-organic-carbon
      content porous medium. Miscible displacement experiments were conducted with
      salicylate as the model compound, and with different initial conditions (e.g.,
      substrate concentrations and cell densities) to attain various degrees of
      microbial growth. For each experiment, salicylate and dissolved oxygen
      concentrations as well as cell densities were monitored in the column effluent.
      Cell densities were also measured in the porous medium at the beginning and end
      of each experiment. Total microbial growth was determined in two ways, one based
      on a cell mass balance for the system and the other based on total amount of
      salicylate degraded. For conditions yielding a considerable amount of microbial
      growth, the majority of the biomass was associated with the aqueous phase (68
      90%). Conversely, under minimal-growth conditions, most cells (approximately 60
      70%) were attached to particle surfaces. Significant cell elution was observed
      for most conditions, the rate of which increased in the presence of the
      substrate. The results suggest that the increase in aqueous-phase cells observed
      for the experiments exhibiting the greatest growth is associated with the
      production of new cells, and that under appropriate conditions aqueous-phase
      biomass can contribute significantly to contaminant biodegradation.

PMID- 12469832
TI  - Low-temperature chromium(VI) biotransformation in soil with varying electron
      acceptors.
AB  - Effective and low-cost strategies for remediating chromium (Cr)-contaminated soil
      are needed. Chromium(VI) leaching from contaminated soil into ground water and
      surface water threatens water supplies and the environment. This study tested
      indigenous Cr(VI) microbial transformation in batch systems at 10 degrees C in
      the presence of various electron acceptors. The effects of carbon addition,
      spiked Cr(VI), and mixing highly contaminated soil with less contaminated soil
      were investigated. The results indicated that Cr(VI) can be biotransformed in the
      presence of different electron acceptors including oxygen, nitrate, sulfate, and
      iron. Sugar addition had the greatest effect on enhancing Cr(VI) removal. Less
      dissolved organic carbon (DOC) was consumed per amount of Cr(VI) transformed
      under anaerobic conditions [0.8-93 mg DOC/mg Cr(VI)] compared with aerobic
      conditions [1.4-265 mg DOC/mg Cr(VI)]. Toxicity of high concentrations (< 160
      mg/L) of spiked Cr(VI) were not evident. At Cr(VI) concentrations > 40 mg/L,
      aerobic conditions promoted faster Cr(VI) reduction than anaerobic conditions
      with nitrate or sulfate present. Biotransformation of Cr(VI) in highly
      contaminated soil (22,000 mg Cr/kg) was facilitated by mixing with less
      contaminated soil. The study results provide a framework for evaluating
      indigenous Cr(VI) microbial transformation and enhance the ability to develop
      strategies for soil treatment.

PMID- 12469833
TI  - Polycyclic aromatic hydrocarbon removal from soil by surfactant solubilization
      and Phanerochaete chrysosporium oxidation.
AB  - Surfactant soil washing can remove polycyclic aromatic hydrocarbons (PAHs) from
      contaminated soil, and the white rot fungus, Phanerochaete chrysosporium Burdsall
      in Burdsall & Eslyn, can oxidize PAHs. The objective of this study was to develop
      a novel bioremediation technology using a combination of abiological surfactant
      soil washing followed by PAH biological oxidation in soil washwater using P.
      chrysosporium in a rotating biological contactor (RBC) reactor. Soil used for
      experimentation was an 11-month aged contaminated soil spiked with a total of
      nine PAHs: acenaphthene, fluorene, phenanthrene, fluoranthene, pyrene, chrysene,
      benzo(a)pyrene, dibenz(a-h)anthracene, and benzo(ghi)perylene. After 11 months of
      aging, recovery percentages of high molecular weight PAHs [i.e., from chrysene to
      benzo(ghi)perylene] were greater than 86%, while those of low molecular weight
      PAHs (i.e., from acenaphthene to pyrene) were less than 19%. Total removal
      efficiency for any of the nine PAHs was greater than 90% using a combination of
      surfactant soil washing and P. chrysosporium oxidation of soil washwater in the
      RBC reactor when used in batch operation, and greater than 76% when used in
      continuous operation. The treatment of PAH-contaminated soil using a combination
      of surfactant soil washing and subsequent PAH removal from the resultant
      washwater in an RBC reactor, in the presence of immobilized P. chrysosporium,
      permits (i) a rapid abiological cleanup of soil for compliance with relevant soil
      quality standards and (ii) PAH biological removal in soil washwater for
      compliance with aqueous discharge standards.

PMID- 12469834
TI  - Soil quality at a national scale in New Zealand.
AB  - New Zealand is a signatory to international conventions on environmental
      performance, and soil quality information is needed for reporting both at a
      national and regional level. Soil quality was measured at 222 sites in five
      regions of New Zealand (12 soil orders and 9 land-use categories). Topsoil (0-100
      mm) properties measured were total carbon and nitrogen, potentially mineralizable
      N, pH, Olsen P, cation exchange capacity, bulk density, total porosity,
      macroporosity, and total available and readily available water. Our objectives
      were to gauge the representativeness of the sample, determine the contribution
      from land use or soil order to variability, rationalize the data set, and
      identify concerns for long-term sustainable land use. Soil and land use
      combinations were both under- or overrepresented in the data set compared with
      national distribution. Soil order and land-use categories explained 55 to 76% of
      the variance in soil properties. Total C contents of pastures were comparable
      with indigenous forest soils, but pastures were less acidic and with higher N and
      P contents. Plantation forests had characteristics similar to indigenous forests
      on comparable soils. Cropland soils comprised <1% of the national land cover and
      generally had high inorganic fertility and low organic matter, with evidence of
      compaction. Seven characteristics (total C, total N, mineralizable N, pH, Olsen
      P, bulk density, and macroporosity) explained 87% of the total variability. The
      findings are being used by monitoring agencies to raise awareness about soil
      quality in the wider community, set land management guidelines, and develop
      policies.

PMID- 12469835
TI  - Environmental and agronomic implications of water table and nitrogen
      fertilization management.
AB  - Nitrate (NO3-) pollution of surface and subsurface waters has become a major
      problem in agricultural ecosystems. Field trials were conducted from 1996 to 1998
      at St-Emmanuel, Quebec, Canada, to investigate the combined effects of water
      table management (WTM) and nitrogen (N) fertilization on soil NO3- level,
      denitrification rate, and corn (Zea mays L.) grain yield. Treatments consisted of
      a combination of two water table treatments: free drainage (FD) with open drains
      at a 1.0-m depth from the soil surface and subirrigation (SI) with a design water
      table of 0.6 m below the soil surface, and two N fertilizer (ammonium nitrate)
      rates: 120 kg N ha(-1) (N120) and 200 kg N ha(-1) (N200). Compared with FD, SI
      reduced NO3(-)-N concentrations in the soil profile by 37% in spring 1997 and 2%
      in spring 1998; and by 45% in fall 1997 and 19% in fall 1998 (1 mg NO3(-)-N L(-1)
      equals approximately 4.43 mg NO3- L(-1)). The higher rate of N fertilization
      resulted in greater levels of NO3(-)-N in the soil solution. Denitrification
      rates were higher in SI than in FD plots, but were unaffected by N rate. The N200
      rate produced higher yields than N120 in 1996 and 1997, but not 1998. Corn yields
      in SI plots were 7% higher than FD plots in 1996 and 3% higher in 1997, but 25%
      lower in 1998 because the SI system was unable to drain the unusually heavy June
      rains, resulting in waterlogging. These findings suggest that SI can be used as
      an economical means of reducing NO3- pollution without compromising crop yields
      during normal growing seasons.

PMID- 12469836
TI  - Leaching of nitrogen and phosphorus during production of forest seedlings in
      containers.
AB  - Little information is available concerning the contamination risk caused by
      forest seedling nurseries to local surface and ground waters compared with
      agricultural and horticultural production. Leaching of nitrogen (N) and
      phosphorus (P) through peat growing medium in containers and nutrient uptake of
      seedlings were monitored in production of silver birch (Betula pendula Roth),
      Norway spruce [Picea abies (L.) Karst], and Scots pine (Pinus sylvestris L.)
      seedlings. About half of the applied nutrients (total amount applied = 149 to 260
      kg N ha(-1) and 60 to 108 kg P ha(-1)) was premixed into the peat medium, as is
      usual in Finnish nursery practice, and the other half was applied to seedlings in
      liquid form with mobile booms. Depending on tree species, 11 to 19% of the
      applied N was recovered in leachates and 15 to 63% in seedlings. The undiscovered
      proportion varied from 19 to 71%. The amounts of leached N were 19 to 41 kg ha(
      1). Only 5 to 31% of the applied P was recovered in seedlings; 16 to 64% (11 to
      56 kg ha(-1)) was found in leachates. Total N and P load to the environment may
      increase substantially if nutrients applied in liquid fertilization outside
      container trays are included. Consequently, it is important to determine the
      sources of nutrient load in container seedling production to mitigate the risk of
      environment contamination.

PMID- 12469837
TI  - Mapping the probability of exceeding critical thresholds for cadmium
      concentrations in soils in The Netherlands.
AB  - The probability of exceeding critical thresholds of Cd concentrations in the soil
      was mapped at a national scale. The critical thresholds in soil were based on
      food quality criteria for Cd in crops or in organs of cattle (Bos taurus), and
      were calculated by inverting a regression model for the Cd concentration in the
      crop, with the Cd concentration in soil, soil organic matter (SOM) content, clay
      content, and pH as predictors. The probability of exceeding the critical
      threshold for Cd in soil per node of a 500- x 500-m grid was approximated by
      Monte Carlo simulation, using the estimated cumulative distribution functions
      (cdf) of SOM, clay, pH, and Cd as input. The cdfs were estimated by simple
      indicator kriging with local prior means. For SOM, clay, and pH, detailed maps of
      soil type and land use were used to define subregions with assumed constant local
      means of the indicators (a priori distributions). The cdfs were sampled by Latin
      hypercube sampling. We accounted for correlation between the actual and critical
      Cd concentrations in soil by drawing Cd values from cdfs conditional on SOM and
      clay. The estimated probability for grassland is negligible, even in areas with
      high Cd concentrations in soil, and for maize (Zea mays L.) land the probability
      is almost everywhere smaller than 5%. For arable soils, however, these
      probabilities commonly are larger than 5% when sugar beet (Beta vulgaris L.) or
      wheat (Triticum aestivum L.) is taken as a reference crop, and locally exceed
      50%.

PMID- 12469838
TI  - Cadmium binding by fractions of dissolved organic matter and humic substances
      from municipal solid waste compost.
AB  - The agricultural practice of amending soils with composted municipal solid waste
      (MSW) adds significant amounts of organic matter and trace metals, including Cd.
      Under these conditions, soluble organic complexes of Cd formed in the compost may
      be more significant than previously thought, due to Cd bioavailability and
      mobility in the soil environment. To study the relative importance of different
      types of organic ligands in MSW compost for the binding of Cd, six fractions of
      the dissolved organic matter (DOM) in addition to humic acid (HA) and fulvic acid
      (FA) were extracted and their complexation of Cd quantified at pH 7 using an ion
      selective electrode (ISE). The highest complexing capacities (CC) for Cd were
      found for the most humified ligands: HA (2386 micromol Cd g(-1) C of ligand),
      predialyzed FA (2468 micromol Cd g(-1) C), and HoA, a fulvic-type, easily soluble
      fraction (1042 micromol Cd g(-1) C). The differences in CC for Cd of the various
      organic ligands were not directly related to total acid-titratable or carboxylic
      groups, indicating the importance of sterical issues and other functional groups.
      The strength of association between Cd and the organic ligands was characterized
      by calculating stability constants for binding at the strongest sites (pK(int))
      and modeling the distribution of binding site strengths. The pK(int) values of
      the DOM fractions ranged between 6.93 (HiN: polysaccharides) and 8.11 (HiB:
      proteins and aminosugars), compared with 10.05 for HA and 7.98 for FA. Hence, the
      highly complex and only partially soluble organic molecules from compost such as
      HA and FA demonstrated the highest capacity to sequester Cd. However, strong Cd
      binding of organic ligands containing N-functional groups (HiB) in addition to a
      high CC of soluble, humified ligands like HoA indicated the relevance of these
      fractions for the organic complexation of Cd in solution.

PMID- 12469839
TI  - Lead phytoextraction from contaminated soil with high-biomass plant species.
AB  - In this study, cabbage [Brassica rapa L. subsp. chinensis (L.) Hanelt cv. Xinza
      No 1], mung bean [Vigna radiata (L.) R. Wilczek var. radiata cv. VC-3762], and
      wheat (Triticum aestivum L. cv. Altas 66) were grown in Pb-contaminated soils.
      Application of ethylenediaminetetraacetic acid (EDTA) (3.0 mmol of EDTA/kg soil)
      to the soil significantly increased the concentrations of Pb in the shoots and
      roots of all the plants. Lead concentrations in the cabbage shoots reached 5010
      and 4620 mg/kg dry matter on Days 7 and 14 after EDTA application, respectively.
      EDTA was the best in solubilizing soil-bound Pb and enhancing Pb accumulation in
      the cabbage shoots among various chelates (EDTA, diethylenetriaminepentaacetic
      acid [DTPA], hydroxyethylenediaminetriacetic acid [HEDTA], nitrilotriacetic acid
      [NTA], and citric acid). Results of the sequential chemical extraction of soil
      samples showed that the Pb concentrations in the carbonate-specifically adsorbed
      and Fe-Mn oxide phases were significantly decreased after EDTA treatment. The
      results indicated that EDTA solubilized Pb mainly from these two phases in the
      soil. The relative efficiency of EDTA enhancing Pb accumulation in shoots
      (defined as the ratio of shoot Pb concentration to EDTA concentration applied)
      was highest when 1.5 or 3.0 mmol EDTA/kg soil was used. Application of EDTA in
      three separate doses was most effective in enhancing the accumulation of Pb in
      cabbage shoots and decreased mobility of Pb in soil compared with one- and two
      dose application methods. This approach could help to minimize the amount of
      chelate applied in the field and to reduce the potential risk of soluble Pb
      movement into ground water.

PMID- 12469840
TI  - pH-dependent release of cadmium, copper, and lead from natural and sludge-amended
      soils.
AB  - The pH-dependent release of cadmium, copper, and lead from soil materials was
      studied by use of a stirred flow cell to quantify their release and release
      rates, and to evaluate the method as a test for the bonding strength and
      potential mobility of heavy metals in soils. Soil materials from sludge-amended
      and nonamended A horizons from a Thai coarse-textured Kandiustult and a Danish
      loamy Hapludalf were characterized and tested. For each soil sample, release
      experiments with steady state pH values in the range 2.9 to 7.1 and duration of 7
      d were performed. The effluent was continuously collected and analyzed. Release
      rates and total releases were higher for the Hapludalf than the Kandiustult and
      higher for the sludge-amended soils than the nonamended soils. With two
      exceptions the relative release rates (release rate/total content of metal in
      soil) plotted vs. steady state pH followed the same curves for each metal,
      indicating similar bonding strengths. These curves could be described by a rate
      expression of the form: relative release rate = k[H+]a, with specific a
      (empirical constant) and k (rate constant) parameters for each metal
      demonstrating that metal release in these systems can be explained by proton
      induced desorption and dissolution reactions. With decreasing pH, pronounced
      increases in release rates were observed in the sequence cadmium > lead > copper,
      which express the order of metal lability in the soils. The flow cell system is
      useful for comparison of metal releases as a function of soil properties, and can
      be used as a test to rank soils with respect to heavy metal leaching.

PMID- 12469841
TI  - Distribution of inorganic nitrogen and phosphorus concentrations in stream flow
      of two Southern Piedmont watersheds.
AB  - Innate distributions or variability of nutrient concentrations within the fluvial
      system must be better understood to establish nutrient guidelines that are
      applicable and to discern which areas or landscape positions within the watershed
      are more vulnerable to nutrient losses. This work was conducted to (1) determine
      the system-wide spatial distribution of N and P concentrations in biweekly stream
      samples from two Southern Piedmont watersheds, and (2) determine the relationship
      between N and P concentrations in biweekly samples and watershed morphological
      features. From December 1998 through December 2000 samples were collected
      biweekly from 17 sampling sites located on Rose Creek and from 18 sampling sites
      located on Greenbrier Creek. The samples were analyzed for ammonium (NH4),
      nitrate (NO3), and dissolved reactive phosphorus (DRP) concentrations. We found
      that spatial autocorrelation of nitrate concentrations was evident and that some
      spatial autocorrelation of DRP concentrations was also present. We further found
      that the fluvial network morphological feature, drainage density, explained part
      of the spatial autocorrelation found for nitrate but did not for DRP. These
      results indicate that innate variability of nutrient concentrations within
      streams exists and suggest that decision makers should begin to consider location
      within the watershed when making nutrient management guidelines and decisions.

PMID- 12469842
TI  - Estimating runoff phosphorus losses from calcareous soils in the Minnesota River
      basin.
AB  - Bioavailable phosphorus (BAP) in stormwater runoff is a key issue for control of
      eutrophication in agriculturally impacted watersheds. Laboratory experiments were
      conducted in soil runoff boxes to determine BAP content in simulated storm runoff
      in 10 (mostly) calcareous soils from the Minnesota River basin in southern
      Minnesota. The soluble reactive phosphorus (SRP) portion of the runoff BAP was
      significantly correlated with soil Mehlich-III P, Olsen P, and water-extractable
      P (all r2 > 0.90 and p < 0.001). A linear relationship (r2 = 0.88, p < 0.001)
      also was obtained between SRP in runoff and the phosphorus saturation index based
      on sorptivity (PSIs) calculated with sorptivity as a measure of the inherent soil
      P sorption capacity. Runoff levels of BAP estimated with iron oxide-impregnated
      paper were predicted well by various soil test P methods and the PSI, of the
      soils, but correlation coefficients between these variables and runoff BAP were
      generally lower than those for runoff SRP. Using these relationships and critical
      BAP levels for stream eutrophication, we found corresponding critical levels of
      soil Mehlich-III P and Olsen P (which should not be exceeded) to be 65 to 85 and
      40 to 55 mg kg(-1), respectively.

PMID- 12469843
TI  - Assessment of spatial variation of cesium-137 in small catchments.
AB  - Surface contamination by bomb-derived and Chernobyl-derived 137Cs has been
      subject to changes due to physical decay and lateral transport of contaminated
      soil particles, which have resulted in an on-going transfer of radionuclides from
      terrestrial ecosystems to surface water, river bed sediments, and flood plains.
      Knowledge of the different sources of spatial variation of 137Cs is particularly
      essential for estimating 137Cs transfer to fluvial systems and for successfully
      applying 137Cs as an environmental tracer in soil erosion studies. This study
      combined a straightforward sediment redistribution model and geostatistical
      interpolation of point samples of 137Cs activities in soil to distinguish the
      effects of sediment erosion and deposition from other sources of variation in
      137Cs in the small Mochovce catchment in Slovakia. These other sources of
      variation could then be interpreted. Besides erosion and deposition processes,
      the initial pattern of 137Cs deposition, floodplain sedimentation, and short
      range spatial variation were identified as the major sources of spatial variation
      of the 137Cs inventory.

PMID- 12469844
TI  - Preferential bromide and pesticide movement to tile drains under different
      cropping practices.
AB  - Subsurface drainage systems are useful tools to study chemical leaching in soils.
      Our objective was to compare the breakthrough behavior of bromide, atrazine (2
      chloro-4-ethylamino-6-isopropylamino-s-triazine) and metolachlor [2-chloro-N-(2
      ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamid] to tile drains under
      two fall tillage practices (conventional tillage [CT] with a moldboard plow, and
      reduced tillage [RT] with a chisel plow) in field plots cultivated with corn (Zea
      mays L.). Leachate volume were greater in RT than in CT, with no statistical
      differences. Soil analysis showed that bromide migrated deeper in the soil
      profile than both herbicides, with little tillage effect. All chemicals were
      detected in drainage water at the same time and followed an event-driven
      behavior. Tillage had no effect on atrazine and metolachlor found in drainage
      water, while bromide concentration peaks were higher in RT than in CT in 1999.
      Concentration peaks were recorded earlier for atrazine and metolachlor than for
      bromide. Plots of cumulative relative chemical mass (cumulative mass divided by
      total mass measured in drainage) as a function of cumulative drainage were mostly
      linear for bromide, while they were S-shaped for both herbicides. Drainage that
      corresponded to 50% of relative cumulative mass ranged from 40 to 55% for bromide
      and from 5 to 28% for both herbicides. Rapid chemical movement to tile drains
      suggested that preferential flow was important in both CT and RT, and that these
      tillage practices had little influence on this phenomena.

PMID- 12469845
TI  - The role of condensed organic matter in the nonlinear sorption of hydrophobic
      organic contaminants by a peat and sediments.
AB  - This study examines the effect of soil organic matter heterogeneity on
      equilibrium sorption and desorption of phenanthrene, naphthalene, 1,3,5
      trichlorobenzene (1,3,5-TCB), and 1,2-dichlorobenzene (1,2-DCB) by soils and
      sediments. Two estuary sediments, a Pahokee peat (PP; Euic, hyperthermic Lithic
      Haplosaprist), and two subsamples (base- and acid-treated peat [TP] and acid
      treated peat [FP]) of the peat were used as the sorbents. The contents of black
      carbon particles were quantified with a chemical extraction method.
      Petrographical examinations revealed the presence of the condensed soil and
      sediment organic matter (SOM) in Pahokee peat. The Freundlich isotherm model in
      two different forms was used to fit both sorption and desorption data. The
      results show that the sorption and desorption isotherms are generally nonlinear
      and that the apparent sorption-desorption hysteresis is present for phenanthrene
      and TCB. Detailed analysis of sorption data for the tested sorbent-sorbate
      systems indicates that black carbon is probably responsible for sorption isotherm
      nonlinearity for the two sediments, whereas the humic substances and kerogen may
      play the dominant role in nonlinear sorption by the peat. This investigation
      suggests that the microporosity of SOM is important for the hydrophobic organic
      contaminant (HOC) sorption capacity on the peat.

PMID- 12469846
TI  - Transport of di(2-ethylhexyl)phthalate (DEHP) applied with sewage sludge to
      undisturbed and repacked soil columns.
AB  - Municipal sewage sludge is often used on arable soils as a source of nitrogen and
      phosphorus, but it also contains organic contaminants that may be leached to the
      ground water. Di(2-ethylhexyl)phthalate (DEHP) is a priority pollutant that is
      present in sewage sludge in ubiquitous amounts. Column experiments were performed
      on undisturbed soil cores (20-cm depth x 20-cm diameter) with three different
      soil types: a sand, a loamy sand, and a sandy loam soil. Dewatered sewage sludge
      was spiked with 14C-labeled DEHP (60 mg kg(-1)) and bromide (5 g kg(-1)). Sludge
      was applied to the soil columns either as five aggregates, or homogeneously mixed
      with the surface layer. Also, two leaching experiments were performed with
      repacked soil columns (loamy sand and sandy loam soil). The DEHP concentrations
      in the effluent did not exceed 1.0 microg L(-1), and after 200 mm of outflow less
      than 0.5% of the applied amount was recovered in the leachate in all soils but
      the sandy loam soil with homogeneous sludge application (up to 3.4% of the
      applied amount recovered). In the absence of macropore flow, DEHP in the leachate
      was primarily sorbed to mobilized dissolved organic macromolecules (DOM, 30.3 to
      81.3%), while 2.4 to 23.6% was sorbed to mobilized mineral particles. When
      macropore flow occurred, this changed to 16.5 to 37.4% (DOM) and 36.9 to 40.6%
      (mineral particles), respectively. The critical combination for leaching of
      considerable amounts of DEHP was homogeneous sludge application and a continuous
      macropore structure.

PMID- 12469847
TI  - Retention equations of nonionic organic chemicals in soil column chromatography
      with methanol-water eluents.
AB  - Research efforts dealing with chemical transportation in soils are needed to
      prevent damage to ground water. Methanol-containing solvents can increase the
      translocation of nonionic organic chemicals (NOCs). In this study, a general log
      linear retention equation, log k' = log k'w - Sphi (Eq. [1]), was developed to
      describe the mobilities of NOCs in soil column chromatography (SCC). The term phi
      denotes the volume fraction of methanol in eluent, k' is the capacity factor of a
      solute at a certain phi value, and log k'w and -S are the intercept and slope of
      the log k' vs. phi plot. Two reference soils (GSE 17204 and GSE 17205) were used
      as packing materials, and were eluted by isocratic methanol-water mixtures. A
      model of linear solvation energy relationships (LSER) was applied to analyze the
      k' from molecular interactions. The most important factor determining the
      transportation was found to be the solute hydrophobic partition in soils, and the
      second-most important factor was the solute hydrogen-bond basicity (hydrogen-bond
      accepting ability), while the less important factor was the solute dipolarity
      polarizability. The solute hydrogen-bond acidity (hydrogen-bond donating ability)
      was statistically unimportant and deletable. From the LSER model, one could also
      obtain Eq. [1]. The experimental k' data of 121 NOCs can be accurately explained
      by Eq. [1]. The equation is promising to estimate the solute mobility in pure
      water by extrapolating from lower-capacity factors obtained in methanol-water
      mixed eluents.

PMID- 12469848
TI  - Nitrogen removal and nitrate leaching for forage systems receiving dairy
      effluent.
AB  - Florida dairies need year-round forage systems that prevent loss of N to ground
      water from waste effluent sprayfields. Our purpose was to quantify forage N
      removal and monitor nitrate N (NO3(-)-N) concentrations in soil water below the
      rooting zone for two forage systems during four 12-mo cycles (1996-2000). Soil in
      the sprayfield is an excessively drained Kershaw sand (thermic, uncoated Typic
      Quartzipsamment). Over four cycles, average loading rates of effluent N were 500,
      690, and 910 kg ha(-1) per cycle. Nitrogen removed by the bermudagrass (Cynodon
      spp.)-rye (Secale cereale L.) system (BR) during the first three cycles was 465
      kg ha(-1) per cycle for the low loading rate, 528 kg ha(-1) for the medium rate,
      and 585 kg ha(-1) for the high. For the corn (Zea mays L.)-forage sorghum
      [Sorghum bicolor (L.) Moench]-rye system (CSR), N removals were 320 kg ha(-1) per
      cycle for the low rate, 327 kg ha(-1) for the medium, and 378 kg ha(-1) for the
      high. The higher N removals for BR were attributed to higher N concentration in
      bermudagrass (18.1-24.2 g kg(-1)) than in corn and forage sorghum (10.3-14.7 g
      kg(-1)). Dry matter yield declined in the fourth cycle for bermudagrass but N
      removal continued to be higher for BR than CSR. The BR system was much more
      effective at preventing NO3(-)-N leaching. For CSR, NO3(-)-N levels in soil water
      (1.5 m below surface) increased steeply during the period between the harvest of
      one forage and canopy dosure of the next. Overall, the BR system was better than
      CSR at removing N from the soil and maintaining low NO3(-)-N concentrations below
      the rooting zone.

PMID- 12469849
TI  - Soil and tree-ring chemistry response to liming in a sugar maple stand.
AB  - An evaluation of the impact of dolomitic lime [CaMg(CO3)2] on soils (five years
      after treatment) and sapwood chemistry (after four growing seasons) was realized
      for a Ca-deficient sugar maple stand at the lake Clair watershed. The effect on
      humus chemistry was significant: exchangeable Mg and Ca, effective acidity (EA),
      base saturation (BSe), pH, and effective cation exchange capacity (CECe)
      significantly increased, while exchangeable Fe significantly decreased. In the B
      horizon, liming increased exchangeable Ca, Mg, and Mn concentrations while
      decreasing other acid cations. No significant temporal trends in element
      concentrations in tree rings could be detected, although the lime treatment
      significantly changed the average xylem Mg and Mn concentrations as well as the
      average Mg/Mn and Ca/Mn ratios of the sapwood. The absence of temporal trends in
      rings from the last 20 yr implied a significant re-equilibration of elements
      through the sapwood. Significant relationships were found between averaged xylem
      Ca/Mn and Mg/Mn ratios and exchangeable humus Ca, Mg, Mn, Al, Fe, and H+
      concentration, EA, CECe, and BSe, suggesting that the average xylem Ca/Mn and
      Mg/Mn ratios are strong indicators of the soil acid-base status.

PMID- 12469850
TI  - Tree-ring strontium-90 and cesium-137 as potential indicators of radioactive
      pollution.
AB  - To examine whether tree rings can be used to detect or assess local historical
      90Sr or 137Cs fallout, such as that resulting from the Hiroshima atomic bomb,
      radial distribution of 90Sr and 137Cs in trees was examined. We studied a
      gymnosperm [Japanese cedar, Cryptomeria japonica (L. f.) D. Don] and an
      angiosperm (Japanese persimmon, Diospyros kaki Thunb.) tree species from the
      vicinity of the atomic bomb hypocenter, and from other locations in Japan. A
      significant amount of 137Cs was detected in tree rings formed before 1945,
      indicating lateral migration of Cs. In contrast, the specific activity of 90Sr in
      the Hiroshima Japanese cedar showed the highest level in 1945, due to relatively
      immobile characteristics of Sr compared with Cs. Strontium-90 and Sr analyses in
      tree rings helped identify and distinguish between residual 90Sr activity from
      the Hiroshima atomic bomb and the atmospheric nuclear testing. This indicates the
      possibility of detecting or assessing previous local 90Sr pollution through with
      treering analysis.

PMID- 12469851
TI  - Growth and yield responses of snap bean to mixtures of carbon dioxide and ozone.
AB  - Elevated CO2 concentrations expected in the 21st century can stimulate plant
      growth and yield, whereas tropospheric O3 suppresses plant growth and yield in
      many areas of the world. Recent experiments showed that elevated CO2 often
      protects plants from O3 stress, but this has not been tested for many important
      crop species including snap bean (Phaseolus vulgaris L.). The objective of this
      study was to determine if elevated CO2 protects snap bean from O3 stress. An O3
      tolerant cultivar (Tenderette) and an O3-sensitive selection (S156) were exposed
      from shortly after emergence to maturity to mixtures of CO2 and O3 in open-top
      field chambers. The two CO2 treatments were ambient and ambient with CO2 added
      for 24 h d(-1) resulting in seasonal 12 h d(-1) (0800-2000 h EST) mean
      concentrations of 366 and 697 microL L(-1), respectively. The two O3 treatments
      were charcoal-filtered air and nonfiltered air with O3 added for 12 h d(-1) to
      achieve seasonal 12 h d(-1) (0800-2000 h EST) mean concentrations of 23 and 72 nL
      L(-1), respectively. Elevated CO2 significantly stimulated growth and pod weight
      of Tenderette and S156, whereas elevated O3 significantly suppressed growth and
      pod weight of S156 but not of Tenderette. The suppressive effect of elevated O3
      on pod dry weight of S156 was approximately 75% at ambient CO2 and approximately
      60% at elevated CO2 (harvests combined). This amount of protection from O3 stress
      afforded by elevated CO2 was much less than reported for other crop species.
      Extreme sensitivity to O3 may be the reason elevated CO2 failed to significantly
      protect S156 from O3 stress.

PMID- 12469852
TI  - Impacts of golf courses on macroinvertebrate community structure in Precambrian
      shield streams.
AB  - The influence of golf course operation on benthic macroinvertebrate communities
      in Precambrian Shield streams was evaluated using rapid bioassessment and the
      reference condition approach. Streams were sampled for water chemistry and
      invertebrates in 1999 and 2000, six on operational golf courses, and seven in
      forested reference locations. Correspondence analysis (CA) was used to determine
      the major patterns in the macroinvertebrate taxa, and canonical correspondence
      analysis (CCA) was used to evaluate relationships with environmental variables.
      The reference streams were used to define the normal range of variation for a
      variety of summary indices to evaluate the golf course streams. In all cases,
      golf course streams were higher in nutrients and dissolved ions and more alkaline
      than the forested reference streams. There was considerable variability in the
      macroinvertebrate fauna from the golf course streams, which was related to
      differences in golf course land management practices and to the potential
      influence of highway runoff. Of the management practices evaluated, fertilizer
      application rates in particular were important, as was the presence of ponds
      upstream on the course. Invertebrate taxa with higher abundances in golf course
      streams included Turbellaria, Isopoda, Amphipoda, Zygoptera, and Trombidiformes.
      Taxa more common in the reference streams included Ephemeroptera, Megaloptera,
      Culicidae, and Plecoptera. There were marked differences in the overall benthic
      macroinvertebrate community in three of the six golf course streams studied
      relative to the forested reference streams, suggesting that golf course land
      management on the Precambrian Shield can be associated with significant
      differences in macroinvertebrate community structure.

PMID- 12469853
TI  - Effect of mineral and manure phosphorus sources on runoff phosphorus.
AB  - Concern over nonpoint-source phosphorus (P) losses from agricultural lands to
      surface waters has resulted in scrutiny of factors affecting P loss potential. A
      rainfall simulation study was conducted to quantify the effects of alternative P
      sources (dairy manure, poultry manure, swine slurry, and diammonium phosphate),
      application methods, and initial soil P concentrations on runoff P losses from
      three acidic soils (Buchanan-Hartleton, Hagerstown, and Lewbeach). Low P (12 to
      26 mg kg(-1) Mehlich-3 P) and high P (396 to 415 mg kg(-1) Mehlich-3 P) members
      of each soil were amended with 100 kg total P ha(-1) from each of the four P
      sources either by surface application or mixing, and subjected to simulated
      rainfall (70 mm h(-1) to produce 30 min runoff). Phosphorus losses from
      fertilizer and manure applied to the soil surface differed significantly by
      source, with dissolved reactive phosphorus (DRP) accounting for 64% of total
      phosphorus (TP) (versus 9% for the unamended soils). For manure amended soils,
      these losses were linearly related to water-soluble P concentration of manure (r2
      = 0.86 for DRP, r2 = 0.78 for TP). Mixing the P sources into the soil
      significantly decreased P losses relative to surface P application, such that DRP
      losses from amended, mixed soils were not significantly different from the
      unamended soil. Results of this study can be applied to site assessment indices
      to quantify the potential for P loss from recently manured soils.

PMID- 12469854
TI  - Acid-base accounting to predict post-mining drainage quality on surface mines.
AB  - Acid-base accounting (ABA) is an analytical procedure that provides values to
      help assess the acid-producing and acid-neutralizing potential of overburden
      rocks prior to coal mining and other large-scale excavations. This procedure was
      developed by West Virginia University scientists during the 1960s. After the
      passage of laws requiring an assessment of surface mining on water quality, ABA
      became a preferred method to predict post-mining water quality, and permitting
      decisions for surface mines are largely based on the values determined by ABA. To
      predict the post-mining water quality, the amount of acid-producing rock is
      compared with the amount of acid-neutralizing rock, and a prediction of the water
      quality at the site (whether acid or alkaline) is obtained. We gathered geologic
      and geographic data for 56 mined sites in West Virginia, which allowed us to
      estimate total overburden amounts, and values were determined for maximum
      potential acidity (MPA), neutralization potential (NP), net neutralization
      potential (NNP), and NP to MPA ratios for each site based on ABA. These values
      were correlated to post-mining water quality from springs or seeps on the mined
      property. Overburden mass was determined by three methods, with the method used
      by Pennsylvania researchers showing the most accurate results for overburden
      mass. A poor relationship existed between MPA and post-mining water quality, NP
      was intermediate, and NNP and the NP to MPA ratio showed the best prediction
      accuracy. In this study, NNP and the NP to MPA ratio gave identical water quality
      prediction results. Therefore, with NP to MPA ratios, values were separated into
      categories: <1 should produce acid drainage, between 1 and 2 can produce either
      acid or alkaline water conditions, and >2 should produce alkaline water. On our
      56 surface mined sites, NP to MPA ratios varied from 0.1 to 31, and six sites
      (11%) did not fit the expected pattern using this category approach. Two sites
      with ratios <1 did not produce acid drainage as predicted (the drainage was
      neutral), and four sites with a ratio >2 produced acid drainage when they should
      not have. These latter four sites were either mined very slowly, had
      nonrepresentative ABA data, received water from an adjacent underground mine, or
      had a surface mining practice that degraded the water. In general, an NP to MPA
      ratio of <1 produced mostly acid drainage sites, between 1 and 2 produced mostly
      alkaline drainage sites, while NP to MPA ratios >2 produced alkaline drainage
      with a few exceptions. Using these values, ABA is a good tool to assess
      overburden quality before surface mining and to predict post-mining drainage
      quality after mining. The interpretation from ABA values was correct in 50 out of
      52 cases (96%), excluding the four anomalous sites, which had acid water for
      reasons other than overburden quality.

PMID- 12469855
TI  - Volatilization and degradation of soil-applied dimethylselenide.
AB  - Dimethylselenide (DMSe) is a highly volatile gas that is produced by indigenous
      microorganisms in seleniferous soils and sediments; however, little is known
      about the soil conditions that affect the persistence of DMSe and its transport
      to the atmosphere. In this study we investigated the effect of moisture content,
      temperature, and organic amendments on the degradation of soil-applied DMSe. The
      degradation of DMSe was entirely a result of biological mechanisms, but changes
      in temperature (20-40 degrees C) and soil moisture content (30-70% of the maximum
      water holding capacity) had little influence on the degradation rate. In
      contrast, amending soil with either 1% casein or gluten (by weight) had an
      inhibitory effect on the degradation of DMSe. After 18 d, 2.1 times more DMSe was
      present in the casein-amended soil and 2.6 times more DMSe was present in the
      gluten-amended soil. The transport of DMSe in packed soil columns was also
      investigated. Increasing the depth to soil surface was found to significantly
      decrease the amount of DMSe transported to the air. After 6 d, 57% of DMSe
      injected 10 cm below the soil surface was volatilized. At an injection depth of
      20 cm the cumulative emissions were reduced by 38% and at 30 cm the cumulative
      emissions were reduced by 51%. In columns containing 1% casein or gluten in the
      top 5 cm of soil the cumulative loss of DMSe was about 9% higher than in
      unamended soil. Increasing our understanding of the soil conditions that
      influence the gaseous diffusion of DMSe should help in determining the
      feasibility of using Se volatilization as a remediation technique.

PMID- 12469856
TI  - Nitrogen and phosphorus availability in composted and uncomposted poultry litter.
AB  - Poultry litter applications to land have been based on crop N requirements,
      resulting in application of P in excess of plant requirements, which may cause
      degradation of water quality in the Chesapeake Bay watershed. The effect of
      litter source (the Delmarva Peninsula and Moorefield, West Virginia) and
      composting of poultry litter on N mineralization and availability of P in two
      soil types (sandy loam and silt loam) was determined in a controlled environment
      for 120 d. Nitrogen mineralization (percent total organic N converted to
      inorganic nitrogen) rates were higher for fresh litter (range of 42 to 64%) than
      composted litter (range of 1 to 9%). The N mineralization rate of fresh litter
      from the Delmarva Peninsula was consistently lower than the fresh litter from
      Moorefield, WV. The N mineralization rate of composted litter from either source
      was not significantly different for each soil type (7 to 9% in sandy loam and 1
      to 5% in silt loam) even though composting conditions were completely different
      at the two composting facilities. Litter source had a large effect on N
      mineralization rates of fresh but not composted poultry litter. Composting
      yielded a more predictable and reliable source of mineralizable N than fresh
      litter. Water-extractable phosphorus (WEP) was similar in soils amended with
      composted litter from WV and fresh litter from both sources (approximately 10 to
      25 and 2 to 14 mg P kg(-1) for sandy loam and silt loam, respectively). Mehlich 1
      extractable phosphorus (MEP) was similar in soils amended with WV fresh litter
      and composted litter from both sources (approximately 100 to 140 and 60 to 90 mg
      P kg(-1) for sandy loam and silt loam, respectively). These results suggest that
      the composting process did not consistently reduce WEP and MEP, and P can be as
      available in composted poultry litter as in fresh poultry litter.

PMID- 12469857
TI  - Phosphorus characteristics of dairy feces affected by diets.
AB  - Phosphorus (P) surplus on dairy farms, especially confined operations,
      contributes to P buildup in soils with increased potential for P loss to waters.
      One approach to reduce P surplus and improve water quality is to optimize P
      feeding and improve P balance on farms. Here we report how varying P
      concentrations in lactating cow diets affects the amount as well as the chemical
      forms and fraction distribution of P in fecal excretion, and the environmental
      implications of this effect. Analysis of fecal samples collected from three
      independent feeding trials indicates that increasing dietary P levels through the
      use of P minerals not only led to a higher concentration of acid digest total
      phosphorus (TP) in feces, but more importantly increased the amount and
      proportion of P that is water soluble and thus most susceptible to loss in the
      environment. For instance, with diets containing 3.4, 5.1, or 6.7 g P kg(-1) feed
      dry matter (DM), the water-soluble fraction of fecal P was 2.91, 7.13, and 10.46
      g kg(-1) fecal DM, respectively, accounting for 56, 77, and 83% of acid digest
      TP. The other fecal P fractions (those soluble in dilute alkaline and acid
      extractants) remained small and were unaffected by dietary P concentration.
      Excess P in the P supplemented diets was excreted in feces as water-soluble
      forms. A simple measure of inorganic phosphorus (Pi) in a single water extract is
      highly responsive to changes in diet P concentrations and hence can be indicative
      of dietary P status. A fecal P indicator concept is proposed and discussed.

PMID- 12469858
TI  - On-farm evaluation of aluminum sulfate (alum) as a poultry litter amendment:
      effects on litter properties.
AB  - Aluminum sulfate [alum; Al2(SO4)3] amendment of poultry litters has been
      suggested as a best management practice to help reduce the potential
      environmental effects of poultry production. Past research has shown that alum
      treatment reduced NH3 emissions from litters, decreased the loss in runoff of P
      and trace metals from litter-amended soils, improved poultry health, and reduced
      the costs of poultry production. We conducted a large scale, "on-farm" evaluation
      of alum as a poultry (broiler) litter amendment on the Delmarva peninsula to
      determine the effect of alum on (i) litter properties and elemental composition
      and (ii) the solubility of several elements in litter that are of particular
      concern for water quality (Al, As, Cu, P, and Zn). Alum was applied over a 16-mo
      period to 97 poultry houses on working poultry farms; 97 houses on other farms
      served as controls (no alum). Litter samples were analyzed initially and after
      approximately seven alum applications. We found that alum decreased litter pH and
      the water solubility of P, As, Cu, and Zn. Alum-treated houses also had higher
      litter total N, NH4-N, and total S concentrations and thus a greater overall
      fertilizer value than litters from the control houses. Higher litter NH4-N values
      also suggest that alum reduced NH3 losses from litters. Thus, alum appears to
      have promise as a best management practice (BMP) for poultry production. Future
      research should focus on the long-term transformations of P, Al, As, Cu, and Zn
      in soils amended with alum-treated litters.

PMID- 12469861
TI  - Influence of plant age and size on simazine toxicity and uptake.
AB  - Improper pesticide management can lead to environmental problems such as water
      quality degradation and ecological stress. Recent research in our laboratory has
      focused on development of constructed wetlands to assimilate pesticide
      contaminated water. For improved aesthetics, these wetlands have been established
      with ornamental plant species. The effectiveness of a plant species for
      phytoremediation depends in part on its tolerance for the contaminant. Plant
      tolerance for pesticides may vary depending on plant age and size. This study
      examined the influence of plant age and size on the uptake, distribution, and
      toxicity of the herbicide simazine [2-chloro-4,6-bis(ethylamino)-1,3,5-triazine]
      in two ornamental wetland plants: parrot feather [Myriophyllum aquaticum (Vell.)
      Verdc.] and canna (Canna x hybrida L. 'Yellow King Humbert'). Plants of different
      ages and sizes were exposed to simazine in 10% Hoagland's nutrient solution.
      Toxicity was characterized using plant growth, water uptake, and photosynthetic
      yield during exposure and postexposure periods. In addition, other plants were
      exposed to [14C] simazine in nutrient medium to characterize pesticide uptake and
      translocation. Four-week-old parrot feather and canna were more tolerant of
      simazine than two-week-old plants. The two-week-old plant tissues of both species
      had higher tissue burdens of simazine than four-week-old plants. Simazine was
      primarily accumulated in the leaves of both parrot feather and canna. These
      results suggest that plants in a constructed wetland designed for simazine
      assimilation would be more vulnerable to simazine toxicity shortly after
      emergence.

PMID- 12469859
TI  - Seasonal variation in microbial communities and organic malodor indicator
      compound concentrations in various types of swine manure storage systems.
AB  - Anaerobic manure storage systems are one of the major contributors to the odor
      and environmental pollution associated with swine (Sus scrofa) production
      systems. The microbial ecology of manure storage systems and the relationships
      between microbial communities and odor production are largely unknown. In this
      study, we used community fatty acid methyl ester (FAME) analysis to generate
      lipid profiles to assess seasonal differences among microbial communities
      inhabiting various types of outdoor swine manure storage systems. Concurrently,
      we measured manure concentrations of several malodor indicator compounds as well
      as pH, temperature, and solids content. Principal components analysis (PCA)
      showed that there are differences in FAME profiles among the swine manure storage
      systems examined and most of the variation was in the relative abundance of 18:0,
      18:1omega7t, 18:1omega7c/omega9t/omega12t, and 16:1omega7t/i15:0 2OH FAMEs. The
      PCA of the FAME profiles revealed that the phototrophic systems were more similar
      to each other and that the nonphototrophic systems were more similar to each
      other than they were to phototrophic lagoons. There were seasonal changes in the
      FAME profiles in the phototrophic systems and the concrete nonphototrophic basin
      (CNPB), and in one phototrophic system, the FAME profiles more closely resembled
      a CNPB FAME profile during the winter than the other phototrophic lagoons. In the
      phototrophic lagoon systems, there was a direct correlation between the abundance
      of the FAMEs identified in the PCA and manure concentrations of phenol, p-cresol,
      and 4-ethyl phenol. In the CNPB, there was a negative correlation between the
      total phenolics concentration and the 18:1omega7t FAME. Our results indicate that
      community FAME profiles could be used as a diagnostic tool for obtaining
      preliminary evidence that management practices are altering the system's
      microbial community to one that favors less air pollution potential.

PMID- 12469860
TI  - Paper mill residuals and compost effects on soil carbon and physical properties.
AB  - Use of organic by-products as soil amendments in agricultural production
      exemplifies a strategy for converting wastes to resources. The overall objective
      of this research was to evaluate the short- and intermediate-term effects of
      repeatedly amending sandy soil with paper mill residuals (PMR) and composted PMR
      in a vegetable rotation in Wisconsin's Central Sands. Specifically, we
      investigated the effects of PMR and composted PMR on total soil C and related
      these to changes in water-holding capacity and plant-available water (PAW).
      Amendment effects on irrigation requirements were estimated with a simple soil
      water balance model. The experimental design was replicated five times as a
      randomized complete block with four organic amendments: raw PMR, PMR composted
      alone (PMRC), PMR composted with bark (PMRB), and peat applied at two rates and a
      non-amended control. All amended treatments significantly increased total soil C
      relative to the nonamended control following applications in 1998 and 1999. One
      year following the second serial amendment, all PMR treatments increased PAW by 5
      to 45% relative to the control. There was a significant positive linear
      relationship between total soil C and PAW. All amended treatments reduced the
      average amount of irrigation water required for potato production by 4 to 30% and
      the number of irrigation events by 10 to 90%. There was a clear trend of greater
      reduction in irrigation requirements with more carbon added. The cumulative
      effects of repeated additions of PMRB suggest that certain composts might sustain
      elevated PAW and reduce irrigation requirements beyond one year.

PMID- 12469863
TI  - Limnological assessment of Verkhne Viiskii Reservoir, Russian Federation.
AB  - Verkhne Viiskii Reservoir (surface area = 6.0 km2; volume = 36.0 hm3), one of two
      water supply reservoirs for the City of Nizhnii Tagil, is located in a forested
      watershed (drainage area = 272 km2) in the Ural Mountain region of the Russian
      Federation. This study, conducted in August 1999, provides a benchmark
      limnological assessment against which to gauge future change. While currently
      meeting local water quality requirements for drinking water sources, the
      reservoir exhibits moderately eutrophic characteristics, including elevated
      epilimnetic nutrient (total P = 0.048-0.115 mg L(-1); total N = 0.421-0.508 mg L(
      1)) and chlorophyll (4-8.4 microg L(-1)) concentrations, and a high rate of
      hypolimnetic oxygen depletion (4.07 g m(-3) mo(-1)).

PMID- 12469862
TI  - Evaluation of the macroalga, muskgrass, for the phytoremediation of selenium
      contaminated agricultural drainage water by microcosms.
AB  - Previous field studies suggested that the macroalga, muskgrass (Chara canescens
      Desv. & Lois), plays an important role in the removal of selenium (Se) from
      agricultural drainage water. This study evaluated the efficiency of Se removal
      from drainage water by muskgrass-vegetated wetland microcosms, and determined the
      extent to which muskgrass removed Se through phytoextraction and
      biovolatilization. Six flow-through wetland microcosms were continuously supplied
      with drainage water containing an average Se concentration of 22 microg L(-1)
      over a 24-d experimental period. The Se mass input and outflow and the rate of Se
      volatilization were monitored daily for each microcosm. Three microcosms
      containing muskgrass reduced the daily mass Se input in the inflow drainage water
      by 72.1%; this compared with a reduction of 50.6% of the mass Se input for three
      unvegetated control microcosms. Selenium accumulated in muskgrass tissues
      accounted for 1.9% of the total mass Se input in the microcosm, followed by 0.5%
      via biological volatilization. The low rates of Se volatilization from selenate
      supplied muskgrass, which were 10-fold less than from selenite, were probably due
      to a major rate limitation in the reduction of selenate to organic forms of Se in
      muskgrass. This conclusion was derived from X-ray absorption spectroscopy
      speciation analysis, which showed that muskgrass treated with selenite contained
      91% of the total Se in organic forms (selenoethers and diselenides), compared
      with 47% in muskgrass treated with selenate.

PMID- 12469864
TI  - Increasing bioavailability of phosphorus from fly ash through vermicomposting.
AB  - Due to the environmental problems created by large-scale fly ash generation
      throughout the world, efforts are being made to recycle these materials. An
      important component of the recycling effort is using fly ash to improve low
      fertility soils. Because availability of many nutrients is very low in fly ash,
      available ranges of such nutrients must be improved to increase the effectiveness
      of fly ash as a soil amendment. In the present study, we assessed the possibility
      of increasing P bioavailability in fly ash through vermicomposting in a yard
      experiment. Fly ash was mixed with organic matter in the form of cow (Bos taurus)
      dung at 1:3, 1:1, and 3:1 ratios and incubated with and without epigeic earthworm
      (Eisenia fetida) for 50 d. The concentration of phosphate-solubilizing bacteria
      (PSB) was found to increase many fold in the earthworm-treated series of fly ash
      and organic matter combinations compared with the series without earthworm. This
      helped to transform considerable amounts of insoluble P from fly ash into more
      soluble forms and thus resulted in increased bioavailability of the nutrients in
      the vermicomposted series. Among different combinations of fly ash and organic
      matter, P availability in fly ash due to vermicomposting was significantly higher
      in the 1:1 fly ash to cow dung treatment compared with the other treatments.

PMID- 12469865
TI  - Evaluation of commercial odor control agents for suppressing Escherichia coli in
      swine manure slurry.
AB  - Ten commercially available manure odor control agents were evaluated in bench
      scale laboratory microcosms for their ability to inhibit or kill Escherichia
      coli, a commonly used indicator of fecal pollution and a potential pathogen. At
      manufacturer recommended rates, none of the agents reduced viable populations of
      E. coli in pure cultures or in swine manure slurry. However, at rates 10-fold
      higher than those recommended by the manufacturer, EnviroPur rapidly reduced
      viable populations of E. coli. Accelerated death of E. coli was observed at
      temperatures as low as 4 degrees C. Chemical analysis of EnviroPur indicated that
      it contains alkylphenol polyethoxylates, common industrial surfactants. These
      results suggest that at manufacturer-recommended rates, the odor-controlling
      agents would not be effective at suppressing E. coli in stored swine manure
      slurry.

PMID- 12469866
TI  - The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a
      model for Parkinson's disease memory disabilities.
AB  - 1. In this article we review the studies of memory disabilities in a rat model of
      Parkinson's disease (PD). 2. Intranigral administration of 1-methyl-4-phenyl
      1,2,3,6-tetrahydropyridine (MPTP) to rats causes a partial lesion in the
      substantia nigra, compact part (SNc) and a specific loss of dopamine and its
      metabolites in the striatum of rats. 3. These animals present learning and memory
      deficits but no sensorimotor impairments, thus modeling the early phase of PD
      when cognitive impairments are observed but the motor symptoms of the disease are
      barely present. 4. The cognitive deficits observed in these animals affect memory
      tasks proposed to model habit learning (the cued version of the water maze task
      and the two-way active avoidance task) and working memory (a working memory
      version of the water maze), but spare long-term spatial memory (the spatial
      reference version of the Morris water maze). 5. The treatment of these animals
      with levodopa in a dose that restores the striatal level of dopamine does not
      reverse these memory impairments, probably because this treatment promotes a high
      level of dopamine in extrastriatal brain regions, such as the prefrontal cortex
      and the hippocampus. 6. On the other hand, the adenosine receptor antagonist,
      caffeine, partly reverse the memory impairment effect of SNc lesion in these
      rats. This effect may be due to caffeine action on nigrostriatal neurons, since
      it induces dopamine release and modulates the interaction between adenosine and
      dopamine receptor activity. 7. These results suggest that the MPTP SNc-lesioned
      rats are a good model to study memory disabilities related to PD and that
      caffeine and other selective A(2A) adenosine receptor antagonists are promising
      drugs to treat this symptoms in PD patients.

PMID- 12469867
TI  - Inhibitory deficit in schizophrenia is not necessarily a GABAergic deficit.
AB  - 1. Current evidence strongly supports the idea of an inhibitory deficit as a
      central pathophysiological mechanism in schizophrenia. This deficit has been well
      documented in sensory gating and paired-pulse studies and may be related to
      decreases in inhibitory interneurons found in schizophrenic patients. 2. The
      GABAergic system has been repeatedly postulated to mediate this deficit, but the
      findings are controversial, at least in some areas, and mostly negative regarding
      treatment with drugs enhancing GABAergic activity. Therefore, the scope of
      mediators of this inhibitory deficit should be widened and the neuromodulator
      adenosine is proposed as a candidate to be further studied. 3. A state of
      adenosinergic hypoactivity in schizophrenia is compatible not only with the
      inhibitory deficit but also with symptoms, clinical response to antipsychotics,
      impaired sensory gating, deteriorating course, increased smoking, and sleep
      alterations reported in schizophrenia. 4. It is concluded that although the
      GABAergic system should be further studied, especially in sensory gating model in
      humans, emphasis on other inhibitory mechanisms may prove useful and provide more
      effective treatment.

PMID- 12469868
TI  - Cellular prion protein: implications in seizures and epilepsy.
AB  - 1. Cellular prion (PrPc) is a plasma membrane protein involved with copper
      uptake, protection against oxidative stress, cell adhesion, differentiation,
      signaling, and survival in the central nervous system. 2. Deletion of PrPc gene
      (Pmp) in mice enhances sensitivity to seizures in vivo and neuronal excitability
      in vitro which can be related to: (i) disrupted Ca(+2)-activated K+ currents,
      with loss of IHAP conductance in hippocampus; (ii) abnormal GABA-A inhibition in
      the hippocampus; (iii) mossy fiber reorganization in the hippocampus; (iv)
      changes in ectonucleotidases in both hippocampus and neocortex; and (v) higher
      levels of neocortical and subcortical oxidative stress. Moreover, postnatal Prnp
      knockout mice showed a significant reduction of after hyperpolarization
      potentials in hippocampal CA1 cells. 3. Taken together, these findings suggest
      that loss of PrPc function contributes to the hyperexcitable and synchronized
      activities underlying epileptic seizures generated in neocortex and hippocampus.
      Hence, the role of PrPc on human symptomatic, cryptogenic or idiopathic epileptic
      syndromes deserves further investigation.

PMID- 12469869
TI  - Participation of CaMKII in neuronal plasticity and memory formation.
AB  - 1. The unique biochemical properties of Ca(2+)/calmodulin (CaM)-dependent protein
      kinase II have made this enzyme one of the paradigmatic models of the forever
      searched "memory molecule." 2. In particular, the central participation of CaMKII
      as a sensor of the Ca(2+) signals generated by activation of NMDA receptors after
      the induction of long-term plastic changes, has encouraged the use of
      pharmacological, genetic, biochemical, and imaging tools to unveil the role of
      this kinase in the acquisition, consolidation, and expression of different types
      of memories. 3. Here we review some of the more exciting discoveries related to
      the mechanisms involved in CaMKII activation and synaptic plasticity.

PMID- 12469870
TI  - Molecular pharmacological dissection of short- and long-term memory.
AB  - 1. It has been discussed for over 100 years whether short-term memory (STM) is
      separate from, or just an early phase of, long-term memory (LTM). The only way to
      solve this dilemma is to find out at least one treatment that blocks STM while
      keeping LTM intact for the same task in the same animal. 2. The effect of a large
      number of treatments infused into the hippocampus, amygdala, and entorhinal,
      posterior parietal or prefrontal cortex on STM and LTM of a one-trial step-down
      inhibitory avoidance task was studied. The animals were tested at 1.5 h for STM,
      and again at 24 h for LTM. The treatments were given after training. 3. Eleven
      different treatments blocked STM without affecting LTM. Eighteen treatments
      affected the two memory types differentially, either blocking or enhancing LTM
      alone. Thus, STM is separate from, and parallel to the first hours of processing
      of, LTM of that task. 4. The mechanisms of STM are different from those of LTM.
      The former do not include gene expression or protein synthesis; the latter
      include a double peak of cAMP-dependent protein kinase activity, accompanied by
      the phosphorylation of CREB, and both gene expression and protein synthesis. 5.
      Possible cellular and molecular events that do not require mRNA or protein
      synthesis should account for STM. These might include a hyperactivation of
      glutamate AMPA receptors, ribosome changes, or the exocytosis of glycoproteins
      that participate in cell addition.

PMID- 12469871
TI  - Effects of estrogens on choline-acetyltransferase immunoreactivity and GAP-43
      mRNA in the forebrain of young and aging male rats.
AB  - 1. Previous work demonstrated that estradiol (E2) treatment prevented the
      abnormal response to stress and the reduction of glucocorticoid receptors (GR) in
      hippocampus from aging male rats. The mechanisms originating these effects were
      unknown. 2. In the present work, we investigated the E2 effects on the
      cholinergic, growth-associated protein (GAP-43) expressing neurons of the medial
      septum (MS) and vertical limb of diagonal band of Broca (VDB). These areas
      project to the hippocampus, and may be involved in the mentioned E2 effects in
      aging animals. Therefore, the response to E2 of choline-acetyltransferase (ChAT)
      in neurons and cell processes and GAP-43 mRNA as a marker of neurite outgrowth
      was studied in young and old male rats. 3. Young (3-4 months) and old (18-20
      months) male Sprague-Dawley rats remained untreated or were implanted s.c. with a
      14 mg pellet of E2 benzoate during 6 weeks. We used immoucytochemistry to
      determine ChAT and isotopic in situ hybridization to analyze GAP-43 mRNA
      expression. 4. Aging males showed a reduction in the number and length of ChAT
      immunoreactive cell processes, but not in the number of positive neurons in MS
      and VDB. E2 reverted both parameters in old rats to levels of young animals.
      Regarding basal levels of GAP-43 mRNA, they were similar in old and young
      animals, but E2 treatment up-regulated GAP-43 mRNA expression in MS and VDB of
      old animals only. 5. Our data suggest that prolonged E2 treatment may affect
      hippocampal function of aging male rats by regulating in part the plasticity of
      cholinergic, GAP-43 expressing neurones of the basal forebrain. Without
      discarding a direct E2 effect on the limbic tissue, effects on the cholinergic
      system may have a pronounced impact on the neuroendocrine and stress responses of
      the aging hippocampus.

PMID- 12469872
TI  - Gene transfer of NMDAR1 subunit sequences to the rat CNS using herpes simplex
      virus vectors interfered with habituation.
AB  - 1. The aim is to study some roles of the hippocampal NMDA receptor, by modifying
      the expression of the essential NR1 subunit, with temporal and spatial
      restrictions in the central nervous system (CNS) of the rat. 2. Due to their
      neurotropism and the size of inserts they can accomodate, herpes simplex virus
      type-1 (HSV-1) derived amplicon vectors were used to transfer sequences, either
      in sense (+) or antisense (-) orientations, of the NR1 subunit gene, or of the
      green fluorescent protein (GFP) gene, into the CNS. 3. Vector expression in cell
      lines was followed by GFP autofluorescence, immunofluorescence and western blot.
      4. The vectors were inoculated into the dorsal hippocampus of adult male Wistar
      rats, which were evaluated for habituation to an open field, and then, for
      expression of the transgenes, by autofluorescence and western blot; the
      expression mainly happened in pyramidal cells of CA1. 5. The animals injected
      with vectors carrying the NR1(+) transgene showed habituation to the new
      environment, as also happened with rats injected with vectors carrying only the
      GFP transgene. 6. In contrast, animals injected with vectors carrying NR1(-)
      sequence, did not show habituation. This might be retrograde amnesia or
      disability to record the trace, suggesting that the NR1 subunit in the dorsal
      hippocampus, is involved in habituation to a new environment. 7. HSV-1 derived
      amplicon vectors appear to be useful tools to modify endogenous gene expression,
      at a defined period, in restricted regions of the CNS.

PMID- 12469873
TI  - Angiotensin and calcium signaling in the pituitary and hypothalamus.
AB  - 1) In the rat pituitary, angiotensin type 1B receptors (AT1B) are located in
      lactotrophs and corticotrophs. 2) Activation of AT1B receptors are coupled to
      Gq/11 (Guanine protein coupled receptor, or GPCR); they increase phospholipase
      beta C (PLC) activity resulting in inositol 1,4,5 triphosphate (InsP3) and
      diacylglycerol (DAG) formation. A biphasic increase in [Ca2+]i triggered by InsP3
      and DAG ensues. 3) As many GPCRs, AT1B pituitary receptors rapidly desensitize.
      4) This was observed in the generation of InsP3, the mobilization of
      intracellular Ca(2+), and in prolactin release. Both homologous and heterologous
      desensitization was evidenced. 5) Desensitization of the angiotensin II type 1
      (AT1) receptor in the pituitary shares similarities and differences with
      endogenously expressed or transfected AT1 receptors in different cell types. 6)
      In the pituitary hyperplasia generated by chronic estrogen treatment there was
      desensitization or alteration in angiotensin II (Ang II) evoked intracellular
      Ca2+ increase, InsP3 generation, and prolactin release. This correlates with a
      downregulation of AT1 receptors. 7) In particular, in hyperplastic cells Ang II
      failed to evoke a transient acute peak in [Ca2+]i, which was replaced by a
      persistent plateau phase of [Ca2+]i increase. 8) Different calcium channels
      participate in Ang II induced [Ca2+]i increase in control and hyperplastic cells.
      While spike phase in control cells is dependent on intracellular stores sensitive
      to thapsigargin, in hyperplastic cells plateau increase is dependent on
      extracellular calcium influx. 9) Signal transduction of the AT1 pituitary
      receptor is greatly modified by hyperplasia, and it may be an important mechanism
      in the control of the hyperplastic process. 10) In the hypothalamus and brain
      stem there is a predominant expression of AT1A and AT2 mRNA. 11) Ang II acts at
      specific receptors located on neurons in the hypothalamus and brain stem to
      elicit alterations in blood pressure, fluid intake, and hormone secretion. 12)
      Calcium channels play important roles in the Ang II induced behavioral and
      endocrine responses. 13) Ang II, in physiological concentrations, can activate
      AT1 receptors to stimulate both Ca2+ release from intracellular stores and Ca2+
      influx from the extracellular space to increase [Ca2+]i in polygonal and stellate
      astroglia of the hypothalamus and brain stem. 14) In primary cell culture of
      neurons from newborn rat hypothalamus and brain stem, it has also been determined
      that Ang II elicits an AT1 receptor mediated inhibition of delayed rectifier K(+)
      current and a stimulation of Ca2+ current. 15) In primary cell cultures derived
      from the subfornical organ or the organum vasculosum laminae terminalis of
      newborn rat pups, Ang II produced a pronounced desensitization of the [Ca2+]i
      response. 16) Hypothalamic and pituitary Ang II systems are involved in different
      functions, some of which are related. At both levels Ang II signals through
      [Ca2+]i in a characteristic way.

PMID- 12469874
TI  - Neuroprotective effect of GMP in hippocampal slices submitted to an in vitro
      model of ischemia.
AB  - 1. Guanosine-5'-monophosphate (GMP) was evaluated as a neuroprotective agent
      against the damage observed in rat hippocampal slices submitted to an in vitro
      model of ischemia with or without the presence of the ionotropic glutamate
      receptor agonist, Kainic acid (KA). 2. Cellular injury was evaluated by MTT
      reduction, lactate dehydrogenase(LDH) release assay, and measurement of
      intracellular ATP levels. 3. In slices submitted to ischemic conditions, 1 mM GMP
      partially prevented the decrease in cell viability induced by glucose and oxygen
      deprivation and the addition of KA. 4. KA or N-methyl-D-aspartate (NMDA) receptor
      antagonists, gamma-D-glutamylamino-methylsulfonate (GAMS) or (+)-5-methyl-10,11
      dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801, 20 microM) also
      prevented toxicity in hippocampal slices under ischemic conditions, respectively.
      5. The association of GMP with GAMS or MK-801 did not induce additional
      protection than that observed with GMP or that classical glutamate receptor
      antagonists alone. 6. GMP, probably by interacting with ionotropic glutamate
      receptors, attenuated the damage caused by glucose and oxygen deprivation in
      hippocampal slices. This neuroprotective action of GMP in this model of
      excitotoxicity is of outstanding interest in the search for effective therapies
      against ischemic injury.

PMID- 12469875
TI  - In vitro effects of thyroid hormones on ectonucleotidase activities in
      synaptosomes from hippocampus of rats.
AB  - 1. Studies have shown that adenosine transport and adenosine A1 receptors in rat
      brain are subjected to regulation by thyroid hormone levels. Since the
      ectonucleotidase pathway is an important source of adenosine extracellular, in
      the present study the in vitro action of T3 and T4 hormones on ectonucleotidase
      activities in hippocampal synaptosomes was evaluated. 2. T3 (Triiodo-l-thyronine)
      significantly inhibited, in an uncompetitive manner, the ATP and ADP hydrolysis
      promoted by ATP diphosphohydrolase activity in hippocampal synaptosomes of adult
      rats. 3. In contrast, T4 (Thyroxine) only inhibited ATP hydrolysis in an
      uncompetitive mechanism, at the concentrations tested (100-500 microM), but at
      the same time did not affect ADP hydrolysis. 4. In the present study, we also
      investigate the in vitro effect of T3 and T4 on 5'-nucleotidase activity.
      However, there are no changes in the activity of this enzyme in the presence of
      T3 and T4 in the hippocampal synaptosomes of rats. 5. These results suggest that
      thyroid hormones could be involved in the regulation of ectonucleotidase
      activities, such as ecto-ATP diphosphohydrolase and ecto-ATPase, possibly
      exerting a modulatory role in extracellular adenosine levels.

PMID- 12469876
TI  - Guanosine enhances glutamate uptake in brain cortical slices at normal and
      excitotoxic conditions.
AB  - 1. The effect of guanosine on L-[2,3-3H]glutamate uptake was investigated in
      brain cortical slices under normal or oxygen-glucose deprivation (OGD)
      conditions. 2. In slices exposed to physiological conditions, guanosine (1-100
      microM) stimulated glutamate uptake (up to 100%) in a concentration-dependent
      manner when a high (100 microM) but not a low (1 microM) concentration of
      glutamate was used. 3. In slices submitted to OGD, guanosine 1 and 100 microM
      also increased 100 microM glutamate uptake (38 and 70%, respectively). 4. The
      increasing of glutamate and taurine released to the incubation medium in cortical
      slices submitted to OGD were significantly attenuated by the presence of
      guanosine in the incubation medium. 5. Guanosine prevented the increase in
      propidium iodide incorporation into cortical slices induced by OGD, indicating a
      protective role against ischemic injury. 6. These results support the hypothesis
      of a protective role for guanosine during brain ischemia, possibly by activating
      glutamate uptake into neural cells.

PMID- 12469877
TI  - Effect of undernutrition on GMP-PNP binding and adenylate cyclase activity from
      rat brain.
AB  - 1. Undernutrition is an insult that affects brain development and functioning.
      Considering that signaling through metabotropic receptors/G proteins is critical
      for normal synaptic transmission and contributes to CNS development and synaptic
      plasticity, the present study investigated the effects of pre- and postnatal
      protein deprivation (diet: 8% protein; normonourished group: 25% protein) on
      brain signal transduction by G proteins. 2. Undernutrition decreased the [3H] GMP
      PNP binding to G proteins and AC activity, in neural plasma synaptic membranes of
      21- and 75-day-old rats. This effect was less pronounced or even absent in old
      rats. 3. Ontogenetically, the dietary treatment effect might be interpreted as a
      retarded development associated with protein malnutrition.

PMID- 12469878
TI  - Developmental changes in S100B content in brain tissue, cerebrospinal fluid, and
      astrocyte cultures of rats.
AB  - 1. We investigated the content of S100B protein by ELISA in three brain regions
      (hippocampus, cerebral cortex, and cerebellum) and in cerebrospinal fluid of rats
      during postnatal development as well as the content and secretion of S100B in pre
      and postconfluent primary astrocyte cultures. 2. An accumulation of S100B
      occurred in all brain regions with similar ontogenetic pattern between second and
      fourth postnatal weeks. However, we observed a decrease in the cerebrospinal
      fluid S100B after the critical period for synaptogenesis in rodents. 3. A similar
      profile of cell accumulation and decrease in basal secretion was also observed
      during aging of astrocyte cultures. 4. These data contribute to the proposal that
      S100B is an important glial-derived protein during brain development and that
      changes in extracellular levels of S100B may be related to glial proliferation
      and synaptogenesis.

PMID- 12469879
TI  - The unilateral spatial neglect phenomenon in patients with arteriovenous
      malformations of deep brain structures.
AB  - Clinical-neuropsychological investigations were performed in 187 patients with
      arteriovenous malformations (AVM) of deep brain structures; 28 had AVM of the
      caudate nucleus, 35 of the thalamus, 45 of the cingulate gyrus, 43 of the
      hippocampus, and 36 of the corpus callosum. A total of 47 patients displayed
      neglect phenomena of different modalities, while unfixed neglect was demonstrated
      in 40 cases using special tests. The vast majority of patients showed neglect of
      left-sided space and the left side of the body, while only three patients showed
      right-sided neglect. These three patients had signs of left-handedness. In the
      development of neglect in all patients was associated with post-hemorrhagic or
      post-operative damage to the white matter (the projections of sensory bundles of
      the parietal and occipital lobes, the periventricular white matter) or the
      thalamus and corpus callosum. In hemispheric lesions, neglect developed on the
      background of the corresponding derangements (hemihypesthesia hemianopsia) and
      were of the same modality. In cases of damage to the corpus callosum, neglect
      could develop without accompanying sensory disturbances or the phenomenon could
      occur on different sides (in cases of simultaneous left hemisphere damage). This
      supports the independent nature of the neglect phenomenon.

PMID- 12469880
TI  - Changes in neuroglial ultrastructure in various parts of the rat brain during
      manganese chloride poisoning.

PMID- 12469881
TI  - Morphofunctional characteristics of the gastrin-releasing peptide-synthesizing
      system of the hypothalamus in normal conditions and in experimental diabetes in
      rats.

PMID- 12469882
TI  - Morphological analysis of the formation of the clustered organization of neurons
      forming corticocortical connections in the visual cortex of the cat during early
      post-natal ontogenesis.

PMID- 12469883
TI  - The effects of glutamate on spontaneous acetylcholine secretion processes in the
      rat neuromuscular synapse.
AB  - Experiments on rat diaphragm muscles showed that glutamate (10 microM-1 mM) had
      no effect on the mean frequency, interspike intervals, and amplitude-time
      characteristics of miniature endplate potentials, but had a suppressive action on
      non-quantum secretion (the intensity of which was assessed in terms of the H
      effect). The effect of glutamate was markedly concentration-dependent and was
      completely overcome by blockade of NMDA receptors, inhibition of NO synthase, and
      by binding of NO molecules in the extracellular space by hemoglobin. It is
      suggested that glutamate can modulate the non-quantum release of acetylcholine,
      initiating the synthesis of NO molecules in muscle fibers via activation of NMDA
      receptors followed by the retrograde action of NO on nerve terminals.

PMID- 12469884
TI  - The effects of exogenous nitric oxide on the function of neuromuscular synapses.
AB  - Extracellular recording experiments using neuromuscular skin/chest muscle
      preparations from lake frogs were performed at low extracellular Ca2+ ion
      concentrations to study the effect of L-arginine (the substrate for nitric oxide
      synthesis) and N(G)-nitro-L-arginine methyl ester (a blocker of NO synthase) on
      the parameters of evoked transmitter secretion and ion currents in motor nerve
      endings. L-arginine at a concentration of 100 microM decreased the amplitude of
      endplate currents as well as their quantum composition, and also increased the
      amplitude of the third phase of the evoked nerve ending response, which reflects
      the kinetics of potassium influx currents. N(G)-nitro-L-arginine methyl ester at
      a condition of 100 microM led to increases in the amplitude and quantum
      composition of endplate currents and decreased the amplitude of the third phase
      of the evoked nerve ending response. It is suggested that endogenous nitric oxide
      is produced in frog neuromuscular synapses, which in normal conditions suppresses
      transmitter secretion and modulates the function of potassium channels in the
      nerve ending.

PMID- 12469885
TI  - The effects of carbachol on the proximal and distal parts of frog motor nerve
      endings.
AB  - Cholinomimetics not only activate postsynaptic cholinoreceptors in neuromuscular
      synapses, but also alter the process of acetylcholine secretion from nerve
      endings. However, the mechanism of action of cholinomimetics on the secretory
      process remains unidentified. We approached the question of the mechanism of the
      presynaptic action of cholinomimetics in the present study by investigating the
      effects of the n,m-cholinomimetic carbachol on nerve ending currents and
      postsynaptic membrane currents. Carbachol induced decreases in the postsynaptic
      response, without affecting the duration and amplitude of the nerve ending
      current in both the central and distal part of the nerve ending. However,
      carbachol increased the time between the arrival of the presynaptic action
      potential and the start of transmitter secretion. This effect on synaptic delay
      was more marked in the distal parts of the ending. The action of another
      potential modulator, extracellular potassium, was accompanied by decreases in
      presynaptic currents and also by increases in synaptic delay. These data provide
      evidence for the suppressive effect of carbachol on acetylcholine secretion
      acting via presynaptic metabotropic cholinoreceptors which control the level and
      time course of secretion of neurotransmitter quanta.

PMID- 12469886
TI  - The disinhibitory zone of the striate neuron receptive field and its sensitivity
      to cross-like figures.
AB  - Acute experiments on immobilized anesthetized cats were used to confirm the
      suggestion that the sensitivity of many neurons on the primary visual cortex to
      cross-shaped, angular, and Y-shaped figures may be determined by the presence
      within their receptive fields of disinhibitory zones, which block end-stopping
      inhibition. A total of 55 neurons (84 functions, i.e.. on and off responses) were
      used for studies of sensitivity to crosses, and responses to single bars of
      different lengths were compared before and after stimulation of an additional
      lateral zone of the field (the presumptive disinhibitory zone), which was located
      in terms of responses to crosses. Seventeen of the 55 cells in which increases in
      the length of a single bar decreased responses, i.e., which demonstrated end
      stopping inhibition, showed significant increases in responses (by an average
      factor of 2.06 +/- 0.16) during simultaneous stimulation of the lateral zone of
      the receptive field, which we interpreted as a disinhibitory effect on end
      stopping inhibition. These data provide the first direct evidence for the role of
      end-stopping inhibition and its blockade by the disinhibitory zone of the
      receptive field in determining the sensitivity of some neurons in the primary
      visual cortex of the cat to cross-shaped figures.

PMID- 12469887
TI  - Induction of the estrogen effect-switching phenomenon by ethanol and its
      correction.
AB  - Female rats (aged three months at the start of the study) were kept for four
      months on drinking water (group 1) or 5% ethanol. Rats drinking ethanol were
      additionally divided into six groups (groups 2-7). During the next two months of
      the experiment, animals of group 2 continued to drink only ethanol, while rats of
      group 3 additionally received N-acetylcysteine, those of group 4 received
      ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E), those of group 5
      received melatonin, those of group 6 received carnosine, and those of group 7
      swam in the so-called training regime for five days a week. All animals underwent
      bilateral ovariectomy 2.5 weeks before experiments ended, and were given daily
      i.m. estradiol (2 microg) during the 11 days before the last experimental day.
      After treatments, blood estradiol and cholesterol levels were measured, along
      with progesterone receptor levels, peroxidase activity, the index of
      proliferation, the proportions of cells in the S and G2/M phases, the thickness
      of the endometrium, and the extent of DNA damage (using the "comet" technique) in
      uterine tissue. Liver estradiol 2-hydroxylase activity was also measured. The
      results led to the conclusion that drinking of 5% ethanol in combination with
      administration of estrogens was accompanied by induction of genotoxic (G) changes
      in the uterus and that this was prevented by administration of N-acetylcysteine
      and melatonin. The combination of vitamins C and E increased some of the
      manifestations of the hormonal (H) effect of estrogens (uterine weight and
      induction of progesterone receptors), but weakened others (the index of
      proliferation). As a result, the combination of N-acetylcysteine and optimum
      doses of ascorbic acid and alpha-tocopherol can be recommended for preventing the
      estrogen effect-switching phenomenon (increases in the G component on the
      background of weakening of the H component), which is seen particularly in
      patients consuming excessive amounts of alcohol, increasing the risk that the
      genotoxic version of hormonal cancerogenesis will develop.

PMID- 12469888
TI  - The effects of corticoliberin at different concentrations on long-term
      potentiation in slices of rat olfactory cortex.
AB  - Experiments were performed to investigate evoked focal potentials in slices of
      rat olfactory cortex. The results showed that 1 microM corticotropin-releasing
      factor (CRF; corticoliberin) increases the frequency of posttetanic potentiation,
      which had a shorter delay phase than in control experiments. Posttetanic
      potentiation during perfusion with 0.1 microM corticoliberin had a longer delay
      phase than in control experiments.

PMID- 12469889
TI  - A method for assessing the kinetics of evoked secretion of transmitter quanta
      determining the generation of multiquantum endplate currents.

PMID- 12469891
TI  - Studies of the mechanism of development of "deprivation" potentiation of
      population responses of neurons in field CA1 of living hippocampal slices.
AB  - Experiments on rat hippocampal slices were performed with testing of the synaptic
      connections of Schaffer collaterals and neurons in field CA1 to study the effects
      of interrupting low-frequency test stimulation (0.05 Hz) on the amplitude of
      population spikes. These studies demonstrated a correlation between the duration
      of pauses in stimulation (form 10 to 120 min) and increases in the amplitude of
      spikes (on average by 30-100% of baseline response magnitude). This "deprivation"
      potentiation was additive and could persist for long periods of time (testing was
      up to 1 h). Preliminary induction of long-term post-tetanic potentiation, which
      prevented the subsequent development of the late, but not the shortterm phase,
      for 1-3 h, led to suppression of the development of "deprivation" potentiation
      after a 60-min pause in stimulation. Similar results were obtained in experiments
      using 20 microM polymyxin B, which blocks protein kinase C and the PKC-dependent
      phase of long-term post-tetanic potentiation; this is evidence supporting the
      previously advanced hypothesis that the development of deprivation potentiation
      and the late. PKC-dependent phase of long-term post-tetanic potentiation share
      common mechanisms, associated with people phosphorylation.

PMID- 12469890
TI  - Somatosensory evoked potentials during natural and learning rearrangements of
      posture accompanied by limb elevation in dogs.
AB  - Changes in the functional state of the sensorimotor cortex associated with
      reorganization of the natural pattern of postural rearrangement before limb
      elevation (the "diagonal" patten and of an artificial rearrangement (the
      "unilateral" pattern) were studied in dogs. The state of cortical structures on
      postural rearrangement was assessed in terms of the pattern of somatosensory
      evoked potentials produced in response to stimulation of the forelimb during
      postural preparation of the animal for elevating the hindlimb (acquired avoidance
      response to a sound signal). Evoked potentials during the natural postural
      preparation (the "diagonal" pattern) were compared with those during the altered
      pattern of postural preparation (the "unilateral" pattern), this preparation
      taking place prior to elevation of the limb. Controls consisted of evoked
      potentials in the resting state. Decreases were seen in the latencies and
      amplitudes of most components of evoked potentials during postural rearrangement.
      In general, changes in evoked potentials were less marked in the "unilateral"
      pattern than in the "diagonal" pattern, though the differences were significant
      only for the amplitude of the first negative component. Changes in evoked
      potentials were similar regardless of whether the supporting forces of the limb
      to which the test stimulus was applied increased or decreased during postural
      rearrangement. It is suggested that differences in evoked potentials may reflect
      changes in the interaction between neuronal populations within the sensorimotor
      cortex during reorganization of the pattern of postural rearrangement associated
      with learning.

PMID- 12469892
TI  - Network activity in neurons of the motor and prefrontal areas of the cortex in
      trained cats in conditions of systemic administration of m-cholinoreceptor
      blockers.
AB  - Experiments on five cats already trained to an operant conditioned food-procuring
      reflex to light were used to study the network activity of cells in the frontal
      and motor areas of the cortex accompanying disruption of conditioned reflex
      behavior in conditions of systemic administration of m-cholinoreceptor blockers.
      The activity of cortical neurons and their network properties were assessed using
      auto- and cross-correlation histograms. Doses of central m-cholinoreceptor
      blockers (the non-selective blocker scopolamine and the relatively selective m1
      cholinoreceptor blocker trihexyphenidyl) disrupted performance of the operant
      motor reflex but had no effect on the appearance of contextual behavior and
      responses to switching on of the conditioned signal (standing up, elevating the
      paw). This was accompanied by 1) changes in the patterns of neuron activity in
      the moor and frontal areas of the cortex, with increases in train, rhythmic, and
      rhythmic train activity in cortical cells; 2) appearance of synchronicity in the
      operation of cortical neurons; 3) decreases in the numbers of direct
      interneuronal connections in the motor and frontal areas of the cortex and in the
      numbers of connections between these structures.

PMID- 12469893
TI  - Extinction of a conditioned defensive reflex in cats after lesioning of the
      entopeduncular nucleus.

PMID- 12469894
TI  - Studies of selective attention in dogs using the energy characteristics of
      neocortical potentials in the frequency range 1-220 Hz.
AB  - Experiments were performed in dogs to study the state of selective attention
      formed during operant food-related training and apparent during interstimulus
      intervals as a state of tense expectation of the conditioned signal. Electrical
      activity in various parts of the neocortex, in both hemispheres, was analyzed in
      the frequency range 1-220 Hz (epidural electrodes) using Fourier transforms. The
      electrical activity of the motor area of the right hemisphere showed a
      predominance of high-frequency (40-200 Hz) components, as did the visual and
      parietal areas of the left hemisphere. The state of selective attention was
      associated with a different functional mosaic in the organization of neocortical
      electrical activity.

PMID- 12469895
TI  - LPS-induced cytokine production in the monocytic cell line THP-1 determined by
      multiple quantitative competitive PCR (QC-PCR).
AB  - BACKGROUND: Quantifying cytokines on the protein level can be problematic because
      of low concentrations or degradation during sample handling. Aiming towards
      finding a simple method by which to quantify cytokines on the mRNA level, we
      combined existing and established molecular biology techniques. Based on the
      principle of quantitative competitive RT-PCR with a DNA-competitor, IL-1beta, IL
      6, IL-12alpha and the housekeeping enzyme GAPDH are measured at levels down to
      200 copies of mRNA. METHODS: As a source of mRNA, the total RNA from 4 samples of
      5 x 10(6) THP-1 cells stimulated with LPS (1 microg/ml for 24 h) was isolated.
      For competitors, we constructed sequences similar to the target sequences, but
      with deletion or insertion of 10-15% of the target length. For validating this
      method, we performed first strand synthesis on different days using different
      amounts of RNA (1-4 microg) isolated from the same pool of cells. Quantitative
      competitive PCR was accomplished using different amounts of cDNA (0.125-4
      microL). Using IL-1beta as an example, the assay was validated for a dynamic
      range of 5-300 x 10(3) copies. RESULTS: A linear correlation was found between
      output and amount of RNA for cDNA synthesis, signifying that the final result of
      the analysis was linearly related to the amount of RNA or cDNA when operating
      within the range 1-4 microg (RNA isolation). CONCLUSION: The quantitative,
      competitive RT-PCR produces highly reproducible results within a 60-fold dynamic
      range.

PMID- 12469896
TI  - Twenty-four-hour blood pressure among Greenlanders and Danes: relationship to
      diet and lifestyle.
AB  - BACKGROUND: Greenlanders have a lower rate of cardiovascular mortality and
      morbidity than Danes, possibly due to lower blood pressure. However, 24-h blood
      pressure has never been measured in Greenlanders. The aim of this study was to
      compare the 24-h blood pressure of Greenlanders and Danes, and to analyse the
      influence of Arctic food and lifestyle on blood pressure. METHODS: Four groups of
      healthy subjects were recruited for the study. Group I: Danes in Denmark
      consuming European food; group II: Greenlanders in Denmark consuming European
      food; group III: Greenlanders in Greenland consuming mainly European food; and
      group IV: Greenlanders in Greenland consuming mainly traditional Greenlandic
      food. All subjects underwent a physical examination, laboratory screening of
      blood and urine samples, and completed a questionnaire on diet, physical
      activity, smoking status, intake of alcohol, liquorices, vitamins and minerals.
      Twenty-four-hour blood pressure was measured. RESULTS: It was found that 24-h
      diastolic blood pressure was lower in Greenlanders than in Danes for the whole 24
      h period and during both day and night-time, whereas systolic blood pressure was
      the same (mean 24-h blood pressure with 95% CI: Danes 123/75 mmHg (120/73
      127/77), Greenlanders 122/ 69 (119/68-124/70)). Among Greenlanders, blood
      pressure increased with age and male gender, and systolic blood pressure
      increased with body mass index (BMI). No association with diet was found. The
      difference between the two populations persisted after controlling for age,
      gender, BMI, outdoor temperature, and lifestyle factors. CONCLUSION: Greenlanders
      have a lower 24-h diastolic blood pressure than Danes, and it is suggested that
      genetic factors are mainly responsible for the lower blood pressure level among
      Greenlanders.

PMID- 12469897
TI  - Development of monoclonal antibodies against creatine kinase MB2.
AB  - An increase of creatine kinase MB (CKMB) in serum has long been used as a marker
      for acute myocardial infarction (AMI). It is important with an early diagnosis
      and since the amount of the CKMB2 isoform rises above reference levels much
      earlier than the total creatine kinase amount, quantification of CKMB isoforms
      could be a feasible alternative for early analysis. The two CKMB isoforms differ
      by only one C-terminal lysine residue, which makes it difficult to separate one
      from the other. To overcome this problem, monoclonal antibodies were produced
      using unique peptides as antigen in hybridoma technology. Two peptides with 16
      and 15 amino acids corresponding to the C-terminal end of the M-subunits of CKMB2
      and CKMB1, respectively, were conjugated to keyhole limpet hemocyanin and used as
      antigens. Sixteen different monoclonal antibodies to these peptides were obtained
      and characterized. Their specificity was analyzed by immunoassay and 10 of the
      antibodies showed cross-reactive binding to creatine kinase. Surface plasmon
      resonance based biosensor analysis was used to determine affinity and kinetics
      towards the peptides and the epitopes of four of the antibodies were studied by
      means of phage display. Some of these antibodies have binding properties that
      might qualify them for use in the establishment of procedures allowing early
      diagnosis of AMI.

PMID- 12469899
TI  - Identification of determinants of the between-operator variation of the total
      protein S antigen assay: a collaborative study of the Dutch Working Group on
      Haemostasis Laboratory Diagnosis.
AB  - In a previous study, a between-operator variability (CVOBETWEEN) of 9.6% and
      15.0%) was observed for total protein S antigen assays in 11 laboratories using a
      frozen or lyophilized reference plasma, respectively, and the need to standardize
      the use of lyophilized reference plasma was identified. The aim of the present
      study was to identify further determinants of this CVOBETWEEN in order to improve
      between-laboratory comparisons of test results for one method for protein S
      antigen assay. Two protocols were carried out: the first again involving local
      execution but using a joint standardized and detailed prescription of the
      technical performance in each laboratory; the second using a central session for
      all operators with the same prescription but with joint reagent and equipment. In
      the present study, improved handling of lyophilized reference plasma was included
      and resulted in comparable CVOBETWEEN of 10.9% and 9.6% for the use of frozen and
      lyophilized reference plasma for the local test performance. An improvement was
      found in the CVOBETWEEN in the central session compared with the standardized
      local performance, showing lower values for the central performance of 8.5 and
      6.6% for frozen and lyophilized reference plasma, respectively. Further analysis
      of the difference between the local and central test performance identified the
      use of different curve fit options of data evaluation software as a significant
      source of this difference. Interestingly, the within-operator variability in the
      central performance was around 2% lower (5.9 and 6.0% for frozen and lyophilized
      plasma, respectively) than that in the local performance (8.1 and 8.0% for frozen
      and lyophilized plasma, respectively). Although the reduction is not
      statistically significant, it suggests an effect of reduction of the workload and
      simplification of procedures for individual operators on the within-operator
      variability. In this study, in which 11 operators/laboratories participated, the
      lowest variability between operators andwithin laboratories was obtained in the
      central test performance, which is suggested to be the lowest attainable
      variability for the measurement of total protein S antigen. The practical factors
      involved in local performance that require attention to reach similar levels of
      variability are mainly liquid handling, curve-fit procedures and simplicity of
      practical procedures.

PMID- 12469900
TI  - Leucocyte activation by collagen-stimulated platelets in whole blood.
AB  - Interaction between vascular cells plays an important role in the initial phases
      of the inflammatory process, but the mechanisms responsible for cell-cell
      communication are not fully understood. In this study, activation of leucocytes
      and platelets in heparinized whole blood was assessed using lumi-aggregometry.
      This technique enables simultaneous measurement of aggregation and oxygen radical
      production by monitoring impedance and luminol-amplified chemiluminescence (CL),
      respectively. Collagen induced aggregation and CL, depending on dose, and
      markedly enhanced subsequent aggregation and CL-response triggered by the
      chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe).
      Collagen stimulation of whole blood down- and upregulated the expression of L
      selectin and CD11b, respectively. Monoclonal antibodies against sialyl LewisX and
      P-selectin caused a pronounced inhibition of the oxidative burst, triggered by
      collagen itself or by a combination of collagen and fMet-Leu-Phe. Furthermore,
      the Arg-Gly-Asp-Ser(RGDS)-peptide effectively inhibited collagen-triggered
      aggregation and CL, and the subsequent enhancement of the fMet-Leu-Phe-induced
      responses. This suggests that fibrinogen plays a part in linking platelet
      GpIIb/IIIa with CD11b on the leucocyte surface. However, neither anti-CD11b nor
      the PI-peptide (containing the gamma-chain motif in fibrinogen that interacts
      with CD11b) counteracted the stimulatory effects of activated platelets on
      leucocyte functions. The selectin- and integrin-antagonizing substances were
      ineffective on the CL-responses induced by fMet-Leu-Phe itself. This study
      suggests that, through selectin- and integrin-dependent interaction, activated
      platelets potentiate leucocyte aggregation and oxygen radical production, which
      might be important for the outcome of inflammatory reactions.

PMID- 12469898
TI  - Reactive oxygen species generation by leukocytes in populations at risk for
      atherosclerotic disease.
AB  - The aim of this study was to investigate intracellular levels of reactive oxygen
      species (ROS) in circulating leukocytes in populations at risk for
      atherosclerosis compared with in healthy individuals. The study populations
      consisted of 27 non-diabetic men (aged 40-69 years) with untreated
      hypercholesterolemia (HC), 13 individuals (aged 39-56 years) with well-controlled
      insulin-dependent diabetes mellitus (DM), and 20 healthy individuals (aged 26-61
      years) (REF). Citrated whole blood was collected in fasting condition. Using flow
      cytometric techniques, the resting levels and the response upon phorbol 12
      myristate 13-acetate (PMA, 100 ng/mL) stimulation of ROS were measured in
      circulating monocytes (MO) and granulocytes (GR). The relative mean fluorescence
      intensity (rMFI) in 10(4) leukocytes of fluorochromes mainly reflecting the
      levels of peroxynitrite (ONOO-) hydrogen peroxide (H2O2) and superoxide anion (O2
      ) was recorded. Significantly, higher basal levels of ONOO- in GR from the
      combined risk population compared with REF were found (1.4 vs. 1.5 rMFI, p<0.05).
      Upon PMA stimulation, significantly lower levels of O2 in GR in the risk
      populations compared to REF (119 vs. 90 Si, p<0.001) were observed. In
      conclusion, increased resting levels of ROS in circulating granulocytes, but
      reduced response to PMA stimulation could be demonstrated in populations at risk
      for atherosclerosis compared with in healthy individuals. This might indicate a
      higher degree of resting oxidative reactions, with partly exhausted cells and
      less capacity to host defence.

PMID- 12469901
TI  - Evidence of increased oxidative stress by simple measurements in patients with
      dilated cardiomyopathy.
AB  - The heart cannot supply sufficient blood for tissue metabolic needs in patients
      with congestive heart failure. Hypoxia and organ hypoperfusion increase oxidative
      activity. It has been reported that free radicals are involved in the genesis of
      heart failure. The aim of this study was to assess the status of oxidative stress
      by simple measurements in patients with dilated cardiomyopathy of ischemic or
      idiopathic etiology. Eleven patients (8 M, 3 F, age range 32 to 65 years) with
      dilated cardiomyopathy of ischemic etiology and 12 patients (8 M, 4 F, age range
      31 to 66 years) with dilated cardiomyopathy of idiopathic etiology were included
      in the study. A control group included 21 healthy subjects (12 M, 9 F, age range
      25 to 67 years). Levels of thiobarbituric acid-reactive substances, total thiols,
      and fluorescent products of lipid peroxidation were measured in plasma/serum
      samples of patients and controls. No statistically significant differences were
      found between the two patient groups for the parameters studied (p>0.05). Levels
      of thiobarbituric acid-reactive substances and fluorescent products of lipid
      peroxidation were higher in both patient groups than in controls (p<0.05),
      whereas concentrations of total thiols were decreased (p<0.05). In conclusion, in
      patients with idiopathic or ischemic dilated cardiomyopathy, there are associated
      abnormalities of a range of markers of increased oxidative stress and lipid
      peroxidation. The plasma/serum constituents studied can be routinely measured in
      order to monitor patients during antioxidant therapy.

PMID- 12469902
TI  - Angiotensin I-converting enzyme gene polymorphism in a Serbian population: a
      gender-specific association with hypertension.
AB  - Human essential hypertension has a multifactorial origin and is caused by a
      delicate interaction between susceptibility genes and environmental factors.
      Candidate genes are selected from the renin-angiotensin system (RAS) and are
      physiologically implicated in blood pressure regulation. We investigated the
      association between insertion/deletion (I/D) polymorphism at the angiotensin
      converting enzyme (ACE) locus and hypertension in a case-control study conducted
      in a population of Caucasians (175 females, 210 males). Case subjects were those
      with untreated borderline hypertension. A significant, moderate, male, gender
      specific independent association between DD genotype and high blood pressure was
      found. Adjusted odds ratio (OR) was 2.0 (95% CI, 1.1 to 3.9; p=0.03) in the whole
      group and 2.5 (95% CI, 1.2 to 5.1; p=0.01) in the group truncated on the basis of
      age (< or = 50 years). Our findings support the hypothesis that ACE is a gender
      specific candidate gene for hypertension.

PMID- 12469903
TI  - Effect of acute Chlamydia pneumoniae infection on lipoprotein metabolism in NIH/S
      mice.
AB  - Chlamydia pneumoniae is a well-known cause of respiratory infections, globally.
      Chronic C. pneumoniae infection has been associated with atherosclerosis. The aim
      of the present study was to investigate the effects of acute C. pneumoniae
      infection on serum lipid levels and some regulatory proteins/enzymes in NIH/S
      mice. Female mice (n=30) were intranasally infected with 5.3*10(5) inclusion
      forming units (IFU) of C. pneumoniae and control mice (n = 30) were inoculated
      with buffer. Six uninoculated mice at day 0 and then six mice from each group 3,
      6, 9, 14 and 20 days post-inoculation were killed and serum samples were
      collected for analysis. Successful infection was confirmed by IgG response to C.
      pneumoniae and positive Chlamydia cultivation from the lungs. Serum triglycerides
      and total cholesterol, as well as the activities of hepatic lipase (HL), lecithin
      cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) and
      the concentration of lipopolysaccharide-binding protein (LBP) were analyzed. In
      C. pneumoniae infected mice, a minor change in triglyceride (corrected p-value
      0.020) levels was observed 9 days post-infection (p.i.). LCAT activity declined
      remarkably, and the lowest activities were measured on day 9 p.i. (67% from the
      baseline value). HL and PLTP activities did not differ from those in the control
      group during the whole experimental period. There was a 2.5-fold increase in the
      serum LBP concentration owing to the C. pneumoniae infection 9 days p.i. The data
      indicate that acute C. pneumoniae infection, although clinically almost
      asymptomatic, causes small, transient changes in serum total lipids and some key
      proteins involved in lipoprotein metabolism in mice.

PMID- 12469904
TI  - Pathophysiology and recent advances in the management of renal osteodystrophy.
AB  - Bone disease is observed in 75-100% of patients with chronic renal failure as the
      glomerular filtration rate (GFR) falls below 60 ml/minute. Hyperparathyroid (high
      turnover) bone disease is found most frequently followed by mixed osteodystrophy,
      low-turnover bone disease, and osteomalacia. With advancing renal impairment,
      "skeletal resistance" to parathyroid hormone (PTH) occurs. To maintain bone
      turnover, intact PTH (iPTH) targets from two to four times the upper normal range
      have been suggested, but whole PTH(1-84) assays indicate that amino-terminally
      truncated fragments, which accumulate in end-stage renal disease (ESRD), account
      for up to one-half of the measured iPTH. PTH levels and bone-specific alkaline
      phosphatase (BSAP) provide some information on bone involvement but bone biopsy
      and histomorphometry remains the gold standard. Calcitriol and calcium salts can
      be used to suppress PTH and improve osteomalacia but there is growing concern
      that these agents predispose to the development of vascular calcification,
      cardiovascular morbidity, low-turnover bone disease and fracture. Newer
      therapeutic options include less calcemic vitamin D analogues, calcimimetics and
      bisphosphonates for hyperparathyroidism, and sevelamer for phosphate control.
      Calcitriol and hormone-replacement therapy (HRT) have been shown to maintain bone
      mineral density (BMD) in certain patients with end-stage renal disease (ESRD).
      After renal transplantation, renal osteodystrophy generally improves but BMD
      often worsens. Bisphosphonate therapy may be appropriate for some patients at
      risk of fracture. When renal bone disease is assessed using a combination of
      biochemical markers, histology and bone densitometry, early intervention and the
      careful use of an increasing number of effective therapies can reduce the
      morbidity associated with this common problem.

PMID- 12469905
TI  - Comprehensive microarray analysis of bone morphogenetic protein 2-induced
      osteoblast differentiation resulting in the identification of novel markers for
      bone development.
AB  - Osteoblasts are cells responsible for matrix deposition during bone development
      and although temporal expression of many genes has been related to osteoblast
      differentiation, a complete description of osteoblast-specific gene regulation
      will lead to a better understanding of osteoblast function. In this study,
      microarray technology was used to analyze gene expression on a broad scale during
      osteoblast differentiation. Expression analysis of 9596 sequences revealed 342
      genes and expressed sequence tags (ESTs) to be modulated differentially during a
      time course experiment in which murine C2C12 mesenchymal progenitor cells were
      induced to differentiate into mature osteoblasts by treatment with bone
      morphogenetic protein 2 (BMP-2). By means of hierarchical clustering, these genes
      were grouped by similarities in their expression profiles, resulting in subsets
      of early, intermediate, and late response genes, which are representative of the
      distinct stages of osteoblast differentiation. To identify new bone markers, the
      bone specificity of the late response genes was determined by comparing BMP
      induced expression in C2C12 and MC3T3 osteoblasts with that in NIH3T3
      fibroblasts. This resulted in the identification of nine novel genes and ESTs
      that were induced specifically in osteoblasts, in addition to the well-known
      markers ALP and osteocalcin. For at least one of these novel genes, Wnt
      inhibitory factor 1, and two of the ESTs, expression in developing bone was
      verified in vivo by in situ hybridization of E16.5 mouse embryos. In conclusion,
      by a combination of in vitro and in vivo screening approaches, a set of new genes
      related to osteoblast differentiation and skeletal development has been
      identified.

PMID- 12469907
TI  - RGD peptides immobilized on a mechanically deformable surface promote osteoblast
      differentiation.
AB  - The major objective of this work was to attach bone cells to a deformable surface
      for the effective transmission of force. We functionalized a silastic membrane
      and treated it with 3-aminopropyltriethoxysilane (APTS). A minimal RGD peptide
      was then covalently linked to the aminated surface. MC3T3-E1 osteoblast-like
      cells were cultured on the arginine-glycine-aspartic acid (RGD)-treated membrane
      for 3-15 days and cell attachment and proliferation was evaluated. We observed
      that cells were immediately bound to the membrane and proliferated. After 8 days
      on the material surface, osteoblasts exhibited high levels of ALP staining,
      indicating that the cells were undergoing maturation. Alizarin red staining and
      Fourier transform infrared (FTIR) analysis showed that the mineral formed by the
      cells was a biological apatite. The second objective was to apply a mechanical
      force to cells cultured on the modified silicone membrane. Dynamic equibiaxial
      strain, 2% magnitude, and a 0.25-Hz frequency were applied to bone cells for 2 h.
      Osteoblasts elicited increased phalloidin fluorescence, suggesting that there was
      reorganization of the cytoskeleton. Furthermore, the applied strain elicited
      increased expression of the alpha(v)beta3 integrin receptor. We concluded that
      the covalent binding of RGD peptides to a silicone membrane provides a compatible
      surface for the attachment and subsequent differentiation of osteoblasts.
      Moreover, the engineered surface transduces applied mechanical forces directly to
      the adherent cells via integrin receptors.

PMID- 12469906
TI  - Microarray analysis of bone morphogenetic protein, transforming growth factor
      beta, and activin early response genes during osteoblastic cell differentiation.
AB  - Bone morphogenetic protein (BMP) 2, a member of the transforming growth factor
      (TGF) beta family, is a potent regulator of osteoblast differentiation. In
      addition, both TGF-beta and activin A can either induce bone formation or inhibit
      bone formation depending on cell type and differentiation status. Although much
      is known about the receptors and intracellular second messengers involved in the
      action of TGF-beta family members, little is known about how selectivity in the
      biological response of individual family members is controlled. In this study, we
      have investigated selective gene induction by BMP-2, TGF-beta1 and activin A in
      relation to their ability to control differentiation of mouse mesenchymal
      precursor cells C2C12 into osteoblastic cells. TGF-beta1 can inhibit BMP-2
      induced differentiation of these cells, whereas activin A was found to be without
      morphogenetic effect. Using a gene expression microarray approach covering 8636
      sequences, we have identified a total of 57 established genes and expressed
      sequence tags (ESTs) that were either up-regulated or down-regulated 2 h after
      treatment with at least one of these three stimuli. With respect to the
      established genes, 15 new target genes for TGF-beta family members thus were
      identified. Furthermore, a set of transcripts was identified, which was
      oppositely regulated by TGF-beta1 and BMP-2. Based on the inverse biological
      effects of TGF-beta1 and BMP-2 on C2C12 cells, these genes are important
      candidates for controlling the process of growth factor-induced osteoblast
      differentiation.

PMID- 12469908
TI  - Bone morphogenetic protein-mediating receptor-associated Smads as well as common
      Smad are expressed in human articular chondrocytes but not up-regulated or down
      regulated in osteoarthritic cartilage.
AB  - Bone morphogenetic proteins (BMPs) are supposed to be important for cartilage
      matrix anabolism. In this study, we investigated whether the intracellular
      mediators of BMP activity, Smads 1, 4, 5, and 8, are expressed in normal human
      articular chondrocytes in vivo and in vitro and whether alterations in expression
      and distribution pattern are found in osteoarthritic cartilage or in vitro after
      stimulation with interleukin (IL)-1, because down-regulation of these mediators
      could be responsible for the decrease of anabolic activity in osteoarthritic
      cartilage. RNA was isolated from normal and osteoarthritic human knee cartilage
      and analyzed by (quantitative) polymerase chain reaction (PCR) technology.
      Articular chondrocytes were cultured in alginate beads and short-term high
      density monolayer cultures with and without stimulation by IL-1. In addition,
      immunolocalization of the receptor-associated Smads (R-Smads) was performed on
      sections of normal and diseased articular cartilage. Reverse-transcription (RT)
      PCR analysis showed a moderate expression of all Smads investigated in normal,
      early degenerative, and late stage osteoarthritic cartilage. Immunolocalization
      detected the R-Smads in most chondrocytes on the protein level in all specimen
      groups investigated. In vitro, the Smads were also expressed and partly up
      regulated by Il-1beta in alginate bead culture. Of note, for Smad 1, two
      truncated splice variants were expressed by articular chondrocytes missing exon 4
      as well as exons 3 and 4. Our study showed that BMP-receptor Smads 1, 5, and 8 as
      well as common Smad (C-Smad) 4 are expressed and present in human normal and
      osteoarthritic articular chondrocytes corroborating the importance of BMPs and
      BMP signaling for articular cartilage. This study is the first to describe
      splicing variants for Smad 1. Smads 1, 4, and 5 are up-regulated in vitro by Il
      1beta, suggesting a linkage of the Il-1 and BMP-signaling pathways within the
      chondrocytes. None of the Smads were grossly up- or down-regulated in
      osteoarthritic chondrocytes, suggesting that differences in overall expression
      levels of the investigated Smad proteins are not relevant for metabolic activity
      of articular chondrocytes in vivo.

PMID- 12469909
TI  - The zinc finger transcription factor Zfp60 is a negative regulator of cartilage
      differentiation.
AB  - The differentiation of many mesenchyme-derived cells, including cells that form
      bone and cartilage, is regulated at the level of gene transcription, but many of
      the factors involved in this regulation remain to be identified. In this study, a
      modified RNA fingerprinting technique was used to identify the KRAB domain zinc
      finger transcription factor Zfp60 as a candidate regulator of cell
      differentiation in mouse calvaria primary cultures. The highest expression of
      Zfp60 mRNA in vivo was found between embryonic day 11 (E11) and E15 during mouse
      embryonic development, coinciding with stages of active organ formation. The
      expression of Zfp60 mRNA and protein was analyzed further in mouse embryos during
      skeletal development. The most prominent expression was found in prehypertrophic
      chondrocytes, where it coincides with the expression of key regulators of
      chondrocyte maturation, Indian hedgehog (Ihh), and the parathyroid hormone
      related peptide (PTHrP) receptor. Zfp60 mRNA was also found transiently expressed
      during chondrogenesis of C1 cells in vitro, preceding collagen type X expression
      and cellular hypertrophy. Overexpression of Zfp60 inhibited cartilage
      differentiation in the chondrogenic ATDC5 cell line. These results suggest a role
      for Zfp60 as a negative regulator of gene transcription, specifically during the
      development and/or differentiation of chondrocytes.

PMID- 12469910
TI  - Tissue transglutaminase and its substrates in bone.
AB  - Tissue transglutaminase (tTG) is an intra- and extracellular, protein-cross
      linking enzyme that has been implicated in apoptosis, matrix stabilization, and
      cell attachment in a variety of tissues. This study provides in vivo evidence in
      bone of TG activity, its tissue localization, and identification of its
      substrates. In microplate- and blotting-based activity assays using biotinylated
      primary amine as a probe, we show TG activity in protein extracts from the
      mineralized compartment of intramembranous rat bone. Avidin affinity purification
      of bone extract labeled with biotinylated primary amine in the presence of tTG,
      in conjunction with Western blotting, permitted identification of three major
      noncollagenous TG substrates in bone: osteopontin (OPN), bone sialoprotein (BSP),
      and alpha2 HS-glycoprotein (AHSG), of which the latter two are novel substrates.
      Cross-linking and labeling of purified proteins confirmed their ability to serve
      as TG substrates, because they readily incorporated biotinylated primary amine
      and formed large protein aggregates in the presence of tTG. All three proteins
      were also identified in the high molecular weight complexes extractable from the
      mineralized compartment of bone. Two-dimensional (2D) gel electrophoretic
      analysis combined with Western blotting indicated that the proteins are not cross
      linked to each other, but form distinct homotypic polymers. In the extracellular
      matrix of bone, tTG and isopeptide bonds were localized by immunohistochemistry
      in the osteoid and in the pericellular matrix surrounding osteocytes. At the
      cellular level, osteoblasts and osteocytes were immunostained for tTG.
      Collectively, these data suggest a role for tTG and its covalently cross-linked
      substrates in cell adhesion and possibly also in bone matrix maturation and
      calcification.

PMID- 12469911
TI  - Familial hypocalciuric hypercalcemia caused by an R648stop mutation in the
      calcium-sensing receptor gene.
AB  - In this study, we report an 84-year-old female proband in a Japanese family with
      familial hypocalciuric hypercalcemia (FHH) caused by an R648stop mutation in the
      extracellular calcium-sensing receptor (CaR) gene. At the age of 71 years, she
      presented with hypercalcemia (11.4 mg/dl), hypocalciuria (Cca/Ccr = 0.003),
      hypermagnesemia (2.9 mg/dl), and a high-serum parathyroid hormone (PTH) level
      (midregion PTH, 3225 [160-520] pg/ml). At the age of 74 years, a family screening
      was carried out and revealed a total of 9 hypercalcemic individuals (all intact
      PTH values <62 pg/dl) among 17 family members tested, thus, being diagnosed as
      FHH. Two and one-half of three clearly enlarged parathyroid glands were resected,
      because persistently high PTH levels (intact PTH, 292 pg/ml; midregion PTH, 5225
      pg/ml) and the presence of a markedly enlarged parathyroid gland by several
      imaging modalities (ultrasonography, computed tomography [CT], magnetic resonance
      imaging [MRI], and subtraction scintigraphy) suggested coexistent primary
      hyperparathyroidism (pHPT); however, hypercalcemia persisted postoperatively.
      Histological and immunohistochemical examination revealed that the resected
      parathyroid glands showed lipohyperplasia as well as normally expressed Ki67,
      vitamin D receptor (VDR), and the CaR. Sequence analysis disclosed that the
      proband and all affected family members had a heterozygous nonsense (R648stop)
      mutation in the CaR gene. This mutation is located in the first intracellular
      loop; thus, it would be predicted to produce a truncated CaR having only one
      transmembrane domain (TMD) and lacking its remaining TMDs, intracellular loops,
      and C-terminal tail. Western analysis of biotinylated HEK293 cells transiently
      transfected with this mutant receptor showed cell surface expression of the
      truncated protein at a level comparable with that of the wild-type CaR. The
      mutant receptor, however, exhibited no increase in intracellular free calcium
      concentration (Ca2+i) when exposed to high extracellular calcium concentrations
      (Ca2+o). The proband's clinical course was complicated because of associated
      renal tubular acidosis (RTA) and nephrotic syndrome. However, it was unclear
      whether their association affected the development of elevated serum PTH and
      parathyroid gland enlargement. This report is the first to show that an R648stop
      CaR mutation yields a truncated receptor that is expressed on the cell surface
      but is devoid of biological activity, resulting in FHH.

PMID- 12469912
TI  - Identification of estrogen-regulated genes of potential importance for the
      regulation of trabecular bone mineral density.
AB  - Estrogen is of importance for the regulation of trabecular bone mineral density
      (BMD). The aim of this study was to search for possible mechanisms of action of
      estrogen on bone. Ovariectomized (OVX) mice were treated with 17beta-estradiol.
      Possible effects of estrogen on the expression of 125 different bone-related
      genes in humerus were analyzed using the microarray technique. Estrogen regulated
      12 of these genes, namely, two growth factor-related genes, 8 cytokines, and 2
      bone matrix-related genes. Five of the 12 genes are known to be estrogen
      regulated, and the remaining 7 genes are novel estrogen-regulated genes. Seven
      genes, including interleukin-1 receptor antagonist (IL-1ra), IL-1receptor type II
      (IL-1RII), insulin-like growth factor-binding protein 4 (IGFBP-4), transforming
      growth factor beta (TGF-beta), granulocyte colony-stimulating factor receptor (G
      CSFR), leukemia inhibitory factor receptor (LIFR), and soluble IL-4 receptor (sIL
      4R) were selected as probable candidate genes for the trabecular bone-sparing
      effect of estrogen, as the mRNA levels of these genes were highly correlated (r2
      > 0.65) to the trabecular BMD. The regulation of most of these seven genes was
      predominantly estrogen receptor alpha (ER-alpha)-mediated (5/7) while some genes
      (2/7) were regulated both via ER-alpha and ER-beta. In conclusion, by using the
      microarray technique, we have identified four previously known and three novel
      estrogen-regulated genes of potential importance for the trabecular bone-sparing
      effect of estrogen.

PMID- 12469913
TI  - Inhibition of 1,25-dihydroxyvitamin D3-dependent transcription by synthetic LXXLL
      peptide antagonists that target the activation domains of the vitamin D and
      retinoid X receptors.
AB  - The vitamin D receptor (VDR) is known to mediate the biological actions of 1,25
      dihydroxyvitamin D3 [1,25(OH)2D3] through its ability to regulate cellular
      programs of gene expression. Although RXR appears to participate as a
      heterodimeric partner with the VDR, absolute evidence for its role remains
      equivocal in vivo. To test this role and to investigate the requirement for
      comodulator interaction, we identified VDR- and retinoid X receptor (RXR)
      interacting LXXLL peptides and examined whether these molecules could block
      vitamin D and 9-cis retinoic acid (9-cis RA) response. We used a mammalian cell
      two-hybrid system to screen a series of nuclear receptor (NR)-reactive LXXLL
      peptides previously identified through phage display screening for hormone
      dependent reactivity with either VDR or RXR. Three categories of peptides were
      identified: those reactive with both VDR and RXR, those selective for RXR, and
      those unreactive to either receptor. Peptide fusion proteins were then examined
      in MC3T3-E1 cells for their ability to block induction of the osteocalcin (OC)
      promoter by 1,25(OH)2D3 or stimulation of a retinoic acid response element
      thymidine kinase (RARE-TK) reporter by 9-cis-RA. Peptides that interacted with
      both VDR and RXR blocked 1,25(OH)2D3-dependent transcription by up to 75%.
      Control LXXLL sequences derived from Src-1 and Grip also suppressed 1,25(OH)2D3
      induced transactivation; peptides that interacted with RXR blocked 9-cis-RA
      induced transcription. Interestingly, two RXR-interacting peptides were also
      found to block 1,25(OH)2D3 response effectively. These studies support the idea
      that comodulator recruitment is essential for VDR- and RXR-mediated gene
      expression and that RXR is required for 1,25(OH)2D3-induced OC gene
      transcription. This approach may represent a novel means of assessing the
      contribution of RXR in various endogenous biological responses to 1,25(OH)2D3.

PMID- 12469914
TI  - Reversal of secondary hyperparathyroidism by phosphate restriction restores
      parathyroid calcium-sensing receptor expression and function.
AB  - Secondary hyperparathyroidism (secondary HPT), a common disorder in chronic renal
      failure (CRF) patients, is characterized by hypersecretion of parathyroid hormone
      (PTH), parathyroid hyperplasia, and decreased expression of the calcium-sensing
      receptor (CaR). Dietary phosphate loading promotes secondary HPT, and phosphate
      restriction prevents and arrests secondary HPT in CRF. This study examined the
      ability of phosphate restriction to restore parathyroid CaR expression and
      function. Uremic rats fed a 1.2% P diet for 2 weeks developed secondary HPT with
      down-regulated CaR expression. Continuation on the 1.2% P diet for 2 more weeks
      worsened the secondary HPT and further decreased CaR, but switching the rats to a
      0.2% P diet for 2 weeks normalized PTH, arrested parathyroid hyperplasia, and
      restored CaR expression to normal. The calcium-PTH relationship was abnormal in
      uremic rats fed a high phosphate (HP) diet with a right-shifted calcium set point
      but was corrected by 2 weeks of phosphate restriction. A time course revealed
      that following the switch to a low phosphate diet, PTH levels were normalized by
      day 1, and growth was arrested by day 2, but CaR expression was restored between
      days 7 and 14. We conclude that although phosphate restriction restores CaR
      expression and function in parathyroid glands of uremic rats, it is a late event
      and not involved in the arrest of secondary HPT.

PMID- 12469915
TI  - The relationship between bone density and incident vertebral fracture in men and
      women.
AB  - Bone mineral density (BMD) is an important predictor of future fracture risk in
      women; however, there are few prospective data in men. The aim of this analysis
      was to determine whether there are differences in the relationship between BMD
      and incident vertebral fracture in men and women. Men and women were recruited
      from population-based registers in 21 European centers. Those recruited were
      interviewed and had spinal radiographs performed. The radiographs were assessed
      morphometrically and prevalent vertebral deformity was defined using the
      McCloskey-Kanis method. Repeat spinal radiographs were performed at a mean of 3.8
      years after the baseline radiographs. Incident fractures were defined using a
      combination of the point prevalence and 20% reduction in vertebral height (plus a
      4-mm reduction in absolute height) criteria. BMD measurements were made in a
      subsample of those recruited. Poisson regression was used to explore the
      influence of gender, age, prevalent deformity, and BMD on the incidence of
      vertebral fracture. Thirty-four hundred sixty-one men and women had both paired
      spinal radiographs and bone density measurements performed. BMD at the spine and
      femoral neck was higher in men than in women. After adjusting for age, the risk
      of incident vertebral fracture was greater in women than in men (relative risk
      [RR] = 2.3; 95% CI, 1.5-3.6) and increased by a factor of 1.4 (95% CI, 1.2-1.8),
      1.5 (95% CI, 1.2-1.8), and 1.6 (95% CI, 1.3-1.9) per decrease of 0.1 g/cm2 in BMD
      at the spine, femoral neck, and trochanter, respectively. After adjusting for BMD
      at the spine or trochanter, the gender difference in the predicted age-specific
      incidence of vertebral fracture was no longer significant (RR = 1.1 and 95% CI,
      0.6-1.9 at the spine; RR = 1.5 and 95% CI, 0.8-2.7 at the trochanter), although
      it persisted after adjusting for femoral neck BMD (RR = 1.9; 95% CI, 1.1-3.3).
      The presence of a prevalent vertebral deformity was a strong risk factor for
      future vertebral fracture, although the strength of the association was reduced
      after adjustment for age, sex, and spine BMD. However, adjustment for the
      presence of a baseline vertebral deformity did not alter the main findings. In
      conclusion, at a given age and spine (although not femoral neck) bone density,
      the risk of incident vertebral fracture is similar in men and women. Incident
      vertebral fractures are more common in women than men because at any age their
      spine BMD is lower.

PMID- 12469916
TI  - Prediction of fracture risk in postmenopausal white women with peripheral bone
      densitometry: evidence from the National Osteoporosis Risk Assessment.
AB  - Low bone mineral density (BMD) is a risk factor for fracture. Although the
      current "gold standard" test is DXA of the hip and spine, this method is not
      universally available. No large studies have evaluated the ability of new, less
      expensive peripheral technologies to predict fracture. We studied the association
      between BMD measurements at peripheral sites and subsequent fracture risk at the
      hip, wrist/forearm, spine, and rib in 149,524 postmenopausal white women, without
      prior diagnosis of osteoporosis. At enrollment, each participant completed a risk
      assessment questionnaire and had BMD testing at the heel, forearm, or finger.
      Main outcomes were new fractures of the hip, wrist/forearm, spine, or rib within
      the first 12 months after testing. After 1 year, 2259 women reported 2340 new
      fractures. Based on manufacturers' normative data and multivariable adjusted
      analyses, women who had T scores < or = -2.5 SD were 2.15 (finger) to 3.94 (heel
      ultrasound [US]) times more likely to fracture than women with normal BMD. All
      measurement sites/devices predicted fracture equally well, and risk prediction
      was similar whether calculated from the manufacturers' young normal values (T
      scores) or using SDs from the mean age of the National Osteoporosis Risk
      Assessment (NORA) population. The areas under receiver operating characteristic
      (ROC) curves for hip fracture were comparable with those published using
      measurements at hip sites. We conclude that low BMD found by peripheral
      technologies, regardless of the site measured, is associated with at least a
      twofold increased risk of fracture within 1 year, even at skeletal sites other
      than the one measured.

PMID- 12469917
TI  - Osteoporosis in men and women: a story about bone mineral density thresholds and
      hip fracture risk.
AB  - In postmenopausal women, the T score for bone mineral density (BMD) is a well
      accepted diagnostic criterion for osteoporosis. It is also used to assess
      fracture risk. However, it is unclear whether in elderly men similar BMD
      thresholds should be used. Different hypotheses have been proposed for the
      relation of BMD with hip fracture risk in men. In this study, we tested those
      hypotheses using a mathematical model and we compared the calculated results with
      observed prospective data from the Rotterdam study. In the model, we combined the
      observed femoral neck BMD distribution for men and women with previously derived
      hip fracture risk functions based on age and BMD. For men, we tested different
      hypotheses for the relation of BMD with hip fracture risk. The relation of BMD
      with hip fracture risk is similar in men and women (scenario 1) or the relative
      risk (RR) per standard deviation (SD) decrease of BMD is either larger or smaller
      in men than in women (scenario 2a and 2b), or, at a similar absolute fracture
      risk, men have a higher BMD (scenario 3). In the prospective data, men with a hip
      fracture had an average BMD that was 0.070 g/cm2 higher than women with a hip
      fracture. The calculated results from the first scenario were consistent with
      those data and were also consistent with the observed hip fracture incidence and
      the observed female-to-male (F/M) risk ratio (1.7). When the RR for each SD
      decrease of BMD was assumed to be either larger or smaller in men than in women
      (second scenario), the calculated average BMD difference in men and women became
      respectively smaller or larger than observed. When men would have a higher
      fracture risk at similar BMD levels (third scenario), the calculated total number
      of hip fractures increased and even exceeded that in women, with an F/M risk
      ratio of 0.94 in our example. In women, a larger proportion of hip fractures
      occurs at a T score below -2.5 than in men using the same absolute BMD threshold,
      but using a male-specific T score largely solves this diagnostic problem. Taken
      together, the average hip fracture risk in men is much lower than in women but
      appeared to be similar at the same BMD. Therefore, we propose the use of the same
      absolute BMD thresholds for decisions about interventions.

PMID- 12469919
TI  - Alendronate in the prevention of bone loss after a fracture of the lower leg.
AB  - Fracture of a leg and the consequent absence from weight-bearing lead to local
      bone loss. A 1-year, single-center, prospective, randomized, double-blind study
      was conducted, to determine whether bone loss would occur in the proximal femur
      and the calcaneus after a fracture of the lower leg and whether this loss could
      be prevented by the antiresorptive drug bisphosphonate alendronate. Twenty-three
      men and 18 women with a recent unstable fracture of the lower leg were randomized
      to receive either 10 mg of alendronate daily or placebo. Bone mineral density
      (BMD) of both hips and the lumbar spine was measured at baseline and 6 weeks and
      3, 6, and 12 months after start of the treatment. Quantitative ultrasound (QUS)
      measurements of the calcaneus were performed at baseline on the noninjured side
      and at 6 weeks and 3, 6, and 12 months after start of treatment on both sides.
      After 1 year, in the placebo group, there was a significant decrease from
      baseline in BMD of the hip on the side of the fracture. In the alendronate group,
      there was no significant change from baseline. The differences in BMD between the
      two treatment groups on the side of the fracture were significant in all sites of
      the hip: 4.4% (p = 0.016) in the trochanter, 4.6% (p = 0.016) in the femoral
      neck, and 3.9% (p = 0.009) in the total hip. In the hip on the contralateral
      side, there were no significant changes from baseline in either treatment group
      and there was no difference between the two treatment groups. BMD in the lumbar
      spine increased in the alendronate group, and after 1 year there was a
      significant difference between the active treatment and placebo group of 3.4% (p
      = 0.04). One year after fracture, ultrasound parameters of the calcaneus in the
      placebo group were significantly lower on the fractured side compared with the
      contralateral side (p < 0.01). In the alendronate group, no significant
      difference between the two sides was observed. In conclusion, BMD of the proximal
      femur was still decreased 1 year after a fracture of the lower leg. Alendronate
      prevented this bone loss.

PMID- 12469918
TI  - Raloxifene, estrogen, and alendronate affect the processes of fracture repair
      differently in ovariectomized rats.
AB  - We investigated the effects of inhibitors of bone resorption (estrogen,
      raloxifene, and alendronate) on the processes of fracture repair in
      ovariectomized (OVX) rats. One hundred forty female Sprague-Dawley rats at 3
      months of age were either OVX or sham-operated and divided into five groups: sham
      control, OVX control, estrogen (17alpha-ethynyl estradiol [EE2], 0.1 mg/kg),
      raloxifene (Rlx, 1.0 mg/kg), and alendronate (Aln, 0.01 mg/kg) groups. Treatment
      began immediately after the surgery. Four weeks postovariectomy, prefracture
      controls were killed and bilateral osteotomies were performed on the femoral
      midshafts and fixed with intramedullary wires. Treatment was continued and
      fracture calluses were excised at 6 weeks and 16 weeks postfracture for
      evaluation by X-ray radiography, quantitative computed tomography (QCT,)
      biomechanical testing, and histomorphometry. At 6 weeks postfracture, Aln and OVX
      had larger calluses than other groups. Sham and OVX had higher ultimate load than
      EE2 and Rlx, with Aln not different from either control. Aln calluses also
      contained more mineral (bone mineral content [BMC]) than all other groups. By 16
      weeks postfracture, OVX calluses were smaller than at 6 weeks and the dimensions
      for Aln had not changed. Aln had higher BMC and ultimate load than OVX, EE2, and
      Rlx. EE2 and Rlx had similar biomechanical properties, which were similar to
      sham. Interestingly, OVX and Aln animals were heavier than other groups at all
      time points; therefore, ultimate load was normalized by body weight to show no
      significant differences in strength of the whole callus between groups at either
      6 weeks or 16 weeks postfracture. However, Aln strongly suppressed remodeling of
      the callus, resulting in the highest content of woven bone, persistent visibility
      of the original fracture line, and lowest content of lamellar bone, compared with
      other groups. Therefore, the larger Aln callus appeared to be a remarkable,
      morphological adaptation to secure the fracture with inferior material. In
      conclusion, OVX-stimulated bone turnover resulted in the fastest progression of
      fracture repair that was most delayed with Aln treatment, consistent with marked
      suppression of bone resorption and formation activity. Estrogen and Rlx had
      similar effects that were generally similar to sham, indicating that mild
      suppression of bone turnover with these agents has insignificant effects on the
      progression of fracture repair.

PMID- 12469920
TI  - Long-term dosing of arzoxifene lowers cholesterol, reduces bone turnover, and
      preserves bone quality in ovariectomized rats.
AB  - Long-term effects of a new selective estrogen receptor modulator (SERM)
      arzoxifene were examined in ovariectomized (OVX) rats. Arzoxifene was
      administered postoperatively (po) at 0.1 mg/kg per day or 0.5 mg/kg per day to 4
      month-old rats, starting 1 week after OVX for 12 months. At study termination,
      body weights for arzoxifene groups were 16-17% lower than OVX control, which was
      caused by mainly reduced gain of fat mass. Longitudinal analysis of the proximal
      tibial metaphysis (PTM) by computed tomography (CT) at 0, 2, 4, 6,9, and 12
      months showed that OVX induced a 22% reduction in bone mineral density (BMD) at 2
      months, which narrowed to a 12% difference between sham-operated (sham) and OVX
      rats by 12 months. Both doses of arzoxifene prevented the OVX-induced decline in
      BMD. Histomorphometry of the PTM showed that arzoxifene prevented bone loss by
      reducing osteoclast number in OVX rats. Arzoxifene maintained bone formation
      indices at sham levels and preserved trabecular number above OVX controls. Micro
      CT analysis of lumbar vertebrae showed similar preservation of BMD compared with
      OVX, which were not different from sham. Compression testing of the vertebra and
      three-point bending testing of femoral shaft showed that strength and toughness
      were higher for arzoxifene-treated animals compared with OVX animals. Arzoxifene
      reduced serum cholesterol by 44-59% compared with OVX. Uteri wet weight from
      arzoxifene animals was 38-40% of sham compared with OVX rats, which were 29% of
      sham. Histology of the uterine endometrium showed that cell heights from both
      doses of arzoxifene were not significantly different from OVX controls. In
      summary, treatment of OVX rats with arzoxifene for nearly one-half of a lifetime
      maintained beneficial effects on cholesterol and the skeleton. These data suggest
      that arzoxifene may be a useful therapeutic agent for osteoporosis in
      postmenopausal women.

PMID- 12469921
TI  - Quantitative magnetic resonance imaging in the calcaneus and femur of women with
      varying degrees of osteopenia and vertebral deformity status.
AB  - Quantitative magnetic resonance imaging (QMRI) allows measurement of two
      parameters that are related to the integrity of the trabecular bone: R2*, the
      rate constant of the free induction signal, and trabecular bone volume fraction
      (BVF), the counterpart of apparent density. In this work, R2* and BVF were
      measured in 68 women (mean age, 58.2 +/- 9.5 years) of varying spinal bone
      mineral density (BMD) T scores (mean, -1.37 +/- 1.54) and vertebral fracture
      status on a commercial 1.5 T whole-body imager using customized image acquisition
      and processing techniques. Twenty-five of the patients had vertebral fractures,
      characterized by the total cumulative deformity burden exceeding 200%. R2* was
      measured in the calcaneus and proximal femur and BVF could be measured in the
      calcaneus only. On a pixel-by-pixel basis, calcaneal R2* and BVF within each
      subject were highly positively correlated (r2 = 0.61 +/- 0.11) but the
      correlation of region-of-interest (ROI) means for different calcaneal sites among
      patients was weaker (r2 = 0.34; p < 0.0001). The strongest discriminator of
      vertebral deformity was R2* of the calcaneus, which was lower in the fracture
      group, consistent with lower trabecular density. Among the calcaneal sites
      examined, the subtalar region, a location characterized by dense nearly
      horizontal trabeculae that transmit the stresses imparted by body weight from the
      tibia to the heel, best discriminated the two groups (p = 0.0001), with 77%
      diagnostic accuracy as determined from the area under the receiver operating
      characteristic (ROC) curve (compared with 66% for vertebral BMD). The cavum
      calcanei, an anterior site of low trabecular density, and the tuber calcanei (the
      location ordinarily used for ultrasound measurements) also had significantly
      reduced R2* in the fracture group (p < 0.005 and p = 0.01, respectively). The
      R2av*, computed as the average of all pixels in the calcaneus, was a strong
      discriminator as well (p < 0.005). On the other hand, calcaneal BVF was only
      marginally discriminating (p = 0.05). Among the BMD sites examined, the lumbar
      spine (average L1-L4) was significant (p = 0.005, 66% diagnostic accuracy), as
      was the femoral neck (p = 0.01). The data suggest the calcaneus to be suited as a
      surrogate site to assess vertebral osteoporosis and that R2* is sensitive to
      alterations in bone quality not captured by density.

PMID- 12469922
TI  - The effect of mechanical loading on the size and shape of bone in pre-, peri-,
      and postpubertal girls: a study in tennis players.
AB  - Exercise during growth results in biologically important increases in bone
      mineral content (BMC). The aim of this study was to determine whether the effects
      of loading were site specific and depended on the maturational stage of the
      region. BMC and humeral dimensions were determined using DXA and magnetic
      resonance imaging (MRI) of the loaded and nonloaded arms in 47 competitive female
      tennis players aged 8-17 years. Periosteal (external) cross-sectional area (CSA),
      cortical area, medullary area, and the polar second moments of area (I(P), mm4)
      were calculated at the mid and distal sites in the loaded and nonloaded arms. BMC
      and I(P) of the humerus were 11-14% greater in the loaded arm than in the
      nonloaded arm in prepubertal players and did not increase further in peri- or
      postpubertal players despite longer duration of loading (both, p < 0.01). The
      higher BMC was the result of a 7-11% greater cortical area in the prepubertal
      players due to greater periosteal than medullary expansion at the midhumerus and
      a greater periosteal expansion alone at the distal humerus. Loading late in
      puberty resulted in medullary contraction. Growth and the effects of loading are
      region and surface specific, with periosteal apposition before puberty accounting
      for the increase in the bone's resistance to torsion and endocortical contraction
      contributing late in puberty conferring little increase in resistance to torsion.
      Increasing the bone's resistance to torsion is achieved by modifying bone shape
      and mass, not necessarily bone density.

PMID- 12469923
TI  - Effect of long-term impact-loading on mass, size, and estimated strength of
      humerus and radius of female racquet-sports players: a peripheral quantitative
      computed tomography study between young and old starters and controls.
AB  - Bone characteristics of the humeral shaft and distal radius were measured from 64
      female tennis and squash players and their 27 age-, height-, and weight-matched
      controls with peripheral quantitative tomography (pQCT) and DXA. The players were
      divided into two groups according to the starting age of their tennis or squash
      training (either before or after menarche) to examine the possible differences in
      the loading-induced changes in bone structure and volumetric density. The used
      pQCT variables were bone mineral content (BMC), total cross-sectional area (TotA)
      of bone, cross-sectional area of the marrow cavity (CavA) and that of the
      cortical bone (CoA), cortical wall thickness (CWT), volumetric density of the
      cortical bone (CoD) and trabecular bone (TrD), and torsional bone strength index
      (BSIt) for the shaft, and compressional bone strength index (BSIc) for the bone
      end. These bone strength indices were compared with the DXA-derived areal bone
      mineral density (aBMD) to assess how well the latter represents the effect of
      mechanical loading on apparent bone strength. At the humeral shaft, the loaded
      arm's greater BMC (an average 19% side-to-side difference in young starters and
      9% in old starters) was caused by an enlarged cortex (CoA; side-to-side
      differences 20% and 9%, respectively). The loaded humerus seemed to have grown
      periosteally (the CavA did not differ between the sites) leading to 26% and 11%
      side-to-side BSIt difference in the young and old starters, respectively. CoD was
      equal between the arms (-1% difference in both player groups). The side-to-side
      differences in the young starters' BMC, CoA, TotA, CWT, and BSIt were 8-22%
      higher than those of the controls and 8-14% higher than those of the old
      starters. Old starters' BMC, CoA, and BSIt side-to-side differences were 6-7%
      greater than those in the controls. The DXA-derived side-to-side aBMD difference
      was 7% greater in young starters compared with that of the old starters and 14%
      compared with that in controls, whereas the difference between old starters and
      controls was 6%, in favor of the former. All these between-group differences were
      statistically significant. At the distal radius, the player groups differed
      significantly from controls in the side-to-side BMC, TrD, and aBMD differences
      only; the young starters' BMC difference was 9% greater, TrD and aBMD differences
      were 5% greater than those in the controls, and the old starters' TrD and aBMD
      differences were both 7% greater than those in the controls. In summary, in both
      of the female player groups the structural adaptation of the humeral shaft to
      long-term loading seemed to be achievedthrough periosteal enlargement of the bone
      cortex although this adaptation was clearly better in the young starters.
      Exercise-induced cortical enlargement was not so clear at the distal radius (a
      trabecular bone site), and the study suggested that at long bone ends also the
      TrD could be a modifiable factor to build a stronger bone structure. The
      conventional DXA-based aBMD measurement detected the intergroup differences in
      the exercise-induced bone gains, although, measuring two dimensions of bone only,
      it seemed to underestimate the effect of exercise on the apparent bone strength,
      especially if the playing had been started during the growing years.

PMID- 12469924
TI  - The pro and con of measles virus in Paget's disease: con.

PMID- 12469925
TI  - Psychological complications of prostate cancer.
AB  - Over the past decade, interest has been growing in the quality of life of men
      with prostate cancer. Traditionally considered a group with few psychological
      complications, 10% to 20% of men with prostate cancer are found to have
      clinically significant levels of psychological distress. This article reviews the
      prevalence of psychiatric symptomatology among prostate cancer patients, the
      psychological challenges of coping with the disease, and general guidelines for
      treatment.

PMID- 12469927
TI  - Live viruses in cancer treatment.
AB  - Although antitumor activity and a low toxicity profile have been demonstrated for
      several oncolytic viruses, the development of viral therapy in cancer treatment
      has been limited by a lack of definitive phase III trials. The use of replicating
      viruses to potentiate the efficacy of standard cancer therapies also awaits
      conclusive clinical testing. Based on preliminary results with new generations of
      oncolytic viruses, ongoing research in this area appears encouraging. This
      article explores the principles of viral therapy for cancer and the past several
      decades of investigations with viruses such as Egypt 101, mumps, Newcastle
      disease, influenza, vaccinia, herpes simplex, and adenovirus serotype 5.

PMID- 12469926
TI  - Rituxan delays disease progression in indolent non-Hodgkin's lymphoma.

PMID- 12469928
TI  - Clinical trials referral resource. Clinical trials in ovarian cancer; Part 1.

PMID- 12469929
TI  - Advances in the treatment of gynecologic malignancies. Part 1: Cancers of the
      cervix and vulva.
AB  - Two recent multicenter randomized trials have greatly advanced our understanding
      of the role of postoperative radiation therapy in operable cervical cancer. In
      locally advanced cervical cancer, such studies have shown a significant
      improvement in survival with the use of concurrent cisplatin-based
      chemoradiotherapy and have redefined standard therapy for women with this
      presentation. In vulvar cancer, adjuvant chemoradiotherapy is emerging as an
      effective therapeutic approach, permitting less morbid surgery. Although the
      results of treatment with concurrent chemoradiotherapy are encouraging in both
      cervical and vulvar cancer, efforts to minimize the associated toxicity are
      needed.

PMID- 12469930
TI  - Distant effects of cancer on the nervous system.
AB  - Paraneoplastic disorders of the nervous system are important to the practicing
      oncologist, because these syndromes, although uncommon, produce significant
      neurologic dysfunction and disability. The neurologic disorder may be the first
      manifestation of an unrecognized systemic malignancy, and appropriate diagnosis
      of the paraneoplastic disorder can lead to a focused search for an underlying
      cancer. Paraneoplastic disorders may involve any component of the central or
      peripheral nervous system, and diagnosis requires careful neurologic assessment.
      The diagnosis is made by recognition of clinical neurologic syndromes and the use
      of selected laboratory studies as indicated by the clinicalpicture. Over the past
      10 years, the application of molecular biologic techniques to the study ofthese
      disorders has elucidated much about the mechanisms that cause neurologic injury.
      In most cases, disordered humoral and cellular immunity has been demonstrated,
      and the role of novel targets for autoimmune attack is being clarified. For some
      paraneoplastic disorders, treatment of the underlying tumor may lead to
      improvement of the neurologic disorder. For others, various forms of
      immunosuppressive therapy may be indicated. Unfortunately, for several of the
      more common paraneoplastic syndromes such as paraneoplastic cerebellar
      degeneration or limbic encephalitis, treatment is still unsatisfactory, and
      further research into the exact pathophysiology is clearly needed.

PMID- 12469931
TI  - Issues in the management of cancer-related thrombocytopenia.
AB  - Thrombocytopenia remains a significant clinical problem for patients with cancer.
      Management approaches include watchful waiting, platelet transfusions, and the
      use of pharmacologic agents. Although platelet transfusion remains the gold
      standard for prophylaxis and treatment of thrombocytopenia, this approach is
      associated with transfusion-transmitted disease, infection, and platelet
      refractoriness. Because of these complications and the expense of platelet
      therapy, recent studies have examined the clinical evidence supporting the widely
      used platelet transfusion trigger of 20,000 cells/microL and found that values of
      5,000 to 10,000 cells/microL are safe for selected patients. Several
      investigational agents offer promise for treatment of thrombocytopenia in
      patients undergoing myelosuppressive and myeloablative therapy. These agents
      include recombinant human interleukin-11, recombinant human thrombopoietin, and c
      Mpl ligand mimetics.

PMID- 12469932
TI  - HER2 testing and correlation with efficacy of trastuzumab therapy.

PMID- 12469933
TI  - High-dose interleukin-2 in metastatic disease: renal cell carcinoma and melanoma.

PMID- 12469934
TI  - Current status of interleukin-2 therapy for metastatic renal cell carcinoma and
      metastatic melanoma.
AB  - Interleukin-2 (IL-2, Proleukin) is one of the most effective agents in the
      treatment of metastatic renal cell carcinoma and metastatic melanoma. High-dose
      IL-2 therapy produces overall response rates of 15% to 20%; however, it is
      associated with significant toxicities that affect essentially every organ
      system. Although IL-2-related toxicities are usually reversible with therapy
      discontinuation, alternative IL-2 regimens have been evaluated. Several phase II
      studies have demonstrated that administering lower doses of IL-2 by IV bolus or
      continuous IV infusion or subcutaneously produces overall response rates similar
      to those with high-dose IL-2 therapy; however, randomized clinical trials have
      not yet been completed. In renal cell carcinoma, combining IL-2 with interferon
      alfa (Intron A, Roferon-A) or chemotherapy agents produces similar or increased
      overall response rates compared with the response rates of IL-2 alone, with no
      survival advantage. Combination IL-2 regimens in metastatic melanoma patients
      have produced variable results. The most promising regimens have included various
      IL-2-based biochemotherapy regimens in other patients. Randomized studies
      confirming the superiority of these regimens over high-dose IL-2 therapy are
      needed.

PMID- 12469935
TI  - Managing toxicities of high-dose interleukin-2.
AB  - Although high-dose interleukin-2 (IL-2, Proleukin), a highly toxic agent used in
      the treatment of renal cell carcinoma and melanoma, was initially associated with
      treatment-related mortality, it can, in the appropriate setting, be administered
      safely. High-dose IL-2 is associated with significant morbidity; however, the
      incidence and severity of toxicities have decreased as clinicians have gained
      experience with this agent and implemented toxicity prevention and management
      strategies. IL-2 toxicity can manifest in multiple organ systems, most
      significantly the heart, lungs, kidneys, and central nervous system. The most
      common manifestation of IL-2 toxicity is capillary leak syndrome, resulting in a
      hypovolemic state and fluid accumulation in the extravascular space. Capillary
      leak syndrome can contribute significantly to development of oliguria, ischemia,
      and confusion. Safe and effective administration of high-dose IL-2 consists of
      five key components: (1) administration by an experienced and knowledgeable
      health-care team, (2) adherence to strict patient-eligibility criteria, (3)
      implementation of standardized administration and patient assessment guidelines,
      (4) adherence to administration criteria, and (5) compliance with retreatment
      contraindications. This article reviews high-dose IL-2 toxicities and symptom
      management strategies and provides practical guidelines to facilitate the safe
      and effective administration of high-dose IL-2.

PMID- 12469936
TI  - Antidepressant drugs and cytokines in mood disorders.
AB  - This article reviews recent developments in cytokine research that pertain to
      pharmacological treatment of mood disorders such as antidepressants and lithium.
      We review the possible involvement of cytokines in mood disorders and their role
      in the therapeutic effects of antidepressant drugs. Growing evidence suggests
      that specific cytokines signal the brain to generate neurochemical, neuroimmune,
      neuroendocrine and behavior changes. An imbalance of cytokines within the central
      nervous system (CNS), or even systemically, may play a role in the
      pathophysiology of mood disorders. Modulation of these cytokines by chronic
      antidepressant treatment may result in restored balance. However, the effect of
      antidepressants on cytokines is still unclear both in clinical and preclinical
      research due to limited data. Further research is needed to clarify the
      involvement of cytokines in mood disorders. Understanding this relationship may
      lead to rational, therapeutic improvements in antidepressant and mood stabilizing
      drugs.

PMID- 12469937
TI  - The stimulatory effects of nasal discharge from patients with perennial allergic
      rhinitis on normal human neutrophils are normalized after treatment with a new
      mixed formula of Chinese herbs.
AB  - In our previous study, we found a new mixed formula of Chinese herbs containing
      Shin-yi-san + Xiao-qing-long-tang + Xiang-sha-liu-jun-zi-tang (9 + 3 + 3 g
      divided in three doses/day) was beneficial to the patients with perennial
      allergic rhinitis (AR) via complicated immunomodulatory effects on both
      mononuclear cells (MNC) and polymorphonuclear neutrophils (PMN). In the present
      study, we further determined the effects of nasal fluid from AR patients on the
      functions of human PMN before and after treatment with the mixed formula. We
      found the nasal discharge, but not serum, from AR group with high serum IgE (H
      IgE, serum IgE >200 KIU/l) before treatment exerted many stimulating effects on
      normal PMN including delayed apoptosis, enhanced production of soluble
      intercellular adhesion molecule 1 (sICAM-1), interleukin 8 (IL-8) and
      prostaglandin E2 (PGE2), increased phagocytosis, and augmented cyclooxygenase 2
      (COX-2) mRNA expression of PMN. However, these stimulating effects of nasal fluid
      on PMN were not found in low IgE group (L-IgE, serum IgE <200 KIU/l). These PMN
      enhancing effects of H-IgE nasal fluid were abolished after 3-month treatment
      with the mixed Chinese herb formula. In conclusion, our results suggest that the
      new mixed herb formula treatment suppressed nasal mucosa inflammation by
      normalizing stimulatory effects of allergic nasal discharge of patients with H
      IgE allergic rhinitis.

PMID- 12469938
TI  - Effects of intraperitoneal and intranasal application of Lentinan on cellular
      response in rats.
AB  - Lentinan (Ajinomoto, Japan) was administrated intraperitoneally (i.p.) and
      intranasally (i.n.) at different doses (1, 5 and 10 mg/kg) to rats. Effectiveness
      of Lentinan treatment was evaluated by comparative testing of cell activation
      (establishing the number, glycolytic and acid phosphatase activity, H2O2
      production and killing ability against Salmonella enteritidis and Staphylococcus
      aureus) at two different compartments--peritoneal and broncho-alveolar cavities.
      The results indicated that Lentinan induced high-grade activation of peritoneal
      cells (PCs) and especially of broncho-alveolar cells (BACs) with markedly
      enhanced effector function (killing ability against S. aureus). Generally,
      Lentinan, known usually with its parenteral routes of application, can be
      successful to stimulate the host cell response in the respiratory tract by
      intranasal route of administration.

PMID- 12469939
TI  - DMSO-treated HL60 cells: a model of neutrophil-like cells mainly expressing PDE4B
      subtype.
AB  - The human promyelocytic HL60 cells acquired a neutrophilic phenotype after a 7-
      to 10-day DMSO treatment. Fc gammaRII was up-regulated. Fc gammaRI was also up
      regulated by an additional IFN-gamma treatment. These cells are able to produce
      O2*- by NADPH oxidase activation in the presence of immune complexes or phorbol
      12-myristate-13-acetate (PMA). A change of their PDE4 subtype profile was also
      observed: PDE4B was the predominant isoenzyme, PDE4D was down-regulated and PDE4A
      was no longer detectable. Additionally, the more NADPH oxidase was activated by
      PMA, the less PDE4A was expressed, suggesting that NADPH oxidase activity could
      be used as a surrogate marker of PDE4A down-regulation. Rolipram and Ariflo
      (cilomilast), two selective PDE4 inhibitors, dose-dependently inhibited receptor
      coupled activation of superoxide. These results suggest that PDE4B is the main
      subtype involved in regulating superoxide induced by Fc gammaRs activation.
      Furthermore, these cells, expressing almost exclusively PDE4B subtype, could be
      useful to identify selective PDE4B inhibitors.

PMID- 12469941
TI  - Elevated kallikrein activity in plasma from stable liver transplant recipients.
AB  - Extensive in vitro conversion of complement components C3 and C4 has been
      observed in EDTA plasma obtained from a number of stable orthotopic liver
      transplant recipients (LTR) [Clin. Chem. 45 (1999) 1190]. Consequently, we
      designed a chromogenic substrate (Ac-Ala-Gly-Leu-Thr-Arg-p-nitroanilide, AGLTR
      pNA), based on the C1s cleavage site in complement component C4, in an attempt to
      identify the plasma proteinase(s) that cleaves C4 in vitro. Average peptidase
      activity in EDTA plasma obtained from stable LTR (n = 16) was significantly
      higher (P<0.01) than that in plasma from healthy non-transplant donors (n = 16).
      This peptidase activity was also detected using commercial substrates designed
      for specific coagulation proteinases. The plasma proteinase was not inhibited by
      hirudin, a thrombin inhibitor, but was inhibited by the plasma kallikrein
      inhibitor D-Phe-Phe-Arg-chloromethylketone, which fails to inhibit C1s. We
      concluded that the peptidase detected inLTR plasma, using chromogenic substrates
      including AGLTR-pNA, was plasma kallikrein. Western blot analysis confirmed the
      presence of kallikrein-alpha-2-macroglobulin complexes (alpha2M) in LTR plasmas.
      We also demonstrated that kallikrein was not the proteinase responsible for the
      in vitro cleavage of C4. Elevation of the plasma peptidase activity correlated
      significantly with recurrent hepatitis C virus (HCV) infection in these liver
      recipients with a P value <0.02. Significant correlation was not observed between
      complement activation (i.e. the C4a levels) and recurrent HCV infection (P>0.15);
      however, C4a levels did correlate with rejection (P<0.02). These results suggest
      that elevation in plasma peptidase activity and activation of complement do
      signal different pathological events in LTR, events that appear related to HCV
      induced infection and immune tissue injury, respectively.

PMID- 12469940
TI  - Complement activation is responsible for acute toxicities in rhesus monkeys
      treated with a phosphorothioate oligodeoxynucleotide.
AB  - The objective of this study was to define the role of complement activation in
      the acute and transient toxicities associated with administration of
      phosphorothioate oligonucleotides in monkeys. In the absence of complement
      inhibitor, complement activation blocker-2 (CAB-2), i.v. infusion of 20 mg/kg
      ISIS 2302 produced increases in the concentrations of the complement split
      products Bb and C5a (100- and 7-fold, respectively). Monkeys also experienced
      marked changes in bloodpressure (hypertension and hypotension), clinical signs of
      toxicity (lethargy and periorbital edema), fluctuations in circulating neutrophil
      counts, and elevations in serum cytokine levels (45-, 12-, and 4-fold increases
      in IL-6, MCP-1, and IL-12, respectively). Changes occurred at or near the end of
      infusion and returned to normal over time. One of the three animals died
      approximately 4 h following infusion of 20 mg/kg ISIS 2302 alone. In contrast,
      prior treatment with CAB-2 effectively blocked complement activation, as well as
      the ISIS 2302-induced hemodynamic and clinical responses. Importantly, plasma
      concentration of ISIS 2302 were unaffected by CAB-2 pretreatment. Thus, the
      protection afforded by CAB-2 was due to its inhibition of complement activation
      rather than to any impact on the disposition of ISIS 2302. These results clearly
      demonstrate the causal relationship between activation of the alternative
      complement pathway and the hemodynamic and clinical responses associated with
      rapid infusion of phosphorothioate oligonucleotides. Demonstration of this
      relationship underscores the importance of avoiding complement activation in
      patients to ensure the continued safe use of phosphorothioate
      oligodeoxynucleotides.

PMID- 12469942
TI  - Immunotoxic and cancerostatic effects of ethyl-4-isothiocyanatobutanoate in
      female Lewis rats with implanted fibrosarcoma.
AB  - Isothiocyanates (ITCs) have been isolated from plants. Naturally occurring and
      synthetic ITCs are known as effective chemopreventive agents. Ethyl 4
      isothiocyanatobutanoate (E-41B) is a derivative of gamma-aminobutyric acid.
      Immunotoxic and canocerostatic effects of E-41B in female inbred Lewis rats
      implanted with experimental fibrosarcoma BP6-TU2 was evaluated in this study. On
      day 5 after subcutaneous application of tumor cells, animals started to be
      treated intraperitoneally three times a week with two different doses of E-41B:
      28 and 35 mg/kg/day during 28 days. High dose of E-41B was close to maximum
      tolerated dose (MTD). Control groups of rats with or without tumors injected
      intraperitoneally only saline or 70% dimethylsulphoxide were added.
      Administrating of E-41B resulted in suppression of thymus, popliteal lymph node,
      spleen weight and spleen cellularity. Hematologic evaluation displayed decreased
      erythrocyte (ERY) count and level of hemoglobin (HB) in rats treated withE-41B.
      Immune assays--the phagocytic activity of polymorphonuclear leukocytes (PMN) and
      monocytes, primary antibody response and in vitro proliferative activity of
      spleen lymphocytes (LY) to mitogens were not significantly affected by E-41B
      treatment E-41B moderately decreased tumor weights, but this decrease was not
      statistically significant in comparison with DMSO-exposed rats with tumors. The
      fibrosarcoma implantation itself increased significantly spleen weight and
      changed hematological parameters (decreased HB, increased mean cell volume of
      ERY, increased leukocyte count, increased % PMN, decreased % LY, decreased % EO).
      Moreover, moderate decreased percentage of CD161+ positive cells (NK cells) were
      found in peripheral blood. Immune assays showed decline in proliferation of
      lymphocytes and phagocytic activity of leukocytes. Our findings indicate that
      administration of E-41B displayed hematoxic effect in rats implanted with
      fibrosarcoma. Immunotoxic effect was shown as decreased lymphoid organ weight and
      spleen cytotoxicity although function of immune cells was not impaired.

PMID- 12469944
TI  - Degradation of Quillaja saponaria Molina saponins: loss of the protective effects
      of a herpes simplex virus 1 subunit vaccine.
AB  - Quillaja saponins (Q. saponins) are readily hydrolyzed at neutral pH to yield
      degraded deacylated saponins (DS-saponins). Degradation of Q. saponins resulted
      in some reduction of their capacity to elicit IgG1, IgG2a and IgG2b isotypes
      against the highly immunogenic envelope glycoprotein D (gD) from herpes simplex
      virus, type 1 (HSV-1). Addition to gD of a dose of DS-saponins tenfold higher
      than the original Q. saponins dose stimulated lower IgG2a and IgG2b titers than
      those obtained with gD alone or combined with native saponins. However, the IgG1
      response was somewhat similar in all the groups. In contrast, Q. saponins'
      deacylation resulted in a significant reduction in both the production of HSV-1
      neutralizing antibodies and survival rates after viral challenge. Vaccination
      with gD alone did not protect mice against a lethal challenge with HSV-1, while
      the addition of Q. saponins to gD resulted in protection against HSV-1. Vaccines
      containing partially deacylated saponins yielded lower survival rates, while
      vaccines containing DS-saponins did not protect mice against HSV-1. Increasing
      the dose of DS-saponins tenfold resulted in a marginal increase in protection.
      These results show that degradation of Q. saponins during storage can have a
      deleterious effect on vaccines' efficacies.

PMID- 12469943
TI  - Characterization of YM-90709 as a novel antagonist which inhibits the binding of
      interleukin-5 to interleukin-5 receptor.
AB  - Interleukin-5 (IL-5) plays an important role in the activation of eosinophils in
      allergic inflammation including asthma and atopic dermatitis. A newly synthesized
      compound, YM-90709, 2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino
      [2,3-b]quinoxaline, is reported here to inhibit the binding of IL-5 to its
      receptor on peripheral human eosinophils and butyric acid-treated eosinophilic HL
      60 clone 15 cells, with IC50 values of 1.0 and 0.57 microM, respectively. In
      contrast, YM-90709 did not affect the binding of granulocyte-macrophage colony
      stimulating factor (GM-CSF) to its receptor on eosinophils and eosinophilic HL-60
      clone 15 cells. In functional assays, YM-90709 inhibited IL-5-prolonged
      eosinophil survival with an IC50 value of 0.45 microM and did not affect the GM
      CSF-prolonged eosinophil survival. Furthermore, YM-90709 inhibited the IL-5
      induced but not GM-CSF-induced tyrosine phosphorylation of Janus kinase 2 (JAK2)
      in eosinophilic HL-60 clone 15 cells. These results indicate that YM-90709 is a
      novel IL-5 inhibitor which selectively blocks the binding of IL-5 to the IL-5
      receptor (IL-5R).

PMID- 12469945
TI  - Flow cytometric detection of intracellular IL-12 release: in vitro effect of
      widely used immunosuppressants.
AB  - Interleukin 12 (IL-12) is a potent regulator of the Th1/Th2 pathway, enhancing
      alloantigen-specific immune functions. In the present study, we developed a flow
      cytometric assay detecting intracellular IL-12 production by human CD14+
      monocytes in order to assess the in vitro effects of widely used
      immunosuppressants, such as cyclosporine (CsA), sirolimus (SRL) and dexamethasone
      (DXM). For the purpose of the study, a two-step activation procedure was
      developed involving the preactivation of peripheral blood mononuclear cells
      (PBMC) with interferon-gamma (IFN-gamma) and reactivation with IFN-gamma and
      lipopolysaccharide (LPS). All immunosuppressive agents were added at the
      initiation of the preactivation or the reactivation step. Following this
      activation protocol, a fourfold to fivefold up-regulation of the percentage of
      CD14+/IL-12+ cells and of the mean fluorescence intensity was observed. CsA did
      not significantly affect the intracellular IL-12 release by CD14+ cells,
      independent of the time point of the addition. SRL exerted an up-regulatory
      effect when added at the initiation of the IFN-gamma pre-incubation, and this was
      manifested as a significant increase in the percentage of CD14+/IL-12+ cells. In
      contrast, DXM effectively repressed both the percentage and the fluorescence
      intensity of IL-12-producing CD14+ cells when added at the initiation of the
      reactivation step. Since only the steroid preparation was shown to down-regulate
      the intracellular release of IL-12, it is tempting to assume that steroid
      addition in immunosuppressive schemes is beneficial for the suppression of Th1
      inducing cytokine production, as well as for the compensation of possible up
      regulation induced by other immunosuppressive agents administered concurrently.

PMID- 12469946
TI  - The role of molecular methods in evaluating biological treatment processes.
AB  - Methods derived from molecular biology provide powerful new tools to analyze
      biological treatment processes. Because molecular methods can be used to directly
      interrogate genetic information about the microbial community, they can provide
      the fine detail that is impossible with the blunt, nondiscriminating information
      usually obtained from more traditional measures such as biochemical oxygen demand
      and volatile suspended solids. Molecular methods allow tracking of critical
      groups of microorganisms, such as ammonia oxidizers, that comprise a small
      fraction of the total biomass. Molecular methods also allow tracking of specific
      metabolic reactions or other functions that are key to the satisfactory
      performance of a system. Despite their power, molecular methods do not provide
      sufficient information when used alone. Aggregated measures and quantitative
      modeling remain necessary to establish mass balances, quantify the function of
      the microbial community, and connect the results of molecular assays to practice.
      Several examples involving nitrifying bacteria in activated sludge illustrate the
      fine detail available with molecular methods and how they can be linked to
      traditional and quantitative analyses. Other manuscripts in this special issue
      also provide examples of the value of using molecular tools in combination with
      traditional methods.

PMID- 12469947
TI  - Microbiology of enhanced biological phosphorus removal in aerated-anoxic Orbal
      processes.
AB  - The traditional process for enhanced biological phosphorus removal (EBPR) in
      wastewater treatment involves an anaerobic zone followed by an aerobic zone.
      Although there is no strict anaerobic zone in aerated-anoxic Orbal processes,
      phosphorus removal in excess of that required for cell growth does occur. The
      microbial ecology of polyphosphate-accumulating organisms (PAO) in two full-scale
      Orbal wastewater treatment plants was investigated using flow cytometry to
      physically separate PAO from non-PAO and fluorescent in situ hybridization (FISH)
      to identify organisms. Although Candidatus Accumulibacter phosphatis, an
      uncultured organism associated with EBPR in acetate-fed laboratory-scale
      reactors, was detected, it did not seem to be the dominant PAO in these
      processes. Comparative FISH analyses of the activated sludge and the PAO-rich
      subpopulation did not reveal the presence of a dominant group of PAO in these
      full-scale plants. Rather, the analysis suggested that the operational
      characteristics of aerated-anoxic processes might select for a diverse PAO
      community that is significantly different from that observed in acetate-fed
      laboratory reactors or in traditional EBPR configurations.

PMID- 12469948
TI  - Microbial community structures in foaming and nonfoaming full-scale wastewater
      treatment plants.
AB  - A survey of full-scale activated-sludge plants in Illinois revealed that
      filamentous foaming is a widespread problem in the state, and that the causes and
      consequences of foaming control strategies are not fully understood. To link
      microbial community structure to foam occurrence, microbial populations in eight
      foaming and nine nonfoaming full-scale activated-sludge systems were quantified
      using oligonucleotide hybridization probes targeting the ribosomal RNA (rRNA) of
      the mycolata; Gordonia spp.; Gordonia amarae; "Candidatus Microthrix parvicella";
      the alpha-, beta-, and gamma-subclasses of the Proteobacteria, and members of the
      Cytophaga-Flavobacteria. Parallel measurements of microbial population abundance
      using hybridization of extracted RNA and fluorescence in situ hybridization
      (FISH) showed that the levels of mycolata, particularly Gordonia spp., were
      higher in most foaming systems compared with nonfoaming systems. Fluorescence in
      situ hybridization and microscopy suggested the involvement of "Candidatus
      Microthrix parvicella" and Skermania piniformis in foam formation in other
      plants. Finally, high numbers of "Candidatus Microthrix parvicella" were detected
      by FISH in foam and mixed liquor samples of one plant, whereas the corresponding
      levels of rRNA were low. This finding implies that inactive "Candidatus
      Microthrix parvicella" cells (i.e., cells with low rRNA levels) can cause
      foaming.

PMID- 12469949
TI  - Microbial community structure and activity in a compartmentalized, anaerobic
      bioreactor.
AB  - The objective of this study was to evaluate staging and its effects on reactor
      performance in a compartmentalized bioreactor, designated the anaerobic migrating
      blanket reactor (AMBR). The AMBR was operated by reversing the flow several times
      per day, which allowed for substantial biomass migration without biomass
      accumulation in the final compartment. During reactor startup, the structures of
      the microbial communities in the five compartments were quite similar despite
      substantial differences in substrate types and concentrations in the different
      compartments. During the rest of the operational period, biomass migration was
      reduced by changing operating conditions and, as a result, a larger difference in
      the structures of the microbial communities developed for the different
      compartments (biomass staging). For example, after changing operating conditions,
      rRNA levels for the acetate-utilizing methanogen Methanosaeta concilii were
      approximately 35 and 10% of the total rRNA in the middle and outside
      compartments, respectively (before changing operating conditions these levels
      were approximately 20 and 12% of the total rRNA, respectively). Promoting larger
      differences in the structures of the microbial communities for the different
      compartments did not improve reactor performance as lower levels of M. concilii
      in the outside compartments hindered acetate removal and compromised effluent
      quality.

PMID- 12469950
TI  - Quantification of Nitrosomonas oligotropha and Nitrospira spp. using competitive
      polymerase chain reaction in bench-scale wastewater treatment reactors operating
      at different solids retention times.
AB  - The effect of solids retention time (SRT) on ammonia-and nitrite-oxidizing
      bacteria was measured by Nitrosomonas oligotropha-like ammonia monooxygenase A
      and Nitrospira 16S rDNA competitive polymerase chain reaction assays in a
      complete-mix, bench-scale, activated-sludge system. During steady-state
      operation, nitrification was complete in the 20- and 10-day SRT reactors, nearly
      complete in the 5-day SRT reactor, and incomplete in the 2-day SRT reactor (76%
      ammonia oxidation and 85% nitrite oxidation). Total microbes, measured by dot
      blot hybridizations, ranged from 3 x 10(11) to 3 x 10(12) cells/L, and increased
      with increasing SRTs. The concentration of the ammonia-oxidizer N. oligotropha
      dropped 100-fold from the 20-day SRT (5 x 10(9) cells/L) to the 2-day SRT (< or =
      4 x 10(7) cells/L). Thus, N. oligotropha became a much smaller fraction of the
      total biomass in the poorly performing 2-day SRT reactor. The concentration of
      Nitrospira cells also decreased (10-fold) as the SRT was reduced from 20 days to
      2 days. However, the number of Nitrospira cells was always greater than the
      number of N. oligotropha cells measured in each reactor (10- to 60-fold). While
      Nitrospira comprised 1 to 2% of the biomass, N. oligotropha represented only 0.04
      to 0.27% of the total population. This low percentage suggests that N.
      oligotropha was not a dominant ammonia oxidizer in the bench-scale systems.

PMID- 12469951
TI  - Nitrifying biofilm development with time: activity versus phylogenetic
      composition.
AB  - The development of nitrifying biofilms collected from a full-scale nitrifying
      trickling filter was evaluated through the application of fluorescent in situ
      hybridization (FISH) and by quantification of nitrification rates in bench-scale
      reactors. Two sampling campaigns were conducted to evaluate the structure and
      function of biofilms between 14 and 70 days old. The structure, or number of
      ammonia-oxidizing bacteria, was quantified with Nso190. The function was
      quantified with bench-scale nitrification rates. The two assays were compared by
      calculating correlation coefficients by simple linear regression of the two data
      sets. The number of ammonia-oxidizing bacteria closely tracked activity data
      (linear correlation, r2 > 0.500). Changes in ammonia-oxidation capacity with time
      (7-day intervals) were mirrored by shifts in the percent of ammonia-oxidizing
      bacteria present. Nitrification rates did not correlate to the EUB338-probe
      stained area (r2 < 0.500), suggesting that nonnitrifying bacteria play a larger
      role in nitrifying biofilm ecology than previously thought. Dry-weight biomass
      accumulations did not correlate to either the EUB338-probe stained area or the
      bench-scale nitrification rates. This suggests that inert materials accumulate in
      the biofilms over time.

PMID- 12469952
TI  - The activated sludge biomolecular database.
AB  - Tremendous advances have recently been made in the development of molecular tools
      for analysis of microbial populations in the environment. However, an appropriate
      scientific basis for quantification of new molecular data must exist to
      effectively use these tools toward increased understanding of complex waste
      treatment environments and implementation of corrective actions to maintain or
      improve system performance. In particular, molecular tools are gaining widespread
      use in the study of activated-sludge microbial communities and have the potential
      to improve monitoring and control of wastewater treatment processes. The authors
      have created a Web-accessible database, the Activated Sludge Biomolecular
      Database, which provides a scientific basis for interpreting activated-sludge
      biomolecular information. The database achieves its goal by accumulating and
      disseminating a large body of knowledge relating the presence and quantity of
      specific biomolecules to process design, operating conditions, and wastewater
      characteristics.

PMID- 12469953
TI  - The reaction mechanisms and kinetics of removing azo reactive dye by indirect
      photolysis approaches.
AB  - The photodegradation of azo reactive dye (RR2) in the presence of acetone (ACE)
      or triethylamine (TEA) via indirect photolysis was investigated. Photolytic
      experiments were conducted in a merry-go-round photoreactor with 253.7-nm
      monochromatic UV lamps. The photodegradation of RR2 in aqueous ACE or TEA
      solution was found to be kinetically controlled by pseudo-first- and zero-order
      kinetics, respectively. Typically, the photodegradation reaction is more
      favorable at higher pH. In the presence of TEA, the rate enhancement primarily is
      a result of the electron transfer from TEA to RR2 and results in the
      photoreduction of dye chromophore. Photosensitization is likely the dominant
      mechanism in the presence of ACE. With respect to the decoloration rate, ACE
      proved to be a promising rate enhancer at elevated concentrations, and the
      solution color faded rapidly within 5 minutes of retention time. The
      photodecoloration of RR2 was found to co-occur with photodechlorination and was
      followed by photodesulfonation at a later stage in which the mineralized end
      products, including hydrogen, chloride, and sulphorate ions, were detected in
      approximately stoichiometric amounts.

PMID- 12469954
TI  - Changing mesophilic wastewater sludge digestion into thermophilic operation at
      Terminal Island Treatment Plant.
AB  - This paper describes the progress up to June 2000 for thermophilic digestion of
      wastewater sludge at the Los Angeles, California, Bureau of Sanitation's Terminal
      Island Treatment Plant. The development of the microorganism culture has followed
      a course similar to that seen at other successful plants for establishment of a
      stable, well-balanced thermophilic culture in a large digester, but at an
      accelerated pace. This study began with rapid heating, increasing the temperature
      of the 4500 m3 (1.2 mil. gal) digester to the target temperature of 55 degrees C
      at approximately 3 degrees C/d. A method of feeding to maximize the rate of
      culture development was used as feeding accelerated to approximately 400 m3/d
      (0.1 mgd). An initial rise of acid concentration (primarily acetate) was seen.
      Within two weeks, acid concentration declined and stabilized, indicating that
      acidogenic and methanogenic microbial communities came into balance. Coliform
      data indicate that digester disinfection was stably effective from the middle of
      April. The salmonella tests done to date satisfy the U.S. Environmental
      Protection Agency (U.S. EPA) class A specification. Testing with helminth ova and
      enteric viruses before and after the digester shows satisfaction of class A
      standard for those organisms. The present combination of low volatile fatty acids
      and low hydrogen sulfide is good news for odor control. The data show increases
      in volatile solids destruction and estimated gas production, compared with the
      previous mesophilic operation; however, large uncertainties have been calculated
      from the data. As the digester is now operating successfully at the current feed
      rate, there seems to be no barriers to processing the entire sludge production of
      the plant. Other results indicate that the U.S. EPA requirements for exceptional
      quality class A biosolids are likely to be achieved.

PMID- 12469955
TI  - A common sense approach to perioperative evaluation.

PMID- 12469956
TI  - Importance of an accurate diagnosis for Achilles rupture.

PMID- 12469958
TI  - Chronic fatigue syndrome and depression.

PMID- 12469959
TI  - Lead poisoning presents a difficult diagnosis.

PMID- 12469957
TI  - Use of feeding tubes in elderly patients with dementia.

PMID- 12469960
TI  - Management of irritable bowel syndrome.
AB  - Irritable bowel syndrome is the most common functional disorder of the
      gastrointestinal tract and is frequently treated by family physicians. Despite
      patients' worries about the symptoms of irritable bowel syndrome, it is a benign
      condition. The diagnosis should be made using standard criteria after red flags
      that may signify organic disease have been ruled out. An effective physician
      patient relationship is vital to successful management. Episodes of diarrhea are
      best managed with loperamide, while constipation often will respond to fiber
      supplements. Antispasmodics or anticholinergic agents may help relieve the
      abdominal pain of irritable bowel syndrome. Refractory cases are often treated
      with tricyclic antidepressants. Newer agents such as tegaserod and ondansetron
      target neurotransmitter receptors in the gastrointestinal tract Some forms of
      psychologic treatment may be helpful, and gastroenterology consultation is
      occasionally needed to reassure the patient. Comorbid conditions such as
      depression or anxiety should be investigated and treated.

PMID- 12469961
TI  - Information from your family doctor. IBS--what you need to know.

PMID- 12469962
TI  - Radiologic imaging in the management of sinusitis.
AB  - Sinusitis is one of the most common diseases treated by primary care physicians.
      Uncomplicated sinusitis does not require radiologic imagery. However, when
      symptoms are recurrent or refractory despite adequate treatment, further
      diagnostic evaluations may be indicated. Plain radiography has a limited role in
      the management of sinusitis. Although air-fluid levels and complete opacification
      of a sinus are more specific for sinusitis, they are only seen in 60 percent of
      cases. Noncontrast coronal computed tomographic (CT) images can define the nasal
      anatomy much more precisely. Mucosal thickening, polyps, and other sinus
      abnormalities can be seen in 40 percent of symptomatic adults; however, clinical
      correlation is needed to avoid overdiagnosis of sinusitis because of nonspecific
      CT findings. Use of CT is typically reserved for difficult cases or to define
      anatomy prior to sinus surgery. Magnetic resonance imaging (MRI) cannot define
      bony anatomy as well as CT. MRI is only used to differentiate soft-tissue
      structures, such as in cases of suspected fungal infection or neoplasm. Referral
      will occasionally be needed in unusual or complicated cases. Immunocompromised
      persons and smokers are at increased risk for serious sinusitis complications.

PMID- 12469963
TI  - Preoperative cardiac risk assessment.
AB  - Heart disease is the leading cause of mortality in the United States. An
      important subset of heart disease is perioperative myocardial infarction, which
      affects approximately 50,000 persons each year. The American College of
      Cardiology (ACC) and American Heart Association (AHA) have coauthored a guideline
      on preoperative cardiac risk assessment, as has the American College of
      Physicians (ACP). The ACC/AHA guideline uses major, intermediate, and minor
      clinical predictors to stratify patients into different cardiac risk categories.
      Patients with poor functional status or those undergoing high-risk surgery
      require further risk stratification via cardiac stress testing. The ACP guideline
      also starts by screening patients for clinical variables that predict
      perioperative cardiac complications. However, the ACP did not feel there was
      enough evidence to support poor functional status as a significant predictor of
      increased risk. High-risk patients would sometimes merit preoperative cardiac
      catheterization by the ACC/AHA guideline, while the ACP version would reserve
      catheterization only for those who were candidates for cardiac revascularization
      independent of their noncardiac surgery. A recent development in prophylaxis of
      surgery-related cardiac complications is the use of beta blockers perioperatively
      for patients with cardiac risk factors.

PMID- 12469964
TI  - Topical tacrolimus: a new therapy for atopic dermatitis.
AB  - Atopic dermatitis is a common problem affecting up to 10 percent of all children.
      The mainstays of therapy have been oral antihistamines, topical emollients,
      topical doxepin, and topical corticosteroids. Side effects associated with higher
      potency topical corticosteroids have limited their use in children and for facial
      areas. Tacrolimus (Protopic) is an immunosuppressive agent typically used
      systemically in transplant patients. Used topically, it has been found to be
      effective in treating moderate to severe atopic dermatitis without causing the
      atrophy that might occur with prolonged use of topical corticosteroids.
      Tacrolimus works equally well in children and adults, with more than two thirds
      of both groups having an improvement of greater than 50 percent. Despite its
      potency, very little of the medication is systemically absorbed, and absorption
      decreases as the atopic dermatitis resolves. The main side effects are burning
      and itching, but these also decrease with improvement of the atopic dermatitis.

PMID- 12469965
TI  - Information from your family doctor. Atopic dermatitis.

PMID- 12469967
TI  - Information from your family doctor. What should I know about removing unwanted
      facial hair?

PMID- 12469966
TI  - Removal of unwanted facial hair.
AB  - Unwanted facial hair is a common problem that is seldom discussed in the primary
      care setting. Although men occasionally request removal of unwanted facial hair,
      women most often seek help with this condition. Physicians generally neglect to
      address the problem if the patient does not first request help. The condition may
      be caused by androgen overproduction, increased sensitivity to circulating
      androgens, or other metabolic and endocrine disorders, and should be properly
      evaluated. Options for hair removal vary in efficacy, degree of discomfort, and
      cost. Clinical studies on the efficacy of many therapies are lacking. Short of
      surgical removal of the hair follicle, the only permanent treatment is
      electrolysis. However, the practice of electrolysis lacks standardization, and
      regulation of the procedure varies from state to state. Shaving, epilation, and
      depilation are the most commonly attempted initial options for facial hair
      removal. Although these methods are less expensive, they are only temporary.
      Laser hair removal, although better studied than most methods and more strictly
      regulated, has yet to be proved permanent in all patients. Eflornithine, a
      topical treatment, is simple to apply and has minimal side effects. By the time
      most patients consult a physician, they have tried several methods of hair
      removal. Family physicians can properly educate patients and recommend treatment
      for this common condition if they are armed with basic knowledge about the
      treatment options.

PMID- 12469968
TI  - Using medications appropriately in older adults.
AB  - Older Americans comprise 13 percent of the population, but they consume an
      average of 30 percent of all prescription drugs. Every day, physicians are faced
      with issues surrounding appropriate prescribing to older patients. Polypharmacy,
      use of supplements, adherence issues, and the potential for adverse drug events
      all pose challenges to effective prescribing. Knowledge of the interplay between
      aging physiology, chronic diseases, and drugs will help the physician avoid
      potential adverse drug events as well as drug-drug and drug-disease interactions.
      Evidence is now available showing that older patients may be underprescribed
      useful drugs, including aspirin for secondary prevention in high-risk patients,
      beta blockers following myocardial infarction, and warfarin for nonvalvular
      atrial fibrillation. There is also evidence that many older adults receive
      medications that could potentially cause more harm than good. Finding the right
      balance between too few and too many drugs will help ensure increased longevity,
      improved overall health, and enhanced functioning and quality of life for the
      aging population.

PMID- 12469969
TI  - Behavioral counseling in primary care to promote physical activity:
      recommendations and rationale.

PMID- 12469970
TI  - CDC releases 2002 guidelines for treating STDs: Part II. Human papillomavirus and
      hepatitis.

PMID- 12469971
TI  - When the side effect is really the symptom.

PMID- 12469972
TI  - A male cardiovascular sexual health clinic.

PMID- 12469973
TI  - Public perceptions of cardiovascular risk.

PMID- 12469974
TI  - Knowledge of stroke symptoms and risk factors among at-risk elderly patients in
      the UK.
AB  - Assessing patient knowledge can help healthcare providers in planning measures
      directed at prevention, early identification and referral of patients. An
      incorrect understanding of stroke symptoms may delay patients seeking emergency
      help, thus missing the benefits of acute stroke treatments. Insufficient
      knowledge about stroke risk factors may affect risk factor control. We conducted
      a questionnaire-based interview among elderly patients at risk of stroke and
      assessed their baseline knowledge of stroke symptoms and risk factors. A large
      proportion were found to have an improper understanding of stroke symptoms and
      risk factors. Stress was considered the commonest risk factor for stroke. Most
      patients did not consider themselves to be at further risk of stroke. Further
      education is needed as part of stroke prevention strategies to remove
      misconceptions. Improved recognition of stroke symptoms when they occur will help
      when seeking emergency medical help.

PMID- 12469975
TI  - Public perceptions of cardiovascular risk in five European countries: the react
      survey.
AB  - Little is known of the attitudes and behaviours of the general public with regard
      to their general and personal risk factors for coronary heart disease (CHD),
      particularly in relation to cholesterol. This study attempted to determine
      patient perceptions of general population and personal risks regarding
      cardiovascular disease. Face-to-face interviews were conducted with 5104 members
      of the public in five countries (France, Germany, Italy, Sweden and the UK). Main
      results showed only 45% of the public correctly identified CHD as the leading
      cause of death in their country, and only 51% were aware that high cholesterol
      increases CHD risk. The presence of cardiovascular disease or risk factors in
      respondents did not appear to alter perceptions of risk compared with the public
      who had no existing disease. Of the different nationalities interviewed, the
      Swedes and the Germans appeared to be most aware of CHD risk factors. Awareness
      and knowledge of LDL-C and HDL-C were very poor in all countries except Italy
      Half of the general public (50%) reported they had never discussed their
      cholesterol levels with a physician and only 33% knew what their target level
      was. Despite this, the most common source of information on CHD and cholesterol
      was the physician (60%). Only 9% of the total sample reported that they were
      currently taking medication for high cholesterol, compared with 20% for
      hypertension. In summary the general public in several European countries has
      major lack of awareness of the risks of CHD. This gap in knowledge is
      particularly marked over the risks of high cholesterol. Significant public health
      education is required.

PMID- 12469976
TI  - Ethnicity and peripheral vascular disease.
AB  - There are well-documented differences in the prevalence of coronary artery
      disease and carotid disease between caucasians, Afro-Caribbeans and Indo-Asians.
      Very little data are available on ethnic differences in peripheral vascular
      disease (PVD). To investigate this further, we surveyed 200 consecutive patients
      attending the vascular surgery service at a city centre hospital serving a
      multiethnic patient catchment population. All patients had proven PVD, with an
      ankle brachial pressure index of less than 0.8. Within this cohort, Afro
      Caribbeans presented more frequently with PVD compared with the proportion of
      this ethnic group in the local population (p = 0.013), with a greater proportion
      with diabetes mellitus than in the other two ethnic groups. There did not appear
      to be a significant difference between the ethnic groups in any of the other
      established risk factors or associations (i.e. treated hypertension, smoking,
      previous history of ischaemic heart disease, atrial fibrillation, previous
      history of cerebrovascular accident or transient ischaemic attack) with PVD. As
      with coronary artery disease and carotid disease, there are ethnic differences in
      the prevalence of PVD, and the underlying risk factors, between caucasians, Afro
      Caribbeans and Indo-Asians. Furthermore, patients of Afro-Caribbean origin
      present more frequently with symptomatic PVD than do either caucasians or Indo
      Asians.

PMID- 12469977
TI  - Percutaneous transluminal renal artery angioplasty: who benefits most?
AB  - We set out to assess the long-term benefits of renal percutaneous transluminal
      angioplasty (PTA) in 107 consecutive hypertensive patients with atheromatous
      renal artery stenosis. During 12-month follow-up, blood pressure fell to normal
      levels in 10 (8.8%) patients and improved in 76 (67.3%); renal function improved
      or remained stable in 74% of patients. In patients with atheromatous disease,
      renal angioplasty was most successful in those with stenosis in a single
      functioning kidney, and in nine patients who presented with symptoms and signs of
      heart failure, in the absence of overt ischaemic or valvular heart disease. In
      the latter group, renal PTA resulted in a large loss of sodium and water,
      resolution of the 'apparent' heart failure, and a marked improvement in blood
      pressure and renal function. It is suggested that all hypertensive patients with
      haemodynamically significant renal artery stenosis (and/or mild to moderate
      impairment in renal function), should be considered for renal PTA. Patients with
      atheromatous stenosis in a single functioning kidney, and those who present with
      signs of sodium and water retention, are likely to benefit most.

PMID- 12469978
TI  - Combined spinal and epidural anaesthesia in elderly patients.
AB  - The study was designed to investigate the effects of simultaneously combined
      spinal-epidural anaesthesia in elderly patients and to evaluate the problems
      encountered during and after performing spinal block following epidural blockade.
      Nineteen ASA grade III elderly patients (mean age 75.8 years) were included in
      the study. The first 10 patients (group 1) were given 0.5% hyperbaric bupivacaine
      2 ml (10 mg) and fentanyl 0.25 ml (12.5 microg) intrathecally. The remaining nine
      patients (group 2) received 0.5% hyperbaric bupivacaine 1 ml (5 mg)
      intrathecally; following the spinal block fixation (about 15 min), fentanyl 1 ml
      (50 microg) in saline 10 ml was injected into the epidural catheter. The highest
      sensory block was achieved at T6 and T9 in groups 1 and 2, respectively. None of
      the patients experienced respiratory depression, sedation, vomiting, shivering or
      headache. In conclusion, simultaneous combination of subarachnoid and epidural
      blockade may provide sufficient anaesthesia with fewer complications.

PMID- 12469979
TI  - A pharmacokinetic comparison of the modified release capsule and a plain tablet
      formulation of mebeverine.
AB  - This study was conducted to compare the pharmacokinetic properties of the
      modified release 200 mg capsule of mebeverine and the plain 135 mg tablet of
      mebeverine after single and multiple doses in 12 healthy subjects in a
      randomised, crossover design. Single doses were given on days 1 and 7 and
      multiple doses (200 mg b.i.d. for the capsule and 135 mg t.i.d. for the tablet)
      on days 2-6 of the study. The 200 mg modified release capsule of mebeverine has
      extended release properties, as indicated by a lower Cmax, a later tmax and a
      longer elimination half-life than the plain tablet, while the bioavailability is
      optimal. No significant accumulation occurs after multiple doses of either
      formulation. The twice-daily dosage regimen of the 200 mg modified release
      capsule is a good alternative to the three times daily dosage regimen of the 135
      mg plain tablet, because the reduced daily intake is likely to benefit patient
      compliance.

PMID- 12469980
TI  - A systematic approach to erectile dysfunction in the cardiovascular patient: a
      Consensus Statement--update 2002.
AB  - Sexual activity is no more stressful to the heart when compared with a number of
      other natural daily activities, e.g. walking one mile on the level in 20 minutes.
      The cardiac risk of sexual activity in patients diagnosed with cardiovascular
      disease is minimal in properly assessed and advised patients. Erectile
      dysfunction (ED) is extremely common, affecting over half of men aged 40-70
      years, and increases in frequency with age. ED and cardiovascular disease share
      many of the same risk factors and commonly coexist. ED in the otherwise
      asymptomatic man may be a marker for underlying coronary artery disease. ED in
      the diagnosed cardiovascular patient should be identified by routine questioning
      in general practice. Modern therapies can restore a sexual relationship in the
      majority of patients with ED and can lead to a substantial improvement in quality
      of life. The majority of patients assessed to be at low or intermediate cardiac
      risk, as defined later in this paper, can be effectively managed in primary care.
      Primary care treatment for ED in patients defined as high risk can be initiated
      following a specialist opinion and/or confirmation that the patient's
      cardiovascular condition is stabilised. There is no evidence that currently
      licensed treatments for ED add to the overall cardiovascular risk in patients
      with or without diagnosed cardiovascular disease. If one form of therapy is not
      effective, follow-up will identify the need for alternative approaches. The pro
      active management of ED in the cardiovascular patient provides an ideal and
      effective opportunity to address other cardiovascular risk factors and improve
      treatment outcomes.

PMID- 12469981
TI  - 17. Psychosocial problems following a diagnosis of breast cancer.
AB  - Most breast cancer patients are not ill but have to cope with major life changes,
      in the knowledge that they have a potentially life-threatening illness.
      Additionally they have to withstand multiple physical and psychological demands
      of local and systemic treatment. The role of the specialist breast care nurse is
      to reinforce information, discuss treatment options, and if the patient has
      further questions to arrange additional appointments with the appropriate member
      of the breast team. Approximately 20% of newly diagnosed patients will experience
      long-term psychological problems, and those at greater risk are cases with a
      previous psychiatric history, lack of support and low expectations of the benefit
      of treatment, sometimes from a previous adverse experience with a family member.
      The breast care nurse is in a good position to identify those at risk and to
      advise on the benefits of surgery and breast reconstruction. Clarification of the
      benefits and side-effects of other treatments such as chemotherapy and
      radiotherapy are also part of the breast care nurse's remit. Patients in need can
      receive support including coping strategies which will improve their
      psychological well-being during the cancer journey.

PMID- 12469982
TI  - 18. Genetics of breast cancer.
AB  - It is well known that breast cancer often occurs in clusters within families.
      This clustering can be attributed to mutations in the breast cancer
      susceptibility genes, BRCA1 and BRCA2, in 16% of familial cases. Women with a
      family history of breast cancer, in whom no mutation is identified, are still at
      increased risk of developing the disease. This review addresses methods for
      estimating and stratifying risk of developing breast cancer based on family
      history. It also indicates how to identify patients likely to carry mutations in
      BRCA1 or BRCA2 and gives recommendations for intervention for women with a family
      history of breast cancer.

PMID- 12469983
TI  - The new role of pharmacotherapy for weight reduction in obesity.
AB  - Obesity is associated with an increased risk for a wide variety of chronic health
      conditions. Despite this fact, less than half of obese patients are advised by
      healthcare professionals to lose weight. Creating a viable plan for losing weight
      and maintaining weight loss is difficult. Lifestyle change is always the
      cornerstone of treatment, but two new therapeutic agents approved for long-term
      use, sibutramine and orlistat, can help maximise success. Increased weight loss
      can lead to reductions in the risk of obesity-related co-morbidities. Sibutramine
      and orlistat offer new weight reduction opportunities for obese patients.

PMID- 12469984
TI  - Management of patients with intermittent claudication.
AB  - Intermittent claudication, the most common symptomatology of peripheral arterial
      disease, is characterised by lower-extremity discomfort induced by exercise and
      relieved by rest. The most serious potential outcome of the condition is
      increased morbidity and mortality from cardiovascular disease, with which it is
      often associated, thus prompt diagnosis and management are crucial. Therapy
      consists of structured exercise and reduction of cardiovascular risk factors,
      followed by or together with pharmacological interventions with anticlaudicants
      (cilostazol or pentoxifylline) and specific antiplatelet agents (aspirin,
      clopidogrel). Revascularisation procedures are indicated in those with limb
      threatening or lifestyle disabling disease.

PMID- 12469985
TI  - Female stress and urge incontinence in family practice: insight into the lower
      urinary tract.
AB  - As many as 25% of all women are affected by urinary incontinence, but only a few
      are treated. This frequent, often medically unrecognised, condition occurs in
      women of all ages. The continence mechanism is based on bladder detrusor control,
      intact anatomical structures in and around the urethra, correct positioning of
      the bladder neck and a comprehensive innervation of the lower urinary tract. Age
      and childbearing are established risk factors for the development of urinary
      incontinence, but other factors are currently suggested. The evaluation of
      urinary incontinence should include history, gynaecological examination, urine
      test, frequency-volume diary and a pad-weighing test. Female urinary incontinence
      can be treated in general practice by simple means, e.g. pelvic floor muscle
      training, bladder training, electrostimulation, drug therapy, or a combination of
      these approaches. This review updates the knowledge of the continence mechanism
      and summarises the epidemiology, risk factors, assessment and treatment of
      urinary incontinence in general practice.

PMID- 12469986
TI  - Type 2 diabetes mellitus and thyrotoxicosis presenting concurrently.
AB  - The symptoms of thyrotoxicosis and diabetes mellitus can be quite similar, and in
      patients presenting with diabetes, thyrotoxicosis could be missed unless
      specifically tested for. There are few reports of the two conditions presenting
      at the same time. We report on two such cases. In a patient who is diagnosed as
      having both conditions concurrently, an oral glucose tolerance test should be
      repeated after successful treatment of thyrotoxicosis before a diagnosis of
      diabetes mellitus is made.

PMID- 12469987
TI  - Sumatriptan nasal spray for migraine: a review of studies in patients aged 17
      years and younger.
AB  - This review considers the epidemiology, clinical manifestations and functional
      consequences of migraine in children and adolescents and surveys the studies
      establishing the efficacy and tolerability of sumatriptan nasal spray in this
      patient population. Although therapeutic advances in paediatric and adolescent
      migraine have lagged behind those in adult migraine, the first systematic studies
      of migraine medications in young patients have brought about progress in the past
      five years. These studies show that therapeutic approaches suitable for adult
      patients are not always applicable to paediatric and adolescent patients. Because
      of the unique characteristics of paediatric and adolescent migraine, it has been
      difficult to demonstrate in young patients the efficacy of oral sumatriptan and
      other triptan tablets, which are the medications of choice for adult migraine.
      With sumatriptan, this finding has proven to be a consequence of the form in
      which the drug was administered rather than the inherent properties of the drug.
      The availability of sumatriptan nasal spray allows the benefits of migraine
      specific therapy to be extended to children and adolescents. In both well
      controlled, single-episode studies and long-term, multiple-episode studies,
      sumatriptan nasal spray has been effective and well tolerated for the acute
      treatment of migraine in children and adolescents. Except for unpleasant taste,
      which is not significantly distressing to patients, sumatriptan nasal spray has a
      tolerability profile similar to thatof placebo in young patients.

PMID- 12469988
TI  - Donepezil: tolerability and safety in Alzheimer's disease.
AB  - The tolerability and safety of donepezil HCI in patients with mild to moderate
      Alzheimer's disease (AD) were examined in an integrated analysis of phase II/III
      placebo-controlled trials. Patients with mild to moderately severe AD (n=1,920)
      were randomised to receive donepezil (n=1,291) or placebo (n=629). Adverse
      events, physical examinations and clinical laboratory tests were assessed. A high
      completion rate (79%) was achieved in these trials. Of the 1,291 patients
      receiving donepezil only, 142 (11%) withdrew because of an adverse event compared
      with 43 of the 629 (7%) placebo patients. The most common adverse events included
      nausea, diarrhoea, headache, insomnia, dizziness, rhinitis, vomiting,
      asthenia/fatigue and anorexia. Donepezil had no clinically significant effect on
      any laboratory evaluations and was not associated with hepatotoxicity. These
      results demonstrate that donepezil is well tolerated and has a favourable safety
      profile at clinically effective, once-daily doses of 5 mg and 10 mg.

PMID- 12469989
TI  - Guidewire-induced dissection of the right coronary artery and adjacent aortic
      wall during percutaneous coronary angioplasty.
AB  - We describe two patients in whom right coronary artery dissection and retrograde
      dissection of the sinus of Valsalva occurred during guidewire advancement for
      percutaneous coronary angioplasty Both patients were treated successfully by
      coronary stenting. These cases illustrate that contrast medium injection can
      detect early complications during guidewire advancement for coronary
      intervention.

PMID- 12469990
TI  - Acute cerebellar ataxia associated with chickenpox.
AB  - A case of a child with acute cerebellar ataxia associated with chickenpox virus
      infection is described. Acute cerebellar ataxia associated with chickenpox is a
      well-recognised complication and the pertinent features of this condition are
      discussed.

PMID- 12469991
TI  - Acute myocardial infarction associated with myocardial bridge and coronary artery
      vasospasm.
AB  - A 65-year-old man was admitted to our hospital with acute myocardial infarction
      (MI). Emergency coronary angiography showed no significant organic lesions, but a
      myocardial bridge was found at the mid-left anterior descending artery An
      acetylcholine provocation test revealed 90% spastic stenosis just proximal to the
      myocardial bridge. His acute MI could have been caused by both a coronary spasm
      and the myocardial bridge.

PMID- 12469992
TI  - A yoga teacher with persistent reflux symptoms.

PMID- 12469993
TI  - The Lindsay Tribunal into HIV and hepatitis C infection in haemophiliacs.

PMID- 12469994
TI  - Treatment of schizophrenia--forging ahead.

PMID- 12469995
TI  - Management of otoscierosis--an Irish perspective.
AB  - The last 30 years have seen a gradual change in the management of otosclerosis.
      The aim of this study is to evaluate the current practice amongst Irish
      otolaryngology consultants by a questionnaire and to compare it with the practice
      currently followed in Great Britain. Thirty-eight responses (67.9%) were
      available for analysis. The overall trend is towards centralisation with a
      reduction in the number of surgeons undertaking stapes surgery (39%). The
      majority of consultants (67%) who undertake stapes surgery would operate for a
      unilateral conductive loss and 67% would undertake bilateral stapes surgery.
      Stapedotomy is the only operation performed (100%) with none of the consultants
      performing partial or total stapedectomies.

PMID- 12469996
TI  - Irish neonatal mortality--12 years on.
AB  - All Paediatricians in Ireland were requested to fill a questionnaire which dealt
      with data pertaining to all live-born infants over 500 g birth weight who died
      within the first 28 days of life in 1999. Deaths were categorized according to
      Wigglesworth Classification into Lethal Malformation, Immaturity (Prematurity),
      Asphyxia and "Specific". Each hospital and patient was assigned a unique ID
      number. Data from questionnaires was entered into a database. Results were
      compared with those previously published by Counahan and Clarke for 1987. Twenty
      one of the 23 paediatric centres in Ireland replied giving a response rate of
      91%. The over-all number of neonatal deaths for 1999 was 186 compared to 310 for
      1987. One hundred and two (55%) were < 1500 grams and 61 (33%) < 1000 g. The
      principal causes of death for 1999 were Congenital Malformations 39%, (n=72),
      Prematurity 37% (n=69) and Asphyxia 3% (n=5). This compares to figures of 39%,
      40% and 8%, respectively for 1987. The overall Neonatal Mortality Rate for 1999
      was 3.48/1000 with a Corrected Neonatal Mortality Rate of 2.1/1000. The Neonatal
      Mortality Rate and Corrected Neonatal Mortality Rate for 1987 were 5.3/1000 and
      3.3/1000 respectively. The decrease in Neonatal Mortality in the past 12 years in
      Ireland is to be applauded. However it can lead to a false sense of security
      regarding standards of neonatal care. While the death of Extremely Low-Birth
      Weight infants can now often be prevented, in many cases it is merely deferred to
      the post-neonatal period. Furthermore, no national data is available on the long
      term outcome and neurodevelopmental status of preterm or asphyxiated infants who
      survive. The possibility of establishing an Irish Neonatal Morbidity Register,
      aimed at improving the effectiveness and efficiency of medical care for newborn
      infants, must now be explored.

PMID- 12469997
TI  - The management of acute myocardial infarction--practical problems in implementing
      the evidence.
AB  - Cardiovascular disease is the leading cause of death in Europe. Acute myocardial
      infarction (AMI) is among the most common of its manifestations. Women and older
      patients are under-represented in most trials of treatment for AMI, as are those
      with significant co-morbidities. These patients also have a worse long term
      outcome after AMI. We sought to evaluate the management of AMI in a small non
      academic general hospital. A review was performed of cases of AMI during 2000.
      Ninety-two cases were analysed, 69% were male. The mean age was 70 years. In
      hospital mortality was 12%; 30-day mortality was 14%. There was no gender or age
      difference in mortality. Of thirty eligible patients, twenty-eight were
      thrombolysed (93%). Aspirin (81%) and beta-blocker (41%) prescription on
      discharge were below published European and American rates. Females were
      significantly less likely to receive aspirin or beta-blockers on discharge. Those
      aged 70 years or more were less likely to receive beta-blockers, statins or ACE
      inhibitors on discharge. Those with co-morbidities were less likely to receive
      beta-blockers or statins on discharge. This study highlights the difficulty in
      realising evidence based guidelines optimal management of AMI in clinical
      practice. While the outcome with regard to mortality is similar to national
      figures, there is a need to enhance care, with particular emphasis on secondary
      pharmacological measures prescribed on discharge.

PMID- 12469998
TI  - Comparison of secondary prevention of heart disease in Europe: lifestyle getting
      worse, therapy getting better in Ireland.
AB  - We compared the implementation of secondary prevention some 18 months following
      acute myocardial infarction or coronary artery bypass surgery in Ireland in 1994
      to that in 15 European countries, including Ireland, in 2000. While there were
      substantial improvements in the use of statins, b-blockers and the availability
      of rehabilitation programmes since the early 1990s, more patients now smoke, take
      no exercise and are overweight. The prevalence of non-insulin dependent diabetes
      has increased by 70%. In comparison with other European countries, we have the
      highest use of aspirin and the highest prevalence of smoking in women. Despite a
      considerable improvement in the use of drug therapy we will not achieve the full
      potential of secondary prevention unless lifestyle factors, including smoking,
      overweight and exercise receive greater attention by patients with coronary heart
      disease.

PMID- 12470000
TI  - Fire breathing pneumonia.
AB  - Rounded lesions on chest x-ray can often be difficult both to diagnose and to
      treat. We report a case of a right middle lobe lesion in a young, previously
      healthy patient who presented with pleurtic chest pain and haemoptysis. His
      symptoms and chest x-ray appearance were caused by exposure to paraffin oil
      (kerosene), a substance commonly used for medical as well as domestic purposes.

PMID- 12469999
TI  - Audit of acute myocardial infarctions at Saint James's Hospital, Dublin, from
      1996 to 1999.
AB  - Saint James' Hospital is a 650-bed tertiary referral hospital. An audit was
      performed of acute transmural myocardial infarctions for the years 1996 to 1999
      inclusive. On average there were 2043 cardiology admissions annually, 9.8% of all
      hospital admissions. Acute transmural myocardial infarction was diagnosed in 178
      patients annually, and was less common during the summer. The figure of 72%
      receiving revascularisation therapy (thrombolysis 67%, primary angioplasty 5%)
      compares favourably with 35% in 1992. The main reason for not receiving
      thrombolysis was late presentation (15%) with contraindications present in only
      5%. The case fatality rate was 16% confirming the higher mortality in clinical
      practice than that of thrombolytic trials. The prescription of aspirin or
      warfarin (99%) and betablockers (67%) was in line with international trials. The
      use of angiotensin converting enzyme inhibitors (34%) and statins (28%) is
      similar to other studies but less than would be expected according to trial
      evidence.

PMID- 12470001
TI  - Diagnosis and management of an intra-articular foreign body in the foot.
AB  - We describe a case of a small intra-articular foreign body in the foot presenting
      48 hours following injury, which at operation showed early evidence of septic
      arthritis. It is essential to accurately localise periarticular foreign bodies in
      the foot and proceed to arthrotomy and debridement in all cases where there is
      radiological or clinical evidence to suggest intra-articular retention of a
      foreign body.

PMID- 12470002
TI  - Protracted neurological recovery after chronic lithium intoxication.

PMID- 12470003
TI  - A survey on sports injuries in general practice.

PMID- 12470004
TI  - Peri-conceptual folic acid.

PMID- 12470005
TI  - An overview of the current practice of diagnosis and management of pyloric
      stenosis in a paediatric population in Ireland 2000.

PMID- 12470006
TI  - Stroke associated with amphetamine use.

PMID- 12470007
TI  - Inequalities in prescribing of secondary preventative therapies for ischaemic
      heart disease in Ireland.

PMID- 12470008
TI  - Sirolimus-eluting stents: the novel application of basic science to coronary
      artery disease.

PMID- 12470009
TI  - Only people can provide high quality healthcare--they should be valued as major
      assets.

PMID- 12470010
TI  - Physical assessment skills: a developing dimension of clinical nursing practice.
AB  - This paper proposes that the current use of physical assessment skills within
      critical care nursing practice is part of a on-going nursing role development
      process. A review of the critical care nursing role highlights how nurses in this
      setting have always been responsive to patient management needs. In exploring one
      recent nursing role development, the critical care outreach nurse, it is
      suggested that enhanced assessment skills enable these practitioners to safely
      and competently assess critically ill patients out of the intensive care
      environment. The use of patient case studies in this paper, demonstrate how the
      theory of a more intensive physical assessment knowledge base can be applied in
      the everyday practice of an critical care outreach nurse. Through such systematic
      patient review, patient management plans can be agreed and ward based
      practitioners can be supported in the on-going treatment of sick ward patients.
      The use of the cases presented also highlights the complexity of the outreach
      nurse's practice in addressing clinical management and team management issues.

PMID- 12470011
TI  - An evaluation of the evidence base related to critical care outreach teams--2
      years on from Comprehensive Critical Care.
AB  - It is now 2 years since the publication of Department of Health [Comprehensive
      Critical Care: A Review of Adult Critical Care Services (2000a)] document
      'Comprehensive Critical Care'. One of its' main recommendations was the
      introduction of critical care outreach services. Many hospitals have since
      established such services and are providing education for ward nurses and house
      officers, and follow-up for patients discharged from intensive care when they
      return to a general ward. Early Warning Scoring (EWS) systems have also been
      introduced onto the wards to improve the identification of patients deteriorating
      into critical illness. However, as yet there appears to be little evidence that
      this investment has been worthwhile in terms of improving patient outcomes, such
      as reduction in cardiac arrests on the wards, reduction in unplanned admissions
      to critical care or earlier referrals to critical care. With many outreach teams
      hoping to expand their services in the future there is a pressing need to
      demonstrate an impact. We must remember however that some outreach teams have
      only been in post for 12 months and so it may therefore be far too early to
      reliably demonstrate any effect.

PMID- 12470012
TI  - Factors influencing the patient during weaning from mechanical ventilation: a
      national survey.
AB  - Successful weaning depends on the application of skilled judgement and decision
      making to nursing and medical interventions. The intensive care nurse is in an
      unique position for adopting a holistic approach to weaning. Such an approach
      needs teamwork and consideration of all the factors that could influence the
      outcome of the weaning phase. The aim of this study was to conduct a survey, to
      establish the factors taken into consideration and documented during weaning at
      the intensive care units (ICUs) in Sweden. A questionnaire was developed and sent
      to all 92 ICUs. The results identified that nutrition, communication, analgesics
      and sedatives, psychological and metabolic factors, as well as weaning methods
      and measurable parameters were taken into consideration. Written instructions for
      weaning were used by only three ICUs and weaning protocols were not common. A
      holistic approach to the discontinuation of mechanical ventilation is a valuable
      means of improving the quality of care and merits further research.

PMID- 12470013
TI  - Barriers to research utilisation: the clinical setting and nurses themselves.
AB  - The advance of the evidence-based practice (EBP) movement has been evident in
      almost every Western country and health system over the past two or three
      decades, fuelled by an ever-rising demand on resources. Nurses at all levels are
      increasingly expected to address the key challenge of EBP, which is to use
      research evidence in a conscientious, explicit and judicious way when making
      decisions about patient care. The main aim of the paper is to encourage nurses to
      embrace the challenge of EBP. First, as background, this paper presents key
      findings from the limited body of research which has examined barriers to
      research utilisation in the nursing context. Nurses generally feel there are many
      barriers, with primary barriers being lack of time, lack of relevant skills, poor
      team-working and several aspects of nursing 'culture' (ritualistic care, no
      authority and no incentives). Some conceptual models in implementation of
      research findings are introduced, and a summary presented of key areas which
      nurses need to address when considering research utilisation.

PMID- 12470014
TI  - A description of patients' report of endotracheal tube discomfort.
AB  - The purpose of this descriptive study was to describe the type, location, and
      amount of endotracheal tube (ETT) discomfort. Twenty-two subjects (mean age 49.2
      years) who had experienced ETT intubation for at least 6 hours (mean: 25.9 hours)
      after cardiac surgery, completed a 100-mm Visual Analogue Scale related to their
      experience with the endotracheal tube within 24 hours after extubation. A semi
      structured interview was also conducted. There was no relationship between the
      duration of intubation and the level of discomfort described (r = -0.24; P =
      0.29) or between the duration of intubation and whether medications relieved the
      discomfort (r = 0.34; P = 17). All subjects described some level of discomfort.
      The majority stated the discomfort was in the throat area. However, 27% (n = 6)
      described the discomfort as located in the chest. There was no difference in the
      level of discomfort based on discomfort location (f = -0.14; P = 0.71). The
      discomfort locations support the notion that ETT irritation occurs at multiple
      levels (i.e. pharyngeal, laryngeal, and tracheal mucosal areas). In addition,
      interventions that focus on ETT stability will not be sufficient to reduce
      discomfort but must re-focus nursing attention on reducing ETT movement as well
      as the movement of all ventilator tubing.

PMID- 12470015
TI  - A renal critical care educator: the interface between paediatric intensive care
      and nephrology.
AB  - This paper describes the new role of a renal critical care educator who is based
      in a regional paediatric renal unit 'outreaching' to three paediatric intensive
      care units (PICUs) within the region. For the first 18 months the objectives of
      training PICU staff in all aspects of haemofiltration has progressed in all units
      using flexible training programs which are under constant evaluation using
      questionnaires. The renal critical care educator has also worked alongside staff
      whilst continuous veno-venous haemofiltration (CVVH) is being performed to
      further instill confidence. Equipment and protocols have been largely
      standardised throughout the region and an ongoing survey of CVVH use has been
      initiated which should help to inform audit standards such as complication rates.
      The renal critical care educator has been the catalyst for the formation of a
      regional haemofiltration group which has shared in the development of guidelines
      and protocols and discussion of clinical data. Since CVVH is used infrequently in
      many PICUs the development of the renal critical care educator post could serve
      as a model for the development and maintenance of skills in other regions.

PMID- 12470016
TI  - Chest X-ray quiz. The left hemidiaphragm is ruptured.

PMID- 12470017
TI  - Long-term cytocompatibility of various endodontic sealers using a new root canal
      model.
AB  - It was the purpose of our study to determine the cytotoxicity of several types of
      root canal sealers in vitro over the period of 1 yr by using a new test model.
      Roots of extracted human teeth were filled with N2, Apexit, Roekoseal, AH Plus,
      Ketac Endo, Endomethasone, and one gutta-percha point. In addition, roots filled
      with laterally condensed gutta-percha/N2. Teeth filled with one gutta-percha
      point only were controls. All specimens were consecutively extracted with
      distilled water for a total period of 1 yr. Extracts were investigated for
      cytotoxicity by using immortalized 3T3 fibroblasts and primary human periodontal
      ligament fibroblasts. Results were statistically analyzed with Dunnett's t tests
      (p < 0.05). Pronounced cytotoxic effects were only caused by N2-extracts in both
      cell cultures (p < 0.05). Furthermore, statistically significant cytotoxic
      alterations were also induced by 10-week eluates of Endomethasone (p < 0.05). All
      other investigated materials did not significantly alter cell metabolism.

PMID- 12470018
TI  - Production of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta by human
      polymorphonuclear neutrophils stimulated with Porphyromonas endodontalis
      lipopolysaccharide.
AB  - This study was undertaken to investigate the capacity of polymorphonuclear
      neutrophils (PMNs) to secrete Macrophage Inflammatory Protein (MIP)-1alpha and
      MIP-1beta after stimulation with Porphyromonas endodontalis lipopolysaccharide
      (LPS). Escherichia coli LPS was used as a positive control. Venous blood was
      collected and PMNs were isolated from healthy volunteers. Cells were cultured
      with various concentrations of LPS for different periods of time. Cell
      supernatants were assayed by enzyme-linked immunosorbent assay. The levels of
      chemokine secretion in PMNs stimulated with each LPS were found to be
      significantly higher than in the unstimulated control cells (p < 0.05), and this
      expression occurred in a time- and dose-dependent manner. E. coli LPS induced
      higher levels of cytokines than P. endodontalis LPS. These findings demonstrated
      that P. endodontalis LPS is capable of stimulating PMNs to produce chemotactic
      cytokines and suggested that PMNs stimulated with P. endodontalis LPS may play a
      crucial role in the inflammatory and immunopathological reactions of pulpal and
      periapical diseases.

PMID- 12470020
TI  - An assessment of microbial coronal leakage of temporary filling materials in
      endodontically treated teeth.
AB  - This in vitro study evaluated the microbial leakage of Cavit, IRM, and Dyract
      when used as temporary filling materials after root canal treatment. The degree
      of coronal leakage was assessed by using a microbiological marker consisting of
      Streptococcus faecalis and Candida albicans. For each of the two organisms, a set
      of 15 maxillary premolars were prepared chemomechanically and obturated with
      thermoplasticized gutta-percha. A 3.5-mm thick layer of one of the three
      temporary filling materials was inserted in the access cavities of the teeth from
      each group (each group was compromised of five teeth). The control teeth (four
      positive and four negative) lacked any filling material over the gutta-percha,
      whereas the orifice and the apical foramen of the negative control were
      completely sealed with nail polish. Each tooth was placed in a well of a 24-well
      tissue culture plate and embedded in trypticase soy broth and 0.5% Bactoagar. An
      organism suspension was inoculated in the access cavity, and microbial
      penetration was detected as an increase in turbidity of the broth. At the end of
      30 days, the results showed that all positive control teeth leaked within 1 week,
      whereas those that served as negative control remained uncontaminated throughout
      the test period. With both organisms, IRM started to leak after 10 days, whereas
      Cavit and Dyract leaked after 2 weeks.

PMID- 12470019
TI  - Microbial susceptibility to calcium hydroxide pastes and their vehicles.
AB  - The aim of this study was to investigate the susceptibility of some
      microorganisms commonly isolated from root canals to calcium hydroxide in
      combination with several vehicles by the agar diffusion method. Stainless-steel
      cylinders were placed on each inoculated agar medium. The test medications and
      their controls were placed inside the cylinders. The zones of growth inhibition
      were measured and recorded after the incubation period for each plate, and the
      results were analyzed statistically. Enterococcus faecalis was most resistant,
      whereas the anaerobic Porphyromonas endodontalis was more susceptible to all
      medications, followed by P. gingivalis and Prevotella intermedial intermedia.
      Ca(OH)2 + CMCP + glycerin showed significantly larger mean zones of inhibition
      when compared with the other medications. We conclude that anaerobic Gram
      negative bacteria are more susceptible to calcium hydroxide pastes than
      facultative Gram-positive microorganisms.

PMID- 12470021
TI  - Fatigue resistance of engine-driven rotary nickel-titanium endodontic
      instruments.
AB  - A comparative study of the fatigue resistance of engine-driven nickel-titanium
      endodontic instruments was performed, aiming to access the influence of the
      cutting flute design and of the size of the files that reach the working length
      in curved canal shaping. Geometrical conditions similar to those found in
      practice were used. Series 29 #5 ProFile, together with #6 and #8 Quantec
      instruments, were tested in artificial canals with a 45-degree angle of curvature
      and 5-mm radius of curvature. It was observed that the size of the instrument,
      which determines the maximum strain amplitude during cyclic deformation, is the
      most important factor controlling fatigue resistance. The effect of heat
      sterilization on the fatigue resistance of the instruments was also examined. The
      results obtained indicate that the application of five sterilization procedures
      in dry heat increases the average number of cycles to failure of unused
      instruments by approximately 70%.

PMID- 12470022
TI  - Fungal infection of the radicular dentin.
AB  - Although fungi have been detected in infected root canals, their precise role as
      endodontic pathogens has not yet been elucidated. The purpose of this study was
      to investigate the pattern of radicular dentin colonization by five fungal
      species. Bovine root sections were infected with each of the following fungal
      species: Candida albicans, Candida glabrata, Candida guilliermondii, Candida
      parapsilosis, and Saccharomyces cerevisiae. After 14 days, the sections were
      fixed in glutaraldehyde, split into two halves, critical point-dried in CO2,
      sputter-coated with gold, and examined under scanning electron microscopy.
      Regardless of the species, single or budding yeast cells were the only fungal
      forms observed. C. albicans colonized most of the specimens. On the other hand,
      the other four fungal species presented discrete or no colonization of the
      radicular dentin. C. albicans showed different patterns of dentin infection. In
      some specimens, colonization of the dentinal surface was slight and no
      penetration within dentinal tubules was observed. In the other specimens, some
      areas of the root canal walls were covered with large colonies of yeast cells and
      some dentinal tubules were heavily infected. The results suggested that whereas
      C. albicans showed the ability to colonize dentin, the other four fungal species
      did not. This can help to explain why C. albicans is the fungal species most
      often found in endodontic infections.

PMID- 12470023
TI  - Differential scanning calorimetric studies of nickel-titanium rotary endodontic
      instruments after simulated clinical use.
AB  - Differential scanning calorimetric (DSC) analyses have been performed between 
      130 degrees and 100 degrees C on single-segment specimens obtained from ProFile
      and Lightspeed nickel-titanium rotary endodontic instruments in the as-received
      condition and after one, three, and six periods of simulated clinical use in
      extracted teeth. The DSC analyses showed that both brands of instruments were
      always in the superelastic condition, although the enthalpy values for the
      transformation from martensitic NiTi to austenitic NiTi were much smaller for the
      Lightspeed instruments. Simulated clinical use had no evident effect upon this
      transformation for both brands, which is attributed to insufficient mechanical
      deformation of the instruments. There were substantial differences in the
      enthalpy change associated with the transformation from martensitic NiTi to
      austenitic NiTi for test segments from different positions along the shafts of
      the instruments and for as-received instruments from two different batches that
      were analyzed in this study and a previous study. These differences are
      attributed to variations in work hardening along the shaft during instrument
      fabrication and to processing differences during production of the two batches of
      each instrument brand.

PMID- 12470024
TI  - The effectiveness of increased apical enlargement in reducing intracanal
      bacteria.
AB  - It has been suggested that the apical portion of a root canal is not adequately
      disinfected by typical instrumentation regimens. The purpose of this study was to
      determine whether instrumentation to sizes larger than typically used would more
      effectively remove culturable bacteria from the canal. Forty patients with
      clinical and radiographic evidence of apical periodontitis were recruited from
      the endodontic clinic. Mandibular cuspids (n = 2), bicuspids (n = 11), and molars
      (mesial roots) (n = 27) were selected for the study. Bacterial sampling was
      performed upon access and after each of two consecutive instrumentations. The
      first instrumentation utilized 1% NaOCI and 0.04 taper ProFile rotary files. The
      cuspid and bicuspid canals were instrumented to a #8 size and the molar canals to
      a #7 size. The second instrumentation utilized LightSpeed files and 1% NaOCl
      irrigation for further enlargement of the apical third. Typically, molars were
      instrumented to size 60 and cuspid/bicuspid canals to size 80. Our findings show
      that 100% of the cuspid/bicuspid canals and 81.5% of the molar canals were
      rendered bacteria-free after the first instrumentation sizes. The molar results
      improved to 89% after the second instrumentation. Of the (59.3%) molar mesial
      canals without a clinically detectable communication, 93% were rendered bacteria
      free with the first instrumentation. Using a Wilcoxon rank sum test,
      statistically significant differences (p < 0.0001) were found between the initial
      sample and the samples after the first and second instrumentations. The
      differences between the samples that followed the two instrumentation regimens
      were not significant (p = 0.0617). It is concluded that simple root canal systems
      (without multiple canal communications) may be rendered bacteria-free when
      preparation of this type is utilized.

PMID- 12470025
TI  - The cellular compatibility of five endodontic sealers during the setting period.
AB  - The purpose of this study was to evaluate the cellular compatibility of five
      endodontic sealers in the first 24 h after mixing. Specimens of N2,
      Endomethasone, Apexit, AH Plus, and Ketac Endo were extracted with cell culture
      medium 0, 1, 5, and 24 h after mixing. Eluates were tested for cytotoxicity with
      immortal 3T3 cells and primary human periodontal ligament fibroblasts using XTT
      assays. Data were analyzed for statistically significant differences by means of
      Dunnett's t tests (p < 0.05). All extracts of N2 completely inhibited cell
      metabolism (p < 0.05). Similar effects were provoked by the first three eluates
      of Endomethasone, but the 24-h extract irritated cells significantly less (p <
      0.05). Severe cytotoxicity was also observed with all Ketac Endo extracts (p <
      0.05). A significant inhibition of mitochondrial activity was induced by the
      first (3T3) or the first and second eluate (periodontal ligament fibroblasts) of
      AH Plus (p < 0.05). The subsequent eluates of this sealer and all extracts of
      Apexit did not reveal any cytotoxic potency.

PMID- 12470026
TI  - Endodontic treatment in cases of allergic reaction to rubber dam.
AB  - The prevalence and severity of latex allergies have rapidly increased recently.
      This article presents two cases of patients with rubber latex allergy. The
      patient in case A was unaware of her sensitivity to latex and presented symptoms
      of contact dermatitis-stomatitis during endodontic treatment. The patient in case
      B reported latex allergy before the initiation of the treatment and a different
      approach was followed. Certain aspects of latex allergy related to the endodontic
      treatment are discussed. Moreover, a protocol is proposed for treatment of
      patients with latex hypersensitivity with safety.

PMID- 12470027
TI  - Global endodontics.

PMID- 12470028
TI  - Impact of cardiopulmonary bypass management on postcardiac surgery renal
      function.
AB  - OBJECTIVE: Cardiac surgery on cardiopulmonary bypass (CPB) is associated with
      postoperative renal dysfunction and up to 4% of patients with normal preoperative
      renal function develop acute renal failure (ARF) requiring dialysis. According to
      recent investigations, CPB management is not evidence-based and, thus, current
      clinical CPB practice may favor renal dysfunction. The purpose of our study was
      to investigate if postcardiac surgery renal dysfunction is influenced by CPB
      management. METHODS: We selected three groups of patients with normal
      preoperative renal function who had been subjected to cardiac surgical procedures
      on CPB: 44 patients with postoperative ARF requiring hemofiltration/dialysis (ARF
      group), 51 patients with postoperative renal dysfunction not requiring
      hemofiltration/dialysis (serum creatinine increase > 0.5 mg/dl within 48 h
      postsurgery: CREA group), and 48 patients with normal postoperative renal
      function (Control group). The patients' on-line CPB records were analyzed for CPB
      duration, CPB perfusion pressure, CPB flow, and periods on CPB at a perfusion
      pressure <60 mmHg. On-CPB diuretic and vasoconstrictor medication was recorded.
      RESULTS: Patient demographics were similar for the three groups. In the ARF
      group, CPB duration was longer (166 +/- 77 [standard deviation, SD] min) compared
      to CREA (115 +/- 41 min; p < 0.001) and to Control groups (107 +/- 40 min; p <
      0.001), and mean CPB flow was lower (2.35 +/- 0.36 l/min/m2) compared to CREA
      (2.61 +/- 0.35 l/min/m2; p = 0.0015) and to Control groups (2.51 +/- 0.33
      l/min/m2; p = 0.09). Mean arterial pressure on CPB (ARF: 61 +/- 10; CREA: 60 +/-
      7; CONTROL: 63 +/- 9 mmHg; p = 0.19) as well as furosemide and norepinephrine
      medication on CPB were similar for the groups. Compared to Control (46 +/- 26
      min), CPB duration at arterial pressures <60 mmHg was longer in ARF (78 +/- 60
      min; p = 0.034) and in CREA (62 +/- 36 min;p = 0.048). CONCLUSIONS: Our data
      suggest that current clinical CPB management impacts postoperative renal
      function. We found that patients with normal preoperative renal function who
      developed postoperative ARF had longer CPB duration, lower CPB perfusion flow,
      and longer periods on CPB at pressures < 60 mmHg compared to patients with no
      post CPB ARF. However, our data do not allow us to separate these CPB-related
      factors from the potential influence of perioperative low cardiac output syndrome
      as a cause for postoperative ARF. Thus, future clinical studies are required to
      elucidate CPB-induced ARF and to optimize CPB management for ARF prevention.

PMID- 12470029
TI  - A combined approach for improving cardiopulmonary bypass in coronary artery
      surgery: a pilot study.
AB  - BACKGROUND: This is a pilot study carried out to assess the feasibility and the
      clinical impact of a combined approach of cardiopulmonary bypass (CPB) with
      reduced anti-coagulation. METHODS: We used a retrospective, non-randomized
      analysis of 45 consecutive patients undergoing coronary artery bypass using
      standard CPB with full anticoagulation (activated clotting time, ACT, > 450 s)
      (Group 1; n = 23) or closed, heparin-coated CPB with low anticoagulation (ACT>250
      s), precise heparin and protamine titration, controlled suction, and retrograde
      autologous prime (Group 2; n = 22). RESULTS: Patients were similar except for a
      higher incidence of three-vessel disease in Group 2 (77.3% versus 47.8%; p <
      0.03). Heparin was reduced by 41% in Group 2 and protamine by 56% (p < 0.0001).
      Total postoperative blood loss was similar between Groups 1 and 2 (429 +/- 149
      versus 435+/-168 ml, respectively). However, the operative hematocrit decrease
      was lower in Group 2 (-1.6 +/- 7.5% versus -6.9 +/- 4.8%; p = 0.007), although
      hemodilution was similar, as reflected by the blood protein level. The need for
      postoperative inotropic support was less frequent in Group 2 (36.4% versus 65.2%;
      p = 0.05). Within the subgroup of patients weaned from CPB without requiring
      inotropic support (n = 35), the cardiac index dropped significantly in Group 1 (p
      = 0.003) 6 h after the start of CPB, whereas it remained stable in Group 2 (p =
      0.92). Using multivariate analyses, Group 2 was found to be more protected than
      Group 1 against myocardial cellular injury (p = 0.046) and need for postoperative
      inotropic support (p = 0.014). CONCLUSION: The pejorative postoperative outcome
      in coronary artery surgery was attenuated through a combined approach aimed at
      improving CPB.

PMID- 12470030
TI  - Improved oxygenation with reduced recirculation during venovenous ECMO:
      comparison of two catheters.
AB  - OBJECTIVES: To determine whether the new double-lumen catheter made by OriGen
      Biomedical (Austin, TX) for venovenous (VV) extracorporeal membrane oxygenation
      (ECMO) would reduce recirculation and improve oxygenation during VV ECMO when
      compared with the Kendall double-lumen catheter (Kendall Healthcare Products,
      Mansfield, MA). DESIGN: Prospective intervention study. SETTING: The animal
      research laboratory at Children's National Medical Center, Washington, DC.
      SUBJECTS: Nine newborn lambs one to seven days old and weighing 4.4 +/- 0.8 kg.
      INTERVENTION: Animals were anesthetized, intubated, and ventilated. The ductus
      arteriosus was ligated. Femoral arterial and venous, cephalic jugular vein, and
      pulmonary artery catheters were placed. After systemic heparinization, the
      catheter to be tested, an OriGen catheter, was placed in the right internal
      jugular vein and advanced into the right atrium. The animal was placed on ECMO
      and stabilized, with the ventilator settings decreased to a peak inspiratory
      pressure of 15-20 cmH2O, peak end-expiratory pressure of 5 cmH2O, rate of 15-25
      breaths/min, and a fractional inspired oxygen concentration of 0.21-0.30. ECMO
      flows were increased in 100-ml increments from 200 to 600 ml/min with
      measurements taken 15 min after each change. The OriGen catheter was removed, the
      Kendall catheter was placed, and the studies were repeated. MEASUREMENTS AND MAIN
      RESULTS: Heart rate, mean blood pressure, PaO2, jugular cerebral oxygen
      saturation, pulmonary artery oxygen saturation, pump venous oxygen saturation,
      and postmembrane circuit pressures were measured at each study period. The OriGen
      catheter improved oxygenation, with higher systemic PaO2, higher pulmonary artery
      and cerebral oxygen saturations, and lower pump venous oxygen saturations
      (indicating less recirculation). With the OriGen catheter, PaO2 levels ranged
      from 69 +/- 18 mmHg [9.2 +/- 2.4 kPa] to 114 +/- 45 mmHg [15.2 +/- 6.0 kPa],
      compared range from 61 +/- 15 mmHg [8.1 +/- 2.0 kPa] to 87 +/- 34 mmHg [11.5+/
      4.5 kPa] for the Kendall catheter. These findings indicate that, at all flow
      rates studied, less recirculation occurred with the OriGen catheter than with the
      Kendall catheter. The postmembrane pressures were significantly lower for the
      OriGen catheter at any given flow (from 30 +/- 5 to 122 +/- 18 mmHg) when
      compared with the Kendall catheter (from 77+/- 16 to 330+/-78 mmHg). CONCLUSIONS:
      These findings indicate that the OriGen catheter resulted in a reduction of
      recirculation, thereby resulting in an improvement in oxygenation while on VV
      ECMO. The lower postmembrane pressure potentially could reduce the risk of ECMO
      circuit complications such as tubing rupture, bleeding complications, as well as
      hemolysis. This new catheter makes VV ECMO more effective and represents a design
      that could be used for neonatal and/or pediatric ECMO.

PMID- 12470031
TI  - The immediate haemodynamic response to the initiation of extracorporeal membrane
      oxygenation in a piglet model of infant hypoxic respiratory failure.
AB  - There is evidence that haemodynamic fluctuations on extracorporeal membrane
      oxygenation (ECMO) increase the risk of cerebral damage. We hypothesized that
      initiation of venovenous (VV) or venoarterial (VA) ECMO itself causes
      haemodynamic fluctuations and, thus, established an infant animal ECMO model in
      order to discuss this hypothesis. Five piglets were cannulated using the jugular
      and femoral veins (VV group) and five using the jugular vein and carotid artery
      (VA group). All animals were subjected to hypoxic ventilation (FiO2 8%) for 10
      min, leading to a PaO2 of < 40 mmHg, and subsequently rescued by ECMO. The heart
      rate (HR) and mean arterial blood pressure (MAP) were recorded at 5-min
      intervals; the arterial blood lactate was measured prior to and after 5 and 10
      min of hypoxia, as well as 30, 60 and 120 min after initiation of ECMO. The
      response to initiation of ECMO was similar in the VV and VA groups with regard to
      HR and lactate, but differed significantly in MAP. HR decreased significantly
      from 135 +/- 7 to 103 +/- 6 beats/min (p < 0.05) and from 132 +/- 8 to 84 +/- 9
      beats/min (p < 0.01) at 5 min (p = NS) after installation; lactate increased from
      1.4 +/- 0.1 to 1.8 +/- 0.2 mmol/l (p = NS) and from 1.4 +/- 0.2 to 1.6 +/- 0.5
      mmol/l (p = NS) after 30 min (p = NS); MAP decreased from 80 +/- 5 to 63 +/- 3
      mmHg (p = NS) and increased from 75 +/- 4 to 84 +/- 3 mmHg (p = NS) at 5 min (p =
      0.001), respectively. The initiation of ECMO is associated with haemodynamic
      fluctuations in both modalities, which differ with regard to blood pressure
      reaction.

PMID- 12470032
TI  - Technique to prevent limb ischemia during peripheral cannulation for
      extracorporeal membrane oxygenation.
AB  - Prolonged extracorporeal support using femoral cannulation may cause limb
      ischemia. A technique is described using antegrade, retrograde arterial perfusion
      and venous drainage to prevent limb ischemia.

PMID- 12470033
TI  - Improved methods for measurement of gaseous microbubbles during extracorporeal
      circulation.
AB  - The detection and quantification of gaseous microbubbles in the arterial line of
      the extracorporeal circuit (ECC) are very important aims for quality assurance of
      perfusion. A system that allows a continuous measurement of microbubble
      distribution in the range of 10 and 120 microm was tested. The two-channel
      ultrasonic bubble counter (UBC) was based on a 2-MHz ultrasound Doppler system
      with propriety ultrasound probes. The bubble size was determined using the
      backscattered Doppler signal and was corrected by means of a reference signal
      based on measurement conditions. Our studies have shown that the quality of this
      signal can be negatively affected in the clinical environment. Different
      influences are involved, such as electrocoagulation or electromagnetic
      disturbances. Various algorithms were tested and new ones were developed in order
      to minimize the effect of such interferences on the accuracy of the bubble
      detection. The on-line data were recorded during the entire surgical time to
      allow an off-line evaluation with different algorithms. This allowed us to obtain
      more exact results. Two clinical studies with 91 patients were performed with
      microbubbles measured in the arterial line during coronary artery bypass grafting
      (CABG) and valve replacement. The results confirmed the expected occurrence of
      microbubbles during various phases of surgery. The measurement itself proved to
      be resistant to different external disturbances.

PMID- 12470034
TI  - Differential regulation of MMP-2, TIMP-2 and IL-6 in valve replacement versus
      CABG patients.
AB  - BACKGROUND: Extracellular matrix degradation may play an important role in left
      ventricular (LV) remodeling. It has been reported that matrix metalloproteinase-2
      (MMP-2) is activated under mechanical stress conditions. Therefore, we examined
      the release of MMP-2, its inhibitor and interleukin-6 (IL-6), which affects MMPs,
      in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB).
      METHODS: Arterial blood samples were obtained from 20 patients undergoing cardiac
      surgery and six patients with descending aortic replacement (as noncardiac
      control) with CPB. Samples were assayed for plasma MMP-2, tissue inhibitors of
      matrix metalloproteinase-2 (TIMP-2) and IL-6 concentration. RESULTS: Plasma MMP-2
      concentrations in the valvular disease patients were greater than in other
      patients (p < 0.05) and correlated with the LV mass (r=0.810, p < 0.0001) prior
      to the operation. Plasma MMP-2 concentrations decreased during CPB and gradually
      recovered to the baseline levels after CPB. Plasma TIMP-2 concentrations
      increased significantly during and after CPB in a biphasic manner. Plasma IL-6
      concentrations also increased significantly during CPB (p < 0.05 versus baseline
      levels). CONCLUSION: Plasma MMP-2 concentrations reflect the state of the left
      ventricle, and changes in plasma MMP-2 and TIMP-2 concentrations during CPB may
      play an important role in LV remodeling after cardiac surgery.

PMID- 12470035
TI  - Intraoperative modality of treatment for peritoneal carcinomatosis: use of
      hyperthermic interperitoneal chemoperfusion.
AB  - The use of hyperthermia as an adjunct to chemotherapy in the treatment of
      peritoneal carcinomatosis is a promising technique for patients who otherwise
      have a poor prognosis for survival. We, herein, report an overview and
      description of our technique for the safe conduct of this treatment. Included in
      these data are a total of 71 patients who underwent an intraoperative treatment
      with Mitomycin C at temperatures of 41-42 degrees C for a 90- to 120-min time
      period. The treatment protocol, perfusion system description, technical
      considerations, and potential complications are also included. The prognosis for
      intraabdominal carcinomatosis is poor with conventional treatments and
      modalities. We believe that the use of this technique offers a very positive
      clinical alternative for patients undergoing treatment for laparoscopic
      palliation of malignant ascites and/or surgical debulking for intraoperative
      treatment and prevention of metastasis.

PMID- 12470036
TI  - Parallel replacement of the oxygenator that is not transferring oxygen: the
      PRONTO procedure.
AB  - We present here a technique to replace a failed oxygenator by inserting a second
      oxygenator in parallel (PRONTO) within the cardiopulmonary bypass (CPB) circuit.
      Oxygenator failure is a potential hazard that may result in patient injury or
      death. Although failures are rare, safety surveys conducted over the last 25
      years suggest that the incidence of oxygenator failures is on the rise. This
      emergency procedure may be easily applied to any standard CPB circuit with a few
      minor alterations. The technique is simple; it can be carried out rapidly. An
      important advantage of this technique is that it may be executed without
      interrupting blood flow to the patient, which may reduce the incidence of patient
      injury or death.

PMID- 12470037
TI  - Is there any impact of the shape of aortic end-hole cannula on stroke occurrence?
      clinical evaluation of straight and bent-tip aortic cannulae.
AB  - OBJECTIVE: To compare the impact of straight and bent-tip aortic cannulae on
      stroke occurrence, location, and severity. METHODS: Prospective data were
      collected on 8,129 patients (coronary artery bypass grafting (CABG) and/or
      valvular surgery). 'Bent-tip' aortic cannulae were used in 15.6% of cases and
      'straight' end-hole cannulae in 84.4% of cases. RESULTS: There were a total of
      137 strokes: right anterior 52, left anterior 39, bilateral 23, posterior 18, and
      location not established 5. With the use of bent-tip cannulae, the incidence of
      strokes was 0.9% versus 1.8% with straight cannulae (chi2, p = 0.026). Bilateral
      and posterior strokes occurred more often with the use of straight cannulae
      (chi2, p = 0.015). Straight cannulae also related to the severity of strokes
      (chi2, p = 0.003). CONCLUSIONS: There is an influence of the type of cannula on
      the occurrence, location, and severity of strokes. Straight cannulae cause
      significantly more often and more severe bilateral and posterior strokes than
      bent-tip cannulae.

PMID- 12470038
TI  - Extracorporeal membrane oxygenation for pneumonitis after a Glenn palliation.
AB  - A five-month old male with a single ventricle palliated with a bidirectional
      cavopulmonary anastomosis developed severe respiratory insufficiency from
      respiratory syncytial virus (RSV) pneumonitis. He was successfully rescued with
      extracorporeal membrane oxygenation (ECMO) therapy and recovered with minimal
      morbidity.

PMID- 12470039
TI  - Timing of closure of open fractures.
AB  - Traditionally, closure of open fractures after initial debridement has been
      delayed to minimize the risk of complications, particularly infection. This
      practice developed before the widespread use of systemic antibiotics, local
      antibiotic bead pouches, advanced debridement methods, and improved fracture
      stabilization techniques. Current evidence indicates that infections after
      treatment of open fractures frequently are not caused by initial contaminating
      organisms but often are acquired in the hospital. Recent studies comparing
      primary with delayed closure have not demonstrated an increased rate of
      complications. Considering the improvements in open fracture wound care, the
      increasing incidence of resistant nosocomial infections, and the cost
      implications of a dogmatic delayed-closure strategy, wound care protocols for
      open fractures should be reevaluated. Because of lack of data specifically
      addressing the timing of closure of such wounds, studies comparing primary versus
      delayed closure are needed.

PMID- 12470040
TI  - Thigh pain after cementless total hip arthroplasty: evaluation and management.
AB  - Data from short- and long-term follow-up studies indicate that thigh pain is a
      significant complication after apparently successful cementless total hip
      arthroplasty. In most cases, reported symptoms are mild to moderate, resolve
      spontaneously or do not progress, and require little or no therapeutic
      intervention. However, persistent thigh pain may be a source of dissatisfaction
      or may present as severe, disabling pain. Possible causes include bone-prosthesis
      micromotion, excessive stress transfer to the femur, periosteal irritation, or a
      mismatch in Young's modulus of elasticity that increases the structural rigidity
      of the prosthetic stem relative to the femur. Thorough diagnostic evaluation of
      thigh pain is essential to rule out prosthetic infection or loosening, stress
      fracture, or spinal pathology as the primary source. Treatment options in the
      aseptic, well-fixed femoral component include medical management, revision of the
      femoral component, or cortical strut grafting at the tip of the implant.

PMID- 12470041
TI  - Perioperative blood management practices in elective orthopaedic surgery.
AB  - Concern about the cost and safety of allogenic blood transfusion, including the
      risk of viral infection and immunosuppression, has led to refinements in and new
      approaches to blood conservation, including the development of transfusion
      practice standards and improvements in surgical practice. Preoperative autologous
      blood collection, the use of hemostatic agents, perioperative blood salvage, and
      the use of recombinant human erythropoietin (epoetin alfa) to stimulate
      erythropoiesis have contributed to decreased use of allogenic blood services.
      Development of appropriate blood management strategies to help reduce or
      eliminate exposure to allogenic blood requires a preoperative assessment of the
      likelihood of transfusion and of the risks as well as costs associated with
      conservation and replacement options. The informed selection of alternatives
      based on preoperative assessment of hematologic status, estimated blood loss, and
      sources for blood replacement may enhance blood management practices in major
      elective orthopaedic surgery.

PMID- 12470042
TI  - Vascular problems of the upper extremity: a primer for the orthopaedic surgeon.
AB  - A focused history and thorough physical examination, combined with a working
      knowledge of the normal vascular anatomy, can help identify most vascular
      abnormalities of the upper extremity. Technologic improvements now allow accurate
      diagnosis by noninvasive methods. Most abnormalities can be categorized into one
      of five major diagnostic groups: traumatic, compressive, occlusive, tumoral
      (malformation), and vasospastic. Behavioral modifications and pharmacologic
      agents may improve symptoms. Appropriately selected surgical candidates often
      experience pain relief and functional improvement.

PMID- 12470043
TI  - Heterotopic ossification after hip and knee arthroplasty: risk factors,
      prevention, and treatment.
AB  - Symptomatic heterotopic ossification (HO) after total hip arthroplasty (THA) and
      total knee arthroplasty (TKA) is relatively rare. Patients at high risk for
      developing HO after THA include men with bilateral hypertrophic osteoarthritis,
      patients with a history of HO in either hip, and patients with posttraumatic
      arthritis characterized by hypertrophic osteophytosis. Patients at moderate risk
      are those with ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis,
      Paget's disease, or unilateral hypertrophic osteoarthritis. Patients at high risk
      for developing HO after TKA include those with limited postoperative knee
      flexion, increased lumbar bone mineral density, hypertrophic arthrosis, excessive
      periosteal trauma and/or notching of the anterior femur, and those who require
      forced manipulation after TKA. Preoperative radiation is effective for preventing
      HO after THA, as are post-operative prophylactic drug regimens and single-dose
      radiation treatments. Recurrence of HO after surgical excision should be expected
      unless prophylaxis is administered. Prophylactic measures against HO after THA
      and TKA should be administered before the fifth postoperative day, optimally
      within 24 to 48 hours.

PMID- 12470044
TI  - Arthrogryposis and amyoplasia.
AB  - Arthrogryposis (multiple congenital joint contractures) is an uncommon problem.
      Because there are many causes, correct diagnosis is important to predict the
      natural history and determine appropriate treatment. Inconsistent terminology has
      caused confusion about both diagnosis and treatment. Amyoplasia, the most common
      type of arthrogryposis, is characterized by quadrimelic involvement and
      replacement of skeletal muscle by dense fibrous tissue and fat. Early physical
      therapy and splinting may improve contractures, but surgical intervention is
      often necessary. Aggressive soft-tissue releases in addition to casting may
      improve joint position. In more severe contractures, osseous surgery also may be
      needed. Deformity recurrence is common, particularly in skeletally immature
      patients.

PMID- 12470045
TI  - The methanol-methanolate CH(3)OH...OCH3(-) bridging ligand: tuning of exchange
      coupling by hydrogen bonds in dimethoxo-bridged dichromium(III) complexes.
AB  - Two bis(mu-methoxo)dichromium(III) complexes, [L(Se)(2)Cr(2)(mu
      OCH(3))(2)(CH(3)OH)(2)] 1 and [L(Se)(2)Cr(2)(mu-OCH(3))(2)(CH(3)OH)(CH(3)O)](-)
      2, where L(Se) represents the dianion of 2,2'-selenobis(4,6-di-tert-butylphenol),
      have been reported to demonstrate the effect of hydrogen bonding on the exchange
      coupling interactions between the chromium(III) centers. The corresponding sulfur
      analogue of the ligand, i.e., 2,2'-thiobis(4,6-di-tert-butylphenol), also yields
      the analogous [L(S)(2)Cr(2)(mu-OCH(3))(2)(CH(3)OH)(2)] 3 and [L(S)(2)Cr(2)(mu
      OCH(3))(2)(CH(3)O)(CH(3)OH)](-) 4, which exhibit similar exchange coupling
      parameters. An acid-base dependent equilibrium between 1 and 2 or 3 and 4 has
      been established by electronic spectral measurements.

PMID- 12470046
TI  - Synthesis of the (dialkylamino)borate, [Ph(2)B(CH(2)NMe(2))(2)](-), affords
      access to N-chelated rhodium(I) zwitterions.
AB  - This paper reports the synthesis of the first bis(amino)borate ligand,
      [Ph(2)B(CH(2)NMe(2))(2)](-), an anionic equivalent of tertiary diamines. Anionic
      [Ph(2)B(CH(2)NMe(2))(2)] is an excellent bidentate ligand auxiliary and is used
      to prepare a series of N-chelated, zwitterionic rhodium(I) complexes.

PMID- 12470047
TI  - Hydrothermal preparation of novel Cd(II) coordination polymers employing 5-(4
      pyridyl)tetrazolate as a bridging ligand.
AB  - The reaction of 4-cyanopyridine with NaN(3) in the presence of H(2)O and a Lewis
      acid (CdCl(2)) affords a novel 3D pillared-layered fluorescent and phosphorescent
      coordination polymer Cd(3)(OH)(2)Cl(2)(4-PTZ)(2) (4-PTZ = 5-(4
      pyridyl)tetrazolate) (1) while the direct reaction of CdCl(2) with H-PTZ gives
      the simpler species Cd(4-PTZ)(2)(H(2)O)(2). The solid-state structure and nature
      of 1 provide an indication of the type of materials that may be formed as
      intermediates in the Sharpless-Demko reaction for the generation of 5-substituted
      1H-tetrazoles.

PMID- 12470048
TI  - Synthesis and crystal structure of Sr(2)AlH(7): a new structural type of alkaline
      earth aluminum hydride.
AB  - The title hydride and its deuteride were successfully synthesized. The heavy atom
      structure and hydrogen positions were determined respectively by X-ray powder
      diffraction and time-of-flight neutron powder diffraction. They crystallize with
      a new monoclinic structure in space group I2 (No. 5); cell parameters: a =
      12.575(1) A, b = 9.799(1) A, c = 7.9911(8) A, beta = 100.270(4) degrees
      (hydride), a = 12.552(1) A, b = 9.7826(8) A, c = 7.9816(7) A, beta = 100.286(4)
      degrees (deuteride), Z = 8. Sr(2)AlH(7) is the first example that consists of
      isolated [AlH(6)] units and infinite one-dimensional twisted chains of edge
      sharing [HSr(4)] tetrahedra along the crystallographic c axis.

PMID- 12470049
TI  - Synthesis, characterization, and reactivity of cationic hydride
      [HPd(diphosphine)(2)](+)CF(3)SO(3)(-), the missing member of the family
      [HM(dppe)(2)](+)X(-) (M = Ni, Pd, Pt). DFT QM/MM structural predictions for the
      [HPd(dppe)(2)](+) moiety.
AB  - The synthesis, characterization, and properties of the cationic hydride
      [HPd(dppe)(2)](+)CF(3)SO3(-).1/8THF, the missing member of the family
      [HM(dppe)(2)](+)X(-) (M = Ni, Pd, Pt), are described. The Pd hydride is not
      stable in solution and may react as either a proton or a hydride donor. DFT QM/MM
      calculations of the [HPd(dppe)(2)](+) moiety have allowed us to predict its
      structure and reactivity.

PMID- 12470050
TI  - Pd(0) and Pt(0) metallocryptands encapsulating a spinning mercurous dimer.
AB  - The deep-red, air-stable complexes [Pt(2)Hg(2)(P(2)phen)(3)](PF(6))(2), 1, or
      [Pd(2)Hg(2)(P(2)phen)(3)](PF(6))(2), 2, (P(2)phen is 2,9-bis(diphenylphosphino)
      1,10-phenanthroline) are most conveniently prepared by the stoichiometric
      reaction of either Pt(dba)(2) or Pd(2)(dba)(3).CHCl(3) (dba is
      dibenzylideneacetone) with P(2)phen and a single drop of elemental mercury in
      refluxing dichloromethane under an atmosphere of nitrogen. The (31)P[(1)H] NMR
      spectrum (CD(3)CN) of 1 shows a single sharp resonance at 43.1 ppm for the
      phosphorus atoms of the P(2)phen ligand with both (195)Pt ((1)J(P-Pt) = 4350 Hz)
      and (199)Hg ((2)J(P-Hg) = 620 Hz) satellites indicating the Hg(2)(2+) unit is
      dynamic. Compound 2 has a similar resonance at 44.9 ppm with (199)Hg satellites
      ((2)J(P-Hg) = 638 Hz). The (199)Hg NMR (CD(2)Cl(2), vs Hg(OAc)(2)) spectrum of 2
      shows a heptet pattern at 833 ppm while for 1 a heptet superimposed on a doublet
      of heptets is observed at 770.8 ppm. The (195)Pt NMR spectrum of 1 displays a
      quartet at -3071 ppm with (199)Hg satellites and a (1)J(Pt-Hg) value of 1602 Hz.
      Characterization of 1 and of 2(BF(4)(2) by single-crystal X-ray diffraction
      studies confirms the metallocryptand structure consisting of three phosphine
      imine ligands forming a D(3) symmetric cage with a Hg(2)(2+) ion in its center
      coordinated to two phenanthroline rings with the Hg-Hg bond (1, 2.7362(6);
      2(BF(4)(2), 2.6881(4) A) oriented perpendicular to the vector between the
      trigonally coordinated Pt(0) or Pd(0) atoms on each end. The Pt-Hg separations in
      1 average 2.8143(6) A while in 2(BF(4)(2) the average Pd-Hg separation is
      2.7698(5) A. Excitation into the low energy excitation bands of 1 (475 nm) and 2
      (430 nm) produces weak emissions centered at 593 nm with shoulders at 530 and 654
      nm in 1 and centered at 524 nm with a shoulder at 545 nm in 2.

PMID- 12470051
TI  - NMR shielding calculations across the periodic table: diamagnetic uranium
      compounds. 2. Ligand and metal NMR.
AB  - In this and a previous article (J. Phys. Chem. A 2000, 104, 8244), the range of
      application for relativistic density functional theory (DFT) is extended to the
      calculation of nuclear magnetic resonance (NMR) shieldings and chemical shifts in
      diamagnetic actinide compounds. Two relativistic DFT methods are used, ZORA
      ("zeroth-order regular approximation") and the quasirelativistic (QR) method. In
      the given second paper, NMR shieldings and chemical shifts are calculated and
      discussed for a wide range of compounds. The molecules studied comprise uranyl
      complexes, [UO(2)L(n)](+/-)(q); UF(6); inorganic UF(6) derivatives, UF(6-n)Cl(n),
      n = 0-6; and organometallic UF(6) derivatives, UF(6-n)(OCH(3))(n), n = 0-5.
      Uranyl complexes include [UO(2)F(4)](2-), [UO(2)Cl(4)](2-), [UO(2)(OH)(4)](2-),
      [UO(2)(CO(3))(3)](4-), and [UO(2)(H(2)O)(5)](2+). For the ligand NMR, moderate
      (e.g., (19)F NMR chemical shifts in UF(6-n)Cl(n)) to excellent agreement [e.g.,
      (19)F chemical shift tensor in UF(6) or (1)H NMR in UF(6-n)(OCH(3))(n)] has been
      found between theory and experiment. The methods have been used to calculate the
      experimentally unknown (235)U NMR chemical shifts. A large chemical shift range
      of at least 21,000 ppm has been predicted for the (235)U nucleus. ZORA spin-orbit
      appears to be the most accurate method for predicting actinide metal chemical
      shifts. Trends in the (235)U NMR chemical shifts of UF(6-n)L(n) molecules are
      analyzed and explained in terms of the calculated electronic structure. It is
      argued that the energy separation and interaction between occupied and virtual
      orbitals with f-character are the determining factors.

PMID- 12470052
TI  - Bimetallic carbonyl thiolates as functional models for Fe-only hydrogenases.
AB  - The anion [Fe(2)(S(2)C(3)H(6))(CN)(CO)(4)(PMe(3))](-) (2(-)) is protonated by
      sulfuric or toluenesulfonic acid to give HFe(2)(S(2)C(3)H(6))(CN)(CO)(4)(PMe(3))
      (2H), the structure of which has the hydride bridging the Fe atoms with the
      PMe(3) and CN(-) trans to the same sulfur atom. (1)H, (13)C, and (31)P NMR
      spectroscopy revealed that HFe(2)(S(2)C(3)H(6))(CN)(CO)(4)(PMe(3)) is
      stereochemically rigid on the NMR time scale with four inequivalent carbonyl
      ligands. Treatment of 2(-) with (Me(3)O)BF(4) gave
      Fe(2)(S(2)C(3)H(6))(CNMe)(CO)(4)(PMe(3)) (2Me). The Et(4)NCN-induced reaction of
      Fe(2)(S(2)C(3)H(6))(CO)(6) with P(OMe)(3) gave
      [Fe(2)(S(2)C(3)H(6))(CN)(CO)(4)[P(OMe)(3)]](-) (4). Spectroscopic and
      electrochemical measurements indicate that 2H can be further protonated at
      nitrogen to give [HFe(2)(S(2)C(3)H(6))(CNH)(CO)(4)(PMe(3))](+) (2H(2)(+)).
      Electrochemical and analytical data show that reduction of 2H(2)(+) gives H(2)
      and 2(-). Parallel electrochemical studies on
      [HFe(2)(S(2)C(3)H(6))(CO)(4)(PMe(3))(2)](+) (3H(+)) in acidic solutions led also
      to catalytic proton reduction. The 3H(+)/3H couple is reversible, whereas the
      2H(2)(+)/2H(2) couple is not, because of the efficiency of the latter as a proton
      reduction catalyst. Proton reduction is proposed to involve protonation of
      reduced diiron hydrides. DFT calculations establish that the regiochemistry of
      protonation is subtly dependent on the coligands but is more favorable to occur
      at the Fe-Fe bond for [Fe(2)(S(2)C(3)H(6))(CN)(CO)(4)(PMe(3))](-) than for
      [Fe(2)(S(2)C(3)H(6))(CN)(CO)(4)(PH(3))](-) or
      [Fe(2)(S(2)C(3)H(6))(CN)(CO)(4)[P(OMe)(3)]](-). The Fe(2)H unit stabilizes the
      conformer with eclipsed CN and PMe(3) because of an attractive electrostatic
      interaction between these ligands.

PMID- 12470053
TI  - Distal metal effects in cobalt porphyrins related to CcO.
AB  - Cobalt(II) porphyrins were studied to determine the influence of distal site
      metalation and superstructure upon dioxygen reactivity in active site models of
      cytochrome c oxidase (CcO). Monometallic, Co(II)(P) complexes when ligated by an
      axial imidazole react with dioxygen to form reversible Co-superoxide adducts,
      which were characterized by EPR and resonance Raman (RR). Unexpectedly, certain
      Co porphyrins with Cu(I) metalated imidazole pickets do not form mu-peroxo
      Co(III)/Cu(II) products even though the calculated intermetallic distance
      suggests this is possible. Instead, cobalt-porphyrin-superoxide complexes are
      obtained with the distal copper remaining as Cu(I). Moreover, distal metals
      (Cu(I) or Zn(II)) greatly enhance the stability of the dioxygen adduct, such that
      Co superoxides of bimetallic complexes demonstrate minimal reversibility. The
      "trapping" of dioxygen by a second metal is attributed to structural and
      electrostatic changes within the distal pocket upon metalation. EPR evidence
      suggests that the terminal oxygen in these bimetallic Co-superoxide systems is H
      bonded to the NH of an imidazole picket amide linker, which may contribute to
      enthalpic stabilization of the dioxygen adduct. Stabilization of the dioxygen
      adduct in these bimetallic systems suggests one possible role for the distal
      copper in the Fe/Cu bimetallic active site of terminal oxidases, which form a
      heme-superoxide/copper(I) adduct upon oxygenation.

PMID- 12470054
TI  - Synthesis, structure, and second-order nonlinear optical properties of copper(II)
      and palladium(II) acentric complexes with N-salicylidene-N'-aroylhydrazine
      tridentate ligands.
AB  - Two new N-salicylidene-N'-aroylhydrazines ligands have been prepared: N-4
      diethylaminosalicylidene-N'-4-nitrobenzoyl-hydrazine (L(1)) and N-4
      diethylaminosalicylidene-N'-4-(4-nitrophenylethylidene)-benzoyl-hydrazine (L(2)).
      The ligands are properly functionalized with strong electron donor-acceptor
      groups and are of potential interest in second-order nonlinear optics (NLO).
      Dimeric copper(II) and palladium(II) complexes with L(1) and L(2) have been
      prepared, and, starting from these, mononuclear acentric adducts with pyridine as
      a further ligand have been prepared and characterized. The X-ray structures of
      three adducts are also reported. The NLO activity of the adducts has been
      determined by EFISH measurements giving mubeta values up to 1500 x 10(-48) esu
      for an incident wavelength of 1.907 microm.

PMID- 12470055
TI  - Room-temperature synthesis and crystal, magnetic, and electronic structure of the
      first silver copper oxide.
AB  - Ag(2)Cu(2)O(3) is the first known silver copper oxide. It was prepared by
      coprecipitation at room temperature and ambient pressure and shows an increased
      thermal stability compared with silver oxides. The crystal structure (tetragonal,
      a = 5.8862(2) A, c = 10.6892(4) A, Z = 4, I4(1)/amd) was refined from neutron and
      X-ray powder diffraction data, and it is related to that of the mineral
      paramelaconite (Cu(4)O(3)). In addition to a thorough characterization (chemical
      and TG analyses, XPS, crystal structure, and electrochemical, magnetic, and
      transport properties), we have carried out band structure calculations [extended
      Huckel tight binding (EHTB) and spin polarized density functional (DFT) band
      calculations] for the title silver copper oxide and for the related
      paramelaconite structure (Cu(II)-Cu(I) mixed-valence system) with special
      incidence into the magnetic behavior and coupling constants in these magnetically
      novel 3-D compounds. This new oxide represents an important precedent in solid
      state inorganic chemistry but also has potential interest concerning its
      magnetic, electrochemical, and catalytic properties.

PMID- 12470056
TI  - A density functional study of S(N)2 substitution at square-planar platinum(II)
      complexes.
AB  - The energetics and reaction path in a series of S(N)2 substitution reactions at
      square-planar Pt(II) complexes have been studied by the application of density
      functional theory (DFT). Calculated free energies show excellent correlation with
      their experimental counterparts, while the enthalpic and entropic contributions
      individually indicate the presence of weak intermolecular interactions not
      accounted for in the present model. The nature of the leaving ligand has been
      shown to be much more significant in determining the activation barrier than that
      of the entering ligand; it is inferred (and confirmed by analysis of individual
      bond energies) that the reaction is driven by the dissociation of the leaving
      ligand, with the entering ligand playing a more passive role. Analysis of the
      intrinsic reaction coordinate indicates, further, that the trans ligand plays an
      unexpectedly dynamic role in stabilizing the transition state due to competition
      between stabilization and the steric effects of the entering and leaving ligands.
      The cis ligands, by contrast, are shown to move only slightly through the course
      of the reaction.

PMID- 12470057
TI  - Fluorometric chemosensors. Interaction of toxic heavy metal ions Pb(II), Cd(II),
      and Hg(II) with novel mixed-donor phenanthroline-containing macrocycles:
      spectrofluorometric, conductometric, and crystallographic studies.
AB  - The macrocycles L(1)-L(3) incorporating N(2)S(3)-, N(2)S(2)O-, and N(2)S(2)-donor
      sets, respectively, and containing the 1,10-phenanthroline unit interact in
      acetonitrile solution with heavy metal ions such as Pb(II), Cd(II), and Hg(II) to
      give 1:1 ML, 1:2 ML(2), and 2:1 M(2)L complex species, which specifically
      modulate the photochemical properties of the ligands. The stoichiometry of the
      complex species formed during spectrofluorometric titrations and their formation
      constants in MeCN at 25 degrees C were determined from fluorescence vs M(II)/L
      molar ratio data. The complexes [Pb(L(1))][ClO(4)](2).(1)/(2)H(2)O (1),
      [Pb(L(2))][ClO(4)](2).MeNO(2) (1a), [Pb(L(3))(2)][ClO(4)](2).2MeCN (1b), and
      [Cd(L(3))][NO(3)](2) (2b) were also characterized by X-ray diffraction studies.
      The conformation adopted by L(1)-L(3) in these species reveals the aliphatic
      portion of the rings folded over the plane containing the heteroaromatic moiety
      with the ligands trying to encapsulate the metal center within their cavity. In
      1, 1a, and 2b the metal ion completes the coordination sphere by interacting with
      counteranion units and solvent molecules. On the contrary, the 1:2 complex 1b
      shows Pb(II) sandwiched between two symmetry-related molecules of L(3) reaching
      an overall [4N + 4S] eight-coordination.

PMID- 12470058
TI  - Variable coordination modes of NO2(-) in a series of Ag(I) complexes containing
      triorganophosphines, -arsines, and -stibines. Syntheses, spectroscopic
      characterization (IR, 1H and 31P NMR, electrospray ionization mass), and
      structures of [AgNO2(R(3)E)(x)] adducts (E = P, As, Sb, x = 1-3).
AB  - Adducts of triorganophosphine, triphenylarsine, and triphenylstibine with
      silver(I) nitrite have been synthesized and characterized both in solution ((1)H,
      (31)P NMR) and in the solid state (IR, single-crystal X-ray structure analysis).
      In addition aggregates of AgNO(2) and ER(3) (E = P, As, Sb) have been identified
      in solution by electrospray ionization mass spectrometry (ESI-MS). The topology
      of the structures in the solid state was found to depend on the nature of ER(3)
      and on the stoichiometric ratio AgNO(2):ER(3). The adducts AgNO(2):EPh(3) (1:1)
      (E = P or Sb) are one-dimensional polymers, the role of NO(2)(-) being to bridge
      successive metal atoms by coordination of the two oxygens to one silver atom and
      the nitrogen lone pair to a successive Ag. The adduct AgNO(2):P(o-tolyl)(3) (1:1)
      is mononuclear, due to steric hindrance of the phosphine, the nitrite being O,O'
      bidentate, a rare example of a quasi-linear P-Ag-X array. AgNO(2):P(p-F
      C(6)H(4))(3) (1:1) is a dimer, the nitrite being coordinated through both
      oxygens, the first unidentate, the second bridging bidentate. P(o-tolyl)(3) and
      Pcy(3) form 1:2 adducts, also mononuclear, the nitrite still an O,O'-chelate. In
      contrast, the adduct AgNO(2):AsPh(3) (1:2) is a centrosymmetric dimer,
      essentially an aggregate of a pair of [Ag(O(2)N)(AsPh(3))(2)] arrays with one
      nitrite oxygen being the bridging atom. The adducts AgNO(2):EPh(3) (1:3) (E = As,
      Sb) are mononuclear, the nitrite behaving as a consistently strong O,O'-chelate.
      The E = As adduct is a triclinic solvated form, whereas the unsolvated E = Sb
      species is monoclinic. ESI-MS spectra of acetonitrile solutions of these
      complexes show the existence of [Ag(ER(3))](+), [Ag(CH(3)CN)](+),
      [Ag(CH(3)CN)(2)](+), [AgCl(2)](-), [Ag(NO(2))(2)](-), [Ag(ER(3))(CH(3)CN)](+),
      and [Ag(ER(3))(2)](+) as well as higher aggregates [Ag(2)(NO(2))(ER(3))(2)](+),
      [Ag(2)(NO(2))(3)](-) and [Ag(2)Cl(2)(NO(2))](-), which are less prevalent.

PMID- 12470059
TI  - Molecular structures of two metal tetrakis(tetrahydroborates), Zr(BH4)(4) and
      U(BH4)(4): equilibrium conformations and barriers to internal rotation of the
      triply bridging BH4 groups.
AB  - The molecular structures of Zr[(mu-H)(3)BH](4) and U[(mu-H)(3)BH](4) have been
      investigated by density functional theory (DFT) calculations and gas electron
      diffraction (GED). The triply bridged bonding mode of the tetrahydroborate groups
      in the former is confirmed, but both DFT calculations and GED structure
      refinements indicate that the BH(4) groups are rotated some 12 degrees away from
      the orientation in which the three bridging B-H bonds are staggered with respect
      to the opposing ZrB(3) fragment. As a result the symmetry of the equilibrium
      conformation is reduced from T(d) to T. Bond distances and valence angles are as
      follows (DFT/GED): Zr-B = 232.2/232.4(5) pm; Zr-H(b) = 214.8/214.4(6) pm; B-H(b)
      = 125.3/127.8(8) pm; B-H(t) = 119.4/118.8(17) pm; angle ZrBH(b) = 66.2/65.6(3)
      degrees; the smallest dihedral angle of type tau(BZrBH(b)) = 48/45(2) degrees.
      DFT calculations on Hf(BH(4))(4) indicate that the structure of this molecule is
      very similar to that of the Zr analogue. Matrix-isolation IR spectroscopy and DFT
      calculations on U(BH(4))(4) show that while the polymeric solid-state structure
      is characterized by terminal triply bridging and metal-metal bridging bidentate
      BH(4) groups, all BH(4) groups are triply bridging in the gaseous monomer.
      Calculations with one of the two nonbonding 5f electrons on U occupying an a(1)
      and the other distributed equally among the three t(2) orbitals indicate that the
      equilibrium conformation has T(d) symmetry, i.e. that the three B-H(b) bonds of
      each tetrahydroborate group are exactly staggered with respect to the opposing
      UB(3) fragment with tau(BUBH(b)) = 60 degrees. Calculations including spin-orbit
      interactions indicate that Jahn-Teller distortions from T(d) symmetry are either
      absent or very small. The best agreement between observed and calculated GED
      intensity data was obtained for a model of T(d) symmetry, but models of T
      symmetry with dihedral angles tau(BUBH(b)) > 42 degrees cannot be ruled out. Bond
      distances and valence angles are as follows (DFT/GED): U-B = 248.8/251.2(4) pm; U
      H(b) = 227.7/231.5(6) pm; B-H(b) = 126.0/131.6(5) pm, B-H(t) = 119.5/117.8(11)
      pm; angle UBH(b) = 65.6/63.1(3) degrees. It is suggested that the different
      equilibrium conformations of the three molecules are determined primarily by
      repulsion between bridging H atoms in different tetrahydroborate groups.

PMID- 12470060
TI  - Does back-bonding involve bonding orbitals in boryl complexes? A theoretical DFT
      study.
AB  - Theoretical calculations at the DFT (B3LYP) level have been undertaken on tris-
      and bis(boryl) complexes. Two model d(6) complexes [Rh(PH(3))(3)(BX(2))(3) and
      Rh(PH(3))(4)(BX(2))(2)(+), X = OH and H] have been studied. In the model
      tris(boryl) complex (X = OH) we find a fac structure as a minimum, in accordance
      with the experimental data. The mer geometries are found to be higher in energy.
      Analysis of the energetic ordering in mer isomers shows that back-bonding in
      these complexes involves a bonding Rh-B orbital (and not a d-block orbital as
      usual). This surprising behavior is rationalized through a qualitative MO
      analysis and quantitative NBO analysis. Results on the bis(boryl) complex confirm
      the preceding analysis. Full optimization of unsubstituted (X = H) complexes
      leads to structures in which the BH(2) moieties are coupled. In the optimal
      geometry of the bis(boryl) complex, the B(2)H(4) ligand resembles the transition
      state of the C(2v)-->D(2d) interconversion of the isolated B(2)H(4) species. In
      the tris(boryl) complex, we find a B(3)H(6) ligand in which the B(3) atoms define
      an isosceles triangle with one hydrogen bridging the shorter B-B bond.

PMID- 12470061
TI  - Paramagnetic 1H NMR spectrum of nickel(II) pseudoazurin: investigation of the
      active site structure and the acid and alkaline transitions.
AB  - The paramagnetic (1)H NMR spectrum of Ni(II) pseudoazurin [(PA)Ni(II)] possesses
      a number of resonances exhibiting sizable Fermi-contact shifts. These have been
      assigned to protons associated with the four ligating amino acids, His40, Cys78,
      His81, and Met86. The shifts experienced by the C(gamma)H protons of the axial
      Met86 ligand are unprecedented compared to other Ni(II)- and Co(II)-substituted
      cupredoxins (the C(gamma)(1)H signal is found at 432.5 ppm at 25 degrees C). The
      large shift of protons of the axial Met86 ligand highlights a strong Ni(II)
      S(Met) interaction in (PA)Ni(II). The paramagnetic (1)H NMR spectrum of
      (PA)Ni(II) is altered by decreasing and increasing the pH value from 8.0. At
      acidic pH a number of the hyperfine-shifted resonances undergo limited changes in
      their chemical shift values. This effect is assigned to the surface His6 residue
      whose protonation results in a structural modification of the active site.
      Increasing the pH value from 8.0 has a more significant effect on the
      paramagnetic (1)H NMR spectrum of (PA)Ni(II), and the alkaline transition can now
      be assigned to two surface lysine residues close to the active site of the
      protein. The effect of altering pH on the (1)H NMR spectrum of Ni(II)
      pseudoazurin is smaller than that previously observed in the Cu(II) protein
      indicating more limited structural rearrangements at the non-native metal site.

PMID- 12470063
TI  - Synthesis and photochemistry of Ru(II) complexes containing phenanthroline-based
      ligands with fused pyrrole rings.
AB  - Hydrolysis of 1,10-phenanthrolinopyrrole ethyl ester leads to the acid derivative
      which is unstable at room-temperature releasing CO(2) and forming 1,10
      phenanthrolinopyrrole (php). The ligand reacts with ruthenium(II) to form a
      series of complexes of the general formula [Ru(php)(n)(bpy)(3-n)](2+), where bpy
      = 2,2'-bipyridine and n = 1-3. The photochemical properties reveal that the
      complexes have longer-lived excited states than the standard complex,
      [Ru(bpy)(3)](2+). Their emission lifetimes range from 9.04 micros (n = 1) to 35.5
      micros (n = 3) at 77 K compared to 7.57 micros for the standard. Similarly, at
      room-temperature, emission lifetimes range from 1.20 micros (n = 1) to 1.70
      micros (n = 3) relative to the standard (0.56 micros). The emission quantum
      yields also have higher values than the standard [Ru(bpy)(3)](2+) under similar
      conditions. The temperature-dependent studies for the complexes establish the
      distribution among the radiative, nonradiative, and (3)MLCT to (3)d-d decay
      channels and are in agreement with the energy gap law.

PMID- 12470062
TI  - Influence of electronic and structural effects on the oxidative behavior of
      nickel porphyrins.
AB  - With the aim of better understanding the electronic and structural factors which
      govern electron-transfer processes in porphyrins, the electrochemistry of 29
      nickel(II) porphyrins has been examined in dichloromethane containing either 0.1
      M tetra-n-butylammonium perchlorate (TBAP) or tetra-n-butylammonium
      hexafluorophosphate (TBAPF(6)) as supporting electrolyte. Half-wave potentials
      for the first oxidation and first reduction are only weakly dependent on the
      supporting electrolyte, but E(1/2) for the second oxidation varies considerably
      with the type of supporting electrolyte. E(1/2) values for the first reduction to
      give a porphyrin pi-anion radical are effected in large part by the electronic
      properties of the porphyrin macrocycle substituents, while half-wave potentials
      for the first oxidation to give a pi-cation radical are affected by the
      substituents as well as by nonplanar deformations of the porphyrin macrocycle.
      The potential difference between the first and second oxidations (Delta/Ox(2) -
      Ox(1)/) is highly variable among the 29 investigated compounds and ranges from 0
      mV (two overlapped oxidations) to 460 mV depending on the macrocycle substituents
      and the anion of the supporting electrolyte. The magnitude of Delta/Ox(2) -
      Ox(1)/ is generally smaller for compounds with very electron-withdrawing
      substituents and when TBAP is used as the supporting electrolyte. This behavior
      is best explained in terms of differences in the binding strengths of anions from
      the supporting electrolyte (ClO(4)(-) or PF(6)(-)) to the doubly oxidized
      species. A closer analysis suggests two factors which are important in modulating
      Delta/Ox(2) - Ox(1)/ and thus the binding affinity of the anion to the porphyrin
      dication. One is the type of pi-cation radical (a proxy for the charge
      distribution in the dication), and the other is the conformation of the porphyrin
      macrocycle (either planar or nonplanar). These findings imply that the redox
      behavior of porphyrins can be selectively tuned to display separate or overlapped
      oxidation processes.

PMID- 12470064
TI  - A density functional study of oxygen atom transfer reactions between biological
      oxygen atom donors and molybdenum(IV) bis(dithiolene) complexes.
AB  - Density functional calculations have been used to investigate oxygen atom
      transfer reactions from the biological oxygen atom donors trimethylamine N-oxide
      (Me(3)NO) and dimethyl sulfoxide (DMSO) to the molybdenum(IV) complexes
      [MoO(mnt)(2)](2-) and [Mo(OCH(3))(mnt)(2)](-) (mnt = maleonitrile-1,2
      dithiolate), which may serve as models for mononuclear molybdenum enzymes of the
      DMSO reductase family. The reaction between [MoO(mnt)(2)](2-) and trimethylamine
      N-oxide was found to have an activation energy of 72 kJ/mol and proceed via a
      transition state (TS) with distorted octahedral geometry, where the Me(3)NO is
      bound through the oxygen to the molybdenum atom and the N-O bond is considerably
      weakened. The computational modeling of the reactions between dimethyl sulfoxide
      (DMSO) and [MoO(mnt)(2)](2-) or [Mo(OCH(3))(mnt)(2)](-) indicated that the former
      is energetically unfavorable while the latter was found to be favorable. The
      addition of a methyl group to [MoO(mnt)(2)](2-) to form the corresponding des-oxo
      complex not only lowers the relative energy of the products but also lowers the
      activation energy. In addition, the reaction with [Mo(OCH(3))(mnt)(2)](-)
      proceeds via a TS with trigonal prismatic geometry instead of the distorted
      octahedral TS geometry modeled for the reaction between [MoO(mnt)(2)](2-) and
      Me(3)NO.

PMID- 12470065
TI  - Synthesis, crystal structures, and redox potentials of 2,3,12,13-tetrasubstituted
      5,10,15,20-tetraphenylporphyrin zinc(II) complexes.
AB  - Zinc(II) complexes of antipodal beta-tetrasubstituted meso-tetraphenylporphyrin
      with trifluoromethyl (Zn(TPP(CF(3))(4)) (1a)), bromine (Zn(TPPBr(4)) (2a)), and
      methyl groups (Zn(TPP(CH(3))(4)) (3a)) were synthesized in order to examine the
      steric and the electronic effects of trifluoromethyl groups on the macrocycle.
      The analysis of X-ray crystal structures of the five-coordinate complexes
      Zn(TPP(CF(3))(4))(EtOH)(3) (1b), Zn(TPPBr(4))(MeOH)(DMF) (2b), and
      Zn(TPP(CH(3))(4))(THF)(1.6)(CHCl(3))(0.4) (3b) revealed distorted macrocyclic
      cores where significant differences in the Zn-N distance between the beta
      substituted and the non-beta-substituted side were observed. The difference was
      significant in 1b due to the strong steric interactions among the peripheral
      substituents and the electronic effects of trifluoromethyl groups. The
      macrocycles of 1b-3b are saddle-distorted and slightly ruffled due to the five
      coordination of zinc(II) and the peripheral substitution. Distortion of the
      macrocycles of 2b and 3b were modest. On the other hand, distortion in 1b was
      severe due to the peripheral strain. Cyclic voltammetric measurements of the four
      coordinate complexes Zn(TPP) and 1a-3a were performed and their redox potentials
      were analyzed together with previously reported potentials of Zn(TPP(CN)(4)). The
      oxidation potential of 1a did not gain as much as expected from the electron
      withdrawing effect of the four trifluoromethyl groups. The HOMO-LUMO gap of 1a
      was very small (1.5 V) and cannot just be explained by macrocyclic distortion.
      The magnitude of this gap is very similar to that of Zn(TPP(CN)(4)). Compound 2a
      also exhibited a modest gap contraction. Compound 3a was easier to oxidize and
      harder to reduce than Zn(TPP), even though the HOMO-LUMO gap of 3a was similar to
      that of Zn(TPP).

PMID- 12470066
TI  - Interplay of light antenna and excitation "energy reservoir" effects in a
      bichromophoric system based on ruthenium-polypyridine and pyrene units linked by
      a long and flexible poly(ethylene glycol) chain.
AB  - Steady-state and time-resolved spectroscopic properties of bichromophoric species
      containing [Ru(bpy)(3)](2+) and pyrene (pyr) units linked together by flexible
      poly(ethylene glycol) chains of variable length, [Ru(bpy)(2)(bpy-pyr)](PF(6))(2)
      (1) and [Ru(bpy)(2)(bpy-O6-pyr)](PF(6))(2) (2), have been investigated in
      acetonitrile solvent. The complexes were designed with the aim of examining the
      intercomponent energy-transfer processes taking place after light absorption at
      the two chromophores and the influence of the distance separation between them;
      in the case of complex 2, the linking chain in the extended conformation is as
      long as 21 A. Direct excitation of the pyrene unit (lambda(exc) = 410 nm) results
      in singlet-to-singlet energy transfer (an antenna effect) to the Ru-based
      component, (1)pyr --> (1)MLCT, which we analyze in terms of the Forster mechanism
      taking place with unit efficiency. Analysis of the time-resolved pyrene
      fluorescence reveals that the actual center-to-center distance separation (d(cc))
      between the photoactive centers changes according to a Gaussian distribution,
      with an average d(cc) = 13.6 A (distribution width, a = 2.8 A) and 12 A (a = 10.2
      A), for 1 and 2, respectively; this is ascribed to folding of the poly(ethylene
      glycol) linking chain. In O(2)-free solvent at room temperature, after population
      of the (1)MLCT level (which takes place either because of direct excitation by
      using lambda(exc) > 355 nm or via the "antenna" effect) and subsequent
      intersystem crossing localized at the Ru center, (1)MLCT --> (3)MLCT, a triplet
      triplet thermal equilibration is established which involves the physically
      separated centers, (3)MLCT <--> (3)pyr, with K(eq) = 11 (the energy gap between
      the two levels is 480 cm(-1), as determined from luminescence data obtained at 77
      K). As a consequence of this equilibrium, the (3)MLCT luminescence lifetime
      becomes tau(Ru) approximately 9 micros both in 1 and 2, i.e., 1 order of
      magnitude longer than for the unsubstituted [Ru(bpy)(3)](2+) luminophore. In air
      equilibrated solvent, diffusional quenching by O(2) effectively depletes the
      (3)pyr level and only the forward (3)MLCT --> (3)pyr energy transfer step is
      observed with k(en) = 4 x 10(8) and 2 x 10(8) s(-1) for 1 and 2, respectively. As
      briefly discussed, reasons for the high rate constants observed for the various
      triplet-triplet steps may be traced back to the folding properties of the linking
      chains.

PMID- 12470067
TI  - Deprotonation-substitution reactions of cyclic methylphenylphosphazenes:
      synthesis and structures of nongeminal P-ethyl, P-phenyl cyclotriphosphazenes.
AB  - The deprotonation-substitution reactions of both the cis and trans isomers of
      nongeminally substituted [(Me)(Ph)P=N](3) were investigated. Treatment of the
      trans isomer, 1, with 3 equiv of n-BuLi followed by 3 equiv of MeI gave only
      nongeminal trans-[(Et)(Ph)P=N](3), 3, while the same reaction sequence on cis
      [(Me)(Ph)P=N](3), 2, gave a mixture of nongeminal di- and trisubstitution
      products, cis-Et(2)MePh(3)P(3)N(3), 4, and cis-Et(3)Ph(3)P(3)N(3), 5. These
      trimers were separated by column chromatography. No changes in the
      stereochemistry of the rings occurred during these reactions. Compound 4 was also
      prepared using 2 equiv of the reactants and was then converted to 5 by treatment
      with a single equivalent of BuLi and MeI. Thermal analysis of the new cyclic
      trimers indicates that ring-opening polymerization does not occur and that
      sublimation occurs at ca. 300 degrees C. The structures of 4 and 5, obtained by X
      ray diffraction, illustrate the basketlike shape of these molecules with an
      aromatic bowl formed by the phenyl rings on the top rim, while the structure of 3
      clearly shows the trans orientation of the substituents. Crystal data for trans
      Et(3)Ph(3)P(3)N(3), 3, at 20 degrees C are as follows: C(24)H(30)N(3)P(3)
      monoclinic, a = 14.273(2) A, b = 9.370(2) A, c = 19.600(3) A, beta = 107.16(1)
      degrees, P2(1/n), Z = 4. Crystal data for cis-Et(2)MePh(3)P(3)N(3), 4, at 20
      degrees C are as follows: C(23)H(28)N(3)P(3), triclinic, a = 10.276(2) A, b =
      10.699(2) A, c = 11.925(2) A, alpha = 72.07(2) degrees, beta = 73.79(1) degrees,
      gamma = 85.87(1) degrees, P1, Z = 2. Crystal data for cis-Et(3)Ph(3)P(3)N(3), 5,
      at 20 degrees C are as follows: C(24)H(30)N(3)P(3) monoclinic, a = 29.488(2) A, b
      = 9.8391(1) A, c = 21.172(2) A, beta = 126.30(1) degrees, C2/c, Z = 8.

PMID- 12470068
TI  - Synthesis and structures of one- and two-electron oxidized forms of
      bis(acetylene)tetrairon clusters Cp'(4)Fe(4)(HCCH)(2) (Cp' = Cp, eta5
      C(5)H(4)Me).
AB  - Air-oxidation of Cp'(4)Fe(4)(HCCH)(2) (Cp' = Cp (1a), C(5)H(4)Me (1b)) in an
      NH(4)PF(6)/CH(3)CN solution afforded the one-electron oxidized clusters
      [Cp'(4)Fe(4)(HCCH)(2)](PF(6)). Oxidation of 1a with excess AgBF(4) in THF
      afforded [1a](BF(4)), while that of 1b with excess AgBF(4) gave [1b](BF(4))(2).
      The X-ray crystal structure analysis of [1a](BF(4)) revealed that the
      monocationic cluster retains the butterfly-type Fe(4)(mu4
      eta(2):eta(2):eta(1):eta(1)-HCCH)(2) framework similar to that of the neutral
      cluster. The average Fe-Fe bond length is shorter by 0.029 A than that in the
      neutral cluster. Electrochemical oxidation of 1a and 1b in 0.1 M
      NH(4)PF(6)/CH(3)CN solution at +0.30 and +0.25 V versus Ag/10 mM AgNO(3),
      respectively, afforded the two-electron oxidized clusters [1a](PF(6))(2) and
      [1b](PF(6))(2). The X-ray crystal structure analysis for [1b](BF(4))(2) shows
      that the butterfly-type cluster core is retained but shrinks more of those of
      neutral and monocationic clusters. The four Fe-Fe bonds in [1b](BF(4))(2) are
      unequivalent: one Fe-Fe bond (2.397(1) A) is apparently shorter than the others
      (2.439(2)-2.461(2) A).

PMID- 12470069
TI  - Hexadentate hydroxypyridonate iron chelators based on TREN-Me-3,2-HOPO: variation
      of cap size.
AB  - TREN-Me-3,2-HOPO, TR322-Me-3,2-HOPO, TR332-Me-3,2-HOPO, and TRPN-Me-3,2-HOPO
      correspond to stepwise replacement of ethylene by propylene bridges. A series of
      tripodal, hexadentate hydroxypyridinone ligands are reported. These incorporate 1
      methyl-3,2-hydroxypyridinone (Me-3,2-HOPO) bidentate chelating units for metal
      binding. They are varied by systematic enlargement of the capping scaffold which
      connects the binding units. The series of ligands and their iron complexes are
      reported. Single crystal X-ray structures are reported for the ferric complexes
      of all four tripodal ligands: FeTREN-Me-3,2-HOPO.0.375C(4)H(10)O.0.5CH(2)Cl(2)
      [P2(1)/n (No. 14), Z = 8, a = 20.478(3) A, b = 12.353(2) A, c = 27.360(3) A; beta
      = 91.60(1) degrees ]; FeTR322-Me-3,2-HOPO.CHCl(3).0.5C(6)H(14).CH(3)OH.0.5H(2)O
      [P2(1)/n (No. 14), Z = 4, a = 12.520(3) A, b = 22.577(5) A, c = 16.525(3) A; beta
      = 111.37(3) degrees ]; FeTR332-Me-3,2-HOPO.3.5CH(3)OH [C2/c (No. 15), Z = 8, a =
      13.5294(3) A, b = 19.7831(4) A, c = 27.2439(4) A; beta = 101.15(3) degrees ];
      FeTRPN-Me-3,2-HOPO.C(3)H(7)NO.2C(4)H(10)O [P1 (No. 2), Z = 2, a = 11.4891(2) A, b
      = 12.3583(2) A, c = 15.0473(2) A; alpha = 86.857(1) degrees, beta = 88.414(1)
      degrees, gamma = 70.124(1) degrees ]. The structures show the importance of
      intermolecular hydrogen bonds and the effect of cap enlargement to the stability
      and geometry of the metal complexes throughout the series. All protonation and
      iron complex formation constants have been determined from solution thermodynamic
      studies. The TREN-capped derivative is the most acidic, with a cumulative
      protonation constant, log beta(014), of 25.95. Corresponding values of 26.35,
      26.93, and 27.53 were obtained for the TR322, TR332, and TRPN derivatives,
      respectively. The protonation constants and NMR spectroscopic data are
      interpreted as being due to the influence of specific hydrogen-bond interactions.
      The incremental enlargement of ligand size results in a decrease in iron-chelate
      stability, as reflected in the log beta(110) values of 26.8, 26.2, 26.42, and
      24.48 for the TREN, TR322, TR332, and TRPN derivatives, respectively. The metal
      complex formation constants are also affected by the acidity of a proximal (non
      metal-binding) amine in the complexes, a trend consistent with the effects of
      internal hydrogen bonding. The ferric complexes display reversible reduction
      potentials (measured relative to the normal hydrogen electrode (NHE)) between 
      0.170 and -0.223 V.

PMID- 12470070
TI  - Heterobimetallic coordination polymers incorporating [M(CN)(2)](-) (M = Cu, Ag)
      and [Ag(2)(CN)(3)](-) units: increasing structural dimensionality via M-M' and
      M...NC interactions.
AB  - A series of new heterometallic coordination polymers has been prepared from the
      reaction of metal-ligand cations and KAg(CN)(2) units. Many of these contain
      silver-silver (argentophilic) interactions, analogous to gold-gold interactions,
      which serve to increase supramolecular structural dimensionality. Compared to
      [Au(CN)(2)](-) analogues, these polymers display new trends specific to
      [Ag(CN)(2)](-), including the formation of [Ag(2)(CN)(3)](-) and the presence of
      Ag...N interactions. [Cu(en)(2)][Ag(2)(CN)(3)][Ag(CN)(2)] (1, en =
      ethylenediamine) forms 1-D chains of alternating [Ag(CN)(2)](-) and
      [Ag(2)(CN)(3)](-) units via argentophilic interactions of 3.102(1) A. These
      chains are connected into a 2-D array by strong cyano(N)-Ag interactions of
      2.572(3) A. [Cu(dien)Ag(CN)(2)](2)[Ag(2)(CN)(3)][Ag(CN)(2)] (2, dien =
      diethylenetriamine) forms a 1-D chain of alternating [Cu(dien)](2+) and
      [Ag(CN)(2)](-) ions with the Cu(II) atoms connected in an apical/equatorial
      fashion. These chains are cross-linked by [Ag(2)(CN)(3)](-) units via
      argentophilic interactions of 3.1718(8) A and held weakly in a 3-D array by
      argentophilic interactions of 3.2889(5) A between the [Ag(CN)(2)](-) in the 2-D
      array and the remaining free [Ag(CN)(2)](-). [Ni(en)][Ni(CN)(4)].2.5H(2)O (4) was
      identified as a byproduct in the reaction to prepare the previously reported
      [Ni(en)(2)Ag(2)(CN)(3)][Ag(CN)(2)] (3). In [Ni(tren)Ag(CN)(2)][Ag(CN)(2)] (5,
      tren = tris(2-aminoethyl)amine), [Ni(tren)](2+) cations are linked in a cis
      fashion by [Ag(CN)(2)](-) anions to form a 1-D chain similar to the [Au(CN)(2)](
      ) analogue. [Cu(en)Cu(CN)(2)Ag(CN)(2)] (6) is a trimetallic polymer consisting of
      interpenetrating (6,3) nets stabilized by d(10)-d(10) interactions between Cu(I)
      Ag(I) (3.1000(4) A). Weak antiferromagnetic coupling has been observed in 2, and
      a slightly stronger exchange has been observed in 6. The Ni(II) complexes, 4 and
      5, display weak antiferromagnetic interactions as indicated by their relatively
      larger D values compared to that of 3. Magnetic measurements on isostructural
      [Ni(tren)M(CN)(2)][M(CN)(2)] (M = Ag, Au) show that Ag(I) is a more efficient
      mediator of magnetic exchange as compared to Au(I). The formation of
      [Ni(CN)(4)](2)(-), [Ag(2)(CN)(3)](-), and [Cu(CN)(2)](-) are all attributed to
      secondary reactions of the dissociation products of the labile KAg(CN)(2).

PMID- 12470071
TI  - Oxidation of organic sulfides by vanadium haloperoxidase model complexes.
AB  - In addition to halide oxidation, the vanadium haloperoxidases are capable of
      oxidizing sulfides to sulfoxides. Four vanadium complexes with tripodal amine
      ligands, K[VO(O(2))(heida)] (1), VO(2)(bpg) (2), K[VO(2)(ada)] (3), and
      K(2)[VO(O(2))(nta)] (4), previously shown to perform bromide oxidation (Colpas,
      G. J.; Hamstra, B. J.; Kampf, J. W.; Pecoraro, V. L. J. Am. Chem. Soc. 1996, 118,
      3469-3477), have now been shown to oxidize aryl alkyl sulfides to the
      corresponding sulfoxides. The oxidation was observed by the disappearance of
      thioanisole's ultraviolet absorption at 290 nm, by the change in the aromatic
      region of the (1)H NMR spectrum of the sulfides, and by changes in the complexes'
      (51)V NMR spectra. The amount of methyl phenyl sulfide oxidized in 3 h was 1000
      equiv (per metal complex). The oxidation product is almost exclusively sulfoxide,
      with very little sulfone (less than 3% over a 3 h experiment) formed. This is
      consistent with an electrophilic oxidation mechanism, as had been proposed for
      oxidation of bromide by 1-4. The rate was found to be first order in substrate
      concentration, similar to the rate law observed for bromide oxidation. Unlike the
      bromide oxidation, the equivalent of acid required for peroxovanadium complex
      activation is not consumed. The complexes 1-4 are not reactive with styrene or
      cyclooctene. The relevance of these reactions to the mechanism of the vanadium
      haloperoxidases and, more generally, peroxovanadium oxygenation of sulfides will
      be discussed.

PMID- 12470072
TI  - Facile pyrazolylborate ligand degradation at lanthanide centers: X-ray crystal
      structures of pyrazolylborinate-bridged bimetallics.
AB  - Adventitious hydrolysis of a number of different complexes with the molecular
      formula Ln(Tp(Me2))(2)X [Tp(Me2) = (HB(dmpz)(3)), where X is a basic anionic
      ligand] in various solvents, yielded crystals of highly insoluble dimers of the
      general formula [Ln(Tp(Me2))(mu-BOp(Me2))](2) (1) [Ln = La, Ce, Sm; BOp(Me2) =
      (HBO(dmpz)(2))(2)(-); dmpzH = 3,5-dimethylpyrazole]. The results of several
      single-crystal X-ray determinations are reported. One metal nitrogen distance,
      that lying across from the two negatively charged bridging oxygen atoms, is 0.06
      A longer than the others, suggesting an unusual trans influence at a lanthanide
      center. The formation of 1 is proposed to involve the intermediacy of
      Ln(Tp(Me2))(2)OH formed by protonolysis with adventitious water.

PMID- 12470073
TI  - Dinuclear oxidative addition of N-H and S-H bonds at chromium. Reaction of
      (*)Cr(CO)(3)(C(5)Me(5)) with [o-(HA)C(6)H(4)S-Cr(CO)(3)(C(5)Me(5))] (A = S, NH)
      yielding [eta(2)-o-(mu-A)C(6)H(4)S-Cr(C(5)Me(5))](2) and H-Cr(CO)(3)(C(5)Me(5)).
AB  - Reaction of the 17-electron radical (*)Cr(CO)(3)Cp* (Cp* = C(5)Me(5)) with 0.5
      equiv of 2-aminophenyl disulfide [(o-H(2)NC(6)H(4))(2)S(2)] results in rapid
      oxidative addition to form the initial product (o-H(2)N)C(6)H(4)S-Cr(CO)(3)Cp*.
      Addition of a second equivalent of (*)Cr(CO)(3)Cp* to this solution results in
      the formation of H-Cr(CO)(3)Cp* as well as (1)/(2)[[eta(2)-o-(mu
      NH)C(6)H(4)S]CrCp*](2). Spectroscopic data show that (o-H(2)N)C(6)H(4)S
      Cr(CO)(3)Cp* loses CO to form [eta(2)-(o-H(2)N)C(6)H(4)S]Cr(CO)(2)Cp*. Attack on
      the N-H bond of the coordinated amine by (*)Cr(CO)(3)Cp* provides a reasonable
      mechanism consistent with the observation that both chelate formation and
      oxidative addition of the N-H bond are faster under argon than under CO
      atmosphere. The N-H bonds of uncoordinated aniline do not react with
      (*)Cr(CO)(3)Cp*. Reaction of the 2 mol of (*)Cr(CO)(3)Cp* with 1,2-benzene
      dithiol [1,2-C(6)H(4)(SH)(2)] yields the initial product (o-HS)C(6)H(4)S
      Cr(CO)(3)Cp and 1 mol of H-Cr(CO)(3)Cp*. Addition of 1 equiv more of
      (*)Cr(CO)(3)Cp to this solution also results in the formation of 1 equiv of H
      Cr(CO)(3)Cp*, as well as the dimeric product (1)/(2)[[eta(2)-o-(mu
      S)C(6)H(4)S]CrCp*](2). This reaction also occurs more rapidly under Ar than under
      CO, consistent with intramolecular coordination of the second thiol group prior
      to oxidative addition. The crystal structures of [[eta(2)-o-(mu
      NH)C(6)H(4)S]CrCp*](2) and [[eta(2)-o-(mu-S)C(6)H(4)S]CrCp*](2) are reported.

PMID- 12470074
TI  - Aqueous reactions of U(VI) at high chloride concentrations: syntheses and
      structures of new uranyl chloride polymers.
AB  - The reactions of UO(3) with acidic aqueous chloride solutions resulted in the
      formation of two new polymeric U(VI) compounds. Single crystals of
      Cs(2)[(UO(2))(3)Cl(2)(IO(3))(OH)O(2)].2H(2)O (1) were formed under hydrothermal
      conditions with HIO(3) and CsCl, and Li(H(2)O)(2)[(UO(2))(2)Cl(3)(O)(H(2)O)] (2)
      was obtained from acidic LiCl solutions under ambient temperature and pressure.
      Both compounds contain pentagonal bipyramidal coordination of the uranyl
      dication, UO(2)(2+). The structure of 1 consists of infinite
      [(UO(2))(3)Cl(2)(IO(3))(mu(3)-OH)(mu(3)-O)(2)](2-) ribbons that run down the b
      axis that are formed from edge-sharing pentagonal bipyramidal [UO(6)Cl] and
      [UO(5)Cl(2)] units. The Cs(+) cations separate the chains from one another and
      form long ionic contacts with terminal oxygen atoms from iodate ligands, uranyl
      oxygen atoms, water molecules, and chloride anions. In 2, edge-sharing
      [UO(3)Cl(4)] and [UO(5)Cl(2)] units build up tetranuclear [(UO(2))(4)(mu
      Cl)(6)(mu(3)-O)(2)(H(2)O)(2)](2-) anions that are bridged by chloride to form one
      dimensional chains. These chains are connected in a complex network of hydrogen
      bonds and interactions of uranyl oxygen atoms with Li(+) cations. Crystal data:
      1, orthorhombic, space group Pnma, a = 8.2762(4) A, b = 12.4809(6) A, c =
      17.1297(8) A, Z = 4; 2, triclinic, space group P1, a = 8.110(1) A, b = 8.621(1)
      A, c = 8.740(1) A, Z = 2.

PMID- 12470075
TI  - New oxamidato-bridged Cu(II)-Ni(II) complexes: supramolecular structures with
      thiocyanate ligands and hydrogen bonds. Magnetostructural studies: DFT
      calculations.
AB  - Four new supramolecular compounds of Cu(II)-Ni(II) have been synthesized and
      characterized: [Cu(Me(2)oxpn)Ni(mu-NCS)(H(2)O)(tmen)](2)(ClO(4))(2) (1),
      [Cu(Me(2)oxpn)Ni(mu-NCS)(H(2)O)(tmen)](2)(PF(6))(2) (2), [Cu(oxpn)Ni(mu-NCS)(NCS)
      (tmen)](n) (3), and [Cu(Me(2)oxpn)Ni(mu-NCS)(NCS)(tmen)](n) (4), where oxpn =
      N,N'-bis(3-aminopropyl)oxamidate, Me(2)oxpn = N,N'-bis(3-amino-2,2'
      dimethylpropyl)oxamidate, and tmen = N,N,N',N'-tetramethylethylenediamine. Their
      crystal structures were solved. Complexes 1 and 2 have the same tetranuclear
      cationic part but a different counteranion. The cationic part consists of two
      [Cu(Me(2)oxpn)Ni] moieties linked by SCN(-) bridged ligands and intra
      tetranuclear hydrogen bonds. In the case of complex 3, a two-dimensional system
      was built, the thiocyanate ligand linking the dinuclear units gives a chain, and
      the chains are linked together by hydrogen bonds; intrachain hydrogen bonds are
      also present. For complex 4, the thiocyanate ligands produce intermolecular
      linkages between the dinuclear entities, giving a one-dimensional system;
      intrachain hydrogen bonds are also present. The magnetic properties of the four
      complexes were studied by susceptibility measurements vs temperature. DFT
      calculations were made to study the contribution of the SCN(-) and hydrogen bond
      bridges in the magnetic coupling.

PMID- 12470076
TI  - Chemistry of a binuclear cadmium(II) hydroxide complex: formation from water,
      CO(2) reactivity, and comparison to a zinc analog.
AB  - Treatment of the bmnpa (N,N-bis-2-(methylthio)ethyl-N-((6-neopentylamino-2
      pyridyl)methyl)amine) ligand with equimolar amounts of Cd(ClO(4))(2).5H(2)O and
      Me(4)NOH.5H(2)O in CH(3)CN yielded the binuclear cadmium hydroxide complex
      [((bmnpa)Cd)(2)(mu-OH)(2)](ClO(4))(2).CH(3)CN (1). Complex 1 may also be prepared
      (a) by treatment of a CH(3)CN solution of (bmnpa)Cd(ClO(4))(2) (2) with 1 equiv
      of n-BuLi, followed by treatment with water or (b) from 2 in the presence of 1
      equiv each of water and NEt(3). The hydroxide derivative 1 is not produced from 2
      and water in the absence of an added base. Complex 1 possesses a binuclear
      structure in the solid state with hydrogen-bonding and CH/pi interactions
      involving the bmnpa ligand. The overall structural features of 1 differ from the
      halide derivative [((bmnpa)Cd)(2)(mu-Cl)(2)](ClO(4))(2) (3), particularly in that
      the Cd(2)(mu-OH)(2) core of 1 is symmetric whereas the Cd(2)(mu-Cl)(2) core of 3
      is asymmetric. In acetonitrile solution, 1 behaves as a 1:2 electrolyte and
      retains a binuclear structure and secondary hydrogen-bonding and CH/pi
      interactions, whereas 3 is a 1:1 electrolyte, indicating formation of a
      mononuclear [(bmnpa)CdCl]ClO(4) species in solution. Treatment of 1 with CO(2) in
      anhydrous CH(3)CN yields the bridging carbonate complex [((bmnpa)Cd)(2)(mu
      CO(3))](ClO(4))(2).CH(3)CN (4). Treatment of a chemically similar zinc hydroxide
      complex, [((benpa)Zn)(2)(mu-OH)(2)](ClO(4))(2) (benpa = N,N-bis-2
      (ethylthio)ethyl-N-((6-neopentylamino-2-pyridyl)methyl)amine, with CO(2) also
      results in the formation of a carbonate derivative, [((benpa)Zn)(2)(mu
      CO(3))](ClO(4))(2) (5), albeit the coordination mode of the bridging carbonate
      moiety is different. Treatment of 4 with added water results in no reaction,
      whereas 5 under identical conditions will undergo reaction to yield the zinc
      hydroxide complex [((benpa)Zn)(2)(mu-OH)(2)](ClO(4))(2).

PMID- 12470077
TI  - Synthesis and structural characterization of nonanuclear lanthanide complexes.
AB  - A series of nonanuclear lanthanide oxo-hydroxo complexes of the general formula
      [Ln(9)(mu(4)-O)(2)(mu(3)-OH)(8)(mu-BA)(8)(BA)(8)](
      )[HN(CH(2)CH(3))(3)](+).(CH(3)OH)(2)(CHCl(3)) (BA = benzoylacetone; Ln = Sm, 1;
      Eu, 2; Gd, 3; Dy, 4; Er, 5) were prepared by the reaction of hydrous lanthanide
      trichlorides with benzoylacetone in the presence of triethylamine in methanol and
      recrystallized from chloroform/methanol (1:10) at room temperature. These five
      compounds are isomorphous. Crystal data for 1: cubic, Pn3n; T = 180 K; a =
      33.8652(4) A; V = 38838.4(8) A(3); Z = 6; D(calcd) = 1.125 g cm(-)(3); R1 =
      3.37%. Crystal data for 2: cubic, Pn3n; T = 180 K; a = 33.8252(8) A; V =
      38700.9(16) A(3); Z = 6; D(calcd) = 1.133 g cm(-)(3); R1 = 4.97%. Crystal data
      for 3: cubic, Pn3n; T = 180 K; a = 33.7061(6) A; V = 38293.5(12) A(3); Z = 6;
      D(calcd) = 1.157 g cm(-)(3); R1 = 5.13%. Crystal data for 4: cubic, Pn3n; T = 180
      K; a = 33.5900(7) A; V = 37899.2(14) A(3); Z = 6; D(calcd) = 1.182 g cm(-)(3); R1
      = 4.03%. Crystal data for 5: cubic, Pn3n; T = 180 K; a = 33.5054(8) A; V =
      37613.6(16) A(3); Z = 6; D(calcd) = 1.202 g cm(-)(3); R1 = 4.86%. The core of the
      anionic cluster comprises two vertex-sharing square-pyramidal [Ln(5)(mu(4)
      O)(mu(3)-OH)(4)](9+) units. The compounds were characterized by elemental
      analysis, IR, fast atom bombardment mass spectra, thermogravimetry, and
      differential scanning calorimetry. The thermal analysis indicated that the
      nonanuclear species were stable up to 150 degrees C. Luminescence spectra of 2
      and magnetic properties of 1-5 were also studied.

PMID- 12470078
TI  - Synthesis and X-ray structures of dilithium complexes of the phosphonate anions
      [PhP(E)(N(t)Bu)(2)](2-) (E = O, S, Se, Te) and dimethylaluminum derivatives of
      [PhP(E)(N(t)Bu)(NH(t)Bu)](-) (E = S, Se).
AB  - The dilithium salts of the phosphonate dianions [PhP(E)(N(t)Bu)(2)](2-) (E = O,
      S, Se) are generated by the lithiation of [PhP(E)(NH(t)Bu)(2)] with n
      butyllithium. The formation of the corresponding telluride (E = Te) is achieved
      by oxidation of [Li(2)[PhP(N(t)Bu)(2)]] with tellurium. X-ray structural
      determinations revealed dimeric structures [Li(THF)(2)[PhP(E)(N(t)Bu)(2)]](2) in
      which the monomeric units are linked by Li-E bonds. In the case of E = Se or Te,
      but not for E = S, transannular Li-E interactions are also observed, resulting in
      a six-rung ladder. By contrast, for E = O, this synthetic approach yields the
      Li(2)O-templated tetramer [(THF)Li(2)[PhP(O)(N(t)Bu)(2)]](4).Li(2)O in THF or the
      tetramer [(Et(2)O)(0.5)Li(2)[PhP(O)(N(t)Bu)(2)]](4) in diethyl ether. The
      reaction of trimethylaluminum with PhP(E)(NH(t)Bu)(2) produces the complexes
      Me(2)Al[PhP(E)(N(t)Bu)(NH(t)Bu)] (E = S, Se), which were shown by X-ray
      crystallography to be N,E-chelated monomers.

PMID- 12470079
TI  - The rhodafluor family. An initial study of potential ratiometric fluorescent
      sensors for Zn2+.
AB  - A new class of ratiometric Zn(2+) sensors that employ a hybrid fluorescein and
      rhodamine fluorophore has been designed, and two members of the rhodafluor family
      of sensors, RF1 and RF2, have been synthesized. The preparation of RF1 (9-(o
      carboxyphenyl)-2-chloro-6-[bis(2-pyridylmethyl)amino]-3-xanthanone, Rhodafluor
      1), uses conventional synthetic methods. Elaboration of the RF1 synthesis in an
      effort to enhance the Zn(2+) affinity was unsuccessful, so palladium-catalyzed
      aryl amination was applied to prepare RF2 (1-[9'-(o-carboxyphenyl)-6'-amino-2'
      chloro-3'-xanthanone]-4,10-(diethyl)-7-(2-pyridylmethyl)-1,4,7,10
      tetraazacyclododecane, Rhodafluor-2). The key step in the synthesis of RF2 is
      coupling of a triprotected tetraazamacrocycle (cyclen) to 3-bromoanisidine. RF2
      binds Zn(2+) with a dissociation constant of 13.5 microM accompanied by an
      approximately 50% increase in quantum yield. Although only small shifts in
      absorption wavelength were observed, because protonation of the amino nitrogen
      atoms of the macrocycle prevents the uncomplexed sensor from adopting the desired
      mesomer, the intensity doubling makes the probe of value for immediate
      application in situations where our previous tight binding (<1 nM) sensors are
      inadequate.

PMID- 12470080
TI  - Cyclic tetramers composed of rhodium(III), iridium(III), or ruthenium(II) half
      sandwich and 6-purinethiones.
AB  - Six new cyclic tetranuclear complexes [[M(Cp*)(L)](4)](4+) and
      [[Ru(II)(L)(cymene)](4)](4+) [Cp* = eta(5)-C(5)Me(5), cymene = eta(6)-p
      MeC(6)H(4)Pr(i); M = Rh(III) and Ir(III); HL = 6-purinethione (H(2)put) and 2
      amino-6-purinethione (H(2)aput)] were prepared in a self-assembly manner and
      characterized by NMR spectroscopy, electrospray ionization mass spectrometry, and
      X-ray crystal structure analysis. The two crystal structures of
      [[Rh(Cp*)(H(0.5)put)](4)](CF(3)SO(3))(2) and [[Ir(Cp*)(Haput)](4)](CF(3)SO(3))(4)
      revealed that they have similar S(4) structures with an alternate chirality array
      of CACA, and all ligands adopt a mu-1kappaN(9):2kappa(2)S(6),N(7) coordination
      mode. The orientations of the four bridging ligands are alternately up and down,
      and they form a central square cavity. Interestingly, the cationic tetramers of
      the former are stacked up along the c axis, resulting in an infinite channel-like
      cavity. The driving force of this stacking is due to intermolecular double
      hydrogen bonds [N(1)-H...N(21) = 2.752(4) A] at both sides of the cavity. In the
      two Rh(III)- and Ru(II)-H(2)aput systems, it turned out that the dimeric species
      are dominantly formed in the reaction solutions but finally convert into the
      tetrameric species.

PMID- 12470081
TI  - Moderating influence of proteins on nonplanar tetrapyrrole deformations: coenzyme
      F430 in methyl-coenzyme-M reductase.
AB  - Normal-coordinate structural decomposition, cluster analysis, and molecular
      mechanics calculations were undertaken to examine the effect of methyl-coenzyme-M
      reductase (MCR) on the nonplanar deformations of coenzyme F430. Although free
      12,13-diepi-F430 has a lower energy conformation than free F430, the protein
      restraints exerted by MCR are responsible for F430 having a lower energy
      conformation than the 12,13-diepimer in MCR. According to the NSD analysis, the
      crystal structure of free diepimerized F430M is highly distorted. In MCR the
      protein prevents 12,13-diepi-F430 from undergoing nonplanar deformations;
      therefore, MCR favors F430 over the 12,13-diepimeric form. The strain imposed on
      12,13-diepi-F430 in the protein is so large that although 88% of free F430 is
      found in the diepimeric form, none of the diepimeric form is found in MCR. This
      is of significance since the two forms have different chemistries. MCR also
      moderates the nonplanar deformations of coenzyme F430, which are known to affect
      redox potentials and axial ligand affinities in tetrapyrroles, suggesting that
      the protein environment (MCR) is responsible for tuning the chemistry of the
      active site nickel ion. F430 is bound to MCR by hydrogen bonds between the
      protein and the F430 carboxylate groups. Conformational searches have shown that
      F430 has very little rotational and translational freedom within MCR.

PMID- 12470082
TI  - Synthetic, structural, electrochemical, and theoretical studies of heterometallic
      aggregates with a [Pt(2)(mu-S)(2)M] core (M = Hg, Au).
AB  - Novel electroactive multimetallic compounds based on the [Pt(2)(mu(2)-S)(2)M]
      core, viz. [Pt(2)(PPh(3))(4)(mu(3)-S)(2)HgFc]PF(6) (1) [Fc = (eta(5)
      C(5)H(4))Fe(eta(5)-C(5)H(5))] and [Pt(2)(PPh(3))(4)(mu(3)
      S)(2)Hg(2)Fc'](PF(6))(2) (2) [Fc' = Fe(eta(5)-C(5)H(4))(2)], have been
      synthesized under the guide of electrospray mass spectrometry. The
      electrochemistry of these ferrocene funtionalized compounds together with the
      reported [Pt(2)(PPh(3))(4)(mu(3)-S)(2)HgPPh(3)](PF(6))(2) (3),
      [Pt(2)(PPh(3))(4)(mu(2)-S)(mu(3)-S)HgPh]PF(6) (4), and [Pt(2)(PPh(3))(4)(mu(2)
      S)(mu(3)-S)AuPPh(3)]PF(6) (5) have been investigated using cyclic voltammetry and
      DFT calculations. These results point to a prominent ligand-based oxidation.

PMID- 12470083
TI  - Polymethylated DOTA ligands. 1. Synthesis of rigidified ligands and studies on
      the effects of alkyl substitution on acid-base properties and conformational
      mobility.
AB  - This work describes the synthesis and the conformational properties of new
      polymethylated macrocyclic ligands of potential interest for magnetic resonance
      imaging. M4cyclen, (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10
      tetraazacyclododecane, was obtained by cyclotetramerization of (2S)-1-benzyl-2
      methylaziridine followed by catalytic hydrogenation. The ligands M4DOTA,
      [(2S,5S,8S,11S)-4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl- 1,4,7,10
      tetraazacyclododecan-1-yl]acetic acid, and M4DOTMA, (R)-2-[(2S,5S,8S,11S)-4,7,10
      tris-((R)-1-carboxyethyl)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1
      yl]propionic acid, were prepared by carboxyalkylation of M4cyclen in the presence
      of Na(2)CO(3). The triacetic ligand M4DO3A, [(2S,5S,8S,11S)-4,7-bis-carboxymethyl
      2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid, was obtained
      in good yields without traces of M4DOTA if NaHCO(3) was the acid scavenger when
      adding the carboxylic arms. In the same conditions, cyclen yielded M4DOTA in 82%
      yield. The difference between the reactivity of cyclen and M4cyclen is assigned
      to the high basicity of the substituted tetraamine as estimated by NMR titration.
      The one- and two-dimensional (1)H and (13)C NMR spectra of M4DOTA and M4DOTMA in
      the H(4)L or H(6)L(2+) forms are interpreted as arising from a slow exchange
      between two elongated geometries in which the methyl substituents are in one of
      the two possible equatorial-like positions, either close to or away from the
      carboxylic arms. The axial-like positions are sterically too crowded and cannot
      be occupied by the methyl groups. An elongated conformation is also adopted by
      DOTMA, (R)-2-[4,7,10-tris-((R)-carboxyethyl)-1,4,7,10-tetraazacyclododecan-1
      yl]propionic acid, in the H(6)L(2+) form. The rigidification of the
      polymethylated ligands allows a detailed NMR analysis that cannot be carried out
      on the parent unsubstituted ligand DOTA.

PMID- 12470084
TI  - Polymethylated DOTA ligands. 2. Synthesis of rigidified lanthanide chelates and
      studies on the effect of alkyl substitution on conformational mobility and
      relaxivity.
AB  - M4DOTA, [(2S,5S,8S,11S)-4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl-1,4,7,10
      tetraazacyclododecan-1-yl]acetic acid (2e), and M4DOTMA, (R)-2-[(2S,5S,8S,11S)
      4,7,10-tris-((R)-1-carboxyethyl)-2,5,8,11-tetramethyl-1,4,7,10
      tetraazacyclododecan-1-yl]propionic acid (3e), are derivatives of ligand DOTA
      (1e) that form sterically crowded lanthanide chelates. M4DOTMA forms highly
      symmetric and totally rigid single Y(3+) and Yb(3+) species in which the ring
      substituents occupy corner positions in a square antiprismatic arrangement as
      shown by molecular mechanics calculations and by a quantitative interpretation of
      the relative magnitudes of the paramagnetic (1)H NMR shifts of dipolar origin.
      The NMR spectrum of YbM4DOTMA(-) displays two intense methyl peaks outside the 0
      10 ppm range whose shift difference is strongly temperature dependent. YbM4DOTMA(
      ) (3d) could be a useful probe in magnetic resonance thermometric imaging. With
      only four methyl substituents on the tetraaza ring, M4DOTA forms three Yb(3+)
      species in solution. The methyl substituents prevent the inversion of
      configuration of the ethylenic groups but not of the acetate arms. Although the
      methyl groups are likely to preferably occupy ring corner positions, the dipolar
      equations do not allow one to distinguish with certainty between the two
      available corner (equatorial) orientations. Reliably applying the dipolar
      equations is less obvious than usually assumed. A single methyl substituent as in
      ligand MDOTA (5e) suffices to rigidify the tetraaza cycle but not the acetate
      arms. Racemic YbMDOTA(-) (5d) is present in solution as four totally asymmetric
      topomers with the methyl groups occupying either one of the two equatorial
      positions. A complete assignment of the solution structures on the basis of the
      dipolar equations is again uncertain. The nuclear magnetic relaxation dispersion
      curves of the Gd(3+) chelates of all the methylated DOTA ligands including DOTMA,
      (R)-2-[4,7,10-tris-((R)-carboxyethyl)- 1,4,7,10- tetraazacyclododecan-1
      yl]propionic acid, are very similar, and intermolecular conformational processes
      appear to have no influence on the relaxivity of these small complexes for which
      the relaxation T(1) is mainly determined by the rotational correlation time
      (tau(r)). The hydration number of the Tb(3+) chelates measured by fluorescence
      decreases from DOTMA to M4DOTMA presumably because steric crowding leads to an
      increase of the metal-water distance.

PMID- 12470085
TI  - [N.1.1]-(2,6)-Pyridinophanes: a new ligand type imposing unusual metal
      coordination geometries.
AB  - A series of new ligands with three pyridines linked into a macrocycle by various
      CH(2), CMe(2), and CH(2)CH(2) groups at all sites ortho to the pyridine nitrogen
      have been synthesized and attached to PdCl(2) or PtMe(2). The ligands bind to
      them through only two nitrogens, and the third pyridine is constrained in close
      proximity to the planar complex with a filled d(z)2 orbital. Rapid reversible
      migration of PdCl(2) or PtMe(2) to the unused pyridine nitrogen is observed at 20
      degrees C in the case of the CH(2)-bridged macrocycle and does not occur in the
      case of the CMe(2)-bridged analogue, and the mechanism of this fluxionality has
      been established by NMR and computational techniques.

PMID- 12470086
TI  - Copper(I) halide complexes with 1,3-propanebis(diphenylphosphine) and
      heterocyclic thione ligands: crystal and electronic structures (DFT) of
      [CuCl(pymtH)(dppp)], [CuBr(pymtH)(dppp)], and [Cu(mu-I)(dppp)](2).
AB  - Reaction of copper(I) chloride or bromide with equimolar amounts of the diphos
      ligand 1,3-propanebis(diphenylphosphine) and a heterocyclic thione (L) in
      acetonitrile/methanol solvent afforded mononuclear complexes of the type
      [CuX(dppp)(L)] with the diphosphine ligand acting as a chelating ligand. In
      contrast, copper(I) iodide under the same conditions gave the dimeric complex
      [Cu(mu-I)(dppp)](2), which contains doubly bridging iodo ligands. The structures
      of three complexes, namely, [CuCl(pymtH)(dppp)], [CuCl(pymtH)(dppp)], and [Cu(mu
      I)(dppp)](2), have been established by single-crystal X-ray diffraction. Density
      functional calculations at the B3LYP level of theory provided a satisfactory
      description of the structural, bonding, electronic, and related properties of the
      [CuX(PH(3))(2)] and [CuX(1,3-pdp)] (1,3-pdp = 1,3-propane-di-phosphine) complexes
      and their dimers along with their associations with the pyrimidine-2-thione
      (pymtH) ligand. The interaction of the pymtH ligand with the Cu(I) metal center
      in these complexes corresponds to loose associations, the computed interaction
      energies predicted to be about 20 kcal/mol for all complexes in the series. The
      bonding mechanism of the thione ligand with the Cu(I) metal centers involves both
      a sigma-dative and pi-back-bonding components. The coordination of the pymtH
      ligand is further stabilized by X...H-N bond formation being more pronounced in
      the chloro than in the iodo derivatives. The Cu-X bond was also found to be a
      composite bond involving sigma- and pi-dative bonding components. Most important
      is the presence of pi-type MOs delocalized over the entire four-membered Cu(mu
      X)(2)Cu ring, which supports a ring current and could probably account for the
      nearly equivalent Cu-X bonds in the rhombus. Moreover, all [Cu(mu
      X)(PH(3))(2)](2) dimers exhibit a sigma-type MO corresponding to weak Cu.Cu
      interactions supporting through-ring intermetallic interactions, which seems to
      be responsible for the stabilization of the otherwise unstable antiaromatic Cu(mu
      X)(2)Cu ring.

PMID- 12470087
TI  - From one-dimensional chain to pentanuclear molecule. Magnetism of cyano-bridged
      Fe(III)-Ni(II) complexes.
AB  - Two cyano-bridged Ni(II)-Fe(III) complexes
      [(H(3)O)[Ni(H(2)L)](2)[Fe(CN)(6)](2).[Fe(CN)(6)].6H(2)O](n) (1) and [K(18-C
      6)(H(2)O)(2)][Ni(H(2)L)](2)[Fe(CN)(6)](3).4(18-C-6).20H(2)O (2) (L = 3,10-bis(2
      aminoethyl)-1,3,6,8,10,12-hexaazacyclotetradecane, 18-C-6 = 18-crown-6-ether)
      have been synthesized and characterized structurally and magnetically. Complex 1
      has a zigzag one-dimensional structure, in which two trans-CN(-) ligands of each
      [Fe(CN)(6)](3)(-) link two trans-[Ni(H(2)L)](4+) groups, and in turn, each trans
      [Ni(H(2)L)](4+) links two [Fe(CN)(6)](3)(-) in a trans fashion. Complex 2 is
      composed of cyano-bridged pentanuclear molecules with moieties connected by the
      trans-CN(-) ligands of [Fe(CN)(6)](3)(-). Magnetic studies show the existence of
      ferromagnetic Ni(II)-Fe(III) interactions in both complexes. The intermetallic
      magnetic coupling constant of both complexes was analyzed by using an approximate
      model on the basis of the structural features.

PMID- 12470088
TI  - Synthesis and properties of stereoregular cyclic polysilanols: cis
      [PhSi(O)OH](4), cis-[PhSi(O)OH](6), and tris-cis-tris-trans-[PhSi(O)OH](12).
AB  - New stereoregular cyclic polysilanols of the general formula [PhSi(O)OH]n (n = 6
      and 12) have been selectively obtained in high yields by the reaction of cagelike
      oligophenylmetallasiloxanes with dilute solutions of hydrochloric acid at low
      temperatures. An alternative method was used to prepare cis-[PhSi(O)OH](4) from
      sodium phenylsiloxanolate, cis-[(Na(+))(4)[PhSi(O)O(-)](4)].(1-butanol)(x). All
      compounds were fully characterized by NMR and IR spectroscopy and molecular
      weight determinations. The structure of cis-[PhSi(O)OH](6) was confirmed by
      single-crystal X-ray analysis. Furthermore, a series of stereoregular
      cyclosiloxanes containing triorganylsiloxy groups at each silicon atom was
      prepared by the reactions of the cyclic polysilanols with triorganylchlorosilanes
      Me(3)SiCl, Me(2)ViSiCl, and Me(2)(CH(2)Cl)SiCl.

PMID- 12470089
TI  - Thermal evolution of carbonate pillared layered hydroxides with (Ni, L) (L = Fe,
      Co) based slabs: grafting or nongrafting of carbonate anions?
AB  - The thermal evolution, from room temperature up to 300 degrees C, of layered
      double hydroxides (LDHs) with (Ni, Co) or (Ni, Fe) based slabs and containing
      intercalated carbonate anions, was studied. A new lamellar phase, exhibiting a
      6.5-6.6 A interslab distance, was observed in the 200-260 degrees C temperature
      range. The infrared study and the chemical analysis results allowed us to give
      prominence to a monografting of carbonate anions to the slabs. The
      thermogravimetric studies seem to indicate that intercalated water is first lost,
      followed by a monografting of carbonate anions. A stay in water of the 200
      degrees C thermally treated phase leads to a reintercalation of water molecules.
      The interslab distance indeed reincreases up to the value of the pristine
      material, reinforcing the hypothesis of the monografing.

PMID- 12470090
TI  - Adamantane-like aluminum amide-phosphate from alumazene.
AB  - A dealkylsilylation reaction between alumazene [2,6-(i-Pr)(2)C(6)H(3)NAlMe](3)
      (1) and tris(trimethylsilyl) ester of phosphoric acid (2) in a 1:3 molar ratio
      provides the heteroadamantane molecule (MeAl)[2,6-(i
      Pr)(2)C(6)H(3)N](3)[Al[OP(OSiMe(3))(3)]](2)(O(3)POSiMe(3)) (3). Compound 3 was
      characterized by analytical and spectroscopic methods, and its molecular
      structure was established by a single-crystal X-ray diffraction experiment.
      Moreover, trialkyl and triaryl phosphates and dialkyl phosphonates react with 1
      at elevated temperature to afford an intractable mixture of products. The
      reaction of phosphonic acids with 1 proceeds under decomposition to yield 2,6
      diisopropylaniline and aluminophosphonates.

PMID- 12470091
TI  - Inorganic heterocyclic bis(phosphines): syntheses and structures of a 1,2
      bis(diazasilaphosphetidino)ethane and its nickel, molybdenum, and rhodium
      complexes.
AB  - Synthesis and characterization of a new, highly electron-rich, chelating
      bis(phosphine), based on the ethanediyl-linked inorganic heterocycle [Me(2)Si(mu
      N(t)Bu)(2)P], are reported. Treatment of nickel chloride with this bis(phosphine)
      afforded square-planar cis-[[Me(2)Si(mu-N(t)Bu)(2)PCH(2)](2)NiCl(2)], which
      features isometric nickel-chloride (2.2220(8) A) and nickel-phosphorus (2.1572(8)
      A) bonds. The ligand reacted with cis-[(piperidine)(2)Mo(CO)(4)] to form
      colorless cis-[[Me(2)Si(mu-N(t)Bu)(2)PCH(2)](2)Mo(CO)(4)], which has distorted
      octahedral geometry and long Mo-P bonds (2.5461(18) A). Because of its potential
      applications in hydrogenation catalysis cis-[[Me(2)Si(mu
      N(t)()Bu)(2)PCH(2)](2)Rh(COD)]BF(4) was synthesized. This square-planar, cationic
      rhodium(I) complex, having symmetrical Rh-P (2.250(2) A) and Rh-C (2.305(6) A)
      bonds, is structurally related to bis(phospholano)- and bis(phosphetano)rhodium
      species.

PMID- 12470092
TI  - Theoretical study of the Fe(phen)(2)(NCS)(2) spin-crossover complex with
      reparametrized density functionals.
AB  - The theoretical study of spin-crossover compounds is very challenging as those
      parts of the experimental findings that concern the electronic structure of these
      compounds can currently hardly be reproduced because of either technical
      limitations of highly accurate ab initio methods or because of inaccuracies of
      density functional methods in the prediction of low-spin/high-spin energy
      splitting. However, calculations with reparametrized density functionals on
      molecules of the thermal spin-crossover type can give improved results when
      compared with experiment for close-lying states of different spin and are
      therefore important for, e.g., transition metal catalysis. A classification of
      transition metal compounds within hybrid density functional theory is given to
      distinguish standard, critical, and complicated cases. From the class of
      complicated cases we choose the prominent spin-crossover compound
      Fe(phen)(2)(NCS)(2) and show in a first step how the electronic contribution to
      the energy splitting can be calculated. In a second step, the vibrational effects
      on the spin flip are investigated within the harmonic force-field approximation
      of the isolated-molecule approach. A main result of the study is the necessity of
      exact-exchange reduction in hybrid density functionals to arrive at reasonable
      electronic energy splittings. The study resolves problems that originated from
      the use of standard density functionals, which are not able to reproduce the
      electronic contribution to the low-spin/high-spin splitting correctly, and
      demonstrates to which extent reparametrized density functionals can be used for
      the prediction of the spin-crossover effect.

PMID- 12470093
TI  - A comparison of percutaneous cryosurgery and percutaneous radiofrequency for
      unresectable hepatic malignancies.
AB  - HYPOTHESIS: The complication and success rates in patients treated with either
      percutaneous cryosurgery (PCS) or percutaneous radiofrequency (PRF) for
      unresectable hepatic malignancies are similar. DESIGN: Retrospective study.
      SETTING: University hospital. PATIENTS AND METHODS: Sixty-four patients were
      treated with either PCS (n = 31) or PRF (n = 33). Patient treatment was based on
      the random availability of the probes. Tumors were evaluated by a blinded
      comparison of pretreatment and posttreatment helical computed tomographic scans.
      All living patients had at least a 6-month follow-up. MAIN OUTCOME MEASURES:
      Complication rate, initial treatment success (complete devascularization of the
      tumor), and local recurrence (tumor revascularization within or at its
      periphery). RESULTS: The distribution of tumor types was similar in the 2 groups
      (P =.76). One patient with cirrhosis died of variceal hemorrhage on day 30 after
      PCS (mortality, 3.2%), while no mortality was observed after PRF (P =.48).
      Complications occurred in 9 (29%) of the patients following PCS and in 8 (24%) of
      the patients following PRF (P =.66). Initial treatment success was comparable in
      the 2 treatment groups (30 [83%] of 36 tumors following PCS vs 34 [83%] of 41
      tumors following PRF). However, local recurrences occurred more frequently after
      PCS than after PRF (16 [53%] of 30 vs 6 [18%] of 34; P =.003). The higher rate of
      local recurrence was identified for metastases (10 [71%] of 14 after PCS vs 3
      [19%] of 16 after PRF; P =.004), while the difference was not significant for
      hepatocellular carcinoma (6 [38%] of 16 after PCS vs 3 [17%] of 18 after PRF; P
      =.25). Multivariate analysis demonstrated that the use of PCS (P =.003) and more
      than 1 treatment (P =.05) were independent risk factors for local tumor
      recurrence. CONCLUSION: While similar initial treatment success and complication
      rates are observed following either PCS or PRF, local recurrences occur more
      frequently following PCS, particularly for metastases.

PMID- 12470095
TI  - Predictive factors of mortality due to polymicrobial peritonitis with Candida
      isolation in peritoneal fluid in critically ill patients.
AB  - BACKGROUND: Candida peritonitis (CP) is generally considered to be a severe
      disease, but its impact on outcome in critically ill patients remains unknown.
      HYPOTHESIS: The predictive factors of mortality due to CP can be determined by
      study of a population of patients with CP. DESIGN: A retrospective review of a
      prospective surgical intensive care unit (ICU) database of patients (January 1,
      1994, through December 31, 2000). SETTING: University hospital in Paris, France.
      PATIENTS: Eighty-three patients with generalized CP. MAIN OUTCOME MEASURES:
      Demographic and microbiologic data and outcome were collected, and nonsurvivors
      were compared with survivors. RESULTS: Overall ICU mortality due to CP was 43
      (52%) of 83 patients. In a stepwise multivariate logistic regression, the
      following 4 variables were independently associated with mortality: APACHE II
      (Acute Physiology and Chronic Health Evaluation II) score on admission of at
      least 17 (odds ratio [OR], 28.4; 95% confidence interval [CI], 5.7-142.5;
      P<.001), respiratory failure on admission (OR, 10.6; 95% CI, 2.2-51.2; P =.003),
      upper gastrointestinal tract site of peritonitis (OR, 7.7; 95% CI, 1.7-34.7; P
      =.007), and results of direct examination of peritoneal fluid that were positive
      for Candida (OR, 4.7; 95% CI, 1.2-19.7; P =.002). CONCLUSIONS: These results
      confirm the severity of CP in ICU patients and emphasize the prognostic value of
      direct examination of peritoneal fluid for Candida in this context.

PMID- 12470097
TI  - Hand-assisted laparoscopic splenectomy vs conventional laparoscopic splenectomy
      in cases of splenomegaly.
AB  - HYPOTHESIS: Laparoscopic splenectomy (LS) is the procedure of choice for elective
      splenectomy. Splenomegaly may preclude safe mobilization and hilar control using
      conventional laparoscopic techniques. Hand-assisted LS (HALS) may offer the same
      benefits of minimally invasive surgery for splenomegaly while allowing safe
      manipulation and splenic dissection. DESIGN: A retrospective review of patients
      with splenomegaly undergoing conventional LS or HALS was performed. SETTING:
      Tertiary care referral center. PATIENTS: Hand-assisted LS was performed at the
      start of the operation for patients with splenomegaly; splenomegaly was
      determined by palpation of the splenic tip extending to the midline or the iliac
      crest, or by a craniocaudal splenic length of greater than 22 cm. Splenomegaly
      was defined as a splenic weight of greater than 700 g after morcellation. MAIN
      OUTCOME MEASURES: Patient demographic characteristics, operative indications,
      splenic weight after morcellation, morbidity, mortality, and clinical outcomes
      were evaluated. RESULTS: Forty-five patients with splenomegaly were identified:
      31 underwent standard LS and 14 underwent HALS. The HALS group had significantly
      larger spleens than the conventional LS group (mean weight, 1516 vs 1031 g; P
      =.02). Mean operative time (177 vs 186 minutes; P =.89), estimated blood loss
      (602 vs 376 mL; P =.17), and length of hospital stay (5.4 vs 4.2 days; P =.24)
      and complication rates (5 [36%] of 14 vs 5 [16%] of 31; P =.70) were similar
      between the HALS and the standard LS groups. No perioperative mortality occurred.
      CONCLUSIONS: Hand-assisted LS is a safe and efficacious procedure for these
      extremely difficult cases. Hand-assisted LS provides the benefits of a minimally
      invasive approach in cases of splenomegaly.

PMID- 12470098
TI  - Epidemiology and prognostic determinants of bloodstream infections in surgical
      intensive care.
AB  - HYPOTHESIS: A set of clinical variables available at the bedside can be used to
      predict outcome in critically ill patients with bloodstream infection (BSI).
      DESIGN: A 3-year retrospective cohort study. SETTING: A surgical intensive care
      unit in Switzerland. PATIENTS: All patients with BSI were potentially eligible.
      MAIN OUTCOME MEASURES: Clinical variables, organ dysfunctions, and outcome.
      RESULTS: Among 4530 admissions to the surgical intensive care unit, 224
      clinically significant episodes of BSI were recorded (incidence, 4.9%), with a 28
      day fatality of 36%. A total of 110 patients had primary bacteremia, of which 39
      (35%) were catheter related. Although gram-positive organisms were the most
      frequently isolated pathogens (58% [159/275]), they were associated with lower
      case-fatality (30%) than BSI due to gram-negative bacteria (44%). Organ
      dysfunctions associated with the highest risk of death were neurologic
      dysfunction (hazard ratio [HR], 6.9; 95% confidence interval [CI], 3.3-14.5),
      hepatic dysfunction (HR, 3.9; 95% CI, 2.1-7.4), and disseminated intravascular
      coagulation (HR, 3.0; 95% CI, 1.5-6.1). By multivariate analysis, 2 independent
      predictors of mortality were the APACHE II (Acute Physiology and Chronic Health
      Evaluation II) score at onset of BSI (HR per 1-point increase, 1.08; 95% CI, 1.04
      1.12) and the number of evolving organ dysfunctions (HR, 1.4; 95% CI, 1.2-1.7).
      Appropriate antimicrobial therapy was associated with improved outcome (HR, 0.4;
      95% CI, 0.2-0.6). CONCLUSIONS: Bloodstream infection in critically ill patients
      is a common and frequently fatal condition. Its outcome can be predicted by the
      severity of illness at onset of BSI and the number of organ dysfunctions evolving
      thereafter. Appropriate antimicrobial therapy is an important determinant for
      survival.

PMID- 12470100
TI  - Telesurgical presence and consultation for open surgery.

PMID- 12470102
TI  - Repeat axillofemoral grafting as treatment for axillofemoral graft occlusion.
AB  - BACKGROUND: Patency of failed axillofemoral (ax-fem) grafts following
      thrombectomy is so poor, aortofemoral grafts are recommended as treatment for ax
      fem graft thrombosis. In patients who are not candidates for aortic grafting,
      repeat ax-fem grafting is an alternative to thrombectomy. This report compares
      our experience treating ax-fem graft thrombosis with replacement or revision vs
      thrombectomy. METHODS: Patients treated with ax-fem grafts from October 1985 to
      April 2001 were identified, and those who underwent reoperation for thrombosis
      were reviewed. Limb salvage and patency of revision procedures (thrombectomy vs
      repeat ax-fem grafting) were determined using Kaplan-Meier curves. RESULTS: Three
      hundred thirty-five patients underwent ax-fem grafting, and 39 (11.6%) of the 335
      required reoperation for graft failure. Twenty-five of these 39 patients had 51
      operations for graft thrombosis: 42 graft replacements and/or anastomotic
      revision(s), and 9 thrombectomies. At 18 months, mean +/- SD patency following
      thrombectomy was 11% +/- 10%, while that for graft replacement or anastomotic
      revision was 54% +/- 8% (P<.001). Limb salvage at 18 months following revision
      for thrombosis was 88% +/- 5%. CONCLUSIONS: The large majority of ax-fem grafts
      do not require reoperation. For failure due to thrombosis, repeat ax-fem grafting
      provides excellent limb salvage. Axillofemoral graft replacement and/or
      anastomotic revision has superior patency to thrombectomy.

PMID- 12470103
TI  - Occlusion of hepatic blood inflow for complex central liver resections in
      cirrhotic patients: a randomized comparison of hemihepatic and total hepatic
      occlusion techniques.
AB  - BACKGROUND: Intermittent occlusion of hepatic blood inflow by means of a
      hemihepatic or total hepatic occlusion technique is essential for reducing
      operative blood loss. Central liver resection to preserve more functioning liver
      parenchyma is mandatory for centrally located liver tumors in patients with
      cirrhosis, but it requires a longer overall hepatic ischemic time because of a
      wide transection plane. No controlled comparison has been performed for the 2
      techniques in these operations. HYPOTHESIS: Hemihepatic inflow occlusion may be
      beneficial in cirrhotic patients who undergo complex central hepatectomy with a
      wide liver transection plane. DESIGN: A prospective, randomized study. SETTING:
      University hospital and tertiary referral center. PATIENTS: During liver
      parenchymal transection, 58 cirrhotic patients who underwent complex central
      liver resections with a wide transection plane were prospectively randomized into
      2 groups. In the group undergoing total hepatic inflow clamping (group T; n =
      28), occlusion of hepatic blood inflow was performed for 15 minutes with
      declamping for 5 minutes. In the group undergoing selective clamping of
      ipsilateral blood inflow (group H; n = 30), clamping was performed for 30 minutes
      with declamping for 5 minutes. INTERVENTION: Comparison of patient backgrounds,
      operative procedures, and early postoperative results. MAIN OUTCOME MEASURES:
      Operative blood loss, need for blood transfusion, and postoperative morbidity.
      RESULTS: The patients' backgrounds, operative procedures, and area of liver
      transection plane were not significantly different between the 2 groups. In all
      patients, the liver transection areas were greater than 60 cm(2) and overall
      liver ischemic times were greater than 60 minutes. The amount of operative blood
      loss and incidence of blood transfusion were significantly greater in group T
      because of greater blood loss during declamping. Overall liver ischemic and total
      operative times, postoperative morbidity, and postoperative changes in liver
      enzyme levels were not significantly different between groups. No in-hospital
      deaths occurred in either group. CONCLUSIONS: Intermittent hemihepatic and total
      occlusion of hepatic blood inflow are safe in cirrhotic patients with an overall
      ischemic time of greater than 60 minutes. However, for complex liver resections
      with an estimated liver transection plane of greater than 60 cm(2), hemihepatic
      occlusion of blood inflow, if feasible, may be recommended in cirrhotic patients
      to reduce operative blood loss and the incidence of blood transfusion under our
      defined occlusion time.

PMID- 12470104
TI  - The use of molecular profiling of early colorectal cancer to predict
      micrometastases.
AB  - BACKGROUND: Approximately one third of node-negative colorectal cancers (CRCs)
      recur, suggesting the failure to detect occult disease. Lymphatic mapping
      followed by focused analysis of the sentinel node is highly accurate in
      identifying micrometastases. HYPOTHESIS: Because aberrant genetic changes occur
      early in tumor progression and are associated with lymphatic metastases, we
      hypothesized that the molecular profiling of specific tumor markers in the
      primary tumor might predict that tumor's metastatic potential. DESIGN: A
      prospective patient series. PATIENTS AND INTERVENTIONS: Forty consecutive
      patients with early CRC underwent lymphatic mapping after subserosal injection of
      1 mL of isosulfan blue dye. All lymph nodes were examined by hematoxylin-eosin
      (HE) staining, and multiple sections of each sentinel node were examined by HE
      and cytokeratin immunohistochemistry (CK-IHC) staining. Primary tumors were
      analyzed for p53 expression using IHC staining and for beta-human chorionic
      gonadotropin (beta-hCG), hepatocyte growth factor receptor (c-Met), and universal
      melanoma antigen (uMAGE) messenger RNA expression using reverse-transcriptase
      polymerase chain reaction and electrochemiluminescence. RESULTS: Nine patients
      (23%) had positive nodes by routine HE staining. Of the remaining 31 patients
      with negative nodes on HE staining, 8 tumors (26%) were upstaged by CK-IHC
      identification of occult micrometastases. There was a direct correlation between
      the number of markers and the T stage (P =.001). The expression of p53, beta-hCG,
      c-Met, and uMAGE in primary tumors was significantly higher in the presence of
      nodal micrometastases vs no metastases (P =.03). CONCLUSIONS: Sentinel lymphatic
      mapping is an accurate method of detecting micrometastases in CRC. Molecular
      profiling of primary CRC tumors, similar to that used for breast cancer, may be
      important in predicting metastatic potential and determining which patients may
      benefit from adjuvant therapy.

PMID- 12470105
TI  - Changes in blood flow and function of the liver after right portal vein
      embolization.
AB  - HYPOTHESIS: Abrupt occlusion of hemihepatic portal vein induced by preoperative
      portal vein embolization (PVE) may result in drastic alterations in blood flow
      and functional mass of the liver. DESIGN: Prospective study investigating the
      outcome of an intervention (PVE). SETTING: University tertiary-care referral
      center. PATIENTS: Thirteen patients who underwent PVE before extended right
      hepatectomy. MAIN OUTCOME MEASURES: The functional plasma flow and functional
      mass of the liver as well as the volumes of the left and right lobes were
      assessed before and after PVE. The functional plasma flow and functional mass of
      the liver were estimated by measuring the hepatic clearances of sorbitol (a high
      extraction drug) and antipyrine (a low-extraction drug), respectively. The liver
      lobar volumes were measured by computed tomography. RESULTS: Hepatic plasma
      clearance of sorbitol (mean +/- SD; before PVE, 632.9 +/- 142.9 mL/min; day 14,
      620.2 +/- 138.3 mL/min; not significant by 1-way repeated analysis of variance)
      and that of antipyrine (before PVE, 27.3 +/- 12.0 mL/min; day 14, 27.9 +/- 13.6
      mL/min; P =.85, by paired t test) were stable after PVE. Fourteen days after PVE,
      the non-PVE-treated lobe was enlarged (mean +/- SD, 137% +/- 30%) and the PVE
      treated lobe was atrophic (mean +/- SD, 87% +/- 15%); however, the total liver
      volume did not change significantly. CONCLUSIONS: The functional mass and plasma
      flow of the entire liver were stable after PVE despite the drastic change in the
      lobar distribution of the portal blood flow, whereas the non-PVE-treated lobe
      increased significantly in size. Our findings suggest that PVE leads to an
      increase in both the volume and the functional capacity of the non-PVE-treated
      lobe.

PMID- 12470106
TI  - Management of patients with colorectal cancer: do Australian surgeons know the
      scientific evidence?
AB  - HYPOTHESIS: Not all Australian surgeons are aware of the status of the current
      evidence for the management of colorectal cancer. DESIGN: Postal survey of
      Fellows of the Royal Australasian College of Surgeons. PARTICIPANTS: One hundred
      ninety-five surgeons (127 general surgeons and 68 subspecialist colorectal
      surgeons) from a response fraction of 89%. MAIN OUTCOME MEASURES: Overall
      awareness score for 23 clinical recommendations and a subscore for 10 of these
      for which evidence is compelling rather than inconclusive (9 for and 1 against
      incorporation in clinical practice). RESULTS: Although no surgeon indicated the
      status of the evidence correctly for all 23 items, 61% of respondents correctly
      identified 12 or more items. Surgeons who practiced in capital cities had
      significantly higher scores than those who practiced outside cities (beta =.16; B
      = 1.01; 95% confidence interval [CI], 0.14-1.89; P =.02). Surgeons who had been
      in practice for relatively more years had significantly lower scores than younger
      surgeons (beta = -.17; B = -0.059; 95% CI, -0.11 to 0.01; P =.02). Surgeons
      involved in research had significantly higher scores (beta =.18; B = 1.11; 95%
      CI, 0.23-1.99; P =.01), as did those respondents who had been involved in
      guideline development (beta =.18; B = 1.42; 95% CI, 0.24-2.63; P =.02). Subscores
      showed a significantly greater awareness of compelling evidence (level I or level
      II) (P<.001). There was no relationship between awareness of the evidence for
      adjuvant therapy and surgeons' perceptions of the usefulness of guidelines about
      this aspect of clinical management. CONCLUSIONS: Our innovative preguidelines
      survey has shown that not all surgeons were aware of the evidence underpinning
      the management of colorectal cancer, affirming the need for guidelines.
      Predictors of low awareness could be used to target efforts to disseminate and
      implement guidelines.

PMID- 12470107
TI  - A systematic review of stapled hemorrhoidectomy.
AB  - HYPOTHESIS: Use of circular stapled hemorrhoidectomy will result in the same or
      improved safety and efficacy outcomes as those of the conventional methods for
      hemorrhoidectomy in patients with hemorrhoids. DATA SOURCES: Studies on stapled
      hemorrhoidectomy were identified using PREMEDLINE and MEDLINE (June 1966-June
      2001), EMBASE (January 1980-June 2001), Current Contents (June 1993-June 2001),
      Ovid HEALTHSTAR (January 1975-June 2001), the National Institutes of Health
      Clinical Trials database (searched June 13, 2001), and The National Coordinating
      Centre for Health Technology Assessment database (searched June 14, 2001). The
      search terms were as follows: haemorrhoid* and (stapl* or convent*) or
      hemorrhoid* and (stapl* or convent*). The Cochrane Library (2001, issue 2) was
      searched using the search terms haemorrhoid* or hemorrhoid*. STUDY SELECTION:
      Articles detailing randomized controlled trials were included if they compared
      circular stapled with conventional hemorrhoidectomy and provided relevant safety
      and efficacy outcome information. DATA EXTRACTION: Data from all included studies
      were extracted using standardized data extraction tables that were developed a
      priori. In addition, the randomized controlled trials were examined with respect
      to the adequacy of allocation concealment, handling of those unavailable for
      follow-up, and any other aspect of the study design or execution that may have
      introduced bias. DATA SYNTHESIS: Seven randomized controlled trials met the
      inclusion criteria. A meta-analysis was conducted when the studies had comparable
      outcomes, inclusion criteria, and follow-up. There was reasonably clear evidence
      in favor of the stapled procedure for bleeding at 2 weeks (relative risk, 0.55;
      95% confidence interval, 0.37-0.82) and length of hospital stay (weighted mean
      difference, -0.89 days; 95% confidence interval, -1.42 to -0.36). Other less
      robust results in favor of the stapled hemorrhoidectomy related to pain,
      bleeding, anal discharge, wound healing, tenderness to per rectal examination,
      incontinence scores, earlier return of bowel function, analgesic requirement, and
      resumption of normal activities. One trial showed that prolapse occurred at
      significantly higher rates in the stapled hemorrhoidectomy group. However, the
      outcomes were poorly reported and generally showed statistically significant
      heterogeneity. CONCLUSIONS: Stapled hemorrhoidectomy may be at least as safe as
      conventional hemorrhoidal surgical techniques. However, the efficacy of the
      stapled procedure compared with the conventional techniques could not be
      determined. More rigorous studies with longer follow-up periods and larger sample
      sizes need to be conducted.

PMID- 12470109
TI  - Impact of laparoscopic and conventional surgery on Kupffer cells, tumor
      associated CD44 expression, and intrahepatic tumor spread.
AB  - BACKGROUND: The oncologic feasibility of laparoscopic surgery for the cure of
      colorectal cancer is under debate. The effect of laparoscopic colorectal cancer
      resection on hepatic tumor spread has not yet been clarified. HYPOTHESIS:
      Laparoscopic surgery affects cell-mediated immune response and hepatic tumor
      spread dependent on intraperitoneal insufflation. METHODS: Thirty WAG/Rij rats
      were randomized into 3 operative groups: carbon dioxide (CO( 2)) laparoscopy (n =
      10), "gasless" laparoscopy (n = 10), and laparotomy (n = 10). To induce liver
      metastases, 50 000 CC531 colon carcinoma cells were injected into the portal vein
      during either laparoscopy or laparotomy. Twenty-eight days after injection,
      specimens were explanted, sectioned, and examined immunohistochemically for CC531
      tumor cells (monoclonal antibody CC52), CD44v5, v6 (monoclonal antibody OX49),
      and Kupffer cells (monoclonal antibody HIS36). For quantification, a morphometric
      analysis system was applied. Data were analyzed using the Kruskal-Wallis, Dunn,
      and Holm tests. RESULTS: No statistically significant differences in hepatic
      tumor growth were found between CO(2) laparoscopy and laparotomy (P =.37).
      However, compared with CO(2) laparoscopy and laparotomy, a significant decrease
      in intrahepatic tumor growth was found after gasless laparoscopy (P =.02).
      Kupffer cells had significantly decreased after CO(2) laparoscopy and laparotomy
      compared with after gasless laparoscopy (P<.001 and P =.002, respectively).
      CD44v5, v6 expression was significantly increased after CO(2) laparoscopy and
      laparotomy compared with after gasless laparoscopy (P =.002 and P =.05,
      respectively). CONCLUSIONS: Hepatic resistance to tumor growth is best preserved
      by gasless laparoscopy as opposed to CO(2) laparoscopy or laparotomy. The amount
      of intra-abdominal pressure with circulatory changes rather than the used gas may
      explain this finding. On the other hand, conventional laparoscopy vs laparotomy
      did not preserve hepatic immune function.

PMID- 12470110
TI  - New journals, new societies, more meetings-do we need them all?: who can do it
      all?

PMID- 12470111
TI  - Bacterial resistance to antibiotics.

PMID- 12470112
TI  - The power of servant leadership to transform health care organizations for the
      21st-century economy.
AB  - Physician leadership is emerging as a vital component in transforming the
      nation's health care industry. Because few physicians have been introduced to the
      large body of literature on leadership and organizations, we herein provide a
      concise review, as this literature relates to competitive health care
      organizations and the leaders who serve them. Although the US health care
      industry has transitioned to a dynamic market economy governed by a wide range of
      internal and external forces, health care organizations continue to be dominated
      by leaders who practice an outmoded transactional style of leadership and by
      organizational hierarchies that are inherently stagnant. In contrast, outside the
      health care sector, service industries have repeatedly demonstrated that
      transformational, situational, and servant leadership styles are most successful
      in energizing human resources within organizations. This optimization of
      intellectual capital is further enhanced by transforming organizations into
      adaptable learning organizations where traditional institutional hierarchies are
      flattened and efforts to evoke change are typically team driven and mission
      oriented.

PMID- 12470114
TI  - Oncologic mathematics: evolution of a new specialty.
AB  - HYPOTHESIS: Mathematical methods and their derivatives have practical
      applications to oncology. They can be used to describe fundamental aspects of
      tumor behavior, such as loss of genetic stability, tumor growth, immunologic
      identity, genesis of diversity, and methods of prognosticating cancer. DATA
      SOURCES: Descriptive models and published literature in the fields of oncology
      and applied mathematics. DATA SYNTHESIS: Cancer does not conform to simple
      mathematical principles. Its irregular mode of carcinogenesis, erratic tumor
      growth, variable response to tumoricidal agents, and poorly understood metastatic
      patterns constitute highly variable clinical behavior. Defining this process
      requires an accurate understanding of the interactions between tumor cells and
      host tissues and ultimately determines prognosis. Applying time-tested and
      evolving mathematical methods to oncology may provide new tools with inherent
      advantages for the description of tumor behavior, selection of therapeutic modes,
      prediction of metastatic patterns, and providing an inclusive basis for
      prognostication. We term this combined field of research "oncologic mathematics."
      As surgeons, we have the unique opportunity to be active participants and assume
      leadership in research that affects selection of the optimal anticancer treatment
      for our patients. Mathematicians describe equations that define tumor growth and
      behavior, whereas surgeons actively deal with biological processes. Oncologic
      mathematics applies these principles to clinical settings. CONCLUSION:
      Experimentally testable, oncologic mathematics may provide a framework to
      determine clinical outcome on a patient-specific basis and increase the growing
      awareness that mathematical models help simplify seemingly complex and random
      tumor behavior.

PMID- 12470115
TI  - Surgery in Costa Rica.

PMID- 12470116
TI  - Breast gangrene as a complication of puerperal sepsis.
AB  - Gangrene of the breast, although rare, has been reported following anticoagulant
      treatment, trauma, and infection. Two cases of breast gangrene due to puerperal
      sepsis have been reported. We report a case of right breast gangrene as a
      complication of puerperal sepsis in a female patient.

PMID- 12470117
TI  - Image of the month. Rapunzel syndrome.

PMID- 12470119
TI  - Succus entericus reinfusion to treat postoperative small-bowel fistula.

PMID- 12470120
TI  - Improving the results of pancreatoduodenectomy.

PMID- 12470122
TI  - Stephen Smith (1823-1922): a forgotten surgical hero.

PMID- 12470123
TI  - Portrait of Dr Gachet.

PMID- 12470124
TI  - Association of promoter variants in the alpha7 nicotinic acetylcholine receptor
      subunit gene with an inhibitory deficit found in schizophrenia.
AB  - BACKGROUND: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene
      (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an
      auditory sensory processing deficit found in the disease, by both genetic linkage
      at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several
      brain regions in schizophrenic subjects compared with control subjects. This
      study presents DNA sequence analysis of the core promoter region for CHRNA7 in
      schizophrenic and control subjects. METHODS: Single-strand conformation
      polymorphism analysis and DNA sequencing were used for mutation screening of the
      core promoter in the CHRNA7 gene. The sample included subjects from 166
      schizophrenic families and 165 controls. Controls had no evidence of current or
      past psychosis and had auditory evoked potentials recorded. RESULTS: Multiple
      polymorphic patterns were identified in the CHRNA7 core promoter in both
      schizophrenic and control subjects. Functional analysis of polymorphisms
      indicated that transcription was reduced. The prevalence of functional promoter
      variants was statistically greater in schizophrenic subjects than in the
      controls. Presence of an alpha7 promoter polymorphism in controls was associated
      with failure to inhibit the P50 auditory evoked potential response. CONCLUSIONS:
      Although linkage disequilibrium with other genetic alterations cannot be
      excluded, the CHRNA7 core promoter variants, found in this study, may contribute
      to a common pathophysiologic feature of schizophrenia.

PMID- 12470125
TI  - Cost-effectiveness and cost offset of a collaborative care intervention for
      primary care patients with panic disorder.
AB  - BACKGROUND: A collaborative care (CC) intervention for patients with panic
      disorder that provided increased patient education and integrated a psychiatrist
      into primary care was associated with improved symptomatic and functional
      outcomes. This report evaluates the incremental cost-effectiveness and potential
      cost offset of a CC treatment program for primary care patients with panic
      disorder from the perspective of the payer. METHODS: We randomly assigned 115
      primary care patients with panic disorder to a CC intervention that included
      systematic patient education and approximately 2 visits with an on-site
      consulting psychiatrist, compared with usual primary care. Telephone assessments
      of clinical outcomes were performed at 3, 6, 9, and 12 months. Use of health care
      services and costs were assessed using administrative data from the primary care
      clinics and self-report data. RESULTS: Patients receiving CC experienced a mean
      of 74.2 more anxiety-free days during the 12-month intervention (95% confidence
      interval [CI], 15.8-122.0). The incremental mental health cost of the CC
      intervention was $205 (95% CI, -$135 to $501), with the additional mental health
      costs of the intervention explained by expenditures for antidepressant medication
      and outpatient mental health visits. Total outpatient cost was $325 (95% CI, 
      $1460 to $448) less for the CC than for the usual care group. The incremental
      cost-effectiveness ratio for total ambulatory cost was -$4 (95% CI, -$23 to $14)
      per anxiety-free day. Results of a bootstrap analysis suggested a 0.70
      probability that the CC intervention was dominant (eg, lower costs and greater
      effectiveness). CONCLUSION: A CC intervention for patients with panic disorder
      was associated with significantly more anxiety-free days, no significant
      differences in total outpatient costs, and a distribution of the cost
      effectiveness ratio based on total outpatient costs that suggests a 70%
      probability that the intervention was dominant, compared with usual care.

PMID- 12470126
TI  - Relapse predictors of patients with bulimia nervosa who achieved abstinence
      through cognitive behavioral therapy.
AB  - BACKGROUND: Little information exists on relapse in patients with bulimia nervosa
      who responded with complete abstinence from binge eating and purging to cognitive
      behavioral therapy. Identification of relapse predictors may be useful to design
      effective early intervention strategies for relapse of susceptible patients with
      bulimia nervosa. METHODS: This multisite study examined relapse in 48 patients
      with bulimia nervosa who had responded to cognitive behavioral therapy with
      complete abstinence from binge eating and purging. Structured interviews and
      questionnaires were used to assess patients before and after treatment and at 4
      months after treatment. RESULTS: Four months after treatment, 44% of the patients
      had relapsed. Those who relapsed had a higher level of preoccupation and
      ritualization of eating and less motivation for change, and had maintained
      abstinence for a shorter time during the treatment period. CONCLUSIONS: The
      predictors of relapse found in this study can be readily determined by
      clinicians. The effectiveness of early additional treatment interventions needs
      to be determined with well-designed studies of large samples.

PMID- 12470127
TI  - Efficacy of paroxetine for relapse prevention in social anxiety disorder: a 24
      week study.
AB  - BACKGROUND: The efficacy of selective serotonin reuptake inhibitors in the acute
      treatment of social anxiety disorder (social phobia) is well established.
      OBJECTIVE: To evaluate whether the efficacy of paroxetine hydrochloride in this
      disorder is maintained in the long term. METHODS: This was a placebo-controlled
      multicenter study comprising a single-blind acute treatment phase (12 weeks) and
      a randomized, double-blind maintenance treatment phase (24 weeks) for patients
      who had responded to paroxetine during the acute phase. Four hundred thirty-seven
      adult patients with social anxiety disorder (according to Diagnostic and
      Statistical Manual of Mental Disorders, Fourth Edition, criteria, code 300.23)
      entered the acute phase, and 323 continued into the maintenance phase (162
      paroxetine and 161 placebo). The principal outcome measure was the proportion of
      patients relapsing during the maintenance phase. RESULTS: Two hundred fifty-seven
      patients completed the study (136 paroxetine-treated and 121 placebo-treated
      patients). Significantly fewer patients relapsed in the paroxetine group than in
      the placebo group (14% vs 39%; odds ratio, 0.24; 95% confidence interval, 0.14
      0.43; P<.001). At the end of the study, a significantly greater proportion of
      patients in the paroxetine group showed improvement as shown on the Clinical
      Global Impression global improvement rating compared with the placebo group (78%
      vs 51%; odds ratio, 3.66; 95% confidence interval, 2.22-6.04; P<.001). Compared
      with placebo, paroxetine treatment significantly (P<.001) improved the symptoms
      of social anxiety as shown on the Liebowitz Social Anxiety Scale, Social Phobia
      Inventory, Sheehan Disability Scale, Symptom Checklist-90 score, and EuroQol
      visual analogue scale, indicating decreased disability and increased well-being.
      Paroxetine was well tolerated. CONCLUSION: Paroxetine is an effective long-term
      treatment for social anxiety disorder.

PMID- 12470128
TI  - Patients with seasonal affective disorder have lower odor detection thresholds
      than control subjects.
AB  - BACKGROUND: Behavioral changes in patients with seasonal affective disorder
      resemble seasonal changes in photoperiodic animals. Because the olfactory system
      has a modulatory role in seasonal photoperiodic responses in certain species, we
      hypothesized that olfactory function may differ between patients with seasonal
      affective disorder and healthy control subjects. METHODS: Fourteen patients who
      had winter seasonal affective disorder and 16 healthy volunteers were studied
      once in winter and once in the subsequent summer. We administered a phenyl ethyl
      alcohol detection threshold test to each side of the nose in a counterbalanced
      order, with the nostril contralateral to the tested site occluded. Patient and
      control data were compared using a 4-way repeated measure analysis of covariance
      (with group and gender as between-subjects factors, season and side-of-the-nose
      as within-subjects factors, and age as a covariate). RESULTS: The patients
      exhibited lower thresholds than did the controls (F(1,25) = 9.2; P =.006). There
      was no main effect of season. CONCLUSION: In humans, marked seasonal behavioral
      rhythms with recurrent winter depression may be associated with a more acute
      sense of smell.

PMID- 12470129
TI  - Shared genetic risk of major depression, alcohol dependence, and marijuana
      dependence: contribution of antisocial personality disorder in men.
AB  - BACKGROUND: Little is known about genetic factors that underlie the
      interrelationships among antisocial personality disorder (ASPD), major depression
      (MD), alcohol dependence (AD), and marijuana dependence (MJD). We examined the
      contribution of genetic effects associated with ASPD to the comorbidity of MD and
      substance use disorders. METHODS: The Vietnam Era Twin Registry is a general
      population registry of male veteran twins constructed from computerized
      Department of Defense files and other sources. A telephone diagnostic interview
      was administered to eligible twins from the Registry in 1992. Of 5150 twin pairs
      who served on active military duty during the Vietnam era, 3360 pairs (1868
      monozygotic and 1492 dizygotic) in which both members completed the pertinent
      diagnostic interview sections were included. The main outcome measures were
      lifetime DSM-III-R ASPD, MD, AD, and MJD. RESULTS: Structural equation modeling
      was performed to estimate additive genetic, shared environmental, and nonshared
      environmental effects common and specific to each disorder. The heritability
      estimates for lifetime ASPD, MD, AD, and MJD were 69%, 40%, 56%, and 50%,
      respectively. Genetic effects on ASPD accounted for 38%, 50%, and 58% of the
      total genetic variance in risk for MD, AD, and MJD, respectively. After
      controlling for genetic effects on ASPD, the partial genetic correlations of MD
      with AD and with MJD were no longer statistically significant. Genetic effects
      specific to MD and AD and familial effects specific to MJD remained statistically
      significant. Nonshared environmental contributions to the comorbidity in these
      disorders were small. CONCLUSIONS: In this sample, the shared genetic risk
      between MD and both AD and MJD was largely explained by genetic effects on ASPD,
      which in turn was associated with increased risk of each of the other disorders.

PMID- 12470130
TI  - Psychiatric disorders in youth in juvenile detention.
AB  - BACKGROUND: Given the growth of juvenile detainee populations, epidemiologic data
      on their psychiatric disorders are increasingly important. Yet, there are few
      empirical studies. Until we have better epidemiologic data, we cannot know how
      best to use the system's scarce mental health resources. METHODS: Using the
      Diagnostic Interview Schedule for Children version 2.3, interviewers assessed a
      randomly selected, stratified sample of 1829 African American, non-Hispanic
      white, and Hispanic youth (1172 males, 657 females, ages 10-18 years) who were
      arrested and detained in Cook County, Illinois (which includes Chicago and
      surrounding suburbs). We present 6-month prevalence estimates by demographic
      subgroups (sex, race/ethnicity, and age) for the following disorders: affective
      disorders (major depressive episode, dysthymia, manic episode), anxiety (panic,
      separation anxiety, overanxious, generalized anxiety, and obsessive-compulsive
      disorders), psychosis, attention-deficit/hyperactivity disorder, disruptive
      behavior disorders (oppositional defiant disorder, conduct disorder), and
      substance use disorders (alcohol and other drugs). RESULTS: Nearly two thirds of
      males and nearly three quarters of females met diagnostic criteria for one or
      more psychiatric disorders. Excluding conduct disorder (common among detained
      youth), nearly 60% of males and more than two thirds of females met diagnostic
      criteria and had diagnosis-specific impairment for one or more psychiatric
      disorders. Half of males and almost half of females had a substance use disorder,
      and more than 40% of males and females met criteria for disruptive behavior
      disorders. Affective disorders were also prevalent, especially among females;
      more than 20% of females met criteria for a major depressive episode. Rates of
      many disorders were higher among females, non-Hispanic whites, and older
      adolescents. CONCLUSIONS: These results suggest substantial psychiatric morbidity
      among juvenile detainees. Youth with psychiatric disorders pose a challenge for
      the juvenile justice system and, after their release, for the larger mental
      health system.

PMID- 12470131
TI  - Dopamine antagonists and the development of breast cancer.
AB  - BACKGROUND: Although animal studies have raised the possibility that prolactin
      elevating dopamine antagonists used to treat psychotic disorders may initiate and
      promote breast cancers, epidemiologic studies in humans have been limited and
      inconsistent. METHODS: A retrospective cohort study was conducted of 52 819 women
      exposed and 55 289 not exposed to dopamine antagonists between January 1, 1989,
      and June 30, 1995. All participants were 20 years or older, initially free of
      breast cancer, and enrolled in the Medicaid or the Pharmaceutical Assistance to
      the Aged and Disabled programs of New Jersey. Incident breast cancer cases were
      identified through the New Jersey Cancer Registry and definitive breast cancer
      surgeries. Adjusted hazard ratios of breast cancer were calculated from
      multivariable proportional hazards models. RESULTS: Use of antipsychotic dopamine
      antagonists was associated with a 16% increase in the risk of breast cancer
      (adjusted hazard ratio, 1.16; 95% confidence interval, 1.07-1.26), with a dose
      response relationship between larger cumulative dosages and greater risk. The
      increased risk was also seen in women who used prolactin-elevating antiemetic
      dopamine antagonists despite having different breast cancer risk profiles than
      antipsychotic dopamine antagonist users. Dopamine antagonist use was not
      associated with risk of colon cancer, a control condition not related to elevated
      prolactin levels. The increased risk of breast cancer among dopamine antagonist
      users was not explained by increased surveillance or protopathic bias.
      CONCLUSIONS: Antipsychotic dopamine antagonist use may confer a small but
      significant risk of breast cancer. In light of the small hazards and the
      possibility of residual confounding, these findings should lead to follow-up
      investigations but not to changes in treatment strategies.

PMID- 12470132
TI  - Hypnotic suggestion and the modulation of Stroop interference.
AB  - BACKGROUND: Hypnosis has been used clinically for hundreds of years and is
      primarily a phenomenon involving attentive receptive concentration. Cognitive
      science has not fully exploited hypnosis and hypnotic suggestion as experimental
      tools. This study was designed to determine whether a hypnotic suggestion to
      hinder lexical processing could modulate the Stroop effect. METHODS: Behavioral
      Stroop data were collected from 16 highly suggestible and 16 less suggestible
      subjects; both naturally vigilant and under posthypnotic suggestion. Subjects
      were urged to only attend to the ink color and to impede reading the stimuli
      under posthypnotic suggestion. RESULTS: Whereas posthypnotic suggestion
      eliminated Stroop interference for highly suggestible subjects, less suggestible
      control subjects showed no significant reduction in the interference effect.
      CONCLUSIONS: This outcome challenges the dominant view that word recognition is
      obligatory for proficient readers, and may provide insight into top-down
      influences of suggestion on cognition.

PMID- 12470133
TI  - Brain metabolic changes during cigarette craving.
AB  - BACKGROUND: In functional brain imaging studies, exposure to cues related to
      cocaine, opiates, and alcohol in dependent individuals is associated with
      activation of the anterior cingulate gyrus, amygdala, orbitofrontal cortex, and
      dorsolateral prefrontal cortex. Craving for these substances positively
      correlates with activity in the orbitofrontal cortex, dorsolateral prefrontal
      cortex, and anterior insula. The objective of this study was to determine changes
      in regional cerebral glucose metabolism and correlations between craving and
      regional metabolism in heavy cigarette smokers exposed to cigarette-related cues.
      METHODS: Twenty heavy smokers (who smoked > or =20 cigarettes per day) and 20
      nonsmoking control subjects underwent 2 fluorine 18-fluorodeoxyglucose positron
      emission tomography scans 10 days apart in randomized order: one while watching a
      videotape that presented cigarette-related cues and handling a cigarette, and the
      other while watching an educational (nature) videotape and handling a neutral
      object (pen). RESULTS: From the neutral to the cigarette cue scan, heavy smokers
      had greater increases than nonsmoking controls in relative glucose metabolism in
      the perigenual anterior cingulate gyrus spanning the midline. Significant
      positive correlations were found between intensity of craving and metabolism in
      the orbitofrontal cortex, dorsolateral prefrontal cortex, and anterior insula
      bilaterally. An unexpected positive association was found between craving and
      metabolism in the right sensorimotor cortex. CONCLUSIONS: Brain regions
      associated with arousal, compulsive repetitive behaviors, sensory integration,
      and episodic memory are activated during exposure to cigarette-related cues and
      cigarette craving. These regional brain activations and associations with craving
      are similar to findings with other addictive substances.

PMID- 12470134
TI  - Immunophenotype of conjunctival melanomas: comparisons with uveal and cutaneous
      melanomas.
AB  - OBJECTIVE: To characterize the immunophenotypic expression pattern of
      conjunctival melanomas, with the use of standard melanoma markers as well as
      microphthalmia transcription factor and p75 neurotrophin receptor. DESIGN: Eleven
      conjunctival melanomas, including 1 caruncular melanoma, were immunolabeled with
      a panel of antibodies that included S100, tyrosinase, melan-A, HMB-45 and HMB-50
      combination, microphthalmia transcription factor, and p75 neurotrophin receptor.
      The results were tabulated on the basis of intensity and pervasiveness of
      labeling and compared with a previous study of uveal melanomas. RESULTS:
      Immunolabeling with S100 was at significantly higher levels in conjunctival
      melanomas than in uveal melanomas. Tyrosinase, HMB-45 and HMB-50 combination,
      melan-A, and microphthalmia transcription factor were expressed at high levels in
      conjunctival melanomas, whereas p75 neurotrophin receptor was not expressed.
      CONCLUSIONS: Melanomas of the conjunctiva, including the caruncle, expressed
      S100, tyrosinase, melan-A, HMB-45 and HMB-50 combination, and microphthalmia
      transcription factor at high levels, suggesting that these are good markers for
      this melanoma subtype. Expression of S100 was significantly higher in
      conjunctival melanomas than in uveal melanomas. The immunophenotypic pattern of
      conjunctival melanomas is most similar to the epithelioid subtype of cutaneous
      melanomas.

PMID- 12470135
TI  - Soluble Fas ligand and transforming growth factor beta2 in the aqueous humor of
      patients with endothelial immune reactions after penetrating keratoplasty.
AB  - BACKGROUND: Excellent long-term prognosis of penetrating corneal grafts has been
      explained by the immunological privilege of the cornea and the anterior chamber.
      In animal models the secretion of transforming growth factor beta(2) (TGF
      beta(2)) into the anterior chamber and the expression of the Fas ligand on
      corneal endothelial cells were identified as important for the integrity of the
      immunological privilege. OBJECTIVE: To determine the TGF-beta(2) and soluble Fas
      ligand (sFasL) levels in the aqueous humor of patients after penetrating
      keratoplasty (PK) who have and who do not have immune reactions. METHODS:
      Anterior chamber puncture was performed in 13 patients who had a cataract without
      PK (group 1), in 31 patients after PK who did not have immune reactions (group
      2), and in 12 patients after PK newly diagnosed as having endothelial immune
      reactions (group 3). Total TGF-beta(2) and sFasL were determined via enzyme
      linked immunosorbent assay. RESULTS: Transforming growth factor beta(2) was
      detected in all patients, irrespective of the underlying condition; there was no
      difference in TGF-beta(2) levels between the different groups (P =.89, analysis
      of variance). None of the patients in group 1, 11 of 31 patients in group 2, and
      8 of 12 patients in group 3 had detectable sFasL concentrations (P =.002, chi(2)
      test). Soluble Fas ligand averaged (mean [SD]) 20.8 (31.1) pg/mL in group 2, and
      38.1 (33.2) pg/mL (P<.01, analysis of variance) in group 3. CONCLUSIONS: It
      appears that total TGF-beta(2) is maintained at high steady-state levels, while
      the level of sFasL is up-regulated in patients who underwent PK, particularily in
      the advent of graft rejection.

PMID- 12470136
TI  - The severity and spatial distribution of visual field defects in primary
      glaucoma: a comparison of primary open-angle glaucoma and primary angle-closure
      glaucoma.
AB  - OBJECTIVE: To compare the characteristics of visual field defects in primary
      angle-closure glaucoma (PACG) and primary open-angle glaucoma (POAG). METHODS:
      Subjects with primary glaucoma aged 30 years and older were prospectively
      considered for inclusion. Automated static white-on-white perimetry was
      performed. A minimum of 2 reliable tests was required with a mean deviation (MD)
      within 2 dB on 2 tests. Subjects with previous symptomatic angle-closure, normal
      tension glaucoma, visually significant cataract, or previous intraocular surgery
      were excluded. RESULTS: Of 234 subjects assessed, 129 had POAG, and 105 had PACG.
      The MDs (POAG group, -13.3 dB; PACG group, -18.0 dB) indicated more severe visual
      loss in subjects with PACG. In subjects with POAG, the superior hemifield was
      more severely affected than the inferior. This was less pronounced in subjects
      with PACG. Following stratification by MD, the difference between hemifields was
      marked in the mild (-10 dB<or=MD) and moderate (-20 dB<or=MD<-10 dB) subgroups
      but was not present in the severe (MD<-20 dB) subgroup. We detected differences
      between POAG and PACG in retinal sensitivity between the superior and inferior
      hemifields, independent of severity of damage. CONCLUSIONS: The pattern of visual
      field loss was different in the 2 diseases. This may give insight into the
      pattern of visual loss in predominantly pressure-dependent glaucomatous optic
      neuropathy.

PMID- 12470137
TI  - Correlation of increased vascular endothelial growth factor with
      neovascularization and permeability in ischemic central vein occlusion.
AB  - OBJECTIVE: To establish a role for vascular endothelial growth factor (VEGF)
      during the onset and clinical course of neovascularization of the iris (NVI) in
      ischemic central retinal vein occlusion. METHODS: Sixteen patients with ischemic
      central retinal vein occlusion were followed up for 12 months by clinical
      examination, retinal and iris angiography, and serial anterior chamber sampling
      of aqueous humor. Aqueous VEGF level was determined by enzyme-linked immunoassay,
      and permeability changes were estimated by capillary zone electrophoretic
      assessment of aqueous albumin. RESULTS: A correlation was found between aqueous
      VEGF concentrations and the onset, persistence, and regression of NVI; extent of
      retinal capillary nonperfusion; and vascular permeability. The NVI occurred when
      aqueous VEGF concentrations were 849 to 1569 pg/mL and regressed fully when they
      fell below 550 pg/mL. Aqueous concentrations of serum albumin, a marker of
      increased permeability, correlated with increased VEGF. Placental growth factor
      was found at low levels only when VEGF levels exceeded 330 pg/mL. The NVI
      remained VEGF-dependent during the course of the disease, regressing only if VEGF
      concentrations were reduced after laser ablation of hypoxic retina. CONCLUSIONS:
      The close temporal correlation between aqueous VEGF levels and the course of
      neovascularization and permeability in human ischemic central retinal vein
      occlusion indicates that increased aqueous VEGF level may predict the need for
      treatment, and that anti-VEGF therapy at an early stage of ischemic central
      retinal vein occlusion may be therapeutically beneficial.

PMID- 12470138
TI  - Chemoreduction for unilateral retinoblastoma.
AB  - OBJECTIVE: To evaluate conservative management of unilateral retinoblastoma using
      chemoreduction and focal treatment. DESIGN: Prospective nonrandomized single
      center clinical trial. SETTING: Ocular Oncology Service at Wills Eye Hospital of
      Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division
      of Oncology at The Children's Hospital of Philadelphia. PARTICIPANTS: Thirty eyes
      of 30 patients with unilateral retinoblastoma treated with chemoreduction between
      June 1, 1994, and August 31, 1999, that would otherwise have been managed with
      enucleation or external beam radiotherapy. INTERVENTION: All patients received
      treatment for retinoblastoma with a planned 6 cycles of chemoreduction using
      vincristine sulfate, etoposide, and carboplatin, combined with focal treatment
      (cryotherapy or thermotherapy) to each retinal tumor. MAIN OUTCOME MEASURES: The
      main outcome measure was the postchemoreduction need for external beam
      radiotherapy or enucleation. The cumulative probability of each outcome was
      estimated using Kaplan-Meier survival analysis. A secondary outcome measure was
      final visual acuity in the affected eye. The clinical features at the time of
      patient presentation were analyzed for their impact on the main outcomes using a
      series of Fisher exact tests and Cox proportional hazards regressions. RESULTS:
      Eighteen eyes (60%) were classified as having Reese-Ellsworth (RE) groups I
      through IV retinoblastoma and 12 eyes (40%), group V retinoblastoma. By using
      Kaplan-Meier estimates, we found a need for either external beam radiotherapy or
      enucleation in 68% of eyes by 5 years. In fact, 38% of those in groups I through
      IV required either treatment, whereas all of those in group V required the
      additional use of either treatment. Specifically, the need for external beam
      radiotherapy occurred in 27% of eyes by 5 years. Eleven percent of those in
      groups I through IV and 50% of group V required external beam radiotherapy by 5
      years. The factors predictive of the need for external beam radiotherapy included
      RE group V disease, tumor thickness greater than 5 mm, and presence of vitreous
      seeds. The need for enucleation occurred in 47% of eyes by 5 years using Kaplan
      Meier analysis. Specifically, 29% of those in groups I through IV and 67% of
      group V required enucleation by 5 years. The factors predictive of the need for
      enucleation included age at diagnosis older than 12 months, RE group V disease,
      tumor base diameter greater than 15 mm, and tumor thickness greater than 5 mm. At
      a mean follow-up of 29 months, the final visual acuity was 20/200 or better in 6
      eyes (20%) and worse than 20/200 in 14 (47%); enucleation was needed in 10 (33%).
      Of the 26 eyes with initial macular involvement of retinoblastoma, final visual
      acuity was 20/200 or better in 6 (23%). No patient developed retinoblastoma
      metastasis, pinealoblastoma, or second malignant neoplasms. CONCLUSIONS:
      Chemoreduction is an option for selected eyes with unilateral retinoblastoma.
      Those with advanced RE group V retinoblastoma showed poorest results, while those
      with less advanced groups I through IV disease showed best results, maintaining
      the globe in 71% of eyes, sometimes with satisfactory functional visual acuity.

PMID- 12470139
TI  - Noncontiguous tumor recurrence of posterior uveal melanoma after transscleral
      local resection.
AB  - OBJECTIVE: To describe the clinical and histopathologic features of noncontiguous
      tumor recurrence after transscleral local resection of posterior uveal melanoma.
      METHODS: Chart review was performed to identify patients with noncontiguous tumor
      recurrences from a series of 494 consecutive patients treated with transscleral
      local resection for uveal melanoma. The clinical and histopathologic features of
      noncontiguous tumor recurrences were studied. RESULTS: Nine cases were
      identified, for an estimated incidence of 1.8%. The average diameter of the
      primary tumors was 16.1 mm (range, 9-22 mm) and the average thickness was 9.8 mm
      (range, 6-14 mm). Noncontiguous tumor recurrences were solitary in 7 cases and
      multiple in 2 cases, with an average diameter of 5.8 mm (range, 3.0-9.5 mm).
      Eight of the 9 patients developed tumor recurrences at multiple intraocular
      sites. With a mean follow-up of 82.1 months (range, 22-171 months), 7 patients
      had a final visual acuity of counting fingers or worse, and there were 3 deaths
      from metastatic disease. CONCLUSIONS: Noncontiguous tumor recurrence after local
      resection appears to be related to intraocular dissemination from the primary
      tumor, either through the natural course of the disease or secondary to surgical
      manipulation. Eyes with large primary uveal melanomas developing noncontiguous
      tumor recurrence have a high risk of developing tumor spread to multiple
      intraocular sites, and aggressive treatment is warranted.

PMID- 12470140
TI  - Evidence-based estimates of outcome in patients irradiated for intraocular
      melanoma.
AB  - BACKGROUND: Melanoma of the eye is the only potentially fatal ocular malignancy
      in adults. Until radiation therapy gained wide acceptance in the 1980s,
      enucleation was the standard treatment for the tumor. Long-term results after
      proton beam irradiation are now available. METHODS: We developed risk score
      equations to estimate probabilities of the 4 principal treatment outcomes-local
      tumor recurrence, death from metastasis, retention of the treated eye, and vision
      loss-based on an analysis of 2069 patients treated with proton beam radiation for
      intraocular melanoma between July 10, 1975, and December 31, 1997. Median follow
      up in surviving patients was 9.4 years. RESULTS: Tumor regrowth occurred in 60
      patients, and 95% of tumors (95% confidence interval, 93%-96%) were controlled
      locally at 15 years. Risk scores were developed for the other 3 outcomes studied.
      Overall, the treated eye was retained by 84% of patients (95% confidence
      interval, 80%-87%) at 15 years. The probabilities for vision loss (visual acuity
      worse than 20/200) ranged from 100% to 20% at 10 years and for death from tumor
      metastases from 95% to 35% at 15 years, depending on the risk group. CONCLUSIONS:
      High-dose radiation treatment was highly effective in achieving local control of
      intraocular melanomas. In most cases, the eye was salvaged, and functional vision
      was retained in many patients. The mortality rate was high in an identifiable
      subset of patients who may benefit from adjuvant therapies directed at
      microscopic liver metastases.

PMID- 12470141
TI  - Visual field defects and multifocal visual evoked potentials: evidence of a
      linear relationship.
AB  - OBJECTIVE: To determine the relationship between spatially localized multifocal
      visual evoked potentials (mfVEPs) and Humphrey visual fields (HVFs) in patients
      with unilateral field defects. METHODS: Humphrey visual fields and mfVEPs were
      obtained from 20 patients with unilateral field losses due to either ischemic
      optic neuropathy or glaucoma. Monocular mfVEPs were obtained for each eye. The
      amplitude of the mfVEP responses was calculated using root-mean-square and signal
      noise ratio measures. Estimates of the HVF loss in the same regions of the field
      used for the mfVEP were obtained by interpolating the 24-2 HVF data. RESULTS:
      Monocular mfVEP amplitude decreased with HVF loss, although small mfVEP signals
      were not uniquely associated with poor fields. On average, the monocular mfVEP
      was indistinguishable from noise for field losses between -5 and -10 dB, and good
      monocular mfVEP amplitudes were never associated with extensive visual field
      loss. The interocular ratio of the mfVEP amplitudes correlated well with the
      difference between the HVF values of the 2 eyes, and this correlation improved
      with increased signal-noise ratio. CONCLUSIONS: The monocular and interocular
      results were consistent with a linear relationship between the amplitude of the
      signal portion of the mfVEP response and linear HVF loss. One way to produce this
      relationship would be if both the signal in the mfVEP and linear HVF loss were
      linearly related to the percentage of local ganglion cells lost. The clinical
      limitations of the mfVEP technique can be understood by taking the signal-noise
      ratio, and the linear model proposed herein, into consideration.

PMID- 12470142
TI  - Involutional lateral entropion of the upper eyelids: a new physical finding in
      asian patients.
AB  - OBJECTIVE: To describe a new physical finding called involutional lateral
      entropion (ILE) of the upper eyelid found in Asian patients. METHODS: A
      prospective case series study of 53 consecutive patients with ILE of the upper
      eyelid, from the practice of one of the authors (J.G.C.), was performed. All of
      the patients in this series were Asian. Clinical findings on ocular examination,
      symptoms, age, and sex were obtained and tabulated. RESULTS: The mean +/- SD age
      of patients was 68.9 +/- 10.1 years (range, 41-88 years); 70% were women and 30%
      were men. All patients presented with in-turning of only the lateral aspect of
      the upper eyelid bilaterally. The presenting symptoms were foreign-body sensation
      (85%), tearing (77%), eye redness (34%), eye pain (26%), and itchiness at the
      lateral canthal area (25%). Clinical findings included lateral dermatochalasis
      (100%), trichiasis (100%), lateral canthal eyelid laxity (100%), localized
      lateral conjunctivitis (42%), punctate epithelial keratopathy (11%), blepharitis
      (11%), and distichiasis (8%). CONCLUSION: We describe ILE of the upper eyelid in
      Asian patients and explain the anatomic correlates responsible for this
      condition.

PMID- 12470143
TI  - Balloon catheter dilation for treatment of older children with nasolacrimal duct
      obstruction.
AB  - OBJECTIVES: To describe the outcomes of balloon catheter dilation of the lacrimal
      duct as the first surgical treatment for older children (>or=18 months) with
      nasolacrimal duct (NLD) obstruction and to examine the effect of the type of
      obstruction on outcome. DESIGN: Retrospective noncomparative case series.
      PARTICIPANTS: Seventy-six children 18 months or older with NLD obstruction who
      had not undergone previous surgery. INTERVENTION: The patients underwent NLD
      probing, infracturing of the inferior turbinate, and balloon catheter dilation of
      the distal NLD. The type of obstruction was noted at surgery. MAIN OUTCOME
      MEASURES: Outcomes were considered excellent if the patient had complete
      resolution of epiphora and dacryocystitis and normal tear drainage on
      examination, good if the patient had only minimal residual symptoms or a
      minimally delayed dye disappearance test result, fair if the patient had moderate
      residual symptoms or delayed tear drainage, and poor if there was no improvement.
      RESULTS: Seventy-six children were treated. Overall, results were excellent in 28
      (37%) patients, good in 30 (39%), fair in 13 (17%), and poor in 5 (7%). Forty
      eight (63%) of the patients had simple membranous obstruction at the Hasner
      valve. Results were good or excellent in 35 (73%) of these patients. Twenty-eight
      (37%) patients had stenosis that extended along the length of the distal NLD.
      Results were good or excellent in 23 (82%) of these patients. CONCLUSIONS:
      Balloon catheter dilation is probably more effective than simple probing for
      older children with NLD obstruction because of stenosis that extends along the
      distal NLD. The procedure does not provide a significant advantage over simple
      NLD probing in patients with typical membranous obstruction at the Hasner valve.

PMID- 12470144
TI  - Complete androgen insensitivity syndrome: effect on human meibomian gland
      secretions.
AB  - OBJECTIVE: To determine whether androgen receptors affect the fatty acid profiles
      of neutral and polar lipids in human meibomian gland secretions. METHODS:
      Meibomian gland secretion samples were obtained from both eyes of (1) women with
      complete androgen insensitivity syndrome, a condition characterized by
      dysfunctional androgen receptors, and (2) age-matched female and male controls.
      Samples were processed for high-performance liquid chromatography, mass
      spectrometry, or both and for analysis of the mass spectra of neutral and polar
      lipid fatty acid fragment ions by 3 different methods. RESULTS: Androgen receptor
      dysfunction is associated with significant alterations in the appearance of
      numerous molecular species in the neutral and polar lipid fractions of meibomian
      gland secretions. The ability to detect these differences, and to assess their
      nature and extent, was facilitated by the use of several analytic approaches. Sex
      related differences exist in the expression of a variety of neutral and,
      especially, polar fatty acid products in meibomian gland secretions. CONCLUSIONS:
      Androgens exert a significant effect on neutral and polar lipids in human
      meibomian gland secretions, and these hormonal effects may be mediated through
      androgen receptors.

PMID- 12470145
TI  - Confocal and electron microscopic studies of laser subepithelial keratomileusis
      (LASEK) in the white leghorn chick eye.
AB  - OBJECTIVES: To evaluate the effect of 20% alcohol on the white leghorn chick
      cornea and to determine the confocal and electron microscopic findings of laser
      subepithelial keratomileusis surgery in the white leghorn chick corneal model.
      METHOD: Laser subepithelial keratomileusis surgery was performed on chick corneas
      and the morphologic changes were examined by transmission electron microscopy.
      Chick corneas were exposed to 20% alcohol for 30 and 45 seconds or 1 and 2
      minutes (5 chicks per group) to evaluate the effect on the corneal epithelium.
      Photorefractive keratectomy using either mechanical or 20% alcohol-assisted
      debridement (5 chicks per group) was also performed. Keratocyte and epithelial
      cell deaths were analyzed 4 hours after surgery using terminal deoxynucleotidyl
      transfer-mediated biotin-dexoyuridine 5-triphosphate nick-end labeling (TUNEL)
      staining and transmission electron microscopy. RESULTS: Exposure of the corneal
      epithelium to 20% alcohol for 30 seconds or longer allowed reproducible
      separation of epithelial flaps in white leghorn chick eyes. Transmission electron
      microscopy immediately after alcohol treatment showed that exposure to 20%
      alcohol for 30 seconds or less had minimal adverse effects on the corneal
      epithelium. The TUNEL staining of corneas obtained 4 hours after surgery revealed
      TUNEL-positive cells in the central superficial stroma and more abundantly in the
      peripheral superficial stroma around the epithelial flap margin and in the
      epithelial flap itself, particularly in the basal epithelial layer. Transmission
      electron microscopy showed similar evidence of apoptosis in the epithelium and
      anterior stroma. CONCLUSIONS: The white leghorn chick eye seems to be a
      reasonable model for laser subepithelial keratomileusis surgery. Treatment with
      20% alcohol for 30 seconds results in reproducible epithelial flap creation in
      the chick cornea and in relatively low levels of stromal and epithelial cell
      death after surgery.

PMID- 12470146
TI  - Statin inhibits leukocyte-endothelial interaction and prevents neuronal death
      induced by ischemia-reperfusion injury in the rat retina.
AB  - BACKGROUND: Retinal ishchemia-induced neuronal death is believed to be a direct
      causal process in the development of many ocular diseases. The 3-hydroxy-3
      methylglutaryl coenzyme A reductase inhibitor, statin, is known to improve
      endothelial function in proinflammatory conditions. OBJECTIVE: To investigate the
      effects of statin on leukocyte accumulation during ischemia-reperfusion injury
      and on subsequent retinal damage. METHODS: Transient retinal ischemia was induced
      in Long-Evans rats for 60 minutes using temporal ligation of the optic nerve.
      Leukocyte-endothelial interactions in the postischemic retina were evaluated in
      vivo with a scanning laser ophthalmoscope. Statin was administered 5 minutes
      before the induction of retinal ischemia. P-selectin and intercellular adhesion
      molecule-1 (ICAM-1) gene expression in the postischemic retina were studied with
      the semiquantitative polymerase chain reaction. Histologic studies were carried
      out to evaluate retinal damage. RESULTS: The preadministration of statin
      attenuated the rolling and accumulation of leukocytes, decreased P-selectin and
      ICAM-1 expression, and reduced the number of apoptotic cells in the retina.
      Furthermore, histologic evaluation 168 hours after reperfusion showed that statin
      significantly diminished the resultant retinal tissue damage. The neuroprotective
      effect of statin was abolished when it was administered along with a nitric oxide
      synthase inhibitor, nitroglycerine-nitro-L-arginine methyl ester. CONCLUSION:
      Statin may exert neuroprotective effects by inhibiting leukocyte-endothelial
      interaction through the release of nitric oxide from the endothelium. CLINICAL
      RELEVANCE: As a result of its efficacy in preventing retinal neuronal death,
      statin may be developed into a novel therapeutic modality for many ocular
      ischemic diseases.

PMID- 12470147
TI  - Microcontact printing on human tissue for retinal cell transplantation.
AB  - OBJECTIVES: To demonstrate that microcontact printing, a modern materials
      fabrication technique, can be used to engineer the surface of human tissue and to
      show that inhibitory molecules can be used to pattern the growth of retinal
      pigment epithelial cells or iris pigment epithelial cells on human lens capsule
      for transplantation. METHODS: Photolithographic techniques were used to fabricate
      photoresist-coated silicon substrates into molds. Poly(dimethylsiloxane)stamps
      for microcontact printing were made from these molds. The poly(dimethylsiloxane)
      stamps were then used to "wet-transfer" growth inhibitory molecules to the
      surface of prepared human lens capsules that were obtained during cataract
      surgery. Human retinal pigment epithelial and rabbit iris pigment epithelial
      cells were grown on a lens capsule substrate in the presence and absence of a
      patterned array of inhibitory factors. RESULTS: We found that human lens capsule
      could be microprinted with a precision similar to that obtained on glass or
      synthetic polymers. Retinal pigment epithelial cells and iris pigment epithelial
      cells cultured onto an untreated lens capsule showed spreading and formed into
      fusiform-appearing cells. In contrast, cells cultured on a lens capsule with a
      hexagonal micropattern of growth inhibitory molecules retained an epithelioid
      form within the inhibitory hexagons. CONCLUSION: Inhibitory growth molecules can
      be micropatterned onto human lens capsule, and these micropatterns can control
      the organization of retinal pigment epithelial cells or iris pigment epithelial
      cells cultured onto the lens capsule surface. CLINICAL RELEVANCE: Microprinting
      on autologous human tissue may facilitate efforts to effectively organize cell
      cultures and transplantations for the replacement of vital ocular tissues such as
      the retinal pigment epithelium in age-related macular degeneration.

PMID- 12470149
TI  - Family score as an indicator of genetic risk of primary open-angle glaucoma.
AB  - OBJECTIVES: To assess the genetic risk of open-angle glaucoma (OAG) in
      individuals by calculating a family score (FS), which summarizes the information
      of all relatives including their disease status, age, sex, and degree of kinship
      and to examine the genetic contribution to OAG with and without an increased
      intraocular pressure. METHODS: Case and control probands, derived from the
      Rotterdam Study, underwent the same ophthalmologic examination as their
      relatives. The FS of each proband was the sum of the differences between observed
      and expected values of OAG for all relatives. The FSs were compared between case
      and control probands using logistic regression analysis, adjusted for intraocular
      pressure. RESULTS: Of 37 case probands, 44 (half-) siblings and 86 children were
      available, and of 83 control probands there were 97 (half-) siblings and 155
      children. Family scores ranged from -0.44 to 7.08 in case probands and from -0.98
      to 2.46 in control probands. One unit increase in FS was significantly associated
      with a higher risk of OAG (odds ratio, 1.59; 95% confidence interval, 1.14-2.23).
      Adjustments for intraocular pressure did not change the odds ratio. CONCLUSIONS:
      These data show that the FS strongly predicts OAG, independent of the intraocular
      pressure. Therefore, the FS is useful to identify individuals with a high genetic
      risk.

PMID- 12470148
TI  - Expression of angiogenic factors Cyr61 and tissue factor in uveal melanoma.
AB  - OBJECTIVE: To study the expression of angiogenic factors Cyr61 and tissue factor
      (TF) in uveal melanoma and its correlation with blood vessel density. METHODS:
      Suppression subtractive hybridization was used to identify genes that are
      differentially expressed between cell lines of uveal melanoma and normal uveal
      melanocytes. Expression of these genes was subsequently verified in primary uveal
      melanomas and correlated with the number of blood vessels in archival specimens
      by immunohistochemical analysis. RESULTS: Cyr61 and TF are expressed at elevated
      levels in cell lines of uveal melanoma compared with normal uveal melanocytes.
      Duplication of a region of chromosome arm 1p, encompassing the genes encoding
      Cyr61 and TF, was observed in the melanoma cell line used in the initial
      subtractive hybridization. Both genes are also expressed in primary uveal
      melanomas, and a correlation was found between expression of TF and the number of
      blood vessels in archival specimens. CONCLUSIONS: Cyr61 and TF may contribute to
      the angiogenic phenotype associated with uveal melanoma. A region of chromosome
      arm 1p also may contain oncogenes or tumor suppressor genes pertinent to the
      origins of this type of ocular tumor. CLINICAL RELEVANCE: New immunotherapies
      have been devised for the treatment of cancer based on the expression of TF.
      Similar approaches may be effective in treating uveal melanoma.

PMID- 12470150
TI  - Lens aging in relation to nutritional determinants and possible risk factors for
      age-related cataract.
AB  - OBJECTIVE: To investigate whether nutritional factors and possible risk factors
      for cataract influence the lens optical density (LOD). DESIGN: Three hundred
      seventy-six subjects, aged 18 to 75 years, were recruited. In a cross-sectional
      design, serum was analyzed for lutein, zeaxanthin, vitamin C, alpha-tocopherol,
      and cholesterol levels. Adipose tissue (n = 187) was analyzed for lutein level.
      The LOD and the macular pigment optical density (MPOD) were measured by spectral
      fundus reflectance. RESULTS: The mean +/- SD LOD at 420 nm was 0.52 +/- 0.17. It
      showed a significant association with age (beta =.008, P<001) and MPOD (beta = 
      .096, P =.02). For subjects 50 years and younger (mean +/- SD LOD, 0.45 +/-
      0.11), we found only a single significant beta coefficient, for age (beta =.006,
      P<.001). For subjects older than 50 years (mean +/- SD LOD, 0.68 +/- 0.16), we
      found significant beta coefficients for age (beta =.011, P<.001) and MPOD (beta =
      -.240, P =.005). Controlling for age, we found no associations between LOD and
      other possible risk factors for age-related cataract or serum or adipose tissue
      concentrations of carotenoids, vitamin C, and alpha-tocopherol. CONCLUSIONS:
      Macular pigment is composed of lutein and zeaxanthin, the only carotenoids found
      in human lenses. The inverse relationship between LOD and MPOD suggests that
      lutein and zeaxanthin may retard aging of the lens.

PMID- 12470151
TI  - Now we number 33: women in ophthalmology at the Massachusetts Eye and Ear
      Infirmary in 2002.

PMID- 12470152
TI  - Clinicopathologic reports, case reports, and small case series: acute myeloid
      leukemia manifesting initially as a conjunctival mass in a patient with acquired
      immunodeficiency syndrome.

PMID- 12470153
TI  - In vivo confocal microscopy of the cornea in nephropathic cystinosis.

PMID- 12470154
TI  - Lymphoepithelial carcinoma of the lacrimal gland.

PMID- 12470155
TI  - Diffuse hyperplasia of intratarsal ectopic lacrimal gland tissue.

PMID- 12470156
TI  - Idiopathic central retinal vein occlusion in 2 siblings with the 20210 G-->A
      prothrombin variant.

PMID- 12470157
TI  - Endogenous fungal retinitis in a patient with acute lymphocytic leukemia
      manifesting as uveitis and optic nerve lesion.

PMID- 12470158
TI  - Bilateral multifocal chorioretinopathy in a woman with cutaneous malignant
      melanoma.

PMID- 12470159
TI  - Photodynamic therapy in adult-onset vitelliform macular dystrophy misdiagnosed as
      choroidal neovascularization.

PMID- 12470160
TI  - Nodular scleritis in a patient with pyoderma gangrenosum.

PMID- 12470161
TI  - Active spontaneous bleeding from optic disc neovascularization during fluorescein
      angiography.

PMID- 12470162
TI  - Intraorbital epithelial cyst formation: a rare complication of silastic
      implantation.

PMID- 12470163
TI  - Delayed orbital foreign body reaction to dicotyledon (hardwood) libriform fibers.

PMID- 12470164
TI  - Papillorenal syndrome in a Brazilian family.

PMID- 12470166
TI  - Bilateral sporadic retinoblastoma in a child born after in vitro fertilization.

PMID- 12470168
TI  - Screening for pineoblastoma in patients with retinoblastoma.

PMID- 12470170
TI  - Ciliochoroidal effusion syndrome induced by sulfa derivatives.

PMID- 12470171
TI  - Pain management: a call for papers.

PMID- 12470172
TI  - Efficacy of carotid endarterectomy translates to being efficacious with
      appropriate surgical skill.

PMID- 12470173
TI  - Nonocclusion and spontaneous recanalization rates in acute ischemic stroke: a
      review of cerebral angiography studies.
AB  - BACKGROUND: Spontaneous recanalization is an understudied phenomenon in stroke.
      It is often overestimated by nonocclusion rates. The heterogeneity of the causes
      and manifestations of stroke and of the studies assessing vascular patency has
      created difficulties in assigning accurate rates of its incidence. METHODS:
      Systematic review of published articles about cerebral angiography in stroke.
      RESULTS: Lack of anticipated occlusions (nonocclusion rates) was noted in 28% of
      patients in suspected vessels 6 hours after stroke onset, whereas documented
      occlusions were noted in 17% of patients who underwent spontaneous lysis at 6 to
      8 hours. At 3 to 4 days, the nonocclusion rate was 50% of studied vessels.
      CONCLUSIONS: In the first 6 to 8 hours from stroke onset, spontaneous
      recanalization occurs in approximately 17% of patients, whereas nonocclusion
      exists in about 28% of patients and up to 50% by 4 days after stroke.

PMID- 12470174
TI  - Hospital and surgeon determinants of carotid endarterectomy outcomes.
AB  - BACKGROUND: Prior studies have found associations between surgeon and hospital
      case volumes and outcomes after carotid endarterectomy (CEA), but they have not
      simultaneously assessed the importance of a number of surgeon and hospital
      characteristics. OBJECTIVE: To simultaneously assess associations between
      hospital case volume, teaching status, clinical trial participation, and surgeon
      specialty and case volume and the outcome after CEA. DESIGN: Analysis of a large
      administrative data-base using logistic regression to correlate adverse outcomes
      after CEA with surgeon and hospital characteristics. SETTING AND PATIENTS: A
      Canadian administrative hospital discharge database of all patients undergoing
      CEA in fiscal years 1994 through 1997. MAIN OUTCOME MEASURES: In-hospital stroke
      and/or death. RESULTS: We found an inverse relationship between both hospital and
      surgeon case volumes and adverse outcomes. Teaching status had no association
      with outcome, but previous clinical trial participation predicted a better
      outcome. General surgeons fared worse than other specialists. Low-volume surgeons
      in low-volume hospitals had a relative risk of 3.5 for adverse outcomes compared
      with high-volume surgeons in high-volume hospitals. CONCLUSIONS: Several
      physician and hospital characteristics are determinants of outcome after CEA, but
      the negative effects of low hospital and surgeon case volumes, in particular,
      suggest that regionalization should be considered for CEA and that surgeons with
      low case volumes should not be performing CEA.

PMID- 12470175
TI  - In vivo hippocampal metabolic dysfunction in human temporal lobe epilepsy.
AB  - BACKGROUND: The nature of functional metabolic disturbances in mesial temporal
      lobe epilepsy remains unclear. OBJECTIVES: To compare in vivo measures of
      hippocampal metabolic abnormalities in mesial temporal lobe epilepsy, as acquired
      with fludeoxyglucose F 18 positron emission tomography and proton magnetic
      resonance spectroscopic imaging, and to determine the relationship between N
      acetylaspartate (NAA) disturbances and well-established derangements of glucose
      metabolism. DESIGN: Measures of hippocampal glucose metabolism from
      fludeoxyglucose F 18 positron emission tomography were normalized to whole brain
      counts to provide a glucose uptake metabolic index. Proton magnetic resonance
      spectroscopic imaging was performed at 4.1 T, and measures of creatinine/NAA
      ratio were made from mostly hippocampal-only voxels. Direct comparisons and
      correlation analysis of measures were performed. SETTING: Presurgical evaluations
      for treatment of intractable epilepsy. PATIENTS: Twenty-nine patients between
      July 1994 and June 1996 who were candidates for anterior-medial temporal
      lobectomy at the epilepsy centers of the University of Alabama at Birmingham and
      Vanderbilt University schools of medicine were studied. RESULTS: The mean
      ipsilateral hippocampal glucose metabolic index (0.85) was normal, while the
      contralateral metabolic index (0.95) was nearly significant for an abnormally
      elevated measure. The mean ipsilateral hippocampal creatinine/NAA (1.26) was
      abnormally elevated; the mean contralateral creatinine/NAA (0.88) was normal.
      Hippocampal glucose and creatinine/NAA measures did not correlate; asymmetry
      measures also did not correlate. CONCLUSIONS: Hippocampal metabolic disturbances
      in mesial temporal lobe epilepsy as measured by fludeoxyglucose F 18 positron
      emission tomography vs proton magnetic resonance spectroscopic imaging reflect
      different mechanisms of biochemical dysfunction. This lack of correlation is
      hypothesized to reflect a differential effect of varying degrees of disturbed
      cellular energy metabolism on mechanisms of glucose use and biosynthesis of NAA.

PMID- 12470176
TI  - Magnetic resonance imaging evidence of hippocampal sclerosis in asymptomatic,
      first-degree relatives of patients with familial mesial temporal lobe epilepsy.
AB  - OBJECTIVE: To investigate the presence of hippocampal atrophy (HA) and other
      magnetic resonance imaging (MRI) signs of hippocampal sclerosis (HS) in
      asymptomatic relatives of patients with familial mesial temporal lobe epilepsy
      (FMTLE). METHODS: We invited first-degree, asymptomatic relatives of patients
      with FMTLE to participate in our MRI protocol. After obtaining informed consent,
      all participating individuals underwent an MRI examination. Hippocampal
      abnormality was determined by qualitative and volumetric analyses, using a
      standard protocol. RESULTS: We studied 52 asymptomatic individuals (27 men), with
      a mean age of 32 years (range, 7-71 years), from 11 families with FMTLE.
      Volumetric studies showed HA in 18 (34%) of 52 individuals: 11 had left HA and 7
      had bilateral HA. In addition, careful visual analysis of T1- and T2-weighted
      images showed additional classic MRI signs of HS (such as abnormal T2 signal
      and/or abnormal internal structure) in 14 of these 18 individuals. There was no
      age difference between individuals with and without HA (t test, P =.80).
      CONCLUSIONS: Our findings indicate that MRI evidence of HS is not necessarily
      related to seizure severity and may occur in individuals who never had seizures.
      In addition, these observations strongly indicate that HS in FMTLE is not a
      consequence of recurrent seizures and is determined by a strong genetic
      predisposition. The determination of seizure severity in patients with FMTLE
      probably depends on the interaction of different factors, both genetic and
      environmental.

PMID- 12470177
TI  - Risk to verbal memory following anterior temporal lobectomy in patients with
      severe left-sided hippocampal sclerosis.
AB  - BACKGROUND: Previous investigations indicate low risk for memory loss following
      anterior temporal lobectomy (ATL) in patients with severe hippocampal sclerosis
      (HS) compared with patients with mild HS. However, these conclusions have been
      established primarily with group-level analyses. OBJECTIVE: To investigate
      individual base rate risk for verbal memory loss following ATL in patients who
      have pathologically verified mild, moderate, or severe HS. PATIENTS AND METHODS:
      One hundred fifteen patients with unilateral temporal lobe epilepsy (68 with left
      sided and 47 with right-sided epilepsy) were included. Acquisition, retrieval,
      and recognition components of verbal memory, as measured by the California Verbal
      Learning Test, were assessed before and after ATL. Postoperatively, the degree of
      neuronal loss and reactive gliosis of the hippocampus was assessed via a 3-tiered
      rating system establishing mild, moderate, and severe pathologic features.
      Patients with preoperative magnetic resonance imaging-based evidence of lesions
      outside the mesial temporal area (side of surgical resection) were excluded.
      RESULTS: Neither seizure laterality nor severity of HS was associated with
      preoperative verbal memory performance. Postoperatively, the left-sided ATL group
      demonstrated significant decline across the acquisition (P<.01), retrival
      (P<.001), and recognition (P<.001) verbal memory components compared with the
      right-sided ATL group. Patients who underwent left-sided ATL and had mild HS
      displayed the largest magnitude and percentage proportion of postoperative
      decline across all verbal memory components. However, 28 (48%) of the 58 patients
      who underwent left-sided ATL and who had moderate and severe HS displayed
      statistically reliable declines on retrieval aspects of verbal memory. Most
      patients undergoing right-sided ATL, regardless of the extent of hippocampal
      pathologic features, displayed no postoperative memory change. CONCLUSIONS:
      Substantial individual heterogeneity of memory outcome exists across groups of
      patients undergoing ATL, with various degrees of pathologically verified HS.
      Patients undergoing left-sided ATL who have mild HS seem at greatest risk for
      broad-spectrum verbal memory decline. However, when examining outcome on a
      patient-by-patient basis, many patients undergoing left-sided ATL who have
      moderate to severe HS were also vulnerable to verbal memory loss. This risk seems
      selective to a retrieval-based aspect of verbal memory.

PMID- 12470178
TI  - Levetiracetam may be more effective for late-onset partial epilepsy.
AB  - BACKGROUND: Many agents are available for treating epilepsy; however, population
      studies have failed to show overall differences in efficacy for a given seizure
      type. Clinical experience suggests that certain individuals will respond to a
      given agent while others with the same seizure type will not. OBJECTIVES: To
      examine a population of patients who received one of the newer antiepileptic
      drugs, levetiracetam, and to identify those who had either a dramatic improvement
      or a significant worsening of seizures. METHODS: Retrospective medical record
      review of patients with refractory epilepsy. RESULTS: Patients who responded well
      to levetiracetam therapy were older at the onset of epileptic seizure than those
      who did not (mean [SD] age, 51 [5] vs 27 [3] years; P<.05). This was also true of
      the subset of patients who had localization-related epilepsy. Patients with
      temporal lobe onset were likely to do well whereas patients with frontal lobe
      onset were not. CONCLUSIONS: These results suggest that certain subpopulations
      may be particularly likely to respond to levetiracetam therapy. These need to be
      confirmed in a larger prospective trial; however, looking for specific
      characteristics of patients who respond to certain drugs may lead to useful
      guidelines for drug choices in treating epilepsy.

PMID- 12470179
TI  - Effect of levetiracetam on rapid motor learning in humans.
AB  - BACKGROUND: The human motor cortex (M1) has a role in motor learning.
      Antiepileptic drugs that suppress M1 excitability may affect learning, presumably
      by inhibiting long-term potentiation. Levetiracetam, a new antiepileptic drug
      with a unique preclinical profile, also suppresses M1 excitability, but in a way
      that is different from other antiepileptic drugs. The effect of levetiracetam on
      motor learning has yet to be addressed. OBJECTIVE: To investigate whether
      levetiracetam alters rapid motor learning in humans. METHODS: We measured pinch
      force and acceleration and motor excitability before and after 30 minutes of
      pinch practice at 0.5 Hz in 10 healthy volunteers. Either 3000 mg of
      levetiracetam or placebo was administered 1 hour before the experiment. RESULTS:
      After practice, pinch acceleration was significantly increased with placebo, but
      not with levetiracetam. All other measures showed no significant change.
      CONCLUSION: Levetiracetam interferes with rapid motor learning; this is
      consistent with a negative influence on long-term potentiation.

PMID- 12470180
TI  - Rectal diazepam gel for treatment of acute repetitive seizures in adults.
AB  - OBJECTIVE: To evaluate the efficacy and tolerability of diazepam (DZP) rectal gel
      (Diastat; Elan Pharmaceuticals, Dublin, Ireland) for the treatment of acute
      repetitive seizures in adult patients in 2 multicenter, double-blind, placebo
      controlled parallel studies. METHODS: Ninety-six adults 18 years or older with
      acute repetitive seizures, 70 of whom received treatment, were randomized into
      the 2 studies. Active and placebo medications were supplied in prefilled,
      identical-appearing delivery systems. In study 001, patients received a second
      dose 4 hours after the initial treatment. Patients in study 003 received only 1
      treatment. Patients were observed for 12 hours after the first dose. RESULTS:
      There was a significant reduction in seizure frequency in patients who received
      DZP compared with the placebo group. The median number of seizures per hour in
      the group treated with DZP rectal gel was 0.00, vs 0.13 in the placebo group (P
      =.002). In addition, significantly more DZP rectal gel-treated patients remained
      seizure-free during the 12-hour observation period (71% [22/31] vs 28% [11/39]).
      Using Kaplan-Meier life-table analysis, time to the next seizure was found to be
      significantly longer in DZP rectal gel-treated than placebo-treated patients
      (P<.001). Global assessment as provided by the caregivers was in favor of DZP
      rectal gel for both study 001 (P =.17) and study 003 (P =.02). Dizziness and
      somnolence were the only central nervous system adverse events that occurred more
      frequently in patients receiving DZP rectal gel than in those receiving placebo.
      CONCLUSION: In adults, rectal DZP formulated as Diastat significantly reduced the
      likelihood of seizure recurrence during an episode of acute repetitive seizures,
      with minimal safety concerns.

PMID- 12470181
TI  - X-linked bulbospinal neuronopathy: Kennedy disease.
AB  - OBJECTIVE: To characterize the earliest symptoms of X-linked bulbospinal
      neuronopathy (Kennedy disease [KD]) during the course of the disease, including a
      definition of the age of onset. METHODS: We describe the earliest symptoms, signs
      on clinical investigation, electrophysiological and muscle biopsy specimen
      findings, and creatine kinase levels in 34 patients with KD. Correlations were
      made among the CAG-repeat length and clinical symptoms, age at onset, and the
      presence of electrophysiological and laboratory findings. RESULTS: Our findings
      indicate that the age at onset of KD is in adolescence which is earlier than
      previously thought. Most frequently early symptoms are gynecomastia, muscle pain,
      and premature muscular exhaustion. Weakness is not a typical initial symptom and
      is frequently found in distal limbs if present early. We found a correlation
      between the of number of CAG repeats and the age at onset of weakness but not to
      the age at onset of KD. Furthermore, no correlations were found between the
      occurrence of gynecomastia, tremor, increased creatine kinase levels, and
      additional myopathic changes in muscle biopsy specimens. CONCLUSIONS: Our data
      show that KD is a multisystem disorder with onset in adolescence. Because of the
      heterogeneity of clinical presentation and no correlation between the number of
      CAG repeats and most of the clinical hallmarks of KD, we suggest that other
      environmental or genetic factors contribute to the manifestation of specific
      organ systems in KD.

PMID- 12470182
TI  - Progressive multifocal leukoencephalopathy and apoptosis of infected
      oligodendrocytes in the central nervous system of patients with and without AIDS.
AB  - CONTEXT: Progressive multifocal leukoencephalopathy (PML) is a demyelinating
      disease of the central nervous system (CNS) caused by JC virus (JCV) that occurs
      in immunocompromised patients. Demyelination of the CNS is a consequence of virus
      induced killing of oligodendrocytes, although the exact mechanism of cell death
      is unknown. OBJECTIVE: To examine archival autopsy and surgical pathologic
      specimens from 8 patients with PML, including 6 patients with human
      immunodeficiency virus (HIV)-associated PML and 2 patients with non-HIV
      associated PML, for evidence of apoptosis. DESIGN: Apoptotic cells were
      identified by TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine
      triphosphate nick end in situ labeling) or immunohistochemical detection of
      activated caspase 3. The JCV-infected cells were identified by in situ
      hybridization for viral transcripts or immunohistochemical analysis for JCV T
      antigen. RESULTS: Apoptosis of JCV-infected oligodendrocyte apoptosis was a
      prominent feature in all cases of both HIV- and non-HIV-associated PML. There
      were no differences between number or distribution of apoptotic cells identified
      by TUNEL or immunohistochemical analysis for activated caspase 3. Bizarre
      astrocytes were occasionally positive for JCV but were not apoptotic. Neurons,
      astrocytes, macrophages, and oligodendrocytes remote from lesions were neither
      apoptotic nor JCV infected. CONCLUSIONS: Our study demonstrates that apoptosis
      occurs in oligodendrocytes associated with demyelinated lesions of patients with
      both HIV-associated and non-HIV-associated PML. There were no differences in
      degree, location, or type of infected or apoptotic cells between patients with
      HIV-associated and non-HIV-associated PML. The extent of apoptosis did not
      correlate with the presence or intensity of host inflammatory response.
      Accumulation of viral particles in nuclei of infected cells made it difficult to
      identify morphologic changes in the nucleus typically associated with apoptosis.

PMID- 12470183
TI  - A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study.
AB  - CONTEXT: Monotherapy with rasagiline mesylate may be useful in early Parkinson
      disease (PD). OBJECTIVE: To evaluate the safety and efficacy of the selective
      monoamine oxidase type B inhibitor rasagiline. DESIGN: Multicenter, 26-week,
      parallel-group, randomized, double-blind, placebo-controlled clinical trial.
      SETTING: Academically based movement disorders clinics. PATIENTS: Patients with
      early PD not requiring dopaminergic therapy (n = 404). INTERVENTION: Research
      participants were randomized to rasagiline mesylate at dosages of 1 mg or 2 mg
      per day or matching placebo. A 1-week escalation period was followed by a 25-week
      maintenance period. MAIN OUTCOME MEASURE: The primary prespecified measure of
      efficacy was the change in the total Unified Parkinson's Disease Rating Scal
      score between baseline and 26 weeks of treatment, comparing each active treatment
      group with the placebo group. RESULTS: Monotherapy with rasagiline was effective
      in this 26-week study. The adjusted effect size for the total Unified Parkinson's
      Disease Rating Scale was -4.20 units comparing 1 mg of rasagiline and placebo
      (95% confidence interval, -5.66 to -2.73 units; P<.001) and -3.56 units comparing
      a 2-mg dosage and placebo (95% confidence interval, -5.04 to -2.08 units;
      P<.001). There were no meaningful differences in the frequency of adverse events
      or premature withdrawals among the treatment groups. CONCLUSIONS: Rasagiline is
      effective as monotherapy for patients with early PD. The 2 dosages in this trial
      were both effective relative to placebo. Further study is warranted to evaluate
      the longer-term effects of rasagiline in PD.

PMID- 12470184
TI  - Spinocerebellar ataxia in monozygotic twins.
AB  - CONTEXT: Although phenotypic heterogeneity in autosomal dominant spinocerebellar
      ataxia (SCA) has been explained in part by genotypic heterogeneity, clinical
      observations suggest the influence of additional factors. OBJECTIVES: To
      demonstrate, quantitate, and localize physiologic abnormalities attributable to
      nongenetic factors in the development of hereditary SCA. DESIGN: Quantitative
      assessments of ocular motor function and postural control in 2 sets of identical
      twins, one with SCA type 2 and the other with episodic ataxia type 2. SETTING:
      University laboratory. MAIN OUTCOME MEASURES: Saccadic velocity and amplitude,
      pursuit gain, and dynamic posturography. RESULTS: We found significant
      differences in saccade velocity, saccade metrics, and postural stability between
      each monozygotic twin. The differences point to differential involvement between
      twins of discrete regions in the cerebellum and brainstem. CONCLUSIONS: These
      results demonstrate the presence of quantitative differences in the severity,
      rate of progression, and regional central nervous system involvement in
      monozygotic twins with SCA that must be owing to the existence of nongermline or
      external factors.

PMID- 12470185
TI  - A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency
      ataxia.
AB  - BACKGROUND: Ataxia with vitamin E deficiency is a recessive autosomal
      neurodegenerative disorder resembling the Friedreich ataxia phenotype but is due
      to mutations in the alpha-tocopherol transfer protein (TTPA) gene. In a recent
      article, we described a patient with ataxia carrying reduced serum vitamin E
      levels and showing CTA/CTG expansions of 320 triplet repeats in the SCA8 gene.
      OBJECTIVES: To perform a screening of the TTPA gene in the patient and to
      evaluate the effects of treatment with vitamin E on the patient's neurologic
      disturbances. PATIENT AND METHODS: We performed a single-strand conformation
      polymorphism and nucleotide sequence analysis of the 5 exons of the TTPA gene in
      the patient's family members. RESULTS: The results indicated the patient to be a
      compound heterozygote for 2 mutations (in exon 3), each transmitted by one of the
      2 parents, yielding a nonfunctional protein. CONCLUSIONS: We describe for the
      first time, to our knowledge, a mutated form of the TTPA gene in a patient also
      carrying an expansion in the SCA8 gene. The lack of improvement in the patient's
      symptoms on supplementation with alpha-tocopherol suggests that the SCA8
      mutations may act in the neurodegeneration process, worsening the neurologic
      signs caused by the vitamin E deficit, and it could be speculated that the co
      occurrence of mutant alleles for 2 distinct loci may influence the clinical
      course of the disease.

PMID- 12470186
TI  - Familial Kleine-Levin syndrome: two siblings with unusually long hypersomnic
      spells.
AB  - Kleine-Levin syndrome is a rare, sporadic disorder, with discrete spells of
      hypersomnolence occurring during adolescence, variously accompanied by
      megaphagia, behavioral changes, psychosis, and mild autonomic symptoms. Familial
      cases have not previously been reported. We describe 2 siblings who shared
      uncharacteristically prolonged episodes of hypersomnolence, and the HLA-DR2
      haplotype. In one patient, levels of cerebrospinal fluid orexin (hypocretin)
      during an attack were normal. The presence of an increased sleep drive, despite
      the occurrence of large amounts of ostensibly restorative sleep, suggests the
      possible existence of a disorder of sleep satiety.

PMID- 12470187
TI  - Pituitary metastasis.

PMID- 12470188
TI  - Influence of early printmaking on the development of neuroanatomy and neurology.

PMID- 12470189
TI  - 18F-Dopa vs dopamine transporter ligands in positron emission tomographic and
      single-photon emission computed tomographic scans for Parkinson disease.

PMID- 12470191
TI  - A null mutation in the CNTF gene is not associated with early onset of multiple
      sclerosis.

PMID- 12470193
TI  - Cerebrotendinous xanthomatosis: juvenile cataract and chronic diarrhea before the
      onset of neurologic disease.

PMID- 12470194
TI  - Mitochondrial membrane potential in cardiac myocytes.
AB  - Mitochondria are involved in cellular functions that transcend the traditional
      role of these organelles as the energy factory of the cell. Their relative
      inaccessibility and the difficulties involved in attempts to study them in their
      natural environment -- the cytosol -- has delayed much of this understanding and
      they still have many secrets to yield. One of the relatively new fields in this
      respect is undoubtedly the analysis of mitochondrial membrane potential. The
      realization that its alteration may have important pathophysiological
      consequences has led to an increased interest in measuring this variable in a
      variety of biological settings, including cardiovascular diseases. Measurements
      of mitochondrial membrane potential tell us much about the role of mitochondria
      in normal cell function and in processes leading to cell death. However, we must
      be aware of the limitations of using isolated mitochondria, single cells and
      different fluorescent indicators.

PMID- 12470195
TI  - Ghrelin -- a new endogenous growth hormone secretagogue.
AB  - Ghrelin is a new endogenous peptide, discovered in 1999 by Kojima et al., as the
      result of a search for an endogenous ligand for an orphan receptor of known
      structure and function. Ghrelin is composed of 28 amino acids and is produced
      mostly by cells of the stomach, hypothalamus, and hypophysis, but it has also
      been detected in other tissues. Its discovery is related to the development of a
      new hypothesis regarding the regulation of growth hormone secretion. It is an
      antagonist of somatostatin. Ghrelin activates the release of growth hormone from
      the somatotrophic cells of the hypophysis. It participates in the regulation of
      energy homeostasis, increases food intake, decreases energy output and exerts a
      lipogenetic effect. Its metabolic effects do not depend on the GH/IGF-I system,
      but are mediated by the NPY/Y1 and AGRP receptor system. Ghrelin influences the
      secretion and motility of the gastrointestinal tract, especially the stomach. The
      presence of ghrelin and its receptors has also been demonstrated in many other
      tissues. Its function in these tissues has not yet been studied, thus providing
      many possibilities for further research.

PMID- 12470196
TI  - Cardiac troponin T following repeated administration of pyridoxal isonicotinoyl
      hydrazone in rabbits.
AB  - Pyridoxal isonicotinoyl hydrazone (PIH) is a new tridentate Fe-chelating agent
      that should be very promising in many pathological states resulting from both an
      iron-overload and formation of free radicals. The aim of our study was to
      investigate the effect of PIH on the cardiovascular system focusing to the
      regulatory protein -- cardiac troponin T (cTnT). The study was carried out in two
      groups of Chinchilla male rabbits: 1) PIH (50 mg/kg dissolved in 10 % Cremophor
      i.p., once a week, 10 administrations, n=8) and 2) Cremophor (2 ml/kg i.p. in the
      same schedule, n=7). Plasma concentrations of cTnT (as a marker of myocardial
      damage) were measured using a commercial kit (Roche). cTnT was within the
      physiological range (i.e. < 0.1 microg/l) during the whole experiment in the
      Cremophor group. In the PIH group, the cTnT levels were not significantly
      increased when compared with the control group or with the initial values (except
      with those before the 5th administration). Furthermore, we analyzed the cytosolic
      and myofibrillar fraction of cTnT in the left ventricular myocardium. Using SDS
      PAGE and Western blot we resolved three isoforms. The profiling of TnT did not
      differ significantly between the PIH-treated group and the Cremophor-treated
      group. Our data concerning cTnT support the opinion that the possible
      cardiotoxicity of PIH is very low.

PMID- 12470197
TI  - Antibodies against beta 2-glycoprotein I (beta 2-GP I) and their relationship to
      fetoplacental antigens.
AB  - Binding of beta 2-GP I to anionic phospholipids is thought to be the major
      antigen required in the reaction of anticardiolipin antibodies to phospholipids.
      The aim of this study was to investigate the changes of anti-beta 2-GP I IgG
      during the first and second trimester of pregnancy and the relationship between
      the levels of anti-beta 2-GP I and fetoplacental antigens and the correlation
      between anti-beta 2-GP I IgG and antibodies against oxidized low-density
      lipoprotein IgG (oLAb) in serum of pregnant women. We determined anticardiolipin
      antibodies (ACA) IgG and maternal serum levels of alpha 1-fetoprotein (AFP),
      human chorionic gonadotrophin (HCG) and trophoblast-specific beta 1-glycoprotein
      (SP1) in 204 pregnant women in the first and second trimester. From this group we
      selected 52 serum samples positive for ACA IgG and 16 samples negative for ACA
      IgG. In the samples of selected patients, the levels of anti-beta 2-GP I IgG and
      oLAb IgG were determined. Anti-beta 2-GP I IgG levels significantly decreased in
      the second trimester (6.2+/-9.3 U/ml, mean +/- S.D.) in comparison with the first
      trimester (8.3+/-10.4 U/ml) (p=0.05). Multiple of median (MoM) AFP correlated
      negatively but not significantly in the first trimester with anti-beta 2-GP I (r
      = -0.261, p = 0.12). In the second trimester this correlation was significantly
      negative (r = -0.278, p = 0.04). The Spearman correlation coefficients for MoM
      HCG and anti-beta 2-GP I were 0.158 for the first trimester and 0.174 for the
      second trimester. MoM SP1 also did not correlate significantly with anti-beta 2
      GP I in both trimesters. The correlation between anti-beta 2-GP I IgG and oLAb
      IgG was not significant (r = -0.06). In the first trimester 40 % serum samples
      were positive for anti-beta 2-GP I IgG and negative for oLAb IgG or vice versa,
      while 60 % samples in the second trimester were positive only for one determined
      autoantibody. We can conclude that the levels of anti-beta 2-GP I IgG decrease
      during the second trimester probably as the result of the effects of some
      immunosuppressive agents associated with pregnancy. The finding of negative
      correlation between AFP and anti-beta 2-GP I suggests that anti-beta 2-GP I has
      an influence on fetus development.

PMID- 12470198
TI  - Serum ex vivo lipoprotein oxidizability in patients with ischemic heart disease
      supplemented with vitamin E.
AB  - The decreased oxidizability of plasma lipoproteins is related to the increased
      vitamin E intake and its association with a relatively lower incidence of
      coronary heart disease has been proposed. We investigated the effect of the in
      vivo vitamin E supplementation on the oxidizability of serum lipids in patients
      with ischemic heart disease and a moderate hypercholesterolemia. Thirty-two
      patients (16 males and 16 postmenopausal women) participated in this placebo
      controlled, randomized trial. They were treated with 400 mg vitamin E/day for 6
      weeks. The copper-induced serum lipid oxidizability ex vivo was assessed by
      measuring conjugated diene formation at 245 nm. We also measured vitamin E,
      malondialdehyde (MDA) and uric acid concentrations in the plasma. Because of
      observed significant differences in parameters of serum lipid oxidizability (lag
      time and maximal rate of oxidation), plasma alpha-tocopherol and MDA levels
      between male patients and postmenopausal women supplemented with vitamin E, the
      results were compared between both genders. Six weeks of vitamin E
      supplementation significantly increased plasma vitamin E levels (by 87 %) in male
      patients but in postmenopausal women only by 34 %. Concomitantly with increased
      plasma levels of vitamin E the decrease in plasma MDA levels was observed in male
      patients (decrease by 20 %; p=0.008), but in postmenopausal women the decrease
      did not attain statistical significance. Plasma uric acid levels were not
      apparently changed in placebo or vitamin E supplemented groups of patients. The
      changes in ex vivo serum lipid oxidizability after vitamin E, supplementation
      have shown a significantly prolonged lag time (by 11 %; p=0.048) and lowered rate
      of lipid oxidation (by 21 %; p=0.004) in male patients in comparison with
      postmenopausal women. Linear regression analysis revealed a significant
      correlation between plasma vitamin E levels and the lag time (r=0.77; p=0.03) and
      the maximal rate of serum lipid oxidation (r=-0.70; p=0.05) in male patients.
      However, in postmenopausal women the correlations were not significant. We
      conclude that 400 mg vitamin E/day supplementation in patients with ischemic
      heart disease and a moderate hypercholesterolemia influenced favorably ex vivo
      serum lipid oxidation of male patients when compared with postmenopausal women.
      The observed differences between both genders could be useful in the selection of
      the effective vitamin E doses in the prevention of coronary heart disease.

PMID- 12470199
TI  - Cardiovascular system of offsprings of hypertensive rats with defective nitric
      oxide production.
AB  - The question was addressed of how nitric oxide synthase (NO synthase) inhibition
      induced hypertension in rat parents would affect the cardiovascular system in
      their offsprings. Two experimental groups were set up: Group I -- offsprings of
      parents who had both been administered NO synthase inhibitor L-nitro-arginine
      methyl ester (L-NAME 40 mg/kg/day) for 5 weeks, the treatment of dams continued
      till week 12. Group II -- offsprings fed by dams administered L-NAME after
      delivery only for a period of 4 weeks. Control age-matched offsprings formed the
      third group. Blood pressure and heart rate in parents and in 3-week-old
      offsprings were determined noninvasively. In the offsprings, body and heart
      weight were measured and the heart/body weight ratio (HW/BW) was calculated. The
      NO synthase activity, and also ornithine decarboxylase activity as a marker of
      polyamine production, were determined in the heart. The acetylcholine-induced
      relaxation of aortic rings was also followed. A marked blood pressure increase
      with a tendency to a decreased heart rate was found in the offsprings of Group I.
      A significant decrease in heart weight and body weight with a decreased HW/BW
      ratio indicated cardiac hypotrophy that contrasted with the decrease in NO
      synthase activity and increase in ornithine decarboxylase activity in the heart.
      Noteworthy was also the finding of completely preserved relaxation of the aorta
      to acetylcholine. Offsprings of Group II were similarly characterized by
      significantly higher blood pressure, a tendency to decreased heart rate, a
      decrease in heart weight, but not of the HW/BW ratio. The contrasting findings of
      heart weight decrease on the one hand and NO synthase activity decrease and
      ornithine decarboxylase increase on the other, were also found in this group.
      Full relaxation of the aorta to acetylcholine was preserved. It can be concluded
      that remarkable alterations in the cardiovascular system were found in offsprings
      of hypertensive NO compromised parents.

PMID- 12470200
TI  - Changes of sodium and ATP affinities of the renal Na,K-ATPase during and after
      nitric oxide-deficient hypertension.
AB  - The aim of this study was to assess the molecular basis of renal Na,K-ATPase
      disturbances in response to NO-deficient hypertension induced in rats by NO
      synthase inhibition with 40 mg/kg/day N(G)-nitro-L-arginine methyl ester (L-NAME)
      for four weeks. After 4-week administration of L-NAME, the systolic blood
      pressure (SBP) increased by 30 %. Three weeks after terminating the treatment,
      SBP recovered to control value. When activating the Na,K-ATPase with its
      substrate ATP, a 36 % increase in K(m) and 29 % decrease in V(max) values were
      observed in NO-deficient rats. During activation with Na+, the V(max) was
      decreased by 20 % and the K(Na) was increased by 111 %, indicating a profound
      decrease in the affinity of the Na+-binding site in NO-deficient rats. After
      spontaneous recovery from hypertension, the V(max) remained at the level as in
      hypertension for both types of enzyme activation. However, in the presence of
      lower concentrations of substrate which are of physiological relevance an
      improvement of the enzyme activity was observed as documented by return of K(m)
      for ATP to control value. The K(Na) value for Na+ was decreased by 27 % as
      compared to hypertension, but still exceeded the corresponding value in the
      control group by 55 % thus resulting in a partial restoration of Na+ affinity of
      Na,K-ATPase which was depressed as a consequence of NO-dependent hypertension.

PMID- 12470201
TI  - Regulation of Na+/H+ exchanger by urogastrone, a potent activator of cell
      proliferation.
AB  - We tested the effects of epidermal growth factor (EGF) on Na+/H+ exchanger (NHE)
      activity using urogastrone for treatment of Wistar rats and rat kidney tissue
      slices. NHE activity was monitored in isolated kidney brush border membrane
      vesicles by following fluorescence quenching of acridine orange. A significant
      increase of NHE activity was detected as early as 5 min after addition of
      urogastrone to rat kidney slices in vitro. In Wistar rats treated with
      urogastrone we also found increased NHE activity (by about 12 %). Both changes of
      NHE activity were the result of a significant rise of V(max) value and an
      apparent decrease in K(m) value in in vitro experiments. The rise of NHE activity
      caused by urogastrone was sensitive to the inhibitors of transcription and
      translation. The presence of phosphatase inhibitor, NaF, elevated NHE activity of
      non-stimulated as well as of urogastrone-stimulated exchanger, suggesting that
      phosphorylation plays an important role in Na+/H+ exchange. Osmolarity of the
      medium seems to regulate NHE activity in such a manner that both hyper- and
      hypoosmolar conditions inhibited NHE activity. The absence of Ca2+ ions produced
      a 60 % decrease of NHE activity. The chemical modification of histidine residues
      with diethyl pyrocarbonate or SH groups with N-ethylmaleimide inhibited NHE
      activity.

PMID- 12470202
TI  - Lidocaine-containing Euro-Collins solution prevents renal injury in the isolated
      perfused canine kidney exposed to prolonged cold ischemia.
AB  - Previous studies have reported a decreased incidence of delayed graft function
      after cadaveric transplantation with the use of lidocaine pretreatment of the
      donor. We evaluated the effects of lidocaine on prolonged cold ischemia and
      reperfusion injury in a canine model of isolated kidney perfusion (IPK). The
      purpose of this study was to evaluate the renal function of isolated perfused
      canine kidneys after 48 h of cold storage with Euro-Collins (EC) solution or EC
      solution plus lidocaine. Isolated perfused canine kidneys were randomized into
      four groups which contained six kidneys: I) cold flush with EC solution and
      immediately reperfused, II) cold flush with EC solution plus lidocaine and
      immediately reperfused, III) 48 h of cold storage with EC and reperfusion, IV) 48
      h of cold storage with EC solution plus lidocaine and reperfusion. The measured
      renal functions were glomerular filtration rate, urine production, perfusate
      flow, urinary lactic dehydrogenase (ULDH), Na reabsorptive capacity, and tissue
      MDA levels. Histological examination was performed after reperfusion. The tubular
      functions of kidneys preserved with EC solution containing lidocaine were better
      when compared with the kidneys preserved with EC alone. Tubular injury marker
      levels (ULDH) in group IV were significantly lower than in group III and
      lidocaine also reduced lipid peroxidation during reperfusion. This is in
      agreement with the histological results. The results of the present study can be
      taken as evidence of the cytoprotective effect of lidocaine, which may therefore
      be accepted as a useful agent for kidney preservation.

PMID- 12470203
TI  - Vitamin D receptor gene polymorphisms, bone mineral density and bone turnover:
      FokI genotype is related to postmenopausal bone mass.
AB  - The relationship between vitamin D receptor (VDR) intragenic polymorphisms FokI,
      BsmI, ApaI and TaqI and bone mineral density (BMD) or biochemical markers of bone
      remodeling were investigated in 114 Czech postmenopausal women, on the average
      62.5+/-8.9 years of age. Restriction fragment length polymorphisms in the VDR
      gene were assessed by PCR amplification and digestion with restriction enzymes
      FokI, BsmI, ApaI, and TaqI recognizing polymorphic sites in the VDR locus. Bone
      mineral density was measured at the lumbar spine and at the hip by dual-energy X
      ray absorptiometry (DEXA, g/cm2). After adjusting for age and the body mass index
      (BMI), subjects with the ff genotype had 9.4% lower BMD at the hip than those
      with the Ff genotype (p=0.0459, Tukey's test). FF individuals had an intermediate
      BMD at the hip. A similar pattern of lower lumbar spine BMD was also found in ff
      individuals, but it did not reach statistical significance. There was no
      relationship between BsmI, ApaI and TaqI VDR polymorphisms and BMD at any
      skeletal site. Subjects with Aa (ApaI) genotypes had higher levels of propeptide
      of type I collagen (PICP) than homozygous AA (p=0.0459, Tukey's test). In FokI,
      BsmI and TaqI restriction sites the biochemical markers of bone remodeling did
      not differ by genotype. In addition, no significant difference was observed in
      VDR genotypic distribution between osteoporotic women and non-osteoporotic
      controls in the study group. To conclude, the FokI genotype of the vitamin D
      receptor gene is related to bone mass at the hip in Czech postmenopausal women,
      whereas the importance of remaining VDR genotypes was not evident.

PMID- 12470204
TI  - Effect of liposomal muramyl tripeptide phosphatidylethanolamine and indomethacin
      on hematopoietic recovery in irradiated mice.
AB  - The effects of liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE/MLV,
      radioprotective immunomodulator; 10 mg/kg) and indomethacin (INDO, inhibitor of
      prostaglandin production; 2 mg/kg) on post-irradiation recovery of hematopoietic
      functions in mice were investigated. Two agents with distinct radioprotective
      mechanisms were administered alone or in combination 24 h and 3 h before exposure
      to 7 Gy (60)Co radiation. In the post-irradiation period (3-14 days) combined pre
      treatment of mice accelerated recovery of bone marrow cellularity, weight of
      spleen and myelopoietic and erythropoietic activity in both hematopoietic organs,
      compared to treatment with MTP-PE/MLV or indomethacin alone. In the peripheral
      blood, improved radioprotective effects of combined drug administration were
      found in the recovery of reticulocytes and platelet count. No further significant
      differences in the recovery of leukocyte count were observed in the examined
      groups until post-irradiation day 14. Within the first 3-6 post-irradiation days,
      the bone marrow and peripheral blood smears of mice pre-treated with indomethacin
      alone or its combination with MTP-PE/MLV more frequently featured blast cells and
      large cells with abundant cytoplasm which could be considered the hematopoietic
      stem cells.

PMID- 12470205
TI  - Escherichia coli administered into pig amniotic cavity appear in fetal airways
      and attract macrophages into fetal lungs.
AB  - Escherichia coli (2 x 10(4) bacteria) of the non-pathogenic O86 strain or
      enteropathogenic O55 strain were administered into the pig amniotic cavity at 79
      to 86 days of gestation for six or ten hours. Translocation of bacteria into
      fetal lungs was confirmed by cultivation as well as by light and electron
      microscopy. Infection caused an influx of macrophages that were immunostained in
      cryostat sections by monoclonal antibody recognizing calprotectin.

PMID- 12470206
TI  - Effects of hyperoxia and allergic airway inflammation on cough reflex intensity
      in guinea pigs.
AB  - Toxic influence of high oxygen concentration on pulmonary function and structures
      has been known for many years. However, the influence of high oxygen
      concentration breathing on defensive respiratory reflexes is still not clear. In
      our previous experiments, we found an inhibitory effect of 100 % oxygen breathing
      on cough reflex intensity in healthy guinea pigs. The present study was designed
      to detect the effects of hyperoxia on cough reflex in guinea pigs with allergic
      airway inflammation. In the first phase of our experiment, the animals were
      sensitized with ovalbumin. Thirty-two sensitized animals were used in two
      separate experiments according to oxygen concentration breathing: 100 % or 50 %
      oxygen for 60 h continuously. In each experiment, one group of animals was
      exposed to hyperoxia, another to ambient air. The cough reflex was induced both
      by aerosol of citric acid before sensitization, then in sensitized animals at 24
      h and 60 h of exposition to oxygen/air in awake animals, and by mechanical
      stimulation of airway mucosa in anesthetized animals just after the end of the
      experiment. In contrast to 50 % oxygen, 100 % oxygen breathing leads to
      significant decrease in chemically induced cough in guinea pigs with allergic
      inflammation. No significant changes were present in cough induced by mechanical
      stimulation of airways.

PMID- 12470207
TI  - Hypercapnia does not affect functional residual capacity enlargement induced by
      chronic hypoxia.
AB  - To determine whether changes in partial pressure of CO2 participate in mechanism
      enlarging the lung functional residual capacity (FRC) during chronic hypoxia, we
      measured FRC and ventilation in rats exposed either to poikilocapnic (group H,
      F(I)O2 0.1, F(I)CO2 <0.01) or hypercapnic (group H+CO2, F(I)O2 0.1, F(I)CO2 0.04
      0.05) hypoxia for the three weeks and in the controls (group C) breathing air. At
      the end of exposure a body plethysmograph was used to measure ventilatory
      parameters (V'(E), f(R), V(T)) and FRC during air breathing and acute hypoxia (10
      % O2 in N2). The exposure to hypoxia for three weeks increased FRC measured
      during air breathing in both experimental groups (H: 3.0+/-0.1 ml, H+CO2: 3.1+/
      0.2 ml, C: 1.8+/-0.2 ml). During the following acute hypoxia, we observed a
      significant increase of FRC in the controls (3.2+/-0.2 ml) and in both
      experimental groups (H: 3.5+/-0.2 ml, H+CO2: 3.6+/-0.2 ml). Because chronic
      hypoxia combined with chronic hypercapnia and chronic poikilocapnic hypoxia
      induced the same increase of FRC, we conclude that hypercapnia did not
      participate in the FRC enlargement during chronic hypoxia.

PMID- 12470208
TI  - Natural products and derivatives as leads to cell cycle pathway targets in cancer
      chemotherapy.
AB  - The influence of natural products upon drug discovery in general has been quite
      impressive; one only has to look at the number of clinically active drugs that
      are in use in cancer therapy to see how many either are natural products or have
      a natural pro-duct pharmacophore. What is now becoming quite apparent is that
      materials from natural sources are excellent probes (indicators) for cellular
      targets that when modulated, may well have a deleterious effect upon the cycling
      of a tumor cell through the conventional cell cycle. If the particular target is
      not expressed in normal cell cycling, then a directed "perturbation" of the tumor
      cell's cycle may well lead to a novel method of treatment for specific tumor
      types. In this review we have not attempted to be exhaustive but have given a
      current overview of how natural products from marine, microbial and plant sources
      have permitted in-depth analyses of various parts of the cell cycle under varying
      conditions with the ultimate aims of attempting to "control or perturb" the
      cycling of tumor cells in a fashion that permits their ultimate removal via
      cellular death, with a minimum of trauma to the host.

PMID- 12470209
TI  - Modulating cell cycle: current applications and prospects for future drug
      development.
AB  - The cell cycle is a highly conserved and ordered set of events, culminating in
      cell growth and division. It is tightly controlled by many regulatory mechanisms
      that either permit or restrain its progression. The main families of regulatory
      proteins that play key roles in controlling cell cycle progression are the
      cyclins, the cyclin dependent kinases (Cdks), their substrate proteins, the Cdk
      inhibitors (CKI) and the tumor suppressor gene products, p53 and pRb. Many cell
      cycle control genes, when deregulated, can cause cells that are not dividing to
      enter the cell cycle and begin to proliferate leading to cancer development. They
      do so by interfacing with the basic cell cycle regulatory machinery to activate
      cell cycle entry. There is at present much optimism about the possibility of
      finding anticancer drug treatment strategies that modulate cell cycle regulatory
      molecules. Candidate targets for such strategies include crucial cell cycle
      molecules involved in G(1) to S phase or G(2) to M phase transition. This review
      will outline the basic regulatory machinery responsible for catalyzing cell cycle
      entry and describe the latest advances made in the field of cell cycle
      regulation. The basis of targeting the cell cycle particularly the Cdks as an
      approach to developing novel, specific and perhaps more effective anticancer
      treatments will be discussed. Examples of novel cell cycle-targeting agents that
      are in, or are close to being in clinical trials will be provided.

PMID- 12470210
TI  - Identifying molecular targets mediating the anticancer activity of histone
      deacetylase inhibitors: a work in progress.
AB  - The anticancer properties of histone deacetylase inhibitors have been known for
      some time. However, it is only recently that the functional identities of the
      intracellular targets mediating the anticancer properties have started to be
      revealed. These targets appear to play significant roles in cell cycle control,
      apoptosis and differentiation. Importantly, the modulation of these activities is
      likely to be mediated by alterations in the acetylation status of both histone
      and non-histone targets. Identification of these targets, and the specific
      histone deacetylase enzymes that modulate them, is an important step in designing
      rational-based therapies for the treatment of cancer. In this review we discuss
      the state of progress in identifying the molecular pathways/events mediating the
      anticancer activity of histone deacetylase inhibitors.

PMID- 12470211
TI  - The use of synthetic oligonucleotides as protein inhibitors and anticode drugs in
      cancer therapy: accomplishments and limitations.
AB  - The function of gene products can be altered at many levels, including the
      mutation of gene sequence and the change in steady state levels of mRNA and/or
      protein by various mechanisms. The cumulative malfunction of specific gene
      products underlies many pathological conditions such as the multi-step and multi
      cause acquisition of cancer. Here we discuss two oligonucleotide-based strategies
      in which these compounds target defective gene products acting either as
      antiprotein or anticode agents. The SELEX technique (systematic evolution of
      ligands by exponential enrichment) is an antiprotein approach in which nuclease
      resistant DNA or RNA aptamers are selected by their ability to bind their protein
      targets with high affinity and specificity of the same range as antibodies. Such
      inhibitors were previously evolved against a great variety of targets, including
      receptors, growth factors and adhesion molecules implicated in the genesis of
      some kinds of cancer. Moreover, some results have already been obtained in animal
      models. The antigene technology interferes with earlier steps in the information
      flow leading from gene to protein. In this approach selective gene silencing is
      provided by the formation of stable and specific complexes between triplex
      forming molecules and their DNA targets. The feasibility of this strategy as well
      as a molecular mechanism for the action of antigene oligonucleotides has been
      demonstrated in cellular systems and in vivo. The use of oligonucleotide drugs
      (of either the antiprotein or the anticode type) as a viable approach to cancer
      therapy is limited by some common problems that will be discussed.

PMID- 12470212
TI  - Glycogen phosphorylase as a molecular target for type 2 diabetes therapy.
AB  - The regulation of the hepatic glucose output through glycogenolysis is an
      important target for type 2 diabetes therapy. Glycogenolysis is catalyzed in
      liver, muscle and brain by tissue specific isoforms of glycogen phosphorylase
      (GP). Because of its central role in glycogen metabolism, GP has been exploited
      as a model for structure-assisted design of potent inhibitors, which may be
      relevant to the control of blood glucose concentrations in type 2 diabetes.
      Several regulatory binding sites have been identified in GP, such as the
      catalytic, the allosteric, and the inhibitor binding sites. Protein
      crystallography has contributed significant structural information on the
      specificity and interactions that distinguish the binding sites, and also
      revealed a new unexpected binding site (new allosteric site). In this review, the
      kinetic, crystallographic binding, and physiological studies of a number of
      compounds, inhibitors of GP, are described, and the essential inhibitory and
      binding properties of specific compounds are analyzed in an effort to provide
      rationalizations for the affinities of these compounds and to exploit the
      molecular interactions that might give rise to a better inhibitor. These studies
      have given new insights into fundamental structural aspects of the enzyme
      enhancing our understanding of how the enzyme recognizes and specifically binds
      ligands, that could be of potential therapeutic value in the treatment of type 2
      diabetes.

PMID- 12470213
TI  - Spinorphin as an endogenous inhibitor of enkephalin-degrading enzymes: roles in
      pain and inflammation.
AB  - It is possible that enkephalins are involved in the pain-modulating mechanism in
      the spinal cord. Enkephalins, however, are short-lived, being rapidly degraded by
      various endogenous enzymes. Many substances that inhibit enkephalin-degradation
      have been investigated and it has been reported that some inhibitors (e.g.
      kelatorphan and RB101) alone showed anti-nociceptive activity. We found an
      endogenous factor that modulated enkephalin-degrading activity and purified it
      from bovine spinal cord based on its inhibitory activity toward enkephalin
      degrading enzymes. Structural analysis revealed the factor to be Leu-Val-Val-Tyr
      Pro-Trp-Thr and it was named spinorphin. It has been found that spinorphin
      inhibited the activity toward various enkephalin-degrading enzymes from monkey
      brain, especially dipeptidyl peptidase III (DPPIII, Ki=5.1 x 10(-7) M). Recently
      we reported that this inhibitor significantly inhibited bradykinin (BK)-induced
      nociceptive flexor responses. Importantly, the mode of inhibition to BK-responses
      by spinorphin was different from the case with morphine. The morphine-induced
      blockade of BK-response was attenuated by pertussis toxin treatment, whereas that
      of spinorphin was not. We also have reported roles for spinorphin in
      inflammation. Spinorphin significantly inhibited the functions of
      polymorphonuclear neutrophils (PMNs) by suppressing the binding of fMLF to its
      receptor on PMNs. Further, this inhibitor suppressed the carrageenan-induced
      accumulation of PMN in mouse air pouches after intravenous administration. These
      results indicate that spinorphin may be an endogenous anti-inflammatory
      regulator. The possible role of spinorphin and its analog as regulators in pain
      and inflammation will be discussed.

PMID- 12470214
TI  - Electrostatics in protein binding and function.
AB  - Protein electrostatic properties stem from the proportion and distribution of
      polar and charged residues. Polar and charged residues regulate the electrostatic
      properties by forming short-range interactions, like salt-bridges and hydrogen
      bonds, and by defining the over-all electrostatic environment in the protein.
      Electrostatics play a major role in defining the mechanisms of protein-protein
      complex formation, molecular recognitions, thermal stabilities, conformational
      adaptabilities and protein movements. For example:- Functional hinges, or
      flexible regions of the protein, lack short-range electrostatic interactions;
      Thermophilic proteins have higher electrostatic interactions than their
      mesophilic counter parts; Increase in binding specificity and affinity involve
      optimization of electrostatics; High affinity antibodies have higher, and
      stronger, electrostatic interactions with their antigens; Rigid parts of proteins
      have higher and stronger electrostatic interactions. In this review we address
      the significance of electrostatics in protein folding, binding and function. We
      discuss that the electrostatic properties are evolutionally selected by a protein
      to perform an specific function. We also provide bona fide examples to illustrate
      this. Additionally, using continuum electrostatic and molecular dynamics
      approaches we show that the "hot-spot" inter-molecular interactions in a very
      specific antibody-antigen binding are mainly established through charged
      residues. These "hot-spot" molecular interactions stay intact even during high
      temperature molecular dynamics simulations, while the other inter-molecular
      interactions, of lesser functional significance, disappear. This further
      corroborates the significance of charge-charge interactions in defining binding
      mechanisms. High affinity binding frequently involves "electrostatic steering".
      The forces emerge from over-all electrostatic complementarities and by the
      formation of charged and polar interactions. We demonstrate that although the
      high affinity binding of barnase-barstar and anti-hen egg white lysozyme (HEL)
      antibody-HEL complexes involve different molecular mechanisms, it is
      electrostatically regulated in both the cases. These observations, and several
      other studies, suggest that a fine tuning of local and global electrostatic
      properties are essential for protein binding and function.

PMID- 12470215
TI  - Prediction of protein signal sequences.
AB  - Newly synthesized proteins have an intrinsic signal sequence, functioning as
      "address tags" or "zip codes", that is essential for guiding them wherever they
      are needed. Owing to such a unique function, protein signals have become a
      crucial tool in finding new drugs or reprogramming cells for gene therapy.
      However, to effectively use protein signals as a desirable vehicle in the field
      of proteomics, the first important thing is to find a fast and powerful method to
      identify the "address tag" or "zip code" entity. Although all signal sequences
      contain a hydrophobic core region, they show great variation in both overall
      length and amino acid sequence. It is this variation that makes it possible to
      deliver thousands of proteins to many different cellular locations by varieties
      of modes. It is also this variation that makes it very difficult to formulate a
      general algorithm to predict signal sequences. Nevertheless, various prediction
      models and algorithms have been developed during the past 17 years. This Review
      summarizes the development in this area, from the pioneering methods to neural
      network approaches, and to the sub-site coupling approaches. Meanwhile, the
      future challenges in this area, as well as some promising avenues for further
      improving the prediction quality, have been briefly addressed as well.

PMID- 12470216
TI  - Modulation of the peripheral and central inflammatory responses by alpha
      melanocyte stimulating hormone.
AB  - Inflammation, a localized response to tissue injury, and disorders characterized
      by inflammation are difficult problems in clinical medicine. This difficulty
      stems in large part from incomplete understanding of inflammatory processes and
      their regulation. Recent development of knowledge of the role of central nervous
      system and neuroendocrine system in host responses has provided a new view of the
      capacity of neuronal and soluble mediators in these systems to influence
      inflammation. One of these mediators is the endogenous neuropeptide alpha
      melanocyte stimulating hormone (alpha-MSH), which is an N-acetyl tridecapeptide
      derived from the cleavage of a larger precursor molecule, pro-opiomelanocortin
      (POMC). alpha-MSH is widely distributed in tissues of higher organisms; it has
      been identified in the pituitary, various brain regions, skin, circulation and
      other sites. The neuropeptide alpha-MSH is important to the natural limitation of
      fever, which is an early host response to endotoxin. In addition to its action
      within the brain to reduce fever, alpha-MSH has potent and broad anti
      inflammatory effects in many forms of inflammation. This review will summarize
      the data on the actions of the peptide on various aspects of peripheral and
      central inflammation. On the basis of the data presented, we may think that the
      anti-inflammatory actions of the peptide via peripheral and / or central
      melanocortin receptors might put the peptide into practice therapeutically in
      near future.

PMID- 12470217
TI  - Protein reconstitution and 3D domain swapping.
AB  - The native structures of proteins are governed by a large number of non-covalent
      interactions yielding a high specificity for the native packing of structural
      elements. This allows for the reconstitution of proteins from disconnected
      polypeptide fragments. The specificity for the native arrangement also enables
      interchange of structural elements with another identical protein chain resulting
      in dimers with swapped segments. Proteins are not static structures, but open up
      repetitively on a timescale of minutes to years depending on the identity of the
      protein and solution conditions. The open protein may self-close and return to
      the native state, or it may close with another polypeptide chain leading to 3D
      domain swapping. The term describes two or more protein molecules swapping
      identical domains or smaller secondary structure elements. The non-covalent intra
      molecular interactions between domains in the monomer are thus broken and
      restored in the oligomer by identical inter-molecular contacts. This review will
      discuss 3D domain swapping in relation to protein reconstitution and fibril
      formation. Examples of reconstituted and domain-swapped proteins will be given.
      The physiological benefits of 3D domain swapping will be discussed, as well as
      its role in the evolution of proteins and pathology.

PMID- 12470218
TI  - Post-translational modifications in prion proteins.
AB  - Prions are a novel class of infectious pathogens that cause a group of fatal
      prion diseases in which the benign cellular form of the prion protein (PrP(C)) is
      transformed into the disease-related scrapie variant (PrP(SC)). The two PrP
      isoforms differ in their structure and resistance to degradation. The molecular
      mechanism by which the PrP(SC) is formed and causes infectivity or
      neurodegeneration is not known. In a compelling and emerging view, post
      translational modifications (or the lack thereof) play roles in the
      transformation of PrP(C) to PrP(SC). Human PrP contains two consensus sites for N
      linked glycosylation, at Asn181 and Asn197. From the functional standpoint,
      glycosylation can modify either the conformation of PrP(C), or the stability of
      PrP(SC) and, hence, the rate of PrP(SC) clearance. So far the NMR structures of
      only recombinant, non-glycosylated prions are known, while the structure of the
      glycosylated form is estimated by molecular modeling. A number of native amino
      acid mutations in PrP can be mapped near the glycosylation sites. Normal prion
      protein has been demonstrated to be a copper binding protein, and increasing
      evidence has shown correlation between the level of PrP expression and tolerance
      to oxidative stress. Moreover, histochemistry for nitrotyrosine is used for
      detection of neuronal labeling, a sign of a peroxynitrite-mediated neuronal
      degradation and a marker for nitrative stress in scrapie-infected mouse brains.
      It is an intriguing proposition that the post-translational modifications alone,
      or in combination with amino acid changes, play dominant roles in the pathogenic
      transformation of PrP(C) to PrP(SC).

PMID- 12470219
TI  - Subcellular detection and localization of the drug transporter P-glycoprotein in
      cultured tumor cells.
AB  - In vitro studies on the cellular location of P-glycoprotein (Pgp) are reported
      with the aim to clarify the relationship between its intracellular expression and
      the multidrug resistance (MDR) level of tumor cells. Pgp was found abnormally
      expressed on the plasma membrane of tumor cells with "classical" MDR phenotype.
      However, Pgp was also often detected on the nuclear envelope and on the membrane
      of cytoplasmic organelles. The hypothesis that this drug pump maintains a
      transport function when located in these compartments, is still under debating.
      Our results, together with those obtained by other researchers, demonstrate that
      cytoplasmic Pgp regulates the intracellular traffic of drugs so that they are no
      more able to reach their cellular targets. In particular, we revealed that in MDR
      breast cancer cells (MCF-7) a significant level of Pgp was expressed in the Golgi
      apparatus. A similar result was found in human melanoma cell lines, which never
      undergone cytotoxic drug treatment and did not express the transporter molecule
      on the plasma membrane. A strict relationship between intracellular Pgp and
      intrinsic resistance was demonstrated in a human colon carcinoma (LoVo) clone,
      which did not express the drug transporter on the plasma membrane. Finally, a
      structural and functional association between Pgp and ERM proteins has been
      discovered in drug-resistant human T- lymphobastoid cells (CEM-VBL 100). Our
      findings strongly suggest a pivotal role of the intracytoplasmic Pgp in the
      transport of drugs into cytoplasmic vesicles, thus actively contributing to their
      sequestration and transport outwards the cells. Thus, intracellular Pgp seems to
      represent a complementary protective mechanism of tumor cells against cytotoxic
      agents.

PMID- 12470241
TI  - Rationally engineered proteins or antibodies with absent or reduced
      immunogenicity.
AB  - One challenge associated with the clinical use of protein therapeutics destined
      for chronic administration is the potential for the development of unwanted anti
      drug immune reactions. The molecular basis for this reactivity is the binding of
      peptide fragments (epitopes) derived from the breakdown of the protein drug to
      the HLA receptors expressed by the patient's immune cells. If these epitopes are
      recognized as "foreign" by the immune system, specific helper T lymphocytes
      (HTL), are activated, which initiate and direct the formation of antibodies
      against the protein drug. These antibodies can bind and neutralize the protein
      drug, resulting in either decreased efficacy or total ineffectiveness of the
      drug. Moreover, various safety concerns, such as allergic reactions and other
      adverse events, are also frequently associated with the formation of anti-drug
      antibodies. Herein, we describe the development of "ImmunoStealth", an integrated
      bioinformatics, biochemical and cellular immunology approach that specifically
      addresses the issue of unwanted immune responses against protein therapeutics.
      Unwanted HTL epitopes are identified using in silico sequence analysis methods
      and high throughput in vitro biochemical evaluations and thereafter confirmed
      using cellular immunogenicity assays. The "offending" epitopes within the drug
      are then rationally modified to alter their HLA binding capacity, and thus render
      them non-recognizable by the immune system. This technology will ultimately
      facilitate the design of safer, more potent and more economical drugs.

PMID- 12470242
TI  - Cytokines and their antagonists as therapeutic agents.
AB  - Cytokines are powerful molecules that the body's immune cells secrete in response
      to an offending agent. Their main function is to direct the immune response into
      the most effective pathway that will eventually result in elimination of the
      offender. The last decade was marked by an enormous and ever growing interest
      that led to discovery of numerous cytokine molecules and their amazing influence
      on the body immune function. The more we are learning about the way cytokines
      modulate and direct the immune responses of the body, the interest in using them
      or their antagonist to change or enhance those responses is growing. Studies are
      currently underway showing the beneficial effect of TNFalpha antagonists on the
      cellular injury mediated by this cytokine in rheumatic diseases, inflammatory
      bowel disease and endotoxemia. Interferon therapies are also tested utilizing
      IFNalpha for treatment of Hepatitis B and C. The discovery of Th1 and Th2
      cytokines had shown that the nature of the immune response is, in essence,
      directed by a few important cytokines. Which immune reactions will develop seems
      to depend on whether IL-2 and IL-12 are secreted (and the immune response becomes
      Th1 with secretion of IFNgamma and efficient removal of some antigens such as
      viruses) or IL-4 is secreted in which case Th2 response results in down
      regulation of IFNgamma and IL-2 secreting effectors. The discovery, isolation and
      purification of these molecules open the possibility to skew the immune response
      in order to facilitate better outcome. For example, studies have now being
      conducted aimed at using IL-2 as an adjuvant therapy in conjunction with HAART in
      HIV patients. Similarly, IL-12 seems to be beneficial in melanoma and has been
      used as a very potent adjuvant for eliciting immune responses to immunization.
      Furthermore, studies with IL-4 knockout mice and those utilizing IL-4 blocking
      agents have shown that this cytokine might play a crucial role in maintaining
      persistent viral infections and in mediating chronic, autoimmune diseases. Using
      body's own immunomodulators is becoming an exciting possibility to target
      inefficient or misdirected immune responses that result in disease. The potential
      benefits in terms of human disease are enormous and still largely unexplained.
      Thus, using cytokines and their antagonists as therapeutic agents is an emerging
      and growing area of research.

PMID- 12470243
TI  - Molecular modeling in the design of peptidomimetics and peptide surrogates.
AB  - The most important natural sources of new leads are plant extracts, bacterial
      broths, animal venoms and peptides isolated from living organisms. However, only
      the three first have been used extensively in the development of new therapeutic
      agents. This is probably due to the low pharmacological profile exhibited by
      peptides, that requires a lengthy transformation to make them suitable as new
      leads. In contrast, bioactive compounds isolated from the other sources are
      regularly closer to be used as lead compounds. Nevertheless, the sources for
      compounds of this category are nowadays scarce. In contrast, there are new
      bioactive peptides discovered quite often and reported as ligands for different
      receptors. Under these circumstances peptides appear as an attractive source of
      prospective new leads. In order to reduce the time involved in the design of a
      potential lead from a peptide, molecular modeling tools have been developed in
      the last few years. The purpose of the present work is to review the different
      techniques available and to report various successful examples of design of new
      peptidomimetics published in the literature.

PMID- 12470244
TI  - Small molecule activators of the insulin receptor: potential new therapeutic
      agents for the treatment of diabetes mellitus.
AB  - Diabetes mellitus refers to a spectrum of syndromes characterized by abnormally
      high levels of glucose in blood. These syndromes are associated with an absolute
      (Type 1 diabetes) or relative (Type 2 diabetes) deficiency of insulin, coupled
      with varying degrees of peripheral resistance to the actions of insulin. Clinical
      studies have shown that controlling hyperglycemia significantly reduces the
      appearance and progression of the vascular complications associated with
      diabetes. Insulin's regulation of glucose homeostasis is mediated by a cascade of
      signaling events that take place upon insulin binding to its cell surface
      receptor. Autophosphorylation of the receptor and activation of its intrinsic
      tyrosine kinase are critical processes for transmitting these intracellular
      signals. Type 1 diabetes patients depend on exogenous insulin to achieve these
      effects, whereas Type 2 diabetes patients can accomplish a similar response
      through oral medications that increase the production of endogenous insulin or
      enhance its actions on the target tissues. Current biochemical and clinical
      evidence suggests that defects within the insulin receptor itself may be a cause
      of insulin resistance leading to Type 2 diabetes. This review focuses on the
      insulin receptor as a target for therapeutic intervention, and describes the
      recent discovery of small molecules that act on the receptor and either enhance
      or directly emulate the actions of insulin both in vitro and in vivo.

PMID- 12470245
TI  - Synthesis and enzyme inhibitory activities of novel peptide isosteres.
AB  - Design and synthesis of metabolically stable peptide analogs that can either
      mimic or block the bioactivity of natural peptides or enzymes is an important
      constituent of bioorganic and medicinal chemistry research. Isosteric replacement
      of a scissile peptide bond represents a viable and popular approach in the
      rational design of peptidomimetics. Peptidomimetics find applications as drugs,
      in protein engineering and so on. This is evident from the wealth of
      therapeutically useful peptidomimetic leads incorporating any of the peptide
      isosteres that are currently available. In this review, we have given a brief
      account of the types of peptide isosteres widely known till date. With this
      background, we have described some of the recent developments in synthetic
      approaches. This includes methods involving a common intermediate to synthesize
      different possible isosteres and their peptide analogs, solid phase synthesis and
      combinatorial approach. One such method involving stereoselective nitrile oxide
      cycloaddition as the key step has been studied extensively in our research
      laboratory. Finally, we have also discussed about some of the recent reports on
      the design and inhibitory activities of peptidic or non-peptidic analogs against
      aspartic proteases (HIV-1, renin, ACE and pepsin) and peptide analogs of an
      immunomodulating hexapeptide.

PMID- 12470246
TI  - Potential therapeutic application of the association of vitamins C and K3 in
      cancer treatment.
AB  - The decision of stressed cells to die or to survive is made by integrating
      signals at different levels through multiple check points. However, initiation
      and continued progression toward cell death by apoptosis in cancer cells may be
      blocked by mutation of the tumor suppressor p53 or overexpression of members of
      the bcl-2 family of proteins. The existence of such mechanisms indicates that
      cancer cells lose the controls regulating their cell cycle. Therefore, the
      activation of their programmed cell death appears as a major therapeutic target.
      Oxidative stress can stimulate growth, trigger apoptosis, or cause necrosis
      depending upon the dose and the exposure time of the oxidizing agent. A large
      body of evidence supports the idea that oxidative stress induced by redox cycling
      of vitamins C and K(3) in association surpasses cancer cellular defense systems
      and results in cell death. The molecular mechanisms underlying such a process
      are, however, still unknown. Indeed, several types of cell death may be produced,
      namely autoschizis, apoptosis and necrosis. Combined vitamin C and K(3)
      administration in vitro and in vivo produced tumor growth inhibition and
      increased the life-span of tumor-bearing mice. CK(3)-treatment selectively
      potentiated tumor chemotherapy, produced sensitization of tumors resistant to
      some drugs, potentiated cancer radiotherapy and caused inhibition of the
      development of cancer metastases without inducing toxicity in the host. We
      propose the association of vitamins C and K(3) as an adjuvant cancer therapy
      which may be introduced into human cancer therapy without any change in the
      classical anticancer protocols, and without any supplementary risk for patients.

PMID- 12470247
TI  - Chemogenomics: bridging a drug discovery gap.
AB  - With the successful completion of the human genome sequencing and the resulting
      plethora of genetic information now available novel technologies and applications
      have to be established to translate the huge amount of data generated into
      successful biological and biomedical research programs. The integration of
      various drug discovery disciplines within the parallel quest for novel targets
      and new molecular entities has meanwhile given rise to a quite popular term in
      pharmaceutical research named "chemogenomics". This review article gives an
      overview of the disciplines involved in this field and discusses the possible
      implications of this novel paradigm in drug discovery for the near future.

PMID- 12470248
TI  - The application of multi-component reactions in drug discovery.
AB  - Multi-component reactions (MCRs) enable the facile, automated and high throughput
      generation of small organic molecules. MCRs have been used to create diversity
      oriented and biased combinatorial libraries, to accomplish the synthesis of
      highly complex natural products as well as for the large-scale production of drug
      candidates. This provides medicinal chemists with a powerful tool to create novel
      chemical diversity, matching the space of biological targets with relevant
      chemistry. The discovery of novel MCRs has become an increasingly active area of
      research, yielding novel chemical scaffolds for drug discovery efforts.

PMID- 12470249
TI  - Trends in virtual combinatorial library design.
AB  - Recent developments in combinatorial molecular design using virtual screening
      methods are summarised. These include similarity-based compound clustering
      techniques, structure-based docking and scoring, and fragment-based de novo
      design. Three major trends have been identified: i) the design of small target
      focused compound libraries yielding activity-enriched sets of molecules; ii)
      advanced prediction methods for "drug-like" molecular properties complement
      activity predictions in the library design process, forming a multi-dimensional
      objective function; iii) "cherry picking" of selected products is increasingly
      used in lead generation and optimisation compared to purely educt-driven library
      design methods aiming at maximising structural diversity.

PMID- 12470250
TI  - Analytical techniques for small molecule solid phase synthesis.
AB  - Although resin-based chemistry offers many practical advantages over conventional
      solution phase for the synthesis of combinatorial libraries, effective monitoring
      of reactions conducted on the support remains a challenge. A number of techniques
      have been developed to enable the analysis of solid phase organic synthesis
      either by monitoring the resin-bound species directly or by the analysis of small
      quantities of material cleaved from the support. This review outlines some of the
      principles of the various techniques for the analysis of intermediates and
      products obtained from solid-phase chemistry.

PMID- 12470251
TI  - Natural product guided compound library development.
AB  - Natural products are biologically validated starting points for the design of
      combinatorial libraries, as they have a proven record of biological relevance.
      This special role of natural products in medicinal chemistry and chemical biology
      can be interpreted in the light of new insights about the domain architecture of
      proteins gained by structural biology and bioinformatics. In order to fulfil the
      specific requirements of the individual binding pocket within a domain family it
      is necessary to optimise the natural product structure by chemical variation.
      Solid-phase chemistry is becoming an efficient tool for this optimisation
      process, and recent advances in this field are highlighted in this review
      article.

PMID- 12470252
TI  - Polymer-supported metal-phosphine complexes for use as catalysts or linkers in
      medicinally-oriented organic synthesis.
AB  - Polymer-supported catalysts and reagents have found many uses in synthetic
      organic chemistry. This review discusses the preparation of polymer-supported
      phosphine ligands and organometallic complexes formed using these and highlights
      their use in reactions that are of particular interest to medicinal chemists. The
      scope of the review is limited to phosphine ligands and their metal complexes
      attached to derivitised polystyrene supports.

PMID- 12470253
TI  - The combinatorial centre of excellence - a unique industrial academic
      partnership.
AB  - The Combinatorial Centre of Excellence (CCE) offers a unique opportunity for the
      exploitation of a broad range of combinatorial methodologies. Many areas of
      activity are under investigation, including high-throughput X-ray of small
      molecules, parallel polymer chemistry and the development of new multi-component
      reactions.

PMID- 12470254
TI  - Accelerating drug discovery by integrative implementation of laboratory
      automation in the work flow.
AB  - Acceleration of the drug discovery process in pre-clinical pharmaceutical
      research is a highly desirable goal and combinatorial chemistry united with
      automation technology promised to accomplish this task. Through the accumulation
      of experience with automated devices over time it became evident that only by
      harmonisation and streamlining of work-flow procedures the efficiency of the
      overall process can be improved. An open architecture of efficient data
      management and appropriate utilisation of automated laboratory protocols provides
      the opportunity to react in a flexible and advisable way. Only an integrative
      workflow concept promotes the enhancement of the overall performance. However,
      the foundation of any efforts towards the accelerated synthesis of new and
      desired compound arrays lies in the development of reliable chemistry protocols
      amenable to solid- and solution phase chemistry.

PMID- 12470256
TI  - NMR and in silico screening.
AB  - NMR-based screening and virtual, or in silico, screening can be highly
      complementary and synergistic. NMR-based screening is a rapid and reliable method
      for validating hits that come from in silico screens. In addition, ligand-binding
      data derived from NMR-based screens can focus and direct subsequent in silico
      screening. We will first give a short overview of existing NMR and in silico
      screening methods, discuss the drawbacks associated with each, and finally
      present applications that highlight the combination of the two technologies.

PMID- 12470255
TI  - Applications of SHAPES screening in drug discovery.
AB  - The SHAPES strategy combines nuclear magnetic resonance (NMR) screening of a
      library of small drug-like molecules with a variety of complementary methods,
      such as virtual screening, high throughput enzymatic assays, combinatorial
      chemistry, X-ray crystallography, and molecular modeling, in a directed search
      for new medicinal chemistry leads. In the past few years, the SHAPES strategy has
      found widespread utility in pharmaceutical research. To illustrate a variety of
      different implementations of the method, we will focus in this review on recent
      applications of the SHAPES strategy in several drug discovery programs at Vertex
      Pharmaceuticals.

PMID- 12470257
TI  - Fluorine-NMR competition binding experiments for high-throughput screening of
      large compound mixtures.
AB  - High-throughput ligand-based NMR screening with competition binding experiments
      is extended to (19)F detection. Fluorine is a favorable nucleus for these
      experiments because of the significant contribution of the Chemical Shift
      Anisotropy (CSA) to the (19)F transverse relaxation of the ligand signal when
      bound to a macromolecular target. A low to moderate affinity ligand containing a
      fluorine atom is used as a reference molecule for the detection and
      characterization of new ligands. Titration NMR experiments with the selected
      reference compound are performed for finding the optimal set-up conditions for
      HTS and for deriving the binding constants of the identified NMR hits. Rapid HTS
      of large chemical mixtures and plant or fungi extracts against the receptor of
      interest is possible due to the high sensitivity of the (19)F nucleus and the
      absence of overlap with the signals of the mixtures to be screened. Finally, a
      novel approach for HTS using a reference molecule in combination with a control
      molecule is presented.

PMID- 12470258
TI  - Integration of NMR and high-throughput screening.
AB  - NMR-based screening has become a powerful method for the identification and
      analysis of low-molecular weight organic compounds that bind to protein targets
      and can be utilized in drug discovery programs. In particular, heteronuclear NMR
      based screening can yield information about both the affinity and binding
      location of potential lead compounds. In addition, heteronuclear NMR-based
      screening has wide applications in complementing and facilitating conventional
      high-throughout screening programs. This article will describe several strategies
      for the integration of NMR-based screening and high-throughput screening. The
      marriage of these two techniques promises to be of tremendous benefit in the
      triage of hits that come from HTS, and can aid the medicinal chemist in the
      identification of quality leads that have high potential for further
      optimization.

PMID- 12470259
TI  - Site-selective labeling strategies for screening by NMR.
AB  - NMR based screening has become an important tool in the pharmaceutical industry.
      Methods that provide information on the location of small molecule binding sites
      on the surface of a drug target (e. g. SAR-by-NMR and related techniques) are of
      particular interest. In order to extend the applicability of such techniques to
      drug targets of higher molecular weight, selective labeling strategies may be
      employed. Dual-amino acid selective labeling and site directed non-native amino
      acid replacement (SNAAR) allow for the selective detection of NMR resonances of a
      specific amino acid residue. This results in significantly reduced spectral
      complexity, which not only enables application to higher molecular weight
      systems, but also eliminates the need for sequential resonance assignment in
      order to identify the binding site. Regio-selective (or segmental) labeling of an
      entire protein domain of a multi domain protein may also be achieved. Labeling
      only a selected part of a multi domain protein (e. g. a catalytic or ligand
      binding domain) is an attractive way to simplify the spectral interpretation
      without disturbing the system under study.

PMID- 12470260
TI  - Utility of NMR in lead optimization: fragment-based approaches.
AB  - NMR has proven to be a valuable tool for identifying small molecule drug leads
      that serve as starting points for lead optimization programs. In addition, NMR
      screening can also be applied during lead optimization in order to improve the
      pharmacokinetic properties of a compound. In this paper we review the NMR methods
      that can be used for this purpose. Several examples are then summarized to
      demonstrate the usefulness of fragment-based approaches in optimizing the
      physical properties of potential drug candidates.

PMID- 12470261
TI  - Competition binding experiments for rapidly ranking lead molecules for their
      binding affinity to human serum albumin.
AB  - Many lead molecules that have high affinity for a therapeutic target in vitro
      exhibit a reduced efficacy in vivo. Drug binding to human serum albumin is a
      major contributor to this reduction in potency, and many drug discovery programs
      expand significant resources preparing compounds that have decreased albumin
      binding. As rational and structure-based approaches have already been
      demonstrated to design compounds that have reduced affinity for albumin, the
      ability to rapidly and accurately assess protein binding will be valuable in lead
      optimization. This review will summarize some of the NMR-based efforts towards
      developing universal, rapid, accurate, and site-specific assays for estimating
      protein binding.

PMID- 12470262
TI  - In vivo toxicity screening programs using metabonomics.
AB  - Metabonomics is an emerging technology that enables rapid in vivo screening for
      toxicity, disease state, or drug efficacy. The technology combines the power of
      high-resolution nuclear magnetic resonance (NMR) techniques with statistical data
      analysis methods to rapidly evaluate the metabolic "status" of an animal.
      Complimentary to other profiling technologies like proteomics and genomics,
      metabonomics provides a fingerprint of the small-molecules contained in a given
      biofluid through the time course of a study. This article reviews the steps in
      implementing a metabonomics-based screening program from study design through
      data analysis. While metabonomics is still a relatively new technology in
      comparison to the other "omics", published results from metabonomics studies
      demonstrate its potential impact in the drug discovery process by enabling the
      incorporation of safety endpoints much earlier in the drug discovery process,
      reducing the likelihood (and cost) of later stage attrition.

PMID- 12470263
TI  - Phage display and colony filter screening for high-throughput selection of
      antibody libraries.
AB  - During the last 12 years, antibody combinatorial libraries have provided a new
      approach for the construction and production of reagents and drugs based on the
      human monoclonal antibodies. Studies employing antibodies or antibody mimics have
      become an important part of the explosive growth of proteomics. This places
      tremendous emphasis on the new approaches for faster library screening, improved
      methods of selection and evaluation of novel applications. The phage display
      system, together with its variants of ribosome and bacterial display, is the most
      extensively used method for the rapid screening of large antibody libraries.
      However, in the last two years the need to improve selection methods together
      with a complex patent situation regarding the phage display system, has also
      directed research towards the possibility of performing antibody selection by
      colony filter screening. Here, we summarise the results obtained by these
      different methods of selection comparing their efficacy and advantages.

PMID- 12470264
TI  - In Ssarch of new anti-bacterial target genes: a comparative/structural genomics
      approach.
AB  - We outline a joint academic/industrial (CNRS/AVENTIS) functional genomics project
      aiming at the discovery of new anti-bacterial gene targets. Starting from all
      publicly available bacterial genomes, a subset of the most evolutionary conserved
      protein-coding genes has been identified. We retained genes with clear homolog in
      E. coli and at least one gram-positive bacterium among B.subtilis, M.
      tuberculosis, L. lactis or S. pyogenes. This subset was further reduced to genes
      encoding non-membrane proteins of unknown or hypothetical functions. The 221 E.
      coli Open Reading Frames (ORFs) identified through this comprehensive
      bioinformatic analysis are now submitted to a systematic 3-D structure
      determination protocol including cloning, protein expression and purification,
      crystallisation and X-ray diffraction. Our strategy was designed to focus on
      promising wide-spectrum targets as well as original biochemical pathways.
      Bioinformatics is used throughout all phases of project, including the initial
      large-scale comparative genomics analyses, the purification/expression and
      crystallisation stages for the detection of helpful sequence-specific features
      (e.g. cofactor binding motifs, non-structured N- or C- term extremities, etc  ),
      and finally for the interpretation of the structures in conjunction with multiple
      sequence alignments for the identification of key residues, interaction areas on
      molecular surfaces, and overall function predictions.

PMID- 12470265
TI  - Optimisation of a peptide library for screening specific RNA ligands by flow
      injection NMR.
AB  - Flow-injection NMR is a very attractive technique for identifying weak but
      specific ligand-macromolecule interactions. The low-sensitivity of this method
      is, however, a major concern which hinders its widespread application to large
      scale screening. Focussing on RNA-targeting ligands, we have shown in this report
      that it is possible to design a peptide library that will simultaneously satisfy
      a number of physico-chemical restraints and sample the sequence space in an
      "optimal" fashion. This library, which contains less than 200 peptides, covers
      most of the allowable tripeptide sequences in a non-redundant fashion. In
      addition, for almost any allowable tetrapeptide sequences, the library contains a
      close neighbor that will differ at the most by a single conservative replacement.
      A subset of this library was actually synthesised and used in a preliminary
      screen against human tRNA(Lys)(3), the primer of HIV-1 reverse transcriptase.

PMID- 12470266
TI  - Software for automating analysis of encoded combinatorial libraries.
AB  - This paper describes the applications which are used to automate the analysis of
      encoded combinatorial libraries. Commercial packages from MDL, Oracle and Agilent
      are linked with application software written in C/C++, in Microsoft Access and in
      ChemStation macro language. Encoding correspondence lists for each of up to three
      synthetic steps are conveniently associated with building block lists using the
      first application, CodeGen. The second application Decode allows the user to
      identify the individual beads picked onto a 96-well plate and the pool number for
      each bead. The decoding chromatography data for each well is then loaded into the
      program. The chromatography data is used to identify the tags used in the
      synthesis. Along with the building block information from ISIS/Host, the building
      block used in each step of the synthesis can be identified. A third routine, Code
      to-Structure, takes the coded library building blocks and creates the connection
      table in ISIS for each structure found by the decode program. For quality control
      of encoded library synthesis, the decoded structures on a set of beads is
      compared to the LC/UV/MS data for the ligand cleaved from the same bead. CAPTURE,
      a GlaxoSmithKline proprietary application, is used to display and analyze the
      decoded structures and associated mass spectral data. This application uses
      simple isotopic composition and electrospray ionization rule sets to predict mass
      spectra and judge the concordance of a structure- mass spectrum data set. An
      ancillary program, EIC, is used to extract predicted single ion chromatograms
      from the full scan LC/MS data.

PMID- 12470267
TI  - Identification of novel alpha-glucosidase inhibitors by screening libraries based
      on N- [4-(benzyloxy) benzoyl] alanine derivatives.
AB  - A library of 72 compounds related to N- [4-(benzyloxy) benzoyl]alanine (I) was
      synthesized, prepared and screened for alpha-glucosidase inhibitory activity.
      Four compounds showed potent inhibition, six compounds moderate inhibition, and
      16 were weak inhibitors. One compound, N- [4-(benzyloxy) benzoyl] serine, was
      found to be a potent inhibitor of alpha-glucosidase with 100% inhibition at 1
      micro M. This inhibitor was at least five times more potent than the lead
      compound I.

PMID- 12470268
TI  - Combinatorial peptide library for the analysis of antigen recognition by T cells.
AB  - Peptides that consist of 19 residues with random sequences (X19) were considered
      to deliver antigenic stimuli to CD4T cells. When IL-4, IL-7, IL-9, IL-15 and
      agonistic Ab to CD29 were co-cultured with single peripheral CD4T cells in the
      presence of X19 and feeder cells, T cells exhibited clonal expansion. These T
      cell clones showed heterogeneous proliferation patterns against KGXXXXXXXXXGK
      based and KGXXXXXXXXXGKGKK-based combinatorial peptide libraries. Pattern-match
      search on one of the T cell clones resulted in peptide ligand candidates, one of
      which induced proliferation, as did protein molecules carrying the corresponding
      sequence. Combinatorial chemistry was useful in determining not only peptide
      ligands but also peptide superagonists. For this purpose, use of reverse-phase
      hydrophobic interaction chromatography and mass spectrometry analysis was
      efficient. Detailed methods are described in the paper.

PMID- 12470269
TI  - Alkylaminopropenones and alkylamino-propenoates as efficient and versatile
      synthons in microwave-assisted combinatorial synthesis.
AB  - A simple and fast one-pot method using microwave irradiation for the synthesis of
      a number of small libraries of diverse heterocycles is described in this paper.
      The two-step one-pot method includes the formation of alkylaminopropenones or
      alkylaminopropenoates in 5 min at 180 degrees C and a subsequent treatment with
      dinucleophiles for 3 to 5 min at 150 degrees C to 180 degrees C to form a variety
      of biologically interesting heterocycles in a cascade-type reaction. The
      combination of combinatorial chemistry and microwave-assisted synthesis was found
      to be very efficient.

PMID- 12470270
TI  - Cascade synthesis with (triphenylphosphoranylidene)-ethenone as a versatile
      reagent for fast synthesis of heterocycles and unsaturated amides under microwave
      dielectric heating.
AB  - A general procedure for the synthesis of a large variety of compounds comprising
      an alpha, beta,-unsaturated carbonyl functionality was developed. The use of one
      pot cascade synthesis with (triphenylphosphora-nylidene)ethenone as a versatile
      reagent for various formations including heterocycles of different ring sizes and
      unsaturated amides in combination with microwave dielectric heating is described.
      The method was used to synthesize a small library of unsaturated amides.

PMID- 12470271
TI  - Evaluation of a method for high throughput solubility determination using a multi
      wavelength UV plate reader.
AB  - Aqueous solubility is a critical physicochemical property and must be addressed
      early during drug discovery research. Due to the difficulty in accurately
      predicting aqueous solubility in silico, high throughput experimental
      determination of aqueous solubility is in great demand. This study evaluates a
      method using a multi-wavelength UV plate reader and disposable 96-well UV plates
      for fast solubility determination. It was demonstrated that this method has the
      sensitivity and reproducibility to effectively determine solubility as low as 1
      micro M. Excellent correlation (R>0.97) was observed between the solubility
      determined using the UV reader method and the HPLC method over the range of 1
      1000 micro M for a diverse set of pharmaceutical compounds. In addition to
      excellent sensitivity and reproducibility, the UV plate reader method also offers
      the flexibility of being able to determine thermodynamic solubility in the
      presence or absence of dimethyl sulfoxide, which is a solvent widely used for
      combinatorial compounds during high throughput screening.

PMID- 12470272
TI  - High molecular recognition: design of "Keys".
AB  - Molecular recognition between molecules is one of the most fundamental processes
      in biology and chemistry. The recognition process is largely driven by non
      covalent forces such as hydrogen bonding, electrostatics, van der Waals forces,
      pi-pi interactions, and conformational energy. The complementarity between the
      receptor and substrate is very similar to the "lock and key" function, first
      described by Emil Fischer over 100 years ago, - the lock being the molecular
      receptor such as a protein or enzyme and the key being the substrate such as a
      drug, that is recognized to give a defined receptor-substrate complex. This
      review focuses on the design of specific ligand systems as "Keys" to enable the
      induced fit of these keys into the target macromolecules, protein/enzyme (Locks)
      with particular emphasis on protein recognition.

PMID- 12470273
TI  - High-density synthetic peptide microarrays: emerging tools for functional
      genomics and proteomics.
AB  - New approaches for manufacturing and application of peptide arrays on planar
      surfaces are emerging, thereby opening advanced opportunities to probe the
      expression and function of the proteome. In complementing DNA and protein array
      analyses, peptide fragment screening directly addresses functional protein
      interaction sites, leading to a detailed insight into the discovered molecular
      recognition events, placing them in the context of the whole genome, and even
      allowing rapid determination of the chemical nature of these interactions. This
      information can then be transferred into powerful small peptide tools that
      interfere with these interactions in vivo and help to link targets with
      phenotypes. With the spreading of new peptide array tools, peptide screening will
      extend its impact on modern genome-driven molecular biology. This will advance
      the systematic discovery and validation of new pharmaceutical targets as well as
      the development of potent molecular diagnostics for medical and ecological
      monitoring.

PMID- 12470274
TI  - Enhancement of combinatorial chemistry by microwave-assisted organic synthesis.
AB  - It was in the 1980 s that the first papers in which the use of either
      combinatorial methods or microwave heating in organic chemistry were published.
      Unlike combinatorial chemistry, which quite readily became an accepted method,
      particularly in the pharmaceutical industry, it is only now that microwave
      heating is truly gaining acceptance. Our aim in this review is to attempt to
      rationalize this slow acceptance and to show the benefits to be gained by
      employing microwave heating in tandem with combinatorial chemistry. We will also
      give a number of examples of successful applications.

PMID- 12470275
TI  - Improvement of "hit-to-lead" optimization by integration of in vitro HTS
      experimental models for early determination of pharmacokinetic properties.
AB  - Development of predictive in vitro surrogate methods for traditional approaches
      assessing bioavailability and pharmacokinetics of lead compounds must be made to
      both keep pace with high-throughput (HT) lead identification and to mitigate the
      high costs associated with progression of compounds with poor chances of
      developmental success. Indeed opportunities for improvement still exist in the
      lead optimization phase versus the lead identification phase, where HT
      methodologies have been nearly optimized. Review of examples, limitations, and
      development of high-throughput microtiterplate-based assays for evaluating
      metabolic liabilities, such as in vitro radiometric and fluorometric assays for
      inhibition of cytochrome p450 (CYP) activity, determination of stability of a
      compound in liver microsomes, or cloned CYPs coupled to reconstituting systems
      are described. Parallel approaches to improve speed, resolution, sample
      preparation, as well as data analysis using LC/MS and LC/MS/MS approaches and
      technologies to assess compound integrity and biotransformation by automation and
      multiplexing are also discussed. Realization of the benefits in automation of
      cell-based models for determining drug permeability to predict drug absorption
      are still hampered by bottlenecks in analytical analysis of compounds. The
      implementation and limitations of surrogate physiochemical methods for passive
      adsorption such as immobilized artificial membranes (IAM) and parallel artificial
      membrane permeation assays (PAMPA), and compound solubility by laser nephelometry
      are reviewed as well. Additionally, data from a high-throughput 96-well
      equilibrium dialysis device, showing good correlation to classical methods, is
      presented. Finally, the impact of improvements in these downstream bottlenecks in
      lead optimization and preclinical drug discovery are discussed in this review.

PMID- 12470276
TI  - Wheat germ cell-free translation system as a tool for in vitro selection of
      functional proteins.
AB  - We have demonstrated that mRNA, ribosome and resulting protein form complexes
      (ternary complexes) in wheat germ cell-free translation system and these
      complexes are stable for at least several hours. The protein folds into a proper
      conformation capable of specific binding with the inhibitor of its enzymatic
      activity. The removal of the stop codon from mRNA does not affect translation and
      mRNA-ribosome-protein complex stability. We have used these results to develop a
      method of isolation of mouse dihydrofolate reductase (mDHFR) encoding mRNA from
      native pool of mouse liver mRNA. The native pool of mouse liver mRNA was
      translated in vitro in a wheat germ cell-free translation system (WG-CFS), and
      enzyme-specific ternary complexes were affinity selected on a methotrexate-BSA
      coated 96-well microtiter plate (methotrexate, MTX, is an inhibitor of DHFR
      enzymatic activity). Bounded ternary complexes were eluted by MTX treatment. mRNA
      from eluates was amplified by template-switch RT-PCR and products of RT-PCR
      analyzed by gel electrophoresis. The cDNA was amplified by one-step reverse
      transcription-PCR and used for transcription, followed by translation and
      determination of the DHFR enzymatic activity in translation mixtures. This method
      is suitable for direct cDNA cloning from mRNA or cDNA libraries and for
      investigation of protein-protein interactions.

PMID- 12470277
TI  - Solution-phase parallel synthesis of an isoflavone library for the discovery of
      novel antigiardial agents.
AB  - Combinatorial chemistry has become a dramatically useful tool for the development
      of new medicinal agents. In the search to discover a novel and effective lead for
      the treatment of giardiasis, solution-phase synthesis of a library of isoflavone
      derivatives has been accomplished. Of the products screened, several compounds
      such as P(A1,B1) and P(A1,B11) exhibited potent antigiardial activity. The
      details of synthesis, in vitro antigiardial assay, and preliminary structure
      activity relationships of these compounds are described.

PMID- 12470278
TI  - Generation of anti-colorectal cancer fab phage display libraries with a high
      percentage of diverse antigen-reactive clones.
AB  - A combinatorial Fab phage display library was generated from the antibody
      variable region genes of each of 2 BALB/c mice immunized with the human
      colorectal cancer cell lines SW480, SW948, and SW837. These libraries were shown
      to be diverse by nucleotide sequencing and diagnostic restriction enzyme
      digestion (fingerprinting) of individual members. The two libraries were combined
      and selected for binding to a suspension of formaldehyde-fixed human colorectal
      cancer cells in two successive rounds of selection and phage amplification by
      infection of bacteria. Analysis of the selected libraries as well as individual
      library clones by ELISA, showed binding to the cancer cell lines in both
      formaldehyde-fixed and native forms. Fifty five percent and 94% of library clones
      were positive for colorectal cancer cell binding after the first and second
      rounds of selection, respectively. Fingerprinting of individual clones showed the
      first round selected library to be very diverse and the second round selected
      library to be of more limited diversity. After absorption with normal human cell
      types, these anti-cancer selected libraries could be used to develop therapeutic
      and/or diagnostic agents.

PMID- 12470279
TI  - High throughput synthesis of ester library utilizing selective molecular
      reactivity and recognition technology.
AB  - This paper reports a new solid support reagent that showed high degrees of
      selective molecular reactivity and molecular recognition in homo-functional
      reactions (reactions having similar reactive functionality in reactants and
      products).

PMID- 12470280
TI  - Predicting drug-likeness: why and how?
AB  - There exists a huge attrition rate of molecules in clinical trials. It was
      expected that high-throughput screening and combinatorial chemistry would make
      the task of producing drugs easier. However, the efforts of the past decade have
      not been an unvarnished success. As a result, a lot of experimental and
      computational efforts are currently being directed at determining the basic
      requirements for a molecule to become a drug. Here we will review the
      physiological, structural, and other requirements for obtaining a molecule that
      will be successful in the clinic. Following this we will provide a description,
      analysis, and commentary on the computational efforts in this direction. We will
      focus both on the traditional computational chemistry perspective of starting
      from the structure of the molecule as well as the traditional computational
      pharmaceutical scientist's perspective of physiologically based simulations. We
      end with a few comments about the future and some ideas on re-organizing the
      pharmaceutical enterprise.

PMID- 12470281
TI  - In Silico and Ex silico ADME approaches for drug discovery.
AB  - The high attrition rate of drug candidates during clinical trials for poor
      pharmacokinetic and metabolic properties has created a need to do these studies
      as early as it is possible during the drug discovery process. In addition the
      most successful drug is often not the most potent one but the one that has the
      suitable level of potency, safety, and pharmacokinetics. Science and technology
      development during the last few years and the generation of last databases and
      information has created the basis for doing early experimental PK and ADME
      studies in addition to eADME. Similarly, testing safety features as early as
      possible is key to affordable drug discovery and development. Throughput and cost
      are crucial for early application. In silico methods have by far the highest
      throughput, followed by the in vitro and in vivo approaches. On the other hand,
      with regard to relevance and reliability of data the ranking is the opposite. The
      great challenge for in silico methods is generation of models that correlate more
      closely with in vivo systems. For the in vitro assays increasing the throughput
      is an absolute must. Ex silico methods that combine in silico predictions with
      experimental methods are new additions to the scientific repertoire (e.g.
      Chromatographic Hydrophobicity Index that is deduced from the reverse phase HPLC
      data can be used for calculation of lipophilicity). The emerging new approaches
      have clear impact on the design of early stage screening and combinatorial
      libraries. In addition to the Lipinski's rules descriptors such as number of
      rotatable bonds, number of aromatic rings, branching behavior and polar surface
      area (PSA) are commonly used is the drug design process.

PMID- 12470282
TI  - Retrospect and prospect of virtual screening in drug discovery.
AB  - We review the prominent technologies in virtual screening, and their applications
      in drug discovery.

PMID- 12470283
TI  - History and evolution of the pharmacophore concept in computer-aided drug design.
AB  - With computer-aided drug design established as an integral part of the lead
      discovery and optimization process, pharmacophores have become a focal point for
      conceptualizing and understanding receptor-ligand interactions.  In the structure
      based design process, pharmacophores can be used to align molecules based on the
      three-dimensional arrangement of chemical features or to develop predictive
      models (e.g., 3D-QSAR) that correlate with the experimental activities of a given
      training set. Pharmacophores can be also used as search queries for retrieving
      potential leads from structural databases, for designing molecules with specific
      desired attributes, or as fingerprints for assessing similarity and diversity of
      molecules.   This review article presents a historical perspective on the
      evolution and use of the pharmacophore concept in the pharmaceutical,
      biotechnology, and fragrances industry with published examples of how the
      technology has contributed and advanced the field.

PMID- 12470284
TI  - The present utility and future potential for medicinal chemistry of QSAR/QSPR
      with whole molecule descriptors.
AB  - Whole-molecule descriptors are obtained computationally from molecular structures
      using a variety of programs. Their applications are reviewed in the areas of
      solubility, bioavailability, bio- and nonbio-degradability and toxicity.

PMID- 12470285
TI  - QSAR: then and now.
AB  - In this review, the evolution of QSAR is traced from the insightful observations
      of Crum-Brown and Frazier to Hammett's critical equations and finally Hansch's
      seminal contributions on hydrophobicity and modelling of biological activity
      based on extrathermodynamic principles. Today's QSAR models can stand alone,
      augment other graphical approaches or be examined in tandem with equations of a
      similar mechanistic genre to truly reveal the power of the paradigm. This review
      will focus on the three standard classifications routinely used in QSAR analysis 
      electronic, hydrophobic, and steric, as well as topological indices. Electronic
      parameters will focus on Hammett sigma constants and their numerous variations.
      Dipole moments, hydrogen bond descriptors and quantum chemical indices as well as
      applications of their utilization will be described. The hydrophobicity parameter
      will be examined by tracing its early history, its operational definition and its
      determination by either experimental methods or computational calculations.
      Steric parameters, which run the gamut from size to shape, will be described by
      Taft's, Hancock's, Charton's, Fujita's, Verloop's and Simon's contributions.
      Topological effects, delineated by connectivity indices, kappa shape and
      electrotopological indices of Kier and Hall are also described. Examples of QSAR
      models incorporating most of these parameters are reviewed. In cases where the
      95% confidence intervals of variables are available, they are listed in
      parentheses. A brief Comparative QSAR analysis of non-nucleoside reverse
      transcriptase inhibitors (NNRTI's) is outlined and various models obtained by
      different groups examining 4, 5, 6, 7-tetrahydro-5-methylimidazo [4, 5,1
      j,k][1,4] benzodiazepin-2(1H)-ones (TIBO) and 1-[(2-hydroxyethoxy)methyl]-6
      (phenylthio)-thymine (HEPT) derivatives are compared for mechanistic insight that
      could be useful in the process of inhibitor design.

PMID- 12470286
TI  - Current state and perspectives of 3D-QSAR.
AB  - Quantitative structure-activity relationships (QSAR) have played an important
      role in the design of pharmaceuticals and agrochemicals. All QSAR techniques
      assume that all the compounds used in analyses bind to the same site of the same
      biological target. However, each method differs in how it describes structural
      properties of compounds and how it finds the quantitative relationships between
      the properties and activities. The Hansch-Fujita approach, the so-called
      classical QSAR, is a representative of QSAR methods. Despite the usefulness,
      classical QSAR techniques cannot be applied to all datasets due to the lack of
      availability of physicochemical parameters of the whole molecule or its
      substituents and often it is difficult to estimate those values. In addition,
      molecular properties based on the three dimensional (3D) structure of compounds
      may be useful in describing the ligand-receptor interactions. Recently, a variety
      of ligand-based 3D-QSAR methods such as Comparative Molecular Field Analysis
      (CoMFA) have been developed and widely used in medicinal chemistry. This review
      describes different 3D-QSAR techniques and indicates their advantages and
      disadvantages. Several studies about 3D-QSAR of ADME-toxicity and perspective of
      3D-QSAR are also described in this review.

PMID- 12470287
TI  - Superior oblique recession update.

PMID- 12470288
TI  - PEDIG study on amblyopia; vision therapy by atropine penalization versus
      occlusion.

PMID- 12470290
TI  - The oval of adequate binocular alignment: just how straight do the eyes of an
      infantile esotropia have to be maintained to preserve stereopsis and binocular
      vision?
AB  - PURPOSE: To measure the maximum exotropic and hypertropic deviations compatible
      with at least gross stereopsis in a group of treated infantile esotropes.
      METHODS: Over a ten year period (1992-2002) all former (i.e. surgically
      corrected) infantile esotropes now ages 10 to 23 years old coming into my office
      for routine long term followup visits were tested for the presence of at least
      gross stereopsis on the classic Titmus Stereo Test (Stereo Optical Co., Inc.,
      3539 N Kenton Ave, Chicago IL 60641). For the approximately 40% who demonstrated
      at least gross stereopsis on this test at near in either the primary position or
      in downgaze, further stereo testing was performed if the patient had a manifest
      deviation in other positions of gazes that was more than two prism diopters more
      than the position in which stereopsis was originally found. Testing in these
      other positions of gaze was performed no more than 20 degrees away from the
      primary position so that the standard Polaroid glasses could be used with the
      test. The deviation at which the patient reported that the "fly went flat" was
      taken as the end point. RESULTS: Among 22 with more XT in a position of gaze away
      from the position where they demonstrated stereopsis, 2 lost stereopsis at 5
      prism diopters (pd) XT, 10 lost stereopsis at 6 pd XT, 8 lost stereopsis at 7 pd
      XT, 1 lost stereopsis at 8 pd XT, and 1 preserved stereopsis until the deviation
      was 9 pd XT. Among 8 with more HT in a position of gaze away from the position
      where they demonstrated stereopsis, 1 lost stereopsis at 2 pd HT, 1 at 5 pd HT, 4
      at 6 pd HT, 1 at 7 pd HT, and 1 at 8 pd HT. The averages were 6.5 pd XT and 6.3
      pd HT (with the 2 pd HT excluded as an outlier). CONCLUSIONS: To maintain
      stereopsis among those infantile esotropes for whom stereopsis is possible, an
      exotropia of more than 6 pd XT or a hypertropia of more than 6 pd HT should not
      be tolerated. These limits can be combined with criteria from other studies to
      produce a diagram, the oval of adequate binocular alignment.

PMID- 12470291
TI  - Maximal subtotal extirpation of the horizontal rectus extraocular muscles for the
      treatment of nystagmus with no null point. A report of four successful human
      cases.
AB  - PURPOSE: To evaluate the visual and restoration of normal appearance results of
      maximal excision of the horizontal rectus muscles in nystagmus patients. SETTING:
      Menelik II Hospital, Addis Ababa, Ethiopia and the Sinskey Eye Institute, Santa
      Monica, California. METHODS: The medial and lateral rectus muscles were
      extirpated as far back as possible with an enucleation snare in four patients
      with horizontal nystagmus. A complete eye examination was performed pre- and
      postoperatively. Using a camcorder, ocular movements were recorded before
      surgery, and at postop; days 1 and 40, and months 1, 3 and 10. RESULTS: All four
      patients had a marked reduction in both abnormal and normal horizontal eye
      movement, and improvement in objective visual acuity. Postoperative residual
      intermittent fine horizontal movement was recorded in the left eye in a 6 year
      old and in both eyes of a 41 year old patient. A residual rotary component was
      recorded in a 15 year-old patient. The 6 and 9 year-old patients each developed a
      moderate exotropia. The 15 and 41 year-old patients maintained binocular fusion
      with some residual ability to converge. Vision increased subjectively in all
      cases. CONCLUSION: Subtotal myectomy of the horizontal muscles in horizontal
      nystagmus with no null point was very effective in improving and/or eliminating
      horizontal eye movement. Restoration of normal or near normal appearance and
      improvement in visual acuity occurred in all cases. None of the patients
      complained of their loss of horizontal gaze and eye movement. More complete
      myectomy of the muscles should produce total elimination of both normal and
      abnormal horizontal eye movement including nystagmus.

PMID- 12470293
TI  - Grand rounds #68: a case of consecutive exotropia after recession of all four
      horizontal rectus muscles for the treatment of nystagmus.

PMID- 12470294
TI  - The attenuating effect of intraglossal atropine on the oculocardiac reflex.
AB  - INTRODUCTION: Bradycardia during strabismus surgery is reduced better by
      intravenous than by intramuscular (deltoid) anticholinergics, but recent studies
      suggest that injection into the tongue works faster than into the deltoid. We
      sought to study this using the suppression of the oculocardiac reflex during eye
      surgery as a parameter. METHODS: 804 children and adults underwent calibrated
      extraocular muscle tensioning during controlled, inhalational general anesthesia.
      A systemic anticholinergic agent was distributed by different routes to patient
      subject sub-groups: preoperative oral, or induction intravenous, intramuscular
      (deltoid) and intraglossal (submucosal at the base of the tongue). A large
      control group received no anticholinergic. RESULTS: The control group had an
      oculocardiac reflex averaging 17.2% heart rate reduction (bradycardia), 6% of
      whom had greater than a 50% heart rate reduction. This oculocardiac reflex
      bradycardia was reduced to only a 6.7% heart rate reduction by oral and
      intradeltoid routes and was essentially eliminated by both intravenous (-2.3%)
      and intraglossal (-0.9%) routes. CONCLUSION: Intraglossal atropine is an
      effective alternative for oculocardiac reflex prophylaxis when intravenous access
      is not readily available in strabismus surgery. The intraglossal route is in fact
      slightly more effective in this regard that the intravenous route per se.

PMID- 12470295
TI  - The Moldova logs. A second report of international ophthalmology in Moldova.

PMID- 12470297
TI  - Targeting of alpha-kinase-anchoring protein (alpha KAP) to sarcoplasmic reticulum
      and nuclei of skeletal muscle.
AB  - The sarcoplasmic reticulum (SR) plays a key role in excitation/contraction
      coupling of skeletal muscle. The SR is composed of two continuous yet
      heterogeneous membrane compartments, the free or longitudinal SR and cisternal
      SR. Cisternal SR is made up of free SR membrane, enriched in Ca(2+) pumps, and
      junctional SR (jSR) membrane, enriched in ryanodine-sensitive Ca(2+)-release
      channels, and contains calsequestrin within its lumen. Protein phosphorylation
      mediated by the Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II) has
      significant, distinct regulatory roles in both Ca(2+) uptake and Ca(2+) release.
      Kinase-anchoring proteins (KAPs) constitute a novel mechanism for achieving cell
      compartmentalization of effectors in phosphorylation pathways. Here, targeting of
      alpha KAP, a CaM kinase II-anchoring protein encoded within the alpha-CaM kinase
      II gene, was studied in transgenic skeletal muscle fibres of the adult rat
      soleus. The transgenes were epitope-tagged versions of alpha KAP and of a
      deletion mutant, allowing their specific immunodetection against the wild-type
      background. Our results show that alpha KAP is largely localized at the free SR
      and thus near the Ca(2+) pump, a protein that can be modulated by CaM kinase II
      phosphorylation. Only minor co-localization was observed with the jSR ryanodine
      sensitive Ca(2+)-release channel, which is a potential CaM kinase II target. In
      non-muscle cells, recombinant alpha KAP is targeted to endoplasmic reticulum
      (ER). Both ER and SR targeting requires the N-terminal hydrophobic region of
      alpha KAP. An unexpected additional specific localization that does not require
      the N-terminus was found in the nucleus, providing a first clue of how CaM kinase
      II can fulfil its nuclear functions in skeletal muscle.

PMID- 12470296
TI  - Potentiation of liver X receptor transcriptional activity by peroxisome
      proliferator-activated receptor gamma co-activator 1 alpha.
AB  - Peroxisome-proliferator-activated receptor (PPAR) gamma co-activator 1 alpha (PGC
      1 alpha/PPARGC1) plays an important role in energy metabolism by co-ordinating
      transcriptional programmes of mitochondrial biogenesis, adaptive thermogenesis
      and fatty acid beta-oxidation. PGC-1 alpha has also been identified to play a
      role in the intermediary metabolism by co-activating key transcription factors of
      hepatic gluconeogenesis and glucose uptake in muscles. In the present study, we
      show that PGC-1 alpha serves as a co-activator for the liver X receptor (LXR)
      alpha, known to contribute to the regulation of cellular cholesterol
      homoeostasis. In transient transfection studies, PGC-1 alpha amplified the LXR
      mediated autoregulation of the LXR alpha promoter in a human brown adipocyte line
      and in 3T3-L1 cells via an LXR response element described previously. LXR
      mediated transactivation via a natural LXR response element from the cholesteryl
      ester transfer-protein gene promoter was also enhanced by PGC-1 alpha in a ligand
      dependent manner. Mutational analysis showed that the LXXLL signature motif (L2)
      of PGC-1 alpha was essential for co-activation of LXR-mediated transcriptional
      responses. This motif is located in the vicinity of the binding region for a
      putative repressor described previously. The repressor sequesters PGC-1 alpha
      from PPAR alpha and the glucocorticoid receptor, and this repressor did not
      interfere with PGC-1 alpha-mediated co-activation of LXR-dependent gene
      transcription. Moreover, inhibition of p38 mitogen-activated protein kinase
      signalling, shown to abolish the co-activation of PPAR alpha by PGC-1 alpha, had
      only a moderate inhibitory effect on the co-activation of LXR. These results
      identify PGC-1 alpha as a bona fide LXR co-activator and implicate distinct
      interfaces of PGC-1 alpha and/or additional cofactors in the modulation of LXR
      and PPAR alpha transcriptional activities.

PMID- 12470298
TI  - Reactive oxygen species mediate the down-regulation of mitochondrial transcripts
      and proteins by tumour necrosis factor-alpha in L929 cells.
AB  - In this study, we show that reactive oxygen species production induced by tumour
      necrosis factor alpha (TNF-alpha) in L929 cells was associated with a decrease in
      the steady-state mRNA levels of the mitochondrial transcript ATPase 6-8.
      Simultaneously, the transcript levels of two nuclear-encoded glycolytic enzymes,
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphofructokinase, were
      increased. These changes were associated with decreased protein levels of the
      ATPase subunit a (encoded by the mitochondrial ATPase 6 gene) and cytochrome c
      oxidase subunit II, and increased protein levels of phosphofructokinase. Since
      TNF-alpha had no effect on the amount of mitochondrial DNA, the results suggested
      that TNF-alpha acted at the transcriptional and/or post-transcriptional level.
      Reactive oxygen species scavengers, such as butylated hydroxianisole and
      butylated hydroxytoluene, blocked the production of free radicals, prevented the
      down-regulation of ATPase 6-8 transcripts, preserved the protein levels of ATPase
      subunit a and cytochrome c oxidase subunit II, and attenuated the cytotoxic
      response to TNF-alpha, indicating a direct link between these two phenomena.

PMID- 12470299
TI  - Murine serpin 2A is a redox-sensitive intracellular protein.
AB  - Murine serpin 2A is expressed at high levels in haemopoietic progenitors and down
      regulated on differentiation. When it is constitutively expressed in the
      multipotent haemopoietic cell line, FDCP-Mix, it causes a delay in
      differentiation and increased clonogenic potential. The serpin is also
      dramatically up-regulated on T-cell activation. It has an unusual reactive site
      Cys-Cys sequence, a unique C-terminal extension and lacks a typical cleavable N
      terminal signal sequence. In spite of these features, the protein is not a member
      of the ovalbumin-serpin family, but is instead most closely related to human
      antichymotrypsin. We have shown that the serpin is intracellular with prominent
      nuclear localization. Transverse urea gradient gels and CD studies show that the
      protein undergoes the stressed-relaxed conformational change typical of
      inhibitory serpins. However, we have not detected complex-forming activity with a
      set of proteases. Thermal denaturation studies also show that the protein has
      decreased structural stability under reducing conditions, although it lacks
      disulphide bonds within the core of the molecule. Our results show that serpin 2A
      is an intracellular protein with the potential to mediate its biological effects
      via interaction with non-protease intracellular targets. Furthermore, the results
      presented suggest a model whereby the serpin interactions could be modulated by
      redox conditions or conformational change induced by cleavage of the reactive
      site loop.

PMID- 12470300
TI  - Assessment of the role of sphingosine 1-phosphate and its receptors in high
      density lipoprotein-induced stimulation of astroglial cell function.
AB  - It has been suggested that lipoproteins in the central nervous system are
      involved in the regulation of several neural functions independent of cholesterol
      metabolism as well as those related to lipid metabolism. We recently demonstrated
      that lipoproteins are carriers for sphingosine 1-phosphate (S1P). This raised the
      possibility that S1P mediates the neural cell functions induced by lipoproteins.
      In the current study, we examined the effects of plasma high-density lipoprotein
      (HDL) on astroglial cell functions, focusing especially on the role of the
      lipoprotein-associated S1P. In rat type I astrocytes or C6 glioma cells, similar
      to S1P, HDL stimulated DNA synthesis and mRNA expression of fibroblast growth
      factor-2, a potent neurotrophic factor, which was associated with the activation
      of extracellular signal-regulated kinase (ERK) in a pertussis toxin-sensitive
      manner. The data from fractionation studies of HDL indicated that S1P may be a
      major component for the activation of ERK. In C6 glioma cells, HDL also induced
      phospholipase C-dependent intracellular Ca(2+) mobilization. Desensitization of
      the C6 glioma cells with S1P abolished these HDL-induced actions. Furthermore,
      overexpression of S1P receptors in C6 glioma cells led to a significant
      enhancement of HDL-induced ERK activation and Ca(2+) mobilization. Thus, at least
      some HDL-induced actions may be mediated by cell-surface S1P receptors in
      astroglial cells. These results imply that S1P might partially mediate
      lipoprotein-induced cholesterol metabolism-independent neural cell functions in
      the central nervous system.

PMID- 12470301
TI  - Treatment of hyperfunctioning thyroid nodules by percutaneous ethanol injection.
AB  - BACKGROUND: Autonomous thyroid nodules can be treated by a variety of methods. We
      assessed the efficacy of percutaneous ethanol injection in treating autonomous
      thyroid nodules. METHODS: 35 patients diagnosed by technetium-99 scanning with
      hyperfunctioning nodules and suppressed sensitive TSH (sTSH) were given sterile
      ethanol injections under ultrasound guidance. 29 patients had clinical and
      biochemical hyperthyroidism. The other 6 had sub-clinical hyperthyroidism with
      suppressed sTSH levels (<0.24 &mgr;IU/ml) and normal thyroid hormone levels.
      Ethanol injections were performed once every 1-4 weeks. Ethanol injections were
      stopped when serum T3, T4 and sTSH levels had returned to normal, or else
      injections could no longer be performed because significant side effects.
      Patients were followed up at 3, 6 and, in 15 patients, 24 months after the last
      injection. RESULTS: Average pre-treatment nodule volume [18.2 PlusMinus; 12.7 ml]
      decreased to 5.7 PlusMinus; 4.6 ml at 6 months follow-up [P < 0.001]. All
      patients had normal thyroid hormone levels at 3 and 6 months follow-up [P < 0.001
      relative to baseline]. sTSH levels increased from 0.09 PlusMinus; 0.02 &mgr;IU/ml
      to 0.65 PlusMinus; 0.8 &mgr;IU/ml at the end of therapy [P < 0.05]. Only 3
      patients had persistent sTSH suppression at 6 months post-therapy. T4 and sTSH
      did not change significantly between 6 months and 2 years [P > 0.05]. Ethanol
      injections were well tolerated by the patients, with only 2 cases of transient
      dysphonia. CONCLUSION: Our findings indicate that ethanol injection is an
      alternative to surgery or radioactive iodine in the treatment of autonomous
      thyroid nodules.

PMID- 12470303
TI  - Psychiatry within Nordic countries.

PMID- 12470304
TI  - Symptom dimensions and their association with outcome and treatment setting in
      long-term schizophrenia. Results of the DSP project.
AB  - National representative samples of 1571 schizophrenia patients discharged from
      mental hospitals in Finland in 1990 and 1994 were interviewed 3 years after
      discharge. The symptom items assessed by the PANSS were factorized and orthogonal
      rotations were performed. Five factor dimensions, negative, positive, depressive,
      hostile and disorganization dimension, were obtained and correlated with data of
      patients' socio-demographic background, clinical history, condition and outcome.
      The negative dimension was more prominent in male and single patients, the
      depressive dimension in female and divorced patients. Patients with early onset
      and long duration of illness had high disorganization scores. Patients with
      disorganized subtype of schizophrenia had high scores in positive and
      disorganization dimensions. High scores in all, especially in negative and
      positive dimensions, were associated with poor psychosocial situation. Symptom
      dimensions varied also according to treatment setting at follow-up. Symptom
      dimensions of long-term schizophrenia patients in the community are closely
      associated with patients' socio-demographic background, clinical history and
      conditions, as well as with outcome and the treatment patients receive. A
      dimensional approach, instead of a categorical one, seems to be important in
      assessing symptomatology and its relation to outcome and interventions in
      schizophrenia.

PMID- 12470302
TI  - Activation of the Syk tyrosine kinase is insufficient for downstream signal
      transduction in B lymphocytes.
AB  - BACKGROUND: Immature B lymphocytes and certain B cell lymphomas undergo apoptotic
      cell death following activation of the B cell antigen receptor (BCR) signal
      transduction pathway. Several biochemical changes occur in response to BCR
      engagement, including activation of the Syk tyrosine kinase. Although Syk
      activation appears to be necessary for some downstream biochemical and cellular
      responses, the signaling events that precede Syk activation remain ill defined.
      In addition, the requirements for complete activation of the Syk-dependent
      signaling step remain to be elucidated. RESULTS: A mutant form of Syk carrying a
      combination of a K395A substitution in the kinase domain and substitutions of
      three phenylalanines (3F) for the three C-terminal tyrosines was expressed in a
      murine B cell lymphoma cell line, BCL1.3B3 to interfere with normal Syk
      regulation as a means to examine the Syk activation step in BCR signaling.
      Introduction of this kinase-inactive mutant led to the constitutive activation of
      the endogenous wildtype Syk enzyme in the absence of receptor engagement through
      a 'dominant-positive' effect. Under these conditions, Syk kinase activation
      occurred in the absence of phosphorylation on Syk tyrosine residues. Although Syk
      appears to be required for BCR-induced apoptosis in several systems, no increase
      in spontaneous cell death was observed in these cells. Surprisingly, although the
      endogenous Syk kinase was enzymatically active, no enhancement in the
      phosphorylation of cytoplasmic proteins, including phospholipase Cgamma2
      (PLCgamma2), a direct Syk target, was observed. CONCLUSION: These data indicate
      that activation of Syk kinase enzymatic activity is insufficient for Syk
      dependent signal transduction. This observation suggests that other events are
      required for efficient signaling. We speculate that localization of the active
      enzyme to a receptor complex specifically assembled for signal transduction may
      be the missing event.

PMID- 12470305
TI  - Alexithymia, social support, psycho-social stress and mental health in a female
      population.
AB  - BACKGROUND: We wanted to look into what impact the level of alexithymia, as
      assessed by the Toronto Alexithymia Scale with 20 items (TAS-20), has on presence
      of social support and vulnerability for psycho-social stress assessed as
      occurrence of serious life-events, in an all-female population. METHODS: A total
      of 1032 of females employed in a child-care programme in Sweden participated.
      They were asked to fill in a questionnaire and 864 (83.6%) delivered complete
      tests. RESULTS: The prevalence of alexithymia was 7.9% and there were significant
      associations between high TAS-20 scores with low level of education. In addition,
      this assessment showed significant relationships between global TAS-20, as well
      as the sub-factors of TAS-20 and lower social support. Having a low level of
      social support was found to be 3.5 times more common in the part of the
      population who was alexithymic. It was also 2.6 times more common for the
      alexithymic part of the population not to have someone to turn to. Alexithymics
      with low support and no life events had overall mean scores on all the three
      variables presenting them as worse off from a mental health point of view. When
      life events were present alexithymics remained worse off than non-alexithymics
      even when a higher level of support was in place. There was a significant direct
      protective (salutary) effect of social support found for social disability in the
      alexithymic population. CONCLUSION: Alexithymics in this study showed a lack of
      social support and a proneness to high levels of negative emotion and to social
      distress.

PMID- 12470306
TI  - Comparison of psychiatric inpatient suicides with suicides completed in the
      surrounding community.
AB  - We compared main characteristics of 58 (22 male and 36 female) psychiatric
      inpatients that committed suicide in the psychiatric hospital with all 1261
      suicides (956 male and 305 female) that occurred outside hospitals in the same
      health district of Slovenia, all these in the period between 1985 and 1993. The
      independent t-test and cross-tabulation were used to compare the two groups on
      age, sex, marital status and suicide method profile. It appeared that female
      suicide is much more frequent in the psychiatric inpatients' group than in
      others. Only male psychiatric inpatients' suicides are younger than other suicide
      victims. Psychiatric inpatients use methods like jumping from high places and
      drowning more often than do others, which goes in line with the availability of
      methods of suicide. Apparently, the studied hospital has some wards on the third
      floor and majority of acute wards are located by the river. However, psychiatric
      inpatients do not differ from other suicide victims on marital status. Higher
      suicide rates in men compared with women in the population, but not in
      psychiatric inpatients, could be explained by the presence of so-called atypical,
      clinically unrecognized depression in the male population.

PMID- 12470307
TI  - Predicting use of coercive measures in Finland.
AB  - The prevalence of use of seclusion and restraints in psychiatric treatment has
      varied dramatically among institutions, according to previous studies. We
      investigated the factors predicting overall and "heavy use" of restrictive
      measures and differences in the population-based rates of use of seclusion and
      restraints in three university psychiatric centres in Finland (Turku, Tampere and
      Oulu) using a retrospective chart review. The material comprised all civil
      admissions to the study hospitals of working-aged people during a period of 6
      months in 1996. There were significant differences among the studied centres as
      to the population-based level of use of seclusion and restraints. Oulu used
      significantly less seclusion but had a significantly higher level of use of
      restraints than Turku and Tampere. The individual institutions best predicted the
      overall use of restrictive interventions, whereas previous commitments and
      involuntary legal status on admission were factors predicting "heavy use" of
      these measures. Our results suggest that the implementation and monitoring of
      restrictive measures could be further harmonized.

PMID- 12470308
TI  - A case-control study of EAS child and parental temperaments in selectively mute
      children with and without a co-morbid communication disorder.
AB  - Clarification of sub-groups of children with selective mutism (SM) may enhance
      the understanding of symptom development. The present case-control study compares
      temperament characteristics applying EAS temperament survey in SM children with a
      co-morbid communication disorder (CoD), SM children without CoD and matched
      controls. Temperament characteristics in the parents are compared as well. The
      results show that SM children with CoD are characterized by more emotional
      stability and higher sociability than SM children without CoD. The parents of the
      SM children with CoD did not differ in temperament characteristics from the
      control parents. The parents of the SM children without CoD differed from the
      controls on the Distress, Fear and Activity scales. The study suggests different
      familial transmission in the two sub-groups of children with SM.

PMID- 12470309
TI  - Family relations, family climate and sexual abuse.
AB  - In Europe, 10-20% of all women and 3-10% of all men have experienced sexual abuse
      before the age of 18, according to surveys. Psychosocial problems are often seen
      as both short- and long-term consequences of such abuse. Family dysfunction may
      be seen as both a risk factor for abuse and a result of the disclosure of abuse.
      The aim of this research was to study how adolescents and adults, sexually abused
      during their childhood, experienced their family life and family climate in their
      family of origin. A clinical sample of 18 adolescent girls and 20 adult women
      comprised the study group. The methods used were a semi-structured interview and
      the questionnaire Family Climate Test. The majority of the participants kept
      quiet about the abuse during their childhood. The abuse took place for an average
      of 2.5 years among the adolescents and 6 years in the adult group. Secrecy,
      isolation and family problems were typical attributes in the interviews. The
      majority of both adolescents and women described their relationships in the
      family of origin as deviant or interrupted, with a reversed (negative) pattern on
      the Family Climate Test. This meant a low level of closeness and a high level of
      distance in the families combined with a low level of spontaneity and a high
      level of chaos. The study, even if relatively small and based on clinical cases,
      gives support to earlier research, which shows that sexual abuse in general, but
      especially intra-familial sexual abuse, is associated with family dysfunction.

PMID- 12470310
TI  - Anorexia nervosa in teenagers: change in family function after family therapy, at
      2-year follow-up.
AB  - Family therapy has emerged as the treatment of choice for young patients with
      anorexia nervosa, yet there is insufficient knowledge about what actually happens
      within the family unit in these cases. The purpose of the present study was to
      investigate how a family undergoing treatment due to an anorectic child changes
      their mode of functioning. Twenty-six families were studied. The concepts chosen
      in the study were closely linked to fundamental principles advocated by the
      therapeutic model used in the treatment, using a multi-method approach with both
      observer ratings and self-rating questionnaires. According to observer ratings,
      the families had changed towards a more functional pattern on all dimensions
      rated. They had a clearer hierarchy and a higher degree of competency. Cohesion
      and Adaptability had changed towards a more balanced pattern, away from
      enmeshment and rigidity. According to self-ratings, the families changed toward
      more expressiveness. Families where the patient had recovered were less enmeshed
      at follow-up. We also found a tendency towards higher degree of competence in
      these families.

PMID- 12470311
TI  - Two decades of "research-practice" encounters in the development of European
      therapeutic communities for substance abusers.
AB  - In 1981, a "research-practice" breakthrough was realized through the foundation
      of the European Federation of Therapeutic Communities (EFTC). Since its
      foundation EFTC regularly organized conferences and symposia. A few years later
      (in 1983), the European Workshop On Drug policy Oriented Research (EWODOR) was
      established at the Erasmus University in Rotterdam, including a special section
      devoted to the therapeutic community (TC). The authors examined the proceedings
      of all meetings organized by EFTC and EWODOR. The major topics presented
      throughout the last 20 years are highlighted in a chronological selection and
      these presentations largely focus on the challenges of the TC and the state of
      the art regarding scientific knowledge. In this overview only those authors who
      published articles in scientific journals indexed in the "Web of Science"
      (Institute for Scientific Information-ISI) were retained. Although research has
      never been the primary consideration in TCs, it played a far from negligible role
      in its development. Research findings prompted innovations and thus often
      provoked resistance, but on the other hand they functioned as a catalyst between
      the necessity of a belief system and the reality of society. The role of "grey"
      literature and the availability of information through the Internet will become
      more and more important in the communication between researchers and
      practitioners.

PMID- 12470312
TI  - Readmission rates and planning of mental health services (increasing readmissions
      in Andalusia, Spain).

PMID- 12470313
TI  - Attention deficit hyperactivity disorder.

PMID- 12470314
TI  - The prevalence of DSM-III-R "prodromal" symptoms of schizophrenia in non
      psychotic psychiatric outpatients.
AB  - A cross-sectional point prevalence study of the DSM-III-R prodromal symptoms in
      non-psychotic (n = 501) consecutive outpatients from a catchment area with 260000
      inhabitants is presented. The relationship between the three most psychosis
      specific prodromal symptoms and the development of psychosis during the following
      6 months was also explored. The prevalence of any prodromal symptom was 25%, the
      most prevalent being impairment of role functioning (14%), isolation and
      withdrawal (11%) and lack of initiative (8%). The most prevalent symptom in
      affective disorders was lack of initiative (14%); in personality disorders, it
      was impairment of role functioning (21%). The prevalences of the most psychosis
      specific symptoms "peculiar behaviour", "magical thinking" and "unusual
      perceptual experiences" was 1-2%. At re-evaluation 6 months later, three of 20
      patients (15%) with one or more such symptoms had become psychotic, two with
      schizoaffective disorder, one with affective psychosis. It was concluded that DSM
      III prodromal symptoms are common among non-psychotic outpatients, but most such
      symptoms are non-specific for psychosis. Persistent peculiar behaviour, magical
      thinking and unusual perceptual experiences have a very low prevalence but may
      indicate an increased risk for psychosis. Such patients should be followed with
      that risk in mind.

PMID- 12470315
TI  - Stress response symptoms in relatives of acutely admitted psychotic patients: a
      pilot study.
AB  - OBJECTIVE: The aim of this study is to identify specific stress response symptoms
      in relatives of acutely admitted psychotic patients, and to compare these
      responses with those of relatives of chronic inpatients. METHOD: Twenty-five
      relatives of acutely hospitalized, psychotic patients and 21 relatives of chronic
      inpatients were assessed within days of the acute patient's admission and 6 weeks
      later. The Impact Event Scale assessed intrusion and avoidance; items from the
      General Health Questionnaire (GHQ) and the Spielberger State Anxiety Inventory
      (STAI) assessed arousal. RESULTS: At the first assessment, relatives of the
      acutely admitted psychotic patients reported higher intensity of intrusive
      symptoms, and more often a high arousal level compared to the relatives of
      chronic inpatients. Six weeks later, relatives of acutely admitted psychotic
      patients revealed both higher intensity and higher number of intrusive and
      avoidance symptoms, and higher level of arousal symptoms. Seven relatives of
      acutely admitted psychotic patients and no relatives of the chronic inpatients
      reported moderate to high level of intrusion, avoidance and arousal at both
      assessments. CONCLUSION: Relatives of acutely admitted psychotic patients
      revealed strong acute and persistent stress responses, similar to those described
      in subjects exposed to severe or life threatening illness. Even relatives of the
      chronic inpatients revealed stress-specific symptoms, but at a lower level.
      Specific stress response symptoms may impair the relatives' well-being, care
      giving abilities, and their co-operation with the mental health system. Our
      results suggest that stress response symptoms in relatives should be given more
      attention.

PMID- 12470316
TI  - Health-related quality of life among patients with major depression.
AB  - The study compared health-related quality of life in 165 patients with major
      depression and 165 randomly selected and with age- and gender-matched controls
      from a population sample. Health-related quality of life was measured with the
      self-report questionnaire (RAND-36), which consists of eight dimensions. Overall,
      perceived quality of life was broadly reduced among depressive outpatients, and
      as compared with the control group, significant impairment was observed for all
      eight dimensions of health-related quality of life. Accompanying somatic diseases
      causing disability had no additional impact on the reduction of quality of life
      in depressive patients. Depression per se impairs an individual's functioning
      ability in a number of ways. It has a significant effect not only on mental well
      being but also on perceived physical functioning and bodily pain, and even on
      general health perceptions. Major depression seems to explain the broad decline
      in the quality of life among depressive patients.

PMID- 12470317
TI  - The Gotland Male Depression Scale: a validity study in patients with alcohol use
      disorder.
AB  - The Gotland Male Depression Scale has been developed to improve the recognition
      of major depression in males. The Gotland Male Depression Scale was compared to
      the Major Depression Inventory in a population of male patients treated for
      alcohol dependency at the Alcohol Outpatients Clinic of Copenhagen University
      Hospital. The prevalence of depression as well as the prescription of
      antidepressants were used as indices of validation. The Gotland Male Depression
      Scale was shown to have an adequate internal validity. The prevalence of
      depression according to the Major Depression Inventory was 17% and according to
      the Gotland Male Depression Scale 39% of the patients had a probable or definite
      depression and should be considered for treatment with antidepressants. The
      Gotland Depression Subscale was found to be better than the Gotland Distress
      Subscale at discriminating between patients treated and not treated with
      antidepressants.

PMID- 12470318
TI  - The prevalence of chronic fatigue syndrome in Iceland - a national comparison by
      gender drawing on four different criteria.
AB  - The study was carried out to estimate the prevalence of chronic fatigue syndrome
      (CFS) in Iceland. No previous prevalence studies known to us have been undertaken
      in Iceland or in Scandinavia. A 95-item custom-made questionnaire was sent to
      4000 randomly selected people. The response rate was 63%. The questionnaire was
      constructed to include questions on all the items found in the four most common
      criteria for diagnosing CFS; the criteria being Australian, British and American.
      Results show very different prevalences according to the criteria used. The
      prevalence ranged from 0 to 4.9%, with the most established criteria yielding a
      prevalence of 1.4%. Re-test validity of the questionnaire was good, the following
      results are based on the selection criteria by Fukuda et al. (Fukuda K, Straus
      SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A, et al. The chronic fatigue
      syndrome: a comprehensive approach to its definition and study. Ann Int Med
      1994;121:953-9). Women were in a majority (78%); their mean age was 44, they were
      fully employed and worked long hours. They believed that the onset of their
      symptoms was stress related. The type of work was unskilled in the majority of
      cases. A significant proportion of the males felt a constant buzzing in their
      ears (P < 0.05). Food suppliants were used daily by significantly more women than
      men (P < 0.01). Men had more frequently phobic symptoms (P < 0.001) than did
      women. Differences were found in the prevalence of phobia and panic (P < 0.001)
      between women in the CFS group compared to healthy ones. A positive correlation
      was found in the prevalence of phobia between women in the CFS group and those
      with Iceland Disease.

PMID- 12470319
TI  - Do Kurdistanian and Swedish parents and children differ in their rating of
      competence and behavioural problems?
AB  - OBJECTIVE: This paper investigates child self-rating of behavioural problems and
      competence as compared with their parents' ratings, in comparative samples of
      Kurdistanian refugee children in Sweden and a group of Swedish children. METHOD:
      Kurdistanian and Swedish comparative samples composed of 32 children each matched
      in age, sex and trauma level, in the same community, and their parents. Among a
      large battery of instruments, the child behavioural checklist (CBCL) was used in
      separate interviews with parents and their children. RESULTS: When compared to
      the children's self-reported problems scores, the Swedish parents reported
      significantly lower scores than their children, compared to the Kurdistanian
      refugee parents. CONCLUSION: Regardless of cultural backgrounds, there were more
      similarities than differences in the children's reporting of their behavioural
      problems and competence. The discrepancy between the Swedish parents' estimation
      of their children's behavioural problems and the children's self-reported
      behavioural problems could be an effect of the individualistic nature of Swedish
      society compared with the more collective nature of Kurdistanian culture.
      However, the results should be considered hypothesis generating rather than
      conclusive.

PMID- 12470320
TI  - Classroom climate and the mental health of primary school children.
AB  - This study was carried out to examine associations between classroom climate and
      pupils' mental health in primary school, and whether pupils who had emotional and
      behavioural problems in the second grade are more vulnerable to the effects of a
      poor classroom climate 4 years later. The study was carried out by means of
      questionnaires to teachers. The students (n = 861) were surveyed in the second
      (aged 8 years, Time 1) and sixth grade (aged 12 years, Time 2). The Rutter
      Teacher Questionnaire (RB2) at Time 1 and the Teacher Report Form (TRF) at Time 2
      were used to measure internalizing, externalizing and total problem scores.
      Classroom climate was measured using a composite variable at Time 2. The results
      show associations between poor sixth-grade classroom climate and an increase in
      emotional and behavioural problems in both boys and girls. In addition, the girls
      who were overall poorly adjusted, particularly those who had externalizing
      problems in the second grade, were especially vulnerable to a poor classroom
      climate in the sixth grade.

PMID- 12470321
TI  - Sleep in patients with treated Wilson's disease. A questionnaire study.
AB  - OBJECTIVE: To examine general sleep habits and sleep disturbances among patients
      with treated Wilson's disease (WD), and in comparison with an age- and sex
      matched reference group (RG). METHODS: Twenty-four patients with WD with a mean
      (+/-s) age of 35.1 +/- 8.7 years and a disease duration of 17.7 +/- 5.1 years
      were investigated using a standardized sleep questionnaire comprising 87
      questions concerning sleep habits, sleeping difficulties, demographic and
      lifestyle variables. The results were compared with those from a random sample of
      72 individuals. RESULTS: There was no significant difference in sleep time during
      the night, but WD patients had a significantly greater number of nocturnal
      awakenings compared with the RG. Fifty-nine per cent of the WD patients reported
      frequently being awake for more than 30 min during the night. Number of nocturnal
      awakenings was correlated to nightmares and palpitations only in the WD group. WD
      patients complained significantly more often than the RG over not feeling rested
      after sleep, taking frequent naps and fatigue during the daytime. Moreover, sleep
      paralysis and cataplexy occurred more often in the WD patients than in the RG.
      CONCLUSION: The sleep pattern of patients with treated WD differed from that of
      the reference group. The spectrum of reported symptoms by patients with treated
      WD suggests an altered REM sleep function. Future studies with objective methods
      are required to elucidate the mechanisms involved.

PMID- 12470322
TI  - Sex differences in cobalamin vitamin B12 opinions of Swedish physicians.
AB  - The aim of the study was to elucidate possible sex differences in knowledge,
      competence and attitudes behind decision-making on cobalamin-associated problems
      (vitamin B(12)). The study was conducted by postal questionnaires to Swedish
      physicians in 1996-98. The participants were recruited by random sampling of
      general practitioners (1996, 1998), and a total sampling of geriatricians (1998).
      The overall response rate was 71%. The study group comprised 480 female
      physicians and 526 male physicians. The responses to 24 statements in the
      questionnaire were measured by means of visual analogue scales. Group differences
      were evaluated by medians and shapes of distributions. The female doctors
      appeared to value patient-related symptoms and signs more than male doctors.
      Conversely, male doctors relied on laboratory tests more than female doctors. As
      reflected by questionnaire answers, female doctors appeared to be more informed
      than male doctors on cobalamin-associated clinical problems. Group differences
      between the sexes were marginal from a numerical point of view. It is suggested
      that the statistical differences observed should be regarded as negligible until
      confirmed by further studies.

PMID- 12470323
TI  - RGE at 25--personal reminiscences.

PMID- 12470324
TI  - Robert Edwards at 55.

PMID- 12470325
TI  - RGE at 75.

PMID- 12470327
TI  - From reproductive immunology to Louise Brown.

PMID- 12470329
TI  - From Louise to ESHRE and the journals.

PMID- 12470330
TI  - Development of gonadotrophins for clinical use.
AB  - The 20th century witnessed the steady development of knowledge about reproductive
      physiology and endocrinology in animals and humans. These advances led to the
      identification of higher centres governing the ovary and its follicles. Effects
      of X-rays on the head and other agents, or excision of the pituitary gland, led
      to anomalies in oestrous and menstrual cycles in animals and women, respectively.
      Studies on pituitary and placental extracts revealed the presence of hormones
      regulating the ovarian follicles and the corpus luteum for the implanting embryo.
      These were identified as follicle stimulating hormone (FSH), luteinizing hormone
      (LH) and human chorionic gonadotrophin (HCG). Increasing understanding of the
      mechanisms of action of these hormones led to treatments of animals and
      amenorrhoeic women with FSH- and LH-containing preparations in order to induce
      the growth of follicles and ovulation. Human FSH-rich preparations were obtained
      by extracting urinary gonadotrophins from the urine of post-menopausal women, and
      thousands of amenorrhoeic and/or anovulatory patients were treated with human
      menopausal gonadotrophin (HMG) and HCG to induce multifolliculation and
      ovulation. The introduction of IVF greatly increased the numbers of women treated
      in this fashion, now including cyclic women. By the mid-1980s, following the
      appearance of Creutzfeld-Jakob disease in women treated with gonadotrophins
      extracted from human pituitaries, and other safety considerations, attempts were
      being made to purify urinary gonadotrophin preparations, using antibodies.
      Increasing interest in recombinant preparations, which were pure, highly specific
      and highly active preparations, characterized the last years of the 20th century
      and the new millennium. These preparations included recombinant FSH (rFSH),
      recombinant LH (rLH) and recombinant HCG (rHCG). Yet, in one sense, the
      recombinant preparations could change the procedures of ovarian stimulation,
      because they focused attention on the membranal receptor in the follicle, and how
      best to stimulate it. Small molecules are currently being investigated, with some
      proving to be very active and specific, and even capable of bypassing many parts
      of the receptor conformation. Here lies the immediate future of this field,
      utilizing small, defined molecules at low cost to stimulate follicle growth,
      ovulation and luteinization, and perhaps one day to remove the need for
      gonadotrophins in clinical work.

PMID- 12470331
TI  - In-vitro maturation of oocytes from unstimulated polycystic ovaries.
AB  - In-vitro fertilization (IVF), an established treatment for infertility, may
      result in pregnancy and live-birth rates higher than following natural conception
      in fertile couples. However, IVF is associated with two major complications,
      namely, multiple pregnancy and ovarian hyperstimulation syndrome. The latter is a
      consequence of the ovarian stimulation required for IVF. Women with polycystic
      ovaries (PCO) are at increased risk of developing this complication. Ovarian
      stimulation is not required for in-vitro maturation (IVM) of immature oocytes.
      This approach is therefore both cheaper and safer than IVF, particularly for
      women with PCO. It has been found that the IVM pregnancy rate is correlated with
      the number of antral follicles present, the peak ovarian stromal blood flow
      velocity at the baseline ultrasound scan, the number of immature oocytes
      collected, absence of a dominant follicle at the time of immature oocyte
      retrieval, and endometrial thickness at embryo transfer. The indications for IVM
      at present would include women requiring IVF who have PCO, those with primarily
      poor quality embryos in repeated previous IVF cycles for no apparent reason, poor
      responders to high dose gonadotrophin stimulation for IVF, and finally, women
      with PCO who are considering egg donation.

PMID- 12470332
TI  - How animal embryo research led to the first documented human IVF.
AB  - Research studies using animal gametes led to the first documented human IVF in
      1969. A key contribution was the development of a reliable culture medium for IVF
      of hamster oocytes, which was then used successfully with human gametes in the
      laboratory. This article describes how this was accomplished. Hamster IVF was
      obtained using a bicarbonate-buffered culture medium based on Tyrode's solution.
      A dose-response experiment showed that IVF in this species was highly dependent
      on the pH of the culture medium. At pH 7.2 or less, very few oocytes were
      penetrated and spermatozoa did not undergo acrosome reactions. Over the pH range
      7.3-7.5, 40% of oocytes were fertilized in vitro, while at pH 7.6 or higher, more
      than 75% of oocytes were fertilized and most spermatozoa exhibited acrosome
      reactions. There was no apparent effect of pH on sperm motility. These
      experiments showed that in the hamster, fertilization in vitro is highly pH
      dependent, most likely through pH effects on the sperm acrosome reaction and
      sperm:zona binding. The data led to formulation of a culture medium, Tyrode-B,
      that consistently supported high levels of IVF of hamster oocytes. When this
      medium was used for human gametes, IVF was observed and documented for the first
      time. Spermatozoa penetrating through the zona pellucida and sperm components
      within the ooplasm were detected, and some oocytes exhibited two pronuclei. These
      observations suggested that human IVF might be useful for alleviation of
      infertility.

PMID- 12470333
TI  - Thoughts on embryo culture conditions.
AB  - This review discusses three topics: (i) the 'back to nature' and empirical
      optimization approaches to the design of chemically defined media for the culture
      of preimplantation embryos, (ii) the evolution of the simplex optimized family of
      media, and (iii) adaptation and stress in preimplantation embryos when placed in
      chemically defined media.

PMID- 12470334
TI  - Time and development.
AB  - The role that biological timers play in gametogenesis and development is reviewed
      through use of selected examples. Some general features of biological timers are
      also reviewed, and two types of timing mechanism are discussed in more detail:
      circadian rhythms and cell-cycle-based timers. In particular, the recent evidence
      that oscillatory ion channel activity may play an important role in timing
      mechanisms is summarized. The activity and properties of an oscillatory K(+)
      channel present during preimplantation mouse development are described, and
      preliminary results from its neutralization are discussed.

PMID- 12470335
TI  - Thoughts and observations on patterning in early mammalian development.
AB  - The preimplantation mammalian conceptus shows an impressive ability to develop
      normally following the loss, gain or rearrangement of cells. This has prompted
      the view that, unlike in other species, patterning in mammals cannot depend on
      information that is already present in the zygote before it begins to cleave.
      However, various findings are hard to reconcile with this conclusion, including
      evidence that the incidence of monozygotic twinning is sensitive to the
      conditions to which eggs or very early concepti are exposed. Possible causes of
      early twinning are discussed, and it is argued that partial hatching of the
      conceptus through a hernia in the zona pellucida cannot account for all cases.
      Moreover, it remains questionable whether studies on aggregated morulae and
      isolated blastomeres really provide compelling evidence against the existence of
      indispensible patterning information in the egg. Finally, regularities in axial
      relationships between the blastocyst and zygote have been revealed employing
      strictly non-invasive techniques. These show that, at least in normal
      development, patterning begins before cleavage.

PMID- 12470336
TI  - Genes associated with the development of the male germ line.
AB  - The development of the mammalian germ line has been well studied, from the
      designation of primordial germ cells and their migration in the embryo to their
      progression through gametogenesis. The pattern of germ cell development, as
      established through classical studies, is now being overlaid with molecular,
      genetic and epigenetic data. Eventually, proteonomics will lead to a deeper
      understanding of the function of these genes. Through knowledge of germ cell gene
      expression patterns, it is now possible to develop transgenic molecular tools for
      the isolation of germ cells at different stages of development. By linking stage
      specific germ cell promoter regions to the green fluorescent protein (GFP)
      reporter gene it is possible to tag these cells genetically for histological
      identification and cell sorting. Our long-term goal is to develop male germ cells
      as stem cells for therapeutic purposes. It is hoped that this goal will be
      achieved by purifying germ cells at different stages in development and gaining a
      deeper understanding of them by studying their gene expression patterns, potency
      and plasticity, both in vivo and in vitro.

PMID- 12470337
TI  - Human embryonic stem cells: mother of all cell and tissue types.
AB  - Pluripotential embryonic stem (ES) cells have been derived very efficiently from
      spare human embryos produced by IVF and grown in culture to the nascent
      blastocyst stage. The inner cell mass (ICM) is isolated by immunosurgery and
      grown on selected embryonic fibroblast monolayer cultures. ICM cells lose their
      memory for axis during formation of ES cell colonies and are then unable to
      integrate tissue formation with a body plan. ES cells form teratomas in vivo with
      cells and tissues representative of the three major embryonic lineages (ectoderm,
      mesoderm, endoderm). The ES cells are continuously renewable and can be directed
      to differentiate into early progenitors of neural stem cells (Noggin cells) and
      from there into mature neurons and glia (astrocytes and oligodendrocytes). The
      neural stem cells formed from human ES cells repopulate the brains of newborn
      mice when injected into the lateral cerebral ventricles, forming astrocytes
      dominantly in the parenchyma. The human neural cells can be observed migrating
      from the subventricular areas along the rostral migratory stream. Human neurons
      can be found in the olfactory bulb. Human ES cells can also be directed into
      cardiomyocytes when co-cultured with visceral endoderm-like cells (END-2). These
      observations provide further scope to explore stem cell therapies, gene therapies
      and drug discovery. For compatible transplantation, ES may need to be derived
      with a range of HLA types or by nuclear transplantation or stem cell fusion.

PMID- 12470338
TI  - Gonadal tissue cryopreservation and transplantation.
AB  - Transplantation of ovarian and testicular tissue has been practised for over a
      century, mainly for experimental purposes. It is now being considered as a
      potential strategy for preserving fertility in young patients, including
      children, undergoing sterilizing treatment for cancer and other diseases. Ovarian
      tissue biopsies can be stored at liquid nitrogen temperatures indefinitely so
      that, after thawing, they can be returned as either ortho- or heterotopic grafts
      to the original patient. A different approach is needed for preserving male germ
      cells to restore fertile potential. Experimental studies have shown that
      spermatogonial stem cells injected into the rete testis/seminiferous tubules can
      re-initiate spermatogenesis after sterilizing treatment with alkylating agents;
      alternatively, in prepubertal cases, testicular biopsies that have been
      cryopreserved can be grafted subcutaneously to generate enough spermatozoa for
      intracytoplasmic sperm injection (ICSI). These strategies have been demonstrated
      in animal models and are now undergoing clinical testing.

PMID- 12470339
TI  - Embryonic stem cells and mouse models of human syndromes: examples from the T-box
      gene family.
AB  - Synergism between the fields of reproduction and development has long been an
      important factor for advances in each field, and the development of gene
      modification technology in mammals has progressed hand in hand with advances in
      reproductive technology. The discovery and exploitation of embryonic stem cells
      for producing targeted gene mutations in the mouse, combined with advances in
      genome analysis, has provided a means of producing mouse models of human genetic
      diseases, including congenital defects. This review presents examples of how gene
      targeting and reproductive biology techniques are being applied to the production
      of mouse models for specific human developmental syndromes caused by mutations in
      genes of the T-box transcription factor gene family. The ulnar-mammary syndrome
      and the DiGeorge syndrome are two developmental syndromes that are currently
      being explored in this way.

PMID- 12470340
TI  - Reproductive strategies for human survival.
AB  - Reproductive strategies for the human species have basically remained unaltered
      since Homo sapiens first appeared, probably in the valleys of Africa: males have
      always attempted to pass their genes to the largest feasible number of females,
      selecting those females capable of providing the best quality of oocytes; females
      invariably have sought a male capable of providing the best means of survival for
      herself and her offspring. This meant that human sexuality has been essentially
      conceptive, although it is reasonable to suppose that it began to lose this
      'exclusive' connotation early in the cultural evolution of the species. Then,
      during the 20th century, major revolutions occurred: first, with the advent of
      contraception, sex without reproduction became a reality; then, with assisted
      reproduction technology, humans devised reproduction without sex; finally, very
      recently, women have begun to reproduce even in menopause. Additional strategies
      will, no doubt, soon be available, although we cannot as yet clearly see whether,
      or when, reproduction without sex and gametes, or in-vitro gestations will become
      available.

PMID- 12470342
TI  - Preimplantation genetic diagnosis for gender selection for family balancing: a
      view from India.
AB  - The use of PGD for sex selection arouses considerable debate, especially in
      countries like India that have a marked cultural preference for boys. It is
      argued that using PGD for sex selection is a treatment option that can be
      ethically offered to couples who desire to use this technology to plan their
      families.

PMID- 12470343
TI  - Embryo sex selection: a social comment on the article by Malpani and Malpani.

PMID- 12470344
TI  - Does preimplantation genetic diagnosis for gender selection really offer a
      solution for family balancing? A response to the article by Malpani and Malpani.

PMID- 12470345
TI  - Preimplantation genetic diagnosis for gender pre-selection in India: a counter
      argument to the article by Malpani and Malpani.

PMID- 12470346
TI  - Incest, gamete donation by siblings and the importance of the genetic link.
AB  - Recently, several requests have emerged in which women wished to be impregnated
      with donor eggs fertilized with spermatozoa of their brother. An important
      argument advanced against such applications is that it is a kind of incest. Four
      definitions of incest are reviewed in this article to evaluate the acceptability
      of these demands. The first three (sexual intercourse, reproduction with gametes
      of first-degree relatives and symbolic incest) do not apply to the cases.
      However, when the sister and her brother intend to raise the child as social
      mother and father, these requests should be considered as "intentional incest".
      If the brother only functions as an uncle, the request of the woman resembles the
      currently accepted practice of oocyte donation from sister to sister. In that
      case, the wish to receive gametes from a first-degree relative is motivated by
      the wish to establish as far as possible a genetic link with the child.

PMID- 12470347
TI  - The use of preimplantation genetic diagnosis in sex selection for family
      balancing in India.
AB  - This paper describes the use of preimplantation genetic diagnosis (PGD) in sexing
      embryos for family balancing in a private IVF clinic in India from April 1999 to
      April 2001. Embryos were biopsied and analysed on day 3, cultured in sequential
      media and then transferred on day 4 or day 5 after morphological selection of the
      best embryos. From a total of 42 cycles started, 14 clinical pregnancies and nine
      live births have been achieved so far, with five ongoing pregnancies. The
      benefits of delayed transfer 24-48 h after the embryo biopsy are that PGD centres
      could use the extra time available to confirm the diagnosis or introduce
      additional diagnostic tests for the same embryo. The selection of blastocysts for
      transfer should also permit the transfer of fewer embryos, thus reducing the risk
      of multiple gestations and increasing the pregnancy rate as a consequence of the
      expected higher implantation rate. This is the first report of the use of PGD in
      sex selection for family balancing in India, where couples place a premium on
      having baby boys, and the social and ethical aspects of the use of this
      technology in this setting are briefly discussed.

PMID- 12470348
TI  - Timing of FSH-stimulation and follicular development in cryopreserved human
      ovarian grafts.
AB  - Cryopreserved human primordial follicles grafted into immunodeficient hosts are
      susceptible to gonadotrophic stimulation but the optimal interval between
      grafting and stimulation has not been determined. The effect of stimulation with
      FSH at different time intervals after grafting was therefore investigated.
      Cryopreserved human ovarian cortical grafts from an androgen pre-treated female
      to-male transsexual patient were transplanted into four groups of four non-obese,
      diabetic severe combined immune deficiency (NOD-SCID) mice. Ten, 12, 14 and 17
      weeks after grafting, stimulation was started with daily intra-peritoneal
      injections of 5 IU of recombinant FSH for 14 days. Grafts were recovered and
      serially sectioned for counting the number of follicles and determining the
      different stages of development. Significantly more primary and secondary
      follicles were found in all stimulated groups compared with the non-stimulated
      control. This progression from the primordial to growing primary and secondary
      stages was most significant in the 14 weeks interval group. Formation of antral
      follicles was scarce and was only noticed in the 10 and 17 week groups. Cystic
      follicles and follicles with structural oocyte abnormalities were encountered in
      each group. Whether this phenomenon is related to the hormonal state of the
      tissue donor or to the cryopreservation and transplantation procedures is the
      subject of further investigation. It is concluded that the interval between
      grafting of ovarian tissue and the start of gonadotrophic stimulation may be
      important for an optimal follicular development after grafting.

PMID- 12470349
TI  - Novel use of laser to assist ICSI for patients with fragile oocytes: a case
      report.
AB  - An inadvertent consequence of intracytoplasmic sperm injection (ICSI) is the
      degeneration of some of the microinjected oocytes. Most patients may not suffer
      any disadvantage through losing oocyte(s) during micromanipulation; however, in
      some circumstances, this can result in a reduction of the chances for pregnancy.
      This study reports a clinical pregnancy obtained by a novel approach using laser
      assisted micro-opening of the zona pellucida prior to ICSI to secure a non
      traumatic microinjection that avoids degeneration of oocytes. A total of 12
      oocytes were obtained from the 36 year old patient in her third IVF treatment
      cycle, following two previously failed attempts where very high degeneration
      rates of oocytes after ICSI were recorded, together with suboptimal embryo
      quality. Five of the 11 matured (MII) oocytes were submitted to conventional ICSI
      and the other six MII oocytes first underwent laser-assisted opening of the zona
      pellucida (5-7 microm hole size was created with a 1.48 microm diode laser)
      before microinjection (LA-ICSI). Three of the five conventionally microinjected
      oocytes degenerated while one oocyte fertilized normally and developed to a good
      quality embryo. After the LA-ICSI procedure, one of the six oocytes degenerated
      and four oocytes fertilized normally; of these, two developed to excellent
      quality embryos, one to a good quality embryo and one to a poor quality embryo.
      The three best embryos (LA-ICSI group) were transferred to the patient on day 3.
      Rising serum human chorionic gonadotrophin concentrations were measured 12 days
      after transfer and on week 7 two implantation sites were detected, together with
      regular heart activity. The results of the present report suggest that laser
      assisted ICSI may provide a safer approach to non-traumatic microinjection of
      oocytes than conventional ICSI, thereby minimizing the risk of degeneration and
      possibly also improving embryo quality. Therefore, it is suggested that laser
      assisted ICSI might be applied in all cases associated with difficult zona
      pellucida penetration or/and fragile oolemma, or where patients have very few
      oocytes available, to improve the chances for pregnancy.

PMID- 12470350
TI  - Effect of donor cell age on the efficiency of nuclear transfer in rabbits.
AB  - The ability of rabbit fibroblasts of different ages to be reprogrammed following
      nuclear transfer (NT) to aged recipient oocytes was evaluated. The rate of NT
      blastocysts reconstructed with presumptive G1 stage morula cells or fetal
      fibroblasts was significantly higher (41.5% and 51.4%) than was those of cloned
      embryos reconstructed with fibroblasts from young (4-month-old) or aged (5-year
      old) animals (16.7% and 7.1%, respectively, P < 0.025). Serum starvation
      significantly increased the development of NT embryos to the morula-blastocyst
      stage (67.6% versus 22.9%, P < 0.025). Transfer of 168 NT embryos derived from
      nuclei of morula cells and 106 control embryos into 21 recipients resulted in 10
      pregnancies, 2 NT and 18 control pups, respectively. In the first experiment,
      transfer of 142 cleaved NT embryos reconstructed with fetal fibroblasts and 86
      control embryos into eight recipient does resulted in five pregnancies and the
      birth of 20 control pups. In the second experiment, after transfer of 112 NT
      embryos derived from fetal fibroblasts into six recipients, 10 (8.9%) sites of
      implantation were revealed in two does (33.3%) on day 14 of gestation. This study
      provides evidence that nuclei of morula cells and fetal and adult fibroblasts
      differ in their ability to be reprogrammed by recipient cytoplasm following
      nuclear transfer.

PMID- 12470351
TI  - Polar body-based preimplantation diagnosis for X-linked disorders.
AB  - Preimplantation diagnosis for X-linked disorders has been performed predominantly
      by gender determination, which, however, leads to the discarding of 50%
      unaffected male embryos. In an attempt to identify X-linked mutation-free embryos
      for transfer, the present authors introduced preimplantation genetic diagnosis
      (PGD), using a sequential first and second polar body analysis, as an alternative
      to gender determination. This method was offered to eight couples at risk for
      having children with X-linked disorders, including haemophilia B, fragile-X
      syndrome (FMR1), myotubular myotonic dystrophy (MTMD), ornithine transcarbamylase
      (OTC) deficiency and X-linked hydrocephalus. The first and second polar bodies
      were removed following maturation and fertilization of oocytes in a standard IVF
      protocol and analysed using a multiplex nested polymerase chain reaction (PCR),
      involving testing for mutations simultaneously with linked markers. Overall, 13
      PGD cycles were performed, resulting in the detection of 25 embryos with the
      predicted mutation-free maternal contribution; these embryos were transferred
      back to the patients in all cycles, yielding four clinical pregnancies. Four
      children were born following these pregnancies, including three unaffected and
      one with misdiagnosis as a result of allele dropout (ADO), which was predictable
      in the case of FMR1. Presented results demonstrate the clinical usefulness of the
      specific polar body testing for X-linked disorders as an alternative to PGD by
      gender determination.

PMID- 12470352
TI  - Diagnosis of trisomy 21 in preimplantation embryos by single-cell DNA
      fingerprinting.
AB  - Many couples presenting for preimplantation genetic diagnosis (PGD) for a single
      gene disorder are of advanced reproductive age (>35 years) and have a greater
      chance of producing embryos with chromosomal aneuploidies. The most common
      chromosomal aneuploidy observed in newborns is trisomy 21, or Down's syndrome.
      Consequently, the availability of a highly reliable system that simultaneously
      detects the heritable gene disorder and trisomy 21 would be beneficial to couples
      at specific risk. A pentaplex chromosome 21 (Ch 21) single-cell DNA
      fingerprinting system was developed in a multiplex fluorescence polymerase chain
      reaction (FL-PCR) on single cells. High reliability and accuracy rates were
      observed, together with low allele dropout (ADO) and preferential amplification
      rates on diploid buccal cells, trisomy 21 buccal cells and blastomeres derived
      from Ch 21 aneuploid embryos. A combined multiplex FL-PCR format was optimized
      with the common cystic fibrosis delta F508 mutation and validated on single
      buccal cells from a carrier of the cystic fibrosis delta F508 mutation. This new
      test is a very powerful technique, which also allows confirmation of the embryo
      parentage and the identification of extraneous DNA contamination that could cause
      a misdiagnosis in PGD cases.

PMID- 12470353
TI  - A novel approach for patients at risk for ovarian hyperstimulation syndrome:
      elective transfer of a single zona-free blastocyst on day 5.
AB  - In this preliminary prospective randomized study of 420 patients undergoing
      ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI), 17 patients
      (4%) developed moderate to severe ovarian hyperstimulation syndrome (OHSS). Re
      evaluation for OHSS on day 4 and 6 after oocyte retrieval identified one patient
      with continuous risk for severe OHSS, resulting in cancellation of the transfer
      (1/17, 5.8%). Prospectively, two of three patients had the zona pellucida of the
      blastocyst removed by pronase exposure prior to transfer. Significantly more
      patients became pregnant when a zona-free blastocyst was transferred in
      comparison to transfer of a single zona-intact embryo (9/11 or 82% versus 1/5 or
      20%; P < 0.01). Higher ongoing singleton pregnancy rates were obtained when the
      zona pellucida was removed prior to the transfer (6/11 and 1/5 respectively).
      This preliminary prospective randomized study indicates that by prolonging the
      evaluation time for patients at risk of developing OHSS for up to 6 days after
      the oocyte retrieval, those patients at risk for developing severe OHSS can be
      identified. Transferring a single zona-free day 5 embryo (blastocyst) and
      freezing of the supernumerary embryos offers the patient with moderate OHSS an
      optimal chance for a singleton pregnancy, while avoiding the serious maternal
      complications of ovarian hyperstimulation syndrome.

PMID- 12470354
TI  - The fine structure of human embryonic stem cells.
AB  - The fine structure of human embryonic stem (ES) cell colonies was analysed by
      transmission electron microscopy (TEM) after 35 passages of in-vitro culture.
      Most cells formed compact, saucer-shaped colonies with epithelioid cells on the
      periphery and polygonal cells within the colony. Three morphological types of
      cells were identified based on their fine structure: undifferentiated cells
      resembling inner cell mass (ICM) cells of blastocysts; protein-synthesizing cells
      at the onset of cellular differentiation; and compact masses of secretory cells
      resembling unicellular goblet cells of the intestine. The predominant cell type
      was the undifferentiated ES cells resembling ICM cells of blastocysts. These
      cells had large nuclei containing reticulated nucleoli, well-developed rough
      endoplasmic reticulum (RER), Golgi complexes, elongated tubular mitochondria,
      lysosomes and typical centrosomes with centrioles associated with microtubules
      and microfilaments, organizing the cytoskeleton. Some ES cells have very large
      nuclei and scanty cytoplasms with fewer organelles. The isolated or attached
      protein-synthesizing cells at the onset of differentiation had extensive RER and
      large Golgi complexes. The morphologically differentiated cells formed compact
      colonies and resembled goblet-like cells in microstructure. They had RER and
      large Golgi complexes associated with secretory vesicles. The epithelioid cells
      at the periphery were columnar and largely polarized by centrosomes associated
      with Golgi complexes. Epithelioid cells in all three categories had specialized
      cell junctions (desmosomes), anchored by tonofilaments, and surface blebs.
      Isolated cells were seen on the surface, towards the centre of the colony, and
      their free surfaces had microvilli and larger blebs. Approximately 3-5% of all
      cells were mitotic, with typical bipolar spindles organized by centrosomes,
      pivotally located at the poles, and appeared to resemble typical somatic cells.

PMID- 12470355
TI  - Uteroplacental circulation during the first trimester of normal and abnormal
      pregnancy.
AB  - The aim of this study was to evaluate the uteroplacental vascular characteristics
      during the first trimester of normal and failed pregnancies. A clinical
      descriptive study was conducted using colour Doppler ultrasound in 45 women with
      normal pregnancies (group A) and 44 with non-embryonic sac or missed abortions
      (group B). The mean gestational age in these two groups was 9.3 and 7.6 weeks
      respectively (P < 0.01). The number of myometrial blood vessels (arteries and
      veins identified by power Doppler mapping), the quantity of intervillous flow,
      the resistance index (RI) for the arterial system, and the pulsatility index (PI)
      of the myometrial arteries were evaluated. The number of myometrial blood vessels
      in group A was lower than that in group B. The intervillous flow was observed in
      some cases from early pregnancy and more often after 10 weeks. This
      characteristic was observed significantly more frequently in group B than in
      group A. The RI and PI in the uterine arteries were significantly higher in group
      A than in group B. The RI and the PI of the uterine arteries decreased with the
      advance of gestational age in both groups. Colour Doppler ultrasound provides
      information about uteroplacental circulation during the first trimester and
      indicates early development of intervillous circulation. Although a greater
      uteroplacental blood circulation was observed in failed pregnancies, the
      overlapping between groups severely limits the application of this characteristic
      in clinical practice.

PMID- 12470356
TI  - Sex selection and preimplantation genetic diagnosis at The Farah Hospital.
AB  - The issue of sex selection by using preimplantation genetic diagnosis (PGD) for
      non-medical reasons has been the subject of heated debate. Although the ethical
      arguments regarding this subject are complex, we would like to extend and express
      some views based on practical experience, with a special focus on individual
      needs in developing countries, taking into consideration: social, cultural,
      religious, financial and scientific aspects.

PMID- 12470357
TI  - Development of a miniature, low-dose, frameless intrauterine levonorgestrel
      releasing system for contraception and treatment: a review of initial clinical
      experience.
AB  - A low-dose levonorgestrel (LNG)-releasing intrauterine system (IUS) (FibroPlant)
      has been clinically developed since 1997 for endometrial suppression during
      hormone replacement therapy in peri- and postmenopausal women, for the treatment
      of menorrhagia in women with normal uteri or with uterine fibroids, for
      contraception, for the treatment of endometrial hyperplasia, and for alleviating
      primary and secondary dysmenorrhoea. Results of preliminary studies confirm the
      promising nature of this all-round drug delivery system. The low dose of LNG
      released accounts for the low hormonal side-effect rate and virtual absence of
      amenorrhoea in premenopausal women. The system has not yet been evaluated in
      tamoxifen users (to protect the endometrium), or in women with rectovaginal
      endometriosis. However, early indications suggest that the system will also be
      suitable for these indications. The frameless drug delivery support of this LNG
      releasing IUS has been optimized to reduce the size of the foreign body and to
      maximize tolerance and continuation of use while simultaneously providing for the
      maximum duration of action.

PMID- 12470358
TI  - Clinical practice of embryo transfer.
AB  - In this review, several embryo transfer methods are considered, together with
      factors involved in achieving an effective transfer. The approach most used is
      transcervical intrauterine transfer. This is described in detail, together with
      the many variables influencing success, e.g. technical ability and training of
      personnel, catheter choice, value of a previous 'dummy transfer' and the need to
      minimize trauma during transfer and so prevent damage to the uterine lining,
      bleeding and uterine contractions. These factors can each negatively impact on
      pregnancy rates. Emphasis is put on quality, developmental stage and number of
      embryos to be transferred to limit multiple pregnancies and their unwanted side
      effects. Culture to blastocyst stages and single embryo transfer when optimal
      quality embryos are available are discussed as means of avoiding multiple
      pregnancies. Reference is made to embryo cryopreservation and fertility following
      frozen embryo transfer. Other techniques, such as ultrasound-controlled
      transcervical intrauterine transfer, and ultrasound-controlled transmyometrial
      transfer, are reviewed. More invasive procedures, generically grouped as surgical
      embryo transfer, including gamete intra-Fallopian transfer (GIFT), zygote intra
      Fallopian transfer (ZIFT), pronuclear stage transfer and embryo intra-Fallopian
      transfer (EIFT), are also described. These techniques had a place in IVF when the
      need to apply assisted reproductive techniques exceeded the capacity of most
      laboratories, but not today thanks to refined laboratory technology and improved
      understanding of implantation. Alternative assisted reproductive technologies,
      such as direct intra-follicular insemination (DIFI), Fallopian spermatic
      perfusion (FSP), peritoneal oocyte stage and sperm transfer and intra-vaginal
      culture (IVC), are mentioned briefly.

PMID- 12470359
TI  - Reproductive rhythms, longevity and cancer.

PMID- 12470360
TI  - Assisted reproductive technology: perspectives on advertising and marketing in
      the USA.

PMID- 12470362
TI  - Editorial.

PMID- 12470361
TI  - Fraudulent publishing continues to trouble Germany.

PMID- 12470363
TI  - Augmentation of reperfusion by noninvasive, transcutaneous delivery of low
      frequency, high-intensity ultrasound.
AB  - There is a need for developing alternative safe, inexpensive and noninvasive
      methods for rapid and effective recanalization of thrombosed arteries and veins
      that can be commenced immediately upon admission to hospital, or even prior to
      admission. Transcutaneous delivery of low-frequency, high-intensity ultrasound
      has the potential to be used clinically in various types of thrombotically
      occluded blood vessels including acute myocardial infarction, strokes, ischemic
      limbs, obliteration of A-V fistulas of patients undergoing hemodialysis, retinal
      vein thrombosis, deep vein thrombosis, and even thrombotically stuck prosthetic
      heart valves. Thus far, various noninvasive ultrasound systems have been used in
      several animal models. These systems vary in the mode of ultrasound delivery
      (continuous versus pulse, diffuse versus concentrated or pulsed beam), frequency
      (between 20 kHz and 1 mHz), and intensity. In general, lower frequencies have
      better penetration through overlying tissue (skin, fat, bone) and, probably,
      better efficacy.

PMID- 12470364
TI  - Clinical and angiographic results with the NIR stent: First International NIR
      Endovascular Stent Study (FINESS-II).
AB  - BACKGROUND: Although safety and efficacy of the NIR trade mark stent have been
      reported, the long-term angiographic and clinical outcomes have yet to be
      investigated. The FINESS-II study (First International NIR Endovascular Stent
      Study) was designed to assess the procedural safety of single 9 and 16 mm NIR
      stent implantation, the six-month restenosis rate and finally the six- and 12
      month clinical outcome of patients treated with this novel coronary stent.
      METHODS: Patients with angina and a single de novo lesion in a native coronary
      artery of >3 and <5 mm diameter were included in this multicentre, prospective,
      observational trial. Clinical follow-up was obtained at one, six and 12 months.
      Angiography was performed before and after the stent implantation and at six
      months. The primary endpoint included major adverse cardiac events (death,
      myocardial infarction and target lesion revascularization) within 30 days after
      the procedure. Major bleeding complications and subacute stent thrombosis within
      the first 30 days were also reported as specific endpoints. Secondary endpoints
      were major cardiac-event-free survival at six- and 12-month follow-up and
      angiographic restenosis at six months. RESULTS: A total of 156 patients (81%
      male, mean age 60 +/- 10 years), with stable (54%), unstable (40%) angina
      pectoris or silent ischemia (6%) were enrolled. The target vessel diameter was
      2.94 +/- 0.54 mm. The minimal lumen diameter pre, post and at follow-up was 1.04
      +/- 0.32 mm, 2.64 +/- 0.42 mm and 1.88 +/- 0.63 mm, respectively. Restenosis rate
      according to the >50% diameter stenosis criterion at six month follow-up was 19%
      (26/136). At 12 months, the event-free survival rate was 83% (two deaths, one Q
      wave and three non-Q-wave myocardial infarctions, four bypass surgery and 17
      target lesion revascularizations), while 87% of the patients were free of angina
      pectoris. CONCLUSION: the outcome of the FINESS-II trial is comparable to those
      observed in previous stent trials (Benestent II), indicating that the coronary
      NIR stent is safe and effective as a primary device for the treatment of native
      coronary artery lesions in patients with (un)stable angina pectoris.

PMID- 12470365
TI  - Laser angioplasty of peripheral arteries after unsuccessful recanalization of the
      superficial femoral artery.
AB  - AIM: To demonstrate the range of applying laser angioplasty after unsuccessful
      recanalization of the superficial femoral artery (SFA) with conventional
      interventional techniques. MATERIALS AND METHODS: In a prospective trial in 94
      cases with occlusion of the SFA and formerly unsuccessful conventional
      percutaneous transluminal angioplasty, laser angioplasty for recanalization was
      applied. The average occlusion length of the SFA was 17.5 cm (range 4-36 cm). The
      recanalization attempt was made using the crossover technique in 78 patients, in
      eight patients with the antegrade technique and in another eight patients using
      the transpopliteal technique. The primary recanalization attempt was performed
      with Terumo wires (curved and straight) as well as different catheters
      (Multipurpose/Vertebralis/Cobra). After the unsuccessful recanalization attempt
      the laser catheter was applied. RESULTS: The application of laser angioplasty
      demonstrated a successful recanalization of the SFA in 76/94 patients (80.9%). In
      18 patients (19.1%) the recanalization was not possible even with percutaneous
      transluminal laser angioplasty (PTLA). The reason for the unsuccessful PTLA was
      in 10 cases due to obstructing calcified material, which was resistant to PTLA
      application. In four cases obstructing calcifications caused the laser catheter
      to be positioned in subintimal tissue, resulting in perforation of the SFA. In
      another four patients there was an aberrant anatomy of the SFA which resulted in
      a direct vessel injury after advancing the laser catheter. After a follow-up
      period of 12 months primary, primary-assisted and secondary patency rates were
      50.0%, 65.8% and 73.7%, respectively. DISCUSSION: In primarily unsuccessful
      recanalization of the SFA, PTLA allows in 80% of cases a successful
      recanalization of the SFA. The technical success rate and the patency rate
      support the application of PTLA.

PMID- 12470366
TI  - In-hospital resource utilization in coronary angioplasty: the impact of increased
      coronary stenting rates and antiplatelet therapy.
AB  - BACKGROUND: The technique of coronary stenting has evolved over recent years,
      with improved stent technology and effective antiplatelet therapies to prevent
      stent thrombosis. In Europe, reductions in stent and equipment costs have
      resulted from increased market competition. The impact of these changes on the in
      hospital procedural cost of percutaneous coronary intervention (PCI) in the
      current clinical setting is not known. METHODS: We compared the initial equipment
      and pharmaceutical costs of one hundred consecutive, unselected patients
      undergoing PCI in 1998 to a similar population who underwent PCI in 1994.
      RESULTS: Similar patient characteristics were noted, yet more complex disease
      (multivessel, AHA type B2/C lesions) was treated in the 1998 population. The
      stent utilization rate (83% vs 15%, p < 0.0001) and use of intravenous and/or
      oral antiplatelet therapy (abciximab, ticlopidine) (64% vs 4%, p < 0.0001) was
      higher in 1998. Similar angiographic success was achieved in each group with low
      complication rates. Mean hospital stay was reduced in the 1998 group (2.6 +/- 2.8
      vs 4.3 +/- 3.8 days, p < 0.001). Repeat PCI was required more frequently in the
      1994 population (26% vs 9%, p < 0.001). Overall there was no significant
      difference in the mean equipment cost between the two groups ( pound 1551 vs
      pound 1422, p=ns). CONCLUSION: Despite the widespread use of coronary stenting
      and antiplatelet therapies there appears to be no difference in current in
      hospital equipment costs for PCI compared to 1994. Improved clinical outcomes in
      the 1998 population imply that stenting is a cost-effective therapy.

PMID- 12470367
TI  - DNA integrity and transgene expression after passage through the NOGA needle
      catheter used for therapeutic myocardial angiogenesis.
AB  - BACKGROUND: The NOGA (Biosense Webster, Markham, ON, Canada) injection catheter
      is an innovative navigational device that provides an ideal platform for intra
      myocardial injection material. However, injection through a long (1.91 m), narrow
      (27G) nitinol needle could result in deterioration in the integrity and
      functionality of DNA. METHODS: To test this possibility, DNA in plasmid form
      (pcDNA3.1) containing the Lac Z transgene (250 micro l) was passed through the
      NOGA needle using a hand-held 1 cc syringe at a gentle hand injection pressure
      (43 +/- 3 PSI, 3.0 +/- 0.2 kg/cm(2)) or at maximal manual pressure (90 +/- 6 PSI,
      6.3 +/- 0.4 kg/cm(2)), either once or 20 times. This DNA, compared to DNA not
      passed through the NOGA needle (control), was then used to transfect primary
      cultures of rat skin fibroblasts (FB) from Fisher 344 rats and the cells were
      subsequently stained for beta galactosidase (betagal). RESULTS: Transfection
      efficiency was significantly reduced by passing the DNA through the needle at
      both 43 +/- 3 PSI (78 +/- 4% of control, n = 10, P < 0.05 versus control) and 90
      +/- 6 PSI (66 +/- 4 % of control, n = 10, P < 0.01 versus control, P < 0.02
      versus 43 +/- 3 PSI). Passage of the DNA through the NOGA needle 20 times
      resulted in a transfection efficiency of only 5 +/- 1% of control (n = 20, P <
      0.1 x 10(-11) versus control). Capillary Electrophoresis revealed that the
      reduction in transfection efficiency was due to a conformational change in the
      DNA from predominantly supercoiled to nicked and linearized DNA. Transfection
      efficiency as compared with control decreased as the concentration of the DNA
      solution which was passed through the needle was increased from 0.3 micro g/
      micro l to 2.4 micro g/ micro l. Recovery experiments confirmed that the
      reduction in transfection efficiency was not due to loss of DNA by binding to the
      NOGA needle. CONCLUSION: These results suggest that DNA is susceptible to shear
      forces when injected through the NOGA needle even at nominal clinical injection
      pressures, suggesting that careful and controlled injections will be required to
      achieve optimal gene integrity and expression.

PMID- 12470368
TI  - Comparison of ReoPro((R)) (abciximab) versus intracoronary thrombolysis for early
      coronary stent thrombosis.
AB  - AIMS: This study evaluated the treatment of early coronary stent thrombosis with
      intracoronary urokinase or the platelet glycoprotein IIb/IIIa receptor inhibitor
      ReoPro (abciximab). METHODS AND RESULTS: Seventy-four patients (126 stents) were
      treated immediately after identification of early (0-30 days) coronary stent
      thrombosis. Twenty-nine patients were treated with intracoronary urokinase (UK)
      (UK alone in 19; UK and additional balloon angioplasty in 10) and another 45
      patients were given ReoPro((R)) (abciximab) (0.25 mg/kg as a bolus alone in 26,
      abciximab with additional balloon angioplasty in 19) within 30 days of stent
      implantation. TIMI grade 3 flow was obtained in 23 patients (79%) in the UK group
      and in 38 (84%) in the abciximab group (nonsignificant). Three patients (10%) in
      the UK group and one (2%) in the abciximab group underwent repeat percutaneous
      transluminal coronary angioplasty (PTCA) (nonsignificant). Five patients (17%) in
      the UK group and three (7%) in the abciximab group were referred for urgent
      coronary artery bypass graft surgery (CABG) because of residual thrombus and
      refractory ischemia (nonsignificant). Repeat revascularization was necessary in
      eight patients (28%) in the UK group versus four (9%) in the abciximab group (p <
      0.05). Five patients (17%) in the UK group and eight (18%) in the abciximab group
      developed myocardial infarction (nonsignificant). Five patients (17%) in the UK
      group (cardiogenic shock (three), cerebral hemorrhage (one) and pneumonia (one))
      and three (6.6%) in the abciximab group (cardiogenic shock (two), heart failure
      (one)) died within 30 days (nonsignificant). Overall, noncardiac complications
      (bleeding including surgical repair of groin) were observed in 11 patients (38%)
      in the UK group and three (7%) in the abciximab group (p < 0.001). CONCLUSION:
      Compared to urokinase, abciximab reduced the need for repeat revascularization
      procedures and the risk of noncardiac events, including bleeding complications in
      patients with early coronary stent thrombosis.

PMID- 12470369
TI  - Local heparin delivery for prevention of second in-stent restenosis. Acute and
      long-term results in 47 consecutive cases.
AB  - BACKGROUND: Heparin has been shown to reduce intimal thickening after arterial
      wall injury by inhibiting vascular smooth muscle cell proliferation and
      migration. The authors studied the acute and long-term results after local
      delivery of heparin after balloon angioplasty for in-stent restenosis. METHODS
      AND RESULTS: Forty-seven in-stent restenosis cases, 32 of them longer than 1 cm,
      were enrolled. After angioplasty local heparin delivery was performed using the
      Dispatch coronary infusion catheter (Scimed Life Systems/Boston Scientific Corp,
      Natick, MA, USA); the infusion rate was 99.9 ml per hour and a target dosage of
      4000 iu heparin per site was intended to be delivered. In nine cases (19.15%)
      heparin delivery had to be stopped because of ischemia. One patient died six days
      after intervention. After a follow-up interval of 6-12 months target vessel
      revascularization rate was 28.26%. CONCLUSIONS: For the protocol used ischemia
      occurred more often than previously reported. Considering the fact that most
      patients had diffuse in-stent restenosis, the target revascularization rate at
      follow-up was acceptable.

PMID- 12470370
TI  - Acute severe thrombocytopenia after c7E3 Fab (abciximab) therapy in a patient
      with unstable angina and stenting of the right coronary artery. Occurrence of
      subacute stent thrombosis and safe readministration of the GPIIb/IIIa inhibitor
      tirofiban.
AB  - This paper reports a case of acute severe thrombocytopenia (platelet count: 1 x
      10(9)/liter) occurring within minutes of an initial abciximab bolus during
      coronary angioplasty and stenting in a patient with unstable angina. After six
      days with platelets again in the normal range the patient developed stent
      thrombosis. The stent was reopened and the glycoprotein receptor inhibitor
      tirofiban (Aggrastat) was administered without any adverse effects on platelet
      count. Antibodies against heparin-platelet factor 4 complexes could be excluded.
      Allo- and autoantibodies (IgG, IgA, IgM) directed against platelets with and
      without binding of abciximab could not be detected by indirect and direct
      platelet fluorescence antiglobulintest. A possible activation or lysis of the
      platelets by abciximab could also be excluded by an in vitro bleeding test
      investigating the effect of abciximab on heparin and citrate blood of the patient
      and two healthy donors. The mechanisms of abciximab-induced thrombocytopenia in
      this case remain unclear. The possible mechanisms are discussed.

PMID- 12470371
TI  - Editorial.

PMID- 12470372
TI  - Catheter-based transendocardial gene delivery for therapeutic myocardial
      angiogenesis.
AB  - Currently it is unknown which is the most effective and safest delivery strategy
      for therapeutic myocardial angiogenesis. The enhancing effect of direct
      intramyocardial injection of angiogenic factors using either open-chest or
      catheter-based approaches on collateral function has been reported to occur in
      experimental models and among patients. This report reviews the rationale and
      current experience of using a catheter-based approach as a promising platform for
      proangiogenic intramyocardial gene delivery strategy.

PMID- 12470373
TI  - Global revascularization: the role of the cardiologist.
AB  - There are compelling reasons for cardiologists to undertake a more global
      approach to patients with peripheral vascular diseases: atherosclerosis is a
      'systemic' disease frequently causing both coronary and peripheral vascular
      problems in the same patient; coronary artery disease is the most common cause of
      morbidity and mortality in patients with peripheral vascular disease; and
      peripheral vascular disease negatively impacts the management of angina pectoris
      and congestive heart failure. There are four major areas of special interest to
      the cardiologist: (1) iliac arteries (vascular access), (2) renal arteries
      (hypertension and volume overload), (3) subclavian arteries (coronary steal with
      a left internal mammary artery [LIMA] graft), and (4) carotid arteries (stroke).
      Technical skills necessary to perform coronary angioplasty are transferable to
      the peripheral vasculature. However, an understanding of the natural history of
      peripheral disease, patient and lesion selection criteria, and knowledge of other
      treatment alternatives are essential to performing these procedures safely and
      effectively. Appropriate preparation and training, and a team approach, including
      an experienced vascular surgeon, are both desirable and necessary before
      interventional cardiologists who are inexperienced in the treatment of peripheral
      vascular disease attempt percutaneous peripheral angioplasty. There are inherent
      advantages for patients when the cardiologist performing the procedure is also a
      clinician. Judgments regarding the indications, timing, and risk/benefit ratio of
      procedures are enhanced by a long-term relationship between physician and
      patient. Finally, in view of the increased incidence of coronary artery disease
      in patients with atherosclerotic peripheral vascular disease, the participation
      of a cardiologist in their care seems appropriate.

PMID- 12470374
TI  - Ultrasound enhancement of thrombolytic therapy: observations and mechanisms.
AB  - Fibrinolytic therapy is a proven approach for achieving reperfusion of occluded
      coronary arteries during myocardial infarction, resulting in reduced mortality
      and preservation of ventricular function. The amount of myocardial muscle loss is
      proportional to the duration of ischemia. Bleeding complications are not
      infrequent. Adjuvant therapy by ultrasound might enhance the rate of fibrinolysis
      and reduce the concentrations of lytic agents required to achieve an equivalent
      degree of clot lysis. Noninvasive ultrasound at low intensities and high
      frequencies, parameters that potentially could be applied and tolerated in vivo,
      have been proven to significantly accelerate the rate of fibrinolysis in both in
      vitro and in vivo models, in pure fibrin as well as whole blood clots. Such
      enhancement is not drug-specific. These effects were achieved by nonthermal
      mechanism. Ultrasound exposure did not cause mechanical fragmentation of the
      clot, did not alter the size of plasmatic derivates and degradation products.
      Ultrasound caused increased flow rate through thrombi, probably by cavitation
      induced changes in fibrin ultrastructure; disaggregation of uncrosslinked fibrin
      fibers into smaller fibers has been shown. This resulted in increased transport
      of the lytic agent into the clot, alteration of binding affinity and increased
      maximum binding. Presence of echo-contrast agent induced further acceleration of
      thrombolysis by ultrasound.

PMID- 12470375
TI  - Low rates of clinical restenosis with the new flexible stainless steel tube
      intracoronary stent: the R Stent. A six-month safety and feasibility study.
AB  - BACKGROUND: Coronary stents have been used with increasing frequency and in
      increasingly complex coronary lesions for the treatment of symptomatic coronary
      artery disease. A new stainless steel coronary stent, the R Stent, has been
      designed to provide maximum flexibility for tracking and high radial strength
      post-deployment. AIMS: To assess the safety and feasibility of the R Stent in
      patients with coronary artery disease. Specific objectives were to assess the R
      Stent's deployment success, angiographic and procedural success (< 20% residual
      stenosis and TIMI 3 flow), safety (absence of complications), 30-day and six
      month clinical follow-up. METHODS: Between April 1998 and January 1999, stent
      deployment was attempted in 36 lesions in 30 patients with stable (43%) or
      unstable (57%) angina pectoris and 29/36 of the lesions were anatomically
      complex. Treated lesions were in the LAD (n = 15), RCA (n = 13) or LCX (n = 8).
      RESULTS: Stent deployment was achieved in 97% with one crossing failure in a
      patient with a long, calcified, proximal LAD lesion. After the procedure,
      patients were scheduled for one- and six-month clinical follow-up. One patient
      experienced a non-Q-wave myocardial infarction in hospital. At one month, there
      were no additional complications. Only one patient experienced recurrence of
      angina (CCS class 2) within the 30 days. At six-month follow-up, one sudden death
      had occurred. Three (10%) patients had anginal complaints, one of them received
      target lesion repeat PTCA. All other patients (87%) were event- and angina-free.
      CONCLUSION: This first clinical experience with the R Stent shows acceptable
      feasibility and safety with good long-term clinical results.

PMID- 12470376
TI  - Clinical and angiographic results with the ACS MULTI-LINK DUET trade mark
      Coronary Stent System - the DUET Study.
AB  - BACKGROUND: The DUET Study is a multicenter prospective efficacy and safety
      evaluation of the ACS MULTI-LINK DUET coronary stainless steel balloon-expandable
      stent. AIMS: The primary objective was to determine the one-month incidence of
      MACE (major adverse cardiac events). The secondary objectives were the acute
      success rate, the restenosis and reocclusion rates (assessed by quantitative
      coronary angiography (QCA)) at six months and the occurrence of MACE in hospital
      and at six months. METHODS: Two hundred and ten patients were enrolled between
      February and June 1998 in 18 European centers. Successful stent placement was
      achieved in 209 patients. All patients were treated with ticlopidine 500 mg/day
      for one month and with aspirin >/=100 mg/day. To allow the investigators to gain
      familiarity with the stent system, the first one to three patients per center
      formed a separate lead-in population leaving an intention-to-treat population of
      157 patients. The majority of the intention-to-treat population were male (79%);
      28% had unstable angina, 69% had stable angina, 44% had had a previous myocardial
      infarction, 15% had had a previous percutaneous transluminal coronary
      angioplasty, and 3% had a history of stroke. The target vessel was 38.5% left
      anterior descending artery, 20.5% left circumflex artery and 41.0% right coronary
      artery. RESULTS: All but one of the intention-to-treat patients were effectively
      stented (17 required multiple stents). Six-month angiographic follow-up was
      available in 90% of the intention-to-treat population. Minimal lumen diameter
      (MLD) postprocedure was 2.61 +/- 0.33 mm, with a residual diameter stenosis of
      16%. Six-month follow-up data showed an MLD of 1.87 +/- 0.56 mm with a residual
      diameter stenosis of 36%. The binary restenosis rate (>/=50% residual stenosis)
      was 15.6%. Up to one month following the procedure 94.9% of the population was
      MACE-free, with two subacute occlusions. At six months all patients were alive,
      of whom 82.8% were MACE-free, and 73% were free of anginal complaints.
      CONCLUSION: The results observed in the current DUET registry are comparable to
      data of other balloon-expandable-stent trials, with a low incidence of clinical
      events at follow-up.

PMID- 12470377
TI  - Recanalization of chronic total coronary occlusions: the impact of a new specific
      guidewire on primary success rate.
AB  - BACKGROUND: Although chronic total occlusions are encountered frequently in
      patients with coronary artery disease, an effective strategy to deal with them
      has yet to be devised. Various new guidewires have been designed in an attempt to
      negotiate chronic occlusions successfully. The authors have analysed the impact
      of the Athlete guidewire on procedural success in this lesion subset. METHODS:
      Sixty-two consecutive patients undergoing percutaneous intervention for chronic
      total occlusions over a two-year period were retrospectively studied. For the
      initial attempt, conventional guidewires were used. In case of failure, further
      attempts were made using the Athlete guidewire. Procedural success rates with the
      use of conventional and Athlete guidewires were assessed. RESULTS: Failure of the
      first attempt with the conventional guidewire occurred in 32 (51.6%) patients and
      success was achieved in 30 (48.4%) patients. In the former patients, a second
      attempt was made using the Athlete guidewire to cross the occlusion. The second
      attempt was successful in 20 patients (60%) in whom the first attempt was
      unsuccessful, while in the remaining 12 (40%) patients the occlusion could not be
      crossed even during the second attempt and the procedure was then terminated.
      Following the use of the Athlete guidewire, the success rate increased to 62% (p
      < 0.001). No complication occurred during the first attempt, while one patient
      had a coronary perforation using the Athlete guidewire, which was managed
      successfully without the need for bypass surgery. CONCLUSION: The use of the
      Athlete guidewire is feasible and safe, and enhances the chances of successfully
      treating chronic total occlusions during percutaneous coronary revascularization
      procedures.

PMID- 12470378
TI  - A nonsurgical porcine model of left ventricular dysfunction. Validation of
      myocardial viability using dobutamine stress echocardiography and positron
      emission tomography.
AB  - BACKGROUND: Although several short-term animal models of stunning and hibernation
      have been studied extensively, it has been difficult to produce a consistent
      animal model of chronic hibernation. The aim of the present study was to develop
      a nonsurgical porcine stent model of coronary stenosis in order to investigate
      the relationship between chronic dysfunctional myocardium and viability using 2D
      echo, dobutamine stress echo (DSE) and positron emission tomography (PET).
      METHODS AND RESULTS: Focal progressive coronary stenosis was induced by
      implantation of an oversized stent in the left anterior descending (LAD) and/or
      circumflex (LCX) coronary artery in a total of 115 pigs, according to various
      experimental protocols: copper stent in the LAD (group I, n = 5); noncoated
      stainless steel stent in the LAD combined with balloon overstretch (group II, n =
      7); poly(organo)phosphazene-coated stent in the LAD (group III, n = 77); and
      poly(organo)phosphazene-coated stent in both the LAD and the LCX (group IV, n =
      26). Occurrence of left ventricular dysfunction was evaluated weekly by 2D-echo.
      At the time of left ventricular dysfunction the presence of viable myocardium
      within the dysfunctional region was investigated with DSE and PET, and confirmed
      by histology. The degree of coronary artery stenosis was measured by quantitative
      coronary angiography and morphometry. Severe coronary artery stenosis in the
      presence of dysfunctional, but viable, myocardium was induced in groups III and
      IV (47% and 11% of the animals, respectively). CONCLUSIONS: The authors developed
      a nonsurgical porcine stent model of progressive coronary stenosis using an
      oversized polymer-coated stent resulting in chronically decreased myocardial
      function, with residual inotropic reserve and viable myocardium. This condition
      may arise from repetitive periods of ischemia, or from sustained hypoperfusion,
      or a combination of these processes eventually leading to myocardial hibernation.

PMID- 12470380
TI  - Editorial.

PMID- 12470379
TI  - Application of beta-irradiation through the struts of a previously deployed
      stent.
AB  - The application of beta-radiation in coronary arteries is a promising new
      technique for the treatment of in-stent restenosis. This is the first case in
      which the 5 F. delivery catheter of the Beta-Cath trade mark system was advanced
      through the struts of a stent, previously deployed in an adjacent branch, so as
      to deliver radiation to the target vessel.

PMID- 12470381
TI  - The role of intravascular ultrasound imaging in vascular brachytherapy.
AB  - Intracoronary brachytherapy has recently emerged as a new therapy to prevent
      restenosis. Initial experimental work was achieved in animal models and the
      results were assessed by histomorphometry. Initial clinical trials used
      angiography to guide dosimetry and to assess efficacy. Intravascular ultrasound
      (IVUS) permits tomographic examination of the vessel wall, elucidating the true
      morphology of the lumen and transmural components, which cannot be investigated
      on the lumenogram obtained by angiography. This paper reviews the use of IVUS in
      the clinical studies of brachytherapy conducted to date. IVUS allows clinicians
      to make a thorough assessment of the remodeling of the vessel and appears to have
      a major role to play in facilitating understanding of the underlying mechanisms
      of action in this emerging field. The authors propose that state-of-the-art IVUS
      techniques should be employed to further knowledge of the mechanisms of action of
      brachytherapy in atherosclerotic human coronary arteries.

PMID- 12470382
TI  - Basic principles of angiogenesis for the interventional cardiologist.
AB  - Despite tremendous advances in the management of coronary artery disease, there
      is a growing population of patients who remain symptomatic with residual
      myocardial ischemia. Therapeutic angiogenesis, designed to promote the
      development of endogenous conduits forming collateral blood vessels that serve to
      bypass coronary artery stenotic lesions, may constitute an alternative treatment
      strategy for patients with extensive tissue ischemia in whom contemporary
      therapies-antianginal medications, angioplasty, bypass surgery-have failed or are
      not feasible. Intensive investigation is now focused on methods that would have
      the potential to stimulate the development of collaterals in humans. In this
      review we summarize the physiology of angiogenesis and its role in development
      and adult life, its regulation, the effects of ischemia and hypoxia, the
      principles of gene therapy for angiogenesis, and an update on the current
      available trials data of angiogenic cytokines administration.

PMID- 12470383
TI  - Clinical and angiographic results with the beStent: the Registry for Optimal
      beStent Evaluation (ROSE) trial.
AB  - BACKGROUND: Although safety and efficacy of the beStent (Medtronic Inc., Santa
      Rosa, CA, USA) have been described, the long-term angiographic and clinical
      outcomes have yet to be investigated. The ROSE (Registry for Optimal beStent
      Evaluation) trial was designed to assess the procedural safety of single 15 mm
      beStent implantation, and the six-month angiographic and 12-month clinical
      outcomes of patients treated with this novel coronary stent. METHODS: Patients
      with angina and a single de novo lesion in a native coronary artery of >/=2.75 mm
      diameter were included in this multicenter, prospective, observational trial.
      Clinical follow-up was obtained at one, six and 12 months. Angiography was
      performed before and after the stent implantation and at six months. The primary
      end-point included major adverse cardiac events (death, myocardial infarction and
      target lesion revascularization), major bleeding complications, and thrombotic
      occlusions at one-month follow-up. Secondary end-points were major cardiac-event
      free survival at six- and 12-month follow-up and angiographic restenosis at six
      months. A total of 120 patients (80% male, mean age 58.6 +/- 10.6 years) with
      stable (48%) or unstable (44%) angina pectoris were allocated. The target vessel
      reference diameter pre-procedure was 2.85 +/- 0.52 mm. RESULTS: Minimal lumen
      diameter pre/post and at follow-up was 0.97 +/- 0.28 mm, 2.53 +/- 0.40 mm and
      1.86 +/- 0.63 mm, respectively. Restenosis rate according to the >50% diameter
      stenosis criterion at six-month follow-up was 21.5%. At 12 months, the event-free
      survival rate was 75% (no deaths, two Q-wave and seven non-Q-wave infarctions,
      five bypass surgery interventions and 16 target lesion revascularizations),
      whilst 87% of the patients were free of angina pectoris. CONCLUSION: Despite the
      relatively high percentage of small vessels, the outcome of the ROSE trial is
      comparable to those observed in previous stent trials, indicating that the
      coronary beStent is safe and effective as a primary device for the treatment of
      native coronary artery lesions in patients with (un)stable angina pectoris.

PMID- 12470384
TI  - Failure to monitor ticlopidine: the case for clopidogrel.
AB  - AIM: Ticlopidine remains unlicensed for use in coronary artery stenting.
      Haematological monitoring at two-weekly intervals of all patients taking
      ticlopidine is recommended because of the risk of neutropaenia. The authors
      assessed their ability to monitor a two-week course of ticlopidine given to
      patients undergoing coronary stenting procedures. METHODS AND RESULTS: One
      hundred and forty-one unselected consecutive patients undergoing coronary
      stenting procedures were prescribed ticlopidine 250 mg twice daily for two weeks,
      in addition to aspirin. Prior to discharge home they and their GPs were given
      written information outlining the side-effects of ticlopidine and the monitoring
      procedures required. One hundred and thirty-three patients (94%) completed the
      full two-week course of ticlopidine; three (2.4%) developed significant
      neutropaenia (neutrophil count <0.5 x 10(9)/mm(3)). Patient compliance with full
      blood count monitoring was 85% at two weeks and 80% at four weeks. Two patients
      (1.4%) suffered subacute stent thrombosis. At six months, there were no deaths,
      one (0.7%) myocardial infarction and nine patients (6%) requiring target vessel
      revascularization. CONCLUSION: A two-week course of ticlopidine is well tolerated
      and does not appear to be associated with an increase in adverse cardiac events.
      However, even with a dedicated monitoring team, adequate haematological follow-up
      was achieved in only 80% of patients. The need for a licensed antiplatelet agent
      which has a lower side-effect profile and does not require haematological
      monitoring is obvious.

PMID- 12470385
TI  - Reversal of slow flow phenomenon during primary stenting by bail-out
      administration of abciximab.
AB  - BACKGROUND: Slow flow or no reflow phenomenon is increasingly being recognized as
      a serious problem during coronary angioplasty and stenting. This phenomenon is
      seen more often during angioplasty in highly thrombogenic milieux, especially in
      a setting of acute myocardial infarction. The treatment of this complication is
      often not satisfactory. In this study the authors assessed the efficacy of
      abciximab, a potent antiplatelet drug, in treating slow flow or no reflow
      phenomenon during primary percutaneous transluminal coronary angioplasty (PTCA)
      for acute myocardial infarction (AMI). METHODS: Twenty-one instances of
      persistent slow flow phenomenon were encountered in 131 consecutive patients
      subjected to primary PTCA for AMI (16%). It was more common in patients
      presenting with AMI complicated by cardiogenic shock (nine of 21, 43%). Of these
      21 cases of slow flow, 10 patients were given injection abciximab during the
      procedure of primary PTCA as a bail-out measure after encountering the
      complication of slow flow or no reflow. A pre-discharge coronary angiography was
      carried out in all patients who survived. RESULTS: In seven of 10 patients in the
      abciximab group flow had improved to TIMI-3. In contrast, in the non-abciximab
      group TIMI flow improved in only four of 11 patients. Patients with persistent
      slow flow had significantly higher mortality at the first 30-day follow-up than
      patients with TIMI-3 flow (33% versus 1.8%, p<0.001). CONCLUSION: In this small
      nonrandomized study significant improvement in coronary flow was achieved by
      using intravenous abciximab after observing slow flow or no reflow phenomenon
      during primary PTCA. More frequent use of this drug in this milieu might help in
      preventing the development of this complication. Larger studies are warranted to
      confirm this life-saving beneficial effect of bail-out administration of
      abciximab during primary angioplasty.

PMID- 12470386
TI  - Coronary stenting using a 6 F. diagnostic catheter: a report of two cases.
AB  - Standard guiding catheters for coronary interventions may not selectively engage
      the coronary ostium despite a successful cannulation with a diagnostic catheter
      of the same curve. This discrepancy is explained by a slight difference in shape
      between the two catheters (shorter tip of the guiding, absence of tip tapering,
      etc.). The authors report on the use of 6 F. coronary diagnostic catheters as
      guiding catheters for coronary angioplasty and stent implantation in two patients
      with critical stenoses: in the right coronary artery distal to a right internal
      mammary artery anastomosis in one and in the ostial right coronary artery in the
      other. In both cases, the use of diagnostic catheters was the key to success
      despite the vessel orifice being unfavourable for the use of different types of
      guiding catheters.

PMID- 12470387
TI  - Isolated bilateral ostial coronary stenosis with proximal right coronary artery
      occlusion.
AB  - The incidence of coronary ostial stenosis in patients undergoing coronary
      arteriography has been found to range between 0.07 and 0.25%. A slightly higher
      incidence has been observed in patients with angiographically confirmed coronary
      artery disease: between 0.13 and 2.7%. Bilateral ostial stenosis is even less
      common. Although cardiovascular syphilis is no longer a prominent condition, it
      must be considered in the differential diagnosis since it carries a very high
      risk (50%) of cardiovascular complications if left untreated. Ostial coronary
      stenosis occurs in 26% of patients with syphilitic aortitis. This paper reports
      on a 41-year-old Wasserman (WR)-positive woman with progressive angina caused by
      bilateral ostial coronary stenosis.

PMID- 12470388
TI  - Images in Cardiovascular Interventions: Triple complication of AVE Microstent:
      splitting, migration and restenosis.

PMID- 12470389
TI  - Hot topics.

PMID- 12470390
TI  - Should we implant ICDs in more patients after myocardial infarction? Can we
      define the patient groups that benefit most?

PMID- 12470391
TI  - Clinical implications of CURE and PCI-CURE in patients with the acute coronary
      syndrome without persistent ST-elevation.

PMID- 12470392
TI  - Which is the optimal operation for the young adult patient with aortic valve
      disease?

PMID- 12470393
TI  - Concerning B. Koul et Al, Scand Cardiovasc J 2002; 36: 48-52.

PMID- 12470394
TI  - QT interval dynamics predict mortality in high-risk patients after myocardial
      infarction.
AB  - OBJECTIVE: The purpose of this study was to evaluate the prognostic properties of
      the QT/RR relationship in survivors of myocardial infarction with severe left
      ventricular dysfunction. DESIGN: The QT/RR interval slope was assessed from 24-h
      electrocardiographic recordings obtained from 241 patients representative of
      survivors of an acute myocardial infarction with an ejection fraction < or =35%.
      During a median follow-up of 752 days, 63 patients died. RESULTS: In a
      multivariate analysis QT/RR at night-time was an independent predictor of all
      cause mortality. A linear all-cause mortality predictor score was calculated from
      age, ejection fraction, QRS duration and QT/RR night, allowing identification of
      a high-risk one-third of the patients with a relative risk of death at 4.0.
      CONCLUSION: This study demonstrates independent prognostic information of night
      time QT/RR dynamics in patients at high risk after myocardial infarction. A
      linear predictor score calculated from age, ejection fraction, QRS duration and
      QT/RR night identifies a high-risk one-third of the patients with a 1-year
      mortality of 36% vs 9% in the remaining patients.

PMID- 12470395
TI  - Improvement of risk-stratification by use of a new combination of Holter
      variables in survivors of myocardial infarction.
AB  - OBJECTIVE: Holter monitoring is one option in risk-stratification after acute
      myocardial infarction (MI). Measurements of heart rate variability (HRV),
      ventricular tachycardia (VT) and ST-segment elevation (ST upward arrow ) have
      been useful in predicting clinical outcome. We investigated if a combination of
      different Holter variables could optimize risk-stratification. DESIGN: One
      hundred and twenty-one men < 70 years old with a first MI were studied. Holter
      monitoring for 24 h was started 11 +/- 5 days after MI and analysed for HRV, VT
      and ST. Follow-up was 10-12 years with cardiac death as endpoint. RESULTS: Thirty
      six patients were positive for > or = 1 Holter variable (HRV in 15, VT in 16, ST
      in 10). At follow-up 22 cardiac deaths had occurred. The prognostic sensitivity
      of individual Holter variables ranged from 23 to 36%, but increased to 64% if
      combined. The cardiac death rate in Holter positive patients (39%) was
      significantly higher than in Holter negative patients (9%) (p < 0.0001).
      CONCLUSION: By combining measurements of HRV, VT and ST the prognostic importance
      of Holter monitoring can be significantly improved. The patients can be
      stratified in a low-risk group with an annual mortality < 1% vs a high-risk group
      with a cardiac death rate around 40% over the following decade.

PMID- 12470396
TI  - Significant decline in case fatality after acute myocardial infarction in Denmark
      -a population-based study from 1994 to 2001.
AB  - OBJECTIVE: We evaluated trends in in-hospital case fatality after acute
      myocardial infarction (AMI) in Denmark and analysed changes in the
      hospitalization rate for AMI. DESIGN: National population-based registries were
      used to identify patients (> or =30 years) who were admitted for their first AMI
      from 1994 to 2001. RESULTS: The annual relative decline in case-fatality rate was
      constant at 10.5% (95% confidence interval (CI) 9.5-11.5%). The decline was
      similar for both genders at all ages. The hospitalization rate decreased from
      1994 to 1999 at an annual average of 4.3% (95% CI 3.4-5.1%). In 2000 and 2001 the
      average annual increase was 7-8%. CONCLUSION: The case-fatality rate after AMI
      declined significantly in Denmark, similar to other Western countries, but the
      level is still higher than that of the USA. The increasing hospitalization rate
      coincided with changes in risk factors in the general population. However, the
      influence of introducing troponins in the diagnosis of AMI and diagnosis-related
      grouping may in particular account for the increased hospitalization rate.

PMID- 12470397
TI  - Influence of left ventricular geometry on regional systolic and diastolic
      function in patients with essential hypertension.
AB  - OBJECTIVE: In essential hypertension, especially in concentric hypertrophy,
      global diastolic function is impaired. But, whether the left ventricular (LV)
      geometric pattern influences regional systolic and diastolic function or not, is
      unknown. This study was aimed to evaluate the influence of left ventricular
      geometric pattern on regional systolic and diastolic function in hypertensive
      patients. DESIGN: Ninety untreated mild to moderate hypertensive patients were
      studied. M-mode parameters, standard Doppler and PW tissue Doppler indices were
      measured. Patients were divided into four groups according to left ventricular
      mass index and relative wall thickness: normal geometry (n = 16), concentric
      remodeling (n = 16), eccentric hypertrophy (n = 32) and concentric hypertrophy (n
      = 26). RESULTS: Age, gender, body mass index, systolic and diastolic blood
      pressure were similar among groups. E/A ratio was significantly lower in the
      concentric hypertrophy group compared with the normal geometry group. Em velocity
      and Em/Am ratio in basal septum and Em velocity in basal inferior were
      statistically lower in the concentric hypertrophy group compared with the normal
      geometry group. In the concentric hypertrophy group, the number of segments with
      diastolic dysfunction was significantly higher compared with the normal geometry
      group. LV ejection fraction and regional S velocity could be compared among
      groups. CONCLUSION: LV regional diastolic function is being impaired in
      concentric hypertrophy. LV regional systolic function does not show a difference
      according to the LV geometric pattern.

PMID- 12470398
TI  - Coronary artery bypass grafting combined with aortic valve replacement in healthy
      octogenarians does not increase postoperative risk.
AB  - OBJECTIVE: Critical aortic stenosis with or without coronary artery disease is
      increasingly common in octogenarians. Surgery is the treatment of choice, but
      indications and results of aortic valve replacement (AVR), particularly when
      combined with coronary artery bypass grafting (CABG) are debated. We investigated
      whether the combined procedure of AVR and CABG increased postoperative risk
      compared with isolated AVR in otherwise healthy octogenarians. DESIGN: In the
      period 1994-1998, AVR was performed in 94 patients above 80 years, the majority
      in NYHA class III and IV. Combined AVR and CABG was performed in 52/94 patients.
      The patients were studied retrospectively by collecting data from hospital
      records and followed for 0-7 years. RESULTS: Mean age was 82 +/- 2.3 years, sex
      (male/female) 33/61, left ventricular ejection fraction 70 +/- 18%, transvalvular
      peak pressure gradient 63 +/- 20 mmHg and aortic valve area 0.5 +/- 0.2 cm(2).
      Early mortality (< 30 days) was 4/42 (9.5%) after AVR and 4/52 (7.6%) after AVR
      and CABG (p = NS between groups). Three-year survival was 33/42 (78.5%) after AVR
      and 42/52 (80.7%) after AVR and CABG (p = NS between groups). CONCLUSION: AVR
      with concomitant CABG in octogenarians with aortic stenosis who are otherwise
      healthy, may be performed without increased risk.

PMID- 12470399
TI  - Increase of intracranial pressure after hypothermic circulatory arrest in a
      chronic porcine model.
AB  - OBJECTIVE: An increase in intracranial pressure has been shown to threaten the
      outcome of patients with ischemic or traumatic brain injury. Its impact on the
      outcome of pigs undergoing hypothermic circulatory arrest has been evaluated in
      this study. DESIGN: Fifty-six pigs underwent a 75-min period of hypothermic
      circulatory arrest at 20 degrees C. Intracranial pressure, cerebral
      microdialysis, hemodynamic and metabolic parameters were monitored throughout the
      experiment. The animals were allowed to survive until the 7th postoperative day
      and, then, electively killed. RESULTS: The 7-day survival rate was 60.7%, and
      among survivors, 20 of them (58.8%) developed brain infarction. A significant
      increase in intracranial pressure as compared with the baseline level was
      observed since the end of cooling (p = 0.047) and the difference became larger
      during all the postoperative intervals (p < 0.0001). Animals that died
      postoperatively tended to have higher intracranial pressure levels during all the
      postoperative intervals, but such a difference reached significance only at the 4
      h postoperative interval (p = 0.040). The same tendency was observed among
      animals that survived until the 7th postoperative day and that developed brain
      infarction or not, but the difference between these two groups did not reach
      statistical significance. The animals that died or developed postoperatively
      brain infarction had higher intracranial pressure values postoperatively as
      compared with those that survived without developing brain infarction and such a
      difference reached significance at the 2-h (p = 0.015) and 4-h postoperative
      intervals (p = 0.035). The peak intracranial pressure was 17.2 mmHg (IQR, 13.7
      20.8) in animals that died or developed brain infarction and 14.1 mmHg (IQR, 11.8
      16.4) in those that survived 7 days without developing brain infarction (p = NS).
      CONCLUSION: Intracranial pressure increases significantly after 75 min of
      experimental hypothermic circulatory arrest and such an increase is associated
      with a high risk of postoperative death and brain infarction.

PMID- 12470400
TI  - Intramyocardial troponin-T monitoring with microdialysis in coronary artery
      bypass surgery.
AB  - OBJECTIVE: To investigate the time course of troponin-T release into the
      extracellular fluid of the myocardium and to distinguish between a rise in
      troponin-T due to implantation trauma and an increase due to cardiac arrest
      during coronary surgery. DESIGN: Microdialysis probes were implanted in the heart
      of seven patients soon after sternotomy. Troponin-T was measured in the
      microdialysates and in peripheral blood from 3 h before to 24 h after heart
      arrest. RESULTS: The troponin-T concentration in the microdialysates increased
      immediately after probe implantation and decreased to baseline within 70 min.
      This early peak is interpreted to reflect a local trauma. Three hours after cross
      clamp release, a second peak of microdialysate troponin-T was recorded; 50 times
      higher than in serum. Eight to 24 h later a third peak occurred in five patients.
      Serum troponin-T was below the detection level at the beginning of the operation
      but increased linearly during the first 3 h of reperfusion and remained at that
      level thereafter. CONCLUSION: Microdialysis is a safe technique providing more
      information on myocardial metabolism during and after bypass surgery than can be
      obtained from peripheral blood. The release of troponin-T in response to cardiac
      arrest can be distinguished in time from the local tissue response to probe
      implantation.

PMID- 12470401
TI  - Predictors of allograft ischemic injury in clinical heart transplantation.
AB  - OBJECTIVES: 1. Identify clinical, biochemical and inflammatory predictors of
      allograft ischemic injury in clinical heart transplantation. 2. Evaluate the
      impact of high dose insulin (GIK) on allograft metabolism during blood
      cardioplegia and post-ischemic injury. DESIGN: A clinical, prospective,
      randomized open trial comprising 25 consecutive heart transplantations at a
      university hospital. Ischemic injury was evaluated from plasma levels of creatine
      kinase isoenzyme MB (CK-MB). Blood cardioplegic arterial and coronary sinus
      concentrations of C3a, IL-6, substrates, amino acids and blood gases were
      measured at the end of the implantation period, prior to reperfusion. Twelve
      patients received high dose insulin with glucose, potassium and amino acids.
      RESULTS: CK-MB increased from 1.9 +/- 0.2 to 161 +/- 13 microg/l (range 47-293
      microg/l). The peak level of CK-MB correlated with donor age (r = 0.48, p = 0.02)
      and implantation time (r = 0.53, p = 0.02); and with recipient plasma IL-6 (r =
      0.56, p = 0.02), allograft oxygen extraction (r = 0.56, p = 0.02), lactate
      release (r = 0.47, p = 0.02) and allograft arterial-coronary sinus (cs) pH (r =
      0.47, p = 0.02) all during final cardioplegia before reperfusion. Seventy-two
      percent of the variance of CK-MB was explained by a model which included donor
      age, art-cs pH difference and arterial IL-6. In contrast, CK-MB was unrelated to
      total ischemic time (r = -0.17, p = 0.38). Insulin infusion had no effect on
      myocardial substrates during cardioplegia, or on post-ischemic CK-MB. CONCLUSION:
      Donor age, duration and quality of the implantation period are significant
      predictors of allograft ischemic injury in heart transplantation. High dose
      insulin had no detectable effects on allograft metabolism during cardioplegia, or
      on subsequent ischemic injury.

PMID- 12470402
TI  - Laparoscopic Nissen fundoplication after failed endoscopic gastroplication.
AB  - Endoscopic techniques to treat gastroesophageal reflux have been developed and
      approved by the U.S. Food and Drug Administration. One of these techniques is
      endoscopic gastroplication with the Bard Endocinch device. Although the technique
      is initially effective, long-term symptom control has not yet been proved. No
      reports have documented the feasibility of laparoscopic fundoplication after
      failed endoscopic gastroplication. We report our experience. Ten patients who
      underwent endoscopic gastroplication subsequently had recurrent symptoms and were
      referred for laparoscopic antireflux surgery. Eight had typical symptoms of
      gastroesophageal reflux disease (GERD), whereas two had atypical symptoms. All
      patients had documented pathologic reflux by 24-hour pH monitoring.
      Preoperatively, all patients completed the GERD health-related quality of life
      (HRQL) symptom severity questionnaire. Nine of the 10 operations were completed
      laparoscopically. The one conversion was carried out because of excessive fat in
      the hiatal region. No patients had scarring of the esophagus or hiatal region.
      All patients with typical symptoms improved (decrease in total GERD-HRQL median
      score from 27 to 4), whereas none of the patients with atypical symptoms did. Six
      patients had persistent dysphagia for longer than 1 month; two required
      esophageal dilation. Laparoscopic Nissen fundoplication is feasible after failed
      endoscopic gastroplication. Symptomatic improvement is similar to that with the
      de novo operation. However, in some patients, dysphagia may persist longer.

PMID- 12470403
TI  - Laparoscopically assisted approach for postoperative ventral hernia repair.
AB  - BACKGROUND: The laparoscopic approach to incisional hernia repair is already well
      established because of its advantages. We evaluated the possibility of using a
      laparoscopically assisted approach whenever conversion to open repair was
      considered. PATIENTS AND METHODS: We operated laparoscopically on 62 patients for
      postoperative ventral hernia (POVH), seven of whom had undergone laparoscopically
      assisted repair. The reasons for considering conversion were mainly technical
      difficulties in adhesiolysis and hernia reduction, and the suspected possibility
      of intestinal injury during dissection. The assisted approach included creation
      of a short incision over the fascial defect, exploration of the hernia contents
      and correction of any intestinal injury, completion of adhesiolysis, closure of
      the abdominal cavity, and laparoscopic accomplishment of the repair. RESULTS:
      Following open exploration, two iatrogenic intestinal perforations and one
      serosal injury were found and repaired. In four cases, only the completion of
      adhesiolysis was necessary. The postoperative convalescence was uneventful, and
      no recurrence has been recorded to date. CONCLUSIONS: The laparoscopically
      assisted approach to difficult POVH repair is feasible and safe, and it helps to
      preserve the advantages of the laparoscopic approach. We recommend this approach
      whenever conversion to open surgical repair is under consideration during
      laparoscopic repair.

PMID- 12470404
TI  - Mini-access for retroperitoneal laparoscopy.
AB  - The purpose of this study was to establish the feasibility of primary mini-access
      to the retroperitoneal space to perform certain retroperitoneoscopic procedures
      in which an enlarged port is not required for extraction of the specimen. Mini
      laparoscopy or needlescopic laparoscopy has been performed in the past via the
      transperitoneal route, but this has not yet been reported for a
      retroperitoneoscopic procedure. Through a 5-mm primary access and 3- or 5-mm
      secondary ports, retroperitoneoscopic surgery was performed in seven adults for
      ureterolithotomy, renal biopsy, simple nephrectomy, nephropexy, cyst
      decortication, or drainage of a subphrenic abscess. The access technique used was
      a mini-version of a previously described percutaneous access technique with some
      modifications. The retroperitoneoscopic procedure was successful in all seven
      patients, and no complications developed. The operative time, blood loss,
      analgesic intake, and length of hospital stay were comparable with those of a
      standard retroperitoneoscopic procedure. However, the cosmetic results were
      better. Mini-retroperitoneoscopy is feasible and is a better alternative for
      patients in whom the whole procedure can be performed through 5-mm or smaller
      ports.

PMID- 12470405
TI  - Comparison of laparoscopic aortic clamps in a pulsatile circulation model.
AB  - PURPOSE: This study was designed to evaluate the fatigue characteristics and the
      safety and effectiveness of laparoscopic aortic clamps in a pulsatile circulation
      model. METHODS: A heart-lung machine was used to create a pulsatile circulation
      model with bovine aortas resembling the vessels being cross-clamped. Four
      different models (A-D) of laparoscopic aortic clamps were investigated, and three
      identical probes of each model underwent testing. Preliminary examinations were
      conducted to define the size and thickness of the bovine aortas that would allow
      effective cross-clamping and to detect gross material or functional deficits of
      the clamps. Then, the instruments were placed in the circulation model, which was
      set at a frequency of 82/min and a pressure of 200/120 mm Hg. Each clamp was
      subjected to these conditions for 120 hours and was opened and closed 40 times to
      stimulate real-life conditions. Clamping failures and mechanical defects were
      recorded, and the clamp parts were afterward examined with an electron
      microscope. RESULTS: Two clamp models had to be eliminated from the study after
      the preliminary examinations. All three probes of model B displayed mechanical
      defects after a few applications. All probes of model D were excluded because
      none effectively occluded the aortas. All probes of model A and one probe of
      model C provided effective cross-clamping during the 120-hour test phase and
      showed no signs of mechanical failure. Two probes of model C broke after 51 and
      57 hours of testing, respectively. Both times, the defect occurred during
      application of the clamps. The detailed analysis of all instruments after the
      testing, including electron microscope imaging, revealed that several
      construction deficits and weak points were responsible for the mechanical
      failures. CONCLUSION: A surprisingly high incidence of clamping failures and
      mechanical deficits were encountered during the testing. Of the four clamps
      tested, only one (model A) seemed to be safe and effective enough for routine
      clinical use. These disappointing results demonstrate the need for further
      cooperation between vascular surgeons and instrument manufacturers to develop
      safe and effective laparoscopic vascular clamps.

PMID- 12470406
TI  - The effects of one- and two-stage orchiopexy on postoperative serum testosterone
      levels and testicular volume in adult patients with bilateral nonpalpable testes.
AB  - In this study, we investigated the effects of one- and two-staged orchiopexy on
      testicular volume and serum testosterone levels in cases with high, abdominally
      localized, bilateral nonpalpable testes. Between March 1996 and April 2001,
      orchiopexy was performed on 46 testes in 23 patients with bilateral nonpalpable
      testes. In 15 of the 23 patients, a two-stage Fowler-Stephens orchiopexy was
      performed, and in 8 of the 23 patients, a one-stage laparoscopic orchiopexy was
      performed. For one patient who lacked both testes, bilateral prosthetic testes
      were inserted. The patients' ages were between 20 and 23 years (average, 21
      years). In the first stage of the two-stage orchiopexy, the spermatic artery was
      ligated laparoscopically. Six months later, open surgery orchiopexy was
      performed. Patients were followed for 2 to 16 months (average, 10 months) and
      were evaluated for testicular atrophy, serum testosterone levels, and
      complications. In all the patients, the preoperative secondary sexual
      characteristics and serum testosterone levels were normal. Among the
      postoperative controls, evaluated at months 3 and 6, one patient's testes were
      found at the pubic area. Testicular atrophy was not observed in any of the
      patients, and the serum testosterone levels were in the normal range. In the two
      stage orchiopexy group, 5 (33%) of the 15 patients had an average 30% volume
      decrease, and in the one-stage group, 2 (25%) of the 8 patients had an average
      40% volume decrease. In this study, it was shown that either two-stage Fowler
      Stephens orchiopexy or laparoscopic orchiopexy can be successfully performed in
      patients with bilateral abdominal testes, and that the testes can be fixed to
      their palpable original positions without interfering with the secretion of
      testosterone. Although the results are similar, our experience suggests that
      single-stage laparoscopic orchiopexy is the preferable method.

PMID- 12470407
TI  - Ectopic pancreatic tissue presenting as submucosal gastric mass.
AB  - BACKGROUND: Ectopic pancreas is pancreatic tissue found outside its usual
      anatomic location without connection to the normal pancreas. We describe the
      presentation and minimally invasive management of four patients with ectopic
      pancreatic tissue in the stomach. METHODS: Data were collected from a
      retrospective chart review of four patients undergoing laparoscopic resection of
      gastric pancreatic rests. RESULTS: Four patients underwent laparoscopic resection
      of gastric pancreatic tissue. All patients were discharged on postoperative day
      3. No complications developed. CONCLUSION: Laparoscopic gastric wedge resection
      is a safe and effective treatment for symptomatic pancreatic rests located in the
      stomach.

PMID- 12470408
TI  - Hand-assisted laparoscopic aortobifemoral bypass versus open bypass for occlusive
      disease.
AB  - BACKGROUND: Aortobifemoral bypass grafting is the treatment of choice for
      patients with symptomatic aortoiliac occlusive disease. Yet, traditional
      operative exposure through a midline laparotomy incision carries significant
      morbidity. The authors compare operative and patient outcomes following hand
      assisted laparoscopic aortobifemoral (HALABF) bypass and open aortobifemoral
      (OABF) bypass. METHODS: An initial series of patients who underwent HALABF bypass
      grafting (n = 8) were compared with a simultaneous cohort of patients treated
      with standard open bypass (n = 10). The two groups were similar with respect to
      age, weight, and sex. Operative parameters, clinical outcomes, and complications
      were compared. RESULTS: HALABF was successfully performed in all eight cases
      attempted. Operative times did not differ between the laparoscopic and open
      groups (234 +/- 42 minutes vs. 206 +/- 43 minutes, P =.99). Mean blood loss
      values were comparable (562 mL [HALABF] vs. 756 mL [OABF], P =.56). There were no
      conversions. Time to resumption of oral intake (1.8 vs. 4.7 days, P =.001) and
      length of stay (3.8 vs. 6.3 days, P =.0004) were significantly shorter in the
      laparoscopic than in the open group. CONCLUSIONS: HALABF is a safe and
      technically feasible procedure. When compared with the traditional open
      operation, this technique may result in shorter hospitalization, more rapid
      return of bowel function, and earlier return to activity.

PMID- 12470409
TI  - Thoracoscopy: the preferred approach for the resection of selected posterior
      mediastinal tumors.
AB  - The posterior mediastinum is a common site for neurogenic tumors. These are
      mostly asymptomatic and detected incidentally during radiologic investigations.
      However, they occasionally present with compressive or neurologic symptoms. The
      tumors are mostly benign but can also be malignant. Left untreated, they continue
      to grow. Therefore, once detected, resection is always advised. Traditionally,
      resection has been performed by standard posterolateral thoracotomy. More
      recently, such tumors have been removed thoracoscopically. We report our
      experience with three such cases and present a comprehensive analysis of cases of
      thoracoscopic resection of posterior mediastinal neurogenic tumors reported in
      the English literature to suggest guidelines for their current management.

PMID- 12470410
TI  - Impact of temperature and humidity of carbon dioxide pneumoperitoneum on body
      temperature and peritoneal morphology.
AB  - BACKGROUND: The insufflation of cold gas during laparoscopic surgery exposes
      patients to the risk for hypothermia. The objectives of this study were to
      investigate whether heating or humidification of insufflation gas could prevent
      peroperative hypothermia in a rat model, and to assess whether the peritoneum was
      affected by heating or humidification of the insufflation gas. METHODS: Rats were
      exposed to insufflation with either cold, dry carbon dioxide CO2 (group I); cold,
      humidified CO2 (group II); warm, dry CO2 (group III); or warm, humidified CO2
      (group IV); another group underwent gasless laparoscopy (group V). Core
      temperature and intraperitoneal temperature were registered in all animals during
      120 minutes. Specimens of the parietal peritoneum were taken directly after
      desufflation and 2 and 24 hours after the procedure. All specimens were analyzed
      with scanning electron microscopy (SEM). RESULTS: During the 120-minute study
      period, core temperature and intraperitoneal temperature were significantly
      reduced in groups I, II, and III. In the animals that underwent warm, humidified
      insufflation (group IV) and the gasless controls (group V), intraoperative
      hypothermia did not develop. At SEM, retraction and bulging of mesothelial cells
      and exposure of the basal lamina were seen in the four insufflation groups
      (groups I-IV) and also in the gasless controls (group V). CONCLUSION:
      Insufflation with cold, dry CO2 may lower the body temperature during
      laparoscopic surgery. Hypothermia can be prevented by both heating and
      humidifying the insufflation gas. Changes of the peritoneal surface occur after
      CO2 insufflation, despite heating or humidifying, and also after gasless surgery.

PMID- 12470411
TI  - Development of a novel method of female sterilization: I. The development of a
      novel method of hysteroscopic sterilization.
AB  - BACKGROUND AND OBJECTIVES: For more than 100 years, gynecologists have attempted
      to effect sterilization via a transuterine approach. Our aim was to develop a
      safe, simple, rapid method of sterilization that could be performed in the
      outpatient clinic. The authors felt that a tubal screw based on a "self-tapping"
      screw would be less likely to become dislodged from the uterine cornu with time
      because multiple backward-pointing threads prevent it from being displaced.
      METHODS: During the development of the technique, many changes had to be made to
      deliver the tubal screw effectively to the uterine cornu. These involved
      overcoming problems of poor cornual distension before screw application,
      effecting the requisite deflection toward the uterine cornu, performing the
      screwing action with a deflected applicator, and finally disimpacting the screw.
      Changes were made to the tubal screw, hysteroscope, method of uterine distension,
      method of deflection, screw applicator, and method of disimpaction. RESULTS AND
      CONCLUSIONS: The system that appears to be the most efficient consists of a 25F
      cystoscope with a variable bridge, a 4-mm 30-degree endoscope, and an unsealed
      spring applicator with bayonet mounting on the screw applied with the use of a
      pressure bag for uterine distension with saline solution.

PMID- 12470412
TI  - Hydro-jet-assisted pneumonectomy: a new technique in a porcine model.
AB  - BACKGROUND AND OBJECTIVES: Hydro-jet technology has long been used to cut various
      materials, such as metal and wood, in the industrial field. In the medical field,
      this technology has been applied successfully in selective cutting of the
      parenchyma of the liver. However, to our knowledge, no data are available on the
      use of the hydro-jet technique for pneumonectomy. The purpose of this study was
      to evaluate a new dissection technique in which a high-pressure water stream
      (hydro-jet) and a new dissection probe for pulmonary resection are used. METHODS:
      Thirty pigs underwent right pneumonectomy. Pigs were randomized to either the
      conventional or hydro-jet-assisted dissection technique. The feasibility of this
      technique and the features of surgical dissection were evaluated and compared
      between the two groups. RESULTS: Pneumonectomy was successful in all animals. The
      mean operative times were 55 and 65 minutes and the mean volumes of blood loss
      were 37 and 65 mL for the hydro-jet and conventional dissection techniques,
      respectively. Complications included vascular injury in 6% and 20% of cases with
      the hydro-jet and conventional techniques, respectively. The use of hydro-jet for
      pneumonectomy had clear technical advantages over the conventional dissection.
      Hydro-jet resulted in a selective dissection of fibrous and connective tissue,
      preserving blood vessels for later ligation. Therefore, the dissection was
      performed in a relatively bloodless field. The ease of dissection with the bent
      tip dissector represents another advantage. The continuous water flow allows a
      clear view for the operator. CONCLUSIONS: This study shows that hydro-jet
      dissection represents an excellent alternative to the conventional technique for
      pulmonary resection. The improved anatomic dissection combined with an almost
      bloodless operating field secondary to continuous water flow may decrease
      dissection-related complications.

PMID- 12470413
TI  - Live streaming video for medical education: a laboratory model.
AB  - At the University of Kentucky (UK), we applied streaming video technology to
      develop a webcast model that will allow institutions to broadcast live and
      prerecorded surgeries, conferences, and courses in real time over networks (the
      Internet or an intranet). We successfully broadcast a prerecorded laparoscopic
      paraesophageal hernia repair to domestic and international clients by using
      desktop computers equipped with off-the-shelf, streaming-enabled software and
      standard hardware and operating systems. A web-based user interface made
      accessing the educational material as simple as a mouse click and allowed clients
      to participate in the broadcast event via an embedded e-mail/chat module. Three
      client computers (two connected to the Internet and a third connected to the UK
      intranet) requested and displayed the surgical film by means of seven common
      network connection configurations. Significantly, no difference in image
      resolution was detected with the use of a connection speed faster than 128
      kilobytes per second (kbps). At this connection speed, an average bandwidth of
      32.7 kbps was used, and although a 15-second delay was experienced from the time
      of data request to data display, the surgical film streamed continuously from
      beginning to end at a mean rate of 14.4 frames per second (fps). The clients
      easily identified all anatomic structures in full color motion, clearly followed
      all steps of the surgical procedure, and successfully asked questions and made
      comments by using the e-mail/chat module while viewing the surgery. With minimal
      financial investment, we have created an interactive virtual classroom with the
      potential to attract a global audience. Our webcast model represents a simple and
      practical method for institutions to supplement undergraduate and graduate
      surgical education and offer continuing medical education credits in a way that
      is convenient for clients (surgeons, students, residents, others). In the future,
      physicians may access streaming webcast material wirelessly with hand-held
      computers, so that they will be freed from computer stations.

PMID- 12470414
TI  - Spilled gallstones after laparoscopic cholecystectomy.
AB  - Spilled gallstones have emerged as a new issue in the era of laparoscopic
      cholecystectomy. We treated a 77-year-old woman who underwent laparoscopic
      cholecystectomy. Subsequently, a right flank abscess developed. During the
      cholecystectomy, the gallbladder was perforated and stones were spilled. After a
      failed attempt to drain the abscess percutaneously, the patient required open
      drainage, which revealed retained gallstones in the right flank. The abscess
      resolved, although the patient continued to have intermittent drainage without
      evidence of sepsis. Review of the literature revealed 127 cases of spilled
      gallstones, of which 44.1% presented with intraperitoneal abscess, 18.1% with
      abdominal wall abscess, 11.8% with thoracic abscess, 10.2% with retroperitoneal
      abscess, and the rest with various clinical pictures. In case of gallstone
      spillage during laparoscopic cholecystectomy, every effort should be made to
      locate and retrieve the stones.

PMID- 12470415
TI  - Laparoscopic repair of small bowel injury in penetrating abdominal trauma.
AB  - A role for laparoscopy in the management of selected trauma patients is now
      possible. We report a case of a patient with a stab wound and a bowel perforation
      who underwent diagnostic and laparoscopic treatment.

PMID- 12470416
TI  - Double cystic duct: a rare biliary anomaly encountered at laparoscopic
      cholecystectomy.

PMID- 12470417
TI  - Hemostats, adhesives, and sealants in endoscopic surgery.

PMID- 12470418
TI  - Interleukin-12 inhibits apoptosis in chronic lymphatic leukemia (CLL) B cells.
AB  - The purpose of the present study was to investigate the effect of interleukin-12
      on apoptosis of chronic lymphatic leukemia (CLL) B cells. Apoptotic indices were
      determined in highly purified CD5(+) B lymphocytes isolated from peripheral blood
      of seven patients with histologically confirmed CLL. Interleukin-4 as a known
      inhibitor of apoptosis was used as control. Quantitative analysis of apoptosis
      was determined by cell death detection ELISA. Our findings indicate that
      interleukin-12 inhibits ex vivo apoptosis in a large proportion of B-CLL patients
      and may be closely involved in the pathogenesis of disease. Therefore, our
      results may help identify potential new therapeutic targets in this malignancy.

PMID- 12470419
TI  - A model for evaluating selective delivery of plasmid DNA to tumours via the
      vasculature.
AB  - A comparative study of plasmid DNA delivery in a newly established rat renal
      solid tumour model was undertaken. Free plasmid, plasmids bound to microspheres,
      and plasmids complexed with liposomes were selectively delivered to tumours via
      arterial catheterisation. Forty-eight hours post delivery, tumour to normal
      kidney tissue chloramphenicol acetyltransferase expression ratios were as
      follows: free (1.8:1), microspherical (3.9:1), and liposomal (1.2:1).
      Microspheres were able to selectively deliver the plasmids to tumours, whereas
      cationic liposomes distributed the plasmids to both kidney parenchymal and tumour
      cells. This tumour model has the potential of screening delivery vehicles as well
      as therapeutic agents for the capacity of selective delivery to tumours via the
      vasculature.

PMID- 12470420
TI  - Death from differentiated thyroid carcinoma: retrospective study of a 40-year
      investigation.
AB  - Differentiated thyroid carcinoma (DTC) usually has a good prognosis, but
      sometimes the course of the disease results in death. The aim of the present
      study was to assess the effect of some variables in time to death on fatal cases
      in our series. A total of 83 patients with DTC who died between 1958 and 1998
      from differentiated thyroid cancer were retrospectively analyzed with respect to
      gender, age at diagnosis, histology, percentage of (131)I uptake by postoperative
      thyroid remnant, site of tumor growth, and its (131)I uptake, metastases and time
      to death. Univariate analysis revealed a significantly shorter time to death in
      local recurrence when comparing local lymph node metastases and distant
      metastases even if neither show (131)I uptake. Multivariate analysis revealed
      that age at diagnosis was the most important factor in conditioning the time to
      death. In conclusion, in those patients who died from DTC an older age at
      diagnosis and presence of local recurrence influenced the time to death
      independently of (131)I uptake.

PMID- 12470421
TI  - Flux through multicellular layers of a technetium-99m-nitroimidazole for imaging
      hypoxia.
AB  - BRU59-21 is a technetium-99m-nitroimidazole being investigated as a noninvasive
      marker of tumor hypoxia. Metabolic depletion of BRU59-21, which is used at
      picomolar concentrations, could limit its ability to reach all hypoxic tumor
      cells. The multicellular layer (MCL) system, an in vitro model of the
      extravascular space, was used to assess the ability of BRU59-21 to diffuse to,
      and beyond, the target population of hypoxic cells. The flux of radioactivity
      through the MCL system was dependent on the oxygen concentration in the gas
      phase. Decreased flux and increased metabolism of BRU59-21 were observed under
      hypoxic compared with aerobic conditions. Analysis of the radioactivity, which
      passes through the hypoxic MCL, revealed that a proportion of the radioactivity
      was unmetabolized BRU59-21, but a significant fraction was free pertechnetate.
      The oxygen dependency of the flux of BRU59-21 required the presence of the
      nitroimidazole group and was not observed at 4 degrees C, indicating an enzymatic
      process is required to observe this effect. These findings suggest that metabolic
      depletion of BRU59-21 is not a major limit to its ability to reach hypoxic cells,
      but drug metabolism resulting in release of the radioactive label may reduce the
      ability of BRU59-21 to selectively label hypoxic cells in solid tumors.

PMID- 12470422
TI  - Octreotide and octreotate derivatives radiolabeled with yttrium: pharmacokinetics
      in rats.
AB  - Distribution profiles and elimination pathways in rats of two new octreotate
      derivatives radiolabeled with yttrium, namely Y-DOTAGA-tate and Y-DOTA-t-GA-tate,
      were compared with those of Y-DOTA-octreotide and Y-DOTA-Tyr(3)-octreotide. All
      synthetic somatostatin analogues under study were rapidly cleared from the blood
      and most organs of rats. The main elimination pathway for all peptides under
      study was urine excretion. High and long-term uptakes of radioactivity in the
      kidneys and also in organs with high density of somatostatin receptors (the
      adrenals and pancreas) were found. Radioactivity concentrations in these
      somatostatin receptor-rich organs were substantially higher for octreotate
      derivatives in comparison with octreotide analogues; the highest values for Y
      DOTAGA-tate were determined. The octreotate derivatives under study appear to be
      specific ligands for treatment of somatostatin receptor-positive tumors if some
      mechanism to decrease their kidney retention is provided.

PMID- 12470423
TI  - Sensitivity of model-based calculations of red marrow dosimetry to changes in
      patient-specific parameters.
AB  - We have investigated several of the key model parameters and assumptions involved
      in the calculation of red marrow absorbed dose in order to better understand the
      sensitivity of the predicted results to changes in these model features and the
      subsequent effect on correlations of the red marrow absorbed dose values with
      observed hematologic toxicity. Red marrow dose calculations based on measured
      blood activity concentrations (to determine red marrow cumulated activity) and
      measured total body cumulated activity have a mass-independent and mass-dependent
      term. Adjustments for patient mass should be made in these calculations when
      patients' lean body masses are more than 10% different from that in the assumed
      standard models. The blood-based red marrow dose methodology has the potential to
      provide a reasonable estimate of red marrow dose as long as there is no specific
      uptake in red marrow or bone due to the presence of free radionuclide, disease,
      or retention of activity due to metabolism by the reticuloendothelial system. If
      these additional sources of red marrow dose are present, the blood-based
      methodology will significantly underestimate red marrow dose. For radiometals,
      such as in (90)Y-labeled antibodies, bone or red marrow uptake of free yttrium or
      catabolized (90)Y products may have a significant impact on the calculated dose,
      assuming fairly low amounts of free (90)Y or marrow activity uptake (5-10%), even
      in the absence of disease in red marrow and/or bone. This is also true for (131)I
      labeled antibodies, although to a lesser extent due to typically reduced activity
      retention in the bone marrow in the absence of disease and lack of bone uptake of
      free radionuclide. Radiation dose calculations for the red marrow must be made as
      carefully as possible, taking into account all possible sources of radiation
      dose, and considering all sources of uncertainties, in order to give the best
      possible correlations of radiation dose with observed toxicity.

PMID- 12470424
TI  - Hepatic arterial administration of activated leukocytes in patients with liver
      metastases.
AB  - BACKGROUND: Liver is the most common site of metastatic disease. Hepatic arterial
      infusion (HAI) of cytotoxic drugs may achieve high objective response rate.
      METHODS: Peripheral blood mononuclear cells were obtained by leukapheresis after
      stimulation with subcutaneous GM-CSF in six patients and with subcutaneous
      interleukin-2 (IL-2) in four patients, all with nonresectable hepatic metastases
      not responsive to conventional regimens. After the cytokine stimulation, the
      cells were administered by HAI either alone, or after HAI of melphalan (50 mg).
      RESULTS: Mean number of 23.1 +/- 4.6 x 10(9) and 19.0 +/- 9.7 x 10(9) mononuclear
      cells were obtained through leukapheresis after GM-CSF and IL-2 priming,
      respectively. Significant cytotoxic activity was observed only after short IL-2
      stimulation. A marked decrease in tumor markers was observed in two patients
      treated by combination of melphalan and activated leukocytes. CONCLUSIONS: HAI is
      a technically feasible way of regional delivery of a high number of activated
      leukocytes obtained after short ex vivo activation.

PMID- 12470425
TI  - Antitumor and anticytopenic effects of aqueous extracts of propolis in
      combination with chemotherapeutic agents.
AB  - Using an ICR mouse model bearing a syngeneic Ehrlich ascitis carcinoma, the
      present study was undertaken to examine the effects of crude, water-soluble
      propolis (CWSP) on tumor progression, chemotherapeutic efficacy, and
      hematopoiesis in the peripheral blood. It was demonstrated that CWSP,
      administered subcutaneously, resulted in marked regression of tumor growth in
      mice, at the early phase after tumor inoculation (CWSP, p < 0.05 vs. saline
      control). Molecular analysis indicated that the CWSP is composed of 8.4% protein,
      4.2% quercetin plus a variety of saccharides with a molecular weight of 29 kDa.
      Orally administered CWSP did not produce any regression for the observation
      period (oral CWSP, p > 0.05 vs. saline control). Peritoneal injection of CWSP
      into neonatal mice resulted in an increased lymphocyte/polymorphonuclear
      leukocyte ratio activity, indicating the potential activation of lymphoid cell
      lineages. These observations suggest that subcutaneously injected CWSP could
      regulate the development of tumors by possibly stimulating multicellular
      immunity. In addition, oral administration of CWSP concurrently with 5
      fluorouracil (5-FU) or mitomycin C (MMC), significantly increased tumor
      regression as compared with the respective chemotherapy alone, illustrating the
      adjuvant effect of orally administered CWSP for tumor regression when combined
      with chemotherapeutic agents. To examine further the potential usefulness of CWSP
      for chemotherapeutic regimens, which induce profound multilineage hematopoietic
      suppression, mice that received CWSP orally in addition to a 5-FU or MMC were
      followed for absolute numbers of platelets and white and red blood cells. The
      oral administration of CWSP significantly ameliorated the cytopenia induced by 5
      FU, resulting in recovery of white as well as red blood cell counts (5-FU plus
      CWSP, p < 0.05 vs. 5-FU alone or water control; white blood cells on day 15, red
      blood cells on day 25), but no marked effects on platelet counts was observed (5
      FU plus CWSP, p > 0.05 vs. 5-FU alone or water control). On the other hand, CWSP
      significantly reduced all three MMC-induced cytopenias, especially at the later
      stage of the chemotherapeutic course (after day 30), suggesting repetitive
      requirements of oral administration of CWSP. In summary, subcutaneous
      administration of an aqueous CWSP resulted in marked regression of transplanted
      tumors. Orally administered CWSP combined with chemotherapeutic agents
      significantly increased tumor regression and ameliorated the cytopenia induced by
      the chemotherapeutic agents alone. These results suggest the benefits of
      potential clinical trials using CWSP combined with chemotherapeutic agents in
      order to maximize enhanced immunity while potentially minimizing
      postchemotherapeutic deteriorated reactions.

PMID- 12470426
TI  - Prognostic significance of a combination of soluble Fas and soluble Fas ligand in
      the serum of patients with Ta bladder cancer.
AB  - Recurrence after transurethral resection is one of the major problems in the
      treatment of superficial bladder cancer. However, there are no potent prognostic
      markers for recurrence in superficial bladder cancer at present. As circulating
      soluble Fas (sFas) and soluble Fas ligand (sFasL) have been implicated in
      protection from Fas-mediated apoptosis against cancers and may interfere with
      immune surveillance against autologous cancers, sFas and sFasL in the serum of
      patients with Ta bladder cancer were evaluated as prognostic tumor markers for
      recurrence. The serum levels of sFas and sFasL were measured by an enzyme-linked
      immunosorbent assay. Patients with Ta bladder cancer with low serum levels of
      both sFas and sFasL had a significantly longer postoperative tumor-free interval
      than those with high serum level of either sFas or sFasL in the 3-year follow-up.
      There was no correlation between the serum levels of sFas and sFasL. The present
      study has demonstrated that elevated serum sFas or sFasL predicts early
      recurrence in patients with Ta bladder cancer. These findings suggest that the
      serum levels of sFas and sFasL can be used as a prognostic indicator for
      recurrence in patients with Ta bladder cancer, and that sFas and sFasL may
      independently inhibit Fas-mediated apoptosis.

PMID- 12470427
TI  - Mitogen information summaries.

PMID- 12470428
TI  - Passionate curiosity: from thoughts to cures through energy's myriad forms.

PMID- 12470429
TI  - Complementary and alternative medicine: 24-hour technical support needed?

PMID- 12470430
TI  - Analyzing data to compare nutrients in conventional versus organic crops.

PMID- 12470431
TI  - External qigong therapy for chronic orofacial pain.

PMID- 12470432
TI  - An overview of acupuncture medicine.

PMID- 12470433
TI  - Asian therapies for cancer--coming of age.

PMID- 12470434
TI  - The National Cancer Institute's perspective and agenda for promoting awareness
      and research on alternative therapies for cancer.
AB  - The widespread use of a variety of nutritional, psychologic, and natural medical
      approaches, collectively termed complementary and alternative medicine (CAM), has
      been well documented. Recent surveys demonstrate that between 9% and 91% of U.S.
      patients with cancer use CAM therapies at some time after their diagnosis.
      However, there is a paucity of data available to indicate whether these CAM
      practices are efficacious and safe. Despite, or possibly because of, this
      controversy there has been considerable growth of interest in CAM by the American
      public. This interest has also resulted in a growth of research resources.
      Concurrently there has been an expansion of interest in the conventional medical
      establishment manifested by the creation of Departments of CAM or Integrative
      Medicine in respected conventional medical institutions, privately funded
      research centers and the National Institutes of Health (NIH) Office of
      Alternative Medicine (OAM)/National Center for Complementary and Alternative
      Medicine (NCCAM). Communication between conventional and unconventional
      practitioners is beginning. These changes are leading to a conversion of the
      dialogue about CAM from a focus on "quackery" to an exploration of the potential
      for novel therapeutics and the beginnings of focused, rigorous research. The
      National Cancer Institute is establishing programs to increase the amount and
      quality of CAM cancer research, support the production of high-quality CAM cancer
      information, and facilitate the dialogue between CAM practitioners and cancer
      researchers.

PMID- 12470435
TI  - Brain cancer: a case of glioblastoma multiforme.

PMID- 12470436
TI  - Bioactive polysaccharides from traditional Chinese medicine herbs as anticancer
      adjuvants.
AB  - PURPOSE OF STUDY: To review the nature, extent, bioactivities, and clinical
      application of polysaccharides in Traditional Chinese Medicine (TCM) especially
      as adjuvants in cancer treatment. METHODOLOGY: Literature review. FINDINGS: Many
      fungal- and plant-derived bioactive polysaccharides with a broad range of
      immunomodulatory activities are found in TCM. Some such polysaccharides have been
      developed into drugs and show clinical efficacy in controlled trials while the
      majority of such compounds remain as nutraceuticals with only preliminary
      research. Such polysaccharides are generally nontoxic and possess other
      bioactivities such as inducing differentiation, stimulating hematopoiesis,
      antimetastasis, and antiangiogenesis, which make them ideal adjuvants in modern
      cancer therapy. CONCLUSION: Bioactive polysaccharides occur extensively in TCM
      herbs and are the basis of potentially useful application of TCM as an adjuvant
      in cancer therapies.

PMID- 12470437
TI  - Anticancer activity of Scutellaria baicalensis and its potential mechanism.
AB  - OBJECTIVE: Scutellaria baicalensis is a widely used Chinese herbal medicine that
      historically is used in anti-inflammatory and anticancer therapy. The aim of the
      study is to determine its ability to inhibit human cancer cells in vitro and to
      determine whether its anticancer activity is because of the inhibition of
      prostaglandin E(2) (PGE(2)) production that is derived from arachidonic acid
      through cyclooxygenase-2 (COX-2) pathway. METHODS: Cell lines from the most
      common human cancers, including squamous cell carcinoma (SCC-25, KB), breast
      cancer (MCF-7), hepatocellular carcinoma (HepG2), prostate carcinoma (PC-3 and
      LNCaP), and colon cancer (KM-12 and HCT-15) were tested. The cells were treated
      with various concentrations of Scutellaria baicalensis (0.1-100 mg/mL) for 72
      hours. Percentage of viable cells after treatment was assessed using a trypan
      blue dye exclusion assay and the level of PGE(2) production was determined by
      enzyme immunoassay (EIA). RESULTS: Scutellaria baicalensis demonstrated a strong
      dose-dependent growth inhibition in all cell lines. Inhibition concentration at
      50% (IC(50)) for HepG2, MCF-7, PC-3, LNCaP, KM-12, HCT-15, KB and SCC-25 cells
      was 1.1, 0.9, 0.52, 0.82, 1.1, 1.5, 1.0, and 1.2 mg/mL, respectively. Three cell
      lines (KB, SCC-25, and HepG2) were assessed for the production of PGE(2) and a
      high level of extracellular (KB and SCC-25) and intracellular PGE(2) (HepG2) was
      noted. In the presence of Scutellaria baicalensis extract, there was a
      significant decrease of PGE(2) in a dose-dependent fashion. CONCLUSIONS:
      Scutellaria baicalensis strongly inhibits cell growth in all cancer cell lines
      tested. However, prostate and breast cancer cells (PC-3, LNCaP, and MCF-7) are
      slightly more sensitive than other type of cancer cells. It also inhibits PGE(2)
      production, indicating that suppression of tumor cell growth may be due to its
      ability to inhibit COX-2 activity. This study supports the notion of using
      Scutellaria baicalensis as a novel anticancer agent to treat various cancers.

PMID- 12470438
TI  - Chemosensitization of carmustine with maitake beta-glucan on androgen-independent
      prostatic cancer cells: involvement of glyoxalase I.
AB  - OBJECTIVE: To improve the poor efficacy (< 10%) of chemotherapy for patients with
      hormone-refractory prostate cancer, we investigated a possible cytotoxic effect
      of carmustine/beta-glucan combination on prostatic cancer PC-3 cells, focusing on
      a glutathione-dependent detoxifying enzyme, glyoxalase I (Gly-I). METHODS:
      Carmustine (BCNU) is an anticancer agent and a putative inhibitor of Gly-I, while
      beta-glucan is a unique, nontoxic polysaccharide extracted from maitake
      mushrooms. The cytotoxic effects of BCNU or other anticancer agents with beta
      glucan on PC-3 cells were assessed by cell-viability testing and Gly-I activity
      was measured using the spectrophotometric method. RESULTS: BCNU, 5-fluorouracil
      (5-FU), and methotrexate (MTX) were capable of inducing approximately a 50%
      reduction in cell viability at 72 hours, while etoposide, cisplatin, and
      mitomycin C were all ineffective. Only the combination of BCNU (50 micro ;mol)
      and beta-glucan (60 micro g/mL) exhibited an enhanced cytotoxicity with an
      approximate 90% cell viability reduction, but little improvement was seen with
      any combinations of 5-FU, MTX, or beta-glucon. Gly-I assays revealed that such a
      profound (approximately 90%) cell death was accompanied by an approximate 80%
      reduction in Gly-I activity by 6 hours. CONCLUSION: This study demonstrates a
      sensitized cytotoxic effect of BCNU with beta-glucan in PC-3 cells, which was
      associated with a drastic (approximately 80%) inactivation of Gly-I. Therefore,
      the BCNU/beta-glucan combination may help to improve current treatment efficacy
      by targeting Gly-I, which appears to be critically involved in prostate cancer
      viability.

PMID- 12470439
TI  - Inhibition of human colon carcinoma development by lentinan from shiitake
      mushrooms (Lentinus edodes).
AB  - OBJECTIVES: Lentinan was extracted from shiitake mushrooms (Lentinus edodes) via
      a new cost-effective procedure that resulted in high purity (88%) and yield.
      Unlike previous reports whereby the lentinan was given parenterally, in this
      study the emphasis was on the oral administration of lentinan. The goal is to
      document whether the efficacy of the antitumor property is still expressed
      through this route of administration. DESIGN: Initial study on the action of
      lentinan was conducted using murine lymphoma (K36) cells in a AKR mouse model.
      Further investigation on the effectiveness of the extracted lentinan was then
      performed using human colon-carcinoma cell lines in mice. Six established human
      colon-carcinoma cell lines segregated into three groups of different degrees of
      differentiation were used in this study. One group was not fed (control) and the
      second group was prefed with lentinan for 7 days prior to inoculations with the
      cancer cells. The size of the tumors that developed was rated after 1 month.
      RESULTS: Significant regression in tumor formation was observed in prefed mice
      compared to control (unfed) mice when K36 or human colon-carcinoma cells were
      used. Significant reductions in the size of the tumors were observed in mice
      prefed with lentinan. Follow-up investigation proceeded with the use of nude mice
      (athymic). Lymphocytes extracted from AKR mice prefed with lentinan for 7 days
      were inoculated into the nude mice. This was then followed by inoculation of the
      human colon-carcinoma cell lines into these mice. Much smaller tumors were formed
      in nude mice inoculated with lymphocytes, in contrast to the larger tumor formed
      in nude mice without lymphocytes inoculation. CONCLUSION: This study showed that
      the antitumor property of lentinan was maintained with oral administration. In
      addition, "primed" lymphocytes, when given passively to immunodeficient mice,
      were able to retard the development of tumors in these mice.

PMID- 12470440
TI  - Effects of extracts of Coriolus versicolor (I'm-Yunity) on cell-cycle progression
      and expression of interleukins-1 beta,-6, and -8 in promyelocytic HL-60 leukemic
      cells and mitogenically stimulated and nonstimulated human lymphocytes.
AB  - OBJECTIVE: The goal of this in vitro study was to test the cytostatic and
      cytotoxic activities of extracts derived from the polysaccharopeptide (PSP), I'm
      Yunity (Integrated Chinese Medicine Holdings Ltd., Kowloon, Hong Kong) prepared
      from strain Cov-1 of the mushroom Coriolus versicolor. DESIGN: Different volumes
      of 70% ethanol and water extracts of I'm-Yunity were incubated with cultures of
      human promyelocytic leukemic HL-60 cells, and compared to nontreated control
      cells. At various times after treatment, cells were harvested and analyzed with
      respect to: (1). proliferation and cell cycle phase distribution, (2). induction
      of apoptosis, and (3). changes in expression of the immunomodulating cytokines
      interleukin (IL)-1 beta, IL-6, and IL-8. To test whether extracts also affected
      normal cells, similar experiments were also performed using isolated peripheral
      blood lymphocytes from healthy volunteers, with and without stimulation by the
      mitogen phytohemagglutinin (PHA). The ability of extracts to affect the secretion
      of IL-1 beta, IL-6, and IL-8 were assessed by enzyme-linked immunosorbent assay.
      RESULTS: HL-60 cells incubated with various amounts (1, 3, 5, 7.5, and 10 micro
      l/mL) of the extracts for 1-3 days showed dose-dependent, time-dependent growth
      suppression and decrease in cell viability. Flow cytometric analysis revealed
      partial cell arrest in the G(1) phase at less than 5 micro L/mL and induction of
      apoptosis at 10 micro L/mL or more of ethanol and water extracts, with the latter
      exhibiting more pronounced inhibition than the former. Experiments performed with
      lymphocytes demonstrated that extracts of I'm-Yunity alone were without effect;
      moreover, they also did not affect the lymphocyte response to PHA. Water extract
      of I'm-Yunity also significantly increased IL-1 beta and IL-6 while substantially
      lowering IL-8. CONCLUSIONS: I'm-Yunity acts selectively in HL-60 leukemic cells,
      resulting in cell cycle restriction through the G(1)/S checkpoint and the
      induction of apoptosis.

PMID- 12470441
TI  - Asian spiritual traditions and their usefulness to practitioners and patients
      facing life and death.

PMID- 12470442
TI  - An assessment of the ayurvedic concept of cancer and a new paradigm of anticancer
      treatment in Ayurveda.
AB  - This paper critically examines the Ayurvedic concept of cancer diathesis and its
      pathogenesis in terms of the theory of Tridosa, Sapta Dhatus (body tissues), the
      Agni or body's biologic fire, Srotamsi (i.e., channels of the body), and the
      generic sequence of events in the genesis of a disease (e.g., Satkriyakala). All
      this depicts a new paradigm of the disease state. This paper also examines the
      scope of plant drugs used in the treatment of cancer. A retrospective meta
      analysis of observations on 85 plant drugs reported to have an anticancer effect
      indicates that herbs with Katu, Tikta, Kasaya Rasa (bitter, pungent, and
      astringent taste), Usna Virya (e.g., hot biopotency), and Katu Vipaka (catabolic
      active metabolites), and herbs with dry, coarse, light, and sharp biophysical
      properties have significantly greater possibilities of producing anticancer
      effects.

PMID- 12470443
TI  - A preliminary study of the effect of external qigong on lymphoma growth in mice.
AB  - OBJECTIVE: To examine the effectiveness of external qigong on the in vivo growth
      of transplantable murine lymphoma cells in mice. BACKGROUND: Qigong is a
      traditional Chinese health practice that is believed by many to have special
      preventive and healing power. Underlying the system is the belief in the
      existence of a subtle energy (qi), which circulates throughout the body, and when
      strengthened or balanced, can improve health and ward off or slow the progress of
      disease. To date, much of the literature showing the effects of qi are presented
      in the non-Western literature, and as such are viewed with considerable
      skepticism. In an attempt to demonstrate qi in a controlled setting, the effect
      of external qigong emission from a qigong healer on the in vivo growth of
      transplantable murine lymphoma cells in mice was explored in two pilot studies.
      METHODS: In study 1, 30 SJL/J mice were injected intravenously with lymphoma
      cells that localize and exhibit aggressive growth in the lymphoid tissues of
      untreated syngeneic recipients. These tumor-injected mice were divided into 3
      groups: (1). qigong treatment (administered by a qigong healer); (2). sham
      treatment; and (3). no-treatment control. The sham group received the same number
      of treatments from a person without training in qigong, who imitated the motions
      of the qigong healer. The control group received no treatment at all. In study 1,
      the mice were sacrificed on the 9th or 11th days after tumor-cell injection, and
      in study 2, the mice were sacrificed on the 10th and 13th days. Tumor growth in
      lymph nodes (LN) was estimated by LN weight expressed as a percentage of total
      body weight. RESULTS: In study 1, LNs from mice in the qigong-treated group were
      significantly smaller than LN from mice in either the control group or in the
      sham treatment group (p < 0.05), suggesting that there was less tumor growth in
      the qigong-treated mice. In study 2, using the same design as study 1, the same
      pattern of difference found in study 1 emerged: LN ratio from mice in the qigong
      treated group was smaller than that in either the control group or in the sham
      group. However, these results did not reach statistical significance, partially
      as a result of larger variances in all groups in this study. CONCLUSIONS: These
      preliminary results, while still inconclusive, suggest that qigong treatment from
      one particular qigong practitioner might influence the growth of lymphoma cells
      negatively. Further studies with different practitioners, more repeated trials,
      and/or different tumor models are needed to further investigate the effects of
      external qigong on tumor growth in mice.

PMID- 12470444
TI  - Bridging the gap in complementary and alternative medicine research:
      manualization as a means of promoting standardization and flexibility of
      treatment in clinical trials of acupuncture.
AB  - INTRODUCTION: An important methodological challenge encountered in acupuncture
      clinical research involves the design of treatment protocols that help ensure
      standardization and replicability while allowing for the necessary flexibility to
      tailor treatments to each individual. Manualization of protocols used in clinical
      trials of acupuncture and other traditionally-based complementary and alternative
      medicine (CAM) systems facilitates the systematic delivery of replicable and
      standardized, yet individually-tailored treatments. OBJECTIVES: To facilitate
      high-quality CAM acupuncture research by outlining a method for the systematic
      design and implementation of protocols used in CAM clinical trials based on the
      concept of treatment manualization. METHODS: A series of treatment manuals was
      developed to systematically articulate the Chinese medical theoretical and
      clinical framework for a given Western-defined illness, to increase the quality
      and consistency of treatment, and to standardize the technical aspects of the
      protocol. In all, three manuals were developed for National Institutes of Health
      (NIH)-funded clinical trials of acupuncture for depression, spasticity in
      cerebral palsy, and repetitive stress injury. In Part I, the rationale underlying
      these manuals and the challenges encountered in creating them are discussed, and
      qualitative assessments of their utility are provided. In Part II, a methodology
      to develop treatment manuals for use in clinical trials is detailed, and examples
      are given. CONCLUSIONS: A treatment manual provides a precise way to train and
      supervise practitioners, enable evaluation of conformity and competence,
      facilitate the training process, and increase the ability to identify the active
      therapeutic ingredients in clinical trials of acupuncture.

PMID- 12470445
TI  - A study of the relative precision of acupoint location methods.
AB  - OBJECTIVE: This study examined the relative precision of four methods of acupoint
      location: two traditional methods (directional and proportional) and two
      contemporary methods (elastic and ruler). DESIGN: Seventy-two (72) subjects
      attempted to locate a fictitious acupoint (FP) with repeated attempts and the
      resulting coordinates were recorded. LOCATION: The research was carried out at
      the Acupuncture Clinic of the University of Technology, Sydney (UTS). SUBJECTS:
      The 72 subjects were selected from undergraduates of the Bachelor of Health
      Science in Acupuncture course. RESULTS: Analysis of the results found no
      significant difference in precision between the two traditional methods, nor
      between the two contemporary methods. However, the contemporary methods were both
      shown to be significantly more precise than the traditional methods (F(3,120) =
      11.74, p < 0.0001). CONCLUSIONS: Based on the scatter size resulting from the use
      of each method, the surface area of the acupoint would need to range from almost
      13 cm(2) for the directional method to less than 3 cm(2) for the ruler method if
      95% of the subjects were to locate the acupoint successfully. Implications and
      recommendations for research and education are discussed.

PMID- 12470446
TI  - Medically supervised water-only fasting in the treatment of borderline
      hypertension.
AB  - BACKGROUND: Hypertension-related diseases are the leading causes of morbidity and
      mortality in industrially developed societies. Surprisingly, 68% of all mortality
      attributed to high blood pressure (BP) occurs with systolic BP between 120 and
      140 mm Hg and diastolic BP below 90 mm Hg. Dietary and lifestyle modifications
      are effective in the treatment of borderline hypertension. One such lifestyle
      intervention is the use of medically supervised water-only fasting as a safe and
      effective means of normalizing BP and initiating health-promoting behavioral
      changes. METHODS: Sixty-eight (68) consecutive patients with borderline
      hypertension with systolic BP in excess of 119 mm Hg and diastolic BP less than
      91 mm Hg were treated in an inpatient setting under medical supervision. The
      treatment program consisted of a short prefasting period (approximately 1-2 days
      on average) during which food consumption was limited to fruits and vegetables
      followed by medically supervised water-only fasting (approximately 13.6 days on
      average). Fasting was followed by a refeeding period (approximately 6.0 days on
      average). The refeeding program consisted of a low-fat, low-sodium, plant-based,
      vegan diet. RESULTS: Approximately 82% of the subjects achieved BP at or below
      120/80 mm Hg by the end of the treatment program. The mean BP reduction was 20/7
      mm Hg, with the greatest decrease being observed for subjects with the highest
      baseline BP. A linear regression of BP decrease against baseline BP showed that
      the estimated BP below which no further decrease would be expected was 96.0/67.0
      mm Hg at the end of the fast and 99.2/67.3 mm Hg at the end of refeeding. These
      levels are in agreement with other estimates of the BP below which stroke events
      are eliminated, thus suggesting that these levels could be regarded as the
      "ideal" BP values. CONCLUSION: Medically supervised water-only fasting appears to
      be a safe and effective means of normalizing BP and may assist in motivating
      health-promoting diet and lifestyle changes.

PMID- 12470447
TI  - A third study on the use of orally administered anhydrous crystalline maltose for
      relief of dry mouth in primary Sjogren's syndrome.
AB  - OBJECTIVES: To examine the safety and efficacy of anhydrous crystalline maltose
      for treatment of dry mouth and other symptoms of dryness in patients with primary
      Sjogren's syndrome. DESIGN: Anhydrous crystalline maltose was delivered orally as
      a 200-mg lozenge given three times daily over a 24-week period to a total of 100
      subjects. All participants had prominent complaints of persistent dry mouth
      associated with primary Sjogren's syndrome. Patients were examined at baseline
      and every 6 weeks of treatment. SETTINGS: Patients were seen in outpatient
      clinics at a total of 27 sites within the United States. OUTCOME MEASURES:
      Unstimulated whole saliva output, a measure of basal salivary gland function, was
      determined at each visit. Symptoms associated with oral and ocular dryness were
      assessed at the same time with the use of 100-mm visual analogue scales. Safety
      was assessed by physical examination and laboratory studies. RESULTS: During this
      clinical trial, a majority of evaluable subjects (39/76) demonstrated an increase
      in unstimulated whole saliva output, and the treatment exhibited an excellent
      safety profile. The anhydrous crystalline maltose treatment led to significant
      improvement in several subjective measures of oral and ocular comfort.
      CONCLUSIONS: In this study, anhydrous crystalline maltose lozenges administered
      three times daily for 24 weeks improved salivary output and decreased complaints
      of dry mouth and eyes in patients with primary Sjogren's syndrome. Side-effects
      were minimal, and treatment was without significant adverse events. These results
      are similar to the benefits observed in two prior studies reported by the
      authors. This safe and simple intervention appears to provide clinical benefit to
      primary Sjogren's syndrome patients with distressing dry mouth symptoms.

PMID- 12470448
TI  - Determinants of the degree of complementary and alternative medicine use among
      patients with cancer.
AB  - OBJECTIVES: This study explored the use of complementary and alternative medicine
      (CAM) by degree of use (nonuse, light, moderate, and heavy) by patients with
      cancer as it relates to sociodemographic and disease characteristics, subjective
      well-being, and dissatisfaction with the health care system. DESIGN AND
      PARTICIPANTS: One hundred and forty-three (143) patients with cancer of Asian,
      Caucasian, and Pacific Islander ethnicities originally recruited through the
      state-wide population-based Hawaii Tumor Registry and interviewed approximately 3
      years postdiagnosis. OUTCOME MEASURES: This study introduced a multidimensional
      measure, degree of CAM use, to rank participants by quantity of CAMs used as well
      as frequency, intensity, and breadth of use. Predictor variables explored were
      sociodemographic variables, disease site, quality-of-life measures, satisfaction
      with conventional treatment and physicians, satisfaction with medical
      information, and perceived severity of illness. RESULTS: Heavier CAM use was
      related to being female, Caucasian, having more education, having breast cancer,
      and having greater symptoms of nausea and vomiting. Heavier use was also
      associated with lower doctor satisfaction and a greater perception of disease
      severity. Sociodemographic and clinical variables accounted for the largest
      proportion of the variance in degree of use, but subjective well-being and health
      care satisfaction provided incremental increases in the variance explained.
      CONCLUSIONS: This study is one of few studies exploring predictors for the
      quantity or degree of use of CAM by patients with cancer. Understanding factors
      related to these patients' heavier or lighter CAM use has implications for health
      care offerings and cancer treatment decision-making.

PMID- 12470449
TI  - Teaching evidence-based complementary and alternative medicine: 4. Appraising the
      evidence for papers on therapy.
AB  - Practicing evidence-based complementary and alternative medicine (CAM) requires
      practitioners to develop an ability to appraise the quality of published studies
      addressing questions related to their clinical practice. This paper describes a
      process by which CAM practitioners can determine the validity of studies
      evaluating therapeutic interventions. The process requires asking two broad
      questions: (1). Do the treatment and control group begin with the same prognosis?
      and (2). Do the treatment and control group remain the same with respect to
      important prognostic factors? Answering these questions requires determining
      whether studies used effective randomization, preserved randomization through
      intention-to-treat analyses, used blinding, and had adequate follow-up of trial
      participants.

PMID- 12470451
TI  - Scientific literature under the microscope.

PMID- 12470450
TI  - Use of the Cochrane electronic library in complementary and alternative medicine
      courses in medical schools: is the giant lost in cyberspace?
AB  - Courses in complementary and alternative medicine (CAM) are increasing in medical
      schools in the United States and, currently, approximately two thirds of U.S.
      medical schools offer at least one such course. As these courses grow in
      popularity, however, concerns are also growing that these courses lack an
      evidence-based perspective. We propose that one interesting and easy way to bring
      an evidence-based perspective to the CAM classroom is to utilize the Cochrane
      Electronic Library (CLIB), which is available in many medical libraries, as a
      teaching tool. The CLIB currently houses more than 80 CAM-related, full-text
      systematic reviews and approximately 5000 CAM-related clinical trials, making it
      a valued resource for people who seek CAM evidence. Moreover, the CLIB commitment
      to publishing reviews regardless of the results make it a resource where one can
      find reviews concluding there is strong evidence of benefit or no evidence of
      benefit. In addition to the access to CAM evidence which the CLIB provides,
      students can learn basic critical appraisal skills by learning the rationale
      behind Cochrane systematic reviews. A survey of CAM course directors, however,
      shows that almost one half of these directors have never used the CLIB. For those
      who have never used the CLIB, this editorial explains the four main databases
      within the CLIB and presents ideas for using them in CAM school courses.

PMID- 12470452
TI  - Light-induced replication of nanobacteria: a preliminary report.
AB  - OBJECTIVE: The purpose of the present study was to investigate the effect of
      light on nanobacteria. BACKGROUND DATA: Since their first description in
      literature, it is not clear whether the nanoparticles called "nanobacteria" are
      alive or not. The 80-1,000-nm-sized spherical particles are protected by a
      crystalline carbonate apatite shell and are culturable in cell culture media.
      Present in mammalians, including humans, nanobacteria seem to cause diseases
      related to biomineralization processes. Mesoscopic structures found on Martian
      meteorites and terrestrial rocks indicated that nanobacteria-like biological
      objects forming apatite, a material fairly transparent to visible light, could
      have been present on the primitive Earth during an era with the sun as the
      principal terrestrial energy source. MATERIALS AND METHODS: To evaluate possible
      biomedical effects of therapeutically relevant irradiation sources on
      nanobacteria, we irradiated nanobacteria cultures with polarized light and laser
      light at low, nonthermal energy density levels. RESULTS: Our observations
      indicated that nanobacteria are alive. Polarized white light was found to clearly
      accelerate their replication in vitro, resulting in significant dose-dependent
      increases in the turbidity of the cultures, compared to nonirradiated controls.
      Laser irradiation did not affect their replication. CONCLUSION: The possibility
      that primordial and present nanobacteria could have been not only exposed to, but
      actively harvested, solar irradiation for their own development suggests itself.
      Considering that there exists no published material on the action of light on
      nanobacteria, the reported effects are expected to have an impact on modeling
      biomineralization processes, associated photoreceptor mechanisms, and
      astrobiological and evolutionary theories-on Earth and in space.

PMID- 12470453
TI  - Morphological changes of bovine mandibular bone irradiated by Er,Cr:YSGG laser:
      an in vitro study.
AB  - OBJECTIVE: The purpose of this study was to investigate the morphological changes
      of bovine mandibular bone following Er,Cr:YSGG laser irradiation in different
      methods in vitro. BACKGROUND DATA: Recently, an erbium, chromium/yttrium,
      scandium, garmet (Er,Cr:YSGG) laser device that emits a laser beam at the
      wavelength of 2.78 micro m was introduced. This type of infrared laser proved to
      ablate dental hard tissues effectively. However, the different effects of bone
      ablation by this laser in different irradiation methods were still unknown.
      MATERIALS AND METHODS: Adult bovine mandibular bones were cut into 24 small
      pieces, 3-4 cm in length. The parameters of Er,Cr:YSGG laser irradiation were as
      follows: wavelength was 2.78 micro m, pulse duration was 140-200 micro sec,
      repetition rate was 20 pulse/sec, power was 4 W, spot size was 1.26 x 10(-3)
      mm(2), and energy density was 160 J/cm(2). Irradiation methods were different in
      four groups (six specimens in each group): group A, fixed position and contact
      mode; group B, fixed position and noncontact mode; group C, nonfixed position and
      contact mode; and group D, nonfixed position and noncontact mode. RESULTS:
      Ablation depth in group A was significantly greater than in group B (p < 0.01).
      In group A, thermal damage was apparent. In group B, C, and D, thermal damage was
      minimal. CONCLUSION: Er,Cr:YSGG laser allows for precise surgical bone cutting
      and ablation with minimal thermal damage to adjacent tissue. Irradiation in
      different methods may achieve different ablation rates and thermal damage.

PMID- 12470454
TI  - Ablation of bone, cartilage, and facet joint capsule using Ho:YAG laser.
AB  - OBJECTIVE: The objective of this study was to determine of the efficiency of
      holmium:YAG laser for bone ablation, compared to cartilage and soft tissue of the
      intervertebral foramen of the lumbosacral spine. BACKGROUND DATA: The holmium:YAG
      (Ho:YAG) laser has been used for ablation of bulging or prolapsed discs and also
      has the potential for decompression of the nerve root when there is narrowing of
      the foraminae (foraminoplasty). It is proposed that laser ablation of bone and
      ligament of the intervertebral foramen for nerve root decompression using the
      Ho:YAG laser is able to produce sufficient bone ablation without inducing
      significant thermal necrosis in surrounding tissues due to its short absorption
      length, which could result in significant clinical advantages. MATERIALS AND
      METHODS: Experiments were performed on samples of laminar bone, facet joint
      capsule, and cartilage for quantitative and qualitative determination of the
      effect of Ho:YAG ablation on tissue mass loss using a range of pulse energies
      from 0.5 to 1.5 J/P at 15 pulses/sec. RESULTS: The results showed a significant
      linear correlation between the mass loss and pulse energy, and between the mass
      loss and radiant exposure. Electron microscopy and histology showed that the
      Ho:YAG ablation resulted in a very sharp and clear border with little charring.
      Applying 0.01 k.J of total energy at two different settings (1.5 J/p, high power,
      and 0.5 J/p, low power) at 15 pulses/sec, the cross-sectional area/mm(2) of the
      ablated bone was measured, using light microscopy and the Scion Image analysis
      program. The ablated areas were 2.28 +/- 0.87 and 1.16 +/- 0.43 mm(2) at high and
      low power, respectively (p = 0.008).

PMID- 12470455
TI  - Enamel caries initiation and progression after argon laser irradiation: in vitro
      argon laser systems comparison.
AB  - OBJECTIVE: The purpose of this in vitro laboratory study was to determine the
      effect of low-fluence argon laser (AL) irradiation delivered from two different
      argon laser systems on enamel caries-like lesion initiation and progression.
      BACKGROUND DATA: Previous in vitro investigations and a recent in vivo pilot
      study have shown that AL irradiation of enamel provided a protective effect
      against in vitro and in vivo cariogenic challenges. MATERIALS AND METHODS: Twenty
      extracted human molars were selected, and 10 teeth were assigned to the HGM argon
      laser group and 10 were assigned to the LaserMed argon laser group. The exposed
      buccal windows of sound enamel were exposed to low-fluence irradiation, while the
      lingual windows of enamel were not exposed to laser irradiation and served as the
      no-treatment (control) group. Enamel caries-like lesions were created using an
      acidified gel. Two longitudinal sections were taken per sample (n = 20 lesions
      per group) and evaluated by polarized light microscopy for body of the lesion
      depths after lesion initiation (8 weeks) and progression (12 weeks) periods.
      RESULTS: After lesion initiation and progression, the body of lesion depths were
      similar for both argon-irradiated groups (p > 0.05). With the no-treatment
      (control) group, there were significant increases in lesion depth with a 61-78%
      increase for the lesion initiation period and a 50-69% increase for the lesion
      progression period when compared with the argon laser-treated groups. CONCLUSION:
      Argon laser irradiation provides a certain degree of protection against in vitro
      enamel caries initiation and progression. Resistance to a continuous caries
      challenge was similar with either argon laser delivery systems (HGM and
      LaserMed). Argon laser irradiation may prove to be beneficial in reducing the
      caries susceptibility of sound enamel and white spot lesions in the clinical
      environment.

PMID- 12470456
TI  - Morphological study of dentin irradiated by solid-state ultraviolet lasers: a
      comparison of wavelength and repetition rate.
AB  - OBJECTIVE: In this study, we examined the surface morphology of dentin after
      being ablated by the third, fourth, and fifth harmonics of the Nd:YAG laser. The
      influences of the repetition rate with respect to the wavelength were also
      investigated. BACKGROUND DATA: Typically, excimer lasers have been used as the
      primary sources of ultraviolet (UV) laser wavelengths to investigate laser
      ablation of dentin. In the past decade, developments in nonlinear optical
      technology have given rise to higher conversion efficiencies of the fourth and
      fifth harmonics of the Nd:YAG laser. To this end, sufficient energy densities of
      the fourth and fifth harmonics of the Nd:YAG laser have been generated to ablate
      dentin. MATERIALS AND METHODS: Thin dentin samples (typically 1 mm) were
      irradiated by the third, fourth, and fifth harmonics of the Nd:YAG laser.
      Ablation occurred at repetition rates of 1, 5, 10, and 20 Hz, using similar
      energy densities for each laser wavelength. An environmental scanning electron
      microscope was used to assess the resultant surface morphology. RESULTS: Dentine
      surfaces after 355-nm ablation exhibited plugging at each repetition rate.
      Similar surfaces were exhibited after 266-nm ablation. "Plugging" over dentine
      tubules was less obvious after 213-nm laser ablation. The results may highlight
      the impact of different absorption characteristics of each wavelength.
      CONCLUSION: Solid-state UV laser ablation of dentin exhibits similar properties
      to excimer laser ablation. At similar energy densities, the deeper UV laser
      wavelengths exhibit less "plugging" of dentin tubules, suggesting a lower thermal
      impact.

PMID- 12470457
TI  - Histological and scanning electron microscope examination of root canal after
      preparation with Er:YAG laser microprobe: a preliminary in vitro study.
AB  - OBJECTIVE: Until now, there has been no study that demonstrates the effectiveness
      of Er:YAG laser microprobes to clean and shape the root canal without using any
      mechanical instrumentation. MATERIALS AND METHODS: The study was conducted on 28
      single-rooted extracted central incisors teeth with straight roots. Fourteen were
      mechanically prepared and served as the control group, and 14 were treated by
      Er:YAG laser only. From every group, half of the teeth were examined
      histiolgically and half by SEM. The instrument tested was an Er:YAG laser with
      microprobes 200-400 micro in diameter and 20 mm in length, coupled onto special
      handpieces, attached to the delivery fiber of an OPUS 20 Er:YAG laser. The Er:YAG
      laser was applied with the following parameters: wavelength 2.94 microm; pulse
      duration 400 msec; repetition rate 10 Hz; energy per pulse 140 mJ for the 400
      micro microprobe and 90 mJ for the 200-micro microprobe. RESULTS: For the control
      group, histologically, large amounts of residual pulp tissue were found in the
      root canal cavity, and open tubules were seen in all the specimens; SEM
      examination showed very uniform root canal, from apical to cervical portion, high
      number of open tubules, and different levels of canal debridment. For the study
      group, histologically, no residual pulp tissue was found in the root canal cavity
      and open tubules were seen in all the specimens; SEM examination showed the root
      canal free of debris, removed smear layer, open dentinal tubules, and different
      levels of enlargement. CONCLUSION: Our results show that the Er:YAG laser special
      microprobes are effective in shaping, cleaning, and enlarging straight root
      canals faster and more efficiently then traditional methods.

PMID- 12470458
TI  - Laser literature watch.

PMID- 12470460
TI  - Percutaneous stone implantation in the pig kidney: a new animal model for
      lithotripsy research.
AB  - PURPOSE: This report describes a new animal model for research on the parameters
      of shockwave delivery and the mechanisms of shockwave action in SWL. MATERIALS
      AND METHODS: Female pigs (approximately 45 kg) were anesthetized for creation of
      an upper pole peripheral caliceal access. The tract was dilated with a 30F
      Nephromax balloon and Amplatz sheath, and a 24F rigid nephroscope was used to
      guide a gypsum artificial stone into a lower pole calix. An internal ureteral
      stent was then placed. After a 2-hour recovery period, lithotripsy was performed
      using an unmodified Dornier HM3 lithotripter. Following SWL, en bloc excision of
      the urinary tract was performed, and the stone fragments were collected. RESULTS:
      As observed by nephroscopy, most stones were surrounded by urine that was free of
      clot or debris. Urine output was >1 mL/kg per minute by the time the animal was
      positioned for SWL after a 2-hour observation period. When the conditions of
      shockwave (SW) exposure were 400 SWs, 20 kV, and 120 SW/min, the efficiency of
      stone fragment recovery was 85% +/- 2% (N = 6 stones). CONCLUSIONS: This
      procedure provides a minimally invasive method for placement of model stones of
      clinically relevant size within the pig kidney. Stone implantation is efficient
      and permits experiments to be conducted in 1 day. Stone fragmentation can be
      quantitated, and the animal can serve as its own control. Long-term experiments
      are also feasible. Overall, this new animal model is appropriate for
      experimentation on the parameters of SW delivery in SWL.

PMID- 12470461
TI  - Role of acellular collagen matrix surgisis in the endoscopic management of
      ureteropelvic junction obstruction.
AB  - PURPOSE: To investigate the role of acellular collagen matrix (Surgisis during
      endopyelotomy. MATERIALS AND METHODS: Nine female pigs (25-35 kg) were enrolled
      in our protocol. The pigs were categorized as follows. Group I (N = 3) had
      endopyelotomy + insertion of SIS, Group II (N = 3) creation of UPJ stricture +
      endopyelotomy + insertion of SIS, and Group III (N = 3) Davis intubated
      ureterotomy using SIS. The contralateral side served as a control for each group
      (one pig in each group). In three pigs (two in Group III and one in Group II),
      Surgisis was treated with India ink prior to insertion at the endopyelotomy site.
      An endopyelotomy stent (14/8 F x 24 cm) was used to stent the ureteropelvic
      junction (UPJ) for 4 weeks. Four weeks after the stent was removed, laparoscopic
      nephroureterectomy was performed, and the animals were euthanized.
      Histopathologic analysis of the Surgisis-regenerated segment of the UPJ was
      performed using hematoxylin and eosin, reticular (collagen), smooth muscle actin,
      and S-100 (nerve) stains. RESULTS: All animals tolerated the procedure. The mean
      operative time was 162 minutes. One pig (Group II) developed pyonephrosis; one
      pig (Group III) developed significant ascites and was sacrificed 2 week before
      the end of the experiment. Histopathologic analysis showed complete
      epithelializaton at 8 weeks. Reticular stain demonstrated abundant collagen
      matrix in the submucosa. Smooth muscle staining revealed myofibroblastic
      proliferation within the SIS-regenerated tissue adjacent to disorganized smooth
      muscle cells. India ink-stained SIS-regenerated tissue did not show smooth muscle
      cells. The S-100 stain did not demonstrate neurons at 8 weeks; however, in three
      pigs, peristaltic activity was noted across the UPJ. CONCLUSION: The use of
      acellular collagen matrix in the endoscopic management of UPJ obstruction is a
      promising technique. The abundance of myofibroblasts and absence of abundant
      smooth muscle regeneration indicates a need to investigate the role of growth
      factors in SIS regeneration of host tissue.

PMID- 12470462
TI  - Endoscopic management of symptomatic caliceal diverticula: a retrospective
      comparison of percutaneous nephrolithotripsy and ureteroscopy.
AB  - BACKGROUND AND PURPOSE: A myriad of minimally invasive options exist for managing
      symptomatic caliceal diverticula, including shockwave lithotripsy, percutaneous
      surgery, retrograde ureteroscopy, and laparoscopy. Yet no direct comparisons have
      been made in the literature of the relative treatment efficacy of ureteroscopy
      (URS) and percutaneous nephrolithotripsy (PNL). A retrospective review of our
      patients was performed to determine the most appropriate endoscopic management
      option for patients with symptomatic caliceal diverticula. PATIENTS AND METHODS:
      Between November of 1994 and April 2001, 39 patients presented with symptomatic
      caliceal diverticula, 37 of which contained calculi. Twenty-two patients (56%)
      underwent PNL, and 17 patients (44%) were managed by URS. Of the PNL group, 82%
      required the creation of a neoinfundibulotomy. The stone burden in the PNL group
      averaged 11.4 x 12.0 mm and that in the URS group 12.7 x 13.0 mm (p > 0.05).
      Pain, recurrent urinary tract infections, and nausea and vomiting were the
      presenting complaints in both subgroups of patients, with pain being by far the
      most common symptom. The average hospital stay was 2.8 days for the PNL group.
      All the URS procedures were performed on a same-day-surgery basis. Results,
      including stone-free, symptom-free, and complication rates, were compared for the
      two groups. RESULTS: Thirty-five percent of the URS group were symptom free at 6
      weeks' follow-up, with an additional 29% reporting an improvement in pain,
      whereas 86% of the PNL group was completely symptom free at 6 weeks' follow-up.
      Only 19% of the URS group were stone free on follow-up intravenous urography v
      78% of those undergoing PNL (three patients failed to return for follow-up
      imaging). It was not possible to identify the ostium of the stenotic infundibulum
      in 4 patients (24%) undergoing URS, and 7 patients (41%) eventually went on to
      PNL with ultimate success. The PNL was statistically better than URS in producing
      stone-free results for diverticula located in the upper pole and for stones <11
      mm (p < 0.05). No complications occurred in the URS group; however, complications
      were identified in four patients after PNL. One patient developed clot urinary
      retention necessitating Foley catheterization and manual bladder irrigation; one
      patient experienced significant bleeding necessitating early cessation of the
      procedure. Two patients sustained intrathoracic complications, one a pneumothorax
      and the other a pneumohemothorax after supra-11(th) rib access. Both were managed
      successfully with tube thoracostomy. CONCLUSIONS: Our review clearly suggests an
      advantage of percutaneous management over ureteroscopy for complex posterior
      symptomatic caliceal diverticula, although with a slightly increased risk of
      complications. Therefore, PNL should be considered the primary modality for
      managing these difficult processes. In cases where the stenotic infundibulum
      cannot be traversed with a guidewire, creation of a neoinfundibulotomy permitted
      secure access to the collecting system while providing effective results.

PMID- 12470463
TI  - Laparoscopic interstitial laser coagulation of renal tissue with and without
      hilar occlusion in the porcine model.
AB  - PURPOSE: To evaluate the safety and efficacy of interstitial laser coagulation
      (ILC), applied via a laparoscopic approach, with and without hilar occlusion in
      the porcine model. MATERIALS AND METHODS: In nine female farm pigs, bilateral
      renal mobilization was performed via a transperitoneal laparoscopic approach.
      Using a 600- micro m bare-tip silicon diode laser fiber inserted 0.5 cm into the
      lower pole of each kidney, diode laser energy (wavelength 805 nm) was applied for
      15 minutes at 6 W. In each pig, the left renal hilum was clamped during ILC.
      Animals were sacrificed immediately (N = 3) or at 2 weeks (N = 3) or 4 weeks (N =
      3). The kidneys were inspected grossly, and the lesions were evaluated
      microscopically. Nicotinamide adenine dinucleotide (NADH) histochemical staining
      was performed to assess viability. RESULTS: Grossly, parenchymal lesions appeared
      firm and white with a central zone of carbonization, cavitation, or both.
      Histopathology examination revealed cellular inflammation in acute lesions;
      chronic lesions demonstrated coagulative necrosis with progressive fibrosis. The
      NADH staining showed residual viable cells within the treatment zone of survival
      animals but not in acute animals. The mean size of the treatment zone in kidneys
      with unoccluded blood flow was 2.4 x 2.1 x 2.0 cm, 4.0 x 3.3 x 2.8 cm, and 3.3 x
      3.5 x 2.0 cm in the acute, 2-week, and 4-week group, respectively. Hilar
      occlusion resulted in a slightly, but statistically insignificantly, larger
      lesion. In the 2-week survival group, one animal had a left subcapsular hematoma
      on the hilar-occluded side. In another 2-week animal, extension of the ILC zone
      was noted beyond the kidney into the psoas muscle. In the 4-week survival group,
      two animals developed gross hematuria; one had a left perinephric urinoma and
      urine leak noted at necropsy. CONCLUSIONS: Renal ILC may represent an alternative
      minimally invasive technique for ablation of renal tumors. However, histologic
      evidence of viable cells within the treatment zone mandates refinement of the
      technique in the animal model before further application in humans. Hilar
      occlusion does not appear to enhance tissue ablation.

PMID- 12470464
TI  - Laparoscopic treatment of retroperitoneal fibrosis.
AB  - BACKGROUND AND PURPOSE: Retroperitoneal fibrosis (RPF) is an uncommon cause of
      ureteral obstruction. Surgical treatment is required in most cases. Open
      ureterolysis, although effective, is associated with significant morbidity and
      mortality rates. We present data on a series of 13 patients undergoing
      laparoscopic ureterolysis for RPF. PATIENTS AND METHODS: Between December 1994
      and October 2000, 13 patients with RPF underwent laparoscopic ureterolysis at our
      institution. Operative time, complications, estimated intraoperative blood loss,
      time to oral intake, amount of parenteral analgesics used, and length of hospital
      stay were reviewed. Postoperative pyelography or diuretic urography was performed
      to assess ureteral patency. RESULTS: Laparoscopic ureterolysis was successful in
      11 patients (85%); two conversions to open surgery were needed (15%). One patient
      required a laparoscopic Boari flap on one side because of intense fibrosis. Four
      postoperative complications (30%) were managed with conservative measures. At a
      mean follow-up of 30 months, intravenous urography or renal scan showed relief of
      obstruction in 92% of the patients. CONCLUSIONS: Laparoscopic ureterolysis is an
      option to treat RPF. It is not free of complications and failures, and its
      precise role in the treatment of RPF still needs to be judged with longer follow
      up and larger number of patients.

PMID- 12470465
TI  - Continent jejunal reservoir dialysis for end-stage renal disease: is it possible?
AB  - With limited organs available for renal transplantation in comparison with the
      number of patients on the waiting list, and with the drawbacks of dialysis, other
      forms of treatment for end-stage renal disease (ESRD) need to be investigated. We
      propose that using a reconfigured segment of bowel as a reservoir in which
      dialysate of various compositions can be instilled to remove metabolic wastes
      usually handled by the kidney may augment or replace renal function in a uremic
      patient. We have chosen the jejunum and have documented our preliminary findings
      using hyperosmotic dialysate along with the unique characteristics of continent
      jejunal reservoir dialysis (CJRD). With further refinements, CJRD may eventually
      be offered as an alternative treatment for ESRD.

PMID- 12470466
TI  - Treatment of bilateral fibroepithelial polyps in a child.
AB  - Ureteral fibroepithelial polyps are extremely rare benign lesions composed of
      stroma with a surface of normal transitional epithelium. Traditionally,
      symptomatic polyps were treated with open exploration and segmental resection. We
      describe the first case of bilateral polyps in a child. One was removed by
      segmental resection and the other by ureteroscopic laser surgery.

PMID- 12470467
TI  - Laser Doppler flowmetric determination of ureteral blood flow after ureteral
      access sheath placement.
AB  - BACKGROUND AND PURPOSE: The ureteral access sheath has positively impacted
      ureteroscopy by decreasing operative times and increasing success rates. However,
      as previous studies have suggested that large-caliber endoscopes may cause
      ureteral ischemia, concern has been raised about the impact of access sheath
      insertion on ureteral blood flow. We sought to determine whether the access
      sheath compromises ureteral blood supply and, if so, causes ischemic damage to
      the ureter during ureteroscopic procedures. MATERIALS AND METHODS: Using a swine
      animal model, ureteral blood flow was measured with a laser Doppler flowmeter.
      Eleven ureteral units were randomized into four study groups: those dilated with
      10F-12F, 12F-14F, and 14F-16F access sheaths (N = 3 per group) and an undilated
      control group (N = 2). Blood flow measurements were obtained from the proximal
      ureter via laser Doppler flowmetry for 70 minutes at 5-minute intervals.
      Hemodynamic variability was controlled for through intraoperative heart rate and
      oxygen saturation monitoring, as well as a second Doppler probe that was placed
      on the animal's skin, from which readings were also taken every 5 minutes.
      Results were correlated with histopathologic findings. RESULTS: The control group
      demonstrated little ureteral blood flow variability over the course of 70
      minutes. The study groups that were dilated with sheaths, however, all showed a
      decrease in ureteral blood flow after access sheath insertion, with the flow in
      animals dilated with 12F-14F and 14F-16F sheaths dropping below 50% of baseline.
      This initial drop in blood flow was followed by a gradual increase from nadir
      toward baseline values over the course of the study. On average, the 14F-16F
      group reached nadir more quickly and took longer to restore its ureteral blood
      flow. All animals remained hemodynamically stable throughout the study, showing
      only minimal variability in heart rate, oxygen saturation, and skin blood flow
      over the 70-minute experiment. Histologically, there was no evidence of ischemic
      damage in any of the study groups at 72 hours. CONCLUSIONS: In this animal model,
      the access sheath does cause a transient decrease in ureteral blood flow.
      Nonetheless, compensatory mechanisms of the ureteral wall restore blood flow to
      near-baseline rates and preserve urothelial integrity, suggesting that use of the
      ureteral access sheath remains a safe adjunct to flexible ureteroscopy. Because
      the chronic effects of the access sheath have yet to be elucidated, care must be
      taken in selecting an appropriate-size sheath for each individual case.
      Preventive measures may be available to help avoid sheath-related ureteral injury
      in those patients identified as high risk.

PMID- 12470468
TI  - Laparoscopic adrenalectomy: the New York-Presbyterian Hospital experience.
AB  - BACKGROUND AND PURPOSE: Laparoscopic adrenalectomy has become the standard
      technique for the surgical removal of the adrenal gland. The advantages of the
      laparoscopic approach include shorter length of stay (LOS), a decrease in
      postoperative pain, faster return to preoperative activity level, improved
      cosmesis, and reduced complications. We report our experience with laparoscopic
      adrenalectomy via a lateral transperitoneal approach. PATIENTS AND METHODS:
      Between September 1993 and April 2001, we performed 100 lateral transperitoneal
      adrenalectomies in 91 patients. In 82 cases, the adrenalectomy was unilateral and
      in the other 9, it was bilateral. A total of 59 left-sided lesions and 41 right
      sided lesions were removed. The indications for surgery were Cushing's syndrome
      (24), aldosteronoma (34), pheochromocytoma (17), nonfunctioning adenoma (13),
      Carney's syndrome (1), and a metastasis from colon cancer (1) RESULTS: The
      overall success rate was 98%. Complications occurred in the two patients who
      required open conversion. In addition, three patients suffered pneumothoraces
      because of direct iatrogenic injury to the diaphragm during laparoscopic
      dissection. One additional patient suffered a splenic laceration. Operative time,
      blood loss, and intraoperative complications were similar in the laparoscopic and
      open surgery control group (N = 32). CONCLUSIONS: Laparoscopic adrenalectomy is
      technically feasible and reproducible. The lateral transperitoneal technique
      offers distinct advantages to the laparoscopist, including better visibility of
      familiar anatomic landmarks, easy access to other organ systems, the use of
      gravity to retract the spleen and liver, and a wide exposure, which allows
      removal of large adrenal lesions.

PMID- 12470469
TI  - Tubular cell-Escherichia coli interaction products modulate migration of
      monocytes through generation of transforming growth factor-beta and macrophage
      monocyte chemoattractant protein-1.
AB  - BACKGROUND: Urinary tract infection is a common occurrence often associated with
      renal interstitial inflammation in the form of accumulation of mononuclear cells.
      We hypothesized that bacteria activate tubular cells to secrete cytokines, which
      may promote migration of mononuclear cells at the site of interaction. MATERIALS
      AND METHODS: We evaluated the migration of monocytes in response to tubular cell
      products (TC-S) and interaction products of E. coli with proximal tubular cells
      (TC-EC-S; concentrations of 5%, 10%, and 25%) using a modified Boyden chamber. To
      determine the molecular mechanism, we evaluated the effect of antibodies against
      macrophage-monocyte chemoattractant protein-1 (MCP-1) and transforming growth
      factor-beta (TGF-beta) on E. coli-tubular cell interaction product-induced
      migration of monocytes. In addition, we studied the effect of free-radical
      scavengers on activation of tubular cells. RESULTS: The TC-EC-S enhanced (p <
      0.0001) migration of monocytes compared with TC-S. Both anti-TGF-beta and anti
      MCP-1 antibodies partly inhibited (p < 0.0001) TC-EC-S-induced monocyte
      migration. The modified TC-EC-S (produced in the presence of superoxide dismutase
      [SOD], dimethyl thiourea [DMTU], or catalase, all scavengers of free radicals)
      induced lesser monocyte migration than did TC-EC-S alone. CONCLUSIONS: These
      results suggest that E. coli activates tubular cells to generate cytokines such
      as MCP-1 and TGF-beta that promote migration of monocytes. Free radicals such as
      superoxide and hydrogen peroxide may be acting as second messengers in E. coli
      induced tubular cell activation.

PMID- 12470470
TI  - Morphine-induced macrophage apoptosis modulates migration of macrophages: use of
      in vitro model of urinary tract infection.
AB  - BACKGROUND: Morphine has been reported to alter immune function. Morphine-induced
      macrophage apoptosis has been shown to contribute to altered immune status in an
      opiate milieu. We studied the effect of morphine-induced macrophage apoptosis on
      the migration of macrophages. Because urinary tract infection (UTI) is one of the
      commonest infections to evoke an inflammatory response; i.e., migration of
      neutrophils and monocytes to the site of infection, we used an in vitro model of
      UTI to test our hypothesis. MATERIALS AND METHODS: We carried out both in vivo
      and in vitro studies. Mice of the FVB/N strain were treated with morphine for
      short (three doses, 24 hours) and long (11 doses, 96 hours) durations, and their
      bone marrow cells were isolated. In addition, apoptotic macrophages were prepared
      by heat treatment. To simulate the in vitro model of UTI, E. coli-activated
      tubular cell (TC)-conditioned medium containing transforming growth factor-beta
      (TGF-beta) and macrophage-monocyte chemoattractant protein-1 (MCP-1) was used to
      test migration of macrophages across a filter in a modified Boyden chamber. In
      addition, migration of macrophages into the peritoneal cavity was evaluated in
      both control and morphine-treated states. The effect of morphine on apoptosis as
      well as migration was studied in murine macrophages and bone marrow cells.
      RESULTS: Morphine not only promoted apoptosis of bone marrow cells (20% apoptotic
      cells) but also inhibited their migration across the filter. Control cells showed
      minimal apoptosis but displayed greater migration. Similarly, heat-treated
      (apoptotic) cells showed minimal migration. In peritoneal macrophage studies,
      morphine treatment retarded migration. CONCLUSION: Morphine inhibits macrophage
      migration both in vivo and in vitro. This attenuated transmigration of
      macrophages seems to be secondary to the apoptotic effect of morphine.

PMID- 12470471
TI  - Potential role for the nuclear transcription factor NF-kappa B in the
      pathogenesis of ureteropelvic junction obstruction.
AB  - BACKGROUND AND PURPOSE: In an effort to better understand the pathophysiology of
      ureteropelvic junction (UPJ) obstruction and to determine possible predisposing
      factors for endopyelotomy failures, we compared the activation of the nuclear
      factor NF-kappa B and proinflammatory cytokines in patients who failed
      endopyelotomy and post-primary pyeloplasty patients. We hypothesized that an
      imbalance toward proinflammatory cytokines may promote fibrosis prior to and
      after endopyelotomy in patients with severe hydronephrosis. PATIENTS AND METHODS:
      The charts of patients who underwent open pyeloplasty at our institution were
      reviewed. Group I was the control group, consisting of 10 patients who had
      undergone radical nephrectomy for renal-cell carcinoma without involvement of the
      renal pelvis. Group II was the endopyelotomy failure group and included 11
      patients over the age of 15 years treated for symptomatic UPJ obstruction. Group
      III included six patients who underwent primary pyeloplasty. Paraffin-embedded
      blocks of UPJ segments from each of these patients were obtained, and
      immunohistochemical detection of NF-kappa B activation, interleukin (IL)-6, and
      hypoxia-inducing factor (HIF) was performed. As an in-vitro model, activation of
      NF-kappa B and cytokine gene expression were also monitored in human bladder T24
      urothelial cells 24 hours after exposure to hypoxia (1% O(2)) in the presence and
      absence of NF-kappa B inhibitor. The activation of NF-kappa B was determined by
      immunocytochemical analysis, whereas cytokine gene expression was measured using
      reverse transcriptase-polymerase chain reaction. RESULTS: Immunoreactivity to NF
      kappa B was observed in the nuclei of the urothelium and muscle layer in all
      patients in group II. Such immunostaining suggests increased nuclear
      translocation and activation of this transcription factor. Those patients with
      increased expression of NF-kappa B demonstrated increases in IL-6 expression as
      well. Hypoxia-inducing factor was identified in all the tissue samples tested in
      group II. Stimulation of the human urothelial cells by hypoxia, known to activate
      NF-kappa B, resulted in an increase in the levels of IL-1 and IL-6 transcripts
      compared with hypoxia-exposed cells in the presence of NF-kappa B inhibitors.
      CONCLUSIONS: The NF-kappa B factor was upregulated and proinflammatory cytokines
      were activated in patients with UPJ obstruction who failed endopyelotomy.
      Proinflammatory cytokines upregulated by this nuclear factor can result in
      fibrosis and affect healing after endopyelotomy. Hypoxia appears to activate this
      nuclear factor. Further studies correlating the degree of hydronephrosis with the
      activation of HIF are necessary to clarify the role of severe hydronephrosis and
      its management in UPJ obstruction.

PMID- 12470472
TI  - Reconstruction of rabbit urethra with surgisis small intestinal submucosa.
AB  - PURPOSE: To evaluate the efficacy of Surgisis, porcine small intestinal
      submucosa, in the reconstruction of iatrogenic urethral defects in rabbits.
      MATERIALS AND METHODS: Eight male white rabbits were enrolled in this protocol. A
      2.5-cm segment of urethra was excised. One control consisted of a normal urethra.
      The other rabbits underwent urethroplasty with Surgisis and 6-0 Vicryl running
      suture. An 8F feeding tube was left in place to divert urine for 2 weeks after
      surgery. Retrograde urethrograms were performed to assess the patency of the
      urethras and to rule out fistula formation prior to sacrifice of the animals. The
      sacrifice protocol began with the control and a urethroplasty animal 6 weeks
      after surgery. The other rabbits were euthanized at 2-week intervals thereafter.
      RESULTS: Surgisis promoted epithelial regeneration in all cases. One animal
      developed a wound infection; this was associated with a small fistula at the
      proximal end of the anastomosis. Good cosmetic and functional results were
      documented. Retrograde urethrograms showed no stricture formation at the site of
      the anastomosis in six rabbits. The histopathologic examination showed complete
      regeneration of all urethral layers, almost indistinguishable from the normal
      urethra. CONCLUSION: Surgisis is an excellent material for urethral
      reconstruction in rabbits. It promotes regeneration of all the components of the
      host urethral layers and is biodegradable.

PMID- 12470473
TI  - High-intensity focused ultrasound ablation of the epididymis in a canine model: a
      potential alternative to vasectomy.
AB  - BACKGROUND AND PURPOSE: High-intensity focused ultrasound (HIFU) is a noninvasive
      technology capable of inducing thermal coagulative necrosis of subsurface
      structures without injuring intervening tissues. We have previously reported on
      the feasibility of HIFU vasectomy in a canine model. In this study, we evaluated
      the feasibility of HIFU ablation of the canine epididymis as an alternative to
      vasectomy. The epididymis may be a better target than the vas deferens because it
      is larger, more easily positioned in the HIFU focal zone, and more susceptible to
      occlusive injury at lower energy levels, thus reducing collateral damage.
      MATERIALS AND METHODS: A hand-held HIFU clamp was used to grasp the epididymides
      of anesthetized dogs (eight surgically exposed and six grasped transcutaneously).
      An ultrasound transducer in the clamp focused energy on a 1 x 3 x 8-mm target
      zone centered between the clamp jaws. Ultrasonic energy (6-19 W) was delivered to
      this target zone for various times (16-150 seconds). The vas, epididymis, and
      testis were harvested for histologic examination 2 weeks after ablation. RESULTS:
      Seven of the eight epididymides ablated after surgical exposure demonstrated
      histologic findings associated with occlusion (fibrosis, hemorrhage, and proximal
      duct dilatation). Five of the six epididymides ablated transcutaneously also
      demonstrated histologic evidence of occlusion. Skin burns were evident overlying
      three epididymides, and one testicular injury was noted adjacent to an ablated
      region of the epididymis. CONCLUSION: High-intensity focused ultrasound ablation
      of the epididymis causes injury and histologic changes associated with epididymal
      occlusion. Further investigations are under way to optimize ablation parameters
      and to confirm azoospermia with ejaculate studies. Refinement of this technology
      may provide a rapid noninvasive alternative to conventional vasectomy.

PMID- 12470474
TI  - Protective, anti-tumor monoclonal antibody recognizes a conformational epitope
      similar to melibiose at the surface of invasive murine melanoma cells.
AB  - Polyclonal and monoclonal antibodies (MAbs) have been raised against B16F10 cells
      collected from growing tumors in vivo or grown in culture media supplemented with
      normal mouse serum to avoid xenogeneic reactivity. Antibody binding to
      glutaraldehyde-fixed melanoma cells and Melan A melanocytes was assayed using
      chemiluminescent-enzyme-linked immunosorbent assay (CL-ELISA) for increased
      sensitivity. Most of the reactivity of antitumor polyclonal IgG (92%) was
      inhibitable by a carbohydrate pool consisting of melibiose, mannose, lactose, and
      sialic acid. Two monoclonal IgG(2a) antibodies, A4 and B11, had their reactivity
      to melanoma cells completely and specifically inhibited by melibiose. MAb A4 did
      not bind to alpha-galactosyl residues abundantly expressed in a protozoan mucin
      used as substrate, and its binding to the tumor cells was not affected by alpha
      galactosidase treatment or addition of alpha-methyl-galactopyranoside or
      raffinose. Recognition of a mimotope similar to melibiose is suggested. MAb is
      cytotoxic in vitro in a complement-mediated reaction and effectively neutralizes
      melanoma cells protecting syngeneic mice against tumor development in vivo. This
      MAb is thus an important tool for further studies on antitumor adjuvant therapy
      combined with other agents associated with immuno- and chemotherapy of invasive
      melanoma.

PMID- 12470475
TI  - Antibody responses to HPV6b E polyproteins and production of monoclonal
      antibodies.
AB  - A range of fusion constructs (expressed in Escherichia coli) were produced that
      contained two or more HPV6b E proteins, producing a single continuous amino acid
      sequence corresponding to the sequences of the individual E proteins. The
      constructs also included a C-terminal hexahistidine tag fused in-frame to aid
      purification. The fusion proteins (polyproteins) were semipurified by Ni(++)
      metal affinity chromatography under denaturing conditions. Immunization of BALB/c
      mice with these polyproteins resulted in the production of specific E protein
      antibodies. The draining lymph nodes from these mice were used to produce
      monoclonal antibodies (MAbs). The specificity of the polyclonal and MAbs was
      confirmed by immunoblotting and by screening for reaction with a series of
      synthetic peptides of E proteins. HPV E polyproteins were found to be immunogenic
      and immunization with the polyproteins resulted in specific antibody responses to
      the component E proteins.

PMID- 12470476
TI  - Monoclonal antibodies to CD44 epitopes on mouse endothelium.
AB  - CD44 is a widely expressed, plasma membrane protein. Many molecular forms of CD44
      are possible as it is encoded by a gene with multiple exons that can be
      alternatively spliced and its deduced protein sequence contains numerous
      glycosylation sites. Through its role as an adhesion molecule, CD44 is involved
      in many and diverse biological processes, including angiogenesis, lymphogenesis,
      wound healing, inflammation, and cancer metastasis. We have developed a new panel
      of rat monoclonal antibodies (MAbs) to murine CD44 by immunization with mouse
      lung endothelial cells (LEII cells). The antibodies were characterized using
      immunoprecipitation, mass spectrometry, competition binding, and cross Western
      blot experiments with MAb 133-13A, which recognizes CD44 expressed on tumor
      cells. The new MAbs recognize three distinct epitope groups. MAbs 531-2A and 531
      32A compete for binding with the MAb 133-13A that was described previously. MAb
      531-30A identifies a CD44 epitope found on low molecular weight forms expressed
      in vivo, while MAb 531-22A appears to recognize an epitope specific for
      endothelial cells. This novel panel of anti-CD44 antibodies has potential for
      investigating the role of CD44 in disease pathogenesis models in the mouse. They
      may be particularly useful for examining the role of endothelial cells in these
      models.

PMID- 12470477
TI  - Development and characterization of murine monoclonal antibodies specific for
      dissimilatoric copper nitrite reductase.
AB  - Several hybridoma cell lines from mice were established, producing monoclonal
      antibodies (MAbs) directed against the dissimilatoric copper nitrite reductase
      (dNIR) to detect actual denitrifying bacteria at the single cell level under
      nondestructive conditions in the environment. The mice were immunized with native
      or recombinant enzyme gained from two different bacteria, Ochrobactrum anthropi
      and Alcaligenes faecalis. The antibodies obtained could be divided into two
      groups according to their different specificities for dNIRs of different
      bacteria: One group of MAbs had a broad specificity for dissimilatoric copper
      nitrite reductases from bacteria of different phylogenetic taxa; the other group
      gave only a clear signal with the corresponding immunogen. None of the raised
      MAbs showed a cross reactivity with the dissimilatoric heme nitrite reductase.
      One MAb from each group (MAb dNIR1a and MAb dNIR29) has been selected for further
      investigation. Data of enzyme-linked immunosorbent assay (ELISA), Western
      blotting, and immunofluorescence-microscopy are presented and compared with
      phylogenetic data. Furthermore, results of Western blotting experiments with
      cells, grown without nitrate under aerobic conditions, and cells cultivated with
      nitrate under anaerobiosis, are shown.

PMID- 12470478
TI  - Characterization of rat monoclonal antibodies against human beta-defensin-2.
AB  - Defensins are a family of cationic antimicrobial peptides that participate in
      host defense. Human beta-defensin (hBD)-2 has a potent bactericidal activity
      against a wide spectrum of microorganisms. Because human gingival epithelium is
      constantly exposed to a variety of microbial challenges, it is considered that
      hBD-2 has an important role in the protective mechanisms against oral bacterial
      infection. However, little is known about the production of hBD-2 in tissues of
      the oral cavity. Six rat monoclonal antibodies (MAbs) raised against chemically
      synthesized hBD-2 have been characterized. Rat MAbs were specific for the
      conformational epitopes on hBD-2, but not to hBD-1. To identify the epitope on
      hBD-2, a series of six overlapping peptides covering the hBD-2 whole sequence
      were synthesized and the immunoreactivities of six MAbs were examined. The
      FCPRRYK domain in hBD-2 was recognized by all six MAbs and suggested to be an
      epitope region. By immunocytochemistry, hBD-2 was localized focally in the
      epidermis of the human gingival tissue using the MAbs. The MAbs specifically
      recognized against hBD-2 will be a useful tool to study the functional role of
      antimicrobial agents and an important asset in the imaging of oral infection
      processes.

PMID- 12470479
TI  - Monoclonal antibodies to molluskan hemocyanin from Concholepas concholepas
      demonstrate common and specific epitopes among subunits.
AB  - We studied the reactivity of mouse monoclonal antibodies (MAbs) against the
      hemocyanin from the Chilean marine gastropod Concholepas concholepas (CCH). This
      protein has been successfully used as a carrier to produce antibodies to haptens
      and peptides. All MAbs (13) belonging to IgG subclass exhibit dissociation
      constants (K(d)) from 1 x 10(-7) M to 1 x 10(-9) M. MAbs were characterized by
      enzyme-linked immunosorbant assay (ELISA) using CCH treated with different
      procedures, including dissociation into CCH-A and CCH-B subunits, Western blot,
      enzymatic digestion, chemical deglycosylation, and thermal denaturation. MAbs
      were classified into three categories, according to subunit specificity by ELISA.
      The epitope distribution shows that CCH subunits display common epitopes (group
      I, 5 MAbs, 1H5, 2A8, 3A5, 3B3, and 3E3), as well as specific epitopes for CCH-A
      subunits (group II, 3 MAbs, 1B8, 4D8, and 8E5) and for CCH-B subunits (group III,
      5 MAbs, 1A4, 1E4, 2H10, 3B7, and 7B4). The results can be summarized as follows:
      (1). six antibodies react with thermal denatured CCH, suggesting that they
      recognize linear epitopes, whereas seven recognize conformational epitopes; (2).
      oxidation of carbohydrate moieties does not affect the binding of the MAbs; (3).
      enzymatic digestion of CCH decreases the reactivity of all antibodies
      irrespective of the protease used (elastase or trypsin); (4). bringing together
      the above data, in addition to epitopic complementarity analysis, we identified
      12 different epitopes on the CCH molecule recognized by these MAbs. The anti-CCH
      MAbs presented here can be useful tools to understand the subunit organization of
      the CCH and its complex structure, which can explain its immunogenic and
      immunostimulating properties in mammals.

PMID- 12470480
TI  - Preparation and characterization of monoclonal antibody against digoxin.
AB  - Mouse-mouse hybridoma cell lines producing stable, highly specific and with good
      affinity monoclonal antibody (MAb) against the cardiac glycoside digoxin were
      established. Balb/c mice were immunized via injection of digoxin-3'-bovine serum
      albumin (BSA). The spleens of which were fused with myeloma cells of SP2/0
      origin. Three clones designated as BBA, MBE, and BMG producing good antibodies
      displayed different patterns of fine specificity for digoxin and low cross
      reaction with several digoxin analogues as elucidated by inhibition enzyme-linked
      immunosorbant assay (ELISA). All three MAbs were of the same class and subclass
      (IgG(1)). Affinity purification was performed for the selected clone BBA
      displaying the highest affinity and nearly no cross-reactivity with any of the
      structurally related molecules. Ultrafiltered concentrated hybrid cell
      supernatant was also purified by polyethylene glycol (PEG) 6000 precipitation for
      large-scale preparation and coated onto the wells of microtiter plates. The
      standard curve was constructed with a sensitivity of 10 pg/well covering up to 10
      ng/well.

PMID- 12470481
TI  - Monoclonal antibody against free beta-subunit of human chorionic gonadotropin.
AB  - Spleen cells from BALB/c mice immunized with free native human chorionic
      gonadotropin hormone beta-subunit (beta hCG) were fused with mouse myeloma cells
      (P3/X63-Ag8) and one hybridoma secreting monoclonal antibodies (MAbs), was
      obtained. This hybridoma specifically recognizes beta hCG and does not cross
      react with other human glycoprotein hormones, such as luteinizing hormone (LH),
      follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and human
      chorionic gonadotropin (hCG). The MAb was of the IgG(1) subclass and ascitic
      fluid from this hybridoma was purified by affinity chromatography on Protein A
      Sepharose CL-4B column to isolate the IgG(1) active fraction. The affinity
      constant of this MAb was 1.5 x 10(10)M(-1).

PMID- 12470482
TI  - Selection and characterization of human antibodies against hepatitis B virus
      surface antigen (HBsAg) by phage-display.
AB  - Hepatitis B virus (HBV) is one of the main pathogens of hepatitis and
      hepatocarcinoma. Human plasma-derived antibody to HBV is being used as a
      prophylactic for postexposure to HBV and liver transplantation currently.
      However, it is required to replace the plasma-derived anti-HBs antibody (Ab) to a
      recombinant antibody because of limited availability of human plasma with high
      anti-HBs Ab titer and possible contamination of human pathogens. We constructed
      an anti-HBs Ab-enriched phage-display library from peripheral blood B cells of
      vaccinated volunteers and the size of library was approximately 1.0 x 10(7). The
      library was panned against hepatitis B surface antigen (HBsAg) and five different
      clones were isolated. All five clones exhibited the same heavy chain sequence; in
      contrast, light-chain exhibited one lambda and four different kappa sequences.
      The Fabs were expressed soluble in E. coli and exhibited affinities of 2.1 x
      10(8) approximately 7.7 x 10(8) M(-1).

PMID- 12470483
TI  - Reactivity and isotype profiling of monoclonal antibodies using multiple
      antigenic peptides.
AB  - The characterisation of monoclonal antibodies (MAbs) is essential for the
      development of assay systems particularly where antigens have been developed
      using synthetic peptides. Indeed some peptide-carrier conjugates fail to induce
      immune responses and may not generate antibodies that bind to native protein. As
      an alternative to peptide-carrier conjugates, multiple antigenic peptides (MAPs)
      have been used for immunization strategies, but with little regard to the
      characteristics of the MAbs produced. In this study, we used 3 MAPs of Epstein
      Barr virus (EBV) latent membrane protein 1 (LMP1) to immunise BALB/c mice.
      Overall, the polyclonal antibody responses from tail bleeds showed that MAPs
      evoked B-cell responses. However, on screening 144 hybridomas, 24 MAb
      supernatants exhibited weak to moderate reactivity in enzyme-linked immunosorbant
      assay (ELISA) and against cell cytospin preparations (B95.8 and AG876 LCL),
      respectively. Isotype profiling of hybridoma supernatants also showed that 11 out
      of 24 were IgM. Further characterization of 6 MAbs in Western blotting showed
      reactivity to recombinant LMP1 and only one MAb (B28D) showed weak reactivity to
      the malignant cells (Hodgkin/Reed-Sternberg; HRS cells) of an EBV+ Hodgkin's
      lymphoma using paraffin-embedded tissue. It is probable that these MAPs failed to
      augment T-cell help and contributed to the production of low affinity (IgM)
      antibodies. These observations may be of importance to future immunization
      strategies, where MAPs are used in the production of monoclonal reagents.

PMID- 12470489
TI  - Technical workshop on human milk surveillance and research on environmental
      chemicals in the United States: an overview.
AB  - Interest in human milk research and monitoring for environmental chemicals is
      growing, and as studies of chemicals in human milk are initiated, it is of the
      utmost importance that these studies be conducted using harmonized methods. Due
      to numerous limitations in previous studies and the fact that few studies on
      environmental chemicals in human milk have been conducted in the United States,
      there is a growing need for a human milk sampling and analysis protocol in this
      country. The Technical Workshop on Human Milk Surveillance and Research on
      Environmental Chemicals in the United States was organized to develop state-of
      the-science protocols describing the various aspects of such a program. An expert
      panel, comprised of specialists in the fields of pediatrics, family medicine,
      nursing, lactation, human milk sampling, analytical chemistry, epidemiology,
      pharmacology, toxicology, nutrition, and risk evaluation and communication, was
      assembled to participate in a 2-day workshop at the Milton S. Hershey Medical
      Center, Pennsylvania State University College of Medicine. The expert panel was
      tasked with carefully describing and defining the components of well-conducted
      human milk surveillance and research studies, including participant selection,
      sample collection and analysis techniques, questionnaire development, chemical
      selection, and data reporting and interpretation, especially for use in the
      United States. The articles that follow this overview describe the results of the
      expert panel's deliberations on the components of human milk surveillance and
      research programs.

PMID- 12470490
TI  - Selection of subjects for human milk surveillance and research studies.
AB  - Subject selection for studies investigating environmental chemicals in human milk
      requires thoughtful consideration of multiple factors. Studies often need to
      produce generalizable and representative data that can be compared to other
      similar studies. Goals of the study determine the selection of subjects. Exposure
      is only one factor that influences the levels of environmental chemicals in human
      milk. Many maternal and infant characteristics should be considered in subject
      selection. Collection procedures of human milk samples also affect subject
      selection, as subject burden may be enough to reduce compliance with the
      collection protocols. Decisions must be made about pooling of samples both within
      subjects and within populations. Guidelines for subject selection are provided by
      the World Health Organization for human milk monitoring, but distinct differences
      in the lactational practices, geography, and ethnic and racial diversity of the
      U.S. population require somewhat different approaches.

PMID- 12470491
TI  - Reporting needs for studies of environmental chemicals in human milk.
AB  - Studies of environmental chemicals in human milk have been carried out in many
      countries, but few have been conducted in the United States. These studies are
      useful for monitoring population trends in exposure to chemicals, for research
      into the determinants of environmental chemicals in milk and relationships
      between the levels found and the health status of the women and their infants,
      and for risk assessment. This article provides practical advice on data and
      information reporting for such studies. Participation in these studies comes at a
      difficult time for the breast-feeding mothers, so it is important that the
      mothers support the study and its goals. A key goal of any study of environmental
      chemicals in human milk must be to ensure that the breast-feeding process is not
      disrupted by unwarranted concerns about harm to the infant from chemicals in
      human milk. Therefore, it is essential that reporting of information be a two-way
      process. Information needs to be supplied to participating mothers before,
      during, and after their participation in the study. Information supplied before
      participation is necessary to satisfy the ethical requirement for informed
      consent; information supplied during participation includes advice on expressing,
      collecting, and storing milk samples, and how to avoid sample contamination; and
      information supplied to each participant at the end of the study includes a
      report of their individual results and a summary of study results and outcomes
      generally. The key instrument for obtaining data from the participants is the
      study questionnaire. This needs to be prepared in accordance with principles of
      good questionnaire development, and preferably should be interviewer
      administered. The questionnaire content will vary according to the objectives of
      the study. Although studies of environmental chemicals in human milk are
      logistically complex and demanding, they are practicable and, with careful
      planning and execution, yield important data.

PMID- 12470492
TI  - Guidelines for collection of human milk samples for monitoring and research of
      environmental chemicals.
AB  - This article addresses sample collection protocols for monitoring and research of
      environmental chemicals in human milk. The process of milk synthesis and
      secretion and variations in contents of constituents that may impact measurement
      of environmental chemicals are presented. Possible sources of variation include
      parity, stage of lactation, method of sampling, maternal nutritional status, and
      dietary intake. General principles regarding how and when to collect milk samples
      are provided. For any previously unstudied environmental chemical in milk, all
      sources of variance must be assessed before a meaningful sampling protocol can be
      devised.

PMID- 12470493
TI  - Guidelines for analysis of human milk for environmental chemicals.
AB  - When analyzing human milk for environmental chemicals, in either a monitoring or
      research project, researchers must ensure that the technique used for measuring
      the target analytes complies with certain analytical criteria and that a quality
      control/quality assurance program is in place. In this report, these analytical
      criteria and the accompanying quality assurance program are elaborated in more
      detail. Examples of representative methods are also given for the determination
      of a number of classes of chemicals of environmental concern, such as
      polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, polychlorinated
      biphenyls, volatile organics, and halogenated flame retardants. Most of these
      techniques are physical/chemical in nature, but the possibility of the use of
      bioassays for screening of analytes in human milk is noted. The described methods
      are not exclusive, but any laboratory undertaking the analysis of human milk
      should demonstrate proficiency in their execution. This is usually accomplished
      by producing reliable data in interlaboratory studies. Human milk is an ideal
      matrix for estimating exposure to certain environmental chemicals, and
      researchers must ensure that the techniques used to determine these compounds
      adhere to known and accepted analytical requirements.

PMID- 12470494
TI  - Human milk surveillance and research of environmental chemicals: concepts for
      consideration in interpreting and presenting study results.
AB  - This article describes issues related to the interpretation, presentation, and
      use of data from human milk surveillance and research studies. It is hoped that
      researchers conducting human milk studies in the future will consider these
      concepts when formulating study conclusions and presenting data. The key issues
      discussed are; (1) communication of information on human milk constituents to
      health care providers and the public; (2) complexities associated with assessing
      risks and benefits when comparing breast-feeding and formula-feeding; (3) use of
      human milk information for trends analysis and assessment of the efficacy of
      restrictions on use/release of chemicals in the environment; and (4) risk
      assessment and regulatory decision-making concepts regarding environmental
      chemicals in human milk. As researchers conduct surveillance and research
      involving human milk, it is of the utmost importance that the results of these
      studies are provided with information on risk and benefits that place the data in
      perspective, so that those involved in decision making regarding infant nutrition
      (e.g., expectant mothers, physicians, midwives, nurses, and lactation
      consultants) can appropriately interpret the research data.

PMID- 12470495
TI  - Conclusions, research needs, and recommendations of the expert panel: technical
      workshop on human milk surveillance and research for environmental chemicals in
      the United States.

PMID- 12470496
TI  - Redox considerations in hepatic injury and inflammation.

PMID- 12470497
TI  - Cytochrome P450 2E1 expression induces hepatocyte resistance to cell death from
      oxidative stress.
AB  - Increased expression of cytochrome P450 2E1 (CYP2E1) occurs in alcoholic liver
      disease, and leads to the hepatocellular generation of toxic reactive oxygen
      intermediates (ROI). Oxidative stress created by CYP2E1 overexpression may
      promote liver cell injury by sensitizing hepatocytes to oxidant-induced damage
      from Kupffer cell-produced ROI or cytokines. To determine the effect of CYP2E1
      expression on the hepatocellular response to injury, stably transfected
      hepatocytes expressing increased (S-CYP15) and decreased (AN-CYP10) levels of
      CYP2E1 were generated from the rat hepatocyte line RALA255-10G. S-CYP15 cells had
      increased levels of CYP2E1 as demonstrated by Northern blot analysis,
      immunoblotting, catalytic activity, and increased cell sensitivity to death from
      acetaminophen. Death in S-CYP15 cells was significantly decreased relative to
      that in AN-CYP10 cells following treatment with hydrogen peroxide and the
      superoxide generator menadione. S-CYP15 cells underwent apoptosis in response to
      these ROI, whereas AN-CYP10 cells died by necrosis. This differential sensitivity
      to ROI-induced cell death was partly explained by markedly decreased levels of
      glutathione (GSH) in AN-CYP10 cells. However, chemically induced GSH depletion
      triggered cell death in S-CYP15 but not AN-CYP10 cells. Increased expression of
      CYP2E1 conferred hepatocyte resistance to ROI-induced cytotoxicity, which was
      mediated in part by GSH. However, CYP2E1 overexpression left cells vulnerable to
      death from GSH depletion.

PMID- 12470498
TI  - Hepatic redox regulation of transcription factors activator protein-1 and nuclear
      factor-kappaB after hemorrhagic shock in vivo.
AB  - Ischemia and reperfusion result in a hepatocellular stress gene response,
      characterized by a zonal heterogeneity with pericentral hepatocytes being the
      primary target. In the present study, we assessed cell type-specific and zonal
      pattern of activation of redox-sensitive transcription factors nuclear factor
      kappaB (NFkappaB) and activator protein-1 (AP-1) in a graded model of hemorrhage
      and their modulation by the antioxidants trolox and tempol. Hemorrhagic
      hypotension (35-40 mm Hg) up to 3 h without subsequent resuscitation led to an
      only moderate activation of NFkappaB and AP-1. In contrast, fluid resuscitation
      after 1 or 2 h of hemorrhage induced a profound activation of AP-1 within the
      first hour of reperfusion. Consistent with a regulation by oxygen free radicals,
      activation of AP-1 was substantially attenuated by antioxidants. The faint
      activation of NFkappaB with various intervals of hemorrhage was unaffected by
      antioxidants and did not exceed activation with sham operation.
      Immunohistochemistry for the AP-1 subunit c-Jun revealed a predominant expression
      in nuclei of pericentral and midzonal hepatocytes. These data suggest activation
      of AP-1 in hepatocytes most susceptible to injury and reprogramming of gene
      expression in low-flow ischemia. Whereas activation of NFkappaB is weak in this
      model and is not modulated by either reperfusion or antioxidants, regulation of
      AP-1 after hemorrhage and subsequent resuscitation seems to depend on oxygen free
      radical formation because it requires reperfusion and is inhibitable by
      antioxidants.

PMID- 12470499
TI  - Acute ethanol binge followed by withdrawal regulates production of reactive
      oxygen species and cytokine-induced neutrophil chemoattractant and liver injury
      during reperfusion after hepatic ischemia.
AB  - This work tests the hypothesis that withdrawal from an acute ethanol binge
      regulates the production of reactive oxygen species (ROS) and chemokines by
      Kupffer cells, and as a result compromises or protects the liver from injury.
      Male Sprague-Dawley rats received an intravenous ethanol bolus (1.75 g/kg),
      followed by an intravenous infusion of 200-300 mg/kg/h for 12 h. At 12 h, ethanol
      infusion was stopped and replaced by saline. At 18 h, rats were subjected to 45
      min of partial hepatic ischemia, followed by 0-24 h of reperfusion (I/R). At
      specific time points, Kupffer cells were isolated for superoxide anion assay and
      CINC (cytokine-induced neutrophil chemoattractant) and MIP-2 (macrophage
      inflammatory protein-2) production in vitro. Alanine transferase (ALT) activity,
      endotoxin, CINC, and MIP-2 were measured in serum samples taken at appropriate
      intervals. Results show that at 3 h post reperfusion, serum ALT was significantly
      elevated in the ethanol-treated group + I/R, compared with the saline + I/R
      group. ROS production by Kupffer cells at this time was also significantly
      increased compared with the saline + I/R group. However, ethanol withdrawal + I/R
      did not significantly alter CINC and MIP-2 production at 3 h of reperfusion.
      After 24 h, serum ALT was lower in the ethanol + I/R group than in the saline +
      I/R group. Superoxide anion and MIP-2 releases by Kupffer cells were not
      statistically significantly different between these two groups at this time. CINC
      production by Kupffer cells from the ethanol-treated + I/R group was
      significantly lower than in the saline + I/R group. Concomitantly, CINC and
      nuclear factor-kappaB (NF-kappaB) mRNAs and NF-kappaB translocation and binding
      in Kupffer cells in this treatment group were down-regulated. Moreover, the
      number of polymorphonuclear neutrophils (PMNs) sequestered in the liver was
      significantly lower in the ethanol + I/R group than in the saline-treated group.
      ROS and chemokine productions in sham animals with or without ethanol were lower
      than in the I/R group. These data suggest that acute ethanol binge followed by
      withdrawal may compromise the liver to injury during the early phase, whereas in
      the later phase it may be protective. Furthermore, these results support the
      notion that Kupffer cells are involved in hepatic injury in the early phase,
      whereas PMNs participate more actively during the later phase of reperfusion.

PMID- 12470500
TI  - Reactive oxygen as modulator of TNF and fas receptor-mediated apoptosis in vivo:
      studies with glutathione peroxidase-deficient mice.
AB  - Reactive oxygen species (ROS) can directly induce or enhance tumor necrosis
      factor (TNF)-mediated apoptosis in a number of different cell lines. To test the
      relevance of intracellular ROS in modulating apoptotic signaling in vivo, we
      evaluated hepatocellular apoptosis mediated by the TNF or Fas receptor in wild
      type and glutathione peroxidase-1 (Gpx1-/-)-deficient mice (129SV/B6 background).
      Apoptosis developed in livers of wild-type animals 4-6 h after intraperitoneal
      administration of 700 mg/kg galactosamine/100 micro g/kg endotoxin. Apoptosis was
      indicated by processing of procaspases-3 (assessed by western blotting), a
      fivefold increase in caspase-3 activity (DEVD-AMC as substrate), and a 44-fold
      increase in DNA fragmentation (ELISA). The time course and magnitude of apoptosis
      were the same in Gpx1-/- mice. In contrast, Gpx1-/- mice had higher plasma
      alanine aminotransferase (ALT) levels and more severe hemorrhage compared to wild
      type animals at 6 h. Treatment of wild-type mice with the anti-Fas antibody Jo-2
      (0.6 mg/kg i.v.) resulted in processing of procaspase-3 and a sevenfold increase
      in caspase-3 activity in both wild-type and Gpx1-/- mice. However, higher plasma
      ALT values in Gpx1-/- mice at 3 h may reflect a trend to develop more rapidly
      secondary necrosis. These data suggest that, under our experimental conditions,
      intracellular ROS did not modulate the death receptor-initiated apoptotic
      signaling cascade in hepatocytes. As Gpx1 is located in the cytosol and in
      mitochondria, which are the main cellular compartments involved in apoptotic
      signaling, our findings indicate that the oxidant stress in vivo was insufficient
      to modulate these signaling pathways. However, Gpx1 deficiency enhances the
      susceptibility for secondary necrosis or neutrophil-induced cell injury.

PMID- 12470501
TI  - Redox regulation of cytokine expression in Kupffer cells.
AB  - Kupffer cells, resident macrophages in the liver, play a central role in the
      homeostatic response to liver injury. Ironically, this defensive mechanism, if
      dysregulated, also works against the liver in acute and chronic liver damage.
      Central to this response is activation of nuclear factor-kappaB (NF-kappaB), a
      redox-sensitive transcription factor that transactivates promoters of many
      inflammatory genes, including cytokines. Much research has been devoted to
      identification of upstream signaling for activation of NF-kappaB, but the precise
      mechanism by which oxidant stress participates in this signaling is yet to be
      determined. Clues to this key question may be attained through studies on the
      mechanisms of sustained and/or accentuated NF-kappaB activation in hepatic
      macrophages in chronic liver diseases. This article reviews the literature on
      redox regulation of cytokine gene expression by Kupffer cells.

PMID- 12470502
TI  - Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative
      stress.
AB  - Heme oxygenase (HO) catalyzes the oxidative cleavage of the alpha-mesocarbon of
      Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXalpha, free
      divalent iron, and carbon monoxide (CO). Among the three isoenzymes cloned to
      date, only HO-1 can be induced by a variety of seemingly disparate stimuli, most
      of which are linked by their ability to provoke oxidative stress. Although
      constitutive expression of HO-1 in the liver is restricted to Kupffer cells, the
      gene is inducible in nonparenchymal as well as in parenchymal liver cells. HO-1
      induction potentially confers protection against oxidative stress in a variety of
      experimental models, such as liver ischemia/reperfusion secondary to
      transplantation or hemorrhage/resuscitation. Induction of HO-1 may protect the
      cell against oxidative injury by (a) controlling intracellular levels of "free"
      heme (a prooxidant), (b) producing biliverdin (an antioxidant), (c) improving
      nutritive perfusion via CO release, and (d) fostering the synthesis of the Fe
      binding protein ferritin. Although protective effects of up-regulation of the HO
      pathway--presumably through production of bile pigments and CO--have been
      reported for a variety of cells and tissues, including the liver, evidence
      suggests that the protective action might be restricted to a rather narrow
      threshold of overexpression. High levels of HO-1 may even sensitize the cell to
      oxidative stress, e.g., through release of reactive iron. Transcriptional
      activation of the HO-1 gene is an integral part of the cellular response to
      oxidative stress, but its induction seems to be neither exclusively
      cytoprotective nor exclusively cytotoxic.

PMID- 12470503
TI  - Induction and regulation of hepatocyte apoptosis by oxidative stress.
AB  - Reactive oxygen intermediates (ROI) have been implicated in the induction of
      hepatocyte apoptosis that results from a variety of forms of liver injury.
      Exogenous oxidants induce hepatocyte apoptosis and may mediate death during
      inflammatory liver injury. Lethal levels of intracellularly generated ROI
      resulting from hepatotoxin metabolism, or the induction of enzymes in the
      cytochrome P450 family, are also important inducers of apoptosis. In addition,
      ROI production may mediate death from a number of diverse factors, including
      tumor necrosis factor-alpha, bile acids, ischemia, and transforming growth factor
      beta1. Oxidants alter many redox-sensitive cellular signaling pathways, including
      mitogen-activated protein kinases and transcription factors such as activator
      protein-1 and nuclear factor-kappaB. The mechanisms of oxidant-induced hepatocyte
      apoptosis remain unclear, but probably involve effects on cell signaling, as well
      as direct chemical interactions. The delineation of stimulus-specific mechanisms
      of oxidant-dependent hepatocyte apoptosis is important to the design of effective
      therapies for a number of forms of liver injury.

PMID- 12470504
TI  - Role of mitochondrial inner membrane permeabilization in necrotic cell death,
      apoptosis, and autophagy.
AB  - Inhibition of mitochondrial oxidative phosphorylation progresses to uncoupling
      when opening of cyclosporin A-sensitive permeability transition pores increases
      permeability of the mitochondrial inner membrane to small solutes. Involvement of
      the mitochondrial permeability transition (MPT) in necrotic and apoptotic cell
      death is implicated by demonstrations of protection by cyclosporin A against
      oxidative stress, ischemia/reperfusion, tumor necrosis factor-alpha exposure, Fas
      ligation, calcium overload, and a variety of toxic chemicals. Confocal microscopy
      directly visualizes the MPT in single mitochondria within living cells from the
      translocation of impermeant fluorophores, such as calcein, across the inner
      membrane. Simultaneously, mitochondria release potential-indicating fluorophores.
      Subsequently, mitochondria swell, causing outer membrane rupture and release of
      cytochrome c and other proapoptotic proteins from the intermembrane space. In
      situ a sequence of decreased NAD(P)H, increased free calcium, and increased
      reactive oxygen species formation within mitochondria promotes the MPT and
      subsequent cell death. Necrotic and apoptotic cell death after the MPT depends,
      in part, on ATP levels. If ATP levels fall profoundly, glycine-sensitive plasma
      membrane permeabilization and rupture ensue. If ATP levels are partially
      maintained, apoptosis follows the MPT. The MPT also signals mitochondrial
      autophagy, a process that may be important in removing damaged mitochondria.
      Cellular features of necrosis, apoptosis, and autophagy frequently occur together
      after death signals and toxic stresses. A new term, necrapoptosis, describes such
      death processes that begin with a common stress or death signal, progress by
      shared pathways, but culminate in either cell lysis (necrosis) or programmed
      cellular resorption (apoptosis), depending on modifying factors such as ATP.

PMID- 12470505
TI  - Redox regulation of vascular angiogenesis.

PMID- 12470506
TI  - Promotion of angiogenesis by low energy laser irradiation.
AB  - The effect of low energy laser (He-Ne) irradiation (LELI) on the process of
      angiogenesis in the infarcted rat heart and in the chick chorioallantoic membrane
      (CAM), as well as the proliferation of endothelial cells in tissue culture, was
      investigated. Formation of new blood vessels in the infarcted rat heart was
      monitored by counting proliferating endothelial cells in blood vessels. In the
      CAM model, defined areas were laser-irradiated or nonirradiated and blood vessel
      density was recorded in each site in the CAM at various time intervals. Laser
      irradiation caused a 3.1-fold significant increase in newly formed blood vessels
      6 days post infarction, as compared with nonirradiated rats. In the CAM model, a
      slight inhibition of angiogenesis up to 2 days post irradiation and a significant
      enhancement of angiogenesis in the laser-irradiated foci as compared with control
      nonirradiated spots were evident. The LELI caused a 1.8-fold significant increase
      in the rate of proliferation in endothelial cells in culture over nonirradiated
      cells. It is concluded that LELI can promote the proliferation of endothelial
      cells in culture, which may partially explain the augmentation of angiogenesis in
      the CAM model and in the infarcted heart. These results may have clinical
      significance by offering therapeutic options to ameliorate angiogenesis in
      ischemic conditions.

PMID- 12470507
TI  - Vitamin E inhibits lysophosphatidylcholine-induced endothelial dysfunction and
      platelet activation.
AB  - Lysophosphatidylcholine (LPC), a lysolipid contained in oxidized low-density
      lipoprotein, is an atherogenic molecule that induces endothelial dysfunction and
      platelet activation and inhibits angiogenesis. Although studies showed that
      vitamin E has antiatherogenic properties, the effects of vitamin E on LPC-induced
      endothelial dysfunction and platelet activation are little known. We examined
      whether vitamin E has protecting actions against LPC-induced alterations of
      endothelial and platelet functions. Incubation of cultured bovine aortic
      endothelial cells (BAECs) with LPC (10 microM) significantly inhibited bradykinin
      (1 microM)-stimulated nitric oxide release, which was prevented by cotreatment
      with vitamin E (50, 100, and 500 microg/ml) in a concentration-dependent manner.
      In isolated human platelets, LPC stimulated P-selectin expression and induced
      leukocyte-platelet interaction, which functionally depends on P-selectin
      expressed on the platelet surface. Vitamin E treatment significantly prevented
      the LPC-induced platelet P-selectin expression and leukocyte-platelet
      interaction. As LPC-induced endothelial dysfunction and platelet activation have
      been shown to involve the protein kinase C (PKC)-dependent signal transduction
      pathway, we examined the effects of vitamin E on LPC-induced PKC activation in
      human platelets and BAECs. Vitamin E significantly inhibited LPC (10 microM)
      stimulated PKC activation in a concentration-dependent manner. It is concluded
      that (a) Vitamin E prevented LPC-induced endothelial dysfunction and preserved
      endothelial nitric oxide release, (b) vitamin E inhibited LPC-induced platelet
      activation (P-selectin expression) and leukocyte-platelet interaction, and (c)
      these mechanisms appeared to be at least partly mediated by suppression of the
      PKC in endothelial cells and platelets. The present findings may provide new
      insights into antiatherogenic mechanisms of vitamin E.

PMID- 12470508
TI  - Generation of nitrotyrosine precedes activation of metalloproteinase in
      myocardium of hyperhomocysteinemic rats.
AB  - The hypothesis is that homocysteine decreases endothelial nitric oxide (NO)
      availability by generating nitrotyrosine. In the absence of NO, and in an attempt
      to reduce endocardial load by dilatation, the matrix metalloproteinase (MMP) is
      activated. To address this hypothesis, homocysteine (0.67 mg/ml) was administered
      in drinking water of Sprague-Dawley rats for 8 weeks. To elicit the reversible
      effects of homocysteine, homocysteine was removed from the water after 8 weeks.
      The plasma levels of homocysteine were 2.79 +/- 0.5 microM in control (n = 6),
      measured by spectrofluorometry. The levels of homocysteine increased to 22 +/-
      1.3 and 17 +/- 2.8 microM following 4 (n = 6) and 8 (n = 6) weeks of homocysteine
      treatment, respectively. The level of homocysteine decreased to 5.8 +/- 1.0
      microM (n = 6) when homocysteine was removed from the drinking water. The mean
      arterial pressure (MAP) of control rats was 108 +/- 10 mm Hg and increased to 128
      +/- 2 and 130 +/- 3 mm Hg following 4 and 8 weeks of homocysteine treatment,
      respectively. When homocysteine was removed from the drinking water, the MAP was
      decreased to 118 +/- 3 mm Hg. Left ventricle (LV) parameters were measured by a
      catheter in the LV through right common carotid artery in anesthetized rats. The
      LV tissue was analyzed for MMP activity by zymography. Levels of nitrotyrosine
      and cardiospecific tissue inhibitor of metalloproteinase-4 (TIMP-4/CIMP) were
      measured by western blot analysis using the respective antibodies. The specific
      bands in zymographic gel and western blot were scanned and normalized with beta
      actin. The results suggest a continuous increase in nitrotyrosine levels at 4 and
      8 weeks after homocysteine administration. The removal of homocysteine did not
      decrease the levels of nitrotyrosine. The zymographic analysis revealed a
      temporal increase in MMP-2 activity from 4 to 8 weeks post homocysteine
      administration. However, removal of homocysteine did not decrease the MMP-2
      activity. The cardiac active diastolic function, -dP/dt, was decreased at 4 weeks
      and stayed depressed up to 12 weeks. The end-diastolic pressure started
      increasing at 8 weeks; at this point the MMP-2 activity was also increased. The
      results suggest that in the absence of endothelial NO, and in an attempt to
      reduce LV load, MMP-2 is activated and CIMP is inactivated, by increasing
      nitrotyrosine.

PMID- 12470509
TI  - Redox signaling of angiogenesis.
AB  - Reactive oxygen species (ROS) play a crucial role in vascular angiogenesis. Both
      in vitro and in vivo studies indicate that angiogenic response in vascular tissue
      is triggered by ROS signaling in a highly coordinated manner. It appears that
      massive amounts of ROS produced during ischemia and reperfusion in the vascular
      tissue, especially in heart, cause significant injury to the cardiomyocyte and
      endothelial cells. However, during the reperfusion, the same ROS potentiates a
      repair process and triggers a signal transduction cascade leading to
      angiogenesis. Although several other factors are likely to be involved for such
      angiogenic response, ROS certainly plays a crucial role as evident from its
      direct role as mediator of angiogenesis and inhibition of angiogenesis with free
      radical scavengers and/or antioxidants. Angiogenesis is regulated by redox
      sensing transcription factors such as nuclear factor-kappaB, and oxidants such as
      hydrogen peroxide and free radicals, such as nitric oxide may function as second
      messengers in this highly coordinated process. Furthermore, expression of many
      angiogenic genes including those for vascular endothelial growth factor,
      fibroblast growth factor, platelet-derived growth factor, and receptors such as
      Flt-1, Flk-1, Ang-1, and Ang-2 are likely to be regulated by redox signaling. It
      is tempting to speculate that the angiogenic response is under the autocrine
      and/or paracrine control of one or more cytokines, which in turn is redox
      regulated. Through angiogenesis, ROS appear to pave the way of repairing the
      vascular tissues that have been damaged during ischemia and reperfusion.

PMID- 12470510
TI  - Constitutive and inducible nitric oxide synthase: role in angiogenesis.
AB  - Since the initial report of nitric oxide (NO) activity, enormous progress has
      been made over the last two decades in the field of NO research. Whereas most
      physiological responses triggered by moderate concentrations of NO are mediated
      by soluble guanylate cyclase activation and the subsequent production of cyclic
      GMP as the major signaling messenger, recent studies have provided evidence of
      alternative signaling pathways triggered by high concentrations of NO. These
      signals operate in part through redox-sensitive regulation of transcription
      factors, gene expression, transcription, cellular activation, proliferation, and
      cell death. Numerous results converge to indicate a role for NO in physiological
      and pathological angiogenesis. Experimental data indicate that NO synthase,
      depending on the isoforms, the timing, and the degree of activation, may display
      contradictory effects, expressed during both physiological and pathological
      angiogenesis. The dual personality of NO will be reviewed in the context of the
      angiogenesis process.

PMID- 12470511
TI  - Nitric oxide and angiogenesis in cardiovascular disease.
AB  - Ischemic heart disease and peripheral artery disease mainly develop as a
      consequence of atherosclerotic lesion formation. Angiogenesis, the formation of
      new blood vessels from the preexisting vascular bed, is of paramount importance
      in the maintenance of vascular integrity both in the repair process of damaged
      tissue (wound healing) and in the formation of collateral vessels in response to
      tissue ischemia. Angiogenesis is a complex process that is orchestrated by a
      multitude of cytokines/chemokines and growth factors. In its broadest sense,
      angiogenesis cannot be viewed as a single process. It is likely that different
      mediators are involved in different phases of angiogenesis. Vascular endothelial
      cells produce nitric oxide (NO), an endothelium-derived labile molecule, which
      maintains vascular homeostasis and thereby prevents vascular atherosclerotic
      changes. In patients with ischemic heart disease and peripheral artery disease,
      the release of endothelium-derived NO is decreased, which plays an important role
      in the atherosclerotic disease progression. In recent years, endothelium-derived
      NO has been shown to modulate angiogenesis in vitro and in vivo. In this review,
      we summarize recent progress in the field of the NO-mediated regulation of
      postnatal angiogenesis.

PMID- 12470512
TI  - Angiogenesis and pulmonary hypertension: a unique process in a unique disease.
AB  - Severe pulmonary hypertension is a fatal condition associated with marked
      alterations of the cellular components of pulmonary arteries. In this review, we
      discuss the component of endothelial cell proliferation present in pulmonary
      arteries in patients with severe pulmonary hypertension. Because these
      proliferated endothelial cells exhibit markers of angiogenesis, we have named
      this process as "disordered or misguided angiogenesis." We also discuss the
      recent evidence that germline or somatic inactivating mutations in tumor
      suppressor or proapoptotic genes may play a significant role in the abnormal
      proliferation of pulmonary endothelial cells. The unraveling of the pathobiology
      of severe pulmonary hypertension may lead us to novel therapies and approaches to
      better diagnose the disease.

PMID- 12470513
TI  - Mechanism of hydrogen peroxide-induced cell cycle arrest in vascular smooth
      muscle.
AB  - Reactive oxygen species such as hydrogen peroxide (H(2)O(2)) can positively and
      negatively modulate vascular smooth muscle cell (VSMC) growth. To investigate
      these paradoxical effects of H(2)O(2), we examined its effect on apoptosis, cell
      cycle progression, and cell cycle proteins. High concentrations of H(2)O(2) (500
      microM to 1 mM) induced apoptosis, whereas moderate concentrations (100 microM)
      caused cell cycle arrest in G1. H(2)O(2) (100 microM) blocked serum-stimulated
      cyclin-dependent kinase-2 (CDK2) activity, but not CDK4 activity, suggesting that
      cell cycle arrest occurred in part by inhibiting CDK2 activity. The serum-induced
      increase in cyclin A mRNA was also completely suppressed by H(2)O(2), whereas
      cyclin D1 mRNA was not affected. In addition, H(2)O(2) caused a dramatic increase
      in expression of the cell cycle inhibitor p21 mRNA (9.67 +/- 0.94-fold at 2 h)
      and protein (8.75 +/- 0.08-fold at 8 h), but no change in p27 protein. Finally,
      H(2)O(2 )transiently increased p53 protein levels (3.16 +/- 1.2-fold at 2 h).
      Thus, whereas high levels of H(2)O(2) induce apoptosis, moderate concentrations
      of H(2)O(2) coordinate a set of molecular events leading to arrest of VSMCs at
      the G1/S checkpoint of the cell cycle. These results provide insight into the
      mechanisms underlying positive and negative regulation of VSMC growth by H(2)O(2)
      in vascular disease.

PMID- 12470514
TI  - Quantification of oxidative/nitrosative modification of CYS(34) in human serum
      albumin using a fluorescence-based SDS-PAGE assay.
AB  - The SH group represented by cysteine in proteins is fundamental to the redox
      regulation of protein structure and function. Albumin is the most abundant serum
      protein whose redox modification modulates its physiologic function, as well as
      serves as a biomarker of oxidative stress. Measurement of selective Cys
      modification (S-oxidation/nitrosation, electrophilic substitution) on specific
      proteins, however, is problematic within complex biological mixtures such as
      plasma. We have utilized a maleimide fluorogenic SH reagent, ThioGlo-1, to
      develop a fluorescence-based quantitative assay of SH modification of human serum
      albumin (hSA) using SDS-PAGE. Fully reduced native albumin containing one free SH
      (Cys(34)) per molecule was utilized as a model protein to characterize the
      kinetics of ThioGlo-1 reaction using a solution-based spectrofluorometric assay.
      Optimum labeling of hSA Cys(34) was achieved within 10 min at 60 degrees C using
      a threefold molar excess of ThioGlo-1 relative to hSA and required SDS.
      Comparison of the solution spectrofluorometric assay to fluorescent image
      analysis of hSA bands localized by SDS-PAGE revealed that SH groups in hSA could
      be quantified after gel electrophoresis. The solution- and gel-based methods were
      in excellent concordance in their ability to quantify SH modification of hSA
      following exposure to phenoxyl radicals and nitric oxide. The application of
      ThioGlo-1 staining and SDS-PAGE quantified the degree of hSA modification in
      complex human plasma exposed to oxidative or nitrosative stress and revealed that
      hSA is more sensitive to S modification than other SH-containing plasma proteins.

PMID- 12470515
TI  - Abstracts of COSMOderm2/LASERderm1. August 31-September 3, 2002. Trieste, Italy.

PMID- 12470516
TI  - Cervicoplasty and facial laser resurfacing: a paired technique for facial
      rejuvenation.
AB  - OBJECTIVE: A specific group of patients interested in facial rejuvenation was
      identified in a plastic surgery practice. These patients were primarily concerned
      with improving their neck contour and correcting their facial rhytides. To
      address those problems a one-stage paired technique was designed - cervicoplasty
      with full-face laser resurfacing. MATERIALS AND METHODS: Thirteen patients were
      treated with this procedure during a 1 year period. RESULTS: The patients
      experienced no significant complications and were extremely satisfied with their
      results. A retrospective study of 206 patients over the same year period revealed
      that the group undergoing the combination procedure: 1) was identifiable by the
      ranking of their specific aesthetic concerns; 2) was averse to undergoing a full
      facelift; and 3) comprised a significant percentage (22%) of surgical patients in
      the study period. CONCLUSIONS: Combining cervicoplasty with full-face laser
      resurfacing is a safe, effective procedure that provides another option in the
      realm of facial rejuvenation.

PMID- 12470517
TI  - Dermal collagen production following irradiation by dye laser and broadband light
      source.
AB  - BACKGROUND: Improvement in the appearance of wrinkles has been observed following
      exposure to short-pulsed 585 nm laser light. The assumed effect is a specific
      absorption of light in the blood vessels of the superficial dermis, resulting in
      release of inflammatory mediators into the interstitium followed by stimulated
      fibroblast activity. The fibroblasts effectively initiate tissue repair
      mechanisms, which include enhanced new collagen production. METHODS: Quantitative
      measures of collagen synthesis rate in the skin can be obtained from
      determinations of the aminoterminal propeptide of type III procollagen level in
      suction blister fluid using a radioimmunoassay. RESULTS: A single laser treatment
      at subpurpura energy level showed that the 585 nm laser source induced an
      increase of 84% (p < 0.05) in the type III procollagen production rate compared
      with a non-treated control site. A broadband, pulsed, white light source at 4
      J/cm(2) showed no measurable increase, whilst the skin area treated with 7
      J/cm(2) increased the procollagen production rate by 17% (NS, p > 0.05). A second
      treatment 2 weeks later further improved the laser-induced increase in
      procollagen production rate to 148% (p < 0.05) compared with the control site.
      The broadband, pulsed, white light-irradiated skin sites showed that at 4 J/cm(2)
      the procollagen production rate was increased by 21.4% and at 7 J/cm(2) by 32.1%
      compared with the corresponding non-treated control site (NS, p > 0.05).
      CONCLUSIONS: Irradiation by the haemoglobin-specific short-pulsed 585 nm laser
      induced a fivefold increase in procollagen production rate compared with a
      biologically comparable fluence delivered in a broadband spectrum. An additional
      treatment after 2 weeks further increased the effect of the short-pulsed 585 nm
      laser to 148% of the control. Vascular-specific light/tissue interactions seem to
      play a key role in stimulating skin collagen production.

PMID- 12470518
TI  - Recurrent pilonidal sinus treated with epilation using a ruby laser.
AB  - BACKGROUND: Surgical treatment of pilonidal sinus disease of the natal cleft has
      a significant failure rate. Reported here is the case of a 33-year-old man who
      first presented at the age of 18 with a pilonidal sinus. METHOD: The patient's
      scar was treated with a ruby laser using a pulse length of 2 ms and energy
      densities of 6.0-7.2 J/cm(2). Treatment was performed five times at 6-week
      intervals. RESULT: The sinus healed and has not recurred to date, 6 months after
      the last treatment. CONCLUSION: It is felt that there may be a future for this
      treatment, either as primary treatment or as an adjunct to surgery in refractive
      cases. It could also be useful in preventing the growth of hairs into wounds that
      have been left open and allowed to granulate.

PMID- 12470519
TI  - Ethics of oocyte cryopreservation in Spain.

PMID- 12470520
TI  - Effect of FSH and its different isoforms on maturation of oocytes from pre
      ovulatory follicles.
AB  - FSH exists as a family of isohormones exhibiting distinct oligosaccharide
      structures, and the released FSH isoform mixtures change during the follicular
      phase of the menstrual cycle. In addition, the pulsatile release of
      gonadotrophins seems to expose follicles to bursts of more less-acidic FSH
      isoforms and the follicle is likely to be exposed to an almost ever changing
      composition of FSH isoforms. The different isoforms causes a number of different
      and divergent biological effects. FSH promotes oocyte maturation, and 5-10 IU/l
      of less-acidic FSH isoforms are sufficient to induce oocyte maturation in vitro.
      Exposure of cumulus-oocyte complexes to less-acidic FSH isoforms in a pulse-like
      fashion results in a rapid pattern of cAMP accumulation exceeding that seen with
      acidic isoforms, which appear to sustain lower but more constant cAMP production.
      The presence of particularly less-acidic isoforms for a period exceeding 30 min
      causes an attenuated cAMP response. In conclusion, it appears that pulsatile and
      intermittent release of less-acidic/short-living FSH isoforms is sufficient to
      induce biological responses, while allowing the granulosa cells to regain
      responsiveness to further FSH stimulation. Together with the interpulse release
      of more acidic isoforms, overall FSH secretion seems to ensure proper follicular
      maturation resulting in the release of developmentally competent oocytes.

PMID- 12470521
TI  - Intact follicle culture: what it can tell us about the roles of FSH glycoforms
      during follicle development.
AB  - An important limiting factor in assisted reproduction treatment success rates is
      oocyte quality. In spite of improved results through several important
      innovations, the pregnancy rate per collected oocyte remains far too low. In
      order to improve this situation, it is necessary to learn more about fundamental
      factors modulating follicular development patterns. FSH is known to be the
      driving force for follicle development, but it is not yet understood how its
      multifarious functions are controlled and modulated. Evidence is accumulating
      that FSH glycoforms may be the key to this mystery. Intact follicle culture is a
      useful tool for the clarification of the actions of the different isoforms
      because the follicle unit is maintained and allowed to develop through several
      critical stages. Additionally important is the availability of the oocyte for
      functional evaluation. Because of these features, relationships can be uncovered
      that are not revealed with single cell test systems. The results so far obtained
      with this system suggest that follicle development pattern and oocyte quality is
      strongly influenced by FSH glycoform range, and that the requirements of the
      follicle may shift during progress through different stages of development. More
      studies are required, but these findings already suggest that the physiological
      shifts of circulating FSH glycoforms may indeed be important, and that attention
      should be paid to the glycoform distribution of exogenously applied FSH.

PMID- 12470522
TI  - Role of transforming growth factor beta in ovarian surface epithelium biology and
      ovarian cancer.
AB  - Ovarian cancers arise out of the ovarian surface epithelium (OSE), which is the
      single layer of epithelial cells covering the ovary. These cells go through
      repeated cycles of proliferation with the growth and rupture of ovarian
      follicles. One growth factor involved in the regulation of OSE is transforming
      growth factor beta (TGFbeta). The different isoforms of TGFbeta (TGFbeta1,
      TGFbeta2 and TGFbeta3) and its receptor are all present in both OSE and the
      underlying ovarian surface stroma. The levels of the TGFbeta isoforms and
      receptors are regulated independently of each other in these different ovarian
      tissues. Observations suggest the existence of multiple autocrine/paracrine
      TGFbeta signalling loops. TGFbeta acts to inhibit proliferation of normal OSE and
      early stage ovarian carcinomas. Conversely, in later stage ovarian cancer the
      inhibitory actions of TGFbeta on epithelial proliferation have been overcome,
      while TGFbeta is able to promote malignant neoplastic behaviours. The regulation
      of TGFbeta signalling by ovarian steroid hormones may be one mechanism by which
      the OSE responds to cyclic changes in the underlying follicles.

PMID- 12470523
TI  - New developments in gonadotrophin pharmacology.
AB  - This article reviews the past, present, and future of gonadotrophin therapy,
      including purification of gonadotrophins from animal or human urine sources and
      production of gonadotrophins through recombinant technology. With the advent of
      recombinant DNA methodologies combined with site-directed mutagenesis, a variety
      of structural modifications becomes possible.

PMID- 12470524
TI  - Impact of urinary FSH price: a cost-effectiveness analysis of recombinant and
      urinary FSH in assisted reproduction techniques in the USA.
AB  - This study compares the cost-effectiveness of recombinant human FSH (r(h)FSH,
      Gonal-F) and urinary FSH (uFSH) in assisted reproduction techniques in the USA,
      using several hypothetical prices for uFSH. A specifically designed Markov model
      and Monte-Carlo simulation techniques were used to model the possible outcomes
      during three treatment cycles. Data included in the model were derived from
      randomized clinical trials and databases. An expert panel determined probability
      distributions for each decision point throughout each virtual treatment cycle.
      The assumed unit cost of r(h)FSH was $58.52 (based on the average retail cost)
      and three unit prices ($49, $45, $40) were used for uFSH. A total of 5000
      simulations was performed on a virtual cohort of 100,000 patients. The mean
      number of assisted reproduction treatment cycles/success (ongoing pregnancy at 12
      weeks) was 4.34 with r(h)FSH and 4.75 with uFSH. The total number of pregnancies
      achieved was 40,665 and 37,890, respectively. The mean cost per successful
      pregnancy with r(h)FSH was $40 688. For uFSH at unit costs of $40, $45 and $49,
      the mean costs per successful pregnancy were $43,500, $44,400 and $45,000,
      respectively (each P < 0.0001 versus r(h)FSH). Thus, despite its greater cost per
      unit dose, r(h)FSH is more cost-effective than uFSH over a wide range of uFSH
      prices, reflecting the greater clinical efficacy of r(h)FSH.

PMID- 12470525
TI  - Successful ICSI in a case of severe asthenozoospermia due to 93% non-specific
      axonemal alterations and 90% abnormal or absent mitochondrial sheaths.
AB  - The use of IVF and intracytoplasmic sperm injection (ICSI) to treat male
      infertility due to severe asthenozoospermia in cases of electron microscopically
      confirmed axonemal abnormalities has been reported. However, even with these
      sophisticated technologies, very few pregnancies and births have been achieved
      with ejaculated spermatozoa in infertility due to this condition. The existence
      of sperm-derived defects preclude normal embryo development, and another reason
      for low success rates may be that the most commonly used method for selecting
      viable spermatozoa for ICSI is sperm motility, which is absent in affected men.
      Consequently, the likelihood of selecting non-viable spermatozoa for ICSI is
      higher in these cases. This report describes a case of a pregnancy achieved by
      ICSI with ejaculated spermatozoa containing 93% non-specific axonemal alterations
      and 90% abnormal or absent mitochondrial sheaths. A total of 14 oocytes was
      obtained from the 31-year-old patient in her first IVF treatment cycle. Three of
      the 13 matured (metaphase II) oocytes were inseminated conventionally, and the
      other 10 metaphase II oocytes were submitted to ICSI. None of the oocytes
      inseminated conventionally were fertilized. Of the 10 oocytes submitted to ICSI,
      four zygotes and cleavage embryos resulted. Three embryos were transferred on day
      3, and a successful pregnancy was achieved. One gestational sac, together with
      regular heart activity, was recorded by ultrasonography at 8 weeks of gestation.
      A pregnancy is currently ongoing.

PMID- 12470526
TI  - Rescue IVF and coasting with the use of a GnRH antagonist after ovulation
      induction.
AB  - The major risks of exogenous gonadotrophin therapy for ovulation induction in a
      patient with polycystic ovaries (PCO) are multiple pregnancies and ovarian
      hyperstimulation syndrome (OHSS). This case report describes a 23-year-old
      patient, who was referred to the Centre for Reproductive Medicine in Brussels
      because of a high risk of developing OHSS and rising LH following ovulation
      induction with a low-dose step-up protocol using gonadotrophins. After
      counselling the patient, the decision was made to perform a rescue IVF cycle. The
      patient was first coasted with 0.25 mg ganirelix; the serum oestradiol
      concentrations decreased and the LH peak was successfully suppressed. No OHSS
      occurred. An ongoing twin pregnancy was achieved after the transfer of two
      embryos. This case report demonstrates the feasibility of coasting with LH
      releasing hormone (LHRH) antagonists (0.25 mg ganirelix) and the usefulness of
      the antagonists for ovulation induction cycles in patients who need rescue IVF.

PMID- 12470527
TI  - The origin of monozygotic twinning.
AB  - The incidence of monozygotic twinning appears to be increasing within the field
      of assisted human reproduction. Many theories have been put forward as to how and
      when this occurs. Whatever the cause, the normal events of embryo development,
      which necessarily involve axis formation, patterning and polarization, need to be
      adhered to in order to obtain a viable offspring. This paper describes the course
      of development in terms of axis formation and polarity and offers suggestions as
      to how either a disruption of this or duplication events in the course of the
      formation of these parameters could prevent or contribute to a twinning event.
      The likelihood of twinning occurring at any point is discussed in terms of the
      establishment of polarity and axes.

PMID- 12470528
TI  - Blastocyst culture: facts and fiction.
AB  - The use of sequential media has made extended culture and transfer of blastocysts
      feasible for human IVF. Embryo transfer on day 5 has been claimed to result in
      higher implantation rates than transfer on day 3, on the basis of retrospective
      comparative studies. This is not supported convincingly, however, in randomized
      controlled trials published to date. Blastocyst culture imposes additional
      requirements in terms of personnel, equipment, education and cost and is
      associated with a greater incidence of monozygotic twinning and cycle
      cancellation rate than in the case of day 3 culture. In order for day 5 transfer
      to replace day 3 transfer, a convincing comparison between the two methods should
      therefore demonstrate the superiority of blastocyst transfer. There is still a
      need for properly designed randomized controlled trials to compare day 3 with day
      5 transfer which will also address the effectiveness of a single blastocyst
      replacement in reducing the incidence of multiple pregnancies as well as the
      value of blastocyst cryopreservation.

PMID- 12470529
TI  - Current features of preimplantation genetic diagnosis.
AB  - More than 4000 preimplantation genetic diagnosis (PGD) cycles have been
      performed, suggesting that PGD may no longer be considered a research activity.
      The important present feature of PGD is its expansion to a variety of conditions,
      which have never been considered as an indication for prenatal diagnosis,
      including the late-onset disorders with genetic predisposition and
      preimplantation non-disease testing, with the further improvement of the accuracy
      of PGD for single gene disorders. PGD has also become a useful tool for the
      improvement of the effectiveness of IVF, through avoiding the transfer of
      chromosomally abnormal embryos, representing more than half of the embryos
      routinely transferred in IVF patients of advanced maternal age and other poor
      prognosis patients. PGD is of particular hope for the carriers of balanced
      chromosomal translocations, as it allows accurate pre-selection of a few balanced
      or normal embryos resulting from the extremely poor meiotic outcome, especially
      in reciprocal translocations. With the current progress in polymerase chain
      reaction- (PCR-) based detection of chromosomal abnormalities in oocytes and
      embryos, PGD may soon be performed for both chromosomal and single gene disorders
      using the same biopsied polar body or blastomere, frequently required with the
      currently expanded PGD application. The available clinical outcome data of more
      than 3000 PGD embryo transfers further suggest an acceptable pregnancy rate and
      safety of the procedure, as demonstrated by the follow-up information available
      for more than 500 children born from these PGD transfers.

PMID- 12470530
TI  - Nuclear transfer for full karyotyping and preimplantation diagnosis for
      translocations.
AB  - Preimplantation genetic diagnosis (PGD) for chromosomal disorders is currently
      performed by interphase fluorescence in-situ hybridization (FISH) analysis. This
      technique is known to have limitations for detecting some translocations and
      complete karyotyping, so visualization of chromosomes in single cells is required
      to improve the PGD accuracy for chromosomal disorders. To achieve this, single
      blastomeres were fused with enucleated or intact mouse zygotes, followed by
      fixing the resulting heterokaryons at the metaphase of the first cleavage
      division, or treating them with okadaic acid to induce premature chromosome
      condensation. This method allowed a significant improvement in the accuracy of
      testing both maternally- and paternally-derived translocations. In all, 437
      blastomeres were tested, achieving full karyotyping in as many as 383 (88%),
      making it possible to pre-select only normal embryos or those with balanced
      chromosomal complements for transfer. Overall, PGD for translocations was applied
      in 94 clinical cycles, resulting in 66 transfers and 20 (30.3%) clinical
      pregnancies, with healthy deliveries of 15 children. Fifty-two of these cycles
      were performed using a nuclear transfer (conversion) technique, which resulted in
      38 transfers of balanced or normal embryos, demonstrating that the technique is
      accurate and reliable for karyotyping single blastomeres for PGD of
      translocations.

PMID- 12470531
TI  - Impact of parental gonosomal mosaicism detected in peripheral blood on
      preimplantation embryos.
AB  - This study evaluated the chromosomal condition of embryos generated by patients
      with an altered karyotype due to gonosomal mosaicism and the clinical outcome
      after preimplantation genetic diagnosis (PGD) for aneuploidy. Thirty-six patients
      aged 34.6 +/- 3.6 years performed 54 treatment cycles and had 295 embryos
      diagnosed by fluorescence in-situ hybridization (FISH). Thirty-seven per cent of
      the embryos were chromosomally normal and generated 19 clinical pregnancies after
      replacement in 39 cycles. Only one pregnancy miscarried, yielding a take-home
      baby rate of 33.3%. Autosomal monosomy and trisomy contributed 36.1% of total
      abnormalities and gonosomal aneuploidy 5.9%, similar to the results detected in
      patients who undergo PGD for increased maternal age. Reanalysis was performed on
      114 non-transferrable embryos: 41 were found to be mosaics, which were grouped in
      three different types, chaotic mosaics (56%), aneuploid mosaics (29%) and
      diploid/haploid/polyploid mosaics (15%). The incidence of aneuploid mosaics was
      higher than expected compared with PGD patients of the same age and resembled the
      condition observed in patients of advanced maternal age. These findings suggest
      that constitutional carriers of sex chromosome mosaicism are predisposed to
      autosomal mosaicism of embryos, possibly due to errors of cell division. There is
      an indication that this tendency is higher in female than male carriers.

PMID- 12470532
TI  - Heterotopic triplet pregnancy: report and video of a case of a ruptured tubal
      implantation with living embryo concurrent with an intrauterine twin gestation.
AB  - This report presents a case of triplet heterotopic gestation after
      intracytoplasmic sperm injection (ICSI)-IVF treatment, with a left ruptured
      ectopic tubal implantation with a living embryo and successful outcome of the
      concurrent intrauterine twin gestation. A couple whose infertility was caused by
      oligoasthenozoospermia was referred for ICSI treatment. Three good quality
      embryos were transferred at the request of the patient. Early gestational control
      was performed by ultrasound at weeks 5 and 7 of gestation. The patient reported
      to the centre during week 7 with severe abdominal pain and with signs of
      peritoneal irritation. Transvaginal ultrasound revealed an extra-uterine ruptured
      implantantion. During the concomitantly performed laparoscopic procedure, a
      living embryo was observed after opening the extra-uterine embryonic sac.
      Heartbeat activity was present and lasted for 5 min after surgical resection of
      the tubal implantation. The patient was discharged from hospital without
      complications. The intrauterine twin gestation was not affected and two healthy
      infants were born at week 38 of gestation. Heterotopic pregnancy should be ruled
      out in patients submitted to IVF-embryo transfer, although no predisposing
      factors are present in some cases. Precise diagnosis may be delayed due to some
      important characteristics of the IVF-embryo transfer treatment. Nevertheless,
      this condition should be diagnosed by ultrasound before tubal rupture to avoid
      obvious complications. Laparoscopy remains the gold standard for diagnosis and
      treatment in these cases. The presentation of the heterotopic pregnancy was
      recorded on video and may be viewed on the internet at
      www.rbmonline.com/Article/710.

PMID- 12470533
TI  - Follow-up of children born after assisted reproductive technologies.
AB  - The course of pregnancies and the health of children born after assisted
      reproductive technologies are two of the most important outcome parameters of the
      quality of the techniques. There is an ongoing discussion as to whether these
      parameters may show poorer results as compared with spontaneous conception.
      Recent studies have shown increased risks for the pregnancy course following
      conventional IVF (e.g. premature birth, low birthweight), and a higher rate of
      major malformations after conventional IVF as well as after intracytoplasmic
      sperm injection. Molecular biological studies may support the idea that these
      risks are not related to the techniques used, but to parental background factors.
      Data from surrogate motherhood also demonstrate that here the risk is lower as
      compared with pregnancies from IVF mothers, who carry their own child to birth.
      Therefore, there are more infertility related problems than those related to
      technique. Finally, however, a risk related to the technique itself cannot be
      excluded completely by currently available data.

PMID- 12470534
TI  - Embryonic development and pregnancies following sequential culture in human tubal
      fluid and a modified simplex optimized medium containing amino acids.
AB  - Pregnancies following human blastocyst transfers were established using a protein
      supplemented modified potassium simplex optimized medium containing amino acids
      (KSOM(AA)). Zygotes were first cultured for 2 days in protein supplemented human
      tubal fluid medium. Resulting embryos (day 3) were subsequently cultured in
      protein supplemented KSOM(AA) until day 5 of development. Pregnancy and
      implantation rates were noted after culture and transfer of blastocysts following
      this culture scheme. The impact of conventional insemination, intracytoplasmic
      sperm injection (ICSI) and maternal age on developmental rates as well as
      pregnancy rates was also evaluated. Maternal age had a significant impact (P <
      0.05) on developmental rates of embryos until day 3 of culture. Overall, rate of
      blastocyst development for cultured day 3 embryos was 62%. Patients >39 years of
      age had lower (P < 0.05) rates of blastocyst development than patients in the
      younger subgroups. ICSI had no impact on developmental rates until day 3 of
      culture or rate of blastocyst development. Ongoing pregnancy and implantation
      rates following culture in KSOM(AA) were 51 and 37% respectively. These results
      indicate that KSOM(AA) supports high rate blastocyst development and resulting
      pregnancy rates.

PMID- 12470536
TI  - Proposed legislation for assisted reproduction technology clinics in India.

PMID- 12470535
TI  - Fundamentals of human embryonic growth in vitro and the selection of high-quality
      embryos for transfer.
AB  - Knowledge of the nature of embryo growth, and the handling and scoring of quality
      in human embryos are significant aspects for embryologists in IVF clinics. This
      review describes the formation, growth and maturation of human oocytes, many
      aspects of fertilization in vitro, embryonic transcription during preimplantation
      stages, and the formation of polarities, timing controls, role of mitochondria
      and functions of endocrine and paracrine systems. Modern concepts are fully
      discussed, together with their significance in the practice of IVF. This
      knowledge is essential for the correct clinical care of human embryos growing in
      vitro, especially in view of their uncharacteristic tendency to vary widely in
      implantation potential. Underlying causes of such variation have not been
      identified. Stringent tests must be enforced to ensure human embryos develop
      under optimal conditions, and are scored for quality using the most advanced
      techniques. Optimal methods of culture are described, including methods such as
      co-culture introduced to improve embryo quality but less important today.
      Detailed attention is given to quality as assessed from embryonic characteristics
      determined by timers, polarities, disturbed embryo growth and anomalous cell
      cycles. Methods for classification are described. Approaches to single embryo
      transfers are described, including the use of sequential media to produce high
      quality blastocysts. These approaches, and others involved in surgical methods to
      remove fragments, transfer ooplasm or utilize newer approaches such as
      preimplantation diagnosis of chromosomal complements in embryos are covered. New
      outlooks in this field are summarized.

PMID- 12470538
TI  - Regulation of therapeutic cloning in the UK.
AB  - The history and responsibilities of the British Human Fertilisation and
      Embryology Authority are described. Its establishment by law in 1990 and its
      duties of licensing clinics, issuing a Code of Practice, maintaining a Register
      of treatments, giving advice and licensing new treatments are traced. Although
      research on embryos was legalized in the UK in 1990, a change in the law was
      required in 2001 to permit therapeutic cloning and research on embryos for the
      purposes of seeking treatments for serious disease. The detailed process of
      licensing stem cell research is described, together with a description of new
      licences issued and the legal challenges to the new law and to the licences that
      have been issued by the Pro-Life Alliance. An account is given of the ban on
      reproductive cloning contained in the Human Reproductive Cloning Act 2001 and the
      findings of the House of Lords Select Committee on Stem Cell Research, 2002. It
      is concluded that the mechanisms exist in Britain to regulate stem cell research
      in an ethical fashion and to prohibit reproductive cloning by law.

PMID- 12470539
TI  - Use of GnRH antagonists in the treatment of endometriosis.
AB  - Endometriosis is an oestrogen-dependent disease that is treatable by oestrogen
      withdrawal, a therapy that has been effectively provided by the use of a
      gonadotrophin-releasing hormone (GnRH) agonist. Complete oestrogen withdrawal
      results in unacceptable side-effects, in particular in accelerated bone density
      loss. This problem has been effectively overcome with 'add-back therapy' using
      low-dose oestrogens and progestins in combination with a GnRH agonist to limit
      these side-effects, while still allowing regression of endometriotic lesions. The
      aim of this study was to determine the feasibility of using a subcutaneous
      injection of GnRH antagonist in the treatment of endometriosis. All patients
      (15/15; 100%) reported a symptom-free period during GnRH antagonist treatment,
      including mood changes, hot flushes, loss of libido, vaginal dryness and other
      symptoms. Serum oestradiol oscillated around a mean concentration of 50 pg/ml
      during therapy. Diagnostic laparoscopy before GnRH antagonist administration
      showed a mean stage III of disease. Regression occurred in 60% of cases (9/15)
      and the degree of endometriosis declined to stage II. Sequential administration
      of the GnRH antagonist cetrorelix (Cetrotide) in a 3 mg dosage once weekly over 8
      weeks creates a new opportunity for medical treatment of symptomatic
      endometriosis. Preserving basic oestrogen production during the course of
      treatment apparently does not influence regression of disease, and has no major
      side-effects.

PMID- 12470540
TI  - High incidence of oligozoospermia and teratozoospermia in human semen infected
      with the aerobic bacterium Streptococcus faecalis.
AB  - Bacterial culture of semen samples from 100 male partners in infertile couples
      revealed the presence of aerobic bacteria in 49 cases. Streptococcus faecalis
      (Enterococcus) was isolated from 53%, micrococci species from 20% and alpha
      haemolytic streptococci from 16% of the infected samples. The incidence of
      oligozoospermia and teratozoospermia was significantly (P < 0.05) higher in men
      whose semen samples contained S. faecalis than those whose semen samples
      contained micrococci or alpha-haemolytic streptococci or those that did not
      contain bacteria. The mean sperm concentration, as well as the mean percentage of
      morphologically normal spermatozoa, was significantly (P < 0.03) lower in semen
      infected with S. faecalis compared with that containing micrococci or alpha
      haemolytic streptococci and the uninfected samples. There is a high incidence of
      semen infection with S. faecalis, and it is associated with compromised semen
      quality in terms of sperm concentration and morphology. The presence of
      micrococci or alpha-haemolytic streptococci does not appear to have any
      detrimental effect on sperm quality.

PMID- 12470541
TI  - The Y chromosome.
AB  - The Y chromosome has evolved to provide sex determination in mammals. In
      association with its evolution, genes important for spermatogenesis have been
      sequestered on this chromosome. Further, X chromosome inactivation has developed
      as a mechanism to prevent over-expression of genetic factors important for
      somatic function in females, with maintenance of their activity in males. The
      multi-repeat organization of the Y chromosome and limited regions of crossover
      with other chromosomes predisposes it to internal recombination and loss of genes
      that may be important for spermatogenesis. Y chromosome microdeletion testing of
      infertile men with non-obstructive azoospermia provides prognostic information
      useful for management of these patients. In the presence of a complete deletion
      of the azoospermic factor a (AZFa) or AZFb regions, sperm retrieval is highly
      unlikely. Recent advances in our understanding of the organization and function
      of the Y chromosome are likely to enhance further the role of the Y chromosome in
      normal spermatogenesis and fertility.

PMID- 12470542
TI  - Ooplasmic transfer: animal models assist human studies.
AB  - Ooplasmic transplantation is based on the premise that ooplasmic components are
      compromised in some individuals. In theory, the transfer of small amounts of
      healthy ooplasm can correct such deficits, allowing for improved development and
      implantation. The technique is based on a well-established background of
      experimental embryology demonstrating that cytoplasmic manipulation in oocytes
      and early embryos can be entirely compatible with normal development. Cytoplasm
      has been manipulated via karyoplast and cytoplast transfer and by cytoplasmic
      injection. Term development has been obtained following such manipulations in a
      variety of mammalian species. While some manipulative scenarios have exhibited
      compromised development, others have exhibited improved development.
      Developmental problems involving specific epigenetic and mitochondrial
      incompatibilities have been observed in a very limited subset of animal studies.
      These studies are based on genetic and physical models that have little relation
      to the actual substance of ooplasmic transplantation in the human. In fact, the
      majority of animal studies suggest that ooplasmic transplantation is well-founded
      and unlikely to result in negative developmental consequences. Furthermore, there
      are considerable physical, physiological and developmental differences between
      human and rodent eggs and embryos. These differences suggest that potentially
      negative issues raised by rodent results may not be relevant in the human.

PMID- 12470543
TI  - Internalization of cellular fragments in a human embryo: time-lapse recordings.
AB  - An observation is reported of internalization of a cellular fragment into a
      blastomere from a human embryo, as documented by time-lapse photography. The
      fragment, created during the first mitotic cleavage was reabsorbed into one of
      the mother blastomeres in less than 5 min. The time-lapse sequence, shown here as
      a series of still photographs, provides the first direct evidence that cellular
      fragments in human embryos can 'disappear' during the culture period, a
      phenomenon that is common in human IVF. The time-lapse sequence itself may be
      viewed on the internet at www.rbmonline.com/Article/633.

PMID- 12470544
TI  - Energy substrates, mitochondrial membrane potential and human preimplantation
      embryo division.
AB  - Carbohydrate additives to modern embryo culture media are based on three basic
      energy sources, glucose, pyruvate and lactate. Although the use of these
      substrates is almost universal, debate continues as to the roles of the
      individual components in the human. This is mainly due to the lack of human
      embryos for research and the reliance on animal model systems. In the present
      work, the human embryo was used to study the role of the above simple substrates
      in the maintenance of the mitochondrial membrane potential and cell division. The
      mitochondrial membrane potential was measured with fluorescence techniques. Cell
      division was scored as the number of blastomeres on day 3. Both the mitochondrial
      membrane potential and cell division were dramatically lost in the absence of
      energy sources. The mitochondrial membrane potential and cell division were
      normal in media containing all three energy sources, or in pyruvate-containing
      media. Both glucose and lactate individually proved poor energy sources for the
      maintenance of the mitochondrial membrane potential. However, cell division
      continued in the presence of glucose, suggesting that some energy production can
      continue. These data suggest that pyruvate is an absolute requirement for
      mitochondrial respiration and cell cleavage during human preimplantation
      development. The role of lactate is as yet unclear.

PMID- 12470545
TI  - Sex ratio: a biological perspective of 'Sex and the City'.
AB  - The primary sex ratio in humans differs remarkably from the theoretically
      expected equality of 1:1, and may be as high as 170 males to 100 females. A
      number of environmental, physiological and genetic factors have been observed to
      impact on the primary sex ratio: sexual behaviour, variation in hormonal
      concentrations, natural disasters, environmental pollutants and timing of
      conception. Nevertheless, no biological mechanism or interaction of factors has
      suitably explained this phenomenon, or that of the prenatal vulnerability of the
      male, the suspected higher sex ratio in spontaneous abortion and the male
      excesses in adult diseases related to the intrauterine environment. Knowledge of
      the environmental effects and causes of natural variation in the primary sex
      ratio will make possible its manipulation, which will have public health
      implications as well as cultural and social consequences.

PMID- 12470546
TI  - Pregnancy following a difficult transfer: a case report.
AB  - Traumatic embryo transfers impact negatively on pregnancy rates. This study
      reports a clinical pregnancy obtained by transferring a blastocyst developed from
      a 72-h embryo, which had been retained on the catheter in a difficult transfer. A
      total of five oocytes was obtained from the 32-year-old patient in her first IVF
      treatment. Only one zygote and cleavage embryo resulted. A traumatic and bloody
      transfer was performed on day 3. The unique embryo was retained on the catheter.
      The embryo was left in culture medium until the blastocyst stage was achieved. A
      second transfer was performed and a successful pregnancy was achieved after
      transferring this blastocyst. A healthy baby was born. The results of the present
      report suggest that in cases of difficult transfers, waiting for the blastocyst
      stage might allow a second, non-traumatic transfer to be performed without
      embryos and cervix under the effects of stress.

PMID- 12470547
TI  - The use of primates as models for assisted reproduction.
AB  - Evidence from donated human oocytes and embryos demonstrates that the
      spermatozoon contributes the 'centrosome', which is critical to fertilization,
      and that some cases of infertility in couples are related to defects in the
      pathways that reconstitute the zygotic centrosome. A greater understanding of
      these microtubule-mediated motility events that ensure normal sperm-oocyte
      interactions has been made easier by the use of non-human primate gametes. Our
      studies using rhesus monkey gametes have shown that the cytoskeletal events
      during fertilization by IVF and intracytoplasmic sperm injection (ICSI) are very
      similar to those of human fertilization, and that manipulations of non-human
      primate gametes may help to test the safety and improve current strategies for
      reproduction, as well as develop new techniques. ICSI results in abnormal nuclear
      remodelling, in part due to the persistence of VAMP (vesicle-associated membrane
      protein), the acrosome and the perinuclear theca on the sperm head, all of which
      are normally removed at, or close to, the oocyte cortex during natural and in
      vitro fertilization. Progression through the first cell cycle in ICSI oocytes
      cannot be completed until these structures have been removed from the forming
      male pronucleus, demonstrating unique differences between ICSI and IVF. While
      ICSI is of enormous therapeutic value for the treatment of male infertility,
      fundamental research using clinically relevant animal models is only now
      unravelling the cellular and molecular events that permit fertilization by sperm
      microinjection.

PMID- 12470548
TI  - Human blastocysts from aggregated mononucleated cells of two or more non-viable
      zygote-derived embryos.
AB  - This study examined the developmental capacity of aggregates of surviving mono
      nucleated cells isolated from several non-viable human embryos on day 3 or day 4
      after fertilization. The results clearly demonstrate that some blastomeres from
      non-viable embryos do indeed maintain their developmental potential and
      regulatory capacity to the extent of being able to contribute to a normally
      organized blastocyst, with as many as 90% diploid cells. Although the chimaeric
      nature of such blastocysts excludes them from use in therapeutic IVF, they are of
      particular relevance to the discussion of embryonic and trophectodermal stem cell
      line production.

PMID- 12470549
TI  - Resumption of fertility with diet in overweight women.
AB  - In young women being overweight appears to be one of the major and still
      neglected causes of subfertility. Not only the excessive amount but also the
      distribution of body fat is clearly related to loss of fertility. The mechanism
      through which obesity impairs ovulation and fertility is largely unknown, but it
      is well known that being overweight lowers the concentration of sex hormone
      binding globulin and increases androgen and insulin secretion and insulin
      resistance. These high concentrations of androgen and insulin in turn are
      important factors in the preferential abnormal localization of body fat. In
      addition, ovulation induction or ovarian stimulation in overweight women is a not
      easy task, since these patients are often unresponsive to the stimulatory drugs
      and, in addition, have a higher rate of miscarriages. Weight reduction improves
      these patients' biochemical indices and fertility rates. The spontaneous
      pregnancy rate can be expected to be around 30%, but an additional 40-50% drug
      induced pregnancy rate can be achieved with a 10-15% weight loss. Drugs
      increasing insulin sensitivity also improve spontaneous ovulation and fertility
      in obese women but still need to be tested in larger controlled trials. In
      conclusion, appropriate counselling about weight reduction through diets and
      exercise can restore both health and fertility, avoiding much frustration, and
      saving time and money.

PMID- 12470550
TI  - The treatment of infertility and its historical context.
AB  - The objective of this review is to analyse and integrate into a semi-historical
      background the alternative treatments available for the alleviation of
      infertility. Data are presented on their causes and success, using compilations
      of data reported in the literature along with personal experience. Results are
      expressed as the outcome of endocrinological and surgical treatments for female
      and male infertility. Clinical pregnancy and delivery rates are reported as the
      measurements of effectiveness of in-vitro fertilization and related techniques.
      Detailed analysis of the most important considerations with respect to a number
      of infertility treatment options are provided, and show how the treatment of
      choice will always depend on the specific context and needs of each patient. New
      technologies are described briefly, and an ethical comment completes the review.

PMID- 12470551
TI  - Pregnancy and birth after assisted reproduction.
AB  - Pregnancy and birth after IVF has attracted much critical attention. Overall,
      pregnancy rates are about 30-40% with three transferred embryos. Abortion rates
      are high before 19 weeks of gestation, at 8% of established pregnancies, and
      ectopic pregnancies are regular occurrences. Pregnancy rates are highest (35%) in
      women aged 20-24 years, declining to 10% at and above age 40. The use of
      intracytoplasmic sperm injection (ICSI) and blastocyst transfer has transformed
      the establishment of pregnancies for couples with differing indications. High
      rates of implantation are achieved with blastocyst transfers, although many
      embryos die in vitro before this stage. Twins and triplets can result in up to
      50% of pregnancies. Heterotopic pregnancies are rare. Abortion afflicts fetuses
      before 12 weeks (vanishing fetuses). Rates of spontaneous abortion can be as high
      as 50% with quadruplets and quintuplets, and may be even higher in cases of fetal
      aneuploidy. At birth, prematurity is high, especially with twins or higher
      multiple pregnancies. Fetal reduction is used to reduce multiple pregnancies for
      singletons. Ovarian hyperstimulation is a risk associated with multiple
      pregnancy.

PMID- 12470552
TI  - New outlooks on IVF spermatozoa.

PMID- 12470553
TI  - FDA regulation of assisted reproductive technology in the USA.

PMID- 12470554
TI  - Side-effects of sublingual misoprostol and insemination terminate study.

PMID- 12470555
TI  - Uterine peristaltic activity during the menstrual cycle: characterization,
      regulation, function and dysfunction.
AB  - Unlike other smooth muscle organs, the uterine muscle was regarded to be normally
      functional for only a brief period, following a lengthy gestation. However,
      recently it has been shown that uterine peristalsis constitutes one of the
      fundamental functions of the non-pregnant uterus. Its morphological basis is the
      archimyometrium, which is the muscular component of the archimetra and which
      preserves a functional bipartition of the primarily unpaired uterus. Three types
      of uterine peristaltic contractions can be distinguished: cervico-fundal, fundo
      cervical and isthmical peristaltic activity, which changes during the menstrual
      cycle and is controlled by the dominant ovarian structure via the secretion of
      sex steroids systemically and into the utero-ovarian vascular countercurrent
      system. Uterine peristalsis of the non-pregnant uterus is actively involved in
      very early reproductive processes, such as rapid and sustained directed sperm
      transport and high fundal implantation, as well as serving retrograde
      menstruation for the preservation of body iron content. Furthermore, it became
      apparent that hyper- and dysfunctions of this contractile activity, such as hyper
      and dysperistalsis, might be causally involved in the development of pelvic
      endometriosis, uterine adenomyosis and infertility, as obtained from
      immunohistochemistry, vaginal sonography, hysterosalpingoscintigraphy and
      magnetic resonance imaging.

PMID- 12470558
TI  - Endoscopic visualization of oocyte release and oocyte retrieval in humans.
AB  - Transvaginal hydrolaparoscopy (THL) allows the inspection of the tubo-ovarian
      structures in their natural position without supplementary manipulation. Saline
      is used at 37 degrees C as distension medium, which keeps the organs afloat.
      Using this technique it was possible to visualize and record for the first time
      the process of oocyte release and capture by the fimbriae in humans. THL was
      performed in the peri-ovulatory period, in order to collect data that would give
      a better insight into events at the moment of ovulation.

PMID- 12470559
TI  - Implantation and immunology: maternal inflammatory and immune cellular responses
      to implantation and trophoblast invasion.
AB  - Implantation and placentation present an immune challenge because of the semi
      allogeneic nature of the conceptus. In this review, histological evidence for
      maternal immune cellular responses at the implantation site is summarized.
      Decidualization of the endometrium itself has features in common with an
      inflammatory response. During decidualization, infiltration by uterine natural
      killer (NK) cells occurs, and these interact with the non-polymorphic human
      leukocyte antigen (HLA) class I antigens expressed by invading extravillous
      trophoblasts. In humans, extension of trophoblast invasion beyond the decidual
      layer into the myometrium presents an additional challenge, which might be
      relevant for pregnancy complications such as pre-eclampsia. How far maternal
      cellular responses to invading trophoblasts seen at later stages of pregnancy can
      be traced back to the implantation period is an open question.

PMID- 12470560
TI  - Endometrial pinopodes: some more understanding on human implantation?
AB  - Endometrial receptivity is a prerequisite for blastocyst implantation. During
      receptivity, the hairy-like epithelial cell microvilli transiently fuse to a
      single flower-like membrane projection called the 'pinopode'. Scanning electron
      microscopy in sequential endometrial biopsies shows that pinopodes appear about 1
      week after ovulation, and they develop and regress within just 2 days.
      Interestingly, the cycle days when pinopodes appear can vary by up to 5 days
      between different individuals. On average, they occur on days 20-21 in natural
      cycles and earlier (days 19-20) in stimulated cycles. The abundance of pinopodes
      relates to implantation success and many patients with multiple implantation
      failures fail to produce pinopodes. Based on these findings, biopsies from
      candidate embryo recipients have been examined in mock cycles and pinopode
      numbers and timing of their appearance assessed. A similar cycle follows where
      embryos are replaced earlier or later, according to the reported timing of
      pinopode formation. If pinopodes are absent, the cycle can be modified.
      Accumulating evidence supports their clinical use as a marker to assess
      endometrial receptivity. Pinopode appearance, loss of steroid receptors and
      maximal expression of a(v)b(3) integrin, osteopontin and leukaemia inhibitory
      factor and receptor have been demonstrated in the same biopsy, showing a
      consistent association of pinopode appearance and other receptivity changes.

PMID- 12470561
TI  - Mechanisms of decidualization.
AB  - The uterus is composed of heterogeneous cell types that undergo cyclic
      synchronized waves of proliferation and differentiation in response to the rise
      and fall of ovarian oestrogen and progesterone. The spatial and temporal
      diversity in cellular responses to ovarian hormones within a given endometrial
      cell compartment is thought to be effected by locally released factors. These
      endometrial polypeptides bind to specific cell surface receptors on target cells,
      resulting in activation of signal transduction pathways by way of coupling to GTP
      binding proteins (G proteins), or through autophosphorylation in response to
      conformational changes induced by the binding of ligand. Within this paradigm,
      the highly complex and coordinated expression of decidua-specific genes by
      differentiating endometrial stroma cells during the late secretory phase of the
      menstrual cycle could be regarded as the result of the convergence of liganded
      steroid hormone receptors and specific activated cytoplasmatic signalling
      pathways.

PMID- 12470562
TI  - The role of preimplantation diagnosis for aneuploidies.
AB  - The clinical application of preimplantation genetic diagnosis (PGD) for
      aneuploidy has confirmed the hypothesis that implantation failure and spontaneous
      abortions are frequently due to aneuploidy. Following PGD, a higher implantation
      rate and a lower incidence of spontaneous abortions are obtained in patient
      categories where aneuploidy is the main cause of reproductive failure: women in
      advanced reproductive age, patients with an altered karyotype due to
      translocations or gonosomal mosaicism, and patients with recurrent spontaneous
      abortions. In these cases, the transfer of euploid embryos overcomes the poor
      prognosis condition in these couples. As expected, aneuploidy increases
      proportionally with female age; however, not all the chromosomes studied show
      this trend, suggesting that segregation errors could occur at different rates for
      each chromosome in relation to maternal age. Furthermore, the retrospective
      analysis of the results obtained in patients who repeated at least twice a PGD
      cycle permitted to estimate their chances of reproducing the same pattern of
      chromosomal abnormalities and consequently evaluating their possibility of a
      pregnancy: when no euploid embryos are detected at the first attempt, the chance
      of on-term pregnancy is below 10%; however, this chance is approximately 30% for
      couples with at least two euploid embryos in the first cycle.

PMID- 12470563
TI  - How to treat hydrosalpinges: IVF as the treatment of choice.
AB  - Two treatment options are available for patients suffering from tubal infertility
      due to hydrosalpinges. Surgical distal tubal repair is appropriate only for
      patients with preserved tubal mucosa, otherwise the subsequent intrauterine
      pregnancy rate is unacceptably low and the ectopic pregnancy rate too high. The
      alternative treatment, IVF, has also demonstrated low success rate in patients
      with untreated hydrosalpinges, possibly due to leakage of fluid into the uterus.
      Salpingectomy has been suggested as a method to overcome the negative influence
      of the hydrosalpingeal fluid on implantation and embryo development. A randomized
      controlled trial in Scandinavia has demonstrated a benefit of salpingectomy in
      patients with hydrosalpinges that were large enough to be visible on ultrasound.
      If only the first cycle was considered, patients having undergone salpingectomy
      expressed significantly higher clinical pregnancy (46% versus 22%) and birth (40%
      versus 17%) rates. It is concluded that patients with large hydrosalpinges and
      without prospect of spontaneous conception should be recommended salpingectomy,
      which truly increases their chances of a successful IVF treatment.

PMID- 12470564
TI  - Minimally invasive exploration of the female reproductive tract in infertility.
AB  - Classically, invasive and non-invasive tests are performed to evaluate the causes
      of infertility. Transvaginal hydrolaparoscopy (THL) allows the exploration of the
      pelvic structures with a mini-endoscope, using a vaginal needle-guided trocar
      introduction technique and saline as a distension medium. A first study on 349
      patients demonstrated the feasibility of the procedure and gave a high patient
      satisfaction. Access to the pouch of Douglas was achieved in 330 patients (94.5%)
      under local anaesthesia and in an ambulatory environment. The mean pain score
      measured on a visual analogue scale of 10 was 2.7, comparable to the score of
      mini-hysteroscopy only and significantly lower than the scores of
      hysterosalpingography with either metal cannula or balloon catheter. A total of
      96% of the patients agreed to repeat the procedure under the same circumstances
      if required. The diagnostic accuracy of the technique was demonstrated in a
      prospective study, in which two independent endoscopists explored 10 patients
      with both THL and standard laparoscopy. The inter-observer agreement for ovarian
      adhesions was 75% for standard laparoscopy and 90% for THL. In addition, in
      patients with mild endometriosis, more peri-ovarian adhesions were detected with
      THL than with standard laparoscopy. A multinational survey to evaluate the risk
      and outcome of bowel injury during THL registered 24 (0.65%) cases in 3667
      procedures. In all cases, the diagnosis was made immediately and the treatment
      was conservative without complications.

PMID- 12470565
TI  - Hysteroscopic treatment of Asherman's syndrome.
AB  - Although Asherman's syndrome (the presence of adhesions inside the cervical canal
      or uterine cavity) is relatively uncommon in the general population, it can be
      the cause of menstrual irregularity and subfertility in high risk women. The
      diagnosis is usually confirmed by hysterosalpinography, and more recently by
      hysteroscopy. Hysteroscopy has also become accepted as the optimum route of
      surgery, the aims being to restore the size and shape of the uterine cavity,
      normal endometrial function and fertility. Treatment can range from simple
      cervical dilatation in the case of cervical stenosis but an intact uterine
      cavity, to extensive adhesiolysis of dense intrauterine adhesions using scissors
      or electro- or laser energy. Patients in whom the uterine fundus is completely
      obscured, and those with a greatly narrowed, fibrotic cavity present the greatest
      therapeutic challenge. Several techniques have described for these difficult
      cases, but outcome is far worse than in patients with mild, endometrial-type
      adhesions. Non-hysteroscopic techniques area also beginning to be developed, but
      whether they will replace the current 'gold' standard of hysteroscopy remains to
      be seen.

PMID- 12470566
TI  - The significance of hysteroscopic treatment of congenital uterine malformations.
AB  - Hysteroscopic surgery replaced abdominal metroplasty and is today the treatment
      of choice for congenital uterine malformations. This is not just because of its
      reproductive results, which are comparable to those achieved with the abdominal
      approach, but mainly because of several post-operative benefits (reduced
      morbidity, convalescence and costs, and no scar tissue on the abdominal and
      uterine walls), improved reproductive performance (no reduction in uterine
      volume, shorter interval to conception after operation) and the mode of delivery
      (avoiding Caesarean section). Decisions on when and how to treat uterine septa,
      in relation to the type of malformation, are discussed. In particular,
      indications for treatment have been broadened to include not only the septate
      uterus associated with adverse reproductive outcome, but also patients before any
      potential obstetric accidents, especially in those with declining fecundity (>35
      years), with reproductive problems (unexplained infertility) and before assisted
      reproductive techniques, as well as in women with no actual desire of pregnancy.
      Two types of hysteroscopic treatment are available: resectoscopic and office
      hysteroscopic surgery. The indications for resectoscopic surgery are broad-based
      septa and complete septa with single or double cervix. The resectoscope allows an
      excellent continuous flow system, providing continuous washing of the uterine
      cavity and a clear view, removing bubbles and debris during the procedure.
      However, an exact measurement of fluid balance must be performed to avoid
      excessive fluid intravasation. Laparoscopic or sonographic monitoring is
      mandatory. Treatment of limited-based small septa whose apex is easily visible
      can be achieved with an outpatient approach using office mini-hysteroscopic
      surgery and the vaginoscopic technique. The intra-operative check of the fundus
      is performed by ultrasonography. No preparation of the endometrium is required,
      except for large, broad-based septa, and hormonal therapy and intrauterine
      devices are not utilized post-operatively. The post-operative follow-up consists
      of a hysteroscopic check performed 1-3 months after surgery.

PMID- 12470567
TI  - The role of laparoscopic myomectomy in women of reproductive age.
AB  - Laparoscopic surgery has gained wide popularity for the treatment of uterine
      fibroids in women of reproductive age. The aim of this study is to evaluate the
      safety of the present surgical technique in order to preserve fertility and to
      achieve a satisfactory uterine repair so as to obtain an uncomplicated, full-term
      pregnancy. Between March 1988 and April 2001, 1170 uterine myomata were
      laparoscopically removed in 635 patients. The number of myomata removed from each
      patient varied from one to nine. The main steps of the surgical technique are
      described. No serious complication occurred. All the myomata proved to be benign.
      A second look was performed in 121 patients, and in two cases adhesions were
      found. A total of 105 patients achieved pregnancy (one triplet and three twin)
      and 91 delivered. No uterine rupture or scar dehiscence was observed. Out of 148
      patients who were infertile with one or more myomata larger than 30 mm, 74
      achieved pregnancy, 63 spontaneously and 11 after IVF.

PMID- 12470568
TI  - Reproductive disorders affecting fertility in endometriosis.
AB  - The classical concept of endometriosis as a cause of infertility is challenged.
      Traditionally, both surgical and medical therapy of endometriosis-associated
      infertility has focused on eliminating or reducing the visible implants. The
      classic 6-month medical approach has been a failure, and surgery may moderately
      enhance fertility, but its benefit in the absence of adhesions is still doubtful.
      Recent studies have shown that endometriosis is characterized by an aberrant
      response to sex steroid hormones, resulting in pleiotropic dysfunctions of the
      reproductive system involving the uterine, peritoneal and ovarian micro
      environment. Studies on endometriosis and IVF have been highly relevant in
      revealing the pleiotropic dysfunctions in patients with endometriosis, although
      the results should be interpreted with caution. The conclusion seems to support
      the view that infertility in patients with endometriosis is primarily
      dysfunctional, rather than lesional, in origin. It is concluded that the place of
      medical therapy in endometriosis should be reviewed and that the surgical
      approach needs to be complemented by appropriate medical therapy to restore
      fertility.

PMID- 12470569
TI  - The place of gonadotrophin-releasing hormone antagonists in reproductive
      medicine.
AB  - Gonadotrophin-releasing hormone (GnRH) antagonists have recently been introduced
      into clinical practice. They appear to offer a promising alternative to the long
      established GnRH agonist regimens for prevention of a premature LH surge during
      ovarian stimulation for assisted reproductive techniques. Clinical outcomes
      achieved with antagonists are comparable with those of a long GnRH agonist
      protocol, while treatment times and gonadotrophin requirements are reduced and
      safety is improved. In particular, the antagonists appear to be associated with a
      lower risk of ovarian hyperstimulation syndrome (OHSS) than do agonists. Patient
      surveys suggest a preference for antagonist over agonist treatment cycles. These
      benefits suggest that GnRH antagonists have the potential to replace agonists as
      the treatment of choice in ovarian stimulation for assisted reproductive
      techniques. Two agents, cetrorelix and ganirelix, are currently in clinical use.
      Cetrorelix is available in single- and multiple-dose formulations, offering
      increased flexibility compared with ganirelix.

PMID- 12470570
TI  - Experience with transvaginal hydrolaparoscopy for reconstructive tubo-ovarian
      surgery.
AB  - The transvaginal approach to tubo-ovarian surgery allows easy and direct access
      to the tubo-ovarian structures and the fossa ovarica without additional
      manipulation. In the absence of a panoramic view, the proximity of the tubo
      ovarian structures allows operative procedures for treatment of superficial and
      cystic ovarian endometriosis, drilling of the ovarian capsule, adhesiolysis and
      salpingostomy. Operative procedures were performed in 78 patients. No conversion
      to standard laparoscopy was necessary, and no complications occurred. All
      procedures were carried out on an ambulatory basis with a very low morbidity.

PMID- 12470571
TI  - Comment on the article discussing preimplantation genetic disorders for gender
      selection for family balancing in India by Malpani and Malpani.

PMID- 12470572
TI  - Pharmacokinetics and pharmacodynamics of recombinant human chorionic
      gonadotrophin in healthy male and female volunteers.
AB  - The pharmacokinetics and pharmacodynamics of recombinant human chorionic
      gonadotrophin (rHCG) were investigated in three studies of healthy volunteers.
      After single intravenous doses of 25, 250 and 1000 microg, rHCG and urinary HCG
      (uHCG) showed linear pharmacokinetics described by a bi-exponential model,
      although the area under the curve (AUC) for uHCG was ~29% lower than for rHCG.
      After intramuscular or subcutaneous administration (absolute bioavailability, 40
      50% for both), rHCG pharmacokinetics could be described by a first-order
      absorption, one-compartment model. During multiple subcutaneous dosing, the
      amount of HCG increased by approximately1.7-fold. A comparison of liquid and
      freeze-dried rHCG and freeze-dried uHCG showed pharmacokinetic bioequivalence. In
      down-regulated male subjects, single doses of 125 microg rHCG, given
      intravenously, intramuscularly or subcutaneously, produced comparable increases
      in serum testosterone, inhibin and 17beta-oestradiol, with little further
      increase during repeated subcutaneous administration (in female subjects, this
      produced a sustained comparable increase in serum androstenedione and
      testosterone concentrations). In conclusion, the pharmacokinetics and
      pharmacodynamics of rHCG are similar to those of uHCG and are not affected by the
      use of different formulations. In healthy subjects, rHCG produces pharmacodynamic
      responses consistent with HCG physiology and is suitable for use in the same
      clinical indications as uHCG. The secured source and high purity of rHCG may
      offer important advantages.

PMID- 12470573
TI  - Localization of species conserved zona pellucida antigens in mammalian ovaries.
AB  - The mammalian zona pellucida (ZP) consists of three glycoproteins (ZP1, ZP2 and
      ZP3), which are variably conserved among species at the genomic and amino acid
      levels. In order to evaluate the expression of ZP during ovarian development, a
      population of antibodies was selected that recognize species conserved antigenic
      domains of the three ZP proteins. Domain specific antibodies were selected from
      sera of rabbits immunized with all three native pig ZP proteins by elution of
      antibodies bound to each of the three human ZP recombinant proteins expressed
      from cDNAs, using the baculovirus expression system in insect cells. Immunoblot
      analysis was used to characterize the specificity of the antibodies and
      immunohistochemistry was used to evaluate the stage specific expression of ZP
      proteins during ovarian follicular development of the mouse, baboon and human.
      This study demonstrates that the conserved domains of all three ZP proteins are
      localized in the oocyte extracellular ZP matrix as well as in a subset of
      granulosa cells. However, this expression does vary among species with respect to
      the stage and cell type during early stages of ovarian follicular development.
      These antibodies should serve as excellent markers for evaluating early stages of
      human ovarian follicular development and in the development of contraceptive
      agents.

PMID- 12470574
TI  - Maturational and developmental competence of immature oocytes retrieved from
      bovine ovaries at different phases of folliculogenesis.
AB  - Immature oocytes recovered from bovine ovaries were studied to determine if their
      maturational and developmental competence is affected by phase of
      folliculogenesis. Ovaries (a total of 39 pairs) were collected from a local
      abattoir. Following examination, each pair of ovaries was assigned to one of
      three groups, according to follicle size and with or without a corpus luteum: (i)
      early phase (n = 13 pairs): all follicles were <or=8 mm in diameter; (ii) late
      phase (n = 13 pairs): the largest follicle was >or=15 mm in diameter; (iii)
      luteal phase (n = 13 pairs): all follicles were <or=8 mm in diameter and there
      was a corpus luteum on one of the ovaries. All follicles were aspirated and
      cumulus-oocytes complexes (COC) were cultured in 1.0 ml maturation medium, TC-199
      medium supplemented with 10% fetal bovine serum (FBS), 0.2 mmol pyruvate, and 75
      mIU/ml FSH and LH (Humegon) at 38.5 degrees C in a humidified atmosphere of 5%
      CO(2) and 95% air for 24 h. Following maturation in vitro, the oocytes were
      inseminated with frozen-thawed semen and cultured for further development in
      vitro. The mean number of oocytes retrieved from early phase ovaries was 32 +/-
      8.1 which was significantly higher (P < 0.05) than other phases (n = 20.1 +/- 5.4
      and 22.7 +/- 6.9). The numbers of degenerated oocytes from early, late and luteal
      phase ovaries were not different (n = 1.6 +/- 0.7, 1.8 +/- 0.5 and 1.5 +/- 0.5,
      respectively). The rates of oocyte maturation (84.4%, 89.2% and 83.6%) and
      fertilization (53.5%, 53.3% and 51.3%) were not significantly different across
      the three groups. In addition, there were no significant differences in the rates
      of cleavage (77.9%, 79.9% and 73.9%) and blastocyst formation (27.4%, 33.0% and
      30.4%) in the three groups. These results indicate that the maturational and
      developmental competence of immature oocytes is not affected by the phase of
      folliculogenesis.

PMID- 12470576
TI  - Circadian clockwork genes are expressed in the reproductive tract and conceptus
      of the early pregnant mouse.
AB  - Circadian genes are expressed in some peripheral tissues, but the expression
      status of the female reproductive tract and the conceptus over the
      preimplantation period is unknown. Oocytes, uterine, oviducal tissues and
      preimplantation conceptuses from days 1-4 of mouse pregnancy were analysed for
      transcript presence by reverse transcription polymerase chain reaction.
      Transcripts encoded by the seven known mammalian canonical circadian genes (Per1
      3, Cry1-2, Bmal1 and Clock), plus the mammalian genetic homologue of the
      Drosophila canonical gene Timeless, were detected in the uteri and oviducts taken
      from mice on days 1-4 of pregnancy and in unfertilized oocytes. After
      fertilization, transcripts for Per1, Cry1, Bmal1, Clock and Tim have been
      detected unambiguously. Transcript levels for each of these five genes fall at
      the two-cell stage, but are restored rapidly for Per1, Cry1 and Bmal1,
      presumptively by zygotic gene expression. In contrast, transcripts for Clock and
      Tim recover more slowly. It is concluded that circadian genes are expressed, and
      may therefore have a role, during the early development of the mammal.

PMID- 12470575
TI  - Genotyping: the HLA system and embryo development.
AB  - The human major histocompatibility complex (MHC), in addition to its role in the
      regulation of cell-cell interactions in the immune response, also influences
      reproductive success. Human leukocyte antigen-G (HLA-G) is an MHC class I gene of
      particular interest in reproductive biology because of its specific expression on
      fetal cytotrophoblast cells, and its reported involvement both in protection of
      the developing fetus from destruction by the maternal immune response and in the
      prevention of maternal pre-eclampsia. HLA-G has 15 known alleles at the DNA
      level, and allelic frequency varies among ethnic groups. This study describes the
      results of an inaugural attempt to correlate an HLA-G genetic polymorphism with
      pregnancy outcome in a patient population undergoing IVF. The study group was
      composed of 102 Caucasian women. A maternal HLA-G genetic polymorphism was
      investigated by polymerase chain reaction (PCR) analysis of DNA collected from
      granulosa cells surrounding oocytes harvested for the IVF procedure. While no
      statistically significant correlation was identified in this initial study,
      larger studies examining DNA from trios of mother, father and offspring are
      planned.

PMID- 12470577
TI  - Blastocyst development after vitrification of multipronuclear zygotes using the
      Flexipet denuding pipette.
AB  - The purpose of this study was to demonstrate the safety and efficacy of
      vitrification of human pronuclear stage (PN) embryos in the human assisted
      reproduction laboratory. Using single pronucleate (1PN) and three pronucleate
      (3PN) zygotes, the impact of vitrification in the Flexipet denuding pipette (FDP)
      as a carrier was assessed in terms of survival, embryonic development and
      blastocyst formation when compared according to the PN number, and unvitrified
      controls. A total of 65 1PN and 152 3PN zygotes were vitrified; after warming 82%
      (53/65) of 1PN and 90% (137/152) of 3PN survived. The overall percentage of
      warmed zygotes (1PN and 3PN) that cleaved and reached 2-cell stage did not differ
      (chi(2); P = 0.32) from the control groups (77%; 147/190 versus 85%; 115/136). In
      addition, when the cleavage behaviour was examined on day 3 for >or=4-cell stage,
      no significant differences (chi(2); P = 0.95) were observed between the vitrified
      group and the unvitrified control groups (74%; 109/147 versus 77%; 89/115).
      Comparing the developmental potential up to cavitation and blastocyst formation
      on day 5, the overall outcome of the vitrified PN was 31% compared with 33% for
      the controls (chi(2); P = 0.76). The simple vitrification protocol used in this
      study, and these data highlight the usefulness of vitrification using FDP as a
      consistent and effective cryopreservation method for pronuclear zygotes, and a
      suitable alternative to slow cryopreservation protocols.

PMID- 12470578
TI  - Cumulative pregnancy rate following IVF and intracytoplasmatic sperm injection
      with ejaculated and testicular spermatozoa.
AB  - The purpose of this study was to calculate the cumulative pregnancy rates of IVF
      cycles with ICSI using ejaculated or testicular spermatozoa. A computerized
      database for the IVF cycles with ICSI performed between January 1996 and December
      1998 was utilized. Cycles with spermatozoa obtained after electro-ejaculation
      were excluded. A multifactorial analysis was performed to define the impact of
      different factors on the success rate of IVF and ICSI. During a 36-month period,
      229 pregnancies were achieved by 643 couples using ejaculated spermatozoa, and 83
      pregnancies by 167 couples who required testicular spermatozoa. The pregnancy
      rates (PR) per cycle, including all treatment cycles with ejaculated spermatozoa,
      remained similar during the first five consecutive cycles achieving a cumulative
      PR of 80.44%. The cumulative pregnancy rates for cycles with testicular
      spermatozoa showed a consistent rise during four consecutive treatments and
      reached 61.84%. The regression analysis of pregnancy rate showed that it was
      significantly positively correlated with oocyte fertilization rate (P = 0.02),
      and negatively correlated with maternal age (P = 0.03). Thus, according to the
      present results, couples with infertility who require IVF with ICSI should be
      offered at least five consecutive attempts if ejaculated spermatozoa are used,
      and at least four cycles whenever testicular spermatozoa are used.

PMID- 12470579
TI  - Social sex selection by preimplantation genetic diagnosis.
AB  - A personal view is presented, exploring the issue of social sex selection by
      preimplantation genetic diagnosis from the dual perspectives of protecting the
      autonomy of the couple and the professional duty of care. It is concluded that
      sex selection by PGD is acceptable in certain circumstances.

PMID- 12470580
TI  - Physiology of gamete and embryo transport through the fallopian tube.
AB  - A great deal is now known about the migration of spermatozoa within the female
      reproductive tract, and how they interact with the oocyte and achieve
      fertilization in a variety of species. The process involves a series of complex
      features. It is a mixture of active and passive transport and active migration,
      with drastic jumps in the numbers of spermatozoa that migrate beyond specific
      physiological checkpoints, and with interactions occurring between spermatozoa,
      epithelium and luminal fluid. A reservoir of spermatozoa forms, at a discrete
      location, to hold and liberate spermatozoa in a gradual fashion. After
      fertilization has occurred, zygotes are passively transported to the uterus by a
      series of closely coordinated mechanical events where activities of cilia and
      smooth muscle predominate. Passage of the embryo from oviduct to uterus is
      regulated and timed by ovarian hormones, signals associated with mating, and
      zygotic substances. The diverse and exquisite patterns and regulatory signals
      typical of sperm migration and ovum transport across many species provide
      fascinating examples of adaptations according with differing reproductive
      strategies in various mammals.

PMID- 12470581
TI  - Mouse and bovine models for human IVF.
AB  - It is obvious that the first prerequisite is to define for what purpose a model
      is needed for humans. There are huge differences in reproductive physiology
      between the mouse, human and cow. As far as maturation is concerned, the
      plasticity of the mouse model is not the same in cows and humans. The final
      stages of oocyte maturation seem to be more finely regulated in cows and humans,
      where a minimum size of follicle is necessary to complete maturation in vitro.
      Bovine and human preimplantation embryos seem to be more similar in terms of
      biochemical and intrinsic paternal and maternal regulatory processes. Once again,
      interactions between the embryo and the corpus luteum are similar in cows and
      humans, but mouse and human embryo implantations are closer. Mouse oocytes and
      embryos should not be overlooked, but excessive generalization between mammalian
      species must be avoided.

PMID- 12470582
TI  - The role of maternal mitochondria during oogenesis, fertilization and
      embryogenesis.
AB  - This review examines the place of mitochondria in the life cycle through
      oogenesis, ovulation and early embryogenesis. Mitochondria are semi-autonomous
      organelles responsible for the bulk of oxidative energy production in the body.
      They play central roles in ageing, in apoptosis and in many non-Mendelian
      inherited bioenergetic and neurological diseases. Originating as free alpha
      proteobacteria that entered into a symbiotic relationship with the ancestral
      eukaryotic organisms, they now have a highly restricted genome of ~16 kb,
      encoding for 37 genes of the oxidative phosphorylation pathway. Mitochondria are
      inherited through the mother and special mechanisms have evolved to eliminate the
      contribution of the spermatozoon in early embryonic development. Most
      mitochondrial genes have become translocated to the nucleus, and nuclear and
      mitochondrial genes have co-evolved. This, coupled with a high mutation rate in
      the remaining mitochondrial DNA, has resulted in a high degree of concordance
      between them. Disharmony between nuclear and mitochondrial genes is thus likely
      to complicate cloning technology and the experimental reconstruction of chimeric
      embryos by cytoplasmic or nuclear transfer.

PMID- 12470583
TI  - Preimplantation genetic diagnosis of numerical and structural chromosome
      abnormalities.
AB  - The causes of the decline in implantation rates observed with increasing maternal
      age are still a matter for debate. Data from oocyte donation strongly suggest
      that in women of advanced reproductive age, the ability to become pregnant is
      largely unaffected while oocyte quality is compromised. The incidence of
      chromosomal abnormalities in embryos is considerably higher than that reported in
      spontaneous abortions, suggesting that a sizable percentage of chromosomally
      abnormal embryos are eliminated before any prenatal diagnosis. Such loss may
      partly account for the decline in implantation in older women. Because of the
      correlation between aneuploidy and reduced implantation, it has been postulated
      that selection of chromosomally normal embryos could reverse this trend.
      Preimplantation genetic diagnosis (PGD) for aneuploidy had three objectives
      relevant to the present paper: (i) to increase rates of implantation, (ii) to
      reduce risks of spontaneous abortion, and (iii) to avoid chromosomally abnormal
      births. Implantation rates did not increase when only five chromosomes were
      analysed in blastomeres. With eight chromosomes, a significant increase in
      implantation was achieved. PGD can significantly reduce the incidence of
      spontaneous abortion. In our clinic, a significant decrease in spontaneous
      abortions was found, from 23 to 11% after PGD. Currently in cases diagnosed at
      Saint Barnabas, 0.8% chromosomally abnormal conceptions have been observed after
      PGD versus an expected 3.2% in a control age-matched group. It seems clear that
      PGD reduces the possibility of trisomic conceptions under all conditions. If a
      couple's main interest is to improve their chances of conceiving (improve
      implantation), then one should consider maternal age and number of available
      embryos. Improvements in conception after PGD again increase after 37 years of
      age with eight or nine probes. Carriers of translocations are at a high risk of
      miscarriage or chromosomally unbalanced offspring, and a high proportion have
      secondary infertility. PGD of translocations has been approached through a
      variety of methods, here reviewed, and has resulted in a significant reduction in
      spontaneous abortions. However, implantation rates in translocation carriers are
      directly correlated with the proportion of normal gametes, and male patients with
      70% or more unbalanced spermatozoa have great difficulty in achieving pregnancy
      with PGD.

PMID- 12470584
TI  - A North European perspective in assisted reproduction-new legislation is coming
      in Finland and in Sweden.

PMID- 12470585
TI  - National Academy of Sciences report reaffirms human cloning for stem-cell therapy
      but condemns human cloning for reproductive purposes.

PMID- 12470586
TI  - Regulation of the immune system by NF-kappaB and IkappaB.
AB  - NF-kappaB/Rel transcription factor family participates in diverse biological
      processes including embryo development, hematopoiesis, immune regulation, as well
      as neuronal functions. In this review, the NF-kappaB/Rel signal transduction
      pathways and their important roles in the regulation of immune system will be
      discussed. NF-kappaB/Rel members execute distinct functions in multiple immune
      cell types via the regulation of target genes essential for cell proliferation,
      survival, effector functions, cell trafficking and communication, as well as the
      formation of lymphoid architecture. Consequently, proper activation of NF
      kappaB/Rel during immune responses to allergens, auto-antigens, allo-antigens,
      and pathogenic infection is crucial for the integrity of host innate and adaptive
      immunity.

PMID- 12470587
TI  - Effects of intraperitoneally administered lipoic acid, vitamin E, and linalool on
      the level of total lipid and fatty acids in guinea pig brain with oxidative
      stress induced by H2O2.
AB  - The aim of our study was to investigate the protective effects of
      intraperitoneally-administrated vitamin E, dlalpha lipoic acid, and linalool on
      the level of total lipid and fatty acid in guinea pig brains with oxidative
      stress that was induced by H2O2. The total brain lipid content in the H2O2 group
      decreased when compared to the H2O2 + vitamin E (p<0.05), H2O2+ linalool
      (p<0.05), ALA (p<0.05), control (p<0.01), linalool (p<0.01), and vitamin E
      (p<0.01) groups. While the proportion of total saturated fatty acid ( infinity
      SFA) in the H2O2 group significantly increased (p<0.005) when compared to the
      vitamin E group, it only slightly increased (p<0.01) when compared to the control
      and H2O2 + vitamin E groups. The ratio of the total unsaturated fatty acid
      (infinity USFA) in the H2O2 groups was lower (p<0.05) than the control, vitamin
      E, and H2O2+ vitamin E groups. The level of the total polyunsaturated fatty acid
      (infinity USFA) in the H2O2 group decreased in when compared to the control,
      vitamin E, and H2O2+vitamin E groups. While the proportion of the total w3 (omega
      3), w6 (omega 6), and PUFA were found to be lowest in the H2O2 group, they were
      slightly increased (p<0.05) in the lipoic acid group when compared to the control
      and H2O2 + lipoic acid groups. However, the level of infinity SFA in the H2O2
      group was highest; the level of infinity USFA in same group was lowest. As the
      proportion of infinity USFA and infinity PUFA were found to be highest in the
      linalool group, they were decreased in the H2O2 group when compared to the
      control group. Our results show that linalool has antioxidant properties, much
      the same as vitamin E and lipoic acid, to prevent lipid peroxidation.
      Additionally, vitamin E, lipoic acid, and linalool could lead to therapeutic
      approaches for limiting damage from oxidation reaction in unsaturated fatty
      acids, as well as for complementing existing therapy for the treatment of
      complications of oxidative damage.

PMID- 12470588
TI  - Identification and characterization of a putative baculoviral transcriptional
      factor IE-1 from Choristoneura fumiferana granulovirus.
AB  - A gene that encodes a protein homologue to baculoviral IE-1 was identified and
      sequenced in the genome of the Choristoneura fumiferana granulovirus (ChfuGV).
      The gene has an 1278 nucleotide (nt) open-reading frame (ORF) that encodes 426
      amino acids with an estimated molecular weight of 50.33 kDa. At the nucleotide
      level, several cis-acting regulatory elements were detected within the promoter
      region of the ie-1 gene of ChfuGV along with other studied granuloviruses (GVs).
      Two putative CCAAT elements were detected within the noncoding leader region of
      this gene; one was located on the opposite strand at -92 and the other at -420 nt
      from the putative start triplet. Two baculoviral late promoter motifs (TAAG) were
      also detected within the promoter region of the ie-1 gene of ChfuGV. A single
      polyadenylation signal, AATAAA, was located 18nt downstream of the putative
      translational stop codon of ie-1 from ChfuGV. At the protein level, the amino
      acid sequence data that was derived from the nucleotide sequence in ChfuGV IE-1
      was compared to those of the Cydia pomonella granulovirus (CpGV), Xestia c-nigrum
      granulovirus (XcGV) and Plutella xylostella granulovirus (PxGV). The C-terminal
      regions of the granuloviral IE-1 sequences appeared to be more conserved when
      compared to the N-terminal regions. A domain, similar to the basic helix-loop
      helix like (bHLH-like) domain in NPVs, was detected at the C-terminal region of
      IE-1 from ChfuGV (residues 387 to 414). A phylogenetic tree for baculoviral IE-1
      was constructed using a maximum parsimony analysis. A phylogenetic estimation
      demonstrates that ChfuGV IE-1 is most closely related to that of CpGV.

PMID- 12470589
TI  - Interaction of Heliothis armigera nuclear polyhedrosis viral capsid protein with
      its host actin.
AB  - In order to find the cellular interaction factors of the Heliothis armigera
      nuclear polyhedrosis virus capsid protein VP39, a Heliothis armigera cell cDNA
      library was constructed. Then VP39 was used as bait. The host actin gene was
      isolated from the cDNA library with the yeast two-hybrid system. This
      demonstrated that VP39 could interact with its host actin in yeast. In order to
      corroborate this interaction in vivo, the vp39 gene was fused with the green
      fluorescent protein gene in plasmid pEGFP39. The fusion protein was expressed in
      the Hz-AM1 cells under the control of the Autographa californica multiple
      nucleopolyhedrovirus immediate early gene promoter. The host actin was labeled
      specifically by the red fluorescence substance, tetramethy rhodamine
      isothicyanete-phalloidin. Observation under a fluorescence microscopy showed that
      VP39, which was indicated by green fluorescence, began to appear in the cells 6 h
      after being transfected with pEGFP39. Red actin cables were also formed in the
      cytoplasm at the same time. Actin was aggregated in the nucleus 9 h after the
      transfection. The green and red fluorescence always appeared in the same location
      of the cells, which demonstrated that VP39 could combine with the host actin.
      Such a combination would result in the actin skeleton rearrangement.

PMID- 12470590
TI  - New action pattern of a maltose-forming alpha-amylase from Streptomyces sp. and
      its possible application in bakery.
AB  - An a-Amylase (EC 3.2.1.1) was purified that catalyses the production of a high
      level of maltose from starch without the attendant production of glucose. The
      enzyme was produced extracellularly by thermophilic Streptomyces sp. that was
      isolated from Thailand's soil. Purification was achieved by alcohol
      precipitation, DEAE-Cellulose, and Gel filtration chromatographies. The purified
      enzyme exhibited maximum activity at pH 6-7 and 60 degrees C. It had a relative
      molecular mass of 45 kDa, as determined by SDS-PAGE. The hydrolysis products from
      starch had alpha-anomeric forms, as determined by 1H-NMR. This maltose-forming
      alpha-Amylase completely hydrolyzed the soluble starch to produce a high level of
      maltose, representing up to 90%. It hydrolyzed maltotetrose and maltotriose to
      primarily produce maltose (82% and 62% respectively) without the attendant
      production of glucose. The high maltose level as a final end-product from starch
      and maltooligosaccharides, and the unique action pattern of this enzyme, indicate
      an unusual maltose-forming system. After the addition of the enzyme in the bread
      baking process, the bread's volume increased and kept its softness longer than
      when the bread had no enzyme.

PMID- 12470591
TI  - Purification and characterization of a collagenase from the mackerel, Scomber
      japonicus.
AB  - Collagenase from the internal organs of a mackerel was purified using acetone
      precipitation, ion-exchange chromatography on a DEAE-Sephadex A-50, gel
      filtration chromatography on a Sephadex G-100, ion-exchange chromatography on
      DEAE-Sephacel, and gel filtration chromatography on a Sephadex G-75 column. The
      molecular mass of the purified enzyme was estimated to be 14.8 kDa by gel
      filtration and SDS-PAGE. The purification and yield were 39.5-fold and 0.1% when
      compared to those in the starting-crude extract. The optimum pH and temperature
      for the enzyme activity were around pH 7.5 and 55 degrees, respectively. The K(m)
      and V(max) of the enzyme for collagen Type I were approximately 1.1mM and 2,343
      U, respectively. The purified enzyme was strongly inhibited by Hg2+, Zn2+, PMSF,
      TLCK, and the soybean-trypsin inhibitor.

PMID- 12470592
TI  - Gamma irradiation-reduced IFN-gamma expression, STAT1 signals, and cell-mediated
      immunity.
AB  - The signal transducer and activator of transcription (STAT)1 is a cytoplasmic
      transcription factor that is phosphorylated by Janus kinases (Jak) in response to
      interferon gamma(IFN-gamma). The phosphorylated STAT1 translocates to the
      nucleus, where it turns on specific sets of IFN-gamma-inducible genes, such as
      the interferon regulatory factor (IRF)-1. We show here that gamma irradiation
      reduces the IFN-gamma mRNA expression. The inhibition of the STAT1
      phosphorylation and the IRF-1 expression by gamma irradiation was also observed.
      In contrast, the mRNA levels of IL-5 and transcription factor GATA-3 were
      slightly induced by gamma irradiation when compared to the non-irradiated sample.
      Furthermore, we detected the inhibition of cell-mediated immunity by gamma
      irradiation in the allogenic-mixed lymphocytes' reaction (MLR). These results
      postulate that gamma irradiation induces the polarized-Th2 response and
      interferes with STAT1 signals, thereby causing the immunosuppression of the Th1
      response.

PMID- 12470593
TI  - Effect of gamma-irradiation on the molecular properties of myoglobin.
AB  - To elucidate the effect of gamma-irradiation on the molecular properties of
      myoglobin, the secondary and tertiary structures, as well as the molecular weight
      size of the protein, were examined after irradiation at various irradiation
      doses. Gamma-irradiation of myoglobin solutions caused the disruption of the
      ordered structure of the protein molecules, as well as degradation, crosslinking,
      and aggregation of the polypeptide chains. A SDSPAGE study indicated that
      irradiation caused initial fragmentation of the proteins and subsequent
      aggregation, due to cross-linking of the protein molecules. The effect of
      irradiation on the protein was more significant at lower protein concentrations.
      Ascorbic acid protected against the degradation and aggregation of proteins by
      scavenging oxygen radicals that are produced by irradiation. A circular dichroism
      study showed that an increase of the irradiation decreased the alpha-helical
      content of myoglobin with a concurrent increase of the aperiodic structure
      content. Fluorescence spectroscopy indicated that irradiation increased the
      emission intensity that was excited at 280 nm.

PMID- 12470594
TI  - Identification and characterization of a conserved baculoviral structural protein
      ODVP-6E/ODV-E56 from Choristoneura fumiferana granulovirus.
AB  - A gene that encodes a homologue to baculoviral ODVP-6E/ODV-E56, a baculoviral
      envelope-associated viral structural protein, has been identified and sequenced
      on the genome of Choristoneura fumiferana granulovirus (ChfuGV). The ChfuGV odvp
      6e/odv-e56 gene was located on an 11-kb BamHI subgenomic fragment using different
      sets of degenerated primers, which were designed using the results of the protein
      sequencing of a major 39 kDa structural protein that is associated with the
      occlusion-derived virus (ODV). The gene has a 1062 nucleotide (nt) open-reading
      frame (ORF) that encodes a protein with 353 amino acids with a predicted
      molecular mass of 38.5 kDa. The amino acid sequence data that was derived from
      the nucleotide sequence in ChfuGV was compared to those of other baculoviruses.
      ChfuGV ODVP-6E/ODV-E56, along with other baculoviral ODVP-6E/ODV-E56 proteins,
      all contained two putative transmembrane domains at their C-terminus. Several
      putative N- and O-glycosylation, N-myristoylation, and phosphorylation sites were
      detected in the ChfuGV ODVP-6E/ODV-E56 protein. A similar pattern was detected
      when a hydrophobicity-plots comparison was performed on ChfuGV ODVP-6E/ODV-E56
      with other baculoviral homologue proteins. At the nucleotide level, a late
      promoter motif (GTAAG) was located at -14 nt upstream to the start codon of the
      ChfuGV odvp-6e/odv-e56 gene. A slight variant of the polyadenylation signal,
      AATAAT, was detected at the position +10 nt that is downstream from the
      termination signal. A phylogenetic tree for baculoviral ODVP-6E/ODV-E56 was
      constructed using a maximum parsimony analysis. The phylogenetic estimation
      demonstrated that ChfuGV ODVP-6E/ODV-E56 is most closely related to those of
      Cydia pomonella granulovirus (CpGV) and Plutella xylostella granulovirus (PxGV).

PMID- 12470595
TI  - RU486 suppresses progesterone-induced acrosome reaction in boar spermatozoa.
AB  - The effects of progesterone on the acrosome reaction, as well as the effects of
      RU486 on the progesterone-induced acrosome reaction in capacitated boar
      spermatozoa, were investigated. Progesterone, a major steroid that is secreted by
      the cumulus cells of oocyte, clearly induced the acrosome reaction in a dose
      dependent manner in capacitated boar spermatozoa, even though it failed to show
      similar effects in non-capacitated spermatozoa. RU486, a potent antiprogestin,
      significantly reduced the effects of progesterone on the progesterone-induced
      acrosome reaction; however, when treated alone, it showed no inhibitory effects
      on the acrosome reaction. The inhibitory effects of RU486 were also shown to be
      dose dependent. These results imply that in addition to the wellknown inducer of
      the acrosome reaction, zona pellucida, progesterone can also induce the acrosome
      reaction through its specific receptors on spermatozoa after the spermatozoa
      undergo capacitation.

PMID- 12470596
TI  - The anti-proliferative gene TIS21 is involved in osteoclast differentiation.
AB  - The remodeling process of bone is accompanied by complex changes in the
      expression levels of various genes. Several approaches have been employed to
      detect differentially-expressed genes in regard to osteoclast differentiation. In
      order to identify the genes that are involved in osteoclast differentiation, we
      used a cDNAarray-nylon membrane. Among 1,200 genes that showed a measurable
      signal, 19 genes were chosen for further study. Eleven genes were up-regulated;
      eight genes were downregulated. TIS21 was one of the up-regulated genes which
      were highly expressed in mature osteoclasts. To verify the cDNA microarray
      results, we carried out RT-PCR and real-time RT-PCR for the TIS21 gene. The TIS21
      mRNA level was higher in differentiated-osteoclasts when compared to
      undifferentiated bone-marrow macrophages. Furthermore, the treatment with 1 mM of
      a TIS21 antisense oligonucleotide reduced the formation of osteoclasts from the
      bone-marrow-precursor cells by approximately 30%. These results provide evidence
      for the potential role of TIS21 in the differentiation of osteoclasts

PMID- 12470597
TI  - Anticarcinogenic effect and modification of cytochrome P450 2E1 by dietary garlic
      powder in diethylnitrosamine-initiated rat hepatocarcinogenesis.
AB  - The purpose of this study was to determine the effects of dietary garlic powder
      on diethylnitrosamine (DEN)- induced hepatocarcinogenesis and cytochrome P450
      (CYP) enzymes in weaning male Sprague-Dawley rats by using the medium-term
      bioassay system of Ito et al. The rats were fed diets that contained 0, 0.5, 2.0
      or 5.0% garlic powder for 8 weeks, beginning the diets with the intraperitoneal
      (i.p.) injection of DEN. The areas of placental glutathione S-transferase (GST-P)
      positive foci, an effective marker for DEN-initiated lesions, were significantly
      decreased in the rats that were fed garlic powder diets; the numbers were
      significantly decreased only in the 2.0 and 5.0% garlic-powder diets. The p
      Nitrophenol hydroxylase (PNPH) activities and protein levels of CYP 2E1 in the
      hepatic microsomes of the rats that were fed the 2.0 and 5.0% garlic powder diet
      were much lower than those of the basal-diet groups. Pentoxyresorufin O
      dealkylase (PROD) activity and CYP 2B1 protein level were not influenced by the
      garlic-powder diets and carcinogen treatment. Therefore, the suppression of CYP
      2E1 by garlic in the diet might influence the formation of preneoplastic foci
      during hepatocarcinogenesis in rats that are initiated with DEN.

PMID- 12470598
TI  - Identification of DC21 as a novel target gene counter-regulated by IL-12 and IL
      4.
AB  - The Th1 vs. Th2 balance is critical for the maintenance of immune homeostasis.
      Therefore, the genes that are selectively-regulated by the Th1 and Th2 cytokines
      are likely to play an important role in the Th1 and Th2 immune responses. In
      order to search for and identify the novel target genes that are differentially
      regulated by the Th1/Th2 cytokines, the human PBMC mRNAs differentially expressed
      upon the stimulation with IL-4 or IL-12, were screened by employing the
      differential display polymerase chain reaction. Among a number of clones
      selected, DC21 was identified as a novel target gene that is regulated by IL-4
      and IL-12. The DC21 gene expression was up-regulated either by IL-4 or IL-12, yet
      counterregulated by co-treatment with IL-4 and IL-12. DC21 is a dendritic cell
      protein with an unknown function. The sequence analysis and conserved-domain
      search revealed that it has two AU-rich motifs in the 3'UTR, which is a target
      site for the regulation of mRNA stability by cytokines, and that it belongs to
      the N-acetyltransferase family. The induction of DC21 by IL-12 peaked around 8-12
      h, and lasted until 24 h. LY294002 and SB203580 significantly suppressed the IL
      12-induced DC21 gene expression, which implies that PI3K and p38/JNK are involved
      in the IL-12 signal transduction pathway that leads to the DC21 expression.
      Furthermore, tissue blot data indicated that DC21 is highly expressed in tissues
      with specialized-resident macrophages, such as the lung, liver, kidney, and
      placenta. Together, these data suggest a possible role for DC21 in the
      differentiation and maturation of dendritic cells regulated by IL-4 and IL-12.

PMID- 12470599
TI  - The Ring-H2 finger motif of CKBBP1/SAG is necessary for interaction with protein
      kinase CKII and optimal cell proliferation.
AB  - Protein kinase CKII (CKII) is required for progression through the cell division
      cycle. We recently reported that the beta subunit of protein kinase CKII
      (CKIIbeta) associates with CKBBP1 that contains the Ring-H2 finger motif in the
      yeast two-hybrid system. We demonstrate here that the Ring-H2 finger-disrupted
      mutant of CKBBP1 does not interact with purified CKIIbeta in vitro, which shows
      that the Ring-H2 finger motif is critical for direct interaction with CKIIbeta.
      The CKII holoenzyme is efficiently co-precipitated with the wild-type CKBBP1, but
      not with the Ring-H2 finger-disrupted CKBBP1, from whole cell extracts when
      epitope-tagged CKBBP1 is transiently expressed in HeLa cells. Disruption of the
      Ring-H2 finger motif does not affect the cellular localization of CKBBP1 in HeLa
      cells. The increased expression of either the wild-type CKBBP1 or Ring-H2 finger
      disrupted CKBBP1 does not modulate the protein or the activity levels of CKII in
      HeLa cells. However, the stable expression of Ring-H2 finger-disrupted CKBBP1 in
      HeLa cells suppresses cell proliferation and causes the accumulation of the G1/G0
      peak of the cell cycle. The Ring-H2 finger motif is required for maximal CKBBP1
      phosphorylation by CKII, suggesting that the stable binding of CKBBP1 to CKII is
      necessary for its efficient phosphorylation. Taken together, these results
      suggest that the complex formation of CKIIbeta with CKBBP1 and/or CKII-mediated
      CKBBP1 phosphorylation is important for the G1/S phase transition of the cell
      cycle.

PMID- 12470600
TI  - Identification of bacteriophage K11 genomic promoters for K11 RNA polymerase.
AB  - Only one natural promoter that interacts with bacteriophage K11 RNA polymerase
      has so far been identified. To identify more, in the present study restriction
      fragments of the phage genome were individually assayed for transcription
      activity in vitro. The K11 genome was digested with two 4-bp-recognizing
      restriction enzymes, and the fragments cloned in pUC119 were assayed with
      purified K11 RNA polymerase. Eight K11 promoterbearing fragments were isolated
      and sequenced. We report that the nine K11 promoter sequences (including the one
      previously identified) were highly homologous from -17 to +4, relative to the
      initiation site at +1. Interestingly, five had -10G and -8A, while the other four
      had -10A and -8C. The consensus sequences with the natural -10G/-8A and -10A/-8C,
      and their variants with -10G/-8C and -10A/-8A, showed nearly equal transcription
      activity, suggesting residues at -10 and -8 do not regulate promoter activity.
      Using hybridization methods, physical positions of the cloned promoter-bearing
      sequences were mapped on SalIand KpnI-restriction maps of the K11 genome. The
      flanking sequences of six cloned K11 promoters were found to be orthologous with
      T7 or T3 genomic sequences.

PMID- 12470602
TI  - Screening for neonatal herpes: physicians' descriptions of discussions with
      parents.
AB  - Screening for possible herpes simplex virus infection in neonates may raise
      feelings of anxiety and distress among parents and physicians. To elicit
      physicians' experiences of communicating with families when screening for
      neonatal herpes, we conducted a series of semi-structured interviews with 15
      physicians from one paediatric institution, and coded the resulting audiotapes
      for common themes. These included how physicians prepared families for screening
      and treatment, how physicians managed stigma, and perceived parental reactions.
      Techniques for fostering good communication included being direct and honest and
      ensuring the time and place for discussion were appropriate; strategies for
      managing stigma included placing the diagnosis in epidemiological context, and
      discussing the potential severity of the disease. Physicians described many
      parental emotional reactions, some of which were herpes-specific, and suggested
      strategies to manage potential discomfort when discussing neonatal herpes with
      families. Future research can determine which strategies are most effective,
      which are associated with negative psychological outcomes, and how medical
      students and residents can be better trained to screen for this diagnosis.

PMID- 12470603
TI  - Treatment of herpes simplex labialis.
AB  - Recurrent herpes simplex labialis is associated with mild morbidity, but remains
      a significant problem for people with frequent and/or severe recurrences. Both
      topical and peroral episodic antiviral treatments of recurrences are modestly
      effective at reducing the duration of signs and symptoms. Recent studies with
      high-dose, short-course valaciclovir suggest that maximum benefit from antiviral
      therapy may be achieved with as little as 1 day of treatment. Topical steroids
      may be useful in combination with an antiviral agent, but more needs to be learnt
      about the appropriate strength and duration of steroid therapy before a general
      recommendation can be made. Selected subgroups of patients are candidates for
      prophylactic treatment with perorally administered nucleoside antiviral agents.
      Prophylaxis with topical agents is not effective.

PMID- 12470604
TI  - Bell's palsy and herpesviruses.
AB  - A growing body of evidence links reactivation of herpesviruses (primarily
      varicella zoster virus and herpes simplex virus type 1) with the development of a
      large proportion of cases of acute peripheral facial palsy, a syndrome commonly
      known by its eponym, Bell's palsy. This article reviews the definition and
      natural history of the disease, its underlying anatomy and pathophysiology, the
      data linking herpetic reactivation with development of signs and symptoms, and
      therapeutic trials utilizing antiviral therapy. In addition, it poses the
      question, would earlier intervention with antivirals make a larger impact on
      outcomes?

PMID- 12470605
TI  - Antivirals in the prevention of genital herpes.
AB  - Genital herpes remains one of the most common sexually transmitted infections.
      Despite best efforts to prevent sexually transmitted diseases in the era of AIDS,
      the incidence of genital herpes continues to rise, and evidence that herpes
      simplex virus type 2 is a significant cofactor in the transmission of HIV
      infection is mounting. Because of the common psychosocial consequences of genital
      herpes transmission, prevention modalities against transmission of genital herpes
      are urgently required from both personal and public health perspectives. Most
      discordant couples are either unaware of genital herpes in one partner or unaware
      of clinical activity of the virus during sexual exposure that results in
      transmission. Yet, the body of evidence available suggests that the antiviral
      drugs currently used in the treatment of genital herpes are effective in
      suppressing asymptomatic virus shedding and, thus, could play a future role in
      reducing transmission. The first study to examine that possibility has recently
      been made public.

PMID- 12470606
TI  - Education and counselling for genital herpes: perspectives from patients.
AB  - The incidence and prevalence of genital herpes continue to increase in the USA,
      and the availability of new, accurate serological tests for herpes simplex virus
      (HSV) may identify millions of previously unrecognized cases. Newly diagnosed
      genital HSV infections place a serious burden on healthcare providers in terms of
      education and counselling. The study was initiated to assess the need for and
      potential use of an improved system for education and counselling of patients
      newly diagnosed with genital herpes. Patients' perspectives on current and ideal
      care, as well as barriers to education and counselling and recommendations are
      discussed. In addition, implications for practice and recommendations for future
      research are suggested.

PMID- 12470607
TI  - Routine use of HSV-1 and HSV-2 antibody testing.

PMID- 12470608
TI  - Differentiation of human gamma-delta T cells towards distinct memory phenotypes.
AB  - Vgamma9/Vdelta2 T cells comprise a small population of peripheral T cells
      responding towards the low molecular weight antigen, (E)-4-hydroxy-3-methyl-but-2
      enyl-pyrophosphate (HMB-PP). HMB-PP-stimulated Vgamma9/Vdelta2 T cells
      proliferated, expressed CCL5/RANTES, and upregulated markers like CD16, CD25,
      CD69, and CD94, in the presence of either IL-15 or IL-21. Vgamma9/Vdelta2 T cells
      grown in the presence of IL-15 differentiated into an effector/memory population
      characterized by production of TNF-alpha, expression of CD45RO and CCR5, and lack
      of CD62L, CD81, and CCR7. In contrast, Vgamma9/Vdelta2 T cells grown with IL-21
      differentiated into putative central memory CD45RO(+) T cells that did not
      produce TNF-alpha, IFN-gamma, or IL-4, and maintained expression of CD62L, CD81,
      and CCR7.

PMID- 12470609
TI  - The N-formylpeptide receptor (FPR) and a second G(i)-coupled receptor mediate
      fMet-Leu-Phe-stimulated activation of NADPH oxidase in murine neutrophils.
AB  - N-Formylypeptides such as fMet-Leu-Phe (fMLF) potently induce superoxide
      production through NADPH oxidase activation. The receptors that mediate this
      response have not been defined. Here, we provide definitive proof using a mouse
      model that formyl peptide receptor (FPR) is a receptor, but not the only
      receptor, that mediates fMLF-induced oxidase activation. In wild-type (FPR(+/+))
      mouse neutrophils, superoxide production is dependent on the concentration of
      fMLF with an EC(50) of approximately 5 microM and a peak at approximately 50
      microM. In contrast, FPR-deficient (FPR(-/-)) mouse neutrophils produced markedly
      less superoxide with an EC(50) of approximately 50 microM and a peak at
      approximately 200 microM. Yet, FPR(+/+) and FPR(-/-) neutrophils showed similar
      oxidase activation kinetics and G(i) protein-dependent pharmacological
      sensitivities. These results suggested that a second receptor, likely FPR2,
      mediates superoxide production at high concentrations of fMLF. This less
      sensitive second pathway may permit continued oxidant generation in response to
      formyl peptides when FPR is desensitized in high concentrations of the
      chemotactic gradient.

PMID- 12470610
TI  - Acquisition of functional MHC class II/peptide complexes by T cells during thymic
      development and CNS-directed pathogenesis.
AB  - This study provides evidence that both rat and mouse thymic and splenic T cells
      express significant levels of MHC class II glycoproteins (MHCII) in vivo.
      Derivation of rat and mouse chimeras revealed that a major source of MHCII on
      thymic T cells was acquired from radioresistant host APC. Expression of MHC on
      thymic T cells appeared physiologically relevant because presentation of rat
      myelin basic protein (RMBP) by nonadherent, radiosensitive thymic T cells was
      associated with the adoptive transfer of tolerance. Mature MBP-specific effector
      T cells isolated from the CNS in both rat and mouse models of EAE also expressed
      significant levels of MHCII. Adoptive transfer of activated B10.PL MBP/I-A(u)
      restricted TCR transgenic T cells into F1(C57BL/6 x B10.PL) mice revealed
      acquisition of allogeneic I-A(b) on encephalitogenic CNS-derived T cells.
      Overall, this study indicates that immature and mature T cells in rats and mice
      acquire functional MHCII in vivo during thymic development and pathogenic
      inflammation.

PMID- 12470611
TI  - Trichostatin A, a histone deacetylase inhibitor, down-regulates interleukin-12
      transcription in SV-40-transformed lung epithelial cells.
AB  - Inhibition of histone deacetylation results in increased gene expression.
      Trichostatin (Ts)A, a specific histone deacetylase (HDAC) inhibitor, up-regulates
      transcription of some genes but represses expression of others. We quantified
      histone acetylation in SV-40-transformed lung epithelial cells using flow
      cytometry. Further, to evaluate the effect of TsA on transcription of genes
      associated with airway inflammation, we measured interleukin (IL)-8 production by
      enzyme-linked immunosorbent assay as well as IL-12 transcription by reverse
      transcription-polymerase chain reaction, in the transformed cells after
      stimulation with lipopolysaccharide (LPS) in the presence of TsA. Pretreatment of
      cells with TsA before LPS stimulation induced hyperacetylation of histones
      (especially in the S phase of the cell cycle), enhanced IL-8 production, and
      suppressed IL-12p35 and IL-12p40 mRNA accumulation. Thus we have demonstrated a
      useful way to detect hyperacetylation at the single-cell level, as well as the
      ability of an HDAC inhibitor to repress genes in epithelial cells.

PMID- 12470612
TI  - Differential expression of a 70 kDa O-glycoprotein on T cells: a possible marker
      for naive and early activated murine T cells.
AB  - We purified a 70 kDa O-glycoprotein that binds to the GalNAc specific lectin from
      Amaranthus leucocarpus (ALLr) and determined its expression pattern on T
      lymphocytes from different murine lymphoid organs. High level of ALLr expression
      was demonstrated in 95-98% of both CD4(+)8(+) and CD4(-)8(+) thymocytes, and in
      80-95% of CD8(+) T cells from peripheral blood, lymph nodes, and spleen, whereas
      a minor fraction of CD4(+)8(-) thymocytes (46-67%) and peripheral CD4(+) T cells
      (9-40%) showed low ALLr expression. Peripheral CD19(+) B cells were ALLr negative
      and most of the peripheral ALL(+) T cells showed a CD62L(hi)CD45RB(hi)CD44(lo/-)
      phenotype, indicating features of naive cells. Mitogenic activation of peripheral
      T cells increased 3-fold the number of ALL(+)CD4(+) T cells 24 h after
      stimulation, as opposed to a >80% decrease in CD8(+) T cells 72 h after
      stimulation. Our results suggest that ALL detects a non-described surface O
      glycoprotein selectively expressed by naive CD8(+) T cells and by early activated
      CD4(+) T cells.

PMID- 12470613
TI  - Candida albicans infection enhances immunosuppression induced by cyclophosphamide
      by selective priming of suppressive myeloid progenitors for NO production.
AB  - Systemic infections caused by fungi after cytoreductive therapies are especially
      difficult to deal with in spite of currently available antimicrobials. However,
      little is known about the effects of fungi on the immune system of
      immunosuppressed hosts. We have addressed this by studying the in vitro T cell
      responses after systemic infection with Candida albicans in cyclophosphamide
      treated mice. After cyclophosphamide treatment, a massive splenic colonization of
      the spleens, but not lymph nodes, by immature myeloid progenitor (Ly
      6G(+)CD11b(+))cells is observed. These cells are able to suppress proliferation
      of T lymphocytes via a nitric oxide (NO)-dependent mechanism. Systemic infection
      with a sublethal dose of C. albicans did not cause immunosuppression per se but
      strongly increased NO-dependent suppression in cyclophosphamide-treated mice, by
      selective priming of suppressive myeloid progenitors (Ly
      6G(+)CD11b(+)CD31(+)CD40(+)WGA(+)CD117(low/-)CD34(low/-)) for iNOS protein
      expression. The results indicate that systemic C. albicans infection can augment
      the effects of immunosuppressive therapies by promoting functional changes in
      immunosuppressive cells.

PMID- 12470614
TI  - Adjuvanticity of an IL-12 fusion protein expressed by recombinant deltaG
      vesicular stomatitis virus.
AB  - The remarkable immunomodulatory and adjuvant properties of rIL-12 have been well
      described. Many early studies documenting the adjuvanticity of IL-12 were
      performed using the murine model of Listeria monocytogenes infection. In this
      report, we describe the construction of an attenuated recombinant vesicular
      stomatitis virus (VSV-deltaG) that encodes a single-chain IL-12 fusion protein
      (IL-12F), and the use of this virus as an expression vector to produce large
      quantities of IL-12F. VSV-expressed IL-12F (vIL-12F) was then co-administered to
      mice along with a poorly immunogenic listerial antigen preparation as a vaccine
      regimen and the resulting immune responses were monitored. The vIL-12F was found
      to have adjuvant properties similar to those observed for rIL-12. Co
      administration of vIL-12F and listerial antigen elicited powerful cell-mediated
      immune responses that conferred long-lived protective listerial immunity. These
      studies demonstrated that VSVdeltaG-IL12F-infected cells secrete bioactive single
      chain IL-12, and laid the foundation for studies using VSVdeltaG-IL12F as a
      vector for delivery of IL-12F in vivo.

PMID- 12470615
TI  - Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7
      agonists, imiquimod and resiquimod.
AB  - The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that
      induce type I interferon in numerous species, including humans. Recently, it was
      shown that plasmacytoid dendritic cells (pDC) are the primary interferon
      producing cells in the blood in response to viral infections. Here, we
      characterize the activation of human pDC with the TLR7 agonists imiquimod and
      resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and
      IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the
      blood. Resiquimod-stimulated pDC also produce a number of other cytokines
      including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker
      expression, CCR7 expression, and pDC viability. Resiquimod was compared
      throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod
      more effectively matures pDC than either IL-3 or IFN-alpha alone. These results
      demonstrate that imidazoquinoline molecules directly induce pDC maturation as
      determined by cytokine induction, CCR7 and co-stimulatory marker expression and
      prolonging viability.

PMID- 12470616
TI  - GP43 from Paracoccidioides brasiliensis inhibits macrophage functions. An evasion
      mechanism of the fungus.
AB  - Macrophages constitute one of the primary cellular mechanisms that impairs
      parasite invasion of host tissues. The phagocytic and microbicidal properties of
      these cells can be modulated by specific membrane receptors involved in cell
      microorganism interactions. Gp43, the main antigen secreted by Paracoccidiodes
      brasiliensis (Pb), the causative agent of Paracoccidioidomycosis, is a high
      mannose glycoprotein. The role played by gp43 in the pathogenesis of the disease
      is not completely known. Here, we describe the influence of this molecule on the
      interaction between peritoneal murine macrophages and Pb. Phagocytosis of Pb,
      live or heat-killed, by adherent peritoneal cells from both, B10.A (susceptible)
      and A/Sn (resistant) mice, was evaluated. Addition of different concentrations of
      gp43 to the culture medium inhibited, in a dose-dependent pattern, phagocytosis
      of live or heat-killed Pb by peritoneal macrophages from both B10.A and A/Sn
      mice. Gp43 also inhibits phagocytosis of zymosan particles but did not interfere
      with the uptake of opsonized sheep red blood cells. It was also shown that both
      gp43 and heat-killed Pb have an inhibitory effect on the release of NO by zymosan
      stimulated macrophages. Finally, we demonstrated that gp43 inhibits the
      fungicidal ability of macrophages from both lineages. Based on these data, it is
      suggested that gp43 can be considered one of the evasion mechanisms for the
      installation of primary infection in susceptible hosts.

PMID- 12470618
TI  - Attention to action and awareness of other minds.
AB  - We have only limited awareness of the system by which we control our actions and
      this limited awareness does not seem to be concerned with the control of action.
      Awareness of choosing one action rather than another comes after the choice has
      been made, while awareness of initiating an action occurs before the movement has
      begun. These temporal differences bind together in consciousness the intention to
      act and the consequences of the action. This creates our sense of agency.
      Activity in the anterior cingulate cortex and medial prefrontal cortex is
      associated with awareness of our own actions and also occurs when we think about
      the actions of others. I propose that the mechanism underlying awareness of how
      our own intentions lead to actions can also be used to represent the intentions
      that underlie the actions of others. This common system enables us to communicate
      mental states and thereby share our experiences.

PMID- 12470617
TI  - Hexokinase translocation during neutrophil activation, chemotaxis, and
      phagocytosis: disruption by cytochalasin D, dexamethasone, and indomethacin.
AB  - Neutrophils expend large amounts of energy to perform demanding cell functions.
      To better understand energy production and flow during cell activation,
      immunofluorescence microscopy was employed to determine the location of the key
      metabolic enzyme hexokinase during various conditions. Hexokinase is translocated
      from the neutrophil's cytosol to its periphery in response to N-formyl-methionyl
      leucyl-phenylalanine (fMLP) and other activating stimuli, but not during exposure
      to the formyl peptide receptor antagonist N-tert-BOC-phe-leu-phe-leu-phe (Boc
      PLPLP). Translocation was observed from 10(-6) to 10(-9)M fMLP. However, fMLP did
      not affect the intracellular distribution of lactate dehydrogenase. Hexokinase
      accumulated at the lamellipodium of cells exposured to an fMLP gradient whereas
      it localized to the phagosome after latex bead uptake. Thus, hexokinase is
      differentially translocated within cells depending upon the prevailing
      physiological conditions. Further studies noted that cytochalasin D,
      dexamethasone, and indomethacin blocked hexokinase translocation. Parallel
      regulation of reactive oxygen metabolite (ROM) production was shown. We speculate
      that hexokinase translocation participates in neutrophil activation.

PMID- 12470619
TI  - What we see: inattention and the capture of attention by meaning.
AB  - Attention is necessary for the conscious perception of any object. Objects not
      attended to are not seen. What is it that captures attention when we are engaged
      in some attention-absorbing task? Earlier research has shown that there are only
      a very few stimuli which have this power and therefore are reliably detected
      under these conditions (for example, Mack & Rock, 1998; Moray, 1959). The two
      most reliable are the observer's own name and a happy face icon which seem to
      capture attention by virtue of their meaning. Three experiments are described
      which explore whether these stimuli are detected under conditions, heretofore
      unexamined, which either cause inattentional blindness or are associated with a
      perceptual failure associated with the limits of attention. The evidence obtained
      indicates that these stimuli have a unique capacity to capture and extend the
      limits of attention under conditions in which this has been deemed highly
      unlikely.

PMID- 12470620
TI  - False predictions about the detectability of visual changes: the role of beliefs
      about attention, memory, and the continuity of attended objects in causing change
      blindness blindness.
AB  - Recently, a number of experiments have emphasized the degree to which subjects
      fail to detect large changes in visual scenes. This finding, referred to as
      "change blindness," is often considered surprising because many people have the
      intuition that such changes should be easy to detect. documented this intuition
      by showing that the majority of subjects believe they would notice changes that
      are actually very rarely detected. Thus subjects exhibit a metacognitive error we
      refer to as "change blindness blindness." Here, we test whether CBB is caused by
      a misestimation of the perceptual experience associated with visual changes and
      show that it persists even when the pre- and postchange views are separated by
      long delays. In addition, subjects overestimate their change detection ability
      both when the relevant changes are illustrated by still pictures, and when they
      are illustrated using videos showing the changes occurring in real time. We
      conclude that CBB is a robust phenomenon that cannot be accounted for by failure
      to understand the specific perceptual experience associated with a change.

PMID- 12470621
TI  - Influences of visibility, intentions, and probability in a peripheral cuing task.
AB  - According to the concept of direct parameter specification, nonconsciously
      registered information can be processed to the extent that it matches currently
      active intentions of a person. This prediction was tested and confirmed in the
      current study. Masked visual information provided by peripheral cues led to
      reaction time (RT) effects only if the information specified one of the required
      responses (Experiments 1 and 3). Information delivered by the same masked cues
      that did not match the intentions was not used. However, the same information
      influenced RT if it was provided by visible cues (Experiments 2 and 3). The
      results suggest that the processing of nonconsciously registered information is
      flexible because it is susceptible to the changing intentions of a person. Yet,
      these processes are apparently restricted, as nonconsciously registered
      information cannot be used as easily for purposes not corresponding to the
      currently active intentions as better visible information.

PMID- 12470622
TI  - Pre-requisites for conscious awareness: clues from electrophysiological and
      behavioral studies of unilateral neglect patients.
AB  - Encoding sensory events entails processing of several physical attributes. Is the
      processing of any of these attributes a pre-requisite of conscious awareness?
      This selective review examines a recent set of behavioral and event-related
      potentials, studies conducted in patients with visual and auditory unilateral
      neglect or extinction, with the aim of establishing what aspects of initial
      processing are impaired in these patients. These studies suggest that
      extinguished visual stimuli excite the sensory cortices, but perhaps to a lesser
      degree than acknowledged stimuli do. However, encoding spatial attributes of
      auditory and visual stimuli appear to be preferentially impaired. In light of
      results from patients with other neuro-behavioral deficits, it is argued that
      egocentric spatial information is an essential pre-requisite for knowing that an
      external event occurred. In contrast, information handled by mostly domain
      specific circuits, such as in the ventral temporal lobe, supports awareness of
      the identity of a stimulus, but not of its mere presence. Without spatial
      information, the stimulus identity will remain implicit.

PMID- 12470623
TI  - Prime-sight and blindsight.
AB  - Listening to subject's commentaries can be a useful spur to novel scientific
      departures, as in studies of blindsight. Recently further testing (after a gap of
      17 years) has been possible with subject DB, who was a blindsight patient (the
      first) tested intensively over a period of 10 years and who was the subject of
      the book, (Blindsight OUP, 1986, 2nd edition, 1998). Essentially his original
      capacity is the same or somewhat more sensitive. Some further types of
      discriminations have now been tested that were not possible in the original
      study. But a new feature was discovered, namely that he describes conscious after
      images of a wide range of inducing stimuli of which he is unconscious. The
      properties of the after-images are briefly described, such as their occurrence
      following unseen colour patches, luminance changes, shape, spatial frequency,
      their long durations, showing inter-ocular transfer, as well as their conforming
      to Emmert's Law. Various approaches are discussed towards finding the source of
      their generation, such as the use of after-images of colour mixes of separate
      inputs to the two eyes ("cortical yellow"). They are also discussed in terms of
      after-images in normal subjects that are generated by imagination. The discovery
      offers a rare potential opportunity to compare the brain activity associated with
      both the conscious and unconscious attributes of the precisely the same stimuli
      in the same locus in the same subject.

PMID- 12470624
TI  - Measuring pain: an introspective look at introspection.
AB  - The measurement of pain depends upon subjective reports, but we know very little
      about how research subjects or pain patients produce self-reported judgments.
      Representationalist assumptions dominate the field of pain research and lead to
      the critical conjecture that the person in pain examines the contents of
      consciousness before making a report about the sensory or affective magnitude of
      pain experience as well as about its nature. Most studies to date have
      investigated what Fechner termed "outer psychophysics": the relationship between
      characteristics of an external stimulus and the magnitude and nature of pain
      experience. In contrast, Fechner originally envisioned that "inner psychophysics"
      should investigate the relationship between physiological states and subjective
      experience. Despite the lack of established research tradition, inner
      psychophysics has a potential utility in elucidating underlying mechanisms for
      the production of phenomenal self-report. We illustrate this, using causal
      modeling analyses of the accuracy of self-reported pain ratings from our
      laboratory. We submit that the results are inconsistent with representationalist
      assumptions. Converging trends from several domains of consciousness studies seem
      to suggest that we need to abandon the unquestioned doctrine of
      representationalism and search for a more viable framework for understanding the
      generation of subjective self-report.

PMID- 12470625
TI  - Integrating experiential-phenomenological methods and neuroscience to study
      neural mechanisms of pain and consciousness.
AB  - Understanding the nature of pain at least partly depends on recognizing its
      inherent first person epistemology and on using a first person experiential and
      third person experimental approach to study it. This approach may help to
      understand some of the neural mechanisms of pain and consciousness by integrating
      experiential-phenomenological methods with those of neuroscience. Examples that
      approximate this strategy include studies of second pain summation and its
      relationship to neural activities and brain imaging-psychophysical studies
      wherein sensory and affective qualities of pain are correlated with cerebral
      cortical activity. The experiential paradigm of offers the possibility of
      improved designs and methods for investigating neural mechanisms underlying pain
      and consciousness.

PMID- 12470626
TI  - The empirical basis of color perception.
AB  - Rationalizing the perceptual effects of spectral stimuli has been a major
      challenge in vision science for at least the last 200 years. Here we review
      evidence that this otherwise puzzling body of phenomenology is generated by an
      empirical strategy of perception in which the color an observer sees is entirely
      determined by the probability distribution of the possible sources of the
      stimulus. The rationale for this strategy in color vision, as in other visual
      perceptual domains, is the inherent ambiguity of the real-world origins of any
      spectral stimulus.

PMID- 12470627
TI  - Qualitative character and sensory representation.
AB  - Perceptual experience seems to involve distinct intentional and qualitative
      features. Inasmuch as one can visually perceive that there is a Coke can in front
      of one, perceptual experience must be intentional. But such experiences seem to
      differ from paradigmatic intentional states in having introspectible qualitative
      character. argues that a perceptual experience's qualitative character is
      determined by intrinsic, nonrepresentational properties. But also argues that
      perceptual experiences have nonconceptual representational content in addition to
      conceptual content and nonrepresentational sensational properties. He thus
      distinguishes between conceptual, nonrepresentational, and nonconceptual but
      representational aspects of perceptual experience. I will argue that Peacocke
      posits too much. Contrary to his (1983) arguments, the sensational properties
      Peacocke claims are nonrepresentational are best construed as representational;
      they are best explained in terms of their relation to the perceptible properties
      they enable us to perceive. Since sensational properties are arguably
      nonconceptual, they are best construed as nonconceptual representational
      properties. I offer the Homomorphism View of sensory qualities, pioneered by, as
      a unified account of qualitative character and nonconceptual sensory
      representation. According to this view, a sensory quality represents a
      perceptible stimulus property in virtue of resembling and differing from other
      sensory qualities in ways parallel to the ways the stimulus property resembles
      and differs from other perceptible properties.

PMID- 12470628
TI  - Counterfactuals cannot count: a rejoinder to David Chalmers.
AB  - The initial argument presented herein is not significantly original--it is a
      simple reflection upon a notion of computation originally developed by Putnam
      (Putnam 1988; see also Searle, 1990) and criticised by Chalmers et al. (Chalmers,
      1994; 1996a, b; see also the special issue, What is Computation?, in Minds and
      Machines, 4:4, November 1994). In what follows, instead of seeking to justify
      Putnam's conclusion that every open system implements every Finite State
      Automaton (FSA) and hence that psychological states of the brain cannot be
      functional states of a computer, I will establish the weaker result that, over a
      finite time window every open system implements the trace of FSA Q, as it
      executes program (P) on input (I). If correct the resulting bold philosophical
      claim is that phenomenal states--such as feelings and visual experiences--can
      never be understood or explained functionally.

PMID- 12470629
TI  - How many kinds of consciousness?
AB  - Ned Block's influential distinction between phenomenal and access consciousness
      has become a staple of current discussions of consciousness. It is not often
      noted, however, that his distinction tacitly embodies unargued theoretical
      assumptions that favor some theoretical treatments at the expense of others. This
      is equally so for his less widely discussed distinction between phenomenal
      consciousness and what he calls reflexive consciousness. I argue that the
      distinction between phenomenal and access consciousness, as Block draws it, is
      untenable. Though mental states that have qualitative character plainly differ
      from those with no mental qualities, a mental state's being conscious is the same
      property for both kinds of mental state. For one thing, as Block describes access
      consciousness, that notion does not pick out any property that we intuitively
      count as a mental state's being conscious. But the deeper problem is that Block's
      notion of phenomenal consciousness, or phenomenality, is ambiguous as between two
      very different mental properties. The failure to distinguish these results in the
      begging of important theoretical questions. Once the two kinds of phenomenality
      have been distinguished, the way is clear to explain qualitative consciousness by
      appeal to a model such as the higher-order-thought hypothesis.

PMID- 12470630
TI  - Emotional introspection.
AB  - One of the most vivid aspects of consciousness is the experience of emotion, yet
      this topic is given relatively little attention within consciousness studies.
      Emotions are crucial, for they provide quick and motivating assessments of value,
      without which action would be misdirected or absent. Emotions also involve
      linkages between phenomenal and intentional consciousness. This paper examines
      emotional consciousness from the standpoint of the representational theory of
      consciousness (RTC). Two interesting developments spring from this. The first is
      the need for the representation of value, which is distinctive of emotional
      experience. The second is an extension of RTC's theory of introspection to
      emotional states, revealing why emotional consciousness is so often introspective
      even though introspective abilities are not needed to experience emotions, and
      also explaining why introspection of emotional states is so much less reliable
      than that of other states of consciousness.

PMID- 12470631
TI  - Sinusoidal efflux of taurocholate correlates with the hepatic expression level of
      Mrp3.
AB  - Multidrug resistance-associated protein 3 (Mrp3/ABCC3), which can mediate the
      cellular extrusion of bile acids, is induced on the hepatic sinusoidal membrane
      of Mrp2/ABCC2-deficient rats (Eisai hyperbilirubinemic rats; EHBRs) and
      phenobarbital-treated Sprague-Dawley rats. In the present study, the correlation
      between the sinusoidal efflux clearance (PS(eff)) of [3H]taurocholate (TC) and
      the hepatic expression of Mrp3 was investigated using perfused liver from these
      rats. A significant correlation was observed between the PS(eff) and the hepatic
      expression level of Mrp3, suggesting a contribution by Mrp3 to the sinusoidal
      efflux of TC. The results of the kinetic analysis also suggested that other
      transporter(s) on the sinusoidal plasma membrane may participate in the efflux of
      TC under physiological conditions. The contribution of Mrp3 to the sinusoidal
      efflux of TC in EHBRs and phenobarbital (80 and 40 mg/kg)-treated rats was
      revealed to be 58%, 48%, and 31%, respectively.

PMID- 12470632
TI  - Fluconazole downregulates metallothionein expression and increases copper
      cytotoxicity in Microsporum canis.
AB  - Azole antifungals are widely used to treat infections with dermatophyte fungi.
      Whereas it is well established that this class of drugs interferes with fungal
      ergosterol synthesis, little is known about its potential other biological
      effects. Here we report the isolation and structural organization of Microsporum
      canis metallothionein gene and demonstrate that fluconazole is able to
      downregulate the baseline as well as copper-induced expression of this gene.
      Since this effect occurred within 30 min after exposure of the fungus to
      fluconazole, it is unlikely that it is due to impaired ergosterol synthesis. Our
      additional demonstration that fluconazole enhances copper toxicity for M. canis
      suggests that inhibition of metallothionein expression by fluconazole is
      biologically relevant and may represent an important additional mode of the
      antifungal action of this drug. Therefore our data indicate that antifungal
      effects of azole derivatives might not only be due to interference with cell wall
      synthesis but may also affect other biological circuits within the fungal cells.

PMID- 12470633
TI  - Leucine promotes glucose uptake in skeletal muscles of rats.
AB  - Soleus muscles isolated from normal rats were incubated to evaluate whether or
      not leucine promotes glucose uptake under insulin-free conditions, using a
      labeled 2-deoxyglucose uptake assay. Glucose uptake was promoted by 2mM leucine.
      A metabolite of leucine, alpha-ketoisocaproic acid (alpha-KIC), also exhibited a
      similar stimulatory effect, although this was not as potent as leucine.
      Stimulation of glucose uptake by leucine was completely canceled by pre-treatment
      with either 10 microM LY294002, a specific inhibitor of phosphatidylinositol 3
      kinase (PI3-kinase), or 6 microM GF109203X, a specific inhibitor of protein
      kinase C (PKC). No significant change was observed by pre-treatment with 1 microM
      rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR). These
      results suggest that leucine stimulates glucose transport in skeletal muscle via
      PI3-kinase and PKC pathways independently of the mammalian target of mTOR. They
      also suggest that leucine stimulates glucose transport by an insulin-independent
      mechanism.

PMID- 12470634
TI  - Arg tyrosine kinase is involved in homologous recombinational DNA repair.
AB  - c-Abl plays important roles in cellular response to DNA damage. However, possible
      roles for Arg (Abl-related gene) in DNA damage response are unknown. Here, we
      show that ionizing radiation (IR)-induced Rad51 focus formation is reduced in Arg
      deficient cells generated from a chicken B cell line by targeted disruption. This
      is consistent with the findings that Arg-deficient cells display hypersensitivity
      to IR, elevated frequencies of IR-induced chromosomal aberrations, and reduced
      targeted integration frequencies. All of these abnormalities in DNA damage repair
      are also observed in ATM-deficient cells but not in c-Abl-deficient cells.
      Finally, we show that Arg interacts with and phosphorylates Rad51 in 293T cells.
      These results suggest that Arg plays a role in homologous recombinational (HR)
      DNA repair by phosphorylating Rad51.

PMID- 12470635
TI  - Subcellular localization of pentachlorophenol 4-monooxygenase in Sphingobium
      chlorophenolicum ATCC 39723.
AB  - We have studied the subcellular localization of pentachlorophenol 4-monooxygenase
      (PCP4MO) in Sphingobium chlorophenolicum ATCC 39723 during induction by
      pentachlorophenol (PCP). Using a monoclonal antibody CL6 specific to the native
      and recombinant PCP4MO, the enzyme was primarily found soluble as determined by
      immunoblot and ELISA analyses of cellular fractions. However, the enzyme was
      observed both in the soluble and membrane-bound forms during induction for 2-4 h,
      suggesting its translocation out from the cytoplasm. Electron microscopy
      confirmed that PCP4MO was predominantly present in the cytoplasm at 1 h, whereas
      at 4 h significant amount was detected also in the membrane and periplasm. After
      6 h, the majority of PCP4MO was in the periplasm and only small amount was bound
      to the inner membrane or present in the cytoplasm. The results indicate that
      after biosynthesis PCP4MO in S. chlorophenolicum is exported via the inner
      membrane to the final location in the periplasm.

PMID- 12470636
TI  - Solution structure of the ribosome-associated cold shock response protein Yfia of
      Escherichia coli.
AB  - The solution structure of the ribosome-associated cold shock response protein
      Yfia of Escherichia coli was determined by nuclear magnetic resonance with a RMSD
      of 0.6A. Yfia shows a global beta-alpha-beta-beta-beta-alpha folding topology
      similar to its homologue HI0257 of Haemophilus influenzae and the double-strand
      binding domain of Drosophila Staufen protein. Yfia and HI0257 differ in their
      surface charges and in the composition of their flexible C-termini, indicating
      their specificity to different target molecules. Both proteins exhibit a
      hydrophobic and polar region, which probably functions as interaction site for
      protein complex formation. Despite their similarity to the dsRBD fold, Yfia does
      not bind to model fragments of 16S ribosomal RNA as determined by NMR titration
      and gel shift experiments.

PMID- 12470637
TI  - Kinetic characterisation of primer mismatches in allele-specific PCR: a
      quantitative assessment.
AB  - A novel method of estimating the kinetic parameters of Taq DNA polymerase during
      rapid cycle PCR is presented. A model was constructed using a simplified sigmoid
      function to represent substrate accumulation during PCR in combination with the
      general equation describing high substrate inhibition for Michaelis-Menten
      enzymes. The PCR progress curve was viewed as a series of independent reactions
      where initial rates were accurately measured for each cycle. Kinetic parameters
      were obtained for allele-specific PCR (AS-PCR) amplification to examine the
      effect of mismatches on amplification. A high degree of correlation was obtained
      providing evidence of substrate inhibition as a major cause of the plateau phase
      that occurs in the later cycles of PCR.

PMID- 12470638
TI  - The function of the nuclear matrix attachment region of silkworm rDNA as an
      autonomously replicating sequence in plasmid and chromosomal replication origin
      in yeast.
AB  - Nuclear matrix attachment regions (MARs) play a crucial role in chromatin
      architecture, gene expression, and DNA replication. Although it is well known
      that yeast autonomously replicating sequences (ARSs) bind nuclear matrix and MARs
      also function as ARS elements in yeast, whether a heterologous MAR or ARS element
      acts as a replication origin in the chromosome has not been elucidated. We
      previously identified a MAR (rMAR) located in the nontranscribed spacer (NTS) of
      silkworm Attacus ricini rDNA. We report here that this rMAR contains 10 copies of
      ARS consensus sequence (ACS) and several DNA unwinding regions. The rMAR employs
      ARS activity in yeast and a rARS element locates in the 3(') region of the rMAR.
      Furthermore, we have also revealed that either the rMAR or the rARS element
      functions as a replication origin in the chromosome. Our results provide the
      first direct evidence to demonstrate that heterologous rMAR and rARS display
      chromosomal origin activity, suggesting that the chromosome structure and
      replication origin of rDNA reserve some common features during evolution.

PMID- 12470639
TI  - Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3
      and ER6 vitamin D responsive elements.
AB  - The nuclear vitamin D receptor (VDR) mediates the effects of 1,25
      dihydroxyvitamin D(3) (1,25D(3)) to alter intestinal gene transcription and
      promote calcium absorption. Because 1,25D(3) also exerts anti-cancer effects, we
      examined the efficacy of 1,25D(3) to induce cytochrome P450 (CYP) enzymes.
      Exposure of human colorectal adenocarcinoma cells (HT-29) to 10(-8)M 1,25D(3)
      resulted in >/=3-fold induction of CYP3A4 mRNA and protein as assessed by RT-PCR
      and Western blotting, respectively. Six vitamin D responsive element (VDRE)-like
      sequences in the promoter region of the CYP3A4 gene were then individually tested
      for their ability to enhance transcription. A canonical DR3-type element in the
      distal region of the promoter (-7719-GGGTCAgcaAGTTCA-7733), and a proximal, non
      classical everted repeat with a spacer of 6 bp (ER6; -169-TGAACTcaaaggAGGTCA-152)
      were identified as functional VDREs in this CYP gene. These data suggest that
      1,25D(3)-dependent, VDR-mediated induction of CYP3A4 may constitute a
      chemoprotective mechanism for detoxification of enteric xenobiotics and
      carcinogens.

PMID- 12470640
TI  - Ghrelin increases anxiety-like behavior and memory retention in rats.
AB  - Ghrelin is a peptide found in the hypothalamus and stomach that stimulates food
      intake and whose circulating concentrations are affected by nutritional state.
      Very little is known about other central behavioral effects of ghrelin, and thus,
      we investigated the effects of ghrelin on anxiety and memory retention. The
      peptide was injected intracerebroventricularly in rats and we performed open
      field, plus-maze, and step-down tests (inhibitory avoidance). The administration
      of ghrelin increased freezing in the open field and decreased the number of
      entries into the open spaces and the time spent on the open arms in the plus
      maze, indicating an anxiogenic effect. Moreover, the peptide increased in a dose
      dependent manner the latency time in the step-down test. A rapid and prolonged
      increase in food intake was also observed. Our results indicate that ghrelin
      induces anxiogenesis in rats. Moreover, we show for the first time that ghrelin
      increases memory retention, suggesting that the peptide may influence processes
      in the hippocampus.

PMID- 12470642
TI  - Detection of protoporphyrin IX in envelope membranes of pea chloroplasts.
AB  - Envelope membranes were prepared from mature pea chloroplasts. The tetrapyrrole
      contents of envelope membranes were analysed. The envelope membranes of pea
      chloroplasts contained substantial amounts of protoporphyrin IX and trace amounts
      of Mg-protoporphyrin IX and its monoester in addition to protochlorophyllide. The
      protoporphyrin IX content of envelope membranes was 89.25 pmol (mg protein)(-1).
      Its content in pea envelope membrane was higher than that of protochlorophyllide.
      The proportion of monovinyl and divinyl forms of protochlorophyllide present in
      pea chloroplast envelope membrane was 3:7. The significance of the presence of
      protoporphyrin IX in the envelope membrane is discussed in relation to plastidic
      Chl biosynthesis.

PMID- 12470641
TI  - Gamma-secretase activity is not involved in presenilin-mediated regulation of
      beta-catenin.
AB  - Presenilins (PS) are involved in gamma-secretase-mediated processing of beta
      amyloid precursor protein (APP) and the Notch family of proteins. In addition,
      presenilin 1 (PS-1) binds to members of the armadillo family of proteins. In this
      study the relationship between PS-1-mediated proteolytic activity and PS-1
      mediated regulation of beta-catenin function was investigated. Incubation of
      cells with a potent, small molecule gamma-secretase inhibitor did not affect PS
      1/beta-catenin interaction as determined by co-immunoprecipitation, or affect the
      regulation of beta-catenin turnover, as determined by pulse-chase analysis, even
      at inhibitor concentrations that completely blocked PS-mediated APP processing.
      Moreover, inhibition of PS-1-mediated proteolytic activity did not affect beta
      catenin trafficking, as determined by immunolocalization and immunoblotting, or
      beta-catenin-mediated transcription. These results indicate that PS-1-mediated
      regulation of gamma-secretase activity and PS-1-mediated regulation of beta
      catenin function can be pharmacologically separated and support the idea that
      these are distinct functions.

PMID- 12470643
TI  - CTGF/Hcs24 interacts with the cytoskeletal protein actin in chondrocytes.
AB  - Connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24
      (CTGF/Hcs24) displays multiple functions in several types of mesenchymal cells,
      including the promotion of proliferation and differentiation of chondrocytes.
      Recently, the internalization and intracellular function of CTGF/Hcs24 were
      indicated as well. In this study, a binding protein for this factor was purified
      from the cytosolic fraction of human chondrosarcoma-derived chondrocytic cell
      line (HCS-2/8) by CTGF/Hcs24-affinity chromatography. The apparent molecular
      weight of the protein was 42kDa and determination of the internal amino acid
      sequence revealed this protein to be beta- or gamma-actin. An in vitro
      competitive binding assay of 125I-labeled recombinant CTGF/Hcs24 with cold
      rCTGF/Hcs24 showed that the binding between actin and 125I-CTGF/Hcs24 was
      specific. Immunoprecipitation analysis also showed that CTGF/Hcs24 bound to actin
      in HCS-2/8 cells. However, rCTGF/Hcs24 had no effects on the expression level of
      gamma-actin mRNA or total actin protein. These findings suggest that a
      significant portion of intracellular CTGF/Hcs24 may regulate certain cell
      biological events in chondrocytes through the interaction with this particular
      cytoskeletal protein.

PMID- 12470644
TI  - A Ca2+ signal is found upstream of cytochrome c release during apoptosis in HeLa
      cells.
AB  - We showed previously that a cytosolic Ca(2+) signal is involved in regulating UV
      induced apoptosis in HeLa cells. In this study, we found evidence that this
      Ca(2+) signal occurs upstream of the release of cytochrome c from mitochondria.
      First, when we abolished [Ca(2+)](i) increases by injecting BAPTA or heparin into
      UV-treated HeLa cells, cytochrome c release was either blocked or severely
      delayed. Second, using a living cell imaging technique, we observed a series of
      transient [Ca(2+)](i) increases (typically lasting about 40-60s) in many
      apoptotic cells induced by either UV- or TNFalpha-treatment. Third, using GFP
      tagged cytochrome c, we found that the Ca(2+) spikes appear in a time window
      before cytochrome c was released. Finally, by fixing the TNFalpha-treated cell at
      the time when it started to display Ca(2+) spikes, we examined the distribution
      of its endogenous cytochrome c using immunostaining. We found that cytochrome c
      was not yet released from mitochondria. These findings suggest the existence of
      certain apoptotic pathways, in which an early Ca(2+) signal is activated upstream
      of cytochrome c release.

PMID- 12470645
TI  - Rab11-FIP4 interacts with Rab11 in a GTP-dependent manner and its overexpression
      condenses the Rab11 positive compartment in HeLa cells.
AB  - We have recently identified Rab11-FIP4 as the sixth member of the Rab11-FIP
      family of Rab11 interacting proteins. Here, we demonstrate that Rab11-FIP4
      interacts with Rab11 in a GTP-dependent manner and that its C-terminal region
      allows the protein to self-interact and interact with pp75/Rip11, Rab11-FIP2, and
      Rab11-FIP3. However, Rab11-FIP4 does not appear to interact directly with Rab
      coupling protein (RCP). We investigated the subcellular localisation of Rab11
      FIP4 in HeLa cells and show that it colocalises extensively with transferrin and
      with Rab11. Furthermore, when overexpressed, it causes a condensation of the
      Rab11 compartment in the perinuclear region. We demonstrate that the carboxy
      terminal region of Rab11-FIP4 (Rab11-FIP4(C-ter)) is necessary and sufficient for
      its endosomal membrane association. Expression of Rab11-FIP4(C-ter) causes a
      dispersal of the Rab11 compartment towards the cell periphery and does not
      inhibit transferrin recycling in HeLa cells. It is likely that Rab11-FIP4 serves
      as a Rab11 effector in a Rab11 mediated function other than transferrin
      recycling.

PMID- 12470646
TI  - RNase E is involved in 5'-end 23S rRNA processing in alpha-Proteobacteria.
AB  - In Rhodobacter capsulatus and Rhizobium leguminosarum, an internal transcribed
      spacer consisting of helices 9 and 10 is removed during 23S rRNA processing,
      which leads to the occurrence of a 5.8S-like rRNA. The particular rRNA maturation
      steps are not known, with exception of the initial RNase III cleavage in helix 9.
      We found that GC-rich stem-loop structures of helix 9, which are released by
      RNase III, are immediately degraded. The degradation of helix 10 is slower and
      its kinetics differs in both species. Nevertheless, the helix 10 processing
      mechanism is conserved and includes cleavages by RNase E.

PMID- 12470647
TI  - Targeted gene correction of hprt mutations by 45 base single-stranded
      oligonucleotides.
AB  - Targeted correction of a single base in a gene of an eucaryotic cell by specific
      oligonucleotides is a yet controversial technique. Here, we introduce the
      correction of point mutations in the hypoxanthine-guanine-phosphoribosyl
      transferase (HPRT) gene as an additional model system to test targeted gene
      correction. In human, Hprt mutations cause Lesch-Nyhan syndrome. Using hamster
      V79 cells, we generated three cell lines with one hprt point mutation each. These
      cell lines were treated with specific single-stranded 45 base phosphothioate
      modified oligonucleotides and selected by HAT medium. The surviving clones were
      investigated for the correction of the respective hprt mutation. Treatment with
      the oligonucleotides was successful in repairing all three hprt mutations (hprt
      cDNA position 74, C --> T; position 151, C --> T; and position 400, G --> A). The
      correction efficiency was very low but reproducible. We suggest that this system
      allows one to investigate targeted gene correction in dependence on the target
      sequence and the oligonucleotides used.

PMID- 12470648
TI  - Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain
      containing protein with homology to tensin.
AB  - Axl receptor tyrosine kinase is implicated in several malignancies and is the
      receptor for the vitamin K-dependent growth factor Gas6. From a yeast two-hybrid
      screen of protein-protein interactions with the Axl cytoplasmic domain, we
      detected a previously uncharacterised SH2 domain-containing protein. We cloned
      two novel splice variants of this protein that give rise to 1409- and 1419-amino
      acid proteins, differing only in their N-terminal residues and yielding a 150-kDa
      protein product by in vitro translation. The Axl-interacting C-terminus contains
      a tandem SH2 and PTB domain combination homologous to the focal adhesion protein
      tensin. We detected interaction of Axl with both domains in mammalian cells by co
      immunoprecipitation and two-hybrid analyses. In addition, the protein possesses
      an N-terminal putative phorbol ester-binding C1 domain as well as a central
      tyrosine phosphatase motif. Thus, we have named the protein C1 domain-containing
      phosphatase and TENsin homologue (C1-TEN). Northern blot analysis of C1-TEN in
      human tissues revealed highest expression in heart, kidney, and liver. In
      summary, we have identified a novel multi-domain intracellular protein that
      interacts with Axl and which may furthermore be involved in other signal
      transduction pathways.

PMID- 12470649
TI  - The C-terminal domain of apolipoprotein A-I is involved in ABCA1-driven
      phospholipid and cholesterol efflux.
AB  - ABCA1, a member of the ATP-binding cassette family, mediates the efflux of
      cellular lipids to free apolipoproteins, mainly apoA-I. The role of the C
      terminal domain of apoA-I in this process has been evaluated by measuring the
      efflux capacity of a truncated form (apoA-I-(1-192)) versus intact apoA-I in
      different cellular models. In stimulated J774 macrophages, cholesterol efflux to
      apoA-I-(1-192) was remarkably lower than that to the intact apoA-I. The truncated
      apoA-I, lacking an important lipid-binding domain, was also significantly less
      efficient in removing phospholipids from stimulated macrophages. No difference
      was detected with stimulated Tangier fibroblasts that do not express functional
      ABCA1. The C-terminal domain of apoA-I is clearly involved in ABCA1-driven lipid
      efflux. Independent of the interaction with the cell surface, it may be the
      decreased ability of the truncated apoA-I to recruit membrane phospholipids that
      impairs its capacity to promote cell cholesterol efflux.

PMID- 12470651
TI  - The bovine lactoferrin region responsible for promoting the collagen gel
      contractile activity of human fibroblasts.
AB  - We have reported that bovine lactoferrin (bLf) promotes the contractile activity
      of collagen gels by WI-38 human fibroblasts via the phosphorylation of myosin
      light chain (MLC). To identify the region of bLf that is responsible for this
      activity, we prepared bLf fragments by limited proteolysis using trypsin and
      investigated the effects of each fragment on gel contractile activity. Lf
      consists of a single polypeptide chain containing two lobes that are independent
      globular structures termed the N- and C-lobes. The fragment corresponding to the
      C-lobe of bLf (amino acids 341-689) had a more prominent effect on collagen gel
      contractile activity than did that of either native bLf or its N-lobe (1-284).
      Further hydrolysis of the C-lobe with either pepsin or trypsin resulted in a loss
      of this activity. The effect of the C-lobe on collagen gel contraction by
      fibroblasts was dose-dependent and was associated with the elevation of MLC
      phosphorylation.

PMID- 12470650
TI  - Identification of differentially expressed mRNA during pancreas regeneration of
      rat by mRNA differential display.
AB  - Pancreatectomy (Px) is known to cause islet hypertrophy and is a putative method
      to mimic hyperglycemia representing type II diabetes mellitus. Therefore, finding
      new genes related to pancreatectomy will help to understand the molecular
      mechanism of hypertrophy and hyperglycemia, and may provide new diagnostic
      markers of type II diabetes. To this end, mRNA differential display was used to
      isolate genes that show transcriptional changes in pancreas of rat after 90%
      partial pancreatectomy. Forty-nine candidate pancreas regeneration-associated
      transcripts were isolated. cDNA sequencing and subsequent database analysis
      revealed that 15 transcripts showed no significant sequence similarity to
      previously reported genes, whereas 34 transcripts showed significant similarity
      with genes deposited in the GenBank. The differential mRNA expression of 49
      transcripts was confirmed using screening of slot blots and Northern blot
      analysis was performed to several genes. It was noteworthy that the Wnt-1
      inducible signaling pathway protein-1 (WISP-1), Ras-associated protein 1B
      (Rap1B), vascular cell adhesion molecule-1 (VCAM-1), and huntingtin interacting
      protein genes (HIP) were observed to be over-expressed during pancreas
      regeneration. Several genes' expression was modified by pancreatectomy. Profiling
      of gene expression in response to pancreatectomy may lead to new insights into
      hypertrophy and hyperglycemia representing type II diabetes, as well as into the
      identification of novel diagnostic markers of type II diabetes.

PMID- 12470652
TI  - Interleukin-2 inhibits proliferation of HPV-associated tumor cells and halts
      tumor growth in vivo.
AB  - Previous studies have shown inhibition of cervical cancer cell growth by
      treatment with high concentrations of IL-2. In the present study, we evaluated
      the in vitro and in vivo effects of recombinant human IL-2 on HPV-associated
      tumor cells (3T3-16). Treatment of 3T3-16 cells with rhIL-2 for 72 h inhibited
      cell growth in a dose-dependent manner and this effect was evidenced at nanomolar
      concentrations. These tumor cells expressed mRNA for beta and gamma subunits of
      the IL-2 receptor, which are required for signal transduction. In experiments to
      explore the effect of IL-2 on the growth of the HPV-associated tumor, mice
      received rhIL-2 through different routes: (i) intraperitoneal; (ii) subcutaneous,
      at the tumor inoculation site; or (iii) subcutaneous, distant from the tumor
      inoculation site. An effective antitumor response was observed only in those
      animals that received IL-2 at the tumor site (P<0.01). These results indicate the
      potential adequacy of therapeutic strategies based on local administration of
      rhIL-2 for cervical carcinoma, not only based on the ability of this cytokine to
      stimulate cellular-mediated immunity but also because of its direct effects on
      tumor cells.

PMID- 12470653
TI  - Design and functional analysis of actomyosin motor domain chimera proteins.
AB  - To gain more structural and functional information on the actomyosin complexes,
      we have engineered chimera proteins carrying the entire Dictyostelium actin in
      the loop 2 sequence of the motor domain of Dictyostelium myosin II. Although the
      chimera proteins were unable to polymerize by themselves, addition of skeletal
      actin promoted polymerization. Electron microscopic observation demonstrated that
      the chimera proteins were incorporated into actin filaments, when copolymerized
      with skeletal actin. Copolymerization with skeletal actin greatly enhanced the
      MgATPase, while the chimera proteins without added skeletal actin hydrolyzed ATP
      at a very low rate. These results indicate that the actin part and the motor
      domain part of the chimera proteins are correctly folded, but the chimera
      proteins are structurally stressed so that efficient polymerization is inhibited.

PMID- 12470654
TI  - Delayed induction of delta-6 and delta-5 desaturases by a peroxisome
      proliferator.
AB  - Delta-6 desaturase (D6D) is the key enzyme for the synthesis of highly
      unsaturated fatty acids (HUFA) such as arachidonic acid (AA) and docosahexaenoic
      acid (DHA) in mammals. Transcription of D6D gene is activated by both sterol
      regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferators
      (PP). This response of D6D is paradoxical because SREBP-1c transactivates genes
      for fatty acid synthesis in liver, while PP induce enzymes for fatty acid
      oxidation. We hypothesized that the induction of D6D gene by PP is a compensatory
      response to the increased HUFA demand caused by peroxisome proliferation and
      induction of fatty acid oxidation. We investigated the time-course effects of a
      PP, Wy14643, on the induction of HUFA metabolizing genes and HUFA profile in rat
      liver. The mRNA of fatty acid oxidation enzymes in the Wy14643 fed group became
      significantly higher than controls at 4 h and reached maximum within 28 h. In
      contrast, the mRNA of delta-6 and delta-5 desaturases in the Wy14643 group was
      not significantly higher than control at 4 h and took >28 h to reach the maximum.
      Despite the induction of HUFA synthetic pathway, the concentration of end
      products (AA and DHA) remained unchanged throughout the 4-day period in liver
      phospholipids and non-esterified fatty acids. Taken together, this study supports
      our hypothesis and suggests that peroxisome proliferation and induction of fatty
      acid oxidation enzymes are the major mechanisms of the induction of HUFA
      synthesis by PP.

PMID- 12470655
TI  - Identification of genes induced by BRCA1 in breast cancer cells.
AB  - Inherited mutations of the BRCA1 gene predispose to breast, ovarian, and other
      cancers. The role of the BRCA1 gene in the maintenance of chromosomal integrity
      is linked to a number of biological properties of its protein product, including
      transcriptional regulation. In the present study, we have used suppression
      subtractive hybridisation (SSH) to identify genes induced by BRCA1 by comparing
      control MCF7 breast carcinoma cells (driver) with MCF7 cells ectopically
      expressing BRCA1 (tester) and generated a forward subtracted cDNA library. We
      screened 500 putative positive clones from this library. Two hundred and ten of
      these clones were positive by differential screening with forward and reverse
      subtracted probes and the 65 cDNA clones which showed more than fivefold increase
      were selected for sequencing analysis. We clustered 46 different genes that share
      high homology with sequences in the GenBank/EMBL databases. Among these, 30 were
      genes whose function had been previously identified while the remaining 16 clones
      were genes with unknown functions. Of particular interest, BRCA1 gene induces the
      expression of genes encoding DNA repair proteins RAD21 and MSH2, ERBB2/HER2
      interacting protein ERBIN, meningioma-associated protein MAC30, and a candidate
      ovarian tumour-suppressor OVCA1. Northern and Western blot analyses confirmed
      that the expression of these five genes are up-regulated following BRCA1
      overexpression in MCF7 and UBR60-bcl2 cells. This is the first study reporting a
      set of BRCA1-induced genes in breast carcinoma cells by the SSH technique. We
      suggest that some known genes identified in this study may provide new insights
      into the tumour-suppressor function of BRCA1.

PMID- 12470656
TI  - Tissue factor pathway inhibitor induces expression of JUNB and GADD45B mRNAs.
AB  - Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that
      regulates tissue factor-triggered blood coagulation. It has previously been
      reported that TFPI inhibits the proliferation of human umbilical vein endothelial
      cells (HUVECs), suggesting that TFPI may act as more than just a mediator of
      coagulation through changes in gene expression. By using DNA-array techniques and
      Northern blot analysis, we here revealed that TFPI transiently induced the mRNA
      expression of JUNB and GADD45B. The inducible effects were not observed in
      TFPIdeltaC (lacking the C-terminal basic region) or antithrombin (heparin-binding
      anticoagulant protease inhibitor). Moreover, the TFPI-induced expression of
      GADD45B was blocked by receptor-associated protein, which masks the ligand
      binding domain of very low density lipoprotein receptor (VLDL-R). In conclusion,
      this is the first report to show an effect of TFPI on mRNA expression, and
      suggests that TFPI modulates cellular functions by inducing JUNB and GADD45B
      expression through binding to VLDL-R.

PMID- 12470657
TI  - Different role of saturated and unsaturated fatty acids in beta-cell apoptosis.
AB  - It is believed that free fatty acids contribute to the pathogenesis of type 2
      diabetes in humans. We have recently shown that lipoapoptosis of human beta-cells
      is specifically induced by saturated fatty acids while unsaturated had no effect.
      In the present study we tested the effect of co-incubation of different saturated
      and unsaturated free fatty acids on lipoapoptosis in beta-cells. RIN1046-38 cells
      and isolated human beta-cells were incubated with combinations of saturated fatty
      acids (palmitate, stearate) and mono- or polyunsaturated fatty acids
      (palmitoleate, oleate, and linoleate). Cells were incubated for 24-72 h with 1mM
      fatty acids. All unsaturated fatty acids tested completely prevented palmitate-
      or stearate-induced apoptosis of rat and human beta-cells as assessed by flow
      cytometric cell cycle analysis and TUNEL assay. This might suggest that apoptosis
      in vivo is predominantly determined by the content of unsaturated fatty acids in
      a mixed fatty acid pool.

PMID- 12470658
TI  - Characterization of the cysteine-rich calcium-binding S100A3 protein from human
      hair cuticles.
AB  - S100A3, a unique protein among all members of the calcium-binding S100 family, is
      specifically expressed at the inner endocuticle of human hair fibers. Upon hair
      damage, S100A3 is released from hair fibers and possibly destabilizes the hair
      tissue architecture. This study describes the purification and characterization
      of native S100A3 isolated from human hair fibers. We extracted native S100A3 from
      cuticles and purified the protein by anion-exchange chromatography. The results
      of 2D gel electrophoresis showed that cuticle S100A3 has a slightly lower
      isoelectric point compared to the recombinant protein. Tandem mass spectrometry
      of the peptides resulting from endoproteinase digest of cuticle S100A3 revealed
      that the N-terminal methionine is replaced with an acetyl group. This is the
      first report on biochemical characteristics of S100A3 in hair cuticle.

PMID- 12470659
TI  - Recruitment of NBS1 into PML oncogenic domains via interaction with SP100
      protein.
AB  - Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized
      by microcephaly, chromosomal instability, radiation sensitivity, and an increased
      incidence of malignancies. NBS1, the protein responsible for NBS, forms a complex
      with MRE11 and RAD50, and plays a vital role in DNA repair, cell cycle
      checkpoint, and telomere maintenance. Here, we show that a BRCA carboxyl terminus
      (BRCT) domain-containing region of NBS1 interacts with a nuclear dots-associated
      protein, SP100. The SP100 and NBS1 proteins co-localized in PODs and APBs in
      normal human fibroblast MRC5 and ALT line VA13 at G2 phase, respectively.
      Introduction of PML and SP100 into NT2 cells, which express no detectable amount
      of PML or SP100 proteins, resulted in localization of NBS1 in ectopically
      expressed PODs. These results indicate that NBS1 is recruited into PODs via
      interaction with SP100 protein. Thus, interaction between the NBS1 and SP100
      proteins may be involved in genomic stability and telomere maintenance.

PMID- 12470660
TI  - PGC-1 and PERC, coactivators of the estrogen receptor-related receptor gamma.
AB  - The mouse nuclear receptor ERRgamma (estrogen receptor-related receptor gamma) is
      highly expressed in heart, skeletal muscle, kidney, and brain, as well as in the
      developing nervous system. We found that the expression of the coactivators PGC-1
      (PGC-1alpha) and PERC (PGC-1beta) in mammalian cells augmented potently the
      transcriptional activation by ERRgamma. The constitutive activation function 2
      (AF-2) of the orphan receptor was important for the synergistic enhancement.
      Functional receptor truncation analysis revealed an additional amino-terminal
      activation function, specific for the ERRgamma2 isoform and PGC-1. In vitro
      experiments showed a direct interaction of ERRgamma with both coactivators. Our
      findings suggest distinct regulatory functions for PGC-1 and PERC as tissue
      specific coactivators for ERRgamma.

PMID- 12470661
TI  - Identification and characterization of P15RS, a novel P15(INK4b) related gene on
      G1/S progression.
AB  - To screen genes involved in P15(INK4b) regulation during cell cycle, differential
      display method was applied to compare mRNAs from G(1) synchronized cells of
      MLIK6, which overexpressed P15(INK4b) gene, and its control MLC2. By using this
      approach, 15 cDNA fragments that were preferentially expressed in MLIK6 cells,
      but not in MLC2 cells, were screened out. A novel gene named P15RS was identified
      with further analysis. Combining the sequence from DD-PCR, homology analysis
      against EST database and RACE, a 4,404 bp complete cDNA sequence of P15RS was
      generated. Sequence analysis revealed that P15RS cDNA encoded a 312-amino-acid
      peptide containing a RAR domain that is involved in regulation of nuclear pre
      mRNA, which suggests that P15RS may be a nuclear regulation protein. Genomic
      sequence analysis demonstrated that human P15RS gene was localized on chromosome
      18q12 with seven exons and six introns. Expressing antisense P15RS in MLIK6 cells
      can up-regulate the expression of cyclinD1 and cyclinE. These data indicate that
      P15RS may act as a negative regulator in G(1) phase.

PMID- 12470662
TI  - Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor
      cells.
AB  - It seems certain that COX-2 is related to tumor and some data suggested that COX
      2 might have relation to tumor malignance and angiogenesis. In order to elucidate
      the relationship between COX-2 and tumor invasive and angiogenic ability, we
      transfected human transitional cell carcinoma (TCC) cell line, EJ, permanently
      with a COX-2 expression vector or the mock vector. The EJ-COX(2) cells, which
      overexpressed COX-2, acquired increased invasiveness and angiogenic ability by
      activation of VEGF, uPA, and MMP-2. Increased invasiveness and angiogenic ability
      were reversed by treatment with either selective COX-2 inhibitor, NS-398, or dual
      COX inhibitor, indomethacin. These results demonstrate that overexpression of COX
      2 can lead to phenotypic changes that alter the metastatic and angiogenic
      potential of TCC cancer cells.

PMID- 12470663
TI  - Generation of a mouse monoclonal TSH receptor antibody with stimulating activity.
AB  - A Balb/c mouse was subjected to genetic immunization with a cDNA construct
      encoding the human thyrotropin receptor (TSHr). The immune response of the mouse
      resulted in the production of immunoglobulins recognizing the TSHr in three
      different assays: (1) flow immunocytometry (FACS) with CHO cells expressing the
      receptor; (2) receptor-dependent stimulation of cAMP production in the same cell
      line; and (3) competition with labeled TSH for binding to the receptor. One
      thousand hybridomas were generated from the spleen of the mouse and their
      supernatants were screened. A single monoclonal, IRI-SAb1, scored positive in all
      three assays and was studied further. It stimulated 13-fold cAMP production in
      TSHr-expressing CHO cells, with an EC50 in the low nanomolar range. When compared
      with bovine TSH, IRI-SAb1 behaved as a partial agonist. Contrary to the
      expectation from the characteristic of autoantibodies of Graves' patients, IRI
      SAb1 recognized a linear epitope, which was localized in a segment encompassing
      the first 281 residues of the receptor.

PMID- 12470664
TI  - The fusion protein core of measles virus forms stable coiled-coil trimer.
AB  - Recent studies have shown that paramyxovirus might adopt a similar molecular
      mechanism of virus entry and fusion in which the attachment glycoprotein binds
      receptor/s and triggers the conformational changes of the fusion protein. There
      are two conserved regions of heptad repeat (HR1 and HR2) in the fusion protein
      and they were shown with fusion-inhibition effects in many paramyxoviruses,
      including measles virus. They also appear to show characteristic structure in the
      fusion core: the HR1/HR2 forms stable six-helix coiled-coil centered by HR1 and
      is surrounded by HR2 (trimer of HR1/HR2), which represents the post-fusion
      conformational structure. In this study, we expressed the HR1 and HR2 of measles
      virus fusion protein as a single chain (named 2-Helix) and subsequently tested
      its formation of trimer. Indeed, the results do show that the HR1 and HR2
      interact with each other and form stable six-helix coiled-coil bundle. This is
      the first member in genus Morbillivirus of family Paramyxoviridae to be confirmed
      with this characteristic structure and provides the basis for the HR2-inhibition
      effects on virus fusion/entry for measles virus.

PMID- 12470665
TI  - A novel anti-rheumatic drug, T-614, stimulates osteoblastic differentiation in
      vitro and bone morphogenetic protein-2-induced bone formation in vivo.
AB  - T-614 (N-[3-(formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl]methanesulfonamide), a
      newly developed anti-rheumatic drug under clinical trial, is an anti-inflammatory
      agent which has been reported to show the inhibitory effect of bone destruction
      in vivo arthritis model. We found that T-614 stimulated osteoblastic
      differentiation of stromal cell line (ST2) and preosteoblastic cell line (MC3T3
      E1) in the presence or absence of recombinant human bone morphogenetic protein-2
      (rhBMP-2). Calcium content of mineralized nodules was 14-fold elevated by the
      addition of T-614 in the presence of rhBMP-2 in ST2 but not MC3T3-E1. Oral
      administration of T-614 to mice also promoted rhBMP-2 induced bone formation in
      vivo. Northern blot analysis showed that transcriptional level of osterix, an
      essential transcription factor for osteoblastic differentiation, was 3-fold
      increased by T-614 with rhBMP-2 in ST2. Taken together, these results suggested
      that T-614 possessed anabolic effects on bone metabolism, besides suppressor of
      bone resorption, by increased expression of osterix.

PMID- 12470666
TI  - The structural transition of DNA-Tris(1,10-phenanthroline) cobalt(III) complexes
      in ethanol-water solution.
AB  - The interaction of DNA with Tris(1,10-phenanthroline) cobalt(III) was studied by
      means of atomic force microscopy. Changes in the morphologies of DNA complex in
      the presence of ethanol may well indicate the crucial role of electrostatic force
      in causing DNA condensation. With the increase of the concentration of ethanol,
      electrostatic interaction is enhanced corresponding to a lower dielectric
      constant. Counterions condense along the sugar phosphate backbone of DNA when
      epsilon is lowered and the phosphate charge density can thus be neutralized to
      the level of DNA condensation. Electroanalytical measurement of DNA condensed
      with Co(phen)(3)(3+) in ethanol solution indicated that intercalating reaction
      remains existing. According to both the microscopic and spectroscopic results, it
      can be found that no secondary structure transition occurs upon DNA condensing. B
      A conformation transition takes place at more than 60% ethanol solution.

PMID- 12470667
TI  - Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma
      cells and preadipocytes.
AB  - SR-BI mediates exchange of cholesterol between HDL and cells, and is a crucial
      factor in the transport of excessive cellular cholesterol from extrahepatic
      tissues to the liver ("reverse cholesterol transport") and, therefore, also for
      cholesterol homeostasis. Hepatic SR-BI mediates transfer of HDL-cholesterol to
      the hepatocytes where cholesterol may be metabolised to bile acids. LXR and SREBP
      are key factors in the regulation of cholesterol metabolism. The purpose of the
      present study was to determine whether these transcription factors are involved
      in the regulation of SR-BI. Here we show that LXRalpha/RXR and LXRbeta/RXR induce
      SR-BI transcription in human and murine hepatoma cell lines, and in 3T3-L1
      preadipocytes independently of SREBP-1. The LXR/RXR response was mapped within 
      1,200 to -937 of the promoter region. Gel mobility shift analysis confirmed that
      the putative LXR response element bound LXRalpha/RXR and LXRbeta/RXR
      heterodimers.

PMID- 12470668
TI  - Molecular identification of the first insect ecdysis triggering hormone
      receptors.
AB  - The Drosophila Genome Project website (www.flybase.org) contains an annotated
      gene sequence (CG5911), coding for a G protein-coupled receptor. We cloned the
      cDNA corresponding to this sequence and found that the gene has not been
      correctly predicted. The corrected gene CG5911 has five introns and six exons (1
      6). Alternative splicing yields two cDNAs called A (containing exons 1-5) and B
      (containing exons 1-4, 6). We expressed these splicing variants in Chinese
      hamster ovary cells and found that the corrected CG5911-A and -B cDNAs coded for
      two different G protein-coupled receptors that could be activated by low
      concentrations of Drosophila ecdysis triggering hormones-1 and -2. Ecdysis
      (cuticle shedding) is an important behaviour, allowing growth and metamorphosis
      in insects and other arthropods. Our paper is the first report on the molecular
      identification of ecdysis triggering hormone receptors from insects.

PMID- 12470669
TI  - Radical-generating coordination complexes as tools for rapid and effective
      fragmentation and fluorescent labeling of nucleic acids for microchip
      hybridization.
AB  - DNA microchip technology is a rapid, high-throughput method for nucleic acid
      hybridization reactions. This technology requires random fragmentation and
      fluorescent labeling of target nucleic acids prior to hybridization. Radical
      generating coordination complexes, such as 1,10-phenanthroline-Cu(II) (OP-Cu) and
      Fe(II)-EDTA (Fe-EDTA), have been commonly used as sequence nonspecific "chemical
      nucleases" to introduce single-strand breaks in nucleic acids. Here we describe a
      new method based on these radical-generating complexes for random fragmentation
      and labeling of both single- and double-stranded forms of RNA and DNA. Nucleic
      acids labeled with the OP-Cu and the Fe-EDTA protocols revealed high
      hybridization specificity in hybridization with DNA microchips containing
      oligonucleotide probes selected for identification of 16S rRNA sequences of the
      Bacillus group microorganisms. We also demonstrated cDNA- and cRNA-labeling and
      fragmentation with this method. Both the OP-Cu and Fe-EDTA fragmentation and
      labeling procedures are quick and inexpensive compared to other commonly used
      methods. A column-based version of the described method does not require
      centrifugation and therefore is promising for the automation of sample
      preparations in DNA microchip technology as well as in other nucleic acid
      hybridization studies.

PMID- 12470670
TI  - Detection of isoelectric profiles of erythropoietin in urine: differentiation of
      natural and administered recombinant hormones.
AB  - Erythropoietin (EPO) is normally present in urine at a low concentration (about
      1IU/L, i.e., about 10ng/L) for a total protein concentration of at least 50mg/L.
      A method to study the isoelectric profile of this hormone from 20-ml urine
      aliquots without previous purification was developed. This method involves
      isoelectric focusing of the retentate from ultrafiltered urine. Both the
      ultrafiltration and the isoelectric focusing required precautionary measures to
      prevent EPO degradation by the proteases that are present in urine. Because
      classical immunoblotting gave rise to an unspecific detection of various urinary
      proteins in the focused retentate, it was essential to use the "double-blotting"
      process developed to solve this problem. Sufficient sensitivity was achieved
      using amplified chemiluminiscent detection after the blotting membrane was
      treated with dithiotreitol. The patterns that were revealed from various urinary
      samples proved to be highly heterogeneous as they were composed of more than 10
      isoforms in a pI range of 3.7-4.7. Clear transformation of the patterns was
      observed in the case of treatment by the recombinant hormone, suggesting that
      this method can be regarded an efficient tool for indicating recombinant EPO
      misuse in sports. It may also open new investigations in the field of physiologic
      or pathologic exploration.

PMID- 12470671
TI  - A streamlined method for the isolation and quantitation of nanomole levels of
      exported polyamines in cell culture media.
AB  - A number of years ago, our laboratory published a method for the isolation of
      small amounts of polyamines from cell culture media using the ion-exchange resin
      Bio-Rex 70. We have used this technique extensively to study the export of
      putrescine and cadaverine from cultured mammalian cells. Unfortunately, this
      method was highly inefficient in isolating the polyamines spermidine and spermine
      and was incapable of recovering the acetylated polyamine N(1)-acetylspermidine.
      In response to these shortcomings, we modified our previous protocol to
      quantitatively isolate the polyamines N(1)-acetylspermidine, putrescine,
      cadaverine, N(1)-acetylspermine, spermidine, and spermine. The new method, which
      is much faster to perform and more efficient than the one previously described,
      employs the use of disposable minicolumns and a single resin washing step using a
      weak solution of sodium carbonate at pH 9.3. This new protocol also eliminates
      the column elution step in favor of directly derivatizing the polyamines with
      dansyl chloride on the ion-exchange resin. High-performance liquid chromatography
      analysis of the dansylated polyamines isolated by this procedure showed that 75%
      of N(1)-acetylspermidine and nearly 100% of the other polyamines present in
      nanomolar levels were recovered from small amounts of cell culture medium. This
      new protocol is a valuable new tool for the study of the
      intracellular/extracellular dynamics of polyamine pools in cultured cells. [A
      detailed laboratory protocol for this procedure (containing all of the
      information in this paper but in a condensed form) can be requested by e-mailing
      the authors.]

PMID- 12470672
TI  - Effect of N-acetylaspartic acid on the diffusion coefficient of water: a proton
      magnetic resonance phantom method for measurement of osmolyte-obligated water.
AB  - N-acetyl-L-aspartic acid (NAA) is an amino acid present in the vertebrate brain
      that is synthesized and stored primarily in neurons, although it cannot be
      hydrolyzed in these cells. Nonetheless, neuronal NAA is dynamic and turns over
      more than once each day by cycling, via extracellular fluids (ECF), between
      neurons and catabolic compartments in oligodendrocytes. One important role of the
      NAA intercompartmental cycle appears to be osmoregulatory, and in this role it
      may be the primary mechanism for the removal of metabolic water, against a water
      gradient, from myelinated neurons. However, the number of water molecules that
      might be cotransported to ECF per NAA molecule released is as yet unclear. In
      this investigation, using a proton nuclear magnetic resonance method and
      diffusion measurements at two magnetic field strengths on water and NAA phantoms
      in vitro, the effect of NAA on the diffusion coefficient of water has been
      measured, and a ratio (K) of obligated water molecules per molecule of NAA has
      been determined. For NAA measured at 100mM and 3 Tesla K=24 and at 7 Tesla K=14.
      Based on these results, apparent K(NAA) varies inversely with field strength, and
      with a computed field strength factor of 2.55mmol water/unit Tesla, K(NAA) in the
      absence of any applied magnetic field strength would be 32.

PMID- 12470673
TI  - Measurement of ATP production and respiratory chain enzyme activities in
      mitochondria isolated from small muscle biopsy samples.
AB  - A set of methods suitable for assessment of respiratory chain function in
      mitochondria isolated from 25mg of muscle is described. This set of methods
      includes determination of the mitochondrial ATP production rate (MAPR) and the
      activities of the respiratory chain complexes I, I+III, II+III, and IV and
      citrate synthase. MAPR is determined with an optimized version of a luminometric
      method previously described. The optimized method measures 50-220% higher
      activities than the original method. The highest MAPRs are recorded using the
      substrate combinations glutamate+succinate and N,N,N(1),N(1)-tetramethyl-1,4
      phenyldiamine+ascorbate. The respiratory chain complex activities are determined
      with standard spectrophotometric methods, adapted to an automated photometer. The
      sensitivity in the determination of complex I, I+III, and II+III activities was
      increased considerably by pretreating the samples with saponin. The set of
      methods was evaluated on double biopsy samples from five healthy volunteers and
      showed coefficients of variation between 7 and 14% when citrate synthase was used
      as reference base. All of the various measures of mitochondrial function showed
      high correlation coefficients to each other (r=0.84-0.98; p<0.01). It is
      concluded that the set of methods is suitable for diagnosis of mitochondrial
      disorders in adults and small children.

PMID- 12470674
TI  - Unmasking venom gland transcriptomes in reptile venoms.
AB  - While structural studies of reptile venom toxins can be achieved using
      lyophilized venom samples, until now the cloning of precursor cDNAs required
      sacrifice of the specimen for dissection of the venom glands. Here we describe a
      simple and rapid technique that unmasks venom protein mRNAs present in
      lyophilized venom samples. To illustrate the technique we have RT-PCR-amplified a
      range of venom protein transcripts from cDNA libraries derived from the venoms of
      a hemotoxic snake, the Chinese copperhead (Deinagkistrodon acutus), a neurotoxic
      snake, the black mamba (Dendroaspis polylepis), and a venomous lizard, the Gila
      monster (Heloderma suspectum). These include a metalloproteinase and
      phospholipase A2 from D. acutus, a potassium channel blocker, dendrotoxin K, from
      D. polylepis, and exendin-4 from H. suspectum. These findings imply that the
      apparent absence and/or lability of mRNA in complex biological matrices is not
      always real and paves the way for accelerated acquisition of molecular genetic
      data on venom toxins for scientific and potential therapeutic purposes without
      sacrifice of endangered herpetofauna.

PMID- 12470675
TI  - Microanalysis of hyaluronan oligosaccharides by polyacrylamide gel
      electrophoresis and its application to assay of hyaluronidase activity.
AB  - We established a rapid, sensitive polyacrylamide gel electrophoresis (PAGE)
      method for the analysis of hyaluronan (HA) oligosaccharides. Using mini-slab
      gels, but not large-slab gels so far reported, HA oligosaccharides of 5 to more
      than 50 repeating disaccharide units could be separated into discrete ladder-like
      bands in a short electrophoresis time of 45 min. Using a combined Alcian blue and
      silver staining protocol, the detection limit was less than 1 ng per band for 11
      repeating disaccharide units, indicating 50 times higher sensitivity than that of
      an earlier-described sensitivity-enhanced PAGE method. Our PAGE method was
      applicable to the assay of hyaluronidase activity. When a total of multiple band
      intensities for 18-24 repeating disaccharide units was used as a measure of
      activity, as little as 3 x 10(-4) NFU of bovine testicular hyaluronidase was
      detectable on a 1-h incubation. This sensitivity permitted rapid measurements of
      human and rabbit serum hyaluronidases, the latter of which having never been
      detected even by a sensitive enzyme-linked immunosorbent assay (ELISA). Since
      this PAGE assay does not require specialized reagents and instruments and since
      it provides information on both the activity and the enzymatic HA degradation
      pattern, there may be many potential applications.

PMID- 12470676
TI  - Magnetic-bead enzyme-linked immunosorbent assay verifies adsorption of ligand and
      epitope accessibility.
AB  - Antigen- and antibody-coated magnetic beads, which are commercially available as
      activated particles and are readily coated with a variety of molecules, are
      excellent devices for selecting specific cell populations. We describe an enzyme
      linked immunosorbent assay (ELISA)-based method that validates the adsorption of
      ligand to magnetic beads and verifies the surface accessibility of specific
      epitopes of the particular ligand. Accordingly, various ligands at a wide range
      of concentrations were incubated with magnetic beads and adsorption was then
      assessed using either a specific primary antibody and a secondary alkaline
      phosphatase-conjugated antibody or a specific primary alkaline phosphatase
      conjugated antibody. The method is straightforward and fast and, due to the very
      low nonspecific background binding, it requires extremely small amounts of beads
      and ligand. It can be easily performed on newly prepared beads before using them
      for selection. Magnetic-bead ELISA also confirms the accessibility of specific
      epitopes on the surface of the beads, which corresponds to the primary antibody
      used in the assay.

PMID- 12470677
TI  - Synthesis and characterization of 6-chloroacetyl-2-dimethylaminonaphthalene as a
      fluorogenic substrate and a mechanistic probe for glutathione transferases.
AB  - Here we demonstrate that the thiol-reactive, environmentally sensitive
      fluorogenic molecules 6-bromoacetyl-2-dimethylaminonaphthalene and 6-acryloyl-2
      dimethylaminonaphthalene are substrates for glutathione transferases (GSTs).
      Product formation can be measured by strong increase in fluorescence of the
      glutathione conjugate. As these substances display a high nonenzymatic background
      reaction rate, we have synthesized and characterized 6-chloroacetyl-2
      dimethylaminonaphthalene, which is less reactive, favoring the enzyme-catalyzed
      reaction. 6-Chloroacetyl-2-dimethylaminonaphthalene was found to be a substrate
      for all GSTs tested. Apparent k(cat)/K(m) values (ranging between 10 and 500 mM(
      1)s(-1)) revealed a strong preference for soluble GSTP1-1, GSTA1-1, and activated
      MGST1. Thus, 6-chloroacetyl-2-dimethylaminonaphthalene can be used in a highly
      sensitive assay of these GSTs. 6-Acetyl-2-dimethylaminonaphthalene derivatives
      are very sensitive toward solvent polarity and potentially also toward properties
      of binding sites in proteins. Upon binding of the conjugate to GSTs the
      fluorescence intensity decreased and the emission maximum was blue-shifted.
      Therefore the interaction of the conjugate with GSTs can be characterized with
      regard to both binding affinity and kinetics by stopped-flow measurements, and 6
      chloroacetyl-2-dimethylaminonaphthalene can be a valuable aid in mechanistic
      investigations of GSTs, especially those which possess low intrinsic
      fluorescence.

PMID- 12470678
TI  - Optimizing the enzymatic determination of galactose in the culture medium of rat
      liver and HepG2 cell spheroids.

PMID- 12470679
TI  - Proteolysis during the isoelectric focusing step of two-dimensional gel
      electrophoresis may be a common problem.

PMID- 12470680
TI  - Competitive enzyme-linked immonosorbent assay for N epsilon gamma-glutamyl
      lysine.

PMID- 12470681
TI  - An improved assay for peroxides in lipid emulsion, adapted for a plate reader.

PMID- 12470682
TI  - Expression of two green fluorescent protein variants in citrate-buffered media in
      Pichia pastoris.

PMID- 12470683
TI  - Aging of the brain, sensorimotor, and cognitive processes.

PMID- 12470684
TI  - Structural changes that occur during normal aging of primate cerebral
      hemispheres.
AB  - Human and non-human primates show cognitive decline during normal aging.
      Originally, the decline was attributed to a loss of cortical neurons, but recent
      studies have shown there is no significant cortical neuronal loss with age.
      Neurons acquire pigment, but the only other obvious changes are in layer 1 of
      neocortex. Layer 1 becomes thinner as apical tufts of pyramidal cells lose
      branches, as well as synapses, and at the same time the glial limiting membrane
      thickens. How dendrites and synapses in deep layers are affected by age is
      uncertain, but there are decreases in the levels of some neurotransmitters and
      receptors. Throughout the brain myelin sheaths show signs of breakdown. This may
      contribute to cognitive decline because it would cause a slowing of conduction
      along nerve fibers, disrupting the timing in neuronal circuits. Concomitantly,
      the myelin-forming oligodendrocytes develop swellings along their processes and
      gain dense inclusions. Microglial cells and astrocytes accumulate large amounts
      of phagocytosed material with age, although the origins of this material are not
      known.

PMID- 12470685
TI  - Age-related changes in primary somatosensory cortex of rats: evidence for
      parallel degenerative and plastic-adaptive processes.
AB  - Aged rats show a characteristic decline of the sensorimotor state, most
      strikingly expressed in an impairment of the hindlimbs leading to significantly
      reduced sensory stimulation on the hindpaw. We review recent studies using
      optical imaging and electrophysiological recordings to investigate the effects of
      aging on somatosensory cortex and to identify age-related changes in terms of
      degeneration or plastic adaptation. For the cortical hindpaw representation,
      reduction of map size, receptive field enlargement and reduced response strength
      were described. None of these changes were reported in the forepaw representation
      in the same individual, however, in both the fore-and hindpaw representations
      response latencies and cerebral blood flow were affected. Changes of latencies
      and blood flow are best explained by degeneration, but the regional and specific
      changes of maps, receptive fields and response strength by plastic phenomena
      arising from the reduced sensory inputs. While the degenerative changes are not
      modifiable by enriched environmental conditions or application of Ca(2+) blocker,
      the plastic changes were fully reversible under these conditions. We discuss the
      implications of these findings for cognitive functions at old age and possible
      treatments of age-related changes in human subjects.

PMID- 12470686
TI  - Assessment of age-associated cognitive deficits in rats: a tricky business.
AB  - Every living organism is affected by changes as a consequence of aging. Perhaps
      the most appropriate concept to describe age-related changes is that of
      'functional age'. Laboratory rodents are especially suited as models of cognitive
      aging in humans, because they have a relatively short life-span and because many
      tests have been developed to investigate their cognitive performance. Examples
      from studies using the Morris water escape task were chosen to describe and
      discuss factors which must be considered before drawing conclusions about age
      related cognitive deficits. In particular, the roles of rearing and housing
      conditions, of sensorimotor impairments, and of motivational differences between
      young and old rats are discussed. Conclusions are drawn about how aging studies
      should be conceived and performed.

PMID- 12470687
TI  - Sensorimotor adaptation in young and elderly humans.
AB  - Our brain's capacity for adaptation allows us to interact meaningfully with an
      ever-changing environment. Experimental evidence suggests that the time course of
      sensorimotor adaptation is preserved or only moderately degraded in old age, and
      that seniors benefit from a previous adaptive experience even more than younger
      subjects. However, experimental evidence suggests that sensorimotor adaptation
      seems to be associated with a higher computational load in the elderly. We
      discuss two possible explanations for this pattern of findings: Older adults may
      take longer to consolidate newly gained information into long-term motor memory,
      or they may have problems to utilize supplementary (e.g. cognitive) strategies.
      In any case, the age-related deficits were relatively mild. If these deficits are
      related to an increased computational load, it should be possible to reduce them
      by extended practice on adaptation tasks.

PMID- 12470688
TI  - Aging, expertise and fine motor movement.
AB  - Age-graded decrements in accuracies and maximum speed of fine motor movements
      observed in numerous experimental studies have nurtured general factor
      explanations like the assumption of general age-related slowing of central
      cognitive processes. This review focuses on two domains of investigation that
      yielded challenges to general factor models. First, experimental approaches
      aiming at the decomposition of fine motor skills provide evidence for the
      dissociability of timing, sequencing, and executive control components that show
      differential rather than general age-related changes. Second, studies on
      cognitive-motor expertise demonstrate that age-related changes in critical skill
      components depend on individuals' time investments into specific practice
      activities. It is argued that the process dissociations observed at the
      behavioral level in developmental (i.e. age and expertise) studies reflect
      individuals' long-term adaptations to internal and external performance
      constraints. The outcomes of these adaptation processes are stable
      interindividual differences in component processes.

PMID- 12470689
TI  - Relations between aging sensory/sensorimotor and cognitive functions.
AB  - Recent evidence is reviewed to examine relations among sensory, sensorimotor, and
      cognitive aging. Age-heterogeneous cross-sectional data sets show substantial
      covariation among sensory, sensorimotor and intellectual abilities, and an
      increase in covariation from adulthood to old and very old age. Recent
      longitudinal analyses suggest that changes in sensory and intellectual
      functioning are interrelated. Experimental studies investigate the
      interdependence between cognitive and sensory/sensorimotor aging by examining the
      effects of simulated sensory loss on cognitive performance, or the effects of
      cognitive load manipulations on sensory or motor performance. Generally, both
      types of manipulations hinder older adults' performance more than that of younger
      adults. Theoretically, the age-associated intensification of the links among
      sensory, sensorimotor and cognitive functions observed both correlationally and
      experimentally may point to (a). common causes influencing all three functions;
      (b). an increase in resource overlap, cross-domain resource competition, and
      compensatory tradeoffs; and (c). a combination of the two. Future research aiming
      at discerning the relative import of these possibilities would profit from an
      integration of experimental and correlational research strategies.

PMID- 12470690
TI  - Functional imaging studies of dopamine system and cognition in normal aging and
      Parkinson's disease.
AB  - Modern functional imaging methods, such as positron emission tomography (PET) and
      single photon emission computed tomography (SPECT), provide non-invasive,
      quantitative tools for the direct measurement of neurotransmitter function in the
      living human brain. The dopamine system has been of key interest; first, because
      it has a prominant role in several cognitive and motor processes, and secondly
      because the tracers currently available for the dopamine system enable an
      effective investigation of various pre, post- and intra-synaptic processes.
      Recent functional imaging findings indicate that certain cognitive deficits
      associated with both normal aging and Parkinson's disease are modulated by
      changes in the brain dopamine system. This review covers the literature related
      to age-associated phenomena in the dopamine system studied with in vivo imaging.
      In particular, the focus is on describing and discussing the relationships
      between aging, cognition and the dopaminergic system in healthy subjects and in
      patients with Parkinson's disease.

PMID- 12470691
TI  - Integrative neurocomputational perspectives on cognitive aging, neuromodulation,
      and representation.
AB  - Besides neuroanatomical changes, neuromodulatory mechanisms are also compromised
      during aging. Neural network models are suitable tools for exploring the
      relatively broad and homogenous neuromodulatory influences on cortical function.
      Computational approaches for understanding neuromodulation of the dynamic
      properties of cortical function and recent neurocomputational theories relating
      different aspects of cognitive aging with declines in neuromodulation are
      reviewed. Considered within an integrative cross-level neurocomputational
      framework, aging-related decline in dopaminergic neuromodulation reduces the
      fidelity of neural information and gives rise to less distinctive neural pattern
      representations that may underlie various facets of aging cognitive and, possibly
      also, sensorimotor phenomena.

PMID- 12470692
TI  - A theory of cognitive control, aging cognition, and neuromodulation.
AB  - A theory is described which links cognitive changes observed in normal aging to
      an underlying decline in the function of the dopamine (DA) system projection to
      prefrontal cortex (PFC). The theory postulates that this neural mechanism is
      integral to the representation, maintenance and updating of context information,
      and as such impacts cognitive control across a wide range of cognitive domains,
      including working memory, attention, and inhibition. Behavioral and brain imaging
      data in support of the theory are discussed, which demonstrate selective
      impairments in context processing among healthy older adults associated with
      abnormal PFC activation. These findings highlight the utility of a computational
      approach to cognitive aging. Current directions for further refinement and
      validation of the model are outlined.

PMID- 12470693
TI  - Hemispheric asymmetry and aging: right hemisphere decline or asymmetry reduction.
AB  - We review evidence for two models of hemispheric asymmetry and aging: the right
      hemi-aging model, which proposes that the right hemisphere shows greater age
      related decline than the left hemisphere, and the hemispheric asymmetry reduction
      in old adults (HAROLD) model, which proposes that frontal activity during
      cognitive performance tends to be less lateralized in older than in younger
      adults. The right hemi-aging model is supported by behavioral studies in the
      domains of cognitive, affective, and sensorimotor processing, but the evidence
      has been mixed. In contrast, available evidence is generally consistent with the
      HAROLD model, which is supported primarily by functional neuroimaging evidence in
      the domains of episodic memory encoding and retrieval, semantic memory retrieval,
      working memory, perception, and inhibitory control. Age-related asymmetry
      reductions may reflect functional compensation or dedifferentiation, and the
      evidence, although scarce, tends to support the compensation hypothesis. The
      right hemi-aging and the HAROLD models are not incompatible. For example, the
      latter may apply to prefrontal regions and the former to other brain regions.

PMID- 12470694
TI  - Age-related declines in prospective memory: behavioral and electrophysiological
      evidence.
AB  - Prospective remembering reflects the ability of an individual to form and later
      realize intentions that must be delayed over minutes, hours, or days. A
      substantial body of literature, primarily based upon the findings of behavioral
      studies, indicates that there are robust declines in the efficiency of
      prospective remembering in later adulthood. However, the cognitive and neural
      mechanisms mediating age-related deficits in prospective remembering are not well
      understood. In this review we consider evidence from recent behavioral and
      electrophysiological studies indicating that decreases in the efficiency of
      prospective memory in older adults results from age-related differences in those
      neural mechanisms supporting the encoding of intentions into memory and the
      detection of prospective memory cues in the environment.

PMID- 12470695
TI  - Individual differences in memory enhancement by encoding enactment: relationships
      to adult age and biological factors.
AB  - Numerous studies have demonstrated an age-related decline in episodic memory
      performance. However, both younger and older adults benefit from various kinds of
      encoding support, suggesting that memory functioning remains plastic in older
      age. The present review is concerned with encoding support in the form of
      enactment. Memory for simple commands is substantially higher if the commands are
      enacted during encoding than only read/heard. Such memory enhancement has been
      demonstrated for many age groups and patient groups, suggesting that it is a
      general effect. Analysis of the results from 1000 participants ranging in age
      between 35 and 80 years revealed that about 5% of the participants had low memory
      performance after enacted encoding and showed no enactment effect. The majority
      of these were older. Comparisons of participants that did or did not show an
      enactment effect for a select set of biological and neuropsychological factors
      provided tentative evidence that a failure to benefit from encoding enactment
      reflects a dysfunctional motor system. This is in agreement with findings from
      recent functional neuroimaging studies that associate the enactment effect with
      motor areas in the brain. Variation in the ability to benefit from encoding
      enactment is discussed in relation to an age-related decline in dopamine
      function.

PMID- 12470696
TI  - Genetic variation in memory functioning.
AB  - On the basis of a review of the literature the contribution of genetic factors
      for individual differences in memory performance is discussed. Explorations of
      such influences on memory have just begun. Most of those studies that have been
      conducted in order to find a quantitative trait locus for memory have focused on
      ApolipoproteinE (ApoE). One form of this gene is strongly associated with
      cardiovascular disease in middle age and to late-onset Alzheimer's disease. Some
      studies have demonstrated an association between ApoE and memory even in non
      demented individuals. Other studies have failed to demonstrate this association.
      Based on data from a prospective cohort study (Betula) in our own laboratory, we
      have assessed and examined associations between three different forms of ApoE and
      performance on episodic memory tests. Cross-sectional comparisons revealed non
      significant differences in episodic memory performance between carriers of the
      three alleles. Analyses of change scores in longitudinal data revealed that
      allele epsilon 4 was related to a lower level of memory performance than alleles
      epsilon 2 and epsilon 3. This effect was most pronounced in tasks providing
      cognitive support at both encoding and retrieval, suggesting a deficit in
      utilizing such support in carriers of the epsilon 4 allele.

PMID- 12470697
TI  - Aging, executive control, and attention: a review of meta-analyses.
AB  - We review the results of a series of meta-analyses by the first author and
      colleagues, examining age-related differences in selective attention (Stroop-task
      survey and negative-priming task survey) and in divided attention (dual-task
      survey and task-switching survey). The four task families all lent themselves to
      state trace analysis, in which performance in baseline conditions was contrasted
      with performance in experimental conditions separately for college-aged subjects
      and for elderly subjects. These analyses found no age-related deficits specific
      to selective attention or local task-switching. Age deficits were found for dual
      task performance and global task-switching. Unlike selective attention and local
      task-switching costs, dual-task and global task-switching costs were found to be
      additive in both young and old subjects, unmodulated by task difficulty. These
      forms of executive intervention then did not alter computational processes
      already present in the simple tasks, but rather added one or more additional
      processing steps or stages to the processing stream. The cost was greater in
      older adults, but was limited to those experimental conditions that activated
      multiple task sets.

PMID- 12470698
TI  - Aging, cognition, and culture: a neuroscientific perspective.
AB  - Behavioral studies have suggested some intriguing differences across cultures in
      cognitive processes such as attention to context, the use of categorization,
      stereotypes about aging, and metamemory judgments. Moreover, there is behavioral
      evidence to suggest that, with age, cultural differences in cognition become less
      pronounced, likely due to decreased cognitive resources that may result in more
      similarity across cultures in cognition. The study of the neuroscience of aging,
      culture and cognition, although in its infancy, potentially provides insight into
      the contributions of experience and neurobiology to cognitive function. We review
      initial findings of cross-cultural behavioral aging research in light of
      cognitive neuroscience of aging research and consider the methodological
      challenges and benefits of adding a cross-cultural dimension to the study of the
      cognitive neuroscience of aging.

PMID- 12470699
TI  - Neonatal monosodium glutamate treatment modifies glutamic acid decarboxylase
      activity during rat brain postnatal development.
AB  - Monosodium glutamate (MSG) produces neurodegeneration in several brain regions
      when it is administered to neonatal rats. From an early embryonic age to
      adulthood, GABA neurons appear to have functional glutamatergic receptors, which
      could convert them in an important target for excitotoxic neurodegeneration.
      Changes in the activity of the GABA synthesizing enzyme, glutamic acid
      decarboxylase (GAD), have been shown after different neuronal insults. Therefore,
      this work evaluates the effect of neonatal MSG treatment on GAD activity and
      kinetics in the cerebral cortex, striatum, hippocampus and cerebellum of the rat
      brain during postnatal development. Neonatal MSG treatment decreased GAD activity
      in the cerebral cortex at 21 and 60 postnatal days (PD), mainly due to a
      reduction in the enzyme affinity (K(m)). In striatum, the GAD activity and the
      enzyme maximum velocity (V(max)) were increased at PD 60 after neonatal MSG
      treatment. Finally, in the hippocampus and cerebellum, the GAD activity and
      V(max) were increased, but the K(m) was found to be lower in the experimental
      group. The results could be related to compensatory mechanisms from the surviving
      GABAergic neurons, and suggest a putative adjustment in the GAD isoform
      expression throughout the development of the postnatal brain, since this enzyme
      is regulated by the synaptic activity under physiological and/or
      pathophysiological conditions.

PMID- 12470700
TI  - PnTx3-6 a spider neurotoxin inhibits K+-evoked increase in [Ca2+](i) and Ca2+
      dependent glutamate release in synaptosomes.
AB  - The present experiments investigated the effect of a neurotoxin purified from the
      venom of the spider Phoneutria nigriventer. This toxic component, P. nigriventer
      toxin 3-6 (PnTx3-6), abolished Ca(2+)-dependent glutamate release with an IC(50)
      of 74.4nM but did not alter Ca(2+)-independent secretion of glutamate when brain
      cortical synaptosomes were depolarized by KCl (33mM). This effect was most likely
      due to interference with the entry of calcium through voltage activated calcium
      channels (VACC), reducing the increase in the intrasynaptosomal free calcium
      induced by membrane depolarization with an IC(50) of 9.5nM. We compared the
      alterations induced by PnTx3-6 with the actions of toxins known to block calcium
      channels coupled to exocytosis. Our results indicate that PnTx3-6 inhibition of
      glutamate release and intrasynaptosomal calcium involves P/Q type calcium
      channels and this toxin can be a valuable tool in the investigation of calcium
      channels.

PMID- 12470701
TI  - Pharmacological heterogeneity of release-regulating presynaptic AMPA/kainate
      receptors in the rat brain: study with receptor antagonists.
AB  - Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate
      receptors mediating hippocampal [(3)H]noradrenaline or [(3)H]serotonin release,
      striatal [(3)H]dopamine release and cortical [(3)H]acetylcholine release were
      pharmacologically characterized using several AMPA/kainate receptor antagonists.
      The releases of the four transmitters elicited by exposing synaptosomes to AMPA
      were antagonized by NBQX, indicating that they reflect AMPA/kainate receptor
      activation. GYKI52466 did not inhibit the AMPA-induced release of
      [(3)H]noradrenaline, [(3)H]dopamine or [(3)H]serotonin, while it weakly affected
      the AMPA-mediated release of [(3)H]acetylcholine. On the contrary, LY300164 and
      LY303070 were potent antagonists able to discriminate among AMPA/kainate receptor
      subtypes. Both compounds blocked the AMPA receptors mediating [(3)H]dopamine and
      [(3)H]acetylcholine release. However, LY303070, but not LY300164, inhibited the
      AMPA-induced release of [(3)H]noradrenaline, while the AMPA-mediated
      [(3)H]serotonin release was sensitive to LY300164 but not to LY303070. SYM2206
      mimicked LY300164 and prevented the AMPA-induced release of [(3)H]dopamine,
      [(3)H]acetylcholine and [(3)H]serotonin, but not that of [(3)H]noradrenaline.
      NS102 failed to antagonize the AMPA-induced release of all four transmitters.
      LY293558 prevented the AMPA-mediated release of [(3)H]noradrenaline,
      [(3)H]dopamine, [(3)H]acetylcholine or [(3)H]serotonin. Differently, LY377770 did
      not inhibit the AMPA-mediated release of [(3)H]noradrenaline and
      [(3)H]acetylcholine, but it potently blocked the AMPA-induced release of
      [(3)H]serotonin and, less so, of [(3)H]dopamine. AMOA inhibited the AMPA-induced
      release of [(3)H]serotonin or [(3)H]acetylcholine, but not that of
      [(3)H]noradrenaline or [(3)H]dopamine. GAMS prevented the AMPA-mediated release
      of [(3)H]acetylcholine and, more weakly, that of [(3)H]dopamine, but it failed to
      inhibit the release of [(3)H]noradrenaline or [(3)H]serotonin elicited by AMPA.
      gamma-DGG did not affect the AMPA-mediated release of any of the four
      transmitters studied. In conclusion, based on the antagonist profiles obtained,
      the four receptors here analyzed all belong to the AMPA-preferring subclass of
      glutamate receptors; however, they appear to differ from each other, probably due
      to differences in subunit composition. The compounds LY300164, LY303070,
      LY377770, AMOA and GAMS may be useful to discriminate among AMPA-preferring
      receptor subtypes.

PMID- 12470702
TI  - Baclofen reestablishes striatal and cortical dopamine concentrations during
      naloxone-precipitated withdrawal.
AB  - The present study analyzes the effects of baclofen (BAC) on mice brain
      neurochemical alterations during the morphine (MOR) withdrawal syndrome. Male
      Swiss-Webster albino mice (27-33 g) were rendered dependent by intraperitoneal
      (i.p.) injection of MOR (2mg/kg), twice daily for 9 days. On day 10, the
      dependent animals were divided into two groups: one receiving naloxone (NAL; 6
      mg/kg i.p.) to precipitate the withdrawal syndrome 60 min after the last dose of
      MOR and the other received BAC (2mg/kg, i.p.) followed by NAL (6 mg/kg, i.p.),
      injected 30 and 60 min after the last dose of MOR, respectively. Ten minutes
      after these treatments, mice were killed by decapitation and the striatum, cortex
      and hippocampus were dissected to determine endogenous concentrations of dopamine
      (DA), 5-hydroxytryptamine (5-HT) and their metabolites using HPLC with
      electrochemical detection. Striatal DA, dihydroxyphenyl acetic acid (DOPAC) and
      homovanillic acid (HVA) concentrations as well as cortical DA concentrations of
      the withdrawal groups decreased significantly with respect to the control groups.
      BAC attenuated the decrease in DA and DOPAC concentrations observed during the
      withdrawal, without modifying per se the control DA concentrations. No changes on
      5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) concentrations were
      observed during the MOR abstinence syndrome. The prevention caused by BAC on the
      decreased concentrations of DA induced by MOR withdrawal could have a therapeutic
      interest for the management of withdrawal syndrome.

PMID- 12470703
TI  - Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal
      sclerosis.
AB  - Induction of cyclooxygenase-2 (COX-2) has been described in a wide range of
      neurological diseases including animal models of epilepsy. The present study was
      undertaken to assess COX-2 expression in hippocampal biopsies from patients with
      therapy-refractive temporal lobe epilepsy (TLE). For this purpose, hippocampal
      CA1 subfield was dissected from epileptic patients with (n=5) or without (n=2)
      hippocampal sclerosis (HS). COX-2 expression was investigated using
      immunohistochemistry and semi-quantitative RT-PCR. COX-2 immunoreactivity in TLE
      patient material in the absence of HS was restricted to a few neurons of the
      hippocampus. In the presence of HS, on the other hand, a significant induction of
      astrocytic COX-2 immunoreactivity associated with a concomitant increase in the
      steady-state level of COX-2 mRNA was observed in the CA1 subfield. These findings
      suggest that induction of astrocytic COX-2 is implicated in the pathogenesis of
      HS in TLE and is consistent with the previous findings of increased
      concentrations of prostaglandins in the cerebrospinal fluid of these patients.

PMID- 12470704
TI  - Sulfatide and GM1 ganglioside modulate the high-affinity dopamine uptake in rat
      striatal synaptosomes: evidence for the involvement of their ionic charges.
AB  - The present study was undertaken to examine the effects of the anionic
      glycolipids GM1 ganglioside and sulfatide on the high-affinity dopamine (DA)
      uptake in rat striatal synaptosomes. After 1h of incubation, GM1 stably bound to
      synaptosomes and modified the activity of the neuronal dopamine transporter
      (DAT). With 1.2 and 12 microM GM1, V(max) decreased by 13 and 23%, respectively,
      reflecting a slight reduction of the number of functional uptake sites and K(m)
      was lowered by 21 and 33%, thus showing an increase of the affinity. Treatment of
      synaptosomes with 1.2 microM of sulfatide, which possesses an anionic sulfated
      group, led to a similar decrease of V(max) (19%) than GM1, but to a significantly
      higher reduction of K(m) (35%). In fact, sulfatide associated to synaptosomes in
      a 3.5-fold higher extent than GM1. Conversely, when GM1 and sulfatide were
      replaced by GM1 alcohol and galactosylceramide, respectively, no modification of
      the DA uptake occurred, although these neutral glycolipids incorporated into the
      synaptosomes to the same extent as the related anionic compounds.Altogether,
      these results demonstrate the key role of negative charges linked to the
      oligosaccharide chains of glycolipids in the modulation of DA transport across
      the synaptosomal membrane.

PMID- 12470705
TI  - Activation of constitutive nitric oxide synthase(s) and absence of inducible
      isoform in aged rat brain.
AB  - In this study, the effect of aging on nitric oxide synthases (NOS) was
      investigated in homogenates and cytosolic fractions from hippocampus, brain
      cortex and cerebellum of adult, old adult and old Wistar rats (3-4, 14, and 24
      months old, respectively). Our results indicate the enhancement of Ca(2+) and
      calmoduline-dependent NOS activity in all investigated aged brain parts.
      Significantly higher NOS activity was found in the cerebellum. In the absence of
      Ca(2+) or in the presence of N-nitro-L-arginine (NNLA) the activity of NOS was
      absent. Inhibitor of constitutive NOS isoforms which preferentially inhibits
      neuronal NOS (nNOS), 7-nitroindazole, decreased NOS activity by 60 and 75% in
      adult and aged brain, respectively. However, using RT-PCR a significantly lower
      amount of mRNA for nNOS was detected in hippocampus. The ratio of NOS activity to
      nNOS mRNA was significantly higher in hippocampus and cerebellum of aged brain.
      No expression of the gene for inducible NOS was observed in adult and aged brain.
      These results indicate that probably nNOS is responsible for higher NOS activity
      in aged brain. Our data suggest that alteration of nNOS phosphorylation state may
      be responsible for the activation of NOS in aged brain. The down-regulation of
      nNOS mRNA expression may be an adaptive mechanism that protects the brain against
      excessive NO release.

PMID- 12470706
TI  - Differential toxicity of nitric oxide, aluminum, and amyloid beta-peptide in SN56
      cholinergic cells from mouse septum.
AB  - A characteristic feature of several encephalopathies is preferential impairment
      of cholinergic neurons. Their particular susceptibility to cytotoxic insults may
      result from the fact that they utilise acetyl-CoA both for energy production and
      acetylcholine synthesis. In addition, phenotypic modifications of cholinergic
      neurons are likely to influence their susceptibility to specific harmful
      conditions. SN56 cholinergic cells were differentiated by the combination of
      dibutyryl cAMP and retinoic acid. Al and sodium nitroprusside (SNP, NO donor)
      exerted direct additive inhibitory effects on mitochondrial aconitase activity.
      However, NO, Al, or amyloid beta (Abeta)(25-35) caused none or only slight
      changes of choline O-acetyl transferase (ChAT) and pyruvate dehydrogenase (PDH)
      activity and relatively small loss of non-differentiated cells (NCs). On the
      other hand, in differentiated cells (DCs) these neurotoxins brought about marked
      decreases of these enzyme activities along with greater than in non
      differentiated ones increase of cell-death rate. Abeta(35-25) had no effect on
      these cell parameters. NO and other compounds aggravated detrimental effect of
      each other particularly in differentiated cells. Thus, differential vulnerability
      of brain cholinergic neurons to various degenerative signals may result from
      their phenotype-dependent ratios of acetylcholine to acetyl-CoA synthesising
      capacities.

PMID- 12470707
TI  - Activation of NMDA receptor partly involved in beta-bungarotoxin-induced
      neurotoxicity in cultured primary neurons.
AB  - In this study, we demonstrated that a snake presynaptic toxin, beta-bungarotoxin
      (beta-BuTX), was capable of binding to NMDA receptors of the cultured primary
      neurons (cerebellar granule neurons, CGNs). We labeled beta-BuTX with fluorescent
      FITC (FITC-beta-BuTX) and showed that the binding of FITC-beta-BuTX was inhibited
      by unlabeled beta-BuTX and MK801 (an NMDA receptor antagonist). Meanwhile, the
      binding of [3H]-MK801 was also reduced by unlabeled MK801 and beta-BuTX. In
      addition, beta-BuTX produced a very potent neurotoxic effect on mature CGNs with
      the EC(50) of 3ng/ml (equivalent to 144pM), but was less effective in immature
      CGNs. We explored the signaling pathway of neuronal death and found that it was
      apparently due to the excessive production of reactive oxygen species (ROS)
      induced by beta-BuTX. MK801 and antioxidants (Vitamin C, N-acetylcysteine (NAC),
      melatonin, epigallocatechin gallate (EGCG), superoxide dismutase (SOD) and
      catalase) attenuated not only ROS production but also beta-BuTX-neurotoxicity.
      The downstream signaling of ROS was identified as the activation of caspase-3.
      Caspase inhibitor (z-DEVD-fmk) and antioxidants depressed both caspase-3
      activation and neurotoxicity. Based on these findings and our previous reports,
      we conclude that the binding and activation of NMDA receptors by beta-BuTX was
      crucial step to produce the potent neurotoxic effect. The binding of NMDA
      receptors resulted in excessive Ca(2+) influx, followed by ROS production and
      activation of caspase-3. This snake toxin is considered not only to be a useful
      tool for exploring the death-signaling pathway of neurotoxicity, but also
      provides a model for searching neuroprotective agents.

PMID- 12470708
TI  - Wnt-1 has multiple effects on the expression of glutamate transporters.
AB  - Central Glia-4 (CG-4) glioma cells exhibit Na(+)-dependent glutamate uptake, and
      mRNA for each of the GLT, GLAST, and EAAC glutamate transporters was found in the
      cells by RT-PCR. However, GLT protein in CG-4 cells was not detected by Western
      blotting. The Wnt-1 oncogene markedly decreased the expression of the mRNAs for
      GLT and GLAST glutamate transporters in CG-4 glioma cells. This effect of Wnt-1
      is in direct contrast to its previously published effects on C6 astrocytoma cells
      where Wnt-1 induces the expression of GLT, but not protein, and on PC12
      pheochromocytoma cells where Wnt-1 induces GLAST. We suggest that these
      differences in the ability of Wnt-1 to induce or repress GLT and GLAST are due to
      differences in Wnt-1 dosages or Wnt-1-induced signaling pathways in these cells.
      The abnormal translation of the GLT RNA in Wnt-1-expressing C6 cells was ascribed
      to some abnormality in the processing of the GLT transcript. Consistent with this
      idea is the finding that GLT mRNA was translated in Wnt-1-expressing C6 cells
      when the GLT mRNA required no splicing before translation occurred.

PMID- 12470709
TI  - GABA-glutamate interaction in the control of BDNF expression in hypothalamic
      neurons.
AB  - Brain derived-neurotrophic factor (BDNF) belongs to the neurotrophin family and
      regulates the survival, differentiation and maintenance of function in different
      neuronal populations. We previously reported that glutamate increases the
      expression of BDNF mRNA, its four transcripts and the BDNF peptide in fetal
      hypothalamic neurons, essentially through NMDA receptor activation. In the
      present study, we investigated whether GABA interacts with glutamate in the
      regulation of BDNF gene expression. BDNF and Trk B (BDNF receptor) mRNAs were
      determined by RNAse protection assay. BDNF transcripts expression levels were
      evaluated by semi-quantitative RT-PCR. BDNF peptide content was analyzed by
      enzyme immunoassay (ELISA).We found that picrotoxin (a GABA(A) receptor
      antagonist) stimulated BDNF mRNA expression and that GABA decreased the glutamate
      induced augmentation with no effect on the expression of mRNA encoding the BDNF
      receptor, Trk B. Measurements of BDNF transcripts levels showed that transcripts
      containing exons I and III were increased by picrotoxin, whereas those containing
      exons II and IV were unchanged. GABA solely diminished the glutamate-stimulated
      expression of transcripts containing exon III. In addition, GABA also inhibited
      the stimulatory effect of glutamate on BDNF peptide content. Our findings show an
      interaction between glutamate and GABA on BDNF expression (mRNA, transcripts and
      peptide) in fetal hypothalamic neurons.

PMID- 12470711
TI  - Synthesis and pharmacological characterisation of 2,4-dicarboxy-pyrroles as
      selective non-competitive mGluR1 antagonists.
AB  - Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein
      coupled receptor (GPCR), and are characterised by a large extracellular N
      terminal domain that contains the glutamate binding site. We have identified a
      new class of non-competitive metabotropic glutamate receptor 1 (mGluR1)
      antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency.
      They interact within the 7 transmembrane (7TM) domain of the receptor and show
      antinociceptive properties when tested in a number of different animal models.

PMID- 12470712
TI  - 2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and
      their effects on feeding behavior in rats.
AB  - The melanocortin-4 receptor (MC4) modulates physiological functions such as
      feeding behavior, nerve regeneration, and drug addiction. Using a high throughput
      screen based on (125)I-NDP-MSH binding to the human MC4 receptor, we discovered
      2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor
      agonists. Through SAR development on the three attached aryl rings, we improved
      the binding affinity from 174 nM to 4.4 nM IC(50). When delivered
      intraperitoneally, compounds 3a, 3b, and 3c induced significant inhibition of
      food intake in a fasting-induced feeding model in rats. When delivered orally,
      these compounds lost activity, mainly due to rapid metabolism to inactive
      imidoylthiourea reduction products.

PMID- 12470713
TI  - N-Thiolated beta-lactam antibacterials: defining the role of unsaturation in the
      C4 side chain.
AB  - N-Methylthio beta-lactams represent a novel family of antibacterial agents for
      methicillin-resistant Staphylococcus aureus (MRSA). The structure-activity
      functions and mechanism of action of these compounds, although still largely
      undefined, differ dramatically from those of all previously reported beta-lactam
      antibiotics. Prior work has established that the N-alkylthio moiety is required
      for antibacterial activity, and that a variety of unsaturated groups can be
      tolerated at C(4) of the lactam ring. This report describes the effect that
      unsaturation within the C(4) substituent has on antibacterial activity of these
      interesting new N-thiolated beta-lactams.

PMID- 12470714
TI  - Synthesis and structure-activity relationship studies of novel 2-diarylethyl
      substituted (2-carboxycycloprop-1-yl)glycines as high-affinity group II
      metabotropic glutamate receptor ligands.
AB  - The major excitatory neurotransmitter in the central nervous system, (S)-glutamic
      acid , activates both ionotropic and metabotropic excitatory amino acid
      receptors. Its importance in connection to neurological and psychiatric disorders
      has directed great attention to the development of compounds that modulate the
      effects of this endogenous ligand. Whereas L-carboxycyclopropylglycine (L-CCG-1)
      is a potent agonist at, primarily, group II metabotropic glutamate receptors,
      alkylation of at the alpha-carbon notoriously result in group II mGluR
      antagonists, of which the most potent compound described so far, LY341495,
      displays IC(50) values of 23 and 10 nM at the group II receptor subtypes mGlu2
      and mGlu3, respectively. In this study we synthesized a series of structural
      analogues of in which the xanthyl moiety is replaced by two substituted-phenyl
      groups. The pharmacological characterization shows that these novel compounds
      have very high affinity for group II mGluRs when tested as their racemates. The
      most potent analogues demonstrate K(i) values in the range of 5-12 nM, being thus
      comparable to LY341495.

PMID- 12470715
TI  - Inhibition of dipeptidyl peptidase IV (DPP IV) by 2-(2-amino-1-fluoro
      propylidene)-cyclopentanecarbonitrile, a fluoroolefin containing peptidomimetic.
AB  - Novel, potent inhibitors of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5, CD26),
      containing the fluoroolefin peptide isostere psi [CFz.dbnd6;C], have been
      prepared via the intermediacy of the Peterson fluoroolefination reaction. The
      nitrile containing inhibitors were found to inhibit dipeptidyl peptidase IV
      competitively with K(i) values for the l-3 and u-3 inhibitors of 7.69 and 6.03
      microM, respectively. In contrast to earlier reported fluoroolefin containing
      inhibitors, the nitriles underwent no detectable degradation at pH 7.6 under
      buffered conditions.

PMID- 12470716
TI  - Synthesis of solution-phase combinatorial library of 4,6-diamino-1,2-dihydro
      1,3,5-triazine and identification of new leads against A16V+S108T mutant
      dihydrofolate reductase of Plasmodium falciparum.
AB  - An efficient method to synthesize solution-phase combinatorial library of 1-aryl
      4,6-diamino-1,2-dihydro-1,3,5-triazine was developed. The strategy involved an
      acid-catalyzed cyclocondensation between arylbiguanide hydrochlorides and
      carbonyl compounds in the presence of triethyl orthoacetate as water scavenger. A
      96-membered combinatorial library was constructed from 6 aryl biguanides and 16
      carbonyl compounds. Screening of the library by iterative deconvolution method
      revealed two candidate leads which are equally active against wild-type
      Plasmodium falciparum dihydrofolate reductase, but are about 100-fold more
      effective against the A16V+S108T mutant enzyme as compared to cycloguanil.

PMID- 12470717
TI  - Synthesis of 2-(5-bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-1H-pyrrole analogues
      and their binding affinities for dopamine D2, D3, and D4 receptors.
AB  - A series of 2-(5-bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-1H-pyrrole analogues
      was prepared and their affinity for dopamine D(2), D(3), and D(4) receptors was
      measured using in vitro binding assays. The results of receptor binding studies
      indicated that the incorporation of a pyrrole moiety between the phenyl ring and
      the basic nitrogen resulted in a significant increase in the selectivity for
      dopamine D(3) receptors. The most selective compound in this series is 2-(5-bromo
      2,3-dimethoxyphenyl)-5-(2-(3-pyridal)piperidinyl)methyl-1H-pyrrole (6p), which
      has a D(3) receptor affinity of 4.3 nM, a 20-fold selectivity for D(3) versus
      D(2) receptors, and a 300-fold selectivity for D(3) versus D(4) receptors. This
      compound is predicted to be a useful ligand for studying the functional role of
      dopamine D(3) receptors in vivo.

PMID- 12470718
TI  - A ribozyme with michaelase activity: synthesis of the substrate precursors.
AB  - The ability to generate RNA molecules that can catalyze complex organic
      transformations not only facilitates the reconstruction and plausibility of
      possible prebiotic reaction pathways but is also crucial for elucidating the
      potential of the application of RNA catalysts in organic syntheses. Iterative RNA
      selection previously identified a ribozyme that catalyzes the Michael addition of
      a cysteine thiol to an alpha,beta-unsaturated amide. This reaction is chemically
      similar to the rate limiting step of the thymidylate synthase reaction, which is
      the corresponding reaction of a cysteine thiol to the double-bond of the uracil
      nucleobase. Here we provide a detailed description of the synthesis of the
      ribozyme substrates and the substrate oligonucleotides used for its
      characterization and the investigation of the background reaction. We also
      describe the further characterization of the ribozyme with respect to substrate
      specificity. We show that the thiol group of the cysteine nucleophile is
      essential for the reaction to proceed. When substituted for a thiomethyl group,
      no reaction takes place.

PMID- 12470719
TI  - Tricyclic pyrazoles. Part 1: synthesis and biological evaluation of novel 1,4
      dihydroindeno[1,2-c]pyrazol-based ligands for CB1and CB2 cannabinoid receptors.
AB  - Cannabinoids receptors, cellular elements of the endocannabinoid system, have
      been the focus of extensive studies because of their potential functional role in
      several important physiological and pathological processes. To further evaluate
      the properties of CB receptors, especially CB(1) and CB(2) subtypes, we have
      designed, using SR141716A as a benchmark, a new series of rigid 1-aryl-1,4
      dihydroindeno[1,2-c]pyrazole-3-carboxamides. Compounds 1 were synthesized from
      substituted 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acids and
      requisite amines. The various analogues were assayed for binding both to the
      brain and peripheral cannabinoid receptors (CB(1) and CB(2)). Seven of the new
      compounds displayed very high in vitro CB(2) binding affinities, especially 1a,
      1b, 1c, 1e, 1g, 1h and 1j which showed K(i) values of 0.34, 0.225, 0.27, 0.23,
      0.385, 0.037 and 0.9 nM, respectively. Compounds 1a, 1b, 1c and 1h showed the
      highest selectivity for CB(2) receptor with K(i)(CB(1)) to K(i)(CB(2)) ratios of
      6029, 5635, 5814 and 9810, respectively. Noticeably, 1h exhibited the highest
      affinity and selectivity for CB(2) receptors.

PMID- 12470720
TI  - Anti-MRSA cephems. Part 2: C-7 cinnamic acid derivatives.
AB  - Forty-five novel cephalosporin derivatives with activity against methicillin
      resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel
      cinnamic acid moieties at C-7 that were synthesized using a key Heck reaction
      followed by nucleophilic aromatic substitution reactions. The most active
      compound (41) displayed an MIC(90) against MRSA of 1.0 microg/mL, and a PD(50) of
      0.8 mg/kg. Compound 14 was found to be very safe in a mouse model of acute
      toxicity.

PMID- 12470721
TI  - Anti-MRSA cephems. Part 3: additional C-7 acid derivatives.
AB  - Twenty-seven novel cephalosporin derivatives with activity against methicillin
      resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel
      acid moieties at C-7 that were synthesized using nucleophilic aromatic
      substitution reactions and Stille couplings. The most interesting compound (6)
      displayed an MIC(90) against MRSA of 3.7 microg/mL, and an average PD(50) of 3.9
      mg/kg.

PMID- 12470724
TI  - Lipid-lipid recognition in fluid bilayers: solving the cholesterol mystery.
AB  - Nearest-neighbour recognition measurements take 'molecular-level snapshots' of
      lipid organization in fluid bilayers by detecting and quantifying the
      thermodynamic tendency of two lipids to become nearest-neighbours. Recent nearest
      neighbour recognition experiments have clarified the structural role that
      cholesterol plays in biological membranes. They have also clarified the influence
      that the linkage region of sphingolipids, the sugar head group of glycolipids,
      and lipid-peptide interactions have on lipid-lipid recognition.

PMID- 12470725
TI  - Aromatic interactions in model systems.
AB  - A thorough knowledge of noncovalent interactions is crucial to the understanding
      of biological complexity. One of the less well understood but significant weak
      interactions in nature is the aromatic interaction. Recent studies have provided
      new insight into the driving force, stability and selectivity of these
      interactions. The contribution of solvophobic and electrostatic interactions have
      been shown to be inextricably linked. Moreover, the influence of electrostatic
      and solvophobic components on the selectivity of aromatic interactions has been
      demonstrated.

PMID- 12470726
TI  - Biological applications of dendrimers.
AB  - In the past year, significant advances have been made in the synthesis and study
      of glycodendrimers and peptide dendrimers. Application of these dendrimers to the
      study of carbohydrate-protein and protein-protein interactions has facilitated
      the understanding of these processes. In addition, dendrimers show great promise
      as DNA- and drug-delivery systems.

PMID- 12470727
TI  - Synthetic membrane transporters.
AB  - An increasing number of synthetic compounds have been shown to facilitate ion and
      polar molecule transport across bilayer membranes. Most notably, recent advances
      in anion transport have yielded synthetic chloride channels and phospholipid
      translocases. Attention has also turned to the ability of short amino acid
      sequences to transport peptides and proteins across cellular membranes.

PMID- 12470728
TI  - Multicomponent metal-ligand self-assembly.
AB  - Self-assembly of pre-designed organic ligands with transition metal atoms is a
      powerful method for construction of novel supramolecular architectures.
      Particularly, various discrete 3-D hollow structures such as cages, cones,
      capsules and boxes have been obtained by multicomponent self-assembly of exo
      multidentate ligands with cis-protected square planar metal complexes,
      [(L)M](NO(3))(2) (where L is ethylenediamine or 2,2'-bipyridine and M is Pd or
      Pt). Furthermore, these hollow structures act as molecular flasks to encapsulate
      guest molecules and regulate/promote specific reactions; for example,
      oligomerization of silanetriols and [2+2] intermolecular photodimerization of
      olefins.

PMID- 12470729
TI  - Modular design of artificial transcription factors.
AB  - Eukaryotic transcription factors are composed of interchangeable modules. This
      has led to the design of a wide variety of modular artificial transcription
      factors (ATFs) that can stimulate or inhibit the expression of targeted genes.
      The ability to regulate the expression of any targeted gene using a
      'programmable' ATF offers a powerful tool for functional genomics and bears
      tremendous promise in developing the field of transcription-based therapeutics.

PMID- 12470730
TI  - Nonnatural substrates for polyketide synthases and their associated modifying
      enzymes.
AB  - Polyketides are a large class of structurally diverse, biologically active
      natural products. Recent experiments add evidence that many of the enzymes
      involved in the biosynthesis of these natural products are intrinsically tolerant
      of nonnatural substrates. In addition, an increasing understanding of structure
      function relationships in various enzyme-substrate systems is aiding efforts to
      begin engineering these proteins for even greater synthetic utility.

PMID- 12470731
TI  - The decomposition of thionitrites.
AB  - The mechanism of thionitrite decomposition, both in vivo and in vitro, remains
      unclear. Thionitrite stability is highly variable; it is a complex function of
      thionitrite structure and environmental condition. Several recent advances
      clarify the role of unimolecular homlytic decomposition, metal-catalyzed
      reductive decomposition and higher-order enzymatic and non-enzymatic processes to
      the overall observed stability of thionitrites.

PMID- 12470732
TI  - Substrate analogues to study cell-wall biosynthesis and its inhibition.
AB  - It has been known for more than 30 years that Lipid II is an intermediate in
      peptidoglycan synthesis. Recently, it has become apparent that it is also an
      important target of numerous antibiotics, including the glycopeptides, the
      lantibiotics and ramoplanin. It is also utilized by sortases in the construction
      of Gram-positive cell walls. Recent progress has been made in the synthesis of
      peptidoglycan intermediates that can be used to study enzymes which make
      peptidoglycan. These intermediates also enable studies to probe the mechanism of
      action of a variety of substrate-binding antibiotics.

PMID- 12470733
TI  - What can surface chemistry do for cell biology?
AB  - Recent research has enhanced the development of substrates that serve as models
      of extracellular matrix and their use in studies of cell adhesion and migration.
      Advances include the development of methods to prepare substrates having ligands
      immobilized in controlled densities and patterns, and recent work that is
      developing dynamic substrates which can modulate, in real-time, the activities of
      ligands. These technologies are providing new opportunities for studies of cell
      extracellular-matrix interactions.

PMID- 12470734
TI  - Antimicrobial peptides from amphibian skin: an expanding scenario.
AB  - Many organisms employ antimicrobial peptides to fend off microbial pathogens.
      Amphibian skin is one of the most generous sources of these peptides. In the past
      couple of years, intriguing additional insights on various aspects of frog skin
      peptides have been reported. Several novel molecules, often with unprecedented
      structural features, have been discovered. Studies focusing on the factors that
      regulate the in vivo synthesis of skin peptides in response to infection have
      gained in prominence. Moreover, recent results indicate new possibilities for the
      development of effective human therapeutics based on antimicrobial peptides and
      partially disclosed the biotechnological potential of these molecules.

PMID- 12470735
TI  - Incorporation of non-natural amino acids into proteins.
AB  - Chemical and biological diversity of protein structures and functions can be
      widely expanded by position-specific incorporation of non-natural amino acids
      carrying a variety of specialty side groups. After the pioneering works of
      Schultz's group and Chamberlin's group in 1989, noticeable progress has been made
      in expanding types of amino acids, in finding novel methods of tRNA
      aminoacylation and in extending genetic codes for directing the positions.
      Aminoacylation of tRNA with non-natural amino acids has been achieved by directed
      evolution of aminoacyl-tRNA synthetases or some ribozymes. Codons have been
      extended to include four-base codons or non-natural base pairs. Multiple
      incorporation of different non-natural amino acids has been achieved by the use
      of a different four-base codon for each tRNA. The combination of these novel
      techniques has opened the possibility of synthesising non-natural mutant proteins
      in living cells.

PMID- 12470736
TI  - Biosensors for DNA sequence detection.
AB  - DNA biosensors are being developed as alternatives to conventional DNA
      microarrays. These devices couple signal transduction directly to sequence
      recognition. Some of the most sensitive and functional technologies use fibre
      optics or electrochemical sensors in combination with DNA hybridization. In a
      shift from sequence recognition by hybridization, two emerging single-molecule
      techniques read sequence composition using zero-mode waveguides or electrical
      impedance in nanoscale pores.

PMID- 12470737
TI  - Single-molecule fluorescence of nucleic acids.
AB  - Less than a decade old, single-molecule fluorescence of nucleic acids has rapidly
      become an important tool in the arsenal of biological probes. A variety of novel
      approaches to investigate conformational dynamics, catalytic mechanisms, folding
      pathways and protein-nucleic-acid interactions have recently been devised for
      nucleic acids using this technique. Combined with biomechanical tools and
      ensemble measurements, single-molecule fluorescence methods extend our ability to
      observe and understand biomolecules and complex biological processes.

PMID- 12470738
TI  - RNAi and related mechanisms and their potential use for therapy.
AB  - Introduction of double-stranded RNAs into cells can suppress gene expression by
      mechanisms such as mRNA degradation or inhibition of translation. In mammalian
      cells, these two responses intersect, a feature that was recently used for the
      development of novel tools for stable and specific gene inactivation. These new
      tools were successfully applied to inhibit tumorigenicity and viral replication.
      Future development of appropriate in vivo delivery systems may make this
      technology useful for disease therapy.

PMID- 12470739
TI  - RNomics: identification and function of small, non-messenger RNAs.
AB  - In the past few years, our knowledge about small non-mRNAs (snmRNAs) has grown
      exponentially. Approaches including computational and experimental RNomics have
      led to a plethora of novel snmRNAs, especially small nucleolar RNAs (snoRNAs).
      Members of this RNA class guide modification of ribosomal and spliceosomal RNAs.
      Novel targets for snoRNAs were identified such as tRNAs and potentially mRNAs,
      and several snoRNAs were shown to be tissue-specifically expressed. In addition,
      previously unknown classes of snmRNAs have been discovered. MicroRNAs and small
      interfering RNAs of about 21-23 nt, were shown to regulate gene expression by
      binding to mRNAs via antisense elements. Regulation of gene expression is exerted
      by degradation of mRNAs or translational regulation. snmRNAs play a variety of
      roles during regulation of gene expression. Moreover, the function of some
      snmRNAs known for decades, has been finally elucidated. Many other RNAs were
      identified by RNomics studies lacking known sequence and structure motifs. Future
      challenges in the field of RNomics include identification of the novel snmRNA's
      biological roles in the cell.

PMID- 12470740
TI  - Oligosaccharyl transferase: gatekeeper to the secretory pathway.
AB  - Oligosaccharyl transferase is part of the macromolecular machinery that processes
      nascent proteins in the endoplasmic reticulum. The enzyme is highly conserved,
      catalyzes the initial step in the biosynthesis of N-linked glycoproteins and acts
      as a 'gatekeeper' for the secretory pathway. As more proteins associated with
      oligosaccharyl transferase are identified, the intricacies of the enzyme and the
      relationship with other proteins in the lumen of the endoplasmic reticulum are
      starting to be unraveled.

PMID- 12470741
TI  - Diverse regulation of protein function by O-GlcNAc: a nuclear and cytoplasmic
      carbohydrate post-translational modification.
AB  - N-Acetylglucosamine O-linked to serines and threonines of cytosolic and nuclear
      proteins (O-GlcNAc) is an abundant reversible post-translational modification
      found in all higher eukaryotes. Evidence for functional regulation of proteins by
      this dynamic saccharide is rapidly accumulating. Deletion of the gene encoding
      the enzyme that attaches O-GlcNAc (OGT) is lethal at the single cell level,
      indicating the fundamental requirement for this modification. Recent studies
      demonstrate a role for O-GlcNAcylation in processes as diverse as transcription
      in the nucleus and signaling in the cytoplasm, suggesting that O-GlcNAc has both
      protein and site-specific influences on biochemistry and metabolism throughout
      the cell.

PMID- 12470742
TI  - Milestones in directed enzyme evolution.
AB  - Directed evolution has now been used for over two decades as an alternative to
      rational design for protein engineering. Protein function, however, is complex,
      and modifying enzyme activity is a tall order. We can now improve existing enzyme
      activity, change enzyme selectivity and evolve function de novo using directed
      evolution. Although directed evolution is now used routinely to improve existing
      enzyme activity, there are still only a handful of examples where substrate
      selectivity has been modified sufficiently for practical application, and the de
      novo evolution of function largely eludes us.

PMID- 12470743
TI  - Design of nanostructured biological materials through self-assembly of peptides
      and proteins.
AB  - Several self-assembling peptide and protein systems that form nanotubes, helical
      ribbons and fibrous scaffolds have recently emerged as biological materials.
      Peptides and proteins have also been selected to bind metals, semiconductors and
      ions, inspiring the design of new materials for a wide range of applications in
      nano-biotechnology.

PMID- 12470744
TI  - Mimicry of bioactive peptides via non-natural, sequence-specific peptidomimetic
      oligomers.
AB  - Non-natural, sequence-specific peptidomimetic oligomers are being designed to
      mimic bioactive peptides, with potential therapeutic application. Cationic,
      facially amphipathic helical beta-peptide oligomers have been developed as
      magainin mimetics. Non-natural mimics of HIV-Tat protein, lung surfactant
      proteins, collagen, and somatostatin are also being developed. Pseudo-tertiary
      structure in beta-peptides and peptoids may herald the creation of entirely
      artificial proteins.

PMID- 12470745
TI  - Experimental and computational studies of determinants of membrane-protein
      folding.
AB  - Recent experiments and analysis have demonstrated the important roles of hydrogen
      bonding and polar-polar interactions in driving transmembrane helix-helix
      association. Further details of the energetics of helix-helix association and
      interhelical packing geometry are being mapped out. Many sequence motifs and a
      few spatial motifs promoting helical associations have also been identified.

PMID- 12470746
TI  - Epithelial ingrowth after laser in situ keratomileusis: clinical features and
      possible mechanisms.
AB  - PURPOSE: To analyze the incidence, clinical course, and possible mechanisms of
      epithelial ingrowth after laser in situ keratomileusis (LASIK). DESIGN:
      Interventional case series. METHODS: Retrospective evaluation of 4,867 eyes of
      2,502 patients who had LASIK. The type of microkeratome (LSK-One or MK-2000),
      corneal flap thickness, and clinical course were analyzed. We also compared the
      cutting characteristics of both microkeratomes in pig cadaver eyes by scanning
      electron microscopy. RESULTS: The frequency of epithelial ingrowth was
      significantly greater in the MK-2000 (34 of 1,680 eyes; 2.0%) than the LSK-One
      group (30 of 3,187 eyes; 0.94%; P =.001). In 24 eyes (37.5%), blood, cell
      infiltration, ointment under the corneal flaps, or epithelial defect were
      detected at the area of epithelial ingrowth postoperatively. The incidence of
      epithelial ingrowth was correlated with the incidence of epithelial defect during
      surgery (P <.001) and with incidence of diffuse lamellar keratitis after surgery
      (P =.003). Flap thickness was thinner in eyes with epithelial ingrowth (126.0 +/-
      29.1 microm) compared with flap thickness in eyes without epithelial ingrowth
      (133.8 +/- 27.3 microm; P <.001). Scanning electron microscopy showed clear
      differences in the appearance of flap edges created by the two types of
      microkeratomes. Epithelial ingrowth disappeared or remained unchanged in 54 eyes
      (90%) and progressed in six cases (10%). CONCLUSIONS: Poor adhesion caused by
      excessive hydration due to epithelial defect as well as by foreign bodies between
      the flap stromal bed and thickness and morphologic characters of the corneal
      flap, depending on the type of microkeratomes, are related factors for
      development of epithelial ingrowth.

PMID- 12470747
TI  - Implantation of scleral expansion band segments for the treatment of presbyopia.
AB  - PURPOSE: To assess the effects of scleral expansion band (SEB) segments on
      accommodative amplitude (primary measure), along with near and distance vision,
      refraction, pupil size and function, keratometry, axial length, intraocular
      pressure, contrast sensitivity, stereopsis, and other parameters (secondary
      measures) in a cohort of 29 emmetropic, presbyopic patients. DESIGN: Multicenter,
      prospective, nonrandomized, unmasked clinical trial in which the nonoperated eye
      served as the control. METHODS: Four polymethylmethacrylate segments were
      surgically implanted in quadrantic scleral pockets created in the dominant eye of
      29 emmetropic patients who were between the ages of 51 and 60 (mean age 54).
      Patients were examined preoperatively and up to 6 months postoperatively. The
      aforementioned tests were performed on the operated and control eye of each
      patient. Data were analyzed using two-sided rank tests. Medians, means, and
      standard deviations are provided for all measurements. RESULTS: Accommodative
      amplitude was measured monocularly using a near-point "push" technique from both
      a 70-cm and 30-cm starting point. An increase in accommodative amplitude of
      surgical eyes by +1.7 +/- 1.5 diopters and +1.5 +/- 1.2 diopters, at these two
      testing distances, respectively, was noted at 6 months postoperatively (P
      <.0001). A smaller increase was also seen in control eyes (+1.2 +/- 1.1 diopters
      and +1.3 +/- 1.2 diopters, respectively). There was notable intercenter variation
      in gains in accommodation, with three of seven centers showing significant
      improvement in near-point accommodative amplitudes relative to the others (P
      =.0003). There was a median improvement of uncorrected near acuity in surgical
      eyes by 0.3 logarithm of the minimal angle of resolution (logMAR) at 30 and 40 cm
      and by 4 lines at 20 cm, with the difference in near acuity improvement at 6
      months between SEB eyes and control eyes statistically significant at 20 cm (P
      <.030). Changes in spherical equivalence, axial length, and central keratometry
      readings were not statistically significant. There were no reports of anterior
      segment ischemia or malignant glaucoma. Adverse effects were limited to a
      transient elevation of intraocular pressure in one patient and misalignment of
      individual SEB segments, due to inadequate scleral pocket formation, in three
      patients. Only one SEB segment in one eye was replaced. It appears that the
      thickness and uniformity of the scleral belt loop is critical to the proper
      positioning and efficacy of the SEB segments. CONCLUSION: While the safety
      profile of SEB segments for the treatment of presbyopia was high, a modest
      improvement in near vision was noted in approximately half the patients using
      subjective methods of testing. The mechanisms that underlie improvement in near
      vision in the nonoperated eye await explanation. This may be due to a centrally
      controlled consensual response, potentiated convergence generating increased
      intravitreal pressure and hydraulic lift of the vitreo-zonular-lens diaphragm, or
      artifact from current testing techniques. Future studies of the SEB procedure
      should address the issue of intercenter variation by further standardizing and
      automating specific aspects of the surgical technique, as well as incorporating
      objective testing methods into the study design.

PMID- 12470748
TI  - Toxic eosinophil granule protein deposition in corneal ulcerations and scars
      associated with atopic keratoconjunctivitis.
AB  - PURPOSE: Recurrent or persistent corneal erosions and ulcerations are typical
      complications of atopic keratoconjunctivitis. Toxic eosinophil granule proteins
      such as major basic protein (MBP) and eosinophil cationic protein (ECP) may be
      involved in this pathogenetic process. This study was designed to demonstrate the
      presence of toxic eosinophil granule proteins in corneal tissue from a patient
      with corneal complications of atopic keratoconjunctivitis. DESIGN: Observational
      case report. METHODS: Three corneal buttons of a patient with atopic
      keratoconjunctivitis associated ulcerations or scarring were examined by light
      microscopy and by immunofluorescence technique. RESULTS: A linear deposition of
      eosinophil granular substance was detected subepithelially above Bowman's
      membrane in all corneal buttons. Indirect immunofluorescence identified this
      material as MBP and ECP. The deposits were not limited to the area of ulceration,
      but were also found underneath intact corneal epithelium. Multiple eosinophils
      were present in the upper corneal stroma. Normal corneas and negative control
      sections of the pathologic buttons revealed only minimal nonspecific staining at
      the surface of the epithelium. CONCLUSIONS: Both MBP and ECP are known to affect
      human corneal epithelial cell viability and morphology in vitro. Moreover, MBP
      was shown to inhibit epithelial migration and protein synthesis. These toxic
      eosinophil proteins may also be responsible for corneal instability, recurrent
      and persistent corneal epithelial defects and ulcerations in patients with atopic
      keratoconjunctivitis.

PMID- 12470749
TI  - Detachment of subfoveal choroidal neovascularization in age-related macular
      degeneration.
AB  - PURPOSE: To report the entity of partial detachment and folding of subfoveal
      choroidal neovascularization (CNV) in age-related macular degeneration (ARMD).
      DESIGN: Interventional case reports. METHODS: Review of the features of CNV
      detachment in two patients with CNV due to ARMD by contact lens slit-lamp
      biomicroscopy, fluorescein angiography, optical coherence tomography, and three
      dimensional confocal scanning laser indocyanine green (ICG) angiography. RESULTS:
      One patient out of approximately 300 (0.5%) ARMD patients treated by photodynamic
      therapy (PDT) developed partial CNV detachment and folding 6 weeks after the
      second PDT treatment. Another patient out of approximately 100 (1.0%) ARMD
      patients treated by transpupillary thermotherapy (TTT) developed partial CNV
      detachment and folding 6 weeks after the second TTT treatment. The CNVs were
      large (2,500 microm to 4,500 microm) and located between the retina and the
      retinal pigment epithelium. In each, these findings were clearly visualized by
      slit-lamp biomicroscopy. Fluorescein angiography demonstrated an associated
      retinal pigment epithelium tear in one patient. Optical coherence tomography
      showed distinctive features and confocal scanning laser ICG further delineated
      the detached folded CNV. The best-corrected visual acuity improved in one patient
      from 20/80 to 20/40 and in the other from counting fingers at 6 feet to 20/200
      after the CNV detachment. CONCLUSIONS: Partial CNV detachment and folding
      represent a unique, not previously reported, and possibly favorable outcome of
      PDT and TTT. The low energy and selectivity of these treatments may explain this
      phenomenon.

PMID- 12470750
TI  - Is early age-related maculopathy related to cognitive function? The
      Atherosclerosis Risk in Communities Study.
AB  - PURPOSE: Age-related maculopathy (ARM) and cognitive impairment are both
      neurodegenerative disorders associated with aging and have been hypothesized to
      share common pathogenic pathways. We describe the association between cognitive
      function and ARM in middle-aged persons. DESIGN: Population-based, cross
      sectional study involving participants of the Atherosclerosis Risk in Communities
      Study, an ongoing cardiovascular investigation of persons 51 to 70 years of age,
      examined every 3 years between 1987 to 1998. METHODS: At visit three (1993-1995),
      retinal photographs were obtained and evaluated for ARM using a modification of
      the Wisconsin ARM Grading System. Cognitive function was assessed using
      standardized tests (Delayed Word Recall, Digit Symbol, and Word Fluency) at
      visits two (1990-1992) and four (1996-1998) and averaged for analysis. Severe
      cognitive impairment was defined as scores falling in the lowest 10th percentile
      of the population. RESULTS: Data were available in 9286 persons after exclusion
      of persons with stroke or using antipsychotic medication. After adjusting for
      age, gender, race, education, diabetes, hypertension, cigarette smoking, and
      alcohol consumption, persons with severe cognitive impairment based on Word
      Fluency Test scores were more likely to have early ARM (odds ratio [OR]: 1.6, 95%
      confidence interval [CI]: 1.1-2.2) and its components, soft drusen (OR: 1.6; 95%
      CI: 1.1-2.3) and pigmentary abnormality (OR: 1.5; 95% CI: 0.9-2.5) than those
      without severe impairment. However, severe cognitive impairment in scores of the
      other two cognitive function tests was not associated with ARM. CONCLUSION: These
      population-based data suggest a weak association between cognitive function and
      early ARM in middle-aged persons.

PMID- 12470751
TI  - Indocyanine green-assisted peeling of the internal limiting membrane in macular
      hole surgery affects visual outcome: a clinicopathologic correlation.
AB  - PURPOSE: To report the ultrastructure of the internal limiting membrane (ILM)
      after macular hole surgery with indocyanine green (ICG) staining and to
      investigate an association with the postoperative functional outcome. DESIGN:
      Retrospective, noncomparative analysis of a consecutive case series. METHODS:
      Twenty eyes of 20 patients after macular hole surgery with ICG staining were
      included. Visual acuity and Goldmann perimetry were obtained before and after
      surgery. The ILM was obtained during three-port pars plana vitrectomy for
      idiopathic macular hole. Twenty-five milligrams of sterile ICG powder was
      dissolved in 5 ml of sterile water as recommended by the manufacturer and then
      diluted in balanced salt solution. The ultrastructure of the ILM was analyzed
      using light and transmission electron microscopy. Osmolarity and pH of the ICG
      solution were measured preoperatively. RESULTS: There was no statistically
      significant improvement of postoperative visual acuity after ICG-assisted peeling
      (P =.755). In seven patients, postoperative visual field defects occurred.
      Indocyanine green-stained specimens revealed cellular elements resembling the
      plasma membrane of Muller cells and other undetermined retinal structures
      adherent to the retinal side of the ILM. Histologic findings disclosed no
      difference between patients with and without visual field defects after the use
      of ICG. The osmolarity of the ICG solution applied was 275 mOsm; pH was 7.5.
      CONCLUSIONS: Intravitreal application of ICG may cause retinal damage by altering
      the cleavage plane to the innermost retinal layers. That may result in less
      improvement of visual acuity and unexpected visual field defects. The underlying
      mechanisms of action remain unclear and are the subject of ongoing
      investigations.

PMID- 12470752
TI  - Association between reproductive and hormonal factors and age-related maculopathy
      in postmenopausal women.
AB  - PURPOSE: The relationships between reproductive risk factors, including use of
      hormone replacement therapy and oral contraceptives and severity of age-related
      maculopathy (ARM) among postmenopausal women were evaluated. We hypothesized that
      exposure to endogenous or exogenous estrogens would be associated with a reduced
      risk of advanced ARM. DESIGN: Cross-sectional study. METHODS: The 394 subjects
      were postmenopausal women with ARM. Logistic regression analysis was used to
      compare the effects of several reproductive factors across two groups: 193
      subjects with nonadvanced ARM and 201 subjects with advanced ARM. RESULTS: Women
      with ARM who had used postmenopausal estrogen therapy in the past had
      significantly lower odds of advanced ARM than nonusers, after controlling for
      other known and potential risk factors (odds ratio [OR] = 0.5, 95% confidence
      interval [CI] = 0.30 to 0.98). Older age at menarche was associated with
      increased odds of advanced ARM (OR = 1.16, 95% CI = 1.00 to 1.35). CONCLUSIONS:
      These findings suggest that exposure to exogenous estrogens may have a beneficial
      effect of reducing the risk of advanced types of ARM in postmenopausal women with
      ARM. Few therapeutic or preventive measures currently exist for ARM; therefore,
      these results deserve further evaluation.

PMID- 12470753
TI  - Reading ability after macular translocation surgery with 360-degree retinotomy.
AB  - PURPOSE: To report reading ability using a standardized reading chart after
      macular translocation with 360-degree retinotomy in eyes with age-related macular
      degeneration (AMD) or with myopic choroidal neovascularization (mCNV). DESIGN:
      Interventional case series. METHODS: In 34 eyes of 34 patients with subfoveal
      choroidal neovascular membrane (AMD, 23; mCNV, 11), macular translocation surgery
      with 360-degree retinotomy and simultaneous extraocular muscle surgery were
      performed. The average age was 67.4 +/- 7.9 years, and the average follow-up
      period was 7.6 +/- 3.3 months. The best-corrected far visual acuity (FVA) was
      measured with a standardized visual acuity chart using Landolt Cs, and the
      critical print size (CPS) was determined with the Japanese version of the
      Minnesota reading chart (MNREAD-J Chart) preoperatively and postoperatively.
      Preoperative and postoperative change in the CPS was compared with the subjective
      visual improvement as assessed by a questionnaire. RESULTS: The postoperative
      improvement of FVA was statistically significant in eyes with mCNV (P =.010) but
      not significant in eyes with AMD (P =.495). The postoperative improvement of CPS
      was statistically significant both in eyes with AMD (P =.027) and in eyes with
      mCNV (P =.004). The subjective visual improvement was significantly correlated
      with the change of CPS in patients after a second better eye surgery.
      CONCLUSIONS: After macular translocation with 360-degree retinotomy, the
      improvement of reading ability was significant in eyes with both AMD and mCNV. We
      conclude that this surgical method is well suited to improve reading ability of
      patients with AMD or mCNV.

PMID- 12470754
TI  - Impact of graphical user interface screen features on computer task accuracy and
      speed in a cohort of patients with age-related macular degeneration.
AB  - PURPOSE: To investigate the impact of graphical user interface screen features on
      computer task performance in patients with age-related macular degeneration
      (AMD). DESIGN: Interventional case series. METHODS: Eighteen patients with visual
      impairment due to AMD were recruited from the Bascom Palmer Eye Institute Low
      Vision Clinic. Each patient underwent evaluation of visual acuity using the Early
      Treatment Diabetic Retinopathy Study protocol, contrast sensitivity using a Pelli
      Robson chart, binocular simultaneous visual field using the Esterman program on
      an automated perimeter, and color vision using Farnsworth D-15. Each subject then
      completed computer icon identification tasks while the following screen features
      of the graphical user interface were varied: size of icons displayed, icon set
      size (number of icons displayed), and background color. Each patient performed
      all 125 computer tasks with each of five icon sizes (9.2 mm, 14.6 mm, 23.2 mm,
      36.8 mm, 58.3 mm), each of five icon set sizes (2, 3, 4, 5, 6), and each of five
      different background colors (black, white, red, green, blue) in a randomly
      ordered fashion. Relationships between computer task performance (accuracy and
      speed) and graphical user interface screen features were studied. RESULTS: Icon
      size and icon set size are significantly associated with computer task accuracy
      (P <.001), whereas background color is not a significant predictor of task
      accuracy (P =.63). The impact of icon size on accuracy is nonlinear, with the
      data indicating that no additional improvement in accuracy is associated with
      increasing the icon size beyond 23.2 mm. The impact of icon set size on accuracy
      is linear, with a smaller icon set size significantly associated with greater
      computer accuracy. A larger icon size is significantly associated with a shorter
      time to task completion (P =.001); this relationship is largely linearly related
      to icon size. There was no significant impact of background color (P =.11) or set
      size (P =.37) on time to task completion. CONCLUSIONS: Modifications of graphical
      user interface design may permit improved computer task performance among
      patients with visual impairment due to AMD.

PMID- 12470755
TI  - Randomized clinical trial of latanoprost and unoprostone in patients with
      elevated intraocular pressure.
AB  - PURPOSE: To compare the intraocular pressure (IOP)-lowering effect and safety of
      latanoprost 0.005% once daily with that of unoprostone 0.15% twice daily for
      patients with primary open-angle glaucoma or ocular hypertension. DESIGN:
      Randomized clinical trial. METHODS: In a prospective, 8-week, investigator
      masked, parallel-group study conducted at numerous centers in the United States,
      165 previously treated patients with IOP >or= 25 mm Hg in one or both eyes after
      washout were randomly assigned to receive either latanoprost 0.005% once daily in
      the evening or unoprostone 0.15% twice daily. Observations procedures were
      Goldmann applanation tonometry, best-corrected visual acuity, slit lamp
      biomicroscopy, and ophthalmoscopy. The main outcome measure was change in the
      mean of the IOPs measured at 8:00 AM, 12 noon, and 4:00 PM between baseline
      (before treatment) and after 8 weeks of treatment. RESULTS: The change in the
      mean +/- SD of the IOPs measured at 8:00 AM, 12 noon, and 4:00 PM was -7.2 +/-
      3.2 mm Hg (28%) for latanoprost (25.3 +/- 2.8 mm Hg at baseline to 18.2 +/- 2.8
      mm Hg at 8 weeks) and -3.9 +/- 2.6 mm Hg (15%) for unoprostone (25.5 +/- 3.3 mm
      Hg at baseline to 21.6 +/- 4.0 mm Hg; P <or=.001. No serious adverse event
      related to either medication was reported. CONCLUSIONS: Over an 8-week period,
      latanoprost 0.005% once daily lowered IOP more than unoprostone 0.15% twice daily
      in patients with elevated IOP. Both agents were safe and well tolerated.

PMID- 12470756
TI  - Effect of aging on human rectus extraocular muscle paths demonstrated by magnetic
      resonance imaging.
AB  - PURPOSE: To compare normal functional anatomy of rectus extraocular muscles
      (EOMs) and pulleys in normal older humans with previously reported findings in
      younger subjects. DESIGN: Experimental study of the orbits of normal healthy
      older volunteers by magnetic resonance imaging (MRI). METHODS: In planes
      perpendicular to the orbital axis, contiguous MRI images spanned the
      anteroposterior extents of 22 orbits in 12 older adults with an average age of
      65.2 years (range, 56-74). Images were obtained in central gaze in all subjects
      and repeated in supraduction, infraduction, abduction, and adduction in some
      subjects. Mean EOM cross-sectional area centroids were normalized to an
      oculocentric coordinate system and plotted over the length of each EOM to
      determine paths. RESULTS: Compared with images obtained using identical technique
      in 12 younger subjects (average age, 28.5 years, range 21-33), the horizontal
      rectus EOMs in the 12 older subjects were significantly displaced inferiorly
      throughout the anteroposterior extent of the orbit. The vertical rectus EOM was
      positioned identically to those of younger subjects. Inflections in EOM paths
      produced by the connective tissue pulleys could not be determined in most older
      subjects, because of difficulties in maintaining extreme eccentric gaze. For one
      subject who was able to do this, the anteroposterior location of the medial
      rectus pulley inferred from path inflection was similar to that of younger
      subjects. CONCLUSIONS: The horizontal rectus EOMs are displaced inferiorly in the
      elderly relative to the globe center. This displacement presumably reflects an
      inferior location of the corresponding pulleys, partially converting horizontal
      rectus EOM force to depression. This may contribute to the observed impairment of
      elevation in older people and predispose them to a characteristic pattern of
      incomitant strabismus.

PMID- 12470757
TI  - Ascorbic acid concentration is reduced in the aqueous humor of patients with
      exfoliation syndrome.
AB  - PURPOSE: To investigate whether there is a role for ascorbic acid in the
      development of exfoliation syndrome (XFS). DESIGN: A case-control study was
      undertaken that included consecutive patients with and without XFS in whom
      cataract surgery was indicated. Patients with ophthalmic conditions other than
      XFS and conditions that may influence ascorbic acid levels were excluded.
      METHODS: A prospective institutional study was undertaken. A small volume of
      aqueous humor was aspirated at the beginning of phacoemulsification cataract
      surgery. Eighty aqueous samples, 40 samples from 40 eyes of 40 cataract patients
      with XFS and 40 samples from 40 eyes of 40 age matched cataract patients without
      XFS, were collected and analyzed. Ascorbic acid concentration was evaluated in
      the aqueous samples with a microplate assay method. RESULTS: The mean +/- SD
      concentration of ascorbic acid in the aqueous from patients with XFS (0.86 +/-
      0.43 mM; range, 0.12 to 1.7 mM) was significantly lower than the concentration of
      ascorbic acid found in the aqueous of age-matched control patients (1.15 +/- 0.50
      mM; range 0.42 to 3.1 mM; P =.0068). Total mean protein concentration was found
      to be significantly higher in the XFS group (481.1 +/- 196.8 pg/dl versus 336.3
      +/- 86.4 pg/dl in the controls; P <.0001). Nevertheless, no correlation could be
      established between ascorbic level and protein concentration. CONCLUSIONS: A
      significantly reduced mean level of ascorbic acid was observed in the aqueous
      humor of patients with XFS. In view of the fact that ascorbic acid is a major
      protective factor against free radical action, a role for free radical action is
      possible in the pathobiology of XFS.

PMID- 12470759
TI  - Ocular manifestations of ataxia-telangiectasia.
AB  - PURPOSE: To report the manifestations of ataxia-telangiectasia (A-T) on the
      ocular sensory and motor systems. DESIGN: A prospective observational case
      series. METHODS: In a single tertiary care institition, a comprehensive
      ophthalmologic evaluation was made of patients with A-T as part of a
      systemic/neurologic evaluation. Sixty-three A-T patients between the ages of 2
      and 28 years were examined. RESULTS: In 58 A-T patients whose visual acuity could
      be measured, best-corrected visual acuity in the better eye was 20/20 to 20/30 in
      39 (67%), 20/40 to 20/50 in 17 (29%), and 20/60 to 20/80 in 2 (4%). The mean
      geometric visual acuity of the better eye was 20/31. Telangiectatic vessels were
      seen in the bulbar conjunctiva in 57 of 63 patients (91%) and on the skin of the
      face of 21 patients (33%). Twenty-four of 63 patients (38%) had strabismus.
      Esodeviations were the most common, seen in 15 individuals. Apraxia of horizontal
      gaze was observed in 19 of 63 patients (30%). Hypometric saccades were evident in
      48 (76%), pursuit abnormalities in 43 (63%), and nystagmus in 18 (29%).
      Accommodation was deficient in the 54 patients in whom it was measured. No
      posterior segment vascular anomalies were detected. CONCLUSIONS: Visual acuity of
      20/50 was present in 96% of the patients we examined. Telangiectatic vessels on
      the bulbar conjunctiva were seen in nearly every patient, though these are of no
      functional significance. Ocular motor abnormalities, especially strabismus, are a
      common finding in A-T. Poor accommodation and abnormal eye movements may lead to
      reading difficulty reported by patients with A-T.

PMID- 12470758
TI  - A case-control comparison of the clinical characteristics of glaucoma and ocular
      hypertensive patients with and without the myocilin Gln368Stop mutation.
AB  - PURPOSE: To determine whether primary open-angle glaucoma (POAG) and ocular
      hypertensive (OHT) patients who harbor the myocilin Gln368Stop mutation differ in
      phenotype or clinical course from patients without the mutation. DESIGN: Case
      control study. METHODS: A retrospective case-control study compared all known
      POAG patients (n = 18) and OHT patients (n = 4) harboring the Gln368Stop mutation
      evaluated by the University of Iowa Glaucoma Service with control patients from
      the same population. Patients and control subjects were matched for diagnosis,
      age, sex, and race and were compared for phenotype and clinical course. RESULTS:
      Mean age of disease onset and mean peak intraocular pressures (IOPs) of cases
      were similar to those reported by other studies. There was no statistically
      significant difference between cases and controls for the following variables:
      age at onset, peak intraocular pressure, Snellen visual acuity, number of
      medications, Humphrey visual field (HVF) mean deviation, HVF pattern deviation,
      number of filtering surgeries performed, time intervals from diagnosis to argon
      laser trabeculoplasty (ALT), diagnosis to first filtering surgery, ALT to first
      filtering surgery, and percent change in IOP after ALT and after first filtering
      surgery. CONCLUSIONS: There is no statistically significant difference between
      the onset and clinical course of POAG and OHT caused by the Gln368Stop mutation
      and POAG and OHT not associated with the mutation.

PMID- 12470760
TI  - Multifocal choroiditis in patients with familial juvenile systemic
      granulomatosis.
AB  - PURPOSE: To document clinical features of uveitis in patients with familial
      juvenile systemic granulomatosis. DESIGN: Retrospective chart review. METHODS:
      Ophthalmologic examination, medical history, and clinical course in 16 patients
      from eight families examined at six academic medical centers. RESULTS: Of the 16
      patients, 15 had evidence of panuveitis with multifocal choroiditis. One patient
      had only an anterior uveitis. Ischemic optic neuropathy, presumably due to a
      small vessel vasculopathy, and retinal vasculopathy each occurred in one patient.
      Ocular complications were common, including cataracts in 11, glaucoma in six,
      band keratopathy in six, cystoid macular edema in six, and optic disk edema in
      six. All 16 patients had polyarthritis, and at least nine had skin rash. Often
      patients were misdiagnosed initially as having either juvenile rheumatoid
      arthritis or sarcoidosis. CONCLUSIONS: Familial juvenile systemic granulomatosis
      is an uncommon genetic disease characterized by polyarthritis and uveitis.
      Panuveitis and multifocal choroiditis often may be present. Patients with a
      diagnosis of juvenile rheumatoid arthritis but having a family history of the
      disease and multifocal choroiditis should be suspected of having familial
      juvenile systemic granulomatosis.

PMID- 12470761
TI  - Proton therapy for exudative age-related macular degeneration: a randomized, sham
      controlled clinical trial.
AB  - PURPOSE: To examine the effect of proton beam irradiation on subfoveal choroidal
      neovascular membranes (CNVM) associated with age-related macular degeneration
      (AMD).Randomized, prospective, sham-controlled, double-masked treatment trial.
      METHODS: Thirty-seven subjects with subfoveal CNVM due to AMD were randomly
      assigned to 16-Gy proton irradiation delivered in two fractions 24 hours apart or
      to sham control treatment. Recruitment was halted at 37 subjects for ethical
      reasons regarding randomization to sham treatment when Food and Drug
      Administration approval of Visudyne was anticipated. RESULTS: Proton irradiation
      was associated with a trend toward stabilization of visual acuity, but this
      association did not reach statistical significance. No correlations were found
      within the fluorescein angiography data, including greatest linear dimension of
      CNVM total size, area of active leakage, area of associated subretinal
      hemorrhage, and intensity. CONCLUSIONS: With the acceptance of photodynamic
      therapy, future studies will require more complex design and larger sample size
      to determine whether radiation can play either a primary or adjunctive role in
      treating these lesions.

PMID- 12470762
TI  - Photodynamic therapy using verteporfin-induced minimal change nephrotic syndrome.
AB  - PURPOSE: To report a case of minimal change nephrotic syndrome (MCNS) after
      photodynamic therapy using verteporfin. DESIGN: Interventional case report.
      METHODS: After four cycles of photodynamic therapy, general weakness with
      generalized edema developed in an otherwise healthy 66-year-old woman, resulting
      in dyspnea and ascites. Urinalysis showed heavy proteinuria (4+) with decreased
      serum total protein and albumin, and increased total cholesterol levels,
      suggesting nephrotic syndrome. Renal biopsy and pathologic diagnosis were
      performed. RESULTS: Renal biopsy revealed normal glomeruli and tubulointerstitium
      by light microscopy, with no immunoglobin or complement deposition. Transmission
      electron microscopy showed diffuse effacement of the foot processes of visceral
      epithelial cells, which is the characteristic finding of minimal change nephrotic
      syndrome. CONCLUSIONS: We herein report a case of minimal change nephrotic
      syndrome after photodynamic therapy using verteporfin.

PMID- 12470763
TI  - Postoperative infection with group A beta-hemolytic Streptococcus after
      blepharoplasty.
AB  - PURPOSE: To report a case of group A beta-hemolytic streptococcal infection with
      signs of early necrotizing fasciitis after cosmetic blepharoplasty in a healthy
      patient. DESIGN: Interventional case report. METHODS: A healthy 59-year-old woman
      underwent outpatient bilateral upper and lower blepharoplasty with midface
      lifting. Thirty hours postoperatively she developed marked pain and edema of the
      left eyelids and face, and a violaceous eyelid bulla, which heralded early
      necrotizing fasciitis. Culture of the serosanguinous exudates from the left
      eyelid revealed group A beta-hemolytic Streptococcus organisms. RESULTS: The
      patient was treated with intravenous antibiotics, intravenous corticosteroids,
      hyperbaric oxygen therapy, and wound debridement. The infection resolved with
      mild cicatrization of the left upper eyelid. CONCLUSIONS: Group A beta-hemolytic
      Streptococcus is an increasingly recognized cause of infection that occurs after
      trauma or surgery, even in highly vascularized areas such as the eyelids and
      face. It is a potentially devastating infection, particularly in vascularly
      compromised patients, and requires immediate and aggressive treatment.

PMID- 12470764
TI  - Benign intracranial hypertension and thyreostimulin suppression hormonotherapy.
AB  - PURPOSE: To report a case of benign intracranial hypertension occurring during
      thyreostimulin suppression hormonotherapy after thyroidectomy for papillary
      cancer. DESIGN: Interventional case report. METHODS: A 45-year-old woman
      underwent total thyroidectomy for a 7-mm papillary cancer. Seventeen years later,
      she experienced headache, dizziness, irritability, sensation of full head, and
      blurred vision of the right eye while being treated with a mix of L thyroxin
      (LT4) and liothyronin (LT3). Ophthalmological data (including the presence of
      papilledema), cerebroorbital magnetic resonance imaging, and lumbar pressure
      evaluation confirmed benign intracranial hypertension. RESULTS: Substitutive
      hormonotherapy was decreased under specialized surveillance, permitting remission
      of benign intracranial hypertension symptoms and papilledema. CONCLUSIONS: Benign
      intracranial hypertension is usually difficult to cure, and its association with
      thyroid hormonotherapy is rare. In our patient, tapering LT4 and withdrawal of
      LT3 until a euthyroidal state was obtained resulted in successful treatment of
      benign intracranial hypertension.

PMID- 12470765
TI  - Ophthalmodynamometric diagnosis of unilateral ischemic ophthalmopathy.
AB  - PURPOSE: To describe a patient presenting with typical signs of vascular
      occlusive retinopathy. DESIGN: Observational case report. METHODS: A 65-year-old
      man experienced painless unilateral loss of vision to 4/20 in his left eye.
      Ophthalmoscopy of the left eye showed pronounced attenuation of the retinal
      arterioles, ischemic retinal edema, and a few intraretinal hemorrhages.
      Fluorescein angiography revealed a diffusely reduced retinal perfusion typical of
      retinal occlusive disease. Using a new ophthalmodynamometer with a pressure
      sensor at the mounting support of a conventional Goldmann contact lens, we
      additionally measured the diastolic central retinal artery collapse pressure.
      RESULTS: The diastolic central retinal artery collapse pressure was significantly
      lower in the left eye than in the right eye (14.7 +/- 2.4 relative units vs 51.7
      +/- 4.3 relative units; P <.001). Both values were significantly (P =.03) lower
      than those in a control group (80.9 +/- 6.9 relative units). Doppler sonography
      revealed a total occlusion of the left carotid artery and a nonrelevant stenosis
      of the right carotid artery. CONCLUSIONS: A new ophthalmodynamometric device
      consisting of a pressure sensor at the mounting support of a Goldmann contact
      lens was helpful in detecting carotid artery occlusion leading to ischemic
      ophthalmopathy.

PMID- 12470766
TI  - Herpes zoster vasculitis presenting as giant cell arteritis with bilateral
      internuclear ophthalmoplegia.
AB  - PURPOSE: To present a case of herpes zoster vasculitis presenting as giant cell
      arteritis. DESIGN: Interventional case report. METHODS: A 77-year-old woman
      presented with sudden onset of diplopia associated with temple headaches and a
      previous history of herpes zoster ophthalmicus. A temporal artery biopsy was
      obtained and in-situ hybridization performed for herpes zoster DNA. RESULTS: The
      patient presented with a bilateral internuclear ophthalmoplegia. Initial
      diagnostic evaluation, including erythrocyte sedimentation rate, C-reactive
      protein, and temporal artery biopsy, was consistent with giant cell arteritis.
      However, in-situ hybridization of the temporal artery specimen was positive for
      herpes zoster DNA. CONCLUSIONS: Herpes zoster vasculitis may mimic giant cell
      arteritis and should be considered in the differential of any patient with
      presumed giant cell arteritis with suspicious findings, central nervous system
      involvement, or previous herpes zoster infection.

PMID- 12470767
TI  - Fomepizole therapy for reversal of visual impairment after methanol poisoning: a
      case documented by visual evoked potentials investigation.
AB  - PURPOSE: To illustrate the safety and efficacy of fomepizole in a case of
      methanol poisoning with initial visual impairment. DESIGN: Interventional case
      report. METHODS: A 60-year-old man was admitted with blurred vision and changes
      in color perception 18 hours after ingesting 100 ml methanol. Fomepizole was
      chosen for antidotal therapy in combination with hemodialysis. Flash
      electroretinogram (fERG) and flash visual evoked potentials (fVEPs) examinations
      were obtained at the bedside 2 hours after admission and on days 1 and 8. The
      monocular pattern-reversal visual evoked potentials (pVEPs) were investigated on
      days 1 and 8. RESULTS: A complete reversal of visual impairment was achieved
      within 20 hours. An abnormal b-wave amplitude and an increased peak III latency
      at VEPs were present on admission and recovered within 24 hours. CONCLUSIONS:
      Fomepizole appeared safe and effective for a patient who had severe methanol
      poisoning presenting with visual impairment.

PMID- 12470768
TI  - Reversible cortical blindness in preeclampsia.
AB  - PURPOSE: To report the clinical course and magnetic resonance imaging (MRI)
      findings in a 28-year-old woman with preeclampsia and reversible cortical
      blindness. DESIGN: Interventional case report. METHODS: The patient presented at
      the 37th week of pregnancy with headache and hypertension. The next day, her
      visual acuity decreased to light perception in both eyes. After emergent cesarean
      section, examination revealed reactive pupils and normal fundi. RESULTS: Magnetic
      resonance imaging of the brain showed areas of increased signal in both occipital
      lobes. One month later, at which time the patient's visual acuity had returned to
      20/20, follow-up MRI showed complete resolution of radiologic abnormalities.
      CONCLUSIONS: Cortical blindness is a rare complication of preeclampsia. In this
      case, cortical blindness was reversible and most likely due to vasogenic edema
      rather than vasospasm.

PMID- 12470769
TI  - Leber hereditary optic neuropathy associated with use of ephedra alkaloids.
AB  - PURPOSE: We report a case of Leber hereditary optic neuropathy in a patient who
      was using ephedra alkaloids at the time of onset of his optic neuropathy. DESIGN:
      Observational case report. METHODS: Bilateral, painless, progressive loss of
      vision developed in a 30-year-old man. He reported a one pack-per day, 10-year
      history of tobacco use and drinking 18 to 24 cans of beer per day as well as the
      use of a dietary supplement containing ephedra and caffeine before the onset of
      vision loss. RESULTS: We report the bilateral, progressive, painless loss of
      vision in a patient with bilateral cecocentral scotomas and optic nerve pallor.
      Mitochondrial DNA testing confirmed a Leber hereditary optic neuropathy mutation
      site at loci 11778. CONCLUSIONS: We propose that our patient's use of a dietary
      supplement containing ephedra alkaloids played an additive role to his tobacco
      and alcohol use in causing stress to the already abnormal mitochondrial function,
      and thereby contributed to the onset of his optic neuropathy. We recommend that
      patients and families with known Leber hereditary optic neuropathy should be
      asked about the use of over-the-counter drugs or supplements, and it may be
      prudent to advise patients against using such dietary supplements.

PMID- 12470770
TI  - Morphometric change analysis of the optic nerve head in unilateral disk
      hemorrhage cases.
AB  - PURPOSE: To measure the changes in optic disk morphology after unilateral disk
      hemorrhage and to compare the changes between eyes. DESIGN: Observational case
      series. METHODS: Ten glaucoma patients who had a unilateral disk hemorrhage were
      enrolled. The baseline measurements obtained by Heidelberg Retina Tomograph (HRT)
      were performed on both eyes when a disk hemorrhage was detected, and the second
      measurements were done after an average of 32 +/- 19 months. The amount of change
      and the percent change in the HRT parameters from the baseline measurements of
      the hemorrhagic eyes were compared with those of the contralateral nonhemorrhagic
      eyes. RESULTS: The reduction in the neuroretinal rim area and the decrease in
      volume were significantly greater in the octant with the disk hemorrhage than
      measured in the contralateral eyes (P =.002, Wilcoxon signed rank test).
      CONCLUSIONS: This study demonstrated quantitatively that the progression of optic
      disk damage in glaucoma is faster in eyes with disk hemorrhage than in eyes
      without disk hemorrhage.

PMID- 12470771
TI  - Bradykinin sensitivity in primary open-angle glaucoma and normal-tension glaucoma
      patients.
AB  - PURPOSE: To report the reaction after intradermal injection of bradykinin in
      nonglaucoma, primary open-angle glaucoma, and normal-tension glaucoma subjects.
      DESIGN: Prospective comparative study. METHODS: The study participants were 14
      healthy control subjects, 16 patients with primary open-angle glaucoma, and 15
      patients with normal-tension glaucoma. In each participant, the wheal response to
      intradermal injection of 10 microg bradykinin in the volar forearm was measured
      by a masked observer. RESULTS: There was no significant difference in the wheal
      response to bradykinin between control subjects and primary open-angle glaucoma
      patients (P =.73) and between primary open-angle glaucoma patients and normal
      tension glaucoma patients (P =.09). However, there was a significant difference
      in the wheal response to bradykinin between control subjects and normal-tension
      glaucoma patients (P =.04). CONCLUSIONS: These in vivo structure-activity studies
      may suggest abnormalities of the tissue kallikrein-kinin system in normal-tension
      glaucoma.

PMID- 12470772
TI  - Changes of ocular aberration with accommodation.
AB  - PURPOSE: To study the effect of accommodation on ocular aberrations. DESIGN:
      Observational case series. METHODS: The ocular aberrations in 33 eyes of 33 young
      adults were measured with a Hartmann-Shack wavefront aberrometer before and
      during 3 diopters of accommodation. RESULTS: The root mean square values of
      wavefront error did not change for a 4-mm and a 6-mm zone; however, spherical
      aberration changed significantly toward negativity for both the 4-mm zone (P
      <.001) and 6-mm zone (P =.022). CONCLUSIONS: During accommodation, the
      significant change in spherical aberration occurs without a change of image
      quality. Therefore, for customized aberration, it may not be advantageous to
      eliminate the physiologic spherical aberration for far vision.

PMID- 12470773
TI  - The effect of an eyelid speculum on intraocular pressure measurement in children.
AB  - PURPOSE: To assess the effect of a pediatric eyelid speculum on the measurement
      of intraocular pressure (IOP) in children. DESIGN: Observational case series.
      METHODS: Intraocular pressure measurements were performed during examination
      under anesthesia immediately after induction. The measurements were made with and
      without a pediatric eyelid speculum in place. RESULTS: Intraocular pressure
      measurements were made in 77 eyes of 45 consecutive children. The mean IOP
      without the speculum was 16.33 mm Hg in the right eye and 16.55 mm Hg in the left
      eye. With the lid speculum in place the mean IOP was 20.26 mm Hg in the right eye
      and 20.05 mm Hg in the left eye (P <.05). CONCLUSIONS: The presence of an eyelid
      speculum raised IOP an average of 4 mm Hg. This effect should be considered when
      interpreting IOP measurements in children.

PMID- 12470774
TI  - Recurrent episodes of spontaneous subconjunctival hemorrhage in patients with
      factor XIII Val34Leu mutation.
AB  - PURPOSE: To report on the occurrence of frequent episodes of spontaneous
      subconjunctival hemorrhage (SCH) in patients with the Leu 34 allele of the
      coagulation factor XIII (FXIII), known to be associated with high hemorrhagic
      risk. DESIGN: Observational case series. METHODS: Five young adults who had
      suffered from recurrent idiopathic SCH not associated with any recognized ocular
      and systemic hemorrhagic risk factor were investigated. Accurate anamnestic,
      ophthalmologic, hematologic, and serologic examinations were performed, together
      with blood pressure measurements, electrocardiogram (ECG), and 24-hour Holter ECG
      recordings. FXIII Val34Leu polymorphism was studied by DNA chain polymerase
      reaction. RESULTS: DNA analyses showed that the hemorrhagic mutated Leu34 allele
      was present in four of our selected patients: two mutated homozygotes (Leu/Leu)
      and two heterozygotes (Val/Leu). In the last subject this polymorphism was not
      detected. All the other clinical evaluations did not disclose any significant
      abnormality. CONCLUSIONS: The FXIII Val34Leu mutation may be associated with an
      increased risk for spontaneous episodes of SCH.

PMID- 12470775
TI  - A novel technique for harvesting keratolimbal allografts from corneoscleral
      buttons.
AB  - PURPOSE: To describe a method for obtaining partial-thickness keratolimbal
      allografts from corneoscleral buttons to be used in corneal limbal stem cell
      transplantation. DESIGN: Description of device design and technique for use.
      METHODS: Cyanoacrylate tissue adhesive, placed on the posterior side of a
      trephinated corneoscleral rim, is used to secure the allograft to a disposable
      acrylic sphere that is attached to a cylindrical base. RESULTS: After fixation of
      the corneoscleral rim to the acrylic sphere, keratolimbal allograft harvesting is
      performed as a continuous strip dissection with a 65 Beaver blade. This technique
      minimizes trauma to the epithelial stem cells, provides excellent stability of
      the corneoscleral rim during harvesting, and preserves the central corneal
      button. CONCLUSIONS: This method for obtaining keratolimbal allografts
      effectively provides tissue stabilization during harvesting, minimizing
      epithelial stem cell trauma and eliminating the need for whole donor globes.

PMID- 12470776
TI  - Magnetic resonance imaging in the diagnosis of subretinal cysticercosis.
AB  - PURPOSE: To report a case of ocular cysticercosis and associated magnetic
      resonance imaging (MRI) findings. DESIGN: Interventional case report. METHODS: A
      56-year-old woman from Ecuador presented with decreased vision and an exudative
      retinal detachment in the left eye. Subretinal cysticercosis was suspected.
      RESULTS: In the left eye, a subretinal cyst evident on fundus examination was
      investigated with B-scan ultrasonography. Ultrasonography showed a cystic
      structure, and MRI of the orbit confirmed the suspicion for cysticercosis.
      Magnetic resonance imaging of the brain also revealed a small parenchymal lesion
      in the left occipital lobe of the brain. CONCLUSIONS: Magnetic resonance imaging
      is a useful adjunct to B-scan ultrasonography in the diagnosis of ocular
      cysticercosis. Magnetic resonance imaging is superior to computed tomography in
      the demonstration of cystic structures in the eye and central nervous system.
      This finding has important therapeutic implications, as any viable cysticercus in
      the eye or cerebral parenchyma can be treated surgically or medically,
      respectively.

PMID- 12470777
TI  - Severe scleritis and urticarial lesions.
AB  - PURPOSE: To report the first known case of bilateral scleritis in a patient with
      hypocomplementemic urticarial vasculitis. DESIGN: Interventional case report.
      METHODS: Medical and ophthalmic history, results of physical and ophthalmic
      examinations, laboratory data, and histologic and immunopathologic examination
      were reviewed and results recorded. RESULTS: A 67-year-old man who presented with
      eye redness and pain, rash, arthralgia, and malaise was found to have
      hypocomplementemic urticarial vasculitis. Treatment with high-dose oral
      corticosteroids and mycophenolate mofetil resulted in the resolution of the rash
      and scleritis. CONCLUSIONS: Ocular involvement may be a helpful clue in the
      diagnosis of this uncommon syndrome.

PMID- 12470778
TI  - Defining ideal body weight.

PMID- 12470793
TI  - "Emerging Alzheimer's disease therapies: focusing on the future".
AB  - The Center for Neurodegenerative Disease Research (CNDR) organized a 1 day
      symposium entitled "Emerging Alzheimer's disease Therapies: Focusing On The
      Future" on November 7th, 2001 at the University of Pennsylvania in Philadelphia,
      PA. The agenda (Fig. 1) focused on novel therapies for Alzheimer's disease (AD)
      designed to prevent/eliminate Abeta deposits in the brains of AD patients. While
      fibrillar Abeta deposits known as senile plaques (SPs) and intraneuronal tau
      fibrils known as neurofibrillary tangles (NFTs) are diagnostic of AD, >50% of
      patients with familial or sporadic AD as well as elderly Down's syndrome patients
      with AD harbor a third type of brain amyloid known as Lewy bodies formed by
      intraneuronal alpha-synuclein fibrils. Thus, AD is a "triple brain amyloidosis"
      since three different proteins (tau, alpha-synuclein) or peptide fragments
      (Abeta) of a larger Abeta precursor protein (APP) fibrillize and aggregate into
      pathological deposits of amyloid within (NFTs, LBs) and outside (SPs) neurons in
      AD brains. The symposium is summarized here followed by reviews from symposium
      speakers who describe potential anti-Abeta therapies some of which are in
      clinical trials.

PMID- 12470794
TI  - Intranasal immunotherapy for the treatment of Alzheimer's disease: Escherichia
      coli LT and LT(R192G) as mucosal adjuvants.
AB  - Alzheimer's disease (AD) is the most common form of dementia worldwide, yet there
      is currently no effective treatment or cure. Extracellular deposition of amyloid
      beta protein (Abeta) in brain is a key neuropathological characteristic of AD. In
      1999, Schenk et al. first reported that an injected Abeta vaccine given to PDAPP
      mice, an AD mouse model displaying Abeta deposition in brain, led to the lowering
      of Abeta levels in brain. In 2000, we demonstrated that intranasal (i.n.)
      immunization with human synthetic Abeta1-40 peptide for 7 months led to a 50-60%
      reduction in cerebral Abeta burden in PDAPP mice; serum Abeta antibody titers
      were low (approximately 26 microg/ml). More recently, we have optimized our i.n.
      Abeta immunization protocol in wild-type (WT) mice. When low doses Escherichia
      coli heat-labile enterotoxin (LT) were given as a mucosal adjuvant with Abeta
      i.n., there was a dramatic 12-fold increase in Abeta antibody titers in WT B6D2F1
      mice treated two times per week for 8 weeks compared to those of mice receiving
      i.n. Abeta without adjuvant. A non-toxic form of LT, designated LT(R192G), showed
      even better adjuvanticity; anti-Abeta antibody titers were 16-fold higher than
      those seen in mice given i.n. Abeta without adjuvant. In both cases, the serum
      Abeta antibodies recognized epitopes within Abeta1-15 and were of the
      immunoglobulin (Ig) isotypes IgG2b, IgG1, IgG2a and low levels of IgA. This new
      and improved Abeta vaccine protocol is now being tested in AD mouse models with
      the expectation that higher Abeta antibody titers may be more effective in
      reducing cerebral Abeta levels.

PMID- 12470795
TI  - A safer vaccine for Alzheimer's disease?
AB  - Recent reports indicate that amyloid-beta (Abeta) vaccine-based therapy for
      Alzheimer's disease (AD) may be on the horizon. There are, however, concerns
      about the safety of this approach. Immunization with Abeta1-42 may not be
      appropriate in humans because it crosses the blood-brain barrier, can seed fibril
      formation, and is highly fibrillogenic. Abeta1-42 fibrils can in turn cause
      inflammation and neurotoxicity. This issue is of a particular concern in the
      elderly who often do not mount an adequate immune response to vaccines. Our
      findings show that vaccination with nonamyloidogenic/nontoxic Abeta derivative
      may be a safer therapeutic approach to impede the progression of Abeta-related
      histopathology in AD. Although the site of action of the anti-Abeta antibodies
      has been suggested to be within the brain, peripheral clearance of Abeta may have
      a greater role in reducing cerebral amyloid plaques in these animals and
      eventually in AD patients. Antibodies in general are predominantly found outside
      the central nervous system (CNS) and will, therefore, primarily clear systemic
      Abeta compared to brain Abeta. This disruption of the equilibrium between central
      and peripheral Abeta should then result in efflux of Abeta out of the brain, and
      subsequent removal of plaques. Abeta therapy can be targeted to the periphery,
      which may result in fewer CNS side effects, such as inflammation. Future Abeta
      derived vaccines should include T(h) epitopes, carriers and/or lipid moieties to
      enhance antibody production in the elderly, the population predominantly affected
      by AD.

PMID- 12470796
TI  - Molecular basis for anti-amyloid therapy in the prevention and treatment of
      Alzheimer's disease.

PMID- 12470797
TI  - Emerging Alzheimer's disease therapies: inhibition of beta-secretase.
AB  - Among the approaches towards disease modifying treatment of Alzheimer's disease
      blocking the initial step of the amyloid cascade, Abeta42 generation, has
      received most attention. Abeta42 generation requires two proteases, beta- and
      gamma-secretase, and inhibition of these enzymes is a key focus of AD drug
      development. Progress in this area has been slow, because these enzymes were not
      identified. Using an expression cloning strategy we have identified a novel
      membrane bound aspartic protease, BACE1, as beta-secretase. The enzyme has been
      characterized in detail. The x-ray crystal structure, which is critical for
      rational inhibitor design, has been solved and shown to be similar to that of
      other pepsin family members. Our recent knockout studies show that BACE1 is
      critical for Abeta generation, but the knockout mice show an otherwise normal
      phenotype, raising the possibility that therapeutic BACE1 inhibition could be
      accomplished without major mechanism based toxicity. However, target-mediated
      toxicity of beta-secretase inhibition cannot be ruled out, as long as the major
      substrates of this enzyme are unknown. While various peptidic beta-secretase
      inhibitors have been published, the key challenge now is the generation of more
      drug-like compounds that could be developed for therapeutic purposes.

PMID- 12470798
TI  - gamma-Secretase: characterization and implication for Alzheimer disease therapy.
AB  - gamma-Secretase is a membrane-bound protease that cleaves within the
      transmembrane region of amyloid precursor protein to generate the C-termini of
      the Abeta peptides which are believed to play a central role in the
      neuropathology of Alzheimer's disease. An in vitro gamma-secretase assay using a
      recombinant substrate C100Flag has been developed to facilitate the
      characterization and identification of this enigmatic protease. Biochemical
      studies establish that gamma-secretase activity is catalyzed by a PS1-containing
      macromolecular complex. Moreover, the fact that the photoreactive active gamma
      secretase inhibitor directed to the active site labels PS1 suggests that PS1
      contains the active site of the protease. Presenilin/gamma-secretase as a
      potential target for AD therapy and its role in regulated intramembrane
      proteolysis are discussed.

PMID- 12470799
TI  - Metal complexing agents as therapies for Alzheimer's disease.
AB  - Modern research approaches into drug development for Alzheimer's disease (AD)
      target beta-amyloid (Abeta) accumulation in the brain. The main approaches
      attempt to prevent Abeta production (secretase inhibitors) or to clear Abeta
      (vaccine). However, there is now compelling evidence that Abeta does not
      spontaneously aggregate, but that there is an age-dependent reaction with excess
      brain metal (copper, iron and zinc), which induces the protein to precipitate
      into metal-enriched masses (plaques). The abnormal combination of Abeta with Cu
      or Fe induces the production of hydrogen peroxide, which may mediate the
      conspicuous oxidative damage to the brain in AD. We have developed metal-binding
      compounds that inhibit the in vitro generation of hydrogen peroxide by Abeta, as
      well as reverse the aggregation of the peptide in vitro and from human brain post
      mortem specimens. Most recently, one of the compounds, clioquinol (CQ; a USP
      antibiotic) was given orally for 9 weeks to amyloid-bearing transgenic mice, and
      succeeded in markedly inhibiting Abeta accumulation. On the basis of these
      results, CQ is being tested in clinical trials.

PMID- 12470800
TI  - Amyloid binding ligands as Alzheimer's disease therapies.
AB  - Extracellular senile plaques (SPs) are hallmark brain lesions of sporadic
      Alzheimer's disease (AD) and the likely consequence of genetic mutations that
      cause familial AD by increasing production of amyloidogenic amyloid-beta (Abeta).
      Although Abeta vaccines and inhibitors of amyloidogenic secretases are potential
      AD therapies, multifaceted strategies may be needed to effectively interrupt
      Abeta amyloidosis and prevent/arrest AD. One such strategy is the inhibition of
      Abeta fibrillization as a potential therapy for AD. Certain amyloid-binding
      molecules, such as Congo red (CR) and chrysamine G (CG) and Thioflavin S (TS)
      have been shown to bind SPs with high affinity and they can also arrest the
      formation of Abeta fibrils; however, CR, CG and TS are unsuitable for AD therapy
      because they do not cross the blood brain barrier (BBB). Therefore, we have
      generated novel CG and TS derivatives that specifically recognize fibrillar Abeta
      in vitro, arrest the formation of Abeta fibrils, and cross the BBB of transgenic
      (TG) mice that model AD amyloidosis. As proof of their ability to cross the BBB
      and of their high specificity for Abeta fibrils in vivo, we show that following
      intravenous injection in TG mice these compounds specifically label AD-like brain
      deposits of fibrillar Abeta. Furthermore, we demonstrate that CG derivative IMSB
      binds to SPs comprised of Abeta40 with much higher affinity than Abeta42 whereas
      TS derivative TDZM shows the opposite affinity. Moreover, IMSB but not TDZM binds
      selectively to neurofibrillary tangles. Significantly both IMSB and TDZM inhibit
      Abeta fibrillization in test tubes and in cultured cells. Thus, small amyloid
      binding molecules such as IMSB and TDZM which cross the BBB are potential
      therapeutic agents for the treatment of AD.

PMID- 12470801
TI  - Addressing the challenges of transforming laboratory advances into Alzheimer's
      Disease treatments.
AB  - This essay addresses the challenges of clinical trials to develop treatments for
      Alzheimer's Disease (AD). The issues covered are enrolling subjects, defining
      clinically meaningful endpoints, and making the claim that a drug slows the
      progression of the disease. The perspective to address these challenges is that
      dementia research should embrace a biopsychosocial model for drug development. In
      this model, the patient and caregiver are seen as interrelated subjects of both
      treatment and research and outcome measures reflect biomarkers of the disease,
      the functional morbidity of AD and the distress of caregiving.

PMID- 12470802
TI  - Abeta as a bioflocculant: implications for the amyloid hypothesis of Alzheimer's
      disease.
AB  - Research into Alzheimer's disease (AD) has been guided by the view that deposits
      of fibrillar amyloid-beta peptide (Abeta) are neurotoxic and are largely
      responsible for the neurodegeneration that accompanies the disease. This 'amyloid
      hypothesis' has claimed support from a wide range of molecular, genetic and
      animal studies. We critically review these observations and highlight
      inconsistencies between the predictions of the amyloid hypothesis and the
      published data. We show that the data provide equal support for a 'bioflocculant
      hypothesis', which posits that Abeta is normally produced to bind neurotoxic
      solutes (such as metal ions), while the precipitation of Abeta into plaques may
      be an efficient means of presenting these toxins to phagocytes. We conclude that
      if the deposition of Abeta represents a physiological response to injury then
      therapeutic treatments aimed at reducing the availability of Abeta may hasten the
      disease process and associated cognitive decline in AD.

PMID- 12470803
TI  - Testing times for the "amyloid cascade hypothesis".

PMID- 12470804
TI  - Bioflocculant hypothesis: a partial endorsement.

PMID- 12470805
TI  - Alzheimer's disease and Alzheimer's dementia: distinct but overlapping entities.
AB  - Much of the controversy about the "amyloid cascade hypothesis" may reflect
      unrecognized differences in the use of language, including the use of the word
      "cause." This commentary proposes that the term Alzheimer disease refer to the
      neuropathological entity and the term Alzheimer dementia to clinical dementia in
      people who also have Alzheimer neuropathology. The ultimate causes of Alzheimer
      disease are proposed to be aging, environmental stresses, and genetic
      predispositions. The fundamental cause of Alzheimer dementia is proposed to be
      Alzheimer disease, i.e. the neurobiological abnormalities in Alzheimer brain. The
      neurobiology of Alzheimer disease includes changes that may initially be adaptive
      but can become excessive and thereby harmful; they include increased expression
      of APP with accumulation of potentially damaging peptides such as Abeta,
      inflammation, and increased ROS activity. The neurobiological abnormality that is
      the proximate cause of Alzheimer dementia appears to be decreases in cerebral
      metabolic rate. Decreased metabolism occurs not only in this but in essentially
      all dementias, and impairing brain metabolism induces neuropsychological deficits
      characteristic of dementias. The immediate cause of Alzheimer dementia is
      proposed to be deficiencies in signaling, both intracellular and intercellular
      (neurotransmission), that follow directly from the decrease in cerebrometabolic
      rate.

PMID- 12470806
TI  - Abeta conformational change is central to Alzheimer's disease.

PMID- 12470807
TI  - Is amyloid beta-peptide neurotoxic or neuroprotective and what is its role in the
      binding of metal ions?

PMID- 12470808
TI  - Evolution and the scientific method.

PMID- 12470809
TI  - Amyloid-beta: a (life) preserver for the brain.

PMID- 12470810
TI  - The amyloid hypothesis: let sleeping dogmas lie?
AB  - The 'amyloid hypothesis' has guided research into Alzheimer's disease (AD) for
      more than a decade. A detailed review of the relevant data led us to conclude
      that some data, particularly those from transgenic mice, are inconsistent with
      the predictions of the amyloid hypothesis. Instead, most data are consistent with
      the notion that amyloid-beta (Abeta) peptide is neuroprotective. The majority of
      commentators agreed with our analysis but some were unwilling to abandon the
      amyloid hypothesis until the outcome of anti-Abeta therapeutic trials puts the
      matter beyond debate. All acknowledged that we had highlighted flaws in the
      amyloid hypothesis which must be addressed. To stimulate a critical reappraisal
      of the amyloid hypothesis we have proposed the 'bioflocculant hypothesis' which
      posits that Abeta serves to bind neurotoxic solutes (pathogens, proteins and
      metal ions) so that they can be phagocytosed and prevented from causing further
      damage. The hypothesis makes clear predictions that are readily falsifiable, and
      it has already gained credibility by predicting the recent negative outcome of
      Abeta vaccination trials in humans.

PMID- 12470812
TI  - Marine phage genomics.
AB  - Marine phages are the most abundant biological entities in the oceans. They play
      important roles in carbon cycling through marine food webs, gene transfer by
      transduction and conversion of hosts by lysogeny. The handful of marine phage
      genomes that have been sequenced to date, along with prophages in marine
      bacterial genomes, and partial sequencing of uncultivated phages are yielding
      glimpses of the tremendous diversity and physiological potential of the marine
      phage community. Common gene modules in diverse phages are providing the
      information necessary to make evolutionary comparisons. Finally, deciphering
      phage genomes is providing clues about the adaptive response of phages and their
      hosts to environmental cues.

PMID- 12470813
TI  - Inferring protein function from genomic sequence: Giardia lamblia expresses a
      phosphatidylinositol kinase-related kinase similar to yeast and mammalian TOR.
AB  - Functional assays of genes have historically led to insights about the activities
      of a protein or protein cascade. However, the rapid expansion of genomic and
      proteomic information for a variety of diverse taxa is an alternative and
      powerful means of predicting function by comparing the enzymes and metabolic
      pathways used by different organisms. As part of the Giardia lamblia genome
      sequencing project, we routinely survey the complement of predicted proteins and
      compare those found in this putatively early diverging eukaryote with those of
      prokaryotes and more recently evolved eukaryotic lineages. Such comparisons
      reveal the minimal composition of conserved metabolic pathways, suggest which
      proteins may have been acquired by lateral transfer, and, by their absence, hint
      at functions lost in the transition from a free-living to a parasitic lifestyle.
      Here, we describe the use of bioinformatic approaches to investigate the
      complement and conservation of proteins in Giardia involved in the regulation of
      translation. We compare an FK506 binding protein homologue and
      phosphatidylinositol kinase-related kinase present in Giardia to those found in
      other eukaryotes for which complete genomic sequence data are available. Our
      investigation of the Giardia genome suggests that PIK-related kinases are of
      ancient origin and are highly conserved.

PMID- 12470814
TI  - Comparative architecture of silks, fibrous proteins and their encoding genes in
      insects and spiders.
AB  - The known silk fibroins and fibrous glues are thought to be encoded by members of
      the same gene family. All silk fibroins sequenced to date contain regions of long
      range order (crystalline regions) and/or short-range order (non-crystalline
      regions). All of the sequenced fibroin silks (Flag or silk from flagelliform
      gland in spiders; Fhc or heavy chain fibroin silks produced by Lepidoptera
      larvae) are made up of hierarchically organized, repetitive arrays of amino
      acids. Fhc fibroin genes are characterized by a similar molecular genetic
      architecture of two exons and one intron, but the organization and size of these
      units differs. The Flag, Ser (sericin gene) and BR (Balbiani ring genes; both
      fibrous proteins) genes are made up of multiple exons and introns. Sequences
      coding for crystalline and non-crystalline protein domains are integrated in the
      repetitive regions of Fhc and MA exons, but not in the protein glues Ser1 and BR
      1. Genetic 'hot-spots' promote recombination errors in Fhc, MA, and Flag. Codon
      bias, structural constraint, point mutations, and shortened coding arrays may be
      alternative means of stabilizing precursor mRNA transcripts. Differential
      regulation of gene expression and selective splicing of the mRNA transcript may
      allow rapid adaptation of silk functional properties to different physical
      environments.

PMID- 12470815
TI  - Molecular evolution of proteins involved in vertebrate phototransduction.
AB  - Vision is one of the most important senses for vertebrates. As a result,
      vertebrates have evolved a highly organized system of retinal photoreceptors.
      Light triggers an enzymatic cascade, called the phototransduction cascade, that
      leads to the hyperpolarization of photoreceptors. It is expected that a
      systematic comparison of phototransduction cascades of various vertebrates can
      provide insights into the diversity of vertebrate photoreceptors and into the
      evolution of vertebrate vision. However, only a few attempts have been made to
      compare each phototransduction protein participating in this cascade. Here, we
      determine phylogenetic trees of the vertebrate phototransduction proteins and
      compare them. It is demonstrated that vertebrate opsin sequences fall into five
      fundamental subfamilies. It is speculated that this is crucial for the diversity
      of the spectral sensitivity observed in vertebrate photoreceptors and provides
      the vertebrates with the molecular tools to discriminate the color of incident
      light. Other phototransduction proteins can be classified into only a few
      subfamilies. Cones generally share isoforms of phototransduction proteins that
      are different from those found in rods. The difference in sensitivity to light
      between rods and cones is likely due to the difference in the molecular
      properties of these isoforms. The phototransduction proteins seem to have co
      evolved as a system. Switching the expression of these isoforms may characterize
      individual vertebrate photoreceptors.

PMID- 12470816
TI  - Application of genomics and proteomics for study of the integrated response to
      zinc exposure in a non-model fish species, the rainbow trout.
AB  - The advent of DNA array technology and proteomics has revolutionised biology by
      allowing global analysis of cellular events. So far, the benefits from these new
      techniques have primarily been realised for well-characterised species. These
      organisms are rarely the most relevant for environmental biology and
      ecotoxicology. Thus, there is a need to explore new ways to exploit
      transcriptomics and proteomics for non-model species. In the present study,
      rainbow trout (Oncorhynchus mykiss) were exposed to a sublethal concentration of
      waterborne zinc for up to 6 days. The response in gill tissue was investigated by
      differential screening of a heterologous cDNA array and by protein profiling
      using Surface Enhanced Laser Desorption/Ionisation (SELDI). The cDNA array, which
      was a high-density spotted library of cDNA from Fugu rubripes gill, revealed
      differentially expressed genes related to energy production, protein synthesis,
      paracellular integrity, and inflammatory response. SELDI analysis yielded seven
      proteins that were consistently present only in zinc-exposed gills, and four
      proteins unique to gills from control fish. A further 11 proteins were
      differentially regulated. Identification of these proteins by bioinformatics
      proved difficult in spite of detailed information on molecular mass, charge and
      zinc-binding affinity. It is concluded that these approaches are viable to non
      model species although both have clear limitations.

PMID- 12470817
TI  - Identification of low-abundance differentially expressed transcripts using
      arrayed cDNA clones.
AB  - Analysis of comparative gene expression by the use of DNA microarrays has become
      a widely used tool. However, this technique is only readily applied to organisms
      where sequence information is known. This paper describes the development of a
      low-cost method of gene discovery by enrichment of differentially expressed
      transcripts, which uses cDNA library arrays of bacterial clones on nylon
      membranes (macroarrays) coupled with a subtractive probe preparation method to
      discover differentially expressed genes. The method requires no prior knowledge
      of the organism's genome sequence and overcomes the inherent insensitivity of
      standard methods of macroarray hybridisation.

PMID- 12470818
TI  - Gene expression analysis of largemouth bass exposed to estradiol, nonylphenol,
      and p,p'-DDE.
AB  - The purpose of this study was to determine the specific expression profile of 132
      genes, some of which are estrogen responsive, in largemouth bass (LMB) following
      exposure to estradiol (E(2)), or to two hormonally active agents, 4-nonylphenol
      (4-NP) and 1,1-dichloro-2, 2-bis (p-chlorophenyl) ethylene (p,p'-DDE), using gene
      array technology. The results of these experiments show that LMB exposed to E(2)
      and 4-NP had similar, but not identical genetic signatures for the genes
      examined, some of which are known to be estrogen-responsive genes. The
      differences suggest that 4-NP may have additional modes of action that are
      independent of the estrogen receptor (ER). We have also shown that exposure of
      male LMB to p,p'-DDE results in an increase in some estrogen-responsive genes.
      But in female LMB, the observed changes were a down-regulation of the normally up
      regulated estrogen responsive genes. Other genes were also down-regulated. These
      results suggest that p,p'-DDE may affect regulation of genes differently in male
      and female LMB. This study further suggests that gene arrays have the potential
      to map out the gene activation pathways of hormonally active compounds.

PMID- 12470819
TI  - Functional genomics and sexual differentiation in amphibians.
AB  - In Xenopus laevis the basic mechanisms underlying sexual differentiation were
      investigated by determining time courses of sexual steroids and their
      corresponding receptors during complete larval development from egg to juveniles.
      Androgens as well as estradiol (E2) are derived from maternal origin and
      accumulate in hatching tadpoles. Sexual steroid contents decreased rapidly after
      hatching and rose again at the end of metamorphosis indicating endogenous
      production. In parallel the mRNA expression for corresponding androgen (AR) and
      estrogen receptors (ER) was measured by means of semiquantitative RT-PCR. Both
      receptor mRNAs increased dramatically just after hatching and decreased only
      moderately until end of metamorphosis. In female juveniles E2 and ER-mRNA levels
      were higher compared with males. Treatment by exogenous E2 elevated both, ER- and
      AR-mRNA, indicating stimulatory functions of E2 for gene expression of both
      receptors. Effects on sexual differentiation during larval development were
      achieved by treatment with E2 and the antiandrogen cyproterone acetate both
      causing feminization, the antiestrogen tamoxifen resulting in neutralization, and
      the androgens, methyltestosterone and dihydrotestosterone, but not testosterone,
      leading to masculinization. The data presented are in accordance with further
      recent findings and suggest a new hypothesis for functional genomics in sexual
      differentiation of amphibians.

PMID- 12470820
TI  - Genomics of the HOX gene cluster.
AB  - The Hox family of homeobox genes encode transcription factors that control
      different aspects of metazoan development. They appear clustered in the genomes
      of those animals in which their relative positions have been mapped. Although
      clustering is assumed to be a general property of Hox genes in all bilaterians,
      just a few species have been studied in sufficient detail to support this claim.
      Linear duplication of genes inside the cluster, as well as full-cluster
      duplications account for the actual complexity of HOX clusters in the different
      animal groups that have been studied (mainly vertebrates). Understanding how the
      Hox genes are regulated during development will depend, ultimately, on the
      generation of more powerful tools for cloning intact HOX clusters and for
      elucidating their cis-regulatory components. To clarify the roles of the Hox
      genes themselves, we will need to characterize in detail their downstream
      targets, and some progress in this direction is coming mainly from the recent use
      of arrayed libraries. Moreover, a comprehensive study of Hox target genes in
      tissues and organisms promises, in the long term, to give us a clear idea of the
      role that Hox genes play during development and how they have evolved over time.

PMID- 12470821
TI  - Parental 5-methylcytosine methylation patterns are stable upon inter-species
      hybridization of Xiphophorus (Teleostei: Poeciliidae) fish.
AB  - Cytosine methylation appears to be established as an important DNA base
      modification involved in regulation of gene expression but is poorly understood
      from an evolutionary viewpoint. Xiphophorus progeny from inter-species crosses
      and backcrosses that are utilized in contemporary tumor induction studies were
      analyzed for cytosine methylation pattern inheritance using Southern blot
      analyses. Methylation patterns at CCGG sequences of 411 independent chromosomes
      in three distinct inter-species crosses were analyzed. In every case the non
      recurrent parental methylation pattern remained unaltered for each of the genes
      studied, once introduced into the recurrent parental genetic background. Through
      F(1) inter-species hybridization and succeeding meiosises leading to first
      generation (BC(1)) and second generation (BC(2)) backcross hybrid progeny, we
      demonstrate that parental species methylation patterns are stable.

PMID- 12470822
TI  - Absence of global genomic cytosine methylation pattern erasure during medaka
      (Oryzias latipes) early embryo development.
AB  - Two techniques were used to analyze global genomic 5-methyl cytosine methylation
      at CCGG sites of medaka embryo DNA. DNA was labeled by incorporation of
      microinjected radiolabeled deoxynucleotide into one-cell embryos. After Hpa II or
      Msp I digestion the radiolabeled DNA was fractionated in agarose gels and the
      distribution of label quantified throughout each sample lane to detect
      differences in fragment distribution. Alternately isolated DNA was digested with
      Hpa II or Msp I and the resulting generated termini end-labeled. The end-labeled
      digestion products were then analyzed for fragment distribution after gel
      fractionation. These techniques proved to be extremely sensitive, allowing
      comparison of genomic DNA methylation values from as few as 640 fish cells. The
      data suggest that in medaka embryos the vast majority (>90%) of genomic DNA is
      methylated at CCGG sites. Furthermore, these data support the conclusion that the
      extent of methylation at these sites does not change or changes very little
      during embryogenesis (from 16 cells to the hatchling). These data argue against
      active demethylation, or loss of methylation patterns by dilution, during the
      developmental stages between the one cell zygote and gastrulation. From a
      comparative viewpoint, these data may indicate that mammals and fishes methylate
      and demethylate their genomes in very different manners during development.

PMID- 12470823
TI  - Status and opportunities for genomics research with rainbow trout.
AB  - The rainbow trout (Oncorhynchus mykiss) is one of the most widely studied of
      model fish species. Extensive basic biological information has been collected for
      this species, which because of their large size relative to other model fish
      species are particularly suitable for studies requiring ample quantities of
      specific cells and tissue types. Rainbow trout have been widely utilized for
      research in carcinogenesis, toxicology, comparative immunology, disease ecology,
      physiology and nutrition. They are distinctive in having evolved from a
      relatively recent tetraploid event, resulting in a high incidence of duplicated
      genes. Natural populations are available and have been well characterized for
      chromosomal, protein, molecular and quantitative genetic variation. Their ease of
      culture, and experimental and aquacultural significance has led to the
      development of clonal lines and the widespread application of transgenic
      technology to this species. Numerous microsatellites have been isolated and two
      relatively detailed genetic maps have been developed. Extensive sequencing of
      expressed sequence tags has begun and four BAC libraries have been developed. The
      development and analysis of additional genomic sequence data will provide
      distinctive opportunities to address problems in areas such as evolution of the
      immune system and duplicate genes.

PMID- 12470824
TI  - Biological aging research today: potential, peeves, and problems.
AB  - Aging research has benefited immensely from the application of genetics during
      the past decade. This success frequently obscures some of the latent difficulties
      associated with this method. Interpretations of many experiments are overly
      optimistic. The emerging functional methods spawned by the knowledge of the
      genome promise a new window on the biological aging process. However, conceptual
      approaches have not quite caught up with the technology. An integrative approach
      to aging is needed, based on systems biology, to tap into this technology and to
      provide a deeper understanding of the operation of this complex process. The
      profound quantitative changes inherent in such phenomena as caloric restriction
      may actually result in stark qualitative changes in metabolism and aging. The
      ultimate goal is to understand the aging of the individual, and not simply to
      describe the mortality trajectories of the population. However, this will require
      the development of indices of frailty and of healthy aging. In the end, we may be
      able to 'cure' aging, but only in a statistical sense which is measured at the
      level of the population.

PMID- 12470826
TI  - Role of the Raf/MEK/ERK and the PI3K/Akt(PKB) pathways in fibroblast senescence.
AB  - Replicative senescence is characterized by numerous phenotypic alterations
      including loss of proliferative capacity and numerous changes in gene expression
      such as impaired serum inducibility of the immediate early gene c-fos and
      increased expression of collagenase. Transcription of c-fos in response to
      mitogens depends on the activation of a multiprotein complex formed on the c-fos
      serum response element (SRE), which includes the transcription factors serum
      response factor (SRF) and ternary complex factor (TCF). TCF is activated after
      phosphorylation by the Extracellular signals Regulated Kinase 1 and 2 (ERK1/2),
      two kinases of the Raf/MEK/ERK signaling pathway. We have previously demonstrated
      that collagenase expression is under positive regulation by the transcription
      factor FKHRL1 and that this transcription factor is under negative regulation by
      the phosphatidylinositol 3-kinase(PI3K)/Akt(PKB) pathway. Although total activity
      of ERK and Akt was similar in total cell lysates from early and late passage
      fibroblasts our data indicate that in senescent cells neither ERK nor Akt are
      able to phosphorylate efficiently their nuclear targets. Our findings suggest
      that although they can be fully activated in the cytosol of both early and late
      passage cells, the Raf/MEK/ERK and the PI3K/Akt pathways, which are essential for
      cellular proliferation, are down regulated in the nuclei of senescent cells.

PMID- 12470827
TI  - Mortalin: present and prospective.
AB  - Mortalin, also known as mthsp70/PBP74/GRP75, resides in multiple subcellular
      sites including mitochondria, ER, plasma membrane, cytoplasmic vesicles and
      cytosol. It is differentially distributed in normal and cancerous cells; the
      latter, when reverted back to normal phenotype, also show change in mortalin
      staining pattern similar to normal cells. Depending on its different subcellular
      niche and binding partner therein, mortalin is expected to perform multiple
      functions relevant to cell survival, control of proliferation and stress
      response.

PMID- 12470828
TI  - Replicative senescence of human fibroblasts: the role of Ras-dependent signaling
      and oxidative stress.
AB  - Replicative senescence of human fibroblasts is a widely used cellular model for
      human aging. While it is clear that telomere erosion contributes to the
      development of replicative senescence, it is assumed that additional factors
      contribute to the senescent phenotype. The free radical theory of aging suggests
      that oxidative damage is a major cause of aging; furthermore, the expression of
      activated oncogenes, such as oncogenic Ras, can induce premature senescence in
      primary cells. The functional relation between the various inducers of senescence
      is not known. The present study was guided by the hypothesis that constitutive
      activation of normal, unmutated Ras may contribute to senescence-induced growth
      arrest in senescent human fibroblasts. When various branches of Ras-dependent
      signaling were investigated, constitutive activation of the Ras/Raf/MEK/ERK
      pathway was not observed. To evaluate the role of oxidative stress for the
      senescent phenotype, we also investigated stress-related protein kinases. While
      we found no evidence for alterations in the activity of p38, we could detect an
      increased activity of Jun kinase in senescent fibroblasts. We also found higher
      levels of reactive oxygen species (ROS) in senescent fibroblasts compared to
      their younger counterparts. The accumulation of ROS in senescent cells may be
      related to the constitutive activation of Jun kinase.

PMID- 12470829
TI  - Serum levels of the senescence biomarker clusterin/apolipoprotein J increase
      significantly in diabetes type II and during development of coronary heart
      disease or at myocardial infarction.
AB  - Clusterin/apolipoprotein J (hereafter ApoJ) is a conserved secreted glycoprotein
      expressed by a wide array of tissues and being implicated in several
      physiological processes. ApoJ has been shown to associate with both normal in
      vitro aging, namely replicative senescence, as well as with stress induced
      premature senescence. In vivo, the protein is up-regulated in many severe
      physiological disturbances that relate to advanced aging, including accumulation
      in the artery wall during the development of atherosclerosis. In the current
      report we have expanded our previous studies that focus in the biological role of
      ApoJ during aging by addressing two interrelated issues: (a) we have examined the
      potential ApoJ association with in vivo aging and (b) we have studied whether its
      accumulation in the artery wall during the development of atherosclerosis is
      combined with a measurable increase of its serum levels, as well as, whether a
      similar effect occurs in diseases, such as diabetes type II, known to represent
      major risk factors of atherosclerosis. By combining a sandwich ELISA assay and
      immunoblotting analysis we demonstrate a measurable increase of ApoJ serum levels
      with age in males and provide evidence that, as compared to healthy donors, the
      serum ApoJ amount increases significantly in diabetic type II patients and in
      patients suffering from either a developing coronary heart disease, or myocardial
      infarction. The highest serum ApoJ levels were found during myocardial infarction
      but no correlation was observed with the number of vessels with documented
      atherosclerotic damage. In conclusion, this report illustrates that ApoJ
      accumulation in serum is probably coupled to a generalized stress mediated
      induction mechanism that is specifically related to certain diseases; moreover
      these data raise the possibility that elevated ApoJ levels in serum may represent
      a strong indication of vascular damage.

PMID- 12470830
TI  - Mitochondrial repair of 8-oxoguanine and changes with aging.
AB  - Reactive oxygen species (ROS) are formed in all living organisms as a by-product
      of normal metabolism (endogenous sources) and as a consequence of exposure to
      environmental compounds (exogenous sources). Endogenous ROS are largely formed
      during oxidative phosphorylation in the mitochondria and, therefore,
      mitochondrial DNA (mtDNA) is at particularly high risk of ROS-induced damage.
      Mitochondria are essential for cell viability, and oxidative damage to mtDNA has
      been implicated as a causative factor in a wide variety of degenerative diseases,
      and in cancer and aging. One of the most common oxidative DNA lesions is 7,8
      dihydro-8-oxoguanine (8-oxoG), which can introduce G/C to T/A transversions after
      DNA replication. Oxidative DNA base lesions, including 8-oxoG, are repaired
      primarily by the base excision repair (BER) pathway. While we know much about how
      this pathway functions in processing the nuclear DNA lesions, little is yet known
      about BER in mitochondria. We have used a number of different approaches to
      explore the mechanisms of DNA damage processing in the mtDNA. We have been able
      to demonstrate that mammalian mitochondria efficiently remove 8-oxoG from their
      genome, and that the efficiency of 8-oxoG incision increases with age in rats and
      mice. Yet 8-oxoG accumulates in mtDNA during aging. Changes in mitochondrial
      function with age have been observed in several organisms and accumulation of DNA
      lesions in mtDNA with age may be an underlying cause for numerous age-associated
      diseases including cancer.

PMID- 12470831
TI  - Psoralen plus UVA (PUVA) induced premature senescence as a model for stress
      induced premature senescence.
AB  - Following psoralen photoactivation (PUVA treatment) human dermal fibroblasts
      undergo long-term growth arrest as well as morphological and functional changes
      reminiscent of replicative senescence. Although the molecular description of
      cellular senescence is still incomplete, replicative senescence of cultured human
      cells has been suggested to reflect cellular aging in vitro. Recently, the term
      stress-induced premature senescence (SIPS) was introduced to define in vitro
      models with longterm growth arrest upon exposure to sublethal stressors (i.e.
      hyperoxia, hydrogen peroxide, ethanol), which are characterized by morphological
      and functional changes common for replicative senescence. This mini review
      focuses on the morphological and functional changes in the fibroblast phenotype
      following exposure to psoralen plus UVA (PUVA) leading to SIPS and the role of
      reactive oxygen species in the switch from the proliferative to the post mitotic
      cell. Additionally, we will discuss the possible in vivo relevance of PUVA-SIPS
      fibroblasts in PUVA-treated patients.

PMID- 12470832
TI  - Poly(ADP-ribose) polymerase-1, DNA repair and mammalian longevity.
AB  - Cellular DNA repair activities can be expected to control the rate of the ageing
      process by keeping the steady-state levels of DNA damage, which is continuously
      induced by endogenous and exogenous damaging agents, at low levels. Poly(ADP
      ribosyl)ation is one of the immediate biochemical reactions of eukaryotic cells
      to DNA damage and is functionally associated with DNA base-excision repair and
      strand break repair. Here we review the current state of the art concerning the
      relationship between DNA strand break repair, poly(ADP-ribosyl)ation, maintenance
      of genomic stability and mammalian life span.

PMID- 12470833
TI  - Age-related increase of protein glycation in peripheral blood lymphocytes is
      restricted to preferential target proteins.
AB  - Advanced glycation end products (AGE) have been analyzed in aging human
      peripheral blood lymphocytes since protein glycation and glycoxidation are
      believed to contribute to the intracellular age-related accumulation of damaged
      proteins, a process that has been associated with the cellular functional
      deficits that occur with age. The appearance of AGE in cell lysates was monitored
      with an enzyme-linked immunosorbent assay using an anti-AGE antibody raised
      against glycated RNAse. When lymphocyte cytosolic extracts from old donors (86-91
      years old) were compared with those from young donors (20-25 years old), a small
      but significant 40% increase of protein glycation was observed. In both age
      groups, further analysis of the pattern of glycated proteins by two-dimensional
      gel electrophoresis followed by western blotting with the same anti-AGE antibody,
      showed that the protein silver stain and the immunoblot patterns were not
      superimposable indicating that glycoxidative modifications are targeting only a
      restricted set of proteins. Among these preferential protein targets, seven of
      them exhibited a significant age-related increased immunoreactivity with the anti
      AGE antibody suggesting that the corresponding modified proteins might serve as
      biomarkers of aging lymphocytes.

PMID- 12470835
TI  - Mild stress-induced stimulation of heat-shock protein synthesis and improved
      functional ability of human fibroblasts undergoing aging in vitro.
AB  - Repeated mild heat-shock (RMHS) treatment has anti-aging hormetic effects on
      human fibroblasts undergoing aging in vitro. Since heat and various other
      stresses induce the transcription and translation of heat-shock proteins (Hsp),
      it was investigated if RMHS treatment affected the basal levels of four major
      stress proteins Hsp27, 70, 90 and Hsc70. The basal levels of Hsp27, Hsc70, and
      Hsp70 increased significantly in late passage senescent cells, which is
      indicative of an adaptive response to cumulative intracellular stress during
      aging. RMHS increased the levels of these Hsp even in early passage young cells
      and were maintained high throughout their replicative lifespan. In comparison,
      the amount of Hsp90 decreased both with aging and RMHS treatment in vitro.
      However, whereas the difference in the levels of Hsp70 and Hsp90 was
      statistically significant, the levels of Hsp27 and Hsc70 were statistically
      similar in normal and RMHS-treated serially passaged cells. These alterations
      were accompanied by an improved functional and survival ability of the cells in
      terms of increased proteasomal activities, increased ability to decompose
      H(2)O(2), reduced accumulation of lipofuscin and enhanced resistance to ethanol,
      H(2)O(2) and UV-A radiation.

PMID- 12470834
TI  - Assays of proteasome activity in relation to aging.
AB  - Proteasomes play a major role in intracellular protein turnover. They exist in
      cells in several different molecular forms including 20S proteasomes, 26S
      proteasomes and PA28-20S proteasome complexes. In this study we have compared the
      properties of these purified proteasome complexes to try to design assays that
      will distinguish between the different complexes (26S proteasome, 20S proteasome,
      PA28-20S proteasome) in cell extracts. Although the different purified complexes
      were found to have differences in stability, and in their sensitivity to low
      concentrations of SDS and salt, the results suggest that it is not
      straightforward to assay selectively for each type of complex in cell extracts.
      The relative contribution of different proteasome complexes varies in different
      cell types and there may be other proteases present which hydrolyse the chosen
      substrate. Proteasome assays carried out under defined conditions allow
      comparisons of activity in cell extracts as a function of age, but separation by
      gel filtration on a Superose 6 column was found to be a useful method for
      determining the level of different proteasome related complexes.

PMID- 12470836
TI  - Human skeletal muscle satellite cells: aging, oxidative stress and the mitotic
      clock.
AB  - Normal satellite cell cultures, isolated from human skeletal muscle, have a
      limited proliferative capacity and inevitably reach replicative senescence. In
      this study, we have focused on the consequences of a single oxidative stress by
      hydrogen peroxide (H(2)O(2)) on both proliferative capacity and myogenic
      characteristics. Treatment with 1mM H(2)O(2) for 30 min causes a small decrease
      in the viability and lifespan while the number of cells which are able to
      proliferate, decreases dramatically. This premature arrest of the cells in a non
      proliferative state was not due to spontaneous differentiation since there was no
      increase in the number of myogenin positive cells. This stress did not affect the
      myogenicity of the cells or their ability to differentiate and fuse to form
      multinucleated myotubes. In addition, the mitotic clock does not seem to be
      modified by oxidative stress treatment since the rate of telomere shortening was
      similar in H(2)O(2)-treated and control cells. This could be the consequence of
      the high level of oxygen consumption with an even higher level of ROS being
      produced in skeletal muscle than in other tissues which would be counteracted by
      an increase in the antioxidant defense system.

PMID- 12470837
TI  - Chronic in vivo exposure to glucocorticoids prolongs cellular lifespan: the case
      of Cushing's syndrome-patients' fibroblasts.
AB  - Glucocorticoid (GC) hypersecretion constitutes the major hormonal response to
      stress. In an effort to investigate the impact of a long-lasting exposure to high
      GC levels in vivo on cellular longevity, we have studied the lifespan of skin
      fibroblasts from patients suffering from Cushing's syndrome, who are
      characterised by chronic endogenous GC excess. Interestingly, we have observed
      that these cells exhibit a significant increase in their proliferative lifespan
      when cultured in vitro, under standard conditions, compared to fibroblasts from
      normal donors. In parallel, these cells secrete lower levels of transforming
      growth factor-beta, known to be implicated in stress-induced premature
      senescence. Furthermore, they also exhibit an intense stress reaction (near 2
      fold, compared to normal cells) in terms of heat-shock protein-70 induction.
      These results support the hypothesis that stress response may have beneficial
      consequences in cellular longevity, as well as in tissue homeostasis.

PMID- 12470838
TI  - Expression of the anti-apoptotic protein Hsp27 during both the keratinocyte
      differentiation and dedifferentiation of HaCat cells: expression linked to
      changes in intracellular protein organization?
AB  - We show here that Hsp27 increases its level of expression during the late phase
      of the keratinocyte differentiation of human HaCat cells. A similar phenomenon
      was observed when differentiated HaCat cells underwent a dedifferentiation
      process. In both cases, Hsp27 accumulated in the form of large native structures,
      which represent the chaperone active form of the protein. Hence, the presence of
      Hsp27 large oligomers does not appear to be the consequence of a particular
      differentiation process but should be considered as a marker of endogenous stress
      conditions. Such conditions may arise when drastic changes in the intracellular
      protein organization occur, such as during differentiation, dedifferentiation and
      probably also during the development of the senescent phenotype.

PMID- 12470839
TI  - Chaperone function and chaperone overload in the aged. A preliminary analysis.
AB  - Chaperones have an important role in the repair of proteotoxic damage, which is
      greatly increased in aged subjects. Chaperone levels and expression were subject
      of numerous studies in aged organisms. However, there were only very few attempts
      to measure chaperone activity in aged animals. Here, we report our initial
      studies showing a decreased chaperone capacity of liver cytosol from aged rats
      compared to those of young counterparts. The amount of Hsc70/Hsp70 was not
      significantly different in livers of young and aged rats. On the contrary, old
      animals showed a significant decrease in their hepatic Hsp90 content, which may
      explain their decreased chaperone activity. The observed decrease in chaperone
      capacity may also reflect a direct proteotoxic damage of chaperones, or an
      increase in chaperone occupancy, i.e. a 'chaperone overload' due to the increased
      amount of damaged hepatic proteins in aged rats. Experiments are in progress to
      elucidate the mechanism of the observed age-induced changes in chaperone
      function.

PMID- 12470840
TI  - What studies on human longevity tell us about the risk for cancer in the oldest
      old: data and hypotheses on the genetics and immunology of centenarians.
AB  - Centenarians are people who escaped from major common diseases, including cancer,
      and reached the extreme limits of human life-span. The analysis of demographic
      data indicates that cancer incidence and mortality show a levelling off around
      the age of 85-90 years, and suggests that oldest old people and centenarians are
      protected from cancer onset and progression. In this paper, we review data of
      recent literature on the distribution in centenarians of germ-line polymorphisms,
      which are supposed to affect the individual susceptibility to cancer (p53, HRAS1,
      BRCA1, glutathione transferases, cytochrome oxidases, steroid-5 alpha-reductase
      enzyme type II). Moreover, we add new data on two p53 polymorphisms in a total of
      1086 people of different age, including 307 centenarians. In addition, we put
      forth the hypothesis that the remodelling of the immune system occurring with age
      is capable of creating a hostile environment for the growth of cancer cells in
      these exceptional individuals. We conclude that future studies on centenarians
      regarding the germ-line variability of genes involved in the control of the
      immune response, including apoptosis (ApoJ), are likely to be of fundamental
      importance in understanding the basic mechanisms for cancer, aging and their
      complex relationship.

PMID- 12470841
TI  - GD3 in cellular ageing and apoptosis.
AB  - Lipid and glycolipid mediators are important components of the adaptive responses
      to stress, including apoptosis. In mammalian cells, the intracellular
      accumulation of ganglioside GD3, an acidic glycosphingolipid, contributes to
      mitochondrial damage, a crucial event during the apoptotic program. GD3 is a
      minor ganglioside in most normal tissues. Its expression increases during
      development and in pathological conditions such as cancer and neurodegenerative
      disorders. Interestingly, GD3 expression also increases with the normal ageing
      process. Moreover, GD3 can also mediate biological events like proliferation and
      differentiation. Since organism integrity requires a tight balance between cell
      proliferation, apoptosis and senescence, controlling the intracellular level of
      GD3 appears of particular importance for cell fate determination.

PMID- 12470842
TI  - Male/female ratio in centenarians: a possible role played by population genetic
      structure.
AB  - All the demographic surveys on the centenarians have highlighted that females
      outnumber males. The centenarians' male/female (M/F) ratio reported by most
      studies ranges between 1:4 and 1:7. A puzzling 1:2 ratio was observed in
      Calabria, a Southern Italian region. To our knowledge only in Sardinia a similar
      phenomenon had been previously observed. We have therefore used the data of the
      Italian Institute of Statistics to figure out the centenarians' M/F ratio in the
      Italian regions. We found that this ratio gradually decreases from South to
      North. Such a result is certainly due to many factors. Thus, we have explored the
      possibility, it is also influenced by the genetic structure of the Italian
      population. In fact, the distribution of the centenarians' M/F ratio turned out
      to be significantly correlated with the genetic structure of the Italian
      population as outlined by the principal component analysis.

PMID- 12470843
TI  - Tau aggregation in the hippocampal formation: an ageing or a pathological
      process?
AB  - Tauopathy is a concept to describe different genetic or metabolic dysfunctions of
      tau proteins that generate most of the known dementing disorders. Tauopathy is a
      degenerating process that also affects the entorhinal formation, and then the
      hippocampal formation in ageing. In Alzheimer's disease (AD), a disease due to
      APP dysfunction, a similar tauopathy process in observed in neocortical areas,
      well correlated to cognitive impairment. One important gap of knowledge is the
      relationship between tauopathy in the hippocampal formation, ageing, AD, and
      cognitive impairment. Here we show that the multidisciplinary analysis of
      numerous brains from non-demented and demented patients suggests the following
      observations: tauopathy of the hippocampal formation in humans is age-related but
      not an age-dependent process, also independent of AD, but amplified by APP
      dysfunctions. Tauopathy in the entorhinal and hippocampal formation could be
      another type of pathological dysfunction of tau proteins, and a therapeutic
      target to delay AD. Relevant animal models are desperately needed to address this
      issue.

PMID- 12470845
TI  - Transcranial Doppler assessment of cerebral vasospasm.
AB  - This review summarizes the use of transcranial Doppler (TCD) for assessment of
      cerebral vasospasm. The basic hemodynamic principles are presented, and used as a
      basis for discussing findings and interpretation methods. The need for additional
      information and measurements to correctly interpret TCD velocities is analyzed,
      and the use of a special extracranial Doppler technique is recommended. The
      advantages and limitations of the 'Lindegaard Index' (LI) are discussed. The
      recent advances in the use of TCD for cerebral autoregulation testing are opening
      up a new and promising avenue in diagnosis, monitoring and treatment of cerebral
      vasospasm.

PMID- 12470846
TI  - Clinical impact of patent foramen ovale diagnosis with transcranial Doppler.
AB  - The role of patent foramen ovale (PFO) in cryptogenic stroke is still debated,
      but from recent follow-up studies it seems that the amount of right-to-left shunt
      (RLS) and the association with atrial septal aneurysm (ASA) are major
      determinants of stroke recurrence. PFO and RLS through the atrial chambers have
      been recently studied in a number of conditions not or marginally related to
      cerebrovascular disease. Historically the first studies addressed the presence of
      RLS in scuba divers as a possible abnormality related to decompression sickness
      (DS) of unknown aetiology. Despite initial debate there is now robust evidence to
      claim that patency of foramen ovale increases the risk of developing DS by two
      and half to four times. Patients with PFO-related DS tend to have early
      occurrence of symptoms after surfacing and a clinical presentation that indicates
      brain or upper cervical spinal cord involvement. Recent reports suggest that
      divers with hemodynamically significant RLS may have an increased risk of
      developing clinically asymptomatic multiple brain lesions. PFO has been found in
      patients suffering from migraine with aura with approximately the same frequency
      as that encountered in cryptogenic stroke patients. This finding has prompted
      speculations on the possible role of RLS in increasing the stroke risk in
      migraineurs and in the pathophysiology of the aura. Recent reports showing that
      migraine with aura is dramatically improved after transcatheter closure of PFO
      suggest that migraine with aura may indeed be triggered by humoral factors that
      reach the brain by escaping the pulmonary filter. A RLS is involved in a rare
      condition known as platypnea-orthodeoxia and perhaps underlies an increased risk
      of cerebral complications after major orthopedic surgery. Valsalva-like
      activities often precede the occurrence of attacks of transient global amnesia
      (TGA) and abnormalities consistent with hypoperfusion of deep limbic structures
      have been reported during a typical TGA episode. This had raised the hypothesis
      that TGA may be triggered by paradoxical embolism of platelets aggregates in the
      posterior circulation, but the search for an increased frequency of PFO in TGA
      patients has yielded conflicting results. Conditions that determine an increase
      in pulmonary pressure may facilitate the opening of the virtual interatrial valve
      and thus promoting shunting of blood to the left heart chambers which in turn
      might contribute to further desaturation of arterial blood. It is therefore not
      surprising that RLS has been found in 70% of patients with chronic obstructive
      pulmonary disease and increased pulmonary pressure and in the same proportion of
      patients with obstructive sleep apnoea, a condition that ultimately may result in
      pulmonary hypertension. In conclusion, from the evidence gathered so far the
      picture is emerging of an important role of PFO in a number of non-stroke
      conditions, either as causative factor or as associated condition predisposing to
      complications. The availability of simple diagnostic techniques such as
      transcranial Doppler (TCD) to assess RLS will undoubtedly contribute a great deal
      of knowledge on the relevance in medicine of this hitherto neglected condition.

PMID- 12470847
TI  - Microembolus detection by transcranial doppler sonography.
AB  - Microembolic signals can be detected by transcranial ultrasound as signals of
      high intensity and short duration. These signals represent circulating gaseous or
      solid particles. To optimize the differentiation from artefacts and the
      background signal and to facilitate the clinical use, several attempts have been
      made to automatize the detection of microemboli. Microemboli occur spontaneously
      in various clinical situations but their clinical impact and possible
      therapeutical implications are still under debate. This article provides a review
      of the actual literature concerning the current state of technical and clinical
      aspects of microembolus detection.

PMID- 12470848
TI  - Cerebral autoregulation studies in clinical practice.
AB  - During the past 15 years several paradigms to study dynamic cerebral
      autoregulation (CA) were developed by measuring cerebral blood flow (CBF)
      velocity with transcranial Doppler (TCD) in response to blood pressure changes.
      As a more indirect approach to measure autoregulation, vasomotor reactivity (VMR)
      can be determined by the use of vasodilatory stimuli. CA or VMR are often
      severely disturbed in occlusive carotid artery disease. Several prospective
      studies have shown that reduced VMR is an important risk factor for stroke or TIA
      in patients with symptomatic and asymptomatic carotid artery stenosis or
      occlusion. Future randomized intervention studies will show whether asymptomatic
      patients with carotid artery stenosis and pathological autoregulation or VMR will
      benefit from revascularization therapy.

PMID- 12470849
TI  - Clinical applications of a non-invasive ICP monitoring method.
AB  - BACKGROUND AND PURPOSE: Until now the assessment of intracranial pressure (ICP)
      requires invasive methods. A previously introduced mathematical model allowed the
      non-invasive estimation of ICP (nICP) from arterial blood pressure (ABP) and
      blood flow velocity (FV). In various studies we have investigated the accuracy of
      this method and possible clinical applications. METHODS AND RESULTS: Selected
      hemodynamic parameters, calculated from the cerebral blood FV and the ABP curves,
      were used to express the relationship between ABP input and ICP output by linear
      transformation rules. In several clinical studies the accuracy and possible
      benefits of this method of non-invasive ICP (nICP) assessment were investigated.
      ASSESSMENT OF ICP PLATEAU WAVES: In 17 severely head injured patients we verified
      this model by comparison of nICP and measured ICP during generation of plateau
      waves, recorded in seven of these patients. In all simulations plateau elevations
      of ICP were well replicated. The correlation coefficient between increase of nICP
      and real ICP was R=0.98; P<0.001. LUMBAR INFUSION TESTS: Twenty one hydrocephalic
      patients were studied. Parallel increases in real ICP and nICP during lumbar
      infusion tests were evidently visible. Resistance of cerebrospinal fluid outflow
      (Rcsf) was computed using nICP and compared with Rcsf computed from real ICP. The
      mean error between real and non-invasive Rcsf was 4.1+/-2.2 mmHg min/ml. CEREBRAL
      AUTOREGULATION: One hundred and forty five patients were studied after severe
      head injuries. The state of autoregulation was assessed by moving correlation of
      cerebral perfusion pressure (CPP=ABP-ICP) and FV (Mx index). nICP instead of ICP
      was used to continuously estimate the state of autoregulation and to dynamically
      adapt the nICP procedure to this state. A median error between ICP and nICP of
      6.0 mmHg was observed. Directly and non-invasively assessed Mx indices correlated
      highly significantly (R=0.9; P<0.001). CONCLUSIONS: The results demonstrate that
      the nICP assessment model constitutes a reliable method to monitor ICP and may
      therefore provide various useful clinical applications.

PMID- 12470850
TI  - The axial imaging plane--the main domain of the transcranial color-coded duplex
      ultrasonography?
AB  - Transcranial color-coded duplex ultrasonography (TCCS) makes possible the
      visualization of basal cerebral arteries through color-coding the flow velocity
      information. This method is well established in the clinical routine for the
      diagnostics of pathological processes in cerebrovascular disease. The present
      review describes the examination technique, normal and pathological findings,
      such as stenosis and occlusion of intracranial arteries, as well as intracranial
      vascular malformations focussing on the advantages of the examination in the
      axial imaging planes.

PMID- 12470851
TI  - Transcranial ultrasonography of cerebral veins and sinuses.
AB  - Transcranial ultrasonography has become a valuable diagnostic tool for the bed
      side evaluation of cerebral hemodynamics. While the assessment of arterial blood
      flow is well established, analysis of venous hemodynamics by transcranial
      ultrasonography is a new application of the method. The present review summarises
      the current state of transcranial venous ultrasound in adults by means of
      transcranial Doppler (TCD) and transcranial colour-coded duplex sonography
      (TCCS). It gives a critical overview regarding current and possible future
      clinical applications of the techniques.

PMID- 12470852
TI  - Sonographic imaging of the brain parenchyma.
AB  - Using B-mode transcranial sonography (TCS), it is possible to image the brain
      parenchyma through the intact skull with conventional low-frequency probes.
      Several brain disorders can be depicted by TCS such as bleedings, brain tumors,
      or enlargement of the ventricular system. More recently there is evidence that
      TCS findings can complement information from other neuroimaging techniques in
      neurodegenerative disorders leading to new insights and pathophysiological
      concepts.

PMID- 12470853
TI  - Impact of ultrasound contrast agents in cerebrovascular diagnostics.
AB  - This review gives a summary on current ultrasound contrast agents and their
      composition. Methods of brain imaging using UCA, like harmonic imaging and
      acoustic emission, are also described. Besides contrast-enhanced conventional
      color duplexsonography of the extracranial brain supplying arteries, transcranial
      contrast investigation of the basal cerebral arteries and visualization of
      cerebral microcirculation are also discussed in this paper. Another main topic
      are the interactions between UCA, human tissue and the ultrasound system.

PMID- 12470854
TI  - Brain perfusion and ultrasonic imaging techniques.
AB  - Advances in neurosonology have generated several techniques of ultrasonic
      perfusion imaging employing ultrasound echo contrast agents (ECAs). Doppler
      imaging techniques cannot measure the low flow velocities that are associated
      with parenchymal perfusion. Ultrasonic perfusion imaging, therefore, is a
      combination of a contrast agent-specific ultrasound imaging technique (CAI) mode
      and a data acquisition and processing (DAP) technique that is suited to observe
      and evaluate the perfusion kinetics. The intensity in CAI images is a measure of
      ECA concentration but also depends on various other parameters, e.g. depth of
      examination. Moreover, ECAs can be destroyed by ultrasound, which is an artifact
      but can also be a feature. Thus, many different DAPs have been developed for
      certain CAI techniques, ECAs and target organs. Although substantial progress in
      ECA and CAI technology can be foreseen, ultrasound contrast imaging has yet to
      reliably differentiate between normal and pathological perfusion conditions.
      Destructive imaging techniques, such as contrast burst imaging (CBI) or time
      variance imaging (TVI), in combination with new DAP techniques provide sufficient
      signal-to-noise ratio (SNR) for transcranial applications, and consider contrast
      agent kinetics and destruction to eliminate depth dependency and to calculate
      semi-quantitative parameters. Since ultrasound machines are widely accessible and
      cost-effective, ultrasonic perfusion imaging techniques should become
      supplementary standard perfusion imaging techniques in acute stroke diagnosis and
      monitoring. This paper gives an overview on different CAI and DAP techniques with
      special focus on recent innovations and their clinical potential.

PMID- 12470855
TI  - Clinical impact of intima media measurement.

PMID- 12470856
TI  - Design of a multicentre study on neurosonology in acute ischaemic stroke. A
      project of the neurosonology research group of the World Federation of Neurology.
AB  - This report summarises the design and organisation of a multicentre study on
      neurosonology in acute ischaemic stroke. The Neurosonology in Acute Ischaemic
      Stroke Study will determine whether extracranial and transcranial Doppler and
      duplex sonography performed within 6 h after onset of stroke improves prediction
      of functional outcome if applied in addition to routine diagnostic admission
      investigations, i.e. medical history, standardised neurological examination,
      brain imaging by computed or magnetic resonance tomography, electrocardiography,
      and baseline laboratory examination. The primary hypothesis is that there is a
      consistent and persuasive difference between patients with an occluded middle
      cerebral artery and those with an open artery in terms of the functional deficit
      after 3 months. Power calculations are based on the assumption of alpha=0.05 (two
      sided test) and a probability of a maximally mild functional deficit of 0.4.
      Detection of a 20% difference with a power of 0.8 resulted in a calculated sample
      of 400 patients to be observed. Calculation took into consideration that only 50%
      of admitted patients would have a moderate to severe neurological deficit of whom
      only 30% will have an occlusion of the corresponding middle cerebral artery.
      Furthermore, the study is designed to evaluate a difference of the functional
      outcome in relation to occurrence and time of recanalisation in-patients
      presenting with an initially occluded middle cerebral artery.

PMID- 12470857
TI  - Therapeutic ultrasound in ischemic stroke treatment: experimental evidence.
AB  - Re-opening of the occluded artery is the primary therapeutic goal in hyper-acute
      ischemic stroke. Systemic treatment with IV rt-PA has been shown to be beneficial
      at least in a 3 h 'door to needle' window and is approved within that interval in
      many countries. Trials of thrombolytic therapy with rt-PA demonstrated a small,
      but significant improvement in neurological outcome in selected patients. As
      recently shown, intra-arterial application of rt-PA is effective and opens the
      therapeutical window to 6 h, but requires invasive intra-arterial angiographic
      intervention in a high number of patients, who do not finally achieve
      thrombolysis. Ultrasound (US) is known to have several biological effects
      depending on the emission characteristics. At higher energy levels US alone has a
      thrombolytic effect. That effect is already used for clinical purposes in
      interventional therapy using US catheters. Recently, there is growing evidence
      that US at lower energy levels (<2 W/cm(2)) facilitates enzymatic mediated
      thrombolysis, most probably by breaking molecular linkages of fibrin polymers and
      therefore, increasing the working surface for the thrombolytic drug. Different in
      vitro and in-vivo experiments have shown increased clot lysis as well as
      accelerated recanalization of occluded peripheral, coronary vessels and most
      recently also intracerebral arteries. Sonothrombolysis at low energy levels,
      however, is of great interest because of the low risk for collateral tissue
      damage, enabling external insonation without the need for local catheterization.
      Whereas little or no attenuation of US can be expected through skin and chest,
      intensity will be significantly attenuated if penetration of bones, particularly
      the skull, is required. That effect, however, is frequency dependent. Whereas
      >90% of intracerebral US intensity is lost (of the output power) in frequencies
      currently used for diagnostic purposes (mostly 2 MHz and up), that ratio is
      nearly reversed in the lower KHz range (<300 kHz). US at these low frequencies,
      however, is efficient for accelerating enzymatic thrombolysis in-vitro as well as
      in vivo within a wide range of intensities, from 0.5 W/cm(2) (MI approximately
      0.3) to several W/cm(2). Since the emitted US beam widens with decreasing
      frequency, low-frequency US can insonate the entire intracerebral vasculature.
      That may overcome the limitation of US in the MHz range being restricted to
      insonation of the MCA mainstem. There are no reports in the preclinical
      literature about intracerebral bleeding or relevant cerebral cellular damage
      (either signs of necrosis or apoptosis) for US energy levels up to 1 W/cm(2).
      Moreover, recent investigations showed no break-down of the blood brain barrier.
      Safety of US exposure of the brain for therapeutic purposes has to address
      heating. Heating depends critically on the characteristics of the US. The most
      significant heating of the brain tissue itself is >1 degrees C/h using a
      continuous wave (CW) 2 W/cm(2) probe, whereas no significant heating could be
      found when using an intermittent (pulsed) emission protocol. The experimental
      data so far help to characterize the optimal US settings for sonothrombolysis and
      support the hypothesis that this combined treatment is a prospective advance in
      optimizing thrombolytic therapy in acute stroke.

PMID- 12470858
TI  - Ultrasound-enhanced thrombolysis for stroke: clinical significance.
AB  - In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA)
      therapy for ischemic stroke, a low rate of early arterial recanalization was
      suspected due to the small numbers of patients who had early dramatic clinical
      improvement. TPA activity can be enhanced with ultrasound including 2 MHz
      transcranial Doppler (TCD). TCD can identify residual signals around the thrombus
      with the thrombolysis in brain ischemia (TIBI) flow grading system and therefore
      expose more thrombus surface to circulating TPA. A phase I clinical study,
      monitoring TPA infusion with diagnostic ultrasound resulted in an unexpectedly
      high rate of complete recanalization (36% of proximal middle cerebral artery
      (MCA) occlusions) and associated early dramatic clinical recovery (24%) among
      treated patients. The external application of diagnostic ultrasound in our
      studies raised the possibility that a synergistic TPA and ultrasound action
      accelerated flow improvement and achieved faster and more complete thrombus
      dissolution as predicted from experimental models. The CLOTBUST (combined lysis
      of thrombus in brain ischemia using transcranial ultrasound and systemic TPA)
      trial is testing this hypothesis in a phase II clinical randomized multi-center
      setting. Dramatic clinical recovery from stroke and complete recanalization
      shortly after TPA bolus are feasible goals for thrombolysis assisted with TCD
      monitoring.

PMID- 12470860
TI  - The hallucinogen d-lysergic acid diethylamide (d-LSD) induces the immediate-early
      gene c-Fos in rat forebrain.
AB  - The hallucinogen d-lysergic acid diethylamide (d-LSD) evokes dramatic somatic and
      psychological effects. In order to analyze the neural activation induced by this
      unique psychoactive drug, we tested the hypothesis that expression of the
      immediate-early gene product c-Fos is induced in specific regions of the rat
      forebrain by a relatively low, behaviorally active, dose of d-LSD (0.16 mg/kg,
      i.p.); c-Fos protein expression was assessed at 30 min, and 1, 2 and 4 h
      following d-LSD injection. A time- and region-dependent expression of c-Fos was
      observed with a significant increase (P<0.05) in the number of c-Fos-positive
      cells detected in the anterior cingulate cortex at 1 h, the shell of the nucleus
      accumbens at 1 and 2 h, the bed nucleus of stria terminalis lateral at 2 h and
      the paraventricular hypothalamic nucleus at 1, 2 and 4 h following systemic d-LSD
      administration. These data demonstrate a unique pattern of c-Fos expression in
      the rat forebrain following a relatively low dose of d-LSD and suggest that
      activation of these forebrain regions contributes to the unique behavioral
      effects of d-LSD.

PMID- 12470859
TI  - Altered GABAergic function accompanies hippocampal degeneration in mice lacking
      ClC-3 voltage-gated chloride channels.
AB  - Mice lacking ClC-3 chloride channels, encoded by the Clcn3 gene, undergo
      neurodegeneration of the hippocampal formation and retina [Neuron, 29 (2001) 185
      196; Genes Cells, 7 (2002) 597-605]. We independently created a mouse lacking the
      Clcn3 gene which demonstrated similar central nervous system abnormalities,
      including early postnatal degeneration of retinal photoreceptors. However, we
      observed a characteristic spatial-temporal sequence of hippocampal
      neurodegeneration that differs from the pattern previously reported. Anterior-to
      posterior degeneration and astrogliosis of the dentate gyrus and hippocampus
      progressed over months. Sequential loss of hippocampal neuronal subpopulations
      began in the dentate gyrus and progressed to CA3, followed by CA1 neurons.
      Projection neurons of the entorhinal cortex degenerated, secondary to the loss of
      their synaptic targets within the hippocampal formation. Other characteristics of
      the Clcn3(-/-) mice included an abnormal gait, kyphosis, and absence of hindlimb
      escape extension upon tail elevation. Spontaneous seizures were observed in four
      adult Clcn3(-/-) mice, and one mouse died during the event. We hypothesized that
      neuronal injury may be related to recurrent seizures. Clcn3(-/-) mice had normal
      serum electrolytes and pH, and exhibited neither hyperglycemia nor rebound
      hypoglycemia following a glucose load. They displayed a greatly reduced
      susceptibility to pentylenetetrazole-induced seizures and an abnormally prolonged
      sedation to benzodiazepines. There was no change in vulnerability to kainic acid
      induced seizures. Immunostaining revealed a progressive loss of GABA synthesizing
      cells in the dentate gyrus. The death of these cells was preceded by increased
      GABA(A) receptor immunoreactivity. These data suggest that GABA(A) inhibitory
      neurotransmission is altered in Clcn3(-/-) mice. The increase in GABA(A) receptor
      density may represent a compensatory response either to chronic excessive
      excitatory stimuli or reduced inhibitory input from local GABAergic interneurons
      within the dentate gyrus.

PMID- 12470861
TI  - Per and neuropeptide expression in the rat suprachiasmatic nuclei:
      compartmentalization and differential cellular induction by light.
AB  - Per1 and Per2, two clock genes rhythmically expressed in the suprachiasmatic
      nucleus (SCN), are implicated in the molecular mechanism of the circadian
      pacemaker and play a major role in its entrainment by light. To date, it is not
      known if every cell of the SCN, a heterogeneous structure in respect of
      neuropeptide content, expresses clock genes equally. The aim of this study was to
      identify, by single and double non-radioactive and/or radioactive hybridizations,
      the cell types (AVP, VIP and GRP) expressing Per1 or Per2 in the SCN of rats, (1)
      when Per are highly expressed during the daytime, and (2) after induction of Per
      expression by a light pulse at night. Our results indicate that, during the
      daytime, Per1 and Per2 genes are both mainly expressed in the AVP cells of the
      dorso-median part of the SCN, whereas only a few VIP cells in the ventral part of
      the SCN exhibit Per gene expression. In contrast, following a light pulse at
      night, there is differential induction of the two Per genes. Per1 expression
      essentially occurs in the ventro-lateral GRP cells, while Per2 expression is not
      restricted to the retinorecipient part of the SCN as it also occurs in AVP cells.
      Altogether, our results suggest that Per1 and Per2 are mainly expressed in AVP
      cells during the daytime and suggest that GRP cells play an important role in
      resetting of the clock by light.

PMID- 12470862
TI  - Protection against gp120-induced neurotoxicity by an array of estrogenic
      steroids.
AB  - gp120, the coat protein of HIV, can be neurotoxic and is thought to contribute to
      AIDS-related dementia complex. Such toxicity involves activation of glutamate
      receptors, mobilization of free cytosolic calcium, and generation of oxygen
      radicals. We have previously shown that the estrogen 17beta-estradiol, in
      concentrations of 100 nM or higher, lessens the neurotoxicity of gp120 in
      hippocampal and cortical cultures, blunts gp120-induced calcium mobilization, and
      lessens the oxidative consequences. In this study, we examined the protective
      potential of other estrogens. We found gp120 neurotoxicity in hippocampal
      cultures to be significantly lessened by estrone, equilin and estriol, although
      with an order of magnitude less potent than 17beta-estradiol. We also found all
      four estrogens to blunt gp120-induced calcium mobilization, with estriol being
      more efficacious than the other three estrogens. These findings give insight both
      into the mechanisms of estrogenic protection (e.g. receptor-dependent versus
      independent actions) as well as into the potential therapeutic use of estrogens
      against AIDS-related dementia complex.

PMID- 12470863
TI  - Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid
      receptor binding.
AB  - The present study examines the degree and distribution of alterations in the
      expression of kappa-opioid receptor subtypes using a model of chronic
      intracerebroventricular (i.c.v.) infusion of butorphanol. Autoradiographic
      characterization of binding for brain kappa(1) ([3H]CI-977)-, kappa(2)
      ([3H]bremazocine in the presence of DAMGO, DPDPE, and U-69,593)- and total kappa
      ([3H]bremazocine in the presence of only DAMGO and DPDPE)-opioid receptors was
      performed. Dependence was induced by a 72 h i.c.v. infusion with butorphanol (26
      nmol/microl per hour) (butorphanol-dependent). Butorphanol withdrawal was
      produced by terminating the infusion of butorphanol in dependent animals.
      Responses were studied 7 h following termination (butorphanol-withdrawal). During
      both dependence and withdrawal phases, the binding signals for both kappa(1)- and
      kappa(2)-opioid receptors were significantly increased in certain regions, with
      especially marked increases in the frontal cortex, nucleus accumbens, parietal
      cortex, dorsomedial hypothalamus, ventral tegmental area and locus coeruleus. In
      contrast, a highly specific decrease in kappa(2)-, but increase in kappa(1)-,
      opioid receptor binding was noted in the hippocampus of rats in both butorphanol
      dependent and-withdrawal groups. Therefore, alterations in kappa(1)- and kappa(2)
      opioid receptors in the hippocampus may be differently involved in both
      adaptation to and recovery from chronic exposure to a mixed agonist/antagonist
      opioid analgesic. These results further illustrate the regional distribution of
      changes in binding characteristics of rat brain kappa(1)- and kappa(2)-opioid
      receptor subtypes in an established model of butorphanol dependence and
      withdrawal.

PMID- 12470864
TI  - Further evidence for the central effect of dexamethasone at the hypothalamic
      level in the negative feedback mechanism.
AB  - The site of action of glucocorticoids (GC) in exerting negative feedback upon the
      hypothalamo-pituitary-adrenocortical (HPA) axis is not yet clear. In the present
      study we have examined whether dexamethasone (Dex) can inhibit the HPA axis
      stress responses by acting locally at the hypothalamic level in freely moving
      male rats. Local micro-injection of Dex in the paraventricular nuclei (PVN; 1
      microg) prevented a decrease of CRH-41 content in the median eminence. The PVN
      Dex injections (0.25-1 microg) also inhibited the rise in plasma ACTH and
      corticosterone (CS) following short photic stimulation in a dose dependent
      manner. In PVN Dex-injected rats, i.v. injection of CRH-41 increased serum ACTH
      and CS levels similar to that observed in rats injected with saline into the PVN
      indicating normal sensitivity of the pituitary gland to CRH-41. Local injection
      of [3H]Dex in the PVN showed that only a negligible amount of radioactivity was
      found in the pituitary. These data indicate that minute amounts of Dex in the
      PVN, which did not affect the pituitary, blocked the HPA axis responses to photic
      stimulation. It is suggested that Dex may exert its inhibitory effect on the HPA
      axis at least in part at the hypothalamic level.

PMID- 12470865
TI  - Basal EGR-1 (zif268, NGFI-A, Krox-24) expression in developing striatal patches:
      role of dopamine and glutamate.
AB  - Egr-1 (also known as zif268, NGFI-A, or Krox 24) is an immediate-early gene of
      the zinc finger family that exhibits relatively high constitutive expression in
      the brain, as well as inducibility by seizure activity, stimulants, and salient
      physiological stimuli. Immunocytochemical detection of the Egr-1 protein in the
      developing striatum revealed that in the late prenatal and early postnatal
      period, Egr-1 protein was expressed selectively in patches of striatal neurons
      under basal conditions. Egr-1 immunoreactivity was co-expressed with known
      markers of striatal patch neurons, indicating that expression was greatest in the
      striatal patch compartment. This patchy expression of Egr-1 transitioned to a
      nearly homogeneous pattern of Egr-1-immunoreactive cells by postnatal day 10, at
      which time most striatal neurons appeared to be Egr-1-immunoreactive. The
      dopamine D1 antagonist SCH23390 (0.5-1.0 mg/kg) reduced Egr-1 expression during
      the first week postnatal, but it was no longer effective at postnatal day 10. On
      the other hand, the noncompetitive NMDA antagonist MK-801 (0.5-1.0 mg/kg) became
      more effective at reducing Egr-1 expression with age. Neonatal destruction of
      nigrostriatal dopamine afferents reduced the basal pattern of Egr-1 expression
      for 2-3 days after the lesion, but then Egr-1 expression returned. Thus, Egr-1
      expression in the developing striatum appears to be driven first by dopaminergic
      afferents, and then later in development by excitatory glutamatergic afferents.

PMID- 12470867
TI  - Methamphetamine exposure from postnatal day 11 to 20 causes impairments in both
      behavioral strategies and spatial learning in adult rats.
AB  - Spatial learning and memory deficits in a water maze have been observed in adult
      animals exposed to a regimen of 4 daily doses of d-methamphetamine (MA) at 2 h
      intervals from postnatal day 11 to 20. An interpretational issue for these long
      term effects of MA is whether they are truly spatial deficits or are secondary to
      alterations in sensorimotor systems. In this experiment, we evaluated the effects
      of a pretraining procedure shown to minimize the influence of drug-induced
      sensorimotor deficits. Animals within a litter were treated with MA or saline.
      Animals were either pretrained for nonspatial task requirements in the water maze
      (i.e., swimming and platform climbing) or were nai;ve to the task. Animals that
      received the pretraining did better than the nai;ve animals. The nai;ve MA
      animals performed worse than the nai;ve control animals as previously observed.
      By contrast, no difference in search time was noted between pretrained MA- and
      SAL-treated animals during the acquisition phase of testing. When the platform
      was relocated in a novel position, spatial learning was impaired for MA animals,
      regardless of pretraining. No increase in the number of platform nonrecognition
      events (swimovers, deflections, or jump-offs) occurred among pretrained or nai;ve
      groups compared to controls. These data suggest that sensorimotor deficits do not
      account for the spatial learning and memory deficits in animals exposed
      neonatally to MA.

PMID- 12470866
TI  - Erythropoietin improves synaptic transmission during and following ischemia in
      rat hippocampal slice cultures.
AB  - Erythropoietin (EPO) prevents neuronal damage following ischemic, metabolic, and
      excitotoxic stress. In this study evoked extracellular field potentials (FP) were
      used to investigate the effect of EPO on synaptic transmission in hippocampal
      slice cultures. EPO treated cultured slices (40 units/ml for 48 h) showed
      significantly increased FP during and following oxygen and glucose deprivation
      compared with untreated control slices. The addition of the Jak2 inhibitor AG490
      (50 microM for 48 h) blocked the EPO effect. These data suggest that EPO improves
      synaptic transmission during and following ischemia in hippocampal slice
      cultures.

PMID- 12470868
TI  - The effects of sympathectomy on capsaicin-evoked fos expression of spinal dorsal
      horn GABAergic neurons.
AB  - Electrophysiological studies have suggested that activity of spinal GABAergic
      interneurons can be enhanced following intradermal injection of capsaicin (CAP).
      This activity is proposed to be involved in the generation of dorsal root
      reflexes (DRRs) that contribute to neurogenic inflammation. We have recently
      reported that NMDA or non-NMDA antagonists by intrathecal pretreatment attenuate
      the increased Fos expression in spinal dorsal horn GABAergic neurons after
      intradermal injection of CAP in rats. Sympathetic efferents have been suggested
      to modulate inflammatory pain possibly by interactions with primary afferent
      terminals. In electrophysiological studies by our group, enhancement of the CAP
      induced DRRs could be prevented by surgical sympathectomy and blocked by
      intraarterial pretreatment of the foot with alpha(1)- but not by alpha(2)
      adrenoceptor antagonists. In order to determine morphologically if surgical
      sympathectomy changes the expression of Fos in GABAergic neurons in the
      lumbosacral spinal cord induced by CAP injection, further experiments were
      performed using immunofluorescence double-labeling staining at 30 min following
      CAP or vehicle injection into the glabrous skin of one hind paw of anesthetized
      rats both in sham-operated and sympathectomized animals. Our results showed that
      the proportion of Fos-positive GABAergic neuronal profiles was significantly
      increased following CAP injection (48.8+/-4.76%) compared to vehicle injection
      (23.8+/-5.1%) in laminae I-V on the ipsilateral side (P<0.05). However, when
      sympathetic efferents were removed surgically 7-10 days prior to the experiment
      (n=6), only 32.07+/-9.03% of GABA-immunoreactive neuronal profiles were stained
      for Fos following CAP injection, a significant reduction in the CAP-evoked Fos
      staining of GABAergic neurons after surgical sympathectomy. These findings
      support our previous electrophysiological studies that GABAergic neurons take
      part in nociceptive processing within the spinal dorsal horn and suggest that
      sympathetic efferents may affect nociceptive transduction in the periphery.

PMID- 12470869
TI  - Effects of L-arginine-derived nitric oxide synthesis on cardiovascular responses
      to stimulus-evoked somatosympathetic reflexes in the gracile nucleus.
AB  - The purpose of these studies was to determine the role of gracile nucleus (Gr)
      and the effects of L-arginine-derived nitric oxide (NO) synthesis in the nucleus
      on the cardiovascular responses to somatosympathetic reflexes (SSR). Electrical
      stimulation of sural and tibial nerve to evoke excitatory and inhibitory SSR was
      carried out in anesthetized Sprague-Dawley rats. Arterial blood pressure and
      heart rate were monitored during stimulus-evoked SSR following microinjections of
      the agents into Gr. Cardiovascular responses to electrical stimulation of the
      sural and tibial nerves were blocked by microinjection of lidocaine into Gr. The
      hypertensive and tachycardiac responses to stimulation of the sural nerve were
      attenuated by bilateral microinjection of L-arginine into Gr, but enhanced by the
      presence of nNOS antisense oligodeoxynucleotides (oligos) in the area.
      Microinjection of L-arginine into Gr facilitated the hypotensive and bradycardic
      responses to stimulation of the tibial nerve while pretreatment with nNOS
      antisense oligos into Gr attenuated the tibial stimulation evoked inhibitory SSR.
      The stimulus-evoked responses were not altered by microinjection of nNOS sense
      oligos into Gr. The results show that the cardiovascular responses to stimulus
      evoked SSR were inhibited by the presence of a blockade of neuronal conduction in
      the Gr. L-Arginine-derived NO synthesis in the Gr attenuates the cardiovascular
      responses to stimulus-evoked excitatory SSR and facilitates the responses to
      inhibitory SSR. We conclude that NO in the Gr plays an inhibitory role in the
      central cardiovascular control through SSR regulation.

PMID- 12470870
TI  - Involvement of a spinal brain-derived neurotrophic factor/full-length TrkB
      pathway in the development of nerve injury-induced thermal hyperalgesia in mice.
AB  - Partial sciatic nerve ligation in mice caused a marked and persistent decrease in
      the latency of paw withdrawal from a thermal stimulus only on the ipsilateral
      side. This thermal hyperalgesia was abolished by repeated intrathecal
      pretreatment with a specific antibody to brain-derived neurotrophic factor
      (BDNF), but not neurotrophin-4, just before and after the nerve ligation. These
      results provide direct evidence that BDNF within the spinal cord may contribute
      to the development of thermal hyperalgesia caused by nerve injury in mice. We
      previously reported that protein level of full-length TrkB, which contains the
      cytoplasmic protein tyrosine kinase domain, were clearly increased on the
      ipsilateral side of spinal cord membranes obtained from sciatic nerve-ligated
      mice. In the present study, we further demonstrated that the increased in the
      protein level of full-length TrkB is completely reversed by concomitant
      intrathecal injection of BDNF antibody. Furthermore, thermal hyperalgesia induced
      by nerve ligation was completely suppressed by repeated intrathecal injection of
      a specific antibody to full-length TrkB and an inhibitor of the protein tyrosine
      kinase activity for the neurotrophin receptor, K-252a. However, repeated
      intrathecal injection of a specific antibody to truncated TrkB, which lacks the
      cytoplasmic protein tyrosine kinase domain, failed to reverse thermal
      hyperalgesia observed in nerve-ligated mice. These findings suggest the
      possibility that the binding of BDNF to full-length TrkB and subsequent its
      activation may play a critical role in the development of neuropathic pain-like
      thermal hyperalgesia induced by nerve injury in mice.

PMID- 12470871
TI  - Phase-locking of spontaneous and elicited ponto-geniculo-occipital waves is
      associated with acceleration of hippocampal theta waves during rapid eye movement
      sleep in cats.
AB  - We investigated the temporal relationship between hippocampal theta waves and
      ponto-geniculo-occipital waves (PGO) during rapid eye movement sleep (REM sleep)
      in cats. In addition, we analyzed the relationship between hippocampal theta
      waves and PGO as elicited by tone stimulus (PGO(E)) in order to quantitively
      characterize the PGO wave generator mechanism. The results showed that a
      spontaneous PGO tended to be phase-locked to the theta wave, which was more
      clearly observed in the single PGO than in the cluster. However, cluster PGO(E)
      tended to be phase-locked as well as single PGO(E). It was therefore suggested
      that the generator of PGO is activated in relation to the hippocampal theta wave.
      An acceleration of the theta wave associated with PGO occurrence was found, and
      was more markedly observed than with the cluster PGO. Although the magnitude of
      it was less than in the spontaneous case, an acceleration around the PGO(E) was
      also observed. These results suggest that the generators of theta and PGO receive
      some common activations, especially when a cluster PGO is generated. The
      interaction between PGO and hippocampal theta waves is expected to be involved in
      the possible functions of REM sleep.

PMID- 12470872
TI  - Neurite outgrowth is impaired on HSP70-positive astrocytes through a mechanism
      that requires NF-kappaB activation.
AB  - In the adult central nervous system (CNS), prominent reactive astrocytosis is
      seen in acute traumatic brain injury, neurodegenerative diseases and a variety of
      viral infections. Reactive astrocytes synthesize a number of factors that could
      play different roles in neuronal regeneration. In this study, the effects of
      thermal stress were evaluated on nuclear factor-kappaB (NF-kappaB) activation and
      proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) secretion in
      primary astrocytic cultures. The ability of HSP70-positive astrocytes to support
      or inhibit neurite outgrowth was investigated in neuron-astrocyte cocultures.
      Cultured astrocytes from cerebral cortex of rats were exposed to transient
      hyperthermia (42 degrees C/30 min) and incubated at 37 degrees C for different
      periods of recovery. During HSP70 accumulation, astrocytes extended large and
      thick processes associated to rearrangement of glial fibrillary acidic protein
      (GFAP) filaments and an increase in protein synthesis and GFAP, suggesting an
      astrogliosis event. A delay of NF-kappaB activation appeared closely related to
      TNF-alpha secretion by HSP70-positive astrocytes. These cells demonstrated a
      functional shift from neurite growth-promoting to non-permissive substrate. We
      also found that gliotoxin, a specific NF-kappaB inhibitor, partially abrogated
      the inhibitory ability of reactive astrocytes. These findings may suggest a
      involvement of NF-kappaB and TNF-alpha in modulating the failure of HSP70
      positive astrocytes to provide functional support to neuritic outgrowth.

PMID- 12470873
TI  - Establishment and characterization of an immortalized Z310 choroidal epithelial
      cell line from murine choroid plexus.
AB  - The choroid plexus plays a wide range of roles in brain development, maturation,
      aging process, endocrine regulation, and pathogenesis of certain
      neurodegenerative diseases. To facilitate in vitro study, we have used a gene
      transfection technique to immortalize murine choroidal epithelial cells. A viral
      plasmid (pSV3neo) was inserted into the host genome of primary choroidal
      epithelia by calcium phosphate precipitation. The transfected epithelial cells,
      i.e., Z310 cells, that survived from cytotoxic selection expressed SV40 large-T
      antigen throughout the life span, suggesting a successful gene transfection. The
      cells displayed the same polygonal epithelial morphology as the starting cells by
      light microscopy. Immunocytochemical studies demonstrate the presence of
      transthyretin (TTR), a thyroxine transport protein known to be exclusively
      produced by the choroidal epithelia in the CNS, in both transfected and starting
      cells. Western blot analyses further confirm the production and secretion of TTR
      by these cells. The mRNAs encoding transferrin receptor (TfR) were identified by
      Northern blot analyses. The cells grow at a steady rate, currently in the 110th
      passage with a population doubling time of 20-22 h in the established culture.
      When Z310 cells were cultured onto a Trans-well apparatus, the cells formed an
      epithelial monolayer similar to primary choroidal cells, possessing features such
      as an uneven fluid level between inner and outer chambers and an electrical
      resistance approximately 150-200 omega-cm(2). These results indicate that
      immortalized Z310 cells possess the characteristics of choroidal epithelia and
      may have the potential for application in blood-CSF barrier (BCB) research.

PMID- 12470874
TI  - FK960, a potential anti-dementia drug, increases synaptic density in the
      hippocampal CA3 region of aged rats.
AB  - There is accumulating evidence suggesting that synapse formation in the adult
      brain is dynamically regulated, and that this regulation plays a role in
      cognitive function. A decrease in synaptic density is reportedly related to
      memory deficits in aged animals as well as in Alzheimer's patients. FK960 [N-(4
      acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel anti-dementia drug,
      has been shown to ameliorate experimental amnesia in rats and monkeys through
      activation of the somatostatinergic nervous system in the hippocampus.
      Furthermore, FK960 has been shown to be considerably more effective in a model of
      spontaneous amnesia in aged rats than cholinesterase inhibitors. In the present
      electron microscopy study, we demonstrated that the density of axodendritic and
      axosomatic synapses in the hippocampal CA3 region of aged rats was reduced
      compared to young rats, and that repeated treatment with FK960 for either 3 or 21
      days dose-dependently reversed these deficits in aged rats. This FK960-induced
      increase in synaptic density was transient and density returned to basal levels
      at 8 days after the final dose. In contrast, FK960 did not alter synaptic density
      in the cingulate cortex or hippocampal CA1 region in aged rats, nor the CA3
      region of young rats. Collectively, these results suggest that FK960 can
      selectively and reversibly increase synaptic density in the hippocampal CA3
      region of aged rats, and that this activity may play a role in its cognitive
      enhancing action.

PMID- 12470875
TI  - An assessment of the cerebroprotective potential of volatile anaesthetics using
      two independent methods in an in vitro model of cerebral ischaemia.
AB  - Previous studies using a rat brain slice model of cerebral 'ischaemia' (hypoxia
      and hypoglycaemia) have suggested that volatile anaesthetics may have
      cerebroprotective potential. In this study, we tested the cerebroprotective
      profile of four volatile anaesthetics in this model by two independent means:
      voltammetric measurement of 'ischaemia'-induced dopamine (DA) release and post
      'ischaemic' tissue staining with 2,3,5-triphenyltetrazolium chloride (TTC).
      'Ischaemia' caused a characteristic pattern of DA release. Halothane, isoflurane
      and enflurane did not affect the time from onset of 'ischaemia' to the initiation
      of DA release. However, all three volatile agents significantly increased
      (P<0.01, P<0.05, P<0.001, respectively) the time taken for 'ischaemia'-induced DA
      release to reach maximum and reduced the rate of DA release. Enflurane, unlike
      halothane or isoflurane, reduced the maximal extracellular DA concentration
      induced by 'ischaemia' (P<0.01). The effects of sevoflurane were inconsistent. At
      the higher concentrations used, the volatile anaesthetics frequently changed the
      character of DA release from monophasic to biphasic, an effect only previously
      seen in this model with Na(+) channel blockers. 'Ischaemia' also diminished the
      subsequent level of tissue staining with TTC. When the effects of the volatile
      agents were analysed by TTC staining, only enflurane showed any cerebroprotective
      effects and these were limited to the striatum (P<0.01). High concentrations of
      halothane, isoflurane and enflurane appeared to have some 'toxic' effects,
      reducing TTC staining in control slices. In summary, we do not find any
      consistent evidence that volatile anaesthetics are cerebroprotective in this
      model.

PMID- 12470876
TI  - Isoflurane decreases AMPA-induced dark cell degeneration and edematous damage of
      Purkinje neurons in the rat cerebellar slices.
AB  - This study was designed to investigate whether isoflurane, a commonly used
      volatile anesthetic with neuroprotective property, reduces alpha-amino-3-hydroxy
      5-methyl-4-isoxazol propionic acid (AMPA)-induced neurotoxicity in a
      concentration- and time (when isoflurane was applied in relation to the AMPA
      exposure)-dependent manner. Cerebellar slices from postnatal 10-14-day-old rats
      were exposed to 30 microM AMPA for 30 min followed by a 120-min AMPA-free
      recovery period at 37 degrees C. This protocol resulted in dark cell degeneration
      (DCD) in the majority of Purkinje neurons (60.8+/-6.9%). Fewer Purkinje neurons
      (31.6+/-5.2%) had edematous damage (ED) characters. Application of isoflurane (1,
      2, or 3%) during both the AMPA exposure and recovery periods significantly
      increased the percentage of morphologically normal Purkinje neurons (neurons
      without DCD or ED changes) but the effects were apparently not dose-dependent.
      Isoflurane (3%) applied before, during or after the AMPA exposure period also
      significantly increased the percentage of morphologically normal Purkinje
      neurons. These isoflurane-induced increases in the percentage of morphologically
      normal Purkinje neurons were mainly due to fewer cells with DCD changes.
      Isoflurane decreased AMPA-induced ED significantly only when isoflurane (1 or 2%)
      was present during both the AMPA exposure and recovery periods. Isoflurane
      applied before, during or after the AMPA exposure period did not significantly
      affect the percentage of cells with ED changes. These results suggest that
      isoflurane time-dependently but not concentration-dependently reduce AMPA-induced
      neurotoxicity. These effects may be one mechanism for the isoflurane-induced
      neuroprotection demonstrated in previous studies.

PMID- 12470877
TI  - Allopregnanolone modulates spontaneous GABA release via presynaptic Cl-
      permeability in rat preoptic nerve terminals.
AB  - The endogenous neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one
      (allopregnanolone) affects presynaptic nerve terminals and thereby increases the
      frequency of spontaneous GABA release. The present study aimed at clarifying the
      mechanisms underlying this presynaptic neurosteroid action, by recording the
      frequency of spontaneous GABA-mediated inhibitory postsynaptic currents (sIPSCs)
      in neurons from the medial preoptic nucleus (MPN) of rat. Acutely dissociated
      neurons with functional adhering nerve terminals were studied by perforated-patch
      recording under voltage-clamp conditions. It was shown that the sIPSC frequency
      increased with the external K(+) concentration ([K(+)](o)). Further, the effect
      of allopregnanolone on the sIPSC frequency was strongly dependent on [K(+)](o).
      In a [K(+)](o) of 5 mM, 2.0 microM allopregnanolone caused a clear increase in
      sIPSC frequency. However, the effect declined rapidly with increased [K(+)](o)
      and at high [K(+)](o) allopregnanolone reduced the sIPSC frequency. The effect of
      allopregnanolone was also strongly dependent on the external Cl(-) concentration
      ([Cl(-)](o)). In a reduced [Cl(-)](o) (40 mM, but with a standard [K(+)](o) of 5
      mM), the effect on sIPSC frequency was larger than that in the standard [Cl(
      )](o) of 146 mM. The dependence of the effect of allopregnanolone on [K(+)](o)
      and on estimated presynaptic membrane potential was also altered by the reduction
      in [Cl(-)](o). As in standard [Cl(-)](o), the effect in low [Cl(-)](o) declined
      when [K(+)](o) was raised, but reversed at a higher [K(+)](o). The GABA(A)
      receptor agonist muscimol also potentiated the sIPSC frequency. Altogether, the
      results suggest that allopregnanolone exerts its presynaptic effect by increasing
      the presynaptic Cl(-) permeability, most likely via GABA(A) receptors.

PMID- 12470878
TI  - Mesotelencephalic dopamine neurochemical responses to glucocorticoid
      administration and adrenalectomy in Fischer 344 and Lewis rats.
AB  - The effects of alterations in peripheral corticosterone levels on multiple
      dopamine neurochemical estimates were examined in inbred Fischer and Lewis inbred
      rat strains. 2x2 ANOVA's (treatment x strain) showed a main effect for treatment
      (1 week CORT versus placebo) on the concentrations of the dopamine metabolites
      homovanillic acid and dihydroxyphenylacetic acid in the medial prefrontal cortex,
      with lower levels after treatment, but no significant treatment versus strain
      interaction. There was no effect of CORT treatment on DA metabolites in the
      nucleus accumbens shell or dorsal striatum. DOPA accumulation in any terminal
      region examined and tyrosine hydroxylase protein content in the ventral tegmental
      area were also not affected by 1 week of corticosterone in either strain. One
      week after adrenalectomy, homovanillic acid but not dihydroxyphenylacetic acid
      concentrations were significantly increased in the medial prefrontal cortex,
      dorsal striatum, and nucleus accumbens shell in the Lewis but not the Fischer
      strain, with a significant treatment x strain interaction only in the dorsal
      striatum. Based on these findings, the effect of adrenalectomy on DOPA
      accumulation and extracellular DA concentrations was examined in the Lewis strain
      only. Adrenalectomy produced a decrease in DOPA accumulation in the dorsal
      striatum with no significant change in the other regions. Adrenalectomy did not
      alter estimates of extracellular dopamine concentrations determined by in vivo no
      net flux microdialysis but did significantly increase in vivo dopamine recovery
      in the dorsal striatum. The findings indicate a pattern of changes in
      neurochemical measurements consistent with a small magnitude inhibition of basal
      dopamine metabolism, but not with a change neuronal activity, release or
      reuptake.

PMID- 12470879
TI  - Effects of excitotoxic lesions of the central or basolateral nucleus of the
      amygdala on naloxone-precipitated withdrawal-induced conditioned place aversion
      in morphine-dependent rats.
AB  - We examined the effects of discrete, bilateral excitotoxic lesions of the central
      or basolateral nucleus of the amygdala on naloxone-precipitated withdrawal
      induced conditioned place aversion in morphine-dependent rats. Lesions of the
      central nucleus significantly attenuated the conditioned place aversion, while
      lesions of the basolateral nucleus had little effect. These results suggest that
      the central nucleus of the amygdala, rather than the basolateral nucleus, plays a
      crucial role in the negative affective component of morphine abstinence.

PMID- 12470880
TI  - Activation of cell-survival signal Akt by GDNF in normal rat brain.
AB  - Glial cell line-derived neurotrophic factor (GDNF) activates protein kinase
      Akt/PKB by phosphorylation (p-Akt) which plays key roles in cell survival. In the
      current study, we investigated a temporal expression of p-Akt by
      immunohistochemical analysis after a topical application of GDNF to normal
      cerebral hemisphere of rats. Although p-Akt immunoreactivity was weakly present
      in the sham control neural cells, GDNF application greatly enhanced it at 3 h,
      which lasted until 1 day. These results indicate that p-Akt is expressed in
      neuronal cells under physiological conditions, and that topical application of
      GDNF greatly enhanced the phosphorylation of Akt in normal rat brain.

PMID- 12470881
TI  - Differential actions and excitotoxicity of glutamate agonists on motoneurons in
      adult mouse cervical spinal cord slices.
AB  - Electrical activity was recorded from motoneurons in adult mouse cervical spinal
      cord (C4-8) slices. Motoneurons showed almost no response to ionophoretic
      application of N-methyl-D-aspartic acid (NMDA) in both control and Mg(2+)-free
      media, but very sensitive to kainate (KA) and amino-3-hydroxy-5-methylisoxazole-4
      propionic acid (AMPA). Bath perfusion of KA, AMPA or glucose/O(2) free Krebs
      Ringer solution, but not bath perfusion of NMDA, caused membrane depolarization
      within 3 min and beading of the dendrite trees after more than 10 min perfusion.
      Our results indicate that adult motoneurons have few or no NMDA receptors.

PMID- 12470882
TI  - Resveratrol protects against global cerebral ischemic injury in gerbils.
AB  - Increased oxidative stress has been implicated in the mechanisms of delayed
      neuronal cell death (DND) following cerebral ischemic insult. In this study, we
      investigated whether resveratrol, a polyphenolic antioxidant enriched in grape,
      may ameliorate ischemia-induced neuron cell death. Mongolian gerbils were divided
      into three groups, namely, sham control, ischemia and ischemia treated with
      resveratrol. Transient global cerebral ischemia was induced by occlusion of both
      common carotid arteries (CCA) for 5 min. Resveratrol was injected i.p. (30 mg/kg
      body weight), either during or shortly after CCA occlusion, and again at 24 h
      after ischemia. Cerebral blood flow was monitored before and during CCA occlusion
      using a laser Doppler flowmeter. Brain sections were immuno-stained for neurons,
      astrocytes and microglial cells. A time course study was also carried out to
      assess the bioavailability of resveratrol in serum, liver and brain using high
      performance liquid chromatography (HPLC). Morphometric measurements indicated
      extensive DND in the hippocampal CA1 region 4 days after ischemia and that neuron
      cell death was marked by the increase in reactive astrocytes and microglial
      cells. Administration of resveratrol, either during or after CCA occlusion,
      significantly (P<0.05) decreased DND as well as glial cell activation. Analysis
      of resveratrol after i.p. injection indicated its presence in serum, liver and
      brain with peak activity at 1, 4 and 4 h, respectively. This study demonstrated
      for the first time that resveratrol, a polyphenolic antioxidant, can cross the
      blood-brain barrier and exert protective effects against cerebral ischemic
      injury.

PMID- 12470883
TI  - Perineuronal nets of extracellular matrix around hippocampal interneurons resist
      destruction by activated microglia in trimethyltin-treated rats.
AB  - The destruction of the extracellular matrix by inflammatory processes may induce
      neuronal dysfunction and accelerate neurodegeneration. We describe that
      chondroitin sulphate proteoglycan-immunoreactive perineuronal nets and the
      enwrapped interneurons persisted 2 weeks after trimethyltin intoxication of rats
      (TMT, 8 mg/kg, i.p.) in all regions of the severely affected hippocampus and
      dentate gyrus, whereas the diffuse immunoreactivity around the CA2 pyramidal
      cells was reduced. Fluoro-Jade staining of degenerating neurons and staining of
      microglia by Griffonia simplicifolia agglutinin showed that net-associated
      neurons survived in the vicinity of damaged pyramidal cells and that perineuronal
      nets were not removed by activated microglia. We conclude that the extracellular
      matrix of perineuronal nets resists destruction after TMT treatment in the
      inflamed neural tissue. A permanent reconstitution of matrix components may be
      one of the factors that may support the viability of distinct types of neurons
      during neurodegenerative diseases.

PMID- 12470884
TI  - Co-localization of AMPA receptor subunits in the nucleus of the solitary tract in
      the rat.
AB  - AMPA-type glutamate receptors in the caudal portions of nucleus of the solitary
      tract (NTS) are critical for responses to excitatory afferents from the viscera,
      including baroreceptors. Using immunocytochemistry combined with electron
      microscopy, the cellular distributions of different AMPA receptor subunits in the
      caudal NTS were found to be distinct. GluR2/3 was found at pre- and postsynaptic
      sites, and in astrocytic glia; while GluR1 was found primarily in small dendrites
      and spines. In dual-labeling studies, GluR1 and GluR2 were co-localized in large
      dendrites, but GluR1 was more often found alone in dendritic spines. Therefore,
      single neurons in the NTS contain both subunits, but there is differential
      trafficking of GluR1 to potential sites for synaptic plasticity.

PMID- 12470885
TI  - The difference of osteocalcin-immunoreactive neurons in the rat dorsal root and
      trigeminal ganglia: co-expression with nociceptive transducers and central
      projection.
AB  - The co-expression of osteocalcin (OC) with the capsaicin receptor (VR1) and
      vanilloid receptor 1-like receptor (VRL-1) was examined in the dorsal root (DRG)
      and trigeminal ganglia (TG). Virtually all OC-immunoreactive (ir) DRG neurons
      were devoid of VR1- and VRL-1-immunoreactivity (ir). In the TG, 14.1% of OC-ir
      neurons were also immunoreactive for VR1. Only 1.7% of OC-ir TG neurons co
      expressed VRL-1-ir. The distribution of OC-ir was also examined in the spinal
      cord and trigeminal sensory nuclei. In the spinal cord, the superficial laminae
      of the dorsal horn were devoid of OC-ir. The neuropil was weakly stained in other
      regions of the spinal horns. The medullary dorsal horn (MDH) contained numerous
      OC-ir varicose fibers in laminae I and II. These fibers were occasionally
      observed originating from the spinal trigeminal tract. The neuropil was weakly
      stained in deeper laminae of the MDH, and the rostral parts of the trigeminal
      sensory nuclei. The present study suggests that OC-ir TG nociceptors send their
      unmyelinated axons to the superficial laminae of the MDH.

PMID- 12470886
TI  - Increase in somatostatin immunoreactivity in the suprachiasmatic nucleus of aged
      Wistar rats.
AB  - Decreased immunoreactivity has been reported for several neuropeptides in the
      aged suprachiasmatic nucleus (SCN). We compared somatostatin (SS) and substance P
      (SP) immunoreactivity (ir) in aged (20-26 months) and young (6 months) Wistar
      rats. The old rat SCN revealed a significant increase in SSir (2.6-fold) and
      SPir. The results show that not all SCN-neuropeptidergic systems decline with
      age, and suggest a specific age-related role for SS in the SCN.

PMID- 12470887
TI  - Degeneration of infrared receptor terminals of snakes caused by capsaicin.
AB  - Capsaicin, the main pungent ingredient in hot peppers (genus Capsicum), caused
      degeneration of the infrared receptor terminals in infrared sensitive snakes,
      Trimeresurus flavoviridis, when it was applied perineurally to a branch of the
      trigeminal nerve. The degeneration of the terminals was found 6 h after the
      application. This finding suggests that capsaicin stimulates this infrared
      receptor terminal, a kind of warm receptor terminal.

PMID- 12470888
TI  - Video-oculography in the gerbil.
AB  - Normative vestibulo-ocular and optokinetic reflexes (VOR and OKR) and pupil
      diameter were measured in young adult gerbils using infrared video-oculography
      with 60 Hz sampling during head-fixed binocular recordings. The pupillary light
      sink technique was preferred over a single-beam retinal reflection method because
      its measurements were less affected by pupil size. Eye movements were generally
      conjugate with occasional independent saccadic movements, and independent
      drifting movements in the dark. The horizontal optokinetic response to sinusoidal
      motion of a randomly spaced white dot pattern was maximal at low velocities (5
      degrees/s), stronger temporonasally, and dropped off quickly at approximately 20
      degrees/s. Constant velocity gain was near unity through 60-80 degrees/s with a
      sharp drop-off. Monocular viewing revealed almost no nasotemporal optokinetic
      response. Pupil diameter was found to vary as a saddle function with optokinetic
      gain from cycle to cycle, but also have a circadian rhythm (smaller at dusk) that
      related inversely to mean horizontal VOR gain. Gerbils with eyes open sometimes
      had no optokinetic response during long stimulus periods, which then resumed
      after a brief vestibular stimulus. The horizontal angular VOR gain was relatively
      flat across 0.1-1.0 Hz and 30-120 d/s sines (phase near zero), with a mean gain
      of approximately 0.78 in the dark, and 1.0 with the fixed pattern surround (n=15,
      for both raw calibrated and normalized data). Most animals also revealed a strong
      slow phase eye velocity asymmetry (dominant during ipsilateral rotation) in the
      half-cycle gain of their horizontal angular VOR response in the dark. A constant
      velocity horizontal optokinetic bias velocity did not change the gain or symmetry
      of the sinusoidal VOR response, but shifted the VOR response velocity in an
      additive (linear) fashion. Both cross-coupling (pitch or roll while rotating) and
      pseudo-OVAR (off-axis counter-rotation) stimuli generated horizontal nystagmus.
      The findings suggest that the gerbil, like other lateral-eyed rodents, relies on
      otolith cues to interpret angular motion.

PMID- 12470889
TI  - Estrogen regulates GFAP-expression in specific subnuclei of the female rat
      interpeduncular nucleus: a potential role for estrogen receptor beta.
AB  - We previously demonstrated that in rat, astrocytic glial fibrillary acidic
      protein- (GFAP) expression in the interpeduncular nucleus (IPN) was responsive to
      testosterone and in females the intensity of GFAP-immunoreactivity (IR) followed
      the periodic hormonal changes of the estrous cycle. The aim of this study was to
      test whether 17beta-estradiol (E(2)), in the absence of other ovarian hormones,
      can influence GFAP-expression within individual subnuclei of the IPN and to
      determine the cellular distribution of estrogen receptor beta (ERbeta) in the
      IPN. Quantitative surface-density analysis was used to compare the intensity of
      GFAP-IR at different anterio-posterior (AP) levels of the IPN in ovariectomized
      female rats 24 h after treatment with E(2) or vehicle. Estrogen-treatment
      resulted in a significant increase in GFAP-IR in the rostrolateral subnucleus of
      the IPN at AP: -5.60, in the lateral-, dorsolateral-, dorsomedial- and central
      subnuclei at -6.04 and in the lateral subnucleus at -6.72. No significant
      differences were observed at -5.80 and -6.30. These results indicate that E(2),
      in the absence of other ovarian hormones, modulates GFAP-expression within select
      IPN subnuclei and that these affects are dependent on position along the AP axis.
      To determine whether ERbeta was a possible mediator of the observed estrogenic
      effects, adjacent section pairs of the IPN were immunostained for ERbeta or GFAP.
      Using the 'mirror' method, ERbeta-IR was detected in the cytoplasm of GFAP
      immunopositive astroglia and in the nuclei of GFAP-immunonegative neurons. These
      findings suggest that in the IPN, E(2) may directly modulate GFAP-expression
      through ERbeta-mediated mechanisms.

PMID- 12470891
TI  - Longevity determination genes in Drosophila melanogaster.
AB  - Identification of longevity mutants is crucial for genetic approach to dissect
      the molecular mechanism of aging and longevity determination. In Drosophila
      melanogaster, several mutations have been shown to extend the longevity:
      methuselah encoding a putative G-protein coupled receptor, Indy encoding a sodium
      dicarboxylate cotransporter, chico encoding insulin receptor substrate, and InR
      encoding the insulin-like receptor. Extended longevity phenotypes were also
      observed in transgenic flies overexpressing antioxidant enzymes, Cu/Zn superoxide
      dismutase and Catalase, Cu/Zn SOD only, or a molecular chaperone, hsp70.
      Pleiotropism of mutations is a limitation associated with conventional
      mutagenesis for efficient detection of longevity determination genes. Using a
      conditional misexpression system, we identified Drosophila POSH (DPOSH), a
      scaffold protein containing RING finger and four SH3 domains, whose ubiquitous
      overexpression in adult stage extends the longevity. Neural-specific
      overexpression of DPOSH is sufficient to extend the longevity, whereas
      overexpression in non-neural tissues during development induces apoptosis through
      activation of JNK/SAPK pathway.

PMID- 12470892
TI  - Mutation theory of aging, assessed in transgenic mice and knockout mice.
AB  - A vital question in the mutation theory of aging is whether mutation accumulates
      with age. If it does, what are the causes and consequences of the accumulation of
      mutation? The recent development of transgenic mice has made it possible to study
      mutation in different kinds of tissues and at a molecular level. An application
      of these mice to the study of age-dependent alteration has revealed that mutation
      does accumulate in the aging process. Studies have also revealed several
      important characteristics of mutation associated with aging. (1) The rate of age
      dependent increase of mutant frequency varies among different types of tissue.
      (2) The rate is not in parallel with the cell proliferation rate of the tissue.
      (3) Some types of mutation are unique to specific tissues, suggesting the
      presence of a mechanism of mutation relative to tissue type. On the other hand,
      several kinds of knockout mice defective in DNA repair have been shown to exhibit
      tissue lesions and shortened life span. These characteristics provide a new view
      on the relationship between aging and the genome maintenance system. Here we
      review the current status of research on the correlation between mutation and
      aging undertaken by the use of transgenic and knockout mice.

PMID- 12470893
TI  - A higher oxidative status accelerates senescence and aggravates age-dependent
      disorders in SAMP strains of mice.
AB  - The SAM strain of mice is actually a group of related inbred strains consisting
      of series of SAMP (accelerated senescence-prone, short-lived) and SAMR
      (accelerated senescence-resistant, longer-lived) strains. Comparing with the SAMR
      strains, the SAMP strains of mice show a more accelerated senescence process,
      shorter lifespan, and an earlier onset and more rapid progress of age-associated
      pathological phenotypes similar to several geriatric disorders observed in
      humans, including senile osteoporosis, degenerative joint disease, age-related
      deficits in learning and memory, olfactory bulb and forebrain atrophy,
      presbycusis and retinal atrophy, senile amyloidosis, immunosenescence, senile
      lungs, and diffuse medial thickening of the aorta. The higher oxidative stress
      observed in the SAMP strains of mice are partly caused by mitochondrial
      dysfunction, and may be one cause of the senescence acceleration and age
      dependent alterations in cell structure and function, including neuronal cell
      degeneration. This senescence acceleration is also observed during
      senescence/crisis in cultures of isolated fibroblast-like cells from SAMP strains
      of mice, and was associated with a hyperoxidative status. These observations
      suggest that the SAM strains are useful tools in the attempt to understand the
      mechanisms of age-dependent degeneration of cells and tissues, and their
      aggravation, and to develop clinical interventions.

PMID- 12470894
TI  - Age-dependent agonist-specific dysregulation of membrane-mediated signal
      transduction: emergence of the gate theory of aging.
AB  - Although a general mechanism for the limited responsiveness of senescent cells
      has yet to be established, reduced responsiveness may in part be ascribed to
      deficits in the apparatus required for cell surface receptor-mediated signal
      transduction. Age-related changes of receptor-mediated signal transduction occur
      at many levels, and are known to include quantitative and qualitative changes in
      growth factor receptors, G-protein coupled receptors, and many other downstream
      signaling molecules. Here, we emphasize the prime role of the cellular surface in
      the perception and transmission of external stimuli in response to the aging
      process. As major means of cellular signal transduction, the receptor tyrosine
      kinase (RTK) system and the G protein-coupled receptor (GPCR) system of senescent
      cells were investigated. We observed that the RTK system was severely damaged,
      while the GPCR system was only partially inactivated by aging. These results
      suggest that the agonist-dependent dysregulation of and imbalance of signal
      transduction pathways might be responsible for the functional deterioration of
      senescent cells, and indicate a possibility of the functional recovery of
      senescent cells through agonist-specific signal system activation. Moreover,
      those data evoke the emerging concept that the senescent phenotype may be
      modulated by the membrance-associated signal system, implying the gate theory of
      aging.

PMID- 12470895
TI  - Adaptive responses to oxidative damage in three mutants of Caenorhabditis elegans
      (age-1, mev-1 and daf-16) that affect life span.
AB  - Oxidative damage shortens the life span of the nematode Caenorhabditis elegans
      (C. elegans), even in an age-1 mutant that is characterized by a long life and
      oxygen resistance. We found that daily short-term exposure (3 h) to hyperoxia
      further extended the life span of age-1, a phenomenon known as an adaptive
      response. age-1 also showed resistance to paraquat and heat. Acute hyperoxic
      treatment did not extend the life spans of wild type, daf-16 or mev-1. daf-16
      mutant had a slightly shorter life span compared to wild type and was sensitive
      to heat and paraquat. The daf-16 phenotype resembles that of mev-1 showing a
      short life and oxygen sensitivity. We measured mRNA levels of superoxide
      dismutase genes (sod-1 through 4), catalase genes (clt-1 and ctl-2), known to
      encode anti-oxidant enzymes, and found they were elevated in age-1 young adults.
      On the other hand, in daf-16 and mev-1, the expression of sod-1, sod-2 and sod-3
      genes was lower rather than in wild type. Conversely, ctl-1 and ctl-2 genes
      expression was significantly elevated in daf-16 and mev-1. This suggests that DAF
      16, a forkhead/winged-helix transcription factor, whose expression is suppressed
      by AGE-1, phosphoinositide 3-kinase (PI3-kinase), regulates anti-oxidant genes as
      well as energy metabolism under atmospheric conditions. However, the level of
      gene expression of SOD and catalase was not elevated by short-term exposure to
      90% oxygen in wild type, mev-1, daf-16 and even age-1. This suggests that SOD and
      catalase do not play a role in the adaptive response against oxidative stress
      under hyperoxia, at least under these experimental conditions.

PMID- 12470896
TI  - Modulation of redox-sensitive transcription factors by calorie restriction during
      aging.
AB  - Oxidative stress is considered to be a major cause of aging and many age-related
      diseases. Calorie restriction (CR) is known to retard deleterious, age-related
      processes. Recent studies document that CR retards the aging process by
      regulating the redox environment through its anti-oxidative properties. Among the
      key cellular components exquisitely sensitive to redox status are transcriptions
      factors such as nuclear factor kappa B (NF-kappaB), activator protein-1 (AP-1),
      and hypoxia inducible factor-1 (HIF-1). Based on available findings and our
      recent supporting evidence, we proposed to use a new term, 'molecular
      inflammation' to emphasize the importance of molecular reaction mechanisms
      distinct from chronic and fully expressed inflammatory phenomena. Currently,
      limited information is available on the age-related and dietary modulations of
      these factors. In this review, we place a major focus on the age effects of NF
      kappaB, AP-1, and HIF-1 regulation, and further delineate how age-related changes
      are modulated by CR. Age-related increases in redox-sensitive NF-kappaB, AP-1,
      and HIF-1 binding activities are concluded to be associated with increased ROS
      and CR to modulate their activations by suppressing oxidative stress. Data on
      cellular regulation provide better molecular insights into the mechanisms
      underlying cellular redox maintenance, which may be the cross-talk between normal
      aging and age-associated pathogenic processes.

PMID- 12470897
TI  - Dose effect of oxidative stress on signal transduction in aging.
AB  - Reactive oxygen species (ROS) during normal metabolism signal cells to stimulate
      proliferation or to cause cellular damages, depending on a specific
      concentration. Energy restriction (ER) increases life span in animals, which can
      explain an effective modulator for reducing oxidative stress. Oxidative stress
      can result from a decrease in the protection against ROS. The deleterious effects
      of oxidative stress generally occur after exposure to a relatively high
      concentration of ROS. Alternatively, it has been suggested that a low
      concentration of ROS can exert important physiological roles in cellular
      signaling and proliferation. Signal pathways are crucial for cell survival or
      death. It is generally acceptable that aged cells have less response to stresses
      such as ROS than young cells. Oxidative stresses induce JNK and p38 kinase
      pathways regulated by redox regulatory proteins: thioredoxin and glutathione s
      transferase, respectively. Antioxidants such as selenium block apoptosis induced
      by ROS through blocking apoptotic signal ASK1 and stimulating survival signal Akt
      activity. Old hepatocytes are more susceptible to ROS-induced apoptosis than
      young hepatocytes, which is associated with low expression of ERK and Akt
      kinases. Pharmacological inhibition of ERK and Akt activation in the young cells
      markedly increase their sensitivity to H(2)O(2), and ER, by preventing loss of
      ERK and Akt activities, enhances survival of old hepatocytes to a level similar
      to those of young cells. Expressions of signal pathways such as survival and
      apoptotic signals can regulate cells' fate and aging process. Further studies on
      the interaction of signal pathways may change the scientific direction of the
      study of aging.

PMID- 12470898
TI  - Paradoxical increase of heat-shock response with age in a substrain of F344 rats:
      comparison between F344/DuCrj and F344/Jcl.
AB  - The ability of hepatocytes isolated from young (7-10 months) and old (31 months)
      male F344/Jcl and F344/DuCrj rats to express heat shock protein (hsp) 27, hsp70
      and hsp90 was determined after a mild heat shock (42.5 degrees C for 30 min). The
      induction of these three mRNA levels by the heat shock was 50-80% lower in
      hepatocytes isolated from old F344/Jcl rats than in those from young rats.
      However, the hepatocytes from old F344/DuCrj showed a marked increase (200-250%)
      in the induction of hsp mRNAs by heat shock when compared to cells from young
      rats. Because heat shock transcription factor (HSF) plays a critical role in
      regulating the transcription of hsp genes, the effect of age on the binding
      activity HSF to heat shock element (HSE) was also studied. Again, the induction
      of binding activity of HSF to HSE was significantly increased with age in
      hepatocytes from F344/DuCrj rats while the reverse was true for the cells from
      F344/Jcl. The induced levels of hsp mRNAs were positively correlated with the
      binding activity of HSF to HSE in hepatocyte extracts from both F344 substrains,
      suggesting that the diverse age-related changes of heat-shock response in F344
      substrains occurs in HSF activity. The contradictory age-related change in the
      heat-shock response is discussed with the differences in biochemical and genetic
      properties of substrains of F344 rats.

PMID- 12470899
TI  - A protein free diet uncovers the potential age-difference in the hepatic
      detoxifying system, glutathione S-transferase, in female mice.
AB  - Female C57BL mice of six different ages (from 6 to 26 months) were given a
      protein free-diet (PFD) for 1 week and then given a normal diet (ND). Mice were
      examined for enzyme activities of glutathione S-transferase (GST) in the hepatic
      cytosol fraction using l-chloro-2, 4-dinitrobenzene (CDNB) as substrate. Enzyme
      activities were very close among the six different age groups when examined for
      basal levels as well as after 1 week of PFD. However, a remarkable age difference
      became manifest when animals were examined 2 days after the start of ND refeeding
      following 1 week of PFD. In young animals (6, 8 months), activities became much
      higher than their respective basal levels while in old animals (24, 26 months)
      enzyme levels remained significantly lower than their basal levels on day 2 of ND
      refeeding. A significant negative linear correlation between enzyme activities (Y
      axis) and animal age (X axis) was demonstrated only on day 2 or 3 of ND
      refeeding, while in control animals or animals given 1 week of PFD diet, no
      significant correlation could be found between enzyme activities and animal age.
      We conclude that liver cytosolic GST activity is a function of animal age only
      after a dietary manipulation such as a PFD and ND refeeding, while basal GST
      activities remain stable throughout the observation period of animal age.

PMID- 12470900
TI  - Amyloid fibril proteins.
AB  - Amyloidosis refers to a group of protein folding diseases. Various innocuous and
      soluble proteins in physiological conditions polymerize to insoluble amyloid
      fibrils in several serious diseases, including Alzheimer's disease (AD) and prion
      diseases. In addition, senile amyloidosis is a form of amyloidosis in which the
      incidence and severity of amyloid deposition increases with age without any
      apparent predisposing conditions and it was thought that the amyloidosis was
      related to some physiological changes which accompany ageing. Although the
      etiology and pathogenesis of amyloid disease are not fully understood, drastic
      structural changes of the amyloid proteins from the normal forms to the unique
      beta-sheet fibrils is the most important event in amyloid diseases. The present
      article introduces the three amyloid diseases, AD, prion diseases and mouse
      senile amyloidosis in which Abeta, PrP(Sc) and AApoAII amyloid fibrils deposit
      respectively. We discuss the nucleation dependent polymerization model as a model
      that explains the kinetics of fibrillization of these amyloid proteins. Exogenous
      amyloid fibrils may act as templates (nuclei) and change the conformation of
      endogenous amyloid protein to polymerize into amyloid fibrils. This hypothesis
      makes the boundary between transmissible and non-transmissible amyloidosis
      ambiguous and proposes the common pathogenesis for them.

PMID- 12470901
TI  - The pathogenic mechanisms of prion diseases.
AB  - Transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of
      fatal neurodegenerative diseases of humans and animals, including bovine
      spongiform encephalopathy (BSE) of cattle, scrapie of sheep, and Creutzfeldt
      Jakob disease (CJD) of humans. Prion diseases have become an important issue in
      public health and in the scientific world not only due to the possible
      relationship between BSE and new variant CJD (nvCJD) but also due to the unique
      biological features of the infectious agent. Although the nature of the
      infectious agent and the pathogenic mechanisms of prion diseases are not fully
      understood, considerable evidence suggests that an abnormal form (PrP(Sc)) of a
      host prion protein (PrP(C)) may compose substantial parts of the infectious agent
      and that various factors such as oxidative stress and calcium cytotoxicity are
      associated with the pathogenesis of prion diseases. Here, we briefly review and
      discuss the pathogenic mechanisms of prion diseases. These advances in
      understandings of fundamental biology of prion diseases may open the
      possibilities for the prevention and treatment of these unusual diseases and also
      suggest applications in more common neurodegenerative disorders such as
      Alzheimer's disease (AD) and Parkinson's disease (PD).

PMID- 12470902
TI  - DNA methylation in cancer and ageing.
AB  - Epigenetic gene silencing through DNA methylation is now clearly thought to be
      one of the important steps in the mechanism underlying tumourigenesis. The
      methylation of several genes increases with age in normal tissues such as the
      colon. Methylation related to cancer and ageing may lead to new biomarkers and
      therapeutic concepts for cancer.

PMID- 12470903
TI  - Involvement of TNF-alpha changes in human cancer development, prevention and
      palliative care.
AB  - Cancer development and ageing are complex sciences. From the study on the process
      of rodent carcinogenesis, we identified tumor necrosis factor-alpha (TNF-alpha)
      as an important mediator of cancer development. This paper presents three
      clinical examples of TNF-alpha up-regulation: by cord factors of Mycobacterium
      tuberculosis, such as trehalose 6-monomycolate, as an activator of protein kinase
      C and by a cord factor like fraction of Microsporum canis obtained in the air
      inside houses in Thailand, both of which are risk factors in human lung cancer
      development, and by Helicobacter pylori gene product, H. pylori membrane protein
      1 (HP-MP1) in relation to human stomach cancer. The second part of this paper
      deals with down-regulation of TNF-alpha by a wide variety of cancer preventive
      agents. Among the various agents, (-)-epigallocatechin gallate (EGCG) and green
      tea polyphenols inhibited TNF-alpha gene expression in the cells induced by tumor
      promoter, mediated through inhibition of NF-kappaB activation. Studying growth
      inhibition of human cancer cell lines by morphine, we found that morphine and the
      new morphine derivatives KT-90 and KT-87 have anticancer activity mediated
      through induction of apoptosis, in addition to analgesic action. We conclude that
      environmental and endogenous factors induce NF-kappaB activation mediated through
      expression of inflammatory cytokine genes, such as TNF-alpha, and that the
      expression pattern of the genes operates similarly in the aging process.

PMID- 12470904
TI  - Spectrum of molecular changes during hepatocarcinogenesis induced by DEN and
      other chemicals in Fischer 344 male rats.
AB  - Unlike other tissues such as breast, colon and renal cell carcinoma, it is not an
      easy task to single out any representative oncogene or tumor suppressor genes in
      the development of hepatocellular carcinoma (HCC), which play a pivotal role. To
      investigate putatively altered main pathways in HCC, F344 male rats were treated
      with a single injection of N-nitrosodiethylamine (DEN), followed by either
      twice/week injections of nodularin for 10 weeks or thioacetamide (TAA) in
      drinking water for 39 weeks. p53 expression was dramatic in both hepatocytes and
      mesenchymal cells after a single injection of DEN, however, PCR-SSCP assay could
      not detect any p53 mutation during the development of hepatocellular adenoma. The
      data indicate that wtp53 response was mostly for removal of damaged cells during
      the initiation of carcinogenesis. When treated with DEN-TAA, induction of
      gankyrin expression during hepatic fibrosis preceded the loss of pRB protein,
      accompanied with significant expressions of G1 phase cyclins and CDKs. Moreover,
      p16(INK4A) exon 1 was hypermethylated during the development of poorly
      differentiated HCCs. These changes would result in complete inactivation of the
      pRB regulatory pathway during hepatocarcinogenesis. Induction of TGF-beta1
      expression with loss of its receptor expression occurred rapidly in the altered
      hepatocytes by DEN-nodularin treatment. CONCLUSION: Therefore, escape from TGF
      beta1 induced apoptosis and severe degradation of pRB protein during the early
      stage of carcinogenesis can perform a symphony to proliferate and to transform
      the altered hepatocytes to tumor cells. Inactivation of p16(INK4A) and p53 genes
      at the later stage of carcinogenesis would endow HCC with malignancy, which is
      highly resistant to any therapeutic trials.

PMID- 12470905
TI  - Replicative senescence and senescence-like state induced in cancer-derived cells.
AB  - Studies on the replicative senescence and premature senescence induced by various
      stresses in normal somatic cells have provided important clues on the role of
      telomere shortening and mechanisms involved in aging processes and
      carcinogenesis. Recent work revealed that cancer cells also are induced to
      undergo replicative senescence state via telomere shortening as well as to enter
      a senescence-like state by the activation of cell cycle inhibitory pathways.
      Although less relevant in terms of aging physiology, studies on these phenomena
      in cancer cells have yielded important information on telomerase regulation and
      the roles of tumor suppressors in senescence and immortalization, and are
      expected to generate valuable anti-cancer strategies. Several features of the
      phenotypes specific for the senescent and senescence-like states induced in
      cancer cells are discussed.

PMID- 12470906
TI  - Health Futures of Youth II: pathways to adolescent health, executive summary and
      overview.

PMID- 12470907
TI  - Health Futures of Youth II: Pathways to Adolescent Health. Proceedings of a
      conference. September 14-16, 1998. Annapolis, Maryland, USA.

PMID- 12470908
TI  - America's adolescents: where have we been, where are we going?
AB  - PURPOSE: To determine historical trends and current status of the health of
      America's youth. METHODS: A thorough literature review was conducted to establish
      the best sources for adolescent data across a wide range of health-related issues
      using major national data sources. Data were collected and synthesized to create
      a comprehensive overview of adolescent health and demographic trends. RESULTS AND
      CONCLUSIONS: Adolescence is a distinct developmental stage posing unique
      challenges. Although generally considered a time of health and well-being,
      traditional health indicators often overlook areas specific to adolescence.
      Despite encouraging improvements in recent years, this population continues to
      have high rates of morbidity and mortality owing to violence, injury, and mental
      health disorders. Also, potentially health-damaging behaviors, such as premature
      and unprotected sexual behavior and substance use, pose significant threats.
      Fortunately, adolescence is a time of great behavioral plasticity. Because the
      vast majority of adolescent health risks are the result of behavioral causes,
      much of this morbidity and mortality is preventable. The adolescent population is
      projected to greatly increase over the next 2 decades. However, older age groups
      are increasing more rapidly, reducing the proportion of adolescents in the
      overall population. The aging population will likely demand increased access to
      scarce resources. The public needs to be educated about the need to support
      programs for youth. If resources are properly allocated, and health professionals
      trained to deal with adolescents' unique needs, America's youth have the
      potential to benefit greatly from successful implementation of new knowledge,
      developing healthy, positive, life-long behaviors.

PMID- 12470909
TI  - Contemporary developmental theory and adolescence: developmental systems and
      applied developmental science.
AB  - PURPOSE: To discuss developmental systems models of human development and explain
      how they offer a productive frame for research, policies, and programs aimed at
      understanding adolescents' development and enhancing their health and positive
      development. Contemporary developmental theory stresses that the multiple levels
      of organization involved in human life (ranging from biology through culture, the
      natural and designed ecology, and history) are systemically integrated across
      ontogeny. Relations within this developmental system are the focus of
      developmental analysis and application. METHODS: The key features of
      developmental systems theories are reviewed, and their use for framing
      scholarship about and applications for improving adolescent development are
      assessed. RESULTS: We demonstrate the potential of contemporary developmental
      theory for understanding the character and dynamics of adolescent development and
      for using this knowledge for the design of effective policies and programs that
      promote positive youth development. CONCLUSIONS: An adequate and sufficient
      science of adolescent development, and one that is able to help in the
      development of successful policies and programs for youth, must integratively
      study the relations between individuals and contexts in an integrated, systemic,
      and temporal manner.

PMID- 12470910
TI  - Reasons to invest in adolescents.
AB  - PURPOSE: To discuss the frequent failure of the United States (and other
      countries) to make the types of investment in youth that would increase the
      future prospects of youth from high-risk backgrounds. I argue that these
      investments are worth making, and describe the types of research and knowledge
      dissemination that will be necessary to promote such investments. APPROACH: I
      begin with a framework for thinking about and working with adolescents. I review
      theories of youth development, the developmental tasks of adolescence, risk and
      resilience, and the strong tendency of current approaches to address single
      problems and symptoms rather than underlying conditions. A conceptual framework
      is presented that combines known elements of risk and protective factors, such as
      antecedents, system markers of current or potential difficulties, risk behaviors,
      and outcomes. I briefly review what we know about youth risk behavior and
      outcomes in various domains, including combined prevalence and patterning. I then
      examine what we know about the payoffs that we can expect from investing in
      activities that promote adolescent health. I end with a set of recommendations
      for researchers and practitioners, and discuss the information that they need to
      put these recommendations into practice.

PMID- 12470911
TI  - The mass media and American adolescents' health.
AB  - American teens today grow up in a world saturated with the mass media. In
      general, the media depict a world in which unhealthy behaviors such as physical
      aggression, unprotected sex, smoking, and drinking are glamorous and risk-free.
      We summarize what is known about the media's effects on four adolescent health
      issues that have been studied most comprehensively: violence and aggression; sex;
      obesity, nutrition, and eating disorders; and alcohol and tobacco use. A number
      of approaches that have potential for helping turn the media into more positive
      forces for adolescents' health are discussed

PMID- 12470912
TI  - Work group I: developing models of healthy adolescent physical development.

PMID- 12470913
TI  - Pathways to adolescent health sleep regulation and behavior.
AB  - There are several converging reasons to focus on sleep regulation in relation to
      healthy adolescent development: (a) Sleep appears to be particularly important
      during periods of brain maturation; (b) there are substantial biological and
      psychosocial changes in sleep and circadian regulation exist across pubertal
      development; (c) interactions between physical and psychosocial domains can lead
      to dramatic alterations in sleep patterns and habits during adolescence; (d)
      increasing evidence that many adolescents frequently obtain insufficient sleep
      exists; (e) there is mounting evidence that sleep deprivation has its greatest
      negative effects on the control of behavior, emotion, and attention, a regulatory
      interface that is critical in the development of social and academic competence,
      and psychiatric disorders; (f) the most obvious direct health consequences of
      insufficient sleep are high-risk behaviors associated with substance abuse and
      automobile accidents; (g) substantial evidence for bidirectional effects between
      sleep and behavioral/emotional regulation exists. Although the past decade has
      seen research progress in these areas, there continue to be major gaps in
      existing knowledge and a paucity of well-controlled studies to guide specific
      health policy decisions and recommendations regarding sleep in adolescence. In
      particular, there is need for improved understanding of the acute and chronic
      effects of inadequate sleep in adolescents, guidelines for defining adequate
      sleep in adolescents, and a better delineation of the links among sleep,
      behavior, and affect regulation. Finally, this paper briefly examines one
      specific application of this knowledge area regarding early starting times among
      some high schools.

PMID- 12470914
TI  - Neurophysiology of puberty.

PMID- 12470915
TI  - Growth at puberty.
AB  - Somatic growth and maturation are influenced by a number of factors that act
      independently or in concert to modify an individual's genetic potential. The
      secular trend in height and adolescent development is further evidence for the
      significant influence of environmental factors on an individual's genetic
      potential for linear growth. Nutrition, including energy and specific nutrient
      intake, is a major determinant of growth. Paramount to normal growth is the
      general health and well-being of an individual; in fact, normal growth is a
      strong testament to the overall good health of a child. More recently the effect
      of physical activity and fitness on linear growth, especially among teenage
      athletes, has become a topic of interest. Puberty is a dynamic period of
      development marked by rapid changes in body size, shape, and composition, all of
      which are sexually dimorphic. One of the hallmarks of puberty is the adolescent
      growth spurt. Body compositional changes, including the regional distribution of
      body fat, are especially large during the pubertal transition and markedly
      sexually dimorphic. The hormonal regulation of the growth spurt and the
      alterations in body composition depend on the release of the gonadotropins,
      leptin, the sex-steroids, and growth hormone. It is very likely that interactions
      among these hormonal axes are more important than their main effects, and that
      alterations in body composition and the regional distribution of body fat
      actually are signals to alter the neuroendocrine and peripheral hormone axes.
      These processes are merely magnified during pubertal development but likely are
      pivotal all along the way from fetal growth to the aging process.

PMID- 12470916
TI  - Work group II: healthy adolescent psychosocial development.

PMID- 12470917
TI  - The development of decision-making.
AB  - PURPOSE: To describe what is currently known and not known about the development
      of decision-making skills during adolescence. METHODS: The author provides a
      definition of competent decision-making, gives a brief overview of the literature
      on the development of this competence, and describes the kinds of studies that
      should be conducted in the near future. RESULTS AND CONCLUSIONS: Although the
      literature is still too sparse to be conclusive at present, the literature as a
      whole suggests that adolescents may have less decision-making competence than
      adults in certain areas (i.e., advice-seeking, evaluation processes, adaptive
      goal-setting, and learning) but may have similar levels of competence in other
      areas (i.e., knowledge of options in familiar areas, response to certain
      moderating factors, and making choices in a number of areas). Moreover, age
      differences in deliberative aspects of competence have not yet been linked to age
      differences in the tendency to pursue good options, although one recent study did
      find a possible link between a post-decisional process (i.e., learning from
      decisions) and age differences in the selection of good options. Additional
      studies are needed to firm up the tentative conclusions that can be drawn from
      the extant research and determine which kinds of interventions improve decision
      making in adolescents and which do not.

PMID- 12470918
TI  - The development of romantic relationships and adaptations in the system of peer
      relationships.
AB  - In this review, it is proposed that a systems approach to the study of the
      development of romantic relationships might enhance our understanding of the
      nature of social relationships, and the links between social relationships and
      individual psychosocial functioning. First, a selected literature review is
      provided on the normative development of romantic relationships during
      adolescence, antecedents of different romantic involvement pathways, and positive
      and negative qualities of these relationships. Second, the focus is placed on the
      how the development of romantic relationships occurs within existing systems of
      relationships including peer networks and close friendships. It is suggested that
      the development of romantic relationships may change the peer network and nature
      of relationships with friends and others, and particular types of transitions in
      social relationships will likely occur. The timing of these transitions and an
      understanding of the entire peer system as romantic relationships develop will
      likely improve our understanding of individual developmental processes such as
      identity formation and the development of externalizing and internalizing
      problems. Finally, it is proposed that adolescents are faced with a complicated
      task that includes developing romantic interests and relationships but managing
      their changing social networks.

PMID- 12470919
TI  - Work group III: identifying effective strategies and interventions for improving
      adolescent health at the individual level.

PMID- 12470920
TI  - Prevention science and positive youth development: competitive or cooperative
      frameworks?
AB  - PURPOSE: To examine the convergence in the critiques and recommendations for the
      future of programs to promote healthy development and prevent problem behaviors
      among children and adolescents. METHODS: A review of literature captures two
      streams of thought, those promoting positive youth development approaches to
      youth programming and those promoting prevention science approaches to youth
      programming. RESULTS: Results suggest that advocates of positive youth
      development and prevention science have similar critiques of single-problem
      focused prevention programs in the 1980s and early 1990s, and have similar
      recommendations for the future of youth programming. Further, review of data on
      youth development suggests that it is important to focus on risk and protection
      in preventing adolescent problems as well as in promoting positive youth
      development. CONCLUSIONS: These results suggest that both youth development and
      prevention science approaches have grown from similar roots and make similar
      recommendations for the future of youth programming. Further, data on precursors
      suggest that focusing on promoting protection and reducing risk is likely to
      prevent problems and promote positive youth development. Yet advocates of these
      approaches often are at odds, suggesting that the approaches provide different
      paradigmatic approaches to youth programming. We conclude that cooperation
      between these two approaches would further progress in the field of youth
      programming.

PMID- 12470921
TI  - Pathways to adolescent health: early intervention.
AB  - OBJECTIVES: The wisdom of early intervention is one of the most strongly held
      beliefs in health care. However, although the intention to intervene early is
      generally believed to be a good one, too often we don't know when to do it, on
      whom to do it, and how to do it. Furthermore, if we consider the effectiveness of
      the interventions that have been used widely over the last 20 years we would have
      to conclude that although we have had some modest gains with issues such as
      teenage pregnancy, we have not been successful with most early intervention
      efforts. The development of more effective early interventions in adolescent
      populations requires a thorough appreciation and application of the theoretical
      and developmental bases of health behaviors and behavioral change. METHODS: These
      analyses were achieved through a review of the literature relevant to
      interventions in a variety of problem behaviors in adolescents.
      RESULTS/CONCLUSIONS: This review has demonstrated that although we don't have all
      of the answers we have the technological means to achieve greater success from
      early intervention. However, these benefits to our youth cannot be realized
      unless policies are developed that support the utilization and implementation of
      the most effective theory-based methodologies. Furthermore, these policies must
      be supported by research that enhances the translation of these effective
      interventions into broad national applications.

PMID- 12470922
TI  - Mentoring programs for adolescents: a research summary.
AB  - This summary reviews the research conducted on youth mentoring programs from the
      mid-1980s through the late 1990s. A number of studies have documented the varied
      benefits youth derive through participation in programmatic mentoring ranging
      from improved relationships to a reduction in the initiation of drug and alcohol
      use. Not all mentors or mentoring programs, however, are equally effective.
      Strategies that mentors use to foster the development of positive relationships
      and effective program practices, related to screening, training, and ongoing
      support are also discussed. Finally, some questions that remain to be addressed
      by the mentoring field are presented.

PMID- 12470923
TI  - Work group IV: increasing the capacity of parents, families, and adults living
      with adolescents to improve adolescent health outcomes.

PMID- 12470924
TI  - Adolescent sexuality and parent-adolescent processes: promoting healthy teen
      choices.
AB  - Trends in adolescent sexual health, the relation between parenting and adolescent
      sexual outcomes, and adolescent sexuality interventions with a parent component
      are reviewed. American adolescents have higher rates of unprotected sex and
      sexually transmitted infections contraction than adults and nine times the teen
      pregnancy rate of their European counterparts. Parenting efforts are related to
      adolescent sexual behavior. The review of 19 relevant programs supports the
      incorporation of theory and the ecological model in program design and
      evaluation.

PMID- 12470925
TI  - Psychological adjustment of urban, inner-city ethnic minority adolescents.

PMID- 12470926
TI  - Work group V: increasing the capacity of schools, neighborhoods, and communities
      to improve adolescent health outcomes.

PMID- 12470927
TI  - Work group VI: exploring the influence of law and public policy on adolescent
      health.

PMID- 12470928
TI  - Advancing the adolescent reproductive health policy agenda: issues for the coming
      decade.

PMID- 12470929
TI  - Schools and adolescent health: strengthening services and improving outcomes.
AB  - School-based health services have made limited contributions to the well-being of
      school-age children. However, they have the potential for promoting health and
      improving service delivery for 50 million children and adolescents enrolled in
      the nation's schools. Recent changes in health care, particularly the spread of
      managed care and development of integrated health service networks, have
      reawakened mainstream interest in school health and created the possibility for
      strengthening its efficiency and effectiveness. Two promising strategies for
      enabling school health programs to fulfill their potential are being implemented
      by the Massachusetts state government and by an Austin, Texas, hospital system.
      These strategies suggest measures to create either closely linked school and
      community health systems or fully integrated school/community child health
      systems that may have widespread benefit for children and their families.
      Barriers to fully implementing these strategies and replicating them in other
      communities will include the challenge of securing adequate funding,
      disagreements regarding the appropriate content of a school health program, and
      opposition to new staffing and employment arrangements from professional and
      union organizations. Whether this moment of opportunity yields gains for child
      health and school health will, for the most part, depend on forces outside school
      health. Success will be particularly dependent on the degree to which the managed
      care plans or large health care organizations see value in building more
      comprehensive child health systems or identify financial benefits from linking
      more closely with school-based services.

PMID- 12470930
TI  - Health issues for adolescents in the justice system.
AB  - Three major health issues for adolescents in the justice system are discussed:
      the lack of mental health resources and services for youth in the system,
      increased prosecution of juveniles as adults (and consequent incarceration of
      youth in adult jails and prisons), and the epidemic of gun violence in this
      country. For each issue, the paper describes the scope of the problem, analyzes
      the components of the problem, and makes recommendations for future research and
      reform efforts. The analysis and recommendations are based on criminal justice,
      legal, service integration, and public health research.

PMID- 12470931
TI  - Financing adolescent health care: legal and policy issues for the coming decade.

PMID- 12470932
TI  - An index of substitution saturation and its application.
AB  - We introduce a new index to measure substitution saturation in a set of aligned
      nucleotide sequences. The index is based on the notion of entropy in information
      theory. We derive the critical values of the index based on computer simulation
      with different sequence lengths, different number of OTUs and different
      topologies. The critical value enables researchers to quickly judge whether a set
      of aligned sequences is useful in phylogenetics. We illustrate the index by
      applying it to an analysis of the aligned sequences of the elongation factor
      1alpha gene originally used to resolve the deep phylogeny of major arthropod
      groups. The method has been implemented in DAMBE.

PMID- 12470933
TI  - Phylogenetic relationships among Bactrocera species (Diptera: Tephritidae)
      inferred from mitochondrial DNA sequences.
AB  - Several members of the dipteran family Tephritdae are serious pests because
      females lay eggs in ripening fruit. The genus Bactrocera is one of the largest
      within the family with over 500 described species arranged in 28 subgenera. The
      phylogenetic relationships among the various species and subgenera, and the
      monophyly of specific groups have not been examined using a rigorous phylogenetic
      analysis. Therefore, phylogenetic relationships among 24 Bactrocera species
      belonging to 9 subgenera were inferred from DNA sequence of portions of the
      mitochondrial 16S rRNA, cytochrome oxidase II, tRNA(Lys), and tRNA(Asp) genes.
      Two morphological characters that traditionally have been used to define the four
      groups within the subgenus Bactrocera were evaluated in a phylogenetic context by
      mapping the character states onto the parsimony tree. In addition, the
      evolutionary trend in male-lure response was evaluated in a phylogenetic context.
      Maximum parsimony analyses suggested the following relationships: (1) the genus
      Bactrocera is monophyletic, (2) the subgenus B. (Zeugodacus) is paraphyletic, (3)
      the subgenus B. (Daculus) is a sister group to subgenus B. (Bactrocera), and (4)
      the subgenus B. (Bactrocera) is monophyletic. The mapping analyses suggested that
      the morphological characters exhibit a simple evolutionary transition from one
      character state to another. Male-lure response was identified as being a labile
      behavior that has been lost on multiple occasions. Cue-lure response was
      plesiomorphic to methyl-eugenol response, and the latter has evolved
      independently within the Bactrocera and Zeugodacus groups of subgenera. The
      implications of our results for devising a coherent, consolidated classification
      for Bactrocera is discussed.

PMID- 12470934
TI  - Phylogeny of ruminants secretory ribonuclease gene sequences of pronghorn
      (Antilocapra americana).
AB  - Phylogenetic analyses based on primary structures of mammalian ribonucleases,
      indicated that three homologous enzymes (pancreatic, seminal and brain
      ribonucleases) present in the bovine species are the results of gene duplication
      events, which occurred in the ancestor of the ruminants after divergence from
      other artiodactyls. In this paper sequences are presented of genes encoding
      pancreatic and brain-type ribonuclease genes of pronghorn (Antilocapra
      americana). The seminal-type ribonuclease gene could not be detected in this
      species, neither by PCR amplification nor by Southern blot analyses, indicating
      that it may be deleted completely in this species. Previously we demonstrated of
      a study of amino acid sequences of pancreatic ribonucleases of a large number of
      ruminants the monophyly of bovids and cervids, and that pronghorn groups with
      giraffe. Here we present phylogenetic analyses of nucleotide sequences of
      ribonucleases and other molecules from ruminant species and compare these with
      published data. Chevrotain (Tragulus) always groups with the other ruminants as
      separate taxon from the pecora or true ruminants. Within the pecora the
      relationships between Bovidae, Cervidae, Giraffidae, and pronghorn (Antilocapra)
      cannot be decided with certainty, although in the majority of analyses
      Antilocapra diverges first, separately or joined with giraffe. Broad taxon
      sampling and investigation of specific sequence features may be as important for
      reliable conclusions in phylogeny as the lengths of analyzed sequences.

PMID- 12470935
TI  - Molecular phylogenetic evidence for multiple gains or losses of ant mutualism
      within the aphid genus Chaitophorus.
AB  - Mutualism with ants is suspected to be a highly labile trait within homopteran
      evolution. We used molecular phylogenetic evidence to test whether the mutualism
      has multiple origins within a single aphid genus. We constructed a molecular
      phylogeny of 15 Chaitophorus Koch (Hemiptera: Aphidoidea) species, using
      mitochondrial cytochrome oxidase I and II sequences. Ant tending evolved, or was
      lost, at least five times during Chaitophorus evolution. Parametric bootstrapping
      rejected the hypothesis of a single origin of ant tending in this genus. Further,
      the Chaitophorus made at least two host genus switches from poplars (Populus) to
      willow (Salix), and four switches in feeding position, from leaf feeding to stem
      feeding or vice versa. This is the first phylogenetic confirmation that ant
      tending is an evolutionarily labile trait in aphids.

PMID- 12470936
TI  - Lifecycle closure, lineage sorting, and hybridization revealed in a phylogenetic
      analysis of European oak gallwasps (Hymenoptera: Cynipidae: Cynipini) using
      mitochondrial sequence data.
AB  - Oak gallwasps are cyclically parthenogenetic insects that induce a wide diversity
      of highly complex species- and generation-specific galls on oaks and other
      Fagaceae. Phylogenetic relationships within oak gallwasps remain to be
      established, while sexual and parthenogenetic generations of many species remain
      unpaired. Previous work on oak gallwasps has revealed substantial intra-specific
      variation, particularly between regions known to represent discrete Pleistocene
      glacial refuges. Here we use statistical phylogenetic inference methods on
      sequence data for a fragment of the mitochondrial cytochrome b gene to
      reconstruct the relationships among 62 oak gallwasp species. For 16 of these we
      also include 23 additional cytochrome b haplotype sequences from different
      Pleistocene refuge areas to test the effect of intra-specific variation on inter
      specific phylogeny reconstruction. The reconstructed phylogenies show good intra
      generic resolution and identify several conserved clades, but fail to reconstruct
      either very recent or very ancient divergences. Nine of the 16 species
      represented by multiple haplotypes are not monophyletic. The apparent discordance
      between the recovered gene tree and the current taxonomic classification can be
      explained through: (a) collapsing of some species currently known only from
      either a sexual or a parthenogenetic generation into a single cyclically
      parthenogenetic entity; (b) sorting of ancestral polymorphism in diverging
      lineages, and (c) horizontal transfer of haplotypes, perhaps due to hybridization
      within glacial refuges. Our conclusions emphasise the need for careful intra
      specific sampling when reconstructing phylogenies for radiations of closely
      related species and imply that for certain taxonomic groups full phylogenetic
      resolution (using molecular markers) may not be attainable.

PMID- 12470937
TI  - A molecular phylogeny of the neotropical butterfly genus Anartia (Lepidoptera:
      Nymphalidae).
AB  - While Anartia butterflies have served as model organisms for research on the
      genetics of speciation, no phylogeny has been published to describe interspecific
      relationships. Here, we present a molecular phylogenetic analysis of Anartia
      species relationships, using both mitochondrial and nuclear genes. Analyses of
      both data sets confirm earlier predictions of sister species pairings based
      primarily on genital morphology. Yet both the mitochondrial and nuclear gene
      phylogenies demonstrate that Anartia jatrophae is not sister to all other Anartia
      species, but rather that it is sister to the Anartia fatima-Anartia amathea
      lineage. Traditional biogeographic explanations for speciation across the genus
      relied on A. jatrophae being sister to its congeners. These explanations invoked
      allopatric divergence of sister species pairs and multiple sympatric speciation
      events to explain why A. jatrophae flies alongside all its congeners. The
      molecular phylogenies are more consistent with lineage divergence due to
      vicariance, and range expansion of A. jatrophae to explain its sympatry with
      congeners. Further interpretations of the tree topologies also suggest how
      morphological evolution and eco-geographic adaptation may have set species range
      boundaries.

PMID- 12470938
TI  - Phylogeography of pipistrelle-like bats within the Canary Islands, based on mtDNA
      sequences.
AB  - Evolution of three Canary Island Vespertilionid bat species, Pipistrellus kuhlii,
      Pipistrellus maderensis, and Hypsugo savii was studied by comparison of
      approximately 1 kbp of mtDNA (from cytochrome b and 16S rRNA genes) between
      islands. mtDNA reveals that both P. kuhlii and P. maderensis exist in sympatry on
      Tenerife (and possibly other islands). Their morphological similarity explains
      why their co-occurrence had not been detected previously. Levels of sequence
      divergence are quite low within P. maderensis. Haplotypes were either identical
      or separated by </=2 mutational steps on two of the islands (La Gomera and El
      Hierro). However there is sufficient between-island divergence between haplotypes
      from Tenerife, La Palma, and La Gomera/El Hierro to suggest that they could
      represent three evolutionary significant units (ESU). H. savii has an overlapping
      island distribution but a contrasting phylogeographical pattern. Most
      significantly, sequence divergence is greatest between La Gomera and El Hierro
      (>/=12 mutational steps) indicating colonization of the latter from the former
      sometime during the last approximately 1.2 Ma, with low subsequent gene flow.
      Unlike P. maderensis the El Hierro population alone appears to represent an ESU.
      The H. savii haplotypes detected in Gran Canaria and Tenerife are identical or
      separated by 1 mutational step.

PMID- 12470939
TI  - Molecular systematics and biogeography of the Neotropical monkey genus, Alouatta.
AB  - We take advantage of the broad distribution of howler monkeys from Mexico to
      Argentina to provide a historical biogeographical analysis on a regional scale
      that encompasses the entire Neotropics. The phylogenetic relationships among 9 of
      the 10 recognized Alouatta species were inferred using three mitochondrial and
      two nuclear genes. The nuclear gene regions provided no phylogenetic resolution
      among howler monkey species, and were characterized by very low levels of
      sequence divergence between Alouatta and the Ateles outgroup. The mtDNA genes, on
      the other hand, produced a well-resolved phylogeny, which indicated that the
      earliest split among howler monkeys separated cis- and trans-Andean clades. Eight
      monophyletic mtDNA haplotype clades were identified, representing six named
      species in South America, including Alouatta seniculus, Alouatta sara, Alouatta
      macconelli, Alouatta caraya, Alouatta belzebul, and Alouatta guariba, and two in
      Mesoamerica, Alouatta pigra and Alouatta palliata. Molecular clock-based
      estimates of branching times indicated that contemporary howler monkey species
      originated in the late Miocene and Pliocene, not the Pleistocene. The causes of
      Alouatta diversification were more difficult to pin down, although we posit that
      the initial cis-, trans-Andean split in the genus was caused by the late Miocene
      completion of the northern Andes. Riverine barriers to dispersal and putative
      forest refuges can neither be discounted nor distinguished as causes of
      speciation in many cases, and one, the other or both have likely played a role in
      the diversification of South American howler monkeys. Finally, we estimated the
      separation of Mesoamerican A. pigra and A. palliata at 3Ma, which corresponds to
      the completion date of the Panama Isthmus promoting a role for this earth history
      event in the speciation of Central American howler monkeys.

PMID- 12470940
TI  - Phylogenetic analysis of Blattabacterium, endosymbiotic bacteria from the wood
      roach, Cryptocercus (Blattodea: Cryptocercidae), including a description of three
      new species.
AB  - Members of the cockroach genus Cryptocercus are wood-feeding, subsocial insects
      that live in temperate forests of the Nearctic and Palaearctic. At present, nine
      species are recognized: Cryptocercus relictus and Cryptocercus kyebangensis in
      eastern Asia and Russia, Cryptocercus primarius and Cryptocercus matilei in
      southwestern China, Cryptocercus clevelandi in the western USA, and Cryptocercus
      darwini, Cryptocercus garciai, Cryptocercus punctulatus, and Cryptocercus wrighti
      in the eastern USA. Like all extant cockroaches, Cryptocercus harbor
      endosymbiotic bacteria, Blattabacterium, in their fat bodies. The endosymbionts
      in all cockroaches have been considered a single species, Blattabacterium
      cuenoti, since their discovery about a century ago. However, a recent analysis of
      DNA sequences from representatives of four cockroach families has indicated that
      there is considerable DNA sequence divergence among B. cuenoti from different
      host species. As a part of our studies on the evolution of Cryptocercus, we
      examined DNA sequence divergence among B. cuenoti from six of the nine known
      Cryptocercus species. Specifically, we sequenced approximately 2,400 bp of the
      16S rRNA and 23S rRNA genes of B. cuenoti from six species of Cryptocercus. We
      found that B. cuenoti in Cryptocercus has differentiated into multiple
      monophyletic lineages distinguishable by DNA sequence of rRNA genes and host
      association. Our sequence divergence estimates were consistent with those
      reported for other, congeneric bacterial species. We propose the recognition of
      three new species of Blattabacterium within Cryptocercus species as follows:
      Blattabacterium relictus sp. nov. in C. relictus, Blattabacterium clevelandi sp.
      nov. in C. clevelandi, and Blattabacterium punctulatus sp. nov. in C. darwini, C.
      garciai, C. punctulatus, and C. wrighti.

PMID- 12470941
TI  - Utility of the dentin matrix protein 1 (DMP1) gene for resolving mammalian
      intraordinal phylogenetic relationships.
AB  - We sequenced exon 6 of the nuclear dentin matrix protein 1 (DMP1) gene from 19
      species of bats (order Chiroptera) to assess the utility of this gene for higher
      level phylogenetic studies. Bayesian analysis revealed high support (posterior
      probabilities >/=0.95) for monophyly of Noctilionoidea (Phyllostomidae,
      Noctilionidae, and Mormoopidae), all genera and most families examined.
      Comparison of the phylogenetic information present in DMP1 with mitochondrial
      rDNA and nuclear RAG2 genes indicated no significant heterogeneity. Thus, we
      concatenated these three data sets into a single "total evidence" phylogenetic
      analysis. Combined analysis was congruent with study of RAG2 and combined RAG2
      and mtrDNA sequences, but improved support (Bayesian posterior probabilities) for
      many nodes. Our results indicate that exon 6 of DMP1 is rapidly evolving, able to
      tolerate non-frame shifting insertion and deletion events, is more variable than
      RAG2, and provides phylogenetic resolution from the interfamilial to infraclass
      levels in mammals.

PMID- 12470942
TI  - Cloning and sequencing of wsp encoding gene fragments reveals a diversity of co
      infecting Wolbachia strains in Acromyrmex leafcutter ants.
AB  - By sequencing part of the wsp gene of a series of clones, we detected an
      unusually high diversity of nine Wolbachia strains in queens of three species of
      leafcutter ants. Up to four strains co-occurred in a single ant. Most strains
      occurred in two clusters (InvA and InvB), but the social parasite Acromyrmex
      insinuator hosted two additional infections. The multiple Wolbachia strains may
      influence the expression of reproductive conflicts in leafcutter ants, but the
      expected turnover of infections may make the cumulative effects on host ant
      reproduction complex. The additional Wolbachia infections of the social parasite
      A. insinuator were almost certainly acquired by horizontal transmission, but may
      have facilitated reproductive isolation from its closely related host.

PMID- 12470943
TI  - Basal actinopterygian relationships: a mitogenomic perspective on the phylogeny
      of the "ancient fish".
AB  - The basal actinopterygians comprise four major lineages (polypteriforms,
      acipenseriforms, lepisosteids, and Amia) and have been collectively called
      "ancient fish." We investigated the phylogeny of this group of fishes in relation
      to teleosts using mitochondrial genomic (mitogenomic) data, and compared this to
      the various alternative phylogenetic hypotheses that have been proposed
      previously. In addition to the previously determined complete mitochondrial DNA
      (mtDNA) sequences from 14 teleosts and two outgroups, we used newly determined
      mitogenomic sequences of 12 purposefully chosen species representing all the
      ancient fish lineages plus related teleosts. This data set comprised concatenated
      nucleotide sequences from 12 protein-coding genes (excluding the ND6 gene and
      third codon positions) and 22 transfer RNA (tRNA) genes (stem regions only) and
      these data were subjected to maximum parsimony, maximum likelihood, and Bayesian
      analyses. The resultant trees from the three methods were well resolved and
      largely congruent, with most internal branches being supported by high
      statistical values. Mitogenomic data strongly supported not only the monophyly of
      the teleosts (osteoglossomorphs and above), but also a sister-group relationship
      between the teleosts and a clade comprising the acipenseriforms, lepisosteids,
      and Amia, with the polypteriforms occupying the most basal position in the
      actinopterygian phylogeny. Although the tree topology differed from any of the
      previously proposed hypotheses based on morphology, it exhibited congruence with
      a recently proposed novel hypothesis based on nuclear markers.

PMID- 12470944
TI  - Major patterns of higher teleostean phylogenies: a new perspective based on 100
      complete mitochondrial DNA sequences.
AB  - A recent preliminary study using complete mitochondrial DNA sequences from 48
      species of teleosts has suggested that higher teleostean phylogenies should be
      reinvestigated on the basis of more intensive taxonomic sampling. As a second
      step towards the resolution of higher teleostean phylogenies, which have been
      described as the "(unresolved) bush at the top of the tree," we reanalyzed their
      relationships using mitogenomic data from 100 purposefully chosen species that
      fully represented all of the higher teleostean orders, except for the
      Batrachoidiformes. Unweighted and weighted maximum parsimony analyses were
      conducted with the data set that comprised concatenated nucleotide sequences from
      12 protein-coding genes (excluding 3rd codon positions) and 21 transfer RNA
      (tRNA) genes (stem regions only) from each species. The resultant trees were well
      resolved and largely congruent, with most internal branches being supported by
      high statistical values. All major, comprehensive groups above ordinal level as
      currently defined in higher teleosts (with the exception of the Neoteleostei and
      several monotypic groups), such as the Eurypterygii, Ctenosquamata,
      Acanthomorpha, Paracanthopterygii, Acanthopterygii, and Percomorpha, appeared to
      be nonmonophyletic in the present tree. Such incongruities largely resulted from
      differences in the placement and/or limits of the orders Ateleopodiformes,
      Lampridiformes, Polymixiiformes, Ophidiiformes, Lophiiformes, Beryciformes,
      Stephanoberyciformes, and Zeiformes, long-standing problematic taxa in systematic
      ichthyology. Of these, the resulting phylogenetic positions of the Ophidiiformes
      and Lophiiformes were totally unexpected, because, although they have
      consistently been considered relatively primitive groups within higher teleosts
      (Paracanthopterygii), they were confidently placed within a crown group of
      teleosts, herein called the Percomorpha. It should be noted that many unexpected,
      but highly supported relationships were found within the Percomorpha, being
      highly promising for the next investigative step towards resolution of this
      remarkably diversified group of teleosts.

PMID- 12470945
TI  - Reconstructing species phylogeny of the carabid beetles Ohomopterus using
      multiple nuclear DNA sequences: heterogeneous information content and the
      performance of simultaneous analyses.
AB  - We attempted a phylogenetic reconstruction for the carabid subgenus Ohomopterus
      (genus Carabus), a notable case of radiation with mitochondrial introgression
      across species. Sequence data from five nuclear single copy loci were used,
      including wingless (Wg), phosphoenolpyruvate carboxykinase (PepCK), cytochrome c
      (Cytc), elongation factor-1alpha (EF-1alpha), and an anonymous single copy locus
      (Carab1). Sequences of Cytc, EF-1alpha, and Carab1 included intron or intron-like
      parts with length variation. The analysis of individual loci resulted in low
      resolution of the phylogenetic relationships, and the monophyly of several
      morphologically recognized species for which multiple specimens were analyzed was
      not revealed. Several specimens were heterozygous, with non-monophyletic alleles
      observed in three of the five loci at which alleles in heterozygotes were
      separated. In a simultaneous analysis of the five loci with ambiguously aligned
      parts eliminated and heterozygotic sites treated as missing, the resulting tree
      was well resolved, but the branch support was generally weak because of
      conflicting phylogenetic signals from different loci. We also attempted to
      incorporate allelic sequence data plus the ambiguously aligned parts in the
      analysis, by using all possible combinations of alleles from different loci in
      heterozygotic individuals, but the resultant tree was not supported more
      strongly. Nonetheless, these simultaneous analyses provided support for the
      monophyly of several species and species groups, and revealed the basic
      evolutionary trend of OHOMOPTERUS: initial widespread groups with simpler
      genitalia and the origination of exaggerated genitalia in a derived clade. This
      study exemplifies problems inherent in the phylogenetic reconstruction of closely
      related organisms where low levels of variation limit the information content
      from each locus, while heterozygosity, different phylogenetic history of multiple
      loci, and alignment ambiguity further hamper phylogenetic reconstruction unless
      several loci converge on a uniform signal.

PMID- 12470946
TI  - The syndermatan phylogeny and the evolution of acanthocephalan endoparasitism as
      inferred from 18S rDNA sequences.
AB  - The phylogeny of the Syndermata (Rotifera: Monogononta, Bdelloidea, Seisonidea;
      Acanthocephala: Palaeacanthocephala, Eoacanthocephala, Archiacanthocephala) is
      key to understanding the evolution of acanthocephalan endoparasitism from free
      living ancestors. In the present study, maximum likelihood, distance/neighbor
      joining, and maximum parsimony analyses have been carried out based on 18S rDNA
      data of 22 species (four new sequences). The results suggest a monophyletic
      origin of the Eurotatoria (Monogononta+Bdelloidea). Seison appears as the
      acanthocephalan sistergroup. Palaeacanthocephala split into an "Echinorhynchus"
      and a "Leptorhynchoides"-group, the latter sharing a monophyletic origin with the
      Eoacanthocephala and Archiacanthocephala. As inferred from the phylogeny obtained
      acanthocephalan endoparasitism evolved from a common ancestor of Seison and
      Acanthocephala that lived epizoically on an early mandibulate. Probably, an
      acanthocephalan stem species invaded the mandibulate host, thus establishing an
      endoparasitic lifestyle. Subsequently, vertebrates (or gnathostomes) became part
      of the parasite's life cycle. In the stem line of the Archiacanthocephala, a
      terrestrial life cycle has evolved, with an ancestor of the Tracheata (Insecta,
      Myriapoda) acting as intermediate host.

PMID- 12470947
TI  - Factorless ribosome assembly on the internal ribosome entry site of cricket
      paralysis virus.
AB  - The cricket paralysis virus (CrPV), a member of the CrPV-like virus family,
      contains a single positive-stranded RNA genome that encodes two non-overlapping
      open reading frames separated by a short intergenic region (IGR). The CrPV IGR
      contains an internal ribosomal entry site (IRES) that directs the expression of
      structural proteins. Unlike previously described IRESs, the IGR IRES initiates
      translation by recruiting 80S ribosomes in the absence of initiator Met-tRNA(i)
      or any canonical initiation factors, from a GCU alanine codon located in the A
      site of the ribosome. Here, we have shown that a variety of mutations, designed
      to disrupt individually three pseudoknot (PK) structures and alter highly
      conserved nucleotides among the CrPV-like viruses, inhibit IGR IRES-mediated
      translation. By separating the steps of translational initiation into ribosomal
      recruitment, ribosomal positioning and ribosomal translocation, we found that the
      mutated IRES elements could be grouped into two classes. One class, represented
      by mutations in PKII and PKIII, bound 40S subunits with significantly reduced
      affinity, suggesting that PKIII and PKII are involved in the initial recruitment
      of the ribosome. A second class of mutations, exemplified by alterations in PKI,
      did not affect 40S binding but altered the positioning of the ribosome on the
      IRES, indicating that PKI is involved in the correct positioning of IRES
      associated ribosomes. These results suggest that the IGR IRES has distinct
      pseudoknot-like structures that make multiple contacts with the ribosome
      resulting in initiation factor-independent recruitment and correct positioning of
      the ribosome on the mRNA.

PMID- 12470948
TI  - Rearrangement of substrate secondary structure facilitates binding to the
      Neurospora VS ribozyme.
AB  - The Neurospora VS ribozyme differs from other small, naturally occurring
      ribozymes in that it recognizes for trans cleavage or ligation a substrate that
      consists largely of a stem-loop structure. We have previously found that cleavage
      or ligation by the VS ribozyme requires substantial rearrangement of the
      secondary structure of stem-loop I, which contains the cleavage/ligation site.
      This rearrangement includes breaking the top base-pair of stem-loop I, allowing
      formation of a kissing interaction with loop V, and changing the partners of at
      least three other base-pairs within stem-loop I to adopt a conformation termed
      shifted. In the work presented, we have designed a binding assay and used
      mutational analysis to investigate the contribution of each of these structural
      changes to binding and ligation. We find that the loop I-V kissing interaction is
      necessary but not sufficient for binding and ligation. Constitutive opening of
      the top base-pair of stem-loop I has little, if any, effect on either activity.
      In contrast, the ability to adopt the shifted conformation of stem-loop I is a
      major determinant of binding: mutants that cannot adopt this conformation bind
      much more weakly than wild-type and mutants with a constitutively shifted stem
      loop I bind much more strongly. These results implicate the adoption of the
      shifted structure of stem-loop I as an important process at the binding step in
      the VS ribozyme reaction pathway. Further investigation of features near the
      cleavage/ligation site revealed that sulphur substitution of the non-bridging
      phosphate oxygen atoms immediately downstream of the cleavage/ligation site,
      implicated in a putative metal ion binding site, significantly altered the
      cleavage/ligation equilibrium but did not perturb substrate binding
      significantly. This indicates that the substituted oxygen atoms, or an associated
      metal ion, affect a step that occurs after binding and that they influence the
      rates of cleavage and ligation differently.

PMID- 12470949
TI  - Insights into substrate binding and catalytic mechanism of human tyrosyl-DNA
      phosphodiesterase (Tdp1) from vanadate and tungstate-inhibited structures.
AB  - Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA repair enzyme that catalyzes the
      hydrolysis of a phosphodiester bond between a tyrosine residue and a DNA 3'
      phosphate. The only known example of such a linkage in eukaryotic cells occurs
      normally as a transient link between a type IB topoisomerase and DNA. Thus human
      Tdp1 is thought to be responsible for repairing lesions that occur when
      topoisomerase I becomes stalled on the DNA in the cell. Tdp1 has also been shown
      to remove glycolate from single-stranded DNA containing a 3'-phosphoglycolate,
      suggesting a role for Tdp1 in repair of free-radical mediated DNA double-strand
      breaks. We report the three-dimensional structures of human Tdp1 bound to the
      phosphate transition state analogs vanadate and tungstate. Each structure shows
      the inhibitor covalently bound to His263, confirming that this residue is the
      nucleophile in the first step of the catalytic reaction. Vanadate in the Tdp1
      vanadate structure has a trigonal bipyramidal geometry that mimics the transition
      state for hydrolysis of a phosphodiester bond, while Tdp1-tungstate displays
      unusual octahedral coordination. The presence of low-occupancy tungstate
      molecules along the narrow groove of the substrate binding cleft is suggestive
      evidence that this groove binds ssDNA. In both cases, glycerol from the
      cryoprotectant solution became liganded to the vanadate or tungstate inhibitor
      molecules in a bidentate 1,2-diol fashion. These structural models allow
      predictions to be made regarding the specific binding mode of the substrate and
      the mechanism of catalysis.

PMID- 12470950
TI  - Characterization of the C-terminal DNA-binding/DNA endonuclease region of a group
      II intron-encoded protein.
AB  - Group II intron retrohoming occurs by a mechanism in which the intron RNA reverse
      splices directly into one strand of a double-stranded DNA target site, while the
      intron-encoded reverse transcriptase uses a C-terminal DNA endonuclease activity
      to cleave the opposite strand and then uses the cleaved 3' end as a primer for
      reverse transcription of the inserted intron RNA. Here, we characterized the C
      terminal DNA-binding/DNA endonuclease region of the LtrA protein encoded by the
      Lactococcus lactis Ll.LtrB intron. This C-terminal region consists of an upstream
      segment that contributes to DNA binding, followed by a DNA endonuclease domain
      that contains conserved sequence motifs characteristic of H-N-H DNA
      endonucleases, interspersed with two pairs of conserved cysteine residues. Atomic
      emission spectroscopy of wild-type and mutant LtrA proteins showed that the DNA
      endonuclease domain contains a single tightly bound Mg(2+) ion at the H-N-H
      active site. Although the conserved cysteine residue pairs could potentially bind
      Zn(2+), the purified LtrA protein is active despite the presence of only sub
      stoichiometric amounts of Zn(2+), and the addition of exogenous Zn(2+) inhibits
      the DNA endonuclease activity. Multiple sequence alignments identified features
      of the DNA-binding region and DNA endonuclease domain that are conserved in LtrA
      and related group II intron proteins, and their functional importance was
      demonstrated by unigenic evolution analysis and biochemical assays of mutant LtrA
      protein with alterations in key amino acid residues. Notably, deletion of the DNA
      endonuclease domain or mutations in its conserved sequence motifs strongly
      inhibit reverse transcriptase activity, as well as bottom-strand cleavage, while
      retaining other activities of the LtrA protein. A UV-cross-linking assay showed
      that these DNA endonuclease domain mutations do not block DNA primer binding and
      thus likely inhibit reverse transcriptase activity either by affecting the
      positioning of the primer or the conformation of the reverse transcriptase
      domain.

PMID- 12470951
TI  - Structural and functional analysis of the S-layer protein crystallisation domain
      of Lactobacillus acidophilus ATCC 4356: evidence for protein-protein interaction
      of two subdomains.
AB  - The structure of the crystallisation domain, SAN, of the S(A)-protein of
      Lactobacillus acidophilus ATCC 4356 was analysed by insertion and deletion
      mutagenesis, and by proteolytic treatment. Mutant S(A)-protein synthesised in
      Escherichia coli with 7-13 amino acid insertions near the N terminus or within
      regions of sequence variation in SAN (amino acid position 7, 45, 114, 125, 193),
      or in the cell wall-binding domain (position 345) could form crystalline sheets,
      whereas insertions in conserved regions or in regions with predicted secondary
      structure elements (positions 30, 67, 88 and 156) destroyed this capacity.
      FACscan analysis of L.acidophilus synthesising three crystallising and one non
      crystallising S(A)-protein c-myc (19 amino acid residues) insertion mutant was
      performed with c-myc antibodies. Fluorescence was most pronounced for insertions
      at positions 125 and 156, less for position 45 and severely reduced for position
      7. By cytometric flow sorting a transformant harbouring the mutant S(A)-protein
      gene (position 125) was isolated that showed an increased fluorescense signal.
      Immunofluorescence microscopy suggested that the transformant synthesized mutant
      S(A)-protein only. PCR analysis of the transformant grown in the absence of
      selection pressure indicated that the mutant allele was stably integrated in the
      chromosome. Proteolytic treatment of S(A)-protein indicated that only sites near
      the middle of SAN are susceptible, although potential cleavage sites are present
      through the entire molecule. Expression in E.coli of DNA sequences encoding the
      two halves of SAN yielded peptides that could oligomerize. Our results indicate
      that SAN consists of a approximately 12kDa N and a approximately 18kDa C-terminal
      subdomain linked by a surface exposed loop. The capacity of S(A)-protein of
      L.acidophilus to present epitopes, up to approximately 19 amino acid residues in
      length, at the bacterial surface in a genetically stable form, makes the system,
      in principle, suitable for application as an oral delivery vehicle.

PMID- 12470952
TI  - Thermodynamics of peptide binding to the transporter associated with antigen
      processing (TAP).
AB  - The ATP-binding cassette (ABC) transporter TAP plays an essential role in antigen
      processing and immune response to infected or malignant cells. TAP translocates
      proteasomal degradation products from the cytosol into the endoplasmic reticulum,
      where MHC class I molecules are loaded with these peptides. Kinetically stable
      peptide-MHC complexes are transported to the cell surface for inspection by
      cytotoxic T lymphocytes. The transport cycle of TAP is initiated by peptide
      binding, which is responsible for peptide selection and for stimulation of ATP
      hydrolysis and subsequent translocation. Here we have analysed the driving forces
      for the formation of the peptide-TAP complex by kinetic and thermodynamic
      methods. First, the apparent peptide association and dissociation rates were
      determined at various temperatures. Strikingly, very high activation energies for
      apparent association (E(a)(ass)=106 kJmol(-1)) and dissociation (E(a)(diss)=80
      kJmol(-1)) of the peptide-TAP complex were found. Next, the temperature
      dependence of the peptide affinity constants was investigated by equilibrium
      binding assays. Along with calculations of free enthalpy deltaG, enthalpy deltaH
      and entropy deltaS, a large positive change in heat capacity was resolved (deltaC
      degrees =23 kJmol(-1)K(-1)), indicating a fundamental structural reorganization
      of the TAP complex upon peptide binding. The inspection of the conformational
      entropy reveals that approximately one-fourth of all TAP residues is rearranged.
      These thermodynamic studies indicate that at physiological temperature, peptide
      binding is endothermic and driven by entropy.

PMID- 12470953
TI  - Crystal structures of two rat MHC class Ia (RT1-A) molecules that are associated
      differentially with peptide transporter alleles TAP-A and TAP-B.
AB  - Antigenic peptides are loaded onto class I MHC molecules in the endoplasmic
      reticulum (ER) by a complex consisting of the MHC class I heavy chain, beta(2)
      microglobulin, calreticulin, tapasin, Erp57 (ER60) and the transporter associated
      with antigen processing (TAP). While most mammalian species transport these
      peptides into the ER via a single allele of TAP, rats have evolved different
      TAPs, TAP-A and TAP-B, that are present in different inbred strains. Each TAP
      delivers a different spectrum of peptides and is associated genetically with
      distinct subsets of MHC class Ia alleles, but the molecular basis for the
      conservation (or co-evolution) of the two transporter alleles is unknown. We have
      determined the crystal structures of a representative of each MHC subset, viz RT1
      A(a) and RT1-A1(c), in association with high-affinity nonamer peptides. The
      structures reveal how the chemical properties of the two different rat MHC F
      pockets match those of the corresponding C termini of the peptides, corroborating
      biochemical data on the rates of peptide-MHC complex assembly. An unusual
      sequence in RT1-A1(c) leads to a major deviation from the highly conserved
      beta(3)/alpha(1) loop (residues 40-59) conformation in mouse and human MHC class
      I structures. This loop change contributes to profound changes in the shape of
      the A-pocket in the peptide-binding groove and may explain the function of RT1
      A1(c) as an inhibitory natural killer cell ligand.

PMID- 12470954
TI  - Backbone dynamics and thermodynamics of Borrelia outer surface protein A.
AB  - Nuclear spin relaxation experiments performed at 298K, 308K and 318K are used to
      characterize the intramolecular dynamics and thermodynamics of outer surface
      protein A (OspA), a key protein in the life-cycle of Borrelia burgdorferi, the
      causative agent of Lyme disease. It has recently been demonstrated that OspA
      specifically binds to the gut of the intermediate tick host (Ixodes scapularis),
      and that this interaction is mediated, at least in part, by residues in the C
      terminal domain of OspA that are largely inaccessible to solvent in all X-ray
      structures of this protein. Our analysis of 15N relaxation parameters in OspA
      shows that the putative-binding region contains and is surrounded by flexible
      residues, which could facilitate accessibility to solvent and ligands. In
      addition, residues with similar activation energies are clustered in a manner
      that suggests locally collective motions. We have used molecular modeling to show
      that these collective motions are consistent with a hinge-bending mechanism that
      exposes residues implicated in binding. Characteristic temperatures describing
      the energy landscape of the OspA backbone are derived from the temperature
      dependence of the N-H bond vector order parameters, and a comparison is made
      between the N and C-terminal globular domains and the unusual single-layer beta
      sheet connecting them. The average characteristic temperatures in the three
      regions indicate that, with an increase in temperature, a larger increase in
      accessible conformational states occurs for N-H bond vectors in the single-layer
      central beta-sheet than for bond vectors in the globular N and C-terminal
      domains. These conformational states are accessible without disruption of
      hydrogen bonds, providing a conformational entropic gain, upon increase in
      temperature, without a significant enthalpic penalty. This increase in heat
      capacity may help to explain the unexpected thermal stability of the unusual
      single-layer beta-sheet.

PMID- 12470955
TI  - Solution NMR structure of S100B bound to the high-affinity target peptide TRTK
      12.
AB  - The solution NMR structure is reported for Ca(2+)-loaded S100B bound to a 12
      residue peptide, TRTK-12, from the actin capping protein CapZ (alpha1 or alpha2
      subunit, residues 265-276: TRTKIDWNKILS). This peptide was discovered by Dimlich
      and co-workers by screening a bacteriophage random peptide display library, and
      it matches exactly the consensus S100B binding sequence ((K/R)(L/I)XWXXIL). As
      with other S100B target proteins, a calcium-dependent conformational change in
      S100B is required for TRTK-12 binding. The TRTK-12 peptide is an amphipathic
      helix (residues W7 to S12) in the S100B-TRTK complex, and helix 4 of S100B is
      extended by three or four residues upon peptide binding. However, helical TRTK-12
      in the S100B-peptide complex is uniquely oriented when compared to the three
      dimensional structures of other S100-peptide complexes. The three-dimensional
      structure of the S100B-TRTK peptide complex illustrates that residues in the
      S100B binding consensus sequence (K4, I5, W7, I10, L11) are all involved in the
      S100B-peptide interface, which can explain its orientation in the S100B binding
      pocket and its relatively high binding affinity. A comparison of the S100B-TRTK
      peptide structure to the structures of apo- and Ca(2+)-bound S100B illustrates
      that the binding site of TRTK-12 is buried in apo-S100B, but is exposed in Ca(2+)
      bound S100B as necessary to bind the TRTK-12 peptide.

PMID- 12470956
TI  - The solution structure of the recombinant hemoglobin from the cyanobacterium
      Synechocystis sp. PCC 6803 in its hemichrome state.
AB  - The product of the cyanobacterium Synechocystis sp. PCC 6803 gene slr2097 is a
      123 amino acid polypeptide chain belonging to the truncated hemoglobin family.
      Recombinant, ferric heme-reconstituted Synechocystis sp. PCC 6803 hemoglobin
      displays bis-histidine coordination of the iron ion. In addition, this protein is
      capable of covalently attaching a reactive histidine to the heme 2-vinyl group.
      The structure of the protein in the low-spin ferric state with intact vinyl
      substituents was solved by NMR methods. It was found that the structure differs
      from that of known truncated hemoglobins primarily in the orientation of the E
      helix, which carries His46 (E10) as the distal ligand to the iron; the length and
      orientation of the F helix, which carries His70 (F8) as the proximal ligand to
      the iron; and the H-helix, which carries His117 (H16), the reactive histidine.
      Regions of enhanced flexibility include the short A helix, the loop connecting
      the E and F helices, and the last seven residues at the carboxy end. The
      structural data allowed for the rationalization of physical properties of the
      cyanobacterial protein, such as fast on-rate for small ligand binding, unstable
      apoprotein fold, and cross-linking ability. Comparison to the truncated
      hemoglobin from the green alga Chlamydomonas eugametos also suggested how the
      endogenous hexacoordination affected the structure.

PMID- 12470957
TI  - The equilibrium unfolding pathway of a (beta/alpha)8 barrel.
AB  - The (beta/alpha)(8) barrel is the most commonly occurring fold among enzymes. A
      key step towards rationally engineering (beta/alpha)(8) barrel proteins is to
      understand their underlying structural organization and folding energetics. Using
      misincorporation proton-alkyl exchange (MPAX), a new tool for solution structural
      studies of large proteins, we have performed a native-state exchange analysis of
      the prototypical (beta/alpha)(8) barrel triosephosphate isomerase. Three
      cooperatively unfolding subdomains within the structure are identified, as well
      as two partially unfolded forms of the protein. The C-terminal domain coincides
      with domains reported to exist in four other (beta/alpha)(8) barrels, but the two
      N-terminal domains have not been observed previously. These partially unfolded
      forms may represent sequential intermediates on the folding pathway of
      triosephosphate isomerase. The methods reported here should be applicable to a
      variety of other biological problems involving protein conformational changes.

PMID- 12470958
TI  - Navigation inside a protease: substrate selection and product exit in the tricorn
      protease from Thermoplasma acidophilum.
AB  - The proposed pathway and mechanism of substrate entry and product egress in the
      hexameric D3 symmetric tricorn protease from Thermoplasma acidophilum were
      explored by crystallographic studies of ligand complexes and by structure-based
      mutagenesis. Obstruction of the pore within the 7-bladed beta-propeller (beta7)
      domain by alkylation or oxidation of an engineered double cysteine mutant
      strongly decreased enzymatic activities. In line herewith, the crystal structure
      of the tricorn protease in complex with a trideca-peptide inhibitor modifying the
      catalytic Ser965 revealed part of the peptide trapped inside the channel of the
      beta7 domain. The cysteine mutation widening the lumen of the 6-bladed beta
      propeller (beta6) domain enhanced catalytic activity, which was restored to
      normal values after its alkylation. A charge reversal mutant at the putative
      anchor site of the substrate C terminus, R131E-R132E, drastically reduced the
      proteolytic activity. The complex crystal structure of a peptide inhibitor with a
      diketo group at the cleavage site mapped the substrate recognition site and
      confirmed the role of Arg131-Arg132 as an anchor site. Our results strongly
      suggest the wider beta7 domain to serve as a selective filter and guide of the
      substrate to the sequestered active site, while the narrower beta6 domain routes
      the product to the surface. Moreover, we identified the role of Arg131-Arg132 in
      anchoring the substrate C terminus.

PMID- 12470960
TI  - Newborns' recognition of changing and unchanging aspects of schematic faces.
AB  - The present study investigated newborns' ability to discriminate, recognize, and
      learn visual information embedded in the schematic face-like patterns preferred
      at birth. Four experiments were carried out using the visual-paired comparison
      paradigm. Results indicated that newborns discriminated face-like stimuli relying
      on their internal features (Experiments 1 and 4) and recognized a perceptual
      invariance between face-like configurations in conditions of low (Experiment 2)
      and high-perceptual variability (Experiment 3) of their inner elements.
      Altogether, data show that the presence of the preferred structure that
      schematically defines a face, displaying a triplet of elements in the correct
      locations for eyes and mouth, does not constitute a limit that constrains
      newborns' face learning processes.

PMID- 12470961
TI  - The role of attachment and cognitive inhibition in children's memory and
      suggestibility for a stressful event.
AB  - There has been increasing interest in children's abilities to report memories of
      and resist misleading suggestions about distressing events. Individual
      differences among children and their parents may provide important insight into
      principles that govern children's eyewitness memory and suggestibility for such
      experiences. In the present study, 51 children between the ages of 3 and 7 years
      were interviewed about an inoculation after a delay of approximately 2 weeks.
      Results indicated that parents' attachment Avoidance was associated with
      children's distress during the inoculation. Parental attachment Anxiety and the
      interaction between parental Avoidance and children's stress predicted children's
      memory for the inoculation. Cognitive inhibition was also a significant predictor
      of children's memory errors and suggestibility. Theoretical implications
      concerning effects of stress and individual differences on children's eyewitness
      memory and suggestibility are discussed.

PMID- 12470962
TI  - Solving spatial tasks with unaligned layouts: the difficulty of dealing with
      conflicting information.
AB  - Previous research has shown that preschool children have difficulty using
      relational information in spatial tasks. The present study investigates whether
      this difficulty is due, in part, to children's inability to deal with situations
      of conflict where both objective and egocentric cues are available and point to
      different responses. Two studies were conducted to compare performance in the
      presence versus absence of conflicting cues. In Study 1, 40 four-year-olds had to
      locate an object in a single layout presented from different perspectives. In
      Study 2, 39 four-year-olds had to transfer locational information between two
      unaligned layouts. The presence of conflict significantly affected children's
      performance in both studies. The results are discussed in the context of similar
      findings in other cognitive domains.

PMID- 12470963
TI  - Children's memories of experienced and nonexperienced events following repeated
      interviews.
AB  - The present study compared 3- and 5-year-olds' reports of a true or false play
      interaction following repeated interviews. Final interviews were conducted either
      by the same researcher or by a new researcher. Age-related improvements in
      performance were evident. Also, 3-year-olds questioned repeatedly about an
      entirely false event made more errors in response to specific questions than 3
      year-olds questioned repeatedly about false details of a true event. Five-year
      olds who were questioned about the false event, however, were particularly
      accurate when answering questions about never-experienced body touch. Interviewer
      familiarity was associated with decreases in the amount of narrative detail 5
      year-olds provided in free-recall and with increases in 3-year-olds' accuracy in
      response to direct questions. Both errors and response latency on a cognitive
      matching task were related to children's suggestibility.

PMID- 12470964
TI  - Inhibition of corneal neovascularization by recombinant adenovirus mediated
      antisense VEGF RNA.
AB  - The expression of vascular endothelial growth factor has been strongly implicated
      in the pathogenesis of conditions leading to inappropriate blood vessel growth in
      the eye. As such, vascular endothelial growth factor is an attractive target for
      anti-angiogenic therapies designed to treat neovascular eye diseases. One such
      therapy, antisense gene therapy, is a technique based on the ability of single
      stranded DNA or RNA sequences to alter the expression of targeted genes.
      Recombinant adenoviruses have demonstrated efficient ocular cell transduction
      with a high level of transgene production. Cauterization of the normally
      avascular rat cornea results in a strong neovascular response, making it an ideal
      animal model for the testing of anti-angiogenic therapies. In this study, a
      recombinant adenovirus system was assessed for the ability to express
      biologically relevant antisense RNA to reduce vascular endothelial growth factor
      expression in a rat model of corneal neovascularization. Recombinant adenovirus
      constructs expressing short and long antisense and sense vascular endothelial
      growth factor cDNA, under the control of cytomegalovirus major immediate early
      promoter or the RNA polymerase III promoter, VA1, were constructed. The
      expression of short and long antisense RNAs was demonstrated by Northern blot
      hybridization. All constructs were capable of producing RNA, and the highest
      level of antisense RNA production was detected in retinal pigment epithelial
      cells which had been transduced with the longer antisense cDNA construct under
      the control of the VA1 promoter. This construct was also the most efficient in
      reducing in vitro vascular endothelial growth factor production (P<0.05) and
      human endothelial cell proliferation. This construct was subsequently injected
      into rat eyes 24hr prior to cauterization of the cornea and antisense vascular
      endothelial growth factor expression was demonstrated by in situ hybridization.
      The resulting neovascular response was clearly inhibited at 4, 7 and 14 days post
      cautery, compared to the control injections which demonstrated an intense
      neovascular response. Only one out of six eyes injected with the long antisense
      cDNA construct under the control of the VA1 promoter demonstrated any vascular
      response to cautery. The reduction in the neovascular response was correlated,
      with significantly lower amounts of vascular endothelial growth factor protein in
      the corneas (P=0.006). These observations suggest that the specific down
      regulation of vascular endothelial growth factor production is sufficient to
      reduce the corneal neovascular response and that recombinant adenovirus might be
      a useful vehicle to produce antisense RNA in situ to down-regulate ocular gene
      expression.

PMID- 12470965
TI  - Pseudomonas aeruginosa strains with lipopolysaccharide defects exhibit reduced
      intracellular viability after invasion of corneal epithelial cells.
AB  - Pseudomonas aeruginosa is a leading cause of infectious keratitis. Many ocular
      isolates of this bacterium invade corneal epithelial cells in vitro and in vivo.
      Antibiotic survival assays have shown that a complete core lipopolysaccharide is
      required for full epithelial invasion by P. aeruginosa. In this study, we show
      that P. aeruginosa mutants with defects in their lipopolysaccharide core and O
      antigen exhibited reduced viability after internalization by corneal epithelial
      cells. Restoration of lipopolysaccharide core and O antigen expression by
      complementation with the plasmid pLPS1 restored intracellular survival. P.
      aeruginosa strains with a complete lipopolysaccharide survived and replicated
      within the cells. The data suggest that lipopolysaccharide is involved in the
      intracellular survival and/or replication of P. aeruginosa, indicating an
      additional mechanism by which this important virulence factor may contribute to
      the pathogenesis of corneal infection.

PMID- 12470966
TI  - TGFbeta induced myofibroblast differentiation of rabbit keratocytes requires
      synergistic TGFbeta, PDGF and integrin signaling.
AB  - There is a growing consensus that corneal myofibroblasts are derived from
      adjacent stromal keratocytes which undergo an orderly phenotypic transition from
      quiescent keratocyte to activated fibroblast to myofibroblast. Both in vivo and
      in vitro studies have shown this transition to be dependent, in part, on
      transforming growth factor beta (TGFbeta). In many fibroblastic cells autocrine
      production of platelet derived growth factor (PDGF) is known to mediate the
      growth up-regulation by TGFbeta. In this study, blocking antibodies to PDGF
      significantly reduced by 80% (P<0.025) the TGFbeta1 stimulated cell cycle entry
      of serum-free cultured rabbit corneal keratocytes. AntiPDGF treatment also
      markedly reduced the TGFbeta1-induced intracellular actin filament re
      organization, fibronectin fibril assembly, and focal contact formation as well as
      reducing by 80% the expression of alpha-smooth muscle (alpha-SM) specific isoform
      of actin characteristic of myofibroblast differentiation. Although PDGF treatment
      of quiescent keratocytes produced an activated, fibroblastic cell type, PDGF
      stimulated keratocytes exhibited the same temporal, myofibroblastic
      differentiation response to TGFbeta1 as did quiescent keratocytes. Furthermore,
      blocking TGFbeta1 induction of myofibroblast differentiation with the Arg-Gly-Asp
      containing peptide, GRGDdSP, for 3 days followed by allowing progression of
      myofibroblast differentiation by removing GRGDdSP did not change the temporal
      response or tyrosine phosphorylation cascade (2-72 hr) leading to myofibroblast
      differentiation. Nor did PDGF treatment of keratocytes reverse the RGD blockade
      of TGFbeta1 induced myofibroblast differentiation. Overall these cumulative
      findings indicate that myofibroblast differentiation in the rabbit corneal
      keratocyte requires synergistic growth factor/integrin signaling involving
      TGFbeta, PDGF, and the fibronectin receptor. Additionally, the similar TGFbeta1
      temporal response of PDGF-stimulated compared to nai;ve keratocytes suggests that
      myofibroblast differentiation does not require transition through a fibroblast
      phenotype.

PMID- 12470967
TI  - Coinduction of nitric oxide synthase and arginine metabolic enzymes in endotoxin
      induced uveitis rats.
AB  - The regulation of expression of the arginine-recycling enzymes and arginase
      isoforms in association with inducible nitric oxide synthase (iNOS) in the eye of
      endotoxin-induced uveitis (EIU) rats is investigated. An animal model of EIU was
      created in Wistar rats by intravitreal injection of lipopolysaccharide (LPS).
      mRNAs for argininosuccinate synthase (AS) and arginase I as well as for iNOS,
      measured by semi-quantitative reverse transcription-polymerase chain reaction (RT
      PCR), were induced in the eye of EIU rats. iNOS mRNA increased markedly 3 hr
      after injection, reached a maximum at 6-12 hr, and then decreased at 24 hr. AS
      mRNA remained little change at 3 hr and increased maximally at 6 hr (by about 3.3
      fold), whereas arginase I mRNA increased later and reached a maximum at 12 hr (by
      about 4.2-fold). iNOS, AS, and arginase I proteins were also induced. AL and
      arginase II mRNAs remained little changed. In immunohistochemical analysis, iNOS,
      AS and arginase I were almost colocalized in infiltrated inflammatory cells in
      the vitreous, iris, ciliary body and inner layers of the retina. In conclusion,
      AS and arginase I are coinduced with iNOS in infiltrated inflammatory cells in
      the eyes of EIU rats, and may regulate NO production by changing intracellular
      concentration of arginine.

PMID- 12470968
TI  - Vasodilatory effects of nipradilol, an alpha- and beta-adrenergic blocker with
      nitric oxide releasing action, in rabbit ciliary artery.
AB  - Nipradilol is a new antiglaucoma ophthalmic agent used in Japan. Topical
      application of nipradilol is reported to increase ocular blood flow. To
      investigate the action of this drug, we studied the effect of nipradilol on the
      isolated rabbit ciliary artery. Under the dissecting microscope, ciliary arteries
      were prepared from rabbit eyes and mounted on a myograph system. The effects of
      nipradilol on the isolated rabbit ciliary artery were investigated using
      isometric tension recording methods. Nipradilol provoked a dose-dependent (10
      microM-1m M) relaxation in ciliary arteries that were pre-contracted with high-K
      solutions (K(+): 100.7 m M). It also inhibited the amplitude of smooth muscle
      contraction evoked by field stimulation. Nipradilol was more effective in
      relaxing phenylephrine-induced contraction (EC(50): 21.6+/-16.3 microM) compared
      to high-K solution-induced contractions (EC(50): 230+/-130 microM). Application
      of N(w)-nitro- L -arginine methylester (300 microM), a nitric oxide (NO) synthase
      inhibitor, or denudations of endothelium by rubbing the inner surface with a
      scalp hair did not affect this relaxation. However, NO scavenger carboxy-PTIO (1m
      M) or methylene blue (10 microM), a guanylate cyclase inhibitor, inhibited the
      nipradilol-induced relaxation. These results indicate that nipradilol relaxes the
      rabbit ciliary artery by two different mechanisms. First, the relaxation is due
      to the NO produced by denitrification of nipradilol itself. Second, nipradilol
      may act as an alpha-adrenergic antagonist. These actions of nipradilol may
      explain the mechanisms of increased ocular blood flow in vivo.

PMID- 12470969
TI  - Modifying subsceral fluid pressure in an experimental model of mitomycin-C
      diffusion.
AB  - BACKGROUND: Episcleral application of mitomycin-C (MMC) during glaucoma
      filtration surgery hinders the post-operative wound healing. Diffusion through
      the sclera might result in a toxic effect on the ciliary body resulting in
      reduced aqueous humor production leading to post-operative hypotony. We developed
      an experimental model to investigate the influence of intraocular pressure on the
      diffusion of MMC through the sclera and in subscleral compartments. METHODS:
      Scleral quadrants of 10 human donor eyes were mounted on PMMA tubes filled with
      saline imitating the intraocular volume. By height variation of a coupled
      infusion line different intraocular pressures were simulated (0, 8, 23 and 80
      mmHg). Additionally the model included a subscleral sponge to mimic the
      compartment of the ciliary body. The episcleral sides of the scleral quadrants
      were exposed for 1 min to sponges soaked with 200 microg ml(-1) MMC. An 8-mm
      diameter scleral disk was punched out with a trephine and horizontally dissected
      with a kryotome. The MMC concentrations of scleral layers, epi-and subscleral
      sponges and the fluid within the tubes were analysed by means of high-performance
      liquid chromatography. RESULTS: The MMC concentration gradually declined from the
      episcleral sponge (165 microg ml(-1)) to the superficial (3.3 microg ml(-1)) and
      deep scleral layers (1.2 microg ml(-1)), and to the subscleral sponge (0.2 microg
      ml(-1)). We were able to detect very small concentrations of MMC in the fluid
      within the PMMA tubes (0.01 microg ml(-1)). CONCLUSION: We developed a new
      experimental in vitro model for investigating transscleral MMC diffusion. The
      different simulated intraocular pressures had no effect on the concentration
      gradient through the investigated compartments of our model.

PMID- 12470970
TI  - Association of type XII collagen with regions of increased stability and
      keratocyte density in the cornea.
AB  - The anterior avian cornea possesses several distinct cellular and extracellular
      regions including the epithelial basal lamina, Bowman's layer and the interfacial
      matrix that separates Bowman's layer from the stroma. These unique regions differ
      biochemically, physically and morphologically but all contain type XII collagen.
      Previously, the collagen fibrils of several of these interfacial regions were
      shown to be stable to thermal and enzymatic denaturation. We reasoned that type
      XII collagen, a fibril-associated collagen, would be a good candidate to confer
      such stabilizing properties. The studies described herein were performed to
      localize type XII collagen and to assess its role in the interfacial matrices
      (IM). Using antibodies that react with both the short and long type XII collagen
      isoforms and that react specifically with the long isoform, we demonstrate that
      it is the short isoform that is present in Bowman's layer and the associated
      interfacial matrix lying between Bowman's and the stroma proper. In situ
      hybridization analyses demonstrate that both the epithelial and endothelial cells
      synthesize type XII collagen. In vitro cell culture analyses, however,
      demonstrate that in addition to epithelial cell synthesis, the stromal
      fibroblasts are capable of synthesizing type XII collagen as well.
      Immunofluorescence analyses performed at elevated temperature demonstrate that
      type XII collagen is thermally stable in Bowman's layer, but not in the anterior
      interfacial matrix or Descemet's layer. In addition, we observed that the
      distribution of type XII collagen during the development of the anterior
      extracellular matrices correlates precisely with an elevated density of
      keratocytes populating the interfacial matrix just deep to Bowman's layer. We
      show that this cellular density is developmentally regulated and does not arise
      from a localized increase in cell proliferation. These data demonstrate that
      Bowman's layer and the anterior interfacial matrix have unique biochemical and
      morphologic properties. Type XII collagen is thermally stable in Bowman's layer
      and, as a surface component of type I collagen fibrils, may contribute to the
      stability of the fibrils in this region. Neither type XII nor type I collagen is
      stable in the adjacent interfacial matrix, suggesting that differences in the
      type I-XII collagen fibril organization may exist between Bowman's layer and IM.

PMID- 12470971
TI  - Relaxographic studies of aging normal human lenses.
AB  - Ten excised normal human lenses of various ages were studied. Seven sections of
      each lens, from anterior outer cortex to posterior outer cortex were imaged and
      the T(1) (spin-lattice) and T(2) (spin-spin) relaxation data on each section were
      collected. T(1) and T(2) relaxation were analysed by fitting pixel intensity to
      one term exponential expressions. Both T(1) and T(2) relaxation times showed
      minimal values in the nuclear region and maxima at the two outer cortexes. The
      pre-exponential terms of the fittings of both T(1) and T(2) relaxation,M(1) and
      M(2), were normalized in order to eliminate instrumental variations over a 2 year
      period. M(2) had a maximum in the nucleus and minima in the two cortexes. M(1)
      exhibited minimal value in the nucleus and maxima at the two cortexes. The
      positional dependence of T(2) relaxation times as well as that of M(2) indicated
      that they represent the behavior of the bound water in the lens. The positional
      dependence of M(1) suggests that this relaxation represents the total water that
      has a minimal value in the nucleus. The T(2) relaxation time decreases with
      increase in the age of the lens at each location. The slope of the change in T(2)
      relaxation time with age is greatest in the outer cortexes and diminishes as one
      proceeds to the nucleus. T(1) relaxation times and M(1) do not show significant
      change with age. This and the age dependence of the other relaxographic
      parameters imply that the aging of the lens involves major changes in its
      hydration properties that are more accentuated in the cortexes. The
      interpretation of these changes is in agreement with the syneretic theory of lens
      aging.

PMID- 12470972
TI  - Developmental death of photoreceptors in the C57BL/6J mouse: association with
      retinal function and self-protection.
AB  - We have investigated the relationship between cell death among photoreceptors and
      the expression of function- and stress-related proteins during the development of
      the retina of the C57BL/6J mouse. Retinas from mice aged P(postnatal day)4 to P63
      (adult) were examined for cell death using the TUNEL technique, and for the
      expression of basic fibroblast growth factor (bFGF), cytochrome oxidase (CO), rod
      opsin and glial fibrillary acidic protein (GFAP), using immunocytochemistry. At
      P4, cell death is most prominent in the inner layers of retina, declining to near
      zero levels by P16. Cell death among photoreceptors occurs in a discrete wave
      commencing at approximately P12 and remaining elevated into the 4th postnatal
      week, beginning, peaking and declining later than in inner retina. The onset of
      photoreceptor death correlates with the expression of function-related molecules,
      such as CO and opsin. The decline in photoreceptor death correlates with the
      expression of the protective factor bFGF in photoreceptors. At the anterior edge
      of the retina photoreceptor death and the expression of bFGF are accelerated, and
      the expression of bFGF and GFAP is upregulated, by an edge-specific stress. We
      conclude that in the mouse photoreceptors undergo a wave of death which culls the
      neonatal population to adult levels. The onset of photoreceptor death is related
      to the acceleration of photoreceptor metabolism and function between P12 and P20.
      The decline of photoreceptor death to the very low levels found in the adult may
      be mediated by the upregulation of protective factors such as bFGF. Photoreceptor
      death and the expression of bFGF and GFAP at the edge of the retina are regulated
      by a still-unidentified, edge-specific stress, from as early as P16.

PMID- 12470973
TI  - Regulation by oxygen of photoreceptor death in the developing and adult C57BL/6J
      mouse.
AB  - We have examined the role of tissue oxygen in the regulation of photoreceptor
      death in the C57BL/6J mouse. Litters of C57BL/6J mice were raised in dim cyclic
      (12 hr dark, 12 hr 50 lx) light. Adults or litters aged P7 or P8 were placed with
      their mothers in plexiglass chambers in which oxygen levels were set at 21%
      (normoxic), 10 or 11% (hypoxic) or 70% (hyperoxic) for up to 22 days. At
      intervals after introduction to these chambers, retinas were examined for cell
      death, using the TUNEL technique. Hypoxia accelerated cell death up to five-fold
      during a critical developmental period from approximately P12 to 18. Thereafter
      hypoxia-induced cell death declined rapidly. Hyperoxia slowed photoreceptor death
      over the same period, to approximately half control levels. At the anterior edge
      of the developing retina the effects of hypoxia and hyperoxia differed markedly
      from the rest of the retina. In the adult, hypoxia accelerated photoreceptor
      death, but the acceleration was an order of magnitude weaker than during the
      critical period of developing retina. Hypoxia-induced photoreceptor death
      remained above control levels after 20 days exposure. Results suggest that the
      naturally occurring wave of photoreceptor death seen in developing mouse retina
      during their development (P12-P20) is regulated by a physiological episode of
      hypoxia. After P20, photoreceptor vulnerability to hypoxia falls to a low but
      significant level. The edge of the retina appears subject to chronic hyperoxic
      stress from P14 into adulthood. Tissue oxygen levels are important determinants
      of photoreceptor death and survival in both developing and adult retina.

PMID- 12470974
TI  - Visualization of sigma1 receptors in eyes by ex vivo autoradiography and in vivo
      positron emission tomography.
AB  - Sigma receptors are present on the neurons of the central nervous system and in
      peripheral organs. They have also been demonstrated in ocular tissues by in vitro
      membrane binding assays. We have investigated whether sigma(1) receptors can be
      demonstrated in rat eyes by ex vivo autoradiography using [(11)C]SA4503, a
      selective radioligand. We also tested whether in vivo positron emission
      tomography (PET) can be used to show sigma(1) receptors in rabbit eyes. In rats,
      a high accumulation of [(11)C]SA4503 was found in the iris-ciliary body and
      retina. A carrier-loading experiment showed that the receptor-specific binding of
      [(11)C]SA4503 was approximately 75% of the total binding in the brain. Sigma(1)
      receptors were also detected in the projecting terminals of the retina to the
      superior colliculus. PET showed radioactivity in the anterior segment including
      the iris-ciliary body and retina, and pretreatment or displacement by a sigma
      receptor ligand (haloperidol), suggested that the PET signal reflects radioligand
      receptor binding. The high density of sigma(1) receptors in the iris-ciliary body
      and retina was confirmed by ex vivo autoradiography. In conclusion, the iris
      ciliary body and retina are rich in sigma(1) receptors, and PET may be used to
      investigate the in vivo distribution of these neuroreceptors in the eye.

PMID- 12470975
TI  - Histology, histochemistry and fine structure of the lacrimal and nictitans gland
      in the South American armadillo Chaetophractus villosus (Xenarthra, Mammalia).
AB  - The anatomical, histological, histochemical and ultrastructural characteristics
      of the lacrimal gland (LG) and nictitans gland (NG) of the armadillo
      Chaetophractus villosus were described. The histochemical and histological
      features of both glands in male and female adult animals were compared. The
      tissues were processed with conventional techniques for light and transmission
      electron microscopy. Fixed specimens were submitted to a battery of tests for
      glycans, glycosaminglycans, glycoconjugates, proteins, and lipids. The LG of the
      armadillo may be considered within the set of glandulae lacrimales superior in
      which primates, carnivores, perisodactyls and artiodactyls are included. The
      localization of the NG was similar to that of other mammals. Lacrimal and NG were
      histologically and histochemically identical. The secretory endpieces consisted
      of three cell types: (1) Mucous cells (MC) with different types of mucous
      secretory granules with neutral and sialic acid-containing glycoconjugates (GCs).
      (2)Seromucous cells (SMC) showing a variety of moderately electron dense
      secretory granules with flocculent material with carboxylated acidic, neutral,
      and sialic acid-containing GCs. Intercellular canaliculi with junctional
      complexes and basolateral intercellular spaces were frequent. (3) Serous cells
      (SC) with electron dense secretory granules. Histochemically, they showed the
      strongest reaction for proteins and neutral, weakly acid and carboxylated acidic
      GCs. The epithelium of the intra- and inter-lobular excretory ducts showed
      secretory activity, junctional complexes, and wide basolateral intercellular
      spaces with lateral folds. The endpieces and ducts were surrounded by
      myoepithelial cells. The stroma was characterized by fenestrated endothelium,
      unmyelinated axons, and abundant plasma cells. MC, SMC, and the duct system were
      richly innervated by hypolemmal nerve terminals.

PMID- 12470977
TI  - The Harderian gland in diabetic sand rats (Psammomys obesus) a light microscopic
      study.
AB  - The purpose of this study was to examine the long-term effects of synthetic diet
      on the sand rat Harderian gland. From the third month, animals showed a diabetic
      syndrome characterized histologically by Harderian gland necrotic changes. Some
      gland tubules and melanocytes were disintegrated and numerous mast cells were
      densely populated in the connective capsule of the gland. Moreover, luminal
      porphyrin accretions and cellular debris were often associated with alcian blue
      positive materials. If the synthetic diet lasted more than 6 months, the gland
      was strongly damaged and numerous plasma cells, macrophages, and lymphocytes
      infiltrated the gland. These results clearly demonstrate that the sand rat
      Harderian gland is affected by the diabetic syndrome induced by the synthetic
      diet.

PMID- 12470976
TI  - Genetic analysis of Nakano Cataract and its modifier genes in mice.
AB  - The Nakano Cataract (NCT) is an autosomal, recessive, single gene mutation in
      mice leading to an osmotic cataract induced by an endogenous inhibitor of Na, K
      ATPase. In this report, we further refined the map position of the mutant locus
      to a <0.7c M segment between D16Mit5 and D16Mit185 in 1,000 BALB/c-nct/nct
      x(BALB/c- nct/nctxMSM)F1 backcrossed mice with PCR-based microsatellite analysis.
      The NCT in the original Nakano mice developed at 3 weeks of age, rapidly formed a
      pin-head type dense opacity, whereas the cataract in the congenic BALB/c- nct/nct
      mice developed at 5-6 weeks of age or later, slowly formed a diffuse opacity. A
      major histological difference was the presence or absence of heavy condensation
      of the lens nucleus. These two types of cataract were segregated in the
      backcrossed mice. Linkage analysis of the two subtypes among the backcrossed mice
      revealed two recessive BALB/c-derived modifier genes on chromosome 3 and 10.

PMID- 12470979
TI  - Controversies in the adjuvant systemic therapy of endocrine-non-responsive breast
      cancer.
AB  - Treatment of breast cancer requires a fully integrated multidisciplinary
      management as well as an ongoing dialogue with laboratory scientists. The growing
      amount of data generated by randomized clinical trials need to be interpreted by
      the clinicians and discussed with patients, so that treatment decisions might be
      better individualized. In early breast cancer, three consensus panels have been
      developed to help with this task: the Early Breast Cancer Trialists Collaborative
      Group or Oxford Overview, the NIH Consensus Conference on Adjuvant Therapy for
      Breast Cancer and the St. Gallen International Consensus Panel on the Treatment
      of Primary Breast Cancer. Nevertheless, even these panels leave us with a good
      deal of uncertainty about the optimal adjuvant systemic treatment of the disease,
      especially when it is classified as "endocrine non-responsive". The two most
      problematic issues regarding the management of endocrine non-responsive breast
      cancer are: (1) which fit woman should not be treated, with two major "to treat
      or not to treat" dilemmas, (a) women above 70 years of age, where available
      evidence is scant and co-morbid conditions more often come into the equation of
      benefit/risk, and (b) women who have very small invasive tumours (<1 cm); and (2)
      what is the optimal chemotherapy regimen (type, doses, schedule, timing and
      duration). The aim of this review is to examine these controversial issues. Two
      difficult clinical cases, which are representative of those frequently
      encountered in daily practice, will also be presented and discussed, with the
      help of a panel of 48 breast cancer experts from different regions of the world.

PMID- 12470980
TI  - DNA-based drug interactions of cisplatin.
AB  - The interactions of cisplatin with other anti-cancer agents on the DNA level have
      been studied extensively in pre-clinical experiments. In general, combination of
      cisplatin with an antimetabolite, taxane, or topoisomerase inhibitor, can result
      in a modulation of platinum pharmacology on the DNA, for example, enhanced
      retention of the platinum-DNA adducts. These interactions are mostly sequence and
      cell type dependent. In cell line models, antimetabolites can enhance the number
      of platinum-DNA adducts, probably by inhibition of DNA repair pathways. However,
      in clinical trials, the opposite effect has been observed, with a reduction of
      these adducts upon combined treatment. For the taxanes it has been shown that
      they can inhibit the formation of platinum-DNA adducts, whereas topoisomerase I
      inhibitors increase the number of adducts, resulting in strong synergistic
      cytotoxicity. For this last interaction a mechanistic model has recently been
      proposed, in which the topoisomerase I enzyme directly binds to the platinum-DNA
      adduct. Thereafter, the topoisomerase I inhibitor binds to this complex, which
      yields large stabilised lesions to the DNA that are probably difficult to repair.
      Ongoing studies will proceed to elucidate the exact mechanism underlying the
      interactions between cisplatin and other anti-neoplastic agents on the DNA level.
      Such increased understanding might help in designing new and more effective
      treatment regimens for cancer. In this paper, we review the pre-clinical and
      clinical studies investigating the observed interactions between cisplatin, the
      antimetabolites, taxanes, and topoisomerase inhibitors on the DNA level.

PMID- 12470981
TI  - The anti-tumour activity of bisphosphonates.
AB  - Bisphosphonates are stable analogues of pyrophosphate (PPi), an endogenous
      regulator of bone mineralisation. A number of placebo-controlled trials have
      demonstrated their positive impact on skeletal-related events (SRE) that occur as
      a consequence of metastatic or myelomatous bone disease. Based upon their
      chemical structure bisphosphonates can be classified into nitrogen-containing
      bisphosphonates, (N-bisphosphonates) (for example zoledronate and pamidronate)
      and non-nitrogen containing (for example, clodronate and etidronate), which more
      closely resemble PPi. Clinical trials investigating bisphosphonates in the
      preventative setting have shown bisphosphonates to not only delay occurrence of
      bone metastases in certain cancers, but in one trial, occurrence of non-osseous
      lesions was delayed, and survival was prolonged. Other trials however have shown
      the opposite. Likewise, in animal models of cancer and metastases, conflicting
      results have been obtained. In vitro work has concentrated on bisphosphonates
      direct action upon tumour cells and has found a variety of anti-tumour effects
      such as apoptosis induction, inhibition of cell growth, inhibition of invasive
      behaviour and inhibition of angiogenic factors. Furthermore it would appear that
      bisphosphonates have the potential to enhance anti-tumour activity of known
      cytotoxic drugs. Ongoing research aims to assess this further, in addition to
      determining more precisely the role of adjuvant bisphosphonates in cancers such
      as breast and prostate cancer.

PMID- 12470982
TI  - Management of the menopause in cancer survivors.
AB  - The consequences of premature menopause are of great importance to cancer
      survivors. Oestrogen replacement therapy (with and without added progestins) is
      the most extensively researched agent for the treatment and prevention of
      menopausal problems. While this may be appropriate for symptom control in
      patients with tumours that are not hormone responsive, patients with hormone
      dependent tumours will require safe and effective alternative treatments for
      menopausal symptoms. This paper will discuss both the short-term and long-term
      consequences of the menopause in cancer survivors and will also offer various
      management strategies.

PMID- 12470983
TI  - Cancer vaccination progress.
AB  - The application of 'new' and 'recognized' tumour antigens in vaccination
      strategies that target CD8(+) and CD4(+) T-cell responses, and the mechanisms by
      which these and other effector cells are activated or respond, were discussed at
      the second 'Progress in Vaccination Against Cancer' meeting, held at the
      Nottingham Trent Djanogly Conference Centre, Nottingham, UK, from 18-20 July
      2002.

PMID- 12470986
TI  - Double jeopardy: Ras and CDK4 co-expression in skin cancer.

PMID- 12470987
TI  - Genetic clues to understanding periodic fevers, and possible therapies.
AB  - Significant breakthroughs in our understanding of the molecular basis of the
      inflammatory response have been achieved in the past five years, with the
      successive identification of the genetic basis of all known hereditary periodic
      fever syndromes. Impaired cytokine recognition and defective signalling molecules
      have been implicated in the inception of recurrent attacks of fever with acute
      phase protein response. Disorders of interleukin-1 processing and of regulation
      of nuclear factor kappaB transcription factor, and possibly defective apoptosis,
      might be involved in the pathogenesis of all but one of these disorders.
      Mutations in genes of both the pyrin and tumour-necrosis-factor-receptor
      superfamilies are postulated to lead to the survival of leukocytes that would
      ordinarily undergo apoptosis, and ultimately to a prolonged inflammatory
      response. Improved therapies have reduced the incidence of systemic amyloidosis,
      but this complication remains the most frequent cause of death.

PMID- 12470988
TI  - Tau gene mutations: dissecting the pathogenesis of FTDP-17.
AB  - Tau is a microtubule-associated protein involved in microtubule assembly and
      stabilization. Abnormal filamentous tau deposits constitute a major defining
      characteristic of several neurodegenerative diseases, including Alzheimer's
      disease. Although the presence of tau pathology correlates with the symptoms of
      Alzheimer's disease, there was no genetic evidence linking tau to
      neurodegeneration until recently. However, since 1998, the identification of more
      than 25 mutations in the tau gene, associated with frontotemporal dementia and
      parkinsonism linked to chromosome 17, has demonstrated that tau dysfunction can
      lead to neurodegeneration and the development of clinical symptoms.

PMID- 12470989
TI  - Probing the structural and molecular diversity of tumor vasculature.
AB  - The molecular diversity of the vasculature provides a rational basis for
      developing targeted diagnostics and therapeutics for cancer. Targeted imaging
      agents would offer better localization of primary tumors and metastases, and
      targeted therapies would improve efficacy and reduce side effects. The
      development of targeted pharmaceuticals requires the identification of specific
      ligand-receptor pairs, and knowledge of their cellular distribution and
      accessibility. Using in vivo phage display, a technique by which we can identify
      organ-specific and disease-specific proteins expressed on the endothelial
      surface, it is now possible to decipher the molecular signature of blood vessels
      in normal and diseased tissues. These studies have already led to the
      identification of peptides that target the normal vasculature of the brain,
      kidney, pancreas, lung and skin, as well as the abnormal vasculature of tumors,
      arthritis and atherosclerosis. Membrane dipeptidase in the lungs, interleukin-11
      receptor in the prostate, and aminopeptidase N in tumors are examples of
      molecular targets on blood vessels. Corresponding confocal-microscopic imaging
      and ultrastructural studies are providing a more complete understanding of the
      cellular abnormalities of tumor blood vessels, and the distribution and
      accessibility of potential targets. The combined approach offers a strategy for
      creating a ligand-receptor map of the human vasculature, and forms a foundation
      for the development and application of targeted therapies in cancer and other
      diseases.

PMID- 12470990
TI  - The relationship between the roles of BRCA genes in DNA repair and cancer
      predisposition.
AB  - The proteins encoded by the breast-cancer-susceptibility genes, BRCA1 and BRCA2,
      have recently been implicated in DNA-repair processes, thereby improving our
      understanding of how the loss of these genes contributes to cancer initiation and
      progression. It appears that the role of BRCA1 in DNA repair, which could involve
      the integration of several pathways, is broader than that of BRCA2. BRCA1
      functions in the signalling of DNA damage and its repair by homologous
      recombination, nucleotide-excision repair and possibly non-homologous end
      joining. BRCA2 has a more specific role in DNA repair, regulating the activity of
      RAD51, which is required for homologous recombination. An improved understanding
      of the interactions of BRCA1 and BRCA2 with other proteins in large
      macromolecular complexes is helping to reveal their exact role in DNA repair.

PMID- 12470991
TI  - Translational control of gene expression and disease.
AB  - In the past decade, translational control has been shown to be crucial in the
      regulation of gene expression. Research in this field has progressed rapidly,
      revealing new control mechanisms and adding constantly to the list of
      translationally regulated genes. There is accumulating evidence that
      translational control plays a primary role in cell-cycle progression and cell
      differentiation, as well as in the induction of specific cellular functions.
      Recently, the aetiologies of several human diseases have been linked with
      mutations in genes of the translational control machinery, highlighting the
      significance of this regulatory mechanism. In addition, deregulation of
      translation is associated with a wide range of cancers. Current research focuses
      on novel therapeutic strategies that target translational control, a promising
      concept in the treatment of human diseases.

PMID- 12470992
TI  - Urea-cycle disorders as a paradigm for inborn errors of hepatocyte metabolism.
AB  - Urea-cycle disorders (UCDs) are a group of inborn errors of hepatocyte metabolism
      that are caused by the loss of enzymes involved in the process of transferring
      nitrogen from ammonia to urea, via the urea cycle (UC). Recent genetic analyses
      of inherited disorders that present with hyperammonemia demonstrate the function
      of cellular transporters that regulate the availability of UC intermediates. The
      regulation of UC intermediates, such as arginine, could have far reaching
      implications on nitric-oxide synthesis and vascular tone. Hence, each UCD and UC
      related disorder constitutes a unique gene-nutrient interaction that is crucial
      for postnatal homeostasis. Recent advances in the diagnosis and management of
      UCDs include the application of in vivo metabolic-flux measurements. Cumulative
      morbidity is still high despite dietary and pharmacological therapies and, hence,
      both cell and gene therapies are being pursued as possible long-term corrective
      treatments. Although gene-replacement therapy has suffered recent clinical
      setbacks, new vector developments offer hope for the treatment of cell-autonomous
      defects of hepatocyte metabolism.

PMID- 12470993
TI  - Hirano bodies in health and disease.

PMID- 12470995
TI  - Surgery for haemorrhoids: ablation or correction.

PMID- 12470997
TI  - Liver transplantation in Asia--challenges and opportunities.

PMID- 12470996
TI  - Perforated peptic ulcer: open versus laparoscopic repair.

PMID- 12470998
TI  - Liver transplantation for hepatocellular carcinoma: an Asian perspective.
AB  - Liver transplantation is an established treatment modality for patients with
      hepatocellular carcinoma (HCC), creating a potential for disease-free, long-term
      survival. In Asia, due to a severe shortage of donors, resection remains the
      treatment of choice for patients with HCC and good liver functional reserve. The
      use of marginal donors, split liver grafts and grafts from living donors are
      potential solutions that are best performed in experienced liver transplant
      centres to ensure an optimal outcome. Ethical issues relating to living donor
      liver transplantation have yet to be fully addressed. The roles of therapies to
      limit tumour progression during the waiting period, such as transarterial
      chemoembolization, need to be further investigated in the setting of a
      prospective trial and their benefits better defined.

PMID- 12470999
TI  - Adult-to-adult living donor liver transplantation at the Asan Medical Center,
      Korea.
AB  - Between February 1997 and December 2001, 311 adult-to-adult living donor liver
      transplants (A-A LDLTs) were performed at the Asan Medical Center for patients
      above 20 years of age. Indications for A-A LDLT were: chronic hepatitis B (203),
      chronic hepatitis C (5), hepatocellular carcinoma (64), alcoholic cirrhosis (9),
      cryptogenic cirrhosis (4), secondary biliary cirrhosis (5), primary biliary
      cirrhosis (1), Wilson' s disease (2), autoimmune hepatitis (1), hepatic
      tuberculosis (1), cholangiocarcinoma (1), fulminant hepatic failure (14) and
      primary non-function of cadaveric liver graft (1). Of 311 A-A LDLTs, 36 were of
      medical high urgency, 20 were for acute and subacute hepatic failure, 15 were for
      hepato-renal syndrome and 1 was for primary non-function. Recipient age ranged
      from 27 to 64 years. Donor age ranged from 16 to 62 years. There was no donor
      mortality. Implanted liver grafts were categorized into seven types: 175 modified
      right lobe (MRL), 70 left lobe, 32 right lobe, 20 dual grafts, 10 left lobe plus
      caudate lobe, three extended right lobe and one posterior segment. In MRL, the
      tributaries of the middle hepatic vein were reconstructed by interpositioning a
      vein graft. Indication for dual graft implantation was the same as single graft A
      A LDLT, and four of 20 were emergency cases. Of 20 dual grafts, 14 received two
      left lobes, four received a left lobe and a lateral segment, one received a right
      lobe and a left lobe and one received a lateral segment and a posterior segment.
      Graft volume ranged from 28% to 83% of the standard liver volume of the
      recipients. There were 33 (10.6%) in-hospital mortalities (< 4 months) among the
      310 patients after 311 A-A LDLTs. Of the 36 patients receiving emergency
      transplants, 31 survived. These encouraging results justify the expansion of A-A
      LDLT in coping with increasing demands, even in urgent situations. We have aimed
      to introduce the establishment of the efficacy of A-A LDLT in various end-stage
      chronic and acute liver diseases, as well as new technical advances to overcome
      small graft-size syndrome by using dual-graft implantation and MRL, both of which
      were first developed in our department.

PMID- 12471000
TI  - Split liver transplantation.
AB  - Greater experience and improved outcomes in liver transplantation have
      necessarily led to longer waiting lists against a constantly limited donor pool.
      Split liver transplantation has been conceived as a means to increase the supply
      of liver grafts. The bipartition of a whole liver provides grafts for two
      recipients in a complex operation with equally complex manpower and logistical
      demands. The in situ technique of splitting offers advantages over the ex vivo
      technique, although after the time-dependent learning curve is overcome, they may
      theoretically be used interchangeably with acceptable outcomes. Aside from
      surgical expertise, donor characteristics and recipient pre-transplant status are
      risk factors for survival. This review will address the salient aspects of split
      liver transplantation, summarize the world experience with this procedure and
      describe the preliminary attempts in Asia.

PMID- 12471001
TI  - Thyrotoxicosis--surgical management in the era of evidence-based medicine:
      experience in western India with 752 cases.
AB  - The three modalities of treatment of thyrotoxicosis, antithyroid therapy (ATT),
      radio-iodine (I131) therapy and surgery are not cause-specific. In this paper, we
      describe our evolving experience with 752 thyrotoxic patients who underwent
      surgery during the last 40 years and discuss the current scenario with evidence
      based data and observations wherever possible. Thyroidectomy was performed in 428
      patients with Grave's disease (GD), 299 patients with toxic multinodular goitre,
      and 25 with toxic solitary nodules (TSN). Whereas 289 patients with GD had
      surgery for failed ATT, the other 139 had primary surgery for controversial or
      debatable indications such as poor socio-economic status, desire for early
      pregnancy, poor drug compliance and severe ophthalmopathy. Preoperatively, all
      patients were administered carbimazole or propylthiouracil. Non-selective b
      blocker propranolol and Lugol's iodine were routinely given. In the 25 patients
      with TSN, hemithyroidectomy was performed. In all others, subtotal thyroidectomy
      (STT), was performed leaving behind 4 to 8 g of thyroid tissue: a larger amount
      was left behind in those with higher antithyroid antibody titres. During the last
      decade, 80 patients received near total thyroidectomy (NTT), mainly to minimize
      recurrence of thyrotoxicosis and to ameliorate severe eye signs. Because of our
      increasing experience, no significant increase in postoperative morbidity was
      encountered with NTT compared to STT. Transient hoarseness was observed in 53
      patients with STT and only in two patients with NTT. Three patients with STT and
      one with NTT developed permanent hoarseness due to recurrent laryngeal nerve
      palsy; voice in these four was normalized by intraglottic injection of Teflon
      paste 6 months after the operation. In patients undergoing STT, transient
      hypoparathyroidism was encountered in 63, and permanent hypoparathyroidism in
      five. The corresponding figures for NTT were 12 and one, respectively. Of the 500
      patients monitored for 1 year or more, hypothyroidism was observed in 135 and
      recurrent thyrotoxicosis in nine. In the same group of 500, exophthalmos was
      ameliorated in 130 of the 265 with positive eye signs. Nineteen glands exhibited
      features of severe Hashitoxicosis with marked destruction of acini and
      considerable lymphoid aggregates and follicles. Carcinoma was observed in three
      other thyroid glands.

PMID- 12471002
TI  - A descriptive study of papillary thyroid carcinoma in a teaching hospital in
      Chennai, India.
AB  - OBJECTIVE: In the 1994 Chennai population-based cancer registry, thyroid
      carcinoma constituted 1% and 2% of all incident cancers among males and females,
      respectively. The aim of our study was to conduct an epidemiological survey of
      the pattern of papillary thyroid carcinoma in the Chennai Government General
      Hospital and the Chennai Cancer Institute. METHODS: Our data base included a
      total of 264 (58 males and 206 females) consecutive cases of papillary thyroid
      carcinoma admitted to the Government General Hospital and 164 (42 males and 122
      females) cases from the Chennai Cancer Institute. RESULTS: There was a female
      preponderance (100 males and 328 females) (p < 0.001). The median age at
      diagnosis was 39 years among males and 32 years among females. The distribution
      of cases by residential area lay scattered from < 1 km to > 100 km, with the
      majority (28%) from the city of Chennai and its suburbs in the Government General
      Hospital, while 52% of the cases in the cancer institute were from the
      neighbouring state. Iodine intake was present in 75% of cases (p < 0.001). The
      diagnosis of thyroid cancer was confirmed by fine needle aspiration cytology in
      most (88%) of the cases. The extent of disease in the Government General Hospital
      and the Cancer Institute were as follows: localized in 66% vs 32%; spread to
      surrounding structure with or without nodal involvement in 26% and 59% presence
      of only secondary nodal involvement in 3% and 1%, distant metastasis in 5% and
      8%, respectively. The primary modality of treatment was surgery with total
      thyroidectomy being performed in 82%, while the rest underwent a
      hemithyroidectomy. CONCLUSION: The cumulative life-time risk of thyroid cancer in
      Chennai was one in 970 in males and one in 565 in females. High dietary intake of
      iodine was the most significant risk factor for the etiology of papillary thyroid
      carcinoma in our study.

PMID- 12471003
TI  - Type IV collagen, type IV collagenase activity and ability of cell proliferation
      in human thyroid tumours.
AB  - BACKGROUND: The processes of malignant tumour invasion and metastasis are known
      to include the destruction of cell stroma and vascular basement membrane. It has
      been suggested that type IV collagenase degrades type IV collagen, a main
      component of the basement membrane. METHODS: In our study, type IV collagenase
      activity in human thyroid tumours was measured by the Liotta method. The degree
      of destruction of diseased regions of thyroid tumours was immunohistochemically
      determined by anti-type IV collagen antibody staining. Cell proliferation in the
      tumours was estimated using anti-proliferating cell nuclear antigen (PCNA) and
      epidermal growth factor receptor (EGFR). RESULTS: T4 thyroid carcinomas with
      higher type IV collagenase activity and very weak type IV discontinuous
      immunostaining for type IV collagen of follicular basement membranes, exhibited
      many PCNA or EGFR positive cells. In benign tumours, normofollicular- or
      macrofollicular-type tumours with low type IV collagenase activity showed few
      PCNA and EGFR positive cells and intact type IV collagen of basement membranes,
      as seen in normal thyroids. Conversely, an atypical adenoma with higher type IV
      collagenase activity showed many PCNA and EGFR positive cells and weak type IV
      discontinuous immunostaining for type IV collagen, as in thyroid carcinomas.
      CONCLUSION: These findings suggest that staining for type IV collagen and type IV
      collagenase activity reflect the ability of cell proliferation, and help predict
      the aggressiveness of invasion and metastasis in human thyroid tumours.

PMID- 12471004
TI  - Prophylactic antiemetic efficacy of granisetron or ramosetron in patients
      undergoing thyroidectomy.
AB  - OBJECTIVE: Thyroidectomy is associated with a high incidence of postoperative
      nausea and vomiting (PONV), ranging from 60% to 84%. We conducted this study to
      compare the antiemetic effects and safety of granisetron 20 micro g/kg and
      ramosetron 4 micro g/kg in patients undergoing elective thyroidectomy under
      standard anaesthetic technique. METHODS: One hundred and thirteen patients were
      randomized to receive placebo (n = 41), granisetron 20 nug/kg (n = 36) or
      ramosetron 4 micro g/kg (n = 36) intravenously over 2-5 minutes immediately
      before the induction of anaesthesia. The incidence of PONV, nausea severity score
      (NSS), adverse events and the need for rescue antiemetics were assessed during
      the first 1 hour (0-1 h) and following 23 hours (1-24 h) after anaesthesia.
      RESULTS: During the first hour after anaesthesia, the incidence of PONV was 36.6%
      for placebo, 11.1% for granisetron (p = 0.012 vs placebo) and 25.0% for
      ramosetron. During 1 hour to 23 hours after anaesthesia, the incidence of PONV
      was 51.2% for placebo, 30.6% for granisetron and 41.7% for ramosetron. There were
      no significant differences between the three groups. Overall (0-24 h), the
      corresponding incidence of PONV were 61.0%, 30.6% and 50.0%, respectively,
      showing a significantly lower value in the granisetron group than in the placebo
      group (p = 0.008). The incidence of vomiting and rescue antiemetic requirement
      during the first 24 hours after anaesthesia was significantly lower with the
      granisetron group than with placebo (p = 0.021 and 0.030, respectively). The most
      common adverse events in the three groups were headache and dizziness.
      CONCLUSION: Only granisetron 20 micro g/kg was superior to placebo for the
      prevention of PONV after thyroidectomy.

PMID- 12471005
TI  - Video-assisted thyroidectomy.
AB  - OBJECTIVE: In 1998, we developed a technique for video-assisted thyroidectomy
      (VAT). In this paper, we report on the entire series of patients who underwent
      VAT and discuss the results obtained. METHODS: Seventy-three patients were
      selected for VAT. Eligibility criteria were: thyroid nodules </=35 mm in maximum
      diameter; estimated thyroid volume within normal range or slightly enlarged;
      small, low-risk papillary carcinomas; no previous neck surgery or irradiation and
      no thyroiditis. The VAT procedure was totally gasless. It was performed under
      endoscopic vision through a single 1.5 to 2.0-cm skin incision, using a technique
      very similar to conventional surgery. RESULTS: Eighty-one VATs were attempted on
      73 patients. Forty-five lobectomies, 24 total thyroidectomies and eight
      completion thyroidectomies were successfully performed. Mean operative time was
      82 minutes for lobectomy, 100 minutes for total thyroidectomy and 77 minutes for
      completion thyroidectomy. The conversion rate was 4.9%. Postoperative
      complications included two transient recurrent nerve palsies, five transient
      symptomatic postoperative hypocalcaemias and one wound infection. The cosmetic
      result was considered excellent by most of the patients. CONCLUSION: VAT is a
      feasible and and safe procedure that allows for excellent cosmetic results. In
      selected cases, it can be a valid option for the surgical treatment of thyroid
      diseases.

PMID- 12471006
TI  - Evidence-based protocols for the management of well-differentiated carcinomas of
      the thyroid.
AB  - OBJECTIVES: In recent years, well-differentiated carcinomas of the thyroid have
      been stratified into low-risk and high-risk groups. The pattern of thyroid cancer
      in India is different from that seen in the West. Moreover, patients present with
      more advanced stages of the disease. Our aim was to develop protocols for the
      management of well-differentiated thyroid cancer, based on the analysis of our
      data and our experience. METHODS: Cases of thyroid carcinoma, which were
      surgically treated at the Tata Memorial Hospital during 1970-5, were studied. The
      survival curves were plotted according to the Kaplan-Meier method. Univariate
      analysis was done using the log rank test. The prognostic factors analyzed were
      age, sex, tumour size, extra-thyroid extension, distant metastases and lymph node
      metastases. Multivariate analysis using the Cox regression model was performed.
      Analyses were separate for follicular and papillary carcinomas. RESULTS: Four
      hundred and seventeen cases were entered in the study, of which 198 were
      follicular and 219 were papillary. Based on the evidence derived from this study,
      we stratified our cases into low- and high-risk groups. The low-risk group
      consisted of patients below 40 years of age, nodules smaller than 5 cm, absence
      of extra-thyroidal spread and absence of distant metastases. For follicular
      carcinoma, the low-risk group had 100% survival at 15 years, compared with 40%
      for the high-risk group. (p < 0.001). For papillary carcinomas, the survival at
      15 years was 95% for the low-risk group and 40% for the high-risk group (p <
      0.001). CONCLUSIONS: We recommend lobectomy for the low-risk group, and total
      thyroidectomy for the high-risk group and for cases with lymph node metastases.
      In the latter, total thyroidectomy facilitates the use of 131I.

PMID- 12471007
TI  - Prognostic factors for well-differentiated thyroid cancer in an endemic area.
AB  - A retrospective analysis of 215 differentiated thyroid cancers was undertaken to
      identify the various prognostic variables. There were 132 papillary and 83
      follicular cancers; both histologic types occurred at an earlier age, with a male
      to female ratio of 1: 1.1 (signifies near parity in both sexes, in contrast to
      marked female preponderance in most of the reports and amongst benign thyroid
      disorders). There was a significant difference in the size of the primary
      tumours; 60/132 (45%) of papillary and 30/83 (36%) of follicular cancers were
      early T0-1 lesions and 20 (15%) papillary and 24 (29%) follicular cancers were
      advanced T3 lesions. Age did not affect the size of the primary tumour. Regional
      lymph node and pulmonary metastases were common in both types of cancer while
      distant metastases occurred more frequently in follicular cancers (p < 0.005).
      Following surgery, contralateral lobe recurrence in the remaining lobe was more
      common in the follicular cancer group, while loco-regional recurrence after near
      total thyroidectomy was more frequent in the papillary cancer group (p > 0.05).
      Mortality in 26/132 (20%) papillary and 28/83 (34%) follicular cancer patients
      was high in both groups, but significantly higher in the follicular cancer group
      (p < 0.05). Although mortality among patients with papillary cancer was higher in
      patients older than 40 years of age (p < 0.05), age did not affect survival in
      patients with follicular cancer. Gender did not affect survival in either group.
      The extent of the disease at presentation was the most important determinant of
      survival, with mortality significantly higher among patients with T3N3M1 lesions
      (p < 0.001).

PMID- 12471008
TI  - Comparison of laparoscopic and open adrenalectomy--a Singapore experience.
AB  - OBJECTIVE: We present our experience with laparoscopic adrenalectomy for benign
      adrenal diseases and compare clinical outcomes with the conventional open
      approach. METHODS: Between 1990 and 2001, two consecutive series of patients who
      underwent adrenalectomy for small, benign adrenal diseases were reviewed
      retrospectively. Patients with large tumours(> 7 cm), cancer and
      phaeochromocytoma were excluded. Fifty-eight patients underwent laparoscopic
      adrenalectomy and 48 patients had open surgery for benign adrenal diseases.
      Perioperative and postoperative records of both approaches were reviewed.
      RESULTS: The two groups were comparable in terms of patient age, sex, weight and
      side of lesion.The common indications for surgery were Conn's syndrome and
      Cushing's syndrome. The sizes of tumour were comparable between the laparoscopic
      and open groups (mean, 2.1 cm vs 2.4 cm). Despite the longer operating time
      (mean, 128 minutes vs 87 minutes), the postoperative morbidity, parenteral
      analgesic requirement and length of postoperative hospital stay (3.2 days vs 7.2
      days) were less inpatients undergoing laparoscopic adrenalectomy. Patients also
      enjoyed earlier return to oral intake and ambulation. There were fewer
      complications in the laparoscopic group. There was no conversion to open surgery.
      CONCLUSION: Laparoscopic adrenalectomy is safe and has become the treatment of
      choice for small, benign adrenal lesions at our institution.

PMID- 12471010
TI  - Reconstruction challenge--combined use of pectoralis major and gastric pull-up
      flaps for massive naso-oropharyngeal/oesophageal defects.
AB  - Massive defects of the upper aerodigestive tract present a reconstructive
      challenge. We report a case in which a large defect of the naso-oropharyngeal and
      oesophagus was reconstructed with a combination of a gastric pull-up and a
      pectoralis major muscle flap. Postoperative function was good and survival was in
      excess of 16 months. The history of such reconstructions and possible alternative
      techniques are also discussed.

PMID- 12471011
TI  - Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase.
AB  - The lung contains two distinct forms of phosphatidic acid phosphatase (PAP). PAP1
      is a cytosolic enzyme that is activated through fatty acid-induced translocation
      to the endoplasmic reticulum, where it converts phosphatidic acid (PA) to
      diacylglycerol (DAG) for the biosynthesis of phospholipids and neutral lipids.
      PAP1 is Mg(2+) dependent and sulfhydryl reagent sensitive. PAP2 is a six
      transmembrane-domain integral protein localized to the plasma membrane. Because
      PAP2 degrades sphingosine-1-phosphate (S1P) and ceramide-1-phosphate in addition
      to PA and lyso-PA, it has been renamed lipid phosphate phosphohydrolase (LPP).
      LPP is Mg(2+) independent and sulfhydryl reagent insensitive. This review
      describes LPP isoforms found in the lung and their location in signaling
      platforms (rafts/caveolae). Pulmonary LPPs likely function in the phospholipase D
      pathway, thereby controlling surfactant secretion. Through lowering the levels of
      lyso-PA and S1P, which serve as agonists for endothelial differentiation gene
      receptors, LPPs regulate cell division, differentiation, apoptosis, and mobility.
      LPP activity could also influence transdifferentiation of alveolar type II to
      type I cells. It is considered likely that these lipid phosphohydrolases have
      critical roles in lung morphogenesis and in acute lung injury and repair.

PMID- 12471012
TI  - The paradox of reactive oxygen species: injury, signaling, or both?

PMID- 12471013
TI  - Coordinate regulation of membrane cAMP by Ca2+-inhibited adenylyl cyclase and
      phosphodiesterase activities.
AB  - Activation of store-operated Ca(2+) entry inhibits type 6 adenylyl cyclase (EC;
      AC(6); Yoshimura M and Cooper DM. Proc Natl Acad Sci USA 89: 6712-6720, 1992)
      activity in pulmonary artery endothelial cells. However, in lung microvascular
      endothelial cells (PMVEC), which express AC(6) and turn over cAMP at a rapid
      rate, inhibition of global (whole cell) cAMP is not resolved after direct
      activation of store-operated Ca(2+) entry using thapsigargin. Present studies
      sought to determine whether the high constitutive phosphodiesterase activity in
      PMVECs rapidly hydrolyzes cAMP so that Ca(2+) inhibition of AC(6) is difficult to
      resolve. Direct stimulation of adenylyl cyclase using forskolin and inhibition of
      type 4 phosphodiesterases using rolipram increased cAMP and revealed Ca(2+)
      inhibition of AC(6). Enzyme activity was assessed using PMVEC membranes, where
      Ca(2+) and cAMP concentrations were independently controlled. Endogenous AC(6)
      activity exhibited high- and low-affinity Ca(2+) inhibition, similar to that
      observed in C6-2B cells, which predominantly express AC(6). Ca(2+) inhibition of
      AC(6) in PMVEC membranes was observed after enzyme activation and inhibition of
      phosphodiesterase activity and was independent of the free cAMP concentration.
      Thus, under basal conditions, the constitutive type 4 phosphodiesterase activity
      rapidly hydrolyzes cAMP so that Ca(2+) inhibition of AC(6) is difficult to
      resolve, indicating that high phosphodiesterase activity works coordinately with
      AC(6) to regulate membrane-delimited cAMP concentrations, which is important for
      control of cell-cell apposition.

PMID- 12471014
TI  - Negative impact of DEP exposure on human airway epithelial cell adhesion,
      stiffness, and repair.
AB  - Epidemiological and experimental studies suggest that diesel exhaust particles
      (DEPs) may be associated with increased respiratory mortality and morbidity.
      Several recent studies have also shown that DEPs increase the production of
      inflammatory cytokines by human bronchial epithelium (HBE) cells in vitro. The
      present study investigates the effects of DEPs on the interaction of l-HBE cells
      (16HBE14o-) with the cell and matrix microenvironment based on evaluation of
      integrin-type cell/matrix ligand expression, cytoskeleton (CSK) stiffness, and
      matrix remodeling via matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9
      expression. The results showed that DEP exposure induced: 1) a net dose-dependent
      decrease in CSK stiffness through actin fibers, 2) a concomitant specific
      reduction of both alpha(3)- and beta(1)-integrin subunits extensively expressed
      on the HBE cell surface, 3) a decrease in the level of CD44, which is a major HBE
      cell-cell and HBE cell-matrix adhesion molecule; and 4) an isolated decrease in
      MMP-1 expression without any change in tissue inhibitor of matrix
      metalloproteinase (TIMP)-1 or TIMP-2 tissue inhibitors. Restrictive modulation of
      cell-matrix interaction, cell-cell connection, CSK stiffness, and fibrillary
      collagen remodeling results in a decreased wound closure capacity and an
      increased deadhesion capacity. In conclusion, on the basis of these results, we
      can propose that, in addition to their ability to increase the production of
      inflammatory cytokines, DEPs could also alter the links between actin CSK and the
      extracellular matrix, suggesting that they might facilitate HBE cell detachment
      in vivo.

PMID- 12471015
TI  - Quantitative analysis of albumin uptake and transport in the rat microvessel
      endothelial monolayer.
AB  - We determined the concentration dependence of albumin binding, uptake, and
      transport in confluent monolayers of cultured rat lung microvascular endothelial
      cells (RLMVEC). Transport of (125)I-albumin in RLMVEC monolayers occurred at a
      rate of 7.2 fmol. min(-1). 10(6) cells(-1). Albumin transport was inhibited by
      cell surface depletion of the 60-kDa albumin-binding glycoprotein gp60 and by
      disruption of caveolae using methyl-beta-cyclodextrin. By contrast, gp60
      activation (by means of gp60 cross-linking using primary and secondary
      antibodies) increased (125)I-albumin uptake 2.3-fold. At 37 degrees C, (125)I
      albumin uptake had a half time of 10 min and was competitively inhibited by
      unlabeled albumin (IC(50) = 1 microM). Using a two-site model, we estimated by
      Scatchard analysis the affinity (K(D)) and maximal capacity (B(max)) of albumin
      uptake to be 0.87 microM (K(D1)) and 0.47 pmol/10(6) cells (B(max1)) and 93.3
      microM (K(D2)) and 20.2 pmol/10(6) cells (B(max2)). At 4 degrees C, we also
      observed two populations of specific binding sites, with high (K(D1) = 13.5 nM,
      1% of the total) and low (K(D2) = 1.6 microM) affinity. On the basis of these
      data, we propose a model in which the two binding affinities represent the
      clustered and unclustered gp60 forms. The model predicts that fluid phase albumin
      in caveolae accounts for the bulk of albumin internalized and transported in the
      endothelial monolayer.

PMID- 12471016
TI  - Apparent normal lung architecture in protein tyrosine phosphatase-sigma-deficient
      mice.
AB  - Protein tyrosine phosphatase-sigma (PTP-sigma) is a member of the mammalian LAR
      family of phosphatases, which is characterized by a cell adhesion-like
      ectodomain, a single transmembrane segment, and two tandemly repeated
      intracellular catalytic domains. The expression of PTP-sigma is developmentally
      regulated in epithelial, neuronal, and neuroendocrine tissues. We previously
      showed that PTP-sigma is strongly expressed within the fetal, but not adult, rat
      lung and is localized to the Clara cells and type II pneumocytes. In view of the
      developmentally regulated pulmonary expression of PTP-sigma, we performed a
      detailed histological and ultrastructural study of the lungs of PTP-sigma
      knockout mice we have generated. Our findings indicate no apparent structural
      abnormalities in the lungs of PTP-sigma-/- mice, including airway and alveolar
      epithelium. In addition, pulmonary neuroendocrine cells also appear normal, in
      contrast to pituitary, pancreatic, and gastrointestinal endocrine cells, in the
      knockout mice, suggesting different developmental regulation of these
      neuroendocrine cells. These observations suggest compensation for the absence of
      PTP-sigma during development by related family member phosphatases, such as LAR.

PMID- 12471017
TI  - GM-CSF increases airway smooth muscle cell connective tissue expression by
      inducing TGF-beta receptors.
AB  - Fibrosis around the smooth muscle of asthmatic airway walls leads to irreversible
      airway obstruction. Bronchial epithelial cells release granulocyte/macrophage
      colony-stimulating factor (GM-CSF) in asthmatics and are in close proximity to
      airway smooth muscle cells (ASMC). The findings in this study demonstrate that GM
      CSF induces confluent, prolonged, serum-deprived cultures of ASMC to increase
      expression of collagen I and fibronectin. GM-CSF also induced ASMC to increase
      the expression of transforming growth factor (TGF)-beta receptors type I, II, and
      III (TbetaR-I, TbetaR-II, TbetaR-III), but had no detectable effect on the
      release of TGF-beta1 by the same ASMC. The presence of GM-CSF also induced the
      association of TGF-beta1 with TbetaR-III, which enhances binding of TGF-beta1 to
      TbetaR-II. The induction of TbetaRs was parallel to the increased induction of
      phosphorylated Smad2 (pSmad2) and connective tissue growth factor (CTGF),
      indicative of TGF-beta-mediated connective tissue synthesis. Dexamethasone
      decreased GM-CSF-induced TbetaR-I, TbetaR-II, TbetaR-III, pSmad2, CTGF, collagen
      I, and fibronectin. In conclusion, GM-CSF increases the responsiveness of ASMC to
      TGF-beta1-mediated connective tissue expression by induction of TbetaRs, which is
      inhibited by corticosteroids.

PMID- 12471018
TI  - Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm
      lambs.
AB  - Antenatal betamethasone (Beta) is widely used in women with asymptomatic
      chorioamnionitis at risk for preterm delivery, but its effects on fetal
      inflammation are unstudied. Groups of ewes at 109 +/- 1 days of gestation
      received the following treatments: intra-amniotic (IA) saline (control), 0.5
      mg/kg intramuscular Beta, 10 mg IA endotoxin (Endo), and Beta + 2 h later Endo
      (Beta + Endo). Beta suppressed Endo-induced lung inflammation at 1 day. However,
      compared with Endo 5 days after treatment, Beta + Endo lambs had increased
      alveolar neutrophils, proinflammatory cytokine mRNA expression, and serum amyloid
      A3 (SAA3) mRNA expression. IL-1beta mRNA expression was localized to the
      inflammatory cells, whereas SAA3 mRNA expression was induced in the bronchial
      epithelium and the inflammatory cells. Compared with Endo, Beta + Endo lambs had
      increased lung inflammation but equivalent lung volumes 15 days after treatment.
      The late increase in inflammation in the Beta + Endo animals suggests that
      glucocorticoids impair the ability of the preterm lung to downregulate Endo
      induced inflammation after fetal clearance of the glucocorticoids. These results
      have implications for lung inflammation and bronchopulmonary dysplasia in preterm
      infants exposed to chorioamnionitis and maternal glucocorticoids.

PMID- 12471019
TI  - Terminal structure mediates 5 S rRNA stability and integration during ribosome
      biogenesis.
AB  - Formation of the eukaryotic ribosomal 5 S RNA-protein complex has been shown to
      be critical to ribosome biogenesis and has been speculated to contribute to a
      quality control mechanism that helps ensure that only normal precursors are
      processed and assembled into active ribosomes. To study the structural basis of
      these observations, the RNA-protein interface in the 5 S RNA-protein complex of
      the yeast (Saccharomyces cerevisiae) ribosome was examined based on a systematic
      introduction of targeted base substitutions in the RNA sequence. Most base
      substitutions had little or no effect on the efficiency of complex formation, but
      large effects were observed when changes disrupted helix I, the secondary
      structure formed between the interacting termini. Again, only modest effects were
      evident when the extended 3' end of the mature RNA molecule was altered, but
      essentially no complex was formed when the 5' end of the mature 5 S RNA sequence
      was artificially extended by one nucleotide. In vitro analyses demonstrated that
      this extension also dramatically altered the maturation of 5 S rRNA precursor
      molecules as well as the stability of the mature 5 S rRNA. Taken together, the
      results indicate that in the course of RNA maturation, the 5 S RNA-binding
      protein binds precisely over or "caps" the termini in a critical manner that
      protects the RNA from further degradation.

PMID- 12471020
TI  - Cloning and characterization of the rat alpha 1a-adrenergic receptor gene
      promoter. Demonstration of cell specificity and regulation by hypoxia.
AB  - Recent studies reveal important and distinct roles for cardiac alpha(1a)
      adrenergic receptors (alpha(1a)ARs). Surprisingly, given their importance in
      myocardial ischemia/reperfusion, hypoxia, and hypertrophy as well as frequent use
      of rat cardiomyocyte model systems, the rat alpha(1a)AR gene promoter has never
      been characterized. Therefore, we isolated 3.9 kb of rat alpha(1a)AR 5'
      untranslated region and 5'-regulatory sequences and identified multiple
      transcription initiation sites. One proximal (P1) and several clustered upstream
      distal promoters (P2, P3, and P4) were delineated. Sequences surrounding both
      proximal and distal promoters lack typical TATA or CCAAT boxes but contain cis
      elements for multiple myocardium-relevant nuclear regulators including Sp1, GATA,
      and CREB, findings consistent with enhanced cardiac basal alpha(1a)AR expression
      seen in Northern blots and reporter constructs. Promoter analysis using deletion
      reporter constructs reveals, in addition to a powerful upstream enhancer, a key
      region (-558/-542) important in regulating all alpha(1a)AR promoters with hypoxic
      stress. Gel shift analysis of this 14-bp region confirms a hypoxia-induced shift
      independent of direct hypoxia-inducible factor binding. Mutational analysis of
      this sequence identifies a novel 9-bp hypoxia response element, the loss of which
      severely attenuates hypoxia-mediated repression of alpha(1a)AR transcription.
      These findings for the alpha(1a) gene should facilitate elucidation of alpha(1)AR
      mediated mechanisms involved in distinct myocardial pathologies.

PMID- 12471021
TI  - Identification of a beta-secretase activity, which truncates amyloid beta-peptide
      after its presenilin-dependent generation.
AB  - The beta-amyloid precursor protein (beta APP) is proteolytically processed by two
      secretase activities to produce the pathogenic amyloid beta-peptide (A beta). N
      terminal cleavage is mediated by beta-secretase (BACE) whereas C-terminal
      intramembraneous cleavage is exerted by the presenilin (PS) gamma-secretase
      complex. The A beta-generating gamma-secretase cleavage principally occurs after
      amino acid 40 or 42 and results in secretion of A beta-(1-40) or A beta-(1-42).
      Upon overexpression of BACE in cultured cells we unexpectedly noticed a reduction
      of secreted A beta-(1-40/42). However, mass spectrometry revealed a truncated A
      beta species, which terminates at amino acid 34 (A beta-(1-34)) suggesting an
      alternative gamma-secretase cut. Indeed, expression of a loss-of-function variant
      of PS1 inhibited not only the production of A beta-(1-40) and A beta-(1-42) but
      also that of A beta-(1-34). However, expression levels of BACE correlate with the
      amount of A beta-(1-34), and A beta-(1-34) is produced at the expense of A beta
      (1-40) and A beta-(1-42). Since this suggested that BACE is involved in a C
      terminal truncation of A beta, we incubated purified BACE with A beta-(1-40) in
      vitro. Under these conditions A beta-(1-34) was generated. Moreover, when
      conditioned media containing Abeta-(1-40) and A beta-(1-42) were incubated with
      cells expressing a loss-of-function PS1 variant together with BACE, A beta-(1-34)
      was efficiently produced in vivo. These data demonstrate that an apparently gamma
      secretase-dependent A beta derivative is produced after the generation of the non
      truncated A beta via an additional and unexpected activity of BACE.

PMID- 12471022
TI  - Probing the mechanism of a membrane transport protein with affinity inactivators.
AB  - Affinity inactivators are useful for probing catalytic mechanisms. Here we
      describe the synthesis and properties of methanethiosulfonyl (MTS) galactose or
      glucose derivatives with respect to a well studied membrane transport protein,
      the lactose permease of Escherichia coli. The MTS-galactose derivatives behave as
      affinity inactivators of a functional mutant with Ala(122)-->Cys in a background
      otherwise devoid of Cys residues. A proton electrochemical gradient
      (Deltamu(H(+))) markedly increases the rate of reaction between Cys(122) and MTS
      galactose derivatives; nonspecific labeling with the corresponding MTS-glucose
      derivatives is unaffected. When the Ala(122)-->Cys mutation is combined with a
      mutation (Cys(154)-->Gly) that blocks transport but increases binding affinity,
      discrimination between the MTS-galactose and -glucose derivatives is abolished,
      and Deltamu(H(+)) has no effect. The results provide strong confirmation that the
      non-galactosyl moiety of permease substrates abuts Ala(122) in helix IV. In
      addition, the findings demonstrate that the MTS-galactose derivatives do not
      react with the Cys residue at position 122 upon binding per se but at a
      subsequent step in the overall transport mechanism. Thus, these inactivators
      behave as unique suicide substrates.

PMID- 12471023
TI  - Fundamental cellular processes do not require vertebrate-specific sequences
      within the TATA-binding protein.
AB  - The 180-amino acid core of the TATA-binding protein (TBPcore) is conserved from
      Archae bacteria to man. Vertebrate TBPs contain, in addition, a large and highly
      conserved N-terminal region that is not found in other phyla. We have generated a
      line of mice in which the tbp allele is replaced with a version, tbp(Delta N),
      which lacks 111 of 135 N-terminal amino acid residues. Most tbp(Delta N/Delta N)
      fetuses die in midgestation. To test whether a disruption of general cellular
      processes contributed to this fetal loss, primary fibroblast cultures were
      established from +/+, Delta N/+, and Delta N/Delta N fetuses. The cultures
      exhibited no genotype-dependent differences in proliferation or in expression of
      the proliferative markers dihydrofolate reductase (DHFR) mRNA (S phase-specific)
      and cdc25B mRNA (G(2)-specific). The mutation had no effect on transcription
      initiation site fidelity by either RNA polymerase II (pol II) or pol III.
      Moreover, the mutation did not cause differences in levels of U6 RNA, a pol III
      dependent component of the splicing machinery, in mRNA splicing efficiency, in
      expression of housekeeping genes from either TATA-containing or TATA-less
      promoters, or in global gene expression. Our results indicated that general
      eukaryotic cell functions are unaffected by deletion of these vertebrate-specific
      sequences from TBP. Thus, all activities of this polypeptide domain must either
      be compensated for by redundant activities or be restricted to situations that
      are not represented by primary fibroblasts.

PMID- 12471024
TI  - The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates
      with cystic fibrosis transmembrane conductance regulator-interacting PDZ
      proteins.
AB  - ClC chloride channels are widely distributed in organisms across the evolutionary
      spectrum, and members of the mammalian family play crucial roles in cellular
      function and are mutated in several human diseases (Jentsch, T. J., Stein, V.,
      Weinreich, F., and Zdebik, A. A. (2002) Physiol. Rev. 82, 503-568). Within the
      ClC-3, -4, -5 branch of the family that are intracellular channels, two
      alternatively spliced ClC-3 isoforms were recognized recently (Ogura, T.,
      Furukawa, T., Toyozaki, T., Yamada, K., Zheng, Y. J., Katayama, Y., Nakaya, H.,
      and Inagaki, N. (2002) FASEB J. 16, 863-865). ClC-3A resides in late endosomes
      where it serves as an anion shunt during acidification. We show here that the ClC
      3B PDZ-binding isoform resides in the Golgi where it co-localizes with a small
      amount of the other known PDZ-binding chloride channel, CFTR (cystic fibrosis
      transmembrane conductance regulator). Both channel proteins bind the Golgi PDZ
      protein, GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein).
      Interestingly, however, when overexpressed, GOPC, which is thought to influence
      traffic in the endocytic/secretory pathway, causes a large reduction in the
      amounts of both channels, probably by leading them to the degradative end of this
      pathway. ClC-3B as well as CFTR also binds EBP50 (ERM-binding phosphoprotein 50)
      and PDZK1, which are concentrated at the plasma membrane. However, only PDZK1 was
      found to promote interaction between the two channels, perhaps because they were
      able to bind to two different PDZ domains in PDZK1. Thus while small portions of
      the populations of ClC-3B and CFTR may associate and co-localize, the bulk of the
      two populations reside in different organelles of cells where they are expressed
      heterologously or endogenously, and therefore their cellular functions are likely
      to be distinct and not primarily related.

PMID- 12471025
TI  - M-LP, Mpv17-like protein, has a peroxisomal membrane targeting signal comprising
      a transmembrane domain and a positively charged loop and up-regulates expression
      of the manganese superoxide dismutase gene.
AB  - M-LP (Mpv17-like protein) has been identified as a new protein that has high
      sequence homology with Mpv17 protein, a peroxisomal membrane protein involved in
      the development of early onset glomerulosclerosis. In this study, we verified the
      peroxisomal localization of M-LP by performing dual-color confocal analysis of
      COS-7 cells cotransfected with green fluorescent protein-tagged M-LP and DsRED2
      PTS1, a red fluorescent peroxisomal marker. To characterize the peroxisomal
      membrane targeting signal, we examined the intracellular localizations of several
      green fluorescent protein-tagged deletion mutants and demonstrated that, of the
      three transmembrane segments predicted, the first near the NH(2) terminus and
      NH(2)-terminal half of the following loop region, which is abundant in positively
      charged amino acids, were necessary and sufficient for peroxisomal targeting. To
      elucidate the function of M-LP, we examined the activities of several enzymes
      involved in reactive oxygen species metabolism in COS-7 cells and found that
      transfection with M-LP increased the superoxide dismutase activity significantly.
      Quantitative real-time PCR analysis revealed that the manganese SOD (SOD2) mRNA
      level of COS-7 cells transfected with M-LP was elevated. These results indicate
      that M-LP participates in reactive oxygen species metabolism.

PMID- 12471026
TI  - Molecular basis of isoform-specific micro-conotoxin block of cardiac, skeletal
      muscle, and brain Na+ channels.
AB  - mu-Conotoxins (mu-CTXs) block skeletal muscle Na(+) channels with an affinity 1-2
      orders of magnitude higher than cardiac and brain Na(+) channels. Although a
      number of conserved pore residues are recognized as critical determinants of mu
      CTX block, the molecular basis of isoform-specific toxin sensitivity remains
      unresolved. Sequence comparison of the domain II (DII) S5-S6 loops of rat
      skeletal muscle (mu1, Na(v)1.4), human heart (hh1, Na(v)1.5), and rat brain (rb1,
      Na(v)1.1) Na(+) channels reveals substantial divergence in their N-terminal S5-P
      linkers even though the P-S6 and C-terminal P segments are almost identical. We
      used Na(v)1.4 as the backbone and systematically converted these DII S5-P isoform
      variants to the corresponding residues in Na(v)1.1 and Na(v)1.5. The Na(v)1.4-
      >Na(v)1.5 variant substitutions V724R, C725S, A728S, D730S, and C731S (Na(v)1.4
      numbering) reduced block of Na(v)1.4 by 4-, 86-, 12-, 185-, and 55-fold
      respectively, rendering the skeletal muscle isoform more "cardiac-like."
      Conversely, an Na(v)1.5--> Na(v)1.4 chimeric construct in which the Na(v)1.4 DII
      S5-P linker replaces the analogous segment in Na(v)1.5 showed enhanced mu-CTX
      block. However, these variant determinants are conserved between Na(v)1.1 and
      Na(v)1.4 and thus cannot explain their different sensitivities to mu-CTX.
      Comparison of their sequences reveals two variants at Na(v)1.4 positions 729 and
      732: Ser and Asn in Na(v)1.4 compared with Thr and Lys in Na(v)1.1, respectively.
      The double mutation S729T/N732K rendered Na(v)1.4 more "brain-like" (30-fold
      downward arrow in block), and the converse mutation T925S/K928N in Na(v)1.1
      reproduced the high affinity blocking phenotype of Na(v)1.4. We conclude that the
      DII S5-P linker, although lying outside the conventional ion-conducting pore,
      plays a prominent role in mu-CTX binding, thus shaping isoform-specific toxin
      sensitivity.

PMID- 12471027
TI  - Isolation and characterization of an aggresome determinant in the NF2 tumor
      suppressor.
AB  - Schwannomin (Sch) is the product of the NF2 tumor suppressor gene. The NF2 gene
      is mutated in patients affected by neurofibromatosis type 2, a syndrome
      associated with multiple tumors of the nervous system. Here we found that Sch,
      when its N-terminal FERM domain was misfolded by the pathogenetic mutation Delta
      F118, formed aggresomes, i.e. aggregates that cluster at the centrosome as a
      result of microtubule-dependent transport. Strikingly the related protein ezrin
      affected by the same mutation did not form aggresomes even though its FERM domain
      was similarly misfolded. By studying ezrin/Sch chimeras, we delineated a sequence
      of 61 amino acids in the C terminus of Sch that determined the formation of
      aggresomes. Aggresome formation by these chimeras was independent from their rate
      of degradation. Sch(535-595) was sufficient to induce aggresomes of a green
      fluorescent fusion protein in vivo and aggregates of a glutathione S-transferase
      fusion protein in vitro. Taken together, these results suggest that aggresome
      formation is controlled primarily by aggresome determinants, which are distinct
      from degradation determinants, or from misfolding, through which aggresome
      determinants might be exposed.

PMID- 12471028
TI  - Dissociation of GDP dissociation inhibitor and membrane translocation are
      required for efficient activation of Rac by the Dbl homology-pleckstrin homology
      region of Tiam.
AB  - Small G proteins of the Rho/Rac/Cdc42 family are associated with lipid membranes
      through their prenylated C termini. Alternatively, these proteins form soluble
      complexes with GDI proteins. To assess how this membrane partitioning influences
      the activation of Rac by guanine nucleotide exchange factors, GDP-to-GTP exchange
      reactions were performed in the presence of liposomes using different forms of
      Rac-GDP. We show that both non-prenylated Rac-GDP and the soluble complex between
      prenylated Rac-GDP and GDI are poorly activated by the Dbl homology-pleckstrin
      homology (DH-PH) domain of the exchange factor Tiam1, whereas prenylated Rac-GDP
      bound to liposomes is activated about 10 times more rapidly. Sedimentation
      experiments with liposomes reveal that the DH-PH region of Tiam1 forms, with
      nucleotide-free prenylated Rac, a membrane-bound complex from which GDI is
      excluded. Taken together, these experiments demonstrate that the dissociation of
      Rac-GDP from GDI and its translocation to membrane lipids favor DH-PH-catalyzed
      nucleotide exchange because the steric hindrance caused by GDI is relieved and
      because the membrane environment favors functional interaction between the DH-PH
      domain and the small G protein.

PMID- 12471029
TI  - Smooth muscle tissues express a major dominant negative splice variant of the
      type 3 Ca2+ release channel (ryanodine receptor).
AB  - It is well known that the type 3 Ca(2+) release channel (ryanodine receptor,
      RyR3) exhibits strikingly different pharmacological and functional properties
      depending on the tissues in which it resides. To investigate the molecular basis
      for this tissue-dependent heterogeneity, we examined the primary structure of
      RyR3 from various tissues by reverse transcription polymerase chain reaction and
      DNA sequence analysis. As many as seven alternatively spliced variants of RyR3
      were detected. Ribonuclease protection assays revealed that one of these splice
      variants, RyR3 (AS-8a), which lacks a 29-amino acid fragment (His(4406)
      Lys(4434)) encompassing a predicted transmembrane helix, was highly expressed in
      smooth muscle tissues, but not in skeletal muscle, the heart, or the brain.
      Although the RyR3 (AS-8a) splice variant did not form a functional Ca(2+) release
      channel when expressed alone in HEK293 cells, it was able to form functional
      heteromeric channels with reduced caffeine sensitivity when co-expressed with the
      wild type RyR3. Interestingly, this RyR3 splice variant was also able to form
      heteromeric channels with and suppress the activity of the type 2 ryanodine
      receptor (RyR2). Tissue-specific expression of RyR3 splice variants is therefore
      likely to account for some of the pharmacological and functional heterogeneities
      of RyR3. These observations also reveal a novel mechanism by which a splice
      variant of one RyR isoform (RyR3) can suppress the activity of another RyR
      isoform (RyR2) via a dominant negative effect.

PMID- 12471030
TI  - Cell density and growth-dependent down-regulation of both intracellular calcium
      responses to agonist stimuli and expression of smooth-surfaced endoplasmic
      reticulum in MC3T3-E1 osteoblast-like cells.
AB  - A two-dimensional intracellular Ca(2+) ([Ca(2+)](i)) imaging system was used to
      examine the relationship between [Ca(2+)](i) handling and the proliferation of
      MC3T3-E1 osteoblast-like cells. The resting [Ca(2+)](i) level in densely cultured
      cells was 1.5 times higher than the [Ca(2+)](i) level in sparsely cultured cells
      or in other cell types (mouse fibroblasts, rat vascular smooth muscle cells, and
      bovine endothelial cells). A high resting [Ca(2+)](i) level may be specific for
      MC3T3-E1 cells. MC3T3-E1 cells were stimulated with ATP (10 microM), caffeine (10
      mM), thapsigargin (1 microM), or ionomycin (10 microM), and the effect on the
      [Ca(2+)](i) level of MC3T3-E1 cells was studied. The percentage of responding
      cells and the degree of [Ca(2+)](i) elevation were high in the sparsely cultured
      cells and low in densely cultured cells. The rank order for the percentage of
      responding cells and magnitude of the Ca(2+) response to the stimuli was
      ionomycin > thapsigargin = ATP > caffeine and suggests the existence of
      differences among the various [Ca(2+)](i) channels. All Ca(2+) responses in the
      sparsely cultured MC3T3-E1 cells, unlike in other cell types, disappeared after
      the cells reached confluence. Heptanol treatment of densely cultured cells
      restored the Ca(2+) response, suggesting that cell-cell contact is involved with
      the confluence-dependent disappearance of the Ca(2+) response. Immunohistological
      analysis of type 1 inositol trisphosphate receptors and electron microscopy
      showed distinct expression of inositol trisphosphate receptor proteins and smooth
      surfaced endoplasmic reticulum in sparsely cultured cells but reduced levels in
      densely cultured cells. These results indicate that the underlying basis of
      confluence-dependent [Ca(2+)](i) regulation is down-regulation of smooth-surfaced
      endoplasmic reticulum by cell-cell contacts.

PMID- 12471031
TI  - GABA(A) receptor composition is determined by distinct assembly signals within
      alpha and beta subunits.
AB  - Key to understanding how receptor diversity is achieved and controlled is the
      identification of selective assembly signals capable of distinguishing between
      other subunit partners. We have identified that the beta1-3 subunits exhibit
      distinct assembly capabilities with the gamma2L subunit. Similarly, analysis of
      an assembly box in alpha1-(57-68) has revealed an absolute requirement for this
      region in the assembly of alphabeta receptors. Furthermore, a selective
      requirement for a single amino acid (Arg-66), previously shown to be essential
      for the formation of the low affinity GABA binding site, is observed. This
      residue is critical for the assembly of alpha1beta2 but not alpha1beta1 or
      alpha1beta3 receptors. We have confirmed the ability of the previously identified
      GKER signal in beta3 to direct the assembly of betagamma receptors. The GKER
      signal is also involved in driving assembly with the alpha1 subunit, conferring
      the ability to assemble with alpha1(R66A) on the beta2 subunit. Although this
      signal is sufficient to permit the formation of beta2gamma2 receptors, it is not
      necessary for beta3gamma2 receptor formation, suggesting the existence of
      alternative assembly signals. These findings support the belief that GABA(A)
      receptor assembly occurs via defined pathways to limit the receptor diversity.

PMID- 12471032
TI  - Molecular sensing of bacteria in plants. The highly conserved RNA-binding motif
      RNP-1 of bacterial cold shock proteins is recognized as an elicitor signal in
      tobacco.
AB  - To detect microbial infection multicellular organisms have evolved sensing
      systems for pathogen-associated molecular patterns (PAMPs). Here, we identify
      bacterial cold shock protein (CSP) as a new such PAMP that acts as a highly
      active elicitor of defense responses in tobacco. Tobacco cells perceive a
      conserved domain of CSP and synthetic peptides representing 15 amino acids of
      this domain-induced responses at subnanomolar concentrations. Central to the
      elicitor-active domain is the RNP-1 motif KGFGFITP, a motif conserved also in
      many RNA- and DNA-binding proteins of eukaryotes. Csp15-Nsyl, a peptide
      representing the domain with highest homology to csp15 in a protein of Nicotiana
      sylvestris exhibited only weak activity in tobacco cells. Crystallographic and
      genetic data from the literature show that the RNP-1 domain of bacterial CSPs
      resides on a protruding loop and exposes a series of aromatic and basic side
      chains to the surface that are essential for the nucleotide-binding activity of
      CSPs. Similarly, these side chains were also essential for elicitor activity and
      replacement of single residues in csp15 with Ala strongly reduced or abolished
      activity. Most strikingly, csp15-Ala10, a peptide with the RNP-1 motif modified
      to KGAGFITP, lacked elicitor activity but acted as a competitive antagonist for
      CSP-related elicitors. Bacteria commonly have a small family of CSP-like proteins
      including both cold-inducible and noninducible members, and Csp-related elicitor
      activity was detected in extracts from all bacteria tested. Thus, the CSP domain
      containing the RNP-1 motif provides a structure characteristic for bacteria in
      general, and tobacco plants have evolved a highly sensitive chemoperception
      system to detect this bacterial PAMP.

PMID- 12471033
TI  - C-terminal processing of the toxoplasma protein MIC2 is essential for invasion
      into host cells.
AB  - Host cell invasion by apicomplexan parasites is accompanied by the rapid,
      polarized secretion of parasite proteins that are involved in cell attachment.
      The Toxoplasma gondii micronemal protein MIC2 contains several extracellular
      adhesive domains, a transmembrane domain, and a short cytoplasmic tail. Following
      apical secretion, MIC2 is transiently present on the parasite surface before
      being translocated backward and released by proteolytic cleavage. Mutations in
      the extracellular domain of MIC2, directly upstream of the transmembrane domain,
      prevented processing and release of the soluble protein into the supernatant. A
      conserved basic residue in MIC2 was essential for cleavage, and basic residues
      are similarly positioned in other microneme proteins. Following the induction of
      secretion, MIC2 processing mutants were stably expressed on the surface of the
      parasite. Surface MIC2-expressing mutants showed increased adhesion to host
      cells, yet were impaired in their capacity to invade. These data demonstrate that
      proteolysis is essential for releasing cell surface adhesins prior to cell entry
      by apicomplexan parasites.

PMID- 12471034
TI  - APH-1 interacts with mature and immature forms of presenilins and nicastrin and
      may play a role in maturation of presenilin.nicastrin complexes.
AB  - APH-1 and PEN-2 genes modulate the function of nicastrin and the presenilins in
      Caenorhabditis elegans. Preliminary studies in transfected mammalian cells
      overexpressing tagged APH-1 proteins suggest that this genetic interaction is
      mediated by a direct physical interaction. Using the APH-1 protein encoded on
      human chromosome 1 (APH-1(1)L; also known as APH-1a) as an archetype, we report
      here that endogenous forms of APH-1 are predominantly expressed in intracellular
      membrane compartments, including the endoplasmic reticulum and cis-Golgi. APH-1
      proteins directly interact with immature and mature forms of the presenilins and
      nicastrin within high molecular weight complexes that display gamma- and epsilon
      secretase activity. Indeed APH-1 proteins can bind to the nicastrin delta312-369
      loss of function mutant, which does not undergo glycosylation maturation and is
      not trafficking beyond the endoplasmic reticulum. The levels of expression of
      endogenous APH-1(1)L can be suppressed by overexpression of any other members of
      the APH-1 family, suggesting that their abundance is coordinately regulated.
      Finally, although the absence of APH-1 destabilizes the presenilins, in contrast
      to nicastrin and PEN-2, APH-1 itself is only modestly destabilized in cells
      lacking functional expression of presenilin 1 or presenilin 2. Taken together,
      our data suggest that APH-1 proteins, and APH-1(1) in particular, may have a role
      in the initial assembly and maturation of presenilin.nicastrin complexes.

PMID- 12471035
TI  - Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor
      receptor EGFRvIII.
AB  - EGFRvIII is a mutant epidermal growth factor that promotes aggressive growth of
      glioblastomas. We made a plasmid that directed the expression of an EGFRvIII with
      three copies of the Flag epitope at its amino terminus. Flag-tagged EGFRvIII was
      expressed at the same levels as unmodified EGFRvIII, and showed the same
      subcellular localization. However, the Flag epitope could only be detected on
      EGFRvIII present in the endoplasmic reticulum; the epitope was covalently
      modified during trafficking of the receptor through the Golgi so that it was no
      longer recognized by anti-Flag antibody. This property was exploited to
      selectively purify nascent EGFRvIII from glioblastoma cells. Nascent EGFRvIII was
      found to copurify with a set of other proteins, identified by mass spectrometry
      as the two endoplasmic reticulum chaperones Grp94 and BiP, and the two cytosolic
      chaperones Hsc70 and Hsp90. The Hsp90-associated chaperone Cdc37 also co-purified
      with EGFRvIII, suggesting that Hsp90 binds EGFRvIII as a complex with this
      protein. Geldanamycin and radicicol, two chemically unrelated inhibitors of
      Hsp90, decreased the expression of EGFRvIII in glioblastoma cells. These studies
      show that nascent EGFRvIII in the endoplasmic reticulum associates with Hsp90 and
      Cdc37, and that the Hsp90 association is necessary to maintain expression of
      EGFRvIII.

PMID- 12471036
TI  - Up-regulation of p300 binding and p50 acetylation in tumor necrosis factor-alpha
      induced cyclooxygenase-2 promoter activation.
AB  - It is well established that p300 plays an important role in mediating gene
      expressions. However, it is less clear how its binding is influenced by
      physiological stimuli and how its altered binding affects transactivator
      acetylation and binding. In this study, we determined p300 binding to a core
      cyclooxygenase-2 (COX-2) promoter region by chromatin immunoprecipitation and
      streptavidin-agarose pull-down assays in basal and tumor necrosis factor-alpha
      (TNFalpha)-treated human foreskin fibroblasts. We found basal binding of p300,
      p50/p65 NF-kappaB, cyclic AMP regulatory element-binding protein-2,
      CCAAT/enhancer-binding protein beta, and c-Jun. p50/p65 and p300 binding was
      selectively increased by TNFalpha. Immunoprecipitation confirmed direct
      interaction of p300 with NF-kappaB and the other involved transactivators. p50
      acetylation was detected in resting cells and was increased by TNFalpha or
      lipopolysaccharide. Overexpression of p300 augmented p50 acetylation, which was
      attenuated by deletion of its histone acetyltransferase domain. Enhanced p50
      acetylation correlated with increased p50 binding to COX-2 promoter and
      transcriptional activation. Co-transfection of E1A with p300 abrogated p50
      acetylation and p50 binding. These findings suggest that up-regulation of p300
      binding and its acetylation of NF-kappaB occupies a central position in COX-2
      promoter activation.

PMID- 12471037
TI  - Association of the atypical protein kinase C-interacting protein p62/ZIP with
      nerve growth factor receptor TrkA regulates receptor trafficking and Erk5
      signaling.
AB  - Previous work demonstrated an essential role for the atypical protein kinase C
      interacting protein, p62, in neurotrophin survival and differentiation signaling.
      Here we show that p62 interacts not only with TrkA but also with TrkB and TrkC,
      which are the primary receptors for brain-derived neurotrophic factor and
      neurotrophin-3. The interaction of p62 with TrkA requires the kinase activity of
      TrkA. Mapping analysis indicates that p62 does not compete with Shc for binding
      to TrkA, and p62 association was confined to the juxtamembrane region of TrkA,
      amino acids 472-493. By immunofluorescence the colocalization of p62 and TrkA was
      observed 30 min post-nerve growth factor treatment within overlapping vesicular
      structures. Upon subcellular fractionation, activated TrkA colocalized to an
      endosomal compartment and p62 was coassociated with the receptor post-nerve
      growth factor stimulation. Moreover, an absence of p62 blocked internalization of
      TrkA without an effect on phosphorylation of either TrkA or MAPK; however, Erk5
      signaling was selectively abrogated. We propose that p62 plays a novel role in
      connecting receptor signals with the endosomal signaling network required for
      mediating TrkA-induced differentiation.

PMID- 12471038
TI  - Targeted replacement of mouse apolipoprotein A-I with human ApoA-I or the mutant
      ApoA-IMilano. Evidence of APOA-IM impaired hepatic secretion.
AB  - Despite a pro-atherogenic profile, individuals carrying the molecular variant
      (R173C) of apolipoprotein (apo)A-I, named apoA-I(Milano) (apoA-I(M)), appear to
      be at reduced risk for cardiovascular disease. To develop an in vivo system to
      explore, in a controlled manner, the effects of apoA-I(M) on lipid metabolism, we
      have used the gene targeting technology, or "gene knock-in" (gene k-in), to
      replace the murine apoA-I gene with either human apoA-I or apoA-I(M) genes in
      embryonic stem cells. As in human carriers, mice expressing apoA-I(M) (A-I(M) k
      in) are characterized by low concentrations of the human apolipoprotein and
      reduced high density lipoprotein cholesterol levels, compared with A-I k-in
      animals. The aim of the present study was to investigate the basic mechanisms of
      hypoalphalipoproteinemia associated with the apoA-I(M) mutation. ApoA-I and apoA
      I(M) mRNA expression, as assessed by Northern blot analysis and quantitative real
      time reverse transcription-PCR, did not exhibit significant differences in either
      liver or intestine. Moreover, human apolipoprotein synthesis rates were similar
      in the k-in lines. When the secretion rate of the human apolipoproteins was
      assessed in cultured hepatocytes from the mouse lines, secretion from apoA-I(M)
      expressing cells was markedly reduced (42% for A-I(M) k-in and 36% for A-I/A-I(M)
      k-in mice) as compared with that of A-I k-in hepatocytes. These results provide
      the first evidence that the hypoalphalipoproteinemia in apoA-I(M) human carriers
      may be partially explained by impaired apoA-I(M) secretion.

PMID- 12471039
TI  - Structure of a human carcinogen-converting enzyme, SULT1A1. Structural and
      kinetic implications of substrate inhibition.
AB  - Sulfonation catalyzed by sulfotransferase enzymes plays an important role in
      chemical defense mechanisms against various xenobiotics but also bioactivates
      carcinogens. A major human sulfotransferase, SULT1A1, metabolizes and/or
      bioactivates many endogenous compounds and is implicated in a range of cancers
      because of its ability to modify diverse promutagen and procarcinogen
      xenobiotics. The crystal structure of human SULT1A1 reported here is the first
      sulfotransferase structure complexed with a xenobiotic substrate. An unexpected
      finding is that the enzyme accommodates not one but two molecules of the
      xenobiotic model substrate p-nitrophenol in the active site. This result is
      supported by kinetic data for SULT1A1 that show substrate inhibition for this
      small xenobiotic. The extended active site of SULT1A1 is consistent with binding
      of diiodothyronine but cannot easily accommodate beta-estradiol, although both
      are known substrates. This observation, together with evidence for a disorder
      order transition in SULT1A1, suggests that the active site is flexible and can
      adapt its architecture to accept diverse hydrophobic substrates with varying
      sizes, shapes and flexibility. Thus the crystal structure of SULT1A1 provides the
      molecular basis for substrate inhibition and reveals the first clues as to how
      the enzyme sulfonates a wide variety of lipophilic compounds.

PMID- 12471040
TI  - Protein kinase C gamma associates directly with the GluR4 alpha-amino-3-hydroxy-5
      methyl-4-isoxazole propionate receptor subunit. Effect on receptor
      phosphorylation.
AB  - Ionotropic glutamate receptors mediate the majority of excitatory synaptic
      transmission in the brain and are thought to be involved in learning and memory
      formation. The activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate
      (AMPA)-type glutamate receptors can be regulated by direct phosphorylation of
      their subunits, which affects the electrophysiological properties of the
      receptor, and the receptor association with numerous proteins that modulate
      membrane traffic and synaptic targeting of the receptor. In the present study we
      investigated the association of protein kinase C (PKC) gamma isoform with the
      GluR4 AMPA receptor subunit. PKC gamma was co-immunoprecipitated with GluR4 AMPA
      receptor subunit in rat cerebellum and in cultured chick retina cell extracts,
      and immunocytochemistry experiments showed co-localization of GluR4 and PKC gamma
      in cultured chick retinal neurons. Pull-down assays showed that native PKC gamma
      binds the GluR4 C-terminal membrane-proximal region, and recombinant PKC gamma
      was retained by GST-GluR4 C-terminal fusion protein, suggesting that the kinase
      binds directly to GluR4. Furthermore, GST-GluR4 C-terminal protein was
      phosphorylated on GluR4 Ser-482 by bound kinases, retained by the fusion protein,
      including PKC gamma. The GluR4 C-terminal segment that interacts with PKC gamma,
      which lacks the PKC phosphorylation sites, inhibited histone H1 phosphorylation
      by PKC, to the same extent as the PKC pseudosubstrate peptide 19-31, indicating
      that PKC gamma bound to GluR4 preferentially phosphorylates GluR4 to the
      detriment of other substrates. Additionally, PKC gamma expression in GluR4
      transfected human embryonic kidney 293T cells increased the amount of plasma
      membrane-associated GluR4. Our results suggest that PKC gamma binds directly to
      GluR4, thereby modulating the function of GluR4-containing AMPA receptors.

PMID- 12471041
TI  - Up-regulation of vascular endothelial growth factor C in breast cancer cells by
      heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling
      pathway.
AB  - Vascular endothelial growth factor C (VEGF-C) is a critical activator of tumor
      lymphangiogenesis that recently has been strongly implicated in the tumor
      metastasis process. In this study, we identified that HRG-beta 1 stimulated up
      regulation of VEGF-C mRNA and protein of human breast cancer cells in a dosage-
      and time-dependent manner and that this up-regulation was de novo RNA synthesis
      dependent. The HRG-beta 1-induced increase in VEGF-C expression was effectively
      reduced by treatment with Herceptin, an antibody specifically against HER2. Also,
      when HER2 was overexpressed in MCF-7 cells that resulted in an evident increase
      in the VEGF-C level, suggesting an essential role of HER2 in mediating VEGF-C up
      regulation by HRG-beta 1. NF-kappa B has been shown to be probably involved in
      interleukin-1 beta- or tumor necrosis factor-alpha-induced VEGF-C mRNA expression
      in human fibroblasts. Here we found that HRG-beta 1 could stimulate NF-kappa B
      nuclear translocation and DNA-binding activity via the I kappa B alpha
      phosphorylation-degradation mechanism. Blockage of the NF-kappa B activation
      cascade caused a complete inhibition of the HRG-beta 1-induced elevation of VEGF
      C. In promoter-reporter assay, the luciferase activities of the reporter
      constructs, including the putative NF-kappa B site deleted and mutated form were
      significantly reduced after HRG-beta 1 treatment as compared with the 1.5-kb VEGF
      C promoter. Although investigating the upstream kinase pathway(s) involved in HRG
      beta 1-elicited NF-kappa B activation and VEGF-C up-regulation, we found that HRG
      beta1 could activate extracellular signal-regulated protein kinase 1/2,
      phosphatidylinositol 3'-kinase, and p38 mitogen-activated protein kinase (MAPK)
      in MCF-7. However, only SB203580 (a specific inhibitor of p38 MAPK), not PD98059
      nor LY294002, blocked the up-regulation of VEGF-C by HRG-beta 1. A similar
      inhibition in VEGF-C expression was obtained by cell transfection with dominant
      negative p38 (p38AF). Interestingly, the HRG-beta 1-induced NF-kappa B activation
      cascade was also effectively blocked by SB203580 treatment or p38AF transfection.
      Our data thus suggests that HRG-beta 1 stimulated a NF-kappa B-dependent up
      regulation of VEGF-C through the p38 MAPK signaling pathway in human breast
      cancer cells.

PMID- 12471042
TI  - Phosphatidylinositol 4-OH kinase is a downstream target of neuronal calcium
      sensor-1 in enhancing exocytosis in neuroendocrine cells.
AB  - Neuronal calcium sensor-1 (NCS-1), the mammalian orthologue of frequenin, belongs
      to a family of EF-hand-containing Ca(2+) sensors. NCS-1/frequenin has been shown
      to enhance synaptic transmission in PC12 cells and Drosophila and Xenopus,
      respectively. However, the precise molecular mechanism for the enhancement of
      exocytosis is largely unknown. In PC12 cells, NCS-1 potentiated exocytosis evoked
      by ATP, an agonist to phospholipase C-linked receptors, but had no effect on
      depolarization-evoked release. NCS-1 also enhanced exocytosis triggered by
      ionomycin, a Ca(2+) ionophore that bypasses K(+) and Ca(2+) channels.
      Overexpression of NCS-1 caused a shift in the dose-response curve of inhibition
      of ATP-evoked secretion using phenylarsine oxide, an inhibitor of
      phosphatidylinositol 4-OH kinase (PI4K). Plasma membrane phosphatidylinositol 4,5
      bisphosphate pools were increased upon NCS-1 transfection as visualized using a
      phospholipase C-delta pleckstrin homology domain-green fluorescent protein
      construct. NCS-1-transfected cell extracts displayed increased
      phosphatidylinositol-4-phosphate biosynthesis, indicating an increase in PI4K
      activity. Mutations in NCS-1 equivalent to those that abolish the interaction of
      recoverin, another EF-hand-containing Ca(2+) sensor, with its downstream target
      rhodopsin kinase, lost their ability to enhance exocytosis. Taken together, the
      present data indicate that NCS-1 modulates the activity of PI4K, leading to
      increased levels of phosphoinositides and concomitant enhancement of exocytosis.

PMID- 12471043
TI  - Branched-chain amino acid supplementation during bed rest: effect on recovery.
AB  - Bed rest is associated with a loss of protein from the weight-bearing muscle. The
      objectives of this study are to determine whether increasing dietary branched
      chain amino acids (BCAAs) during bed rest improves the anabolic response after
      bed rest. The study consisted of a 1-day ambulatory period, 14 days of bed rest,
      and a 4-day recovery period. During bed rest, dietary intake was supplemented
      with either 30 mmol/day each of glycine, serine, and alanine (group 1) or with 30
      mmol/day each of the three BCAAs (group 2). Whole body protein synthesis was
      determined with U-(15)N-labeled amino acids, muscle, and selected plasma protein
      synthesis with l-[(2)H(5)]phenylalanine. Total glucose production and
      gluconeogenesis from alanine were determined with l-[U-(13)C(3)]alanine and [6,6
      (2)H(2)]glucose. During bed rest, nitrogen (N) retention was greater with BCAA
      feeding (56 +/- 6 vs. 26 +/- 12 mg N. kg(-1). day(-1), P < 0.05). There was no
      effect of BCAA supplementation on either whole body, muscle, or plasma protein
      synthesis or the rate of 3-MeH excretion. Muscle tissue free amino acid
      concentrations were increased during bed rest with BCAA (0.214 +/- 0.066 vs.
      0.088 +/- 0.12 nmol/mg protein, P < 0.05). Total glucose production and
      gluconeogenesis from alanine were unchanged with bed rest but were significantly
      reduced (P < 0.05) with the BCAA group in the recovery phase. In conclusion, the
      improved N retention during bed rest is due, at least in part, to accretion of
      amino acids in the tissue free amino acid pools. The amount accreted is not
      enough to impact protein kinetics in the recovery phase but does improve N
      retention by providing additional essential amino acids in the early recovery
      phase.

PMID- 12471044
TI  - Nonreversible conductive airway ventilation heterogeneity in mild asthma.
AB  - A multiple-breath washout technique was used to assess residual ventilation
      heterogeneity in the conductive and acinar lung zones of asthmatic patients after
      maximal beta(2)-agonist reversibility. Reversibility was assessed in 13 patients
      on two separate visits corresponding to a different baseline condition in terms
      of forced expiratory volume in 1 s [FEV(1); average FEV(1) over 2 visits: 92 +/-
      21% of predicted (SE)]. On the visit corresponding to each patient's best
      baseline, 400 micro g salbutamol led to normal acinar ventilation heterogeneity,
      normal FEV(1), and normal peak expiratory flow; i.e., none was significantly
      different from that obtained in 13 matched controls. By contrast, conductive
      ventilation heterogeneity and forced expiratory flow after exhalation of 75%
      forced vital capacity remained significantly different from controls (P < or =
      0.005 on both indexes). In addition, the degree of postdilation conductive
      ventilation heterogeneity was similar to what was previously obtained in
      asthmatic individuals with a 19% lower baseline FEV(1) and twofold larger acinar
      ventilation heterogeneity (Verbanck S, Schuermans D, Noppen M, Van Muylem A,
      Paiva M, and Vincken W. Am J Respir Crit Care Med 159: 1545-1550, 1999). We
      conclude that, even in the mildest forms of asthma, the most consistent pattern
      of non-beta(2)-agonist-reversible ventilatory heterogeneity is in the conductive
      lung zone, most probably in the small conductive airways.

PMID- 12471045
TI  - Inter- and intraregional ventilation inhomogeneity in hypergravity and after
      pressurization of an anti-G suit.
AB  - This study assessed the effects of increased gravity in the head-to-foot
      direction (+G(z)) and anti-G suit (AGS) pressurization on functional residual
      capacity (FRC), the volume of trapped gas (V(TG)), and ventilation distribution
      by using inert- gas washout. Normalized phase III slope (Sn(III)) analysis was
      used to determine the effects on inter- and intraregional ventilation
      inhomogeneity. Twelve men performed multiple-breath washouts of SF(6) and He in a
      human centrifuge at +1 to +3 G(z) wearing an AGS pressurized to 0, 6, or 12 kPa.
      Hypergravity produced moderately increased FRC, V(TG), and overall and inter- and
      intraregional inhomogeneities. In normogravity, AGS pressurization resulted in
      reduced FRC and increased V(TG), overall, and inter- and intraregional
      inhomogeneities. Inflation of the AGS to 12 kPa at +3 G(z) reduced FRC markedly
      and caused marked gas trapping and intraregional inhomogeneity, whereas
      interregional inhomogeneity decreased. In conclusion, increased +G(z) impairs
      ventilation distribution not only between widely separated lung regions, but also
      within small lung units. Pressurizing an AGS in hypergravity causes extensive gas
      trapping accompanied by reduced interregional inhomogeneity and, apparently,
      results in greater intraregional inhomogeneity.

PMID- 12471046
TI  - Immunolocalization of a Na-K-2Cl cotransporter in human tracheobronchial smooth
      muscle.
AB  - Inhibition of the Na-K-2Cl (NKCC) cotransporter by loop diuretics is associated
      with airway relaxation, but there has been no direct evidence for the expression
      of this protein in airway smooth muscle. Thus we hypothesized that a NKCC
      cotransporter is present and functional in airway smooth muscle cells. Monoclonal
      and polyclonal antibodies were used first to demonstrate the presence of a NKCC
      cotransporter protein in isolated human fetal trachea and normal human bronchial
      smooth muscle cells (BSMC) by Western blotting. The cotransporter protein was
      then localized by immunohistochemical staining to airway smooth muscle cells in
      culture and in situ. The localization was confirmed by indirect
      immunofluorescence and laser confocal microscopy in the BSMC. Cotransporter
      function in BSMC was also confirmed in vitro by bumetanide-mediated inhibition of
      rubidium uptake. Our present findings thus document the presence of a functional
      NKCC cotransporter in human airway smooth muscle, providing a basis for defining
      the role of this ion cotransporter in airway smooth muscle function.

PMID- 12471047
TI  - A simulation study to examine the use of cross-correlation as an estimate of
      surface EMG cross talk.
AB  - Cross-correlation between surface electromyogram (EMG) signals is commonly used
      as a means of quantifying EMG cross talk during voluntary activation. To examine
      the reliability of this method, the relationship between cross talk and the cross
      correlation between surface EMG signals was examined by using model simulation.
      The simulation results illustrate an increase in cross talk with increasing
      subcutaneous fat thickness. The results also indicate that the cross-correlation
      function decays more rapidly with increasing distance from the active fibers than
      cross talk, which was defined as the normalized EMG amplitude during activation
      of a single muscle. The influence of common drive and short-term motor unit
      synchronization on the cross-correlation between surface EMG signals was also
      examined. While common drive did not alter the maximum value of the cross
      correlation function, the correlation increased with increasing motor unit
      synchronization. It is concluded that cross-correlation analysis is not a
      suitable means of quantifying cross talk or of distinguishing between cross talk
      and coactivation during voluntary contraction. Furthermore, it is possible that a
      high correlation between surface EMG signals may reflect an association between
      motor unit firing times, for example due to motor unit synchronization.

PMID- 12471048
TI  - Serial changes in nasal potential difference and lung electrical impedance
      tomography at high altitude.
AB  - Recent work suggests that treatment with inhaled beta(2)-agonists reduces the
      incidence of high-altitude pulmonary edema in susceptible subjects by increasing
      respiratory epithelial sodium transport. We estimated respiratory epithelial ion
      transport by transepithelial nasal potential difference (NPD) measurements in 20
      normal male subjects before, during, and after a stay at 3,800 m. NPD
      hyperpolarized on ascent to 3,800 m (P < 0.05), but the change in potential
      difference with superperfusion of amiloride or isoprenaline was unaffected. Vital
      capacity (VC) fell on ascent to 3,800 m (P < 0.05), as did the normalized change
      in electrical impedance (NCI) measured over the right lung parenchyma (P < 0.05)
      suggestive of an increase in extravascular lung water. Echo-Doppler-estimated
      pulmonary artery pressure increases were insufficient to cause clinical pulmonary
      edema. There was a positive correlation between VC and NCI (R(2) = 0.633) and
      between NPD and both VC and NCI (R(2) = 0.267 and 0.418). These changes suggest
      that altered respiratory epithelial ion transport might play a role in the
      development of subclinical pulmonary edema at high altitude in normal subjects.

PMID- 12471049
TI  - High concentrations of 17beta -estradiol attenuate the exercise pressor reflex in
      male cats.
AB  - Previously, intravenous injection of 17beta-estradiol in decerebrate male cats
      was found to attenuate central command but not the exercise pressor reflex. This
      latter finding was surprising because the dorsal horn, the spinal site receiving
      synaptic input from thin-fiber muscle afferents, is known to contain estrogen
      receptors. We were prompted, therefore, to reexamine this issue. Instead of
      injecting 17beta-estradiol intravenously, we applied it topically to the L(7) and
      S(1) spinal cord of male decerebrate cats. We found that topical application (150
      200 micro l) of 17beta-estradiol in concentrations of 0.01, 0.1, and 1 micro g/ml
      had no effect on the exercise pressor reflex, whereas a concentration of 10 micro
      g/ml attenuated the reflex. We conclude that, in male cats, estrogen can only
      attenuate the exercise pressor reflex in concentrations that exceed the
      physiological level.

PMID- 12471050
TI  - T cell anergy.
AB  - T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically
      functionally inactivated following an antigen encounter, but remains alive for an
      extended period of time in a hyporesponsive state. Models of T cell anergy
      affecting both CD4(+) and CD8(+) cells fall into two broad categories. One,
      clonal anergy, is principally a growth arrest state, whereas the other, adaptive
      tolerance or in vivo anergy, represents a more generalized inhibition of
      proliferation and effector functions. The former arises from incomplete T cell
      activation, is mostly observed in previously activated T cells, is maintained by
      a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40
      signaling, and usually does not result in the inhibition of effector functions.
      The latter is most often initiated in naive T cells in vivo by stimulation in an
      environment deficient in costimulation or high in coinhibition. Adaptive
      tolerance can be induced in the thymus or in the periphery. The cells proliferate
      and differentiate to varying degrees and then downregulate both functions in the
      face of persistent antigen. The state involves an early block in tyrosine kinase
      activation, which predominantly inhibits calcium mobilization, and an independent
      mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance
      reverses in the absence of antigen. Aspects of both of the anergic states are
      found in regulatory T cells, possibly preventing them from dominating initial
      immune responses to foreign antigens and shutting down such responses
      prematurely.

PMID- 12471051
TI  - Transcriptome analysis of human autosomal trisomy.
AB  - We present transcriptome analyses of primary cultures of human fetal cells from
      pregnancies affected with trisomy 21 (t21) and trisomy 13 (t13). Pooled mRNA
      samples from t21 and t13 cases were used for comparative hybridizations to cDNA
      arrays with pooled mRNA from normal cells. When the array cDNAs were grouped by
      chromosomal location the relevant trisomic chromosome could be clearly identified
      as showing the most significant misregulation. The average level of transcription
      on the trisomic chromosome was increased only approximately 1.1-fold compared to
      normal cells on array analysis. Since the karyotype could be accurately predicted
      by the transcriptome this could provide a novel method of detecting aneusomy of
      unknown position. Subsequent analysis of individuals cases demonstrated that
      variation in transcriptional profiles between samples within each class made
      transcriptional karyotyping difficult without pooling or the use of arrays with a
      higher proportion of all human cDNAs. Interestingly, consistent differences in
      the relative expression levels between chromosomes were detected suggesting that
      genomic control mechanisms may act over larger distances than previously thought.
      Most (>95%) >+/-2 SD misregulated genes did not map to the trisomic chromosome
      and significant misregulation was more common in t13 than t21. These data support
      a model of a subtle primary upregulation of genes on the trisomic chromosome
      resulting in a secondary, generalized and more extreme transcriptional
      misregulation. It seems likely that the degree of this misregulation determines
      the severity of the phenotype in most aneuploidy.

PMID- 12471052
TI  - A gene fusion method to screen for regulatory effects on gene expression:
      application to the LDL receptor.
AB  - We have evaluated the feasibility of using fusion genes to link transcriptional
      promoters of biomedical interest to reporter genes to screen for pharmacological
      or genetic regulatory effects. Using gene targeting, we generated two lines of
      embryonic stem (ES) cells expressing human alpha-fetoprotein (hAFP) under control
      of the endogenous promoter for the LDL receptor (LDLR). In one line, hAFP was
      introduced into the first intron after the translational start codon; in the
      other, hAFP was positioned in the 3'-untranslated region leaving the potential
      for expression of LDLR intact. In both lines, an internal ribosome entry site
      (IRES) was included to facilitate translation. Readily measurable levels of hAFP
      were found in the medium with both targeted ES cell lines, compared with
      undetectable levels with the starting cell line. The expectation that the level
      of hAFP would reflect the steady-state level of mRNA for the fusion transcript
      and secondarily transcriptional control of LDLR was confirmed by correlating hAFP
      levels with the abundance of LDLR and fusion transcripts. We also generated mice
      carrying the LDLR-hAFP fusion in the 3'-untranslated region and these mice
      produced detectable levels of hAFP in serum. Levels of hAFP in culture medium and
      in serum were increased by simvastatin, a drug known to up-regulate LDLR. These
      ES cell clones and mice are suitable for pharmacological and genetic screening to
      detect effects on expression of LDLR. The data demonstrate the feasibility of
      using gene fusions to screen for drugs and genetic factors that affect expression
      of a wide variety of genes of interest.

PMID- 12471053
TI  - The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in
      both androgenetic and biparental complete hydatidiform moles.
AB  - Hydatidiform mole (HM) is an abnormal gestation characterized by trophoblast
      hyperplasia and overgrowth of placental villi. The genetic basis in the vast
      majority of cases is an excess of paternal to maternal genomes, suggesting that
      global misexpression of imprinted genes is the common molecular mechanism
      underlying the genesis of this condition. Although most complete HM are
      androgenetic in origin, a rare, frequently familial, biparental variant has been
      described. Here we evaluate the expression of p57(KIP2), the product of CDKN1C,
      an imprinted, maternally expressed gene in a series of these rare, biparental
      complete HM (BiCHM). We observed dramatic underexpression of p57(KIP2) in BiCHM,
      identical to that seen in complete HM of androgenetic origin (AnCHM). The series
      included two sisters, both of whom had BiCHM. Genotyping of this family
      identified a 15 cM region of homozygosity for 19q13.3-13.4 similar to that found
      in three other families with recurrent BiCHM. These results demonstrate that
      BiCHM, like AnCHM, result from abnormal expression of imprinted genes. In
      addition we provide further evidence for a major control gene on 19q13.3-13.4
      which regulates expression of imprinted genes on other chromosomes.

PMID- 12471054
TI  - Cell complementation using Genebridge 4 human:rodent hybrids for physical mapping
      of novel mitochondrial respiratory chain deficiency genes.
AB  - The mapping and identification of respiratory chain deficiency genes is
      particularly tedious owing to the large number of genes encoding catalytic
      subunits and involved in respiratory chain (RC) assembly and maintenance. We have
      developed a functional complementation approach by: (i) growing the patient's
      fibroblasts in a highly selective medium; and (ii) transferring human chromosome
      fragments into RC-deficient fibroblasts by microcell-mediated transfer. In the
      absence of carbohydrates in the culture medium, the deficient cells rapidly
      disappeared unless they were rescued by a chromosome fragment carrying the
      disease gene. Microcells prepared from human:rodent Genebridge 4 panel of whole
      genome radiation hybrids were fused with fibroblast strains of two patients with
      complex II or I+IV deficiency and allowed to map the disease-causing genes to
      small intervals (4 and 12 Mb) on chromosomes 12p13 and 7p21, respectively. These
      intervals are similar to that obtained by genetic linkage analyses in large
      informative families. The recovery of normal RC enzyme activity in deficient skin
      fibroblasts supported the relevance of the transferred chromosome fragment in the
      disease. This approach makes the physical mapping of the disease genes feasible
      in some sporadic cases of RC deficiency.

PMID- 12471055
TI  - Gene expression profiling in dysferlinopathies using a dedicated muscle
      microarray.
AB  - We have performed expression profiling to define the molecular changes in
      dysferlinopathy using a novel dedicated microarray platform made with 3'-end
      skeletal muscle cDNAs. Eight dysferlinopathy patients, defined by western blot,
      immunohistochemistry and mutation analysis, were investigated with this
      technology. In a first experiment RNAs from different limb-girdle muscular
      dystrophy type 2B patients were pooled and compared with normal muscle RNA to
      characterize the general transcription pattern of this muscular disorder. Then
      the expression profiles of patients with different clinical traits were
      independently obtained and hierarchical clustering was applied to discover
      patient-specific gene variations. MHC class I genes and genes involved in protein
      biosynthesis were up-regulated in relation to muscle histopathological features.
      Conversely, the expression of genes codifying the sarcomeric proteins titin,
      nebulin and telethonin was down-regulated. Neither calpain-3 nor caveolin, a
      sarcolemmal protein interacting with dysferlin, was consistently reduced. There
      was a major up-regulation of proteins interacting with calcium, namely S100
      calcium-binding proteins and sarcolipin, a sarcoplasmic calcium regulator.

PMID- 12471056
TI  - Systematic mutagenesis of the functional domains of AIRE reveals their role in
      intracellular targeting.
AB  - Mutations in the human autoimmune regulator (AIRE ) gene cause a multi-systemic
      autoimmune syndrome that is known as autoimmune polyendocrinopathy-candidiasis
      ectodermal dystrophy (APECED). To date more than 39 different disease mutations
      have been identified. They span the entire region of the AIRE gene that encodes a
      polypeptide with multiple functional domains: an N-terminal homogeneously
      staining region (HSR), a bipartied nuclear localization signal (NLS), a SAND
      domain, two PHD fingers and four nuclear receptor targeting motifs. The APECED
      mutations include insertions, deletions, substitutions and introduction of
      premature termination codons, while most mutations disrupt one of the functional
      domains. We have constructed a series of deletion mutants systematically removing
      one or more functional domain(s) and investigated the stability and sub-cellular
      compartmentalization of the corresponding polypeptides. Here we show that the
      first 188 amino acids, containing the HSR domain and the NLS proved necessary for
      both cytoplasmic filament formation and nuclear targeting. Deletion of the SAND
      domain and even point mutations in the SAND domain, resulted in the aggregation
      of the polypeptides in the cytoplasm and interfered with the proper nuclear
      targeting. The PHD fingers seemed to be necessary for the formation of
      characteristic dot-like complexes in the nucleus, but their deletion did not
      interfere with nuclear entry.

PMID- 12471057
TI  - Molybdenum cofactor-deficient mice resemble the phenotype of human patients.
AB  - Human molybdenum cofactor deficiency is a rare and devastating autosomal
      recessive disease for which no therapy is known. The absence of active sulfite
      oxidase-a molybdenum cofactor-dependent enzyme-results in neonatal seizures and
      early childhood death. Most patients harbor mutations in the MOCS1 gene, whose
      murine homolog was disrupted by homologous recombination with a targeting vector.
      As in humans, heterozygous mice display no symptoms, but homozygous animals die
      between days 1 and 11 after birth. Biochemical analyis of these animals shows
      that molydopterin and active cofactor are undetectable. They do not possess any
      sulfite oxidase or xanthine dehydrogenase activity. No organ abnormalities were
      observed and the synaptic localization of inhibitory receptors, which was found
      to be disturbed in molybdenum cofactor deficient-mice with a Gephyrin mutation,
      appears normal. MOCS1(-/-) mice could be a suitable animal model for biochemical
      and/or genetic therapy approaches.

PMID- 12471058
TI  - Functional requirements for fukutin-related protein in the Golgi apparatus.
AB  - Two forms of congenital muscular dystrophy (CMD), Fukuyama CMD and CMD type 1C
      (MDC1C) are caused by mutations in the genes encoding two putative
      glycosyltransferases, fukutin and fukutin-related protein (FKRP). Additionally,
      mutations in the FKRP gene also cause limb-girdle muscular dystrophy type 2I
      (LGMD2I), a considerably milder allelic variant than MDC1C. All of these diseases
      are associated with secondary changes in muscle alpha-dystroglycan expression. To
      elucidate the function of FKRP and fukutin and examine the effects of MDC1C
      patient mutations, we have determined the mechanism for the subcellular location
      of each protein. FKRP and fukutin are targeted to the medial-Golgi apparatus
      through their N-termini and transmembrane domains. Overexpression of FKRP in CHO
      cells alters the post-translational processing of alpha- and beta-dystroglycan
      inhibiting maturation of the two isoforms. Mutations in the DxD motif in the
      putative active site of the protein or in the Golgi-targeting sequence, which
      cause FKRP to be inefficiently trafficked to the Golgi apparatus, did not alter
      dystroglycan processing in vitro. The P448L mutation in FKRP that causes
      congenital muscular dystrophy changes a conserved amino acid resulting in the
      mislocalization of the mutant protein in the cell that is unable to alter
      dystroglycan processing. Our data show that FKRP and fukutin are Golgi-resident
      proteins and that FKRP is required for the post-translational modification of
      dystroglycan. Aberrant processing of dystroglycan caused by a mislocalized FKRP
      mutant could be a novel mechanism that causes congenital muscular dystrophy.

PMID- 12471059
TI  - Prevention of pathology in mdx mice by expression of utrophin: analysis using an
      inducible transgenic expression system.
AB  - Duchenne muscular dystrophy results from the absence of dystrophin, a
      cytoskeletal protein. Previously, we have shown in a transgenic mouse model of
      the disease (mdx) that high levels of expression of the dystrophin-related
      protein, utrophin can prevent pathology. We developed a new transgenic mouse
      model where muscle specific utrophin expression was conditioned by addition of
      tetracycline in water. Transgene expression was turned on at different time
      points: in utero, at birth, 10 and 30 days after birth. We obtained moderate
      levels of expression, variable from fibre to fibre (mosaicism) but sufficient to
      induce a correct localization of the dystro-sarcoglycan complex. Histology
      revealed a reduction of necrotic foci and of the percentage of centronucleated
      fibres, which remained still largely above the normal level. Isometric force was
      not improved but the resistance to eccentric contractions was significantly
      stronger. When utrophin expression was activated 30 days after birth,
      improvements were marginal, suggesting that the age at which utrophin therapy is
      initiated could be an important factor. Our results also provide an unexpected
      insight into the pathogenesis of the dystrophinopathies. We observed a complete
      normalization of the characteristics of the mechano-sensitive/voltage-independent
      Ca(2+) channels (occurrence, open probabilities and Ca(2+) currents), while the
      classical markers of dystrophy were still abnormal. These observations question
      the role of increased Ca(2+) channel activity in initiating the dystrophic
      process. The new model shows that utrophin therapy, initiated after birth, can be
      effective, but the extent of correction of the various symptoms of
      dystrophinopathy critically depends on the amount of utrophin expressed.

PMID- 12471060
TI  - Expression analyses and interaction with the anaphase promoting complex protein
      Apc2 suggest a role for inversin in primary cilia and involvement in the cell
      cycle.
AB  - Homozygous inv mice lack a functional inversin protein and exhibit situs inversus
      plus severe cystic changes in the kidney and pancreas. Although the inversin
      sequence has provided few clues to its function, we and others have previously
      identified calmodulin as a binding partner. We now provide evidence that inversin
      interacts with the anaphase promoting complex protein Apc2. As expected of an
      Apc2 target, inversin possesses D-boxes and site-directed mutagenesis of the well
      conserved D-box residues abrogates inversin-Apc2 interaction. An inversin
      specific antibody reveals a dynamic expression pattern throughout the cell cycle
      and strong expression in the primary cilia of renal epithelium. Our data support
      a role for inversin in primary cilia and involvement in the cell cycle. Mutations
      of the proteins polaris, cystin and polycystin-2 which are expressed in renal
      epithelium primary cilia, lead to renal cystic changes. Aberrant cell
      proliferation is also involved in cyst development. The data reported here
      suggest that inversin may provide a link between these two mechanisms.

PMID- 12471061
TI  - Progressive retinal degeneration and dysfunction in R6 Huntington's disease mice.
AB  - Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) belong to a
      group of progressive neurodegenerative diseases caused by polyglutamine (polyQ)
      expansions. SCA7 is the only one to display degeneration in the retina, a tissue
      usually spared in HD. We previously described a SCA7 transgenic retinal model
      expressing mutant full length ataxin-7 in rod photoreceptors. These mice develop
      a severe and characteristic retinopathy. We show here that R6 transgenic mice,
      which reproduce many features of HD, express mutant huntingtin in the retina
      leading to strong vision deficiencies and retinal dystrophy. These two different
      polyQ mouse models exhibit comparable early and progressive retinal degeneration
      and dysfunction. These abnormalities are reminiscent of other retinal
      degeneration phenotypes (in particular rd7/rd7 mice) where photoreceptor cell
      loss occurs. Retinopathy in R6 and R7E models can be monitored in living mice by
      ERG and fundus examination, which can facilitate in vivo evaluation of
      therapeutic agents in polyQ disorders.

PMID- 12471062
TI  - Identification of the gene responsible for the cblB complementation group of
      vitamin B12-dependent methylmalonic aciduria.
AB  - The methylmalonic acidurias are metabolic disorders resulting from deficient
      methylmalonyl-CoA mutase activity, a vitamin B(12)-dependent enzyme. We have
      cloned the gene for the cblB complementation group caused by deficient activity
      of a cob(I)alamin adenosyltransferase. This was accomplished by searching
      bacterial genomes for genes in close proximity to the methylmalonyl-CoA mutase
      gene that might encode a protein with the properties of an adenosyltransferase. A
      candidate was identified in the Archaeoglobus fulgidus genome and was used to
      probe the human genome database. It yielded a gene on chromosome 12q24 that
      encodes a predicted protein of 250 amino acids with 45% similarity to PduO in
      Salmonella enterica, a characterized cob(I)alamin adenosyltransferase. A northern
      blot revealed an RNA species of 1.1 kb predominating in liver and skeletal
      muscle. The gene was evaluated for deleterious mutations in cblB patient cell
      lines. Several mutations were identified including a 5 bp deletion
      (5del572gggcc576), two splice site mutations (IVS2-1G>T, IVS3-1G>A), andt several
      point mutations (A135T, R186W, R191W and E193K). Two additional amino acid
      substitutions (R19Q and M239K) were found in several patient cell lines but were
      found to be common polymorphisms (36% and 46%) in control alleles. The R186W
      mutation, which we suggest is disease-linked, is present in four of the six
      patient cell lines examined (homoallelic in two) and in 4 of 240 alleles in
      control samples. These data confirm that the identified gene, MMAB, corresponds
      to the cblB complementation group and has the appearance of a cob(I)alamin
      adenosyltransferase, as predicted from biochemical data.

PMID- 12471063
TI  - Structure and function of natural killer cell surface receptors.
AB  - Since mid-1990, with cloning and identification of several families of natural
      killer (NK) receptors, research on NK cells began to receive appreciable
      attention. Determination of structures of NK cell surface receptors and their
      ligand complexes led to a fast growth in our understanding of the activation and
      ligand recognition by these receptors as well as their function in innate
      immunity. Functionally, NK cell surface receptors are divided into two groups,
      the inhibitory and the activating receptors. Structurally, they belong to either
      the immunoglobulin (Ig)-like receptor superfamily or the C-type lectin-like
      receptor (CTLR) superfamily. Their ligands are either members of class I major
      histocompatibility complexes (MHC) or homologs of class I MHC molecules. The
      inhibitory form of NK receptors provides the protective immunity through
      recognizing class I MHC molecules with self-peptides on healthy host cells. The
      activating, or the noninhibitory, NK receptors mediate the killing of tumor or
      virally infected cells through their specific ligand recognition. The structures
      of activating and inhibitory NK cell surface receptors and their complexes with
      the ligands determined to date, including killer immunoglobulin-like receptors
      (KIRs) and their complexes with HLA molecules, CD94, Ly49A, and its complex with
      H-2Dd, and NKG2D receptors and their complexes with class I MHC homologs, are
      reviewed here.

PMID- 12471064
TI  - The role of dynamics in enzyme activity.
AB  - Although protein function is thought to depend on flexibility, precisely how the
      dynamics of the molecule and its environment contribute to catalytic mechanisms
      is unclear. We review experimental and computational work relating to enzyme
      dynamics and function, including the role of solvent. The evidence suggests that
      fast motions on the 100 ps timescale, and any motions coupled to these, are not
      required for enzyme function. Proteins where the function is electron transfer,
      proton tunneling, or ligand binding may have different dynamical dependencies
      from those for enzymes, and enzymes with large turnover numbers may have
      different dynamical dependencies from those that turn over more slowly. The
      timescale differences between the fastest anharmonic fluctuations and the barrier
      crossing rate point to the need to develop methods to resolve the range of
      motions present in enzymes on different time- and lengthscales.

PMID- 12471065
TI  - An unknown: lung growth and development after very preterm birth.

PMID- 12471066
TI  - Nicotine, serotonin, and sudden infant death syndrome.

PMID- 12471067
TI  - Cystic fibrosis: when to refer for lung transplantation-is the answer clear?

PMID- 12471068
TI  - Idiopathic pneumonia after marrow transplantation: when are antioxidants
      effective?

PMID- 12471069
TI  - Compliance (COMmunicate PLease wIth Less Abbreviations, Noun Clusters, and
      Exclusiveness).

PMID- 12471070
TI  - High adventure in pulmonary hypertension: acute and chronic hypoxia are not the
      same.

PMID- 12471071
TI  - Worsening of V'maxFRC in infants with chronic lung disease in the first year of
      life: a more favorable outcome after high-frequency oscillation ventilation.
AB  - Little is known about the development of maximal flow at functional residual
      capacity, a measure of airway patency, in infants with chronic lung disease
      (CLD). In a follow-up study, we evaluated V'maxFRC in very low birth weight
      infants with CLD, treated with high-frequency oscillation ventilation (HFOV) or
      conventional mechanical ventilation. In 36 infants with CLD, V'maxFRC was
      evaluated at 6 and/or 12 months corrected age, and the relationship between
      perinatal factors and lung function was studied. Mean (SD) birth weight and
      gestational age were 837 (152) g and 26.8 (1.7) weeks, respectively. At 6 and 12
      months, mean V'maxFRC was significantly below normal. Between 6 and 12 months,
      there was a mean (95% confidence interval) reduction in V'maxFRC (Z score) of 0.5
      (0.2-0.7) (p < 0.001). At 12 months, the mean V'maxFRC (Z score) was higher for
      children initially treated with HFOV (n = 15), as compared with children treated
      with conventional mechanical ventilation (n = 16): mean (95% confidence interval)
      difference was 0.6 (0.2-1.0) (p = 0.008). We conclude that very low birth weight
      infants with CLD have decreased V'maxFRC that worsen during the first year of
      life. Initial treatment with HFOV was associated with a more favorable outcome of
      V'maxFRC at 12 months corrected age.

PMID- 12471072
TI  - Prenatal nicotine exposure blunts the cardiorespiratory response to hypoxia in
      lambs.
AB  - Because smoking during pregnancy is a major risk factor for late fetal death and
      the sudden infant death syndrome, we investigated cardiorespiratory defense
      mechanisms to hypoxia in 7 prenatally nicotine-exposed (N) lambs (approximate
      maternal dose: 0.5 mg/kg/day) and 11 control (C) lambs all at an average age of 5
      days. The ventilatory response to 10% oxygen (hyperpnea) was significantly
      attenuated during quiet sleep in N lambs compared with C lambs and in N lambs
      aroused from sleep later compared with C lambs (161 +/- 90 versus 75 +/- 66
      seconds, p < 0.05). The ventilatory response to hypoxia was similar in the two
      groups during wakefulness (W), whereas the heart rate response (tachycardia) was
      significantly lower in N lambs compared with C lambs during both activity states.
      The ventilatory response to hyperoxia was significantly lower in N lambs compared
      with C lambs during both activity states. Transition from W to quiet sleep was
      associated with a significant decrease in ventilation in C lambs but not in N
      lambs. In conclusion, prenatal nicotine exposure, at a dose comparable with
      moderate smoking, blunts major elements of the cardiorespiratory defense to
      hypoxia, i.e., the heart rate and ventilatory and arousal responses, and
      abolishes the normal decrease in ventilation during sleep compared with W.

PMID- 12471073
TI  - Idiopathic pneumonia syndrome after syngeneic bone marrow transplant in mice.
AB  - Idiopathic pneumonia syndrome is characterized by noninfectious diffuse lung
      injury after myeloablative chemotherapy and bone marrow transplant. Because
      little is known about its pathogenesis after autologous-based regimens, we have
      developed a murine model that closely mimics the human lung disease process.
      Using an autologous regimen similar to that used for patients with metastatic
      breast cancer, mice developed pulmonary injury as early as 1 day posttransplant.
      This lung injury was most dramatically characterized by decreased lung compliance
      that was associated with an intense monocytic cellular infiltrate of activated
      macrophages. This influx was preceded by an acute elevation in monocyte
      chemotactic protein-1 and macrophage inflammatory protein-1alpha. The
      conditioning regimen caused substantial oxidative stress as manifest by
      elevations in lung lipid peroxidation and oxidized glutathione. To test the
      hypothesis that oxidation is directly responsible for the lung toxicity, we
      administered the antioxidant, n-acetylcysteine. These mice showed substantially
      less lung injury, thus providing direct evidence that oxidative stress plays a
      distinct role in the development of lung injury in the early periautologous bone
      marrow transplant period. Attenuation of lung oxidative stress and/or
      inflammation in patients undergoing autologous bone marrow transplant may reduce
      the subsequent development of idiopathic pneumonia syndrome.

PMID- 12471074
TI  - The relationship of reticular basement membrane thickness to airway wall
      remodeling in asthma.
AB  - Assessment of airway wall remodeling in asthma is difficult in vivo. The
      thickness of deposited extracellular matrix proteins below the epithelium, the
      reticular basement membrane, can be assessed by bronchial biopsy of proximal
      airways. The aim of this study was to determine the relationship between the
      thickness of the reticular basement membrane in a sample equivalent to a central
      airway biopsy and the dimensions of the airway wall measured on transverse
      sections of both central and peripheral airways. Large and small cartilaginous
      and membranous airways from persons who had died from asthma (fatal asthma, n =
      5) or from nonrespiratory causes with asthma (nonfatal asthma, n = 5) or without
      asthma (control subjects, n = 5) were studied. Reticular basement membrane
      thickness correlated with the percentage of smooth muscle, submucosal mucous
      gland, and inner wall area (p < 0.05) in large cartilaginous airways, and with
      inner wall area and area of smooth muscle (p < 0.01) in small cartilaginous
      airways, but was not related to airway wall dimensions in membranous airways.
      These findings show that reticular basement membrane thickness of central
      airways, which may be assessed by endobronchial biopsy, is correlated with airway
      remodeling in cartilaginous airways but not with airway wall dimensions of
      membranous airways.

PMID- 12471075
TI  - Alpha1-antitrypsin determines the pattern of emphysema and function in tobacco
      smoke-exposed mice: parallels with human disease.
AB  - Cigarette smoking in humans is associated with various patterns of emphysema and
      functional consequences. We tested the hypothesis that variations in alpha1
      antitrypsin expression modulate the pattern of emphysema and functional
      consequences in cigarette smoke-exposed mice. We compared the effects of up to 6
      months of cigarette smoke exposure in C57BL/6J (C57) mice and in low-alpha1
      antitrypsin, C57BL/6J pa+/pa+ (pallid) mice. At the end of the experiment, we
      determined lung mechanical properties, the extent (mean linear intercept) and
      type of emphysema, and the cellular inflammatory response. After 4 months of
      cigarette smoking, pallid smoking mice, but not C57 smoking mice, had a
      significant increase in mean linear intercept. After 6 months of smoke exposure,
      C57 smoking mice and pallid smoking mice had similar degrees of emphysema. The
      pattern of emphysema in pallid smoking mice was more diffuse than in C57 smoking
      mice, affecting all airspaces. Pallid mice, but not C57 mice, developed a T cell
      inflammation in the alveolar wall after 6 months of smoking (p < 0.01). Although
      lung compliance was not changed in C57 smoking mice after smoke exposure, it
      increased significantly in pallid smoking mice over the 6 months of exposure (p <
      0.0082). In summary, cigarette smoking induces emphysema in C57 and pallid mice,
      but the emphysema, inflammatory infiltrate, and resulting physiologic
      abnormalities were substantially different in the two strains, with the C57 and
      pallid mice exhibiting features similar to centrilobular and panlobular
      emphysema, respectively.

PMID- 12471076
TI  - Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm
      electrodes.
AB  - In patients with ventilator-dependent tetraplegia, phrenic nerve pacing (PNP)
      provides significant clinical advantages compared with mechanical ventilation.
      This technique however generally requires a thoracotomy with its associated risks
      and in-patient hospital stay and carries some risk of phrenic nerve injury. We
      have developed a method by which the phrenic nerves can be activated via
      intramuscular diaphragm electrodes. In one patient with ventilator-dependent
      tetraplegia, two intramuscular diaphragm electrodes were implanted into each
      hemidiaphragm near the phrenic nerve motor points via laparoscopic surgery. The
      motor points were identified employing a previously devised mapping technique.
      Because inspired volumes were suboptimal on the right, a second laparoscopic
      procedure was necessary to position electrodes near the anterior and posterior
      branches of the right phrenic nerve. During bilateral stimulation, inspired
      volume was 580 ml. After a reconditioning program of progressively increasing
      diaphragm pacing, maximum inspired volumes on the left and right hemidiaphragms
      increased significantly. Maximum combined bilateral stimulation was 1120 ml.
      Importantly, the patient has been able to comfortably tolerate full-time pacing.
      If confirmed in additional patients, PNP with intramuscular diaphragm electrodes
      via laparoscopic surgery may provide a less invasive and less costly alternative
      to conventional PNP.

PMID- 12471077
TI  - On the abuse of acronyms.

PMID- 12471078
TI  - Cell-mediated immunity in asthma?

PMID- 12471079
TI  - Potential conflict of interest in AJRCCM.

PMID- 12471081
TI  - Chairman's Summary: Oxidants and antioxidants: Transatlantic Airway Conference
      2002.

PMID- 12471082
TI  - Reactive oxygen species and cell signaling: respiratory burst in macrophage
      signaling.
AB  - Phagocytes such as neutrophils and macrophages produce reactive oxygen species
      (ROS) during phagocytosis or stimulation with a wide variety of agents through
      activation of nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase
      that is assembled at the plasma membrane from resident plasma membrane and
      cytosolic protein components. One of the subunits of the phagocyte NADPH oxidase
      is now recognized as a member of a family of NADPH oxidases, or NOX, present in
      cells other than phagocytes. Physiologic generation of ROS has been implicated in
      a variety of physiologic responses from transcriptional activation to cell
      proliferation and apoptosis. The increase in superoxide and hydrogen peroxide
      (H2O2) that results from stimulation of the NADPH oxidase is transient, in part
      due to the presence of the antioxidant enzymes, which return their concentrations
      to the prestimulation steady state level. Thus, the antioxidant enzymes may
      function in the "turn-off" phase of signal transduction by ROS. During its
      transient elevation, H2O2 may act as a modifier of key signaling enzymes through
      reversible oxidation of critical thiols. The rapid reaction of thiols with H2O2
      when in their unprotonated state would provide a potential mechanism for the
      specificity that is necessary for physiologic cell signaling.

PMID- 12471083
TI  - Reactive nitrogen species and cell signaling: implications for death or survival
      of lung epithelium.
AB  - Reactive nitrogen species such as nitric oxide, peroxynitrite, and nitrogen
      dioxide have been implicated in the pathophysiology of inflammatory lung
      diseases. Yet, the molecular mechanisms and cell signaling events responsible for
      cellular injury remain to be elucidated. Two major signaling pathways, co
      ordinately regulated and responsible for cell survival and cell death, involve
      nuclear factor kappa B and c-Jun-N-terminal kinase, respectively. A review of
      these pathways, their modes of action, and their importance in executing
      oxidative stress responses in lung epithelial cells are discussed.

PMID- 12471084
TI  - Airway chemotransduction: from oxygen sensor to cellular effector.
AB  - The process of sensing, transducing, and acting on environmental cues is critical
      to normal physiologic function. Furthermore, dysfunction of this process can lead
      to the development of disease. This is especially true of the homeostatic
      mechanisms that have evolved to maintain the carriage of O2 to respiring tissues
      during acute hypoxic challenge. During periods of reduced O2 availability, three
      major mechanisms act conjointly to increase ventilation and optimize the
      ventilation-perfusion ratio throughout the lung by directing pulmonary blood flow
      to better ventilated areas of the lung. These mechanisms are as follows: (1)
      increased carotid sinus nerve discharge rate to the respiratory centers of the
      brain, (2) intrinsic hypoxic vasoconstriction of pulmonary resistance vessels,
      and (3) potential local and central modulation via stimulation of neuroepithelial
      bodies of the lung. The key to the rapid response to the O2 signal is the ability
      of each of these tissues to sense acutely the changes in PO2, to transduce the
      signal, and for cellular effectors to initiate compensatory mechanisms that will
      offset rapidly the reduction in PO2 before O2 availability to tissues is
      compromised. This review concentrates on the signal transduction mechanism that
      links altered PO2 to depolarization in the recently proposed airway chemosensory
      element, the neuroepithelial body (and its immortalized cellular counterpart, the
      H146 cell line), and discusses the pertinent similarities and differences that
      exist between airway, carotid body, and pulmonary arteriolar O2 sensing.

PMID- 12471085
TI  - The isoprostanes: their role as an index of oxidant stress status in human
      pulmonary disease.
AB  - The isoprostanes are a unique series of prostaglandin-like compounds formed in
      vivo from the free radical-initiated peroxidation of arachidonic acid independent
      of the cyclooxygenase enzyme. This article summarizes selected aspects regarding
      our current knowledge of these compounds and what are considered avenues for
      future research. Novel aspects related to the biochemistry of isoprostane
      formation are discussed first, followed by a summary of methods by which these
      compounds are analyzed. A considerable portion of this article deals with the
      utility of measuring isoprostanes as markers of oxidant injury in vitro and in
      vivo, particularly in pulmonary diseases. Studies performed over the past decade
      have shown that these compounds are extremely accurate measures of lipid
      peroxidation in animals and humans and have illuminated the role of oxidant
      injury in a number of human diseases, including those related to the lung.

PMID- 12471086
TI  - Analysis of expired air for oxidation products.
AB  - Chronic inflammation is a critical feature of chronic obstructive pulmonary
      disease, cystic fibrosis, and asthma. This inflammation is associated with the
      increased production of reactive oxygen species or oxidative stress in the lungs.
      Oxidative stress may have several adverse effects and may amplify the
      inflammatory process; however, monitoring oxidative stress is difficult and may
      not be reflected by changes in blood markers. We have therefore developed several
      noninvasive markers in the exhaled breath that may indicate oxidative stress in
      the lungs, and we studied these in relationship to the severity of chronic
      inflammatory lung diseases. We analyzed the exhaled breath for the content of
      nitric oxide as a marker of inflammation, carbon monoxide as a marker of
      oxidative stress, and ethane, which is one of the end products of lipid
      peroxidation. In addition, we measured the concentration of markers of oxidative
      stress such as isoprostanes in exhaled breath condensate. Our results confirm
      that there are increased inflammation, oxidative stress, and lipid peroxidation
      in lung disease, as shown by elevated levels of nitric oxide, carbon monoxide,
      and ethane, respectively. The finding of lower levels of these gases in patients
      on steroid treatment and of higher levels in those with more severe lung disease,
      as assessed by lung function tests and clinical symptoms, reinforces the
      hypothesis that the noninvasive measurement of exhaled gases maybe useful in
      monitoring the underlying pathologic pathways of lung disease. Longitudinal
      studies are required to assess the clinical usefulness of these measurements in
      the monitoring of chronic inflammatory lung disease.

PMID- 12471087
TI  - Oxidative stress in airways: is there a role for extracellular superoxide
      dismutase?
AB  - Airways are exposed to high levels of environmental oxidants, yet they also have
      enriched extracellular antioxidants. Airways disease such as asthma, cystic
      fibrosis, and chronic obstructive pulmonary disease have evidence of increased
      oxidative stress, suggesting that reactive oxygen and nitrogen species may
      overwhelm antioxidant defenses in airway diseases. Extracellular superoxide
      dismutase is abundant in pulmonary tissues and protects the lung from increased
      oxidative stress; however, its role in asthma and other airway diseases has not
      been fully elucidated. Proteolytic processing of extracellular superoxide
      dismutase decreases its affinity for the extracellular matrix and may be a
      mechanism to regulate its distribution during conditions of inflammation or
      oxidative stress.

PMID- 12471088
TI  - Environmental oxidant pollutant effects on biologic systems: a focus on
      micronutrient antioxidant-oxidant interactions.
AB  - Oxidative atmospheric pollutants represent a significant source of stress to both
      terrestrial plants and animals. The biosurfaces of plants and surface-living
      organisms are directly exposed to these pollutant stresses. These surfaces,
      including respiratory tract surfaces, contain integrated antioxidant systems that
      would be expected to provide a primary defense against environmental threats
      caused by atmospheric reactive oxygen species. When the biosurface antioxidant
      defenses are overwhelmed, oxidative stress to the cellular components of the
      exposed biosurfaces can be expected, inducing inflammatory, adaptive, injurious,
      and reparative processes. Studies of mutants and/or transformed plants and
      insects, with specific alterations in key components of antioxidant defense
      systems, offer opportunities to dissect the complex systems that maintain surface
      defenses against environmental oxidants. In this article, we use a comparative
      approach to consider interactions of atmospheric oxidant pollutants with selected
      biosystems, with focus on O3 as the pollutant; plants, flies, skin, and lungs as
      the exposed biosystems; and nonenzymatic micronutrient antioxidants as
      significant contributors to overall antioxidant defense strategies of these
      varied biosystems. Parallelisms among several living organisms, with regard to
      their protective strategies against environmental atmospheric oxidants, are
      presented.

PMID- 12471089
TI  - Transgenic and knockout models for studying the role of lung antioxidant enzymes
      in defense against hyperoxia.
AB  - Although a role for antioxidant enzymes in preventing lung injury from hyperoxic
      exposure has been implicated in a number of early studies, a direct test for the
      hypothesis was not available. We intended to address this question using
      genetically modified mice in which the expression of a single antioxidant enzyme
      was either enhanced or diminished. We reasoned that if an antioxidant enzyme
      functions in protecting lung cells against oxidant-mediated injury, the level of
      its gene expression would correlate with the degree of tolerance to hyperoxia.
      Overexpression of functional human manganese superoxide dismutase (MnSOD) in lung
      alveolar type I and type II cells, fibroblasts, and capillary endothelial cells
      in strain B6C3 mice was achieved by incorporating a human beta-actin promoter
      based MnSOD transgene into the mouse genome. However, MnSOD overexpression failed
      to prolong the survival of transgenic mice on exposure to greater than 99% oxygen
      compared with wild-type mice. In addition, mice deficient in copper-zinc
      superoxide dismutase or cellular glutathione peroxidase exhibited a marked
      sensitivity to numerous models of oxidant tissue injury but were not
      hypersensitive to hyperoxia. These data suggest that the role of these three
      antioxidant enzymes in preventing oxidant-mediated lung injury from hyperoxic
      exposure is negligible, and other cellular antioxidant enzymes and systems may be
      primarily used by the lungs in defense against hyperoxia.

PMID- 12471090
TI  - Lactoperoxidase and hydrogen peroxide metabolism in the airway.
AB  - Hydrogen peroxide (H2O2) is known to play an important role in airway
      homeostasis. For this reason its levels and thus its synthesis and consumption
      are important mechanisms for controlling airway functions. We have identified the
      major macromolecular consumer of H2O2 in sheep airway secretions to be
      lactoperoxidase (LPO), a heme peroxidase previously studied in milk and saliva.
      This enzyme uses H2O2 to oxidize the anion thiocyanate to an antibiotic compound
      that prevents growth of bacteria, fungi, and viruses. LPO was isolated from sheep
      airways and proved to be a major constituent comprising about 1% of the soluble
      protein in airway secretions. The isolated airway LPO was catalytically active
      and displayed the enzymatic characteristics previously described for the enzyme
      isolated from bovine milk. Airway LPO activity was shown to increase the rate of
      bacterial clearance from sheep airways. The role of this enzyme in the airway
      host defense strongly suggests that an active H2O2 production system exists to
      supply appropriate substrate for the enzyme. The identity of this H2O2 synthesis
      system is an important, yet unknown feature of airway oxygen radical metabolism.

PMID- 12471091
TI  - Vitamin E as an antioxidant of the lung: mechanisms of vitamin E delivery to
      alveolar type II cells.
AB  - Oxidants play an important role in the development of acute and chronic lung
      injuries. Alveolar surfactant is the first target of air-borne oxidants.
      Surfactant contains, besides dipalmitoyl phosphatidylcholine, cholesterol and
      polyunsaturated phospholipids that play an important functional role. Therefore,
      vitamin E could be important for protecting surfactant lipids against oxidation
      and subsequent lung injury. Alveolar type II cells play a central role in
      synthesis and secretion of surfactant lipids and also supplement the surfactant
      with vitamin E during intracellular assembly. High density lipoprotein (HDL) is
      the primary source of vitamin E for type II cells. The uptake of vitamin E by
      specific lipid transfer is mediated by at least three HDL-specific receptors
      (scavenger receptor BI, membrane dipeptidase, and HDL-binding protein-2). In
      addition, cubilin and megalin mediate in a cooperative manner HDL-holoparticle
      uptake by alveolar type II cells. A temporary vitamin E deficiency induces a
      reversible change of the expression of pro- and antiinflammatory markers and of
      markers defining apoptosis, and reduces surfactant lipid synthesis in alveolar
      type II cells. These metabolic changes of type II cells may prime the lung to
      develop clinically manifest injury in response to an additional insult, e.g.,
      hyperoxia.

PMID- 12471092
TI  - Cutting edge: virus-specific CD4+ memory T cells in nonlymphoid tissues express a
      highly activated phenotype.
AB  - Recent studies have shown that CD4(+) memory T cells persist in nonlymphoid
      organs following infections. However, the development and phenotype of these
      peripheral memory cells are poorly defined. In this study, multimerized MHC-Ig
      fusion proteins, with a covalently attached peptide sequence from the Sendai
      virus hemagglutinin/neuraminidase gene, have been used to identify virus-specific
      CD4(+) T cells during Sendai virus infection and the establishment of peripheral
      CD4(+) memory populations in the lungs. We show declining frequencies of virus
      specific CD4(+) T cells in the lungs over the course of approximately 3 mo after
      infection. Like peripheral CD8(+) T cells, the CD4(+) have an acutely activated
      phenotype, suggesting that a high level of differentiation is required to reach
      the airways and persist as memory cells. Differences in CD25 and CD11a expression
      indicate that the CD4(+) cells from the lung airways and parenchyma are distinct
      memory populations.

PMID- 12471093
TI  - Cutting edge: B7/CD28 interactions regulate cell cycle progression independent of
      the strength of TCR signaling.
AB  - The role of B7/CD28 signals in Ag-induced cell cycle progression of CD4(+) T
      cells was examined using the technique of CFSE dye dilution and flow cytometry.
      In wild-type T cells, proliferation was directly related to the concentration of
      Ag available to the APC. Consistent with this, the rate of G(0)-->G(1) cell cycle
      progression varied with the concentration of Ag. However, cell division by T cell
      blasts occurred at a constant rate, independent of Ag concentration. G(0)-->G(1)
      phase progression by CD28-deficient CD4(+) T cells or wild-type T cells cultured
      in the presence of neutralizing anti-B7 mAbs was slowed, confirming that a
      synergy does exist between TCR and CD28 signaling in the initial activation of
      the T cells. However, unlike the TCR, the strength of CD28 stimulation was also
      shown to play a unique role in controlling the rate of cell division by T cell
      blasts.

PMID- 12471094
TI  - Cutting edge: distal regulatory elements are required to achieve selective
      expression of IFN-gamma in Th1/Tc1 effector cells.
AB  - Using a transgenic approach, we analyzed the contribution of introns located
      within the IFN-gamma gene and distal regulatory regions to IFN-gamma gene
      expression. Intron 1 and 3 from the IFN-gamma gene displayed strong enhancer
      activity. This activity appeared to be dependent upon integration into the genome
      but resulted in a loss of Th1 selectivity. We also found that distal regulatory
      elements are not required for high level expression of the human IFN-gamma gene,
      but rather for cell lineage-specific expression. An 8.6-kb human IFN-gamma
      transgene was sufficient to yield high level expression but a 191-kb IFN-gamma
      transgene with approximately 90 kb of flanking 5' and 3' sequence was necessary
      to achieve both high level and Th1 selective expression of human IFN-gamma.

PMID- 12471095
TI  - Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that
      preferentially activates the IFN-beta promoter in the Toll-like receptor
      signaling.
AB  - MyD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling
      pathways via Toll-like receptor (TLR) family. However, accumulating evidence
      demonstrates the existence of a MyD88-independent pathway, which may explain
      unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR
      domain-containing adapter protein (TIRAP)/MyD88 adapter-like, a second adapter
      harboring the TIR domain, is essential for MyD88-dependent TLR2 and TLR4
      signaling pathways, but not for MyD88-independent pathways. Here, we identified a
      novel TIR domain-containing molecule, named TIR domain-containing adapter
      inducing IFN-beta (TRIF). As is the case in MyD88 and TIRAP, overexpression of
      TRIF activated the NF-kappaB-dependent promoter. A dominant-negative form of TRIF
      inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. Furthermore,
      TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. Dominant
      negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent
      and IFN-beta promoters. TRIF associated with TLR3 and IFN regulatory factor 3.
      These findings suggest that TRIF is involved in the TLR signaling, particularly
      in the MyD88-independent pathway.

PMID- 12471096
TI  - Cutting edge: differential chemokine production by myeloid and plasmacytoid
      dendritic cells.
AB  - To examine the different roles of myeloid dendritic cells (M-DCs) and
      plasmacytoid dendritic cells (P-DCs) in the induction and regulation of immune
      response, we have studied chemokine secretion by freshly isolated DC subsets in
      response to bacterial, viral, and T cell-derived stimuli. M-DCs selectively
      produced very high levels of the homeostatic chemokines CC chemokine ligand
      (CCL)17 and CCL22, while P-DCs produced very little if any. In contrast, the
      proinflammatory chemokine CCL3 was secreted mostly by P-DCs, whereas CCL4 and CXC
      chemokine ligand 8 were produced by both subsets. The selective production of
      CCL17 and CCL22 by M-DCs but not P-DCs was confirmed in vivo by immunohistology
      on human reactive lymph node sections. The high production of CCR4 ligands by M
      DCs suggests their capacity to selectively recruit at sites of inflammation T
      cells with regulatory properties or with a Th2 phenotype, whereas P-DCs, by
      preferentially secreting CCR1/CCR5 ligands, would mostly recruit effector T cells
      and, in particular, Th1-type cells.

PMID- 12471097
TI  - Cutting edge: inflammatory signals drive organ-specific autoimmunity to normally
      cross-tolerizing endogenous antigen.
AB  - Links have been observed between infections and the development of autoimmunity.
      Proposed explanations include activation of self-Ag-bearing APC. Using a model
      system in which transgenic OVA is expressed in enterocytes, we showed that CD8 T
      cell recognition of cross-presented Ag in gut-associated lymph nodes was
      tolerogenic. However, concomitant infection with vesicular stomatitis virus
      encoding OVA abrogated tolerance and induced disease. We now show that following
      transfer of naive OT-I T cells, the addition of wild-type vesicular stomatitis
      virus, oral cholera toxin, or CD40 triggering can induce intestinal disease in
      transgenic mice. Tissue damage accompanied dramatic increases in cytokine release
      by activated OT-I cells in the intestine. The data indicated that products of
      antigenically unrelated infections can combine with cross-presented self-Ags on
      APC to prime autoaggressiveness, independent of additional Ag release. These
      results help explain how diverse pathogens, lacking any homology to self
      proteins, could be causative agents in induction of organ-specific autoimmunity.

PMID- 12471098
TI  - Cutting edge: a new tool to evaluate human pre-erythrocytic malaria vaccines:
      rodent parasites bearing a hybrid Plasmodium falciparum circumsporozoite protein.
AB  - Malaria vaccines containing the Plasmodium falciparum Circumsporozoite protein
      repeat domain are undergoing human trials. There is no simple method to evaluate
      the effect of vaccine-induced responses on P. falciparum sporozoite infectivity.
      Unlike the rodent malaria Plasmodium berghei, P. falciparum sporozoites do not
      infect common laboratory animals and only develop in vitro in human hepatocyte
      cultures. We generated a recombinant P. berghei parasite bearing P. falciparum
      Circumsporozoite protein repeats. These hybrid sporozoites are fully infective in
      vivo and in vitro. Monoclonal and polyclonal Abs to P. falciparum repeats
      neutralize hybrid parasite infectivity, and mice immunized with a P. falciparum
      vaccine are protected against challenge with hybrid sporozoites.

PMID- 12471099
TI  - Cutting edge: selection of B lymphocyte subsets is regulated by natural IgM.
AB  - Natural IgM has a wide range of actions in the immune system. Here we demonstrate
      that mice lacking serum IgM have an expansion in splenic marginal zone B cells
      with a proportionately smaller reduction in follicular B cells. The increase in
      the marginal zone-follicular B cell ratio (and an expansion in peritoneal B1a
      cells) is fully reversed by administration of polyclonal IgM, but not by two IgM
      monoclonals. Mice engineered to have a secreted oligoclonal IgM repertoire with
      an endogenous membrane IgM also exhibited a similar expansion of marginal zone B
      cells. We propose that natural IgM, by virtue of its polyreactivity, enhances Ag
      driven signaling through the B cell receptor and promotes the formation of
      follicular B cells. These results demonstrate that natural IgM regulates the
      selection of B lymphocyte subsets.

PMID- 12471100
TI  - Cutting edge: dynamic redistribution of tetraspanin CD81 at the central zone of
      the immune synapse in both T lymphocytes and APC.
AB  - The tetraspanin CD81 has been involved in T-dependent B cell-mediated immune
      responses. However, the behavior of CD81 during immune synapse (IS) formation has
      not been elucidated. We determined herein that CD81 redistributed to the contact
      area of T cell-B cell and T cell-dendritic cell conjugates in an Ag-dependent
      manner. Confocal microscopy showed that CD81 colocalized with CD3 at the central
      supramolecular activation complex. Videomicroscopy studies with APC or T cells
      transiently expressing CD81-green fluorescent protein (GFP) revealed that in both
      cells CD81 redistributed toward the central supramolecular activation complex. In
      T lymphocytes, CD81-GFP rapidly redistributed to the IS, whereas, in the APC,
      CD81-GFP formed a large accumulation in the contact area that later concentrated
      in a discrete cluster and waves of CD81 accumulated at the IS periphery. These
      results suggest a relevant role for CD81 in the topography of the IS that would
      explain its functional implication in T cell-B cell collaboration.

PMID- 12471101
TI  - Murine CD4 T cells selected in a highly disparate xenogeneic porcine thymus graft
      do not show rapid decay in the absence of selecting MHC in the periphery.
AB  - CD4 repopulation can be achieved in T cell-depleted, thymectomized mice grafted
      with xenogeneic porcine thymus tissue. These CD4 T cells are specifically
      tolerant of the xenogeneic porcine thymus donor and the recipient, but are
      positively selected only by porcine MHC. Recent studies suggest that optimal
      peripheral survival of naive CD4 T cells requires the presence of the same class
      II MHC in the periphery as that of the thymus in which they were selected. These
      observations would suggest that T cells selected on porcine thymic MHC would die
      rapidly in the periphery, where porcine MHC is absent. Persistent CD4
      reconstitution achieved in mice grafted with fetal porcine thymus might be due to
      increased thymic output to compensate for rapid death of T cells in the
      periphery. Comparison of CD4 T cell decay after removal of porcine or murine
      thymic grafts ruled out this possibility. No measurable role for peripheral
      murine class II MHC in maintaining the naive CD4 pool originating in thymic
      grafts was demonstrable. However, mouse class II MHC supported the conversion to,
      survival, and/or proliferation of memory-type CD4 cells selected in fetal porcine
      thymus. Thus, the same MHC as that mediating positive selection in the thymus is
      not critical for maintenance of the memory CD4 cell pool in the periphery. Our
      results support the interpretation that xenogeneic thymic transplantation is a
      feasible strategy to reconstitute CD4 T cells and render recipients tolerant of a
      xenogeneic donor.

PMID- 12471102
TI  - Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented
      bone marrow cultures are immature APCs.
AB  - The putative counterparts of human plasmacytoid pre-dendritic cells (pDCs) have
      been described in vivo in mouse models and very recently in an in vitro culture
      system. In this study, we report that large numbers of bone marrow-derived murine
      CD11c(+)B220(+) pDCs can be generated with Flt3 ligand (FL) as the sole exogenous
      differentiation/growth factor and that pDC generation is regulated in vivo by FL
      because FL-deficient mice showed a major reduction in splenic pDC numbers. We
      extensively analyzed bone marrow-derived CD11c(+)B220(+) pDCs and described their
      immature APC phenotype based on MHC class II, activation markers, and chemokine
      receptor level of expression. CD11c(+)B220(+) pDCs showed a nonoverlapping Toll
      like receptor pattern of expression distinct from that of classical CD11c(+)B220(
      ) dendritic cells and were poor T cell stimulators. Stimulation of
      CD11c(+)B220(+) pDCs with oligodeoxynucleotides containing certain CpG motifs
      plus CD40 ligand plus GM-CSF led to increased MHC class II, CD80, CD86, and
      CD8alpha expression levels, to a switch in chemokine receptor expression that
      affected their migration, to IFN-alpha and IL-12 secretion, and to the
      acquisition of priming capacities for both CD4(+) and CD8(+) OVA-specific TCR
      transgenic naive T cells. Thus, the in vitro generation of murine pDCs may serve
      as a useful tool to further investigate pDC biology as well as the potential role
      of these cells in viral immunity and other settings.

PMID- 12471104
TI  - Macrophages and dendritic cells use the cytosolic pathway to rapidly cross
      present antigen from live, vaccinia-infected cells.
AB  - Professional APCs (pAPC) can process and present on their own MHC class I
      molecules Ags acquired from Ag donor cells (ADC). This phenomenon of cross
      presentation is essential in the induction of CD8(+) T cell responses to viruses
      that do not infect pAPC and possibly contributes to the induction of CD8(+)
      responses to many other viruses. However, little is known about the mechanisms
      underlying this process. In this study, we show that dendritic cells and
      macrophages cross-present a model Ag supplied by vaccinia virus-infected ADC via
      the cytosolic route. Strikingly, we also found that cross-presentation of Ags
      provided by vaccinia-infected cells occurs within a couple of hours of pAPC/ADC
      interaction, that the duration of cross-presentation lasts for only 16 h, and
      that cross-presentation can occur at early times of infection when the ADC are
      still alive.

PMID- 12471103
TI  - The role of the MHC class II transactivator in class II expression and antigen
      presentation by astrocytes and in susceptibility to central nervous system
      autoimmune disease.
AB  - The role of the MHC class II transactivator (CIITA) in Ag presentation by
      astrocytes and susceptibility to experimental autoimmune encephalomyelitis (EAE)
      was examined using CIITA-deficient mice and newly created transgenic mice that
      used the glial fibrillary acidic protein promoter to target CIITA expression in
      astrocytes. CIITA was required for class II expression on astrocytes. Like class
      II-deficient mice, CIITA-deficient mice were resistant to EAE by immunization
      with CNS autoantigen, although T cells from immunized CIITA-deficient, but not
      class II-deficient, mice proliferated and secreted Th1 cytokines. CIITA-deficient
      splenic APC presented encephalitogenic peptide to purified wild-type
      encephalitogenic CD4(+) T cells, indicating that CIITA-independent mechanisms can
      be used for class II-restricted Ag presentation in lymphoid tissue. CIITA
      deficient mice were also resistant to EAE by adoptive transfer of
      encephalitogenic class II-restricted CD4(+) Th1 cells, indicating that CIITA
      dependent class II expression was required for CNS Ag presentation. Despite
      constitutive CIITA-driven class II expression on astrocytes in vivo, glial
      fibrillary acidic protein-CIITA transgenic mice were no more susceptible to EAE
      than controls. CIITA-transfected astrocytes presented peptide Ag, but in contrast
      to IFN-gamma-activated astrocytes, they could not process and present native Ag.
      CIITA-transfected astrocytes did not express cathepsin S without IFN-gamma
      activation, indicating that CIITA does not regulate other elements that may be
      required for Ag processing by astrocytes. Although our results demonstrate that
      CIITA-directed class II expression is required for EAE induction, CIITA-directed
      class II expression by astrocytes does not appear to increase EAE susceptibility.
      These results do not support the role of astrocytes as APC for class II
      restricted Ag presentation during the induction phase of EAE.

PMID- 12471105
TI  - Phospholipase C gamma 2 is essential for specific functions of Fc epsilon R and
      Fc gamma R.
AB  - Phospholipase Cgamma2 (PLCgamma2) plays a critical role in the functions of the B
      cell receptor in B cells and of the FcRgamma chain-containing collagen receptor
      in platelets. Here we report that PLCgamma2 is also expressed in mast cells and
      monocytes/macrophages and is activated by cross-linking of Fc(epsilon)R and
      Fc(gamma)R. Although PLCgamma2-deficient mice have normal development and numbers
      of mast cells and monocytes/macrophages, we demonstrate that PLCgamma2 is
      essential for specific functions of Fc(epsilon)R and Fc(gamma)R. While PLCgamma2
      deficient mast cells have normal mitogen-activated protein kinase activation and
      cytokine production at mRNA levels, the mutant cells have impaired Fc(epsilon)R
      mediated Ca(2+) flux and inositol 1,4,5-trisphosphate production, degranulation,
      and cytokine secretion. As a physiological consequence of the effect of PLCgamma2
      deficiency, the mutant mice are resistant to IgE-mediated cutaneous inflammatory
      skin reaction. Macrophages from PLCgamma2-deficient mice have no detectable
      Fc(gamma)R-mediated Ca(2+) flux; however, the mutant cells have normal Fc(gamma)R
      mediated phagocytosis. Moreover, PLCgamma2 plays a nonredundant role in
      Fc(gamma)R-mediated inflammatory skin reaction.

PMID- 12471106
TI  - Activation of CD8 T cells by antigen expressed in the pituitary gland.
AB  - Ag expressed exclusively in the anterior pituitary gland and secreted locally by
      pituitary somatotrophs can gain access to the MHC class I presentation pathway
      and activate CD8 T cells. Influenza nucleoprotein (NP) was expressed as a
      transgene under the control of the human growth hormone (GH) locus control
      region. Activation of monoclonal F5 CD8 T cells specific for NP resulted in
      spontaneous autoimmune pathology of the pituitary gland in mice transgenic for
      both NP and the F5 TCR. Destruction of somatotrophs resulted in drastically
      reduced GH levels in adult mice and a dwarf phenotype. Adoptive transfer of F5 T
      cells into NP-transgenic hosts resulted in full T cell activation, first
      demonstrable in regional lymph nodes, followed by their migration to the
      pituitary gland. Despite the presence of activated, IFN-gamma-producing CD8 T
      cells in the pituitary gland and a slight reduction in pituitary GH levels, no
      effect on growth was observed. Thus, CD8 T cells have access to the
      neuroendocrine system and get fully activated in the absence of CD4 help, but Ag
      recognition in this location causes autoimmune pathology only in the presence of
      excessive CD8 T cell numbers.

PMID- 12471107
TI  - Regulation of N-formyl peptide-mediated degranulation by receptor
      phosphorylation.
AB  - One of the major functions of the N-formyl peptide receptor (FPR) is to mediate
      leukocyte degranulation. Phosphorylation of the C-terminal domain of the FPR is
      required for receptor internalization and desensitization. Although arrestins
      mediate phosphorylation-dependent desensitization, internalization, and
      initiation of novel signaling cascades for a number of G protein-coupled
      receptors, their roles in FPR regulation and signaling remain unclear. CXCR1
      mediated degranulation of RBL-2H3 cells is promoted by arrestin binding. To
      determine whether receptor phosphorylation or arrestin binding is required to
      promote FPR-mediated degranulation, we used RBL-2H3 cells stably transfected with
      either the wild-type FPR or a mutant form, DeltaST, which is incapable of
      undergoing ligand-stimulated phosphorylation. We observed that stimulation of
      wild-type FPR resulted in very low levels of degranulation compared with that
      mediated by cross-linking of the Fc(epsilon)RI receptor. Stimulation of the
      DeltaST mutant, however, resulted in levels of degranulation comparable to those
      of the Fc(epsilon)RI receptor, demonstrating that neither receptor
      phosphorylation nor arrestin binding was necessary to initiate FPR-mediated
      degranulation. Degranulation initiated by the DeltaST mutant was proportional to
      the level of active cell surface receptor, suggesting that either receptor
      internalization or desensitization may be responsible for terminating
      degranulation of the wild-type FPR. To distinguish between these possibilities,
      we used a partially phosphorylation-deficient mutant of the FPR that can undergo
      internalization, but not desensitization. Degranulation by this mutant FPR was
      indistinguishable from that of the DeltaST mutant, indicating that FPR
      phosphorylation or binding of arrestin but not internalization terminates the
      degranulation response.

PMID- 12471108
TI  - Cross-regulation of T cell growth factor expression by p53 and the Tax oncogene.
AB  - In this study, we demonstrate that p53 directly inhibits expression of the T cell
      growth factor (IL-2) in activated T cells. This repression is independent of the
      intrinsic transcriptional activity of p53 and is mediated by the Tax-responsive
      CD28RE-3'-12-O-tetradecanoylphorbol-13-acetate response element (AP1) element of
      the IL-2 promoter. Coexpression of the Tax oncogene causes full reversal of this
      repression through coordinate targeting of p300, CREB, and the NF-kappaB
      pathways. Paradoxically, IL-2 repression by p53 is not reversed by mdm2. Instead,
      mdm2 represses the IL-2 promoter by a mechanism that is synergistic with p53 and
      resistant to Tax reversal. The p300 structure-function studies show that these
      effects are linked to competitive associations among p53, Tax, and mdm2 with
      multiple domains of p300. The functional outcome of these antagonistic
      associations is revealed further by the observation that Tax and p53 induce
      apoptosis in activated T cells through separate and mutually exclusive pathways.
      Interestingly, both pathways are abrogated by mdm2. These results provide
      evidence that a dynamic interplay, between Tax and specific elements of the p53
      network, mediates growth factor expression and programmed cell death in activated
      T cells.

PMID- 12471109
TI  - The role of T cell antagonism and original antigenic sin in genetic immunization.
AB  - To counter highly mutable pathogens like HIV-1, a number of vaccines are being
      developed to deliver multiple mutant forms of viral Ags to provoke multivalent
      antiviral CTLs. However, it is uncertain whether such multiple mutant epitope
      vaccines will generate the diverse CTL responses desired or will instead create
      immune interference. To characterize the role of immune interference by mutant
      epitopes in this process, we have tested a "worst case" scenario in which the
      immunodominant epitope of OVA (SIINFEKL) and its in vitro TCR antagonist
      (SIINFEDL) have been used to genetically immunize C57BL/6 mice. We demonstrate
      here that sequential delivery of these mutant epitopes provokes original
      antigenic sin in CD8 T cells as demonstrated by attenuation of CTLs,
      intracellular IFN-gamma production, and MHC I peptide-tetramer staining. By
      contrast, simultaneous exposure of the immune system to this agonist/antagonist
      pair not only fails to generate T cell antagonism in vivo, but also avoids
      original antigenic sin. These observations suggest that simultaneous immunization
      with vaccines containing mutant epitopes, even T cell antagonists, can indeed
      generate a diverse array of T cell responses and that at least some immune
      interference can be avoided by delivering mutant Ags to the immune system
      simultaneously.

PMID- 12471110
TI  - Lyn and Syk kinases are sequentially engaged in phagocytosis mediated by Fc gamma
      R.
AB  - Recent data indicate that phagocytosis mediated by FcgammaRs is controlled by the
      Src and Syk families of protein tyrosine kinases. In this study, we demonstrate a
      sequential involvement of Lyn and Syk in the phagocytosis of IgG-coated
      particles. The particles isolated at the stage of their binding to FcgammaRs (4
      degrees C) were accompanied by high amounts of Lyn, in addition to the signaling
      gamma-chain of FcgammaRs. Simultaneously, the particle binding induced rapid
      tyrosine phosphorylation of numerous proteins. During synchronized
      internalization of the particles induced by shifting the cell to 37 degrees C,
      Syk kinase and Src homology 2-containing tyrosine phosphatase-1 (SHP-1) were
      associated with the formed phagosomes. At this step, most of the proteins were
      dephosphorylated, although some underwent further tyrosine phosphorylation.
      Quantitative immunoelectron microscopy studies confirmed that Lyn accumulated
      under the plasma membrane beneath the bound particles. High amounts of the gamma
      chain and tyrosine-phosphorylated proteins were also observed under the bound
      particles. When the particles were internalized, the gamma-chain was still
      detected in the region of the phagosomes, while amounts of Lyn were markedly
      reduced. In contrast, the vicinity of the phagosomes was heavily decorated with
      anti-Syk and anti-SHP-1 Abs. The local level of protein tyrosine phosphorylation
      was reduced. The data indicate that the accumulation of Lyn during the binding of
      IgG-coated particles to FcgammaRs correlated with strong tyrosine phosphorylation
      of numerous proteins, suggesting an initiating role for Lyn in protein
      phosphorylation at the onset of the phagocytosis. Syk kinase and SHP-1
      phosphatase are mainly engaged at the stage of particle internalization.

PMID- 12471111
TI  - Naive B lymphocytes undergo homeostatic proliferation in response to B cell
      deficit.
AB  - Naive peripheral B cells are maintained in sufficient numbers and diversity to
      mount effective immune responses against infectious agents. However, the size and
      repertoire of this B cell pool is constantly diminished by normal cell turnover
      and Ag activation. Homeostatic (Ag-independent) proliferation in response to B
      cell depletion is one mechanism to compensate for this cell loss. We have used
      purified CFSE-labeled B cells and an adoptive transfer model system to show that
      immature and mature B cells divide in a variety of B cell-deficient (scid, xid,
      IL-7(-/-), and sublethally irradiated) hosts. Homeostatic B cell proliferation is
      T cell independent, and B cells that have replicated by this mechanism retain the
      antigenic phenotype of naive B cells. Replication is significantly reduced in B
      cell-sufficient normal or B cell-reconstituted immunodeficient recipients by the
      action of competing mature follicular B cells. Using xid mice and transcription
      factor knockouts, we show that the activation signal(s) that lead to homeostatic
      B cell proliferation require Bruton's tyrosine kinase; however, c-Rel, a Bruton's
      tyrosine kinase-induced NF-kappaB/Rel transcription factor critical for Ag and
      mitogen stimulation, is dispensable, indicating the uniqueness of this activation
      pathway. Survival and replication signals can also be separated, because the
      transcription factor p50 (NF-kappaB1), which is required for the survival of
      peripheral B cells, is not necessary for homeostatic replication. Homeostatic B
      cell proliferation provides an Ag-independent mechanism for the maintenance and
      expansion of naive B cells selected into the mature B cell pool.

PMID- 12471112
TI  - WY14,643, a PPAR alpha ligand, has profound effects on immune responses in vivo.
AB  - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated
      transcription factors with diverse actions. PPARalpha and PPARgamma are expressed
      in different lymphocyte subpopulations. Recently, we have observed that PPARalpha
      ligands elicit augmented IL-4 expression in cultures of mitogen-activated
      splenocytes. The following studies were undertaken to characterize the in vivo
      effects of WY14,643, a PPARalpha ligand. Our studies demonstrate that oral
      administration of WY14,643 markedly reduces splenocyte number in immunized and
      nonimmunized C57BL/6 mice. Mice fed WY14,643 display impaired IgG responses to
      myelin oligodendrocyte glycoprotein peptide 35-55 (pMOG(35-55)), following
      immunization with pMOG(35-55)/CFA. Following in vitro restimulation with pMOG(35
      55), splenocytes harvested from WY14,643-fed mice demonstrate impaired production
      of IFN-gamma, IL-6, and TNF-alpha despite similar proliferative responses. We
      also demonstrate higher expression of PPARalpha in B than T cells. Finally, to
      obtain an understanding of the cause of splenocyte depletion with fibrate
      therapy, we studied the effect of WY14,643 on apoptosis of activated splenocytes.
      WY14,643 in vitro induces apoptosis in lymphocytes and this effect appears to
      occur in a PPARalpha-independent manner. Thus WY14,643, a fibrate, is a profound
      immunosuppressive agent.

PMID- 12471113
TI  - A TNF family member LIGHT transduces costimulatory signals into human T cells.
AB  - DcR3/TR6 is a secreted protein belonging to the TNFR family. It binds to Fas
      ligand, LIGHT, and TL1A, all of which are TNF family members. LIGHT is expressed
      on activated T cells. Its known receptors are TR2 and LTbetaR on the cell
      surface, and TR6 in solution. In the present study, we report soluble TR6-Fc or
      solid-phase TR6-Fc costimulated proliferation, lymphokine production, and
      cytotoxicity of human T cells in the presence of TCR ligation. These
      costimulating effects were blocked by soluble LIGHT but not by soluble Fas-Fc.
      TR6-Fc could also effectively costimulate gld/gld mouse T cells. We further
      demonstrated that TR6 bound to both Th1 and Th2 cells, according to flow
      cytometry, and that the association was inhibited by soluble LIGHT. Cross-linking
      Th1 and Th2 cells with solid-phase TR6-Fc along with a suboptimal concentration
      of anti-CD3 enhanced proliferation of both Th1 and Th2 cells, and augmented Th1
      but not Th2 lymphokine production. These data suggest that TR6 delivers
      costimulation through its ligand(s) on the T cell surface, and at least the major
      part of such costimulation is via LIGHT.

PMID- 12471114
TI  - Antibody repertoire development in fetal and neonatal piglets. VIII. Colonization
      is required for newborn piglets to make serum antibodies to T-dependent and type
      2 T-independent antigens.
AB  - Cesarean-derived piglets were reared for 5 wk under germfree conditions or
      monoassociated with a benign Escherichia coli (G58-1) or a enterohemorrhagic
      strain (933D) derived from O157:H7, and immunized i.p. with the T-dependent (TD)
      Ags fluorescein-labeled (FL) keyhole limpet hemocyanin or trinitrophenylated
      (TNP) keyhole limpet hemocyanin and the type 2 T-independent Ags TNP-Ficoll or FL
      Ficoll. Only colonized piglets showed an increase in serum IgG, IgA, and IgM and
      had serum Abs to FL, TNP, and colonizing bacteria. While serum Abs to FL or TNP
      appeared following colonization alone, secondary responses were restricted to
      piglets immunized using TD carriers. While animals colonized with 933D had
      significantly higher total serum IgG and IgM levels and specific IgG Abs than
      those colonized with G58-1, no differences were seen in serum IgA levels, B cell
      diversification in the ileal Peyer's patches, and specific activity (ELISA
      activity per micrograms of Ig) of pre-boost serum IgG and IgM anti-TNP and anti
      FL Abs. Serum IgA Abs to TNP, FL, or bacteria were not detected. Ag-driven
      responses, as measured by an increase in specific Ab activity, were only observed
      in secondary responses to TD Ags and to colonizing, pathogenic E. coli. We
      propose that germline-encoded, isotype-switched B cells in newborn piglets
      differentiate to Ab-secreting cells 1) after stimulation by bacteria-activated
      APCs or 2) through direct stimulation by bacterial products. We further propose
      that Ag-driven systemic responses require both bacterial colonization and TD Ags
      translocated to the peritoneum.

PMID- 12471115
TI  - Peroxisome proliferator-activated receptor gamma-mediated NF-kappa B activation
      and apoptosis in pre-B cells.
AB  - The role of peroxisome proliferator-activated receptor gamma (PPARgamma) in
      adipocyte physiology has been exploited for the treatment of diabetes. The
      expression of PPARgamma in lymphoid organs and its modulation of macrophage
      inflammatory responses, T cell proliferation and cytokine production, and B cell
      proliferation also implicate it in immune regulation. Despite significant human
      exposure to PPARgamma agonists, little is known about the consequences of
      PPARgamma activation in the developing immune system. Here, well-characterized
      models of B lymphopoiesis were used to investigate the effects of PPARgamma
      ligands on nontransformed pro/pre-B (BU-11) and transformed immature B (WEHI-231)
      cell development. Treatment of BU-11, WEHI-231, or primary bone marrow B cells
      with PPARgamma agonists (ciglitazone and GW347845X) resulted in rapid apoptosis.
      A role for PPARgamma and its dimerization partner, retinoid X receptor
      (RXR)alpha, in death signaling was supported by 1) the expression of RXRalpha
      mRNA and cytosolic PPARgamma protein, 2) agonist-induced binding of PPARgamma to
      a PPRE, and 3) synergistic increases in apoptosis following cotreatment with
      PPARgamma agonists and 9-cis-retinoic acid, an RXRalpha agonist. PPARgamma
      agonists activated NF-kappaB (p50, Rel A, c-Rel) binding to the upstream kappaB
      regulatory element site of c-myc. Only doses of agonists that induced apoptosis
      stimulated NF-kappaB-DNA binding. Cotreatment with 9-cis-retinoic acid and
      PPARgamma agonists decreased the dose required to activate NF-kappaB. These data
      suggest that activation of PPARgamma-RXR initiates a potent apoptotic signaling
      cascade in B cells, potentially through NF-kappaB activation. These results have
      implications for the nominal role of the PPARgamma in B cell development and for
      the use of PPARgamma agonists as immunomodulatory therapeutics.

PMID- 12471116
TI  - The roles of IL-12 in providing a third signal for clonal expansion of naive CD8
      T cells.
AB  - Stimulation of an effective in vitro or in vivo response by naive CD8 T cells
      requires three signals: TCR engagement, costimulation/IL-2, and a third signal
      that can be provided by IL-12. In addition to being required for acquisition of
      cytolytic function, IL-12 is required for optimal IL-2-dependent proliferation
      and clonal expansion. In experiments examining in vitro stimulation of naive CD8
      T cells, IL-12 is shown to stimulate expression of the IL-2R alpha-chain (CD25)
      to much higher levels than are reached in response to just TCR and costimulation
      and/or IL-2. In addition, high CD25 expression is substantially prolonged in the
      presence of IL-12. As a consequence, the cells proliferate more effectively in
      response to low levels of IL-2. Examination of adoptively transferred TCR
      transgenic CD8 T cells responding to peptide Ag confirmed that IL-12 up-regulates
      CD25 in vivo, even when B7-mediated costimulation is largely blocked. TCR- and IL
      2-dependent proliferation of CD8 T cells from mice deficient in CD25 was also
      found to increase in the presence of IL-12, indicating that CD25 up-regulation is
      not the only mechanism by which IL-12 increases clonal expansion of the cells. IL
      2 and IL-12 both act to increase expression of both CD25 and the IL-12R, thus
      providing positive cross-regulation of receptor expression. These results suggest
      that when cross-priming dendritic cells present class I/Ag and costimulatory
      ligands, and produce IL-12, naive CD8 T cells will begin to produce IL-2 and both
      receptors will be optimally up-regulated to insure that an effective response is
      generated.

PMID- 12471117
TI  - Porcine endothelial cells, unlike human endothelial cells, can be killed by human
      CTL via Fas ligand and cannot be protected by Bcl-2.
AB  - In clinical transplantation host CTL are major effectors of acute rejection, and
      graft endothelial cells (EC) are major targets of the CTL response. It is unclear
      what roles CTL will play in pig-into-human xenotransplantation. We compared the
      mechanisms of killing used by human CTL (huCTL) vs allogeneic and pig xenogeneic
      EC targets. Both responses show MHC class I restriction of target cell
      recognition. A granzyme B inhibitor peptide completely blocks anti-human and
      partially blocks anti-pig responses, while inhibitory Fas ligand Ab only blocks
      killing of porcine cells despite similar levels of Fas expression in both target
      cell types. Transduction of Bcl-2 completely protects human EC from huCTL, but
      has no effect on huCTL-mediated killing of porcine EC despite its efficacy vs
      drug-induced apoptosis. Bcl-2 effectively protects human EC rendered sensitive to
      Fas ligand by overexpressing Fas from huCTL, yet fails to protect porcine aortic
      endothelial cells from huCTL in the presence of anti-Fas ligand Ab. These data
      reveal differences in the susceptibility of human and porcine targets to huCTL.

PMID- 12471118
TI  - Mycobacterium tuberculosis antigens induce the differentiation of dendritic cells
      from bone marrow.
AB  - We show in this study that incubation of freshly isolated bone marrow cells with
      Mycobacterium tuberculosis (M. tb) secretory Ag (MTSA), in the absence of any
      growth or differentiation-inducing factor, differentiates them into dendritic
      cell (DC)-like APCs. These DCs expressed moderate to high levels of various
      markers typical of DCs. These included T cell costimulatory molecules CD80, CD86,
      CD40, and CD54 and high levels of surface MHC class I and II on CD11c(+) cells.
      The levels and the kinetics of up-regulation of these molecules were comparable
      with those of GM-CSF-differentiated DCs. Furthermore, these DCs exhibited
      morphology characteristics to DCs like the presence of dendritic processes. These
      DCs were also potent stimulators of allogeneic T cells and preferentially induced
      the secretion of IFN-gamma over IL-10 from the interacting T cells.
      Interestingly, the differentiation of bone marrow cells into DC-like APCs was
      obtained with many other M. tb Ags, including whole cell extract of M. tb.
      Further characterization of MTSA-differentiated DCs showed that they were
      immature in nature, as stimulation of these DCs with TNF-alpha, anti-CD40, or LPS
      further up-regulated the surface levels of various molecules together with an
      increase in their T cell stimulatory capacity. The Ag-specific T cell responses
      of MTSA-differentiated DCs were mainly contributed by the CD4(+) subset,
      indicating that MTSA was largely MHC II restricted. Furthermore, stimulation of
      bone marrow cells with MTSA induced the nuclear translocation of the
      transcription factor NF-kappaB, thereby indicating its role during MTSA-induced
      differentiation of DCs.

PMID- 12471119
TI  - B cell selection and affinity maturation during an antibody response in the mouse
      with limited B cell diversity.
AB  - The quasi-monoclonal mouse has limited B cell diversity, whose major
      (approximately 80%) B cell Ag receptors are comprised of the knockin V(H) 17.2.25
      (V(H)T)-encoded H chain and the lambda1 or lambda2 L chain, thereby being
      specific for 4-hydroxy-3-nitrophenylacetyl. The p-nitrophenylacetyl (pNP) was
      found to be a low affinity analog of nitrophenylacetyl. We examined affinity
      maturation of anti-pNP IgG by analyzing mAbs obtained from quasi-monoclonal mice
      that were immunized with this low affinity Ag. The results are: 1) Although
      V(H)T/lambda1 and V(H)T/lambda2 IgM were equally produced, V(H)T/lambda2 IgG
      almost exclusively underwent affinity maturation toward pNP. 2) A common mutation
      in complementarity-determining region 3 of V(H)T (T313A) mainly contributed to
      generating the specificity for pNP. 3) Because mutated V(H)T-encoded gamma-chains
      could form lambda1-bearing IgG in Chinese hamster ovary cells, apparent absence
      of V(H)T/lambda1 anti-pNP IgG may not be due to the incompatibility between the
      gamma-chains and the lambda1-chain, but may be explained by the fact that
      V(H)T/lambda1 B cells showed 50- to 100-fold lower affinity for pNP than
      V(H)T/lambda2 B cells. 4) Interestingly, a pNP-specific IgM mAb that shared
      common mutations including T313A with high affinity anti-pNP IgG was isolated,
      suggesting that a part of hypermutation coupled with positive selection can occur
      before isotype switching. Thus, even weak B cell receptor engagement can elicit
      an IgM response, whereas only B cells that received signals stronger than a
      threshold may be committed to an affinity maturation process.

PMID- 12471120
TI  - B cell development arrest upon insertion of a neo gene between JH and Emu:
      promoter competition results in transcriptional silencing of germline JH and
      complete VDJ rearrangements.
AB  - Previous targeting experiments within the IgH locus have shown that V(D)J
      recombination was affected by an insertion of a neo gene within E(mu) upstream of
      the core enhancer, but not by insertions downstream of the enhancer. Similarly,
      class switch recombination to a given (C) gene was affected only by interposition
      of neo in between that gene and the 3' IgH enhancers. Here we show that insertion
      of neo upstream E(mu) only marginally impairs V(D)J recombination, but results in
      an altered D and J(H) gene usage and completely blocks transcription of the
      germline J(H) region and the rearranged VDJ segments. Although transcriptional
      silencing of J(H) occurs upstream of the insertion and results in the lack of
      mature B cells in homozygous mutant animals, IgH transcription is maintained
      downstream of the insertion together with neo transcription and can be up
      regulated by LPS stimulation or upon fusion with plasmacytoma cells. Altogether
      these data argue for a polarized "neo effect" involving promoter competition and
      further show that V(D)J rearrangement can be uncoupled from transcription.

PMID- 12471121
TI  - TNFR-associated factor-3 is associated with BAFF-R and negatively regulates BAFF
      R-mediated NF-kappa B activation and IL-10 production.
AB  - TALL-1 is a member of the TNF family that is critically involved in B cell
      survival, maturation, and progression of lupus-like autoimmune diseases. TALL-1
      has three receptors, including BCMA, TACI, and BAFF-R, which are mostly expressed
      by B lymphocytes. Gene knockout studies have indicated that BAFF-R is the major
      stimulatory receptor for TALL-1 signaling and is required for normal B cell
      development. The intracellular signaling mechanisms of BAFF-R are not known. In
      this report, we attempted to identify BAFF-R-associated downstream proteins by
      yeast two-hybrid screening. This effort identified TNFR-associated factor (TRAF)3
      as a protein specifically interacting with BAFF-R in yeast two-hybrid assays.
      Coimmunoprecipitation experiments indicated that BAFF-R interacts with TRAF3 in B
      lymphoma cells and this interaction is stimulated by TALL-1 treatment. Domain
      mapping experiments indicated that both a 6-aa membrane proximal region and the C
      terminal 35 aa of BAFF-R are required for its interaction with TRAF3. Moreover,
      overexpression of TRAF3 inhibits BAFF-R-mediated NF-kappaB activation and IL-10
      production. Taken together, our findings suggest that TRAF3 is a negative
      regulator of BAFF-R-mediated NF-kappaB activation and IL-10 production.

PMID- 12471122
TI  - Hyperconservation of the putative antigen recognition site of the MHC class I-b
      molecule TL in the subfamily Murinae: evidence that thymus leukemia antigen is an
      ancient mammalian gene.
AB  - "Classical" MHC class I (I-a) genes are extraordinarily polymorphic, but
      "nonclassical" MHC class I (I-b) genes are monomorphic or oligomorphic. Although
      diversifying (positive) Darwinian selection is thought to explain the origin and
      maintenance of MHC class I-a polymorphisms, genetic mechanisms underlying MHC
      class I-b evolution are uncertain. In one extreme model, MHC class I-b loci are
      derived by gene duplication from MHC class I-a alleles but rapidly drift into
      functional obsolescence and are eventually deleted. In this model, extant MHC
      class I-b genes are relatively young, tend to be dysfunctional or pseudogenic,
      and orthologies are restricted to close taxa. An alternative model proposed that
      the mouse MHC class I-b gene thymus leukemia Ag (TL) arose approximately 100
      million years ago, near the time of the mammalian radiation. To determine the
      mode of evolution of TL, we cloned TL from genomic DNA of 11 species of subfamily
      Murinae: Every sample we tested contained TL, suggesting this molecule has been
      maintained throughout murine evolution. The sequence similarity of TL orthologs
      ranged from 85-99% and was inversely proportional to taxonomic distance. The
      sequences showed high conservation throughout the entire extracellular domains
      with exceptional conservation in the putative Ag recognition site. Our results
      strengthen the hypotheses that TL has evolved a specialized function and
      represents an ancient MHC class I-b gene.

PMID- 12471124
TI  - The activation and subsequent regulatory roles of Lyn and CD19 after B cell
      receptor ligation are independent.
AB  - The cell surface glycoprotein CD19 and the Src-related protein tyrosine kinase
      Lyn are key mediators of, respectively, positive and negative signaling in B
      cells. Despite the apparent opposition of their regulatory functions, a recent
      model of the biochemical events after B cell receptor (BCR) ligation intimately
      links the activation of Lyn and CD19. We examined the biochemical consequences of
      BCR ligation in mouse B cells lacking either Lyn or CD19 for evidence of
      interaction or codependence. In contrast to published results, we found CD19
      phosphorylation after BCR ligation to be unaffected by the absence of Lyn, yet
      dependent on Src family protein tyrosine kinases as it was inhibited fully by
      PP2, an Src family-specific inhibitor. Consistent with normal CD19
      phosphorylation in lyn(-/-) B cells, the recruitment of phosphoinositide-3 kinase
      to CD19 and the ability of CD19 to enhance both intracellular calcium flux and
      extracellular signal-regulated kinase 1/2 activation after coligation with the
      BCRs were intact in the absence of Lyn. Similarly, unique functions of Lyn were
      found to be independent of CD19. CD19(-/-) B cells were normal for increased Lyn
      kinase activity after BCR ligation, inhibition of BCR-mediated calcium flux after
      CD22 coligation, and inhibition of extracellular signal-regulated kinase
      phosporylation after FcgammaRIIB coligation. Collectively, these data show that
      the unique functions of Lyn do not require CD19 and that the signal amplification
      mediated by CD19 is independent of Lyn. We conclude that the roles of Lyn and
      CD19 after BCR ligation are independent and opposing, one being primarily
      inhibitory and the other stimulatory.

PMID- 12471123
TI  - Defective thymocyte maturation by transgenic expression of a truncated form of
      the T lymphocyte adapter molecule and Fyn substrate, Sin.
AB  - Adapter molecules that promote protein-protein interactions play a central role
      in T lymphocyte differentiation and activation. In this study, we examined the
      role of the T lymphocyte-expressed adapter protein and Src kinase substrate, Sin,
      on thymocyte function using transgenic mice expressing an activated, truncated
      allele of Sin (SinDeltaC). We found that SinDeltaC expression led to reduced
      numbers of CD4(+) and CD8(+) single-positive cells and reduced thymic cellularity
      due to increased thymocyte apoptosis. Because the adapter properties of Sin are
      mediated by tyrosine-based motifs and given that Sin is a substrate for Src
      tyrosine kinases, we examined the involvement of these kinases in the inhibitory
      effects of SinDeltaC. We found that in transgenic thymocytes, SinDeltaC was
      constitutively phosphorylated by the Src kinase Fyn, but not by the related
      kinase Lck. Using SinDeltaC and fyn(-/-) animals, we also found that the
      expression of Fyn was required for the inhibitory effect of SinDeltaC on
      thymocyte apoptosis but not for SinDeltaC-mediated inhibition of T cell
      maturation. The inhibitory effect of SinDeltaC on thymocyte maturation correlated
      with defective activation of the mitogen-activated protein kinase extracellular
      signal-regulated kinase. Our results suggest that the Sin mutant inhibits
      thymocyte differentiation through Fyn-dependent and -independent mechanisms and
      that endogenous Sin may be an important regulator of thymocyte development.

PMID- 12471125
TI  - Positive and negative transcriptional states of a variegating immunoglobulin
      heavy chain (IgH) locus are maintained by a cis-acting epigenetic mechanism.
AB  - Analyses of transgene expression have defined essential components of a locus
      control region (LCR) in the J(H)-C(mu) intron of the IgH locus. Targeted deletion
      of this LCR from the endogenous IgH locus of hybridoma cells results in
      variegated expression, i.e., cells can exist in two epigenetically inherited
      states in which the Ig(mu) H chain gene is either active or silent; the active or
      silent state is typically transmitted to progeny cells through many cell
      divisions. In principle, cells in the two states might differ either in their
      content of specific transcription factors or in a cis-acting feature of the IgH
      locus. To distinguish between these mechanisms, we generated LCR-deficient,
      recombinant cell lines in which the Ig(mu) H chain genes were distinguished by a
      silent mutation and fused cells in which the mu gene was active with cells in
      which mu was silent. Our analysis showed that both parental active and silent
      transcriptional states were preserved in the hybrid cell, i.e., that two alleles
      of the same gene in the same nucleus can exist in two different states of
      expression through many cell divisions. These results indicate that the
      expression of the LCR-deficient IgH locus is not fully determined by the cellular
      complement of transcription factors, but is also subject to a cis-acting, self
      propagating, epigenetic mark. The methylation inhibitor, 5-azacytidine,
      reactivated IgH in cells in which this gene was silent, suggesting that
      methylation is part of the epigenetic mark that distinguishes silent from active
      transcriptional states.

PMID- 12471126
TI  - HLA-DP4, the most frequent HLA II molecule, defines a new supertype of peptide
      binding specificity.
AB  - Among HLA-DP specificities, HLA-DP4 specificity involves at least two molecules,
      HLA-DPA1*0103/DPB1*0401 (DP401) and HLA-DPA1*0103/DPB1*0402 (DP402), which differ
      from each other by only three residues. Together, they are present worldwide at
      an allelic frequency of 20-60% and are the most abundant human HLA II alleles.
      Strikingly, the peptide-binding specificities of these molecules have never been
      investigated. Hence, in this study, we report the peptide-binding motifs of both
      molecules. We first set up a binding assay specific for the immunopurified HLA
      DP4 molecules. Using multiple sets of synthetic peptides, we successfully defined
      the amino acid preferences of the anchor residues. With these assays, we were
      also able to identify new peptide ligands from allergens and viral and tumor Ags.
      DP401 and DP402 exhibit very similar patterns of recognition in agreement with
      molecular modeling of the complexes. Pockets P1 and P6 accommodate the main
      anchor residues and interestingly contain only two polymorphic residues, beta86
      and beta11, respectively. Both positions are almost dimorphic and thus produce a
      limited number of pocket combinations. Taken together, our results support the
      existence of three main binding supertypes among HLA-DP molecules and should
      significantly contribute to the identification of universal epitopes to be used
      in peptide-based vaccines for cancer, as well as for allergic or infectious
      diseases.

PMID- 12471127
TI  - Complement C3b/C3d and cell surface polyanions are recognized by overlapping
      binding sites on the most carboxyl-terminal domain of complement factor H.
AB  - Factor H (FH) is a potent suppressor of the alternative pathway of C in plasma
      and when bound to sialic acid- or glycosaminoglycan-rich surfaces. Of the three
      interaction sites on FH for C3b, one interacts with the C3d part of C3b. In this
      study, we generated recombinant constructs of FH and FH-related proteins (FHR) to
      define the sites required for binding to C3d. In FH, the C3d-binding site was
      localized by surface plasmon resonance analysis to the most C-terminal short
      consensus repeat domain (SCR) 20. To identify amino acids of FH involved in
      binding to C3d and heparin, we compared the sequences of FH and FHRs and
      constructed a homology-based molecular model of SCR19-20 of FH. Subsequently, we
      created an SCR15-20 mutant with substitutions in five amino acids that were
      predicted to be involved in the binding interactions. These mutations reduced
      binding of the SCR15-20 construct to both C3b/C3d and heparin. Binding of the
      wild-type SCR15-20, but not the residual binding of the mutated SCR15-20, to C3d
      was inhibited by heparin. This indicates that the heparin- and C3d-binding sites
      are overlapping. Our results suggest that a region in the most C-terminal domain
      of FH is involved in target recognition by binding to C3b and surface polyanions.
      Mutations in this region, as recently reported in patients with familial
      hemolytic uremic syndrome, may lead to indiscriminatory C attack against self
      cells.

PMID- 12471128
TI  - L-MBP is expressed in epithelial cells of mouse small intestine.
AB  - The mannan-binding proteins (L-MBP and S-MBP, also denoted MBL-C and MBL-A),
      mainly produced in liver and existing in liver and serum, play important roles in
      the innate immunity against a variety of pathogens. Total RNA from mouse tissues
      were screened for MBP mRNA by RT-PCR. In addition to liver, S-MBP mRNA was
      detected in lung, kidney, and testis, and L-MBP mRNA was detected in kidney,
      thymus, and small intestine. Quantitative RT-PCR revealed that the small
      intestine is a predominant site of extrahepatic expression of L-MBP. Western
      blotting with polyclonal Abs against rat L-MBP demonstrated this protein in
      Triton X-100 extracts of the small intestine obtained from mice that had
      undergone systemic perfusion. Immunohistochemical staining with an mAb against
      mouse L-MBP and in situ hybridization revealed that L-MBP is selectively
      expressed in some villous epithelial cells of the small intestine. These findings
      suggest that L-MBP plays a role in mucosal innate immunity.

PMID- 12471129
TI  - Conservation of CD1 intracellular trafficking patterns between mammalian species.
AB  - Dendritic cells (DC) are potent APCs that sample Ags from the surrounding
      environment and present them to naive T cells using cell surface Ag-presenting
      molecules. The DC in both lymphoid and nonlymphoid tissues express high levels of
      CD1, a cell surface glycoprotein capable of presenting lipids and glycolipids to
      T cells. Distinct group 1 CD1 isoforms (CD1a, -b, -c) in man are known to traffic
      to different parts of the endocytic system where microbial Ags may be sampled.
      Guinea pigs are the only known rodent species that express the group 1 CD1
      proteins. Therefore, we examined the expression and trafficking of guinea pig CD1
      (gpCD1) isoforms on isolated DC. Confocal microscopy using mAbs specific for
      individual gpCD1 isoforms revealed differential trafficking of two distinct CD1b
      isoforms within DC. Colocalization of MHC class II was observed with the gpCD1b1
      isoform, consistent with localization in the late endosomes of DC. In contrast,
      the gpCD1b3 isoform lacks an endosomal sorting motif and remains on the cell
      surface. Following incubation with Mycobacterium tuberculosis lipoarabinomannan,
      colocalization of endocytosed lipoarabinomannan with the gpCD1b1 isoform was
      observed but not with the gpCD1b3 isoform, which remained primarily on the cell
      surface. These data demonstrate that guinea pig DC express CD1 isoforms with
      unique trafficking patterns that recapitulate the patterns seen for human CD1
      isoforms. This suggests evolutionary pressure for a conserved mechanism in
      mammals that allows CD1 to sample lipid Ags from various subcompartments of the
      endocytic system.

PMID- 12471130
TI  - Nippostrongylus brasiliensis can induce B7-independent antigen-specific
      development of IL-4-producing T cells from naive CD4 T cells in vivo.
AB  - Th2 immune responses to a number of infectious pathogens are dependent on B7-1/B7
      2 costimulatory molecule interactions. We have now examined the Th2 immune
      response to Nippostrongylus brasiliensis (Nb) in B7-1/B7-2(-/-) mice and show
      that Th2 effector cells develop that can mediate worm expulsion and produce
      substantial Th2 cytokines comparable with wild-type infected mice; however, in
      marked contrast, B cell Ag-specific Ab production is abrogated after B7 blockade.
      To examine the mechanism of T cell activation, OVA-specific DO11.10 T cells were
      transferred to recipient mice, which were then immunized with a combination of Nb
      plus OVA or either alone. Only the combination of Nb plus OVA triggered T cell
      differentiation to OVA-specific Th2 cells, suggesting that Nb acts as an adjuvant
      to stimulate Ag-specific naive T cells to differentiate to effector Th2 cells.
      Furthermore, using the DO11.10 TCR-transgenic T cell adoptive transfer model, we
      show that blocking B7-1/B7-2 interactions does not impair nonparasite Ag-specific
      DO11.10 Th2 cell differentiation; however, DO11.10 T cell cycle progression and
      migration to the B cell zone are inhibited.

PMID- 12471131
TI  - Requisite elements in vaccine immunity to Blastomyces dermatitidis: plasticity
      uncovers vaccine potential in immune-deficient hosts.
AB  - Understanding fundamental mechanisms of vaccine immunity will allow proper use
      and optimization of vaccines. Vaccination with a genetically engineered, live,
      attenuated strain of Blastomyces dermatitidis carrying a targeted deletion at the
      BAD1 locus confers sterilizing immunity against experimental lethal pulmonary
      infection. We found in this study that alphabeta T cells are requisite for
      durable vaccine immunity, whereas other T and B cells are dispensable. In immune
      competent animals, CD4(+) T-cell derived cytokines TNF-alpha and IFN-gamma
      mediate vaccine immunity. Surprisingly, these factors are dispensable in immune
      deficient animals, which rely on alternate mechanisms for robust vaccine
      immunity, yet still require O(2)(-) production rather than generation of NO. Our
      results clarify the cellular and molecular bases behind the first genetically
      engineered fungal vaccine. They also illustrate a sharp difference in vaccine
      mechanisms between immune-competent and immune-deficient hosts, which underscores
      the plasticity of residual immune elements in compromised hosts, and points to
      the feasibility of developing vaccines against invasive fungal infection in this
      fast growing patient population.

PMID- 12471132
TI  - Protection against Helicobacter pylori infection following immunization is IL-12
      dependent and mediated by Th1 cells.
AB  - The regulatory roles of Th1 and Th2 cells in immune protection against
      Helicobacter infection are not clearly understood. In this study, we report that
      a primary H. pylori infection can be established in the absence of IL-12 or IFN
      gamma. However, IFN-gamma, but not IL-12, was involved in the development of
      gastritis because IFN-gamma(-/-) (GKO) mice exhibited significantly less
      inflammation as compared with IL-12(-/-) or wild-type (WT) mice. Both IL-12(-/-)
      and GKO mice failed to develop protection following oral immunization with H.
      pylori lysate and cholera toxin adjuvant. By contrast, Th2-deficient, IL-4(-/-),
      and WT mice were equally well protected. Mucosal immunization in the presence of
      coadministered rIL-12 in WT mice increased Ag-specific IFN-gamma-producing T
      cells by 5-fold and gave an additional 4-fold reduction in colonizing bacteria,
      confirming a key role of Th1 cells in protection. Importantly, only protected IL
      4(-/-) and WT mice demonstrated substantial influx of CD4(+) T cells in the
      gastric mucosa. The extent of inflammation in challenged IL-12(-/-) and GKO mice
      was much reduced compared with that in WT mice, indicating that IFN-gamma/Th1
      cells also play a major role in postimmunization gastritis. Of note,
      postimmunization gastritis in IL-4(-/-) mice was significantly milder than WT
      mice, despite a similar level of protection, indicating that immune protection is
      not directly linked to the degree of gastric inflammation. Only protected mice
      had T cells that produced high levels of IFN-gamma to recall Ag, whereas both
      protected and unprotected mice produced high levels of IL-13. We conclude that IL
      12 and Th1 responses are crucial for H. pylori-specific protective immunity.

PMID- 12471133
TI  - Cationic polypeptides are required for antibacterial activity of human airway
      fluid.
AB  - In a search for direct evidence leading to the biological relevance of airway
      secretions in innate host defense, we characterized the antibacterial function of
      cationic polypeptides within minimally manipulated nasal fluid. In this study, we
      show that cationic antimicrobial polypeptides are responsible for most of the
      bactericidal activity of whole nasal fluid. The removal of cationic polypeptides
      using a cation-exchange resin ablated the activity of nasal fluid against
      Escherichia coli, Listeria monocytogenes, and Pseudomonas aeruginosa. By using a
      novel proteomic approach, we identified a dozen cationic peptides and proteins
      within nasal fluid, all of which either are known antimicrobial polypeptides or
      have other proposed roles in host defense. Of the three most abundant cationic
      polypeptides in nasal fluid, lysozyme was more effective than either lactoferrin
      or secretory leukoprotease inhibitor in restoring the antibacterial activity of
      the cationic polypeptide-depleted fluid against a mucoid cystic fibrosis isolate
      of P. aeruginosa.

PMID- 12471134
TI  - High affinity mimotope of the polysaccharide capsule of Cryptococcus neoformans
      identified from an evolutionary phage peptide library.
AB  - Cryptococcus neoformans causes a life-threatening meningoencephalitis in a
      significant percentage of AIDS patients. Mice immunized with a glycoconjugate
      vaccine composed of the glucuronoxylomannan (GXM) component of the cryptococcal
      capsular polysaccharide conjugated to tetanus toxoid (TT) produce Abs that, based
      on the epitope recognized, can be either protective or nonprotective. Since
      nonprotective Abs block the efficacy of protective Abs, we are interested in
      developing a vaccine that would focus the immune response specifically to
      protective epitopes. Previously, we screened a phage display library with 2H1, a
      protective anti-GXM mAb, and isolated PA1, a representative peptide that had a
      K(d) of 295 nM for 2H1. Mice immunized with PA1 conjugated to keyhole limpet
      hemocyanin developed high anti-peptide (1/13,000), but low anti-GXM (maximum,
      1/200) titers. We now report our efforts to improve this vaccine by screening a
      sublibrary with six random amino acids added to either end of the PA1 motif to
      identify higher affinity peptides. P206.1, a peptide isolated from this
      sublibrary, had 80-fold higher affinity for 2H1 (K(d) = 3.7 nM) than PA1. P206.1
      bound protective, but not nonprotective, anti-GXM Abs. Mice immunized with P206.1
      conjugated to various carriers did not mount an Ab response to GXM despite
      developing high anti-peptide titers. However, mice primed with GXM-TT and boosted
      with P206.1-TT developed significant anti-GXM titers (maximum, 1/180,000). This
      latter immunization scheme focused the immune response on protective epitopes,
      since only 2-5% of these titers were directed against nonprotective de-O
      acetylated GXM epitopes compared with 20-60% in animals primed and boosted with
      GXM-TT.

PMID- 12471135
TI  - Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell
      derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor
      cells.
AB  - CD26/dipeptidylpeptidase IV (DPPIV) is a membrane-bound extracellular peptidase
      that cleaves dipeptides from the N terminus of polypeptide chains. The N terminus
      of chemokines is known to interact with the extracellular portion of chemokine
      receptors, and removal of these amino acids in many instances results in
      significant changes in functional activity. CD26/DPPIV has the ability to cleave
      the chemokine CXCL12/stromal cell-derived factor 1alpha (SDF-1alpha) at its
      position two proline. CXCL12/SDF-1alpha induces migration of hemopoietic stem and
      progenitor cells, and it is thought that CXCL12 plays a crucial role in
      homing/mobilization of these cells to/from the bone marrow. We found that
      CD26/DPPIV is expressed by a subpopulation of CD34(+) hemopoietic cells isolated
      from cord blood and that these cells have DPPIV activity. The involvement of
      CD26/DPPIV in CD34(+) hemopoietic stem and progenitor cell migration has not been
      previously examined. Functional studies show that the N-terminal-truncated
      CXCL12/SDF-1alpha lacks the ability to induce the migration of CD34(+) cord blood
      cells and acts to inhibit normal CXCL12/SDF-1alpha-induced migration. Finally,
      inhibiting the endogenous CD26/DPPIV activity on CD34(+) cells enhances the
      migratory response of these cells to CXCL12/SDF-1alpha. This process of
      CXCL12/SDF-1alpha cleavage by CD26/DPPIV on a subpopulation of CD34(+) cells may
      represent a novel regulatory mechanism in hemopoietic stem and progenitor cells
      for the migration, homing, and mobilization of these cells. Inhibition of the
      CD26/DPPIV peptidase activity may therefore represent an innovative approach to
      increasing homing and engraftment during cord blood transplantation.

PMID- 12471136
TI  - Repression of rac2 mRNA expression by Anaplasma phagocytophila is essential to
      the inhibition of superoxide production and bacterial proliferation.
AB  - Anaplasma phagocytophila, the etiologic agent of human granulocytic ehrlichiosis,
      is an emerging bacterial pathogen that invades neutrophils and can be cultivated
      in HL-60 cells. Infected neutrophils and HL-60 cells fail to produce superoxide
      anion (O(2)(-)), which is partially attributable to the fact that A.
      phagocytophila inhibits transcription of gp91(phox), an integral component of
      NADPH oxidase. cDNA microarray and RT-PCR analyses demonstrated that
      transcription of the gene encoding Rac2, a key component in NADPH oxidase
      activation, was down-regulated in infected HL-60 cells. Quantitative RT-PCR
      demonstrated that rac2 mRNA expression was reduced 7-fold in retinoic acid
      differentiated HL-60 cells and 50-fold in neutrophils following A. phagocytophila
      infection. Rac2 protein expression was absent in infected HL-60 cells. Rac1 and
      Rac2 are interchangeable in their abilities to activate NADPH oxidase. HL-60
      cells transfected to express myc-tagged rac1 and gp91(phox) from the CMV
      immediate early promoter maintained the ability to generate O(2)(-) 120 h
      postinfection. A. phagocytophila proliferation was severely inhibited in these
      cells. These results directly attribute the inhibition of rac2 and gp91(phox)
      transcription to the loss of NADPH oxidase activity in A. phagocytophila-infected
      cells and demonstrate its importance to bacterial intracellular survival.

PMID- 12471137
TI  - C-reactive protein mediates protection from lipopolysaccharide through
      interactions with Fc gamma R.
AB  - C-reactive protein (CRP) is a component of the acute phase response to infection,
      inflammation, and trauma. A major activity of acute phase proteins is to limit
      the inflammatory response. It has been demonstrated that CRP protects mice from
      lethal doses of LPS. In the mouse, CRP binds to the regulatory receptor,
      FcgammaRIIb, and to the gamma-chain-associated receptor, FcgammaRI. The goal
      ofthis study was to determine whether FcgammaRs are necessary for the protective
      effect of CRP. The ability of CRP to protect mice from a lethal dose of LPS was
      confirmed using injections of 500 and 250 micro g of CRP at 0 and 12 h. CRP
      treatment of FcgammaRIIb-deficient mice increased mortality after LPS challenge
      and increased serum levels of TNF and IL-12 in response to LPS. CRP did not
      protect FcR gamma-chain-deficient mice from LPS-induced mortality. Treatment of
      normal mice, but not gamma-chain-deficient mice, with CRP increased IL-10 levels
      following LPS injection. In vitro, in the presence of LPS, CRP enhanced IL-10
      synthesis and inhibited IL-12 synthesis by bone marrow macrophages from normal,
      but not gamma-chain-deficient mice. The protective effect of CRP appears to be
      mediated by binding to FcgammaRI and FcgammaRII resulting in enhanced secretion
      of the anti-inflammatory cytokine IL-10 and the down-regulation of IL-12. These
      results suggest that CRP can alter the cytokine profile of mouse macrophages by
      acting through FcgammaR leading to a down-regulation of the inflammatory
      response.

PMID- 12471138
TI  - Hydrogen peroxide induces murine macrophage chemokine gene transcription via
      extracellular signal-regulated kinase- and cyclic adenosine 5'-monophosphate
      (cAMP)-dependent pathways: involvement of NF-kappa B, activator protein 1, and
      cAMP response element binding protein.
AB  - Hydrogen peroxide (H(2)O(2)) has been shown to act as a second messenger that
      activates chemokine expression. In the present study, we investigated the
      mechanisms underlying this cellular regulation in the murine macrophage cell line
      B10R. We report that H(2)O(2) increases mRNA expression of various chemokines,
      macrophage-inflammatory protein (MIP)-1alpha/CC chemokine ligand (CCL)3, MIP
      1beta/CCL4, MIP-2/CXC chemokine ligand 2, and monocyte chemoattractant protein
      1/CCL2, by activating the extracellular signal-regulated kinase (ERK) pathway and
      the nuclear translocation of the transcription factors NF-kappaB, AP-1, and CREB.
      Blockage of the ERK pathway with specific inhibitors against mitogen-activated
      protein kinase kinase 1/2 and ERK1/ERK2 completely abolished both the H(2)O(2)
      mediated chemokine up-regulation and the activation of all NF studied. Similarly,
      selective inhibition of cAMP and NF-kappaB strongly down-regulated the induction
      of all chemokine transcripts as well as CREB and NF-kappaB activation,
      respectively. Of interest, we detected a significant decrease of NF-kappaB, AP-1,
      and CREB DNA binding activities by reciprocal competition for these binding sites
      when either specific cold oligonucleotides (NF-kappaB, AP-1, and CREB) or Abs
      against various transcription factor subunits (p50, p65, c-Fos, Jun B, c-Jun, and
      CREB-1) were added. These findings indicate that cooperation between ERK- and
      cAMP-dependent pathways seems to be required to achieve the formation of an
      essential transcriptional factor complex for maximal H(2)O(2)-dependent chemokine
      modulation. Finally, experiments performed with actinomycin D suggest that
      H(2)O(2)-mediated MIP-1beta mRNA up-regulation results from transcriptional
      control, whereas that of MIP-1alpha, MIP-2, and monocyte chemoattractant protein
      1 is due to both gene transcription activation and mRNA posttranscriptional
      stabilization.

PMID- 12471139
TI  - IFN-gamma amplifies IL-6 and IL-8 responses by airway epithelial-like cells via
      indoleamine 2,3-dioxygenase.
AB  - Respiratory viral infections increase inflammatory responses to concurrent or
      secondary bacterial challenges, thereby worsening disease outcome. This
      potentiation of inflammation is explained at least in part by IFN-gamma promoting
      increased sensitivity to TNF-alpha and LPS. We sought to determine whether and,
      if so, how IFN-gamma can modulate proinflammatory responses to TNF-alpha and LPS
      by epithelial cells, which are key effector cells in the airways. Preincubation
      of airway epithelial-like NCI-H292 cells with IFN-gamma resulted in a
      hyperresponsive IL-6 and IL-8 production to TNF-alpha and LPS. The underlying
      mechanism involved the induction of indoleamine 2,3-dioxygenase, which
      catabolized the essential amino acid, tryptophan. Depletion of tryptophan led to
      stabilization of IL-6 and IL-8 mRNA and increased IL-6 and IL-8 responses,
      whereas supplementing tryptophan largely restored these changes. This novel
      mechanism may be implicated in enhanced inflammatory responses to bacterial
      challenges following viral infection.

PMID- 12471140
TI  - Differential role of IFN-gamma-inducible protein 10 kDa in a cockroach antigen
      induced model of allergic airway hyperreactivity: systemic versus local effects.
AB  - The ability of IFN-gamma to antagonize established Th2 type allergic responses is
      well documented. To investigate the role of IFN-gamma-inducible protein 10 kDa
      (IP10) in the allergic response, we chose to investigate the effect of IP10
      neutralization on an established Th2 response. Systemic neutralization of IP10 at
      the time of allergen challenge increased airway hyperreactivity as well as airway
      eosinophil accumulation. Interestingly, IFN-gamma levels were markedly reduced in
      both the lung and peripheral lymph node following IP10 neutralization.
      Furthermore, the number of CXCR3(+)CD4(+) T cells was decreased in the peripheral
      lymph node following neutralization of IP10. Introduction of exogenous IP10 into
      the airway at the time of allergen challenge also dramatically increased
      eosinophil accumulation in the airway. Protein levels of IL-4, IL-5, and IL-13
      were significantly increased in the lung following exogenous airway
      administration of IP10 with allergen. Interestingly, airway hyperreactivity was
      significantly decreased at early time points following concurrent IP10 and
      allergen challenge but rebounded at 24 and 48 h post allergen challenge. Although
      IP10 may initially be acting locally to dampen the allergic response, its ability
      to recruit eosinophils may ultimately supersede any immunomodulatory effect it
      may have in an established allergic response. These results suggest that while
      systemic levels of IP10 are beneficial in controlling the allergic response,
      possibly by regulating cellular trafficking in the lymph node, local
      administration of exogenous IP10 into an established allergic response may be
      detrimental.

PMID- 12471141
TI  - Interactions between hemopoietically derived TNF and central nervous system
      resident glial chemokines underlie initiation of autoimmune inflammation in the
      brain.
AB  - Tumor necrosis factor is a proinflammatory cytokine that induces directly many of
      the components required for inflammation to proceed rapidly. We show in this
      study that the interplay between TNF and chemokines, now recognized to be
      essential for normal secondary lymphoid tissue development, is also a feature of
      CNS inflammation, and that the two apparently dissimilar biological processes
      share many properties. Thus, induction of seven chemokines, including T cell
      activation gene 3 (TCA3), monocyte chemoattractant protein-1, and IFN-gamma
      inducible protein-10 within the CNS during experimental autoimmune
      encephalomyelitis fails to occur early in the inflammatory process in TNF
      deficient mice, despite local expression of monokines and IFN-gamma. The critical
      source of TNF in CNS inflammation is the infiltrating hemopoietic cell, and, in
      its absence, chemokine expression by irradiation-resistant CNS-resident cells
      fails. The CCR8 ligand, TCA3, is shown to be produced predominantly by resident
      microglia of the CNS in response to TNF. Using CCR8(-/-) mice, evidence is
      provided that TCA3-CCR8 interactions contribute to rapid-onset CNS inflammation.
      Thus, through TNF production, the hemopoietic compartment initiates the signals
      for its own movement into tissues, although the tissue ultimately defines the
      nature of that movement. Chemokines are a major, although not exclusive,
      mechanism by which tissues regulate leukocyte movement in response to TNF.

PMID- 12471142
TI  - An aspirin-triggered lipoxin A4 stable analog displays a unique topical anti
      inflammatory profile.
AB  - Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate
      leukocyte trafficking and promote the resolution of inflammation. To assess the
      potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin
      A(4) analog, 15-epi-16-p-fluorophenoxy-lipoxin A(4) methyl ester (ATLa), was
      synthesized by total organic synthesis and examined for efficacy relative to a
      potent leukotriene B(4) (LTB(4)) receptor antagonist (LTB(4)R-Ant) and the
      clinically used topical glucocorticoid methylprednisolone aceponate. In vitro,
      ATLa was 100-fold more potent than LTB(4)R-Ant for inhibiting neutrophil
      chemotaxis and trans-epithelial cell migration induced by fMLP, but was
      approximately 10-fold less potent than the LTB(4)R-Ant in blocking responses to
      LTB(4). A broad panel of cutaneous inflammation models that display pathological
      aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used
      to directly compare the topical efficacy of ATLa with that of LTB(4)R-Ant and
      methylprednisolone aceponate. ATLa was efficacious in all models tested:
      LTB(4)/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced
      inflammation and trimellitic anhydride-induced allergic delayed-type
      hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation
      models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil
      infiltration, and epidermal hyperproliferation. We conclude that the LXA(4) and
      aspirin-triggered LXA(4) pathways play key anti-inflammatory roles in vivo.
      Moreover, these results suggest that ATLa and related LXA(4) analogs may have
      broad therapeutic potential in inflammatory disorders and could provide an
      alternative to corticosteroids in certain clinical settings.

PMID- 12471143
TI  - A novel dendritic cell-induced model of erosive inflammatory arthritis: distinct
      roles for dendritic cells in T cell activation and induction of local
      inflammation.
AB  - Transferring collagen-pulsed, bone marrow-derived dendritic cells (DCs) into
      congenic DBA/1 recipient mice produced arthritis in joints adjacent to the site
      of DC transfer and could be inhibited by treatment with TNF antagonists. Disease
      was Ag specific, as transfer of control, unpulsed DCs, or DCs pulsed with OVA did
      not produce arthritis. In contrast to other experimental arthritis models, DC
      induced arthritis localized to the site of injection and did not spontaneously
      generalize to uninvolved joints, despite the demonstration of circulating
      collagen-reactive T cells. Similarly, transfer of T cells primed by collagen/DCs
      was not sufficient to produce arthritis in recipient mice. In collagen/DC-primed
      mice however, disease could be induced in uninvolved joints by local
      administration of noncollagen-pulsed DCs and this could be reduced through TNF
      inhibition. Similarly, injection of collagen/DC-primed mice with low-dose TNF
      also resulted in local induction of arthritis, as did administration of TNF to
      mice receiving T cells from collagen/DC but not OVA/DC-primed mice. Thus, we have
      demonstrated for the first time that administration of collagen-pulsed mature DCs
      is sufficient for the induction of arthritis. Furthermore, this disease process
      is mediated through both adaptive and innate effects of DCs; first, priming of
      autoreactive T cells and, second, induction of local inflammation via mediators
      such as TNF.

PMID- 12471144
TI  - Mitochondrial reactive oxygen species regulate spatial profile of proinflammatory
      responses in lung venular capillaries.
AB  - Cytokine-induced lung expression of the endothelial cell (EC) leukocyte receptor
      P-selectin initiates leukocyte rolling. To understand the early EC signaling that
      induces the expression, we conducted real-time digital imaging studies in lung
      venular capillaries. To compare receptor- vs nonreceptor-mediated effects, we
      infused capillaries with respectively, TNF-alpha and arachidonate. At
      concentrations adjusted to give equipotent increases in the cytosolic Ca(2+),
      both agents increased reactive oxygen species (ROS) production and EC P-selectin
      expression. Blocking the cytosolic Ca(2+) increases abolished ROS production;
      blocking ROS production abrogated P-selectin expression. TNF-alpha, but not
      arachidonate, released Ca(2+) from endoplasmic stores and increased mitochondrial
      Ca(2+). Furthermore, Ca(2+) depletion abrogated TNF-alpha responses partially,
      but arachidonate responses completely. These differences in Ca(2+) mobilization
      by TNF-alpha and arachidonate were reflected in spatial patterning in the
      capillary in that the TNF-alpha effects were localized at branch points, while
      the arachidonate effects were nonlocalized and extensive. Furthermore,
      mitochondrial blockers inhibited the TNF-alpha- but not the arachidonate-induced
      responses. These findings indicate that the different modes of Ca(2+)
      mobilization determined the spatial patterning of the proinflammatory response in
      lung capillaries. Responses to TNF-alpha revealed that EC mitochondria regulate
      the proinflammatory process by generating ROS that activate P-selectin
      expression.

PMID- 12471145
TI  - Essential role of the adhesion receptor LFA-1 for T cell-dependent fulminant
      hepatitis.
AB  - Viral hepatitis affects more than 2 billion people worldwide. In particular, no
      effective treatment exists to abrogate death and liver damage in fulminant
      hepatitis. Activation of T cells is an initial and critical event in the
      pathogenesis of liver damage in autoimmune and viral hepatitis. The precise
      molecular mechanisms that induce T cell-mediated hepatocyte injury remain largely
      unclear. In mice, T cell-dependent hepatitis and acute liver damage can be
      modeled using ConA. In this study, we examined the role of the adhesion receptor
      LFA-1 in ConA-induced acute hepatic damage using LFA-1(-/-) (CD11a) mice. Massive
      liver cell apoptosis and metabolic liver damage were observed in LFA-1(+/+) mice
      following ConA injection. By contrast, LFA-1(-/-) mice were completely resistant
      to ConA-induced hepatitis and none of the LFA-1(-/-) mice showed any hepatic
      damage. Whereas activated hepatic T cells remained in the liver in LFA-1(+/+)
      mice, activated T cells were rapidly cleared from the livers of LFA-1(-/-) mice.
      Mechanistically, T cells from LFA-1(-/-) mice showed markedly reduced
      cytotoxicity toward liver cells as a result of impaired, activation-dependent
      adhesion. Importantly, adoptive transfer of hepatic T cells from LFA-1(+/+) mice,
      but not from LFA-1(-/-) mice, sensitized LFA-1(-/-) mice to ConA-induced
      hepatitis. Thus, LFA-1 expression on T cells is necessary and sufficient for T
      cell-mediated liver damage in vivo. These results provide the first genetic
      evidence on an adhesion receptor, LFA-1, that has a crucial role in fulminant
      hepatitis. These genetic data identify LFA-1 as a potential key target for the
      treatment of T cell-mediated hepatitis and the prevention of liver damage.

PMID- 12471146
TI  - Use of single point mutations in domain I of beta 2-glycoprotein I to determine
      fine antigenic specificity of antiphospholipid autoantibodies.
AB  - Autoantibodies against beta(2)-glycoprotein I (beta(2)GPI) appear to be a
      critical feature of the antiphospholipid syndrome (APS). As determined using
      domain deletion mutants, human autoantibodies bind to the first of five domains
      present in beta(2)GPI. In this study the fine detail of the domain I epitope has
      been examined using 10 selected mutants of whole beta(2)GPI containing single
      point mutations in the first domain. The binding to beta(2)GPI was significantly
      affected by a number of single point mutations in domain I, particularly by
      mutations in the region of aa 40-43. Molecular modeling predicted these mutations
      to affect the surface shape and electrostatic charge of a facet of domain I.
      Mutation K19E also had an effect, albeit one less severe and involving fewer
      patients. Similar results were obtained in two different laboratories using
      affinity-purified anti-beta(2)GPI in a competitive inhibition ELISA and with
      whole serum in a direct binding ELISA. This study confirms that anti-beta(2)GPI
      autoantibodies bind to domain I, and that the charged surface patch defined by
      residues 40-43 contributes to a dominant target epitope.

PMID- 12471147
TI  - IL-12p35-deficient mice are susceptible to experimental autoimmune
      encephalomyelitis: evidence for redundancy in the IL-12 system in the induction
      of central nervous system autoimmune demyelination.
AB  - Experimental autoimmune encephalomyelitis (EAE) serves as a model for multiple
      sclerosis and is considered a CD4(+), Th1 cell-mediated autoimmune disease. IL-12
      is a heterodimeric cytokine, composed of a p40 and a p35 subunit, which is
      thought to play an important role in the development of Th1 cells and can
      exacerbate EAE. We induced EAE with myelin oligodendrocyte glycoprotein (MOG)
      peptide 35-55 (MOG(35-55)) in C57BL/6 mice and found that while IL-12p40
      deficient (-/-) mice are resistant to EAE, IL-12p35(-/-) mice are susceptible.
      Typical spinal cord mononuclear cell infiltration and demyelination were observed
      in wild-type and IL-12p35(-/-) mice, whereas IL-12p40(-/-) mice had normal spinal
      cords. A Th1-type response to MOG(35-55) was observed in the draining lymph node
      and the spleen of wild-type mice. A weaker MOG(35-55)-specific Th1 response was
      observed in IL-12p35(-/-) mice, with lower production of IFN-gamma. By contrast,
      a Th2-type response to MOG(35-55) correlated with disease resistance in IL-12p40(
      /-) mice. Production of TNF-alpha by microglia, CNS-infiltrating macrophages, and
      CD4(+) T cells was detected in wild-type and IL-12p35(-/-), but not in IL-12p40(
      /-), mice. In addition, NO production was higher in IL-12p35(-/-) and wild-type
      mice than in IL-12p40(-/-) mice. These data demonstrate a redundancy of the IL-12
      system in the induction of EAE and suggest that p40-related heterodimers, such as
      the recently cloned IL-23 (p40p19), may play an important role in disease
      pathogenesis.

PMID- 12471148
TI  - APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit
      hepatic graft-versus-host disease.
AB  - Host APCs are required for initiating T cell-dependent acute graft-vs-host
      disease (GVHD), but the role of APCs in the effector phase of acute GVHD is not
      known. To measure the effect of tissue-resident APCs on the local development of
      acute GVHD, we selectively depleted host macrophages and DCs from the livers and
      spleens, but not from the skin, peripheral lymph nodes (PLN), or mesenteric lymph
      nodes (MLN), of C57BL/6 (B6) mice by i.v. administration of liposomal clodronate
      before allogeneic bone marrow transplantation. Depletion of host hepatic and
      splenic macrophages and DCs significantly inhibited the proliferation of donor
      C3H.SW CD8(+) T cells in the spleen, but not in the PLN or MLN, of B6 mice. Such
      organ-selective depletion of host tissue APCs also markedly reduced the
      trafficking of allogeneic CD8(+) T cells into the livers and spleens, but not PLN
      and MLN, of B6 recipients compared with that of the control mice. Acute hepatic,
      but not cutaneous, GVHD was inhibited as well, resulting in improved survival of
      liposomal clodronate-treated B6 recipients. When C3H.SW CD8(+) T cells were
      activated in normal B6 recipients, recovered, and adoptively transferred into
      secondary B6 recipients, activated donor CD8(+) T cells rapidly migrated into the
      livers and spleens of control B6 recipients but were markedly decreased in B6
      mice that were depleted of hepatic and splenic macrophages and DCs. Thus, tissue
      resident APCs control the local recruitment of allo-reactive donor T cells and
      the subsequent development of acute GVHD.

PMID- 12471149
TI  - IL-13 receptor-targeted cytotoxin cancer therapy leads to complete eradication of
      tumors with the aid of phagocytic cells in nude mice model of human cancer.
AB  - Tumor-directed therapeutic approaches require unique or overexpressed specific Ag
      or receptor as a target to achieve selective tumor killing. However,
      heterogeneous expression of these targets on tumor cells limits the efficacy of
      this form of therapy. In this study, we forced abundant expression of IL
      13Ralpha2 chain by plasmid-mediated gene transfer in head and neck, as well as
      prostate tumors to provide a potential target. This was followed by successfully
      treating xenograft tumor-bearing nude mice with IL-13R-directed cytotoxin (IL13
      PE38QQR). Although we did not observe an indirect cytotoxic bystander effect
      conveyed to nontransduced tumor cells in vitro, our approach in vivo led to a
      complete regression of established tumors transfected with IL-13Ralpha2 chain in
      most animals. We found that the tumor eradication was achieved in part by
      infiltration of macrophages and NK cells, assessed by immunohistochemistry.
      Moreover, head and neck tumors xenografted in macrophage-depleted nude mice were
      less sensitive to the antitumor effect of IL-13 cytotoxin. Because we did not
      observe vector-related toxicity in any vital organs, our novel combination
      strategy of gene transfer of IL-13Ralpha2 chain and receptor-directed cytotoxin
      therapy may be a useful approach for the treatment of localized cancer.

PMID- 12471150
TI  - Critical requirement for professional APCs in eliciting T cell responses to novel
      fragments of histidyl-tRNA synthetase (Jo-1) in Jo-1 antibody-positive
      polymyositis.
AB  - Polymyositis (PM) is an autoimmune muscle disease characterized by oligoclonal T
      cell infiltrates mediating myocytotoxicity. Although antigenic triggers for this
      process remain undefined, clinically homogeneous subsets of PM patients are
      characterized by autoantibodies directed against nuclear and cytoplasmic Ags that
      include histidyl-tRNA synthetase (Jo-1). Available evidence suggests that
      formation of anti-Jo-1 autoantibodies is Ag-driven and therefore dependent on
      CD4(+) T cells that may also direct cytolytic CD8(+) T cells involved in myocyte
      destruction. To assess peripheral blood T cell responses to Jo-1, we first
      subcloned full-length human Jo-1 as well as novel fragments of Jo-1 into the
      maltose-binding protein expression vector pMALc2. Expressed proteins were then
      used in standard proliferation assays with either PBMC or autologous DCs as
      sources of APCs. Although PBMC-derived APCs and DCs both supported peripheral
      blood T cell proliferation when primed with full-length human Jo-1, only DCs
      promoted proliferative responses to a unique amino-terminal fragment of Jo-1. mAb
      blockade of different HLA Ags revealed that these responses were MHC class II
      dependent. Therefore, for the first time, these studies demonstrate anti-Jo-1 T
      cell responses in Jo-1 Ab-positive PM patients as well as in healthy control
      subjects. More importantly, this work underscores the critical importance of APC
      type in dictating T cell responses to a novel antigenic fragment of Jo-1.

PMID- 12471152
TI  - Stomatocyte-discocyte-echinocyte sequence of the human red blood cell: evidence
      for the bilayer- couple hypothesis from membrane mechanics.
AB  - Red-cell shape is encoded in the mechanical properties of the membrane. The
      plasma membrane contributes bending rigidity; the protein-based membrane skeleton
      contributes stretch and shear elasticity. When both effects are included,
      membrane mechanics can reproduce in detail the full stomatocyte-discocyte
      echinocyte sequence by variation of a single parameter related to the bilayer
      couple originally introduced by Sheetz and Singer [Sheetz, M. P. & Singer, S. J.
      (1974) Proc. Natl. Acad. Sci. USA 71, 4457-4461].

PMID- 12471153
TI  - Genetic analysis of iron citrate toxicity in yeast: implications for mammalian
      iron homeostasis.
AB  - Deletion of the yeast homologue of frataxin, YFH1, results in mitochondrial iron
      accumulation and respiratory deficiency (petite formation). We used a genetic
      screen to identify mutants that modify iron-associated defects in respiratory
      activity in Deltayfh1 cells. A deletion in the peroxisomal citrate synthase CIT2
      in Deltayfh1 cells decreased the rate of petite formation. Conversely,
      overexpression of CIT2 in Deltayfh1 cells increased the rate of respiratory loss.
      Citrate toxicity in Deltayfh1 cells was dependent on iron but was independent of
      mitochondrial respiration. Citrate toxicity was not restricted to iron-laden
      mitochondria but also occurred when iron accumulated in cytosol because of
      impaired vacuolar iron storage. These results suggest that high levels of citrate
      may promote iron-mediated tissue damage.

PMID- 12471154
TI  - Initiation factor eIF5B catalyzes second GTP-dependent step in eukaryotic
      translation initiation.
AB  - Initiation factors IF2 in bacteria and eIF2 in eukaryotes are GTPases that bind
      Met-tRNA(i)(Met) to the small ribosomal subunit. eIF5B, the eukaryotic ortholog
      of IF2, is a GTPase that promotes ribosomal subunit joining. Here we show that
      eIF5B GTPase activity is required for protein synthesis. Mutation of the
      conserved Asp-759 in human eIF5B GTP-binding domain to Asn converts eIF5B to an
      XTPase and introduces an XTP requirement for subunit joining and translation
      initiation. Thus, in contrast to bacteria where the single GTPase IF2 is
      sufficient to catalyze translation initiation, eukaryotic cells require
      hydrolysis of GTP by both eIF2 and eIF5B to complete translation initiation.

PMID- 12471156
TI  - A pH-sensitive histidine residue as control element for ligand release from HLA
      DR molecules.
AB  - Class II MHC molecules undergo conformational changes on shifts of the pH. As a
      consequence, low-affinity peptides tightly bound at pH 7.0 can be released at pH
      5.0. The imidazole group of histidine is the only amino acid side chain affected
      within this range. At pH 5.0 the group is positively charged, polar, and
      hydrophilic, whereas at pH 7.4 it is neutral, apolar, and hydrophobic. In this
      study, we used soluble forms of HLA-DR and substituted conserved histidine
      residues with tyrosine, an isosteric analogue to the uncharged form of histidine.
      The goal of this substitution was to identify crucial His residues by an increase
      in pH stability of the ligand complex. HLA-DM-mediated release experiments
      revealed that substitution of His-33 in the alpha(1) domain of the HLA-DR
      molecule almost doubled the half-life of HLA-DR1class II-associated invariant
      chain peptide complexes. The divergence in the off-rate of WT and H33Y mutated
      complex was strictly pH-dependent and correlated with the theoretical titration
      curve of the imidazole group. For both HLA-DR1 and HLA-DR4 molecules the mutation
      resulted in a shift of class II-associated invariant-chain peptide release curves
      by up to 0.5 pH units. His-33alpha1 is present in all HLA-DR and H-2E molecules.
      It connects the alpha(1) and alpha(2) domains in its noncharged form by
      hydrophobic interactions with residue Val-136alpha2. It is located in close
      proximity to the putative interface with HLA-DM and may function as a pH
      sensitive "button," which is closed at pH 7.0 but opens below pH 6.0 to allow
      conformational transitions necessary for ligand exchange.

PMID- 12471157
TI  - Extensive mosaic structure revealed by the complete genome sequence of
      uropathogenic Escherichia coli.
AB  - We present the complete genome sequence of uropathogenic Escherichia coli, strain
      CFT073. A three-way genome comparison of the CFT073, enterohemorrhagic E. coli
      EDL933, and laboratory strain MG1655 reveals that, amazingly, only 39.2% of their
      combined (nonredundant) set of proteins actually are common to all three strains.
      The pathogen genomes are as different from each other as each pathogen is from
      the benign strain. The difference in disease potential between O157:H7 and CFT073
      is reflected in the absence of genes for type III secretion system or phage- and
      plasmid-encoded toxins found in some classes of diarrheagenic E. coli. The CFT073
      genome is particularly rich in genes that encode potential fimbrial adhesins,
      autotransporters, iron-sequestration systems, and phase-switch recombinases.
      Striking differences exist between the large pathogenicity islands of CFT073 and
      two other well-studied uropathogenic E. coli strains, J96 and 536. Comparisons
      indicate that extraintestinal pathogenic E. coli arose independently from
      multiple clonal lineages. The different E. coli pathotypes have maintained a
      remarkable synteny of common, vertically evolved genes, whereas many islands
      interrupting this common backbone have been acquired by different horizontal
      transfer events in each strain.

PMID- 12471158
TI  - Grafted neural stem cells develop into functional pyramidal neurons and integrate
      into host cortical circuitry.
AB  - In vitro expanded neural stemprogenitor cells can undergo region-specific
      differentiation after transplantation to the developing or adult brain, and
      display morphologies and markers characteristic of mature neurons. Here we have
      used patch-clamp techniques to explore whether grafted stem cells also can
      develop physiological properties of mature neurons and become functionally
      integrated within host neural circuitry. The immortalized neural progenitor cell
      line, RN33B, prelabeled with GFP by using a lentiviral vector, was transplanted
      into the cortex or hippocampus of neonatal rats. We found that the grafted GFP
      positive cells differentiated into cells with morphological features of cortical
      or hippocampal pyramidal neurons, and that many of them had established
      appropriate cortico-thalamic and contralateral hippocampal connections,
      respectively, as revealed by retrograde tracing. Whole-cell patch-clamp
      recordings from grafted cells with morphological characteristics of pyramidal
      neurons showed that they were able to generate action potentials, and received
      functional excitatory and inhibitory synaptic inputs from neighboring cells.
      These data provide evidence that grafted neural progenitors can differentiate
      into morphologically mature pyramidal projection neurons, establish appropriate
      long-distance axonal projections, exhibit normal electrophysiological properties,
      and become functionally integrated into host cortical circuitry.

PMID- 12471159
TI  - An Ethiopian pattern of human adaptation to high-altitude hypoxia.
AB  - We describe, in Ethiopia, a third successful pattern of human adaptation to high
      altitude hypoxia that contrasts with both the Andean "classic" (erythrocytosis
      with arterial hypoxemia) and the more recently identified Tibetan (normal venous
      hemoglobin concentration with arterial hypoxemia) patterns. A field survey of 236
      Ethiopian native residents at 3,530 m (11,650 feet), 14-86 years of age, without
      evidence of iron deficiency, hemoglobinopathy, or chronic inflammation, found an
      average hemoglobin concentration of 15.9 and 15.0 gdl for males and females,
      respectively, and an average oxygen saturation of hemoglobin of 95.3%. Thus,
      Ethiopian highlanders maintain venous hemoglobin concentrations and arterial
      oxygen saturation within the ranges of sea level populations, despite the
      unavoidable, universal decrease in the ambient oxygen tension at high altitude.

PMID- 12471160
TI  - The gastric biology of Helicobacter pylori.
AB  - Helicobacter pylori is a neutralophilic, gram-negative, ureolytic organism that
      is able to colonize the human stomach but does not survive in a defined medium
      with a pH <4.0 unless urea is present. In order to live in the gastric
      environment, it has developed a repertoire of acid resistance mechanisms that can
      be classified into time-independent, acute, and chronic responses. Time
      independent acid resistance depends on the structure of the organism's inner and
      outer membrane proteins that have a high isoelectric point, thereby reducing
      their proton permeability. Acute acid resistance depends on the constitutive
      synthesis of a neutral pH optimum urease that is an oligomeric Ni(2+)-containing
      heterodimer of UreA and UreB subunits. Gastric juice urea is able to rapidly
      access intrabacterial urease when the periplasmic pH falls below approximately
      6.2 owing to pH-gating of a urea channel, UreI. This results in the formation of
      NH3, which then neutralizes the bacterial periplasm to provide a pH of
      approximately 6.2 and an inner membrane potential of -101 mV, giving a proton
      motive force of approximately -200 mV. UreI is a six-transmembrane segment
      protein, with homology to the amiS genes of the amidase gene cluster and to UreI
      of Helicobacter hepaticus and Streptococcus salivarius. Expression of these UreI
      proteins in Xenopus oocytes has shown that UreI of H. pylori and H. hepaticus can
      transport urea only at acidic pH, whereas that of S. salivarius is open at both
      neutral and acidic pH. Site-directed mutagenesis and chimeric analysis have
      identified amino acids implicated in maintaining the closed state of the channel
      at neutral pH and other amino acids that play a structural role in channel
      function. Deletion of ureI abolishes the ability of the organism to survive in
      acid and also to colonize the mouse or gerbil stomach. However, if acid secretion
      is inhibited in gerbils, the deletion mutants do colonize but are eradicated when
      acid secretion is allowed to return, showing that UreI is essential for gastric
      survival and that the habitat of H. pylori at the gastric surface must fall to pH
      3.5 or below. The chronic response is from increased Ni(2+) insertion into the
      apo-enzyme, which results in a threefold increase in urease, which is also
      dependent on expression of UreI. This allows the organism to live in either
      gastric fundus or gastric antrum depending on the level of acidity at the gastric
      surface. There are other effects of acid on transcript stability that may alter
      levels of protein synthesis in acid. Incubation of the organism at acidic pH also
      results in regulation of expression of a variety of genes, such as some outer
      membrane proteins, that constitutes an acid tolerance response. Understanding of
      these acid resistance and tolerance responses should provide novel eradication
      therapies for this carcinogenic gastric pathogen.

PMID- 12471161
TI  - Lipid receptors in cardiovascular development.
AB  - To most people, concerns over the link between lipids and cardiovascular health
      most likely end with monitoring their daily consumption of dietary fats. However,
      it has become increasingly clear that, in addition to effects on adult
      cardiovascular physiology, lipids also play key roles in the formation of a
      functioning cardiovascular system. The lysophospholipids, lysophosphatidic acid
      (LPA) and sphingosine 1-phosphate (S1P), have come to the forefront as
      developmental and physiological regulators of the cardiovascular system. In this
      review, we discuss the function of the G protein-coupled receptors responsible
      for transducing LPA and S1P signals during development of the vertebrate
      cardiovascular system, focusing first on their role in angiogenesis and then on
      their function during embryonic development.

PMID- 12471162
TI  - Permeation and selectivity in calcium channels.
AB  - Recent advances-both experimental and theoretical-provide a tentative image of
      the structures in Ca channels that make them exceptionally selective. The image
      is very different from K channels, which obtain high selectivity with a rigid
      pore that tightly fits K(+) ions and is lined by carbonyl oxygens of the
      polypeptide backbone. Ca channels rely on four glutamate residues (the EEEE
      locus), whose carboxyl side chains likely reach into the pore lumen to interact
      with passing Ca(2+) ions. The structure is thought to be flexible, tightly
      binding a single Ca(2+) ion in order to block Na(+) flux but rearranging to
      interact with multiple Ca(2+) ions to allow Ca(2+) flux. The four glutamates are
      not equivalent, a fact that seems important for Ca(2+) permeation. This review
      describes the experimental evidence that leads to these conclusions and the
      attempts by theorists to explain the combination of high selectivity and high
      flux that characterizes Ca channels.

PMID- 12471163
TI  - Aminophospholipid asymmetry: A matter of life and death.
AB  - Maintenance of membrane lipid asymmetry is a dynamic process that influences many
      events over the lifespan of the cell. With few exceptions, most cells restrict
      the bulk of the aminophospholipids to the inner membrane leaflet by means of
      specific transporters. Working in concert with each other, these proteins correct
      for sporadic incursions of the aminophospholipids to the outer membrane leaflet
      as a result of bilayer imbalances created by various cellular events. A shift in
      the relative contribution in each of these activities can result in sustained
      exposure of the aminophospholipids at the cell surface, which allows capture of
      the cells by phagocytes before the integrity of the plasma membrane is
      compromised. The absence of an efficient recognition and elimination mechanism
      can result in uncontrolled and persistent presentation of self-antigens to the
      immune system, with development of autoimmune syndromes. To prevent this,
      phagocytes have developed a diverse array of distinct and redundant receptor
      systems that drive the postphagocytic events along pathways that facilitate cross
      talk between the homeostatic and the immune systems. In this work, we review the
      basis for the proposed mechanism(s) by which apoptotic ligands appear on the
      target cell surface and the phagocyte receptors that recognize these moieties.

PMID- 12471164
TI  - Phosphoinositide regulation of the actin cytoskeleton.
AB  - Phosphoinositides [PPIs, which collectively refer to phosphorylated derivatives
      of phosphatidylinositol (PI)] have a pivotal role as precursors to important
      second messengers and as bona fide signaling and scaffold targeting molecules.
      This review focuses on recent advances that elucidate how PPIs, particularly
      PI(4,5)P2 (PIP2), directly regulate the actin cytoskeleton in vivo by modulating
      the activity and targeting of actin regulatory proteins. The role of PIP2 in
      stimulating actin polymerization and in establishing cytoskeleton-plasma membrane
      linkages is emphasized. In addition, the review presents tantalizing evidence
      that suggests how binding of selected cytoskeletal proteins to membrane PPIs may
      promote PPI clustering into raft lipid microdomains, alter their accessibility to
      other proteins, and even distort the bilayer conformation. These actions have
      profound implications for many other PPI-regulated membrane functions that are
      beginning to be uncovered, and they suggest how PPIs can mediate crosstalk
      between the actin cytoskeleton and an expanding spectrum of essential cellular
      functions.

PMID- 12471165
TI  - Insulin receptor knockout mice.
AB  - To examine the role of the insulin receptor in fuel homeostasis, we and others
      have carried out genetic ablation studies in mice. Mice lacking insulin receptors
      are born with normal features, but develop early postnatal diabetes and die of
      ketoacidosis. In contrast, mice lacking insulin receptors in specific cell types
      as a result of conditional mutagenesis develop mild metabolic and reproductive
      abnormalities. These experiments have uncovered novel functions of insulin
      receptors in tissues such as brain and pancreatic beta-cells. Combined knockout
      studies of insulin and Igf1 receptors indicate that the insulin receptor also
      promotes embryonic growth. Experimental crosses of mice with insulin receptor
      haploinsufficiency have been instrumental to the genetic analysis of insulin
      action by enabling us to assign specific roles to different insulin receptor
      substrates and identify novel elements in insulin signaling.

PMID- 12471167
TI  - The physiology of cellular liporegulation.
AB  - Here we explore the physiologic role of leptin as a liporegulatory hormone
      responsible for maintaining intracellular homeostasis in the face of wide
      variations in caloric intake. Normally, rats can tolerate a 60% fat diet because
      96% of the surplus fat is deposited in adipocytes. In contrast, when leptin is
      congenitally absent or inactive, even on a normal diet, unutilized dietary fat is
      deposited in nonadipose tissues, causing dysfunction (lipotoxicity) and possible
      cell death (lipoapoptosis). We theorize that in diet-induced obesity, acquired
      leptin resistance may also develop as the result of increase in certain leptin
      resistance factors. Acquired leptin resistance occurs in aging, obesity,
      Cushing's syndrome, and acquired lipodystrophy, and preliminary evidence suggests
      that ectopic lipid deposition is increased. We speculate that the metabolic
      syndrome may be the human equivalent of the lipotoxic syndrome of rodents.

PMID- 12471168
TI  - Functional genomics and the comparative physiology of hypoxia.
AB  - Comparative physiology has proven a powerful approach to our understanding of how
      animals function under hypoxic conditions and to identifying potential
      adaptations to environmental oxygen levels. This review considers the potential
      for using a similar comparative approach with functional genomics to understand
      the genetic basis of such physiological processes and evolutionary adaptations.
      Comparative functional genomics is currently limited by genome data, which are
      available for only a few model organisms. However, comparative studies between
      model organisms of the same species having slightly different genomes (e.g., in
      bred strains of laboratory rodents, transgenic mice, and consomic rats)
      demonstrate the types of results, as well as the analytical challenges, that are
      possible if comparative functional genomics is applied to more species. Results
      from wild and domestic animal studies suggest new models to investigate
      physiological and evolutionary responses to oxygen levels with functional
      genomics.

PMID- 12471166
TI  - G protein-coupled receptor rhodopsin: a prospectus.
AB  - Rhodopsin is a retinal photoreceptor protein of bipartite structure consisting of
      the transmembrane protein opsin and a light-sensitive chromophore 11-cis-retinal,
      linked to opsin via a protonated Schiff base. Studies on rhodopsin have unveiled
      many structural and functional features that are common to a large and
      pharmacologically important group of proteins from the G protein-coupled receptor
      (GPCR) superfamily, of which rhodopsin is the best-studied member. In this work,
      we focus on structural features of rhodopsin as revealed by many biochemical and
      structural investigations. In particular, the high-resolution structure of bovine
      rhodopsin provides a template for understanding how GPCRs work. We describe the
      sensitivity and complexity of rhodopsin that lead to its important role in
      vision.

PMID- 12471169
TI  - Application of microarray technology in environmental and comparative physiology.
AB  - DNA microarray technology is revolutionizing many aspects of biological research,
      allowing the expression of many thousands of gene transcripts to be monitored
      simultaneously. This provides powerful tools for the genome-wide correlation of
      gene transcript levels with physiological responses and alterations in
      physiological states. To date, microarray analyses have been applied almost
      exclusively to a few model species for which the abundant gene sequence data
      permit the fabrication of whole-genome microarrays. However, many interesting
      physiological traits and responses are poorly expressed or absent in model
      species and may be better illustrated in nonmodel organisms. Comparative
      approaches to understanding function traditionally focus on species that by
      virtue of their unusual adaptations, lifestyles, and phylogeny are particularly
      suited to address a specific biological process or problem. In this review, we
      show that microarray technology can be successfully applied to these nonmodel
      species and used to generate new insights of comparative and evolutionary
      significance into animal function.

PMID- 12471170
TI  - Hyperpolarization-activated cation currents: from molecules to physiological
      function.
AB  - Hyperpolarization-activated cation currents, termed If, Ih, or Iq, were initially
      discovered in heart and nerve cells over 20 years ago. These currents contribute
      to a wide range of physiological functions, including cardiac and neuronal
      pacemaker activity, the setting of resting potentials, input conductance and
      length constants, and dendritic integration. The hyperpolarization-activated,
      cation nonselective (HCN) gene family encodes the channels that underlie Ih. Here
      we review the relation between the biophysical properties of recombinant HCN
      channels and the pattern of HCN mRNA expression with the properties of native Ih
      in neurons and cardiac muscle. Moreover, we consider selected examples of the
      expanding physiological functions of Ih with a view toward understanding how the
      properties of HCN channels contribute to these diverse functional roles.

PMID- 12471171
TI  - Long-range resonance energy transfer in molecular systems.
AB  - The current state of understanding of molecular resonance energy transfer (RET)
      and recent developments in the field are reviewed. The development of more
      general theoretical approaches has uncovered some new principles underlying RET
      processes. This review brings many of these important new concepts together into
      a generalization of Forster's original theory. The conclusions of studies
      investigating the various approximations in Forster theory are summarized. Areas
      of present and future activity are discussed. The review covers Forster theory
      for donor-acceptor pairs and electronic coupling for singlet-singlet, triplet
      triplet, and superexchange-mediated energy transfer. This includes the transition
      density picture of Coulombic coupling as well as electronic coupling between
      molecular aggregates (excitons). Spectral overlaps and ensemble energy transfer
      rates in disordered aggregates, the role of dielectric properties of the medium,
      weak versus strong coupling, and new models for energy transfer in complex
      molecular assemblies are also described.

PMID- 12471172
TI  - Some pleasures in chemical physics.

PMID- 12471173
TI  - In search of perfection: understanding the highly defect-selective chemistry of
      anisotropic etching.
AB  - Anisotropic etchants selectively reveal a specific crystallographic plane.
      Although prized industrially, these etchants are poorly understood because they
      target specific defect sites on a surface. New methods, which rely on a
      combination of scanning tunneling microscopy, kinetic Monte Carlo simulations,
      and infrared spectroscopy, have been developed to quantify these reactions. By
      correlating the measured reaction rates with the structure of the defects,
      information about reaction mechanisms can be obtained. These techniques have also
      been extended to allow for the quantification of impurity reactions such as the
      reaction of dissolved O2, and of nonetching additives, such as alcohols. A
      complementary macroscopic technique, which utilizes microfabricated arrays of
      miscut surfaces to measure orientation-dependent kinetics, is also described.

PMID- 12471174
TI  - 2,5-hexanedione-induced testicular injury.
AB  - Now in its third decade of mechanistic investigation, testicular injury caused by
      2,5-hexanedione (2,5-HD) exposure is a well-studied model with a rich database.
      The development of this model reflects the larger changes that have moved biology
      from a branch of chemistry into the molecular age. Critically examined in this
      review is the proposed mechanism for 2,5-HD-induced testicular injury in which
      germ cell maturation is disrupted owing to alterations in Sertoli cell
      microtubule-mediated functions. The goal is to evaluate the technical and
      conceptual approaches used to assess 2,5-HD-induced testicular injury, to
      highlight unanswered questions, and to identify fruitful avenues of future
      research.

PMID- 12471175
TI  - Growth hormone therapy in adults.
AB  - Growth hormone (GH) is classically linked with linear growth in childhood but
      continues to have important metabolic actions throughout life. GH deficiency in
      adulthood causes a distinct syndrome with significant morbidities. These include
      increased total and visceral fat, decreased muscle mass and aerobic capacity,
      affective disturbances, abnormal lipids, and increased vascular mortality, all of
      which are ameliorated with GH replacement. The possibility of adult GH deficiency
      (AGHD) should always be considered in individuals with a history of childhood GH
      deficiency or significant hypothalamic-pituitary damage, and the diagnosis should
      then be confirmed by biochemical testing. Adult GH dosing is much lower than that
      in pediatric practice, as appropriate for physiologic reconstitution. Hormonal
      side effects are minimized by stepwise dose titration. Lingering concerns remain
      regarding the possibility of increased cancer risk with long-term treatment, but
      this hazard has not been unequivocally demonstrated. Compared with AGHD, there is
      much less information about GH replacement in other diseases or in normal aging,
      or about the use of supraphysiologic GH doses to treat catabolic states. In
      critical illness, high-dose GH therapy has proven clearly harmful, and the
      balance of risks and benefits of GH administration in most adult contexts other
      than AGHD has not been defined.

PMID- 12471177
TI  - The biomedical challenges of space flight.
AB  - Space medicine has evolved considerably through past U.S. missions. It has been
      proven that humans can live and work in space for long durations and that humans
      are integral to mission success. The space medicine program of the National
      Aeronautics and Space Administration (NASA) looks toward future long-duration
      missions. Its goal is to overcome the biomedical challenges associated with
      maintaining the safety, health, and optimum performance of astronauts and
      cosmonauts. This program investigates the health effects of adaptation to
      microgravity: the nature of their pathologies, the effects of microgravity on
      pathophysiology, and the alterations in pharmacodynamics and treatment. A
      critical capability in performing research is the monitoring of the health of all
      astronauts and of the spacecraft environment. These data support the evidence
      based approach to space medicine, incorporating past studies of microgravity
      related conditions and their terrestrial counterparts. This comprehensive
      approach will enable safe and effective exploration beyond low Earth orbit.

PMID- 12471176
TI  - Molecular genetics of lung cancer.
AB  - Lung cancer results from multiple changes in the genome of susceptible pulmonary
      cells caused by exposure to carcinogens found in tobacco smoke, the environment,
      or the workplace. Recent studies suggest that histologically apparent lung cancer
      is due to the sequential accumulation of specific genetic and morphologic changes
      to the normal epithelial cells of the lung. Positive signallers, such as those
      mediated by the oncogene RAS, and negative signallers, such as those mediated by
      the tumor suppressor retinoblastoma protein (RB), contribute to unchecked cell
      growth and proliferation. Other key molecular derangements can also be considered
      hallmarks of cancer, including evasion of apoptosis and senescence, angiogenesis,
      tissue invasion, and metastases. Epigenetic inactivation of genes via DNA
      methylation provides another novel way of evading normal cellular control
      mechanisms. The new knowledge of the human genome coupled with global methods of
      detecting genetic abnormalities and profiling gene expression in tumor cells may
      enable us to understand the signaling pathways of lung cancer cells. These are
      molecular targets for new cancer therapeutics such as receptor tyrosine kinase
      inhibitors. This information could advance risk assessment, early detection,
      prognosis, and therapy for lung cancer.

PMID- 12471178
TI  - Technology-driven triage of abdominal trauma: the emerging era of nonoperative
      management.
AB  - Selective nonoperative management of blunt or penetrating abdominal trauma is
      safe, has eliminated the complications associated with nontherapeutic
      laparotomies, and is cost-effective. Appropriately selected investigations, such
      as focused abdominal sonography for trauma, diagnostic peritoneal lavage, spiral
      computed tomography (CT) scan, diagnostic laparoscopy, or thoracoscopy and
      angiography, play a critical role in the triage of patients. Future technological
      advances, such as improvement of the ultrasonic hardware and software that
      provide automated interpretation and the availability of portable CT scan
      machines in the emergency room, may improve the speed and accuracy of the initial
      evaluation. Improvement of the optical system of minilaparoscopes may allow
      reliable bedside laparoscopy for suspected diaphragmatic injuries.

PMID- 12471179
TI  - The Food and Drug Administration and reprocessing of single-use medical devices:
      a revised policy and new questions.

PMID- 12471180
TI  - Can labeled single-use devices be reused? An old question in the new era.

PMID- 12471181
TI  - Chronic renal ischemia: implications for cardiovascular disease risk.
AB  - Chronic renal ischemia caused by atherosclerotic renal artery stenosis (RAS) is
      gaining recognition as a potentially important risk factor for cardiovascular
      (CV) morbidity and mortality. The etiology of increased risk of CV events is
      multifaceted and includes direct physiologic changes that increase risk as well
      as intermediate clinical effects that are associated with worse outcome.
      Physiologic changes associated with increased CV risk in patients with RAS
      include increased production of fibrogenic and vasoactive peptides such as renin,
      angiotensin, endothelin, and catecholamines, as well as endothelial cell
      dysfunction. Clinical intermediate conditions associated with higher incidences
      of CV events seen in patients with renal ischemia include hypertension, systemic
      atherosclerosis, chronic renal failure, and left ventricular hypertrophy and
      dysfunction. More thorough understanding of the myriad physiologic changes seen
      in patients with RAS will likely improve patient selection for renal artery
      revascularization. Clinical trials should examine a full range of CV and renal
      outcomes, not just blood pressure, to adequately assess the merits of
      revascularization.

PMID- 12471182
TI  - Treatment of occluded central venous catheters with alteplase: results in 1,064
      patients.
AB  - PURPOSE: Thrombosis of central venous access devices (CVADs) is a relatively
      frequent complication. Alteplase (tissue plasminogen activator) has been used to
      salvage dysfunctional devices. The purpose of this study was to analyze the
      safety and efficacy of alteplase after administration of a maximum of two 2-mg/2
      mL doses to thrombosed CVADs. MATERIALS AND METHODS: A combined analysis was
      performed of two pivotal prospective phase-III clinical trials (Cardiovascular
      thrombolytic to Open Occluded Lines [COOL] Trials) involving 80 centers enrolling
      patients from November 1999 through December 2000. Patients 2 years of age or
      older (with body weights >10 kg) with dysfunctional nondialysis CVADs were
      eligible, including those with peripherally inserted central catheters, apheresis
      catheters, and ports. Alteplase (2 mg/2 mL) was instilled into the lumen of the
      central venous catheter and allowed to dwell for as long as 120 minutes. For
      patients with body weights of 10-30 kg, 110% of the internal lumen volume of
      alteplase (2 mg/2 mL) was administered. If the device was still occluded after a
      maximum of 120 minutes, a second alteplase dose was given and allowed to dwell
      for as long as 120 minutes. The primary efficacy endpoint was designated as
      restored function after a maximum of two doses. The primary safety endpoint was
      intracranial hemorrhage (ICH) within 5 days. RESULTS: A total of 1,064 patients
      (465 men, 599 women; mean age, 50.7 y; range, 2-91 y) with dysfunctional
      catheters were treated. After alteplase administration, function was restored in
      798 patients (75.0%; 95% CI: 72.3%, 77.6%) after one dose and 905 (85.1%; 95% CI:
      82.8%, 87.2%) after two doses. Efficacy rates were similar among catheter types
      (single-, double-, and triple-lumen catheters, and ports). Serious adverse events
      monitored within 30 days of treatment included ICH (0.0%), embolic events (0.0%),
      gastrointestinal bleeding (0.3%), thrombosis (0.3%), and sepsis (0.4%). One event
      (fever) was attributed to the study drug. Efficacy was independent of age, sex,
      body weight, and catheter type. CONCLUSION: A regimen of as many as two 2-mg
      doses of alteplase is safe and effective for restoring flow to occluded central
      venous access devices.

PMID- 12471183
TI  - Estimated costs for uterine artery embolization and abdominal myomectomy for
      uterine leiomyomata: a comparative study at a single institution.
AB  - PURPOSE: To determine and compare the costs associated with uterine artery
      embolization (UAE) and abdominal myomectomy for the treatment of symptomatic
      leiomyomata. MATERIALS AND METHODS: Charge information was gathered and analyzed
      from 23 patients who underwent UAE and 17 who underwent abdominal myomectomy in a
      single institution. The mean charges for each procedure were calculated from the
      patients' billing data. Cost-to-charge ratios were applied to the mean charges to
      estimate costs. The work relative value units (RVUs) for all physician services
      for each procedure were calculated. These total work RVUs for each intervention
      were multiplied by the appropriate Medicare conversion factors to estimate a
      uniform physician fee. These costs were totaled and compared with use of the
      unpaired t test to estimate the cost difference between UAE and abdominal
      myomectomy. RESULTS: The estimated hospital cost for UAE was $3,193, which was
      significantly lower than the $5,598 estimated for abdominal myomectomy (P
      <.0001). The discrepancy was caused primarily by increased hospital care and
      operating room costs for abdominal myomectomy. The total professional costs were
      significantly higher for UAE ($2,220) than for abdominal myomectomy ($1,611) (P
      =.002). When all associated costs, including typical imaging costs, were
      considered, there was a trend toward lower costs for UAE ($6,708) compared to
      abdominal myomectomy ($7,630) (P =.086). CONCLUSION: UAE had lower procedure
      related costs than abdominal myomectomy despite higher physician costs. When
      typical imaging costs were included, there was still a trend toward lower costs
      for UAE.

PMID- 12471184
TI  - Procedural success and patency after percutaneous treatment of thrombosed
      autogenous arteriovenous dialysis fistulas.
AB  - PURPOSE: To retrospectively evaluate success and midterm patency after
      percutaneous thrombectomy, lytic therapy, and angioplasty for thrombosed
      autogenous arteriovenous dialysis fistulas. MATERIALS AND METHODS: From March
      1996 to September 2001, 24 patients with 25 fistulas presented with 30 episodes
      of thrombosis of their autogenous fistulas, including 19 forearm radiocephalic
      fistulas in 18 patients and six upper arm brachiocephalic fistulas in six
      patients. Patients presented for percutaneous therapy within 48 hours of fistula
      thrombosis, with the exception of one patient who presented 7 days after
      thrombosis. Lytic therapy with urokinase or recombinant tissue plasminogen
      activator (rt-PA) was administered as a bolus into the fistula in 24 cases, with
      the exception of one case in which a 16-hour infusion of rt-PA was initiated. A
      mechanical thrombectomy device was used in a single case. Balloon thrombectomy
      was performed for residual clot. Angioplasty was performed at the arterial
      inflow, fistula, and outflow veins as required for identified areas of stenosis
      and/or maceration of thrombus. RESULTS: Clinical success was achieved in 73% of
      cases (22 of 30). All patients were followed for a maximum of 66 months (mean, 12
      mo). Primary patency rates were 36% at 3 months (95% CI, 18%-54%), 28% at 6
      months (95% CI, 12%-46%), and 24% at 1 year (95% CI, 10%-42%). The assisted
      primary patency rate was 40% (95% CI, 21%-58%) at 3 months and stabilized at 32%
      at 6 months (95% CI, 15%-50%). The secondary patency rate stabilized at 3 months
      at 44% (95% CI, 24%-62%) for 15 months. Patency rates after clot removal were not
      significantly different between upper and lower arm fistulas (P =.14). Total
      observation time of the cohort of 25 fistulas was 296 months. The complication
      rate was 7% (two of 30), with one major complication and one minor complication.
      CONCLUSION: Salvage of function after percutaneous clot removal from autogenous
      fistulas involves a steep learning curve initially and is possible with 3-month
      patency rates that approximate Kidney Disease Outcomes Quality Initiative
      recommendations for clot removal from polytetrafluoroethylene grafts.

PMID- 12471185
TI  - Repeated intervention for in-stent restenosis of the renal arteries.
AB  - PURPOSE: To assess the long-term technical success of repeated endovascular
      intervention in stenosed renal artery stents. MATERIALS AND METHODS: Fifteen
      patients with stenoses >or=50% in a renal stent placed because of an ostial
      atherosclerotic renal artery stenosis were included in this study. In the
      presence of increased blood pressure or decreased renal function, the in-stent
      restenosis was treated with percutaneous transluminal angioplasty (PTA) in the
      stent or placement of a second stent if the stenosis was located too distally in
      the stent. The results of these repeat interventions were evaluated by
      angiography. RESULTS: The 15 patients had a total of 20 stenosed stents. Eighteen
      of these in-stent stenoses were treated with PTA and two were treated with
      placement of a second stent. Angiographic follow-up was available in 16 arteries,
      showing in-stent restenosis in four (25%; mean follow-up, 11 mo). The cumulative
      patency rates after repeat endoluminal intervention were 93% (95% CI: 80%-106%)
      and 76% (95% CI: 52%-101%) after 6 and 12 months, respectively. Renal function
      remained stable or improved in most patients (80%) after repeated intervention in
      the stent, and hypertension was classified as improved or cured in 47% of
      patients after 1 year. CONCLUSION: Patients with stenosed renal artery stents can
      be treated successfully with PTA in a majority of cases, with a long-term success
      rate of 75% and stable renal function 1 year after repeated intervention.

PMID- 12471186
TI  - Radiofrequency ablation combined with chemoembolization in hepatocellular
      carcinoma: treatment response based on tumor size and morphology.
AB  - PURPOSE: To evaluate local therapeutic efficacy of radiofrequency (RF) ablation
      after chemoembolization for hepatocellular carcinoma (HCC) based on tumor size
      and morphology. MATERIALS AND METHODS: Sixty-four patients underwent RF ablation
      under ultrasonographic or real-time computed tomographic (CT) fluoroscopic
      guidance within 2 weeks after chemoembolization. One hundred eight lesions were
      treated. Sixty-five lesions were small (<or=3 cm), 32 were intermediate in size
      (3.1-5 cm), and 11 were large (5.1-12 cm). Seventy-four of the HCCs were nodular
      lesions and the other 34 were nonnodular (multinodular and infiltrative) lesions.
      Response to treatment was evaluated by dynamic enhanced CT and magnetic resonance
      imaging. Tumor necrosis was considered to be complete when no foci of enhancement
      were seen within the tumor and at its periphery. RESULTS: Complete necrosis was
      achieved in all lesions regardless of tumor size or morphology. There have been
      no local recurrences in small and intermediate-sized lesions regardless of tumor
      morphology during a mean follow-up of 12.5 months. In large HCCs, nodular lesions
      showed no recurrence, but two of six of nonnodular lesions recurred beyond the
      thermal lesions created around the tumor. The estimated 1-year survival rate was
      98.0% in all patients. CONCLUSIONS: This combined therapy has a therapeutic
      effect on small and intermediate-sized HCCs regardless of tumor morphology and is
      a promising treatment option for large nodular lesions. Control of large
      nonnodular lesions is still a challenging problem.

PMID- 12471187
TI  - Complications of percutaneous transhepatic portal vein embolization.
AB  - PURPOSE: Percutaneous transhepatic portal vein (PV) embolization (PTPE) is a
      useful preoperative procedure for extended liver resection. The purpose of the
      present study was to assess the frequency of technical complications of PTPE and
      to discuss the risks of this procedure. MATERIALS AND METHODS: PTPE was performed
      in 46 patients. Forty-seven procedures were performed because an initial puncture
      failure required that the procedure be performed twice in one patient. The
      technical success rate and technical complications were assessed. Complications
      were analyzed with regard to approach methods and puncture sites. Approach
      methods were categorized as contralateral or ipsilateral. Puncture sites were
      categorized into anterior, posterior, and lateral segments. The results were
      compared statistically with use of the Fisher exact test. RESULTS: Technical
      success was achieved in 45 of 47 procedures (95.7%). Complications occurred in
      seven of 47 procedures (14.9%), including pneumothorax in two, subcapsular
      hematoma in two, arterial puncture in one, pseudoaneurysm in one, hemobilia in
      one, and PV thrombosis in one. Subcapsular hematoma and pseudoaneurysm occurred
      in the same procedure. No patient died as a result of complications. There was no
      significant difference between the contralateral and ipsilateral approaches. The
      incidence of complications was significantly higher in procedures involving
      puncture of the posterior segment than in those involving puncture of the
      anterior segment (P =.0374). CONCLUSION: In cases in which the anterior segment
      cannot be visualized for puncture, PTPE via the lateral segment or transileocolic
      portal embolization should be considered rather than PTPE via the posterior
      segment.

PMID- 12471188
TI  - Effects of brachytherapy on intimal hyperplasia in arteriovenous fistulas in a
      porcine model.
AB  - PURPOSE: The hypotheses of this investigation were that endovascular radiation
      would reduce intimal hyperplasia in arteriovenous fistulas (AVFs) and that this
      reduction would be associated with decreased expression of vascular endothelial
      growth factor (VEGF), platelet-derived growth factor (PDGF)-A, and tumor necrosis
      factor (TNF)-alpha. MATERIALS AND METHODS: Bilateral end jugular vein-to-side
      carotid artery fistulas were constructed in pigs. At 48 hours, one AVF was
      randomly selected for endovascular radiation with (192) Iridium. The
      contralateral fistula received no radiation and served as a control. Animals in
      group 1 (n = 7) received 14 Gy of radiation at a depth of 2 mm and tissue was
      harvested at 29 days; animals in group 2 received 7 Gy of radiation at a depth of
      2 mm and tissue was harvested at 29 days (n = 8); and animals in group 3 received
      7 Gy of radiation at a depth of 2 mm and tissue was harvested at 56 days (n = 8).
      The area and maximum thickness of intimal hyperplasia were then measured blindly.
      Immunohistochemical results for VEGF, PDGF-A, and TNFalpha were obtained and
      analyzed blindly by assigning a score of 0-3, with 0 indicating no staining and 3
      indicating maximum staining. RESULTS: Irradiation with 14 Gy caused severe
      fibrosis in the media of the vein, with thrombosis of three of seven AVFs.
      Compared with the control group, the group that underwent irradiation with 7 Gy
      had significantly reduced intimal area at 56 days (9.9 mm(2) +/- 4.9 vs 2.1 mm(2)
      +/- 1.1; P =.001). This reduction correlated with significant reduction in the
      expression of VEGF (score of 2.2 +/- 0.1 vs 1.2 +/- 0.2; P =.001) and TNFalpha
      (1.3 +/- 0.1 vs 0.9 +/- 0.1; P =.04). CONCLUSION: Fourteen grays is an excessive
      radiation dose for veins, causing medial fibrosis and thrombosis of the AVF.
      Irradiation with 7 Gy effectively inhibited the formation of intimal hyperplasia
      in AVF. This inhibition correlated with decreased expression of VEGF and
      TNFalpha.

PMID- 12471189
TI  - Inhibition of neointimal hyperplasia by heat stress in an experimental model.
AB  - PURPOSE: To evaluate the potential effect of heat stress in inhibiting neointimal
      hyperplasia after angioplasty in an experimental model. MATERIALS AND METHODS: In
      vitro, proliferation and migration of heat-stress-induced and noninduced cells
      were compared with use of an endothelial cell/smooth muscle cell coculture model
      (five culture dishes in each experiment). Mild heat stress was induced via
      exposure of cultures to a temperature of 42 degrees C for 2 hours. In vivo, the
      neointimal thickness of ear arteries of Japanese white rabbits 7 days after
      denudation of endothelium was histologically evaluated in the control and heat
      stress-induced groups (three rabbits in each group). RESULTS: Proliferation of
      heat-stress-induced smooth muscle cells declined significantly compared with that
      of noninduced cells in single-culture and coculture models. The migration rates
      of neither endothelial cells nor smooth muscle cells were significantly affected
      by heat stress. In vivo, the mean neointimal thickness was 13.8 micro m +/- 8.0
      in the control group and 3.9 micro m +/- 2.1 in the induced group (P <.05).
      CONCLUSION: Induction of mild heat stress has great potential to reduce
      neointimal hyperplasia after angioplasty because it inhibits smooth muscle cell
      proliferation without inhibiting endothelial migration in vitro and suppresses
      neointimal growth in vivo.

PMID- 12471190
TI  - Recurrent TIPS thrombosis after polyethylene stent-graft use and salvage with
      polytetrafluoroethylene stent-grafts.
AB  - Increasing data support the use of polytetrafluoroethylene (PTFE) stent-grafts
      for de novo and revision transjugular intrahepatic portosystemic shunt (TIPS)
      applications. Animal experiments have indicated that polyethylene terephthalate
      (PET) stent-grafts provide no improvement or actually worsen TIPS patency
      compared with controls, but human TIPS experience with PET grafts is more
      limited. Herein we describe three patients who underwent de novo creation of TIPS
      with PET-covered stent-grafts at outside institutions, which resulted in
      immediate and recurring TIPS thromboses despite repeated thrombectomies. After
      the failed TIPS were revised with PTFE stent-grafts, the presenting symptoms
      resolved and uninterrupted patency was achieved.

PMID- 12471191
TI  - Vein of Galen technique for occluding the aneurysmal sac of pulmonary
      arteriovenous malformations.
AB  - In seven of 255 consecutive patients (2.7%) who underwent pulmonary arteriovenous
      malformation (PAVM) embolization at our center between July 1, 1996, and July 1,
      2000, the feeding artery was considered too short for safe occlusion with use of
      standard stainless-steel coils or detachable balloons. These patients were
      successfully treated with use of a modified vein of Galen technique similar to
      the one used for managing intracranial vein of Galen aneurysms. In this article,
      the authors report their experience with this technique in safely occluding the
      aneurysmal sacs of PAVMs in patients with short (<2 cm) feeding pulmonary
      arteries.

PMID- 12471192
TI  - Sacroplasty: a new treatment for sacral insufficiency fracture.
AB  - Sacroplasty, a variation of the vertebroplasty technique for treatment of a
      sacral insufficiency fracture, is described herein in technical detail. The
      procedure provided symptom relief and resulted in no complications. This result
      suggests that successful treatment of a sacral insufficiency fracture with use of
      sacroplasty is technically feasible.

PMID- 12471193
TI  - Snare retrieval of intracranial thrombus in patients with acute stroke.
AB  - Intravenous or intraarterial thrombolysis of intracranial emboli is becoming an
      accepted clinical treatment modality for acute ischemic stroke, but not all
      emboli respond to the lytic drug regimens available today. If drug therapy fails,
      mechanical retrieval seems warranted. Four patients whose condition was resistant
      to intravenous and intraarterial thrombolytic drug treatment underwent at least
      partial clot removal with use of a snare, and almost immediate clinical
      improvement was noted. A fifth patient's clot was removed before lytic drugs were
      administered. All five patients, who presented with a sudden onset of stroke,
      were evaluated by arterial angiography; then, after a failed trial of
      intraarterial fibrinolytic drugs, they were treated by passing a 2- or 4-mm snare
      through a microcatheter. The snare wire was guided around the thrombus, gently
      brought back toward the microcatheter-but not into it-and the entire
      microcatheter and snare assembly was then removed. In four of the five cases,
      follow-up angiography performed immediately after the retrieval showed wider
      distal branches than normal. Follow-up computed tomography results were abnormal
      in all cases, showing hyperdense material in the territory that was previously
      ischemic. This hyperdensity subsided within 48 hours in all but one patient who
      developed small parenchymal hemorrhages; however, he remained asymptomatic. The
      snare device offers an additional or alternative therapy until completely
      effective thrombolytic agents become available. Although use of a snare is not
      ideal, device improvements should make the retrieval less technically challenging
      and more effective. There is a need for improved mechanical extraction devices,
      especially in light of the patient improvement that occurred. This experience
      also suggests that immediate removal of a mature clot could reduce the total time
      of brain ischemia more quickly than administration of thrombolytic drugs.

PMID- 12471194
TI  - Temporary IVC filtration before patent foramen ovale closure in a patient with
      paradoxic embolism.
AB  - Pulmonary embolism (PE) and associated acute peripheral ischemia suggest the
      diagnosis of paradoxic embolism. The most common intracardiac defect associated
      with paradoxic emboli is a patent foramen ovale (PFO). Therapeutic options
      include anticoagulation, thrombolysis, inferior vena cava (IVC) filtration, and
      closure of the intracardiac defect. The authors discuss the diagnosis and
      treatment of a young female athlete who presented with massive PE complicated by
      a paradoxic embolus to the right subclavian artery. Systemic and catheter
      directed thrombolysis, IVC filtration, and percutaneous closure of a PFO were
      performed in an effort to return the patient to the level of competitiveness she
      desired.

PMID- 12471195
TI  - Refractory biliary leak from intrahepatic biliary-enteric anastomosis treated by
      selective portal vein embolization.
AB  - A 66-year-old woman underwent partial hepatectomy and pylorus-preserving
      pancreaticoduodenectomy for advanced Klatskin-type cholangiocarcinoma, and five
      intrahepatic biliary-enteric anastomoses were created. One anastomosis between
      the anterior-superior segmental bile duct and the jejunum developed a refractory
      biliary leak. Selective portal venous embolization with use of ethanol was
      performed in the anterior-superior portal branch to eliminate the production of
      bile by the target segment. The patient's clinical course was uneventful and the
      leak resolved after portal vein embolization.

PMID- 12471196
TI  - Re: Treatment of a splenic artery aneurysm with use of a stent-graft.

PMID- 12471197
TI  - Risk assessment and management of high risk familial breast cancer.
AB  - The demand for genetic services by women with a family history of breast cancer
      has increased exponentially over the last few years. It is important that risks
      to women are accurately assessed and that processes are in place for appropriate
      counselling and management. The classification of risk into average, moderate,
      and high, depending upon the assessed lifetime risk of breast cancer, allows for
      the management of moderate risk women within cancer units and high risk women
      within the regional genetic centres. Management of high risk women includes
      discussion of options including screening, chemoprevention, and preventive
      surgery. The majority of these options are still unproven in the long term and
      continuing research is needed for their evaluation. Mutation screening and
      predictive testing are now a reality for a minority of families, allowing for a
      more informed basis for decisions regarding management options.

PMID- 12471198
TI  - Transient neonatal diabetes, a disorder of imprinting.
AB  - Transient neonatal diabetes (TND) is a rare but distinct type of diabetes.
      Classically, neonates present with growth retardation and diabetes in the first
      week of life. Apparent remission occurs by 3 months but there is a tendency for
      children to develop diabetes in later life. Evidence suggests it is the result of
      overexpression of an imprinted and paternally expressed gene/s within the TND
      critical region at 6q24. Two imprinted genes, ZAC (zinc finger protein associated
      with apoptosis and cell cycle arrest) and HYMAI (imprinted in hydatidiform mole)
      have been identified as potential candidates. Three genetic mechanisms have been
      shown to result in TND, paternal uniparental isodisomy of chromosome 6,
      paternally inherited duplication of 6q24, and a methylation defect at a CpG
      island overlapping exon 1 of ZAC/HYMAI.

PMID- 12471199
TI  - Thrombocytopenia-absent radius syndrome: a clinical genetic study.
AB  - The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation
      syndrome characterised by bilateral absence of the radii and a thrombocytopenia.
      The lower limbs, gastrointestinal, cardiovascular, and other systems may also be
      involved. Shaw and Oliver in 1959 were the first to describe this condition, but
      it was Hall et al in 1969 who reported the first major series of patients. Since
      then most reports have been based on single or small numbers of cases. We report
      the results of a clinical study looking at the phenotype of 34 patients with TAR
      syndrome. All cases had a documented thrombocytopenia and bilateral radial
      aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal
      anomalies, and 15% cardiac anomalies. Congenital anomalies not previously
      described in association with TAR syndrome included facial capillary
      haemangiomata, intracranial vascular malformation, sensorineural hearing loss,
      and scoliosis. Karyotype analysis, chromosome breakage studies including
      premature centromeric separation and fluorescence in situ hybridisation studies
      looking for a deletion of chromosome 22q11 were undertaken. Two abnormal
      karyotypes were identified.

PMID- 12471200
TI  - Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2
      and familial juvenile hyperuricaemic nephropathy.
AB  - INTRODUCTION: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile
      hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases
      characterised by juvenile onset of hyperuricaemia, gout, and progressive renal
      failure. Clinical features of both conditions vary in presence and severity.
      Often definitive diagnosis is possible only after significant pathology has
      occurred. Genetic linkage studies have localised genes for both conditions to
      overlapping regions of chromosome 16p11-p13. These clinical and genetic findings
      suggest that these conditions may be allelic. AIM: To identify the gene and
      associated mutation(s) responsible for FJHN and MCKD2. METHODS: Two large,
      multigenerational families segregating FJHN were studied by genetic linkage and
      haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit
      refinement of the candidate interval and localisation of candidate genes, an
      integrated physical and genetic map of the candidate region was developed. DNA
      sequencing of candidate genes was performed to detect mutations in subjects
      affected with FJHN (three unrelated families) and MCKD2 (one family). RESULTS: We
      identified four novel uromodulin (UMOD) gene mutations that segregate with the
      disease phenotype in three families with FJHN and in one family with MCKD2.
      CONCLUSION: These data provide the first direct evidence that MCKD2 and FJHN
      arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI
      anchored glycoprotein and the most abundant protein in normal urine. We postulate
      that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible
      for the clinical changes of interstitial renal disease, polyuria, and
      hyperuricaemia found in MCKD2 and FJHN.

PMID- 12471201
TI  - Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation
      t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism
      (MMEP) phenotype.
AB  - A patient with microcephaly, microphthalmia, ectrodactyly, and prognathism (MMEP)
      and mental retardation was previously reported to carry a de novo reciprocal
      t(6;13)(q21;q12) translocation. In an attempt to identify the presumed causative
      gene, we mapped the translocation breakpoints using fluorescence in situ
      hybridisation (FISH). Two overlapping genomic clones crossed the breakpoint on
      the der(6) chromosome, locating the breakpoint region between D6S1594 and
      D6S1250. Southern blot analysis allowed us to determine that the sorting nexin 3
      gene (SNX3) was disrupted. Using Inverse PCR, we were able to amplify and
      sequence the der(6) breakpoint region, which exhibited homology to a BAC clone
      that contained marker D13S250. This clone allowed us to amplify and sequence the
      der(13) breakpoint region and to determine that no additional rearrangement was
      present at either breakpoint, nor was another gene disrupted on chromosome 13.
      Therefore, the translocation was balanced and SNX3 is probably the candidate gene
      for MMEP in the patient. However, mutation screening by dHPLC and Southern blot
      analysis of another sporadic case with MMEP failed to detect any point mutations
      or deletions in the SNX3 coding sequence. Considering the possibility of
      positional effect, another candidate gene in the vicinity of the der(6)
      chromosome breakpoint may be responsible for MMEP in the original patient or,
      just as likely, the MMEP phenotype in the two patients results from genetic
      heterogeneity.

PMID- 12471202
TI  - Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple
      myeloma, a tumour characterised by aberrant class switch recombination.
AB  - The DNA double stranded break (DSB) repair mechanism, non-homologous end joining
      (NHEJ) represents an essential step in antigen receptor gene rearrangement
      mechanisms, processes believed to be intimately involved in the aetiology of
      lymphoproliferative disease. We investigated the potential impact that previously
      undescribed polymorphisms identified within NHEJ DNA ligase IV (LIG4) have upon
      predisposition to several lymphoproliferative disorders, including leukaemia,
      lymphoma, and multiple myeloma. Two LIG4 polymorphisms were examined, both C>T
      transitions, which result in the amino acid substitutions A3V and T9I.
      Inheritance of the LIG4 A3V CT genotype was found to be significantly associated
      with a two-fold reduction in risk of developing multiple myeloma (OR 0.49, 95% CI
      0.27 to 0.89). Similarly, inheritance of the LIG4 T9I CT and the T9I TT genotypes
      were found to associate with a 1.5-fold reduction (OR 0.77, 95% CI 0.51 to 1.17)
      and a four-fold reduction (OR 0.22, 95% CI 0.07 to 0.70) in risk of developing
      multiple myeloma respectively, suggesting a gene dosage effect for this
      polymorphism. The LIG4 A3V and T9I variant alleles are in linkage disequilibrium
      (D'=0.95, p<0.0001), and the protective effect associated with these
      polymorphisms was found to be the result of inheritance of the A3V-T9I CT and A3V
      T9I TT haplotypes. These data suggest that genetic variants of NHEJ LIG4 may
      modulate predisposition to multiple myeloma, a tumour characterised by aberrant
      immunoglobulin (Ig) class switch recombination.

PMID- 12471204
TI  - Clinical and genetic studies of Birt-Hogg-Dube syndrome.
AB  - Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant cancer syndrome
      characterised by benign skin tumours, renal tumours, and spontaneous
      pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently
      identified, expressing a novel protein called folliculin. We report the clinical
      and genetic studies of four sporadic BHD cases and four families with a total of
      23 affected subjects. Haplotype analysis of these families using BHD linked
      markers showed they did not share the same affected alleles, excluding common
      ancestry. Mutation analysis of the BHD gene identified two germline mutations on
      exon 11 (c.1733insC and c.1733delC) in three of four families as well as two of
      four sporadic cases. A novel somatic mutation, c.1732delTCinsAC, was detected in
      a BHD related chromophobe renal carcinoma. Our results confirmed the (C)8 tract
      in exon 11 as a mutational hot spot in BHD and should always be considered for
      future genetic testing. Our observation also indicated that the second hit (of
      Knudson's two hit theory) in some BHD related tumours is in the form of somatic
      mutation rather than LOH. In a large French family in which eight affected
      subjects carry the c.1733delC mutation, a phenocopy who has multiple episodes of
      spontaneous pneumothorax was identified. A total of five mutation carriers (aged
      between 37 to 66) did not have any evidence of BHD features, suggesting either
      reduced penetrance or late age of onset of the disease. In addition, six out of
      eight affected subjects who have positive germline mutation have confirmed
      neoplastic colonic polyps, indicating that colorectal neoplasia is an associated
      feature of BHD in some families. Our studies have observed several interesting
      genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot
      spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset
      of disease; (4) association with colorectal neoplasia in some families; and (5)
      somatic mutation instead of LOH as the second hit in BHD tumours.

PMID- 12471205
TI  - SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac
      arrhythmias and sudden death in a white family.
AB  - Cardiac arrhythmias cause 400 000 sudden deaths annually in the United States
      alone. Mutations in the cardiac sodium channel gene SCN5A on chromosome 3p21
      cause cardiac arrhythmias and sudden death. In this study, we define an SCN5A
      mutation, S1103Y, in a white family associated with syncope, ventricular
      fibrillation, and sudden death. A very recent study reported the same mutation in
      13.2% of African Americans, but not in the white population. Our study shows that
      mutation S1103Y does exist in the white population, and it is associated with a
      considerable risk of syncope, ventricular arrhythmia, ventricular fibrillation,
      and sudden death in this population.

PMID- 12471207
TI  - Longevity in Schimke immuno-osseous dysplasia.

PMID- 12471206
TI  - Evolution and expression of FOXL2.

PMID- 12471208
TI  - Relationship between clinical and genetic diagnosis of Prader-Willi syndrome.

PMID- 12471209
TI  - Report of a new case of "genitopatellar" syndrome which challenges the importance
      of absent patellae as a defining feature.

PMID- 12471210
TI  - Calculating predictive values for the large repeat alleles at the SCA8 locus in
      patients with ataxia.

PMID- 12471211
TI  - Germline mutation of the tumour suppressor PTEN in Proteus syndrome.

PMID- 12471212
TI  - Low rate of TP53 germline mutations in breast cancer/sarcoma families not
      fulfilling classical criteria for Li-Fraumeni syndrome.

PMID- 12471213
TI  - Physical and psychomotor development of 1799 children born after second trimester
      amniocentesis for maternal serum positive triple test screening and normal
      prenatal karyotype.

PMID- 12471214
TI  - Behavioural phenotype of Bardet-Biedl syndrome.

PMID- 12471215
TI  - Autosomal dominant (AD) pure spastic paraplegia (HSP) linked to locus SPG4
      affects almost exclusively males in a large pedigree.

PMID- 12471216
TI  - PRKAR1A, one of the Carney complex genes, and its locus (17q22-24) are rarely
      altered in pituitary tumours outside the Carney complex.

PMID- 12471217
TI  - Hereditary duplication of proximal chromosome 1q (q11q22) in a patient with T
      lymphoblastic lymphoma/leukaemia: a family study using G banding and comparative
      genomic hybridisation.

PMID- 12471218
TI  - A comparative study between infertile males and patients with Turner syndrome to
      determine the influence of sex chromosome mosaicism and the breakpoints of
      structurally abnormal Y chromosomes on phenotypic sex.

PMID- 12471219
TI  - Frequency of mutations in the early growth response 2 gene associated with
      peripheral demyelinating neuropathies.

PMID- 12471220
TI  - Maternally inherited non-syndromic hearing impairment in a Spanish family with
      the 7510T>C mutation in the mitochondrial tRNA(Ser(UCN)) gene.

PMID- 12471221
TI  - Correlation between a specific Wilms tumour suppressor gene (WT1) mutation and
      the histological findings in Wilms tumour (WT).

PMID- 12471222
TI  - Comparison of genetic services with and without genetic registers: knowledge,
      adjustment, and attitudes about genetic counselling among probands referred to
      three genetic clinics.
AB  - Genetic register services incorporating long term follow up and a proactive
      approach to at risk subjects have been recommended as a way of improving access
      to genetic counselling for families with dominant or X linked genetic disorders
      and chromosome translocations. The aims of the present study were to evaluate the
      psychosocial benefits and drawbacks of long term family contact, and to evaluate
      the attitudes of probands and their general practitioners towards proactive
      genetic counselling. We interviewed 192 people referred to three regional genetic
      clinics because of a family history of Duchenne or Becker muscular dystrophy,
      myotonic dystrophy, or chromosome translocations, and 43 of the referring GPs.
      Probands attending the centre using a genetic register approach were compared
      with those from the two centres offering the standard clinical genetic service. A
      very high proportion of probands in both groups were well informed about the
      genetic risks to themselves and their children, were satisfied with the service
      they had received from their local genetic clinic, and felt adequately prepared
      to discuss the family illness with their children. The register probands
      expressed approval of the ongoing contact and open access provided by the
      register service. Asked whether previously unaware relatives should be informed
      of their at risk status, 98% (188/192) said it was acceptable for this
      information to be disclosed by a family member, while three quarters of the
      probands (149/192) and just over half the GPs (27/43) thought it acceptable for
      the genetic service to approach them; a similar proportion of both GPs and
      probands also found it acceptable for GPs to do so. More than half the probands
      (107/190) thought it was the family's responsibility to pass on genetic risk
      information, but 43% said that either the genetic service or the GP should be
      responsible for this. The findings show that the genetic register approach
      incorporating long term follow up and a proactive approach to genetic counselling
      is highly acceptable to the families concerned, and although the register and non
      register probands did not differ significantly on any of the main outcome
      measures used in this relatively short term study, it may be that the continuing
      contact associated with the register approach offers long term benefits,
      especially for those genetic conditions where medical surveillance may have an
      impact on the prognosis.

PMID- 12471223
TI  - Comparison of genetic services with and without genetic registers: access and
      attitudes to genetic counselling services among relatives of genetic clinic
      patients.
AB  - The pedigrees of 192 subjects at risk of Duchenne or Becker muscular dystrophy,
      myotonic dystrophy, or balanced chromosome translocations attending three
      regional genetic clinics were inspected to identify relatives who were themselves
      at high risk of these disorders. Of the 342 relatives eligible for inclusion, 43%
      (63/147) of the register relatives and 26% (50/195) of the non-register relatives
      had had contact with the clinical genetic services, a significant difference
      (p<0.02). Relatives from families with muscular dystrophy were significantly more
      likely to have been in contact with genetic services than those from BT families.
      Fifty-two relatives were interviewed about their experience and attitudes
      regarding genetic counselling. Almost all regarded knowledge about the family
      genetic disorder as helpful, and only one thought it unacceptable for relatives
      to be informed that they are at risk; 94% thought it was acceptable for this
      information to come from family members, 92% from general practitioners, and 90%
      from the clinical genetic service. A majority of relatives (53%) thought it was
      the family's responsibility to pass on genetic risk information, but 22% said the
      genetic service should be responsible and 18% thought it should be the GP. These
      data, together with the findings from the study of probands attending genetic
      clinics for these disorders, indicate that the genetic register approach
      incorporating long term follow up and a proactive approach to genetic counselling
      is acceptable to the families concerned and improves access to genetic services
      for at risk relatives.

PMID- 12471224
TI  - In praise of petroleum?

PMID- 12471225
TI  - Medical research. Inquiry turns into OK corral for U.K. primate research.

PMID- 12471226
TI  - Genomics. Sequence tells mouse, human genome secrets.

PMID- 12471227
TI  - European research. Mystery academy holds first powwow in private.

PMID- 12471228
TI  - Planetary science. A smashing source of early Martian water?

PMID- 12471229
TI  - Planetary science. And an icy patch at Mars's south pole.

PMID- 12471230
TI  - Medical research. U.K. researchers hope for clarity in tissue use.

PMID- 12471231
TI  - Cell proliferation. Common control for cancer, stem cells.

PMID- 12471232
TI  - Astronomy. Sensing the hidden heat of the universe.

PMID- 12471233
TI  - Archaeology. Oldest New World writing suggests Olmec innovation.

PMID- 12471234
TI  - Digital information systems. Mapping the future.

PMID- 12471235
TI  - Marine geology. Nations look for an edge in claiming continental shelves.

PMID- 12471236
TI  - Canada. New research chairs mean brain gain for universities.

PMID- 12471237
TI  - Portraits of science. Kurt Godel--separating truth from proof in mathematics.

PMID- 12471238
TI  - Development. A tail of transdifferentiation.

PMID- 12471239
TI  - Ecology. Looking beneath the surface.

PMID- 12471240
TI  - Chemistry. The simplest "enzyme".

PMID- 12471241
TI  - Molecular biology. Untangling checkpoints.

PMID- 12471242
TI  - Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein
      kinases.
AB  - Multicellular organisms have three well-characterized subfamilies of mitogen
      activated protein kinases (MAPKs) that control a vast array of physiological
      processes. These enzymes are regulated by a characteristic phosphorelay system in
      which a series of three protein kinases phosphorylate and activate one another.
      The extracellular signal-regulated kinases (ERKs) function in the control of cell
      division, and inhibitors of these enzymes are being explored as anticancer
      agents. The c-Jun amino-terminal kinases (JNKs) are critical regulators of
      transcription, and JNK inhibitors may be effective in control of rheumatoid
      arthritis. The p38 MAPKs are activated by inflammatory cytokines and
      environmental stresses and may contribute to diseases like asthma and
      autoimmunity.

PMID- 12471243
TI  - The protein kinase complement of the human genome.
AB  - We have catalogued the protein kinase complement of the human genome (the
      "kinome") using public and proprietary genomic, complementary DNA, and expressed
      sequence tag (EST) sequences. This provides a starting point for comprehensive
      analysis of protein phosphorylation in normal and disease states, as well as a
      detailed view of the current state of human genome analysis through a focus on
      one large gene family. We identify 518 putative protein kinase genes, of which 71
      have not previously been reported or described as kinases, and we extend or
      correct the protein sequences of 56 more kinases. New genes include members of
      well-studied families as well as previously unidentified families, some of which
      are conserved in model organisms. Classification and comparison with model
      organism kinomes identified orthologous groups and highlighted expansions
      specific to human and other lineages. We also identified 106 protein kinase
      pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes
      and revealed that 244 kinases map to disease loci or cancer amplicons.

PMID- 12471245
TI  - Generating and exploiting polarity in bacteria.
AB  - Bacteria are often highly polarized, exhibiting specialized structures at or near
      the ends of the cell. Among such structures are actin-organizing centers, which
      mediate the movement of certain pathogenic bacteria within the cytoplasm of an
      animal host cell; organized arrays of membrane receptors, which govern
      chemosensory behavior in swimming bacteria; and asymmetrically positioned septa,
      which generate specialized progeny in differentiating bacteria. This polarization
      is orchestrated by complex and dynamic changes in the subcellular localization of
      signal transduction and cytoskeleton proteins as well as of specific regions of
      the chromosome. Recent work has provided information on how dynamic subcellular
      localization occurs and how it is exploited by the bacterial cell. The main task
      of a bacterial cell is to survive and duplicate itself. The bacterium must
      replicate its genetic material and divide at the correct site in the cell and at
      the correct time in the cell cycle with high precision. Each kind of bacterium
      also executes its own strategy to find nutrients in its habitat and to cope with
      conditions of stress from its environment. This involves moving toward food,
      adapting to environmental extremes, and, in many cases, entering and exploiting a
      eukaryotic host. These activities often involve processes that take place at or
      near the poles of the cell. Here we explore some of the schemes bacteria use to
      orchestrate dynamic changes at their poles and how these polar events execute
      cellular functions. In spite of their small size, bacteria have a remarkably
      complex internal organization and external architecture. Bacterial cells are
      inherently asymmetric, some more obviously so than others. The most easily
      recognized asymmetries involve surface structures, e.g., flagella, pili, and
      stalks that are preferentially assembled at one pole by many bacteria. "New"
      poles generated at the cell division plane differ from old poles from the
      previous round of cell division. Even in Escherichia coli, which is generally
      thought to be symmetrical, old poles are more static than new poles with respect
      to cell wall assembly (1), and they differ in the deposition of phospholipid
      domains (2). There are many instances of differential polar functions; among
      these is the preferential use of old poles when attaching to host cells as in the
      interaction of Bradyrhizobium with plant root hairs (3) or the polar pili
      mediated attachment of the Pseudomonas aeruginosa pathogen to tracheal epithelia
      (4). An unusual polar organelle that mediates directed motility on solid surfaces
      is found in the nonpathogenic bacterium Myxococcus xanthus. The gliding motility
      of this bacterium is propelled by a nozzle-like structure that squirts a
      polysaccharide-containing slime from the pole of the cell (5). Interestingly, M.
      xanthus, which has nozzles at both poles, can reverse direction by closing one
      nozzle and opening the other in response to end-to-end interactions between
      cells.

PMID- 12471246
TI  - Anterior-posterior polarity in C. elegans and Drosophila--PARallels and
      differences.
AB  - The eggs of Caenorhabditis elegans and Drosophila bear little similarity to each
      other, yet both depend on the par genes for control of anterior-posterior
      polarity. Here we explore possible common roles for the par genes (pars) in
      converting transient asymmetries into stably polarized axes. Although clear
      mechanistic parallels remain to be established, par-dependent regulation of
      microtubule dynamics and protein stability emerge as common themes.

PMID- 12471247
TI  - Shaping the vertebrate body plan by polarized embryonic cell movements.
AB  - Polarized cell movements shape the major features of the vertebrate body plan
      during development. The head-to-tail body axis of vertebrates is elongated in
      embryonic stages by "convergent extension" tissue movements. During these
      movements cells intercalate between one another transverse to the elongating body
      axis to form a narrower, longer array. Recent discoveries show that these
      polarized cell movements are controlled by homologs of genes that control the
      polarity of epithelial cells in the developing wing and eye of the fruit fly,
      Drosophila.

PMID- 12471248
TI  - Composition and formation of intercellular junctions in epithelial cells.
AB  - The polarized nature of epithelial cells is manifested by the nonrandom
      partitioning of organelles within the cells, the concentration of intercellular
      junctions at one pole, and the asymmetric distribution of proteins and lipids
      within the plasma membrane. These features allow epithelia to fulfill their
      specific tasks, such as targeted uptake and secretion of molecules and the
      segregation of different tissue compartments. The accessibility of Drosophila
      melanogaster and Caenorhabditis elegans to genetic and cell biological analyses,
      combined with the study of mammalian cells in culture, provides an ideal basis
      for understanding the mechanisms that control the establishment and maintenance
      of epithelial cell polarity and tissue integrity. Here, we focus on some of the
      best-studied junctions and membrane-associated protein complexes and their
      relation to cell polarity. Comparisons between fly, worm, and vertebrate
      epithelia reveal marked similarities with respect to the molecules used, and
      pronounced differences in the organization of the junctions themselves.

PMID- 12471249
TI  - Molecular mechanisms of axon guidance.
AB  - Axons are guided along specific pathways by attractive and repulsive cues in the
      extracellular environment. Genetic and biochemical studies have led to the
      identification of highly conserved families of guidance molecules, including
      netrins, Slits, semaphorins, and ephrins. Guidance cues steer axons by regulating
      cytoskeletal dynamics in the growth cone through signaling pathways that are
      still only poorly understood. Elaborate regulatory mechanisms ensure that a given
      cue elicits the right response from the right axons at the right time but is
      otherwise ignored. With such regulatory mechanisms in place, a relatively small
      number of guidance factors can be used to generate intricate patterns of neuronal
      wiring.

PMID- 12471250
TI  - Dissolved organic carbon support of respiration in the dark ocean.

PMID- 12471251
TI  - Cavitation-induced reactions in high-pressure carbon dioxide.
AB  - The feasibility of ultrasound-induced in situ radical formation in liquid carbon
      dioxide was demonstrated. The required threshold pressure for cavitation could be
      exceeded at a relatively low acoustic intensity, as the high vapor pressure of
      CO2 counteracts the hydrostatic pressure. With the use of a dynamic bubble model,
      the formation of hot spots upon bubble collapse was predicted. Cavitation-induced
      radical formation was used for the polymerization of methyl methacrylate in CO2,
      yielding high-molecular-weight polymers. These results show that sonochemical
      reactions can be performed in dense-phase fluids, which allows the
      environmentally benign CO2 to replace conventional organic solvents in many
      reaction systems.

PMID- 12471252
TI  - Closed-shell molecules that ionize more readily than cesium.
AB  - We report a class of molecules with extremely low ionization enthalpies, one
      member of which has been determined to have a gas-phase ionization energy (onset,
      3.51 electron volts) lower than that of the cesium atom (which has the lowest gas
      phase ionization energy of the elements) or of any other known closed-shell
      molecule or neutral transient species reported. The molecules are dimetal
      complexes with the general formula M2(hpp)4 (where M is Cr, Mo, or W, and hpp is
      the anion of 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine), structurally
      characterized in the solid state, spectroscopically characterized in the gas
      phase, and modeled with theoretical computations. The low-energy ionization of
      each molecule corresponds to the removal of an electron from the delta bonding
      orbital of the quadruple metal-metal bond, and a strong interaction of this
      orbital with a filled orbital on the hpp ligands largely accounts for the low
      ionization energies.

PMID- 12471253
TI  - Recent Earth oblateness variations: unraveling climate and postglacial rebound
      effects.
AB  - Earth's dynamic oblateness (J2) has been decreasing due to postglacial rebound
      (PGR). However, J2 began to increase in 1997, indicating a pronounced global
      scale mass redistribution within Earth's system. We have determined that the
      observed increases in J2 are caused primarily by a recent surge in subpolar
      glacial melting and by mass shifts in the Southern, Pacific, and Indian oceans.
      When these effects are removed, the residual trend in J2 (-2.9 x 10(-11) year-1)
      becomes consistent with previous estimates of PGR from satellite and eclipse
      data. The climatic significance of these rapid shifts in glacial and oceanic
      mass, however, remains to be investigated.

PMID- 12471254
TI  - Environmental effects of large impacts on Mars.
AB  - The martian valley networks formed near the end of the period of heavy
      bombardment of the inner solar system, about 3.5 billion years ago. The largest
      impacts produced global blankets of very hot ejecta, ranging in thickness from
      meters to hundreds of meters. Our simulations indicated that the ejecta warmed
      the surface, keeping it above the freezing point of water for periods ranging
      from decades to millennia, depending on impactor size, and caused shallow
      subsurface or polar ice to evaporate or melt. Large impacts also injected steam
      into the atmosphere from the craters or from water innate to the impactors. From
      all sources, a typical 100-, 200-, or 250-kilometers asteroid injected about 2,
      9, or 16 meters, respectively, of precipitable water into the atmosphere, which
      eventually rained out at a rate of about 2 meters per year. The rains from a
      large impact formed rivers and contributed to recharging aquifers.

PMID- 12471255
TI  - Regulation of oceanic silicon and carbon preservation by temperature control on
      bacteria.
AB  - We demonstrated in laboratory experiments that temperature control of marine
      bacteria action on diatoms strongly influences the coupling of biogenic silica
      and organic carbon preservation. Low temperature intensified the selective
      regeneration of organic matter by marine bacteria as the silicon:carbon
      preservation ratio gradually increased from approximately 1 at 33 degrees C to
      approximately 6 at -1.8 degrees C. Temperature control of bacteria-mediated
      selective preservation of silicon versus carbon should help to interpret and
      model the variable coupling of silicon and carbon sinking fluxes and the spatial
      patterns of opal accumulation in oceanic systems with different temperature
      regimes.

PMID- 12471256
TI  - Olmec origins of Mesoamerican writing.
AB  - A cylinder seal and carved greenstone plaque bearing glyphs dating to
      approximately 650 B.C. have been uncovered near the Olmec center of La Venta in
      Tabasco, Mexico. These artifacts, which predate others containing writing, reveal
      that the key aspects of the Mesoamerican scripts were present in Olmec writing:
      the combination of pictographic and glyphic elements to represent speech; the use
      of the sacred 260-day calendar; and the connection between writing, the calendar,
      and kingship. They imply that Mesoamerican writing originated in the La Venta
      polity.

PMID- 12471257
TI  - Grassland responses to global environmental changes suppressed by elevated CO2.
AB  - Simulated global changes, including warming, increased precipitation, and
      nitrogen deposition, alone and in concert, increased net primary production (NPP)
      in the third year of ecosystem-scale manipulations in a California annual
      grassland. Elevated carbon dioxide also increased NPP, but only as a single
      factor treatment. Across all multifactor manipulations, elevated carbon dioxide
      suppressed root allocation, decreasing the positive effects of increased
      temperature, precipitation, and nitrogen deposition on NPP. The NPP responses to
      interacting global changes differed greatly from simple combinations of single
      factor responses. These findings indicate the importance of a multifactor
      experimental approach to understanding ecosystem responses to global change.

PMID- 12471258
TI  - A general model for designing networks of marine reserves.
AB  - There is debate concerning the most effective conservation of marine
      biodiversity, especially regarding the appropriate location, size, and
      connectivity of marine reserves. We describe a means of establishing marine
      reserve networks by using optimization algorithms and multiple levels of
      information on biodiversity, ecological processes (spawning, recruitment, and
      larval connectivity), and socioeconomic factors in the Gulf of California. A
      network covering 40% of rocky reef habitat can fulfill many conservation goals
      while reducing social conflict. This quantitative approach provides a powerful
      tool for decision-makers tasked with siting marine reserves.

PMID- 12471259
TI  - Ectoderm to mesoderm lineage switching during axolotl tail regeneration.
AB  - Foreign environments may induce adult stem cells to switch lineages and populate
      multiple tissue types, but whether this mechanism is used for tissue repair
      remains uncertain. Urodele amphibians can regenerate fully functional,
      multitissue structures including the limb and tail. To determine whether lineage
      switching is an integral feature of this regeneration, we followed individual
      spinal cord cells live during tail regeneration in the axolotl. Spinal cord cells
      frequently migrate into surrounding tissue to form regenerating muscle and
      cartilage. Thus, in axolotls, cells switch lineage during a real example of
      regeneration.

PMID- 12471260
TI  - Inhibition of excess nodal signaling during mouse gastrulation by the
      transcriptional corepressor DRAP1.
AB  - The formation and patterning of mesoderm during mammalian gastrulation require
      the activity of Nodal, a secreted mesoderm-inducing factor of the transforming
      growth factor-beta (TGF-beta) family. Here we show that the transcriptional
      corepressor DRAP1 has a very specific role in regulation of Nodal activity during
      mouse embryogenesis. We find that loss of Drap1 leads to severe gastrulation
      defects that are consistent with increased expression of Nodal and can be
      partially suppressed by Nodal heterozygosity. Biochemical studies indicate that
      DRAP1 interacts with and inhibits DNA binding by the winged-helix transcription
      factor FoxH1 (FAST), a critical component of a positive feedback loop for Nodal
      activity. We propose that DRAP1 limits the spread of a morphogenetic signal by
      down-modulating the response to the Nodal autoregulatory loop.

PMID- 12471261
TI  - Regulation of spermatogenesis by testis-specific, cytoplasmic poly(A) polymerase
      TPAP.
AB  - Spermatogenesis is a highly specialized process of cellular differentiation to
      produce spermatozoa. This differentiation process accompanies morphological
      changes that are controlled by a number of genes expressed in a stage-specific
      manner during spermatogenesis. Here we show that in mice, the absence of a testis
      specific, cytoplasmic polyadenylate [poly(A)] polymerase, TPAP, results in the
      arrest of spermiogenesis. TPAP-deficient mice display impaired expression of
      haploid-specific genes that are required for the morphogenesis of germ cells. The
      TPAP deficiency also causes incomplete elongation of poly(A) tails of particular
      transcription factor messenger RNAs. Although the overall cellular level of the
      transcription factor TAF10 is unaffected, TAF10 is insufficiently transported
      into the nucleus of germ cells. We propose that TPAP governs germ cell
      morphogenesis by modulating specific transcription factors at posttranscriptional
      and posttranslational levels.

PMID- 12471262
TI  - A role for the protease falcipain 1 in host cell invasion by the human malaria
      parasite.
AB  - Cysteine proteases of Plasmodium falciparum are required for survival of the
      malaria parasite, yet their specific cellular functions remain unclear. We used a
      chemical proteomic screen with a small-molecule probe to characterize the
      predominant cysteine proteases throughout the parasite life cycle. Only one
      protease, falcipain 1, was active during the invasive merozoite stage. Falcipain
      1-specific inhibitors, identified by screening of chemical libraries, blocked
      parasite invasion of host erythrocytes, yet had no effect on normal parasite
      processes such as hemoglobin degradation. These results demonstrate a specific
      role for falcipain 1 in host cell invasion and establish a potential new target
      for antimalarial therapeutics.

PMID- 12471263
TI  - Signaling of rat Frizzled-2 through phosphodiesterase and cyclic GMP.
AB  - The Frizzled-2 receptor (Rfz2) from rat binds Wnt proteins and can signal by
      activating calcium release from intracellular stores. We show that wild-type Rfz2
      and a chimeric receptor consisting of the extracellular and transmembrane
      portions of the beta2-adrenergic receptor with cytoplasmic domains of Rfz2 also
      signaled through modulation of cyclic guanosine 3',5'-monophosphate (cGMP).
      Activation of either receptor led to a decline in the intracellular concentration
      of cGMP, a process that was inhibited in cells treated with pertussis toxin,
      reduced by suppression of the expression of the heterotrimeric GTP-binding
      protein (G protein) transducin, and suppressed through inhibition of cGMP
      specific phosphodiesterase (PDE) activity. Moreover, PDE inhibitors blocked Rfz2
      induced calcium transients in zebrafish embryos. Thus, Frizzled-2 appears to
      couple to PDEs and calcium transients through G proteins.

PMID- 12471264
TI  - Resetting the circadian clock by social experience in Drosophila melanogaster.
AB  - Circadian clocks are influenced by social interactions in a variety of species,
      but little is known about the sensory mechanisms underlying these effects. We
      investigated whether social cues could reset circadian rhythms in Drosophila
      melanogaster by addressing two questions: Is there a social influence on
      circadian timing? If so, then how is that influence communicated? The experiments
      show that in a social context Drosophila transmit and receive cues that influence
      circadian time and that these cues are likely olfactory.

PMID- 12471265
TI  - Functional neuroimaging of speech perception in infants.
AB  - Human infants begin to acquire their native language in the first months of life.
      To determine which brain regions support language processing at this young age,
      we measured with functional magnetic resonance imaging the brain activity evoked
      by normal and reversed speech in awake and sleeping 3-month-old infants. Left
      lateralized brain regions similar to those of adults, including the superior
      temporal and angular gyri, were already active in infants. Additional activation
      in right prefrontal cortex was seen only in awake infants processing normal
      speech. Thus, precursors of adult cortical language areas are already active in
      infants, well before the onset of speech production.

PMID- 12471267
TI  - Bose-Einstein condensation of cesium.
AB  - Bose-Einstein condensation of cesium atoms is achieved by evaporative cooling
      using optical trapping techniques. The ability to tune the interactions between
      the ultracold atoms by an external magnetic field is crucial to obtain the
      condensate and offers intriguing features for potential applications. We explore
      various regimes of condensate self-interaction (attractive, repulsive, and null
      interaction strength) and demonstrate properties of imploding, exploding, and non
      interacting quantum matter.

PMID- 12471266
TI  - Rates of behavior and aging specified by mitochondrial function during
      development.
AB  - To explore the role of mitochondrial activity in the aging process, we have
      lowered the activity of the electron transport chain and adenosine 5'
      triphosphate (ATP) synthase with RNA interference (RNAi) in Caenorhabditis
      elegans. These perturbations reduced body size and behavioral rates and extended
      adult life-span. Restoring messenger RNA to near-normal levels during adulthood
      did not elevate ATP levels and did not correct any of these phenotypes.
      Conversely, inhibiting respiratory-chain components during adulthood only did not
      reset behavioral rates and did not affect life-span. Thus, the developing animal
      appears to contain a regulatory system that monitors mitochondrial activity early
      in life and, in response, establishes rates of respiration, behavior, and aging
      that persist during adulthood.

PMID- 12471268
TI  - Exposed water ice discovered near the south pole of Mars.
AB  - The Mars Odyssey Thermal Emission Imaging System (THEMIS) has discovered water
      ice exposed near the edge of Mars' southern perennial polar cap. The surface H2O
      ice was first observed by THEMIS as a region that was cooler than expected for
      dry soil at that latitude during the summer season. Diurnal and seasonal
      temperature trends derived from Mars Global Surveyor Thermal Emission
      Spectrometer observations indicate that there is H2O ice at the surface. Viking
      observations, and the few other relevant THEMIS observations, indicate that
      surface H2O ice may be widespread around and under the perennial CO2 cap.

PMID- 12471269
TI  - Public health, GIS, and spatial analytic tools.
AB  - We review literature that uses spatial analytic tools in contexts where
      Geographic Information Systems (GIS) is the organizing system for health data or
      where the methods discussed will likely be incorporated in GIS-based analyses in
      the future. We conclude the review with the point of view that this literature is
      moving toward the development and use of systems of analysis that integrate the
      information geo-coding and data base functions of GISystems with the geo
      information processing functions of GIScience. The rapidity of this projected
      development will depend on the perceived needs of the public health community for
      spatial analysis methods to provide decision support. Recent advances in the
      analysis of disease maps have been influenced by and benefited from the adoption
      of new practices for georeferencing health data and new ways of linking such data
      geographically to potential sources of environmental exposures, the locations of
      health resources and the geodemographic characteristics of populations. This
      review focuses on these advances.

PMID- 12471270
TI  - One foot in the furrow: linkages between agriculture, plant pathology, and public
      health.
AB  - Plant pathology is a field of biology that focuses on understanding the nature of
      disease in plants as well as on more practical aspects of preventing and
      controlling plant diseases in crop plants that are important to agriculture.
      Throughout history, plant diseases have had significant effects on human health
      and welfare. Several examples, in both historical and contemporary contexts, are
      presented in this review to show how plant pathogens, biotechnology, and farming
      practices have affected public health. Specific topics illustrating clear
      linkages between agriculture and human health include allergens in the
      environment, food-safety and agricultural practices, mycotoxigenic fungi,
      agrobioterrorism, and the biological control of plant diseases. The further
      argument is made that in order to monitor and ensure that good health and safety
      practices are maintained from "farm to fork," public health specialists may
      benefit from the resources and expertise of agricultural scientists.

PMID- 12471271
TI  - The anatomy of a disparity in infant mortality.
AB  - This article suggests that while disparities in infant mortality have been
      longstanding, the mechanisms of disparity creation are undergoing intense change.
      This dynamic character is explored by first developing an analytic model that
      examines the interaction between social factors and the public health and
      clinical capacity to intervene. Disparities in infant mortality are then broken
      down into their component parts and linked to specific arenas of intervention.
      Disparities in postneonatal mortality are being shaped by differential access to
      interventions designed to prevent infant death from congenital anomalies and the
      Sudden Infant Death Syndrome. Disparities in neonatal mortality are primarily
      determined by factors that influence the birthrate of extremely premature infants
      and access to specialized obstetrical and pediatric care. This analysis suggests
      that the epidemiology and social meaning of disparities in infant mortality are
      intensely dynamic and increasingly reflect the interaction between social forces
      and technical innovation.

PMID- 12471272
TI  - Methodologic advances and ongoing challenges in designing community-based health
      promotion programs.
AB  - Community intervention trials continue to attract researchers as potential ways
      to achieve widespread, long-term change in health behaviors. The first
      generations of community studies were somewhat unsophisticated in design and
      analysis, and their promise may have been overstated. As design and analysis
      issues were better defined, as secular trends caught up with the behaviors that
      researchers were trying to change, or as other unknown variables affected
      community studies, small effects of interventions were observed in community
      trials. Discussions were held in professional meetings and reported in the
      literature: Should community trials be discontinued? In general, the answer was a
      qualified no. In this paper, we briefly review some of the many advances made in
      community intervention trials, and address in more detail the challenges ahead.

PMID- 12471273
TI  - The role of health plans in tobacco control.
AB  - Health plans play an important role in tobacco control. In this chapter we
      present an overview of the scientific research on health plan involvement in
      clinical and community interventions regarding tobacco use. Also included are
      interventions that have been undertaken by health plans to lower smoking rates
      among their members and the general population. We conclude with a new model that
      can be used to engage health plans in tobacco control efforts and a case study
      that outlines how one health plan has implemented this new model.

PMID- 12471274
TI  - Measuring quality of care and performance from a population health care
      perspective.
AB  - Population health care is health information and clinical services provided to
      individuals of a defined population. From a population health care perspective,
      quality of care involves the health status of the entire population, and thus
      issues of access, cost of care, and efficiency matter. In this paper, we describe
      the definitions of quality health care and the framework for measuring quality,
      with emphasis on the performance of organizations involved in the delivery and
      assurance of population health care. We describe quality measurement sets and
      systems, criteria for the choice of measures, data sources, and how quality
      measurements are used to improve health care and outcomes from a population
      health care perspective.

PMID- 12471275
TI  - Geographic information systems and public health.
AB  - Geographic information systems (GIS) and analyses based on GIS have become
      widespread and well accepted. GIS is not the complete solution to understanding
      the distribution of disease and the problems of public health but is an important
      way in which to better illuminate how humans interact with their environment to
      create or deter health.

PMID- 12471276
TI  - Managed care spillover effects.
AB  - In addition to influencing care for patients enrolled in managed care plans,
      growth in managed care could lead to broad changes in the structure and
      functioning of the health care system that could ultimately influence care for
      all patients, even those not covered by managed care plans. This paper summarizes
      the mechanisms by which these effects could arise, including shifts in the types
      of services available in markets and changes in physician practice patterns. The
      paper summarizes available empirical evidence on broad-level effects of managed
      care, concluding that the literature supports the view that managed care can have
      generalized effects on health care spending, utilization patterns, and
      infrastructure, although existing literature has not clearly identified effects
      on health outcomes.

PMID- 12471278
TI  - [The efficacy of droperidol, metoclopramide, propofol, and ondansetron for the
      prevention of nausea and vomiting following middle ear surgery].
AB  - OBJECTIVES: The efficacy and reliability of prophylactic antiemetic therapy with
      low dose propofol, droperidol, metoclopramide, and ondansetron were evaluated in
      a randomized, double-blind, and prospective design. PATIENTS AND METHODS: A total
      of 101 ASA I-II patients (34 females, 67 males; age range 16 to 53 years)
      undergoing middle ear surgery for chronic otitis media or its sequelae were
      randomly assigned to receive prophylactic antiemetic therapy with propofol (n=21,
      0.5 mg/kg), droperidol (n=19, 20 mg/kg), metoclopramide (n=23, 0.2 mg/kg),
      ondansetron (n=21, 4 mg), and placebo (n=20, 0.9% NaCl). All drugs were
      administered intravenously five minutes before extubation. RESULTS: In the early
      postoperative period (0 to 3 hours), the percentages of patients free from nausea
      and vomiting were 100% with droperidol, 71.4% with ondansetron and propofol,
      52.1% with metoclopramide, and 35% with placebo. Ondansetron (90.4%) was found
      the most effective to prevent and control nausea and vomiting during the
      postoperative 3 to 24 hours, followed by droperidol (84.2%), propofol (57.1%),
      metoclopramide (47.8%), and placebo (40%). Compared with controls, the number of
      patients without nausea and vomiting was significantly greater in each treatment
      group but metoclopramide (p<0.05). No significant differences were detected with
      respect to adverse effects. CONCLUSION: Droperidol and ondansetron seem to exert
      the highest efficacy to prevent nausea and vomiting during the postoperative 0 to
      3 hours and 3 to 24 hours, respectively.

PMID- 12471279
TI  - [Hyperbaric oxygen treatment in sudden hearing loss after unsuccessful medical
      treatment].
AB  - OBJECTIVES: We evaluated the efficacy of hyperbaric oxygen (HBO) treatment in
      patients with sudden hearing loss unresponsive to medical treatment. PATIENTS AND
      METHODS: Fifty-one patients (37 males, 14 females; mean age 37 years; range 9 to
      63 years) with sudden hearing loss were treated with HBO following unsuccessful
      medical treatment. Time elapsed from the occurrence of sudden hearing loss ranged
      between 15 to 45 days. Treatment included two sessions daily for the first three
      days, followed by a single daily session, to make 20 sessions of 90 minutes.
      Treatment was discontinued because of early recovery in two patients. Audiometric
      examinations were made at the end of every five sessions. The patients were
      classified according to age, gender, and audiogram curves. RESULTS: The mean
      hearing thresholds were 75.3 dB and 65.6 dB before and after treatment,
      respectively. Recovery was rated as complete in two patients (3.9%), moderate in
      two patients (3.9%), mild in 19 patients (37.25%), and as no recovery in 28
      patients (54.9%). No significant differences were found between the patient
      groups in terms of improvement and hearing gain (p>0.05). CONCLUSION: We propose
      that HBO be resorted to when other means of medical treatment prove unsuccessful
      in patients with sudden hearing loss.

PMID- 12471280
TI  - [Evaluation of hearing performance in cochlear implant patients].
AB  - OBJECTIVES: To determine the speech perception levels of cochlear implant
      patients and to evaluate the possible effects of implant type, duration of
      deafness, and bacterial meningitis on the patients' hearing performance. PATIENTS
      AND METHODS: A three-section test battery on speech perception was administered
      to 21 cochlear implant patients (12 males, 9 females; mean age 25 years; range 9
      to 40 years). The patients' performance was assessed with respect to single- or
      multi-channel implant design, duration of hearing loss, and etiologic factors of
      hearing loss. RESULTS: The overall mean success score was 74.6 (range 49-100). No
      significant difference was found between patients using single- or multi-channel
      implants. The mean score of 12 patients whose duration of hearing loss was below
      the average (8.2 years) was significantly higher than those of nine patients with
      a longer history of hearing loss (85.7 versus 59.6, p=0.001). Patients with
      meningitis-associated hearing loss exhibited a significantly lower performance
      than those presenting with other etiologic factors (61.9 versus 84.1, p=0.001).
      CONCLUSION: Early diagnosis and rehabilitation are essential to achieve better
      performance following cochlear implantation.

PMID- 12471281
TI  - [The effect of nasal packing with or without an airway on arterial blood gases
      during sleep].
AB  - OBJECTIVES: We investigated the effect of postoperatively applied nasal packing
      with or without an airway on partial arterial oxygen (PaO(2)) and carbon dioxide
      (PaCO(2)) pressures during sleep. PATIENTS AND METHODS: The study included 40
      patients (24 men, 16 women; mean age 29 years; range 18 to 60 years) who
      underwent septoplasty operation. The patients were randomly assigned to
      postoperative nasal packings with (n=20) or without (n=20) an airway. PaO(2) and
      PaCO(2) levels were measured during sleep on the preoperative night and on the
      postoperative first and second nights. The findings were compared. RESULTS: No
      significant differences were found between the preoperative and postoperative
      PaO(2) and PaCO(2) levels obtained with nasal packing containing an airway.
      However, the mean PaO(2) level measured on the postoperative second night
      significantly decreased in patients wearing a nasal packing without an airway,
      when compared with the mean preoperative value and with that obtained from the
      other group on the same night (p<0.05). On the other hand, increases in the mean
      PaCO(2) levels did not reach significance. In both groups, postoperative PaO(2)
      and PaCO(2) values were within acceptable limits. No signs of hypoxia or
      hypercapnia were detected. CONCLUSION: To prevent decreases in the PaO(2) levels,
      the use of nasal packings with an airway seems to be more appropriate in patients
      susceptible to hypoxia.

PMID- 12471282
TI  - [The efficacy of combined medical treatment (antihistaminics, steroids, and
      macrolide antibiotics) in patients with nasal polyposis: preliminary results].
AB  - OBJECTIVES: We evaluated the efficacy of combined medical treatment in cases with
      bilateral nasal polyposis without a history of any surgical or medical treatment.
      PATIENTS AND METHODS: Twenty-five patients (19 males, 6 females; mean age 45
      years; range 30 to 60 years) who had not received any treatment for bilateral
      nasal polyposis were included. Treatment was comprised of an oral anti-histaminic
      agent (single dose daily for 3 weeks), and a topical steroid (as a nasal spray,
      twice daily for 6 months) and a single dose of intramuscular systemic steroid.
      Patients who did not respond to this therapy at the end of three weeks were
      administered a macrolide antibiotic (clarithromycin). The results were evaluated
      before treatment, and three weeks and six months after treatment with the use of
      a patient questionnaire, computed tomography and endoscopic examination findings.
      RESULTS: The patients' complaints improved by 85.5% and 79% at the end of three
      weeks and six months, respectively (p<0.005). Radiologic improvement was found to
      be 64% at the end of six months (p<0.005). The overall decrease in the size of
      the polyps was significant (p<0.005). No treatment-associated complications were
      encountered. CONCLUSION: Significant improvement achieved favors the use of
      combined medical treatment before surgery in selected patients with nasal
      polyposis.

PMID- 12471283
TI  - [Orbital decompression by endoscopic transnasal and transantral approach in
      thyroid-associated ophthalmopathy].
AB  - OBJECTIVES: We evaluated the results of orbital decompression in patients with
      Graves' disease. PATIENTS AND METHODS: Orbital decompression was performed by
      endoscopic transnasal medial wall approach and transantral inferior wall approach
      in 18 eyes of 12 patients (8 males, 4 females; mean age 41 years; range 24 to 65
      years). The degree of exophthalmos was evaluated with the use of the Hertel
      exophthalmometer preoperatively, and postoperatively in the 24th hour, first and
      third months. RESULTS: At the end of the third month, exophthalmos decreased by a
      mean of 4.4 mm (range 3 to 7 mm). Visual acuity and field defects improved
      considerably in all patients. Complications occurred in three cases (25%)
      including diplopia, displacement of one eye inferiorly, and maxillary sinusitis
      caused by the encroachment of the adipose tissue upon the ostium, respectively.
      CONCLUSION: With the increasing ease of surgical procedures and enhanced
      experience on the part of surgeons, successful treatment of exophthalmos has
      become possible with decreased complication rates.

PMID- 12471284
TI  - [Gastric pull-up in hypopharyngeal and cervical esophageal cancers].
AB  - OBJECTIVES: Gastric pull-up is a common technique in the reconstruction of
      gastrointestinal continuity following surgery for the primary esophageal and
      hypopharyngeal tumors with involvement of the esophagus. We evaluated the results
      of surgery in patients with cervical esophageal and hypopharyngeal cancers.
      PATIENTS AND METHODS: Eleven patients (4 women, 7 men; mean age 46 years; range
      18 to 70 years) underwent surgery for hypopharyngeal and cervical esophageal
      epidermoid carcinoma. Surgery included pharyngolaryngoesophagectomy, subtotal
      thyroidectomy, and gastric pull-up in all patients. In addition, nine patients
      had radical neck dissection on the involved side and modified radical neck
      dissection on the contralateral side. One patient had bilateral radical neck
      dissection. Patients who were alive were followed-up for a mean period of 27
      months (range 14 to 46 months). RESULTS: The one-, two-, and three-year survival
      rates were 54% (6/11), 36% (4/11) and 18% (2/11), respectively. Three patients
      died from early postoperative complications, two from organ failure due to
      locoregional recurrence (7th month) and to distant metastasis (11th month).
      CONCLUSION: Despite the small size of the study, the results favor the use of
      gastric pull-up in selected patients with cervical esophageal and hypopharyngeal
      cancers.

PMID- 12471285
TI  - Metastasis to infraclavicular lymph nodes in head and neck cancer: a report of
      three cases.
AB  - Metastasis predominantly occurs via the lymphatic system in head and neck tumors.
      The disturbance of the lymphatic system in the cervical region resulting from
      neck dissection or radiotherapy may result in unusual patterns of metastasis in
      patients with recurrent tumors. This is more frequent when the recurrent tumor
      invades the myocutaneous flap used for the primary reconstruction. We encountered
      three patients (2 men, 1 woman) with infraclavicular lymph node metastasis. All
      were previously treated by surgery, postoperative radiation therapy, and
      reconstruction with the use of the pectoralis major myocutaneous flap.

PMID- 12471286
TI  - Synovial sarcoma arising from the hypopharynx: a case report.
AB  - Synovial sarcoma is a relatively rare soft tissue tumor. About 3 to 10% of cases
      arise in the head and neck, with the majority in the parapharyngeal region. We
      hereby report a 22-year-old male patient with synovial sarcoma confined to the
      hypopharynx. Treatment included wide surgical excision followed by radiotherapy.
      It is of interest that the lesion recurred 12 years after the initial primary
      surgery for synovial sarcoma at the same site. The patient has been disease-free
      for five years.

PMID- 12471287
TI  - Two cases of nasal natural killer T-cell lymphoma.
AB  - Nasal natural killer T-cell lymphoma is a very aggressive and destructive disease
      with a poor prognosis. We hereby present two male patients in whom diagnostic
      problems and a mortal course were encountered. One patient (age 31 years) had
      progressive ulceration in the nasal area. Two biopsies that had been taken
      elsewhere were inconclusive. The other patient (age 40 years) was referred with a
      previous histopathologic diagnosis of squamous cell carcinoma. He complained of
      an unhealing wound in the hard palate. Biopsies were repeated in each case.
      Diagnosis was made by immunohistochemical examination. Both patients died shortly
      after the diagnosis. The importance of obtaining an adequate and deep biopsy
      sample and employing sophisticated immunohistochemical examination is emphasized
      for an accurate diagnosis.

PMID- 12471288
TI  - Effects of exercise on physiological and psychological variables in cancer
      survivors.
AB  - PURPOSE: The primary purpose of this study was to examine the effect of aerobic
      exercise on physiological and psychological function in patients rehabilitating
      from cancer treatment. A second purpose was to evaluate the differential effects
      of low- and moderate-intensity exercise on these variables. METHODS: Eighteen
      survivors of breast or colon cancer (15 female and 3 male, 40-65 yr of age)
      served as subjects. The subjects were matched by aerobic capacity and scores on a
      Quality of Life questionnaire, and then randomly assigned to a control, low- (25
      35% heart rate reserve (HRR)), or a moderate- (40-50% HRR) intensity exercise
      group. The exercise groups performed lower-body aerobic exercise three times a
      week for 10 wk. After the exercise training, there were no statistically
      significant differences between the two exercise groups on any of the
      physiological variables. Therefore, the exercise groups were combined into one
      group for the final analysis. RESULTS: The results revealed statistically
      significant increases in aerobic capacity (P < 0.001) and lower-body flexibility
      (P = 0.027), a significant decrease in body fat (P < 0.001), and a significant
      increase in quality of life (P < 0.001) and a measure of energy (P = 0.038) in
      the exercise group when compared with the control group. CONCLUSION: Low- and
      moderate-intensity aerobic-exercise programs were equally effective in improving
      physiological and psychological function in this population of cancer survivors.
      Aerobic exercise appears to be a valuable and well-tolerated component of the
      cancer-rehabilitation process.

PMID- 12471289
TI  - Strength/endurance training versus endurance training in congestive heart
      failure.
AB  - PURPOSE: The aim of this study was to compare the effects of endurance training
      alone (ET) with combined endurance and strength training (CT) on hemodynamic and
      strength parameters in patients with congestive heart failure (CHF). METHODS:
      Twenty male patients with CHF were randomized into one of two training regimens
      consisting of endurance training or a combination of endurance and resistance
      training. Group ET had 40-min interval cycle ergometer endurance training three
      times per week. Group CT combined endurance and strength training with the same
      interval endurance training for 20 min, followed by 20 min of strength training.
      Left ventricular function was assessed at baseline and after 40 training sessions
      by echocardiography and radionuclide ventriculography. Work capacity was measured
      with cardiopulmonary exercise test (CPX) and lactate determination. Strength was
      measured with an isokinetic dynamometer. RESULTS: After 40 sessions, the ET group
      improved functional class, work capacity, peak torque, and muscular endurance.
      However, peak O2 remained unchanged. Left ventricular ejection fraction (LVEF)
      and fractional shortening (FS) decreased, whereas left ventricular end-diastolic
      diameter (LVED) increased. The CT group improved NYHA score, working capacity,
      peak O2, and peak lactate; peak torque and muscular endurance, LVEF, and FS
      increased, whereas LVED decreased. Compared with ET, CT was significantly (P <
      0.05) better in improving LV function. CONCLUSION: Combined endurance/strength
      training was superior to endurance training alone concerning improvement of LV
      function, peak VO2, and strength parameters. It appears that for stable CHF
      patients, a greater benefit can be derived from this training modality.

PMID- 12471290
TI  - Heart rate reserve as a predictor of cardiovascular and all-cause mortality in
      men.
AB  - This study examined the relationship of heart rate reserve (HRR: maximal heart
      rate - resting heart rate) and cardiovascular disease mortality (CVD) or all
      cause mortality among healthy men. METHODS: Subjects were 27,459 healthy men, age
      20-59 yr, who completed a maximal treadmill exercise test and answered a health
      questionnaire at the baseline examination. We followed study participants from
      the baseline visit to the date of death or December 31, 1996, for survivors.
      RESULTS: Over an average follow-up of 13.0 +/- 6.2 yr, there were 724 deaths, 205
      (28.3%) from CVD. For analyses, the men were stratified into two age groups:
      younger (20-39 yr) and older (40-59 yr). Cox regression analysis was used to
      adjust for age, resting heart rate, cardiorespiratory fitness (CRF), resting
      systolic blood pressure (SBP), SBP difference, cholesterol, triglycerides, body
      mass index (BMI), smoking, and alcohol consumption. Among younger men, HRR was
      the only factor associated with CVD mortality (instantaneous relative risk (RR)
      and 95% confidence interval for HRR = 0.6, 0.5-0.9 for CVD mortality by 10
      beats.min(-1) increment), whereas only CRF and BMI were associated with all-cause
      mortality. Among older men, HRR was inversely associated with CVD and all-cause
      mortality, as were several other known risk factors, including CRF (RR(per 2
      METs), and 95% CI for HRR = 0.7, 0.5-0.9 for CVD mortality and 0.8, 0.7-0.9 for
      all-cause mortality). CONCLUSIONS HRR, independent from CRF, was inversely
      associated with CVD mortality among men in this study. HRR may be an important
      exercise test parameter to predict CVD mortality in younger men, whereas CRF and
      other established risk factors are better predictors of CVD and all-cause
      mortality in older men.

PMID- 12471291
TI  - Physical therapy alters recruitment of the vasti in patellofemoral pain syndrome.
AB  - PURPOSE: To investigate the effect of physical therapy treatment on the timing of
      electromyographic (EMG) activity of the vasti in individuals with patellofemoral
      pain syndrome (PFPS). METHODS: Sixty-five (42 female, 23 male) participants aged
      40 yr or less (29.2 +/- 7.8 yr) diagnosed with PFPS. Participants were randomly
      allocated into physical therapy treatment (McConnell-based) or placebo groups.
      Treatment programs were standardized and consisted of six-treatment sessions over
      6 wk. Vastus medialis oblique (VMO) and vastus lateralis (VL) EMG activity was
      recorded with surface electrodes during a stair-stepping task and onsets of EMG
      activity were measured pre- and post-treatment. RESULTS: Before treatment, the
      EMG onset of VL occurred before that of VMO in both participant groups. After
      physical therapy intervention, there was a reduction in symptoms, and this
      improvement was associated with a significant change in the time of onset of VMO
      EMG compared with that of VL in both phases of the stair-stepping task. After
      physical therapy treatment, the onset of VMO preceded VL in the eccentric phase
      and occurred at the same time in the concentric phase of the stair-stepping task.
      There was no change in time of EMG onset in the placebo group. CONCLUSION: This
      study demonstrates that a "McConnell"-based physical therapy treatment regime for
      PFPS alters the motor control of VMO relative to VL in a functional task and this
      is associated with a positive clinical outcome.

PMID- 12471292
TI  - Acute mountain sickness: influence of susceptibility, preexposure, and ascent
      rate.
AB  - PURPOSE: We examined the interaction of various established risk factors for
      acute mountain sickness (AMS) in a setting relevant for mountaineering and
      trekking. METHODS: Questionnaires were obtained from 827 mountaineers on the day
      of arrival at the Capanna Margherita (4559 m) and on the next morning.
      Susceptibility to AMS was assessed by type and frequency of symptoms during
      previous exposures. AMS was defined as an AMS-C score >/= 0.7 (environmental
      symptom questionnaire) on the morning after arrival at 4559 m. Preexposure was
      defined as having spent more than 4 d above 3000 m during the 2 months preceding
      the climb to the Capanna Margherita. Slow ascent was defined as ascending in more
      than 3 d. A risk model was developed by multiple logistic regression and
      prospectively validated on independent data. RESULTS: In susceptible individuals,
      the prevalence of AMS was 58% with rapid ascent and no preexposure, 29% with
      preexposure only, 33% with slow ascent only, and 7% with both preexposure and
      slow ascent. The corresponding values for nonsusceptible individuals were 31%,
      16%, 11%, and 4%. The overall odds ratio for developing AMS in susceptible versus
      nonsusceptible individuals was 2.9 (95% confidence interval, 2.1-4.1). Age,
      gender, training, body mass index, alcohol intake, and cigarette smoking had no
      significant effect in bivariate analyses or in multivariate logistic regressions.
      CONCLUSION: Individual susceptibility, rate of ascent, and preexposure are the
      major, independent determinants for prevalence of AMS.

PMID- 12471293
TI  - Effects of warm-up before eccentric exercise on indirect markers of muscle
      damage.
AB  - PURPOSE: To test whether active and passive warm-up conducted before eccentric
      exercise attenuates clinical markers of muscle damage. METHODS: Untrained
      subjects were exposed to one of five conditions: low-heat passive warm-up (N =
      10), high-heat passive warm-up (N = 4), or active warm-up (N = 9), preceding
      eccentric exercise; eccentric exercise without warm-up (N = 10); or high-heat
      passive warm-up without eccentric exercise (N = 10). Passive warm-up of the elbow
      flexors was achieved using pulsed short-wave diathermy, and active warm-up was
      achieved by concentric contraction. Creatine kinase (CK) activity, strength,
      range of motion, swelling, and muscle soreness were observed before treatment
      (baseline) and 24, 48, 72, and 168 h after treatment. RESULTS: High-heat passive
      warm-up without eccentric exercise did not affect any marker of muscle damage and
      was used as our control group. Markers of muscle damage were not different
      between groups that did or did not conduct warm-up before eccentric exercise. The
      active warm-up and eccentric groups exhibited a greater circumferential increase
      than controls (P < 0.0002), however, that was not observed after passive warm-up.
      Additionally, the active warm-up group exhibited a greater CK response than
      controls at 72 h (P < 0.05). The high-heat passive warm-up before eccentric
      exercise group exhibited significant change from controls at the least number of
      time points, but due to a small sample size (N = 4), these data should be viewed
      as preliminary. CONCLUSION: Our observations suggest that passive warm-up
      performed before eccentric exercise may be more beneficial than active warm-up or
      no warm-up in attenuating swelling but does not prevent, attenuate, or resolve
      more quickly the other clinical symptoms of eccentric muscle damage as produced
      in this study.

PMID- 12471295
TI  - Attentional demands and postural sway: the effect of the calf muscles fatigue.
AB  - PURPOSE: The purpose of the present experiment was to investigate whether the
      calf muscle fatigue affects postural sway in bipedal stance and requires
      additional attentional demands. METHODS: Nine healthy university students had to
      respond as rapidly as possible to an unpredictable auditory stimulus while
      maintaining stable seated and upright postures with their eyes closed in two
      conditions of no-fatigue and fatigue of the calf muscles. Center of foot pressure
      (COP) displacements were recorded using a force platform. Reaction times (RTs)
      values were used as an index of the attentional demand necessary for regulating
      postural sway. RESULTS: Fatigue yielded a significant anterior shift of mean
      position of the COP and increased range, mean speed, and dispersion of COP
      displacements. An increased attentional demand for regulating postural sway also
      was observed with fatigue. CONCLUSIONS: These results suggest that muscular
      fatigue may put the individuals at higher risk of falling, especially when
      engaging in concurrent tasks.

PMID- 12471294
TI  - Chronic exertional compartment syndrome: muscle changes with isometric exercise.
AB  - Chronic exertional compartment syndrome (CECS) is a well-documented cause of
      lower leg pain in active individuals. The pathophysiology is unclear, although it
      is generally believed to be associated with increased intramuscular pressure, but
      there is very little information about muscle function in relation to the onset
      of pain. PURPOSE: To investigate strength, fatigue, and recovery of the anterior
      tibial muscles in CECS patients and healthy subjects during an isometric exercise
      protocol. METHODS: Twenty patients and 22 control subjects (mean age 27.6 yr and
      33.0 yr, respectively) performed a 20-min isometric exercise protocol consisting
      of intermittent maximal voluntary contractions (MVC). Central fatigue was
      evaluated by comparing changes in electrically stimulated (2 s at 50 Hz) and
      voluntary contraction force before and during the exercise, and then throughout
      10 min of recovery. Muscle size was measured by ultrasonography. Pain and
      cardiovascular parameters were also examined. RESULTS: The absolute MVC forces
      were similar, but MVC:body mass of the patients was lower (P < 0.05) as was the
      ratio of MVC to muscle cross-sectional area (P < 0.01). The extent of central and
      peripheral fatigue was similar in the two groups. The patients reported
      significantly higher levels of pain during exercise (P < 0.05 at 4 min) and after
      the first minute of recovery (P < 0.001). An 8% increase in muscle size after
      exercise was observed for both groups. There were no differences in the
      cardiovascular responses of the two groups. CONCLUSIONS: CECS patients were
      somewhat weaker than normal but fatigued at a similar rate during isometric
      exercise. Patients reported higher pain than controls despite comparable changes
      in muscle size, suggesting that abnormally tight fascia are not the main cause of
      CECS symptoms.

PMID- 12471296
TI  - Effects of rope-jump training on the os calcis stiffness index of postpubescent
      girls.
AB  - PURPOSE: The specific aims of the study were to 1) determine what effects dose
      dependent rope jumping had on os calcis stiffness index (OCSI) and 2) determine
      whether OCSI values measured by quantitative ultrasound (QUS) were dependent or
      independent of the values of bone mineral content (BMC) determined by dual energy
      x-ray absorptiometry (DXA) at the lumbar spine and proximal femur (femoral neck;
      greater trochanter). METHODS: Upon study entry, girls were randomly assigned to
      either one of two treatment groups (high volume; low volume) or a control group.
      Thirty-seven high school girls were recruited to participate in the study. QUS
      and DXA measurements were made at baseline and at 4-month follow-up. Students in
      the high-volume and low-volume groups jumped rope for 10 and 5 min, respectively.
      RESULTS: The follow-up mean OCSI values for the high-volume, low-volume, and
      control conditions were 103.95 +/- 12.55, 102.09 +/- 12.70, and 99.05 +/- 9.84,
      respectively. A statistically significant difference (P = 0.033) was identified
      between the high-volume and control groups. Baseline and follow-up OCSI values
      were significantly correlated with baseline and follow-up BMC measures of the
      femoral neck (r = 0.60, r = 0.59), greater trochanter (r = 0.47, r = 0.40), and
      lumbar spine (r = 0.56, r = 0.56). CONCLUSIONS: High-volume rope jumping
      increases the OCSI more than the control condition in postpubescent girls.
      Furthermore, the OCSI measured by QUS is moderately related to proximal femur and
      lumbar spine BMC measured by DXA.

PMID- 12471298
TI  - No association between high-altitude tolerance and the ACE I/D gene polymorphism.
AB  - PURPOSE: The absence (deletion allele [D]) of a 287 base-pair fragment in the ACE
      gene is associated with higher ACE tissue activity than its presence (insertion
      allele [I]) and, as such, may enhance vasoconstriction and fluid retention
      through increased levels of angiotensin II and aldosterone. Because fluid
      retention is found in acute mountain sickness (AMS) and exaggerated pulmonary
      hypertension is essential in the pathophysiology of high-altitude pulmonary edema
      (HAPE), we hypothesized that the DD genotype is associated with increased
      susceptibility to these illnesses. METHODS: ACE genotype was thus determined in
      83 mountaineers staying over night at 4559 m and related to AMS symptoms.
      Genotype was similarly determined in 76 mountaineers who had participated in
      previous studies at 4559 m; 38 of the latter group had a history of HAPE, and 25
      had developed HAPE again during these studies. RESULTS: The allele frequency was
      in Hardy-Weinberg equilibrium in both investigations. Neither the history nor the
      observed episodes of HAPE nor the prevalence of AMS defined as an AMS-C score >/=
      0.70 (environmental symptom questionnaire) in the first study or in both studies
      taken together were significantly different between the genotypes DD, ID, and II.
      CONCLUSION: We conclude that I/D-ACE gene polymorphism has no important effect on
      susceptibility to AMS or HAPE.

PMID- 12471297
TI  - Physical training improves insulin resistance syndrome markers in obese
      adolescents.
AB  - INTRODUCTION: The purpose of this study was to test the hypothesis that physical
      training (PT), especially high-intensity PT, would have a favorable effect on
      components of the insulin resistance syndrome (IRS) in obese adolescents.
      METHODS: Obese 13- to 16-yr-olds (N = 80) were randomly assigned to one of the
      following 8-month interventions; 1) lifestyle education (LSE)-alone every 2 wk,
      2) LSE+moderate-intensity PT, and 3) LSE+high-intensity PT. PT was offered 5 d x
      wk(-1). Plasma triacylglycerol (TAG), total cholesterol (TC), high-density
      lipoprotein cholesterol (HDLC), very low-density lipoprotein cholesterol (VLDLC),
      low-density lipoprotein cholesterol (LDLC), low-density lipoprotein (low density
      lipoprotein (LDL)) particle size, apolipoproteins AI and B, glucose, insulin, and
      blood pressure were measured with standardized methods. RESULTS: The intent-to
      treat analyses for all subjects who completed pre- and post-tests regardless of
      their adherence to the interventions showed that the LSE+high-intensity PT group
      had more favorable changes than the LSE-alone group in TAG level (P = 0.012),
      TC/HDLC (P = 0.013), and diastolic blood pressure (P = 0.031). For efficacy
      analyses, all PT subjects who attended at least 2 d x wk(-1) (40%) were combined
      into one group (LSE+PT) and compared with the LSE-alone group. These two-group
      analyses showed significant interactions (P < 0.001) between baseline values and
      group membership for deltaTAG, deltaVLDLC, and deltaTC/HDLC, such that subjects
      who had the least favorable baseline values showed the most beneficial impact of
      the PT. Of particular interest was a favorable effect of the PT on LDL particle
      size. CONCLUSION: PT, especially high-intensity PT, had a favorable effect on
      several IRS markers in obese adolescents.

PMID- 12471299
TI  - Blood volume and hemoglobin mass in endurance athletes from moderate altitude.
AB  - PURPOSE: To determine whether total hemoglobin (tHb) mass and total blood volume
      (BV) are influenced by training, by chronic altitude exposure, and possibly by
      the combination of both conditions. METHODS: Four groups (N = 12, each) either
      from locations at sea level or at moderate altitude (2600 m) were investigated:
      1) sea-level control group (UT-0 m), 2) altitude control group (UT-2600 m), 3)
      professional cyclists from sea level (C-0 m), and 4) professional cyclists from
      altitude (C-2600 m). All subjects from altitude were born at about 2600 m and
      lived all their lives (except during competitions at lower levels) at this
      altitude. tHb and BV were determined by the CO-rebreathing method. RESULTS:
      VO2max (mL x kg(-1) x min(-1)) was significantly higher in UT-0 m (45.3 +/- 3.2)
      than in UT-2600 m (39.6 +/- 4.0) but did not differ between C-0 m (68.2 +/- 2.7)
      and C-2600 m (69.9 +/- 4.4). tHb (g x kg(-1)) was affected by training (UT-0 m:
      11.0 +/- 1.1, C-0 m: 15.4 +/- 1.3) and by altitude (UT-2600 m: 13.4 +/- 0.9) and
      showed both effects in C-2600 m (17.1 +/- 1.4). Because red cell volume showed a
      behavior similar to tHb and because plasma volume was not affected by altitude
      but by training, BV (mL x kg(-1)) was increased in C-0 m (UT-0 m: 78.3 +/- 7.9; C
      0 m: 107.0 +/- 6.2) and in UT-2600 m (88.2 +/- 4.8), showing highest values in
      the C-2600 m group (116.5 +/- 11.4). CONCLUSION: In endurance athletes who are
      native to moderate altitude, tHb and BV were synergistically influenced by
      training and by altitude exposure, which is probably one important reason for
      their high performance.

PMID- 12471300
TI  - Effect of exercise, heat stress, and hydration on immune cell number and
      function.
AB  - PURPOSE: The purpose of this study was to determine the effect of thermal stress
      and hydration status on immune function during exercise. METHODS: Ten trained men
      completed four cycle ergometer rides at 55% VO2peak under the following
      conditions: EN (euhydrated neutral; 22 degrees C, 30% RH), DN (dehydrated
      neutral), EH (euhydrated hot; 38 degrees C, 45% RH), and DH (dehydrated hot).
      During EN and EH, a carbohydrate/electrolyte beverage was consumed at a rate
      matching sweat loss, and during DN and DH, no fluid was ingested. Blood samples
      were drawn pre- and postexercise, and at 2 and 24 h of recovery. Cell counts were
      determined by automated counting and flow cytometry. Neutrophil activity was
      assessed as superoxide production, lymphocyte function was determined via PHA
      stimulated mitogenesis, and natural killer (NK) cell activity was measured with a
      51Cr-release assay. Cortisol was assayed via RIA. RESULTS: Lymphocytes
      proliferation was depressed 2 h after exercise in all conditions (P < 0.05);
      however, when expressed on a per cell basis, function was greater in the DH and
      EH conditions. NK activity (max x 10(3) cells) was greater post compared with
      preexercise in all conditions (EH = 25.5 +/- 16.8, DH = 26.2 +/- 10.5, EN = 19.3
      +/- 11.0, and DN = 16.5 +/- 8.7) but was not different between conditions.
      Leukocyte, neutrophil, lymphocyte, and NK cell counts were also elevated
      postexercise with the former two remaining elevated 2 h postexercise in the EH
      and DH conditions. Cortisol was greater postexercise in EH (22.1 +/- 1.3) and DH
      (27.7 +/- 1.3) compared with EN (17.8 +/- 2.1) and DN (18.9 +/- 1.6 microg x dL(
      1). CONCLUSION: Euhydration did not affect cell number or function when compared
      with a dehydrated state; however, the hot environment caused more severe
      disturbances in these measures compared with a neutral environment.

PMID- 12471301
TI  - Left ventricular dynamics during early recovery from maximal exercise in boys and
      men.
AB  - A transient increase in left ventricular emptying has been reported in adults
      during the early recovery from submaximal upright exercise. PURPOSE: To
      investigate whether this "overshoot" occurs also after maximal exercise, and
      whether it is an age-related phenomenon. METHODS: Ten healthy young men (mean
      age: 22.5 +/- 1.5 yr) and 17 healthy prepubertal boys (11.5 +/- 0.8 yr) performed
      an upright cycle test until exhaustion. Respiratory gas exchange, heart rate,
      left ventricular dimensions (two-dimensional echocardiography method) as well as
      blood pressures (manual sphygmomanometry) were assessed and systemic vascular
      resistances were calculated at rest, during the final minute of the test, and
      during a 10-min recovery period. RESULTS: An improvement of cardiac emptying,
      characterized by a decrease in left ventricular end-systolic diameter, was
      observed in adults only. Moreover, during the first minute of recovery, a larger
      decrease in heart rate -21.8 +/- 7.6% and -13.7 +/- 6.3 beat.min, respectively,
      in children and adults, P < 0.01) and a larger increase in systemic vascular
      resistance (+24.1 +/- 18.2% and +6.4 +/- 12.6%, P < 0.05) were observed in the
      boys rather than in the adults. CONCLUSION: Our results suggest that a higher
      increase in cardiac afterload and a more prominent decrease in heart rate may be
      responsible in part for the absence of cardiac overshoot in children.

PMID- 12471302
TI  - Age does not influence the bone response to treadmill exercise in female rats.
AB  - PURPOSE: Because it is believed that bone may respond to exercise differently at
      different ages, we compared bone responses in immature and mature rats after 12
      wk of treadmill running. METHODS: Twenty-two immature (5-wk-old) and 21 mature
      (17-wk-old) female Sprague Dawley rats were randomized into a running (trained, P
      = 10 immature, 9 mature) or a control group (controls, P = 12 immature, 12
      mature) before sacrifice 12 wk later. Rats ran on a treadmill five times per week
      for 60-70 min at speeds up to 26 m.min. Both at baseline and after intervention,
      we measured total body, lumbar spine, and proximal femoral bone mineral, as well
      as total body soft tissue composition using dual-energy x-ray absorptiometry
      (DXA). After sacrificing the animals, we measured dynamic and static
      histomorphometry and three-point bending strength of the tibia. RESULTS: Running
      training was associated with greater differences in tibial subperiosteal area,
      cortical cross-sectional area, peak load, stiffness, and moment of inertia in
      immature and mature rats (P < 0.05). The trained rats had greater periosteal bone
      formation rates (P < 0.01) than controls, but there was no difference in tibial
      trabecular bone histomorphometry. Similar running-related gains were seen in DXA
      lumbar spine area (P = 0.04) and bone mineral content (BMC; P = 0.03) at both
      ages. For total body bone area and BMC, the immature trained group increased
      significantly compared with controls (P < 0.05), whereas the mature trained group
      gained less than did controls (P < 0.01). CONCLUSION: In this model, where a
      similar physical training program was performed by immature and mature female
      rats, we demonstrated that both age groups were sensitive to loading and that
      bone strength gains appeared to result more from changes in bone geometry than
      from improved material properties.

PMID- 12471303
TI  - Daily physical movement and bone mineral density among a mixed racial cohort of
      women.
AB  - PURPOSE: The impact of lifestyle physical activity on bone mineral density (BMD)
      is unclear. We examined the influence of physical activities typical of everyday
      life on BMD among 151 women (52.0 +/- 0.9 yr). These women were of low
      socioeconomic status, and 57.6% were Hispanic, 17.2% black, and 24.5% white.
      METHODS: BMD was measured at the calcaneus by ultrasound with a Hologic Sahara
      sonometer. We measured physical activity with two questions from the Yale
      Physical Activity Survey that assessed h x d(-1) spent in motion typical of the
      past month and number of flights of stairs climbed up daily. Multivariate ANCOVA
      adjusted for adiposity and nutrients and medications known to influence BMD
      determined whether BMD differed between categories of physical activity (<2 vs >
      or = 2 flights x d(-1) and <7 vs > or = 7 h x d(-1)), menopausal status (pre- vs
      post-), and ethnic group (white vs nonwhite). RESULTS: Among the premenopausal
      women (N = 63, 43.2+/-0.9 yr), adjusted mean calcaneal BMD and BMD T-score were
      similar between categories of stair climbing and accumulated daily movement
      regardless of ethnic origin (P > 0.05). Among the postmenopausal women (N = 88,
      58.1 +/- 1.0 yr), adjusted mean calcaneal BMD (0.561 +/- 0.019 g x cm(-2) vs
      0.503 +/- 0.016) (P = 0.022) and BMD T-score (-0.172 +/- 0.166 vs -0.695 +/-
      0.143) (P = 0.020) were higher with more flights of stairs climbed daily in the
      Hispanic and black women only. Similarly, calcaneal BMD (0.579 +/- 0.023 g x cm(
      2) vs 0.505 +/- 0.014) (P = 0.010) and BMD T-score (-0.020 +/- 0.209 vs -0.678 +/
      0.129) (P = 0.010) were higher with greater amounts of daily movement in only
      the older Hispanic and black women. CONCLUSION: Lifestyle physical activity
      positively impacted BMD indicators in a mixed racial cohort of postmenopausal
      women. Older Hispanic and black women should be encouraged to engage in physical
      activities typical of everyday life to attenuate age-related bone loss.

PMID- 12471304
TI  - Plasma organochlorine concentrations in endurance athletes and obese individuals.
AB  - PURPOSE: Organochlorines are lipophilic compounds that are ingested with food and
      that accumulate in adipose tissue. Their plasma concentrations were compared in
      three groups of individuals with different body fatness characteristics:
      endurance athletes, lean sedentary subjects, and obese individuals. METHODS: The
      relationship between body fat mass and total plasma organochlorine concentration
      adjusted for age was analyzed by pooling data of sedentary lean and obese
      subjects. The regression equation derived from this analysis was also used to
      predict residual scores of total organochlorine concentrations in trained
      individuals, which were compared to measured values in these subjects. RESULTS:
      Plasma organochlorine concentrations tended to be lower in athletes in comparison
      with values measured among lean sedentary individuals. Their concentrations were
      higher in obese individuals than in lean sedentary subjects and athletes. Total
      plasma organochlorine concentration was positively associated to body fat mass in
      the sedentary group (lean and obese combined, reference population). CONCLUSION:
      Large adipose tissue compartment such as observed in obese individuals is
      associated with increased levels of circulating organochlorines, whereas leaner
      sedentary and trained persons have a lower plasma concentration of these
      compounds.

PMID- 12471305
TI  - Clenbuterol diminishes aerobic performance in horses.
AB  - PURPOSE: The purpose of this 8-wk study was to examine the effect of therapeutic
      levels of clenbuterol on aerobic performance and hemodynamics associated with
      exercise. METHODS: Twenty-three unfit Standardbred mares were divided into four
      experimental groups, clenbuterol (2.4 microg x kg(-1) body weight twice daily)
      plus exercise (20 min at 50% O2max; CLENEX; N = 6), clenbuterol only (CLEN; N =
      6), exercise only (EX; N = 5), and control (CON; N = 6). All horses performed an
      incremental exercise test (GXT) to measure maximal oxygen consumption (O2max),
      blood lactate concentration, total plasma protein concentration, and hematocrit.
      Plasma volume, heart rate, right ventricular pressure (RVP), and pulmonary artery
      pressure (PAP) were measured before and after the treatment/training. Each horse
      also performed an exercise capacity test (ECT) in which they ran at their
      pretreatment O2max speed until exhausted. RESULTS: There were no significant
      changes in blood lactate, total protein, or hematocrit for any group during
      either the GXT or ECT. CLENEX decreased (P < 0.05) O2max (-6.2%) and velocity to
      O2max (-10.0%), whereas both CLENEX and CLEN decreased (P < 0.05) in time to
      exhaustion (-20.5+/-4.7 and -20.9 +/- 5.6%). EX alone increased (P < 0.05) O2max
      (+6.5%), velocity to O2max (+10.0%), velocity to produces lactate concentration
      of 4 mmol (+13.5%), and time to exhaustion (+32.3 +/- 15.0%). Plasma volume was
      altered (P < 0.05) in CLENEX (-10%) and EX (+27%) but not in CLEN. Posttest
      recovery HR was higher (P < 0.05) at 2 min post-GXT in the CLENEX, CLEN, and CON
      compared with their pretest values; RVP remained elevated at 2 min of recovery in
      the CLEN and CON groups; however, in the EX, recovery HR and RVP had returned to
      pre-GXT levels by 2 min of recovery. CONCLUSIONS: These data suggest that the
      combined effect of therapeutic levels of clenbuterol and training decrease
      aerobic performance and that the resultant reduction in plasma volume may affect
      improvements in cardiovascular function during recovery normally seen with
      exercise training.

PMID- 12471306
TI  - The reliability and validity of the Adolescent Physical Activity Recall
      Questionnaire.
AB  - PURPOSE: This study assessed the test-retest reliability and validity of the
      Adolescent Physical Activity Recall Questionnaire (APARQ) among 13- and 15-yr-old
      Australians. METHODS: Two studies were conducted using the same instrument. Self
      reported participation in organized and nonorganized physical activity was
      summarized into four measures: a three-category measure of activity, a two
      category measure, and estimated energy expenditure expressed as a continuous
      variable and as quintiles. The reliability study (N = 226) assessed strength of
      agreement for all measures between responses to two administrations of the
      questionnaire. The validity study (N = 2026) assessed the relationship between
      the APARQ and performance on the Multistage Fitness Test (MFT). RESULTS:
      Reliability study: for the three-category measure, percent agreement ranged 67
      83% and weighted kappa ranged 0.33-0.71. For the two-category measure, percent
      agreement ranged 76-90% and kappa ranged 0.25-0.74. For energy expenditure
      expressed as a continuous variable, the intraclass correlations coefficients were
      generally greater than 0.6 for grade 10 students, but most were below 0.5 for
      grade 8 students. Validity study: for the three-category measure, mean laps were
      higher in the adequately and vigorously active categories than the inactive
      category for girls, but only the mean laps in the vigorously active and inactive
      categories were significantly different for boys. For the two-category measure,
      mean laps were higher in the active category than the inactive category for all
      groups. Correlations between energy expenditure and MFT laps were 0.15, 0.21,
      0.14, and 0.39 for grade 8 boys, grade 8 girls, grade 10 boys, and grade 10
      girls, respectively. CONCLUSION: The APARQ has acceptable to good reliability and
      acceptable validity, but further validation using other methods and in other
      population groups is required.

PMID- 12471307
TI  - Correlates of adults' participation in physical activity: review and update.
AB  - PURPOSE: To review and update the evidence relating to the personal, social, and
      environmental factors associated with physical activity (PA) in adults. METHODS:
      Systematic review of the peer-reviewed literature to identify papers published
      between 1998 and 2000 with PA (and including exercise and exercise adherence).
      Qualitative reports or case studies were not included. RESULTS: Thirty-eight new
      studies were located. Most confirmed the existence of factors already known to be
      correlates of PA. Changes in status were noted in relation to the influence of
      marital status, obesity, smoking, lack of time, past exercise behavior, and eight
      environmental variables. New studies were located which focused on previously
      understudied population groups such as minorities, middle and older aged adults,
      and the disabled. CONCLUSION: The newly reported studies tend to take a broader
      "ecological" approach to understanding the correlates of PA and are more focused
      on environmental factors. There remains a need to better understand environmental
      influences and the factors that influence different types of PA. As most of the
      work in this field still relies on cross-sectional studies, longitudinal and
      intervention studies will be required if causal relationships are to be inferred.

PMID- 12471308
TI  - Symposium: Immune function in environmental extremes--an introduction.

PMID- 12471309
TI  - Exercise and hypoxia: effects on leukocytes and interleukin-6-shared mechanisms?
AB  - Stress-induced immunological reactions to exercise have stimulated much research
      into stress immunology and neuroimmunology. It has been suggested that exercise
      can be employed as a model of temporary immunosuppression, which occurs during
      physical stress, such as hypoxia. Acute exercise and acute hypoxia mediate in
      principle identical effects on circulating lymphocyte and neutrophil numbers.
      Thus, during exercise and hypoxia, lymphocytes are recruited to the blood. After
      the stress, the number of lymphocytes declines after the stress, whereas the
      neutrophil number continues to increase. When exercise is performed during
      hypoxia, the exercise-induced immune changes are pronounced. There is some
      evidence that the exercise- and hypoxia-induced changes in leukocyte
      subpopulations are mediated by neuroendocrinological factors such as
      catecholamines, growth hormone, and cortisol. In contrast, although exercise, as
      well as hypoxia, is associated with increased plasma levels of IL-6, the
      mechanisms are not likely to be the same. Thus, during exercise, contracting
      skeletal muscles are the main source of IL-6 production, whereas the source of IL
      6 during hypoxia has not been demonstrated. The increased level of adrenaline
      contributes to the enormous increase in plasma IL-6 only to a minor degree during
      strenuous exercise. However, the only modest increase in IL-6 during hypoxia may
      be linked to hormonal changes, whereas the prolonged increase in IL-6 during
      chronic hypoxia is likely to be multifactorial.

PMID- 12471310
TI  - Cold exposure: human immune responses and intracellular cytokine expression.
AB  - It is commonly believed that exposure to cold environmental temperatures
      depresses immune function and increases the risk for infection. This review paper
      will 1) present an overview of human physiological responses to cold exposure, 2)
      present the human studies examining the effects of cold exposure on immune
      responses, and 3) summarize recent experiments from our laboratories examining
      the effects of exercise and fatigue on immune responses during subsequent cold
      exposure. Based on the review of the literature, there is no support for the
      concept that cold exposure depresses immune function.

PMID- 12471311
TI  - The immune system in space and microgravity.
AB  - Space flight and models that created conditions similar to those that occur
      during space flight have been shown to affect a variety of immunological
      responses. These have primarily been cell-mediated immune responses including
      leukocyte proliferation, cytokine production, and leukocyte subset distribution.
      The mechanisms and biomedical consequences of these changes remain to be
      established. Among the possible causes of space flight-induced alterations in
      immune responses are exposure to microgravity, exposure to stress, exposure to
      radiation, and many more as yet undetermined causes. This review chronicles the
      known effects of space flight on the immune system and explores the possible role
      of stress in contributing to these changes.

PMID- 12471312
TI  - Three-dimensional kinetic analysis of side-foot and instep soccer kicks.
AB  - PURPOSE: The purpose of this study was to identify the kinetic aspects of side
      foot and instep soccer kicks to understand the different mechanics underlying the
      two kicks. METHODS: The motions of both kicks were captured using a three
      dimensional cinematographic technique. The kicking leg was modeled as a three
      link kinetic chain composed of thigh, shank, and foot, from which joint torques
      and angular velocities were computed. RESULTS: The ball velocity of the side-foot
      kick (23.4 +/- 1.7 m x s(-1)) was significantly slower than that of the instep
      kick (28.0 +/- 2.1 m.s(-1)). Significant differences were also observed between
      the two kicks for the magnitude of hip external rotation torque (56 +/- 12 N.m in
      the side-foot kick; 33 +/- 8 N.m in the instep kick) and hip external rotation
      angular velocity (11.1 +/- 2.4 rad x s(-1) in the side-foot kick; 6.0 +/- 2.0 rad
      x s(-1) in the instep kick). CONCLUSION: These results indicated that to hit the
      ball with the medial side of the foot, a complicated series of rotational motions
      are required for the side-foot kick. The hip external rotation torque dominantly
      exhibited in the side-foot kick caused the clockwise rotation of the thigh-shank
      plane at the later stage of kicking. This may allow the hip external rotation
      motion to increase directly the forward velocity of the side foot, with which
      players can squarely impact the ball.

PMID- 12471313
TI  - Effects of vibration in inline skating on the Hoffmann reflex, force, and
      proprioception.
AB  - PURPOSE: The objective of this study was to examine the effects of vibrations
      induced by inline skating on the Hoffmann (H) reflex, maximal voluntary isometric
      (MVC) force, and ankle proprioception. METHODS: Accelerometers were used to
      measure the frequencies and amplitudes of the vibrations encountered at the skate
      and mid-tibia levels. The soleus H reflex was recorded before and after (for 30
      min) inline skating for 30 min. Maximal plantarflexor contractions were performed
      against a strain gauge while EMG was recorded from the soleus and medial
      gastrocnemius muscles. An ankle position-matching test was carried out to measure
      proprioception at the ankle. A Modified Borg Scale was used to obtain the
      appreciation of leg numbness and fatigue during inline skating. RESULTS: The
      vibrations measured at the skate chassis level had a mean frequency of 141.8 +/-
      25.2 Hz and an amplitude of </=5 g. These vibrations were transmitted to the
      lower limb as measured by a mean frequency of 34.4 +/- 27.7 Hz and an amplitude
      of </=2 g at the mid-tibia level. The results demonstrate a clear inhibition (
      approximately 35%) of the H reflex after skating that persisted for >35 min after
      skating. A 10% drop in MVC plantarflexor force was observed after inline skating.
      There was no accompanying change in EMG signal parameters. The ankle
      proprioception of the subjects decreased after skating, resulting in reproduction
      errors twice as large as before skating. CONCLUSION: Vibrations encountered
      during inline skating resulted in modifications of neuromotor functions related
      to the muscle spindles' primary afferent. These changes may partially be
      explained by presynaptic inhibition; however, a more plausible mechanism may be a
      decrease in the Ia afferent transmission induced by the vibration.

PMID- 12471314
TI  - Comparison of pedometer and accelerometer measures of free-living physical
      activity.
AB  - PURPOSE: The purpose of this investigation was 1) to evaluate agreement between
      dual-mode CSA accelerometer outputs and Yamax pedometer outputs assessed
      concurrently under free-living conditions; 2) to determine the relationship
      between pedometer-steps per day and CSA-time spent in inactivity and in light-,
      moderate-, and vigorous-intensity activities; and 3) to identify a value of
      pedometer-steps per day that corresponds with a minimum of 30 CSA-min x d(-1) of
      moderate ambulatory activity. METHODS: Data were analyzed from 52 participants
      (27 men, 25 women; mean age = 38.2 +/- 12.0 yr; mean BMI = 26.4 +/- 4.5 kg x m(
      2)) who were enrolled in the International Physical Activity Questionnaire study
      and wore both motion sensors during waking hours for 7 consecutive days. RESULTS:
      Participants averaged 415.0+/-159.5 CSA-counts x min(-1) x d(-1), 357,601 +/-
      138,425 CSA-counts x d(-1), 11,483 +/- 3,856 CSA-steps x d(-1), and 9,638 +/-
      4,030 pedometer-steps x d(-1). There was a strong relationship between all CSA
      outputs and pedometer outputs (r = 0.74-0.86). The mean difference in steps
      detected between instruments was 1845+/-2116 steps x d(-1) (CSA > pedometer; t =
      6.29, P < 0.0001). There were distinct differences (effect sizes >0.80) in mean
      CSA-time (min x d(-1)) in moderate and vigorous activity with increasing
      pedometer-determined activity quartiles; no differences were noted for inactivity
      or light activity. Approximately 33 CSA-min x d(-1) of moderate activity
      corresponded with 8000 pedometer-steps x d(-1). CONCLUSION: Differences in mean
      steps per day detected may be due to differences in set instrument sensitivity
      thresholds and/or attachment. Additional studies with different populations are
      needed to confirm a recommended number of steps per day associated with the
      duration and intensity of public health recommendations for ambulatory activity.

PMID- 12471315
TI  - Glenohumeral joint total rotation range of motion in elite tennis players and
      baseball pitchers.
AB  - The amount of glenohumeral joint internal and external rotation used during
      overhead sport activities has been measured experimentally by sports scientists.
      Clinical measurement of glenohumeral joint internal and external rotation using
      goniometry is an integral part of a shoulder evaluation after injury or surgery
      or during preseason or preventative musculoskeletal screenings. PURPOSE: This
      study measured glenohumeral joint internal and external rotation in two groups of
      unilaterally dominant upper extremity athletes to compare the total arc of
      rotational range of motion between the dominant and nondominant extremities.
      METHODS: A total of 163 elite athletes (117 male junior tennis players and 46
      male baseball pitchers) were measured for glenohumeral joint internal and
      external rotation at 90 degrees of abduction. Total rotation range of motion was
      calculated by summing internal and external rotation measures in each extremity.
      RESULTS: An ANOVA with post hoc testing revealed no significant difference (P >
      0.05) between extremities in baseball pitchers for total rotation range of motion
      (145.7 vs 146.9), whereas significantly less (P < 0.001) dominant arm total
      rotation range of motion was identified in the elite junior tennis players (149.1
      vs 158.2). CONCLUSION: This study has identified unique glenohumeral joint
      rotational patterning in unilaterally dominant upper extremity athletes that has
      ramifications for rehabilitation after injury and for both injury prevention and
      performance enhancement.

PMID- 12471316
TI  - Reliability and validity of the Borg and OMNI rating of perceived exertion scales
      in adolescent girls.
AB  - PURPOSE: To examine the reliability and validity of the Borg and OMNI rating of
      perceived exertion (RPE) scales in adolescent girls during treadmill exercise.
      METHODS: Adolescent girls (N = 57, age = 15.3+/-1.5 yr) were randomly assigned to
      use an RPE scale (Borg or OMNI) during one of three treadmill submaximal exercise
      conditions (walking, walking uphill, or jogging). After RPE assessment, exercise
      intensity was increased until participants achieved volitional exhaustion
      (O2max). Expired respiratory gases and heart rate (HR) were measured continuously
      during exercise. Reliability of the RPE scales was assessed using ANOVA
      (intraclass) and Spearman-Brown prophecy formula (single trial) measures.
      Validity estimates were calculated using Pearson Product Moment correlations,
      with % HRmax and % O2max as criterion measures. RESULTS: Intraclass and single
      trial reliability estimates were higher for the OMNI (r(xx) = 0.95 and r(kk) =
      0.91, respectively) compared with the Borg (r(xx) = 0.78 and r(kk) = 0.64,
      respectively) RPE scale. Validity estimates were also higher for the OMNI scale
      compared with the Borg scale. Validity coefficients (r(xy)) for %HRmax and %O2max
      comparisons were 0.86 and 0.89, respectively, for the OMNI, compared with 0.66
      and 0.70, respectively, for the Borg. CONCLUSION: The OMNI cycle pictorial scale
      was found to be reliable and valid for use with adolescent girls. It also appears
      to be more reliable and valid than the Borg scale for use in this population
      during treadmill exercise.

PMID- 12471317
TI  - Effect of cycling experience and pedal cadence on the near-infrared spectroscopy
      parameters.
AB  - PURPOSE: Previously we demonstrated that the method to reorder near-infrared
      spectroscopy (NIRS) parameters against crank angle could serve as a useful
      measure in providing circulatory dynamics and metabolic changes in a working
      muscle during pedaling exercise. To examine further applicability of this method,
      we investigated the effects of cycling experience and pedal cadence on the NIRS
      parameters. METHODS: Noncyclists (NON), triathletes (TRI), and cyclists (CYC)
      performed pedaling exercises at a work intensity of 75% VO2max while changing
      pedal cadence (50, 75, 85, and 95 rpm). Physiological and biomechanical responses
      and NIRS parameters were measured. RESULTS: NIRS measurements determined with the
      reordered NIRS change demonstrated significant differences depending on the
      factors. The bottom peak of reordered NIRS changes in muscle blood volume and
      oxygenation level shifted upward with an increase in pedal cadence in NON but
      remained unchanged in CYC. The reordered NIRS change demonstrated a temporary
      increase at the crank angle corresponding to the relaxation phase of the working
      muscle. This temporary increase was observed even in the highest pedal cadence in
      CYC. The difference in levels between the peak of the temporary increase and the
      bottom peak of reordered NIRS change (LPB-diff) for CYC at 85 rpm was
      significantly larger than that for NON. The results with NIRS parameters
      corresponded to changes in pedal force and myoelectric activity during pedal
      thrust. CONCLUSIONS: The bottom peak level of the reordered NIRS changes and LPB
      diff determined for blood volume are available to detect noninvasively the
      differences in circulatory dynamics and metabolic change during pedaling
      exercises performed at different pedal cadences and also to estimate the
      difference of physiological and technical developments for endurance cycling in
      athletes.

PMID- 12471318
TI  - Peak power in obese and nonobese adolescents: effects of gender and braking
      force.
AB  - PURPOSE: The aim of this study was to determine the cycling peak power (CPP) of
      obese compared with nonobese adolescents and to identify possible effects of
      braking force (BF) and gender on CPP. To adjust for differences in body size, we
      used ratio standard and allometric model. METHODS: Obese (26 girls, 18 boys) and
      nonobese (30 girls, 20 boys) adolescents participated. Fat-free mass (FFM) was
      determined by dual-energy x-ray absorptiometry (DEXA) in obese and by
      anthropometric method in nonobese groups. A force-velocity test was used to
      measure peak power (flywheel inertia included) for BF corresponding to applied
      load: 25, 50, and 75 g x kg(-1) body mass (BM). The highest peak power was
      defined as CPP. RESULTS: CPP was independent of BF in nonobese adolescents but
      dependent in obese adolescents. The optimal braking load is approximately 6.5%
      FFM. Absolute CPP was higher in obese than nonobese adolescents. Related to BM,
      CPP was significantly lower in obese than nonobese adolescents, using the
      standard ratio or the allometric model. These differences disappeared when CPP
      was related to FFM. Multiple stepwise regression showed that FFM was the most
      important explanatory variable of the variance of CPP (72%) in obese and nonobese
      adolescents. No significant difference between obese and nonobese adolescents
      occurred when Fopt was related to FFM (standard or power function ratios used).
      There was no gender effect on CPP, and the manner of expressing CPP did not
      affect the results. However, girls showed a higher FFM-related Fopt than boys,
      using standard and power function ratios. CONCLUSION: There was no significant
      difference between obese and nonobese girls and boys for anaerobic performance
      (CPP and Fopt) when FFM was taken into account.

PMID- 12471319
TI  - Inverse relationship between VO2max and economy/efficiency in world-class
      cyclists.
AB  - PURPOSE: To determine the relationship that exists between VO2max and cycling
      economy/efficiency during intense, submaximal exercise in world-class road
      professional cyclists. METHODS Each of 11 male cyclists (26+/-1 yr (mean +/-
      SEM); VO2max: 72.0 +/- 1.8 mL x kg(-1) x min(-1)) performed: 1) a ramp test for
      O2max determination and 2) a constant-load test of 20-min duration at the power
      output eliciting 80% of subjects' VO2max during the previous ramp test (mean
      power output of 385 +/- 7 W). Cycling economy (CE) and gross mechanical
      efficiency (GE) were calculated during the constant-load tests. RESULTS: CE and
      GE averaged 85.2 +/- 2.3 W x L(-1) x min(-1) and 24.5 +/- 0.7%, respectively. An
      inverse, significant correlation was found between 1) VO2max (mL x kg(-0.32) x
      min(-1)) and both CE (r = -0.71; P = 0.01) and GE (-0.72; P = 0.01), and 2)
      VO2max (mL x kg(-1) x min(-1)) and both CE (r = -0.65; P = 0.03) and GE (-0.64; P
      = 0.03). CONCLUSIONS: A high CE/GE seems to compensate for a relatively low
      VO2max in professional cyclists.

PMID- 12471320
TI  - Physiological responses to high-speed, open-wheel racecar driving.
AB  - High-speed auto racing has been demonstrated to produce accelerated heart rate
      (HR) during competition. However, it has not been determined whether the increase
      in HR was due to physical work efforts or a result of emotional stress. PURPOSE:
      The purpose of this investigation was to examine the physiological responses
      associated with open-wheel automobile driving at competitive speeds. METHODS:
      Oxygen consumption and HR were assessed in seven professional automobile racing
      drivers during two incrementally paced driving sessions. A portable metabolic
      analyzer and EKG were directly attached to the subjects as they participated in
      driving tests on an oval speedway and a roadway course. Maximal physiological
      responses of the subjects were also determined during a graded treadmill test.
      RESULTS: During treadmill testing, maximal oxygen consumption (VO2max) ranged
      from of 42.0 to 59.7 mL x kg(-1) x min(-1) (mean +/- SD = 47.6+/-8.1). The road
      course and oval speedway testing at competitive speeds elicited mean VO2 values
      of 38.5 and 21.9 mL x kg(-1) x min(-1), respectively, which correspond to 79% and
      45% of VO2max. Road course driving produced mean HR values of 152 beats x min(-1)
      with 142 beats x min(-1) recorded when driving at competitive speed on the
      speedway course. CONCLUSIONS: Professional open-wheel race drivers possess
      cardiorespiratory capacity similar to athletes participating in sports such as
      basketball, football, and baseball. The VO2 and HR responses to road course
      driving were similar to those previously reported in traditional sports settings.
      The findings of this study suggest that professional open-wheel racing drivers
      should be regarded as athletes that encounter significant physiological
      stresses.(2)

PMID- 12471321
TI  - Effect of active warm-up on metabolism prior to and during intense dynamic
      exercise.
AB  - PURPOSE: This study investigated whether active warm-up (AW) would increase
      muscle acetylcarnitine concentration before exercise, thereby reducing the
      reliance on nonoxidative ATP production during subsequent high-intensity
      exercise. METHODS: Six female subjects performed a 30-s sprint at 120% of their
      maximal power output on an electronically braked cycle ergometer 5 min after
      undertaking an active warm-up. To exclude any effect of muscle temperature (Tm)
      on metabolism, AW was compared with control (C), which involved passively heating
      the muscle to the same temperature as that achieved by active warm-up (37.1 +/-
      0.3 vs 37.2 +/- 0.2 degrees C AW and C, respectively). RESULTS: Active warm-up
      significantly increased the concentration of acetylcarnitine from 4.5 +/- 1.5
      mmol x kg(-1) dry muscle (dm)(-1) at rest to 9.4 +/- 1.6 mmol x kg dm(-1) before
      the onset of exercise. There was no change in acetylcarnitine concentration in C.
      During exercise the accumulation of muscle lactate was significantly less in AW
      compared with C (21.9 +/- 3.8 vs 34.3 +/- 2.3 mmol.kg dm, respectively).
      CONCLUSION: The main finding of this study was that there was less accumulation
      of blood and muscle lactate during intense dynamic exercise preceded by active
      warm-up, which could not be accounted for by a difference in T between trials
      immediately before the onset of exercise(m)

PMID- 12471322
TI  - Prediction of the aerobic demand of walking in children.
AB  - PURPOSE: The purpose of this study was to develop a generalized equation to
      predict VO2 during level treadmill walking in young boys and girls. METHODS: On
      an annual basis from ages 6 to 10, 23 able-bodied children (14 girls, 9 boys)
      completed six 5-min walking bouts at speeds ranging from 40.2 to 107.2 m x min(
      1). Before testing, each child received 60 min of treadmill walking practice.
      During the last 2 min of each walking trial, a 2-min sample of expired gas was
      collected in a meteorological balloon and analyzed to determine VO2. RESULTS:
      Stepwise regression analyses indicated that the following equation was best
      suited to predict walking VO2: VO2 = 24.852 + 0.003214 (walking speed in m x min(
      1))2 - 0.995 (age in yr) - 0.263 (walking speed); R = 0.95; SEE = 1.74 mL x kg(
      1) x min(-1). Bland-Altman analysis revealed that 95% of the differences between
      actual and predicted VO2 values fell within a range of 3.39 to -3.43 mL x kg(-1)
      x min(-1). CONCLUSION: We conclude that VO2 during level treadmill walking can be
      predicted accurately in healthy young children.

PMID- 12471323
TI  - Effects of aquatic resistance training on neuromuscular performance in healthy
      women.
AB  - PURPOSE: The purpose of this study was to investigate the effects of a
      progressive 10-wk aquatic resistance training on neuromuscular performance and
      muscle mass of the knee extensors and flexors in healthy women. METHODS: Twenty
      four healthy women (34.2 +/- 3.9 yr) were randomly assigned into aquatic exercise
      (N = 12) and control group (N = 12). Maximum knee extension and flexion torques
      were measured isometrically and at constant angular velocities of 60 degrees x s(
      1) and 180 degrees x s(-1) (isokinetic) with simultaneous electromyography (EMG)
      recordings of the quadriceps and hamstrings. The lean muscle mass (LCSA) of the
      quadriceps and hamstring muscles was determined by computed tomography scanning.
      RESULTS: Significant interaction of group by time was observed in each of the
      measured parameters. The change in extension and flexion isometric/isokinetic
      torque varied between 8 and 13% and in EMGs between 10 and 27% in the exercise
      group. The change in the quadriceps LCSA of the exercise group was 4% and in
      hamstrings 5.5%. CONCLUSIONS: The results of the present study showed that 10 wk
      of progressive aquatic resistance training resulted in significant improvement in
      muscle torque of the knee extensors and flexors accompanied with proportional
      improvement in neural activation and with significant increase in the LCSA of the
      trained muscles. Aquatic training can be recommended for neuromuscular
      conditioning in healthy persons.

PMID- 12471324
TI  - Association of swim distance and age with body composition in adult female
      swimmers.
AB  - PURPOSE: The purpose of this investigation was to examine the relationship
      between average weekly swimming distance and age with body composition in adult
      female endurance swimmers. METHODS: Thirty-five women, aged 21-73 yr, volunteered
      to participate. Weekly swimming distance was determined from a self-reported
      exercise log. Body composition was estimated by dual-energy x-ray absorptiometry
      (DXA), waist circumference, abdominal sagittal diameter, and skinfold thickness
      measures. Associations between swimming distance and age with body composition
      were examined using regression analysis. RESULTS: Swimming distance had shared
      variances as follows: 23% with percent body fat, 26% with waist circumference,
      20% with abdominal sagittal diameter, and 20%, 24%, and 22% with subscapular,
      suprailiac, and triceps skinfolds, respectively. Abdominal sagittal diameter was
      the only adiposity measure demonstrating a stronger relationship with age (R2 =
      0.29, P = 0.00) than with swimming distance (R2 = 0.20, P = 0.03). Bone mineral
      content was linearly related to swimming distance and age having a negative
      association with age (r2 = 0.18, P = 0.01) and a positive one with swimming
      distance (r2 = 0.12, P = 0.05). In addition, there was a negative linear
      association observed between swimmer age and bone mineral density (r2 = 0.12, P =
      0.05). CONCLUSION: In these female adults, endurance swimming was mildly
      associated with body adiposity. Age was not associated with body fat mass
      independently from swimming activity except with that measure reflecting
      abdominal visceral fat deposits. These data suggest that greater fat mass in
      female swimmers is more strongly related to lower levels of exercise than to age
      but that there is an additional influence of age on fat accumulation in the intra
      abdominal area of the body.

PMID- 12471325
TI  - Exercise effects on fitness and bone mineral density in early postmenopausal
      women: 1-year EFOPS results.
AB  - PURPOSE: To determine the effect of an intense exercise training on physical
      fitness, coronary heart disease (CHD), bone mineral density (BMD), and parameters
      related to quality of life in early postmenopausal women with osteopenia.
      METHODS: Fifty-nine fully compliant women (55.1 +/- 3.4 yr) without any
      medication or illness affecting bone metabolism took part in intensive exercise
      training (>2 sessions per week); 41 women served as nontraining control. Both
      groups received calcium and vitamin D (cholecalciferol) up to a maximum of 1500
      mg x d(-1) calcium and 500 IU x d(-1) vitamin D. Bone density of the lumbar spine
      and hip (DXA Hologic QDR 4500), maximum isometric and dynamic strength (Schnell
      M3, Schnell-Trainer), VO2max (ZAN 600), and quality of life parameters including
      vasomotor symptoms related to menopause were measured at baseline and after 14
      months. RESULTS: After 14 months, there were significant differences between
      exercise and control groups concerning changes of bone density (LS exercise:
      +1.3%, P < 0.001 vs control: -1.2%, P < 0.001), maximum isometric strength
      (exercise: +11 to +32% (P < 0.001) vs control: -1.1 to +3.9%), VO2max (exercise:
      +11% (P < 0.001) vs control: -4% (P < 0.05)), and quality of life parameters
      (e.g., lower back pain). Dynamic strength (1RM tests) at four exercises, which
      was assessed in the exercise group only, increased significantly by 15-43% (all P
      < 0.001). CONCLUSION: The intense exercise training program presented here was
      effective in improving strength, endurance, quality of life parameters, and even
      BMD in women in their critical early postmenopausal years.

PMID- 12471333
TI  - [Statistical modelization of geographic variations: a major challenge in
      epidemiology and statistics].

PMID- 12471334
TI  - [How to choose in practice a model to describe the geographic variation of cancer
      incidence? Example of gastrointestinal cancers from Cote-d'Or].
AB  - BACKGROUNDS: In epidemiology, standardized Incidence Ratio (SIR) can have large
      variance and it is then difficult to distinguish random fluctuations from real
      spatial variations when describing spatial variations in the rate of cancer. In
      this context, hierarchical model produce smoothed relative risks estimations
      helpful for solving this problem. The main advantage of these methods is to
      combine information of each geographical area with that obtained from prior
      assumption on the similarity between geographical sub-units. Nevertheless
      different assumptions produce different geographical maps of incidence of cancer,
      and the purpose of the present study was the development of a strategy to choose
      the most satisfactory description of the incidence of digestive cancer in a
      French department. METHODS: The strategy to choose the most satisfactory
      geographical map depends on the following criteria: variability between
      geographical sub-units, auto-correlation, and variability within geographical sub
      unit. These criteria have been estimated from observed data for each site of
      cancer. RESULTS: This strategy was applied to digestive tract cancers diagnosed
      between 1976 and 1997 in the department of Cote-d'Or, France. High-risk areas
      were often detected in the urban zone of the department, but without
      autocorrelation in most cases. CONCLUSION: This strategy permitted to describe
      cancers in very small areas, avoiding to a large extent the danger of focusing on
      falsely positive high-risk areas.

PMID- 12471335
TI  - [Incidence and prevalence estimations for breast and colorectal cancer in the
      Picardy region].
AB  - OBJECTIVES: To provide incidence and prevalence data on breast and colorectal
      cancer in the Picardie area of France. METHODS: An age-period-cohort method was
      used to estimate regional incidence and prevalence of cancer from regional cancer
      mortality data and patient survival data recorded in the Somme Cancer Registry.
      RESULTS: European standardized breast incidence for 1998 was 110 per 100000
      inhabitants. The incidence for colorectal cancer was 67 per 100000 for men and 47
      per 100000 for women. Prevalence was 9656 for breast cancer and 6283 (2941 for
      men and 3342 for women) for colorectal cancer. Incidence of breast cancer
      increased considerably (80.9%) between 1979 and 1998. CONCLUSION: These results
      provide data on breast cancer and colorectal cancer which are useful for planning
      demand for healthcare or medical surveillance in the Picardie area.

PMID- 12471336
TI  - [Quality of medical records in the "Medical Information System Program":
      application of the lot quality assurance sampling method].
AB  - BACKGROUND: The aim of this study was to validate a new method of quality control
      of medical records of the "Medicalisation of Information System Program"
      (P.M.S.I.) in Limoges university hospital. METHODS: Lot quality assurance
      sampling (L.Q.A.S.), developed to meet industrial quality control needs, has been
      applied. This method allows to give an opinion on the quality of a lot from a
      sample randomised in this lot. Ten hospital units have been randomised. During
      three months, these medical units have recoded ten medical units abstracts
      (R.U.M.) which were randomised each month within their stays. If five or more
      R.U.M. had been modified on Principal Diagnosis (D.P.), Associated Significant
      Diagnosis (D.A.S.) or Diagnosis Related Group (D.R.G.), the lot was rejected. The
      hospital unit had then less 70% R.U.M. of good quality (alpha=5%). The global
      errors rates were compared to the results of usually performed quality control
      (1998). RESULTS: Nine hospital units were included. Hospital units which already
      had a low quality rate during the 1998 quality control had also an insufficient
      quality by L.Q.A.S. method. Among these, 33.7 [CI(95%): 21.6-45.8] R.U.M. have
      been modified. Medical units had a poorer data quality than surgical ones. No
      statistically significant difference was shown between 1998 errors rates and
      L.Q.A.S. rates, except for D.P. (p=0.002). CONCLUSION: L.Q.A.S. is easy to apply,
      could be repeated more frequently than usual controls, and allows to detect
      hospital units which require a faster action. This process could be applied to
      P.M.S.I., in which the search of quality is necessary because of the new cost
      model which includes secondary D.R.G.

PMID- 12471337
TI  - [Nutritional status on admission and hospital mortality of under-five year old
      children with infectious diseases in Ouagadougou, Burkina Faso].
AB  - BACKGROUND: It is known that malnutrition in childhood interacting with
      infectious diseases contributes to increase mortality. In Burkina Faso,
      infectious pathologies and malnutrition are public health problems. We examined
      the impact of malnutrition status, using the Weight-for-age (WA) index, on
      mortality of children hospitalized for infectious diseases. METHODS: This
      retrospective study uses a systematic sample derived from the year 1999 hospital
      register. In total data of 1573 children from 0 to 59 months were analyzed. The
      association between mortality and dependent variables was measured by relative
      risks (RR) in univariate analysis. A logistic regression was realized and
      attributable risk percent (etiologic fraction among exposed) of death was
      calculated. RESULTS: The total intra-hospital lethality amounted to 15.3%. Age,
      diagnosis, type of care recourse and malnutrition (low WA index) on admission
      were associated to mortality. The logistic regression model confirmed the high
      risks of deaths for young children (0-11m), children in malnutrition (low WA
      index) and those with severe malaria. The attributable risk percent of death
      indicates that, 87% of deaths are statically attributable to severe malnutrition
      (WA Z-score<=-3) and 64.3% of deaths are statically attributable to moderate
      malnutrition (WA Z-score]-3, -2]). CONCLUSION: Nutritional status evaluation
      would allow to select children at risk and reduce mortality by including
      nutritional intervention in standard treatment of children hospitalized for
      infectious diseases.

PMID- 12471338
TI  - [Dependence for daily life activities in the prison population in Western
      France].
AB  - OBJECTIVE: As the mean age of the penitential population rises and the duration
      of imprisonment grows longer, health services are confronted with the problem of
      prisoners dependent for daily life activities. The purpose of this study was to
      determine the number of prisoners dependent for daily life activities and
      quantify their dependency on human and material support. METHODS: A survey was
      conducted in the summer of 2,000 in the western region of France (19 prisons in
      the following regions: Pays-de-Loire, Brittany, Lower Normandy). RESULTS: Among
      the 4,168 persons incarcerated in these regions, 32 dependent prisoners were
      identified: 21 men (mean age 57 years) and 11 women (mean age 48 years). Among
      these persons, 19 suffered from major or moderate dependence (GIR 1-4). The main
      problems involved toilet facilities, dressing, transfers, and moving about. When
      human support was available, it was generally provided by other prisoners.
      Material help was scarce. DISCUSSION: The questions of prisoner's rights, human
      assistance, the status of caregivers, and the need for adapted architectural,
      material, and medical facilities are discussed. The information collected here
      provides a better knowledge of prisoners' needs for support and for changes which
      would be necessary in the prison environment.

PMID- 12471339
TI  - [Application of medical guidelines for the prescription of statins].
AB  - BACKGROUND: The efficacy of statins to prevent coronary heart disease (CHD) is
      well documented. This class of lipid-lowering drugs is now widely prescribed and
      was demonstrated to be cost effective in high risk patients. OBJECTIVE: To assess
      the appropriateness of statins use, regarding initiation and follow-up of the
      treatment, as compared to the guidelines elaborated in 1996 by National Agency
      for the Development of Medical Evaluation (ANDEM). These guidelines were based on
      stratification of patients according to cardiovascular risk. METHODS: Two groups
      of patients living in Ile-de-France region were defined, using Health Insurance
      computer database, on reimbursements. The first group named "new users" included
      patients in whom statin therapy was initiated during March 2000. The second group
      named "long term users" included patients who have been treated by statin therapy
      for one year or more. A sample of patients were randomly selected among these two
      groups. Trained Health Insurance advisors analyzed in depth the patients medical
      history and diet. All biological results were recorded and a complete history of
      medical therapy was assessed for each patient. An algorithm allowed the advisor
      to rate for nonadherence according to French medical guidelines. RESULTS: "New
      users": the random sample consisted of 460 patients, among whom 398 (87%) were
      free of CHD in whom the nonadherence rate was 72.4% (68.0% to 76.8%).
      Nonadherence concerned: LDL cholesterol level not tested (32%) and/or absence of
      prior fat-free diet (37%) and/or LDL cholesterol value before drug therapy was
      below the guidelines/threshold. "Long term users": the random sample consisted of
      582 patients, among whom 381 (65%) were free of CHD. The nonadherence rate was
      71.1% (66.5% to 75.7%). In addition, the nonadherence rate for patients in
      secondary prevention was 82.1% (79.7% to 84.6%) respectively, corresponding to:
      LDL cholesterol level not tested (41% and 34%); and/or no change dietary (18% and
      12%); and/or unreach the LDL-C target level (24% and 45%). CONCLUSION: This study
      shows that the implementation of guidelines needs to be improved in clinical
      practice.

PMID- 12471340
TI  - [Evaluation of prevention strategies for congenital toxoplasmosis: a critical
      review of medico-economic studies].
AB  - BACKGROUND: Congenital toxoplasmosis (CT) may lead to serious neurological or
      sensory consequences. A serological screening of women at risk of acquiring
      toxoplasmosis became mandatory in France, first during the visit before wedding
      (1978), then during the visit for pregnancy declaration (1985) and at last with a
      monthly follow-up during pregnancy since 1992. The efficacy and the profitability
      of the program was never assessed, in spite of the modification of the
      epidemiological context. However medico-economical studies were conducted in
      countries in which no prevention program for CT was available to determine the
      interest of an antenatal screening similar to the French one or of other
      prevention strategies. METHODS: Eight studies comparing at least two strategies
      were selected. Methodologies used in those studies were analyzed by two
      independent readers with the help of a standardized scale. A score was calculated
      for each study. RESULTS: Each study analyzed suffered from methodological
      limitations, in particular concerning the estimation of antenatal treatment
      efficacy, which could lead to invalidate their conclusion. The most reliable
      studies in regard to methodological guidelines, that is with the higher score,
      concluded that antenatal screening was not contributive. However, they could not
      be transposed directly in the present French situation, because of the difference
      of the epidemiological and economical context. CONCLUSIONS: Given the difficulty
      to obtain a clear conclusion, it seems necessary to perform a rigorous decision
      analysis to identify the more effective and acceptable program in terms of human
      and financial costs for preventing congenital toxoplasmosis.

PMID- 12471341
TI  - [The contribution of multilevel models in contextual analysis in the field of
      social epidemiology: a review of literature].
AB  - Using contextual factors beyond individual factors, contextual analysis allows a
      more accurate identification of at-risk populations, which could be useful when
      planning health programs. Multilevel models, widely used in British and North
      American social epidemiology research but less frequently in France, are
      particularly suitable to analyse contextual data, because they take into account
      their hierarchical structure. This paper addresses methodological issues in the
      utilization of multilevel models, and reports some results which illustrate their
      potentials compared to those of more conventional statistical methods. As well as
      other methods, multilevel models are able to take into account the hierarchical
      structure of the data when estimating parameters. Furthermore, and more
      specifically, these models can also be viewed as useful tools to investigate
      contextual effects. Their particular interest is to disentangle individual-level
      variability and between-group variability. Comparing the group-level variance
      before and after introduction of individual-level characteristics allows to
      assess the extent to which between-group variability is linked to compositional
      effects. Multilevel models can also help examine whether the between-group
      variations affect all the members of the groups, or only specific sub-groups.
      Finally, they can estimate how much of this complex between-group variability is
      explained by the contextual factors included in the model. The overall conclusion
      is that multilevel statistical methods should be used in social epidemiology
      studies dealing with individual and contextual data, to produce results that are
      both richer and more consistent.

PMID- 12471343
TI  - [Human trabecular cells and apoptosis: in vitro evaluation of the effect of
      betaxolol with or without preservative].
AB  - PURPOSE: Trabecular meshwork, which is involved in aqueous outflow resistance, is
      deeply modified in glaucoma patients, with a decrease in the trabecular cell
      number. Trabecular toxicity of antiglaucoma medications cannot be excluded. On a
      human cultured trabecular cell line, we investigated the potential proapoptotic
      effect of a beta-blocker with or without preservative, benzalkonium chloride
      (0.01% BAC), by flow cytometry and confocal microscopy. MATERIAL: and METHODS: A
      human immortalized trabecular cell line (HTM-5) obtained from a normal donor was
      cultured under normal conditions. Preserved 0.25% betaxolol suspension (betaxolol
      BAC +), unpreserved 0.25% betaxolol suspension, and 0.01% BAC were respectively
      added to the culture medium in a 1/10 or 1/100 dilution for 15 minutes. After a
      24-hour recovery period in normal culture conditions, cell size and the
      expression of an apoptotic marker, Apo 2.7, were evaluated by flow cytometry and
      confocal microscopy. Untreated trabecular cells were used as control cells.
      RESULTS: Preserved and unpreserved betaxolol in a 1/10 dilution induced a
      significant decrease in trabecular cell size compared to controls. However, this
      cell size decrease was less pronounced than that induced by BAC at the same
      dilution. Similar results were obtained with betaxolol and BAC in a 1/100
      dilution. Trabecular cell Apo 2.7 expression was significantly increased after
      treatment with betaxolol BAC + and BAC- in a 1/10 dilution compared to controls
      (36.8%, 28.1%, and 15.4%, respectively p<0.005). However, this proapoptotic
      activity was much less pronounced than that induced by BAC- at the same dilution
      (96.9%, p<10(-4)). Unpreserved betaxolol in a 1/100 dilution had no apoptotic
      activity on trabecular cells. Trabecular cell Apo 2.7 expression slightly
      increased with betaxolol BAC + at a 1/100 dilution (24.9%, p=0.04), while it was
      greatly increased with BAC at the same dilution (39.9%; p<10(-4)). CONCLUSION: In
      our model, unpreserved betaxolol at a low concentration displayed no proapoptotic
      activity on trabecular cells. On the other hand, preserved betaxolol displayed a
      moderate proapoptotic activity by triggering cell death of around 25% of cells.
      Trabecular cell toxicity appeared to be mainly due to the preservative
      benzalkonium chloride (BAC). Taken together, our results demonstrated that the
      strong apoptotic activity of BAC was greatly reduced within the preserved eye
      drops, probably through the interaction of BAC with the active compound.

PMID- 12471344
TI  - [Creating a specific quality-of-life questionnaire in patients with glaucoma:
      item generation].
AB  - The methods for developing Health-Related Quality-of-Life (HRQoL) measures and
      their application in medical research have demonstrated their utility in various
      chronic, progressive, or life-threatening diseases. The efforts made to allow the
      patient's perspective to be included in the methodological framework of evidence
      based medicine have been successful. The assumption of a strong relationship
      between clinical status and daily life is certainly valid in ophthalmology.
      However, there is a lack of specific HRQoL measures dedicated to ophthalmic
      diseases. Our work aimed at creating the first Glaucoma-specific Quality of Life
      scale - the Glau-QoL questionnaire - to provide researchers and physicians with a
      comprehensive, practical, and validated tool. This article describes the first
      stage of the process, which consisted in generating items and formatting them in
      order to create a questionnaire that exhaustively covers the relevant concepts.
      The whole process was conducted by an expert committee including clinicians and
      methodologists. The standard recommendations in the development of a HRQoL
      questionnaire were followed: we first identified existing tools and performed a
      preliminary collection of concepts from the published literature; we then
      designed an interview guide with the help of clinicians; a trained psychologist
      interviewed 22 patients at various disease severity stages (from isolated
      hypertonic to severely impaired); the interviews were tape-recorded and scripted;
      general domains and related detailed concepts were identified from the script;
      they were then analyzed and organized; the format of the questionnaire was set
      up; and questions were derived from the patient's verbatim to capture the
      identified detailed concepts. The test questionnaire was applied to seven
      patients for cognitive debriefing. We finally amended the test questionnaire and
      designed the pilot questionnaire according to the patients' tests and the
      clinician's review. The test questionnaire was well accepted by the patients,
      despite a completion duration ranging from 14 to 35 minutes. The pilot
      questionnaire contained 151 items, grouped into 5 sections: (1) vision problems,
      physicians, and daily treatment (49 items); (2) activities of daily living (37
      items); (3) self-expression (37 items); (4) vision problems and mood (14 items);
      and (5) other questions (14 items). The next step of our work will be the item
      reduction process and the psychometric validation of the Glau-QoL questionnaire.

PMID- 12471345
TI  - [How patients react when glaucoma is diagnosed?].
AB  - PURPOSE: Evaluate the psychological consequences of announcing the diagnosis of
      glaucoma. MATERIALS AND METHODS: Two hundred patients completed a 20-item
      questionnaire designed to analyze the context in which glaucoma was discovered
      and the patients' reaction to this diagnosis. Behavioral modification in patients
      and their families are specified as well as their perception of the information
      received. COMMENTS: Most patients had open-angle glaucoma and showed either an
      anxious or a passive reaction to the announcement of the diagnosis. Severe
      anxiety led to prescription of minor tranquilizers or antidepressants in 11% of
      cases. Nearly half of the patients declared that they had modified their behavior
      after receiving the diagnosis, indicating a need to play an active role in
      disease management. A large majority of the patients were conscious of the risk
      of blindness related to glaucoma; however, they did not feel  ill  but rather 
      handicapped . Most were dissatisfied with the information provided by their
      doctor and sought other sources of information. CONCLUSION: Announcing a
      diagnosis of glaucoma is a decisive step in the physician-patient relationship,
      known to be important in future treatment compliance. Better adapted information
      with regular reevaluation of the need for additional information is necessary.
      The psychological impact should be evaluated regularly in order to promote an
      active role on the part of the patient and avoid a decline in quality of life.

PMID- 12471346
TI  - [Orbscan: a new device for iridocorneal angle measurement].
AB  - PURPOSE: To evaluate the accuracy and reproducibility of iridocorneal angle
      measurement obtained with a slit-lamp method (Orbscan). METHODS: The iridocorneal
      angle was measured in 100 normal eyes of 50 patients using the Orbscan II device.
      Angles were measured in eight meridians using both the "plane" and "polynomial"
      modes. For each eye, two exams were taken successively and the reproducibility
      was calculated by analyzing the difference between both measurements. Angle value
      was correlated with subjective spherical equivalent and other biometric
      measurements obtained by Orbscan (i.e., anterior chamber depth, axial length,
      corneal diameter). RESULTS: Reproducibility of the angle measurement was
      significantly better with the plane mode than with the polynomial mode (5.4%+/
      4.7 versus 7.2%+/-6.2; p<0.001). Reproducibility significantly varied with
      localization (p<0.001). Significant differences were found between reconstruction
      modes (49.3 degrees +/-4.6 degrees for plane mode versus 42.8 degrees +/-6.7
      degrees for the polynomial mode; p<0.001) and according to localization (p=0.02).
      Correlation with the other biometric measurements was higher for the plane mode
      than for the polynomial mode. Angle measurement with the plane mode showed
      significant correlation with subjective spherical equivalent (r(s)=-0.59;
      p<0.001), the anterior chamber depth measurement (r(s)=-0.74; p<0.001), the axial
      length measurement (r(s)=-0.34; p<0.002), and the corneal diameter measurement
      (r(s)=-0.34; p<0.002). CONCLUSION: The iridocorneal angle measure obtained with
      the plane mode showed high reproducibility and it significantly correlated with
      clinical parameters. It appears to be useful for clinical application.

PMID- 12471347
TI  - [The vision of welders in France].
AB  - PURPOSE: A study was conducted to measure the impact of welding on the vision of
      welders. METHODOLOGY: This study was conducted in France by the occupational
      medicine staff of large companies on 1.131 people, namely 850 welders and 281
      control subjects. This investigation included two examinations at the beginning
      and the end of a year. The investigative procedure examined the different welding
      processes, the percentage of working time spent on welding activity, the length
      of exposure in years, as well as the medical variables: the optical correction
      type and history of ocular traumatology. The Visiotest or the Ergovision were
      used for the visual examination, equipment in common use by occupational medicine
      departments. RESULTS: The welders were comparatively young (59.53% of them were
      less than 45 years old). Moreover, for 69.75% of the welders, more than 75% of
      their activity was devoted to welding. All currently used welding processes were
      represented, including the modern PLASMA-TIG welding process. No excessive blood
      alcohol levels were observed in all subjects, but welders did smoke slightly more
      than the control subjects (40% vs 33%). Self-medication was rather less frequent
      among the welders, except as regards the use of eye drops, where the proportions
      were clearly inverted. Optical correction for hyperopia was similar between the
      two groups; however, as regards myopia, the welders were corrected less often.
      Lastly, contact lens use was exceptional among the welders. Nearsightedness
      varied logically with age, but also, inexplicably, with the welding processes.
      Vision recovery time after exposure to glare was much longer among the welders,
      except for the PLASMA-TIG processes. No difference was observed in the other
      parameters of the study. No change in the visual functions studied was noted
      between the two examinations. DISCUSSION: The examination techniques used showed
      no impairment of the studied visual functions, probably because companies use
      protective and preventive eye care methods. Moreover this study is the first to
      examine the type of welding used by workers and particularly the modern PLASMA
      TIG process. The vision recovery time after exposure to glare seems better for
      the PLASMA-TIG process may be the result of the lower luminous intensity of this
      process. CONCLUSION: This study was conducted for preventive purposes to
      contribute to better monitoring of safety and comfort for welding workers and has
      shown no alteration of the visual function among welders in general.

PMID- 12471348
TI  - [Bilateral peripheral retinal neovascularization in a patient with multiple
      sclerosis].
AB  - We present the case of a 32-year-old man suffering from multiple sclerosis who
      had developed bilateral peripheral neovascularization of the retina. The main
      disease had been diagnosed 10 years before, whereas in his ophthalmic history the
      patient reported an incident of retrobulbar optic neuritis in his left eye
      occurring 3 years before. The patient was referred to our clinic in order to
      investigate the cause of a sudden loss of vision in his left eye. Ophthalmic
      examination and fluorescein angiography revealed the presence of a bilateral
      peripheral retinal neovascularization with an intravitreous hemorrhage in the
      left eye. Systemic clinical and laboratory investigation were negative for other
      causes of retinal neovascularization except multiple sclerosis, which is
      associated with periphlebitis in 10% of cases. Chronic retinal ischemia may lead
      to retinal neovascularization.

PMID- 12471349
TI  - [Inferior branch retinal artery occlusion in a young adult revealing rheumatismal
      valvular disease].
AB  - INTRODUCTION: Inferior branch retinal artery occlusion is uncommon in young
      adults. Through a case report and data from the literature, we describe the
      clinical, fluorescein angiography, and progressive details of this disease. CASE
      REPORT: A 26-year-old man suddenly presented superior scotoma in the left eye. He
      underwent a full ophthalmologic examination, which showed visual acuity limited
      to 5/10 P4 and ischemia of the inferior retina at the fundus exam. Fluorescein
      angiography of the left eye revealed delayed filling of the inferior branch
      retinal artery. The ophthalmologic exam of the right eye was normal. RESULTS: The
      search for an etiologic explanation revealed double rheumatismal mitral and
      aortic valvular disease, which was referred to and treated in appropriate
      department. The condition has progressed slowly but favorably over 2 months, with
      visual acuity reaching 6/10 P3. DISCUSSION: Branch retinal artery occlusion
      commonly occurs in older adults. When it happens to the young adult, it may be
      dangerous and often reveals cardiac embolic disease, particularly rheumatismal
      valvular disease. CONCLUSION: Branch retinal artery occlusion in the young adult
      remains a rare and dangerous disease where the prognosis depends on the degree of
      artery repermeabilization and on the etiology of the thromboembolic disease.

PMID- 12471350
TI  - [Isolated palpebral tumor revealing Von Recklinghausen's neurofibromatosis: a
      case report].
AB  - INTRODUCTION: Von Recklinghausen's neurofibromatosis is the most frequent of
      phakomatoses. Its incidence is 1/2,500-3,000 births. It is inherited through a
      dominant autosomal mode with a strong prevalence and changing expression. Eye and
      skin signs are essential to diagnosis and this case provided a noteworthy example
      of a unilateral upper palpebral tumor revealing this disease. CLINICAL CASE: We
      report a case of a 6-year-old boy whose original clinical manifestation was a
      tumor on the upper eyelid of the right eye, present at birth. According to the
      anamnesis, this palpebral tumor gradually increased in size, causing a full
      ptosis. A biopsy exeresis of the tumor was carried out with an
      anatomicopathological study of the biopsy specimen, confirming the diagnosis.
      CONCLUSION: The anatomicopathological study of the biopsy specimen enabled
      diagnosis of a neurofibromatosis revealed by this isolated palpebral localization
      responsible for significant aesthetic and functional damage.

PMID- 12471351
TI  - [Retinal vein occlusion and carotid Doppler imaging].
AB  - PURPOSE: To investigate retinal vein occlusion with B-mode ultrasonography
      carotid and color Doppler imaging. METHODS: In 223 patients (225 eyes) presenting
      with retinal vein occlusion, we retrospectively investigated vascular risk
      factors (hypertension, diabetes, hyperlipidemia, cardiovascular history, smoking,
      and glaucoma), standard laboratory tests, and color Doppler imaging of the
      carotid artery. RESULTS: The data from 106 women (47.54%) and 117 men (52.46%),
      with a mean age of 65 years, were studied, with 169 patients presenting a central
      retinal vein occlusion (CRVO) and 56 a branch retinal vein occlusion (BRVO).
      Thirteen patients (6%) had significant carotid artery stenosis (>=70%), which was
      the single etiology. Forty patients (18%) had nonsignificant carotid artery
      stenosis (<70%) with a risk of embolism production. Such carotid artery lesions
      found in color Doppler imaging in the RVO investigations were significantly more
      frequent in older patients (>65 years) who presented at least two RVO risk
      factors (p<0.001). CONCLUSION: This study has shown the the advantages of carotid
      Doppler imaging in retinal vein occlusion.

PMID- 12471352
TI  - [Sarcoid granuloma simulating amelanotic melanoma of the iris: a case report].
AB  - We report the case of a unilateral vascular iris tumor in a 24-year-old patient.
      Clinically, the iris lesion appeared similar to amelanotic melanoma. A systemic
      work-up (initial check-up), including an angiotensin-converting enzyme
      determination, provided the diagnosis of sarcoid granuloma. A biopsy confirmation
      was not needed. We concluded that iris granuloma can be the only ocular
      manifestation of sarcoidosis and this context is likely to be confused with
      amelanotic melanoma and metastatic carcinoma.

PMID- 12471353
TI  - [Bilateral papilledema in young women: two case reports of benign intracranial
      hypertension?].
AB  - We report two cases of bilateral papilledema in young women. The first patient
      was 15 years old and had experienced headaches and vomiting for one month, but no
      visual loss. Cerebral tomodensitometry results were normal, but lumbar puncture
      showed increased pressure and normal biology. Benign intracranial hypertension
      was diagnosed. Recent treatment with minocycline for acne vulgaris was the only
      etiology. Papilledema was totally regressed at 6 weeks, after interruption of the
      antibiotic treatment. A prescription of acetazolamide was added for a short
      period of 10 days. The second patient, aged 29 years, presented bilateral
      papilledema with severe visual loss, with vision limited to light perception with
      mydriasis of the right eye. Lumbar puncture was not indicated because of a
      hypophyseal microadenoma revealed on MRI investigation. No other associated
      abnormalities were observed, in particular, no cerebral sinus thrombosis.
      Corticotherapy using prednisolone for 72 hours had no clinical effect. Fast
      visual recovery was obtained with intravenous acetazolamide therapy and was
      completely resolved at 2 months. Right visual field defects persisted.
      Minocycline and obesity are recognized as precipitating factors in pseudotumor
      cerebri syndrome. The literature advocates consideration of surgical treatment by
      optic nerve sheath fenestration if antiedematous treatment has no effect and the
      eye is nearly blind.

PMID- 12471354
TI  - [Uncomplicated orbital varix: a difficult therapeutic problem].
AB  - The authors describe a case of right orbital varix discovered in a 34-year-old
      female. She was referred by her ophthalmologist because she was experiencing a
      functional disorder with esthetic consequences. With physical effort, she had
      intermittent exophthalmia and moderate diplopia. The symptoms disappeared with
      rest. The diagnosis was made by NMR examination before and after the Vasalva
      maneuver. Because of the patient's excellent visual acuity, we did not propose a
      therapeutic solution.

PMID- 12471356
TI  - [Selection and training in Canadian ophthalmology residency. A concept to be
      meditated?].
AB  - The authors describe in detail the modalities for the selection of students
      applying to the ophthalmology programs in the various Canadian universities; the
      university of Montreal will serve as a model. The characteristics of their 5-year
      training assured by numerous teachers and short training rotations as well as by
      a compulsory research project are explained. They highlight the meticulous
      organization and the compulsory constraints for students, teachers and
      universities. In absence of evaluation criteria on the efficiency of
      interventionist training compared to less detailed apprenticeship-program
      training such as that dispensed in France, they note the differences between the
      two systems, a necessary precursor to the standardization of training programs
      which would allow more complete recognition of degrees in the context of a
      globalization of professional activities.

PMID- 12471355
TI  - [Current place of laser in the management of glaucomas].
AB  - With laser iridotomy, argon laser trabeculoplasties, cyclophotocoagulations with
      diode laser and Nd: YAG goniopunctures after deep sclerectomy, among other
      procedures, the laser has offered a very wide range of treatments for managing
      glaucomatous patients for roughly twenty years. In this paper we provide a
      general review of the present applications of lasers in the treatment of
      glaucoma, focusing on the indications, results and complications of the most
      frequently used procedures in daily clinical practice.

PMID- 12471357
TI  - [Breast cancer metastases].

PMID- 12471358
TI  - [Bilateral keratoconus: a case report].
AB  - Among corneal dystrophies, the keratoconus is one of the most frequently observed
      among young adults. A clinico pathological case is reported in a 13-year-old-girl
      of African origin. The diagnosis of bilateral keratoconus was established based
      on the obvious changes of the corneal curvature and thickness. After an
      unsuccessful attempt to improve vision with contact lenses, a keratoplasty was
      finally performed on one side to remove the pathological cornea. Its
      histopathological study found the characteristic changes of keratoconus: breaks
      of Bowman's layer and corneal thinning.

PMID- 12471359
TI  - [The use of color vision].

PMID- 12471360
TI  - Digital cineradiographic swallow study: our experience.
AB  - PURPOSE: Swallowing disorders can be secondary to different types of diseases in
      which, at least initially, patients succeed in establishing voluntary or
      involuntary compensatory mechanisms that enable them to maintain a sufficient
      nutritional state. When the compensatory mechanisms become insufficient massive
      food aspiration into the airways can occur and suffocation may prove to be the
      main pathology. It has been calculated that in the USA about 8,000-10,000 people
      die each year due to suffocation. The dynamic radiological examination of
      swallowing is considered important not only for diagnosis, but also for planning
      a rehabilitation therapy and type of nutrition for the patient and for verifying
      the results of the therapy. The aim of this study is to analyse the results of
      our experience in the use of the digital cineradiography system to evaluate
      patients with normal and pathological swallowing. MATERIALS AND METHODS: We
      reviewed the digital cineradiography of 220 patients that at no time had
      undergone surgery and presented no organic pharyngeal or oesophageal disease
      (excluding hiatus hernia). All the exams followed a standard protocol that
      included the dynamic evaluation of the larynx, soft palate, pharynx, and gastro
      oesophageal junction with a cineradiographic sequence of 12 frames/second with a
      512x1024 matrix. There was also an archive of the film in a post-processing
      console. The patients received single photograms (printed on laserfilm),
      videotape recordings or CD-ROM of the dynamic exam. RESULTS: 137 (62%) of the
      patients did not present swallowing alterations although only 7 patients had a
      negative examination. In 35 cases hiatus hernia was appreciable while in 69 cases
      the hernia was associated with gastro-oesophageal reflux. In 23 cases aspecific
      functional disorders of the oesophagus were demonstrated and in 3 cases
      achalasia. The remaining 83 patients (38%) (37 males and 46 females, average age
      57.02 yrs) presented alterations of the oral and/or pharyngeal stages of
      swallowing: reduction in soft-palate motility (2 cases), unilateral paralysis of
      the vocal chords (1 case), incontinence of the bolus during the oral stage (8
      cases), lingual movement anomalies (4 cases), subepiglottic penetration (62
      cases), asymmetric epiglottic tilt, aspiration of the contrast medium in the
      airway (17 cases), reduction of laryngeal and hyoid bone movement (9 cases),
      bolus retained in the valleculae and pyriform sinus (13 cases), cricopharyngeal
      spasm (6 cases), pharyngeal paralysis (1 case); hiatus hernia was also evident in
      20 cases and gastro-oesophageal reflux was associated in 13 of them. Overall, 36%
      of the cases presented an isolated form while 64% of the cases presented a
      complex dysfunction with several simultaneous alterations. DISCUSSION AND
      CONCLUSIONS: The videofluorographic swallow study is an important step in the
      diagnostic evaluation of a dysphagic patient not only as regards the analysis of
      the main alteration and its capacity to confirm the presence or absence of
      contrast medium aspiration in the airway, but also because it provides important
      information on rehabilitation and nutritional orientation (oral/no oral), as well
      as on the results of the therapy. The recent diffusion of the digital X-ray
      equipment has made possible its use for the study of the organic and functional
      diseases of the upper alimentary tract. Currently a standard protocol for the
      study of swallowing with digital fluorography is not available. The technique we
      applied, already verified in a significant number of dysphagic patients, has
      allowed us to distinguish patients with normal swallowing from those with
      disorders of the oral and pharyngeal stage, and thus to identify disturbance and
      establish an appropriate rehabilitation treatment.

PMID- 12471361
TI  - Isolated hydatid disease of the spleen: CT findings in 4 patients and
      differential diagnosis.
AB  - AIM: To report our experience with four cases of isolated hydatid disease of the
      spleen studied by spiral Computed Tomography (CT) and to review the literature
      with special attention to the differential diagnosis with other focal lesions of
      the spleen. MATERIALS AND METHODS: The spiral CT images and clinical records of
      four patients (1 man, 3 women; age range 26-45 yrs) affected by isolated hydatid
      disease of the spleen were retrospectively evaluated. None of the patients had a
      history of hydatid disease. All the patients were evaluated by plain and enhanced
      spiral CT of the abdomen. All patients underwent preoperative chest X-ray and
      surgery; all surgical specimens were studied by histology. RESULTS: Spiral CT
      depicted all the hydatid lesions of the spleen. It showed the location, size, low
      density of their content without enhancement after iv contrast medium injection,
      the possible presence of daughter cysts, the appearance of the wall with
      calcifications, and excluded the presence of complications. The preoperative
      chest X-ray was negative for focal pulmonary lesions in all cases. Pathology
      confirmed the diagnosis of hydatid disease in all cases. CONCLUSIONS: According
      to our results and to the literature, spiral CT plays an important role in the
      pre-surgical evaluation of patients with hydatid disease of the spleen, and
      provides useful information for differentiating the disease from other isolated
      cyst-like lesions of the spleen.

PMID- 12471362
TI  - Soft tissue liposarcoma: histological subtypes, MRI and CT findings.
AB  - PURPOSE: Liposarcoma is the second most common malignancy of soft tissues. The
      commonly accepted classification of liposarcoma includes five basic histological
      categories: well-differentiated, myxoid, round cell, dedifferentiated and
      pleomorphic liposarcoma. The clinical behaviour of liposarcoma closely reflects
      its histological appearance, so that to identify the histological subtypes is
      very important for both prognosis and therapy. The aim of this study was to
      ascertain whether the histological features of liposarcoma subtypes can be
      correlated with MRI (Magnetic Resonance Imaging) and CT (Computed Tomography)
      findings by retrospectively evaluating nineteen cases of histologically-proved
      liposarcoma. MATERIALS AND METHODS: The MRI examinations performed over the past
      eight years on nineteen patients affected by liposarcoma were retrospectively
      reviewed. All patients underwent ultrasound and MRI examination; T2 and T1
      weighted sequences were available in all cases and fat-saturated sequences in 4
      cases; all patients were administered paramagnetic contrast material. CT scans
      were obtained in twelve patients. All patients had a biopsy, surgical resection
      and histology. RESULTS: The study group had 7 well-differentiated, 8 myxoid, 3
      pleomorphic and 1 round cell liposarcoma. Well-differentiated liposarcomas had
      largely lipomatous appearance on both CT and MRI, typically with septa and areas
      showing high signal intensity on T2w MR images and low signal intensity on T1w
      images, and slightly hypodense compared to the muscle in CT, representing the
      sarcomatous areas. Myxoid liposarcomas were mildly heterogeneous with typical
      high signal intensity on T2w images and isointense to the muscle in T1w images,
      with lacy or linear septa of fatty tissue in six cases. The pleomorphic and round
      cell subtypes demonstrated marked heterogeneity on MR images, with areas of
      necrosis and heterogeneous contrast enhancement, indistinguishable from other
      high-grade sarcomas. DISCUSSION AND CONCLUSIONS: Well-differentiated liposarcoma
      may be distinguished from other types of liposarcoma by its largely lipomatous
      appearance. Myxoid liposarcoma may be distinguished on the basis of its
      homogeneous or mildly heterogeneous structure due to the large amounts of the
      extracellular myxoid material that give it its typical MR appearance. Both well
      differentiated and myxoid liposarcomas, the most common types accounting for
      about 50% of all liposarcomas, have a more favourable clinical behaviour than the
      other histological types. Differentiation of these from the other histological
      types of liposarcoma therefore has a high significance for prognosis and
      therapeutical approach. On the basis of our experience and of the literature, we
      believe that diagnostic imaging and in particular the MR examination may lead to
      a correct diagnosis.

PMID- 12471363
TI  - Pitfalls and limitations of Magnetic Resonance Imaging in bucket-handle tears of
      knee menisci.
AB  - PURPOSE: The aim of the present study was to assess the accuracy of magnetic
      resonance imaging (MRI) in the diagnosis of bucket-handle tears of the knee
      menisci, determining the sensitivity and specificity of the imaging for each of
      the signs typical of these tears. MATERIALS AND METHODS: MR examinations of 495
      patients suffering from knee traumas were assessed retrospectively. Forty-eight
      patients had arthroscopically-proven bucket-handle tears of the meniscus. MR
      examinations were performed using a 0.5-T superconducting magnet, with T1
      weighted spin-echo (SE) and gradient-echo (GE) T2*-weighted sequences. Imaging
      findings used for the diagnosis were: a) double posterior cruciate ligament sign;
      b) flipped meniscus sign; c) presence of a displaced fragment of the meniscus in
      the intercondylar notch, visible in coronal and axial images; d) truncated
      triangular shape of the peripheral non-displaced portion of the meniscus, visible
      in coronal images. RESULTS: A total of 43 out of 48 bucket-handle tears of the
      meniscus were correctly diagnosed at MR, thus overall MR accuracy was 98%. In 12
      (28%) cases three signs were present simultaneously the double posterior cruciate
      ligament (sensitivity 28%, specificity 99%, accuracy 93%) + the displaced
      fragment in the intercondylar notch (sensitivity 69.8%, specificity 98.7%,
      accuracy 96.2%) + the truncated triangular shape of the peripheral portion of the
      meniscus (sensitivity 74.4%, specificity 98%, accuracy 96%). In 18 (42%) cases
      two signs were present together the displaced fragment of the meniscus + the
      truncated triangular shape of the peripheral portion of the meniscus. In 13 (30%)
      cases only one sign was presenting two cases the truncated triangular shape of
      the peripheral portion of the meniscus and in 11 cases the flipped meniscus sign
      (sensitivity 25.6%, specificity 93.4%, accuracy 87.5%). No statistically
      significant differences were found comparing the results for tears of the medial
      meniscus with those for the lateral meniscus. CONCLUSIONS: MR imaging is highly
      accurate in diagnosing bucket-handle tears of the menisci due to its ability to
      identify a displaced fragment of the meniscus in the intercondylar notch or
      flipped over the anterior horn of the meniscus of origin. We speculate that
      bucket-handle tears not found by MR imaging are cases where the meniscus was
      displaced after MR examination.

PMID- 12471364
TI  - Rotational angiography of the carotid artery bifurcation: technical aspects and
      preliminary results.
AB  - PURPOSE: Rotational Angiography (RA), a new modality for performing conventional
      catheter angiography, enables an accurate evaluation of the artery to be obtained
      from different points of view by means of the contemporary rotation of the X-ray
      tube and image intensifier during intrarterial selective injection of contrast
      media. This paper describes the examination technique and compares the diagnostic
      accuracy of the RA oblique projections with the data obtained in the antero
      posterior (AP) and latero-lateral (LL) projections in the study of the carotid
      bifurcation. MATERIALS AND METHODS: Thirty patients underwent RA of the supra
      aortic vessels to evaluate the degree of a stenosis at the carotid bifurcation
      suspected at color Doppler imaging. The angiographic examinations were performed
      on a Philips Integris Allura system able to rotate the arc at a speed of 55
      degrees /s with selective catheterisation of both common carotid arteries.
      RESULTS: The frame showing the greatest degree of stenosis was compared with the
      frames obtained in the AP and LL projections. 57/60 carotid bifurcations were
      assessable (3 cases of internal carotid arteries were obstructed). The degree of
      stenosis evaluated on the most significant of the oblique projections was
      superior to that shown in the AP and LL projections for 16/30 cases on the right
      side and for 14/27 cases on the left side. In 4/57 cases (7%) the degree of
      stenosis was modified from less than 70% to more than 70%. No adverse event was
      observed due to catheterisation. CONCLUSIONS: RA enables the complete three
      dimensional evaluation of the carotid bifurcation, and generally yields more
      accurate information on the degree of the stenosis in comparison with AP and LL
      technique. The study was successfully carried out in all cases, however slightly
      longer examination times due to the setup requirements of the system. This was
      largely compensated by the quality of the information yielded, which required no
      additional projections to be performed. Moreover, the high frame rate of 25
      frames per second showed the haemodynamic flow through the lesion.

PMID- 12471365
TI  - Computed Tomography of dental arches with dedicated software: current state of
      applications.
AB  - Since the introduction of the "Dentascan" reconstruction program, the use of CT
      in the field of odontostomatology has attracted growing interest from both
      radiologists and dentists. Over the years, the potential applications of
      Dentascan have extended from the management of implantology-related issues to the
      study of all jaw bone diseases relevant to dentists. This paper describes the
      technical aspects and current diagnostic capabilities of computed tomography of
      the dental arches with dedicated software, by presenting a wide selection of case
      studies.

PMID- 12471366
TI  - The websites of the Societa Italiana di Radiologia Medica: one year of activity.

PMID- 12471367
TI  - Wired and wireless network solution for the integrated management of data and
      images.
AB  - PURPOSE: This paper reports on the authors' experience with the implementation of
      an internal network with open structure model (extranet) inside a private
      healthcare institution. MATERIALS AND METHODS: An integrated clinical
      administrative internal network was set up within a private orthopaedic hospital
      with about 90 beds. The system consists of a DICOM-based HIS-RIS network
      connected to the radiological department PACS, and is implemented through an
      internal web-server over a mixed wired-wireless network. The strengths of the
      system are: the use of an open-structure model allowing external access; the
      inclusion of a wireless component of the network, which extends access to mobile
      workstations; the possibility of conducting the quality assurance procedures
      directly from outside the hospital. RESULTS: The system allows the diagnostic
      images generated by the various equipment (Rx, CT, NMR, etc.) to be filed in
      compliance with the AIPA (Italian Authority for Information Technology in Public
      Administration) regulations; the images and electronic clinical records are made
      available to the departments by means of an internal web server. The use of the
      wireless component of the network has several additional advantages: for example,
      it enables healthcare personnel to view clinical records and diagnostic images on
      their laptop monitors from any department or hospital room, and it makes every
      change or addition readily available to the healthcare personnel. In this way the
      laptops represent an evolution of the traditional paper-based clinical record.
      Moreover, a direct connection was set up with the University Department of Image
      Processing with a view to increasing the hospital's efficiency and productivity.
      This connection allows adequate quality assurance procedures to be carried out on
      the radiological department equipment without requiring the physical presence of
      specialised staff, and therefore reducing costs and machine idle time. A second
      phase of the project is currently being tested. This consists in the
      collaboration of a pilot group of twenty family doctors to test system
      functionality during telebooking, teleconsulting and information exchange with
      specialists, as well as the possibility of keeping track of the patients'
      diagnostic work-up and clinical therapy. DISCUSSION AND CONCLUSIONS: In the
      context of the Italian healthcare system, the creation of adequate hospital
      information systems (HIS) and their integration with PACS was at first a
      prerogative of a few large hospitals. Recently, however, more and more patients
      have started to approach the healthcare world directly through the Internet, at
      first to request only information (leading to the diffusion of specialised web
      sites, or portals) and later also e-services. This new demand led us to create a
      Hospital Information System able to organise the internal activity of the
      hospital and offer several external services such as telebooking and
      teleconsulting, and therefore increase the hospital's efficiency and
      productivity. a method of choice for following patients after interventional
      procedures or as a mass-screening tool to select patients to be referred for
      coronary angiography.

PMID- 12471368
TI  - A computer science approach to managing security in health care.
AB  - The security of electronic medical information is very important for health care
      organisations, which have to ensure confidentiality, integrity and availability
      of the information provided. This paper will briefly outline the legal measures
      adopted by the European Community, Italy and the United States to regulate the
      use and disclosure of medical records. It will then go on to highlight how
      information technology can help to address these issues with special reference to
      the management of organisation policies. To this end, we will present a modelling
      example for the security policy of a radiological department.

PMID- 12471369
TI  - Census of radiological machines in Radiodiagnostic Services of public and
      recognized hospitals in the Campania Region.
AB  - AIM: The present study provides a census of equipment in use by Radiodiagnostic
      Services in public hospitals and institutes recognized by the Region of Campania
      in the year 2000. The type, date of installation and distribution of the
      equipment were considered in relation to the number of hospital beds and the
      resident population. MATERIALS AND METHODS: A census was taken of all the public
      hospitals and institutes recognized by the Region of Campania in the period
      running from January 1999 to April 2000. Data were collected using an appropriate
      form asking for details of the number of machines and the model, manufacturer and
      year of installation, under six categories: traditional radiology, mammography,
      US, CT, MR and angiography. The data were analyzed by provinces, combining the
      different machines into five-year periods depending on the date of their
      installation. RESULTS: Traditional radiology equipment accounts for 71% of the
      total. The mean for the Region stands at 23 machines per 1000 beds. The mean date
      of installation was 1986. Mammography machines account for 8% of the total. The
      mean for the Region stands at 2.6 machines per 1000 beds. The mean date of
      installation was 1991. Echography machines account for 10.3% of the total. The
      mean for the Region stands at 3.4 machines per 1000 beds. The mean date of
      installation was 1992. Angiography machines account for 3.2% of the total. The
      mean for the Region stands at 1.1 machines per 1000 beds. The mean date of
      installation was 1985. CTs account for 6.4% of the total. The mean for the Region
      stands at 2.1 machines per 1000 beds. The mean date of installation was 1993. MR
      account for 1.1% of the total. The mean for the Region stands at 0.4 machines per
      1000 beds. The mean date of installation was 1995. CONCLUSIONS: Technological and
      scientific improvements and growing attention to the quality of medical care
      expected by patients mean that constant modification and adaptation are needed to
      meet demands. In planning measures designed to provide new radiological equipment
      and modernize existing equipment in the Region it would certainly be useful to
      eliminate the unevenness of the services provided. In conclusion, it is crucial
      that the local administrations and health authorities in the Campania Region
      establish a regular census, with proper assessment of the obsolescence of
      radiological equipment and its distribution throughout the area, in order to
      comply with international standards.

PMID- 12471370
TI  - Eosinophilic bone granuloma in an adult patient.

PMID- 12471371
TI  - Bulky fibroma of the heart. MR imaging findings in a young woman.

PMID- 12471372
TI  - Pseudoaneurism of the left internal maxillary artery following mandibular condyl
      fracture: diagnosis by color Doppler ultrasonography. A case report.

PMID- 12471373
TI  - Spontaneous rupture of the thoracic vertebral artery. A case report.

PMID- 12471374
TI  - Treatment of a splenic aneurysm by percutaneous arterial embolisation using
      volumetric controlled-release coils. Case report and review of the literature.

PMID- 12471375
TI  - Aorto-enteric fistula after percutaneous treatment of abdominal aortic aneurysm:
      a case report.

PMID- 12471376
TI  - Unconventional tethering of Ulp1 to the transport channel of the nuclear pore
      complex by karyopherins.
AB  - The ubiquitin-like protein SUMO-1 (small ubiquitin-related modifier 1) is
      covalently attached to substrate proteins by ligases and cleaved by
      isopeptidases. Yeast has two SUMO-1-deconjugating enzymes, Ulp1 and Ulp2, which
      are located at nuclear pores and in the nucleoplasm, respectively. Here we show
      that the catalytic C-domain of Ulp1 must be excluded from the nucleoplasm for
      cell viability. This is achieved by the noncatalytic N-domain, which tethers Ulp1
      to the nuclear pores. The bulk of cellular Ulp1 is not associated with
      nucleoporins but instead associates with three karyopherins (Pse1, Kap95 and
      Kap60), in a complex that is not dissociated by RanGTP in vitro. The Ulp1 N
      domain has two distinct binding sites for Pse1 and Kap95/Kap60, both of which are
      required for anchoring to the nuclear pore complex. We propose that Ulp1 is
      tethered to the nuclear pores by a Ran-insensitive interaction with karyopherins
      associated with nucleoporins. This location could allow Ulp1 to remove SUMO-1
      from sumoylated cargo proteins during their passage through the nuclear pore
      channel.

PMID- 12471377
TI  - [Public health, genetics and ethics].
AB  - Genetics research has shown enormous developments in recent decades, although as
      yet with only limited clinical application. Bioethical analysis has been unable
      to deal with the vast problems of genetics because emphasis has been put on the
      principlism applied to both clinical and research bioethics. Genetics
      nevertheless poses its most complex moral dilemmas at the public level, where a
      social brand of ethics ought to supersede the essentially interpersonal
      perspective of principlism. A more social understanding of ethics in genetics is
      required to unravel issues such as research and clinical explorations, ownership
      and patents, genetic manipulation, and allocation of resources. All these issues
      require reflection based on the requirements of citizenry, consideration of
      common assets, and definition of public policies in regulating genetic endeavors
      and protecting the society as a whole Bioethics has privileged the approach to
      individual ethical issues derived from genetic intervention, thereby neglecting
      the more salient aspects of genetics and social ethics.

PMID- 12471378
TI  - [Prevalence of associated microorganisms in genital discharge, Argentina].
AB  - OBJECTIVE: There was a significant increase in the number of women demanding
      gynecological care in public hospital of the Great Buenos Aires, Argentina,
      between 1997 and 1998. It was necessary to update the prevalence of associated
      microorganisms in order to review the laboratory support and adjust prevention
      and control guidelines. METHODS: Samples from vaginal and endocervical discharge,
      from total cases: 84 adolescents (15 to 19 years) and 784 adults (20-60 years)
      attended in 1997-1998, were studied. Neisseria gonorrhoeae, Streptococcus
      agalactiae, Trichomonas vaginalis, Candida spp, and bacterial vaginosis, were
      diagnosed applying direct detection methods and specific culture isolation.
      Chlamydia trachomatis (antigen detection), Ureaplasma urealyticum and Mycoplasma
      hominis (culture) were also studied in part of the population. RESULTS: Patient
      care increased steadily from 1997 and there was an increase of 2.1 times from the
      first semester to the last one in 1998. Bacterial vaginosis was the most
      prevalent disease in the adult group, with 23.8%; followed by Candida spp 17.8%;
      S. agalactiae 5.6%; T.vaginalis 2.4%. In 50.3% of total adult cases neither
      bacterial vaginosis or presence of any sought microorganisms, was detected. In
      the adolescents group the most frequent detection was Candida spp with a 29.7%;
      bacterial vaginosis in 17.8%; followed by S. agalactiae 3.6%, T.vaginalis 2.4%.
      Also in this group on an important number of cases, 46.4%, none bacterial
      vaginosis or the presence of the sought microorganism were found. In some of the
      adult group, C. trachomatis (7/400) 1.76%, U. urealyticum (209/340) 61.4% and M.
      hominis (45/272) 16.5% were detected. CONCLUSIONS: Bacterial vaginosis and
      Candida spp prevalence is important in both groups. The absence of N. gonorrhoeae
      and lower prevalence of T. vaginalis and C. trachomatis is remarkable. A high
      prevalence of U. urealyticum and M. hominis were also detected, but the actual
      pathogenic role in adult women is still under discussion. The significant
      increase of attendance in the public system is due to social changes in the
      population and not due to changes in any particular pathology. Laboratory support
      has to be adjusted to the most cost-effective procedures to solve the most
      prevalent problems.

PMID- 12471379
TI  - [Trends in antimicrobial utilization in a university hospital, 1990-1996].
AB  - OBJECTIVE: There is a worldwide concern about rational drug use, more
      specifically related to antimicrobial utilization. In developing countries, few
      resources are intended for monitoring on rational drug use. Moreover, there are
      limited data on the use of antimicrobial agents in hospitals. A study was carried
      out to describe patterns of use of antimicrobial agents over a 7-year period
      (1990 to 1996). METHODS: The study was conducted in a 690-bed tertiary care
      university hospital in Porto Alegre, Brazil. Hospital records were reviewed to
      identify inpatient antibiotics use. Results were expressed in defined daily dose
      per 100-beds/day. Cluster analysis was performed to determine the trends in use
      of individual agents. RESULTS: Antimicrobials use increased year after year, from
      83.8 DDD per 100 beds-day in 1990 to 124.58 DDD per 100 beds-day in 1996.
      Penicillins were the drug group mostly used (39.6%), followed by cephalosporins
      (15.0%), aminoglycosides (14.4%), sulfonamides (12.8%), glycopeptides (3.6%), and
      lincosamides (3.1%). These groups were responsible for around 90% of all agents
      used. The use of antimicrobial agents was divided into thirteen groups based on
      cluster analysis. CONCLUSIONS: Antimicrobial use increased dramatically in the
      study period, and this increase was significantly higher when compared to other
      studies. When newer alternative agents became available in the hospital, the use
      of already existing drugs decreased and in some cases remained relatively stable.
      After implementing specific interventions, such as an effort for the correct use
      of cefoxitin, the expected changes in use were observed.

PMID- 12471380
TI  - [Geoprocessing and health promotion: social and environmental inequalities,
      Brazil].
AB  - OBJECTIVE: To characterize social inequalities that represent risk conditions for
      respiratory tract diseases in children and to describe geoprocessing techniques
      to identify homogeneous social groups and intervention actions for health
      promotion. METHODS: The study area comprised the surroundings of a health school
      center in the city of S o Paulo. Based on 1991 census, housing data on 49 census
      units in the study area were statistically analyzed and it was obtained the mean
      of characteristic social and environment variables in these units. Together with
      local representatives, variables were selected that made up composite indicators
      related to social insertion and housing quality to allow identifying different
      conditions of potential exposure to respiratory tract diseases. Using
      geoprocessing techniques, four homogeneous groups were identified in terms of
      potential exposure to risk conditions for respiratory diseases. RESULTS: It was
      obtained a spatial configuration of the groups reflecting different needs in the
      study area. The methodological instruments used revealed to be important for the
      development of local actions to be implemented in services that operate in
      specific geographical areas. CONCLUSIONS: The study contributed to the
      identification of risk conditions in the health center area, making it possible
      the joint and inter-sector discussion of conditions related to respiratory tract
      diseases in children, aiming at promoting equity and improving child health.

PMID- 12471381
TI  - [Effect of environmental stress on blood pressure during the work shift].
AB  - OBJECTIVE: To evaluate blood pressure (BP) and heart rate (HR) behavior in
      individuals during the working journey in two environments with different work
      stressors. METHODS: The study comprised 46 male individuals working in a wood
      processing factory in Botucatu, Brazil. Twenty seven (27.4+/-5.4 yrs, mean+/-SD)
      worked in the production line performing intense physical activity (G1) at high
      room temperatures and noise levels. Nineteen (33.2+/-7.6 yrs old) performed
      managerial tasks mostly comfortably seated at low noise, air-conditioned offices
      (G2). After anthropometric measurements (obesity, total and local adiposity) and
      blood biochemistry analyses (glucose, triglycerides and cholesterol), their BP
      and HR were registered during three consecutive days at 3 different time of the
      day: in the beginning, in the middle and at the end of the working journey.
      RESULTS: There were similar BP and HR changes during the journey for G1 and G2,
      but G1 showed higher rates. Due to the wide variability of BP responses within
      each group, participants were divided in two subgroups: responders (GR1 and GR2)
      with BP increase >10%, and non-responders (GN1 and GN2). Both subgroups showed
      similar anthropometric and biochemical patterns differing only in their BP
      response and, in the case of GR1,family history for hypertension. GR1 showed
      higher BP and HR than GR2. CONCLUSIONS: Individual changes of BP and HR responses
      to environmental stressors during the working journey indicates that these
      factors should be considered while evaluating BP measurements and might be
      considered as potential factors for hypertension.

PMID- 12471382
TI  - [Occupational accidents in an oil refinery in Brazil].
AB  - OBJECTIVE: Work in oil refineries involves the risk of minor to major accidents.
      National data show the impact of accidents on this industry. A study was carried
      out to describe accident profile and evaluate the adequacy of accident reporting
      system. METHODS: Data on all accidents reported in an oil refinery in the state
      of Rio de Janeiro for the year 1997 were organized and analyzed. The study
      population consisted of 153 injury cases, 83 hired and 69 contracted workers. The
      variables were: type of accident, operation mode and position of the worker
      injured. RESULTS: Among hired workers, minor accidents predominated (54.2%) and
      they occurred during regular operation activities (62.9%). Among contracted
      workers, there also predominated minor accidents (75.5%) in a higher percentage,
      but they occurred mainly during maintenance activities (96.8%). CONCLUSIONS: The
      study results showed that there is a predominance of accidents in lower hierarchy
      workers, and these accidents occur mainly during maintenance activities. There is
      a need to improve the company's accident reporting system and accident
      investigation procedures.

PMID- 12471383
TI  - [Advanced life support: care provided to motor vehicle crash victims].
AB  - OBJECTIVE: To analyze the performance of Advanced Life Support care mode (ALS)
      applied to car crash victims using indicators by means of the Revised Trauma
      Score (RTS) in prehospital phase. METHODS: It were analyzed 643 reports of car
      crash victims cared by public ALS services that occurred in highways of the city
      of Sao Paulo, from April 1999 to April 2000. Time intervals assessed were:
      response time, on-scene time, transport time, and total time. Correct screening
      decision analysis considered RTS< or = 1 for tertiary hospitals. Changes in RTS
      and its parameters were observed using the following equation: RTSfinal -
      RTSinitial. RESULTS AND CONCLUSIONS: Of 643 victims, 90.8% were RTS=12 and 5.2%
      were RTS < or = 0. The response time ranged from 8 to 9 minutes, while on-scene
      and transport time were higher in RTS < or = 0 cases. Of RTS < or = 0 victims,
      45.5% were correctly transported to tertiary hospitals. Screening decision
      misjudgments were identified. Maintenance or improvement of RTS values occurred
      in 98.8% of the cases. Respiratory rate was the parameter that showed better
      improvement followed by systolic blood pressure.

PMID- 12471384
TI  - [Obstetrical inpatient care and hospitalization risks in hospitals of Brazil].
AB  - OBJECTIVE: To analyze variations in early neonatal mortality, stillbirth rates,
      and a set of indicators collected from obstetric hospitals affiliated to the
      Brazilian National Unified Health System (SUS) for their monitoring through the
      Hospital Data System (SIH/SUS) and Live Births Data System (SINASC). METHODS: One
      hundred and thirty five hospitals in the state of Rio de Janeiro were assessed in
      1997. Factor analysis was conducted using principal components. Score
      distribution for the first two components were established, which allowed to
      classify hospitals according to maternal risk profile and care outcomes. RESULTS:
      Hospitals affiliated to SUS were responsible for 77.8% of all deliveries in the
      state of Rio de Janeiro and 23% of them performed fewer than 100 deliveries a
      year. Among hospitals of extreme high maternal risk and low performance, there
      were several units considered as referral centers for high-risk pregnancy. It was
      also observed that 5% of hospital units with low complexity infrastructures
      showed a profile of high maternal risk and questionable care outcomes.
      CONCLUSIONS: The Hospital Information Data System affiliated to the National
      Unified Health System has proven to be an important information source for
      monitoring hospital stillbirth and early neonatal mortality rates as well as for
      planning surveillance actions for health services providing obstetric and/or
      neonatal care.

PMID- 12471385
TI  - [Anticaries effectiveness of fluoride toothpaste: a meta-analysis].
AB  - OBJECTIVE: To carry out a meta-analysis on the effectiveness of fluoride
      toothpaste for reducing dental caries to calculate the effect size of different
      hypothesis. METHODS: MEDLINE and LILACS databases were studied in the period from
      1980 to 1998. To evaluate the quality of the studies, methodological rigor
      criteria proposed by Kay & Locker (1996) were applied after the criteria were
      submitted to an expert committee of CNPq (National Scientific Council of Brazil)
      senior researchers. Of 43 papers selected, 22 met the proposed criteria. The
      effect size of intervention was calculated from differences among the groups and
      the overall effect of five groups of hypothesis. RESULTS: The high concentration
      of fluoride in the toothpaste is associated with a larger effect (overall effect
      = -0.17 CI 95% -0.22/-0.12). The largest caries reductions were observed when
      comparing fluoride toothpastes and no fluoride toothpastes (overall effect = 
      0.29 IC 95% -0.34/-0.24). The addiction of antimicrobial agents (overall effect =
      -0.03 IC 95% -0.07/+0.02), differences in abrasive systems (overall effect = 
      0.02 IC 95% -0.09/+0.04) and active components do not increase the effectiveness
      of fluoride toothpastes (overall effect = -0.04 IC 95% -0.10/+0.01). CONCLUSIONS:
      The highest caries reductions were seen in studies where there was supervised
      tooth brushing. This review reinforced the importance of tooth brushing with
      fluoride toothpastes for controlling dental caries. However it showed the
      emphasis put on medical approaches for disease control rather than specific
      educational actions. The heterogeneity of the results shows the need to consider
      issues such as the scenario for implementing preventive methods in the evaluation
      process.

PMID- 12471386
TI  - [Periodontal conditions and diabetes mellitus in the Japanese-Brazilian
      population].
AB  - OBJECTIVE: To evaluate the relationship between diabetic status and periodontal
      conditions in the Japanese-Brazilian population. METHODS: The sample consisted of
      1,315 subjects, of both sexes, first (Issei) and second (Nisei) generations, aged
      30 to 92 years, living in Bauru, Brazil. Edentulism and presence of 6 null
      sextants were the exclusion criteria for the sample. The Community Periodontal
      Index and Periodontal Attachment Loss Index were determined using the probing of
      10 teeth in a sample of 831 subjects. The diagnosis of diabetes mellitus was
      based on fasting blood sugar and blood sugar 2 hours after 75 mg of glucose
      overload. Statistical analysis was conducted using Kappa test and Chi-square
      test. RESULTS: Regarding periodontal conditions, 25.5% of the sample were healthy
      people, 12.5% showed bleeding on probing, 49.4% calculus, 10.4% pockets of 4-5 mm
      deep, and 2.2% pockets deeper than 6 mm. The percentage of subjects with an
      attachment loss of 0-3 mm was 24.2%; 4-5 mm, 36.7%; 6-8 mm, 23.7%; 9-11 mm,
      11.3%; and up to 12 mm or more, 4.1%. The association between the periodontal
      condition and diabetes mellitus showed no statistical significance (p<0.05),
      although diabetic subjects have a higher percentage of deeper pockets and
      attachment loss >6 mm than non-diabetics, as tested by Chi-square test.
      CONCLUSIONS: Epidemiological studies relating oral health and systemic disease,
      such as diabetes mellitus, can provide important contributions for preventing the
      worsening of such diseases.

PMID- 12471387
TI  - [Muscoid dipterans as helminth eggs mechanical vectors at the zoological garden,
      Brazil].
AB  - OBJECTIVE: To assess muscoid dipterae species who are able to carry helminth eggs
      and larvae and to evaluate the potential contamination of trapped dipterae.
      METHODS: The study was conducted in two different sites of the Zoological Garden
      of Rio de Janeiro from May 1996 to April 1998. Flies were captured weekly using
      traps containing putrefied fish, left out in the open for an hour at two sites in
      the zoo: Site 1 was next to the garbage and Site 2 was near the hippopotamus and
      birds of prey cages. Of the 41,080 flies captured, Chrysomya megacephala was the
      most representative species (69.34%), followed by Chrysomya albiceps (11.22%),
      Musca domestica (7.15%), Chrysomya putoria (4.52%), Fannia sp. ( 3.12%), Ophyra
      sp. ( 2.53%), and Atherigona orientalis (2.08%). Captured flies had their body
      surface washed out with distilled water and their gut dissected. RESULTS: Among
      the species studied, C. megacephala and M. domestica presented higher helminth
      eggs on their body surface and in their intestinal content. Ascaroidea and
      Trichinelloidea eggs prevailed in the intestinal content of C. megacephala. The
      helminth eggs found on the body surface and in the intestinal content were
      identified as Ascaris sp., Toxascaris sp., Toxocara sp., Trichuris sp.,
      Capillaria sp., Oxyuridae, Trichostrongylidae and Acantocephala. Besides eggs it
      was also found helminth larvae on the body surface of flies. There were
      significant differences between the two different capture sites related to the
      number of helminth eggs found on the flies. CONCLUSIONS: Faeces of zoo animals
      frequently found in their cages and in the zoo garbage contributed to the
      proliferation of muscoid dipterans who play an important role in spreading
      helminth eggs, mainly by direct contact of the flies' body with the animals'
      food.

PMID- 12471388
TI  - [Experimental Encephalitozoon cuniculi infection in dexamethasone
      immunosuppressed mice].
AB  - OBJECTIVE: Microsporidian Encephalitozoon cuniculi has been recognized as an
      opportunistic pathogen in immunosuppressed individuals, such as AIDS patients.
      The objective of the study was to develop pharmacologically immunosuppressed
      animals as a model of the natural occurring E. cuniculi infection. METHODS:
      Distinct groups of adult Balb-C mice were immunosuppressed with different doses
      of dexamethasone (Dx, 3 or 5 mg/kg/day, intraperitoneal route - IP) and
      inoculated with E. cuniculi spores by IP route intraperitoneally. Control groups
      (inoculated animals but non-immunosuppressed and non- inoculated animals but
      immunosuppressed) were also used. The spores of E. cuniculi were previously
      cultivated in MDCK cells. The animals were sacrificed and necropsied at 7, 14,
      21, 28 and 35 days post-inoculation. Tissue fragments were collected and
      processed for light microscopy studies, using Gram-chromotrope and hematoxylin
      eosin staining techniques. RESULTS: In all immunosuppressed and inoculated
      inoculated immunosuppressed mice,specially in those that received 5 mg/kg/day of
      dexamethasone, the most prominent necropsy findings were hepatomegaly and
      splenomegaly. The experimental inoculation resulted in a disseminated non-lethal
      infection, characterized by granulomatous lesions in several organs (liver,
      lungs, kidneys, gut and brain) but notably in the hepatic tissue. Spores of E.
      cuniculi were only seen in few animals treated with 5 mg/kg/day of Dx at 35 days
      post-infection. CONCLUSIONS: Microsporidiosis in Dx-immunosuppressed mice
      provides a useful model for studies of the microsporidial infection, resembling
      that one naturally occurring in immunodeficient individuals with AIDS.

PMID- 12471389
TI  - [Main breeding-containers for Aedes aegypti and associated culicids, Argentina].
AB  - Breeding containers for Aedes (Stegomyia) aegypti were identified in two cities
      of Chaco Province (northeast Argentina): Presidencia Roque Saenz Pena and
      Machagai. All water-retaining recipients found in house backyards capable to
      retain water were classified according to their type and size, counted and
      checked. Aedes aegypti and Culex quinquefasciatus were the most frequently
      collected species, being also found Cx. maxi, Cx. saltanensis and Ochlerotatus
      scapularis. Tires and car batteries represented the most important type of
      container where immature forms of culicids could be found. Rain was an important
      factor for Ae. aegypti proliferation, as well as the widespread habit of the
      population of keeping useless containers at home, which allows the development of
      culicids.

PMID- 12471390
TI  - [An accident involving Tityus serrulatus and its epidemiological implications in
      Brazil].
AB  - This is a case report of the first accident involving a scorpion Tityus
      serrulatus in the city of Porto Alegre, Brazil, that occurred in March, 2001. A
      21-year-old male patient, while handling vegetables proceeding from other
      Brazilian states, was bitten by a scorpion Tityus serrulatus, developing local
      and systemic reactions, requiring an anti-scorpion antidote. The authors
      highlight the epidemiological importance of this case in the South of Brazil.

PMID- 12471391
TI  - [Motivation on plaque control and gingival bleeding in school children].
AB  - The objective of the study is to evaluate the impact of two pedagogical
      motivational approaches for plaque and gingival bleeding control among 135
      students of local public schools in Santa Tereza, Brazil, in 1999 The
      motivational program consisted of different educational strategies offered to two
      distinct groups: Group A, who attended only one explanatory session about oral
      hygiene, and Group B, who attended a total of four pedagogical sessions. In order
      to evaluate the methodology applied, the visible plaque index (according to
      Ainamo & Bay, 1975) and gingival bleeding index (according to L e and Silness,
      1963) were calculated. A highly statistically significant reduction in the
      visible plaque index and gingival bleeding index was observed in both groups
      after the educational sessions (p<0.001). Moreover, a higher reduction in the
      gingival bleeding index and an even more accentuated decrease in the visible
      plaque index was found in group B when compared to group A (p<0.001). In
      conclusion, the motivational reinforcement in educational and preventive programs
      has a positive effect for the reduction and control of gingival bleeding and
      bacterial plaque.

PMID- 12471392
TI  - [Health promotion evaluation: focus on "healthy cities"].
AB  - Since the Healthy City movement is a health promotion strategy, an update study
      was carried out to put into context the health promotion evaluation debate
      stressing the principles to be considered in an evaluation initiative and in the
      problematic of Health Cities projects. A literature review of "Healthy Cities"
      was conducted. A typology based on of Healthy Cities papers found in MEDLINE,
      LILACS and published in the "Health Promotion International" between 1985 and
      2000 was proposed taking into consideration the main focus of each paper.
      Articles on evaluation were analyzed in more details according to stressing
      methods, research tools, indicators, study results, and critical appraisal of
      their models. Finally, it is highlighted initiatives that would come close to the
      principles of "Health Promotion" and adopt evaluation as a tool for building up
      capabilities and the empowerment of community groups involved with Healthy Cities
      initiatives.

PMID- 12471393
TI  - [Non-pharmacological treatments in the stimulation of osteogenesis].
AB  - Mechanical loads cause bone deformation leading to bone resorption and an
      increase in local bone formation. However, the stimulus for bone formation
      depends on the amount and frequency of bone deformation. High calcium intake is
      required to increase bone formation. There are also non-pharmacological
      treatments, such as electrical stimulation, low-intensity ultrasound, and laser,
      which revealed to promote osteogenesis. The article intends to evaluate non
      pharmacological, alternative methods which assist in the increase of bone
      formation or in the osteogenic stimulus. A literature review was carried out for
      the period between 1982 to 2001.

PMID- 12471394
TI  - Violence is a health issue.

PMID- 12471395
TI  - The worldwide problem of lead in petrol.

PMID- 12471396
TI  - Factors associated with elevated blood lead concentrations in children in
      Karachi, Pakistan.
AB  - OBJECTIVES: To confirm whether blood lead concentrations in Karachi were as high
      as reported in 1989 and to identify which types of exposure to lead contribute
      most to elevated blood lead concentrations in children in Karachi. METHODS: A
      total of 430 children aged 36-60 months were selected through a geographically
      stratified design from the city centre, two suburbs, a rural community and an
      island situated within the harbour at Karachi. Blood samples were collected from
      children and a pretested questionnaire was administered to assess the effect of
      various types of exposure. Cooked food, drinking-water and house dust samples
      were collected from households. FINDINGS: About 80% of children had blood lead
      concentrations 10  g/dl, with an overall mean of 15.6  g/dl. At the 5% level of
      significance, houses nearer to the main intersection in the city centre,
      application of surma to children's eyes, father's exposure to lead at workplace,
      parents' illiteracy and child's habit of hand- to-mouth activity were among
      variables associated with elevated lead concentrations in blood. CONCLUSION:
      These findings are of public health concern, as most children in Karachi are
      likely to suffer some degree of intellectual impairment as a result of
      environmental lead exposure. We believe that there is enough evidence of the
      continuing problem of lead in petrol to prompt the petroleum industry to take
      action. The evidence also shows the need for appropriate interventions in
      reducing the burden due to other factors associated with this toxic element.

PMID- 12471397
TI  - Measles vaccine effectiveness and risk factors for measles in Dhaka, Bangladesh.
AB  - OBJECTIVE: To evaluate vaccine effectiveness and to assess risk factors for
      measles in Dhaka, Bangladesh. METHOD: A case-control study, involving 198 cases
      with 783 age-matched neighbourhood controls and 120 measles cases with 365 age
      matched hospital controls, was conducted in 1995-96 in three large hospitals in
      Dhaka. FINDINGS: Measles vaccine effectiveness was estimated at 80% (95%
      confidence interval (CI) = 60-90%) using neighbourhood controls; very similar
      results were obtained using hospital controls. Visits to a health facility 7-21
      days before onset of any symptoms were associated with increased risk of measles
      compared with neighbourhood (adjusted odds ratio (OR) = 7.0, 95% CI = 4.2-11.6)
      or hospital (adjusted OR = 1.7, 95% CI = 1.01-2.8) controls. Cases were more
      likely than controls to come from a household where more than one child lived
      (adjusted OR = 1.6, 95% CI = 1.1-2.5 versus neighbourhood controls; adjusted OR =
      1.8, 95% CI = 1.02-3.0 versus hospital controls). CONCLUSIONS: To improve measles
      control in urban Dhaka missed immunization opportunities must be reduced in all
      health care facilities by following WHO guidelines. For measles elimination, more
      than one dose of vaccine would be required.

PMID- 12471398
TI  - Use of remote sensing and a geographical information system in a national
      helminth control programme in Chad.
AB  - OBJECTIVE: To design and implement a rapid and valid epidemiological assessment
      of helminths among schoolchildren in Chad using ecological zones defined by
      remote sensing satellite sensor data and to investigate the environmental limits
      of helminth distribution. METHODS: Remote sensing proxy environmental data were
      used to define seven ecological zones in Chad. These were combined with
      population data in a geographical information system (GIS) in order to define a
      sampling protocol. On this basis, 20 schools were surveyed. Multilevel analysis,
      by means of generalized estimating equations to account for clustering at the
      school level, was used to investigate the relationship between infection patterns
      and key environmental variables. FINDINGS: In a sample of 1023 schoolchildren,
      22.5% were infected with Schistosoma haematobium and 32.7% with hookworm. None
      were infected with Ascaris lumbricoides or Trichuris trichiura. The prevalence of
      S. haematobium and hookworm showed marked geographical heterogeneity and the
      observed patterns showed a close association with the defined ecological zones
      and significant relationships with environmental variables. These results
      contribute towards defining the thermal limits of geohelminth species.
      Predictions of infection prevalence were made for each school surveyed with the
      aid of models previously developed for Cameroon. These models correctly predicted
      that A. lumbricoides and T. trichiura would not occur in Chad but the predictions
      for S. haematobium were less reliable at the school level. CONCLUSION: GIS and
      remote sensing can play an important part in the rapid planning of helminth
      control programmes where little information on disease burden is available.
      Remote sensing prediction models can indicate patterns of geohelminth infection
      but can only identify potential areas of high risk for S. haematobium.

PMID- 12471399
TI  - Treatment uptake by individuals infected with Plasmodium falciparum in rural
      Gambia, West Africa.
AB  - OBJECTIVE: To find out what proportion of Plasmodium falciparum infections are
      treated in rural Gambia. METHODS: Subjects from four villages in the Gambia were
      followed over nine months through visits to village health workers. Monthly cross
      sectional malaria surveys measured the prevalence of P. falciparum infection.
      Linked databases were searched for treatment requests. Treated cases were
      individuals with parasitaemia who requested treatment during narrow or extended
      periods (14 or 28 days, respectively) before or after a positive blood film was
      obtained. FINDINGS: Parasite prevalence peaked in November 1998, when 399/653
      (61%) individuals had parasitaemia. Parasite prevalence was highest throughout
      the study in children aged 5-10 years. Although access to treatment was better
      than in most of sub-Saharan Africa, only 20% of infected individuals sought
      medical treatment up to 14 days before or after a positive blood film. Within two
      months of a positive blood film, 199/726 (27%) individuals with parasitaemia
      requested treatment. Despite easy access to health care, less than half (42%) of
      those with parasite densities consistent with malaria attacks (5000/ l) requested
      treatment. High parasite density and infection during October-November were
      associated with more frequent treatment requests. Self-treatment was infrequent
      in study villages: in 3/120 (2.5%) households antimalarial drugs had been used in
      the preceding malaria season. CONCLUSION: Many P. falciparum infections may be
      untreated because of their subclinical nature. Intermittent presumptive treatment
      may reduce morbidity and mortality. It is likely that not all untreated
      infections were asymptomatic. Qualitative research should explore barriers to
      treatment uptake, to allow educational interventions to be planned.

PMID- 12471400
TI  - Sex- and age- specific relations between economic development, economic
      inequality and homicide rates in people aged 0-24 years: a cross-sectional
      analysis.
AB  - OBJECTIVE: To test whether relations between economic development, economic
      inequality, and child and youth homicide rates are sex- and age-specific, and
      whether a country's wealth modifies the impact of economic inequality on homicide
      rates. METHODS: Outcome variables were homicide rates around 1994 in males and
      females in the age ranges 0-4, 5-9, 10-14, 15-19 and 20-24 years from 61
      countries. Predictor variables were per capita gross domestic product (GDP), GINI
      coefficient, percentage change in per capita gross national product (GNP) and
      female economic activity as a percentage of male economic activity. Relations
      were analysed by ordinary least squares regression. FINDINGS: All predictors
      explained significant variances in homicide rates in those aged 15-24.
      Associations were stronger for males than females and weak for children aged 0-9.
      Models that included female economic inequality and percentage change in GNP
      increased the effect in children aged 0-9 and the explained variance in females
      aged 20-24. For children aged 0-4, country clustering by income increased the
      explained variance for both sexes. For males aged 15-24, the association with
      economic inequality was strong in countries with low incomes and weak in those
      with high incomes. CONCLUSION: Relations between economic factors and child and
      youth homicide rates varied with age and sex. Interventions to target economic
      factors would have the strongest impact on rates of homicide in young adults and
      late adolescent males. In societies with high economic inequality, redistributing
      wealth without increasing per capita GDP would reduce homicide rates less than
      redistributions linked with overall economic development.

PMID- 12471401
TI  - Aerosolized measles and measles-rubella vaccines induce better measles antibody
      booster responses than injected vaccines: randomized trials in Mexican
      schoolchildren.
AB  - OBJECTIVE: To compare antibody responses and side-effects of aerosolized and
      injected measles vaccines after revaccination of children enrolling in elementary
      schools. METHODS: Vaccines for measles (Edmonston-Zagreb) or measles-rubella
      (Edmonston-Zagreb with RA27/3) were given by aerosol or injection to four groups
      of children. An additional group received Schwarz measles vaccine by injection.
      These five groups received vaccines in usual standard titre doses. A sixth group
      received only 1000 plaque-forming units of Edmonston-Zagreb vaccine by aerosol.
      The groups were randomized by school. Concentrations of neutralizing antibodies
      were determined in blood specimens taken at baseline and four months after
      vaccination from randomized subgroups (n = 28-31) of children in each group.
      FINDINGS: After baseline antibody titres were controlled for, the frequencies of
      fourfold or greater increases in neutralizing antibodies did not differ
      significantly between the three groups that received vaccine by aerosol (range
      52%-64%), but they were significantly higher than those for the three groups that
      received injected vaccine (range 4%-23%). Mean increases in titres and post
      vaccination geometric mean titres paralleled these findings. Fewer side-effects
      were noted after aerosol than injection administration of vaccine. CONCLUSION:
      Immunogenicity of measles vaccine when administered by aerosol is superior to
      that when the vaccine is given by injection. This advantage persists with
      aerosolized doses less than or equal to one-fifth of usual injected doses. The
      efficacy and cost-effectiveness of measles vaccination by aerosol should be
      further evaluated in mass campaigns.

PMID- 12471402
TI  - Evaluation of the Haemoglobin Colour Scale and comparison with the HemoCue
      haemoglobin assay.
AB  - OBJECTIVE: To evaluate the Haemoglobin Colour Scale developed by WHO for
      estimating haemoglobin concentration and to compare the results obtained using it
      and the HemoCue assay with those determined using a reference method, the
      Technicon H3 analyser. METHODS: The Colour Scale and HemoCue assay were used to
      test 408 blood samples. Subsequently, Bland-Altman plots were determined and the
      proximity of the test results to those obtained using the reference method was
      determined. FINDINGS: The mean difference between the Haemoglobin Colour Scale
      and the reference method was 0.19 g/dl (95% confidence interval: 3.50 g/dl below
      to 3.11 g/dl above); the corresponding value for the HemoCue assay was 0.50 g/dl
      (1.16 g/dl below to 0.16 g/dl above). Only 46.08% of the results obtained by
      means of the Colour Scale were within 1.0 g/dl of the reference method, whereas
      95.34% of the HemoCue results fell within this limit; 22.79% of the Colour Scale
      results but none of the HemoCue results lay more than 2.0 g/dl from the reference
      method. CONCLUSION: The Haemoglobin Colour Scale test is too inaccurate for
      general use, particularly if devices such as the HemoCue are available.

PMID- 12471403
TI  - A public-private partnership for malaria control: lessons from the Malarone
      Donation Programme.
AB  - In 1996, Glaxo Wellcome offered to donate up to a million treatment courses
      annually of Malarone, a new antimalarial, with a view to reducing the global
      burden of malaria. The Malarone Donation Programme (MDP) was established the
      following year. Eight pilot sites were selected in Kenya and Uganda to develop
      and evaluate an effective, locally sustainable donation strategy that ensured
      controlled and appropriate use of Malarone. The pilot programme targeted
      individuals who had acute uncomplicated Plasmodium falciparum malaria that had
      not responded to first-line treatments with chloroquine or sulfadoxine
      pyrimethamine. Of the 161 079 patients clinically diagnosed at the pilot sites as
      having malaria, 1101 (0.68%) met all the conditions for participation and
      received directly observed treatment with Malarone. MDP had a positive effect at
      the pilot sites by improving the diagnosis and management of malaria. However,
      the provision of Malarone as a second-line drug at the district hospital level
      was not an efficient and effective use of resources. The number of deaths among
      children and adults ineligible for MDP at the pilot sites suggested that high
      priority should be given to meeting the challenges of malaria treatment at the
      community level.

PMID- 12471404
TI  - The impact of the Global Polio Eradication Initiative on the financing of routine
      immunization: case studies in Bangladesh, C te d'Ivoire, and Morocco.
AB  - To determine if the Global Polio Eradication Initiative (PEI) affected financing
      of routine immunization programmes, we compared sources and uses of funds for
      routine immunization programmes and PEI activities in Bangladesh, C te d'Ivoire,
      and Morocco for the years 1993-98. We also examined funding trends for these
      years in these countries and assessed the effect of the initiative on the
      availability of specific resources in national immunization programmes, such as
      cold-chain equipment and personnel time spent on activities related to national
      immunization days and surveillance of poliomyelitis and acute flaccid paralysis.
      We found that all three governments and the majority of donors and international
      organizations continued to fund routine immunization programmes at levels similar
      to those before the PEI. Trend analysis also indicated that financing for routine
      immunization in each of the countries continued to increase after the PEI was
      introduced. The results show that the PEI did not reduce funding for routine
      immunizations in these countries.

PMID- 12471405
TI  - Surgical services for children in developing countries.
AB  - There is growing evidence that childhood surgical conditions, especially
      injuries, are common in developing countries and that poor care results in
      significant numbers of deaths and cases of disability. Unfortunately, however,
      surgical care is not considered an essential component of most child health
      programmes. Strategies for improving paediatric surgical care should be evidence
      based and cost-effective and should aim to benefit the largest possible number of
      children. The most likely way of achieving policy change is to demonstrate that
      childhood surgical conditions are a significant public health problem. For
      paediatric purposes, special attention should also be given to defining a cost
      effective package of surgical services, improving surgical care at the community
      level, and strengthening surgical education. Surgical care should be an essential
      component of child health programmes in developing countries.

PMID- 12471406
TI  - The implications for TB control of the growth in numbers of private practitioners
      in developing countries.

PMID- 12471408
TI  - One good decision at the Earth Summit: to improve sanitation.

PMID- 12471407
TI  - Evaluation of the haemoglobin colour scale.

PMID- 12471409
TI  - Music, dancing -- and a national policy-- are challenging violence in Brazil.

PMID- 12471410
TI  - New non-profit organization will support research to combat neglected diseases.

PMID- 12471412
TI  - Change of leadership for WHO in 2003.

PMID- 12471411
TI  - Europe finds US$ 200 million to support African clinical trials.

PMID- 12471413
TI  - WHO releases global reference guide on 325 essential medicines.

PMID- 12471414
TI  - European report shows growing inequities in wealth and health.

PMID- 12471415
TI  - Million-kronor prize will help launch Healthy Environments for Children
      initiative.

PMID- 12471416
TI  - Zigman Brener (7/9/1928 - 23/9/2002).

PMID- 12471417
TI  - Experimental models of Schistosoma mansoni infection.
AB  - Experimental models of Schistosoma mansoni infections in mammals have contributed
      greatly to our understanding of the pathology and pathogenesis of infection. We
      consider here hepatic and extrahepatic disease in models of acute and chronic
      infection. Experimental schistosome infections have also contributed more broadly
      to our understanding of granulomatous inflammation and our understanding of Th1
      versus Th2 related inflammation and particularly to Th2-mediated fibrosis of the
      liver.

PMID- 12471418
TI  - Enterocytozoon bieneusi (microsporidia) in faecal samples from domestic animals
      from Galicia, Spain.
AB  - In this survey we examined 87 domestic animal stool samples in order to detect
      the possible presence of microsporidia in animals in close contact with humans in
      Galicia (NW, Spain). The detection of Enterocytozoon bieneusi spores was
      confirmed in faecal samples from two dogs and one goat by polymerase chain
      reaction. None of the positive samples for microsporidia in the staining method
      were amplified with species-specific primers for Encephalitozoon intestinalis, E.
      hellem and E. cuniculi. Four rabbits faecal samples reacted with anti-E. cuniculi
      serum. Our results could indicate the importance of domestic animals as zoonotic
      reservoirs of microsporidial human infections.

PMID- 12471419
TI  - High prevalence anti-Trypanosoma cruzi antibodies, among blood donors in the
      State of Puebla, a non-endemic area of Mexico.
AB  - Blood transfusion is the second most common transmission route of Chagas disease
      in many Latin American countries. In Mexico, the prevalence of Chagas disease and
      impact of transfusion of Trypanosoma cruzi-contaminated blood is not clear. We
      determined the seropositivity to T. cruzi in a representative random sample, of
      2,140 blood donors (1,423 men and 647 women, aged 19-65 years), from a non
      endemic state of almost 5 millions of inhabitants by the indirect
      hemagglutination (IHA) and enzyme linked immunosorbent assay (ELISA) tests using
      one autochthonous antigen from T. cruzi parasites, which were genetically
      characterized like TBAR/ME/1997/RyC-V1 (T. cruzi I) isolated from a Triatoma
      barberi specimen collected in the same locality. The seropositivity was up to
      8.5% and 9% with IHA and ELISA tests, respectively, and up to 7.7% using both
      tests in common. We found high seroprevalence in a non-endemic area of Mexico,
      comparable to endemic countries where the disease occurs, e.g. Brazil (0.7%),
      Bolivia (13.7%) and Argentina (3.5%). The highest values observed in samples from
      urban areas, associated to continuous rural emigration and the absence of control
      in blood donors, suggest unsuspected high risk of transmission of T. cruzi,
      higher than those reported for infections by blood e.g. hepatitis (0.1%) and AIDS
      (0.1%) in the same region.

PMID- 12471420
TI  - Prevalence and genotypes of GB virus C/hepatitis G virus among blood donors in
      Central Brazil.
AB  - A survey was conducted in a blood donor population of Central Brazil aiming to
      investigate the prevalence of GB virus C (GBV-C)/hepatitis G virus (HGV)
      infection and also to analyze the virus genotypes distribution. A total of 241
      voluntary blood donors were interviewed at the State Blood Bank in Goiania, State
      of Goias, Brazil. Blood samples were collected and serum samples tested for GBV
      C/HGV RNA by polymerase chain reaction. Genotypes were determined by restriction
      fragment length polymorphism (RFLP) analysis. Seventeen samples were GBV-C/HGV
      RNA-positive, resulting in a prevalence of 7.1% (95% CI: 4.2-11.1). A significant
      trend of GBV-C/HGV RNA positivity in relation to age was observed, with the
      highest prevalence in donors between 29-39 years old. Ten infected individuals
      were characterized by reporting parenteral (30%), sexual (18%), both (6%) and
      intrafamiliar (6%) transmission. However, 7 (40%) GBV-C/HGV RNA-positive donors
      did not mention any potential transmission route. RFLP analysis revealed the
      presence of genotypes 1 and 2 of GBV-C/HGV; more precisely, 10 (58.9%) samples
      were found belonging to the 2b subtype, 4 (23.5%) to the 2a subtype, and 3
      (17.6%) to genotype 1. The present data indicate an intermediate endemicity of
      GBV-C/HGV infection among this blood donor population, and a predominant
      circulation of genotype 2 (subtype 2b) in Central Brazil.

PMID- 12471421
TI  - Parasitic arthropods of some wild rodents from Jureia-Itatins Ecological Station,
      State of Sao Paulo, Brazil.
AB  - A study of the associations between three species of rodents in the Atlantic
      forest and their parasitic arthropods was undertaken at the Jureia-Itatins
      Ecological Station, located in the State of Sao Paulo, Southeastern Brazil, from
      March 1989 to February 1990. Individuals of three species, Oryzomys russatus,
      Proechimys iheringi and Nectomys squamipes were captured and examined for
      ectoparasites. Eleven species of parasitic arthropods were found, including four
      species of insects and seven of Acari. Parasitism intensity, phenology, and
      rainfall were positively correlated with the abundance of the ectoparasites and
      their hosts. The most abundant host was O. russatus (Muridae: Sigmodontinae), and
      the most common parasite on it was the laelapid mite Gigantolaelaps oudemansi.
      The cuterebrid Metacuterebra apicalis caused myiasis in O. russatus. A
      mutualistic association between the staphylinid beetle Amblyopinus sp. and its
      host P. iheringi (Echimyidae) was observed. The few N. squamipes captured had
      small numbers of ectoparasites.

PMID- 12471422
TI  - Clinical and epidemiological aspects of human parvovirus B19 infection in an
      urban area in Brazil (Niteroi city area, State of Rio de Janeiro, Brazil).
AB  - This study was designed to analyse the clinical and epidemiological data from
      human parvovirus B19 cases in a six-year study of rash diseases conduct in an
      urban area in Brazil (Niteroi city area, State of Rio de Janeiro). A total of 673
      patients with acute rash diseases were seen at two primary health care units and
      at a general hospital. A clotted blood sample was collected from all subjects at
      the time of consultation. Forty-nine per cent (330 cases) of the patients were
      negative for dengue, rubella and measles IgM or for low avidity IgG to HHV-6. Of
      these 330, 105 (31.8%) were identified as IgM positive to parvovirus B19 by using
      an antibody capture EIA. During the study period, three distinct peaks of
      parvovirus infection were detected, suggesting that the disease appears to cycle
      in approximately 4-5 years. B19 infection was characterized by variable
      combinations of fever, flu-like symptoms, arthropathy, and gastrointestinal
      symptoms. Frequency of fever and arthropathy was substantially higher in adults,
      75% [chi2 (1 D.F.) = 11.39, p = 0.0007] and 62.5% [chi2 (1 D.F.) = 29.89, p =
      0.0000], respectively. "Slapped-cheek" appearance and reticular or lace-like rash
      were seen in only 30.1% of the children. No adult presented this typical rash.
      The lack of the typical rash pattern in a large proportion of parvovirus B19 and
      the similarity of clinical manifestations to other rash diseases, specially to
      rubella, highlight the difficulty of diagnosing B19 infection on clinical grounds
      alone.

PMID- 12471423
TI  - Field trials of an improved cost-effective device for detecting peridomestic
      populations of Triatoma infestans (Hemiptera: Reduviidae) in rural Argentina.
AB  - An improved device for detecting peridomestic Triatoma infestans consisting of
      one-liter recycled Tetra Brik milk boxes with a central structure was tested
      using a matched-pair study design in two rural areas in Argentina. In Olta (La
      Rioja), the boxes were installed beneath the thatched roofs and on the vertical
      wooden posts of each peridomestic structure. After a 5-month exposure, at least
      one of the recovered boxes detected 88% of the 24 T. infestans-positive sites,
      and 86% of the 7 negative sites by timed manual collections at baseline. In Amama
      (Santiago del Estero), the boxes were paired with the best performing prototype
      tested before (shelter unit). After 3 months, some evidence of infestation was
      detected in 89% (boxes) and 79% (shelters) of 18-19 sites positive by timed
      collections, whereas 19% and 16% of 32 negative sites were positive,
      respectively. Neither device differed significantly in the qualitative or
      quantitative collection of every sign of infestation. The installation site did
      not modify significantly the boxes' sampling efficiency in both study areas. As
      the total cost of each box was half as expensive as each shelter unit, the boxes
      are thus the most cost-effective and easy-to-use tool for detecting peridomestic
      T. infestans currently available.

PMID- 12471424
TI  - B-cell infiltration and frequency of cytokine producing cells differ between
      localized and disseminated human cutaneous leishmaniases.
AB  - Biopsies from human localized cutaneous lesions (LCL n = 7) or disseminated
      lesions (DL n = 8) cases were characterized according to cellular
      infiltration,frequency of cytokine (IFN-gamma, TNF-alpha) or iNOS enzyme
      producing cells. LCL, the most usual form of the disease with usually one or two
      lesions, exhibits extensive tissue damage. DL is a rare form with widespread
      lesions throughout the body; exhibiting poor parasite containment but less tissue
      damage. We demonstrated that LCL lesions exhibit higher frequency of B
      lymphocytes and a higher intensity of IFN-gamma expression. In both forms of the
      disease CD8+ were found in higher frequency than CD4+ T cells. Frequency of TNF
      alpha and iNOS producing cells, as well as the frequency of CD68+ macrophages,
      did not differ between LCL and DL. Our findings reinforce the link between an
      efficient control of parasite and tissue damage, implicating higher frequency of
      IFN-gamma producing cells, as well as its possible counteraction by infiltrated B
      cells and hence possible humoral immune response in situ.

PMID- 12471425
TI  - First characterization of Candida albicans by random amplified polymorphic DNA
      method in Nicaragua and comparison of the diagnosis methods for vaginal
      candidiasis in Nicaraguan women.
AB  - A total of 106 women with vaginitis in Nicaragua were studied. The positive rate
      for the identification of Candida species was 41% (44 positive cultures out of
      106 women with vaginitis). The sensitivity of microscopic examination of wet
      mount with the potassium hydroxide (KOH) was 61% and 70% with Gram's stain when
      using the culture of vaginal fluid as gold standard for diagnosis of candidiasis.
      Among the 44 positives cultures, isolated species of yeast from vaginal swabs
      were C. albicans (59%), C. tropicalis (23%), C. glabrata (14%) and C. krusei
      (4%). This study reports the first characterization of 26 C. albicans stocks from
      Nicaragua by the random amplified polymorphic DNA method. The genetic analysis in
      this small C. albicans population showed the existence of linkage disequilibrium,
      which is consistent with the hypothesis that C. albicans undergoes a clonal
      propagation.

PMID- 12471426
TI  - Complete nucleotide sequence analysis of a Brazilian dengue virus type 2 strain.
AB  - In the last decade, dengue fever (DF) in Brazil has been recognized as an
      important public health problem, and an increasing number of dengue haemorrhagic
      fever (DHF) cases have been reported since the introduction of dengue virus type
      2 (DEN-2) into the country in 1990. In order to analyze the complete genome
      sequence of a DEN-2 Brazilian strain (BR64022/98), we designed primers to amplify
      contiguous segments of approximately 500 base pairs across the entire sequence of
      the viral genome. Twenty fragments amplified by reverse transcriptase-PCR were
      cloned, and the complete nucleotide and the deduced amino acid sequences were
      determined. This constitutes the first complete genetic characterization of a DEN
      2 strain from Brazil. All amino acid changes differentiating strains related to
      the Asian/American-Asian genotype were observed in BR64022/98, indicating the
      Asiatic origin of the strain.

PMID- 12471427
TI  - Morphological and polymerase chain reaction-restriction fragment lenght
      polymorphism characterization of Biomphalaria kuhniana and Biomphalaria amazonica
      from Colombia.
AB  - In Colombia, five Biomphalaria planorbid species are known: B. kuhniana, B.
      straminea, B. peregrina, B. canonica and B. oligoza(var. B. philippiana). Among
      them, B. straminea is intermediate host of Schistosoma mansoni and B. peregrina
      has been found to be experimentally susceptible to this parasite. B. straminea is
      commonly confused with B. kuhniana and they have been clustered together with B.
      intermedia in the complex named B. straminea. The difficulties involved in the
      specific identification, based on morphological data, have motivated the use of
      new techniques as auxiliary tools in cases of inconclusive morphological
      identification of such planorbid. In the present study, five Biomphalaria
      populations from the Colombian Amazon region and from Interandian Valleys were
      morphologically identified and characterized by polymerase chain reaction
      restriction fragment lenght polymorphism directed at the internal transcribed
      spacer region of the rRNA gene, followed by digestion of the generated fragment
      with restriction enzymes (DdeI, AluI, RsaI, MvaI and HaeIII). Known profiles of
      the Brazilian species B. straminea, B. peregrina, B. kuhniana, B. intermedia and
      B. amazonica, besides B. kuhniana from Colombia, were used for comparison. The
      five populations under study were morphologically and molecularly identified as
      B. kuhniana and B. amazonica.

PMID- 12471428
TI  - IS6110 fingerprinting of sensitive and resistant strains (1991-1992) of
      Mycobacterium tuberculosis in Colombia.
AB  - The standardized method to study the polymorphism of IS 6110 was used to
      characterize 53 isolates of Mycobacterium tuberculosis obtained during 1991-1992
      from 14 regions in Colombia. In Valle region cluster rate was 25% (4/16). The
      mean number of IS6110 band was 10 +/- 3. Similarity between strains was of 60% in
      81% of strains and this tended to be correlated with geographic origin. For the
      first time M. tuberculosis without IS6110 bands in restriction fragment length
      polymorphism analysis was found in Colombia. Additional studies are necessaries
      in order to best characterize the situation in relation to human immunodeficiency
      virus epidemic and recent changes in tuberculosis control program.

PMID- 12471429
TI  - Detection of antibodies to the 97 kDa component of Toxoplasma gondii in samples
      of human serum.
AB  - This study was carried out to investigate the immune response against 97 kDa
      (p97) molecular marker of Toxoplasma gondii that has been characterized as a
      cytosolic protein and a component of the excreted-secreted antigens from this
      parasite. A total of 60 serum samples from patients were analyzed by enzime
      linked immunosorbent assay and Western blot for toxoplasmosis. These samples were
      organized in three groups, based on clinical symptoms and results of serological
      tests. Group I: 20 samples reactive to IgG and IgM (acute phase); group II: 20
      non-reactive samples (control group); and group III: 20 samples reactive only to
      IgG (chronic phase). Western blot was performed with total antigenic extracts or
      with excreted and secreted antigen from T. gondii to identify the fraction
      correspondent to p97. It was observed that this cytosolic component from T.
      gondii stimulates the immunologic system to produce both IgM and IgG antibodies
      in the beginning of the acute infection and IgG throughout the chronic stage of
      the asymptomatic toxoplasmosis.

PMID- 12471430
TI  - Evaluation of the direct agglutination test and the rK39 dipstick test for the
      sero-diagnosis of visceral leishmaniasis.
AB  - The direct agglutination test (DAT) based on a freeze-dried antigen and the rK39
      dipstick test were evaluated for the sero-diagnosis of visceral leishmaniasis
      (VL). The sensitivity and specificity of both tests were determined using sera
      from confirmed VL patients (n = 21), healthy controls (n = 19) and from patients
      with other confirmed infectious diseases (n = 42). The DAT had a sensitivity and
      a specificity of 100%. The rK39 had a sensitivity of 85.7% and a specificity of
      82%. Both tests were also used to screen blood samples of confirmed VL patients
      (n = 15) and serum samples of VL suspects (n = 61). The DAT found all blood
      samples of confirmed VL patients positive and tested 98.4% of the serum samples
      of the VL suspects positive. In contrast, rK39 detected in 9/15 blood samples
      (60%) antibodies against Leishmania chagasi and found 85.3% of the serum samples
      of the suspected patients positive. Although the rK39 dipstick is more rapid and
      user friendlier than the DAT, the latter has a superior sensitivity and
      specificity. Furthermore, the reagents used for DAT do not require cold storage,
      whereas the buffer of the rK39 must be stored at 4oC. Therefore, the DAT is the
      most suitable test for the sero-diagnosis of VL under field conditions.

PMID- 12471431
TI  - Pathology of intracardiac nerves in experimental Chagas disease.
AB  - Severe destruction of intrinsic cardiac nerves has been reported in experimental
      acute Chagas myocarditis, followed by extensive regeneration during the chronic
      phase of the infection. To further study this subject, the sympathetic and para
      sympathetic intracardiac nerves of mice infected with a virulent Trypanosoma
      cruzi strain were analyzed, during acute and chronic infection, by means of
      histological, histochemical, morphometric and electron microscopic techniques. No
      evidences of destructive changes were apparent. Histochemical demonstration for
      acetylcholinesterase and catecholamines did not reveal differences in the amount
      and distribution of intracardiac nerves, in mice with acute and chronic Chagas
      myocarditis or in non-infected controls. Mild, probably reversible
      ultrastructural neural changes were occasionally present, especially during acute
      myocarditis. Intrinsic nerves appeared as the least involved cardiac structure
      during the course of experimental Chagas disease in mice.

PMID- 12471432
TI  - Screening of some plants used in the Brazilian folk medicine for the treatment of
      infectious diseases.
AB  - Extracts of 13 Brazilian medicinal plants were screened for their antimicrobial
      activity against bacteria and yeasts. Of these, 10 plant extracts showed varied
      levels of antibacterial activity. Piper regnellii presented a good activity
      against Staphylococus aureus and Bacillus subtilis, a moderate activity on
      Pseudomonas aeruginosa, and a weak activity against Escherichia coli. Punica
      granatum showed good activity on S. aureus and was inactive against the other
      standard strains. Eugenia uniflora presented moderate activity on both S. aureus
      and E. coli. Psidium guajava,Tanacetum vulgare, Arctium lappa, Mikania glomerata,
      Sambucus canadensis, Plantago major and Erythrina speciosa presented some degree
      of antibacterial activity. Spilanthes acmella, Lippia alba, and Achillea
      millefolium were considered inactive. Five of the plant extracts presented
      compounds with Rf values similar to the antibacterial compounds visible on
      bioautogram. Of these, three plants belong to the Asteraceae family. This may
      mean that the same compounds are responsible for the antibacterial activity in
      these plants. Anticandidal activity was detected in nine plant extracts (P.
      guajava, E. uniflora, P. granatum, A. lappa, T. vulgare, M. glomerata, L. alba,
      P. regnellii, and P. major). The results might explain the ethnobotanical use of
      the studied species for the treatment of various infectious diseases.

PMID- 12471433
TI  - In vitro chloroquine resistance modulation study on fresh isolates of Brazilian
      Plasmodium falciparum: intrinsic antimalarial activity of phenothiazine drugs.
AB  - Phenothiazine drugs - fluphenazine, chlorpromazine, methotrimeprazine and
      trifluoperazine - were evaluated as modulating agents against Brazilian
      chloroquine-resistant fresh isolates of Plasmodium falciparum. Aiming to simulate
      therapeutic schedules, chloroquine was employed at the concentration used for
      sensitive falciparum malaria treatment and anti-psychotic therapeutic
      concentrations of the phenothiazine drugs were adopted in two-fold serial
      dilutions. The in vitro microtechnique for drug susceptibility was employed.
      Unlike earlier reported data, the phenothiazine modulating effect was not
      observed. However, all the drugs demonstrated intrinsic antiplasmodial activity
      in concentrations lower than those described in the literature. In addition, IC50
      estimates have been shown to be inferior to the usual anti-psychotic therapeutic
      concentrations. Statistical analysis also suggested an increase in the
      parasitaemia rate or, even, a predominant antiparasitic effect of phenothiazine
      over chloroquine when used in combination.

PMID- 12471434
TI  - Study of the safety, immunogenicity and efficacy of attenuated and killed
      Leishmania (Leishmania) major vaccines in a rhesus monkey (Macaca mulatta) model
      of the human disease.
AB  - We have compared the efficacy of two Leishmania (Leishmania) major vaccines, one
      genetically attenuated (DHFR-TS deficient organisms), the other inactivated
      [autoclaved promastigotes (ALM) with bacillus Calmete-Guerin (BCG)], in
      protecting rhesus macaques (Macaca mulatta) against infection with virulent L.
      (L.) major. Positive antigen-specific recall proliferative response was observed
      in vaccinees (79% in attenuated parasite-vaccinated monkeys, versus 75% in ALM
      plus-BCG-vaccinated animals), although none of these animals exhibited either
      augmented in vitro gamma interferon (IFN-gamma) production or positive delayed
      type hypersensitivity (DTH) response to the leishmanin skin test prior to the
      challenge. Following challenge, there were significant differences in blastogenic
      responses (p < 0.05) between attenuated-vaccinated monkeys and naive controls. In
      both vaccinated groups very low levels of antibody were found before challenge,
      which increased after infective challenge. Protective immunity did not follow
      vaccination, in that monkeys exhibited skin lesion at the site of challenge in
      all the groups. The most striking result was the lack of pathogenicity of the
      attenuated parasite, which persisted in infected animals for up to three months,
      but were incapable of causing disease under the conditions employed. We concluded
      that both vaccine protocols used in this study are safe in primates, but require
      further improvement for vaccine application.

PMID- 12471435
TI  - Dynamics of evolution and resistance to starvation of Triatoma vitticeps (Stal
      1859) (Reduviidae: Triatominae), submitted to two different regimens of food
      deprivation.
AB  - The resistance to starvation of Triatoma vitticeps has been analyzed
      comparatively, according to different regimens of food deprivation under
      laboratory conditions. One cohort, composed of 100 specimens of each evolutionary
      nymphal stage, was submitted to continuous fasting until death; the second group,
      arranged in the same way, was fed once on chicken. Through this work, it was
      possible not only to compare the results obtained from the first group with other
      authors' results but, also, to analyze the dynamics of evolution, molting,
      longevity and the increase in insect longevity, in the second group. The average
      values recorded for survival time revealed statistical differences between the
      two groups. Among the important results detected, there is one that deserves to
      be emphasized: the incredible increase in longevity among insects that received
      only one feed - an average increase in survival time that reached 2.95 to 3.30
      times in nymphs of 3rd and 4th stages, respectively. One 5th stage nymph survived
      for up to 350 days and the females may triplicate their survival rate, what
      represents an important epidemiological factor. The knowledge about this type of
      biological characteristic of T. vitticeps may contribute to prevent the
      domiciliation of this species, what seems to be incipient in some municipal
      districts, in Brazil.

PMID- 12471436
TI  - Gregarine Cephaloidophora communis mawrodiadi, 1908 in the barnacle Euraphia
      rhyzophorae, Oliveira, 1940 from Brazil.
AB  - The gregarine Cephaloidophora communis was observed for the first time in Brazil
      in the barnacles Euraphia rhyzophorae collected in Angra dos Reis, Rio de
      Janeiro, Brazil, between 1990 and 1996. Histological studies showed growth phases
      of the parasite in specific parts of the digestive system. The intracellular
      forms occurred in the vacuoles of the intestinal cells. Syzygy was frequent, and
      the most common form following syzygy was cylindrical, with a single membrane.
      The cytoplasm of the gregarines was always irregular, dense, and occasionally
      presenting a dark stoch area.

PMID- 12471437
TI  - Feeding and defaecation behaviour of Triatoma patagonica (Del Ponte, 1929)
      (Hemiptera: Reduviidae).
AB  - Among the vectors of Chagas disease, Triatoma patagonica is a species in the
      process of adaptation to the human environment being recently registered in urban
      and suburban zones. However, its importance as a vector of Chagas disease is
      unknown. The aim of this work was to evaluate two aspects of vectorial
      competence: the feeding behaviour and the defaecation pattern. These processes
      were studied in females of T. patagonica fed ad libitum on a restrained pigeon.
      The results showed that the blood meal size was negatively correlated with the
      time of first defaecation (r = -0.42). The first defaecation was emitted before
      the first 10 min and defaecations during feeding were frequent. A total of 73% of
      females, defaecated during the first 30 min post-feeding. These results suggest
      that if this species subsequently colonizes the domicile, it would be capable of
      transmitting Trypanosoma cruzi.

PMID- 12471438
TI  - Caballerocotyla lenti n. sp., a capsalid monogenean from Auxis thazard
      (Scombridae) from off the southeastern coast of Brazil.
AB  - Caballerocotyla lenti n. sp. (Monogenea: Capsalidae), recovered from the gills of
      Auxis thazard (Lacepede) captured off the coast of Rio de Janeiro, Brazil, is
      described using light and scanning electron microscopy. The new species is
      characterized by: a tegument with 2-5 rows of dorso-marginal, unicuspid spines;
      53-54 round testes; a constricted pharynx with numerous papillae on its border;
      and a haptor with a plicate marginal border, a central polygonal area and seven
      complete septa. C. manteri (Price, 1951) and C. gouri Chauhan, 1953 sensu
      Murugesh (1995) are figured and commented upon.

PMID- 12471440
TI  - The essential Drosophila melanogaster gene wds (will die slowly) codes for a WD
      repeat protein with seven repeats.
AB  - We have isolated and characterized the will die slowly (wds) gene of Drosophila
      melanogaster, formerly known as l(1)zw8 or l(1)3Ad. The gene codes for a 2.0-kb
      RNA that is transcribed at all stages of development. The RNA has been localized
      by in situ hybridization to imaginal discs, larval brain, to nurse cells in the
      ovary, and to spermatogonia and spermatocytes in the testis. The putative
      translation product contains seven WD-repeats and is, therefore, a new member of
      the family of WD-proteins. Clear homologues of the Drosophila WDS protein exist
      in three other fully sequenced higher eukaryotes - human, Caenorhabditis elegans
      and Arabidopsis. A genomic fragment containing the wds transcription unit is able
      to rescue two different lethal wds alleles, thus proving that we have indeed
      isolated the wds gene.

PMID- 12471441
TI  - The complete sequence of the rice (Oryza sativa L.) mitochondrial genome:
      frequent DNA sequence acquisition and loss during the evolution of flowering
      plants.
AB  - The entire mitochondrial genome of rice (Oryza sativa L.), a monocot plant, has
      been sequenced. It was found to comprise 490,520 bp, with an average G+C content
      of 43.8%. Three rRNA genes, 17 tRNA genes and five pseudo tRNA sequences were
      identified. In addition, eleven ribosomal protein genes and two pseudo ribosomal
      protein genes were found, which are homologous to 13 of the 16 genes for
      ribosomal proteins in the mitochondrial genome of the liverwort (Marchantia
      polymorpha). A greater degree of variation in terms of presence/absence and
      integrity of genes was observed among the ribosomal protein genes and tRNA genes
      of rice, Arabidopsis and sugar beet. Transcription and post-transcriptional
      modification (RNA editing) in the rice mitochondrial sequence were also examined.
      In all, 491 Cs in the genomic DNA were converted to Ts in cDNA. The frequency of
      RNA editing differed markedly depending upon the ORF considered. Sequences
      derived from plastid and nuclear genomes make up 6.3% and 13.4% of the
      mitochondrial genome, respectively. The degree of conservation of plastid
      sequences in the mitochondrial genome ranged from 61% to 100%, suggesting that
      sequence migration has occurred very frequently. Three plastid DNA fragments that
      were incorporated into the mitochondrial genome were subsequently transferred to
      the nuclear genome. Nineteen fragments that were similar to transposon or
      retrotransposon sequences, but different from those found in the mitochondrial
      genomes of dicots, were identified. The results indicate frequent and independent
      DNA sequence flow to and from the mitochondrial genome during the evolution of
      flowering plants, and this may account for the range of genetic variation
      observed between the mitochondrial genomes of higher plants.

PMID- 12471442
TI  - Genetic analyses of essential genes in cytological region 61D1-2 to 61F1-2 of
      Drosophila melanogaster.
AB  - We performed a systematic mutagenesis screen for lethals in the genomic region
      61D1-2 to 61F1-2 on chromosomal arm 3L of Drosophila melanogaster. Our genetic
      analyses revealed that this region contains eight essential complementation
      groups including trio, Glut1 and extra macrochaetae (emc). For the trio locus, 22
      mutant alleles were identified, and all of the alleles analyzed resulted in
      defects in the central nervous system of embryos, indicating that trio functions
      in the control of axon extension or guidance. Western analysis showed that at
      least three proteins are derived from trio and also suggested that a polypeptide
      of over 200 kDa plays a crucial role in embryonic or larval development. In
      addition, a newly identified emc allele was associated with several defects in
      embryonic morphogenesis, including abnormalities in head involution, gut
      formation and dorsal closure, thus revealing multiple roles for emc in embryonic
      development. We also performed preliminary phenotypic analyses on stocks bearing
      mutations belonging to the other lethal complementation groups. These genes
      function in essential biological events, but the mutations do not result in gross
      morphological changes during embryonic stages. The present study extends our
      knowledge of the Drosophila gene set, by identifying most of the essential genes
      in the chromosomal region 61D1-2 to 61F1-2.

PMID- 12471443
TI  - Bacillus subtilis functional genomics: genome-wide analysis of the DegS-DegU
      regulon by transcriptomics and proteomics.
AB  - The DegS-DegU two-component regulatory system of Bacillus subtilis controls
      various processes that characterize the transition from the exponential to the
      stationary growth phase, including the induction of extracellular degradative
      enzymes, expression of late competence genes and down-regulation of the sigma(D)
      regulon. The degU32(Hy) mutation stabilizes the phosphorylated form of DegU (DegU
      P), resulting in overproduction of several extracellular degradative enzymes. In
      this study, the pleiotropic DegS-DegU regulon was characterized by combining
      proteomic and transcriptomic approaches. A comparative analysis of wild-type B.
      subtilis and the degU32(Hy) mutant grown in complex medium was performed during
      the exponential and in the stationary growth phase. Besides genes already known
      to be under the control of DegU-P, novel putative members of this regulon were
      identified. Although the degU32(Hy) mutant is assumed to contain high levels of
      phosphorylated DegU in the exponential as well as in the stationary growth phase,
      many genes known to be positively regulated by DegU-P did not show enhanced
      expression in the mutant strain during exponential growth. This is consistent
      with the fact that most genes belonging to the DegS-DegU regulon are subject to
      multiple regulation; this is also reflected in the strong stationary-phase
      induction of these genes in the mutant strain. As expected, during the
      exponential growth phase, the sigma(D) regulon was expressed at significantly
      lower levels in the degU32(Hy) mutant than in the wild type.

PMID- 12471444
TI  - Sec20p-interacting proteins (Tip20p, Ufe1p) in the retrograde secretory pathway
      of the fungal pathogen Candida albicans.
AB  - Sec20p is an essential Type-II membrane protein of the human fungal pathogen
      Candida albicans, which is thought to be involved in mediating retrograde vesicle
      traffic from the Golgi to the endoplasmic reticulum (ER). Using an epitope-tagged
      Sec20p we obtained evidence for its localization in ER membranes, which is
      consistent with its proposed role in an ER-tSNARE complex. Two genes encoding
      potential interaction partners for Sec20p, Tip20p and Ufe1p, were identified in
      genomic sequences of C. albicans; these show 18% and 27% identity, respectively,
      to homologues in Saccharomyces cerevisiae. An interaction between the cytoplasmic
      domain of Sec20p and Tip20p was demonstrated by two-hybrid analysis; in addition,
      Tip20p was found to form homodimers. Interaction between Sec20p and Tip20p in
      vivo was verified by co-immunoprecipation experiments. CaUFE1, which encodes a
      potential ER-tSNARE, was able to complement a thermosensitive ufe1 mutation in S.
      cerevisiae, suggesting functional conservation between the two fungal proteins.
      Thus, although the sequences of some components of the ER-tSNARE complex have
      diverged considerably during evolution, it appears that they have retained
      similar functions in C. albicans and S. cerevisiae.

PMID- 12471445
TI  - Characterization of Xanthomonas axonopodis pv. citri LexA: recognition of the
      LexA binding site.
AB  - Levels of l exA transcripts are markedly increased upon exposure of Xanthomonas
      axonopodis pathovar citri ( X. a. pv. citri) to the DNA-damaging agent mitomycin
      C. Preliminary electrophoretic mobility-shift data led us to propose that binding
      of LexA protein to the sequence upstream of the lexA coding region is responsible
      for low promoter activity in the uniduced state. We determined that the LexA
      protein binds to the region located between the transcription start site and the
      translation initiation codon of the lexA gene of X. a. pv. citri. Using a DNase I
      footprinting technique, we identified a 19-bp palindromic sequence,
      TTAGTAGTAATACTACTAA (TTAGN(11)CTAA), located in this region as the binding
      sequence for the LexA protein of X. a. pv. citri, and showed that the two halves
      of the palindrome have to be in the inverted repeat orientation to permit binding
      of LexA. We also showed that almost any mutation in this sequence, including
      changes in the length of the spacer region of the palindrome, destroyed its
      ability to bind LexA both in vitro and in vivo.

PMID- 12471446
TI  - Cereal genes similar to Snf2 define a new subfamily that includes human and mouse
      genes.
AB  - Genes from the SNF2 family play important roles in transcriptional regulation,
      maintenance of chromosome integrity and DNA repair. This study describes the
      molecular cloning and characterization of cereal genes from this family. The
      predicted proteins exhibit a novel C-terminal domain that defines a new subfamily
      designated SNF2P that includes human and mouse proteins. Comparison between
      genomic and cDNA sequences showed that cereal Snf2P genes consisted of 17 exons,
      including one only 8 bp long. Two barley alleles differed by the presence of a
      7.7-kb non-LTR retrotransposon in intron 6. An alternative annotation of the
      orthologous Arabidopsis gene would improve its similarity with the other members
      of the subfamily. Intron 2 was not spliced out in approximately half of the rice
      Snf2P mRNAs present in leaves, resulting in a premature stop codon. Transcripts
      from the barley and wheat Snf2P genes were found in apexes, leaves, sheaths,
      roots and spikes. The Snf2P genes exist as single copies on wheat chromosome arm
      5A(m)L and in the colinear regions on barley chromosome arm 4HL and rice
      chromosome 3. High-density genetic mapping and RT-PCR suggest that Snf2P is not a
      candidate gene for the tightly linked vernalization gene Vrn2.

PMID- 12471447
TI  - Identification of a phosphofructokinase-encoding gene from Streptococcus
      thermophilus CNRZ1205--a novel link between carbon metabolism and gene
      regulation?
AB  - In order to isolate genes encoding so-called Two-Component Regulatory Systems
      from the lactic acid bacterium Streptococcus thermophilus, a cloning strategy was
      employed based on suppression of the alkaline phosphatase-negative phenotype
      displayed by the Escherichia coli strain ANCC22. Several suppressing clones were
      obtained which were shown to produce alkaline phosphatase activity. Sequence
      analysis of four of these clones revealed the presence of overlapping DNA inserts
      representing two ORFs, designated pfkT and pykT, whose deduced protein products
      exhibit significant similarity to phosphofructokinases and pyruvate kinases,
      respectively, from a variety of bacteria. A plasmid bearing pfkT was shown to
      complement a phosphofructokinase-negative mutant of E. coli, showing that this
      gene indeed specifies phosphofructokinase activity. It was shown that suppression
      of the alkaline phosphatase-negative phenotype of E. coli ANCC22 due to the
      presence of pfkT is caused by modulation of the intracellular level of acetyl
      phosphate.

PMID- 12471448
TI  - Distribution of 5-methylcytosine residues in 5S rRNA genes in Arabidopsis
      thaliana and Secale cereale.
AB  - Bisulfite genomic sequencing was used to localise 5-methylcytosine residues (mC)
      in 5S rRNA genes of Arabidopsis thaliana and Secale cereale. The maps of mC
      distribution were compared with the previously published map of the corresponding
      region in Nicotiana tabacum. In all three species, the level of methylation of 5S
      rRNA genes was generally higher than the average for the entire genome. The ratio
      of 5S rDNA methylation to average overall methylation was 44%/30-33% for N.
      tabacum, 27%/4-6% for A. thaliana and 24%/20-22% for S. cereale. With the
      exception of one clone from S. cereale, no methylation-free 5S rDNA was detected.
      The level of methylation at different sequence motifs in 5S rDNA was calculated
      for N. tabacum/A. thaliana/ S. cereale, and this analysis yielded the following
      values (expressed as a percentage of total C): mCG 90%/78%/85%, mCWG 89%/41%/53%,
      mCmCG 72%/32%/16%, mCCG 4%/2%/0%, mCHH 15%/6%/1%, where W=A or T, and H=A or C or
      T. Non-symmetrical methylation was almost negligible in the large genome of S.
      cereale but relatively frequent in N. tabacum and A. thaliana, suggesting that
      the strict correlation between genome size and cytosine methylation might be
      violated for this type of methylation. Among non-symmetrical motifs the mCWA
      triplets were significantly over-represented in Arabidopsis, while in tobacco
      this preference was not as pronounced. The differences in methylation levels in
      different sequence contexts might be of phylogenetic significance, but further
      species in related and different taxa need to be studied before firm conclusions
      can be drawn.

PMID- 12471449
TI  - Transcriptional analysis of the pst operon of Escherichia coli.
AB  - The pst operon of Escherichia coli, which encodes the phosphate-specific
      transport system, is composed of five genes, pstS, pstC, pstA, pstB and phoU,
      whose transcription is induced by phosphate starvation. A phosphate-regulated
      promoter located upstream of the most proximal gene ( pstS) controls the
      transcription of the entire operon. Though the full-length pst mRNA could be
      detected by an improved RT-PCR protocol, Northern analysis using several pst
      specific probes failed to reveal this transcript. Instead, smaller but distinct
      pst mRNA species were evident. Primer-extension experiments localized the 5' ends
      of pst mRNAs within the operon. The data suggest that the full-length mRNA is
      rapidly processed post-transcriptionally.

PMID- 12471450
TI  - Activation of the urease of Schizosaccharomyces pombe by the UreF accessory
      protein from soybean.
AB  - Plant orthologs of the bacterial urease accessory genes ureD and ureF, which are
      required for the insertion of the nickel ion at the active site, have been
      isolated from soybean ( Glycine max L. Merr.), tomato ( Lycopersicon esculentum)
      and Arabidopsis thaliana. The functionality of soybean UreD and UreF was tested
      by measuring their ability to complement urease-negative mutants of
      Schizosaccharomyces pombe, a eukaryote which produces a "plant-like" urease of
      ~90 kDa. The S. pombe ure4 mutant was complemented by a 12-kb fragment of S.
      pombe genomic DNA, which was shown by PCR to contain a putative ureD gene.
      However, ure4 was not complemented by a UreD cDNA soybean, expressed under the
      control of a strong promoter. In contrast, an S. pombe ure3 mutation was
      complemented by both a 10-kb fragment of S. pombe DNA containing ureF and the
      UreF cDNA from soybean. Soybean Eu2 is a candidate urease accessory gene; its
      product cooperates with the Eu3 protein in activating apourease in vitro.
      However, the sequences of UreD and UreF transcripts from two eu2/eu2 mutants,
      recovered as RT-PCR products, revealed no mutational alteration, suggesting that
      Eu2 encodes neither UreD nor UreF.

PMID- 12471451
TI  - Complex evolution of vitellogenin genes in salmonid fishes.
AB  - Vitellogenins (Vtg) are usually encoded by small multigene families containing up
      to six genes. With 20 tandemly arranged genes, the rainbow trout ( Oncorhynchus
      mykiss) is an exception to this rule. PCR amplification, cloning and sequence
      analysis of Vtg genes in other salmonid species revealed the existence of two
      paralogous gene clusters, designated Vtg-A and Vtg-B. Southern hybridization
      showed that the number of genes varies from 2 to 30 copies from one species to
      another, as well as between the two gene clusters. All Coregonus, Thymallus,
      Salmo and Salvelinus species studied have both gene clusters, while Oncorhynchus
      species possess only the Vtg-A locus. Phylogenetic trees constructed from Vtg
      sequences revealed conflicting nodes with the consensus tree based on
      morphological and anatomical data. Vtg sequences support the grouping ( Salmo, (
      Salvelinus, Oncorhynchus)) instead of the accepted consensus ( Salvelinus, (
      Salmo, Oncorhynchus)). Structural data on gene organization also support the
      contention that Salvelinus and Oncorhynchus are sister taxa. Evolutionary
      implications for the Vtg gene clusters in salmonids are discussed.

PMID- 12471452
TI  - Analysis of DNA methylation in Arabidopsis thaliana based on methylation
      sensitive AFLP markers.
AB  - AFLP analysis using restriction enzyme isoschizomers that differ in their
      sensitivity to methylation of their recognition sites has been used to analyse
      the methylation state of anonymous CCGG sequences in Arabidopsis thaliana. The
      technique was modified to improve the quality of fingerprints and to visualise
      larger numbers of scorable fragments. Sequencing of amplified fragments indicated
      that detection was generally associated with non-methylation of the cytosine to
      which the isoschizomer is sensitive. Comparison of EcoRI/ HpaII and EcoRI/ MspI
      patterns in different ecotypes revealed that 35-43% of CCGG sites were
      differentially digested by the isoschizomers. Interestingly, the pattern of
      digestion among different plants belonging to the same ecotype is highly
      conserved, with the rate of intra-ecotype methylation-sensitive polymorphisms
      being less than 1%. However, pairwise comparisons of methylation patterns between
      samples belonging to different ecotypes revealed differences in up to 34% of the
      methylation-sensitive polymorphisms. The lack of correlation between inter
      ecotype similarity matrices based on methylation-insensitive or methylation
      sensitive polymorphisms suggests that whatever the mechanisms regulating
      methylation may be, they are not related to nucleotide sequence variation.

PMID- 12471453
TI  - The Schizosaccharomyces pombe genes sep10 and sep11 encode putative general
      transcriptional regulators involved in multiple cellular processes.
AB  - We have previously described the genetic analysis of eleven complementation
      groups ( sep6- sep16) defined by Schizosaccharomyces pombe mutants that are
      defective in cell separation and sexual differentiation. Here we report on the
      cloning and characterisation of two members of this set, sep10 and sep11.
      Sequencing of the full-length sep10 revealed a continuous ORF that encodes a
      conserved protein with possible functions in general transcriptional regulation.
      The coding region of sep11 is interrupted by introns and the putative s ep11
      protein shows no sequence similarity with known proteins of other species.
      Disruption of each gene causes temperature sensitivity. Simultaneous disruption
      of both genes is lethal, demonstrating that sep10 and sep11 perform related,
      overlapping functions. Overexpression of aff1/ste11, a pivotal regulator of
      sexual development, suppresses the sterility of sep10 (-) cells, which suggests
      that sep10 is needed for the activity of aff1/ste11.

PMID- 12471454
TI  - On the neuronal/neuroblastic nature of medulloblastomas: a tribute to Pio del Rio
      Hortega and Moises Polak.
AB  - The concept that medulloblastomas represent cerebellar neuroblastic tumours was
      championed by del Rio Hortega in the 1930s and was critically reappraised in the
      1960s by Moises Polak. Whereas the aetiology and molecular pathogenesis of
      medulloblastomas remain unresolved, there is now compelling evidence in support
      of a fundamentally neuronal tumour phenotype. Tumour cells express in a
      differentiation-dependent manner a repertoire of neuronal cytoskeletal, synaptic,
      and other lineage-associated proteins. Neuronal differentiation is more
      pronounced in the so-called nodular/desmoplastic medulloblastomas, which are
      typified by areas of neoplastic neuritogenesis ("pale islands") marked by the co
      expression of neuronal marker proteins and neurotrophin receptors TrkA and TrkC,
      low proliferative indices, and apoptosis. The pale islands contain meshworks of
      reactive astrocytes as part of mutually inductive tumour-stromal cell
      interactions. However, overt glial differentiation or gliomatous transformation
      are uncommon. There is growing evidence to support the hypothesis that distinct
      subtypes of medulloblastomas may implicate transformed neuroblasts from two
      separate neuroepithelial sources: (a) the velum medullare for a subset of classic
      medulloblastomas, and (b) the external granule layer for the nodular/desmoplastic
      medulloblastomas as well as certain classic medulloblastomas. The nosological
      position of medulloblastomas is discussed in the context of the so-called
      embryonal central nervous system tumours with emphasis on the cerebral and
      cerebellar neuroblastomas. We give credence to the view that the medulloblastoma
      belongs to a group of central neuronal/neuroblastic tumours and call for a
      critical re-evaluation of its present taxonomic placement.

PMID- 12471455
TI  - Incidence of cerebrovascular lesions in Alzheimer's disease: a postmortem study.
AB  - Recent epidemiological and clinico-pathological data suggest overlaps between
      Alzheimer's disease (AD) and cerebrovascular lesions (CVL) that may show some
      synergistic effects, but the results of studies of the relationship between AD
      and stroke have been controversial. The objective of this study was to compare
      the frequency of cerebral infarcts, hemorrhages and minor cerebrovascular lesions
      in autopsy-confirmed AD and age-matched control brains. Using current routine and
      immunohistochemical methods 173 consecutive cases of autopsy-confirmed AD and 130
      age-matched controls were compared. The total incidence of vascular pathology
      (56.5%) in AD was significantly less than in a previously reported smaller AD
      autopsy cohort (82.3%) (P<0.01), and was higher than in controls (42.4%). The
      incidence of severe CVL (old and recent infarcts, hemorrhages) in our cohort was
      slightly higher (12.7%) than in controls (8.5%), that of minor to moderate CVL
      (lacunes, cerebral amyloid angiopathy with or without minor vascular lesions) was
      more frequent in AD (43.8%) than in controls (33.9%), but the results were not
      statistically significant (P<0.03). The brain weight and severity of cognitive
      decline did not correspond to the degree of vascular pathology, but higher
      neuritic Braak scores and reduced brain weight contributed to the production of
      cognitive impairment. Like previous findings in Parkinson's disease, our data do
      not indicate a protective effect from stroke or a significantly greater
      susceptibility to death from stroke in AD in the population studied, but further
      prospective clinico-pathological studies are necessary.

PMID- 12471456
TI  - Intrafusal fiber type composition of muscle spindles in the first human lumbrical
      muscle.
AB  - We studied muscle spindles in the first lumbrical muscle of adult humans using
      myofibrillar ATPase (mATPase) activity. We found that muscle spindles exhibited a
      marked variability with respect to the number, position, length and detailed
      histochemical features of nuclear bag1, nuclear bag2 and nuclear chain fibers.
      Regarding mATPase activity, the nuclear bag2 fibers displayed lower alkali-stable
      mATPase activity along their length and many nuclear bag1 fibers tended to have
      lower acid-stable activity in the outer B region, whereas nuclear chain fibers
      exhibited medium acid-stable mATPase activity at pH 4.6. Almost 10% of spindle
      fibers displayed atypical features, as they were either located only at one
      spindle pole or exhibited mixed characteristics at either pole. The number of
      intrafusal fibers per spindle varied between 8 and 24. Strikingly, only 2 pairs
      from 22 muscle spindles had identical allotments of their intrafusal fibers.
      Muscle spindles in the first human lumbrical muscle contained more intrafusal
      fibers (12.3 +/- 4 per spindle on average) and especially relatively more nuclear
      bag fibers compared to other human skeletal muscles. Since each spindle
      apparently represents a unique morphological and physiological entity, the
      observed variability in the number and characteristics of intrafusal fibers in
      the first human lumbrical muscle likely reflects a wide range of finely tuned
      muscle spindle responses.

PMID- 12471457
TI  - Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism
      in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele.
AB  - The apolipoprotein E epsilon4 allele (APOE, gene; apoE, protein) is widely
      accepted as a risk factor for Alzheimer's disease (AD). Our previous studies
      found that APOEepsilon4 promotes AD pathogenesis by fostering the early
      deposition of the amyloidogenic peptide Abeta in the aging brain. Recent reports
      suggest that polymorphisms in the upstream promoter region of APOE differentially
      affect the production of apoE and also may have an important influence on the
      probability of developing AD. In this study, we asked whether APOE promoter -491
      (A/T) variants interact with APOE polymorphisms to modulate the degree of beta
      amyloid- and tau-related pathology in the medial temporal lobe of the non
      demented elderly. Our results confirm that APOEepsilon4 is associated with
      increased formation of senile plaques, cerebrovascular amyloid, and
      neurofibrillary tangles in the medial temporal lobe. We also found that
      homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with
      increased Abeta17-24 and Abeta42 deposition in APOEepsilon4-positive cases, but
      not in cases lacking the epsilon4 allele. In comparison, Abeta burden is
      significantly less in epsilon4 carriers with the -491AT and -491TT promoter
      allelotypes. There was no effect of -491 polymorphisms on Abeta40 deposition
      (which is relatively sparse in the non-demented elderly), on the number of
      activated microglia, or on the amount of neurofibrillary tangles. We conclude
      that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the
      APOE promoter that enhance apoE production.

PMID- 12471458
TI  - Adverse effects of maternal ethanol consumption on development of dorsal
      hippocampus in rat offspring.
AB  - We examined the laminar structure and distribution of mossy fiber terminal fields
      in the dorsal hippocampus, an important area for spatial learning, in rats
      exposed to ethanol during gestational days 10-21. Pyramidal cells in the CA3a
      subfield were loosely packed compared to control rats. Aberrant infra- and
      intrapyramidal mossy fibers were found in the CA3 region, especially in the CA3a
      subfield, throughout the dorsal hippocampus of ethanol-exposed rats. Aberrant
      mossy fiber terminals were observed more frequently in the rostral than the
      caudal level of the dorsal hippocampus. At the most caudal level of the dorsal
      hippocampus, disarrangement of pyramidal cells was seen in the CA3c subfield
      along with disturbed mossy fiber terminals. Immunohistochemical studies revealed
      that neural cell adhesion molecule (NCAM) was not related to aberrant
      distribution of mossy fiber terminals after prenatal exposure to ethanol.
      Parvalbumin immunoreactivity was increased in the dorsal hippocampus of ethanol
      exposed rats compared with control rats. Abnormal development of the dorsal
      hippocampus induced by prenatal ethanol exposure may be associated with the
      defect of spatial memory seen in fetal alcohol syndrome children and their animal
      models.

PMID- 12471459
TI  - Matrix metalloproteinases-9 and -2 in secondary vasculitic neuropathies.
AB  - Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteinases
      that play an important role in inflammation and tissue degradation. MMP-9 and MMP
      2 are gelatinases that have been implicated in the degradation of the blood-brain
      or blood-nerve barrier. We present an immunohistochemical study on 11 nerve
      biopsy samples of inflammatory and non-inflammatory polyneuropathies. Perineurium
      and endothelium were positive for MMP-2 in all tissue sections. In addition,
      there was a specific up-regulation of MMP-2 in stromal cells of chronic
      inflammatory demyelinating polyneuropathy (CIDP) and even more in vasculitic
      neuropathies. MMP-9-positive cells were detected in vessel walls, infiltrates,
      epineurium and endoneurium of vasculitic neuropathies. In CIDP, MMP-9-positive
      cells were prominent in vessel walls. Only a few MMP-9-positive cells were
      detected in noninflammatory controls in blood vessels and adhering to vessel
      walls. Double staining indicated that the infiltrating cells were T cells and
      macrophages. Our findings suggest that MMP-9 plays an important role in
      inflammatory peripheral neuropathy probably as means for inflammatory cell
      invasion.

PMID- 12471460
TI  - 125I-labeled galanin binding sites in congenital innervation defects of the
      distal colon.
AB  - Neuropeptides have turned out to be promising new parameters, in addition to the
      routinely performed histochemical diagnosis, of Hirschsprung's disease (HD).
      Studies of the peptidergic innervation of the affected intestinal segment of
      patients with HD have demonstrated a marked reduction in the density of several
      neuropeptide-containing nerve fibers. The frequency of nerve fibers storing the
      neuropeptide galanin (GAL) was found to be unchanged or slightly reduced in HD,
      but nothing is known about the occurrence of GAL receptors. In this study, in
      vitro receptor autoradiography using (125)I-labeled GAL and GAL
      immunofluorescence have been performed on frozen tissue sections from colon
      biopsies of 10 patients diagnosed with HD, 8 patients with intestinal neuronal
      dysplasia (IND B) and 20 patients with chronic obstruction but normal
      innervation. Binding sites were mainly detected in the mucosal and muscular
      layer, in acetylcholinesterase-positive nerve fiber bundles and ganglia within
      the submucosal layer and in close association to blood vessels. An increased
      population of GAL receptor positive, parasympathetic nerve fibers was seen in the
      aganglionic segment of HD as compared to controls and IND B. In contrast, GAL
      immunostaining which was unchanged in HD revealed a significant lack of GAL
      positive structures in IND B colon biopsies. Colocalization of GAL and GAL
      binding sites was only observed in thick nerve fibers in the submucosa. The
      presence of GAL binding sites in different cellular structures suggests an
      involvement of GAL in various physiological functions of the gastrointestinal
      tract.

PMID- 12471461
TI  - Expression of extracellular matrix components in a highly infiltrative in vivo
      glioma model.
AB  - This work demonstrates the expression of extracellular matrix (ECM) components in
      a highly infiltrative brain tumor model developed by simple inoculation of
      spheroids from five human glioma biopsy tissues directly into the brains of
      immunodeficient rats. Non-invasive tumors derived from one glioblastoma biopsy
      specimen and two glioma cell lines (D-54MG and U-251MG) were also included in
      this study. The extent of tumor cell infiltration was studied using a pan-human
      monoclonal anti-vimentin antibody. The cellular origin for several of these ECM
      components was identified using human-specific monoclonal antibodies and
      polyclonal antibodies detecting epitopes from both species. Immunostaining
      revealed a diffuse parenchymal staining of glioma-produced tenascin, whereas
      vitronectin was produced mainly by the invading glioma cells. ECM components such
      as laminin, fibronectin and collagen type IV were most probably produced by the
      host and were mainly associated with the blood vessels in the tumors. However,
      some parenchymal staining with regional variations was observed. The expression
      pattern of these components was different in cell lines tumors as compared to the
      biopsy specimen tumors. The alpha3 and beta1 integrin subunits were mainly
      observed in areas of tumor cell invasion in the invasive tumors. In conclusion,
      the observed staining patterns clarify the cellular origin and indicate the
      possible biological function of tenascin, vitronectin, laminin, fibronectin and
      collagen type IV in these highly invasive malignant tumors of glial origin.

PMID- 12471462
TI  - Induction of MC-1 immunoreactivity in axons after injection of the Fc fragment of
      human immunoglobulins in macaque monkeys.
AB  - Although previous studies have suggested an increased activation of humoral
      immunity in neurodegenerative diseases, it remains unclear whether this
      phenomenon is secondary to lesion formation or contributes directly to their
      development. Using stereotaxic injections in macaque monkey cerebral cortex, we
      studied the effects of human immunoglobulins on the neuronal cytoskeleton. Under
      these conditions, several MC-1-immunoreactive axons were observed in the vicinity
      of injection site. No MC-1 or TG-3 staining was detected in neuronal soma.
      Ultrastructurally, several axons in the same area displayed curly formations and
      accumulation of twisted tubules but not paired helical filaments. These data
      suggest that Fc fragment induce conformational changes of tau and subtle
      structural alterations in axons in this model. Immunocytochemical analyses in
      human autopsy materials revealed the presence of human Fc fragments as well as Fc
      receptors only in large pyramidal neurons known to be vulnerable in brain aging
      and Alzheimer's disease, further supporting a possible role of immunoglobulins in
      neurodegeneration.

PMID- 12471463
TI  - Molecular genetic diagnosis of a primary central nervous system T cell lymphoma.
AB  - Primary central nervous system T cell lymphomas are rare tumors. Histologically,
      they may be indistinguishable from other entities like inflammatory processes. In
      such cases, molecular genetic verification of clonal T cell receptor (TCR) gene
      rearrangements is an indispensable diagnostic tool. Here we present a case where
      identification of TCR beta and gamma gene rearrangements by polymerase chain
      reaction was used to differentiate between a vasculitis and a primary CNS T cell
      lymphoma, which has profound consequences for therapy management and outcome.

PMID- 12471464
TI  - The A8344G mutation in mitochondrial DNA associated with stroke-like episodes and
      gastrointestinal dysfunction.
AB  - We report an unusual case of encephalo-entero-myopathy associated with the A8344G
      mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). This patient had
      mitochondrial myopathy, multiple lipomatosis, mild hearing loss, stroke-like
      episodes, and paralytic ileus, but she lacked the canonical clinical features of
      MERRF, myoclonus, epilepsy, or ataxia. We conducted genetic, biochemical,
      histochemical, and immunohistochemical studies in skeletal muscle, brain,
      intestine, and lipoma tissue. The mutation was abundant in all tissues, and
      cytochrome c oxidase (COX) activity was selectively decreased in brain and small
      intestine. COX deficiency was also documented histochemically and
      immunohistochemically in the small intestine, suggesting that mitochondrial
      dysfunction played a role in the pathogenesis of paralytic ileus. This case
      illustrates an unusual and dramatic clinical phenotype of the A8344G mutation,
      characterized by stroke-like episodes and acute ileus.

PMID- 12471465
TI  - Clinico-pathological study of a case of familial parkinsonism with striatal
      degeneration.
AB  - The clinico-pathological study of a new type of familial parkinsonism with
      striatal degeneration is reported. The inheritance mode was autosomal recessive,
      and three out of four offspring of married cousins developed parkinsonism in
      their early adulthood. Their clinical signs were rigidity, bradykinesia, postural
      instability and dysarthria. These symptoms were slowly progressive and responsive
      to levodopa therapy to a variable degree. On cerebral magnetic resonance imaging,
      T2 and proton density-weighted images showed hyperintensity in the bilateral
      putamina. The neuropathological study of one case revealed atrophy of the
      bilateral putamina and caudate nuclei, and a severe neuronal loss and gliosis in
      the putamina. Patchy mosaicism of normal and degenerated tissue was observed in
      the putamina. A similar mode of the degeneration was mildly seen in the caudate
      nuclei. The substantia nigra showed atrophy of the pars reticulata, and mild to
      moderate neuronal loss of the pars compacta with rostral dominance, but no Lewy
      bodies were observed. These neuropathological findings differed from those of
      Parkinson's disease or juvenile parkinsonism, but mimic to those of X-linked
      dystonia parkinsonism (Lubag). It seems that this familial bilateral striatal
      degeneration is a new variant of familial parkinsonism.

PMID- 12471466
TI  - Frontotemporal dementia with cerebral intraneuronal ubiquitin-positive inclusions
      but lacking lower motor neuron involvement.
AB  - A case of frontotemporal dementia with cerebral intraneuronal ubiquitin-positive,
      tau- and alpha-synuclein-negative inclusions is reported. A 50-year-old female
      patient exhibited mental changes; however, no clinical evidence of motor neuron
      disease was detected in her 11-year history. Neuronal loss and spongiform changes
      were mainly found in the frontotemporal cortices. Degeneration of the pyramidal
      tract was observed. Depletion of Betz cells was observed, whereas motor neurons
      of the hypoglossal nuclei and spinal anterior horn were well preserved.
      Immunohistochemically, intraneuronal ubiquitin-positive, tau and alpha-synuclein 
      negative inclusions were present in the small neurons of the dentate gyrus,
      frontal cortices and putamen. Neither Betz cells nor the anterior horn cells
      contained any inclusions. Fragmentation of the Golgi apparatus was visible only
      in 2.2% of anterior horn cells. A large number of tau-positive glial structures
      lacking argyrophilia were seen in the area of the frontopontine tract in the
      cerebral peduncle. The pyramidal tract lesions of the present case may be based
      on frontal lobe degeneration with spread of lesions to the motor cortex. Except
      for the pyramidal tract lesions, our case is similar to cases of motor neuron
      disease-inclusion dementia.

PMID- 12471468
TI  - Total parenteral nutrition-induced apoptosis in mouse intestinal epithelium:
      regulation by the Bcl-2 protein family.
AB  - Apoptosis of intestinal epithelial cells (EC) plays a role in total parenteral
      nutrition (TPN)-induced villus atrophy. Among the mediators of apoptosis in EC
      are some members of the Bcl-2 family of proteins. Bcl-2 members can either be
      anti- (Bcl-2, Bcl-x(L), Bcl-w) or pro-apoptotic (Bax, Bak, Bid, Bad, Bcl-x(S)).
      To determine whether the observed increase in apoptosis induced by TPN is
      associated with an alteration in these Bcl-2 members' mRNA expression, mice were
      randomized to either TPN or oral feeding (controls). Animals were killed after 7
      days and the intestine was harvested. EC were purified with magnetic beads.
      Apoptosis was detected by cell-surface expression of phosphatidylserine using
      flow cytometry. EC mRNA expression was determined by reverse-transcriptase
      polymerase chain reaction. Results were expressed relative to beta-actin. TPN
      resulted in a significant ( P < 0.05, unpaired t-test) increase in apoptosis: TPN
      29.4 +/- 11.3% versus control 14.4 +/- 5.1%. The expression of the pro-apoptotic
      members Bax, Bak, Bid, and Bcl-x(S) was significantly ( P < 0.05) decreased after
      TPN. In contrast, a significant increase was observed in the anti-apoptotic
      member Bcl-2. mRNA expression of Bcl-w, Bad, and Bcl-x(L) was not significantly
      different between the control and TPN groups. Thus TPN-induced apoptosis was
      associated with an increased expression of anti-apoptotic factors and a decrease
      in pro-apoptotic factors. This contrasts with other reports where these factors
      showed converse effects under apoptotic conditions. Our results may demonstrate a
      unique regulatory pathway that may counter the observed increase in TPN-induced
      EC apoptosis.

PMID- 12471469
TI  - Cell death in the early adriamycin rat model.
AB  - The adriamycin rat model (ARM) exhibits many features of the VACTERL association.
      Adriamycin is a cytotoxic drug used in cancer chemotherapy. Although its exact
      mode of action is not clear, it is presumed to have a similar cytotoxic role in
      the developing embryo. Lysotracker red (LT) is a dye that stains phagolysosomes
      and apoptotic bodies and allows entire rodent embryos to be stained for
      apoptosis. We hypothesised that there was increased cell death in adriamycin
      exposed embryos. To investigate this hypothesis, adriamycin (1.75 mg/kg) was
      given intraperitoneally to rats on days 7, 8, and 9 of pregnancy. A control group
      was given saline on the same schedule. Embryos were recovered at 3, 12, 24, and
      48 h following the last dose and also at term (21 days) to confirm that the usual
      incidence of congenital anomalies found in the ARM was obtained in our animal
      model. Embryos were embedded in resin, sectioned, and studied by light
      microscopy. Embryos from the 3-h and 24-h groups were studied using LT and
      confocal microscopy to search for evidence of apoptosis. All term newborns (100%)
      from the adriamycin-treated group demonstrated the typical abnormalities found in
      the ARM, i.e., oesophageal atresia, multiple gastrointestinal atresias, vertebral
      malformations, absent tails, ureterohydronephrosis, etc. In the 9.5-day
      adriamycin group there was no difference in appearance between the experimental
      and control embryos. Specifically, no cellular debris or increased cell turnover
      indicative of adriamycin cytotoxicity was observed in the experimental group. At
      day 10.5, 90% of embryos from two separate litters had evidence of notochordal
      distortion and tethering to the gut or gut-tube abnormalities. These findings
      were not observed in the control embryos. Confocal microscopy and LT examination
      of the embryos from litters killed at 3 and 24 h following the last dose of
      adriamycin demonstrated no evidence of increased cell death in adriamycin-exposed
      embryos compared to control embryos. The absence of significant apoptosis in the
      developing embryos in the immediate period following administration of adriamycin
      suggests that the teratogenic effect of adriamycin is not caused by cell death.

PMID- 12471470
TI  - Location of stem cells for the enteric nervous system.
AB  - Hirschsprung disease is the result of aganglionosis of a variable length of the
      terminal bowel, which arises from the incomplete colonisation of the embryonic
      gut by vagal neural crest-derived cells (NCC) that migrate caudally from the
      pharyngeal gut to the rectum. We have previously shown that a very small group of
      NCC, at the leading edge of this wave of migration, can proliferate and
      differentiate to innervate the entire distal gut. It remains unknown if this
      capability is unique to those cells at the leading edge of NCC migration. The
      hypothesis tested was that NCC capable of acting as stem cells are found
      throughout the developing enteric nervous system (ENS). Gut was taken from mice
      at embryonic day 11.5 as the leading edge of NCC migration enters the colon.
      Terminal colon was separated as aganglionic recipient gut and its rostral end
      juxtaposed to the caudal end of the small intestine or caecum. The explants were
      cultured on nitrocellulose filters for up to 120 h, after which time the apposed
      segments had fused. The gut was then fixed and examined by immunohistochemistry
      to detect the neuronal markers PGP9.5 and nitric-oxide synthase (NOS) to assess
      development of enteric ganglia. NCC migrated from the proximal gut into the
      terminal colon, colonising it along its entire length. The pattern of NCC
      colonisation and differentiation of NOS-positive neurons was the same, regardless
      of whether the NCC were derived from the leading edge of migration in the caecum
      or from more proximal regions of the small intestine. Vagal NCC have the capacity
      to migrate into separated aganglionic terminal colon and differentiate into
      neurons. NCC at the leading edge of migration and those located more proximally
      within the gut demonstrate equivalent ability to migrate to and differentiate in
      the terminal rectum. Further studies are required to confirm which of these
      migrating NCC have the properties of ENS stem cells.

PMID- 12471471
TI  - Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture
      model.
AB  - Enteral probiotics such as Lactobacillus casei GG (LGG) have been used in the
      treatment of a variety of intestinal disorders in infants and children, including
      diarrhea, malabsorption, and Clostridium difficile colitis. Previous studies have
      identified the gene locus for mucin (MUC-2) and its expression in Caco-2 cells.
      Others have demonstrated that mucin, located on the surface of the intestinal
      epithelium, inhibits bacterial translocation (BT). We previously demonstrated
      that both mucin and the probiotic bacterium LGG have an inhibitory effect on BT
      in both an in-vitro Caco-2 cell model and a neonatal rabbit model. We
      hypothesized that the decline in BT by LGG is mediated by up-regulation of
      epithelial MUC-2. Human enterocyte Caco-2 cells were grown to confluence and
      incubated at 37 degrees C with either medium (control group) or 10(4) or 10(8)
      LGG for 180 min. Non-adherent LGG was washed away. Caco-2 cells were then lysed,
      purified, and quantified for MUC-2 protein and mRNA. The addition of LGG to the
      enterocyte monolayer surface resulted in significantly ( P < 0.05) increased MUC
      2 expression compared to the untreated monolayers. Protein densities for MUC-2
      significantly ( P < 0.05) increased with LGG. Density (expressed as ratio to
      control group) was 8.6 +/- 1.3 in the low-dose group (10(4) LGG) and 15.6 +/- 2.3
      in the high-dose group (10(8) LGG). LGG may thus bind to specific receptor sites
      on the enterocyte and stimulate the up-regulation of MUC-2, resulting in
      increased inhibition of BT.

PMID- 12471472
TI  - Lysophosphatidylcholine alters enterocyte monolayer permeability via a protein
      kinase C/Ca2+ mechanism.
AB  - The activity of phospholipase A(2) (PLA(2)) is elevated in the intestinal
      epithelia of patients with inflammatory bowel disease. We recently reported that
      PLA(2) mediates the hydrolysis of phosphatidylcholine (PC) to
      lysophosphatidylcholine (L-PC) when both are applied to the apical surface of
      cultures enterocyte monolayers, resulting in increased bacterial translocation
      (BT) and decreased transepithelial electrical resistance (TEER). However, the
      mechanism by which the converted L-PC affects tight-junction permeability (TJP)
      as reflected by decreased TEER is unknown. There are some reports that protein
      kinase C (PKC) or Ca(2+) mediate TJP in enterocyte monolayer models. To
      investigate whether the observed change in TJP was mediated via PKC or Ca(2+) in
      our Caco-2 monolayer model, human Caco-2 enterocytes were grown to confluence on
      porous filters in the apical chamber of a two-chamber cell culture system. The
      filters were then transferred to an Ussing chamber for precise, real-time
      resistance measurements. After 30 min equilibration, PC (0.1 or 1 mM) and L-PC
      (0.01, 0.1 or 1 mM), PMA 200 or 300 nM (phorbol 12-myristate 13-acetate, PCK
      activator), or staurosporine 12 nM (PKC inhibitor) were added to the apical
      chamber and TEER was measured every 20 s for 2 h. The concentration of
      intracellular free Ca(2+) in the monolayers before and after treatment with L-PC
      (1 mM) was measured by fluorometry of whole monolayers using the fluorescent
      calcium indicator fura-2. Neither PC at any dose nor the 0.01-mM L-PC dose had an
      effect on TEER. The 0.1-mM dose of L-PC had its greatest effect (47% +/- 3.5%
      reduction in TEER vs control) within 6 min following its addition, with TEER
      recovery to control levels (100%) at 2 h ( P < 0.05). The 1-mM dose of L-PC had
      its greatest effect (6% +/- 0.5% reduction in TEER vs control) within 3 min after
      its addition, but the TEER did not recover to control levels after 2 h of
      incubation ( P < 0.05). The addition of 200 or 300 nM PMA inhibited the observed
      recovery of TEER by L-PC. Conversely, the addition of 12 nM staurosporine
      enhanced TEER recovery to control levels. The 1-mM dose of L-PC increased the
      concentration of intracellular free Ca(2+) immediately after the addition of L
      PC. These results suggest that L-PC alters TJP via a PKC/Ca(2+) interaction in
      our Caco-2 monolayer model.

PMID- 12471473
TI  - In-vivo retroviral gene transfer to the liver is cancelled by an immune response
      against the corrected cells. Can it be avoided?
AB  - Highly efficient retroviral-mediated gene transfer into hepatocytes in vivo has
      been previously reported in rats, but some reports described transient expression
      of the transgene that may be related to induction of an immune response against
      the transgene product. To devise a surgical approach to circumvent this drawback,
      two-thirds partial hepatectomy was performed in Wistar male rats to induce the
      hepatocyte division required to achieve retrovirus integration. Delivery of
      amphotrophic retroviral vectors (RVV) encoding Escherichia coli beta
      galactosidase was performed 24 h after partial hepatectomy. In a first group (n =
      11), gene delivery was performed by peripheral injection of 2 ml retrovirus
      containing medium. For the second group (n = 11), asanguineous perfusion of the
      regenerating liver after complete vascular exclusion was carried out with 20 ml
      viral solution. Liver biopsies were performed sequentially in each group. In the
      first group, beta-galactosidase was expressed at day 7 in 7 +/- 6.3% of
      hepatocytes and the labeled hepatocytes had disappeared in less than 4 weeks.
      Polymerase chain reaction experiments demonstrated the elimination of the
      transduced cells and the appearance of antibodies against beta-galactosidase. Of
      the 11 rats in the second group, 8 were still able to express beta-galactosidase
      more than 6 weeks after asanguineous perfusion with no detectable antibody
      response. Asanguineous perfusion of the regenerating liver with RVV after
      complete vascular exclusion enabled long-term expression in rats and avoided the
      immune response present after peripheral delivery in most animals. These results
      suggest that the immune reaction is secondary to viral infection of antigen
      presenting cells. Asanguineous perfusion could thus be a way to perform gene
      therapy for inherited liver diseases without immunosuppressive therapy.

PMID- 12471474
TI  - Effects of vitamin A on malformations of neural-crest-controlled organs induced
      by nitrofen in rats.
AB  - Vitamin A (vit A) alleviates the effects of nitrofen in exposed rat pups. The
      present study examines the effects of early exposure to vitamin A on the neural
      crest-related cardiovascular, thymic, parathyroid, and thyroid malformations
      previously reported in the rat model of congenital diaphragmatic hernia (CDH).
      Pregnant rats were exposed on gestational day 9.5 to 100 mg 2-4-dichlorophenyl-p
      nitrophenyl ether (nitrofen) alone or followed by 15,000 IU vit A. Controls were
      treated only with oil or oil + vit A. The fetuses were recovered near term and
      diaphragmatic, lung, heart, and thymic malformations were sought after
      dissection. The parathyroids and thyroid were histologically investigated. The
      hearts were also examined for protein, DNA, and proportion of proliferating
      cells. None of the control fetuses had malformations, whereas 41% of nitrofen and
      27% of nitrofen + vit A fetuses had CDH. Anomalies of the heart outflow tract and
      pharyngeal arteries were seen in 64% and 43%, respectively, in both groups. Heart
      and thymic hypoplasia, which were severe in the nitrofen group with significant
      decreases of total DNA and percent proliferating cells, were significantly
      improved in the nitrofen + vit A group. The hypoplastic thymus was malformed in
      53% and 27% of fetuses, respectively, and the parathyroids were abnormal in 48%
      and 35%, respectively. Only minimal anomalies of the thyroid were found. The
      significant improvement of heart and thymic hypoplasia associated with vit A was
      not seen for the other variables studied, but there was a trend in this direction
      for all of them. Vit A definitely improved heart hypoplasia induced by nitrofen
      by stimulating myogenesis. It also improved thymic hypoplasia, but had limited
      beneficial effects on malformations of the cardiac outflow tract and pharyngeal
      derivatives that accompany CDH in rats exposed to nitrofen.

PMID- 12471475
TI  - Effects of early embryonal exposure to dexamethasone on malformations of neural
      crest derivatives induced by nitrofen in rats.
AB  - Prenatal corticosteroids reverse to some extent lung and heart hypoplasia in
      nitrofen-exposed rat pups. The present study examines the effects of early
      exposure to dexamethasone on the neural crest-related malformations of the
      cardiovascular system, thymus, parathyroids, and thyroid observed in this model.
      Pregnant rats were exposed on gestational day 9.5 to either 100 mg 2-4
      dichlorophenyl-p-nitrophenyl ether (nitrofen) alone or followed on days 10.5 and
      11.5 by 0.4 mg/kg dexamethasone (dexa) i.p. Controls were treated with either oil
      alone or oil+dexa alone. The fetuses were recovered near term and diaphragmatic,
      lung, heart, and thymic malformations were sought after dissection. The
      parathyroids and thyroid were histologically investigated. Control fetuses had no
      malformations whereas 68% of nitrofen and 65% of nitrofen + dexa fetuses had
      congenital diaphragmatic hernias (CDH). Heart-outflow tract and pharyngeal artery
      anomalies were seen in 62% and 61%, respectively in both groups. Heart
      hypoplasia, which was severe in the nitrofen group, was fully reversed in
      nitrofen+dexa pups. In contrast, thymic hypoplasia was of similar severity in
      both groups. The hypoplastic thymus was malformed in 29% and 39%, the
      parathyroids in 50% and 41%, and the thyroid in 25% and 16% of fetuses,
      respectively. These differences were not significant. Early exposure to dexa in
      rat fetuses previously treated with nitrofen thus does not produce any benefit on
      the incidence or severity of malformations of the cardiac outflow tract and
      pharyngeal derivatives that accompany CDH in rats exposed to nitrofen. However,
      even administered so early, this medication prevents heart hypoplasia, suggesting
      a favorable effect on early heart organogenesis.

PMID- 12471476
TI  - The role of contractile microfilaments in the morphogenesis of the developing
      foregut of chick embryos.
AB  - The cellular processes that lead to changes in shape (morphogenesis) and organ
      formation (organogenesis) are poorly understood. Local contraction of
      microfilaments can change cell shape and lead to changes of tissue shape. To
      clarify the role of contractile microfilaments in the foregut morphogenesis of
      chick embryos, 2- to 4-day-old embryos were exposed to cytochalasin D (CD), which
      is known to disrupt microfilaments. Untreated age-matched embryos were used as
      controls. Sections of treated embryos and controls were stained with phalloidin,
      which binds to actin, and examined with a fluorescence microscope. Microdissected
      specimens were examined using a scanning electron microscope (SEM).
      Immunofluorescent staining showed a bright signal belt toward the apical cell
      region of the foregut epithelium in controls. This signal was not evident in CD
      exposed embryos. SEM micrographs of the controls showed the cranial foregut as a
      smooth, even, cylindrical structure in all stages studied. The lumen was narrow
      and perfectly straight, the ventral and dorsal walls were in close apposition.
      The foregut of CD-exposed specimens, however, showed a wide lumen and the walls
      were separated from each other. The structure seemed atonic and appeared conical,
      curved, or tilted. We observed a dense microfilament network toward the apical
      cell pole of the epithelial foregut cells of controls that was no longer evident
      after CD exposure. This network seems to play an important role in foregut
      morphogenesis, since actin-filament disruption by CD causes loss of the normal
      shape.

PMID- 12471477
TI  - Lipopolysaccharide endotoxemia reduces cell proliferation and decreases
      enterocyte apopotosis during intestinal adaptation in a rat model of short-bowel
      syndrome.
AB  - Sepsis is frequently associated with or complicates short-bowel syndrome (SBS).
      To investigate the effects of lipopolysaccharide (LPS) endotoxemia on enterocyte
      proliferation and death via apoptosis in a rat model of SBS, adult male Sprague
      Dawley rats were divided into three experimental groups: sham rats underwent
      bowel transection and reanastomosis; SBS rats underwent 75% small-bowel
      resection; and SBS-LPS rats underwent 75% bowel resection and were given
      intraperitoneal injections of LPS 10 mg/kg. Parameters of intestinal adaptation
      (bowel and mucosal weights, mucosal DNA and protein, villus height, and crypt
      depth), enterocyte proliferation, and death via apoptosis were determined on day
      15 after the operation. Statistical analysis was determined by Student's and
      ANOVA tests with a P less than 0.05 considered significant. SBS-LPS animals
      demonstrated a significant decrease (vs SBS rats) in duodenal (20%), jejunal
      (30%), and ileal (15%) overall weight, duodenal (20%), jejunal (27%), and ileal
      (18%) mucosal weight, jejunal (20%) and ileal (30%) mucosal DNA, jejunal (29%)
      and ileal (31%) villus height, and jejunal (14%) and ileal (29%) crypt depth. LPS
      endotoxemia led to reduced cell proliferation and enterocyte apoptosis compared
      to untreated SBS animals. Thus, in a rat model of SBS, LPS endotoxemia inhibits
      intestinal adaptation. A possible mechanism may be decreased cell proliferation.
      Decreased enterocyte loss via apoptosis may reflect a reduced number of
      enterocytes. Other mechanisms (necrosis) may be mainly responsible for cell death
      following LPS injection.

PMID- 12471478
TI  - Effect of bowel resection and high-fat diet on heart CD36/fatty-acid translocase
      expression in a rat model of short-bowel syndrome.
AB  - Long-chain fatty acids (LCFA) are the major energy substrates for the heart. In
      short-bowel syndrome (SBS), LCFA delivery to the myocardium decreases due to fat
      malabsorption. Fatty-acid translocase (FAT)/CD36 has recently been identified as
      a LCFA-binding protein in heart tissue. To determine the effects of bowel
      resection and a high-fat diet (HFD) on myocardial CD36 expression, male Sprague
      Dawley rats were randomly assigned to one of three groups: sham rats fed normal
      chow (Sham-NC); SBS rats fed NC (SBS-NC), and SBS rats fed a HFD (SBS-HFD).
      Control rats underwent transection and anastomosis; SBS animals underwent 75%
      small-bowel resection. Rats were killed at 3 or 14 days. Total body weight, heart
      weight, heart-tissue total lipid, serum cholesterol, and triglycerides were
      determined at death. Total RNA from the myocardium was extracted using TRIZOL
      reagent. Northern-blot analysis was used to determine FAT/CD36 mRNA. Statistical
      significance was determined by Student's t-test with P values below 0.05
      considered significant. SBS-NC and SBS-HFD rats had significantly lower body
      weights compared with Sham-NC animals. The heart weights and myocardial total
      lipid did not vary among experimental groups. Decreases in plasma triglycerides
      (38.2 +/- 3.8 vs 58.8 +/- 5.5 mg/dl, P < 0.05) and cholesterol (38.2 +/- 6.9 vs
      55.3 +/- 8.2 mg/dl, P < 0.05) in SBS-NC compared to Sham-NC rats on day 3 was
      accompanied by a twofold increase ( P < 0.05) in myocardial CD36/FAT mRNA levels.
      Early exposure to HFD led to increased (vs SBS-NC) plasma cholesterol (82.9 +/-
      5.7 vs 38.2 +/- 6.9 mg/dl, P < 0.05) and triglycerides (62.5 +/- 15.6 vs 38.2 +/-
      3.8 mg/dl, P < 0.05), and a concomitant decrease in CD36/FAT mRNA levels (45.1 +/
      17.8 vs 86.6 +/- 15%, respectively, P < 0.05). Plasma lipid concentration and
      myocardial CD36/FAT mRNA levels on day 14 were not significantly different among
      the experimental groups. In this rat model of SBS, the heart thus reacts to
      decreased LCFA delivery by increased tissue CD36/FAT mRNA levels and,
      consequently, active LCFA uptake. A HFD increased plasma lipid concentrations and
      decreased CD36/FAT levels.

PMID- 12471479
TI  - Nitric oxide synthase isoenzyme activities in a premature piglet model of
      necrotizing enterocolitis: effects of nitrergic manipulation.
AB  - Nitric oxide (NO) plays a major role in gut mucosal protection and motility.
      Having demonstrated the protective effects of intravenous L-arginine (L-arg) and
      the NO donor, sodium nitroprusside (SNP), in an in-vivo premature piglet
      intraluminal model of necrotizing enterocolitis (NEC) that incorporates both
      mucosal damage and intestinal dysmotility, we measured the effects on NO synthase
      (NOS) isoenzyme activities during i.v. manipulation of the nitrergic system in
      the NEC-injured gut. In newborn premature Yorkshire piglets, NEC was induced in
      four groups by intraluminal injection of acidified casein solution in closed test
      loops of bowel separated by normal saline-injected control loops. Group 1 (n = 4)
      underwent no further treatment. Group 2 (n = 4) received concomitant continuous
      i.v. L-arg, a NO substrate. Group 3 (n = 6) received concomitant continuous i.v.
      SNP, a NO donor. Group 4 (n = 5) received concomitant continuous i.v. N-omega
      nitro-L-arginine-methyl-ester (L-NAME), a non-selective NO inhibitor. Control and
      test gut specimens were harvested after 3 h. NO synthase activity in frozen gut
      segments was assessed using the (14)C-L-arg to (14)C-L-citrulline conversion
      assay. Total NOS (TNOS), constitutive NOS (cNOS), and inducible NOS (iNOS)
      activities were compared. The mean and standard error were calculated for each
      specimen. Group means were used to compare test and control gut enzyme activities
      in the different treatment groups. One-way analysis of variance and the
      Bonferroni post test were used to compare differences among groups. A P value of
      less than 0.05 was considered significant. In the L-NAME group, cNOS activity was
      lower than in the untreated NEC group. The SNP group had higher iNOS and TNOS
      activities than the L-arg group; cNOS was also higher in test and control loops
      in the SNP versus both L-arg and L-NAME groups. However, in L-arg control loops,
      cNOS activity was greater than in the L-NAME group. SNP and L-arg treatment of
      NEC did not significantly modify NOS isoenzyme activities. Thus, in this
      premature piglet 3-h model of NEC, i.v. L-NAME significantly decreases cNOS
      activity and correlates with our previously published histopathologic findings
      confirming the protective role of cNOS-derived NO in NEC-injured gut mucosa. In
      order to further elucidate the mechanisms involved in the mucosal protection
      afforded by i.v. L-arg and SNP in this NEC model, studies of a longer duration
      have been undertaken.

PMID- 12471480
TI  - The role of nitric oxide in reflux nephropathy.
AB  - Reflux nephropathy (RN) is recognized as a major cause of end-stage renal failure
      in children and young adults. Inhibition of nitric oxide (NO) exacerbates and
      enhanced production ameliorates tubulointerstitial fibrosis (TIF) in experimental
      obstructive uropathy. NO is synthesised by NO synthase (NOS), three distinct
      isoforms of which have been identified: inducible (iNOS), endothelial (eNOS), and
      neuronal (nNOS). It has been reported that iNOS induces immunologic injury to
      glomerular cells and enhances accumulation of extracellular matrix in the
      glomerulus and tubulointerstitial space. Furthermore, it has been suggested that
      nNOS and eNOS have beneficial effects in ameliorating TIF. We investigated the
      expression of different isoforms of NOS in severe refluxing kidneys in order to
      further understand the pathogenesis of RN in kidney specimens from nine children
      with severe RN obtained at nephrectomy. Control material included normal kidney
      specimens from three adult patients undergoing partial nephrectomy for small
      kidney tumours. Histochemistry for NO was performed using nicotinamide adenine
      dinucleotide phosphate (NADPH)-diaphorase. Single-label immunofluorescence
      histochemistry was carried out using polyclonal antibodies to nNOS, iNOS, eNOS,
      and transforming growth factor (TGF)-beta 1 employing laser-scanning confocal
      microscopy. The TUNEL method was used to assess tubular apoptosis. Strong NADPH
      staining was observed in the proximal tubules of RN kidneys compared to controls,
      where there was weak staining. Control kidneys demonstrated weak immunoreactivity
      for iNOS in the proximal tubules and a lack of immunoreactivity for nNOS and
      eNOS. RN kidneys demonstrated strong immunoreactivity for nNOS in the
      tubulointerstitial space, for eNOS in the glomerulus, and for iNOS in the
      glomerulus and proximal tubules. Strong immunoreactivity for TGF beta 1 was seen
      in the glomerulus and proximal tubules identical to iNOS. Increased
      immunoreactivity for iNOS and TGF-beta 1 strongly correlated with the severity of
      apoptosis in RN. Our data demonstrate that NO derived from nNOS, iNOS, and eNOS
      is strongly expressed in RN. The selective shunting of NO via iNOS may induce
      renal fibrosis in RN. The upregulation of nNOS and eNOS in RN appears to be a
      compensatory mechanism of ameliorating TIF.

PMID- 12471481
TI  - Up-regulation of angiotensin-converting enzyme (ACE) gene expression induces
      tubulointerstitial injury in reflux nephropathy.
AB  - Reflux nephropathy (RN) is the cause of end-stage renal failure in 3%-25% of
      children and 10%-15% of adults. Angiotensin-converting enzyme (ACE) converts the
      inactive decapeptide angiotensin I (Ang I) to the active octapeptide angiotensin
      II (Ang II), a potent vasoconstrictor. ACE is localized in highest concentrations
      on the luminal surface of endothelial cells, but is also found in several other
      cell types, including the epithelial cells of the proximal renal tubule. Recent
      studies have suggested that ACE increases production of the components of
      extracellular matrix (ECM) such as fibronectin (Fib) mediated through Ang II.
      Since RN is a primary tubulointerstitial disease, we hypothesized that local
      overexpression of ACE may induce renal fibrosis via up-regulation of Ang II. In
      this study, we investigated the expression of ACE in severely refluxing kidneys
      from eight patients (age range 6 months-14 years) with severe RN secondary to
      primary high-grade vesicoureteral reflux at nephrectomy. Control material
      included normal kidney specimens obtained from three adult patients during
      partial nephrectomy for an incidentaloma. Soluble enzyme immunohistochemistry was
      carried out using polyclonal antibodies to ACE and Fib. In-situ hybridization
      (ISH) was performed utilizing biotin-labelled antisense oligonucleotide probe.
      Reverse transcription-polymerase chain reaction (RT-PCR) was performed to
      evaluate the relative amount of ACE mRNA. In the refluxing kidney, there was
      strong ACE immunoreactivity in the glomerulus and proximal tubules and moderate
      to-strong immunoreactivity in the distal tubules accompanied by strong Fib
      immunoreactivity in the glomerulus, proximal tubule, and interstitial space.
      There was strong ACE mRNA expression in the glomerulus and proximal tubules and
      moderate expression in the distal tubules. In the control kidneys, homogeneous
      weak ACE immunoreactivity and mRNA expression was demonstrated only in the
      proximal tubules. RT-PCR showed strong ACE expression in the refluxing kidneys
      compared to controls. Up-regulation of ACE in RN accompanied by an increase in
      ECM in the tubulointerstitial space suggests that ACE is involved in the
      pathogenesis of the renal parenchymal damage in patients with RN. Pharmacologic
      blockade of ACE may be helpful in preventing the renal fibrosis associated with
      RN.

PMID- 12471482
TI  - Organ-specific maturation of the major histocompatibility antigens in rats.
AB  - The essential role of major histocompatibility complex (MHC) class I and II in
      the process of rejection has been documented, and some studies suggest that fetal
      transplants could enjoy an organ-specific immunologic privilege. However, little
      is known as to when these antigens develop in fetal organs and which tissues
      mainly present them. This study investigated the dynamics of immunogenicity in
      the developing transplant organs of rats. The study focused on the classic
      transplant organs including lung, heart, liver, pancreas, intestine, and kidney.
      Fetal organs (14th and 20th day of gestation), organs at the 3rd, 7th, 10th, 14th
      and 28th days postpartum (pp), 2 and 3 months pp, and adult organs were taken and
      snap-frozen in liquid nitrogen. MHC expression was analyzed applying the APAAP
      technique on serial cryosections by two well-defined monoclonal antibodies (mAb)
      generated against rat MHC class I (Ox 18) and class II (Ox 6). Immunoreactivities
      were compared to those of different monoclonal markers against endothelial cells
      (HIS52, CD 31), histiocytes (ED 1, ED 2), dendritic cells (Ox-62), granulocytes
      (HIS48), B-cells (RLN-9D3), T-cells (Ox-52), CD 4 (Ox-35), CD 8 (Ox-8a), natural
      killer cells (10/78), and CD 45 (Ox-1, leukocyte common antigen). A non specific
      mAb (MR 12/53) served as a negative control. In all stages of organ maturation,
      MHC I expression was found predominantly on immunocompetent cells, endothelial
      cells, and certain parenchymal cells, whereas MHC II was almost entirely
      restricted to dendritic cells. In organ development, the onset of MHC I
      expression and the number of MHC II-positive cells varied in a time-dependent
      manner. However, between the 2nd and 3rd month pp the expression pattern was
      comparable to adult organs. The study indicates that each organ carries a
      variable immunologic burden, that matures heterogeneously. Consequently, the
      variable content of MHC I/II in organ maturation needs to be considered for any
      transplantation model.

PMID- 12471483
TI  - Birdsong: integrating physics, physiology, and behavior.

PMID- 12471484
TI  - Measurement of the linear and nonlinear mechanical properties of the oscine
      syrinx: implications for function.
AB  - We have measured the vibrational modes of the sound producing membrane in the
      syrinx of zebra finches and canaries. Excised syringes were driven with a
      frequency-swept acoustic pressure wave through the trachea, and the resulting
      vibrations measured using a laser interferometer. The frequency-dependent
      membrane compliance was measured at 10-20 different positions, giving a detailed
      picture of the linear vibrational modes of the two membrane components, the
      medial labium and the medial tympaniform membrane. Nonlinear properties of the
      membrane were determined by measuring the linear response at several superimposed
      static pressures. The membrane compliance is dominated by the lowest vibrational
      mode, a narrow mechanical resonance, at roughly 700 Hz in the zebra finch, that
      extends over the entire membrane. Several higher-frequency modes were also
      observed. The frequency of the lowest vibrational mode is determined largely by
      the mass of the heavier medial labium, rather than the thinner medial tympaniform
      membrane, suggesting that the medial labium is critical in determining the
      oscillatory frequency of the syrinx. The difference in mass of the medial labium
      and medial tympaniform membrane may serve to produce a wave-like motion of the
      membranes during flow-driven oscillations, thus increasing the efficiency of
      sound production. Implications for mechanisms of frequency tuning are discussed.

PMID- 12471485
TI  - New perspectives on mechanisms of sound generation in songbirds.
AB  - The physical mechanisms of sound generation in the vocal organ, the syrinx, of
      songbirds have been investigated mostly with indirect methods. Recent direct
      endoscopic observation identified vibrations of the labia as the principal sound
      source. This model suggests sound generation in a pulse-tone mechanism similar to
      human phonation with the labia forming a pneumatic valve. The classical avian
      model proposed that vibrations of the thin medial tympaniform membranes are the
      primary sound generating mechanism. As a direct test of these two hypotheses we
      ablated the medial tympaniform membranes in two species (cardinal and zebra
      finch) and found that both were still able to phonate and sing without functional
      membranes. Small changes in song structure (harmonic emphasis, frequency control)
      occurred after medial tympaniform membrane ablation and suggest that the medial
      tympaniform membranes play a role in adjusting tension on the labia. Such a role
      is consistent with the fact that the medial tympaniform membranes are directly
      attached to the medial labia. There is no experimental support for a third
      hypothesis, proposing an aerodynamic model for generation of tonal sounds.
      Indirect tests (song in heliox atmosphere) as well as direct (labial vibration
      during tonal sound) measurements of syringeal vibrations support a vibration
      based sound-generating mechanism even for tonal sounds.

PMID- 12471486
TI  - Evaluating theories of bird song learning: implications for future directions.
AB  - Studies of birdsong learning have stimulated extensive hypotheses at all levels
      of behavioral and physiological organization. This hypothesis building is
      valuable for the field and is consistent with the remarkable range of issues that
      can be rigorously addressed in this system. The traditional instructional
      (template) theory of song learning has been challenged on multiple fronts,
      especially at a behavioral level by evidence consistent with selectional
      hypotheses. In this review I highlight the caveats associated with these theories
      to better define the limits of our knowledge and identify important experiments
      for the future. The sites and representational forms of the various conceptual
      entities posited by the template theory are unknown. The distinction between
      instruction and selection in vocal learning is not well established at a
      mechanistic level. There is as yet insufficient neurophysiological data to choose
      between competing mechanisms of error-driven learning and reinforcement learning.
      Both may obtain for vocal learning. The possible role of sleep in acoustic or
      procedural memory consolidation, while supported by some physiological
      observations, does not yet have support in the behavioral literature. The
      remarkable expansion of knowledge in the past 20 years and the recent development
      of new technologies for physiological and behavioral experiments should permit
      direct tests of these theories in the coming decade.

PMID- 12471487
TI  - Towards quantification of vocal imitation in the zebra finch.
AB  - The transition from an amorphous subsong into mature song requires a series of
      vocal changes. By tracing song elements during development, we have shown that
      the imitation trajectory to the target could not be predicted based on monotonic
      progression of vocal changes, indicating an internal component that imposes
      constraints on song development. Here we further examine the nature of
      constraints on song imitation in the zebra finch. We first present techniques for
      identifying and tracing distinctive vocal changes, and then we examine how
      sequences of vocal change are expressed and coordinated. Examples suggest two
      types of constraints on song imitation, based on the nature of the temporal
      context. Developmentally diachronic constraints are imposed by sequential
      dependencies between vocal changes as a function of developmental time, whereas
      developmentally synchronic constraints are given by the acoustic context of notes
      within the song. Finally, we show that the tendency of birds to copy certain
      sounds in the song model before others might be related to such constraints. We
      suggest that documenting the full range of distinctive vocal changes and the
      coordination of their expression would be useful for testing mechanisms of vocal
      imitation.

PMID- 12471488
TI  - A bird's eye view: top down intracellular analyses of auditory selectivity for
      learned vocalizations.
AB  - The "song system" refers to a group of interconnected brain nuclei necessary for
      the utterance of learned song and for the generation of vocal plasticity
      important to both song learning and adult song maintenance. Although song
      learning and, in some species, song maintenance depend on auditory feedback, how
      audition influences vocalization remains unknown. One attractive idea is that
      auditory signals propagate directly to those telencephalic nuclei implicated in
      song patterning, providing a convenient substrate for sensorimotor integration.
      Consistent with this idea, auditory neurons highly selective for the bird's own
      song have been detected in telencephalic song nuclei, and lesions of these
      structures can impair song perception as well as song production. This review
      discusses evidence for an auditory-perceptual role of the song system, the
      anatomical pathways by which auditory information enters the song system, the
      synaptic events underlying highly selective action potential responses to learned
      song, and the possible roles such activity could play in song learning and
      maintenance.

PMID- 12471489
TI  - The relationship between perception and production in songbird vocal imitation:
      what learned calls can teach us.
AB  - Songbirds produce calls as well as song. This paper summarizes four studies of
      the zebra finch long call, used by both sexes in similar behavioral contexts.
      Female long calls are acoustically simpler than male long calls, which include
      acoustic features learned during development. Production of these male-typical
      features requires an intact nucleus robustus archistriatalis, the sexually
      dimorphic source of the telencephalic projection to brainstem vocal effectors. In
      experiments that quantified the long calls produced in response to long call
      playbacks, intact adult zebra finch males, but not females, show a categorical
      preference for the long calls of females over those of males. Experiments with
      synthetic stimuli showed that males classify long call stimuli that they hear by
      gender, using both spectral and temporal information, but that females use only
      temporal information. Juvenile males (<45 days) did not show the categorical
      preference, but it emerged during the same period when the robustus
      archistriatalis matures anatomically and the first male-typical vocalizations are
      produced. Adult males with robustus archistriatalis lesions lost the categorical
      preference for female long calls, suggesting that the robustus archistriatalis
      plays a role in long call discrimination. These results demonstrate that calls
      complement song as a potent tool for studying the neurobiology of vocal
      communication.

PMID- 12471490
TI  - Bilateral LMAN lesions cancel differences in HVC neuronal recruitment induced by
      unilateral syringeal denervation. Lateral magnocellular nucleus of the anterior
      neostriatum.
AB  - Twenty-six-day-old male zebra finches received (1) unilateral section of their
      tracheosyringeal nerve, (2) bilateral lesions of the lateral magnocellular
      nucleus of the anterior neostriatum (LMAN), and (3) both operations. All birds
      were kept with an adult, singing male as a tutor until day 65. Tracheo-syringeal
      nerve-cut birds were able to imitate this model, but LMAN-lesioned birds were
      not. Bromodeoxyuridine, a marker of cell division, was injected intramuscularly
      during post-hatching days 61-65 and all birds were killed at 91 days of age. The
      number of bromodeoxyuridine+ neurons in the high vocal center of the
      tracheosyringeal-cut birds was twice as high in the intact as in the nerve cut
      side. This asymmetry disappeared when nerve section was combined with bilateral
      LMAN lesions. The latter operation, by itself, had no effect on new neuron
      counts. We suggest that the single nerve cut produced a hemispheric asymmetry in
      learning, reflected in new neuron recruitment, which disappeared when LMAN
      lesions blocked learning.

PMID- 12471491
TI  - Neural strategies for learning during sensitive periods of development.
AB  - Precise patterns of neural connectivity and synaptic communication are modified
      by experience during restricted "sensitive" periods of development, and the
      circuitry and associated behaviors that emerge during such periods are frequently
      preserved throughout the lifespan. In many neural systems, the expression of
      various molecules that influence synaptic transmission and neuronal morphology
      are developmentally regulated and may serve to constrain the timing of enhanced
      sensitivity to experiential inputs. In this highly selective review I concentrate
      on recent findings from the visual system and the song system that provide novel
      insights into the mechanisms that regulate sensitive period plasticity, and that
      raise new questions concerning what makes sensitive periods so sensitive.

PMID- 12471492
TI  - Comparative approaches to avian song system function: insights into auditory and
      motor processing.
AB  - Many fundamental advances in our understanding of basic neural function have been
      made using bird song learning and performance as a model system. These advances
      have included a greater understanding of higher-order neural processing,
      developmental and hormonal influences on behavior, and the realization that
      neurogenesis plays an important role in normal adult brain function. The great
      diversity of passerine birds and song-related behaviors they exhibit suggest that
      oscine songbirds are ideally suited for comparative studies. While the
      comparative approach has been used successfully in the past to study song-related
      phenomena at anatomical and behavioral levels, it has been underutilized in
      addressing questions at the neurophysiological level. Most neurophysiological
      studies of songbird auditory and motor processing have been performed in one
      species, the zebra finch (Taeniopygia guttata). We present and compare
      neurophysiological studies we have performed in zebra finches and song sparrows
      (Melospiza melodia), species that differ markedly in their singing behavior and
      song repertoire characteristics. Interspecific similarities, and striking
      differences, in song neural processing are apparent. While preliminary, these
      data suggest that comparative neurophysiological studies of species carefully
      chosen for their vocal repertoire and singing behavior will contribute
      significantly to our understanding of vertebrate sensory and motor neural
      processing.

PMID- 12471493
TI  - Mapping vocal communication pathways in birds with inducible gene expression.
AB  - Expression mapping of activity-dependent genes has been very useful to reveal
      brain activation patterns associated with specific stimuli or behavioral
      contexts. In addition, activity-induced neuronal gene expression is likely
      associated with neuronal plasticity and may be part of the mechanism(s) involved
      in long-term memory formation. Analysis of the immediate-early gene zenk has been
      used to generate high-resolution maps of brain activation associated with
      perceptual and motor aspects of vocal communication in songbirds and other avian
      groups. This molecular approach has generated novel insights into the
      organization of perceptual and motor control pathways for vocal communication in
      birds. Its impact on the neurobiology of birdsong will be reviewed here. Emphasis
      will be given to the caudomedial neostriatum, the area that shows the most robust
      zenk induction upon presentation of song to songbirds. Another focal point will
      be the comparative analysis of vocally induced zenk expression patterns across
      the avian orders that evolved vocal learning (i.e., songbirds, parrots, and
      hummingbirds). New research directions indicated by this molecular analysis will
      be discussed throughout.

PMID- 12471495
TI  - A comparative study of avian auditory brainstem responses: correlations with
      phylogeny and vocal complexity, and seasonal effects.
AB  - We conducted a comparative study of the peripheral auditory system in six avian
      species (downy woodpeckers, Carolina chickadees, tufted titmice, white-breasted
      nuthatches, house sparrows, and European starlings). These species differ in the
      complexity and frequency characteristics of their vocal repertoires.
      Physiological measures of hearing were collected on anesthetized birds using the
      auditory brainstem response to broadband click stimuli. If auditory brainstem
      response patterns are phylogenetically conserved, we predicted woodpeckers,
      sparrows, and starlings to be outliers relative to the other species, because
      woodpeckers are in a different Order (Piciformes) and, within the Order
      Passeriformes, sparrows and starlings are in different Superfamilies than the
      nuthatches, chickadees, and titmice. However, nuthatches and woodpeckers have the
      simplest vocal repertoires at the lowest frequencies of these six species. If
      auditory brainstem responses correlate with vocal complexity, therefore, we would
      predict nuthatches and woodpeckers to be outliers relative to the other four
      species. Our results indicate that auditory brainstem responses measures in the
      spring broadly correlated with both vocal complexity and, in some cases,
      phylogeny. However, these auditory brainstem response patterns shift from spring
      to winter due to species-specific seasonal changes. These seasonal changes
      suggest plasticity at the auditory periphery in adult birds.

PMID- 12471496
TI  - Cultures, genes, and neurons in the development of song and singing in brown
      headed cowbirds (Molothrus ater).
AB  - In brown-headed cowbirds, Molothrus ater, as in many songbird species,
      vocalizations are fundamental to reproduction. In our studies, experiments
      utilizing different social housing regimes and geographic comparisons have
      indicated the social learning of males' vocalizations and associated abilities to
      use vocalizations effectively during the breeding season. Here, we describe
      studies indicating roles of cultural and genetic background, and of social
      influences from females, on male vocal development. These influences can interact
      with neural regions, including song learning and song control nuclei, but also
      visual-processing nuclei, in the development of signaling. We argue that a
      developmental systems approach to the study of vocal behavior provides a
      structure to organize these different influences and how they may interact with
      one another over development. A systems approach requires that researchers study
      the social context in which signals and signalers develop - both the ontogenetic
      arena in which young animals learn their signals from older animals, and the
      functional arena in which young and older animals socially interact with one
      another.

PMID- 12471494
TI  - A framework for integrating the songbird brain.
AB  - Biological systems by default involve complex components with complex
      relationships. To decipher how biological systems work, we assume that one needs
      to integrate information over multiple levels of complexity. The songbird vocal
      communication system is ideal for such integration due to many years of
      ethological investigation and a discreet dedicated brain network. Here we
      announce the beginnings of a songbird brain integrative project that involves
      high-throughput, molecular, anatomical, electrophysiological and behavioral
      levels of analysis. We first formed a rationale for inclusion of specific
      biological levels of analysis, then developed high-throughput molecular
      technologies on songbird brains, developed technologies for combined analysis of
      electrophysiological activity and gene regulation in awake behaving animals, and
      developed bioinformatic tools that predict causal interactions within and between
      biological levels of organization. This integrative brain project is fitting for
      the interdisciplinary approaches taken in the current songbird issue of the
      Journal of Comparative Physiology A and is expected to be conducive to
      deciphering how brains generate and perceive complex behaviors.

PMID- 12471497
TI  - Brain development, song learning and mate choice in birds: a review and
      experimental test of the "nutritional stress hypothesis".
AB  - The nutritional stress hypothesis explains how learned features of song, such as
      complexity and local dialect structure, can serve as indicators of male quality
      of interest to females in mate choice. The link between song and quality comes
      about because the brain structures underlying song learning largely develop
      during the first few months post-hatching. During this same period, songbirds are
      likely to be subject to nutritional and other stresses. Only individuals faring
      well in the face of stress are able to invest the resources in brain development
      necessary to optimize song learning. Learned features of song thus become
      reliable indicators of male quality, with reliability maintained by the
      developmental costs of song. We review the background and assumptions of the
      nutritional stress hypothesis, and present new experimental data demonstrating an
      effect of nestling nutrition on nestling growth, brain development, and song
      learning, providing support for a key prediction of the hypothesis.

PMID- 12471498
TI  - Dissimilation of the C2 sulfonates.
AB  - Organosulfonates are widespread in the environment, both as natural products and
      as xenobiotics; and they generally share the property of chemical stability. A
      wide range of phenomena has evolved in microorganisms able to utilize the sulfur
      or the carbon moiety of these compounds; and recent work has centered on
      bacteria. This Mini-Review centers on bacterial catabolism of the carbon moiety
      in the C2-sulfonates and the fate of the sulfonate group. Five of the six
      compounds examined are subject to catabolism, but information on the molecular
      nature of transport and regulation is based solely on sequencing data. Two
      mechanisms of desulfonation have been established. First, there is the specific
      monooxygenation of ethanesulfonate or ethane-1,2-disulfonate. Second, the
      oxidative, reductive and fermentative modes of catabolism tend to yield the
      intermediate sulfoacetaldehyde, which is now known to be desulfonated to acetyl
      phosphate by a thiamin-diphosphate-dependent acetyltransferase. This enzyme is
      widespread and at least three subgroups can be recognized, some of them in
      genomic sequencing projects. These data emphasize the importance of acetyl
      phosphate in bacterial metabolism. A third mechanism of desulfonation is
      suggested: the hydrolysis of sulfoacetate.

PMID- 12471499
TI  - Regulation of formation of the intracellular beta-galactosidase activity of
      Aspergillus nidulans.
AB  - The regulation of formation of the single intracellular beta-galactosidase
      activity of Aspergillus nidulans was investigated. beta-Galactosidase was not
      formed during growth on glucose or glycerol, but was rapidly induced during
      growth on lactose or D-galactose. L-Arabinose, and -- with lower efficacy -- D
      xylose also induced beta-galactosidase activity. Addition of glucose to cultures
      growing on lactose led to a rapid decrease in beta-galactosidase activity. In
      contrast, in cultures growing on D-galactose, addition of glucose decreased the
      activity of beta-galactosidase only slightly. Glucose inhibited the uptake of
      lactose, but not of D-galactose, and required the carbon catabolite repressor
      CreA for this. In addition, CreA also repressed the formation of basal levels of
      beta-galactosidase and partially interfered with the induction of beta
      galactosidase by D-galactose, L-arabinose, and D-xylose. D-Galactose
      phosphorylation was not necessary for beta-galactosidase induction, since
      induction by D-galactose occurred in an A. nidulans mutant defective in galactose
      kinase, and by the non-metabolizable D-galactose analogue fucose in the wild-type
      strain. Interestingly, a mutant in galactose-1-phosphate uridylyl transferase
      produced beta-galactosidase at a low, constitutive level even on glucose and
      glycerol and was no longer inducible by D-galactose, whereas it was still
      inducible by L-arabinose. We conclude that biosynthesis of the intracellular beta
      galactosidase of A. nidulans is regulated by CreA, partially repressed by
      galactose-1-phosphate uridylyl transferase, and induced by D-galactose and L
      arabinose in independent ways.

PMID- 12471500
TI  - New genes involved in chromate resistance in Ralstonia metallidurans strain CH34.
AB  - Chromate resistance in Ralstonia metallidurans CH34 is based on chromate efflux
      catalyzed by ChrA efflux pumps. The bacterium harbors two chromate resistance
      determinants, the previously known chr(1) on plasmid pMOL28 (genes chrI, chrB(1),
      chrA(1), chrC, chrE, chrF(1)) and chr(2) on the chromosome (genes chrB(2),
      chrA(2), chrF(2)). Deletion of the genes chrI, chrC, chrA(2), chrB(2) and chrF(2)
      influenced chromate resistance and transcription from a chrBp(1) ::lacZ fusion.
      Deletion of the plasmid-encoded gene chrB(1) did not change chromate resistance
      or chrBp(1) regulation. Northern hybridization and primer-extension experiments
      were used to study transcription of the plasmid-encoded chr(1) determinant.
      Transcription of chrB(1), chrA(1) and chrC was induced by chromate. The presence
      of sulfate influenced transcription positively. The chrBp(1), chrAp(1) and
      chrCppromoters showed some similarity to heat-shock promoters. Transcription of
      the gene rpoH encoding a putative heat-shock sigma factor was also induced by
      chromate, but rpoH was not essential for chromate resistance. The ChrC protein
      was purified as a homotetramer and exerted superoxide dismutase activity. Thus,
      possible regulators for chromate resistance (ChrI, ChrB(1), ChrB(2), ChrF(1), and
      ChrF(2)) and an additional detoxification system (ChrC) were newly identified as
      parts of chromate resistance in R. metallidurans.

PMID- 12471502
TI  - Enterobacter cloacae rpoS promoter and gene organization.
AB  - The upstream region of the Enterobacter cloacae strain CECT960 rpoS gene was
      sequenced. An IS 10R element was found within the nlpD gene, between rpoSp and
      rpoS. The rpoS promoter, although functional, did not drive transcription of the
      gene in this strain. However, rpoS transcription depended on this promoter in
      strains that lacked the insertion sequence in nlpD. rpoSp showed growth-phase
      dependent, sigma(S)-independent regulation. Transcription from rpoSp was strongly
      inhibited by glucose even though it was cAMP-receptor-protein (CRP)-independent.
      Its functionality was also independent of both integration host factor (IHF) and
      the alarmone ppGpp. RpoS-dependent resistance to some environmental stresses
      showed a quantitative response to RpoS levels under some conditions (alkaline pH
      and high osmolarity) but not others (acidic pH, high temperature, and UV
      irradiation).

PMID- 12471501
TI  - Biotin synthase of Bacillus subtilis shows less reactivity than that of
      Escherichia coli in in vitro reaction systems.
AB  - The biotin synthases of Bacillus subtilis and Escherichia coli were compared in a
      physiological reduction system using cell-free extracts and in a artificial
      reduction system using photo-reduced deazariboflavin. The biotin synthase of B.
      subtilis was less active than that of E. coli in both reaction systems and showed
      at least ten-fold less biotin-forming activity than that of E. coli in the
      artificial reduction system. The physiological reduction system using the biotin
      synthases and cell-free extracts of B. subtilis and E. coli showed species
      specificity. The results suggest that the activity of the physiological reduction
      system of B. subtilisis weaker than that of E. coli. Addition of excess
      dethiobiotin inhibited biotin formation by growing cells of B. subtilis, but not
      by E. coli.

PMID- 12471503
TI  - Aeropyrum pernix K1, a strictly aerobic and hyperthermophilic archaeon, has two
      terminal oxidases, cytochrome ba3 and cytochrome aa3.
AB  - Aeropyrum pernix K1 is a strictly aerobic and hyperthermophilic archaeon that
      thrives even at 100 degrees C. The archaeon is quite interesting with respect to
      the evolution of aerobic electron transport systems and the thermal stability of
      the respiratory components. An isolated membrane fraction was found to oxidize
      bovine cytochrome c. The activity was solubilized in the presence of detergents
      and separated into two fractions by successive chromatography. Two cytochrome
      oxidases, designated as CO-1 and CO-2, were further purified. CO-1 was a ba(3)
      type cytochrome containing at least two subunits. Chemically digested fragments
      of CO-1 revealed a peptide with a sequence identical to a part of a putative
      cytochrome oxidase subunit I encoded by the gene ape1623. CO-2, an aa(3)-type
      cytochrome, was present in lower amounts than CO-1 and was immunologically
      identified as a product of aoxABC gene (DDBJ accession no. AB020482). Both
      cytochromes reacted with carbon monoxide. The apparent K(m) values of CO-1 and CO
      2 for oxygen were 5.5 and 32 micro M, respectively, at 25 degrees C. The terminal
      oxidases CO-1 and CO-2 phylogenetically correspond to the SoxB and SoxM branches,
      respectively, of the heme-copper oxidase tree.

PMID- 12471504
TI  - Transport of molybdate in the cyanobacterium Anabaena variabilis ATCC 29413.
AB  - Heterocyst-forming filamentous cyanobacteria, such as Anabaena variabilis ATCC
      29413, require molybdenum as a component of two essential cofactors for the
      enzymes nitrate reductase and nitrogenase. A. variabilis efficiently transported
      (99)Mo (molybdate) at concentrations less than 10(-9) M. Competition experiments
      with other oxyanions suggested that the molybdate-transport system of A.
      variabilis also transported tungstate but not vanadate or sulfate. Although
      tungstate was probably transported, tungsten did not function in place of
      molybdenum in the Mo-nitrogenase. Transport of (99)Mo required prior starvation
      of the cells for molybdate, suggesting that the Mo-transport system was repressed
      by molybdate. Starvation, which required several generations of growth for
      depletion of molybdate, was enhanced by growth under conditions that required
      synthesis of nitrate reductase or nitrogenase. These data provide evidence for a
      molybdate storage system in A. variabilis. NtcA, a regulatory protein that is
      essential for synthesis of nitrate reductase and nitrogenase, was not required
      for transport of molybdate. The closely related strain Anabaena sp. PCC 7120
      transported (99)Mo in a very similar way to A. variabilis.

PMID- 12471505
TI  - The Vibrio fischeri sapABCDF locus is required for normal growth, both in culture
      and in symbiosis.
AB  - Inactivation of the sapABCDF genes results in a loss of virulence in several
      bacterial pathogens of animals and plants. The role of this locus in the growth
      physiology of Vibrio fischeri, and in the symbiotic colonization of the squid
      Euprymna scolopes was investigated. In rich medium, a V. fischeri sapA insertion
      mutant grew at only 85% the rate of its wild-type parent. While a similar effect
      has been attributed to a potassium-transport defect in sap mutants of enteric
      bacteria, the V. fischeri mutant grew more slowly regardless of the potassium
      concentration of the medium. Similarly, the growth-rate defect was independent of
      the source of either carbon, nitrogen, or phosphorous, indicating that the V.
      fischeri sap genes do not encode functions required for the transport of a
      specific form of any of these nutrients. Finally, while a delay in colonizing the
      nascent light organ of the squid could be accounted for by the lower growth rate
      of the mutant, a small but statistically significant reduction in its final
      population size in the host, but not in medium, suggests that the sap genes play
      another role in the symbiosis. All of these phenotypic defects could be
      genetically complemented in trans by the sapABCDF genes, but not by the sapA gene
      alone, indicating that the insertion in sapA is polar to the four downstream
      genes in the locus. Thus, while the sap locus is important to the normal growth
      of V. fischeri, it plays different physiological roles in growth and tissue
      colonization than it does in enteric pathogens.

PMID- 12471506
TI  - A possible role of poly-3-hydroxybutyric acid in antibiotic production in
      Streptomyces.
AB  - The occurrence of poly-3-hydroxybutyric acid (PHB) in 12 different strains of the
      genus Streptomyces was investigated. Gas chromatographic estimation indicated
      that all the strains produced PHB and the range of maximum PHB accumulation was
      between 1.5 and 11.8% dry cell weight. PHB was isolated from Streptomyces
      coelicolor A3(2) M145 and characterized using Fourier transform-infrared (FT-IR)
      spectroscopy. The correlation between PHB utilization and antibiotic production
      in S. coelicolor A3(2) M145, was studied; results indicated a possible role of
      PHB as a carbon reserve material used for antibiotic production.

PMID- 12471507
TI  - Properties of a laccase produced by Phanerochaete flavido-alba induced by
      vanillin.
AB  - Phanerochaete flavido-alba is able to remove simple and polymeric phenols from
      the recalcitrant wastes of the olive oil industry, in a process in which a
      laccase is involved. This report describes the characterization of a laccase
      produced by P. flavido-alba and induced by vanillin. Although the amino acid
      composition of the purified enzyme is typical for laccases, other molecular
      characteristics show that it is quite different from fungal laccases. The
      purified laccase oxidized preferably o- and p-biphenols.

PMID- 12471509
TI  - [New technology in refractive and intraocular surgeries: toward an optimization
      of correction?].

PMID- 12471508
TI  - [Management of visual loss secondary to giant cell arteritis].

PMID- 12471510
TI  - [Therapeutic strategies for retinal degenerations].

PMID- 12471511
TI  - [Interface diffuse keratitis].
AB  - Diffuse interface keratitis is a new clinical entity. It is becoming
      significantly more common due to the increasing of laser assisted in situ
      keratomileusis (LASIK) procedures. The knowledge we have about this uncommon but
      potentially sight-threatening complication is expanding. It appears in the early
      postoperatory LASIK, even in well-executed procedures. In this review we present
      an updated strategy for the diagnose and treatment of this syndrome, based on our
      own experience and an updated literature review. Early identification,
      evaluation, staging, and appropriate intervention, may help preventing visual
      loss associated with this entity.

PMID- 12471512
TI  - [Intraocular phakic lens ZSAL-4 for high myopia correction].
AB  - PURPOSE: To evaluate the effectiveness, safety and predictability of the phakic
      intraocular lens (IOL) ZSAL-4 for correction of high myopia. METHODS: In this
      retrospective study 28 IOL in 19 patientes were implanted. The following data
      were recorded, preoperatively, one week, one month, 3, 6 and 12 months
      postoperatively: spherical equivalent (SE), astigmatism, uncorrected visual
      acuity (UCVA), best corrected visual acuity (BCVA), endothelial cell density
      (CD), coefficient of variation (CV) and intraocular pressure (IOP). We performed
      LASIK in 3 eyes to correct a residual refractive defect. RESULTS: The mean age
      was 29.7 S.D. 5.77 years and the mean following 7.62 S.D. 7.29 months. Six months
      postoperatively, the preoperative SE of -14.91 S.D. 2.88 was reduced to -1.29
      S.D. 0.53; the BCVA varied from 0.56 S.D. 0.16 to 0.58 S.D. 0.12; the CD changed
      from 2670 S.D. 252 cells/mm2 to 2344 S.D. 262. The CV showed stability. The UCVA
      six months postoperatively was 0.39 S.D. 0.15. No eyes lost any line of BCVA;
      during the first month 63% of the eyes won 2 or more lines. The efficacy index
      was 0.83 S.D. 0.24 one month postoperatively and 0.63 S.D. 0.32 one year
      postoperatively; the safety index was 1.44 D.S. 0.34 and 1.30 S.D. 0.35
      respectively. One IOL was explanted the second day due to pupilary blockage; 7
      eyes had transient high IOP; 2 eyes developed pupilary ovalization and in 4 cases
      the IOL suffered some degree of rotation. One eye presented a flat retinal
      detachment one year postoperatively but with no other complications. The 3 eyes
      submitted to LASIK presented 0.8 of BCVA the third month after LASIK.
      CONCLUSIONS: ZSAL-4 IOL implantation is an effective and safe procedure with an
      acceptable predictability which, in some cases, could be improved with LASIK.

PMID- 12471513
TI  - [Development of an automatic discrimination system for glaucomatous visual fields
      based on neuro-fuzzy nets].
AB  - PURPOSE: To provide a useful tool in the diagnosis of glaucoma by developing an
      automatic system for visual field classification based on neuro-fuzzy rules.
      METHOD: A total of 212 visual fields (OCTOPUS 123 program G1X), from 198
      patients, were analysed: 61 normal (controls) and 151 with glaucomatous damage
      (49% with incipient damage, 29.1% with moderate damage, and 21.9% advanced).
      Inclusion criteria for glaucomatous patients were: Visual acuity >0.5, IOP < 20
      mm Hg (with treatment), refraction <5 Dp and previous perimetric experience.
      EXCLUSION CRITERIA: miotics, other ocular pathologies which could interfere with
      visual field examination, and for control subjects: visual acuity >0.5, no ocular
      pathologies and refraction < 5 Dp. A neuro-fuzzy classifier (NEFCLASS) is a
      system consisting in a series of fuzzy rules, obtained after a learning process,
      which attempts to assign to each piece of data input its corresponding output.
      Initially, the characteristics of each data input are established (input units).
      Then, based on previous knowledge, a set of rules are defined, and finally, the
      learning process allows the optimisation of the classifier parameters to generate
      an output. RESULTS: Input units were defined by using the mean defects calculated
      at specific areas of the visual field; five rules were then created which
      generated sensitivity and specificity values of 96.0% and 93.4% respectively.
      CONCLUSIONS: The use of neuro-fuzzy rules for visual field classification in
      normal vs glaucomatous can provide results which can match the quality of those
      obtained with other techniques such as discriminatory analysis or neural
      networks.

PMID- 12471514
TI  - [Trabeculectomy and phacoemulsification. One site vs. two site approach. A
      comparative study].
AB  - PURPOSE: To compare the results of combined phacotrabeculectomy by means of a one
      site versus two-site approach. MATERIALS AND METHODS: A retrospective study has
      been performed over 35 glaucomatous patients with a coexisting cataract, treated
      with a one-site (19 cases) or a two-site (16 cases) phacotrabeculectomy. First,
      effectiveness of both procedures has been proved by statisticly analysing the IOP
      and visual acuity changes after surgery. Normal distribution, homogeneity and
      homocedasticity from both groups have been checked. Finally, visual acuity and 6
      month postoperatively IOP among both groups have been compared by means of a
      <<mean difference t Student test for independent samples>>. RESULTS: No
      statistical differences among both procedures have been found (p>0.05). Also,
      postoperative complications were similar among groups. CONCLUSIONS: Combined
      trabeculectomy and phacoemulsification surgery is a useful treatment for
      glaucomatous patients with coexisting cataract, and provides good visual and
      ocular-pressure results. One-site and two-site surgical approachs provide the
      same six-month follow-up results.

PMID- 12471515
TI  - [Bilateral neurotrophic keratitis secondary to encephalic trunk metastasis].
AB  - CASE REPORT: We report the case of a 69-year-old man with a lung carcinoma
      history. The patient showed signs of conjuntival hyperemia, painless bilateral
      corneal edema, persistent epitelial defects and reported to have decreasing
      visual acuity for a week. The clinical examination revealed a bilateral
      neurotrophyc keratitis with both a decreased frequency of blinking and a
      bilateral atrophy mandibular muscles. Local ocular patology was excluded.
      Systemic exploration showed a meningeal neoplasic infiltration and metastasis on
      the initial trigeminal nerve stretch. In our knowledge, this is the first case
      reported in the literature. DISCUSSION: Ophthalmic signs should be considered in
      the diagnosis of systemic pathology.

PMID- 12471516
TI  - [Topical treatment with mitomycin C in considerably raised conjunctival
      intraepithelial neoplasia].
AB  - CASE REPORT: We present a case of recurrent conjunctival intraepithelial
      neoplasia, treated previously on two occasions with excisional biopsy. Although
      the lesion was considerably raised, topical treatment with mitomycin-C 0.04% was
      applied, achieving the complete regression of the tumor. DISCUSSION: Topical
      mitomycin-C acts at the ocular surface. However, successive treatment cycles can
      achieve complete regression, even in considerably thick tumors.

PMID- 12471517
TI  - [About eyeglasses, glasses, lenses or spectacles].

PMID- 12471518
TI  - [Friedrich (Fritz) Stowasser. Vienna, 1928 - Queen Elizabeth II, 2000].

PMID- 12471519
TI  - [Magnetic resonance imaging in ankylosing spondylitis (Marie-Struempell-Bechterew
      disease)].
AB  - Ankylosing spondylitis (AS) is the prototypical form of the
      spondyloarthropathies, which at a prevalence of 2 % is among the most frequent
      rheumatic diseases. Spondyloarthropathy comprises the following five disorders:
      AS, reactive arthritis, psoriatic arthritis, enteropathic arthritis in Crohn's
      disease, and ulcerosing colitis as well as undifferentiated spondyloarthropathy.
      In 99 % of the patients with AS initial abnormal findings affect the sacroiliac
      joints. The radiographic changes required for diagnosing AS occur as late as 5 -
      9 years after the onset of clinical symptoms. MRI of the sacroiliac joints
      reliably demonstrates both chronic inflammatory changes (erosions, sclerotic
      changes, bone bridges) and acute inflammatory changes (synovitis, capsulitis,
      osteitis) and allows for grading the chronicity and acuity of such changes.
      Enthesitis of the interosseous ligaments of the retroarticular space is a
      manifestation of AS. Spondylodiscitis (Andersson 1937) may occur as an
      inflammatory or non-inflammatory process (transdiscal fatigue fracture).
      Inflammations of the facet and costospinal joints developing into ankylosis are
      typical of AS. Changes of the vertebral bodies occur as anterior (Romanus 1952),
      posterior, and marginal spondylitis. All forms of spondyloarthropathies are
      furthermore characterized by asymmetrical synovitis of the large joints,
      particularly of the legs (gonarthritis, coxitis, tarsitis, peripheral
      oligoarthritis), rheumatic fibroosteitis (pelvic enthesitis, rheumatic
      calcaneopathy), and peri- and synchondritis of the pubic symphisis and sternal
      synchondrosis. Since early inflammatory changes of the spinal column and of the
      extravertebral localizations in AS are demonstrated by MRI before they become
      apparent on radiographs, and thereby the diagnostic gap could be closed, the
      early use of MRI for diagnostic and follow-up is commendable, when new
      therapeutical options like the so-called "biologicals" are employed.

PMID- 12471520
TI  - Dose reduction in multi-slice CT of the heart by use of ECG-controlled tube
      current modulation ("ECG pulsing"): phantom measurements.
AB  - PURPOSE: To evaluate the effect of ECG-controlled tube current modulation on
      radiation exposure in retrospectively-ECG-gated multislice CT (MSCT) of the
      heart. MATERIAL AND METHODS: Three different cardiac MSCT protocols with
      different slice collimation (4 x 1, and 4 x 2.5mm), and a pitch-factor of 1.5 and
      1.8 were investigated at a multi-slice CT scanner Somatom Volume Zoom, Siemens.
      An anthropomorphic Alderson-Rando phantom was equipped with LiF
      thermoluminescence dosimeters at several organ sites, and effective doses were
      calculated using ICRP-weighting factors. Scan protocols were performed with ECG
      controlled tube current modulation ("ECG pulsing") at two different heart rates
      (60 and 80 bpm). These data were compared to previous data from MSCT of the heart
      without use of "ECG pulsing". RESULTS: Radiation exposure with (60 bpm) and
      without tube current modulation using a 2.5 mm collimation was 1.8 mSv and 2.9
      mSv for females, and 1.5 mSv and 2.4 mSv for males, respectively. For protocols
      using a 1 mm collimation with a pitch-factor of 1.5 (1.8), radiation exposure
      with and without tube current modulation was 5.6 (6.3) mSv and 9.5 (11.2) mSv for
      females, and 4.6 (5.2) mSv and 7.7 (9.2) mSv for males, respectively. At higher
      heart rates (80 bpm) radiation exposure is increased from 1.5 - 1.8 mSv to 1.8 -
      2.1 mSv, using the 2.5 mm collimation, and from 4.6 - 5.6 mSv to 5.9 - 7.2 mSv,
      for protocols using 1 mm collimation. CONCLUSIONS: The ECG-controlled tube
      current modulation allows a dose reduction of 37 % to 44 % when retrospectively
      ECG-gated MSCT of the heart is performed. The tube current - as a function over
      time - and therefore the radiation exposure is dependent on the heart rate.

PMID- 12471521
TI  - [Endovascular therapy of high-degree stenoses of the neck vessels-stent-supported
      percutaneous angioplasty of the carotid artery without cerebral protection].
AB  - PURPOSE: Technical essentials and therapeutic results of carotid stenting without
      cerebral protection are presented. MATERIALS AND METHODS: In 161 patients, 167
      high grade carotid stenoses were stented, followed by percutaneous transluminal
      angioplasty, with subsequent evaluation of the clinical and angiographic results.
      Diffusion-weighted MRI was carried out in 108 patients to detect cerebral
      sequelae. RESULTS: Endovascular therapy was successful (residual stenosis < 25 %)
      in 166 stenoses (99.4 %). Twelve patients (7.5 %) had cerebrovascular
      complications within the 30-day perioperative period, seven of which occurred
      during the procedure. After treatment, diffusion-weighted MRI disclosed at least
      one new cerebral lesion in 40 patients (37 %), which were symptomatic in six
      patients. CONCLUSION: Even without cerebral protection, high grade carotid
      stenosis can be safely treated with stent-protected percutaneous angioplasty.
      Microemboli detected by postoperative MRI are infrequently symptomatic.

PMID- 12471522
TI  - [Lumbar meningeal enhancement after surgery in the posterior cranial fossa: a
      normal finding in children?].
AB  - PURPOSE: Spinal meningeal Gd-DTPA enhancement after cranial surgery is a known
      observation of a not well understood underlying mechanism. This paper
      demonstrates that this MRI finding is a normal meningeal reaction to subarachnoid
      hemorrhage, which should not be mistaken for metastatic spread. MATERIAL AND
      METHODS: Three pediatric patients were examined by MRI for metastatic spread of
      malignant infratentorial tumors along the spinal canal two to nine days after the
      removal of the primary cerebral lesion. The findings were compared with a control
      group that underwent cranial surgery (cyst resection or fenestration of the
      posterior cranial fossa) without major bleeding into the subarachnoid space.
      Unenhanced and enhanced sequences were obtained to prove that the high signal
      within the CSF is caused by an abnormal Gd-DTPA uptake and not by methemoglobin.
      RESULTS: Meningeal enhancement was observed in all patients with intraoperative
      bleeding resembling subarachnoid masses on enhanced T 1 -weighted images. This
      was not present in any patient of the control group. This finding lasts for
      approximately two weeks. CONCLUSION: The meningeal enhancement renders immediate
      postoperative studies inconclusive for the detection of metastatic spread.
      Consequently, the obligatory tumor staging along the spinal canal should ideally
      be done prior to the resection of a cerebral tumor.

PMID- 12471523
TI  - [Implementation of BIRADSTM together with an organization of percutaneous breast
      biopsies: experiences, reactions].
AB  - PURPOSE: To record the acceptance and reactions of radiologists and physicians
      who recommend patients for mammography after simultaneous establishment of BIRADS
      TM and a registration of the results of percutaneous breast biopsies. MATERIALS
      AND METHODS: To improve clarity of mammographic reports and to provide guidance
      concerning any necessary percutaneous breast biopsies the Breast Imaging Data And
      Reporting System (BIRADS TM) has been introduced regionally together with a
      registration of percutaneous breast biopsies. Using a questionnaire, 25
      radiologists and 230 referring physicians were asked on acceptance and reactions
      concerning the established system. RESULTS: Of the 15 answering radiologists, 93
      % considered BIRADS TM a worthwhile effort and 87 % found the biopsy guidelines
      to be useful. They regarded the acceptance of the referring physicians and
      patients as high (80 %). Up to 69 % of the 52 participating physicians stated a
      better understanding of the mammographic reports, an easier comprehension of the
      dignity classification of a mammographic lesion and the feeling of an improvement
      in their work. Preoperative assessment of histology was found to be valuable by
      94 % of the referring physicians. They believe that more than half of the
      patients benefit from the biopsy guidelines and that the majority of patients
      accept this approach. CONCLUSION: BIRADS TM is useful to standardize and improve
      mammographic reports. It is advantageous to link BIRADS TM with guidelines for
      percutaneous breast biopsies.

PMID- 12471524
TI  - [Electrical impedance scanning in the differentiation of suspicious breast
      lesions: comparison with mammography, ultrasound and histopathology].
AB  - PURPOSE: To assess the value of Electrical Impedance Scanning (EIS) in the
      differentiation of suspicious breast lesions in comparison to mammography (MG)
      and ultrasound (US). METHODS: In 95 female patients (median 53.1 ys) 95
      suspicious breast lesions (BI-RADS TM III - V) in MG or US underwent targeted EIS
      (TransScan TS 2000(R); TransScan Medical, Israel; Siemens Elema, Sweden).
      Histopathologic proof (vacuum-assisted biopsy or surgical biopsy) was obtained in
      all cases. MG, US and EIS were independently assessed by two radiologists in
      consensus. Chi-square tests as well as variance-analysis for ROC-statistics were
      performed. RESULTS: Of 95 lesions, 44 were benign, 51 malignant. Sensitivity,
      specificity, positive and negative predictive values were, respectively for MG
      95.3 %, 23.5 %, 51.3 % and 85.7 %, for US 86.5 %, 44.2 %, 57.1 % and 79.1 %, for
      EIS 77.3 %, 82.3 %, 79.1 % and 80.8 %. The ROC-analysis revealed a significant
      greater area under the curve for EIS than for MG and US. The sensitivity for EIS
      was higher in lesions < 10 mm (n = 26; 100 %) and in invasive cancers (n = 31;
      80.6 %). The negative predictive value of EIS was higher in BI-RADS TM-IV-lesions
      (83.9 %) as well as in dense breast parenchyma on the mammogram (86.7 %).
      CONCLUSION: EIS shows potential adjunctive value to MG and US in the
      differentiation of suspicious breast lesions.

PMID- 12471525
TI  - [Cardiac MRI in suspected myocarditis].
AB  - PURPOSE: To evaluate the potential of ECG-gated breath-hold MRI in diagnosing
      acute myocarditis. MATERIAL AND METHODS: Cardiac MRI was performed on 21
      consecutive patients with suspected myocarditis. ECG-gated breath-hold T2
      weighted images with fat suppression were acquired in 3 standard views. T1
      weighted imaging (FLASH) was performed 10 min after IV administration of Gd-DTPA.
      Laboratory data included creatine kinase, troponin T and serological tests, ECG
      findings and echocardiography. Imaging findings were retrospectively compared to
      the discharge diagnoses. Signal alterations were semiquantitatively classified.
      RESULTS: Acute myocarditis was diagnosed in 9 patients and cardiac sarcoidosis in
      2 patients. Late enhancement was observed in 4 patients with acute myocarditis
      and in both patients with cardiac sarcoidosis. Semiquantitative evaluation
      revealed 9 true positive, 9 true negative, 1 false positive and 2 false negative
      results. CONCLUSION: Cardiac MRI has the potential to detect acute myocarditis
      and to diagnose cardiac sarcoidosis. Late enhancement of Gd-DTPA can be found in
      both viral myocarditis and cardiac sarcoidosis.

PMID- 12471527
TI  - [Age- and gender-related distribution of bone mineral density and mechanical
      properties of the proximal humerus].
AB  - PURPOSE: To evaluate age- and gender-related mechanical properties and bone
      mineral density (BMD) of the proximal humerus at different levels and regions.
      MATERIALS AND METHODS: Mechanical indentation testing, DXA, QCT, pQCT and the
      radiogrammetry (Cortical Index, CI) were carried out in 70 freshly harvested
      humeri from 46 human cadavers (23 females, 23-males; median age 70.5 years).
      RESULTS: In the female group, a high correlation between age and BMD was found
      (rho = 0.62 to -0.70, p < 0.01) with statistically significant differences
      between specimens of patients 69 years or younger, and 70 years or older (p <
      0.05). In the group of female specimens of age 70 years or older, BMD values were
      found to be significantly lower compared to their male counterparts (p < 0.05).
      Regardless of the specimen's age, the highest BMD and bone strength were found in
      the proximal aspect and in the medial and dorsal regions of the proximal humerus.
      CONCLUSION: These findings provide an insight into the fracture mechanism of the
      proximal humerus and should be the basis for designing structure-oriented
      implants with improved implant-bone stability in osteoporotic patients.

PMID- 12471526
TI  - [MRI in postoperative assessment of univentricular heart disease: correlation
      with echocardiography and angiography].
AB  - PURPOSE: To determine the value of MRI in the postoperative evaluation of a
      singular ventricle compared to echocardiography and cardiac catheterization.
      MATERIALS AND METHODS: Thirty-one patients (range: 6 months to 30 years) with a
      functional single ventricle following palliative corrective operations. Five
      patients had a Blalock-Taussig-Shunt, 8 patients a Glenn-Anastomosis and 18 a
      cavopulmonary shunt (6 with classic Fontan-Circulation, 12 with modified
      cavopulmonary anastomosis). The results in terms of postoperative morphologic
      changes were compared to percutaneous echocardiography (31/31) and cardiac
      catheterization (6/31). RESULTS: Echocardiography, which was performed on all
      patients, could not visualize the entire length of the tunnel, the Glenn
      Anastomosis or the central pulmonary arteries in 70 % of the patients due to an
      inadequate acoustic window. MRI was able to show the entire tunnel in 11/12
      patients and the central pulmonary arteries in 30/31 patients. The exact anatomy
      was seen in all 6 patients undergoing cardiac catheterization. CONCLUSION: MRI is
      useful in the postoperative evaluation of a functionally single ventricle. It is
      superior to echocardiography. Cardiac catheterization should be reserved for
      patients with inconclusive MRI findings.

PMID- 12471528
TI  - [Evaluation of TSE- and T1-3D-GRE-sequences for focal cartilage lesions in vitro
      in comparison to ultrahigh resolution multi-slice CT].
AB  - PURPOSE: Evaluation of TSE- and T 1 -3D-GRE-sequences for focal cartilage lesions
      in vitro in comparison to ultrahigh resolution multi-slice CT. MATERIALS AND
      METHODS: Forty artificial cartilage lesions in ten bovine patellae were immersed
      in a solution of iodinated contrast medium and assessed with ultrahigh resolution
      multi-slice CT. Fat-suppressed TSE images with intermediate- and T 2 -weighting
      at a slice thickness of 2, 3 and 4 mm as well as fat-suppressed T 1 -weighted 3D
      FLASH images with an effective slice thickness of 1, 2 and 3 mm were acquired at
      1.5 T. After adding Gd-DTPA to the saline solution containing the patellae, the T
      1 -weighted 3D-FLASH imaging was repeated. RESULTS: All cartilage lesions were
      visualised and graded with ultrahigh resolution multi-slice CT. The TSE images
      had a higher sensitivity and a higher inter- and intraobserver kappa compared to
      the FLASH-sequences (TSE: 70 - 95 %; 0.82 - 0.83; 0.85 - 0.9; FLASH: 57.5 - 85 %;
      0.53 - 0.72; 0.73 - 0.82, respectively). An increase in slice thickness decreased
      the sensitivity, whereby deep lesions were even reliably depicted on TSE images
      at a slice thickness of 3 and 4 mm. Adding Gd-DTPA to the saline solution
      increased the sensitivity by 10 % with no detectable advantage over the T 2 
      weighted TSE images. CONCLUSION: TSE sequences and application of Gd-DTPA seemed
      to be superior to T 1 -weighted 3D-FLASH sequences without Gd-DTPA in the
      detection of focal cartilage lesions. The ultrahigh resolution multi-slice CT can
      serve as in vitro reference standard for focal cartilage lesions.

PMID- 12471529
TI  - [Long-term results after recanalization of acute and subacute thrombotic
      occlusions of the infra-aortic arteries and bypass-grafts using a rotational
      thrombectomy device].
AB  - BACKGROUND: Evaluation of the acute and long-term results after recanalization of
      thrombotic occlusions of infra-aortic native arteries, stented arteries and
      bypass-grafts using a rotational thrombectomy device (8F Straub-Rotarex TM).
      MATERIALS AND METHODS: From July 2000 to February 2002, in 98 patients (64 %
      male, mean age 66 +/- 9 (range 47 to 90) years, mean duration of occlusion 31 +/-
      33 (range 0 to 140) days, mean occlusion length 21 +/- 11 [range 2 to 40] cm) 100
      vessel recanalizations were performed. 42 % of the interventions were performed
      during the first 14 days after the onset of the symptoms (acute occlusions).
      These patients were classified according to the after the TASC protocol modified
      SVS/ISCVS-classification: Class I: n = 22 (52 %); class lla: n = 13 (32 %); class
      llb: n = 6 (14 %); class III: n = 1 (2 %). Subacute and chronic occlusions were
      classified according to Rutherford (58 %): Stage 1: n = 5 (9 %); stage 2 and 3: n
      = 39 (68 %); stage 4: n = 6 (10 %); stage 5: n = 8 (13 %). RESULTS: Primary
      success rate was 96 % (ipsilateral interventions 99 %, cross-over 40 %). The
      restenosis rate after a mean follow-up of 13 +/- 4 months was 33 % for native
      arteries (group 1), 74 % for instent-recanalizations (group 2) and 86 % for
      bypass-graft occlusions (group 3). 3 % severe complications occurred: two
      amputations below the knee after unsuccessful recanalizations of a native artery
      and a bypass-graft, respectively. One death because of multiorgan failure in
      patient who was already in cardiac shock before the successful intervention.
      Further 16 complications could be solved periinterventionally. The ancle-brachial
      index was significantly improved during follow-up (from 0.37 +/- 0.19 to 0.82 +/-
      0.22 before discharge, 0.70 +/- 0.21 after 12 months, p < 0.001). CONCLUSION: The
      Straub-Rotarex TM device is useful in the treatment of acute and subacute
      thrombotic occlusions of infra-aortic arterial and bypass-graft occlusions, with
      promising long-term results in native vessels but unchanged high restenosis of
      stented arteries and bypass-grafts.

PMID- 12471530
TI  - [Multi-slice CT (MSCT) in cardiac function imaging: threshold-value-supported 3D
      volume reconstructions to determine the left ventricular ejection fraction in
      comparison to MRI].

PMID- 12471531
TI  - [CT-expo--a novel program for dose evaluation in CT].
AB  - CT-Expo is a novel MS Excel application for assessing the radiation doses
      delivered to patients undergoing CT examinations, based on computational methods
      that were used to analyze the data collected in the German survey on CT practice
      in 1999. The program enables the calculation of all dose quantities of practical
      value, such as axial dose free-in-air, weighted CTDI, dose-length product,
      effective dose and uterine dose. In contrast to existing programs for CT dose
      assessment, CT-Expo offers a number of unique features, such as gender-specific
      dose calculation for all age groups (adults, children, newborns), applicability
      to all existing scanner models including correction of scanner-specific
      influences, and the possibility of comparison with the results from the German CT
      survey on CT practice. Three different application modules offer free and
      standardized dose calculations as well as a comprehensive benchmarking section
      including guidance on dose optimization. The program is available as shareware in
      both German and English version. Additional information and a demo version free
      of charge can be requested via e-mail from the author's address stamm.georg@mh
      hannover. de) or from the web page http://www.mh
      hannover.de/kliniken/radiologie/str_04.html.

PMID- 12471532
TI  - [A case of spinal elastofibroma].

PMID- 12471533
TI  - [Primary malignant non-Hodgkin's lymphoma of the heart].

PMID- 12471534
TI  - [A rare manifestation of schwannoma in the main nasal cavity].

PMID- 12471535
TI  - Eight years' experience of gastrostomy tube management.
AB  - BACKGROUND AND STUDY AIMS: Increasingly, patients fed by gastrostomy tube are
      surviving the lifespan of the device. Data are scarce concerning the factors
      affecting the longevity and failure of gastrostomy tubes or the criteria for
      selection of replacement devices which leads to cost-effective patient
      management. The aims of the study were: to set criteria for selection of
      replacement gastrostomy tubes; to determine the causes of gastrostomy tube
      failure, and the factors affecting device longevity; and to examine the effect of
      initiating an educational programme for caregivers on resource utilization in
      long-term enteral nutrition patients. MATERIALS AND METHODS: We analyzed the
      clinical gastrostomy tube database compiled prospectively over 8 years by the
      nutrition team at Ninewells Hospital, Dundee. RESULTS: For 363 gastrostomy tubes
      inserted in 304 patients (160 women; median age 71), the median duration of
      gastrostomy tube use was 138 days. The total follow-up was 294 patient-years.
      Death occurred before the first gastrostomy tube replacement in 48 % of patients,
      but 20 % resumed oral nutrition. Tube failure mechanisms were: dislodgment, 28 %;
      perishing of tube material, 25 %; tube-related Candida albicans infection, 16 %;
      leakage, 7 %; and unspecified, 7 %. Of the balloon tubes and gastrostomy buttons,
      8 % needed early replacement due to dislodgment and/or leakage. The cost per day
      for replacement percutaneous endoscopic gastrostomy (PEG) was Euro 2.12, for
      balloon tubes it was Euro 0.62, and for gastrostomy buttons Euro 1.80. Despite an
      increasing PEG insertion rate throughout the study period, yearly referrals for
      PEG-related problems dropped by 30 % between 1997 to 1999, coinciding with the
      initiation of an educational programme for caregivers. CONCLUSION: Tube longevity
      is mainly limited by the patient's diagnosis and prognosis. The choice of
      replacement device should be based on clinical factors. The use of more durable
      materials in the manufacture of gastrostomy tubes may prolong tube life and
      reduce cost. Education of patients and caregivers by a multidisciplinary
      nutrition support team promotes independence and limits demand on the service.

PMID- 12471536
TI  - A comparison of three types of biopsy forceps in the endoscopic surveillance of
      Barrett's oesophagus.
AB  - BACKGROUND AND STUDY AIMS: Periodic endoscopic biopsy surveillance is recommended
      for selected patients with Barrett's oesophagus. A new angled swing-jaw forceps
      has become available which is said to facilitate tangential oesophageal biopsy
      sampling. We examined the size and quality of oesophageal biopsies obtained with
      the forceps of angled design in comparison with the large cup disposable forceps
      and the conventional reusable upper gastrointestinal forceps. PATIENTS AND
      METHODS: In this prospective comparative study, three biopsies were taken at each
      of three levels, using a different design of forceps at each level, in each of 48
      patients undergoing endoscopic surveillance. The order in which the forceps were
      used was randomized. A pathologist assessed the size and quality of each set of
      biopsies obtained. RESULTS: The mean biopsy diameter was significantly greater at
      3.00 mm with the angled forceps (P < 0.01), in comparison with 2.52 mm with the
      elliptical forceps and 2.07 mm with the conventional forceps. Fewer biopsies
      obtained with the angled forceps were graded as inadequate (8.3 %) compared with
      those obtained using the disposable large cup and conventional forceps (25 % and
      22.9 %, respectively). CONCLUSIONS: The design of forceps used influences the
      size and quality of tissue obtained during endoscopic surveillance of Barrett's
      oesophagus. The angled swing-jaw forceps are recommended as the most suitable for
      this purpose.

PMID- 12471538
TI  - Endosonographic features of Brunner's gland hamartomas which were subsequently
      resected endoscopically.
AB  - BACKGROUND AND STUDY AIMS: Brunner's gland hamartomas are uncommon duodenal
      submucosal tumors. We aim to describe their morphological characteristics, with
      particular attention to the endosonographic features. PATIENTS AND METHODS: We
      reviewed the radiological, endoscopic, endosonographic, and histological findings
      from six Brunner's gland hamartomas which were completely removed by endoscopic
      resection. RESULTS: The lesions appeared as broad-based, sessile, or pedunculated
      submucosal tumors, measuring 0.7 to 2 cm in maximal diameter. Three lesions
      contained tiny dimple-like depressions on the surface; in one lesion these were
      only recognized following the use of an endoscopic dye-spraying technique. All
      the lesions could be safely removed by endoscopic resection after endosonographic
      confirmation of the layer origin within the submucosa. The internal echo
      structure of the tumors appeared to be solid echogenic in two, simple cystic in
      two, and multicystic in the remaining two lesions. In three lesions with an
      indistinct boundary, some stromal proliferation and solid Brunner's glands were
      recognized in an area extending from the mucosa to the submucosa. These
      endosonographic features corresponded to histological findings comprising stromal
      proliferation and various degrees of solid and cystic glandular Brunner's glands.
      CONCLUSIONS: Brunner's gland hamartoma is characterized endosonographically by a
      heterogeneous solid and/or cystic mass within the submucosa.

PMID- 12471537
TI  - Long-term follow-up and factors predictive of recurrence in Barrett's esophagus
      treated by argon plasma coagulation and acid suppression.
AB  - BACKGROUND AND STUDY AIMS: In several series, argon plasma coagulation (APC)
      combined with acid suppression has led to short- or medium-term eradication of
      Barrett's esophagus. The present study was designed to assess the long-term
      outcome after this treatment. PATIENTS AND METHODS: 39 patients with Barrett's
      esophagus, seven of them with low-grade dysplasia, underwent APC and received 40
      mg omeprazole daily for eradication of the metaplastic epithelium. After the
      treatment period, patients were randomly assigned to receive 20 or 40 mg
      omeprazole daily for long-term acid suppression. Histological and endoscopic
      changes were evaluated annually. Univariate and multivariate analyses were used
      to test the following 10 variables as predictors of sustained reversal of
      Barrett's esophagus at the end of follow-up: age, gender, length of diseased
      segment, presence of hiatal hernia, circumferential nature of lesion, presence of
      low-grade dysplasia at initial biopsy, number of coagulation sessions, result of
      pH monitoring under protein pump inhibitor (PPI) treatment, omeprazole dosage,
      and initial response to therapy (after 1 month). RESULTS: The median follow-up
      period was 36 months (range 12 - 48). The endoscopic and histological relapse
      rates at 1, 12, and 24 months, and end of follow-up were, respectively, 30 % and
      44 % (12/39 and 17/39), 57 % and 54 % (16/28 and 15/28), 60 % and 57 % (17/28 and
      16/28), and 62 % for both rates (23/37). According to multivariate analysis,
      shorter length of diseased segment and normalization of pH with PPI treatment
      were the only independent predictors of sustained long-term re-epithelialization.
      Among the seven patients with low-grade dysplasia, four experienced relapse after
      1 month, and during the long-term follow-up, one was lost to follow-up and all
      the others experienced relapse, but only one developed low-grade dysplasia again.
      Cancer was found in two cases after 12 and 18 months, respectively. CONCLUSIONS:
      Persistence of acid reflux and greater length of diseased segment are the major
      factors associated with a high relapse rate after successful initial reversal.
      APC for ablation of Barrett's esophagus cannot be recommended.

PMID- 12471539
TI  - A useful approach to the differential diagnosis of small polypoid lesions of the
      gallbladder, utilizing an endoscopic ultrasound scoring system.
AB  - BACKGROUND AND STUDY AIMS: The purpose of this study was to assess the accuracy
      of endoscopic ultrasonography (EUS) in making a differential diagnosis of small
      (< or = 20 mm in diameter) polypoid lesions of the gallbladder, and to construct
      an EUS scoring system. PATIENTS AND METHODS: The EUS findings were
      retrospectively analyzed in 70 surgical cases of small polypoid lesions
      classified into two groups: neoplastic (adenocarcinoma in 11, and adenoma in 7),
      and non-neoplastic (cholesterol polyp in 44, inflammatory polyp in 7 and fibrous
      polyp in 1). The EUS variables were the maximum diameter and height/width ratio
      of the largest polyps, echo level, internal echo pattern, surface patterns,
      number and shape of polyps, presence of hyperechoic spotting, complication of
      gallbladder stones. The EUS data were used for the construction of an EUS scoring
      system to ascertain the risk of neoplasia. RESULTS: Three EUS variables, i. e.
      tumor maximum size, internal echo pattern, and hyperechoic spotting were
      statistically significant according to multivariate analysis using stepwise
      logistic regression models (P < 0.01, P < 0.05, and P < 0.01, respectively). The
      total EUS score based on the coefficient of multivariate analysis was as follows:
      (maximum diameter in mm) + (internal echo pattern score; where heterogeneous = 4,
      homogeneous = 0) + (hyperechoic spot[s] score; where presence = - 5, absence =
      0). According to our EUS scoring system, the sensitivity, specificity, and
      accuracy for the risk of neoplastic polyps with scores of 12 or higher were 77.8
      %, 82.7 % and 82.9 %, respectively. CONCLUSIONS: The EUS scoring system will be a
      useful means of differentiating between neoplastic and non-neoplastic polyps of
      the gallbladder.

PMID- 12471540
TI  - Endosonographic Doppler-guided manometry of esophageal varices: experimental
      validation and clinical feasibility.
AB  - BACKGROUND AND STUDY AIMS: The risk of variceal bleeding cannot be accurately
      predicted using endoscopy alone. Although variceal pressure has been demonstrated
      to be a major determinant for the rupture of esophageal varices, direct
      determination by needle puncture is unsuitable for routine clinical use. Due to
      their operator-dependency, current noninvasive endoscopic methods for
      determination of variceal pressure have not gained wide acceptance. We have
      developed a new method of measuring variceal pressure, using endoscopic power
      Doppler imaging to monitor the manometry of esophageal varices. The aims of this
      study were to test in vitro the accuracy of Doppler-guided manometry and to
      assess the clinical feasibility of this method. MATERIALS AND METHODS:
      Experimental validation of this technique was performed using an in vitro model
      of artificial varices of different sizes. A linear-array endosonography (EUS)
      probe with power Doppler capability was used to assess flow in the varices and a
      balloon for manometry of esophageal varices was attached to the tip of the probe.
      Pressure readings were made at the time of disappearance of the Doppler signal
      during variceal compression by the balloon. Linear regression analysis was used
      to compare the results of Doppler-guided and direct intraluminal pressure
      measurement in the artificial varices. Variceal pressure was then measured with
      this technique in 28 patients with portal hypertension and esophageal varices
      without previous bleeding, and the results were compared with portal pressure
      assessed according to the hepatic vein pressure gradient (HVPG). RESULTS: In
      vitro studies demonstrated a good correlation between the pressure measured with
      Doppler monitoring and the actual intravariceal pressure (r > or = 0.922; P <
      0.001). The determination of variceal pressure with this method was technically
      successful in 26/28 patients (93 %). The intraoperator variance was 9.3 +/- 8.6
      %. Overall, the mean variceal pressure was significantly lower than the mean HVPG
      (21.2 +/- 5.3 mmHg vs. 24.3 +/- 7.8 mmHg; P < 0.01). Variceal pressure and portal
      pressure (as assessed by the HVPG) correlated significantly (r = 0.64; P <
      0.001). CONCLUSIONS: Our preliminary results indicate that EUS Doppler-guided
      manometry of esophageal varices is feasible and accurate. This technique may
      become a more reliable method for noninvasive measurement of variceal pressure
      and warrants further investigation.

PMID- 12471541
TI  - Is endoscopic ultrasonography indispensable in assessing the appropriateness of
      endoscopic resection for gastric cancer?
AB  - BACKGROUND AND STUDY AIMS: Endoscopic resection is increasingly being used in the
      treatment of early gastric cancer. The aim of the present study was to
      investigate the accuracy of pretherapeutic staging techniques for assessing the
      appropriateness of endoscopic resection. PATIENTS AND METHODS: Both endoscopy and
      endosonography were carried out at our institution in the treatment of 234 early
      gastric cancers, with histological confirmation of malignancy following surgical
      resection (137 lesions) or endoscopic resection (97 lesions). The accuracy in
      detecting intramucosal cancer with each of the diagnostic procedures was
      assessed. RESULTS: The accuracy rates for detecting intramucosal cancer using
      endoscopy and endosonography were calculated as 84 % (197 of 234) and 78 % (182
      of 234), respectively. The accuracy tended to be lower in lesions located in the
      upper third of the stomach, in those measuring 2 cm or more in diameter, and in
      those with an undifferentiated histology with ulcer fibrosis. However, there were
      no significant differences in the accuracy rates between endoscopy and
      endosonography. Precise staging was achieved by endoscopy alone in 103 of 109
      differentiated adenocarcinomas without ulcer fibrosis, where the lesions measured
      less than 2 cm in diameter. CONCLUSIONS: Endoscopic resection is indicated in
      intramucosal gastric cancer lesions showing differentiated histology, no ulcer
      fibrosis and a diameter of less than 2 cm. EUS may additionally be used for
      further evaluation in these patients.

PMID- 12471542
TI  - Transabdominal ultrasound for visualizing gastric submucosal tumors diagnosed by
      endosonography: can surveillance be simplified?
AB  - BACKGROUND AND STUDY AIMS: Management options for gastric submucosal tumors
      (SMTs) include tumor removal or surveillance. If the latter is chosen, it
      requires repeated measurements of the tumor diameter. Although this can be
      achieved using endoscopy or endosonography (EUS), a less invasive and cheaper
      method would be welcome. The aim of this prospective study was to assess the
      proportion of gastric SMTs that can be visualized using transabdominal ultrasound
      of the water-filled stomach. PATIENTS AND METHODS: Fifty-one consecutive patients
      with endosonographically diagnosed gastric SMTs underwent transabdominal
      ultrasound examinations of the water-filled stomach performed immediately after
      EUS; both procedures were carried out by the same investigator. Transabdominal
      ultrasound was considered positive only if: firstly, the tumor was visualized
      unequivocally; secondly, its dimensions could be measured; and thirdly,
      photographic documentation could be recorded. In each case, a positive result had
      to be confirmed by an independent investigator, who reviewed the photographic
      documentation. RESULTS: The median size of SMTs on EUS was 25 mm (range 4 - 55
      mm). Twelve tumors were located in the antrum, 25 in the gastric body, and 14 in
      the gastric fundus or cardia. Transabdominal ultrasound demonstrated the tumor in
      35 of 51 patients (69 %). For tumors < or = 30 mm, the visualization rate was 61
      % (22 of 36). The location of the tumor and its EUS features did not
      significantly affect the sensitivity of transabdominal ultrasound. CONCLUSIONS:
      In 69 % of patients with endosonographically diagnosed gastric SMTs, the tumor
      can also be visualized (and measured) using transabdominal ultrasound of the
      water-filled stomach. This noninvasive and inexpensive method may potentially be
      useful for surveillance in patients with SMTs, and further evaluation in this
      setting is warranted.

PMID- 12471543
TI  - Three-dimensional magnetic resonance cholangiopancreatography with respiratory
      triggering in the diagnosis of primary sclerosing cholangitis: comparison with
      endoscopic retrograde cholangiography.
AB  - BACKGROUND AND STUDY AIMS: The purpose of this study was to evaluate the accuracy
      of respiratory-triggered three-dimensional magnetic resonance
      cholangiopancreatography (3D-MRCP) for the detection of primary sclerosing
      cholangitis (PSC) and to compare the specific findings of magnetic resonance
      cholangiography and endoscopic retrograde cholangiography in patients with PSC.
      PATIENTS AND METHODS: The MRCP findings were evaluated in 150 patients with
      clinical symptoms (progressive fatigue, pruritus followed by icterus) and/or
      elevated values for alkaline phosphatase and serum aspartate transaminase, and
      occasionally an elevated serum concentration of bilirubin as a sign of
      cholestasis, who were consecutively referred for magnetic resonance imaging. Two
      observers independently classified bile duct abnormalities and established the
      MRCP diagnosis in a consensus reading. The results of MRCP were compared with the
      definitive diagnosis, which was based on the clinical history and laboratory and
      histological data, as well as on endoscopic retrograde cholangio-pancreatography
      (ERCP) findings. In a second step, the observers compared the delineation of the
      biliary system and morphological findings using MRCP and ERCP in patients with
      confirmed PSC. RESULTS: Diagnostic examinations were obtained in 146 of the 150
      MRCPs (97 %). The diagnosis of PSC was confirmed by clinical data and ERCP in 34
      of these 150 patients (23 %). The sensitivity and specificity of MRCP for
      diagnosing PSC were 88 % (29 of 33) and 99 % (108 of 109), respectively. MRCP and
      ERCP yielded similar scores for the delineation of the biliary system (P = 0.2)
      in patients with PSC. However, different bile duct abnormalities leading to the
      diagnosis of PSC were depicted by MRCP and ERCP; more bile duct stenoses and
      pruning were seen with ERCP and more skip dilatation with MRCP (P < 10(-4)).
      CONCLUSION: In patients with PSC, MRCP is a highly sensitive method and its
      diagnostic accuracy is comparable to that of ERCP.

PMID- 12471545
TI  - Diagnosis of gastroesophageal reflux disease in general practice: a Belgian
      national survey.
AB  - BACKGROUND AND STUDY AIMS: The aim of the present study was to analyze the
      results of a prospective national survey conducted in Belgium to investigate
      discrepancies between general practitioners' attitudes and the available
      guidelines on the management of new patients with symptoms of gastroesophageal
      reflux disease (GERD). METHODS: A total of 641 general practitioners (GPs) were
      asked to complete a questionnaire on each consultation by a patient with
      suspected GERD. RESULTS: The study population included 2234 patients (mean age +/
      SD: 47.37 +/- 16.23 years; 52 % aged 45 or older) consulting for the first time
      for GERD symptoms, without previous endoscopy. Symptoms were classified as mild,
      moderate, or severe in 39.5 %, 48.0 %, and 11.3 % respectively, and as typical,
      atypical, or "alarm" in 87.5 %, 16.8 %, and 10.5 % respectively. Upper
      gastrointestinal endoscopy was requested by GPs in 24.7 % of patients (553 of
      2234; including 186 cases that were not justified according to the guidelines),
      while it should have been requested in 56.6 % (1266 of 2234) if the GPs had
      respected the national guidelines. Only 28.4 % of the 1171 patients aged 45 or
      older and 52.6 % of the 95 patients under 45 presenting with alarm symptoms had
      an endoscopy requested at the first visit. A stepwise multiple logistic
      regression analysis showed that anemia and symptom severity were the two main
      factors prompting the GPs to request endoscopy for these patients. CONCLUSIONS:
      There are major discrepancies between GP practice and national or international
      guidelines for GERD diagnosis. GPs clearly underused endoscopy in patients with
      alarm symptoms of GERD and in older patients with a new onset of GERD symptoms.
      GPs are more strongly influenced by the severity of symptoms than by the type of
      symptoms.

PMID- 12471544
TI  - Complications of endoscopic sphincterotomy: results from a single tertiary
      referral center.
AB  - BACKGROUND AND STUDY AIMS: Complications of endoscopic sphincterotomy (ES) have
      been assessed in recent multicenter studies. The aim of this series was to report
      and identify risk factors for complications of ES at a single tertiary referral
      center. PATIENTS AND METHODS: Between 1996 and 2000, 1159 consecutive endoscopic
      retrograde cholangiopancreatographies (ERCP) procedures were performed and their
      related complications were assessed. A total of 658 patients (57 %) underwent ES.
      All the clinical, radiological and biological data were carefully recorded within
      the 30 days following the procedure. Multivariate analysis was performed using a
      stepwise logistic model. RESULTS: The morbidity rate for ES was 7.7 %, being
      moderate to severe in 5 %. Morbidity included acute pancreatitis (3.5 %),
      perforations (1.8 %), sepsis (1.2 %) and bleeding (1.2 %). The 30-day mortality
      was 0.9 %. In the 1159 ERCP procedures, 231 patients underwent precut papillotomy
      (20 %) followed by sphincterotomy in 174 cases. Using logistic regression
      analysis, the risk factors for ES were precut papillotomy (relative risk, RR
      2.76), confidence interval, (CI 1.39 - 5.49) and the presence of sphincter of
      Oddi dysfunction (RR, 7.72, CI 3.2 - 18.4). CONCLUSIONS: In this single-center
      series, we found a complication rate of ES in about 7 %, comparable to that in
      multicenter series. Precut papillotomy and sphincter of Oddi dysfunction were the
      main independent risk factors for ES.

PMID- 12471546
TI  - There's more to a PEG than just putting one in.

PMID- 12471547
TI  - Is Barrett's esophagus dangerous?

PMID- 12471548
TI  - Colonoscopic barotrauma treated by conservative management: role of high-flow
      oxygen inhalation.
AB  - Most patients with colonoscopy-induced colonic perforation require urgent
      surgical intervention. Certain patients may, however, recover with conservative
      management. If the colonic perforation has been induced by barotrauma, there may
      be an extravasation of air which may lead to collection and tracking of air along
      the tissue planes, involving the retroperitoneum, peritoneal cavity, mediastinum,
      pleura, pericardium, or even the scrotum. The conservative treatment of colonic
      perforation includes bowel rest and antibiotics. Absorption of air collected in
      different body cavities may take some time, and inhalation of high-concentration
      oxygen may enhance the rate of gaseous absorption. We describe here a patient
      with colonic perforation induced by barotrauma, who recovered fully on
      conservative management with inhalation of high-concentration oxygen. We
      recommend that this approach should be used more frequently in such a situation.

PMID- 12471549
TI  - Adenocarcinoma arising from an ectopic pancreas in the stomach.
AB  - Ectopic pancreas is rare, being found in between 0.6 % and 15 % at autopsy.
      Heterotopic pancreas is usually an asymptomatic condition which is found
      incidentally at surgery or at autopsy. Occasionally, significant symptoms arise
      from complications, such as recurrent upper gastrointestinal bleeding, biliary or
      intestinal obstruction, or malignant degeneration. Malignant change is very rare.
      We report a case of malignant change (adenocarcinoma) in an ectopic pancreas in
      the stomach. In the literature, there are eight reported cases of malignant
      change in ectopic gastric pancreas. The prognosis in the other reported cases is
      unknown, but in our patient, the tumor was confined to the muscle of the stomach
      and there was no lymph node invasion.

PMID- 12471550
TI  - Wireless capsule endoscopic detection of Meckel's diverticulum after
      nondiagnostic surgery.
AB  - A patient aged 26 was investigated for recurrent severe gastrointestinal
      bleeding. Over a 4-year period, he was transfused more than 400 units of blood.
      Multiple investigations included three negative Meckel's scans. A right
      hemicolectomy for supposed angiodysplasia failed to control his bleeding.
      Wireless capsule endoscopy demonstrated the presence of a Meckel's diverticulum.
      At a repeat laparotomy, the ulcerated Meckel's diverticulum was identified and
      resected. The patient had no further bleeding and had a normal haemoglobin level
      on repeat blood tests up to 12 months after surgical excision of the
      diverticulum.

PMID- 12471551
TI  - Is ERCP a safe procedure, but for experts only?

PMID- 12471553
TI  - Duodenal air dissection secondary to intramural hematoma in necrotizing
      pancreatitis.

PMID- 12471554
TI  - Large-bowel obstruction secondary to localized rectal giant pseudopolyposis
      complicating ulcerative colitis: first reported case.

PMID- 12471555
TI  - Mucinous gastric adenocarcinoma with morphological change from polypoid to
      depressed lesion within a short period.

PMID- 12471556
TI  - A simple method to determine the location of the capsule and thus whether
      prokinetic drugs are needed during video capsule endoscopy.

PMID- 12471557
TI  - Duodenal duplication cyst.

PMID- 12471558
TI  - Aphagia caused by accidental banding of the esophageal circumference.

PMID- 12471559
TI  - Endoscopic band ligation for rectal Dieulafoy's lesion: serial endoscopic images.

PMID- 12471560
TI  - Endoscopic discovery of a Taenia in the duodenal bulb.

PMID- 12471561
TI  - Identification of CRYM as a candidate responsible for nonsyndromic deafness,
      through cDNA microarray analysis of human cochlear and vestibular tissues.
AB  - Through cDNA microarray analysis of gene expression in human cochlea and
      vestibule, we detected strong expression of mu-crystallin (CRYM; also known as
      "NADP-regulated thyroid hormone-binding protein") only in these inner-ear
      tissues. In a subsequent search for mutations of CRYM, among 192 patients with
      nonsyndromic deafness, we identified two mutations at the C-terminus; one was a
      de novo change (X315Y) in a patient with unaffected parents, and the other was a
      missense mutation (K314T) that segregated dominantly in the proband's family.
      When the mutated proteins were expressed in COS-7 cells, their subcellular
      localizations were different from that of the normal protein: the X315Y mutant
      showed vacuolated distribution in the cytoplasm, and the K314T mutant localized
      in perinuclear areas, whereas normal protein was distributed homogeneously in the
      cytoplasm. Aberrant intracellular localization of the mutated proteins might
      cause dysfunction of the CRYM product and result in hearing impairment. In situ
      hybridization analysis using mouse tissues indicated its expression in the
      lateral region of the spiral ligament and the fibrocytes of the spiral limbus,
      implying its possible involvement in the potassium-ion recycling system. Our
      results strongly implicate CRYM in normal auditory function and identify it as
      one of the genes that can be responsible for nonsyndromic deafness.

PMID- 12471562
TI  - Recombinant enzyme therapy for Fabry disease: absence of editing of human alpha
      galactosidase A mRNA.
AB  - For more than a decade, protein-replacement therapy has been employed
      successfully for the treatment of Gaucher disease. Recently, a comparable therapy
      has become available for the related lipid-storage disorder Fabry disease. Two
      differently produced recombinant alpha-galactosidase A (alpha-gal A) preparations
      are used independently for this purpose. Agalsidase alpha is obtained from human
      fibroblasts that have been modified by gene activation; agalsidase beta is
      obtained from Chinese hamster ovary cells that are transduced with human alpha
      gal A cDNA. It has previously been claimed that alpha-gal A mRNA undergoes
      editing, which may result in coproduction of an edited protein (Phe 396 Tyr) that
      might have a relevant physiological function. We therefore analyzed the
      occurrence of alpha-gal A editing, as well as the precise nature, in this
      respect, of the therapeutic enzymes. No indications were obtained for the
      existence of editing at the protein or RNA level. Both recombinant enzymes used
      in therapy are unedited and are capable of functionally correcting cultured
      fibroblasts from Fabry patients in their excessive globotriaosylceramide
      accumulation. Although RNA editing is apparently not relevant in the case of
      alpha-gal A, a thorough analysis of the potential occurrence of editing of
      transcripts is nevertheless advisable in connection with newly developed protein
      replacement therapies.

PMID- 12471563
TI  - Clostridium difficile-associated diarrhea: epidemiological data from Western
      Australia associated with a modified antibiotic policy.
AB  - The incidence of Clostridium difficile-associated diarrhea (CDAD) has increased
      dramatically in hospitals worldwide during the past 2 decades. In Western
      Australia, this increase was most obvious during the 1980s, when there was also
      an increase in the use of third-generation cephalosporin antibiotics. A study of
      the epidemiology of CDAD and the use of third-generation cephalosporins during
      1993-2000 was undertaken. From 1993 through 1998, the incidence of CDAD remained
      relatively stable (2-3 cases per 1000 discharges annually). Then, a significant
      decrease in the incidence occurred, from 2.09 cases per 1000 discharges (95%
      confidence interval [CI], 1.71-2.47) in 1998 to 0.87 cases per 1000 discharges
      (95% CI, 0.63-1.11) in 1999 (P<.0001); this decrease persisted into 2000. A
      decrease in third-generation cephalosporin use occurred during the period of the
      study because of changes in the prescribing policy. These findings suggest that a
      reduction in the use of third-generation cephalosporins can reduce the occurrence
      of CDAD.

PMID- 12471564
TI  - Methodology for clinical trials involving patients with cancer who have febrile
      neutropenia: updated guidelines of the Immunocompromised Host
      Society/Multinational Association for Supportive Care in Cancer, with emphasis on
      outpatient studies.
AB  - Two multinational organizations, the Immunocompromised Host Society and the
      Multinational Association for Supportive Care in Cancer, have produced for
      investigators and regulatory bodies a set of guidelines on methodology for
      clinical trials involving patients with febrile neutropenia. The guidelines
      suggest that response (i.e., success of initial empirical antibiotic therapy
      without any modification) be determined at 72 h and again on day 5, and the
      reasons for modification should be stated. Blinding and stratification are to be
      encouraged, as should statistical consideration of trials specifically designed
      for showing equivalence. Patients enrolled in outpatient studies should be
      selected by use of a validated risk model, and patients should be carefully
      monitored after discharge from the hospital. Response and safety parameters
      should be recorded along with readmission rates. If studies use these guidelines,
      comparisons between studies will be simpler and will lead to further improvements
      in patient therapy.

PMID- 12471565
TI  - Efficacy and safety of dihydroartemisinin-piperaquine (Artekin) in Cambodian
      children and adults with uncomplicated falciparum malaria.
AB  - The safety and efficacy of a novel combination of dihydroartemisinin (DHA) and
      piperaquine, Artekin (Holleykin Pharmaceuticals), were assessed in 106 patients
      (76 children and 30 adults) with uncomplicated falciparum malaria from 2 remote
      areas in Cambodia. Age-based doses were given at 0, 8, 24, and 32 h. Mean total
      DHA and piperaquine doses were 9.1 and 73.9 mg/kg, respectively, for children and
      6.6 and 52.9 mg/kg for adults. All patients became aparasitemic within 72 h.
      Excluding the results for 1 child who died on day 4, there was a 96.9% 28-day
      cure rate (98.6% in children and 92.3% in adults). Patients who had recrudescent
      infection received low doses of Artekin. Side effects were reported by 22
      patients (21%) but did not necessitate premature cessation of therapy. Although
      Artekin is a promising and inexpensive option for antimalarial therapy, further
      efficacy and pharmacokinetic studies are needed, especially for its use in
      children.

PMID- 12471566
TI  - Molecular diversity and routes of colonization of Candida albicans in a surgical
      intensive care unit, as studied using microsatellite markers.
AB  - To evaluate the colonization of Candida species and the importance of cross
      contamination with Candida albicans, we prospectively screened clinical specimens
      obtained from surgical patients in the intensive care unit (ICU) who had a high
      risk of yeast colonization. Genotyping of C. albicans was performed using
      microsatellite markers. Thirty-six of 94 patients acquired nosocomial yeast
      colonization and/or infection. A total of 1126 specimens were cultured, 167 (15%)
      of which yielded yeasts. All 122 isolates of C. albicans recovered from the 30 C.
      albicans-positive patients were genotyped. Twenty-four different genotypes were
      identified. No genotype was systematically associated with a specific room or
      time. Isolates recovered from different body sites of patients at different times
      had identical genotypes. Acquisition of C. albicans in the surgical ICU seems to
      be mainly endogenous. Microsatellite markers should also be developed for typing
      non-albicans Candida species to learn whether their epidemiology differs from
      that of C. albicans.

PMID- 12471567
TI  - Epidemiology of bloodstream infection in nursing home residents: evaluation in a
      large cohort from multiple homes.
AB  - This study sought to reevaluate the epidemiology of bloodstream infection in
      nursing home residents. The records of 166 nursing home residents admitted to an
      urban, public, university-affiliated hospital with 169 episodes of bloodstream
      infection between January 1997 and April 2000 were retrospectively reviewed. The
      most common organisms isolated were Escherichia coli (27% of isolates),
      Staphylococcus aureus (18%; 29% were methicillin-resistant strains), and Proteus
      mirabilis (13%). There was minimal resistance to quinolones and third-generation
      cephalosporins among aerobic gram-negative bacilli. The most common sources were
      the urinary tract (51% of episodes) and the lungs (11%); a source was not
      identified in 22% of episodes. Hospital mortality was 18%. Independent predictors
      of hospital mortality were a pulmonary source of infection, systolic blood
      pressure <90 mm Hg, and leukocytosis >20,000 cells/mm3. Compared with other
      studies published in the past 2 decades, mortality was lower. The most common
      resistant organism was methicillin-resistant S. aureus.

PMID- 12471568
TI  - The effect of renal dysfunction on antimicrobial use measurements.
AB  - The defined daily dose, a popular measurement of antimicrobial use, may
      underestimate the use of antimicrobials that are dose-adjusted in patients with
      renal insufficiency. To evaluate the effect of renal dysfunction on these
      measures, we performed a retrospective cohort study that involved patients
      receiving ceftriaxone, levofloxacin, or vancomycin, with use of defined daily
      doses and 2 methods based on therapy duration--stop-start days (i.e., entire
      therapy duration) and transaction days (i.e., unique therapeutic days). The
      vancomycin use rate for patients with renal insufficiency was 36% lower than that
      of patients with normal renal function for defined daily doses, and it was 23%
      lower for transaction days; for levofloxacin, there was a 27% rate reduction for
      the defined daily dose. No significant reduction was noted when the stop-start
      day method was used. Compared with the defined daily dose method, measures of
      therapy duration are less affected by renal function and may improve comparisons
      between populations.

PMID- 12471569
TI  - Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate
      atovaquone-proguanil.
AB  - In an open-label trial carried out on the northwest border of Thailand, 1596
      patients with uncomplicated multidrug-resistant falciparum malaria were randomly
      assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or
      artesunate-mefloquine and were followed up for 42 days. All 3 regimens were
      highly effective and well tolerated. Fever duration and parasite clearance times
      were significantly shorter among patients who received artesunate (P<.001).
      Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13
      patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone
      proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%).
      Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95%
      confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold
      (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation
      of treatment were more common among artesunate recipients, but after day 2,
      dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common
      among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a
      highly effective and well-tolerated treatment for multidrug-resistant falciparum
      malaria.

PMID- 12471570
TI  - Widespread use of fluoroquinolones versus emerging resistance in pneumococci.
AB  - During the past decade, respiratory-tract pathogens have shown an increase in
      resistance to all classes of antimicrobial agents. Although the increasing
      prevalence of penicillin-resistant Streptococcus pneumoniae has resulted in an
      increased reliance on newer classes of agents, such as the fluoroquinolones, the
      broad use of these agents has contributed to increasing prevalence of strains
      with in vitro fluoroquinolone resistance, which are associated with treatment
      failures, nosocomial outbreaks, and patient fatalities. Strategies to limit this
      emerging dilemma and preserve the clinical utility of these agents are needed.

PMID- 12471571
TI  - Recipient screening prior to solid-organ transplantation.
AB  - Screening a potential transplant recipient for infectious diseases is an
      important component of the transplantation process. Such screening may lead to
      the discovery and treatment of occult active infection, may help determine
      posttransplant prophylactic strategies, or may disqualify the recipient from
      receiving a transplant. The pretransplant period also affords an opportunity for
      updating vaccination status and providing education regarding the reduction of
      posttransplant infectious risks. The present brief review will outline the
      investigation of preexisting active infection, as well as latent bacterial,
      mycobacterial, fungal, parasitic, and viral infections. Recommendations for
      pretransplant immunization and education are provided.

PMID- 12471572
TI  - Approaching eradication of highly active antiretroviral therapy-persistent human
      immunodeficiency virus type 1 reservoirs with immune activation therapy.
AB  - Highly active antiretroviral therapy (HAART) has dramatically altered the human
      immunodeficiency virus type 1 (HIV-1) pandemic in the developed world. Most
      patients treated with HAART will maintain clinically undetectable plasma virus
      loads with concomitant dramatic decreases in mortality and morbidity.
      Nevertheless, HAART does not eradicate HIV-1 infection on the basis of persistent
      low-level or cryptic viral replication and, of importance, latent provirus in
      resting CD4+ T lymphocytes. New approaches are now being developed for
      stimulation of "HAART-persistent" reservoirs. Immune activation therapy (IAT) has
      begun to be used in attempts to stimulate the HIV-1 latent reservoir. These
      studies and new approaches to activating latent virus in resting CD4+ T cells are
      reviewed and critically analyzed in the present report. Development of novel IAT
      may lead to long-term remission or viral eradication in the future.

PMID- 12471573
TI  - Efficacy of induction therapy with high-dose interferon for patients with
      hemophilia and human immunodeficiency virus-hepatitis C virus coinfection.
AB  - To evaluate the efficacy of high-dose interferon (IFN) on human immunodeficiency
      virus (HIV) and hepatitis C virus (HCV) infection, 15 HIV-positive patients and
      15 age-matched HIV-negative patients with hemophilia were treated with 9 million
      units (MU) of IFN-alpha2a daily for 2 weeks, followed by 9 MU of IFN-alpha2a 3
      times/week for a further 22 weeks. At week 2, HIV RNA levels decreased from
      7410+/-2190 to 320+/-130 copies/mL, and HCV RNA levels decreased from 390x10(3)+/
      80x10(3) to 70x10(3)+/-30x10(3) copies/mL in the HIV-positive group and from
      300x10(3)+/-80x10(3) to 10x10(3)+/-10x10(3) copies/mL in the HIV-negative group.
      HCV RNA was undetectable after treatment in 4 of 12 HIV-positive and 6 of 15 HIV
      negative patients. IFN therapy was discontinued because of adverse effects in 3
      HIV-positive patients. Induction therapy and the dose of IFN should be evaluated
      in combination therapy with IFN and ribavirin.

PMID- 12471574
TI  - Thrombotic microangiopathy in patients with acquired immunodeficiency syndrome
      before and during the era of introduction of highly active antiretroviral
      therapy.
AB  - The incidence of thrombotic microangiopathy (TMA) was retrospectively evaluated
      in a cohort of 1223 patients with acquired immunodeficiency syndrome (AIDS) who
      were observed from January 1985 through December 1996 (before the era of highly
      active antiretroviral therapy [HAART]), and the incidence was prospectively
      assessed for 347 patients with AIDS during the period of January 1997 through
      December 2000 (during the HAART era). Seventeen cases were reported in the former
      cohort (1.4%). The increased risk of developing TMA was statistically significant
      in patients with cryptosporidiosis or AIDS-related cancer but not in those with
      other diseases. In the 1997-2000 cohort, no cases were observed during follow-up.
      TMA is associated with conditions observed in the advanced phases of human
      immunodeficiency virus infection. The disappearance of TMA during the HAART era
      may be explained by the lower percentage of patients with long-lasting CD4+ T
      cell depletion, advanced AIDS, or cryptosporidiosis or who have undergone
      multiple courses of chemotherapy for treatment of cancer.

PMID- 12471575
TI  - The effect of race/ethnicity on the outcome of highly active antiretroviral
      therapy for human immunodeficiency virus type 1-infected patients.
AB  - We performed a population-based cohort study to assess the impact of nonwhite
      origin on the outcome of highly active antiretroviral therapy (HAART) for a
      Danish cohort of human immunodeficiency virus (HIV)-infected patients. A total of
      389 whites and 135 nonwhites started receiving HAART before 1 April 2001. After 1
      year of treatment, 78% of nonwhites and 76% of whites achieved a virus load of
      <500 HIV RNA copies/mL. No major differences were found between the 2 groups with
      respect to achievement of a virus load of <500 copies/mL (relative risk [RR],
      0.94; 95% confidence interval [CI], 0.74-1.18), risk of clinical progression (RR,
      0.63; 95% CI, 0.32-1.24), or response measured by total CD4+ cell count. One year
      after fulfilling Danish recommendations for initiation of HAART, 91% of nonwhites
      and 93% of whites had started receiving HAART. Race and ethnic origin play no
      major role in the outcome associated with HAART if access to health care is free.

PMID- 12471576
TI  - Regional occurrence of plasmid-mediated SHV-7, an extended-spectrum beta
      lactamase, in Enterobacter cloacae in Philadelphia Teaching Hospitals.
AB  - Although the production of extended-spectrum beta-lactamases (ESBLs) by
      Klebsiella pneumoniae and Escherichia coli is an emerging problem, limited data
      are available regarding the frequency of ESBL production in other organisms. We
      provide the only description of regional occurrence of SHV-7 in
      Enterobacteriaceae other than E. coli or K. pneumoniae in the United States, and
      we emphasize that, among Enterobacter cloacae strains, not all resistance to
      extended-spectrum cephalosporins is the result of hyperproduction of AmpC beta
      lactamase.

PMID- 12471577
TI  - Helicobacter species ribosomal DNA recovered from the liver tissue of chinese
      patients with primary hepatocellular carcinoma.
AB  - Using polymerase chain reaction (PCR), we examined 16S ribosomal DNA (rDNA) of
      Helicobacter species in liver tissue specimens obtained from 15 patients with
      hepatocellular carcinoma. Sixty percent (9 of 15) of these specimens were found
      to be positive for Helicobacter species. Four 16S rDNA fragments from positive
      PCR samples were directly sequenced. By sequence comparison, all were found to be
      99% identical to the 16S rRNA of Helicobacter pylori.

PMID- 12471578
TI  - Papular purpuric rash due to parvovirus B19 with distribution on the distal
      extremities and the face.
AB  - We describe 3 patients who presented with a distinctive clinical picture of the
      purpuric rash called "gloves-and-socks syndrome" which was characterized by an
      acral distribution of the rash that involved not only the distal part of the
      extremities but also the chin and perioral area. Serologic analysis for
      parvovirus B19 yielded positive results. Parvovirus B19 should be included in the
      evaluation of febrile purpura.

PMID- 12471579
TI  - Prospective immunogenicity study of multiple intradermal injections of rabies
      vaccine in an effort to obtain an early immune response without the use of
      immunoglobulin.
AB  - The present study sought to determine whether increasing and accelerating rabies
      vaccine administration would result in earlier protective levels of neutralizing
      antibody. Results indicated that the 8-site and double-dose Thai Red Cross
      intradermal regimens produced higher antibody titers by day 14 but not
      significantly higher titers by days 5 and 7. Administration of rabies
      immunoglobulin into and around bite wounds on the first day of rabies prophylaxis
      should remain the optimal postexposure treatment.

PMID- 12471580
TI  - Amputation-sparing treatment by nature: "surgical" maggots revisited.
AB  - Maggots were used as adjunct treatment for infected wounds that showed no
      response to the classical approach of wound debridement and antibiotic therapy.
      We summarize findings for 11 patients with necrotic wounds who received treatment
      with "surgical" maggots (100-2900 applied in 3-10 changes of dressing) for 11-34
      days, which apparently aided in tissue remodeling and cure, and describe 2
      typical patients in detail.

PMID- 12471582
TI  - Does the use of fluoroquinolones for the empiric treatment of pneumonia delay
      initiation of treatment of tuberculosis?

PMID- 12471583
TI  - Practical aspects of choosing antibiotic therapy for patients with a reported
      antibiotic allergy.

PMID- 12471584
TI  - Pulmonary tuberculosis presenting as community-acquired pneumonia.

PMID- 12471586
TI  - Clinical manifestations of discordance between cerebrospinal fluid and plasma HIV
      1 loads.

PMID- 12471587
TI  - Urban trench fever in a healthy man from the southeastern United States.

PMID- 12471588
TI  - Clinical and economic outcomes of conventional amphotericin B-associated
      nephrotoxicity.
AB  - A retrospective 9-year cohort study was conducted to identify the hospitalization
      costs, length of hospital stay, and mortality associated with nephrotoxicity (NT)
      among 494 inpatients who were treated with conventional amphotericin B (CAB).
      Survival regression methods were used to model the effect of NT. The rate of NT
      was 12%; the overall in-hospital mortality rate was 22%. After adjustment for
      confounding, NT was associated with a 2.7-fold higher risk of death (P<.001).
      Although the unadjusted effects of NT on length of hospital stay and
      hospitalization costs after the initiation of CAB were consistent with small
      increases, such effects were not significant in multivariate models (time ratio,
      1.2 [P=.2]; cost ratio, 1.1 [P=.8]). The greater the number of days before the
      onset of NT that were included in the analysis, the greater the apparent effect
      of NT on costs. CAB-associated NT was associated with increased mortality, but it
      did not impact the costs and length of hospital stay.

PMID- 12471589
TI  - Immune reconstitution cryptococcosis after initiation of successful highly active
      antiretroviral therapy.
AB  - Five of 10 patients who commenced successful highly active antiretroviral therapy
      (HAART) for infection with human immunodeficiency virus type 1 (HIV-1) concurrent
      with or soon after a diagnosis of cryptococcal infection experienced clinical
      events characterized by sterile inflammation. Two patients developed aseptic
      meningitis with elevated intracranial pressure, 1 developed intrathoracic
      lyphadenopathy with hypercalcemia, 1 developed cavitary pneumonia at the site of
      a cryptococcal nodule, and 1 developed a supraclavicular abscess. These events
      occurred 2-11 months after initiation of HAART. For 3 patients, biopsy
      demonstrated findings atypical for acquired immunodeficiency syndrome-associated
      cryptococcosis. Results of fungal cultures were negative for all 5 patients, and
      cryptococcal antigen levels had declined markedly in 4 patients. The timing and
      clinical features of and biopsy findings for these cases of cryptococcosis
      suggest the existence of a paradoxical reaction to Cryptococcus infection that
      occurs in the context of HIV immune restoration.

PMID- 12471590
TI  - Gammadelta T lymphocytosis associated with granulomatous disease in a patient
      with common variable immunodeficiency.
AB  - Common variable immunodeficiency (CVID) is a heterogeneous group of
      immunodeficiency syndromes that involves defective production of specific
      antibodies and decreased serum concentrations of > or =1 immunoglobulin isotype.
      We describe a patient with an atypical case of CVID who had extensive
      granulomatous lesions that were partially attributable to mycobacterial
      infection. In the peripheral blood, there was a massive increase in the number of
      double-negative CD3+ T cells that expressed the gammadelta T cell receptor.

PMID- 12471591
TI  - Cystic Fibrosis and Burkholderia pseudomallei Infection: An Emerging Problem?
AB  - We recently managed 4 patients with cystic fibrosis who had acquired Burkholderia
      pseudomallei infection after exposure in a region of endemicity. Person-to-person
      transmission between 2 siblings may have occurred; otherwise, the evidence
      suggests that cystic fibrosis may increase the likelihood of infection with this
      organism, and patients should be warned of this possibility and cautioned to
      avoid high-risk activities.

PMID- 12471592
TI  - Vertebral osteomyelitis due to Bartonella henselae in adults: a report of 2
      cases.
AB  - We describe 2 adult patients (1 of whom was infected with human immunodeficiency
      virus) with osteomyelitis due to Bartonella henselae. Diagnosis was established
      on the basis of direct identification of the microorganism in one case and
      seroconversion in the other. Both patients recovered completely within 3 months.

PMID- 12471593
TI  - Common sequence variants of the macrophage scavenger receptor 1 gene are
      associated with prostate cancer risk.
AB  - Rare germline mutations of macrophage scavenger receptor 1 (MSR1) gene were
      reported to be associated with prostate cancer risk in families with hereditary
      prostate cancer (HPC) and in patients with non-HPC (Xu et al. 2002). To further
      evaluate the role of MSR1 in prostate cancer susceptibility, at Johns Hopkins
      Hospital, we studied five common variants of MSR1 in 301 patients with non-HPC
      who underwent prostate cancer treatment and in 250 control subjects who
      participated in prostate cancer-screening programs and had normal digital rectal
      examination and PSA levels (<4 ng/ml). Significantly different allele frequencies
      between case subjects and control subjects were observed for each of the five
      variants (P value range.01-.04). Haplotype analyses provided consistent findings,
      with a significant difference in the haplotype frequencies from a global score
      test (P=.01). Because the haplotype that is associated with the increased risk
      for prostate cancer did not harbor any of the known rare mutations, it appears
      that the observed association of common variants and prostate cancer risk are
      independent of the effect of the known rare mutations. These results consistently
      suggest that MSR1 may play an important role in prostate carcinogenesis.

PMID- 12471594
TI  - Exponential decay kinetics in "downhill" protein folding.
AB  - The observation of single-exponential kinetic phases in early stages of protein
      folding is often interpreted as evidence that these phases are rate limited by
      significant energy or entropy barriers. However, although the existence of large
      barriers reliably implies exponential kinetics, the reverse is not necessarily
      true. A simple model for the hydrophobic collapse of a chain molecule
      demonstrates that a barrierless or "downhill" diffusional relaxation can give
      rise to kinetics that are practically indistinguishable from a pure exponential.
      Within this model, even a highly nonlinear experimental probe such as resonance
      energy transfer (Forster transfer) could exhibit a large amplitude decay (greater
      than 90% in fluorescence) that deviates from a simple exponential by less than
      0.5%. Only a detailed analysis of the dynamics is likely to reveal that a free
      energy barrier is absent.

PMID- 12471595
TI  - Protein-based virtual screening of chemical databases. II. Are homology models of
      G-Protein Coupled Receptors suitable targets?
AB  - The aim of the current study is to investigate whether homology models of G
      Protein-Coupled Receptors (GPCRs) that are based on bovine rhodopsin are reliable
      enough to be used for virtual screening of chemical databases. Starting from the
      recently described 2.8 A-resolution X-ray structure of bovine rhodopsin, homology
      models of an "antagonist-bound" form of three human GPCRs (dopamine D3 receptor,
      muscarinic M1 receptor, vasopressin V1a receptor) were constructed. The homology
      models were used to screen three-dimensional databases using three different
      docking programs (Dock, FlexX, Gold) in combination with seven scoring functions
      (ChemScore, Dock, FlexX, Fresno, Gold, Pmf, Score). Rhodopsin-based homology
      models turned out to be suitable, indeed, for virtual screening since known
      antagonists seeded in the test databases could be distinguished from randomly
      chosen molecules. However, such models are not accurate enough for retrieving
      known agonists. To generate receptor models better suited for agonist screening,
      we developed a new knowledge- and pharmacophore-based modeling procedure that
      might partly simulate the conformational changes occurring in the active site
      during receptor activation. Receptor coordinates generated by this new procedure
      are now suitable for agonist screening. We thus propose two alternative
      strategies for the virtual screening of GPCR ligands, relying on a different set
      of receptor coordinates (antagonist-bound and agonist-bound states).

PMID- 12471596
TI  - Efficient RMSD measures for the comparison of two molecular ensembles. Root-mean
      square deviation.
AB  - Quantitative measures are presented for comparing the conformations of two
      molecular ensembles. The measures are based on Kabsch's formula for the root-mean
      square deviation (RMSD) and the covariance matrix of atomic positions of
      isotropically distributed ensembles (IDE). By using a Taylor series expansion, it
      is shown that the RMSD can be expressed solely in terms of the IDE matrices. A
      fast approximate method is introduced for the pairwise RMSD determination whose
      computational cost scales linearly with the number of structures. A similarity
      measure for two structural ensembles that is based on the trace metric of the
      differences of powers of the IDE matrices is presented. The measures are
      illustrated for conformational ensembles generated by a molecular dynamics
      computer simulation of a partially folded A-state analog of ubiquitin.

PMID- 12471597
TI  - Long- and short-range interactions in native protein structures are
      consistent/minimally frustrated in sequence space.
AB  - We show that long- and short-range interactions in almost all protein native
      structures are actually consistent with each other for coarse-grained energy
      scales; specifically we mean the long-range inter-residue contact energies and
      the short-range secondary structure energies based on peptide dihedral angles,
      which are potentials of mean force evaluated from residue distributions observed
      in protein native structures. This consistency is observed at equilibrium in
      sequence space rather than in conformational space. Statistical ensembles of
      sequences are generated by exchanging residues for each of 797 protein native
      structures with the Metropolis method. It is shown that adding the other category
      of interaction to either the short- or long-range interactions decreases the
      means and variances of those energies for essentially all protein native
      structures, indicating that both interactions consistently work by more-or-less
      restricting sequence spaces available to one of the interactions. In addition to
      this consistency, independence by these interaction classes is also indicated by
      the fact that there are almost no correlations between them when equilibrated
      using both interactions and significant but small, positive correlations at
      equilibrium using only one of the interactions. Evidence is provided that protein
      native sequences can be regarded approximately as samples from the statistical
      ensembles of sequences with these energy scales and that all proteins have the
      same effective conformational temperature. Designing protein structures and
      sequences to be consistent and minimally frustrated among the various
      interactions is a most effective way to increase protein stability and
      foldability.

PMID- 12471598
TI  - Subcellular location prediction of apoptosis proteins.
AB  - Apoptosis proteins have a central role in the development and homeostasis of an
      organism. These proteins are very important for understanding the mechanism of
      programmed cell death. Many efforts in pharmaceutical research have been aimed at
      understanding their structure and function. Unfortunately, thus far, very few
      apoptosis protein structures have been determined. In contrast, many apoptosis
      protein sequences are known, and many more are expected to come in the near
      future. Because of the extremely unbalanced state, it would be worthwhile to
      develop a fast sequence-based method to identify their subcellular location so as
      to gain some insight about their biological function. In view of this, a study
      was initiated in an attempt to identify the subcellular location of apoptosis
      proteins according to their sequences by means of the covariant discriminant
      function, which was established based on the Mahalanobis distance and Chou's
      invariance theorem (Chou, Proteins 1995;21:319-344). The results were quite
      promising, indicating that the subcellular location of apoptosis proteins are
      predictable to a considerably accurate extent if a good training data set can be
      established. It is expected that, with a continuous improvement of the training
      data set by incorporating more and more new data, the current method might
      eventually become a useful tool in this area because the function of an apoptosis
      protein is closely related to its subcellular location.

PMID- 12471599
TI  - Beyond the rotamer library: genetic algorithm combined with the disturbing
      mutation process for upbuilding protein side-chains.
AB  - The disturbing genetic algorithm, incorporating the disturbing mutation process
      into the genetic algorithm flow, has been developed to extend the searching space
      of side-chain conformations and to improve the quality of the rotamer library.
      Moreover, the growing generation amount idea, simulating the real situation of
      the natural evolution, is introduced to improve the searching speed. In the
      calculations using the pseudo energy scoring function of the root mean squared
      deviation, the disturbing genetic algorithm method has been shown to be highly
      efficient. With the real energy function based on AMBER force field, the program
      has been applied to rebuilding side-chain conformations of 25 high-quality
      crystallographic structures of single-protein and protein-protein complexes. The
      averaged root mean standard deviation of atom coordinates in side-chains and
      veracities of the torsion angles of chi(1) and chi(1) + chi(2) are 1.165 A, 88.2
      and 72.9% for the buried residues, respectively, and 1.493 A, 79.2 and 64.7% for
      all residues, showing that the method has equal precision to the program SCWRL,
      whereas it performs better in the prediction of buried residues and protein
      protein interfaces. This method has been successfully used in redesigning the
      interface of the Basnase-Barstar complex, indicating that it will have extensive
      application in protein design, protein sequence and structure relationship
      studies, and research on protein-protein interaction.

PMID- 12471600
TI  - Ion permeation through the gramicidin channel: atomically detailed modeling by
      the Stochastic Difference Equation.
AB  - Atomically detailed descriptions of ionic solution, membrane, and the gramicidin
      channel are used to compute molecular dynamics trajectories of ion permeation.
      The microsecond trajectories are calculated with the Stochastic Difference
      Equation (SDE), which provides approximate solutions to the equations of motions
      (with filtered high-frequency modes) of extended timescales. The relative
      permeations of lithium, sodium, and potassium are estimated by using a novel,
      kinetic cycle protocol and are compared with experiment. The transport through
      native gramicidin and one fluoro-valine variant is considered as well.
      Qualitative agreement between theory and experiment is obtained. The faster
      permeation rate of sodium compared to lithium is reproduced in the calculations.
      The calculations also reproduce the slower diffusion through a gramicidin with
      fluorinated valine compared to native gramicidin. The calculations are
      inconclusive about the relative rates of potassium and sodium. The experiment
      suggests that potassium permeates more quickly. We directly probe the kinetics of
      a biophysical process at a relevant time window without reducing the atomically
      detailed description of the system. The calculations were able to capture subtle
      balances between binding and diffusion that determine permeation rates. The same
      model gave the correct ordering of diffusion rates for cases in which
      electrostatic binding has opposite effects and must be supplemented by dynamic
      factors. Diffusion rates are faster when favorable electrostatic interactions of
      ions in the channel (compared to the solvent) are observed. Studies of a
      gramicidin variant suggest an opposite effect, in which permeation is faster for
      the less polar channel, indicating dynamic effects. Although both trends can be
      explained qualitatively, it is not possible to predict (before doing the SDE
      calculations) which factor is more important.

PMID- 12471601
TI  - Virtual screening to enrich hit lists from high-throughput screening: a case
      study on small-molecule inhibitors of angiogenin.
AB  - "Hit lists" generated by high-throughput screening (HTS) typically contain a
      large percentage of false positives, making follow-up assays necessary to
      distinguish active from inactive substances. Here we present a method for
      improving the accuracy of HTS hit lists by computationally based virtual
      screening (VS) of the corresponding chemical libraries and selecting hits by
      HTS/VS consensus. This approach was applied in a case study on the target-enzyme
      angiogenin, a potent inducer of angiogenesis. In conjunction with HTS of the
      National Cancer Institute Diversity Set and ChemBridge DIVERSet E (approximately
      18,000 compounds total), VS was performed with two flexible library
      docking/scoring methods, DockVision/Ludi and GOLD. Analysis of the results
      reveals that dramatic enrichment of the HTS hit rate can be achieved by selecting
      compounds in consensus with one or both of the VS functions. For example, HTS
      hits ranked in the top 2% by GOLD included 42% of the true hits, but only 8% of
      the false positives; this represents a sixfold enrichment over the HTS hit rate.
      Notably, the HTS/VS method was effective in selecting out inhibitors with
      midmicromolar dissociation constants typical of leads commonly obtained in
      primary screens.

PMID- 12471602
TI  - Role of the protein side-chain fluctuations on the strength of pair-wise
      electrostatic interactions: comparing experimental with computed pK(a)s.
AB  - The effect of the protein side-chain fluctuations on the strength of
      electrostatic interactions was studied. The effect was modeled on 7 different
      crystal structures on the same enzyme as well as on 20 molecular dynamics
      snapshot structures. It was shown that the side-chain flexibility affects
      predominantly the magnitude of the strong pair-wise interactions, that is, the
      pair-wise interaction among ion pairs, and practically does not affect the
      interactions with the rest of the protein. This was used to suggest a correction
      function that should be applied to the original pair-wise electrostatic
      interaction to mimic the effects of the fluctuations. The procedure is applied on
      three ion pairs identified in lysozyme. It was shown that sampling different side
      chain rotamers and modifying the strength of the pair-wise interaction energies
      makes calculated pK(a)s less sensitive to the fluctuations of the structure and
      improves the prediction accuracy.

PMID- 12471603
TI  - Calcium binding to the transmembrane domain of the sarcoplasmic reticulum Ca2+
      ATPase: insights from molecular modeling.
AB  - Sarcoplasmic reticulum Ca(2+)- ATPase pumps Ca(2+) ions from muscle cells to the
      sarcoplasmic reticulum. Here we use molecular dynamics and electrostatic modeling
      to investigate structural and dynamical features of key intermediates in the
      Ca(2+) binding process of the protein. Structural models of the protein
      (containing either two, one, or no calcium ions in the transmembrane domain) are
      constructed based on the X-ray structure by Toyoshima et al. (Nature 2000;405:647
      655). The protein is embedded in a water/octane bilayer, which mimics the
      water/membrane environment. Our calculations provide information on the hydration
      of the two Ca(2+) ions, not emerging from the X-ray structure. Furthermore, they
      indicate that uptake of the metal ions causes large structural rearrangements of
      the metal binding sites. In addition, they suggest that the two ions reach their
      binding sites via two specific pathways. Finally, they allow identification of
      residues in the outer mouth of the protein that might interact with the Ca(2+)
      ions during the binding process.

PMID- 12471604
TI  - A knowledge-based scale for amino acid membrane propensity.
AB  - In this article, a membrane-propensity scale for amino acids is derived using
      only two ingredients: (i) a set of transmembrane helices segments from membrane
      protein crystal structures and (ii) the request that each component of the set
      has a free energy lower than that of a typical soluble protein sequence of the
      same length. Although the most widely used hydropathy scales satisfy this
      request, we use an optimization procedure that allows for extraction of an
      optimal scale, which correlates equally well with those scales. We show that, if
      the choice of the sequence database is accurate, significant knowledge-based
      scales, which are robust with respect to changes in the learning set, can be
      easily derived. The obtained scales can be used for transmembrane helices
      prediction. The predictive power of one of these scales is tested on membrane
      proteins, soluble proteins, and signal peptides databases, finding that its
      performances is comparable with those of the hydropathy scales.

PMID- 12471605
TI  - Structural plasticity of thermophilic serine hydroxymethyltransferases.
AB  - Serine hydroxymethyltransferase (SHMT) catalyzes the reversible cleavage of
      serine to form glycine and monocarbonic groups, essential in several biosynthetic
      pathways. The availability of crystallographic structures of SHMT from mesophilic
      organisms and information produced by the genomic projects prompted the analysis
      of the adaptation of SHMT to "extreme" environments, such as high temperatures,
      by exploitation of structural data from thermophilic organisms. The sequences of
      10 thermophilic/hyperthermophilic SHMTs were multiply aligned to 53 mesophilic
      homologs and analyzed by a comparative approach, examining the amino acid
      compositions and preferred residue exchanges between mesophiles and
      extremophiles. The structural basis of the observed exchanges was further
      investigated through the application of homology modeling to the 10 extremophilic
      SHMTs. The results of this study indicate that, in SHMT, thermal stability can be
      achieved mainly through three strategies: (i) increased number of charged
      residues at the protein surface; (ii) increased hydrophobicity of the protein
      core; and (iii) substitution of thermolabile residues exposed to the solvent.
      Additional features of the archaeal SHMTs, for which no structural data are
      available yet, were also investigated to explain their quaternary assemblage and
      the interaction with modified folates.

PMID- 12471606
TI  - Analysis of the binding energies of testosterone, 5alpha-dihydrotestosterone,
      androstenedione and dehydroepiandrosterone sulfate with an antitestosterone
      antibody.
AB  - Molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface
      area (MM-PBSA) free energy calculations were used to study the binding of
      testosterone (TES), 5alpha-dihydrotestosterone (5ADHT), androstenedione (AND),
      and dehydroepiandrosterone sulfate (DHEAS) to the monoclonal antitestosterone
      antibody 3-C(4)F(5). The relative binding free energy of TES and AND was also
      calculated with free energy perturbation (FEP) simulations. The antibody 3
      C(4)F(5) has a relatively high affinity (3 x 10(8) M(-1)) and on overall good
      binding profile for testosterone but its cross-reactivity with DHEAS has been the
      main reason for the failure to use this antibody in clinical immunoassays. The
      relative binding free energies obtained with the MM-PBSA method were 1.5 kcal/mol
      for 5ADHT, 3.8 kcal/mol for AND, and 4.3 kcal/mol for DHEAS, as compared to TES.
      When a water molecule of the ligand binding site, observed in the antibody-TES
      crystal structure, was explicitly included in MM-PBSA calculations, the relative
      binding energies were 3.4, 4.9, and 5.4 kcal/mol for 5ADHT, AND, and DHEAS,
      respectively. The calculated numbers are in correct order but larger than the
      corresponding experimental energies of 1.3, 1.5, and 2.6 kcal/mol, respectively.
      The fact that the MM-PBSA method reproduced the relative binding free energies of
      DHEAS, a steroid having a negatively charged sulfate group, and the neutrally
      charged TES, 5ADHT, and AND in satisfactory agreement with experiment shows the
      robustness of the method in predicting relative binding affinities. The 800-ps
      FEP simulations predicted that the antibody 3-C(4)F(5) binds TES 1.3 kcal/mol
      tighter than AND. Computational mutagenesis of selected amino acid residues of
      the ligand binding site revealed that the lower affinities of AND and DHEAS as
      compared to TES are due to a combined effect of several residues, each
      contributing a small fraction to the tighter binding of TES. An exception to this
      is Tyr99H, whose mutation to Ala lowered the binding of DHEAS 0.7 kcal/mol more
      than the binding of TES. This is probably due to the hydrogen bonding interaction
      formed between the OH group of Tyr99H and the sulfate group of DHEAS.
      Computational mutagensis data also showed that the affinity of the steroids to
      the antitestosterone antibody 3-C(4)F(5) would be enhanced if Trp47H were
      repositioned so that it would make more extensive contacts with the bound
      ligands. In addition, the binding of steroids to antitestosterone,
      antiprogesterone, and antiestradiol antibodies is discussed.

PMID- 12471607
TI  - Testing similarity measures with continuous and discrete protein models.
AB  - There are many ways to define the distance between two protein structures, thus
      assessing their similarity. Here, we investigate and compare the properties of
      five different distance measures, including the standard root-mean-square
      deviation (cRMSD). The performance of these measures is studied from different
      perspectives with two different protein models, one continuous and the other
      discrete. Using the continuous model, we examine the correlation between energy
      and native distance, and the ability of the different measures to discriminate
      between the two possible topologies of a three-helix bundle. Using the discrete
      model, we perform fits to real protein structures by minimizing different
      distance measures. The properties of the fitted structures are found to depend
      strongly on the distance measure used and the scale considered. We find that the
      cRMSD measure very effectively describes long-range features but is less
      effective with short-range features, and it correlates weakly with energy. A
      stronger correlation with energy and a better description of short-range
      properties is obtained when we use measures based on intramolecular distances.

PMID- 12471608
TI  - Implicit solvent models for flexible protein-protein docking by molecular
      dynamics simulation.
AB  - The suitability of three implicit solvent models for flexible protein-protein
      docking by procedures using molecular dynamics simulation is investigated. The
      three models are (i) the generalized Born (GB) model implemented in the program
      AMBER6.0; (ii) a distance-dependent dielectric (DDD) model; and (iii) a surface
      area-dependent model that we have parameterized and call the NPSA model. This is
      a distance-dependent dielectric model modified by neutralizing the ionizable side
      chains and adding a surface area-dependent solvation term. These solvent models
      were first tested in molecular dynamics simulations at 300 K of the native
      structures of barnase, barstar, segment B1 of protein G, and three WW domains.
      These protein structures display a range of secondary structure contents and
      stabilities. Then, to investigate the performance of the implicit solvent models
      in protein docking, molecular dynamics simulations of barnase/barstar
      complexation, as well as PIN1 WW domain/peptide complexation, were conducted,
      starting from separated unbound structures. The simulations show that the NPSA
      model has significant advantages over the DDD and GB models in maintaining the
      native structures of the proteins and providing more accurate docked complexes.

PMID- 12471609
TI  - X-ray structure of an M. jannaschii DNA-binding protein: implications for
      antibiotic resistance in S. aureus.

PMID- 12471610
TI  - Current status of the molecular genetics of human prostatic adenocarcinomas.
AB  - Molecular genetic mechanisms involved in the progression of prostate cancer are
      not well understood due to extensive tumor heterogeneity and lack of suitable
      models. New methods such as fluorescence in-situ hybridization (FISH),
      comparative genomic hybridization (CGH) and microsatellite analysis have
      documented losses or gains on various chromosomes. Altered chromosomal regions
      have been associated with the activation of oncogenes and the inactivation of
      tumor suppressor genes or defects in mismatch repair (MMR) genes. It is suggested
      that increased genomic instability is associated with decreased androgen
      responsive and progressive behavior of human prostate tumors, but it remains
      unclear whether this genomic instability is causing the progression of cancer or
      is the consequence of cancer. Extended studies on hereditary prostate cancer have
      identified 7 prostate cancer susceptibility loci on several chromosomes, but no
      specific gene has been confined for a large proportion of susceptibility. In this
      review we summarize the ongoing molecular genetic events associated with the
      sporadic and hereditary prostate cancer development and progression.

PMID- 12471611
TI  - Effect of methylenetetrahydrofolate reductase 677C-->T polymorphism on toxicity
      and homocysteine plasma level after chronic methotrexate treatment of ovarian
      cancer patients.
AB  - MTHFR is a critical enzyme that regulates the metabolism of folate and
      methionine, both of which are important factors in DNA methylation and synthesis.
      Subjects with the 677C-->T variant have impaired remethylation of Hcy to
      methionine that could determine hyperhomocysteinemia. Remethylation of Hcy into
      methionine and DNA methylation are also affected by MTX treatment. Thus, a
      combined effect between MTX and reduced activity of the MTHFR 677C-->T
      polymorphism could occur, leading to toxicity. In a clinical trial, 43 ovarian
      cancer patients were treated with low doses of MTX. During MTX therapy, 12
      patients (27.9%) developed G3/4 WHO toxicity. In these 12 patients, we observed 6
      G3/4 thrombocytopenias, 1 G3 neutropenia, 1 G3 anemia, 9 G3 mucositis cases and 1
      G4 mucositis case. A significant association was observed between toxicity and TT
      MTHFR 677 genotype (p < 0.0001). G3/4 toxicity occurred in 10 of 13 (77%), 1 of
      17 (6%) and 1 of 13 (8%) patients with the TT, CT and CC MTHFR genotypes,
      respectively. According to the logistic regression model, patients with the TT
      genotype had a relative risk of 42.0 (95% CI 4.2-418.6) of developing G3/4
      toxicity compared to patients with the CC and CT genotypes. Patients with the TT
      genotype had Hcy plasma levels after MTX therapy significantly (p = 0.0001)
      higher than basal levels (mean +/- SD = 16.71 +/- 4.72 vs. 12.48 +/- 3.57
      micromol/l); moreover, they also had higher Hcy plasma levels after MTX than
      patients with other MTHFR 677 genotypes (CC mean +/- SD = 9.87 +/- 3.61
      micromol/l and CT mean +/- SD = 11.48 +/- 3.13 micromol/l). Finally, significant
      associations were observed between G3/4 WHO toxicity and higher Hcy plasma levels
      after MTX treatment (p = 0.0004). In conclusion, our data suggest that the TT
      MTHFR 677 genotype is associated with marked MTX-induced hyperhomocysteinemia and
      could represent a pharmacogenetic marker for toxicity after chronic treatment
      with low doses of MTX.

PMID- 12471612
TI  - The effect of melatonin treatment regimen on mammary adenocarcinoma development
      in HER-2/neu transgenic mice.
AB  - The effect of various regimens of treatment with melatonin on the development of
      mammary tumors in HER2/neu transgenic mice was investigated. Female HER-2/neu
      mice starting from the age of 2 months were kept under standard light/dark
      regimen and as given melatonin with tap water (20 mg/l) during the night time 5
      times monthly (interrupted treatments) or constantly to natural death. Intact
      mice served as controls. Treatment with melatonin slowed down age-related
      disturbances in estrous function most in the group exposed to interrupted
      treatment with the hormone. Constant treatment with melatonin decreased incidence
      and size of mammary adenocarcinomas, and incidence of lung metastases, compared
      to controls. The number of mice bearing 4 and more tumors was reduced in the
      group with constant melatonin treatment. Interrupted treatment with melatonin
      promote mammary carcinogenesis in HER-2/neu transgenic mice. The data demonstrate
      the regimen-dependent inhibitory effect of melatonin on the development of
      spontaneous mammary tumors in HER-2/neu mice but not on overall survival with
      implication about the likely cause of the effect. Polycystic kidney disease is
      common in this transgenic line. Adverse effect of melatonin on the life span in
      our study may be unique to the transgenic model used and may not be relevant to
      the suppressive effect of melatonin in delay of mammary cancer.

PMID- 12471613
TI  - Quantification of expression of netrins, slits and their receptors in human
      prostate tumors.
AB  - Recently, DCC (Deleted in Colorectal Cancer) protein has been forwarded as a
      receptor for netrin. The Netrin/DCC complex is critical for axon guidance and
      cell migration. In the developing nervous system, netrin protein secreted by
      midline cells attracts commissural axons by activating the DCC receptor on growth
      cones. This attraction can be switched to repulsion or silenced completely,
      depending on the DCC binding partner. The potential suppressor function of DCC in
      prostate tumorigenesis, through a still unknown mechanism, prompted us to
      quantify the expression of several genes involved in this axon guidance pathway.
      The relative expression levels of DCC, NEO1, NTN1, NTN2L, NTN4, UNC5C, Slit1,
      Slit2, Slit3, Robo1 and Robo2 were simultaneous quantified in 48 tumors and 7
      normal prostate tissues by using real-time quantitative reverse transcriptase
      polymerase chain reaction (RT-PCR). A reduction in DCC, NEO1, NTN1 and NTN4
      expression was observed in prostate tumors, while many of the same prostate
      tumors over-expressed either Slit genes or their receptors, Robo.

PMID- 12471614
TI  - Beta2-microglobulin induces caspase-dependent apoptosis in the CCRF-HSB-2 human
      leukemia cell line independently of the caspase-3, -8 and -9 pathways but through
      increased reactive oxygen species.
AB  - Exogenous beta(2)-microglobulin (beta(2)m) induces significant apoptosis in the
      CCRF-HSB-2 human lymphoblastic leukemia cell line as detected by DNA
      fragmentation, DAPI staining and annexin V binding assay. beta(2)m treatment
      induced the release of cytochrome c and apoptosis-inducing factor (AIF) from the
      mitochondria, but no change in mitochondrial membrane potential (DeltaPsim) was
      observed during apoptosis, suggesting that cytochrome c may be released through a
      mechanism independent of mitochondrial permeability transition (MPT) pore
      formation. Moreover, the beta(2)m-induced release of cytochrome c and AIF from
      the mitochondria in CCRF-HSB-2 cells was caspase-independent, since Z-VAD-fmk, a
      general inhibitor of caspases, did not block the release of these factors.
      However, Z-VAD-fmk treatment significantly blocked beta(2)m-induced apoptosis,
      while Western blot analysis revealed that caspases-1, -2, -3, -6, -7, -8 and -9
      are not activated during beta(2)m-induced apoptosis in these cells. These results
      collectively indicate that a post-mitochondrial caspase-dependent mechanism is
      involved in beta(2)m-induced apoptosis. Moreover, beta(2)m significantly enhanced
      the production of reactive oxygen species (ROS) during 12-48 hr treatment, and
      beta(2)m-induced apoptosis was almost totally inhibited in cells pre-treated with
      the antioxidant N-acetylcysteine (NAC), providing evidence that beta(2)m-induced
      apoptosis in CCRF-HSB-2 cells is ROS-dependent. Therefore, these results reveal
      that beta(2)m-induced apoptosis in CCRF-HSB-2 cells may occur through an unknown
      caspase-dependent and ROS-dependent mechanism(s) that is associated with
      cytochrome c and AIF release from mitochondria, but is independent of the caspase
      -3, -8 and -9 pathways.

PMID- 12471615
TI  - Quantitative analysis of follicle-stimulating hormone receptor in ovarian
      epithelial tumors: a novel approach to explain the field effect of ovarian cancer
      development in secondary mullerian systems.
AB  - The role of FSHR expression in ovarian cancer development is not clear. We
      examined quantitative expression of FSHR in different types of OET, presumed
      precursor lesions and peritoneal implants and further discussed FSH as a key
      growth-promotion factor for the process of ovarian epithelial tumorigenesis.
      Thirty-five primary OET specimens, including 5 serous cystadenomas, 4 papillary
      serous cystadenomas, 9 SBTs and 17 serous carcinomas, were examined for
      quantitative FSHR expression. Ten paired samples (3 benign cystadenomas, 5 SBTs
      and 2 carcinomas) were obtained from several morphologically different areas,
      including benign-looking, borderline and cancerous areas in the same OETs, and
      from the remaining ovarian tissue and contralateral ovaries. Competitive RT-PCR
      was performed to measure the quantitative expression of FSHR in each tissue
      sample. FSHR expression levels were compared among nonpaired samples and within
      paired samples. We found that OSE had the lowest FSHR expression, whereas antral
      follicles had the highest level. Within benign OETs, papillary serous
      cystadenomas have 4.9-fold higher FSHR levels than nonpapillary serous
      cystadenomas. SBTs had the highest level of FSHR expression, which was 12.8-fold,
      2.7-fold and 2.4-fold higher than that of serous cystadenomas, papillary serous
      cystadenomas and grade 1 carcinomas, respectively. A similarly high level of FSHR
      mRNA was found in peritoneal implants, which were associated with SBTs. FSHR
      levels among serous carcinomas decreased with an increase in carcinoma grade.
      Grade 3 carcinomas had the lowest FSHR level, which was similar to that of serous
      cystadenomas, while grade 1 carcinomas had 6.5-fold higher FSHR levels than those
      in serous cystadenomas. Our results suggest that not only serum FSH but also FSHR
      in ovarian epithelium may play important roles in ovarian OET development. Both
      the receptor and ligand may act in a synergistic way to promote tumor growth. The
      observation that high FSHR levels are present in peritoneal implants suggests
      that FSH may also play a similar role in the development of peritoneal serous
      tumors. From this perspective, circulating FSH may be considered a driving force
      in the field effect theory for the development of both ovarian neoplasms and
      their associated peritoneal implants. However, the exact role of FSH and/or FSHR
      in the development of epithelial tumors arising in both the ovary and peritoneum
      needs further investigation.

PMID- 12471616
TI  - Differential response of primary and metastatic melanomas to neutrophils
      attracted by IL-8.
AB  - IL-8 is a strong chemoattractant for neutrophils, and it is constitutively
      produced by many tumors, including human melanomas. To determine the biologic
      importance of IL-8 for melanoma cells from primary and metastatic lesions, we
      transduced selected cell lines constitutively producing low levels of IL-8 with
      IL-8 cDNA using a replication-deficient adenoviral vector. Nontumorigenic SBcl2
      primary melanoma cells formed tumors when transduced with increasing plaque
      forming units of IL-8 per cell. However, at high IL-8 transduction levels (100
      ng/ml/10(5) cells in 48 hr), tumor growth was impaired due to massive neutrophil
      infiltration. A similar biphasic response was observed in WM115 primary
      melanomas, which are tumorigenic but not metastatic. Depletion of neutrophils
      with an antibody that blocks the accumulation of granulocytes at the site of
      inflammation enabled transduced primary melanomas secreting high levels of IL-8
      to survive and grow. In contrast, highly tumorigenic and metastatic 451Lu cells
      showed marked increases in tumor growth and number of metastatic foci in the
      lungs depending on the expression levels of IL-8. Cytotoxicity assays with
      isolated neutrophils confirmed the preferential killing of primary over
      metastatic melanoma cells. SBcl2 cells stimulated by IL-8 to form tumors in
      immunodeficient mice were induced to produce VEGF, suggesting that the angiogenic
      response is enhanced due to increased growth factor production. Our results
      demonstrate that nontumorigenic primary melanomas depend on IL-8 stimulation in
      vivo for growth and that tumor growth depends on the level of neutrophil
      infiltration. Metastatic melanomas proliferate in vivo independently of
      infiltrating neutrophils.

PMID- 12471617
TI  - Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor
      activation and normal mammary cell adhesion.
AB  - The collagen-induced phosphorylation of discoidin domain receptor 1 (DDR1) in Wnt
      5a-expressing HB2 mammary cells was effectively inhibited by pertussis toxin, but
      not by cholera toxin or antibodies blocking beta(1) integrins. Moreover,
      pertussis toxin reduced adhesion of the cells to collagen by approximately 50%,
      and antibodies against beta(1) integrins had a similar effect that was in fact
      additive to that of pertussis toxin. Cholera toxin had accordingly no such effect
      on adhesion. By comparison, pertussis toxin did not influence adhesion of Wnt-5a
      antisense HB2 cells or MCF-7 mammary tumor cells, neither of which express Wnt-5a
      or exhibit activation of DDR1. In accordance with these results, direct
      mastoparan-induced activation of G-proteins in Wnt-5a-deficient MCF-7 cells
      enabled collagen-induced phosphorylation of DDR1 and enhanced their adhesion. The
      inactive analogue mastoparan-17 had no such effects on MCF-7 cells nor did active
      mastoparan affect adhesion of Wnt-5a-expressing HB2 cells. A possible explanation
      for how DDR1, a receptor tyrosine kinase (RTK), potentiates mammary cell adhesion
      comes from our observations that pertussis toxin also inhibited the recruitment
      of the cytoskeletal regulator phosphatidylinositol 3-kinase (PI3K) to DDR1 as
      well as its phosphorylation/activation. In accordance with that, the PI3K
      inhibitor wortmannin significantly impaired adhesion of normal Wnt-5a-expressing
      HB2 cells but had little effect on adhesion of Wnt-5a-antisense HB2 cells. Thus,
      a G(i/o)-protein signaling pathway mediates the effect of Wnt-5a expression by
      enabling collagen-induced activation of DDR1, which, in parallel with beta(1)
      integrins, regulates adhesion of mammary cells.

PMID- 12471618
TI  - Geldanamycin decreases Raf-1 and Akt levels and induces apoptosis in
      neuroblastomas.
AB  - Neuroblastomas are the most common extracranial solid tumors of childhood. These
      tumors are associated with an overall poor prognosis, particularly for advanced
      stage disease. The benzoquinone ansamycin antibiotic, geldanamycin (GA), exhibits
      potent antitumor activity in certain cancer cell lines by destabilizing important
      signal transduction proteins (e.g., Raf-1 and Akt). The purpose of our study was
      to determine whether GA can alter the expression of Raf-1 and Akt, which have
      been shown to be critical for neuronal cell survival, and induce apoptosis of
      neuroblastoma cells. Human neuroblastoma cells (SH-SY5Y, SK-N-SH and LAN-1) were
      treated with GA for a variable period of time. Cell viability was assessed with
      MTT assays. Apoptosis was assessed with DNA fragmentation ELISA, TUNEL-flow
      cytometric assay, Western blot and caspase activities. We found that GA decreases
      cell viability and induces apoptosis in the SH-SY5Y human neuroblastoma cell
      line. These effects were mediated through activation of caspase-9 and -3,
      mitochondrial release of cytochrome c and subsequent PARP cleavage. GA-induced
      apoptosis was associated with a reduction in the level and activity of Raf-1 and
      Akt. The importance of these proteins was further demonstrated by induction of
      apoptosis in SH-SY5Y cells by a combination of U0126 (MEK1/2 inhibitor) and
      LY294002 (an inhibitor of PI3K). Similar to SH-SY5Y cells, other human
      neuroblastoma cells (SK-N-SH and LAN-1) were sensitive to the effects of GA
      induced apoptosis. Taken together, our findings suggest that GA may be a novel
      therapeutic agent, which may be effective in the treatment of neuroblastomas.

PMID- 12471619
TI  - Apoptosis induced by cryo-injury in human colorectal cancer cells is associated
      with mitochondrial dysfunction.
AB  - Cryotherapy, a method of in situ ablation, is used in the treatment of colorectal
      liver metastases with variable results. During the treatment, the central area of
      treated tumor undergoes necrotic destruction by lethal cryo-injury; however, the
      cellular response of tumor exposed to sublethal cryo-injury at the peripheral
      zone is unclear. In our study, we have identified the induction of apoptosis by
      cryo-injury at -10 degrees C in 4 colorectal cancer cell lines (HT29, HCT116,
      KM12C and KM12SM). The apoptosis was characterized by chromatin condensation,
      transferase-mediated dUTP nick end-labeling (TUNEL) staining, proteolytic
      cleavage of poly(ADP-ribose) polymerase (PARP) and cytokeratin 18, and activation
      of caspase-3. The occurrence and intensity of cryo-induced apoptosis did not
      correlate with the functional status of p53 in the cell lines studied. The
      expression of anti-apoptotic proteins (Bcl-2, Bcl-X(L)) and pro-apoptotic
      proteins (Bax, Bcl-X(S), Bad, and Bak) in response to cryo-injury varied in this
      cell line panel. The basal level of Bcl-2/Bax protein ratio correlated inversely
      to the apoptotic rate. We further demonstrated that Bax level decreased in
      cytosol and increased in mitochondria, followed by a loss of mitochondrial
      membrane potential after cryo-injury in HT29 cells. These findings indicate that
      cryo-injury induces apoptosis in colorectal cancer cells via disruption of
      mitochondrial integrity. The cryo-induced apoptosis was also identified in a nude
      mouse tumor xenograft model. Our elucidation of the apoptosis pathway induced by
      cryo-injury implies that synergistic combination of cryosurgery with
      pharmacological agents that augment of apoptosis induction may have clinical
      relevance in treating colorectal liver metastasis.

PMID- 12471620
TI  - Upregulation of galectins-1 and -3 in human colon cancer and their role in
      regulating cell migration.
AB  - To probe the potential contribution of beta-galactoside-contributing epitopes and
      receptor proteins (gal-1 and gal-3) to colon malignancy, we first examined the
      expression of galectins and binding sites in clinical specimens by lectin and
      immunohistochemistry. Sixty-seven colonic surgical resections were studied,
      including 10 normal, 10 mild dysplasias, 10 severe dysplasias and 37 cancers. gal
      1 and gal-3 were expressed in variable amounts in the epithelial cells and the
      connective tissue of normal colon. Their expression significantly increased with
      the degree of dysplasia, suggesting that gal-1 and gal-3 and their binding sites
      are related to malignant progression, while gal-8 has been associated with
      suppressor activity. To study the functional aspects, the influence of these
      galectins on the migration of 4 human colorectal cancer cell lines (HCT-15, LoVo,
      DLD-1, CoLo201) was studied. In agreement with histopathologic monitoring, these
      tumor cells were found to produce gal-3, while only CoLo201 was positive for gal
      1. Except for DLD-1 and gal-1, the lines exhibited gal-1 binding sites on the
      surface, prompting study by computer-assisted videomicroscopy of the effect on
      cell migration of the presence of galectin on the culture substrate. The level of
      cell migration for HCT-15, LoVo and CoLo201 cells was significantly reduced by
      0.15 microg/cm(2) gal-1, and the presence of a blocking antibody at least reduced
      this effect. gal-3 significantly reduced cell migration in all 4 of the in vitro
      cell lines.

PMID- 12471621
TI  - Induction of IL-8 and monoclyte chemoattractant protein-1 by doxorubicin in human
      small cell lung carcinoma cells.
AB  - We previously demonstrated doxorubicin-induced urokinase expression in human H69
      SCLC cells by the microarray technique using Human Cancer CHIP version 2 (Takara
      Shuzo, Kyoto, Japan), in which 425 human cancer-related genes were spotted on
      glass plates (Kiguchi et al., Int J Cancer 2001;93:792-7). Microarray analysis
      also revealed significant induction of IL-8, a member of the CXC chemokines. We
      have, therefore, extended the observation by testing the effects of doxorubicin
      on expression of the chemokine family and provide here definitive evidence that
      doxorubicin induces IL-8 and MCP-1, one of the CC chemokines, at least in 2 human
      SCLC cells, H69 and SBC-1. IL-8 antigen levels, measured by ELISA, were markedly
      increased in both H69 and SBC-1 conditioned media after doxorubicin treatment, in
      parallel with mRNA levels; and this was dependent on the dose of doxorubicin. The
      ribonuclease protection assay, using a multiprobe template set for human
      chemokines, revealed induction of not only IL-8 but also MCP-1 in doxorubicin
      treated H69 cells. MCP-1 antigen levels increased approximately 100-fold in
      doxorubicin-treated H69 cells. RT-PCR using specific primers for MCP-1 suggested
      that doxorubicin also induced MCP-1 expression in SBC-1 and SBC-3 SCLC cells.
      Futhermore, CAT analysis using IL-8 promoter implicated the PEA3 transcriptional
      factor, whose binding site was located immediately upstream of the AP-1 and NF
      kappaB binding sites. Thus, it is suggested that doxorubicin induces IL-8 and MCP
      1 chemokines in human SCLC cells by activating gene expression, in which at least
      PEA3 is involved. IL-8 and MCP-1 are major chemoattractants for neutrophils and
      monocytes/macrophages, respectively; therefore, extensive induction of IL-8 and
      MCP-1 may provoke the interaction between inflammatory/immune cells and tumor
      cells under doxorubicin stimulation and influence many aspects of tumor cell
      biology.

PMID- 12471622
TI  - Cyclopentenyl cytosine primes SK-N-BE(2)c neuroblastoma cells for cytarabine
      toxicity.
AB  - CPEC is a potent inhibitor of CTP synthetase and causes depletion of CTP and dCTP
      pools. AraC is an analog of dCyd and a chemotherapeutic agent. Here, we
      demonstrate that, upon incubation with CPEC, both the anabolism and cytostatic
      effect of AraC in SK-N-BE(2)c neuroblastoma cells were increased. Cotreatment of
      CPEC (50-250 nM) and AraC (37.5-500 nM) decreased the 4-day ED(50) value for AraC
      2- to 8-fold in the SK-N-BE(2)c cell line, while pretreatment with CPEC followed
      by incubation with AraC alone decreased the 4-day ED(50) value for AraC 1- to 19
      fold. Preincubation of SK-N-BE(2)c cells with 100 nM CPEC followed by incubation
      with 500 nM [(3)H]AraC increased the total amount of AraC nucleotides and
      incorporation of [(3)H]AraC into DNA by 392% and 337%, respectively, compared to
      non-CPEC-treated cells. When 20 nM [(3)H]AraC was used, the maximum incorporation
      of [(3)H]AraC into DNA was 1,378% compared to non-CPEC-treated cells.
      Incorporation of AraC into DNA correlated well with the accumulation of cells in
      S phase of the cell cycle caused by CPEC. DNA synthesis was almost completely
      inhibited (>91%) when 100 nM CPEC and 500 nM AraC were combined. CPEC alone and
      the combination of CPEC and AraC increased caspase-3 activity 3-fold, indicating
      induction of apoptosis in SK-N-BE(2)c cells. In contrast, AraC alone did not
      induce caspase-3 activity. Our results demonstrate that low concentrations of
      CPEC profoundly increase the cytostatic properties of AraC toward SK-N-BE(2)c
      human neuroblastoma cells.

PMID- 12471623
TI  - Beta2-microglobulin aberrations in diffuse large B-cell lymphoma of the testis
      and the central nervous system.
AB  - Human leukocyte antigen (HLA) class I molecules are expressed on the surface of
      all nucleated cells and present antigenic peptides to cytotoxic T cells, thereby
      playing an important role in initiating the cellular anti-tumor immune response.
      We previously reported that loss of HLA class I expression in diffuse large B
      cell lymphoma (DLBCL) of the central nervous system (CNS) and the testis is a
      common event. Loss of expression and mutations of the light chain of the HLA
      class I molecule, beta(2)-microglobulin (beta(2)m) have been described in a
      variety of human tumors and cell lines. In our study, we screened 15 DLBCL cases
      with a combined loss of HLA class I and beta(2)m expression for mutations in the
      latter gene by direct sequencing. Frame shift mutations in repetitive sequences
      within the beta(2)m gene leading to loss of functional beta(2)m were detected in
      2 cases. Loss of heterozygosity (LOH) and fluorescent in situ hybridization
      (FISH) analysis for chromosome 15 exhibited loss of the remaining copy of the
      beta(2)m gene in both cases but also hemizygous deletions and monosomies in 6
      additional cases. Since similar mutations in the beta(2)m gene have been
      associated with microsatellite instability (MSI), we used 8 markers to study MSI
      involvement in DLBCL. Low MSI was more frequent (33%) as compared to nodal DLBCL
      (n=15) but did not correlate with the beta(2)m mutations. Our data indicate that
      multiple mechanisms lead to downregulation of beta(2)m and concomitant loss of
      HLA class I expression in DLBCL.

PMID- 12471624
TI  - Activation of T cells via tumor antigen specific chimeric receptors: the role of
      the intracellular signaling domain.
AB  - T cells engineered to express hybrid receptors with antibody defined specificity
      can successfully be targeted to tumor cells. In order to select intracellular
      domains of chimeric receptors capable of efficiently activate T cells in vitro
      and in vivo, we compared the function of receptors, which share the same
      extracellular antigen-binding part, joined to different intra-cellular signal
      transduction units. The antigen binding domain of the receptors was a single
      chain fragment of a monoclonal antibody, which recognize a High Molecular Weight
      Melanoma-Associated Antigen with high affinity. The intracellular tails were
      derived from the T-cell receptor zeta chain (TCR-zeta), from the B-cell receptor
      Ig-alpha molecule and from a mutated Ig-alpha molecule able of stronger signal
      transduction. We compared the activity of the different chimeric receptors at a
      single-cell level by using a T-cell line that expressed an activation-dependent
      EGFP-reporter gene. Upon cross-linking with immobilized antibodies, all receptors
      were able to induce EGFP expression in the majority of the T cells. In contrast,
      EGFP expression was induced by contact to melanoma cells in vitro only in T cells
      that expressed the chimeric receptor that contained the TCR-zeta intracellular
      tail. In these T cells, the co-expression of chimeric receptors that contain a
      mutated Ig-alpha tail lowers the threshold of T-cell activation and facilitates
      tumor recognition in vitro and in vivo. Given their specificity and efficiency, T
      cells grafted with these type of receptors may represent potential candidates for
      cancer passive immunotherapy.

PMID- 12471625
TI  - Infiltrating immune cells, but not tumour cells, express FasL in non-small cell
      lung cancer: No association with prognosis identified in 3-year follow-up.
AB  - Non-small cell lung cancer (NSCLC) remains a difficult disease to treat and
      independent prognostic markers other than tumour stage and histology have not
      emerged. The immune cell content of solid tumours has been associated with tumour
      regression and at times, tumour progression. The involvement of immune cells in
      prognosis of NSCLC is poorly described. Poor immune responses within solid
      tumours have been linked with tumour production of immunosuppressive cytokines.
      Tumour expression of FasL is thought to disarm responses through the transduction
      of a death signal in Fas-expressing T cells. The existence of the 'tumour
      counterattack' in vivo has been questioned. We undertook to measure T cell and
      macrophage infiltration of the tumour bed in NSCLC and report the association
      between immune cell content and prognosis in a limited, 3-year analysis of
      survival (n = 113). In addition we investigated FasL expression (n = 45). T cells
      and macrophages were found to frequently infiltrate lung tumours, albeit in small
      numbers. Generally there were more T cells infiltrating than macrophages. T cell
      and macrophage numbers were not associated with prognosis. Lung tumours were
      found not to express FasL, although occasional immune cells surrounding tumour
      cells were strongly positive. FasL expression was not associated with prognosis
      in this series. Thus, immune cells infiltrating NSCLC are not capable of
      suppressing tumour growth, nor are they associated with tumour progression. We
      report that lung tumours do not express the FasL, and that although some immune
      cells are FasL positive, this is not a reflection of general immune cell
      activation.

PMID- 12471626
TI  - Prevalence of human papillomavirus infection in women in Busan, South Korea.
AB  - To investigate the prevalence of and the risk factors for human papillomavirus
      (HPV) infection in South Korea, we interviewed and examined a randomly selected
      sample of 863 sexually active women (age range = 20-74 years, median 44) and 103
      self-reported virgins from Busan. The presence of DNA of 34 different HPV types
      in cervical exfoliated cells was tested among sexually active women by means of a
      PCR-based assay. IgG antibodies against L1 virus-like particles (anti-VLPs) of
      HPV types 16, 18, 31, 33 and 58 were also evaluated by means of ELISA. The
      overall prevalence of HPV DNA was 10.4% (95% confidence interval, CI: 8.5-12.7%).
      The most often found HPV DNA types were HPV 70, HPV 16 and HPV 33; 19.8% (95% CI:
      17.2-22.0) of sexually active women had antibodies against one or more HPV types.
      The most common anti-VLPs were against HPV 18, 31 and 16. Prevalences
      standardized by age on the basis of the world standard population were 13.0% for
      HPV DNA and 17.1% for anti-VLPs. The concordance between the 2 HPV markers at an
      individual level was modest, but the risk factors for detection of HPV DNA and
      anti-VLPs were similar: number of lifetime sexual partners (odds ratio, OR for
      >/= 4 vs. 1 = 3.5 and 5.4, respectively), seropositivity for herpes simplex virus
      2 antibodies (OR = 2.6 and 2.5, respectively) and being single or divorced. HPV
      DNA, but not anti-VLPs, were elevated among women whose husbands were thought by
      their wives to have extra-marital affairs and those who had undergone vasectomy.
      Among 103 virgins, 4.9% had anti-VLPs (1/73 among those aged 24 years or less).

PMID- 12471627
TI  - Prospective and randomised public-health trial on neural network-assisted
      screening for cervical cancer in Finland: results of the first year.
AB  - Our objective was to evaluate the feasibility and relative validity of
      interactive neural network assisted screening (Papnet) in primary mass screening
      for cervical cancer as a public health policy (routine screening). A randomized,
      ongoing trial involved 152,969 invitees and 108,686 attendees in the organized
      mass screening in Finland in 1999. Drawing invitations from the population
      registry, women were randomized 2:1 at an individual level to have their smear
      analyzed either conventionally or with Papnet. The distribution of smears to
      different cytological categories, detection rates of dysplasias, in situ
      carcinomas and cancers were estimated with smears analyzed either conventionally
      (72,461) or by Papnet (36,225). A total of 108,686 smears were screened and 449
      were histologically confirmed as dysplasias and carcinomas. The detection rates
      for histologically verified carcinoma in situ/severe dysplasia, moderate and mild
      dysplasias were 0.14%, 0.14% and 0.13% with conventional and 0.14%, 0.14% and
      0.11% with Papnet, respectively. The detection rate of invasive cancer was 0.06
      per thousand (n = 4) with conventional method and 0.08 per thousand (n = 3) with
      Papnet. None of the differences were statistically significant (p > 0.05). Papnet
      was able to identify 92.5% of healthy women (normal cytology), and the
      specificity of conventional smear was 92.9%. The positive predictive value (Pap
      Classes III-V) of Papnet was slightly but not significantly better (55% vs. 51%).
      Papnet screening was feasible as a part of routine screening and performed
      equally well compared to conventional one methods used in Finland. Organized mass
      screening was practiced very successfully in the last 38 years. We are going to
      continue the trial to study the potential trends in cervical cancer incidence in
      both study arms.

PMID- 12471628
TI  - BRCA2 Arg372Hispolymorphism and epithelial ovarian cancer risk.
AB  - The BRCA2 372 HH genotype defined by the BRCA2 N372H nonconservative amino acid
      substitution polymorphism was recently reported to be associated with a small
      increased risk of breast cancer. We investigated whether this polymorphism was
      associated with ovarian cancer risk by conducting British and Australian case
      control comparisons in parallel, including a total sample of 1,121 ovarian cancer
      cases and 2,643 controls. There was no difference in genotype frequency between
      control groups from the 2 studies (p = 0.9). The HH genotype was associated with
      an increased risk of ovarian cancer in both studies, and the risk estimate for
      the pooled studies was 1.36 (95% CI 1.04-1.77, p = 0.03). There was also a
      suggestion that this risk may be greater for ovarian cancers of the serous
      subtype for both studies, with an OR (95% CI) of 1.66 (1.17-2.54) for the 2
      studies combined (p = 0.005). The BRCA2 372 HH genotype appears to be associated
      with an increased risk of ovarian cancer of a similar magnitude to that reported
      for breast cancer.

PMID- 12471629
TI  - Evidence against involvement of p53 polymorphism in breast cancer predisposition.

PMID- 12471631
TI  - Radial maze proficiency of adult Wistar rats given prenatal complex magnetic
      field treatments.
AB  - Exposure to sinusoidal (power-frequency) magnetic fields during prenatal
      development is implicated in adulthood behavioral impairments. However, the
      effects of prenatal exposure to weak-intensity, nonsinusoidal complex magnetic
      fields (CMFs), an increasingly common feature of the modern environment, have not
      been rigorously examined. In the present study, male and female Wistar-strain
      rats were exposed continually during prenatal development to one of three
      extremely low-frequency CMFs or a sham condition. As adults, rats were trained in
      an acquisition/reversal radial maze task. All rats exposed to the prenatal CMFs
      increased their commission of reference memory errors, but differences in working
      memory and motivation to complete the maze task were specific to the type of
      prenatal CMF. These results provide the first evidence that prenatal exposures to
      specific shapes of CMFs impair complex learning behaviors into adulthood.

PMID- 12471632
TI  - Fetal cyclic motor activity in diabetic pregnancies: sensitivity to maternal
      blood glucose.
AB  - Spontaneous fetal movement in the last third of human gestation is dominated by
      irregular oscillations on a scale of minutes (cyclic motility, CM). The core
      properties of these oscillations are stable during the third trimester of
      gestation in normal fetuses, but disrupted by poorly controlled maternal
      diabetes. Here we investigated whether fetal CM is linked to short-term
      instabilities in maternal glucose metabolism. The fetuses of 40 mothers with type
      I (n = 28) or gestational (n = 12) diabetes were studied one to six times between
      27 and 40 postmenstrual weeks of gestation. Fetal movement and maternal blood
      glucose concentration were measured during two separate periods of fetal activity
      in each session. Fetal CM was quantified with spectral analysis. Early in the
      third trimester, changes in the rate of oscillation in fetal CM between the two
      periods of activity were inversely related to changes in maternal blood glucose
      levels. Fetal CM was unrelated to concurrent maternal blood glucose levels at any
      point in the third trimester. The pattern of results suggests that disruption of
      the temporal organization of spontaneous fetal motor activity in pregnancies
      complicated by maternal diabetes represents an acute response to fluctuations in
      the metabolic environment rather than an alteration of CM development.

PMID- 12471633
TI  - Maternal behavior changes after immune challenge of neonates with developmental
      effects on adult social behavior.
AB  - To examine whether maternal responsiveness during interactions with endotoxin
      treated pups contributes to long-term effects on social development, neonatal
      mice were fostered on postnatal day 1 to dams from three selectively bred lines
      that differ in social behaviors. On day 5, neonates were administered saline or
      0.5 mg/kg endotoxin (lipopolysaccharide, i.p.). Observations of undisturbed dams
      and litters on days 2, 4, 6, and 8 showed modest line differences in maternal
      behaviors. At the peak intensity of the transient illness induced by endotoxin (3
      hr postinjection on day 5), dams increased licking and decreased time off-nest
      for endotoxin, but not saline-treated pups. As adults, fostered-reared males were
      observed in brief social interactions. Males exposed to endotoxin early in life
      showed changes in adult social behaviors that depended on foster dam line as well
      as individual differences in maternal responsiveness. Maternal responsiveness to
      stressed neonates can ameliorate the social-developmental effects of early
      illness.

PMID- 12471634
TI  - The development of "roughness" in the play fighting of rats: a Laban Movement
      Analysis perspective.
AB  - With increasing age, rats, when play fighting, become rougher. In part, this
      change can be accounted for by the increasing likelihood of using adult-typical
      fighting tactics. However, even when using the same tactics, adults appear
      rougher than juveniles in their play. In this study, videotaped sequences of play
      fighting in rats from the juvenile (30 days) to the post-pubertal (70 days)
      period were analyzed using Laban Movement Analysis (LMA). Movement qualities
      called Effort Factors in LMA captured the character of some of this change.
      Juveniles tended to use Indulging Efforts, whereas older rats tended to use
      Condensing Efforts. The latter are related to performing movements that are more
      controlled. This greater level of control was also evident in the way older rats
      maintained postural support during play fights. When standing over supine
      partners, juveniles are more likely to stand on the partner with all four paws,
      reducing their postural stability, and hence ability to control their partner's
      movements. Older rats are more likely to place their hind paws on the ground,
      thus providing a firmer anchor for movements with their upper bodies and
      forepaws. These age-related changes in behavior were found for both males and
      females. The findings lend support to a growing body of evidence that play
      fighting in the juvenile phase of rats is not just a more frequently occurring
      version of that present in adults, but rather, has unique organizational
      properties.

PMID- 12471635
TI  - Long-term effects of infant rearing condition on the acquisition of dominance
      rank in juvenile and adult rhesus macaques (Macaca mulatta).
AB  - We examined the effects of early rearing experience on the development of
      dominance status in 53 juvenile (age 3) and then in 38 adult (ages 5-8) rhesus
      macaques. Based on previous research investigating the behavioral outcomes of
      nursery-rearing, we predicted that mother-reared (MR) monkeys would outrank peer
      only reared (PR) monkeys, which would in turn outrank surrogate/peer-reared (SPR)
      subjects. Juvenile MR and PR subjects did not differ in ranks, but monkeys from
      both rearing backgrounds outranked SPR cage-mates at age 3. Independent of
      rearing condition, high-ranking juveniles gained the most weight between ages 1
      3, suggesting that low status may be associated with decreases in early weight
      gain. Adult MR subjects outranked both PR and SPR subjects, with PR animals
      occupying intermediate ranks. These results indicate that impoverished early
      experiences, such as adult absence and limited social interaction, are useful
      predictors of future social success in rhesus macaques.

PMID- 12471636
TI  - Neonatal social isolation alters both maternal and pup behaviors in rats.
AB  - The development of emotional behavior is dependent on the early experiences of
      the infant and the quality of maternal care. In these experiments, the effects of
      social isolation during the preweaning period on both pup behavior and maternal
      responsivity were examined. In the first study, the number of ultrasonic
      vocalizations (USVs) emitted after brief maternal separation was measured in
      neonatal rats with differing histories of social isolation. The social isolation
      procedure consisted of 5 days of daily separation from the dam and littermates
      for either 3 or 6 hr. At both ages tested, socially isolated pups vocalized
      significantly less than control pups. In the second study, the effects of prior
      isolation either daily for 5 previous days (Chronic Isolation) or for 4 hr prior
      to testing (Acute Isolation) were examined in a T-maze choice test. Pup
      vocalizations in the presence of the dam and dams' maternal behavior were
      assessed. When the dam was confined to the start box or during the maternal free
      access period, both Chronic and Acute Isolates vocalized less than pups that had
      never left the home nest. Dams spent more time with and licked and groomed more
      frequently and for a longer time both Chronic and Acute Isolates compared to pups
      that had always been with dams in the home nest. These results suggest that early
      isolation experience can alter subsequent responses to separation stress in
      neonatal rats and that maternal behavior is sensitive to the prior experiences of
      offspring.

PMID- 12471637
TI  - Developmental and contextual influences on autonomic reactivity in young
      children.
AB  - Studies of cardiovascular reactivity in young children have generally employed
      integrated, physiologically complex measures, such as heart rate and blood
      pressure, which are subject to the multiple influences of factors such as blood
      volume, hematologic status, thermoregulation, and autonomic nervous system (ANS)
      tone. Reactivity studies in children have rarely employed more differentiated,
      proximal measures of autonomic function capable of discerning the independent
      effects of sympathetic and parasympathetic responses. We describe 1) the
      development, validity, and reliability of a psychobiology protocol assessing
      autonomic reactivity to challenge in 3- to 8-year-old children; 2) the influences
      of age, gender, and study context on autonomic measures; and 3) the distributions
      of reactivity measures in a normative sample of children and the prevalences of
      discrete autonomic profiles. Preejection period (PEP) and respiratory sinus
      arrythmia (RSA) were measured as indices of sympathetic and parasympathetic
      nervous system reactivity, respectively, and autonomic profiles were created to
      offer summative indices of PEP and RSA response. Results confirmed the protocol's
      validity and reliability, and showed differences in autonomic reactivity by age
      and study context, but not by gender. The studies' findings offer guidelines for
      future research on autonomic reactivity in middle childhood and support the
      feasibility of examining sympathetic and parasympathetic responses to challenge
      in 3- to 8-year-old children.

PMID- 12471638
TI  - The neonatal rat as a developmental animal model of attention deficit
      hyperactivity disorder: Effects of frontal lesions on activity and learning.
AB  - We examined a developmental animal model of Attention Deficit Hyperactivity
      Disorder (ADHD) by evaluating the effects of suppressed frontal cortical
      functioning on habituation in neonatal rats. Frontal cortical activity was
      suppressed with brain transections in neonatal rats 3, 6, 9, or 12 days of age.
      Pups were tested in a habituation-to-odor paradigm and behaviors (general
      activity, headwaving, probing, and rolling) were recorded. Frontal cortical
      suppression via brain transection resulted in significantly higher activity
      levels in 3-day-old rats, particularly with regard to rolling, suggesting that
      the frontal cortex is involved in the regulation of this age-dependent behavior.
      Frontal transections also increased probing during the odor habituation test in
      12-day-old pups. Results are consistent with the neuropsychological research
      regarding frontal cortical functioning and inhibition in children with ADHD, and
      suggest that neonatal rats with frontal lesions may provide a useful
      developmental animal model for studying ADHD.

PMID- 12471639
TI  - Sexual interactions of maturing male guinea pigs with their mothers, sisters, and
      unfamiliar adult females in the home cage.
AB  - During observations in the home cage in the light and dark on days 5, 15, 25, 35,
      and 45, male guinea pigs mounted and exhibited anogenital investigation of the
      mother, though appropriately directed mounting occurred infrequently and was not
      shown by all males. Mothers nipped and kicked advancing males. No mounting of a
      female sibling was observed. When behavioral interactions of approximately 35-day
      old males with the mother or an unfamiliar adult female were compared during 1-hr
      tests in the home cage, males exhibited much higher levels of mounting and
      anogenital investigation, and received many more nips and kicks, when with the
      unfamiliar female. The results 1) demonstrate that limited maternally directed
      sexual behavior occurs in the home cage, 2) support earlier findings indicating
      that continuous housing with the mother suppresses maternally directed sexual
      behavior in periadolescent guinea pig males, and 3) suggest that sexual behavior
      toward female siblings also is suppressed.

PMID- 12471640
TI  - Categorization of infant-directed speech: development from 4 to 6 months.
AB  - To extend a previous finding that 6-month-old infants categorized low-pass
      filtered infant-directed (ID) utterances, we examined a) 6-month-old infants'
      categorization of more naturalistic, unfiltered ID utterances and b) the
      developmental progression of ID-speech categorization. In Experiment 1, 6-month
      olds heard seven different unfiltered tokens from one class of ID utterance
      (approving or comforting), followed by a novel token from either the same or an
      unfamiliar category. Infants recovered, responding only to the unfamiliar
      category token, suggesting that they categorized naturalistic ID utterances. Four
      month-olds' categorization of filtered and unfiltered versions of the ID
      utterances was assessed in Experiments 2 and 4. Four-month-olds did not recover,
      responding to a test token from an unfamiliar class, suggesting that they did not
      categorize either filtered or unfiltered ID utterances. Experiment 3 demonstrated
      that 4-month-old infants' failure to categorize did not result from their
      inability to complete the procedure. These results suggest that infants'
      processing of ID speech changes from 4 to 6 months of age.

PMID- 12471641
TI  - [Deep venous thrombosis: epidemiology, acquired risk factors].
AB  - Deep vein thrombosis is a frequent disease with an annual incidence reaching 5
      per thousand among subjects over 75 years. Major acquired risk factors for venous
      thrombosis include surgery, neoplasm, reduced mobility or paresis, and a previous
      episode of deep vein thrombosis. Among women, hormonal status (pregnancy, oral
      contraceptive, hormone replacement therapy) is responsible for the majority of
      all venous thrombotic events. The impact of other factors is controversial:
      obesity, tobacco use and varicose veins. Venous thrombosis is a multifactorial
      disease and analysis of the interactions between acquired and inherited risk
      factors is an extremely interesting field of investigation.

PMID- 12471642
TI  - [Genetic risk factors of thrombosis].
AB  - Genetic risk factors became a frequent predisposing cause of venous
      thromboembolism (VTE) since the discovery of two mutations: factor V Leiden and
      G20210A mutation of prothrombin gene. One of these both mutations is associated
      with around 25% of VTE events. Interaction of genetic risk factors, such as
      interaction of FV Leiden or G20210A mutation of prothrombin with antithrombin,
      protein C or protein S deficiencies, as well as interaction with acquired risk
      factors, have demonstrated that venous thrombosis is a multifactorial disease.
      The search for thrombophilia must be done in VTE occurring before the age of 45,
      in case of recurrencies and in case of familial history of VTE.

PMID- 12471643
TI  - [Diagnosis of deep venous thrombosis of the lower limbs: performance of
      diagnostic tests].
AB  - Deep-vein thrombosis is a frequent affection that needs precise diagnosis.
      Indeed, the clinical complications (from post-thrombotic syndrome to fatal
      pulmonary embolism) as well the risk of anticoagulant treatment require a precise
      diagnosis. Since clinical evaluation cannot assure reliably diagnosis by lack of
      sensitivity and specificity, complementary exams are needed. However, clinical
      assessment is an important part to decide further examinations. D-dimers
      assessment allows to role out the diagnosis of deep-vein thrombosis in a number
      of cases. Plethysmography and continuous Doppler are progressively given up.
      Compressive venous ultrasonography is now the exam of first choice. Scintigraphy,
      scanner and RMI must still be validated. Phlebography remains the gold standard
      in case of negative compressive venous ultrasonography and a high clinical
      probability.

PMID- 12471644
TI  - [When to suspect pulmonary embolism in a patient with deep venous thrombosis?].
AB  - The approach to take in trying to establish or disprove a diagnosis of pulmonary
      embolism in the presence of deep vein thrombosis is the subject of some
      controversy nowadays. Systematic perfusion lung scan can be proposed, given the
      mediocre specificity of the clinical symptoms of embolism or the high frequency
      of asymptomatic pulmonary embolism. This strategy, however, is not validated in
      terms of cost-efficacy. In practical terms, favourable evolution and the low rate
      of recurrent embolism observed with a well executed anticoagulant treatment
      pleads against systematic scintigraphy. Because of its moderate sensitivity,
      systematic echocardiography probably should not be an element of the assessment
      of asymptomatic pulmonary embolism. The advent of spiral CT scan in the
      management of such patients could however make it necessary to reconsider this
      position, by allowing complete venous and pulmonary examination in thrombo
      embolic disease.

PMID- 12471646
TI  - [Outpatient treatment of acute deep venous thrombosis of the lower limbs].
AB  - The outpatient management of acute deep vein thrombosis could replace the
      inpatient care for most patients. Fixed-dose, weight-adjusted low-molecular
      weight heparins, as efficacious and safe as unfractionated heparin, allow home
      treatment for selected and eligible patients. The main exclusion criteria are
      severe renal insufficiency, high risk of bleeding, pulmonary embolism with
      unstable hemodynamics, allergy to heparin and suspected non-compliance. Programs
      for outpatient management need, after appropriate selection, adequate patient
      education, easy access to health-care professionals and daily follow-up during
      heparin treatment.

PMID- 12471645
TI  - [Antiphospholipid syndrome].
AB  - Since 1987 the antiphospholipid syndrome has been recognized as a major cause of
      acquired thrombophilia, whether it is associated with systemic lupus
      erythematosus or occurs as a free-standing syndrome (primary form). This
      autoimmune condition associates in young patients recurrent thrombosis (both
      venous and/or arterial) and/or a variety of obstetric complications with the
      persistent presence of antiphospholipid antibodies (aPL). These traditionally
      comprise anticardiolipin antibodies and lupus anticoagulants, respectively
      detected by immunological and clotting tests. Despite their name aPL do not bind
      to phospholipids per se, but are directed at phospholipid-binding plasma
      proteins, especially beta 2-glycoprotein I and prothrombin. Because the risk of
      recurrence is high, the standard of care is prolonged and high-intensity warfarin
      (INR near 3) after a venous thromboembolic event, together with the management of
      associated vascular risk factors. Prevention of adverse obstetric outcomes is
      frequently achieved by a combination of low-dose aspirin and heparin.

PMID- 12471647
TI  - [Duration of oral anticoagulant therapy in deep venous thrombosis of the lower
      limbs].
AB  - The optimal duration of oral anticoagulant therapy is a matter of debate. It is
      essential to balance the desired effect of the anticoagulants in reducing
      recurrences against the risk of major bleeding. Recent data suggest that it is
      necessary to tailor the duration of anticoagulation individually according to the
      topography of deep vein thrombosis (DVT) and the presence of risk factors. A six
      week treatment for patients with isolated calf DVT is sufficient. For proximal
      DVT and/or pulmonary embolism, a short anticoagulant course seems sufficient in
      patients with temporary risk factors (three months) and a longer anticoagulant
      course (six months at least) is recommended for cases with permanent risk factors
      or idiopathic DVT. The inherited or acquired hypercoagulable states can be
      divides into those that are common and associated with a modest risk of
      recurrence (i.e. isolated factor V Leiden or G20210A prothrombin gene) and those
      are uncommon but associated with a high risk of recurrence (i.e. antithrombin,
      protein C or S deficiencies and anticardiolipin antibodies). Thus, the presence
      of one of these last abnormalities favours more prolonged anticoagulant therapy.
      For the high-risk of recurrence patients, there is a paucity of evidence based
      medicine particularly for patients with biological thrombophilia, and randomised
      controlled trials in this population are required. An assessment of low- or fixed
      dose oral anticoagulation is also necessary in order to reduce the bleeding risk.

PMID- 12471648
TI  - [Oral anticoagulant treatment: practical aspects and significance of
      anticoagulant clinics].
AB  - Vitamin K antagonists (VKA) decrease the synthesis of the active forms of four
      coagulation factors (factors II, VII, IX, X) and three inhibitors (proteins C, S,
      Z). There are VKA having a short half life (Sintrom, Pindione) and VKA having a
      long half life (Apegmone, Previscan, Coumadine). The treatment is monitored by
      the INR which in the majority of the indications must range between two and
      three. The first INR is usually performed 36 to 72 h after starting the
      treatment. There are a number of drug interactions. The rate of major bleedings
      range from 1.1 to 4.9 for 100 patient-year according to the published studies.
      Since around 600,000 patients are treated by VKA in our country, the absolute
      number of serious bleeding is high (> or = 17,000 per year). Anticoagulant
      clinics are structures aimed to instruct the patient and to advise the general
      practitioner to monitor the treatment, using computer assisted methods. It has
      been reported that these structures reduce the incidence of bleeding and of
      thrombotic events by 3 to 4 times.

PMID- 12471649
TI  - [Role of plasminogen activators in the treatment of deep venous thrombosis].
AB  - In deep vein thrombosis, thrombolytic agents can improve vein patency more
      rapidly than conventional anticoagulant therapy. The clinical benefit of
      thrombolytic use would be a reduction in the incidence and severity of the
      postthrombotic syndrome and limb salvage in "phlegmatia caerulea". A literature
      review suggests that streptokinase and rt-PA do better than heparin regarding
      vein patency. A clinical benefit on postthrombotic syndrome can only be suggested
      by available evidence. The risk of major bleeding is increased by thrombolytic
      agents as compared with heparin. Mortality for cerebral bleeding is about 0.5%.
      Currently, thrombolytic therapy is only recommended for limb salvage in
      phlegmatia caerulea.

PMID- 12471650
TI  - [Treatment of deep venous thrombosis by low molecular weight heparins. Comments
      on the recommendations of the North American Consensus].
AB  - LMW heparins have recently come into use in North America for treatment of venous
      thrombosis. Their first line recommendation is a major innovation of the last
      north american consensus conference on antithrombotics published in Chest at the
      beginning of 2001. This recommendation is grade 1A regarding its advantageous
      benefit-risk ratio. An earlier oral vitamine K antagonist treatment and a more
      regular nomogram use allow to reduce the relay duration and to obtain more often
      the targeted INR. The more predictable anticoagulant response with weight-based
      doses induces a simplified anti-Xa activity survey limited to renal dysfunction
      and obese or less than 50 Kg body weight persons but a regular platelet count
      remains mandatory. Several questions need to be discussed: once or twice daily
      subcutaneous injection use and treatment duration which seem related to the
      persistence of triggering factors, the variety of thrombophilia and comorbidity
      conditions. Due to a greater evidence-based medicine, the antithrombotic strategy
      becomes more related to a closer evaluation of the individual thrombotic risk
      level.

PMID- 12471651
TI  - [In the "Annales", there is much that is new].

PMID- 12471652
TI  - [Should the French paradox be cast away?].

PMID- 12471653
TI  - [For rational use and interpretation of the determination of troponin].

PMID- 12471654
TI  - [ASSENT III and GUSTO V: is it the end of combination therapy with GPIIb/IIIa
      blockers and thrombolytics in myocardial infarction?].

PMID- 12471655
TI  - [Beneficial effects of direct call to Emergency Medical Services on time delays
      and management of patients with acute myocardial infarction. The RICO
      (obseRvatoire des Infarctus de Cote-d'Or) data].
AB  - The influence of direct calls to specialized Emergency Medical Services in case
      of suspected myocardial infarction has not been extensively studied. The RICO
      registry is an exhaustive registry implemented in all six institutions
      participating in primary care of patients with acute myocardial infarction in one
      French administrative department (Cote-d'Or). From January 2001 to October 2001,
      322 patients were admitted for acute myocardial infarction, among whom only 57
      (18%) had directly called emergency medical services after the onset of symptoms.
      The baseline characteristics of patients who had directly called the emergency
      services were not different from those of the patients who had not. However, the
      time from symptom onset to first medical intervention (48 versus 105 minutes, p =
      0.02) and from first medical intervention to hospital admission (60 versus 103
      minutes, p = 0.02) were markedly shorter in patients who had directly called the
      emergency medical services. This resulted in a significant increase in the use of
      reperfusion therapy (70% versus 38%, p = 0.003), including a higher proportion of
      primary angioplasty (33% versus 20%, p = 0.04). This study documents the
      beneficial effect of a direct call to the Emergency Medical Services by the
      patients themselves. Too few patients, however use this opportunity and actions
      should be taken for informing the lay public of the benefits of this medical
      service.

PMID- 12471657
TI  - [Efficacy of early reperfusion therapy at the acute stage of myocardial
      infarction in elderly patients: the USIK database].
AB  - The role of early reperfusion therapy at the acute stage of myocardial infarctus
      in elderly patients is debated. The aim of this study was to analyze the
      prognostic role of reperfusion with i.v. thrombolysis or primary PTCA in the
      nationwide USIK database, which prospectively included all pts admitted to a CCU
      for an AMI < 48 hours in France in November 1998. For the purpose of the present
      study, only patients admitted within 24 hours of AMI and with one-year follow-up
      available were included. Of the 1838 patients included, 785 were > 70 years-old,
      of whom 225 (29%) had early reperfusion therapy with thrombolysis (N = 173) or
      primary PTCA (N = 52). Patients treated with early reperfusion had a baseline
      profile that differed substantially from that of patients treated conventionally:
      women (31% vs 50%, p < 0.001), admission within six hours of symptom onset (84%
      vs 55%, p < 0.001), history of systemic hypertension (48% vs 60%, p < 0.002),
      stroke (5% vs 11%, p < 0.01), peripheral arterial disease (8% vs 18%, p < 0.001);
      congestive heart failure (5% vs 20%, p < 0.001) or previous MI (12% vs 25%, p <
      0.001), more anterior location of current MI (40% vs 28%, p < 0.002). Overall one
      year Kaplan-Meier survival was 78% for patients with versus 64% for those without
      reperfusion therapy (p < 0.01). In patients with Q wave myocardial infarction,
      Cox multivariate analysis showed that reperfusion therapy was an independent
      predictor of survival (RR 0.66; 95% Confidence Interval: 0.45-0.96), along with
      age, anterior location and history of congestive heart failure. Therefore, data
      from this large "real life" registry indicate that reperfusion therapy with
      either thrombolysis or primary PTCA is associated with improved one-year survival
      in patients over 70 years of age.

PMID- 12471656
TI  - [Baseline characteristics and management of patients less than 45 years of age
      hospitalized for acute coronary syndromes: results from the nationwide French
      PREVENIR 1 and PREVENIR 2 studies].
AB  - Of 2,626 patients admitted for acute coronary syndromes and participating in the
      PREVENIR 1 and 2 registries, 202 (8%) were aged less than 45 years. Younger
      patients were more often smokers (79% versus 37%), but systemic hypertension and
      diabetes were less frequent. Reperfusion therapy was more frequently used in the
      younger patients (63% versus 46%). At hospital discharge, aspirin and angiotensin
      converting enzyme inhibitors were prescribed as often in younger and older
      patients. In contrast, beta-blocking agents and statins were used more often in
      the younger patients. More younger patients participated in a cardiac
      rehabilitation programme. Left ventricular ejection fraction was less altered in
      the younger age group and none of the younger patients died between hospital
      discharge and six months follow-up.

PMID- 12471658
TI  - [Worsening of heart failure during hospital course in myocardial infarction is a
      factor of poor prognosis. Apropos of a prospective cohort study of 2,507 patients
      hospitalized with myocardial infarction: the PRIMA study].
AB  - BACKGROUND: Worsening of heart failure in patients with myocardial infarction is
      seldom studied, elderly patients often are not included, and multivariate
      analysis is uncommon. AIMS: The prospective PRIMA study (Prise en charge de
      l'Infarctus du Myocarde Aigu; management of acute myocardial infarction) sought
      to determine the incidence of heart failure worsening, its risk factors, and its
      prognostic importance in patients with myocardial infarction, regardless of age
      and hospital facilities, in the "real world" in a region in France, using
      multivariate analysis. METHODS: Data were prospectively collected in all patients
      with myocardial infarction admitted in all hospitals in three departments in the
      Rhone-Alpes region in France between September 1, 1993 and January 31, 1995.
      RESULTS: Among 2,507 patients, 33% were in Killip classes II-IV at admission.
      Four hundred and sixteen patients (17%) had worsening of Killip class during the
      first five days. In-hospital mortality (overall: 14%) increased dramatically with
      Killip class at admission (9% in class I; 62% in class IV) and with worsening of
      Killip class during the first five days (36% vs 8% if no worsening). In
      multivariate analysis, older age, diabetes mellitus and anterior Q-wave
      myocardial infarction were significant predictors of Killip class at admission
      and of its worsening. The significant predictors of in-hospital mortality were
      older age, Killip class III at admission and worsening of Killip class during the
      first five days. CONCLUSION: This large, unselected cohort revealed that among
      patients with myocardial infarction, heart failure and its worsening are
      frequent, especially in the elderly, and dramatically worsen the in-hospital
      mortality.

PMID- 12471659
TI  - [Beating heart in "aortic no-touch off-pump" techniques: a simple answer to
      complex surgical situations].
AB  - Three cases reports illustrate the concept of beating heart cardiac surgery and
      its advantages regarding the prevention of arterial emboli.

PMID- 12471660
TI  - [Cellular injury associated with extracorporeal circulation].
AB  - Circulation of blood extracorporeally through plastic tubing causes severe shear
      stresses to blood cells and activates several regulatory cascades. These various
      pathways include the cytokine cascades, complement and coagulation. Interleukine
      1, -6, -8, tumor necrosis factor-alpha have been implicated. Among various
      mediators of tissue injury released by activated neutrophils, elastase and
      metalloproteinases have been considered to be relevant in postoperative organ
      dysfunction in cardiac operations. Endothelial cells are extremely sensitive to
      insults that occur during cardiopulmonary bypass (CPB). These insults lead to
      disruption of barrier function and leukocyte adhesion. Immunoglobulins such as
      ICAM-1 and VCAM-1 are expressed on endothelium cells and act as ligands for
      integrins. It is also important to remember that during cardiac operations, the
      interest on the metabolism of in free radicals has focused on the heart and the
      lungs because they are exposed to ischemia and subsequent reperfusion. Increased
      production of free radicals during CPB is associated with myocardial and
      pulmonary dysfunctions. Now it is well recognized that the whole body
      inflammatory response induced by CPB is mainly responsible for postoperative
      organ dysfunctions.

PMID- 12471661
TI  - [Should echocardiography be systematic before primary PTCA in acute myocardial
      infarction?].

PMID- 12471662
TI  - [Echocardiography is essential at the acute stage of myocardial infarction].

PMID- 12471663
TI  - Fluctuating asymmetry--indicator of what?
AB  - In a population the optimal phenotype is promoted by buffering mechanisms that
      keep inter- and intra-individual variation low. A link exists between
      canalization, that controls phenotypic variation, and developmental stability,
      mostly measured as fluctuating asymmetry of bilateral traits (FA). Both types of
      variation are associated with the functional importance of a trait, and both are
      increased by stress of various kinds. But there are also several instances of non
      congruence. The concept of developmental stability has been found elusive, and
      low FA is not the unambiguous measure of well being and good genes that has been
      claimed. It can be concluded that developmental stability is partly governed by
      specific, as yet unknown, molecular processes.

PMID- 12471664
TI  - Genetic diversity and the phylogeography of parthenogenesis: comparing bisexual
      and thelytokous populations of Nemasoma varicorne (Diplopoda: Nemasomatidae) in
      Denmark.
AB  - The millipede, Nemasoma varicorne, represents a textbook example of geographic
      parthenogenesis with thelytokous populations being distributed north, east, south
      and west of the distribution of the bisexual ancestor in the deciduous forests of
      central Europe. We here describe variation in amplified fragment length
      polymorphisms (AFLP's) in sympatric bisexual and thelytokous populations of N.
      varicorne in Denmark and compare the relationships of Danish populations with
      animals from The Czech Republic, England and Poland. Thelytokes from Denmark,
      England and Poland form a monophyletic cluster that differs from bisexuals from
      Denmark and Czechia for about 30% of the fragments. A single clone is widely
      spread over Denmark (34 of 38 localities), with rare clones being detected at
      four other localities. The phylogenetic pattern implies strongly that thelytoky
      evolved prior to the post-glacial colonization of northern Europe. This further
      suggests that the two forms have interacted extensively during this colonization
      and that the thelytokes have been excluded from older forests by competition with
      the bisexual forms. Our results further suggest that the success of the
      thelytokous form, at least in Denmark, is not due to abundant clonal diversity as
      hypothesized by the frozen niche variation model.

PMID- 12471665
TI  - Differential effects of cultivated and wild barley 5H chromosomes on heading
      characters in wheat-barley chromosome addition lines.
AB  - Wheat (Triticum aestivum L.)-barley (Hordeum vulgare L.) chromosome addition
      lines are possible vehicles for transferring barley genes into wheat. The barley
      5H chromosome has genetic effects on the heading characters in wheat-barley
      addition lines: accelerating narrow-sense earliness, decreasing vernalization
      requirement and/or increasing photoperiodic sensitivity. To elucidate the effects
      of different 5H chromosomes under an identical wheat genetic background, two
      wheat-barley addition lines, i.e. cultivated barley 'New Golden' 5H chromosome
      added to 'Shinchunaga' wheat (Shi-NG5H) and wild barley H. vulgare ssp.
      spontaneum 5H chromosome added to 'Shinchunaga' wheat (Shi-Spn5H), were examined
      for their heading characters. The addition line Shi-NG5H showed a significantly
      lower vernalization requirement in comparison with 'Shinchunaga' wheat, whereas
      Shi-Spn5H did not. Furthermore, both NG5H and Spn5H chromosomes shortened narrow
      sense earliness and increased photoperiodic sensitivity in wheat, but the effects
      of Spn5H were weaker than those of NG5H. The fact that NG5H and Spn5H showed
      differential effects on heading characters in wheat demonstrated that the heading
      characters were altered by the function of the barley genes located on 5H
      chromosomes, not merely by the aneuploid effect alone.

PMID- 12471666
TI  - Genetic analysis of durable powdery mildew resistance in a common wheat line.
AB  - Genetic studies using monosomic and hybridological analyses had confirmed that
      resistance of a common wheat line k-15560 to powdery mildew in seedling stage was
      conditioned by one dominant gene located on chromosome 7B, and resistance in
      adult stage was controlled by two dominant genes. Cytological analysis of meiosis
      in the F1 monosomic hybrids has revealed reciprocal translocation involving
      chromosomes 2A/7A. In the F1 monosomic hybrids genes, causing a decrease in
      pairing were found on chromosomes 3B and 4D, and genes enhancing pairing--on
      chromosomes 2A and 3A.

PMID- 12471667
TI  - Inbreeding depression in a rare plant, Scabiosa canescens (Dipsacaceae).
AB  - Plants from a population of Scabiosa canescens, a locally rare species with a
      narrow ecological amplitude, were raised under uniform growth conditions to
      examine the phenotypic effects of one generation selfing and outcrossing.
      Particular attention was given to direct components of fitness (seedling biomass,
      rosette leaf number, head number, flower number per head), but two morphological
      characters (plant height, flower size) were also considered. Estimates of
      inbreeding depression (delta), adjusted for maternal effects and lack of balance,
      were compared and tested for significance using randomization and boostrap
      procedures. Inbreeding significantly depressed several characters during both
      early and late stages of the life cycle, with delta ranging from 0.14 (flower
      size) to 0.37 (seedling biomass). Based on these and other results, we propose
      that S. canescens is susceptible to inbreeding and that the genetic basis of
      inbreeding depression varies across life stages.

PMID- 12471668
TI  - Chromosomal location of genes for resistance to powdery mildew in Chinese wheat
      lines Jieyan 94-1-1 and Siyan 94-1-2.
AB  - Two Chinese wheat lines Jieyan 94-1-1 and Siyan 94-1-2 are resistant to all 120
      isolates of Blumeria graminis f. sp. tritici maintained in Weihenstephan,
      Germany. Monosomic analyses employing the susceptible set of 21 Chinese Spring
      monosomic lines revealed that the line Jieyan 94-1-1 carries one dominant gene on
      translocated wheat/rye chromosome 1B/1R and one recessive gene on chromosome 7B,
      whereas line Siyan 94-1-2 possesses one recessive gene on chromosome 7B and one
      dominant gene on chromosome 5D. Allelism tests in combination with the use of
      specific isolates comfirmed that the dominant genes in Jieyan 94-1-1 and Siyan 94
      1-2 are Pm8 and Pm2, respectively. The recessive genes present in each of the two
      lines are shown to be new alleles located on chromosome 7B at the pm 5 locus. The
      two genes are tentatively designated mljy in Jieyan 94-1-1 and mlsy in Siyan 94-1
      2, respectively.

PMID- 12471669
TI  - Genetic basis of trichome production in Arabidopsis lyrata.
AB  - Leaf trichomes may protect plants against herbivorous insects, and may increase
      tolerance to drought and UV-radiation. The perennial herb Arabidopsis lyrata
      (Brassicaceae) is polymorphic for trichome production and occurs in a glabrous
      and trichome-producing form. In addition, there is quantitative variation in
      trichome density among trichome-producing plants. To examine the genetic basis of
      glabrousness, we conducted controlled crosses with plants originating from two
      natural populations in Sweden (one polymorphic for trichome-production, and one
      consisting of glabrous plants only). In addition, we estimated the heritability
      of trichome number from parent-offspring regressions for plants originating from
      the polymorphic population. Crosses between glabrous plants resulted in glabrous
      offspring only, whereas crosses between glabrous and trichome-producing plants,
      and crosses between trichome-producing individuals, resulted in either all
      trichome-producing offspring or both phenotypes. In segregating crosses between
      trichome-producing plants, the ratio of glabrous:trichome-producing offspring did
      not deviate significantly from 1:3, while in segregating crosses between glabrous
      and trichome-producing individuals the ratio did in most cases not deviate from
      1:1. Within- and between-population crosses gave similar results. The
      heritability of trichome number estimated from regression of offspring on mid
      parent was high (h2 +/- SE, 0.65 +/- 0.15). The results suggest that glabrousness
      is inherited in a simple Mendelian fashion, with the allele coding for trichome
      production being dominant over that for glabrousness. They further indicate that
      glabrousness is due to a mutation at the same locus in both populations.

PMID- 12471670
TI  - NORs inheritance analysis in crossings including individuals from two stocks of
      rainbow trout (Oncorhynchus mykiss).
AB  - Silver nitrate staining of rainbow trouts (Oncorhynchus mykiss) chromosomes, for
      the identification of the nucleolar organizing regions (NORs), revealed that in
      individuals from Nucleo Experimental de Salmonicultura de Campos do Jordao
      (Brazil) NORs were located in the long arms of submetacentric pair while in
      specimens from Mount Shasta (USA) NORs were located in the short arms of a
      submetacentric pair. Cytogenetic analysis of the offspring, obtained through
      artificial crosses including individuals from both stocks, allowed the
      identification of NORs in two submetacentric chromosomes, one in the short arms
      and the other in the long arms, confirming the effectiveness of the hybridization
      process. Complementary results obtained using the FISH technique with 18S and 5S
      rDNA probes showed that NOR-bearing chromosomes exhibited a cluster of 5S genes
      located in tandem with the 18S gene cluster in both stocks. The results allow us
      to suggest that the difference in NOR-bearing chromosomes found between the two
      stocks is likely to be due to pericentric inversion involving the chromosome
      segment where 18S and 5S rDNA genes are located. The presence of ribosomal genes
      in the long arms of a submetacentric chromosome is apparently a particular
      characteristic of the rainbow trout stock of Campos do Jordao and might be used
      as a chromosome marker in studies of controlled crosses in this species.

PMID- 12471671
TI  - Comparative studies of genetic diversity in kenaf (Hibiscus cannabinus L.)
      varieties based on analysis of agronomic and RAPD data.
AB  - Kenaf (Hibiscus cannabinus L.) is a fiber crop classified in the genus Hibiscus
      (Malvaceae), and has a great potential for its multipurpose utilization, in
      addition to its traditional usage. Varietal identification of kenaf is always
      problematic and knowledge on genetic diversity of kenaf varieties is also
      limited, which significantly hindered our effective utilization and conservation
      of the valuable kenaf germplasm. In order to find a proper method for identifying
      kenaf varieties and studying their variation, morpho-agronomic characters and
      random amplified polymorphic DNA (RAPD) markers were analyzed among 14 kenaf
      varieties commonly used in Japan. Data from morphological analysis showed that
      the included kenaf varieties could be divided into three major groups. The
      characters, such as middle stem diameter, whole stalk weight, and days to 50%
      flowering, are highly responsible for the variation of the kenaf varieties, but
      it is difficult to identify individual varieties merely by the morpho-agronomic
      characters. On the other hand, clearly separation of the kenaf varieties was
      achieved based on the RAPD variation patterns. Genetic relationship of the kenaf
      varieties can also be traced through the analysis of RAPD and morph-agronomic
      variation. It is concluded from the present study that RAPD analysis is an
      effective tool in identifying of kenaf varieties and determining their genetic
      relationships, particularly when combined with the analysis of morpho-agronomic
      characters.

PMID- 12471672
TI  - Genetic divergence within the Drosophila mayaguana subcluster, a closely related
      triad of Caribbean species in the repleta species group.
AB  - The mayaguana triad of the Drosophila repleta species group includes D.
      mayaguana, D. straubae, and D. parisiena, the latter two of which are very
      similar when examined morphologically. Many morphological characters used to
      define these taxa are quantitative and overlap substantially among some forms--it
      is only through suites of such characters that species can be identified. We
      apply Population Aggregation Analysis and tree building methods to five rapidly
      evolving gene regions--the mitochondrial AT rich region and the nuclear
      acetylcholinesterase, hunchback, mastermind, and vestigial loci to test the
      morphological species delineations within the morphocryptic mayaguana triad. We
      find that D. mayaguana is diagnosable using DNA sequences, but the other two
      species form a non-diagnosable paraphyletic assemblage. A single ecological
      factor, oviposition substrate, is an important diagnostic character
      distinguishing D. straubae from D. parisiena, highlighting the importance of
      examining a diverse array of data (morphological, molecular, ecological, and
      behavioral) when defining species limits.

PMID- 12471673
TI  - Isolation of novel microsatellite loci in the Rocky Mountain apollo butterfly,
      Parnassius smintheus.

PMID- 12471674
TI  - ISSR (inter simple sequence repeats) as genetic markers in noctuids
      (Lepidoptera).

PMID- 12471675
TI  - Hybridization and apparent hybridization between meadow pipit (Anthus pratensis)
      and water pipit (A. spinoletta).

PMID- 12471676
TI  - Fructose utilization of human spermatozoa after cooling and freezing.

PMID- 12471678
TI  - Ovulation in the post partum period.

PMID- 12471677
TI  - Attachment of rat and mouse blastocysts onto uterine epithelium.

PMID- 12471679
TI  - Prostaglandins in human seminal plasma and their effects on human myometrium.

PMID- 12471680
TI  - Effect of seminal plasma on epididymal spermatozoa in the bull.

PMID- 12471681
TI  - Capacitation of spermatozoa.

PMID- 12471682
TI  - Differentiation of sex as determined by ovulation timing.

PMID- 12471684
TI  - [Stress and systemic hypertension: why should we inform the patients?].

PMID- 12471683
TI  - Histologic changes in the uterine cervix of the guinea pig induced by homologous
      immunization.

PMID- 12471685
TI  - [Assessment of acute blood pressure variability during a stress test].

PMID- 12471686
TI  - [Cardiovascular impact of psychological stress].
AB  - The cardiovascular impact of stress depends on, first individual perception of
      stress and second individual cardiovascular reactivity to a stressful
      stimulation. Psychological stressors are filtered by cognitive appraisal
      mechanisms before causing biological response so that, for the same strain,
      individual effects may differ. Therefore, due to complexity of stress personal
      management, a multilevel stress measurement strategy is needed. To measure stress
      cardiovascular impact, stress should be precisely quantified. Recently,
      questionnaires have been developed to score not only the strain but also the
      personal perception of the strain. Individual stress reactivity can be evaluated
      by hormone response (epinephrine, norepinephrine, steroids) or by cardiovascular
      reactivity to a stress test. Until now, all the studies found that stress was
      independently related to blood pressure especially in active people. Prospective
      studies are still ongoing to definitively prove that stress could explain
      hypertension in a subset of hypertensives.

PMID- 12471687
TI  - [Medical stress and blood pressure].
AB  - BP measurement by a physician may trigger a blood pressure and heart rate
      increase often referred to as the white coat effect. This pressure response may
      occur both in normotensive and hypertensive subjects. The identification of such
      individuals is usually not possible on a clinical basis. This identification is
      however important because white coat effect and permanent hypertension do not
      share the same prognosis, the white coat effect being associated with a low rate
      of cardiovascular complications. To avoid an important overestimation of the real
      blood pressure level due to this white coat effect, it is possible to increase
      the delay before blood pressure measurements (beyond 15 minutes) or to take into
      account measurements made by nurses. Reading may also have a favorable
      consequence. However, a blood pressure recording outside the office, that is an
      ambulatory or a home blood pressure measurement, is the only way to confirm the
      presence of a white coat effect. The decision to treat is based on this
      measurement.

PMID- 12471688
TI  - [Assessment of the effects of antihypertensive drugs on stress-induced
      cardiovascular changes].
AB  - The authors reviewed some of the most relevant studies dedicated to the
      assessment of the effects of the antihypertensive drugs on the stress-induced
      cardiovascular changes. The rises in both blood pressure and heart rate turned
      out not to be significantly altered by calcium channel blockers, ACE inhibitors,
      moxonidine, nor beta-blockers, whereas they seemed to be slightly blunted by
      alpha-blocking drugs. However, since baseline blood pressure was significantly
      lower in treated hypertensives than in placebo-given patients, all
      antihypertensive drugs eventually resulted in a lower blood pressure level during
      stress, as compared with untreated patients. Regarding white coat effect, which
      has to be considered as a very particular stress, it appeared to be lowered to
      the same extent by placebo and antihypertensive drugs; moreover, its changes were
      not associated with any clinical beneficial effect.

PMID- 12471689
TI  - [A walk through the epistemology of stress].

PMID- 12471690
TI  - [Stress psychology and the role of stress management].

PMID- 12471691
TI  - [Stress in our society].

PMID- 12471692
TI  - [Nitric oxide synthases and peripheral cardiovascular system].
AB  - The synthesis of nitric oxide (NO) is catalysed by nitric oxide synthases which
      exist in at least three distinct isoforms. These enzymes catalyse the oxidation
      of the amino acid L-arginine to give rise to L-citrulline and NO. The different
      cell types comprising cardiac muscle express one or more of the three isoforms
      (neuronal, inductible, endothelial) of NO synthases. Recently, a mitochondrial
      nitric oxide synthase has been isolated. A complexity of NO synthase exists with
      distinct domains and multitude of cofactors. NO synthases are able to produce not
      only NO but also superoxide O2-. (uncoupled reaction). These two products can
      react together extremely rapidly to form the potent oxidant peroxynitrite. The
      formation of peroxynitrite has been implicated in the pathology of a large number
      of conditions involving oxidative stress such as atherosclerosis and heart
      failure.

PMID- 12471693
TI  - Anatomy of sweat glands.

PMID- 12471694
TI  - Pathophysiology of sweating.

PMID- 12471695
TI  - 'Good' and 'bad' body odours.

PMID- 12471697
TI  - Generalized hyperhidrosis and its systemic treatment.

PMID- 12471696
TI  - Topical pharmacological treatment.

PMID- 12471698
TI  - Tap water iontophoresis.

PMID- 12471699
TI  - Axillary sweat gland excision.

PMID- 12471700
TI  - Thoracic sympathectomy.

PMID- 12471701
TI  - The history of botulism.

PMID- 12471702
TI  - Botulinum toxin: from poison to pharmaceutical. The history of a poison that
      became useful to mankind.

PMID- 12471703
TI  - Botulinum toxin in warfare.

PMID- 12471704
TI  - Physiology and pharmacology of therapeutic botulinum neurotoxins.

PMID- 12471705
TI  - Botulinum neurotoxins are metalloproteases specific for SNARE proteins involved
      in neuroexocytosis.

PMID- 12471706
TI  - Storage and dilution of botulinum toxin.

PMID- 12471707
TI  - Dose-dependent anhidrotic effect of botulinum toxin.

PMID- 12471708
TI  - Complications and side-effects of botulinum toxin A.

PMID- 12471709
TI  - Hyperhidrosis of the axilla.

PMID- 12471710
TI  - Hyperhidrosis of the palms and soles.

PMID- 12471711
TI  - Frey's syndrome. Treatment with botulinum toxin.

PMID- 12471712
TI  - Rare forms of hyperhidrosis.

PMID- 12471713
TI  - Treatment of wrinkles with Botox.

PMID- 12471714
TI  - Botulinum toxin and anal fissure.

PMID- 12471715
TI  - Botulinum toxin and the eye.

PMID- 12471716
TI  - Botulinum toxin A and the face.

PMID- 12471717
TI  - [Current therapeutic strategy of hepatocellular carcinoma with extensive portal
      thrombus].
AB  - Prognosis of the patients with hepatocellular carcinoma with tumor thrombi in the
      portal vein is known to be extremely poor. The current results of various
      therapies, such as surgery, chemotherapy, immuno-therapy, radiation and
      combination therapy were reviewed, herein. Our recent therapeutic strategy for
      hepatocellular carcinoma with tumor thrombi in portal vein is also shown.

PMID- 12471718
TI  - [Gene therapy of eye diseases].

PMID- 12471719
TI  - [Antihypertensive effect and safety evaluation of vegetable drink with peptides
      derived from sardine protein hydrolysates on mild hypertensive, high-normal and
      normal blood pressure subjects].
AB  - A randomized double-blind placebo-controlled study was conducted on 63 subjects
      to determine the antihypertensive effect of a vegetable drink in which sardine
      protein hydrolysates containing a dipeptide, Valyl-Tyrosine (VY), were
      incorporated. The subjects, consisting of people with mild hypertension, high
      normal blood pressure and normal blood pressure, were randomly divided into test
      (male/female = 25/6, average age 50.1 +/- 10.4 years old) and control groups
      (26/6, 49.0 +/- 5.0). Each subject in the test group was given 195 g of the
      vegetable drink containing 0.5 g of sardine peptides (sardine protein
      hydrolysates) with 0.4 mg of VY (test drink) once a day for 13 weeks in a row,
      and subjects in the control group were given the same amount of the vegetable
      drink without sardine peptides (control drink) in the same manner. In the test
      group, 40 subjects with mild hypertension or high-normal blood pressure (130 mmHg
      < or = systolic blood pressure (SBP) < 160 mmHg and/or 80 mmHg < or = diastolic
      blood pressure (DBP) < 100 mmHg) showed a significant decrease in SBP, from 142.0
      +/- 10.3 mmHg at the start of the test to 134.4 +/- 11.1 mmHg during the first
      week of the test period, after which similar values were seen throughout the test
      period (13 weeks). Compared to the control group, the difference in SBP from
      baseline was statistically significant in the test group throughout the intake
      period. DBP also decreased significantly from 88.0 +/- 7.9 mmHg at baseline to
      83.5 +/- 8.6 mmHg after 13 weeks. In the control group, SBP and DBP were 140.8 +/
      8.4 mmHg and 90.5 +/- 6.6 mmHg respectively at the start of the test, and
      neither decreased during the test period. In subjects with normal blood pressure,
      neither those in the test group nor those in the control group showed a
      significant change in SBP and DBP during the test period. An excessive ingestion
      test was performed on 25 subjects with hypertension, mild hypertension, high
      normal blood pressure, and normal blood pressure by giving 585 g (3 times the
      recommended amount of intake) of the test drink for 14 days in a row. As a
      result, a significant decrease of blood pressure was observed in the
      hypertension, mild hypertension and high-normal blood pressure groups, but no
      excessive decline in blood pressure or any side-effects were associated with any
      subjects during the test period. In the groups with normal blood pressure, the
      excessive ingestion of the test drink did not affect blood pressure. In these two
      studies, physical check-ups and biochemical analyses of blood and urine were also
      conducted in all subjects, and no abnormalities were observed. These results
      suggest that the test drink containing sardine protein hydrolysates exhibited the
      antihypertensive effect in only the subjects with mild hypertension or high
      normal blood pressure. No adverse effects were observed in either hypertensive or
      normotensive subjects.

PMID- 12471720
TI  - [Minute pulmonary arteriovenous fistula successfully identified and resected
      under an ultrasonic guidance].
AB  - A 49-year-old male was admitted because of an abnormal nodule on chest CT taken
      during examination for chest oppression and a solitary nodular arteriovenous
      fistula was identified in the right S6 by high resolution CT. Surgical resection
      was indicated because of single lesion and of history of embolism such as acute
      myocardial infarction and himilateral myopia. Under an ultrasonic guidance, the
      lesion was successfully identified and resected with a minimal margin using a
      harmonic scalpel. The patient recovered uneventfully and was discharged on the
      7th postoperative day.

PMID- 12471721
TI  - Endoluminal ultraflex stent for palliative treatment of malignant rectosigmoidal
      obstruction.
AB  - Rectosigmoidal obstruction due to a malignant tumor usually requires emergency
      surgical treatment, and colostomy is usually inevitable. This report describes
      our experience with the use of endoluminal self-expanding metallic stents in the
      treatment for rectosigmoidal obstruction in patients with unresectable recurrent
      colorectal cancer or intra-abdominal dissemination. A total of 5 cases were
      included (4 male and 1 female) with a mean age of 70.8 (range, 63-80) years. A
      self-expanding noncovered Ultraflex, 10 cm in length and 22 mm in diameter, was
      emplaced at the site of the obstruction under both endoscopic and fluoroscopic
      guidance. Each patient had a recurrent malignancy (colorectal cancer, 3; ovarian
      cancer, 1; gastric cancer, 1). No subsequent surgery was planned due to ascites
      or extensive intra-abdominal dissemination. There was no mortality related to the
      procedure. Immediate decompression with symptomatic relief was achieved. One
      stent later became obstructed due to tumor ingrowth, and in two cases there was
      intermittent bleeding from the tumor and these were treated by argon plasma
      coagulation (APC) endoscopically. The use of self-expanding Ultraflex stent
      provides good palliation for unresectable advanced tumors that cause left colonic
      obstruction.

PMID- 12471722
TI  - Immune responses (CD4 and CD8) to acute vibration stress.
AB  - The aim of the experiments was to observe whether or not there is an immune
      system reaction to vibration stress. Three vibration frequencies were randomly
      given to 6 male volunteers. The 63 Hz vibration frequency produced a significant
      decrease in the ratio of CD4 T-cell to CD8 T-cell. This finding suggests that
      acute vibration stress suppresses the immune system activity in humans body.

PMID- 12471723
TI  - Intraocular lenses in patients with uveitis.
AB  - To evaluate the cataract surgery with intraocular lens (IOL) implantation in
      patients with uveitis, we retrospectively compared the outcome and complications
      between 63 eyes with uveitis-associated cataract and 42 eyes with age-related
      cataract, and between 27 uveitis eyes implanted with acrylic IOL and 36 uveitis
      eyes implanted with heparin-surface-modified IOL. There was a significant
      difference in the incidence of postoperative complications between patients with
      uveitis and age-related cataract. Major postoperative complications in uveitis
      group were posterior capsule opacification (13%) and cystoid macular edema (13%).
      Flare intensity measured with the laser flare-cell meter in patients with uveitis
      was higher than that with age-related cataract. There was no significant
      difference in the incidence of the postoperative complications and flare
      intensity between eyes with acrylic IOL and with heparin-surface-modified IOL in
      uveitis group, but there was a significant difference in the intensity of
      astigmatism in short-term after the surgery between the two groups. Careful
      attention to preoperative activity of uveitis and postoperative complications
      should be paid in cataract surgery with IOL implantation in patients with
      uveitis. Acrylic IOL is as useful as heparin-surface-modified IOL.

PMID- 12471724
TI  - Heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) and bikunin are up
      regulated during calcium oxalate nephrolithiasis in rat kidney.
AB  - We reported that expression of both HSPG and of bikunin are increased in calcium
      oxalate (CaOx) nephrolithic rat kidneys (lida et al., J. Am. Soc. Nephrol. 1999,
      Urol. Res. 1997). However, these findings were obtained from separate
      experiments. The present study evaluates whether levels of HSPG and bikunin
      expression differ in the rat kidney during calcium oxalate nephrolithiasis.
      Twenty-four male Wistar rats weighing 200-250 g were assigned to one of four
      groups (n = 6 each group) and administered with 0.5% ethylene glycol daily and
      0.5 microgram of 1 alpha-OH-D3 every other day to induce CaOx nephrolithiasis.
      Animals were sacrificed 1 or 2 weeks later and both kidneys were excised. The
      cortex was separated from the medulla and papillary tips in the right kidney,
      then stored in liquid nitrogen for quantitative competitive-reverse transcription
      polymerase chain reaction (QC-RT-PCR). The left kidney was fixed in 10% buffered
      formalin for histochemical studies. We assessed the variable gene expression of
      both HSPG and bikunin by QC-RT-PCR. Immunohistochemical analyses of left kidney
      tissue samples determined the localization of HSPG and bikunin. Normal rats
      serving as controls (n = 6 each) were also sacrificed and processed in the same
      manner as the experimental groups. QC-RT-PCR confirmed that HSPG and bikunin mRNA
      expression is significantly increased in nephrolithic kidneys (p < 0.05; Mann
      Whitney test), and that medulla and papillary tips tended to express more mRNA of
      both. Immunohistochemical studies revealed that the production of HS and bikunin
      was increased in both the distal and proximal tubules of nephrolithic kidneys.
      These findings suggest that the increased expression of both HSPG and bikunin
      play an important role during calcium oxalate stone formation. In addition, this
      phenomenon might be associated with the progression of urothelial damage.

PMID- 12471725
TI  - Validity of the responses to self-administered questionnaires as compared with
      the responses to interviews using a structured questionnaire.
AB  - A comparison of responses obtained in interviews using a structured questionnaire
      and those obtained using a self-administered questionnaire about parental history
      of liver diseases and personal smoking and drinking habits was made to evaluate
      whether the self-administered questionnaire is an effective means for collecting
      information on these variables in place of an interview. The subjects used in the
      present analyses were 46 male hepatocellular carcinoma (HCC) cases and 46
      hospital controls who were interviewed between January, 1996 and January, 1997
      for HCC cases and between January, 1996 and April, 1997 for hospital controls.
      Ages at start or stop of smoking and drinking were grouped into four categories
      as categorical variables. The cumulative number of cigarettes and cumulative
      alcohol consumption were also grouped into four categories. Generally speaking,
      the degree of agreement was substantially high for both categorical and
      continuous variables, particularly for parental history of liver diseases, and
      smoking (ICC = 0.929 and 0.912 for cases and controls, respectively) and drinking
      (ICC = 0.899 and 0.882, respectively) habits that are originally nominal
      categorical variables. On the other hand, the cumulative number of cigarettes
      (ICC = 0.928 and 0.716, respectively) and the cumulative alcohol consumption (ICC
      = 0.761 and 0.825, respectively) seemed to have a lower degree of agreement than
      other variables. For these variables, there was a tendency for the self
      administered questionnaire to produce larger values compared with the interview.
      Therefore, the self-administered questionnaire seemed to be an effective means
      for collecting information on categorical variables, while the interview using a
      structured questionnaire seemed to be preferable to the self-administered
      questionnaire with regard to the lifetime exposure to cigarettes and alcohol.

PMID- 12471726
TI  - Fas-mediated lysis of target cell by IL-2 treated cytotoxic T lymphocytes.
AB  - Interleukin-2 (IL-2) plays an important role as an immunoregulatory mediator. It
      is also known to enhance the killing activity of killer cells such as natural
      killer (NK) cells or lymphokine-activated killer (LAK) cells. When cytotoxic T
      lymphocytes (CTL) lyse antigen (Ag)-treated target cells, the presence of IL-2
      enhances the killing activity of CTL. In the present study, we examined the
      mechanisms by which IL-2 treated CTL lyse normal target cells at the cellular and
      mRNA levels. Our results suggest that IL-2 treated CTL can lyse target cells
      predominantly via Fas-mediated mechanism and to a lesser extent via a granule
      exocytosis-based mechanism. Interestingly, the level of FasL mRNA in CTL clone
      remained unchanged following IL-2 treatment, whereas the level of expression of
      Fas ligand (FasL) on CTL surface was slightly enhanced. On the other hand,
      treatment with metalloproteinase inhibitor augmented the level of FasL expression
      on the cell surface of CTL as well as the activity of target cell killing. Our
      results indicate that IL-2 plays a crucial role in the regulatory mechanisms of
      target cell killing by CTL without TCR-stimulation.

PMID- 12471727
TI  - Factors contributing to tooth retention among elderly women.
AB  - The purpose of this study is to identify factors contributing to tooth retention.
      A questionnaire was prepared which includes 22 main items concerning oral health
      care. The questionnaire was answered by 144 females in their 80's at 4 Health and
      Welfare Centers for the Aged in the City of Naha in July 1995 through interview
      format. Data were analyzed using multiple logistic regression, in which the
      dependent variable was tooth retention. The results were as follows: 1) The mean
      number of teeth of those in their 80's was 3.8 +/- 7.2; 2) A high percentage, 122
      (84.7%), were observed to be in moderate or excellent health; 3) Less than half,
      63 (43.7%), were observed to have a strong family history of oral health; 4)
      Character (p < 0.01), those having a periodical oral health checkup from their
      50's (p < 0.01) and total oral health care in their 50's (p < 0.05) were
      statistically significant. The results also suggest that the multiple logistic
      regression model consisted of character (odds ratio (OR) = 11.62); having a
      periodical oral health checkup from their 50's (OR = 9.39); and total oral health
      care in their 50's (OR = 4.23) among elderly females in their 80's in Okinawa
      Prefecture.

PMID- 12471728
TI  - Long-term functional evaluation of congenital hydrocephalus in infants and
      children.
AB  - In the past 20 years, 43 patients with congenital hydrocephalus underwent
      surgical treatment for hydrocephalus in our clinic (Myelomeningocele, Dandy
      Walker syndrome, holoprosencephaly and hydranencephaly, which are frequently
      associated with dysgenesis of the corpus callosum, were excluded). The
      gestational stage at the onset of hydrocephalus was assessed on the basis of the
      morphology of the corpus callosum. The patients were then divided into four
      groups according to stage of onset. A relation between the stage of onset and the
      long-term functional scores was demonstrated. The earlier the gestational stage
      at which the hydrocephalus occurred, the lower was the long-term functional
      score.

PMID- 12471729
TI  - Transanal dilation using circular stapling for benign rectal stenosis: report of
      a case.
AB  - When a simple procedure such as bougie, balloon dilation and transanal incision
      are not effective for severe stenosis after colorectal anastomotic leakage, a
      surgical operation is required. We report a case of transanal dilation using
      circular stapling for severe stricture in the colorectal anastomosis following
      low anterior resection.

PMID- 12471730
TI  - Early gastric carcinoma associated with amyloidosis: a case report.
AB  - We have experienced a case of early gastric carcinoma associated with
      amyloidosis. The patient was a 63-year-old woman diagnosed as having early
      gastric cancer type 0 Ila at the anterior wall on the greater curvature of the
      antrum, and multiple polypoid lesions on the antrum to the body of the stomach.
      We performed total gastrectomy, and rho-Roux-en-Y reconstruction. The tumor
      lesion was recognized at the anterior wall of the prepylorus, and the multiple
      polypoid lesions which were composed of amyloid masses were recognized on the
      whole stomach. The histological findings of the biopsy specimens from the rectum
      and the skin showed no amyloid-deposit. The urine examination was negative for a
      Bence-Jones protein reaction. This was a rare case of early gastric carcinoma
      associated with stomach amyloidosis, apparently confined to the stomach.

PMID- 12471731
TI  - A long-term survival case of gastric cancer treated by continuous low-dosage 5
      fluorouracil and cisplatin: a case report.
AB  - We have experienced a case of long-term survival after treatment with low dosage
      5-fluorouracil (5-FU) and cisplatin (FP regimen). The patient was a 60-year-old
      man diagnosed as having advanced gastric cancer type 3 with numerous large lymph
      node metastases. After treatment with 2 courses of FP regimen, the primary tumor
      and para-aortic lymph nodes were decreased in size by 41% and 92%, respectively,
      and the serum level of alpha-fetoprotein was decreased to normal. We then
      recommended surgery, but the patient did not consent. Therefore, he was treated
      with a third course of FP regimen. He died at 3 years later. These results
      suggested that the FP regimen was an effective treatment for advanced gastric
      cancer which was difficult for curative resection because of the numerous large
      lymph node metastases.

PMID- 12471732
TI  - Two cases of acute cholecystitis in which percutaneous transhepatic gallbladder
      aspiration (PTGBA) was useful.
AB  - We report 2 patients with acute cholecystitis for which percutaneous transhepatic
      gallbladder aspiration (PTGBA) was useful. In Case 1, the patient was a 75-year
      old woman who experienced a sudden onset of back pain and upper abdominal pain at
      night. Abdominal ultrasound (US) showed enlargement of the gallbladder with
      thickening of the wall, a sonolucent layer, and a stone in the neck of the
      gallbladder, which led to a diagnosis of acute cholecystitis. Magnetic resonance
      imaging (MRI) demonstrated thickening of the gallbladder wall and 2 areas of low
      intensity signal. The pain and fever persisted, for which we performed PTGBA,
      aspirating about 113 ml of infected bile. Subsequently, the pain and fever
      subsided, and abdominal US revealed a reduction in the enlargement of the
      gallbladder with the persistence of thickening of the wall. On the eighth day
      after PTGBA, open abdominal cholecystectomy was performed. In Case 2, the patient
      was a 56-year-old woman who had right hypochondriac pain after supper. The pain
      gradually increased in severity. Abdominal US showed enlargement of the
      gallbladder with a thickened wall, a sonolucent layer, and a gallstone in the
      neck of the gallbladder, which led to a diagnosis of acute cholecystitis.
      Magnetic resonance cholangiopancreatography (MRCP) showed enlargement of the
      gallbladder with no abnormalities in the common bile duct. After admission to
      hospital, the pain and fever persisted, for which we performed PTGBA, aspirating
      about 50 ml of infected bile. Subsequently, the pain and fever vanished.
      Abdominal US revealed a reduction in the enlargement of the gallbladder with the
      persistence of thickening of the wall. On the seventh day after PTGBA,
      laparoscopic cholecystectomy was performed. PTGBA seems useful for early
      alleviation of the symptoms of acute cholecystitis because of low invasiveness
      and ease of performance.

PMID- 12471733
TI  - Incomplete rupture of the esophagus--a case report.
AB  - Patients with an intramural rupture of the esophagus are likely to present to the
      emergency department with a history of vomiting bright red blood and associated
      chest pain. Most esophageal tears begin as esophageal hematomas. Interventions
      that induce further emesis can exacerbate the problem, further disrupting the
      mucosa and esophageal muscle layers. We suggest that naso-gastric tube placement
      should therefore be avoided whenever possible in situations in which esophageal
      damage is suspected.

PMID- 12471734
TI  - The diagnosis of bacterial vaginosis: established criteria versus reality in a
      community-based family practice residency program.
AB  - Vaginal discharge is a frequent presenting complaint in the primary care setting,
      with bacterial vaginosis (BV) being one of the most common causes. Amsel's
      criteria is widely used to make the diagnosis of BV. A review of the literature
      reveals extensive discussion on the diagnostic criteria but no studies were found
      as to how well these criteria were used by residents to make this common
      diagnosis. Documentation of Amsel's criteria from the patient encounter form was
      recorded and 201 randomly selected charts were reviewed. Each resident was given
      a survey designed to assess their knowledge and use of Amsel's criteria. Data
      from the two showed a significant difference between what the residents perceived
      use and actual use of clue cells (p < .0001), Whiff (p < .0001), and vaginal
      discharge (p < .0228) to diagnosis BV.

PMID- 12471735
TI  - Breastfeeding: a public health challenge.
AB  - Since antiquity, breastfeeding has been known to benefit the infant. In the past
      40 years, some of the reasons have been discovered such as the provision of
      complete infant nutrition, transfer of antibodies leading to a decreased
      incidence of infectious disease and psychosocial benefit to both the mother and
      child. Yet, in spite of this knowledge and increased national and international
      attention, the United States has not achieved its goal of 75% of mothers who are
      breastfeeding their infants at hospital discharge. Physicians play a vital role
      in the encouragement and sustaining of breastfeeding. Each should encourage all
      new mothers to breastfeeding for the benefits to both the infant and the mother.

PMID- 12471736
TI  - Breastfeeding.

PMID- 12471738
TI  - Lost sleep.

PMID- 12471737
TI  - Smallpox in the post-eradication era.
AB  - Smallpox is a recently extinct human viral infection for which herd immunity has
      rapidly waned. The threat of smallpox during a bioterrorist event using caches of
      virus outside reference repositories would lead to epidemics of great and
      predictable mortality. The result would be short-term societal chaos. Control of
      smallpox requires vaccination and quarantine, the same measures that eliminated
      this disease in the 1970's. Extensive coordination and planning would be needed
      among the healthcare infrastructure, law enforcement agencies and political
      leadership for effective responses to this public health threat. Despite this
      challenge, we must remind ourselves that smallpox transmission and vaccinia
      effectiveness are well understood. Strategies that successfully eradicated
      smallpox 25 years ago, if appropriately implemented again, would undoubtedly lead
      to its elimination once again.

PMID- 12471739
TI  - [Vibrio cholerae in Madagascar: study of a multiresistant strain].
AB  - Madagascar was cholera free until March 1999. The first case was reported in
      Mahajanga, a north west coast harbor. Ten months later and despite a massive use
      of tetracycline as prophylactic drug, cholera had reached every region of the
      island. All suspected cholera samples were analysed at the Pasteur Institute of
      Madagascar where susceptibility to tetracycline was systematically performed. On
      February 2000, a multidrug resistant strain of V. cholerae was isolated. We
      studied this strain by performing Minimal Inhibitory Concentration (MIC) and by
      plasmidic and conjugative assay. As the original strain, this multiresistant V.
      cholerae showed a resistance to cotrimoxazole, to streptomycin and
      chloramphenicol but, in addition to, appeared strongly resistant to ampicillin
      and tetracycline. This strain harboured a 26 kb self-transmissible plasmid.
      Conjugation tests showed the possibility of plasmidic segregates or acquisition
      of two different plasmids. The weak transfer rate could explain why we have
      isolated only one multiresistant strain. The emergence of a such multiresistant
      strain should encourage the medical authorities to reinforce the epidemic survey
      in every medical Malagasy district and to carry out new antimicrobial surveys to
      describe the mechanisms of the spread of these resistances.

PMID- 12471740
TI  - [Recrudescence and geographic extension of the plague in Madagascar from 1980 to
      1999].
AB  - Plague was introduced to Madagascar in 1898, and it has been characterized by a
      predominant distribution to the central highlands in the following decades. An
      increase of plague cases has been observed in the past 20 years, in particular in
      the capital, Antananarivo, and in the coastal town, Mahajanga, after long periods
      of silence in 28 and 63 years, respectively. A total of 2,982 confirmed or
      presumptive cases were reviewed in order to describe the changes in the
      epidemiological pattern of the disease from 1980 through 1999. The mean annual
      number of plague cases has increased from 33 during the 1980-1984 period to 298
      during the 1995-1999 period. A similar trend of distribution has been observed
      from the first period to the second by an increase of endemic districts above 800
      m altitude from 17 to 37. However, the lethality rate has in the same 20 years
      observation period decreased from 41.6% to 20.7%, probably due to re-enforcing
      measures as part of the national control program.

PMID- 12471741
TI  - [The plague at the Tsenabe Isotry market in Antananarivo: a complex epidemiologic
      situation].
AB  - The transmission of Yersinia pestis is intense among rats in the wholesale market
      Tsenabe Isotry in the capital Antananarivo (anti-F1 sero-prevalence 80%, flea
      index 8.4 for a cut-off risk index of > 1). However, the number of plague
      suspected (not laboratory confirmed) human cases has only been 3 in this district
      during a four years period from 1995 to 1999. A seroepidemiological survey among
      the market vendors was undertaken in June 1999 to test the hypothesis that the
      low incidence of human plague is due to acquired immunity. In addition,
      surveillance of the rat and the flea populations in the market was carried out.
      Only 3 (3.2%) of 95 screened vendors were anti-F1 IgG positive, whereas the
      markers of plague transmission among rodents and fleas were still high. This
      result suggests that the low incidence of human plague was not due to acquired
      immunity but to other factors such as the limited contact between humans and the
      rat fleas because of the abundance of rats, the absence of epizootic due to the
      resistance of rats in the capital and a particular behaviour of the predominant
      rat Rattus norvegicus.

PMID- 12471742
TI  - [Epidemiologic surveillance system and control of malaria in the central
      highlands of Madagascar: results 1999-2000].
AB  - The central highlands in Madagascar are characterized by an unstable occurrence
      of malaria with the risk of sporadic outbreaks. In major parts of the region DDT
      indoor spraying campaigns have been carried out from 1993 to 1998. This strategy
      was in 1999 replaced by another anti-vector intervention program targeting
      residual foci as detected by a surveillance and early warning system. This system
      is based on monitoring of presumptive malaria cases in the communities by which
      the number of presumptive cases exceeded a defined warning threshold value per
      month. The system was in the follow-up period shown to be very sensitive to
      variation of the coverage of anti-vector interventions: the number of presumptive
      cases decreased in the villages in which indoor spraying had been carried out and
      a minor increase was observed in those villages, where indoor spraying has been
      suspended. An increase of malaria cases was observed in 44 (20.8%) out of 212
      study sites in the same period. The increase was in particular predominant in
      areas at lower attitude at the outer zones of the central highlands.

PMID- 12471743
TI  - [Geographic approach in malaria control in the central highlands of Madagascar].
AB  - Following the severe malaria outbreak in the central highlands in Madagascar in
      1986, a vector control program by use DDT pm 75 house-spraying has been
      implemented to operate in areas located at altitudes between 1000 and 1500 m.
      Early treatment with chloroquine has also been incorporated in the control
      program. To detect areas at particular high risk for malaria outbreak the
      Geographic Information System (GIS) has been applied and tested. The study has
      shown that the system can be used in malaria surveillance in order to identify
      areas in which an intense distribution of Anopheles funestus can be anticipated
      and, hence, targeted in spraying campaigns. The system may also be used to
      monitor changes in anti-malarial drug resistance, in addition, to control of
      other vector-born diseases.

PMID- 12471744
TI  - [African Swine Fever introduction into Madagascar, history and lessons from an
      emergence].
AB  - African Swine Fever (ASF) was diagnosed for the first time in Madagascar in 1998.
      ASF has apparently been introduced from the African continent to the southern
      part of the island with a subsequent spread to other regions except for areas in
      the north and in the west. The epidemic has had severe economic consequences for
      the home market of pork meat production. This article reviews the course of the
      epidemic with particular emphasis on the vectors involved in the transmission of
      the virus, such as the soft tick, Ornithodoros moubata porcinus. Presence of this
      vector and of the bushpig, Potamochoerus larvatus, as a potential wild reservoir,
      are some of the major obstacles in control of ASF in Madagascar. A veterinary
      disease surveillance system has to be urgently warranted.

PMID- 12471745
TI  - [Detection of leptospirosis reservoirs in Madagascar using the polymerase chain
      reaction technique].
AB  - A polymerase chain reaction (PCR) technique was used for detection of the
      Leptospira interrogans rrs gene in kidney tissue from 115 rats, 50 zebu cattles
      and 13 pigs in an attempt to identify a possible animal reservoir of
      leptospirosis in Madagascar. In addition, serological testing of 105 individuals
      in close contact with animals was carried out. The PCR analysis was negative for
      all the samples tested and only one person was found seropositive at a low titer.
      The findings suggest that leptospirosis, if prevalent in Madagascar, is likely
      rare.

PMID- 12471746
TI  - [Diagnosis of tuberculosis by immunocapture of the tuberculous bacillus (using
      magnetic beads)].
AB  - Tuberculosis is worldwide considered as a major health problem with high
      morbidity and mortality rates. Diagnosis of tuberculosis can be problematic.
      Microscopy, as the basic diagnostic method, stands inadequately alone due to a
      low sensitivity, and culture suffers from being time-consuming. A rapid,
      sensitive and simple diagnostic test, applicable in the field is therefore highly
      needed. A diagnostic method for the detection of M. tuberculosis by immunocapture
      technique has been developed using magnetic beads coated with polyclonal anti-M.
      tuberculosis. The detection of captured bacilli using biotinylated anti-APA
      monoclonal antibody (APA is a minor secreted antigen) was found more sensitive
      than microscopy. The results suggest that the development of a rapid strip test
      to detect major antigen could be a useful tool for the control of tuberculosis.

PMID- 12471747
TI  - [Identification of communities endemic for urinary bilharziosis by the "Lot
      Quality Assurance Sampling" method in Madagascar].
AB  - Reduction of morbidity is the main component in the National Schistosomiasis
      Control Program in Madagascar. The lot quality assurance sampling (LQAS) method
      has previously been shown as a useful tool in assessment of immunization
      coverage. A study was carried in the western part of Madagascar aiming to
      evaluate the applicability of the method in measuring the level of Schistosoma
      haematobium endemic level in different communities. Parasitological examination
      of urine samples from 1,124 children aged 5 to 19 years from 12 different schools
      by use of filtration technique constituted the reference in determining the
      prevalence. Three schools were found hyper-endemic (prevalence more than 60%), 5
      schools were intermediate-endemic (prevalence between 30 to 59%), and 4 were hypo
      endemic (prevalence less than 30%). Those figures indicate a heterogeneous
      distribution of S. haematobium in the study area. A sampling plan (16.6) was then
      tested in the same area while other sampling plans were simulated in the
      laboratory. School teachers randomized under supervision the children to
      participate in this study and collected urine samples. All sampling plans (16.6),
      (14.5), (12.4), (10.3), (8.2), (6.1) et (4.0) allowed correct identification of
      hyper-endemic and hypo-endemic areas. Misclassifications occurred frequently for
      intermediate-endemic areas. The study confirms that the LQAS method by use of a
      (16.6) sampling plan constitute a valuable tool for large scale screening of
      hyper-endemic areas for therapeutic intervention as part of the control program.
      The study has also shown that school teachers may offer a potential source of
      manpower locally in such screening operations.

PMID- 12471748
TI  - [Evaluation of the effect of Knox-Out microencapsulated V.O. 240 and K-othrine
      powder on rat lice in two villages in the Betafo region].
AB  - The effect of two different insecticides on flea control was tested from January
      to March 2000 in the Ivory village and the Ambatolahy village: Knox-Out, a
      microcapsulated formulation of diazinon, organophosphorous compound (240 gr/L)
      and the deltamethrin powder (2 g/kg ai), respectively. The villages are located
      2.5 km apart in the Betafo region in Madagascar. Deltamethrin is a pyrethroid and
      is still used in the National Plague Control Program, whereas diazinon has not
      previously been applied in plague control in Madagascar. The flea index and the
      prevalence of rats carrying fleas in the two villages before and after (at one
      and two months follow-up, respectively) were measured to evaluate the effect of
      each insecticide. Flea index decreased significantly in both villages by at the
      first month follow-up. However, at the second month follow-up no significant
      differences in comparison to pre-treatment index values were observed in any of
      the villages. This study has demonstrated a similar immediate effect of
      deltamethrin and of diazinon, and confirmed the absence of remanent action of the
      two insecticides.

PMID- 12471749
TI  - [Analysis of tick-host parasitic specificity. Evaluation of the Madagascar
      situation and intense samplings].
AB  - Ticks are traditionally considered being host-specific parasites. The pattern of
      tick-host relationship was elucidated by exhaustive collection from a
      considerable number of potential hosts from numerous sites in the Malagasy mid
      altitude forest. It can from the findings be concluded that the Malagasy ticks
      found on small mammals may be distinguished as either having a broad host
      specificity or being highly host-specific. The results may provide important
      information in respect to phylogenetic studies with regards to the geological
      history of Madagascar and its endemic fauna.

PMID- 12471750
TI  - [Diagnosis of neurocysticercosis: a case report].
AB  - Neurocysticercosis is the most frequent parasitosis of central nervous system in
      the world. Neurological manifestations are in relation with locations number and
      topography, inflammatory reactions level and state of development of the
      parasite. Epilepsy is the main revealing symptom. Among other neurological
      manifestations, chronic headache, focal neurological signs, ataxia, language and
      behaviour disorder are the most anecdotal. The authors report a case of
      neurocysticercosis in a 71-year-old man with dysarthria and memory problems.
      Suspected by computed tomography, diagnosis was confirmed by immunoserologic
      assays such as enzyme-linked immunosorbent assay (ELISA) or enzyme-linked
      immunoelectrotransfer blot assay (EITB). This later emphasized on active form of
      the cyst. Specific treatment used albendazole as antihelminthic drug. Clinical
      evolution was good: neuroimaging and immunoserology results were normal
      respectively 2 and 6 months after the drug therapy.

PMID- 12471751
TI  - [Avidity of IgG anti-Toxoplasma gondii. Study to establish a new decision tree
      for screening].
AB  - Toxoplasmosis infection is commonly asymptomatic, but it may have severe
      teratogenic consequences. The authors review the literature on serologic
      screening in the first trimester of pregnancy.

PMID- 12471752
TI  - [Puffer fish poisoning in Madagascar: four case reports].
AB  - An outbreak of puffer fish poisoning in a family with four cases of which one was
      fatal is reported. The outbreak occurred in July 1998 in Nosy Be, an island
      located at the north-western part of Madagascar. Diagnostic investigation with
      application of the mouse bioassay suggested poisoning with a tetrodotoxin as the
      etiology. The amount of the toxin was 16 MU (mouse unit) per gram meal. A
      continuing surveillance of the seafood intoxications either in the country or in
      the west Indian Ocean region is needed.

PMID- 12471753
TI  - [Trichobezoars, a little known clinical entity].
AB  - A voluminous trichobezoar was discovered in an 11-year-old girl without major
      clinical implications. The diagnosis was made by endoscopy and surgery was
      performed without complications.

PMID- 12471754
TI  - [Etiologic approach in infertile couples in Mahajanga].
AB  - In Madagascar, as in other places in the world, infertility is associated with
      social stigmatism and an underlaying long-term risk for separation of the couple.
      A 12 months prospective study was carried out in 1999 in the Department of
      Gynecology, Obstetrics and Reproductive Health at the University Hospital in
      Mahajanga in order to collect data related to possible causes of infertility. For
      the women, serologic tests for Treponema pallidum (syphilis) and Chlamydia
      trachomatis were performed. And, in addition to sonography and
      hysterosalpingography, cervico-vaginal smears were obtained as part of the pelvic
      examination. A semen sample was obtained from each male partner. Of the 37
      couples enrolled in the study 35 were classified as primary infertile (n = 9) or
      secondary infertile (n = 28). The mean age of the women and the men was 30.7
      years (ranged 20 to 41 years) and 34.3 years (ranged 24 to 46 years),
      respectively. Various potential causes of infertility among the women were
      observed, such as hormonal disturbance (76%), tubal occlusion (76%), genital
      infection (70%). The figures indicate that there seems to coexist the possibility
      of multiply causes of infertility. Of 37 semen samples 24 (65%) were found with
      abnormalities, predominantly of oligospermia type. In 21 couples a possibly cause
      of infertility was observed in both partners.

PMID- 12471755
TI  - [Geographic Information Systems and health: application to Antananarivo city].
AB  - The general health status of the population in the capital, Antananarivo, is
      determined by a number of different socio-economical and environmental factors. A
      study was undertaken in 1998 by which the Geographic Information System (GIS) was
      implemented in order to describe characteristics in town areas (fokontany)
      suffering from a high disease burden. It was observed that there was a
      heterogeneous distribution of health care supporting facilities in comparison to
      population density in the different areas of the capitol. A risk-score system by
      use of an image-technique was elaborated. The most important problem encountered
      in the study was the reduced availability of standardized collected data. The
      results suggest that GIS constitutes a useful tool in assessment of urban health
      problems in order to identify fokontany in particular need of additional health
      care support.

PMID- 12471756
TI  - The challenge of the computer-based patient record to the rule of confidentiality
      and to the respect of patient's privacy.

PMID- 12471757
TI  - The protection of the patient's private life: a vast normative landscape. First
      Part.
AB  - The debate on the protection of people's private life is stronger than ever,
      particularly in the health care sector, where choices have to be made in order to
      decide between the conflicting interests at stake. This Article gives an overview
      of the general provisions that aim, for the time being, at guaranteeing this
      protection to the patient. His or her right to respect for private life, which
      aims at protecting not only the confidentiality of his or her private realm and
      relationships with others, but also his or her freedom of choice regarding this
      private realm and these relationships, is indeed expressed, in various forms, in
      a large number of texts of every possible origin. It would be a mistake to regard
      these as a heap of redundant rules. These texts can be distinguished according to
      their content, the time of their elaboration and their authors. Although complex,
      the normative structure that they form is not void of effectiveness. A next
      article will examine how they are extended and supplemented by provisions trying
      to answer, at the level of the respect of private life, to the growing use of
      computers in medical practice.

PMID- 12471758
TI  - Eleven years of endografts--what have we learned?

PMID- 12471759
TI  - Endovascular treatment of thoracic aortic dissection and its variants.
AB  - The acute aortic syndrome (AAS) is described. Its pathophysiology is discussed
      for each of the three entities (penetrating aortic ulcer, intramural hematoma and
      aortic dissection). The natural history of these three pathologies is reviewed.
      Diagnostic features and investigation imaging techniques are summarized. The
      technique of stentgraft-placement is described in detail. The authors report
      their clinical experience with 127 patients, presenting acute type B aortic
      dissection or its variants, and treated with an endovascular stent-graft-device.
      These results are in part compared with a group of control patients with acute
      type B dissection, submitted to medical non-invasive therapy.

PMID- 12471760
TI  - Endovascular treatment of thoracic dissection.

PMID- 12471761
TI  - Thoracoabdominal endaortectomy in case of type B aortic dissection.
AB  - Despite remarkable progress in both, diagnostic and therapeutic development in
      treating aortic dissections, this continues to be one of the most severe vascular
      disorders and is subject to high mortality rates. While aortic dissections of
      Type A can be treated surgically today, in the majority of patients with Type B
      dissections hypotensive treatment is the method of choice, providing a better
      chance of survival and the effective prevention of aneurysm formation and rupture
      at the site of the intimal tear. However in certain cases, Type B dissection
      generates either isthmic aneurysm formation, or, with distal progression, may
      result in long segmental thoracic, thoraco-abdominal or abdominal deterioration
      of the aorta and its side branches. The spinal, visceral, renal and lower limb
      ischemia threatens the viability of these organs and hypotensive medication may
      enhance this risk. Emergency diagnostic work-up and selective surgical
      reconstruction could lead to reduced mortality. In our department we have
      undertaken 33 thoracoabdominal endoaortectomies with meticulous reconstruction of
      renal and visceral orifices. The mortality rate in this subgroup of patients was
      6%. Based on our experience with Type B aortic dissections we recommend open
      "endoaortectomy" in selected cases in order to improve the long-term outcome.

PMID- 12471762
TI  - Coagulopathy, hypothermia and acidosis in trauma patients: the rationale for
      damage control surgery.
AB  - Severe trauma to the torso or extremities often results in significant
      hemorrhage, which contributes to morbidity and mortality. The pathophysiological
      mechanisms contributing to this traumatic blood loss are complex. We review its
      major components: coagulopathy, acidosis and hypothermia, which have led to the
      concept of damage control surgery.

PMID- 12471763
TI  - Chlamydia pneumoniae and atherosclerosis.
AB  - Chlamydia pneumoniae, a human respiratory pathogen, has been linked to
      atherosclerotic disease based on sero-epidemiologic studies, direct detection of
      the organism in atherosclerotic lesions, animal experiments and tissue culture.
      In this review paper we propose to interpret results in line with the biology of
      Chlamydia with persistence of Chlamydia pneumoniae antigens in the pathogenesis
      of atherosclerosis rather than viable bacteriae.

PMID- 12471764
TI  - Contributions of the video-assisted approach to thyroid and parathyroid surgery.
AB  - BACKGROUND: The authors report their initial experience with partial and total
      thyroidectomy, and neck exploration for hyperparathyroidism using the video
      assisted approach. PATIENTS AND METHODS: Between June 1999 and March 2001, 114
      patients underwent a thyroid (n = 57) or parathyroid (n = 57) operation using a
      video-assisted cervical approach. Video-assisted neck exploration was conducted
      in all cases under general anaesthesia leading to a partial or total
      thyroidectomy, and to a selective adenoma removal in PHPT or to a subtotal
      parathyroid resection in SHPT. RESULTS: IN THE THYROID GROUP: The mean cranio
      caudal and transversal diameter of the resected specimen were respectively 4.9 +/
      0.9 and 2.8 +/- 0.6 cm, and mean total lobar weight was 11.7 +/- 5.8 g.
      Conversion to conventional surgery was required in 5 patients (8.8%). The mean
      operative time was 133.9 +/- 26.9 and 86.5 +/- 22.5 minutes for total and partial
      thyroidectomy respectively. The laryngeal nerve was identified in 96% of cases.
      The mean length of skin incision was 24.0 +/- 2 mm. There were 3 cases of
      postoperative hypocalcemia, and 2 cases of postoperative hoarseness. The
      postoperative hospital stay was less than 24 hours for 72.7% of patients. The
      pain intensity at day one (VAS) was 2.1 +/- 1.3. IN THE PARATHYROID GROUP: Seven
      of the 44 patients who underwent PHPT (15.9%) and 4 of the 13 patients who
      underwent surgery for SHPT (30.8%) were converted to a conventional surgical
      technique. The mean operative time in PHPT and SHPT was 47.3 +/- 22.3 minutes and
      136.8 +/- 18.7 minutes, respectively. Recurrent laryngeal nerve was identified in
      53.1% of the patients. The median diameter and weight of the resected parathyroid
      glands were 1.5 cm (range 0.8-2.7) and 0.9 g (range 0.5-7), respectively. The
      length of skin incision was 24 +/- 2 mm. All but 2 patients are currently cured.
      Postoperative complications included hematoma and transient hoarseness each in
      one patient (1.75%). The median pain intensity at day one (VAS) was 0.5 (range: 0
      to 3.6). In the PHPT group, the postoperative hospital stay was less than 24
      hours for 56.7% of the patients, and less than 48 hours for 91.9% of them.
      CONCLUSION: The video-assisted approach for thyroid and parathyroid surgery is
      feasible, safe and effective in selected cases. Benefits for the patients should
      be further assessed in future prospective comparative trials.

PMID- 12471765
TI  - Impairment and return to work after intra-articular fractures of the calcaneus.
AB  - Intra-articular fractures of the calcaneus typically occur in individuals working
      on ladders, scaffolding or roofs. Male individuals in their productive age are
      most at risk. The functional problems that frequently persist are a well-known
      risk since they may obstruct a safe resumption of the former job. According to
      the data of the National Institute for Sickness and Invalidity Insurance the
      number of calcaneal fractures in Belgium have stabilised over the last ten years.
      These figures indicate the necessity for a better prevention policy. Scientific
      literature about the problem of impairment and disability in these cases is rare
      and lacks uniformity. A retrospective study was therefore performed on 65 private
      insurance compensation patients who were treated for intra-articular calcaneal
      fractures. The mean period of work incapacity was 260.5 days and the mean
      percentage of impairment was 12.3%. A large group (86.2%) were able to resume
      their former activities including the height workers. More than half of the
      patients (57%) needed a supportive device. Working at heights and falls from a
      height were a significant risk factor for long-term work incapacity. The figures
      are compared with the limited literature and further discussed.

PMID- 12471766
TI  - Can negative appendectomy rate be decreased by using spiral computed tomography
      without contrast material?
AB  - Approximately 15-20% of error in the diagnosis of acute appendicitis argues for
      new diagnostic methods. In recent years it has been proposed that Computed
      Tomography be used in the diagnosis of acute appendicitis with high sensitivity
      and specificity. In our study, the effect of Computed Tomography on the diagnosis
      of acute appendicitis and on negative appendectomy was investigated on patients
      with suspected acute appendicitis. In the last 18 months, spiral Computed
      Tomography without contrast material has been used for 65 patients. The history,
      physical findings, laboratory results and Computed Tomography images of patients
      were compared and the final decision to operate was always made by an attending
      surgeon. The results of Computed Tomography have been correlated with the reports
      of pathology and operation findings. Other patients who have not been operated on
      have been followed up clinically. Correlating Computed Tomography results with
      operation findings revealed; 42 true positive, 3 false positive, 17 true negative
      and 3 false negative results. The sensitivity and specificity of CT have been
      found to be 93.3% and 85% respectively. Forty-eight out of 65 patients have been
      operated on for acute appendicitis and the negative appendectomy rate has been
      calculated as 6.25%. As a consequence, it was thought that in the diagnosis of
      acute appendicitis the use of Computed Tomography could decrease the negative
      appendectomy rate when used together with clinical follow-up.

PMID- 12471767
TI  - Surgical attitude towards carcinoid tumour of the appendix. Review of the
      literature.
AB  - Carcinoid tumours of the gastrointestinal tract are most frequently located at
      the appendix. We report two cases: In the first case, we realized a simple
      appendicectomy. In the second case, two weeks after the appendicectomy was
      performed, according to the histological characteristics of the tumoral specimen,
      the patient underwent a laparoscopic right hemicolectomy with regional
      lymphadenectomy. In both cases, 5-HIAA (5 HydroxyIndolAceticAcid) is assayed
      regularly and remains normal.

PMID- 12471768
TI  - Symptomatic solitary nonparasitic liver cysts.
AB  - Symptomatic solitary nonparasitic liver cysts are rare, and are treated by
      aspiration, deroofing or total resection. We present two recent cases of women
      with very large such cysts, who were successfully treated by conventional
      deroofing and omentoplasty, since that is in our vision the treatment of choice
      for this benign pathology.

PMID- 12471769
TI  - Mirizzi syndrome with a double biliary fistula.
AB  - Mirizzi syndrome is a partial obstruction of the biliary tree caused by a stone
      impacted in the cystic duct, with or without development of a cholecystobiliary
      fistula. Clinical signs are non-specific and suggest at first an obstructive
      jaundice. We describe a patient with a type I Mirizzi syndrome with a
      cholecystocolic and a cholecysto-internal biliary fistula. The diagnosis was
      suggested by ultrasonography and tomodensitometry, and confirmed by endoscopic
      retrograde cholangiopancreatography. A partial cholecystectomy with a Roux-en-Y
      hepaticojejunostomy reconstruction was performed. A review of the literature
      covering its clinical presentation, diagnosis and surgical treatment is
      presented.

PMID- 12471770
TI  - Perforation due to ileocaecal salmonellosis.
AB  - A 54-year old male patient was admitted with a tentative diagnosis of biliary
      pancreatitis. After 3 days, he developed an acute abdomen with a
      pneumoperitoneum. A laparotomy was performed: multiple perforations of the
      terminal ileum and a necrotic gallbladder were found. A right hemicolectomy with
      30 cm of the terminal ileum and a cholecystectomy were carried out. At the same
      time, positive blood cultures for Salmonella typhi were obtained and this
      confirmed the diagnosis of ileal perforation due to salmonella typhi infection.
      This case illustrates that Salmonella typhi infection can be a surgical problem
      in the western countries.

PMID- 12471771
TI  - Skeletal muscle metastasis from a conventional renal cell carcinoma, two years
      after nephrectomy: a case report.
AB  - In this paper, we describe a case of skeletal muscle metastasis from a
      conventional (clear cell) renal cell carcinoma, two years after nephrectomy. Our
      first clinical tentative diagnosis was soft tissue tumour, showing the mimicking
      capacity of renal cell carcinoma. A review of literature shows that skeletal
      muscle metastases from renal cell carcinoma are extremely rare: only 16 cases
      have been described. In 5/16, the muscle mass was the initial manifestation of
      the renal tumour. In the other 11/16, the muscle masses were metachronous (10
      months-16 years). We conclude that, when confronted with a patient with a muscle
      mass and a history of renal cell carcinoma, one should always keep in mind the
      possibility of a (late) renal cell carcinoma metastasis.

PMID- 12471772
TI  - Undiagnosed rupture of right hemidiaphragm--hepatothorax: a case report.
AB  - A case of late diagnosis of right diaphragmatic rupture due to blunt trauma is
      presented. Traumatic diaphragmatic rupture is an uncommon but severe problem in a
      patient with multiple injuries. One third of left-sided ruptures and half of
      right-sided ruptures have been undetected for several days. Traumatic
      diaphragmatic rupture should be suspected on the basis of an abnormal chest X-ray
      in patients with multiple injuries. Imaging studies like computed tomography,
      scan and magnetic resonance imaging can be helpful for differential diagnosis.
      Right-sided injuries occur more commonly than previously thought and often
      require thoracotomy.

PMID- 12471773
TI  - Therapeutic concept for acute leg and pelvic venous thrombosis.
AB  - Combination treatment in acute deep venous thrombosis essentially consists of a
      highly dosed locoregional thrombolysis of the valve-carrying crurofemoral axis
      and a mechanical thrombectomy of the valveless pelvic axis by Fogarty catheter.
      The success of this method is due to the fact that it largely eliminates the
      disadvantages of systemic thrombolysis, as well as those at conventional surgical
      thrombectomy, whilst retaining the advantages. Using combination treatment in
      acute leg and pelvic venous thrombosis within the first 7 days can result in
      restitutio ad integrum, i.e. complete desobliteration with maintained valve
      function in more than 80% of the cases.

PMID- 12471774
TI  - Gender-specific health care in the 21st century: a focus on developing countries.

PMID- 12471775
TI  - The aging male and developed countries in the 21st century.

PMID- 12471776
TI  - Is aging a disease? A review of the Serono Symposia Workshop held under the
      auspices of the 3rd World Congress on the Aging Male. February 9, 2002, Berlin,
      Germany.
AB  - On February 9, 2002, Serono Symposia sponsored a workshop at The 3rd World
      Congress on The Aging Male that was held in Berlin, Germany at the Hotel Inter
      Continental. The title of the workshop 'Is aging a disease?', was intended to
      convey recent interest in the subject of aging as a clinically relevant entity
      and to discuss causes and approaches to its management. The Workshop was co
      chaired by Drs Viktor Buber and Richard F. Walker. Speakers included Drs George
      R. Merriam, Heinrich M. Schulte, Felice Strollo and Richard F. Walker. Topics
      were arranged to proceed from a general overview of fundamental aspects of the
      aging process and their clinical consequences to specific aspects of the
      diagnosis and treatment of age-related disorders that could be associated with
      neuroendocrine dysfunction. F. Strollo initiated the series of lectures by
      reviewing some of the biological theories of aging and suggesting that
      maladaptive changes within the central nervous and endocrine systems play a major
      role in contributing to the cascade of events defined as senescence. R. Walker
      expanded upon this background by differentiating aging and disease. He suggested
      that while the process of aging is not a disease, it is directly responsible for
      the development of functional decrements causal of the intrinsic disease, frailty
      and general morbidity that occur in direct relation to advancing chronological
      age. From this generalized approach of linking age and disease, G. Merriam
      discussed a specific example in which age-related decrements in neuroendocrine
      dysfunction could contribute, at least in part, to senescent changes in body
      composition and physiological function. Specifically, he provided evidence that
      the gradual decline in growth hormone (GH) and testosterone secretion during
      aging is accompanied by anatomical and functional changes resembling pathogenic
      hormone deficiency. He went on to discuss possible interventions into this
      process, specifically showing data to support the view that a combination of GH
      secretagogues and sex hormones may be of value in sustaining health and vitality
      in the elderly. As an extension of this discussion, H. M. Schulte compared and
      contrasted age changes in sex hormone secretion between genders, and also
      stressed that the diagnosis and management of endocrine changes during life has
      become a serious challenge to those physicians intending to intervene in the
      aging process. Because the relationship of reduced hormone secretion to disease
      in the elderly is presently unclear, the Workshop concluded on a note of caution
      that guidelines for the replacement of endocrine substances as a prophylactic
      approach to aging have yet to be defined.

PMID- 12471777
TI  - Diagnosis of hypogonadism in the aging male.
AB  - The diagnosis of hypoandrogenism in the aging male is still difficult, since the
      symptomatology is aspecific and multifactorial, and it is unknown whether the
      androgen requirements of elderly men are the same as those of young men. Indeed,
      there are arguments for decreased (increased androgen feed-back sensitivity) as
      well as for increased (decreased concentration of androgen receptors)
      requirements in elderly men. In the absence of a reliable, clinically useful,
      parameter of androgen activity, we have to rely on plasma androgen level, an
      indirect parameter. In the absence of convincing arguments for altered
      requirements with age, we consider that the normal range of (free) testosterone
      levels in young adults is also valid for elderly men, the lower normal limit
      being 11 nmol/l for total testosterone and 0.225 nmol/l for free testosterone.
      There are indirect, suggestive clinical arguments for accepting these limit
      values. The diagnosis of hypoandrogenism in elderly males requires both the
      presence of clinical symptoms and decreased (free) testosterone levels. The best
      methods for determining free or bioavailable testosterone, are equilibrium
      dialysis and ammonium sulfate precipitation, respectively. They are, however,
      time-consuming techniques which are not easily automated. Calculation of the free
      androgen index (testosterone/sex hormone binding globulin (SHBG)) is not a valid
      method for male serum. Calculation of free testosterone from total testosterone,
      SHBG and albumin concentration, yields values that are in good agreement with
      values obtained by dialysis or ammonium sulfate precipitation. Several conditions
      should, however, be fulfilled: reliable methods for the determination of
      testosterone and SHBG, SHBG measurement in serum and not in plasma, use of fresh
      serum (not repeatedly frozen and thawed), absence of (exogenous) steroids
      competing for binding sites on SHBG and blood samples taken between 08.00 and
      10.00 in the fasting state. Under these conditions an excellent correlation with
      dialysis and bioavailable testosterone (ammonium sulfate precipitation) is
      generally obtained.

PMID- 12471778
TI  - Intracavernous injection as an option for aging men with erectile dysfunction.
AB  - Sexuality remains a vital aspect of life in spite of aging. Advances in impotence
      research and increased knowledge of the pathophysiology of erection have
      completely changed the treatment of erectile dysfunction. Before oral therapy,
      intracavernous injection was considered as the first-line therapy for impotent
      patients. However, the new simple oral treatment raises the question as to
      whether intracavernous injection therapy is still a useful tool for treatment of
      aging men with erectile dysfunction. The efficacy and safety of oral therapy and
      intracavernous injection are reviewed.

PMID- 12471779
TI  - Gerokomikon: a brief survey of the history of geriatrics from creation to the
      16th century.

PMID- 12471780
TI  - [Colloids and perioperative hemostasis: don't forget the context, please!].

PMID- 12471781
TI  - [Spinal anesthesia in children: comparative study of hyperbaric bupivacaine with
      or without clonidine].
AB  - OBJECTIVE: To evaluate the effect of intrathecal clonidine in children. STUDY
      DESIGN: A prospective randomised study. PATIENTS AND METHODS: 45 children, 6 to
      15 years old, were randomised in two groups; receiving either 0.5% hyperbaric
      bupivacaine or 0.5% hyperbaric bupivacaine added to clonidine 2 micrograms.kg-1.
      We assessed quality and length of motor and sensory blocks and side effects of
      clonidine: hypotension, bradycardia and sedation. RESULTS: Clonidine was
      associated with prolongation of motor block. 190 +/- 42 min vs 150 +/- 35 min (p
      < 0.01), but the difference was not significant. Postoperative analgesia was
      longer in clonidine group, 490 +/- 35 min vs 200 +/- 50 min (mean +/- SD), p <
      0.001. Clonidine was associated with higher incidence of hypotension 54 vs 36%
      and bradycardia 30 vs 0%. CONCLUSION: These data suggest that intrathecal
      clonidine 2 micrograms.kg-1 is associated with extending duration of
      postoperative analgesia but with moderate side effects.

PMID- 12471782
TI  - [Evaluation of the learning curve of a new intubation technique: intubating
      laryngeal mask].
AB  - OBJECTIVE: Assessment of the learning curve of a new device for blind orotracheal
      intubation: Intubating laryngeal mask. STUDY DESIGN: Prospective clinical study.
      METHODS: Ten persons practicing anaesthesia (specialist, fellow, nurse) underwent
      videotape learning and manikin training required with the device. Each person had
      to carry out a tracheal intubation in ten consecutive patients undergoing
      scheduled surgery. No patient presented history or clinical sign of difficult
      airway management. Results were expressed as mean +/- SD. Main percentages were
      provided with their 95% confidence interval; the percentage comparison were
      performed using Chi 2 test. The significance level for overall analysis was p <
      0.05. RESULTS: One hundred patients were included. The overall success rate of
      tracheal intubation with the intubating laryngeal mask was 88%. An easy learning
      curve was obtained according to the low failure rate that was observed. No
      failure was noticed after eight procedures. Significant diminution of the delay
      for tube insertion was observed during the practice (3 +/- 1.30 min for the first
      procedure and 1.16 +/- 0.60 min for the tenth procedure). Circumstances of the
      oral intubation were improved with muscle relaxation. Finally, all failure with
      the intubating laryngeal mask were followed by successful intubation using direct
      laryngoscopy. CONCLUSION: The intubating laryngeal mask is a new device for blind
      orotracheal intubation with an easy learning curve in patients without difficulty
      in airway management, even for non-selected operators.

PMID- 12471783
TI  - [Audit of preoperative antibiotic prophylaxis in a surgical site infections
      surveillance network].
AB  - OBJECTIVE: To evaluate the preoperative antibiotic prophylaxis (PAP)
      prescriptions in a surgical site infection (SSI) surveillance network. STUDY
      DESIGN: Auto-evaluative audit in a prospective multicenter cohort included in a
      surveillance system. PATIENTS AND METHODS: Since 1997, surgical wards in
      volunteer centers monitored all surgery patients each year during a period of two
      months. Patients were evaluated for SSI during the 30 days following surgery.
      Participating centers were asked in 2000 to participate to a PAP practice
      assessment. For each surgery patient, a questionnaire was completed. The
      "Guidelines for Antibiotic Prophylaxis Prescription in Surgery" edited in 1999 by
      the Societe francaise d'anesthesie et de reanimation was used as gold standard.
      RESULTS: 6109 patients were included in the survey from 34 health care centers
      and 3881 received PAP. 90% of patients received PAP intravenously and 63%
      received twice the curative dose. PAP was administered within 90 minutes prior to
      incision in 70% of cases. 78% of PAP lasted less than 24 hours. PAP indication
      with regards to the type of surgical procedures was assessed in 4629 patients.
      PAP guidelines were observed in 1573 (34%) patients: 999 patients in whom PAP was
      not indicated did not receive PAP and 574 received it in compliance with
      recommended dose and indications. CONCLUSION: Efforts should be made to improve
      PAP prescription according to standards guidelines.

PMID- 12471784
TI  - [Evaluation of practices in surgical antimicrobial prophylaxis in the Franche
      Comte before and after implementation of an information program].
AB  - OBJECTIVES: To assess the practices of surgical antimicrobial prophylaxis in the
      Franche-Comte region of France before and after the implementation of information
      program. STUDY DESIGN: Prospective multicenter transversal study type
      before/after. The information program included a feedback on the observed results
      during the period before and a meeting with opinion leaders. PATIENTS AND
      METHODS: Data were collected by 28 pairs of surgeons/anaesthetists. Prescriptions
      were analysed to answer five questions about antibiotic prophylaxis practices in
      surgery: did the surgical procedure require antibiotic prophylaxis and was this
      carried out? Was the appropriate antibiotic used? Was the timing of the first
      injection optimal? Was the total duration of the treatment correct? Was the dose
      correct? Our data were compared to national recommendations (updated in 1999).
      RESULTS: The overall frequency of conformity was about 40% both before and after
      the implementation of an information/awareness campaign. Only the conformity of
      the total duration of the prophylaxis was significantly higher after the action,
      but only for interventions that lasted less than two hours. [RR = 2.09 (1.32
      3.31), p = 0.001]. This improvement in the total duration of regulation seemed to
      be related to the more frequent use of written protocols in the surgical units.
      CONCLUSION: Our study confirms that information campaign have little effect
      within the framework of the good use of antibiotics. We agree with the experts
      who claim that only an overall strategy including organization, education and
      restriction will really improve the frequency of conformity of the practices of
      surgical prophylaxis.

PMID- 12471785
TI  - [Is length of stay in the recovery room a risk factor for cross infections?].
AB  - OBJECTIVE: To assess cross contamination for patients at the time of their stay
      in the recovery room (RR). STUDY DESIGN: Prospective study. PATIENTS AND METHODS:
      A prospective survey over 3 weeks with 75 adult patients admitted to RR after
      thoracic or neck surgery. Samples for bacterial analysis were systematically
      taken from all patients before they left the operating theatre and just before
      discharge of RR (nose-throat and skin adjacent to the surgical wound). During
      this period, hand's health care workers (HCW) and environmental surfaces were
      sampled. RESULTS: There were 3 groups of patients: endoscopy (41%), thoracic
      surgery (39%). And thyroidectomy (20%), 392 samples were analysed. Potentially
      pathogenic floras were found on the admission for 25 patients and at discharge
      for 31 patients. A pathogenic flora was detected at discharge in 13 patients,
      whereas none was found at admission in RR. These patients were principally in the
      thyroidectomy group and their stay in RR was longer than 20 minutes. There is no
      significant difference concerning the nosocomial risk between 3 groups.
      Pathogenic flora was found in 19% of HCW (8 of 42). CONCLUSION: Cross
      contamination can exist in recovery room and educative measures are to be taken
      regarding handwhashing, isolation precautions and environmental cleaning.

PMID- 12471786
TI  - [Effects of plasma substitutes on hemostasis].
AB  - OBJECTIVE: Data synthesis on haemostasis effects of cristalloids and colloids and
      clinical implications for their use for plasma volume replacement. DATA SOURCES:
      Data were searched in the Medline database from 1954 to 2000 using the following
      key-words: cristalloids, colloids, albumin, gelatin, dextran, hydroxyethyl
      starch, haemostasis, von Willebrand disease, haemodilution. DATA EXTRACTION:
      Publications from 1954 to 1990 were selected depending on the quality of their
      methodology. Most of articles published after 1990 and all types including case
      report were accepted. DATA SYNTHESIS: Cristalloids induces a moderate
      hypercoagulable state with 10 to 30% haemodilution. Hypocoagulation is observed
      above 50% haemodilution. Albumin does not impair hemostasis except with a 50% or
      more haemodilution where hypocoagulation is observed. Dextran dramatically
      impairs haemostasis and fibrinolysis. With increasing dose, a progressive
      decrease of all von Willebrand multimers, mostly the largest, is observed. Till
      50% haemodilution, gelatin has a moderate impact on hemostasis, but platelet
      aggregation is moderately modified. However this moderate impairment of
      haemostasis may potentiate the haemostatic effect of other colloids when used in
      association with gelatin. More than 30% haemodilution with hydroxyethyl starch
      (HES) has a serious effect in vitro on platelet function and fibrinoformation. In
      most studies in human, less than 20 ml.kg-1 plasma volume replacement has no
      clinical impact, but in some evaluations postoperative bleeding is more important
      with HES, particularly HES 450, in comparison to other colloids. With HES 450 and
      HES 200 highly substituted (0.6 of degree of substitution) intravascular
      cumulation of large molecules leads to type I von Willebrand syndrome when doses
      overtake 80 ml.kg-1. Dextran and HES are prohibited in patients with impaired
      haemostasis due to congenital disease (haemophilia and von Willebrand disease) or
      acquired defect (thrombocytopenia). Caution is required in patients with renal
      failure or receiving antithrombotic or non-steroidal anti-inflammatory agents.
      Patients without a haemorrhagic diathesis must not received more than 1.5 g.kg
      1.j-1 of dextran and restrictive conditions of use must be respected with HES.
      CONCLUSION: Except isotonic cristalloids, all colloids induce haemostastic
      changes particularly for haemodilution over 30%. Effects are more pronounced with
      HES and dextran.

PMID- 12471787
TI  - [Chest pain and sulprostone during postpartum hemorrhage].
AB  - A case of chest pain in a 31-year-old woman after vaginal delivery with epidural
      analgesia during sulprostone administration is described. Chest pain occurred
      shortly after sulprostone was started and disappeared when sulprostone was
      stopped. Ischaemia related data were negative. Angiographically coronary arteries
      were normal. Coronary artery spasm aetiology was retained. Sulprostone
      pharmacology is summarized. Coronary artery effects are compared with literature
      reports. Recommendations before sulprostone use are underlined.

PMID- 12471788
TI  - [Anesthesia for cesarean section in a Marfan patient with complicated aortic
      dissection].
AB  - We report the anaesthetic management of a 32-year-old pregnant women with aortic
      dissection and Marfan syndrome for caesarean section. The patient has presented
      at 31 weeks gestation of a first pregnancy an aortic dissection that required an
      emergency aortic replacement. Three years later, she presented at 31 weeks
      gestation with aortic dissection, mitral valve dysfunction and acute pulmonary
      oedema. She was treated in intensive care unit with deslanoside, diuretic and
      twice a day echographic examination. Delivery was planned by caesarean section
      after haemodynamic stabilisation on the sixth day. Combined spinal and epidural
      anaesthesia was performed after monitoring. The initial intrathecal injection of
      bupivacaine, morphine and fentanyl provided rapid onset of analgesia. Epidural
      anaesthesia was used with diluted lidocaine and fentanyl boluses. With
      appropriate preoperative care and monitoring, uneventful combined spinal and
      epidural anaesthesia for Caesarean section was achieved in a patient with Marfan
      syndrome in the presence of aortic dissection complicated by mitral valve
      dysfunction and acute pulmonary oedema.

PMID- 12471789
TI  - [Shaken baby syndrome: improvement of cerebral blood flow velocity after a
      subdural external derivation in a six-month old infant].
AB  - The shaken baby syndrome is a severe form of child abuse. The intracranial
      injuries are associated with a high morbidity and mortality rates. A 6 month-old
      healthy infant presented at home a cardiorespiratory arrest. After a
      cardiopulmonary resuscitation, radiological survey showed sub-dural haematomas
      and retinal haemorrhages, without a history of trauma. The diagnosis of shaken
      baby syndrome was made. Despite medical management and a fontanelle tap, clinical
      signs of intracranial hypertension worsened. Transcranial Doppler examination
      found the cerebral blood flow velocities to be decreased while the pulsatility
      index was increased. A sub-dural-external drainage allowed the cerebral blood
      flow to increase and the pulsatility index to decrease. We conclude that
      transcranial Doppler examination can be helpful for the clinician caring children
      presenting a shaken baby syndrome.

PMID- 12471790
TI  - [Convulsions induced by ropivacaine after midhumeral block].
AB  - We report a case of central nervous system toxicity induced by ropivacaine
      following a brachial block at the humeral canal. Forty millilitres 0.75%
      ropivacaine (4.28 mg.kg-1) were used uneventfully, with slow injections and
      negative intermittent aspirations. Fifteen minutes later, the patient presented
      two episodes of generalised convulsions treated by diazepam, 20 mg. The total
      venous ropivacaine concentration measured two hours after the block was 2.3 mg.l
      1.

PMID- 12471791
TI  - [Can hyperchloremic acidosis during volume expansion by explained by the Stewart
      approach of acid-base?].

PMID- 12471792
TI  - [Intrinsic PEEP for diagnosis of tracheo-obstruction during mechanical
      ventilation].

PMID- 12471793
TI  - [Is parascalene approach possible for catheter insertion?].

PMID- 12471794
TI  - [Atherothrombosis: the same process for different arterial territories?].
AB  - Atherothrombosis is a diffuse disease. Is it the same process whatever the
      territory? or are there specific features depending upon the location of the
      lesions? At the level of the plaque, from a pathophysiological standpoint, the
      available literature suggests a similar process whatever the territory (slow
      growth of the plaque, inflammation, rupture and erosion, thrombosis,
      embolization). The consequences of atherothrombosis may however vary from one
      territory to another; this may be related to differences in arterial circulations
      or in cell tolerance to ischemia or in adaptative mechanisms such as collateral
      growth.

PMID- 12471795
TI  - [Acute myocardial infarction management in a hospital center with emergency
      ambulance service and intensive care unit, without cardiac catheterization
      laboratory].
AB  - OBJECTIVES: We report our experience about acute myocardial infarction management
      in a small hospital with no possibility of coronarography. MATERIALS AND METHODS:
      In 1998, 60 patients were hospitalized for acute myocardial infarction < 10 days.
      We studied characteristics of patients, the management of myocardial infarction,
      the mortality. RESULTS: Our population consisted of 83% of men and 17% of women
      with a mean age of 63.5 and 74 years respectively. An out-hospital doctor was
      first warned by 60% of patients. For hospitalization, the emergency ambulance
      service (SMUR) was used in 45% of cases, out-hospital doctors using these means
      of transport in 36% of cases. The global time of intervention was 18h30. The mean
      time for patients managed in the first sixth hours was 2h10. A thrombolysis was
      applied for 35% of patients (15% in prehospital that is to say 32% of "SMUR
      patients", and 20% in hospital). A transfer to the neighbouring university
      hospital for primary or rescue coronary angioplasty was decide for 41% of
      patients. A total of 77% of our patients underwent a coronarography. The global
      mortality at 10 days was 13.3% (< 75 years: 10.6%; > 75 years: 23%). CONCLUSIONS:
      A low volume centre and with no possibility of coronarography can manage the
      acute phase of myocardial infarction with results closed to those of the
      literature.

PMID- 12471796
TI  - [Heart and sports: modifications of electrocardiogram, late potentials and
      echocardiography. Study of 75 sportsmen and 46 witnesses].
AB  - The authors report the results of prospective study, which compared 75 sports
      subjects and 45 witnesses. All subjects were male, the differentiating parameter
      being the type of sport practiced. This work analysed surface
      Electrocardiogramme, thransthoracic echocardiography and high amplification ECG.
      The statistical study used the student test t compare means and the Chi2 test for
      the percentages, the signification limit was fixed to 5%. Clinically, our two
      series didn't show a significant statistical difference, concerning: age, weight,
      height or arterial pressure. On the electrocardiographical level, the sport's men
      have a lower cardiac frequency (p = 0.005), a larger PR space (p = 0.05), an
      important Sokolow parameter (p < 0.005), and repolarisation disorders
      represented, essentially by negative T waves (p = 0.02) and an upper movement of
      ST segment in V2-V3 (p < 0.005). Echocardiography showed a dilatation of the
      right cavities: right auricular (p = 0.0125) and right ventricular (p = 0.025).
      Move over, it has been showed that the sport's men left ventricular walls were
      tabor (septal wall, p = 0.0125), (posterior wall, p = 0.025), despite a
      difference in the values of the left ventricular telediastolic diameter (4 mm
      average in the two series). The signification limit was not reached and it was
      also showed that the left auricular was also dilated (p = 0.025). The study of
      the delayed Potentials, tried to bring an explication to certain sudden deaths of
      sport's men which are to date unexplained and which could have a rhythmical
      origin? It is also to be noted that sport's men present more delayed ventricular
      Potentials. However, the statistical signification was not reached (p = 0.07).

PMID- 12471797
TI  - [Routine electrocardiographic criteria for the diagnosis of left ventricular
      hypertrophy: performance in Black Africans].
AB  - OBJECTIVE: To determine, in Black Africans, the performance of routine
      electrocardiographic criteria in the diagnosis of left ventricular hypertrophy
      (LVH). METHODS: Thirty voluntary healthy subjects and 154 patients were explored
      at echocardiography (according to Pen convention) and 12-lead electrocardiography
      (ECG). The performance of Lewis, Sokolow and Cornell (Cornell S1 for a threshold
      of 28 mm in men, and Cornell S2, for a threshold of 24 mm) criteria were defined
      by their sensitivity, specificity, positive and negative predictive values.
      RESULTS: The prevalence of LVH in the 154 patients ranged from 15.6% to 35.7%,
      according to the ECG criteria. Sensitivities were of 0.19, 0.43, 0.30 and 0.76
      for the Lewis, Sokolow, Cornell S1 respectively, and the specificities were of
      0.89, 0.73, 0.91 and 0.54. Positive predictive value ranged from 0.16 (Cornell
      S2) to 0.91 (Cornell S2), and the negative predictive value, from 0.48 (Lewis) to
      0.86 (Cornell S2). CONCLUSION: Routine ECG criteria for the diagnosis LVH have
      low performance in Black African. There is a need of new ECG criteria with better
      performance.

PMID- 12471798
TI  - [Isolated and asymptomatic Brugada syndrome. A case report].
AB  - The case report of a 32-year-old man with a Brugada syndrome is presented. He was
      asymptomatic and without familial history of sudden death or syncope. Diagnosis
      criteria for Brugada syndrome were 1--a pattern of right bundle branch block and
      ST-segment elevation in leads V1 and V2 on the ECG, 2--no cardiac structural
      anomalies. Symptomatic patients with this electrical anomaly are at high risk of
      sudden death and need an automatic implantable defibrillator. The outcome and the
      treatment of asymptomatic patients are a matter of debate and are discussed in
      this report.

PMID- 12471800
TI  - Contrast echocardiography and acute coronary syndromes.
AB  - Since microvascular perfusion parallels myocardial viability, myocardial contrast
      echocardiography (MCE) can provide informations regarding myocardial recovery
      after an acute myocardial infarction (AMI). Recent studies have demonstrated the
      role of MCE to evaluate the value of perfusion and function during rest and
      dobutamine stress echo in patients early after AMI in terms of risk
      stratification and management of these patients.

PMID- 12471799
TI  - [Left ventricular opacification: improved detection of global and regional wall
      motion at rest].
AB  - Contrast echocardiography is officially validated for improvement of endocardial
      visualization in patients with poor acoustic window. In fact, and due to its
      cost, contrast injection is nowadays limited to few cases in standard
      echocardiography: LV volume measurement, LV thrombi, wall motion analysis.

PMID- 12471801
TI  - [Physiopathology of coronary microcirculation].
AB  - Coronary microcirculatory is the main target of contrast echocardiography.
      Coronary flow is one of the parameters which influence the myocardial blood flow
      but not the only one. Therefore, the knowledge of microcirculatory
      physiopathology is required in order to analyze datas from contrast echo.

PMID- 12471802
TI  - [Microbubbles-ultrasound interactions].
AB  - Echographic contrast agents have a dynamic behaviour in the ultrasound field
      which is the base of their detection as well as that of myocardial perfusion
      quantification.

PMID- 12471804
TI  - Myocardial contrast echocardiography in the perfusion imaging in coronary
      occlusion and reperfusion.
AB  - The availability of myocardial contrast echocardiography (MCE) has potential for
      several applications in coronary diseases. Experimental studies have demonstrated
      a good correlation between measurements of myocardial blood flow and regional
      contrast intensity, and therefore capabilities of MCE in detecting myocardial
      ischemia during stress. Clinical studies must then demonstrate the value of such
      approaches in comparison with existing techniques such as stress echo and
      radionuclide imaging.

PMID- 12471803
TI  - [Left ventricular opacification and stress echocardiography].
AB  - Stress echocardiography has been completely validated in the diagnosis and follow
      up of ischemic diseases. However, for difficult patient with poor ultrasound
      window, reliability of this examination can be altered. In these situations,
      contrast echocardiography significantly increases sensitivity and specificity of
      stress echo by improving the endocardial delineation.

PMID- 12471805
TI  - [Image analysis in contrast echocardiography].
AB  - The visualization of contrast agents in echocardiography is obtained with complex
      acquisition sequences and their analysis is dependent on operator experience. In
      order to be more accessible, images analysis is essential and the main objective
      is to integrate qualitative and quantitative data in one single image.

PMID- 12471806
TI  - [Contrast media in ultrasonography: from synthesis to clinical use. The Sonovue
      example].
AB  - Ultrasound contrast agents are commonly described as microbubbles structures
      composed with a low molecular weight gaz (perfluorocarbon, sulfur hexafluor)
      surrounded by a stabilizing shell (phospholipids, albumin, etc.). This specific
      composition allows these microbubbles to be detected in the myocardium after an
      intravenous injection.

PMID- 12471807
TI  - Quantification methods.
AB  - Ultrasound contrast agents can be assimilated to intravascular flow tracers
      opening the field of myocardial blood flow (MBF) quantification. However, tracer
      theories are invalidated because of microbubble unstable structure and peripheral
      injection. In order to overcome these limitations, new models have been developed
      as destruction/refilling sequences allowing MBF assessment.

PMID- 12471808
TI  - [Target and therapeutic microbubbles].
AB  - Because ultrasound microbubbles lower the threshold for cavitation by ultrasound
      energy, they may be used as cavitation nuclei for drug and gene delivery. By
      tailoring the physical properties of microbubbles and coating materials, drugs
      and genetic drugs can be incorporated into ultrasound contrast agents. As the
      microbubbles enter the region of insonation, the microbubbles cavitate, locally
      releasing the therapeutic agents.

PMID- 12471809
TI  - [Adaptation of perfusion flow during reperfusion to protect ischemic myocardium
      from calcium loading].
AB  - The aim of this study was (i) to evaluate calcium exchanges occurring during the
      first stage of reperfusion, and (ii) to investigate the effect of reperfusion
      flow applied on safe and ischemic hearts. Pig hearts (n = 20) were arrested with
      cardioplegia and randomly assigned into 2 groups: an ischemic group (1 hour in
      vitro ischemia at 38 degrees C) versus control group, before being subjected to
      aortic reperfusion (using 1 and 0.1 ml min-1 g-1 perfusion flow). Both oedema and
      arterio-venous differences in calcium were analysed during reperfusion. The data
      showed myocardial Ca++ loading in control hearts reperfused at low flow (p <
      0.01) and in ischemic hearts reperfused at high flow (p < 0.01), whereas a low
      flow reperfusion appeared to protect ischemic hearts. In all groups, reperfusion
      oedema was greater than 20%. In conclusion, the data suggest that reperfusion
      flow of arrested hearts should be adapted to the state of the heart: a high flow,
      necessary for a safe heart, can be deleterious for ischemic heart, whereas a low
      flow, protective for ischemic hearts, can be deleterious for safe heart.

PMID- 12471810
TI  - [Studies on xenogenic acellular dermal matrix as a filling material].
AB  - OBJECTIVE: To explore the biological reaction of swine acellular dermal matrix as
      a filling material for body surface deformity. METHODS: Xenogenic acellular
      dermal matrix was implanted into the hypoderm of rabbits. The implants were
      measured and observed with pathological and transmission electron microscopic
      technique at regular times. The results were compared with implantation of
      autologous dermis and swine dermis. RESULTS: The implanted xenogenic acellular
      dermal matrix and autologous dermis had slight inflammatory reaction. At 2 weeks
      there were fibroblasts and capillaries in the implants. The absorptivity of the
      xenogenic acellular dermal matrix was lower than the swine dermis. The xenogenic
      acellular dermal matrix was used in 2 clinical cases and obtained good result.
      CONCLUSION: The xenogenic acellular dermal matrix is an ideal material with good
      compatibility feature and low absorptivity.

PMID- 12471811
TI  - [Experimental study on the inflammatory and immune responses of xenogenic
      acellular dermal matrix transplantation combined with thin split-thickness skin
      autograft].
AB  - OBJECTIVE: To investigate the dynamic process of the inflammatory response and
      the profile of Th1/Th2 cytokines after xenogenic acellular dermal matrix (ADM)
      transplantation with thin split-thickness skin autograft overlay. METHODS: SD
      rats were used in the study. In the control group, thin split-thickness skin
      autograft (STSG) was transplanted in the full-thickness skin defect of the SD
      rats; in the experimental group, the xenogenic acellular dermal matrix combined
      with thin split-thickness skin autograft was transplanted. The inflammatory
      response was examined histologically and Th1/Th2 cytokine mRNA expression in skin
      grafts was determined by reverse transcription-polymerase chain reaction.
      RESULTS: Inflammatory reaction was induced by ADM at the early stage of
      transplantation and decreased gradually. Th2 cytokine mRNA expression was higher
      in the ADM group than that of the control group whereas the Th1 cytokine mRNA
      expression was undetected in both groups. CONCLUSION: Xenogenic acellular dermal
      matrix is immunogenic. The increased expression of Th2 cytokines may be related
      to the humoral immune responses and the absence of ADM graft rejection.

PMID- 12471812
TI  - [A clinical study on composite transplantation of meshed split-thickness
      autograft and heterologous dermal matrix].
AB  - OBJECTIVE: To investigate the feasibility of the composite transplantation of 1:3
      meshed split-thickness autograft and acellular heterologous (porcine) dermal
      matrix. METHODS: 9 inpatients with full thickness skin burn or hypertrophic scar
      were selected in this study. After the eschar or scar was excised, the wound was
      covered with acellular heterologous dermal matrix. Then the meshed (1:3) split
      thickness autologous skin sheet was grafted on the dermal matrix. Before dressing
      up, the radiated pigskin was placed on the composite transplants. RESULTS: The
      composite transplantation was successfully used in 9 cases. The meshed split
      thickness autograft was expanded 3 times and covered the dermal matrix tightly.
      The clinical results of the composite transplantation were similar to that of
      intermediate split thickness skin graft or full thickness skin graft. CONCLUSION:
      The composite transplantation of meshed (1:3) split-thickness autograft and
      acellular heterologous (porcine) dermal matrix allowed the expansion of the
      autologous skin sheet to 3 times. The clinical results were similar to that of
      intermediate split thickness skin graft or full thickness skin graft.

PMID- 12471813
TI  - [The clinical application of xenogenic (porcine) acellular dermal matrix grafting
      with thin autogenic skin on deep wounds].
AB  - OBJECTIVE: To observe the effectiveness of xenogenic(porcine) acellular dermal
      matrix grafting with thin autogenic skin on deep wounds with good wound-bed.
      METHODS: 52 cases of patients with deep wounds were transplanted with
      xenogenic(porcine) acellular dermal matrix grafting and thin autogenic skin by
      two step method from Jan. 2000 to Feb. 2002. RESULTS: 37 cases of patients
      achieved complete take(71.1%) and 15 cases got 95 percent take (28.9%) with none
      needing grafting again. 3-6 months' following up showed that skins of complex
      grafting had well-acceptable color and quality compared to nearby skin.
      CONCLUSION: This kind of xenogenic(porcine) acellular dermal matrix can be widely
      used on deep wounds with good wound bed as complex graft.

PMID- 12471814
TI  - [Application of meshed acellular dermis xenograft (pigskin) with scalp thin skin
      autograft in 15 patients].
AB  - OBJECTIVE: To present the clinical application of the meshed acellular dermis
      xenograft with scalp thin split-thickness skin autograft. METHODS: The meshed
      acellular dermis xenograft (pigskin) was placed on the granulation or defects
      after scar resection. Four or five days afterwards, scalp thin split-thickness
      skin was transplanted. A total of 15 patients with 25 wounds were treated using
      this technique. The survival rates and quality of the grafts were observed.
      RESULTS: The survival rate of the meshed acellular dermis xenograft was (96.40 +/
      2.60)% and the scalp thin split-thickness skin autograft was (97.44 +/- 3.50)%.
      All grafts showed normal skin-alike color and elastic and smooth texture.
      CONCLUSION: The combined use of meshed acellular dermis xenograft and scalp skin
      autograft demonstrated an ideal way for the repair of full-thickness skin burn or
      defects from scar resection. The scalp can provide thin skin graft repeatedly
      without influence of the hair.

PMID- 12471815
TI  - [Reconstruction of the lower face and the anterior neck with a bipedicled
      expanded flap].
AB  - OBJECTIVE: To explain a method for lower face and anterior neck reconstruction.
      METHODS: Tissue expanders were implanted subcutaneously beside the defect. When
      the skin was properly expanded, the bipedicled expanded skin flap was created and
      transferred to the lower face and the anterior neck. If the defect can not be
      repaired by one stage, the expanded skin was re-expanded for the rest. RESULTS:
      11 patients have been treated with this method since 1990. All flaps survived and
      all the defects have been successfully repaired with satisfactory results.
      CONCLUSION: The bipedicled expanded flap, which provided good blood supply,
      improved the survival rate of the flap and reduced the incision scar on the face,
      is an effective surgical procedure.

PMID- 12471816
TI  - [The effect of basic fibroblast growth factor (bFGF) on neovascularization and
      prefabricated flap survival].
AB  - OBJECTIVE: To observe the effect of basic fibroblast growth factor (bFGF) on
      neovascularization and prefabricated flap survival. METHODS: Male New-Zealand
      rabbits weighting 2.0-2.5 kg were used in this study. The experimental model used
      a prefabricated neck flap, supplied by the transferred and implanted central
      vascular bundle of the ear. 9 micrograms bFGF and 0.2 ml of normal saline was
      instilled in the vascular pedicle of the experimental and the control group
      respectively. After 1, 2, 3 weeks of operation, the neovascularization was
      studied by confocal laser scanning microscope (CLSM) and flap survival was
      observed. RESULTS: The neovascularization and survival of the prefabricated flap
      was different in the experimental and the control groups. The experimental group
      was better than the control group. CONCLUSION: bFGF treatment improved sprouting
      of the implanted vessel and the prefabricated flap survival.

PMID- 12471817
TI  - [The influence of over-expansion on the blood supply of an axial-pattern flap].
AB  - OBJECTIVE: To investigate the influence of over-expansion on the viability and
      vascularity of an axial-pattern flap. METHODS: Tissue expanders were implanted
      subcutaneously on the buttock of the mini-pig. After over expansion, an axial
      pattern over-expanded skin flap was elevated in the pig of the experimental
      group. The differences in flap survival, LDF, MDA content and fluorescein stain
      were observed between the control and the experimental groups. The vascular
      architecture changes were also recorded using histological and clearing specimen
      examination. RESULTS: The microcirculation in the distal segment of the axial
      flap was significantly weakened after over-expansion. There were injury
      manifestation, change in vessel distribution and reduction of vascular territory
      in the axial over-expanded flap. CONCLUSIONS: Over-expansion could cause chronic
      injuries to the axial vessel network and damage the blood supply of the axial
      pattern flap.

PMID- 12471818
TI  - [Microcirculation of lateral groin skin flaps: monitoring and clinical
      application].
AB  - OBJECTIVE: To monitor the microcirculation of lateral groin skin flaps. METHODS:
      The microcirculation in 12 lateral groin skin flaps was monitored continuously by
      laser doppler flowmetry (LDF). RESULTS: The microcirculatory changes in lateral
      groin skin flaps were divided into two phases: rapid rising (2-6 days after
      operation) and plateau (6-11 days after operation). PU values were 2.83 +/- 0.46,
      3.21 +/- 0.41, 3.66 +/- 0.43, 4.77 +/- 0.71, 7.08 +/- 0.37; 7.53 +/- 0.41, 7.57
      +/- 0.62, 7.70 +/- 0.44, 7.60 +/- 0.26, 7.58 +/- 0.17. CONCLUSION: In clinical
      application, division of the lateral groin skin flaps within the plateau, and the
      values (PU) returned to or exceeded 50% of that values (PU) determined before
      application of the tourniquet, causes flaps survival (100%). The time of division
      was decreased to 8-11 postoperative days in our clinical application.

PMID- 12471819
TI  - [Auricular reconstruction with Medpor framework and temporal-parietal fascia
      flap].
AB  - OBJECTIVE: In search of a simpler and safer technique for auricular
      reconstruction with good appearance. METHODS: Medpor implant was used as
      auricular framework, and covered by temporal fascia flap and skin graft. RESULTS:
      Ear reconstruction was successfully achieved in 19 cases, the newly formed ears
      all had good appearance after edema disappeared 1 or 2 months postoperatively.
      CONCLUSION: Medpor is a kind of good implant material because it is steady in
      nature, easy to be sculptured. Temporal fascia flap is rich in blood supply,
      tough and tensile in biomechanics. So the combination of Medpor implant framework
      with temporal fascia flap is preferable in auricular reconstruction.

PMID- 12471820
TI  - [Correction of prominent malar complex by L-type osteotomy].
AB  - OBJECTIVE: To present a new method for correction of prominent malar complex by L
      shaped osteotomy through an intraoral incision. METHODS: Based on the anatomical
      characteristics of the malar complex, we designed a new L-shaped osteotomy for
      malar eminence reduction. The procedure includes oblique incision of the upper
      part of the mala, vertical incision of the anterior part of the mala and
      "greenstick" fracture of the zygomatic arches. According to the severity of malar
      prominence, we resect part of the anterior-inferior part of the mala and lower
      the malar complex. RESULTS: This method was used in 39 patients with prominent
      malar complex. Of them, 32 were symmetrical and 7 were unsymmetrical. All the
      patients obtained good results. CONCLUSION: L-shaped osteotomy for correction of
      prominent malar complex is a relatively ideal surgical method with the advantages
      of simpler manipulation, fewer complications, better result, and ensuring the
      intactness of the structural characteristics of the malar complex.

PMID- 12471821
TI  - [Nerve injury and neurosensory recovery following bilateral mandibular sagittal
      split osteotomy].
AB  - OBJECTIVE: The purpose of this study was to determine the incidence of temporary
      and permanent sensory disturbance of the inferior alveolar nerve (IAN) after
      bilateral sagittal split osteotomy (BSSO) of the mandible. METHODS: 14 patients
      were selected for this study. Before BSSO and at 1 week, 1, 3, 6 and 12 months
      after BSSO, the sensibility of bilateral inferior alveolar nerves were examined
      using sharp-blunt testing, 2-point discrimination, electronic pain response test
      (ZGK-1 electrometer). RESULTS: With conventional sharp-blunt and 2-point
      discrimination test, electronic pain response test, the incidence of temporary
      impairment of IAN after BSSO was 78% (22/28). Obvious sensory recovery of IAN was
      found 6 to 12 months postoperatively. Permanent sensory disturbance of unilateral
      inferior alveolar nerve occurred in 2 patients. CONCLUSIONS: Sensory recovery of
      the inferior alveolar nerve after bilateral sagittal split osteotomy of the
      mandible would take 6 to 12 months. Serious injury of the IAN would cause
      permanent neurosensory deficits.

PMID- 12471822
TI  - [Analysis of 5459 cleft lip and palate cases].
AB  - OBJECTIVE: To analyse the constitution of 5459 cleft lip and palate cases and to
      review the development of surgical treatment to them. METHODS: The data of the
      5459 cleft lip and palate cases were collected and classified. The ratio of sex
      and disease pattern were calculated and analyzed statistically. Also, by means of
      classification of the disease pattern, the operation methods and the operation
      time, the change of the surgical methods and the first operation age were
      analyzed. RESULTS: In the cleft lip and palate cases, the sex ratio is different.
      There were obvious differences in the first operative ages in different periods.
      The main repair methods for cleft lip and palate changed with time. CONCLUSION:
      The male is more than the female in the cleft lip and palate patients. The
      average first operation age has been decreased and the main repair methods have
      changed since 1980.

PMID- 12471823
TI  - [Surgical depilation in low hairline aurical reconstruction].
AB  - OBJECTIVE: Low hairline is one of the most troublesome problem in auricle
      reconstruction. There was no satisfactory way to manage the problem. This article
      discuss surgical depilation to deal with this problem and reconstructed auricle.
      METHODS: According to the degree of the low hairline, Postaurical scalp was
      expanded and part of the lower follicles within the dermal were removed, or
      postaurical scalp that part of lower follicles and dermal had been removed was
      expanded and covered skeleton of ear with this expanded skin to reconstructed
      auricle. RESULTS: Auricles were reconstructed with this method in 152 lowhairline
      microtial cases, the result was very satisfactory. CONCLUSION: This procedure is
      an effective way to deal with low hairline in reconstructing auricle.

PMID- 12471824
TI  - [An experimental study on c-myc gene mRNA expression of endothelial cell induced
      by bFGF].
AB  - OBJECTIVE: To investigate the molecular biological mechanism of endothelial cell
      proliferation induced by bFGF. METHODS: Cultured rat myocardial microvascular
      endothelial cells were stimulated with bFGF of various concentrations. By
      northern blot analysis, the levels of c-myc mRNA expression were detected.
      RESULTS: The expression of c-myc mRNA in the bFGF-treated groups increased (P <
      0.05) with a dose- and stimulating time-dependent manner. The c-myc mRNA
      expression reached to a peak level at 2 hours. CONCLUSIONS: C-myc expression may
      be an important component in controlling the transit of cells through the cell
      cycle.

PMID- 12471825
TI  - [The influence of expansion maintenance period upon in vivo skin tension and
      immediate stretch-back rate of the expanded skin].
AB  - OBJECTIVE: The study was to investigate the influence of maintenance period of
      expansion upon skin tension and immediate stretch-back rate of the expanded skin.
      METHODS: 30 expanders (240 ml) were implanted in six adult dogs, which were
      divided into four groups: group A with 2-week saline injection of the expander;
      group B with 6-week injection; group C with sham-operation and group D as the
      blank control group. The first two groups were subdivided into three groups
      respectively according to different maintaining times of one week, two weeks and
      four weeks. When full inflation was finished, a 4 cm x 7 cm expanded flap was
      created and in vivo skin tension and stretch-back ratio of the flap were
      measured. The Comparison was made in terms of in vivo skin tension and immediate
      stretch-back ratio between different injection and different maintenance periods.
      RESULTS: With expansion maintenance time increasing, the in vivo skin tension and
      immediate stretch-back ratio decreased. After the capsule of the expand skin flap
      was removed, the in vivo skin tension and immediate stretch-back rate
      significantly reduced. Based on the experimental results, 16 patients were
      treated with implantation of 23 expanders. Their average expander injection time
      was 14 days and the average maintenance time was 25 days. All expanders obtained
      good results except one extrusion. CONCLUSION: In skin and soft tissue expansion,
      in vivo skin tension and immediate stretch-back ratio can be reduced through
      prolonged maintenance of expansion and capsule removal from the expanded skin
      flap.

PMID- 12471827
TI  - Management of people who have received Menomune meningococcal vaccine since 16
      May, 2001.

PMID- 12471826
TI  - [Computer-aided tissue expansion 3D profilometry and surgery planning system].
AB  - OBJECTIVE: To develop and evaluate the computer-aided system in measurement of
      expanded skin and preoperative planning. METHODS: Stereophotogrammetric technique
      was used to gain the 3D image-pairs, from which the contours of the expanded
      sites were restored. The 3D surface data were provided to the specially developed
      "computer-aided tissue expansion 3D profilometry and surgery planning system", to
      calculate the expansion area and help the preoperative design. RESULTS: The
      system has been applied clinically in 16 tissue expansion sites of 11 patients
      with fairly good results since March 1999. Compared with the traditional method,
      this system is accurate, repeatable and feasible. CONCLUSION: This technique is
      useful and promising for improving the operation of tissue expansion.

PMID- 12471828
TI  - Who's response to the threat of the deliberate use of biological and chemical
      agents to cause harm.

PMID- 12471829
TI  - [Atrial natriuretic peptides reception and physiological effects].
AB  - The review presents current data on production, release and reception of
      natriuretic peptides (NUP) with special focus on NUP effects on blood
      circulation, urination in arterial hypertension and cardiac failure; analyses
      interaction between NUP and renin-angiotensin-aldosterone system, effects of new
      drugs influencing these systems.

PMID- 12471830
TI  - [Free radical processes and their role in pathogenesis of some gastrointestinal
      diseases (part 1)].
AB  - The authors studied enzymatic and non-enzymatic modes of active oxygen forms
      formation, mechanisms of their damage to live cells, in particular, initiation of
      free radical lipid peroxidation; investigated anti- and prooxidant systems of
      body defense responsible for balance between appearance, metabolism and
      utilization of active oxygen forms. Impairment of this balance converts
      physiological processes into pathological ones. Peculiarities of free radical
      processes and their role in pathogenesis of some gastrointestinal diseases are
      described.

PMID- 12471831
TI  - [Pathogenetic assessment of cardiac arrhythmia and myocardial ischemia in
      hemodynamic stroke].
AB  - 330 patients with ischemic stroke entered the trial. They were divided into two
      groups: 72 (21.8%) patients with hemodynamic stroke (group 1) and the rest 258
      (78.2%) patients with other pathogenetic subtypes of stroke (group 2). Heart
      rhythm and myocardial ischemia were studied using ECG and Holter monitoring.
      Electrocardiographically, hemodynamic stroke is characterized by frequent
      ventricular extrasystole, sick sinus syndrome and transient atrioventricular
      block of the second and third degree with pauses 2 s and longer, ventricular
      fibrillation and painless myocardial ischemia. Perpetual and paroxysmal atrial
      fibrillation and paroxysmal ventricular tachycardia are not pathognomonic for
      hemodynamic stroke though these disorders can be also considered as independent
      pathogenetic factors of hemodynamic cerebral focal lesion.

PMID- 12471832
TI  - [Role of thyroid pathology in pathogenesis of arterial hypertension in diabetes].
AB  - 190 patients with diabetes mellitus (DM) were examined: 24 patients with DM type
      1 and 166 with DM type 2. Frequency of arterial hypertension (AH) in diabetics is
      higher than in population. AH in different DM types varies by pathogenesis.
      Symptomatic renal AH is typical for DM1, essential AH combining with renal one in
      1/3 of cases--for DM2. Treatment of AH and DM often provokes hypothyroidism which
      can be iatrogenic because of continuous intake of sugar reducing and
      antihypertensive drugs with antithyroid and strumogenic actions. Hypothyroidism
      aggravates an AH course: arterial pressure becomes high and resistant to
      hypotensive therapy. DM makes difficulties in selection of hypotensive drugs as
      many of them alter metabolism and due to negative attitude of the patients to
      continuous intake of sugar reducing, antihypertensive drugs, thyroid hormones.
      Therefore, hypertensive diabetics should be prepared for treatment
      psychologically and receive only prolonged hypotensive drugs. In DM with AH
      medication of choice is ACE inhibitors as they are nephroprotective, had no
      negative effect on carbohydrate, fat metabolism and thyroid system.

PMID- 12471833
TI  - [Variants of left ventricular hypertrophy in patients on programmed
      hemodialysis].
AB  - Programmed hemodialysis (PHD) was successfully used in 189 of 207 patients with
      chronic renal failure (CRF) treated in Ulyanovsk Regional Hemodialysis Center for
      10 years. To improve PHD results and prevent fatal complications, a search for
      objective prognostic indices of cardiovascular disease function was initiated.
      Left ventricular hypertrophy (LVH) development was compared in two groups of
      patients of different age (group 1--69 young patients aged 18-40 years; group 2-
      48 elderly patients aged 55-73 years. Concentric LVH transformed into excentric
      or mixed one in parallel to an increase of the patients' "dialysis age". This
      trend was prognostically unfavourable in both groups of patients especially in
      older patients.

PMID- 12471834
TI  - [Clinicofunctional characteristics of the heart in hemorrhagic fever with renal
      syndrome].
AB  - A clinicofunctional analysis of the heart was made in 50 patients suffering from
      hemorrhagic fever with renal syndrome (HFRS) in the acute period and at the stage
      of outpatient rehabilitation. Comparison with healthy subjects was made by
      physical, ECG, echo-CG data, changes in the levels of creatinphosphokinase (MB
      fraction) (CPK-MB), asparagine and alanine aminotransferase in the serum.
      Clinical symptoms of heart pathology, their incidence rate in different periods
      of the disease, dynamics of ECG deviations, state of heart chambers and left
      ventricular systolic function are described. The most manifest changes of the
      studied parameters were observed in acute disease and depended on the disease
      severity. The detected changes in the end part of the ventricular complex on ECG
      associated with a relative depression of left ventricular systolic function as
      well as a rise in the level of CPK-MB indicate affection of the myocardium.
      Variants of combination and dynamics of the above disorders allowed to single out
      the most probable syndromes of heart affection in HFRS.

PMID- 12471835
TI  - [Biochemical and immunological markers of osteoporosis in patients with chronic
      obstructive pulmonary disease].
AB  - A cytokine profile and changes in bone metabolism were studied in 95 patients (30
      females and 65 males) with chronic obstructive pulmonary disease (COPD).
      Subnormal bone density was diagnosed in 78% patients with COPD. Frequency of
      osteoporosis discovery in emphysema was higher than in chronic obstructive
      bronchitis and the degree of density loss in bone tissue depended on ventilation
      disturbance. Intensification of bone resorption in relatively stable osteogenesis
      was encountered in 73.6% patients and manifested in elevated CrossLaps
      concentration. A close correlation exists between proinflammatory cytokines, bone
      density and indices of bone metabolism in COPD. This suggests a significant role
      of cytokine-mediated mechanisms in pathogenesis of pulmonogenic osteopenia.

PMID- 12471836
TI  - [Soluble vascular adhesion-1 molecule in Sneddon syndrome: clinical and
      prognostic value].
AB  - Clinical significance of a soluble vascular adhesion-1 molecule (pVCAM-1) in
      Sneddon's syndrome (SS) was studied in 48 SS patients by examination of serum
      pVCAM-1 level using enzyme immunoassay (R&D, USA). High serum concentration of
      pVCAM-1 registered in 62.6% of SS patients was associated with extracerebral
      thromboses, not with severity of cerebral vessel damage. Lethal outcomes for 2
      years of follow-up occurred more frequently in patients with a high basal level
      of pVCAM-1 than in patients with normal level. Thus, development of the
      pathological process in SS is associated with elevated concentration of serum
      pVCAM-1 and may serve an additional laboratory indicator of developing extrabrain
      thrombotic disorders and marker of unfavourable prognosis.

PMID- 12471837
TI  - [Processes of cyclicity in the course of ulcer disease].
AB  - 4171 cases with exacerbation of peptic ulcer were identified at endoscopic
      examination of 23,779 patients. Changes in metabolic-trophic processes (MTP) in
      gastric mucosa (GM) were studied in 210 patients with duodenal ulcer. A complex
      chronobiological correlation exists between solar activity and progress of peptic
      ulcer. Cyclic alterations in MTP were detected in GM. Fluctuations were found at
      all the levels of body functioning--from systemic structures to molecular ones.
      The data obtained can be used for optimization of preventive measures in ulcer
      patients.

PMID- 12471838
TI  - [Pharmacotherapy of non-associated with Helicobacter pylori ulcer].
AB  - Examination and pharmacotherapy were performed in 77 patients with ulcer disease
      (48 patients with duodenal ulcer, 29 patients had gastric ulcer). The disease was
      not associated with Helicobacter pylori. Ulcer disease free of Helicobacter
      pylori was treated with famotidine within 5 days since the recurrence onset (in
      acute phase of ulcer defect) followed by intake of phosphalugel (in duodenal
      ulcer) or de-nol (in gastric ulcer). Such treatment appeared more effective than
      ranitidine therapy as it consolidates stable remission and produced minimal side
      effects.

PMID- 12471839
TI  - [A comparative clinico-pharmacological study of adalat, foridone, siskor, lomir
      effects on cerebral and peripheral circulation in patients with arterial
      hypertension].
AB  - The results of a comparative clinicopharmacological study of adalate, foridone,
      siskor and lomir effects on cerebral and peripheral blood flow are presented for
      46 patients with arterial hypertension stage I-III. It was found that all the
      four drugs relieve tonicity and enhance blood flow in a. cerebri media and a.
      carotis communis. Lomir and adalate had more potent effects on central
      hemodynamics. A maximal dilating effect on regional peripheral arteries was
      observed after a single intake of siskor and adalate, while lomir's and
      foridone's single doses were weaker. In course treatment with the above drugs
      these differences are less.

PMID- 12471840
TI  - [Acute fatty gestational hepatosis in infectious and obstetrical clinic].
AB  - Moscow infection hospital N 1 admitted in 1970-2000 fifty seven pregnant women
      with acute fatty gestational hepatosis (AFGH). 10 women died. AFGH is a severe
      complication of pregnancy. It occurs rather rarely, has clinical variants, can be
      mistaken for infectious diseases, primarily for viral hepatitides. When AFGH
      diagnosis is verified, the patient must immediately deliver otherwise the
      prognosis is poor.

PMID- 12471841
TI  - [Bronchoconstriction in administration of ACE inhibitors].
AB  - The aim of the study was assessment of bronchial capacity in the treatment with
      ACE inhibitors. 92 patients with essential hypertension stage I-II (mean age 52
      years), ischemic heart disease and bronchial asthma (a mild, moderate and severe
      course) in a relative remission were treated for arterial hypertension with ACE
      inhibitors enalapril and diroton. Enalapril improved cough indices by 38.3%,
      diroton--by 13.3%. This was accompanied by a rise in the level of natural
      antibodies to bradikinin.

PMID- 12471842
TI  - [Difficulties in differential diagnosis of abdominal pain].
AB  - The authors discuss difficulties of differential diagnosis in acute abdominal
      pain; analyse cause of misdiagnosis in recurrent abdominal colicky pain, report
      three cases of mistakes in making diagnosis of acute pancreatitis, thrombosis of
      the mesenterial vessels in a patient with ischemic heart disease and chronic
      aneurysm of the left ventricular anterior wall, gastric ulcer complicated by
      hemorrhage in combination with new-onset diabetes mellitus with ketoacidosis.

PMID- 12471843
TI  - [Primary antiphospholipid syndrome in combination with heterozygous mutation in
      prothrombin (G20210A) gene: a case report].
AB  - A 47-year-old man had residual effects of acute disorders of cerebral circulation
      in the territory of the median cerebral artery. Computer tomography confirmed the
      presence of the postischemic focus in the area of the head of the caudate
      nucleus. Also, thrombosis of small branches of the coronary arteries with
      development of postinfarction cardiosclerosis and arrhythmia, thrombosis of deep
      veins in the left leg gave grounds for verification of primary antiphospholipid
      syndrome (PAS). The diagnosis was serologically confirmed by the presence of
      anticardiolipin antibodies and the presence of lupus anticoagulant. A genetic
      examination detected heterozygous mutation G20210A in prothrombin gene but failed
      to identify G1691A (Leiden) mutation in gene of factor V and C677T in gene 5,10
      methylentetrahydrofolatreductase. A family history was collected. Thrombotic
      complications were found in grandmother and aunt (by mother), in sister and
      brother. The latter had also a heterozygous mutation of prothrombin gene. Genetic
      mutations in PAS patients are an additional risk factor of recurrent thrombosis.

PMID- 12471844
TI  - [Difficulties in diagnosis of intermittent porphyria].
AB  - A case of acute intermittent porphyria (AIP) in a woman aged 51 years with a
      lethal outcome is reported. The diagnosis was made late because of insufficient
      knowledge of physicians about this disease. The article gives diagnostic criteria
      and methods of examination in AIP which provide timely diagnosis and adequate
      treatment.

PMID- 12471845
TI  - Demography and the social contract.
AB  - As the most demographically complex nation in the world, the United States faces
      ever more formidable challenges to fulfill its commitment to the democratic
      values of equity and inclusion as the foreign-born share of the population
      increases. Immigration, the major source of the contemporary diversification of
      the population, provides several lessons about how to prepare for that future
      within a framework of social justice and how to realign recent demographic trends
      with cherished democratic principles. A review of historical and contemporary
      controversies about the representation of the foreign-born and alien suffrage
      both illustrates the reemergence of ascriptive civic hierarchies and highlights
      some potentially deleterious social and civic consequences of recent demographic
      trends.

PMID- 12471846
TI  - Assessing immigrant policy options: labor market conditions and postreform
      declines in immigrants' receipt of welfare.
AB  - Researchers infrequently have focused on assessing the degree to which the
      changes in welfare policy legislated during the 1990s have affected immigrants'
      receipt of welfare. Using data from the March Current Population Survey, we
      analyze the contribution of local labor market conditions to the explanation of
      relative declines in immigrants' receipt of welfare from 1994 to 2000. The
      results of a series of models that included labor market-area and state fixed
      effects indicate that employment and unemployment rates across metropolitan
      statistical areas and states account for at least one-third of the observed
      relative decrease among immigrants. The policy implications of the findings are
      discussed.

PMID- 12471847
TI  - Diversity and change in the institutional context of immigrant adaptation:
      California schools 1985-2000.
AB  - This article brings attention to a structural dimensions of the schooling context
      that may affect the incorporation of immigrant youths. Using administrative data
      about students in California public schools, we found that Spanish-speaking,
      limited English-proficient (LEP) children have become increasingly more likely to
      attend schools with low-income, minority, and LEP students than other non-LEP and
      LEP groups. Nearly all the change in school composition can be attributed to
      statewide shifts in the composition of the school-aged population. But
      compositional changes have disproportionately occurred in schools attended by
      Spanish-speaking LEP students as a result of district-level patterns of
      segregation by income, race/ethnicity, and language.

PMID- 12471848
TI  - Private schools and "Latino flight" from black schoolchildren.
AB  - Several recent studies provided evidence that white students' choice between
      private and public schools is influenced by the racial composition of the local
      student population. None of these studies, however, examined whether Latinos are
      also fleeing to private schools in response to black schoolchildren. I explore
      the "Latino-flight" hypothesis using data from the National Educational
      Longitudinal Study and a recently released confidential data set from the
      National Center for Educational Statistics. In probit regressions for the
      probability of Latinos attending private schools, I found a large, positive, and
      statistically significant coefficient on the black share of the school-age
      population. The coefficient estimates imply that a 10-percentage point increase
      in the black share increases the probability of private school attendance by
      25.7% to 33.2% among Latino 8th graders and 35.2% to 52.2% among Latino 10th
      graders. I interpret these results as providing evidence of "Latino flight" from
      public schools into private schools. I did not find evidence that Latinos respond
      differently to black schoolchildren than do whites.

PMID- 12471849
TI  - Whites who say they'd flee: who are they, and why would they leave?
AB  - Questions have been raised about whether white flight--one factor contributing to
      U.S. residential segregation--is driven by racial, race-associated, or neutral
      ethnocentric concerns. I use closed- and open-ended survey data from the Multi
      City Study of Urban Inequality to explore who says they would leave and their
      reasons for doing so. Thirty-eight percent of white respondents said they would
      leave one of the integrated neighborhoods, with Detroiters and those endorsing
      negative racial stereotypes especially likely to do so. When asked why they might
      leave, whites focused on the negative features of integrated neighborhoods.
      Expressions of racial prejudice were also common, but neutral ethnocentrism rare.
      The results of an experiment asking about integration with Asians and Latinos are
      also discussed.

PMID- 12471850
TI  - A regression approach to estimating the average number of persons per household.
AB  - In the housing unit method, population is calculated as the number of households
      times the average number of persons per household (PPH), plus the population
      residing in group quarters facilities. Estimates of households and the group
      quarters population can be derived directly from concurrent data series, but
      estimates of PPH have traditionally been based on previous values or estimates
      for larger areas. In our study, we developed several regression models in which
      PPH estimates were based on symptomatic indicators of PPH change. We tested these
      estimates using county-level data in four states and found them to be more
      precise and less biased than estimates based on more commonly used methods.

PMID- 12471851
TI  - Social networks and changes in contraceptive use over time: evidence from a
      longitudinal study in rural Kenya.
AB  - The impacts of social networks on changes in contraception in rural Kenya are
      investigated using special data from a longitudinal household survey. An analytic
      model, informed by detailed knowledge of the setting, yielded estimates that
      indicate that (1) social networks have substantial effects even after unobserved
      factors (e.g., homophily) that may determine social networks are controlled; (2)
      controlling for these unobserved factors may substantially alter the estimated
      effects of networks (these controls were not used in previous studies); (3)
      network effects are important for both men and women; and (4) network effects are
      nonlinear and asymmetric, suggesting that networks provide information primarily
      through social learning, rather than by exerting social influence.

PMID- 12471852
TI  - Fertility and development: evidence from Brazil.
AB  - Using microdata from the Brazilian demographic censuses of 1960, 1970, 1980, and
      1991, aggregated into 518 consistently defined spatial units called microregions,
      we estimated fertility and mortality and constructed indicators of development
      and living conditions in the rural and urban areas of the microregions in each
      census. We then estimated cross-sectional and fixed-effects models to answer
      questions about the degree to which changes in these indicators are associated
      with changes in fertility and whether the relationship between fertility and
      development shifts through time. We found strong and consistent relationships
      between the decline in fertility and measurable changes in social and economic
      circumstances.

PMID- 12471854
TI  - Extracorporeal shockwave therapy for chronic proximal plantar fasciitis.
AB  - Although much enthusiasm surrounds applying extracorporeal shock wave therapy for
      various musculoskeletal conditions, its effects are not well understood and
      warrant continued study. Certain body tissues or organs may be damaged either
      acutely or chronically by ESWT; however, it is unequivocal that lung tissue may
      be damaged. It is theorized that neovascularization is responsible for
      improvement in symptoms of plantar fasciitis. Neovascularization is the direct
      effect of macrophage stimulation through cytokines. ESWT has effects at the
      cellular level--does it interfere with metabolic activity or enhance it? The
      noninvasive nature and minimal complications of appropriately applied ESWT are
      its primary advantages. Symptoms may continue to improve for three weeks to six
      months after treatment; the effects of shock wave therapy seem to be time
      dependent. ESWT is an effective form of treatment for proximal insertional
      plantar fasciitis after exhaustive, conservative forms of treatment have failed.

PMID- 12471853
TI  - Does race matter? Children's height in Brazil and South Africa.
AB  - I examine racial differences in child stunting in mid-1990s South Africa and
      Brazil, two multiracial societies with different histories of legal support for
      racial discrimination. Using data from nationally representative household
      samples linked to community-level measures, the analysis shows that racial
      inequality in the distribution of socioeconomic resources across households and
      communities explains much of the racial difference in stunting in both countries.
      Even after these factors are controlled, however, the results indicate that in
      South Africa, nonwhite children are still at greater risk of growth faltering
      than are white children. The nature of socioeconomic and racial differences in
      children's growth is examined, and major determinants are discussed. These
      findings suggest that although state-sanctioned racism may help to explain the
      greater racial inequality in stunting in South Africa than in Brazil, the
      eradication of a disadvantage for nonwhites will depend on changes in the same
      fundamental socioeconomic inequalities that characterize both nations.

PMID- 12471855
TI  - X-ray evaluation using the X-PODite digital radiograph analyzer. A preliminary
      study.
AB  - The traditional methods of manual radiograph measurement lack standardization and
      are often inaccurate and time consuming. By addressing the documented variables
      that create these inaccuracies, the X-PODite Digital Radiograph Analyzer appears
      to maximize the accuracy, reproducibility, and usefulness of radiographic
      measurements. Additionally, the time required for an evaluation, ease of use, and
      database capabilities of the X-PODite system facilitate thorough clinical
      evaluations and important outcomes research. Although the authors plan to
      evaluate this new system further, opportunities exist for applications and
      studies using X-PODite's HAV, biomechanical, tailor's bunion, and calcaneal
      trauma evaluation options.

PMID- 12471856
TI  - Cost-effective management of recalcitrant diabetic foot ulcers.
AB  - The worldwide increase in prevalence of type 2 diabetes has resulted in a
      parallel increase in diabetic foot ulcers--a pervasive and significant problem
      associated with this disease [2]. Currently, an estimated 10.3 million people
      have been diagnosed with diabetes, while an additional estimated 5.4 million
      people with diabetes remain undiagnosed, representing a sixfold increase in the
      incidence of diabetes over the past four decades [9]. Approximately 15% (more
      than 2 million individuals, based on these estimates) of all people with diabetes
      will develop a lower-extremity ulcer during the course of the disease [10-12].
      While most of these ulcers can be treated successfully on an outpatient basis,
      some will persist and become infected. Ultimately, between 14% and 20% of
      patients with lower-extremity diabetic ulcers will require amputation of the
      affected limb [13-15]. Diabetic foot ulcers can result in staggering financial
      burdens for both the healthcare system and the patient. For example, analysis of
      the 1995 Medicare claims revealed that lower-extremity ulcer care accounted for
      $1.45 billion in Medicare costs and contributed substantially to the high cost of
      care for diabetics, compared with Medicare costs for the general population [5].
      Therapies that promote rapid and complete healing and reduce the need for
      expensive surgical procedures would impact these costs substantially. Results of
      this analysis suggest that becaplermin may ultimately be more cost-effective for
      the treatment of chronic diabetic foot ulcers than other treatment modalities,
      despite its higher initial dollar cost. This finding may be attributed to a
      combination of factors. First, expenses incurred in more prolonged treatment,
      such as office visits and the need for additional dressings, can be avoided when
      healing completes in a shorter period. Second, rapid and complete ulcer healing
      may reduce the incidence of significant morbidities (such as amputation or
      infection) and premature mortality; consequently, the financial burden associated
      with these complications would be reduced. Finally, the value of improved quality
      of life in patients with healed ulcers and the reduction in financial burden for
      patients who return to work cannot be ignored. These promising results warrant
      further investigation in larger controlled clinical studies to define more
      clearly the cost-effectiveness of becaplermin in this patient population.

PMID- 12471857
TI  - Depression and chronic diabetic foot disability. A case report of suicide.
AB  - Evidence at the scene of death and the postmortem examination led the pathologist
      to conclude suicide by intentional insulin overdose. The examination was
      conducted one day after the patient's death. The amount of insulin injected is
      not known, but levels of insulin in the vitreous gel were extremely high. While
      glucose and insulin are more stable in vitreous than in postmortem blood, the
      longer the delay between death and sample collection, the greater the uncertainty
      of the exact concentrations of substances at the time of death [42]. Patients
      with diabetes may have at their disposal the resources to end their lives; misuse
      of insulin and suicide by insulin overdose are presumably underreported events.
      Not only do diabetics have insulin available, but they may also have narcotics,
      tricyclic antidepressants or other drugs that are toxic at high doses. Even in
      the absence of depression, all patients with diabetes face multiple emotional
      issues related to the diagnosis and course of the disease. Diabetes often
      requires significant lifestyle changes, such as diet and physical activity, upon
      its diagnosis. Patients face the possibility of long-term, possibly debilitating,
      complications: vision loss, sexual dysfunction, and amputation. Any podiatrist
      who treats a large number of diabetic patients will encounter the situation of a
      patient at risk of losing a limb. A patient may consciously or unconsciously view
      amputation as punishment; limb loss interferes physically with bodily function
      and has extensive emotional consequences as well. It is important for patients to
      be involved with a healthcare team (including primary care physician, nurse
      educator, ophthalmologist, and podiatrist) that provides support throughout their
      lives [3]. As learned early on in podiatry school, podiatric physicians don't
      treat feet; they treat patients who have foot problems. It is as important to
      know when to refer a patient to the primary care physician or a psychiatrist for
      mental health complaints as it is to know when to refer a patient to an
      orthopedic surgeon for hip pain or to an ophthalmologist for vision problems. We
      do not propose that this patient's diabetic foot disease was the direct cause of
      his depression and suicide; however, the prevalence of depression in the general
      population and its even higher rates in patients with chronic medical illness
      require awareness of these problems by all members of the medical profession.

PMID- 12471858
TI  - Diagnosis and treatment of ankle pain with the use of arthroscopy.
AB  - One of the most common pathologies associated with chronic ankle pain is
      anterolateral ankle impingement secondary to an inversion ankle sprain. An
      average of one ankle sprain per 10,000 people occur every day. After an ankle
      sprain 10% to 50% of patients have some form of chronic ankle pain, which the
      authors consider to be pain that lasts over three months. The use of ankle
      arthroscopy allows us to directly inspect all of the intra-articular structures
      at a magnified view without the need for multiple arthrotomies.

PMID- 12471859
TI  - Behcet's disease: a case report.
AB  - While Behcet's disease is an uncommon presentation to a podiatric clinical
      setting, it is nonetheless a fascinating and poorly understood disease as
      demonstrated by the current and historical research available about the topic.
      Much debate remains about the disease cause, course and treatment goals. Only
      through further research into the specific components of this multisystem disease
      will medicine be more fully able to address the needs of the patient. This
      discussion should offer the podiatric physician an overview of the disease as
      well as available treatment options.

PMID- 12471860
TI  - Pigmented villonodular synovitis. A literature review and unusual case report.
AB  - The literature contains various nomenclature and classifications regarding the
      pigmented villonodular pathology that have proven to be quite confusing. This
      article clarifies this and emphasizes the fact that there is a spectrum of
      inflammatory pathologies that may affect synovial tissue. The primary focus of
      this article is pigmented villonodular Synovitis (PVNS) which refers to joint
      pathology.

PMID- 12471861
TI  - Health promotion advocates: initiation, introducing legislation, and exploring
      for the future.

PMID- 12471862
TI  - The impact of a health education program targeting patients with high visit rates
      in a managed care organization.
AB  - PURPOSE: To determine if a mailed health promotion program reduced outpatient
      visits while improving health status. DESIGN: Randomized controlled trial.
      SETTING: A midsized, group practice model, managed care organization in Ohio.
      SUBJECTS: Members invited (N = 3214) were high utilizers, 18 to 64 years old,
      with hypertension, diabetes, or arthritis (or all). A total of 886 members agreed
      to participate, and 593 members returned the initial questionnaires. The 593
      members were randomized to the following groups: 99 into arthritis treatment and
      100 into arthritis control, 94 into blood pressure treatment and 92 into blood
      pressure control, and 104 into diabetes treatment and 104 into diabetes control.
      MEASURES: Outpatient utilization, health status, and self-efficacy were followed
      over 30 months. INTERVENTIONS: Health risk appraisal questionnaires were mailed
      to treatment and control groups before randomization and at 1 year. The treatment
      group received three additional condition-specific (arthritis, diabetes, or
      hypertension) questionnaires and a health information handbook. The treatment
      group also received written health education materials and an individualized
      feedback letter after each returned questionnaire. The control group received
      condition-specific written health education materials and reimbursement for
      exercise equipment or fitness club membership after returning the 1-year end of
      the study questionnaire. RESULTS: Changes in visit rates were disease specific.
      Parameter estimates were calculated from a Poisson regression model. For
      intervention vs. controls, the arthritis group decreased visits 4.84 per 30
      months (p < 0.00), the diabetes group had no significant change, and the
      hypertension group increased visits 2.89 per 30 months (p < 0.05), the overall
      health status improved significantly (-6.5 vs. 2.3, p < 0.01) for the arthritis
      group but showed no significant change for the other two groups, and coronary
      artery disease and cancer risk scores did not change significantly for any group
      individually. Overall self-efficacy for intervention group completers improved by
      -8.6 points (p < 0.03) for the arthritis group, and the other groups showed no
      significant change. CONCLUSIONS: This study demonstrated that in a population of
      18 to 64 years with chronic conditions, mailed health promotion programs might
      only benefit people with certain conditions.

PMID- 12471863
TI  - Comparing changes in health risk factors and medical costs over time.
AB  - PURPOSE: This study was designed to examine the association between health
      status/behaviors and changes in these measures over time with health costs.
      DESIGN: This study employed a 6-year (1993-1998) retrospective cohort design to
      examine the relationship between health indicator variables, health insurance
      costs, and utilization. The outcome variables of interest were measures of health
      insurance costs and utilization of health care services. SETTING: Public employer
      located in the northeastern United States. SUBJECTS: In all, 1940 employees were
      included in the study on the basis of their membership in the worksite health
      plan and their having complete health indicator data collected during each of the
      two time periods (1993-1995 and 1996-1998). MEASURES: The health insurance data
      were obtained directly from the organization's Third Party Administrator. The
      health indicator variables included blood pressure, cholesterol, body mass index,
      and smoking status. RESULTS: At-risk employees had a greater probability of
      submitting health insurance claims than did no-risk employees in approximately
      70% of the 18 Major Diagnostic Codes that were examined. Higher costs were
      associated with the at-risk classification (mean = $3237 and median = $433) over
      time, and lower costs (mean = $1626 and median = $49) were associated with
      maintaining a no-risk status over time. CONCLUSIONS: These findings support the
      notions that lower health risk and maintaining a no-risk status over time are
      associated with lower health insurance costs.

PMID- 12471864
TI  - Complete health: prevalence and predictors among U.S. adults in 1995.
AB  - PURPOSE: To operationalize, estimate the prevalence, and ascertain the
      epidemiology of complete health. DESIGN: Cross-sectional analyses of self
      reported survey data collected via a telephone interview and a self-administered
      questionnaire. SETTING: Households in the 48 contiguous states in the United
      States in 1995. SUBJECTS: Random-digit dialing sample of 3032 adults between the
      ages of 25 and 74, with a response rate of 61%. MEASURES: Physical illness and
      health were measured with a total of 37 items--a checklist of 29 chronic health
      conditions, a six-item scale of limitations of daily living, and a single item
      for perceived current health and for perceived 5-year change in energy. Mental
      illness and health were measured with the Composite International Diagnostic
      Interview Short Form diagnostic scale of major depression, panic, and generalized
      anxiety disorders and three established multi-item scales of subjective well
      being (emotional, psychological, and social well-being). Completely healthy
      adults have high levels of physical and mental health and low levels of physical
      and mental illnesses; completely unhealthy adults have high levels of physical
      and mental illnesses and low levels of physical and mental health. Incompletely
      healthy adults consisted of two groups: one group is physically healthy (high
      physical health and low physical illness) and mentally unhealthy, and the second
      group is mentally healthy (high mental health and low mental illness) and
      physically unhealthy. RESULTS: Nineteen percent of adults were completely
      healthy, 18.8% were completely unhealthy, and 62.2% had a version of incomplete
      health. Compared with completely unhealthy adults, completely healthy adults are
      likely to be young (25-34 years of age) or old (55-64 and 65-74 years), are
      married, are male, are college educated, and have higher household incomes.
      CONCLUSIONS: Operationalizing complete health highlights objectives for
      increasing the prevalence of complete health, and reducing the prevalence of
      complete ill-health and incomplete health.

PMID- 12471865
TI  - Heart check: the development and evolution of an organizational heart health
      assessment.
AB  - PURPOSE: The purpose of this article is to document the development, testing, and
      application of an organizational assessment tool used to measure employer support
      for heart health. Additional information is presented on its future research and
      applications plan. DESIGN: This article represents the pooling of results from
      multiple studies using a variety of designs, including pilot tests, cross
      sectional analyses, and quasi-experiments. SETTING: Worksites covering the
      spectrum of employers across industry types and size, and throughout all of New
      York State. SUBJECTS: Over 10,000 New York employees and 1000 New York employers
      are represented in the multiple phases of this research. MEASURES: Heart Check is
      a 226-item inventory designed to measure such features in the worksite as
      organizational foundations, administrative supports, tobacco control, nutrition
      support, physical activity support, stress management, screening services, and
      company demographics. Additional side studies used professional judgments and
      behavioral surveys. RESULTS: As an assessment tool Heart Check shows evidence for
      reliability and validity. Applications of the instrument show characteristics
      that define high-scoring companies, quasi standards for New York employers, and,
      when applied during interventions, positive changes in organizational support
      levels. CONCLUSIONS: A relatively inexpensive, easy-to-use, and metrically tested
      instrument exists for measuring the construct of organizational support for
      employee heart health. The instrument shows promise as part of a system to
      enhance heart health through public health-based interventions in the workplace.

PMID- 12471866
TI  - Primary and metastatic intrathoracic germ cell tumors.

PMID- 12471867
TI  - Genetics and biology of male germ cell tumors.
AB  - The application of cytogenetic and molecular genetic techniques to the study of
      germ cell tumors has yielded many clues to the etiology and chemosensitivity of
      these tumors. With the advent of expression profiling and genome-scanning
      technologies, it may be possible to identify molecular markers of germ cell tumor
      outcome and molecular networks important in human development and
      chemotherapeutic response.

PMID- 12471868
TI  - Primary mediastinal malignant germ cell neoplasms: imaging features.
AB  - Mature teratomas are the most frequent primary mediastinal GCN. These are
      spherical multilocular cystic masses with thin, soft tissue septa and frequent
      internal fat attenuation. Primary mediastinal malignant GCNs are rare and should
      be included in the differential diagnosis of anterior mediastinal masses in young
      adult males. Seminomas are typically homogeneous masses indistinguishable from
      lymphomas. Radiologically nonseminomatous malignant germ cell neoplasms are
      large, locally invasive heterogeneous masses with central low-attenuation and
      frond-like peripheral soft tissue. Gonadal primary malignancy and intervening
      abdominal lymph node involvement should be excluded. Tumor markers play a crucial
      role in the initial evaluation of anterior mediastinal masses in these patients
      and in evaluating response to therapy and possible recurrence. Follow-up imaging
      is helpful in detection and characterization of residual neoplasm.

PMID- 12471869
TI  - Presentation and management of benign mediastinal teratomas.
AB  - Mediastinal teratomas are uncommon, making up only about five to ten percent of
      all mediastinal tumors and are thought to occur in approximately 1 in 3400
      hospital admissions. There are many names for this tumor, but the term "benign
      teratoma" is fitting. The word "teratoma" is derived from the Greek word "teras",
      meaning monsters. They have been defined as "tumors that are composed of tissue
      that is foreign to the organ or anatomic site in which they arise" Alternatively,
      mediastinal teratomas may arise from cells adjacent to the third or fourth
      brachial cleft. Whatever the cell of origin, these tumors have potential to
      express all three of the germ cell layers, ectoderm, mesoderm and neuroderm.

PMID- 12471870
TI  - Diagnosis, staging, and clinical characteristics of the patient with mediastinal
      germ cell carcinoma.
AB  - When an anterior mediastinal mass is found in a young male patient, mediastinal
      germ cell tumors should always be one of the leading diagnostic considerations.
      The staging evaluation and diagnostic procedures should be performed rapidly.
      Every patient with a mediastinal germ cell tumor should be approached with
      curative intent, and appropriate treatment should be initiated as soon as the
      brief diagnostic procedure has been completed. Currently, treatment is curative
      in most patients (> 80%) with pure mediastinal seminoma, even in patients with
      huge mediastinal tumors and evidence of distant metastases. Although the cure
      rate is lower for patients with nonseminomatous germ cell tumors, the overall
      cure rate of 35% to 40% makes these tumors one of the most effectively treated
      advanced cancers. Further details regarding the treatment of mediastinal germ
      cell tumors are presented elsewhere in this issue.

PMID- 12471871
TI  - The pre and post chemotherapy pathologic spectrum of germ cell tumors.

PMID- 12471872
TI  - Chemotherapeutic and surgical strategies for germ cell tumors.
AB  - Testicular cancer has become a model for a curable neoplasm. Studies of cisplatin
      combination chemotherapy performed by the author's group allow the following
      conclusions: (1) short-duration, intensive induction therapy with the most active
      agents in optimal dosage is more important than maintenance therapy; (2) a modest
      dose escalation increases toxicity without improving therapeutic efficacy; (3) it
      is possible to develop curative salvage therapy for refractory germ cell tumors;
      and (4) preclinical models predicting synergism, such as vinblastine plus
      bleomycin or cisplatin plus etoposide, have clinical relevance. Testicular cancer
      has also become a model for new drug development. Cisplatin has been approved by
      the US Food and Drug Administration for testis and ovarian cancer and VP-16 and
      ifosfamide for refractory germ cell tumors. The success of these studies confirms
      the importance of the continued search for new investigational drugs in all solid
      tumors.

PMID- 12471873
TI  - Surgical techniques and outcomes for primary nonseminomatous germ cell tumors.
AB  - Patients with primary mediastinal nonseminomatous germ cell tumors are usually
      young men with large anterior mediastinal masses. The diagnosis can usually be
      established with measurement of serum tumor markers and a fine-needle aspiration
      biopsy. The mainstay of treatment is cisplatin-based chemotherapy. Resection of
      the residual postchemotherapy mass is usually necessary and is performed even
      with persistently elevated tumor markers if a clean resection is possible. The
      finding of necrotic tumor predicts long-term survival, whereas persistent germ
      cell cancer has a less favorable prognosis.

PMID- 12471874
TI  - Imaging of intrathoracic metastases of nonseminomatous germ cell tumors.
AB  - Radiologic imaging is crucial in the evaluation of intrathoracic metastatic
      nonseminomatous germ cell tumors. Helical CT is the workhorse of radiologic
      staging and is sensitive in the detection of parenchymal nodules and mediastinal
      lymphadenopathy. CT may also demonstrate other less common sites of metastatic
      disease. Although, currently, no radiologic procedure is effective in
      distinguishing viable tumor or teratoma from residual fibrosis and necrosis,
      cross-sectional imaging remains essential in the presurgical evaluation of
      potential metastatic disease. FDG PET and CT-guided needle biopsy may be useful
      in select, high-risk patients.

PMID- 12471875
TI  - Surgical techniques for nonseminomatous germ cell tumors metastatic to the lung.
AB  - NSGCT is a curable disease, even when metastases are present at the time of
      diagnosis. Surgery serves as adjuvant therapy to initial treatment with
      chemotherapy but complete resection of residual postchemotherapy disease plays a
      critical part in offering patients a long-term cure. A variety of surgical
      techniques and approaches are appropriate for pulmonary metastasectomy in this
      patient population, which can be accomplished with excellent results when the
      extent of disease and the patient's preoperative medical condition are carefully
      considered.

PMID- 12471876
TI  - Surgical techniques for testicular nonseminomatous germ cell tumors metastatic to
      the mediastinum.
AB  - Since 1980, the author and his colleagues have performed over 400 thoracic
      surgical procedures to remove residual mediastinal disease after cisplatin-based
      chemotherapy in nearly 300 patients with testicular nonseminomatous germ cell
      tumors [6]. Presurgical planning is individualized and may require coordination
      with urologic and head and neck surgeons to minimize the overall number of
      surgical procedures while maximizing exposure. Careful and systematic dissection
      can remove teratomatous residual disease from major blood vessels and
      intrathoracic nerves with minimal morbidity. The operative mortality rate has
      been low (1%), which is not unexpected in these otherwise young and healthy
      patients. The 10-year survival rate has been 78% from the time of diagnosis with
      removal of benign residual mediastinal disease pathologically consisting of
      either necrosis or teratoma. This success justifies an aggressive thoracic
      surgical approach in these cases. Commonly, multiple surgical procedures are
      required to remove bilateral or multiple levels of residual mediastinal disease
      or disease that presents during long-term follow-up. Prolonged survival seems
      possible following the resection of limited areas of persistent nonseminomatous
      germ cell tumors or nonseminomatous germ cell tumor degeneration into non-germ
      cell cancer within the mediastinum. Salvage surgery to remove chemotherapy
      refractory mediastinal disease represents a situation in which significantly
      poorer long-term survival is anticipated; however, an aggressive surgical
      approach is justified in select patients.

PMID- 12471877
TI  - The future of therapy for nonseminomatous germ cell tumors.
AB  - This article has reviewed recent advances in understanding the molecular
      mechanisms of germ cell transformation, germ cell tumor differentiation, and germ
      cell tumor chemotherapy sensitivity and resistance. Future developments should
      include the following: The use of high-throughput techniques to assess tumor
      biology and evaluate new markers will allow more sophisticated assessment of
      prognosis. Future therapy will use oligonucleotide chips, perhaps specific to
      germ cell tumors or gene products associated with drug resistance, to assign
      treatment (radiation, RPLND, chemotherapy). The pathways associated with
      metastases and resistance will either replace or amplify the current risk
      algorithms and the clinician's ability to select therapy. The same high
      throughput techniques will identify critical molecules and pathways, providing
      new specific treatment targets. Cell cycle-specific targets are an ideal focus of
      study, because genes abrogating normal cell cycle control and promoting germ cell
      tumorigenesis are increasingly identified. In germ cell tumors, CCND2 and KIT are
      open to study. Molecular and genetic markers of differentiation are additional
      resistance markers and should be a focus of study. In this context, the treatment
      of malignant transformation and the prediction of teratoma at metastatic sites
      will take on a greater importance. Over the past 2 decades, the treatment of germ
      cell tumors has become well-defined. Further improvement requires that
      investigators find new markers corresponding to tumor phenotype. This achievement
      will prevent unnecessary treatment in patients destined to have a favorable
      outcome, and will target biologically unfavorable or resistant disease for new
      therapy developed specifically to target the molecular or genetic defects that
      disrupt normal cell cycle control.

PMID- 12471878
TI  - Assessing patient satisfaction and quality of care through observation and
      interview.
AB  - The purpose of this study was to investigate patient satisfaction using an in
      depth approach rather than the more common patient survey method. The authors
      conducted patient interviews and participant-oriented observations between
      patients, family members, and medical staff in a large teaching hospital to
      assess patients' perceptions of the quality of care provided on a medical
      surgical unit. The observations were classified according to the Donabedian model
      of quality of care: technical care, interpersonal care, and amenities of care.
      Technical interactions (92.5%, or n = 123) were most common, followed by
      interpersonal interactions (5%, or n = 7) and interactions related to amenities
      of care (2%, or n = 3). Of the patients interviewed, 89% (n = 40) were satisfied
      with the treatment and quality of care they received. Of the 10% (n = 9) of
      patients who reported dissatisfaction with the hospitalization, most of the
      complaints were related to surgical procedures. Observations and patient
      interviews may provide a more informative and accurate assessment of patient
      satisfaction than a reliance on patient surveys as the sole measure.

PMID- 12471879
TI  - Supervisory power and its influence on staff members and their customers.
AB  - The authors examined supervisors' selective use of legitimate, reward, coercive,
      referent, and expert powers and these power bases' influence on two outcomes: (a)
      employee perception of organizational support and (b) employee willingness to
      engage in service recovery activities with the customer. The authors found that
      the supervisor's use of expert, referent, and reward powers were positively
      related to perceived organizational support and that the use of coercive power
      was important in contributing to service recovery initiatives, particularly with
      regard to the employee's empathetic presentation to the customer.

PMID- 12471880
TI  - The educational needs of healthcare managers and executives in the key strategic
      areas of healthcare.
AB  - Management approaches used by many healthcare organizations lag behind those of
      similar competitive industries. The authors of this article report findings from
      an exploratory study of executives' perceptions of training needs in managerial
      strategy. The authors asked executives to rate the level of knowledge required
      for each of five key areas in strategic management and then to assess actual
      levels of knowledge in the field. They found that (a) strategic management is
      vital in this competitive industry, (b) there is a disconnect between what
      healthcare managers should know and what they actually know about the tasks of
      strategic management, and (c) more resources need to be devoted to strategic
      management training and the development of managers at all levels of healthcare
      organizations.

PMID- 12471881
TI  - Collective bargaining in the nursing profession: salient issues and recent
      developments in healthcare reform.
AB  - This article examines practical workplace issues and recent developments related
      to collective bargaining in the nursing profession, with emphasis on issues
      affected by recent reforms in the healthcare industry. Included are examples of
      issues most salient to nurses in their efforts to organize, given the reforms. An
      overview of recent developments in the political, legal, and local areas is also
      provided.

PMID- 12471882
TI  - Hospital executive leadership: a critical component for improving care at the end
      of life.
AB  - End-of-life care and its planning by individuals, in concert with their families
      and professional healthcare givers, pose important social, legal, and ethical
      issues. The authors evaluate the results of a multi-year (1997-2001)
      collaborative effort among representatives of Georgia healthcare providers,
      healthcare payers, and the general public that was designed to (a) improve end-of
      life care through a community-focused field effort to increase public awareness,
      execution, and institutional management of advance directives and (b) impact
      institutional and state government systems and policies around end-of-life care.
      The authors conclude that a proactive presence of senior management is integral
      in implementing systematic change in hospital-based end-of-life care and offer
      practical recommendations to hospital leaders to affect real change in their
      institutions.

PMID- 12471883
TI  - Health services management ethics: a primer.

PMID- 12471884
TI  - Organ donation among African Americans: opportunities for increasing donor rates.

PMID- 12471885
TI  - Introduction: the mechano-biochemistry of molecular motors.

PMID- 12471886
TI  - F1-ATPase: a highly efficient rotary ATP machine.
AB  - A single molecule of F1-ATPase is by itself a rotary motor in which a central
      subunit, gamma, rotates against a surrounding stator cylinder made of alpha 3
      beta 3 hexamer. Driven by the three beta subunits that hydrolyse ATP
      sequentially, the motor runs with discrete 120 degrees steps at low ATP
      concentrations. Over broad ranges of load and speed, the motor produces a
      constant torque of 40 pN.nm. The mechanical work the motor does in the 120
      degrees step, or the work per ATP hydrolysed, is also constant and amounts to 80
      90 pN.nm, which is close to the free energy of ATP hydrolysis. Thus this motor
      can work at near 100% efficiency.

PMID- 12471887
TI  - Motors in muscle: the function of conventional myosin II.
AB  - Solution measurements indicate that actin and myosin alternately bind and
      dissociate during one ATP hydrolysis cycle. Crystallographic studies indicate at
      least two basic conformations of the myosin head exist in which the regulatory
      domain swings through an angle of about 70 degrees. Actin must further modulate
      these conformations, but high-resolution information about the actomyosin
      interface is lacking. One-to-one coupling between the ATPase cycle and a
      mechanical cycle involving myosin-head bending could account for about a 10 nm
      stroke size. At high sliding velocities, discrepancies remain which suggest that
      a myosin head may undergo repetitive interactions with actin for each ATP
      hydrolysed.

PMID- 12471888
TI  - Unconventional myosins.
AB  - Myosins constitute a large superfamily of F-actin-based motor proteins found in
      many organisms from yeast to humans. A phylogenetic comparison of their head
      sequences has allowed them to be grouped into 15 different classes.
      Unconventional myosins can be monomeric or dimeric, but are thought not to form
      filaments, unlike conventional myosin. The double-headed class-V myosins are good
      candidates for transporting vesicles, organelles and (mRNA) particles along actin
      filaments. Class-I myosins are involved in membrane dynamics and actin
      organization at the cell cortex, thus affecting cell migration, endocytosis,
      pinocytosis and phagocytosis. A class-III myosin from Drosophila is required for
      phototransduction and maintenance of the rhabdomere. Class-IX myosins negatively
      regulate the small G-protein Rho, a signalling molecule that regulates the
      organization of the actin cytoskeleton. Protein kinases that are regulated by
      members of the Rho small G-protein family regulate the motor activities of
      different myosins.

PMID- 12471889
TI  - Muscle, myosin and single molecules.
AB  - Whereas we have a great deal of information about myosin, there remain
      fundamental questions about its mechanism (and those of other motor proteins).
      Single-molecule technologies enable us to make measurements we cannot make from
      large ensembles of molecules. Optical tweezers (and similar techniques) are used
      to measure the mechanical aspects of actomyosin interactions, including force,
      displacement and stiffness. Single-molecule fluorescence has been used to observe
      the binding and release of nucleotide by myosins. A combination of these
      measurements has the potential to solve the problem of coupling of ATP hydrolysis
      to mechanical work in motor proteins.

PMID- 12471890
TI  - Motor proteins of the kinesin superfamily: structure and mechanism.
AB  - Kinesins are ATP-driven microtubule motor proteins that produce directed force.
      The kinesin superfamily currently encompasses over 100 eukaryotic proteins
      containing a common motor domain. Both the nucleotide-binding fold and active
      site chemistry of the motor domain are also present in the actin-based motor,
      myosin. Kinesins can be classified into three groups based on the position of
      their motor domains: N-terminal, C-terminal and internal kinesins. Conventional
      kinesin operates as a dimer, walking in a co-ordinated, hand-over-hand fashion
      along a microtubule protofilament. X-ray crystal structures and EM
      reconstructions show major differences in the quaternary arrangement of kinesin
      domains in minus-end- and plus-end-directed motors. Kinesin's neck region,
      directly adjacent to the motor domain, dictates directionality.

PMID- 12471891
TI  - The molecular anatomy of dynein.
AB  - Recent molecular, genetic and functional studies have led to an unparalleled
      growth in our understanding of dynein and the roles played by the various
      polypeptides of these massive macromolecular assemblies. Dyneins are highly
      complex 1-2MDa complexes that function as molecular motor and move the cargo to
      which they are attached towards the minus-end of a microtubule. Dynein motor
      function is a property of the heavy chains, whereas the intermediate chains are
      involved in attachment to the appropriate cargo. In order for useful work to be
      obtained, motor and cargo-binding activities must be tightly controlled. Current
      data suggest that this is the role played by certain accessory light-chain
      proteins. The LC8 is highly conserved and found in many enzyme systems. This
      protein is essential in multicellular organisms. The dynein light chains Tctex1
      and Tctex2 have been implicated in the non-Mendelian transmission of variant
      forms of mouse chromosome 17.

PMID- 12471892
TI  - Microtubule-based transport along axons, dendrites and axonemes.
AB  - MTs in cytoplasmic extensions including axons, dendrites and axonemes serve as
      polarized tracks for vectorial intracellular transport driven by MT-based motor
      proteins. Although axons and axonemes serve very different functions, increasing
      evidence suggests that the transport events, MT organization and the motors
      involved in their formation and function are conserved. Thus, there are obvious
      similarities in the mechanisms of axonal transport and IFT. The MT arrays of
      axons and axonemes are parallel, whereas those of dendrites are anti-parallel,
      but the functional significance of this difference and its consequences for
      mechanisms of transport along these processes are unclear. MT-based motor
      proteins of the dynein and kinesin superfamilies transport a variety of cargos
      including membrane-bound vesicles and macromolecular complexes along MTs of
      axons, dendrites and axonemes, and thus contribute to the formation, maintenance
      and function of these cytoplasmic extensions. Chemosensory neurons in the
      nematode C. elegans represent an appealing system for studying transport events
      along dendrites and axonemes that occur sequentially in a single cell.

PMID- 12471893
TI  - The molecular motors of cilia and eukaryotic flagella.
AB  - Axonemal dyneins occur in two rows (as inner and outer arms) on each of the nine
      doublets. Axonemal dynein binds reversibly to the B-microtubule and has an ATP
      insensitive anchorage to the A-microtubule of the adjacent doublet. The heavy
      chains have the form of globular heads and are responsible for chemo-mechanical
      transduction. The B-tubule-binding site is on a tenuous extension of the head.
      There is only one type of ODA. A 12 nm shift in the globular heads is associated
      with the hydrolysis cycle. There are three types of IDA. No functional changes
      have been recognized in their complex conformation. There is plentiful evidence
      that the axonemal dyneins produce interdoublet displacement. Doubt remains on how
      much sliding occurs per cycle of ATP hydrolysis. The mechanism for transforming
      sliding into bending is not yet explained.

PMID- 12471894
TI  - Translational elongation factor G: a GTP-driven motor of the ribosome.
AB  - EF-G is a large, five-domain GTPase that promotes the directional movement of
      mRNA and tRNAs on the ribosome in a GTP-dependent manner. Unlike other GTPases,
      but by analogy to the myosin motor, EF-G performs its function of powering
      translocation in the GDP-bound form; that is, in a kinetically stable ribosome-EF
      G(GDP) complex formed by GTP hydrolysis on the ribosome. The complex undergoes an
      extensive structural rearrangement, in particular affecting the small ribosomal
      subunit, which leads to mRNA-tRNA movement. Domain 4, which extends from the
      'body' of the EF-G molecule much like a lever arm, appears to be essential for
      the structural transition to take place. In a hypothetical model, GTP hydrolysis
      induces a conformational change in the G domain of EF-G which affects the
      interactions with neighbouring domains within EF-G. The resulting rearrangement
      of the domains relative to each other generates conformational strain in the
      ribosome to which EF-G is fixed. Because of structural features of the tRNA
      ribosome complex, this conformational strain results in directional tRNA-mRNA
      movement. The functional parallels between EF-G and motor proteins suggest that
      EF-G differs from classical G-proteins in that it functions as a force-generating
      mechanochemical device rather than a conformational switch. There are other multi
      domain GTPases that may function in a similar way.

PMID- 12471895
TI  - How to proteins move along DNA? Lessons from type-I and type-III restriction
      endonucleases.
AB  - Protein-mediated communications on DNA are universally important. The
      translocation of DNA driven by a high-energy phosphoryl potential allows long
      stretches of DNA to be traversed without dissociation. Type-I and type-III
      enzymes both use a common DNA-tracking mechanism to move along DNA, dependent on
      the hydrolysis of ATP. Type-I enzymes cleave DNA at distant DNA sites (and in
      some cases close to the site), due to a stall in enzyme motion. This can be due
      to collision with another translocating type-I enzyme or, on circular DNA, due to
      an increased topological load. ATP hydrolysis is considerable, and continues
      after DNA cleavage. Type-III enzymes only cleave DNA proximal to their sites due
      to collision between two endonucleases tracking with defined polarity. ATP
      hydrolysis is less than with the type-I enzymes. Homology to DNA helicases has
      been found within the HsdR and Res subunits. Mutagenesis of the DEAD-box motifs
      affects both ATP hydrolysis and DNA cleavage. This demonstrates a tight link
      between ATPase and endonuclease activities. A strand-separation mechanism akin to
      the DNA helicases is a possibility. The DNA-based motor proteins are
      mechanistically ill-defined. Further study using some of the techniques pioneered
      with classical motor proteins will be needed to reveal more detail.

PMID- 12471896
TI  - Molecular motors in the heart.
AB  - The contractile apparatus of muscle is a highly efficient and adaptable mechanism
      for producing movement and is exploited throughout the animal kingdom. Molecular
      biology is yielding important insights into the intricate functioning of muscular
      contraction, especially in the heart, and in explaining the genesis of inherited
      myopathies. Mutational analyses of the sarcomeric-protein genes in conjunction
      with clinical assessment have shown that certain mutations indicate a more
      serious prognosis in HCM. Detecting these mutations in individuals is important
      for screening other family members for the disease. Understanding the contractile
      apparatus at the molecular level could contribute to the design of more effective
      drugs for treatment of cardiac diseases.

PMID- 12471897
TI  - The roles of unconventional myosins in hearing and deafness.
AB  - The proper expression and function of several unconventional myosins are
      necessary for inner-ear function. Mutations in MYO7A and MYO15 cause deafness in
      humans, and mice. Whereas mutations in Myo6 cause inner-ear abnormalities in
      mice, as yet no human deafness has been found to the result of mutations in MYO6.
      In the mammalian inner ear there are at least nine different unconventional
      myosin isozymes expressed. Myosin 1 beta, VI, VIIa and probably XV are all
      expressed within a single cell in the inner ear, the hair cell. The myosin
      isozymes expressed in the hair cell all have unique domains of expression and in
      some areas, such as the pericuticular necklace, several domains overlap. This
      suggests that these myosins all have unique functions and that all are
      individually targeted within the hair cell. The mouse is proving to be a useful
      model organism for studying both human deafness and elucidating the normal
      functions of unconventional myosins in vivo.

PMID- 12471898
TI  - Protein targeting and translocation at the endoplasmic reticulum membrane-
      through the eye of a needle?
AB  - SRP-dependent and SRP-independent targeting routes deliver precursor proteins to
      the ER membrane translocon. These precursors are translocated into (for membrane
      proteins) and across (for secretory protein) the ER membrane via aqueous channels
      composed of oligomers of the Sec61 complex. Both ends of the ER translocon are
      'gated' and the opening and closing of these gates are closely regulated. The
      lateral exit of hydrophobic polypeptide regions into the phospholipid bilayer
      also appears to be a carefully controlled process. Accessory components are
      transiently associated with active ER translocation sites and modify the nascent
      polypeptide as it appears on the luminal side of the membrane.

PMID- 12471899
TI  - The immunological properties of endoplasmic reticulum chaperones: a conflict of
      interest?
AB  - ER chaperones are abundant and highly conserved proteins that display both
      peptide binding and chaperone activity. Of the family of chaperones present in
      the mammalian ER, GRP94 and calreticulin are apparently unique in their ability
      to elicit CD8+ T-cell responses against components of their bound-peptide pools.
      The ability of GRP94 and calreticulin to elicit CD8+ T-cell responses indicates
      that both proteins bind peptides suitable for assembly on to MHC class-I
      molecules. The capacity to function as molecular chaperones and as peptide
      binding proteins capable of transferring, directly or indirectly, peptides on to
      class-I molecules, indicates that GRP94 and calreticulin participate in the
      regulation of both peptide and polypeptide traffic in the ER. Perspectives on the
      regulation of and interplay between the peptide binding and chaperone activity of
      GRP94 and calreticulin are discussed.

PMID- 12471900
TI  - Glycosylation and protein transport.
AB  - Transport along the secretory pathway is largely signal-mediated. Proteins in the
      secretory pathway can be covalently modified with various carbohydrate
      structures, most commonly O-glycans, N-glycans and/or proteoglycans. Carbohydrate
      modifications can change the physical properties of proteins or can function as
      specific recognition epitopes. Glycosylation can act as an apical sorting signal
      in polarized epithelial cells and provide a signal for surface transport in non
      polarized fibroblasts. Homologues of leguminous plant lectins have been
      identified in yeast, fruitflies, worms and humans. Intracellular lectins are
      candidate receptors in the secretory pathway to mediate concentration of cargo in
      carrier vesicles.

PMID- 12471901
TI  - Vesicular transport.
AB  - The minimal requirements for COP I and COP II vesicle formation from liposomes
      are the small GTPases Arf1 and Sar1, GTP and the coat complexes themselves. Coat
      nucleating factors including specific GTP-GDP exchange factors, SNAREs and other
      cargo molecules are likely to determine the site of vesicle formation. Tethering
      mediated by long rod-like coiled-coil proteins precedes docking of vesicles with
      their target membrane and contributes to specific recognition of this membrane.
      NSF/Sec18p acts prior to membrane fusion to prime specific SNARE complexes for
      docking of vesicles with their targets, while the SNAREs are likely to be the
      minimal membrane-fusion machinery.

PMID- 12471902
TI  - Functions and origins of the chloroplast protein-import machinery.
AB  - The vast majority of chloroplast proteins are nuclear-encoded and are imported
      into the organelle after synthesis in the cytoplasm. Targeting to chloroplasts is
      mediated by a variety of intrinsic targeting signals that direct the preprotein
      to its proper organelle subcompartment. Translocation at the envelope membrane is
      directed by the interactions of an N-terminal transit sequences on the preprotein
      and a general import machinery composed of the outer-membrane Toc machinery and
      the inner-membrane Tic machinery. The Toc and Tic components interact to bypass
      the intermembrane space and provide direct transport of preproteins from the
      cytoplasm to the stroma. There are at least four targeting pathways to the
      thylakoid membrane, the cpSec pathway, the delta pH pathway, the cpSRP pathway
      and the spontaneous pathway. These pathways require distinct intrinsic targeting
      signals, and apparently evolved to accommodate the translocation of classes of
      proteins with particular characteristics. Proteins similar to some components of
      the envelope and thylakoid translocation pathways are found in bacterial systems.
      However, a number of components do not have bacterial counterparts and are unique
      to the chloroplast pathways. It therefore appears that the chloroplast
      translocation systems have evolved from membrane-transport systems that were
      present in the original endosymbiont by incorporating proteins necessary to adapt
      to the constraints of endosymbiosis.

PMID- 12471903
TI  - Mechanisms of mitochondrial protein import.
AB  - Mitochondria import most of their proteins from the cytosol. Precursor forms of
      most matrix proteins as well as some IM and IMS proteins are synthesized on
      cytoplasmic ribosomes with N-terminal cleavable signal sequences. Many other
      mitochondrial proteins including IM carrier proteins contain internal targeting
      sequences. Three multisubunit translocases, one in the OM and two in the IM,
      participate in the import process. These translocases co-operate with cytosolic
      chaperones, chaperone-like soluble proteins in the IMS as well as chaperones in
      the matrix. Insertion of carrier proteins into the IM only requires a membrane
      potential. On the other hand, translocation of preproteins across the IM into the
      matrix requires (i) a membrane potential, (ii) GTP hydrolysis, which occurs at
      the outer side of the IM, and (iii) ATP-dependent interactions occurring at the
      matrix side. Following import, the cleavable signal sequence of most preproteins
      is removed in one step by the MPP. In some cases, removal of the signal sequence
      is achieved in two steps; first by MPP and second by either mitochondrial
      intermediate peptidase or by IM peptidases. Imported proteins must be folded
      properly to perform their functions.

PMID- 12471904
TI  - Pore relations: nuclear pore complexes and nucleocytoplasmic exchange.
AB  - NPCs are the sole sites of exchange between the nucleus and cytoplasm. A large
      family of transport factors carry cargo between the nucleus and cytoplasm through
      the NPC. The NPC is a huge symmetric octagonal structure comprised of dozens of
      NUPs. NUPs make many contacts with surrounding structures, including the NE, the
      cytoplasm and nuclear interior. A subset of NUPs contain repeated peptide motifs
      that serve as docking sites for transport factors. The directionality of
      transport is determined by the transport factor, and its interactions with the
      small GTPase Ran and NUPs. Very little is known about how the NPC mediates
      transport, NPC assembly and the NPC's role in regulating transport, but these
      areas of research are beginning to emerge.

PMID- 12471905
TI  - Nuclear transport: never-ending cycles of signals and receptors.
AB  - Proteins transported into and out of the nucleus require amino acid motifs called
      NLSs and NESs, respectively. The amino acid sequences of these signals vary
      considerably. A superfamily of transport receptors has been identified and each
      member contains three transport-related domains. Transport receptors bind to the
      signal sequences, either directly or through adapter proteins, to promote
      nucleocytoplasmic transport. The diversity of signals, receptors and adapter
      proteins suggests that there are many pathways for nuclear entry or exit. The
      direction of transport (into or out of the nucleus) is regulated in part by the
      small GTPase Ran as well as by intrinsic substrate motifs.

PMID- 12471906
TI  - The control of gene expression by regulated nuclear transport.
AB  - Many proteins show distinct nuclear- and cytoplasmic-localization patterns. For
      proteins above the diffusion limit of the NPC, this localization is governed by
      the activity of NLSs and/or NESs contained in the protein. Structural
      modification of proteins can affect NLS and NES activities. Ligand binding,
      phosphorylation and proteolysis are each capable of modifying the
      nucleocytoplasmic distribution of proteins. In the case of transcription factors,
      control of these structural modifications affects access of the transcription
      factor to the chromatin. This management of cellular distribution, in turn,
      regulates gene expression.

PMID- 12471907
TI  - RNA export: insights from viral models.
AB  - The retroviruses export intron-containing RNA. The complex retroviruses encode a
      Rev protein that uses a leucine-rich NES to interact with CRM1 and the U snRNA
      export pathway. Other viruses encode proteins with a Rev-like NES. The type-D
      retroviruses contain a CTE that binds the cellular protein TAP to export intron
      containing RNA through the mRNA pathway. Intronless viral transcripts contain
      post-transcriptionally acting RNA elements that may compensate for the lack of an
      intron. The functions of elements in intronless RNA are not fully understood but
      may be in export and/or 3'-end processing.

PMID- 12471909
TI  - Promoting safe motherhood in the community: the case for strategies that include
      men.
AB  - Although a decade has now passed since the launching of the Safe Motherhood
      Initiative, maternal mortality continues to be the health indicator showing the
      greatest disparity between developed and developing countries. Recently revised
      WHO and UNICEF figures indicate that an estimated 90% of the 585,000 worldwide
      maternal deaths that occur each year take place in sub-Saharan Africa and Asia.
      In terms of the lifetime risk of maternal death, this disparity remains striking:
      1 in 12 women in parts of sub-Saharan Africa, compared with 1 in 4,000 women in
      Northern Europe. In addition, for every woman who dies, an estimated 16-17 will
      suffer from pregnancy-related complications. Research suggests that, in addition
      to biomedical interventions and the strengthening of health care services,
      improving awareness of obstetric complications among members of a pregnant
      woman's immediate and wider social network is an important step in improving her
      chances of survival when such complications occur. Many of the interventions
      implemented so far have focused exclusively on improving women's knowledge and
      practices as they relate to maternal health issues. Nevertheless, it is now
      increasingly being recognised that the actions required to achieve improvements
      in reproductive health outcomes in general, and maternal health in particular,
      should involve communities in the process and encourage men's active
      participation. Despite this, very few studies on risk perceptions or
      interventions to raise community awareness of obstetric risk factors, their
      complications and their consequences have targeted men. The present article
      argues for the development and testing of risk awareness interventions, which, in
      addition to women, target men in their familial and social roles within
      communities and as workers within health care services as a means of improving
      maternal health outcomes.

PMID- 12471908
TI  - Routine screening for HIV infection in booked antenatal women: how justified in
      developing countries?

PMID- 12471910
TI  - Tasting the forbidden fruit: the social context of debut sexual encounters among
      young persons in a rural Nigerian community.
AB  - What circumstances surround the initial sexual encounters of young persons? And
      what are their implications for adolescent sexual and reproductive health status?
      These questions, although rarely raised in reproductive health discourse, appear
      to be critical in broadening the systematic understanding of key issues that
      impose themselves on adolescent sexual and reproductive health. Against this
      background, the present study attempts to use the circumstances surrounding the
      debut sexual encounters of young persons in a rural Nigerian community as an
      entry point to understanding their vulnerability to sexual and reproductive
      health problems. Data for the study were gathered using in-depth interviews of
      180 persons aged 11-25 years. Emerging evidence shows that first sexual encounter
      took place under conditions that exposed young people to infections, disability,
      and even death. The study recommends that there is need to build on the clear
      evidence that good sex and reproductive health education for young persons delay
      the onset of sexual activity and makes it safer when it eventually commences.

PMID- 12471911
TI  - Risk factors in Mozambican women with eclampsia: a case-referent study.
AB  - In Maputo 133 consecutive eclamptic patients were compared with 393 non-eclamptic
      referent women. Significant risk factors for eclampsia were age < or = 18 years,
      household size < or = 3 individuals, unwanted pregnancy, walking to antenatal
      clinics and, in the thrid trimester, headache, foot oedema, hand or face oedema,
      epigastric pain, visual disturbance, ear buzzing and dizziness. Significantly
      more cases than referents reported no blood pressure measurements in antenatal
      clinics. It is concluded that the quality of antenatal clinics can be improved by
      enhanced community awareness of danger signs, by early recognition of risk
      factors and by better management of prodromal symptoms of eclampsia.

PMID- 12471912
TI  - Gender differences in the reasons for participation in spouse sharing among the
      Okun in Nigeria.
AB  - This report examines the reasons for participation in spouse sharing among the
      Okun with a view to identifying some factors that may present particular
      obstacles to women and enhance their vulnerability to the practice. A total of
      1029 sexually active respondents in 5 settlements where spouse sharing is being
      practiced participated in the questionnaire survey aspect of the study, while 82
      respondents participated in the focus group discussions. About 65% of respondents
      reported having ale or alase and were involved in the practice of spouse sharing.
      Reasons for involvement in spouse sharing include the need for economic support,
      sexual satisfaction, increased social status, procreation, the problems of
      separation/divorce and widowhood. The focus group discussions revealed a possible
      exploitation of the gender-based economic weakness of the women by the men in the
      initiation and sustenance of the practice in the Okun communities. It is
      recommended that for any program to achieve a considerable reduction in the
      practice, differences in the reasons for participation in spouse sharing among
      the men and women must be documented with a view to solving those problems that
      compel women to participate.

PMID- 12471913
TI  - Clinicopathological study of carcinoma of the breast in Benin City.
AB  - Morbidity and mortality from breast cancer have continued to be a source of
      concern to surgeons in many countries. Over a period of 10 years--January 1987 to
      December 1996--117 patients presented with carcinoma of the breast at the
      University of Benin Teaching Hospital in Benin City, Nigeria. The case files of
      77 patients were available and were analysed retrospectively. There were 75
      females and 2 males. Sixty seven per cent of the female patients had large and
      grossly advanced lesions. Most of them were multiparous and they practiced
      prolonged breastfeeding. Seventy eight per cent of the patients delayed for over
      3 months before presenting to the hospital. The five-year survival was 8.7%. We
      conclude that carcinoma of the breast is common in this community and that most
      of the patients present late to the hospital.

PMID- 12471914
TI  - Prevalence of sexual activity and outcome among female secondary school students
      in Port Harcourt, Nigeria.
AB  - Sexual activity among 534 Nigerian female secondary school students was studied
      using self-administered questionnaire. Prevalence of sexual intercourse was
      25.7%. There was no significant difference between the junior (48.2%) and senior
      (51.8%) students (p > 0.05). Seventeen (12.4%) students had initiated sexual
      intercourse before 11 years. The frequency of sexual exposure was high, with
      34.3% of the students having intercourse more than once in a week. Pregnancy rate
      among sexually active females was 27.0%, with 24.8% rate of induced abortion.
      Early sexual health education starting from primary school would be helpful in
      influencing the reproductive decisions and sexual behaviour of the students,
      including contraceptive acceptance and usage, to avoid teenage pregnancy.
      Education of parents is also recommended in order to overcome the cultural
      barriers that discourage parents from providing sex education to their children
      at home.

PMID- 12471915
TI  - The relationship between prenatal care and subsequent modern contraceptive use in
      Bolivia, Egypt and Thailand.
AB  - Determinants of modern contraceptive use are usually examined in isolation of the
      effect of exposure to other aspects of health care systems. Maternal interaction
      with organised health service provision during post-conception and postpartum
      stages of reproduction can provide an opportunity to transfer contraceptive
      service information and counselling. We found that living in a community in which
      women have widespread health service contact is related to both prenatal care use
      and subsequent modern contraceptive use. After controlling for effects of living
      in high health service contact areas and various demographic and background
      factors, our results suggest that prior use of prenatal care has a strong
      influence on subsequent use of modern contraception in Bolivia, Egypt and
      Thailand.

PMID- 12471916
TI  - Knowledge, attitude and practice of family planning amongst women in a high
      density low income urban of Enugu, Nigeria.
AB  - A total of 334 Nigerian, non-pregnant women, living in a high density, low-income
      urban area of Enugu, Nigeria, were interviewed on knowledge, attitude and
      practice of family planning. About 97.6% were found literate. Knowledge and
      approval of family planning was high, 81.7% and 86.2% respectively, but the
      practice of family planning was low, as only 20% of the women were on a family
      planning method. The commonest methods for both ever use and current use were
      safe period/Billings, condom, IUCD and injectables. The commonest source of
      family planning information was health workers, while the commonest single reason
      for non-practice of a method was rejection by the husband. It is concluded that
      despite their high level of education/literacy, with the attendant high knowledge
      and approval rate of family planning, the socio-cultural influence of men on
      their wives is a major stumbling block to the use of modern family planning in
      this part of Nigeria. Policy makers should, therefore, increase male involvement
      in family planning programs.

PMID- 12471918
TI  - [Pregnancy among single women in Niamey (Niger)].
AB  - The objectives of this study are to describe the socio-economic profile of single
      mothers and to specify the influence of this status on pregnancy and delivery.
      Between April 1995 and February 1996, a cohort study in Niamey allowed the
      selection of 181 single mothers, matched by age and parity with married pregnant
      women living in the same district. We used the McNemar's and Wilcoxon's statistic
      tests. In parallel, qualitative open interviews were conducted with patients and
      health care providers. Single mothers represent 6.1% of the study population. The
      median age was 19 years and 72% were primiparas. They received some level of
      education, at least primary and were well integrated in their districts. Twenty
      four per cent were employed and 31% had no income. Single mothers' attendance and
      punctuality at prenatal care centre were not as good as married women and also as
      their compliance with iron prophylactic treatment. The mode of delivery was
      identical but the risk of low birthweight infant was 2.4 more frequent in single
      mothers. Finally, knowledge of contraceptive methods and access to them were
      identical, but single mothers used them more frequently than married women.

PMID- 12471917
TI  - Maternal mortality at the University of Nigeria Teaching Hospital, Enugu, before
      and after Kenya.
AB  - A comparative retrospective analysis of maternal deaths at the University of
      Nigeria Teaching Hospital, Enugu, Nigeria, was carried out for two ten-year
      periods--1976-1985 and 1991-2000--in order to evaluate the effect of Safe
      Motherhood Initiative on maternal mortality in the hospital. Variables for the
      two periods were compared by means of the t-test at 95% confidence level.
      Maternal mortality ratio was significantly higher in Period II than in Period I
      (1406 versus 270 per 100,000, p = 0.00). The leading causes of maternal death
      were uterine rupture for Period I and septicaemia for Period II. Although from
      the first to the second ten-year period there was a significant decrease in the
      number of midwives, physicians and nurse anaesthetists, there was more than a
      proportionate decrease in the number of deliveries. There was also increase in
      the incidence of anaemia due to diminished standards of living and in the mean
      decision-intervention interval (1.5 +/- 0.5 versus 5.8 +/- 1.2 hours; p = 0.000)
      as a result of worker dissatisfaction and changes in hospital policies. We
      conclude that since the launching of the Safe Motherhood Initiative, MMR at the
      University of Nigeria Teaching Hospital, Enugu, Nigeria, has increased five-fold
      as a result of institutional delays and a deterioration in the living standards
      of Nigerians, both consequences of a depressed economy. To halt this trend, we
      recommend that the living standard of all Nigerians should be improved.
      Furthermore, healthcare personnel should be motivated through enhanced salaries
      and provision of working materials including efficient mobile telephone services.

PMID- 12471919
TI  - [Family planning among teenage mothers in a Cameroonian centre].
AB  - This study was carried out in Yaounde (Cameroon) in 1995 to determine the
      knowledge, attitude and behaviour of teenage mothers towards family planning. The
      study was based on a questionnaire administered at household level drawn from
      previously determined clusters. It was accomplished by recruiting 462 teenage
      mothers with ages ranging from 14 to 19 years and who had 1 to 3 children. On the
      whole, 93.9% had heard of family planning, 72.5% had heard of family planning
      centres, but only 43% had been to one of these centres at least once. With
      regards to contraceptive prevalence, 62.1% affirmed the use of a contraceptive
      method at the time of the study with periodic abstinence being the most widely
      used (35.9%). Besides the common methods, some teenage mothers made use of herbal
      concoctions and vaginal douching, sometimes with permanganate or the taking of
      tablets. Nineteen per cent of respondents had had between one and four episodes
      of induced abortion. According to these teenagers, the ideal average age for
      first delivery is 19.7 +/- 2.5 years, whereas that of nubility is 22.8 +/- 3.3
      years, a difference of 3 years. This suggests that on the whole, teenage mothers
      believe that first delivery must precede marriage.

PMID- 12471920
TI  - [How do Ivorien rural populations perceive family planning?].
AB  - The government of Cote d'Ivoire has recently adopted its population policy. One
      of the objectives of this policy is to reduce the high rate of population growth
      through family planning. The success of the family planning program will depend
      not only on the strength of effort to be deployed, but also on the acceptability
      of the idea of family planning to the population, given the pronatalist nature of
      the society, especially in rural areas. The aim of this study is to assess the
      acceptability of family planning to the rural population. The study is based on a
      survey conducted in rural areas of the country on various issues including the
      social representation of family planning. Analyses rely on simple methods such as
      frequency tables and cross tabulation. The results show that rural populations,
      somehow, have an open mind towards family planning. They are interested in using
      family planning services if they are provided with them. However, implementation
      of family planning programs in rural areas requires some precautions--birth
      limitation should not be included among the objectives, at least at the beginning
      of the program; a preliminary advocacy program at the level of rural community
      leaders is required; there is need to adapt program strategies to the level of
      infrastructural development of the villages; etc.

PMID- 12471921
TI  - Storage beyond three hours at ambient temperature alters the biochemical and
      nutritional qualities of breast milk.
AB  - The effect of storage on stability of human breast milk was investigated in 30
      lactating mothers. Samples stored for 3, 6 and 24 hours at ambient temperature of
      302K (29 degrees) were analysed for protein, lactose, pH, and microbial content.
      There were significant (p < 0.01) decreases in protein, lactose and pH upon
      storage for 6 and 24 hours, compared with storage for 3 hours as control. The
      mean +/- SEM values for protein for 6 and 24 hours were 15.56 +/- 0.48 and 13.27
      +/- 0.50, compared with 17.26 +/- 0.41 for 3 hours. For lactose, corresponding
      values for 6 and 24 hours were 0.08 +/- 0.005 and 0.07 +/- 0.006, compared with 3
      hours (0.09 +/- 0.005). The pH values were 6.1 +/- 0.09, 5.9 +/- 0.07 in 3, 6 and
      24 hour samples rspectively. The skin floras investigated were Streptococcus
      viridians, Straphylococcus aureus and Staphylococcus albus. The microbial content
      increased with increase in storage time from 3 to 24 hours. The predominant
      bacterial specie was S. Albus, followed by S.viridians and S. aureus. A positive
      correlation (r = 0.453, p < 0.01) between lactose level and pH were obtained.
      These results suggest that breast milk is stable for 3 hours, beyond which
      significant changes occur in its biochemical composition and nutritional quality.
      The implications of these findings are discussed with respect to its consequences
      on their child's survival.

PMID- 12471922
TI  - Plasma cardiolipin in postmenopausal women in mauritius.
AB  - Data concerning the relationship between anti-cardiolipin antibodies and several
      diseases including myocardial infarction are not readily available for Mauritius.
      Anticardiolipin antibodies were measured using commercially available ELISA kits.
      Haematological profiles were measured using a Coulter Counter in the study
      population. Our study revealed significantly higher IgG and IgA levels as well as
      a strong correlation between decreased platelet levels and increased
      anticardiolipin status in the women during postmenopause. It is concluded that
      abnormal cardiolipin level could be an important risk factor for cardiovascular
      accidents among postmenopausal women in Mauritius.

PMID- 12471923
TI  - Induction of labour with intravaginal misoprostol after prior cesarean delivery.

PMID- 12471924
TI  - Gendered socialisation: a neglected issue in adolescent sexual and reproductive
      health in Africa.

PMID- 12471925
TI  - Adolescent reproductive health in Africa: a problem or a priority?

PMID- 12471926
TI  - Gender and decision-making over condom use in two districts in Uganda.
AB  - Based on a survey of couples in long-term unions in Masaka and Lira districts in
      Uganda, we critically examine the role of gender inequality in the domain of
      decision-making about fertility and sex in the discussion and use of condoms.
      First, we document the sexual context and process of condom negotiation from the
      perspectives of women and men. Next, we test the hypothesis that increases in the
      relative influence of women, compared to their male partners, in decision-making
      about sex and fertility should enhance the likelihood of discussion and use of
      condoms. The result point to barriers that exist for both men and women but show
      a clear disadvantage for women. They also suggest that, for both partners, a
      sense of control over fertility has a positive effect on condom use, and that the
      effect of women's empowerment does not seem to diminish the effect of men's
      empowerment.

PMID- 12471927
TI  - The role of MCH and family planning services in HIV/STD control: is integration
      the answer?
AB  - During the mid 1990s, high HIV and sexually transmitted disease (STD) prevalence
      led to calls for the integration of effective services with maternal and child
      health and family planning (MCH/FP) programs. There are advantages and
      disadvantages to integration, but little evidence existed to assess the
      practicalities of implementing this policy. Analysis of policy development for
      integration was conducted in Ghana, Kenya, South Africa, and Zambia. Semi
      structured interviews were conducted with policy-makers at national, provincial
      and district levels and a survey of facilities was undertaken to identify gaps
      between policy intent and implementation. Significant advances had been made at
      the national level to formulate policies to integrate reproductive health and
      primary health care. However, barriers to implementation included entrenched
      HIV/STD and MCH/FP vertical programs; diverse demands on district managers and
      providers, such as on-going institutional reform; and conflicting objectives of
      international donors. Policy-makers need to address conflicting objectives
      between the needs for vertical accountability and the reality of providing
      integrated services. More careful consideration of implementation is required at
      earlier stages of policy design. Increased consultation with those who are to
      implement and provide integrated services is recommended.

PMID- 12471928
TI  - Risk factors associated with maternal deaths in health units in Uganda.
AB  - This study was conducted to assess the magnitude of maternal deaths in health
      units in Uganda, and the risk factors associated with such deaths. A
      retrospective study of maternal deaths in 20 hospitals and 54 randomly selected
      health centres was conducted in 12 randomly selected districts of Uganda. The
      reference period for documenting maternal deaths was September 1992 to September
      1993. The International Classification of Diseases 10 was used to define a
      maternal death. Data on maternal deaths and associated risk factors was obtained
      from admission and patient case notes. SPSS/PC statistical package was used to
      carry out advanced statistical analysis. Log linear analysis was used to rank
      risk factors for maternal deaths. A total of 418 maternal deaths and 75,000 live
      births were recorded, giving a maternal mortality ratio of 557 per 100,000 live
      births. Three hundred and sixty (86.1%) mothers died within one hour of
      admission. The risk factors identified were inadequate antibiotic supply,
      intravenous drug fluids and blood for transfusion in health units; non-use of
      family planning, use of traditional medicine; mothers aged 15-19 and 30-50 years.
      Others included those who had a history of two or more abortions and stillbirths;
      parity of five and above; and living within a distance of more than 10 km to the
      nearest health unit. We conclude that the focus on risk factors for maternal
      deaths have policy implications.

PMID- 12471929
TI  - Risk factors for syphilis among HIV-1 infected pregnant women in Dar es Salaam,
      Tanzania.
AB  - This study was conducted to determine the risk factors for recent (active)
      syphilis among HIV-1 seropositive pregnant women (N = 1058) in Dar es Salaam,
      Tanzania, Recruitment of study participants (N = 1058) was done between April
      1995 and June 1997 at four main prenatal clinics in Dar es Salaam city. Study
      subjects were interviewed to obtain information about potential risk factors, and
      blood and genital specimens were collected for detection of syphilis and other
      genital infections. The prevalence of active syphilis was 5.9%. After adjusting
      for other risk factors, women without their own source of income had a 50% lower
      risk of syphilis (OR = 0.5, 95% CI: 0.3-0.9). The risk of active syphilis was
      significantly increased among women with genital ulceration on examination (OR =
      8.4, 95% CI: 1.5-47.7), and in those with trichomoniasis (OR = 2.2, 95% CI: 1.2
      3.8). HIV-related immunodeficiency was not associated with increased risk of
      syphilis. These results show that syphilis and other genital infections are a
      major problem among HIV infected women. Prevention of syphilis and other genital
      infections is urgently needed in this population.

PMID- 12471930
TI  - Behavioural effects of infant and child mortality on fertility in Kenya.
AB  - This paper analyses the behavioural effects of infant and child mortality on
      birth intervals in Kenya. Analysing the behavioural effects of infant and child
      mortality on fertility independent of its biological effects has been considered
      a difficult task. In this paper, a procedure for analysing these effects
      separately is developed and applied to the 1989 Kenya Demographic and Health
      Survey (KDHS) data. The results of the analysis suggests that women in Kenya
      adopt various strategies such as curtailing the duration of breastfeeding,
      increasing frequency of coitus, and to a lesser extent use of contraception in
      order to replace infant or children who have died or to insure against those who
      are likely to die. These findings suggest the existence of behavioural effects of
      infant and child mortality on fertility in Kenya.

PMID- 12471931
TI  - Population mobility and multi-partner sex in Botswana: implications for the
      spread of HIV/AIDS.
AB  - For cultural and economic reasons, Botswana has one of the most mobile
      populations in the world. People move around the country frequently for
      employment opportunities and because of the nature of the settlement patterns.
      Also, there is extensive multi-partner sexual activity in the country. This study
      analyses the relationship between population mobility and multi-partner sex and
      their implications for the spread of HIV and AIDS in Botswana. The unit of
      analysis is a sample of 292 mobile working in rural and urban settings in four
      selected districts of the country.

PMID- 12471932
TI  - Vaginal discharge: a perceived side effect and minor reason for discontinuation
      in hormonal injectable users in South Africa.
AB  - Poor compliance and high discontinuation rates have been observed in users of
      injectable hormonal contraception in South Africa. The objective of this study
      was to assess the side effects and reasons for discontinuation in new users of
      both depot-medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET
      EN). One hundred and eighty nine women were recruited into a two-year follow-up
      study. At each visit for a repeat injection, users were asked about bleeding
      patterns and side effects. Vaginal discharge, often described as watery in
      consistency, was perceived to be a problem amongst women and their partners. In
      total, one fifth (20%) of women reported an increase in discharge during use of
      the method and three women cited this discharge to be the primary reason for
      discontinuation of the method. This side effect was mainly noted in the first few
      months of use. Health care providers believed that this was a side effect of both
      DMPA and NET-EN, and women who presented with this complaint were rarely
      investigated for presence of sexually transmitted diseases.

PMID- 12471933
TI  - Norplant expansion in Kenya.
AB  - Norplant is a long-acting contraceptive that has been introduced into family
      planning programs all over the world. Its efficacy, safety and acceptability in
      the introductory phases have been widely tested, and most studies point to the
      need for good provider training in insertion and removal; good client counseling
      on side effects, suitable client selection to limit early removal, and attention
      to client access to removal services. Some problems with the method in the
      developed world, and a belief that it is too costly for developing countries,
      have led to a waning of support by international donors. Few studies have
      examined how service delivery expansion in the developing world can minimise and
      address potential problems as well as maintain Norplant's cost-effective edge
      against other methods. We examine the expansion of Norplant services in Kenya
      between 1992 and 1996, specifically in relation to client access to services,
      removal issues, and cost. Well-supervised and careful expansion has resulted in
      quality services being provided at more than 70 sites in the country. Early
      removal is limited, removals seem to have posed few problems, and Norplant offers
      a welcome and cost-effective addition to the family planning method mix.

PMID- 12471934
TI  - Gestational health and predictors of newborn weight amongst pregnant women in
      rural Malawi.
AB  - This study was conducted to provide community-based data on maternal health and
      predictors of newborn weight in rural Malawi. Data were obtained prospectively
      from a community-based cohort of 581 pregnant women who attended an antenatal
      clinic and delivered a term, live-born, singleton infant in Lungwena, rural
      Malawi. Morbidity from infectious diseases and anaemia was common. Maternal
      weight gain in rural Malawi was slower but fundal height gain was comparable to
      that of an affluent western population. The mean +/- SD weight of term newborns
      was 3.2 +/- 0.5 kilograms. A regression model including data from all routine
      investigations explained only 24% of the variance in newborn weights, suggesting
      that routine antenatal measurements had a limited power to predict the size of
      term live-born babies. Maternal parity, initial weight, the duration of pregnancy
      and gestational weight gain were associated with newborn weights and should,
      therefore, be systematically recorded in rural Malawian antenatal clinics.

PMID- 12471935
TI  - Adolescent reproductive health practices in Nigeria.
AB  - Adolescents have become a focal point of discussions of sexuality and
      reproductive health matters because they belong to a most active segment of the
      population and because of practical concerns in resolving problems such as
      unintended pregnancy and sexually transmitted diseases, including HIV/AIDS
      Employing in-depth interviews and focus group discussion techniques, this study
      of 2,510 respondents from four tertiary educational institutions in Nigeria
      examined various forms of reproductive health practices, their origins,
      reproductive health services available in the institutions, and the role of
      gender relations in reproductive health concerns. The findings show that
      respondents engage in a wide range of folk practices and do-it-yourself
      procedures to maintain personal hygiene, prevent and treat STDs, as well as
      prevent and terminate unwanted pregnancies. These practices, which involve the
      use of every day commodities such as lime, antacid and other drugs in particular
      ways, are learnt from and passed on through peers. The practices are considered
      more confidential and are preferred to the reproductive health services in the
      institutions' clinics. There are obvious implications for avoidable
      complications, morbidity and mortality, all of which need to be redressed through
      intervention.

PMID- 12471936
TI  - Experience of sexual coercion among adolescents in Ibadan, Nigeria.
AB  - This study surveyed 1,025 adolescent students and apprentices in Ibadan, Nigeria,
      to document their sexual behaviour and experience of sexual coercion including
      verbal threats, unwanted touch, unwanted kiss, assault, deception, drugging,
      attempted rape, and rape. Sixty five per cent of male and 48% of female
      apprentices were sexually experienced, compared to 32% of male and 24% of female
      students. More males than females reported sex with multiple partners and contact
      with a sex worker while females had exchanged sex for money and gifts. Fifty five
      per cent of all the subjects had been victims of at least one type of sexual
      coercion, the commonest being unwanted kiss and touch of breasts (47%). Although
      both males and females were victims of coercion, females were disproportionately
      affected--68% of female students and 70% of apprentices had experienced one
      coercive behaviour, compared to 42% of male students and 40% of apprentices.
      Female apprentices fared worst, with 19% of them raped. The main perpetrators of
      the coercion were persons well known to the victims including neighbours, peers
      and boy/girlfriends. We recommend multiple intervention programs including skills
      training for young persons, sensitisation workshop for training health workers,
      and media advocacy for the public to challenge stereotypes that favour sexual
      coercion of adolescents.

PMID- 12471937
TI  - Dealing with the risks of unwanted pregnancy and sexually transmitted infections
      among adolescents: some experiences from Kenya.
AB  - Studies have suggested the persistence of risky sexual practices among
      adolescents in Kenya but relatively less is known about the perceptions, norms
      and gender relations that govern the sexual behaviour of adolescent females and
      males, or the strategies they use to deal with the twin risks of unwanted
      pregnancy and STI/HIV infection. This study was, therefore, conducted to explore
      these issues through data drawn from 16 FGDs among 184 rural male and female
      adolescents aged 15-19 years in Makueni District of Eastern Kenya. Findings
      suggest that adolescents are quite aware of risky behaviours and the protective
      role of abstinence, faithfulness to one uninfected partner and condom use.
      However, adolescents face a number of obstacles in translating this knowledge
      into safer sex practices. Misinformation concerning ways to protect themselves
      abound. Both females and males report reticence in communicating about sexual
      matters and contraception with their partners. At the same time, they are
      reluctant to seek condoms in public places for fear of disclosure and reproach.
      Females face difficulties in negotiating safe sex, in reconciling the desire for
      condom use with norms demanding submissiveness and lack of assertiveness in
      contraceptive decision-making. Findings suggest the need for programs that
      promote communication skills among young male and especially female adolescents,
      and that seek to change masculine and feminine gender ideologies and redress
      gender double standards.

PMID- 12471938
TI  - Obstacles to negotiating dual protection: perspectives of men and women.
AB  - This article presents findings from a qualitative study on the perspectives of
      sexually active men and women about the risks of unwanted pregnancy and HIV/AIDS.
      The study found that there is a high level of awareness of the risk of unwanted
      pregnancy and HIV/AIDS. Knowledge of condoms as a method of preventing pregnancy
      and HIV/AIDS is also relatively good. However, there are many real and perceived
      barriers to condom use especially in stable sexual relationships. In stable long
      term relationships, resistance to condom use was found to be strongly related to
      its association with STIs (including HIV/AIDS). Men and women do not see the need
      for condoms in stable, ongoing sexual relationships if a more effective method is
      used for pregnancy prevention. Condom use in such relationships may be seen as a
      clear sign of infidelity. These attitudes represent a major obstacle to the use
      of condoms as a dual method of protection.

PMID- 12471939
TI  - Pre-marital sexual behaviour among out-of-school adolescents: motives, patterns
      and meaning attributed to sexual partnership in rural Tanzania.
AB  - This paper presents data from a qualitative study on pre-marital sexual
      behaviours among out-of-school adolescents residing in rural communities from
      farming and lakeshore settings in Magu District, Northwestern Tanzania. The study
      found that large numbers of out-of-school adolescents are sexually experienced,
      that the period from acquaintance or dating to sexual relations is typically
      short, and that sexual encounters are typically risky. The exchange of money and
      gifts for sex was reported by both female and male adolescents but perception and
      interpretation differed widely. Males perceived that females engage in sex
      largely for material gain while the females saw it as a display, or a partner's
      love or commitment. These findings call for interventions to empower sexual
      negotiation skills among adolescents, promote condom use, and at the same time
      redress gender disparities in expectations and interpretations of sexual
      relationships.

PMID- 12471940
TI  - The forgotten fifty per cent: a review of sexual and reproductive health research
      and programs focused on boys and young men in sub-Saharan Africa.
AB  - This paper reviews existing literature on sexual and reproductive health research
      and programming among boys and young men in sub-Saharan Africa. While there is
      growing body of literature on adolescent and young adult women, much less is
      known about male sexual and reproductive health and its potential connection to
      well being, and in particular the risk of contracting and spreading HIV/AIDS. The
      author's premise is that both societal and individual vulnerability to HIV/AIDS
      infection are heavily influenced by socio-cultural factors and societal norms,
      and that gender and sexuality are among the most powerful of these elements. In
      keeping with this perspective, potential gaps in the literature are identified
      using a modification of Dixon-Mueller's framework, which illustrates how
      sexuality and gender influence reproductive health outcomes. The framework
      focuses on several interrelated elements of sexuality--sexual partnerships,
      sexual acts, sexual meaning, sexual drives and enjoyment, and sexual knowledge
      and awareness.

PMID- 12471941
TI  - "When men speak women listen": gender socialisation and young adolescents'
      attitudes to sexual and reproductive issues.
AB  - This paper discusses findings from separate focus group discussions among boys,
      girls, and parents in two communities in Ghana on the kinds of attitudes
      expressed with regard to specific gender roles and sexual and reproductive
      behaviour. The FGDs also point to some of the ways adolescents recognise sex role
      disparities in their own socialisation and that of other young people. The two
      communities reflect two lineage types, one matrilineal and the other patrilineal.
      The data show that with few exceptions patriarchal attitudes essentially prevail
      across age, sex and lineage type. The paper concludes by suggesting programmatic
      implications for strengthening the abilities of young males to be responsible in
      their sexual relations.

PMID- 12471942
TI  - An additive genetic gamma frailty model for linkage analysis of diseases with
      variable age of onset using nuclear families.
AB  - Many late-onset complex diseases exhibit variable age of onset. Efficiently
      incorporating age of onset information into linkage analysis can potentially
      increase the power of dissecting complex diseases. In this paper, we treat age of
      onset as a genetic trait with censored observations. We use multiple markers to
      infer the inheritance vector at the disease susceptibility (DS) locus in order to
      extract information about the inheritance pattern of the disease allele in a
      pedigree. Given the inheritance distribution at the DS locus, we define the
      genetic frailty for each individual within a nuclear family as the sum of
      frailties due to a putative major disease gene and a polygenic effect due to any
      remaining DS loci. Conditioning on these frailties we use the proportional
      hazards model for the risk of developing disease. We show that a test of linkage
      can be formulated as a test of zero variance due to a specific locus of the
      additive gamma frailties. Maximum likelihood estimation, using the EM algorithm,
      and likelihood ratio tests are employed for parameter estimation and tests of
      linkage. A simulation study presented indicates that the proposed method is well
      behaved and can be more powerful than the currently available allele-sharing
      based linkage methods. A breast cancer data example is used for illustration.

PMID- 12471943
TI  - Correction of the p-value after multiple tests in a Cox proportional hazard
      model.
AB  - We consider a situation which is common in epidemiology, in which several
      transformations of an explanatory variable are tried in a Cox model and the most
      significant test is retained. The p-value should then be corrected to take
      account of the multiplicity of tests. Bonferroni method is often too conservative
      because the tests may be highly positively correlated. We propose an
      asymptotically exact correction of the p-value. The method uses the fact that the
      tests are asymptotically normal to compute numerically the distribution of the
      maximum of several tests. Counting processes theory is used to derive estimators
      of the correlations between tests. The method is illustrated by a simulation and
      an analysis of the relation between concentration of aluminum in drinking water
      and risk of dementia.

PMID- 12471944
TI  - Maximum likelihood inference for multivariate frailty models using an automated
      Monte Carlo EM algorithm.
AB  - We present a maximum likelihood estimation procedure for the multivariate frailty
      model. The estimation is based on a Monte Carlo EM algorithm. The expectation
      step is approximated by averaging over random samples drawn from the posterior
      distribution of the frailties using rejection sampling. The maximization step
      reduces to a standard partial likelihood maximization. We also propose a simple
      rule based on the relative change in the parameter estimates to decide on sample
      size in each iteration and a stopping time for the algorithm. An important new
      concept is acquiring absolute convergence of the algorithm through sample size
      determination and an efficient sampling technique. The method is illustrated
      using a rat carcinogenesis dataset and data on vase lifetimes of cut roses. The
      estimation results are compared with approximate inference based on penalized
      partial likelihood using these two examples. Unlike the penalized partial
      likelihood estimation, the proposed full maximum likelihood estimation method
      accounts for all the uncertainty while estimating standard errors for the
      parameters.

PMID- 12471945
TI  - Sample size calculation for rank tests comparing K survival distributions.
AB  - Rank tests, such as logrank or Wilcoxon rank sum tests, have been popularly used
      to compare survival distributions of two or more groups in the presence of right
      censoring. However, there has been little research on sample size calculation
      methods for rank tests to compare more than two groups. An existing method is
      based on a crude approximation, which tends to underestimate sample size, i.e.,
      the calculated sample size has lower power than projected. In this paper we
      propose an asymptotically correct method and an approximate method for sample
      size calculation. The proposed methods are compared to other methods through
      simulation studies.

PMID- 12471946
TI  - Choice of parametric accelerated life and proportional hazards models for
      survival data: asymptotic results.
AB  - We discuss the impact of misspecifying fully parametric proportional hazards and
      accelerated life models. For the uncensored case, misspecified accelerated life
      models give asymptotically unbiased estimates of covariate effect, but the shape
      and scale parameters depend on the misspecification. The covariate, shape and
      scale parameters differ in the censored case. Parametric proportional hazards
      models do not have a sound justification for general use: estimates from
      misspecified models can be very biased, and misleading results for the shape of
      the hazard function can arise. Misspecified survival functions are more biased at
      the extremes than the centre. Asymptotic and first order results are compared. If
      a model is misspecified, the size of Wald tests will be underestimated. Use of
      the sandwich estimator of standard error gives tests of the correct size, but
      misspecification leads to a loss of power. Accelerated life models are more
      robust to misspecification because of their log-linear form. In preliminary data
      analysis, practitioners should investigate proportional hazards and accelerated
      life models; software is readily available for several such models.

PMID- 12471947
TI  - The correct "ball bearings" data.
AB  - The famous data on fatigue failure times of ball bearings have been quoted
      incorrectly from Lieblein and Zelen's original paper. The correct data include
      censored values, as well as non-fatigue failures that must be handled
      appropriately. They could be described by a mixture of Weibull distributions,
      corresponding to different modes of failure.

PMID- 12471948
TI  - Comparing k cumulative incidence functions through resampling methods.
AB  - Tests for the equality of k cumulative incidence functions in a competing risks
      model are proposed. Test statistics are based on a vector of processes related to
      the cumulative incidence functions. Since their asymptotic distributions appear
      very complicated and depend on the underlying distribution of the data, two
      resampling techniques, namely the well-known bootstrap method and the so-called
      random symmetrization method, are used to approximate the critical values of the
      tests. Without making any assumptions on the nature of dependence between the
      risks, the tests allow one to compare k risks simultaneously for k > or = 2 under
      the random censorship model. Tests against ordered alternatives are also
      considered. Simulation studies indicate that the proposed tests perform very well
      with moderate sample size. A real application to cancer mortality data is given.

PMID- 12471949
TI  - State's hospitals collaborate for disaster preparedness.

PMID- 12471950
TI  - OIG's special advisory bulletin on inducements to beneficiaries.

PMID- 12471951
TI  - New treatment for Meniere's disease.

PMID- 12471952
TI  - Osteoporosis after coeliac disease wrongly excluded in childhood.

PMID- 12471953
TI  - Assessment and management of the patient presenting with snoring.
AB  - BACKGROUND: Snoring is experienced regularly by approximately 30% of male adults,
      of whom one in seven will have obstructive sleep apnoea syndrome. Women
      experience snoring and apnoea at a rate of approximately half of that of men.
      OBJECTIVE: General practitioners have a key role in the management of snoring.
      Patients whose symptoms of excessive sleepiness and loud habitual snoring more
      than three times per week, should alert the GP to the presence of apnoeas.
      DISCUSSION: The co-existence of systemic essential hypertension, especially if
      more than two drugs are required for its control, or any other cardiovascular
      disease, would increase suspicion of significant sleep apnoea. Conservative
      measures such as reduction in weight, alcohol and nasal resistance can be
      instigated in such patients immediately. Patients who have failed conservative
      treatment, or have suspected moderate to severe apnoea, need to be referred to a
      physician trained in sleep disorders for further evaluation and management.
      Snoring represents a trumpeters introduction to the three spectra of sleep
      related breathing disorders. These vary from simple snoring to profoundly severe
      snoring associated with obstructive sleep apnoea syndrome and cardiovascular
      sequelae, through to orthopnoea, paroxysmal nocturnal dyspnoea and fragmented
      sleep associated with unstable or decompensated cardiovascular and/or pulmonary
      disease.

PMID- 12471954
TI  - Parasomnias. Things that go thump in the night.
AB  - BACKGROUND: General practitioners are well versed with patients presenting to the
      surgery with sleep symptoms, however, the approach to evaluating these symptoms
      is often haphazard. Insomnia is the commonest presenting complaint. Sleep apnoea,
      although readily treatable, carries with it significant morbidity and mortality.
      OBJECTIVE: This article aims to highlight those disorders that occur infrequently
      during the night but which interrupt sleep--the parasomnias. DISCUSSION:
      Knowledge of the spectrum of parasomnias and their symptoms usually allows a
      reasonably accurate clinical diagnosis and the assistance of a sleep physician or
      sleep laboratory is not often required. Parasomnias may be classified by the
      sleep phase during which they occur. Nonrapid eye movement (NREM) parasomnias are
      most likely to occur during the first episode of stages 3 and 4 of NREM sleep
      (slow wave sleep) which is approximately one hour after sleep onset. Rapid eye
      movement (REM) sleep density is usually greatest in the last few hours of sleep,
      therefore REM sleep parasomnias are most likely to occur during this time.

PMID- 12471955
TI  - Insomnia. Diagnosis and management.
AB  - BACKGROUND: Insomnia is a complaint of perceived poor sleep quality resulting in
      impairment of daytime function. It is the commonest clinical sleep disorder with
      approximately 6-12% of adults complaining of chronic insomnia. OBJECTIVE: To
      review current knowledge on causes and effects of insomnia and to provide a brief
      evidence based review of management options for the family practitioner.
      DISCUSSION: Patients with insomnia are characterised by excessive arousal and an
      inability to sleep despite reported reduced sleep hours and poor sleep quality.
      Current management approaches are focussed on reducing this 'hyperarousal' and
      its behavioural manifestations by a range of behavioural treatments. Good
      evidence exists for the efficacy of hypnotics for short term insomnia but long
      term data is currently lacking. Nonbenzodiazepine hypnotics (zopiclone, zolpidem)
      have less adverse effects and similar efficacy to benzodiazepines.

PMID- 12471956
TI  - Settling and sleep problems in babies and young children.

PMID- 12471957
TI  - Trends and outcomes for women diagnosed with ovarian cancer in Australia.
AB  - BACKGROUND: Cancer of the ovary is the sixth most common cancer in women and the
      leading cause of death from a gynaecological malignancy. Early disease is
      asymptomatic and often results in a late diagnosis with approximately two-thirds
      of all cases presenting at an advanced stage. OBJECTIVE: To provide an overview
      of ovarian cancer trends and disease management, and the implications of these
      for general practice. DISCUSSION: There has been little change in the incidence
      and mortality of ovarian cancer in the past two decades, despite an increase in
      the proportion of women receiving surgical treatment to manage the disease. The
      aetiology of ovarian cancer remains obscure. There is an urgent need for new
      techniques to be developed that will allow diagnosis to occur at an early stage
      in the disease process if real improvements in morbidity and mortality outcomes
      are to be achieved. The general practitioner has an important role in the initial
      diagnosis of ovarian cancer by assessing female patients' risk of the disease and
      by making the appropriate referral to a gynaecological oncologist.

PMID- 12471958
TI  - The duty of care of GPs and receptionists to treat patients requiring urgent
      medical attention.

PMID- 12471959
TI  - Test your knowledge: pathology quiz. Rash and deafness.

PMID- 12471960
TI  - Test your knowledge: radiology quiz. A case of headache in a liver transplant
      recipient.

PMID- 12471961
TI  - What is Cochrane all about?

PMID- 12471962
TI  - The future of general practitioners in the management of divisions of general
      practice.
AB  - BACKGROUND: The role of divisions of general practice has changed significantly
      since its inception. Divisions have evolved from simply assisting general
      practitioners in their practices and providing complementary support to existing
      health services through project work, to becoming major instruments of
      organisational change. OBJECTIVE: This article looks at the short history of
      divisions of general practice and explores options for the future that may help
      build a better interface between practical medicine and the growing bureaucratic,
      organisational and managerial demands being placed upon divisions. DISCUSSION: In
      the process of the change in the role of divisions we have experienced a paradigm
      clash between the essential work of GPs as effective medical practitioners, and
      their role in divisions as managers and leaders of the wider health care system
      change.

PMID- 12471963
TI  - The importance of prognostic research.

PMID- 12471964
TI  - Dying.

PMID- 12471965
TI  - Are we living in the dark ages? The importance of sunlight.

PMID- 12471966
TI  - Quality in general practice. Some perspectives.

PMID- 12471967
TI  - Post-traumatic stress disorder in a group of Australian general practices.
AB  - BACKGROUND: Some authorities regard post-traumatic stress disorder (PTSD) as a
      well characterised condition that is under diagnosed in general practice. We
      aimed to explore its prevalence in Australian general practice. METHOD: 'Medic
      GP' contains the records of 58,941 patients over a period of six years. We
      searched the database for PTSD and synonyms in individual records, looking for
      diagnostic criteria and comorbidities. RESULTS: Post-traumatic stress disorder
      was diagnosed in 337 patients, an annual incidence of 88/100,000 patients over a
      6.5 year period. Specialists diagnosed 312 (93%) after referral by general
      practitioners. The GPs diagnosed 25 (7%) themselves, of whom only five patients
      (20%) had all seven diagnostic criteria recorded, and only 16% were free of
      comorbidities. DISCUSSION: General practitioners diagnosed PTSD infrequently, and
      at levels lower than that seen in the community. The usual psychiatric criteria
      were seldom recorded. Comorbid conditions were common.

PMID- 12471968
TI  - Hepatitis C caseload and models of care for rural GPs working in northern New
      South Wales.

PMID- 12471969
TI  - The job related burnout questionnaire. A multinational pilot study.
AB  - OBJECTIVE: In preparation for investigating burnout among general practitioners
      internationally, we examined the validity and reliability of an instrument called
      the Maslach Burnout Inventory (MBI). METHOD: Twenty-four members from 16 European
      countries who attended the European General Practice Workshop in Gdansk, Poland
      (Autumn, 2001) were mailed a draft version of the MBI, and asked to administer it
      to a small group of family physicians. CONCLUSION: This pilot study suggests the
      MBI scale is reliable and valid. We believe it of use in identifying GPs at risk
      of, or already experiencing, burnout.

PMID- 12471970
TI  - The measurement of whole-word productions.
AB  - Attempts to measure phonological acquisition have largely focused on segments,
      with less effort made to examine whole-word productions. This article proposes
      four measures designed to estimate a child's whole-word abilities: 1. the
      phonological mean length of utterance, a measure of whole-word complexity for
      both child and target words, 2. the proportion of whole-word proximity, a measure
      of the proximity between the child's word and its target form, 3. The Proportion
      of whole-word correctness, a measure of the number of words produced correctly
      relative to the sample size, and 4. the proportion of whole-word variability, a
      measure of how often a child produces words in distinct phonological shapes. The
      central measure is the Phonological Mean Length of Utterance, which can be used
      to identify a child's stage of acquisition, to assess proximity to target words,
      and to evaluate the complexity of words. The value of the new measures will be
      demonstrated through preliminary applications to a range of contexts; i.e.
      monolingual children acquiring English (five children, 0;11 to 1;5), Cantonese
      (one child, 1;7), and Spanish (5 children, 2;2 to 2;11), bilingual children
      acquiring Hungarian-English (one child, 2;0) and Spanish-English (3 children, 2;4
      to 2;11), children with phonological impairment (eighteen children, 2;11 to 5;3),
      and children with cochlear implants (six children, 4;5 to 7;11).

PMID- 12471971
TI  - Early lexical development in German: a study on vocabulary growth and vocabulary
      composition during the second and third year of life.
AB  - This paper focuses on aspects of early lexical acquisition in German. There have
      been conflicting results in the literature concerning both the pattern of
      vocabulary growth and the composition of the early lexicon. Our study describes
      the development of various categories of words and questions the preponderance of
      nouns in spontaneous speech. 32 children were studied longitudinally through
      recordings made at age 1;1, 1;3, 1;9 and 3;0. The following properties of the
      data were investigated: vocabulary size in relation to age, frequency of word
      use, and distribution of word categories. The results show that use of both types
      and tokens increases with time. A trend analysis indicates an exponential
      increase in vocabulary production in the second year, followed by a further
      expansion. This vocabulary spurt-like pattern can be observed in the use of word
      types and tokens. The findings in regard to vocabulary composition illustrate the
      dynamics present in the development of word categories. In the beginning,
      children use mostly relational words, personal-social words and some onomatopoeic
      terms. These categories are gradually complemented with nouns, verbs, function
      words and other words so that we see a balanced lexicon by 3;0. Trend analyses
      clarify characteristic developmental patterns in regard to certain word
      categories. Our spontaneous speech data does not support a strong noun-bias
      hypothesis.

PMID- 12471972
TI  - Does preemption help children learn verb transitivity?
AB  - Children's acquisition of the transitivity status of novel verbs was examined to
      test whether preemption helps children learn to avoid nonconventional uses of
      verbs. Given that many English verbs alternate between transitive and
      intransitive usage (e.g., break, roll), how do children learn the fixed
      transitive status of verbs such as hit or the fixed intransitive status of verbs
      such as fall? 48 four-year-olds and 48 six- and seven-year-olds learned two novel
      verbs, with one verb modelled as transitive and the other as intransitive.
      Exposure conditions varied the occurrence and type of preemptive evidence
      potentially facilitating learning of the verbs' transitivity status. In
      comparison to a No Preemption group, only six- to seven-year-olds exposed to
      novel verbs in alternative construction (that allowed them to talk about the
      actions from the perspective of the agent or patient without changing the verbs'
      assigned transitivity) produced fewer utterances violating the verbs' fixed
      transitivity. The results identify limits in children's usage of indirect
      negative evidence in acquiring verb argument structure constructions.

PMID- 12471973
TI  - Going, going, gone: the acquisition of the verb 'go'.
AB  - This study investigated different accounts of early argument structure
      acquisition and verb paradigm building through the detailed examination of the
      acquisition of the verb Go. Data from 11 children followed longitudinally between
      the ages of 2;0 and 3;0 were examined. Children's uses of the different forms of
      Go were compared with respect to syntactic structure and the semantics encoded.
      The data are compatible with the suggestion that the children were not operating
      with a single verb representation that differentiated between different forms of
      Go but rather that their knowledge of the relationship between the different
      forms of Go varied depending on the structure produced and the meaning encoded.
      However, a good predictor of the children's use of different forms of Go in
      particular structures and to express particular meanings was the frequency of use
      of those structures and meanings with particular forms of Go in the input. The
      implications of these findings for theories of syntactic category formation and
      abstract rule-based descriptions of grammar are discussed.

PMID- 12471974
TI  - Continuity and development in the acquisition of inversion in yes/no questions:
      dissociating movement and inflection.
AB  - This paper examines two- to five-year-old children's knowledge of inversion in
      English yes/no questions through a new experimental study. It challenges the view
      that the syntax for inversion develops slowly in child English and tests the
      hypothesis that grammatical competence for inversion is present from the earliest
      testable ages of the child's sentence production. The experimental design is
      based on the premise that a valid test of this hypothesis must dissociate from
      inversion various language-specific aspects of English grammar, including its
      inflectional system. An elicited imitation method was used to test parallel,
      lexically-matched declarative and question structures across several different
      verb types in a design which dissociated subject-auxiliary inversion from the
      English-specific realization of the inflectional/auxiliary system. Using this
      design, the results showed no significant difference in amount or type of
      children's errors between declarative (non-inverted) and question (inverted)
      sentences with modals or auxiliary be, but a significant difference for sentences
      with main verbs (requiring reconstruction of inflection through do-support) and
      copula be. The results from sentences with auxiliary be and those with modals
      indicate that knowledge of inversion is present throughout our very young sample
      and does not develop during this time. We argue that these results indicate that
      the grammar of inversion is present from the youngest ages tested. Our results
      also provide evidence of development relevant to the English-specific
      inflectional system. We conclude with a new developmental hypothesis: development
      in question formation occurs in integrating language-specific knowledge related
      to inflection with the principles of Universal Grammar which allow grammatical
      inversion.

PMID- 12471975
TI  - What's the difference between 'toilet paper' and 'paper toilet'? French-English
      bilingual children's crosslinguistic transfer in compound nouns.
AB  - Bilingual acquisition can shed light on the cues children used in acquiring
      language. The purpose of this paper was to examine whether frequency, ambiguity
      or language dominance could explain crosslinguistic transfer in compound nouns.
      Crosslinguistic transfer would appear in the form of compound reversals. 25
      monolingual English children between the ages of three and four years and 25 age
      matched French-English bilingual children were asked to create and indicate their
      understanding of novel compound nouns. In production, the bilingual children
      reversed compounds in English more often than the monolingual children but
      equally often in French and English. In comprehension, there were no differences
      between groups. These results cannot be explained by any previous explanation of
      transfer. Implications for the theory of language acquisition are discussed.

PMID- 12471976
TI  - There is no evidence for a 'no overt subject' stage in early child Spanish: a
      note on Grinstead (2000).
AB  - Grinstead (2000) argues that there is a stage in both Spanish and Catalan
      children's grammatical development when they are restricted to using verbs
      without overt subjects. However, the evidence for a 'no overt subjects' stage in
      early child Spanish is based on very thin data from a single child: Juan between
      the ages of 1;7 and 2;1. In the present note we reanalyse the data from Juan and
      compare it with data from another child Maria at 1;7 and 1;8. Our results show
      that Juan produces his first overt subject during the same session as his first
      non-imperative verb form, and that Maria produces a relatively high proportion of
      verbs with overt subjects in both of her first two transcripts. They thus provide
      no support for the claim that there is a 'no overt subject' stage in early child
      Spanish.

PMID- 12471977
TI  - The countering of overgeneralization.
AB  - Commenting on Goldberg's (1995) 'construction grammar', Tomasello (1998) proposes
      a model of language acquisition in which children move from highly specific
      utterance-event pairings to abstract, verb-general structures. Despite their many
      strengths, models of this kind predict considerably more overgeneralization of
      the argument structures of verbs than seems to occur. In recognition of this, the
      paper explains (and supports with data from a previously unpublished study of 44
      children aged 2;0 to 4;4) how processes which are side effects of the emergence
      of the verb form class could counter the overgeneralizing tendencies. It is
      argued that these processes are consistent not just with the model proposed by
      Tomasello but also (in large part) with the grammatical theory developed by
      Goldberg.

PMID- 12471978
TI  - Word order preferences for direct and indirect objects in children learning
      Korean.
AB  - Pre-school Korean children typically manifest higher comprehension rates on the
      'unmarked' SOV sentences of their language than on the 'scrambled' OSV patterns.
      To date, however, scant attention has been paid to children's ordering
      preferences with respect to direct and indirect objects. The results of an act
      out comprehension experiment involving 40 subjects (aged 4;0 to 7;0) show a
      strong, statistically significant preference for the accusative-dative order,
      despite evidence that the reverse order is more common in mother-to-child speech.
      Two hypotheses are considered, one involving the relationship between word order
      and grammatical relations and the other involving the relationship between word
      order and the types of situations denoted by the sentences in question. The
      results of a follow-up study involving transitive verbs with instrument arguments
      provide strong evidence in favour of the latter hypothesis.

PMID- 12471979
TI  - Patterns of spontaneous production of novel words and gestures within an
      experimental setting in children ages 1;6 and 2;2.
AB  - This study presents an analysis of children's spontaneous production of words and
      gestures during an experimental symbol learning task. Namy & Waxman (1998)
      previously reported that children aged 1;6 interpreted novel arbitrary words
      (e.g., blicket) and manual gestures (e.g., a dropping motion) as names for object
      categories (e.g., fruit) but that at 2;2, children interpreted words as names
      more readily than gestures. Based on this finding and other observational
      evidence of gesture use, it has been suggested that the younger infants have an
      initial general symbolic capacity that encompasses both words and gestures. Over
      time, as infants acquire greater experience with language, words begin to take on
      a greater priority in the infant's communicative repertoire. The current study
      examines this hypothesis by analyzing children's spontaneous production of the
      novel symbols in Namy & Waxman's original task. At 1;6, children rarely produced
      either the novel words or gestures. At 2;2, children frequently produced both
      symbolic forms; however, words were produced in a referential manner while
      gestures were produced in a non-referential manner. These findings are consistent
      with the argument that over time, words supplant gestures as a symbolic medium.

PMID- 12471980
TI  - Comparison, basic-level categories, and the teaching of adjectives.
AB  - We tested 24 caregivers of preschool children to determine whether their
      strategies for teaching novel adjectives are consistent with children's
      demonstrated abilities to learn these words (e.g., Waxman & Klibanoff, 2000). On
      each of four trials, caregivers had to select one of two cards, both of which
      showed a familiar object bearing an unfamiliar property. On the within-basic
      card, the object was accompanied by a second object from the same basic-level
      category; on the across-basic card, this second object came from a different
      basic-level category. Caregivers' task was to choose the card that would be more
      helpful to teach a novel adjective for the unfamiliar property. If the second
      object differed from the first in terms of a novel target property, caregivers (N
      = 12) stated a strong preference for the within-basic card. If the two objects
      agreed in terms of the novel property, caregivers (N = 12) indicated a clear
      preference for the across-basic card. The findings offer new insight into the
      speed and efficiency of lexical development, by revealing that word teachers,
      like word learners (cf. Waxman & Klibanoff, 2000), are sensitive to the
      conditions under which certain contrasts (in property or in basic-level category)
      are effective in promoting the successful acquisition of novel adjectives.

PMID- 12471981
TI  - Pitch modification when interacting with elders: Japanese women with and without
      experience with infants.
AB  - Twenty Japanese-speaking twenty-six- to twenty-seven-year-old women were recorded
      as they conversed with an infant, an elder, or another young adult. When their
      utterances were acoustically compared among the three settings with regard to
      prosodic characteristics, elevated pitch and increased pitch range were found
      when their speech was directed to both the infant and the elder as compared to
      when it was directed to the young adult. The degree to which such modifications
      occurred was greater in those women who were experienced with children than in
      those women who were not experienced. Moreover, the degree of the modification
      showed a highly positive correlation in each participant when the speech was
      directed to the infant and when it was directed to the elder. Prosodic
      modifications of speech styles to infants and to elders are both exaggerated
      consistently through the experience with children.

PMID- 12471982
TI  - The Telemedical Information Society: doctors' playground or a contribution to the
      evolution of healthcare?

PMID- 12471983
TI  - The history of telemedicine.

PMID- 12471984
TI  - The communication revolution goes on--global high-speed networks: setting the
      pace for future multimedia applications.

PMID- 12471985
TI  - Image and video compression: the principles behind the technology.

PMID- 12471986
TI  - Teledermatology delivery modalities: real time versus store and forward.

PMID- 12471987
TI  - Teleteaching tools in dermatology on the Web.

PMID- 12471988
TI  - Telemedical training at the Department of Gynaecology, University Hospital
      Zurich.

PMID- 12471989
TI  - Towards a virtual education in pharmaceutical sciences. An innovative E-learning
      approach.

PMID- 12471990
TI  - Changes patients expect to result from telemedicine.

PMID- 12471991
TI  - Satisfaction of paramedical personnel.

PMID- 12471992
TI  - Economic aspects--saving billions with telemedicine: fact or fiction?

PMID- 12471993
TI  - Secure transfer of medical data over the Internet: from regulatory data
      protection jam to framework-based requirements.

PMID- 12471994
TI  - Potential of telemedicine in primary care.

PMID- 12471995
TI  - Telemedicine for the family doctor.

PMID- 12471996
TI  - Teleradiology.

PMID- 12471997
TI  - Telemedicine applications in surgery.

PMID- 12471998
TI  - Modern telepathology: a distributed system with open standards.

PMID- 12471999
TI  - Telecardiology.

PMID- 12472001
TI  - Telemedicine in ophthalmology.

PMID- 12472000
TI  - Telemedicine in oncology.

PMID- 12472002
TI  - Implementation of a telepsychiatric network in northern Finland.

PMID- 12472003
TI  - Telemedicine and real-time monitoring of climbers.

PMID- 12472004
TI  - Telemedicine in corrections.

PMID- 12472005
TI  - Dermanet--a tailor-made tool for teledermatology....

PMID- 12472006
TI  - Aspects of quality: face-to-face versus teleconsulting.

PMID- 12472007
TI  - Teledermatology in the nursing home.

PMID- 12472008
TI  - A survey among dermatologists in practice about teledermatology.

PMID- 12472009
TI  - Dermatology online with interactive technology (DOIT).

PMID- 12472010
TI  - Telematics-based teaching in dermatology.

PMID- 12472011
TI  - Image archives, audio- and video-sequences for teleteaching.

PMID- 12472012
TI  - Dermatology Course 2000: an interactive multimedia dermatology course for
      students. Programme description and first results.

PMID- 12472013
TI  - Teledermoscopy.

PMID- 12472014
TI  - Teledermatoscopy in daily routine--results of the first 100 cases.

PMID- 12472015
TI  - HistoClinC: a Web-based telemedicine application for clinicopathologic
      correlations in dermatopathology.

PMID- 12472016
TI  - Teledermatology in North America.

PMID- 12472017
TI  - Telemedicine experience in North America.

PMID- 12472018
TI  - Teledermatology in sub-Saharan Africa.

PMID- 12472019
TI  - Telemedicine in Europe.

PMID- 12472020
TI  - Telemedicine in Germany.

PMID- 12472021
TI  - Teledermatology in Switzerland.

PMID- 12472022
TI  - Reaction from a long-term ventilating tube.

PMID- 12472023
TI  - Isolated ethmoid sinus mucocele.

PMID- 12472024
TI  - Saccular cyst.

PMID- 12472025
TI  - Electronystagmography in a patient with recent disequilibrium and a family
      history of otosclerosis.

PMID- 12472028
TI  - Integrated imaging.

PMID- 12472026
TI  - Cerebrospinal fluid fistula associated with an empty sella.

PMID- 12472027
TI  - Evaluation of flaps following pharyngoesophageal reconstruction.

PMID- 12472029
TI  - Hemangioma of the parotid.

PMID- 12472030
TI  - Orbital infection as a complication of sinusitis: are diagnostic and treatment
      trends changing?
AB  - Orbital infection has long been the most common complication of sinusitis. In
      light of our increased knowledge of sinusitis, improved diagnostic tools, and new
      pharmacologic and surgical treatments, we investigated whether trends in
      diagnosis and treatment are changing. We reviewed the charts of all 43 patients
      who had been referred to our institution with orbital complications of sinusitis
      between Jan. 1, 1985, and Dec. 31, 1999. Nine of the 43 patients had been
      diagnosed between Jan. 1, 1985, and Dec. 31, 1990 (mean: 1.5 patients/yr) and 34
      had been diagnosed between Jan. 1, 1991, and Dec. 31, 1999 (mean: 3.8
      patients/yr). Of the 43 patients, 27 had cellulitis and 16 had an abscess (one of
      the 16 had two abscesses--one subperiosteal and one supraorbital). All 17
      abscesses were treated surgically. Five of the 7 abscesses operated on from 1985
      through 1990 were treated via an open external approach, whereas 7 of the 10
      abscesses that were operated on later were treated via an endoscopic approach. We
      conclude that orbital complications of sinonasal origin are being recognized more
      frequently than they were in the past and that endoscopy has supplanted the open
      external approach as the preferred method of drainage.

PMID- 12472031
TI  - Cholangiocarcinoma metastatic to the neck: first report of a case.
AB  - We describe a unique case of a cholangiocarcinoma that metastasized to a cervical
      lymph node--to our knowledge the only such case ever reported. The diagnosis was
      based on fine-needle aspiration cytology and confirmed by excision biopsy. This
      case illustrates the importance of keeping all possible options in mind when
      diagnosing head and neck masses.

PMID- 12472032
TI  - Penetrating trauma to the head and neck from a nail gun: a unique mechanism of
      injury.
AB  - Published reports of nail gun injuries to the head and neck are rare. We describe
      the cases of three patients who sustained nail gun injuries to the head and who
      were managed at our institution. All patients were treated successfully and all
      recovered with minimal morbidity. Any physician who is called on to manage a nail
      gun injury to the head or neck should understand that most likely the patient
      will have sustained a surprisingly limited amount of tissue injury, owing to the
      relatively low velocity of the projectile compared with that delivered by
      firearms. Computed tomography and selective angiography can play a vital role in
      assessing the integrity of relevant vascular structures. Moreover, catheter
      angiography with embolization can be a most useful nonsurgical adjunct to control
      the extent of vascular injury.

PMID- 12472033
TI  - Demyelination of vestibular nerve axons in unilateral Meniere's disease.
AB  - We conducted a study to determine whether vestibular nerves in patients with
      unilateral Meniere's disease whose symptoms are refractory to medical management
      exhibit neuropathologic changes. We also endeavored to determine whether
      retrocochlear abnormalities are primary or secondary factors in the disease
      process. To these ends, we obtained vestibular nerve segments from five patients
      during retrosigmoid (posterior fossa) neurectomy, immediately fixed them, and
      processed them for light and electron microscopy. We found that all five segments
      exhibited moderate to severe demyelination with axonal sparing. Moreover, we
      noted that reactive astrocytes produced an extensive proliferation of fibrous
      processes and that the microglia assumed a phagocytic role. We conclude that the
      possible etiologies of demyelination include viral and/or immune-mediated factors
      similar to those seen in other demyelinating diseases, such as multiple sclerosis
      and Guillain-Barre syndrome. Our findings suggest that some forms of Meniere's
      disease that are refractory to traditional medical management might be the result
      of retrocochlear pathology that affects the neuroglial portion of the vestibular
      nerve.

PMID- 12472035
TI  - Tuberculous otitis media: two case reports and literature review.
AB  - Tuberculous otitis media can be difficult to diagnose because it can easily be
      confused with other acute or chronic middle ear conditions. Compounding this
      problem is the fact that physicians are generally unfamiliar with the typical
      features of tuberculous otitis media. Finally, the final diagnosis can be
      difficult because it requires special culture and pathologic studies. To increase
      awareness of this condition, we describe two cases of tuberculous otitis media
      and we review the literature.

PMID- 12472034
TI  - Bilateral vocal process papillomas: report of a case.
AB  - We describe a case of bilateral vocal process lesions in a 65-year-old man. His
      history was strongly suggestive of vocal process granulomas: previous
      gastroesophageal reflux, intubation, smoking, and oral squamous cell carcinoma.
      Medical management with a proton-pump inhibitor, reflux precautions, voice
      therapy, and adequate hydration yielded no results. Subsequent surgical
      intervention revealed that he had squamous papillomas. We also provide a brief
      review of vocal process granulomas and squamous papillomas.

PMID- 12472036
TI  - Unifocal Langerhans' cell histocytosis and frontal sinus agenesis: report of a
      rare case.
AB  - Unifocal Langerhans' cell histiocytosis of the frontal bone is rare. We report a
      most unusual case of Langerhans' cell histiocytosis of the frontal bone in a
      patient who had been affected by frontal sinus agenesis. We believe this is the
      first reported case of its kind. We also review previously reported cases of
      solitary eosinophilic granuloma of the frontal bone and we discuss its clinical,
      radiologic, and histopathologic features.

PMID- 12472037
TI  - Lower extremity arterial disease. Diagnostic aspects.
AB  - The prevalence of peripheral arterial disease (PAD) continues to increase, with
      recent data suggesting that almost 30% of patients in at-risk populations have
      PAD. Interest in the management of PAD has increased, partly secondary to the
      technologic advancement of devices and procedures capable of treating a wide
      array of vascular disorders via endoluminal techniques. A thorough clinical
      evaluation and accurate noninvasive testing remain the cornerstones of successful
      patient management and will promote improved outcomes through better patient
      selection. The utility of physiologic tests for determination of the presence and
      severity of PAD and more sophisticated imaging studies will allow the
      cardiovascular specialist to make appropriate decisions about management options.
      The currently accepted methods for determining the presence of PAD include a
      historic review of patient symptoms and atherosclerotic risk factors, physical
      examination, and the appropriate use of noninvasive modalities and X-ray digital
      subtraction angiography.

PMID- 12472038
TI  - Magnetic resonance angiographic techniques for the diagnosis of arterial disease.
AB  - Magnetic resonance angiography (MRA) techniques use inherent magnetization
      properties of tissues in combination with pharmacologic contrast agents, such as
      gadolinium, that shorten T1 relaxation time. The availability of powerful
      magnetic field gradients along with a variety of post-processing algorithms make
      MRA possible. MRA is widely used for the diagnosis of disease in a variety of
      vessels, including aorta, carotids, renals, mesenteric, and peripheral vessels.
      Performance of high-quality 3D contrast MRA requires appropriate understanding of
      MRA methodologies, including the critical dependence of bolus timing and ways to
      optimize it. Additionally, recognition of artifacts and learning to avoid them is
      important.

PMID- 12472039
TI  - Approach to the patient with acute limb ischemia: diagnosis and therapeutic
      modalities.
AB  - Good patient outcomes depend on the rapidity and completeness with which re
      establishment of arterial blood flow to the limbs occurs. Patients with a greater
      magnitude of ischemic tissue--such as with an acute aortic occlusion--have worse
      outcomes than patients with a segmental artery occlusion such as a popliteal
      arterial thrombosis. Limb loss is high in any situation in which a delay in
      diagnosis occurs. It is unclear whether or not endovascular therapy will
      supercede traditional surgery because the etiologies of ALI are too broad to make
      sweeping conclusions at this time. The author and others [14,15], including those
      who have promulgated the use of thrombolytic therapy, have come to reasonable
      conclusions regarding how to deal with ALI: The diagnosis of ALI should be
      established rapidly. Determine its classification based on the patient's history
      and physical examination, and promptly institute anticoagulant therapy. Determine
      whether or not the patient should be taken emergently for surgical
      thromboembolectomy or a revascularization procedure versus arteriogram and
      possible thrombolysis. Adjunctive therapy such as antiplatelet agents (e.g.,
      GIIb/IIIa antagonists) and other anticoagulant agents must be better investigated
      before recommendations can be made. Save life over limb. Emergent guillotine
      amputation is sometimes required to save a patient's life.

PMID- 12472040
TI  - Management of intermittent claudication.
AB  - Medical management of PAD is a considerable challenge. Although patients
      typically present with IC, there is a substantial pool of subclinical PAD
      patients. PAD, whether symptomatic or not, confers a marked cardiovascular risk;
      with affected patients dying of heart attack or stroke, identification of index
      patients and aggressive medical treatment can offer health benefits far in excess
      of improvement in IC or related symptoms. Management of risk factors, lifestyle
      interventions, and pharmacologic treatment with agents to provide symptomatic
      relief have a central role in improving function and quality of life and slowing
      the progression to advanced endpoints, such as the rest pain, nonhealing ulcers,
      gangrene, and cardiac death. Surgical or percutaneous revascularization for aorto
      iliac disease provides durable treatment for individuals with disabling symptoms.
      Newer treatments, such as angiogenic growth factor treatments, are being tested
      in clinical trials and seem promising. There are limited treatment choices for
      individuals with predominant infra-popliteal disease. In the future, the
      availability of newer stents and therapies to prevent re-stenosis may extend the
      applicability of endovascular treatment to difficult-to-treat infra-inguinal
      lesions.

PMID- 12472041
TI  - Management of chronic critical limb ischemia.
AB  - The patient with CLI is challenging and requires a multi-disciplinary approach to
      effective management that involves a team of individuals proficient in various
      aspects of vascular disease. Fig. 4 details the approach at the University of
      Michigan's comprehensive vascular medicine program.

PMID- 12472042
TI  - Atherosclerotic renal artery disease.
AB  - Atherosclerotic renal artery stenosis may present with hypertension, renal
      failure (ischemic nephropathy), or congestive heart failure. The prevalence of
      renal artery stenosis is increasing in patients with other manifestations of
      atherosclerosis. The diagnosis is being made more frequently due to better
      screening tests such as duplex ultrasound and magnetic resonance angiography.
      Renal artery stenosis is discovered incidentally during imaging studies performed
      for other reasons. Revascularization should be performed using angioplasty and
      stenting in patients who have hypertension that cannot be adequately controlled
      with medications, in patients with severe bilateral renal artery stenosis or
      stenosis to a solitary functioning kidney and in patients with congestive heart
      failure when no other clear cut cause can be found.

PMID- 12472043
TI  - Abdominal aortic aneurysms. Surgical treatment.
AB  - The purpose of this chapter is to provide a brief overview of the current place
      of open surgical repair for abdominal aortic aneurysms with respect to the
      factors influencing clinical decision-making, the operative techniques most
      frequently used, and some of the complications commonly encountered in the
      postoperative period.

PMID- 12472044
TI  - Endovascular treatment of aneurysmal disease.
AB  - Endovascular repair of abdominal aortic aneurysm using stent grafts that are
      delivered intraluminally by catheters is a less invasive alternative to open
      surgical repair. Endovascular surgery has been studied for over a decade, and
      early results are comparable to open repair. With extended follow-up care,
      however, postoperative complications and graft failures have been reported in
      some patients, resulting in reintervention, conversion to open repair, and death.
      The high incidence of secondary interventions causes some researchers to question
      the durability of endograft repair and emphasizes the need for detailed long-term
      follow-up care. This article describes the evolution of endovascular treatment of
      abdominal aortic aneurysm from its origin to its current state and discusses the
      future direction of endovascular therapy.

PMID- 12472045
TI  - Percutaneous treatment for carotid stenosis.
AB  - Stroke is the leading cause of serious long-term disability in the United States.
      A substantial portion of strokes are caused by atherosclerotic carotid artery
      disease. The conventional risk factors for coronary atherosclerosis are also
      responsible for carotid atherosclerosis. Carotid stenosis is encountered in
      medical practice in either symptomatic or asymptomatic states. In symptomatic
      patients, medical management with antiplatelet agents does not provide adequate
      protection against stroke. Carotid endarterectomy can help reduce the risk of a
      subsequent stroke. Asymptomatic patients with severe carotid stenosis can also
      benefit from surgical intervention if endarterectomy can be performed at a low
      operative risk. In recent years, percutaneous carotid stenting using self
      expanding stents has become popular for the treatment of carotid stenosis.
      Although this initial experience has been reported from a high-risk patient
      population, the results are encouraging, with acceptable periprocedural stroke
      rates. Moreover, emboli protection devices, modern adjuvant pharmacotherapy, and
      modern self-expanding stents were not utilized in these studies. With rapidly
      expanding technology and advances in interventional pharmacology, improvement of
      clinical outcome is likely. Table 3 summarizes current recommendations for
      carotid stenting based on a panel of cardiologists, radiologists, and vascular
      surgeons. At this stage, randomized trials to compare endarterectomy with carotid
      stenting are underway. Cautious optimism is necessary until the optimal
      equipment, emboli protection devices, and adjuvant pharmacotherapies are fully
      investigated. Until then, carotid stenting should be restricted to high-risk
      candidates for carotid endarterectomy, including patients with severe cardiac
      comorbidities, previous neck surgeries or radiation, restenosis after
      endarterectomy, or other technical contraindications for surgery.

PMID- 12472046
TI  - Carotid stenosis: medical and surgical aspects.
AB  - Medical treatment for carotid disease is similar to the treatment of
      atherosclerosis, with some recent data suggesting that there is a benefit to an
      aspirin-dipyridamole combination. CEA has revolutionized the treatment of
      symptomatic and asymptomatic carotid stenosis. This approach remains the gold
      standard for the surgical treatment of carotid artery stenosis, against which
      emerging modalities such as percutaneous carotid stenting should be compared.
      Higher-risk, asymptomatic patients can safely undergo CEA in high-volume centers
      for stenosis greater than 80% as defined by ultrasound.

PMID- 12472047
TI  - Mesenteric arterial occlusive and aneurysmal disease.
AB  - Mesenteric arterial diseases are a heterogeneic group of clinically significant
      illnesses that have become recognized with increasing frequency because of the
      more common imaging of the intestinal circulation when studying both vascular and
      nonvascular diseases of the abdomen. Considerable knowledge exists regarding some
      of these diseases, whereas the understanding of others is anecdotal. It is
      important for clinicians to recognize differences among common ischemic diseases
      and common splanchnic aneurysms.

PMID- 12472048
TI  - Upper extremity arterial disease.
AB  - Upper extremity arterial disease is much less common than lower extremity
      involvement and typically presents as arm claudication, Raynaud's syndrome, rest
      pain, ischemic ulcerations, or gangrene. The disease can reflect an underlying
      systemic disorder. In addition to clinical examination, diagnostic studies
      include noninvasive vascular studies, serologic, immunologic, and hematologic
      studies (when indicated), and selective arteriography. Atherosclerotic disease is
      the most common cause of large vessel obstruction, but it can also cause small
      vessel obstruction by atheromatous embolization or thromboembolism. Treatment
      varies from pharmacological therapy for vasospastic and vasculitic syndromes to
      operative approaches for endarterectomy or bypass of focal lesions. Angioplasty
      and stent techniques also can provide an effective treatment option.

PMID- 12472049
TI  - Molecular approaches for the treatment of atherosclerosis.
AB  - Advances in vascular biology and the study of molecular pathophysiology have
      enabled the design and initial testing of therapeutic principles for
      cardiovascular intervention at the level of gene expression. This approach can
      offer an avenue to greatly impact the onset and progression of vascular disease
      at its roots. Early translations of basic research into human clinical protocols
      might provide novel alternatives for patients without traditional therapeutic
      options and might provide means of improving and prolonging the success of
      standard therapies. As the understanding of the genetic basis of vascular disease
      continues to grow and the tools for in vivo genetic manipulation continue to
      improve, vascular gene therapies might someday become a part of routine patient
      care.

PMID- 12472050
TI  - Intensive process proves invaluable.

PMID- 12472051
TI  - Introducing waste segregation.

PMID- 12472052
TI  - Positive attitudes needed when UCV units fail tests.

PMID- 12472053
TI  - Cathodic protection of steel in concrete.

PMID- 12472054
TI  - Firecode--past, present and future.

PMID- 12472055
TI  - Japanese facilities in focus.

PMID- 12472057
TI  - Radiant panel performance proved.

PMID- 12472056
TI  - Top grade solutions for Norwegian hospital.

PMID- 12472058
TI  - Milton controller introduced.
AB  - Hamworthy Heating has recently introduced the Milton boiler sequence controller,
      a microprocessor based control system designed for use with Hamworthy Sherborne
      modulating boilers and the newly launched Wessex 220M Series of fully modulating
      boilers.

PMID- 12472059
TI  - Printing progression at Portsmouth.

PMID- 12472060
TI  - Darwinian evolution across the disciplines.

PMID- 12472061
TI  - The success of science and social norms.
AB  - In this paper I characterize science in terms of both invisible hand social
      organization and selection. These two processes are responsible for different
      features of science. Individuals working in isolation cannot produce much in the
      way of the warranted knowledge. Individual biases severely limit how much secure
      knowledge an individual can generate on his or her own. Individuals working in
      consort are required, but social groups can be organized in many different ways.
      The key feature of the social organization in science is that only working
      scientists can confer the most important reward in science--use--and scientists
      must use each other's work in order to succeed in realizing this goal. An
      analysis of science as a selection process serves quite a different function.
      Individual scientists strive to come up with novel solutions to significant
      problems. The question then becomes how to be creative. From a selective
      perspective, science as a process involves the production of numerous
      alternatives and a selection among them. A single scientist solving an important
      problem makes science look very efficient. Treating science as a selection
      process casts it in a very different light. In this paper I combine an invisible
      hand mechanism with a selective perspective in order to explain why science is as
      successful as it is. I do not make recourse to evolutionary epistemology in any
      of its traditional senses.

PMID- 12472062
TI  - Life and evolution in computers.
AB  - This paper argues for the possibility of 'artificial life' and computational
      evolution, first by discussing (via a highly simplified version) John von
      Neumann's self-reproducing automation and then by presenting some recent work
      focusing on computational evolution, in which 'cellular automata', a form of
      parallel and decentralized computing system, are evolved via 'genetic
      algorithms'. It is argued that such in silico experiments can help to make sense
      of the question of whether we can eventually build computers that are intelligent
      and alive.

PMID- 12472063
TI  - Darwin, Veblen and the problem of causality in economics.
AB  - This article discusses some of the ways in which Darwinism has influenced a small
      minority of economists. It is argued that Darwinism involves a philosophical as
      well as a theoretical doctrine. Despite claims to the contrary, the uses of
      analogies to Darwinian natural selection theory are highly limited in economics.
      Exceptions include Thorstein Veblen, Richard Nelson, and Sidney Winter. At the
      philosophical level, one of the key features of Darwinism is its notion of
      detailed understanding in terms of chains of cause and effect. This issue is
      discussed in the context of the problem of causality in social theory. At least
      in Darwinian terms, the prevailing causal dualism--of intentional and mechanical
      causality--in the social sciences is found wanting. Once again, Veblen was the
      first economist to understand the implications for economics of Darwinism at this
      philosophical level. For Veblen, it was related to his notion of 'cumulative
      causation'. The article concludes with a discussion of the problems and potential
      of this Veblenian position.

PMID- 12472064
TI  - Built for speed, not for comfort. Darwinian theory and human culture.
AB  - Darwin believed that his theory of evolution would stand or fall on its ability
      to account for human behavior. No species could be an exception to his theory
      without imperiling the whole edifice. The ideas in the Descent of Man were widely
      discussed by his contemporaries although they were far from being the only
      evolutionary theories current in the late nineteenth century. Darwin's specific
      evolutionary ideas and those of his main followers had very little impact on the
      social sciences as they emerged as separate disciplines in the early Twentieth
      Century. Not until the late twentieth century were concerted, sophisticated
      efforts made to apply Darwinian theory to human behavior. Why such a long delay?
      We argue that Darwin's theory was rather modern in respects that conflicted with
      Victorian sensibilities and that he and his few close followers failed to
      influence any of the social sciences. The late Twentieth Century work takes up
      almost exactly where James Baldwin left off at the turn of the century.

PMID- 12472065
TI  - Religious groups as adaptive units.
AB  - This essay provides a sketch of religion as a set of biologically and culturally
      evolved adaptations that enable human groups to function as adaptive units.
      Recent developments in evolutionary biology make such a group-level
      interpretation of religion more plausible than in the past. A brief survey of
      relevant concepts is followed by a relatively detailed interpretation of
      Calvinism as a religious system in which explicit behavioral prescriptions,
      beliefs about God and his relationship with people, and numerous social control
      mechanisms combined to change the city of Geneva from a collection of warring
      factions to a unified population.

PMID- 12472066
TI  - Adaption and evolution. Essay review.

PMID- 12472067
TI  - Obesity and the risk of heart failure.

PMID- 12472068
TI  - Obesity and the risk of heart failure.

PMID- 12472069
TI  - Obesity and the risk of heart failure.

PMID- 12472070
TI  - Obesity and the risk of heart failure.

PMID- 12472071
TI  - Risperidone in children with autism and serious behavioral problems.

PMID- 12472072
TI  - Risperidone in children with autism and serious behavioral problems.

PMID- 12472073
TI  - Availability of neonatal intensive care and neonatal mortality.

PMID- 12472074
TI  - Availability of neonatal intensive care and neonatal mortality.

PMID- 12472075
TI  - Availability of neonatal intensive care and neonatal mortality.

PMID- 12472076
TI  - The pediatric residency match: a worrisome horizon.

PMID- 12472077
TI  - Predictive genetic testing for conditions that present in childhood.
AB  - There is a general consensus in the medical and medical ethics communities
      against predictive genetic testing of children for late onset conditions, but
      minimal consideration is given to predictive testing of asymptomatic children for
      disorders that present later in childhood when presymptomatic treatment cannot
      influence the course of the disease. In this paper, I examine the question of
      whether it is ethical to perform predictive testing and screening of newborns and
      young children for conditions that present later in childhood. I consider the
      risks and benefits of (1) predictive testing of children from high-risk families;
      (2) predictive population screening for conditions that are untreatable; and (3)
      predictive population screening for conditions in which the efficacy of
      presymptomatic treatment is equivocal. I conclude in favor of parental discretion
      for predictive genetic testing, but against state-sponsored predictive screening
      for conditions that do not fulfill public health screening criteria.

PMID- 12472078
TI  - Patient autonomy and the challenge of clinical uncertainty.
AB  - Bioethicists have articulated an ideal of shared decision making between
      physician and patient, but in doing so the role of clinical uncertainty has not
      been adequately confronted. In the face of uncertainty about the patient's
      prognosis and the best course of treatment, many physicians revert to a model of
      nondisclosure and nondiscussion, thus closing off opportunities for shared
      decision making. Empirical studies suggest that physicians find it more difficult
      to adhere to norms of disclosure in situations where there is substantial
      uncertainty. They may be concerned that acknowledging their own uncertainty will
      undermine patient trust and create additional confusion and anxiety for the
      patient. We argue, in contrast, that effective disclosure will protect patient
      trust in the long run and that patients can manage information about uncertainty.
      In situations where there is substantial uncertainty, extra vigilance is required
      to ensure that patients are given the tools and information they need to
      participate in cooperative decision making about their care.

PMID- 12472079
TI  - Patently controversial: markets, morals, and the President's proposal for
      embryonic stem cell research.
AB  - This essay considers the implications of President George W. Bush's proposal for
      human embryonic stem cell research. Through the perspective of patent law,
      privacy, and informed consent, we elucidate the ongoing controversy about the
      moral standing of human embryonic stem cells and their derivatives and consider
      how the inconsistencies in the president's proposal will affect clinical practice
      and research.

PMID- 12472080
TI  - Somatostatin analogues in the treatment of endocrine tumors of the
      gastrointestinal tract.
AB  - Somatostatin and its long-acting analogues have been introduced for the treatment
      of endocrine tumours of the gastrointestinal tract as they have been shown to
      effectively control symptoms resulting from excessive hormone release in patients
      with carcinoid, Verner-Morrison and glucagonoma syndromes. This beneficial effect
      is due to the presence of somatostatin receptors in high densities on the
      majority of endocrine tumours. The symptomatic effect is less pronounced in
      insulinomas, since 30 - 50% of these tumours lack or express only a few
      somatostatin receptors. With respect to symptomatic control, somatostatin
      receptor subtypes 2 and 5 are the most important and the currently available long
      acting analogues octreotide and lanreotide bind preferentially to these receptor
      subtypes. Long-term studies have shown that somatostatin analogues are safe and
      that the most important adverse advent is the development of gallstones. The
      antiproliferative potency of somatostatin and its analogues in vitro and in
      experimental tumour models prompted a number of studies in patients with
      metastatic endocrine tumours that are generally unresponsive to conventional
      chemotherapeutic protocols. Stabilisation of tumour growth lasting for months to
      a few years was the most favourable result, occurring in 30 - 70% of patients.
      However, definite proof of antiproliferative potency in man is still pending
      since placebo-controlled studies are not available. Radioligand therapy based on
      111Indium, 90Yttrium and 177Lutetium coupled to somatostatin analogues via
      bifunctional chelators is currently under investigation with promising data
      concerning long-lasting control of symptoms and tumour growth from Phase I
      trials.

PMID- 12472081
TI  - Theory skepticism and moral dilemmas.
AB  - Moral-theory skepticism is not an option in any sort of thinking that could
      actually be used in resolving dilemmas in applied ethics, since its
      characteristic doctrines entail positions that in practice often will lead to a
      kind of paralysis in in moral reasoning, where persons faced with having to
      decide what to do in particularly difficulty cases are unable to rule out the
      most implausible conclusions. Moral-theory skepticism thus makes it difficult to
      formulate decision-making procedures that will provide guidance in action, and,
      so, seems not to succeed as a fully coherent account of moral reasoning.

PMID- 12472082
TI  - What should IRBs consider when applying the privacy rule to research?

PMID- 12472083
TI  - Bioethics and cloning, part I.

PMID- 12472084
TI  - Contribution of histidine residues to oligomerization of theta-toxin
      (perfringolysin O), a cholesterol-binding cytolysin.
AB  - Theta-toxin (perfringolysin O) modified by diethyl pyrocarbonate, a histidine
      specific reagent, lost its hemolytic activity. The modified toxin retains the
      activities of binding to and insertion into cholesterol-containing membranes but
      lacks the ability to form oligomers. These results suggest that histidine
      residues of theta-toxin contribute their share to cytolysis, especially the
      oligomerization process.

PMID- 12472085
TI  - [Reduction of severe gastro-intestinal complications after the use of
      celecoxib:evidence available in the literature].

PMID- 12472086
TI  - An internal racism.

PMID- 12472087
TI  - Psychiatric ethics.
AB  - Psychiatric ethics spans several overlapping domains, including the guidelines
      for ethical research in psychiatry, the professional ethics required in the
      practice of psychiatry, and a broader set of moral and ethical problems and
      dilemmas distinctive to, or at least magnified by, the mental health care
      setting. Reviewed here are selected issues arising in the last two domains, some
      seemingly inevitable components of mental disorder and its cultural history and
      others resultant from recent changes and discoveries. Even as science explains
      and demystifies mental disorder, it is concluded, new ethical problems will
      continue to arise in psychiatry and certain recalcitrant problems will likely
      persist.

PMID- 12472088
TI  - [Is primary care specialization of child care of any benefit?].

PMID- 12472089
TI  - Morals, suicide, and psychiatry: a view from Japan.
AB  - In this paper, I argue that within the Japanese social context, the act of
      suicide is a positive moral act because the values underpinning it are directly
      related to a socially pervasive moral belief that any act of self-sacrifice is a
      worthy pursuit. The philosophical basis for this view of the self and its
      relation to society goes back to the writings of Confucius who advocated a life
      of propriety in which being dutiful, obedient, and loyal to one's group takes
      precedence over the desires of the individual selves that make up the group. I
      argue that this philosophical perspective poses formidable challenges to Japanese
      psychiatry (which accepts a contrary western perspective) because, as western
      psychiatry is based on the concept of autonomous individuality, the Japanese
      conceive of the self as socially embedded. Because suicide in Japan is viewed as
      a potentially honorable, virtuous, and even beautiful act of self-sacrifice
      expressing one's duty to one's group, the western perspective is quite foreign to
      the Japanese self-conceptual framework. Therefore, since Japanese psychiatry and
      law have embraced the western medical tradition of viewing suicide as a non
      rational response to mental illness, which runs counter to the cultural view that
      suicide is a moral (and rational) act, I argue that western explanations of
      suicide present significant cross-cultural problems for Japanese psychiatry.

PMID- 12472090
TI  - Supporting irrational suicide.
AB  - In this essay, we present three case studies which suggest that sometimes we are
      better off supporting a so-called irrational suicide, and that emotional or
      psychological distress--even if medically controllable--might justify a suicide.
      We underscore how complicated these decisions are and how murky a physician's
      moral role can be. We advocate a more individualized route to end-of-life care,
      eschewing well-meaning, principled, generalizations in favor of highly
      contextualized, patient-centered approach. We conclude that our Western
      traditions of promoting reasoned behavior and life themselves may at times be
      counter-productive.

PMID- 12472091
TI  - Case study 4: a patient with an old myocardial infarction.

PMID- 12472092
TI  - A phenomenological account of users' experiences of assertive community
      treatment.
AB  - Assertive community treatment (ACT) is a widely propagated team approach to
      community mental health care that 'assertively' engages a subgroup of individuals
      with severe mental illness who continuously disengage from mental health
      services. It involves a number of interested parties--including clients, carers,
      clinicians and managers. Each operates according to perceived ethical principles
      related to their values, mores and principles. ACT condenses a dilemma that is
      common in psychiatry. ACT proffers social control whilst simultaneously holding
      therapeutic aspiration. The clients' perspective of this dilemma was studied in
      interviews with 12 clients using the 'grounded theory' approach. Results suggest
      that clients' disengagement is as much a historical and cultural phenomenon as a
      result of lack of insight. Many clients had experienced rejection of early help
      seeking behaviour and all had been subject to coercive interventions. These
      coercive interventions were experienced as an attack on identity. All felt that
      their voice had not been listened to in previous interactions with psychiatric
      services. Consequentially the clients had an increased level of arousal around
      issues of power, which needs to be incorporated when examining the ethics of
      community psychiatry. Traditional notions of the difference between persuasion
      and coercion--for example--may need to be adapted for this client group. Results
      are compared with the provider perspective. We conclude that the perspectives
      differ on two key dimensions. Such an empirical approach to examining psychiatric
      ethics may ensure that we incorporate the subjectivities of various interested
      parties in the clinical decision-making process.

PMID- 12472093
TI  - Reflections on determining competency.
AB  - Psychiatrists are the health care professionals most frequently called upon to
      determine the competence of a patient to refuse treatment. The motives for
      determining competency vary in morally significant ways. This paper explores what
      I term 'the ideal motivational situation' for determining a patient's competency:
      a desire to respect the patient's autonomy, a desire to promote the patient's
      overall best interests, and a belief that when these two motives conflict the
      patient's autonomy should not be dismissed out of hand as a partial patient
      interest which is naturally outweighed by the totality of his or her interests. I
      claim that in a liberal, democratic society autonomy ought to trump best
      interests and be the sole criterion of patient competence. I conclude by offering
      an essentially aesthetic criterion for determining autonomy.

PMID- 12472094
TI  - Cardiovascular adverse effects of coxibs.
AB  - (1) All nonsteroidal antiinflammatory drugs (NSAIDs), including coxibs, can
      worsen arterial hypertension and heart failure. (2) Combining a standard NSAID
      with a vitamin K antagonist increases the risk of bleeding. The same applies to
      coxibs. (3) Available data point to a higher risk of severe cardiovascular events
      with rofecoxib than with naproxen. (4) There is no reason to postpone aspirin
      therapy at antiplatelet doses in patients who are also receiving another NSAID.
      Rofecoxib should not be used in patients with coronary disease

PMID- 12472095
TI  - Vigabatrin and visual field disorders.

PMID- 12472096
TI  - Severe ulcers on celecoxib.

PMID- 12472097
TI  - Hypokalaemia and hyponatraemia due to indapamide.

PMID- 12472098
TI  - French dapsone survey.

PMID- 12472099
TI  - Paediatric pharmacovigilance.

PMID- 12472100
TI  - Treatment of postherpetic neuralgia: tricyclic antidepressants still the
      reference.
AB  - (1) Pain generally disappears when herpes zoster lesions have healed, but the
      risk of postherpetic neuralgia, though it is low, increases with age. (2)
      Antivirals prescribed during the acute phase do not reduce the risk of
      postherpetic neuralgia, but they do reduce its duration. (3) Common non specific
      analgesics such as paracetamol seem inadequate against postherpetic neuralgia.
      Amitriptyline and desipramine, despite their limited efficacy, are the reference.
      Gabapentin, although somewhat less effective, is a possible second line option.
      It is unclear how long treatment should last.

PMID- 12472101
TI  - Fibrosis due to ergot derivatives: exposure to risk should be weighed up.
AB  - (1) Ergot derivatives are used for a variety of indications, including migraine,
      Parkinson's disease, endocrine disorders, and cognitive and neurosensory deficits
      in elderly people. (2) Fibrosis is a common complication of treatment with ergot
      derivatives. (3) Retroperitoneal fibrosis is the commonest form. Pleuropulmonary
      and pericardial fibrosis also occur. (4) Cardiac valve damage has been linked to
      some ergot derivatives. (5) Fibrosis occurs during long-term treatment. (6)
      Renal, pulmonary and cardiac complications can be serious. The fibrosis is often
      reversible if the drug is stopped quickly. (7) In practice, this risk of serious
      adverse effects tips the scales against these drugs for poorly established
      indications such as cognitive and neurosensory deficits in elderly people. The
      possibility of drug induced fibrosis should be considered at the first sign of
      renal, cardiac or pulmonary fibrosis in a patient on ergot derivatives.

PMID- 12472102
TI  - Performing phase III clinical trials: never an easy task.

PMID- 12472103
TI  - Celecoxib and the CLASS trial: data massaging by industry.

PMID- 12472106
TI  - [Address of the Vice-rector of Charles University on the 210th anniversary of the
      founding of the General Hospital].

PMID- 12472104
TI  - The war against nicotine and tobacco: new tools?

PMID- 12472107
TI  - Role of cyclooxygenase-2 in breast cancer.
AB  - Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to
      prostaglandin H2, is expressed in normal brain and kidney, activated macrophages,
      synoviocytes during inflammation, and malignant epithelial cells. COX-2
      expression is stimulated by a number of inflammatory cytokines, growth factors,
      oncogenes, lipopolysaccharides, and tumor promoters. There is evidence that COX-2
      plays a key role in tumorigenesis through stimulating epithelial cell
      proliferation, inhibiting apoptosis, stimulating angiogenesis, enhancing cell
      invasiveness, mediating immune suppression, and by increasing the production of
      mutagens. Results of several studies using mouse models of colon cancer and the
      results of clinical trials have shown COX-2 to be a useful target for the
      prevention and treatment of colon cancer. Studies with several other epithelial
      cancers involving different organ sites, e.g., breast, prostate, bladder, lung,
      and pancreas, suggest that COX-2 plays an important role in the pathogenesis of
      these cancers. In this review, we summarize the studies that pertain to the
      involvement of COX-2 in breast cancer. COX-2 overexpression affects the
      physiological processes at different organ sites in a similar manner, although
      specific effectors and targets of COX-2 may differ at different sites. Thus in
      reviewing the data on the involvement of COX-2 in breast cancer, we have also
      considered the findings regarding the role of COX-2 in other organ sites. Studies
      from mouse models of mammary tumorigenesis and from human breast cancer cell
      lines provide evidence that COX-2 overexpression plays an important role in the
      pathogenesis of malignant breast cancer in humans. Because of availability of
      effective and relatively safe COX-2 inhibitors, it should be soon possible to
      evaluate their effectiveness in the clinic for the prevention and treatment of
      breast cancer. It is likely that the COX-2 inhibitors will be effective in the
      treatment regimens involving combination chemotherapies.

PMID- 12472108
TI  - Methods used to study intestinal nutrient transport: past and present.
AB  - BACKGROUND: Vitally important to the future of surgical care is the study of
      nutrition and nutrient uptake. Advances in this field of research have become
      increasingly dependent upon the disciplines of immunology, histology, and
      molecular biology. The fusion of these sciences has deepened our insight into the
      relationship between molecular structure and physiologic function. The ability to
      apply new technologies to this endeavor will enable the surgeon-investigator to
      further widen our understanding of nutrient transport. MATERIALS AND METHODS:
      Medline and current literature review. RESULTS AND CONCLUSIONS: We summarize many
      of the methods used to measure the uptake of nutrients by the intestinal
      epithelium, providing a historical perspective.

PMID- 12472109
TI  - Rationing mental health care: parity, disparity, and justice.
AB  - Recent policy debates in the US over access to mental health care have raised
      several philosophically complex ethical and conceptual issues. The defeat of
      mental health parity legislation in the US Congress has brought new urgency and
      relevance to theoretical and empirical investigations into the nature of mental
      illness and its relation to other forms of sickness and disability. Manifold,
      nebulous, and often competing conceptions of mental illness make the creation of
      coherent public policy exceedingly difficult. Referencing a variety of approaches
      to ethical reflection on health care, and drawing from the empirical literature
      on therapeutic efficacy and economic efficiency, we argue that differential
      rationing, 'disparity,' is unjustifiable.

PMID- 12472111
TI  - [The impact factor].

PMID- 12472110
TI  - Going to the roots of the stem cell controversy.
AB  - The purpose of this paper is to describe the scientific background to the current
      ethical and legislative debates about the generation and use of human stem cells,
      and to give an overview of the ethical issues underlying these debates. The
      ethical issues discussed are 1) stem cells and the status of the embryo, 2) women
      as the sources of ova for stem cell production, 3) the use of ova from other
      species, 4) slippery slopes towards reproductive cloning, 5) the public
      presentation of stem cell research and 6) the evaluation of scientific
      uncertainty and its implications for public policy.

PMID- 12472112
TI  - The embryonic stem cell lottery and the cannibalization of human beings.
AB  - One objection to embryonic stem (ES) research is that it 'cannibalizes' human
      beings, that is, kills some human beings to benefit others. I grant for
      argument's sake that the embryo is a person. Nonetheless, killing it may be
      justified. I show this through the Embryonic Stem Cell Lottery. Whether killing a
      person is justified depends on: (1) whether innocent people at risk of being
      killed for ES cell research also stand to benefit from the research and (2)
      whether their overall chances of living are higher in a world in which killing
      and ES cell research is conducted. I call this kind of killing 'risk reductive.'

PMID- 12472113
TI  - Principles of ethical decision making regarding embryonic stem cell research in
      Germany.
AB  - The availability of embryonic stem (ES) cells isolated from human blastocysts may
      open novel avenues for medical treatment of otherwise incurable diseases. Yet the
      generation of human ES cells requires the destruction of early human embryos.
      This confronts us with the moral problem of whether it is justifiable to
      sacrifice human life in order to treat other human life. This article outlines
      the development of the German debate about research with ES cells and explicates
      the arguments that are central to that debate with respect to the aims and means
      of research with ES cells. With regard to the means, the isolation of ES cells
      from human embryos raises the question of the moral status of the human embryo. A
      restrictive position acknowledges the human dignity of the embryo in its very
      early stage of development and claims that the embryo's life must be protected
      accordingly. In contrast, a gradualist position acknowledges human dignity, and
      therefore the full level of protection, only when the embryo has reached a
      certain stage of development. In addition, the intentions behind the generation
      of human embryos, i.e. exclusively for research purposes, and the mode of
      generating them, i.e. by nuclear transfer technology, have strong ethical
      relevance in the German debate. Based on these results, the ethical reasoning
      underlying the draft of a Stem Cell Act recently passed by the German Parliament
      is outlined.

PMID- 12472114
TI  - Defective apoptosis and tumorigenesis: role of p53 mutation and Fas/FasL system
      dysregulation.
AB  - The transcription factor p53 and the cytokine receptor FasL are two of the most
      famous regulators of cell life, and their alterations can cause a large number of
      pathologies, including cancer. In this review, we focused on how they can
      determine defective apoptosis, one of the causes of tumorigenesis and tumor
      progression. The importance of this knowledge lies in the new perspectives that
      gene therapy can offer to cure cancer.

PMID- 12472115
TI  - Microgravity-induced apoptosis in cultured glial cells.
AB  - Apoptosis is a form of naturally occurring cell death that plays fundamental
      roles during embryonic developement. In adults, it neatly disposes of cells
      damaged by injuries provoked by external causes such as UV radiation, ionisation
      and heat shock. Alteration of the gravity vector may be one of the external
      apoptosis inducers. Neurophysiological impairment signs were seen during space
      flights in astronauts, but very few studies were carried out on the nervous
      system and none at the cellular level. In this study, we submitted cultured C6
      glioma cells to microgravity (0xg) of varying duration, obtained by clinorotation
      in a Fokker three-dimensional clinostat for 15 min, 30 min, 1h, 20h or 32h. After
      30 min at 0xg, numerous nuclei underwent the classical morphological alterations
      (chromatin condensation, nuclear fragmentation, apoptotic bodies) that lead to
      the programmed cell death. After 30 min at 0xg, immunostaining for the enzyme
      caspase-7 was present in the cytoplasm of many cells concurrently with DNA
      fragmentation identified by the TUNEL method. At 32h, the number of apoptotic
      nuclei was much reduced indicating the ability of glial cells to adapt to altered
      gravity.

PMID- 12472116
TI  - DNA immunisation. New histochemical and morphometric data.
AB  - Splenic germinal center reactions were measured during primary response to a
      plasmidic DNA intramuscular injection. Cardiotoxin-pretreated Balb/c mice were
      immunized with DNA plasmids encodmg or not the SAG1 protein, a membrane antigen
      of Toxoplasma gondii. Specific anti-SAG1 antibodies were detected on days 16 and
      36 after injection of coding plasmids. The results of ELISAs showed that the SAG1
      specific antibodies are of the IgG2a class. Morphometric analyses were done on
      serial immunostained cryosections of spleen and draining or non-draining lymph
      nodes. This new approach made it possible to evaluate the chronological changes
      induced by DNA immunisation in the germinal centres (in number and in size).
      Significant increases in the number of germinal centres were measured in the
      spleen and only in draining lymph nodes after plasmid injection, the measured
      changes of the germinal centers appeared to result from the adjuvant stimulatory
      effect of the plasmidic DNA since both the coding and the noncoding plasmid DNA
      induced them. No measurable changes were recorded in the T-dependent zone of
      lymph organs.

PMID- 12472117
TI  - PACAP activated adenylate cyclase in human sweat glands. An ultracytochemical
      study.
AB  - The ultracytochemical localization of adenylate cyclase (AC) was studied after
      stimulation with pituitary adenylate cyclase activating peptide (PACAP) in human
      sweat glands. PACAP stimulated AC in both eccrine and apocrine glands. In the
      secretory cells, enzymatic activity was associated with membranes involved in the
      secretory mechanism. In both glands, the cells of the excretory duct and
      myoepithelial cells presented AC activity. These localizations of enzymatic
      activity suggest a role for PACAP in regulating glandular secretion.

PMID- 12472118
TI  - An immunohistochemical study of pancreatic endocrine cells in SKH-1 hairless
      mice.
AB  - The regional distribution and frequency of the pancreatic endocrine cells in the
      SKH-1 hairless mouse were studied by an immunohistochemical (peroxidase anti
      peroxidase; PAP) method using four types of specific antisera against insulin,
      glucagon, somatostatin and human pancreatic polypeptide (PP). The pancreas of
      mice were divided into three portions; pancreatic islets, exocrine and pancreatic
      ducts. The pancreatic islets were further subdivided into three regions (central,
      mantle and peripheral region) according to their located types of immunoreactive
      cells. In the pancreatic islet portions, insulin-immunoreactive cells were
      located in the central and mantle regions with 84.60 +/- 7.65 and 33.00 +/-
      12.45/100 cells frequencies, respectively, but most of somatostatin-, glucagon-
      and PP-immunoreactive cells were detected in the mantle and peripheral regions.
      In the mantle region, somatostatin-, glucagon- and PP-immunoreactive cells were
      demonstrated with 28.70 +/- 9.91, 52.00 +/- 14.05 and 2.60 +/- 1.51/100 cells
      frequencies, respectively, and showed 6.20 +/- 2.86, 15.30 +/- 5.31 and 21.50 +/-
      10.28/100 cells frequencies, respectively in peripheral regions. However,
      glucagon-immunoreactive cells were also demonstrated in the central regions with
      4.00 +/- 2.83/100 cells frequency. In the exocrine portions, insulin-, glucagon-,
      somatostatin- and PP-immunoreactive cells were demonstrated in the SKH-1 mouse
      with 0.90 +/- 0.74, 0.80 +/- 0.79,4.90 +/- 3.54 and 2.70 +/- 1.34/100 cells
      frequencies, respectively. In the pancreatic duct portions, insulin-, glucagon-
      and somatostatin-immunoreactive cells were demonstrated in the subepithelial
      connective tissues and showed islet-like appearances with 30.30 +/- 14.67, 2.70
      +/- 3.13 and 5.90 +/- 4.23/100 cells frequencies, respectively. However, no PP
      immunoreactive cells were demonstrated in these regions. In conclusion, some
      peculiar distributional patterns of pancreatic endocrine cells were found in the
      SKH-1 hairless mouse.

PMID- 12472119
TI  - Simultaneous demonstration of acid phosphatase and glucose-6-phosphate
      dehydrogenase in mouse hepatocytes. A novel electron-microscopic dual staining
      enzyme-cytochemistry.
AB  - Acid phosphatase (ACPase) and glucose-6-phosphate dehydrogenase (G6PD) play
      important roles in cell biology/disease pathophysiology in various organs
      including the liver. The purpose of the present report is to introduce a new
      enzymecytochemical method to simultaneously demonstrate the subcellular
      localization of ACPase and G6PD within the same hepatocyte in the mouse liver.
      The ultrastructural localization of ACPase and G6PD were demonstrated, with
      concomitant use of the cerium method and the copper-ferrocyanide method,
      respectively. ACPase labelings were localized in the lysosomes, and G6PD
      labelings were visible in the cytoplasm and on the cytosolic side of the
      endoplasmic reticulum of the hepatocyte. This novel double staining procedure may
      be a useful histochemical tool for the study of liver functions in both
      physiological and pathological conditions.

PMID- 12472120
TI  - Glucose-6-phosphate dehydrogenase in rat lung alveolar epithelial cells. An
      ultrastructural enzyme-cytochemical study.
AB  - Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme of the pentose
      phosphate pathway in carbohydrate metabolism, and it plays an important role in
      cell proliferation and antioxidant regulation within cells in various organs.
      Although marked cell proliferation and oxidant/antioxidant metabolism occur in
      lung alveolar epithelial cells, definite data has been lacking as to whether
      cytochemically detectable G6PD is present in alveolar epithelial cells. The
      distribution pattern of G6PD within these cells, if it is present, is also
      unknown. The purpose of the present study was to investigate the subcellular
      localization of G6PD in alveolar cells in the rat lung using a newly-developed
      enzyme-cytochemistry (copper-ferrocyanide) method. Type I cells and stromal
      endothelia and fibroblasts showed no activities. Electron-dense precipitates
      indicating G6PD activity were clearly visible in the cytoplasm and on the
      cytosolic side of the endoplasmic reticulum of type II alveolar epithelial cells.
      The cytochemical controls ensured specific detection of enzyme activity. This
      enzyme may play a role in airway defense by delivering substances for cell
      proliferation and antioxidant forces, thus maintaining the airway architecture.

PMID- 12472121
TI  - Expression of collagen type I, II, X and Ki-67 in osteochondroma compared to
      human growth plate cartilage.
AB  - In order to characterize the consequences for the process of endochondral
      ossification we performed an immunohistochemical study and compared the
      expression of collagen type I, II and X as markers of cartilage differentiation
      and Ki-67 as a marker of cell proliferation in solitary (7-26 years, n=9) and
      multiple (11-42 years, n=6) osteochondromas with their expression in human fetal
      and postnatal growth plates. In fetal and young postnatal controls, we found a
      thin superficial layer of articular cartilage that stained positive for collagen
      type I while collagen II was expressed in the rest of the cartilage and collagen
      type X was restricted to the hypertrophic zone. Osteochondromas from children
      showed lobular collagen type II-positive areas surrounded by collagen type I. In
      adults, the separation of collagen type I- and type II-positive areas was more
      blurred, or the cartilaginous cap was missing. Collagen type X was detected in a
      pericellular distribution pattern within hypertrophic zones but also deeper
      between bone trabecula. The proliferative activity of osteochondromas from
      children younger than 14 years of age was comparable to postnatal growth plates,
      whereas in cartilage from individuals older than 14 years of age, we could not
      detect significant proliferative activity.

PMID- 12472122
TI  - Immunohistochemical study of subepidermal connective of molluscan integument.
AB  - Sections of integument from gastropod, bivalve and cephalopod species were
      studied immunohistochemically to determine reactivity to antibody against the
      type I-like collagen from Sepia cartilage and antibodies against components of
      the extracellular matrix (ECM) of vertebrate connective tissue: type I, III, IV,
      V, and VI collagens, laminin, nidogen and heparan sulphate. All samples exhibited
      similar reactivities to the antibodies, although differences in the intensity and
      localization of the immunostaining were found that were clearly correlated with
      between-species differences in integumental ultrastructure. These findings
      indicate that the composition of the integumental ECM is similar in the three
      classes of molluscs examined and that several types of collagen are present.
      However molluscan subepidermal connective tissue differs from the ECM of
      vertebrate dermis: molluscan integumental ECM contains collagens similar to type
      I, V and VI collagens but has no type III-similar collagen. Furthermore molecules
      similar to the type IV collagen, laminin, nidogen and heparan sulphate of
      vertebrates were present ubiquitously in molluscan basement membrane, confirming
      the statement that the structure and composition of basement membrane have
      remained constant throughout the evolution of all animal phyla.

PMID- 12472123
TI  - Endogenous jaagsiekte sheep retrovirus RNA is expressed by different cell types
      in ovine foetus and placenta.
AB  - The endogenous retroviruses are inherited elements transmitted trough the
      germline of most animal species and their biological role is still controversial.
      Ovine Pulmonary Carcinoma (OPC) represents a good model for studying the
      interactions of endogenous retroviruses with their exogenous counterparts. The
      type D exogenous retrovirus known as Jaagsiekte Sheep Retro-Virus (JSRV) is
      necessary and sufficient to cause OPC in domestic and wild sheep, but both
      affected and unaffected animals host in their genome 15 to 20 copies of related
      endogenous retroviruses named endogenous JSRV (enJSRV). In this study we
      evaluated the expression of enJSRV gag sequences in ovine foetal and placental
      tissues. RNA in situ hybridisation was performed on tissue sections of thymi,
      lymph nodes and lungs from ovine foetuses and related placentas, taken at a late
      stage of development. Reverse transcriptase-in situ polymerase chain reactions
      were also carried out on placental samples to better define the involved cells.
      In foetal tissues, specific signals were observed in the thymus medulla, lymph
      nodes and, at a lesser extent, in foetal bronchiolar cells. In the placental
      tissues, positive areas were detected in various cell types in the sincythium-and
      cyto-trophoblast. These data demonstrate that en JSRV RNA is largely expressed in
      a broad spectrum of cells including tissues which are critical for the
      development of the immune system.

PMID- 12472124
TI  - Management of Barrett's esophagus with high-grade dysplasia.
AB  - About 38% to 73% of patients diagnosed with BE with HGD and who went on to have
      an esophagectomy already had esophageal ACA. The low 5-year survival rate of
      invasive esophageal ACA places pressure on the physician to find a way to prevent
      or to remove the cancer. Endoscopic ablative therapies have been developed, but
      these new technologies are to be considered as a secondary option. Although there
      are many recent improvements in surveillance strategies and endoscopic ablative
      therapies, series are small and follow-up is short. These modalities do show
      promise and may be a good option in the future for patients who are poor surgical
      candidates. At the present time, the standard of care for BE with HGD in good
      surgical candidates is still esophagectomy.

PMID- 12472125
TI  - New techniques for staging esophageal cancer.
AB  - Correct staging is essential for treatment selection, discussion of prognosis,
      and scientific communication. The CT scan has long been the essential tool for
      staging esophageal cancer and still remains valuable for initial screening for
      distant metastases. The development of endoscopic ultrasonography (EUS), with EUS
      fine-needle aspiration, positron emission tomography, and minimally invasive
      surgical staging via thoracoscopy and laparoscopy has resulted in more precise
      staging. These new tools will allow better definition of patient subsets that may
      benefit from selected therapies and clinical investigations.

PMID- 12472126
TI  - Minimally invasive resection for esophageal cancer.
AB  - MIE is technically demanding with a steep learning curve. Operative times
      decrease from 7 to 8 hours to 4.5 to 5 hours after the surgeons and assistants in
      the authors' center had performed 20 operations. In the authors' experience the
      operation was performed safely in the context of the authors' extensive
      experience with open esophageal surgery and advanced minimally invasive
      procedures. In the authors' first 77 cases, the 30-day operative mortality was
      zero, with a median hospital stay of 7 days, which compares favorably to many
      open series. Prospective studies will be required to determine whether
      postoperative pain, recovery time, and cost are improved. The optimal surgical
      approach for each patient should be decided based on surgical experience, tumor
      characteristics, and patient preference. A multi-institutional prospective trial
      is planned to evaluate the clinical and oncologic results of MIE for cancer
      compared with traditional open surgery.

PMID- 12472127
TI  - Multimodality therapy for esophageal cancer.
AB  - Esophageal cancer is undergoing a major shift in its epidemiology. Its incidence
      is dramatically growing and it more commonly affects younger and healthier
      patients. Based on the published data, there is no strong evidence to recommend
      routine preoperative chemotherapy for the treatment of surgically resectable
      esophageal carcinoma. It might be that a large-scale randomized study-which will
      be published in the near future-will shed some different light on this subject.
      The role of preoperative CRT remains undetermined. To settle this issue, larger,
      clinical, controlled trials are needed. Improvement in the preoperative regimen
      and use of new drugs should be evaluated. Concomitant CRT should be considered
      for potential benefit in survival and local control in patients who have
      localized disease and are candidates for radical non-surgical treatment. Patients
      with pCR following neoadjuvant therapy have a consistent, substantial survival
      benefit. Biologic markers can be used to predict response to therapy and might
      allow designation of treatment based on the individual tumor. Pretreatment
      staging is necessary for standardization of patients undergoing treatment
      protocols and for outcome evaluation. Pretreatment staging will be even more
      important in the future for adjusting treatment to individual patient. Video
      assisted thoracoscopy and laparoscopy have been found to be the most accurate
      lymph node staging techniques.

PMID- 12472128
TI  - Endoluminal palliation for dysphagia secondary to esophageal carcinoma.
AB  - There are now a variety of treatment options available to palliate dysphagia in
      patients with advanced esophageal carcinoma. The decision as to which therapy to
      recommend for a patient should be based on a though understanding of the
      therapies and must be individualized for each patient and on the experience of
      the endoscopist or surgeon. In addition, consideration should be given as to
      resource availability at a particular institution. External beam radiation
      currently has little role as primary treatment for dysphagia. Brachytherapy is
      labor intensive; requires 2 to 3 weekly treatments, highly specialized radiation
      equipment, and an experienced radiation oncologist; and is therefore limited to
      tertiary care centers. Endoluminal YAG-laser tumor ablation is feasible at many
      institutions and provides immediate dysphagia relief but has limited durability
      (weeks) if not followed by adjuvant therapy, and requires an endoscopist with
      significant laser experience. PDT is relatively easy to perform and has a lower
      perforation rate and longer durability than YAG laser therapy but it is
      relatively costly and less patient friendly due to the morbidity of its attendant
      6 weeks of photosensitivity. Advances in stent technology have rendered this a
      safe, readily available treatment for the palliation of dysphagia. Palliation of
      dysphagia is an important but difficult goal that may require creative use of a
      variety of endoscopic interventions, either in combination or serially. Ideally,
      physicians who palliate dysphagia secondary to esophageal cancer should be facile
      in both endoscopic ablative and stenting techniques and have a close working
      relationship with both radiation and medical oncologists.

PMID- 12472129
TI  - Minimally invasive surgery for esophageal motility disorders.
AB  - Laparoscopic Heller myotomy has emerged as an excellent primary treatment for
      patients with dysphagia secondary to achalasia. A laparoscopic rather than
      thoracoscopic approach has stood the test of time. An antireflux procedure
      combined with the myotomy is crucial to the maintenance of the antireflux
      barrier. Thoracoscopic long myotomy offers effective relief for spastic disorders
      of the esophagus. Endoscopic stapled diverticulotomy is a safe and effective
      procedure for Zenker's diverticulum and has potential advantages over the open
      approach.

PMID- 12472130
TI  - Lung volume reduction: where do we stand?
AB  - The concept of lung volume resection (LVR) was introduced in 1995 for the
      treatment of end-stage emphysema patients utilizing stapled resection through a
      median stenotomy approach. This article discusses this procedure and the trials
      that have been instituted. LVR might prove to be a viable alternative treatment
      modality for selected, end-stage emphysema patients in the future.

PMID- 12472131
TI  - Malignant mesothelioma: options for management.
AB  - In the past, there has been a tendency to think of diffuse malignant pleural
      mesothelioma as one disease in therapeutic terms, regardless of histological type
      and tumor stage. This does not happen with other tumors, yet it is equally
      illogical and inappropriate in mesothelioma. As with other tumors, early
      diagnosis-while the disease is still in stage I, or even at an in situ stage-must
      be the goal so that therapy can be maximized, particularly if immunotherapy or
      gene therapy is to be used. Patients with pure epithelial mesothelioma have a
      better prognosis and respond better to trimodality therapy. Stage I patients who
      meet fitness criteria should be offered the option of radical surgery in
      combination with chemotherapy and radiotherapy. Further research is required to
      determine the optimum neoadjuvant and adjuvant modalities, particularly the
      timing of individual drugs, use of hyperthermia, and route of administration. The
      place of immunotherapy and gene therapy as adjunctive treatments also remains to
      be defined. For example, it may be possible to reduce tumor bulk and perhaps
      downstage the disease with immunotherapy before radical surgery, if treatment is
      started early enough. Gene therapy may have a role either preoperatively or in
      destroying the microscopic disease that remains after radical surgery. These and
      other combinations of treatment need to be tested in well-designed clinical
      trials, probably on a multicenter basis (to enroll a sufficient number of
      patients). Finding the means to improve treatment for sarcomatous and mixed
      histology mesothelioma remains a challenge. At present, radical surgery does not
      seem worthwhile for these patients when combined with currently employed
      chemotherapy and radiotherapy; however, chemotherapy combinations used for
      treating other sarcomas need to be evaluated as adjunctive therapy before radical
      surgery is abandoned altogether as a mode of treatment. A collaborative approach
      involving thoracic surgeons, basic scientists and oncologists, and physicians
      with experience in treating mesothelioma is essential. Despite its increasing
      frequency, mesothelioma is still a relatively rare tumor, so treatment should be
      concentrated in relatively few supraregional centers to maximize expertise and
      allow innovative treatment combinations to be implemented with the greatest
      chance of success. Evaluation of new therapeutic approaches will be achieved more
      rapidly if these supraregional centers collaborate in multicenter trials. The
      nihilistic approach of simply waiting until the mesothelioma epidemic eventually
      begins to decline spontaneously in 20 or 30 years is untenable in view of the
      hundreds of thousands of deaths that will result if no effective treatment is
      found.

PMID- 12472132
TI  - Advances in thoracostomy tube management.
AB  - This article summarizes several of the studies utilizing randomized trials or
      predetermined algorithms for chest tube management. The classification system,
      when to use wall suction, when to use water seal, and how to safely discharge
      patients by the fourth postoperative day-even with air leaks-are outlined.

PMID- 12472133
TI  - Acute and chronic pain syndromes after thoracic surgery.
AB  - Pain is one of the most important considerations in the care of thoracic surgical
      patients. Failure in pain management is associated with increased mortality and
      morbidity. Acute pain management aspires to stop the painful stimuli before it is
      transferred to the CNS. The authors recommend (1) a thorough explanation of the
      operation and the expected outcome to the patient, (2) preoperative pulmonary
      rehabilitation for those with marginal lung function, (3) choosing the least
      painful surgical approach with acceptable exposure, (4) minimizing tissue trauma
      during surgery, (5) preemptive analgesia, and (6) early ambulation as
      prophylactic measures that should be employed during hospitalization. Good acute
      pain control should reduce the incidence of chronic pain. Mediansternotomy and
      VATS seem to be less acutely painful approaches than thoracotomy for most
      thoracic surgery. One should rule out recurrent malignancy as the etiology for
      chronic or recurrent pain. Opioids and NSAIDs are sufficient to produce optimal
      pain control in patients who undergo VATS and sternotomv. TEA is typically
      reserved for patients who have a thoracotomy. Opioid PCA can be used instead of
      or after the discontinuation of-the epidural catheter. Chronic pain can be
      treated in many ways, and input from a pain clinic might be beneficial. The
      single best approach to chronic pain is to prevent it. This can be achieved by
      selecting the right incisional approach, instituting early physical therapy, and
      achieving optimal postoperative pain control.

PMID- 12472134
TI  - Malignant pleural effusions.
AB  - The management of pleural effusions and, in particular, recurrent MPE require an
      accurate assessment of the characteristics of the pleural fluid and the relief of
      the patient's symptoms. Although a common problem, treatment of pleural effusions
      and MPE is highly variable. Selection of optimal treatment for the individual
      patient (or population of patients) requires a careful assessment of the benefits
      and associated risks of the therapy. Pleurodesis is an artificial measure of
      success that is hospital centered, not patient centered. Because patients with
      MPE have limited life expectancy, efforts to palliate or eliminate dyspnea,
      optimize function, eliminate hospitalization, and reduce excessive end-of-life
      medical care costs may be best achieved with a chronic indwelling pleural
      catheter. The need for expensive supplies may temper the use of such outpatient
      management. Alternative techniques of tube thoracostomy, drainage, and sclerosis
      or thoracoscopy with drainage and talc poudrage also have benefits but are
      associated with variable hospitalization and increased medical costs.

PMID- 12472135
TI  - Control of ovulation with a GnRH agonist after superstimulation of follicular
      growth in buffalo: fertilization and embryo recovery.
AB  - The potential to use a GnRH agonist bioimplant and injection of exogenous LH to
      control the time of ovulation in a multiple ovulation and embryo transfer (MOET)
      protocol was examined in buffalo. Mixed-parity buffalo (Bubalus bubalis; 4-15
      year-old; 529 +/- 13 kg LW) were randomly assigned to one of five groups (n = 6):
      Group 1, conventional MOET protocol; Group 2, conventional MOET with 12 h delay
      in injection of PGF2alpha; Group 3, implanted with GnRH agonist to block the
      preovulatory surge release of LH; Group 4, implanted with GnRH agonist and
      injected with exogenous LH (Lutropin, 25 mg) 24 h after 4 days of
      superstimulation with FSH; Group 5, implanted with GnRH agonist and injected with
      LH 36 h after superstimulation with FSH. Ovarian follicular growth in all
      buffaloes was stimulated by treatment with FSH (Folltropin-V, 200 mg)
      administered over 4 days, and was monitored by ovarian ultrasonography. At the
      time of estrus, the number of follicles >8 mm was greater (P < 0.05) for
      buffaloes in Group 2 (12.8) than for buffaloes in Groups 1(8.5), 3 (7.3), 4 (6.1)
      and 5 (6.8), which did not differ. All buffaloes were mated by Al after
      spontaneous (Groups 1-3) or induced (Groups 4 and 5) ovulation. The respective
      number of buffalo that ovulated, number of corpora lutea, ovulation rate (%), and
      embryos + oocytes recovered were: Group 1 (2, 1.8 +/- 1.6, 18.0 +/- 13.6, 0.2 +/-
      0.2); Group 2 (4,6.1 +/- 2.9, 40.5 +/- 17.5, 3.7 +/- 2.1); Group 3 (0, 0, 0, 0);
      Group4 (6, 4.3 +/- 1.2, 69.3 +/- 14.2, 2.0 +/- 0.9); and Group 5 (1, 2.5 +/- 2.5,
      15.5 +/- 15.5, 2.1 +/- 2.1). All buffaloes in Group 4 ovulated after injection of
      LH and had a relatively high ovulation rate (69%) and embryo recovery (46%). It
      has been shown that the GnRH agonist-LH protocol can be used to improve the
      efficiency of MOET in buffalo.

PMID- 12472136
TI  - Differential requirement for pulsatile LH during the follicular phase and
      exposure to the preovulatory LH surge for oocyte fertilization and embryo
      development in cattle.
AB  - The requirement for pulsatile LH and the LH surge for the acquisition of oocyte
      fertilizing potential and embryo developmental competency was examined in Zebu
      heifers. Follicular growth was superstimulated using the GnRH agonist-LH protocol
      in which pulsatile LH and the preovulatory LH surge are blocked. In experiment 1,
      heifers were assigned on Day 7 of the estrous cycle to receive: group 1A (n = 5),
      1.5 mg norgestomet (NOR) implant; group 1B (n = 5), GnRH agonist implant.
      Follicular growth was superstimulated with 2x daily injections of FSH from Day 10
      (a.m.) to Day 13 (p.m.), with PGF2alpha injection on Day 12 (a.m.). Heifers were
      ovariectomized on Day 15 (a.m.) and oocytes were placed immediately into
      fertilization, without 24 h maturation. Respective cleavage and blastocyst
      development rates were: group 1A, 0/64 oocytes (0%) and 0/64 (0%); group 1B,
      34/70 oocytes (48.6%) and 2/70 (2.9%). In experiment 2, heifers were assigned on
      Day 7 of the estrous cycle to receive: group 2A (n = 10), 1.5 mg NOR implant;
      group 2B (n = 10), GnRH agonist implant; group 2C (n = 10), GnRH agonist implant.
      Follicular growth was superstimulated as in experiment 1 above. Heifers in groups
      2A and 2B received an injection of 25 mg LH on Day 14 (p.m.) and all heifers were
      ovariectomized on Day 15 (a.m.); oocytes were placed immediately into
      fertilization without 24 h maturation. Cleavage rates were similar for heifers in
      group 2A (84/175 oocytes, 48.0%), group 2B (61/112 oocytes, 54.5%) and group 2C
      (69/163, 42.3%). Blastocyst development rates were similar for heifers in group
      2A (22/175 oocytes, 12.6%) and group 2B (25/112 oocytes, 22.3%) and lower (P <
      0.05) for heifers in group 2C (9/163 oocytes, 5.5%). Oocytes obtained from
      heifers treated with GnRH agonist, without injection of exogenous LH, underwent
      cleavage indicating that neither pulsatile LH nor the preovulatory LH surge are
      obligatory for nuclear maturation in cattle oocytes. Exposure to a surge-like
      increase in plasma LH increased embryo developmental competency indicating that
      the preovulatory LH surge promotes cytoplasmic maturation. The findings have
      important implications for controlling the in vivo maturation of oocytes before
      in vitro procedures including nuclear transfer.

PMID- 12472137
TI  - Effect of 17beta-estradiol on the in vitro maturation of bovine oocytes.
AB  - Although 1 microg/ml of 17beta-estradiol (E2) is often used in routine in vitro
      maturation (IVM) and in vitro fertilization (IVF), its effect remains
      controversial. The objective of our study was to investigate the effects of E2 on
      bovine oocyte IVM and subsequent embryo development, using a defined medium.
      Bovine cumulus oocyte complexes (COCs), aspirated from 2 to 8 mm follicles of
      slaughterhouse ovaries, were matured in TCM199 in the presence of 1 microg/ml E2
      with or without 0.05 IU/ml recombinant hFSH. Cultures without E2, FSH or both
      served as controls. COCs were matured for 22 h at 39 degrees C in a humidified
      atmosphere of 5% CO2 in air. To investigate the effect of E2 with and without FSH
      on nuclear maturation, COCs were fixed after maturation and the nuclear stage was
      assessed following DAPI staining. Similarly, denuded oocytes (DO) were matured in
      the presence of E2 and the nuclear stage assessed after 22 h. To investigate the
      effect of E2 with and without FSH during IVM on subsequent embryo development, in
      vitro matured COCs were fertilized in vitro and after removal of the cumulus
      cells, the presumed zygotes were cocultured on BRL monolayer for 11 days. At Day
      4, the number of cleaved embryos, and at Days 9 and 11, the number of
      blastocysts, were assessed. Addition of 1 microg/ml E2 to TCM199 significantly
      decreased the percentage of Metaphase II (MII) compared to control (56.3 and
      74.0%, respectively), and increased the percentage of nuclear aberrations
      compared to control (13.3 and 2.1%, respectively). The negative effect of E2 on
      nuclear maturation was stronger when DO were matured; 25.1 and 60.0% of the
      oocytes reached MII stage for the E2 and control groups, respectively. When COCs
      were matured in TCM199 supplemented with FSH, the addition of 1 microg/ml E2 did
      not influence the proportion of MII oocytes, although a higher percentage of
      nuclear aberrations as compared to control was observed. Presence of E2 during
      IVM also decreased the blastocyst rate (14.4 and 10.0% for control and E2 groups,
      respectively). However, when FSH was present, the addition of E2 had no effect on
      the cleavage rate and blastocyst formation (20.3 and 21.7% for control and E2
      groups, respectively). In conclusion, supplementation of 1 microg/ml E2 to a
      serum free maturation medium negatively affects bovine oocyte nuclear maturation
      and subsequent embryo development. Although these effects are attenuated in the
      presence of FSH, we strongly suggest omission of E2 in routine maturation
      protocols of bovine oocytes.

PMID- 12472138
TI  - Fertility in postpartum dairy cows in winter or summer following estrus
      synchronization and fixed time AI after the induction of an LH surge with GnRH or
      hCG.
AB  - In this study, the fertility of postpartum dairy cows after a sequence of
      treatments with GnRH (Day 0), PGF2alpha (Day 7) and GnRH (Day 9) (GnRH group; n =
      164) or hCG (Day 0), PGF2alpha (Day 7) and hCG (Day 9) (group hCG; n = 166) was
      investigated in summer and winter seasons. All cows were artificially inseminated
      without estrus detection, 16-18 h after the end of treatment. Control cows (CONT;
      n = 226) were not treated and were inseminated at natural estrus. The pregnancy
      rates at Day 90 (46% versus 33%; P < 0.05) and at Day 135 (76% versus 62%; P <
      0.05) postpartum were significantly lower in CONT cows in summer compared to
      winter months but this effect was not observed in the two treated groups. The
      number of days from calving to conception was significantly lower in GnRH and hCG
      treatment groups compared to CONT cows in cold months (102 +/- 3.2, 106 +/- 4.2,
      126 +/- 3.1, respectively; P < 0.001) and in hot months (112 +/- 3.2, 114 +/-
      4.2, 139 +/- 3.1, respectively; P < 0.001). The concentration of insulin was
      significantly higher in winter (P < 0.001). There were no differences in average
      plasma concentration of glucose (P = 0.474), GH (P = 0.441) or IGF-I (P = 0.190).
      In conclusion, we have shown that veterinary supervision combined with a program
      of estrous synchronization and fixed time insemination can improve fertility of
      cows suffering heat stress.

PMID- 12472139
TI  - In vitro maturation of bitch oocytes from advanced preantral follicles in
      synthetic oviduct fluid medium: serum is not essential.
AB  - The ability of oocytes from preantral follicles to mature in vitro was assessed
      using a synthetic oviduct fluid (SOF) medium. Advanced preantral follicles
      (approximately 210 microm diameter) were isolated from the ovaries of domestic
      bitches and assigned to one of four treatment groups: (1) SOF (n = 230); (2) SOF
      + 3 mg/ml bovine serum albumin (+BSA, n = 220); (3) SOF + 20% fetal bovine serum
      (+FBS, n = 227); or (4) SOF + 3 mg/ml BSA + 20% FBS (+BSA+FBS, n = 232), then
      cultured for up to 72 h. A group of control follicles was not cultured (n = 103).
      The percentages of oocytes reaching metaphase I to metaphase II stages (MI to
      MII) did not differ between treatments at each culture period. Within treatments,
      the percentages of oocytes at MI to MII stages did not differ with duration of
      culture. However, when compared to the control group (0.97%) the percentages of
      oocytes at MI to MII increased (P < 0.05) in the SOF group after 48 h (10.0%) and
      72 h (12.2%) of culture. In the +BSA (10.1%) and +FBS (9.7%) groups, the
      percentages of oocytes at MI to MII increased (P < 0.05) above control values
      only after 72 h of culture. The percentage of oocytes at MI to MII did not
      significantly increase in the +BSA+FBS group (3.9,6.6 and 7.6% at 24,48 and 72 h
      of culture, respectively) compared to the control group. These results indicate
      that under the described conditions supplementation of culture medium with BSA or
      FBS is not essential, and the simple medium SOF can support nuclear maturation of
      a small proportion of bitch oocytes in vitro.

PMID- 12472140
TI  - Uterine prolapse with an interesting vascular anomaly in a cheetah: a case
      report.
AB  - A 5-year-old cheetah suffered a complete prolapse of the left uterine horn after
      the birth of her second litter. Two attempts to reduce the prolapse
      transvaginally failed. The animal was hospitalized 13 days after the prolapse
      first occurred, and an ovariohysterectomy was performed to resolve the prolapse.
      The prolapsed uterine horn had been mutilated: its tip, together with the
      ipsilateral ovary was absent. Laparotomy revealed no sign of recent or past
      hemorrhage or adhesions, or any signs of the left ovarian artery or left ovarian
      vein in the remnants of the left mesovarium. A large vein crossed the uterine
      body from the left uterine horn to join the right uterine vein, presumably
      serving as the only route of venous drainage for the prolapsed uterine horn. A
      possible cause for the prolapse is excessive mobility of the uterus due to prior
      rupture of its mesial support. The animal died 24 days after surgery due to
      chronic renal failure, as a result of severe renal amyloidosis.

PMID- 12472141
TI  - Follicular recruitment and ovulatory response to FSH treatment initiated on day 0
      or day 3 postovulation in goats.
AB  - The present study evaluates the effect of the presence of a large growing
      follicle at the onset of superovulatory treatment on follicular recruitment and
      ovulatory response in dairy goats. The treatment consisted of six equal doses of
      pFSH given every 12 h (total dose: 200 mg NIH-FSH-P1) which was initiated at Day
      0 (Group D0) or Day 3 (Group D3) postovulation. Two half-doses of an analogue of
      prostaglandin F2alpha (delprostenate, 80 microg each) were administered together
      with the last two FSH doses to ensure luteolysis. A dose of a GnRH analogue
      (busereline acetate, 10.5 microg) was administered at the onset of estrus.
      Ovarian changes were evaluated twice a day by transrectal ultrasonography.
      Follicles were classified according to follicular diameter as small (3 to < 4
      mm), medium (4 to < 5 mm) and large follicles (> or = 5 mm). The number of
      corpora lutea (CL) was recorded after laparotomy performed 6 days after estrus.
      The work was conducted in replicates. In the first trial, the does were assigned
      to either the D0 (n = 4) or D3 group (n = 4) and in the second replicate, each
      goat was assigned to the alternate group. No large follicles were recorded and
      the diameter of the largest follicle was 3.3 +/- 0.1 mm (mean +/- S.E.M.) at the
      initiation of the treatment in D0-treated goats. In contrast, a growing large
      follicle was present (6.7 +/- 0.4 mm, P < 0.01) when the treatment was initiated
      in D3-treated goats. In these goats, the number of small follicles increased 24 h
      after ovulation but then declined 48 h later, temporally correlated with the
      growth of the largest follicle of the first follicular wave. The number of small
      follicles recruited by the FSH treatment was significantly higher and occurred
      earlier in D0- than in D3-treated goats (9.0 +/- 1.3 versus 5.6 +/- 1.1
      follicles; P < 0.05; and 24 h versus 48 h from the onset of the treatment,
      respectively). The number of large follicles at the onset of estrus was higher in
      D0- than in D3-treated goats (14.4 +/- 1.9 versus 10.3 +/- 1.3; P < 0.05).
      Consequently, the number of CL recorded 6 days after estrus were higher in D0-
      than in D3-treated goats (13.6 +/- 1.9 versus 10.4 +/- 1.9; P < 0.05,
      respectively). These results demonstrate that the presence of a dominant follicle
      at the time of initiation of super-stimulatory treatment is detrimental to
      ovulatory response. This study supports the advantages of the so-called Day 0
      protocol, e.g. treatment starting soon after ovulation, when the emergence of the
      first follicular wave takes place and there are no dominant follicles.

PMID- 12472142
TI  - Effect of supranutritional level of dietary alpha-tocopheryl acetate and selenium
      on rabbit semen.
AB  - This research examined the effects of dietary alpha-tocopheryl acetate (50 or 200
      mg/kg diet) and selenium (Se, 0 or 0.5 ppm) supplementation on motion
      characteristics, oxidative stability and fertilizing ability of rabbit
      spermatozoa, fresh and stored for 24 h at 5 degrees C. The higher amount of
      dietary alpha-tocopheryl acetate increased the level of Vitamin E in the fresh
      semen (1.75 mmol/l versus 0.95 mmol/l) and its oxidative stability
      (thiobarbituric acid reactive substances-TBARS 12.44 nmol malondialdehyde/10(8)
      sperm versus 21.4 nmol malondialdehyde/10(8) sperm). Dietary Se increased
      gluthatione peroxidase activity (GPx) in erythrocytes (285 U/g Hb versus 207 U/g
      Hb), seminal plasma (270 U/l versus 190 U/l) and spermatozoa (1338 mU/10(9) sperm
      versus 1103 mU/10(9) sperm), whereas it did not show any effect on alpha
      tocopherol level and TBARS. No synergy between Vitamin E and Se was shown.
      Storage for 24 h at 5 degrees C increased the TBARS level in all the experimental
      groups. Neither live and acrosome reacted spermatozoa, nor kinetic parameters,
      nor fertility rate were modified by dietary supplementation.

PMID- 12472143
TI  - Flow cytometric cell cycle analysis of somatic cells primary cultures established
      for bovine cloning.
AB  - An important factor governing developmental rates of somatic cloned embryos is
      the phase of the cell cycle of donor nuclei. The aim of this experiment was to
      investigate the distribution of cell cycle phases in bovine cumulus and
      fibroblast cells cultured using routine treatment, and under cell cycle-arresting
      treatments. The highest percentages of cumulus cells in the G0 + G1 stage were
      observed in uncultured, frozen/thawed cells originating from immature oocytes
      (79.8 +/- 2.2%), fresh and frozen/thawed cells from in vitro matured oocytes
      (84.1 +/- 6.2 and 77.8 +/- 5.7%, respectively), and in cycling cells (72.7 +/-
      16.3 and 78.4 +/- 11.2%, respectively for cumulus cells from immature and in
      vitro matured oocytes). Serum starvation of cumulus cultures markedly decreased
      percentages of cells in G0 + G1, and prolonged starvation significantly increased
      (P < 0.05) percentages of cells in G2 + M phase. Culture of cumulus cells to
      confluency did not increase percentages of cells in G0 + G1. Contrary to findings
      in cumulus cells, significantly higher percentages of cells in G0 + G1 were
      apparent when fibroblast cells were cultured to confluency or serum starved, and
      significantly increased (P < 0.01) as the starvation period was prolonged. It is
      concluded that for particular cell types specific strategies should be used to
      attain improvements in the efficiency of cloning procedures.

PMID- 12472144
TI  - Price competition in hospital markets: the significance of managed care.
AB  - Anticompetitive conduct in the healthcare industry is often hard to detect, and
      has been ignored by some courts that appear to lack an understanding of managed
      care and its significance in maintaining price competition. These courts have
      adopted an approach that is far too historical and mechanistic, and is
      characterized by outdated factors analyzed in isolation from each other. In order
      to preserve effective price competition, the courts should embrace a realistic
      analysis that accurately reflects the workings of health services markets. This
      article describes the many facets of market power and anticompetitive conduct,
      and how they affect healthcare prices. The author then tums to an analysis of two
      recent hospital antitrust decisions, and critiques them for their failure to
      properly analyze the dynamics of local hospital markets.

PMID- 12472145
TI  - Nursing home quality-of-care cases after Mikes v. Straus.
AB  - The quality of care rendered to residents of nursing facilities continues to gain
      attention from legislators, regulators, and the courts. Advocates for
      improvements in the quality of care by government-funded healthcare providers
      have identified the False Claims Act (FCA) as a potent tool. The Second Circuit
      decision in Mikes v. Straus might be viewed as a barrier to FCA claims against
      nursing facilities. Any impediment imposed by this decision, however, is limited
      by the facts of the case; the authors believe that carefully-crafted pleadings
      can enable litigants to rely upon the FCA in pursuing quality-of-care claims
      against nursing facilities.

PMID- 12472146
TI  - Navigating the minefield: legal ethics and healthcare law.
AB  - Practicing law in the healthcare field is a daunting task due to the highly
      regulated nature of the field and the increasing scrutiny of the conduct of
      industry providers, payors, and vendors. Attorneys must provide difficult
      opinions regarding matters with civil, criminal, and reimbursement implications
      and often are asked to represent multiple parties in healthcare-related settings.
      This article discusses some legal ethics issues for the healthcare practitioner
      and touches on some of the recent changes to the Model Rules of Professional
      Conduct, which were adopted by the American Bar Association's House of Delegates
      at its mid-February 2002 meeting. The authors conduct their analysis by applying
      the model rules to a number of hypothetical fact situations typical of those
      encountered in the day-to-day practice of healthcare law.

PMID- 12472147
TI  - HIPAA standards for privacy of individually identifiable health information: an
      introduction to the consent debate.
AB  - On March 27, 2002, DHHS published proposed amendments to the Privacy Standards
      under HIPAA. The most controversial of these changes is the removal of the
      requirement that providers obtain patient consent before using or disclosing
      protected health information for treatment, payment, and healthcare operations.
      Some see this change as a rejection of privacy rights, while others see it as an
      acknowledgement of practical reality. This comment introduces the reader to the
      issues that are debated immediately following in the articles by Geralyn A.
      Kidera and Kristen Rosati.

PMID- 12472148
TI  - DHHS wisely proposed to remove the "consent" requirement from the HIPAA privacy
      standards. Department of Health and Human Services.
AB  - The author contends that requiring advance written consent to use and disclose
      health information interferes with patient care, is unnecessary in view of other
      rigorous privacy protections, and imposes an unwarranted burden on healthcare
      providers. Consequently, the author commends DHHS for taking the "practical and
      apolitical step" of removing this requirement.

PMID- 12472149
TI  - The proposed changes to the final privacy rule suggest a disturbing reduction in
      an individual's ability to exercise a right to healthcare privacy.
AB  - The author contends that, in eliminating HIPAA's mandatory consent requirement,
      which is the initial step in the patient's Patient Consent exercise of the right
      to health information privacy, DHHS has turned its back on privacy protection.
      She posits that the proposed change is the result of a disturbing focus on an
      elimination of the industry's administrative burdens, rather than on the
      protection of patient healthcare information. The article concludes that
      elimination of the consent requirement is a step backwards in the arena of
      personal privacy.

PMID- 12472150
TI  - Mea culpa, mea culpa: a call for privilege for self-disclosure of error in the
      setting of primary medical education.
AB  - Medical errors cause 44,000 to 98,000 deaths per year, which is due, in part, to
      the lack of privileged self-reporting systems. Such systems are of great value to
      the medical community, especially to new doctors and to medical students.
      Nonetheless, because documents produced for self-reporting conferences and
      statements made against self-interest are admissible in court, many observers
      believe that doctors are discouraged from self-reporting errors. The author
      proposes the creation of a new medical self-disclosure privilege to protect and
      promote self-reporting systems, which will lead to a reduction in medical errors.

PMID- 12472151
TI  - Global intercomparison for the determination of chlorinated pesticides, PCBs and
      petroleum hydrocarbons in sediment sample IAEA-417.
AB  - A world-wide interlaboratory comparison exercise was organised using a lagoon
      sediment as sample material (IAEA-417) for the analyses of chlorinated
      pesticides, PCB congeners and petroleum hydrocarbons. The sample material was
      analysed by 97 laboratories from 46 countries, representing a rather wide
      distribution for such an interlaboratory comparison exercise. Whereas quite
      variable results were reported for most chlorinated pesticides, more consistent
      interlaboratory results were obtained for PCB congeners and polycyclic aromatic
      hydrocarbons (PAHs). Nevertheless, many laboratories reported results in
      sufficiently dose agreement that after statistical screening of the data,
      consensus values were obtained for the concentration of several analytes in this
      sediment sample. The results allow reference concentration values to be assigned
      for several analytes. Thus, the sediment sample IAEA-417 can be used as a
      reference material for quality control of data in the determination of
      chlorinated compounds and petroleum hydrocarbons in moderately polluted
      sediments.

PMID- 12472152
TI  - Dissipation of chlorpyrifos from tap, river and brackish waters in glass aquaria.
AB  - Persistence of Dursban 2E formulation of chlorpyrifos was studied in aerated and
      unaerated tap, river and brackish water, under laboratory conditions. Adsorption
      of residues onto a glass surface over 12-24 h was 12%. The half-lives of the
      residues in aerated and unaerated (data in parenthesis) tap, river and brackish
      waters were 23 and (403) h, 3.2 and (60) h, and 5.8 and 232 h, respectively. The
      kinetics of dissipation of residues from aerated and unaerated tap, river and
      brackish waters suggested a linear relationship for most of the data sets, and
      could not be ascribed to distinct first- or second-order models.

PMID- 12472153
TI  - Fate of 14C-chlorpyrifos in the tropical estuarine environment.
AB  - The distribution and fate of 14C-chlorpyrifos were investigated in microcosms
      simulating the conditions of the tropical estuarine environment of North Vietnam.
      The microcosms containing brackish water, sediment, clams (Meretrix meretrix) and
      green algae (Gracilaria verucosa) from the Red River estuary, were maintained for
      30 days. The results show that chlorpyrifos released into the water was rapidly
      adsorbed onto sediment. However, only 1-2% of the initial amount of 14C
      chlorpyrifos could be detected in the sediment by the end of the experiment. The
      accumulation of chlorpyrifos in fauna and flora attained, respectively, a maximum
      of 5.8% and 2.2% of the initial activity observed at days 3 and 2 after
      application. The compound 3,4,5-trichloro-2pyridinol (TCP) was the major
      transformation product of chlorpyrifos found in the microcosm. TCP accumulated in
      the clam's soft tissues, and, 3 days after application, reached a maximum of 0.5%
      of the total 14C-activity. The balance of the 14C-activity at the end of the
      experiment suggests that the main loss of the insecticide from the system was
      through volatilisation of chlorpyrifos and escape to the atmosphere. The
      persistence half-time of the compound in the aquatic microcosms was computed at 5
      days.

PMID- 12472154
TI  - The distribution of organochlorine pesticides in marine samples along the Indian
      Ocean coast of Kenya.
AB  - The concentrations of organochlorine residues of lindane, aldrin, alpha
      endosulfan, dieldrin, endrin, p,p'-DDE, p,p'-DDD and p,p'-DDT in samples of
      seawater, sediment, fish and seaweed from different locations along the coast of
      Kenya are discussed in relation to the geographical location of the sampling
      sites and potential sources of residue over a period of two years. All sediment
      samples were found to contain very low levels of organic carbon except those
      sampled from Sabaki River that had high (4.7%) organic carbon due to greater
      primary activity. Most of the pesticides residues (112 samples analysed in 1997
      and 258 analysed in 1998/99) were detected in fish, water, sediments and seaweed.
      The concentration of some residues was higher during the wet season than the dry
      season in 1997, but no marked seasonal variation was observed in 1998/99.
      Lindane, aldrin, p,p'-DDT and p,p'-DDE were the most frequently observed residues
      in all samples while alpha-endosulfan, dieldrin, p,p'-DDD and endrin were either
      present low concentrations or absent in most samples. Water samples had the
      lowest concentrations of residues (range 0.503 - 9.025 ng g(-1)). Sediments had
      the second highest levels of pesticides residues with a range of 0.584 - 59.00 ng
      g(-1) while fish lipid content had the highest levels of residues in 1989/99 with
      p,p'-DDT concentration of 1011 ng g(-1) and 418 ng g(-1) p,p'-DDD in Siganus
      rivulatus.

PMID- 12472155
TI  - Pesticides distribution in sediments of a tropical coastal lagoon adjacent to an
      irrigation district in northwest Mexico.
AB  - This work presents the content of organochlorine (OCs) pesticides in sediments of
      both, agricultural drains from the Irrigation District 076, El Carrizo, Sinaloa,
      and of the adjacent coastal lagoon ecosystem of Agiabampo-Bacorehuis-Jitzamuri,
      located in northwest Mexico. A questionnaire was applied to the farmers of this
      irrigation district, to evaluate the usage of pesticides and to determine if
      banned OCs are still used. Around 31 tons of active ingredients were applied in
      the autumn-winter cycle (1997-1998). There were eighteen different pesticides; of
      them 61% are insecticides, 28% herbicides, 6% fungicides and 6% other compounds.
      Around 73% of the pesticides applied are organophosphorus, carbamates and sulfur,
      OCs are still applied and represent 4% of the total. All the pesticides applied
      in the irrigation district are authorized in the Official Pesticide Catalog,
      nevertheless forbidden and restricted compounds were detected in the sediment
      samples. The presence of heptachlor, heptachlor epoxide, alpha-endosulfan, beta
      endosulfan, endosulfan sulfate, alpha-HCH, beta-HCH, lindane, delta-HCH, aldrin,
      dieldrin p,p'-DDT, p,p'-DDE and p,p'-DDD was recorded in the sediment sample. The
      analysis of the sediments suggest that the principal pesticides input to the
      coastal ecosystem is mainly through three of the seven agricultural drains, that
      collect the excess irrigation water and runoff from the district surface. A
      gradient of pesticide residues in sediments exists from the agricultural drains
      (52 ng OCs g(-1) dry weight) to the Jitzamuri bay (32 ng OCs g(-1) dry weight).

PMID- 12472156
TI  - Distribution, fate and effects of pesticide residues in tropical coastal lagoons
      of northwestern Mexico.
AB  - Analyses of pesticide residues in sediments, water and biota of the Altata
      Ensenada del Pabellon coastal lagoon system in Sinaloa, Mexico, showed the
      presence of organochlorine and organophosphorus compounds. For all the compounds
      analysed, concentrations in sediments were higher near the points of water
      discharge from ponds and drainage from the agricultural area. Among the
      organochlorines, total DDTs displayed the largest sedimentary reservoir, followed
      by total endosulfans and chlorpyrifos. In sediments, as well as in biota, pp'-DDT
      concentrations were lower than those of DDT metabolites, which confirms the
      reduction in the previous massive use of this compound in agriculture. Endosulfan
      is currently used in the region and endosulfan residues in lagoon sediments
      attained levels considered to be toxic to meiofauna, therefore constituting an
      ecological risk to lagoon ecosystems. There was a large sedimentary reservoir of
      chlorpyrifos but its ecotoxicological risk is difficult to assess due to lack of
      adequate comparative data. Nevertheless, concentrations of chlorpyrifos which
      approach acute toxic levels for shrimp were recorded in lagoon water. This
      suggests that drainage from agricultural fields during high runoff may, on
      occasion, cause mass mortality of shrimp and fish Organophosphorus pesticides are
      widely regarded to degrade very rapidly in aquatic systems. Experimental research
      performed with 14C-labelled chlorpyrifos and parathion has shown that they may be
      stabilised for relatively long periods of time through sediment-water
      partitioning. This extension of their environmental half-lives increases their
      potential for impacting on coastal ecosystems. Since organophosphorus pesticides
      are highly toxic for aquatic organisms at concentrations generally lower than
      organochlorines, their presence in the lagoon water and sediment is a matter for
      much concern. The increased use of tropical coastal lagoons for shrimp and fish
      farming requires the implementation of environmental management practices to
      protect these ecosystems from the impact of agricultural activities.
      Environmental management aims to preserve the ecosystem integrity of these
      coastal lagoons and, through improving the water quality, to allow the
      development of aquaculture and reduce human exposure to pesticide residues in
      food.

PMID- 12472158
TI  - Toxicity, bioaccumulation and tissue partitioning of dieldrin by the shrimp,
      Macrobrachium faustinum de Sassure, in fresh and brackish waters of Jamaica.
AB  - The 2-week no observed effect (NOEC) and lowest observed effect (LOEC)
      concentrations of dieldrin were determined for Macrobrachium faustinum de Sassure
      in fresh and brackish waters. LOEC1,10,50,95 values in fresh water were 0.001,
      0.003, 0.011 and 0.058 microg l(-1), respectively, and in brackish water,
      0.00006, 0.00027, 0.00165, and 0.0172 microg l(-1), respectively. The 96-hr LC10,
      LC50 and LC95 values were 0.029, 0.123 and 0.771 microg l(-1), respectively. It
      is proposed that NOEC and LOEC be redefined to take into account the percentage
      of individuals affected, the severity of symptoms and the recovery of poisoned
      individuals. Two new terms are proposed--Median Observable Effect Concentration
      (MOEC) for pronounced toxic symptoms in most individuals but mortality in <50%,
      and Pronounced Observed Effect Concentration (POEC), which inflicts mortality in
      >50% individuals. Bioaccumulation of dieldrin by M. faustinum from surrounding
      fresh and brackish waters were rapid and fairly uniform for the first 48 h when
      the bioconcentration equilibrium (14.4 +/- 0.42 ng g(-1) at 0.001 microg l(-1)
      and 42.5 +/- 1.72 ng g(-1) at 0.01 phi g l(-1)) was achieved. Relative
      partitioning of residues (ng g(-1) wet wt.), after 24h exposure to 0.001 microg
      l(-1) of dieldrin in fresh water, in the different tissues was hepatopancreas >
      gonads > gills > large claws > muscle and exoskeleton. Shrimp which had
      accumulated 10.5 +/- 0.52 ng g(-1) dieldrin in fresh and brackish water,
      eliminated only about 52% of the residues after eight days in uncontaminated
      water.

PMID- 12472157
TI  - Metabolism of 14C-naphthalene in marine sediments.
AB  - Metabolism of 14C-naphthalene was studied in aerobic and anaerobic marine
      sediments from the Mumbai coast, India using a continuous flow-through system for
      5 weeks. There was no volatilisation of naphthalene from anaerobic sediment.
      Naphthalene underwent more extensive mineralization in aerobic sediment (31.6% of
      the applied activity) than in anaerobic sediment (5% of the applied activity). No
      metabolite of naphthalene was present in sediments at the end of the incubation
      period.

PMID- 12472159
TI  - Accumulation, distribution and metabolism of 14C-1,1,1-trichloro-2, 2-, bis-(p
      chlorophenyl)ethane (p,p'-DDT) residues in a model tropical marine ecosystem.
AB  - Accumulation, distribution and metabolism of ring labelled, 14C-1,1,1,-trichloro
      2,2-bis(p-chlorophenyl)ethane (p,p'-DDT) in a model marine aquatic ecosystem
      consisting of seawater, sediment, oysters (Isognomonon alatus) and Humbug fish
      (Dascillus aruanus) were studied in the laboratory. 14C-p,p'-DDT distributes
      rapidly in the ecosystem immediately after application on the water surface with
      reduction of its concentration in the water phase from 1.18 ng g(-1) to 0.71 ng
      g(-1) after 2 hours and an increase in its content in the sediment and oysters.
      The bioconcentration factor reached a maximum of 19 x 10(3) in oysters, and 1657
      in Humbug fish after 24 hours. The sediment concentration reached 117 ng g(-1)
      after 168 hours from start of application. A peak bioconcentration factor of 111
      x 10(3) was calculated after 120 hours when 0.24 mg kg(-1) of 14C-p,p'-DDT was
      maintained through dosing every 24 hours with 0.002 mg kg(-1) of a mixture of
      labelled and non-labelled pesticide. The rate of depuration of accumulated 14C
      p,p'-DDT sediment residues was up to 78.3% after 24 hours while oysters lost only
      14.0% during the same period. The loss in Humbug fish was only 22.2% in three
      days. Volatilisation and sorption losses from seawater alone (without
      sediment/biota) were found to be very high in the range of 73.8 - 91.5% over 24 h
      for p,p'-DDT in aerated and nonaerated ecosystem. Gas chromatograph and TLC
      analysis of water, sediment and oyster samples revealed presence of p,p'-DDT and
      substantial amounts of p,p'-DDE and p,p'-DDD three days after pesticide dosage.

PMID- 12472160
TI  - Degradation, release and bioavailability of 14C DDT and 14C DDE sediment residues
      to oysters and mussels.
AB  - Sediment borne pesticides are one of the major routes of transport of pesticides
      into the aquatic environment and could affect biota living closely in contact
      with it. Sediment residues of DDT were found to be easily adsorbed (95.0%) and
      were released in hard water (8.4%) and seawater (0.1%). DDT and DDE sediment
      residues were released into sterile and nonsterile brackish water indicating
      minimal role of micro-organisms. DDT was detected in oyster and in mussel with an
      average of 46-62% in the shell, 19-31% in the tissues and 19-23% in the fluids.
      Most of the sediment residues were extractable and released residues in water
      were in the form of DDT. In the presence oysters, bound was transformed into
      extractable DDT in sediment after 30 days equivalent to 26% of the total
      concentration. Most biota residues were extractable and an average of 46% was
      transformed to DDE. Uptake of residues depend on whether the source of
      contamination was by direct addition to the water or through sediment residues,
      if food was given or not, if the source of sediment residues were either aged or
      freshly treated and if residues were extractable or non-extractable.

PMID- 12472161
TI  - Behaviour of pesticides in a water/sediment system under laboratory and field
      conditions.
AB  - Experiments were conducted in order to evaluate the behaviour of some pesticides
      commonly used in rice production. At a laboratory scale, but exposed to the
      environmental conditions, a known concentration of pesticides in water flowed
      through a cement channel over a sediment layer, at a constant flow rate. The
      collected water was homogenised and analysed by gas chromatography/HPLC to assess
      the concentration of each pesticide. Under these conditions, the reduction of
      each pestcide concentration in water depends on the nature of it and on the water
      flow rate. The lower the flow rate, the grater the reduction in the concentration
      of pesticides in the water that ran over the sediment layer. Experiments were
      also carried out under field conditions, using a 1200 m length, 2 m width and 0.3
      m depth rice field channel. A pesticide mixture of known concentration was poured
      on the flowing water and mixed thoroughly. After the arrival of this contaminated
      water at preestablished sampling points down the stream, the concentration of
      each pesticide in water was determined. The longer the distance of the sampling
      points downstream from the starting point, the lower the pesticide concentration
      found. Only a few pesticides were detected at the 1200 m sampling point, but at
      very low concentration. The others were not detected. It was pointed out that the
      channel length was the most important factor in the reduction of the pesticide
      concentration in the flowing water. The influence of the flow rate on this
      reduction could not be clearly related as in the laboratory experiments.

PMID- 12472162
TI  - Uptake of 14C-chlorpyrifos by clams.
AB  - The uptake of 14C-chlorpyrifos by clams (Katalysia opima) was studied to
      determine the bioaccumulation potential over a period of five days. Chlorpyrifos
      was applied to a model ecosystem in beakers at the rate of 3 mg l(-1) of
      seawater. Clams showed a maximum uptake of 14C-chlorpyrifos in the first 8 hours
      of exposure. Subsequently these residues decreased significantly and at the end
      of 5 days about 1.5% of the applied activity could be recovered from the clam
      samples. The half-life of chlorpyrifos in this marine water system was about a
      day. However, after 5 days about 28% of the applied 14C-activity was present in
      water. This may be significant and could possibly play a role in finding the
      residue of this insecticide in water bodies. Clams brought about rapid
      degradation of chlorpyrifos in the first 48 hours. The stabilised residues in
      water were reflected later in clams.

PMID- 12472163
TI  - Bioaccumulation, elimination, and tissue distribution of chlorpyrifos by red
      hybrid Tilapia in fresh and brackish waters.
AB  - Bioaccumulation, degradation, elimination and tissue partitioning of chlorpyrifos
      (Dursban 25E) was studied under static conditions for 3-4 days, in fresh (FW) and
      brackish (BW) waters by two methods: in the renewal method, fish were transferred
      every 24 h to FW or BW aquaria containing 0.05 mg l(-1) of the insecticide; in
      the spiking method, the original concentration of 0.005 mg l(-1) was spiked every
      8 h. Samples of fish and water were collected at regular intervals and residues
      determined gas chromatographically. In the renewal experiments with 0.05 mg l(
      1), bioconcentration reached its peak within 8 h of exposure in FW (1.25 mg l(
      1)) and within 1 h in BW (0.95 mg g(-1)); in spiking experiments with 0.005 mg l(
      1), these peaks were attained in 48 h in FW (3.8 mg g(-1)) and 8-24 h in BW (1.67
      mg g(-1)). Thereafter, the concentrations declined. The concentrations of an
      unidentified metabolite were generally but not always correlated with that of the
      parent compound. Upon exposure of contaminated fish to uncontaminated waters, 72%
      was eliminated within the first 12 h and 4% later in 60 h in FW, and only 23% in
      1 h and another 21% in the following 60 h in BW. Concentration of the metabolite
      was very high during the elimination. In the renewal experiment with 0.05 mg l(
      1) of chlorpyrifos, tissue distribution was much higher in FW than in BW, while
      the reverse was true in spiking experiments with 0.005 mg l(-1) of the chemical.
      Testis, heart and brain had the highest levels of residues, followed by ovaries
      and other tissues.

PMID- 12472164
TI  - Tracheal agenesis: a case report.
AB  - Tracheal agenesis is a rare congenital anomaly which results inevitably in
      immediate respiratory distress after delivery. Since the first report of the case
      in 1900, more than 150 cases reported in the Japanese and world literature.
      Attempts to save these children have failed to permit survival although a slight
      prolongation of life was achieved in some. We treated a baby girl with tracheal
      agenesis associated with other multiple anomalies and surgical intervention was
      attempted but without success due to incorrectable anatomy. Herein we describe
      her clinical picture and autopsy findings. Along with a review of the Japanese
      literature, we discuss this rare anomaly in terms of its anatomy, associated
      anomalies, pathogenesis, and clinical management.

PMID- 12472165
TI  - A comparison of purging and non-purging eating disorder patients in comorbid
      personality disorders and psychopathology.
AB  - OBJECTIVE: We evaluated the significance of purging behavior in the diagnosis of
      eating disorders through an objective assessment of eating disorder
      psychopathology including personality disorders. METHODS: Subjects were 42
      consecutive outpatients with eating disorders who visited the Outpatient
      Psychiatric Clinic at Tokai University Hospital (Kanagawa, Japan). Diagnosis of
      eating and personality disorders was established using the modified Structured
      Clinical Interviews for DSM-III-R and DSM-III-R-Axis II. Eating disorder symptoms
      and psychopathology were assessed with the Eating Disorder Examination, Eating
      Disorder Inventory 2, Beck Depression Inventory, and Leyton Obsessional Inventory
      Results were compared between purgers and non-purgers. RESULTS: Purgers had
      severe borderline or avoidant personality disorder, mixed personality disorder,
      eating attitude, depressive symptoms, and obsessive symptoms. CONCLUSION: Purging
      behavior in eating disorder patients is associated with personality disorders,
      depression, and obsessive symptoms. Assessment of this behavior is critical in
      the diagnosis and treatment of eating disorders.

PMID- 12472166
TI  - Difficult placement of Univent tube blocker due to aberrant right subclavian
      artery aneurysm.
AB  - There have been few reports on aneurysms of the anomalous branch of the aortic
      arch. We present a rare case in which correct placement of the movable blocker of
      a Univent tube was difficult due to an aberrant right subclavian artery aneurysm.
      A 72-year-old man with a history of hypertension had manifested coughing and
      wheezing for four months prior to admission to our hospital. A chest computed
      tomogram revealed that his aortic arch had four branches and that the right
      subclavian artery did not originate from the first branch, but was the fourth
      branch. The angiogram disclosed that an aneurysm had developed in the anomalous
      artery close to the aorta, and behind the other three branches, trachea, and
      esophagus. The aneurysm not only had pushed the trachea out of place but was also
      pressing against it. After anesthetic induction, his trachea was intubated using
      an endotracheal tube with a movable blocker, the Univent tube, for single-lung
      ventilation. The blocker could not be advanced into the left main bronchus due to
      the tracheal deviation caused by the aneurysm. Several methods of blocker
      placement, including those recommended in the manual attached to the product,
      were attempted without success. Finally, the trachea was intubated again using a
      Univent tube with the blocker tip bent manually, which permitted entrance of the
      blocker into the bronchus. Blocker placement should be modified to suit patients
      with a problem in the trachea or bronchi.

PMID- 12472167
TI  - The microendoscope for ciliary process photocoagulation in neovascular glaucoma.
AB  - The safety and efficacy in endoscopic ciliary body photocoagulation was evaluated
      in 6 patients with intractable neovascular glaucoma secondary to proliferative
      diabetic retinopathy. After a mean follow-up of 8 weeks, the mean intraocular
      pressure (IOP) decreased from 39.2 +/- 5.0 mmHg preoperatively t o 19.5 +/- 3.8
      mmHg postoperatively (p < 0.05, Wilcoxon signed-ranks test). Although intense
      inflammation was observed as an immediate postoperative complication, fibrin, eye
      pain and phthisis did not develop in any of the patients.

PMID- 12472168
TI  - Measurement of atmospheric NO2 concentrations in Antarctica with NO2 filter badge
      and tube.
AB  - Nitrogen dioxide (NO2) levels in Antarctica were monitored to determine
      background levels and distribution profile. The NO2 levels were higher than those
      reported from tropical remote areas. The NO2 concentrations gradually increased
      proceeding from the edge of the continent to the polar region, suggesting global
      pollutant transportation. To avoid artificial contamination of the data, a sled
      was used because motor vehicles discharge high levels of NO2. NO2 tubes and
      filter badges were selected as monitoring devices because of their convenience of
      transportation in Antarctica. They are small in size, light and easy-to-handle,
      and usually employed in personal NO2 exposure measurements. Because of severe
      Antarctica climate, the devices needed to be protected from the bitter cold. For
      that purpose, we designed an insulation container to shield the devices. The
      fixed NO2 monitoring site was Patriot Hill, located on the coast of the Weddell
      Sea. We also measured NO2 concentration along the expedition route from the fixed
      site to the South Pole, along with the 80 degrees west longitude. The survey
      periods were during November 1992 and January 1993. NO2 concentrations in
      Antarctica ranged from 1.0 to 2.8 ppb, which were relatively higher than
      previously reported background concentrations. The NO2 concentrations increased
      when nearing to the South Pole, supporting the theory that atmospheric
      circulation converges in the polar regions. This indicated that air pollutants
      discharged in populated regions were widely spread to isolated areas, like the
      South Pole.

PMID- 12472169
TI  - Expression and significance of c-met protein in papillary thyroid carcinoma.
AB  - The c-met protein, encoded by the c-met oncogene and its ligand, the
      hepatocellular growth factor/scatter factor, are known to be responsible for the
      motility and mitogenesis of epithelial cells including cancer cells. Recent
      studies have reported the prognostic significance of the c-met protein in
      malignant tumors. Papillary thyroid carcinoma, the most common histological type
      of thyroid carcinoma, can easily metastasize to regional lymph nodes, reflecting
      the activated motility and invasiveness of the carcinoma cells. We examined the
      expression of c-met protein in papillary thyroid carcinomas to assess its
      significance. Immunohistochemical staining of the c-met protein was performed on
      archival materials. The c-met protein was expressed in 10 cases of papillary
      thyroid carcinoma with recurrence, and in 5 of 10 cases without recurrence.
      Normal thyroids were negative for c-met protein. Expression of the c-met protein
      was statistically associated with recurrence of the thyroid carcinoma (p =
      0.016). It is suggested that expression of the c-met protein plays a role in the
      recurrence of papillary thyroid carcinoma.

PMID- 12472170
TI  - Genetic association analysis using microsatellite markers in atopic dermatitis.
AB  - Atopic dermatitis (AD) is presumed to be influenced by genetic and environmental
      factors. In this study, 54 patients with AD were examined for disease association
      by the use of 12 microsatellite markers. Several significant associations were
      recognized in the alleles on chromosome 5, 7 and 11. AD genes were mapped near
      the FC epsilon RI beta gene (around D11S1314 locus) on chromosome 11, the IL4
      gene cluster on chromosome 5 and the TCR gamma gene on chromosome 7. This
      distribution in close proximity to candidate loci for AD is very similar to that
      of atopic genes, therefore implying that an atopic trait is genetically
      responsible for the development of AD.

PMID- 12472171
TI  - Penetrating the blind in a study of an SSRI.
AB  - We assessed blind integrity in a double-blinded study comparing paroxetine 20 mg
      with inert placebo in 20 volunteer subjects who were attempting to stop using
      methamphetamines. At the end of the study, the blinded clinicians reviewed
      subject charts and attempted to identify the assigned conditions for the 13
      subjects who completed two or more weeks of the study. The three subjects who
      completed the entire study also attempted to identify their conditions on a
      questionnaire. We conclude that the blind may unwittingly be broken when the
      treatments under study are placebo and the selective serotonin reuptake inhibitor
      (SSRI) paroxetine. The integrity of the blind should be tested in all double
      blind SSRI studies.

PMID- 12472172
TI  - Cognitive processing, memory, and the development of PTSD symptoms: two
      experimental analogue studies.
AB  - Memory deficits are implicated in the development of posttraumatic stress
      disorder (PTSD). Intentional recall of trauma memories is frequently disorganised
      or incomplete, whilst involuntary memory fragments are easily triggered by
      perceptual cues. Ehlers and Clark (Behaviour Research and Therapy 38 (2000) 319
      345) propose that a predominance of data-driven processing (i.e., processing
      sensory impressions) during the trauma contributes to the development of this
      memory pattern, and therefore, predicts PTSD symptoms after trauma. Two
      experimental studies examined these hypotheses. Student volunteers viewed a
      distressing videotape as an analogue for a traumatic event. In Study 1, cognitive
      processing was manipulated; in Study 2, extreme scorers on a processing screening
      questionnaire were pre-selected. The results indicated that data-driven
      processing is associated with the development of PTSD-like memories and analogue
      symptoms.

PMID- 12472173
TI  - The effect of situational structure on the social performance of socially anxious
      and non-anxious participants.
AB  - Twenty-six socially anxious and 24 low-anxious female undergraduate students were
      observed in brief unstructured and structured hetero-social interactions with a
      confederate. The unstructured interaction was a naturalistic interaction in which
      participants were observed surreptitiously. The structured interaction was a role
      play in which participants were instructed to try and get to know as much as
      possible about their partner. Videotapes of the interactions were subsequently
      rated on subjective and objective measures of social skill. The results showed
      that high socially anxious females performed somewhat worse than low socially
      anxious females in both situations. However, this difference was far larger in
      the unstructured social situation and was relatively small in the structured
      social situation. It appears that socially anxious females do perform more poorly
      in social interactions than do low-anxious females, but a large component of this
      poor performance may be a result of avoidance rather than a lack of ability.

PMID- 12472174
TI  - Mindsets in social anxiety: a new look at selective information processing.
AB  - According to the Rubicon Model of Action Phases (in: J. Gollwitzer, 1996),
      Motivation, volition, and action, Enzyclopedia of psychology, series "motivation
      and emotion", Vol. 4, Hogrefe, Gottingen, 1996, pp. 531-582), different stages in
      goal pursuit are accompanied by different mindsets that enhance processing of
      mindset-congruous information. Before people engage in action, they usually
      deliberate possible goals for a given situation (deliberative mindset). Once a
      goal is chosen, they plan how to achieve this particular goal (implemental
      mindset). The present experiments tested the hypothesis that people with social
      anxiety show a reversal of mindsets when approaching social situations. In
      Experiment 1, 20 students were asked to either deliberate goals for a
      hypothetical social conflict (deliberation), or to think about steps to solve the
      conflict (implementation). An unexpected recognition test demonstrated different
      recognition memory for deliberation-related versus implementation-related
      information in the two groups, consistent with the hypothesis of different
      mindsets. In Experiment 2, 48 students who were either high or low in social
      anxiety were randomly assigned to either the deliberation or the implementation
      condition. Participants high in social anxiety showed a pattern in the
      recognition test that was consistent with a reversal of mindsets. When asked to
      plan social situations, they showed an inappropriate deliberative mindset. In
      contrast, they lacked a deliberative mindset when deliberating goals for the
      social situation. The result indicate that socially anxious people engage in
      information processing that interferes with successful goal attainment when
      approaching social situations.

PMID- 12472175
TI  - The Implicit Association Test as a tool for studying dysfunctional associations
      in psychopathology: strengths and limitations.
AB  - Dysfunctional beliefs and associations are assumed to play a crucial role in
      various forms of psychopathology. Recently, it has been suggested that the
      Implicit Association Test (IAT) provides a better way to assess those
      associations than traditional self-report measures. During the IAT, participants
      classify items as belonging to one of four concepts. Results show that
      performance is superior when associated concepts are assigned to the same
      response than when associated concepts are assigned to different responses. I
      present an overview of the available literature on the IAT and evaluate the
      usefulness of this task as a tool for clinically oriented research.

PMID- 12472176
TI  - Effect of IL-18 on the release of IL-6 and its soluble receptors: sIL-6Ralpha and
      sgp130 by human neutrophils.
AB  - The biological activities of IL-18 include its ability to induce the production
      of inflammatory cytokines such as IL-1 or IL-8 by immunocompetent cells. Our
      previous study demonstrated that rhIL-18 induces IL-1beta and, to a lesser exted,
      the secretion of IL-1beta regulatory proteins involving interleukin-1 receptor
      antagonist (IL-IRa) and soluble interleukin-1 receptor II (sIL-1RII) by
      neutrophils (PMN), suggesting a significant role of IL-18 in the reactions
      mediated by IL-1beta. In this study, we estimated the effect of rhIL-18 on the
      induction of IL-6 and its soluble receptors - sIL-6Ralpha and sgp130 by these
      cells. Results obtained indicate that IL-18 is a promising candidate for the
      enhanced secretion of IL-6 by human neutrophils. In contrast, we have not found a
      significant effect of IL-18 on the release of both soluble receptors of IL-6. The
      influence of IL-18 on the IL-6 production by PMN appears to indicate a potential
      role of IL-18 in the early steps of the inflammatory cascade and other immune
      reactions mediated by IL-6.

PMID- 12472177
TI  - Increased expression of phospholipase D1 in the sciatic nerve of rats with
      experimental autoimmune neuritis.
AB  - Phospholipase D1 (PLD1) expression in the sciatic nerve was studied in induced
      experimental autoimmune neuritis (EAN) in Lewis rats. PLD1 immunoreactivity was
      seen in some Schwann cells in the sciatic nerves of normal rats. In parallel with
      the progression of EAN, PLD1-positive Schwann cells significantly increased in
      number and showed intense immunoreactivity. PLD1 was also detected in some ED1+
      macrophages in EAN lesions. These results suggest that PLD1 in macrophages and
      Schwann cells plays an important role in the activation of these cells in the
      pathogenesis of EAN, an animal model of human peripheral demyelinating disease.

PMID- 12472178
TI  - Decreased IL-12 production by polymorphonuclear leukocytes in patients with
      active systemic lupus erythematosus.
AB  - Polymorphonuclear leukocytes (PMN) play an important role in eradicating
      bacterial infections. To test if PMN of patients with systemic lupus
      erythematosus (SLE) have defective capacity to produce IL-12, IL-12 p35 gene
      transcription and p70 excretion by PMN were evaluated in SLE patients and normal
      subjects. Peripheral blood PMN from 25 patients with active SLE and 25 normal
      individuals were stimulated with lipopolysaccharide (LPS, 100ng/mL) in the
      presence or absence of recombinant interferon (IFN)-gamma (5-200IU/mL). The IL-12
      p35 gene transcripts were analyzed by reverse transcription - polymerase chain
      reaction (RT-PCR) and the IL-12 p70 in culture supenatants was quantified by
      enzyme immunoassay (EIA). At the 6th hour of stimulation, IL-12 expression in PMN
      of SLE patients was less prominent than that of the normal controls. The IL-12
      was produced by normal PMN on LPS stimulation in the absence of IFN-gamma. IFN
      gamma enhanced the IL-12 production by normal PMN stimulated with LPS, but it
      inhibited the IL-12 production in PMN from active lupus patients in the presence
      of LPS. Analysis with PCR using the same primers on the chromosomal DNA showed
      that p35 gene was intact in SLE patients. These results have suggested that SLE
      PMN may have defect in IL-12 expression and the defect may be exaggerated in the
      presence of IFN-gamma which normally stimulates IL-12 production. This may
      account for increased susceptibility to multiple infections in patients with
      active SLE.

PMID- 12472179
TI  - Expression of tumor-associated Thomsen-Friedenreich antigen (T Ag) in
      Helicobacter pylori and modulation of T Ag specific immune response in infected
      individuals.
AB  - We tested the hypothesis that the gastric cancer associated bacteria,
      Helicobacter pylori (H. pylori) express the cancer-related Thomsen-Friedenreich
      (T) antigen. We also analysed whether infection with H. pylori alters the amount
      of natural anti-T antibodies in the patients' sera. Cell surface membrane
      extracts of H. pylori NCTC 11637 strain and clinical isolates of H. pylori (n =
      13) were analysed by immunoblotting and cell-ELISA with five different T antigen
      specific monoclonal antibodies (MAbs). Two major protein bands of approximately
      68 kDa and 58 kDa were immunostained on blots of H. pylori extracts with T
      specific MAbs but not immunostained with unrelated MAb. The specificity was shown
      in that immunostaining was blocked with peanut agglutinin (PNA) and rabbit
      antiserum to T antigen. The binding of T specific MAb to the 58 kDa protein band
      was also blocked by rabbit antiserum against heat shock proteins of H. pylori.
      The relative expression of T antigen-related proteins differed among H. pylori
      strains, with 68 kD associated T antigen expression higher in patients with more
      severe pathology. The level of IgG antibody to T epitope in patients with gastric
      cancer (n = 66) and normal blood donors (n = 62) were compared and the level of
      anti-T Ab in gastric cancer patients was significantly lower than that in normal
      blood donors. A significant positive correlation between T specific antibody in
      serum and H. pylori IgG antibody level was found in H. pylori-infected normal
      blood donors (P < 0.001), but this correlation was not found in H. pylori
      infected cancer patients. In summary, the cancer related T epitope is expressed
      in H. pylori and modulation of T antigen-specific immune response in H. pylori
      infected individuals suggests that H. pylori infection may alter natural immune
      mechanisms against cancer.

PMID- 12472180
TI  - Production and characterization of an anti-idiotypic single chain Fv that
      recognizes an anti-DNA antibody.
AB  - A well-characterized recombinant anti-idiotype to an anti-DNA antibody can be
      useful for studies of the regulation of anti-DNA-producing B cells. Using a
      hybridoma technique, a monoclonal anti-idiotypic antibody, designated O2F3, was
      obtained, and its scFv gene was constructed. O2F3 single chain Fv (scFv) was
      produced against an idiotope of a monoclonal anti-DNA antibody, 3D8, that was
      obtained from an autoimmune-prone mouse, MRL-lpr/lpr. Here we describe the
      production and in vitro characterization of the O2F3 scFv, and compare it with
      its parent monoclonal antibody, O2F3 IgM. To characterize O2F3 scFv and O2F3 IgM,
      we generated recombinant 3D8 fragments, including 3D8 scFv, 3D8 VH, and 3D8 VL,
      that were used as antigens in several assays. ELISA and Western blot analysis
      showed that both O2F3 scFv and O2F3 IgM recognized a conformational determinant
      formed by the association of the variable region heavy and light chains of the
      3D8 antibody, suggesting that O2F3 scFv retained a similar binding pattern to its
      parent O2F3 antibody. The idiotope recognized by O2F3 was shown by competitive
      ELISA to be outside of the DNA binding site of the 3D8 antibody. This
      characterized O2F3 scFv could be applied for the regulation of anti-DNA antibody
      production and the manipulation of recombinant antibody-based proteins to which
      toxins, enzymes, and chemical agents can be connected.

PMID- 12472181
TI  - Antibodies against the human heat shock protein hsp70 in patients with severe
      coronary artery disease.
AB  - Heat shock proteins (hsps) play complex role in the function of the immune
      system, they can activate both humoral and cellular immune response, as well the
      complement system. Although autoimmunity to hsp70 was implicated in certain
      autoimmune diseases and other conditions, the exact role of anti-hsp70 antibodies
      is not known. It was demonstrated by our previous work and other's findings that
      antibodies against the 60 kDa hsps are strongly associated with coronary
      atherosclerosis and carotis disease. It is also known that there is increased
      hsp70 expression at different sites of atherosclerosis. Therefore our aim was to
      study whether level of anti-hsp70 antibodies correlate with the presence of
      severe coronary artery disease (CAD). We measured and compared anti-hsp70 IgG
      antibody levels in CAD patients (n = 99) and healthy subjects (n = 99) with
      ELISA. The frequency of these antibodies was high in both groups and there was no
      significant difference in the median level of anti-hsp70 antibodies between
      patients with severe CAD and controls (653 (400-1141) vs. 630 (326-1152) AU/mL, P
      = 0.337). Adjustment for age, sex, BMI and lipid parameters did not change this
      result. Furthermore we did not find a correlation between anti-hsp70 antibody
      levels and certain risk factors of CAD (age, lipid parameters, body mass index, C
      reactive protein, gender, smoking, diabetes and anti-hsp60 antibodies). By
      contrast, in accordance with our previous findings, anti-hsp60 and anti-hsp65
      antibody levels were significantly higher in CAD patients, compared to this
      control group (p < 0.0001 for both variables). We did not find any correlation
      between the levels of anti-hsp70 and anti-hsp60 or anti-hsp65 antibodies either
      in the patients or the controls. The exact role of hsp70 in atherosclerosis is
      controversial, but we suggest that humoral immunity against human hsp70 does not
      contribute to coronary atherosclerosis in contrast to antibodies against 60kDa
      hsps.

PMID- 12472182
TI  - A simple method for the purification of human peripheral blood antigen presenting
      cells (dendritic cells, monocytes/macrophages, and B lymphocytes).
AB  - An adherence method was developed that enriches for antigen presenting cells
      (dendritic cells, monocytes/macrophages, and B lymphocytes) from peripheral blood
      mononuclear cell (PBMC) preparations. This method utilizes the cells' natural
      adherence to polystyrene tissue culture dishes and their subsequent removal with
      K3EDTA after incubation at 4 degrees, with gentle pipeting. Flow cytometric
      analysis revealed that on average, the enrichment of CD83+ dendritic cells, CD14+
      monocytes/ macrophages, and CD19+ B cells increased by 12.5 to 20, 2, and 4 fold,
      respectively, compared to their initial numbers present in PBMC preparations.
      Cell viability, determined by trypan blue exclusion, was between 90 and 98%.
      After the enrichment procedure, the cells could still be activated by tetanus
      toxoid and this was shown by flow cytometric analysis, as enhancement of class II
      major histocompatibility complex (MHC) (31% increase) (after antigen treatment).
      This is a fast and economical alternative to other established methods for the
      preparation of pure, functionally competent antigen presenting cells derived from
      peripheral blood.

PMID- 12472183
TI  - Cross reaction of tetanus and botulinum neurotoxins A and B and the boosting
      effect of botulinum neurotoxins A and B on a primary anti-tetanus antibody
      response.
AB  - The present studies were carried out in order to investigate the cross-reaction
      of botulinum neurotoxins (BoNTs) with human and mouse antibodies against tetanus
      neurotoxin (TeNT) and determine whether injection of BoNT into a host that has
      been primed with TeNT would result in boosting of the response to the injected
      BoNT. Human antisera against TeNT obtained from 9 individuals were found to
      exhibit substantial cross-reaction with BoNTs A and B. We prepared antibodies
      (Abs) against inactivated tetanus neurotoxin (TeNT) in outbred mice and
      determined the binding of these Abs to active TeNT and active botulinum
      neurotoxins (BoNTs) A and B. Blood samples were collected before immunization
      (day 0) and on days 42, 82 and 125 after the first injection. The reactions of
      these sera with the immunizing antigen (inactivated TeNT), active TeNT, active
      BoNT/A and active BoNT/B were determined. At a fixed dilution (1:62.5 v/v), the
      sera contained high levels of Abs that reacted with TeNT and also with BoNTs A
      and B. Throughout the test period (up through day 125) and at different dilutions
      the cross-reactions of the antisera with BoNT/B were almost twice those with
      BoNT/A. The reactions of the antisera with the immunizing antigen (inactive TeNT)
      or with active TeNT were essentially equal throughout the dilution range tested
      (1:16-1:500 v/v). To determine whether injection of BoNT/A or B into a host that
      had been primed with TeNT resulted in boosting of the response to the priming
      antigen (TeNT) as well as BoNT/A or B, mice were primed with TeNT and boosted 21
      days later with TeNT, BoNT/A or BoNT/B. Appropriate controls were also employed.
      Blood samples were collected prior to TeNT priming (day -1) and on days 21, 32,
      46 and 67 after priming. In TeNT-primed mice, BoNTs A or B boosted the anti-TeNT
      Ab responses slightly but had no significant boosting effect on the Ab
      populations that bind to BoNTs A or B. It is concluded that while Abs against
      TeNT cross react with BoNTs and the cross reaction with BoNT/B is almost double
      that of BoNT/A, injection of BoNTs A or B in the presence of a prior active
      immunity against TeNT is not very likely to make the host mount an Ab response
      against the injected BoNT.

PMID- 12472184
TI  - Immunoglobulin purification by affinity chromatography using protein A mimetic
      ligands prepared by combinatorial chemical synthesis.
AB  - Affinity chromatography using protein A from Staphylococcus aureus as the ligand
      has been widely used for the isolation of immunoglobulin G (IgG) from various
      species. Since ligand leakage from the affinity support can occur, time consuming
      analytical controls are required to detect the presence of contaminants
      associated with the isolated IgG prior to its use for therapeutic purpose in
      humans. Besides, protein A is an expensive bacterial product, whose isolation
      involves complex and labor intensive procedures. Combinatorial chemistry enables
      the synthesis of a wide variety of ligands within a short period of time.
      Therefore, chemically defined, stable and inexpensive ligands, which can mimic
      the action of protein A, have been developed to isolate immunoglobulins. Two
      different types of ligands, synthesized following the techniques of combinatorial
      chemistry, have been used to isolate immunoglobulins. One of them is a synthetic
      peptide (TG 19318) comprising four identical tripeptide chains linked to a
      central polylysine core. Immobilized TG 19318 has been used to isolate polyclonal
      and monoclonal antibodies of different classes (IgG, IgM, IgA, IgE) from
      different sources (serum, ascities and cell supernatants) and species. The ligand
      has a binding capacity that can reach upto 25mg IgG/mL of the support. It is
      stable when treated with sanitation agents such as ethanol and 0.1 M sodium
      hydroxide. Computer-aided molecular design and combinatorial chemistry have been
      used to develop an IgG binding affinity ligand (22/8), which consists of two
      organic aromatic amines (3-aminophenol and 4-amino-1-napthol) linked to a
      scaffold of cyanuric chloride (triazine). Ligand 22/8 displayed wider specificity
      than protein A, as it isolated IgG from a number of species, the order of
      adsorption being human> chicken > cow > rabbit > pig > horse > rat > goat > sheep
      > mouse. It showed an apparent binding capacity of 51.9 mg IgG/g moist gel and
      can isolate human IgG from plasma in 60% yield with a purity of 92%. The ligand
      is stable, as it withstood incubation in 1M NaOH for a week without loss of
      binding capacity for IgG. These findings suggest that synthetic affinity ligands,
      which are inexpensive, stable and specific can facilitate the purification of
      immunoglobulins in a cost-effective manner.

PMID- 12472185
TI  - The global reach of HIV: preventing mother-to-child transmission.
AB  - This article focuses on the effects of the worldwide human immunodeficiency virus
      (HIV) epidemic on the lives of pregnant women and their infants in the developing
      world. It discusses the natural history of mother-to-child transmission (MTCT) in
      HIV, including the role of breastfeeding and the effectiveness of various
      treatment/prevention schemes in resource-poor communities. Although the treatment
      schemes are not the same as those used in North America, the underlying
      principles of transmission are the same. Understanding the mechanisms of MTCT and
      recognizing the benefits of even short-term therapies can promote appropriate
      interventions when complete perinatal antiretroviral therapy is impossible.

PMID- 12472186
TI  - Challenges and opportunities: the health of women and newborns in the Russian
      Federation.
AB  - Dramatic socio-political, economic, and health care changes are occurring in the
      Russian Federation. Over time they are projected to have a positive impact on the
      health and well-being of women and newborns. The key to health care reforms is
      the emergence of a strong nursing profession. Notably, international
      collaborative efforts are strengthening the work of Russian nurses in improving
      perinatal health. In this millennium of global migration, where the world is
      growing increasingly smaller, it is important to understand health care systems
      and the health concerns of women and newborns living in other countries.
      Celebrating cultural differences, while embracing global similarities, is
      essential in ensuring that culturally sensitive and competent care is provided to
      women and newborns.

PMID- 12472187
TI  - Acculturation and perinatal outcomes in Mexican immigrant childbearing women: an
      integrative review.
AB  - Despite several sociocultural factors associated with increased risk for low
      birth weight and infant mortality, the rate for infants born to first-generation
      and less acculturated Mexican immigrant women is the same as that of non-Hispanic
      whites, and half that of African Americans with similar risks. It appears that
      sociocultural rather than genetic variables are the primary factors associated
      with this phenomenon. Higher levels of acculturation to North American values and
      lifestyle in Mexican American childbearing women have been correlated with poor
      perinatal outcomes, including low birth weight. Acculturation is emerging as an
      important variable that should be considered when providing health care to
      Mexican immigrant childbearing women and their families.

PMID- 12472188
TI  - Health promotion for childbearing women in Rubanda, Uganda.
AB  - A train-the-trainer intervention, based on the World Health Organization's Safe
      Motherhood Initiative, was successful in changing some health beliefs and health
      practices among village men and women of childbearing age in a remote area of
      Uganda. Specifically, more villagers reported attending postpartum care and
      beginning prenatal care earlier in pregnancy. Some beliefs were not changed (eg,
      belief in bewitchment), but some beliefs (eg, use of herbal medicines during
      labor) were not as widely held as a result of this cost-effective and easily
      sustainable program.

PMID- 12472189
TI  - Care of substance-exposed infants: the current state of practice in Canadian
      hospitals.
AB  - Many practices related to care of infants exposed to drugs and alcohol during th
      e prenatal period have been developed on an anecdotal basis. There are few
      available research studies to validate these interventions. This study describes
      current practices used in daily care, discharge planning, and community support
      for drug- and alcohol-exposed infants, their families, and alternate caregivers
      in one country. A survey of Canadian hospitals with annual birth rates of greater
      than 500 was conducted with a 51% return rate. Variations were noted in the
      perception of the importance of the issue of perinatal substance use, nursery
      care, discharge planning, and community support. Nurses are encouraged to
      consider these results within the context of their own communities to evaluate
      and develop standards of practice for substance-exposed infants and their
      families and caregivers.

PMID- 12472190
TI  - Attachment behaviors in mothers of premature infants: a descriptive study in Thai
      mothers.
AB  - Prematurity and the associated maternal-infant separation after birth can affect
      the attachment process. The role of nurses in facilitating the process of
      attachment should be based on an understanding of these behaviors. This
      descriptive study explored the attachment behaviors demonstrated by mothers
      during their first visit with their premature infant in the neonatal care unit.
      The results revealed that all mothers demonstrated most attachment behaviors (ie,
      inspection, facial expression, touching, verbal expression, and eye-to-eye
      contact) except holding during their first visit. However, some mothers spent
      little time with their infant. The findings suggest that nurses should encourage
      mothers to interact with their infants in order to enhance maternal-infant
      attachment.

PMID- 12472191
TI  - Development of a neonatal intensive care unit in Uganda, Africa.
AB  - Developing nations face tremendous challenges in providing care to mothers and
      children. Uganda has some of the highest maternal and infant mortality rates in
      the world. The Luwero Triangle in central Uganda is one of the poorest areas of
      Uganda. In the late 1990s, the ISIS Foundation began developing a neonatal
      intensive care unit (NICU) in this area. The article describes NICU development
      and relates the author's experiences in working with the staff of Kiwoko
      Hospital. The overall goal of this effort has been to assist the hospital to be
      more self-sufficient using a train-the-trainer approach.

PMID- 12472192
TI  - Effects of gentamicin, lipopolysaccharide, and contrast media on immortalized
      proximal tubular cells.
AB  - Aminoglycosides are widely used in the treatment of gram-negative bacterial
      infections. Gentamicin (GE) acts mainly in proximal tubular cells, where it is
      uptake via organic anion transport system and it induces a high incidence of
      nephrotoxicity, which is characterized by tubular necrosis [5] leading to acute
      renal failure in 10 to 50% of patients. Gram-negative bacteria has
      lipopolysaccharide (LPS) which is an endotoxin that cause renal damage. [1]
      Moreover, many patients are undergone exams using radiologic contrast, which is a
      risk factor to induce a hemodynamic change in the kidney and to develop acute
      renal failure. [6] Intracellular calcium [Ca2+]i is involved in renal cellular
      injury [7,3] and maybe mediate the effects provoked by these drugs. This study
      was performed to evaluate necrosis, apoptosis, and intracellular calcium levels
      ([Ca2+]i) in LLC-PK1 (epithelial cell line from pig kidney) induced by GE
      associated with LPS and a low-osmolality media, Hexabrix (HE).

PMID- 12472193
TI  - Antioxidants modulate adenosine metabolism in rat mesangial cells cultured under
      high glucose conditions.
AB  - Glomerular mesangial cells play a major role in glomerular hemodynamics,
      considered also as antigen-presenting cells participating in immune response.
      Mesangial dysfunction and proliferation are typical lesions of diabetic
      glomerulopathy. Adenosine, a local hormone, produced by mesangial cells is a
      metabolic regulator of renal blood flow, capable of decreasing glomerular
      filtration rate (GFR), exerting immunosuppressive, antiproliferative and anti
      inflammatory properties. Since it was well established that antioxidants confer
      protection against increased oxidative stress that occurs in diabetes, the effect
      of captopril, reduced glutathione and melatonin on adenosine metabolism was
      investigated. Glomerular mesangial cells obtained from collagenase treated
      glomeruli, isolated from renal cortex of Sprague-Dowley rats, were grown under
      high glucose conditions (30 mmol/L) as a model of diabetic microenvironment. The
      activity of adenosine metabolizing enzymes: 5'-nucleotidease (5'-NU) responsible
      for its production and adenosine deaminase (ADA) responsible for its degradation
      were investigated. Hyperglycemic conditions led to decreased adenosine production
      via 5'-NU and decreased removal via ADA. Captopril, given in therapeutic
      concentration induced enzyme activities in normoglycemic conditions and restored
      hyperglycemia-induced decrease. In order to investigate if the presence of SH
      groups may be responsible for this improvement, the cells were exposed to reduced
      glutathione, and it exerted almost equal effect, given in physiological and
      higher concentrations. Melatonin increased 5'-NU activity only in physiological
      glucose conditions. Presented results confirm potential renoprotective effect of
      SH-group containing antioxidant supplementation during diabetes in restoring
      adenosine metabolism.

PMID- 12472194
TI  - Monocyte chemoattractant protein-1 expression correlates with monocyte
      infiltration in the post-ischemic kidney.
AB  - Chemokines play a prominent role in the acute inflammatory response in several
      models of kidney disease. We reported that monocyte chemotactic peptide-1 (MCP-1)
      mRNA is increased by ischemia-reperfusion injury. In this report, we examined the
      effects of ischemia-reperfusion injury on the kinetics and location of MCP-1
      protein expression, the excretion of MCP- 1 protein in the urine and on the
      infiltration of mononuclear cells in the kidney. Pair-fed Sprague-Dawley rats
      underwent bilateral renal ischemia (50 min) or sham ischemia and placed in
      metabolic cages for daily urine collections. Kidneys were harvested at d. 1, 3,
      7, and 10 after ischemia-reperfusion (I-R) or sham-ischemia (S-I). Kidney MCP-1
      mRNA levels were increased on d. I and 3 post-ischemia. Kidney MCP-1 protein
      levels were increased in the I-R group on d. 1 and 3. MCP-1 expression occurred
      predominantly in the distal tubule segments by immunohistology. There was an
      increase in monocytes/macrophages infiltration in the I-R group, compared to the
      S-I or controls by d. 1. Urinary MCP-1 excretion increased 3-fold in the I-R
      group, and remained elevated above the S-I group and baseline levels, on d. 3
      through d. 8. Kidney MCP-1 mRNA levels, protein levels and urinary MCP-1
      excretion rates are increased by ischemia-reperfusion injury. The areas of
      increase in MCP-1 chemoattractant expression correlates with an increase in
      monocyte infiltration in the kidney. Although its pathophysiologic role remains
      to be determined, MCP-1 may participate in, and be a biomarker for, the
      mononuclear inflammatory processes that occur after ischemia-induced acute renal
      failure.

PMID- 12472195
TI  - Effects of N-acetylcysteine on myoglobinuric-acute renal failure in rats.
AB  - Oxygen metabolites play an important role in renal injury during myoglobinuric
      acute renal failure (ARF). This study was designed to determine the protective
      influence of N-acetylcysteine (NAC), a hydroxyl radical scavenger, and treatment
      in an experimental model of myoglobinuric-ARF induced by intramuscular injection
      of hypertonic glycerol in rats. The rats were randomly distributed into five
      groups: Group 0 (n = 10), was assigned to receive 2mL saline (0,9%)
      intraperitoneally (ip); Group 1 (n = 10), NAC ip in a dose of 0 mg/100 g of body
      weight 30 min before the intramuscular (im) injection of 50% glycerol (10 mg/kg);
      Group 2 (n = 10), received saline 0,9% ip in a equivalent volume of NAC in Group
      I before the im injection of glycerol; Group 3 (n = 10), received NAC ip in a
      dose of 10 mg/100 g after im injection of glycerol; Group 4 (n = 10), saline 0,9%
      ip in a equivalent volume of NAC of the Group 3 after im administration of
      glycerol. After 24 h rats were sacrificed and kidney morphology and renal
      function were determined. A severe renal failure was produced by glycerol
      injection in the Groups 1, 2, 3, and 4, with significant tubular proximal
      necrosis and cast formation, and creatinine and urea concentrations were elevated
      in these groups without significant differences among groups, but Group 0 where
      the values were significantly lower. The results of this study suggests that ip
      administration of NAC in rats before or after glycerol injection do not confer
      protection against impairment of renal function under these conditions in this
      model of myoglobinuric-ARF.

PMID- 12472196
TI  - Effects of melatonin administration to rats with glycerol-induced acute renal
      failure.
AB  - Melatonin, the pineal hormone with antioxidative properties was administered to
      rats with glycerol-induced myoglobinuric acute renal failure (Gly-ARF). This
      model is characterized by acute tubular necrosis mediated by heme-iron oxidative
      stress. Rats received melatonin (20 mg/kg) concomitant and 3 h after glycerol
      injection. Gly-ARF rats showed at 24 h a 78% reduction in glomerular filtration
      rate, whereas this decrement was significantly reduced to 35% in the melatonin
      treated Gly-ARF rats. Tubular function evaluated by tubular reabsorption of
      sodium and lithium was also preserved in melatonin treated rats. The histologic
      analysis revealed extensive cortical tubular necrosis that was significantly
      reduced by melatonin treatment. The renal concentration of malondialdehyde (MDA)
      was increased 6 h after glycerol injection in Gly-ARF and this elevation was
      prevented when melatonin was administered. Renal concentration of reduced
      glutathione (GSH) was decreased at 6 h in Gly-ARF and melatonin did not reverse
      this decrease. It was concluded that melatonin administration attenuated the
      renal injury in the glycerol model of acute renal failure and reduced kidney
      oxidative stress through a GSH-independent mechanism.

PMID- 12472197
TI  - The role of determining the levels of serum collagen type IV in diagnosing early
      diabetic nephropathy.
AB  - Two molecules of type IV collagen are linked via the COOH-terminal non
      collagenous domain (NCI domain). In this way, type IV collagen forms the main
      framework of basement membrane. We have developed sandwich Enzyme-Linked
      Immunosorbent Assay (ELISA) for human serum type IV collage peptide monoclonals
      for CO5 and CO6 recognizing two different determinants on the central triplex of
      human collagen molecules. Using this, we explored the possibility that serum
      levels of type IV collagen (Col IV) are an indicator of early diabetic
      nephropathy (DN). Serum type IV collagen levels were determined by ELISA in 36
      patients with diabetic nephropathy. Serum hemoglobin A1c (HbA1c) and in twenty
      four hour urinary albumin excretion rates (UAER) were measured at the same time.
      A relationship was found between serum levels of this collagen IV and the
      presence of diabetic nephropathy. That is, serum levels of type IV collagen in
      diabetic nephropathy were significantly higher than those found in non-insulin
      dependent diabetic (NIDDM) patients without nephropathy and in healthy subjects
      (HS). It is possible that an elevated serum collagen type IV level reflects
      increased synthetic activity in basement membrane collagen type IV. Serum type IV
      collagen may be a useful marker for monitoring the dynamics of basement membrane
      metabolism and in this way serve as a clinical indicator of the progression or
      the activity of diabetic nephropathy and a marker for the assessment of
      therapeutic effects.

PMID- 12472198
TI  - An ex-vivo evaluation of vascular catheters for continuous hemofiltration.
AB  - OBJECTIVES: To measure outflow and inflow hydraulic resistance in double-lumen
      catheters used for hemofiltration under standardized laboratory conditions.
      SETTING: ICU Laboratory of tertiary unit. METHODS: Heparinized spent red cells
      diluted in polygeline solution to a constant hematocrit of 32% at 37 degrees C
      were pumped using a standard Prisma M60 circuit through several hemofiltration
      catheters. Blood pump speed was increased and decreased in steps of 30mL/min (30,
      60, 90, 120, 150, and 180 mL/min) and catheter outflow and inflow pressures
      recorded and used to define the pressure flow relationship (line of hydraulic
      resistance) for each. RESULTS: Double-lumen catheters posed different resistances
      to outflow or inflow. Among the < 15 cm long catheters, the 11.5 Fr Quinton
      Mahurkar (0.56 mmHg/mL/min) catheter offered the least resistance to outflow,
      while the Medcomp 11.5 Fr catheter offered the least resistance to inflow (0.78
      mmHg/mL/min). Among the >19 cm long catheters, the 13.5 Fr Vascath Niagara
      catheter showed the lowest blood flow resistance to both outflow (0.63 mmHg/
      mL/min) and inflow (0.83 mmHg/mL/min). Longer catheters did not pose
      statistically greater resistance to both outflow and inflow. Resistance to inflow
      was consistently greater than resistance to outflow (p = 0.003). Overall, the
      Prisma M60 blood circuit alone accounted for 40% of the total extracorporeal
      circuit blood flow resistance. CONCLUSIONS: Proprietary hemofiltration catheters
      have variable resistance to blood flow under standard ex-vivo conditions. This ex
      vivo information might be useful to clinicians in guiding their choice of
      catheters for clinical use.

PMID- 12472199
TI  - The impact of nasal carriage of methicillin-resistant and methicillin-susceptible
      Staphylococcus a ureus (MRSA & MSSA) on vascular access-related septicemia among
      patients with type-II diabetes on dialysis.
AB  - BACKGROUND: Fairly higher nasal carriage rates among type-II diabetics place them
      at a greater risk of endogenous Staphylococcus aureus linked vascular access
      related septicemia (VRS) that is also dependent on the type of vascular access
      used for hemodialysis (HD). The prevalence of nasal carriage of methicillin
      susceptible and methicillin-resistant S. aureus (MSSA and MRSA) and its impact on
      VRS was determined in order to identify most vulnerable group and plan potential
      prophylactic strategies, accordingly. METHODS: Five standardized nasal swab
      cultures were performed in 208 patients enrolled for long-term HD through July
      1996 to July 1999. Persistent nasal carriage was defined by two or more positive
      cultures for MSSA or MRSA. Peripheral blood cultures were collected on clinical
      suspicion of septicemia. RESULTS: The prevalence of type-II diabetes of 28.0%
      with 72.4% of nasal carriage rate and three folds higher S. aureus related VRS
      (RR-3.19, p<0.0001) than diabetic non-carriers on HD, was observed. Type-II
      diabetics also had higher MSSA and MRSA nasal carriage rates (53.4% and 19.0%)
      than non-diabetic nasal carriers (18.6 and 6.0%) yet, carried a comparable (RR
      4.0 vs. 4.5) risk of VRS between MSSA and MRSA nasal carriers. Among diabetic
      type-II S. aureus nasal carriers, central venous catheters (CVCs) carried 35 and
      38 times higher collective risk of developing MSSA and MRSA nasal carriage
      related VRS respectively than Arterio-venous fistula (AVF). The AVF recorded the
      lowest risk of developing MSSA and MRSA nasal carriage-related VRS (0.013 and
      0.010 episodes/patient-year) in both diabetic type-II MSSA and MRSA nasal carrier
      groups. CONCLUSIONS: Diabetic type-II S. aureus nasal carriers on HD through CVCs
      make an extremely high-risk group for MSSA and MRSA nasal carriage-related VRS.
      The incidence of S. aureus nasal carriage-related VRS could reasonably be reduced
      through a challenging obligation of optimizing AVF prevalence in this high-risk
      group, while limiting the use of CVCs, at the same time.

PMID- 12472200
TI  - Effect of dialysis on erythrocyte membrane of chronically hemodialyzed patients.
AB  - The present work examines the role of uremia and the effect of dialysis treatment
      on red blood cells (RBCs) membrane properties of hemodialysis patients. The
      results showed that, the uremic patients had a lower values of erythrocyte
      deformability than that of healthy control subject. The median osmotic fragility
      (MOF) showed a significant increase in hemodialyzed patients than that for
      control group. The osmotic resistance to hemolysis was improved after dialysis.
      The solubilization process of the RBCs membrane showed that the detergent
      concentration needed to solubilize the RBCs membrane for uremic patient was much
      higher than that for control group. The abnormalities of the present results for
      RBCs membrane properties are mostly related to membrane fluidity, which are
      slightly improved after dialysis. Biochemical analysis showed a decreasing trend
      in RBCs count, urea nitrogen, creatinine, potassium,

PMID- 12472201
TI  - Diffuse alveolar hemorrhage in systemic lupus erythematosus: a single center
      retrospective study in Taiwan.
AB  - This study is to describe our clinical experience of diffuse alveolar hemorrhage
      (DAH) in patients with systemic lupus erythematosus (SLE) in Taiwan. From July
      1994 to June 2001, eight patients of DAH among 1541 different SLE patients
      (0.52%) admitted to the Chang Gung Memorial Hospital were included for chart
      review. Dyspnea (100%) and fever (87.5%) were the most common symptoms instead of
      hemoptysis (62.5%). The most common extrapulmonary presentation was renal
      involvement (100%), which included clinical nephritis, nephrotic syndrome or
      acute renal failure. The overall mortality rate was 50%. Two pregnant patients
      were successfully treated with combined plasmapheresis and continuous venovenous
      hemofiltration in addition to high dose corticosteroid. Analysis of the
      prognostic factors showed that the higher APACHE II (Acute physiology, Age and
      Chronic Health Evaluation) and organ system failure (OSF) scores, but not the SLE
      activity index (SLEDAI), were associated with the greater mortality. The higher
      serum creatinine level or the need of hemodialysis did not adversely affect the
      survival. In conclusion, DAH in SLE patients are often accompanied with multiple
      organ failure, aggressive immunosuppressive therapy and multiple modalities of
      extracorporeal organ support should be started early for a favorable outcome.

PMID- 12472202
TI  - Does type 2 diabetes mellitus delay renal failure in autosomal dominant
      polycystic kidney disease?
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is a common renal disease
      without an effective therapeutic intervention to delay renal failure. Within
      kindreds, renal dysfunction often develops at a similar age in affected
      individuals, although there are known modifying factors. Two kindreds with ADPKD
      have shown a striking pattern of delayed onset of renal insufficiency in those
      individuals also suffering from type 2 diabetes mellitus. Eight nondiabetic
      patients with ADPKD had onset of dialysis or renal death at ages 38-52 years,
      (mean +/- SEM 46 +/- 1.9, n = 7) as compared with four diabetics who started
      dialysis or are still off dialysis at the age of 61 +/- 2.8 years (p < 0.01). Two
      of the four diabetics still have reasonable renal function at age 61 and 66. The
      diabetes was diagnosed at age 32 +/- 2 years and was treated with oral
      hypoglycemics for 19 +/- 2 years before institution of insulin. Cardiovascular
      disease dominated the clinical picture in the diabetics. In conclusion, onset of
      renal failure in ADPKD was delayed for over 15 years in individuals who also
      suffered from type 2 diabetes mellitus, in two ADPKD kindreds. Possible
      mechanisms are discussed, including glibenclamide inhibition of the cystic
      fibrosis transmembrane conductance regulator. The striking delay associated with
      type 2 diabetes mellitus in ADPKD induced renal failure should be evaluated
      further.

PMID- 12472203
TI  - Bronchiectasis-related amyloidosis as a cause of chronic renal failure.
AB  - Bronchiectasis is defined as acquired and permanent abnormal dilation and
      destruction of the bronchial walls. Secondary amyloidosis is a disorder
      characterized by the deposition of amyloid A (AA) in multiple organs and tissues
      in the body. End-stage renal disease (ESRD) secondary to bronchiectasis-related
      amyloidosis has only been mentioned in case reports. Little is known about the
      complications of bronchiectasis-related amyloidosis and the outcomes in patients
      who develop ESRD due to amyloid deposition in the kidneys. The aim of this study
      was to identify the clinical characteristics of this patient group, and to report
      the outcomes of these cases relative to bronchiechtasis type. We assessed the
      records of 40 patients with AA-type amyloid nephropathy and ESRD who were on
      hemodialysis (HD) at Baskent University Hospital between 1997 and 2000. The
      diagnosis of amyloidosis was based on histopathological findings in kidney,
      rectum, bone marrow, lymph node, thyroid, bladder, liver, and stomach biopsies.
      Bronchiectasis was diagnosed on the basis of history and findings on physical
      examination, chest X-ray, and thoracic high-resolution computerized tomography
      (HRCT). The patients' records were retrospectively evaluated for cause of
      secondary amyloidosis, and cases with causes other than bronchiectasis were
      excluded. Secondary amyloidosis due to bronchiectasis and recurrent pulmonary
      infection was identified in 40% (16 patients) of the 40 patients. For each of
      these 16 cases, we recorded patient age, duration of bronchiectasis, duration of
      HD, amount of lung involvement, and biopsy site(s). The means for age, duration
      of bronchiectasis, and duration of HD in the 16 patients were 50.6 +/- 13.5
      years, 22.18 +/- 12.02 years (range, 6-42 years), and 30.81 +/- 36.94 months
      (range, 4-144 months), respectively. The most common biopsy site was the rectum
      (n = 8). Thoracic HRCT revealed cystic bronchiectasis in 8 cases (50%). Four of
      these 8 patients (25% of the group of 16) died from sepsis within 3-year follow
      up period. Two of the four patients who died had bilateral cystic bronchiectasis,
      and the other two had unilateral cystic bronchiectasis. In the other eight
      patients in the group, thoracic HRCT showed chronic fibrotic changes in the
      pulmonary parenchyma and minimal traction bronchiectasis. Four of these patients
      exhibited apical fibrosis and bronchiectasis (25% of the group of 16), and these
      radiological findings were considered sequelae of previous tuberculosis
      infections. In conclusion, chronic respiratory infections and associated
      bronchiectasis remain a serious problem in Turkey due to insufficient prevention,
      diagnosis, and treatment. It is important that patients with progressive cystic
      and diffuse bronchiectasis be followed carefully, as they may develop amyloidosis
      and ESRD in time. Also, the clinical course in patients with cystic
      bronchiectasis may be worse than that in other types of bronchiectasis due to
      complicating pulmonary infections.

PMID- 12472204
TI  - Relations between oxidative stress, hepatocyte growth factor, and liver disease
      in hemodialysis patients.
AB  - BACKGROUND: Hepatocyte growth factor (HGF) and copper/zinc superoxide dismutase
      (Cu/Zn SOD) protect against tissue injury, including that due to oxidative stress
      (SOX). We studied whether they could be associated with each other, SOX markers,
      prevalence of viral hepatitis, and cardiovascular disease (CVD) and their
      laboratory surrogates in maintenance hemodialysis (HD) patients. METHODS: In 24
      patients, pre-dialysis serum HGF, plasma Cu/Zn SOD, total lipid peroxides, and
      serum autoantibodies against oxidized LDL were measured by ELISAs. Viral
      hepatitis B and C markers were determined by third generation microparticle
      ELISAs, and CVD was identified on a clinical basis. RESULTS: In HD patients,
      circulating HGF, Cu/Zn SOD, and the other SOX markers were higher than in healthy
      controls, and HGF directly correlated with Cu/Zn SOD levels (P = 0.0006). Both
      HGF (P = 0.021) and Cu/Zn SOD (P=0.017) were positively associated with
      prevalence of viral hepatitis and serum alanine aminotransferase activity (P =
      0.021 and P=0.040, respectively). Presence of CVD directly correlated with HGF (P
      = 0.001) but not with Cu/Zn SOD levels (P = 0.087). Circulating HGF positively
      related to serum C-reactive protein (P = 0.043). In patients without viral
      hepatitis and CVD, both HGF and Cu/Zn SOD were lower than in those with, and
      higher than in healthy controls. CVD (P = 0.003) and viral hepatitis (P = 0.024)
      were independent predictors of increased HGF, while positive viral hepatitis
      marker predicted increased Cu/Zn SOD levels (P = 0.019) in HD patients. There
      were no associations between HGF and the SOX markers in controls. CONCLUSIONS: In
      maintenance HD patients, circulating Cu/Zn SOD and HGF levels are increased,
      likely as a part of the reparatory reaction against liver damage. Viral hepatitis
      status and liver function should be considered in further studies of Cu/Zn SOD in
      these subjects.

PMID- 12472205
TI  - Possible strategies to prolong circuit life during hemofiltration: three
      controlled studies.
AB  - BACKGROUND AND AIMS: The prevention of filter clotting is an important goal in
      the management of continuous renal replacement therapy (CRRT). Anticoagulation is
      the mainstay of such prevention. However, other strategies might prolong filter
      life without increasing the risk of bleeding. We tested the effectiveness of
      three strategies (use of flat plate configuration, heparin administration into
      the air chamber and use of a larger membrane surface) aimed at prolonging circuit
      life without increasing the dose of anticoagulation. METHODS: Thirty-one
      critically ill patients with acute renal failure (ARF) managed with continuous
      venovenous hemofiltration (CVVH) were studied. Filters were randomized in a
      crossover design to three consecutive studies: (1) filtration with either hollow
      fiber or flat-plate hemofilters, (2) administration of heparin dose pre-filter or
      divided into pre-filter and directly into the bubble trap chamber and (3) use of
      two different surface areas with Filtral 8 (surface area 0.75 m2) vs. Filtral 12
      (surface area 1.30 m2) hemofilters. RESULTS: Mean circuit life for flat-plate and
      hollow-fiber hemofilters (cohort 1) was 14.7 +/- 4.7 h and 17.1 +/- 2.8h
      respectively (NS). Mean circuit life for single heparin administration site vs.
      double site administration (cohort 2) was 17 +/- 3.2 h and 18 +/- 3.1 h
      respectively (NS). Mean circuit lifespan for 0.75 m2 and 1.30 m2 hemofilters was
      16 +/- 12.2 h and 15.7 +/- 14.3 h respectively (NS) (cohort 3). Visible clot
      formation in the bubble trap chamber was a frequent cause of circuit failure.
      CONCLUSION: Neither flat plate membrane configuration nor increasing membrane
      surface area, nor heparin administration in the air chamber prolong circuit life
      during CWH. The bubble trap chamber is a frequent site of circuit clotting.

PMID- 12472206
TI  - Postpartum hemorrhage complicated with irreversible renal failure and central
      diabetes insipidus.
AB  - Sheehan's syndrome is a rare complication of pregnancy with multiple hormone
      deficiency. The exact pathogenetic mechanism is not well understood, because such
      endocrine abnormalities are not obvious in most women with severe hemorrhage.
      Central diabetes insipidus with fluid and sodium disturbances occurred in about
      5% of the patients. [1,2] There are very few existing literature discussing
      concomitant Sheehan's syndrome and acute renal failure. The following case
      reports a patient showing Sheehan's syndrome, irreversible acute renal failure
      and central diabetes insipidus concurrently.

PMID- 12472208
TI  - Cholestasis and renal failure in a patient with secondary amyloidosis.
AB  - Amyloid, was first described in the 19th century by Virchow, which means starch
      or cellulose. Extracellular deposition of this unique protein fibrils in tissues,
      often leading organ dysfunction is known as amyloidosis. In systemic amyloidosis,
      amyloid fibrils may deposit in different organs including kidneys, heart and
      liver. Although liver is effected frequently, clinical liver disease is rare.
      There are a few cases that secondary amyloidosis presented with hepatic
      involvement and cholestasis which seems to be limited to primary amyloidosis.
      Hepatic amyloidosis with cholestasis may be a predictor of involvement of other
      organs and thus of poor prognosis. We report a case of a 67 year old man with
      renal failure and prominent cholestasis due to AA amyloid deposition in the
      liver.

PMID- 12472207
TI  - Pregnancy during chronic hemodialysis: a single dialysis-unit experience with
      five cases.
AB  - BACKGROUND: Pregnancy is uncommon in women with end-stage renal disease (ESRD)
      requiring chronic dialysis. An increasing number of successful pregnancies in
      women in hemodialytic treatment have been recently reported but few institutions
      experienced more than one or two cases of pregnancy. METHODS: Between 1988-1998
      five pregnancies in patients receiving hemodialysis were observed in our center.
      Medical records of these patients were reviewed. RESULTS: At the conception the
      mean age was 27 years. One patient started dialysis after conception. All
      patients received bicarbonate dialysis. Three patients were dialyzed six times
      per week, the other two patients three-four times per week. The dry weight was
      increased progressively; on average of 1.2 +/- 0.5 kg in the first trimester and
      of 0.5 kg per week since the second trimester. The predialysis BUN was maintained
      between 50-100 mg/dL (17.85-35,70 mmol/L) during the pregnancy. Four patients
      were treated with erythropoietin to maintain hematocrit between 30-35%.
      Erythropoietin related-complications were not observed. Polyhydramnios was
      observed in all cases. All deliveries occurred before term. The mean gestational
      age of infants was 28.6 +/- 4 weeks. Four out of five pregnancies resulted in
      liveborn infants. Two infants had an Apgar score of zero. All neonates were of
      low birth weight (1,431 +/- 738 g) with percentile of birth weight in the normal
      range. No one was small for date. CONCLUSION: A successful pregnancy is possible
      in women on chronic dialysis. Prematurity occurs frequently as well as low weight
      birth leading to increased perinatal morbidity and mortality.

PMID- 12472209
TI  - Subarachnoid hemorrhage and rhabdomyolysis induced acute renal failure
      complicating organophosphate intoxication.
AB  - Organophosphate is extremely uncommon cause of rhabdomyolysis. This article
      describe two cases with rhabdomyolysis induced acute renal failure complicating
      by monocrotophos, an organophosphate compound. First patient had rhabdomyolysis
      induced acute renal failure and subarachnoid hemorrhage. This is the first
      reported case of subarachnoid hemorrhage, which may be related with
      organophosphate intoxication in literature. Second patient described here had
      rhabdomyolysis induced acute renal failure after organophosphate overdose.

PMID- 12472210
TI  - Prognostic significance of changes in the internal acoustic meatus caused by
      vestibular schwannoma.
AB  - The prognostic significance of the variety of changes in the internal auditory
      meatus (IAM) caused by vestibular schwannoma was retrospectively analyzed in 69
      consecutive patients with vestibular schwannoma. Preoperative bone-window
      computed tomography was used to classify IAM changes into extensive destruction
      (17%), widening (46%), and normal IAM (36%). Extensive destruction (47 +/- 19
      years) and widening (48 +/- 13) occurred in significantly younger patients than
      normal IAM (59 +/- 9). Preoperative hearing was significantly more severely
      disturbed in patients with extensive destruction than in those with widening or
      normal IAM. IAM change was significantly related to the tumor consistency, as
      normal IAM was more common in patients with cystic tumor than in those with solid
      tumor. Postoperative hearing and facial function were worse in patients with
      severe IAM change, although the relationship between the IAM change and the
      surgical result was not significant. One patient with extensive destruction
      developed postoperative cerebrospinal fluid (CSF) leakage through the air cells
      around the IAM, and needed surgical repair. Severe IAM change occurs with solid
      tumor and causes severely disturbed preoperative hearing in younger patients,
      which reflects the tumor aggressiveness. Severe IAM change increases the
      technical difficulty of tumor removal and the risk of postoperative CSF leakage,
      and is associated with a poorer prognosis for patients with vestibular
      schwannoma.

PMID- 12472211
TI  - Surgical experience with skull base approaches for foramen magnum meningioma.
AB  - The surgical treatment of patients with foramen magnum meningioma remains
      challenging. This study evaluated the outcome of this tumor according to the
      evolution of surgical approaches during the last 29 years. A retrospective
      analysis of medical records, operative notes, and neuroimages of 492 meningioma
      cases from 1972 to 2001 identified seven cases of foramen magnum meningioma
      (1.4%). All patients showed various neurological symptoms corresponding with
      foramen magnum syndrome. The tumor locations were anterior in five cases and
      posterior in two. Surgical removal was performed through a transoral approach in
      one patient, the suboccipital approach in three, and the transcondylar approach
      in two. Total removal was achieved in all patients, except for one who refused
      any surgical treatment. The major complications were tetraparesis and lower
      cranial nerve paresis for tumors in anterior locations, and minor complications
      for posterior locations. One patient died of atelectasis and pneumonia after a
      long hospitalization. The transcondylar approach is recommended for anterior
      locations, and the standard suboccipital approach for posterior locations.

PMID- 12472212
TI  - Outcome of long-term vagus nerve stimulation for intractable epilepsy.
AB  - The outcome of long-term vagus nerve stimulation (VNS) was evaluated in 13
      Japanese patients with intractable epilepsy, all followed up for more than 4
      years (48-91 months, median 56 months). VNS achieved a long-lasting and
      cumulative seizure-control effect in nine of 13 patients. The mean reduction of
      seizure frequency in the 1st to 4th year was 28%, 47%, 54%, and 63%,
      respectively. The percentage of patients with >60% seizure reduction in the 1st
      to 4th year was 15%, 46%, 54%, and 69%, respectively. One patient did not respond
      to the treatment at all. No patient became completely free from seizure or free
      from medication, but the number and/or dosage of antiepileptic drugs was reduced
      in five patients. Ten patients underwent exchange of the generator and continued
      treatment, and two patients underwent removal of the generator because of the
      unsatisfactory result. VNS controlled more disabling seizures earlier and more
      efficiently than less disabling seizures in seven patients. The cumulative
      reduction of seizures was partly associated with changes in the device setting
      toward increased stimulation. These effects were similar in patients with or
      without previous resective surgery. Long-term VNS therapy achieved a favorable
      outcome in a significant proportion of patients with intractable epilepsy.

PMID- 12472213
TI  - Spontaneous resolution of nontraumatic bilateral intracranial vertebral artery
      dissections.
AB  - A 49-year-old man presented with nontraumatic bilateral intracranial vertebral
      artery dissections without subarachnoid hemorrhage manifesting as Wallenberg's
      syndrome on the right. Magnetic resonance imaging revealed an infarct in the
      right dorsolateral aspect of the medulla oblongata. Antiplatelet therapy was
      administered. Vertebral angiography performed on the 9th hospital day (Day 9)
      revealed pearl and string sign in the right vertebral artery and narrowing of the
      left vertebral artery. Second angiography performed on Day 25 showed no change,
      but third angiography performed on Day 74 revealed spontaneous resolution of the
      bilateral vertebral artery dissections. Magnetic resonance angiography performed
      on Day 250 showed no evidence of dissection. However, magnetic resonance imaging
      revealed a small infarct in the splenium of the corpus callosum. Spontaneous
      resolution of stenotic dissections of the bilateral vertebral arteries is
      extremely unusual. Serial cerebral angiography and magnetic resonance angiography
      are very important for monitoring the time course of changes in patients with
      vertebral artery dissections.

PMID- 12472214
TI  - Late recurrence of subarachnoid hemorrhage due to regrowth of aneurysm after neck
      clipping surgery.
AB  - Late recurrence of subarachnoid hemorrhage (SAH) due to regrowth of aneurysm
      after neck clipping surgery occurred in four patients. Two patients underwent
      surgical treatment, and two patients received endovascular treatment.
      Endovascular treatment was successful in one case, but emergent surgery was
      necessary for the other case because of possible pseudoaneurysm formation.
      Postoperative course of all patients was excellent. Late recurrence of SAH can
      occur even after complete clipping, and further treatment should be considered.

PMID- 12472215
TI  - Intraventricular tuberculoma.
AB  - A 38-year-old female presented with headaches, fever, and malaise. Computed
      tomography showed an intraventricular peripheral ring-enhanced lesion with
      central necrosis. The lesion was totally excised. Histological examination
      revealed a tuberculoma. The patient was treated with antituberculous
      chemotherapy. The patient was asymptomatic at 9 months. Ventricular involvement
      in neurotuberculosis is rare, but should be considered in the presence of other
      indicators of tuberculous infection.

PMID- 12472216
TI  - Intracranial meningeal melanocytoma.
AB  - A 59-year-old man presented with a rare intracranial meningeal melanocytoma in
      the left cerebellopontine angle. The patient underwent partial surgical excision
      and radiosurgery for successful control of the tumor. Meningeal melanocytoma is
      an essentially benign melanotic tumor, derived from the melanocytes of the
      leptomeninges, and may occur anywhere in the cranial and spinal meninges.
      Preoperative differential diagnosis of intracranial meningeal melanocytoma from
      malignant melanoma is difficult based on magnetic resonance imaging.
      Ultrastructural findings are essential to establish the diagnosis. The prognosis
      of this tumor is not always favorable with occasional local recurrence. Total
      resection is the best treatment, but gamma knife radiosurgery is effective for
      the residual tumor following partial resection.

PMID- 12472217
TI  - Giant cell reparative granuloma of the temporal bone: neuroradiological and
      immunohistochemical findings.
AB  - A 38-year-old man presented with a giant cell reparative granuloma (GCRG) of the
      left temporal bone. Computed tomography showed a osteolytic middle cranial mass
      lesion. Magnetic resonance (MR) imaging showed the lesion as low intensity with
      heterogeneous enhancement by gadolinium on the T1-weighted images, and extremely
      low intensity on the T2-weighted images. Angiography showed the lesion as highly
      vascular and fed by branches of the left external carotid artery. After
      preoperative embolization, gross total removal of the tumor was performed. The
      postoperative course was uneventful and no evidence of recurrence has been found
      for more than 4 years. Histological examination revealed GCRG with multinucleated
      giant cells in the fibrous background, abundant collagen bundles, hemosiderin
      deposits, and trabeculae of reactive bone. Some of the mononuclear stromal cells
      and almost all of the giant cells were positive for CD68, suggesting histiocytic
      differentiation. These histological features reflect the marked decrease in
      signal intensity on T2-weighted MR images.

PMID- 12472218
TI  - Chondroblastoma of the temporal base with high mitotic activity.
AB  - A 24-year-old man presented with a rare chondroblastoma of the temporal base
      manifesting as local pain accompanied by difficulty in opening the mouth. Gross
      total removal was achieved at initial surgery, but the tumor demonstrated rapid
      and destructive regrowth from a very small residual volume without definite
      histological malignant transformation. Growth activity estimated by MIB-1
      staining increased spontaneously from 2.5% at the initial operation to 18.7% at
      recurrence. Further extensive radical tumor removal by surgeons from multiple
      disciplines was performed. The patient has been free of recurrence for 3 years
      without radiotherapy. Chondroblastoma of the temporal bone is widely accepted as
      a benign tumor and regrowth after gross total removal is very rare. However, some
      cases of chondroblastoma have potentially high mitotic activity.

PMID- 12472219
TI  - Recovery of audition after favorable resection of vagal schwannoma.
AB  - Two patients with vagal schwannoma manifesting as deafness with no lower cranial
      nerve paresis were treated surgically. A 42-year-old male underwent partial
      resection of the tumor, which was tightly adhered to the cranial nerves, to
      prevent lower cranial nerve paresis. A 29-year-old female underwent total removal
      of the tumor without complications. The patients recovered useful audition with
      no postoperative deficit.

PMID- 12472220
TI  - A comparison of within- and between-day reliability of discrete 3D lower
      extremity variables in runners.
AB  - It is important to understand the day-to-day variability that is attributed to
      repositioning of markers especially when assessing a treatment effect or response
      over time. While previous studies have reported reliability of waveform patterns,
      none have assessed the repeatability of discrete points such as peak angles,
      velocities and angular excursions which are often used when making statistical
      and clinical comparisons. The purpose of this study was to compare the within-
      and between-day variability of discrete kinematic, kinetic, and ground reaction
      force (GRF) data collected during running. Comparisons for 20 recreational
      runners were evaluated for within- and between-day reliability of discrete 3D
      kinematic, kinetic, and GRF variables. The results indicated that within-day
      comparisons were more reliable than between-day. Joint angular velocity and
      angular excursion values were more reliable between-days as compared to absolute
      peak angle measures and may be more useful in interpreting changes in treatment
      over time. Between-day kinematic and kinetic sagittal plane values were more
      reliable than secondary plane values. Reliability of GRF data was greater than
      kinematic and kinetic data for between-day comparisons.

PMID- 12472221
TI  - Comparison of commonly used orthopaedic outcome measures using palm-top computers
      and paper surveys.
AB  - INTRODUCTION: Measuring patient-perceived outcomes following orthopaedic
      procedures have become an important component of clinical research and patient
      care. General and disease-specific outcomes measures have been developed and
      applied in orthopaedics to assess the patients' perceived health status.
      Unfortunately, paper-based, self-administered instruments remain inefficient for
      collecting data because of: (a) missing data (b) respondent error, and (c) the
      costs to administer and enter data. OBJECTIVE: To study the comparability of palm
      top computer devices and paper-pencil self-administered questionnaires in the
      collection of health-related quality of life (HRQL) information from patients.
      METHODS: The comparability of administering HRQL questionnaires using palm-top
      computer and traditional paper-based forms was tested in a sample of 96 patients
      with complaints of hip and/or knee pain. Each patient completed mailed versions
      of the Medical Outcomes Study (MOS), 36-item Health Survey (SF-36), and Western
      Ontario and McMasters University Arthritis Index (WOMAC) three weeks prior to
      presenting to clinic. At the clinic they were asked to complete the same outcomes
      measures using the palm-top computer or a paper-and-pencil version. ANALYSIS: In
      the analysis, scale distributions, floor and ceiling effects, internal
      consistency and retest reliability of scales were compared across the two data
      collection methods. Because the baseline characteristics of the groups were not
      strictly comparable according to age, the data were analyzed for the entire
      sample and stratified according to age. RESULTS: Few statistically significant
      differences were found for the means, variances and intra-class correlation
      coefficients between the methods of administration. While the scale distribution
      between the two methods was comparable, the internal consistency of the scales
      was dissimilar. CONCLUSIONS: Administration of HRQL questionnaires using portable
      palm-top computer devices has the potential advantage of decreased cost and
      convenience. These data lend some support for the comparability of palm-top
      computers and paper surveys for outcomes measures widely used in the field of
      orthopaedic surgery. The present study identified the lack of reliability across
      modes of administration that requires further study in a randomized comparability
      trial. These mode effects are important for orthopaedic surgeons to appreciate
      before implementing innovative data-capture technologies in their practices.

PMID- 12472222
TI  - J-integral fracture toughness and tearing modulus measurement of radiation cross
      linked UHMWPE.
AB  - Radiation and chemical cross-linking of medical grade ultrahigh molecular weight
      polyethylene (UHMWPE) has recently been utilized in an effort to improve wear
      performance of total joint replacement components. However, reductions in
      mechanical properties with cross-linking are cause for concern regarding the use
      of cross-linked UHMWPE for high-stress applications such as in total knee
      replacement prostheses. In this study, the fracture behavior of radiation cross
      linked UHMWPE was compared to that of uncross-linked UHMWPE. The Rice and
      Sorensen model that utilizes mechanical parameters obtained from uniaxial tensile
      and compact tension tests was used to calculate the steady state J-integral
      fracture toughness, Jss, for radiation cross-linked UHMWPE. Jss decreased
      monotonically with increase in radiation dose. UHMWPE exhibited tough, ductile
      tearing behavior with stable crack growth when it was cross-linked using a gamma
      radiation dose of 0-50 kGy. However, in cross-linked UHMWPE irradiated to a dose
      of 100 and 200 kGy, unstable fracture occurred spontaneously upon attaining the
      initial crack driving force, J1c. This indicates that a high degree of cross
      linking is less desirable for high-stress applications in orthopaedic implants.
      However, a substantial increase in J1c, even at a low degree of cross-linking,
      suggests that a low degree of cross-linking may be beneficial for resistance to
      delamination and catastrophic failure, both of which require an initiation step
      for the fracture to propagate in the material. This mechanical test should,
      however, be considered along with fatigue tests and joint simulator testing
      before determination of an appropriate amount of cross-linking for total joint
      replacement prostheses that experience high stresses.

PMID- 12472223
TI  - Rheology of joint fluid in total knee arthroplasty patients.
AB  - While the properties of joint fluid may affect the tribology of joint replacement
      prostheses, the flow parameters of joint fluid have not yet been examined in the
      context of total knee arthroplasty (TKA). The objective of this study was to
      evaluate the flow properties of joint fluids in patients undergoing index TKA or
      revision TKA. We hypothesized that an alteration of the properties of joint fluid
      would result from TKA. The steady-shear viscosity and storage and loss moduli
      were evaluated in joint fluid from 35 arthritis patients undergoing TKA, 14
      patients undergoing revision of a previous TKA, and two patients presenting with
      joint effusion after TKA. The same properties were also evaluated in two
      commercially available sodium hyaluronate preparations and bovine serum, which is
      used as a lubricant in joint simulators. The steady-shear viscosity varied over
      three orders of magnitude among samples obtained from patients undergoing TKA,
      spanning previously established "normal" and "diseased" ranges. Fluid obtained at
      index TKA was more likely to exhibit normal viscous properties than fluid
      obtained at revision TKA (p = 0.01). Other viscous parameters distinguished the
      two groups, but the difference did not reach statistical significance. Both
      groups exhibited degenerate flow properties when compared to synovial fluid from
      healthy individuals. Further examination of the connection between flow
      properties and the tribology of joint replacement prostheses is warranted.

PMID- 12472224
TI  - COX-2 selective NSAID decreases bone ingrowth in vivo.
AB  - Whether non-steroidal anti-inflammatory drug (NSAID)-induced suppression of bone
      ingrowth is due to cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2)
      inhibition, or through a yet unidentified pathway is unknown. In this study, the
      effects of a non-specific COX-1 and COX-2 inhibitor, versus a specific COX-2
      inhibitor on bone ingrowth and tissue differentiation are examined in vivo.
      Harvest chambers were implanted unilaterally in the tibiae of eight mature, New
      Zealand white rabbits. After a 6-week period for osseointegration of the chamber,
      the following oral treatments were given for 4 weeks each, followed by a harvest
      in each case: drinking water with no NSAID (control 1), Naproxen sodium--a COX-1
      and COX-2 non-specific inhibitor at a dose of 110 mg/kg/day in the drinking
      water, drinking water with no NSAID (control 2), and Rofecoxib-a COX-2 inhibitor
      at a dose of 12.5 mg/day inserted directly into the rabbit's mouth. Harvested
      specimens were snap frozen, cut into serial 6 microm sections and stained with
      hematoxylin and eosin for general morphological characterization, and alkaline
      phosphatase (osteoblast marker). Sections were also processed for
      immunoperoxidase staining using monoclonal antibodies to identify cells
      expressing the vitronectin receptor (osteoclast-like cells). With drinking water
      alone, the percentage of bone ingrowth averaged 24.8 +/- 2.9% and 29.9 +/- 4.5%
      respectively. Naproxen sodium in the drinking water and oral Rofecoxib decreased
      bone ingrowth significantly (15.9 +/- 3.3%. p = 0.031 and 18.5 +/- 2+/-4%, p =
      0.035 compared to drinking water respectively). Both Naproxen sodium (p = 0.026)
      and Rofecoxib (p = 0.02) decreased the number of CD51 positive osteoclast-like
      cells per section compared with drinking water alone. Rofecoxib decreased the
      area of osteoblasts per section area (p = 0.014) compared to controls, although
      the value for Naproxen sodium did not reach statistical significance. The results
      of the present study suggest that bone formation is suppressed by oral
      administration of an NSAID which contains a COX-2 inhibitor. COX-2 inhibitors
      currently taken for arthritis and other conditions may potentially delay fracture
      healing and bone ingrowth.

PMID- 12472225
TI  - CDMP-2 induces bone or tendon-like tissue depending on mechanical stimulation.
AB  - Cartilage derived morphogenetic proteins (CDMPs, also known as growth and
      differentiation factors, GDFs) are a subgroup of the bone morphogenetic protein
      (BMP) gene family. As most BMPs, they are known to induce cartilage or bone
      formation when implanted subcutaneously or intramuscularly on an appropriate
      carrier. However, similar implantation experiments with CDMPs have also reported
      the formation of a tendon-like tissue, without any cartilage or bone. A solution
      to this apparent contradiction might be offered by the mechanical tissue
      differentiation theory, suggesting that tissue differentiation depends on the
      mechanical environment. This study analyzes the response to CDMP-2 implants at
      different sites and under different loading conditions in the rat. Collagen
      sponges carrying CDMP-2 were implanted subcutaneously, intramuscularly or inside
      a freshly created defect in the achilles tendon. Large amounts of bone were
      induced subcutaneously, smaller amounts intramuscularly, and in the tendons, only
      small amounts of bone or cartilage were seen in few animals. Thus, the amount of
      bone appeared inversely related to the degree of mechanical stimulus. To confirm
      this, CDMP was also injected into tendon defects that were either loaded or
      partially unloaded. All the unloaded tendons showed bone induction after one CDMP
      2 injection, whereas only 4 of 10 loaded ones showed any cartilage or bone (p =
      0.0005). Single injections of a similar dose of CDMP-2 have previously been shown
      to augment tendon repair by increasing the size of the tendon callus. This study
      suggests that the response to CDMP-2 is dependent on the mechanical situation at
      the site where it is applied.

PMID- 12472226
TI  - Titanium particles suppress expression of osteoblastic phenotype in human
      mesenchymal stem cells.
AB  - Long-term stability of arthroplasty prosthesis depends on the integration between
      osseous tissue and the implant biomaterial. Integrity of the osseous tissue
      requires the contribution of mesenchymal stem cells and their continuous
      differentiation into an osteoblastic phenotype. This study aims to investigate
      the hypothesis that exposure to wear debris particles derived from orthopaedic
      biomaterials affects the osteoblastic differentiation of human mesenchymal stem
      cells (hMSC). Upon in vitro culture in the presence of osteogenic supplements
      (OS), we observe that cultures of hMSCs isolated from femoral head bone marrow
      are capable of osteogenic differentiation, expressing alkaline phosphatase,
      osteocalcin, and bone sialoprotein (BSP), in addition to producing collagen type
      I and BSP accompanied by extracellular matrix mineralization. Exposure of OS
      treated hMSCs to submicron commercially pure titanium (cpTi) particles suppresses
      BSP gene expression, reduces collagen type I and BSP production, decreases
      cellular proliferation and viability, and inhibits matrix mineralization. In
      comparison, exposure to zirconium oxide (ZrO2) particles of similar size did not
      alter osteoblastic gene expression and resulted in only a moderate decrease in
      cellular proliferation and mineralization. Confocal imaging of cpTi-treated hMSC
      cultures revealed patchy groups of cells displaying disorganized cytoskeletal
      architecture and low levels of extracellular BSP. These in vitro findings suggest
      that chronic exposure of marrow cells to titanium wear debris in vivo may
      contribute to decreased bone formation at the bone/implant interface by reducing
      the population of viable hMSCs and compromising their differentiation into
      functional osteoblasts. Understanding the nature of hMSC bioreactivity to
      orthopaedic wear debris should provide additional insights into mechanisms
      underlying aseptic loosening.

PMID- 12472227
TI  - Tenofovir treatment at 30 mg/kg/day can inhibit cortical bone mineralization in
      growing rhesus monkeys (Macaca mulatta).
AB  - The acyclic nucleoside phosphonate analog, 9-[2-(R)
      (phosphonomethoxy)propyl]adenine (PMPA; Tenofovir: Gilead Sciences, Inc., Foster
      City, CA), has been shown to effectively inhibit simian immunodeficiency virus
      (SIV) replication in rhesus macaques by blocking reverse transcription. However,
      chronic long-term tenofovir treatment at 30 mg/kg/day, intended to reduce viral
      replication and illness, has been shown to result in bone deformities and
      spontaneous fractures in rhesus monkeys. Based on these findings, we studied the
      effects of tenofovir treatment and pathogenic SIV infection on cortical bone
      remodeling in rhesus monkeys. Tibiae from tenofovir-treated or untreated, SIV
      infected or uninfected, rhesus macaques were evaluated for bone microdamage and
      remodeling. We found that tenofovir treatment had a significant effect on osteoid
      (unmineralized bone) seam width in tibial cross-sections. Regardless of SIV
      infection status, half of the tenofovir-treated animals had significantly
      increased osteoid seam widths in tibial cortical bone resulting in an
      osteomalacia-like condition. Pathogenic SIV infection significantly increased
      tibial resorption cavity density. and this increase was normalized by tenofovir
      treatment. These results suggest that tenofovir treatment at 30 mg/kg/day
      inhibits mineralization of newly formed bone. SIV infection results in increased
      tibial resorption cavity density, while tenofovir treatment tends to minimize
      this increase. Both defective mineralization of newly formed bone and increased
      resorption cavity density may result in greater bone fragility.

PMID- 12472228
TI  - Identification of the molecular chaperone alpha B-crystallin in demineralized
      bone powder and osteoblast-like cells.
AB  - Bone is subjected to a variety of physiological, as well as cell-deforming
      biomechanical stresses, including hydrostatic compression and fluid flow.
      However, little is known about the molecular mechanisms that protect bone cells
      from mechanical, ischemic, or oxidative damage. Crystallins are 20 kD heat shock
      proteins that function as molecular chaperones. We tested the hypothesis that
      alpha B-crystallin (alphaB-crystallin), the most widely expressed vertebrate
      crystallin, is present in bone and osteoblast-like cells. Noncollagenous proteins
      (NCPs) were extracted from human demineralized bone matrix with 4 M guanidine HCI
      containing 0.5 M CaCl2 and protease inhibitors, defatted, dialyzed against 0.2%
      (v/v) Triton X-100 in 100 mM Tris-HCI (pH 7.2) and water, centrifuged, and
      lyophilized. The NCPs were separated by 2D IEF/SDS-PAGE. The two most abundant 20
      kD spots, with apparent pIs of 7.85 and 7.42 in urea gels, were excised,
      subjected to matrix-assisted laser desorption ionization/time-of-flight mass
      spectrometry, and identified as alphaB-crystallins. Indirect immunofluorescence
      localized alphaB-crystallin to the interphase nucleus, cytoskeleton and cytoplasm
      of proliferating MC3T3-E1 mouse osteoblast-like cells, as well as the
      cytoskeleton and cytoplasm of confluent cells. In conclusion, alphaB-crystallin
      is present in bone and osteoblast-like cells. We hypothesize that alphaB
      crystallin may play a role in protecting the osteoblast cytoskeleton from
      mechanical stress and may be important in modulating nuclear or cellular
      functions, such as transcription or apoptosis, as observed in other tissues.

PMID- 12472229
TI  - Effect of repeated irrigation and debridement on fracture healing in an animal
      model.
AB  - The initial management of open fractures often requires repeated irrigation and
      debridement of the open wound and stabilization of the fracture. However, washing
      out the fracture hematoma could delay the early healing process of stable
      fractures. Because delayed union and non-union are serious complications, the
      effect of repeated irrigation and debridement on the fracture healing process was
      investigated. Twenty-four rabbits received unilateral, transverse. mid-tibial
      open osteotomies with a 3 mm gap. The osteotomy site was thoroughly irrigated and
      stabilized with double-bar external fixators. The osteotomy sites in the study
      groups underwent repeat irrigation and debridement on either the third day (Group
      II), the fourth day (Group III), or consecutively on the first and second days
      (Group IV) after the index procedure. The bone healing was assessed with weekly
      radiographs and peripheral quantitative computerized tomographs. In Group I
      (control), all osteotomies healed radiographically before the tenth week. In
      Group II, five out of six osteotomies healed radiographically before the tenth
      week. In Group III, only two of five osteotomies healed before the tenth week. In
      Group IV, none of the osteotomies had healed by week fifteen. All of the non
      healed osteotomies exhibited atrophic non-unions at fifteen weeks. Compared to
      the control group at the tenth week, the average bone mineral content at the
      osteotomy site and the area of high mineral density callus (> or = 890 mg/cm3)
      were significantly lower in Groups III (63%, p = 0.002 and 95%, p = 0.05,
      respectively) and IV (99%, p < 0.001 and 100%, p = 0.05, respectively). The
      results of this study suggest that repeated irrigation and debridement,
      associated with persistent rigid immobilization, may contribute to the
      development of delayed unions or atrophic non-unions.

PMID- 12472230
TI  - High-pressure pulsatile lavage irrigation of contaminated fractures: effects on
      fracture healing.
AB  - To evaluate the effects of high-pressure pulsatile lavage (HPPL) irrigation on
      new bone formation and fracture union in a contaminated intraarticular fracture,
      45 New Zealand white rabbits were divided into three equal groups. The control
      group (C) underwent an osteotomy of the medial femoral condyle, contamination
      with a slurry of clay mixed with Staphylococcus aureus, stabilization and
      closure. The bulb syringe and pulsatile groups (B and P) underwent an identical
      procedure, with the addition of irrigation with 11 of saline by bulb syringe or
      pulsatile lavage system. Two fluorescent bone stains that mark new bone formation
      were administered subcutaneously: xylenol orange at the time of surgery and
      calcein green one week postoperatively. Animals were euthanized two weeks
      postoperatively and femurs were retrieved for histological analysis. Union was
      determined by examination of microradiographs. The viability of bone along the
      osteotomy site in the first and second weeks after irrigation was determined by
      evaluation of the two fluorescent stains. The density of new bone two weeks after
      irrigation was assessed by digitization of the microradiographs. Nonunion was
      present in 77%, 53%, and 43% of animals in groups C, B, and P, respectively.
      There was an increase in the presence of bands of both fluorescent stains along
      the osteotomy site in the groups B and P compared to group C. There was no
      statistically significant difference between groups B and P in either fluorescent
      stain. On digitization of microradiographs, there was more calcified new bone on
      postoperative day 14 in group P than in either group B or C (p = 0.04). The
      addition of contamination and foreign material to an intraarticular fracture
      model results in lower rates of new bone formation and fracture union. Irrigation
      in this setting is clearly beneficial, whether the irrigant is delivered by bulb
      irrigation or by HPPL. The results of this study indicate using HPPL in this
      setting does not cause greater damage than using bulb syringe irrigation.

PMID- 12472231
TI  - The effects of blood glucose control upon fracture healing in the BB Wistar rat
      with diabetes mellitus.
AB  - Several clinical series, analyzing fracture healing in patients with diabetes
      mellitus (DM). demonstrated significant incidence of delayed union, non-union,
      and pseudarthrosis. In this study, analysis was performed to evaluate the effects
      of blood glucose (BG) control on fracture healing in the DM BB Wistar rat, a rat
      strain that represents a close homology to Type I DM in man. Our study showed
      decreased cell proliferation at the fracture site as well as decreased mechanical
      stiffness and bony content in the poorly controlled DM rats. To determine the
      effect of BG control, DM rats were treated with insulin sufficient to maintain
      physiologic BG levels throughout the course of the study. Values of cellular
      proliferation, biomechanical properties and callus bone content in tightly
      controlled DM animals were not significantly different from values of non-DM
      control values. This study suggests that insulin treatment with resultant
      improved BG control will ameliorate the impaired early and late parameters of DM
      fracture healing.

PMID- 12472232
TI  - Pedicular fixation in the osteoporotic spine: a pilot in vivo study on long-term
      ovariectomized sheep.
AB  - Spinal instrumentation success is greatly affected by the presence of
      osteoporosis. To date, however, no data exist on in vivo investigations on
      biomaterial and surgical techniques in the osteoporotic spine. In the present
      study 24 uncoated and 24 HA-coated screws were implanted in the L3, L4 and L5
      pedicles of eight sheep (four ovariectomized, OVX Group; four sham-operated,
      Control Group). At four months, uncoated screws showed a significant decrease of
      about -22% in the extraction torque of the OVX Group as compared to the Control
      Group (p < 0.005). The extraction torque of HA-coated screws significantly (p <
      0.0005) improved in both groups when compared to that of uncoated screws and
      showed increases ranging from 133% to 157%. Pedicle trabecular bone of OVX sheep
      showed a significant decrease in BV/TV (-30%; p < 0.05) and Tb.Th (-33%; p <
      0.01). The affinity index (AI) results revealed significant (p < 0.0005)
      differences between uncoated and HA-coated screws for both groups: values were
      lower for uncoated than HA-coated screws by about -35%. A significant difference
      was also found for the AI data of uncoated screws between the OVX and Control
      Groups (-13%, p < 0.005). The current findings have demonstrated that long-term
      ovariectomized sheep can be used to study in vivo osteointegration in the
      osteoporotic spine. The HA coating has proven to improve bone purchase and bone
      screw interface strength in healthy and osteopenic animals.

PMID- 12472233
TI  - The adaptation of soleus and edl in a rat model of distraction osteogenesis: IGF
      1 and fibrosis.
AB  - The distraction rate of 0.5 mm/day produces good osteogenesis in small rodents;
      however, the effects of this distraction rate on muscle are not well documented.
      We evaluated the soleus and the extensor digitorum longus (EDL) after two weeks
      of lengthening distraction osteogenesis (DO) at 0.5 mm/day in skeletally mature
      rats. We found a modest but significant local increase of insulin like growth
      factor-1 (IGF-1) in the EDL, however, muscle growth indicated by developmental
      forms of myosin heavy chain (MHC) was not detected by mRNA (RT-PCR). To the
      contrary. the data suggested a decrease in cross-sectional area of the muscle
      fibers as well as a decrease in mRNA for slow MHC. Immunolabeling of fibronectin
      in cryosections of the EDL indicated fibrosis of the perimuscular connective
      tissue while assessment of the passive joint motion did not suggest a lack of
      excursion on the part of the dorsal flexors. While the literature suggests that
      IGF-1 facilitates muscle growth especially in young animals, excess of IGF-1 in
      muscle from adults may exacerbate DO-induced fibrosis.

PMID- 12472234
TI  - Transplanted bone marrow cells localize to fracture callus in a mouse model.
AB  - Bone marrow contains many cellular elements that may contribute to fracture
      repair. We used a pluripotential stromal cell in a mouse model to demonstrate the
      presence of transplanted cells in fracture hematoma and subsequently in maturing
      fracture callus. Cells were transduced with traceable genes (lac Z and neomycin
      resistance) and traced in vivo after intravenous injection into syngeneic mice.
      These transduced cells home to bone marrow, suggesting that they might be
      detected in fracture callus. Cells were injected intravenously into mice and
      stabilized femoral shaft fractures were induced. Control mice received
      intravenous lactated-Ringer's solution prior to fracture. Callus tissue and
      marrow were examined histologically from I to 10 weeks after fracture to detect
      transplanted cells. Transplanted cells were detected in fracture callus in areas,
      and at times, of most active bone formation. Control specimens showed minimal
      staining of the callus tissue. Levels of the traceable gene in fracture callus
      increased, reached a peak between 3 and 4 weeks after fracture, then diminished
      and disappeared by 10 weeks post-fracture as woven bone at the fracture site was
      replaced by lamellar bone with cells from the host mouse. The results show that
      pluripotent bone marrow cells home to the marrow after systemic injection and
      localize in fracture callus.

PMID- 12472235
TI  - The effect of recombinant human osteogenic protein-1 (bone morphogenetic protein
      7) impregnation on allografts in a canine intercalary bone defect.
AB  - The utility of cortical allografts in repairing large bone defects is limited by
      their slow and incomplete incorporation into host bone. In order to determine the
      effects of recombinant human osteogenic protein-1 (rhOP-1) impregnation on
      allograft incorporation, we used a canine intercalary bone defect model.
      Bilateral resection of a 4 cm segment of the femoral diaphysis and reconstruction
      with structural bone allografts were performed. In one limb, the allograft was
      soaked in solution with rhOP-1 for 1 h before implantation. In the other limb,
      the allograft was soaked in the same solution without rhOP-1. Dynamic load
      bearing, radiographic analysis, biomechanical testing, and histomorphometric
      analysis were conducted. Radiographic analysis showed significantly larger
      periosteal callus area in the rhOP-1 treated group at week 2. The rhOP-1
      significantly increased allograft bone porosity and significantly increased the
      number of active osteons in the allografts. There were no significant differences
      between the rhOP-1 treated and non-treated allografts in load bearing and
      biomechanical analyses. These findings indicate that rhOP- I increases
      intercalary allograft remodeling without deleterious effects in mechanical and
      functional strength.

PMID- 12472236
TI  - Prostaglandin E1 analog inhibits the microglia function: suppression of
      lipopolysaccharide-induced nitric oxide and TNF-alpha release.
AB  - Release of nitric oxide and TNF-alpha, a toxic cytokine, have been reported to
      accelerate neuronal damage under several pathological conditions, such as trauma
      or ischemia in the central nervous system. In the present study, we tested the
      effect of alprostadil alfadex, a prostaglandin E1 analog, on cultured microglia
      from the rat spinal cord. The cultured microglia were exposed to
      lipopolysaccharide (LPS) (100 ng/ml), an endotoxin, for 24 h, then the released
      nitric oxide and TNF-alpha in the culture media was analyzed. The released nitric
      oxide was detected by the Griess reaction and released TNF-alpha was measured
      using ELISA method. The LPS-induced nitric oxide release was inhibited by the
      simultaneous addition of alprostadil alfadex in a dose-dependent manner (0.1-100
      microM). The LPS-induced TNF-alpha release was also inhibited by alprostadil
      alfadex addition (0.1-100 microM). The IC50 values of alprostadil alfadex on
      nitric oxide and TNF-alpha release were about 1 and 10 microM, respectively.
      These results suggest that prostaglandin E1 possibly protects spinal cord neurons
      from several types of neurodegenerative damage, not only via increased blood
      supply, but also via inhibition of pathological immunoreactions of activated
      microglia.

PMID- 12472237
TI  - Cryopreservation of intact human articular cartilage.
AB  - Damaged articular cartilage (AC) impairs joint function and many treatment
      techniques are being investigated to determine their long term results.
      Successful cryopreservation of AC can provide a reliable source of intact matrix
      with viable chondrocytes to maintain the cartilage over long periods of time.
      This study investigated the application of an established cryopreservation
      protocol to determine the recovery of intact chondrocytes from human AC. Ten
      millimeter diameter osteochondral dowels were harvested from two human donors.
      The cryopreservation protocol was performed and the samples were rapidly warmed
      from varying experimental holding temperatures (-10, -20, -30, -40 degrees C),
      with and without plunging into liquid nitrogen, using 1 M dimethyl sulfoxide as
      cryoprotectant. The cartilage was stained with membrane integrity dyes and viewed
      under fluorescence microscopy. The percent of intact chondrocytes was compared to
      fresh controls. Low recovery of intact chondrocytes was recorded from all
      temperature levels with and without cryoprotectant. The results of this
      experiment demonstrated that the cryopreservation procedure used to achieve
      moderate success with intact sheep AC was not successful with intact human AC and
      further investigation is required.

PMID- 12472238
TI  - Selective joint denervation promotes knee osteoarthritis in the aging rat.
AB  - Osteoarthritis is the most common joint disorder with aging, but its cause is
      unknown. Mice lose joint afferents with aging, and this loss precedes development
      of osteoarthritis. We hypothesized a loss of joint afferents is involved in the
      pathogenesis of osteoarthritis. To test this hypothesis, we denervated knee
      joints of 16 rats at age 2 months, by intra-articular injection of an
      immunotoxin. The immunotoxin killed neurons after retrograde axonal transport to
      the cell body. At 16 or 24 months follow-up, each joint was histologically
      assessed and assigned an osteoarthritis score. At follow-up, the number of joint
      afferents had spontaneously decreased by 42% in control knees and 69% in
      denervated knees. We found that control knees developed osteoarthritic changes
      with aging. However, denervated knees had far more severe changes, as evidenced
      by a 54% higher average osteoarthritis score than control knees (P = 0.0016, both
      groups 16 knees). These results suggest a loss of afferents predisposes a joint
      to osteoarthritis. We propose the spontaneous loss of neurons with aging may be a
      normal developmental process. To explain the mechanism causing osteoarthritis, we
      suggest denervation permits aberrant joint loading, either by disturbing
      neuromuscular joint control, or by inducing joint laxity after neurogenic loss of
      tissue homeostasis.

PMID- 12472239
TI  - Cyclic compression of cartilage/bone explants in vitro leads to physical
      weakening, mechanical breakdown of collagen and release of matrix fragments.
AB  - Mechanical loading of articular cartilage can produce catabolic and anabolic
      changes in tissue metabolism. Most previous studies in this area have focussed on
      aggrecan. Little information concerning load-induced collagen modifications has
      been obtained. We have therefore conducted studies where mechanical loads are
      applied in vitro to full thickness cartilage explants retaining a thin layer of
      bone, in order to investigate mechanically induced collagen breakdown and
      consequent turnover, in addition to aggrecan changes and mechanical property
      alterations. Tissue explant disks were subjected to unconfined compression and
      either immediately frozen or kept in static culture for 10 days. Mechanical tests
      of the disks immediately prior to and just after the cyclic loading period were
      also performed. They showed a weakening of the collagen network and an increased
      hydraulic permeability due to the cyclic loading. Load-induced alterations of the
      extracellular matrix was then clearly evidenced by an increase in denatured
      collagen in the disks frozen immediately after loading compared to unloaded
      controls. Loaded disks maintained in culture for 10 additional days following
      cyclic loading no longer expressed this increase in denatured collagen suggesting
      that mechanically denatured collagen II had undergone a removal process which
      could represent turnover or repair, or the beginning of progressive degradation.
      Indeed matrix fragments of collagen II and glycosaminoglycans were found to be
      released to post-loading culture medium in increased quantities compared to
      unloaded controls. Our data further demonstrates the ability of mechanical load
      of articular cartilage to modulate turnover and metabolism of collagen and
      proteoglycan in a complex and multifactorial manner that may be of particular
      significance in the pathogenesis of osteoarthritis and in the development of
      pharmacological agents to modulate its progression.

PMID- 12472240
TI  - Development-associated differences in integrative cartilage repair: roles of
      biosynthesis and matrix.
AB  - A recurring problem in tissue transplantation therapies for articular cartilage
      defects is the lack of integration between the implant and the host cartilage.
      Previous studies have shown that in vitro integration between explants of calf
      cartilage is markedly higher than that between fetal cartilage, despite similarly
      high levels of deposition of newly synthesized collagen. The aim of this study
      was to determine if cellular biosynthesis and extracellular matrix each
      contribute to these development-associated differences in integrative repair in
      vitro. The approach taken was to examine integration between specific
      combinations of cartilage explants that were apposed for two weeks. The cartilage
      matrix showed different propensities for repair, as integration of calf live
      cartilage to calf devitalized cartilage was greater than that of calf live
      cartilage to fetal devitalized cartilage. An inhibiting factor appeared to be
      present in fetal cartilage matrix since guanidine treatment of fetal devitalized
      cartilage was able to enhance its integration. The difference between integration
      to living cartilage and integration to devitalized cartilage, for calf and fetal
      tissue, indicated that the biosynthetic contribution to integration by calf
      cartilage was greater than the biosynthetic contribution by fetal cartilage.
      Thus, the increasing level of integration between fetal and fetal cartilage,
      fetal and calf cartilage, and calf and calf cartilage appeared to reflect both
      biosynthetic and matrix differences. Therapeutic strategies to enhance
      integration to cartilage may thus target both the extracellular components and
      the cellular biosynthetic activities of implants and host cartilage.

PMID- 12472241
TI  - Excessive degradation of type II collagen in articular cartilage in equine
      osteochondrosis.
AB  - Articular osteochondrosis (OCD) occurs in both man and animals. The etiology
      remains to be determined. Studies of OCD lesions in animals may provide clues as
      to its pathogenesis. The aim of our study was to determine whether there was
      evidence for increased degradation namely proteoglycan (PG) release and type II
      collagen cleavage in articular cartilage harvested from OCD lesions. We examined
      ex vivo explants at post-mortem from equine OCD lesions and macroscopically
      normal site and age matched cartilage. These were cultured over a 10 day period
      in serum-free medium. Type II collagen cleavage was measured in articular
      cartilage and media using an Elisa assay to detect the COL2-3/4C(short) epitope,
      which is generated on cleavage of the triple helix of type II collagen by
      collagenases. PG release was measured by a dye-binding assay. Cumulative release
      of PG and COL2-3/4C(short) and their contents in cartilage at the end of the
      culture period were determined. In OCD lesions there was a significant increase
      in type II collagen cleavage by collagenase but no evidence for increase of PG
      degradation. These findings point to a selective increase in type II collagen
      cleavage by collagenases, in OCD lesions of the kind observed in osteoarthritis.
      Further work is needed to determine whether changes represent primary or
      secondary events in the pathogenesis of OCD.

PMID- 12472242
TI  - Parathyroid hormone-related peptide and indian hedgehog expression patterns in
      naturally acquired equine osteochondrosis.
AB  - Early changes in parathyroid hormone-related peptide (PTH-rP) and Indian hedgehog
      (Ihh) expression were examined in equine articular osteochondrosis (OC) as a
      model of a naturally acquired dyschondroplasia. Cartilage was harvested from OC
      affected femoropatellar or scapulohumeral joints from immature horses and normal
      control horses of similar age. PTH-rP expression levels were assessed by semi
      quantitative PCR, in situ hybridization, and immunohistochemistry. Ihh protein
      expression levels were assessed by immunohistochemistry. Elevated PTH-rP protein
      and mRNA expression were identified in the deeper layers of affected articular
      cartilage and the fibrous tissue of interposing clefts. These changes were
      confined to the chondrocytes in the OC-affected cartilage, which had
      significantly increased PTH-rP protein and mRNA expression when compared to
      control cartilages. Ihh protein expression showed similar distribution as PTH-rP
      in the deeper layers of articular cartilage; however, only a trend for increased
      Ihh immunostaining was evident in the OC cartilage when compared to the normal
      cartilage. Increased PTH-rP expression in prehypertrophic chondrocytes of
      diseased OC cartilage suggests a possible link between this peptide and the
      delayed ossification, which is a consistent histologic alteration in OC. More
      evidence is necessary to determine the role of Ihh in articular cartilage and if
      a similar feedback cycle exists as previously described for the growth plate.

PMID- 12472243
TI  - Expression of monocyte chemoattractant protein-1 in primary cultures of rabbit
      intervertebral disc cells.
AB  - Macrophages are considered essential for herniated disc resorption, and
      chemokines may play a role in their recruitment. Here we demonstrate that
      intervertebral disc cells are capable of producing monocyte chemoattractant
      protein-1 (MCP-1), a CC chemokine that is chemotactic for macrophages. Nucleus
      pulposus cells and anulus fibrosus cells were harvested from intervertebral discs
      of healthy rabbits, and the cells were stimulated with either interleukin (IL)
      1beta or tumor necrosis factor (TNF)alpha. Reverse transcriptase polymerase chain
      reaction demonstrated that IL-1beta and TNFalpha induced mRNA expression for MCP
      1 in nucleus pulposus and anulus fibrosus cells. Protein concentrations of MCP-1
      in the culture supernatants were quantitated by fluoroimmunoassay, which showed
      that nucleus pulposus and anulus fibrosus cells dose- and time-dependently
      produced MCP-1 after IL-1beta- and TNFalpha-stimulation, an event that was
      completely abrogated by IL-1 receptor antagonist and anti-TNFalpha monoclonal
      antibody, respectively. Nucleus pulposus cells produced significantly higher
      levels of MCP-1 than did anulus fibrosus cells. Immunohistochemically, the
      intensity of MCP-1 positive cells in nucleus pulposus cells was stronger than
      that in anulus fibrosus cells. Altogether, our data clearly demonstrated the
      production of MCP-1 in intervertebral disc cells, suggesting the possible
      involvement of disc cells in an early stage of macrophage infiltration.

PMID- 12472244
TI  - Effect of irrigation solutions for arthroscopic surgery on intraarticular tissue:
      comparison in human meniscus-derived primary cell culture between lactate
      Ringer's solution and saline solution.
AB  - In order to determine whether there is a difference in effect on cell morphology
      and function between two common arthroscopic irrigation solutions, primary
      cultures of cells derived from the surgically excised human menisci were
      incubated for 3 or 6 h in lactated Ringer's solution, isotonic sodium chloride
      solution, or serum-free cell culture medium (negative-control condition). Cell
      integrity was blindly evaluated by three independent examiners scoring
      photomicrographs of the cell cultures on a battery of five-point scales for
      abnormality of cell shape, irregularity of cell membrane, change of cell size and
      cell density. Cell cultures were also quantitatively assayed by semi-quantitative
      reverse-transcription-polymerase-chain-reaction for mRNA of alpha1 (I)
      procollagen, alpha1 (II) procollagen, aggrecan and heat-shock protein 70 to
      assess functional consequences of exposure to the solutions. There was a
      statistically significant difference in cell integrity scores between either
      lactated Ringer's solution or serum-free cell-culture medium and isotonic sodium
      chloride solution with greater damage to cells displayed. Scores for lactated
      Ringer's solution did not differ from those for serum-free cell-culture medium.
      There were no significant differences in mRNA expression level among the
      treatment conditions. It was concluded that the lactated Ringer's solution better
      maintained human meniscus cell integrity than the isotonic saline.

PMID- 12472245
TI  - In situ strain and stress of nerve conduction blocking in the brachial plexus.
AB  - The objective of the present study was to determine the in situ strain and stress
      of nerve conduction blocking in the brachial plexus. The measurement of the in
      situ tension stress inducing functional failure of the brachial plexus consisted
      of two steps. Step I (in vivo): The brachial plexus of the rabbit was stretched
      laterally until electrophysiological conduction blocking occurred. The distance
      between two dye marks placed on the lower trunk was simultaneously recorded using
      a video dimensional analyzer system. Step II (in vitro): The lower trunk that was
      removed was loaded again, and the nerve tension was recorded. The load at
      complete conduction blocking was determined by a load-elongation curve. The
      results showed that when the in situ nerve strain reached 8.1 +/- 0.5%, the
      compound muscle action potential was not evoked. The in situ load and stress were
      2.5 +/- 0.4 N and 0.89 +/- 0.14 MPa, respectively, at complete conduction
      blocking. These findings should be helpful in understanding the mechanism of
      brachial plexus traction injury.

PMID- 12472246
TI  - A potential mechanism for age-related declines in patellar tendon biomechanics.
AB  - Injuries to soft tissues such as tendons are becoming ever more frequent among
      the elderly. While increasing levels of activity likely contribute to these
      injuries, age-related declines in tendon strength may also be important. Whether
      these declines in biomechanical properties are associated with changes in fibril
      diameter or collagen type remains in question. In this study, age-related changes
      were investigated in patellar tendons from young adult rabbits (1-year old, n =
      17) and from rabbits at the onset of senescence (4-year old, n = 33). Patellar
      tendon biomechanics was correlated with both collagen fibril diameter and with
      the presence of type V collagen, a known regulator of collagen fibril diameter.
      We hypothesize that (a) aging from I to 4 years results in significant reductions
      in patellar tendon biomechanical properties, and (b) these age-related declines
      are associated with smaller fibril diameters and with the presence of type V
      collagen. Maximum stress declined 25% between I and 4 years of age (100.7 +/- 5.6
      MPa and 74.3 +/- 3.4 MPa, respectively, p < 0.0003) (mean +/- SEM) and strain
      energy density declined 40% (p < 0.001). The distribution of collagen fibrils
      from 4-year old rabbits was skewed significantly towards smaller diameters
      compared to fibrils from 1-year old rabbits (p < 0.001). Type V collagen was
      observed only in the 4-year old rabbit tendons. These correlations suggest that
      with increasing age after skeletal maturity, type V collagen may help to regulate
      the assembly and thus diameter of collagen fibrils and thereby adversely affect
      patellar tendon strength.

PMID- 12472247
TI  - Increased reflex activation of the peroneus longus following application of an
      ankle brace declines over time.
AB  - Two experiments were performed to document the time-dependent characteristics of
      the peroneus longus short latency stretch reflex amplitude following application
      of an ankle brace. In Experiment 1, stretch reflexes were induced in 15
      weightbearing subjects during an unbraced condition and braced condition. In
      Experiment 2, stretch reflexes were induced in 15 weightbearing subjects before
      and after 3 h of wearing the brace. In Experiment 1. the amplitude of the stretch
      reflex increased in the braced condition by about 25% relative to the non-braced
      condition (p = 0.006). In Experiment 2 the amplitude of the stretch reflex
      increased about 18% immediately after application of the brace relative to the
      non-braced condition (p = 0.037). After 3 h, the stretch reflex amplitude was not
      different from that of initial non-braced condition. Given the importance of the
      peroneus longus muscle in ankle complex stability, further attention should be
      directed to whether the increased stretch reflex gain can be exploited during
      rehabilitation from ankle complex injuries. The findings provide a framework by
      which the effect of ankle braces on ankle joint proprioception, muscle activation
      profiles and balance may be physiologically interpreted.

PMID- 12472248
TI  - Wrist kinetics after luno-triquetral dissociation: the changes in moment arms of
      the flexor carpi ulnaris tendon.
AB  - Wrist biomechanics after luno-triquetral (LT) dissociation is important for
      understanding the clinical sequelae of the disease and for determining its
      treatment options. The LT interosseous ligament plays an important role in
      stabilizing the joint and damage to the ligament would be expected to
      significantly increase moment arms of tendon of the flexor carpi ulnaris (FCU),
      the principal ulnar wrist flexor. We investigated the changes in moment arms of
      FCU tendon after various amounts of sectioning of the ligaments proven to be
      associated with LT dissociation. In six fresh frozen cadaveric upper extremities,
      excursions of the FCU tendon were recorded simultaneously with wrist joint
      angulation during wrist flexion-extension and radioulnar deviation. Tendon
      excursions were measured in intact wrists, in wrists with sectioning of the
      dorsal portion of the LT interosseous ligament, in wrists with sectioning of the
      entire LT interosseous ligament, and finally in wrists with further sectioning of
      the dorsal radiotriquetral and intercarpal ligaments. Moment arms of the tendon
      were calculated from tendon excursions and joint motion angulations and expressed
      as percentage changes from those in the intact wrist. During wrist flexion
      extension, moment arms of the FCU tendon after sectioning of the entire LT
      interosseous ligament and after sectioning of the two capsular ligaments were 112
      +/- 7% and 114 +/- 8%, respectively; these values were significantly greater than
      those in the intact wrist. During radioulnar deviation, the moment arms were 114
      +/- 11% after sectioning of the dorsal portion of the LT interosseous ligament,
      134 +/- 15% after sectioning of the entire ligament, and 153 +/- 18% after
      sectioning of the capsular ligaments, again being significantly greater than the
      normal wrist. Increase in moment arms of the FCU tendon after loss of integrity
      of the LT interosseous ligament and dorsal capsular ligaments may contribute to
      clinical sequelae of LT dissociation and difficulty in treating this disorder.

PMID- 12472249
TI  - Thoracolumbar spine mechanics contrasted under compression and shear loading.
AB  - The mechanical properties of the human spine have been studied extensively in
      compression, but there remains a lack of fundamental data in shear. The overall
      goal of this study was to contrast the mechanics of the thoracolumbar functional
      spinal unit (FSU) under compression and shear-type loads by evaluating endplate
      deformation, disc pressures, and kinematics between the different loading types.
      Eleven T12-L1 and one L1-L2 human FSUs were tested. Compression loads consisted
      of pure compression, extension-compression, flexion-compression, lateral left and
      right compression applied individually to a maximum of 500 N. Shear loading
      consisted of posterior, anterior, left, and right shear to a maximum of 500 N.
      Intervertebral motions, disc pressure, and vertebral body deformations were
      recorded for all loads. The deformations were measured using strain gauge
      rosettes at three points on the inferior vertebral body and one on the superior
      endplate of the inferior vertebra. The disc pressures and endplate deformations
      measured were significantly less in shear loading compared to compression and did
      not change significantly with the type of compression load. Vertebral rim strains
      were generally greater under shear loading compared with compression. The
      mechanics of load transfer in compression was the production of high disc
      pressures which were not linearly correlated with the central endplate
      deformation. In shear, the mechanism appears to be via the annulus fibrosus
      without the development of significant disc pressure. These differences between
      compression and shear loading may have implications for injury mechanisms in the
      thoracolumbar spine.

PMID- 12472250
TI  - Development of the attachment zones in the rat anterior cruciate ligament:
      changes in the distributions of proliferating cells and fibrillar collagens
      during postnatal growth.
AB  - The development of the attachment zones of the anterior cruciate ligament (ACL)
      is an important consideration when examining the structural properties. The aim
      of this study was to elucidate the morphological changes and the distribution of
      proliferating cells and collagen types I, II and III at the attachment zones of
      the rat ACL during postnatal growth. The majority of proliferating cell nuclear
      antigen (PCNA) immunostained cells were noted near the ligament insertion,
      especially at the tibial site, and these cells gradually changed to
      fibrochondrocyte-like cells but still produced collagen types I and III at birth
      until one month old when rapid longitudinal growth of the ACL took place. After
      one month when the rate of the ligament growth decreased to one thirtieth of that
      during the first month and the epiphyseal cartilage at the attachment zone had
      been replaced by bone, these fibrochondrocyte-like cells began to produce
      collagen type II and reveal safranin O staining. The immunolabelling pattern to
      collagen type III was similar to that of PCNA immunostaining during the growth
      phase. Our findings show that the fibrochondrocytes at the attachment zone may
      develop from the ligament cells and act as a growth zone for the ligament during
      the period of ligament growth, and that subsequently, these cells begin to
      synthesis collagen type II and proteoglycans after epiphyseal ossification. These
      observations mainly occurred at the tibial attachment zone.

PMID- 12472251
TI  - Effects of combined administration of transforming growth factor-beta1 and
      epidermal growth factor on properties of the in situ frozen anterior cruciate
      ligament in rabbits.
AB  - The mechanical properties of tendon autografts used in reconstruction of the
      anterior cruciate ligament (ACL) are reduced after surgery. Previous studies
      showed that growth factors such as transforming growth factor-beta1 (TGF-beta1)
      and epidermal growth factor (EGF) can stimulate fibroblast proliferation and
      increase collagen and noncollagenous protein synthesis by these cells. These
      factors might be useful, therefore, in preventing graft deterioration after
      transplantation or accelerating mechanical restoration of the deteriorated graft.
      The purpose of our study, therefore, was to clarify the effects of TGF-beta1 and
      EGF on biomechanical properties using an in situ freeze-thaw ACL model in the
      rabbit. A total of 142 rabbits underwent the freeze-thaw treatment in the right
      ACL and were then divided into four groups. Group I served as a freeze-thaw, but
      otherwise untreated control. In Group II. a delivery vehicle (fibrin sealant)
      alone was applied. In Group III, 4-ng TGF-beta1 and 100-ng EGF mixed with the
      vehicle were applied. In Group IV, higher doses (2-microg TGF-beta1 and 50-microg
      EGF) of growth factors were mixed with the vehicle. The groups were compared at 6
      and 12 weeks on the basis of mechanical properties, water content, and
      histological and ultrastructural observations. The cross-sectional area of Group
      III (average, 7.1 mm2) was significantly less than that of Groups I, II, and IV
      (9.0. 8.2. and 9.4 mm2. respectively) at 12 weeks. The tensile strength of Group
      lII (62.2 MPa) was significantly greater than that of Groups I, II, and IV (35.6,
      43.7, and 36.9 MPa, respectively) at 12 weeks, while the water content of Group
      III (70.7%) was significantly lower than that of Group I (75.2%). No other
      significant differences occurred among Groups I, II, and IV. A unimodal
      distribution of collagen fibril diameters was noted in Groups I and II, while a
      bimodal pattern was found in Group III. This study demonstrated that low-dose
      application of TGFbeta1 and EGF significantly inhibited not only the increased
      water content and cross-sectional area, but also the decreased tensile strength
      caused by the freeze-thaw treatment, while a high dose of TGF-beta1 and EGF does
      not have the same beneficial effects.

PMID- 12472252
TI  - Increased content of type III collagen at the rupture site of human Achilles
      tendon.
AB  - We compared the type I and III collagen amounts and cross-linked telopeptides at
      the rupture site and two other sites of the same tendon. Tendon samples of ten
      individuals with total Achilles tendon rupture and six healthy cadavers were
      collected. The newly synthesized type I and III procollagens were assessed by
      extracting the soluble propeptides PINP, PICP and PIIINP. The insoluble matrix
      was solubilized by heat denaturation and trypsin digestion. Hydroxyproline, the
      cross-linked telopeptide structures of type I (ICTP and SP 4) and III collagens
      (IIINTP) and the degradation product of type III collagen (tryptic PIIINP) were
      measured from the digests. The type III collagen content was significantly
      increased at the rupture site when compared to control sites (5- and 12-fold
      increased) or cadavers (5-fold increased). No changes in the amounts of newly
      synthesized type I and III procollagens were observed. The ICTP content decreased
      and the SP 4/ICTP ratio increased along with ageing, suggesting a structural
      change in the type of cross-link in the carboxyterminal telopeptide of type I
      collagen. Type III collagen has accumulated at the rupture site probably due to
      microtraumas and the subsequent healing process. The increased content of type
      III collagen can cause thinner collagen fibers, decrease the tensile strength and
      may finally result in total rupture of the tendon. The age-related change in the
      nature of the cross-link in the carboxyterminal telopeptide may contribute to
      this weakening.

PMID- 12472253
TI  - Fibronectin, MMP-1 and histologic changes in rotator cuff disease.
AB  - This study was designed to investigate human surgical specimens from patients
      with impingement (n = 16), ruptured supraspinatus tendons (n = 7), frozen
      shoulder (n = 2) and controls (n = 9) with respect to histological changes and
      the presence of fibronectin and Matrix metalloprotease-1 (MMP-1). The biopsy of
      the middle part of the supraspinatus tendons was analyzed microscopically after
      staining with hematoxyline eosin, Van Giesons hematoxyline and Phospho Tungstic
      Acid Hematoxyline for visualization of fibrin. Immunofluorescent stainings for
      fibronectin and MMP-1 were performed. Histology and immunofluorescence were
      assessed blindly. Necrotic tendinous tissue and fibrin were found only in some
      specimens from ruptures. The staining for fibronectin was significantly increased
      among patients with a rupture. MMP-1 was, however, only infrequently found in
      specimens from patients with impingement and ruptures. Fibrosis and thinning of
      fascicles seemed to be a more non-specific finding, appearing in control,
      impingement and rupture specimens. In conclusion, necrotic tendinous tissue,
      fibrin and fibronectin appear to be signs of tendon degeneration, whereas
      fibrosis and thinning of fascicles were found also in controls.

PMID- 12472254
TI  - Interleukin-1-induced glenohumeral synovitis and shoulder pain in rotator cuff
      diseases.
AB  - Synovitis of the subacromial bursa has been identified as a main source of
      shoulder pain in rotator cuff diseases. Little interest, however, has been paid
      into the synovitis of glenohumeral joint. The mRNA expression levels of
      interleukin-1beta (IL-1beta) and interleukin-1 receptor antagonists produced in
      the synovitis reflect the magnitude of inflammation. The present study was
      undertaken to determine the relationship between mRNA expression levels of IL
      1beta and its receptor antagonists (secreted interleukin-1 receptor antagonist
      (IL-1ra) and intracellular IL-1ra) in the synovium of the glenohumeral joint and
      shoulder pain in rotator cuff diseases, analyzing the synovial specimens by
      reverse transcriptase polymerase chain reaction. Thirty-five patients with
      rotator cuff diseases were candidates. Based on the presence of cuff perforation,
      they were divided into two categories: 16 with non-perforating tears and 19 with
      perforating tears. The degree of shoulder pain was evaluated by use of a visual
      analogue scale. The pain degree of non-perforating tears was significantly
      greater than that of perforating tears (P < 0.01). In contrast, the expression
      levels of the cytokine-mRNAs were constitutively greater in perforating tears
      than in non-perforating tears (P < 0.01, respectively). The expression levels of
      the cytokine-mRNAs were inversely correlated with the degree of pain (IL-1beta: r
      = 0.930; secreted IL-1ra: r = 0.861; intracellular IL-1ra: r = 0.932, P < 0.001
      respectively). These results suggest that the expression levels of the cytokine
      mRNAs in the synovium of the glenohumeral joint contribute less to the generation
      of shoulder pain in rotator cuff diseases.

PMID- 12472255
TI  - Apoptosis in rotator cuff tendonopathy.
AB  - The aim of this study was to investigate the involvement of apoptosis (programmed
      cell death) in the pathogenesis of rotator cuff disorders. The edges of torn
      supraspinatus rotator cuff tendons were collected from patients with rotator cuff
      tear (n = 25). Samples of the intra-articular portion of subscapularis tendons
      were collected from patients without rotator cuff tear as control (n = 6). To
      minimize individual variance, we also collected six pairs of supraspinatus tendon
      and subscapularis tendon from six patients with rotator cuff tears. Apoptosis was
      detected by in situ DNA end labelling assay and DNA laddering assay.
      Immunohistochemical staining was performed to identify cells undergoing
      apoptosis. Control subscapularis tendon had normal morphology. Tendon from torn
      supraspinatus rotator cuff showed significant mucoid degeneration. Within the
      areas of degeneration, there were large numbers of apoptotic cells. The
      percentage of apoptotic cells in the degenerative rotator cuff (34%) was
      significantly higher than that in controls (13%) (p < 0.001). The excessive
      apoptosis detected in degenerative rotator cuff tissue was confirmed by DNA
      laddering assays. This is the first report of excessive apoptosis in degenerating
      rotator cuff tendon. Cells undergoing apoptosis in rotator cuff were mainly
      fibroblast-like cells. These finding indicate that apoptosis may play an
      important role in the pathogenesis of rotator cuff degeneration.

PMID- 12472256
TI  - Mechanical stretching force promotes collagen synthesis by cultured cells from
      human ligamentum flavum via transforming growth factor-beta1.
AB  - Although mechanical stress as a result of spinal instability is known to cause
      hypertrophy of the ligamentum flavum resulting in degenerative spinal canal
      stenosis, the mechanism of the ligament hypertrophy is not well understood. In
      the present study, we investigated the effect of mechanical stretching force on
      collagen synthesis and transforming growth factor-beta1 (TGF-beta1) production
      using ligament cells isolated from human ligamentum flavum in vitro. Ligamentum
      flavum cells (LFCs) were isolated from human ligamentum flavum obtained from
      patients who underwent lumbar spine surgery. The LFCs were subjected to a
      mechanical stretching force using a commercially available stretching device that
      physically deformed the cells. Collagen synthesis and TGF-beta1 production levels
      in the LFCs were then examined. Notable increases were observed in the gene
      expressions of collagen types I, III, and V in LFCs subjected to mechanical
      stretching force. The increase in collagen gene expression of LFCs was inhibited
      in the presence of anti-TGF-beta1 antibodies. Production of TGF-beta1 by the LFCs
      also increased significantly by the mechanical stretching force. Exogenous
      application of TGF-beta1 was confirmed to increase collagen synthesis of the
      LFCs. This data indicated that mechanical stretching force can promote TGF-beta1
      production by LFCs, resulting in hypertrophy of the ligament.

PMID- 12472257
TI  - The Whitaker Foundation: the end will be just the beginning.

PMID- 12472258
TI  - First IEEE symposium on biomedical imaging.

PMID- 12472259
TI  - Imaging of spatiotemporal coincident states by DC optical tomography.
AB  - The utility of optical tomography as a practical imaging modality has, thus far,
      been limited by its intrinsically low spatial resolution and quantitative
      accuracy. Recently, we have argued that a broad range of physiological phenomena
      might be accurately studied by adopting this technology to investigate dynamic
      states (Schmitz et al., 2000; Barbour et al., 2000; Graber et al., 2000; Barbour
      et aL, 2001; and Barbour et aL, 1999). One such phenomenon holding considerable
      significance is the dynamics of the vasculature, which has been well
      characterized as being both spatially and temporally heterogeneous. In this
      paper, we have modeled such heterogeneity in the limiting case of spatiotemporal
      coincident behavior involving optical contrast features, in an effort to define
      the expected limits with which dynamic states can be characterized using two
      newly described reconstruction methods that evaluate normalized detector data:
      the normalized difference method (NDM) and the normalized constraint method
      (NCM). Influencing the design of these studies is the expectation that spatially
      coincident temporal variations in both the absorption and scattering properties
      of tissue can occur in vivo. We have also chosen to model dc illumination
      techniques, in recognition of their favorable performance and cost for practical
      systems. This choice was made with full knowledge of theoretical findings arguing
      that separation of the optical absorption and scattering coefficients under these
      conditions is not possible. Results obtained show that the NDM algorithm provides
      for good spatial resolution and excellent characterization of the temporal
      behavior of optical properties but is subject to interparameter crosstalk. The
      NCM algorithm, while also providing excellent characterization of temporal
      behavior, provides for improved spatial resolution, as well as for improved
      separation of absorption and scattering coefficients. A discussion is provided to
      reconcile these findings with theoretical expectations.

PMID- 12472260
TI  - Efficient fully 3-D iterative SPECT reconstruction with Monte Carlo-based scatter
      compensation.
AB  - Quantitative accuracy of single photon emission computed tomography (SPECT)
      images is highly dependent on the photon scatter model used for image
      reconstruction. Monte Carlo simulation (MCS) is the most general method for
      detailed modeling of scatter, but to date, fully three-dimensional (3-D) MCS
      based statistical SPECT reconstruction approaches have not been realized, due to
      prohibitively long computation times and excessive computer memory requirements.
      MCS-based reconstruction has previously been restricted to two-dimensional
      approaches that are vastly inferior to fully 3-D reconstruction. Instead of MCS,
      scatter calculations based on simplified but less accurate models are sometimes
      incorporated in fully 3-D SPECT reconstruction algorithms. We developed a
      computationally efficient fully 3-D MCS-based reconstruction architecture by
      combining the following methods: 1) a dual matrix ordered subset (DM-OS)
      reconstruction algorithm to accelerate the reconstruction and avoid massive
      transition matrix precalculation and storage; 2) a stochastic photon transport
      calculation in MCS is combined with an analytic detector modeling step to reduce
      noise in the Monte Carlo (MC)-based reprojection after only a small number of
      photon histories have been tracked; and 3) the number of photon histories
      simulated is reduced by an order of magnitude in early iterations, or photon
      histories calculated in an early iteration are reused. For a 64 x 64 x 64 image
      array, the reconstruction time required for ten DM-OS iterations is approximately
      30 min on a dual processor (AMD 1.4 GHz) PC, in which case the stochastic nature
      of MCS modeling is found to have a negligible effect on noise in reconstructions.
      Since MCS can calculate photon transport for any clinically used photon energy
      and patient attenuation distribution, the proposed methodology is expected to be
      useful for obtaining highly accurate quantitative SPECT images within clinically
      acceptable computation times.

PMID- 12472261
TI  - Analytic determination of the pinhole collimator's point-spread function and RMS
      resolution with penetration.
AB  - Pinhole collimators are widely used to image small organs and animals. The
      pinhole response function (PRF) of knife-edge pinhole collimators has been
      estimated previously using geometric constructions without considering
      penetration and using "roll-off" models that employ an exponential model for the
      flux. An analytic expression for the PRF on the imaging plane that includes the
      effect of aperture penetration is derived in this paper by calculating the flux
      for photons passing through the aperture and those passing through the
      attenuating material. The PRF is then used to approximate the angular-dependent
      root-mean-square resolution in the directions parallel and perpendicular to the
      tilt of the point source. The corresponding aspect ratio is then obtained. The
      formulas are then compared with experimental data.

PMID- 12472262
TI  - Deformable triangular surfaces using fast 1-D radial Lagrangian dynamics-
      segmentation of 3-D MR and CT images of the wrist.
AB  - We developed a new triangulated deformable surface model, which is used to detect
      the boundary of the bones in three-dimensional magnetic resonance (MR) and
      computed tomography (CT) images of the wrist. This surface model is robust to
      initialization and provides wide geometrical coverage and quantitative power. The
      surface is deformed by applying one-dimensional (1-D) radial Lagrangian dynamics.
      For initialization a tetrahedron is placed within the bone to be segmented. This
      initial surface is inflated to a binary approximation of the boundary. During
      inflation, the surface is refined by the addition of vertices. After the surface
      is fully inflated, a detailed, accurate boundary detection is obtained by the
      application of radial scale-space relaxation. In this optimization stage, the
      image intensity is filtered with a series of 1-D second-order Gaussian filters.
      The resolution of the triangulated mesh is adapted to the width of the Gaussian
      filter. To maintain the coherence between the vertices, a resampling technique is
      applied which is based on collapsing and splitting of edges. We regularized the
      triangulated mesh by a combination of volume-preserving vertex averaging and equi
      angulation of edges. In this paper, we present both qualitative and quantitative
      results of the surface segmentations in eight MR and ten CT images.

PMID- 12472263
TI  - Volumetric segmentation of brain images using parallel genetic algorithms.
AB  - Active model-based segmentation has frequently been used in medical image
      processing with considerable success. Although the active model-based method was
      initially viewed as an optimization problem, most researchers implement it as a
      partial differential equation solution. The advantages and disadvantages of the
      active model-based method are distinct: speed and stability. To improve its
      performance, a parallel genetic algorithm-based active model method is proposed
      and applied to segment the lateral ventricles from magnetic resonance brain
      images. First, an objective function is defined. Then one instance surface was
      extracted using the finite-difference method-based active model and used to
      initialize the first generation of a parallel genetic algorithm. Finally, the
      parallel genetic algorithm is employed to refine the result. We demonstrate that
      the method successfully overcomes numerical instability and is capable of
      generating an accurate and robust anatomic descriptor for complex objects in the
      human brain, such as the lateral ventricles.

PMID- 12472264
TI  - Adaptive elastic segmentation of brain MRI via shape-model-guided evolutionary
      programming.
AB  - This paper presents a fully automated segmentation method for medical images. The
      goal is to localize and parameterize a variety of types of structure in these
      images for subsequent quantitative analysis. We propose a new hybrid strategy
      that combines a general elastic template matching approach and an evolutionary
      heuristic. The evolutionary algorithm uses prior statistical information about
      the shape of the target structure to control the behavior of a number of
      deformable templates. Each template, modeled in the form of a B-spline, is warped
      in a potential field which is itself dynamically adapted. Such a hybrid scheme
      proves to be promising: by maintaining a population of templates, we cover a
      large domain of the solution space under the global guidance of the evolutionary
      heuristic, and thoroughly explore interesting areas. We address key issues of
      automated image segmentation systems. The potential fields are initially designed
      based on the spatial features of the edges in the input image, and are subjected
      to spatially adaptive diffusion to guarantee the deformation of the template.
      This also improves its global consistency and convergence speed. The deformation
      algorithm can modify the internal structure of the templates to allow a better
      match. We investigate in detail the preprocessing phase that the images undergo
      before they can be used more effectively in the iterative elastic matching
      procedure: a texture classifier, trained via linear discriminant analysis of a
      learning set, is used to enhance the contrast of the target structure with
      respect to surrounding tissues. We show how these techniques interact within a
      statistically driven evolutionary scheme to achieve a better tradeoff between
      template flexibility and sensitivity to noise and outliers. We focus on
      understanding the features of template matching that are most beneficial in terms
      of the achieved match. Examples from simulated and real image data are discussed,
      with considerations of algorithmic efficiency.

PMID- 12472265
TI  - Active shape model segmentation with optimal features.
AB  - An active shape model segmentation scheme is presented that is steered by optimal
      local features, contrary to normalized first order derivative profiles, as in the
      original formulation [Cootes and Taylor, 1995, 1999, and 2001]. A nonlinear kNN
      classifier is used, instead of the linear Mahalanobis distance, to find optimal
      displacements for landmarks. For each of the landmarks that describe the shape,
      at each resolution level taken into account during the segmentation optimization
      procedure, a distinct set of optimal features is determined. The selection of
      features is automatic, using the training images and sequential feature forward
      and backward selection. The new approach is tested on synthetic data and in four
      medical segmentation tasks: segmenting the right and left lung fields in a
      database of 230 chest radiographs, and segmenting the cerebellum and corpus
      callosum in a database of 90 slices from MRI brain images. In all cases, the new
      method produces significantly better results in terms of an overlap error measure
      (p < 0.001 using a paired T-test) than the original active shape model scheme.

PMID- 12472266
TI  - An accurate and efficient bayesian method for automatic segmentation of brain
      MRI.
AB  - Automatic three-dimensional (3-D) segmentation of the brain from magnetic
      resonance (MR) scans is a challenging problem that has received an enormous
      amount of attention lately. Of the techniques reported in the literature, very
      few are fully automatic. In this paper, we present an efficient and accurate,
      fully automatic 3-D segmentation procedure for brain MR scans. It has several
      salient features; namely, the following. 1) Instead of a single multiplicative
      bias field that affects all tissue intensities, separate parametric smooth models
      are used for the intensity of each class. 2) A brain atlas is used in conjunction
      with a robust registration procedure to find a nonrigid transformation that maps
      the standard brain to the specimen to be segmented. This transformation is then
      used to: segment the brain from nonbrain tissue; compute prior probabilities for
      each class at each voxel location and find an appropriate automatic
      initialization. 3) Finally, a novel algorithm is presented which is a variant of
      the expectation-maximization procedure, that incorporates a fast and accurate way
      to find optimal segmentations, given the intensity models along with the spatial
      coherence assumption. Experimental results with both synthetic and real data are
      included, as well as comparisons of the performance of our algorithm with that of
      other published methods.

PMID- 12472267
TI  - Computional cost of nonrigid registration algorithms based on fluid dynamics.
AB  - Though fluid dynamics offer a good approach to nonrigid registration and give
      accurate results, even with large-scale deformations, its application is still
      very time consuming. We introduce and discuss different approaches to solve the
      core problem of nonrigid registration, the partial differential equation of fluid
      dynamics. We focus on the solvers, their computional costs and the accuracy of
      registration. Numerical experiments show that relaxation is currently the best
      approach, especially when reducing the cost/iteration by focusing the updates on
      deformation spots.

PMID- 12472268
TI  - Measures of folding applied to the development of the human fetal brain.
AB  - Previous work has suggested the existence of differences between the cerebral
      cortex of normal individuals, and those of patients with diseases such as
      epilepsy and schizophrenia. These shape abnormalities may be of developmental
      origin. Improved shape measures could provide useful tools for neuroscience
      research and patient diagnosis. We consider the theoretically desirable
      properties of measures of brain shape. We have implemented seven measures, three
      from the neuroscience literature, and four new to this field. Three of the
      measures are zero-order and four are second-order with respect to the surface. We
      validate the measures using simple geometrical shapes, and a collection of
      magnetic resonance scans of ten histologically normal ex vivo fetal brains with
      gestational ages from 19-42 weeks. We then apply the measures to MR scans from
      two histologically abnormal ex vivo brains. We demonstrate that our
      implementation of the measures is sensitive to anatomical variability rather than
      to the discreteness of the image data. All the measures were sensitive to changes
      in shape during fetal development. Several of the measures could distinguish
      between the normal and abnormal fetal brains. We propose a multivariate approach
      to studying the shape of the cerebral cortex, in which both zero-order and second
      order measures are used to quantify folding.

PMID- 12472269
TI  - Understanding phase maps in MRI: a new cutline phase unwrapping method.
AB  - This paper describes phase maps. A review of the phase unwrapping problem is
      given. Different structures, in particular fringelines, cutlines, and poles,
      contained within a phase map are described and their origin and behavior
      investigated. The problem of phase unwrapping can then be addressed with a better
      understanding of the source of poles or inconsistencies. This understanding,
      along with some assumptions about what is being encoded in the phase of a
      magnetic resonance image, are used to derive a new method for phase unwrapping
      which relies only on the phase map. The method detects cutlines and distinguishes
      between noise-induced poles and signal undersampling poles based on the length of
      the fringelines. The method was shown to be robust to noise and successful in
      unwrapping challenging clinical cases.

PMID- 12472270
TI  - Anti-aliasing weighting functions for single-slice helical CT.
AB  - Spatially variant longitudinal aliasing plagues most volumes reconstructed from
      single-slice helical computed tomography data, and its presence can degrade
      resolution and distort image structures. We have recently developed a Fourier
      based approach to longitudinal interpolation in helical computed tomography that
      can, for scans performed at pitch 1 or lower, essentially eliminate this
      longitudinal aliasing by exploiting a generalization of the Whittaker-Shannon
      sampling theorem whose conditions are satisfied by the interlaced pairs of direct
      and complementary longitudinal samples. However, the algorithm is computationally
      intensive and cannot be pipelined. In this paper, we address this shortcoming by
      deriving two spatial-domain, projection-data weighting functions that approximate
      the application of the Fourier-based approach, and preserve its aliasing
      suppression properties to some degree, while allowing for a pipelined
      implementation. The first approach, which we call simply 180AA, for anti
      aliasing, is a direct spatial-domain approximation of the 180FT approach. The
      second approach, which we call 180BSP, is based on an approximate generalized
      interpolation approach making use of B-splines. Studies of aliasing and
      resolution properties in reconstructions from simulated data indicate that while
      the 180AA and 180BSP approaches do not perfectly replicate the favorable aliasing
      suppression and resolution properties of the 180FT approach, they do represent an
      improvement over the clinically standard 180LI approach on these fronts.

PMID- 12472271
TI  - A head-mounted operating binocular for augmented reality visualization in
      medicine--design and initial evaluation.
AB  - Computer-aided surgery (CAS), the intraoperative application of biomedical
      visualization techniques, appears to be one of the most promising fields of
      application for augmented reality (AR), the display of additional computer
      generated graphics over a real-world scene. Typically a device such as a head
      mounted display (HMD) is used for AR. However, considerable technical problems
      connected with AR have limited the intraoperative application of HMDs up to now.
      One of the difficulties in using HMDs is the requirement for a common optical
      focal plane for both the realworld scene and the computer-generated image, and
      acceptance of the HMD by the user in a surgical environment. In order to increase
      the clinical acceptance of AR, we have adapted the Varioscope (Life Optics,
      Vienna), a miniature, cost-effective head-mounted operating binocular, for AR. In
      this paper, we present the basic design of the modified HMD, and the method and
      results of an extensive laboratory study for photogrammetric calibration of the
      Varioscope's computer displays to a real-world scene. In a series of 16
      calibrations with varying zoom factors and object distances, mean calibration
      error was found to be 1.24 +/- 0.38 pixels or 0.12 +/- 0.05 mm for a 640 x 480
      display. Maximum error accounted for 3.33 +/- 1.04 pixels or 0.33 +/- 0.12 mm.
      The location of a position measurement probe of an optical tracking system was
      transformed to the display with an error of less than 1 mm in the real world in
      56% of all cases. For the remaining cases, error was below 2 mm. We conclude that
      the accuracy achieved in our experiments is sufficient for a wide range of CAS
      applications.

PMID- 12472272
TI  - Volume rendering of segmented image objects.
AB  - This paper describes a new method of combining ray-casting with segmentation.
      Volume rendering is performed at interactive rates on personal computers, and
      visualizations include both "superficial" ray-casting through a shell at each
      object's surface and "deep" ray-casting through the confines of each object. A
      feature of the approach is the option to smoothly and interactively dilate
      segmentation boundaries along all axes. This ability, when combined with
      selective "turning off" of extraneous image objects, can help clinicians detect
      and evaluate segmentation errors that may affect surgical planning. We describe
      both a method optimized for displaying tubular objects and a more general method
      applicable to objects of arbitrary geometry. In both cases, select three
      dimensional points are projected onto a modified z buffer that records additional
      information about the projected objects. A subsequent step selectively volume
      renders only through the object volumes indicated by the z buffer. We describe
      how our approach differs from other reported methods for combining segmentation
      with ray-casting, and illustrate how our method can be useful in helping to
      detect segmentation errors.

PMID- 12472273
TI  - Proteomics.

PMID- 12472274
TI  - The time for accurate Fuhrman grading of renal cell carcinomas has arrived.

PMID- 12472275
TI  - Value of interphase FISH for the diagnosis of t(11:14)(q13;q32) on skin lesions
      of mantle cell lymphoma.
AB  - The diagnosis of skin lesions of mantle cell lymphoma (MCL) may be difficult at
      the onset of the disease. We observed 2 patients with papules of the trunk and 1
      with diffuse infiltration of the trunk and the face and 2 subcutaneous nodules.
      Skin samples showed diffuse infiltration of the dermis (n = 1) or perivascular
      infiltration (n = 2). The infiltrate corresponded to centrocytic cells (n = 2) or
      pleomorphic blastoid cells (n = 1) with a B-cell phenotype: CD3-, CD5+ (2/3),
      CD20+, CD23-, and CD43+. In only 1 case was cyclin D1 immunoreactivity detected,
      and the t(11;l4)(q13;q32) breakpoint was amplified from both lymph node and skin
      DNA. Competitive reverse transcriptase-polymerase chain reaction was not
      contributive for skin specimens. In all 3 cases, interphase fluorescence in situ
      hybridization (FISH) demonstrated t(11;14) fusion signals either on paraffin
      sections or on fresh frozen touch preparations of skin biopsies. The recognition
      of skin lesions of MCL from other B-cell infiltrates can be established by
      interphase FISH.

PMID- 12472276
TI  - Expression of mu-BCR-ADL transcripts in chronic neutrophilic leukemia.
AB  - The classification of chronic neutrophilic leukemia (CNL) is controversial. Our
      purpose was to correlate clinical, pathologic, and molecular analyses in 2 cases
      of CNL. In both cases, the patients were referred because of a substantially
      increased peripheral WBC count noted during routine examination. Bone marrow
      biopsies and aspirate smears revealed hypercellularity with myeloid/erythroid
      ratios of 4:1 and 11:1, respectively. The bone marrow aspirate results were as
      follows: case 1: blasts, 2%; promyelocytes, 2%; myelocytes, 6%; metamyelocytes,
      16%; band neutrophils, 13%; segmented neutrophils, 34%; and case 2: blasts, 1%;
      promyelocytes, 2%; myelocytes, 15%; metamyelocytes, 20%; band neutrophils, 24%;
      neutrophils, 19%. Reverse transcriptase in situ polymerase chain reaction studies
      demonstrated expression of mu-BCR-ABL transcripts in 13% and 25% of the bone
      marrow cells, respectively. In both cases, the positive signal was noted mainly
      in the early granulocytic precursors and was present in occasional mature
      neutrophils. To our knowledge, this is thefirst in situ demonstration of mu-BCR
      ABL expression in CNL Ourfindings reinforce the usefulness of this messenger RNA
      as a molecular marker of CNL.

PMID- 12472277
TI  - Composite angioimmunoblastic T-cell lymphoma and diffuse large B-cell lymphoma: a
      case report and review of the literature.
AB  - We report a rare case of composite angioimmunoblastic T-cell lymphoma (AILT) and
      diffuse large B-cell lymphoma occurring in a 48-year-old woman with generalized
      lymphadenopathy and hepatosplenomegaly. The patient initially sought care at a
      local hospital with a single enlarged left cervical lymph node. Histologic
      examination of the node was interpreted as an atypical immunoblastic
      proliferation. She developed generalized lymphadenopathy 10 months later and was
      referred to our institution for further evaluation. The recent biopsy of the
      cervical node showed typical features of AILT Flow cytometric immunophenotyping
      identified an aberrant CD4+ T-cell population that lacked surface CD3. Polymerase
      chain reaction analysis of the T-cell receptor gamma gene revealed a clonal
      rearrangement. In addition to the AILT, the lymph node showed partial involvement
      by a diffuse large B-cell lymphoma. The B lymphoma cells and admixed
      immnunoblasts and Reed-Sternberg-like B cells in the AILT were positive for
      Epstein-Barr virus (EBV) by in situ hybridization. Ourfindings raise the
      possibility that the EBV-associated large B-cell lymphoma is a secondary event in
      AILT via EBV infection or reactivation followed by clonal expansion of an
      immortalized EBV-infected B cell clone.

PMID- 12472278
TI  - Effect of marathon running on hematologic and biochemical laboratory parameters,
      including cardiac markers.
AB  - Participants in marathon races may require medical attention and the performance
      of laboratory assays. We report the changes in basic biochemical parameters,
      cardiac markers, CBC counts, and WBC differentials observed in participants in a
      marathon before, within 4 hours, and 24 hours after a race. The concentrations of
      glucose, total protein, albumin, uric acid, calcium, phosphorus, serum urea
      nitrogen, creatinine, bilirubin, alkaline phosphatase, alanine aminotransferase,
      aspartate aminotransferase, total creatine kinase, creatine kinase-MB, myoglobin,
      and the anion gap were increased after the race, consistent with the effects of
      exertional rhabdomyolysis and hemolysis. The increase in WBC counts was due
      mainly to neutrophilia and monocytosis, with a relative decrease in circulating
      lymphocytes, consistent with an inflammatory reaction to tissue injury. A
      significant percentage of laboratory results were outside the standard reference
      ranges, indicating that modified reference ranges derivedfrom marathon runners
      might be more appropriatefor this population. We provide a table of modified
      reference ranges (or expected ranges) for basic biochemical, cardiac, and
      hematologic laboratory parameters for marathon runners.

PMID- 12472279
TI  - Anti-gp43 antibodies in the cerebrospinal fluid of patients with central nervous
      system involvement by paracoccidioidomycosis.
AB  - Paracoccidioidomycosis (PCM) is a chronic granulomatous infectious disease,
      endemic in subtropical areas of Central and South America. The diagnosis of the
      central nervous system (CNS) involvement with PCM (neuroparacoccidioidomycosis
      [NPCM]) frequently is difficult. A definitive diagnosis usually is made by
      visualization or isolation of Paracoccidioides brasiliensis from CNS biopsy or
      necropsy material. In the present study, we determined the presence of anti-gp43
      antibodies in the cerebrospinalfluid (CSF) of patients with CNS involvement in
      PCM by enzyme-linked immunosorbent assay (ELISA) in 9 cases of NPCM and 15
      control cases. ELISA anti-gp43 was compared with double immunodiffusion (DID).
      ELISA anti-gp43 was positive in 8 (89%) of 9 CSF samples from patients with NPCM
      and negative in all CSF samples of the control group. DID was negative in all CSF
      samples from patients with NPCM and control samples. ELISA anti-gp43 in CSF
      samples is better than DID for the diagnosis of NPCM. It is a sensitive and
      specific diagnostic method and has high predictive values. To our knowledge, this
      is thefirst time ELISA anti-gp43 was applied to CSF.

PMID- 12472280
TI  - Proteomic evaluation of archival cytologic material using SELDI affinity mass
      spectrometry: potential for diagnostic applications.
AB  - Proteomic studies of cells via surface-enhanced laser desorption/ionization
      spectrometry (SELDI) analysis have enabled rapid, reproducible protein profiling
      directly from crude samples. We applied this technique to archival cytology
      material to determine whether distinct, reproducible protein fingerprints could
      be identifiedfor potential diagnostic purposes in blinded specimens. Rapid
      Romanowsky-stained cytocentrifuged specimens from fine-needle aspirates of
      metastatic malignant melanoma (with both known cutaneous primary and unknown
      primary sites), clear cell sarcoma, and renal cell carcinoma and reactive
      effusions were examined using the SELDI technology. A unique characteristic
      fingerprint was identified for each disease entity. Fifteen "blinded" unknown
      samples then were analyzed. When the protein profilefingerprints were plotted
      against the known fingerprints for the aforementioned diagnoses, the appropriate
      match or diagnosis was obtained in 13 (87%) of 15 cases. These preliminary
      findings suggest a substantial potential for SELDI applications to specific
      pathologic diagnoses.

PMID- 12472281
TI  - Comparison of standardized and nonstandardized nuclear grade of renal cell
      carcinoma to predict outcome among 2,042 patients.
AB  - We compared the ability of original nuclear grades from surgical pathology
      reports and grades reviewed by a urologic pathologist to predict death due to
      renal cell carcinoma (RCC) for 2,042 patients treated with radical nephrectomy
      between January 1970 and December 1998. Reviewed grade I tumors had small, round
      nuclei with inconspicuous nucleoli visible at x400; grade 2 contained round to
      slightly irregular nuclei with mildly enlarged nucleoli visible at x200; grade 3
      had round to irregular nuclei with prominent nucleoli visible at x100; grade 4
      contained enlarged pleomorphic or giant cells. Predictive abilities were compared
      using R2 values from Cox proportional hazards models. There were 1,733 (84.87%)
      clear cell, 222 (10.87%) papillary, and 87 (4.26%) chromophobe tumors. Reviewed
      grades were more predictive of death due to RCC than original grades for clear
      cell (R2, 21% vs 16%), papillary (R2, 16% vs 13%), and chromophobe (R2, 39% vs
      27%) RCC. Among patients with clear cell and papillary RCC, this difference was
      apparent even after adjusting for the 1997 TNM stage. Standardized nuclear grades
      were more predictive of death due to RCC than nonstandardized grades for all
      subtypes studied.

PMID- 12472282
TI  - Paranuaclear E-cadherin in gastric adenocarcinoma.
AB  - Decreased E-cadherin expression permits dissociation and widespread dissemination
      of gastric adenocarcinoma cells. We studied the relationship between paranuclear
      E-cadherin distribution and the histopathologic characteristics of gastric
      adenocarcinomas. E-cadherin immunostains of 173 gastric adenocarcinoma sections
      revealed paranuclear; punctate to vesicular staining in 18% (16/87) of the
      intestinal-type adenocarcinomas, 30% (17/56) of the diffuse-type adenocarcinomas,
      and 30% (9/30) of the mired adenocarcinomas. These data suggest that in some
      gastric adenocarcinomas, there is a defect in transport of E-cadherin to the cell
      surface, which may prevent intercellular adhesion and encourage dissemination. Of
      34 cancers with paranuclear E-cadherin staining, 20 (59%) had paranuclear
      staining within the nonneoplastic epithelium, but only 22.0% of 100 carcinomas
      with absent or membranous E-cadherin staining were accompanied by morphologically
      benign epithelium with paranuclear E-cadherin. In surface epithelium, paranuclear
      E-cadherin staining colocalized with Griffonia simplicifolia lectin II in the
      Golgi apparatus. The presence of paranuclear E-cadherin in cancer-associated
      benign epithelium suggests that the alteration in the E-cadherin molecule
      responsible for the paranuclear distribution may be an early change in gastric
      adenocarcinoma progression.

PMID- 12472283
TI  - Intraoperative cytology increases the diagnostic accuracy of frozen sections for
      the confirmation of various tissues in the parathyroid region.
AB  - The identification of parathyroid gland tissue and its distinction from adjacent
      structures such as thyroid gland, lymphoid, fibroadipose, and, rarely, thymic
      tissues on frozen section (FS) may be challenging owing to freezing artifact.
      Intraoperative cytology (IC) provides valuable complementary morphologic details.
      We evaluated 72 specimens with IC alone (group 1), followed by interpretation
      with FS to reach a final interpretation using IC and FS together (group 2). An
      additional 105 specimens were evaluated by FS alone (group 3). Permanent section
      diagnosis was used as the "gold standard." Sensitivity and specificity were 100%
      for group 2, compared with lower values for group 1 (98% and 100%, respectively)
      and group 3 (94% and 94%, respectively). IC is a valuable adjunct to FS during
      intraoperative consultation for evaluation of tissue in a parathyroid location.

PMID- 12472284
TI  - Potential pitfalls in the frozen section evaluation of parenchymal margins in
      nephron-sparing surgery.
AB  - With advances in radiographic imaging, there has been an increase in the
      incidental detection of small renal cell carcinomas, with a resultant increase in
      partial nephrectomies for these tumors. Partial nephrectomy often necessitates
      assessment of renal parenchymal margins by frozen section. To determine the most
      common problematic "lesions" encountered on renal parenchymal margins, we
      evaluated all diagnostically challenging frozen sections that had been referred
      to a genitourinary pathologist. Frozen sections with detached atypical cells and
      crushed tubules were the most common lesions that presented diagnostic
      uncertainty. We found that normal constituents of renal parenchyma, namely
      tubules and glomeruli, can be mistaken for neoplasia. Neoplastic tubules of low
      grade renal cell carcinomas may be misinterpreted as thickly cut, crushed benign
      tubules, and the significance of tubulopapillary "adenomas" in frozen sections is
      unclear. The present report highlights diagnostic difficulties that pathologists
      may encounter on frozen sections of renal parenchymal margins.

PMID- 12472285
TI  - Comparison of thyroid transcription factor-1 and hepatocyte antigen
      immunohistochemical analysis in the differential diagnosis of hepatocellular
      carcinoma, metastatic adenocarcinoma, renal cell carcinoma, and adrenal cortical
      carcinoma.
AB  - We compared the effectiveness of thyroid transcription factor-1 (TTF-1,
      cytoplasmic reactivity) and hepatocyte antigen (HPA) as markers for
      characterization of hepatocellular carcinoma (HCC) and as discriminators to
      distinguish HCC from its histologic and cytologic mimics. Formalin-fixed,
      paraffin-embedded sections of 258 specimens, including 76 HCCs, 85 metastatic
      adenocarcinomas, 75 renal cell carcinomas (RCCs), and 22 adrenal cortical
      carcinomas (ACCs), were evaluated. Specimens included tissue sections and
      cytologic material (cell blocks). Following heat-induced epitope retrieval,
      immunohistochemical studies were performed using an indirect immunoperoxidase
      technique. Cytoplasmic reactivity for TTF-1 was noted for 54 (71%) of 76 HCCs, 3
      (4%) of 85 adenocarcinomas, none of 72 RCCs, and none of 22 ACCs. Cytoplasmic
      reactivity for HPA was observedfor 50 (66%) of 76 HCCs, 1 (1%) of 83
      adenocarcinomas, none of 74 RCCs, and none of 21 ACCs. Cytoplasmic reactivity for
      TTF-1 and HPA is highly specific for HCC, although a minority of HCCs,
      particularly poorly differentiated tumors, may be nonreactive. Thus, these
      markers are usefulfor the characterization of HCC in tissue sections and cell
      blocks and are highly effective for distinguishing these tumors from other
      neoplasms included in the differential diagnosis.

PMID- 12472286
TI  - CAS (cellular apoptosis susceptibility) gene expression in ovarian carcinoma:
      Correlation with 20q13.2 copy number and cyclin D1, p53, and Rb protein
      expression.
AB  - We immunohistochemically analyzed cellular apoptosis susceptibility (CAS) protein
      expression and compared it with 20q13.2 copy number and the expression of cell
      cycle-associated proteins retinoblastoma (Rb), cyclin D1, and p53 and prognosis
      on paraffin-embedded tissue from 69 ovarian carcinomas (OCs). CAS protein
      reactivity was present in 100%, Rb in 54%, cyclin D1 in 47%, and p53 in 49%.
      Significant reciprocal correlation was observed between high levels of CAS and
      histologic type, FIGO (International Federation of Obstetrics and Gynecology)
      stage III and grade 3, residual tumor (>2 cm), 20q13.2 (ZNF217 gene)
      amplification (>4 copies in >20% cells), and high expression of cyclin D1 (all P
      < .05). No association was found between cyclin D1, p53, or Rb levels with
      clinicopathologic factors. In univariate analysis, residual tumor, FIGO stage and
      grade, ZNF217 amplification, and CAS levels predicted outcome (all P < .05). In
      multivariate analysis, stage, grade, amount of residual tumor, and ZNF217
      amplification showed independent prognostic value (all P < .05). In OC,
      alteration of CAS and ZNF217 genes, both located at 20q13, is frequent and
      relevant prognostically. Cyclin D1, Rb, and p53 seem to have a secondary role.

PMID- 12472287
TI  - Comparison of five antibodies as markers in the diagnosis of melanoma in
      cytologic preparations.
AB  - We determined the sensitivity and specificity of 3 novel antibodies
      (microphthalmia transcription factor [Mitf], Melan-A, and tyrosinase) as markers
      for melanoma in cytologic preparations and compared the results with those of
      commonly used markers (S-100 protein [S-100] and HMB-45). We stained 72 cell
      blocks from 40 patients with melanoma and 32 with nonmelanocytic malignant
      neoplasms with antibodies against S-100, HMB-45, Mitf, Melan-A, and tyrosinase.
      Histologic correlation was available in more than 95% of cases. Nuclear
      stainingfor Mitf and cytoplasmic stainingfor S-100, HMB-45, Melan-A, and
      tyrosinase in more than 10% of tumor cells was considered positive. All 3 novel
      markers demonstrated sensitivity superior to S-100 and HMB-45. HMB-45, Melan-A,
      and Mitf demonstrated specificities of 97%. S-100 protein and tyrosinase were
      less specific. Sensitivity and specificity for the combination Mitf+/Melan-A+
      were 95% and 100%, respectively, whereas they were 80% and 100%, respectively,
      for S-100+/HMB-45+. Mitf Melan-A, and tyrosinase are sensitive markersfor
      epithelioid melanoma. Mitf and Melan-A seem more specific than S-100 and
      tyrosinase. An antibody panel consisting of Mitf and Melan-A is superior to a
      panel of S-100 and HMB-45 in the diagnosis of melanoma in cytologic specimens.

PMID- 12472288
TI  - Spontaneous resolution of RARalpha rearrangement in bone marrow recovery with a
      predominance of CD117- and CD11B-negative promyelocytes.

PMID- 12472289
TI  - Uterine granulomas: tuberculosis, an important cause.

PMID- 12472290
TI  - Exponential growth in the number of clinical trials and research in general
      involving humans.

PMID- 12472291
TI  - Using nursing science does not guarantee nursing excellence.
AB  - Nursing excellence is usually defined in terms of having and applying more and
      more knowledge, especially from nursing science--the more nurses know, the better
      their practice. This conceptualization of nursing practice has similarities with
      the ancient Greek mode of reasoning called techne but cannot adequately deal with
      the ambiguities of everyday nursing. Nursing excellence does occur, however, with
      phronetic, ontological practice in which a nurse's morals, habits, and
      dispositions guide practice. Of course, nurses need a comprehensive knowledge and
      skill base, but phronetic nurses negotiate the "rough ground" of nursing practice
      because ontological dispositions are guiding practice rather than simply applying
      generalizable and communal knowledge from nursing science. Techne-ical practice
      leads to competent nursing, but only phronetic practice results in nursing
      excellence. Included in this article is a description of techne-ical practice,
      its limitations for nursing excellence, and rationale for adopting a phronetic
      conceptualization of nursing practice.

PMID- 12472292
TI  - Caring for medically fragile children in the home: an alternative theoretical
      approach.
AB  - Medically fragile children require extensive, ongoing care that is typically
      provided in the home environment. The phenomenon of "caregiver burden" has been
      the topic of many studies in which the hardships and everyday life stressors of
      families with medically fragile children are examined. These studies are limited
      in that they focus merely on the difficulties of care, which represent only one
      dimension of the larger phenomenon of caregiving. It is the purpose of this
      article to review the literature from an alternative perspective in an attempt to
      provide a more thorough understanding of the dynamic of caregiving for a
      medically fragile child.

PMID- 12472293
TI  - The Medication Adherence Model: a guide for assessing medication taking.
AB  - The Medication Adherence Model (MAM) was developed to describe the process of
      medication adherence and guide health care providers in assessing medication
      taking in individuals with hypertension. The MAM was structured with the idea
      that two types of nonadherence contribute to inconsistent medication taking, the
      intentional decision to miss medications, and the unintentional interruptions
      that cause medications not to be taken. The three core concepts identified in the
      model are: (a) Purposeful Action, (b) Patterned Behavior, and (c) Feedback.
      Patients' initiating and sustaining medication adherence are dependent on the
      deliberate decision to take medications based on perceived need, effectiveness,
      and safety (Purposeful Action). Then they establish medication-taking patterns
      through access, routines, and remembering (Patterned Behavior). Individuals use
      information, prompts, or events (Feedback) during the appraisal process to
      evaluate health treatment that, in return, influences individuals' levels of
      Purposeful Action and Patterned Behavior (Johnson, 2002; Johnson, Williams, &
      Marshall, 1999). The MAM depicts the dynamic process of initiating and
      maintaining medication adherence from the hypertensive patient's perspective. The
      model describes the key components of existing cognitive and self-regulatory
      models, and identifies an additional behavioral component. The succinct
      organization of the MAM may facilitate health care providers' ability to evaluate
      and individualize interventions for promoting medication taking.

PMID- 12472294
TI  - The relationships among racial identity, self-esteem, sociodemographics, and
      health-promoting lifestyles.
AB  - The purpose of this study was to explore the relationships between racial
      identity, self-esteem, sociodemographic factors, and health-promoting lifestyles
      in a sample of African Americans. African American mortality rates are
      disproportionately high. These rates are associated with health behaviors that
      are driven by many factors including lifestyle practices. Other factors may be
      self-esteem and racial identity. Research shows gender differences in health
      behaviors, but no studies have explored a racial identity and gender interaction.
      Exploring these relationships may lead to the improved health status of African
      Americans. A convenience sample of 224 was recruited consisting of 48% males (n =
      108). The mean age was 37.2 years (SD = 12.6). Regression analyses demonstrated
      that the internalization racial identity stage (beta = .12; p < .001) and self
      esteem (beta = .50; p < .001) contributed to the variance in health-promoting
      lifestyles. Self-esteem did not mediate the relationship between immersion and
      health-promoting lifestyle scores (beta = -.16; p = .03). The full model Beta
      values show that racial identity remains significant with sociodemographics and
      interactions controlled, but moderators do not. Racial identity, while not a
      strong predictor, has some impact on health-promoting lifestyles regardless of
      sociodemographics.

PMID- 12472295
TI  - Nursing information.

PMID- 12472296
TI  - A glimpse over the horizon.

PMID- 12472297
TI  - Introduction to the special issue on the impact of childhood psychopathology
      interventions on subsequent substance abuse: pieces of the puzzle.
AB  - Studies of adolescents and adults have reported high levels of co-occurrence of
      substance abuse with other psychiatric disorders, suggesting influence between
      the conditions. The comorbidity seems complex and variable, indicating that there
      may be more than I type of association between the comorbid disorders. When
      occurring in childhood. some of the frequently comorbid psychopathologies
      typically precede later drug and alcohol abuse and may have implications for
      substance abuse prevention as early risk indicators and as targets for
      intervention. Research discussed in this article and in this special issue
      provides a foundation for investigating the question of whether effective
      treatment of childhood psychopathologies can prevent or at least mitigate
      substance abuse for some adolescents. Clinical, research, and policy implications
      are discussed.

PMID- 12472298
TI  - Measuring risks and outcomes in substance use disorders prevention research.
AB  - Assessment planning in substance use disorder prevention research entails the
      identification of measurement domains and the selection of corresponding
      instruments needed to fulfill specific project goals. The study design,
      developmental periods examined, feasibility constraints, and anticipated
      statistical analyses are important considerations in optimally designing the
      assessment protocol. As a conceptual framework to organize the domains considered
      here as examples, the multifactorial model of complex disorders with elaborations
      emphasized by the discipline of developmental psychopathology is applied. Risks
      reviewed include family history, childhood maltreatment, peer relationships, and
      psychopathology. The substance involvement dimensions germane as outcomes include
      substance type, consumption quantity and frequency, and substance-related
      problems. Comprehensive diachronic evaluation over critical developmental periods
      provides the technical foundation for etiology and intervention research.

PMID- 12472299
TI  - Community studies on adolescent substance use, abuse, or dependence and
      psychiatric comorbidity.
AB  - A literature review on community studies of adolescent substance use, abuse, or
      dependence (SU/AID) and psychiatric comorbidity yielded 22 articles from 15
      studies with information on rates, specificity, timing, and differential patterns
      of comorbidity by gender, race/ethnicity, and other factors. Results revealed
      that 60% of youths with SU/A/D had a comorbid diagnosis, and conduct disorder
      (CD) and oppositional defiant disorder (not attention-deficit/hyperactivity
      disorder) were most commonly associated with SU/A/D, followed by depression.
      Child psychopathology (particularly CD) was associated with early onset of
      substance use and abuse in later adolescence. The authors suggest that available
      data relevant to SU/A/D and psychiatric comorbidity can be used to better address
      such questions.

PMID- 12472300
TI  - Review of the evidence base for treatment of childhood psychopathology:
      internalizing disorders.
AB  - This article reviews the empirical literature on psychosocial,
      psychopharmacological, and adjunctive treatments for children between the ages of
      6 and 12 with internalizing disorders. The aim of this review was to identify
      interventions that have potential to prevent substance use disorders in
      adolescence by treating internalizing disorders in childhood. Results suggest
      that a variety of behavioral, cognitive-behavioral, and pharmacological
      interventions are effective in reducing symptoms of childhood depression,
      phobias, and anxiety disorders. None of the studies reviewed included substance
      abuse outcomes. Thus, little can be said about the relationship between early
      treatment and the prevention of later substance use. The importance of evaluating
      the generalizability of research-supported interventions to community settings is
      highlighted and recommendations for future research are offered.

PMID- 12472301
TI  - Review of the evidence base for treatment of childhood psychopathology:
      externalizing disorders.
AB  - This article reviews controlled research on treatments for childhood
      externalizing behavior disorders. The review is organized around 2 subsets of
      such disorders: disruptive behavior disorders (i.e., conduct disorder,
      oppositional defiant disorder) and attention-deficit/hyperactivity disorder
      (ADHD). The review was based on a literature review of nonresidential treatments
      for youths ages 6-12. The pool of studies for this age group was limited, but
      results suggest positive outcomes for a variety of interventions (particularly
      parent training and community-based interventions for disruptive behavior
      disorders and medication for ADHD). The review also highlights the need for
      additional research examining effectiveness of treatments for this age range and
      strategies to enhance the implementation of effective practices.

PMID- 12472302
TI  - The impact of childhood psychopathology interventions on subsequent substance
      abuse: policy implications, comments, and recommendations.
AB  - This article makes observations about policy implications and offers a
      combination of commentary and recommendation regarding the special issue on the
      impact of childhood psychopathology interventions on subsequent substance abuse.
      The authors mention forward-looking directives to expand the mandate for early
      intervention, to expand the research agenda for randomized clinical trials, and
      to develop a policy-oriented evidence base. They also note topics that require
      consideration and offer recommendations with regard to how to proceed. The
      special issue, as well as this discussion, will spark thought and action directed
      toward the evaluation of interventions for youths to assess the degree to which
      treating mental disorders has beneficial effects on the sequelae of the initial
      intervention target.

PMID- 12472303
TI  - A piece of my mind. Beyond folklore.

PMID- 12472304
TI  - Bariatric surgery and long-term control of morbid obesity.

PMID- 12472305
TI  - IOM public health report urges massive change.

PMID- 12472306
TI  - Practice makes perfect: risk-free medical training with patient simulators.

PMID- 12472311
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472312
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472313
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472314
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472315
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472316
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472317
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472318
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472319
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472320
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472321
TI  - Risks of postmenopausal hormone replacement.

PMID- 12472322
TI  - Hormone replacement following early menopause.

PMID- 12472324
TI  - Efficacy of recombinant human erythropoietin in critically ill patients: a
      randomized controlled trial.
AB  - CONTEXT: Anemia is common in critically ill patients and results in a large
      number of red blood cell (RBC) transfusions. Recent data have raised the concern
      that RBC transfusions may be associated with worse clinical outcomes in some
      patients. OBJECTIVE: To assess the efficacy in critically ill patients of a
      weekly dosing schedule of recombinant human erythropoietin (rHuEPO) to decrease
      the occurrence of RBC transfusion. DESIGN: A prospective, randomized, double
      blind, placebo-controlled, multicenter trial conducted between December 1998 and
      June 2001. SETTING: A medical, surgical, or a medical/surgical intensive care
      unit (ICU) in each of 65 participating institutions in the United States.
      PATIENTS: A total of 1302 patients who had been in the ICU for 2 days and were
      expected to be in the ICU at least 2 more days and who met eligibility criteria
      were enrolled in the study; 650 patients were randomized to rHuEPO and 652 to
      placebo. INTERVENTION: Study drug (40 000 units of rHuEPO) or placebo was
      administered by subcutaneous injection on ICU day 3 and continued weekly for
      patients who remained in the hospital, for a total of 3 doses. Patients in the
      ICU on study day 21 received a fourth dose. MAIN OUTCOME MEASURES: The primary
      efficacy end point was transfusion independence, assessed by comparing the
      percentage of patients in each treatment group who received any RBC transfusion
      between study days 1 and 28. Secondary efficacy end points identified
      prospectively included cumulative RBC units transfused per patient through study
      day 28; cumulative mortality through study day 28; change in hemoglobin from
      baseline; and time to first transfusion or death. RESULTS: Patients receiving
      rHuEPO were less likely to undergo transfusion (60.4% placebo vs 50.5% rHuEPO;
      P<.001; odds ratio, 0.67; 95% confidence interval [CI], 0.54-0.83). There was a
      19% reduction in the total units of RBCs transfused in the rHuEPO group (1963
      units for placebo vs 1590 units for rHuEPO) and reduction in RBC units transfused
      per day alive (ratio of transfusion rates, 0.81; 95% CI, 0.79-0.83; P =.04).
      Increase in hemoglobin from baseline to study end was greater in the rHuEPO group
      (mean [SD], 1.32 [2] g/dL vs 0.94 [1.9] g/dL; P<.001). Mortality (14% for rHuEPO
      and 15% for placebo) and adverse clinical events were not significantly
      different. CONCLUSIONS: In critically ill patients, weekly administration of 40
      000 units of rHuEPO reduces allogeneic RBC transfusion and increases hemoglobin.
      Further study is needed to determine whether this reduction in RBC transfusion
      results in improved clinical outcomes.

PMID- 12472325
TI  - Collaborative care management of late-life depression in the primary care
      setting: a randomized controlled trial.
AB  - CONTEXT: Few depressed older adults receive effective treatment in primary care
      settings. OBJECTIVE: To determine the effectiveness of the Improving Mood
      Promoting Access to Collaborative Treatment (IMPACT) collaborative care
      management program for late-life depression. DESIGN: Randomized controlled trial
      with recruitment from July 1999 to August 2001. SETTING: Eighteen primary care
      clinics from 8 health care organizations in 5 states. PARTICIPANTS: A total of
      1801 patients aged 60 years or older with major depression (17%), dysthymic
      disorder (30%), or both (53%). INTERVENTION: Patients were randomly assigned to
      the IMPACT intervention (n = 906) or to usual care (n = 895). Intervention
      patients had access for up to 12 months to a depression care manager who was
      supervised by a psychiatrist and a primary care expert and who offered education,
      care management, and support of antidepressant management by the patient's
      primary care physician or a brief psychotherapy for depression, Problem Solving
      Treatment in Primary Care. MAIN OUTCOME MEASURES: Assessments at baseline and at
      3, 6, and 12 months for depression, depression treatments, satisfaction with
      care, functional impairment, and quality of life. RESULTS: At 12 months, 45% of
      intervention patients had a 50% or greater reduction in depressive symptoms from
      baseline compared with 19% of usual care participants (odds ratio [OR], 3.45; 95%
      confidence interval [CI], 2.71-4.38; P<.001). Intervention patients also
      experienced greater rates of depression treatment (OR, 2.98; 95% CI, 2.34-3.79;
      P<.001), more satisfaction with depression care (OR, 3.38; 95% CI, 2.66-4.30;
      P<.001), lower depression severity (range, 0-4; between-group difference, -0.4;
      95% CI, -0.46 to -0.33; P<.001), less functional impairment (range, 0-10; between
      group difference, -0.91; 95% CI, -1.19 to -0.64; P<.001), and greater quality of
      life (range, 0-10; between-group difference, 0.56; 95% CI, 0.32-0.79; P<.001)
      than participants assigned to the usual care group. CONCLUSION: The IMPACT
      collaborative care model appears to be feasible and significantly more effective
      than usual care for depression in a wide range of primary care practices.

PMID- 12472326
TI  - Effect of a clinical practice improvement intervention on Chlamydial screening
      among adolescent girls.
AB  - CONTEXT: Chlamydia trachomatis infection is a serious public health concern that
      disproportionately affects adolescent girls. Although annual C trachomatis
      screening of sexually active adolescent girls is recommended by health
      professional organizations and is a Health Employer Data and Information Set
      (HEDIS) performance measure, this goal is not being met. OBJECTIVE: To test the
      effectiveness of a system-level, clinical practice improvement intervention
      designed to increase C trachomatis screening by using urine-based tests for
      sexually active adolescent girls identified during their routine checkups at a
      pediatric clinic. DESIGN, SETTING, AND PARTICIPANTS: A randomized cluster of 10
      pediatric clinics in the Kaiser Permanente of Northern California health
      maintenance organization, where adolescent girls aged 14 to 18 years had a total
      of 7920 routine checkup visits from April 2000 through March 2002. INTERVENTION:
      Five clinics were randomly assigned to provide usual care and 5 to provide the
      intervention, which required that leadership be engaged by showing the gap
      between best practice and current practice; a team be assembled to champion the
      project; barriers be identified and solutions developed through monthly meetings;
      and progress be monitored with site-specific screening proportions. MAIN OUTCOME
      MEASURE: Chlamydia trachomatis screening rate for sexually active 14- to 18-year
      old girls during routine checkups at each participating clinic. RESULTS: The
      population of adolescents was ethnically diverse with an average age of 15.4
      years. Twenty-four percent of girls in the experimental clinics and 23% in the
      control clinics were sexually active. Of the 1017 patients eligible for screening
      in the intervention clinic, 478 (47%) were screened; of 1194 eligible for
      screening in the control clinic, 203 (17%) were screened. At baseline, the
      proportion screened was 0.05 (95% confidence interval [CI], 0.00-0.17) in the
      intervention and 0.14 (95% CI, 0.01-0.26) in the control clinics. By months 16 to
      18, screening rates were 0.65 (95% CI, 0.53-0.77) in the intervention and 0.21
      (95% CI, 0.09-0.33) in the control clinics (time period by study group
      interaction, F(6,60) = 5.33; P<.001). The average infection rate for the
      experimental clinics was 5.8% (23 positive test results out of 393 total urine
      tests and a total of 3986 clinic visits) vs 7.6% in controls (12 positive test
      results out of 157 tests and 3934 clinic visits). CONCLUSIONS: Implementation of
      this clinical practice intervention in a large health maintenance organization
      system is feasible, and it significantly increased the C trachomatis screening
      rates for sexually active adolescent girls during routine checkups.

PMID- 12472327
TI  - Secondary aerosolization of viable Bacillus anthracis spores in a contaminated US
      Senate Office.
AB  - CONTEXT: Bioterrorist attacks involving letters and mail-handling systems in
      Washington, DC, resulted in Bacillus anthracis (anthrax) spore contamination in
      the Hart Senate Office Building and other facilities in the US Capitol's
      vicinity. OBJECTIVE: To provide information about the nature and extent of indoor
      secondary aerosolization of B anthracis spores. DESIGN: Stationary and personal
      air samples, surface dust, and swab samples were collected under semiquiescent
      (minimal activities) and then simulated active office conditions to estimate
      secondary aerosolization of B anthracis spores. Nominal size characteristics,
      airborne concentrations, and surface contamination of B anthracis particles
      (colony-forming units) were evaluated. RESULTS: Viable B anthracis spores
      reaerosolized under semiquiescent conditions, with a marked increase in
      reaerosolization during simulated active office conditions. Increases were
      observed for B anthracis collected on open sheep blood agar plates (P<.001) and
      personal air monitors (P =.01) during active office conditions. More than 80% of
      the B anthracis particles collected on stationary monitors were within an
      alveolar respirable size range of 0.95 to 3.5 micro m. CONCLUSIONS: Bacillus
      anthracis spores used in a recent terrorist incident reaerosolized under common
      office activities. These findings have important implications for appropriate
      respiratory protection, remediation, and reoccupancy of contaminated office
      environments.

PMID- 12472328
TI  - Paresis acquired in the intensive care unit: a prospective multicenter study.
AB  - CONTEXT: Although electrophysiologic and histologic neuromuscular abnormalities
      are common in intensive care unit (ICU) patients, the clinical incidence of ICU
      acquired neuromuscular disorders in patients recovering from severe illness
      remains unknown. OBJECTIVES: To assess the clinical incidence, risk factors, and
      outcomes of ICU-acquired paresis (ICUAP) during recovery from critical illness in
      the ICU and to determine the electrophysiologic and histologic patterns in
      patients with ICUAP. DESIGN: Prospective cohort study conducted from March 1999
      to June 2000. SETTING: Three medical and 2 surgical ICUs in 4 hospitals in
      France. PARTICIPANTS: All consecutive ICU patients without preexisting
      neuromuscular disease who underwent mechanical ventilation for 7 or more days
      were screened daily for awakening. The first day a patient was considered awake
      was day 1. Patients with severe muscle weakness on day 7 were considered to have
      ICUAP. MAIN OUTCOME MEASURES: Incidence and duration of ICUAP, risk factors for
      ICUAP, and comparative duration of mechanical ventilation between ICUAP and
      control patients. RESULTS: Among the 95 patients who achieved satisfactory
      awakening, the incidence of ICUAP was 25.3% (95% confidence interval [CI], 16.9%
      35.2%). All ICUAP patients had a sensorimotor axonopathy, and all patients who
      underwent a muscle biopsy had specific muscle involvement not related to nerve
      involvement. The median duration of ICUAP after day 1 was 21 days. Mean (SD)
      duration of mechanical ventilation after day 1 was significantly longer in
      patients with ICUAP compared with those without (18.2 [36.3] vs 7.6 [19.2] days;
      P =.03). Independent predictors of ICUAP were female sex (odds ratio [OR], 4.66;
      95% CI, 1.19-18.30), the number of days with dysfunction of 2 or more organs (OR,
      1.28; 95% CI, 1.11-1.49), duration of mechanical ventilation (OR, 1.10; 95% CI,
      1.00-1.22), and administration of corticosteroids (OR, 14.90; 95% CI, 3.20-69.80)
      before day 1. CONCLUSIONS: Identified using simple bedside clinical criteria,
      ICUAP was frequent during recovery from critical illness and was associated with
      a prolonged duration of mechanical ventilation. Our findings suggest an important
      role of corticosteroids in the development of ICUAP.

PMID- 12472329
TI  - Interventions to enhance patient adherence to medication prescriptions:
      scientific review.
AB  - CONTEXT: Low adherence with prescribed treatments is ubiquitous and undermines
      treatment benefits. OBJECTIVE: To systematically review published randomized
      controlled trials (RCTs) of interventions to assist patients' adherence to
      prescribed medications. DATA SOURCES: A search of MEDLINE, CINAHL, PSYCHLIT,
      SOCIOFILE, IPA, EMBASE, The Cochrane Library databases, and bibliographies was
      performed for records from 1967 through August 2001 to identify relevant articles
      of all RCTs of interventions intended to improve adherence to self-administered
      medications. STUDY SELECTION AND DATA EXTRACTION: Studies were included if they
      reported an unconfounded RCT of an intervention to improve adherence with
      prescribed medications for a medical or psychiatric disorder; both adherence and
      treatment outcome were measured; follow-up of at least 80% of each study group
      was reported; and the duration of follow-up for studies with positive initial
      findings was at least 6 months. Information on study design features,
      interventions, controls, and findings (adherence rates and patient outcomes) were
      extracted for each article. DATA SYNTHESIS: Studies were too disparate to warrant
      meta-analysis. Forty-nine percent of the interventions tested (19 of 39 in 33
      studies) were associated with statistically significant increases in medication
      adherence and only 17 reported statistically significant improvements in
      treatment outcomes. Almost all the interventions that were effective for long
      term care were complex, including combinations of more convenient care,
      information, counseling, reminders, self-monitoring, reinforcement, family
      therapy, and other forms of additional supervision or attention. Even the most
      effective interventions had modest effects. CONCLUSIONS: Current methods of
      improving medication adherence for chronic health problems are mostly complex,
      labor-intensive, and not predictably effective. The full benefits of medications
      cannot be realized at currently achievable levels of adherence; therefore, more
      studies of innovative approaches to assist patients to follow prescriptions for
      medications are needed.

PMID- 12472330
TI  - Helping patients follow prescribed treatment: clinical applications.
AB  - Low adherence to prescribed medical regimens is a ubiquitous problem. Typical
      adherence rates are about 50% for medications and are much lower for lifestyle
      prescriptions and other more behaviorally demanding regimens. In addition, many
      patients with medical problems do not seek care or drop out of care prematurely.
      Although accurate measures of low adherence are lacking for many regimens, simple
      measures, such as directly asking patients and watching for appointment
      nonattendance and treatment nonresponse, will detect most problems. For short
      term regimens (< or =2 weeks), adherence to medications is readily achieved by
      giving clear instructions. On the other hand, improving adherence to long-term
      regimens requires combinations of information about the regimen, counseling about
      the importance of adherence and how to organize medication taking, reminders
      about appointments and adherence, rewards and recognition for the patient's
      efforts to follow the regimen, and enlisting social support from family and
      friends. Successful interventions for long-term regimens are all labor-intensive
      but ultimately can be cost-effective.

PMID- 12472331
TI  - Should patients in intensive care units receive erythropoietin?

PMID- 12472332
TI  - Does pornography-blocking software block access to health information on the
      Internet?
AB  - CONTEXT: The Internet has become an important tool for finding health
      information, especially among adolescents. Many computers have software designed
      to block access to Internet pornography. Because pornography-blocking software
      cannot perfectly discriminate between pornographic and nonpornographic Web sites,
      such products may block access to health information sites, particularly those
      related to sexuality. OBJECTIVE: To quantify the extent to which pornography
      blocking software used in schools and libraries limits access to health
      information Web sites. DESIGN AND SETTING: In a simulation of adolescent Internet
      searching, we compiled search results from 24 health information searches (n =
      3206) and 6 pornography searches (n = 781). We then classified the content of
      each site as either health information (n = 2467), pornography (n = 516), or
      other (n = 1004). We also compiled a list of top teen health information sites (n
      = 586). We then tested 6 blocking products commonly used in schools and libraries
      and 1 blocking product used on home computers, each at 2 or 3 levels of blocking
      restrictiveness. MAIN OUTCOME MEASURE: Rates of health information and
      pornography blocking. RESULTS: At the least restrictive blocking setting,
      configured to block only pornography, the products blocked a mean of only 1.4% of
      health information sites. The differences between blocking products was small
      (range, 0.6%-2.3%). However, about 10% of health sites found using some search
      terms related to sexuality (eg, safe sex, condoms) and homosexuality (eg, gay)
      were blocked. The mean pornography blocking rate was 87% (range, 84%-90%). At
      moderate settings, the mean blocking rate was 5% for health information and 90%
      for pornography. At the most restrictive settings, health information blocking
      increased substantially (24%), but pornography blocking was only slightly higher
      (91%). CONCLUSIONS: Blocking settings have a greater impact than choice of
      blocking product on frequency of health information blocking. At their least
      restrictive settings, overblocking of general health information poses a
      relatively minor impediment. However, searches on some terms related to sexuality
      led to substantially more health information blocking. More restrictive blocking
      configurations blocked pornography only slightly more, but substantially
      increased blocking of health information sites.

PMID- 12472338
TI  - JAMA patient page. Bariatric surgery.

PMID- 12472339
TI  - Recurrent erythema multiforme/Stevens-Johnson syndrome: response to mycophenolate
      mofetil.

PMID- 12472340
TI  - Sweet syndrome as the presenting symptom of relapsed hairy cell leukemia.

PMID- 12472342
TI  - Dermoscopy of pigmented seborrheic keratosis: a morphological study.
AB  - OBJECTIVES: To describe morphological features of seborrheic keratosis as seen by
      dermoscopy and to investigate their prevalence. DESIGN: Prospective cohort study
      using macrophotography and dermoscopy for the documentation of seborrheic
      keratosis. SETTINGS: Seborrheic keratoses were prospectively collected in 2
      sites: a private practice in Plantation, Fla (site 1), and the Department of
      Dermatology at the University Hospital Geneva in Switzerland (site 2). PATIENTS:
      A total of 203 pigmented seborrheic keratoses (from 192 patients) with complete
      documentation were collected (111 from site 1 and 93 from site 2). INTERVENTIONS:
      Screening for new morphological features of seborrheic keratosis and evaluation
      of all lesions for the prevalence of these criteria. MAIN OUTCOME MEASURES:
      Identification of new morphological criteria and evaluation of frequency.
      RESULTS: A total of 15 morphological dermoscopic criteria were identified.
      Standard criteria such as milialike cysts and comedolike openings were found in a
      high number of cases (135 and 144, respectively). We found network and
      networklike structures to be present in 94 lesions (46%). Using standard
      diagnostic criteria for seborrheic keratosis, 30 lesions would not have been
      diagnosed as such. CONCLUSIONS: The classic dermoscopic criteria for seborrheic
      keratosis (milialike cysts and comedolike openings) have a high prevalence but
      the use of additional dermoscopic criteria such as fissures, hairpin blood
      vessels, sharp demarcation, and moth-eaten borders improves the diagnostic
      accuracy. The proper identification of pigment network and networklike structures
      is important for the correct diagnosis.

PMID- 12472343
TI  - Prevalence of melanoma clinically resembling seborrheic keratosis: analysis of
      9204 cases.
AB  - OBJECTIVE: To estimate the prevalence of melanoma clinically mimicking seborrheic
      keratosis. DESIGN: Retrospective review of cases submitted for histological
      examination with a clinical diagnosis of seborrheic keratosis or with a
      differential diagnosis that included seborrheic keratosis. SETTING: A tertiary
      medical care center-based dermatopathology laboratory serving academic
      dermatology clinics that have a busy pigmented lesion clinic. MATERIALS AND
      METHODS: A total of 9204 consecutive pathology reports containing a diagnosis of
      seborrheic keratosis in the clinical information field were identified between
      the years 1992 and 2001 through a computer database search. Reports with a final
      histological diagnosis of melanoma were selected for further review and
      clinicopathological analysis. MAIN OUTCOME MEASURE: Histological diagnosis, which
      was correlated with the preoperative clinical diagnosis. RESULTS: Melanoma was
      identified in 61 cases (0.66%) submitted for histological examination with a
      clinical diagnosis that included seborrheic keratosis. Melanoma was in the
      clinical differential diagnosis of 31 cases (51%). The remaining lesions had a
      differential diagnosis of seborrheic keratosis vs melanocytic nevus (17 cases,
      28%), basal cell carcinoma (7 cases, 12%), or a squamous proliferation (3 cases,
      5%). In 3 cases (5%), seborrheic keratosis was the only clinical diagnosis. All
      histological types of melanoma were represented. CONCLUSIONS: Our results confirm
      that melanoma can mimic seborrheic keratosis. These data strongly support the
      current policy of submitting for histological examination all specimens that have
      been removed from patients.

PMID- 12472344
TI  - Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their
      relationship to race, ethnicity, and sex.
AB  - BACKGROUND: Hemangiomas of infancy vary widely in appearance, size, and depth of
      cutaneous involvement. There is currently no standard classification system for
      these lesions. While they occur in any race, an increased incidence occurs in
      girls, light-skinned whites, and premature infants, especially those weighing
      less than 1500 g. Other epidemiologic and demographic factors have not been well
      characterized. OBJECTIVE: To determine any correlations between hemangioma
      subtype and anatomic location with demographic factors, complications, and other
      associated anomalies. DESIGN: Retrospective chart review of 327 patients with
      hemangioma of infancy seen between 1997 and 2000 in an ambulatory referral
      center. MAIN OUTCOMES MEASURES: Demographic and gestational information, lesion
      size, associated anomalies, complications, treatments, and outcomes were analyzed
      together with classification of hemangiomas into 4 groups: localized, segmental,
      indeterminate, and multifocal. Subtypes were correlated with race and ethnicity,
      the incidence of complications, and overall outcome. RESULTS: Of 472 hemangiomas
      (327 patients), 339 (72%) were localized, 84 (18%) were segmental, 37 (8%) were
      indeterminate, and 12 (3%) were multifocal (8 or more noncontiguous lesions).
      Segmental lesions were larger and were more frequently associated with
      developmental abnormalities. They also required more intensive and prolonged
      therapy and were associated with more complications and a poorer overall outcome
      (P<.001). Lesions on Hispanic patients were more likely to involve mucous
      membranes, to be segmental (P<.004), to be associated with abnormalities (P
      =.05), especially PHACE syndrome (P =.05), and to have more complications (P
      =.01). Increased incidence of segmental hemangiomas was the only factor in
      Hispanic infants associated with complications, more extensive treatment, or
      associated anomalies. CONCLUSIONS: Hemangiomas of infancy can usually be
      classified as localized, segmental, indeterminate, and multifocal, based on
      clinical features. Segmental lesions have a higher frequency of complications and
      associated abnormalities, and this type of hemangioma seems to present with
      increased frequency in Hispanic infants.

PMID- 12472345
TI  - Efficacy of glycolic acid peels in the treatment of melasma.
AB  - BACKGROUND: Melasma is an acquired hypermelanosis that is often recalcitrant to
      treatment with hypopigmenting agents. OBJECTIVE: To assess the efficacy of 4%
      hydroquinone cream vs 4% hydroquinone cream combined with glycolic acid peels as
      treatment for melasma. METHODS: Twenty-one Hispanic women with bilateral
      epidermal and mixed melasma were enrolled in a split-faced prospective trial
      lasting 8 weeks. Patients underwent 20% to 30% glycolic acid peels every 2 weeks
      to one side of the face only in addition to twice-daily full-face application of
      4% hydroquinone cream and sun protective factor 25 UV-B sunscreen each morning.
      Pigmentation was measured objectively using a mexameter and the Melasma Area and
      Severity Index and subjectively using a linear analog scale and physician and
      patient global evaluation. RESULTS: Hydroquinone treatment alone and treatment
      with the combination of hydroquinone and glycolic acid had a significant effect
      in reducing skin pigmentation compared with baseline (P<.001). However, no
      significant difference was found using combination therapy compared with
      hydroquinone alone (P =.75). CONCLUSIONS: Use of 4% hydroquinone and a daily
      sunscreen is effective in the treatment of melasma; however, the addition of 4
      glycolic acid peels did not enhance the hypopigmenting effect of hydroquinone
      treatment alone.

PMID- 12472346
TI  - Acne vulgaris: a disease of Western civilization.
AB  - BACKGROUND: In westernized societies, acne vulgaris is a nearly universal skin
      disease afflicting 79% to 95% of the adolescent population. In men and women
      older than 25 years, 40% to 54% have some degree of facial acne, and clinical
      facial acne persists into middle age in 12% of women and 3% of men.
      Epidemiological evidence suggests that acne incidence rates are considerably
      lower in nonwesternized societies. Herein we report the prevalence of acne in 2
      nonwesternized populations: the Kitavan Islanders of Papua New Guinea and the
      Ache hunter-gatherers of Paraguay. Additionally, we analyze how elements in
      nonwesternized environments may influence the development of acne. OBSERVATIONS:
      Of 1200 Kitavan subjects examined (including 300 aged 15-25 years), no case of
      acne (grade 1 with multiple comedones or grades 2-4) was observed. Of 115 Ache
      subjects examined (including 15 aged 15-25 years) over 843 days, no case of
      active acne (grades 1-4) was observed. CONCLUSIONS: The astonishing difference in
      acne incidence rates between nonwesternized and fully modernized societies cannot
      be solely attributed to genetic differences among populations but likely results
      from differing environmental factors. Identification of these factors may be
      useful in the treatment of acne in Western populations.

PMID- 12472347
TI  - Diet and acne revisited.

PMID- 12472348
TI  - Consequences of using escharotic agents as primary treatment for nonmelanoma skin
      cancer.
AB  - BACKGROUND: The use of escharotic or caustic pastes to treat skin cancer is based
      on the centuries-old observation that selected minerals and plant extracts may be
      used to destroy certain skin lesions. Zinc chloride and Sanguinaria canadensis
      (bloodroot) are 2 agents that are used as part of the Mohs chemosurgery fixed
      tissue technique. The use of escharotics without surgery has been discredited by
      allopathic medicine but persists and is promoted among alternative practitioners.
      Patients may now purchase "herbal supplements" for the primary self-treatment of
      skin cancer, and physicians will see patients who elect this therapy for their
      skin cancers. OBSERVATIONS: We reviewed the history of escharotic use for skin
      disease and performed an Internet search for the availability and current use of
      escharotics. Our search located numerous agents for purchase via the Internet
      that are advertised as highly successful treatments for skin cancer. We report 4
      cases from our practice in which escharotic agents were used by patients to treat
      basal cell carcinomas in lieu of the recommended conventional treatment. One
      patient had a complete clinical response, but had a residual tumor on follow-up
      biopsy. A second patient successfully eradicated all tumors, but severe scarring
      ensued. A third patient disagreed with us regarding his care and was lost to
      follow-up. One patient presented with a nasal basal cell carcinoma that "healed"
      for several years following treatment elsewhere with an escharotic agent but
      recurred deeply and required an extensive resection. The lesion has since
      metastasized. CONCLUSIONS: Escharotic agents are available as herbal supplements
      and are being used by patients for the treatment of skin cancer. The efficacy of
      these agents is unproven and their content is unregulated. Serious consequences
      may result from their use. Conventional medicine has an excellent track record in
      treating skin cancer. Physicians should recommend against the use of escharotic
      agents for skin cancer, and the Food and Drug Administration should be given the
      authority to regulate their production and distribution.

PMID- 12472349
TI  - Should pentoxifylline be used as an adjuvant for the treatment of venous leg
      ulcer?

PMID- 12472350
TI  - Systematic review of imiquimod for the treatment of genital warts: all that
      glitters is not gold.

PMID- 12472351
TI  - Another vehicle-controlled study of 1% pimecrolimus in atopic dermatitis: how
      does it help clinicians and patients, and is it ethically sound?

PMID- 12472352
TI  - Fluconazole for cutaneous leishmaniasis: looking for a better treatment.

PMID- 12472353
TI  - Recurrent blisters on the hands and face.

PMID- 12472354
TI  - Erythematous nodulous lesion on the hard palate.

PMID- 12472355
TI  - Painful skin nodules and epididymo-orchitis.

PMID- 12472356
TI  - Earlobe dermatitis.

PMID- 12472357
TI  - Herbal is not synonymous with safe.

PMID- 12472358
TI  - Mycosis fungoides and follicular mucinosis.

PMID- 12472360
TI  - Follicular mucinosis.

PMID- 12472361
TI  - Scald or pseudoscald?

PMID- 12472362
TI  - Mycophenolate mofetil for the treatment of cutaneous lupus erythematosus with
      smoldering systemic involvement.

PMID- 12472363
TI  - Rapid and preferential sebum secretion of ivermectin: a new factor that may
      determine drug responsiveness in patients with scabies.

PMID- 12472364
TI  - Treatment of vitiligo with the 308-nm xenon chloride excimer laser.

PMID- 12472366
TI  - Luteinising hormone releasing hormone analogues in the treatment of prostate
      cancer.
AB  - The use of the luteinising hormone releasing hormone (LHRH) analogues--goserelin
      (Zoladex, AstraZeneca) and leuprorelin (Prostap, Wyeth)--is well established and
      forms the backbone of the treatment of locally advanced and metastatic prostate
      cancer. Comparable efficacy with orchidectomy and, historically,
      diethylstilbestrol (DES) is accepted, with the advantages of reversibility and
      limited thromboembolic and cardiovascular toxicity, respectively. Side effects
      such as hot flushes, loss of libido, lethargy and decreased bone mineral density
      have recently stimulated more interest in the use of non-steroidal anti-androgens
      such as bicalutamide (Casodex, AstraZeneca) in locally advanced disease. Although
      better tolerated, bicalutamide has significant problems with gynaecomastia and
      breast pain. Maximal androgen blockade using LHRH analogues and their adjuvant
      use with radiotherapy are discussed, as well as their experimental application in
      intermittent androgen suppression therapy. Similar side effect profiles are
      reported for the LHRH analogues but injection tolerability differs with the
      smaller 23G needle for Prostap 3 compared to the 16G needle for Zoladex LA. There
      is no evidence to suggest a difference in the efficacy between the LHRH analogues
      goserelin and leuprorelin, although no direct comparison has yet been undertaken.

PMID- 12472367
TI  - Taxanes for advanced non-small cell lung cancer.
AB  - The emergence of novel chemotherapeutic agents with promising anticancer activity
      in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded
      role for chemotherapy in the management of this disease. The taxanes (paclitaxel
      and docetaxel) are novel microtubule stabilising agents, and have become an
      integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes
      inhibit the growth of lung cancer cell lines, exhibit synergistic interaction
      with other chemotherapy agents and enhance the efficacy of radiation in vitro.
      When used in low doses (metronomic dosing), they have important antiangiogenic
      properties. Several Phase II and III clinical trials have established the
      efficacy of the taxanes, as single agents and when used in combination with a
      platinum compound, in the treatment of advanced NSCLC. The use of a taxane in
      combination with a platinum compound has become an acceptable standard for
      patients with advanced or metastatic NSCLC. In addition to its efficacy in the
      first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent
      for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing
      the efficacy of combining molecularly targeted agents with taxane-based regimens
      for the treatment of advanced NSCLC.

PMID- 12472368
TI  - Pharmacological management of obesity.
AB  - Obesity is a major chronic health problem in adults. It is a complex,
      multifactorial disorder characterised by excess accumulation of adipose tissue.
      It is associated with a number of complications including cardiovascular disease,
      hypertension, type 2 diabetes, dyslipidaemia and cancer. A weight loss in the
      order of 5-10% is associated with clinically meaningful reductions with respect
      to all comorbidities. Diet and exercise has been the cornerstone of weight
      management therapy, but this approach has limitations, especially for weight
      maintenance. Previous drugs used in obesity had serious side effects including
      valvular heart disease. However, recent drugs like orlistat and sibutramine have
      been rigorously tested and proven safe. Orlistat, a lipase inhibitor, inhibits
      absorption of dietary fat by approximately 30%. Taken with a hypocaloric diet, it
      produces and maintains clinically meaningful weight loss. Sibutramine is a
      centrally-acting agent which enhances satiety and thermogenesis by inhibiting
      serotonin and noradrenaline re-uptake. It is appropriate for patients who are
      unable to lose weight by lifestyle modification.

PMID- 12472369
TI  - Pharmacotherapy of pulmonary embolism.
AB  - Pulmonary embolism (PE) and deep vein thrombosis are common causes of illness and
      death. The pharmacological approach to pulmonary embolism includes the use of
      anticoagulants, unfractionated heparin for the acute phase, and oral
      anticoagulants for prophylaxis. In massive PE, the use of thrombolytic agents is
      suggested to reduce systemic hypotension and right ventricular failure and
      increase cardiac output. Thrombolytic agents act on pulmonary vascular
      obstruction. In clinical practice, thrombolytic therapy is recommended in case of
      massive embolism with haemodynamic failure. Recent studies suggest the use of
      thrombolytic drugs in patients with normal systemic blood pressure who show right
      ventricular dysfunction at echocardiographic examination. A large randomised
      trial on lytic agents in submassive PE is therefore needed. Anticoagulants were
      primarily indicated for prevention of recurrences. Due to the development of low
      molecular weight heparin, the role of anticoagulants needs to be re-evaluated.

PMID- 12472370
TI  - Current concepts in the pharmacotherapy of benign prostatic hyperplasia.
AB  - Benign prostatic hyperplasia is a major men's health issue, with approximately
      80% of all men developing this condition within their lifetime. A variety of oral
      treatments is available, including alpha-adrenoceptor antagonists (alpha
      blockers), 5alpha reductase inhibitors, aromatase inhibitors and phytotherapy. A
      large number of alpha-blockers can be administered, but no single agent has
      demonstrated a clear superiority over the other drugs. 5alpha Reductase
      inhibitors have demonstrated similar efficacy in larger volume prostates but most
      evidence suggests that there is no benefit in combining them with alpha-blockers.
      The use of phytotherapy is not entirely novel but requires further long-term
      evaluation before it can be endorsed for clinical use in benign prostatic
      hyperplasia.

PMID- 12472371
TI  - Myocet (liposome-encapsulated doxorubicin citrate): a new approach in breast
      cancer therapy.
AB  - Doxorubicin, either as a single agent or in combination regimens, is considered
      to be one of the most active chemotherapeutic agents in the treatment of
      metastatic breast cancer. However, its clinical utility is limited by a
      cumulative, dose-dependent cardiac myopathy that can lead to potentially fatal
      congestive heart failure. Considerable research has gone into improving the
      therapeutic index of doxorubicin-based regimens. A new liposomal formulation of
      doxorubicin (Myocet, Elan Pharmaceuticals) has a significantly improved
      therapeutic index compared with conventional doxorubicin. The development of
      Myocet, a less cardiotoxic, better tolerated and equally efficacious doxorubicin,
      extends the therapeutic options in the overall management of breast cancer.

PMID- 12472372
TI  - An update on bimatoprost in glaucoma therapy.
AB  - Bimatoprost, a prostamide, effectively lowers intraocular pressure (IOP) in
      patients with open-angle glaucoma and ocular hypertension. In clinical trials,
      bimatoprost has demonstrated superiority to the beta-adrenergic antagonist
      timolol and has consistently provided approximately 1-2 mmHg greater mean IOP
      lowering than the prostaglandin latanoprost. Bimatoprost is more effective than
      either timolol or latanoprost in allowing patients to reach the low target
      pressures that best protect the visual field. Patients on bimatoprost therapy
      achieve low pressures throughout the day and night. Moreover, 1-year trials have
      shown that the efficacy of bimatoprost is sustained with long-term use. The most
      common side effects have been conjunctival hyperaemia, graded as trace or mild,
      and eyelash growth. No safety concerns have arisen in postmarketing surveillance.
      Bimatoprost appears to be a valuable new agent for glaucoma therapy.

PMID- 12472373
TI  - Niacin extended-release/lovastatin: combination therapy for lipid disorders.
AB  - The new combination of niacin extended-release (ER) and lovastatin (Advicor, Kos
      pharmaceuticals), is a powerful lipid modifying agent and takes advantage of the
      different mechanisms of action of its two components. Niacin decreases hepatic
      atherogenic apolipoprotein (apo) B production whereas lovastatin increases apoB
      removal. Whereas niacin potently increases high density lipoprotein (HDL) levels
      by decreasing hepatic removal of antiatherogenic apoA-I particles, 3-hydroxy-3
      methylglutaryl coenzyme A (HMGCoA) reductase inhibitors ('statins') appear to
      increase production of apoA-I. Although there is no outcome data with this
      combination product, each component has been independently associated with a
      reduction of cardiovascular event risk by approximately 25 - 35%. The results of
      a long-term trial in 814 patients, where > 600 had been treated for 6 months and
      > 200 for 1 year, found reductions of 45 and 42% in low density lipoprotein
      cholesterol and triglycerides, respectively, at the maximum dose (niacin ER 2000
      mg/ lovastatin 40 mg). HDL cholesterol increased by 41%. In addition, the
      combination decreased lipoprotein (a) by 25% and C-reactive protein by 24%. The
      niacin ER/lovastatin combination was generally well-tolerated. Flushing was the
      most common side effect, with approximately 10% of patients intolerant to niacin
      ER/lovastatin. Hepatotoxicity in this study was 0.5% and myopathy did not occur.
      Recent studies indicate that niacin can be used safely in diabetic patients who
      have good glucose control (HbA(1c) < 9%). Once-daily niacin ER/lovastatin
      exhibits potent synergistic actions on multiple lipid risk factors and represents
      an effective new agent in the clinical management of dyslipidaemia. Outcome
      studies are needed to evaluate if combination therapy would result in additive
      effects on morbidity and mortality.

PMID- 12472374
TI  - Aripiprazole: profile on efficacy and safety.
AB  - Aripiprazole (Abilitat, Bristol-Myers Squibb) is the most recent addition to the
      new class of atypical antipsychotic medications, following the release of
      clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Aripiprazole
      exhibits typical antagonism at dopamine (D2) receptors in the mesolimbic pathway,
      as well as having unique partial agonist activity at D2 receptors in the
      mesocortical pathway. As exemplified by other atypical antipsychotics, it
      displays strong 5-HT(2a) receptor antagonism and is similar to ziprasidone in
      also having agonistic activity at the 5-HT(1a) receptor. Among the atypical
      antipsychotics, aripiprazole displays the lowest affinity for alpha(1)adrenergic
      (alpha(1)), histamine (H1) and muscarinic (M1) receptors. This combination of
      effects may be responsible for its efficacy in positive and negative symptoms of
      schizophrenia and in bipolar disorder. Similarly, this profile may be the reason
      for the low rates of reported side effects observed. This includes general
      adverse events, a low incidence of reported weight gain and a low liability for
      inducing movement disorders. Other early data suggest that aripiprazole may
      induce reductions in plasma prolactin, as well as in plasma glucose and lipid
      profiles. Finally, results also support the proposition that aripiprazole may
      lead to reductions in corrected QT interval and have minimal drug interactions.

PMID- 12472375
TI  - T-bet as a possible therapeutic target in autoimmune disease.
AB  - The prominent role of pro-inflammatory cytokines produced by T helper-1 (T(H1))
      cells in regulating autoimmune responses in vitro and in vivo has been
      demonstrated. Recent observations of T cell polarisation by regulatory
      transcription factors--especially T-bet (T-box expressed in T cells)--raise the
      question of their influence in controlling autoimmune diseases. Here, the authors
      summarise recent observations of the role of T-bet in controlling chronic
      inflammatory and autoimmune diseases and discuss the implications of these
      findings for future therapeutic approaches.

PMID- 12472376
TI  - The Ca2+-activated K+ channel of intermediate conductance:a possible target for
      immune suppression.
AB  - The intermediate conductance Ca2+-activated K+ (IK) channel is distinguished from
      the functionally related Ca2+-activated K+ channels of smaller and larger unitary
      conductance by its molecular structure, pharmacology, tissue distribution and
      physiology. Like many K+ channels, IK is an assembly of four identical subunits
      each spanning the membrane six times and each contributing equally to the K+
      selectivity pore positioned centrally in the complex. The IK channel gains its
      high sensitivity to intracellular Ca2+ from tightly bound calmodulin, and its
      activity is independent of the membrane potential. Several toxins including
      charybdotoxin and the more selective mutant, Glu32-charybdotoxin, maurotoxin and
      stichodactyla toxin potently block IK channels. Among blockers of the IK channel
      are also several small organic molecules including the antimycotic clotrimazole
      and the close analogues TRAM-34 and ICA-17043, as well as the antihypertensive,
      nitrendipine. The IK channel is distributed in peripheral tissues, including
      secretory epithelia and blood cells, but it appears absent from neuronal and
      muscle tissue. An important physiological role of the IK channel is to help
      maintain large electrical gradients for the sustained transport of ions such as
      Ca2+ influx that controls T lymphocyte (T cell) proliferation. In this review,
      special attention is given to an analysis of the use of IK blockers as potential
      immunosuppressants for the treatment of autoimmune disorders such as rheumatoid
      arthritis, inflammatory bowel disease and multiple sclerosis.

PMID- 12472377
TI  - Protein tyrosine phosphatases as drug targets: PTP1B and beyond.
AB  - Protein tyrosine phosphatases (PTPs) control signal transduction pathways and
      have recently emerged as potential drug targets. Inhibition of individual PTPs
      can result in the activation of therapeutically relevant kinase cascades. This is
      particularly useful in cases where disease is associated with hormonal
      resistance, such as insensitivity to insulin or leptin. Currently, PTP1B is being
      investigated by a number of companies as a promising target for leptin/insulin
      mimetics and in the treatment of diabetes and obesity. Since all 90-100 PTPs have
      been identified in the human genome, the challenge now is to identify the
      function of these enzymes and the therapeutic indications that may exist for
      specific PTP inhibitors.

PMID- 12472378
TI  - Emerging therapeutic targets in chronic heart failure: part I.
AB  - Chronic heart failure (CHF) is a life threatening disease with an enormous
      medical requirement. Approximately 15 million people worldwide suffer from CHF.
      The prevalence will inevitably increase due to the ageing population.
      Nevertheless, current treatment options based on angiotensin-converting enzyme
      inhibitors and beta-adrenergic receptor antagonists merely slow progression of
      the disease. Novel treatment concepts based on new therapeutic targets must have
      the capability to reverse the severity of this disease. This review, focusing on
      the emerging targets in the most promising therapeutic areas for the treatment of
      CHF, will be divided into two parts. In Part I, disease concepts such as altered
      calcium handling and ion channel activity, pathophysiological hypertrophy and
      inefficient cardiac metabolism are discussed. Validation status and potential
      therapeutic value for new targets in each research field is given by summarising
      the results of in vitro and in vivo studies.

PMID- 12472379
TI  - Targeting the Raf kinase cascade in cancer therapy--novel molecular targets and
      therapeutic strategies.
AB  - The mitogen-activated protein kinases (MAPKs) are a group of signal transducers
      with oncogenic potential in an assortment of cell types. Dysregulated signalling
      from any of the members of this family has been shown to result in development of
      human malignancies. Consequently, the collective goal of the scientific community
      is to inhibit aberrant signalling initiated from these molecules whilst
      minimising toxicity associated with such inhibition. This review covers events
      responsible for MAPK activation in detail, with an emphasis placed upon possible
      points of pharmacological intervention. A discussion addressing numerous
      chemotherapeutic approaches that have been developed over the previous decade for
      MAPK inhibition is also included. In addition, emphasis is placed upon the
      various arrays of kinase inhibitors, small molecule inhibitors, competitive
      inhibitors, nucleic acid aptamers and other molecules which have been proven
      effective in prevention of MAPK signalling. Finally, the potential therapeutic
      promise of many of these compounds is addressed in a manner that encompasses the
      complexities of MAPK signal transduction, in addition to concerns surrounding the
      development of drug resistance.

PMID- 12472380
TI  - Emerging techniques for the discovery and validation of therapeutic targets for
      skeletal diseases.
AB  - Advances in genomics and proteomics have revolutionised the drug discovery
      process and target validation. Identification of novel therapeutic targets for
      chronic skeletal diseases is an extremely challenging process based on the
      difficulty of obtaining high-quality human diseased versus normal tissue samples.
      The quality of tissue and genomic information obtained from the sample is
      critical to identifying disease-related genes. Using a genomics-based approach,
      novel genes or genes with similar homology to existing genes can be identified
      from cDNA libraries generated from normal versus diseased tissue. High-quality
      cDNA libraries are prepared from uncontaminated homogeneous cell populations
      harvested from tissue sections of interest. Localised gene expression analysis
      and confirmation are obtained through in situ hybridisation or
      immunohistochemical studies. Cells overexpressing the recombinant protein are
      subsequently designed for primary cell-based high-throughput assays that are
      capable of screening large compound banks for potential hits. Afterwards,
      secondary functional assays are used to test promising compounds. The same
      overexpressing cells are used in the secondary assay to test protein activity and
      functionality as well as screen for small-molecule agonists or antagonists. Once
      a hit is generated, a structure-activity relationship of the compound is
      optimised for better oral bioavailability and pharmacokinetics allowing the
      compound to progress into development. Parallel efforts from proteomics, as well
      as genetics/transgenics, bioinformatics and combinatorial chemistry, and
      improvements in high-throughput automation technologies, allow the drug discovery
      process to meet the demands of the medicinal market. This review discusses and
      illustrates how different approaches are incorporated into the discovery and
      validation of novel targets and, consequently, the development of potentially
      therapeutic agents in the areas of osteoporosis and osteoarthritis. While current
      treatments exist in the form of hormone replacement therapy, antiresorptive and
      anabolic agents for osteoporosis, there are no disease-modifying therapies for
      the treatment of the most common human joint disease, osteoarthritis. A massive
      market potential for improved options with better safety and efficacy still
      remains. Therefore, the application of genomics and proteomics for both diseases
      should provide much needed novel therapeutic approaches to treating these major
      world health problems.

PMID- 12472381
TI  - The situation on antimicrobial agents and chemotherapy in 2002: highlights of the
      42nd ICAAC.
AB  - The 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy took
      place in San Diego on 27-30 September 2002. The meeting was held in the light of
      current events. Bioterrorism, malaria, issues of surveillance and multiple
      resistance were discussed in depth. Few truly new drugs or potential targets were
      presented. Peptide deformylase inhibitors and several other metalloenzymes as new
      targets were among the most promising results.

PMID- 12472382
TI  - Reoperation for tricuspid regurgitation after total correction of tetralogy of
      Fallot.
AB  - BACKGROUND: The aim of this study is to review the outcome of reoperation for
      severe tricuspid regurgitation after repair of tetralogy of Fallot. METHODS:
      Between 1972 and 2000, 12 patients underwent reoperation on the tricuspid valve
      after total correction of tetralogy of Fallot. The mean age at the time of
      reoperation was 17 years (range, 1 to 39 years). The mean interval between the
      initial correction and the reoperation was 7.8 years (range, 10 days to 19
      years). The functional class was New York Heart Association class II in 2
      patients and class III or IV in 10. Six patients underwent tricuspid valve
      repair, and the others underwent tricuspid valve replacement. RESULTS: Hospital
      mortality was 16.7% (2/12). Three patients (30%, 3/10) required a second
      reoperation 1.6, 9.2, and 15.6 years after the most recent reoperation with no
      deaths. The reasons for second reoperation were failure of the tricuspid valve
      repair in two and a thrombosed valve in one. There were two late deaths. Mean
      overall event-free actuarial survival at 10 years was 46.3%. CONCLUSION:
      Reoperation for severe tricuspid regurgitation after total correction of
      tetralogy of Fallot was associated with a high operative mortality and
      disappointing long-term results. Tricuspid regurgitation after corrective surgery
      for tetralogy of Fallot must be diagnosed promptly and cured, as tolerance is
      poor because of postoperative right ventricular insufficiency.

PMID- 12472383
TI  - The left internal thoracic artery and radial artery composite graft in off-pump
      coronary artery bypass grafting.
AB  - Arterial multivessel bypass grafting without extra corporeal circulation and
      manipulation of the ascending aorta should be a good surgical option for the
      treatment of coronary artery disease. An internal thoracic artery (ITA)-radial
      artery (RA) composite graft was used for this purpose. Between July 2000 and
      October 2001, we employed the LITA-RA composite graft for off-pump coronary
      artery bypass in 15 cases. Mean patient age was 71.3 +/- 5.8 years old. Left main
      trunk disease was present in six patients and triple-vessel disease in four
      patients. Preoperative concomitant disease was renal dysfunction in three cases,
      cerebrovascular disease in four and diabetes mellitus in five cases. Two patients
      had a so-called bad aorta. Twelve elective operations and three urgent operations
      were carried out for unstable angina. Two to four (mean 2.6 +/- 0.7) anastomoses
      were performed per patient. Complete revascularization was achieved in 12 out of
      15 patients. Mean operating time was 335 +/- 53 min. Mean intraoperative blood
      loss was 595 +/- 375 ml and nine patients underwent the operation without blood
      transfusion. There was no PMI, no brain disorder, and no death. Postoperative
      coronary angiography in all patients documented a good patency rate (LITA 15/15,
      RA 21/21, right gastroepiploic artery (RGEA) 2/2, and saphenous vein graft (SVG)
      0/2). LITA-RA composite grafting in off-pump coronary artery bypass enables
      arterial multivessel revascularization using an aortic no touch technique. This
      can be done with minimum postoperative complications and without risk of cerebral
      infarction even in patients at high risk for extracorporeal circulation (ECC).

PMID- 12472384
TI  - Minimally invasive direct redo coronary artery bypass grafting.
AB  - Redo coronary artery bypass grafting due to graft failure and the progression of
      new lesions has been increasing in frequency recently. We are often forced to
      revascularize only the left anterior descending artery (LAD) in very elderly
      patients with a high risk to median sternotomy. We performed reoperative
      minimally invasive direct coronary artery bypass grafting (MIDCABG) in seven
      patients. The target sites were as follows: LAD, 7; first diagonal branch, 1; and
      the graft material was the left internal thoracic artery (LITA), 7; and saphenous
      vein graft (SVG), 1. Complete revascularization was accomplished in all patients,
      by including hybrid therapy in three patients and axillo-coronary bypass grafting
      with SVGs in two patients. Postoperative angiography showed all patent grafts and
      all patients were discharged. During a mean follow-up period of 2.4 years (range:
      0.5 to 3.5 years), all were free from cardiac events, except for one patient who
      had recurrent angina due to failure of a previously patent graft 3 years after
      redo MIDCAB. These results suggest that MIDCABG via left antero-lateral
      thoracotomy is an effective and safe technique in redo cases, as well as an
      alternative procedure for hybrid revascularization that combines minimally
      invasive revascularization of LAD with additional catheter interventional
      therapy.

PMID- 12472385
TI  - Coronary artery bypass surgery in patients with abdominal aortic aneurysm:
      detection and treatment of concomitant coronary artery disease.
AB  - OBJECTIVES: Complication due to coronary artery disease (CAD) is a major cause of
      mortality in the surgical treatment of abdominal aortic aneurysm (AAA). The
      purpose was to show 1) the incidence of patients who required coronary artery
      bypass grafting (CABG), and 2) risk factors for the necessity of CABG in patients
      with AAA. METHODS: Subjects were consecutive 159 patients (132 males and 27
      females) undergoing elective repair of non-ruptured AAA between May 1993 and
      March 2002. Most patients (n=145) underwent routine preoperative coronary
      angiography (CAG) and received coronary revascularization when necessary.
      Clinical atherosclerotic risk factors were subjected to univariate and
      multivariate analysis to determine predictors for the necessity of CABG. RESULTS:
      Of 43 patients (27.0%) with significant coronary stenosis, 7 patients (4.4%)
      underwent CABG concomitantly (n=1) or prior to the AAA repair (n=6) in the same
      admission. Other patients received percutaneous transluminal coronary angioplasty
      (PTCA) (n=14) and isolated medical treatment (n=22). Overall mortality of 159
      patients undergoing AAA repair was 2.5% and there were no deaths in 7 patients
      undergoing CABG. Univariate and multivariate analysis indicated only the history
      of angina as significant for the necessity of CABG in patients with AAA. Of 155
      survivors, 5 patients underwent CABG later in the follow-up period. CONCLUSIONS:
      The incidence of patients who required CABG in the treatment of AAA was 4.4% in
      our institute. It was difficult to predict the necessity of CABG without
      conducting CAG in patients with asymptomatic myocardial ischemia. These results
      may justify the routine enforcement of preoperative CAG in patients with AAA.

PMID- 12472386
TI  - Delayed sternal closure is a life saving decision.
AB  - Nineteen hundred and fifty open heart operations were performed between January
      1995 and December 2000 at the cardiac surgery department of Chest Disease
      Hospital in Kuwait. Sternal closure was delayed in 40 patients (2%), because of
      hemodynamic instability limiting primary closure in 23 patients and
      uncontrollable bleeding in 17 patients. Four patients died in the immediate
      postoperative period while the chest was open, due to persistent low cardiac
      output secondary to myocardial failure. The sternum was closed in 36 patients on
      an average of 22 +/- 0.3 hours (range, 8 to 48 hours) postoperatively. Two
      patients died in the late postoperative period prior to hospital discharge after
      sternal closure. Wound infections occurred in 8 patients. The 34 survivors (85%)
      were discharged and followed up for a mean of 13.2 months. This study
      demonstrates that delayed sternal closure is an effective and life saving
      decision with unstable hemodynamics and uncontrollable hemorrhage.

PMID- 12472387
TI  - A case report of inflammatory pseudotumor of the lung: rapid recurrence appearing
      as multiple lung nodules.
AB  - An inflammatory pseudotumor (IPT), known as a plasma cell granuloma, is a
      relatively uncommon neoplasm with an unidentified etiology. To our knowledge, an
      early relapse with multiple lung nodules following lung resection and occurrences
      in multiple organs is extremely rare. The patient was a 49-year-old man who
      presented with left chest pain and fever. A chest film demonstrated an 8x8 cm
      mass in the left lower lobe. During thoracotomy in April 2001, a mass was seen to
      have invaded the diaphragm with remarkable pleural adhesion. The intraoperative
      pathological diagnosis was infiltration of inflammatory cells with no malignancy.
      Therefore, a partial resection of the left lower lobe was performed. Three months
      after the thoracotomy, a chest CT scan disclosed multiple nodular opacities
      bilaterally, and an open lung-biopsy of the right lung was performed in January
      2002. His past history included an excision of a mass on the penis in another
      hospital in 1994 and a subcutaneous mass that appeared on the right thigh and
      disappeared spontaneously following a needle biopsy in 1999. Pathologically there
      was no fundamental difference among his present lesion and the former two. The
      pathological diagnosis at each occurrence was inflammatory pseudotumor (IPT). In
      immunohistochemical study, the staining with smooth muscle actin cells was
      positive, but was negative for the staining with anaplastic lymphoma kinase
      (ALK). With no evidence of a neoplastic process, these histopathological and
      immunohistochemical findings could imply that this case may be a postinflammatory
      reparative reaction, although his condition exhibited the clinically aggressive
      behavior of suspected lung metastasis.

PMID- 12472388
TI  - Successful emergency repair of blunt right atrial rupture after a traffic
      accident.
AB  - A 53-year-old man crashed his motorcycle into a vehicle and was transported to
      our hospital by ambulance after about 30 min. Echocardiography revealed cardiac
      tamponade. Pericardiocentesis was immediately performed using a 5 Fr catheter via
      the subxiphoid approach and the results suggested cardiac injury. Surgery was
      commenced via median sternotomy about 2.5 hours after the accident. Patients with
      cardiac rupture who reach hospital alive can be saved by rapid transport, early
      detection, and early surgery. In particular, rapid echocardiography and
      pericardiocentesis via the subxiphoid approach under ultrasonic guidance are easy
      and helpful methods of making a diagnosis and achieving hemodynamic improvement
      prior to surgical intervention.

PMID- 12472389
TI  - Successful management in the case of mesenteric ischemia complicated with acute
      type a dissection.
AB  - We report a case of acute type A dissection with ischemic enterocolitis due to
      blood flow insufficiency in the superior mesenteric artery. A 67 year-old man,
      with medicated ischemic heart disease and hypertension, presented to another
      hospital with chest pain radiating to the back and epigastrium. Contrast-enhanced
      computed tomography revealed a type A dissecting aneurysm, that extended from the
      ascending aorta to the left common iliac artery, with a 50-mm diameter in the
      ascending aorta. Celiac trunk and left renal artery arose from the false lumen,
      and the superior mesenteric artery (SMA) was compressed by the thrombosed false
      lumen. Symptoms of acute mesenteric ischemia clearly developed. Then, a large
      amount of tarry stool (melena) was discharged. First, an emergency saphenous vein
      bypass was performed from the common iliac artery to the superior mesenteric
      artery at the orifice of the ileocolic artery where it was free from dissection.
      Then total arch replacement was performed using cardiopulmonary bypass. The
      patient's postoperative course was uneventful, and the abdominal symptoms
      completely disappeared. This case demonstrates that prompt surgical relief of
      ischemia in major organs is important to save lives in the cases of acute aortic
      dissection with ischemic complications.

PMID- 12472390
TI  - Spontaneous and isolated dissection of the main trunk of the superior mesenteric
      artery.
AB  - A 42-year-old man was admitted to another hospital complaining of acute abdominal
      pain that was induced by eating. Abdominal computed tomography and selective
      angiography revealed an intimal flap separating true and false lumens that was
      located 3 cm from the origin of the superior mesenteric artery (SMA). Emergency
      surgery was performed because of the sudden recurrence of diffuse abdominal pain
      after eating and abdominal aorta-SMA bypass grafting was done using a radial
      artery graft. Postoperative angiography revealed that the graft showed good
      patency. The postoperative course was uneventful and abdominal pain no longer
      occurred after eating. This excellent result was achieved by early diagnosis
      using CT scanning and angiography plus an aggressive surgical repair with a
      radial artery bypass graft for isolated dissection of the superior mesenteric
      artery.

PMID- 12472391
TI  - Coronary artery surgery results 2000.
AB  - We have reported on changes in the nature and outcome of coronary artery bypass
      surgery over the past 30 years, focusing on surgery performed last year, from
      January 1 to December 31, 2000. The operative mortality for patients who
      underwent only coronary artery bypass surgery was 2.75% in 2000. Mortality for
      initial elective surgery was 1.73%. These are the best results obtained since
      surveys were started. The percentage of elderly patients undergoing coronary
      artery bypass surgery is rising annually. In 2000, 40.8% of patients were aged 70
      years or older and 5.3% were aged 80 years or older. Mortality in elderly
      patients undergoing initial elective surgery is decreasing, with a mortality of
      2.5% for patients aged 70 years or older and 2.9% for patients aged 80 years or
      older. Off-pump coronary artery bypass grafting was performed on 3,356 patients
      in 2000. Median sternotomy was used in the majority of cases, with 2,988 patients
      undergoing surgery by this approach. Use of minimally invasive direct coronary
      artery bypass (MIDCAB) peaked in 1998 but is becoming less common, with only 280
      patients undergoing this procedure in 2000.

PMID- 12472392
TI  - Preoperative concurrent chemotherapy and radiation therapy followed by surgery
      for esophageal cancer.
AB  - Currently, the most promising strategy to improve the prognosis of advanced
      esophageal cancer is preoperative chemoradiation (CRT) followed by surgery. The
      superiority of CRT over radiation therapy alone has been demonstrated by several
      randomized studies. Many phase II studies of CRT followed by surgery have shown
      that the pathologic complete response (CR) rate ranges from 17 to 40%, and the
      median survival time (MST) is 12 to 31.3 months. Five randomized trials have
      compared preoperative CRT followed by surgery with surgery alone for resectable
      esophageal cancer, and four of them did not find any significant survival benefit
      for the combined treatment group. There are several issues in interpreting these
      findings, such as the quality of the surgery, the accuracy of the preoperative
      staging, the statistical power and design of the trials. Until comprehensive
      evaluation can be done, the standard therapy for resectable esophageal cancer
      should be considered to be surgery alone. The histological response in the
      resected specimen correlates well with the prognosis. Patients with pathologic CR
      display significantly better survival than those with microscopic residual cancer
      cells in the resected specimens. These findings suggest that more potent regimens
      leading to higher pathologic CR rates should improve the prognosis. Chemotherapy
      or radiation therapy sensitivity testing needs to be established. If accurate
      prediction of the response is possible prior to therapy, non-responders can be
      excluded. Cell cycle-related genes, apoptosis-related genes, and drug
      metabolizing genes have been investigated in many pilot studies and need to be
      evaluated by large-scale clinical studies. At present, pathologic CR can not be
      accurately diagnosed before surgery. Endoscopic biopsy is also unreliable for the
      diagnosis. In the future, new diagnostic tools such as positron emission
      tomography scanning, a sensitivity test or molecular markers may enable accurate
      diagnosis of pathologic CR to guide the choice of treatment strategies for
      individual patients.

PMID- 12472393
TI  - 15 Years in surgical management of pulmonary hydatidosis.
AB  - OBJECTIVES: Echinococcosis remains an endemic surgical problem in countries where
      sheep and cattle raising is carried out, particularly in many Mediterranean
      countries. This study aims to evaluate the management of different presentations
      of pulmonary hydatidosis and their outcome over 15 years. DESIGN: Retrospective
      study. SETTING: Thoracic surgical department, Chest Diseases Hospital, Kuwait.
      PATIENTS: Sixty patients operated upon for hydatid disease were evaluated pre-
      and post- operatively; 35 males, 25 females with a mean age of 28.4 years. Most
      patients were investigated by laboratory, serological and radiological studies.
      Different surgical techniques were used to remove the hydatid cyst from the lung.
      RESULTS: The most common presenting symptoms were cough (41 patients), and 12
      patients were asymptomatic. Chest X-ray showed a rounded shadow in 42 patients;
      19 cases were of vigorous size >10 cm. Thoracotomy was done in 57 patients; two
      chest wall cases were managed by minimal skin incision and enucleation, one
      hydatid cyst of the heart was approached through a median sternotomy. The mean
      hospital stay was 9 days. Postoperative complications occurred in 9 patients;
      prolonged air leak in 4 patients, pleural effusion in 3, pneumothorax, and wound
      infection in one patient each. One patient (65 years old) died on the 6th post
      operative day most probably from pulmonary embolism. In a follow-up period of 2
      15 years, 4 recurrences have been noted. CONCLUSION: Surgical excision of
      pulmonary hydatidosis with maximum preservation of the lung parenchyma is the
      main stay of treatment.

PMID- 12472394
TI  - Off-pump on-pump coronary artery bypass decision-making.
AB  - BACKGROUND: Coronary revascularization on the beating heart is an attractive to
      option conventional coronary artery bypass graft (CABG) but remains
      controversial. Our study encourages sufficient proper time for decision-making
      when changing CABG from off-pump to on-pump CABG. We report herein patients who
      changed from off-pump CABG to on-pump CABG. METHODS: A retrospective analysis of
      240 patients operated upon at Cardiology Hospital of Lyon University between July
      1998 and July 2000, and at one unit of Cardiac Surgery, yielded 88 patients with
      off-pump coronary surgery (off CAB), 21 patients changed from off-pump CABG to on
      pump CABG. The other 131 patients were operated on as on-pump CABG. RESULTS:
      There was no operative mortality. One month postoperative mortality was only one
      patient out of 21 due to cardiac failure and arrhythmias. There was no
      significant difference in the postoperative intensive care unit (ICU) time and
      length of hospital stay compared with off-pump CABG. CONCLUSION: Our data suggest
      that a fair number of patients are potential candidates for off CAB. The only
      contraindication is the technical limitation or the surgeon comfort level.
      Changing from off CAB to on CAB can be decided for the patient's safety within
      the appropriate time intraoperatively without fear of more postoperative
      complications than with off CAB surgery.

PMID- 12472395
TI  - Off-pump CABG attenuates myocardial enzyme leakage but not postoperative brain
      natriuretic peptide secretion.
AB  - BACKGROUND: Off-pump coronary artery bypass surgery is considered to be less
      invasive compared with a conventional coronary artery bypass surgery, while
      objective assessment of its invasiveness has not been well established. The grade
      of invasiveness of off-pump CABG was evaluated by biochemical markers released
      from the myocardium. METHODS: Perioperative serial changes of myocardial enzyme
      leakage (creatine kinase-MB isoenzyme and troponin T) were evaluated in 217
      patients who underwent coronary artery bypass surgery (28 off-pump CABG patients
      and 189 conventional CABG patients). Serial changes of atrial natriuretic peptide
      and brain natriuretic peptide secretion as markers of heart failure were also
      evaluated in 12 off-pump CABG patients and 49 conventional CABG patients.
      RESULTS: Myocardial enzyme leakage was significantly less in the off-pump CABG
      group, while increase of brain natriuretic peptides secretion were similar in
      both groups with its peak at the first postoperative day (246+/-46 pg/ml in the
      off-pump CABG group and 312+/-57 pg/dl in the conventional CABG group).
      CONCLUSIONS: Although off-pump CABG seems to be less invasive to the myocardial
      cells from the aspect of enzyme leakage, ischemic stress to the heart assessed by
      brain natriuretic peptide secretion was similar to that of conventional CABG.
      Careful monitoring and management throughout postoperative period is mandatory
      even in off-pump CABG procedure.

PMID- 12472396
TI  - Early angiographic and clinical results of branch conduits attached proximally to
      left internal thoracic arteries.
AB  - BACKGROUND: We assessed the characteristics of composite branch conduits attached
      proximally to an in-situ left internal thoracic artery (LITA). METHODS: Sixty
      nine patients underwent coronary artery bypass grafting (CABG) using composite
      branch conduits. Overall 35 distal LITAs, 4 RITAs, 18 radial artery grafts (RAG),
      and 13 inferior epigastric artery grafts (IEA) (both the distal LITA and IEA were
      used in one patient) were used. Clinical and angiographic results were assessed.
      RESULTS: Patency of branch conduit was 97.1% in distal LITAs, 100% in RITAs, 100%
      in RAGs, and 90.9% in IEAs. All in-situ LITAs were patent. Ten branch conduits
      exhibited the string sign. The string sign was caused by competitive flow in
      seven patients. In three of seven patients with competitive flow, the string sign
      had resolved at one year after operation as the proximal stenosis of the native
      coronary artery increased in severity. CONCLUSIONS: The results of CABG using
      branch conduits were satisfactory. It is feasible to observe and follow patients
      with composite grafts exhibiting the string sign in the absence of ischemia.

PMID- 12472397
TI  - A case of lung cancer with hypercalcemia which was incidentally complicated with
      primary hyperparathyroidism due to parathyroid adenoma.
AB  - In lung cancer patients, hypercalcemia is a fairly common metabolic problem
      associated with malignancy. However, the occurrence of hypercalcemia in lung
      cancer patients means an ominous prognostic sign. As hypercalcemia often causes
      early death, quick diagnosis and treatment for hypercalcemia are required. A 69
      year-old woman was admitted to our hospital with anorexia caused by
      hypercalcemia. On admission, serum level of PTH was elevated and PTHrP was
      normal. From the results of CT findings and transbronchial lung biopsy, the cause
      of the hypercalcemia was determined as lung cancer incidentally complicated with
      primary hyperparathyroidism. First, serum calcium level was returned to normal
      through hydration with saline and bisphosphonates. Next, left hemithyroidectomy
      for primary hyperparathyroidism was performed. Histologically, the tumor was
      diagnosed as parathyroid adenoma. Fifteen days later, left lower lobectomy for
      primary lung cancer was performed under a video-assisted thoracoscopic approach.
      Histologically, the tumor was diagnosed as a moderately differentiated
      adenocarcinoma. Four years and three months after the operation, the patient is
      alive and well with no sign of recurrence. When a lung cancer patient is
      complicated with hypercalcemia, we need to consider that primary
      hyperparathyroidism is a possible cause of the hypercalcemia.

PMID- 12472398
TI  - The UPAO test in preoperative evaluation for major pulmonary resection: an
      operative case with markedly improved ventilatory function after radical
      pulmonary resection for lung cancer associated with pulmonary emphysema.
AB  - A 65-year-old man was admitted to our hospital for treatment of a squamous cell
      carcinoma in his right lung. Respiratory function testing showed an extremely
      reduced forced expiratory volume in 1 second (FEV1) of 1.0 l (29.9% of
      predicted), and a reduced FEV1/FVC ratio of 24.1%. Arterial blood gases on room
      air showed a pH of 7.41, a PaCO(2) of 36.7 mmHg, and a PaO(2) of 79.3 mmHg. To
      assess the predictive postoperative cardiopulmonary function, unilateral
      pulmonary artery occlusion (UPAO) testing was performed. In the condition of
      right main PA occlusion, the mean pulmonary artery pressure (mPAP), cardiac index
      (CI) and total pulmonary vessel resistance index (TPVRI) was 18 mmHg, 3.2
      l/min/m(2) and 443.37 dyne.sec.cm(-5)/m(2), respectively. He underwent a middle
      lobectomy with combined partial resection of both the upper and lower lobes. He
      also underwent simultaneous resection of a giant bulla arising from the right
      upper lobe as lung volume reduction surgery. At 80 days after the operation, his
      FEV1 rose to 1.88 l, and the PaO(2) on room air was improved to 88.9 mmHg. UPAO
      testing was suggested to be more useful than routine pulmonary function test to
      determine the accurate predictive postoperative cardiopulmonary function and to
      decide indication for a radical operation.

PMID- 12472399
TI  - Slowly progressive adenocarcinoma of the lung: report of a case.
AB  - A case report of a slowly progressive adenocarcinoma of the lung, followed by
      computed tomography is herein discussed. The patient was a 76-year-old woman, who
      was operated on about four years after a small lung nodule on her left upper lobe
      was discovered. The tumor was suspected to be either well differentiated
      adenocarcinoma or atypical adenomatous hyperplasia (AAH) by the findings of chest
      computed tomography before the operation, and the resected specimen demonstrated
      well differentiated adenocarcinoma, without lymph node metastasis. This case
      demonstrates the possibility that some adenocarcinomas with particular histology
      are slowly progressive, and also there might be the option of lobectomy or
      segmentectomy for treating such tumors.

PMID- 12472400
TI  - Thymic carcinoma presenting as an intraluminal growth into the great vessels and
      the cardiac cavity.
AB  - A rare case of thymic carcinoma with an intraluminal growth to the left
      brachiocephalic vein, the superior vena cava and the right atrium is described.
      Venogram and cardiac echogram were useful for evaluating the vascular permeation
      of the tumor. The patient underwent successful enbloc excision of the tumor under
      conditions of cardiopulmonary bypass.

PMID- 12472401
TI  - Simultaneous carotid endarterectomy, coronary artery bypass grafting and
      abdominal aortic aneurysm surgery.
AB  - A case with a disease triad of an ulcerative lesion in the left internal carotid
      artery (LICA), severe coronary insufficiency, and an infrarenal abdominal aortic
      aneurysm (AAA) is presented in whom we performed simultaneous carotid
      endarterectomy (CEA), coronary artery bypass grafting (CABG), and Y-graft
      replacement of the AAA. The operative technique is detailed and justification of
      the simultaneous approach in such patients is discussed.

PMID- 12472402
TI  - Infected polypropylene suture repair of a ventricular aneurysm.
AB  - Infections associated with the prosthetic material used for ventriculotomy
      closure require repeat operation and removal of all infected material for
      eradication of the infection. This has consistently been reported with Teflon
      closure in the past and we present the first report of infection where only
      polypropylene suture was used for the repair. This potential also has
      implications for aneurysms repaired by endo-ventricular patching.

PMID- 12472403
TI  - Rupture of a smoldering mycotic aneurysm of the thoracic aorta into the lung.
AB  - A 65-year-old man was a diagnosed with meningitis and bacteremia, as
      Streptococcus pneumoniae was isolated from spinal fluid and blood cultures. After
      three weeks of antibiotic therapy, computed tomography revealed a ruptured
      aneurysm of the descending thoracic aorta. The aneurysm had appeared during the
      first episode of meningitis but had remained silent for two years. The patient
      underwent in situ Dacron graft replacement and his postoperative course was
      uneventful with no infectious complication.

PMID- 12472404
TI  - Spontaneous and isolated dissection of the external iliac artery: a case report.
AB  - Spontaneous and isolated dissection of the limb arteries without involvement of
      the aorta is extremely rare. We present a 36-year-old male who has 95% tapering
      stenosis and dissection of the left external iliac artery with abrupt onset with
      total thrombosis in the false lumen until the level of the inguinal ligament. We
      also suggest that endovascular stent graft placement is a useful treatment for
      isolated arterial dissections prior to operation in consideration of the
      technical ease and safety of guiding intravascular ultrasound like in this case.

PMID- 12472405
TI  - Resection of thymic carcinoma in a patient with thoracic aortic aneurysm.
AB  - A 72-year-old man with a history of brain infarction presented with left sided
      anterior chest pain secondary to a thymic carcinoma. He received induction
      radiotherapy, 45 Gy. Preoperative computed tomography showed the tumor was
      adherent to a thoracic aortic aneurysm (TAA) which had extensive mural thrombus
      and calcification. To obtain adequate exposure without exerting tension on the
      fragile aneurysmal wall, ribs were resected to allow us to separate the tumor
      from the TAA, after which median sternotomy was performed uneventfully, creating
      generous exposure. The tumor had invaded the sternum, ribs, innominate vein,
      phrenic and recurrent laryngeal nerves, and lung. The tumor was removed en bloc,
      and the chest wall was reconstructed. Intra- and post-operative brain infarction
      and rupture of the TAA were avoided. The patient is alive and well without
      recurrence 10 months after surgery.

PMID- 12472406
TI  - A technique for the prevention of hoarseness during surgery for distal aortic
      arch aneurysm.
AB  - Hoarseness occurs frequently after surgery to repair distal aortic arch aneurysms
      when using only a median sternotomy approach. We describe a useful technique
      which protects the left recurrent laryngeal nerve during this procedure and
      reduces the incidence of postoperative hoarseness.

PMID- 12472407
TI  - Bicuspid aortic valve.
AB  - The bicuspid aortic valve is a common congenital cardiac anomaly, having an
      incidence in the general population of 0.9% to 2.0% and a frequency of 54% in all
      patients aged >15 years with valvular aortic stenosis. In most cases it remains
      undetected until infective endocarditis or calcification supervenes. The bicuspid
      aortic valve may function normally throughout life, may develop progressive
      calcification and stenosis or may develop regurgitation with or without
      infection. The association of the bicuspid aortic valve with dissection of the
      aorta is also common. The recognition of the bicuspid valve in patients with
      aortic valve disease remains an important challenge to the clinician, whereas
      preoperative knowledge of valve morphology would be helpful in planning the
      surgery. Antibiotic prophylaxis is also recommended in such patients, since these
      valves are likely to become the most important intrinsic cardiac predisposition
      for infective endocarditis with the virtual disappearance of rheumatic fever in
      developed countries.

PMID- 12472408
TI  - Development of a new hollow fiber silicone membrane oxygenator for ECMO: the
      recent progress.
AB  - Throughout the last 50 years, many improvements have been made for a more
      effective oxygenator. A large plate type membrane oxygenator, used by Clowes, and
      a coil type, used by Kolff, has evolved into the small hollow fiber oxygenator.
      The complex bubble oxygenator, or rotating disk oxygenator, has become a small
      disposable bubble oxygenator. The currently available oxygenators are extremely
      small, efficient, and can be used for extended periods of time. However, there
      are some problems with extracorporeal membrane oxygenation (ECMO). Currently in
      the United States, there are no clinically applicable hollow fiber ECMO
      oxygenators available, in spite of the extended ECMO application. Therefore, the
      development of a small, yet efficient, silicone hollow fiber membrane oxygenator
      for long-term ECMO usage was attempted. Based on the results of many experimental
      models, preclinical oxygenator models for long-term ECMO were developed in our
      laboratory using an ultra-thin silicone rubber hollow fiber membrane.

PMID- 12472409
TI  - Effects of a left ventricular assist device with a centrifugal pump on left
      ventricular diastolic hemodynamics.
AB  - The purpose of this investigation was to analyze how left ventricular assist
      device (LVAD) with a centrifugal pump alters left ventricular diastolic
      hemodynamics and energy by means of a left ventricular pressure volume
      relationship. Fifteen anesthetized normal pig hearts were studied after placement
      of an apical drainage LVAD with a centrifugal pump. Indices of the left
      ventricular isovolumic relaxation phase, left ventricular filling phase and
      general hemodynamic data were recorded with the LVAD in on and off situations.
      The pump assist rate was adjusted to 25%, 50% and 75%. Left ventricular stroke
      work, with a high correlation with oxygen consumption, decreased as the assist
      rate increased. Left ventricular relaxation delayed as the assist rate increased,
      but the atrioventricular pressure gradient increased in the left ventricular
      rapid filling phase. This finding clarifies left ventricular rapid filling. In
      this study, it was suggested that although left ventricular isovolumic relaxation
      was affected, 75% assistance is the most effective for the pump flow in terms of
      circulation support and restoration of cardiac function.

PMID- 12472410
TI  - A modified infarct exclusion technique for a post-infarction ventricular septal
      defect.
AB  - BACKGROUND: Operative mortality for a post-infarction ventricular septal defect
      (VSD) remains high. The infarct exclusion technique has been producing a
      favorable outcome for repairing this serious defect. However, there is the
      technical weakness, namely running suture along the base of the necrotic septum.
      We sutured a pericardial patch using multiple interrupted mattress sutures in
      such a manner as to exclude the infarct and VSD. METHODS: Over the past seven
      years, nine consecutive patients with a post-infarction VSD underwent an early
      repair in the same manner. The VSD was anterior in eight patients and posterior
      in one. We sutured a xenopericardial patch to the healthy myocardium around the
      infarct using interrupted mattress sutures instead of running sutures as the
      infarct exclusion technique. In addition, on the postero-inferior margin of the
      patch, one or two mattress sutures passing through the full thickness of the
      anterior papillary muscle were used. RESULTS: Only one patient died of pneumonia
      50 days after surgery. The other eight patients were followed up and were
      functionally classified as NYHA class I or II. CONCLUSIONS: These findings
      suggest that our modified infarct exclusion technique using multiple mattress
      sutures is an effective alternative surgical technique.

PMID- 12472411
TI  - Superoxide radical concentration and superoxide dismutase (SOD) enzyme activity
      in varicose veins.
AB  - The aim of this study is to measure the level of both the superoxide dismutase
      (SOD) enzyme and its substrate, superoxide radicals, in the wall of varicose
      veins. A total of 44 vein specimens were collected from 24 patients who underwent
      surgery for varicose veins at Asir Central Hospital (ACH), Abha, Saudi Arabia
      during the period from October 1999 to November 2000. The patients were 4 males
      and 20 females with a mean age of 35.3+/-SD 10.4 years (15-62 years). At
      operation, vein specimens were collected from both the stripped, mid-thigh long
      saphenous vein (LSV) and the avulsed distal calf varicosities, as appropriate.
      The samples were processed and both the SOD level and the superoxide radicals
      concentration were estimated using spectrophotometry. The mean SOD level in the
      distal calf varicosities (14.7+/-6.0 units/mg protein) was significantly higher
      than that in the mid-thigh LSV (8.2+/-2.9 units/mg protein, P<0.05). The mean
      superoxide radical concentration in the distal calf varicosities (69.5+/-11.9
      nmol/ml) was also significantly higher than that in the mid-thigh LSV (33.8+/
      10.5 nmol/ml, P<0.05). These results suggest that superoxide radicals play an
      important role in the pathogenesis of varicose veins.

PMID- 12472412
TI  - Histological study on the influences of an ultrasonic scalpel on skeletonized
      vessel wall.
AB  - OBJECTIVE: The objective of this study was to histologically clarify the
      difference of vascular wall damage when an ultrasonic scalpel is used in varied
      ways in the vicinity of a vessel. SUBJECTS AND METHODS: 1) The surface of sodium
      carbonate-containing jelly was manually brushed with the edge of a dissecting
      hook type Harmonic Scalpel (HS), and the thickness of the air bubble layer was
      measured to investigate the range to which the vibrations of the instrument
      reached. 2) The internal thoracic artery (ITA), radial artery (RA) and vein
      skeletonized were cut bluntly or brushed using HS ex vivo, and tissue damages
      were observed histologically. 3) The depth of thermal degeneration (TD) of
      residual stumps of ITAs skeletonized by HS using an output power level (level) of
      2 and the quick touch method at the time of coronary arterial bypass grafting
      (CABG) were investigated histologically. RESULTS: 1) The mean thickness of the
      air bubble layers by single brushing was 3.7, 3.7 and 3.1 mm at level 4, 3 and 2,
      and no significant difference. When brushed 5 times, it was 6.9, 5.5 and 6.7 mm,
      respectively, showing marked increases compared with single brushing. 2) A: One
      side of the RA stump cut with a dissecting hook at level 2 was nicely occluded by
      a degenerated protein coagulum, but the contralateral had no coagulum. An ITA cut
      by a shear type blade at level 3 showed that both stumps were nicely occluded,
      but the vessel wall was introverted and fragmented. B: ITAs brushed 5 or 10 times
      at level 2 showed that TD occurred in tunica externa, the mean depth of 100 or
      203 microm, and never exceeded the external elastic lamella. RAs brushed 10 times
      at level 2 and 3 showed that TD and air bubble generation occurred in the tunica
      externa, and the mean depth was 203 and 203 microm. However, TD exceeded the
      external lamella in some cases at level 3. Veins brushed 10 times at level 3
      showed that TD spread to all layers. 3) The depth of TD in ITAs skeletonized
      clinically by HS was 400 to 530 microm, and apart from the external elastic
      lamella. CONCLUSIONS: 1) Though the air bubble layer was very thick in jelly, it
      was observed only in tunica externa ex vivo. 2) For coagulation and cut of small
      blood vessels, it is vital to press an HS blade edge onto the vessel so as to
      press equally both portions to be cut. There is a possibility of a fragmented and
      introverted vessel wall into the lumen. 3) By dissecting ITA and RA using HS at
      level 2 and the quick touch method, TD can be limited to the depth of the
      connective tissue of tunica externa.

PMID- 12472413
TI  - Upper limb vascular trauma in the Asir region of Saudi Arabia.
AB  - Upper limb vascular trauma is associated with major morbidity and mortality, but
      little is known about its incidence or nature in the Asir region of southern
      Saudi Arabia. During the five and a half-year period from May 1996 to December
      2001, 27 patients were admitted to Asir Central Hospital (ACH), Abha, Saudi
      Arabia with upper limb vascular injury. The patients were 21 males and 6 females
      with a mean age of 27+/-12.6 years. Although penetrating trauma was more frequent
      than blunt trauma (59%), road traffic accident (RTA) was the most common single
      mechanism of trauma (33%). The brachial artery was the most frequently affected
      artery and interposition vein grafting was the most commonly employed type of
      vascular repair. Fifty-two percent of the patients had associated orthopedic
      injury and 60% had associated nerve injury. One patient underwent delayed above
      elbow amputation and two patients died from other associated injuries. Vascular
      repair was successful in 24 out of the 26 patients in whom it was attempted
      (92%). However, the functional outcome of the limbs depended on the presence of
      associated nerve injury.

PMID- 12472414
TI  - Atypical carcinoid of the esophagus: report of a case.
AB  - We present a case of an atypical carcinoid in the midthoracic esophagus.
      Esophagectomy was performed with a three-incisional approach. Although both
      postoperative chemotherapy and radiation therapy were given, the patient died 11
      months postoperatively of liver metastasis and cachexia. We suggest that the
      aggressive behavior of atypical carcinoid of the esophagus precludes the use of
      limited surgical resection and requires adjuvant chemoradiotherapy.

PMID- 12472415
TI  - Methylene blue administration in severe systemic inflammatory response syndrome
      (SIRS) after thoracic surgery.
AB  - A 66-year-old male patient developed significant pleural effusion on the right
      side six years after coronary bypass grafting and mitral valve replacement. After
      pleurocentesis, hemo-pneumothorax developed and finally resulted in complete
      atelectasis of the right lung. Three weeks later, the patient was transferred to
      our department, and underwent a right lateral thoracotomy. The hematoma was
      removed and a complete decortication was performed. Four hours postoperatively
      the patient developed severe SIRS with beginning multiorgan failure. Even
      extremely high doses of norepinephrine could not raise the systemic vascular
      resistance. Single intravenous administration of methylene blue lead to
      significant and permanent improvement of the hemodynamic status.

PMID- 12472416
TI  - Reoperation for a patient 25 years after a Starr-Edwards ball mitral valve was
      installed.
AB  - A 45-year-old female suffered from increasing dyspnea during exercise and edema
      of lower extremities from January 2000. She had undergone mitral valve
      replacement with Starr-Edwards ball prosthesis (model 6320) due to mitral valve
      regurgitation 25 years ago. The cardiac catheterization and echocardiography
      documented mitral, aortic and tricuspid valves regurgitation grade III. Left
      ventricular ejection fraction rate was 49% and the pressures of CVP, RA, RV and
      PA were also increased. Laboratory examination showed slight hemolytic anemia.
      Double valve replacement (ATS valve) and tricuspid annuloplasty were carried out
      in April 2000. Strut cloth wear was confirmed at operation. Her postoperative
      course was uneventful. We hereby review the published paper of all cases with an
      implanted Starr-Edwards ball valve who required redo valve replacement with over
      15 years follow-up. We consider that cloth injury is the main cause for
      reoperation and it usually associated with hemolytic anemia; cloth wear not only
      involves the aortic position but also frequently involves the mitral position for
      over 15 years follow-up patients and can be corrected by reoperation. Cloth wear
      should be concerned for those surviving patients who have received the Starr
      Edwards ball valve during long-term follow-up.

PMID- 12472418
TI  - Experience in heart transplantation after dynamic cardiomyoplasty.
AB  - We report a case undergoing heart transplantation due to gradual progression of
      heart failure four years and one month after dynamic cardiomyoplasty. This case
      reports a 61-year-old man who received drug therapy after being diagnosed as
      having idiopathic dilated cardiomyopathy, but his heart failure progressed to New
      York Heart Association (NYHA) class III-IV, and heart transplantation was thought
      to be indicated. However, dynamic cardiomyoplasty was performed because this
      patient rejected heart transplantation. An implantable cardioverter/defibrillator
      (ICD) was implanted for postoperative ventricular arrhythmia. After that, his
      symptoms rapidly improved, but his heart failure gradually worsened two years
      after surgery and heart transplantation was performed four years and one month
      after dynamic cardiomyoplasty. Since transplantation he has had an uneventful
      postoperative course without rejection or complications.

PMID- 12472417
TI  - A report of a surgical case of left atrial free floating ball thrombus in the
      absence of mitral valve disease.
AB  - A 77-year-old woman was admitted to our hospital with transient dysarthria. The
      patient had atrial fibrillation without a history of valvular disease.
      Echocardiographic examination showed evidence of a floating mass going and
      returning between the left atrium and the mitral orifice. With this finding, the
      cause of the brain embolic episode was found to be due to the thrombus in the
      heart. Under surgery, a ball thrombus was removed, the size and weight of which
      were 40x30x25 mm and 15 g, respectively. The patient's postoperative course was
      uneventful, and she was discharged from the hospital on the 16th postoperative
      day.

PMID- 12472419
TI  - Beyond implantable first generation cardiac prostheses for treatment of end-stage
      cardiac patients with clinical results in a multicenter.
AB  - After 30 years of research and development effort for both ventricular assist
      device (VAD) and total artificial heart (TAH) in the United States, they have
      been demonstrating effectiveness in the bridge to transplantation and destination
      therapy. Smaller size, long-term durable second generation and third generation
      blood pumps are now being tested in animals and moving to clinical applications.
      These are now combined with genetic engineering, tissue engineering and
      regenerative medical therapy techniques to provide newer treatment methodologies
      for end-stage cardiac patients. In Japan, heart transplantation was restarted in
      1999, but to date only 13 transplants have been performed. Shortage in donor
      hearts is hindering the prevalence of heart transplantation. Over a dozen of end
      stage cardiac patients are waiting for heart transplantation in hospital with a
      paracorporeal pneumatic VAD. Although implantable VADs have been imported from
      the USA, they have not acquired a wide clinical use yet because of their large
      size and high cost. There is a great need for development of a compact, low cost,
      totally implantable VAD and TAH in Japan to improve the quality of life of end
      stage cardiac patients. This paper reviews the current status of the first
      generation pulsatile VAD and TAH as a bridge to transplantation and destination
      therapy around the world, followed with a review of the second and third
      generation blood pumps beyond the limitations of the first generation systems.
      Future recommendations are also discussed to improve the systems in Japan.

PMID- 12472421
TI  - Meeting the educational challenges of enhanced professional responsibilities.

PMID- 12472422
TI  - Optometric therapeutic competency standards 2000.
AB  - BACKGROUND: Competency standards for entry-level to the profession of optometry
      in Australia were first developed in 1993 and then revised in 1997. The
      competencies require that optometrists entering the profession have the skills to
      use ocular diagnostic drugs but did not consider the prescription of topical
      therapeutic ocular drugs by optometrists. Following the introduction of
      legislation in the Australian state of Victoria that permitted optometrists to be
      licensed by the relevant state registration board to prescribe topical
      therapeutic ocular medication, Optometrists Association Australia (OAA) was asked
      to develop therapeutic competency standards that could be used in the assessment
      of the suitability of optometrists for such licensing. METHODS: Expert members of
      the profession and representatives from optometry schools, registration boards in
      Australia and New Zealand, state divisions of OAA and the New Zealand Association
      of Optometrists (NZAO) were consulted in the process of developing these
      standards. RESULTS: Nine new performance criteria with associated indicators,
      within Units 3 and 5 of the revised entry-level standards, were developed.
      Additions were made to the indicators for 25 of the previously developed
      performance criteria (within all six original units of competency). The modified
      therapeutic competency standards were adopted on behalf of the profession by the
      National Council of OAA in March 2000. DISCUSSION: These therapeutic competency
      standards may be used as a basis for licensing authorities to develop an
      assessment process to determine suitability of optometrists for licensing to
      prescribe topical therapeutic ocular medications. At this stage, the therapeutic
      competencies cannot be regarded as entry-level competencies in Australia but as
      second-tier competencies. However, it is anticipated that the therapeutic
      competencies will come to be regarded as entry-level over the coming years.

PMID- 12472423
TI  - Monochromatic aberrations and characteristics of retinal image quality.
AB  - BACKGROUND: Patients use a wide variety of terms to describe the characteristics
      of their vision. These descriptions encompass the effects of their eyes'
      monochromatic aberrations. METHODS: To illustrate the effect of monochromatic
      aberrations on the quality of the retinal image, we mathematically reconstructed
      the image falling on the retina. This has been achieved by combining the
      properties of various scenes with the optical characteristics of the eye.
      RESULTS: The effects of some common monochromatic aberrations are illustrated. We
      also show examples of the retinal image characteristics for two eyes, one with a
      decentred corneal apex and a second with a decentred refractive surgery ablation.
      CONCLUSIONS: The image reconstruction technique provides a powerful tool for
      investigating the quality of the retinal image. It provides the capacity for
      clinicians to better understand a patient's visual performance. The image
      reconstruction technique can also broaden our knowledge of the effects of various
      forms of aberrations on retinal image quality for complex real-world scenes.

PMID- 12472424
TI  - Trends in Australian contact lens prescribing 2000.
AB  - BACKGROUND: This study was conducted to ascertain current modes of contact lens
      prescribing in Australia. METHODS: One thousand questionnaires were randomly
      distributed to proportionate samples of optometrists in each state of Australia.
      The profession fits the majority of contact lenses in Australia and the sample
      represents 55 per cent of all optometrists. We requested details of the first 10
      patients fitted with contact lenses after receipt of the questionnaire. RESULTS:
      We received 224 completed questionnaires, detailing contact lens fits to 2,230
      patients. The mean age of the patient group was 32.3 +/- 12.9 years and 65 per
      cent of these were female. Sixty per cent of patients were existing wearers, the
      remainder being new fits. The data indicated that 94 per cent of new fits were
      with soft lenses, of which six per cent were for extended wear. For refits 83 per
      cent were soft lenses and 24 per cent were extended wear. It was clear that the
      lens of first choice was mid-water-content (52 per cent of all soft lens fits).
      Only nine per cent of all soft fits were for lenses which were not replaced on a
      planned basis. The majority of rigid lenses were prescribed using mid-Dk
      materials (71 per cent). Analysis of solution prescribing indicates that
      multipurpose products were the most common regimens for planned replacement soft
      lenses. The percentage of hydrogen peroxide prescribed increased as lens
      replacement became less frequent. CONCLUSIONS: Non-planned replacement lenses are
      now rarely prescribed to patients. Extended wear lenses and rigid lenses are
      prescribed more to existing contact lens wearers. The impact of multifocal lens
      designs on contact lens prescribing is very small, namely, five per cent of soft
      contact lenses and eight per cent of rigid lenses, despite 20 per cent of
      patients being over 45 years of age.

PMID- 12472426
TI  - Profile: J Lloyd Hewett.

PMID- 12472425
TI  - Stickler syndrome.
AB  - Stickler syndrome is a relatively rare condition (approximately 1 in 10,000),
      caused by a defective collagen gene and characterised by high myopia, high risk
      of retinal detachment and flattened facial features. An outline of the condition,
      its systemic and ocular manifestations and optometric management are described.

PMID- 12472427
TI  - Contact lens practice and a very soft option.

PMID- 12472428
TI  - Gas discharge headlights and visibility of coloured road signs.
AB  - BACKGROUND: Automotive headlamps mostly use the tungsten halogen bulb but several
      years ago a new type of headlamp, the gas discharge bulb, was introduced. Because
      of the different spectral output of this type of lamp, there has been a
      suggestion that it may affect the colour recognition and sign conspicuity under
      night-time conditions. In this study, the visibility of the road signs is used to
      examine the effect of the gas discharge lamp's spectrum compared with that of the
      conventional halogen headlamp. METHODS: The spectral output of the lamps and the
      spectral reflectance of common-coloured road signs were measured using a Spectra
      Pritchard spectroradiometer. Using luminous reflectance data, chromaticity co
      ordinates and the colorimetric shift of the road signs, when illuminated by gas
      discharge lamps, were plotted using CIE x,y co-ordinate system. Colour rendering
      indices of the lamp were calculated using Munsell samples and road signs as
      proscribed by the CIE Publication. In addition, the visibility index of the road
      signs was calculated using Adrian's 'Visibility of Target' model. RESULTS: The
      gas discharge headlamp has more energy in the blue region and less energy in the
      red region of the spectrum than the halogen headlamp. The general colour
      rendering index of the gas discharge lamp is higher than that of the halogen
      lamp. When compared with daylight, all coloured road signs used in this study
      have less colorimetric shift when illuminated by the gas discharge headlamp than
      by the halogen headlamp. CONCLUSION: The result indicates that the gas discharge
      lamp, while having a very different spectrum from daylight or tungsten halogen
      lamps, should not have a deleterious effect on sign detection or recognition,
      when compared to daylight or tungsten halogen lamps.

PMID- 12472429
TI  - Ocular allergy: causes and therapeutic options.
AB  - Ocular allergic eye conditions are among the most common anterior eye problems
      encountered in optometric practice. There are six common forms of ocular allergy:
      seasonal allergic conjunctivitis, perennial allergic conjunctivitis, vernal
      keratoconjunctivitis, atopic keratoconjunctivitis, contact lens associated
      papillary conjunctivitis and contact ocular allergy. Here, we review the current
      understanding of the pathophysiology underlying ocular allergic conditions and
      describe the different causes and forms of allergic eye disease and different
      treatment options.

PMID- 12472430
TI  - Benign intracranial hypertension with minocycline therapy.
AB  - A 17-year-old Caucasian female patient, who had been prescribed minocycline for
      acne vulgaris, presented with postural visual obscurations. Ophthalmoscopic
      examination revealed papilloedema in each eye. Neuro-imaging of the brain and
      orbits was normal. A diagnosis of minocycline induced benign intracranial
      hypertension was made. Withdrawal of minocycline led to resolution of her
      symptoms and the papilloedema.

PMID- 12472431
TI  - Pattern dystrophies of the retinal pigment epithelium.
AB  - We describe a family that shows autosomal dominant pattern dystrophy of the
      retinal pigment epithelium. There were 10 affected family members encompassing
      three generations. The various manifestations of these dystrophies, their
      inheritance characteristics, affects on vision function and their pathogenesis
      are discussed.

PMID- 12472433
TI  - Profile: William George Kett.

PMID- 12472432
TI  - Preferred walking speed for assessment of mobility performance: sighted guide
      versus non-sighted guide techniques.
AB  - BACKGROUND: If visually impaired people had their sight fully restored, it is
      assumed that they would walk at their optimal speeds. Previous mobility studies
      have used preferred walking speed (PWS) to measure walking efficiency of visually
      impaired adults. Therefore, the actual speeds that visually impaired people adopt
      on a route can be expressed as a percentage of their preferred walking speed
      (PPWS). There have been two approaches used in previous studies for determining
      preferred walking speed. 1. the sighted guide technique (SG), which requires a
      subject to walk with a sighted guide and regard the latter as a perfect mobility
      aid, with the subject setting the preferred (optimal) walking pace 2. the non
      sighted guide technique (NonSG), which requires a subject to walk alone along an
      unobstructed straight path for a certain distance, adopting the preferred
      (optimal) walking speed. There is some debate on which technique is the better.
      This study was conducted to determine if there is any difference between the two
      techniques for determining visually impaired subjects' preferred walking speeds.
      METHODS: Fourteen visually impaired adult subjects were recruited. PWS was
      determined by recording the time taken for a subject to walk an unobstructed,
      straight 20-metre corridor path using each technique. RESULTS: There was no
      significant difference in PWS using the sighted guide and non-guided techniques.
      CONCLUSIONS: Either the SG or NonSG techniques can be used to determine PWS for a
      heterogeneous group of visually impaired subjects.

PMID- 12472434
TI  - Optometry in Hong Kong.

PMID- 12472435
TI  - Strabismic amblyopia. Part 2. Neural processing.
AB  - This is the second of a two-part survey of current literature concerning
      strabismic amblyopia. The aim of this review is to bring the optometric community
      up to date on the status of scientific research into strabismic amblyopia. Part 1
      in this series discussed research into strabismic amblyopia from the viewpoint of
      psychophysical experiments, which investigate both spatial and temporal
      behavioural deficits accompanying strabismic amblyopia. These include deficits in
      contrast sensitivity, spatial localisation, fixation, ocular motility,
      accommodation, crowding, attention, motion perception and temporal processing.
      Part 2 concerns neural processing in regards to strabismic amblyopia. It
      discusses current understanding of more fundamental aspects of central processing
      of visual information and in particular current theories regarding neural sites
      and mechanisms involved in amblyopia.

PMID- 12472436
TI  - Ocular ischaemic syndrome.
AB  - Ocular ischaemic syndrome is a rare condition. It often results in blindness and
      is linked to serious systemic morbidity. Its presentation is usually subtle and
      it can be misdiagnosed due to its diverse signs and symptoms. A case of ocular
      ischaemic syndrome is presented and current diagnostic procedures and treatment
      described. Recognition by the clinician is important because of the severe ocular
      and potential systemic sequelae.

PMID- 12472437
TI  - Epiretinal membrane with macular pucker.
AB  - BACKGROUND: Epiretinal membranes are a common finding in people over the age of
      50 years. Clinically, they usually cause minor visual distortion. However, in
      some patients, there may be a significant visual loss and/or metamorphopsia and
      surgery may be required in more severe cases. CASE HISTORY: In this report, we
      document the findings of a patient having an epiretinal membrane with macular
      pucker. The patient underwent surgery consisting of posterior vitrectomy and
      peeling away of the membrane. DISCUSSION: The classification and terminology
      commonly used to describe epiretinal membranes are reviewed. In addition, the
      aetiology, prevalence, symptoms, differential diagnosis, treatment and
      complications of epiretinal membranes are discussed.

PMID- 12472439
TI  - Profile: Dr Rodney D Watkins.

PMID- 12472438
TI  - An investigation of the effectiveness of Bolle's.
AB  - BACKGROUND: Specifically, Bolle claims the Competivision lens will enhance the
      ability of a player to visually perceive a tennis ball and may subsequently
      improve athletic performance. This study examined the impact on tennis
      performance of wearing Bolle Competivision tennis sport-glasses. METHODS: Twenty
      subjects of three tennis skill levels were measured in relation to their hitting
      accuracy and movement initiation speed while hitting ground strokes projected
      from a sports action machine. Each participant completed 40 test trials under
      three conditions: wearing Competivision lenses, wearing clear lens glasses (used
      as a placebo to create an expectancy of improved performance) and not wearing
      glasses. RESULT: No significant differences were found between any treatment
      conditions or skill groups for movement initiation time. There was a significant
      difference in hitting accuracy between the skill levels, with the advanced and
      intermediate skill groups being more advanced than the novices, but this
      difference was independent of treatment condition. Additionally, there was no
      significant difference in hitting accuracy between the treatment conditions.
      DISCUSSION: Possible causes of the results include the role of ball flight
      information for successful hitting performance and the transfer of colour
      contrast sensitivity to enhanced sports performance.

PMID- 12472440
TI  - Obituary: Reginald Robert Etherington.

PMID- 12472442
TI  - The Right to Sight.

PMID- 12472441
TI  - An evidence-based approach to glaucoma therapy.

PMID- 12472443
TI  - Hippocrates to Duke-Elder: an overview of the history of glaucoma.
AB  - OBJECTIVE: To briefly trace the history of the diagnosis, understanding and
      treatment of glaucoma. METHOD: Selective review of the early literature on
      glaucoma to the mid-20th century.

PMID- 12472444
TI  - Diagnosis and management of open angle glaucoma: suggested guidelines for
      optometrists.
AB  - OBJECTIVE: The aims of this review are to define open angle glaucoma, to outline
      its prevalence and its financial and personal costs, to discuss the difficulties
      encountered in establishing the diagnosis and monitoring treatment, and to
      suggest initial clinical guidelines for the comanagement of glaucoma between
      ophthalmologists and optometrists. METHODS: The literature was selectively
      reviewed to permit deductions that can be directed toward an effective
      comanagement strategy for patients with open angle glaucoma. CONCLUSIONS:
      Comanagement of patients having open angle glaucoma is a viable option, provided
      the opportunity for improved monitoring and better compliance is available. The
      basis for successful management rests with the ability to detect change in the
      optic disc and surrounding retina, visual fields and intraocular pressure. All
      these signs are continuous variables for which there are no known limits of
      normality. The division of responsibilities of management will be established
      initially by legislation and in the future modified according to experience and
      the emergence of new therapies.

PMID- 12472445
TI  - Visual fields in glaucoma: a clinical overview.
AB  - Static automated visual field testing is now an integral part of the detection
      and monitoring of primary open angle glaucoma. However, although many aspects of
      testing are automated, interpretation of the large amounts of data produced by
      these instruments is not. Two major challenges facing the practitioner are
      differentiating between the visual fields of a patient with early glaucoma and
      those of a normal patient, and identifying whether small reductions in
      sensitivity are due to a true defect or a product of other factors. This paper
      presents a clinical overview of how to systematically review visual field plots
      and how to recognise defects arising from patient factors, as well as some of the
      alternative testing techniques available for the assessment of the glaucoma
      patient.

PMID- 12472446
TI  - Management of ocular hypertension and primary open angle glaucoma.
AB  - BACKGROUND: Glaucoma and ocular hypertension are among the most common
      pathologies encountered in clinical practice. Within the next 20 years, patients
      with these two problems will increase threefold as the population ages. The
      growing burden of glaucoma worldwide will also become a significant public health
      problem. The effective management of glaucoma will require the introduction of
      new screening strategies and better therapeutic approaches to these disorders.
      METHODS: Our current understanding of the epidemiology of primary open angle
      glaucoma and ocular hypertension is reviewed. Diagnosis and treatment strategies
      are discussed in the context of the current best available clinical trial and
      laboratory data. RESULTS: While few patients with ocular hypertension will
      require therapy, it is the conventional practice to lower the intraocular
      pressure by at least one-third once glaucomatous optic neuropathy is detected.
      Topical beta-adrenergic antagonists have been the preferred first-line therapy
      for primary open angle glaucoma for the past 20 years, but with the advent of
      topical prostaglandin analogues and alpha-2 agonists, the effectiveness of
      medical therapy has improved significantly. The decision to perform glaucoma
      filtering surgery or laser trabeculoplasty must be carefully considered and based
      on the past response to medication, the extent and rate of progression of any
      visual field loss, and on the life expectancy and wishes of the patient.
      CONCLUSION: The treatment of chronic glaucoma is directed at preserving vision
      and interfering with the quality of life of the patient as little as possible.
      Many older patients who develop primary open angle glaucoma may have a limited
      life expectancy and do not require aggressive medical therapy or surgery. Many
      new medications have become available that permit less frequent dosing with fewer
      local and systemic side-effects. In the near future, therapies that address the
      underlying molecular basis of glaucomatous optic neuropathy might become
      available and further reduce the risk of glaucoma blindness.

PMID- 12472447
TI  - The many faces of glaucomatous optic neuropathy.
AB  - BACKGROUND: Glaucoma manifests mostly in the elderly, who frequently have
      otherocular changes that frustrate clear visualisation of the optic nerve head or
      nerve fibre layer. In the past, a large or asymmetric cup/disc ratio has been
      used to indicate the possibility of glaucoma. In this paper, I will argue that
      cup/disc ratios alone have poor sensitivity to glaucoma, and a more sophisticated
      approach is needed to make the earliest diagnosis. METHODS: This paper reviews
      the literature and describes the changes that occur at the optic nerve head and
      in the peripapillary region as a consequence of glaucomatous optic neuropathy
      (GON). RESULTS: The concept of 'risk factors' is developed to help screen for
      glaucoma. Glaucoma suspects require a full clinical investigation (visual field,
      IOP, assessment of anterior chamber, disc features and nerve fibres) and need to
      be monitored annually. For future reference, they should have their disc features
      recorded by instrumental methods or with photography at an early age. As no
      single sign provides the perfect diagnostic marker for the disease, clinicians
      need to examine for a group of signs before making the diagnosis. A clinical
      logic is developed in this paper to enhance the detection of glaucoma.
      CONCLUSION: Adoption of a protocol similar to that detailed in this paper will
      enhance the early and reliable detection of glaucoma.

PMID- 12472448
TI  - Normal tension glaucoma: diagnostic features and comparisons with primary open
      angle glaucoma.
AB  - BACKGROUND: A significant proportion of patients diagnosed under the broad
      classification of open angle glaucoma actually has normal tension glaucoma (NTG).
      It has many clinical features that overlap with primary open angle glaucoma
      (POAG), yet there is a question of whether it has a different aetiology in which
      intraocular pressure plays less of a role. METHODS: The epidemiology and clinical
      features of normal tension glaucoma are reviewed with particular reference to
      possible differences from primary open angle glaucoma, which might permit
      differentiation. The pathophysiology is discussed, outlining recent research in
      cell death (apoptosis), axonal damage and neuroprotection. DISCUSSION AND
      CONCLUSION: There is considerable evidence that NTG develops with little
      contribution from the effect of intraocular pressure. However, the clinical
      diagnosis of NTG is often one of exclusion and the differentiation of NTG from
      POAG remains difficult because many clinical signs are suggestive but not
      definitive of NTG. More accurate diagnosis may be possible when individual
      patients exhibit a greater number of signs. Some evidence suggests that NTG with
      relatively high pressures (greater than 15 mmHg) is more likely to progress than
      NTG with relatively low pressures. Clinicians must be particularly alert to the
      possibility of NTG because IOP, a clinical marker for some glaucomas, is absent.

PMID- 12472449
TI  - Clinical features of pseudoexfoliation of the lens capsule: suggested management.
AB  - BACKGROUND: Pseudoexfoliation of the lens capsule (PEX) is found in widely
      varying proportions across the population of regional groups. It is strongly
      associated with open angle glaucoma and to a lesser extent angle closure
      glaucoma. This association makes PEX a very important risk factor for glaucoma,
      which should be sought actively in all patients over 50 years of age who seek eye
      care. Our ageing population may give rise to a future high caseload of PEX
      glaucoma, which will create challenges in diagnosis and treatment. METHOD:
      Selected literature is reviewed. It includes a description of the course of PEX
      and suggested optometric clinical procedures to diagnose and assess the
      significance of PEX. An algorithm for guidance of optometric and ophthalmological
      management is presented. CONCLUSIONS: PEX is a common condition in the aged. It
      is an easily detected strong indicator of open angle glaucoma and to a lesser
      extent the risk of angle closure glaucoma. The presence of PEX should alert the
      clinician to the need for a full glaucoma assessment.

PMID- 12472450
TI  - Optic nerve blood flow in glaucoma.
AB  - BACKGROUND: Glaucomatous optic neuropathy often occurs in the absence of elevated
      intraocular pressure and, conversely, elevated intraocular pressure may occur
      without associated damage of the optic nerve. These findings challenge the simple
      explanation of intraocular pressure being the sole cause of neural loss and have
      led to theories of ischaemic causes of the morbidity. This paper reviews the
      vascular anatomy of the optic disc, the factors that control its blood flow and
      the existing techniques for measurement of the blood flow. It also briefly
      discusses the possible role of apoptosis in glaucomatous visual loss. METHOD:
      Literature review. CONCLUSIONS: The posterior ciliary artery circulation is the
      main source of the blood supply to the optic nerve head with additional lesser
      supply via the central retinal artery and the choroidal circulation. There is
      considerable individual variation in the distribution of this circulation and
      complex regulatory systems govern its function. It is likely that
      microcirculatory changes in the vascular supply of the optic disc play a role in
      glaucoma, either as the primary abnormality or as a co-factor that increases
      susceptibility to damage from increased intraocular pressure through impaired
      auto-regulation. Clinical trials are currently in progress for the treatment of
      glaucoma with systemically administered agents that are antagonists of the
      receptors that mediate glutamine toxicity, a factor in the process of apoptosis.

PMID- 12472451
TI  - The management of normal tension glaucoma.
AB  - OBJECTIVE: To outline the difficulties in making management decisions associated
      with normal tension glaucoma. To suggest treatment strategies according to the
      clinical presentation of the disease. METHOD: Literature review and findings
      based on clinical experience. CONCLUSIONS: The treatment of normal tension
      glaucoma involves many difficult decisions including whether to intervene and, if
      so, when and how to treat. Providing the patient with information is essential to
      gain co-operation and confidence. At present, the treatment objectives are to
      prevent further visual field loss by reduction of intraocular pressure by 30 per
      cent or more. This may be achieved by using medical or surgical regimens.
      Recently, there has been emphasis on the use of neuroprotective drugs that may
      act independently of the effect of intraocular pressure lowering. The balance
      between protecting vision and iatrogenic damage is not always easy.

PMID- 12472452
TI  - Secondary glaucoma.
AB  - PURPOSE: To review the common causes of secondary glaucoma. METHODS: Review of
      current literature. RESULTS: Secondary open and closed angle glaucomas are an
      important cause of ocular morbidity and vision loss in our community. Secondary
      glaucoma occurs with acquired ocular diseases (pigment dispersion,
      pseudoexfoliation, intraocular infection, intraocular inflammation and retinal
      vascular disease), blunt anterior segment injury, intraocular surgery (especially
      corneal grafting and congenital cataract surgery) and topical corticosteroid use.
      The medical treatment of secondary glaucoma is different from that of primary
      open angle glaucoma and must be tailored for the individual patient. Surgical
      treatment of secondary glaucoma carries a higher risk of complications and a
      lower rate of success than does surgical treatment of primary open angle
      glaucoma. CONCLUSIONS: Secondary glaucoma occurs with a variety of intraocular
      conditions and after a variety of intraocular insults. Awareness of patients at
      high risk should enable early detection and referral for appropriate management.

PMID- 12472453
TI  - Publishing Clinical and Experimental Optometry on the web.

PMID- 12472454
TI  - Strabismic amblyopia. Part 1. Psychophysics.
AB  - This is a two-part survey of current literature concerning strabismic amblyopia.
      The aim of this review is to bring the optometric practitioner up to date on the
      status of scientific research into strabismic amblyopia. Part 1 in this series
      discusses research into strabismic amblyopia from the viewpoint of psychophysical
      experiments that investigate both spatial and temporal behavioural deficits
      accompanying strabismic amblyopia. These include deficits in contrast
      sensitivity, spatial localisation, fixation, ocular motility, accommodation,
      crowding, attention, motion perception and temporal processing. Part 2 will
      evaluate neural processing in regard to strabismic amblyopia. It will discuss
      current understanding of aspects of central processing of visual information and
      theories regarding neural sites and mechanisms involved in amblyopia.

PMID- 12472455
TI  - Herpes zoster opthalmicus.
AB  - INTRODUCTION: Herpes zoster is a common disease which may cause serious ocular
      sequelae when it affects the trigeminal nerve. Although involvement of the
      nasociliary branch of the first division of the trigeminal nerve is well
      recognised to be associated with serious and direct ocular morbidity, the need
      for careful long-term follow-up of cases of frontal branch involvement is perhaps
      less well known. METHODS: The pathogenesis, epidemiology, risk factors, clinical
      course and treatment of herpes zoster are discussed with emphasis on trigeminal
      nerve involvement. A case report is presented which illustrates the importance of
      continuing management when the frontal branch of the trigeminal nerve is
      affected. DISCUSSION: Clinical guidelines are suggested for optometric management
      of these cases in cooperation with medical practitioners.

PMID- 12472456
TI  - Degenerative retinoschisis threatening central vision.
AB  - A 65-year-old white male patient presented with asymptomatic bilateral
      degenerative retinoschises. The striking feature of this case was the posterior
      extent of the retinoschises. In each eye the posterior margin of the
      retinoschisis lay within 15 degrees of the macula, thereby potentially
      endangering central vision. The posterior border of a retinoschisis often lies
      posterior to the equator. However, it seldom reaches the major retinal vascular
      arcades. It is even rarer for a retinoschisis to approach the macula.

PMID- 12472457
TI  - Near esophoria is associated with high myopia.
AB  - BACKGROUND: A retrospective study was undertaken to examine the hypothesis that
      esophoria is associated with higher amounts of myopia. METHODS: One hundred and
      forty-four subjects were selected from the files of optometry clinics at the
      Department of Optometry, National University of Malaysia, from the years 1995 to
      1998 inclusive. These subjects were matched in terms of age group, sex, race and
      near phoria group. Near phorias were determined by Maddox wing technique and were
      classified into three groups: more than six prism dioptres exophoria, zero to six
      prism dioptres exophoria and any esophorias. RESULTS: One way analysis of
      variance revealed that there were significant differences in mean myopias between
      the three phoria groups (ANOVA, F(2,141) = 5.34, p < 0.01). Further analysis with
      the Student-Newman-Keuls test showed that the amount of myopia is significantly
      higher in the esophoric group than in the other two groups. CONCLUSIONS: The
      results support the hypothesis that near esophoria is associated with high
      myopia. This study suggests that near phoria might be an important factor in
      myopia development.

PMID- 12472458
TI  - Some variables to consider to avoid the need for LASIK surgical enhancements.
AB  - BACKGROUND: The predictability of LASIK refractive surgery is important both to
      the patient and the surgeon in obtaining an optimal result and in reducing the
      need for enhancement surgery. Some instruments, large ablation zones and possibly
      other variables may increase hyperopic overcorrection. METHODS: A retrospective
      study was undertaken of 345 myopic LASIK eyes (175 patients) treated with a Nidek
      EC-5000. The need for additional surgery in the form of an enhancement was
      determined after the patient had a stable refraction. The variables measured in
      the study were the patient's refractive correction, corneal curvature using an
      Alcon EH-290 topographer, the patient's age and Nidek excimer laser ablation
      optic and transition zone size. The same nomogram was used for all eyes and where
      possible bilateral surgery was conducted on all patients. The effect of ablation
      sizes, refractive errors, patient age and corneal curvature on the enhancement
      surgeries was evaluated using SPSS 6.0. RESULTS: The most significant variable
      that precipitated a LASIK enhancement was an optic zone of 6.5 mm with a
      transition zone of 7.5 mm (paired t-test, p < 0.0025). Multivariate analysis
      indicates that the older the patient and the larger the refractive error, the
      greater the risk of not achieving a residual refractive error of +/- 0.50 D at
      three months. The steeper pre-operative corneas have a greater chance of
      enhancement (mean of sample 44.48 +/- 1.47 D and mean of enhancements 45.30 +/-
      1.65 D, p = 0.01, independent sample test). The smaller optic zone was associated
      with a smaller refractive over-refraction after LASIK surgery (mean for 5.5 mm
      optic zone, +0.71 +/- 0.29 D; mean, for 6.5 mm optic +1.27 +/- 0.50 D, paired t
      test p < 0.0001). CONCLUSIONS: In this study, the 5.5 mm optic zone appears to
      dampen or reduce the undesirable refractive results. The optic zone size of
      choice with the Nidek EC-5000 laser should be 5.5 mm if the patient has small
      pupils and steep corneas. In this sample, the targeted emmetropic refractive
      state (range plano to +0.50 D sphere and plano to -0.50 D cylinder) was achieved
      in 93.3 per cent of cases after three months.

PMID- 12472459
TI  - Profile: Helen Gail Robbins.

PMID- 12472460
TI  - Eighty-three - or is it 87? - and still going strong.

PMID- 12472461
TI  - The effect of myelination on perimetry and retinal nerve fibre analysis.
AB  - BACKGROUND: Myelinated retinal nerve fibres around the optic nerve head can lead
      to an enlargement of blind spot with kinetic perimetry. Presumably extensive
      myelination will also decrease the visual sensitivity with static perimetry. This
      study reports the effect of myelination on static perimetry in several patients.
      Scanning laser polarimetry can measure the retinal nerve fibre layer thickness
      around the optic nerve head in vivo. This technique was applied at the
      myelination to investigate its effect on retinal nerve fibre layer thickness
      determination. METHODS: Four eyes of three subjects with myelination around the
      optic nerve head were tested with Bjerrum screen at one metre to measure the
      blind spot size. They were followed by Humphrey Visual Field Analyser with a
      custom pattern to quantify the threshold level at the blind spot region. A GDx
      Nerve Fiber Analyser was used to measure the retinal nerve fibre layer thickness
      around the optic nerve head. RESULTS: All the patients demonstrated an
      enlargement of the blind spot, with different extents, corresponding to the area
      of myelination. Threshold testing revealed a depression in the myelinated
      regions. The results for retinal nerve fibre layer were not conclusive with two
      eyes demonstrating thickening and two eyes showing no effect from myelination.
      CONCLUSIONS: A static field test with a modern visual field analyser may help to
      quantify the effect of myelination on visual sensitivity. More studies on the
      effect of myelination on retinal nerve fibre layer thickness measurement are
      suggested with more subjects involved.

PMID- 12472462
TI  - Addition lens alleviates reading-induced ocular stress.
AB  - BACKGROUND: Near tasks have been associated with binocular stress to induce
      myopia. The aim of this study was to investigate the effects of accommodation on
      reading-induced near heterophoria. METHODS: We measured the near heterophoria of
      22 young adults before and after 30 minutes of reading. The reading task
      comprised a column of local English newsletter studied monocularly at 33 cm. One
      of three addition lenses (that is, 0.00 D, +1.50 D and +3.00 D) was randomly
      incorporated into the optical prescription. The difference in near heterophoria
      between the pre- and post-reading task was recorded. The experiment was completed
      on separate days for the other lens powers. RESULTS: Reading for 30 minutes with
      a plano lens addition (control) increased the near heterophoria by 3.81 +/- 0.95
      prism dioptres (SEM) toward exo-deviation (p < 0.002). Addition of a +3.00 D lens
      significantly decreased the reading-induced exophoric shift to 1.36 +/- 0.55
      prism dioptres (SEM). Similarly, a +1.50 D lens reduced the exophoric shift to
      3.14 +/- 0.85 prism dioptres (SEM) but the difference was not statistically
      significant when compared with the control. CONCLUSIONS: The results showed that
      close work might cause eye strain via the extraocular muscles. Incorporation of
      plus lens into the optical correction caused a power-dependent reduction in the
      stress, that is, smaller exophoric shift. Whether binocular stress contributes to
      myopia and its response to addition lens therapy deserve further investigation.

PMID- 12472463
TI  - A survey of ocular therapeutic pharmaceutical agents in optometric practice.
AB  - BACKGROUND: In all Australian states optometrists are permitted to use diagnostic
      topical ocular drugs in the practice of their profession. In addition,
      legislation has just been passed in Victoria allowing optometrists to prescribe
      topical S4 medications for ocular conditions. Changing optometric legislation to
      incorporate S4 ophthalmic agents is a topical issue within optometry. METHODS: By
      postal survey, we asked Queensland optometrists to gauge their level of
      education, current mode of practice and whether they were in favour of gaining
      access to prescription-only therapeutic medications. Their opinions on the
      education requirements, perceived potential public benefits and the possible
      barriers to optometrists gaining prescribing rights to therapeutic agents were
      also investigated. RESULTS: A 45 per cent response rate to the survey (231
      responses out of 517) was obtained. The majority of respondents (88 per cent)
      wanted to be able to prescribe therapeutic agents. Over 50 per cent considered
      themselves competent and believed they were capable of treating dry eye,
      blepharitis, allergic conjunctivitis, corneal abrasions and contact lens induced
      papillary conjunctivitis. Over 90 per cent would be confident recommending
      topical lubricants and antihistamines, while 65 per cent felt they were
      adequately prepared to prescribe topical antibiotics. Education level, in
      particular the completion of a therapeutic drugs course, was the main factor that
      determined whether the respondents practised or were willing to practise at a
      higher level. CONCLUSION: The majority of Queensland optometrists are well aware
      of the issues surrounding the use of pharmaceutical agents. Many optometrists
      feel they are well prepared for prescribing ocular therapeutic agents.

PMID- 12472464
TI  - Management of patients undergoing hydroxychloroquine (Plaquenil) therapy.
AB  - The quinolines, hydroxychloroquine (Plaquenil) and chloroquine are used primarily
      for their anti-inflammatory effects in the treatment of auto-immune conditions
      such as rheumatoid arthritis. Another common use of these drugs is the
      prophylaxis and suppression of malaria. The use of quinolines may cause several
      ocular side-effects. The most significant complication is irreversible macular
      damage resulting in both visual acuity and visual field loss. However, the Royal
      College of Ophthalmologists, UK (RCO) recently recommended against the monitoring
      of patients receiving quinoline therapy as it was deemed to be too costly, given
      the low incidence of retinal complications. In this article, we present a case of
      hydroxychloroquine retinopathy, describe the ocular changes associated with
      quinoline therapy and recommend an optometric review schedule for patients who
      are currently taking these drugs. Furthermore, we recommend a proactive approach
      toward medical practitioners prescribing these drugs for optometric-based
      monitoring of these patients.

PMID- 12472465
TI  - Obituary: Arthur Hillyar Ley.

PMID- 12472466
TI  - Nucleoside diphosphate kinase of Saccharomyces cerevisiae, Ynk1p: localization to
      the mitochondrial intermembrane space.
AB  - Nucleoside diphosphate kinase (NDPK) is a highly conserved multifunctional
      enzyme. It catalyses the transfer of gamma phosphates from nucleoside
      triphosphates to nucleoside diphosphates by a mechanism that involves formation
      of an autophosphorylated enzyme intermediate. The phosphate is usually supplied
      by ATP. NDPK activity in different subcellular compartments may regulate the
      crucial balance between ATP and GTP or other nucleoside triphosphates. NDPKs are
      homo-oligomeric proteins and are predominantly localized in the cytosol. In this
      paper, we demonstrate that in Saccharomyces cerevisiae a small fraction of total
      NDPK activity encoded by YNK1 is present in the intermembrane space (IMS) of
      mitochondria, and the corresponding protein Ynk1p in the IMS represents approx.
      0.005% of total mitochondrial proteins. Ynk1p, synthesized as a single gene
      product, must therefore be partitioned between cytoplasm and mitochondrial IMS
      fractions. A mechanism for this partitioning is suggested by our observations
      that interaction with a 40 kDa protein of the translocase of outer mitochondrial
      membrane (Tom40p), occurs preferentially with unfolded, unphosphorylated forms of
      Ynk1p. A population of newly translated, but not yet folded or
      autophosphorylated, Ynk1p intermediates may be imported into the IMS of
      mitochondria and trapped there by subsequent folding and oligomerization. Within
      the small volume of the IMS, Ynk1p may be more concentrated and may be required
      to supply GTP to several important proteins in this compartment.

PMID- 12472467
TI  - Late Simian virus 40 transcription factor is a target of the phosphoinositide 3
      kinase/Akt pathway in anti-apoptotic Alzheimer's amyloid precursor protein
      signalling.
AB  - The association of familial Alzheimer's disease (FAD) with mutations in
      Alzheimer's amyloid precursor protein (APP) suggests important functions for APP
      in the central nervous system. Mutations in APP impair its function to confer
      resistance to apoptosis in cells under stress, and this may contribute to
      neurodegeneration in Alzheimer's disease (AD) brain, but the mechanisms involved
      are unknown. We examined the role of the late Simian virus 40 transcription
      factor (LSF), in anti-apoptotic APP pathways. We show that in APP-deficient B103
      cells, expression of wild-type human APP (hAPPwt), but not of FAD-mutant APP,
      inhibited staurosporine (STS)-induced apoptosis. This inhibition was further
      enhanced by expression of LSFwt, although LSFwt alone was not sufficient to
      inhibit STS-induced apoptosis. In contrast, expression of dominant-negative LSF
      led to a marked increase in STS-induced cell death that was significantly blocked
      by hAPPwt. These effects of APP were accompanied by LSF nuclear translocation and
      dependent gene transcription. The activation of LSF is dependent on the
      expression of hAPPwt and is inhibited by the expression of dominant-negative
      forms of either phosphoinositide 3-kinase or Akt. These results demonstrate that
      LSF activation is required for the neuroprotective effects of APP via
      phosphoinositide 3-kinase/Akt signalling. Alterations in this pathway by
      aberrations in APP and/or LSF could promote neuronal loss in AD brain, due to
      secondary insults. Thus a link is established between APP and LSF and AD.

PMID- 12472468
TI  - Hetero-oligomeric tagging diminishes non-specific aggregation of target proteins
      fused with Anthozoa fluorescent proteins.
AB  - The tendency for tetramerization is the main disadvantage in the green
      fluorescent protein homologues from Anthozoa species. We report a universal
      method called hetero-oligomeric tagging, which diminishes troublesome
      consequences of tetramerization of Anthozoa-derived fluorescent proteins (FP) in
      intracellular protein labelling. This approach is based on the co-expression of
      the FP-tagged protein of interest together with an excess of free non-fluorescent
      FP mutant. The resulting FP heterotetramers contain only a single target
      polypeptide and, therefore, can be considered pseudo-monomeric. Feasibility of
      the method has been demonstrated with a red FP fused with cytoplasmic beta-actin
      or tubulin-binding protein Tau34. In addition, heterotetramers appeared to be a
      unique model for biophysical characterization of Anthozoa FPs in pseudo-monomeric
      state.

PMID- 12472470
TI  - Changing role of in vivo models in columnar-lined lower esophagus.
AB  - Columnar-lined lower esophagus (CLE) or Barrett's esophagus (BE) is caused by
      chronic reflux of the gastrointestinal tract and can progress to invasive
      adenocarcinoma. However, the pathophysiology, cell of origin, and management of
      this condition is incompletely understood. This review evaluates the role of in
      vivo models in resolving these debates. A search was performed on the Ovid and
      Pub Medline for 1964-2001 and Cochrane Collaboration. The keywords used were
      adenocarcinoma, animal model, Barrett's esophagus, columnar-lined esophagus,
      esophageal neoplasms, and esophageal carcinogenesis. All relevant papers were
      scrutinized and an attempt at tabulation was made. In vivo models have been used
      at several stages of debate on the pathophysiology of BE. They provide conclusive
      evidence for its acquired nature secondary to duodenogastroesophageal reflux. The
      cell of origin of experimental BE may arise from adjacent columnar epithelium,
      basal layer multipotent cells, or esophageal glands. Experimental work on BE is
      lacking in assessing therapeutic modalities.

PMID- 12472471
TI  - Experimental esophageal carcinogenesis: technical standardization and results.
AB  - The aim of this research was to determine the occurrence of epidermoid carcinoma
      of the esophagus induced by diethylnitrosamine (DEN) in Wistar rats. DEN was
      administered (250-300 g) in drinking water (10 mg/kg body weight) to four groups
      of rats for 72 h/week, for a duration of 90, 120, 150, or 200 days (groups T90,
      T120, T150, and T200). Ten animals whose drinking water did not contain DEN
      constituted the control group. All rats were sacrificed and their esophaguses
      studied macro- and microscopically. The control group did not exhibit either
      carcinomas or preneoplasic lesions. The T120 and T200 groups presented,
      respectively, 47 and 58 in situ carcinomas; 1 and 20 submucosal carcinomas (P <
      0.05); 4 and 17 microinvasive carcinomas (P < 0.05); 4 and 11 advanced carcinomas
      (P < 0.05); and 1 and 1 cases of benign hyperplasia. Pulmonary and liver
      carcinomas were also found in the T200 group. The majority of advanced
      macroscopic lesions in the T200 group were polypoid, exophytic, and not
      microscopically invasive in the esophageal wall. This research confirms the
      effectiveness of the DEN in bringing about carcinogenesis in the Wistar rat
      esophagus and also shows that the lesions are dosage dependent.

PMID- 12472469
TI  - Thermodynamic characterization of yeast triosephosphate isomerase refolding:
      insights into the interplay between function and stability as reasons for the
      oligomeric nature of the enzyme.
AB  - The reasons underlying the oligomeric nature of some proteins such as
      triosephosphate isomerase (TIM) are unclear. It has been proposed that this
      enzyme is an oligomer, mainly because of its stability rather than for functional
      reasons. To address this issue, the reversible denaturation and renaturation of
      the homodimeric TIM from baker's yeast ( Saccharomyces cerevisiae ) induced by
      guanidinium chloride and urea have been characterized by spectroscopic,
      functional and hydrodynamic techniques. The unfolding and refolding of this
      enzyme are not coincident after 'conventional' equilibrium times. Unfolding
      experiments did not reach equilibrium, owing to a very slow dissociation and/or
      unfolding process. By contrast, equilibrium was reached in the refolding
      direction. The simplest equilibrium pathway compatible with the obtained data was
      found to be a three-state process involving an inactive and expanded monomer. The
      Gibbs energy changes for monomer folding (delta G (0)(fold) = -16.6+/-0.7 kJ x
      mol(-1)) and monomer association (delta G (0)(assoc) = -70.3+/-1.1 kJ x mol(-1))
      were calculated from data obtained in the two denaturants. From an analysis of
      the present data and data from the literature on the stability of TIM from
      different species and for other beta/alpha barrels, and model simulations on the
      effect of stability in the catalytic activity of the enzyme, it is concluded that
      the low stability of the monomers is neither the only, nor the main, cause for
      the dimeric nature of TIM. There is interplay between function and stability.

PMID- 12472472
TI  - Recurrent columnar-lined esophageal segments--study of the phenotypic
      characteristics using intestinal markers.
AB  - Barrett's metaplasia is recognized by specialized columnar epithelium on the
      distal esophagus. The events involved in the transformation from squamous to
      Barrett's epithelium remain unclear. The present study describes the
      characteristics observed during the recurrence of four cases of columnar-lined
      esophagus. Red velvet, gastric-like, esophageal mucosa was observed to develop
      above the anastomosis during follow-up of four patients submitted to surgery for
      esophageal and junctional adenocarcinoma. The areas of recurrence were associated
      with reflux symptoms and inflammation, with ulceration in two cases. Biopsies
      from the upper gastrointestinal endoscopies were examined histologically using
      periodic acid-Schiff/Alcian blue to detect acid mucins and a monoclonal antibody
      raised against the enterocytic enzyme sucrase-isomaltase. In all cases the
      recurrent columnar-lined segments displayed intestinal features recognized
      morphologically, histochemically, and/or immunohistochemically. There was no
      evidence of specialized columnar epithelium in three cases. The fourth patient
      developed specialized columnar epithelium during the tenth year of surveillance.
      The presence of AB-positive columnar cells was a frequent and early event.
      Columnar cells with unequivocal apical sucrase-isomaltase were observed only in
      association with specialized columnar epithelium. Four conclusions were reached:
      that the development of columnar-lined mucosa without specialized columnar
      epithelium may be the earliest event in Barrett's metaplasia; that histochemistry
      is a useful method of recognizing a population with cryptic intestinal features;
      that acid mucin secretion precedes the production of enterocytic enzymes by
      columnar cells; and that a cell population with enterocytic differentiation, as
      assessed by sucrase-isomaltase expression, is associated with the development of
      specialized columnar epithelium. These characteristics of Barrett's esophagus
      development are clinically relevant as they suggest that patients with columnar
      lined esophagus without specialized columnar epithelium may acquire 'true'
      intestinal phenotype, justifying them being considered as high- risk patients.

PMID- 12472473
TI  - Adenocarcinoma of the esophagogastric junction: could the characteristics of
      adjacent intestinal metaplasia help in the understanding of biopathogenesis?
AB  - We report a case of early adenocarcinoma arising in foci of intestinal metaplasia
      (IM) at a normal-appearing gastroesophageal junction (GEJ). The tumor infiltrated
      the submucosa without nodal involvement (T1N0). Non-neoplastic mucosa adjacent to
      neoplasia had foci of incomplete IM with a band-like CK20 positivity of the
      surface epithelium and a diffuse CK7 staining of both superficial and deep
      glands. There were histological features of reflux esophagitis as well as chronic
      non-atrophic, Helicobacter pylori-related pangastritis, without IM, at the
      extensively assessed gastric mucosa. In this case, the CK7/20 pattern of IM
      adjacent to neoplasia, the demonstration of reflux esophagitis, and the absence
      of IM in the stomach favor the theory that the pathogenesis of IM and associated
      adenocarcinoma of the GEJ is related to gastroesophageal reflux rather than H.
      pylori infection.

PMID- 12472474
TI  - Squamous cell carcinoma and adenocarcinoma of the lower third of the esophagus
      and gastric cardia: similarities and differences.
AB  - Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the lower esophagus and
      gastric cardia were compared in their clinical features and long-term prognosis.
      Two hundred and ninety-five patients with SCC and 263 with ADC were reviewed.
      Resectability rates for SCC and ADC were 74.2% and 73.2% respectively (P=0.8).
      Among those who underwent resection, ADC was more advanced, with 22.3% at stage
      IV compared with 7.4% for SCC (P=0.001). Postoperative cardiac events occurred in
      24.2% of SCC patients and 14.7% of ADC patients (P=0.015), and major respiratory
      complications in 20.1% and 8.6% respectively (P=0.001). Thirty-day mortality
      rates were 2.7% and 4% (P=0.46), and hospital mortality rates were 11.4% and 7.6%
      (P=0.19). Median survival rates were 12.5 months for SCC and 11.6 months for ADC
      (P=0.99) and 5-year survival rates were 19.9% and 17.6% (P=0.55) respectively.
      Squamous cell carcinoma of the lower esophagus and ADC of the cardia differed in
      patient demographics and clinical features but long-term prognoses were similar.

PMID- 12472475
TI  - Evolution and critical appraisal of anastomotic technique following resection of
      esophageal adenocarcinoma.
AB  - The aim of this study was to critically evaluate acute and long-term
      complications of hand-sewn and semimechanical cervical esophagogastric
      anastomosis following resection of primary esophageal adenocarcinoma. Between
      February 1991 and 2001, 91 consecutive patients underwent subtotal esophagectomy
      (transthoracic, n=49; transhiatal, n=42), transposing a gastric tube based on the
      right gastroepiploic artery. All esophagogastric anastomoses were performed in
      the left neck using a hand-sewn technique (n=53) and, from September 1997, a side
      to-side semimechanical technique (n=38). Outcomes evaluated were anastomotic leak
      rates, length of stay, and development of strictures. Postoperative mortality was
      4.4% (all cardiopulmonary causes). Fifty-eight patients (63.7%) had an
      uncomplicated postoperative course, with a median postoperative length of stay of
      10 days (vs. 20 days with associated morbidity; P </= 0.001). Anastomotic leaks
      were the leading cause of postoperative morbidity (16.5%, 15/91), and were
      classified into four types based on severity. The semimechanical anastomotic
      technique was associated with a reduced leak rate compared with the hand-sewn
      technique (7.9%, 3/38 vs. 22.6%, 12/53; P=0.08), although different patterns of
      anastomotic failure were seen following semimechanical anastomoses, with
      increased mediastinal and pleural sepsis. Anastomotic strictures developed in
      nine (17.0%) hand-sewn and three (7.9%) semimechanical anastomoses. Our
      conclusion was that a semimechanical technique for cervical esophagogastrostomy
      is associated with reduced anastomotic leak rates compared with hand-sewn
      anastomoses, resulting in a shorter postoperative stay. Patterns of anastomotic
      failure varied between each technique, possibly as a consequence of a longer
      cervical esophageal segment required for construction of a semimechanical
      anastomosis. The association between anastomotic technique and stricture
      development was not clear from this study.

PMID- 12472476
TI  - Modified stapling technique of esophagojejunal anastomosis.
AB  - The most dangerous complication of total gastrectomy, often causing postoperative
      death, is dehiscence of esophagojejunal anastomosis. After analyzing more then
      300 patients undergoing surgery for gastric and/or cardiac carcinoma at our
      department in the period 1992-96, we concluded that the main cause of anastomotic
      dehiscence was a technically insufficient anastomosis, and the main risk factor
      was hypertrophied muscular layer of the esophagus (predominantly in advanced
      cardiac carcinoma). In this paper we discuss indications for, and the surgical
      technique of, our own modification of mechanical esophagojejunal anastomosis. In
      the period between 1 January 1997 and 1 March 2001, 148 procedures were performed
      using the modified anastomotic technique. In only two patients (1.35%) were
      radiological signs of small anastomotic leakage observed. The described
      modification of mechanical esophagojejunal anastomosis is safe and is not a time
      consuming procedure. It is highly recommended in the treatment of the obstructive
      cardiac carcinoma with a compensatory hypertrophied muscular layer of the
      esophagus.

PMID- 12472477
TI  - Vigorous achalasia in Chagas' disease.
AB  - The study investigated the esophageal motility of 98 patients with Chagas'
      disease and 40 asymptomatic volunteers, with the objective of comparing patients
      with vigorous achalasia (distal amplitude contractions >/= 37 mmHg) and patients
      with classical achalasia (amplitude < 37 mmHg). The Chagas' disease patients had
      normal esophageal radiologic transit (n=60) or esophageal slow transit and
      retention without dilation (n=38). The manometric method with continuous
      perfusion was used to study esophageal motility. Comparison of classical and
      vigorous achalasia showed no difference in duration of contractions, lower and
      upper esophageal sphincter pressure, proportion of patients with dysphagia, or
      the number of multipeaked contractions. The number of failed contractions was
      higher in patients with classic achalasia than in patients with vigorous
      achalasia. We conclude that the distinction between classical and vigorous
      achalasia does not seem to be important for the classification of Chagas'
      disease.

PMID- 12472478
TI  - Laparoscopic fundoplication for patients with symptoms but no objective evidence
      of gastroesophageal reflux.
AB  - In general terms, all patients who undergo a laparoscopic fundoplication
      procedure should have objective evidence of gastroesophageal reflux. However,
      occasionally patients without objective evidence of reflux disease are referred
      for surgery. This study assessed the outcome of a highly selected group of
      patients who underwent laparoscopic fundoplication without objective evidence of
      reflux at either preoperative endoscopy or pH monitoring. Data from all patients
      undergoing laparoscopic fundoplication in our department over a 9-year period
      from December 1991 to January 2001 were collected prospectively. From a total of
      1,003 patients, a subgroup of 15 patients was identified who had no evidence of
      ulcerative oesophagitis at endoscopy or abnormal reflux on 24-h pH monitoring.
      Eight of these patients had typical symptoms of reflux (four had predominantly
      heartburn, four had predominantly volume regurgitation) and seven patients had
      atypical symptoms such as cough, bloating, chest pain, or sore throat. All
      patients had tried medication for acid suppression before surgery, with five
      gaining little or no benefit. The mean acid exposure time was 2% (range 0.1
      3.6%). A correlation between typical symptoms and reflux events of over 50% was
      noted in three patients. All patients underwent laparoscopic fundoplication, with
      one conversion to an open procedure. Mean patient satisfaction score (0-10 linear
      score) was 8.7 at 3 months and 1 year postoperatively. Three patients failed to
      improve following surgery. These three all had atypical symptoms, a symptom
      correlation of less than 50% with acid reflux on pH monitoring, and two of the
      three had a poor response to medication. All other patients benefited
      symptomatically from surgery. We concluded that the absence of objective evidence
      of reflux should not always preclude patients from a laparoscopic fundoplication.
      Carefully selected patients with typical reflux symptoms can have a good outcome.
      However, patients who do not have typical symptoms and who respond poorly to acid
      suppression are not likely to benefit from surgery.

PMID- 12472479
TI  - Results of surgical treatment for recurrent postoperative gastroesophageal
      reflux.
AB  - The rate of recurrence of reflux esophagitis after classic antireflux surgery
      (fundoplication) is 10-15%. This rate is different in patients with esophagitis
      with and without Barrett's esophagus. We evaluated the clinical and laboratory
      findings in 104 patients with postoperative recurrent reflux esophagitis,
      determining the results of repeat antireflux surgery or an acid suppression-bile
      diversion procedure. Repeat fundoplication was performed in 26 patients, and
      truncal vagotomy, antrectomy, and Roux-en-Y gastrojejunostomy in 78 patients.
      Esophagectomy as a third operation was performed in seven patients. After repeat
      antireflux surgery, endoscopic evaluation demonstrated improvement of esophagitis
      in a small proportion of patients. Barrett's esophagus remained unchanged, and no
      regression of ulcer or stricture was observed. These complications improved
      significantly after acid suppression-bile diversion surgery. Incompetent lower
      esophageal sphincter (LES) was present in 55.8% after initial surgery and in 23%
      after reoperation. Acid reflux, initially present in 94.6% of patients, was also
      observed in 93.6% after fundoplication, 68.8% after redo fundoplication, and
      16.6% after treatment with the acid suppression-bile diversion technique. A
      positive Bilitec test was present in 78% of patients before the operation and
      56.6% after the repeat operation, and was negative after bile diversion surgery.
      Among 13 patients (50%) submitted to repeat surgery alone, esophagectomy as a
      third operation was necessary as a result of severe non-dilatable stricture in
      seven patients. Our conclusions are that repeat antireflux surgery alone failed
      to improve Barrett's esophagus complications and that the best results were
      obtained in patients submitted to acid suppression-bile diversion surgery.

PMID- 12472480
TI  - Laparoscopic transhiatal resection of epiphrenic diverticulum.
AB  - Our experience with videolaparoscopic operations for hiatus hernia and achalasia,
      which have almost replaced classical procedures, enabled us to use the same
      technique for other interventions in the distal third of the thoracic esophagus.
      Thus, we were able to treat epiphrenic diverticulum using a minimally invasive
      approach. We report our experience with videolaparoscopic diverticulum resection.
      The procedure was performed in three patients, all of them elderly men with
      ventilation limitation and a history of a chest intervention. The procedure
      included myotomy and an antireflux procedure. No significant complications
      occurred during the operations or postoperative periods; a minor leak that was
      successfully managed conservatively occurred in one patient. We conclude that
      videolaparoscopy could be a possible alternative to the standard classical left
      side thoracotomy approach for patients in whom a classical operation is not
      feasible.

PMID- 12472481
TI  - Rare case of inflammatory fibrous polyp of the esophagus.
AB  - Esophageal inflammatory fibrous polyps are extremely rare benign neoplasms. The
      manuscript illustrates a case of a man complaining of pyrosis and
      gastroesophageal reflux symptoms. Diagnostic work-up showed an expansive lesion
      of the distal esophagus simulating malignancy but with negative, repeated,
      multiple biopsies. The considerable size of the lesion, and the suspicion of a
      malignant tumor because of the presence of ulceration, indicated esophagectomy
      with extensive lymphadenectomy and intrathoracic esophagogastroplasty. The
      diagnosis of inflammatory polyp of the esophagus was achieved postoperatively.
      The Discussion deals with a review of the literature and considers the performed
      operation a good choice considering the hypothesis of a malign neoplastic
      evolution of this lesion.

PMID- 12472482
TI  - Two cases of steakhouse syndrome associated with nutcracker esophagus.
AB  - The most common type of esophageal food-related foreign body is the meat bolus,
      which is frequently associated with underlying esophageal stenosis. Herein, we
      report two cases of meat bolus impaction associated with nutcracker esophagus. In
      the first case, the 63-year-old male patient had chest discomfort and swallowing
      difficulty after ingestion of butcher's meat. In the second case, the 55-year-old
      male patient had complained of swallowing difficulty after ingestion of chicken.
      In both cases, no pathologic findings were observed endoscopically after removal
      of the esophageal meat bolus. We performed esophageal manometry, which showed
      very high amplitudes of esophageal pressure in the mid- and distal esophagus.
      These findings were consistent with nutcracker esophagus. These cases show that
      esophageal motility disorder may be the cause of esophageal foreign body
      impaction, and esophageal manometry should be performed for evaluation of the
      cause of foreign body, especially in an endoscopically normal patient.

PMID- 12472483
TI  - Paget's disease of the esophagus.
AB  - We describe the case of a 72-year-old male patient who was suffering from
      Pagetoid spread to the esophageal mucosa from adenocarcinoma located in the
      distal esophagus and proximal stomach. Esophageal Paget's disease is rare. The
      histogenesis of extramammary Paget's disease has remained controversial. In the
      majority of cases, it originates from a primary esophageal tumor. In this report,
      we describe a patient who was suffering from esophageal adenocarcinoma and
      discuss the origin of extramammary Paget's disease in the light of the
      literature.

PMID- 12472484
TI  - Adult case of squamous cell carcinoma arising on congenital esophageal stenosis
      due to fibromuscular hypertrophy.
AB  - This study relates to an adult case of squamous cell carcinoma arising on
      congenital esophageal stenosis. The patient was a 65-year-old man who had
      suffered from dysphagia and vomiting since birth and was diagnosed as having
      congenital esophageal stenosis. The patient had not received any treatment
      because his symptoms were mild. The patients suffered from severe dysphagia since
      he was 20 years old and had received balloon therapies several times; however,
      the effects were transient. After admission to our hospital, he underwent a
      transhiatal esophagectomy without thoracotomy. Histopathological examination of
      the resected specimen revealed a thick muscular mucosae associated with
      hypertrophic fibromuscular components and poorly to moderately differentiated
      squamous cell carcinoma in the region of stenosis. This case report is the first
      of a patient with squamous cell carcinoma arising on congenital esophageal
      stenosis.

PMID- 12472485
TI  - Cervical esophageal perforation with severe mediastinitis due to an impacted
      dental prosthesis.
AB  - We herein report about a case of perforation of the cervical esophagus by an
      artificial denture, which had been swallowed by the patient after a horse-related
      injury. Impactation of the foreign body at the level of the upper esophageal
      sphincter was followed by its penetration through the esophageal wall, causing
      severe infection of the cervical soft tissue, mediastinitis and sepsis. We
      discuss the well-known phenomena of prosthesis ingestion and frequently delayed
      diagnosis, as well as our treatment strategy of cervical esophageal perforation
      with placement of a T-tube into the cervical esophagus and mediastinal drainage.

PMID- 12472487
TI  - Modulating diseased skin with tissue engineering: actinic purpura treated with
      Apligraf.
AB  - BACKGROUND: Actinic purpura (AP) is an important medical issue and quality of
      life issue in the elderly. Current treatment of AP is limited to prevention of
      cutaneous aging. OBJECTIVE: To assess the utility of tissue engineered skin
      (Apligraf, Organogenesis, Canton, MA) as a tissue modulator in diseased skin and
      as treatment for AP. METHODS: A thin partial-thickness section of AP was removed
      from the forearm of an elderly gentleman and replaced with fenestrated Apligraf.
      Healing, durability and cosmetic outcome were assessed. RESULTS: Apligraf-treated
      skin healed rapidly with good clinical "take." Lack of new skin tears and
      resultant erosions or ulcer formation suggests improved durability of the
      Apligraf-treated area occurred. CONCLUSION: These results suggest that tissue
      engineered skin modulates aged dermal tissue to behave in a more sturdy fashion.
      Furthermore, in selected cases Apligraf may represent a treatment option for AP.

PMID- 12472489
TI  - Rejuvenation of photoaged skin: 5 years results with intense pulsed light of the
      face, neck, and chest.
AB  - BACKGROUND: Photorejuvenation involves the use of lasers or light sources to
      reverse signs of photoaging. Multiple devices have been shown to be effective
      over the short-term. OBJECTIVE: To investigate the long-term clinical results on
      the face, neck and chest at 4 years using filtered flashlamp intense pulsed light
      (IPL) for treatment of photoaging changes of telangiectasias, dyspigmentation,
      and rough skin texture. METHODS: A chart review of 80 randomly selected patients
      with skin types I-IV who were treated by IPL during 1996 and 1997 was performed.
      Photos and patient self-assessment were graded for features of textural
      smoothness, telangiectasia severity, and blotchy pigmentation into four
      categories of worse, no change, slightly better (less than 50% improvement) and
      much better (greater than 50% improvement). RESULTS: At 4 years following initial
      treatment, skin textural improvement was noted in 83% of the subjects.
      Telangiectasias were improved in 82% of subjects, while pigmentation remained
      improved in 79%. The median number of treatments was 3. The face responded
      slightly better than the chest or neck. Most common side-effects included
      temporary mild crusting (19%), erythema (15%) and purpura (6%). CONCLUSION: Signs
      of photoaging including telangiectasias and mottled pigmentation of the face,
      neck, and chest, can be improved by IPL with a long-lasting result. Minimal or no
      downtime with minimal adverse effects can be achieved with the settings reported.
      Skin textural smoothing, although not easily quantified, is an additional benefit
      observed long-term.

PMID- 12472488
TI  - Evaluation of tissue-engineered skin (human skin substitute) and secondary
      intention healing in the treatment of full thickness wounds after Mohs
      micrographic or excisional surgery.
AB  - BACKGROUND: Human Skin Substitute (Apligraf, Organogenesis, Inc., Canton, MA) is
      a bi-layered tissue-engineered living biological dressing developed from neonatal
      foreskin. It consists of a bovine collagen matrix containing human fibroblasts
      with an overlying sheet of stratified human epithelium containing living human
      keratinocytes. Human Skin Substitute (HSS) appears to be immunologically inert,
      and has shown usefulness in the treatment of chronic and acute wounds. OBJECTIVE:
      Primary objectives were to evaluate the safety and efficacy of HSS in the
      treatment of full-thickness wounds in a prospective case series. Secondary
      objectives were to determine the rate of complete wound reepithelialization,
      incidence of complete wound healing, pain at wound site, overall cosmetic
      outcome, and patient satisfaction. METHODS: Fourteen patients were enrolled in
      the study, of which 12 were evaluable. HSS was applied in a blinded fashion to 6
      of the patients immediately following Mohs or excisional surgery for skin cancer.
      The remaining 6 patients were allowed to heal by secondary intention. Both groups
      were evaluated at weekly appointments until complete reepithelialization
      occurred. During each evaluation, wound quality was assessed through the
      Vancouver Burn Scar Assessment Scale by the investigator and an independent
      blinded dermatologist. The investigator, blinded observer, and patient further
      evaluated the cosmetic outcome of the wound through the use of a Visual Analog
      Scale over a 6-month period. RESULTS: HSS patients and secondary intention
      patients were equivalent in comorbid factors such as pain, erythema, edema,
      exudate, infection, or hematoma between the groups. The incidence of complete
      wound healing at 6 months was 100% for both groups. Both groups also appeared to
      heal at similar rates, as defined by the complete reepithelialization of the
      wound. HSS patients ultimately resulted in more pliable and less vascular wounds
      as defined by the Vancouver Burn Scar Assessment Scale. Patient satisfaction with
      cosmetic outcome in both groups was positive at 6 months. CONCLUSIONS: HSS
      appears to be a safe, well-tolerated biological dressing with equivalent comorbid
      factors to secondary intention healing. HSS, however, seems to produce a more
      pliable and less vascular scar than those developed through healing by secondary
      intention. HSS also appears to produce more satisfactory cosmetic results when
      compared to secondary intention healing.

PMID- 12472490
TI  - The effect of combination treatment of the recalcitrant pigmentary disorders with
      pigmented laser and chemical peeling.
AB  - BACKGROUND: The pigmentary disorders including melasma, freckles,
      postinflammatory hyperpigmentation, or acquired bilateral nevus of Ota-like
      macules, etc. are usually resistant to all treatment modalities, and are
      therefore very frustrating to the patient and clinician. OBJECTIVE: The purpose
      of this study was to demonstrate the effect of the combination treatment of
      recalcitrant pigmentary disorders with pigmented laser and chemical peeling and
      to observe any side-effects. METHODS: Twenty-four patients with recalcitrant
      facial pigmentary disorders were treated with the Q-switched alexandrite laser at
      fluences of 7.0-8.0 J/cm2 or the pigmented lesion dye laser (PLDL) at fluences of
      2.0-2.5 J/cm2, and at the same session, 15-25% trichloroactic acid (TCA) with or
      without Jessner's solution were used for the chemical peeling. And the results
      were clinically analyzed. RESULTS: In the assessment by the patients, 63% of them
      considered the result as "clear, excellent, or good" in respect to the color and
      54% of them assessed that the size of the lesion had cleared more than 50%. In
      the assessment by a clinician, 67% of the patients were categorized into the
      grade of clear, excellent, or good. There were no significant complications with
      this combination method. CONCLUSIONS: The combination treatment with pigmented
      laser and chemical peeling is effective, safe, and relatively inexpensive
      treatment modalities in the recalcitrant pigmentary disorders.

PMID- 12472491
TI  - Intense pulsed light in the treatment of striae distensae.
AB  - BACKGROUND: Intense Pulsed Light (IPL) is a noncoherent, nonlaser, filtered
      flashlamp, emitting a broadband visible light. Its efficacy has been reported
      recently in the treatment of photodamaged facial skin, promoting the production
      of neo collagen and ordering of elastic fibers. We don't know however, its
      efficacy in the treatment of striae distensae. OBJECTIVE: To assess gross and
      microscopical changes that occur in the striae distensae when treated by IPL.
      METHODS: A prospective study was carried out in 15 women, all of them having late
      stage striae distensae of the abdomen. Five sessions of IPL were performed in
      each one, once every two weeks. Skin biopsies and before and after photographs
      were taken of all the patients. Data concerning skin features (number of stretch
      marks in a square of 5 cm per side, sum of all the stretch marks to determine the
      total length, discolorations and general appearance) were all assessed before
      each session and at the end of the study. Microscopical changes were all
      carefully assessed. For the statistical analysis a "t" test for small samples was
      used. RESULTS: All patients showed clinical and microscopical improvement in each
      one of the parameters assessed. The "t" test for small samples showed a
      statistically significative difference (p < 0.01) in the post treatment dermal
      thickness. CONCLUSION: Striae distensae improved clinically and microscopically
      after IPL. It seems to be a promising method of treatment for this common problem
      with minimal side-effects, a wide safety margin and no downtime.

PMID- 12472492
TI  - Side-effects after IPL photodepilation.
AB  - BACKGROUND: Intense pulsed light (IPL) has been successfully used as an efficient
      hair removal system; however, possible side-effects have been not specifically
      addressed in the literature. OBJECTIVE: To assess all possible side-effects after
      IPL hair removal in a series of 49 females with facial hirsutism during a total
      of 390 treatment sessions of IPL photodepilation. METHODS: Immediate post
      treatment clinical, photography evaluation, and a two-month post-treatment
      questionnaire were done in 49 females with facial hirsutism submitted to
      photodepilation with an IPL source (EpiLight trade mark, ESC, Israel). RESULTS:
      Side-effects observed were: transient erythema (n = 30), late evanescent erythema
      (n = 3), mild pain (n = 43), moderate pain (n = 6), crust formation (n = 9),
      superficial burning (n = 1), isolated vesicles (n = 3), transient
      hyperpigmentation (n = 8), transient hypopigmentation (n = 1), paradoxical effect
      (n = 5), persistent local heat sensation (n = 1), and minimal scar (n = 1).
      CONCLUSION: Even though common, most side-effects secondary to IPL
      photodepilation are mild and transient. Permanent side-effects such as scars are
      unlikely but they may occur. Growth of new, fine and dark hair may be seen in
      untreated areas in close proximity to the treatment area, especially in the neck,
      a side-effect that is reported for the first time in the literature.

PMID- 12472493
TI  - A new foam girdle for the significant reduction of ecchymoses post-liposuction.
AB  - BACKGROUND: Reston foam (3M, St. Paul, MN) has been used in the past for the
      reduction of ecchymoses postliposuction surgery. The application of this
      modality, however, can cause allergic dermatitis, bullae formation and
      postinflammatory hyper-pigmentation, and it takes approximately 30 minutes to
      apply. OBJECTIVE: To develop a girdle that protects the skin from the
      aforementioned problems while incorporating the concepts of foam compression.
      METHODS: A garment was developed that incorporates foam into a lycra covering.
      Velcro straps are placed throughout the entire length of the girdle so that the
      surgeon can adjust the pressure according to specific needs. This garment is kept
      on for two to three days. RESULTS: No cases of allergic dermatitis, bullae
      formation or postinflammatory pigmentations were found with using this garment in
      over 800 cases. CONCLUSION: In most cases, Reston foam is a good adjunct to
      liposuction surgery. However, it can occasionally cause allergic dermatitis,
      bullae formation or postinflammatory hyper-pigmentation and can take an
      inordinately long time to apply. The author presents a new garment that
      incorporates the foam into a lycra covering that includes velcro-adjustable
      straps along the entire length of the girdle. This garment has not caused the
      aforementioned problems of dermatitis, bullae formation or postinflammatory hyper
      pigmentation in over 800 cases.

PMID- 12472494
TI  - Recurrence rates of primary nonmelanoma skin cancers treated by surgical excision
      compared to electrodesiccation-curettage in a private dermatological practice.
AB  - BACKGROUND: The incidence of nonmelanoma skin cancer, the most common form of
      cancer in the United States, continues to increase. It is important that
      physicians know what treatment modalities will be the most efficacious.
      OBJECTIVE: The purpose of this study was to compare recurrence rates by treatment
      modality for primary basal and squamous cell carcinomas in a private
      dermatological practice. METHODS: Between June 1993 and December 1994, 268
      consecutive primary nonmelanomic tumors were treated by surgical excision or
      electrodesiccation and curettage in our practice. The charts of the 191 patients
      treated were retrospectively reviewed, and recurrence data were compared by
      treatment modality. RESULTS: The recurrence rates between the two types of
      treatment were not found to be significantly different. CONCLUSION: In contrast
      to other studies reported from academic centers in which surgical excision has
      been found to have lower recurrence rates than tumors treated with curettage and
      electrodesiccation, this study found recurrence rates for two treatments to be
      approximately the same.

PMID- 12472495
TI  - Dietary factors in the prevention and treatment of nonmelanoma skin cancer and
      melanoma.
AB  - BACKGROUND: The endogenous antioxidant system of the skin scavenges reactive
      oxygen species and combats ultraviolet induced oxidative skin damage. Supporting
      this cutaneous defense system with topical or oral antioxidants may provide a
      successful strategy for the treatment and prevention of skin cancer. OBJECTIVE:
      Review evidence regarding treatment and prevention of melanoma and nonmelanoma
      skin cancers through dietary and topical antioxidants, vitamins, and herbal
      supplements. METHODS: Literature review. RESULTS: Review of the literature
      demonstrates that the administration of synthetic retinoids has not proved
      beneficial for otherwise healthy patients with nonmelanoma skin cancer. Selenium
      supplementation has reduced the incidence of several internal malignancies but
      not of nonmelanoma skin cancer. Synergistic use of beta-carotene with vitamins C
      and E has demonstrated prophylaxis against reactive oxygen radicals involved in
      nonmelanoma skin cancer and reduced sunburn reactions significantly. 1,25
      dihydroxyvitamin D3 analog CB1093 has demonstrated promise as a therapeutic agent
      in the regression of the early stages of melanoma in specific cell lines.
      CONCLUSION: Delivery of exogenous antioxidants in combination appears to be a
      more successful strategy for enhancing the cutaneous antioxidant system than the
      administration of isolated antioxidants alone. Vitamin D analogs may have a role
      in the medical therapy of melanoma. However, avoiding exposure to ultraviolet
      light appears to be the only true panacea against the development of melanoma and
      NMSC.

PMID- 12472496
TI  - Cosmetic color improvement of the nipple-areola complex by optimal use of
      tretinoin and hydroquinone.
AB  - BACKGROUND: A successful treatment to improve the color of nipple-areola complex
      (NAC) has never been reported, although the number of women seeking the more
      attractively colored NAC is not small. OBJECTIVE: To determine the effectiveness
      of our bleaching protocol for cosmetic improvement of the NAC. METHODS: The
      protocol was composed of two phases: bleaching phase (4-8 weeks) and healing
      phase (4-6 weeks). 0.2-0.4% tretinoin aqueous gel was applied concomitantly with
      5% hydroquinone, 7% lactic acid ointment for bleaching twice a day. Tretinoin was
      applied to the NAC with a small cotton applicator, while hydroquinone was widely
      applied beyond the NAC area. After obtaining sufficient improvement in NAC color,
      the application of tretinoin was discontinued and hydroquinone alone was
      continually applied in the healing phase until the reactive erythema was
      eliminated. Fifteen female patients were involved in this study. RESULTS: The
      average treatment period was 16.6 weeks. Improvement of NAC color was obtained in
      12 patients (80%) by the physician's estimation, and 11 patients (73%) satisfied
      with their final results. The treatment was repeated after a 1-month interval of
      tretinoin application in 4 patients: 2 desired further improvement in color, and
      2 had the second course conducted to treat the postinflammatory hyperpigmentation
      on the surrounding mound induced by the first course. CONCLUSION: This approach
      appeared to be most effective for cosmetic improvement of NAC color among
      treatments available so far.

PMID- 12472497
TI  - Dermatologic surgery and the Federal Anti-Kickback statute.

PMID- 12472498
TI  - Burow's wedge advancement flaps for reconstruction of adjacent surgical defects.

PMID- 12472499
TI  - Repair of a conchal bowl defect extending through the conchal cartilage.

PMID- 12472500
TI  - Mohs micrographic surgery of a papillary eccrine adenoma.
AB  - BACKGROUND: Papillary eccrine adenoma (PEA) is a rare benign sweat gland neoplasm
      first described by Rulon and Helwig in 1977. Although these lesions typically
      behave in a benign fashion, PEA's on the volar surfaces may demonstrate more
      aggressive biologic behavior. Additionally, aggressive digital papillary adenomas
      (ADPA) may histologically simulate PEAs and behave in a more malignant fashion.
      OBJECTIVE: To present a case report of a patient with an incompletely excised PEA
      that was successfully extirpated using Mohs micrographic surgery (MMS). METHODS:
      A 51-year-old black woman was evaluated for the treatment of an incompletely
      excised PEA located on the dorsum of her left hand at the base of the thumb. Mohs
      micrographic surgery was felt to be the ideal treatment choice because of
      incomplete prior resections, ill-defined clinical borders, the need for
      conservative surgical excision to preserve sensory and motor function of the left
      hand, and the previously reported more aggressive nature of this tumor when
      located on volar surfaces. The patient underwent a two-stage, six section
      micrographically controlled excision using the fresh tissue technique. RESULTS:
      Complete resection of the PEA without significant damage to neurovascular
      structures. CONCLUSION: This case demonstrates the increasingly important role
      MMS is playing in the surgical management of a wide variety of cutaneous tumors.
      To our knowledge, this is the first time MMS has been used in the resection of a
      PEA.

PMID- 12472501
TI  - Skin allograft in the treatment of toxic epidermal necrolysis (TEN).
AB  - BACKGROUND: TEN is a severe form of exfoliative dermatitis. Its course is acute
      and its outcome fatal in 40% of cases. Wound cover to prevent fluid/protein loss
      and infections and to control pain, is the first step, as for burns. Skin
      allograft can be successfully used for this purpose. OBJECTIVE: We report two
      cases of TEN with de-epithelialization of 50 and 70% of the total body surface
      area. The patients were given support therapy and treated with human glycerol
      preserved skin allografts for wound cover. METHODS: Patients were grafted with
      glycerol-preserved donor skin, obtained from a skin bank. RESULTS: Re
      epithelization of treated areas was complete in 8 days; pain relief was obtained
      soon after the graft. CONCLUSIONS: Glycerol-preserved skin allograft is an
      effective treatment in extensive skin loss, for its barrier and analgesic effect.
      Quality standards of this product ensure safety and simplicity of use at limited
      cost.

PMID- 12472502
TI  - Successful treatment of multiple bursal cysts in systemic sclerosis.
AB  - BACKGROUND: Bursitis frequently occurs in the various conditions of autoimmune
      disorders including rheumatoid arthritis, but there have been few cases of
      effusive bursitis in systemic sclerosis. OBJECTIVE: To present a case of systemic
      sclerosis with multiple bursitis on upper, lower extremities, and trunk with or
      without joint involvement. METHODS: Case report and review of the literature.
      RESULTS: Multiple asymptomatic cystic masses contained yellow and chalky sterile
      fluid, all of which were diagnosed as effusive bursitis. Most of them were
      treated with a surgical resection, a continuous drainage, and an injection of
      highly concentrated ethanol into their internal spaces. However, an intrabursal
      injection of emulsified triamcinolone acetonide was the only effective treatment
      for the giant mass that occurred on the right chest wall. CONCLUSION: Successful
      treatment of multiple bursal cysts with systemic sclerosis was presented.

PMID- 12472503
TI  - Treatment of an amalgam tattoo with a Q-switched alexandrite (755 nm) laser.
AB  - BACKGROUND: Amalgam tattoos result from deposition of metallic particles (eg,
      silver, mercury, copper, zinc, and tin) into the oral mucosa. Their clinical and
      histologic appearance is similar to that of decorative tattoos. OBJECTIVE: To
      describe the successful use of a Q-switched alexandrite laser for removal of an
      amalgam tattoo. MATERIALS AND METHODS: An amalgam tattoo on the buccal mucosa and
      gingiva was treated with a QS 755 nm alexandrite laser. Three treatments were
      delivered at 8-week time intervals (average fluence = 6.8 J/cm2). RESULTS:
      Significant lightening of the tattoo was achieved after each of the three
      treatments without adverse sequelae. CONCLUSION: Q-switched alexandrite laser
      irradiation can safely and effectively eradicate amalgam tattoos.

PMID- 12472504
TI  - Pigmented Spitz nevi.

PMID- 12472505
TI  - Should dermatologic surgeons discontinue hormonal therapy prior to tumescent
      liposuction?

PMID- 12472507
TI  - Local anesthesia in hair transplant surgery.

PMID- 12472508
TI  - Integrity in medical research and publication.

PMID- 12472509
TI  - The Epley manoeuvre for benign paroxysmal positional vertigo--a systematic
      review.
AB  - Benign paroxysmal positional vertigo (BPPV) is a syndrome characterized by short
      lived episodes of vertigo in association with rapid changes in head position.
      Current treatment approaches include rehabilitative exercises and physical
      manoeuvres including the Epley manouevre. Randomized clinical trials of the Epley
      manoeuvre were identified. Outcome measures that were considered include:
      frequency and severity of attacks of vertigo; proportion of patients improved by
      each intervention; and conversion of a 'positive' Dix-Hallpike test to a
      'negative' Dix-Hallpike test. Patients who received the Epley manoeuvre were more
      likely to have complete resolution of their symptoms [odds ratio 4.92 (95% C.I.
      1.84-13.16)], and more likely to convert from a positive to negative Dix-Hallpike
      test [odds ratio 5.67 (95% C.I. 2.21-14.56)]. There were no serious adverse
      effects of treatment. There is some evidence that the Epley manouevre is a safe
      effective treatment for posterior canal BPPV.

PMID- 12472510
TI  - Combating bacterial resistance in otorhinolaryngology.
AB  - Bacterial resistance appears to be an ever-increasing problem and is threatening
      to spiral out of control. The scare caused by the rapid spread of methicillin
      resistant Staphylococcus aureus among hospitals in the UK is the most recent.
      Otorhinolaryngology is deeply involved in this problem, as one of the reasons
      often cited for increasing bacterial resistance is the use of antibiotics in
      suspected bacterial infections in ear, nose and throat by primary care
      physicians. This speciality is also involved in the development of guidelines for
      antimicrobial use by primary and secondary care. This review attempts to discuss
      the reason for the development of antimicrobial resistance especially in relation
      to otorhinolaryngology, what can be done to contain this menace and the
      surveillance system developed to monitor the trend in the development of
      bacterial resistance.

PMID- 12472511
TI  - 11Beta-hydroxysteroid dehydrogenase 1 expression in squamous cell carcinomas of
      the head and neck.
AB  - 11Beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been identified as a
      major detoxification enzyme of one of the most potent tobacco smoke-derived
      carcinogens, NNK. If not metabolized by 11beta-HSD1, activation of NNK by
      cytochrome p450 mono-oxidase 2D6 (CYP2D6) results in an electrophile intermediate
      responsible for DNA damage. Interindividual variability in the expression of
      11beta-HSD1 and CYP2D6 has been found to influence the susceptibility to lung
      cancer. The aim of this study was to compare 11beta-HSD1 mRNA expression and
      CYP2D6 metabolizer status in pharyngeal tissues of patients with oropharyngeal
      carcinoma and controls. In 20 patients with oropharyngeal cancer and 15 non
      smoking controls, the 11beta-HSD1 mRNA expression was assessed with RT-PCR. The
      frequency of genetic polymorphisms of the CYP2D6 gene was assessed using RFLP. It
      was found that 11beta-HSD1 mRNA is expressed in human pharyngeal mucosa. It is
      upregulated in mucosa exposed to tobacco smoke. In tumour tissues, 11beta-HSD1
      expression was significantly lower than in non-affected mucosa. The frequency
      distribution of CYP2D6 gene polymorphisms was similar in patients and controls.
      Chronic tobacco abuse results in 11beta-HSD1 enzyme induction. A reduction of
      11beta-HSD1 expression in tumour tissues could be a consequence of malignantly
      transformed cells. It remains unclear if the lower 11beta-HSD1 expression gives
      rise to an increased rate of additional mutations.

PMID- 12472512
TI  - Sudden deafness: long-term follow-up and recurrence.
AB  - We examined the long-term outcome for patients with idiopathic sudden
      sensorineural hearing loss (sudden deafness), including the incidence of
      recurrence of sudden deafness. The subjects were 1,798 individuals who came to
      Nagoya University hospital within 2 weeks of the onset of unilateral sudden
      deafness. Only 14 of the patients had a history of being diagnosed with sudden
      deafness. After their visit to our hospital, one patient had a recurrence in the
      ipsilateral ear and four patients experienced sudden deafness in the
      contralateral ear. We performed hearing examinations on 88 patients who revisited
      our hospital more than 10 years after unilateral sudden deafness. Of these
      patients, there was one with a recurrence in the ipsilateral ear and one with
      sudden deafness in the contralateral ear. Thus, in this series the recurrence of
      sudden deafness was rare.

PMID- 12472513
TI  - Benefit from endoscopic sinus surgery.
AB  - Benefit and satisfaction following endoscopic sinus surgery were assessed using
      the Glasgow Benefit Inventory (GBI) and a validated outcome satisfaction score.
      In total, 140 patients were invited to participate; 101 (71%) responded. ESS
      produces significant benefit as assessed by the GBI and satisfaction, and the
      benefit compares favourably with other otorhinolaryngological procedures.
      Greatest benefit was derived by patients undergoing surgery for polyp disease.
      Patients whose cardinal preoperative symptom was nasal obstruction or headache
      tended to report higher benefit. Co-existent asthma, allergic rhinitis or aspirin
      intolerance appeared not to result in a significant decrease in benefit after
      surgery, except in patients with non-polyp disease, who also have both aspirin
      intolerance and asthma. Also, for non-polyp disease, postoperative medication
      with nasal steroids or antihistamines does not appear to influence benefit.

PMID- 12472514
TI  - Paroxysmal hemicrania and cluster headache: two discrete entities or is there an
      overlap?
AB  - Paroxysmal hemicrania has been described as an excruciating unilateral pain,
      which is usually ocular and frontotemporal with short-lasting (2-45 min),
      frequent attacks (usually more than five per day); with marked autonomic features
      (rhinorrhoea, nasal congestion, conjunctival injection, lacrimation) and
      unilateral to the pain. A response to indomethacin is essential using the current
      criteria for the diagnosis. It is a rare condition but when it occurs it is
      misdiagnosed as being due to sinusitis. A retrospective analysis of 11 patients
      seen in the period 1995-2001 suggests that there is an overlap between paroxysmal
      hemicrania and cluster headache. Four patients had all the characteristics of
      paroxysmal hemicrania and responded to indomethacin. Four other patients
      fulfilled the criteria except for the frequency and length of the attacks. They
      only had one attack per day and these lasted more than 2 h. Another patient had
      all the symptoms of paroxysmal hemicrania and did not respond to indomethacin,
      but responded to triptans and pizotifen. Patients with cluster headache typically
      respond to these. Two patients were unable to continue taking indomethacin owing
      to severe gastrointestinal upset. In the same period, we also had 30 patients
      with cluster headaches. There is increasing evidence that paroxysmal hemicrania
      and cluster headache share a similar pathogenesis and that they may not always be
      so discrete in either their response to indomethacin or their periodicity.

PMID- 12472515
TI  - Are hearing and middle ear statuses at risk in Chinese patients undergoing
      orthognathic surgery?
AB  - Orthognathic surgery, which is performed to correct dentofacial abnormalities,
      has been associated with postoperative reduction in hearing sensitivity and
      middle ear dysfunction. In this study, the pre- and postoperative hearing status
      and middle ear function of 37 Chinese subjects who underwent orthognathic
      surgery, as well as subjective reports of aural symptoms, particularly hearing
      loss, tinnitus, fullness and otalgia, were investigated. There was a significant
      increase in the number of subjects with measured loss, perceived loss and aural
      fullness from pre-surgery to 1 week post surgery. However, the percentage of
      increase was small compared with previous findings. This difference in findings
      was attributed to the type of surgical techniques used, and to the fact that the
      Chinese population appears to be less susceptible to middle ear effusion.
      Subjective complaints of aural symptoms may not be accompanied by measured loss.

PMID- 12472516
TI  - The use of topical nasal anaesthesia before flexible nasendoscopy: a double
      blind, randomized controlled trial comparing cophenylcaine with placebo.
AB  - The objective was to evaluate the necessity to use topical nasal anaesthesia
      before flexible nasendoscopy and to compare its use with placebo. The study was
      carried out using a double-blind randomized controlled trial, with three
      treatment arms, at the out-patient department at Raigmore Hospital, Inverness.
      The participants were 90 patients attending the otolaryngology out-patient
      department who required flexible nasendoscopy as part of their assessment. Each
      participant was randomized to one of three groups. Group 1 received cophenylcaine
      spray, group 2 received a placebo spray, and group 3 received no nasal
      preparation. Flexible nasendoscopy was carried out via a stated protocol and the
      patient's diagnosis and findings were discussed in the usual way. After the
      consultation, the patient filled in a questionnaire marking answers on a visual
      analogue scale. The main outcome measures were pain and overall unpleasantness of
      procedure. Patient anxiety and willingness to be examined again in the same way
      if necessary were also assessed. Ease of examination and quality of view were
      asked from the operator's perspective. The mean scores on a visual analogue scale
      showed the main outcome measures to be as follows. Pain score measured 1.7 for
      cophenylcaine, 2.1 for no spray and 2.2 for placebo. Overall unpleasantness
      scores were 2.0 for cophenylcaine, 1.9 for no spray and 2.4 for placebo. On a
      visual analogue scale of 0-10, none of these mean main outcome measures reached
      levels of significance. It was concluded that the use of cophenylcaine spray
      before flexible nasendoscopy does not give significant advantages over the use of
      no nasal preparation.

PMID- 12472517
TI  - A randomized double-blind study to compare the effects of nasal fluticasone and
      betamethasone on the hypothalamo-pituitary-adrenal axis and bone turnover in
      patients with nasal polyposis.
AB  - Treatment of nasal polyposis with topical betamethasone is associated with
      suppression of the hypothalamo-pituitary-adrenal (HPA) axis and, potentially, has
      adverse effects on bone turnover. Fluticasone propionate is a potent
      corticosteroid with negligible absorption across the nasal mucosa and extensive
      first-pass hepatic metabolism. We performed a randomized double-blind study, in
      patients with nasal polyposis, comparing the effects of 8 weeks' treatment with
      betamethasone drops or fluticasone nasules on the HPA axis using the 1 micro g
      tetracosactide test, and on bone turnover using two serum markers. Nine patients
      were allocated to each treatment. Betamethasone resulted in significant
      suppression in the tetracosactide test (P = 0.006), but fluticasone did not (P =
      0.113). There were no differences in bone turnover or treatment efficacy between
      treatments. Treatment of nasal polyposis with topical betamethasone drops, but
      not with fluticasone nasules, suppresses the HPA axis and, given comparable
      efficacy, fluticasone administered via nasule should be the preferred agent.

PMID- 12472518
TI  - Sequelae of otitis media with effusion among children with cleft lip and/or cleft
      palate.
AB  - Otitis media with effusion (OME) is common among children with cleft palate, and
      may lead to such long-term consequences as hearing loss, tympanic membrane
      retraction, and chronic otitis media (COM). In total, 104 children with cleft lip
      and/or palate treated for OME at our institution were reviewed. Mean duration of
      follow-up was 6.9 years, and mean age at latest follow-up was 9.6 years. The
      incidence of COM was 19%, and the incidence of cholesteatoma was 1.9%. Ears
      showing such long-term sequelae of OME as hearing loss, tympanic membrane
      retraction, and chronic otitis media, were noted to have undergone a
      significantly greater number of ventilation tube insertions than ears not showing
      these sequalae. Our findings would suggest that a conservative approach to the
      management of OME in children with cleft palate is more likely to be beneficial
      in the long term.

PMID- 12472519
TI  - Prognosis is predicted by early hearing improvement in patients with idiopathic
      sudden sensorineural hearing loss.
AB  - The time-course of the recovery of the hearing level after treatment in 90
      patients with idiopathic sudden sensorineural hearing loss was examined. The
      improvement rate calculated relative to the hearing level of the opposite ear was
      investigated to estimate the hearing recovery. Follow-up audiograms were
      performed once per week for 1 month after treatment and once per month
      thereafter. There were two groups that differed with respect to the
      characteristics of hearing recovery. One group showed an improvement rate of over
      50% at 1-2 weeks and a good improvement rate at 3 months after treatment. In the
      other group, the improvement rate did not reach 50% at 1-2 weeks, and the
      improvement rate was poor at 3 months after treatment. The patients with
      improvement rates of over 50% at 1-2 weeks had earlier initial visits and had
      mild hearing loss, whereas the patients with profound hearing loss had
      improvement rates under 50% and poor long-term prognosis. We conclude that the
      improvement rate at 1-2 weeks after treatment predicts the long-term prognosis
      for recovery of hearing level in patients with sudden sensorineural hearing loss.

PMID- 12472520
TI  - p53 Expression and keratinocyte hyperproliferation in middle ear cholesteatoma.
AB  - Keratinocytes in middle ear cholesteatoma have hyperproliferative properties.
      There is controversy regarding the role of p53 and its effect on cellular
      proliferation in cholesteatoma. This study was instituted to examine this.
      Cholesteatoma and deep meatal skin control specimens were analysed for MIB-1 (n =
      7, controls = 7), a marker of cellular proliferation, and p53 (n = 17, controls =
      17) expression by immunocytochemistry. Expression of p53 was minimal or absent in
      both cholesteatoma and controls (P = 0.2). MIB-1 expression was higher, but not
      significantly so, in cholesteatoma than in controls (P = 0.09). Our study has
      shown no significant p53 expression in cholesteatoma epithelium. This suggests
      that there is no dysfunction in the p53-mediated cell cycle control mechanisms in
      cholesteatoma.

PMID- 12472521
TI  - Changes in external ear resonance after mastoidectomy: open cavity mastoid versus
      obliterated mastoid cavity.
AB  - The creation of an open mastoid cavity changes the acoustic characteristics of
      the external ear. The aim of this study was to ascertain the acoustic change in
      the external auditory canal caused by an open mastoid cavity and to compare it
      with mastoid obliteration. The external ear resonance characteristics were
      measured in 40 normal adult ears, 20 ears with an open mastoid cavity and 40 ears
      with an obliterated mastoid. The measurement of resonance characteristics was
      performed using a real ear analyser. An open mastoid cavity changed the mean peak
      resonant frequency of the external ear from 2.1 kHz to 2.3 kHz (P < 0.02), with a
      mean attenuation of 8 dB SPL at 4 kHz. An obliterated mastoid produced higher
      resonance frequencies from 2.5 kHz to 2.8 kHz. The sound pressure gain of the
      external auditory canal with an open mastoid cavity was higher than with an
      obliterated mastoid. The author concludes that an open mastoid cavity can affect
      the resonance frequency, and that this effect is reduced by mastoid obliteration.
      Therefore, mastoid obliteration results in a more normal ear canal both
      anatomically and functionally.

PMID- 12472522
TI  - Prognostic indicators for malignant tumours of the parotid gland.
AB  - The best treatment of malignant parotid tumours still remains to be defined, and
      a better knowledge about the tumour features that predict the treatment result is
      needed. The histological classification of parotid tumours may present
      difficulties on account of their great morphological diversity. In a series of
      152 patients with a malignant tumour of the parotid gland, the prognostic factors
      and treatment results were investigated over a 25-year period. Treatment
      consisted of surgery, radiation therapy or a combination (49%, 13% and 38%
      respectively). Crude 5-year survival was 50% with significant differences related
      to stage (stage I, 65%; stage II, 50%; stage III, 21%; and stage IV, 9%). With
      respect to histopathology, the adenoid cystic carcinomas and the acinic cell
      carcinomas had the best prognosis (76% and 67% 5-year crude survival and 53% and
      67% 10-year crude survival respectively). There was a significant difference in
      crude survival between well/intermediate and poorly differentiated tumours (P =
      0.007). In a Cox hazard regression analysis including 136 patients and using
      death from cancer as the end-point, the following parameters were independent
      prognostic predictors: T-classification (P = 0.002), M-classification (P <
      0.0001), N-classification (N+versus N0) (P = 0.005), local invasion (P = 0.003)
      and histological differentiation of the tumour (P = 0.03). The TNM system is a
      good predictor of treatment outcome for malignant parotid tumours. The use of a
      combination of clinical and histological factors will assist the design of
      treatment strategies for parotid gland tumours.

PMID- 12472523
TI  - Risk-adjusted comparative audit. Is Possum applicable to head and neck surgery?
AB  - Possum (the physiological and operative severity score for the enumeration of
      mortality) is used in many surgical specialities for comparative audit. We
      investigated its validity in relation to head and neck surgery by retrospectively
      scoring 301 operative interventions. We also applied the P-Possum (Portsmouth
      Possum) equation for mortality. We compared our observed with the predicted
      outcomes. We introduced two new variables, radiotherapy and previous surgery to
      the operative site, to test their association with outcome. We found that Possum
      is valid for morbidity but predicts more accurately for high-risk than for low
      risk groups. Neither Possum or P-Possum accurately predicts mortality.
      Radiotherapy and previous surgery were both significant for the development of
      postoperative complications (P = 0.002, P = 0.007 respectively) and are worthy of
      inclusion in a Possum score for head and neck surgery.

PMID- 12472524
TI  - Facial migraine in a rhinological setting.
AB  - This study aims to investigate the incidence of migraine involving the face in a
      rhinology clinic and to describe its characteristics. It is a study of a cohort
      of 973 patients consecutively presenting to the outpatient clinic with symptoms
      of facial pain and/or rhinosinusitis. The study subgroup consisted of patients
      with facial pain and migraine excluding cluster headache and paroxysmal
      hemicrania. We studied the features of 51 patients who had facial pain with
      migraine. The diagnosis was based on the criteria used by the International
      Headache Society and was also supported by the outcome and response to treatment
      after a mean of 2 years and 2 months. Of the 973 consecutive patients, 409 (42%)
      had symptoms of facial pain and/or head pain or pressure. Fifty-one (12%) had
      migraine. Of these, 39 (76%) had unilateral pain and, in 12 (24%), it was
      bilateral. The distribution affected the forehead and/or eye or cheek in 32 (63%)
      patients. Twenty-four (47%) had migraine isolated to the second division of the
      trigeminal nerve. Twelve per cent of patients attending a rhinology clinic with
      facial pain had migraine. Of particular interest were the 6% of patients with
      facial pain who had migraine confined to the second division of the trigeminal
      nerve. This entity is not widely recognized and has rarely been described in the
      literature.

PMID- 12472525
TI  - Has the internet overtaken other traditional sources of health information?
      Questionnaire survey of patients attending ENT outpatient clinics.
AB  - The aim of this study was to find out whether patients attending ENT clinics
      obtain health information about their medical condition and to assess
      satisfaction with the sources of health information, including the internet.
      Three hundred and thirty patients attending ENT outpatient clinics at District
      General Hospitals in Wigan and Warrington during June 2001 were asked to complete
      detailed questionnaires. Fifty-seven per cent of patients attempted to obtain
      health information before their visit to the specialist clinic. Forty-five per
      cent of patients had access to the internet, but only 13% used it to obtain
      health information. General practitioners were the source of health information
      for 64%, but the NHS-Direct help line was only used by 16%. Patients also trusted
      the health information provided by their GPs the most. In the twenty-first
      century, patients turn to their GP as the main source of health information.

PMID- 12472526
TI  - Middle ear instillation of gentamicin and streptomycin in chinchillas:
      electrophysiological appraisal of selective ototoxicity.
AB  - The purpose of this study was to investigate selective vestibular ototoxicity of
      gentamicin and streptomycin in the chinchilla model. In total, 10 chinchillas
      underwent left middle ear instillation of one of three agents: gentamicin,
      streptomycin and saline. Electrophysiological data (otoacoustic emissions (OAEs),
      auditory brainstem evoked response (ABRs), and ice-water electronystagmography
      were recorded before and after instillation. Animals were sacrificed for temporal
      bone studies using scanning electron microscopy. Morphological changes in the
      cochlear and vestibular neuroepithelia were correlated with electrophysiological
      changes. Widespread ipsilateral cochlear and vestibular neuroepithelial injuries
      were observed and correlated with loss of OAEs, ABRs and ice-water caloric
      response. This study provides no evidence of selective vestibular ototoxicity of
      gentamicin or streptomycin. Morphological damage correlates with, but precedes
      loss of electrophysiological parameters. Chinchillas, like other small mammals,
      may not be an ideal model for the study of human ototoxicity.

PMID- 12472527
TI  - Analysis of intra-operative bleeding and recurrence of juvenile nasopharyngeal
      angiofibromas.
AB  - The purpose of this study is to present our experience with 34 patients diagnosed
      with juvenile nasopharyngeal angiofibromas and treated in the Chinese PLA General
      Hospital between 1986 and 1999, and to examine the factors influencing intra
      operative bleeding and tumour recurrence. The age of the patient, the duration of
      symptoms and tumour stage were related to the amount of intra-operative bleeding.
      The tumours were totally resected in 30 patients and recurred in five patients
      (16.7%), with a mean follow-up time of 77 months. The mean time to tumour
      recurrence after operation was 3.2 months (1-6 months). The incidence of
      recurrence had no correlation with the age of the patient, duration of symptoms,
      peri-operative treatment or surgical approaches (P > 0.05); but strongly
      correlated with tumour stage (P < 0.05).

PMID- 12472528
TI  - Conservation surgery in the management of T1 and T2 oropharyngeal squamous cell
      carcinoma: the Birmingham UK experience.
AB  - The aim of this paper was to evaluate our experience using conservation surgery
      in the management of T1 and T2 oropharyngeal squamous cell carcinoma. Eighteen
      patients underwent conservation surgery between 1993 and 2000 and were analysed
      retrospectively. The mean age was 54 years and the male to female ratio was 8:1.
      There were 14 tonsil and 4 tongue base tumours and 83% of cases presented with
      neck nodes, thereby classifying them as having advanced disease (stages 2-4). All
      patients received postoperative radiotherapy. All patients were followed up to
      December 2001. The median follow-up time was 3.8 years (minimum was 1.5 years).
      The 2-year and 5-year survival rates were 100% and 92% respectively.
      Approximately 66% of patients returned the EORTC and GHQ/12 quality-of-life
      questionnaires. Of these, seventy-five percent had a high healthy level of
      general functioning in accordance with the EORTC general health section. These
      results show that conservation surgery techniques are effective in the treatment
      of T1 and T2 oropharyngeal squamous carcinoma associated with significant
      metastatic neck disease. The techniques are well tolerated, produce minimal
      functional deficit and do not have a negative impact on the patients quality of
      life in either the immediate postoperative period or up to 4 years post
      treatment.

PMID- 12472529
TI  - Artefacts produced by suture traction during incisional biopsy of oral lesions.
AB  - The aim of this study is to compare the artefacts ascribed to the technique of
      incisional biopsy using a punch or scalpel and the influence of suture use for
      traction and delivery of the specimen. A total of 160 samples were obtained from
      10 fresh pig tongues by four experienced oral surgeons. Handling artefacts
      (squeeze artefacts): crush, splits, fragmentation and pseudocysts were assessed.
      No differences were identified in terms of crush, fragmentation or pseudocysts
      between samples obtained with a punch or scalpel. Splits were more frequent in
      those biopsies taken with a scalpel (chi2 = 9.26; P= 0.0023). Artefacts in the
      punch biopsy group were significantly less than in the group that combined punch
      and suture traction (P < 0.01). The scalpel and suture traction group showed
      significantly more artefacts than the group without suture. It is concluded the
      use of a stitch for traction in small incisional biopsies causes squeeze
      artefacts, so its use should be restricted to specimen orientation.

PMID- 12472531
TI  - Epidermolysis bullosa and cancer.
AB  - Epidermolysis bullosa (EB) encompasses a group of inherited blistering skin
      disorders classified into three main subtypes of simplex, junctional and
      dystrophic. In recent years there have been substantial advances in our
      understanding of the molecular basis of these conditions and in the management of
      such patients. In spite of this progress, squamous cell carcinoma (SCC) is still
      a major cause of morbidity and mortality, particularly in Hallopeau--Siemens
      recessive dystrophic EB. The reason why dystrophic EB patients readily develop
      SCC with such a poor prognosis remains a mystery. This article reviews the
      epidemiology of cancer in inherited EB and also discusses the clinical features,
      histological assessment and treatment options of SCC in EB.

PMID- 12472532
TI  - Lipoid proteinosis.
AB  - Lipoid proteinosis is a rare, autosomal recessive disorder that presents in early
      infancy with hoarseness, followed by pox-like and acneiform scars, along with
      infiltration and thickening of the skin and certain mucous membranes.
      Histological and ultrastructural examination reveals widespread deposition of
      hyaline-like material and disruption/reduplication of basement membrane around
      blood vessels and at the dermal--epidermal junction. Recently, lipoid proteinosis
      was mapped to 1q21 and pathogenetic loss-of-function mutations were identified in
      the extracellular matrix protein 1 gene (ECM1). This article reviews the
      molecular basis of lipoid proteinosis and reassesses the clinico-pathological
      features of this disorder in light of the new genetic discoveries.

PMID- 12472533
TI  - Nonablative laser resurfacing: a systematic review of the literature.
AB  - 'Nonablative laser resurfacing' is a new treatment for photoaged skin, the aim of
      which is to wound the upper dermis in order to induce dermal fibrosis and improve
      the clinical appearance. Unlike conventional laser resurfacing or dermabrasion,
      the epidermis is protected and retained to avoid the problems associated with
      open wounds and reepithelialization. A number of lasers and light sources have
      been developed or adapted for this purpose.

PMID- 12472534
TI  - Clinical, histopathological and immunological distinction in two cases of IgA
      pemphigus.
AB  - Two cases of IgA pemphigus, one of the subcorneal pustular dermatosis (SPD) type
      and one of the intraepidermal neutrophilic IgA dermatosis (IEN) type, are
      described. IgA anti-keratinocyte cell surface antibodies reacted only with the
      uppermost epidermis in the SPD type but with the entire epidermis in the IEN
      type. A cDNA transfection test for desmocollins (Dsc) revealed that IgA
      antibodies of the SPD type reacted with Dsc1, but the IEN type did not react with
      any of the Dsc isoforms (Dsc1-3). ELISA for desmoglein 1 (Dsg1) and Dsg3 showed
      that neither of the cases had antibodies to Dsg - of either the IgG or IgA
      subtype. These results confirm that the autoantigen in SPD-type IgA pemphigus is
      Dsc1, whereas the antigen in most cases of IEN-type IgA pemphigus is unknown.

PMID- 12472535
TI  - Topical pseudocatalase mousse and narrowband UVB phototherapy is not effective
      for vitiligo: an open, single-centre study.
AB  - We report an open single-centre trial to assess the efficacy of topical
      pseudocatalase mousse applied twice daily to the hands and face of vitiligo
      patients, in combination with twice-weekly suberythemogenic narrowband UVB
      phototherapy. The regime was generally safe and well tolerated, although several
      patients experienced mild transient skin rashes in association with application
      of the mousse and one patient suffered severe pruritus. The primary efficacy
      variable was the percentage change in area affected by vitiligo as assessed by
      digital interpretation of standardized photographs of the face and hands. There
      was no clear evidence of the efficacy of the regime and in fact a slight tendency
      overall to worsening of the patients' vitiligo.

PMID- 12472536
TI  - Diffuse hypertrichosis and faun-tail naevus as cutaneous markers of spinal
      dysraphism.
AB  - We describe two cases of spinal dysraphism where detection of the cutaneous signs
      - namely a faun-tail naevus and diffuse hypertrichosis - led to early recognition
      of the occult neurological abnormalities and institution of corrective surgery.
      The dermatologist may be the first physician to observe these skin changes and an
      early neurosurgical referral can prevent subsequent neurological complications.

PMID- 12472537
TI  - Type 1 segmental cutaneous leiomyomatosis.
AB  - Cutaneous leiomyomas are rare benign tumours of the skin, which present in
      multiple disseminated, segmental or solitary forms. The pathogenesis of segmental
      cutaneous leiomyomatosis is not yet fully known. Most recently two types of
      segmental manifestation of autosomal dominant inherited diseases were postulated.
      Type 1 reflects heterozygosity for the underlying mutation with a clinical
      picture similar to that in a non-mosaic phenotype. In type 2, loss of
      heterozygosity leads to homo- or hemizygosity with a pronounced segmental
      manifestation of lesions in the affected segment. In our patient the lesions were
      restricted to one segment and therefore she most probably has a type 1 segmental
      cutaneous leiomyomatosis.

PMID- 12472538
TI  - Cardiac complications in Behcet's disease.
AB  - Behcet's disease (BD) is a multisystem disease of unknown aetiology characterized
      by chronic relapsing oro-genital ulcers, uveitis, and systemic involvement
      including articular, gastrointestinal, cardiopulmonary, neurologic and vascular
      pathology. Vascular involvement is observed in 30% of cases. Although the
      pathogenic mechanisms underlying the thrombotic disposition in BD are not well
      known, prothrombin (PT) gene mutations may be one factor that contributes to the
      development of vascular involvement in this disorder. We report a case of BD with
      a PT gene mutation, presenting with cardiovascular involvement.

PMID- 12472539
TI  - Hereditary hypotrichosis simplex: report of a family.
AB  - We report a family with hereditary hypotrichosis simplex of the scalp, a rare
      disorder that was first described in 1974. In our family, four out of 10 siblings
      were affected, including three females and one male. Examination showed thinning
      of the scalp hair and sparse body hair. Eyebrows, eyelashes, pubic and axillary
      hair were normal. Skin, nails and teeth were also normal. Hair shaft examination
      did not reveal any structural abnormalities. Normal follicular units, hair shafts
      within follicles, eccrine glands and a lack of inflammation were seen on
      histopathology. The primary pathology underlying this genodermatosis is unclear,
      but the anagen phase of the hair cycle is clearly compromised.

PMID- 12472540
TI  - Polymorphic eruption of pregnancy developing in the puerperium.
AB  - Polymorphic eruption of pregnancy is an uncommon disorder, usually developing in
      the third trimester and rapidly resolving in the first few weeks postpartum. It
      has been suggested that multiple pregnancy and excessive weight gain are
      associated features. We report a patient with the clinical and histological
      features of polymorphic eruption of pregnancy, whose rash developed 4 weeks after
      delivery of a singleton pregnancy. An unusual feature of this case was the
      occurrence of the rash on the face. We discuss this case with respect to the
      recent literature.

PMID- 12472541
TI  - Neonatal erythema multiforme major.
AB  - A 25-day-old neonate developed an unusual eruption with bullae and marked
      systemic symptoms. Investigation for bacterial, viral, autoimmune and
      immunobullous causes did not reveal any identifiable trigger and histological
      examination was highly suggestive of bullous erythema multiforme. Pulmonary
      infiltrates were noted late in the course of the disease. Differential diagnoses
      included bullous impetigo, primary herpes simplex infection, immunobullous
      disease, neonatal lupus and erythema multiforme. This case illustrates the
      difficulties in diagnosing and managing an unwell child with bullae and
      emphasizes the need to exclude treatable underlying causes.

PMID- 12472542
TI  - Psoriasis bullosa acquisita.
AB  - We report a 51-year-old man with a 20-year history of chronic plaque psoriasis
      who developed an autoimmune subepidermal blistering eruption that had clinical
      features of bullous pemphigoid, erythema multiforme and epidermolysis bullosa
      acquisita. Investigations revealed a 1 : 400 titre circulating and in vivo bound
      IgG autoantibody that mapped to the dermal side of 1 m NaCl-split skin and
      localized to the lower lamina lucida/upper lamina densa on immunogold electron
      microscopy. Immunoblotting, using dermal extracts, showed serum binding to
      antigens of approximately 200- and approximately 260 kDa. Indirect
      immunofluorescence microscopy, using the patient's serum on archival skin
      sections taken from selected individuals with different forms of inherited
      epidermolysis bullosa as substrate, showed normal basement membrane labelling on
      all samples apart from recessive dystrophic epidermolysis bullosa skin (with
      inherent mutations in the type VII collagen gene): in these cases there was a
      complete absence of immunostaining. Clinically, the patient responded rapidly to
      combination treatment with intravenous immunoglobulin and oral corticosteroids,
      dapsone and mycophenolate mofetil. Autoimmune subepidermal blistering has been
      reported in other patients with psoriasis, although no specific target antigen
      has ever been determined. Our study provides preliminary evidence that, for this
      patient at least, the autoantibody may be targeted against a skin component
      closely associated with type VII collagen (the epidermolysis bullosa acquisita
      antigen). Therefore, we propose the term 'psoriasis bullosa acquisita' for this
      and possibly other patients with similar skin eruptions.

PMID- 12472543
TI  - Thiazide-induced lichenoid photosensitivity.
AB  - We report the case of a 77-year-old male who developed a florid photosensitive
      eruption while taking thiazide diuretics for heart failure. The lesions were
      lichenoid in appearance and this was confirmed histologically. The eruption
      cleared on withdrawal of the drug. Although thiazide-induced photosensitivity is
      a well-documented phenomenon, there have been no histologically proven cases of a
      lichenoid eruption in light exposed areas in the recent literature.

PMID- 12472544
TI  - Kindler syndrome in a Saudi kindred.
AB  - We report a large consanguineous Saudi-Arabian pedigree containing 11 individuals
      with the autosomal recessive genodermatosis, Kindler syndrome. Three affected
      cases died in infancy but the remaining eight had signs of photosensitivity,
      generalized poikiloderma, webbed fingers, loss of dermatoglyphics and nail
      dystrophy. The majority also had oral involvement with bleeding gums. Additional
      features seen in some cases included pseudoainhum of the toes, sclerotic bands on
      the wrists and hand deformities. The aetiology of Kindler syndrome is not yet
      known, but the underlying defect leads to both cutaneous and oral inflammation,
      along with photosensitivity and scarring.

PMID- 12472545
TI  - Linear IgA disease: successful treatment with erythromycin.
AB  - Conventional first-line treatments for linear IgA disease (and the related
      chronic immunobullous disease of childhood) include topical steroids and dapsone,
      both of which may be associated with potentially serious side-effects.
      Alternative anti-inflammatory therapies such as tetracycline and macrolide
      antibiotics, have been used to treat other immunobullous disorders and we now
      report an adult case of linear IgA disease and a paediatric case of mixed
      immunobullous disease of childhood that both responded to the macrolide
      antibiotic erythromycin. The mode of action is speculative and anti-inflammatory
      mechanisms are unclear. Nevertheless, from a clinical perspective, erythromycin
      may have a role in the treatment of linear IgA disease and could be considered
      ahead of many other, perhaps potentially more toxic, therapies.

PMID- 12472546
TI  - Congenital erythropoietic porphyria: dilemmas in present day management.
AB  - Congenital erythropoietic porphyria is a rare autosomal recessive disorder of
      haem biosynthesis caused by a deficiency of uroporphyrinogen III synthetase.
      There is resultant accumulation and hyperexcretion of porphyrinogens of the
      isomer I variety. These are converted by spontaneous oxidation into their
      corresponding photoactive porphyrins leading to photodamage. Accumulation of
      porphyrins results in haemolysis and extensive photosensitivity. The consequences
      of chronic haemolysis are splenomegaly, reactive erythroid hyperplasia,
      erythrodontia, bone fragility, extreme photosensitivity and photomutilation. We
      present a 35-year-old man who has the severe infantile form and illustrates the
      haematological and photodestructive complications despite attempts at treatment
      with hypertransfusion, oral charcoal therapy and beta-carotene. Allogenic bone
      marrow transplantation has been considered but because of the high associated
      mortality this procedure has been discounted at present in the management of our
      patient.

PMID- 12472547
TI  - Mechanisms of desmosome assembly and disassembly.
AB  - In skin, desmosomes constitute critical adhesion complexes between adjacent
      keratinocytes that help maintain an intact epidermis. However, individual
      keratinocytes need to migrate and differentiate and therefore desmosomes must
      have an inherent dynamic capacity to assemble and disassemble. This review
      highlights the role of the different structural junctional components involved in
      desmosome formation and turnover, as well as the possible signalling processes
      and pathways that may be implicated in desmosome homeostasis. Clues to the
      intricate nature of desmosome assembly and disassembly have been derived from
      human inherited and acquired blistering skin diseases as well as animal models
      and basic cell biology studies. The key implications for understanding desmosome
      dynamics from these findings are summarized in this review.

PMID- 12472548
TI  - Percutaneous absorption of benzophenone-3, a common component of topical
      sunscreens.
AB  - Benzophenone-3 (BZ-3) is a commonly used, chemical UV-absorber. It has been used
      for many years to protect against UV-radiation. Previous studies have shown that
      BZ-3 penetrates the skin, and it can be found in urine, faeces, and blood. In
      this study we examined the percutaneous absorption of BZ-3. The amount of BZ-3
      absorbed was measured in urine, as experimental studies in the rat have shown
      that urine is the major route of excretion. Eleven volunteers applied the
      recommended amount of a commercially available sunscreen and urine samples were
      collected during a 48-h period after application. The average total amount
      excreted was 11 mg, median 9.8 mg, which is approximately 0.4% of the applied
      amount of BZ-3. Some of the volunteers still excreted BZ-3 48 h after
      application. It is evident that BZ-3 undergoes conjugation in the body to make it
      water soluble. However, we do not know at what age the ability to conjugate is
      fully developed, and therefore for children physical filters such as titanium
      dioxide and/or zinc oxide might still be considered a more appropriate sunscreen
      component.

PMID- 12472549
TI  - Twice-daily vs. once-daily inpatient dithranol for psoriasis.
AB  - The aim of this study was to compare the efficacy and tolerability of twice-daily
      vs. once-daily regimes of dithranol (anthralin) in Lassar's paste. Over a 4-year
      period, 61 inpatients with stable plaque psoriasis gave informed consent and
      entered a randomized controlled trial, having twice or once-daily application of
      dithranol in Lassar's paste as part of otherwise standard Ingram's regime.
      Primary outcome measurements were time required in hospital, nursing time,
      changes in total body surface area affected by psoriasis and thickness of a
      target plaque and in some patients, an assessment of the recurrence of psoriasis.
      Doctors were blinded as to the regime being used. At entry, mean patient age,
      lesional surface area and target plaque thickness were comparable in both groups
      and no patient had received systemic therapy in the preceding 3 months. Forty-two
      patients completed the study, two (11%) in the twice-daily group withdrawing due
      to skin irritation or 'burning'. Mean lesional surface area and target plaque
      thickness were similar in both groups at hospital discharge. Mean (+/- SD) time
      spent in hospital was not significantly different in each group, being 13.3 (+/-
      6.2) days and 13.9 (+/- 4.5) days for the twice-daily and once-daily groups,
      respectively (P = 0.36). Duration of hospitalization did not correlate with
      surface area or plaque thickness on admission. Mean (+/- SD) nursing time spent
      on treatment was significantly greater in the twice-daily group, at 0.82 (+/-
      0.33) hours per day compared with 0.51(+/- 0.25) hours per day in the once-daily
      group. Relapse rate at 6 months was not different between the two groups.

PMID- 12472550
TI  - Allergic reactions to glyceryl trinitrate and isosorbide dinitrate demonstrating
      cross-sensitivity.
AB  - Glyceryl trinitrate (nitroglycerin) has been in use for relief of angina for over
      a hundred years, but allergic reactions to it or to other organic nitrates rarely
      feature in the medical literature. Most of the case reports describe reactions to
      transdermally applied nitroglycerin. We report a case of a localized allergic
      reaction to nitroglycerin transdermal patches that developed when these were worn
      for the first time after 7 days of uneventful treatment with intravenous
      isosorbide dinitrate. The reaction evolved into a severe and generalized
      maculopapular rash with facial swelling when intravenous isosorbide dinitrate was
      re-administered 10 days later. Subsequent patch testing with a transdermal
      nitroglycerin patch and a placebo nitroglycerin-free patch provoked a reaction to
      the nitroglycerin patch but not to the placebo, thus excluding allergy to other
      constituents of the nitroglycerin patch.

PMID- 12472551
TI  - Topical photodynamic therapy in disseminated superficial actinic porokeratosis.
AB  - Photodynamic therapy (PDT) has been reported to be useful in treating certain
      nonmelanoma skin cancers and a variety of benign skin conditions. We examined
      whether PDT might be effective in the treatment of disseminated superficial
      actinic porokeratosis. Three patients with classical disseminated superficial
      actinic porokeratosis had a small test area treated with topical aminolaevulinic
      acid PDT. Following the first treatment, the disorder cleared in the test area in
      one patient, but failed to respond in the other two patients. After subsequent
      treatment, the initial benefit seen in the first patient was not sustained, and
      no response was seen in the second patient, while the third patient was not
      retreated due to hyperpigmentation induced by the procedure. The results obtained
      in this small case series suggest that topical PDT is not a promising treatment
      for disseminated superficial actinic porokeratosis.

PMID- 12472552
TI  - Quality of life in epidermolysis bullosa.
AB  - The quality of life of people with epidermolysis bullosa (EB) living in Scotland
      was assessed by postal questionnaire using the Dermatology Life Quality Index
      (DLQI) and the Children's Dermatology Life Quality Index (CDLQI). There were 143
      people with EB simplex (EBS) and 99 individuals with non-Hallopeau--Siemens
      subtypes of dystrophic EB (DEB). A further six individuals had the severe
      Hallopeau--Siemens subtype of DEB (RDEB-HS). The overall response was 48% (EBS
      52%, DEB 40% and RDEB-HS 83%). Impairment of quality of life (QOL) was greatest
      in those with RDEB-HS, mean scores (adults, 18; children, 22) exceeding those of
      any skin disorder previously assessed. The effect on QOL of EBS and other
      subtypes of DEB was similar to that of moderately severe psoriasis and eczema.
      EBS had a greater impact on QOL than the non-Hallopeau--Siemens subtypes of DEB
      (EBS adults mean score, 10.7; EBS children mean score, 15; DEB adults mean score,
      7.5; DEB children mean score, 11.5).

PMID- 12472553
TI  - Issues regarding nonattendance at a paediatric dermatology centre.
AB  - Nonattendance in paediatric dermatology clinics is a significant problem. We
      reviewed the charts of all 400 new referrals to the Prince of Wales Hospital
      (PWH) paediatric dermatology clinic in the year 2000. Sixty-six patients (17%)
      did not attend. The mean age +/- SD of attenders (7.5 +/- 5.1 years) and
      nonattenders (7.7 +/- 4.5 years) did not differ significantly. Forty-eight per
      cent of the referrals were females, 50% of the attenders were females and 67% of
      the nonattenders were male. Males were 2.1-fold more likely not to attend clinic
      relative to females (95% confidence interval 1.14-3.71, P = 0.010). Nonattendance
      was significantly higher among referrals from the PWH emergency department,
      compared with referrals by private practitioners (P = 0.05) and referrals by
      other clinics in the PWH. Data in this retrospective study confirm that there is
      a gender disparity in hospital nonattendance. More dermatological referrals but
      more nonattendance were associated with the male patients.

PMID- 12472554
TI  - Two cases of comedonal Darier's disease.

PMID- 12472555
TI  - Food allergy diets - a cautionary tale.

PMID- 12472556
TI  - Digitate dermatosis associated with ulcerative colitis?

PMID- 12472557
TI  - Association between subacute cutaneous lupus erythematosus and epidermoid
      carcinoma of the lung: a paraneoplastic phenomenon?

PMID- 12472558
TI  - Acute onset vesiculo-bullous dermatomyositis associated with massive mucosal
      necrosis of the intestines.

PMID- 12472559
TI  - Palmoplantar pustulosis associated with gastric Helicobacter pylori infection.

PMID- 12472560
TI  - Erythema annulare centrifugum and osteoarthritis treated with hyaluronic acid.

PMID- 12472562
TI  - Cardiac involvement in non-Hodgkin's lymphoma.

PMID- 12472563
TI  - Haemopoietic and neuroglial progenitors are promoted during cord blood ex vivo
      expansion.

PMID- 12472564
TI  - Red cell agglutination: the first description by Creite (1869) and further
      observations made by Landois (1875) and Landsteiner (1901).

PMID- 12472565
TI  - Historical aspects and present knowledge of idiopathic thrombocytopenic purpura.

PMID- 12472566
TI  - Fanconi and Glanzmann: the men and their works.

PMID- 12472567
TI  - Investigatory and analytical approaches to differential gene expression profiling
      in mantle cell lymphoma.
AB  - Mantle cell lymphoma (MCL) is a non-Hodgkin's lymphoma of B-cell lineage. The
      blastoid variant of MCL, characterized by high mitotic rate, is clinically more
      aggressive than common MCL. We used the cDNA array technology to examine the gene
      expression profiles of both blastoid variant and common MCL. The data was
      analysed by regression analysis, principal component analysis and the naive
      Bayes' classifier. Eight genes were identified as differentially deregulated
      between the two groups. Oncogenes CMYC, BCL2 and PIM1 were upregulated more
      frequently in the blastoid variant than in common MCL. This implied that the
      gp130-mediated signal transducer and activator of transcription 3 (STAT3)
      signalling pathway was involved in the blastoid variant transformation of MCL.
      Other differentially deregulated genes were TOP1, CD23, CD45, CD70 and NFATC. By
      using the eight differentially deregulated genes, we created a classifier to
      distinguish the blastoid variant from common MCL with high accuracy. We also
      identified 18 genes that were deregulated in both groups. Among them, BCL1,
      CALLA/CD10 and GRN were suggested to be oncogenes. The products of RGS1, RGS2,
      ANX2 and CD44H were suggested to promote tumour metastasis. CD66D was suggested
      to be a tumour suppressor gene.

PMID- 12472568
TI  - Intrasinusoidal bone marrow infiltration: a common growth pattern for different
      lymphoma subtypes.
AB  - We report a retrospective immunohistochemical study on bone marrow biopsies of 43
      patients with different types of lymphomas showing unusual intrasinusoidal
      infiltration. Most of these patients presented with splenomegaly (74.4%) and
      peripheral lymphocytosis (83%). In 20/43 patients, lymphoid infiltrates were not
      detectable on haematoxylin-eosin sections. After immunohistochemistry on bone
      marrow biopsies and blood and bone marrow smear examinations, the following
      diagnoses were made: splenic marginal zone lymphoma with villous lymphocytes
      (SLVL) in 24 patients, large granular lymphocyte (LGL) leukaemia in 14 patients,
      hepatosplenic T-cell lymphoma in two patients, anaplastic large cell lymphoma in
      two patients and intravascular large B-cell lymphoma in one patient. In the
      presence of intrasinusoidal infiltrates of small lymphocytes, a B-cell phenotype
      (CD20+, CD76/DBA44+/-) was associated with splenic marginal zone lymphoma whereas
      intrasinusoidal CD3/CD45RA-positive T-cell infiltrates were strongly suggestive
      of LGL leukaemia. Intrasinusoidal bone marrow infiltration appears to be a common
      feature of distinct lymphoma subtypes. Immunohistochemical analysis is essential
      to detect intrasinusoidal medullary infiltrates (which may be minimal) and should
      be systematically performed in patients with splenomegaly and peripheral
      lymphocytosis.

PMID- 12472569
TI  - Acquired immunodeficiency syndrome-associated lymphomas are efficiently lysed
      through complement-dependent cytotoxicity and antibody-dependent cellular
      cytotoxicity by rituximab.
AB  - Rituximab (Mabthera) and alemtuzumab (Campath(R), Mabcampath(R)) are non
      conjugated IgG1 therapeutic monoclonal antibodies directed against the CD20 and
      CD52 surface antigens respectively. They are presently used in the therapy of
      indolent B-cell non-Hodgkin's lymphoma (B-NHL) and of B-cell chronic lymphocytic
      leukaemia, and are thought to act mainly through complement-dependent
      cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Here we
      have analysed the capacity of these two monoclonal antibodies to lyse cell lines
      of acquired immunodeficiency syndrome (AIDS)-related B-NHL through either
      complement activation or antibody-dependent cytotoxicity. Rituximab strongly
      activated both CDC and ADCC against CD20-positive AIDS-NHL cells lines, inducing
      up to 60-98% and 20% specific lysis respectively. In contrast, alemtuzumab was a
      poor activator of CDC, even in the AIDS-NHL cell lines expressing high amounts of
      CD52, leading to a lysis of only 1-30%, whereas it was at least as strong as
      rituximab in inducing ADCC of the same lines (up to 30% specific lysis).
      Altogether, these data offer a first in vitro rationale supporting the
      therapeutic use of rituximab for CD20-positive AIDS-NHL.

PMID- 12472570
TI  - A study on 289 consecutive Korean patients with acute leukaemias revealed
      fluorescence in situ hybridization detects the MLL translocation without
      cytogenetic evidence both initially and during follow-up.
AB  - Translocations involving the MLL gene on the chromosome 11 (11q23) are frequently
      observed in acute leukaemia. The detection of this genetic change has a unique
      significance as a result of its implication of poor prognosis. To reveal the
      utility of fluorescence in situ hybridization (FISH) in detecting the MLL
      translocation, we analysed 289 consecutive Korean patients (children and adults)
      with acute leukaemias using both conventional cytogenetic analysis (CC) and FISH,
      placing an emphasis on the result discrepancies. Twenty-two of 289 patients
      (7.6%) had the 11q23/MLL translocation. In nine of 22 patients (41%), only FISH
      detected the translocation. In eight of these 22 patients, a total of 19 follow
      up examinations were performed, of which FISH detected a significant level of
      leukaemic cells harbouring the MLL translocation in five patients (26%) without
      cytogenetic evidence. In addition to the MLL translocation, FISH detected
      submicroscopic amplification, partial deletion of the MLL gene and trisomy 11 in
      12 patients without cytogenetic evidence. In summary, up to 41% of the MLL
      translocations at initial work-up and 26% during follow-up were detected by FISH
      without cytogenetic evidence. Thus, we recommend that MLL FISH should be
      performed in the diagnosis and monitoring of acute leukaemias in combination with
      CC.

PMID- 12472571
TI  - Altered expression of retinoblastoma protein-interacting zinc finger gene, RIZ,
      in human leukaemia.
AB  - The retinoblastoma protein-interacting zinc finger gene (RIZ), a member of the
      nuclear protein methyltransferase superfamily, is characterized by the presence
      of the N-terminal PR domain. The RIZ gene encodes for two proteins, RIZ1 and
      RIZ2. While RIZ1 contains the PR (PRDI-BF1 and RIZ homologous) domain, RIZ2 lacks
      it. RIZ gene expression is altered in a variety of human cancers and RIZ1 is now
      considered to be a candidate tumour suppressor. To investigate the role of RIZ in
      leukaemogenesis, we analysed the differential expression of RIZ1 and RIZ2 by
      quantitative real-time reverse-transcription polymerase chain reaction assay. Our
      results showed that the expression of RIZ1 was significantly decreased in
      leukaemia cell lines (14 out of 17, 82%) and in patients with acute myeloblastic
      leukaemia (eight out of 14, 57%). In contrast, RIZ2 expression was increased in
      patients with acute lymphoblastic leukaemia (eight out of 11, 73%), compared with
      normal bone marrow cells. These findings indicate that suppression of RIZ1
      expression or enhancement of RIZ2 expression may have an important role in
      leukaemogenesis.

PMID- 12472572
TI  - The naive T-lymphocyte compartment is well preserved in patients with chronic
      myelogenous leukaemia in chronic phase.
AB  - In chronic myelogenous leukaemia (CML), clonal change occurs in all myeloid and B
      cell lineages, but very rarely T-cell lineages. A detailed three-colour
      cytometric analysis of peripheral lymphocytes was performed in 22 patients with
      chronic-phase CML (CP-CML). CD45 gating analysis was used to discriminate between
      lymphocytes and basophils. The peripheral lymphocyte pool was comprised of a
      significant proportion of naive CD4 cells, defined by a CD4+45RA+ phenotype [47.0
      +/- 19.6% (mean +/- SD) of the total CD4+ cells], and naive CD8 cells, defined by
      a CD8+CD45RA+CD28+ phenotype (35.1 +/- 19.7% of total CD8+ cells), even in
      patients with long disease duration. The percentage of CD8 naive T cells showed
      inverse correlation with age, whereas no correlation was observed with disease
      duration. Possible explanations for the preservation of naive lymphocytes include
      (1) that the naive T cells differentiated from co-existing normal stem cells or
      (2) that long-lived naive T cells persisted from the CML onset and expanded
      peripherally (thymus independent). Either mechanism or a combination of both
      mechanisms might contribute to maintaining the naive compartment size.

PMID- 12472573
TI  - Etoposide-mediated deregulation of the G2M checkpoint in myeloid leukaemic cell
      lines results in loss of cell survival.
AB  - The K562 leukaemic cell line expresses an inherent survival signal due to the
      antiapoptotic properties of Bcr-abl, which is, in part, mediated by prolonging
      the G2M checkpoint and allowing DNA repair mechanisms to operate post genotoxic
      insult. Arrest of the cell cycle is mediated by retaining an inactivating state
      of phosphorylation of cyclin-dependent kinase 1 (Cdk1) on tyrosine 15. Our data
      confirmed that cell survival in K562 was promoted by cell cycle arrest at G2M in
      response to the genotoxin etoposide. There was no predicted cell cycle arrest in
      Bcr-abl-positive derivative cell lines of K562 that did not survive the same
      genotoxic insult but, paradoxically, Cdk1 tyrosine phosphorylation was enhanced
      to a higher extent compared with the parental cell line where arrest of the cell
      cycle was observed. To ascertain that this was not an anomaly of the derivative
      lines, HL60 cells were treated with concentrations of etoposide that induced
      arrest of the cell cycle or apoptosis. Only HL60 cells that subsequently
      underwent apoptosis elicited the same effect of increased Cdk1 tyrosine
      phosphorylation. It is proposed that the augmented tyrosine phosphorylation
      status of Cdk1 is associated with the abolition of cell survival, in addition to
      the previously reported induction of cell cycle arrest in myeloid cell lines.

PMID- 12472574
TI  - Histone deacetylase inhibitors potently repress CXCR4 chemokine receptor
      expression and function in acute lymphoblastic leukaemia.
AB  - The chemokine receptor CXCR4 plays a crucial role in the survival and trafficking
      of leukaemia cells and requires further attention as human immunodeficiency virus
      type I (HIV-I) utilises CXCR4 as the major coreceptor for cellular entry. We
      demonstrated that inhibitors of histone deacetylases, currently being tested in
      clinical trials for the treatment of various tumours, extensively downregulated
      CXCR4 protein and mRNA levels in leukaemia cell lines and lymphoblasts from
      patients with childhood acute leukaemia. As a result, the ability of stromal cell
      derived factor-1 to induce cellular migration was impaired. Repression of CXCR4
      transcription by inhibitors of histone deacetylases might therefore represent a
      promising novel approach in the treatment of acute leukaemias.

PMID- 12472575
TI  - Novel flow-cytometric analysis based on BCD5+ subpopulations for the evaluation
      of minimal residual disease in chronic lymphocytic leukaemia.
AB  - We describe a new flow-cytometric analysis using quadruple labelling with anti
      CD19, CD20, CD5, CD79b monoclonal antibodies and sequential gating. We determined
      a novel criteria defined by BCD5+CD79b-/low/total BCD5+ cells ratio (BCD5+R), and
      compared it with the previous definition of phenotypic remission, based on
      CD19+CD5+ coexpression, and with complementarity-determining region 3 polymerase
      chain reaction (CDR3 PCR) and clonotypic PCR (cPCR). A series of 54 peripheral
      blood samples from 21 chronic lymphocytic leukaemia (CLL) patients in complete
      haematological remission and a series of 16 from normal volunteers were analysed.
      In normal controls, the BCD5+R was always < 0.2. The sensitivity of the BCD5+R
      was 1 x 10-4vs 5 x 10-2 for CDR3 PCR and 1 x 10-5 for cPCR. Among the 54 CLL
      samples, 35 had a BCD5+R < 0.2 and showed polyclonal CDR3 PCR, whereas the cPCR
      was positive in 12 out of 20 tested. In the remaining 19 samples, BCD5+R was >
      0.2, CDR3 PCR was monoclonal in 16 out of 19 and cPCR positive in 14 out 14
      tested, including one out of three samples with polyclonal CDR3 amplification.
      Even though cPCR remains the most sensitive method to evaluate MRD, this new,
      sensitive and specific flow cytometric parameter, the BCD5+R, is more suitable
      than CDR3 PCR for routine clinical MRD assessment in CLL.

PMID- 12472576
TI  - Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or
      relapsed chronic lymphocytic leukaemia.
AB  - We evaluated the efficacy and toxicity of fludarabine combined with
      cyclophosphamide and mitoxantrone (FCM) in patients with relapsed or resistant
      chronic lymphocytic leukaemia (CLL). In total, 37 patients with recurrent or
      resistant CLL received FCM: fludarabine 25 mg/m2 intravenously (IV), d 1-3;
      cyclophosphamide 200 mg/m2 IV, d 1-3; and mitoxantrone 6 mg/m2 IV, d 1, at 4-week
      intervals for up to six courses. Moreover, 23 patients received FCM with
      cyclophosphamide 600 mg/m2 i.v. and mitoxantrone 8 mg/m2 i.v. on d 1. In addition
      to clinical methods, response was assessed using cytofluorometric and molecular
      techniques. 'In vitro' sensitivity to the FCM regimen was also analysed in 20
      samples. The median number of courses given was 3 (range: 1-6). Overall, 30
      patients (50%) achieved complete response (CR), including 10 cases of negative
      minimal residual disease (MRD(-)) (17%), and 17 (28%) partial response (PR). The
      median duration of response was 19 months. 'In vitro' sensitivity also correlated
      with CR achievement (P = 0.04). Main toxicity consisted of neutropenia,
      infections (8% of courses), and nausea and vomiting. The treatment-related
      mortality was 5%. FCM did not hamper stem cell harvesting in patients who were
      candidates for autologous stem cell transplantation. FCM induced a high CR rate,
      including an important number of MRD(-), in patients with previously treated CLL.

PMID- 12472577
TI  - Genetic polymorphisms in the tumour necrosis factor locus in childhood acute
      lymphoblastic leukaemia.
AB  - Genetic polymorphisms in the tumour necrosis factor (TNF) locus influence the
      outcome of non-Hodgkin's lymphoma (NHL). We investigated whether these
      polymorphisms might contribute to the clinical course of childhood acute
      lymphoblastic leukaemia (ALL). Genomic DNA from 214 childhood ALL patients was
      analysed. Patients with a high-risk haplotype were older than patients with low
      risk haplotype (P = 0.024). No statistically significant associations were found
      between TNF haplotype and sex, WBC counts, central nervous system involvement,
      immunophenotype, response to chemotherapy, and event-free survival. These data
      suggest that genetic polymorphisms in the TNF locus have a limited effect on the
      outcome of childhood ALL.

PMID- 12472578
TI  - Infrequent hypermethylation of CEBPA promotor in acute myeloid leukaemia.
AB  - The gene CEBPA, encoding the transcription factor C/EBPalpha, is crucial for
      granulocyte differentiation. We investigated the frequency of aberrant CEBPA
      promotor methylation with the methylation-specific polymerase chain reaction in
      70 patients with acute myeloid leukaemia (AML). Two patients, both with M2
      morphology, were found to have methylated CEBPA. In one of them, the fusion gene
      AML1/ETO, reported to cause transcription repression of CEBPA, was also present,
      suggesting that more than one mechanism might collaborate to suppress CEBPA gene
      expression. Aberrant CEBPA methylation is infrequent in AML, but may occur
      preferentially in the M2 phenotype.

PMID- 12472579
TI  - Protein A Sepharose immunoadsorption can restore the efficacy of platelet
      concentrates in patients with Glanzmann's thrombasthenia and anti-glycoprotein
      IIb-IIIa antibodies.
AB  - Type I Glanzmann's thrombasthenia is a rare congenital platelet function
      disorder, characterized by undetectable platelet membrane glycoprotein IIb-IIIa
      (GPIIb-IIIa). Severe bleeding is controlled by transfusion of normal platelets,
      leading in some cases to the occurrence of anti-GPIIb-IIIa isoantibodies, which
      induces a loss of transfused platelet efficacy. We used immunoadsorption on
      protein A Sepharose (IA-PA), which has been shown to be efficient in decreasing
      the titre of antibodies in several immune diseases, in three patients with
      Glanzmann's thrombasthenia and anti-GPIIb-IIIa isoantibodies on five different
      occasions. IA-PA was well tolerated with no deleterious side-effects reported. It
      induced a dramatic decrease of total immunoglobulin (Ig)G, including anti-GPIIb
      IIIa isoantibody levels, as assessed by the monoclonal antibody-specific
      immobilization of platelet antigens test and the ex vivo inhibition of normal
      platelet aggregation induced by the patient's platelet-rich or platelet-poor
      plasma. Elimination of the antibody was associated with a correction of the
      bleeding time following platelet transfusion. IA-PA combined with platelet
      transfusion made it possible to control two life-threatening haemorrhages, and
      allowed two surgical procedures and one bone marrow transplantation to be
      performed safely. Our experience suggests that IA-PA, which restores the
      haemostatic efficacy of platelet transfusion, is a valuable therapeutic strategy
      in patients with Glanzmann's thrombasthenia and anti-GPIIb-IIIa isoantibodies.

PMID- 12472580
TI  - Dissociation between fibrinogen and fibrin interaction with platelets in patients
      with different subtypes of Glanzmann's thrombasthenia: studies in an ex vivo
      perfusion chamber model.
AB  - To explore the possible role of a residual or variant alphaIIbbeta3 integrin
      (alphaIIbbeta3) in thrombogenesis, we used a new ex vivo perfusion chamber model
      to examine blood from patients with different subtypes of Glanzmann's
      thrombasthenia (GT). Non-anticoagulated blood was perfused through capillaries
      coated with type III collagen for 4.5 min (shear rate: 1600/s). Platelet
      deposition was quantified as platelet adhesion and mean thrombus size volume;
      fibrin and von Willebrand Factor (VWF) were specifically revealed by
      immunohistochemistry. In two patients with variant and in one patient with type
      II GT, platelet adhesion was maximal and we observed an unexpected formation of
      thrombi that were smaller than normal in size. These thrombi were surrounded by a
      thick meshwork that displayed a strong staining for fibrin and VWF. In two
      patients with heterozygous GT, platelet adhesion and thrombogenesis were normal.
      In two patients with type I GT, there was no thrombus formation, although
      platelet adhesion was also maximal. These data suggest the existence of a
      substitute pathway for thrombogenesis mediated by fibrin and possibly
      alphaIIbbeta3 (alphaIIbbeta3 at a reduced level, as in type II, and/or abnormal)
      as this fibrin network was not observed in type I GT with no alphaIIbbeta3. These
      interactions might facilitate haemostasis and even lead to thrombosis under
      certain favourable conditions. Furthermore, these data might have pharmacological
      relevance to the development of anti-alphaIIbbeta3 antithrombotic agents.

PMID- 12472581
TI  - Anticardiolipin antibodies as a risk factor for venous thromboembolism in a
      population-based prospective study.
AB  - Anticardiolipin antibodies, one of the family of 'antiphospholipid' antibodies,
      increase the risk of venous thromboembolism in the presence of autoimmune
      disease. Our objective was to determine prospectively whether there is a positive
      association between anticardiolipin antibodies and venous thromboembolism in
      ostensibly healthy adults. We conducted a nested case-control study (n = 317
      patients and n = 655 control subjects) in a longitudinal study of over 20 000
      participants. Baseline (prediagnosis) anticardiolipin IgG and IgM antibodies were
      assessed by enzyme-linked immunoassays. Venous thromboembolism was validated
      using standardized criteria for venous thrombosis and pulmonary embolism. There
      was no association between anticardiolipin antibodies and subsequent venous
      thromboembolism occurrence, overall or in any subgroup. For example, the
      multivariate-adjusted relative risk was 0.88 (95% confidence interval, 0.43,
      1.78) for greater than versus less than the 95th percentile of anticardiolipin
      IgG. In conclusion, in this general population sample, an elevated
      anticardiolipin antibody level was not a risk factor for venous thromboembolism.

PMID- 12472582
TI  - Impaired circadian variations of haemostatic and fibrinolytic parameters in
      tetraplegia.
AB  - Spinal cord injured patients are at increased risk of developing deep vein
      thrombosis (DVT). Whether these patients have increased blood levels of
      prothrombotic markers remains to be clarified. In general, the risk of developing
      DVT is highest in the morning hours. In healthy humans, several haemostatic and
      fibrinolytic parameters exhibit circadian variations, but it is not known whether
      this also applies to those with spinal cord injury. The aim of the present study
      was to examine possible circadian variations in prothrombotic markers in
      tetraplegic patients. We studied six patients with complete tetraplegia and eight
      control subjects with repetitive blood sampling over a 24 h period. While the
      control subjects showed marked circadian variations in factor VIII activity,
      prothrombin fragments 1+2 and D-dimer levels, the tetraplegic patients did not (P
      < 0.05). Circadian variation in plasminogen activator inhibitor type-1 was
      present in both groups, being most marked (P < 0.05) in tetraplegia. We conclude
      that the circadian variations of several factors of the haemostatic and
      fibrinolytic systems are impaired in spinal cord injury. This could possibly
      reflect a deregulated autonomic nervous system, leading to a dysfunctional link
      between central and peripheral circadian oscillators.

PMID- 12472583
TI  - Increased resistance to activated protein C after short-term oral hormone
      replacement therapy in healthy post-menopausal women.
AB  - As hormone replacement therapy is associated with an early excess risk of venous
      thrombosis, we investigated the effect of different oral hormone replacement
      therapies on resistance to activated protein C, and on levels of factor VIII
      antigen (FVIII:Ag) and factor XI antigen (FXI:Ag). In a prospective, randomized,
      placebo-controlled 12-week study, 60 healthy post-menopausal women daily received
      either placebo (n = 16) or 2 mg of micronized 17beta-oestradiol, either alone
      (E2, n = 16) or sequentially combined with dydrogesterone 10 mg (E2 + D, n = 14)
      or trimegestone 0.5 mg (E2 + T, n = 14). Medication was given orally. Normalized
      activated protein C sensitivity ratios (nAPCsr) were determined by quantifying
      the effect of activated protein C on the endogenous thrombin potential. FVIII:Ag
      and FXI:Ag were determined by enzyme-linked immunosorbent assay. Compared with
      baseline and placebo, the nAPCsr increased (92% to 142%; all P < 0.001) in all
      active treatment groups after both 4 and 12 weeks. Compared with placebo, hormone
      replacement therapy was not associated with significant changes in FVIII:Ag.
      After 4 and 12 weeks, FXI:Ag levels were significantly decreased in the E2 group
      (mean percentage changes from baseline versus placebo: -15.0%, P = 0.001 at 4
      weeks and -16.6%, P = 0.003 at 12 weeks) and in the E2 + D group (-10.4%, P =
      0.02 and -10.4%, P = 0.02). In conclusion, all hormone replacement regimens were
      associated with a large increase in resistance to activated protein C. In
      contrast, hormone replacement therapy had no effect on FVIII:Ag. Oral E2 and E2 +
      D had a small, favourable effect on FXI:Ag.

PMID- 12472584
TI  - Activation of integrin alphaIIbbeta3 expressed in Chinese hamster ovary cells is
      required for interaction with solid-phase von Willebrand factor.
AB  - Dithiothreitol (DTT) is known to induce an active conformation of alphaIIbbeta3
      integrin and to promote the aggregation of Chinese hamster ovary (CHO)
      alphaIIbbeta3 cells in the presence of soluble fibrinogen (Fg). The aim of this
      study was to compare adhesion and spreading with Fg or von Willebrand factor
      (VWF) of CHO-alphaIIbbeta3 cells in the presence or absence of DTT. Our results
      indicate that DTT treatment was required to induce cell spreading on VWF. In
      contrast, CHO-alphaIIbbeta3 cell spreading on Fg was already optimal in the
      absence of DTT. We used a small perfusion chamber coupled to videomicroscopy to
      demonstrate that CHO-alphaIIbbeta3 cells that were adherent and spread on VWF
      required DTT activation to resist to detachment under increasing shear rates (50
      1600/s). In contrast, untreated or DTT-treated cells spread on Fg were able to
      resist to extremely high flow rates. These data provide novel evidence that
      activated alphaIIbbeta3 is absolutely required for spread cells to resist
      detachment and strengthens the importance of the alphaIIbbeta3 activation step
      for adhesion and spreading to VWF.

PMID- 12472585
TI  - Mechanisms involved in the antiplatelet activity of magnesium in human platelets.
AB  - In this study, magnesium sulphate dose-dependently (0.6-3.0 mmol/l) inhibited
      platelet aggregation in human platelets stimulated by agonists. Furthermore,
      magnesium sulphate (3.0 mmol/l) markedly interfered with the binding of
      fluorescein isothiocanate-triflavin to the glycoprotein (GP)IIb/IIIa complex in
      platelets stimulated by collagen. Magnesium sulphate (1.5 and 3.0 mmol/l) also
      inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in human
      platelets stimulated by collagen. Magnesium sulphate (3.0 mmol/l) significantly
      inhibited thromboxane A2 formation stimulated by collagen in platelets. Moreover,
      magnesium sulphate (1.5 and 3.0 mmol/l) obviously increased the fluorescence of
      platelet membranes tagged with diphenylhexatriene. In addition, magnesium
      sulphate (1.5 and 3.0 mmol/l) increased the formation of cyclic adenosine
      monophosphate (AMP) in platelets. Phosphorylation of a protein of Mr 47 000 (P47)
      was markedly inhibited by magnesium sulphate (1.5 mmol/l). In conclusion, the
      antiplatelet activity of magnesium sulphate may involve the following two
      pathways. (1) Magnesium sulphate may initially induce membrane fluidity changes
      with resulting interference of fibrinogen binding to the GPIIb/IIIa complex,
      followed by inhibition of phosphoinositide breakdown and thromboxane A2
      formation, thereby leading to inhibition of both intracellular Ca2+ mobilization
      and phosphorylation of P47. (2) Magnesium sulphate might also trigger the
      formation of cyclic AM, ultimately resulting in inhibition of the phosphorylation
      of P47 and intracellular Ca+2 mobilization.

PMID- 12472586
TI  - Activation and inactivation of human factor X by proteases derived from Ficus
      carica.
AB  - We investigated the effect of proteases derived from Ficus carica (common fig) on
      human blood coagulation. The milky sap (latex) of several Ficus (F.) species
      contain ficin, which is a mixture of proteases. Ficin derived from Ficus carica
      shortened the activated partial thromboplastin time and the prothrombin time of
      normal plasmas and plasmas deficient in coagulation factors, except plasma
      deficient in factor X (FX) and generated activated FX (FXa) in defibrinated
      plasma. Chromatographic separation of ficin from Ficus carica yielded six
      proteolytic fractions with a different specificity towards FX. We isolated two
      factor X activators with molecular masses of 23.2 and 23.5 kDa, and studied their
      action on purified human FX. Factor X was converted to activated FXbeta by
      consecutive proteolytic cleavage in the heavy chain between Leu178 and Asp179,
      Arg187 and Gly188, and Arg194and Ile195 (FX numbering system) with concomitant
      release of a carboxy-terminal peptide. The cleavage pattern of FXa degradation
      products in the light chain was influenced by Ca2+ and Mn2+. These data suggest
      the haemostatic potency of Ficus proteases is based on activation of human
      coagulation factor X.

PMID- 12472587
TI  - Two double heterozygous mutations in the F7 gene show different manifestations.
AB  - We sequenced the factor VII gene (F7) in two unrelated Japanese patients with
      factor VII (FVII) deficiency. In the first (an asymptomatic 46-year-old man with
      FVII activity and antigen levels of 1.2% and 21% of normal respectively), novel
      E25K and H348Q mutations were identified in the doubly heterozygous state. In
      transiently transfected HEK293 cells, the level of FVII-E25K mutant activity in
      the culture media was significantly lower than that of FVII wild type, whereas
      the antigen levels of both proteins were similar. This suggests that the E25K
      mutation is associated with a dysfunctional FVII molecule. In the second patient
      (a 47-year-old woman with FVII activity and antigen levels of less than 1% and 6%
      respectively), an IVS4+1 mutation and a novel -96C to T transition were detected
      in the double heterozygous state. In electrophoretic mobility shift assays, the 
      96T mutation was shown to disrupt binding of Sp1.

PMID- 12472588
TI  - Clonal T cell-mediated cyclic thrombocytopenia.
AB  - Cyclic thrombocytopenia is a rare disorder characterized by periodic platelet
      count fluctuations of unknown aetiology. We report on a female patient with
      cyclic changes of platelet counts ranging from 6 x 10(9)/l to 753 x 10(9)/l in 4
      week intervals. Platelet counts were inversely correlated to thrombopoietin
      levels suggesting production failure. Reticulocyte counts and neutrophil counts
      showed similar, but less prominent, fluctuations. Clonal T-cell receptor
      rearrangement was detected in bone marrow samples as well as in peripheral blood.
      Cell typing of blood lymphocytes revealed a relative increase in CD3+ T cells.
      Treatment with cyclosporine A resulted in a substantial improvement of platelet
      counts. Taken together, we provide evidence for clonal T-cell mediated bone
      marrow failure with cyclic impairment of thrombopoiesis responsive to
      cyclosporine therapy.

PMID- 12472589
TI  - Does isochromosome 7q mandate bone marrow transplant in children with Shwachman
      Diamond syndrome?
AB  - We report on nine children with Shwachman-Diamond syndrome (SDS), eight of whom
      had clonal abnormalities of chromosome 7. Seven children had an isochromosome 7
      [i(7)(q10)] and one a derivative chromosome 7, all with an apparently identical
      (centromeric) breakpoint. Children with SDS are predisposed to myelodysplasia
      (MDS) and acute myeloid leukaemia (AML) often with chromosome 7 abnormalities.
      Allogeneic transplants have been used to treat these children, however, they are
      a high-risk transplant group and require careful evaluation. Three of the
      children were transplanted but only one survived, who to our knowledge remains
      the longest surviving SDS transplant patient (4.5 years +). The six non
      transplanted children are well. In classic MDS, chromosome 7 abnormalities are
      associated with rapid progression to acute leukaemia; however, we present
      evidence to suggest that isochromosome 7q may represent a separate disease entity
      in SDS children. This is a particularly interesting finding given that the SDS
      gene has recently been mapped to the centromeric region of chromosome 7. Our
      studies indicate that i(7)(q10) is a relatively benign rearrangement and that it
      is not advisable to offer allogeneic transplants to SDS children with i(7)(q10)
      alone in the absence of other clinical signs of disease progression.

PMID- 12472590
TI  - Expression and function of pituitary tumour transforming gene for T-lymphocyte
      activation.
AB  - Pituitary tumour transforming gene (PTTG) isolated from pituitary tumour cells
      transforms cells in vitro and causes in vivo tumour formation. PTTG is expressed
      in several human tumours and cell lines. In normal adult tissues, the testis
      expresses abundant levels of PTTG mRNA comparable to that found in tumour cells.
      Although PTTG is not expressed in resting T cells, we showed here that activation
      of normal adult human T cells using either immobilized anti-CD3 antibodies or
      phytohaemagglutinin was accompanied by marked PTTG induction, reaching levels
      observed in human tumour cells. Inhibitors of T-cell functions, such as
      cyclosporin A and hydrocortisone, decreased induction of PTTG mRNA expression.
      During T-cell activation, PTTG mRNA abundance corresponded with the increase in S
      phase cells, suggesting PTTG involvement in cell cycle-dependent processes. These
      results showed that PTTG-1 expression follows cell cycling patterns in T
      lymphocytes, providing a convenient model for studying PTTG functions in normal
      cells.

PMID- 12472591
TI  - Results and follow-up of a phase III randomized study of recombinant human
      granulocyte stimulating factor as support for immunosuppressive therapy in
      patients with severe aplastic anaemia.
AB  - In patients with idiopathic severe aplastic anaemia who are treated with
      immunosuppressive agents to combat T lymphocyte-mediated destruction of
      haematopoietic progenitor cells, neutropenia is a major cause of infections and
      toxicity. Evidence from preliminary studies suggests that recombinant human
      glycosylated granulocyte colony-stimulating factor (lenograstim) increases the
      number and functionality of neutrophils in patients with severe aplastic anaemia.
      This randomized, parallel-group, multicentre study was conducted to evaluate the
      efficacy and safety of subcutaneous lenograstim during the first 12 weeks of
      standard immunosuppressive therapy in 102 patients with de novo severe aplastic
      anaemia. The addition of lenograstim to standard therapy resulted in an increase
      in the proportion of patients showing complete neutrophil response (83.0%vs
      44.9%; P < 0.0001). This was seen even among patients with very severe aplastic
      anaemia (69.2%vs 31.6%; P = 0.012). In patients receiving lenograstim, median
      time to complete neutrophil response was shorter (6.3 vs 16.1 weeks; P = 0.0001)
      and mean duration of first neutrophil response was longer (P = 0.0248) than in
      the control group. At a median follow-up of 5 years, no difference was observed
      between the groups in term of survival, haematological response and occurrence of
      secondary leukaemia (one patient in each group). We conclude that lenograstim
      support of immunosuppressive therapy might be used for patients with severe
      aplastic anaemia as it significantly enhances neutrophil recovery but does not
      modify the overall response and survival.

PMID- 12472592
TI  - Human bone marrow angiogenesis: in vitro modulation by substance P and neurokinin
      A.
AB  - We have previously described a culture system for human bone marrow endothelial
      cells that organize into capillary tubes associated to pericytes. In the present
      work, we used this model to assess the angiogenic properties of tachykinins,
      which have been demonstrated to be involved in neuro-immuno-haematopoietic
      interactions. The substance P (SP) and neurokinin A (NKA) were similarly potent
      at increasing in vitro angiogenesis, via NK1 and NK2 receptors respectively.
      These mediators were not produced by cells in culture, suggesting that in vivo
      they may be released by nerve fibres in the bone marrow. Therefore, we looked for
      in situ innervation of the human bone marrow, unknown to date, using
      immunohistochemistry techniques. As in rodents, arterioles were largely
      innervated, associated with between one and 10 nerve fibres. Capillary
      innervation was more restrictive as a unique thin nerve fibre was found in the
      vicinity of only 6% of these vessels. Finally, no nerve fibres were observed in
      the vicinity of sinus walls. In conclusion, both in vitro results and the
      anatomical display of nerve fibres suggest a role in human bone marrow for the
      vasoactive neuropeptides SP and NKA, which were secreted into a perivascular
      location. These neural mediators might modulate blood flow in the bone marrow
      both in the short term by adjusting vascular tone and in the long term by
      inducing angiogenesis.

PMID- 12472593
TI  - Treatment of adult systemic mastocytosis with interferon-alpha: results of a
      multicentre phase II trial on 20 patients.
AB  - Systemic mastocytosis (SM) is characterized by proliferation of mast cells in
      various organs, which may release a wide variety of mediators, thereby explaining
      the broad clinical spectrum of disease manifestations. The potentially life
      threatening systemic symptoms and tumoral proliferation are poorly controlled
      despite the use of several cytotoxic chemotherapies and/or symptomatic
      treatments. Twenty consecutive adult SM patients with histologically confirmed
      bone marrow (BM) involvement received interferon-alpha subcutaneously (1-5
      million units/m2/d, with progressive dose intensification over the first month of
      treatment) and were evaluated after 6 months of therapy. Seven of them had
      previously received symptomatic treatments, including steroids, which were
      ineffective. Among the 13 patients treated for at least 6 months, seven partial
      and six minor responses, mainly concerning vascular congestion and skin lesions,
      were obtained, while BM infiltration remained unchanged in 12 patients. The
      significant reduction of mast-cell mediator levels after 6 months of treatment
      was not predictive of clinical remission. The rate of depression was unexpectedly
      high (seven patients; 35%). Two patients died soon after starting therapy (one
      myocardial infarction, one septic shock). Six months of interferon-alpha may
      relieve vascular congestion in adults with SM, probably by inhibiting mast-cell
      degranulation.

PMID- 12472595
TI  - A 3'UTR mutation affects beta-globin expression without altering the stability of
      its fully processed mRNA.
AB  - Determinants of mRNA stability are frequently positioned in the 3'UTR where they
      are not subject to disruption by actively translating ribosomes. Two related
      individuals with beta thalassaemia who carry a beta-globin gene containing a 13
      nt deletion in its 3'UTR have recently been described. Its position within the
      3'UTR, as well as its relative distance from other known functionally important
      elements, suggested that the deletion might overlay previously unrecognized
      determinants of beta-globin mRNA stability. We studied the impact of the Delta13
      mutation on beta-globin gene expression in vitro and in vivo. The adverse effect
      of the Delta13 mutation on beta-globin expression was confirmed in studies
      utilizing reticulocytes from a betaDelta13 heterozygote, which indicated a
      sixfold reduction in the relative level of the mutant mRNA. Additional in vitro
      analysis indicated that the deletion did not affect the capacity of the
      betaDelta13 mRNA to assemble an mRNA-stabilizing mRNP 'beta-complex'.
      Unexpectedly, functional tests in both primary erythroid cells and in a
      transgenic mouse model demonstrated that the betaDelta13 mRNA was fully stable,
      suggesting that the Delta13 mutation affects accumulation of the fully processed
      mRNA at an earlier step. Consistent with this, there was a relative excess of
      unprocessed betaDelta13 mRNA in erythroid progenitors from a betaDelta13
      heterozygote. Taken together, these results define a new thalassaemic
      determinant, which acts to decrease beta-globin mRNA levels by inhibiting the
      efficiency of nuclear processing events, and suggest a previously unanticipated
      complexity to the role of the 3'UTR elements in the regulation of beta-globin
      gene expression.

PMID- 12472594
TI  - Hydroxyurea exerts bi-modal dose-dependent effects on erythropoiesis in human
      cultured erythroid cells via distinct pathways.
AB  - Hydroxyurea (HU) has been shown to increase the proportion of fetal haemoglobin
      (HbF) in most sickle cell patients. A low-dosage regimen increased total
      haemoglobin (Hb) levels in some thalassaemia intermedia patients by
      preferentially increasing beta-globin biosynthesis. To further characterize these
      apparent dose-dependent effects of HU, we examined erythroid cells exposed to HU
      (5-100 micro mol/l) in two-phase liquid culture. Low doses (from 5 to 25 micro
      mol/l) increased Hb levels by up to 2.7-fold, and a high dose (100 micro mol/l)
      increased Hb levels when added at d 3-6 of phase II, with no significant changes
      in response to HU during the late stage of phase II culture (> or = 9 d). HU
      exposure during d 0-3 of phase II culture increased the number of erythroid
      colonies to a maximum of fivefold at 5 micro mol/l HU. GATA-1 mRNA was
      downregulated at a high dose and GATA-2 was dose dependently upregulated over a
      lower dosage range. Treatment with 100 micro mol/l HU dramatically upregulated
      the death receptor DR-5, caspase 3, as determined by cDNA microarray analysis. In
      contrast, 10 micro mol/l HU modestly upregulated mRNA levels of the early growth
      response gene. Our results suggest that HU exerts concentration-dependent effects
      on HbF production and erythropoiesis and that these two effects are mediated by
      distinct molecular mechanisms.

PMID- 12472596
TI  - Comparison of outcome following allogeneic bone marrow transplantation with
      cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide
      conditioning regimens for acute myelogenous leukaemia in first remission.
AB  - We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia
      free survival (LFS) and overall survival (OS) in patients receiving busulphan and
      cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI)
      prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous
      leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)
      matched sibling transplants using BuCy were compared with 200 transplants using
      CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive
      disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0.009). Risks of
      acute and chronic GVHD were similar. In multivariate analysis, relapse risk was
      higher in the BuCy group [relative risk (RR) = 1.72; 95% confidence interval
      (CI), 1.05-2.81; P = 0.031]. Eleven of 373 evaluable patients in the BuCy group
      had a central nervous system relapse in contrast to none of 194 evaluable
      patients in the CyTBI group (P = 0.016). There were no differences in TRM, LFS
      and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM,
      LFS and OS to BuCy for HLA-matched sibling transplantation in first remission
      AML.

PMID- 12472597
TI  - Respiratory virus infections in transplant recipients after reduced-intensity
      conditioning with Campath-1H: high incidence but low mortality.
AB  - Respiratory virus infections can cause serious morbidity and mortality after
      conventional allogeneic stem cell transplantation. However, the incidence and
      outcome of these infections after reduced intensity conditioning has not been
      reported. Between 1997 and 2001, 35 episodes of respiratory virus infections were
      noted in 25 of 83 transplant recipients conditioned with fludarabine, melphalan
      and Campath-1H, and 80% of them received early antiviral therapy. Parainfluenza
      virus (PIV) 3 was the commonest isolate (45.7%) followed by respiratory syncytial
      virus (37%). Patients with myeloma were more susceptible to these infections
      [odds ratio (OR) 4.1, P = 0.01] which were often recurrent in patients with
      severe acute or chronic graft-versus-host disease (GVHD) (OR 10.6, P = 0.03).
      Infection within the first 100 d (OR 5.0, P = 0.05) and PIV 3 (OR 9.2, P = 0.01)
      isolation were risk factors for developing lower respiratory infection. Although
      more than half of the episodes progressed to lower respiratory infection, the
      mortality was only 8%. This could have been due to early initiation of antiviral
      therapy, but the attenuation of pulmonary damage due to the reduced-intensity
      conditioning, low incidence of GVHD and, paradoxically, the low CD4+ T-cell
      subset in this setting might also have been contributory factors.

PMID- 12472598
TI  - The TNFd4 allele is correlated to moderate-to-severe acute graft-versus-host
      disease after allogeneic stem cell transplantation.
AB  - Certain cytokine gene polymorphisms may be associated with severe acute graft
      versus-host disease (GVHD) after allogeneic stem cell transplantation. The
      present study analysed 196 patients and their donors for TNF-308, TNFd, IL-10
      1064 and IL-10-1082 gene polymorphisms. Serum analysis of tumour necrosis factor
      alpha (TNF-alpha) and interleukin 10 (IL-10) levels during conditioning therapy
      was also performed. Among patients with sibling donors, the TNFd allele 4 was
      significantly correlated with acute GVHD grades II-IV (P < 0.01). Acute GVHD
      grades II-IV were more common among patients homozygous for the IL-10-1064 allele
      13 (P = 0.02). Patients homozygous for the TNF-308 allele (AA) correlated with
      higher TNF-alpha serum levels during conditioning (P = 0.02).

PMID- 12472599
TI  - Oral anticoagulation and dental extractions.

PMID- 12472600
TI  - Low-grade rectal malt lymphoma occurring in a patient with chronic lymphocytic
      leukaemia.

PMID- 12472601
TI  - How frequent is mutation in the mitochondrial cytochrome c oxidase gene in
      patients with myelodysplastic syndromes?

PMID- 12472603
TI  - Recurrent thromboembolism in a familial pseudohyperkalaemia patient with an
      intact spleen.

PMID- 12472606
TI  - Men's health promotion by general practitioners in a workplace setting.
AB  - A project to promote men's health through diabetes education and screening was
      undertaken throughout rural industries in 1999/2000 in the south-west of Western
      Australia. Five hundred and twenty-five men aged 40-65 years participated from 27
      industries. Sixty-four per cent of these men were identified at high-risk of
      developing diabetes and were referred to their general practitioner (GP) for
      follow-up. Seventy-six per cent of those at-risk visited their GP and hence the
      strategy adopted has been appropriate in engaging men in the preventive concept
      of seeking care, that is, getting them to attend their GP when they only have the
      risk factors but not the disease. However, men were left short of knowing how to
      achieve a change in their lifestyle behaviour and take appropriate action. Given
      the constraints of rural practice and the need to prioritise those with disease
      and gaps in service provision for both health services and GPs, there are two
      challenges: identifying those at-risk and modifying their behaviour.

PMID- 12472607
TI  - Obesity, smoking and hazardous drinking among men admitted to the surgical wards
      of a regional hospital.
AB  - The purpose of the study was to determine the prevalence of obesity, smoking and
      hazardous drinking, and identify opportunities for their reduction, among men
      admitted to the surgical wards of a regional hospital. A random sample of 80
      patients were interviewed. Nineteen per cent were obese, 29% smoked and 16% drank
      hazardously. Forty-seven per cent and 52% of those who were obese or smokers,
      respectively, had tried unsuccessfully to reduce their weight or smoking before
      admission, but mostly without professional support. A further 13% wanted to
      reduce their smoking but had not tried. Fifty-five per cent continued to try or
      still wanted to reduce these factors 3 months after discharge. Obesity and
      smoking could be common among male surgical inpatients in regional hospitals, a
      significant proportion of whom may welcome professional help with improving their
      lifestyle, but a larger multi-hospital study is needed to confirm this.

PMID- 12472608
TI  - Indigenous men taking their rightful place in society? A preliminary analysis of
      a participatory action research process with Yarrabah Men's Health Group.
AB  - Men's groups are increasingly being accepted as an important strategy in
      improving health and well-being, especially in Indigenous communities. However,
      it is hard to find systematic documentation and evaluation of such initiatives in
      the literature. This paper analyses the formative stages of a participatory
      action research (PAR) process which aims to engage and support the members of the
      Yarrabah Men's Health Group plan, implement and evaluate their activities. Data
      for the paper are based on a combination of a review of relevant literature,
      analysis of project documentation, participant observation and discussion and
      reflection with the participants of the men's group. The paper highlights the
      importance of (a) using a reflective approach, such as PAR, to engage men's
      support groups to clearly define the principles and values which both define them
      and to which they aspire and (b) personal development, education and employment,
      as a prerequisite for Indigenous men taking greater control and responsibility
      for their lives. These types of micro-level studies have important implications
      for the way community development is perceived and approached in Indigenous
      settings. There are also implications for the roles that academic researchers can
      play in supporting and adding value to community-driven initiatives to the mutual
      benefit of both parties.

PMID- 12472609
TI  - One approach to improving indigenous health care through medical education.
AB  - The present paper discusses some of the issues relating to the poorer health and
      shorter life expectancy of Australian Aboriginal and Torres Strait Islander
      peoples. The barriers to improvement include funding of the medical service, the
      nature of early contact between Indigenous peoples and the European settlers, and
      the complex nature of Indigenous cultures. The role of the new medical school at
      James Cook University is discussed in relation to its mission of meeting the
      health care needs of the population of tropical and rural North Queensland.
      Indigenous representation in the management of the Medical School, staff
      selection, student selection, and curriculum content are discussed, and
      recommendations are made for a partnership approach to achieving improvements in
      the functioning of the health system of the area.

PMID- 12472610
TI  - Does one size really fit all? Why the mental health of rural Australians requires
      further research.
AB  - In this paper the need for further investigation into the mental health of rural
      Australians will be discussed. It will be argued that while research to date has
      yielded valuable information, the volume and scope of existing studies has been
      inadequate to address the needs of the diverse and dynamic communities in non
      metropolitan Australia. The diversity that exists within rural Australia is
      examined and the potential effects of this diversity on mental health status are
      highlighted. Then a number of issues that are relevant to people living in non
      metropolitan areas that underscores the need for further study into rural mental
      health are identified. Finally, some specific areas that require further
      examination are outlined and some guiding principles for future mental health
      research are proposed.

PMID- 12472611
TI  - The mental health of rural Australians: developing a framework for strategic
      research.
AB  - This paper argues that lack of adequate research is a barrier to the long-term
      improvement of the mental health and well-being of rural Australians. Following
      from national mental health policy, potential research avenues in four broad
      domains (prevention and early intervention, pathways to care, outcome of illness
      and aetiology) are defined. These four broad domains are interdependent and
      research into them can be brought together into a simple framework or model. This
      model could be used to guide research into rurality and mental health. The
      proposed model uses the inclusive concept of place to capture the potential
      complexities of the rural locale as a variable in mental health and disorder. The
      model's predictor variables include both risk and resilience factors, and the
      outcome variables extend beyond morbidity to positive psychological wellness. It
      is proposed that this provisional model, and the strategic research that it
      directs, will act as a useful counterpoint to the more immediate evaluation and
      resourcing needs that confront rural mental health.

PMID- 12472612
TI  - Outcome measurement in rural mental health care: a field trial of rooming-in
      models.
AB  - The main objectives of this project, in rural Western Australia, were to collect
      information, compare and evaluate the functioning of novel types of psychiatric
      services, including rooming-in facilities, using outcome measurement tools, and
      to assess the attitude of mental health professionals towards routine outcome
      measurement. For the first time in rural health services, two outcome measurement
      tools were used for this purpose: the Health of the Nation Outcome Scales and the
      World Health Organization Short Disability Assessment Schedule. While staff at 11
      rural sites were trained in the use of outcome measurements, only staff from
      three sites were able to participate in the data collection that spanned for a
      year and shed information on 39 patients. Two of these sites were rooming-in
      facilities with different models of care and patient characteristics. Shortage of
      staff, lack of adequate local information technology support on sites and
      technical difficulties limited participation. The assessment of staff attitudes
      towards routine outcome measurement revealed a need to provide staff with reasons
      and incentives for incorporating outcome measurement into routine practice, in
      addition to provision of a thorough and on-going training and support in time and
      resources from management.

PMID- 12472613
TI  - Revisiting the past: the association for Australian rural nurses comes of age.

PMID- 12472617
TI  - Genital heat stress in men of barren couples: a prospective evaluation by means
      of a questionnaire.
AB  - Exposure to genital heat stress among men of barren couples was evaluated in a
      prospective study. Five hundred and forty-two consecutive patients referred for
      andrological examination were asked to complete a specific questionnaire at their
      first visit. For 449 patients who answered all questions, the individual score
      values could be calculated by scoring each answer with points. Patients with
      'idiopathic' oligoasthenoteratozoospermia had significantly higher score values
      when compared with men showing normozoospermia (P < 0.01), 'symptomatic'
      oligoasthenoteratozoospermia as a result of defined andrological disorders (P <
      0.01), cryptozoospermia (P < 0.01) or other pathological semen profiles (P <
      0.05). These data support the hypothesis that patients with 'idiopathic'
      oligoasthenoteratozoospermia are more exposed to genital heat stress than
      normozoospermic men. Moreover, in patients with a varicocele impairment semen
      quality was associated with significantly higher score values compared with the
      subgroup of men with normal semen profiles (P < 0.05). In contrast, the score
      values did not significantly differ between equivalent subgroups of men with a
      history of a retractile testis. Our observations indicate that the questionnaire
      used in the present study allows an integrative assessment of genital heat
      stress, which is superior to single factor analysis. Notably, the group of men
      with 'idiopathic' oligoasthenoteratozoospermia showed the highest mean score
      values for 10 of the 18 questions compared with the other groups. Prolonged
      sitting in a vehicle represented the only single factor with significantly
      different score values in patients with 'idiopathic' oligoasthenoteratozoospermia
      and those with normozoospermia (P < 0.05).

PMID- 12472618
TI  - Optimum usage of prilocaine-lidocaine cream in premature ejaculation.
AB  - Premature ejaculation is a common male sexual disorder in which orgasm and
      ejaculation occur before the desired moment. The primary therapeutic approach to
      premature ejaculation has been behavioural and pharmacotherapy. In this study, we
      evaluated the efficacy and optimum usage of lidocaine-prilocaine cream 5% in
      preventing premature ejaculation. Forty patients were examined in the study group
      and randomized into four groups, each comprising 10 patients. Patients in group 1
      applied lidocaine-prilocaine cream 5% for 20 min, the patients in group 2 applied
      it for 30 min, and the patients in group 3 applied the cream for 45 min before
      sexual contact, with all patients covering the penis with a condom. Patients in
      the fourth group applied a base cream as placebo. In group 1, the pre-ejaculation
      period increased to 6.71 +/- 2.54 min without any adverse effects. In group 2,
      although the pre-ejaculation period increased in four patients up to 8.70 +/-
      1.70 min, six patients in this group and all patients in group 3 had erection
      loss because of numbness. In the placebo group, there was no change in their pre
      ejaculation period. Therefore, lidocaine-prilocaine cream 5% is effective in
      premature ejaculation and 20 min of application time before sexual contact is the
      optimum period.

PMID- 12472619
TI  - Deterioration of spermatozoal plasma membrane is associated with an increase of
      sperm lyso-phosphatidylcholines.
AB  - Spermatozoa with plasma membranes that lost their asymmetry or permeability for
      larger molecules can be identified by binding of annexin V to membrane
      phosphatidylserine (PS). Paramagnetic annexin-V-conjugated microbeads (AN-MB) can
      be used to eliminate these spermatozoa by magnetic activated cell sorting (MACS).
      Semen samples of six healthy volunteers with normal spermiogram parameters were
      divided into two sperm fractions by MACS as a function of bound AN-MB, and their
      individual lipid compositions were examined by matrix-assisted laser desorption
      and ionisation time-of-flight mass spectrometry (MALDI-TOF MS). As a model
      system, liposomes composed of phosphatidylcholines (PC) from egg yolk were
      digested by phospholipase A2 (PLA2). The MALDI-TOF mass spectra of organic
      extracts of both sperm subpopulations differed significantly. The ratio between
      lyso-phosphatidylcholine LPC 16 : 0 and PC 16 : 0/22 : 6 was approximately 2.5
      4.7-fold higher (median 2.9) in the sperm group binding AN-MB than in spermatozoa
      with intact membrane unable to bind AN-MB. The ratio between LPC 22 : 6 and PC 16
      : 0/22 : 6 was also enhanced in the spermatozoa with impaired membrane structure
      (factor in the range: 1.9-3.9; median 2.6). These alterations corresponded to the
      effects of PLA2 on artificial phospholipids. It is concluded that spermatozoa
      with deteriorated membrane and exposed PS are characterized by an increased lyso
      phosphatidylcholine content that is likely generated by phospholipases.

PMID- 12472620
TI  - Effect of Lepidium meyenii (MACA) on sexual desire and its absent relationship
      with serum testosterone levels in adult healthy men.
AB  - This study was a 12-week double blind placebo-controlled, randomized, parallel
      trial in which active treatment with different doses of Maca Gelatinizada was
      compared with placebo. The study aimed to demonstrate if effect of Maca on
      subjective report of sexual desire was because of effect on mood or serum
      testosterone levels. Men aged 21-56 years received Maca in one of two doses:
      1,500 mg or 3,000 mg or placebo. Self-perception on sexual desire, score for
      Hamilton test for depression, and Hamilton test for anxiety were measured at 4, 8
      and 12 weeks of treatment. An improvement in sexual desire was observed with Maca
      since 8 weeks of treatment. Serum testosterone and oestradiol levels were not
      different in men treated with Maca and in those treated with placebo (P:NS).
      Logistic regression analysis showed that Maca has an independent effect on sexual
      desire at 8 and 12 weeks of treatment, and this effect is not because of changes
      in either Hamilton scores for depression or anxiety or serum testosterone and
      oestradiol levels. In conclusion, treatment with Maca improved sexual desire.

PMID- 12472621
TI  - First-trimester pregnancy loss and active Chlamydia trachomatis infection:
      correlation and ultrastructural evidence.
AB  - The incidence of Chlamydia trachomatis (Ct) infection and the possible
      correlation between couples presenting with first-trimester spontaneous abortions
      and active Ct infection was assessed. Additionally, the ability of Ct to infect
      zona-free hamster oocytes was explored by incubating the oocytes with spermatozoa
      from infected patients. A total of 961 women and 750 men consulting our
      reproductive medicine centre were screened for Ct using direct
      immunofluorescence. The general incidence of Ct infection was 9.4% in females (90
      of 961) and 13.9% in males (104 of 750). In women with spontaneous abortions the
      incidence of Ct was 21.0% (14 of 66) compared with 8.9% (23 of 59) for women
      without spontaneous abortions and term pregnancies (chi-square, P < 0.05). When
      both partners of the couples were considered (one or both partners infected), the
      incidence rose to 68.8% (22 of 32) (chi-square, P < 0.001). In vitro studies
      using electron microscopy demonstrated the presence of Ct on the surface of and
      inside the oocyte. These results indicate a correlation between an active Ct
      infection and spontaneous abortion. Electron microscopy studies suggested the
      possibility of direct oocyte infection by Ct. Two models are proposed for the
      pathogenesis of Ct-related early abortions: (i) direct zygote infection, and (ii)
      immune response to heat shock proteins expressed by the zygote and triggered by
      previous Ct infections.

PMID- 12472622
TI  - Computer-assisted analysis of sperm morphology with the aid of lectin staining.
AB  - Lectins are useful for staining the acrosome, which is a pre-requisite for the
      assessment of acrosome reaction in vitro. We tested wheat germ agglutinin, peanut
      agglutinin and pisum sativum agglutinin. The determination of the categories of
      normal and abnormal spermatozoa as defined by the World Health Organization,
      including an additional category 'acrosome-less cell', was performed with the aid
      of a system of computer-assisted semen analysis (CASA) in comparison with visual
      estimation. The acrosome reaction in vitro was induced by calcium ionophore
      A23187. Incubation with A23187 decreased the percentage of normal sperm heads and
      increased the number of acrosome-less sperm heads in comparison with the control
      samples. This shift was demonstrable with all three lectin staining procedures.
      No significant differences were observed in the comparison of sperm classes
      obtained by visual assessment or determination by CASA with two of the lectin
      staining procedures. After staining with pisum sativum agglutinin the classes of
      normal and of acrosome-less spermatozoa were significantly different between
      visual and CASA estimation. Our results indicate that estimation of the acrosomal
      status in vitro is possible by CASA when lectin staining is used.

PMID- 12472623
TI  - Expression of hyperacetylated histone H4 during normal and impaired human
      spermatogenesis.
AB  - Histone-to-protamine exchange in haploid spermatids is preceded by
      hyperacetylation of core histones resulting in decreased DNA-histone interaction.
      During normal spermatogenesis, immunohistochemistry with a polyclonal
      antihyperacetylated histone H4 antibody displayed a strong signal in nuclei of
      elongating spermatids and, in addition, spermatogonia. Quantitative analysis
      revealed 98.2 +/- 1.1% of immunopositive spermatids. The percentage of positive
      spermatids was significantly reduced in infertile men exhibiting at least
      qualitatively normal spermatogenesis (scores 10-8, 93.1 +/- 6.6%) and impaired
      spermatogenesis (scores 7-1, 74.9 +/- 23.4%). In seminiferous tubules showing
      spermatogenic arrest at the level of round spermatids, only 59.5 +/- 16.5% of
      spermatids were immunopositive for hyperacetylated histone H4. These data
      demonstrate that the decrease of histone acetylation in spermatids associated
      with impaired spermatogenesis corresponds with the well known reduction of
      protamine expression in these cells and confirms the essential role of histone
      hyperacetylation for correct histone-to-protamine exchange. In seminiferous
      tubules exhibiting round spermatid maturation arrest, there was an additional
      signal in nuclei of spermatocytes, suggesting that premature hyperacetylation of
      histone H4 may result in precocious histone-to-protamine exchange followed by
      infertility. This is in accordance with data from transgenic mice, where it has
      been demonstrated that premature expression of protamine-1 results in precocious
      chromatin condensation followed by sterility.

PMID- 12472624
TI  - The effects of melatonin on sperm motility in vitro in Wistar rats.
AB  - The effects of physiological concentrations of melatonin on motility of
      spermatozoa from Wistar rats were assessed in vitro. Melatonin had dose-dependent
      negative effects on sperm forward progression, the quality of sperm motility and
      on a sperm motility index. Some, but not all of these effects were due to ethanol
      (0.5% final concentration) which was used as a solvent for melatonin. Addition of
      ethanol to the incubation medium altered the pH, and increased pH had a
      significant negative effect on all aspects of sperm motility. Finally, the
      overlay of oil, which is a routine part of many sperm culture systems, had an
      ameliorating effect that was probably because of the lipophilic nature of
      melatonin.

PMID- 12472625
TI  - Sperm evaluation in cryopreserved bovine semen recovered by two selection
      methods.
AB  - Previous experiments have established that various semen manipulation techniques
      are able to increase the qualitative features of the spermatozoa used in
      different techniques of assisted reproduction, but practically no comparative
      data on frozen-thawed bovine semen have been found. The aim of this study was to
      compare the efficacy of two sperm selection methods: centrifugation on Percoll
      gradient and filtration through a Sephadex ion-exchange column, to improve the
      recovery of motile and morphologically normal spermatozoa, without inducing sperm
      damage, from cryopreserved bovine semen samples. Semen samples were thawed and
      centrifuged on a discontinuous Percoll gradient, or were filtered through a
      Sephadex G-15-120 column with the addition of ion exchangers. Sperm
      concentration, percentages of motile spermatozoa, acrosome integrity, superoxide
      dismutase activity and lipid peroxidation were evaluated in recovered samples and
      controls. The motility of spermatozoa obtained by Sephadex ion-exchange
      filtration (88.87 +/- 6.37%) and by Percoll gradient centrifugation (83.00 +/-
      6.21%) were significantly greater than that of control samples (60.14 +/- 8.44%).
      Other results disclosed that both sperm selection methods significantly increased
      the percentage of intact acrosome and superoxide dismutase activity. In both
      cases, the number of recovered spermatozoa diminished significantly versus
      untreated samples. Although the number of recovered spermatozoa was low, these
      methods were effective to select viable sperm from cryopreserved bovine semen.

PMID- 12472628
TI  - Complementary therapies for addictions: not an alternative.

PMID- 12472629
TI  - Reassessing the marijuana gateway effect.
AB  - AIMS: Strong associations between marijuana use and initiation of hard drugs are
      cited in support of the claim that marijuana use per se increases youths' risk of
      initiating hard drugs (the 'marijuana gateway' effect). This report examines
      whether these associations could instead be explained as the result of a common
      factor-drug use propensity-influencing the probability of both marijuana and
      other drug use. DESIGN: A model of adolescent drug use initiation in the United
      States is constructed using parameter estimates derived from US household surveys
      of drug use conducted between 1982 and 1994. Model assumptions include: (1)
      individuals have a non-specific random propensity to use drugs that is normally
      distributed in the population; (2) this propensity is correlated with the risk of
      having an opportunity to use drugs and with the probability of using them given
      an opportunity, and (3) neither use nor opportunity to use marijuana is
      associated with hard drug initiation after conditioning on drug use propensity.
      FINDINGS: Each of the phenomena used to support claims of a 'marijuana gateway
      effect' are reproduced by the model, even though marijuana use has no causal
      influence over hard drug initiation in the model. CONCLUSIONS: Marijuana gateway
      effects may exist. However, our results demonstrate that the phenomena used to
      motivate belief in such an effect are consistent with an alternative simple,
      plausible common-factor model. No gateway effect is required to explain them. The
      common-factor model has implications for evaluating marijuana control policies
      that differ significantly from those supported by the gateway model.

PMID- 12472630
TI  - 'Gateway effects': insights from economics are needed.

PMID- 12472631
TI  - Death of the 'stepping-stone' hypothesis and the 'gateway' model? Comments on
      Morral et al.

PMID- 12472632
TI  - An alternative model is feasible, but the gateway hypothesis has not been
      invalidated: comments on Morral et al.

PMID- 12472633
TI  - Evidence does not favor marijuana gateway effects over a common-factor
      interpretation of drug use initiation: responses to Anthony, Kenkel & Mathios and
      Lynskey.

PMID- 12472634
TI  - Witnessing heroin-related overdoses: the experiences of young injectors in San
      Francisco.
AB  - AIMS: Assessment of young injectors' exposure and response to others' heroin
      related overdose. DESIGN: Cross-sectional survey. SETTING: San Francisco, CA,
      United States. PARTICIPANTS: Nine hundred and seventy-three street-recruited
      current injectors under 30 years old. MEASUREMENTS: Self-reported experiences of
      witnessing heroin-related overdoses from structured interviews. FINDINGS: Seven
      hundred and nine of 973 (73%) had ever witnessed at least one heroin-related
      overdose, and 491 of 973 (50%) had witnessed an overdose in the last 12 months.
      Fourteen per cent of those who had witnessed an overdose in the past year
      reported that the outcome of the overdose was death. Emergency services were
      called to 52% of most recent witnessed overdoses. Cardiopulmonary resuscitation
      (CPR) or expired air resuscitation (EAR or 'rescue breathing') was performed in
      61% of cases. Inappropriate strategies such as injection with stimulants or
      application of ice were rare. In 67% of cases in which emergency services were
      not called the witness said this was because the victim regained consciousness.
      In the remaining 33%, 56% stated emergency services were not called due to fear
      of the police. CONCLUSIONS: Respondents were willing to act at overdoses at which
      they were present, but frequently did not do so in the most efficacious manner.
      Fear of police was identified as the most significant barrier to the ideal first
      response of calling emergency services.

PMID- 12472636
TI  - The impact of regular ecstasy use on memory function.
AB  - AIM: To assess memory impairment in a group of regular users of ecstasy compared
      with a group of regular users of cannabis, after accounting for possible
      confounding factors such as other drug use, premorbid intelligence and
      psychopathology. METHOD: Comparative and regression analysis was used to
      determine the presence or absence of a difference in memory function between 40
      regular ecstasy users and 37 regular users of cannabis, who were interviewed at
      the National Drug and Alcohol Research Centre in Sydney, Australia. Regression
      analysis was used to find associations between life-time exposure to ecstasy use
      and memory performance. Memory function was assessed using an age-standardized
      memory test. Other scales were used to assess premorbid intelligence, physical
      and psychological health, drug withdrawal and other drug use. RESULTS: Initial
      comparative analysis showed a trend towards a significantly poorer performance by
      the regular ecstasy-using group on the 'auditory immediate memory' and 'auditory
      delayed memory' indices. When regression analysis was performed an estimate of
      verbal intelligence was found to be the most predictive of most memory indices
      including 'auditory immediate memory' and 'auditory delayed memory'. Life-time
      exposure to ecstasy was not predictive of the memory indices. The current
      frequency of cannabis use was found to have some predictive effect for immediate
      and delayed visual memory. CONCLUSION: This study does not show memory impairment
      in a group of ecstasy users relative to cannabis using controls. The previously
      reported association of life-time exposure to ecstasy and memory was not found.
      The findings may indicate a confounding role of cannabis use, as has been
      recently reported.

PMID- 12472635
TI  - Recent contact with health and social services by drug misusers in Glasgow who
      died of a fatal overdose in 1999.
AB  - AIM: To explore the recent contact with health and social services by drug
      misusers who died of a fatal overdose and identify opportunities for preventive
      intervention. DESIGN: Retrospective case analysis. SUBJECTS: Eighty-seven
      residents of the Greater Glasgow area who died of a drug misuse-related overdose
      in 1999. METHODS: Analysis of matched data from several sources: Strathclyde
      Police; University of Glasgow Department of Forensic Medicine and Science; the
      Scottish Prison Service; general practitioners' medical notes, including records
      of accident and emergency attendances and psychiatric assessments; and five
      specialist agencies for drug misusers or the homeless. FINDINGS: Most of those
      who died of an overdose were males, long-standing heroin injectors and resident
      in a deprived area. Heroin caused most deaths, either alone or with other drugs.
      Twenty-three per cent died within 2 weeks of release from prison. For the 77
      whose medical records were available, 90% had seen their general practitioner
      (32% in the month before death), 48% had attended accident and emergency services
      and 22% had received a psychiatric assessment in the year before death. Over 40%
      of the 87 used a drug agency in the year before death and 20% had used more than
      one agency. CONCLUSIONS: Previous suicidal ideation, attempted suicide and
      depression were common among those who died of an overdose, as was recent release
      from prison. Almost all had been in contact with and several were receiving
      specific treatment from health or specialist addiction services in their last
      weeks or months. The findings highlight both the numerous opportunities for
      intervention and the challenge of using them to prevent death.

PMID- 12472637
TI  - The content of ecstasy tablets: implications for the study of their long-term
      effects.
AB  - AIMS: To examine the variation in the content of ecstasy tablets seized in the
      north-west of England during 2001 and to compare it to the UK average from 1991
      to 2001. MEASUREMENTS: All tablets submitted to the Forensic Science Service in
      the north-west of England during 2001 were analysed by high performance liquid
      chromatography with diode array detection (HPLC-DAD). The mean MDMA content of
      these tablets are reported and compared to results from all Forensic Science
      Service laboratories in the United Kingdom from 1991 to 2001. Multiple samples
      (n= 80) from a single large seizure of White Dove tablets were analysed to
      determine the variation due to manufacturing. FINDINGS: All tablets submitted
      from the north-west of England to the Forensic Science Service in 2001 were found
      to contain 3,4-methylenedioxymethamphetamine (MDMA) and some also contained 3,4
      methylenedioxyethamphetamine (MDEA). The MDMA content of these tablets ranged
      from 20 to 109 mg and the mean was in the 60-69 mg range. Mitsubishi tablets were
      the most common type and they were found across the whole range. The low
      variation of MDMA content in the White Dove tablets suggests that these tablets
      were well manufactured. The data from the north-west of England in 2001 are in
      agreement with tablet analyses over the past 10 years which show that the average
      MDMA content is falling. CONCLUSIONS: The amount of MDMA in ecstasy tablets is
      axiomatic to the discussion of their long-term effects. In order for the observed
      differences in ecstasy users to be the result of MDMA-induced neurotoxicity it is
      necessary for them to have ingested one or more neurotoxic doses. These data
      indicate that the amount of MDMA in ecstasy tablets is dropping and that dose
      effect relationships need to take this into account.

PMID- 12472638
TI  - Parental substance use as a modifier of adolescent substance use risk.
AB  - AIMS: A major question in national substance use prevention efforts is how much
      influence parents have on their children's substance use, answers to which could
      determine whether current school-based prevention programs that address peer
      pressure are sufficient or whether parents need to be involved. The present study
      examines whether parents act as gatekeepers by testing the moderator effects of
      parents' substance use on the relationships of friends' substance use to
      adolescent substance use (cigarettes, alcohol and marijuana). DESIGN: A
      longitudinal school-based trial for prevention of substance use in adolescents.
      SETTING: Indianapolis, Indiana, USA. PARTICIPANTS: As part of a large substance
      use prevention trial, entering middle school students were surveyed prospectively
      at baseline, 6 months and 18 months (n = 1807 from 57 schools). MEASUREMENTS: A
      self-reported survey was used to measure behaviors, attitudes and social
      influences related to adolescent substance use. FINDINGS: Results of logistic
      regression analyses and multiple group structural equation modeling showed that
      increasing numbers of parents and friends using substances were associated with
      greater risk of adolescent substance use, as were more substance offers and lower
      levels of refusal self-efficacy. Additionally, refusal self-efficacy mediated the
      effects of baseline use and substance offers on subsequent use. However, non
      using parents had a buffering effect on friends' influences to use substances,
      such that friends' use did not affect adolescent use when parents were non-users,
      and the effects of substance offers on refusal self-efficacy were weaker.
      CONCLUSIONS: The findings suggest that parent substance use should be addressed
      in adolescent substance use prevention programs, and that continuing non-use by
      parents should be reinforced.

PMID- 12472639
TI  - Drug use and initiation in prison: results from a national prison survey in
      England and Wales.
AB  - AIMS: To investigate heroin and cocaine use in a sample of British prisoners, and
      to explore the characteristics of inmates who use these drugs for the first time
      while in prison. DESIGN, PARTICIPANTS: A cross-sectional survey of all prisons in
      England and Wales conducted as part of a major national study of psychiatric
      morbidity. A total of 3142 prisoners (88.2% of those selected) completed a
      structured interviewer-administered questionnaire. MEASUREMENTS: Interview
      measures of personal demographics, social history, psychiatric morbidity and drug
      use. Personality disorders were diagnosed via the Structured Clinical Interview
      for DSM-IV (SCID-II) and neurotic symptoms were assessed using the revised
      Clinical Interview Schedule (CIS-R). FINDINGS: More than 60% of the heroin users
      and cannabis users reported that they had used these drugs in prison compared
      with less than a quarter of the life-time cocaine users. More than a quarter of
      the heroin users reported that they had initiated use of this drug in prison. The
      extent of an individual's experience of prison was related more consistently to
      heroin and/or cocaine use in and out of prison than other personal background,
      social history or psychiatric variables assessed. CONCLUSIONS: The findings
      indicate that prisons are a high-risk environment for heroin and other drug
      initiation and use. Although related to drug use, psychiatric variables were not
      generally associated with initiation in prison, which was dominated by prison
      exposure. There is a need to explore ways of reducing heroin initiation in prison
      as part of a broader risk-prevention strategy.

PMID- 12472640
TI  - An international comparison of tobacco smoking, beliefs and risk awareness in
      university students from 23 countries.
AB  - AIMS: To assess the prevalence of current tobacco smoking, associations with
      beliefs about the health benefits of not smoking and awareness of risks for lung
      cancer and heart disease in university students sampled from 23 countries, and to
      explore the utility of the World Health Organization (WHO) model of the world
      wide tobacco epidemic in understanding differences between countries. DESIGN:
      Anonymous questionnaire survey. PARTICIPANTS: A total of 19 298 university
      students (8482 men, 10 816 women) aged 17-30 years from 23 countries, studying
      courses unrelated to health. MEASUREMENTS: Standardized measures of smoking, wish
      to stop smoking, ratings of beliefs in the importance of not smoking for health
      and awareness of the influence of smoking on lung cancer and heart disease.
      FINDINGS: Prevalence varied widely, being highest in samples from South European
      countries and lowest in developing countries (Thailand, South Africa). The
      pattern of tobacco use and differences between men and women conformed largely to
      the WHO model. Health beliefs were associated strongly with smoking behaviour
      both within and between countries. Awareness of specific health risks of smoking
      was very variable, with particularly low levels in Asian, South American and
      developing country samples. Risk awareness was inconsistently related to
      behaviour. CONCLUSIONS: The pattern of tobacco smoking in well-educated young
      adults appears to conform with wider international patterns of tobacco use.
      Awareness of specific health risks is poor, and modifying attitudes must be a
      central element in modifying tobacco use world-wide.

PMID- 12472641
TI  - Young people and alcohol: an econometric analysis.
AB  - AIMS: To analyse the determinants of youth drinking behaviour within an economic 
      theoretical framework. The paper focuses especially on the effects of (a) having
      parents willing to supply alcohol, (b) living in a single-parent household, (c)
      having parents who are currently unemployed and (d) having received education
      about alcohol, narcotics and tobacco. DESIGN, SETTING AND PARTICIPANTS: A Swedish
      cross-sectional survey data on 833 individuals aged 12-18 years was used to
      analyse the effects of the above variables on participation in drinking,
      frequency of drinking, intensity of drinking and binge drinking. Separate
      analyses were conducted for beer, wine and spirits. Care was taken in using
      appropriate econometric methods for the questions posed (negative binomial
      regression, censored regression and probit regression). FINDINGS: Having parents
      willing to supply alcohol increased frequency (P < 0.05) of beer, wine and
      spirits consumption, intensity (P < 0.05) of wine, spirits and illicit alcohol
      consumption, and increased probabilities (P < 0.10) of binge drinking and
      participation in drinking (P < 0.05). No effects were seen from living in a
      single-parent household. Having received education about alcohol, narcotics and
      tobacco had a negative association only with intensity (P < 0.10) of beer
      consumption. Having a father who was currently unemployed was associated with an
      increased (P < 0.05) probability of binge drinking but a reduced (P < 0.05)
      frequency of wine consumption. CONCLUSIONS: The positive effect of having parents
      willing to supply alcohol could reflect that these individuals face lower
      acquisition costs or lower psychological costs in consumption. It could also
      reflect a price effect, if the individual receives the alcohol free from his or
      her parents.

PMID- 12472642
TI  - More Canadian students drink but American students drink more: comparing college
      alcohol use in two countries.
AB  - AIMS: To compare alcohol use among US and Canadian college students. DESIGN:
      Results of the 1999 College Alcohol Study and the 1998 Canadian Campus Survey are
      compared. SETTING: One hundred and nineteen nationally representative US 4-year
      colleges and universities in 40 states and 16 nationally representative Canadian
      4-year universities. PARTICIPANTS: Randomly selected students under 25 years (12
      344 US and 6729 Canadian). MEASUREMENTS: Self-reports of alcohol use and heavy
      alcohol use. FINDINGS: The prevalence of life-time and past year alcohol use is
      significantly higher among Canadian students than US students (92% versus 86%,
      87% versus 81%). The prevalence of heavy alcohol use (typically consuming five or
      more drinks in a row for males/four or more for females) among past-year and past
      week drinkers is significantly higher among US students than Canadian students
      (41% versus 35%, 54% versus 42%). In both countries older [corrected] students
      and students living at home with their parents are less likely to be heavy
      drinkers; students who report first drunkenness before the age of 16 are more
      likely to be heavy drinkers in college. CONCLUSION: Programs aimed at students'
      heavy alcohol use should target freshman at entry or earlier. Since students
      living with their parents are less likely to be heavy drinkers, parents may play
      a potentially important role in prevention efforts. The patterns of drinking in
      both countries may be influenced by the legal minimum drinking age. However, the
      relationship is complex and must be viewed in the context of other variables such
      as chronological age.

PMID- 12472643
TI  - Alcoholism and somatic comorbidity among homeless people in Mannheim, Germany.
AB  - AIMS: To assess the prevalence of alcoholism and somatic codisorders of homeless
      people. DESIGN: Epidemiological cross-sectional field study in a sample of the
      homeless in the area. SETTING: The study was conducted from 1997 to 1999 in the
      inner-city area of Mannheim, Germany (approximately 320 000 inhabitants).
      PARTICIPANTS: One hundred and two single homeless people (15-16% of the estimated
      total population of single homeless people in the city). MEASUREMENT: Alcoholism,
      substance abuse and mental disorders were diagnosed with the SCID. Medical
      examinations were performed by an experienced physician. Blood samples were taken
      and urine samples collected. Further assessments were conducted for factors
      potentially correlating with mental or physical state. FINDINGS: Of the study
      probands, 63.7% presented with the alcohol dependence syndrome or harmful use,
      61.7% had current somatic problems or disorders. Probands with alcohol dependence
      had significantly more frequent somatic disorders in total, more cerebral
      degeneration, liver disease or alcoholic polyneuropathies. Multiple stepwise
      regression identified alcoholism, life-satisfaction, duration of homelessness and
      lacking social support as significant explanatory factors for having a somatic
      disorder. Alcoholism increased the risk of physical ill-health more than
      fourfold. CONCLUSION: Alcoholism is a major contributor to the physical ill
      health of homeless people. Treatment or rehabilitation of addictive behaviour
      among the homeless should be of major concern for adequate service planning or
      provision.

PMID- 12472644
TI  - Measuring problem video game playing in adolescents.
AB  - AIMS: Some researchers suggest that for some people, video game playing is an
      addictive behaviour similar to substance dependence. Our aim was to design and
      validate a scale to measure the problems associated with the apparently addictive
      use of all types of video games and video game systems, because there is no
      instrument at the present time that can be used for this purpose. DESIGN: We
      reviewed the DSM-IV criteria for substance dependence and for pathological
      gambling, as well as the literature on the addictions in order to design a short
      scale (PVP; problem video game playing) that is quick and easy to apply.
      PARTICIPANTS: The scale was administered to 223 Spanish adolescents aged between
      13 and 18 years. The study was carried out in Granada and Algeciras, Spain.
      FINDINGS: Psychometric analyses show that the PVP seems to be unidimensional and
      has acceptable internal consistency (Cronbach's alpha) at 0.69. The pattern of
      associations between the scale scores and alternative measures of problem play
      supports its construct validity (higher total scores in the scale were associated
      with higher frequency of play, mean and longest times per session, self and
      parents' perception of playing to excess, and scores in the Severity of
      Dependence Scale). CONCLUSIONS: Our results confirm that the excessive use of
      video games is associated with a number of problems which resemble a dependence
      syndrome, and the PVP appears as a useful instrument for the measurement of such
      problems.

PMID- 12472645
TI  - Beyond the U-curve: a reply to Peretti-Watel et al.

PMID- 12472646
TI  - Sports involvement can be both formal and informal at the same time: a comment on
      Peretti-Watel et al.

PMID- 12472647
TI  - More about sport and drugs use: context, competition and 'integrative' drugs.

PMID- 12472648
TI  - Managerial considerations in implementing hepatitis B vaccination programs among
      drug-using cohorts.

PMID- 12472656
TI  - Tumor escape from killing: role of killer inhibitory receptors and acquisition of
      tumor resistance to cell death.
AB  - Immunotherapy of cancer has always been a very attractive fourth-modality
      therapeutic approach. Over the past few years, advances in the identification of
      tumor antigens have offered new perspectives and provided new opportunities for
      more accurate immunotherapy for cancer. However, when applied to patients with
      established tumors, it rarely leads to an objective response. This is partly due
      to the fact that tumors evade host immunity at both the induction and effector
      phases. Thus, understanding tumor escape mechanisms may be the key to successful
      immunotherapy for cancer. In the present review, we will focus on how the
      expression of killer Ig receptors (KIR) on tumor infiltrating lymphocytes can
      compromise their function and how tumors evade apoptotic death - two additional
      mechanisms of tumor escape.

PMID- 12472657
TI  - HLA polymorphism in a Majorcan population of Jewish descent: comparison with
      Majorca, Minorca, Ibiza (Balearic Islands) and other Jewish communities.
AB  - 'Chueta' was the name given to the Catholic descendants of Jewish victims of the
      last Spanish Inquisition process in Majorca Island in the western Mediterranean.
      We have studied the allele distribution of HLA-A, -B, -Cw, -DRB1 and -DQB1 loci
      of 103 random, healthy, unrelated individuals belonging to the ancient Majorcan
      Jewish community, known locally as Chuetas, and 589 individuals from the Balearic
      population selected because of their typical Balearic - Majorca, Minorca or Ibiza
      - lineages and according to their ancestor's place of birth. Our aim was to
      establish the genetic relationship between Majorcan Chuetas, and Balearic and
      other Jewish and Mediterranean populations. Our results have shown that, to a
      remarkable extent, they have retained their biological identity, with a unique
      pattern, in terms of gene and haplotype frequencies, separate from the other
      populations of Majorca. The Chuetas were found to be more related to Moroccan and
      Libyan Jews than other Majorcans. Characteristic Jewish haplotypes, A26-B38
      DRB1*13, A24-B38-DRB1*11, A1-B52-DRB1*15/16, were found in our study. Some
      peculiarities were observed in the distribution of common haplotypes among the
      three main Balearic Islands. The Ibizan population was genetically different from
      the other Balearic populations, with a high frequency of some haplotypes, for
      example, A29-Cw*16-B44-DRB1*07-DQB1*03; A1-Cw*07-B8-DRB1*03-DQB1*02. We also
      found a new haplotype, A25-Cw*12-B39-DRB1*11-DQB1*03(3.5%), in Ibizans and a more
      limited variability in the HLA alleles that were expressed, perhaps because of
      genetic isolation. The genetic diversity of the populations from Majorca and
      Minorca were similar and more related to the mainland Spanish population.

PMID- 12472658
TI  - Psoriasis is associated with a SNP haplotype of the corneodesmosin gene (CDSN).
AB  - A psoriasis susceptibility locus has been mapped to the HLA region in the
      proximity of the HLA-C locus. This critical region also contains the CDSN gene
      coding for the corneodesmosin protein. In a case-control association study of
      psoriasis in the Sardinian population, we analyzed the allele distribution of
      eight intragenic SNPs (positions 619, 767, 1215, 1118, 1236, 1243, 1331, 1593) of
      the CDSN gene and the six haplotypes that are coded by these SNPs. Our study
      showed that these CDSN haplotypes are very stable and well-conserved in the
      Sardinian population. The CDSN2 haplotype was found to be associated with
      susceptibility to psoriasis. The association did not depend upon any one of the
      intragenic SNPs taken separately. At the HLA-C locus, the Cw6 and Cw7 alleles
      were dragged along by linkage disequilibrium with the CDSN2 haplotype and only
      revealed a trend towards association with the disease. Therefore, the intragenic
      SNPs of the CDSN gene and the HLA-Cw6 and Cw7 alleles are not directly involved
      in susceptibility to psoriasis. However, the strong association of the CDSN2
      haplotype suggests a possible role for the CDSN gene and its chromosome region in
      susceptibility to psoriasis.

PMID- 12472659
TI  - Conserved TCR beta chain usage in reactive arthritis; evidence for selection by a
      putative HLA-B27-associated autoantigen.
AB  - Previous work suggested that expanded CD8+ T-cell clones in the synovial fluid
      (SF) of HLA-B27+ patients with reactive arthritis (ReA) preferentially use the T
      cell receptor variable region (TCRBV) 1, similar CDR3 sequences, and joining
      region (BJ) 2S3. To determine the range of conservation and disease-specificity
      of CDR3-sequences, we analyzed the TCRBV1-J2S3 repertoire from 33 healthy HLA
      B27+ individuals, patients with various types of spondyloarthropathies (SpA), and
      with rheumatoid arthritis (RA) by CDR3-spectratyping. After collection and
      database submission of all available TCRB-CDR3 from HLA-B27-restricted or SpA
      derived T cells, we systematically screened the entire human sequence database
      for sequences similar to the B27/SpA-related CDR3. Spectratyping revealed
      expanded T cell clones using conserved TCRBV1J2S3 in the SF from 5/6 of the
      patients with acute ReA but not among the controls. In database searches, 50 HLA
      B27 or SpA-related CDR3-sequences generated similar clusters of matched
      sequences, and matched reciprocally. Identical or closely related sequences were
      identified in 15 different individuals and a canonical ReA-associated TCRB was
      defined [BV1-CASSVG(V/I/L)(Y/F)STDTQYF-J2S3]. All but one patient-derived
      conserved sequences originated from acute stage ReA-patients, and were not
      present among approximately 3800 other human TCRB sequences in the database. Five
      of the conserved sequences originated from T cell clones that recognized
      uninfected cells in an HLA-B27-restricted fashion, implying a role of HLA-B27
      restricted CD8+ T cells specific for a ubiquitous self- or cross-reactive
      microbial determinant in the early phase of ReA. Related sequences were
      independently identified in four different laboratories. The consensus TCRB motif
      could be a helpful diagnostic marker in HLA-B27-associated 'undifferentiated
      arthritis'.

PMID- 12472660
TI  - HLA-A and -B allele associations with secondary dengue virus infections correlate
      with disease severity and the infecting viral serotype in ethnic Thais.
AB  - Little is known of the role of classical HLA-A and -B class I alleles in
      determining resistance, susceptibility, or the severity of acute viral
      infections. Appropriate paradigms for immunogenetic studies of acute viral
      infections are dengue fever (DF) and dengue hemorrhagic fever (DHF). Both primary
      and secondary infections with dengue virus (DEN) serotypes 1, 2, 3 or 4, can
      result in either clinically less severe DF or the more severe DHF. In secondary
      exposures, a memory response is induced in immunologically primed individuals,
      which can both clear the infecting dengue virus and contribute to its pathology.
      In a case-control study of 263 ethnic Thai patients infected with either DEN-1, 
      2, -3 or -4, we detected HLA class I associations with secondary infections, but
      not in immunologically naive patients with primary infections. HLA-A*0203 was
      associated with the less severe DF, regardless of the secondary infecting virus
      serotype. By contrast, HLA-A*0207 was associated with susceptibility to the more
      severe DHF in patients with secondary DEN-1 and DEN-2 infections only.
      Conversely, HLA-B*51 was associated with the development of DHF in patients with
      secondary infections, and HLA-B*52 was associated with DF in patients with
      secondary DEN-1 and DEN-2 infections. Moreover, HLA-B44, B62, B76 and B77 also
      appeared to be protective against developing clinical disease after secondary
      dengue virus infection. These results confirm that classical HLA class I alleles
      are associated with the clinical outcome of exposure to dengue virus, in
      previously exposed and immunologically primed individuals.

PMID- 12472661
TI  - Recognition of ADP-ribosylation factor 4-like by HLA-A2-restricted and tumor
      reactive cytotoxic T lymphocytes from patients with brain tumors.
AB  - Although specific immunotherapy is one candidate treatment of brain tumor, the
      molecular basis of T-cell-mediated recognition of brain tumors has not yet been
      elucidated. In this study, we tried to identify brain tumor antigens using HLA-A2
      restricted and tumor-reactive cytotoxic T lymphocytes (CTLs). As an HLA-A2
      restricted OK-CTL line contained CTLs capable of responding to HLA-A2+ malignant
      glioma cells, this cell line was used for identification of brain tumor antigens.
      After screening a cDNA library from brain tumor cells, this CTL line was found to
      produce interferon (IFN)-gamma when cultured with COS-7 cells, which were
      cotransfected with both a cDNA clone (clone 1) and HLA-A0207 cDNA. Data base
      searches indicated that the clone 1 was 98% identical to that of the human ADP
      ribosylation factor 4-like (ARF4L). Two peptides, ARF4L 15-24 and ARF4L 69-77,
      possessed the ability to induce HLA-A2-restricted and tumor-reactive CTLs from
      peripheral blood mononuclear cells of patients with brain tumors. Although ARF4L
      seemed to be ubiquitously expressed at the mRNA level, ARF4L-reactive CTLs failed
      to exhibit cytotoxicity against normal lymphoid blasts. These results indicate
      that these two ARF4L peptides could be targets for immunotherapy of HLA-A2+
      patients with brain tumors.

PMID- 12472662
TI  - Molecular and serological identification of the HLA-A*3404 allele.
AB  - In this report we describe a novel HLA-A*34 allele, A*3404, which was initially
      detected by an unusual serological pattern in two unrelated individuals.
      Sequencing revealed that the new allele was identical to A*3402 in exons 2 and 3,
      except for a single nucleotide difference at position 238, changing codon 56 from
      glycine to arginine. The codon change resulted in positive serological reactions
      with several sera recognizing A30 and/or A31, implicating an important role for
      this position in epitope recognition. The allele was identified twice on the
      haplotype A*3404, B*1402, Cw*0802, DRB1*14, DQB1*05.

PMID- 12472663
TI  - Sequence of the HLA-B*1573 allele.
AB  - We report here the sequence of an HLA B*15 allele, B*1573. Initially, a cord
      blood unit from the Umbilical Cord Bank of Barcelona was typed by sequence
      specific oligonucleotide hybridization and revealed an unusual hybridization
      pattern. After the cloning, the sequence-based typing assigned two different
      alleles: B*07021, and a second allele identical to B*1558 in exons 2 and 3,
      except for a single nucleotide substitution in exon 3, which changed codon 140
      from Phe to Leu (TTX-->TTA).

PMID- 12472664
TI  - Point mutation in the beta sheet of the HLA-C alpha2 domain generates a novel HLA
      C allele, HLA-Cw*08012, in a Puyuma Aboriginal individual in Taiwan.
AB  - We report herein the identification of a new HLA-C allele using sequence-based
      typing (SBT). This novel allele, HLA-Cw*08012, was found in an Aboriginal
      individual from the Puyuma tribe in the southern part of Taiwan. This individual
      was typed by the SBT method as having an HLA genotype of HLA-A*2402/2402, HLA
      B*1502/4801, HLA-Cw*08011/08012, HLA-DRB1*15011/08032, HLA-DRB5*01011, and
      DPB1*0501/1401. This new allele differs from HLA-Cw*08011 in one of the
      nucleotides of the polymorphic exon 3 at codon 99 [TAT-->TAC; both code for
      tyrosine]. This residue is located in the beta sheet of the HLA-C alpha2 domain.
      This new allele was detected in a few individuals of the Puyuma tribe in Taiwan,
      but has not yet been observed in other populations in Taiwan.

PMID- 12472665
TI  - Macrophage-stimulating protein and RON receptor tyrosine kinase: potential
      regulators of macrophage inflammatory activities.
AB  - Macrophage-stimulating protein (MSP) is a serum protein belonging to the
      plasminogen-related growth factor family. The specific receptor for MSP is the
      RON (recepteur d'origine nantais) receptor tyrosine kinase - a member of the MET
      proto-oncogene family. Activation of RON by MSP exerts dual functions on
      macrophages. The stimulatory activities include the induction of macrophage
      spreading, migration and phagocytosis. However, MSP also inhibits
      lipopolysaccharide (LPS)-induced production of inflammatory mediators, including
      inducible nitric oxide and prostaglandins. These suppressive effects are mediated
      by RON-transduced signals that block LPS-induced enzymatic cascades that activate
      nuclear factor kappa-B (NFkappaB) pathways. Recent in vivo studies demonstrated
      that inactivation of the RON gene results in increased inflammatory responses and
      susceptibility to LPS-induced septic death in mice, suggesting that RON
      expression is required for attenuating the extent of inflammatory responses in
      vivo. Thus, MSP and RON are potential regulators that control macrophage
      activities during bacterial infection in vivo.

PMID- 12472666
TI  - Sublethal concentrations of complement can effectively opsonize Borrelia
      burgdorferi.
AB  - The fate of borreliae invading a human may depend on the early innate response
      they induce. The interactions of human complement system and neutrophils with two
      strains of the Lyme borreliosis spirochete Borrelia burgdorferi were studied.
      Borrelia burgdorferi sensu stricto B31 (resistant to a 28% concentration of
      normal human serum (NHS)) and Borrelia garinii Bg A218/98 (sensitive to 7% NHS)
      were examined. Both strains induced neutrophil oxidative burst in a complement
      dependent manner. B31 required the presence of 7% NHS, but Bg A218/98 required
      the presence of only 0.7% NHS for optimal induction of the burst. At all
      concentrations of NHS, the proportion of the spirochetes with C3bi on their
      surfaces and the relative amount of C3bi bound per spirochete were larger with Bg
      A218/98 than with B31. Bg A218/98 was able to induce an oxidative burst, when
      provided with serum with blocked classical pathway of complement, whereas B31
      required the presence of the classical pathway. We suggest a role for the
      opsonizing effect of complement in controlling borreliae that are either
      resistant to direct killing by complement or located in the compartments of the
      human body at sublethal concentrations of the same.

PMID- 12472667
TI  - CD40, CD154, Bax and Bcl-2 expression in Sjogren's syndrome salivary glands: a
      putative anti-apoptotic role during its effector phases.
AB  - Sjogren's syndrome (SS) is an autoimmune rheumatic disorder characterized by
      chronic lymphocytic infiltration and decreased secretion in the salivary glands
      (SGs). For some time, apoptosis has been suggested to constitute the major
      mechanism for acinar epithelial destruction during the effector phases; however,
      this is still controversial. We have recently demonstrated that despite the
      expression of Fas and FasL, the incidence of apoptosis is not increased in SS
      patients compared with control individuals. Our aim was therefore to further
      evaluate the expression of the pro- and anti-apoptotic Bax and Bcl-2 proteins.
      CD40 and CD154 expression was also investigated, as CD40 ligation has been
      suggested to protect cells from Fas-mediated apoptosis. Immunohistochemical
      staining was performed on SG tissue from primary and secondary SS patients, a
      group of patients with non-SS-related degenerative changes as well as on healthy
      control individuals. The frequency of stained cells in the foci of infiltrating
      mononuclear cells (IMCs) and in the acinar and ductal epithelium was determined.
      We found the expression of Bcl-2 but rarely Bax in SS SG IMCs. Bcl-2 in
      epithelial cells was sparse, while Bax expression occurred frequently and with no
      significant difference between the patient groups. CD40 and CD154 expression was
      high among SS IMCs, while CD40 levels were slightly decreased in SS epithelium
      compared with controls. Elevated CD154 expression was found in SS epithelium,
      being significantly increased in the ducts. In conclusion, our study further
      supports the hypothesis about apoptosis resistance among SS focal IMCs and
      suggests a putative protective role of CD40 ligation in SS SG epithelium.

PMID- 12472668
TI  - TSST-1 induces Th1 or Th2 differentiation in naive CD4+ T cells in a dose- and
      APC-dependent manner.
AB  - Superantigens are potent activators of the immune system, causing a variety of
      diseases, ranging from food poisoning to septic shock. Here, we examined the
      effects of different toxic shock syndrome toxin 1 (TSST-1) concentrations on the
      activation, proliferation and synthesis of interferon-gamma (IFN-gamma) and
      interleukin-4 (IL-4) in purified naive human CD4+ T cells in a serum-free in
      vitro system. TSST-1 given in low doses (1-10 pg/ml) generates a pronounced T
      helper 2 (Th2)-like cytokine profile, characterized by elevated IL-4-expressing T
      cell populations and reduced IFN-gamma-producing populations, whereas higher
      doses (100 pg/ml) induce a Th1-like profile, with increased expression of IFN
      gamma and reduced expression of IL-4. These patterns were even more pronounced by
      adding exogenous cytokines like IL-12 and IL-4 and by the type of antigen
      presenting cells (APCs). Thus, B cells induced Th2 shifts, whereas monocytes
      favoured Th1 induction. Moreover, IL-12 in conditions with B cells counteracted
      their Th2 bias. Interestingly, in purified naive T-cell cultures, containing a
      small population of HLA-DR+ T cells, Th1/Th2 differentiation can be induced by
      TSST-1 too. There, Th-cell polarization is strongly dependent on TSST-1
      concentration, indicating that this is a key parameter in regulating the
      differentiation of T cells. In conclusion, our data show that Th1/Th2
      differentiation of TSST-1-stimulated naive T cells is controlled by the type of
      APCs, and in APC-depleted cultures, it depends on the presence of HLA-DR+ cells
      and TSST-1 concentration.

PMID- 12472669
TI  - Cross-reaction between mammalian cell entry (Mce) proteins of Mycobacterium
      tuberculosis.
AB  - In addition to the previously cloned Mce1A and Mce1E genes of the Mce1 operon of
      Mycobacterium tuberculosis (Ahmad et al. Scand J Immunol 1999;50:510-8), Mce1B,
      Mce1D and Mce1F were cloned and expressed as glutathione-S-transferase (GST)
      fusion proteins in recombinant Escherichia coli. Polyclonal antibodies against a
      predicted B-cell epitope of each of the Mce1 proteins of M. tuberculosis were
      produced by immunizing rabbits with synthetic peptides coupled to keyhole limpet
      haemocyanin. These antibodies reacted specifically with the corresponding fusion
      protein, except for GST-Mce1F. A mouse monoclonal antibody, TB1-5 76C, raised
      against a synthetic 60-mer peptide corresponding to the residues 106-165 in the N
      terminal part of Mce1A, reacted strongly with GST-Mce1A. The antibody cross
      reacted with GST-Mce1F, but not with the other recombinant GST-Mce1 fusion
      proteins or free GST. Bioinformatic analysis revealed only slight homology
      between Mce1A and Mce1F, along the length of the polypeptide chains. Higher
      homology was found between the residues 106-165 of Mce1A and the residues 347
      406, further into the mature Mce1F polypeptide chain. There was a striking,
      localized homology, indicating that the epitope reacting with the monoclonal
      antibody TB1-5 76C may be narrowed to the KRRITPKD region, the residues 131-138
      in Mce1A corresponding to the residues 372-379 in Mce1F. This was confirmed in
      enzyme-linked immunosorbent assay, showing binding of TB1-5 76C to a 17-mer
      synthetic peptide containing the KRRITPKD sequence.

PMID- 12472670
TI  - C1-inhibitor reduces the ischaemia-reperfusion injury of skeletal muscles in mice
      after aortic cross-clamping.
AB  - BACKGROUND: Both C1-inhibitor (C1-INH) and antibodies against the CD18 adhesion
      molecule have been shown to reduce ischaemia-reperfusion injuries. The objective
      of this study was to investigate the effect of increased ischaemia times and to
      determine whether inhibiting C1 or blocking the CD18 function was protective in
      skeletal muscle ischaemia-reperfusion injury after aortic cross-clamping.
      MATERIALS AND METHODS: BALB/c mice were subjected to aortic cross-clamping below
      the renal artery for 60, 75 or 105 min, followed by 3 h of reperfusion. Two
      thirds of a total dose of anti-CD18 antibody (40 mg/kg) or human C1-INH (1,000
      IU/kg) was given by intraperitoneal injection before ischaemia and one-third
      immediately after the clamping. Creatine kinase (CK) in the plasma was used as an
      indicator of muscle injury severity. RESULTS: There was a consistent rise in the
      plasma CK concentration proportional to the length of ischaemia (P < 0.0005). C1
      INH treatment significantly (P = 0.012) reduced the plasma CK for the ischaemia
      times of 75 and 105 min. The anti-CD18 antibody did not have any effect, as
      demonstrated by the CK values that were similar to controls (P = 0.836).
      CONCLUSION: The data support a beneficial role for C1-INH in the treatment of
      ischaemia-reperfusion injuries of skeletal muscles.

PMID- 12472671
TI  - Analysis of gene expression during maturation of immature dendritic cells derived
      from peripheral blood monocytes.
AB  - Dendritic cells (DCs) are the most important antigen-presenting cells. Many
      recent studies have compared the function of immature DCs (iDCs) and mature DCs
      (mDCs), but there have been few reports of the molecular changes that occur in
      DCs during maturation. Here, we report on differential gene expression in iDCs
      generated from peripheral blood monocytes compared with mDCs. Gene expression was
      evaluated using the differential display method after activation of iDCs with a
      low concentration of lipopolysaccharide (LPS) to induce maturation. Proteasome
      subunit alpha type 3 (PSMA3), transcription factor EC (TFEC) isoform and BTK
      region clone 2f10-rpi were transiently upregulated. Tryptophanyl-tRNA synthetase
      and CD63 antigen were upregulated for at least 24 h. Neuronal apoptosis
      inhibitory protein (NAIP) and transforming growth factor-beta-induced 68 kDa
      protein were downregulated. This is the first report of NAIP expression in human
      DCs. By comparing the expression of NAIP with that of other members of the
      inhibitor of apoptosis protein (IAP) family and the Bcl-2 family, only NAIP was
      found to be strongly expressed in iDCs before stimulation by LPS. PSMA3 was also
      induced in the DCs stimulated with immune complex. These findings might
      contribute to our understanding of DC maturation and the effectiveness of DC
      based vaccines.

PMID- 12472672
TI  - IL-15 induces unspecific effector functions in human peptide-specific CD8+ T-cell
      cultures.
AB  - Antigen (Ag)-specific CD8+ T cells are a major host defence against viral
      infections. In the present study, we generated human CD8+ T-cell lines specific
      towards influenza matrix peptide (IMP)-pulsed Ag-presenting cells. We compared
      the effect of interleukin-2 (IL-2) and IL-15 on the proliferation and cytotoxic
      activity of primary and secondary IMP-specific cytotoxic T lymphocyte (CTL)
      culture. In primary CTL cultures, IL-15-induced cell expansion was considerably
      reduced as compared with IL-2-induced cell expansion, and IL-15 favoured the
      outgrowth of CTLs without peptide specificity in these cultures. Secondary IMP
      specific CD8+ T cells were generated by the addition of IL-2 during two cycles of
      restimulation. From the third restimulation, identical CTL cultures were expanded
      with either IL-2 or IL-15 in parallel. Cell expansion as well as Ag specificity
      was considerably reduced after a 5 day culture period in the presence of IL-15.
      No or low CD69 expression was observed in IL-15-cultured CTLs, whereas IL-2
      cultured CTLs contained high fractions of CD69+ cells. Furthermore, a high
      fraction of these latter cells coexpressed the cytotoxic marker CD56. However, IL
      15-cultured CTLs exhibited cytotoxic activity without detectable expression of
      CD56, suggesting that CD56 is not essential for cytotoxic activity. Thus, the
      results presented suggest that IL-15 favours the outgrowth of unspecific
      cytotoxic effector T cells.

PMID- 12472674
TI  - Polymorphisms in interleukin-1beta and interleukin-1 receptor antagonist genes
      and malaria in Ghanaian children.
AB  - We have investigated the possible associations between polymorphisms in two
      interleukin-1 (IL-1) genes and severity of Plasmodium falciparum malaria in
      Ghanaian children with cerebral malaria, severe anaemia or uncomplicated malaria
      and controls. There was no significant difference in genotype and allele
      frequencies in IL-1beta exon 5 or interleukin-1 receptor antagonist (IL-1ra)
      polymorphisms between the studied groups, suggesting that the two polymorphisms
      may not be involved in the pathogenesis of severe malaria. When parasitaemias in
      uncomplicated malaria patients were evaluated, a significantly higher level of
      parasitaemia was observed among carriers of IL-1beta A2 allele as compared with
      noncarriers of this allele (P = 0.01). The mean parasitaemia in an age-matched
      asymptomatic group did not reveal such associations. These data suggest that IL
      1beta exon 5 allele 2 may play a possible role in the clinical outcome of
      uncomplicated malaria.

PMID- 12472673
TI  - IL-18 production in human pulmonary and pleural tuberculosis.
AB  - Interleukin-18 (IL-18) has multiple important pro-inflammatory effects, including
      the induction of interferon-gamma (IFN-gamma) in various diseases. In this study,
      we investigated the IL-18-producing activities in human pulmonary and pleural
      tuberculosis (TB) in response to purified protein derivative (PPD) antigen (Ag)
      from Mycobacterium tuberculosis. The most significant IL-18 production was found
      in chronic refractory TB (CRTB) patients. However, IFN-gamma production in CRTB
      patients was significantly less than that in healthy tuberculin reactors or in
      patients with tuberculous pleurisy (TBP). Elevated levels of both IL-18 and IFN
      gamma were found in pleural fluids from TBP patients. In vitro production of IL
      18 was dramatically decreased following an 18 h stimulation with PPD. However,
      IFN-gamma was markedly increased in pleural mononuclear cells from TBP patients
      after in vitro stimulation with PPD. The mesothelial cell type was the main
      source of pro-IL-18 in pleural cells from TBP patients, suggesting an important
      role for these cells in TBP. Taken together, these data indicate that IL-18 is
      elevated in peripheral blood mononuclear cells from CRTB patients, as well as at
      the site of TBP, indicating a possible role for IL-18 in both protective immunity
      and pathologic responses in human TB.

PMID- 12472675
TI  - Do autoantibodies predict autoimmune liver disease in primary Sjogren's syndrome?
      Data of 180 patients upon a 5 year follow-up.
AB  - OBJECTIVE: To evaluate the clinical value of autoantibodies as serological
      markers to predict autoimmune liver diseases in primary Sjogren's syndrome (SS).
      MATERIALS AND METHODS: 180 patients who met the European diagnostic criteria for
      SS but without a history of liver disease were studied upon a 5 year follow-up.
      Sera taken at enrolment were evaluated by immunofluorescence analysis (IF-AMA) on
      rat liver, stomach and kidney sections, enzyme-linked immunosorbent assay using
      rat mitochondrial, microsomal and soluble liver antigens and Western blot (WB)
      analysis using rat mitochondrial antigens. RESULTS: At presentation, 152 (84%)
      sera had autoantibodies. Antinuclear antibodies (ANA) were expressed in 58% of
      patients and displayed three distinct patterns (speckled, homogenous and
      anticentromere). Smooth muscle autoantibodies (SMAs) and parietal cell
      autoantibodies were found in 39 and 4.5% of patients, respectively. Three
      patients presented antimitochondrial antibodies by IF-AMA, and two of them
      developed symptomatic primary biliary cirrhosis (PBC). Two patients without IF
      AMA and without evidence of cholestasis had PBC-specific AMA (anti-PDC-E2 and
      anti-BCKADC-E2). However, these two patients and the third IF-AMA-positive woman
      remained free from symptoms and biochemical signs of PBC. Autoimmune hepatitis
      (AIH) (n = 2), 'overlap syndrome' of AIH and chronic hepatitis C (n = 1) and
      autoimmune cholangiopathy (AIC) (n = 1) were diagnosed in four patients.
      CONCLUSIONS: Patients with IF-AMA usually develop symptomatic PBC upon a 5 year
      follow-up. Our findings support the idea that patients without IF-AMA, who
      express PBC-specific AMA, are in early, asymptomatic stage of the disease. High
      titre SMA and IF-AMA are the most specific indicators for AIH and PBC.

PMID- 12472676
TI  - Analysis of the relationship between mannose-binding lectin (MBL) genotype, MBL
      levels and function in an Australian blood donor population.
AB  - The mannose-binding lectin (MBL) pathway of complement activation is an important
      component of innate host defence. Numerous studies have described associations
      between the MBL genotype, MBL levels and disease susceptibility. However,
      genotyping and quantitative assays used in these studies have frequently been
      limited, and comprehensive data examining the interaction between structural and
      coding MBL genetic variants, MBL antigenic levels and MBL functional activity are
      lacking. Such data may be important for accurate planning and interpretation of
      studies of MBL and disease. This study has examined MBL in a cohort of 236
      Australian blood donors. Five MBL promoter and coding single nucleotide
      polymorphisms were genotyped using polymerase chain reaction-sequence-specific
      priming (PCR-SSP). Plasma levels of MBL antigen were quantified using a double
      antibody enzyme-linked immunosorbent assay (ELISA), and functional MBL levels
      were quantified using a mannan-binding assay. Activation of the complement
      pathway by MBL was measured in a C4-deposition assay. Significant associations
      were found between both coding and promoter polymorphisms and MBL antigenic and
      functional levels. There was significant correlation between the results of MBL
      double-antibody, mannan-binding and C4-deposition assays. Comprehensive MBL
      genotyping and functional MBL quantitation using mannan-binding and C4-deposition
      assays have the potential to be highly informative in MBL disease association
      studies.

PMID- 12472677
TI  - Neutralization titres and vertical HIV-1 transmission.
AB  - Replication of the human immunodeficiency virus type 1 (HIV-1) isolate MN in CEM
      cells was less neutralized by the plasma from the mothers of infected children
      (MIC) in comparison with the plasma from the mothers of uninfected children
      (MUC). Significantly higher neutralization titres were observed for the sera from
      MUCs compared with MICs, and only the sera from MUC showed 100% neutralization of
      the HIV-1 MN strain. We suggest that a simple neutralization assay as described
      here could be useful in prognostic analyses.

PMID- 12472678
TI  - Structural, quantitative and functional comparison of amyloid P component in sera
      from patients with systemic lupus erythematosus and healthy donors.
AB  - Serum amyloid P component (SAP) is a serum protein that has a function as opsonin
      and is known to bind nuclear material with high affinity. Quantitative and/or
      qualitative deficiencies in SAP may possibly lead to the impairment of normal
      homoeostatic mechanisms of tissue turnover. Thus, SAP knockout mice display
      systemic lupus erythematosus (SLE)-like manifestations such as nephritis and
      circulating antinuclear antibodies. In the present study, we investigated whether
      there are changes in the structure, function or serum levels of SAP in serum from
      SLE patients as compared with those from healthy donors. We found that SAP in SLE
      sera has the same molecular mass as that of in the sera of normal individuals,
      when analysed by online immunoaffinity reversed phase mass spectrometry. Also,
      the serum levels of SAP did not differ significantly between the two groups.
      Finally, as an estimate of function, SAP from SLE patients appeared to have the
      same affinity for heparin and nucleosomes as SAP from normal individuals, when
      analysed by crossed affinity immunoelectrophoresis and enzyme-linked
      immunosorbent capture assay (ELISA). In conclusion, the data do not support
      alterations in the levels, structure or function of SAP circulating in SLE
      patients.

PMID- 12472679
TI  - Interferon-gamma-secreting T cells localize to the epithelium in coeliac disease.
AB  - Increased levels of interferon-gamma (IFN-gamma) transcripts have previously been
      found in duodenal biopsy specimens from patients with untreated coeliac disease
      (CD). Such samples and duodenal control mucosa were therefore studied to locate
      and phenotype cells spontaneously secreting IFN-gamma. Specimens were collected
      from consecutively recruited patients with untreated (seven), treated (four) or
      refractory (three) CD and from five histologically normal controls. Morphological
      and immunohistochemical examinations were performed, and epithelial and lamina
      propria cell suspensions were prepared from parallel samples. Unstimulated viable
      cells secreting IFN-gamma were identified and phenotyped with a new fluorescence
      activated cell sorter-based assay, and IFN-gamma messenger RNA (mRNA) was
      analysed in snap-frozen aliquots of the same suspensions. Untreated CD cases had
      the highest fraction of IFN-gamma+ cells in the epithelial compartment (median
      2.6%, range 1.6-6.2%) and, less strikingly, in the lamina propria compartment
      (1.6%, range 0.3-3.6%), followed by refractory (1.4%, 1.0-1.9%; and 0.3%, 0.0
      1.2%) and treated (0.8%, 0.5-0.9%; and 0.7%, 0.2-1.1%) disease and finally the
      controls (0.5%, 0.3-0.9%; and 0.2%, 0.1-0.7%). IFN-gamma mRNA data supported
      these findings. IFN-gamma+ intraepithelial lymphocytes were mostly CD3+ and CD8+,
      whereas many positive lamina propria cells were CD8-. We conclude that isolated T
      cells spontaneously secreting IFN-gamma localize preferentially in the epithelium
      of patients with classical and refractory CD.

PMID- 12472681
TI  - Polyribosome loading of spinach mRNAs for photosystem I subunits is controlled by
      photosynthetic electron transport.
AB  - In light-, but not in dark-grown spinach seedlings, the mRNAs for the nuclear
      encoded photosystem I subunits D, F and L are associated with polyribosomes and
      this association is prevented by the application of 3-(3',4'-dichlorophenyl)-1,1'
      dimethyl urea (DCMU), an inhibitor of the photosynthetic electron transport. To
      identify the cis-elements which are responsible for this regulation, we generated
      a series of chimeric PsaD constructs and tested them in transgenic tobacco. The
      spinach PsaD 5'-untranslated region is sufficient to confer light- and
      photosynthesis-dependent polyribosome association onto the uidA reporter gene,
      while the tobacco PsaD 5'-untranslated region directs constitutive polyribosome
      association. These results are discussed with regard to signals from
      photosynthetic electron flow which control processes in the cytoplasm.

PMID- 12472682
TI  - Differential regulation of TGA transcription factors by post-transcriptional
      control.
AB  - Transcription factors often belong to multigene families and their individual
      contribution in a particular regulatory network remains difficult to assess. We
      show here that specific members from a family of conserved Arabidopsis bZIP
      transcription factors, the TGA proteins, are regulated in their protein stability
      by developmental stage-specific proteolysis. Using GFP fusions of three different
      Arabidopsis TGA factors that represent members of distinct subclasses of the TGA
      factor family, we demonstrate that two of these TGA proteins are specifically
      targeted for proteolysis in mature leaf cells. Using a supershift gel mobility
      assay, we found evidence for similar regulation of the cognate proteins as
      compared to the GFP fusion proteins expressed under the cauliflower mosaic virus
      (CaMV) 35S promoter. Using various inhibitors, we showed that the expression of
      at least one of these three TGA factors could be stabilized by inhibition of
      proteasome-mediated proteolysis. This study indicates that TGA transcription
      factors may be regulated by distinct pathways of targeted proteolysis that can
      serve to modulate the contribution of specific members of a multigene family in
      complex regulatory pathways.

PMID- 12472683
TI  - RCY1, an Arabidopsis thaliana RPP8/HRT family resistance gene, conferring
      resistance to cucumber mosaic virus requires salicylic acid, ethylene and a novel
      signal transduction mechanism.
AB  - The dominant locus, RCY1, in the Arabidopsis thaliana ecotype C24 confers
      resistance to the yellow strain of cucumber mosaic virus (CMV-Y). The RCY1 locus
      was mapped to a 150-kb region on chromosome 5. Sequence comparison of this region
      from C24 and a CMV-Y-susceptible C24 mutant predicts that the RCY1 gene encodes a
      104-kDa CC-NBS-LRR-type protein. The RCY1 gene from C24, when expressed in the
      susceptible ecotype Wassilewskija (Ws), restricted the systemic spread of virus.
      RCY1 is allelic to the resistance genes RPP8 from the ecotype Landsberg erecta
      and HRT from the ecotype Dijon-17, which confer resistance to Peronospora
      parasitica biotype Emco5 and turnip crinkle virus (TCV), respectively.
      Examination of RCY1 plants defective in salicylic acid (SA), jasmonic acid (JA)
      and ethylene signaling revealed a requirement for SA and ethylene signaling in
      mounting a resistance response to CMV-Y. The RCY1 nahG etr1 double mutants
      exhibited an intermediate level of susceptibility to CMV-Y, compared to the
      resistant ecotype C24 and the susceptible ecotypes Columbia and Nossen. This
      suggests that in addition to SA and ethylene, a novel signaling mechanism is
      associated with the induction of resistance in CMV-Y-infected C24 plants.
      Moreover, our results suggest that the signaling pathways downstream of the RPP8,
      HRT, and RCY1 have evolved independently.

PMID- 12472684
TI  - Mutation in domain II of IAA1 confers diverse auxin-related phenotypes and
      represses auxin-activated expression of Aux/IAA genes in steroid regulator
      inducible system.
AB  - Most of Aux/IAA genes are rapidly induced by auxin. The Aux/IAA proteins are
      short-lived nuclear proteins sharing the four conserved domains. Domain II is
      critical for rapid degradation of Aux/IAA proteins. Among these gene family
      members, IAA1 is one of the earliest auxin-inducible genes. We used a steroid
      hormone-inducible system to reveal putative roles and downstream signaling of
      IAA1 in auxin response. Arabidopsis transgenic plants were generated expressing
      fusion protein of IAA1 (IAA1-GR) or IAA1 with a mutation in domain II (iaa1-GR)
      and the glucocorticoid hormone-binding domain (GR). IAA1-GR transgenic plants did
      not exhibit any discernable phenotypic differences by DEX treatment that allows
      nuclear translocation of the fusion protein. In contrast, diverse auxin-related
      physiological processes including gravitropism and phototropism were impaired by
      DEX treatment in roots, hypocotyls, stems, and leaves in iaa1-GR transgenic
      plants. Auxin induction of seven Aux/IAA mRNAs including IAA1 itself was
      repressed by DEX treatment, suggesting that IAA1 functions in the nucleus by
      mediating auxin response and might act as a negative feedback regulator for the
      expression of Aux/IAA genes including IAA1 itself. Auxin induction of Aux/IAA
      genes in the presence of cycloheximide can be repressed by DEX treatment, showing
      that the repression of transcription of the Aux/IAAs by the iaa1 mutant protein
      is primary. Wild-type IAA1-GR could not suppress auxin induction of IAA1 and
      IAA2. These results indicate that inhibition of auxin-activated transcription of
      Aux/IAA genes by the iaa1 mutant protein might be responsible for alteration of
      various auxin responses.

PMID- 12472685
TI  - An Arabidopsis thaliana knock-out mutant of the chloroplast triose
      phosphate/phosphate translocator is severely compromised only when starch
      synthesis, but not starch mobilisation is abolished.
AB  - The Arabidopsis thaliana tpt-1 mutant which is defective in the chloroplast
      triose phosphate/phosphate translocator (TPT) was isolated by reverse genetics.
      It contains a T-DNA insertion 24 bp upstream of the start ATG of the TPT gene.
      The mutant lacks TPT transcripts and triose phosphate (TP)-specific transport
      activities are reduced to below 5% of the wild type. Analyses of diurnal
      variations in the contents of starch, soluble sugars and phosphorylated
      intermediates combined with 14CO2 labelling studies showed, that the lack of TP
      export for cytosolic sucrose biosynthesis was almost fully compensated by both
      continuous accelerated starch turnover and export of neutral sugars from the
      stroma throughout the day. The utilisation of glucose 6-phosphate (generated from
      exported glucose) rather than TP for sucrose biosynthesis in the light bypasses
      the key regulatory step catalysed by cytosolic fructose 1,6-bisphosphatase.
      Despite its regulatory role in the feed-forward control of sucrose biosynthesis,
      variations in the fructose 2,6-bisphosphate content upon illumination were
      similar in the mutant and the wild type. Crosses of tpt-1 with mutants unable to
      mobilise starch (sex1) or to synthesise starch (adg1-1) revealed that growth and
      photosynthesis of the double mutants was severely impaired only when starch
      biosynthesis, but not its mobilisation, was affected. For tpt-1/sex1 combining a
      lack in the TPT with a deficiency in starch mobilisation, an additional
      compensatory mechanism emerged, i.e. the formation and (most likely) fast
      turnover of high molecular weight polysaccharides. Steady-state RNA levels and
      transport activities of other phosphate translocators capable of transporting TP
      remained unaffected in the mutants.

PMID- 12472686
TI  - Molecular analysis of herbivore-induced condensed tannin synthesis: cloning and
      expression of dihydroflavonol reductase from trembling aspen (Populus
      tremuloides).
AB  - In order to study condensed tannin synthesis and its induction by herbivory, a
      dihydroflavonol reductase (DFR) cDNA was isolated from trembling aspen (Populus
      tremuloides). Bacterial overexpression demonstrated that this cDNA encodes a
      functional DFR enzyme, and Southern analysis revealed that DFR likely is a single
      copy gene in the aspen genome. Aspen plants that were mechanically wounded showed
      a dramatic increase in DFR expression after 24 h in both wounded leaves and
      unwounded leaves on wounded trees. Feeding by forest tent caterpillar (Malacosoma
      disstria) and satin moth (Leucoma salicis) larvae, and treatment with methyl
      jasmonate, all strongly induced DFR expression. DFR enzyme activity was also
      induced in wounded aspen leaves, and phytochemical assays revealed that condensed
      tannin concentrations significantly increased in wounded and systemic leaves. The
      expression of other genes involved in the phenylpropanoid pathway were also
      induced by wounding. Our findings suggest that the induction of condensed
      tannins, compounds known to be important for defense against herbivores, is
      mediated by increased expression of DFR and other phenylpropanoid genes.

PMID- 12472687
TI  - Pasticcino2 is a protein tyrosine phosphatase-like involved in cell proliferation
      and differentiation in Arabidopsis.
AB  - The pasticcino2 (pas2) mutant shows impaired embryo and seedling development
      associated with cell de-differentiation and proliferation. This process is
      specifically enhanced in presence of cytokinins leading to callus-like structure
      of the apical part of the seedling. Cell proliferation concerns localized and
      stochastic nodules of dividing cells. In absence of cytokinins, cell
      proliferation leads to small calli on stems but, most often, cell proliferation
      is associated with post-genital organ fusion. The PAS2 gene was identified by
      positional cloning. PAS2 expression was found in every plant organ and was not
      regulated by PAS1 and PAS3 genes. PAS2 encodes the Arabidopsis member of the
      protein tyrosine phosphatase-like (Ptpl) family, a new PTP family originally
      described in mice and humans and characterized by a mutated PTP active site. This
      family of proteins has a yeast homolog that is essential for cell viability. The
      absence of yeast PAS2 homolog can be functionally replaced by the Arabidopsis
      PAS2 protein, demonstrating that PAS2 function is conserved between higher and
      lower eukaryotes.

PMID- 12472688
TI  - Analysis of far-red light-regulated genome expression profiles of phytochrome A
      pathway mutants in Arabidopsis.
AB  - Phytochrome A (phyA) is the primary photoreceptor responsible for various far-red
      (FR) light-mediated responses. Previous studies have identified multiple phyA
      signaling mutants, including both positive and negative regulators of the phyA
      mediated responses. How these defined intermediates act to mediate FR light
      responses is largely unknown. Here a cDNA microarray was used to examine effects
      of those mutations on the far-red light control of genome expression. Clustering
      analysis of the genome expression profiles supports the notion that phyA
      signaling may entail a network with multiple paths, controlling overlapping yet
      distinct sets of gene expression. FHY1, FAR1 and FHY3 most likely act upstream in
      the phyA signaling network, close to the phyA photoreceptor itself. FIN219, SPA1
      and REP1 most likely act somewhere more downstream in the network and control the
      expression of smaller sets of genes. Further, this study also provides genomics
      evidence for the partial functional redundancy between FAR1 and FHY3. These two
      homologous proteins control the expression of a largely overlapping set of genes,
      and likely act closely together in the phyA-mediated FR light responses.

PMID- 12472689
TI  - Prenylcysteine alpha-carboxyl methyltransferase expression and function in
      Arabidopsis thaliana.
AB  - Farnesylated proteins undergo a series of post-translational modifications,
      including carboxyl terminal isoprenylation, proteolysis, and methylation. In
      Arabidopsis thaliana, protein farnesylation has been shown to be necessary for
      negative regulation of ABA signaling. However, the role of post-isoprenylation
      protein processing in ABA signal transduction has not been described. Here, we
      show that the A. thaliana genome contains two distinct genes on chromosome V,
      AtSTE14A and AtSTE14B, which encode functional prenylcysteine alpha-carboxyl
      methyltransferases. AtSTE14B encodes a methyltransferase with lower apparent Kms
      for prenylcysteine substrates and higher specific activities than the previously
      described AtSTE14A-encoded methyltransferase. Furthermore, whereas AtSTE14A
      transcription is restricted to root and shoot tips, young leaves, and vascular
      tissue, AtSTE14B transcription is observed in all organs except hypocotyls and
      petioles. Pharmacological inhibitors of prenylcysteine alpha-carboxyl
      methyltransferase activity cause increased ABA sensitivity, seed dormancy, and
      stomatal closure, consistent with the hypothesis that prenylcysteine alpha
      carboxyl methylation is necessary for negative regulation of ABA signaling. These
      results suggest that carboxyl methylation, which is a reversible and potentially
      regulated step in the processing, targeting, and function of isoprenylated plant
      proteins, may be an important biochemical target for introducing altered ABA
      sensitivity and drought tolerance into plants.

PMID- 12472690
TI  - Spatio-temporal expression of patatin-like lipid acyl hydrolases and accumulation
      of jasmonates in elicitor-treated tobacco leaves are not affected by endogenous
      levels of salicylic acid.
AB  - We have previously isolated three tobacco genes (NtPat) encoding patatin-like
      proteins, getting rapidly induced during the hypersensitive response (HR) to
      tobacco mosaic virus, in advance to jasmonate accumulation. NtPAT enzymes are
      lipid acyl hydrolases that display high phospholipase A2 (PLA2) activity and may
      mobilize fatty acid precursors of oxylipins. Here, we performed a detailed study
      of NtPat gene regulation under various biotic and abiotic stresses. PLA2 activity
      was poorly induced in response to drought, wounding, reactive oxygen
      intermediates, salicylic acid (SA) or methyl-jasmonate (MJ) whereas the ethylene
      (ET) precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), provoked a moderate
      induction. In contrast, PLA2 activity was strongly induced when ACC was combined
      with MJ, and in response to the bacterium Erwinia carotovora or to the fungus
      Botrytis cinerea, as well as to treatment with beta-megaspermin, a cell death
      inducing protein elicitor. A simplified system based on the infiltration of beta
      megaspermin into leaves was used to dissect the spatio-temporal activation of
      PLA2 activity with regards to the accumulation of jasmonates and to the influence
      of endogenous SA. NtPat-encoded PLA2 activity was rapidly induced in the
      infiltrated zone before the appearance of cell death and with some delay in the
      surrounding living cells. A massive accumulation of 12-oxo-phytodienoic and
      jasmonic acids occurred in the elicitor-infiltrated zone, but only low levels
      were detectable outside this area. A similar picture was found in SA-deficient
      plants, showing that in tobacco, accumulation of jasmonates is not affected by
      the concomitant HR-induced build-up of endogenous SA. Finally, ET-insensitive
      plants showed a weakened induction of PLA2 activity outside the elicitor
      infiltrated tissue.

PMID- 12472691
TI  - Multiple plastid signals regulate the expression of the pea plastocyanin gene in
      pea and transgenic tobacco plants.
AB  - The expression of nuclear genes encoding photosynthesis-related proteins is
      regulated by signals from plastids. To investigate how the pea PetE gene encoding
      plastocyanin is regulated by plastid signals, the effects of norflurazon,
      lincomycin and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), specific
      inhibitors of plastid-located processes generating plastid signals, have been
      examined. RNA-gel blot analysis of 7-day-old pea and tobacco seedlings containing
      the pea PetE gene showed that treatment with norflurazon and lincomycin, but not
      DCMU, decreased the accumulation of transcripts of pea PetE and endogenous Lhcb1
      genes. Analysis of chimeric PetE gene constructs in tobacco seedlings showed that
      an intact PetE mRNA 5' terminus and elements within the PetE coding region were
      required to confer sensitivity to norflurazon and lincomycin, suggesting post
      transcriptional regulation. Analysis of 4-week-old tobacco plants containing
      chimeric PetE constructs showed that DCMU treatment decreased the accumulation of
      pea PetE and Lhcb1 transcripts, but had opposite effects on the transcription of
      the genes in nuclear run-on assays. DCMU upregulated transcription from the pea
      PetE promoter whereas transcription of tobacco Lhcb1 genes was decreased. These
      experiments provide evidence for multiple plastid signals operating at different
      developmental stages and affecting transcriptional and post-transcriptional
      processes regulating expression of the pea PetE gene.

PMID- 12472692
TI  - Tobacco plants were transformed by Agrobacterium rhizogenes infection during
      their evolution.
AB  - We discovered that the origin of cT-DNA in the genome of wild-type Nicotiana
      glauca is the T-DNA of the mikimopine-type Ri plasmid (pRi) harbored in
      Agrobacterium rhizogenes. The cT-DNA was inserted into the genomic DNA of N.
      glauca from the position corresponding to the right border of mikimopine-type
      pRi. The cT-DNA contained two mikimopine synthase gene (mis) homologs, NgmisL and
      NgmisR, both of which were transcribed at low level in all N. glauca organs.
      NgMisR protein expressed in Escherichia coli has preserved Mis activity, which
      converts l-histidine and alpha-ketoglutaric acid to mikimopine. The mis homolog
      was also found in the genome of three other Nicotiana species: N. tomentosa, N.
      tomentosiformis, and N. tabacum; however, the site of insertion differed from
      that in N. glauca, suggesting that A. rhizogenes harboring mikimopine-type pRi
      independently infected the ancestors of some Nicotiana plants. This is the first
      clear evidence of a host-parasite relationship during the early evolution of
      Nicotiana plants. We propose that a new phylogenetic approach using opine type cT
      DNA is applicable for presuming divergence in the genus Nicotiana.

PMID- 12472693
TI  - The NPK1 mitogen-activated protein kinase kinase kinase contains a functional
      nuclear localization signal at the binding site for the NACK1 kinesin-like
      protein.
AB  - The tobacco mitogen-activated protein kinase kinase kinase NPK1 localizes to the
      equatorial region of phragmoplasts by interacting with kinesin-like protein
      NACK1. This leads to activation of NPK1 kinase at late M phase, which is
      necessary for cell plate formation. Until now, its localization during interphase
      has not been reported. We investigated the subcellular localization of NPK1 in
      tobacco-cultured BY-2 cells at interphase using indirect immunofluorescence
      microscopy and fusion to green fluorescent protein (GFP). Fluorescence of anti
      NPK1 antibodies and GFP-fused NPK1 were detected only in the nuclei of BY-2 cells
      at interphase. Examination of the amino acid sequence of NPK1 showed that at the
      carboxyl-terminal region in the regulatory domain, which contains the binding
      site of NACK1, NPK1 contained a cluster of basic amino acids that resemble a
      bipartite nuclear localization signal (NLS). Amino acid substitution mutations in
      the critical residues in putative NLS caused a marked reduction in nuclear
      localization of NPK1 in BY-2 cells, indicating that this sequence is functional
      in tobacco BY-2 cells. We also found that the 64-amino acid sequence at the
      carboxyl terminus that contains NLS sequence is essential for interaction with
      NACK1, and that mutations in the NLS sequence prevented NPK1 from interacting
      with NACK1. Thus, the amino acid sequence at the carboxyl-terminal region of NPK1
      has dual functions for nuclear localization during interphase and binding NACK1
      in M phase.

PMID- 12472694
TI  - Arabidopsis thaliana root non-selective cation channels mediate calcium uptake
      and are involved in growth.
AB  - Calcium is a critical structural and regulatory nutrient in plants. However,
      mechanisms of its uptake by root cells are poorly understood. We have found that
      Ca2+ influx in Arabidopsis root epidermal protoplasts is mediated by voltage
      independent rapidly activating Ca2+-permeable non-selective cation channels
      (NSCCs). NSCCs showed the following permeability (P) sequence: PCa (1.00) = PBa
      (0.93) > PZn (0.51), PCa/PNa = 0.19, PCa/PK = 0.14. They were inhibited by
      quinine, Gd3+, La3+ and the His modifier diethylpyrocarbonate, but not by the
      Ca2+ or K+ channel antagonists, verapamil and tetraethylammonium (TEA+). Single
      channel conductance measured in 20 mm external Ca2+ was 5.9 pS. Calcium-permeable
      NSCCs co-existed with hyperpolarisation-activated Ca2+ channels (HACCs), which
      activated 40-60 min after forming the whole-cell configuration. HACCs activated
      at voltages <-130 to -150 mV, showed slow activation kinetics and were regulated
      by cytosolic Ca2+ ([Ca2+]cyt). Using aequorin-expressing plants, a linear
      relationship between membrane potential (Vm) and resting [Ca2+]cyt was observed,
      indicating the involvement of NSCCs. Intact root 45Ca2+ influx was reduced by
      Gd3+ (NSCC blocker) but was verapamil and TEA+ insensitive. In the root
      elongation zone, both root net Ca2+ influx (measured by Ca2+-selective vibrating
      microelectrode) and NSCC activity were increased compared to the mature
      epidermis, suggesting the involvement of NSCC in growth. A Ca2+ acquisition
      system based on NSCC and HACC co-existence is proposed. In mature epidermal
      cells, NSCC-mediated Ca2+ influx dominates whereas in specialised root cells
      (root hairs and elongation zone cells) where elevated [Ca2+]cyt activates HACCs,
      HACC-mediated Ca2+ influx predominates.

PMID- 12472695
TI  - Expression of Arabidopsis LINEs from two promoters.
AB  - Most Arabidopsis long interspersed elements (LINEs, called ATLNs) have two open
      reading frames, orf1 and orf2. In the 5' untranslated regions (UTRs) located
      upstream of orf1, the most proximal segments of tens of base pairs long are not
      homologous even in two ATLN members with almost identical sequences. In this
      study, we first show that RT-PCR products from ATLN39, a member of ATLN, can be
      detected only in total RNA from the hypomethylation mutant ddm1 or from
      suspension-cultured cells treated with a DNA methylation inhibitor 5-azacytidine,
      indicating that the expression of ATLN39 is negatively regulated by DNA
      methylation. We then show that orf1 fused in frame with the luciferase (luc) gene
      is expressed in suspension-cultured cells of A. thaliana when the 5' UTR is
      present in the region upstream of orf1. Analysis of deletion in the 5' UTR
      revealed that the 5' UTR has two promoters, designated here as P1 and P2.
      Analysis of transcripts by 5' RACE showed that their 5' ends were located at
      sites immediately upstream of the P1 region or at sites downstream of the P2
      region. This observation and the fact that the P1 region contains no TATA
      sequence indicate that P1 is an internal promoter that initiates transcription
      from sites upstream of the promoter. A sequence containing GGCGA with a CpG
      methylatable site is conserved in the P1 regions in members closely related to
      ATLN39. The P2 region, however, contains the TATA sequence as well as another
      sequence with a CpG site. The TATA sequence is conserved in members closely
      related to ATLN39 but not in the other ATLN members, suggesting that P2 is the
      promoter uniquely present in the ATLN39-related members. Transcripts from
      promoter P1 can be used as templates to give new copies proficient in
      retroposition, but those from promoter P2 cannot because of the lack of the
      proximal half region of the 5' UTR sequence. Transcripts from promoter P2, as
      well as those from promoter P1 can, however, be used for the production of a
      sufficient amount of proteins for retroposition. Only a short sequence of the non
      homologous region is present at the 5' ends of transcripts from promoter P1, thus
      suggesting that the non-homologous regions seen in the most proximal regions in
      ATLN elements are not generated in transcription.

PMID- 12472696
TI  - Activation tagging of the two closely linked genes LEP and VAS independently
      affects vascular cell number.
AB  - The complex dominant Arabidopsis thaliana mutant lettuce (let) shows the
      conversion of the leaf petiole into a leaf blade caused by an ectopic leaf blade
      formation. This is the result of the activation tagging of the LEAFY PETIOLE
      (LEP) gene encoding an AP2/EREBP-like transcription factor. Here, we report that
      in addition to this leafy petiole phenotype, the size of the vascular bundles is
      increased in all aerial organs in let as a result of an increase in the number of
      xylem, phloem (pro)cambial and pericycle cells. This vascular phenotype is caused
      by activation tagging of the two genes VASCULAR TISSUE SIZE (VAS) and LEP. These
      genes are closely linked and arranged in tandem. Activation tagging of LEP only
      caused a specific increase in the number of xylem cells. This increased xylem
      cell number, together with the ectopic leaf blade formation, indicates that LEP
      functions as a cell division-promoting factor. The activation tagging of VAS only
      resulted in a specific increase in phloem (pro)cambial and pericycle cells. We
      conclude that activation tagging of LEP and VAS results in additive phenotypes.
      Insertional mutants for LEP and VAS display wild-type vascular development,
      indicating the relevance of activation tagging for functional analysis of novel
      genes involved in plant development.

PMID- 12472697
TI  - A chromatin immunoprecipitation (ChIP) approach to isolate genes regulated by
      AGL15, a MADS domain protein that preferentially accumulates in embryos.
AB  - AGAMOUS-like-15 (AGL15) is a member of the MADS-domain family of DNA-binding
      regulatory factors that accumulates preferentially in tissue developing in an
      embryonic mode. To better understand how AGL15 functions, we developed a
      chromatin immunoprecipitation (ChIP) approach to isolate genes regulated directly
      by AGL15. ChIP allows purification of in vivo protein-DNA complexes. The co
      purified DNA is recovered and used to isolate the putatively regulated gene.
      Several tests must be performed to show that the putative downstream target gene
      is truly regulated by the DNA-binding protein. The DNA-binding regulatory protein
      must interact with cis regulatory elements. The downstream gene expression
      pattern should respond to the level of the trans-acting regulatory factor. The
      cis element should be able to confer regulation in response to the trans-acting
      factor. We describe, in this report, our ChIP protocol, and discuss in detail,
      tests to confirm regulation by AGL15 for two targets identified by ChIP. These
      targets are referred to as Downstream Target of AGL15 (DTA1 and DTA2). Expression
      of DTA1, which encodes a protein with high similarity to GA-2 oxidase-like
      proteins, is induced by AGL15. DTA2 encodes a novel protein and expression of
      this target is repressed by AGL15.

PMID- 12472698
TI  - Construction of a 'unigene' cDNA clone set by oligonucleotide fingerprinting
      allows access to 25 000 potential sugar beet genes.
AB  - Access to the complete gene inventory of an organism is crucial to understanding
      physiological processes like development, differentiation, pathogenesis, or
      adaptation to the environment. Transcripts from many active genes are present at
      low copy numbers. Therefore, procedures that rely on random EST sequencing or on
      normalisation and subtraction methods have to produce massively redundant data to
      get access to low-abundance genes. Here, we present an improved oligonucleotide
      fingerprinting (ofp) approach to the genome of sugar beet (Beta vulgaris), a
      plant for which practically no molecular information has been available. To
      identify distinct genes and to provide a representative 'unigene' cDNA set for
      sugar beet, 159 936 cDNA clones were processed utilizing large-scale, high
      throughput data generation and analysis methods. Data analysis yielded 30 444 ofp
      clusters reflecting the number of different genes in the original cDNA sample. A
      sample of 10 961 cDNA clones, each representing a different cluster, were
      selected for sequencing. Standard sequence analysis confirmed that 89% of these
      EST sequences did represent different genes. These results indicate that the full
      set of 30 444 ofp clusters represent up to 25 000 genes. We conclude that the ofp
      analysis pipeline is an accurate and effective way to construct large
      representative 'unigene' sets for any plant of interest with no requirement for
      prior molecular sequence data.

PMID- 12472699
TI  - SVISS - a novel transient gene silencing system for gene function discovery and
      validation in tobacco plants.
AB  - We developed a novel, two-component transient gene silencing system in which the
      satellite tobacco mosaic virus (STMV) is used as vector for the delivery of
      inhibitory RNA into tobacco plants and the tobacco mosaic virus strain U2 (TMV
      U2) is used as helper virus for supplying replication and movement proteins in
      trans. The main advantage of the system is that by uncoupling virus replication
      components from silencing induction components, the intensity of silencing
      becomes more pronounced. We call this system satellite virus-induced silencing
      system (SVISS) and will demonstrate here its robustness, speed and effectiveness.
      We were able to obtain pronounced and severe knockout phenotypes for a range of
      targeted endogenous genes belonging to various biochemical pathways and expressed
      in different plant tissues, such as genes involved in leaf and flower
      pigmentation, genes for cell wall synthesis in leaf, stem and root tissues or a
      ubiquitous RNA polymerase gene. By tandem insertion of more than one target gene
      sequence into the vector, we were able to induce simultaneous knockouts of an
      endogenous gene and a transgene. SVISS is the first transient gene silencing
      system for Nicotiana tabacum, which is a genetically well-characterized bridging
      species for the Solanaceae plant family.

PMID- 12472700
TI  - Is there a place for desflurane in paediatric anaesthesia?

PMID- 12472701
TI  - The choice of inhalation anaesthetic for major abdominal surgery in children with
      liver disease.
AB  - Many children with liver disease undergo major abdominal surgery. Maintenance of
      anaesthesia is thus an important consideration in this surgical population.
      Despite a comprehensive and painstaking review of the literature, a sound
      evidence base, on which a choice of inhalation anaesthetic may be made, is
      lacking due to limited research in these patients. Differences between the more
      recent agents such as isoflurane, sevoflurane and desflurane are minor.
      Sevoflurane is favoured in paediatric practice for gaseous induction, but
      desflurane or isoflurane are marginally the preferred agents for maintenance of
      anaesthesia in children with liver disease undergoing major abdominal surgery.
      However, on the evidence that exists, much of it admittedly in animals and in
      adults, all three are preferable to halothane in this group of patients. More
      work is needed in this area before sound conclusions can be drawn and one agent
      proved to be definitely superior to the others.

PMID- 12472702
TI  - Unconscious sedation in children: a prospective multi-arm clinical trial.
AB  - BACKGROUND: We report the evaluation of six sedative-hypnotic and analgesic
      combinations administered to children undergoing brief periods of unconscious (or
      deep) sedation for painful procedures. METHODS: In a prospective, open-label,
      randomized, controlled study of six groups of 27-30 children each, patients were
      randomly assigned to receive propofol or methohexital for sedation-hypnosis, and
      one of three incremental doses of fentanyl or remifentanil, respectively.
      RESULTS: An infusion of methohexital (10 mg.ml-1) combined with remifentanil
      (6.67 micro g.ml-1) provided significantly shorter geometric mean times to
      initial emergence, to eye-opening and to discharge, and required airway
      interventions that were not significantly more frequent than all groups sedated
      with propofol and fentanyl. CONCLUSIONS: The combination of methohexital and
      remifentanil appears to be a satisfactory method for unconcious sedation for
      short painful procedures in children.

PMID- 12472703
TI  - Spinal versus peripheral effects of adjunct clonidine: comparison of the
      analgesic effect of a ropivacaine-clonidine mixture when administered as a caudal
      or ilioinguinal-iliohypogastric nerve blockade for inguinal surgery in children.
AB  - BACKGROUND: The adjunctive use of clonidine to local anaesthetics has been
      reported to enhance analgesia both after spinal and peripheral administration.
      However, no attempt has been made to compare spinal and peripheral application of
      clonidine in the same surgical context in order to further explore the mechanism
      for the analgesic action of clonidine when administered together with local
      anaesthetics. METHODS: Using a prospective, randomized, observer-blinded study
      design, 40 patients, aged 1-7 years, who were undergoing elective surgery for
      inguinal hernia repair or orchidopexy, were randomly allocated to receive either
      a caudal block (group C: n = 20; ropivacaine 0.2%, 1 ml.kg-1 + clonidine 2 micro
      g.kg-1) or an ilioinguinal-iliohypogastric nerve block (group I: n = 20;
      ropivacaine 0.2%, 0.4 ml.kg-1 + clonidine 2 micro g.kg-1) following the induction
      of a standardized sevoflurane based anaesthetic. Postoperative analgesia [maximum
      Objective Pain Scale (OPS) score and requirement for supplemental analgesia] and
      sedation (three-point scale) were assessed at predetermined intervals during the
      first 24 h postoperatively. RESULTS: Fourteen children in group I and nine
      children in group C did not require rescue analgesia (P = 0.17). No difference in
      maximum OPS scores could be detected between the two study groups. The mean time
      to full recovery regarding sedation was 149 min and 153 min in groups C and I,
      respectively. CONCLUSIONS: This pilot study demonstrates a trend for better
      postoperative analgesia following peripheral administration of clonidine compared
      with central application. However, the main mechanism for the adjunct analgesic
      effect of clonidine when administered together with local anaesthetics requires
      further study.

PMID- 12472704
TI  - Premedication with midazolam in young children: a comparison of four routes of
      administration.
AB  - BACKGROUND: We undertook a study to determine the effects of four routes of
      administation on the efficacy of midazolam for premedication. METHODS: In a
      randomized double-blind study, 119 unmedicated children, ASA I-II, aged 1.5-5
      years, who were scheduled for minor elective surgery and who had been planned to
      received midazolam as a premedicant drug, were randomly assigned to one of four
      groups. Group I received intranasal midazolam 0.3 mg.kg-1; group II, oral
      midazolam 0.5 mg x kg(-1); group III, rectal midazolam 0.5 mg x kg(-1); and group
      IV, sublingual midazolam 0.3 mg x kg(-1). A blinded observer assessed the
      children for sedation and anxiolysis every 5 min prior to surgery. Quality of
      mask acceptance for induction, postanaesthesia care unit behaviour and parents'
      satisfaction were evaluated. Thirty patients were enrolled in each of groups I,
      III and IV. Twenty-nine patients were enrolled in group II. RESULTS: There were
      no significant differences in sedation and anxiety levels among the four groups.
      Average sedation and anxiolysis increased with time, achieving a maximum at 20
      min in group I and at 30 min in groups II-IV. Patient mask acceptance was good
      for more than 75% of the children. Although the intranasal route provides a
      faster effect, it causes significant nasal irritation. Seventy-seven percent of
      the children from this group cried after drug administration. Most parents in all
      groups (67-73%) were satisfied with the premedication. CONCLUSIONS: Intranasal,
      oral, rectal and sublingual midazolam produces good levels of sedation and
      anxiolysis. Mask acceptance for inhalation induction was easy in the majority of
      children, irrespective of the route of drug administration.

PMID- 12472705
TI  - A comparison of two different doses of ketamine with midazolam and midazolam
      alone as oral preanaesthetic medication on recovery after sevoflurane anaesthesia
      in children.
AB  - BACKGROUND: This investigation prospectively evaluated the effect of oral
      premedication of two different doses of ketamine with midazolam and midazolam
      alone on the recovery of children after sevoflurane anaesthesia. METHODS: In a
      randomized, double-blind study, 79 children (aged 1-8 years, ASA physical status
      I or II) were assigned to receive one of three premedications in a volume of 0.5
      ml x kg(-1): group 1 received midazolam 0.5 mg x kg(-1) (MD); group 2 received
      midazolam 0.5 mg x kg(-1) with ketamine 1.8 mg x kg(-1) (MK-1); and group 3
      received midazolam 0.5 mg x kg(-1) with ketamine 3 mg x kg(-1) (MK-2). The
      reactions of the children during administration were noted. Anaesthesia was
      induced by facemask with incremental sevoflurane administration. All children
      received alfentanil (15 micro g x kg(-1)). Tracheal intubation was facilitated by
      mivacurium (0.2 mg x kg(-1)). Anaesthesia was maintained with sevoflurane and an
      additional dose of alfentanil, if necessary. During recovery, the time interval
      between discontinuation of anaesthesia and arousal (spontaneous ventilation,
      extubation) were recorded. RESULTS: Emergence (spontaneous ventilation,
      extubation) and recovery times (discharge, Aldrete score=9) did not differ
      significantly between groups (P=0.24, P=0.59 and P=0.145, respectively).
      CONCLUSIONS: The combination of midazolam and ketamine as oral preanaesthetic
      medication did not significantly affect the recovery time of children after
      sevoflurane anaesthesia.

PMID- 12472706
TI  - Preemptive diclofenac reduces morphine use after remifentanil-based anaesthesia
      for tonsillectomy.
AB  - BACKGROUND: We investigated the effect of preincisional rectal diclofenac on pain
      scores and postoperative morphine requirements of children undergoing
      tonsillectomy after remifentanil-propofol anaesthesia in a randomized clinical
      trial. METHODS: Induction and maintenance of anaesthesia were with remifentanil
      and propofol. Forty children were randomly assigned into two groups before
      incision. The diclofenac group (n=20) received diclofenac suppositories
      (approximately 1 mg x kg(-1)) and the control group (n=20) received no treatment.
      Following discontinuation of remifentanil, patient-controlled analgesia (PCA)
      with morphine (a loading dose 50 micro g x kg(-1), a background infusion 4 micro
      g x kg(-1) x h(-1) and a demand dose 20 micro g x kg(-1) with 5-min intervals)
      was started. We assessed pain score [verbal analogue scales (VAS), 0-10] and
      sedation level at 5-min intervals and recorded the total morphine consumption of
      the first hour in the PACU. Patients were discharged to the ward with a new PCA
      morphine programme (a demand dose 20 micro g.kg-1 with a lockout time of 30 min,
      for 4 h), and total morphine consumption was recorded. RESULTS: The mean VAS
      score of the diclofenac group was significantly lower than the control group on
      arrival in the PACU (2.85 +/- 0.77, 7.60 +/- 0.83, respectively, P < 0.01) and it
      remained significantly lower in the PACU stay of the children. The mean total
      morphine consumption of the diclofenac group was less than the control group in
      the PACU (130.33 +/- 11.26 and 169.92 +/- 9.22, respectively, P=0.012) and the
      ward (50.80 +/- 11.38 and 87.77 +/- 10.55, respectively, P=0.021). CONCLUSIONS:
      Preemptive diclofenac given rectally reduced pain intensity and morphine
      requirements of children anaesthetized with remifentanil for tonsillectomy.

PMID- 12472707
TI  - Anaesthetic management of children with tuberous sclerosis.
AB  - BACKGROUND: Tuberous sclerosis (TS) is a hamartomatous disease that usually
      presents with cutaneous and intracranial lesions, but can also affect other organ
      systems. METHODS: In this report, we retrospectively reviewed the perioperative
      course of 24 children with TS who had medically intractable seizures as the
      primary disease process. RESULTS: Cardiac rhabdomyoma was detected in 11 of 18
      patients who had a cardiac evaluation, and coexisting congenital heart defects
      were diagnosed in six. Ten of 17 patients who had a renal evaluation were
      diagnosed with renal TS, presenting with azotaemia in one and hypertension in
      four. The major perioperative complications in the 52 anaesthetics, included
      death (a neonate after cardiac rhabdomyoma resection), seizures (five patients)
      and bradyarrhythmias (two patients). CONCLUSIONS: Patients with TS and
      neurological disorders frequently have coexisting cardiac and renal disease as
      well. Patients with TS should be evaluated for these organ specific disorders
      prior to surgery.

PMID- 12472708
TI  - Perioperative management of tetralogy of Fallot with absent pulmonary valve.
AB  - BACKGROUND: Tetralogy of Fallot with absent pulmonary valve is a rare form of
      congenital heart disease. The records of patients with this lesion were reviewed
      over a 6(1/2) year period, and the perioperative management of 13 patients is
      described. METHODS: We found that our patients could be divided into two groups
      by age. The younger group failed medical management and was referred for surgery
      at less than 1 year of age. This group of patients had considerable respiratory
      disease at the time of surgery, greater ventilatory problems during surgery and
      prolonged recovery. Most patients in this group have residual respiratory
      disease. RESULTS: There were significant differences in postoperative outcome
      between younger versus older patients: days of ventilation 37 +/- 41 versus 1 +/-
      0.6 days, length of ICU stay 28 +/- 31 versus 3 +/- 1 days and length of hospital
      stay 64 +/- 48 versus 9 +/- 5 days.

PMID- 12472709
TI  - Incidence of postoperative nausea and vomiting in paediatric ambulatory surgery.
AB  - BACKGROUND: We performed a prospective descriptive study over a 5-month period to
      determine the incidence of postoperative nausea and vomiting (PONV) during the
      first 24 h following elective ambulatory paediatric surgery, excluding head and
      neck procedures. METHODS: Four hundred and seven patients, aged 15 days to 16
      years, were analysed prospectively. RESULTS: The incidence of PONV was 9.4%,
      occurring most frequently during the first 3 h after anaesthesia and in hospital
      but rarely during the journey home. It was associated with age, previous history
      of PONV, tracheal intubation or use of the laryngeal mask airway (LMA trade mark
      ), controlled or manual ventilation, opioids and absence of oral intake of
      liquids or solids. Conversely, type of surgery, premedication, induction mode,
      association of regional anaesthesia, inhaled nitrous oxide, duration of
      anaesthesia, stay in the postanaesthesia care unit and duration of journey after
      discharge were not significantly associated with PONV. CONCLUSIONS: PONV never
      induced complications or delayed patient discharge and curative treatment was
      rapidly effective.

PMID- 12472710
TI  - Flush volumes delivered from pressurized bag pump flush systems in neonates and
      small children.
AB  - BACKGROUND: The aim of this study was to measure the volumes of fluid delivered
      with a fast flush bolus from a flow regulating device. METHODS: In-vitro fast
      flush bolus volumes, the volumes delivered from a bag pump flush system while
      opening the flow regulating device for 1, 2 or 5 s, were gravimetrically measured
      through a 22-G and a 24-G cannula. In-vivo 1- and 2-s fast flush bolus volumes
      and the volume required to purge the tubing between stopcock and arterial cannula
      from visible blood after blood sampling were recorded in 12 anaesthetized
      neonates and infants (mean age 2.17 +/- 1.97 months, range 0.26-5.37 months) with
      a 24-G radial arterial cannula by continuously weighing the bag pump flush system
      at manometer pressures of 100, 200 and 300 mmHg. RESULTS: In-vitro fast flush
      bolus volumes ranged from 0.23 +/- 0.04 ml (1-s, 100 mmHg, 24-G cannula) to 2.95
      +/- 0.38 ml (5-s, 300 mmHg, 22-G cannula). Volumes were larger using a 22-G
      cannula than a 24-G cannula (P < 0.01) and increased with longer flushing periods
      (P < 0.0001) and higher manometer pressures (P < 0.0001). In-vivo 1- and 2-s fast
      flush bolus volumes correlated well with driving pressures (infusion pressure
      minus mean arterial pressure) (r2 = 0.81/0.72). 1-s fast flush bolus volumes
      delivered (ml) were 0.0025 x mmHg driving pressure and 2-s fast flush bolus
      volumes delivered (ml) were 0.0043 x mmHg driving pressure. The mean volume
      delivered to purge blood from the arterial pressure tubing was 0.94 +/- 0.18 ml
      (range 0.61-1.34 ml). CONCLUSIONS: Fast bolus flushing from pressurized infusion
      bag systems, using the flow regulating device tested, can be applied during
      neonatal and paediatric anaesthesia without delivering uncontrolled amounts of
      fluid.

PMID- 12472711
TI  - Jet ventilation for anterior paediatric scoliosis surgery.
AB  - Single-lung anaesthesia for thoracotomy is usually achieved with endobronchial
      intubation, a double-lumen tube or an endobronchial blocker. High-frequency jet
      ventilation (HFJV) is seldom described for thoracotomy in children, although it
      is used for both laryngology procedures in the operating room and as a
      ventilation mode in intensive care. HFJV was used in three children, aged 10-12
      years, who presented for scoliosis correction involving thoracotomy. The jet
      ventilation catheter was passed through a tracheal tube to reduce the risk of
      outflow obstruction and allow a smooth conversion to intermittent positive
      pressure ventilation when required. Mean airway pressures measured at the tip of
      the HFJV catheter were at or below 4 cmH2O. Surgical opening of the nondependent
      lung pleura resulted in sufficient collapse of the pulmonary parenchyma with the
      patient in the lateral decubitus position for the surgical procedure. Arterial
      blood gas analyses performed during thoracotomy were within normal limits, with
      no CO2 retention. HFJV is an alternative ventilation strategy for thoracotomy in
      children because of its unique ability to deliver small tidal volumes at low mean
      airway pressures via a narrow catheter.

PMID- 12472712
TI  - Acute rhabdomyolysis after cardiac transplantation: a diagnostic conundrum.
AB  - A 13-year-old girl presented with right ventricular failure secondary to
      Ebstein's malformation (downward displacement of the tricuspid valve leaflets
      with adherence to the right ventricular muscle and redundancy or dysplasia of the
      tricuspid valve leaflets). She subsequently required a heart transplant but
      developed rhabdomyolysis early in the postoperative period and required
      ventilatory support for more than 3 weeks. A variety of causes were considered,
      but her condition improved only when cyclosporin was eliminated from the
      immunosuppression regimen. We believe it is likely that the rhabdomyolysis has
      been caused by cyclosporin. If so, this has occurred both earlier in the clinical
      course and at lower serum concentrations than previously described.

PMID- 12472713
TI  - Postintubation tracheal stenosis in an 11-year-old boy: a surgical and
      anaesthetic challenge.
AB  - We present a case of postintubation tracheal stenosis in an 11-year-old boy
      occurring after a relatively short period of intubation. He had been intubated
      and ventilated in a paediatric intensive care unit after a road traffic accident.
      Clinical symptoms manifested by oxygen desaturation and wheeziness, finally
      leading to deterioration of the level of consciousness, occurred a few hours
      after the first attempt at extubation after 48 h requiring reintubation.
      Endoscopic examination performed a few weeks later revealed a tracheal stenosis.
      Consequently, he underwent an initial period of conservative treatment consisting
      of balloon dilatation and intralesional injection of steroids, followed by a
      tracheal resection and reconstruction. The anaesthetic management of patients
      with tracheal stenosis presenting for laryngo-tracheobronchoscopy and balloon
      dilatation is discussed.

PMID- 12472714
TI  - Use of ultrasound bladder monitoring in children after caudal anaesthesia.
AB  - Urinary retention occurring after caudal anaesthesia in children has a low
      incidence. Most children will void within 12 h of surgery, although the incidence
      of retention is higher after hypospadias repair. However, overdistention causing
      bladder atony that is temporary, or may become permanent, is described in adults.
      Long-term effects of overdistention in children have not been described. Urine
      volume, used to describe overdistention, is traditionally measured after
      catheterization. We report two children suffering from urine retention after
      caudal anaesthesia (bupivacaine 0.25%) was used to supplement a general
      anaesthetic. Ultrasound bladder monitoring was used to assist with the clinical
      diagnosis of bladder distension in the postanaesthesia care unit (PACU) and
      subsequent management. In-out catheterization was required in a 1-year-old-girl
      with a bladder volume of 12 ml.kg-1 after external manual compression over the
      bladder was unable express urine. Spontaneous micturation occurred within the
      subsequent 8 h. A 10-year-old boy suffered distress in PACU with a bladder
      volume, measured by ultrasound, of 5 ml.kg-1. Catheterization relieved distress
      and spontaneous micturation returned 18 h after surgery. Measured urine volumes
      were similar to those estimated by ultrasound. Ultrasound bladder monitoring is a
      simple, noninvasive technique that can be used to assist with the diagnosis and
      management of urinary retention in children. It may replace catheterization as
      the prefered technique to measure urine volume. The correlation between measured
      bladder volumes and urine volume appears reasonable. A volume of approximately 10
      mg.kg-1 may be considered as causing overdistension.

PMID- 12472715
TI  - The use of lubricants to achieve tracheal intubation in neonates and infants.

PMID- 12472716
TI  - New way to mask induce a child.

PMID- 12472717
TI  - Serological differences in three Blastomyces dermatitidis strains.
AB  - Yeast phase lysate antigens, prepared from three isolates of Blastomyces
      dermatitidis (T-58, Tennessee dog; 48089, Zaire human; ERC-2, Wisconsin dog) were
      assayed for their ability to detect antibodies in human sera, dog sera and sera
      from rabbits immunized with each of the lysate antigens. The dog sera were from
      animals diagnosed with blastomycosis from various endemic regions in North
      America. T-58 and ERC-2 lysate antigens exhibited a high reactivity with the
      serum from dogs infected with blastomycosis; however, 48089 lysate showed low
      reactivity with the same sera. With the immunized rabbit sera, 48089 lysate was
      the only lysate with a high reactivity with the 48089 serum and it exhibited
      little reactivity with the heterologous sera. The T-58 and ERC-2 lysate antigens
      reacted minimally with the 48089 serum but reacted highly with both the T-58 and
      ERC-2 sera. The human sera were from individuals potentially exposed to B.
      dermatitidis while working on a prairie dog relocation project in Colorado.
      Remarkably, all three lysate antigens could detect antibodies in the individuals
      diagnosed with blastomycosis. This study indicated that there were serological
      differences in the 48089 Zaire lysate compared with the other lysate antigens and
      it may be designated serotype 2.

PMID- 12472718
TI  - Exopolysaccharides and capsules in human pathogenic Exophiala species.
AB  - The black yeasts Exophiala spinifera and E. dermatitidis produce extracellular
      slimes, which may be either in the form of a well-delimited capsule or of
      diffusely exuded exopolysaccharides (EPS). The optimal conditions for their
      production were studied. The presence or absence of polysaccharide material can
      be used for recognition of the two species. Five-day-old cultures grown on potato
      glucose agar at 24 degrees C were observed in India ink, and positive
      identification for E. spinifera was obtained when significant halos were seen
      around yeast cells. In contrast, E. dermatitidis had irregular EPS with a
      fibrillar substructure made visible by alcian blue staining. Other Exophiala
      species produce insignificant amounts of extracellular mucus or none at all. The
      diagnostic method is particularly useful with yeast-like primary cultures, which
      often consist entirely of budding cells and lack the characteristic structures of
      the filamentous Exophiala synanamorph.

PMID- 12472719
TI  - Physiological characters of Sporothrix schenckii isolates.
AB  - Sporotrichosis is endemic in three regions (east, north and south) in India. The
      colony morphology and physiological characteristics of 49 clinical isolates from
      these three regions (25 from north India, 17 from east India and seven from south
      India) were analysed in both mycelial and yeast forms. No difference in colony
      character was seen among the 49 isolates on three different media. Growth of all
      isolates was inhibited at 40 degrees C. The yeast forms were found to be more
      tolerant to osmotic pressure and salt concentrations. Most mycelial forms grew
      well between pH 3-12.0 whereas most yeast forms could tolerate a pH range of 2.4
      to 9.5. Variations in assimilation of arabinose, dextrin, raffinose, rhamnose and
      starch was observed among strains from different geographical regions. The yeast
      forms did not show any urease activity but the mycelial forms of all isolates
      could split urea. Phenol oxidase and potassium nitrate assimilation were positive
      and gelatinase activity and casein hydrolysis were negative for all isolates.

PMID- 12472720
TI  - Evaluation of different commercial ELISA methods for the serodiagnosis of
      systemic candidosis.
AB  - Different commercial enzyme-linked immunsorbent assays (ELISA) were evaluated in
      a preliminary study for diagnosis of systemic candidosis: Biomerica and Virotech
      GmbH, which allowed immunoglobulin G detection, and Platelia, which associated
      total antibody to antigen detection. They were tested with a home-made ELISA and
      compared with the routine techniques used in the hospital laboratory: indirect
      immunofluorescence and counter-immunoelectrophoresis. Sera were obtained from
      patients with probable or proven systemic candidosis (groups 3 and 4, n=8 and
      n=14, respectively) and from patients without systemic candidosis who were
      divided into controls (n=10), those hospitalized without Candida isolation (group
      1, n=10) and those hospitalized with Candida isolation in a peripheral site
      (group 2, n=18). The immunoglobulin G ELISAs showed a higher sensitivity
      associated with lower specificity compared to the indirect immunofluorescence,
      counter-immunoelectrophoresis and total immunoglobulin ELISAs. Mannan antigen
      detection showed the highest specificity (78.9%). Its association with the
      detection of total anti-Candida immunoglobulins was more sensitive than the
      association of indirect immunofluorescence with counter-immunoelectrophoresis
      (95.4% versus 59%, respectively) with a specificity of 52.6% (versus 55.2%).
      Interest in the use of commercial ELISAs, more particularly the Platelia tests,
      has to be confirmed in a prospective study with follow-up of the patients.

PMID- 12472721
TI  - Semi-quantitative adsorption for detection of antibodies to Candida albicans germ
      tubes by indirect immunofluorescence test.
AB  - Adsorption of antibodies against antigens expressed on the Candida albicans
      blastoconidia cell walls was standardized for the detection of antibodies to germ
      tubes by an indirect immunofluorescence test (IIFT). Sera from rabbits immunized
      with C. albicans bearing germ tubes, were diluted by two-fold serial dilutions to
      obtain specimens 1 : 640-1 : 20 positive by IIFT. Different volumes of specimens
      were adsorbed with different amounts of whole, heat-inactivated C. albicans
      blastoconidia. It was found that a 1 : 640 titre serum should be adsorbed at 30
      microl by 50 mg cells, down to a 1 : 20 titre serum at 110 microl by 12.5 mg
      cells. Accurate detection of anti-germ tube antibodies by IIFT depends on the
      semi-quantitative relation between the positive titre of the specimen and the
      amount of blastoconidia used in adsorption.

PMID- 12472722
TI  - Adherence of Candida strains isolated from the human gastrointestinal tract.
AB  - The adherence of different Candida strains isolated from the human
      gastrointestinal tract was studied. The 23 Candida strains isolated from faeces
      were C. albicans (12), C. glabrata (2), C. krusei (2), C. parapsilosis (2), C.
      tropicalis (2), C. colliculosa (1), C. kefyr (1) and C. lusitaniae (1). Buccal
      epithelial cells from different healthy donors were used. Adherence values were
      maximal for C. albicans and minimal for C. krusei. A relation exists between
      yeast adherence capacity and the ability to colonize mucosal surfaces.

PMID- 12472723
TI  - Outbreak of nosocomial fungemia caused by Candida glabrata.
AB  - An outbreak of Candida glabrata fungemia that was thought to be associated with
      bottles used for milk feeds occurred at our children's infectious diseases
      clinic. This cluster of cases was investigated using a case-control study.
      Isolates were identified by conventional methods and karyotyped using pulsed
      field gel electrophoresis (PFGE) of genomic DNA. Potential risk factors for nine
      hospitalized children with candidemia and 14 controls were long-term
      hospitalization and treatments with more than two antibiotics. Electrophoretic
      karyotyping showed a single chromosomal pattern for these outbreak isolates and,
      in addition, they all had the same antifungal susceptibility results. These
      findings suggest that clonal dissemination of a single strain was responsible for
      this outbreak. Karyotyping by PFGE appears to be a useful molecular typing method
      for strains of C. glabrata.

PMID- 12472724
TI  - Antifungal effect of Hevea brasiliensis latex with various fungi. Its synergistic
      action with amphotericin B against Candida albicans.
AB  - Antifungal activity of latex from Hevea brasiliensis was observed with various
      fungi in macrobroth dilution assays. The strongest antifungal effect was obtained
      with Trichosporon cutaneum (MIC 80% = 40.615 microg protein ml(-1), Kaff = 0.075
      microg(-1) protein ml) and Cryptococcus neoformans (MIC 80% = 56.078 microg
      protein ml(-1), Kaff = 0.059 microg(-1) protein ml). Amphotericin B was
      synergized with all H. brasiliensis latex concentrations tested. The rates of
      synergy were about 50, 44 and 55% with 15, 30 and 60 microg protein ml(-1) latex,
      respectively. The putative role of glycosidase activities measured in crude
      latex, especially alpha-d-mannosidase and N-acetyl-beta-d-glucosaminidase
      activities which are potentially able to split off intraparietal linkages between
      glycosidic residues, is discussed. The possible role of another antifungal factor
      associated with rubber particles of latex is suggested.

PMID- 12472725
TI  - Mathematical modelling of antifungal action.
AB  - In this paper a simplified modelling approach indicated that yeast growth was
      inhibited by an antifungal drug according to an exponential function. In
      addition, the corresponding inhibition rate followed a hyperbolic function the
      parameters of which permit us to determine the percentage of maximum inhibition
      and the minimum inhibitory concentration for 80%. From the equation of a
      hyperbola it was also possible to calculate an affinity constant Kaff
      corresponding to the inverse of the concentration of antifungal drugs giving half
      the maximal inhibition. The affinity constant was demonstrated to be
      characteristic of the yeast strain and of the antifungal drug employed.
      Simulation of the mathematical modelling enabled determination of a theoretical
      inhibition level corresponding to strong concentrations of antifungal drugs which
      cannot be carried out for technical reasons (precipitates, opacity etc.). The
      interest of this mathematical modelling of growth and inhibition to predict the
      doses of antifungals which can act synergistically is discussed.

PMID- 12472726
TI  - Fungal flora of human toe webs.
AB  - A total of 100 young adults (67 males and 33 females) participated in the study.
      Clinical evaluation showed that only 10 of the volunteers showed some scaling,
      fissuring and peeling of the toe webs. Four of these complained of occasional
      itching. Fourteen different genera of fungi were recovered from 78 of the 100
      youths screened. Yeasts were recovered from 21 (27%) of the positive cases,
      nondermatophytes from 38 (49%) and dermatophytes from 19 (24%). Microsporum
      gypseum was the most commonly recovered dermatophyte. Rhizopus stolonifer and
      Trichosporon cutanueum were the most frequently recovered nondermatophytic mould
      and yeast, respectively. More males (62.8%) harboured these organisms than
      females (37.2%). The study further showed that human toe webs that are apparently
      healthy harbour a variety of fungi, that may be potential pathogens.

PMID- 12472727
TI  - Tinea capitis in Van, Turkey.
AB  - Forty patients with an average age of 6.5 +/- 3.2 years (28 male 12 female) who
      applied to the YYU Medical Faculty Dermatology Department outpatient clinic were
      investigated. Tinea capitis profunda was determined as the most frequent clinical
      type. The isolated dermatophytic flora of the patients consisted of Trichophyton
      verrucosum (43%), T. violaceum (30%), T. rubrum (23%) and T. mentagrophytes (3%).
      The patients with tinea capitis profunda were mostly from rural areas.

PMID- 12472728
TI  - Isolation of keratinophilic fungi from elementary schools and public parks in
      Isfahan, Iran.
AB  - A total of 330 dust and soil samples collected from different sites at 13
      elementary schools and seven public parks in the province of Isfahan, Iran were
      examined for the frequency of keratinophilic fungi by the hair-baiting technique.
      Two hundred and fourteen isolates of keratinophilic fungi belonging to seven
      species were identified. The most frequent isolate was Chrysosporium
      keratinophilum (54.2%). The frequency and distribution of these keratinophilic
      fungi are discussed in relation to the presence of children in these
      environments.

PMID- 12472729
TI  - Case report. Isolation of Cladosporium cladosporioides from cerebrospinal fluid.
AB  - Cladosporium cladosporioides was isolated from three subsequent cerebrospinal
      fluid specimens and from a brain biopsy specimen of a human patient.
      Susceptibility testing of the isolate was performed against seven antifungal
      agents.

PMID- 12472730
TI  - Case Reports. Chronic and acute Aspergillus meningitis.
AB  - Cerebral aspergillosis usually occurs in severely immunocompromized hosts, is
      difficult to diagnose, and has a poor prognosis. After 14 months of chronic
      meningitis, ventriculitis, choroid plexitis, and lumbar arachnoiditis, which was
      complicated by acute hydrocephalus, Aspergillus, suspected to be from the
      candidus group, was isolated from the cerebrospinal fluid (CSF) of a previously
      healthy man. Thereafter Aspergillus antigen was found in stored plasma and CSF
      samples. He was treated with voriconazole and itraconazole. In a haemodialysis
      patient affected by an acute meningococcal meningitis, following a 3-day symptom
      free interval, symptoms and signs of acute meningitis had reappeared and were
      unresponsive to a broad antimicrobial coverage. However, they resolved within 5
      days after liposomal amphotericin B treatment had been started. From his CSF
      Aspergillus-DNA was identified and Aspergillus fumigatus isolated by culture.
      These two different clinical cases show that Aspergillus-DNA and antigen
      detection tests represent an advance in the diagnosis and liposomal amphotericin
      B, voriconazole, and itraconazole are an advance in the treatment of Aspergillus
      meningitis.

PMID- 12472731
TI  - Case Report. Keratomycosis due to Alternaria alternata in a diabetic patient.
AB  - A case of keratitis caused by Alternaria alternata in a diabetic male, after
      traumatic corneal injury with a sharp object, is described. The patient was
      treated with topical amphotericin B solution and a full uneventful recovery was
      achieved. This is the first reported case of fungal keratamycosis in Malta, which
      was substantiated with both positive direct microscopy and a positive culture of
      the fungus.

PMID- 12472732
TI  - Case Reports. Tinea capitis due to Trichophyton soudanense and Trichophyton
      schoenleinii.
AB  - Four cases of tinea capitis, two due to Trichophyton soudanense in Italian
      children who had had contact with Africans, and two due to Trichophyton
      schoenleinii in an African and an Italian child, respectively, are reported.
      Infections caused by anthropophilic dermatophytes are rare in Italy and are
      related to immigration. The most frequent agents of tinea capitis in Italy are
      zoophilic dermatophytes.

PMID- 12472735
TI  - Research in medical education: asking the right questions.

PMID- 12472736
TI  - Global standards in medical education for better health care.

PMID- 12472737
TI  - Patients' global ratings of student competence. Unreliable contamination or gold
      standard?
AB  - PURPOSE: To determine whether global ratings by patients are valid and reliable
      enough to be used within a major summative assessment of medical students'
      clinical skills. METHOD: In 11 stations of an 18-station objective structured
      clinical examination (OSCE), where a student was asked to educate or take a
      history from a patient, the patient was asked, 'How likely would you be to come
      back and discuss your concerns with this student again?' These 11 opinions were
      aggregated into a single patient opinion mark and correlated with other measures
      of student competence. The patients were not experienced in student assessment.
      RESULTS: A total of 204 students undertook the OSCE. Reliability of patient
      opinion across all 11 stations revealed a Cronbach alpha of 0.65. The correlation
      coefficient between the patient ratings and the total OSCE score was good (r =
      0.74; P < 0.001) and was better than the correlation between any single OSCE
      station and the total OSCE score. It was also better than the correlation between
      the aggregated patient opinion and tests of student knowledge (r = 0.47).
      CONCLUSION: It is known that patients can reliably complete checklists of
      clinical skills and that doctors can reliably provide global ratings of students.
      We have now shown that, by controlling the context, asking the right question and
      aggregating several opinions, untrained patients can provide a reliable and valid
      global opinion that contributes to the assessment of a student's clinical skills.

PMID- 12472738
TI  - Views of junior doctors on the specialist registrar (SpR) training scheme:
      qualitative study of UK medical graduates.
AB  - OBJECTIVE: To report junior doctors' views on specialist registrar (SpR)
      training. DESIGN: In 1999, as part of ongoing studies of doctors' careers, we
      surveyed all doctors who had qualified from UK medical schools in 1993.
      Structured questions about recipients' careers were accompanied by a form
      inviting free text comments. Comments about the SpR scheme were extracted for
      analysis. RESULTS: Doctors commented that there were insufficient national
      training numbers (NTNs) for those who wanted them, and that more than the minimum
      entry requirements seemed necessary for shortlisting. Strengthening curricula
      vitae through research and published work could prolong the duration of training
      and did not guarantee success. Specialist registrar training was considered by
      some respondents to be narrow and inflexible, with service work taking priority
      over training needs. As a result, some respondents feared they would not be
      competent to practise as consultants. There was a perceived shortage of
      consultant vacancies and 6 months was considered insufficient time for obtaining
      a suitable post. DISCUSSION: It is inevitable that doctors may not necessarily be
      able to pursue their initially chosen career paths. Trainers need to provide
      realistic advice about career opportunities. Provision of information about NTN
      availability and formal career counselling could help to prevent delays in career
      progression. The shortened and more structured programme of training has reduced
      its flexibility in some doctors' experience. Improvements in educational content
      will need greater input from consultants, which may require an increase in
      consultant posts. Time will tell whether concerns about competence to practise as
      consultants and consultant post availability will be justified.

PMID- 12472739
TI  - Hostile teaching hospitals and friendly district general hospitals: final year
      students' views on clinical attachment locations.
AB  - CONTEXT: The NHS Plan has indicated the need to increase the number of doctors in
      the NHS. To accommodate the substantial increase in student numbers in
      Birmingham, clinical teaching will need to expand from its traditional base
      within established teaching hospitals (THs) to district general hospitals (DGHs).
      Previous studies elsewhere have suggested the experience of students who
      undertake clinical attachments in DGHs is different from that of students
      attached to THs. We sought to investigate whether such differences exist in the
      West Midlands region and to explore the opportunities and problems such
      differences may present to educators and students alike. METHODS: A questionnaire
      based survey of the TH and DGH experiences of all medical students in their final
      year (2000/01) of undergraduate training at the University of Birmingham Medical
      School was carried out. RESULTS: A total of 80% of students responded.
      Respondents indicated that both the identification of learning objectives and the
      provision of teaching to meet such objectives were likely to occur in TH and DGH
      settings equally. However, other differences emerged, suggesting that DGHs offer
      a friendlier and more supportive learning environment, with greater opportunities
      for the acquisition of hands-on practical experience. CONCLUSIONS: At present,
      the popularity of DGHs derives from the attitudes of staff and the opportunities
      for hands-on experience. However, as student numbers increase, DGHs may be
      required to take on additional teaching commitments. Will DGHs be able to retain
      their existing educational characteristics or will they take on those associated
      with established THs?

PMID- 12472740
TI  - Medical students' attitudes towards and perception of the basic sciences: a
      comparison between students in the old and the new curriculum at the University
      Medical Center Utrecht, The Netherlands.
AB  - OBJECTIVES: The attitudes towards the basic sciences of medical students enrolled
      in either of 2 different curricula at the University of Utrecht Medical School in
      The Netherlands were investigated. The purpose of this study was threefold:
      first, to compare students (beginning clerks) in a conventional and an innovative
      curriculum; second, to compare beginning clerks with advanced clerks; and third
      to compare the present results with those of 2 previous American and Canadian
      studies in which the same questionnaire was used. SETTING: Beginning clerks in
      the old and in the innovative curriculum, and advanced clerks in the old
      curriculum, rated 9 statements on a 5-point (disagree - agree) Likert scale. The
      statements assessed students' attitudes toward the basic sciences. RESULTS: The
      results showed that beginning clerks in our innovative curriculum, unlike those
      in a conventional curriculum, consider the basic sciences as somewhat less
      important for medical practice and do not think that as many biomedical facts as
      possible should be learned before entering clinical practice. On the other hand,
      students in the innovative curriculum are more excited by the faculty's teaching
      of the basic sciences. This latter result confirms the findings in a previous
      Canadian study. No significant differences were found between beginning and
      advanced clerks in the conventional curriculum. CONCLUSION: Students experience
      teaching of the basic sciences as more exciting when they are integrated in organ
      system blocks with clinical bearings, though they are somewhat less positive
      about the actual importance of these sciences.

PMID- 12472742
TI  - Christmas quiz 2002.

PMID- 12472741
TI  - In our Christmas stockings.

PMID- 12472743
TI  - The case of the missing lawyer (as if anyone cares), with apologies (this time)
      to Sir Arthur Conan Doyle.

PMID- 12472744
TI  - Moving to the land of disease and pestilence.

PMID- 12472745
TI  - Breaking out of your comfort zone!

PMID- 12472746
TI  - It's Christmas: time to get ready for examinations!

PMID- 12472747
TI  - Medical expertise and mashed potatoes.

PMID- 12472748
TI  - Music and medical education.

PMID- 12472749
TI  - Is MD your final answer?

PMID- 12472750
TI  - Knees up Dr Brown?

PMID- 12472751
TI  - Medical practitioners' knowledge of Latin.

PMID- 12472752
TI  - What can clinical teachers learn from Harry Potter and the Philosopher's Stone?
AB  - Many clinical teachers acquire a working knowledge of the principles of teaching
      and learning through observation, by adopting positive and rejecting negative
      examples of clinical instruction. Well selected vignettes of teaching behaviours
      taken from contemporary film and literature may provide rich substrate by which
      to engage clinical teachers in discourse about instructional technique. This
      paper draws on J K Rowling's novel and its companion film, Harry Potter and the
      Philosopher's Stone, and critically analyses the teaching styles of the staff at
      Hogwarts School of Wizardry and Witchcraft in the context of contemporary generic
      and medical education literature. Specifically, it argues that effective teachers
      demonstrate not only an in-depth knowledge of their discipline but possess a keen
      appreciation of the cognitive changes that occur in their students during the
      learning process. They are, furthermore, proficient in core instructional skills
      such as small group facilitation, feedback and questioning. Most importantly,
      effective teachers model appropriate attitudes in their professional setting and
      possess highly developed personal qualities such as creativity, flexibility and
      enthusiasm.

PMID- 12472753
TI  - Alligator attack: an illustration of the impact of early clinical exposure.
AB  - CONTEXT AND PROCESS: The authors recount the importance of mentoring during
      medical education. A personal narrative of clinical exposure as a University of
      South Florida (USF) student at Tampa General Hospital illustrates the
      unparalleled value of unique clinical situations such as the emergency care of a
      patient following an alligator attack. The benefits of early clinical experience
      and integrated medical education to be obtained through a mentor relationship are
      explored. CONCLUSION: The clinical exposure of medical students is central to
      their development as clinicians.

PMID- 12472754
TI  - What is happening to bedside clinical teaching?
AB  - BACKGROUND: Bedside clinical teaching, an essential component of clinical
      training, was widely practised during the 1960s and early 1970s but has since
      declined substantially. OBJECTIVE: To highlight the importance of bedside
      teaching, giving examples of its significance, and to discuss the factors that
      have led to its decline. DESIGN: Review style. MAIN FINDINGS: There is much that
      can be gained from teaching at the bedside. It allows trainees to learn
      professionalism and to grasp the principles of communication with real patients.
      Unfortunately, the medical profession, like other fields of endeavour, has been
      invaded by computer technology. This has led to a decline in the frequency of
      bedside teaching and thus inflicted serious damage on the attainment of clinical
      skills by young doctors, despite their continuing interest in bedside teaching.
      Moreover, the increasing clinical, administrative and research duties of senior
      doctors have further contributed to this decline. CONCLUSION: Every effort should
      be made to reinstate bedside teaching as a leading component of medical training.

PMID- 12472755
TI  - Perceiving clinical evidence.
AB  - BACKGROUND: This paper demystifies clinical perception by explaining its
      mechanisms, using insights from neuroscience and evolutionary biology. Clinical
      diagnosis begins with rapid recognition using our imaging, perceptual (but non
      verbal) brain, followed by guided search using our slower, verbal, reasoning
      brain. Experiential cognition can be (more or less) achieved by integrating these
      two ways of knowing. Perceptual expertise requires alertness and persistence to
      ensure clinical accuracy. Each clinician, as a self-aware participant-observer
      (SAPO) keeping track of what they're thinking 'as it happens', can study their
      perceptual accuracy, pattern matching, interpretation, motivation and judgement.

PMID- 12472756
TI  - Testing learning theories: the NUL hypothesis.
AB  - INTRODUCTION: In the spirit of Scrooge and the Grinch, I describe the nasty
      unpalatable learning (NUL) hypothesis as a new theory of learning. This is an
      exercise to explore how difficult it would be to develop a new learning theory by
      reversing the social and altruistic tenets of most existing learning theories.
      THE NUL HYPOTHESIS: The NUL hypothesis has four propositions. These are: (1) the
      value of rote learning; (2) the usefulness of authority figures in teaching
      within a clear hierarchy; (3) the use of fear in teaching, and (4) the value of
      internal consistency without any necessary connection to the outside world.
      CONCLUSIONS: The NUL hypothesis may promote reflection not only on the
      construction of learning theories, but also on the design of critical
      experiments. It also seems to imply that efficiency may be a better measure of
      learning success than effectiveness.

PMID- 12472757
TI  - A trading-card game teaching about host defence.
AB  - OBJECTIVES: To heighten the understanding of host-disease interactions by
      adolescents and young adults, using a trading card game format. DESIGN: A trading
      card game was developed in which paired students attack one another with
      pathogens or parry those attacks with appropriate defences. Twenty-five
      infectious pathogens or cancers, 30 defence agents and 6 health status modifying
      conditions were included. SETTING: A middle school, upper school and medical
      school in the United States. SUBJECTS: 8th grade, 10th grade and first year
      medical students. RESULTS: The game was tested using pre-test/post-test
      evaluations in 8th graders, 10th graders and medical students. Factual
      information, pathogen-organ specificity, and general concepts were tested. There
      was a significant increase in test scores, from 39% to 58% correct in the 8th
      graders (P < 0.0001), from 47% to 59% among 10th graders (P = 0.0007), and from
      80% to 88% (P = 0.049) among the medical students. Responses to control questions
      unrelated to the game did not improve. CONCLUSION: An interactive trading card
      format is a useful method for conveying information about host defence.

PMID- 12472758
TI  - What do Australian junior doctors think of white coats?
AB  - OBJECTIVE: To determine the attitudes of Australian junior doctors towards white
      coats. METHODS: We carried out a multicentred mail survey in 13 Australian
      teaching hospitals. A total of 337 junior medical officers (JMOs) completed an
      eight-item questionnaire. The survey sought to establish JMOs' views and
      preferences regarding the wearing of white coats and the reasons behind them.
      RESULTS: Very few Australian JMOs wear white coats. Many reasons for not wearing
      white coats were given, the most common being 'No one else wears a white coat'
      (70%). A total of 60% of JMOs are against wearing white coats; 24% are
      indifferent on the issue and only 16% expressed a general preference for white
      coats. Junior medical officers who did prefer white coats indicated reasons of
      convenience for carrying items, identification and/or professionalism, and
      hygiene and/or cleanliness. CONCLUSIONS: White coats have largely disappeared
      from Australian teaching hospitals and the majority of junior doctors in
      Australia oppose the wearing of white coats.

PMID- 12472759
TI  - How to enjoy your mentee's success and learn from it.
AB  - Mentoring plays a central role in academic life. It is based mainly on mutual
      respect between mentor and mentee, and requires effort, continuity and
      consideration for different learning styles. It demands hard work, discipline,
      rigour, creativity, honesty and integrity. Both mentor and mentee must profit and
      learn from the process of mentoring in order to fulfil an essential purpose of
      the university. Their relationship represents the bond between the past and the
      future.

PMID- 12472760
TI  - Mark Albanese.

PMID- 12472763
TI  - Parathyroid hormone (PTH), PTH-derived peptides, and new PTH assays in renal
      osteodystrophy.
AB  - Parathyroid hormone (PTH), PTH-derived peptides, and new PTH assays in renal
      osteodystrophy. Reliable measurements of parathyroid hormone (PTH) concentrations
      in serum or plasma are critical for the appropriate diagnosis and management of
      patients with renal osteodystrophy. With the introduction of second generation
      immunometric assays for PTH, it is now possible to measure exclusively full
      length, biologically active PTH(1-84). In contrast, first generation immunometric
      assays that have been used widely for many years detect not only PTH(1-84), but
      also other large amino-terminally-truncated, PTH-derived peptides. This
      development will require a careful re-evaluation of PTH measurements, as
      determined by either first or second generation immunometric assays, and their
      relationship to bone histology and bone remodeling rates in patients with end
      stage renal disease (ESRD). Such information is essential for proper clinical
      management, but only limited bone biopsy data are available to guide the
      interpretation of PTH results using second generation PTH assays. The different
      performance characteristics of first and second generation immunometric PTH
      assays also makes it possible to quantify the plasma levels of amino-terminally
      truncated, PTH-derived peptides, which may accumulate disproportionately in
      patients with ESRD. Recent experimental evidence indicates that one or more of
      these peptides can modify bone cell activity and skeletal remodeling, possibly by
      interacting with a PTH receptor distinct from the type I PTH receptor that binds
      to the amino-terminal portion of PTH and mediates the classical biological
      actions of the hormone. The putative C-PTH receptor interacts with mid- and/or
      carboxyterminal regions of PTH and other amino-terminally-truncated PTH-derived
      peptides; signaling through it may contribute to the skeletal resistance to PTH
      that characterizes ESRD. The current review discusses certain aspects of the
      molecular structure of PTH and its interaction with various receptors, briefly
      comments about selected components of PTH secretion, highlights recent technical
      advances in PTH assays, and summarizes the effects of various PTH-derived
      peptides on bone cells and on skeletal metabolism.

PMID- 12472764
TI  - Anti-inflammatory and immunomodulatory effects of statins.
AB  - Anti-inflammatory and immunomodulatory effects of statins. 3-Hydroxy-3-methyl
      gutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins constitute the most
      powerful class of lipid-lowering drugs. Clinical trials have demonstrated a
      marked reduction in cardiovascular mortality in patients treated with statins.
      However, the benefits observed with statin therapy appear to be related, at least
      in part, with their cholesterol-lowering independent effects. Extensive research
      carried out mainly in the last decade suggests that the clinical benefits of
      these drugs could be related to an improvement in endothelial dysfunction, a
      reduction in blood thrombogenicity, anti-inflammatory properties, and, recently,
      immunomodulatory actions. In this sense, statins decrease T cell activation, the
      recruitment of monocytes and T cells into the arterial wall, and enhance the
      stability of atherosclerotic lesions. Many of these effects are related with the
      inhibition of isoprenoid synthesis, which serve as a lipid attachment for a
      variety of proteins implicated in intracellular signaling. In fact, small G
      proteins, whose proper membrane localization and function are dependent on
      isoprenylation, may play an important role in the lipid-lowering independent
      effects of HMG-CoA reductase inhibitors. This article summarizes the anti
      inflammatory and immunomodulatory effects of statins and their participation in
      the different steps of atherosclerotic lesion formation.

PMID- 12472765
TI  - A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and
      Bartter syndromes.
AB  - BACKGROUND: Gitelman syndrome (GS) and Bartter syndrome (BS) are hereditary
      hypokalemic tubulopathies with distinct phenotypic features. GS has been
      considered a genetically homogeneous disorder caused by mutation in the gene
      encoding the NaCl cotransporter (TSC) of the distal convoluted tubule. In
      contrast, BS is caused by mutations in the genes encoding either the Na-K-2Cl
      cotransporter (NKCC2), the K+ channel (ROMK) or the Cl- channel (ClC-Kb) of the
      thick ascending limb. The purpose of this study was to examine the clinical,
      biochemical and genetic characteristics of a very large inbred Bedouin kindred in
      Northern Israel with hereditary hypokalemic tubulopathy. METHODS: Twelve family
      members affected with hypokalemic tubulopathy, as well as 26 close relatives were
      clinically and biochemically evaluated. All study participants underwent genetic
      linkage analysis. Mutation analysis was performed in affected individuals.
      RESULTS: Evaluation of affected family members (age range 3 to 36 years) revealed
      phenotypic features of both GS and classic Bartter syndrome (CBS). Features
      typical of GS included late age of presentation (>15 years) in 7 patients (58%),
      normal growth in 9 (75%), hypomagnesemia (SMg <0.7mmol/L) in 5 (42%),
      hypermagnesiuria (FEMg>5%) in 6 (50%) and hypocalciuria (urinary
      calcium/creatinine mmol/mmol <0.15) in 5 (42%). Features typical of CBS included
      early age of presentation (<1 year) in 3 (25%), polyuria/dehydration in 4 (33%),
      growth retardation in 3 (25%), hypercalciuria (urinary calcium/creatinine
      mmol/mmoverline>0.55) in 4 (33%) and nephrolithiasis in 1 (8%). Linkage analysis
      in affected patients excluded the TSC gene, SLC12A3, as the mutated gene, but
      demonstrated linkage to the Cl- channel gene, CLCNKB, on chromosome 1p36.
      Mutation analysis by direct sequencing revealed a novel homozygous missense
      mutation, arginine 438 to histidine (R438H), in exon 13 of CLCNKB in all
      patients. A restriction fragment length polymorphism (RFLP) analysis has been
      developed to aid in genotyping of family members. CONCLUSIONS: Our findings
      demonstrate intrafamilial heterogeneity, namely the presence of GS and CBS
      phenotypes, in a kindred with the CLCNKB R438H mutation. We conclude that GS can
      be caused by a mutation in a gene other than SLC12A3. The exact role of the
      CLCNKB R438H mutation in the pathogenesis of the electrolyte and mineral
      abnormalities in GS and CBS remains to be established.

PMID- 12472766
TI  - Growth factor-mediated phosphorylation of proapoptotic BAD reduces tubule cell
      death in vitro and in vivo.
AB  - BACKGROUND: Exogenous growth factors administered during unilateral ureteral
      obstruction (UUO) in neonatal rats significantly reduce apoptosis and tubular
      atrophy. Because the mechanism underlying these salutary effects is largely
      unknown, we investigated signaling pathways potentially activated by growth
      factors to determine their roles in therapeutic action. METHODS: Mechanical
      strain was applied to confluent cultures of immortalized rat proximal tubule
      cells to simulate obstruction-induced stretch injury in vivo. Growth factors,
      inhibitory antibodies or pharmacological inhibitors were added to cultures that
      were subsequently processed for TUNEL analysis or immunoblots to identify
      signaling pathways that could be modulating cell survival. For in vivo studies,
      kidneys harvested from rats +/- UUO +/- epidermal growth factor (EGF) were fixed
      or frozen for immunohistochemistry or immunoblot analysis. RESULTS: Treatment
      with EGF or insulin-like growth factor-1 (IGF-1) during stretch decreased
      apoptosis by 50% (P < 0.001). Neutralizing antibodies (Abs) directed against
      either growth factor or its receptor blocked the reduction in apoptosis. Stretch
      decreased BAD phosphorylation by approximately 50% (P < 0.001) relative to
      unstretched cells and each growth factor restored phosphorylation to basal
      levels. Kinase-specific inhibitors that blocked growth factor-mediated BAD
      phosphorylation promoted apoptosis in vitro. BAD phosphorylation decreased by
      approximately 50% (P < 0.001) in the tubules of obstructed hydronephrotic rat
      kidneys and administration of EGF restored BAD phosphorylation to basal levels.
      CONCLUSIONS: Signaling pathways converging at BAD phosphorylation are key to
      growth factor-mediated attenuation of stretch-induced apoptosis in vitro and in
      vivo.

PMID- 12472767
TI  - Therapeutic benefit of spironolactone in experimental chronic cyclosporine A
      nephrotoxicity.
AB  - BACKGROUND: Cyclosporine A (CsA) is an immunosuppressive drug used to prevent
      tissue allograft rejection. However, its long-term utilization is limited due to
      chronic nephrotoxicity for which no prevention is available. This study evaluated
      the effect of spironolactone on renal functional and structural alterations
      induced by CsA, and assessed whether the protective effect was associated with a
      reduction of transforming growth factor-beta (TGF-beta) and the change of
      extracellular matrix protein mRNA level. METHODS: Male Wistar rats fed with low
      sodium diet were divided in four treatment groups: vehicle, CsA (30 mg/kg),
      spironolactone (20 mg/kg), or CsA+spironolactone. After 21 days, creatinine
      clearance (CCr), blood CsA, arteriolopathy in renal tissue, and TGF-beta,
      collagen I, collagen IV, fibronectin, and epidermal growth factor (EGF) mRNA
      levels in renal cortex were determined. RESULTS: CsA reduced the CCr and up
      regulated TGF-beta, collagen I and fibronectin mRNA expression with a significant
      development of arteriolopathy, and reduced EGF mRNA levels. In contrast,
      spironolactone administration prevented the fall in renal function and TGF-beta,
      collagen I, and fibronectin up-regulation, together with a reduction of
      arteriolopathy and tubulointerstitial fibrosis. CONCLUSION: Our data show that
      aldosterone plays an important role as a mediator of renal injury induced by CsA.
      Thus, mineralocorticoid receptor blockade may be a potential strategy to prevent
      CsA nephrotoxicity.

PMID- 12472768
TI  - Expression of somatostatin receptors 3, 4, and 5 in mouse kidney proximal
      tubules.
AB  - BACKGROUND: Systemic infusion of somatostatin (SRIF) induces many physiological
      changes in human and rodent kidneys, including alterations in glomerular
      filtration, solute transport, and water clearance. Although somatostatin can bind
      to five different G-protein coupled receptors (SSTRs), only SSTR1 and SSTR2A
      proteins have been described convincingly in rat and/or human kidneys. Both are
      expressed primarily in collecting ducts, despite clear evidence that somatostatin
      also can bind to proximal tubules. Our aim was to characterize the expression of
      somatostatin receptors three to five in adult mouse kidneys. METHODS: Reverse
      transcriptase-polymerase chain reaction (RT-PCR) was performed followed by
      Southern blotting on mouse kidney RNA for SSTR3, SSTR4, and SSTR5.
      Immunohistochemistry and dual-labeling immunofluorescence also were performed to
      localize the receptors in the kidney. RESULTS: Messenger RNA was detected for
      somatostatin receptors 3 to 5 in the mouse kidney by RT-PCR, with confirmation by
      Southern blotting. By immunohistochemistry and dual-labeling immunofluorescence,
      the proteins for all three receptors were abundantly expressed, but exclusively
      localized to the proximal tubules. SSTR3 was present in intracellular granules,
      while SSTR4 and SSTR5 were expressed on the lumenal membranes of the tubules.
      CONCLUSIONS: Expression of SSTR3, SSTR4, and SSTR5 in mouse proximal tubules
      complements the expression of SSTR1 and SSTR2 in collecting ducts as seen in
      other species. Taken together, the kidney is one of few organs expressing all
      five somatostatin receptors outside of the nervous system and pancreas.

PMID- 12472769
TI  - Renoprotective effects of VPI versus ACEI in normotensive nephrotic rats on
      different sodium intakes.
AB  - BACKGROUND: Control of blood pressure (BP) and optimal reduction of proteinuria
      (Uprot) are necessary for long-term renoprotection. Unfortunately, angiotensin
      converting enzyme inhibitors (ACEI) and angiotensin II (Ang II) antagonists are
      not effective during sodium repletion. Vasopeptidase inhibitors (VPI) cause dual
      inhibition of ACE and neutral endopeptidase, the latter resulting in decreased
      atrial natriuretic peptide (ANP) breakdown and thus enhanced natriuresis.
      Therefore, in contrast with ACEI, VPI may be effective during high sodium intake.
      METHODS: To test this hypothesis, the renoprotective actions of the new VPI
      gemopatrilat (GEM) were studied during low (0.05% NaCl) and high (3.0% NaCl)
      sodium diets in normotensive Wistar rats with established adriamycin nephrosis.
      The ACEI lisinopril (LIS) was used as control. Rats received either GEM (0.3 mg/g
      chow), an equihypotensive dose of LIS (75 mg/L drinking water), or vehicle (VEH)
      from week 6 (that is, established Uprot) until sacrifice. The effect of therapy
      was monitored by measuring systolic BP and Uprot (weekly) and structural renal
      damage at the end of study (week 16). RESULTS: During low sodium, GEM effectively
      reduced Uprot (-48 +/- 4%), but LIS was more effective (-80 +/- 2%), while Uprot
      slightly increased in VEH (+23 +/- 2%). The focal glomerulosclerosis (FGS) score
      after GEM (38 +/- 14) was lower than in the VEH group (79 +/- 27), although this
      was not significant. LIS (18 +/- 6) reduced FGS significantly. Remarkably, on
      high sodium, GEM was completely ineffective in reducing BP, Uprot and structural
      renal injury, just like LIS. CONCLUSIONS: The renoprotective actions of VPI
      depend on dietary sodium intake in normotensive nephrotic rats: therapeutic
      efficacy is fully blunted by a high sodium diet. During a low sodium diet,
      gemopatrilat was renoprotective, but less effective than lisinopril. Whether
      higher doses of the VPI could improve its renoprotective efficacy remains to be
      elucidated.

PMID- 12472770
TI  - Direct involvement of the receptor-mediated apoptotic pathways in cisplatin
      induced renal tubular cell death.
AB  - BACKGROUND: Tumor necrosis factor (TNF) receptor family members, such as Fas and
      TNF receptor 1 (TNFR1), are thought to induce apoptosis in a variety of cells and
      organs. Although a number of potential scenarios have been postulated for the
      involvement of these receptors in the pathogenesis of acute renal failure (ARF),
      direct evidence for their involvement in death of renal tubular cells (RTCs) and
      renal dysfunction is preliminary. METHODS: This study examined the roles of these
      receptors in RTC death in two systems: (1). in vivo murine and rat models of
      cisplatin-induced ARF, and (2). murine proximal tubular cells (PTCs), which were
      isolated from C57BL/6 (B6) mice, Fas-mutant B6-lpr/lpr mice and TNFR1-deficient
      mice, and normal rat kidney (NRK52E) cells in vitro. RESULTS: Reverse
      transcription-polymerase chain reaction indicated cisplatin-induced up-regulation
      of Fas, Fas ligand and TNF-alpha mRNAs in the kidney in vivo and in RTCs in
      vitro, both in mice and rats. In contrast, the level of TNFR1 mRNA was
      substantial but did not change in response to cisplatin. TNF-alpha production in
      cell culture medium determined by enzyme-linked immunosorbent assay (ELISA) and
      Fas expression determined by fluorescence-activated cell sorter (FACS) analysis
      increased following incubation with cisplatin in B6 PTCs. In order to examine
      whether Fas and TNFR1 are directly involved in RTC death and renal dysfunction,
      we compared cell resistance to cisplatin using a cell viability assay and FACS
      analysis with fluorescein isothiocyanate-conjugated annexin V and propidium
      iodide staining. The ratios of cell viability loss and cell death, both from
      apoptosis and necrosis, were higher in B6 PTCs than in other cells, while the
      ratios were comparable between Fas-mutant PTCs and TNFR1-deficient PTCs. Caspase
      8 activity was increased in B6 PTCs, but not in Fas-mutant PTCs and TNFR1
      deficient PTCs. Furthermore, the renal dysfunction and RTC death, both apoptosis
      and necrosis, induced by cisplatin were more severe in B6 mice in vivo.
      CONCLUSION: Based on these data, we conclude that the Fas- and TNFR1-mediated
      apoptotic pathways are directly involved in the pathogenesis of cisplatin-induced
      RTC death process.

PMID- 12472771
TI  - Adoptive transfer studies demonstrate that macrophages can induce proteinuria and
      mesangial cell proliferation.
AB  - BACKGROUND: Glomerular macrophage accumulation is a feature of proliferative
      human and experimental glomerulonephritis. However, our understanding of the role
      of macrophages in the induction of renal injury is based upon indirect evidence
      from depletion studies, most of which lack specificity for this cell type.
      Therefore, an adoptive transfer approach was used to directly assess the
      potential of macrophages to induce renal injury. METHODS: Accelerated anti
      glomerular basement membrane (anti-GBM) disease was induced in rats by
      immunization with sheep IgG (day -5), followed by administration of sheep anti
      rat GBM serum (day 0), with animals killed on day 2. To facilitate the adoptive
      transfer studies, immunized animals were made leukopenic by cyclophosphamide
      (CyPh) given on day -2. Bone marrow-derived (BM) or NR8383 macrophages were
      transferred by tail vein injection 24 hours after injection of anti-GBM serum,
      with animals killed 3 or 24 hours after transfer. RESULTS: Pretreatment with CyPh
      prevented glomerular leukocyte accumulation and completely inhibited proteinuria,
      glomerular cell proliferation and hypercellularity in accelerated anti-GBM
      disease. Adoptive transfer led to significant glomerular accumulation of BM or
      NR8383 macrophages within 3 hours of injection, and this was still evident 24
      hours later. Adoptive transfer of BM or NR8383 macrophages induced proteinuria
      (63 +/- 16 BM vs. 5 +/- 2 mg/24 h CyPh control; P < 0.001), glomerular cell
      proliferation (5.1 +/- 1.2 BM vs. 0.5 +/- 0.1 PCNA+ cells/gcs CyPh; P < 0.001)
      and glomerular hypercellularity (51.2 +/- 2.0 BM vs. 41.9 +/- 0.9 nuclei/gcs
      CyPh; P < 0.001). The degree of renal injury correlated with the number of
      transferred glomerular macrophages. Two-color immunostaining demonstrated that
      most glomerular proliferative cell nuclear antigen+ (PCNA+) proliferating cells
      were OX-7+ mesangial cells. CyPh treatment did not prevent up-regulation of
      glomerular intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion
      molecule (VCAM-1) expression or an increase in urinary monocyte chemoattractant
      protein-1 (MCP-1) excretion. CONCLUSION: This study provides the first direct
      evidence that macrophages can induce renal injury in terms of proteinuria and
      mesangial cell proliferation.

PMID- 12472772
TI  - Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil
      activation by ANCA.
AB  - BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
      (statins) may modulate cellular inflammatory functions independent of serum
      cholesterol. We tested the hypothesis that statins decrease respiratory burst
      activity of human polymorphonuclear neutrophils (PMN) in response to anti
      neutrophil cytoplasmic antibodies (ANCA). METHODS: Neutrophils were isolated from
      healthy human volunteers, human immunoglobulins were isolated from patients with
      proteinase-3 (PR3)- and myeloperoxidase (MPO)-ANCA. Superoxide generation was
      measured by the ferricytochrome C assay and the nitro blue tetrazolium (NBT)
      test. ANCA antigen expression was measured by flow cytometry and phosphorylation
      of mitogen-activated protein kinase (MAPK) was assessed by Western blotting.
      RESULTS: Cerivastatin and simvastatin inhibited respiratory burst activity to
      ANCA dose-dependently (1 to 25 micromol/L). Tumor necrosis factor-alpha (TNF
      alpha)-primed neutrophils released 26.7 +/- 2.8 nmol O2-/0.75 x 106 PMN/45 min
      and 10 micromol/L simvastatin reduced this amount to 18.0 +/- 2.1 nmol. The
      inhibitory effect was confirmed by the NBT test. The respiratory burst decrease
      could not be reversed by 500 micromol/L mevalonic acid (MVA). In this assay, both
      statins also inhibited the response to human ANCA. PR3-ANCA resulted in 19.4 +/-
      2.0 nmol O2- nmol. This amount was decreased to 6.0 +/- 1.2 nmol by preincubation
      with 10 micromol/L simvastatin (P < 0.01). For MPO-ANCA, the values were 22.6 +/-
      2.8 nmol for controls versus 16.7 +/- 3.1 nmol with statin (P < 0.01). By FACS,
      simvastatin decreased TNF-alpha-mediated ANCA antigen translocation (from 219 +/-
      33 to 180 +/- 35 MFI for PR3 and 24.0 +/- 2.4 to 18.3 +/- 1.1 for MPO). Finally,
      since p38 MAPK and ERK control TNF-alpha priming, we studied the effects of both
      statins on MAPK. Western blotting showed that statins inhibited TNF-alpha-induced
      ERK phosphorylation in a dose dependent fashion, but had no effect on p38.
      CONCLUSION: These findings demonstrate that HMG-CoA reductase inhibitors decrease
      respiratory burst activity of human PMN in response to ANCA. This effect was
      independent of mevalonate, but involved inhibition of ERK activation during TNF
      alpha priming. Our data suggest that HMG-CoA reductase inhibitors may help limit
      inflammatory responses.

PMID- 12472773
TI  - Hypercholesterolemia is a prerequisite for puromycin inducible damage in mouse
      kidney.
AB  - BACKGROUND: The mouse, as opposed to the rat, is relatively resistant to the
      experimental nephrosis induced by puromycin aminonucleoside. The reason for this
      species specificity is not known. Apolipoprotein E (apoE)-deficient mice were
      used to determine whether hypercholesterolemia plays a role in inducing
      proteinuria. METHODS: Thirty-two mice were divided into normal and high
      cholesterol diet groups and then divided further into four subgroups: puromycin,
      puromycin+probucol, probucol and control. Urinary albumin of these mice was
      analyzed by nephelometry. The lipid peroxidation (LPO) end products
      malonyldialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were detected by
      immunohistochemistry, and the expression level of the glomerular slit diaphragm
      protein, nephrin, was studied by immunohistochemistry and real time RT-PCR.
      RESULTS: Overt proteinuria was induced by puromycin only in the apoE knockout
      mice ingesting the high cholesterol diet. The staining intensities of MDA and 4
      HNE were stronger in the glomeruli of proteinuric mice compared to glomeruli of
      non-proteinuric mice. When serum cholesterol levels were reduced by probucol,
      proteinuria decreased and fewer LPO end products were seen immunohistochemically.
      Three and eight days after puromycin injection the level of nephrin mRNA in the
      kidneys of proteinuric mice decreased in comparison to the controls. Puromycin
      treated mice kidneys demonstrated a clearly reduced reactivity to the nephrin
      antibodies. CONCLUSIONS: Hypercholesterolemia, possibly via LPO, is a
      prerequisite for puromycin-inducible glomerular damage in the mouse. Furthermore,
      nephrin protein and mRNA levels appear to be candidate markers of glomerular
      damage in the mouse.

PMID- 12472774
TI  - Mitotic cell cycle proteins increase in podocytes despite lack of proliferation.
AB  - BACKGROUND: Podocyte proliferation is an uncommon response to glomerular injury
      and its lack may underlie the development of glomerulosclerosis. However, whether
      podocytes have the capacity to enter and finish mitosis and cytokinesis is not
      known. METHODS: The expression of mitotic cell cycle proteins (phosphorylated
      Histone 3, Cdc2, cyclin B1 and B2) was examined by immunohistochemistry in
      kidneys of embryonal mice, transgenic HIV-mice, and rats with experimental
      membranous nephropathy (passive Heymann nephritis, PHN). Mitotic proteins also
      were measured by Western blot in glomerular protein from PHN-rats and the
      activity of mitotic cyclins was quantified by histone kinase assay. RESULTS:
      Mitotic proteins were increased in embryonal mouse glomeruli during the S- and
      comma-shaped stages and were absent at the capillary loop stage and in mature
      rodent glomeruli. There was an increase in podocyte expression of Cdc2, cyclin B1
      and B2 and phosphorylated histone 3 in PHN rats, and in HIV transgenic mice.
      CONCLUSIONS: Podocytes have the ability to increase cell cycle proteins required
      for mitosis. Without obvious differences in the expression of the major mitotic
      proteins in PHN- and HIV-nephropathy, a regulatory disturbance in cytokinesis
      might be responsible for the development of polynucleated cells and a lack of
      podocyte proliferation in experimental glomerular disease.

PMID- 12472775
TI  - Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses
      the SR-B1 cholesterol transporter.
AB  - BACKGROUND: Previous studies demonstrate that renal cortical/proximal tubule
      cholesterol accumulation is part of the renal "stress response." The present
      study was performed to help define underlying mechanisms, using experimental
      sepsis as a test model. METHODS: Male CD-1 mice and female low-density
      lipoprotein receptor (LDLR) knockout mice were injected with a heat-killed
      Escherichia coli suspension. Renal cortex and serum were obtained from these and
      control mice either 4, 6, or 18 hours later. Tissues samples were assayed for
      free cholesterol (FC), cholesteryl esters (CE), HMG CoA reductase (HMGCR) mRNA,
      and SR-B1 [the high-density lipoprotein (HDL) receptor/cholesterol transporter].
      Statin effects on renal cortical HMGCR mRNA and FC/CE levels also were assessed.
      Finally, the impact of serum from septic versus normal mice on cultured proximal
      tubule (HK-2) cell cholesterol levels was assessed. RESULTS: Sepsis induced
      approximately 30% and 300 to 500% increases in renal FC and CE content,
      respectively. Cholesterol accumulation was not blunted in LDLR-/- mice versus
      their controls. Statin therapy also did not alter sepsis-induced renal FC/CE
      accumulation. However, statin treatment exerted no discernible intra-renal
      activity (for example, no rise in renal HMGCR mRNA), despite significant extra
      renal activity (25% reduction in serum cholesterol; 400% increase in hepatic
      HMGCR mRNA). HK-2 cells exposed to septic serum sustained a 40% cholesterol
      increase, compared to cells exposed to control serum. This response was
      completely statin inhibited, proving that de novo synthesis was involved. Sepsis
      markedly suppressed renal levels of SR-B1 (an FC efflux protein). Renal HMGCR
      mRNA did not fall despite sepsis triggered cholesterol loading, indicating a
      failure of negative feedback activity. CONCLUSIONS: Sepsis-induced renal
      cholesterol accumulation is not simply an intrinsic renal response, since it can
      be enhanced by circulating "stress factors" that drive HMGCR activity. Sepsis
      also down-regulates SR-B1. Thus, decreased cell FC efflux, coupled with increased
      synthesis, may synergistically induce the post-sepsis cholesterol overload state.

PMID- 12472776
TI  - A small molecule C5a receptor antagonist protects kidneys from
      ischemia/reperfusion injury in rats.
AB  - BACKGROUND: C5a has been implicated in numerous pathophysiological conditions,
      including ischemia/reperfusion (I/R) injury of the kidney. We examined whether a
      novel and specific C5a receptor antagonist, the cyclic compound AcF-[OPdChaWR]
      could moderate I/R-induced renal injury in rats. METHODS: Female Wistar rats were
      subjected to renal ischemia (60 min) and reperfusion (5 h). Rats were treated
      with either 1 mg/kg IV in 5% ethanol/saline or 10 mg/kg PO in 25% ethanol/saline
      prior to ischemia. I/R injury was characterized by significant tissue hemorrhage
      with increased microvascular permeability, elevated renal tissue levels of tumor
      necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO), increased serum
      levels of creatinine and aspartate aminotransferase (AST) and hematuria. RESULTS:
      Pre-ischemic treatment with the C5a receptor (C5aR) antagonist (1 mg/kg IV or 10
      mg/kg PO) substantially inhibited or prevented I/R-induced hematuria, vascular
      leakage, tissue levels of TNF-alpha and MPO, and serum levels of AST and
      creatinine. Histological examination of kidneys from antagonist pretreated I/R
      animals showed a marked reduction in tissue damage compared to drug-free I/R
      rats. This antagonist, however, did not inhibit complement-mediated lysis of red
      blood cells, suggesting unimpaired formation of the membrane attack complex
      (MAC). CONCLUSIONS: The results demonstrate for the first time that a selective
      antagonist of both human and rat C5a receptors, given either intravenously or
      orally, significantly protects the kidney from I/R injury in the rat. We conclude
      that C5a is an important pathogenic agent in renal I/R injury, and that C5a
      receptor antagonists may be useful therapeutic agents for the pretreatment of
      anticipated renal reperfusion injury in humans.

PMID- 12472777
TI  - Urate transport via human PAH transporter hOAT1 and its gene structure.
AB  - BACKGROUND: We recently cloned the human organic anion transporter 1 (hOAT1) as a
      p-aminohippurate (PAH) transporter. Whether urate is transported by the PAH
      transporter in humans remains unclear. Familial juvenile gouty nephropathy (FJGN)
      is thought to develop as a result of an abnormality in the urate transporter.
      METHODS: To determine if hOAT1 transported urate, the cellular uptakes of PAH and
      urate were determined, as were the inhibition profiles of inorganic anions, and
      uricosuric and antiuricosuric agents using a mouse S2 cell line expressing hOAT1.
      The hOAT1 gene was cloned from a genomic library using full-length hOAT1-1 cDNA
      as a probe. The coding regions of the hOAT1 genes of two sisters with FJGN were
      sequenced. Also, immunohistochemical fluorescence analysis of hOAT1 in the kidney
      of the younger sister with FJGN was performed. RESULTS: The Km and Vmax values of
      urate transport via hOAT1 were 943 +/- 84 micromol/L and 1286 +/- 162 pmol/mg
      protein/min, respectively. The order of the IC50 of urate transport via hOAT1 was
      benzbromarone < probenecid < salicylate or pyrazine carboxylic acid. The 10.9 kb
      hOAT1 gene was found to be interrupted by nine introns. Mutations in the coding
      region of the hOAT1 gene from the two sisters with FJGN were undetectable.
      Immunohistochemical fluorescent staining showed that hOAT1 in the kidney of the
      younger sister was similar to that of control individuals. CONCLUSIONS: Our data
      show that hOAT1 transports urate, and the inhibition profiles of uricosuric and
      antiuricosuric agents are defined. hOAT1 is not responsible for FJGN in the two
      sisters examined in this study.

PMID- 12472778
TI  - Potential importance of glomerular citrate synthase activity in remnant
      nephropathy.
AB  - BACKGROUND: Aldosterone fosters progressive renal injury, but the mechanism is
      unknown. Both Wistar-Furth rats, which are resistant to aldosterone actions, and
      adrenalectomized Sprague-Dawley rats, which lack aldosterone, are characterized
      by resistance to remnant nephropathy and by reduced whole kidney citrate synthase
      activity. Increase in citrate synthase activity is a well-characterized, specific
      renal response to aldosterone. Therefore, we performed experiments to test the
      hypothesis that enhanced citrate synthase activity contributes to remnant
      nephropathy. METHODS: Rat models included Wistar (control for Wistar-Furth),
      Wistar-Furth (resistant to aldosterone), Sprague-Dawley (normal), adrenalectomy
      (lacking aldosterone), and 5/6 nephrectomy (renal injury). Glomeruli were
      obtained by differential sieving. Citrate synthase activity was determined
      spectrophotometrically. Binding characteristics of cytosolic mineralocorticoid
      receptors were determined by equilibrium competition binding between tritiated
      and unlabeled aldosterone. Gene sequencing was performed with reverse
      transcription-polymerase chain reaction (RT-PCR) and fluorescent dye terminators.
      RESULTS: In glomeruli isolated from adrenalectomized Wistar rats with intact
      renal mass, aldosterone stimulated a threefold increase in citrate synthase
      activity; this stimulation was not observed in glomeruli from Wistar-Furth rats.
      Similarly, citrate synthase activity in glomeruli isolated from adrenally intact
      Sprague-Dawley rats was 65% greater than that from adrenalectomized Sprague
      Dawley rats. Compared to sham surgery, subtotal nephrectomy resulted in 100%
      greater glomerular citrate synthase activity in Sprague-Dawley rats. In Wistar
      Furth rats, mineralocorticoid receptor binding was not reduced, and mutations in
      the mineralocorticoid receptor DNA binding segment were not found. CONCLUSION:
      Citrate synthase activity is elevated in remnant glomeruli, and experimental
      models characterized by reduced glomerular citrate synthase activity (Wistar
      Furth rats, adrenalectomized Sprague-Dawley rats) are protected from remnant
      nephropathy.

PMID- 12472779
TI  - Reverse pharmacological effect of loop diuretics and altered rBSC1 expression in
      rats with lithium nephropathy.
AB  - BACKGROUND: Renal urinary concentration is associated with enhanced expression of
      rBSC1, a rat sodium cotransporter, in the thick ascending limb of Henle.
      Increased expression of rBSC1 was reported recently in nephrogenic diabetes
      insipidus induced by lithium chloride (Li nephropathy). However, the
      pathophysiological implication of altered rBSC1 expression has not yet been
      investigated. METHODS: Li nephropathy was induced in rats by an oral
      administration of 40 mmol lithium/kg dry food. In rats with reduced urinary
      osmolality to less than 300 mOsm/kg H2O, we examined the expression of rBSC1 mRNA
      and protein, plasma arginine vasopressin (AVP) and RNA expression of kidney
      specific water channel, aquaporin-2 (AQP2), of collecting ducts. Rats with Li
      nephropathy were treated with furosemide (3 mg/kg body weight), which blocks the
      activity of rBSC1, and changes in urine concentration, plasma AVP, medullary
      accumulation of Li ions, and apical AQP2 expression were determined. RESULTS:
      Rats with Li nephropathy showed increased rBSC1 RNA and protein expression and
      reduced AQP2 RNA. In these rats, furosemide, which induces dilution of urine and
      polyuria in normal rats, resulted in a progressive and significant rise in urine
      osmolality from 167 +/- 11 (mean +/- SD) at baseline to 450 +/- 45 mOsm/kg H2O at
      three hours after administration, and significant oliguria. In the same rats,
      plasma AVP decreased significantly from 5.7 to 3.0 pg/mL. In addition, recovery
      of apical AQP2 expression was noted in a proportion of epithelial cells of the
      collecting ducts. Although Li+ in the renal medulla was slightly lower in rats
      with Li nephropathy treated with furosemide, statistical significance was not
      achieved. CONCLUSIONS: Our results suggest that dehydration or high plasma AVP
      results in an enhanced rBSC1 expression in Li nephropathy, and that rBSC1
      expression is closely associated with the adverse effects of Li ions on
      collecting duct function.

PMID- 12472780
TI  - Glomerular hemodynamics and the renin-angiotensin system in patients with type 1
      diabetes mellitus.
AB  - BACKGROUND: Many studies have reported that blocking the renin-angiotensin-system
      (RAS) with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin
      receptor blocker in the patient with diabetes mellitus leads to an increase in
      renal plasma flow (RPF), no change in glomerular filtration rate (GFR), and a
      fall in filtration fraction. This constellation is generally attributed to
      predominant efferent arteriolar dilation. METHODS: This study examined the renal
      hemodynamic response to blocking the RAS with both captopril and candesartan on
      separate days in 31 patients with type 1 diabetes mellitus. RESULTS: There was a
      wide range of changes in RPF and GFR in response to the two agents, each
      administered at the top of its dose-response range. The RPF response to the two
      agents was strongly concordant (r = 0.65; P < 0.001), as was the GFR response (r
      = 0.81; P < 0.001). Moreover, there was a strong correlation between the RPF
      response and the change in GFR with each agent (r = 0.83 and 0.66; P < 0.01). A
      significant rise in RPF was followed by a rise in GFR. The RPF dependency of GFR
      in the type 1 diabetics suggests strongly that glomerular filtration equilibrium
      exists in the glomeruli of the diabetic kidney: Simple notions of local control
      based on afferent:efferent arteriolar resistance ratios are too simplistic.
      CONCLUSION: Our data suggest that the intrarenal RAS is activated in over 80% of
      patients with type 1 diabetes mellitus. Abundant evidence suggests that this
      activation predisposes to diabetic nephropathy.

PMID- 12472781
TI  - Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in
      renal insufficiency.
AB  - BACKGROUND: Chronic renal failure (CRF) is associated with oxidative stress, the
      mechanism of which remains uncertain. Superoxide is the primary oxygen free
      radical produced in the body, NAD(P)H oxidase is the major source of superoxide
      production and superoxide dismutase (SOD) is responsible for removal of
      superoxide. We hypothesized that CRF-induced oxidative stress may be due to
      increased production and/or decreased dismutation of superoxide. METHODS:
      Immunodetectable superoxide dismutase isoforms (Cu Zn SOD and Mn SOD), as well
      as, NAD(P)H oxidase (gp91 phox subunit) proteins and xanthine oxidase (XO)
      activity were determined in the kidney and liver of CRF (5/6 nephrectomized) and
      sham-operated control rats. Subgroups of animals were treated with SOD-mimetic
      drug, tempol and blood pressure and urinary nitric oxide metabolites (NOx) were
      monitored. RESULTS: The CRF group showed marked down-regulations of CuZn SOD and
      Mn SOD and significant up-regulation of gp91 phox in the liver and kidney, which
      are among the metabolically most active tissues. In contrast, XO activity was
      depressed in both tissues. Arterial pressure and nitrotyrosine abundance were
      elevated while urinary NOx excretion was depressed, pointing to increased NO
      inactivation by superoxide and decreased NO availability in CRF animals.
      Administration of SOD-mimetic agent, tempol, for one week, ameliorated
      hypertension, reduced nitrotyrosine abundance and increased urinary NOx excretion
      in the CRF animals. CONCLUSIONS: CRF is associated with depressed SOD and
      elevated NAD(P)H oxidase expression, which can contribute to oxidative stress by
      increasing superoxide. This is evidenced by favorable response to administration
      of SOD-mimetic drug, tempol, and increased nitrotyrosine that is the footprint of
      NO interaction with superoxide.

PMID- 12472782
TI  - Superoxide dismutase, catalase, glutathione peroxidase and NADPH oxidase in lead
      induced hypertension.
AB  - BACKGROUND: Earlier studies from this laboratory have revealed the presence of
      oxidative stress and its role in the pathogenesis of lead-induced hypertension
      (HTN). We have further shown evidence of increased hydroxyl radical (.OH) and
      superoxide production in lead-treated rats and cultured endothelial cells. This
      study was designed to determine whether oxidative stress in animals with lead
      induced HTN is associated with dysregulation of the main antioxidant enzymes
      namely superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase
      (GPX) or increased superoxide producing enzyme nicotinamide adenine dinucleotide
      (phosphate) oxidase [NAD(P)H]. METHODS: Male Sprague-Dawley rats were randomly
      assigned to lead-exposed and control groups. Animals in the lead-exposed group
      were provided with drinking water containing 100 ppm lead acetate for 12 weeks.
      The control group was provided with regular drinking water. At the conclusion of
      the experiment, immunodetectable Cu Zn SOD, Mn SOD, CAT, GPX and gp91 phox
      subunit of NAD(P)H oxidase were determined by Western analysis in the kidney,
      brain and left ventricle of control and lead-exposed rats. Subgroups of the study
      animals were treated with IV infusion (180 micromol/kg/h) of the superoxide
      trapping agent, tempol, and arterial pressure and urinary nitric oxide (NO)
      metabolite (NOx) excretion were determined. RESULTS: Lead exposure for 12 weeks
      resulted in a marked rise in systolic blood pressure, a significant reduction in
      urinary NOx excretion, a significant increase in kidney and brain Cu, Zn SOD, a
      significant increase in brain and insignificant increase in kidney and heart gp91
      phox. In contrast, Mn SOD, CAT and GPX in the kidney, brain and left ventricle
      were unchanged. Incubation with lead acetate did not alter SOD activity in vitro.
      Infusion of tempol significantly lowered arterial pressure and raised urinary NOx
      excretion in the lead-exposed group (but had no effect in the control group)
      pointing to increased superoxide production in the lead-exposed animals.
      CONCLUSION: Animals with lead-induced hypertension exhibited oxidative stress
      which was associated with mild up-regulation of superoxide-generating enzyme,
      NAD(P)H oxidase, with no evidence of quantitative SOD, CAT or GPX deficiencies.

PMID- 12472783
TI  - Effects of diabetes, insulin and antioxidants on NO synthase abundance and NO
      interaction with reactive oxygen species.
AB  - BACKGROUND: Earlier studies have provided evidence for increased production of
      reactive oxygen species (ROS) and altered nitric oxide (NO) metabolism in
      diabetes. This study was intended to explore the effect of type I diabetes and
      its treatment with insulin alone or insulin plus antioxidant-fortified diet on
      expression of NOS isoforms and ROS interactions with lipids, glucose and NO.
      METHODS: Rats with streptozotocin-induced diabetes were divided into once-daily
      insulin (ultralente)-treated, insulin plus antioxidant (vitamin E and vitamin C)
      treated and untreated groups. After four weeks, plasma malondialdehyde (MDA) and
      tissue endothelial (eNOS), neuronal (nNOS) NO synthases, carboxymethyllysine
      (CML) and nitrotyrosine were determined. RESULTS: The untreated diabetic animals
      exhibited severe hyperglycemia, elevated blood pressure, increased plasma MDA,
      high tissue CML and reduced tissue nitrotyrosine denoting enhanced lipid, glucose
      and protein oxidation but reduced NO oxidation by ROS. This was coupled with
      significant reduction of eNOS and nNOS expression in renal cortex and eNOS in the
      left ventricle. Insulin therapy partially lowered blood pressure, tissue CML,
      plasma glucose and MDA, but significantly raised eNOS expression and
      nitrotyrosine abundance to supranormal levels. Combined insulin and antioxidant
      therapies resulted in normalization of blood pressure, plasma MDA, tissue CML and
      nitrotyrosine without affecting glucose level or NOS expression. CONCLUSION:
      Oxidative stress in untreated diabetes is associated with down-regulation of NOS
      isoforms and increased ROS-mediated oxidation of lipid and glucose, but not NO.
      Amelioration of hyperglycemia with once-daily insulin administration alone
      results in up-regulation of NOS isoforms, reduction of lipid and glucose
      oxidation and increased NO oxidation. However, insulin plus antioxidant
      supplementation can normalize all three parameters.

PMID- 12472784
TI  - Renal oxygenation defects in the spontaneously hypertensive rat: role of AT1
      receptors.
AB  - BACKGROUND: The spontaneously hypertensive rat (SHR) has oxidative stress and
      enhanced O2 usage (Q(O2)) relative to tubular sodium transport (TNa). Angiotensin
      II (Ang II) acting on Type I receptors (AT1-R) causes renal oxidative stress and
      functional nitric oxide (NO) deficiency that could enhance O2 usage. Therefore,
      we investigated the hypothesis that AT1-Rs mediate the inefficient renal
      oxygenation in the SHR. METHODS: Groups of SHR and WKY received vehicle (Veh),
      candesartan (Cand) or hydralazine + hydrochlorothiazide + reserpine (HHR) for two
      weeks. RESULTS: Compared to WKY + Veh, the elevated BP of SHR + Veh (153 +/- 3 vs
      115 +/- 3 mm Hg; P < 0.001) was normalized by Cand (117 +/- 4) or HHR (113 +/- 5
      mm Hg). The reduced renal blood flow of SHR + Veh (2.4 +/- 0.3 vs. 4.1 +/- 0.3
      mL. min-1. 100 g-1) was increased (P < 0.05) by Cand (3.6 +/- 0.3) and HHR (3.2
      +/- 0.2). Compared to WKY + Veh, SHR + Veh had a 50% reduction in TNa: (16.9 +/-
      2.0 vs. 7.8 +/- 0.9 micromol: micromol-1, P < 0.01) that was unchanged by HHR
      (8.6 +/- 1.1), but was increased by Cand (13.2 +/- 1.4; P < 0.01). The pO2 of
      outer cortex was lower in SHR + Veh than WKY + Veh (31 +/- 3 vs. 41 +/- 2 mm Hg;
      P < 0.05) and it was not changed significantly by HHR (37 +/- 2) but was
      normalized by Cand (44 +/- 3 mm Hg; P < 0.01). The pO2 in the deep cortex also
      was lower in SHR + Veh than WKY + Veh (18 +/- 3 vs. 30 +/- 3 mm Hg; P < 0.005)
      and was not changed significantly by HHR (19 +/- 2), but was increased by Cand
      (25 +/- 3 mm Hg; P < 0.05). CONCLUSIONS: The reduced pO2 in outer and inner
      cortex, and inefficient utilization of O2 for Na+ transport in the SHR kidney can
      be ascribed to the effects of AT1-R, largely independent of blood pressure.

PMID- 12472785
TI  - Mycophenolate mofetil prevents the development of glomerular injury in
      experimental diabetes.
AB  - BACKGROUND: Experimental and clinical evidence suggests that inflammation plays a
      role in the pathogenesis of diabetic nephropathy, in addition to, or in concert
      with, the associated hemodynamic and metabolic changes. The present study
      assessed the effects of chronic anti-inflammatory therapy in experimental
      diabetic nephropathy. METHODS: Adult male Munich-Wistar rats were made diabetic
      with streptozotocin after uninephrectomy, kept moderately hyperglycemic by daily
      injections of NPH insulin and distributed among three groups: C, non-diabetic
      rats; DM, rats made diabetic and treated with insulin as described earlier; and
      DM+MMF, diabetic rats receiving insulin and treated with mycophenolate mofetil
      (MMF), 10 mg/kg once daily by gavage. Renal hemodynamic studies were performed 6
      to 8 weeks after induction of diabetes. Additional rats were followed during 8
      months, at the end of which renal morphological studies were performed. RESULTS:
      After 6 to 8 weeks, diabetic rats exhibited marked glomerular hyperfiltration and
      hypertension. Diabetic rats developed progressive albuminuria and exhibited
      widespread glomerulosclerotic lesions associated with macrophage infiltration at
      8 months. Treatment with MMF had no effect on blood pressure, glomerular dynamics
      or blood glucose levels, but did prevent albuminuria, glomerular macrophage
      infiltration and glomerulosclerosis. Thus, the renoprotective effect of MMF was
      not associated with a metabolic or renal hemodynamic effect, and must have
      derived from its well-known anti-inflammatory properties, which include
      restriction of lymphocyte and macrophage proliferation and limitation of the
      expression of adhesion molecules. CONCLUSIONS: These findings are consistent with
      the notion that inflammatory events are central to the pathogenesis of diabetic
      nephropathy and suggest that MMF may help prevent the progression of diabetic
      nephropathy.

PMID- 12472787
TI  - Development and progression of nephropathy in type 2 diabetes: the United Kingdom
      Prospective Diabetes Study (UKPDS 64).
AB  - BACKGROUND: The progression of nephropathy from diagnosis of type 2 diabetes has
      not been well described from a single population. This study sought to describe
      the development and progression through the stages of microalbuminuria,
      macroalbuminuria, persistently elevated plasma creatinine or renal replacement
      therapy (RRT), and death. METHODS: Using observed and modeled data from 5097
      subjects in the UK Prospective Diabetes Study, we measured the annual probability
      of transition from stage to stage (incidence), prevalence, cumulative incidence,
      ten-year survival, median duration per stage, and risk of death from all-causes
      or cardiovascular disease. RESULTS: From diagnosis of diabetes, progression to
      microalbuminuria occurred at 2.0% per year, from microalbuminuria to
      macroalbuminuria at 2.8% per year, and from macroalbuminuria to elevated plasma
      creatinine (>or=175 micromol/L) or renal replacement therapy at 2.3% per year.
      Ten years following diagnosis of diabetes, the prevalence of microalbuminuria was
      24.9%, of macroalbuminuria was 5.3%, and of elevated plasma creatinine or RRT was
      0.8%. Patients with elevated plasma creatinine or RRT had an annual death rate of
      19.2% (95% confidence interval, CI, 14.0 to 24.4%). There was a trend for
      increasing risk of cardiovascular death with increasing nephropathy (P < 0.0001),
      with an annual rate of 0.7% for subjects in the stage of no nephropathy, 2.0% for
      those with microalbuminuria, 3.5% for those with macroalbuminuria, and 12.1% with
      elevated plasma creatinine or RRT. Individuals with macroalbuminuria were more
      likely to die in any year than to develop renal failure. CONCLUSIONS: The
      proportion of patients with type 2 diabetes who develop microalbuminuria is
      substantial with one quarter affected by 10 years from diagnosis. Relatively
      fewer patients develop macroalbuminuria, but in those who do, the death rate
      exceeds the rate of progression to worse nephropathy.

PMID- 12472786
TI  - Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions
      in iron dextran-sensitive and dextran-tolerant patients.
AB  - BACKGROUND: Iron dextran administration is associated with a high incidence of
      adverse reactions including anaphylaxis and death. Although dextran, rather than
      iron, is believed to be the cause of these reactions, it is not known whether
      iron dextran-sensitive patients can be safely administered another form of
      parenteral iron, sodium ferric gluconate in sucrose (SFGC). METHODS: In a 69
      center, prospective, double-blind, controlled trial of safety and tolerability of
      SFGC, the rate of reactions to SFGC and placebo in 144 iron dextran-sensitive
      patients was compared with 2194 patients who were previously tolerant to iron
      dextran preparations. Serum tryptase levels, a marker of mast cell degranulation,
      also were measured. RESULTS: Among 143 iron dextran-sensitive patients exposed to
      SFGC, three (2.1%) were intolerant. All three had suspected allergic events to
      SFGC, including one patient with a serious reaction (0.7%). One dextran-sensitive
      patient (0.7%) had a suspected allergic reaction after placebo. In contrast,
      among 2194 iron dextran-tolerant patients, reactions to SFGC were significantly
      less common, with SFGC intolerance seen in seven patients (0.3%; P = 0.020),
      including five (0.2%) who had suspected allergic events (P = 0.010), but none who
      had serious events (0.0%; P = 0.061). Two iron dextran-tolerant patients (0.09%)
      had allergic-like reactions following placebo injections. Two of the three
      suspected allergic events in the iron dextran-sensitive group were confirmed as
      mast cell dependent by a 100% increase in serum tryptase, while there were no
      confirmed allergic events in the iron dextran-tolerant group. Long-term exposure
      to SFGC in iron dextran-sensitive patients resulted in intolerance in only one
      additional patient and no serious adverse events. CONCLUSIONS: Patients with a
      history of iron dextran sensitivity had approximately sevenfold higher rates of
      reaction to both placebo and SFGC compared to iron dextran tolerant patients.
      However, logistic regression analysis, performed to account for the higher
      reaction rate to placebo, suggests that this increased reactivity was not drug
      specific nor immunologically mediated, but represented host idiosyncrasy. These
      results support the conclusions that reactions to SFGC can be attributed to
      pseudoallergy, and that SFGC is not a true allergen.

PMID- 12472788
TI  - Familial collapsing glomerulopathy: clinical, pathological and immunogenetic
      features.
AB  - BACKGROUND: Collapsing glomerulopathy (CG) is an aggressive form of glomerular
      injury frequently seen in association with HIV infection, although it is also
      recognized in non-HIV patients as a primary disease. Until now, the occurrence of
      CG in a familial pattern has not been reported. METHODS: We studied five members
      of a family (siblings), admitted for evaluation of proteinuria and nephrotic
      syndrome. They had no other family history of renal disease. Blood samples for
      major histocompatibility complex (MHC) analysis were obtained from the five
      siblings, both parents and four relatives. RESULTS: Renal biopsy performed in
      four out of the five siblings revealed capillary collapse and retraction with
      visceral epithelial cell swelling and reabsorption droplets, consistent with CG.
      Two of the patients had suggestive symptoms of systemic lupus erythematosus, such
      as arthritis, rash, hair loss, moderate leukopenia and lymphopenia, low titers of
      antinuclear antibodies (ANA) and anti-SSA/Ro antibodies, but no immune complex
      deposition on renal biopsy. IgG serology for parvovirus B19 (PVB-19) was positive
      only in two siblings but polymerase chain reaction (PCR) was negative.
      Immunogenetic analysis showed that all patients shared the same MHC haplotype
      inherited from the mother. CONCLUSIONS: CG can present in a familial pattern.
      Since a similar MHC haplotype was observed in affected and non-affected members
      of the family, we conclude that the environment plays an important role in the
      development of the disease.

PMID- 12472789
TI  - Long-term combined treatment with thiazide and potassium citrate in
      nephrolithiasis does not lead to hypokalemia or hypochloremic metabolic
      alkalosis.
AB  - BACKGROUND: Potassium citrate is commonly used in combination with a thiazide
      diuretic in the medical management of recurrent hypercalciuric nephrolithiasis.
      However, concerns have been raised that administration of this nonchloride
      potassium alkali with a kaliuretic and natriuretic agent such as thiazide may not
      be efficacious in correcting or preventing hypokalemia, and may produce
      hypochloremic metabolic alkalosis. This retrospective analysis was conducted to
      determine if these two potential complications are encountered in patients on
      long-term potassium citrate and thiazide therapy. METHODS: Data were collected on
      95 patients who had been on combination therapy for at least 4 months from the
      stone clinics of the University of Texas Southwestern Medical Center, Duke
      University Medical Center, and Ochsner Clinic. RESULTS: Mean serum potassium
      concentration remained within normal limits without a significant decrease during
      combined therapy. Serum chloride was significantly lower from pretreatment but by
      only 1 mEq/L and remained within normal limits throughout treatment. There was a
      small increase in serum bicarbonate concentration compared to the baseline level
      of less than 1 mEq/L at 8 to 12 and 18 to 24 months, but not at other treatment
      periods. CONCLUSION: Co-administration of potassium citrate did not induce
      hypokalemia or hypochloremic metabolic alkalosis in our thiazide-treated patient
      population.

PMID- 12472790
TI  - The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in
      secondary hyperparathyroidism.
AB  - BACKGROUND: A need exists for a therapy that lowers parathyroid hormone (PTH)
      without increasing calcium x phosphorus in patients with secondary
      hyperparathyroidism. The calcimimetic AMG 073 increases the sensitivity of the
      parathyroid calcium-sensing receptor to extracellular calcium, thereby reducing
      PTH secretion. Consequently, AMG 073 may provide a novel therapy for secondary
      hyperparathyroidism. METHODS: Seventy-eight hemodialysis patients with secondary
      hyperparathyroidism were enrolled into this 18-week, double-blind, randomized,
      placebo-controlled, dose titration study. Daily oral AMG 073 doses were
      administered to determine the effect on PTH, serum calcium, phosphorus, and
      calcium x phosphorus. RESULTS: The mean baseline PTH was similar in patients
      administered AMG 073 or placebo (632 +/- 280.1 pg/mL vs. 637 +/- 455.9 pg/mL,
      respectively). PTH decreased by 26.0% in the AMG 073-treated group, compared with
      an increase of 22.0% in the placebo group (P < 0.001). A greater proportion in
      the AMG 073 group (38%) had a decrease in PTH >or=30%, compared with the placebo
      group (8%) (P = 0.001). Decreases in PTH were independent of baseline vitamin D
      usage. Patients receiving AMG 073 had an 11.9% decrease in calcium x phosphorus
      compared with a 10.9% increase in the placebo group (P < 0.001). Use of vitamin D
      sterols, as well as both calcium and noncalcium-containing phosphate binders.
      were similar between treatment groups. Administration of AMG 073 was safe and
      well tolerated in this 18-week study. CONCLUSIONS: The calcimimetic AMG 073
      decreases both PTH and calcium x phosphorus levels in hemodialysis patients with
      secondary hyperparathyroidism.

PMID- 12472792
TI  - Severe bone disease and low bone mineral density after juvenile renal failure.
AB  - BACKGROUND: Little is known about the late effects of juvenile end-stage renal
      disease (ESRD) on bone integrity. To establish clinical manifestations of
      metabolic bone disease and bone mineral density (BMD) in young adult patients
      with juvenile ESRD, we performed a long-term outcome study. METHODS: A cohort was
      formed of all Dutch patients with onset of ESRD between 1972 and 1992 at age 0 to
      14 years, born before 1979. Data were collected by review of medical charts,
      current history, physical examination, and performing dual energy x-ray
      absorptiometry (DEXA) of the lumbar spine and the femoral neck. RESULTS: Clinical
      information was retrieved in 247 out of 249 patients. Of all of these patients,
      61.4% had severe growth retardation (<-2 SD), 36.8% had clinical symptoms of bone
      disease, and 17.8% were disabled by bone disease. Growth retardation and clinical
      bone disease were associated with a long duration of dialysis. DEXA was performed
      in 140 out of 187 living patients. Mean BMD +/- SD corrected for gender and age
      (Z score) of the lumbar spine was -2.12 +/- 1.4 and of the femoral neck was -1.77
      +/- 1.4. A low lean body mass was associated with a low lumbar spine and a low
      femoral neck BMD; male gender, physical inactivity and aseptic bone necrosis were
      associated with a low lumbar spine BMD. CONCLUSION: Bone disease is a major
      clinical problem in young adults with pediatric ESRD. Further follow-up is needed
      to establish the impact of the low bone mineral densities found in these
      patients.

PMID- 12472791
TI  - Urine stone risk factors in nephrolithiasis patients with and without bowel
      disease.
AB  - BACKGROUND: The prevalence of nephrolithiasis among patients with bowel disease
      is higher than in the general population. We examined urine stone risk factors
      and clinical characteristics of these patients, contrasted with a large group of
      stone forming patients without systemic disease. METHODS: A total of 180 patients
      with bowel disease were compared with a group of 2048 nephrolithiasis patients
      with calcium or uric acid stones and without systemic diseases. Bowel diseases
      included inflammatory bowel disease with and without bowel resections, bowel
      resections from cancer or trauma, and bypass procedures for obesity or
      hypercholesterolemia. Urine stone risk factors, stone rates, stone compositions,
      and creatinine clearance were measured. RESULTS: Compared to ordinary stone
      forming patients, bowel patients formed stones higher in rate of recurrence and
      in uric acid content. Uric acid content was highest when colon surgery had
      occurred. Urine volumes were low among all bowel patients except those with a
      bypass. Average creatinine clearance values were low among all bowel patients.
      Urine oxalate excretion was modestly elevated after small bowel resection, but
      very high with bypass. Supersaturations were increased mainly by low urine volume
      and-for uric acid-low pH. Patients with no surgery were indistinguishable from
      routine stone formers. CONCLUSIONS: Low urine volume and pH are the main stone
      forming abnormalities in bowel disease patients. Hyperoxaluria is extreme after
      bypass, but only modest after small bowel surgery. In the absence of surgery,
      bowel disease patients with stones cannot be distinguished from common stone
      formers by comprehensive stone risk measurements.

PMID- 12472793
TI  - Renal function and outcome of PTRA and stenting for atherosclerotic renal artery
      stenosis.
AB  - BACKGROUND: Prior studies of percutaneous transluminal renal artery angioplasty
      and stenting (PTRAS) for atherosclerotic renal artery stenosis (RAS) have shown
      that renal function is improved in about 25%, stabilizes in about 40%, but
      worsens in about 25% of patients. The factors predicting benefit remain
      controversial. We tested the hypothesis that the baseline glomerular filtration
      rate (GFR) predicts the changes in GFR and blood pressure (BP) after PTRAS.
      METHODS: Treated hypertensive patients with positive renal color-coded duplex
      Doppler velocimetry and clinical criteria were screened by arteriography.
      Patients (N = 105) were included if they had an RAS >or=70%, a transluminal
      pressure gradient >or=30 mm Hg and, they had more than 100 days of follow-up. GFR
      was calculated from the serum creatinine concentration (SCr). Patients were
      divided by baseline GFR into subgroups with normal to mildly impaired (N = 52) or
      moderately to severely impaired (N = 53) initial GFR, according to a GFR >or=50
      or <50 mL. min-1 respectively. All received PTRAS. RESULTS: For the entire group,
      after a mean follow-up period of 371 days, there were significant reductions in
      systolic and diastolic BP (before, 160 +/- 26/91 +/- 12 vs. after, 145 +/- 20/83
      +/- 10 mm Hg, respectively; mean +/- SD; P < 0.0001), and a modest increase in
      the calculated GFR (before, 54 +/- 26 vs. after, 62 +/- 28 mL. min-1; mean +/-
      SD; P < 0.007). However, in the subgroup of patients with an initially lower GFR
      there was a significant increase in the calculated GFR (from 33.3 +/- 10 to 54 +/
      24 mL. min-1; mean +/- SD; P < 0.0001) despite no significant change in BP (161
      +/- 27/90 +/- 12 vs. 151 +/- 21/86 +/- 12; P = NS). In contrast, in the subgroup
      with an initially higher GFR, there were significant (P < 0.0001) reductions in
      systolic BP (from 159 +/- 25 to 138 +/- 16 mm Hg) and diastolic BP (from 91 +/-
      11 to 81 +/- 9 mm Hg), but no significant change in the calculated GFR (from 75
      +/- 21 to 70.2 +/- 30 mL. min-1; P = NS). The significance of GFR variation in
      subgroups remained after correction of baseline data to exclude the influence of
      the expected regression to the mean. CONCLUSIONS: Patients with atherosclerotic
      RAS fulfilling strict criteria of severity may have significant improvements in
      BP one year after PTRAS but only modest in GFR. The initial GFR may anticipate
      whether the benefits in the outcome will be in renal function enhancement (those
      with an initially depressed GFR) or in hypertension control (those with an
      initially normal or mildly impaired GFR).

PMID- 12472794
TI  - Impaired K+ regulation contributes to exercise limitation in end-stage renal
      failure.
AB  - BACKGROUND: Patients with end-stage renal failure (ESRF) exhibit grossly impaired
      maximal exercise performance. This study investigated whether K+ regulation
      during exercise is impaired in ESRF and whether this is related to reduced
      exercise performance. METHODS: Nine stable hemodialysis patients and eight
      controls (CON) performed incremental cycling exercise to volitional fatigue, with
      measurement of peak oxygen consumption (VO2 peak). Arterial blood was sampled
      during and following exercise and analyzed for plasma [K+] (PK). RESULTS: The VO2
      peak was approximately 44% less in ESRF than in CON (P < 0.001), whereas peak
      exercise PK was greater (7.23 +/- 0.38 vs. 6.23 +/- 0.14 mmol x L-1,
      respectively, P < 0.001). In ESRF, the rate of rise in PK during exercise was
      twofold greater (0.43 +/- 0.05 vs. 0.23 +/- 0.03 mmol. L-1x min-1, P < 0.005) and
      the ratio of rise in PK relative to work performed was 3.7-fold higher (90.1 +/-
      13.5 vs. 24.7 +/- 3.3 nmol. L-1. J-1, P < 0.001). A strong inverse relationship
      was found between VO2 peak and the DeltaPK. work-1 ratio (r = -0.80, N = 17, P <
      0.001). CONCLUSIONS: Patients with ESRF exhibit grossly impaired extrarenal K+
      regulation during exercise, demonstrated by an excessive rise in PK relative to
      work performed. We further show that K+ regulation during exercise was correlated
      with aerobic exercise performance. These results suggest that disturbed K+
      regulation in ESRF contributes to early muscle fatigue during exercise, thus
      causing reduced exercise performance.

PMID- 12472795
TI  - Muscle atrophy in patients receiving hemodialysis: effects on muscle strength,
      muscle quality, and physical function.
AB  - BACKGROUND: Dialysis patients are less active and have reduced functional
      capacity compared to individuals with normal renal function. Muscle atrophy and
      weakness may contribute to these problems. This investigation was undertaken to
      quantify the extent of atrophy in the lower extremity muscles, to determine
      whether defects in muscle specific strength (force per unit mass) or central
      nervous system (CNS) activation are present, and to assess the relationship
      between muscle size and physical performance in a group of patients on
      hemodialysis. METHODS: Thirty-eight dialysis subjects (aged 55 +/- 15 years) and
      nineteen healthy sedentary controls (aged 55 +/- 13 years) were enrolled.
      Magnetic resonance imaging of the lower leg was used to determine the total cross
      sectional area (CSA) and the area of contractile and non-contractile tissue of
      the ankle dorsiflexor muscles. Isometric dorsiflexor strength was measured during
      a maximal voluntary contraction with and without superimposed tetanic stimulation
      (N = 22 for dialysis subjects, N = 12 for controls). Physical activity was
      measured by accelerometry, and gait speed was recorded as a measure of physical
      performance. RESULTS: Dialysis subjects were weaker, less active, and walked more
      slowly than controls. Total muscle compartment CSA was not significantly
      different between dialysis subjects and controls, but the contractile CSA was
      smaller in the dialysis patients even after adjustment for age, gender, and
      physical activity. Central activation and specific strength were normal. Gait
      speed was correlated with contractile CSA. CONCLUSIONS: Significant atrophy and
      increased non-contractile tissue are present in the muscle of patients on
      hemodialysis. The relationship between contractile area and strength is intact in
      this population. Muscle atrophy is associated with poor physical performance.
      Thus, interventions to increase physical activity or otherwise address atrophy
      may improve performance and quality of life.

PMID- 12472796
TI  - Glucose degradation products in PD fluids: do they disappear from the peritoneal
      cavity and enter the systemic circulation?
AB  - BACKGROUND: Glucose degradation products (GDP) are generated in peritoneal
      dialysis (PD) fluid during heat sterilization and storage. They are thought to
      adversely affect the peritoneal membrane. The fate of GDP within the peritoneal
      cavity has not been well characterized. METHODS: A clinical study was designed to
      determine (1). whether during the dwell in the peritoneal cavity GDP
      concentration decreases in the PD fluid as assessed by ex vivo formation of AGE;
      (2). whether exposure to GDP-containing PD fluids increases plasma fluorescence
      (as an index of plasma AGE concentration) as well as plasma carboxymethyllysine
      (CML) concentration; and (3). whether exposure to GDP-containing PD fluids
      adversely affects glycoprotein CA 125 concentration. A two-group crossover design
      was adopted comprising two consecutive observation periods of eight weeks each.
      Stable PD patients were exposed in random order either to conventional PD fluid
      (heat sterilized at pH 5.5) and subsequently to PD test fluid (or the 2 fluids in
      reverse order). The PD test fluid was sterilized using a multicompartment bag
      system separating highly concentrated glucose at pH 3 from the buffer solution.
      Conventional and test fluids differed with respect to concentrations of GDP, that
      is, 3-deoxyglucosone (118 vs. 12.3 micromol/L), methylglyoxal (5.3 micromol/L vs.
      below detection threshold), 3, 4-dideoxyglucosone-3-ene (10 micromol/L vs. below
      detection threshold) and acetaldehyde (226 vs. <1 micromol/L). RESULTS: The
      following results were obtained. First, methylglyoxal disappeared completely as
      early as two hours after intraperitoneal instillation of conventional PD fluid.
      Second, when spent conventional dialysate was recovered after a two hour and
      particularly an eight hour dwell and subsequently incubated ex vivo with 40 mg of
      human serum albumin, there was a continuous decrease of AGE-forming capacity,
      that is, less generation of fluorescence (AGE) and pyrraline (non-fluorescent
      Amadori product), and an increase of advanced oxidation protein products (AOPP)
      in the spent dialysate. Third, plasma fluorescence (exc. 350/em. 430 nm) as an
      index of circulating AGE compounds as well as plasma CML concentrations were
      significantly higher in the conventional PD fluid period versus low GDP PD fluid
      period. Fourth, CA 125 concentrations in spent dialysate were higher during the
      low GDP PD fluid period compared to the conventional PD fluid period. CONCLUSION:
      Conventional PD fluid undergoes modifications during intraperitoneal dwell with a
      loss of AGE forming capacity, suggesting breakdown, precipitation or resorption
      of GDP in vivo. This is accompanied by an increase in plasma AGE compounds.

PMID- 12472797
TI  - Inhibition of nuclear factor-kappaB activation by pyrrolidine dithiocarbamate
      prevents chronic FK506 nephropathy.
AB  - BACKGROUND: Chronic tacrolimus (FK506) nephrotoxicity is characterized by renal
      fibrosis with interstitial inflammation. Since nuclear factor-kappaB (NF-kappaB)
      plays a key role in chronic inflammatory diseases including renal disease, the
      present study was conducted to elucidate the role of NF-kappaB in the
      pathogenesis of chronic FK506-induced nephropathy. METHODS: FK506 (1 mg/kg/day,
      SC) was administered daily to rats maintained on low sodium diet for 42 days.
      Some rats were treated with a putative NF-kappaB inhibitor, pyrrolidine
      dithiocarbamate (PDTC; 100, 200 mg/kg/day, by gavage). The renal function, renal
      histology, renal NF-kappaB-DNA binding activity and gene expression profile were
      examined. RESULTS: FK506 caused a decline in glomerular filtration and induced
      characteristic renal morphologic changes including arteriolopathy, tubular
      atrophy and interstitial fibrosis. FK506 markedly activated renal cortical NF
      kappaB-DNA binding. PDTC administration inhibited NF-kappaB-DNA binding activity
      in a dose dependent manner. With higher dose, NF-kappaB-DNA binding activity was
      decreased to a control level. PDTC had little effect on FK506-induced renal
      dysfunction. Renal cortical monocyte/macrophage infiltration observed in FK506
      treated rats was dramatically suppressed by PDTC. FK506 up-regulated renal
      cortical gene expression of chemoattractant proteins, monocyte chemoattractant
      protein-1 (MCP-1) and osteopontin. PDTC significantly blocked MCP-1 gene
      expression but had no effect on osteopontin gene expression. Tubular atrophy and
      tubulointerstitial fibrosis, but not arteriolopathy, were significantly
      attenuated by PDTC. FK506 increased renal mRNA expression of fibrogenic molecules
      and extracellular matrices that also were attenuated by PDTC treatment.
      CONCLUSIONS: NF-kappaB plays an important role in mediating cortical
      monocyte/macrophage infiltration and in the pathogenesis of tubular injury and
      interstitial fibrosis in experimental FK506-induced chronic nephropathy.

PMID- 12472798
TI  - Impact of albumin synthesis rate and the acute phase response in the dual
      regulation of fibrinogen levels in hemodialysis patients.
AB  - BACKGROUND: Fibrinogen is a risk factor for cardiovascular disease. It also is an
      acute phase protein (APP) and its plasma concentration increases with
      inflammation. Fibrinogen synthesis correlates with albumin synthesis in nephrotic
      patients and in patients with an expanded plasma volume even when serum albumin
      is normal and there is no inflammatory disease. The relationships among albumin
      synthesis, the acute phase response and plasma fibrinogen levels in hemodialysis
      patients are unknown. METHODS: In 74 hemodialysis patients, albumin synthesis,
      plasma volume (PV) and acute phase proteins (APPs) C-reactive protein (CRP),
      alpha1 acid glycoprotein (alpha1 AG), ceruloplasmin (Cer), and interleukin 6 (IL
      6) were measured in serum and fibrinogen in plasma, and the results analyzed by
      multiple regression analysis. CRP, IL-6, alpha1 AG, Cer and fibrinogen were
      measured monthly, which enabled us to determine whether changes in these APPs
      correlated with the levels of and variability in plasma fibrinogen over time
      using a longitudinal modeling approach. Length of follow-up for the 74 patients
      ranged from 3.25 to 67.5 months. RESULTS: Baseline fibrinogen (548.6 +/- 106. 4
      mg/dL) was significantly greater than levels reported for normal adults and
      correlated positively with albumin synthesis (P < 0.001), age (P < 0.001) and log
      CRP (P = 0.002) and negatively with PV (P < 0.001). Longitudinally, fibrinogen
      varied positively with long-lived APPs, Cer and alpha1 AG, as well as the short
      lived APP, CRP. CONCLUSION: Plasma fibrinogen concentration is high in HD
      patients and directly correlates with increased albumin synthesis rates and the
      serum levels of APPs. Fibrinogen levels also correlate negatively with PV.
      Fibrinogen levels vary over time in synchrony with levels of other long-lived
      APPs, supporting the hypothesis that fibrinogen is regulated in part as a
      component of the acute phase response and in part by factors that increase
      albumin synthesis.

PMID- 12472799
TI  - Creation, cannulation and survival of arteriovenous fistulae: data from the
      Dialysis Outcomes and Practice Patterns Study.
AB  - BACKGROUND: An arteriovenous (A-V) fistula is the optimal vascular access for
      hemodialysis. The National Kidney Foundation Dialysis Outcomes Quality Initiative
      (DOQI) recommends that fistulae should mature for at least one month before
      cannulation, but this recommendation is not evidence-based. If fistulae are
      created prior to ESRD and cannulation is possible earlier without compromising
      fistula survival, the need for temporary catheters would be reduced. METHODS:
      Prospective observational data were analyzed for a random sample (N = 3674) of
      incident patients at the time of initiating hemodialysis, hemofiltration or
      hemodiafiltration in 309 facilities in France, Germany, Italy, Japan, Spain, the
      United Kingdom, and the United States, taking part in the Dialysis Outcomes and
      Practice Patterns Study (DOPPS). RESULTS: Although the proportion of patients who
      had pre-dialysis care by a nephrologist differed little between countries, there
      were large variations in the proportion of patients who commenced hemodialysis
      via an A-V fistula, A-V graft or central venous catheter. The usual time interval
      between referral and creation of A-V fistulae also differed greatly between
      countries. For new hemodialysis (HD) patients initiating HD with an A-V fistula
      (N = 894) the following results were observed: (1). median time to first
      cannulation varied greatly between countries: Japan and Italy (25 and 27 days),
      Germany (42 days), Spain and France (80 and 86 days), UK and US (96 and 98 days).
      (2). No association was found between cannulation <or=28 days versus>28 days for
      patient characteristics of age, gender, and fifteen different classes of patient
      co-morbid factors. (3). Risk of A-V fistula failure was increased for incident
      patients who had a prior temporary access [relative risk (RR) = 1.81, P = 0.01]
      or who were female (RR = 1.52, P = 0.02). (4). Cannulation <or=14 days after
      creation was associated with a 2.1-fold increased risk of subsequent fistula
      failure (P = 0.006) compared to fistulae cannulated>14 days. (5) No significant
      difference in A-V fistula failure was seen for fistulae cannulated in 15 to 28
      days compared with 43 to 84 days. CONCLUSION: Significant differences in clinical
      practice currently exist between countries regarding the creation of A-V fistulae
      prior to starting hemodialysis and the timing of initial cannulation. Cannulation
      within 14 days of creation is associated with reduced long-term fistula survival.
      Fistulae ideally should be left to mature for at least 14 days before first
      cannulation.

PMID- 12472800
TI  - Affinity adsorption of glucose degradation products improves the biocompatibility
      of conventional peritoneal dialysis fluid.
AB  - BACKGROUND: Reactive carbonyl compounds (RCOs) present in peritoneal dialysis
      (PD) fluid have been incriminated in the progressive deterioration of the
      peritoneal membrane in long-term PD patients. They are initially present in fresh
      conventional heat-sterilized glucose PD fluid and are supplemented during dwell
      time by the diffusion of blood RCOs within the peritoneal cavity. In the present
      study, RCO entrapping agents were immobilized on affinity beads to adsorb RCOs
      both in fresh PD fluid and in PD effluent. METHODS: The RCO trapping potential of
      various compounds was assessed in vitro first by dissolving them in the tested
      fluid and subsequently after coupling with either epoxy- or amino-beads. The
      tested fluids include fresh heat-sterilized glucose and non-glucose PD fluids,
      and PD effluent. Their RCOs contents, that is, glyoxal (GO), methylglyoxal (MGO),
      3-deoxyglucosone (3-DG), formaldehyde, 5-hydroxymethylfuraldehyde, acetaldehyde,
      and 2-furaldehyde were monitored by reverse-phase high-pressure liquid
      chromatography. The biocompatibility of PD fluid was assessed by a cytotoxic
      assay with either human epidermoid cell line A431 cells or with primary cultured
      human peritoneal mesothelial cells. RESULTS: Among the tested RCO entrapping
      agents, hydrazine coupled to epoxy-beads proved the most efficient. It lowered
      the concentrations of three dicarbonyl compounds (GO, MGO, and 3-DG) and those of
      aldehydes present in fresh heat-sterilized glucose PD fluid toward the low levels
      observed in filter-sterilized glucose PD fluid. It did not change the glucose and
      electrolytes concentration of the PD fluid but raised its pH from 5.2 to 5.9.
      Hydrazine-coupled epoxy-bead also lowered the PD effluent content of total RCOs,
      measured by the 2,4-dinitrophenylhydrazone (DNPH) method. The cytotoxicity of
      heat-sterilized PD fluid incubated with hydrazine-coupled epoxy-beads was
      decreased to the level observed in filter-sterilized PD fluid as the result of
      the raised pH and the lowered RCOs levels. CONCLUSION: Hydrazine-coupled epoxy
      beads reduce the levels of a variety of dicarbonyls and aldehydes present in heat
      sterilized glucose PD fluid to those in filter-sterilized PD fluid, without
      altering glucose, lactate, and electrolytes contents but with a rise in pH.
      Incubated with PD effluents, it is equally effective in reducing the levels of
      serum-derived RCOs. RCO entrapping agents immobilized on affinity beads improve
      in vitro the biocompatibility of conventional heat-sterilized glucose PD fluid.
      Their clinical applicability requires further studies.

PMID- 12472801
TI  - Prevention of Staphylococcus aureus biofilm on dialysis catheters and adherence
      to human cells.
AB  - BACKGROUND: Dialysis patients, often carriers of Staphylococcus aureus in their
      nares, are at high risk of S. aureus infections. METHODS: We examined whether
      RNAIII inhibiting peptide (RIP), which interferes with quorum sensing mechanisms,
      reduces adherence of S. aureus to host cells and to dialysis catheter polymers in
      vitro. Adherence was tested by spectroscopy using safranin staining, by confocal
      scanning laser microscopy and by atomic force microscopy. RESULTS: RIP inhibited
      bacterial adherence to HaCat and HEp-2 cells and reduced adherence and biofilm
      formation not only on polystyrene, but also on both polyurethane- and silicone
      made dialysis catheters, with a preponderant effect on silicone, to which
      bacteria were more adherent. CONCLUSION: RIP opens a new perspective in anti-S.
      aureus prophylaxis, particularly in dialysis patients.

PMID- 12472802
TI  - Gender differences in outcomes of arteriovenous fistulas in hemodialysis
      patients.
AB  - BACKGROUND: The prevalence of arteriovenous (A-V) fistula use is lower among
      female than male hemodialysis patients. This difference may be due, in part, to
      smaller vessel diameter in women. However, even when routine preoperative
      vascular mapping is used to select vessels with suitable diameters, fistulas are
      still less likely to mature in women than in men. METHODS: To explore the reasons
      for this gender discrepancy, we evaluated the outcomes of 230 A-V fistulas placed
      at our institution after preoperative mapping. Vessel diameters, radiologic and
      surgical interventions, and fistula adequacy for dialysis were assessed. RESULTS:
      Fistula adequacy for dialysis was lower in women than men (31 vs. 51%, P =
      0.001). The inferior outcome of fistulas in women was observed for both forearm
      fistulas (18 vs. 43%, P = 0.02) and upper arm fistulas (39 vs. 60%, P = 0.04).
      Differences in vessel diameter did not explain the lower patency rate of fistulas
      among women. Among fistulas not lost due to technical failure or early
      thrombosis, 31% underwent one or more interventions (salvage procedures) due to
      failure to mature. These interventions included angioplasty, ligation of
      tributaries, superficialization, and surgical revision of the anastomosis. A
      salvage procedure was more likely in women than in men (42 vs. 23%, P = 0.04).
      The likelihood of fistula maturation after an intervention was similar among
      women and men (50 vs. 37%, P = 0.40). Salvage procedures increased the proportion
      of adequate fistulas to a greater degree in women than in men (relative increases
      of 68 and 15%, respectively). CONCLUSIONS: These data suggest that fistulas are
      less likely to be useable for dialysis in women than in men, despite routine
      preoperative mapping and frequent interventions undertaken to salvage immature
      fistulas.

PMID- 12472803
TI  - Effects of high-flux hemodialysis on oxidant stress.
AB  - BACKGROUND: Neutrophil oxygen radical production is increased in end-stage renal
      disease (ESRD) patients and it is further enhanced during dialysis with low-flux
      cellulosic membranes. This increased oxygen radical production may contribute to
      the protein and lipid oxidation observed in ESRD patients. We tested the
      hypothesis that high-flux hemodialysis does not increase oxygen radical
      production and that it is not associated with protein oxidation. METHODS:
      Neutrophil oxygen radical production was measured during dialysis with high-flux
      dialyzers containing polysulfone and cellulose triacetate membranes. Free
      sulfhydryl and carbonyl groups and advanced oxidation protein products were
      measured to assess plasma protein oxidation. RESULTS: Pre-dialysis, neutrophil
      oxygen radical production was significantly greater than normal and increased
      significantly as blood passed through the dialyzer in the first 30 minutes of
      dialysis. Post-dialysis, however, neutrophil oxygen radical production had
      decreased and was not different from normal. Pre-dialysis, significant plasma
      protein oxidation was evident from reduced free sulfhydryl groups, increased
      carbonyl groups, and increased advanced oxidation protein products. Post
      dialysis, plasma protein free sulfhydryl groups had increased to normal levels,
      while plasma protein carbonyl groups increased slightly, and advanced oxidation
      protein products remained unchanged. CONCLUSIONS: The results of this study show
      that neutrophil oxygen radical production normalizes during high-flux dialysis,
      despite a transient increase early in dialysis. This decrease in oxygen radical
      production is associated with an improvement in some, but not all, measures of
      protein oxidation.

PMID- 12472804
TI  - Blood pressure reduction with HMG-CoA reductase inhibitors in renal transplant
      recipients.
AB  - BACKGROUND: Besides lowering lipid levels, 3-hydroxy-3-methylglutaryl coenzyme A
      (HMG-CoA) reductase inhibitors (statins) modulate endothelial function and
      decrease vascular tone. The effect of statin therapy on blood pressure has not
      been previously examined in renal transplant recipients. METHODS: We identified
      113 stable recipients with graft survival>1 year and started on a statin >or=1
      year post-transplant with no subsequent alteration in type or dose, as well as
      >or=6 months' follow-up post-statin introduction along with no changes in
      antihypertensive medication type or dosage. This "statin" group was compared to a
      control group matched 1:1 by age, gender, donor source, year of transplant, and
      time since transplant who met identical criteria but were not begun on a statin.
      Baseline, 6 months, and 12 months outpatient blood pressure were reviewed and
      compared along with other possible blood pressure predictors. A multivariate
      analysis was performed controlling for other influences on blood pressure change.
      RESULTS: Blood pressure and baseline characteristics other than lipid levels were
      similar in the two groups. The systolic, diastolic, and mean arterial blood
      pressure decreased by 7 mm Hg (P = 0.005), 3 mm Hg (P = 0.05), and 4 mm Hg (P =
      0.007), respectively, at 12 months' post-statin introduction, while no blood
      pressure change was seen in the control group (P = NS). At 12 months, the
      systolic, diastolic, and mean arterial blood pressures were lower in the statin
      group compared to the control group (P = 0.05, 0.03, and 0.02, respectively).
      These changes in blood pressure were independent of changes in serum lipid
      levels. CONCLUSION: Renal transplant recipients exhibit a significant blood
      pressure reduction associated with statin therapy. This finding has important
      mechanistic and clinical implications in the management of cardiovascular disease
      risk factors in this population.

PMID- 12472805
TI  - Morphogenesis during mouse embryonic kidney explant culture.
AB  - BACKGROUND: Renal organogenesis is routinely studied using cultured murine
      embryonic kidneys, but the application of this model has not yet been subjected
      to rigorous standards. METHODS: We measured ex vivo growth and morphogenesis of
      day 13 murine kidneys and evaluated the importance of culture conditions and
      biological variables. RESULTS: Kidney size was measured in two dimensions as
      planar surface area and was shown to correlate highly with volume (R2 = 0.60, P <
      0.005). The final surface area of kidneys was directly dependent on the initial
      starting size (R2 = 0.61, P < 0.05), suggesting that the final surface area is
      not a valid outcome measurement unless starting size is equal among treatments.
      Relative growth rate, defined as (final surface area - initial surface
      area)/initial surface area, was a good measure of growth and independent of size
      and anatomical position (P> 0.05). Significant differences in size and growth
      rates were observed among litters (P < 0.05), implying that kidneys from a given
      litter must be randomized to avoid confounding results. Planar surface area of
      each explant increased in proportion to ureteric bud branching (R2 = 0.6854, P <
      0.05). In a comparison of a variety of base media and supplements, kidney
      explants were observed to grow best in Dulbecco's modified Eagle's medium
      (DMEM)/F12 with 5% fetal bovine serum and to sustain growth for up to 96 hours,
      despite decreased proliferation and increased apoptosis at this time point.
      CONCLUSIONS: These results represent an important step in establishing
      standardized procedures for the use of cultured embryonic kidneys and will
      improve our ability to apply the model to better understand kidney morphogenesis.

PMID- 12472806
TI  - Immunosuppression for diabetic glomerular disease?

PMID- 12472807
TI  - Fibrinogen in hemodialysis: the worst of both worlds?

PMID- 12472808
TI  - Tumor-suppressive effect of connexin 32 in renal cell carcinoma from maintenance
      hemodialysis patients.

PMID- 12472809
TI  - Calcium on trial: beyond a reasonable doubt?

PMID- 12472810
TI  - Calcium on trial: beyond a reasonable doubt?

PMID- 12472811
TI  - Calcium on trial: beyond a reasonable doubt?

PMID- 12472812
TI  - Calcium on trial: beyond a reasonable doubt?

PMID- 12472815
TI  - Mental breakdown and recovery in the UK.

PMID- 12472814
TI  - Light at the end of the TUNEL: HIV-associated thrombotic microangiopathy.

PMID- 12472816
TI  - Patients' experience of involuntary psychiatric care: good opportunities and
      great losses.
AB  - Patients who are involuntary admitted to psychiatric care are extremely
      vulnerable as a consequence of the control from others, and of the personal
      limitations due to a psychiatric disease that can influence their own control of
      their lives. This group of patients are seldom asked about their experiences of
      being cared for. In this study five involuntary hospitalized psychiatric patients
      narrated their experience of being subjected to involuntary psychiatric care. The
      aim of the study was to obtain a deeper understanding of this experience. The
      interview text was analysed by means of a phenomenological hermeneutic method.
      The result of the analysis gave a complex picture of both support and violation.
      On the one hand experiences of not being seen or heard, of loss of liberty and of
      violation of integrity were found. On the other hand, there were experiences of
      respect and caring and opportunities to take responsibility for oneself were
      offered. Being treated involuntarily in psychiatric care was interpreted as a
      balancing act between good opportunities and great losses.

PMID- 12472817
TI  - Violence risk assessment: combining actuarial and clinical information to
      structure clinical judgements for the formulation and management of risk.
AB  - Throughout history most societies have assumed a link between mental disorder and
      violence to others. In recent times there has been increasing concern in the
      United Kingdom over law and order, specifically the risk of violence, and these
      issues are now high on the political and mental health agenda. Nurses and staff
      working in National Health Service Mental Health Service Trusts are the groups
      most at risk of violence. Many clinical decisions are based on risk. Mental
      health nurses play a pivotal role in the assessment and management of risk and it
      is argued that they need to adopt a clear structured approach to violence risk
      assessment and management, which is evidence-based. The advantages of clinical
      and actuarial approaches to risk assessment are briefly reviewed and a structured
      clinical judgement approach is proposed that combines these approaches. A method
      of linking the assessment process with the management plan via a risk formulation
      is discussed.

PMID- 12472818
TI  - Mental health nursing and the promotion of physical activity.
AB  - Evidence and recent policy initiatives support the promotion of physical activity
      and exercise within acute inpatient settings. Mental health nurses may perform an
      important role in encouraging physical activity and legitimizing its
      incorporation within care planning. This exploratory study aimed to investigate
      perceptions of the role of exercise and physical activity as a therapeutic
      strategy within inpatient settings. Given the exploratory nature of the study, a
      qualitative design using semistructured interviews was considered most
      appropriate. As part of a larger study regarding the promotion of physical
      activity within one United Kingdom (UK) Mental Health Trust, 12 mental health
      nurses were interviewed. All participants identified a need for increasing
      opportunities for physical activity on inpatient wards. Three interrelated themes
      emerged that related to how physical activity and exercise was conceptualized by
      the participants. First, exercise and physical activity was seen as a potentially
      beneficial distracting strategy rather than an adjunctive strategy in its own
      right. Secondly, exercise was considered as a lifestyle choice and an individual
      responsibility. Thirdly, a difficulty in articulating a possible relationship
      between the 'physical' and the 'mental' was predominant. The implications of
      these perceptions are discussed in relation to developing a greater profile for
      physical activity and exercise on acute wards.

PMID- 12472819
TI  - Suspicion, resistance, tokenism and mutiny: problematic dynamics relevant to the
      implementation of clinical supervision in nursing.
AB  - In this paper I will discuss some of the more common pitfalls inherent in
      attempts to introduce clinical supervision to hospital wards or community teams.
      I will consider pre-existing relationships and how these may, if unexamined and
      unaccounted for, result in clinical supervision becoming less than optimally
      effective. Drawing upon the theory of Transactional Analysis, in particular the
      concept of 'psychological distance', I consider four possible interpersonal
      dynamics and examine how these may impact upon the implementation of clinical
      supervision. These problematic dynamics can result in undue resistance,
      suspicion, tokenism or interpersonal difficulties. Finally, I will consider ways
      in which the aforementioned problems may be addressed and their effects minimized
      through the use of co-operative contracting.

PMID- 12472820
TI  - The work and values of mental health nurses observed.
AB  - While there is agreement among stakeholders that change is required in mental
      healthcare, yet the precise nature of this change and how it should be brought
      about are relatively under-explored. Research has looked at developments taking
      place in primary mental health services, but relatively little has examined the
      work of community mental health nurses (CMHNs), especially those working at the
      interface between primary and secondary care. This study used a 39-item
      questionnaire to explore how CMHNs perceive their role and the degree to which
      they are able to carry it out. The findings suggests that while CMHNs are
      enthusiastic about their work and are keen to see mental health services develop
      in primary care, many are concerned about how they are perceived by other health
      personnel, deficiencies in their therapeutic skills and the level of support they
      currently receive. The study concludes by suggesting areas that managers,
      commissioners and educators should target to enable CMHNs to continue to play
      their part in a service that relies heavily upon them.

PMID- 12472821
TI  - Tolerance for depression: are there cultural and gender differences?
AB  - This study examined tolerance for depression among Jewish and Protestant men and
      women in the United Kingdom. A measure of tolerance for depression was developed,
      which examined willingness to admit to and seek help for depression. More
      specifically, the items in the measure (developed from extended interviews)
      covered empathy towards sufferers, potential virtues of the illness, hopes for
      treatment, seeing the illness as 'normal', and telling other people about it.
      Existing evidence suggested that tolerance for depression might be greater
      amongst Jews compared with Protestants, and women compared with men. Also, Jewish
      men were expected to be more tolerant than Protestant men, whereas Protestant and
      Jewish women were not expected to differ from each other. It was found that
      tolerance for depression was greater amongst Jews than Protestants, and this is
      consistent with the elevated levels of depression amongst Jewish men as compared
      with Protestant men. However, findings relating to gender were mixed and were not
      always consistent with our expectations. The findings suggest that there may be
      some cultural variations in willingness to admit to and seek help for depression,
      and this may be worth examining in other cultural-religious groups. Individual
      variations in tolerance for depression may be clinically significant.

PMID- 12472822
TI  - Philosophy, care and treatment on the psychiatric intensive care unit: themes,
      trends and future practice.
AB  - Psychiatric intensive care units (PICUs) were first developed in the UK in the
      early 1970s and have become an integral part of inpatient services. This paper
      reviews all aspects of PICU provision from its origins to the most recent studies
      of intensive care treatment and philosophy. A search of CINAHL, MEDLINE and
      British Nursing Index databases revealed ample research and discussion papers
      from the past 30 years to permit a thorough review of the available literature.
      This divides roughly into discussion and descriptive research on topics related
      to: (a) the infrastructure of PICUs, including bed numbers, staffing levels,
      admission criteria and aspects of the physical environment; and (b) the treatment
      provided to patients on the PICU, both pharmacological and psychosocial, plus a
      limited amount of evaluative research on the efficacy of PICU care. This paper
      provides a summary and overview of these issues based upon currently available
      literature. It concludes that there is strong evidence for wide variation in the
      provision and nature of PICU care, reflecting idiosyncratic and localized
      development of services. Moreover, there is an almost complete lack of evidence
      on the efficacy of PICU care for particular types of patients and problems,
      leaving a paucity of research upon which PICU infrastructure, policy and
      therapeutic approach can be based.

PMID- 12472823
TI  - Voting as a means of social inclusion for people with a mental illness.
AB  - People suffering from mental illness are often disenfranchized from many
      functions of society. Voting is one such area where disenfranchizement and
      exclusion are unnecessarily experienced. The emphasis on service provision as a
      means of achieving social inclusion for those with mental illness may relegate it
      to a principle of treatment compliance. Should measures of social function remain
      the main indicators of successful community care or should measures of social
      integration be identified, assessed and maintained? Mental health professionals
      should actively pursue users' voting rights in light of the changing legal
      climate and the introduction of human rights legislation into United Kingdom law.
      With the potentially huge political capital in this area the author believes that
      the current debate regarding social inclusion cannot be adequately addressed
      unless this fundamental and democratic principle is included more extensively.

PMID- 12472824
TI  - Women's experiences of hospital admission.
AB  - The primary aim of this study was to examine women's experiences of inpatient
      psychiatric services. A secondary aim was to use the emerging themes in service
      planning and to develop an evaluation tool. Focus groups and individual
      interviews with women in receipt of psychiatric services in Croydon were used.
      The findings suggest continuity with both negative and positive aspects of
      institutional care described before the policy of community care was introduced.
      The attempts to 'normalize' institutional care by desegregating wards appear
      rather to have compounded problems faced by women. Women were clear about what
      they felt they wanted and needed. Women are dissatisfied about many aspects of
      care aside from the problems associated specifically with mixed sex wards. This
      suggests that sexual segregation of wards alone is a necessary but an
      insufficient measure to improve inpatient care. The findings can inform
      development of a women-only service in Croydon and of a tool to evaluate it.

PMID- 12472825
TI  - The use of discharge risk assessment tools in general psychiatric services in the
      UK.
AB  - Closure of asylums dismantled a system of risk control based on containment,
      resulting in a rise in homicides and suicides by discharged patients. Remedial
      action centred on a structured approach to managing multidisciplinary care (the
      Care Programme Approach) and a system of independent inquiries into homicides. A
      need for better discharge risk assessment was identified by government and health
      professions. The literature points to inherent limitations in the predictive
      power of actuarially based tools, restricting them to augmenting clinical
      judgement. This paper addresses the development and effective use of tools to
      predict risk to patients and public following discharge into the community.
      Methods used were: (i) a questionnaire to NHS Trusts in the UK; (ii) an analysis
      of documentation on tools in use; and (iii) interviews of hospital and community
      mental health teams at eight NHS Trusts. Findings point to: (i) a sporadic
      development of risk assessment tools at Trust level; (ii) that this has been
      stimulated by clinical governance but is unguided by any coherent national
      strategy; and (iii) that information technology for risk data collection is not
      well used in the UK, where there is reliance on use of paper records and informal
      communication. The implications for management and health professions are
      discussed.

PMID- 12472826
TI  - A literature review of dementia care mapping: methodological considerations and
      efficacy.
AB  - Dementia care mapping (DCM) is a popular method for evaluating the quality of
      care and well-being of people with dementia in formal care settings. Keywords and
      thesaurus searches were conducted between 1992 and June 2001 using a range of
      bibliographic databases. Studies that had specifically examined the efficacy of
      DCM or, had used DCM as the main outcome measure, were included in the review.
      Nine studies met the inclusion criteria and were evaluated in this review. The
      review highlights some methodological limitations in the DCM studies to date,
      including sampling bias, inadequate sample size, short evaluation periods and a
      lack of consideration of the confounding variables commonly associated with
      dementia. The evidence presented for DCM suggests that it has good face validity
      and reliability. However, other aspects of validity remain less convincing and it
      can only be regarded as a moderately valid instrument. Whilst its theoretical
      background makes DCM particularly appealing to nurses wishing to improve the
      quality of their care, it is a very time-consuming method and requires
      considerable investment in terms of nursing resources. Consequently, it is
      essential that more scientifically based studies are conducted to enable other
      aspects of validity to be developed, thus enhancing the value of DCM as an
      outcome measure of nursing care.

PMID- 12472827
TI  - The construction and implementation of a psychosocial interventions care pathway
      within a low secure environment: a pilot study.
AB  - This paper builds on previous articles that explore the use of psychosocial
      interventions within inpatient settings. There are obvious difficulties in the
      implementation of psychosocial interventions in practice. The authors suggest
      that one method of developing psychosocial interventions within services is to
      provide organizational support to clinicians. This paper explores the development
      and initial implementation of a psychosocial care pathway within an inpatient
      setting to provide such support. It concludes with a summary of the immediate
      effect of the pathway on care.

PMID- 12472828
TI  - Judgement impossible.

PMID- 12472833
TI  - Expression of receptor activator of NF-kappa B ligand and osteoprotegerin in
      culture of human periodontal ligament cells.
AB  - The receptor activator of NF-kappa B ligand (RANKL) and its decoy receptor,
      osteoprotegerin (OPG), are the important proteins implicated in
      osteoclastogenesis. In this study, we investigated the expressions of RANKL and
      OPG in cultured human periodontal ligament (PDL) cells and their roles in
      osteoclastogenesis. Northern blotting revealed that the OPG mRNA was down
      regulated remarkably by application of 10-8 m one-alpha, 25-dihydroxyvitamin
      D3[1,25-(OH)2D3] and 10-7 m dexamethasone (Dex). In contrast, RANKL mRNA was up
      regulated by the same treatment. Western blotting demonstrated decrease of OPG by
      the application of 1,25-(OH)2D3 and Dex. Tartrate-resistant acid phosphatase
      positive multinuclear cells were markedly induced when the PDL cells were
      cocultured with mouse bone marrow cells in the presence of an anti-OPG antibody
      together with 1,25-(OH)2D3 and Dex. These results indicate that PDL cells
      synthesize both RANKL and OPG and that inactivation of OPG may play a key role in
      the differentiation of osteoclasts.

PMID- 12472834
TI  - Oral mucosa alterations induced by cyclosporin in mice: morphological features.
AB  - BACKGROUND AND OBJECTIVE: The mechanisms involved in the pathogenesis of
      cyclosporin A-induced gingival hyperplasia are not well understood. The present
      work aimed at developing a mouse model with the characteristics of the human
      process, i.e. time of appearance, dose dependency and the capacity of developing
      in a variety of genetic backgrounds. This model would present the advantages of
      using a very well known animal species, small and easy to handle, with a number
      of experimental reagents (antibodies, etc.) already available against its
      products. METHODS: Three different strains of mice were used: CBA, F1(C57Bl x
      DBA), Balb/c. Groups of mice received different concentrations of cyclosporin A
      (CSA) (10 mg/kg, 25 mg/kg and 40 mg/kg body weight) intraperitoneally five times
      a week. Anatomical and histological alterations were recorded at various time
      intervals. RESULTS: All strains of mice presented gingival hyperplasia after 8
      weeks of CSA treatment. A dose-dependency was observed with regard to the time of
      first appearance of alterations. Increased redness was seen in all animals at the
      sixth week, independent of the dosage used. Histologic examination exhibited
      increased vascularization, epithelial and connective tissue thickening, edema and
      a mononuclear infiltrate. CONCLUSIONS: It was possible to develop CSA-induced
      gingival hyperplasia in mice with the characteristics described in humans and
      other species. The use of this animal model may help in the elucidation of the
      process involved in CSA-induced gingival overgrowth.

PMID- 12472835
TI  - Interaction of human salivary mucin MG2, its recombinant N-terminal region and a
      synthetic peptide with Actinobacillus actinomycetemcomitans.
AB  - The antimicrobial properties of human salivary mucin MG2 against the periodontal
      pathogen, Actinobacillus actinomycetemcomitans (A. actinomycetemcomitans), were
      investigated using purified MG2, rNMUC7 (a recombinant polypeptide containing
      residue 1-144 of MG2) and synthetic peptides PEP1 (residue 1-17) and PEP2
      (residue 47-63). MG2 and rNMUC7 bound to A. actinomycetemcomitans strains SUNY75,
      SUNY465, SUNY523, 652 and JP2 in a liquid phase binding assay. The bactericidal
      activities of rNMUC7, PEP1 and PEP2 against A. actinomycetemcomitans SUNY523 were
      examined in a colony forming unit killing assay. The LD50 for rNMUC7 was 9
      microM, for PEP2 was 20 microM and PEP1 did not exhibit bactericidal activity.
      The primary structure of these polypeptides was analyzed and a direct
      relationship between net positive charge and bactericidal activity was found.
      Screening of saliva samples from 60 individuals on Western blots probed with an
      anti-MG2 antibody against PEP2 revealed that a 20 kDa MG2 fragment was present in
      66% of subjects and that this fragment was not present in glandular secretions.
      Matrix-assisted laser desorption ionization time-of-flight mass spectrometry of
      tryptic peptides derived from the 20 kDa fragment confirmed that this fragment
      contained a portion of the amino terminal region of MG2. The present study showed
      that the N-terminal region of MG2 and a subdomain within this region are
      microbicidal against A. actinomycetemcomitans and that a 20 kDa fragment of MG2
      occurs in whole saliva. This suggests that cleavage of MG2 in vivo may produce
      fragments with microbicidal properties and that this may represent a novel
      mechanism of host defense.

PMID- 12472836
TI  - Identification of a new variant of fimA gene of Porphyromonas gingivalis and its
      distribution in adults and disabled populations with periodontitis.
AB  - Porphyromonas gingivalis fimbriae are critical for the promotion of bacterial
      infection. The fimA gene encoding fimbrillin, a subunit of fimbriae, has been
      classified into five genotypes (types I to V) based on their nucleotide
      sequences. Using a fimA type-specific PCR assay, our previous study demonstrated
      a close relationship between P. gingivalis possessing type II and type IV fimA
      genes and adult periodontitis. In that study, some clinical specimens were found
      to be positive for both types I- and II- fimA specific primers, likely due to the
      coexistence of two clonal types or a single clone of an unknown genotype in the
      samples. In the present study, we cloned a new variant of the fimA gene,
      designated as type Ib fimA, from P. gingivalis HG1691. The nucleotide sequence of
      the cloned fimA gene showed a 97.1% homology with that of type I fimA, indicating
      it as a clonal variant of type I fimA. Organisms with type Ib fimA were detected
      in 13.5% of periodontitis patients and in 2.9% of periodontal healthy adults.
      Statistical analysis revealed a strong relationship between periodontitis and
      specific fimA types such as type Ib [odds ratio (OR) 6.51], type II (OR 77.8),
      and type IV (OR 7.54). Moreover, type Ib fimA-organisms were also found to be
      related to periodontitis in Down's syndrome (OR 1.91) and mentally disabled
      populations (OR 4.00). These findings suggest that P. gingivalis with type Ib
      fimA is closely associated with the progression of periodontitis, similar to
      organisms with type II and IV fimA.

PMID- 12472837
TI  - Improvement of periodontal status by green tea catechin using a local delivery
      system: a clinical pilot study.
AB  - The purpose of this study was to determine the usefulness of green tea catechin
      for the improvement of periodontal disease. The minimum inhibitory concentration
      (MIC) and bactericidal activity of green tea catechin against black-pigmented,
      Gram-negative anaerobic rods (BPR) were measured. Hydroxypropylcellulose strips
      containing green tea catechin as a slow release local delivery system were
      applied in pockets in patients once a week for 8 weeks. The clinical, enzymatic
      and microbiological effects of the catechin were determined. Green tea catechin
      showed a bactericidal effect against Porphyromonas gingivalis and Prevotella spp.
      in vitro with an MIC of 1.0 mg/ml. In the in vivo experiment, the pocket depth
      (PD) and the proportion of BPR were markedly decreased in the catechin group with
      mechanical treatment at week 8 compared with the baseline with significant
      difference. In contrast, PD and BPR were similar to the baseline and the value at
      the end of the experimental period in the placebo sites of scaled groups. The
      peptidase activities in the gingival fluid were maintained at lower levels during
      the experimental period in the test sites, while it reached 70% of that at
      baseline in the placebo sites. No morbidity was observed in the placebo and
      catechin groups without mechanical treatment. Green tea catechin showed a
      bactericidal effect against BPR and the combined use of mechanical treatment and
      the application of green tea catechin using a slow release local delivery system
      was effective in improving periodontal status.

PMID- 12472838
TI  - Epidemiology of necrotizing ulcerative gingival lesions in adolescents.
AB  - OBJECTIVE AND BACKGROUND: Relatively little is known about the epidemiology of
      necrotizing ulcerative gingival lesions (NUG) in adolescent populations. Most
      studies have comprised special target groups, such as military recruits, HIV
      patients, or severely malnourished subjects. METHODS: A multistage random cluster
      sampling scheme was used to obtain a sample of 9203 students aged 12-21 years
      from 98 of a total of 618 high schools in Santiago, Chile. Students were given a
      clinical oral examination and questionnaire information was obtained on smoking
      and oral hygiene habits, dental attendance patterns, and diabetic status. The
      diagnostic criteria for NUG were the presence of necrosis and ulceration of at
      least one interproximal papillae. RESULTS: The estimated prevalence of NUG was
      6.7% (95% CI = [6.2; 7.3]). A multivariable logistic regression analysis showed
      that last seeing a dentist more than 1 year ago (OR = 1.60), or never (OR =
      1.93), and reporting diabetes (OR = 2.12) showed a significant positive
      association with the presence of NUG; whereas neither gender nor smoking were
      important predictors. Students aged 18-21 years were more, albeit statistically
      insignificantly, likely to have NUG than were younger students (OR = 1.40).
      CONCLUSIONS: Our observation that reporting to be diabetic was positively
      associated with the presence of NUG is interesting, as diabetes has never been
      addressed as a possible risk factor. As the association between diabetes and
      periodontitis in adults is thought to relate to impaired function of neutrophils,
      microangiopathy, and impaired wound healing this finding suggests a significant
      role of the host response also for the occurrence of NUG.

PMID- 12472839
TI  - Treponema denticola may stimulate both epithelial proliferation and apoptosis
      through MAP kinase signal pathways.
AB  - Mitogen-activated protein kinases (MAP kinases) play a key role in the regulation
      of cell survival and death. Effects of Treponema denticola ATCC 35405 on ERK, p38
      and JNK MAP kinases, and cell behavior was studied using non-keratinizing
      periodontal ligament epithelial cells (PLE) in vitro. Compared to Chinese hamster
      ovary cells, human cervix adenocarcinoma cells, human osteosacroma cells and
      human gingival fibroblasts, PLE cells were much more resistant to T. denticola
      induced reduction in cell viability, assayed by tetrazolium and crystal violet
      assays. A low dose of 5 x 10(7) T. denticola cells/ml increased DNA synthesis
      ([3H]thymidine uptake) in PLE cells but at higher concentrations DNA synthesis
      was decreased. TUNEL staining analysis showed that about 50% of epithelial cells
      in onolayers died through apoptosis when exposed to a high dose of 10(11) T.
      denticola/ml for 24 h. Morphological light and electron microscopic analysis
      supported the idea that both apoptotic and necrotic cell death took place.
      Rounding, membrane damage, fragmentation and detachment were observed in
      selective cells of both mono- and multilayered PLE cultures challenged with T.
      denticola. Western blot analysis using MAP kinase phosphospecific antibodies
      showed that T. denticola strongly but transiently activated ERK1 and ERK2,
      signals mediating cell proliferation, and JNK and p38, kinases mediating
      apoptosis. While a specific inhibitor of the ERK MAP kinase pathway prevented the
      T. denticola stimulation of cell proliferation, inhibitor of p38 increased the
      cell numbers in T. denticola-treated cultures. The results suggest that T.
      denticola activates epithelial cell MAP kinase signal pathways controlling cell
      proliferation and cell survival. In addition, T. denticola exerts cytotoxic
      effects that appear to predominate at higher bacterial concentrations.

PMID- 12472840
TI  - Merkel-like cells in Malassez epithelium in the periodontal ligament of cats: an
      immunohistochemical, confocal-laser scanning and immuno electron-microscopic
      investigation.
AB  - The cellular heterogeneity of Malassez epithelium (ME) residing in the
      periodontal ligament has recently been reported, and the presence and coexistence
      of the neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP) and
      vasoactive intestinal peptide (VIP) in single cells in ME has been shown (1).
      However, the identity of these neuroendocrine cells has so far not been verified.
      This study was undertaken in order to elucidate the identity of the
      neuroendocrine cells in ME by means of transmission electron microscopy, confocal
      scanning microscopy and immunohistochemistry using antibodies to protein gene
      product (PGP) 9.5 and cytokeratin 20 (CK). Gingival tissue was included in the
      study as a positive control for identification of Merkel-like cells in oral
      epithelium. CK 20 immunopositive cells were present in both Malassez epithelium
      and in basal cell layers of gingival epithelium showing a distribution consistent
      with PGP 9.5 labelled cells in both epithelia. The results from PGP 9.5 immuno
      electron microscopy clearly evidenced the presence of single, intensely labelled
      cells and some nerve fibres invested between the Malassez epithelial cells. The
      conformity of the immunopositive cells in Malassez and gingival epithelium
      verified by double immunolabelling with PGP 9.5 and CK 20, indicates that the
      labelled neuroendocrine cells are identical in ME and in gingival epithelium.
      This demonstrates that Malassez epithelium not only exhibits neuroendocrine
      cells, but additionally that the neuroendocrine cells represent Merkel-like
      cells.

PMID- 12472841
TI  - Gingipains in the culture supernatant of Porphyromonas gingivalis cleave CD4 and
      CD8 on human T cells.
AB  - Porphyromonas gingivalis has been shown to attack host defense systems through
      proteolytic cleavage of a wide variety of members of the systems. In this study,
      we examined the ability of P. gingivalis culture supernatant to alter the
      expression of human T cell surface proteins. As judged by flow cytometric
      analysis, detection of CD4 expression was completely eliminated by the
      supernatant, but CD8 was less sensitive. When the culture supernatant was added
      with reducing agents, proteolytic activity was enhanced, resulting in the
      cleavage of CD8. Mitogenic response of T cells to phytohemagglutinin or
      concanavalin A was decreased by the treatment of the cells with the culture
      supernatant of P. gingivalis. The three forms of gingipains (high molecular mass
      arginine-specific gingipain, arginine-specific gingipain 2 and lysine-specific
      gingipain) purified from the culture supernatant of P. gingivalis actively
      cleaved CD4 and CD8 on human T cells, indicating that proteolytic activity of the
      culture supernatant was due to gingipains. These results suggest that cysteine
      proteinases like gingipains released from P. gingivalis cleave T cell surface
      proteins and impede T cell function.

PMID- 12472843
TI  - Practical assay and molecular mechanism of aggregation inhibitors of beta
      amyloid.
AB  - Beta-Amyloid peptide (Abeta) is the main protein component of neuritic plaques in
      the brain of patients of Alzheimer's disease (AD), and its neurotoxicity would be
      exposed by the formation of aggregates. The aggregation inhibitors composed of an
      Abeta recognition element (KLVFF) and a hydrophilic moiety are evaluated by a
      novel fluorescence assay. These compounds inhibit growth of the model aggregates
      on the KLVFF immobilized surface. In addition, some compounds also possess
      disrupting activities of preformed aggregates. These compounds could be a key
      candidate for therapeutic drugs for AD by their novel molecular mechanisms.

PMID- 12472844
TI  - Purification of two depressant insect neurotoxins and their gene cloning from the
      scorpion Buthus martensi Karsch.
AB  - Insect-specific neurotoxins are important components of scorpion venoms. In this
      study, two toxins from the scorpion Buthus martensi Karsch (BmK) were purified.
      They shared high sequence homology with other depressant insect toxins and were
      designated BmK ITa and BmK ITb, respectively. They were able to suppress the
      action potential of cockroach isolated axon, which is due to a decrease in the
      peak sodium current. Furthermore, the effect of BmK ITb was lower than that of
      BmK ITa, and some of the electrophysiological characteristics of BmK ITb even
      resemble that of excitatory insect toxins. Their primary structures were
      determined by N-terminal partial sequence determination and cDNA cloning. The
      differences in their structures, especially the 31st residues, may result in the
      unique activity of BmK ITb.

PMID- 12472845
TI  - Synthesis and immunogenic properties of phosphopeptides related to the human
      insulin receptor.
AB  - Two phosphoserine tetradecapeptides corresponding to sequences 987-1000 (peptide
      pSer994) and 1017-1030 (peptide pSer1023/1025) from the human insulin receptor
      involved in the regulation of its activity were successfully synthesized using
      Fmoc-based chemistry. Phosphorylation was performed by post-assembly
      phosphitylation followed by oxidation. The selective phosphorylation of Ser
      residues was achieved incorporating into the peptide chain the Ser (Trt)
      derivative and t-Bu blocking groups at sites other than those intended to be
      phosphorylated. The Trt group was selectively removed with dichloroacetic acid
      while under this condition t-Bu protecting groups remained unaltered. Following
      conjugation to keyhole limpet hemocyanin phosphopeptides were used as immunogens
      to generate sequence-specific phosphoserine antibodies. Peptide pSer994 induced
      antibodies in New Zealand white rabbits which discriminated between the
      phosphorylated and nonphosphorylated forms of the peptide, thus representing
      promising candidates to recognize signaling pathways associated to the regulation
      of the human insulin receptor.

PMID- 12472846
TI  - Conformational studies of antimetastatic laminin-1 derived peptides in different
      solvent systems, using solution NMR spectroscopy.
AB  - Due to its critical role in cancer progression, interactions between laminin-1
      and the 67 kDa Laminin-Binding Protein (the 67 kDa LBP) have been the focus of a
      number of structural and biological studies. As laminin-1 is such a large and
      complex molecule, research interests have turned to the investigation of
      bioactive peptides derived from binding domains of laminin-1. Two peptides of
      interest, CDPGYIGSR (peptide 11) and YIGSR, both derived from the beta1 chain of
      laminin-1, have been shown to block invasion of basement membranes by tumor
      cells. Substituting the C-terminal arginine to lysine, a conservative
      substitution, results in a loss of peptide antimetastatic activity. This
      difference in bioactivity has been attributed, based on numerous modeling studies
      of free peptide conformations, to structural differences between YIGSR and YIGSK.
      Yet the nature of the 'active' free peptide backbone conformation has been a
      matter of debate and controversy. In order to test the validity of the structural
      modeling claims, we have undertaken detailed conformational studies of the two
      laminin-1 derived peptides YIGSR and CDPGYIGSR along with the biologically
      inactive YIGSK analog by two-dimensional solution 1H NMR spectroscopy in three
      different solvent systems. Herein we report that although both the active (YIGSR,
      CDPGYIGSR) and the inactive (YIGSK) peptides can adopt several closely related
      conformations in solution, the two peptides share similar conformational
      preferences, and there are no significant structural differences between the
      active and inactive peptides, contrary to previously reported modeling data. We
      conclude that the basis of the peptide biological activity, in contrast to
      published models, cannot be attributed to well-defined structural preferences of
      the free peptides. We infer that the difference in bioactivity observed between
      YIGSR and YIGSK originates primarily from the chemical nature of the arginine
      versus lysine sidechain substitution, rather than being due to a structural
      change in the free peptide conformations.

PMID- 12472848
TI  - Secondary caries susceptibility of teeth with long-term performing composite
      restorations.
AB  - The aim of this study was to assess retrospectively the caries susceptibility of
      posterior teeth with composite restorations after 18 and 20 years. The sample was
      selected out of the recall of a dental office. Sixteen restorations were
      reassessed after 18 and 20 years. All findings have been rated according to the C
      criteria of the CPM index. For the micromorphological evaluation with SEM,
      replicas were made using a two-step impression technique. All restorations
      demonstrated marginal imperfections and a predominant rough surface. At the 18
      year-evaluation two restorations exhibited secondary caries. Despite of extended
      marginal gap formations none of the 12 restorations reexamined at 20 years showed
      secondary caries. Direct composite restorations can serve over a long period of
      time despite of poor qualitative parameters. Micromorphological marginal
      deterioration and clinical gap formation do not necessarily result in a higher
      risk for secondary caries.

PMID- 12472847
TI  - Dermorphin-based potential affinity labels for mu-opioid receptors.
AB  - Dermorphin and [Lys7]dermorphin, selective micro -opioid receptor ligands
      originating from amphibian skin, have been modified with various electrophiles in
      either the 'message' or 'address' sequences as potential peptide-based affinity
      labels for micro -receptors. Introduction of the electrophilic isothiocyanate and
      bromoacetamide groups on the para position of Phe3 and Phe5 was accomplished by
      incorporating Fmoc-Phe(p-NHAlloc) into the peptide followed by selective
      deprotection and modification. The corresponding amine-containing peptides were
      also prepared. The pure peptides were evaluated in radioligand binding
      experiments using Chinese hamster ovary (CHO) cells expressing micro - and delta
      opioid receptors. In dermorphin, introduction of the electrophilic groups in the
      'message' domain lowered the binding affinity by > 1000-fold; only [Phe(p
      NH2)3]dermorphin retained nanomolar affinity for micro -receptors. Modifications
      in the 'address' region of both dermorphin and [Lys7]dermorphin were relatively
      well tolerated. In particular, [Phe(p-NH2)5,Lys7]dermorphin showed similar
      affinity to dermorphin, with almost 2-fold higher selectivity for micro 
      receptors. [Phe(p-NHCOCH2Br)5]- and [Phe(p-NHCOCH2Br)5,Lys7]dermorphin exhibited
      relatively high affinity (IC50 = 27.7 and 15.1 nm, respectively) for micro 
      receptors. However, neither of these peptides inhibited [3H]DAMGO binding in a
      wash-resistant manner.

PMID- 12472849
TI  - Validation of the clinical diagnostic criteria for temporomandibular disorders
      for the diagnostic subgroup - disc derangement with reduction.
AB  - Research is needed to assess the validity of the clinical diagnostic criteria for
      temporomandibular disorders (CDC/TMD). The purpose of this study was to test the
      reliability of the clinical diagnosis of temporomandibular joint (TMJ) internal
      derangement type (ID)-I as compared with the magnetic resonance imaging (MRI)
      'gold standard'. The study comprised 168 TMJs in 84 patients, who were assigned a
      clinical TMJ-related diagnosis of ID-I (disc displacement with reduction) in at
      least one TMJ. Bilateral sagittal and coronal MR images were obtained
      subsequently to establish the corresponding diagnosis of the disc-condyle
      relationship. For the CDC/TMD interpretations, the positive predictive value
      (PPV) of ID-I for disc displacement with reduction (DDR) was 44%, and for the
      presence of an ID 69%. The overall diagnostic agreement for ID-I was 47.6% with a
      corresponding K-value of 0.05. Most of the disagreement was the result of the
      false-positive interpretations of ID-I, and false-negative interpretations of an
      'absence of ID'. The results suggest CDC/TMD for ID-I to be insufficient reliable
      for determination of ID and/or DDR. Patients assigned a clinical TMJ-related
      diagnosis of ID-I may need to be supplemented by evidence from MRI to determine
      the functional 'disc-condyle relationship'.

PMID- 12472850
TI  - The expression of cyclooxygenase-2 in human temporomandibular joint samples: an
      immunohistochemical study.
AB  - The aim of this investigation was to evaluate the immunohistochemical expression
      of cyclooxygenase-2 (COX-2) in the temporomandibular joint (TMJ) and to compare
      it with that control specimens. Expression of COX-2 in the TMJ disc and the
      synovial membrane in 26 human TMJ samples (internal derangement of TMJ; n=16, and
      control; n=10) was measured by an immunohistological technique using paraffin
      embedded tissue and specific antihuman COX-2 polyclonal antibody. There were
      obvious distinction of COX-2 immunoreactivity between the control specimens and
      internal derangement cases, in the region of posterior and/or anterior loose
      connective tissues. In particular, intensive COX-2 expression was detected in the
      synovial membrane of internal derangement cases. The findings of the present
      study suggest that COX-2 might be an important mechanism regulating inflammation
      in the synovial membrane with internal derangement of TMJ.

PMID- 12472851
TI  - Microfracture behaviour of composite resins containing irregular-shaped fillers.
AB  - Microfracture behaviour of composite resins containing irregular-shaped fillers
      was understood by filler morphology observation, fracture toughness test and
      acoustic emission (AE) detecting method. The fracture toughness (KIC) was
      obtained by using single edge notched specimens. AE, the elastic wave due to the
      debonding of filler from the resin matrix or the fracture of filler itself, was
      detected during fracture toughness test. The reasons for the different fracture
      toughness values of composite resin, in spite of having almost the same
      morphology and filler content, were understood by the results of fracture surface
      finding and AE releasing behaviour during fracture toughness test.

PMID- 12472852
TI  - Analysis of the area and length of masticatory cycles in male and female
      subjects.
AB  - It is difficult to determine the existence of a normal or physiological
      masticatory cycle, because there exists great individual diversity. This study
      presents some data about two parameters of masticatory cycles according to the
      frontal plane, i.e. the area and length of right-sided and left-sided cycles in a
      group of 30 young people, 18 women and 12 men. For our study the Myotronics K6-1
      kinesiograph was used. It registers the magnetic field and allows us to obtain
      graphic recordings of the jaw movement in the three space planes. Other authors
      have analysed these parameters, but none of those reviewed provides information
      about the distribution to each side or according to the gender of sampling
      subjects selected for the analysis. We have tried to describe the normal
      morphology of the masticatory cycles and, also, establish a reference so as to
      provide help in the diagnosis of the functional pathology of the masticatory
      system.

PMID- 12472853
TI  - Degree of polymerization of resin composites by different light sources.
AB  - The purpose of this study was to determine the effectiveness of polymerization in
      the newly introduced blue light emitting diode (LED) (Experimental, SNU, Korea),
      and plasma arc curing (PAC) (Apollo 95E, Elite, DMD, USA) compared with
      conventional halogen lamp (Spectrum 800, Dentsply, USA). Various irradiation time
      with fixed intensity of light-curing units (LCUs) were irradiated to produce the
      same total light energy. The degree of double bond conversion (DC) of three resin
      composite (shade A3) was measured with a Fourier-transform infrared (FT-IR)
      spectrophotometer at various depths from the surface. Immediately after exposure
      to light, 100 microm thickness of resin composite was sectioned at the 1, 2, 3
      and 4 mm from the top surface. The infrared spectrum of uncured resin and each
      wafer specimen were then obtained. The results were as follows: DC was
      significantly influenced by three variables of material, depth from the surface,
      and light source and energy level (P < 0.01). When the same light energy was
      irradiated, DC by plasma arc and LED was not significantly different from the
      halogen lamp (P > 0.05). When light energy was increased twice, no significant
      difference in DC was observed up to 2 mm from the surface (P > 0.05), but DC
      increased significantly from 3 mm (P < 0.05).

PMID- 12472854
TI  - Bite force determination in children with primary dentition.
AB  - The aim of this study was to determine the bite force with primary dentition in
      30 children with normal occlusion (group I), cross bite (group II) and open bite
      (group III). The magnitude of the bite force was determined through a pressurized
      transmitter tube (pressure sensor MPX 5700 Motorola), which was connected to a
      converse analog/digital electronic circuit. The children bit the tube with
      maximum force three times successively for 5 s, with a 10 s interval among each
      bite, and the sign was sent directly to the computer. The highest value of the
      three, for each patient, was considered. Analysis of variance evaluated
      difference among the three groups. The means of maximum bite force were 213 17,
      249 63 and 241 19 N for the groups, respectively, and there were no significant
      statistical differences among them (P > 0.05). The analysis of correlation showed
      that the weight, height and bite force presented weak positive correlation
      (r=0.24 and 0.23). It was concluded that in the studied groups the type of
      occlusion did not affect the maximum values of the bite force and body variables
      had a small influence in this magnitude.

PMID- 12472855
TI  - Effect of stabilization splint therapy on pain during chewing in patients
      suffering from myofascial pain.
AB  - Masticatory myofascial pain (MFP) condition is a musculoskeletal disorder that
      compromises the functional capacities of the masticatory system. As such, the
      incorporation of an intensive chewing test as a discriminatory exercise for the
      diagnosis of this condition and evaluation of treatment success has considerable
      potential. Various splint designs have been used successfully, which have posed a
      question of whether the therapeutic effect of the splint is a placebo or has some
      other curative properties. The purpose of this study was to evaluate the efficacy
      of the stabilization appliance to reduce signs and symptoms in MFP patients and
      to compare the pain experience during the chewing test between two groups of
      patients, with and without splints. Myofascial pain patients (n = 37) who
      reported exacerbation of pain in function participated in the study. Patients
      perfomed a 9-min chewing test, followed by 9-min rest and marked their pain
      intensity on a visual analogue scale every 3 min. Of the 37 patients, 21 received
      a stabilization flat occlusal splint for night use and 16 were equally monitored
      clinically without a splint. At the end of 8 weeks, a second clinical examination
      and chewing test were performed. Student's t-test was used to analyse differences
      between study groups. Analysis of variance and covariance (ancova) with repeated
      measures was applied to analyse the effect of treatment. Level of pain at
      baseline prior to the chewing test (P0) was introduced as a co-variant. At
      baseline both groups showed relatively high scores of pain intensity and did not
      show any significant differences among the collected variables. At the end of the
      experiment, the splint group had a statistically significant reduction in pain
      intensity, in mean muscle sensitivity to palpation and in the pain experience
      during the chewing test compared with no change in the controls. A stabilization
      splint has a therapeutic value beyond its placebo effects. Thus, it should be an
      integral part of the treatment modalities in MFP disorder patients. An intensive
      chewing test is an effective tool to evaluate the treatment modality efficacy in
      MFP patients.

PMID- 12472856
TI  - In situ microhardness evaluation of glass--ionomer/composite resin hybrid
      materials at different post-irradiation times.
AB  - The purpose of this paper was to evaluate in situ the microhardness of a
      composite resin, two resin-modified glass-ionomers and two polyacid-modified
      composite resins at different post-irradiation times. The materials analysed
      were: Z 100/3M (Z1); Fuji II LC/GC Corporation (Fu); Vitremer/3M (Vi);
      Freedom/SDI (Fr); and Dyract/Dentsply (Dy). Palatal intra-oral acrylic resin
      appliances were made for each of the 24 volunteers in the experiment. In each
      appliance, a specimen of each material was fixed. Microhardness tests were
      performed at 30 min, 1, 2, 4, 8, 24 and 48 h, 7, 10, 14, 17 and 21 days after
      initial light-curing. The analysis of variance followed by the Tukey test showed
      significant differences of microhardness among all materials (Fu < Vi < Fr < Dy <
      Z1) up to 48 h. From the seventh to the fourteenth day, statistical differences
      were not found between Freedom and Dyract (Fu < Vi < Fr=Dy < Z1). On the
      seventeenth and twenty-first days, Vitremer, Freedom and Dyract did not present
      statistical differences, but differed from Fuji II LC and Z 100 (Fu < Vi=Fr=Dy <
      Z1). The polynomial regression showed an increase of microhardness over time for
      the glass-ionomers/composite resin hybrid materials, although there were
      differences of microhardness among these materials. There was no significant
      changes in microhardness levels for the composite resin over time.

PMID- 12472857
TI  - The role of posterior guidances under the altered anterior guidance.
AB  - In five subjects, bilateral condylar movement was assessed during lateral
      excursions with different tooth guidance angles without changing the intercuspal
      position. Statistical analysis of anova (P < 0.01) revealed that when the incisal
      path angle became steeper than the natural tooth guidance, distances of the non
      working side condyle paths (centre of condyle) decreased significantly, while
      distances of the working side condyle paths (centre of condyle) remained
      unchanged. Directions of the working side condyle paths were random, while
      directions of the non-working side condyle paths remained stable. By analysing
      six points around the centre of the condyle, it was not possible to confirm any
      affect on the working side condyle movement by changing the tooth guidance angle.
      It was revealed that the non-working side condyle had an 'active' role during
      lateral excursions, and that the working side condyle moved as a result of
      mandibular movement that was changed because of a steepening of the incisal path
      angle during lateral excursions. This suggests the possibility that the working
      side condyle movements were affected 'passively' by altering the tooth guidance.

PMID- 12472858
TI  - Incidence of temporomandibular disorders (TMDs) in senior dental students in
      Taiwan.
AB  - Two-hundred and fifty-four (159 male, 95 female) senior dental students (mean
      age: 22.34 +/- 1.2 years) were asked to answer 14 questions. Scoring instructions
      accompanying this questionnaire indicated that the number of 'yes' responses was
      directly related to the probability of temporomandibular disorders (TMD). This
      survey of students was used to determine the prevalence of TMD. In addition, item
      analysis was performed to determine if there were any differences between male
      and female responses. The results of the study were as follows. The most
      prominent symptom suggesting TMD was the presence of clicking sound(s), both in
      females and males. The second most prominent symptom in female students was an
      awareness of stress, whereas teeth sensitivity was second in male students.
      Female students 18.95% and male students 29.56% did not answer 'yes' to these
      questions, and significantly (P < 0.05) higher in males than in females. The
      frequency of more than four 'yes' answers was 15.79% in the female group and
      5.66% in the male group, and significantly (P < 0.001) lower in males than in
      females. The type of symptoms and the frequency of TMDs were higher in female
      students than in male students and jaw click was the most common finding both in
      male and female dental students. The difference in reported problems between male
      and female students centred on a dentition factor in males and a psychological
      factor in female students.

PMID- 12472859
TI  - Comparison of microleakage properties of three different filling materials. An
      autoradiographic study.
AB  - The aim of this study was to compare the microleakage behaviour of three
      restorative materials using the autoradiographic method. The study was
      accomplished in vitro using freshly extracted human molars and a Ca45
      radioisotope and autoradiography. Twenty-seven molar teeth were divided into
      three experimental groups of seven specimens each. Class II cavities were
      prepared at the mesio-occlusal aspect and restored with amalgam and two different
      composite resins. The restorations were finished, thermocycled and tested for
      microleakage, using the Ca45 radioisotope. The results were analysed using the
      Kruskal-Wallis analysis test. Amalgam exhibited more leakage compared with
      composite resins. However the differences among the leakage behaviours of three
      filling materials were not statistically significant (P=0.064).

PMID- 12472861
TI  - New directions in nursing management.

PMID- 12472862
TI  - Talk to us, care agency boss tells NHS.

PMID- 12472863
TI  - Australian nurse supervisors' styles and their perceptions of ethical dilemmas
      within health care.
AB  - AIM: To examine clinical nurse supervisors' styles, in terms of models,
      organization, focus on supervision and theories used in supervision, as well as
      their perceptions of ethical dilemmas within health care. BACKGROUND: The
      importance of clinical supervision in clinical practice has been reported.
      However, literature dealing with its implementation is rare. METHODS: This study
      is a descriptive-correlational study. Data were collected by means of a
      questionnaire from two groups of nurse supervisors randomly selected from a
      university (n = 55) and a hospital (n = 31). Data were analysed using descriptive
      and inferential statistics. RESULTS: The models most frequently used were 'case
      oriented' and 'decision-making oriented'. The nurse supervision was reported as
      being organized on a one-to-one basis. The focus of supervision was on 'patient
      problems' and 'cooperation in team'. The theory most commonly used was the theory
      of reflection. The supervisors' perceptions of moral dilemmas were related to
      'decision making' and actions impacting on quality of care resulting from their
      supervisor styles. CONCLUSION: By correlating the supervisors' styles and their
      perceptions of ethical dilemmas, we conclude that it is important to contribute
      to further research on supervisors' styles in order to ensure successful
      supervision.

PMID- 12472864
TI  - From conflict to collaboration? Contrasts and convergence in the development of
      nursing and management theory (2).
AB  - AIM: This paper examines the development of theory in the occupation of
      management, in order to determine how this process is similar to that which has
      occurred in nursing. 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 was conducted in a previous paper and serves as a point of
      reference in identifying areas of contrast and convergence in the development of
      nursing and management ideologies. This paper focuses on the development of
      theory in the occupation of management. CONCLUSION: A consideration of the nature
      of nursing and management is beneficial because it provides insights which can
      help practitioners in their transition from nurse to manager. In the past the
      relationship between nursing and management has been presented somewhat
      simplistically and this paper demonstrates that the situation is much more
      complex. If this complexity is recognized it can be taken into account and serve
      as a basis for removing barriers between these two key groups of personnel.
      Ultimately, this may lead to the collaboration and co-operation necessary to
      deliver the responsive services identified as targets in recent policy
      pronouncements.

PMID- 12472865
TI  - Clinical supervision as a model for clinical leadership.
AB  - Clinical leadership and clinical supervision are topical areas of nursing
      development. A project was established to facilitate the growth of leadership
      ability with a group of ward sisters through individual clinical supervision. The
      work revealed that ward managers struggled to fulfil their leadership roles
      largely because of embodied ways of relating within a prevailing organizational
      culture that constrained them. The paper also reflects on the impact of
      supervision to develop leadership practice.

PMID- 12472866
TI  - The recruitment of newly qualified nurses to their local hospital: can
      improvements be made?
AB  - AIM: This project aimed to improve the recruitment of locally qualifying student
      nurses. BACKGROUND: Newly qualified nurses are an important resource, but the
      recruitment rate of locally qualifying nurses appeared to be low in one acute
      hospital NHS Trust. A collaborative working party was established, to address
      this situation. METHOD: A survey approach was used to collect data from one group
      of qualifying students prior to a new strategy for recruitment being implemented.
      Two subsequent groups of qualifying students were surveyed to evaluate the new
      strategy, and again 6 months post-employment. FINDINGS: After implementation of
      the new strategy, recruitment rose from 22% to 82%, with 41% of respondents
      stating that it had influenced their decision to stay in the Trust. Reasons given
      for recruitment to the Trust included convenience, familiarity, loyalty,
      enjoyment of clinical placements and perceived supportiveness of the Trust.
      CONCLUSIONS: Recruitment of qualifying students to their local Trust can be
      approached more effectively and good results obtained. The benefits of working
      collaboratively in relation to recruitment issues are also highlighted.

PMID- 12472867
TI  - Nurse Directors' jobs - a European perspective.
AB  - BACKGROUND OF STUDY: The European Nurse Directors Association (ENDA) was founded
      in 1996. Members agree on an annual action plan based on the three main aims of
      the Association to strengthen the nursing contribution to policy making within
      Europe, further nursing leadership and to establish a communication network of
      experts Nurse Directors across Europe. This study supports the above aims by
      examining issues relating to the job of Nurse Directors across Europe. AIM: The
      aim of the study was to identify shared aspects of the job from which further
      work could emerge to support the three aims of the Association and, in
      particular, to further nursing leadership across Europe. METHOD: An action
      centred research method (strengths, weaknesses, opportunities and threats [SWOT]
      analysis) was chosen which gave the opportunity for respondents to expand on key
      points. The texts were submitted in French, German and English with opportunities
      built in to individually discuss statements in order to minimize inaccuracies
      which could have emerged during translation. RESULTS: Nurse Directors of today
      give a clear indication of 'can-do' mentality and the strengths and weaknesses
      which are demonstrated indicate that there are areas which need to be further
      explored and supported. The findings were presented at the 5th Congress of ENDA
      in Rotterdam in 2001 and were well received. Funding has been obtained from the
      National Nursing Leadership Centre to expand the research. LIMITATIONS: This
      study is a snapshot only of those working at the leading edge in nursing. The
      responses also reflect feedback from nurses working in mainly acute hospitals and
      further work needs to be undertaken to include additional European countries.
      CONCLUSION: It has been demonstrated how Nurse Directors in Europe are taking and
      making opportunities to lead influence nursing and healthcare. Areas of further
      work that need to be addressed have emerged.

PMID- 12472868
TI  - Nurse managers' conceptions of quality management as promoted by peer
      supervision.
AB  - AIM: The aim of the study was to describe nurse managers' conceptions of quality
      management in their work as promoted by peer supervision. BACKGROUND: Quality
      management is one of the topical issues in a nurse manager's demanding and
      changing work. As first-line managers, they have a key role in quality management
      which is seen to create the system and environment for high quality services and
      quality improvement. Despite the official recommendations and definitions of
      quality management, several published reports have shown that there is no single
      solution for quality management. Peer supervision or the support provided by it
      to nursing managers have rarely been a subject of study. This study was carried
      out at Tampere University Hospital between 1996 and 1998. The peer supervision
      intervention was organized once a month, 2 hours at a time and in closed
      supervisor-led groups of nine nurse managers. METHODS: Data were collected by
      themed interviews. Fifteen nurse managers participated in the study. The data
      were analysed using the phenomenographic method. FINDINGS: Two main categories
      were formed of nurse managers' conceptions. The first described supportive and
      reflective characteristics of peer supervision. This main category was described
      by horizontal, hierarchical categories of support from peer group and reflection.
      The second main category described nurse managers' conceptions of individual
      development of leadership during peer supervision. This main category was also
      described by three horizontal categories: personal growth, finding psychological
      resources and internalization of leadership. CONCLUSION: The finding of this
      study show that peer supervision benefited nurse managers in quality management
      through reflection and support. The reflective and supportive characteristics of
      peer supervision promoted the nurse managers' individual development, but also
      that of leadership. It can be concluded that peer supervision promotes quality
      management in nurse managers' work.

PMID- 12472869
TI  - Influence of a merger on nurses' emotional well-being: the importance of self
      efficacy and emotional reactivity.
AB  - The influence of the merger of two major medical centres on the emotional well
      being of nurses was investigated by use of a questionnaire on emotional distress,
      perception of threat, self-efficacy and emotional reactivity. Evaluations were
      carried out 1 month prior to the merger at the official announcement, and again
      half a year after the merger took place. Before the merger, threat perception was
      higher in the transferring nurses, but the difference was of borderline
      significance (P = 0.05). There was a significant positive correlation between
      threat perception and both emotional reactivity and emotional distress, and a
      significant negative correlation between self-efficacy and both threat perception
      and emotional distress (P < 0.001 for all). After the merger, the transferring
      nurses showed more emotional distress (P = 0.009). There was a significant
      positive correlation between threat perception, emotional distress and negative
      outcome variables such as burnout and stress (P < 0.001), and a significant
      negative correlation between threat perception and positive outcome variables
      such as growth (P < 0.01). This study identifies some personal characteristics
      that can affect the way nurses deal with hospital mergers and need to be
      considered during organizational changes in order to maintain job satisfaction.

PMID- 12472871
TI  - Editorial: Blue on blue doesn't work.

PMID- 12472872
TI  - Editorial commentary: Ready to burst?

PMID- 12472873
TI  - Neurosecretory and non-neurosecretory parvocellular neurones of the hypothalamic
      paraventricular nucleus express distinct electrophysiological properties.
AB  - Parvocellular neurones of the hypothalamic paraventricular nucleus (PVN) comprise
      neurosecretory and non-neurosecretory subpopulations. We labelled neurosecretory
      neurones with intravenous injection of the retrograde tracer, fluoro-gold, and
      recorded from fluoro-gold-positive and negative PVN parvocellular neurones in
      hypothalamic slices. Non-neurosecretory parvocellular neurones generated a low
      threshold spike (LTS) and robust T-type Ca2+ current, whereas neurosecretory
      neurones showed no LTS and a small T-current. LTS neurones were located in non
      neurosecretory regions of the PVN, and non-LTS neurones were located in
      neurosecretory regions of the PVN. These findings indicate that neurosecretory
      and non-neurosecretory subtypes of parvocellular PVN neurones express distinct
      membrane electrical properties.

PMID- 12472874
TI  - Changes in the active membrane properties of rat supraoptic neurones during
      pregnancy and lactation.
AB  - To better understand the plasticity of intrinsic membrane properties of
      supraoptic magnocellular neuroendocrine cells associated with reproductive
      function, intracellular recordings were performed in oxytocin (OT) and
      vasopressin (VP) neurones from virgin, late pregnant (E19-22), and lactating (8
      12 days of lactation) rats in vitro, using hypothalamic explants. OT neurones
      from virgin rats displayed a narrower spike width than neurones from pregnant and
      lactating rats, characterized by faster rise and decay times. Spike width changes
      in VP neurones were not as prominent as those observed in OT neurones. In OT
      neurones, the amplitude and the decay of the afterhyperpolarization following
      spike trains was significantly larger and faster, respectively, in pregnant and
      lactating rats compared to virgin rats. These properties did not change during
      pregnancy and lactation in VP neurones. The incidence of the depolarizing
      afterpotential following spikes significantly increased from approximately 20% in
      virgin rats to 40-50% during pregnancy and lactation in OT neurones, but was
      stable (80-90%) across states in VP neurones. Repetitive firing properties
      (frequency adaptation, the first interspike interval frequency and frequency
      current (F-I) relationship) were altered during pregnancy and lactation in OT
      neurones, but not VP neurones. The increased incidence of depolarizing
      afterpotentials in OT neurones enhances excitability, while the increased
      afterhyperpolarization results in suppression of firing rate. Thus, the changes
      may favour the short bursting activity seen in OT neurones during lactation.
      These results confirmed reproductive state-dependent changes in intrinsic
      membrane properties of OT neurones during lactation, and suggest these changes
      are in place during late pregnancy. This argues that the plasticity in the
      electrical properties in OT neurones associated with lactation is not instigated
      by suckling.

PMID- 12472875
TI  - Evidence for the biosynthesis of a prolactin-releasing factor from the ovine pars
      tuberalis, which is distinct from thyrotropin-releasing hormone.
AB  - This study demonstrates the presence of two prolactin-releasing (PR) factors in
      media conditioned by primary pars tuberalis cells prepared from dispersed pars
      tuberalis tissue. One factor was identified as thyrotropin-releasing hormone
      (TRH) on the basis of immunoreactivity and following purification by high
      performance liquid chromatography and mass spectrometry. The origin of TRH in the
      pars tuberalis conditioned media was investigated by measuring the expression of
      glutaminyl-cyclase (QC) by in situ hybridization. QC expression was not detected
      in pars tuberalis-specific cells, but was relatively abundant in cells in the
      pars distalis and hypothalamic paraventricular nucleus. These data suggest that
      TRH is not synthesized by the ovine pars tuberalis and more likely originated
      from the hypothalamic neuronal processes from the paraventricular nucleus that
      terminate in the median eminence. The second component of the conditioned media
      PR bioactivity was insensitive to the TRH-antiserum, less than 1 kDa and was not
      retained by the C18 reverse-phase column. The biosynthesis of the PR bioactivity
      by pars tuberalis cells was investigated using cycloheximide, forskolin and
      melatonin. Cycloheximide reduced the level of PR bioactivity produced by the pars
      tuberalis cells. Melatonin inhibited the increased level of PR bioactivity
      stimulated by forskolin. Collectively, these data demonstrate the synthesis of at
      least one regulator of prolactin secretion by ovine pars tuberalis-specific
      cells.

PMID- 12472876
TI  - Functional cooperation between neurosteroids and D2 dopamine antagonists on KCl
      evoked [3H]noradrenaline release: modulation by calcium channel blockers.
AB  - It has recently been proposed that neurosteroids, such as dehydroepiandrosterone
      sulphate and pregnenolone sulphate, interfere with the dopamine system in the
      central nervous system. According to our previous report showing that the
      butyrophenone, spiperone, slightly enhances the evoked release of [3H]
      noradrenaline ([3H]NA) in the presence of these sulphated steroids, the present
      study was carried out to document the putative interplay between steroids and
      spiperone, which is known to be a prototypic D2 dopamine antagonist and also a 5
      HT2 serotonin antagonist. For this purpose, the paradigm of KCl-evoked [3H]NA
      release from preloaded rat hippocampal slices was used to investigate the
      interactions between neurosteroids, spiperone and the voltage-sensitive calcium
      channels (VSCCs). The selective 5-HT2 serotonin antagonist ritanserine was
      ineffective, whereas sulpiride, a selective D2 dopamine antagonist mimicked the
      action of spiperone, thus suggesting that the blockade of D2 dopamine receptors
      accounted for the modulatory effect of spiperone on neurosteroid-induced
      modulation of evoked [3H]NA release. In addition, this facilitation of KCl-evoked
      [3H]NA release by the combination of a steroid and a D2 dopamine antagonist was
      partially inhibited by the L- and N-type VSCC blockers nifedipine and omega
      conotoxin GVIA, respectively. The present results provide in-vitro functional
      evidence for the putative role of VSCCs in the interplay between steroids and D2
      dopamine receptors.

PMID- 12472877
TI  - Oxytocin inhibits aggression in female Syrian hamsters.
AB  - Dominant subordinate relationships are formed as the result of social conflict
      and are maintained at least in part by communication. At this time, little is
      known about the neural mechanisms that are responsible for coordinating the
      social behaviours (e.g. aggression) that occur in association with the formation
      and maintenance of these relationships. The purpose of the present study was to
      investigate the role of oxytocin (OXT) within the medial preoptic anterior
      hypothalamic continuum (MPOA-AH) in the control of aggression in female hamsters.
      OXT injected into the MPOA-AH immediately before testing significantly reduced
      the duration of aggression in a dose-dependent manner. Injection of an OXT
      antagonist 30 min before testing significantly increased the duration of
      aggression. In contrast, the duration of aggression was not altered when hamsters
      were tested either 30 min after injection of OXT or immediately following
      injection of an OXT-antagonist. These data support the hypothesis that OXT
      release within the MPOA-AH regulates social behaviours important in the formation
      and maintenance of dominant subordinate relationships in female hamsters.

PMID- 12472878
TI  - Changes in the arginine-vasopressin immunoreactive systems in male mice lacking a
      functional aromatase gene.
AB  - In male rodents, the arginine-vasopressin-immunoreactive (AVP-ir) neurones of the
      bed nucleus of the stria terminalis (BNST) and medial amygdala are controlled by
      plasma testosterone levels (decreased after castration and restored by exogenous
      testosterone). AVP transcription in these nuclei is increased in adulthood by a
      synergistic action of the androgenic and oestrogenic metabolites of testosterone
      and, accordingly, androgen and oestrogen receptors are present in both BNST and
      medial amygdala. We used knockout mice lacking a functional aromatase enzyme
      (ArKO) to investigate the effects of a chronic depletion of oestrogens on the
      sexually dimorphic AVP system. Wild-type (WT) and ArKO male mice were perfused 48
      h after an i.c.v. colchicine injection and brain sections were then processed for
      AVP immunocytochemistry. A prominent decrease (but not a complete suppression) of
      AVP-ir structures was observed in the BNST and medial amygdala of ArKO mice by
      comparison with the WT. Similarly, AVP-ir fibres were reduced in the lateral
      septum of ArKO mice and but not in the medial preoptic area, a region where the
      AVP system is not sexually dimorphic in rats. No change was detected in the
      supraoptic and suprachiasmatic nuclei. However, a decrease in AVP-ir cell numbers
      was however, detected in one subregion of the paraventricular nucleus. These data
      support the hypothesis that the steroid-sensitive sexually dimorphic AVP system
      of the mouse forebrain is mainly under the control of aromatized metabolites of
      testosterone.

PMID- 12472879
TI  - Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine.
AB  - Mitochondria are not only the principal source of high energy intermediates, but
      play an important role in intracellular calcium buffering, are main producers of
      reactive oxygen species, and are the source of pro- and antiapoptotic key
      factors. Moreover, the mitochondria are of a ubiquitous nature and the
      respiratory chain has a dual genetic basis, i.e. the mitochondrial and the
      nuclear DNAs. Thus mitochondrial impairment could provide an explanation for the
      tremendous heterogeneity of clinical and pathological manifestations in
      schizophrenia. This article reviews several independent lines of evidence that
      suggest an involvement of mitochondrial dysfunction in schizophrenia. Among them
      are altered cerebral energy metabolism, mitochondrial hypoplasia, dysfunction of
      the oxidative phosphorylation system and altered mitochondrial related gene
      expression. In addition, the interaction between dopamine, a predominant
      etiological factor in schizophrenia, and mitochondrial respiration is considered
      as a possible mechanism underlying the hyper- and hypo-activity cycling in
      schizophrenia. Understanding the role of mitochondria in schizophrenia may
      encourage novel treatment approaches, the identification of candidate genes and
      new insights into the pathophysiology and etiology of the disorder.

PMID- 12472880
TI  - Different roles for Gi and Go proteins in modulation of adenylyl cyclase type-2
      activity.
AB  - The effect of Gi/o protein-coupled receptors on adenylyl cyclase type 2 (AC2) has
      been studied in Sf9 insect cells. Stimulation of cells expressing AC2 with the
      phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) led to a twofold
      stimulation of cAMP synthesis that could be blocked with the protein kinase C
      inhibitor GF109203X. Activation of a coexpressed alpha2A-adrenoceptor or
      muscarinic M4 receptor inhibited the stimulation by TPA almost completely in a
      pertussis toxin-sensitive manner. Activation of Gs proteins switched the response
      of the alpha2A-adrenoceptor to potentiation of prestimulated AC2 activity. The
      potentiation, but not the inhibition, could be blocked by a Gbetagamma scavenger.
      A novel methodological approach, whereby signalling through endogenous G proteins
      was ablated, was used to assess specific G protein species in the signal pathway.
      Expression of Go proteins (alphao1 + beta1gamma2) restored both the inhibition
      and the potentiation, whereas expression of Gi proteins (alphai1 + beta1gamma2)
      resulted in a potentiation of both the TPA- and the Gs-stimulated AC2 activity.
      The data presented supports the view of AC2 as a molecular switch and implicates
      this isoform as a target for Go protein-linked signalling.

PMID- 12472881
TI  - Altered processing of amyloid precursor protein in the human neuroblastoma SH
      SY5Y by chronic hypoxia.
AB  - Alzheimer's disease (AD) is more prevalent following an ischemic or hypoxic
      episode, such as stroke. Indeed, brain levels of amyloid precursor protein (APP)
      and the cytotoxic amyloid beta peptide (Abeta) fragment are enhanced in these
      patients and in animal models following experimental ischaemia. We have
      investigated the effect of chronic hypoxia (CH; 2.5% O2, 24 h) on processing of
      APP in the human neuroblastoma, SH-SY5Y. We demonstrate that constitutive and
      muscarinic-receptor-enhanced secretion of the alpha-secretase cleaved fragment of
      APP, sAPPalpha, was reduced by approximately 60% in CH cells. The caspase
      inhibitor BOC-D(Ome)FMK did not reverse this effect of CH, and CH cells were as
      viable as controls, based on MTT assays. Thus, loss of sAPPalpha is not related
      to cell death or caspase processing of APP. Pre-incubation with antioxidants did
      not reverse the effect of CH, and the effect could not be mimicked by H2O2,
      discounting the involvement of reactive oxygen species in hypoxic loss of
      sAPPalpha. CH did not affect muscarinic activation of extracellular-signal
      regulated kinase. However, expression of ADAM 10 (widely believed to be alpha
      secretase) was decreased approximately 50% following CH. Thus, CH selectively
      decreases processing of APP by the alpha-secretase pathway, most likely by
      decreasing levels of ADAM 10.

PMID- 12472882
TI  - Analysis of the PC12 cell transcriptome after differentiation with pituitary
      adenylate cyclase-activating polypeptide (PACAP).
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP) promotes neurite
      outgrowth and inhibits proliferation of rat pheochromocytoma (PC12) cells.
      Characterizing the PACAP-differentiated PC12 cell transcriptome should provide
      genetic insight into how these processes occur in these cells, and in neuronal
      precursors in vivo. For this purpose, RNA samples were collected from PC12 cells
      before or after a 6-h treatment with PACAP, from which a labeled cDNA was
      hybridized to a high-density cDNA array containing 15 365 genes. The genomic
      response to PACAP involves at least 73 genes. Among the genes differentially
      expressed in the presence of PACAP, 71% were up regulated, and 29% down
      regulated, 2-fold or more. Sixty-six percent of the messages affected by PACAP
      code for functionally categorized proteins, most not previously known to be
      regulated during PC12 cell differentiation. PACAP has been shown to induce PC12
      cell neurite outgrowth through the mitogen-activated protein kinase kinase (MEK)
      pathway independently of protein kinase A (PKA). Therefore treatments were
      conducted in the absence or presence of the PKA inhibitor H89, or the MEK
      inhibitor U0126 in order to identify subsets of genes involved in specific
      aspects of PC12 cell differentiation. Co-treatment of PC12 cells with PACAP plus
      H89 revealed a cluster of five genes specifically regulated through the PKA
      pathway and co-treatment of the cells with PACAP and U0126 revealed a cluster of
      13 messages specifically activated through the MEK pathway. Many of the known
      genes regulated by PACAP have been associated with neuritogenesis (i.e. villin 2
      or annexin A2) or cell growth (i.e. growth arrest specific 1 or cyclin B2). Thus,
      some of the expressed sequence tags (ESTs) that exhibit the same regulation
      pattern (i.e. AU016391 or AW552690) may also be involved in the neuritogenic and
      anti-mitogenic effects of PACAP in PC12 cells. Among the 73 PACAP regulated
      genes, 10 are disqualified on pharmacological grounds as actors in PACAP-mediated
      neurite outgrowth or growth arrest, leaving 63 new PACAP-regulated genes
      implicated in neuronal differentiation. Thirteen of these are candidates for
      mediating ERK-dependent neurite outgrowth, and 47 are possibly involved in the
      ERK-independent growth arrest induced by PACAP.

PMID- 12472883
TI  - Induction of COX-2 and reactive gliosis by P2Y receptors in rat cortical
      astrocytes is dependent on ERK1/2 but independent of calcium signalling.
AB  - The present study has been aimed at characterizing the ATP/P2 receptor (and
      transductional pathways) responsible for the morphological changes induced in
      vitro by alphabetamethyleneATP on rat astrocytes obtained from cerebral cortex, a
      brain area highly involved in neurodegenerative diseases. Exposure of cells to
      this purine analogue resulted in elongation of cellular processes, an event
      reproducing in vitro a major hallmark of in vivo reactive gliosis.
      alphabetamethyleneATP-induced gliosis was prevented by the P2X/P2Y blocker
      pyridoxalphosphate-6-azophenyl-2'-4'-disulfonic acid, but not by the selective
      P2X antagonist 2',3'-O-(2,4,6-trinitrophenyl)-ATP, ruling out a role for ligand
      gated P2X receptors. Conversely, the Gi/Go protein inactivator pertussis toxin
      completely prevented alphabetamethyleneATP-induced effects. No effects were
      induced by alphabetamethyleneATP on intracellular calcium concentrations. RT-PCR
      and western blot analysis showed that alphabetamethyleneATP-induced gliosis
      involves up-regulation of cyclooxygenase-2 (but not lipooxygenase). Also this
      effect was fully prevented by pyridoxalphosphate-6-azophenyl-2'-4'-disulfonic
      acid. Experiments with inhibitors of mitogen-activated protein kinases (MAPK)
      suggest that extracellular signal regulated protein kinases (ERK)1/2 mediate both
      cyclooxygenase-2 induction and the associated in vitro gliosis. These findings
      suggest that purine-induced gliosis involves the activation of a calcium
      independent G-protein-coupled P2Y receptor linked to ERK1/2 and cyclooxygenase-2.
      Based on the involvement of cyclooxygenase-2 and inflammation in
      neurodegenerative diseases, these findings open up new avenues in the
      identification of novel biological targets for the pharmacological manipulation
      of neurodegeneration.

PMID- 12472884
TI  - Heterogeneity of the calcium-induced permeability transition in isolated non
      synaptic brain mitochondria.
AB  - Calcium overload of neural cell mitochondria plays a key role in excitotoxic and
      ischemic brain injury. This study tested the hypothesis that brain mitochondria
      consist of subpopulations with differential sensitivity to calcium-induced inner
      membrane permeability transition, and that this sensitivity is greatly reduced by
      physiological levels of adenine nucleotides. Isolated non-synaptosomal rat brain
      mitochondria were incubated in a potassium-based medium in the absence or
      presence of ATP or ADP. Measurements were made of medium and intramitochondrial
      free calcium, light scattering, mitochondrial ultrastructure, and the elemental
      composition of electron-opaque deposits within mitochondria treated with calcium.
      In the absence of adenine nucleotides, calcium induced a partial decrease in
      light scattering, accompanied by three distinct ultrastructural morphologies,
      including large-amplitude swelling, matrix vacuolization and a normal appearance.
      In the presence of ATP or ADP the mitochondrial calcium uptake capacity was
      greatly enhanced and calcium induced an increase rather than a decrease in
      mitochondrial light scattering. Approximately 10% of the mitochondria appeared
      damaged and the rest contained electron-dense precipitates that contained
      calcium, as determined by electron-energy loss spectroscopy. These results
      indicate that brain mitochondria are heterogeneous in their response to calcium.
      In the absence of adenine nucleotides, approximately 20% of the mitochondrial
      population exhibit morphological alterations consistent with activation of the
      permeability transition, but less than 10% exhibit evidence of osmotic swelling
      and membrane disruption in the presence of ATP or ADP.

PMID- 12472886
TI  - In depolarized and glucose-deprived neurons, Na+ influx reverses plasmalemmal K+
      dependent and K+-independent Na+/Ca2+ exchangers and contributes to NMDA
      excitotoxicity.
AB  - Cerebellar granule cells (CGCs) express K+-dependent (NCKX) and K+-independent
      (NCX) plasmalemmal Na+/Ca2+ exchangers which, under plasma membrane-depolarizing
      conditions and high cytosolic [Na+], may reverse and mediate potentially toxic
      Ca2+ influx. To examine this possibility, we inhibited NCX or NCKX with KB-R7943
      or K+-free medium, respectively, and studied how gramicidin affects cytosolic
      [Ca2+] and 45Ca2+ accumulation. Gramicidin forms pores permeable to alkali
      cations but not Ca2+. Therefore, gramicidin-induced Ca2+ influx is indirect; it
      results from fluxes of monovalent cations. In the presence of Na+, but not Li+ or
      Cs+, gramicidin induced Ca2+ influx that was inhibited by simultaneous
      application of KB-R7943 and K+-free medium. The data indicate that gramicidin
      induced Na+ influx reverses NCX and NCKX. To test the role of NCX and/or NCKX in
      excitotoxicity, we studied how NMDA affects the viability of glucose-deprived and
      depolarized CGCs. To assure depolarization of the plasma membrane, we inhibited
      Na+,K+-ATPase with ouabain. Although inhibition of NCX or NCKX reversal failed to
      significantly limit 45Ca2+ accumulation and excitotoxicity, simultaneously
      inhibiting NCX and NCKX reversal was neuroprotective and significantly decreased
      NMDA-induced 45Ca2+ accumulation. Our data suggest that NMDA-induced Na+ influx
      reverses NCX and NCKX and leads to the death of depolarized and glucose-deprived
      neurons.

PMID- 12472885
TI  - Heterogeneous expression of the triggering receptor expressed on myeloid cells-2
      on adult murine microglia.
AB  - Microglial activation is an early and common feature of almost all
      neuropathologies, including multiple sclerosis, Alzheimer's disease and
      mechanical injury. To better understand the relative contributions microglia make
      toward neurodegeneration and neuroprotection, we used TOGA(R) to identify
      molecules expressed by microglia and regulated by inflammatory signals.
      Triggering receptor expressed on myeloid cells-2 (TREM-2) was among the mRNAs
      identified as being expressed by unactivated microglia, but down-regulated by
      lipopolysaccharide/interferon gamma. In the healthy CNS, not all microglia
      expressed TREM-2. Microglial expression of TREM-2 varied not only between brain
      regions but also within each brain region. Brain regions with an incomplete blood
      brain barrier had the lowest percentages of TREM-2- expressing microglia, whereas
      the lateral entorhinal and cingulate cortex had the highest percentages. A novel
      form of TREM-2b that lacked a transmembrane domain was detected, perhaps
      indicating a soluble form of the protein. Taken together, these data suggest that
      (1) subsets of microglia are specialized to respond to defined extracellular
      signals; and (2) regional variations in TREM-2 expression may contribute to the
      varying sensitivities of different brain regions to similar pathological signals.

PMID- 12472887
TI  - Increased synthesis but decreased processing of neuronal proCCK in prohormone
      convertase 2 and 7B2 knockout animals.
AB  - In addition to its role as a gut hormone, cholecystokinin (CCK) is a widespread
      and potent neurotransmitter. Its biosynthesis requires endoproteolytic cleavage
      of proCCK at several mono- and dibasic sites by subtilisin-like prohormone
      convertases (PCs). Of these, PC1 and PC2 are specific for neuroendocrine cells.
      We have now examined the role of PC2 and its binding protein, 7B2, in the
      neuronal processing of proCCK by measurement of precursor, processing
      intermediates and bioactive end-products in brain extracts from PC2- and 7B2-null
      mice and from corresponding controls. PC2-null mice displayed a nine-fold
      increase of cerebral proCCK concentrations, and a two-fold increase in the
      concentrations of the processing-intermediate, glycine-extended CCK, whereas the
      concentrations of transmitter-active (i.e. alpha-amidated and O-sulfated) CCK
      peptides were reduced (61%). Chromatography showed that O-sulfated CCK-8 still is
      the predominant transmitter-active CCK in PC2-null brains, but that the fraction
      of intermediate-sized CCK-peptides (CCK-58, -33 and -22) was eight-fold
      increased. 7B2-null brains displayed a similar pattern but with less pronounced
      precursor accumulation. In contrast with the cerebral changes, PC2 deficiency was
      without effect on proCCK synthesis and processing in intestinal endocrine cells,
      whereas 7B2 deficiency halved the concentration of bioactive CCK in the
      intestine. The results show that PC2 plays a major neuron-specific role in the
      processing of proCCK.

PMID- 12472888
TI  - Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes
      and reduction of hydrogen peroxide-induced cell death.
AB  - Induction of heat shock proteins (HSPs) protects cells from oxidative injury.
      Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat
      astrocytes, and protection against oxidative stress was investigated. Astrocytes
      were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to
      cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death
      was evaluated at different time points. Arsenite triggered strong induction of
      HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell
      loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP
      nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were
      abrogated by pre-treatment with arsenite, which prevented cell loss and
      significantly reduced the number of dead cells. The protective effect of arsenite
      was not detected in the presence of CHX. Pre-treatment with arsenite increased
      protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2)
      phosphorylation after H2O2. However, while Akt phosphorylation was prevented by
      CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that
      transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent,
      Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective
      activation of Akt following H2O2. It is suggested that HSP expression at the time
      of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell
      death by means of pro-survival Akt.

PMID- 12472889
TI  - Effect of tumor necrosis factor-alpha converting enzyme (TACE) and
      metalloprotease inhibitor on amyloid precursor protein metabolism in human
      neurons.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is implicated in inflammatory processes
      and much effort is being directed at inhibiting the release of TNF-alpha for
      treatment of inflammatory conditions. In this context, the drug CP-661,631 has
      been developed to inhibit the TNF-alpha converting enzyme (TACE). However, TACE
      is also implicated in amyloid precursor protein secretion. Amyloid precursor
      protein (APP) undergoes constitutive and regulated secretion by alpha-secretase
      endoproteolytic cleavage within the amyloid beta peptide (Abeta) domain.
      Alternative cleavage at the N- and C-terminus of the Abeta domain by beta- and
      gamma-secretases results in the production of Abeta. In many cellular and in vivo
      animal models, increased secretion of APP results in a concomitant decrease in
      the production of Abeta suggesting that the two pathways are intricately linked.
      However, in human primary neuron cultures, increased APP secretion is not
      associated with a decrease in total Abeta production. To determine if the use of
      CP-661,631 may enhance amyloidogenic processing in human brain, we have assessed
      the effect of CP-661,631 on APP metabolism in primary cultures of human neurons.
      Our results show that CP-661,631 effectively prevents regulated APP secretion but
      does not increase total Abeta levels in human primary neuron cultures.

PMID- 12472890
TI  - A caspase-3-dependent pathway is predominantly activated by the excitotoxin
      pregnenolone sulfate and requires early and late cytochrome c release and cell
      specific caspase-2 activation in the retinal cell death.
AB  - This study investigates the implication of mitochondria- and caspase-dependent
      pathways in the death of retinal neurones exposed to the neurosteroid
      pregnenolone sulfate (PS) shown to evoke apoptosis and contribute to
      amplification and propagation of excitotoxicity. After a brief PS challenge of
      intact retinas, caspase-3 and caspase-2 activation and cytochrome c release occur
      early and independent of changes in the oxidative state measured by superoxide
      dismutase activity. The temporal and spatial relationship of these events
      suggests that a caspase-3-dependent pathway is activated in response to
      cytochrome c release and requires caspase-2 activation and a late cytochrome c
      release in specific cellular subsets of retinal layers. The protection by caspase
      inhibitors indicates a predominant role of the pathway in PS-induced retinal
      apoptosis, although a limited use of caspase inhibitors is upheld on a
      conceivable shift from apoptosis toward necrosis. Conversely, 3alpha-hydroxy
      5beta-pregnan-20-one sulfate and 17beta-oestradiol provide complete prevention of
      PS-induced retinal death.

PMID- 12472891
TI  - Nicotine-induced phosphorylation of Akt through epidermal growth factor receptor
      and Src in PC12h cells.
AB  - Nicotine treatment triggers calcium influx into neuronal cells, which promotes
      cell survival in a number of neuronal cells. Phosphoinositide (PI) 3-kinase and
      downstream PI3-kinase target Akt have been reported to be important in the
      calcium-mediated promotion of survival in a wide variety of cells. We
      investigated the mechanisms of nicotine-induced phosphorylation of Akt in PC12h
      cells, in comparison with nicotine-induced ERK phosphorylation. Nicotine induced
      Akt phosphorylation in a dose-dependent manner. A nicotinic acetylcholine
      receptor (nAChR) alpha7 subunit-selective inhibitor had no significant effect on
      nicotine-induced Akt phosphorylation, while a non-selective nAChR antagonist
      inhibited the phosphorylation. L-type voltage-sensitive calcium channel (VSCC)
      antagonists, calmodulin antagonist, and Ca2+/calmudulin-dependent protein kinase
      (CaM kinase) inhibitor prevented the nicotine-induced Akt phosphorylation. Three
      epidermal growth factor receptor (EGFR) inhibitors prevented the nicotine-induced
      phosphorylation of both extracellular signal-regulated protein kinase (p42/44 MAP
      kinase, ERK) and Akt. In contrast, an inhibitor of the Src family tyrosine kinase
      prevented the nicotine-induced Akt phosphorylation but not ERK phosphorylation.
      These results suggested that nicotine induces the activation of both PI3
      kinase/Akt and ERK pathways via common pathways including non-alpha7-nAChRs, L
      type VSCC, CaM kinase II and EGFR in PC12h cells, but Src family tyrosine kinases
      only participate in the pathway to activate Akt.

PMID- 12472892
TI  - Identification of a peptide mimic of the L2/HNK-1 carbohydrate epitope.
AB  - The L2/HNK-1 carbohydrate is carried by many neural recognition molecules and is
      involved in neural cell interactions during development, regeneration in the
      peripheral nervous system, synaptic plasticity, and autoimmune-based
      neuropathies. Its key structure consists of a sulfated glucuronic acid linked to
      lactosaminyl residues. Because of its biological importance but limited
      availability, the phage display method was used to isolate a collection of
      peptide mimics that bind specifically to an L2/HNK-1 antibody. The phages
      isolated from a 15-mer peptide library by adsorption to this antibody share a
      consensus sequence of amino acids. The peptide mimicked several important
      functions of the L2/HNK-1 carbohydrate, such as binding to motor neurons in
      vitro, and preferential promotion of in vitro neurite outgrowth from motor axons
      compared with sensory neurons. A scrambled version of the peptide had no
      activity. The combined observations indicate that we have isolated a mimic of the
      L2/HNK-1 carbohydrate that is able to act as its functional substitute.

PMID- 12472894
TI  - Circadian regulation of a transcription factor, ApC/EBP, in the eye of Aplysia
      californica.
AB  - The transcription factor, ApC/EBP (Aplysia CCAAT enhancer-binding protein) is an
      immediate early gene that is rapidly induced by serotonin and the cAMP signaling
      pathway. ApC/EBP acts as an important link following the activation of protein
      kinase A (PKA) in the consolidation of long-term memory in Aplysia californica.
      In this study, we report that levels of ApC/EBP mRNA in the eye of Aplysia are
      modulated by serotonin or light. These responses of ApC/EBP to serotonin and
      light are mimicked by analogs of cAMP and cGMP. Expression of ApC/EBP in the eye
      is also under the control of the circadian oscillator with circadian rhythms of
      ApC/EBP mRNA present under constant dark conditions. Therefore, ApC/EBP is a
      candidate gene for a circadian transcription factor to mediate circadian
      responses activated by the cAMP and cGMP second messenger signaling pathways.

PMID- 12472893
TI  - Ontogeny and the possible function of a novel epidermal growth factor-like repeat
      domain-containing protein, NELL2, in the rat brain.
AB  - In this study we investigated the mRNA expression of NELL2, a neural tissue
      specific epidermal growth factor (EGF)-like repeat domain-containing protein, in
      the developing and adult rat CNS using in situ hybridization histochemistry and
      northern blot analysis. The possible candidates that interact with or be
      regulated by NELL2 were screened with a cDNA expression array in antisense (AS)
      NELL2 oligodeoxynucleotide (ODN)-injected rat hypothalami. NELL2 mRNA was
      detected as early as embryonic day 10, and was predominant in the CNS throughout
      the pre-natal stages. Its expression gradually increased during embryonic
      development and its strong expression was observed throughout the CNS until
      embryonic day 20. It was detected in the ventricular zone of the spinal cord,
      medulla and pons in 12-day-old-embryos, suggesting that NELL2 plays a role in the
      neurogenesis of these areas. After birth its expression gradually decreased, but
      high levels of expression could be observed in the tenia tecta, piriform cortex,
      hippocampus, dentate gyrus, cerebellar cortex, ambiguus nucleus, and inferior
      olivary nucleus of adult rat brains. The analysis of cDNA expression arrays
      revealed that the administration of AS NELL2 ODN markedly decreased the
      expression of several Ca2+-binding proteins and those involved in the transport
      and release of vesicles such as EF-hand Ca2+-binding protein p22 and rab7. This
      finding was confirmed by relative reverse transcription-polymerase chain
      reaction. The effect of NELL2 on synaptic vesicle content in median eminence (ME)
      nerve terminals was determined with synaptophysin levels as a marker protein in
      the AS NELL2 ODN-injected rat. It was significantly decreased by the AS ODN.
      These data suggest that NELL2 may play an important role in the development of
      the CNS as well as maintenance of neural functions, by regulating the
      intracellular machinery involving Ca2+ signaling, synaptic transport and/or
      release of vesicles.

PMID- 12472895
TI  - Participation of protein kinase C alpha isoform and extracellular signal
      regulated kinase in neurite outgrowth of GT1 hypothalamic neurons.
AB  - In the present study, we investigated the selective role of protein kinase C
      (PKC) isoforms on neurite outgrowth of the GT1 hypothalamic neurons using several
      PKC isoform-selective inhibitors and transfection-based expression of enhanced
      green fluorescence protein (EGFP)-fused PKC isoforms. 12-O-Tetradecanoylphorbol
      13-acetate (TPA) induced neurite outgrowth and growth cone formation, effects
      that were blocked by GF 109203X (a PKC inhibitor), safingolTM(a PKCalpha
      selective inhibitor), but not by rottlerinTM (a PKCdelta-selective inhibitor),
      indicating that PKCalpha may be selectively involved in neurite outgrowth and
      cytoskeletal changes of filamentous actin and beta-tubulin. To define the
      differential localization of PKC isoforms, EGFP-tagged PKCalpha, PKCgamma, and
      PKCdelta were transfected into GT1 neuronal cells. TPA treatment induced
      relocalization of PKCalpha-EGFP to growth cones and cell-cell adhesion sites,
      PKCgamma-EGFP to the nucleus, and PKCdelta-EGFP to the membrane ruffle,
      respectively. An EGFP chimera of the catalytic domain of PKCalpha (PKCalpha-Cat
      EGFP), the expression of which was inducible by doxycycline, was employed to
      directly ascertain the effect of PKCalpha enzymatic activity on neurite outgrowth
      of GT1 cells. Transient transfection of PKCalpha-Cat-EGFP alone increased the
      neurite-outgrowth and doxycycline treatment further augmented the number of
      neurite-containing cells. We also examined the involvement of the extracellular
      signal-regulated kinase (ERK) MAP kinase in TPA-induced neurite outgrowth. TPA
      treatment increased phosphorylated ERK MAP kinase, but not p38 MAP kinase.
      Specific inhibition of PKCalpha with safingol blocked the phosphorylation of ERK
      induced by TPA. More importantly, both neurite outgrowth and phosphorylation of
      ERK by TPA were blocked by PD 098059, a specific inhibitor of MEK (MAP kinase/ERK
      kinase-1), but not by SB203580, a specific inhibitor of p38 MAP kinase. These
      results demonstrate that PKCalpha isoform-specific activation is involved in
      neurite outgrowth of GT1 hypothalamic neuronal cells via ERK, but not the p38 MAP
      kinase signal pathway.

PMID- 12472896
TI  - Regional differences in processing of locally translated prohormone in
      peptidergic neurons of Aplysia californica.
AB  - Earlier work showed that cell bodies and neurites of the peptidergic bag cell
      neurons of Aplysia californica contain mRNA for egg-laying hormone. The purpose
      of the present study was to determine if egg-laying hormone synthesis and
      prohormone processing is similar in the pleurovisceral connective nerves
      (containing neurites of bag cell neurons) and the bag cell neuron clusters
      (containing both cell bodies and neurites of bag cell neurons). Initial
      experiments confirmed by RT-PCR and sequencing that egg-laying hormone mRNA was
      present in the pleurovisceral connective nerves. To investigate possible regional
      differences in translation of mRNA and prohormone processing, clusters were
      separated from connective nerves and newly synthesized egg-laying hormone
      immunoreactive proteins were analyzed. Results showed that synthesis and
      processing of prohormone occurred in both the clusters and isolated connective
      nerves; however, the relative abundance of prohormone, processing intermediates,
      and egg-laying hormone was different. Pulse-chase experiments showed that
      prohormone was processed more slowly in the connective nerves than in the
      clusters. These results show that mRNA in isolated neural processes of
      neuroendocrine cells can be translated, and that the cellular machinery for
      protein synthesis is present, but processing of the ELH prohormone is
      significantly compromised.

PMID- 12472897
TI  - Astrocytic but not neuronal increased expression and redistribution of parkin
      during unfolded protein stress.
AB  - Parkin is a ubiquitin ligase that facilitates proteasomal protein degradation and
      is involved in a common autosomal recessive form of Parkinson's disease. Its
      expression is part of the unfolded protein response in cell lines where its
      overexpression protects against unfolded protein stress. How parkin expression is
      regulated in brain primary cells under stress situations is however, less well
      established. Here, the cellular and subcellular localization of parkin under
      basal conditions and during unfolded protein stress was investigated in primary
      cultures of rat astrocytes and hippocampal neurons. Immunofluorescense microscopy
      and biochemical analysis demonstrated that parkin is mainly associated with the
      endoplasmic reticulum (ER) in hippocampal neurons while it is associated with
      Golgi membranes, the nuclei and light vesicles in astrocytes. The constitutive
      parkin expression was high in neurons as compared with astrocytes. However,
      unfolded protein stress elicited a selective increase in astrocytic parkin
      expression and a change in distribution, whereas neuronal parkin remained largely
      unmodified. The cell specific differences argue in favour of different cellular
      binding sites and substrates for the protein and a pathogenic role for astrocytes
      in Parkinson's disease caused by parkin dysfunction.

PMID- 12472898
TI  - Corticosterone acutely prolonged N-methyl-d-aspartate receptor-mediated Ca2+
      elevation in cultured rat hippocampal neurons.
AB  - This work reports the first demonstration that corticosterone (CORT) has a rapid
      and transient effect on NMDA receptor-mediated Ca2+ signaling in cultured rat
      hippocampal neurons. Using single cell Ca2+ imaging, CORT and agonists of
      glucocorticoid receptors were observed to modulate the NMDA receptor-mediated
      Ca2+ signals in a completely different fashion from pregnenolone sulfate. In the
      absence of steroids, 100 micro m NMDA induced a transient Ca2+ signal that lasted
      for 30-70 s in 86.1% of the neurons prepared from postnatal rats (3-5 days old).
      After pre-treatment with 0.1-100 micro m CORT for 10-20 min, NMDA induced
      extremely prolonged Ca2+ elevation. This prolonged Ca2+ elevation was terminated
      by the application of MK-801 and followed by washing out of CORT. The proportion
      of CORT-modulated neurons within the NMDA-responsive cells increased from 25.1 to
      95.5% when the concentration of CORT was raised from 0.1 to 50 micro m.
      Substitution of BSA-conjugated CORT produced essentially the same results. When
      hippocampal neurons were preincubated with 10 micro m cortisol and 1 micro m
      dexamethasone for 20 min, a very prolonged Ca2+ elevation was also observed upon
      NMDA stimulation. The CORT-prolonged Ca2+ elevation caused a long-lasting
      depolarization of the mitochondrial membrane, as observed with rhodamine 123. In
      contrast, incubation with 100 micro m pregnenolone sulfate did not considerably
      alter the time duration of NMDA-induced transient Ca2+ elevation, but caused a
      significant increase in the peak amplitude of Ca2+ elevation in hippocampal
      neurons. These results imply that high levels of CORT induce a rapid and non
      genomic prolongation of NMDA receptor-mediated Ca2+ elevation, probably via
      putative membrane surface receptors for CORT in the hippocampal neurons.

PMID- 12472900
TI  - Constitutive activation of the opioid receptor-like (ORL1) receptor by mutation
      of Asn133 to tryptophan in the third transmembrane region.
AB  - We have introduced a series of point mutations into the human opioid receptor
      like (ORL1) receptor and characterized them for their ability to constitutively
      activate G protein-coupled receptor signalling pathways. Among the 12 mutants
      generated, mutation at Asn133 (N133W) gave increased basal signalling through
      three separate pathways. N133W increased the basal activity of G14- and G16
      dependent pathways by two- to three-fold. The constitutive activity of the mutant
      was confirmed by the finding that the enhanced activity is dependent on the level
      of receptor expression. In HEK-293 cells stably expressing N133W, signalling
      through Gi/o-dependent pathways was also observed. Radioligand binding studies
      revealed that the affinity for nociceptin of the wild-type ORL1 receptor and the
      N133W mutant do not differ significantly, suggesting that the ligand binding and
      signalling functions of constitutively active mutants of G protein-coupled
      receptors are not necessarily intrinsically linked. In conclusion, our results
      demonstrate that a mutation in the third transmembrane domain is able to increase
      the basal signalling activity of the human ORL1 receptor.

PMID- 12472899
TI  - Type-specific inositol 1,4,5-trisphosphate receptor localization in the
      vomeronasal organ and its interaction with a transient receptor potential
      channel, TRPC2.
AB  - The vomeronasal organ (VNO) is the receptor portion of the accessory olfactory
      system and transduces chemical cues that identify social hierarchy, reproductive
      status, conspecifics and prey. Signal transduction in VNO neurons is apparently
      accomplished via an inositol 1,4,5-trisphosphate (IP3)-activated calcium
      conductance that includes a different set of G proteins than those identified in
      vertebrate olfactory sensory neurons. We used immunohistochemical (IHC) and SDS
      PAGE/western analysis to localize three IP3 receptors (IP3R) in the rat VNO
      epithelium. Type-I IP3R expression was weak or absent. Antisera for type-II and 
      III IP3R recognized appropriate molecular weight proteins by SDS-PAGE, and
      labeled protein could be abolished by pre-adsorption of the respective antibody
      with antigenic peptide. In tissue sections, type-II IP3R immunoreactivity was
      present in the supporting cell zone but not in the sensory cell zone. Type-III
      IP3R immunoreactivity was present throughout the sensory zone and overlapped that
      of transient receptor potential channel 2 (TRPC2) in the microvillar layer of
      sensory epithelium. Co-immunoprecipitation of type-III IP3R and TRPC2 from VNO
      lysates confirmed the overlapping immunoreactivity patterns. The protein-protein
      interaction complex between type-III IP3R and TRPC2 could initiate calcium
      signaling leading to electrical signal production in VNO neurons.

PMID- 12472901
TI  - Rat MYH, a glycosylase for repair of oxidatively damaged DNA, has brain-specific
      isoforms that localize to neuronal mitochondria.
AB  - Mitochondrial genomes are exposed to a heavy load of reactive oxygen species
      (ROS) that damage DNA. Since in neurons, mitochondrial DNA integrity must be
      maintained over the entire mammalian life span, neuronal mitochondria most likely
      repair oxidatively damaged DNA. We show that the Escherichia coli MutY DNA
      glycosylase homolog (MYH) in rat (rMYH) involved in repair of oxidative damage is
      abundantly expressed in the rat brain, with isoforms that are exclusive to brain
      tissue. Confocal microscopy and western analyses reveal localization of rMYH in
      neuronal mitochondria. To assess involvement of MYH in the neuronal response to
      oxidative DNA damage, we used a rat model of respiratory hypoxia, in which
      acutely reduced blood oxygenation leads to generation of superoxide, and
      formation and subsequent removal of 8-hydroxy-2'-deoxyguanosine (8OHdG). Removal
      of 8OHdG is accompanied by a spatial increase in rMYH immunoreactivity in the
      brain and an increase in levels of one of the three mitochondrial MYH isoforms,
      suggesting that inducible and non-inducible MYH isoforms exist in the brain. The
      mitochondrial localization of oxidative DNA damage repair enzymes in neurons may
      represent a specialized neuronal mechanism that safeguards mitochondrial genomes
      in the face of routine and accidental exposures to heavy loads of injurious ROS.

PMID- 12472902
TI  - Microarray analysis of selected genes in neural stem and progenitor cells.
AB  - To access and compare gene expression in fetal neuroepithelial cells (NEPs) and
      progenitor cells, we have used microarrays containing approximately 500 known
      genes related to cell cycle regulation, apoptosis, growth and differentiation. We
      have identified 152 genes that are expressed in NEPs and 209 genes expressed by
      progenitor cells. The majority of genes (141) detected in NEPs are also present
      in progenitor populations. There are 68 genes specifically expressed in
      progenitors with little or no expression in NEPs, and a few genes that appear to
      be present exclusively in NEPs. Using cell sorting, RT-PCR, in situ hybridization
      or immunocytochemistry, we have examined the segregation of expression to
      neuronal and glial progenitors, and identified several that appeared to be
      enriched in neuronal (e.g. CDK5, neuropilin, EphrinB2, FGF11) or glial (e.g.
      CXCR4, RhoC, CD44, tenascin C) precursors. Our data provide a first report of
      gene expression profiles of neural stem and progenitor cells at early stages of
      development, and provide evidence for the potential roles of specific cell cycle
      regulators, chemokines, cytokines and extracellular matrix molecules in neural
      development and lineage segregation.

PMID- 12472903
TI  - Assembly of tau in transgenic animals expressing P301L tau: alteration of
      phosphorylation and solubility.
AB  - Transgenic mice (JNPL3), which develop neurofibrillary degeneration and express
      four-repeat human tau with P301L missense mutation, were characterized
      biochemically to determine whether the development of aggregated tau from soluble
      tau involves an intermediate stage. Homogenates from mice of different ages were
      separated into buffer-soluble (S1), sarkosyl- and salt-extractable (S2) and
      sarkosyl-insoluble pellet (P3) fractions, and analyzed for human tau
      distribution, phosphorylation and filament formation. S1 and S2 fractions
      contained 50-60-kDa tau whereas the S2 fraction also had 64-kDa tau. The level of
      tau in the P3 fraction increased in an age-dependent manner and correlated
      positively with the soluble tau concentration. The P3 fraction from 2.5-6.5-month
      old mice contained 64- and 50-60-kDa tau, whereas that from 8.5-month and older
      transgenic animals contained mostly 64-kDa and higher molecular weight tau. The
      S2 and P3 fractions contained comparable amounts of 64-kDa tau. The 64-kDa tau
      was predominantly human, and phosphorylated at multiple sites: Thr181,
      Ser202/Thr205, Thr212, Thr231, Ser262, Ser396/Ser404, Ser409 and Ser422. Most of
      these sites were phosphorylated to a lesser extent in S2 than in P3 fractions.
      Tau polymers were detected in P3 fractions from 3-month and older female JNPL3
      mice, but not in non-transgenic controls. The results suggest that tau in S2
      represents an intermediate from which insoluble tau is derived, and that
      phosphorylation may play a role in filament formation and/or stabilization.

PMID- 12472904
TI  - Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural
      progenitor cell homeostasis, in models of Alzheimer's disease.
AB  - Neurogenesis occurs in the adult mammalian brain and may play roles in learning
      and memory processes and recovery from injury, suggesting that abnormalities in
      neural progenitor cells (NPC) might contribute to the pathogenesis of disorders
      of learning and memory in humans. The objectives of this study were to determine
      whether NPC proliferation, survival and neuronal differentiation are impaired in
      a transgenic mouse model of Alzheimer's disease (AD), and to determine the
      effects of the pathogenic form of amyloid beta-peptide (Abeta) on the survival
      and neuronal differentiation of cultured NPC. The proliferation and survival of
      NPC in the dentate gyrus of the hippocampus was reduced in mice transgenic for a
      mutated form of amyloid precursor protein that causes early onset familial AD.
      Abeta impaired the proliferation and neuronal differentiation of cultured human
      and rodent NPC, and promoted apoptosis of neuron-restricted NPC by a mechanism
      involving dysregulation of cellular calcium homeostasis and the activation of
      calpains and caspases. Adverse effects of Abeta on NPC may contribute to the
      depletion of neurons and cognitive impairment in AD.

PMID- 12472905
TI  - Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP
      share Trk B-dependent mechanisms.
AB  - The effects of brain-derived neurotrophic factor (BDNF) and cAMP on the neuronal
      serotoninergic phenotype were studied in primary cultures of E14 rat embryonic
      rostral raphe. Short treatments (for 18 h) with BDNF or dibutyryl-cAMP induced an
      almost two-fold increase in the number of serotoninergic neurones and a dramatic
      extension and ramification of their neurites. These changes were associated with
      marked increases in the levels of mRNAs encoding the serotonin transporter, the 5
      HT1A and 5-HT1B receptors and the BDNF receptor tyrosine kinase B (TrkB).
      Concomitant blockade of tyrosine kinases by genistein suppressed all the up
      regulating effects of BDNF and cAMP on 5-hydroxytryptamine (5-HT) neurones. These
      findings suggest that an auto-amplifying mechanism underlies the promoting effect
      of BDNF on the differentiation of serotoninergic neurones through TrkB
      activation, which is also triggered by cAMP.

PMID- 12472906
TI  - Spatial learning deficit in transgenic mice that conditionally over-express GSK
      3beta in the brain but do not form tau filaments.
AB  - Deregulation of glycogen synthase kinase-3 (GSK-3) activity in neurones has been
      postulated as a key feature in Alzheimer's disease (AD) pathogenesis. This was
      further supported by our recent characterization of transgenic mice that
      conditionally over-express GSK-3beta in hippocampal and cortical neurones. These
      mice, designated Tet/GSK-3beta, showed many of the biochemical and cellular
      aspects of AD neuropathology such as tau hyperphosphorylation and somatodendritic
      localization, decreased nuclear beta-catenin, neuronal death and reactive
      gliosis. Tet/GSK-3beta mice, however, did not show tau filament formation up to
      the latest tested age of 3 months at least. Here we report spatial learning
      deficits of Tet/GSK-3beta mice in the Morris water maze. In parallel, we also
      measured the increase in GSK-3 activity while further exploring the possibility
      of tau filament formation in aged mice. We found a significant increase in GSK-3
      activity in the hippocampus of Tet/GSK-3beta mice whereas no tau fibrils could be
      found even in very old mice. These data reinforce the hypothesis of GSK-3
      deregulation in AD pathogenesis, and suggest that Tet/GSK-3beta mice can be used
      as an AD model and, most remarkably, can be used to test the therapeutic
      potential of the selective GSK-3 inhibitors that are currently under development.
      Additionally, these experiments suggest that destabilization of microtubules and
      alteration of intracellular metabolic pathways contribute to AD pathogenesis
      independent of toxicity triggered by the aberrant tau deposits.

PMID- 12472908
TI  - Inflammatory bowel disease: new insights into pathogenesis and treatment.
AB  - Despite all the advances in our understanding of the pathophysiology of
      inflammatory bowel disease (IBD), we do not know the cause. Some of the most
      recently available data have been discussed here and yet it is now becoming
      increasingly accepted that immunogenetics play an important role in the
      predisposition, modulation, and perpetuation of IBD. The mucosal immune system is
      the central effector of intestinal inflammation and injury, with cytokines
      playing a central role in modulating inflammation. The role of intestinal milium,
      and enteric flora in particular, appears to be of greater significance than
      previously held. A review is made of the main areas of research exploring the
      mechanisms more intimately associated with the development of IBD, providing
      advances in the agents currently used, and identifying a host of new therapeutic
      agents potentially interacting with or interrupting specific targets in the
      genesis of IBD.

PMID- 12472909
TI  - Folic acid enhances endothelial function and reduces blood pressure in smokers: a
      randomized controlled trial.
AB  - OBJECTIVE: Cigarette smoking is associated with increased plasma homocysteine
      concentrations, endothelial dysfunction and arterial stiffening. Homocysteine per
      se induces endothelial dysfunction and arterial stiffening and might account, at
      least partly, for the vascular abnormalities observed in smokers. We sought to
      determine whether folic acid supplementation, by reducing plasma homocysteine
      concentrations, enhanced endothelial function and reduced arterial stiffness in
      smokers. DESIGN: Double-blind, randomized controlled, parallel-group, trial.
      SETTING: Academic medical centre. SUBJECTS: A consecutive sample of 24 healthy
      cigarette smokers (age 37.8 +/- 2.5 years, mean +/- SEM). INTERVENTION: Subjects
      were randomly assigned to 4-week folic acid 5 mg day-1 or placebo. MAIN OUTCOME
      MEASURES: The following were measured before and after treatment: (i) peripheral
      vasoreactivity (forearm arterial blood flow, FABF) during intra-arterial
      administration of endothelium-dependent (acetylcholine 1.5, 4.5 and 15 microg min
      1) and endothelium-independent (sodium nitroprusside 1, 2 and 4 microg min-1)
      vasodilators; (ii) carotid-femoral pulse-wave velocity (PWV); (iii) blood
      pressure (BP). RESULTS: Folic acid reduced homocysteine concentrations (10.8 +/-
      0.6 vs. 8.2 +/- 0.5 micromol L-1, P < 0.001) and enhanced endothelium-dependent
      vasodilatation during each acetylcholine infusion rate (ratio between the FABF in
      the infused and control arm during increasing infusion rates at baseline 1.09 +/-
      0.03 vs. 1.41 +/- 0.09 after treatment, P < 0.01; 1.39 +/- 0.07 vs. 1.83 +/-
      0.12, P < 0.01; 1.65 +/- 0.16 vs. 2.72 +/- 0.36, P < 0.05) whilst endothelium
      independent vasodilatation was unaffected. A significant fall in BP was also
      observed (mean BP 88 +/- 2 vs. 83 +/- 1 mmHg, P < 0.01). By contrast, PWV did not
      significantly change (8.4 +/- 0.3 vs. 7.8 +/- 0.4 m s-1). No significant changes
      in plasma homocysteine concentrations, FABF, BP, and PWV were observed in the
      placebo group. A multiple regression analysis showed that changes in folic acid
      plasma concentrations independently predicted both FABF changes during maximal
      acetylcholine-mediated vasodilatation (P < 0.01) and BP changes (P = 0.01).
      CONCLUSIONS: Short-term folic acid supplementation significantly enhanced
      endothelial function and reduced BP in young chronic smokers. These effects were
      largely independent from the homocysteine lowering effects. Thus, a simple,
      nontoxic, and relatively inexpensive vitamin intervention might be useful in
      primary cardiovascular prevention in this high-risk group.

PMID- 12472910
TI  - A plasma glucose concentration below 2.5 mmol L-1 is not an appropriate criterion
      to end the 72-h fast.
AB  - CONTEXT: The classical end-point to terminate the 72-h fast in a patient
      evaluated for a hypoglycaemic disorder is the occurrence of hypoglycaemic
      symptoms in association with a low plasma glucose level. However, neither the
      symptoms nor the plasma glucose level have been exactly defined. OBJECTIVE: To
      determine whether a useful cut-off plasma glucose concentration as criterion to
      end the prolonged fast in the absence of neuroglycopenic symptoms can be defined.
      DESIGN: Single centre case-control study. SETTING: Tertiary referral hospital in
      Switzerland. SUBJECTS: The 72-h fast was prospectively performed in 23
      consecutive patients (17 women and six men) following a standardized protocol
      between July 1999 and January 2002. All patients were referred to our clinic for
      evaluation of suspected hypoglycaemia. The criterion to end the fast before 72 h
      was defined by the occurrence of symptoms or signs typical for neuroglycopenia
      irrespective of plasma glucose levels. MAIN OUTCOME MEASURE: Insulin levels and
      insulin to plasma glucose ratios in insulinoma patients and in individuals
      without insulin-secreting tumours at termination of the fast and at plasma
      glucose levels </=2.5 mmol L-1, prior to the occurrence of neuroglycopenic
      symptoms. RESULTS: In seven patients, the fast was terminated before 72 h because
      they developed neuroglyco-penic symptoms. Insulin-secreting tumours were found
      and successfully removed in these seven patients. Sixteen individuals developed
      no neuroglycopenic symptoms throughout the 72-h fast and an insulin-secreting
      tumour could be excluded in these 16 patients. Five of these 16 individuals had
      plasma glucose levels </=2.5 mmol L-1 during the 72-h fast. Insulin levels and
      insulin to glucose ratios in insulinoma patients and healthy individuals
      overlapped during as well as at termination of the fast. Prior to the occurrence
      of neuroglycopenic symptoms and at venous plasma glucose </=2.5 mmol L-1, insulin
      to plasma glucose ratios dropped in insulinoma patients to values within the
      normal range on several occasions. CONCLUSIONS: Terminating the fast at plasma
      glucose levels </=2.5 mmol L-1 does not allow confirmation or exclusion of an
      insulin-secreting tumour. Thus, the occurrence of symptoms or signs typical for
      neuroglycopenia is the prerequisite criterion to end the fast before 72 h.

PMID- 12472911
TI  - Nosocomial enterococcal endocarditis: a serious hazard for hospitalized patients
      with enterococcal bacteraemia.
AB  - OBJECTIVES: Enterococci are a major leading cause of infectious endocarditis and
      also a common cause of hospital-acquired bacteraemia, which is not believed to
      represent a serious hazard for the endocarditis. The incidence and risk factors
      for infectious endocarditis in patients with hospital-acquired enterococcal
      bacteraemia is determined. METHODS: Prospective analysis of 116 patients with
      enterococcal bacteraemia admitted to medical or surgical wards of a tertiary
      care, university affiliated hospital during a period of 5 years. Echocardiography
      was performed when indicated by clinical criteria. RESULTS: Seventy-five (61.4%)
      episodes were hospital-acquired and 47 (38.5%) were community-acquired. Most
      patients had one or more underlying chronic diseases and major abdominal (58.6%)
      or genitourinary (38.6%) surgery. Seventeen patients (14.6%) developed
      enterococcal endocarditis. By univariate analysis the risk factors associated
      with endocarditis were community-acquired infection (P 0.012); monomicrobial
      bacteraemia (P 0.006); three or more positive blood cultures (P < 0.001);
      underlying valvulopathy (P < 0.001); presence of a prosthetic valve (P < 0.001)
      and age (P 0.012). Six patients (8%) developed nosocomial endocarditis. In this
      group of patients, three or more positive blood cultures (P < 0.01), bacteraemia
      as a result of Enterococcus faecalis (P 0.007); underlying valvulopathy (P <
      0.001) and presence of a prosthetic valve (P < 0.001) were associated with
      endocarditis. By logistic regression, the presence of underlying valvulopathy and
      three or more positive blood cultures were associated with endocarditis (OR 21.0;
      CI 95% 1.65-26.9; P 0.019). CONCLUSIONS: The risk of developing infectious
      endocarditis in patients with hospital-acquired enterococcal bacteraemia is
      significant. Patients with underlying valvulopathy and three or more positive
      blood cultures with E. faecalis are prone to nosocomial enterococcal
      endocarditis.

PMID- 12472912
TI  - Acquired platelet dysfunction may be an aetiologic factor in Heyde's syndrome-
      normalization of bleeding time after aortic valve replacement.
AB  - BACKGROUND: There is a well-documented relationship, with unknown aetiology,
      between aortic valve stenosis and occult gastrointestinal bleeding in elderly
      patients. Despite several studies attempting to determine the prevalence and to
      discuss the aetiology, there are still many unanswered questions. METHODS: A
      total of 288 consecutive patients with valvular aortic stenosis--mean age 73 +/-
      9 years aortic stenosis group (ASG)--were compared with 129 pacemaker-treated
      patients, mean age 73 +/- 9 years control group (CG). Screening for occult blood
      in stools was performed in both groups. Those with a positive Hemocult test or a
      history of gastrointestinal bleeding were scheduled for further examination
      including upper endoscopy and colonoscopy. Template bleeding time was performed
      on patients in both groups and in patients with a prolonged bleeding time with an
      extended coagulation evaluation was carried out. Patients referred to aortic
      valve replacement and with a preoperatively prolonged bleeding time were re
      examined after surgery. RESULTS: There was a significant difference in the number
      of subjects with prolonged bleeding time between groups (ASG 19; CG 2; P =
      0.028). Re-examination of the bleeding time after aortic valve surgery revealed
      normalized values in nine of 12 (P = 0.0003). The number of patients with
      positive Hemocult test did not differ between groups (ASG 29; CG 12; NS).
      Comparison of the pressure gradient over the aortic valve demonstrated a
      significantly higher maximal gradient amongst patients with a preoperatively
      prolonged bleeding time (113 mm HG vs. 90 mmHG; P = 0.005). CONCLUSION: Prolonged
      bleeding time is related to valvular aortic stenosis and seems to be caused by
      acquired platelet dysfunction. The normalization of the bleeding time after valve
      surgery supports the hypothesis that the calcified cusps may interact with the
      platelet function.

PMID- 12472913
TI  - Is low birth weight a risk factor for the development of diabetic nephropathy in
      patients with type 1 diabetes? A population-based case-control study.
AB  - OBJECTIVES: To investigate if low birth weight as a consequence of intrauterine
      malnutrition is a risk factor for the later development of diabetic nephropathy.
      DESIGN AND SUBJECTS: In a case-control set-up a group of type 1 diabetic subjects
      with diabetic nephropathy (n = 51) and a matched control group with normal kidney
      function (n = 51) were compared. Diabetic nephropathy and normal kidney function
      were defined as urinary albumin excretion rate above 200 microg min-1 and below
      20 microg min-1, respectively. The birth weights were all obtained from the
      midwives' original records. SETTING: The patients were identified from a
      population-based study of chronic diabetic complications in the Funen County,
      Denmark. MAIN OUTCOMES: Birth weights according to the presence of diabetic
      nephropathy. RESULTS: The median (10-90 percentile) birth weights were 3,600 g
      (2,960-4,274) in the group with diabetic nephropathy and 3,600 g (2,880-4,220) in
      the group without nephropathy, P = 0.52. In the lower quartile of birth weights
      the median (10-90 percentile) birth weights were 3,000 g (2,780-3,200) in the
      group with nephropathy versus 2,850 g (2,250-3,175) in the group without
      nephropathy, P = 0.07. In the upper quartile the median (10-90 percentile) birth
      weights were 4,225 g (4,000-4,741) in the nephropathy group and 4,000 g in the
      group without nephropathy, P = 0.13. We found no significant correlation between
      birth weights and log urinary albumin excretion rate (r = 0.148, P = 0.14) and no
      difference in the number of patients with nephropathy in the lower versus upper
      quartiles of birth weights. CONCLUSION: We found no evidence of low birth weight
      as a risk factor for the development of diabetic nephropathy.

PMID- 12472914
TI  - Sudden cardiac death in 15-35-year olds in Sweden during 1992-99.
AB  - OBJECTIVES: To study the incidence, pathogenesis and symptoms preceding sudden
      cardiovascular death amongst 15-35-year olds without substance abuse in Sweden
      during 1992-99. DESIGN: This was a register study of a national database of
      forensic medicine, Rattsbase. Clinical details were obtained from forensic,
      police and medical records and from interviews with family members. SETTING: The
      whole nation of Sweden. SUBJECTS: Individuals having suffered a sudden cardiac
      death. RESULTS: We found 181 cases of sudden cardiovascular death in a nationwide
      database, Rattsbase, in 15-35-year olds, of which 132 (73%) were male and 49
      (27%) were female, and a rather stable incidence of 0.93 per 100,000 per year.
      Preceding symptoms were seen in half of the cases. The most common forensic
      diagnoses were: no structural abnormality (21.0%), coronary atherosclerosis
      (17.7%), dilated cardiomyopathy (12.2%), hypertrophic cardiomyopathy (10.5%) and
      myocarditis (10.5%). CONCLUSION: Sudden cardiovascular death was uncommon in the
      young, but the incidence was not decreasing. Postmortem diagnoses were often
      difficult to establish. There was a high frequency of structurally normal hearts.
      Because premortal cardiac-related symptoms are relatively common and treatment
      methods are developing, we should learn to recognize early symptoms of heart
      disease. To identify individuals at risk, further studies of preceding symptoms,
      life-style factors and electrocardiogram (ECG) changes are needed.

PMID- 12472915
TI  - Longitudinal bone loss in postmenopausal women with primary biliary cirrhosis and
      well-preserved liver function.
AB  - OBJECTIVES/DESIGN: Increased rate of bone loss has been reported in women with
      primary biliary cirrhosis (PBC) and varying degree of liver dysfunction. Whether
      bone loss is increased in patients without liver dysfunction is unclear. The aim
      of this study was to estimate retrospectively the rate of bone loss in
      postmenopausal women with PBC and well-preserved liver function.
      SUBJECTS/INTERVENTIONS: Forty-three women with PBC, and classified as Child-Pugh
      class A, were included. Bone mineral density (BMD) was measured by dual energy X
      ray absorptiometry at the lumbar spine and the femoral neck. RESULTS: Median time
      between measurements of BMD was 26 months (range, 12-48 months). Twenty women
      were not receiving any bone protective treatment, i.e. hormone replacement
      therapy (HRT), bisphosphonates or vitamin D/calcium supplementation, whilst 23
      women received such treatment. Mean annual bone loss in the former group was 0.38
      +/- 2.56% and 0.42 +/- 2.29% at the lumbar spine and the femoral neck,
      respectively. Women receiving treatment, however, increased their BMD by 1.92 +/-
      3.76% and 0.15 +/- 2.75% at the lumbar spine and the femoral neck, respectively.
      At the lumbar spine the difference with regard to changes in BMD between
      untreated and treated women was statistically significant (P = 0.02). Women who
      received HRT (n = 11) increased their BMD at the lumbar spine by 2.95 +/- 3.91%,
      P = 0.03 when compared with untreated women. CONCLUSION: Bone loss in
      postmenopausal women with PBC and well-preserved liver function is not increased
      above normal. Treatment with bone protective treatment, mainly HRT, improves BMD
      at the lumbar spine.

PMID- 12472916
TI  - Obesity and myocardial infarction--vulnerability related to occupational level
      and marital status. A 23-year follow-up of an urban male Swedish population.
AB  - BACKGROUND: People, who are single, have a blue-collar job or low income have an
      increased cardiovascular risk. This study on myocardial infarction sought to
      explore whether the socio-economic pattern of disease has any relationship with
      obesity. METHODS: In the cohort are 20,099 middle-aged men of whom 9,150 were
      manual and 9,190 nonmanual workers and 1,759 were self-employed. A total of 4,081
      were single, 16,018 cohabiting. The body mass index (BMI) cut-off values for
      overweight and obesity were 25-30 and >/=30 kg m-2, respectively. Local and
      national registers were used to monitor incidence of events over 18 years.
      RESULTS: Obesity was associated with an increased incidence of coronary events
      and deaths in each occupational group. Being single significantly increased the
      risk associated with obesity. After stratification for civil status the risk
      associated with obesity was limited to those who were single and who either had a
      blue-collar job or were self-employed. The multivariate-adjusted relative risk
      (RR) of coronary events and deaths in obese manual workers who were single was
      1.91 (95% confidence interval: 1.21-3.02) and 2.54 (1.74-3.69), respectively,
      times higher than it was amongst those who were cohabiting. Amongst those who
      were self-employed, the corresponding age-adjusted RRs were 4.79 (1.69-13.57) and
      3.80 (1.62-8.93). CONCLUSIONS: Adjusted for lifestyle and biological risk
      factors, the increased risk of coronary events and death for obese men with
      manual jobs was applicable only to those who were single. It is concluded that
      being single significantly increases the cardiovascular risk associated with
      obesity.

PMID- 12472918
TI  - Significant predictors of poor prognosis in women aged </=65 years hospitalized
      for an acute coronary event.
AB  - OBJECTIVES: The aim of this study was to evaluate the importance of different
      clinical parameters predicting long-term cardiac prognosis in younger women with
      an acute coronary event. DESIGN: The Stockholm Female Coronary Risk Study is a
      follow-up study in women </=65 years. SETTING: Patients were included between
      1991 and 1994 from all 10 coronary care or intensive care units in the greater
      Stockholm area. SUBJECTS: A total of 335 consecutive female patients hospitalized
      for an acute coronary event. MAIN OUTCOME MEASURES: Cardiac death and nonfatal
      myocardial infarction (AMI). RESULTS: During the follow-up period of 5 years
      there were 26 (8%) all cause deaths and 39 (12%) recurrent cardiac events. In the
      group that participated in the complete study, the following age adjusted
      parameters were found as strong predictors of adverse outcome: AMI as index event
      [Hazard Ratio (HR) 9.13, 95% CI 3.09-26.99], diabetes mellitus (HR 4.13, 95% CI
      1.68-10.17), left ventricular dysfunction (HR 3.94, 95% CI 1.52-10.17), serum HDL
      cholesterol <1.0 mmol L-1 (HR 4.01, 95% CI 1.62-6.12), and serum triglycerides
      >2.0 mmol L-1 (HR 2.46, 95% CI 1.06-5.54). AMI as index event and diabetes
      mellitus were the most significant predictors in a multivariate statistical
      model. Diabetes mellitus was the strongest predictor when the analysis was
      repeated in the total patient cohort, integrating patients that did not
      participate in the extended investigations. CONCLUSION: Women aged </=65-year-old
      hospitalized for an acute coronary event has a low rate of cardiac events during
      the following 5-year period. Easily obtained clinical variables such as diabetes
      mellitus predict adverse prognosis and implicates a need for a more active
      diagnostic and treatment strategy.

PMID- 12472917
TI  - Risk factors for coronary heart disease in 55- and 35-year-old men and women in
      Sweden and Estonia.
AB  - OBJECTIVE: To illustrate the geographical West-to-East division of coronary heart
      disease (CHD) by comparing a population from Sweden, that represents a Western
      country to a population from Estonia, that represents an Eastern country. Estonia
      has an approximately 2-4-fold higher CHD prevalence for 55-year-old women and
      men, respectively, than Sweden. DESIGN: Randomized screening of 35- and 55-year
      old men and women in Sollentuna county, Sweden and Tartu county, Estonia. Eight
      hundred subjects, 100 from each cohort, were invited to participate in the study,
      272 Swedes and 277 Estonians participated. SETTING: Preventive cardiology,
      administered by a primary health care centre at the Karolinska Hospital, Sweden
      and a cardiology centre at Tartu University Hospital, Estonia. MAIN OUTCOME
      MEASURES: The CHD risk factors (smoking, blood pressure, concentrations of
      lipoproteins, fibrinogen, and glucose) and certain environmental factors and
      attitudes related to CHD risk by questionnaires (fat-type and alcohol ingestion,
      self-assessed rating of CHD susceptibility). RESULTS: Of the 55-year-old men, 57%
      smoked in Estonia and 20% smoked in Sweden. Similar, although less pronounced
      differences showing higher smoking prevalence, were seen for 35-year-old Estonian
      men and women, whilst for 55-year-old women, less than 20% smoked in either
      country. Estonian 55-year-old women had lower HDL cholesterol and higher LDL
      cholesterol serum concentrations than Swedish 55-year-old women. Estonians
      reportedly ate food containing more saturated fats than Swedes, as indicated by
      the scale-score questionnaire. Estonians, relative to Swedes, rated their chance
      of developing CHD higher, and paradoxically, Estonians did to a much lesser
      degree believe that life style influences the risk of developing CHD.
      CONCLUSIONS: Elevated smoking prevalence is a striking difference between the
      Estonian and Swedish populations likely to explain the much higher CHD prevalence
      in Estonian men. The lower HDL cholesterol and higher LDL cholesterol in Estonian
      55-year-old women may explain the higher CHD prevalence in Estonian women.
      Furthermore, the SWESTONIA CHD study (i.e. comparison between Sweden and Estonia)
      shows several environmental differences between the countries populations related
      to fat content in food, alcohol drinking patterns, and views on CHD risk and the
      importance of lifestyle intervention, that could contribute to the higher CHD
      prevalence in Estonia.

PMID- 12472919
TI  - Bezafibrate-induced improvement in glucose uptake and endothelial function in
      protease inhibitor-associated insulin resistance.
AB  - Protease inhibitors used as therapy for HIV-1 infection have been associated with
      metabolic side-effects such as peripheral fat wasting, central adiposity,
      hyperlipidaemia and insulin resistance. This metabolic disorder is known as the
      lipodystrophy syndrome. This syndrome can be recognized by the early appearance
      of an increase in serum triglyceride, cholesterol and plasma-free fatty acid
      levels. Here, we describe an HIV-1 positive patient with the lipodystrophy
      syndrome in whom a decline in serum triglycerides was seen along with a
      significant improvement in glucose uptake following treatment with bezafibrate
      for 3 months. This improvement may be a consequence of the Randle effect, i.e.
      increased availability of plasma-free fatty acids is negatively correlated to
      glucose uptake. We also noted a significant improvement in endothelial-dependent
      flow-mediated dilatation after treatment with bezafibrate. This effect could
      result from the increased glucose uptake observed and a decrease in insulin
      resistance secondary to the lowered triglyceride levels by bezafibrate. We
      conclude that bezafibrate may be of clinical utility in the lipodystrophy
      syndrome, through its beneficial effects on insulin resistance, glucose uptake
      and endothelial dysfunction.

PMID- 12472920
TI  - D-dimer test in deep vein thrombosis.

PMID- 12472922
TI  - Dietary prevention of carcinogenesis in smokers.

PMID- 12472924
TI  - Is primary angioplasty for some as good as primary angioplasty for all?
AB  - OBJECTIVES: To investigate whether proper patient selection might allow most of
      the benefits of population-wide primary coronary angioplasty to be captured in a
      subgroup of high-risk patients. BACKGROUND: Despite growing evidence that
      angioplasty yields better outcomes, thrombolytic therapy remains the most common
      form of reperfusion therapy in acute myocardial infarction (AMI) because of
      limited capacity for primary coronary angioplasty at most hospitals. METHODS: We
      used a validated logistic regression model, based on individual patient
      characteristics, to estimate the distribution of mortality risk in a community
      based sample of 1,058 patients who received reperfusion therapy for AMI. To
      estimate the benefits across different baseline risks, we examined the results of
      10 randomized controlled trials using meta-regression techniques. RESULTS:
      Assuming a constant relative risk reduction, 68% of all mortality benefits in our
      community-based patient sample could be captured by treating only those patients
      in the highest quartile of mortality risk and 87% of the benefit could be
      captured by treating those in the highest half. Moreover, meta-regression of the
      results from the 10 clinical trials suggests that patients with a mortality risk
      of less than 2% may be unlikely to receive any mortality benefit. With this risk
      benefit relationship, treatment of only the 39% of patients with the highest risk
      would yield equivalent mortality outcomes to population-wide angioplasty.
      CONCLUSION: Most of the incremental benefits of primary angioplasty can be
      achieved by treating high-risk patients. For these patients, thrombolytic therapy
      may be difficult to justify if nearby primary angioplasty is available. For most
      patients, however, thrombolytic therapy appears to be an effective alternative.

PMID- 12472925
TI  - Atherosclerotic risk factor reduction in peripheral arterial diseasea: results of
      a national physician survey.
AB  - OBJECTIVE: Individuals with peripheral arterial disease (PAD) have a 3- to 6-fold
      increased risk of coronary heart disease and stroke compared to those without
      PAD. We documented physician-reported practice behavior, knowledge, and attitudes
      regarding atherosclerotic risk factor reduction in patients with PAD. DESIGN:
      National physician survey. PATIENTS/PARTICIPANTS: General internists (N = 406),
      family practitioners (N = 435), cardiologists (N = 473), and vascular surgeons (N
      = 264) randomly identified using the American Medical Association's physician
      database. MEASUREMENTS AND MAIN RESULTS: Physicians were randomized to 1 of 3
      questionnaires describing a) a 55- to 65-year-old patient with PAD; b) a 55- to
      65-year-old patient with coronary artery disease (CAD), or c) a 55- to 65-year
      old patient without clinically evident atherosclerosis (no disease). A mailed
      questionnaire was used to compare physician behavior, knowledge, and attitude
      regarding risk factor reduction for each patient. Rates of prescribed
      antiplatelet therapy were significantly lower for the patient with PAD than for
      the patient with CAD. Average low-density lipoprotein levels at which physicians
      "almost always" initiated lipid-lowering drugs were 121.6 +/- 23.5 mg/dL, 136.3
      +/- 28.9 mg/dL, and 149.7 +/- 24.4 mg/dL for the CAD, PAD, and no-disease
      patients, respectively (P <.001). Physicians stated that antiplatelet therapy (P
      <.001) and cholesterol-lowering therapy (P <.001) were extremely important
      significantly more often for the CAD than for the PAD patient. Perceived
      importance of risk factor interventions was highly correlated with practice
      behavior. Compared to other specialties, cardiologists had lowest thresholds,
      whereas vascular surgeons had the highest thresholds for initiating cholesterol
      lowering interventions for the patient with PAD. Cardiologists were significantly
      more likely to report "almost always" prescribing antiplatelet therapy for the
      patient with PAD than were all other physicians. CONCLUSIONS: Deficiencies in
      physician knowledge and attitudes contribute to lower rates of atherosclerotic
      risk factor reduction for patients with PAD. Reversing these deficiencies may
      reduce the high rates of cardiovascular morbidity and mortality associated with
      PAD.

PMID- 12472926
TI  - Insurance and quality of care for adults with acute asthma.
AB  - OBJECTIVE: The relationship between health care insurance and quality of medical
      care remains incompletely studied. We sought to determine whether type of patient
      insurance is related to quality of care and subsequent outcomes for patients who
      arrive in the emergency department (ED) for acute asthma. DESIGN: Using
      prospectively collected data from the Multicenter Airway Research Collaboration,
      we compared measures of quality of pre-ED care, acute severity, and short-term
      outcomes across 4 insurance categories: managed care, indemnity, Medicaid, and
      uninsured. SETTING AND PARTICIPANTS: Emergency departments at 57 academic medical
      centers enrolled 1,019 adults with acute asthma. RESULTS: Patients with managed
      care ranked first and uninsured patients ranked last on all 7 unadjusted quality
      measures. After controlling for covariates, uninsured patients had significantly
      lower quality of care than indemnity patients for 5 of 7 measures and had lower
      initial peak expiratory flow rates than indemnity insured patients. Patients with
      managed care insurance were more likely than indemnity-insured patients to
      identify a primary care physician and report using inhaled steroids in the month
      prior to arrival in the ED. Patients with Medicaid insurance were more likely
      than indemnity-insured patients to use the ED as their usual source of care for
      problems with asthma. We found no differences in patient outcomes among the
      insurance categories we studied. CONCLUSIONS: Uninsured patients had consistently
      poorer quality of care and than insured patients. Despite differences in
      indicators of quality of care between types of insurance, we found no differences
      in short-term patient outcomes by type of insurance.

PMID- 12472927
TI  - The good news about giving bad news to patients.
AB  - BACKGROUND: There are few data available on how physicians inform patients about
      bad news. We surveyed internists about how they convey this information. METHODS:
      We surveyed internists about their activities in giving bad news to patients. One
      set of questions was about activities for the emotional support of the patient
      (11 items), and the other was about activities for creating a supportive
      environment for delivering bad news (9 items). The impact of demographic factors
      on the performance of emotionally supportive items, environmentally supportive
      items, and on the number of minutes reportedly spent delivering news was analyzed
      by analysis of variance and multiple regression analysis. RESULTS: More than half
      of the internists reported that they always or frequently performed 10 of the 11
      emotionally supportive items and 6 of the 9 environmentally supportive items
      while giving bad news to patients. The average time reportedly spent in giving
      bad news was 27 minutes. Although training in giving bad news had a significant
      impact on the number of emotionally supportive items reported (P <.05), only 25%
      of respondents had any previous training in this area. Being older, a woman,
      unmarried, and having a history of major illness were also associated with
      reporting a greater number of emotionally supportive activities. CONCLUSIONS:
      Internists report that they inform patients of bad news appropriately. Some
      deficiencies exist, specifically in discussing prognosis and referral of patients
      to support groups. Physician educational efforts should include discussion of
      prognosis with patients as well as the availability of support groups.

PMID- 12472929
TI  - Assessment and reporting of perioperative cardiac risk by Canadian general
      internists: art or science?
AB  - OBJECTIVE: Physicians may use several validated risk indices to estimate
      perioperative cardiac risk, but there is little evidence for interventions to
      reduce this risk. We were interested in evaluating how general internists assess,
      define, communicate, and attempt to modify perioperative cardiac risk. DESIGN:
      Cross-sectional survey of all 312 general internists in the Canadian Society of
      Internal Medicine with Canadian mailing addresses; 117 (38%) responded. RESULTS:
      Respondents' mean age was 46 years, 79% were male, and on average they did 17
      preoperative consults per month. Of the 104 respondents who routinely performed
      preoperative assessments, 96% (100/104) informed patients of their perioperative
      cardiac risk, but 77% did so only subjectively (i.e., stating risk as low,
      moderate, or high). Respondents provided 8, 27, and 12 different definitions for
      low, moderate, and high risk, respectively, with marked variability in the range
      of definitions they provided: from <1% to < 20% for "low risk," from 1% to 2% to
      20% to 50% for "moderate risk," and from >2% to >50% for "high risk." The 67% of
      respondents who reported using a perioperative cardiac risk index used a variety
      of indices and exhibited just as much variability in their risk estimates and
      definitions as those who didn't use risk indices. While virtually all advised
      perioperative beta blockade in patients with known coronary artery disease, they
      varied substantially in the recommended agent or dose; further, these internists
      were evenly split on whether antiplatelet agents should be held or continued
      perioperatively. CONCLUSIONS: These physicians differed widely in their
      assessment of perioperative cardiac risk and their definitions of low, moderate,
      or high risk. This raises concerns about whether patients (and surgeons) are
      provided with adequate information to make fully informed decisions about the
      potential risks of elective surgical operations.

PMID- 12472928
TI  - Protein-energy undernutrition and life-threatening complications among the
      hospitalized elderly.
AB  - OBJECTIVE: To determine whether elderly patients with protein-energy
      undernutrition at admission are at increased risk for subsequent life-threatening
      events after controlling for illness severity. DESIGN: Prospective cohort study.
      SETTING: University-affiliated Department of Veterans Affairs hospital. PATIENTS:
      Five hundred eighty-six nonterminal patients (mean age 74 +/- 6 [SD] years, 98%
      male, 86% white) with a length of stay of 3 days or more. MAIN OUTCOME MEASURES:
      Life-threatening complications. RESULTS: Subsequent to admission, 37 subjects
      (6.3%) experienced at least 1 life-threatening complication. All of the putative
      nutrition variables examined and many non-nutrition, illness severity measures
      were strongly correlated with the risk of a life-threatening complication by
      univariate analyses (P <.05 for all analyses). After controlling for illness
      severity, admission serum albumin, prealbumin, and cholesterol were no longer
      significantly correlated with the outcome. In contrast, weight loss (>5% within 6
      months), body mass index, mid-arm circumference, and suprailiac skinfold
      thickness remained strong independent predictors. The adjusted relative risk of a
      life-threatening complication ranged from 2.9 (95% confidence interval [CI], 1.3
      to 6.4) for a body mass index <22 kg/m2 to 7.1(95% CI, 2.0 to 25.7) for a
      suprailiac skinfold thickness in the lower tertile for the study population. The
      putative nutrition and illness severity variables were highly intercorrelated.
      CONCLUSIONS: There is a complex interrelationship between nutritional status,
      illness severity, and clinical outcomes among the hospitalized elderly. The serum
      secretory proteins and cholesterol are correlated with other indicators of
      illness severity and adverse outcomes, but may not be good markers of nutritional
      risk. In contrast, weight loss, a low body mass index, and other indicators of
      lean and fat mass depletion appear to place the patient at increased risk for
      adverse outcomes independent of illness severity. Whether it is possible to
      reverse such established nutritional deficits and reduce complication risk in the
      acute care setting remains to be determined.

PMID- 12472930
TI  - Management of patients with hypertensive urgencies and emergencies: a systematic
      review of the literature.
AB  - BACKGROUND: Hypertensive urgencies and emergencies are common clinical
      occurrences in hypertensive patients. Treatment practices vary considerably to
      because of the lack of evidence supporting the use of one therapeutic agent over
      another. This paper was designed to review the evidence for various
      pharmacotherapeutic regimens in the management of hypertensive urgencies and
      emergencies, in terms of the agents' abilities to reach predetermined "safe" goal
      blood pressures (BPs), and to prevent adverse events. METHODS: medline was
      searched from 1966 to 2001, and the reference lists of all the articles were
      retrieved and searched for relevant references, and experts in the field were
      contacted to identify other relevant studies. The Cochrane Library was also
      searched. Studies that were eligible for inclusion in this review were systematic
      reviews of randomized control trials (RCTs) and individual RCTs, all-or-none
      studies, systematic reviews of cohort studies and individual cohort studies, and
      outcomes research. No language restrictions were used. RESULTS: None of the
      trials included in this review identified an optimal rate of BP lowering in
      hypertensive emergencies and urgencies. The definitions of hypertensive
      emergencies and urgencies were not consistent, but emergencies always involved
      target end-organ damage, and urgencies were without such damage. Measures of
      outcome were not uniform between studies. The 4 hypertensive emergency and 15
      hypertensive urgency studies represented 236 and 1,074 patients, respectively.
      The evidence indicated a nonsignificant trend toward increased efficacy with
      urapidil compared to nitroprusside for hypertensive emergencies (number needed to
      treat [NNT] for urapidil to achieve target BP, 12; 95% confidence interval [95%
      CI], number of patients needed to harm [NNH], 5 to NNT, 40 compared to
      nitroprusside). Several medications were efficacious in treating hypertensive
      urgencies, including: nicardipine (NNT for nicardipine compared to plabebo, 2 in
      one study [95% CI, 1 to 5] and 1 in another [95% CI, 1 to 1]); lacidipine (NNT,
      2; 95% CI, 1 to 8 for lacidipine vs nifedipine) or urapidil (NNT for urapidil
      compared to enalaprilat and nifedipine, 4; 95% CI, 3 to 6); and nitroprusside and
      fenoldopam (all patients reached target BP in 2 studies). The studies reported 2
      cases of cerebral ischemia secondary to nifedipine. CONCLUSIONS: Many effective
      agents exist for the treatment of hypertensive crises. Because of the lack of
      large randomized controlled trials, many questions remain unanswered, such as
      follow-up times and whether any of the studied agents have mortality benefit.

PMID- 12472931
TI  - Genetic testing for lung cancer risk: if physicians can do it, should they?
AB  - Advances in genetics have increased our ability to assess an individual's genetic
      risk for disease. There is a hypothesis that genetic test results will motivate
      high-risk individuals to reduce harmful exposures, to increase their surveillance
      for disease, or to seek preventive treatments. However, genetic testing for genes
      associated with an increased risk of lung cancer would not change physicians'
      recommendations regarding smoking cessation. Limited studies suggest that test
      results that demonstrate an increased risk of lung cancer do not improve smoking
      cessation success. These test results may even distort an individual's risk
      perceptions. Before recommending genetic testing to assess risk for disease,
      physicians need to consider whether knowledge about genetic susceptibility will
      alter patient management.

PMID- 12472932
TI  - The best of JGIM.

PMID- 12472933
TI  - Malnutrition and bad outcomes.

PMID- 12472937
TI  - Summary and recommendations of single theme conferences on hepatitis B and C:
      Indian Association for Study of the Liver (INASL).

PMID- 12472938
TI  - Non-cirrhotic portal hypertension versus idiopathic portal hypertension.
AB  - Portal hypertension occurs in a number of disorders other than cirrhosis and they
      are collectively called non-cirrhotic portal hypertension (NCPH). The common
      causes of NCPH include idiopathic portal hypertension (IPH), non-cirrhotic portal
      fibrosis (NCPF) and extrahepatic portal venous thrombosis (EHPVT). Other causes
      include schistosomiasis, hepatic venous outflow tract obstruction, veno-occlusive
      disease and congenital hepatic fibrosis. Patients with IPH and EHPVT present with
      upper gastrointestinal bleeding, splenomegaly, ascites after gastrointestinal
      bleeding, features of hypersplenism, growth retardation and jaundice due to
      portal biliopathy. The diagnosis is usually made by abdominal ultrasound, upper
      gastrointestinal endoscopy, normal liver function tests and normal liver
      histology. Variceal bleeding in NCPH has lower mortality as compared with
      cirrhosis because of better liver functions in NCPH. Treatment for NCPH includes
      primary prophylaxis for variceal bleeding and prevention of repeat bleeding using
      drugs like beta-blockers, endoscopic sclerotherapy and endoscopic band ligation
      of varices. In patients with uncontrolled variceal bleeding or symptomatic
      hypersplenism, porto-systemic shunt surgery or splenectomy are required.

PMID- 12472939
TI  - Non-cirrhotic portal fibrosis.
AB  - Non-cirrhotic portal hypertension (NCPH) comprises of diseases having an increase
      in portal pressure (PP) due to intraheptic or prehepatic lesions, in the absence
      of cirrhosis. The lesions are generally vascular, either in the portal vein, its
      branches or in the perisinusoidal area. Because the wedged hepatic venous
      pressure (WHVP) is near normal, measurement of intravariceal or intrasplenic
      pressure is needed to assess portal pressure. The majority of the diseases
      included in the category of NCPH are well characterized disease entities where
      portal hypertension (PHT) is a late manifestation and hence, these are not
      discussed. Two diseases which present only with features of PHT and are common in
      developing countries are NCPF and extra-hepatic portal vein obstruction (EHPVO).
      Non-cirrhotic portal fibrosis is a syndrome of obscure etiology, characterized by
      'Obliterative portovenopathy' leading to PHT, massive splenomegaly, repeated well
      tolerated episodes of variceal bleeding and anemia in young adults from low socio
      economic strata of life. The hepatic parenchymal functions are nearly normal.
      Jaundice, ascites and hepatic encephalopathy are rare. Management of variceal
      bleeding remains the main concern as nearly 85% of patients with NCPF present
      with variceal bleeding. Endoscopic variceal ligation or sclerotherapy are equally
      effective in about 90-95% of the patients. Gastric varices are seen in about 25%
      patients and a bleed from them can be managed with cyanoacrylate glue injection
      or surgery. Other indications for surgery include failure of endoscopic therapy
      to control acute bleed and symptomatic hypersplenism. The prognosis of patients
      with NCPF is good and 5-years survival rates in patients in whom variceal
      bleeding can be controlled is about > 95%.

PMID- 12472940
TI  - Spectrum of portal vein thrombosis in the West.

PMID- 12472941
TI  - Portal hypertension in children: an Indian perspective.

PMID- 12472942
TI  - Novel approaches to treat portal hypertension.

PMID- 12472943
TI  - Pathogenesis of ascites and predictors of resistance to therapy.
AB  - Ascites is one of the most frequent complications of cirrhosis. Its appearance is
      considered as the marker of the transition from the compensated to the
      decompensated stage of the disease. Appearance of ascites also has prognostic
      significance, as it causes a sharp drop in the expected survival rate. Portal
      hypertension is a sine qua-non for the development of ascites. Although no
      precise portal pressure threshold has been defined for the development of
      ascites, the latter rarely develops with portal pressures below 12 mmHg. In
      addition, in patients treated with interventions that markedly decrease portal
      pressure, such as surgical porta-caval shunts or transjugular intrahepatic
      portalsystemic shunts, a disappearance or a marked reduction of ascites can be
      observed. The currently most accepted theory of ascites formation is the so
      called 'forward' theory. According to this theory, the development of ascites is
      related to the presence of severe sinusoidal portal hypertension, which causes
      marked splanchnic arterial vasodilation and a forward increase in the splanchnic
      production of lymph. Splanchnic arterial vasodilation also causes a significant
      reduction of the effective blood volume, leading to activation of sodium and
      water-retaining mechanisms. The retained sodium and water, however, while
      increasing total plasma volume, are unable to compensate for the reduced
      effective blood volume, initiating a vicious cycle. In the advanced stages of
      cirrhosis, the extreme underfilling of the arterial circulation leads to a
      maximal stimulation of the vasoconstrictor mechanisms which override the
      protective effect of renal vasodilator factors and cause renal vasoconstriction,
      further aggravating ascites and leading to functional renal insufficiency. Renal
      insufficiency is also one of the main causes of resistance to diuretic therapy.
      While several studies have investigated the predictors of survival in cirrhotic
      patients with ascites, this has not been done for the occurrence of resistance to
      therapy. However, as the mechanisms of refractoriness are associated with
      advanced disease and short survival, the models developed for predicting survival
      should be employed also to verify if they can exert such additional prediction.

PMID- 12472944
TI  - Hepatorenal syndrome.

PMID- 12472945
TI  - Portopulmonary hypertension and hepatopulmonary syndrome.

PMID- 12472946
TI  - Pathogenesis of hepatic encephalopathy.
AB  - Hepatic encephalopathy (HE) is a neuropsychiatric syndrome during the course of
      acute or chronic liver disease. It is functional in nature, potentially
      reversible and precipitated by rather heterogeneous factors. At the
      neurophysiological level HE is characterized by a low frequent cortico-cortical
      electrical coupling, which may explain the cognitive deficits and a low frequent
      corticomuscular coupling, which may explain the fine motor deficits. Current
      evidence suggests that HE is the consequence of a low grade chronic glial edema
      with subsequent alterations of glioneuronal communication. Different factors,
      such as ammonia, benzodiazepines, inflammatory cytokines can induce or aggravate
      astrocyte swelling, which results in the activation of osmosignaling cascades,
      protein modifications, alterations in gene expression and neurotransmission.
      Among the protein modifications nitration of critical tyrosine residues in glial
      proteins may play an important role. Several proteins, which are nitrated in
      response to ammonia, benzodiazepines, hypoosmotic astrocyte swelling or
      inflammatory cytokines have been identified, including glutamine synthetase and
      the peripheral type benzodiazepine receptor.

PMID- 12472947
TI  - Management of hepatic encephalopathy.
AB  - Hepatic encephalopathy (HE) is seen as a clinical manifestation of low grade
      chronic cerebral edema, which is accompanied by alterations in glioneural
      communication. Different factors such as ammonia, inflammatory cytokines,
      benzodiazepines and electrolyte imbalances may precipitate or aggravate glia
      edema, thereby explaining precipitation of HE episodes by a variety of unrelated
      factors. Recognition and rigorous treatment of these precipitating factors is the
      most important measure in HE therapy which may be augmented by dietary and
      medical approaches. Among these approaches, evidence for proven therapeutical
      efficacy in HE on the basis of placebo-controlled trials is existing only for
      transplantation, protein restriction, administration of vegetable proteins,
      ornithine-aspartate, oral branched-chain amino acid treatment as well as
      lactulose enemas. The efficacy of oral lactulose has not been demonstrated on the
      basis of placebo-controlled trials.

PMID- 12472948
TI  - Etiopathogenesis of acute hepatic failure: Eastern versus Western countries.
AB  - Etiopathogenesis of acute hepatic failure (AHF) in Eastern and Western countries
      is distinct. In the East hepatitis viruses cause AHF in more than 95% of such
      cases, while causes of AHF in the West are quite heterogenous. Hepatitis E virus
      is the major etiological agent of AHF in countries like India where the virus is
      hyperendemic. Occult HBV infection may also be causing AHF in a sizable
      proportion of cases in areas where chronic HBV infection frequency is high.
      Paracetamol causes AHF in about 70% cases in the UK and about 20% cases in USA,
      whereas in France and Denmark, non-steroidal anti-inflammatory drugs are more
      frequently associated with AHF. Hepatitis B virus causes AHF in about one-third
      of cases in the latter two countries.

PMID- 12472949
TI  - Treatment of patients with hepatic failure.

PMID- 12472950
TI  - Molecular adsorbent recirculating system: albumin dialysis-based extracorporeal
      liver assist device.
AB  - Extracorporeal liver assist devices have been used for more than five decades to
      support patients with liver failure. Numerous modifications have been made to
      both biological as well as mechanical liver assist devices. Possibly, an ideal
      liver assist device would be one that would perform optimal detoxification and
      synthetic functions of the liver, be simple to set up and yet be cost-effective.
      An albumin dialysis-based device that uses a hybrid albumin-impregnated membrane
      to get rid of albumin-bound toxins that circulate in abundance in liver failure,
      called the molecular adsorbent recirculating system (MARS) has been in clinical
      use for nearly four years now. Results with the use of this device in both acute
      and acute-on-chronic liver failure have shown consistent improvement in
      biochemical profile, resolution of encephalopathy, correction in hemodynamics,
      reduction in intracranial pressure and some improvement in the synthetic function
      of the liver. In a number of studies, albeit of small sample size, survival
      advantage has also been observed. The timing of initiation of therapy with MARS,
      duration of treatment, frequency of sessions and 'maintenance therapy' are still
      some of the unresolved issues with the use of this device. Large multicentric
      trials on the use of this technique are expected to throw light on these issues
      and help optimize the potential of this liver assist device.

PMID- 12472951
TI  - Hepatocyte transplantation.
AB  - Repopulation of the liver with transplanted cells holds significant promise for
      developing novel therapies. The liver is a most suitable target for treating a
      variety of genetic, metabolic and acquired diseases. Liver disease, such as
      chronic viral hepatitis, constitutes an enormous burden worldwide. Advancing
      liver cell therapy requires insights into mechanisms of cell engraftment and
      proliferation, as well as unique requirements of specific diseases for correction
      by cell transplantation. This review highlights recent developments in the area
      of hepatocyte transplantation. Aspects concerning modulation of cell engraftment,
      regulation of gene expression and proliferation of transplanted cells are
      discussed. Other issues concern the current status of clinical applications of
      hepatocyte transplantation, as well as novel sources of cells that could benefit
      cell therapy in the future. The general conclusion is that cell therapy has
      become more practical in recent years and insights into how the normal liver and
      the diseased liver can be repopulated will offer effective ways to treat many
      disorders in the near future.

PMID- 12472952
TI  - Liver transplantation.

PMID- 12472953
TI  - Scoring severity of chronic liver disease.

PMID- 12472954
TI  - Hepatic fibrosis: from bench to bedside.
AB  - Antifibrotic therapies are preferentially targeted to the activated mesenchymal
      cells in the liver that synthesize an excess of matrix proteins and resemble the
      myofibroblasts of healing wounds. These cells derive from normally quiescent
      hepatic stellate cells and (myo-) fibroblasts. Their activation is triggered and
      maintained by several fibrogenic modulators and cytokines, but also by mechanical
      stress. Whereas many agents inhibit stellate cell/myofibroblast proliferation and
      collagen synthesis in vitro, only few of them are tolerable or effective in
      suitable animal models in vivo. An antifibrotic effect was demonstrated for
      silymarin, a defined mixture of flavonoids, sho-saiko-to which contains the
      related compound baicalein, for halofuginone, another plant-derived agent, for
      the phosphodiesterase inhibitor pentoxifylline and for LU135252, an oral
      inhibitor of the endothelin-A-receptor. The retrospective finding that interferon
      alpha therapy for hepatitis C may halt or even reverse fibrosis, has to be
      confirmed in prospective randomized trials. Strategies to inhibit the
      profibrogenic cytokines transforming growth factor (TGF)-beta or connective
      tissue growth factor (e.g. by soluble decoy receptors) are evolving, but have not
      been convincing yet. Drug targeting to the fibrogenic liver cells is now possible
      by use of cyclic peptides that bind to receptors which are specifically up
      regulated on activated stellate cells, for example those for platelet-derived
      growth factors or collagen type VI. In addition, blockade of such activation
      receptors can induce stress-relaxation which reverts the fibrogenic cells to a
      fibrolytic, collagen degrading phenotype. Combined with the evolving validation
      of serological markers of fibrogenesis and fibrolysis an effective and
      individualized treatment of liver fibrosis can be anticipated.

PMID- 12472955
TI  - Antiviral treatment of patients with HBV-related cirrhosis.

PMID- 12472956
TI  - Hepatitis B e-antigen negative chronic hepatitis B.

PMID- 12472957
TI  - Clinical relevance of viral dynamics and genotypes in hepatitis B virus.
AB  - Advances in molecular diagnostic technology make it possible to accurately
      measure viral loads and this has allowed the detailed study of viral dynamics of
      HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV). Following antiviral
      therapy, there are at least two phases of viral load decay: one corresponding to
      clearance of free virions and a second, slower phase corresponding to eradication
      of infected cells. Application of mathematical models allows for the assessment
      of antiviral efficacy and improved design of therapeutic regimens. The clinical
      application of these tools should help optimize patient outcome. Another
      advantage of molecular diagnostics is characterization of the heterogeneity of
      viruses in particular patient populations under selective pressure situations.
      The HBV can be classified into seven major genotypes (A-G) that have mainly a
      geographic distribution. Recent genotypic studies have revealed the clinical and
      therapeutic relevance of viral genotyping in HBV infections.

PMID- 12472958
TI  - Immunogenetics of hepatitis B virus infection.

PMID- 12472959
TI  - Management of YMDD mutations during lamivudine therapy in patients with chronic
      hepatitis B.
AB  - Lamivudine is a nuleoside analog with potent inhibitory effects on hepatitis B
      virus (HBV) replication. Prolonged therapy is required for sustained suppression.
      However, HBV species with mutations in the tyrosine-methionine-aspartate
      aspartate (YMDD) locus of the HBV-RNA-dependent DNA polymerase confering
      resistance to lamivudine may emerge after 6-9 months therapy with an incidence of
      38% and 67% after 2 and 4 years of lamivudine therapy, respectively. During
      continued lamivudine therapy, patients with YMDD mutant HBV usually show serum
      alanine aminotransferase (ALT) and HBV-DNA elevations at lower median levels than
      their baseline. Marked flare of serum ALT or acute exacerbation may occurred as
      the results of cytotoxic T lymphocyte mediated immune response directed against
      YMDD mutant. Although viral clearance with or without emergence of distinct
      lamivudine resistant mutants may occur after such exacerbations, 20% of the
      exacerbations are complicated with decompensation or even fatality. The
      exacerbations appear to be more severe than those occur during the natural course
      of wild type HBV chronic infection. The current practice of continuing lamivudine
      therapy, therefore, requires careful evaluation. Alternatives include interferon
      therapy but this seems ineffective. Adefovir dipivoxil and entecavir may
      effectively suppress the YMDD mutant but these treatments have not yet been
      available for use. Recent studies have shown no benefit to continuing lamivudine
      therapy in patients with YMDD mutantions. Before a rescue drug becomes available,
      the most cost-effective strategy is to select patients with stronger endogenous
      anti-HBV immunity to increase efficacy and to shorten the duration of lamivudine
      therapy to avoid the emergence of YMDD mutations.

PMID- 12472960
TI  - Combination and newer therapies for chronic hepatitis B.
AB  - Worldwide the need for effective therapy for chronic hepatitis B is similar to
      that for chronic hepatitis C. Current licensed treatment for chronic hepatitis B
      (interferon (IFN)-alpha, lamivudine) does not significantly alter the natural
      history of the disease because the frequency of sustained response is too low;
      however, a sustained response to antiviral therapy improves survival. Conversion
      of active chronic hepatitis B to the inactive hepatitis B carrier state
      (persistently HBeAg-negative, HBV-DNA < 10(5) copies/mL and alanine
      aminotransferase (ALT) normal) is the major therapeutic goal. If present 6-12
      months after stopping treatment, a sustained response is assumed. Clinical
      benefit is also likely if HBV-DNA levels < 10(5) copies/mL and ALT normality are
      being maintained long-term by antiviral therapy. New drugs are adefovir,
      entecavir, and pegylated IFN. The two nucleoside analogs are active against
      lamivudine-resistant hepatitis B and are as yet not associated with resistance.
      Peg-IFN has higher efficacy than standard IFN; its tolerance is similar.
      Combination therapy appears most effective: IFN-lamivudine combination for
      induction of a sustained response, and lamivudine-adefovir for long-term
      antiviral therapy. Uncertainty exists whether the additional effect outweighs the
      burden of adverse effects and cost. Chronic hepatitis B affects a rather
      heterogeneous patient population. Differentiation based on HBeAg status is fading
      with emergence of categorization based on disease stage and immune competence.

PMID- 12472961
TI  - Molecular mechanisms of hepatitis virus-hepatocyte interactions.

PMID- 12472962
TI  - Polyethylene glycol-interferon: current status in hepatitis C virus therapy.
AB  - In chronic hepatitis C infection, combination therapy with interferon (IFN)-alpha
      and ribavirin leads to sustained virological response rates of 40-45%. However,
      treatment outcome is still disappointing in patients infected with hepatitis C
      virus (HCV) genotype 1, high viral load or advanced liver fibrosis. Due to
      significant side-effects of therapy, dose reductions and discontinuations of
      therapy are frequent and lead to further decreased response rates. The
      development of modified IFN is the latest step to improve treatment options for
      chronic hepatitis C. Conjugation of the polymer polyethylene glycol (PEG) to IFN
      extends half-life in comparison to conventional IFN and thereby increases
      antiviral activity. It allows once-weekly dosing and increases sustained response
      rates without changing the safety profile. The PEG-IFN monotherapy is twice as
      effective as IFN-alpha three times weekly. The combination of PEG-interferon and
      ribavirin improves the overall sustained response rates to 54-56% and represents
      the new standard therapy for patients with chronic hepatitis C infection in most
      patients.

PMID- 12472963
TI  - Mechanisms of drug resistance and novel approaches to therapy for chronic
      hepatitis C.
AB  - Hepatitis C virus (HCV) is now the major cause of transfusion-associated and
      parenterally transmitted viral hepatitis and accounts for a significant
      proportion of hepatitis cases worldwide. The majority of infections become
      persistent and approximately 20% of chronically infected individuals develop
      cirrhosis, which is strongly associated with progression to hepatocellular
      carcinoma. Molecular biological investigations into the structure and function of
      HCV and its genes has led to the identification of a number of potential targets
      for selective antiviral intervention. The present review summarizes current
      research activity into these novel drug targets and addresses the basis for
      clinical non-response in the current interferon-alpha-based therapies. Future
      therapeutic strategies that utilize HCV-specific antiviral agents should prove
      effective in controlling active viral replication, but the risk of emergence of
      drug-resistance will need to be addressed due to the quasispecies feature of HCV
      replication.

PMID- 12472964
TI  - A new enzyme immunoassay for the detection of antibody to hepatitis E virus.
AB  - BACKGROUND AND AIM: The purpose of the present study was to develop enzyme
      immunoassay (EIA) for the detection of IgG anti-hepatitis E virus (HEV) activity
      using two new recombinant proteins as antigenic targets, and to evaluate these
      EIA with the aid of statistical methods. METHODS: Two proteins, a mosaic protein
      and pB166 containing region 452-617 aa of the ORF2 of the HEV Burma strain, were
      used to develop the new HEV EIA. This EIA was evaluated using several panels of
      serum specimens obtained from: (i) acutely HEV-infected patients; (ii) patients
      with non-A, non-C hepatitis; (iii) normal blood donors (NBD) from non-endemic
      countries; and (iv) experimentally infected chimpanzees. RESULTS: A new HEV EIA
      was developed using two new recombinant proteins. This assay was able to detect
      anti-HEV activity in all specimens from acutely HEV-infected patients. When NBD
      were tested, more than 15% of specimens were found to be IgG anti-HEV positive.
      All NBD anti-HEV-positive specimens were tested with overlapping synthetic
      peptides spanning the entire HEV ORF2-encoded protein. More than 90% of the anti
      HEV-positive NBD specimens immunoreacted with an average of 15 synthetic peptides
      derived from different regions of the HEV ORF2 protein. These data suggest that
      the HEV EIA is at least 90% specific in detecting remote HEV infections.
      CONCLUSION: The new HEV EIA developed in the present study is a highly specific
      diagnostic assay for the detection of anti-HEV activity in serum specimens
      obtained from different epidemiologic settings.

PMID- 12472965
TI  - DNA vaccination against hepatitis E virus infection in cynomolgus macaques.
AB  - BACKGROUND: : The feasibility of DNA vaccination against hepatitis E in non-human
      primates has not been evaluated. In the present study a full-length hepatitis E
      virus (HEV) open reading frame (ORF)2 (Burmese strain) was assembled, cloned, and
      used for genetic immunization of cynomolgus macaques (cynos), which were
      subsequently challenged with a heterologous HEV strain (Mexico). METHODS: : Four
      cynos were vaccinated intramuscularly with the HEV ORF2 DNA cassette and one
      animal was vaccinated with a mock DNA construct. RESULTS: : Following vaccination
      anti-HEV antibodies were detected in the four HEV-DNA-vaccinated cynos, but not
      in the control animal. When challenged, two of the four HEV-DNA-vaccinated cynos
      were protected against HEV infection and had no elevated alanine aminotransferase
      activity, viremia, or fecal shedding. The two other DNA-vaccinated animals
      developed HEV infection and disease. CONCLUSION: : These findings demonstrate the
      feasibility of DNA vaccination for the protection of HEV infection and warrant
      further studies to explore routes other than intramuscular for induction of a
      stronger and efficacious immune response.

PMID- 12472966
TI  - Herbal medicines for liver diseases in India.
AB  - The use of natural remedies for the treatment of liver diseases has a long
      history, starting with the Ayurvedhic treatment, and extending to the Chinese,
      European and other systems of traditional medicines. The 21st century has seen a
      paradigm shift towards therapeutic evaluation of herbal products in liver
      diseases by carefully synergizing the strengths of the traditional systems of
      medicine with that of the modern concept of evidence-based medicinal evaluation,
      standardization of herbal products and randomized placebo controlled clinical
      trials to support clinical efficacy. The present review provides the status
      report on the scientific approaches made to herbal preparations used in Indian
      systems of medicine for the treatment of liver diseases. In spite of the
      availability of more than 300 preparations for the treatment of jaundice and
      chronic liver diseases in Indian systems of medicine using more than 87 Indian
      medicinal plants, only four terrestrial plants have been scientifically
      elucidated while adhering to the internationally acceptable scientific protocols.
      In-depth studies have proved Sylibum marianum to be anti-oxidative,
      antilipidperoxidative, antifibrotic, anti-inflammatory, immunomodulating and
      liver regenerative. Glycyrrhiza glabra has been shown to be hepatoprotective and
      capable of inducing an indigenous interferon. Picrorhiza kurroa is proved to be
      anti-inflammatory, hepatoprotective and immunomodulatory. Extensive studies on
      Phyllanthus amarus have confirmed this plant preparation as being anti-viral
      against hepatitis B and C viruses, hepatoprotective and immunomodulating, as well
      as possessing anti-inflammatory properties. For the first time in the Indian
      systems of medicine, a chemo-biological fingerprinting methodology for
      standardization of P. amarus preparation has been patented.

PMID- 12472967
TI  - Non-alcoholic steatohepatitis: definitions and pathogenesis.

PMID- 12472968
TI  - Treatment of non-alcoholic fatty liver disease.

PMID- 12472969
TI  - Autoimmune hepatitis and overlap syndromes.
AB  - Autoimmune hepatitis is a well-established chronic liver disease. It primarily
      affects women, is characterized by circulating autoantibodies and elevated
      gammaglobulins and is associated with extrahepatic immune-mediated syndromes.
      Treatment regimens have remained unchanged for a number of years because of the
      high efficacy of steroid monotherapy, or combination therapy of azathioprine and
      steroids. In approximately 90% of patients remission of the disease is reached by
      medical therapy, which is usually administered lifelong because long-term
      remission after drug withdrawal is achieved in only 17% of patients. In 10% of
      patients treatment failure is observed. The challenge of remission induction
      involves the use of transplant immunosuppressants such as cyclosporine,
      mycophenolate moffetil, and tacrolimus. The challenge of maintenance therapy
      minimizing steroid side-effects involves the evaluation of topical steroids and
      the use of azathioprine monotherapy. Overlap syndromes occur in approximately 20%
      of autoimmune liver diseases. The diagnosis is broadly based on serological,
      biochemical, clinical and histological parameters. Most common are the overlap of
      autoimmune hepatitis and primary biliary cirrhosis, as well as autoimmune
      hepatitis with primary sclerosing cholangitis. These yet incompletely defined
      syndromes are an important differential diagnosis in the difficult-to-treat
      patient with autoimmune hepatitis.

PMID- 12472970
TI  - Chronic cholestatic liver diseases.

PMID- 12472971
TI  - Copper metabolic defects and liver disease: environmental aspects.
AB  - Copper (Cu) is an essential trace element for many biological processes. Cu
      homeostasis is generally well maintained by inbuilt controls in intestinal
      absorption, biliary excretion and intrahepatic storage. Copper deficiency
      disorders are rare. Acute Cu toxicity occurs occasionally in accidental poisoning
      with Cu sulfate. Chronic Cu toxicity in the form of liver cirrhosis and damage to
      other organs is seen classically in Wilson's Disease (genetic abnormality of Cu
      metabolism) and in the presumed environmental disorder Indian Childhood Cirrhosis
      (ICC). The clinical, epidemiological and treatment aspects of ICC are described.
      The evidence linking ICC to environmental Cu is (i) greatly increased hepatic Cu;
      (ii) early introduction of Cu contaminated milk boiled or stored in brass
      vessels; (iii) dramatic decline in ICC throughout the country coincident with
      change in feeding vessels; and (iv) continued long-term remission in d
      penicillamine-treated patients after withdrawal of the drug. The nature and role
      of a second factor in the causation of ICC remains unclear, although a genetic
      predisposition is strongly suspected. Scattered reports of an ICC-like illness
      from the West (Idiopathic Cu Toxicosis, Endemic Tyrolean Infantile Cirrhosis),
      suggest that different mechanisms (environmental, genetic or both) can lead to
      the same end stage liver disease-'ecogenetic' disorders.

PMID- 12472972
TI  - Antituberculous drugs in patients with chronic liver disease.

PMID- 12472973
TI  - Viral pathogenesis of hepatocellular carcinoma.

PMID- 12472974
TI  - Surgery for hepatocellular carcinoma.
AB  - Today there is an array of therapeutic modalities available for the patients with
      hepatocellular carcinoma (HCC). However, surgery, be it resection or
      transplantation, offers the only hope of long-term disease-free survival.
      Unfortunately, because the majority of HCC in Asia is associated with cirrhosis,
      surgical resection is restricted to only a small proportion of these patients.
      However, in selected candidates resection may offer a 5-year survival of up to
      70%. With the clinical application of adult-to-adult living donor liver
      transplantation, an increasing number of patients with small HCC and
      decompensating cirrhosis are undergoing transplantation.

PMID- 12472975
TI  - Treatment of non-resectable hepatocellular carcinoma.

PMID- 12472976
TI  - Evidence-based medicine in the treatment of hepatocellular carcinoma.
AB  - The incidence of hepatocellular carcinoma is increasing worldwide. Diagnosis at
      early stage is crucial to allow the application of curative treatments, that are
      the sole hope to increase their life expectancy. Surgical resection and liver
      transplantation are considered the first line options for early tumors, although
      there is no agreement on which is the best treatment approach. Resection achieves
      excellent results in patients with single tumors, absence of portal hypertension
      and normal bilirubin, but is limited by the high recurrence rate. Liver
      transplantation also achieves excellent results in patients with single tumors
      smaller than 5 cm or even three nodules smaller than 3 cm. However, this
      procedure is hampered by the shortage of donors and the increasing waiting times
      that have reduced their intention-to-treat outcomes. Treatment while waiting for
      a donor is controversial, but radical antitumoral therapies seem cost-effective
      in long waiting times. Percutaneous therapies are reserved for patients with
      single non-surgical tumors. More than 60 randomized clinical trials have been
      published to assess treatments for patients with advanced tumors, but there is no
      definitive evidence of survival benefits. A recent randomized trial reported that
      chemoembolization may benefit HCC patients in terms of survival, but additional
      studies to confirm this data are recommended.

PMID- 12472977
TI  - Progression from chronic hepatitis to hepatocellular carcinoma: natural course
      and treatments.

PMID- 12472978
TI  - Herbal medication: potential for adverse interactions with analgesic drugs.
AB  - The use of herbal supplements in the US has increased dramatically in recent
      years. These products are not regulated by the Food and Drug Administration (FDA)
      with the same scrutiny as conventional drugs. Patients who use herbal supplements
      often do so in conjunction with conventional drugs. This article is a review of
      potential adverse interactions between some of the commonly used herbal
      supplements and analgesic drugs. Non-steroidal anti-inflammatory drugs (NSAIDs),
      particularly aspirin, have the potential to interact with herbal supplements that
      are known to possess antiplatelet activity (ginkgo, garlic, ginger, bilberry,
      dong quai, feverfew, ginseng, turmeric, meadowsweet and willow), with those
      containing coumarin (chamomile, motherworth, horse chestnut, fenugreek and red
      clover) and with tamarind, enhancing the risk of bleeding. Acetaminophen may also
      interact with ginkgo and possibly with at least some of the above herbs to
      increase the risk of bleeding. Further, the incidences of hepatotoxicity and
      nephrotoxicity may be augmented by acetaminophen when concomitantly used with the
      potentially hepatotoxic herbs Echinacea and kava, and with herbs containing
      salicylate (willow, meadowsweet), respectively. The concomitant use of opioid
      analgesics with the sedative herbal supplements, valerian, kava and chamomile,
      may lead to increased central nervous system (CNS) depression. The analgesic
      effect of opioids may also be inhibited by ginseng. It is suggested that health
      care professionals should be more aware of the potential adverse interactions
      between herbal supplements and analgesic drugs, and take appropriate
      precautionary measures to avoid their possible occurrences. However, as most of
      the interaction information available is based on individual case reports, animal
      studies and in vitro data, further research is needed to confirm and assess the
      clinical significance of these potential interactions.

PMID- 12472979
TI  - Simple and simultaneous determination of sulphapyridine and acetylsulphapyridine
      in human serum by column-switching high-performance liquid chromatography.
AB  - OBJECTIVE: A high-performance liquid chromatography (HPLC) with an automated on
      line column-switching system was used for the simultaneous determination of
      sulphapyridine and acetylsulphapyridine, two major active metabolites related to
      the adverse effects of sulphasalazine, in human serum. METHODS: Serum samples
      were directly injected into the HPLC, with the valve automatically switched on to
      remove serum proteins and other hydrophilic components remaining in the pre
      column after elution of sulphapyridine and acetylsulphapyridine to the analytical
      column. RESULTS: Serum proteins did not interfere with the analysis of either
      compound. The recoveries of SLP and Ac-SLP from drug-free human serum were 93.03
      99.18% and CV were 2.88-4.34%. The within-run reproducibility of assays was
      excellent with relative standard deviations (RSD) of 1.01-3.90% (SLP) and 0.77
      5.56% (Ac-SLP). The limit of quantification of sulphapyridine and
      acetylsulphapyridine was 3.13 microg/mL and 0.50 microg/mL, respectively. The
      serum concentrations in a patient with ulcerative colitis, who took 1.0 g
      sulphasalazine twice daily, were 31.20 microg/mL for sulphapyridine and 14.64
      microg/mL for acetylsulphapyridine at 7 h after ingestion. CONCLUSION: The
      present simple and reproducible assay was useful for the monitoring of serum
      sulphapyridine and acetylsulphapyridine.

PMID- 12472980
TI  - Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in
      acute soft tissue injuries: a randomized, double-blind study.
AB  - The efficacy of a novel, proprietary topical formulation of ibuprofen 5% gel
      (Ibugel) and ibuprofen 400 mg tablets (1200 mg daily) was compared in a double
      blind, double-dummy, parallel group study in patients with acute soft tissue
      injuries. Patients received either active gel plus placebo tablets (n = 50) or
      active tablets plus placebo gel (n = 50) for at least 7 days. The gel was applied
      and one tablet was taken three times daily. The two treatments showed similar
      efficacy. There were no significant differences between the groups for either the
      primary efficacy endpoint, the median time for the injury to be rated as
      'completely better' by the patients (>14 days active gel, 13.5 days active
      tablets; P = 0.59), or for other efficacy measures including the times to
      clinically significant relief from pain at rest or on movement and swelling. In
      summary, ibuprofen gel shows similar efficacy to oral ibuprofen 400 mg and may
      offer improved tolerability.

PMID- 12472981
TI  - Population pharmacokinetics of intravenous valproic acid in Korean patients.
AB  - OBJECTIVE: To determine population-based pharmacokinetic parameters for
      intravenous valproic acid, and the factors influencing these parameters, in
      Korean adults. METHODS: Valproic acid concentrations were obtained using a peak
      and trough sampling scheme for 102 Korean epileptic patients who were not taking
      concurrent antiepileptic medication. Three hundred and fifty-four serum
      concentrations were analysed according to a one-compartment model with a mixed
      effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg),
      height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age
      on volume of distribution (Vd) and clearance (CL) was assessed in the course of
      analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No
      significant influence of the other screened covariates was observed. The final
      regression model was: [equation: see text]. Interindividual variabilities
      (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual
      error including intraindividual variability was 26.7%. CONCLUSION: The current
      results may be used as a basic reference to optimize drug therapy with
      intravenous valproic acid. Further research on the paediatric population is
      necessary to confirm the non-linearity of the relation between body-weight and
      Vd.

PMID- 12472982
TI  - Effect of vigabatrin on the pharmacokinetics of carbamazepine.
AB  - OBJECTIVE: To evaluate a possible interaction between vigabatrin and
      carbamazepine in epileptic patients. METHODS: Steady-state serum concentrations
      of carbamazepine with and without vigabatrin were compared. The study group
      consisted of 15 patients (eight females, seven males, and mean age 31 +/- 12
      years), with refractory partial epilepsy. They received vigabatrin as add-on
      therapy. Patients received carbamazepine monotherapy for at least 6 months and
      the carbamazepine-vigabatrin combination for at least 3 months. Blood samples
      were obtained in the morning, before the first daily dose and the carbamazepine
      plasma concentrations were analysed by fluorescence polarization immunoassay (TDx
      System). RESULTS: No statistically significant differences were found in mean
      carbamazepine daily dose. Mean trough concentrations were 7.9 +/- 1.4 microg/mL
      with carbamazepine alone, and 6.5 +/- 2.0 microg/mL with carbamazepine-vigabatrin
      association (P < 0.03). The mean values of pharmacokinetic parameters were:
      level/dose ratio (L/D) = 0.59 +/- 0.20 vs. 0.45 +/- 0.15 (P < 0.05) and plasma
      clearance (Cl) = 78.5 +/- 25.8 vs. 105.8 +/- 38.9 mL/h/kg (P < 0.05), with
      carbamazepine alone and carbamazepine-vigabatrin combination, respectively.
      CONCLUSION: Vigabatrin produced a statistically significant increase in the
      plasma clearance of carbamazepine when the two drugs were given simultaneously.

PMID- 12472983
TI  - Ethical dilemmas in antibiotic prescribing: analysis of everyday practice.
AB  - OBJECTIVE: To explore general practitioners' (GP's) views on their obligations
      with respect to diagnosing infections and prescribing antibiotics. METHODS: The
      GP's reflections and prioritization were studied by means of interviews and
      observations. We analysed how their prioritization complied with an ethical
      guidance that ranked patient autonomy and welfare highest, then competence
      obligations and obligations to society, followed by fraternal obligations.
      RESULTS: Balancing of pros and cons was prominent in our informants' decision
      making but often resulted in decisions that deviated from the ethical guidance.
      The ranking varied much between the GPs. The highest priorities in the GPs'
      practice were related to the patient's everyday life (sometimes autonomy,
      sometimes beneficence in a broad sense), doctor-patient relationship
      (communication competence), the patient's perceived importance on the job market
      (society) and relationship with colleagues (fraternal). Perceived lack of
      resources and uncertainty with respect to both diagnostic and treatment decisions
      frequently influenced decision making.

PMID- 12472984
TI  - Patient characteristics and prescription patterns of atypical antipsychotics
      among patients with schizophrenia.
AB  - BACKGROUND: Schizophrenia, one of the leading causes of disability, contributes
      substantially to the use of medical and mental health services. The treatment of
      schizophrenia is therefore particularly important to reduce deficits across a
      large number of neurocognitive domains. OBJECTIVE: To describe the prescription
      (e.g. initiation and switching) patterns of atypical antipsychotic agents and
      examine the extent to which patient sociodemographic and clinical characteristics
      are associated with the prescription patterns of atypical antipsychotics among
      patients with schizophrenia. METHODS: Using unique data sources from the Veterans
      Health Administration (VA), the study identified 89 107 patients with
      schizophrenia based on at least one inpatient or more than or equal to two
      outpatients' ICD-9-CM codes (> or =7 days apart). We defined a prior 6-month
      (1/1/99 to 6/30/99) and a post 6-month (7/1/99 to 12/31/99) period to describe
      patterns of initiation and switching of atypical antipsychotics. RESULTS: Only a
      small number of patients were on clozapine (1.8%) and quetiapine (1.4%). More
      patients were prescribed olanzapine (23%) than risperidone (20%) (P < 0.001).
      Compared with patients who were on risperidone, those who were on olanzapine were
      younger (P < 0.001), more likely Hispanic (P < 0.001), more likely married (P <
      0.05), had more service-connected disability (P < 0.001), had fewer numbers of
      physical comorbidities (P < 0.001), and a lower body mass index (BMI) (P < 0.05).
      CONCLUSION: Olanzapine and risperidone appear to be prescribed to patients with
      different sociodemographic and clinical characteristics. Future research needs to
      explore the reasons for those differences.

PMID- 12472985
TI  - Diazoxide in the treatment of schizophrenia: novel application of potassium
      channel openers in the treatment of schizophrenia.
AB  - OBJECTIVE: Schizophrenia is a very common disorder, affecting 1% of the world
      population. People who develop schizophrenia experience severe suffering and
      approximately 10% commit suicide. The causes of schizophrenia are still largely
      unknown. The relative ineffectiveness of dopamine antagonists to treat some
      symptoms of schizophrenia has promoted many investigators to postulate the
      involvement of the neuronal system in the pathophysiology of this disease. It has
      been suggested that the dopamine-coupled adenosine triphosphate (ATP)-sensitive
      channels may function by hyperpolarizing cells during metabolic stress, a
      function that may be disrupted in people with schizophrenia. Therefore,
      application of potassium channel openers/activators may be beneficial in
      schizophrenia. Diazoxide is a benzothiadiazine derivative related to the thiazide
      diuretics and a potassium channel opener. The purpose of the present
      investigation was to assess the efficacy of diazoxide, as an adjuvant agent in
      the treatment of schizophrenia. METHODS: Forty-two patients who met the DSM IV
      criteria for chronic schizophrenia completed the study. Patients were randomized
      to haloperidol 20 mg/day plus diazoxide 200 mg/day (21 subjects) or to
      haloperidol 20 mg/day plus placebo (21 subjects) in this 8-week double-blind
      study. RESULTS: Although both protocols significantly decreased the score of the
      positive, negative and general psychopathological symptoms over the trial period,
      the combination of haloperidol and diazoxide showed a significant superiority
      over haloperidol alone in the treatment of positive and general psychopathology
      symptoms as well as positive and negative syndrome scale (PANSS) total scores. In
      addition, in the diazoxide group a rapid onset of action on the positive symptoms
      was observed in week 2, whereas in the placebo group there was no significant
      effect at week 2. No significant differences were observed between the two
      protocols on the negative scores. CONCLUSION: The results of this study present a
      novel application for potassium channel openers/activators in the
      neuropsychiatric disorders and diazoxide may be an effective adjuvant agent in
      the management of schizophrenia.

PMID- 12472986
TI  - Effect of proguanil interaction on bioavailability of cloxacillin.
AB  - METHODS: To investigate a potential drug-drug interaction between proguanil (PG)
      and cloxacillin (Clox). Seven healthy adult volunteers received a single oral
      dose of Clox plus coadministration of single oral doses of PG and Clox in a
      simple cross-over manner after a wash-out period of 1 week. Total urine voided
      was collected at predetermined time intervals over 12 h. Amount of Clox in urine
      was determined by a reversed-phase high-pressure liquid chromatography method.
      RESULTS: The mean maximum excretion rate [(dDu/dt)max] of Clox when taken alone
      was 16.13 +/- 2.92 mg/h at tmax of 1.86 +/- 01.07 hours, whereas in the presence
      of PG, it was 7.72 +/- 3.24 mg/h at tmax of 2.43 +/- 00.98 hours (P < 0.0001).
      The total amount of Clox excreted in urine (Du infinity) in 12 h was markedly
      reduced by coadministration with PG by up to 48% with Du infinity of 49.57 +/-
      8.16 mg after Clox alone and 25.81 +/- 8.46 mg in the presence of PG (P <
      0.0001). The tmax and t1/2-values obtained from the excretion rate plot were
      lengthened by 23 and 34%, respectively, in the presence of PG but the differences
      were not statistically significant (P > 0.05). CONCLUSION: These pharmacokinetic
      values indicate slowed and diminished absorption (bioavailability) of Clox when
      concurrently administered with PG. The clinical implication is unknown. However,
      concomitant administration of the two drugs during antibacterial therapy should
      be done with caution so as to avoid subtherapeutic levels of Clox, which can lead
      to treatment failure and facilitate drug resistance.

PMID- 12472987
TI  - Alternative venlafaxine kinetics in overdose.
AB  - The pharmacokinetics of venlafaxine in therapeutic doses is well established. It
      is metabolized by the cytochrome P450 enzymes including CYP2D6. The
      toxicokinetics in overdose is less well known. CASE REPORT: A 33-year-old
      Caucasian female who ingested 3.0 g venlafaxine, and 210 mg zolpidem. The patient
      remained symptomatic for the following 24 h. Plasma pharmacokinetic analysis
      demonstrated a prolonged elimination half-life of venlafaxine, estimated to be
      15.3 h. We postulate that the patient was a slow metabolizer of substrates for
      CYP2D6, an enzyme known to exhibit polymorphism.

PMID- 12472988
TI  - Using effectiveness studies for prescribing research, part 2.
AB  - Trials that consider the effects of interventions on prescribing behaviour
      amongst clinicians often have complex design implications resulting in data that
      has inherent hierarchical structure. It follows that both experimental design and
      analysis plans must account for this structure and thus results should be
      considered in terms of clinician behaviour rather than individual patient
      response. We describe this change in perspective and the necessity for using
      statistical techniques that allow incorporation of potential confounding effects.
      We also discuss the appropriateness of some specific outcomes in relation to
      these trials.

PMID- 12472989
TI  - Antiplaque biocides and bacterial resistance: a review.
AB  - Modern dentistry emphasizes the importance of dental plaque control to improve
      oral health. The use of oral care formulations with antiplaque biocides plays a
      crucial role in patient-directed approaches for plaque control. The antiplaque
      efficacies of these formulations have been extensively studied in many long-term
      clinical studies designed in accordance with well-accepted guidelines. The
      results from these studies conclusively demonstrate that long-term use of oral
      care formulations with well-known antiplaque biocides such as chlorhexidine and
      triclosan reduce supragingival plaque and gingivitis. This review summarizes
      microbiological results from clinical studies conducted with oral care
      formulations containing antiplaque biocides. Results from a number of long-term
      clinical studies conducted under real-life use conditions indicate no adverse
      alterations in the bacteria found in dental plaque or emergent microbial
      resistance. Additionally, microbial sampling of dental plaque subsequent to
      extended use of antiplaque biocides reveals no increase in resistant microflora.
      Large numbers of common oral bacteria isolated from patients using chlorhexidine
      indicate no increase in microbial resistance to chlorhexidine or to commonly used
      antibiotics. The effects of antiplaque biocides containing oral care formulations
      on dental plaque that exists naturally as a biofilm are examined. These
      formulations contain biocide, surfactants, polymers and other components that are
      effective against the biofilm. In summary, the results of studies on the real
      life use of oral care formulations with antiplaque biocides show no emergence of
      resistant microflora or alterations of the oral microbiota, while such
      formulations have been found to provide the benefits of reducing plaque and
      gingivitis.

PMID- 12472990
TI  - Meta-analysis of the effect of scaling and root planing, surgical treatment and
      antibiotic therapies on periodontal probing depth and attachment loss.
AB  - OBJECTIVE: This paper reports a meta-analysis of studies that have investigated
      the effect of scaling and root planing on periodontal probing depth and
      attachment loss. MATERIAL AND METHODS: The criteria used for inclusion of studies
      were as follows: root planing and scaling alone was one of the primary treatment
      arms; patients or quadrants of each patient were randomly assigned to study
      groups; 80% of patients enrolled were included in first year follow-up
      examinations; periodontal probing depth and attachment loss were reported in mm;
      the sample size of each study and substudy was reported. Sample size was used to
      weight the relative contribution of each study since standard errors were not
      reported by many studies and sample size is highly correlated with standard error
      and therefore statistically able to explain a substantial portion of the standard
      error on studies that use similar measures. RESULTS: The meta-analysis results
      show that periodontal probing depth and gain of attachment level do not improve
      significantly following root planing and scaling for patients with shallow
      initial periodontal probing depths. However, there was about a 1-mm reduction for
      medium initial periodontal probing depths and a 2-mm reduction for deep initial
      periodontal probing depths. Similarly, there was about a 0.50-mm gain in
      attachment for medium initial periodontal probing depth measurements and slightly
      more than a l-mm gain in attachment for deep initial periodontal probing depth
      measurements. Surgical therapy for patients with deep initial probing depths
      showed better results than scaling and root planing in reducing probing depths.
      When patients were followed up over 3 years or more, these differences were
      reduced to less than 0.4 mm. Antibiotic therapy showed similar results to scaling
      and root planing. However, a consistent improvement in periodontal probing depth
      and gain of attachment is demonstrated when local antibiotic therapy is combined
      with root planing and scaling.

PMID- 12472991
TI  - Viability of cultured periodontal pocket epithelium cells and Porphyromonas
      gingivalis association.
AB  - OBJECTIVES: Porphyromonas gingivalis, one of the key pathogens in the development
      of periodontitis, produces a number of virulence factors that might explain its
      pathogenicity. One of them is the ability to adhere and invade pocket epithelium.
      The aim of this study was to follow, over time, the association of P. gingivalis
      and consequent morphological changes of the pocket epithelium cells. MATERIAL AND
      METHODS: The association capacity of four P. gingivalis serotypes [K1, K2, K4, K-
      (nonencapsulated)] with in vitro cultured mono-layers from periodontal pocket
      epithelial cells of patients with periodontitis, was followed by fluorescence
      microscopy and bacterial culture. The contact time between bacteria and
      epithelium cells ranged from 45 min to 8 h. The microscopic evaluation allowed
      differentiation between dead and living cells (bacteria as well as epithelium)
      and description of the morphological changes after association. RESULTS: A highly
      significant difference in the number of associating bacteria was found between
      dead and living epithelium cells, and between non-capsulated and capsulated
      strains. A significant increase in the proportion of dead pocket epithelium cells
      was found with prolonged association time. The morphological changes (rounding of
      the epithelial cell, detachment from the glass cover-slip and loss of
      intercellular contact) occurred faster for mono-layers inoculated with the non
      encapsulated P. gingivalis strain. CONCLUSIONS: This study indicates that dead
      pocket epithelium cells harbor more P. gingivalis cells, and that a positive
      correlation exists between contact time and cell death. For the P. ginigvalis
      species, non-encapsulated strains associate in higher number. As a result, the
      damage they cause to the host cell seems to occur faster than occurs in
      encapsulated strains. As such, cell death can be seen as the end-result of
      bacterial association.

PMID- 12472992
TI  - A cross-sectional study of dentine hypersensitivity.
AB  - AIM: The aim of this study was to establish the prevalence of dentine
      hypersensitivity in a cross-sectional study of patients visiting general dental
      practitioners in the United Kingdom over a period of one calendar month. METHODS:
      Nineteen dental practioners examined 4841 patients over a period of one calendar
      month and patients that had dentine hypersensitivity diagnosed were questioned
      further about their occupation and smoking habits. The amount of buccal gingival
      recession associated with the sensitive teeth was also recorded using a study
      form. RESULTS: 201 patients were diagnosed as having dentine hypersensitivity,
      giving a prevalence figure of 4.1%. The commonest teeth affected were the upper
      premolar teeth and the commonest initiating factor was cold drinks. A tendency
      for a greater number of sensitive teeth was also found for patients with
      periodontal disease who also smoked. There was also a tendency for the patients
      with sensitive teeth to come from higher social groups.

PMID- 12472993
TI  - Residual periodontal defects distal to the mandibular second molar 6-36 months
      after impacted third molar extraction.
AB  - AIM: This retrospective study investigated the periodontal conditions distal to
      mandibular second molars 6-36 months after routine surgical extraction of
      adjacent impacted third molars. METHOD: Subjects were randomly selected by
      systematic sampling from computer records of 3211 surgical mandibular third molar
      extractions in the Hong Kong dental teaching hospital. Records and pre-extraction
      radiographs of the selected cases were retrieved. Selected subjects (n = 283)
      were invited for an interview followed by a clinical examination. Community
      Periodontal Index (CPI) protocol was used for the assessment of the general
      periodontal status (excluding the mandibular second molar of interest, i.e. the
      subject tooth) followed by a detailed periodontal examination of the subject
      tooth. RESULTS: In all, 158 subjects, aged 29 +/- 7 years, were examined with
      only 6% (nine subjects) having a highest CPI score of 4 (excluding the subject
      tooth), but local periodontal defects were prevalent at the distal surface of
      subject mandibular second molars: mean probing pocket depth (PPD) was 5.4 +/- 1.9
      mm with 67% (106 subjects) exhibiting PPD >or= 5 mm and 23% (36 subjects)
      exhibiting PPD >or= 7 mm; mean recession was 0.8 +/- 1.0 mm; bleeding on probing
      96% and suppuration on probing 5%. Multiple linear regression analysis was used
      to analyse the effects of 12 independent variables on the PPD at the distal
      surface of the involved mandibular second molar. Three possible risk indicators
      (P < 0.001, R2 = 0.27) associated with localised increased PPD at the distal
      surface of the mandibular second molars were identified: 1) third molar 'mesio
      angular' impaction; 2) pre-extraction crestal radiolucency and 3) inadequate post
      extraction local plaque control. CONCLUSION: The results suggest that periodontal
      breakdown initiated and established on the distal surface of a mandibular second
      molar in the vicinity of a 'mesio-angular' impacted third molar evidenced by pre
      extraction crestal radiolucency in association with inadequate plaque control
      after extraction can predispose to a persistent localised periodontal problem.

PMID- 12472994
TI  - Interactions between stress, interleukin-1beta, interleukin-6 and cortisol in
      periodontally diseased patients.
AB  - BACKGROUND/AIMS: The aim of the present study was to measure interleukin-1beta,
      interleukin-6 and cortisol levels in the peripheral blood of periodontally
      diseased patients in order to record any interactions with psychosocial stress.
      MATERIAL AND METHODS: The test group comprised 16 patients with untreated and 14
      with treated aggressive generalized periodontitis (AGP), five patients with
      untreated aggressive localized periodontitis (ALP) and five with chronic
      generalized periodontitis (CGP). The control group comprised 40 periodontally
      healthy probands. Blood was taken from the cephalic vein of all patients and
      controls at the same time (8 a.m.) each day. IL-1beta, IL-6 and cortisol levels
      were then measured with a sensitive ELISA, the 'Quantikine HS Immunoassay Kit'
      (Biermann Diagnostica, Bad Nauheim, FRG). The clinical examination covered
      probing depth, gingival recession, gingival index, plaque index and clinical
      attachment level. A questionnaire was used to ask the patients and controls about
      their attitude to life and the stress induced by their jobs and their families.
      Previous and current levels of tobacco consumption were also recorded.
      Statistical evaluation was based on the Mann-Whitney U-Wilcoxon test for
      comparison of blood serum values and clinical parameters between patients and
      controls, and the Kruskal-Wallis test for intergroup comparison. All data were
      correlated by means of Spearman's rank correlation coefficient, and significance
      levels relating to stress and smoking were determined with the chi-square test.
      RESULTS: With respect to cortisol, the results showed no significant differences
      either between the patient groups or in comparison with the controls. IL-1beta
      was detected only in the AGP patients and their controls, but with no significant
      differences. IL-6 was detected in virtually all patients and controls, but with
      no significant differences. Only in the untreated AGP patients was IL-6
      significantly elevated (P < 0.05) and a slight correlation with attachment loss
      recorded. In all AGP patients a slight correlation between IL-1beta and IL-6 was
      recorded. Evaluation of the questionnaire revealed a higher proportion of
      untreated AGP patients than of controls with a pessimistic attitude to life. In
      all AGP patients, family-induced stress and smoking were found to correlate with
      attachment loss. In the untreated AGP patients, smoking correlated with IL-1beta
      protein content, and in the controls there was a moderate correlation between
      smoking and IL-6 levels. CONCLUSIONS: The present study found no correlation
      between the immunological mediators (IL-1beta, IL-6), glucocorticoids (cortisol)
      and the registered stress values. However, the patients with untreated AGP showed
      signs of a pessimistic attitude to life, and an elevated IL-6 level was recorded
      in the peripheral blood. As a restrictive factor it should be borne in mind that
      the number of patients investigated was too small for adequate conclusions to be
      drawn.

PMID- 12472995
TI  - Porphyromonas gingivalis, Bacteroides forsythus and other putative periodontal
      pathogens in subjects with and without periodontal destruction.
AB  - BACKGROUND AND AIMS: Bacteria play an essential role in the pathogenesis of
      destructive periodontal disease. It has been suggested that not all bacteria
      associated with periodontitis may be normal inhabitants of a periodontally
      healthy dentition. In particular, Porphyromonas gingivalis and Actinobacillus
      actinomycetemcomitans have been isolated infrequently from subjects without
      periodontitis. The aim of the present study was to compare prevalence and
      proportions of a number of periodontal bacteria in periodontitis patients and
      control subjects. MATERIAL AND METHODS: In all, 116 consecutive subjects
      diagnosed with moderate to severe periodontitis (mean age 42.4) and 94 subjects
      without radiographic evidence of alveolar bone loss (mean age 40.4) were
      recruited for the study. The gingival condition in the control group varied
      between gingival health and various degrees of gingivitis. In patients, the
      deepest pocket in each quadrant was selected for microbiological sampling. In
      control subjects all mesial and distal sites of all first molars were selected
      for sampling. All paper points from a patient were pooled and processed for
      anaerobic cultivation within 6 h after sampling. Clinical variables of sampled
      sites included bleeding index, probing pocket depth and clinical attachment
      level. RESULTS: A. actinomycetemcomitans, P. gingivalis, Prevotella intermedia,
      Bacteroides forsythus, Fusobacterium nucleatum and Peptostreptococcus micros were
      significantly more often prevalent in patients than in controls. The highest odds
      ratios were found for P. gingivalis and B. forsythus (12.3 and 10.4 resp.). Other
      odds ratios varied from 3.1 to 7.7 for A. actinomycetemcomitans and P. micros,
      respectively. Absolute numbers of target bacteria were all higher in patients,
      but only the mean percentage of B. forsythus was significantly higher in patients
      in comparison to controls (P < 0.001). CONCLUSIONS: A. actinomycetemcomitans, P.
      gingivalis, P. intermedia, B. forsythus, F. nucleatum and P. micros are all
      significant markers for destructive periodontal disease in adult subjects. Based
      on calculated odds ratios, B. forsythus and P. gingivalis are the strongest
      bacterial markers for this disease and are infrequently cultured from subjects
      without periodontal bone loss.

PMID- 12472996
TI  - Relationship between oral health and mortality rate.
AB  - BACKGROUND/AIMS: Some symptoms of diseases or causes of death are often related
      to oral health, especially cardiovascular diseases. The purpose of this study was
      to investigate the relationship between poor oral health and mortality risk,
      especially when cases of fatal cardiovascular diseases were excluded. MATERIAL
      AND METHODS: An odontological investigation was made on a sample of 1393
      individuals, aged 18-65 years, in 1970 in the County of Stockholm with a follow
      up in 1997, when the mortality rate and causes of death in the sample during the
      time period 1971-1996 were registered. Oral health was defined as a sum of scores
      for number of missing teeth, apical lesions, caries lesions and marginal bone
      loss. RESULTS: A significant correlation was found between poor oral health and
      an increased mortality risk even when persons dying from cardiovascular diseases
      were excluded from the analyses. CONCLUSION: Poor oral health was found to be a
      risk indicator of all-cause mortality. The lack of specificity of the
      associations between oral health and mortality strengthens the hypothesis that
      the significant correlations could be explained by not identified confounding
      factors.

PMID- 12472997
TI  - Tissue structure, and IL-1beta, IL-8, and TNF-alpha secretions after contact by
      engineered human oral mucosa with dentifrices.
AB  - The use of dentifrice is part of an oral prophylaxis that aims at keeping
      bacteria in check within the dental plaque. When introduced into the oral cavity,
      dentifrice also comes in close contact with the oral epithelium. Our goal was to
      evaluate the effects of dentifrices on tissue structure and pro-inflammatory
      mediator release by epithelial cells. For this purpose, tri-dimensional
      engineered human oral mucosa (EHOM) was produced using normal human palatal
      fibroblasts and epithelial cells. EHOMs were either treated with Aquafresh(R) or
      Crest(R) for 1, 4, 8, and 24 h, or untreated, then used for cell viability
      assessment and structural analyses. Cultured supernatants were used to evaluate
      cytokine (interleukin (IL)-1beta, IL-8 and tumor necrosis factor (TNF)-alpha)
      secretion, and metalloproteinase (MMP)-2 and -9 activities. The present in vitro
      study using engineered oral mucosa confirms that dentifrices (Aquafresh and
      Crest) contribute to tissue desquamation. The desquamation was substantial at 24
      h of contact but was limited to the upper layers of the treated tissues. Cell
      death in these tissues was not increased, suggesting that the dentifrice had
      accelerated desquamation of the layers containing differentiated cells.
      Measurement of cytokines revealed that dentifrices up-regulated IL-1beta while
      down-regulating IL-8 and TNF-alpha secretion, thus indicating an impaired cascade
      of inflammatory responses. These dentifrices may also impair normal repair
      mechanisms as suggested by an up-regulation of gelatinase activities. In
      conclusion, this study suggested that, via cytokines, dentifrice contributes to
      the modulation of the inflammatory (pro-inflammatory/anti-inflammatory responses)
      process.

PMID- 12472998
TI  - A clinical comparison of three powered toothbrushes.
AB  - AIM: The purpose of the present study was to compare the ability of the Braun
      Oral-B 3D Excel power toothbrush (BPT), the Sonicare power toothbrush (SPT) and
      the Philips Sensiflex 2000 (HX 2550) power toothbrush (PPT) to control plaque and
      reduce experimentally induced gingivitis. MATERIALS AND METHODS: Two experiments
      were carried out in two different groups of subjects using a split-mouth design
      whereby the two halves of the mandible which had been allowed to develop
      gingivitis were brushed over a 4-week period with the test toothbrushes.
      Experiment 1 compared the BPT with the SPT (n = 35) and experiment 2 compared the
      BPT with the PPT (n = 32). The study used a run-in period of 2 weeks, which,
      together with the 3-week experimental gingivitis phase, represented the pretrial
      phase of the experiment. The purpose of this phase was two-fold: first, to enable
      the subjects to become acquainted with the two power brushes and for them to
      receive proper oral hygiene instruction, and, second, to develop a reasonable
      level of gingivitis on the mandible. Those subjects with at least 40% of sites
      exhibiting bleeding in each quadrant in the mandible at day 21 of the
      experimental gingivitis phase were allowed to continue with the trial. During the
      next 4 weeks (treatment phase) of each experiment, subjects were told to brush
      according to a split-mouth design, the right and left sides of the mouth being
      randomly allocated to a toothbrush. During this period, no rinsing with an
      antiseptic mouthwash or flossing was allowed and a standard toothpaste
      (Zendium(R)) was used. After 1, 2 and 4 weeks, the plaque index (Quigley & Hein)
      and the bleeding tendency on marginal probing were assessed in the mandible.
      RESULTS: Experiment 1 showed that the bleeding score was reduced from 1.63 to
      1.12 at 4 weeks by the BPT and from 1.65 to 1.26 by the SPT. This reduction was
      more rapid and greater with the BPT (P < 0.05). The plaque index was reduced from
      2.19 at day 21-1.03 at 4 weeks by the BPT, and from 2.18 to 1.20 by the SPT. The
      difference between the two toothbrushes was not significant. Experiment 2 showed
      that the bleeding score was reduced from 1.77 at day 21 to 1.07 at 4 weeks by the
      BPT and from 1.75 to 1.24 by the PPT. This reduction was more rapid and greater
      with the BPT (P < 0.05). There was no significant difference in plaque index at 4
      weeks (BPT, 1.09; PPT, 0.95). Data from the questionnaire at the end of the study
      revealed that, in both experiments, most subjects preferred the BPT. CONCLUSIONS:
      The data from this study show that the design and action of the Braun Oral-B 3D
      Excel power toothbrush are more effective in resolving gingivitis than the
      Sonicare & the Philips Sensiflex 2000 power toothbrushes.

PMID- 12472999
TI  - Oral myofibromatosis: an unusual cause of gingival overgrowth.
AB  - BACKGROUND: This case report describes a rare benign tumour, which presented as
      discrete areas of gingival hyperplasia affecting both the mandible and the
      maxilla. METHOD: Surgical excision of the lesions was carried out under local
      anaesthetic. Histopathological examination confirmed the diagnosis of oral
      myofibromatosis. RESULTS: The condition responded to surgical excision and
      appears to have limited growth potential. It affects a wide spectrum of ages and
      can be alarming due to rapid enlargement and ulceration, so careful diagnosis is
      important to avoid unnecessary aggressive treatment.

PMID- 12473001
TI  - Effects of exercise training on frailty in community-dwelling older adults:
      results of a randomized, controlled trial.
AB  - OBJECTIVES: Although deficits in skeletal muscle strength, gait, balance, and
      oxygen uptake are potentially reversible causes of frailty, the efficacy of
      exercise in reversing frailty in community-dwelling older adults has not been
      proven. The aim of this study was to determine the effects of intensive exercise
      training (ET) on measures of physical frailty in older community-dwelling men and
      women. DESIGN: Randomized controlled trial. SETTING: Medical school research
      center. PARTICIPANTS: One hundred fifteen sedentary men and women (mean age +/-
      standard deviation = 83 +/- 4) with mild to moderate physical frailty, as defined
      by two of the following three criteria: Modified Physical Performance Test
      (modified PPT) score between 18 and 32, peak oxygen uptake (VO2 peak) between 10
      and 18 mL/kg/min, and self-report of difficulty or assistance with one basic
      activity of daily living (ADL), or two instrumental ADLs. INTERVENTION:
      Participants were randomly assigned to a control group that performed a 9-month
      low-intensity home exercise program (control) or an exercise-training program
      (ET). The control intervention primarily consisted of flexibility exercises. ET
      began with 3 months of flexibility, light-resistance, and balance training.
      During the next 3 months, resistance training was added, and, during the next 3
      months, endurance training was added. MEASUREMENTS: Modified PPT score, VO2 peak,
      performance of ADLs as measured by the Older Americans Resources and Services
      instrument, and the Functional Status Questionnaire (FSQ). RESULTS: ET resulted
      in significantly greater improvements than home exercise in three of the four
      primary outcome measures. Adjusted 95% confidence bounds on the magnitude of
      improvement in the ET group compared with the control group were 1.0 to 5.2
      points for the modified PPT score, 0.9 to 3.6 mL/kg/min for VO2 peak, and 1.6 to
      4.9 points for the FSQ score. CONCLUSIONS: Our results show that intensive ET can
      improve measures of physical function and preclinical disability in older adults
      who have impairments in physical performance and oxygen uptake and are not taking
      hormone replacement therapy better than a low-intensity home exercise program.

PMID- 12473002
TI  - Exercise adherence and 10-year mortality in chronically ill older adults.
AB  - OBJECTIVES: To compare mortality of adherents and nonadherents of an exercise
      program. DESIGN: Prospective intervention study. SETTING: Supervised geriatric
      fitness program called Gerofit. PARTICIPANTS: One hundred thirty-five adults aged
      65 and older who enrolled in Gerofit between January 1, 1990, and November 30,
      1999. All participants had a baseline medical screen and exercise test. They were
      classified as adherent (n = 70) if they participated in Gerofit for more than 47
      sessions or nonadherent (n = 65) if they did not complete 47 sessions within the
      first 6-month period. INTERVENTION: Program participation was voluntary and
      consisted of aerobic, strength, flexibility, and balance exercises. The program
      met three times week for 90 minutes. MEASUREMENTS: All-cause mortality. RESULTS:
      Twenty-six deaths occurred within the 10-year follow-up period. Using
      proportional hazards, time to death was not related to adherence group. However,
      in multivariate analyses controlling for age, sex, race, baseline risk/health
      status, history of heart disease, cancer, diabetes mellitus, and baseline smoking
      status, there was significant group-by-time interaction (P =.004), indicating a
      crossover in mortality risk. The initial survival benefit observed in nonadherers
      changed over time, resulting in a long-term protective survival effect on
      mortality for the adherent group (hazard rate = 0.75, 95% confidence interval =
      0.61-0.91 for the interaction term). CONCLUSIONS: Older adults with chronic
      diseases experience a long-term beneficial mortality effect from participation in
      exercise programs. Physicians should strongly encourage their patients, including
      those with comorbidities, to maintain a regular exercise program.

PMID- 12473003
TI  - Effect of exercise on ease in performing activities of daily living and
      instrumental activities of daily living from age 70 to 77: the Jerusalem
      longitudinal study.
AB  - OBJECTIVES: To determine the prevalence of independence and ease of performance
      in activities of daily living (ADLs) and instrumental activities of daily living
      (IADLs) at ages 70 and 77 in a well-characterized cohort and to measure the
      effect of regular exercise at age 70 on independence and ease of performance 7
      years later. DESIGN: Two stages of a longitudinal study of an age-homogeneous
      cohort employing extensive interview data, physical examination, and clinical
      laboratory investigation. SETTING: Home-based interviews and examinations in
      Jerusalem. PARTICIPANTS: Two hundred eighty-seven west Jerusalem residents, born
      between June 1920 and May 1921, who participated fully in two phases of an
      ongoing longitudinal cohort study. Subjects were culled from a larger study
      population of 605 in the first phase and 1,021 in the second phase. MEASUREMENTS:
      Two-stage comprehensive demographic, social, and economic profile; medical
      history and examination; cognitive and affective assessment; and clinical
      laboratory studies performed in 1990-91 and 1997-98. The investigation
      questionnaire included details of ADL and IADLs and voluntary exercise. RESULTS:
      Most aspects of personal and social life did not change from age 70 to 77.
      Independence in ADLs remained high, as did self-reliance in IADLs for women. A
      more-sensitive marker of diminished function was reported ease in performance,
      which declined for use of the toilet, dressing, and all spheres of IADLs. For
      nearly every task, subjects who reported exercising 4 days a week at age 70 were
      more likely to report ease in performance at age 77. In a logistic regression
      accounting for the presence of diabetes mellitus, hypertension, obesity, chronic
      back pain, loneliness, and performance with ease at age 70 and deterioration in
      self-assessed health from age 70 to 77, ease of performance in at least three of
      four ADL tasks was independently related to exercise at age 70 for women (odds
      ratio (OR) = 8.5, 95% confidence interval (CI) = 2.0-36.2) and for men (OR = 4.3,
      95% CI = 1.1-17.1). Ease of independent function in at least four of five IADL
      tasks also correlated to exercise for men in this regression (OR = 3.7, 95% CI =
      1.1-12.2) but not for women (OR = 2.0, 95% CI = 0.6-6.3). Ease in shopping,
      alternatively, correlated with physical activity for men (OR = 4.3, 95% CI = 1.5
      12.0) and women (OR = 2.6, 95% CI = 1.1-6.1). CONCLUSIONS: Subjects remained
      active and independent at age 77. Reported ease of performance declined and
      revealed changes in function. Exercise at least four times a week at age 70
      preserved ease of performance at age 77 independent of the influence of specific
      disease or general self-assessed health.

PMID- 12473004
TI  - Effect of cilostazol on treadmill walking, community-based walking ability, and
      health-related quality of life in patients with intermittent claudication due to
      peripheral arterial disease: meta-analysis of six randomized controlled trials.
AB  - OBJECTIVES: To assess whether cilostazol, a phosphodiesterase III inhibitor,
      improves treadmill and community-based walking ability and health-related quality
      of life (HQL) in patients with intermittent claudication resulting from
      peripheral arterial disease (PAD). DESIGN: Retrospective meta-analysis of data
      pooled from six Phase 3, multicenter, double-blind, placebo-controlled, parallel
      group, randomized studies. SETTING: Patients were recruited from outpatient
      ambulatory medical care facilities. PARTICIPANTS: Patients' (n = 1,751) mean age
      +/- standard deviation was 65 +/- 9, and they had a history of PAD for 6 months
      or longer and an ankle brachial index (ABI) of 0.90 or less. INTERVENTION:
      Cilostazol 50 mg bid or 100 mg bid for 12, 16, or 24 weeks. MEASUREMENTS: ABI;
      maximal walking distance (MWD); pain-free walking distance on a graded and
      constant-load treadmill; and HQL, measured using the Walking Impairment
      Questionnaire (WIQ) and the Medical Outcomes Study Short Form-36 (SF-36).
      RESULTS: Maximal treadmill walking distance improved more in both cilostazol
      groups than in the placebo group (both P <.0001). WIQ and SF-36 physical summary
      scores improved significantly more with cilostazol than with placebo (for
      instance, WIQ distance score, P <.0001 and SF-36 physical summary score, P
      <.0001, comparing persons taking cilostazol with controls). Improved MWD
      correlated with improvements in WIQ (correlation with distance score, r = 0.34, P
      <.0001) and SF-36 physical summary scores (r = 0.29, P <.0001). CONCLUSIONS:
      Treatment with cilostazol was associated with greater improvements in community
      based walking ability and HQL in patients with intermittent claudication than
      treatment with placebo. These improvements correlated with increased MWD. This
      analysis of effects of cilostazol on improving walking ability in persons with
      claudication is the first cilostazol study focused on community-based measures of
      functional status and HQL. Questionnaires assessing walking ability and HQL
      provide important patient-based information about clinical outcomes of
      claudication therapy.

PMID- 12473005
TI  - Change in muscle strength explains accelerated decline of physical function in
      older women with high interleukin-6 serum levels.
AB  - OBJECTIVES: To test whether accelerated sarcopenia in older persons with high
      interleukin (IL)-6 serum levels plays a role in the prospective association
      between inflammation and disability found in many studies. DESIGN: Cohort study
      of older women with moderate to severe disability. PARTICIPANTS: Six hundred
      twenty older women from the Women's Health and Aging Study in whom information on
      baseline IL-6 serum level was available. MEASUREMENTS: Self-report of functional
      status, objective measures of walking performance, and knee extensor strength
      were assessed at baseline and over six semiannual follow-up visits. Potential
      confounders were baseline age, race, body mass index, smoking, depression, and
      medical conditions. RESULTS: At baseline, women with high IL-6 were more often
      disabled and had lower walking speed. After adjusting for confounders, women in
      the highest IL-6 tertile (IL-6>3.10 pg/mL) were at higher risk of developing
      incident mobility disability (risk ratio (RR) = 1.50, 95% confidence interval
      (CI) = 1.01-2.27), disability in activities of daily living (RR = 1.41, 95% CI =
      1.01-1.98), and severe limitation in walking (RR = 1.61, 95% CI = 1.09-2.38) and
      experienced steeper declines in walking speed (P <.001) than women in the lowest
      IL-6 tertile (IL-6 < or =1.78 pg/mL). Decline in knee extensor strength was also
      steeper, but differences across IL-6 tertiles were not significant. After
      adjusting for change over time in knee extensor strength, the association between
      high IL-6 and accelerated decline of physical function was no longer
      statistically significant. CONCLUSIONS: Older women with high IL-6 serum levels
      have a higher risk of developing physical disability and experience a steeper
      decline in walking ability than those with lower levels, which are partially
      explained by a parallel decline in muscle strength.

PMID- 12473006
TI  - Heterogeneity in older people: examining physiologic failure, age, and
      comorbidity.
AB  - OBJECTIVES: To derive a clinically relevant age-independent physiologic failure
      scoring system and to use this system to examine aspects of the association of
      physiologic failure, age, and comorbidity with inpatient mortality. DESIGN:
      Retrospective, secondary analysis of a derivation and validation cohort selected
      from the Cleveland Health Quality Choice Coalition data set. SETTING: Thirty
      hospitals in greater Cleveland. PARTICIPANTS: Thirty-one thousand nine hundred
      seventy-six inpatients aged 50 and older discharged in 1993 with a diagnosis of
      congestive heart failure, pneumonia, or stroke. MEASUREMENTS: The Inpatient
      Physiologic Failure Score (IPFS) was developed and used to calculate physiologic
      failure. Forty-four candidate variables were examined for their association with
      inpatient mortality, and 12 were selected. A point value (2, 3, 4, or 6) based on
      adjusted odds ratio was assigned for an abnormal result for each of the 12 common
      physiologic variables. Each patient's abnormal physiology points were summed to
      produce a physiologic failure score (range 0-39). Comorbidity was quantified
      using the Patient Management Category Severity Scale. The association between
      mortality and increasing physiologic failure, increasing age and comorbidity, and
      distribution of physiologic failure with increasing age and comorbidity were
      examined. A threshold age was sought. Models for predicting inpatient mortality
      were developed. RESULTS: Twelve physiologic variables constitute the IPFS.
      Increasing physiologic failure, age, and comorbidity were associated with
      increasing mortality. Increasing physiologic failure was not associated with
      increasing age or comorbidity. We did not find a threshold age. The area under
      the receiver operating characteristic (ROC) curve for predicting inpatient
      mortality for IPFS was 0.730, and for comorbidity was 0.741 (not significant).
      The area under the ROC curve for a mortality prediction model based on age was
      significantly less (0.603). Accounting for patient age did not significantly
      improve the predictive ability of the IPFS model (area = 0.752, P <.05). The
      complete model best predicted mortality (0.829). CONCLUSIONS: The IPFS represents
      a clinically relevant method for scoring physiologic failure. Physiologic
      failure, age, and comorbidity are independently and differently associated with
      inpatient mortality. Physiology fails independent of age and comorbidity.

PMID- 12473007
TI  - Adverse drug reactions as cause of hospital admissions: results from the Italian
      Group of Pharmacoepidemiology in the Elderly (GIFA).
AB  - OBJECTIVES: To determine the prevalence of adverse drug reaction (ADR)-related
      hospital admissions in an older population, to describe the most common clinical
      manifestations and drugs most frequently responsible for ADR-related hospital
      admissions, and to identify independent factors predictive of these ADRs. DESIGN:
      Multicenter pharmacoepidemiology survey conducted between 1988 and 1997. SETTING:
      Eighty-one academic hospitals throughout Italy. PARTICIPANTS: Twenty-eight
      thousand four hundred eleven patients consecutively admitted to participating
      centers during the survey periods. MEASUREMENTS: For each suspected ADR at
      admission, a physician, who coded description, severity, and potentially
      responsible drugs, completed a questionnaire. RESULTS: Mean age +/- standard
      deviation of the patients was 70 +/- 16. One thousand seven hundred four ADRs
      were identified upon hospital admission. In 964 cases (3.4% of all admissions),
      ADRs were considered to be the cause of these hospital admissions. Of these, 187
      ADRs were coded as severe. Gastrointestinal complaints (19%) represented the most
      common events, followed by metabolic and hemorrhagic complications (9%). The
      drugs most frequently responsible for these ADRs were diuretics, calcium channel
      blockers, nonsteroidal antiinflammatory drugs, and digoxin. Female sex (odds
      ratio (OR) = 1.30, 95% confidence interval (CI) = 1.10-1.54), alcohol use (OR =
      1.39, 95% CI = 1.20-1.60), and number of drugs (OR = 1.24, 95% CI = 1.20-1.27 for
      each drug increase) were independent predictors of ADR-related hospital
      admissions. For severe ADRs, age (OR = 1.50, 95% CI = 1.01-2.23 for age 65-79 and
      OR = 1.53, 95% CI = 1.00-2.33 for age > or =80, respectively), comorbidity (OR =
      1.12, 95% CI = 1.05-1.20 for each point in the Charlson Comorbidity Index), and
      number of drugs (OR = 1.18, 95% CI = 1.11-1.25 for each drug increase) were the
      only predisposing factors. CONCLUSIONS: The most important determinant of risk
      for ADR-related hospital admissions in older patients is number of drugs being
      taken. When considering only severe ADRs, risk is also related to age and
      frailty.

PMID- 12473008
TI  - Subcortical vascular disease and functional decline: a 6-year predictor study.
AB  - OBJECTIVES: To identify predictors of activity of daily living (ADL) and
      instrumental activity of daily living (IADL) decline in a population with
      subcortical vascular dementia (SVD) and to evaluate potential mechanism of
      decline. DESIGN: Longitudinal. SETTING: Hospital-based. PARTICIPANTS: Computed
      tomographic (CT) scanning identified 77 participants as having subcortical
      infarction. MEASUREMENTS: Participants were neurologically, neuropsychologically,
      behaviorally, and functionally assessed four times over 5.82 years. Baseline data
      were grouped into four modules: basic demographic and risk factor, CT scan,
      neurological and other clinical, and neuropsychological and behavioral.
      Multivariate analysis determined predictors of decline in ADLs and IADLs.
      RESULTS: Predictors of ADL decline were age, alcohol consumption, coordination,
      snout reflex, and performance on a neuropsychological test (Block Design).
      Predictors of IADL decline were predominantly cognitive and included the presence
      of paratonia and performance on the two neuropsychological tests (attention and
      memory tasks). CONCLUSION: These findings suggest that cognitive impairments are
      most likely to have an effect on IADL function, because the skills involved are
      complex and involve integrative activity, whereas physical and cognitive
      impairments combined are likely to compromise ADL function, given the more basic
      and physical nature of the functions involved. These findings indicate that in
      people with SVD, both ADL and IADL status should be monitored, because, for many,
      decline in function over time is likely, and thus the provision of appropriate
      support required.

PMID- 12473009
TI  - Cognitive and functional decline in adults aged 75 and older.
AB  - OBJECTIVES: To simultaneously examine the influence of functional disability on
      the development of cognitive impairment and the influence of cognitive status on
      the development of functional disability over time and compare findings across
      ethnic groups. DESIGN: A population-based longitudinal study. SETTING: Galveston
      County, Texas. PARTICIPANTS: Three hundred sixty-five community-dwelling Hispanic
      Americans, African Americans, and non-Hispanic whites, aged 75 and older.
      MEASUREMENTS: Baseline measures included demographics, self-reported chronic
      medical conditions, functional disability, and cognitive status. Longitudinal
      measures included functional decline and cognitive decline. RESULTS: Substantial
      functional decline was associated with each additional error on the mental status
      measure; substantial cognitive decline was associated with each additional
      antecedent disability. These findings were evident across all three ethnic
      groups, even when taking into account the effects of demographic factors and
      chronic health conditions, although the specific chronic health conditions that
      influenced cognitive and functional decline were found to vary across the three
      ethnic groups. CONCLUSION: Our findings suggest that, rather than simply being
      correlated markers of increasing frailty, cognitive and functional decline appear
      to influence the development of one another. Clinicians need to be aware of these
      associations, which may affect the direction of preventive care and
      rehabilitation in the oldest old. Appropriate intervention may result in the
      prevention or delay of functional disability and cognitive decline. Awareness of
      the specific chronic health conditions that increase the risk for cognitive or
      functional decline in various ethnic groups, and the effect of comorbid disease,
      may also help efforts to prevent decline in older adults.

PMID- 12473010
TI  - Nursing home facility risk factors for infection and hospitalization: importance
      of registered nurse turnover, administration, and social factors.
AB  - OBJECTIVES: Determine the relationship between a broad array of structure and
      process elements of nursing home care and (a) resident infection and (b)
      hospitalization for infection. DESIGN: Baseline data were collected from
      September 1992 through March 1995, and residents were followed for 2 years;
      facility data were collected at the midpoint of follow-up. SETTING: A stratified
      random sample of 59 nursing homes across Maryland. PARTICIPANTS: Two thousand
      fifteen new admissions aged 65 and older. MEASUREMENTS: Facility-level data were
      collected from interviews with facility administrators, directors of nursing, and
      activity directors; record abstraction; and direct observation. Main outcome
      measures included infection (written diagnosis, a course of antibiotic therapy,
      or radiographic confirmation of pneumonia) and hospitalization for infection
      (indicated on medical records). RESULTS: The 2-year rate of infection was 1.20
      episodes per 100 resident days, and the hospitalization rate for infection was
      0.17 admissions per 100 resident days. Except for registered nurse (RN) turnover,
      which related to both infection and hospitalization, different variables related
      to each outcome. High rates of incident infection were associated with more
      Medicare recipients, high levels of physical/occupational therapist staffing,
      high licensed practical nurse staffing, low nurses' aide staffing, high intensity
      of medical and therapeutic services, dementia training, staff privacy, and low
      levels of psychotropic medication use. High rates of hospitalization for
      infection were associated with for-profit ownership, chain affiliation, poor
      environmental quality, lack of resident privacy, lack of administrative emphasis
      on staff satisfaction, and low family/friend visitation rates. Adjustment for
      resident sex, age, race, education, marital status, number of morbid diagnoses,
      functional status, and Resource Utilization Group, Version III score did not
      alter the relationship between the structure and process of care and outcomes.
      CONCLUSIONS: The association between RN turnover and both outcomes underscores
      the relationship between nursing leadership and quality of care in these
      settings. The relationship between hospitalization for infection and for-profit
      ownership and chain affiliation could reflect policies not to treat acute
      illnesses in house. The link between social factors of care (environmental
      quality, prioritizing staff satisfaction, resident privacy, and facility
      visitation) and hospitalization indicates that a nonmedical model of care may not
      jeopardize, and may in fact benefit, health-related outcomes. All of these
      facility characteristics may be modifiable, may affect healthcare costs, and may
      hold promise for other, less-medical, forms of residential long-term care.

PMID- 12473011
TI  - Nutritional status using mini nutritional assessment and subjective global
      assessment predict mortality in geriatric patients.
AB  - OBJECTIVES: To evaluate the clinical assessment of nutritional status and
      mortality in geriatric patients. DESIGN: Prospective follow-up study. SETTING:
      Acute geriatric inpatient ward. PARTICIPANTS: Eighty-three consecutive acute
      geriatric patients (mean age +/- standard deviation = 83 +/- 7; 68% women).
      MEASUREMENTS: Patients were classified as (1) having protein-energy malnutrition
      (PEM), (2) having moderate PEM or being at risk for PEM, or (3) being well
      nourished according to Subjective Global Assessment (SGA) and Mini Nutritional
      Assessment (MNA). Body mass index ((BMI) kg/m2), arm anthropometry, and handgrip
      strength were determined. In a subgroup of patients (n = 39), body composition
      was analyzed using dual energy x-ray absorption and bioelectrical impedance.
      Three-year mortality data were obtained from the Swedish population records.
      RESULTS: Twenty percent and 26% of the patients were classified as having PEM
      based on SGA and MNA, respectively, whereas 43% and 56%, respectively, were
      classified as having moderate PEM or being at risk for PEM. Objective measures,
      such as BMI, arm anthropometry, handgrip, and body fat were 20% to 50% lower in
      the malnourished group than in the well-nourished subjects (P <.05). Moreover,
      mortality was higher in those classified as being malnourished, ranging from 40%
      after 1 year to 80% after 3 years, compared with 20% after 1 year (P =.03-0.17)
      and 50% after 3 years (P <.01) in patients classified as being well nourished.
      CONCLUSION: Fewer than one-third of newly admitted geriatric patients had a
      normal nutritional status according to SGA and MNA. BMI, arm anthropometry, body
      fat mass, and handgrip strength were reduced, and 1-, 2-, and 3-year mortality
      was higher in patients classified as malnourished. The present data justify the
      use of SGA and MNA for the assessment of nutritional status in geriatric
      patients.

PMID- 12473012
TI  - Prevalence and correlates of depressive symptoms in a community sample of people
      suffering from heart failure.
AB  - OBJECTIVES: To examine the rates and correlates of depressive symptoms and
      syndromal depression in people with self-reported heart failure participating in
      a community study of people aged 70 and older. DESIGN: Cross-sectional. SETTING:
      Community-based epidemiological study of older people from the continental United
      States. PARTICIPANTS: Six thousand one hundred twenty-five older people
      participating in the longitudinal study of Assets and Health Dynamics.
      Participants had to be born in 1923 or earlier. MEASUREMENTS: The short-form
      Composite International Diagnostic Interview assessed syndromal depression, and a
      revised version of the Center for Epidemiologic Studies-Depression scale assessed
      depressive symptoms. Medical illness was based on self-report. The authors
      compared the rates of syndromal depression and individual depressive symptoms in
      people with self-reported heart failure (n = 199) with those in people with other
      heart conditions (n = 1,856) and with no heart conditions (n = 4,070). RESULTS:
      Eleven percent of those with heart failure met criteria for syndromal depression,
      compared with 4.8% of people with other heart conditions and 3.2% of those with
      no heart conditions. The association between heart failure and depression held
      even after controlling for disability, reported fatigue and breathlessness, and
      number of comorbid chronic illnesses. CONCLUSION: Community-living older people
      with self-reported heart failure were at approximately twice the risk for
      syndromal depression of the rest of the community. Although fatigue and
      functional disability were also related to depression in this sample, these
      variables did not account for the association between syndromal depression and
      self-reported heart failure.

PMID- 12473013
TI  - Effects of aerobic exercise training in community-based subjects aged 80 and
      older: a pilot study.
AB  - OBJECTIVES: To assess the ability of sedentary, frail subjects aged 80 and older
      to train in a community-based exercise program and to evaluate clinical factors
      that predict improvements in peak oxygen consumption (VO2peak). DESIGN: Pretest,
      posttest. SETTING: Charlestown Retirement Community, Catonsville, Maryland
      PARTICIPANTS: Twenty-two (11 male, 11 female; mean age +/- standard deviation =
      84 +/- 4.0, range 80-92) self-referred. INTERVENTION: Six months of moderate
      intensity aerobic exercise training, two to three sessions/week, 20 to 30 minutes
      per session. Training modes included treadmill walking and/or stationary cycling.
      MEASUREMENTS: Baseline and follow-up maximal exercise treadmill tests (ETTs) with
      electrocardiogram monitoring and respiratory gas analysis. RESULTS: Six months of
      aerobic exercise training resulted in significant increases (mean +/- standard
      deviation) in ETT duration (11.9 +/- 3.3 vs 15.9 +/- 4.3 minutes; P =.01),
      VO2peak (1.23 +/- 0.37 vs 1.31 +/- 0.36 L/min; P =.04), and oxygen pulse (9.3 +/-
      2.8 vs 10.1 +/- 3.2; P =.03). Mean heart rate was significantly lower during
      submaximal ETT stages 1 through 4 (P <.05), and resting systolic blood pressure
      decreased (146 +/- 18 vs 133 +/- 14 mmHg; P =.01) after training. Multiple
      regression analysis indicated that baseline VO2peak (r = 0.75, P =.002) and the
      total amount of time spent in exercise training (r = 0.55, P =.008) were
      independent predictors of the training-related improvements in VO2peak.
      CONCLUSION: Subjects aged 80 and older can increase aerobic capacity and reduce
      systolic blood pressure in a community-based exercise program of moderate
      intensity. The most important predictors of change in VO2peak were baseline
      VO2peak and the time spent in exercise training. Subjects with a lower baseline
      VO2peak had the greatest improvements in VO2peak after training.

PMID- 12473014
TI  - Total plasma homocysteine, age, systolic blood pressure, and cognitive
      performance in older people.
AB  - OBJECTIVES: To investigate the relationship between total plasma homocysteine
      (tHcy) levels, blood pressure (BP) variables, renal function, and measures of
      cognitive performance in older people. DESIGN: Initial cross-sectional analysis
      of a prospective cohort. SETTING: United Kingdom (Oxfordshire) community sample.
      PARTICIPANTS: One hundred fifty-eight community-dwelling volunteers aged 60 to
      91. MEASUREMENTS: Neuropsychological tests (Cambridge Examination for Mental
      Disorders of the Elderly-Cognitive Section (CAMCOG), Mini-Mental State
      Examination (MMSE), and Geriatric Depression Scale), biochemical studies (tHcy,
      serum folate, vitamin B12, and serum cystatin C), BP, and other vascular risk
      factors. RESULTS: tHcy, age, systolic BP (SBP), and CAMCOG performance were
      significantly interrelated. tHcy was negatively associated with total CAMCOG
      score independent of years of education, serum folate, vitamin B12, and cystatin
      C levels. Older participants with higher tHcy levels had lower CAMCOG scores
      especially men aged 70 and older. Higher tHcy levels were associated with poorer
      performance on the memory and perception subscores of CAMCOG but not with the
      other cognitive subscales or MMSE score. SBP also demonstrated a significant
      negative association with total CAMCOG and MMSE scores. CONCLUSIONS: These
      results suggest independent associations between tHcy (modified by age and sex)
      and SBP and cognitive performance in older people. Further longitudinal study
      will define whether optimization of tHcy and systolic BP contributes to the
      maintenance of cognitive performance with successful aging.

PMID- 12473015
TI  - Alzheimer's disease patients' and caregivers' capacity, competency, and reasons
      to enroll in an early-phase Alzheimer's disease clinical trial.
AB  - OBJECTIVES: To examine the capacity, competency, and reasons for enrolling of
      patients with Alzheimer's disease (AD) and of their caregivers in an early phase
      AD clinical trial. DESIGN: Interviews were conducted with patients with AD,
      nondemented older persons, and caregivers. SETTING: Participants' homes.
      PARTICIPANTS: Fifteen patients with mild to moderate AD, 15 age- and education
      matched nondemented older persons, and 15 patient caregivers. MEASUREMENTS:
      Capacity was measured using the MacArthur Competency Assessment Tool for Clinical
      Research (MacCAT-CR); a study coordinator who reviewed audiotapes of the capacity
      interviews judged competency, and the reasons for a decision were determined by
      coding the capacity interviews. RESULTS: On all measures except the ability to
      make a choice, patients performed worse than controls (understanding: z = 3.2, P
      =.001; appreciation: z = 2.8, P =.005; reasoning: z = 3.5, P =.0005), and
      caregivers (understanding: z = 3.8, P =.0002; appreciation: z = 3.0, P =.003;
      reasoning: z = 3.6, P =.0003). Using the controls' performance to set
      psychometric criteria to define capacity, the proportions of patients with
      adequate understanding, appreciation, and reasoning were six of 15 (40%), three
      of 15 (20%), and five of 15 (33%). All caregivers and nine of the 15 (60%)
      patients were competent. Reasons for enrolling typically featured the potential
      benefit to the patients' health or well-being and altruism that was expressed as
      a desire to help other patients and their families or a desire to contribute to
      scientific knowledge. CONCLUSIONS: The MacCAT-CR, in particular its understanding
      scale, is a reliable and valid way to assess patient capacity and competency to
      enroll in an early-phase clinical trial. Although many patients have significant
      impairments in their capacity, some mild-stage patients are competent. Reasons
      for enrolling in an early-phase trial blend an expectation of therapeutic benefit
      and a desire to help others.

PMID- 12473016
TI  - Angiotensin-converting enzyme gene polymorphism may influence blood loss in a
      geriatric population undergoing total hip arthroplasty.
AB  - OBJECTIVES: To evaluate how angiotensin-converting enzyme (ACE) gene polymorphism
      is associated with perioperative blood loss in hip arthroplasty in a geriatric
      population. DESIGN: A case-control study of subjects consecutively undergoing
      total hip arthroplasty. SETTING: A department of orthopedic surgery in Italy.
      PARTICIPANTS: One hundred five patients, mean age +/- standard deviation 68.6 +/-
      10.4, undergoing total hip arthroplasty. MEASUREMENTS: ACE gene polymorphism was
      analyzed using polymerase chain reaction. Decrement of hemoglobin (Hb) and
      hematocrit (Ht) was calculated as the difference between the preoperative and the
      lowest postoperative value, measured 1, 2, and 3 days after surgery. Total blood
      loss was calculated as the sum of intra- and postoperative blood loss. RESULTS:
      Patients carrying the deletion homozygous and insertion/deletion heterozygous
      genotypes of the ACE gene show a higher decrement of Hb (P <.01) and Ht (P <.01)
      and higher total blood loss (P <.007) after hip surgery than subjects carrying
      the insertion (II) homozygous. The role of ACE gene polymorphism seems
      hypertension independent. Logistic regression analysis showed that II genotype
      reduces total blood loss. CONCLUSIONS: This is the largest study evaluating the
      distribution of ACE gene genotypes in patients undergoing hip arthroplasty and
      the first investigating the association between bleeding and ACE gene
      polymorphism. Our data suggest that II genotype is associated with lower total
      blood loss.

PMID- 12473017
TI  - Is satisfaction with pain management a valid and reliable quality indicator for
      use in nursing homes?
AB  - OBJECTIVES: To determine whether satisfaction with pain management can be
      measured reliably in nursing homes and to gather preliminary data about the
      validity of satisfaction assessments in this population. DESIGN: Cross-sectional
      interview study. SETTING: Two urban nursing homes. PARTICIPANTS: Sixty-six
      nursing home residents with pain. MEASUREMENTS: Overall satisfaction with pain
      management, satisfaction with pain medication, experiences related to pain
      management, cognitive function, depressive symptoms, and retest reliability of
      overall satisfaction rating. RESULTS: Most residents (60/66; 91%) could rate
      their overall satisfaction with pain management. Overall satisfaction was weakly
      correlated with pain severity at the time of the interview (Spearman correlation
      coefficient = -0.28; P =.033) and over the past week (-0.27; P =.038). Overall
      satisfaction was also negatively associated with the Geriatric Depression Scale
      score (-0.50; P <.001). Satisfaction with pain medication was associated with
      several ratings of the medication's beneficial effects, including improved
      activity, sleep, and speed of relief, but not with the frequency with which it
      caused side effects. Ratings of overall satisfaction showed good reliability
      overall (kappa = 0.62; P <.001) and for those with Mini-Mental State Examination
      scores greater than 21 (kappa = 0.70; P <.001) and 21 or less (kappa = 0.54; P
      =.004). CONCLUSION: These results suggest that satisfaction with pain management
      can be measured reliably when residents are able to report their pain, but
      further research is needed before satisfaction with pain management can be
      incorporated into routine assessments in nursing homes.

PMID- 12473018
TI  - Attitudinal barriers to effective treatment of persistent pain in nursing home
      residents.
AB  - OBJECTIVES: To systematically explore nursing home (NH) resident and staff
      attitudes that serve as barriers to detection and management of persistent pain.
      DESIGN: Survey. SETTING: Six community-based and one Veterans Affairs long-term
      care facility PARTICIPANTS: Seventy-five NH nurses, 75 certified nursing
      assistants (CNAs), and 75 communicative NH residents who reported some pain or
      discomfort "every day or almost every day." MEASUREMENTS: Three structured pain
      attitudes questionnaires (one each for NH residents, CNAs, and nurses) that
      incorporated constructs gleaned from a comprehensive literature review were
      designed. One-week test-retest reliability was calculated on a subsample of 25
      residents, 19 CNAs, and 26 nurses. Attitudinal differences between the three
      groups were evaluated using multivariate analysis of variance (MANOVA). RESULTS:
      Of 12 constructs evaluated, 10 had fair to excellent reliability indices
      (residents 0.46-0.80; CNAs 0.57-0.76; nurses 0.62-0.94). Of these 10 reliable
      constructs, MANOVA indicated significant overall attitude differences between the
      three groups. Follow-up analyses indicated that attitudes endorsed most strongly
      by residents were that chronic pain does not change, belief in external pathology
      over pain reports, fear of addiction, and fear of dependence. CNAs attitudes
      endorsed most strongly were lack of time and complaints unheard. The nurse
      attitude endorsed most strongly was complaints unheard. CONCLUSIONS: These
      findings suggest that, if residents' fears regarding addiction, worsening
      dependence, and the immutable nature of persistent pain were quelled, and if CNAs
      could feel that adequate time is available for pain assessment, perhaps improved
      pain management in the NH would result.

PMID- 12473019
TI  - Cytokines and cognition--the case for a head-to-toe inflammatory paradigm.
AB  - The brain is not only immunologically active of its own accord, but also has
      complex peripheral immune interactions. Given the central role of cytokines in
      neuroimmmunoendocrine processes, it is hypothesized that these molecules
      influence cognition via diverse mechanisms. Peripheral cytokines penetrate the
      blood-brain barrier directly via active transport mechanisms or indirectly via
      vagal nerve stimulation. Peripheral administration of certain cytokines as
      biological response modifiers produces adverse cognitive effects in animals and
      humans. There is abundant evidence that inflammatory mechanisms within the
      central nervous system (CNS) contribute to cognitive impairment via cytokine
      mediated interactions between neurons and glial cells. Cytokines mediate cellular
      mechanisms subserving cognition (e.g., cholinergic and dopaminergic pathways) and
      can modulate neuronal and glial cell function to facilitate neuronal regeneration
      or neurodegeneration. As such, there is a growing appreciation of the role of
      cytokine-mediated inflammatory processes in neurodegenerative diseases such as
      Alzheimer's disease and vascular dementia. Consistent with their involvement as
      mediators of bidirectional communication between the CNS and the peripheral
      immune system, cytokines play a key role in the hypothalamic-pituitary-adrenal
      axis activation seen in stress and depression. In addition, complex cognitive
      systems such as those that underlie religious beliefs, can modulate the effects
      of stress on the immune system. Indirect means by which peripheral or central
      cytokine dysregulation could affect cognition include impaired sleep regulation,
      micronutrient deficiency induced by appetite suppression, and an array of
      endocrine interactions. Given the multiple levels at which cytokines are capable
      of influencing cognition it is plausible that peripheral cytokine dysregulation
      with advancing age interacts with cognitive aging.

PMID- 12473020
TI  - The effect of do-not-resuscitate orders on physician decision-making.
AB  - The effect of do-not-resuscitate (DNR) orders on physicians' decisions to provide
      life-prolonging treatments other than cardiopulmonary resuscitation (CPR) for
      patients near the end of life was explored using a cross-sectional mailed survey.
      Each survey presented three patient scenarios followed by 10 treatment decisions.
      Participants were residents and attending physicians who were randomly assigned
      surveys in which all patient scenarios included or did not include a DNR order.
      Response to three case scenarios when a DNR order was present or absent were
      measured. Response from 241 of 463 physicians (52%) was received. Physicians
      agreed or strongly agreed to initiate fewer interventions when a DNR order was
      present versus absent (4.2 vs 5.0 (P =.008) in the first scenario; 6.5 vs 7.1 (P
      =.004) in the second scenario; and 5.7 vs 6.2 (P =.037) in the third scenario).
      In all three scenarios, patients with DNR orders were significantly less likely
      to be transferred to an intensive care unit, to be intubated, or to receive CPR.
      In some scenarios, the presence of a DNR order was associated with a decreased
      willingness to draw blood cultures (91% vs 98%, P =.038), central line placement
      (68% vs 80%, P =.030), or blood transfusion (75% vs 87%, P =.015). The presence
      of a DNR order may affect physicians' willingness to order a variety of
      treatments not related to CPR. Patients with DNR orders may choose to forgo other
      life-prolonging treatments, but physicians should elicit additional information
      about patients' treatment goals to inform these decisions.

PMID- 12473021
TI  - Advanced practice nursing in the care of frail older adults.
AB  - Models of care for frail older adults have increasingly used advanced practice
      nurses (APNs) to achieve outcomes. Knowledge of the common APN functions and
      skills that contribute to the success of these models could better inform
      education and evidence-based practice and guide further research, but published
      investigations associated with models of gerontologic care neither describe fully
      these functions and skills nor link the activities of the APN with specific
      outcomes. Using examples primarily from the University of Pennsylvania School of
      Nursing, this paper identifies, describes, and analyzes common functions and
      skills of APNs in published gerontologic care models; examines the strength of
      the evidence for the effect of APNs on outcomes of care; and identifies areas for
      further study.

PMID- 12473022
TI  - Managing end-of-life care: comparing the experiences of terminally Ill patients
      in managed care and fee for service.
AB  - There have been no published empirical studies comparing the experiences of
      terminally ill patients in managed care organizations (MCOs) and those in fee for
      service (FFS). This investigation represents the first empirical study to
      systematically compare substantive outcomes between populations of terminally ill
      patients enrolled in MCO and FFS healthcare delivery systems. The investigators
      interviewed 988 patients whose physicians judged them to be terminally ill and
      893 of their caregivers. Outcomes assessments were made in six domains: patient
      physician relationship; access to care and use of health care; prevalence of
      symptoms; and planning for end-of-life care, care needs, and economic burdens.
      Overall, the two populations of terminally ill patients were found to have
      comparable outcomes, but several significant differences were present. MCO
      patients were more likely than their FFS counterparts to use an inconvenient
      hospital (P =.02), spend more than 10% of their income on medical care (P =.02),
      and have been bedridden more than 50% of the time during the last 4 weeks of life
      (P =.03). Caregivers of MCO patients were as likely as the caregivers of FFS
      patients to report a substantial caregiving burden (P =.59). Despite concerns
      about the threats of MCOs to the physician-patient relationship, few differences
      in the quality of the relationship between the two cohorts were found. Finally,
      terminally ill patients in MCOs did not show better experiences than those in FFS
      on any outcome measure. Additional research is required to explore how MCOs may
      improve upon the care available to dying patients.

PMID- 12473023
TI  - Nursing homes: the family's journey.

PMID- 12473024
TI  - The lost art of caring.

PMID- 12473025
TI  - Exercise in the oldest old: some new insights and unanswered questions.

PMID- 12473026
TI  - When a dose of advanced practice nursing is the treatment.

PMID- 12473027
TI  - Aging and current perception threshold measured by neurometer in normal Taiwanese
      adults.

PMID- 12473028
TI  - Medical comorbidity and complexity of the rehabilitative procedures for older
      patients with functional impairments.

PMID- 12473029
TI  - Elevation of neutrophils and interleukin-8 in bronchoalveolar lavage fluid from
      old-old patients with cerebrovascular disease.

PMID- 12473030
TI  - The "Oldest Man on the Planet".

PMID- 12473031
TI  - New possible role of statins in age-related diseases.

PMID- 12473032
TI  - Second-generation issues in the management of depression in nursing homes.

PMID- 12473034
TI  - Treatment of delirium in older medical inpatients: a challenge for geriatric
      specialists.

PMID- 12473035
TI  - Older persons in the emergency medical care system.

PMID- 12473036
TI  - Colonization of residents with antimicrobial-resistant pathogens in skilled care
      facilities.

PMID- 12473037
TI  - The two-factor method--a new approach to categorizing the clinical stages of
      malnutrition in geriatric patients.

PMID- 12473038
TI  - Tribute to Professor Jane J.A. Robinson for her contribution to Journal of
      Advanced Nursing as Editor and then Editor-in-Chief, from 1997 to 2002.

PMID- 12473040
TI  - A review of physical restraint minimization in the acute and residential care
      settings.
AB  - OBJECTIVES: The objective of this review was to investigate physical restraint
      minimization in acute and residential care settings. The first aim was to
      determine the effectiveness of attempts to minimize the use of physical
      restraint, and the second was to generate a description of the characteristics of
      restraint minimization programmes. METHOD: A comprehensive search was undertaken
      involving all major databases and the reference lists of all relevant papers. To
      be included in the review studies had to be an evaluation of restraint
      minimization in an acute or residential care setting. As only a single randomized
      controlled trial (RCT) was identified, it was not possible statistically to pool
      the findings of different studies on the effectiveness of restraint minimization.
      To generate a description of the characteristics of restraint minimization
      programmes, the reported components of these programmes were identified and
      categorized. RESULTS: A total of 16 studies evaluating restraint minimization
      were identified: three in acute care and 13 in residential care. Of these, only
      one was an RCT, with the most common approach being the before and after study
      design. Based on the findings of the single RCT, education supported by expert
      consultation effectively reduced the use of restraint in residential care. There
      has been little evaluation of restraint minimization in acute care settings. The
      common approach to restraint minimization has involved a programme of multiple
      activities, with restraint education being the characteristic common to most
      programmes. DISCUSSION: Evidence suggests that physical restraint can be safely
      reduced in residential care settings through a combination of education and
      expert clinical consultation. There is little information on restraint
      minimization in acute care settings. The major finding of this review is the need
      for further investigation into all aspects of restraint minimization.

PMID- 12473041
TI  - Methodological issues in male caregiver research: an integrative review of the
      literature.
AB  - PURPOSE OF THE PAPER: The purpose of this integrative review of the literature is
      to identify sampling and analysis issues related to gender in caregiver research
      in the nursing and health literature. BACKGROUND: Men provide approximately 28%
      of the care in the home to functionally impaired elders in the United States of
      America (USA), and because of demographic predictions are expected to provide
      more in the future. Social science research related to male caregivers has been
      criticized as having many limitations. A critical review of the nursing and
      health literature would be helpful to nursing researchers and clinicians by
      identifying limitations in caregiving research related to gender and providing
      direction for future research. METHODS: A literature search using the CINAHL
      database and the terms 'family caregiver', 'dementia', and 'male' was conducted.
      Thirty-six articles were retrieved, reviewed, and abstracted. FINDINGS: Thirteen
      articles were qualitative studies, 22 were quantitative, and one had both
      qualitative and quantitative components. Many of the studies used small samples,
      and no analysis was included by gender. Most of the samples were convenience
      samples, with many being self-selected. There was also a lack of analysis of data
      by family relationship. No qualitative studies and only nine of the quantitative
      studies included analysis of the data by gender. Studies that reported by gender
      were all cross-sectional. CONCLUSIONS: There is a need for caregiver research
      that has larger samples of males, and includes analysis by gender and family
      relationship. There is also a need for more intervention studies that are well
      controlled, and evaluate the effect of the intervention on both male and female
      caregivers.

PMID- 12473042
TI  - Journeying from the philosophical contemplation of constructivism to the
      methodological pragmatics of health services research.
AB  - AIM: This paper presents our journey through a contemplation of the philosophical
      origins of constructivism to consider its role as an active methodology in
      qualitative research. METHOD: The first part of the paper summarizes the
      philosophical background of constructivism and the five principles underpinning
      this paradigm as described through the works of Guba and Lincoln. The
      philosophical roots of constructivism are then compared with postpositivism,
      critical realism and participatory inquiry. The paper moves on to consider their
      common methodological steps, before examining how the constructivist research
      strategy is being adopted and adapted within the pragmatics of health service
      research. Recent studies will be drawn upon to illustrate the use of
      constructivist methodology. CONCLUSION: Questions are raised about the role of
      philosophy and the extent to which it should or does underpin or influence
      qualitative research strategies. We believe that if researchers gain an
      understanding of both philosophy and methodology a richer and more robust study
      is likely to result.

PMID- 12473043
TI  - Response to: 'Editorial: use and abuse of statistics in nursing research' by H.O.
      Dickinson (2002) Journal of Advanced Nursing 39, 405-407.

PMID- 12473044
TI  - Response to: J. Paley's JAN Forum (2002) Journal of Advanced Nursing 39, 103-105.

PMID- 12473045
TI  - Response to: 'Power dressing and meta-analysis: incorporating power analysis into
      meta-analysis' by S. Muncer (2002) Journal of Advanced Nursing 38, 274-280.

PMID- 12473046
TI  - Voices from the Gila: health care issues for rural elders in south-western New
      Mexico.
AB  - BACKGROUND AND RATIONALE: A goal of the Healthy People 2010 initiative is to
      reduce or eliminate health disparities in vulnerable populations, including
      populations from rural and minority ethnic backgrounds. Rural communities,
      including elderly populations, experience lower rates of personal income,
      educational attainment, health-insurance coverage, access to emergency and
      specialty care services, and reported health status than do urban communities. A
      need exists to address identified research priorities, such as the perceptions of
      rural elders, their family members, and health care providers. AIMS: The purposes
      of this study were to explore the health care perceptions, needs, and definitions
      of health for multicultural rural elders in one county of south-western New
      Mexico, and to consider practice implications. ETHICAL ISSUES AND APPROVAL:
      Informed consent procedures followed the University of New Mexico Health Sciences
      Center Human Research Review Committee guidelines. Research methods. This
      critical ethnography incorporated ethnographic interviews, ethnographic
      participant observation, photography, review of pertinent documents, and analysis
      of contextual factors. The sample consisted of 22 participants. RESULTS/FINDINGS:
      Definitions of health varied with socioeconomic status, encompassing avoidance of
      contact with the health care system, obtaining needed medications, remaining
      independent, a sense of spiritual belonging, eating wisely, and exercising
      moderately. Three major concerns emerged from the analysis: the escalating cost
      of prescription drugs, access-to-care issues, and social isolation. STUDY
      LIMITATIONS: The primary limitation was the small sample size. Although the
      researcher's position as an outsider to local communities may also have affected
      the outcome, it provided fresh insight to regional problems. CONCLUSIONS: The
      study addressed national research priorities for a vulnerable group of rural
      elders. Nursing implications include the need for expanded knowledge and
      educational preparation regarding elder issues and community-level services,
      inclusion of elders' perspectives in the planning and delivery of health
      services, and the need for community-level, interdisciplinary collaboration and
      advocacy.

PMID- 12473047
TI  - Health-related quality of life and health service use following total hip
      replacement surgery.
AB  - AIMS OF THE STUDY: The study investigated health-related quality of life in
      relation to demographic and clinical factors, and health service use and
      satisfaction by older total hip replacement (THR) patients following discharge
      from one Australian Hospital. RATIONALE: Understanding health-related quality of
      life and patterns of service use during recovery informs caregiving and patient
      and family education needs for discharge planning and case management.
      BACKGROUND: Post-discharge, older THR patients have a high rate of health
      services use. Few valid measures of outcomes link nursing discharge or case
      management to patient-identified health status or service needs. RESEARCH
      METHODS: Ward nurses conducted telephone interviews to study self-perceived
      health-related quality of life using Medical Outcomes Study Short-Form (SF-36)
      and responses to an accompanying questionnaire on demographics, service use and
      satisfaction at 1, 2, 4, 8, and 12 weeks postdischarge. SF-36 scores were
      compared with Australian population norms according to age and gender to
      determine the relative extent of postdischarge recovery. RESULTS: Psychosocial
      recovery preceded physical recovery, which steadily improved. Physical component
      summary scores reached population norms and mental component summary scores
      exceeded norms by week 1. No differences in quality of life were found by age,
      but women took longer to recover physically. Those who lived alone did not have
      lower scores than those with residential support. General practitioners were seen
      most often; nursing visits were frequent only in weeks 1 and 2, specialist visits
      occurred at weeks 8 and 12. Allied health, hospital and pathology services were
      used less often. Most patients were satisfied or very satisfied with all services
      used. DISCUSSION/CONCLUSIONS: An almost immediate impact on quality of life was
      evident, probably indicating successful pain alleviation. Service use indicated
      adequate discharge planning and successful recovery. Having ward nurses as
      researchers was instrumental to continuity of communication between patients,
      families and service providers, which suggests increased potential for continuity
      of care.

PMID- 12473048
TI  - Gender influences beliefs about health and illness in diabetic subjects with
      severe foot lesions.
AB  - BACKGROUND: No studies have been found regarding beliefs about health and illness
      in patients with diabetic foot ulcers investigated from a patient perspective.
      Beliefs might affect self-care and health. AIM: To explore beliefs about health
      and illness among patients with severe diabetic foot lesions that might affect
      self-care practice and care-seeking behaviour. METHOD: The study design was
      explorative. A purposive sampling procedure was used. Focus group interviews were
      held, with 10 women and 11 men under 65 years (working age) and six women and 12
      men over 65 years (range 23-83 years) with present or previous diabetic foot
      lesions managed at a specialized multidisciplinary diabetic foot clinic.
      FINDINGS: Foot problems were perceived by participants as caused by both external
      and internal factors related to the individual. Self-care was practised to
      restore health when ill and in daily foot care. When help was needed it was
      sought in the professional sector. Women were active in self-care and preventive
      care, searched for information and tried to adapt to the situation. Men more
      often sought help for acute problems, discussed more foot-related problems, had a
      pessimistic view of the future, showed a passive attitude, accepted information
      given and used more complementary care from the lay sector (wife) and/or the
      professional sector (district nurse, home care staff, podiatrist). Foot lesions
      caused deterioration of perceived health and quality of life due to decreased
      ability to be active. CONCLUSION: The present study emphasizes the need to take
      into account the existence of different beliefs about health and illness,
      especially regarding gender, in the prevention and management of the diabetic
      foot.

PMID- 12473049
TI  - Implementation of the pain and symptom assessment record (PSAR).
AB  - BACKGROUND: Symptom control is a major component of care for the terminally ill
      patients. Although uncontrolled pain is distressing for patients and families,
      there are other symptoms that can be distressing such as dyspnea and fatigue.
      Determining methods to consistently assess and manage pain and other symptoms is
      a challenge for nurses, physicians and other health care professionals. In the
      Ottawa Region of Canada, health care providers raised concerns related to
      inconsistencies in pain assessment due to a variety of formats used, as the
      patient moved through the health care system. Recognizing the need for a common
      assessment tool, a working group was formed composed of 14 nurses associated with
      institutions and agencies delivering palliative care services in the Ottawa
      region, as well as a faculty member of the School of Nursing of the University of
      Ottawa. The mandate of the working group was to develop a consistent method to
      assess patients' pain and symptoms in order to facilitate communication among
      health care professionals within various health care settings. The Pain and
      Symptom Assessment Record (PSAR) was developed over 24 months. AIM: To determine
      the feasibility of implementing the PSAR in a variety of settings. METHODS: This
      exploratory study used focus groups and chart audits to gather data related to
      the utility of the PSAR. Education sessions were used to introduce the tool to
      nurses in the various settings. RESULTS: The tool was implemented in 12 settings.
      Thirty-seven education sessions were given to nurses prior to use of the tool and
      the feedback revealed that this is an important process in tool introduction. The
      results of the chart audits indicated that pain was assessed 93% of the time.
      Symptoms were less documented but fatigue was most prominent. Overall, patients
      were satisfied with their pain and symptom control. Data from the focus groups
      were analysed using content analysis and the two themes that emerged related to
      the tool were 'structure' and 'process'. CONCLUSION: There were many challenges
      in this project and lessons learned will be discussed. Based on the results, the
      tool has been modified and is currently utilized in diverse settings.

PMID- 12473050
TI  - Pain management problems in patients' terminal phase as assessed by nurses in
      Finland.
AB  - BACKGROUND: This study is part of a larger questionnaire survey concerned with
      the views of nursing staff on physical, emotional and spiritual support for
      terminally ill patients and decision making on the transition to the terminal
      phase of treatment. AIM: This article discusses the results concerning the
      prevalence of physical pain in patients and with problems in pain management.
      METHODS: A total of 328 nurses working on the inpatient wards of 32 municipal
      health centres in finland took part. Data were collected with multiple-choice
      items and one open-ended question, which were part of a larger structured
      questionnaire. The data were analysed by means of the SPSS statistical software
      and content analysis. FINDINGS: Dying patients often suffered from pain, which
      was most commonly because of cancer. Intractable pain was common. The problems of
      pain management concerned attitudes and qualifications related to treating pain,
      the assessment of the pain, pain management per se and the organization of pain
      management. CONCLUSION: The study highlights the need to increase pain education,
      discussion and agreement on the principles of pain management in municipal health
      centres in Finland.

PMID- 12473051
TI  - The work of district nurses: first assessment visits.
AB  - BACKGROUND: District nurses are the largest group of community nurses in the
      United Kingdom and overall responsibility for assessing and planning how
      patients' and families' needs are met remains an essential element of their role.
      AIM: To explore the nature of the knowledge required by district nurses to carry
      out first assessment visits and the relationship of this to the decisions they
      make. METHODS: An ethnographic design was used. The sample was 11 district nurses
      and the principal data collection methods were participant observation and two
      semi-structured interviews. The first interview, which took place immediately
      after the visit, was designed to explore general areas in relation to assessment
      and particular issues from the visit (phase 1). Following analysis of the phase 1
      interview and fieldnote data, questions for the second interview were generated
      to facilitate further exploration and clarification of important issues that had
      arisen (phase 2). The second interviews were conducted approximately 1 year later
      and data were collected during 1997 and 1998. FINDINGS: The findings revealed a
      breadth and depth of community nursing knowledge that seemed to incorporate an
      amalgam of theoretical (knowing that) with practice-based (knowing how)
      knowledge. The findings depict the range and scope of knowledge in use by
      district nurses and reflexive character of the assessment process, and challenge
      the use of theoretical models that remove knowledge from the context in which
      district nurse-patient interactions take place. CONCLUSION: The information
      search in assessment was paced to cope with the uncertainty that existed in many
      of the complex multifaceted situations encountered by the district nurses.
      Understanding assessment as a paced process was linked to making the best
      judgement at the time of the visit.

PMID- 12473052
TI  - Evaluating Emergency Nurse Practitioner services: a randomized controlled trial.
AB  - BACKGROUND: Emergency Nurse Practitioners (ENP) are increasingly managing minor
      injuries in Accident and Emergency departments across the United Kingdom. This
      study aimed to develop methods and tools that could be used to measure the
      quality of ENP-led care. These tools were then tested in a randomized controlled
      trial. METHODS: A convenience sample of 199 eligible patients, over 16 years old,
      and with specific minor injuries was randomized either to ENP-led care (n = 99)
      or Senior House Officer (SHO)-led care (n = 100) and were diagnosed, treated,
      referred or discharged by this lead clinician. Following treatment, patients were
      asked to complete a patient satisfaction questionnaire related to the
      consultation. Clinical documentation was assessed using a 'Documentation Audit
      Tool'. A follow-up questionnaire was sent to all patients at 1 month. Return
      visits to the department and missed injuries were monitored. RESULTS: Patients
      were satisfied with the level of care from both ENPs and SHOs. However, they
      reported that ENPs were easier to talk to (P = 0.009); gave them information on
      accident and illness prevention (P = 0.001); and gave them enough information on
      their injury (P = 0.007). Overall they were more satisfied with the treatment
      provided by ENPs than with that from SHOs (P < 0.001). ENPs' clinical
      documentation was of higher quality than SHOs (P < 0.001). No differences were
      found in recovery times, level of symptoms, time off work or unplanned follow-up
      between groups. Missed injuries were the same for both groups (n = 1 in each
      group). CONCLUSION: The study was sufficiently large to demonstrate higher levels
      of patient satisfaction and clinical documentation quality with ENP-led than SHO
      led care. A larger study involving 769 patients in each arm would be required to
      detect a 2% difference in missed injury rates. The methods and tools used in this
      trial could be used in Accident and Emergency departments to measure the quality
      of ENP-led care.

PMID- 12473053
TI  - The essence of cancer care: the impact of training on nurses' ability to
      communicate effectively.
AB  - BACKGROUND: The importance of effective communication between health
      professionals and patients with cancer is widely recognized. Training programmes
      aimed at improving key communication skills are becoming increasingly available.
      PURPOSE: To evaluate a communication skills programme delivered to 308 cancer
      nurses as part of degree/diploma courses. Based on previous work, it was
      hypothesized that a statistically significant improvement between pre- and
      postintervention scores would be observed. METHODS: Audiotaped nursing
      assessments with patients were undertaken before and after the course. These were
      evaluated according to coverage of nine previously identified key areas of
      communication. RESULTS: Mean postcourse scores rose by 5.9 points (P < 0.001) to
      16.3 (out of a possible 27). All nine individual areas of the assessment showed
      statistically significant improvements postintervention (P < 0.001). The areas
      showing most improvement were those with a high emotional content. CONCLUSIONS:
      This study has demonstrated that an integrated approach to communication skills
      training has the potential to improve nurses' skills, particularly in emotionally
      laden areas across the spectrum of roles in cancer care.

PMID- 12473054
TI  - A lived experience of dualism between the natural and human science paradigms in
      nursing.
AB  - AIM: To describe the use of narrative as both phenomenon and method to illuminate
      college nurse educators' nursing knowledge development through their day-to-day
      stories on the institutional landscape, which shape and are shaped by health-care
      and nursing education changes. BACKGROUND: The Ontario health-care reform in
      Canada and a shift in nursing curriculum have brought to light a different
      dimension of a theory-practice issue. The traditional predominant natural science
      approach in nursing is now no longer considered responsive to the unique
      characteristics of patients' health-care needs. Emerging from current nursing
      education is an emphasis on a human science paradigm. However, as many college
      nurse educators moved back and forth between their classrooms to clinical
      settings, they experienced tremendous tensions in living between the new caring
      paradigm and the old culture of biomedical science ideology. Compounding this
      challenge is a lack of understanding by the policymakers and administrators of
      the importance of nurses' contribution vis-a-vis an ailing health-care system.
      This growing complexity demands that nursing, as a practice discipline, should
      articulate its unique body of knowledge for advancing contributions in health
      care. METHODS: My stories of experience and those of my participants were
      analysed narratively to determine the knowledge and understanding developed from
      living the complex and interwoven changes in nursing education and practice.
      FINDINGS: Through living, telling, retelling and reliving our stories, my
      participants and I recognized a false dualism between the seemingly polarized
      biomedical and human science paradigms. CONCLUSION: The meaning of certainty
      uncertainty inherent in nursing teaching and practice demands that nurse
      educators rethink how stories of experience play out in their understanding of
      teaching future graduates the interrelationships between these two approaches.

PMID- 12473056
TI  - The biological actions of estrogens on skin.
AB  - There is still extensive disparity in our understanding of how estrogens exert
      their actions, particularly in non-reproductive tissues such as the skin.
      Although it has been recognized for some time that estrogens have significant
      effects on many aspects of skin physiology and pathophysiology, studies on
      estrogen action in skin have been limited. However, estrogens clearly have an
      important function in many components of human skin including the epidermis,
      dermis, vasculature, hair follicle and the sebaceous, eccrine and apocrine
      glands, having significant roles in skin aging, pigmentation, hair growth, sebum
      production and skin cancer. The recent discovery of a second intracellular
      estrogen receptor (ERbeta) with different cell-specific roles to the classic
      estrogen receptor (ERalpha), and the identification of cell surface estrogen
      receptors, has provided further challenges to understanding the mechanism of
      estrogen action. It is now time to readdress many of the outstanding questions
      regarding the role of estrogens in skin and improve our understanding of the
      physiology and interaction of steroid hormones and their receptors in human skin.
      Not only will this lead to a better understanding of estrogen action, but may
      also provide a basis for further interventions in pathological processes that
      involve dysregulation of estrogen action.

PMID- 12473057
TI  - Evidence that the keratinocyte colony number is genetically controlled.
AB  - We tested five inbred strains and two outbred stocks of female mice in a
      quantitative assay for clonogenic keratinocytes from the cutaneous epithelium. We
      found three significantly different subsets of colony counts such that: C57BL/6
      C3H = DBA/2 = SENCAR = BALB/c > FVB = CD(-1) in culture conditions optimized for
      CD(-1) 0. C57BL/6 and BALB/c, two inbred parental strains, were chosen for
      further analysis. The F1 generation of these two parental strains had an
      intermediate number of colonies. The keratinocyte colony number from the two
      backcross generations was significantly different, while the colony number in the
      F2 generation was intermediate between the two backcrosses. We conclude that the
      number of keratinocyte colonies represents a new genetically definable
      quantitative trait. Analysis suggests that this trait is multigenic where the
      genes have an additive but not necessarily equal effect. We have therefore laid
      the foundation for identifying these stem cell regulatory genes, which may
      provide a new perspective on the mechanism of carcinogenesis and a new target for
      gene therapy.

PMID- 12473058
TI  - Induction of HSP27 nuclear immunoreactivity during stress is modulated by vitamin
      C.
AB  - For the investigation of the skin irritancy potential of chemicals in an in vitro
      model it is necessary to have sensitive endpoints that predict the effects of
      those compounds on native human skin. Recently, we have identified that 27-kDa
      heat shock protein (HSP27) can serve as a sensitive marker of skin irritation, as
      exposure of human skin to sodium lauryl sulfate (SLS) both in vitro and in vivo
      induced relocalization of HSP27 from the cytoplasm to the cell nucleus. The aim
      of the present study was to determine whether nuclear localization of HSP27 could
      be used as a parameter for evaluation of potential skin irritants in screening
      assays in vitro. For this purpose, human skin equivalent consisting of epidermis
      reconstructed on de-epidermized dermis was exposed to SLS or UV light. Stress
      induced nuclear relocalization of HSP27 was observed in excised skin exposed to
      SLS or UV light and in reconstructed epidermis only when the latter was generated
      in the absence of vitamin C. The omission of vitamin C results in an impaired
      barrier function. In the presence of vitamin C, however, the barrier function was
      comparable with excised skin, suggesting that vitamin C may control the response
      to stress in the reconstructed epidermis. Besides the presence of vitamin C, the
      response of skin equivalents may strongly depend on other conditions under which
      they are generated, because the stress-induced HSP27 relocalization was not
      detected in the commercially available epidermal kit EpiDerm. The results of the
      present study show that HSP27 nuclear staining can serve as a sensitive marker
      for skin irritation or cellular stress in excised skin as well as in certain well
      characterized human skin equivalents in vitro.

PMID- 12473059
TI  - Mapping of the associated phenotype of an absent granular layer in ichthyosis
      vulgaris to the epidermal differentiation complex on chromosome 1.
AB  - Ichthyosis vulgaris (IV) is a mild to severe scaling disorder of uncertain
      etiology estimated to affect as many as 1 : 250 in the population. Family studies
      have shown that in many cases IV follows an autosomal dominant inheritance
      pattern, but gene mapping studies have not been reported. To investigate the
      genetic basis for inherited IV, we have performed gene linkage studies in two
      multigenerational families where affected individuals have clinical features of
      IV but distinct histological features. The epidermis in this disorder
      characteristically displays non-specific orthohyperkeratosis. Notably, a subset
      of IV patients with a reduced or absent granular epidermal layer (AGL) have been
      reported, and decreased filaggrin levels have been described in others. The
      prominent role of profilaggrin in human keratohyalin suggests that defects in the
      gene for profilaggrin (FLG), its processing of profillagrin to filaggrin, or a
      gene involved in profilaggrin regulation may underlie or modify the pathology in
      IV. Family 1 had seven individuals with IV, severe heat intolerance and epidermis
      with 1-3 granular layers (consistent with normal epidermal histology). Ichthyosis
      vulgaris in this family did not segregate with FLG or other genes in the
      epidermal differentiation complex. In contrast, five of the six IV patients in
      Family 2, all siblings, had epidermis with no granular layer. Significant
      evidence was obtained for linkage of IV with the associated AGL phenotype to the
      epidermal differentiation complex (which includes FLG) assuming either a
      recessive (max Lod 3.4) or dominant (max Lod 3.6) inheritance model. Sequence
      analysis of FLG did not reveal a mutation in the amino or carboxyl terminal
      portions of the coding sequence adjacent to filaggrin repeats. The AGL may
      represent an endophenotype for IV, and the presence of a modifier of IV pathology
      at this locus is discussed.

PMID- 12473060
TI  - Distinct TCR delta repertoires are present in the cutaneous lesions and inflamed
      duodenum of patients with dermatitis herpetiformis.
AB  - Intraepithelial gammadelta T cells are increased in the inflamed small bowel and
      are also found in increased numbers in cutaneous lesions from patients with
      dermatitis herpetiformis (DH). Thus, these cells might play an important role in
      the pathogenesis of the disease. We investigated the T-cell receptor (TCR) delta
      repertoire in involved and non-involved skin and compared it with the TCR delta
      repertoire of the inflamed duodenum and peripheral blood of the same patients. An
      identical TCR delta repertoire in the small bowel and in the cutaneous lesions
      would suggest a migration of antigen-specific gammadelta T cells from the
      intestine to the skin which cross-react with cutaneous antigens. T-cell receptor
      DV1-DV3 transcripts were amplified by reverse transcriptase (RT)-PCR and analyzed
      by complementarity determining region 3 (CDR3) size spectratyping and nucleotide
      sequencing. Our results indicate that the cutaneous TCR delta repertoires were
      oligoclonal and identical dominant gammadelta T-cell clones were present in the
      involved and non-involved skin. Furthermore, the TCR delta repertoire of the skin
      was distinct from that in the small bowel. The peripheral blood exhibited a
      restricted TCR delta repertoire, which differed from that in the intestine and
      skin. Thus, cutaneous gammadelta T cells are not specifically expanded within the
      involved skin and are unlikely to be derived from the inflamed duodenum.

PMID- 12473061
TI  - Procyanidin B-3, isolated from barley and identified as a hair-growth stimulant,
      has the potential to counteract inhibitory regulation by TGF-beta1.
AB  - With the aim of identifying natural products, which possess hair-growing
      activity, we examined more than 1000 plant extracts with respect to their growth
      promoting effects on hair epithelial cells. We discovered intensive growth
      promoting activity, about 140% relative to controls, in barley extract. Our
      strategy for identifying active compounds in barley extract involved subjecting
      it to column chromatography using HP-20 resin columns, an LH-20 resin column, and
      preparative high-performance liquid chromatography (HPLC) using an ODS column.
      The 60% (v/v) aqueous methanol eluted fraction from the HP-20 column and the 75%
      (v/v) aqueous methanol eluted fraction from the subsequent LH-20 column showed
      high hair-growing activity in vivo. We isolated two major substances from the LH
      20 active fraction using preparative HPLC. By means of mass spectrometry, 1H-NMR,
      and 13C-NMR analyses, one substance was revealed to be procyanidin B-3 and the
      other substance was identified as (+)-catechin. Purified procyanidin B-3 showed
      high hair-growing activity in the form of in vitro hair epithelial cell growth
      promoting activity and in vivo anagen-inducing activity; however (+)-catechin
      showed no hair-growing activity. For the purpose of examining the hair-growing
      mechanisms of procyanidin B-3, we examined its relationship to the TGF-beta
      signal pathway, which is known to be a regulator of catagen induction. Addition
      of TGF-beta1 to hair epithelial cell cultures dose-dependently decreased the cell
      growth, and addition of procyanidin B-3 to the culture neutralized the growth
      inhibiting effect of TGF-beta1. From these results, it is concluded that
      procyanidin B-3 can directly promote hair epithelial cell growth in vitro, has
      the potential to counteract the growth-inhibiting effect caused by TGF-beta1 in
      vitro, and has potential to stimulate anagen induction in vivo.

PMID- 12473062
TI  - Genes that are differentially expressed in rat vibrissa follicle germinative
      epithelium in vivo show altered expression patterns after extended organ culture.
AB  - Hair growth depends on maintenance of signalling between the dermal papilla and
      the germinative epithelium (GE), from which the differentiated layers of the hair
      fibre originate. Because no molecular studies have been reported which
      concentrate specifically on GE cells either in vivo or in vitro, we prepared a
      cDNA library enriched for messages which were highly expressed in GE cells to
      identify genes that may be involved in hair growth control. Of 35 subtracted
      library clones sequenced, 23 shared extensive homology with previously determined
      cDNA sequences, including LEF-1 and id4. Hair follicle organ culture models are
      often used to investigate the molecular basis of hair growth, although hair
      growth arrest occurs relatively rapidly in vitro. As an indicator of their role
      in follicle activities, we compared the expression of GE-specific clones in
      different regions of freshly isolated vibrissa follicles, with the corresponding
      regions of growth arrested, cultured follicles. Changes in the expression of some
      of these clones indicates that they could be related to fundamental cellular
      activities in the follicle. A library enriched for GE-specific clones therefore
      provides a useful source of candidate molecules for studies of follicular
      epithelial cell behaviour, both in vivo and in vitro.

PMID- 12473063
TI  - Decreased frequency of intracellular IFN-gamma producing T cells in whole blood
      preparations from patients with atopic dermatitis.
AB  - There have been contradictory reports on the shift in the T-cell cytokine
      expression pattern of peripheral blood mononuclear cells from patients with
      atopic dermatitis (AD); more specifically the interleukin (IL)-4 and interferon
      (IFN)-gamma profiles. The aim of this study was to shed further light on this
      contradiction by measuring the intracellular cytokines IL-4 and IFN-gamma by flow
      cytometry on unseparated whole blood to obtain results that, as accurately as
      possible, reflect the situation in circulating cells in vivo. The patient group
      including 64 patients with AD was compared with 18 nonatopic healthy adults. The
      results showed that the percentage of CD4+ T cells expressing IFN-gamma was
      significantly decreased (P < or = 0.001), as well as the percentage expressing IL
      4 (P < 0.05) in AD patients compared with healthy controls. Furthermore, in
      supernatants from whole blood samples stimulated with phorbol 12-myristate 13
      acetate and ionomycin, production of IFN-gamma was significantly decreased, while
      IL-4 production remained unchanged in AD patients compared with healthy controls.
      We also investigated if there was a relationship between serum IgE level and
      Phadiatop, a screening test for atopy, vs. the levels of IL-4 and IFN-gamma, but
      found no correlation with either. However, there was a significant correlation
      between disease severity and the level of total IgE (r = 0.67, P < 0.05). In
      conclusion, our results support the evidence for a decreased ability of
      peripheral CD4+ T cells to produce IFN-gamma among AD patients.

PMID- 12473064
TI  - Augmentation of monocyte interleukin-8 production by psoralen/UVA-treated CD4+ T
      cells.
AB  - Treatment of cells with psoralen and ultraviolet A light (UVA) modulates their
      cytokine production. As extracorporeal photochemotherapy has been reported to
      induce cytokine production by monocytes, we quantified interleukin-8 (IL-8), a
      representative chemokine produced by monocytes, in culture supernatants from
      human peripheral blood mononuclear cells (PBMC) treated with 8-methoxypsoralen (8
      MOP) and UVA. Lipopolysaccharide stimulated IL-8 production in 8-MOP-phototreated
      PBMC more efficiently than those untreated or treated with 8-MOP or UVA. More
      interestingly, when cultured with T-cell-stimulating anti-CD3 and anti-CD28
      antibodies, 8-MOP/UVA-treated PBMC produced enhanced amounts of IL-8 with an
      increased level of IL-8 mRNA expression. Depletion of CD4 but not CD8 T cells
      from PBMC abrogated this augmented IL-8 elaboration, and CD4 T cells per se
      secreted no substantial amount of IL-8 even upon CD3/CD28 stimulation. Thus, 8
      MOP/UVA-treated CD4 T cells stimulated monocytes to secrete IL-8. The IL-8
      overproduction was induced by direct contact of monocytes with 8-MOP/UVA-treated
      CD4 T cells but not by cytokines from the treated CD4 T cells. These findings
      imply that in extracorporeal photochemotherapy, monocytes effectively produce IL
      8 by cell-to-cell contact with 8-MOP/UVA-treated malignant CD4 T cells. The
      augmentation of monocyte cytokine/chemokine production by 8-MOP/UVA may be one of
      the mechanisms underlying the therapeutic efficacy of extracorporeal
      photochemotherapy.

PMID- 12473065
TI  - Pathways involved in proliferating, senescent and immortalized keratinocyte cell
      death mediated by two different TRAIL preparations.
AB  - Properly regulated keratinocyte cell death is fundamentally important to maintain
      structural integrity and homeostatic function of epidermis. Moreover, from an
      oncological perspective, therapeutic approaches selectively targeting apoptosis
      of malignant cell types while sparing normal keratinocytes in surrounding skin is
      desirable. Apo2Ligand/tumor necrosis factor-related apoptosis-inducing ligand
      (Apo2L/TRAIL) has been observed to preferentially induce cytopathic effects on
      transformed/malignant cell types compared with their non-neoplastic counterparts.
      In this report, two different biologically active preparations of Apo2L/TRAIL, a
      non-tagged version, NT-Apo2L/TRAIL, and a leucine zipper fusion protein, LZ
      Apo2L/TRAIL, were examined for their ability to trigger apoptosis in normal human
      keratinocytes, and in an immortalized cell line (HaCaT cells). Differences
      between these preparations were observed, including: NT-Apo2L/TRAIL induced less
      keratinocyte apoptosis compared with LZ-Apo2L/TRAIL; NT-Apo2L/TRAIL also induced
      less apoptosis of HaCaT cells compared with LZ-Apo2L/TRAIL; LZ-Apo2L/TRAIL but
      not NT-Apo2L/TRAIL induced cytotoxic effects when keratinocytes became growth
      arrested due to undergoing spontaneous replicative senescence--a biological state
      previously observed to be resistant to UV-light-induced apoptosis. Similarities
      between preparations included: an enhanced ability for both Apo2L/TRAIL
      preparations to kill a greater relative percentage of HaCaT cells compared with
      keratinocytes; enhanced cytotoxicity towards keratinocytes that had their NF-B
      activity inhibited; a dependence of both Apo2L/TRAIL preparations on FADD and
      caspase activation; triggering of the same caspase cascades including caspase 8
      and 3; and an ability to induce apoptosis even when HaCaT cells and keratinocytes
      were transduced to overexpress either Bcl-2 or Bcl-x(L) (survival factors that
      reduce susceptibility to UV-light-induced apoptosis). These results indicate that
      while both preparations of Apo2L/TRAIL possess biological activity, there are
      important differences as regards their ability to induce apoptosis in normal and
      immortalized keratinocytes. Moreover, the death receptor pathway triggered by LZ
      Apo2L/TRAIL can overcome the apoptotic resistance normally observed in response
      to UV-light mediated by Bcl-2/Bcl-x(L), as well as by the state of cellular
      senescence. Unraveling the molecular basis for these differential biological
      effects may reveal a new strategic role for these death receptor/ligands linked
      to apoptosis in maintaining the dynamic balance of keratinocyte proliferation,
      differentiation, and cell death necessary to achieve a homeostatic thickness and
      function of normal skin. In addition, it may be possible to utilize these
      Apo2L/TRAIL preparations for the treatment of various sun-induced skin cancers as
      they can differentially trigger apoptosis of transformed keratinocytes, or
      keratinocytes with abnormal NF-kappaB signaling, while sparing adjacent normal
      keratinocytes.

PMID- 12473066
TI  - Neutrophil gelatinase-associated lipocalin is a marker for dysregulated
      keratinocyte differentiation in human skin.
AB  - Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein initially
      isolated from the specific granules of human neutrophils. It is a member of the
      highly heterogeneous lipocalin protein family, which shares a common tertiary
      structure. Its synthesis is induced in gastrointestinal epithelium in association
      with inflammation and malignancy. To gain insight into its potential role in
      other epithelia we have investigated the expression of NGAL in human skin
      embryonic development, in normal adult skin, and in skin associated with
      inflammation and neoplastic transformation. In the present study we report that
      the embryonic expression of NGAL appears to be regulated in a spatio-temporal
      pattern. It was induced in the interfollicular epidermis at 20-24 weeks of
      gestational age but thereafter progressively receded towards the hair follicles.
      In normal adult skin, NGAL was detected solely in association with hair
      follicles. However, strong induction of NGAL in the epidermis was seen in a
      variety of skin disorders characterized by dysregulated epithelial
      differentiation such as psoriasis, pityriasis rubra and squamous cell carcinoma.
      In these tissues production of NGAL was confined to spatially distinct
      subpopulations of keratinocytes underlying areas of parakeratosis, whereas skin
      samples lacking parakeratotic epithelium such as lichen ruber planus, acute
      contact eczema and basal cell carcinoma were negative for NGAL. Consistent with
      being a marker for disturbed terminal differentiation, NGAL immunoreactivity
      showed an inverse pattern when compared with that of the differentiation marker
      filaggrin. The biologic functions of NGAL in epithelia are not fully known,
      although an immunomodulatory role in host defense has been proposed. In addition,
      the transient interfollicular NGAL expression during skin embryogenesis along
      with the induction of NGAL in adult parakeratotic epidermis suggests it play a
      role in epithelial differentiation pathways.

PMID- 12473067
TI  - Transcriptional regulation of tumor necrosis factor-alpha in keratinocytes
      mediated by interleukin-1beta and tumor necrosis factor-alpha.
AB  - Irritant contact dermatitis (ICD) is an inflammatory skin reaction in which
      cytokines are thought to play a crucial role. In particular, tumor necrosis
      factor-alpha (TNF-alpha) has been implicated in the mechanism of this reaction.
      We report that interleukin-1beta (IL-1beta) that has been reported up-regulated
      in many inflammatory skin conditions is capable of increasing TNF-alpha mRNA and
      protein expression in murine keratinocytes. Furthermore, we show that TNF-alpha
      is capable of up-regulating itself in keratinocytes most likely in an autocrine
      manner. The signalling mechanisms involved in both IL-1beta- and TNF-alpha
      mediated regulation of TNF-alpha are critically dependent upon protein kinase C
      (PKC), as demonstrated by blocking studies using protein kinase inhibitors.
      Furthermore, the increase in TNF-alpha mRNA expression seen after stimulation
      with rTNF-alpha and rIL-1beta involved increased transcription of TNF-alpha mRNA.
      This was demonstrated in a chloramphenicol acetyltransferase (CAT) assay using a
      CAT-construct containing the full-length TNF-alpha promoter. These observations
      support the notion of keratinocytes functioning as an amplifier of pro
      inflammatory cytokine generation in the epidermis during ICD and other
      inflammatory skin conditions.

PMID- 12473068
TI  - Abstracts of the 3rd European Symposium on Teledermatology. Graz, Austria,
      November 8-9, 2002.

PMID- 12473069
TI  - Tonically active neurons in the primate striatum and their role in the processing
      of information about motivationally relevant events.
AB  - Analysis of recordings of single neuronal activity in the striatum of monkeys
      engaged in behavioural tasks has shown that tonically active neurons (TANs) can
      be distinguished by their distinct spontaneous firing and functional properties.
      As TANs are assumed to be cholinergic interneurons, the study of their
      physiological characteristics allows us to gain an insight into the role of a
      particular type of local-circuit neuron in the processing of information at the
      striatal level. In monkeys performing various behavioural tasks, the change in
      the activity of TANs, unlike the diversity of task-related activations exhibited
      by the phasically active population of striatal neurons, involves a transient
      depression of the tonic firing related to environmental events of motivational
      significance. Such events include primary rewards and stimuli that have acquired
      a reward value during associative learning. These neurons also respond to an
      aversive air puff, indicating that their responsiveness is not restricted to
      appetitive conditions. Another striking feature of the TANs is that their
      responses can be modulated by predictions about stimulus timing. Temporal
      variations in event occurrence have been found to favour the responses of TANs,
      whereas the responses are diminished or abolished in the presence of external
      cues that predict the time at which events will occur. These data suggest that
      the TANs respond as do detectors of motivationally relevant events, but they also
      demonstrate that these neurons are influenced by predictive information based on
      past experience with a given temporal context. TANs represent a unique subset of
      striatal neurons that might serve a modulatory function, monitoring for temporal
      relationships between environmental events.

PMID- 12473070
TI  - Vagal motor neurons in rats respond to noxious and physiological gastrointestinal
      distention differentially.
AB  - Low-pressure gastrointestinal distention modulates gastrointestinal function by a
      vago-vagal reflex. Noxious visceral distention, as seen in an obstruction of the
      gastrointestinal tract, causes abdominal pain, vomiting and affective changes.
      Using single neuron recording and intracellular injection techniques, we
      characterized the neuronal responses of neurons in the dorsal motor nucleus of
      the vagus (DMNV) to low- and high-pressure distensions of stomach and duodenum.
      Low-pressure gastric distention inhibited the mean activity of the DMNV neurons
      whereas high-pressure gastric distention excited many neurons. Of 47 DMNV
      neurons, low-pressure gastric distention inhibited 39, excited four, and did not
      affect four neurons. High-pressure gastric distention inhibited 26, excited 20,
      and left one unaffected. Thirteen of the 39 DMNV neurons inhibited by low
      pressure distention of the stomach reversed their response to excitation during
      high-pressure gastric distention. Among 47 DMNV neurons, low-pressure duodenal
      distention inhibited 30, excited 10, and did not affect the remaining seven
      neurons. High-pressure distention of the duodenum inhibited 25 and excited 22
      neurons. Eight DMNV neurons inhibited by low-pressure duodenal distention were
      excited in early response to high-pressure distention of the duodenum. High
      pressure duodenal distention caused an early excitation and late inhibition in
      the mean activity of the DMNV neurons while low-pressure duodenal distention only
      produced late inhibition. These results suggest that different reflexes are
      present between physiological distention and noxious stimulation of
      gastrointestinal tract.

PMID- 12473071
TI  - Diversity, developmental regulation and distribution of murine PR55/B subunits of
      protein phosphatase 2A.
AB  - Protein phosphatase (PP2A) 2A is a hetero-trimeric holoenzyme that consists of a
      core dimer composed of a catalytic subunit that is tightly complexed with the
      scaffolding subunit PR65/A. This core dimer associates with variable regulatory
      subunits of the PR55/B, PR61/B', PR72/B" and PR93/PR110/B"' families. As PP2A
      holoenzymes containing PR55/B have been shown to be involved in the pathogenesis
      of Alzheimer's disease, we characterized the PR55/B family with particular
      emphasis on its distribution and expression in the brain. We determined the
      genomic organization of all members of the PR55/B family and cloned their murine
      cDNAs. Thereby, two novel splice variants of PR55/Bbeta were identified. In
      addition, Northern blot analysis revealed multiple transcripts for the different
      PR55 subunits, suggesting a higher variability within the PR55 family. In situ
      hybridization analysis revealed that all PR55/B subunits were widely expressed in
      the brain. PR55/Balpha and Bbeta protein expression varies significantly in areas
      of the brain affected by neurodegenerative diseases such as the hippocampus or
      cerebellum. At the cellular level, PR55/Bbeta protein expression was confined to
      neurons, whereas PR55/Balpha was also expressed in activated astrocytes
      indicating that the PR55 isoforms confer a different function to the holoenzyme
      complex. As PP2A dysfunction has been demonstrated to contribute to various human
      diseases, dissecting the PP2A holoenzyme and its particular function in different
      cell types will assist in the development of novel therapeutic strategies.

PMID- 12473072
TI  - Molecular phenotype of rat striatal neurons expressing the dopamine D5 receptor
      subtype.
AB  - Dopamine is one of the principal neurotransmitters in the basal ganglia, where it
      plays a critical role in motor control and cognitive function through its
      interactions with the specific dopamine receptors D1 to D5. Although the
      activities mediated by most dopamine receptor subtypes have already been
      determined, the role of the D5 receptor subtype in the basal ganglia has still
      not been established. Furthermore, it is often difficult to distinguish between
      dopamine D5 and D1 receptors as they are stimulated by the same ligands, and they
      have a similar molecular structure and pharmacology. In an effort to understand
      the differences between these two receptor subtypes, we have studied the
      distribution of neurons containing D5 receptors in the striatum, and their
      molecular phenotype. As a result, we show that the D5 receptor subtype is present
      in two different populations of striatal neurons, projection neurons and
      interneurons. Overall, the abundance of this receptor subtype in the striatum is
      low, particularly in striatal projection neurons of both the direct and indirect
      projection pathways. In contrast, the expression of D5 receptors in striatal
      interneurons (cholinergic, somatostatin- or parvalbumin-positive neurons) is
      high, while low to moderate expression was observed in calretinin-positive
      neurons. Our results demonstrate the presence of D5 receptors in all the striatal
      cell populations so far described, although at different intensities in each. The
      fact that a large number of striatal neurons express the D5 receptor subtype
      suggests that this receptor fulfils an important function in the process of
      integrating information in the striatum.

PMID- 12473073
TI  - Neuro-glia interaction effects on GFAP gene: a novel role for transforming growth
      factor-beta1.
AB  - Central nervous system (CNS) development is highly guided by microenvironment
      cues specially provided by neuron-glia interactions. By using a transgenic mouse
      bearing part of the gene promoter of the astrocytic maturation marker GFAP (glial
      fibrillary acidic protein) linked to the beta-galactosidase (beta-Gal) reporter
      gene, we previously demonstrated that cerebral cortical neurons increase
      transgenic beta-Gal astrocyte number and activate GFAP gene promoter by secretion
      of soluble factors in vitro. Here, we identified TGF-beta1 as the major mediator
      of this event. Identification of TGF-beta1 in neuronal and astrocyte extracts
      revealed that both cell types might synthesize this factor, however, addition of
      neurons to astrocyte monolayers greatly increased TGF-beta1 synthesis and
      secretion by astrocytes. Further, by exploiting the advantages of cell culture
      system we investigated the influence of neuron and astrocyte developmental stage
      on such interaction. We demonstrated that younger neurons derived from 14
      embryonic days wild-type mice were more efficient in promoting astrocyte
      differentiation than those derived from 18 embryonic days mice. Similarly,
      astrocytes also exhibited timed-schedule developed responsiveness to neuronal
      influence with embryonic astrocytes being more responsive to neurons than newborn
      and late postnatal astrocytes. RT-PCR assays identified TGF-beta1 transcripts in
      young but not in old neurons, suggesting that inability to induce astrocyte
      differentiation is related to TGF-beta1 synthesis and secretion. Our work reveals
      an important role for neuron-glia interactions in astrocyte development and
      strongly implicates the involvement of TGF-beta1 in this event.

PMID- 12473074
TI  - Calcium-dependent inactivation and depletion of synaptic cleft calcium ions
      combine to regulate rod calcium currents under physiological conditions.
AB  - L-type Ca2+ currents (I(Ca)) in rod photoreceptors exhibit Ca2+-dependent
      inactivation. Perforated-patch whole-cell recordings were obtained from isolated
      rods of the tiger salamander using 1.8 mm Ca2+ in the bathing medium to determine
      the extent of Ca2+-dependent inactivation of I(Ca) with physiological [Ca2+] and
      endogenous buffering. I(Ca) was measured with voltage ramps applied before and
      after 5-s steps to -40, -30, -20, or -10 mV. Long depolarizing steps in isolated
      rods produced inactivation of I(Ca) ranging from 15% at -40 mV to > 80% at -10
      mV. Because, in addition to Ca2+-dependent inactivation, depletion of synaptic
      cleft Ca2+ accompanying activation of I(Ca) can reduce presynaptic I(Ca) at
      calycal synapses, we investigated whether a similar mechanism worked at the
      invaginating rod synapse. Rods from retinal slices with intact synapses were
      compared with isolated rods in which synaptic cleft depletion is absent. I(Ca)
      was more strongly depressed by depolarization of rods in retinal slices, with ICa
      reduced by 47% following voltage steps to -40 mV. The depression of currents by
      depolarization was also greater for rods from retinal slices than isolated rods
      when Ca2+ was replaced with Ba2+ to reduce Ca2+-dependent inactivation. The
      stronger depolarization-evoked inhibition of I(Ca) in retinal slices compared to
      isolated rods probably reflects depletion of synaptic cleft Ca2+ arising from
      sustained Ca2+ influx. Inactivation of I(Ca) exhibited slow onset and recovery.
      These findings suggest that Ca2+-dependent inactivation and depletion of synaptic
      cleft Ca2+ may combine to regulate I(Ca) in response to light-evoked changes in
      rod membrane potential.

PMID- 12473075
TI  - Chemoreceptor activity is normal in mice lacking the NK1 receptor.
AB  - Substance P has been proposed to be an important neurotransmitter in the carotid
      body with the neurokinin 1 (NK1) receptor, mediating excitation between the
      glomus cells and afferent nerve endings. In order to better understand the role
      of substance P, this study examined chemoreceptor afferent activity, in vitro,
      and tissue catecholamine levels and release in adult, wild-type mice and mice
      lacking the gene for the NK1 receptor (NK1-KO). Groups did not differ
      significantly in body weight, carotid body dopamine content or carotid body
      norepinephrine content. In wild-type mice, single unit activity increased from
      0.59 +/- 0.14 Hz to 19.78 +/- 2.27 Hz during superfusion with strong hypoxia (PO2
      approximately 25 Torr). Chemoreceptor activity in NK1-KO mice, increased from
      0.71 +/- 0.23 to 21.50 +/- 3.62 Hz, and neither baseline or peak frequencies were
      significantly different from the wild-type group. Less severe hypoxia (PO2
      approximately 45 torr), evoked peak activities of 12.50 +/- 1.88 and 10.64 +/-
      3.72 Hz in wild-type and NK1-KO mice, which were also not significantly
      different. In response to severe hypoxia, free-tissue catecholamine increased to
      4.92 +/- 0.85 microm in wild-type mice and 4.26 +/- 0.63 microm in NK1-KO mice,
      which were also not significantly different. It may therefore be concluded that
      loss of NK1 receptors has little effect on chemoreceptor function in the mouse,
      and thus they play, at best, a minor role in the hypoxic chemoreception process.

PMID- 12473076
TI  - Effects of polyunsaturated fatty acids on voltage-gated K+ and Na+ channels in
      rat olfactory receptor neurons.
AB  - Although the polyunsaturated fatty acids arachidonic acid (AA) and
      docosahexaenoic acid (DHA) are enriched in the olfactory mucosa, their possible
      contribution to olfactory transduction has not been investigated. This study
      characterized their effects on voltage-gated K+ and Na+ channels of rat olfactory
      receptor neurons. Physiological (3-10 microm) concentrations of AA and DHA
      potently and irreversibly inhibited the voltage-gated K+ current in a voltage
      independent manner. In addition, both compounds significantly reduced the
      inhibitory potency of the odorants acetophenone and amyl acetate at these
      channels. By comparison, the steady-state effects of both AA and DHA on the
      voltage-gated Na+ channel were relatively weak, with half-maximal inhibition
      requiring approximately 35 microm of either compound. However, a surprising
      finding was that the initial application of 3 microm AA to a naive neuron caused
      a strong but transient inhibition of the Na+ current. The channels became almost
      completely resistant to this inhibition within 1 min, and a 2-min wash in control
      solution was insufficient to restore the strong inhibitory effect. These
      observations suggest that polyunsaturated fatty acids have the potential to
      strongly influence the coding of odorant information by olfactory receptor
      neurons.

PMID- 12473077
TI  - Substance P mobilizes intracellular calcium and activates a nonselective cation
      conductance in rat spiral ganglion neurons.
AB  - We demonstrate the expression of functional tachykinin receptors in rat spiral
      ganglion neurons (SGNs) using calcium signal measurement and whole-cell patch
      clamp recording. Substance P (SP; 10 microm, 1 s application) induced a transient
      increase in intracellular calcium. The SP dose-response study showed an EC50 of
      18.8 microm and a Hill slope of 0.77. Comparison between specific agonists for
      the three tachykinin receptor (NKR) types showed the potency NKR3 > NKR1 > NKR2
      at 10 microm. The Ca2+ response could be evoked in Ca2+-free medium and was
      blocked by N-ethylmaleimide and U-73122, indicating that Ca2+ was released from
      intracellular stores via a G-protein and phospholipase C pathway. Under whole
      cell voltage clamp recording at a holding potential of -50 mV, SP (10 microm, 1
      s) evoked a slowly developing transient inward current. The current reversed near
      to 0 mV and ionic permeability experiments revealed a cation nonselective
      conductance also permeable to large organic cations such as N-methyl-D-glucamine
      and tetraethylammonium. Neither removing extracellular calcium nor chelating
      intracellular calcium with 10 mm BAPTA could block the SP-evoked current. This
      conductance appeared coupled to G-protein activation as intracellular GDP-betaS
      blocked the SP-evoked current. Mutual desensitization and occlusion studies with
      acetylcholine and ATP showed that the SP-evoked conductance share effector
      channels and/or intracellular processes with the purinergic/cholinergic
      conductance. In SGNs, SP could have both a trophic action, via a calcium
      response, and a neuromodulatory role, by a depolarizing action through the
      activation of nonselective cation channels.

PMID- 12473078
TI  - Silymarin protects dopaminergic neurons against lipopolysaccharide-induced
      neurotoxicity by inhibiting microglia activation.
AB  - An inflammatory response in the central nervous system mediated by activation of
      microglia is a key event in the early stages of the development of
      neurodegenerative diseases. Silymarin is a polyphenolic flavanoid derived from
      milk thistle that has anti-inflammatory, cytoprotective and anticarcinogenic
      effects. In this study, we first investigated the neuroprotective effect of
      silymarin against lipopolysaccharide (LPS)-induced neurotoxicity in mesencephalic
      mixed neuron-glia cultures. The results showed that silymarin significantly
      inhibited the LPS-induced activation of microglia and the production of
      inflammatory mediators, such as tumour necrosis factor-alpha and nitric oxide
      (NO), and reduced the damage to dopaminergic neurons. Therefore, the inhibitory
      mechanisms of silymarin on microglia activation were studied further. The
      production of inducible nitric oxide synthase (iNOS) was studied in LPS
      stimulated BV-2 cells as a model of microglia activation. Silymarin significantly
      reduced the LPS-induced nitrite, iNOS mRNA and protein levels in a dose-dependent
      manner. Moreover, LPS could induce the activation of p38 mitogen-activated
      protein kinase (MAPK) and c-jun N-terminal kinase but not extracellular signal
      regulated kinase. The LPS-induced production of NO was inhibited by the selective
      p38 MAPK inhibitor SB203580. These results indicated that the p38 MAPK signalling
      pathway was involved in the LPS-induced NO production. However, the activation of
      p38 MAPK was not inhibited by silymarin. Nevertheless, silymarin could
      effectively reduce LPS-induced superoxide generation and nuclear factor kappaB
      (NF-kappaB) activation. It suggests that the inhibitory effect of silymarin on
      microglia activation is mediated through the inhibition of NF-kappaB activation.

PMID- 12473079
TI  - Interferon-gamma differentially modulates the release of cytokines and chemokines
      in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and
      macrophages.
AB  - During bacterial infections of the CNS, activated microglia could support
      leucocyte recruitment to the brain through the synthesis of cyto- and chemokines.
      In turn, invading leucocytes may feedback on microglial cells to influence their
      chemokine release pattern. Here, we analyzed the capacity of interferon-gamma
      (IFNgamma) to serve as such a leucocyte-to-microglia signal. Production of cyto-
      and chemokines was stimulated in mouse microglia cultures by treatments with
      lipopolysaccharide (LPS) from Gram-negative Escherichia coli or cell walls from
      Gram-positive Streptococcus pneumoniae (PCW). IFNgamma presence during the
      stimulation (0.1-100 ng/mL) modulated the patterns of LPS- and PCW-induced cyto-
      and chemokine release in a dose-dependent, potent and complex manner. While
      amounts of TNFalpha and IL-6 remained nearly unchanged, IFNgamma enhanced the
      production of IL-12, MCP-1 and RANTES, but attenuated that of KC, MIP-1alpha and
      MIP-2. Release modulation was obtained with IFNgamma preincubation (treatment of
      cells before LPS or PCW administration), coincubation and even delayed addition
      to an ongoing LPS or PCW stimulation. Together the changes observed for the
      microglial chemokine release under IFNgamma would shift the chemoattractive
      profile from favouring neutrophils to a preferential attraction of monocytes and
      T lymphocyte populations--as actually seen during the course of bacterial
      meningitis. The findings support the view of activated microglia as a major
      intrinsic source for an instant production of a variety of chemokines and suggest
      that leucocyte-derived IFNgamma could potentially regulate the microglial
      chemokine release pattern.

PMID- 12473080
TI  - Activity-dependent modulation of GABAergic synapses in developing rat spinal
      networks in vitro.
AB  - The role of activity-dependent plasticity in modulating inhibitory synapses was
      investigated in embryonic rat spinal cord slice cultures, by chronic exposure to
      non-NMDA receptor blockers. GABAergic synaptic efficacy in control and chronic
      treated cultures was investigated by patch-recordings from visually identified
      spinal interneurons. In both culture groups proximal stimulation induced the
      appearance of postsynaptic currents (PSCs), which were fully antagonized by 20
      microM bicuculline application and reverse polarity at potential values close to
      those reported for spontaneous GABAergic PSCs. In chronically treated cells
      GABAergic evoked PSCs displayed a larger failure rate and a smaller coefficient
      of variation of mean PSC amplitude, when compared to controls. As opposed to
      controls, chronic GABAergic evoked PSCs did not facilitate upon paired-pulse
      stimulation. Facilitation at chronic synapses was observed when extracellular
      calcium levels were decreased below physiological values (< 2 mM). Kainate was
      used to disclose any functional differences between control and treated slices.
      In accordance with the presynaptic action of kainate, the application of this
      drug along with GYKI, an AMPA receptor selective antagonist, changed, with
      analogous potency, short-term plasticity of GABAergic synapses from control and
      treated cultures. Nevertheless, in chronic cultures, the downstream effects of
      such activation unmasked short-term depression. Ultrastructural analysis of
      synapses in chronically treated cultures showed a reduction both in symmetric
      synapses and in the number of vesicles at symmetric terminals. Thus, based on
      electrophysiological and ultrastructural data, it could be suggested that during
      the development of spinal circuits, GABAergic synapses are modulated by
      glutamatergic transmission, and thus implying that excitatory transmission
      regulates the strength of GABAergic synapses.

PMID- 12473081
TI  - Aggresome-related biogenesis of Lewy bodies.
AB  - Neurodegenerative disorders such as Parkinson's disease (PD) and 'dementia with
      Lewy bodies' (DLB) are characterized pathologically by selective neuronal death
      and the appearance of intracytoplasmic protein aggregates (Lewy bodies). The
      process by which these inclusions are formed and their role in the
      neurodegenerative process remain elusive. In this study, we demonstrate a close
      relationship between Lewy bodies and aggresomes, which are cytoplasmic inclusions
      formed at the centrosome as a cytoprotective response to sequester and degrade
      excess levels of potentially toxic abnormal proteins within cells. We show that
      the centrosome/aggresome-related proteins gamma-tubulin and pericentrin display
      an aggresome-like distribution in Lewy bodies in PD and DLB. Lewy bodies also
      sequester the ubiquitin-activating enzyme (E1), the proteasome activators PA700
      and PA28, and HSP70, all of which are recruited to aggresomes for enhanced
      proteolysis. Using novel antibodies that are specific and highly sensitive to
      ubiquitin-protein conjugates, we revealed the presence of numerous discrete
      ubiquitinated protein aggregates in neuronal soma and processes in PD and DLB.
      These aggregates appear to be being transported from peripheral sites to the
      centrosome where they are sequestered to form Lewy bodies in neurons. Finally, we
      have shown that inhibition of proteasomal function or generation of misfolded
      proteins cause the formation of aggresome/Lewy body-like inclusions and
      cytotoxicity in dopaminergic neurons in culture. These observations suggest that
      Lewy body formation may be an aggresome-related event in response to increasing
      levels of abnormal proteins in neurons. This phenomenon is consistent with
      growing evidence that altered protein handling underlies the etiopathogenesis of
      PD and related disorders.

PMID- 12473082
TI  - The effect of moving textures on the responses of cells in the cat's dorsal
      lateral geniculate nucleus.
AB  - Neurons in the dorsal lateral geniculate nucleus (dLGN) of the anaesthetized cat
      were activated with test stimuli (flashing spots, counterphased gratings and
      moving bars) in the presence of a moving background texture. Moving texture alone
      produced mild excitation, as a result of stimulation of the receptive field
      centre. Fast moving coarse textures were more effective than fine slow moving
      textures. The predominant effect of texture motion, however, was to reduce the
      response to all test stimuli displayed in the receptive field centre. The effects
      were similar for X- and Y-like cells. In the case of flashed spots, the sustained
      response was more strongly suppressed than the transient response. The direction
      of motion of the texture and differences in the relative motion of bar and
      texture had no influence on the degree of suppression. These observations are
      similar to effects seen on cat retinal ganglion cells, and are probably a form of
      gain control. Such suppressive effects are transmitted to the cortex and are
      likely to be evoked by large gratings, textures and by natural stimuli, all of
      which activate extensive regions of the receptive field surround.

PMID- 12473083
TI  - Kindling-induced overexpression of Homer 1A and its functional implications for
      epileptogenesis.
AB  - Despite an extensive research on the molecular basis of epilepsy, the essential
      players in the epileptogenic process leading to epilepsy are not known. Gene
      expression analysis is one strategy to enhance our understanding of the genes
      contributing to the functional neuronal changes underlying epileptogenesis. In
      the present study, we used the novel MPSS (massively parallel signature
      sequencing) method for analysis of gene expression in the rat kindling model of
      temporal lobe epilepsy. Kindling by repeated electrical stimulation of the
      amygdala resulted in the differential expression of 264 genes in the hippocampus
      compared to sham controls. The most strongly induced gene was Homer 1A, an
      immediate early gene involved in the modulation of glutamate receptor function.
      The overexpression of Homer 1A in the hippocampus of kindled rats was confirmed
      by RT-PCR. In order to evaluate the functional implications of Homer 1A
      overexpression for kindling, we used transgenic mice that permanently overexpress
      Homer 1A. Immunohistochemical characterization of these mice showed a marked
      Homer 1A overexpression in glutamatergic neurons of the hippocampus. Kindling of
      Homer 1A overexpressing mice resulted in a retardation of seizure generalization
      compared to wild-type controls. The data demonstrate that kindling-induced
      epileptogenesis leads to a striking overexpression of Homer 1A in the
      hippocampus, which may represent an intrinsic antiepileptogenic and
      anticonvulsant mechanism in the course of epileptogenesis that counteracts
      progression of the disease.

PMID- 12473084
TI  - Increased BDNF and trk-B mRNA expression in cortical and limbic regions following
      formation of a social recognition memory.
AB  - Brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor
      kinase (trk-B), play important roles in neural plasticity, long-term potentiation
      and memory formation. Sheep form a selective recognition memory for their lambs
      within 2 h of birth. Initially, this memory is exclusively based on olfactory
      cues; however, as it consolidates over a 12-h recognition period it extends to
      incorporate visual cues. We investigated whether changes in BDNF and trk-B mRNA
      expression occurred in both olfactory and visual processing systems at 4.5 h
      postpartum, 2-3 h after the behavioural manifestations of an olfactory
      recognition memory were found. Animals that formed a recognition memory showed
      increased BDNF mRNA expression in the inferior part of the temporal cortex,
      subfield CA1 of the hippocampus, the diagonal band, basolateral amygdala and the
      anterior cingulate, medial frontal, entorhinal and pyriform cortices. No
      increases were observed in either the olfactory bulbs or the dentate gyrus.
      Expression of trk-B mRNA was significantly increased only in the medial temporal,
      entorhinal and pyriform cortices. These findings demonstrate that by 2-3 h
      following the initial formation of olfactory recognition memory there are
      BDNF/trk-B-mediated plasticity changes in brain areas involved in the
      consolidation of olfactory memory (the pyriform and entorhinal cortices).
      However, similar changes also occur in areas of the brain involved in visual
      memory, face and object recognition (the temporal cortex, entorhinal cortex,
      hippocampal subfield CA1 and basolateral amygdala), and in areas of the brain
      with integrative and attentional functions (the medial frontal and anterior
      cingulate cortices and diagonal band). This suggests that reorganization of
      neural circuits underlying the visual recognition of lambs or the integration of
      olfactory/visual information is occurring even at this time even though accurate
      behavioural recognition at this stage can only be made using olfactory cues.

PMID- 12473085
TI  - Water maze performance, exploratory activity, inhibitory avoidance and
      hippocampal plasticity in aged superior and inferior learners.
AB  - In 28- to 30-month-old rats, in vitro short-term and long-term potentiation (STP
      and LTP) were measured in area CA1 of the hippocampus in seven superior and seven
      inferior learners, that were selected from a pool of 40 rats based on water maze
      escape performance over a period of 9 days. The aim was to examine whether levels
      of STP and LTP could account for group differences in learning of water maze
      escape, spatial preference and wall (thigmotaxis)-avoidance and in short-term
      retention of an inhibitory avoidance task. There was no significant group
      difference in open-field exploration, i.e. the number of rearings. In contrast to
      expectation, the superior and inferior learners did not differ significantly from
      each other in levels of STP and LTP. However, variability in escape and spatial
      learning, but not thigmotaxis-avoidance learning, was significantly predicted by
      variability in STP and LTP in the superior group. Also, open-field exploratory
      rearings were significantly correlated with STP and LTP as well as with maze
      escape learning in the superior group. The results show that, in the aged
      superior group, levels of CA1 STP and LTP coincided with residual water maze
      escape and spatial preference learning as well as open-field exploration, i.e.
      behavioural expressions known to be related to hippocampal functioning, but not
      with learning to avoid thigmotaxis in the maze. The lack of such correlations in
      the inferior group may be due to the severe impairment in escape and spatial
      preference learning and/or the influence of yet unknown third variables on these
      relationships.

PMID- 12473086
TI  - Involvement of medullary A2 noradrenergic neurons in the activation of oxytocin
      neurons after conditioned fear stimuli.
AB  - Fear-related stimuli activate oxytocin neurons in the hypothalamus and facilitate
      oxytocin release from the pituitary. Oxytocin neurons in the supraoptic nucleus
      receive direct noradrenergic innervations from the A1 and A2 cell groups in the
      medulla oblongata. In the present study, we investigated the role of hypothalamic
      projecting noradrenergic neurons in controlling oxytocin cell activity following
      fear-related stimuli in rats. An unconditioned fear stimulus (intermittently
      applied footshock) or conditioned fear stimulus induced expression of Fos
      protein, a protein product of an immediate-early gene, in magnocellular oxytocin
      neurons in the supraoptic or paraventricular nucleus. A neurotoxin, 5-amino-2,4
      dihydroxy-alpha-methylphenylethylamine, microinjected into the vicinity of the
      supraoptic nucleus, selectively depleted the noradrenaline contents of the
      nucleus and blocked the Fos expression in the supraoptic nucleus after the
      unconditioned or conditioned fear stimulus. In the medulla oblongata, the
      unconditioned fear stimulus induced expression of Fos protein in both A2/C2 and
      A1/C1 catecholaminergic neurons. On the other hand, the conditioned fear stimulus
      induced expression of Fos protein preferentially in the A2/C2 neurons.
      Furthermore, the unconditioned fear stimulus induced Fos expression in the A1/C1
      and A2/C2 catecholaminergic neurons labelled with retrograde tracers previously
      injected into the supraoptic nucleus. The conditioned fear stimulus induced Fos
      expression preferentially in the A2/C2 catecholaminergic neurons labelled with
      the retrograde tracers. These data suggest that the conditioned fear-induced
      oxytocin cell activity is mediated by the A2 noradrenergic neurons projecting to
      oxytocin neurons, while the unconditioned fear response is mediated by both A2
      and A1 noradrenergic neurons.

PMID- 12473087
TI  - Effects of cholinergic enhancement on conditioning-related responses in human
      auditory cortex.
AB  - It has previously been shown that cholinergic blockade attenuates conditioning
      related neuronal responses in human auditory cortex. The present study was
      conducted to investigate the effect of cholinergic enhancement on such experience
      dependent cortical responses. The cholinesterase inhibitor physostigmine, or a
      placebo control, were continuously infused into healthy young volunteers, during
      differential aversive conditioning whilst brain activity was measured using event
      related functional magnetic resonance imaging (fMRI). Volunteers were presented
      with two tones, one of which (CS+) was conditioned by pairing with an electrical
      shock whereas the other was always presented without the shock (CS-).
      Conditioning-related activations, expressed as an enhanced blood oxygenation
      level dependent (BOLD) response to the salient CS+, were evident in left auditory
      cortex under placebo but not under physostigmine. This absence of conditioning
      related activations under physostigmine was due to enhanced responses to the CS-
      under physostigmine as compared to placebo. We suggest that an overactive
      cholinergic system leads to increased processing of behaviourally irrelevant
      stimuli and thus attenuates differential conditioning-related cortical
      activations.

PMID- 12473088
TI  - Human cortical representation of virtual auditory space: differences between
      sound azimuth and elevation.
AB  - Sounds convolved with individual head-related transfer functions and presented
      through headphones can give very natural percepts of the three-dimensional
      auditory space. We recorded whole-scalp neuromagnetic responses to such stimuli
      to compare reactivity of the human auditory cortex to sound azimuth and
      elevation. The results suggest that the human auditory cortex analyses sound
      azimuth, based on both binaural and monaural localization cues, mainly in the
      hemisphere contralateral to the sound, whereas elevation in the anterior space
      and in the lateral auditory space in general, both strongly relying on monaural
      spectral cues, are analyzed in more detail in the right auditory cortex. The
      binaural interaural time and interaural intensity difference cues were processed
      in the auditory cortex around 100-150 ms and the monaural spectral cues later
      around 200-250 ms.

PMID- 12473089
TI  - Developmental event-related gamma oscillations: effects of auditory attention.
AB  - This study describes maturational changes in topographical patterns, stability,
      and functional reactivity of auditory gamma band (31-63 Hz) responses (GBRs) as
      brain electrical correlates relevant for cognitive development during childhood.
      GBRs of 114 healthy children from 9 to 16 years were elicited in an auditory
      focused attention task requiring motor responding to targets, and analyzed by
      means of the wavelet transform (WT). The effects of age and task variables
      (attended side and stimulus type relevance) were examined for GBR power and phase
      locking within 120 ms after stimulation. Similar to the spontaneous gamma band
      power, the power and phase-synchronization of GBRs did not depend on the age.
      However, the functional reactivity of GBRs at specific locations changed in the
      course of development. In 9-12-year-old children, GBRs at frontal locations were
      larger and better synchronized to target than to nontarget stimulus type, and
      were larger over the left hemisphere (contralateral to the responding hand), thus
      manifesting sensitivity to external stimulus features and motor task. In 13-16
      year-old adolescents, GBRs at parietal sites were enhanced by active attending to
      the side of stimulation, thus being associated with a maintenance of attentional
      focus to stimulus location. The results indicate that (i) specific aspects of
      task-stimulus processing engage distinct spatially localized gamma networks at
      functionally relevant areas, and (ii) the neuronal substrates of gamma band
      networks and the ability to synchronize them in relation to task-specific
      processes are available in all age groups from 9 to 16 years. However, the mode
      and efficiency with which gamma networks can be entrained depends on the age.
      This age-dependent reactivity of GBRs to different task variables may reflect a
      transition in processing strategies emerging at approximately 12-13 years in
      relation to the maturation of cognitive and executive brain functions.

PMID- 12473090
TI  - Task-induced modulation of motor evoked potentials in upper-leg muscles during
      human gait: a TMS study.
AB  - The aim of this study was to determine the relative involvement of the
      corticospinal (CS) pathway in voluntarily controlled walking compared to
      unconstrained walking. In the voluntarily controlled walking condition, subjects
      had to walk at the same speed as in unconstrained walking with a mechanical
      constraint, which is known to affect specifically the upper-leg muscles. The
      motor cortex was activated transcranially using a focal magnetic stimulation coil
      in order to elicit motor evoked potentials (MEPs) in the rectus femoris (RF) and
      the biceps femoris (BF). The magnetic stimulation was delivered at the end of the
      swing (at 90% of the cycle duration), when the EMG backgrounds were similar in
      the two experimental conditions. For each subject in each condition, MEPs were
      measured for several stimulus intensities in order to establish the input/output
      (I/O) curve (MEPs amplitude plotted against stimulus strength). The results
      showed a significant increase in the MEPs amplitude of both the RF and BF in
      voluntarily controlled walking compared to unconstrained walking, which is the
      first evidence of cofacilitation of MEPs in antagonist upper-leg muscles during
      human gait. In conclusion, although a lot of studies have emphasized a privileged
      input of the corticospinal pathway to the distal lower-leg muscles, this study
      shows that, if a locomotory task requires fine control of the proximal upper-leg
      muscles, a selective facilitation of MEPs is observed in these muscles.

PMID- 12473091
TI  - Metabotropic glutamate receptor 2/3-dependent long-term depression in the nucleus
      accumbens is blocked in morphine withdrawn mice.
AB  - The nucleus accumbens (NAc) plays a crucial role in addiction. We have recently
      shown that activation of presynaptic metabotropic glutamate 2/3 receptors
      (mGlu2/3) induces long-term depression (LTD) at glutamatergic synapses in the
      mouse nucleus accumbens (NAc) through the long lasting inhibition of P/Q-type
      Ca2+ channels and the cAMP/protein kinase A (PKA) pathway. Because presynaptic
      mGlu2/3 functions are augmented in the ventral tegmental area of morphine
      withdrawn rats, we have evaluated the consequences of opiate treatment on mGlu2/3
      LTD at prelimbic NAc glutamatergic synapses. Here we report that mGlu2/3 LTD is
      abolished after 1 week of withdrawal from chronic morphine treatment; in the
      morphine-withdrawn group LTD measured 5.99 +/- 4.84% (P < 0.05) compared with
      21.13 +/- 5.42% in the sham group. In contrast, chronic morphine treatment did
      not alter the mechanisms normally underlying mGlu2/3 LTD, such as the cAMP/PKA
      pathway or P/Q-type Ca2+ channels. This study shows that one long-term
      consequence of morphine treatment is an alteration of synaptic plasticity at
      glutamatergic synapses in the NAc. Considering that mGlu2/3 agonists (e.g. LY
      354740 used in the present study to induce LTD) reduce behavioural symptoms of
      morphine withdrawal, these findings could be important in the understanding of
      the cellular events underlying the dependence-inducing properties of opiates.

PMID- 12473092
TI  - AMPA receptor antagonist LY293558 reverses preproenkephalin mRNA overexpression
      in the striatum of 6-OHDA-lesioned-rats treated with L-dopa.
AB  - Striatal neurons that contain GABA and enkephalin and project to the external
      segment of the pallidum are thought to be overactive in Parkinson's disease.
      Furthermore, it has been shown that the appearance of L-dopa-induced dyskinesias
      is correlated to an increase of preproenkephalin (PPE) mRNA expression and that
      some antagonists of glutamate receptors can prevent and reverse L-dopa-induced
      dyskinesias in parkinsonian rats. The aim of this study was therefore to analyse
      the effect of a systemic treatment with glutamate receptor antagonists, alone or
      in combination with L-dopa, on the PPE mRNA level in rats with a 6
      hydroxydopamine-induced unilateral lesion of the nigrostriatal pathway. In
      vehicle-treated animals, PPE mRNA levels were markedly increased in the striatum
      on the lesioned side. Sub-chronic L-dopa treatment, with bi-daily injections for
      22 days, induced a further increase in PPE mRNA expression in the denervated
      striatum. Administration of the AMPA receptor antagonist, LY293558, partially
      reversed the lesion-induced and L-dopa-induced increases in PPE mRNA expression.
      However, although the administration of the NMDA receptor antagonist MK801 showed
      a tendency to decrease this L-dopa induced overexpression, it did not reach
      significance. This study provides evidence that glutamatergic antagonists, and
      particularly AMPA antagonists, tend to reverse PPE neurochemical changes at the
      striatal level induced by L-dopa in hemiparkinsonian rats.

PMID- 12473093
TI  - Reduced stress-induced hyperthermia in mGluR5 knockout mice.
AB  - It hs been suggested that metabotropic glutamate receptor subtype 5 (mGluR5) play
      a role in the expression of anxiety, based on anxiolytic-like effects of the
      selective mGluR5 antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) in rodent
      models of anxiety, including stress-induced hyperthermia (SIH). To examine the
      suggested role of mGlu5 receptors in the expression of anxiety, we examined the
      stress response in mice lacking mGluR5 in several variations of the SIH
      procedure. In this paradigm, stress causes a mild increase in body temperature
      that can be blocked by known anxiolytic agents. Three procedures were employed:
      classical SIH using rectal-probe measurement of body temperature, and
      radiotelemetric measurement of body temperature in response to either saline
      injection or to the introduction of an intruder into the home cage. In all three
      procedures the mGluR5-knockout mice displayed a significant attenuation of the
      hyperthermic response to stress compared to littermate wild-type control mice. To
      confirm that our observations were likely to be due to the absence of mGluR5 in
      the knockout mice we also tested the effect of the recently described selective
      mGluR5 antagonist MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) in both
      the wild-type and mGluR5 knockout mice. Administration of MTEP in the wild-type
      mice, but not the mGluR5 knockout mice, attenuated SIH. That the mGluR5 knockout
      mice displayed an anxiolytic-like phenotype and that the mGluR5 antagonist, MTEP,
      showed a anxiolytic-like effect only in mice possessing mGluR5 further supports
      the suggestion that mGluR5 antagonists may be useful in the treatment of anxiety.

PMID- 12473094
TI  - Dynamic mechanism of nick recognition by DNA ligase.
AB  - DNA ligases are the enzymes responsible for the repair of single-stranded and
      double-stranded nicks in dsDNA. DNA ligases are structurally similar, possibly
      sharing a common molecular mechanism of nick recognition and ligation catalysis.
      This mechanism remains unclear, in part because the structure of ligase in
      complex with dsDNA has yet to be solved. DNA ligases share common structural
      elements with DNA polymerases, which have been cocrystallized with dsDNA. Based
      on the observed DNA polymerase-dsDNA interactions, we propose a mechanism for
      recognition of a single-stranded nick by DNA ligase. According to this mechanism,
      ligase induces a B-to-A DNA helix transition of the enzyme-bound dsDNA motif,
      which results in DNA contraction, bending and unwinding. For non-nicked dsDNA,
      this transition is reversible, leading to dissociation of the enzyme. For a
      nicked dsDNA substrate, the contraction of the enzyme-bound DNA motif (a)
      triggers an opened-closed conformational change of the enzyme, and (b) forces the
      motif to accommodate the strained A/B-form hybrid conformation, in which the
      nicked strand tends to retain a B-type helix, while the non-nicked strand tends
      to form a shortened A-type helix. We propose that this conformation is the
      catalytically competent transition state, which leads to the formation of the DNA
      AMP intermediate and to the subsequent sealing of the nick.

PMID- 12473095
TI  - Novel fish hypothalamic neuropeptide.
AB  - Recently, we identified novel avian and amphibian hypothalamic neuropeptides that
      inhibited gonadotropin release and stimulated growth hormone release. They were
      characterized by a similar structure including the C-terminal LPLRF-NH2 motif. To
      clarify that the expression of these novel hypothalamic neuropeptides is a
      conserved property in vertebrates, we characterized a cDNA encoding a similar
      novel peptide, having LPLRF-NH2 from the goldfish brain, by a combination of 3'
      and 5' rapid amplification of cDNA ends (RACE). The deduced peptide precursor
      consisted of 197 amino acid residues, encoding three putative peptide sequences
      that included -LPXRF (where X is L or Q) at their C-termini. Mass spectrometric
      analyses revealed that a tridecapeptide (SGTGLSATLPQRF-NH2) was derived from the
      precursor in the brain as an endogenous ligand. Southern blotting analysis of
      reverse-transcriptase-mediated PCR products demonstrated a specific expression of
      the goldfish peptide gene in the diencephalon. In situ hybridization revealed the
      cellular localization of goldfish peptide mRNA in the nucleus posterioris
      periventricularis in the hypothalamus. Immunoreactive cell bodies were also
      restricted to the the nucleus posterioris periventricularis and the nervus
      terminalis and immunoreactive fibers were distributed in several brain regions
      including the nucleus lateralis tuberis pars posterioris and pituitary. Thus, the
      goldfish hypothalamus expresses a novel neuropeptide containing the C-terminal 
      LPQRF-NH2 sequence, which may possess multiple regulatory functions and act, at
      least partly, on the pituitary to regulate pituitary hormone release.

PMID- 12473096
TI  - Monitoring the structural consequences of Phe12-->D-Phe and Leu15-->Aib
      substitution in human/rat corticotropin releasing hormone. Implications for
      design of CRH antagonists.
AB  - A new human/rat CRH analogue has been synthesized using the Fmoc/tBu solid-phase
      synthetic protocol. The sequence of the new peptide differs from the original in
      two positions, 12 and 15, at which the native amino acids l-phenylalanine 12 and
      l-leucine 15 have been replaced by the nonprotein amino acids d-phenylalanine and
      alpha-aminoisobutyric acid (Aib), respectively. The high resolution three
      dimensional solution structure of [d-Phe12, Aib15]CRH has been determined by 688
      distance constraints (656 meaningful NOE and 32 H-bonds distance limits) and 21
      angle constraints. A family of 40 energy-minimized conformers was obtained with
      average rmsd of 0.39 +/- 0.16 A and 0.99 +/- 0.13 A for backbone and heavy atoms,
      respectively, and distance penalty functions of 0.42 +/- 0.03 A2. The NMR data
      acquired in a solvent system of water/trifluoroethanol (34%/66%, v/v) revealed
      that this 41-polypeptide adopts an almost linear helical structure in solution
      with helical content which reaches an 84% of the residues. Structural analysis
      confirmed the existence of two helical peptide fragments. The first was comprised
      of residues Ile6-Arg16 and the second of residues Glu20-Ile40, forming an angle
      of 34.2 degrees. The structural differences with respect to the native peptide
      have been identified in the region d-Phe12-Glu20 where double substitution at
      positions 12 and 15 seems to perturb the elements of the native 35-residue helix.
      These structural rearrangements promote non-native intramolecular interactions in
      the region of the molecule between either the hydrophobic side-chains of d-Phe12,
      Aib15 and Leu18, or the charged groups of the residue pairs Arg16-Glu20 and His13
      Glu17 being responsible for changes in hormonal functionality. This CRH analogue
      currently exhibits lack of any activity.

PMID- 12473097
TI  - A polymer with a backbone of 3-deoxy-D-glycero-D-galacto-non-2-ulopyranosonic
      acid, a teichuronic acid, and a beta-glucosylated ribitol teichoic acid in the
      cell wall of plant pathogenic Streptomyces sp. VKM Ac-2124.
AB  - Structures of cell wall anionic polymers of the strain Streptomyces sp. VKM Ac
      2124, a causative agent of potato scab, which is phylogenetically the closest to
      plant pathogenic species S. setonii and S. caviscabies, were studied. The strain
      contains three anionic glycopolymers, viz., a teichuronic acid with a
      disaccharide repeating unit -->6)-alpha-d-Glcp-(1-->4)-beta-d-ManpNAc3NAcA-(1-->,
      a beta-glucosylated polymer of 3-deoxy-d-glycero-d-galacto-non-2-ulopyranosonic
      acid (Kdn), and a beta-glucosylated 1,5-poly(ribitol phosphate). The strain
      studied is the second representative of plant pathogenic streptomycetes inducing
      potato scab disease, the cell wall anionic polymers of which were shown to
      contain a Kdn-polymer. Presumably, the presence of Kdn-containing structures in
      the surface regions of pathogens is essential for their efficient attachment to
      host plant cells.

PMID- 12473098
TI  - Activation of transcription through the ligand-binding pocket of the orphan
      nuclear receptor ultraspiracle.
AB  - The invertebrate nuclear receptor, ultraspiracle (USP), an ortholog of the
      vertebrate RXR, is typically modelled as an orphan receptor that functions
      without a ligand-binding activity. The identification of a ligand that can
      transcriptionally activate USP would provide heuristic leads to the structure of
      potentially high affinity activating compounds, with which to detect unknown
      regulatory pathways in which this nuclear receptor participates. We show here
      that the application of the sesquiterpenoid methyl epoxyfarnesoate (juvenile
      hormone III) to Sf9 cells induces transcription from a transfected heterologous
      core promoter, through a 5'-placed DR12 enhancer to which the receptor
      ultraspiracle (USP) binds. Isolated, recombinant USP from Drosophila melanogaster
      specifically binds methyl epoxyfarnesoate, whereupon the receptor homodimerizes
      and changes tertiary conformation, including the movement of the ligand-binding
      domain alpha-helix 12. Ligand-binding pocket point mutants of USP that do not
      bind methyl epoxyfarnesoate act as dominant negative suppressors of methyl
      epoxyfarnesoate-activation of the reporter promoter, and addition of wild-type
      USP rescues this activation. These data establish a paradigm in which the USP
      ligand-binding pocket can productively bind ligand with a functional outcome of
      enhanced promoter activity, the first such demonstration for an invertebrate
      orphan nuclear receptor. USP thus establishes the precedent that invertebrate
      orphan receptors are viable targets for development of agonists and antagonists
      with which to discern and manipulate transcriptional pathways dependent on USP or
      other orphan receptors. The demonstration here of these functional capacities of
      USP in a transcriptional activation pathway has significant implications for
      current paradigms of USP action that do not include for USP a ligand-binding
      activity.

PMID- 12473099
TI  - Expanding the scorpion toxin alpha-KTX 15 family with AmmTX3 from Androctonus
      mauretanicus.
AB  - A novel toxin, AmmTX3 (3823.5 Da), was isolated from the venom of the scorpion
      Androctonus mauretanicus. It showed 94% sequence homology with Aa1 from
      Androctonus australis and 91% with BmTX3 from Buthus martensi which,
      respectively, block A-type K+ current in cerebellum granular cells and striatum
      cultured neurons. Binding and displacement experiments using rat brain
      synaptosomes showed that AmmTX3 and Aa1 competed effectively with 125I-labelled
      sBmTX3 binding. They fully inhibited the 125I-labelled sBmTX3 binding (Ki values
      of 19.5 pm and 44.2 pm, respectively), demonstrating unambiguously that the three
      molecules shared the same target in rat brain. The specific binding parameters of
      125I-labelled AmmTX3 for its site were determined at equilibrium (Kd = 66 pm,
      Bmax = 22 fmol per mg of protein). Finally, patch-clamp experiments on striatal
      neurons in culture demonstrated that AmmTX3 was able to inhibit the A-type K+
      current (Ki = 131 nm).

PMID- 12473100
TI  - ER-resident chaperone interactions with recombinant antibodies in transgenic
      plants.
AB  - In this study, we demonstrate that the folding and assembly of IgG in transgenic
      tobacco plants is orchestrated by BiP (binding protein), an endoplasmic reticulum
      resident chaperone. Expression of BiP and calreticulin was examined in transgenic
      tobacco plants that express immunoglobulin chains, either singly or in
      combination to form IgG antibody. BiP mRNA expression was lowest in wild-type
      nontransformed plants and those that expressed immunoglobulin light chain alone.
      Higher mRNA levels were detected in plants expressing fully assembled
      immunoglobulin (light and heavy chains), and the most abundant levels of RNA
      transcript were found in those plants that expressed immunoglobulin heavy chain
      alone. Estimation of total BiP demonstrated a similar pattern, with the highest
      levels detected in plants expressing immunoglobulin heavy chain alone.
      Immunoprecipitation studies demonstrated that BiP was associated with
      immunoglobulin chains extracted from protoplast lysates, but not from secreted
      fluids. Again, most BiP was coprecipitated from plants expressing heavy chain
      only and those that produced full length IgG. The binding of BiP to Ig heavy
      chains was ATP-sensitive. Co-expression of heavy and light chain resulted in IgG
      assembly and displacement of BiP from the heavy chain as the amount of light
      chain increased. Although calreticulin mRNA and total protein levels varied in a
      similar manner to those of BiP in the transgenic plants, there was no evidence
      for association between calreticulin and Ig chains, by coimmunoprecipitation. The
      results indicate that BiP, but not calreticulin, takes part in immunoglobulin
      folding and assembly in transgenic plants.

PMID- 12473101
TI  - Functional analysis of DM64, an antimyotoxic protein with immunoglobulin-like
      structure from Didelphis marsupialis serum.
AB  - Bothrops snake venoms are known to induce local tissue damage such as hemorrhage
      and myonecrosis. The opossum Didelphis marsupialis is resistant to these snake
      venoms and has natural venom inhibitors in its plasma. The aim of this work was
      to clone and study the chemical, physicochemical and biological properties of
      DM64, an antimyotoxic protein from opossum serum. DM64 is an acidic protein
      showing 15% glycosylation and with a molecular mass of 63 659 Da when analysed by
      MALDI-TOF MS. It was cloned and the amino acid sequence was found to be
      homologous to DM43, a metalloproteinase inhibitor from D. marsupialis serum, and
      to human alpha1B-glycoprotein, indicating the presence of five immunoglobulin
      like domains. DM64 neutralized both the in vivo myotoxicity and the in vitro
      cytotoxicity of myotoxins I (mt-I/Asp49) and II (mt-II/Lys49) from Bothrops asper
      venom. The inhibitor formed noncovalent complexes with both toxins, but did not
      inhibit the PLA2 activity of mt-I. Accordingly, DM64 did not neutralize the
      anticoagulant effect of mt-I nor its intracerebroventricular lethality, effects
      that depend on its enzymatic activity, and which demonstrate the dissociation
      between the catalytic and toxic activities of this Asp49 myotoxic PLA2.
      Furthermore, despite its similarity with metalloproteinase inhibitors, DM64
      presented no antihemorrhagic activity against Bothrops jararaca or Bothrops asper
      crude venoms, and did not inhibit the fibrinogenolytic activity of jararhagin or
      bothrolysin. This is the first report of a myotoxin inhibitor with an
      immunoglobulin-like structure isolated and characterized from animal blood.

PMID- 12473102
TI  - Structural diversity and transcription of class III peroxidases from Arabidopsis
      thaliana.
AB  - Understanding peroxidase function in plants is complicated by the lack of
      substrate specificity, the high number of genes, their diversity in structure and
      our limited knowledge of peroxidase gene transcription and translation. In the
      present study we sequenced expressed sequence tags (ESTs) encoding novel heme
      containing class III peroxidases from Arabidopsis thaliana and annotated 73 full
      length genes identified in the genome. In total, transcripts of 58 of these genes
      have now been observed. The expression of individual peroxidase genes was
      assessed in organ-specific EST libraries and compared to the expression of 33
      peroxidase genes which we analyzed in whole plants 3, 6, 15, 35 and 59 days after
      sowing. Expression was assessed in root, rosette leaf, stem, cauline leaf, flower
      bud and cell culture tissues using the gene-specific and highly sensitive reverse
      transcriptase-polymerase chain reaction (RT-PCR). We predicted that 71 genes
      could yield stable proteins folded similarly to horseradish peroxidase (HRP). The
      putative mature peroxidases derived from these genes showed 28-94% amino acid
      sequence identity and were all targeted to the endoplasmic reticulum by N
      terminal signal peptides. In 20 peroxidases these signal peptides were followed
      by various N-terminal extensions of unknown function which are not present in
      HRP. Ten peroxidases showed a C-terminal extension indicating vacuolar targeting.
      We found that the majority of peroxidase genes were expressed in root. In total,
      class III peroxidases accounted for an impressive 2.2% of root ESTs. Rather few
      peroxidases showed organ specificity. Most importantly, genes expressed
      constitutively in all organs and genes with a preference for root represented
      structurally diverse peroxidases (< 70% sequence identity). Furthermore, genes
      appearing in tandem showed distinct expression profiles. The alignment of 73
      Arabidopsis peroxidase sequences provides an easy access to the identification of
      orthologous peroxidases in other plant species and will provide a common platform
      for combining knowledge of peroxidase structure and function relationships
      obtained in various species.

PMID- 12473103
TI  - Complexation of ytterbium to human transferrin and its uptake by K562 cells.
AB  - There is an increasing interest in the use of lanthanides in medicine. However,
      the mechanism of their accumulation in cells is not well understood. Lanthanide
      cations are similar to ferric ions with regard to transferrin binding, suggesting
      transferrin-receptor mediated transport is possible; however, this has not yet
      been confirmed. In order to clarify this mechanism, we investigated the binding
      of Yb3+ to apotransferrin by UV-Vis spectroscopy and stopped-flow
      spectrophotometry, and found that Yb3+ binds to apotransferrin at the specific
      iron sites in the presence of bicarbonate. The apparent binding constants of
      these sites showed that the affinity of Yb3+ is lower than that of Fe3+and
      binding of Yb3+ in the N-lobe is kinetically favored while the C-lobe is
      thermodynamically favored. The first Yb3+ bound to the C-lobe quantitatively with
      a Yb/apotransferrin molar ratio of < 1, whereas the binding to the other site is
      weaker and approaches completeness by a higher molar ratio only. As demonstrated
      by 1H NMR spectra, Yb3+ binding disturbed the conformation of apotransferrin in a
      manner similar to Fe3+. Flow cytometric studies on the uptake of fluorescein
      isothiocyanate labeled Yb3+-bound transferrin species by K562 cells showed that
      they bind to the cell receptors. Laser scanning confocal microscopic studies with
      fluorescein isothiocyanate labeled Yb3+-bound transferrin and propidium iodide
      labeled DNA and RNA in cells indicated that the Yb3+ entered the cells. The Yb3+
      transferrin complex inhibited the uptake of the fluorescein labeled ferric
      saturated transferrin (Fe2-transferrin) complex into K562 cells. The results
      demonstrate that the complex of Yb3+-transferrin complex was recognized by the
      transferrin receptor and that the transferrin-receptor-mediated mechanism is a
      possible pathway for Yb3+ accumulation in cells.

PMID- 12473104
TI  - Trehalose-phosphate synthase of Mycobacterium tuberculosis. Cloning, expression
      and properties of the recombinant enzyme.
AB  - The trehalose-phosphate synthase (TPS) of Mycobacterium smegmatis was previously
      purified to apparent homogeneity and several peptides from the 58 kDa protein
      were sequenced. Based on that sequence information, the gene for TPS was
      identified in the Mycobacterium tuberculosis genome, and the gene was cloned and
      expressed in Escherichia coli with a (His)6 tag at the amino terminus. The TPS
      was expressed in good yield and as active enzyme, and was purified on a metal ion
      column to give a single band of approximately 58 kDa on SDS/PAGE. Approximately
      1.3 mg of purified TPS were obtained from a 1-L culture of E. coli (
      approximately 2.3 g cell paste). The purified recombinant enzyme showed a single
      band of approximately 58 kDa on SDS/PAGE, but a molecular mass of approximately
      220 kDa by gel filtration, indicating that the active TPS is probably a
      tetrameric protein. Like the enzyme originally purified from M. smegmatis, the
      recombinant enzyme is an unusual glycosyltransferase as it can utilize any of the
      nucleoside diphosphate glucose derivatives as glucosyl donors, i.e. ADP-glucose,
      CDP-glucose, GDP-glucose, TDP-glucose and UDP-glucose, with ADP-glucose, GDP
      glucose and UDP-glucose being the preferred substrates. These studies prove
      conclusively that the mycobacterial TPS is indeed responsible for catalyzing the
      synthesis of trehalose-P from any of the nucleoside diphosphate glucose
      derivatives. Although the original enzyme from M. smegmatis was greatly
      stimulated in its utilization of UDP-glucose by polyanions such as heparin, the
      recombinant enzyme was stimulated only modestly by heparin. The Km for UDP
      glucose as the glucosyl donor was approximately 18 mm, and that for GDP-glucose
      was approximately 16 mm. The enzyme was specific for glucose-6-P as the glucosyl
      acceptor, and the Km for this substrate was approximately 7 mm when UDP-glucose
      was the glucosyl donor and approximately 4 mm with GDP-glucose. TPS did not show
      an absolute requirement for divalent cations, but activity was increased about
      twofold by 10 mm Mn2+. This recombinant system will be useful for obtaining
      sufficient amounts of protein for structural studies. TPS should be a valuable
      target site for chemotherapeutic intervention in tuberculosis.

PMID- 12473105
TI  - The membrane-bound [NiFe]-hydrogenase (Ech) from Methanosarcina barkeri: unusual
      properties of the iron-sulphur clusters.
AB  - The purified membrane-bound [NiFe]-hydrogenase from Methanosarcina barkeri was
      studied with electron paramagnetic resonance (EPR) focusing on the properties of
      the iron-sulphur clusters. The EPR spectra showed signals from three different
      [4Fe-4S] clusters. Two of the clusters could be reduced under 101 kPa of H2,
      whereas the third cluster was only partially reduced. Magnetic interaction of one
      of the clusters with an unpaired electron localized on the Ni-Fe site indicated
      that this was the proximal cluster as found in all [NiFe]-hydrogenases. Hence,
      this cluster was assigned to be located in the EchC subunit. The other two
      clusters could therefore be assigned to be bound to the EchF subunit, which has
      two conserved four-Cys motifs for the binding of a [4Fe-4S] cluster. Redox
      titrations at different pH values demonstrated that the proximal cluster and one
      of the clusters in the EchF subunit had a pH-dependent midpoint potential. The
      possible relevance of these properties for the function of this proton-pumping
      [NiFe]-hydrogenase is discussed.

PMID- 12473106
TI  - Structural analysis of Francisella tularensis lipopolysaccharide.
AB  - The structure of the lipid A and core region of the lipopolysaccharide (LPS) from
      Francisella tularensis (ATCC 29684) was analysed using NMR, mass spectrometry and
      chemical methods. The LPS contains a beta-GlcN-(1-6)-GlcN lipid A backbone, but
      has a number of unusual structural features; it apparently has no substituent at
      O-1 of the reducing end GlcN residue in the lipid part in the major part of the
      population, no substituents at O-3 and O-4 of beta-GlcN, and no substituent at O
      4 of the Kdo residue. The largest oligosaccharide, isolated after strong alkaline
      deacylation of NaBH4 reduced LPS had the following structure: where Delta-GalNA
      (1-3)-beta-QuiNAc represents a modified fragment of the O-chain repeating unit.
      Two shorter oligosaccharides lacking the O-chain fragment were also identified. A
      minor amount of the disaccharide beta-GlcN-(1-6)-alpha-GlcN-1-P was isolated from
      the same reaction mixture, indicating the presence of free lipid A, unsubstituted
      by Kdo and with phosphate at the reducing end. The lipid A, isolated from the
      products of mild acid hydrolysis, had the structure 2-N-(3-O-acyl4-acyl2)-beta
      GlcN-(1-6)-2-N-acyl1-3-O-acyl3-GlcN where acyl1, acyl2 and acyl3 are 3
      hydroxyhexadecanoic or 3-hydroxyoctadecanoic acids, acyl4 is tetradecanoic or
      (minor) hexadecanoic acids. No phosphate substituents were found in this
      compound. OH-1 of the reducing end glucosamine, and OH-3 and OH-4 of the
      nonreducing end glucosamine residues were not substituted. LPS of F. tularensis
      exhibits unusual biological properties, including low endoxicity, which may be
      related to its unusual lipid A structure.

PMID- 12473107
TI  - Characterization of a low redox potential laccase from the basidiomycete C30.
AB  - A new exocellular laccase was purified from the basidiomycete C30. LAC2 is an
      acidic protein (pI = 3.2) preferentially produced upon a combined induction by
      copper and p-hydroxybenzoate. The spectroscopic signature (UV/visible and EPR) of
      this isoform is typical of multicopper oxidases, but its enzymatic and physico
      chemical properties proved to be markedly different from those of LAC1, the
      constitutive laccase previously purified from the same organism. In particular,
      the LAC2 kcat values observed for the oxidation of the substrates syringaldazine
      (kcat = 65 600 min-1), ABTS (2,2-azino-bis-[3-ethylthiazoline-6-sulfonate] (kcat
      = 41 000 min-1) and guaiacol (kcat = 75 680 min-1) are 10-40 times those obtained
      with LAC1 and the redox potential of its T1 copper is 0.17 V lower than that of
      LAC1 (E degrees = 0.73 V). This is the first report on a single organism
      producing simultaneously both a high and a low redox potential laccase. The cDNA,
      clac2, was cloned and sequenced. It encodes a protein of 528 amino acids that
      shares 69% identity (79% similarity) with LAC1 and 81% identity (95% similarity)
      with Lcc3-2 from Polyporus ciliatus (AF176321-1), its nearest neighbor in
      database. Possible reasons for why this basidiomycete produces, in vivo, enzyme
      forms with such different behaviors are discussed.

PMID- 12473108
TI  - Double-stranded RNA-activated protein kinase interacts with apoptosis signal
      regulating kinase 1. Implications for apoptosis signaling pathways.
AB  - Double-stranded RNA-activated protein kinase (PKR), a serine/threonine kinase, is
      activated in virus-infected cells and acts as an antiviral machinery of type I
      interferons. PKR controls several stress response pathways induced by double
      stranded RNA, tumor necrosis factor-alpha or lipopolysaccharide, which result in
      the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase and
      p38 of the mitogen-activated protein kinase family. Here we showed a novel
      interaction between PKR and apoptosis signal-regulating kinase 1 (ASK1), one of
      the members of the mitogen-activated protein kinase kinase kinase family, which
      is activated in response to a variety of apoptosis-inducing stimuli. PKR and ASK1
      showed predominant cytoplasmic localization in COS-1 cells transfected with both
      cDNAs, and coimmunoprecipitated from the cell extracts. A dominant negative
      mutant of PKR (PKR-KR) inhibited both the apoptosis and p38 activation induced by
      ASK1 in vivo. Consistently, PKR-KR inhibited the autophosphorylation of ASK1 in
      vitro, and exposure to poly(I)-poly(C) increased the phosphorylation of ASK1 in
      vivo. These results indicate the existence of a link between PKR and ASK1, which
      modifies downstream MAPK.

PMID- 12473109
TI  - Loss-of-function variants of the human melanocortin-1 receptor gene in melanoma
      cells define structural determinants of receptor function.
AB  - The alpha-melanocyte-stimulating hormone (alphaMSH) receptor (MC1R) is a major
      determinant of mammalian skin and hair pigmentation. Binding of alphaMSH to MC1R
      in human melanocytes stimulates cell proliferation and synthesis of
      photoprotective eumelanin pigments. Certain MC1R alleles have been associated
      with increased risk of melanoma. This can be theoretically considered on two
      grounds. First, gain-of-function mutations may stimulate proliferation, thus
      promoting dysplastic lesions. Second, and opposite, loss-of-function mutations
      may decrease eumelanin contents, and impair protection against the carcinogenic
      effects of UV light, thus predisposing to skin cancers. To test these
      possibilities, we sequenced the MC1R gene from seven human melanoma cell (HMC)
      lines and three giant congenital nevus cell (GCNC) cultures. Four HMC lines and
      two GCNC cultures contained MC1R allelic variants. These were the known loss-of
      function Arg142His and Arg151Cys alleles and a new variant, Leu93Arg. Moreover,
      impaired response to a superpotent alphaMSH analog was demonstrated for the cell
      line carrying the Leu93Arg allele and for a HMC line homozygous for wild-type
      MC1R. Functional analysis in heterologous cells stably or transiently expressing
      this variant demonstrated that Leu93Arg is a loss-of-function mutation abolishing
      agonist binding. These results, together with site-directed mutagenesis of the
      vicinal Glu94, demonstrate that the MC1R second transmembrane fragment is
      critical for agonist binding and maintenance of a resting conformation, whereas
      the second intracellular loop is essential for coupling to the cAMP system.
      Therefore, loss-of-function, but not activating MC1R mutations are common in HMC.
      Their study provides important clues to understand MC1R structure-function
      relationships.

PMID- 12473110
TI  - Transcriptional activity of interferon regulatory factor (IRF)-3 depends on
      multiple protein-protein interactions.
AB  - Virus infection results in the activation of a set of cellular genes involved in
      host antiviral defense. IRF-3 has been identified as a critical transcription
      factor in this process. The activation mechanism of IRF-3 is not fully
      elucidated, yet it involves a conformational change triggered by the virus
      dependent phosphorylation of its C-terminus. This conformational change leads to
      nuclear accumulation, DNA binding and transcriptional transactivation. Here we
      show that two distinct sets of Ser/Thr residues of IRF-3, on phosphorylation,
      synergize functionally to achieve maximal activation. Remarkably, we find that
      activated IRF-3 lacks transcriptional activity, but activates transcription
      entirely through the recruitment of the p300/CBP coactivators. Moreover, we show
      that two separate domains of IRF-3 interact with several distinct regions of
      p300/CBP. Interference with any of these interactions leads to a complete loss of
      transcriptional activity, suggesting that a bivalent interaction is essential for
      coactivator recruitment by IRF-3.

PMID- 12473111
TI  - RING finger, B-box, and coiled-coil (RBCC) protein expression in branchial
      epithelial cells of Japanese eel, Anguilla japonica.
AB  - An RBCC (RING finger, B-box, and coiled-coil) protein was identified that belongs
      to the superfamily of zinc-binding proteins and is specifically expressed in the
      gill of eel, Anguilla japonica. Euryhaline fishes such as eels can migrate
      between freshwater and seawater, which is considered to be accomplished by
      efficient remodeling of the architecture and function of the gill, a major
      osmoregulatory organ. To identify molecules involved in such adaptive changes, we
      performed differential display using mRNA preparations from freshwater and
      seawater eel gills and obtained an RBCC clone among several differentially
      expressed clones. The clone encoded a protein of 514 amino acid residues with
      structural features characteristic of the RBCC protein; we therefore named it
      eRBCC (e for eel). eRBCC mRNA was specifically expressed in the gills with a
      greater extent in the gills of freshwater eels. Immunohistochemistry revealed
      that the expression of eRBCC is confined to particular epithelial cells of the
      gills including freshwater-specific lamellar chloride cells. The RING finger of
      eRBCC was found to have a ubiquitin ligase activity, suggesting an important
      regulatory role of eRBCC in the remodeling of branchial cells.

PMID- 12473112
TI  - Expression and characterization of recombinant vitamin K-dependent gamma-glutamyl
      carboxylase from an invertebrate, Conus textile.
AB  - The marine snail Conus is the sole invertebrate wherein both the vitamin K
      dependent carboxylase and its product, gamma-carboxyglutamic acid, have been
      identified. To examine its biosynthesis of gamma-carboxyglutamic acid, we studied
      the carboxylase from Conus venom ducts. The carboxylase cDNA from Conus textile
      has an ORF that encodes a 811-amino-acid protein which exhibits sequence
      similarity to the vertebrate carboxylases, with 41% identity and approximately
      60% sequence similarity to the bovine carboxylase. Expression of this cDNA in COS
      cells or insect cells yielded vitamin K-dependent carboxylase activity and
      vitamin K-dependent epoxidase activity. The recombinant carboxylase has a
      molecular mass of approximately 130 kDa. The recombinant Conus carboxylase
      carboxylated Phe-Leu-Glu-Glu-Leu and the 28-residue peptides based on residues 
      18 to +10 of human proprothrombin and proFactor IX with Km values of 420 micro m,
      1.7 micro m and 6 micro m, respectively; the Km for vitamin K is 52 micro m. The
      Km values for peptides based on the sequence of the conotoxin epsilon-TxIX and
      two precursor analogs containing 12 or 29 amino acids of the propeptide region
      are 565 micro m, 75 micro m and 74 micro m, respectively. The recombinant Conus
      carboxylase, in the absence of endogenous substrates, is stimulated up to
      fivefold by vertebrate propeptides but not by Conus propeptides. These results
      suggest two propeptide-binding sites in the carboxylase, one that binds the Conus
      and vertebrate propeptides and is required for substrate binding, and the other
      that binds only the vertebrate propeptide and is required for enzyme stimulation.
      The marked functional and structural similarities between the Conus carboxylase
      and vertebrate vitamin K-dependent gamma-carboxylases argue for conservation of a
      vitamin K-dependent carboxylase across animal species and the importance of gamma
      carboxyglutamic acid synthesis in diverse biological systems.

PMID- 12473113
TI  - O-GalNAc incorporation into a cluster acceptor site of three consecutive
      threonines. Distinct specificity of GalNAc-transferase isoforms.
AB  - O-Glycosylation of three consecutive Thr residues in a fluorescein-conjugated
      peptide PTTTPLK - which mimics a portion of mucin 2 - by four isozymes of UDP-N
      acetylgalactosaminyltransferases (pp-GalNAc-T1, T2, T3, or T4) was investigated.
      Partially glycosylated versions of this peptide, PT*TTPLK, PTTT*PLK, PT*TT*PLK,
      PTT*T*PLK, PT* degrees TTPLK, and PTTT* degrees PLK (*, N-acetylgalactosamine;
      degrees, galactose), were also tested. The products were separated by RP-HPLC and
      characterized by MALDI-TOF MS and peptide sequencing. The first and the third Thr
      residues act as the peptide's initial glycosylation sites for pp-GalNAc-T4, which
      were different from the sites for pp-GalNAc-T1 and T2 (the first Thr residue) or
      T3 (the third Thr residue) shown in our previous report. All pp-GalNAc-T isozymes
      tested exhibited distinct specificities toward glycopeptides. The most notable
      findings were: (a) prior incorporation of an N-acetylgalactosamine residue at the
      third Thr greatly enhanced N-acetylgalactosamine incorporation into the other Thr
      residues when pp-GalNAc-T2, T3, or T4 were used; (b) the enhancing effect of the
      N-acetylgalactosamine residue on the third Thr was completely abrogated by
      galactosylation of this N-acetylgalactosamine; (c) prior incorporation of an N
      acetylgalactosamine at the first Thr did not have any enhancing effect; (d) pp
      GalNAc-T2 was unique as it transferred N-acetylgalactosamine into the second Thr
      residue only when N-acetylgalactosamine was attached to the third one.

PMID- 12473114
TI  - Oxidation of propionate to pyruvate in Escherichia coli. Involvement of
      methylcitrate dehydratase and aconitase.
AB  - The pathway of the oxidation of propionate to pyruvate in Escherichia coli
      involves five enzymes, only two of which, methylcitrate synthase and 2
      methylisocitrate lyase, have been thoroughly characterized. Here we report that
      the isomerization of (2S,3S)-methylcitrate to (2R,3S)-2-methylisocitrate requires
      a novel enzyme, methylcitrate dehydratase (PrpD), and the well-known enzyme,
      aconitase (AcnB), of the tricarboxylic acid cycle. AcnB was purified as 2
      methylaconitate hydratase from E. coli cells grown on propionate and identified
      by its N-terminus. The enzyme has an apparent Km of 210 micro m for (2R,3S)-2
      methylisocitrate but shows no activity with (2S,3S)-methylcitrate. On the other
      hand, PrpD is specific for (2S,3S)-methylcitrate (Km = 440 micro m) and catalyses
      in addition only the hydration of cis-aconitate at a rate that is five times
      lower. The product of the dehydration of enzymatically synthesized (2S,3S)
      methylcitrate was designated cis-2-methylaconitate because of its ability to form
      a cyclic anhydride at low pH. Hence, PrpD catalyses an unusual syn elimination,
      whereas the addition of water to cis-2-methylaconitate occurs in the usual anti
      manner. The different stereochemistries of the elimination and addition of water
      may be the reason for the requirement for the novel methylcitrate dehydratase
      (PrpD), the sequence of which seems not to be related to any other enzyme of
      known function. Northern-blot experiments showed expression of acnB under all
      conditions tested, whereas the RNA of enzymes of the prp operon (PrpE, a
      propionyl-CoA synthetase, and PrpD) was exclusively present during growth on
      propionate. 2D gel electrophoresis showed the production of all proteins encoded
      by the prp operon during growth on propionate as sole carbon and energy source,
      except PrpE, which seems to be replaced by acetyl-CoA synthetase. This is in good
      agreement with investigations on Salmonella enterica LT2, in which disruption of
      the prpE gene showed no visible phenotype.

PMID- 12473115
TI  - The C-terminal domain of perfringolysin O is an essential cholesterol-binding
      unit targeting to cholesterol-rich microdomains.
AB  - There is much evidence to indicate that cholesterol forms lateral membrane
      microdomains (rafts), and to suggest their important role in cellular signaling.
      However, no probe has been produced to analyze cholesterol behavior, especially
      cholesterol movement in rafts, in real time. To obtain a potent tool for
      analyzing cholesterol dynamics in rafts, we prepared and characterized several
      truncated fragments of theta-toxin (perfringolysin O), a cholesterol-binding
      cytolysin, whose chemically modified form has been recently shown to bind
      selectively to rafts. BIAcore and structural analyses demonstrate that the C
      terminal domain (domain 4) of the toxin is the smallest functional unit that has
      the same cholesterol-binding activity as the full-size toxin with structural
      stability. Cell membrane-bound recombinant domain 4 was detected in the floating
      low-density fractions and was found to be cofractionated with the raft-associated
      protein Lck, indicating that recombinant domain 4 also binds selectively to
      cholesterol-rich rafts. Furthermore, an enhanced green fluorescent protein-domain
      4 fusion protein stains membrane surfaces in a cholesterol-dependent manner in
      living cells. Therefore, domain 4 of theta-toxin is an essential cholesterol
      binding unit targeting to cholesterol in membrane rafts, providing a very useful
      tool for further studies on lipid rafts on cell surfaces and inside cells.

PMID- 12473116
TI  - Requirement of caspase and p38MAPK activation in zinc-induced apoptosis in human
      leukemia HL-60 cells.
AB  - Zinc (Zn), an endogenous regulator of apoptosis, and has abilities both to induce
      apoptosis and inhibit the induction of apoptosis via the modulation of caspase
      activity. Due to the multifunctions of Zn, the intracellular Zn level is strictly
      regulated by a complex system in physiological and pathological conditions. The
      commitment of Zn to the regulation of apoptosis is not fully understood. In the
      present study, we investigated the role of intracellular Zn level in the
      induction of apoptosis in human leukemia cells (HL-60 cells) using a Zn ionophore
      [pyrithione (Py)]. Treatment of HL-60 cells with Zn for 6 h in the presence of Py
      (1 micro m) exhibited cytotoxicity in a Zn dose-dependent manner (25-200 micro
      m). Necrotic cells, assayed by trypan blue permeability, increased in number in a
      Zn dose-dependent fashion (50-100 micro m), but the appearance of apoptotic
      cells, assayed by formation of a DNA ladder and terminal
      deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling method, peaked
      at 25 micro m, suggesting the dependence of intracellular Zn level on the
      execution of apoptosis. In fact, treatment with Py resulted in increases in
      intracellular Zn levels, and N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine,
      a cell-permeable Zn chelator, inhibited DNA ladder formation induced by Py/Zn
      treatment (1 micro m Py and 25 micro m Zn). Py/Zn treatment activated the
      caspases, as assessed by the proteolysis of poly(ADP-ribose) polymerase (PARP),
      which is a substrate of caspase, and activated p38 mitogen-activated protein
      kinase (p38MAPK), which is a transducer of apoptotic stimuli to the apparatus of
      the apoptosis execution. Z-Asp-CH2-DCB, a broad-spectrum inhibitor of caspase,
      attenuated proteolysis of PARP and DNA ladder formation by Py/Zn, indicating that
      apoptosis induced by Py/Zn is mediated by caspase activation. The p38MAPK
      specific inhibitor SB203580 also inhibited induction of apoptosis by Py/Zn.
      Although SB203580 suppressed the proteolysis of PARP, Z-Asp-CH2-DCB did not
      inhibit the phosphorylation of p38MAPK, raising the possibility that apoptosis
      triggered by Py/Zn might be mediated by the p38MAPK/caspase pathway.

PMID- 12473117
TI  - Thermolysin-linearized microcin J25 retains the structured core of the native
      macrocyclic peptide and displays antimicrobial activity.
AB  - Microcin J25 (MccJ25) is the single macrocyclic antimicrobial peptide belonging
      to the ribosomally synthesized class of microcins that are secreted by
      Enterobacteriaceae. It showed potent antibacterial activity against several
      Salmonella and Escherichia strains and exhibited a compact three-dimensional
      structure [Blond et al. (2001) Eur. J. Biochem., 268, 2124-2133]. The molecular
      mechanisms involved in the biosynthesis, folding and mode of action of MccJ25 are
      still unknown. We have investigated the structure and the antimicrobial activity
      of thermolysin-linearized MccJ25 (MccJ25-L1-21: VGIGTPISFY10GGGAGHVPEY20F), as
      well as two synthetic analogs, sMccJ25-L1-21 (sequence of the thermolysin-cleaved
      MccJ25) and sMccJ25-L12-11 (C-terminal sequence of the MccJ25 precursor:
      G12GAGHVPEYF21V1GIGTPISFYG11). The three-dimensional solution structure of MccJ25
      L1-21, determined by two-dimensional NMR, consists of a boot-shaped hairpin-like
      well-defined 8-19 region flanked by disordered N and C termini. This structure is
      remarkably similar to that of cyclic MccJ25, and includes a short double-stranded
      antiparallel beta-sheet (8-10/17-19) perpendicular to a loop (Gly11-His16). The
      thermolysin-linearized MccJ25-L1-21 had antibacterial activity against E. coli
      and S. enteritidis strains, while both synthetic analogues lacked activity and
      organized structure. We show that the 8-10/17-19 beta-sheet, as well as the Gly11
      His16 loop are required for moderate antibacterial activity and that the Phe21
      Pro6 loop and the MccJ25 macrocyclic backbone are necessary for complete
      antibacterial activity. We also reveal a highly stable 8-19 structured core
      present in both the native MccJ25 and the thermolysin-linearized peptide, which
      is maintained under thermolysin treatment and resists highly denaturing
      conditions.

PMID- 12473118
TI  - Structural and compositional changes in very low density lipoprotein
      triacylglycerols during basal lipolysis.
AB  - Triacylglycerols secreted by liver and carried by very low density lipoprotein
      (VLDL) are hydrolysed in circulation by lipoprotein and hepatic lipases. These
      enzymes have been shown to have positional and fatty acid specificity in vitro.
      If there were specificity in basal lipolysis in vivo, triacylglycerol
      compositions of circulating and newly secreted VLDL would be different. To study
      this we compared the composition of normal fasting VLDL triacylglycerol of Wistar
      rats to that obtained after blocking lipolysis by Triton WR1339, which increased
      plasma VLDL triacylglycerol concentration about 4.7-fold in 2 h. Analyses of
      molecular species of sn-1,2- and sn-2,3-diacylglycerol moieties and
      stereospecific triacylglycerol analysis revealed major differences between the
      groups in the VLDL triacylglycerol composition. In nontreated rats, the
      proportion of 16:0 was higher and that of 18:2n-6 lower in the sn-1 position. The
      proportion of 14:0 was lower in all positions and that of 18:0 was lower in the
      sn-1 and sn-3 positions in nontreated rats whereas the proportions of 20:4n-6,
      20:5n-3, 22:5n-3 and 22:6n-3 were higher in the sn-1 and lower in the sn-2
      position. These results suggest that the fatty acid of the sn-1 position is the
      most decisive factor in determining the sensitivity for hydrolysis of the
      triacylglycerol. In addition, triacylglycerol species with highly unsaturated
      fatty acids in the sn-2 position also favoured hydrolysis. The in vivo substrate
      specificity followed only partly that obtained in in vitro studies indicating
      that the nature of molecular association of fatty acids in natural
      triacylglycerol affects its susceptibility to lipolysis. To conclude, our results
      indicate that preferential basal lipolysis leads to major structural differences
      between circulating and newly secreted VLDL triacylglycerol. These differences
      extend beyond those anticipated from analysis of total fatty acids and constitute
      a previously unrecognized feature of VLDL triacylglycerol metabolism.

PMID- 12473119
TI  - Reconstructing the replication complex of AcMNPV.
AB  - Baculoviruses are well known for their large, circular, double-stranded DNA
      genomes. The type member, AcMNPV, is the best characterized and undergoes a
      succession of early, late and very late gene expression during its infection
      cycle. The viral genes involved in DNA replication have previously been
      identified and their products are required for the activation of late gene
      expression. In this study, we FLAG- and HA-tagged the replication late expression
      factors of AcMNPV, examined their expression and functional activities by CAT
      assay and Western blot analysis, and determined their subcellular localization in
      transfected cells by subcellular fractionation and immunofluorescent microscopy.
      We found that all replication LEFs with the exception of P143 and P35 resided in
      the nucleus of transfected cells. We further investigated the interactions among
      various replication LEFs using both yeast two-hybrid and coprecipitation
      strategies. A summary of the interactive properties of the replication LEFs is
      presented and a model for a putative AcMNPV replication complex is offered.

PMID- 12473120
TI  - Identification and characterization of a novel activated RhoB binding protein
      containing a PDZ domain whose expression is specifically modulated in thyroid
      cells by cAMP.
AB  - In a search for genes regulated in response to cAMP we have identified a new
      protein, p76RBE, whose mRNA and protein expression is enhanced in thyrocytes
      following thyrotropin stimulation of the cAMP transduction cascade. This protein
      presents important similarities with Rhophilin and contains different protein
      protein interaction motifs. The presence of HR1 and PDZ motifs as well as a
      potential PDZ binding domain motif suggests that p76RBE could be implicated in
      targeting or scaffolding processes. By yeast two-hybrid screenings and
      coimmunoprecipitation, we show here that p76RBE is a specific binding protein of
      RhoB and binds selectively to the GTP-bound form of this small GTPase. p76RBE
      also binds in vitro to components of the cytoskeleton, including cytokeratin 18.
      p76RBE is essentially cytoplasmic in transfected COS-7 mammalian cells and seems
      to be recruited to an endosomal compartment when coexpressed with the activated
      form of RhoB. p76RBE was shown to be mainly expressed in tissues with high
      secretion activity. Our data suggest that p76RBE could play a key role between
      RhoB and potential downstream elements needed under stimulation of the
      thyrotropin/cAMP pathway in thyrocytes and responsible for intracellular motile
      phenomena such as the endocytosis involved in the thyroid secretory process.

PMID- 12473121
TI  - Stepwise adaptations of citrate synthase to survival at life's extremes. From
      psychrophile to hyperthermophile.
AB  - The crystal structure of citrate synthase from the thermophilic Archaeon
      Sulfolobus solfataricus (optimum growth temperature = 85 degrees C) has been
      determined, extending the number of crystal structures of citrate synthase from
      different organisms to a total of five that span the temperature range over which
      life exists (from psychrophile to hyperthermophile). Detailed structural analysis
      has revealed possible molecular mechanisms that determine the different
      stabilities of the five proteins. The key to these mechanisms is the precise
      structural location of the additional interactions. As one ascends the
      temperature ladder, the subunit interface of this dimeric enzyme and loop regions
      are reinforced by complex electrostatic interactions, and there is a reduced
      exposure of hydrophobic surface. These observations reveal a progressive pattern
      of stabilization through multiple additional interactions at solvent exposed,
      loop and interfacial regions.

PMID- 12473122
TI  - Determinants of antagonist binding at the alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid receptor subunit, GluR-D. Role of the conserved arginine
      507 and glutamate 727 residues.
AB  - Previous structural and mutagenesis studies indicate that the invariant alpha
      amino and alpha-carboxyl groups of glutamate receptor agonists are engaged in
      polar interactions with oppositely charged, conserved arginine and glutamate
      residues in the ligand-binding domain of alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid receptor. To examine the role of these residues (R507 and
      E727 in the GluR-D subunit) in the discrimination between agonists and
      antagonists, we analyzed the ligand-binding properties of homomeric GluR-D and
      its soluble ligand-binding domain with mutations at these positions. Filter
      binding assays using [3H]AMPA, an agonist, and [3H]Ro 48-8587, a high-affinity
      antagonist, as radioligands revealed that even a conservative mutation at R507
      (R507K) resulted in the complete loss of both agonist and antagonist binding. In
      contrast, a negative charge at position 727 was necessary for agonist binding,
      whereas the isosteric mutation, E727Q, abolished all agonist binding but retained
      high-affinity binding for [3H]Ro 48-8587, displaceable by 7,8-dinitroquinoxaline
      2,3-dione. Competition binding studies with antagonists representing different
      structural classes in combination with ligand docking experiments suggest that
      the role of E727 is antagonist-specific, ranging from no interaction to weak
      electrostatic interactions involving indirect and direct hydrogen bonding with
      the antagonist molecule. These results underline the importance of ion pair
      interaction with E727 for agonist activity and suggest that an interaction with
      R507, but not with E727, is essential for antagonist binding.

PMID- 12473123
TI  - Heterologous expression and folding analysis of a beta-tubulin isotype from the
      Antarctic ciliate Euplotes focardii.
AB  - Mammalian tubulins and actins attain their native conformation following
      interactions with CCT (the cytosolic chaperonin containing t-complex polypeptide
      1). To study the beta-tubulin folding in lower eukaryotes, an isotype of beta
      tubulin (beta-T1) from the Antarctic ciliate Euplotes focardii, was expressed in
      Escherichia coli. Folding analysis was performed by incubation of the 35S
      labeled, denatured beta-T1 in the presence, or absence, of purified rabbit CCT
      and cofactor A, a polypeptide that stabilizes folded monomeric beta-tubulin. We
      show for the first time in protozoa that beta-tubulin folding is assisted by CCT
      and requires cofactor A. In addition, we observed that E. focardiibeta-T1
      competes with human beta5 tubulin isotype for binding to CCT. The affinity of CCT
      to E. focardiibeta-T1 and beta5 tubulin are compared. Finally, the mitochondrial
      chaperonin mt-cpn60 binds to beta-T1 but is unable to release it in a native or
      quasi-native state.

PMID- 12473124
TI  - Purification and characterization of two secreted purple acid phosphatase
      isozymes from phosphate-starved tomato (Lycopersicon esculentum) cell cultures.
AB  - Two secreted acid phosphatases (SAP1 and SAP2) were markedly up-regulated during
      Pi-starvation of tomato suspension cells. SAP1 and SAP2 were resolved during
      cation-exchange FPLC of culture media proteins from 8-day-old Pi-starved cells,
      and purified to homogeneity and final p-nitrophenylphosphate hydrolyzing specific
      activities of 246 and 940 micro mol Pi produced.min-1 mg.protein-1, respectively.
      SDS/PAGE, periodic acid-Schiff staining and analytical gel filtration
      demonstrated that SAP1 and SAP2, respectively, exist as 84 and 57 kDa
      glycosylated monomers. SAP1 and SAP2 are purple acid phosphatases (PAPs) as they
      displayed an absorption maximum at 518 and 538 nm, respectively, and were not
      inhibited by l-tartrate. The respective sequence of a SAP1 and SAP2 tryptic
      peptide was very similar to a portion of the deduced sequence of several putative
      Arabidopsis thaliana PAPs. CNBr peptide mapping indicated that SAP1 and SAP2 are
      structurally distinct. Both isozymes displayed a pH optimum of approximately pH
      5.3 and were heat stable. Although they exhibited wide substrate specificities,
      the Vmax of SAP2 with various phosphate-esters was significantly greater than
      that of SAP1. SAP1 and SAP2 were activated by up to 80% by 5 mm Mg2+, and
      demonstrated potent competitive inhibition by molybdate, but mixed and
      competitive inhibition by Pi, respectively. Interestingly, both SAPs exhibited
      significant peroxidase activity, which was optimal at approximately pH 8.4 and
      insensitive to Mg2+ or molybdate. This suggests that SAP1 and SAP2 may be
      multifunctional proteins that operate: (a) PAPs that scavenge Pi from
      extracellular phosphate-esters during Pi deprivation, or (b) alkaline peroxidases
      that participate in the production of extracellular reactive oxygen species
      during the oxidative burst associated with the defense response of plants to
      pathogen infection.

PMID- 12473125
TI  - Relaxin-like bioactivity of ovine Insulin 3 (INSL3) analogues.
AB  - Relaxin is an insulin-like peptide consisting of two separate chains (A and B)
      joined by two inter- and one intrachain disulfide bonds. Binding to its receptor
      requires an Arg-X-X-X-Arg-X-X-Ile motif in the B-chain. A related member of the
      insulin superfamily, INSL3, has a tertiary structure that is predicted to be
      similar to relaxin. It also possesses an Arg-X-X-X-Arg motif within its B-chain,
      although this is displaced by four amino acids towards the C-terminus from the
      corresponding position within relaxin. We have previously shown that synthetic
      INSL3 itself does not display relaxin-like activity although analogue (Analogue
      A) with an introduced arginine residue in the B-chain giving it an Arg cassette
      in the exact relaxin position does possess weak activity. In order to identify
      further the structural features that impart relaxin function, solid phase peptide
      synthesis was used to prepare three additional analogues for bioassay. Each of
      these contained point substitutions within the arginine cassette. Analogue D
      contained the full human relaxin binding cassette, Analogue G consisted of the
      native INSL3 sequence containing an Arg to Ala substitution, and Analogue E was a
      further modification of Analogue A, with the same substitution. Each analogue was
      fully chemically characterized by a number of criteria. Detailed circular
      dichroism spectroscopy analyses showed that the changes caused little alteration
      of secondary structure and, hence, overall conformation. However, each analogue
      displayed only weak relaxin-like activity. These results indicate that while the
      arginine cassette is vital for relaxin-like activity, there are additional, as
      yet unidentified structural requirements for relaxin binding.

PMID- 12473126
TI  - Characterization of the lectin from females of Phlebotomus duboscqi sand flies.
AB  - Lectin from females of the important sand fly vector, Phlebotomus duboscqi
      (Diptera: Psychodidae), was isolated by immunoaffinity chromatography using a
      minicolumn with immobilized anti-lectin immunoglobulins. Carbohydrate-binding
      specificity of active fractions corresponded to that of midgut and salivary gland
      lysates. Haemagglutination was inhibited by d-glucosamine, d-galactosamine and d
      mannosamine. The homogeneity and molecular mass of the purified lectin was
      examined by SDS/PAGE in both reducing and nonreducing conditions. The active
      fractions showed one band strongly stained by Coomassie blue or silver nitrate;
      the molecular mass of the lectin was 42 kDa under nonreducing and 44 kDa under
      reducing conditions. SDS/PAGE of active fractions from the gel filtration
      revealed four to six protein bands, but the 42/44-kDa protein present in all
      active fractions was the only component reacting with specific antibodies in
      Western blots. Localization of the lectin in the gut of females was studied using
      indirect immunofluorescence on sections. The positive reaction of specific
      antibodies was localized in the lumen and along the microvillar surfaces of
      epithelial cells. The lectin was partially sequenced and characterized by MS.
      Peptide maps were obtained by MALDI-TOF MS, and several sequence tags were
      identified from tandem mass spectra on an ion trap. These sequences displayed
      high similarity to salivary protein precursors previously identified in a cDNA
      library of the sand flies Phlebotomus papatasi and Lutzomyia longipalpis. Two
      main hypotheses on the role of female lectin in Leishmania development are
      discussed.

PMID- 12473127
TI  - Cloning, expression and characterization of a gene encoding nitroalkane-oxidizing
      enzyme from Streptomyces ansochromogenes.
AB  - A nitroalkane-oxidizing enzyme gene (naoA) was cloned from a genomic DNA library
      of Streptomyces ansochromogenes 7100. The deduced protein (NaoA) of this gene
      contains 363 amino acids and has high similarity to several nitroalkane-oxidizing
      enzymes from various micro-organisms. The naoA gene was subcloned into an
      expression vector pET23b and overexpressed in Escherichia coli BL21(DE3). The
      protein was then purified, and its characteristics were studied. Experimental
      results showed that NaoA can convert 1-nitropropane, 2-nitropropane and
      nitroethane into the corresponding carbonyl compounds. The optimal pH and
      temperature for NaoA was found to be pH 7-8 and 48-56 degrees C, respectively.
      The Km of NaoA for nitroethane is approximately 26.8 mm. NADH and nitro blue
      tetrazolium are strong inhibitors of NaoA, and thiol compounds and superoxide
      dismutase partially inhibit the enzyme activity. Therefore, superoxide may be an
      essential intermediate in the oxidation of nitroalkane by NaoA.

PMID- 12473128
TI  - Transfusion medicine illustrated. Maternofetal transfusion detected by gel-based
      typing.

PMID- 12473129
TI  - Nitric oxide: nature's third respiratory gas.

PMID- 12473130
TI  - Vasovagal donor reactions: an important issue with implications for the blood
      supply.

PMID- 12473131
TI  - IgG1 and IgG3 anti-D in maternal serum and on the RBCs of infants suffering from
      HDN: relationship with the severity of the disease.
AB  - BACKGROUND: Anti-D IgG antibodies that are responsible for severe cases of HDN
      belong chiefly to IgG1 and IgG3 subclasses. The relationship between the
      concentrations of IgG1 anti-D and IgG3 anti-D in maternal serum and the amount
      bound to the surface of infants' RBCs is not known. In addition, the contribution
      of the two subclasses to the severity of HDN is not well established. STUDY
      DESIGN AND METHODS: Blood samples from 40 infants suffering from severe forms of
      HDN due to anti-D were collected before transfusion together with sera from their
      respective mother. The amount of total anti-D IgG as well as IgG1 anti-D and IgG3
      anti-D on infants' RBCs and the concentration in maternal sera were determined by
      ELISA. RESULTS: The median percentages of IgG1 anti-D and of IgG3 anti-D in
      maternal sera were 90 and 10 percent, respectively, whereas on infants' RBCs they
      were 97 and 3 percent, respectively. The differences between maternal and
      infantile percentages were significant (p < 0.001). IgG1 and IgG3 anti-D bound to
      infants' RBCs increased concomitantly with the concentration of IgG1 and IgG3
      anti-D in maternal sera. The severity of HDN correlated positively with the
      concentration of IgG1 anti-D in maternal sera, but negatively with the amount of
      IgG3 anti-D bound to infants' RBCs. In addition, the existence of a high
      proportion of IgG3 anti-D in maternal serum was associated with a delayed risk of
      fetal anemia. CONCLUSION: The proportion of IgG3 anti-D relative to the total
      anti-D IgG on infants' RBCs is only one- third of the proportion present in
      maternal serum. The study of the correlations between the amount of IgG1 anti-D
      and IgG3 anti-D and the severity of HDN suggests that IgG1 anti-D are more
      important than IgG3 anti-D in the pathogenesis of fetal anemia.

PMID- 12473132
TI  - Severe autoimmune hemolytic anemia caused by a warm IgA autoantibody directed
      against the third loop of band 3 (RBC anion-exchange protein 1).
AB  - BACKGROUND: Autoimmune hemolytic anemia associated with only IgA autoantibodies
      reacting optimally at 37 degrees C (WAIHA) is exceedingly rare. When identified,
      warm IgA autoantibodies specificities are usually directed to antigens of the Rh
      system. However, like IgG autoantibodies, the specificity of the majority of
      these antibodies is not identified. CASE REPORT: A case of a 3-year-old boy in
      whom a life-threatening IgA WAIHA occurred suddenly is reported. Following
      initial RBC transfusions and treatment with steroids at a dose of 3 mg per kg,
      which was slowly tapered, stabilization to a state of compensated hemolysis was
      achieved, persisting 4 months before complete resolution. There was no recurrence
      within a 16-month follow-up. STUDY DESIGN AND METHODS: The standard DAT in a gel
      column method with anti-IgG and anticomplement reagents was negative. However,
      the same method with an anti-IgA was strongly positive. RESULTS: The serum and
      the eluate obtained after acid elution reacted with all normal RBCs tested.
      Enzymatic treatment of panel RBCs by alpha-chymotrypsin and pronase abolished the
      reactivity. The reaction was completely inhibited by RBC incubation with four
      different MoAbs directed against the third extracellular loop of band 3, the RBC
      anion-exchange protein 1 (AE1), whereas MoAbs against other specificities showed
      no effect. CONCLUSIONS: This is the first report of an IgA autoantibody directed
      against the band 3 (AE1) protein and, more specifically, against the third loop.
      Moreover, this case underlines the importance of including IgA research in the
      initial diagnostic evaluation when a hemolytic anemia is suspected to be
      autoimmune and when IgG and complement are not detected on the patient's RBCs.

PMID- 12473133
TI  - Development of a DNA-based genotyping method for the Diego blood group system.
AB  - BACKGROUND: The paucity of appropriate reagents for serologic typing of the Diego
      blood group has hindered the identification of the rare Di(b-) blood donors
      needed to transfuse a Dib antigen-negative patient who presented with anti-Dib.
      Development of an alternative Di typing approach as a supplement to the current
      serologic typing method is an important and necessary goal. STUDY DESIGN AND
      METHODS: DI1 and DI2 alleles result from a single C to T substitution at
      nucleotide 2561 in exon 19 of the human anion exchanger gene causing a proline
      (DI1) to leucine (DI2) change at amino acid position 854. Allele-specific primers
      were designed to specifically amplify the DI1 and DI2 alleles using a PCR-based
      assay system. RESULTS: A PCR sequence-specific primer (SSP) method for Di
      genotyping was developed, and the specificity and reproducibility of the method
      were assessed in a blind control study using serologic tests, family segregation,
      and DNA sequencing analyses. A total of 1,766 DNA samples from unrelated blood
      donors were typed for DI1 and DI2 alleles and a single Di(b-) donor was
      identified. The frequency of DI1 and DI2 alleles among Chinese blood donors was
      0.0357 and 0.9643, respectively. CONCLUSION: A simple, accurate, and inexpensive
      DNA-based PCR-SSP method was established for Di genotyping. The typing results
      can be visualized on a single photograph within 3 hours, making this reliable
      method suitable for large-scale typing of potential blood donors without
      serologic backup.

PMID- 12473134
TI  - Vasovagal reactions in high school students: findings relative to race, risk
      factor synergism, female sex, and non-high school participants.
AB  - BACKGROUND: High school (HS) students have a high incidence of vasovagal
      reactions and are a good population for the study of vasovagal reactions. STUDY
      DESIGN AND METHODS: Data from 1,076 Caucasian students, 226 African-American
      students, and 157 nonstudents from HS blood drives in 2001 were entered into a
      database. Race, high-risk-factor synergism, the phenomenon of "survivorship," and
      female sex were evaluated. In addition, non-HS student participants were
      described. RESULTS: Vasovagal reactions were 84 percent lower in African-American
      HS students than in Caucasian HS students (3 of 226 vs. 88 of 1,076; 1.3 vs. 8.2
      percent; p = 0.0001; relative risk, 6.2). In Caucasian HS students, first-time
      donor status increased the vasovagal reaction rate to 9.4 percent (vs. 3.6% in
      repeat donors, p < 0.004). Low weight (</= 130 lb) increased the reaction rate to
      13.6 percent (vs. 3.3% in weight > 81.2 kg, p < 0.001). Together they increased
      the reaction rate to 16.0 percent (vs. 3.2%, p < 0.0001). Females had more
      reactions than males (11.3 vs. 4.8%, p < 0.001), but the reaction rates equalized
      when donors under 150 lb were excluded (5.7 vs. 4.6%, p = 0.66). CONCLUSION:
      African-American HS students had a significantly lower vasovagal reaction rate
      than Caucasian HS students. There was synergy among high-risk factors in
      Caucasian HS students. Female and male vasovagal reaction rates were similar when
      low-weight donors were excluded.

PMID- 12473135
TI  - Vasovagal reactions in apheresis donors.
AB  - BACKGROUND: The incidence rate of vasovagal reactions (VVRs) in apheresis is
      known to be higher in women than in men donors. VVRs in women apheresis donors
      were therefore analyzed to find out possible factors for their high incidence.
      STUDY DESIGN AND METHODS: VVR incidence was compared between whole blood (WB) and
      apheresis donation in relation mainly to age and circulatory blood volume (CBV).
      In addition, blood pressure and pulse rate were measured during apheresis.
      RESULTS: In WB donors, the VVR incidence was 0.83 and 1.25 percent, while in
      apheresis donors it was 0.99 and 4.17 percent in men and women, respectively. The
      VVR incidence decreased with age in WB donors, but age dependence was very weak
      in apheresis donors. In elderly women, the incidence increased with repeating
      cycle of apheresis. There were three different patterns of pulse fluctuation
      during apheresis, that is, stable (type A), increased rate during blood
      withdrawal (type B), and irregular pattern (type C). Elderly women donors and
      donors who suffered from VVRs mostly showed type B fluctuation. There was no
      particular fluctuation in blood pressure in relation to apheresis cycles.
      CONCLUSION: The VVR incidence rate was particularly high in women apheresis
      donors over 45 years old and increased with repeating cycles of apheresis.
      Smaller CBV, high sensitivity of low-pressure baroreceptors, and citrate effects
      on cardiovascular reflex might be major factors involved in the high incidence of
      VVRs.

PMID- 12473136
TI  - Early diagnosis and successful treatment of a patient with transfusion-associated
      GVHD with autologous peripheral blood progenitor cell transplantation.
AB  - BACKGROUND: Transfusion-associated GVHD (TA-GVHD) is an uncommon complication of
      blood transfusion. Diagnosis of TA-GVHD is difficult, and it is usually rapidly
      fatal. There are few documented sur- vivors of TA-GVHD. CASE REPORT: A 61-year
      old woman with chronic lymphocytic leukemia (CLL) was treated with fludarabine
      followed by combination chemotherapy and high-dose radioimmunotherapy and
      peripheral blood progenitor cell (PBPC) rescue. She was transfused with
      nonirradiated blood components at an outside hospital and presented 10 days later
      with rash, elevated liver enzymes, and progressive pancytopenia. Skin biopsy was
      consistent with GVHD, and HLA typing of lymphocytes from the patient demonstrated
      mixed chimerism. The patient was treated with solumedrol and cyclosporin A,
      followed by high-dose cyclophosphamide and antithymocyte globulin and autologous
      PBPC infusion. She had rapid engraftment, resolution of skin rash, and
      normalization of liver function abnormalities. She is in good health with normal
      blood counts and no evidence of CLL 34 months after transplantation. CONCLUSION:
      TA-GVHD occurs in the setting of an immunocompromised recipient receiving
      nonirradiated blood components. A typical presentation includes skin rash, liver
      function abnormalities, and pancytopenia. Demonstration of mixed chimerism by HLA
      typing facilitated diagnosis in this patient. High-dose immunosuppression,
      facilitated by the availability of autologous PBPCs, resulted in a successful
      outcome.

PMID- 12473137
TI  - Cryopreserving human peripheral blood progenitor cells with 5-percent rather than
      10-percent DMSO results in less apoptosis and necrosis in CD34+ cells.
AB  - BACKGROUND: The grade of toxicity experienced by patients when cryopreserved
      peripheral blood progenitor cells (PBPCs) are reinfused is related to the amount
      of DMSO present in the PBPC concentrate. This study was initiated to investigate
      whether cell viability, apoptosis, and necrosis would be altered in CD34+ cells
      if PBPCs were cryopreserved with 5-percent as opposed to the conventional 10
      percent DMSO. STUDY DESIGN AND METHODS: Samples of PBPCs from consecutive
      patients were mixed in parallel with 5- and 10-percent DMSO, frozen at a
      controlled rate, and stored in liquid nitrogen for periods of 3 to 22 months. Two
      different flow cytometric methods were used to measure both the absolute count of
      total and viable CD34+ cells as well as the fraction of apoptotic and necrotic
      cells in the post-thaw samples frozen with 5- and 10-percent DMSO. RESULTS: Both
      the number of total and viable CD34+ cells were higher (n = 18) or equal (n = 1)
      in all the samples cryopreserved with 5-percent as opposed to 10-percent DMSO.
      The percentage of viable CD34+ cells in the PBPC sample was significantly higher,
      and the fraction of apoptotic and necrotic CD34+ cells was significantly lower in
      the samples frozen with 5-percent as compared to 10-percent DMSO. CONCLUSION:
      Cryopreserving PBPC with 5-percent rather than 10-percent DMSO results in
      improved CD34+ cell viability and possibly a higher potential for in vivo
      engraftment and ex vivo manipulations of HPCs.

PMID- 12473138
TI  - Coagulant stability and sterility of thawed S/D-treated plasma.
AB  - BACKGROUND: Units of frozen S/D-treated plasma (SDP) must be transfused within 24
      hours after thawing. To avoid waste, an attempt was made to determine how long
      SDP could be therapeutically effective after thawing and storing it at 20 degrees
      C. STUDY DESIGN AND METHODS: The microbiologic safety and the activity of labile
      coagulation factors were evaluated in units stored at 20 degrees C of thawed SDP
      units and FFP within 24 hours of collection (FFP24). Five SDP and FFP24 samples
      of each ABO blood group were cultured and assayed for coagulation factors daily
      over 5 days. Assays included FV, FVII, FVIIa, FVIII, F IX, FXI, protein S,
      antiplasmin, fibrinogen, prothrombin times (PTs), and activated partial
      thromboplastin times (aPTTs). RESULTS: None of the 80 bacterial cultures
      demonstrated growth under either aerobic or anaerobic conditions. FV, FVIII, F
      IX, FXI, fibrinogen, and the aPTT appeared to be stable in both thawed FFP24 and
      SDP. The PT increased slightly in thawed FFP24 and insignificantly in SDP. FVII
      decreased slightly in FFP24 but remained in the normal range, and FVIIa was low
      and constant. FVII was increased in SDP and FVIIa was markedly increased. Protein
      S decreased from initial normal values in FFP24 to very low values. Protein S was
      very low immediately after thawing in the SDP and continued to decline.
      Antiplasmin was normal and stable in thawed FFP24 but was low in SDP and remained
      constant after thawing. CONCLUSION: Sterile SDP that is stored at 20 degrees C
      provides sufficient coagulant activity of labile FV and FVIII to transfuse it for
      up to 5 days after thaw. Caution is warranted by decreases in Protein S and
      antiplasmin, clinical evidence of coagulopathy in some recipients of SDP, and a
      recent manufacturer's warning.

PMID- 12473139
TI  - Relationship between tick bites and the seroprevalence of Babesia microti and
      Anaplasma phagocytophila (previously Ehrlichia sp.) in blood donors.
AB  - BACKGROUND: Tick-borne diseases, particularly babesiosis and ehrlichiosis,
      represent recently emerging infections. Despite an increased recognition of the
      threat tick-borne agents pose to blood safety, our understanding of the
      prevalence and transmissibility of these agents in blood donors is limited. STUDY
      DESIGN AND METHODS: Babesia microti and Anaplasma phagocytophila (previously
      Ehrlichia sp.) seroprevalence was determined in random Connecticut and Wisconsin
      donors, and subsequently in Connecticut donors reporting tick bites. In the
      interim, a postcard survey regarding tick bites during the previous 6 months was
      sent to 6,000 random donors in six geographically distinct collection regions.
      RESULTS: In total, 3 of 999 Wisconsin donors (0.3%) and 6 of 1,007 Connecticut
      donors (0.6%) had antibodies to B. microti. Of 992 donors tested for A.
      phagocytophila, 5 Wisconsin donors (0.5%) and 35 Connecticut donors (3.5%) were
      seropositive. A total of 2,482 donors (41.4%) completed the survey; 103 (4.1%)
      reported a tick bite. Of 848 Connecticut donors (0.4%) reporting tick bites, 3
      had B. microti antibodies, while 8 (0.9%) had A. phagocytophila antibodies. These
      rates were not significantly different from control donors. CONCLUSION: Blood
      donors seropositive for B. microti and A. phagocytophila are present in
      Connecticut and Wisconsin. Donors readily recall previous tick bites, but self
      reported bites are not reliable indicators of serologic status. The exposure of
      blood donors to tick-borne pathogens does suggest a need to better understand the
      transfusion transmission potential of these agents.

PMID- 12473140
TI  - Transfusion-transmitted HBV infection in an endemic area: the necessity of more
      sensitive screening for HBV carriers.
AB  - BACKGROUND: By NAT, HBV DNA is occasionally detectable in blood donors with past
      HBV infection but negative for HBsAg. Whether or not these donors can cause
      transfusion-transmitted HBV infections is uncertain. STUDY DESIGN AND METHODS: To
      determine whether or not donors with past HBV infection but negative for HbsAg
      can cause HBV transfusion-transmitted infections, recipients followed for blood
      transfusion in a university medical center in Taiwan were studied. HBV DNA and
      serologic markers were tested in donors and recipients. RESULTS: Of 1,038
      enrolled recipients, 910 completed the 6-month post-transfusion follow-up visit.
      Of these, only 39 patients (4.3%) tested negative on the pretransfusion sample
      for HBsAg, anti-HBs, anti-HBc, and HBV DNA by PCR. These 39 HBV-naive recipients
      had been transfused with blood from 147 donations for which stored samples were
      available for HBV DNA testing by PCR; 11 of these HBsAg-negative samples tested
      positive for HBV DNA and anti-HBc. Two of the 11 patients who received the HBV
      DNA-positive donations (18%) became positive for HBV DNA, and one seroconverted
      to anti-HBc and finally to anti-HBs, with a mild transient elevation of serum ALT
      activities. Based on the one confirmed case of HBV transmission, a projection was
      made that approximately 200 post-transfusion HBV infections could occur in one
      million units of transfused blood in Taiwan. CONCLUSIONS: In HBV-endemic areas
      like Taiwan, where blood donors are screened for HBsAg only, the risk of
      transfusion-transmitted HBV appears to be substantial. Implementation of NAT for
      blood screening in these settings warrants consideration.

PMID- 12473141
TI  - Profound ionized hypomagnesemia induced by therapeutic plasma exchange in liver
      failure patients.
AB  - BACKGROUND: Various adverse effects, including cardiac arrest, have been induced
      by plasma exchange (PE). Electrolyte derangement is frequently observed. The
      purpose of this study was to assess the effect of PE on the serum ionized
      magnesium (Mg2+) concentration in acute liver failure patients. STUDY DESIGN AND
      METHODS: Seven liver failure patients requiring PE were enrolled in this study.
      PE was performed 21 times in total. Blood samples were drawn before PE and
      serially after the start of the PE. Serum Mg2+ was measured by the ion- selective
      electrode method. RESULTS: After PE was started, Mg2+ concentrations began to
      fall significantly. The low Mg2+ blood concentration continued during PE. After
      PE, the Mg2+ level recovered to about 80 percent of the control value within 2
      hours in six patients. However, in one patient, the Mg2+ concentration was still
      low even at 2 hours after PE. This patient complained of chest discomfort during
      PE and ECG analysis showed sporadic supraventricular premature contractions.
      CONCLUSION: Profound ionized hypomagnesemia was induced by PE in liver failure
      patients.

PMID- 12473142
TI  - Nitric oxide in RBCs.

PMID- 12473143
TI  - A puzzling case of anemia.
AB  - BACKGROUND: Iron deficiency anemia in adults is most frequently due to chronic
      blood loss. When the clinical course is complicated by sudden, severe declines in
      Hb concentration, the cause, nature, and lo- cation of bleeding may require an
      extensive clinical evaluation. CASE REPORT: A 39-year-old woman was admitted for
      management of refractory hypoparathyroidism related to total thyroidectomy for
      Graves' disease. Two weeks before admission, her Hb level was 7.0 g per dL.
      Despite transfusion with four units of RBCs during this interval, her admission
      Hb level was 5.7 g per dL. There was no evidence of blood loss or hemolysis.
      Laboratory values were consistent with an iron-deficient state. The patient's
      hospital course included repeated instances of sharp Hb drop and appropriate but
      unsustained response to RBC transfusion. Extensive work-up identified no occult
      source of bleeding. Clinical suspicion raised the possibility of self-inflicted
      blood loss. The patient subsequently admitted to repeatedly drawing blood from
      her indwelling catheter and discarding it in the lavatory. CONCLUSION: Munchausen
      syndrome should be considered in cases of unexplained anemia, especially in the
      target demographic group: young, female, healthcare professionals. Early
      diagnosis may prevent morbidity, multiple hospitalizations, and the risk of
      invasive diagnostic procedures.

PMID- 12473144
TI  - Preoperative autologous blood donation in Europe.

PMID- 12473146
TI  - HBV DNA in serum of HBsAg-negative, anti-HBc-positive blood donors.

PMID- 12473147
TI  - Immunoprophylaxis for D- patients receiving platelet transfusions from D- donors?
      Transfusion. 2002;42:136-8.

PMID- 12473149
TI  - The rise and fall of preoperative autologous blood donation (editorial).
      Transfusion. 2001;41:1459-62.

PMID- 12473150
TI  - Mannan-binding lectin and its role in innate immunity.
AB  - Mannan-binding lectin (MBL) is a plasma collectin (C-type lectin with a collagen
      like domain) and is considered an important component of innate immunity.
      Circulating MBL is genetically determined for the major part, but plasma
      concentration is also markedly influenced by nongenetic factors. The carbohydrate
      binding ability of MBL can be inhibited by simple sugars like mannose, fucose and
      N-acetylglucosamine, but its greatest avidity appears to be for repeating mannose
      based structural patterns typical of microbial surfaces. By this means, MBL can
      bind to a wide variety of bacteria and other microbes, neutralizing them and/or
      opsonizing them by activating complement using the recently discovered lectin
      pathway of complement activation. Individual humans differ 1000-fold in MBL
      concentration, and individuals with low circulating MBL appear to be more
      vulnerable to infections in a number of clinical settings, especially when
      combined with secondary immune deficiency. The best evidence that MBL deficiency
      or insufficiency is physiologically relevant comes from a rapidly expanding
      literature of clinical studies. MBL insufficiency appears to be a significant
      risk factor for infections in infants, and for individuals of any age undergoing
      chemotherapy or post-transplant immunosuppression. Moreover, MBL appears to have
      a significant influence on the course of certain chronic diseases like rheumatoid
      arthritis and cystic fibrosis. Replacement therapy with a plasma-derived product
      is safe and seems promising, while recombinant MBL provides hope for large-scale
      therapeutic applications. Randomized clinical trials of MBL therapy, which are
      now on the horizon, should provide unambiguous evidence for the physiological
      significance of MBL in innate immunity.

PMID- 12473151
TI  - Are changes in admission practices for elective surgery posing a transfusion
      threat to patients?
AB  - There is an increasing emphasis on reducing in-patient hospital stay for elective
      surgical procedures. As a result, pre-operative stay has shortened, with less
      time available for performing baseline investigations before surgery, including
      those required to ensure a supply of safe, compatible blood. We have estimated
      the frequency of failure to complete 'group and screen' (G&S) testing before
      surgery where indicated, so that neither group-compatible blood nor crossmatched
      blood could be provided promptly if an unexpected haemorrhage occurs.
      Retrospective data were obtained from elective surgical procedures performed over
      a 3-week period. Of the 309 procedures performed, 21 patients were exposed to the
      risk of failure to provide appropriately matched blood had an emergency arisen.
      (In 20, a G&S was required; in one, a crossmatch was required.) Late samples and
      lack of information on the request form regarding the date and time of surgery
      were the main causes. Procedures requiring G&S only as opposed to crossmatch
      posed the greatest risk. Urgent measures are needed to ensure that, where
      indicated, a pre-operative G&S result is available before surgery begins.
      Educating colleagues, redesigning request forms and improving out-of-hour
      laboratory services and hospital information systems are the main steps needed to
      reduce this latent risk.

PMID- 12473152
TI  - Intervention to promote appropriate blood use in India.
AB  - The decision to transfuse should be guided by information on the risks and
      benefits of transfusion. Safer alternatives should be considered. Properly
      screened blood or components from a reputable source should be used. In this
      study, a simple, self-educating transfusion request form was developed, and its
      effects on transfusion practice were assessed, using a cluster-randomized trial.
      Transfusions at six study hospitals and six control hospitals at four locations
      in India (Delhi, Bangalore, Nasik and Imphal) were monitored over a 4-month pre
      intervention period and a 5-month post-intervention period. During the trial, 56
      171 units were transfused to in-patients at the participating hospitals. Among
      the six intervention hospitals, there was some evidence of a nonsignificant post
      intervention reduction in all the three main outcome measures: number of
      transfusion requests per admission (P = 0.09), number of units transfused per
      admission (P = 0.11) and number of crossmatches per admission (P = 0.06). No such
      changes were seen at control sites over the same period. Simple interventions to
      promote good clinical practice can have an effect, but may be better placed
      within longer term, broad-based strategies that are able to consider some of the
      background factors. Lack of clinical training, the hospital environment and
      fragmented blood bank services influence the way blood is used in India. It is
      thought that the intervention was ultimately unsuccessful because these factors
      remained as detrimental influences. A focus on education, policy and
      infrastructure in line with the new National Blood Policy will be important in
      coming years.

PMID- 12473153
TI  - Harvesting of CD34 antigen-expressing cells with a new programme for the
      collection of mononuclear cells with use of the Amicus (Baxter) blood cell
      separator.
AB  - A study was performed to evaluate a new programme for peripheral blood stem cell
      (PBSC) collection with the use of the Amicus (Baxter) blood cell separator.
      Healthy donors (n = 9) and oncology patients (n = 21) scheduled for PBSC
      transplant were studied. Ten PBSC harvests were performed in the donors and 30 in
      the patients. A median of 6.37 x 106 CD34+ cells per kg recipient body weight
      (range 3.08-11.06 x 106) were collected from the donors in a product weight of
      169.5 g (118-186). From the patients, 6.26 x 106 CD34+ cells per kg body weight
      (range 0.2-53.6 x 106) were harvested in a product weighing 121.5 g (range 92
      190). The median platelet contamination was 0.93 x 1011 (range 0.45-1.23 x 1011)
      per donor product and 0.2 x 1011 (range 0.05-0.86 x 1011) per patient product. No
      severe side effects were observed during or after the PBSC collection procedures.

PMID- 12473154
TI  - A modified Kleihauer technique for the quantification of foetomaternal
      haemorrhage.
AB  - The Kleihauer technique, based on acid elution of maternal red cells, is the
      mostly widely used technique in the UK to screen for, and estimate the volume of,
      foetomaternal haemorrhage (FMH) and for determining the need for additional doses
      of anti-D immunoglobulin to prevent maternal alloimmunization. However,
      technicians often report difficulties in identifying and accurately counting
      maternal red cells in the blood film, leading to imprecision in the calculated
      FMH. In this report, we describe a simple modification of the standard Kleihauer
      technique, based on performing acid elution of only half of the film. Compared to
      the standard method, the modified technique showed improved accuracy and reduced
      interobserver variability across a range of simulated FMH volumes. There was a
      high degree of correlation between the new technique and FMH estimated by flow
      cytometry (r2 = 0.916, P < 0.001). Technicians found the new technique easy to
      incorporate into routine practice in a busy teaching hospital laboratory and were
      impressed by the relative ease of counting maternal ghost cells. The modified
      technique has been used routinely in our laboratory for 3 years, during which
      time our performance in the UK National External Quality Assurance Scheme for FMH
      has been uniformly satisfactory.

PMID- 12473155
TI  - Outcome of consecutive pregnancies in a patient with Bombay (Oh) blood group.
AB  - A young lady with a rare Bombay (Oh) blood group had two successive uneventful
      pregnancies. Her serum contained a potent high-titre anti-H and serological as
      well as chemiluminescence tests, suggesting that the antibody was haemolytic. Her
      husband was of the normal H status. Theoretically, both babies should have been
      positive for the H antigen and should have suffered from haemolytic disease of
      the newborn. This apparent conundrum could be owing to the weak expression of the
      H antigens on the infant red cells.

PMID- 12473156
TI  - An unusual case of hyperkalaemia-induced cardiac arrest in a paediatric patient
      during transfusion of a 'fresh' 6-day-old blood unit.
AB  - A well-recognized complication of the transfusion of red blood cells (RBCs) is
      hyperkalaemia. This occurs in paediatric or adult patients receiving massive
      transfusion and can lead to cardiac arrest. Hyperkalaemia may follow the
      transfusion of 'stored' RBCs and/or haemolysed units, and depends on the quantity
      and rate of transfusion. We report on an unusual case of hyperkalaemia-induced
      cardiac arrest during transfusion of a 'fresh' blood unit. A 62-day-old baby girl
      was scheduled for a construction of a Blalock-Taussig shunt, after the completion
      of anastomosis, and upon release of vascular control, there was bleeding at the
      anastomotic site that was controlled with a suture placement. To compensate for
      the blood loss, a stat order was given for a push of 120 mL of RBCs over 10 min
      through the inferior vena cava central line. The blood unit was 6 days old and
      had been gamma-irradiated 48 h earlier. Shortly after the transfusion, the
      patient's electrocardiogram showed changes typical of hyperkalaemia; she then
      went into cardiac asystole. The blood unit potassium concentration was 55.3 mmol
      L-1, which flushed the atrioventricular node during transfusion. This is the
      first report of a high potassium level found in a 'fresh', less than 7 days old,
      nonhaemolysed RBC blood unit. The high concentration of potassium in this unit
      seems to be due to accelerated alterations of the RBC sodium/potassium adenosine
      triphosphatase pump (Na+/K+ pump), resulting in the release of intracellular
      potassium. This early and severe alteration of the pump and the unusually high
      potassium level may be due to as yet unexplained causes, warranting awareness,
      future investigation and routine saline washing of 'fresh' RBCs for paediatric
      patients who are candidates for central line transfusion.

PMID- 12473157
TI  - Transfusion-related acute lung injury: a 5-year look-back study.

PMID- 12473158
TI  - Limited efficacy of universal leucodepletion in reducing the incidence of febrile
      non-haemolytic reactions in red cell transfusion.

PMID- 12473160
TI  - Silent coronary artery disease in type 2 diabetes mellitus: the role of
      Lipoprotein(a), homocysteine and apo(a) polymorphism.
AB  - BACKGROUND: There is little data on the relationship between novel cardiovascular
      risk factors and silent coronary artery disease (CAD) in diabetic patients. We
      investigated whether Lipoprotein(a), homocysteine and apolipoprotein(a)
      polymorphism are associated with angiographically assessed asymptomatic coronary
      artery disease (CAD) in diabetic patients. METHODS: 1,971 type 2 diabetic
      patients without clinical signs of cardiovascular diseases and with a negative
      history of CAD were consecutively evaluated. Among them, 179 patients showed
      electrocardiographic abnormalities suggestive of ischemia or previous
      asymptomatic myocardial infarction. These 179 patients were subjected to a non
      invasive test for CAD (ECG stress testing and/or scintigraphy). Among patients
      with a highly positive stress testing (n = 19) or a positive scintigraphy (n =
      74), 75 showed an angiographically documented CAD (CAD group). Seventy-five
      patients without CAD (NO CAD group) were matched by age, sex and duration of
      diabetes to CAD patients. In NO CAD patients an exercise ECG test, a 48-hour
      ambulatory ECG and a stress echocardiogram were negative for CAD. RESULTS:
      Lipoprotein(a) levels (22.0 +/- 18.9 versus 16.0 +/- 19.4 mg/dl; p < 0.05),
      homocysteine levels (13.6 +/- 6.6 versus 11.4 +/- 4.9 mmol/l; p < 0.05) and the
      percentage of subjects with at least one small apolipoprotein(a) isoform (70.7%
      versus 29.3%; p < 0.0001) were higher in CAD than NO CAD group. Logistic
      regression analysis showed that apolipoprotein(a) polymorphism (OR:8.65;
      95%CI:3.05-24.55), microalbuminuria (OR:6.16; 95%CI:2.21-17.18), smoking
      (OR:2.53; 95%CI:1.05-6.08), HDL (OR:3.16; 95%CI:1.28-7.81), homocysteine
      (OR:2.25; 95%CI:1.14-4.43) and Lipoprotein(a) (OR:2.62; 95%CI:1.01-6.79) were
      independent predictors of asymptomatic CAD. CONCLUSIONS: The present
      investigation shows an independent association of Lipoprotein(a), homocysteine
      and apo(a) polymorphism with silent CAD. Other studies are needed to establish
      whether these parameters are suitable for CAD screening in diabetic patients.

PMID- 12473161
TI  - Quality and correlates of medical record documentation in the ambulatory care
      setting.
AB  - BACKGROUND: Documentation in the medical record facilitates the diagnosis and
      treatment of patients. Few studies have assessed the quality of outpatient
      medical record documentation, and to the authors' knowledge, none has
      conclusively determined the correlates of chart documentation. We therefore
      undertook the present study to measure the rates of documentation of quality of
      care measures in an outpatient primary care practice setting that utilizes an
      electronic medical record. METHODS: We reviewed electronic medical records from
      834 patients receiving care from 167 physicians (117 internists and 50
      pediatricians) at 14 sites of a multi-specialty medical group in Massachusetts.
      We abstracted information for five measures of medical record documentation
      quality: smoking history, medications, drug allergies, compliance with screening
      guidelines, and immunizations. From other sources we determined physicians'
      specialty, gender, year of medical school graduation, and self-reported time
      spent teaching and in patient care. RESULTS: Among internists, unadjusted rates
      of documentation were 96.2% for immunizations, 91.6% for medications, 88% for
      compliance with screening guidelines, 61.6% for drug allergies, 37.8% for smoking
      history. Among pediatricians, rates were 100% for immunizations, 84.8% for
      medications, 90.8% for compliance with screening guidelines, 50.4% for drug
      allergies, and 20.4% for smoking history. While certain physician and patient
      characteristics correlated with some measures of documentation quality,
      documentation varied depending on the measure. For example, female internists
      were more likely than male internists to document smoking history (odds ratio
      [OR], 1.90; 95% confidence interval [CI], 1.27 - 2.83) but were less likely to
      document drug allergies (OR, 0.51; 95% CI, 0.35 - 0.75). CONCLUSIONS: Medical
      record documentation varied depending on the measure, with room for improvement
      in most domains. A variety of characteristics correlated with medical record
      documentation, but no pattern emerged. Further study could lead to targeted
      interventions to improve documentation.

PMID- 12473162
TI  - DNA sequence conservation between the Bacillus anthracis pXO2 plasmid and genomic
      sequence from closely related bacteria.
AB  - BACKGROUND: Complete sequencing and annotation of the 96.2 kb Bacillus anthracis
      plasmid, pXO2, predicted 85 open reading frames (ORFs). Bacillus cereus and
      Bacillus thuringiensis isolates that ranged in genomic similarity to B.
      anthracis, as determined by amplified fragment length polymorphism (AFLP)
      analysis, were examined by PCR for the presence of sequences similar to 47 pXO2
      ORFs. RESULTS: The two most distantly related isolates examined, B. thuringiensis
      33679 and B. thuringiensis AWO6, produced the greatest number of ORF sequences
      similar to pXO2; 10 detected in 33679 and 16 in AWO6. No more than two of the
      pXO2 ORFs were detected in any one of the remaining isolates. Dot-blot DNA
      hybridizations between pXO2 ORF fragments and total genomic DNA from AWO6 were
      consistent with the PCR assay results for this isolate and also revealed nine
      additional ORFs shared between these two bacteria. Sequences similar to the B.
      anthracis cap genes or their regulator, acpA, were not detected among any of the
      examined isolates. CONCLUSIONS: The presence of pXO2 sequences in the other
      Bacillus isolates did not correlate with genomic relatedness established by AFLP
      analysis. The presence of pXO2 ORF sequences in other Bacillus species suggests
      the possibility that certain pXO2 plasmid gene functions may also be present in
      other closely related bacteria.

PMID- 12473163
TI  - A randomized controlled trial of an extensive lifestyle management intervention
      (ELMI) following cardiac rehabilitation: study design and baseline data.
AB  - BACKGROUND: Cardiac rehabilitation programs (CRP) represent comprehensive
      interventions that are typically limited to four months. Following completion of
      CRP, it appears that risk factors and lifestyle behaviours may deteriorate. The
      Extensive Lifestyle Management Intervention (ELMI) Following Cardiac
      Rehabilitation trial will investigate the benefits of a randomized intervention
      to prevent these adverse changes. METHODS: Patients with ischemic heart disease
      (IHD) were randomized following a standard CRP to the ELMI or to usual care. The
      ELMI program is a case-managed intervention aimed at individualizing risk factor
      and lifestyle management based on current treatment guidelines. The program
      consists of cardiac rehabilitation sessions, telephone follow-up and risk factor
      and lifestyle counselling sessions. Health professionals work with participants
      using behavioural counselling and communications with participants' family
      physicians. Usual care participants return to their family physicians' care, and
      come to the study clinic only to undergo annual outcomes assessment. The primary
      outcome is change in IHD global risk after four years. Secondary outcomes include
      combined cardiovascular events, health care utilization, lifestyle adherence,
      quality of life and risk factors. RESULTS: Over 28 months, 302 men and women were
      randomized. This represented 29% of the total population screened. The average
      age of study participants is 64 years, 18% are women, 53% have had a previous
      myocardial infarction, 73% have undergone previous revascularization and 20% have
      diabetes mellitus. Ischemic heart disease risk factors for the entire cohort
      improved significantly after subjects had gone through previous CRPs. Baseline
      risk factors, lifestyle behaviours and medications were similar between the
      groups. CONCLUSIONS: This study population is representative of patients
      completing a standard CRP. Results of the ELMI trial will provide valuable
      information for the future design of CRPs.

PMID- 12473164
TI  - Prolactin signaling and Stat5: going their own separate ways?
AB  - Miyoshi et al. compared the role of the prolactin receptor (PrlR) and its
      downstream mediator, the signal transducer and activator of transcription 5
      (Stat5), in mammary epithelial cells in vivo by studying PrlR-/- and Stat5ab-/-
      mouse mammary epithelial transplants during pregnancy. At first glance, the two
      mutant epithelia appear to have similar defects in the differentiation of the
      alveolar epithelium. However, a closer examination by Miyoshi et al. revealed
      defects in the epithelial architecture of the smallest ducts of Stat5ab-/-
      transplants not apparent in the PrlR-/- transplants, suggesting that Stat5 is
      more than a simple mediator of PrlR action.

PMID- 12473165
TI  - Has tamoxifen had its day?
AB  - Tamoxifen is probably the most important drug in the history of the management of
      breast cancer and its development is a tribute to cross talk between laboratory
      scientists and clinical investigators. Its use as adjuvant therapy has led to a
      decrease of 20-30% in age-adjusted cause-specific mortality in the developed
      world and it is approved in the USA for the chemoprevention of breast cancer in
      high-risk women. The recent ATAC and IBIS trials have challenged the supremacy of
      tamoxifen. The present paper is a personal view of the implications for the
      future use of this drug in competition with the oral aromatase inhibitors. In the
      opinion of the author tamoxifen will probably remain the mainstay for adjuvant
      therapy of postmenopausal women with hormone-responsive disease, but maturation
      of the ATAC data may allow a choice in selected cases. Anastrozole looks like a
      competitor for the future but we may have to wait another 10 years to find out.

PMID- 12473166
TI  - A new day dawns: women without oestrogen or is a balance best?
AB  - Building on the 30-year success story with tamoxifen, the question now is whether
      one agent can be used for treatment and prevention or should new medicines be
      targeted to specific applications? The early results with anastrozole suggest it
      could replace tamoxifen for treatment and should be tested as a preventive.
      Unfortunately, long-term testing of aromatase inhibitors will be required to
      avoid concerns about osteoporosis, Alzheimer's disease and coronary heart
      disease. Most importantly, the knowledge gained with tamoxifen has resulted in a
      new generation of selective oestrogen receptor modulators that can be used to
      prevent osteoporosis, breast cancer and uterine cancer. It is now clear that
      strategies utilising aromatase inhibitors and selective oestrogen receptor
      modulators will provide much needed options for individualised treatments.

PMID- 12473167
TI  - Estrogen-progestin replacement therapy: regulatory action needed.
AB  - It is now established that the most commonly prescribed estrogen-progestin
      replacement therapy regimen significantly increases breast cancer risk. What are
      the risks associated with other regimens? Studies with breast cancer as the
      outcome cannot answer these questions in the right timeframe. It is incumbent on
      us to agree that some intermediate marker of risk must be used to show the
      probable effect of a regimen. We should then act as if the effect on the marker
      is a quantitative guide to the probable effect on breast cancer risk. Regulatory
      authorities need to require such studies on all current regimens.

PMID- 12473168
TI  - The importance of being a myoepithelial cell.
AB  - The mammary myoepithelial cell was named the 'Cinderella of mammary cell biology'
      in light of the earlier focus on the luminal cell. Mammary myoepithelial cells
      have recently been described as 'natural tumour suppressors'. We now need to
      understand more about their origin and to reconsider their place in the complex
      process of mammary morphogenesis. In the present review, we discuss the lineage
      segregation of mammary myoepithelial cells and their functions in mammary gland
      development. These functions include their effects on luminal cell growth and
      differentiation, their key role in the establishment of the polarised mammary
      epithelial bilayer and the control of stromal invasion in breast cancer.

PMID- 12473169
TI  - Insulin-like growth factors and insulin-like growth factor binding proteins in
      mammary gland function.
AB  - Insulin-like growth factor (IGF)-mediated proliferation and survival are
      essential for normal development in the mammary gland during puberty and
      pregnancy. IGFs interact with IGF-binding proteins and regulate their function.
      The present review focuses on the role of IGFs and IGF-binding proteins in the
      mammary gland and describes how modulation of their actions occurs by association
      with hormones, other growth factors and the extracellular matrix. The review will
      also highlight the involvement of the IGF axis in breast cancer.

PMID- 12473170
TI  - Progesterone receptors--animal models and cell signalling in breast cancer.
      Diverse activation pathways for the progesterone receptor: possible implications
      for breast biology and cancer.
AB  - Progesterone and estradiol, and their nuclear receptors, play essential roles in
      the physiology of the reproductive tract, the mammary gland and the nervous
      system. Estrogens have traditionally been considered associated with an increased
      risk of breast cancer. There is, however, compelling evidence that progesterone
      plays an important role in breast cell proliferation and cancer. Herein, we
      review the possible role of progestins and the progesterone receptor-associated
      signaling pathways in the development of breast cancer, as well as the
      therapeutic possibilities arising from our growing knowledge of the activation of
      the progesterone receptor by other proliferative mechanisms.

PMID- 12473171
TI  - Progesterone receptors--animal models and cell signalling in breast cancer.
      Implications for breast cancer of inclusion of progestins in hormone replacement
      therapies.
AB  - Progestins are included in menopausal hormone replacement therapy to counteract
      the increased risk for endometrial cancer associated with estrogen replacement
      therapy. Studies of hormone replacement therapy and breast cancer risk and of
      changes in mammographic density according to different regimens of hormone
      replacement therapy suggest that, for the most part, estrogen-progestin
      replacement therapy has a more adverse effect on breast cancer risk than does
      estrogen replacement therapy. Many questions remain unresolved, however,
      including risk associated with different regimens of estrogen-progestin
      replacement therapy, and whether the effects vary according to tumor
      characteristics, such as histology, extent of disease, and hormone receptor
      status.

PMID- 12473172
TI  - Workshop on The Epidemiology of the ATM Gene: Impact on Breast Cancer Risk and
      Treatment, Present Status and Future Focus, Lillehammer, Norway, 29 June 2002.
AB  - The role of ataxia-telangiectasia mutated (ATM) heterozygosity in cancer is
      uncertain. In vitro studies of cells from ATM heterozygotes provide strong
      evidence of radiation sensitivity. Some, but not all, clinical studies suggest an
      increased risk of breast cancer among ATM gene carriers, and this risk may be
      greater among those exposed to radiation. This possible excess risk of breast
      cancer associated with ATM heterozygosity constitutes the basis for several
      genetic epidemiological studies designed to clarify the role that the ATM gene
      plays in the etiology of breast and other cancers. The primary focus of this
      international, multidisciplinary, National Cancer Institute-sponsored workshop
      was to discuss ongoing and planned epidemiologic studies aimed at understanding
      the complexities of the ATM gene and its role in carcinogenesis. The invited
      participants were from diverse disciplines including molecular and clinical
      genetics, radiation biology and physics, epidemiology, biostatistics, pathology,
      and medicine. In the present meeting report, the aims of each project are
      described.

PMID- 12473173
TI  - Inhibition of E2-induced expression of BRCA1 by persistent organochlorines.
AB  - BACKGROUND: Environmental persistent organochlorines (POCs) biomagnify in the
      food chain, and the chemicals are suspected of being involved in a broad range of
      human malignancies. It is speculated that some POCs that can interfere with
      estrogen receptor-mediated responses are involved in the initiation and
      progression of human breast cancer. The tumor suppressor gene BRCA1 plays a role
      in cell-cycle control, in DNA repair, and in genomic stability, and it is often
      downregulated in sporadic mammary cancers. The aim of the present study was to
      elucidate whether POCs have the potential to alter the expression of BRCA1.
      METHODS: Using human breast cancer cell lines MCF-7 and MDA-MB-231, the effect on
      BRCA1 expression of chemicals belonging to different classes of organochlorine
      chemicals (the pesticide toxaphene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and
      three polychlorinated biphenyls [PCB#138, PCB#153 and PCB#180]) was measured by a
      reporter gene construct carrying 267 bp of the BRCA1 promoter. A twofold
      concentration range was analyzed in MCF-7, and the results were supported by
      northern blot analysis of BRCA1 mRNA using the highest concentrations of the
      chemicals. RESULTS: All three polychlorinated biphenyls and 2,3,7,8
      tetrachlorodibenzo-p-dioxin reduced 17beta-estradiol (E2)-induced expression as
      well as basal reporter gene expression in both cell lines, whereas northern blot
      analysis only revealed a downregulation of E2-induced BRCA1 mRNA expression in
      MCF-7 cells. Toxaphene, like E2, induced BRCA1 expression in MCF-7. CONCLUSION:
      The present study shows that some POCs have the capability to alter the
      expression of the tumor suppressor gene BRCA1 without affecting the cell-cycle
      control protein p21Waf/Cip1. Some POCs therefore have the potential to affect
      breast cancer risk.

PMID- 12473174
TI  - Breast cancer incidence and mortality trends in an affluent population: Marin
      County, California, USA, 1990-1999.
AB  - BACKGROUND: Elevated rates of breast cancer in affluent Marin County, California,
      were first reported in the early 1990s. These rates have since been related to
      higher regional prevalence of known breast cancer risk factors, including low
      parity, education, and income. Close surveillance of Marin County breast cancer
      trends has nevertheless continued, in part because distinctive breast cancer
      patterns in well-defined populations may inform understanding of breast cancer
      etiology. METHODS: Using the most recent incidence and mortality data available
      from the California Cancer Registry, we examined rates and trends for 1990-1999
      for invasive breast cancer among non-Hispanic, white women in Marin County, in
      other San Francisco Bay Area counties, and in other urban California counties.
      Rates were age adjusted to the 2000 US standard, and temporal changes were
      evaluated with weighted linear regression. RESULTS: Marin County breast cancer
      incidence rates between 1990 and 1999 increased 3.6% per year (95% confidence
      interval, 1.8-5.5), six times more rapidly than in comparison areas. The increase
      was limited to women aged 45-64 years, in whom rates increased at 6.7% per year
      (95% confidence interval, 3.8-9.6). Mortality rates did not change significantly
      in Marin County despite 3-5% yearly declines elsewhere. CONCLUSION: Patterns of
      breast cancer incidence and mortality in Marin County are unlike those in other
      California counties, and they are probably explained by Marin County's unique
      sociodemographic characteristics. Similar trends may have occurred in other
      affluent populations for which available data do not permit annual monitoring of
      cancer occurrence.

PMID- 12473175
TI  - Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast
      cancer.
AB  - BACKGROUND: A growing body of evidence suggests that variations in the levels of
      folate may contribute to the development of cancer. A functional polymorphic
      variant (C-->T substitution at nucleotide 677) in the 5,10
      methylenetetrahydrofolate reductase (MTHFR) gene results in the conversion of an
      alanine to a valine and may modify the risk of breast and other cancers. METHOD:
      We have investigated the possible influence of this MTHFR variant on breast
      cancer risk in a case-control study of 233 healthy women and 335 women who had
      breast cancer that occurred under the age of 40 years, bilateral breast cancer or
      a family history of breast cancer. RESULTS: A significant excess of the valine
      genotypes was observed among the cases (odds ratio 1.43, 95% confidence interval
      1.02-2.00). The effect was more pronounced among the cases with a breast cancer
      diagnosis under the age of 40 years, with an odds ratio of 1.66 (95% confidence
      interval 1.12-2.41). A nonsignificant excess of the valine genotypes was observed
      among the cases with a family history of breast cancer or bilateral breast
      cancer. CONCLUSIONS: The low activity C677T (valine) genotype of MTHFR may
      increase the risk of early onset breast cancer.

PMID- 12473176
TI  - No evidence for association of ataxia-telangiectasia mutated gene T2119C and
      C3161G amino acid substitution variants with risk of breast cancer.
AB  - BACKGROUND: There is evidence that certain mutations in the double-strand break
      repair pathway ataxia-telangiectasia mutated gene act in a dominant-negative
      manner to increase the risk of breast cancer. There are also some reports to
      suggest that the amino acid substitution variants T2119C Ser707Pro and C3161G
      Pro1054Arg may be associated with breast cancer risk. We investigate the breast
      cancer risk associated with these two nonconservative amino acid substitution
      variants using a large Australian population-based case-control study. METHODS:
      The polymorphisms were genotyped in more than 1300 cases and 600 controls using
      5' exonuclease assays. Case-control analyses and genotype distributions were
      compared by logistic regression. RESULTS: The 2119C variant was rare, occurring
      at frequencies of 1.4 and 1.3% in cases and controls, respectively (P = 0.8).
      There was no difference in genotype distribution between cases and controls (P =
      0.8), and the TC genotype was not associated with increased risk of breast cancer
      (adjusted odds ratio = 1.08, 95% confidence interval = 0.59-1.97, P = 0.8).
      Similarly, the 3161G variant was no more common in cases than in controls (2.9%
      versus 2.2%, P = 0.2), there was no difference in genotype distribution between
      cases and controls (P = 0.1), and the CG genotype was not associated with an
      increased risk of breast cancer (adjusted odds ratio = 1.30, 95% confidence
      interval = 0.85-1.98, P = 0.2). This lack of evidence for an association
      persisted within groups defined by the family history of breast cancer or by age.
      CONCLUSION: The 2119C and 3161G amino acid substitution variants are not
      associated with moderate or high risks of breast cancer in Australian women.

PMID- 12473177
TI  - Expression and prognostic significance of lysozyme in male breast cancer.
AB  - BACKGROUND: Lysozyme, one of the major protein components of human milk that is
      also synthesized by a significant percentage of breast carcinomas, is associated
      with lesions that have a favorable outcome in female breast cancer. Here we
      evaluate the expression and prognostic value of lysozyme in male breast cancer
      (MBC). METHODS: Lysozyme expression was examined by immunohistochemical methods
      in a series of 60 MBC tissue sections and in 15 patients with gynecomastia.
      Staining was quantified using the HSCORE (histological score) system, which
      considers both the intensity and the percentage of cells staining at each
      intensity. Prognostic value of lysozyme was retrospectively evaluated by
      multivariate analysis taking into account conventional prognostic factors.
      RESULTS: Lysozyme immunostaining was negative in all cases of gynecomastia. A
      total of 27 of 60 MBC sections (45%) stained positively for this protein, but
      there were clear differences among them with regard to the intensity and
      percentage of stained cells. Statistical analysis showed that lysozyme HSCORE
      values in relation to age, tumor size, nodal status, histological grade, estrogen
      receptor status, metastasis and histological type did not increase the
      statistical significance. Univariate analysis confirmed that both nodal
      involvement and lysozyme values were significant predictors of short-term relapse
      free survival. Multivariate analysis, according to Cox's regression model, also
      showed that nodal status and lysozyme levels were significant independent
      indicators of short-term relapse-free survival. CONCLUSION: Tumor expression of
      lysozyme is associated with lesions that have an unfavorable outcome in male
      breast cancer. This milk protein may be a new prognostic factor in patients with
      breast cancer.

PMID- 12473178
TI  - The roles of sex steroid receptor coregulators in cancer.
AB  - Sex steroid hormones, estrogen, progesterone and androgen, play pivotal roles in
      sex differentiation and development, and in reproductive functions and sexual
      behavior. Studies have shown that sex steroid hormones are the key regulators in
      the development and progression of endocrine-related cancers, especially the
      cancers of the reproductive tissues. The actions of estrogen, progesterone and
      androgen are mediated through their cognate intracellular receptor proteins, the
      estrogen receptors (ER), the progesterone receptors (PR) and the androgen
      receptor (AR), respectively. These receptors are members of the nuclear receptor
      (NR) superfamily, which function as transcription factors that regulate their
      target gene expression. Proper functioning of these steroid receptors maintains
      the normal responsiveness of the target tissues to the stimulations of the
      steroid hormones. This permits the normal development and function of
      reproductive tissues. It can be inferred that factors influencing the expression
      or function of steroid receptors will interfere with the normal development and
      function of the target tissues, and may induce pathological conditions, including
      cancers. In addition to the direct contact with the basal transcription
      machinery, nuclear receptors enhance or suppress transcription by recruiting an
      array of coactivators and corepressors, collectively named coregulators.
      Therefore, the mutation or aberrant expression of sex steroid receptor
      coregulators will affect the normal function of the sex steroid receptors and
      hence may participate in the development and progression of the cancers.

PMID- 12473179
TI  - Leishmania species and zymodemes isolated from endemic areas of cutaneous
      leishmaniasis in Jordan.
AB  - BACKGROUND: Cutaneous leishmaniasis (CL) is endemic in the Middle Eastern
      countries. New cases are emerging in areas previously free of the disease. In
      Jordan, the diagnosis of cases during the 1960s and 1970s was mainly reported in
      military hospitals in Amman. Endemicity of the disease was ascertained after
      reporting a total of 524 cases during 1973-1978. RESULTS: Leishmania major and
      Leishmania tropica were isolated from seventy-six autochthonous and imported
      cases of CL, during eight-year period. The highest infection rates recorded were
      in the central part of Jordan (60.5%), in males (72.4%) and in the age group 21
      30 years (30.5%). Lesions were on the exposed sites of the body, mainly on the
      face (40%). Both Leishmania spp. were isolated from all parts of the country,
      although L. major was the predominant species (75% of cases) in all areas except
      in the north part of Jordan. Isoenzyme characterization of the isolates
      identified four previously undescribed zymodemes (Z). Four Leishmania major
      zymodemes were found, one of which was a new zymodeme (ZMON-103 variant in
      GLUD220); L. major ZMON-103 was the most common zymodeme. Four Leishmania tropica
      zymodemes were identified, of which three were previously unreported. Of these,
      ZMON-54 var PGD96-97 was isolated from autochthonous cases, whereas ZMON-59 var
      MDH100 and ZMON-75 var FH110 were obtained from both autochthonous and imported
      cases, or from an imported CL case, respectively. CONCLUSION: The findings of
      this study indicate the emergence of the CL disease in new areas. New foci are
      reported, where the sporadic nature of the cases indicates recent spread of the
      disease to these areas and the urge for the implementation of control measures.

PMID- 12473180
TI  - Cardiac arrhythmia classification using autoregressive modeling.
AB  - BACKGROUND: Computer-assisted arrhythmia recognition is critical for the
      management of cardiac disorders. Various techniques have been utilized to
      classify arrhythmias. Generally, these techniques classify two or three
      arrhythmias or have significantly large processing times. A simpler
      autoregressive modeling (AR) technique is proposed to classify normal sinus
      rhythm (NSR) and various cardiac arrhythmias including atrial premature
      contraction (APC), premature ventricular contraction (PVC), superventricular
      tachycardia (SVT), ventricular tachycardia (VT) and ventricular fibrillation
      (VF). METHODS: AR Modeling was performed on ECG data from normal sinus rhythm as
      well as various arrhythmias. The AR coefficients were computed using Burg's
      algorithm. The AR coefficients were classified using a generalized linear model
      (GLM) based algorithm in various stages. RESULTS: AR modeling results showed that
      an order of four was sufficient for modeling the ECG signals. The accuracy of
      detecting NSR, APC, PVC, SVT, VT and VF were 93.2% to 100% using the GLM based
      classification algorithm. CONCLUSION: The results show that AR modeling is useful
      for the classification of cardiac arrhythmias, with reasonably high accuracies.
      Further validation of the proposed technique will yield acceptable results for
      clinical implementation.

PMID- 12473181
TI  - Community cooperatives and insecticide-treated materials for malaria control: a
      new experience in Latin America.
AB  - BACKGROUND AND OBJECTIVES: Insecticide-treated materials (ITMs) are effective in
      substantially reducing the burden of malaria and other vector-borne diseases; but
      how can high coverage rates of ITMs be achieved and maintained? In south Mexico
      and on the Pacific and Atlantic coasts of Colombia 14 community-based
      cooperatives offering three different kinds of ITM services (sale of impregnation
      services; sale of impregnated nets; production of nets and sale of impregnated
      nets) were formed and supervised by a national health service (IMSS-SOLIDARIDAD,
      Mexico) and by an academic institution (the Colombian Institute of Tropical
      Medicine) along with local district health services. The objectives of this
      research were to analyse the processes and results of this approach and to
      identify the favourable and limiting factors. METHODS: The methods used for data
      collection and analysis were group discussions, individual and semi-structured
      interviews with users and non-users of ITMs, individual in-depth interviews with
      cooperative members and supervisors, checks of sales book and observation of
      impregnation services. RESULTS: Coverage with unimpregnated nets was above 50% in
      all study areas. The fastest increase of ITM coverage was achieved through the
      exclusive sale of impregnation services. Low-cost social marketing techniques
      were used to increase demand. The large-scale production of nets in two
      cooperatives was only possible with the aid of an international NGO which ordered
      impregnated bednets for their target group. A number of favourable and limiting
      factors relating to the success of ITM cooperatives were identified. Of
      particular importance for the more successful Mexican cooperatives were: a)
      support by health services, b) smaller size, c) lesser desire for quick returns
      and d) lower ITM unit costs. CONCLUSIONS: ITM community cooperatives supported
      and supervised by the health services have good potential in the Latin American
      context for achieving and maintaining high impregnation rates.

PMID- 12473182
TI  - Triangular test applied to the clinical trial of azithromycin against relapses in
      Plasmodium vivax infections.
AB  - BACKGROUND: Sequential analysis enables repeated statistical analyses to be
      performed throughout a trial recruitment period, while maintaining a pre
      specified power and type I error. Thus the trial can be stopped as soon as the
      information accumulated is considered sufficient to reach a conclusion.
      Sequential tests are easy to use and their statistical properties are especially
      suitable to trials with very straightforward objectives such as non-comparative
      phase II trials. We report on a phase II study based on the triangular test (TT)
      aiming at assessing the effectiveness of azithromycin in preventing Plasmodium
      vivax relapses. METHODS: To test whether the P. vivax relapse rate was either
      <12% or >or= 45% in patients treated with azithromycin, a sequential analysis
      based on the TT was as used. Patients infected with P. vivax were treated with
      azithromycin, 1.2 g daily, for 7 days. The onset of a relapse infection was
      monitored. RESULTS: Five patients presenting with an acute P. vivax infection
      were included in the study. All the patients were initially cured. Three patients
      reported mild gastrointestinal adverse effects. When the third patient relapsed,
      the sample path crossed the upper boundary of the TT, and the trial was stopped.
      CONCLUSIONS: Using the triangular test, with only a small number of patients, we
      concluded that azithromycin was not effective enough in preventing P. vivax
      relapses to warrant further evaluation in phase III. It is suggested that a wider
      use of sequential analysis in phase II anti-infective drugs trials may have
      financial and ethical benefits.

PMID- 12473183
TI  - Protein kinase C delta (PKC delta): activation mechanisms and functions.
AB  - Protein kinase C (PKC)delta was the first new/novel PKC isoform to be identified
      by the screening of mammalian cDNA libraries, based on the structural homology of
      its nucleotide sequences with those of classical/conventional PKC isoforms. PKC
      delta is expressed ubiquitously among cells and tissues. It is activated by
      diacylglycerol produced by receptor-mediated hydrolysis of membrane inositol
      phospholipids as well as by tumor-promoting phorbol ester through the binding of
      these compounds to the C1 region in its regulatory domain. It is also cleaved by
      caspase to generate a catalytically active fragment, and it is converted to an
      active form without proteolysis through the tyrosine phosphorylation reaction.
      Various lines of evidence indicate that PKC delta activated in distinct ways
      plays critical roles in cellular functions such as the control of growth,
      differentiation, and apoptosis. This article briefly summarizes the regulatory
      mechanisms of PKC delta activity and its functions in cell signaling.

PMID- 12473184
TI  - Protein kinase C-theta (PKC theta): a key enzyme in T cell life and death.
AB  - The novel protein kinase C (PKC) isoform, PKC theta, is expressed in a relatively
      selective manner in T lymphocytes (and muscle). Recent analysis of this PKC
      isotype in T cells and the characterization of PKC theta-deficient mice revealed
      important clues about its function and regulation. PKC theta does not have an
      obvious role in T cell development, but it is essential for the activation of
      mature T cells. The requirement of PKC theta for T cell activation, proliferation
      and cytokine production reflects the essential role of this isotype in inducing
      signaling pathways leading to the activation of the transcription factors AP-1
      and NF-kappa B in a T cell-specific manner. A unique feature of PKC theta is its
      highly selective translocation to the central region of the immunological synapse
      (IS) in antigen-stimulated T cells, a property apparently important for its
      proper signaling functions. This localization implies unique pathway(s) that
      regulate the translocation and/or activation of this enzyme. Our work suggests
      that sustained PKC theta membrane translocation and phosphorylation are
      relatively independent of phospholipase C (PLC) activation and diacylglycerol
      (DAG) production. Instead, a pathway that requires Vav, phosphatidylinositol 3
      kinase (PI3-K), Rac1 and actin cytoskeleton reorganization mediates these events.
      Additionally, PKC theta provides an important survival signal to T cells.
      Nevertheless, several questions regarding the function and regulation of PKC
      theta and the identity of its immediate targets/substrates remain open.
      Resolution of these questions could open the way to the development of selective
      PKC theta inhibitors, which may have therapeutic potential in immunological
      diseases and in cancer.

PMID- 12473185
TI  - Protein kinase C-epsilon (PKC-epsilon): its unique structure and function.
AB  - Protein kinase C (PKC)-epsilon was first discovered among novel PKC isotypes by
      cDNA cloning, and characterized as a calcium-independent but phorbol
      ester/diacylglycerol-sensitive serine/threonine kinase. PKC-epsilon is targeted
      to a specific cellular compartment in a manner dependent on second messengers and
      on specific adapter proteins in response to extracellular signals that activate G
      protein-coupled receptors, tyrosine kinase receptors, or tyrosine kinase-coupled
      receptors. PKC-epsilon then regulates various physiological functions including
      the activation of nervous, endocrine, exocrine, inflammatory, and immune systems.
      The controlled activation of PKC-epsilon plays a protective role in the
      development of cardiac ischemia and Alzheimer's disease, whereas its uncontrolled
      chronic activation results in severe diseases such as malignant tumors and
      diabetes. This review summarizes recent progress in our understanding of the
      unique structure and physiological and pathological roles of PKC-epsilon with a
      focus mainly on knockout, transgenic, and mutational studies.

PMID- 12473186
TI  - Protein kinase C eta (PKC eta): its involvement in keratinocyte differentiation.
AB  - The eta isoform of protein kinase C (PKC eta) is classified into the Ca2+
      independent novel PKC subfamily and assigned to human chromosome 14 (14q22-23)
      and mouse chromosome 12 (12C3-D2). It is highly expressed in epithelial tissues
      especially in squamous epithelia. PKC eta is unique in that it is specifically
      activated by cholesterol sulfate and sulfatide, sulfated metabolites of
      cholesterol and cerebroside, respectively. PKC eta overexpression induces G1
      arrest and differentiation in keratinocytes. PKC eta-induced differentiation is
      accompanied by the transcriptional activation of transglutaminase I, a key enzyme
      in squamous differentiation, and involucrin, a precursor of cornified envelopes.
      In keratinocytes, PKC eta associates with the cyclin E/cdk2/p21 complex and
      inhibits the cdk2-kinase activity, leading to G1 arrest. Cholesterol sulfate
      inhibits the promotional phase of skin carcinogenesis. Moreover, PKC eta-knockout
      mice show a much higher sensitivity to carcinogenesis, suggesting that PKC eta is
      negatively involved in tumor promotion through stimulation of keratinocyte
      differentiation. In addition to epithelial cells, recent studies revealed that
      PKC eta acts as a key regulator in early B-cell development. Although the
      functions of PKC eta in other cell types are not yet fully elucidated, available
      evidence indicates that this particular isoform plays crucial roles in the
      signaling of cell differentiation in a cell-type-specific manner.

PMID- 12473187
TI  - Crystallization and preliminary X-ray crystallographic studies of Trypanosoma
      brucei prostaglandin F(2 alpha) synthase.
AB  - Prostaglandin F(2 alpha) is a potent mediator of various physiological and
      pathological processes. Trypanosoma brucei prostaglandin F(2 alpha) synthase
      (TbPGFS) catalyzes the NADPH-dependent reduction of 9,11-endoperoxide PGH(2) to
      PGF(2 alpha), and could thus be involved in the elevation of the PGF(2 alpha)
      concentration during African trypanosomiasis. In the present report, the
      purification and crystallization of recombinant TbPGFS are described. The active
      recombinant enzyme was crystallized by the hanging-drop vapor-diffusion meth-od
      using ammonium sulfate as a precipitant. The crystal belonged to a tetragonal
      space group, P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters of a = b = 112.3
      A, and c = 140.0 A. Native data up to 2.6 A resolution were collected from the
      crystal using our home facility.

PMID- 12473188
TI  - pH-dependent aggregate forms and conformation of Alzheimer amyloid beta-peptide
      (12-24).
AB  - The conformational transition to a beta-structure and the aggregation process of
      Alzheimer amyloid beta-peptide (12-24) [abbreviated as A beta(12-24)] were
      studied. The influence of sample dissolution methods for the aggregate structure
      was examined by electron microscopy (EM). The difference in the width of the
      aggregate of A beta(12-24) depended on the pH immediately after sample
      dissolution. Two types of sample dissolution methods, F and R, were employed. For
      dissolution method F, the peptide sample was immediately dissolved in water and
      then adjusted to pH 2.2 by adding buffer, while for dissolution method R, the
      peptide was directly dissolved in the buffer solution. In the latter case, the
      starting pH was 3.0. Slight fibrils (10-12 nm in diameter) were observed with
      method F, and wider ribbon-like aggregates (17-20 nm in diameter) with method R,
      despite the same pH range. A difference between methods F and R was also detected
      in the CD spectra, especially at pHs near 5.0. The CD intensity of the 214 nm
      band with method R changed with pH, with the highest value at pH 3.7, whereas
      that with method F was unchanged at pHs below 5.0. The temperature-dependent CD
      results showed that a thermostable aggregate of A beta(12-24) occurs at higher
      pHs than 3.0. NMR analysis showed that deprotonation of the C-terminal
      carboxylate group in A beta(12-24) triggered the aggregate formation, and the
      transition from a random coil to a beta-conformation in the C-terminal region of
      V18-V24 was detected on analysis of the (3)Ja(N) coupling constant in the pH
      range of 2.2 to 3.0.

PMID- 12473189
TI  - Characterization of functional regions for nuclear localization of NPAT.
AB  - NPAT plays a role in S phase entry as a substrate of cyclin E-CDK2 and activation
      of histone gene transcription. Although analysis of its sequence indicates that
      NPAT contains typical nuclear localization signals (NLS) comprising segments of
      positively charged amino acids, there are currently no experimental data to show
      that these predictive NLS are functional. To investigate whether these sequences
      are effective for nuclear transport of NPAT, an NPAT-green fluorescent protein
      fusion (NP-GFP) was constructed. After transfection of the fusion gene containing
      the full coding region of NPAT into cultured cells, the NP-GFP product was found
      exclusively in the nucleus. As expected, some deletion mutants that retained the
      basic amino acid clusters at the carboxyl terminus also localize the fusion
      protein in the nucleus. However, other fusions that lacked one of the three basic
      amino acid-clusters were distributed throughout the nucleus and cytoplasm.
      Therefore all three clusters of basic residues are necessary for localization of
      NPAT to the nucleus. However, another sequence outside the carboxyl terminal
      region functions similarly to NLS. Construction of GFP fusions with a series of
      truncated forms of NPAT indicated that a short peptide sequence consisting of
      mainly hydrophobic amino acids near the central domain of NPAT also contributes
      to localizing the protein in the nucleus.

PMID- 12473190
TI  - Growth hormone has dual stage-specific effects on the differentiation of 3T3-L1
      preadipocytes.
AB  - Reports vary on the role of growth hormone (GH) in adipocyte differentiation. In
      this study, we showed that GH exerted dual effects depending on the stage of
      differentiation, using a serum-free culture of 3T3-L1 preadipocytes. GH promoted
      the differentiation when added to the medium during differentiation-inducing
      treatment with a hormone cocktail, but apparently suppressed it when added after
      the treatment. Only the suppressive effect was observed in the presence of 10%
      fetal bovine serum (FBS). Immunodepletion study showed that GH contributes to the
      differentiation-promoting activity of FBS. Insulin-like growth factor-1 could not
      replicate either the stimulative or the suppressive effect of GH. Stimulation of
      differentiation by GH involved the enhanced expression of mRNA of middle to late
      adipocyte markers. Among the key regulators of adipogenesis, peroxisome
      proliferator-activated receptor (PPAR) gamma and CCAAT/enhancer binding protein
      (C/EBP) alpha, but not C/EBPbeta, were stimulated for mRNA expression by GH added
      during the treatment with hormone cocktail. The stimulation of adipogenesis by GH
      was indeed due to the increase in the ratio of differentiated cells, though GH
      also promoted cell growth.

PMID- 12473191
TI  - Occurrence of secretory glycoprotein-specific GalNAc beta 1-->4GlcNAc sequence in
      N-glycans in MDCK cells.
AB  - Many reports show that N-glycans of glycoproteins play important roles in
      vectorial transport in MDCK cells. To assess whether structural differences in N
      glycans exist between secretory glycoproteins and membrane glycoproteins, we
      studied the N-glycan structures of the glycoproteins isolated from MDCK cells.
      Polarized MDCK cells were metabolically labeled with [3H]glucosamine, and (3)H
      labeled N-glycans of four glycoprotein fractions, secretory glycoproteins in
      apical and basolateral media, and apical and basolateral membrane glycoproteins,
      were released by glycopeptidase F. The structures of the free N-glycans were
      comparatively analyzed using various lectin column chromatographies and
      sequential glycosidase digestion. The four samples commonly contained high
      mannose-type glycans and bi- and tri-antennary glycans with a bisected or non
      bisected trimannosyl core. However, secretory glycoproteins in both media
      predominantly contained (sialyl)LacdiNAc sequences, +/-Sia alpha 2-->6GalNAc beta
      1-->4GlcNAc beta 1-->R, which linked only to a non-bisected trimannosyl core.
      beta1-->4N-acetylgalactosaminyltransferase (beta 4GalNAc-T) activity in MDCK
      cells preferred non-bisected glycans to bisected ones in accordance with the
      proposed N-glycan structures. This secretory glycoprotein-predominant LacdiNAc
      sequence was also found in the case of human embryonic kidney 293 cells. These
      results suggest that the secretory glycoprotein-specific (sialyl)LacdiNAc
      sequence and the corresponding beta 4GalNAc-T are involved in transport of
      secretory glycoproteins.

PMID- 12473192
TI  - Efficient construction of a diabody using a refolding system: anti
      carcinoembryonic antigen recombinant antibody fragment.
AB  - Recombinant fragments of the variable region of antibodies are useful in many
      experimental and clinical applications. However, it can be difficult to obtain
      these materials in soluble form after their expression in bacteria. Here, we
      report an efficient procedure for preparing several variable-domain fragments
      (Fv), single-chain Fv (scFv), and a diabody (the smallest functional bispecific
      antibody) of anti-carcinoembryonic antigen (CEA) antibody by overexpression in
      Escherichia coli in inclusion bodies, using a refolding system to obtain
      renatured proteins. Two types of refolded Fv were prepared: (i) Heavy and light
      chains of the immunoglobulin variable regions (VH and VL, respectively) were
      coexpressed with a dicistronic expression vector (designated Fv(co)); (ii) VH and
      VL were expressed separately, mixed stoichiometrically, and refolded (designated
      Fv(mix)). All samples refolded with high efficiency; Fv(co), Fv(mix), scFv, and
      the bispecific diabody bound to several CEA-positive cell lines, exactly as did
      soluble Fv fragments secreted by E. coli (Fv(sol)) and the parent IgG. The
      refolded fragments inhibited binding of the parent IgG to CEA-positive cell
      lines, indicating that their epitope is identical to that of IgG. The bispecific
      diabody, which combined variable-region fragments of anti-CEA antibody with
      variable-region fragments of anti-CD3 antibody, was also prepared using the
      refolding system. This refolded diabody could bind to lymphokine-activated killer
      cells. In addition, its cytotoxicity toward human bile duct carcinoma TFK-1 and
      other several other CEA-positive cell lines was concentration-dependent. Taken
      together, our results suggest that a refolding procedure can be used to prepare
      various functional antibody fragments (Fv, scFv, and diabody).

PMID- 12473193
TI  - Signal transduction mechanism leading to enhanced proliferation of primary
      cultured adult rat hepatocytes treated with royal jelly 57-kDa protein.
AB  - A 57-kDa protein in royal jelly (RJ) was previously shown to stimulate hepatocyte
      DNA synthesis and prolongs the proliferation of hepatocytes as well as increasing
      albumin production [Kamakura, M., Suenobu, N., and Fukushima, M. (2001) Biochem.
      Biophys. Res. Commun. 282, 865-874]. In this study, I investigated the signal
      transduction mechanisms involved in the induction of hepatocyte DNA synthesis and
      the promotion of cell survival by this 57-kDa protein in primary cultures of
      adult rat hepatocytes. Hepatocyte DNA synthesis induced by the 57-kDa protein was
      not influenced by several alpha- and beta-adrenoceptor antagonists, but was dose
      dependently abolished by an inhibitor of a tyrosine-specific protein kinase,
      genistein. A phospholipase C inhibitor (U-73122) and a protein kinase C (PKC)
      inhibitor (sphingosine) inhibited 57-kDa protein-stimulated he-patocyte DNA
      synthesis, whereas a protein kinase A inhibitor (H-89) did not. The 57-kDa
      protein also activated PKC in rat hepatocytes. Various inhibitors of
      intracellular signal transduction elements (PD98059, p21 ras farnesyltransferase
      inhibitor, wortmannin and rapamycin) also blocked hepatocyte DNA synthesis
      induced by the 57-kDa protein. Furthermore, the 57-kDa protein activated mitogen
      activated protein (MAP) kinase in rat hepatocytes. The activation of MAP kinase
      by the 57-kDa protein was inhibited by PD98059 and sphingosine. The 57-kDa
      protein also activated protein kinase B, which is a key regulator of cell
      survival. These results suggest that, like growth factors, the 57-kDa protein
      activates several important intracellular signaling factors involved in the
      stimulation of hepatocyte DNA synthesis and the protection of cells from
      apoptosis.

PMID- 12473194
TI  - Phosphoinositide 3-kinase accelerates calpain-dependent proteolysis of fodrin
      during hypoxic cell death.
AB  - We have shown recently that phosphoinositide 3-kinase (PI 3-kinase) accelerates
      the hypoxia-induced necrotic cell death of H9c2, derived from rat cardiomyocytes,
      by enhancing metabolic acidosis. Here we show the downstream events of acidosis
      that cause hypoxic cell death. Hypoxia induces the proteolysis of fodrin, a
      substrate of calpain. Intracellular Ca(2+) chelation by BAPTA, and the addition
      of SJA6017, a specific peptide inhibitor of calpain, also reduces cell death and
      fodrin proteolysis, indicating that Ca(2+) influx and calpain activation might be
      involved in these events. The overexpression of wild type PI 3-kinase accelerates
      fodrin proteolysis, while dominant-negative PI 3-kinase reduces it. Both (N-ethyl
      N-isopropyl)amiloride (EIPA), an inhibitor of the Na(+)/H(+) exchanger, and KB
      R7943, an inhibitor of the Na(+)/Ca(2+) exchanger, reduce hypoxic cell death and
      fodrin proteolysis. The depletion of intracellular Ca(2+ )stores by thapsigargin,
      an inhibitor of endoplasmic reticulum Ca(2+)-ATPase, also reduces cell death and
      fodrin proteolysis, indicating that Ca(2+ )release from intracellular Ca(2+
      )stores might be also involved. These results indicate that PI 3-kinase might
      accelerate hypoxic cell death by enhancing the calpain-dependent proteolysis of
      fodrin.

PMID- 12473195
TI  - Crystal structure of bovine trypsin and wheat germ trypsin inhibitor (I-2b)
      complex (2:1) at 2.3 a resolution.
AB  - The Bowman-Birk trypsin inhibitor (BBI) from wheat germ (I-2b) consists of 123
      amino acid residues with two inhibitory loops. The crystal structure of a bovine
      trypsin-wheat germ trypsin inhibitor (I-2b) complex (2:1) has been determined at
      2.3 A resolution to a final R-factor of 0.177. A distance of 37.2 A between the
      contiguous contact loops allows them to bind and inhibit two trypsin molecules
      simultaneously and independently. Each domain shares the same overall fold with 8
      kDa BBIs. The five disulfide bridges in each domain are a subset of seven
      disulfide bridges in the 8 kDa BBIs. I-2b consists of ten beta-strands and the
      loops connecting these strands but it lacks alpha-helices. The conformations of
      the contiguous contact loops of I-2b are in a heart-like structure. The reactive
      sites in both domains, Arg 17 and Lys 76, are located on the loop connecting anti
      parallel beta-strands, beta 1/beta 2 and beta 6/beta 7. Strands beta 1 and beta 6
      are in direct contact with trypsin molecules and form stable triple stranded beta
      sheet structures via hydrogen bonds.

PMID- 12473196
TI  - Functions of the D-ribosyl moiety and the lower axial ligand of the nucleotide
      loop of coenzyme B(12) in diol dehydratase and ethanolamine ammonia-lyase
      reactions.
AB  - The roles of the D-ribosyl moiety and the bulky axial ligand of the nucleotide
      loop of adenosylcobalamin in coenzymic function have been investigated using two
      series of coenzyme analogs bearing various artificial bases. The 2
      methylbenzimidazolyl trimethylene analog that exists exclusively in the base-off
      form was a totally inactive coenzyme for diol dehydratase and served as a
      competitive inhibitor. The benzimidazolyl trimethylene analog and the
      benzimidazolylcobamide coenzyme were highly active for diol dehydratase and
      ethanolamine ammonia-lyase. The imidazolylcobamide coenzyme was 59 and 9% as
      active as the normal coenzyme for diol dehydratase and ethanolamine ammonia
      lyase, respectively. The latter analog served as an effective suicide coenzyme
      for both enzymes, although the partition ratio (k(cat)/k(inact)) of 630 for
      ethanolamine ammonia-lyase is much lower than that for diol dehydratase. Suicide
      inactivation was accompanied by the accumulation of a cob(II)amide species,
      indicating irreversible cleavage of the coenzyme Co-C bond during the
      inactivation. It was thus concluded that the bulkiness of a Co-coordinating base
      of the nucleotide loop is essential for both the initial activity and continuous
      catalytic turnovers. Since the k(cat)/k(inact) value for the imidazolylcobamide
      in diol dehydratase was 27-times higher than that for the imidazolyl trimethylene
      analog, it is clear that the ribosyl moiety protects the reaction intermediates
      from suicide inactivation. Stopped-flow measurements indicated that the rate of
      Co-C bond homolysis is essentially unaffected by the bulkiness of the Co
      coordinating base for diol dehydratase. Thus, it seems unlikely that the Co-C
      bond is labilized through a ground state mechanochemical triggering mechanism in
      diol dehydratase.

PMID- 12473197
TI  - Inhibitory effects of alcohols on thermolysin activity as examined using a
      fluorescent substrate.
AB  - Alcohols inhibit the thermolysin-catalyzed hydrolysis of N-[3-(2-furyl)acryloyl]
      Gly-L-Leu-NH(2) and decrease the NaCl-induced activation of thermolysin in a
      concentration-dependent manner [K. Inouye et al. (1997) J. Biochem. 122, 358
      364]. In this study, the inhibitory effects of alcohols on thermolysin activity
      were examined in detail using 10 different alcohols and a fluorescent substrate,
      (7-methoxycoumarin-4-yl) acetyl-L-Pro-L-Leu-Gly-L-Leu-[N(3)-(2,4-dinitrophenyl)-L
      2,3-diamino-propionyl]-L-Ala-L-Arg-NH(2). The inhibition by all alcohols examined
      is completely reversible, and thermolysin activity is recovered by dilution. The
      inhibitor constants (K(i)) are in the range of 35-430 mM, and the order of the
      inhibitory effect is 1-pentanol, 1-propanol, 2-butanol, 2-methyl-1-propanol > 1
      butanol > 2-propanol > ethanol, tert-amyl alcohol >> tert-butyl alcohol >>
      methanol. Linear and secondary alcohols whose mains chains consist of more than 3
      carbons inhibit thermolysin effectively. Thermolysin activity is decreased by
      decreasing the dielectric constant, D, of the reaction medium containing the
      alcohol, and the decrease depending on the D value was almost the same manner for
      all alcohols except methanol, tert-butyl alcohol, and tert-amyl alcohol. Alcohols
      may inhibit thermolysin activity both by binding to the active site, most
      possibly to the S1' subsite, of thermolysin and by altering the electrostatic and
      hydrophobic environment around the thermolysin molecule.

PMID- 12473198
TI  - The human MYOD1 transgene is suppressed by 5-bromodeoxyuridine in mouse
      myoblasts.
AB  - 5-Bromodeoxyuridine (BrdU) immediately and clearly suppresses expression of the
      mouse Myod1 and human MYOD1 genes in myoblastic cells. Despite various studies,
      its molecular mechanism remains unknown. We failed to identify a BrdU-responsive
      element of the genes in experiments in which reporter constructs containing known
      regulatory sequences were transferred to mouse C2C12 myoblasts. Therefore, we
      transferred human chromosome 11 containing the MYOD1 gene to the cells by
      microcell-mediated chromosome transfer. In the resulting microcell hybrids, BrdU
      suppressed expression of the transgene, as determined by quantitative real-time
      RT-PCR analysis. We then transfected human PAC clones containing the MYOD1 gene
      to the cells. In the resulting transfectants, BrdU suppressed the transgene
      similarly. Deletion analysis suggested that a BrdU-responsive element or
      chromatin structure exists between 24 and 47 kb upstream of the gene. These
      results are the first demonstrating BrdU-responsiveness of a transgene for the
      known BrdU-responsive genes and facilitating determination of its precise
      responsible structure.

PMID- 12473199
TI  - Analysis of fluorogenic Smith degradation products of 7-(1,3-disulfonaphtyl)amino
      disaccharides for linkage position analysis of carbohydrates.
AB  - The linkage position of a glycosidic bond to the reducing-end residue of a
      pyridylamino (PA-) sugar can be determined sensitively by Smith degradation and
      HPLC [K. Omichi and S. Hase, (1994) J. Biochem. 115, 429-434]. With the aim of
      enhancing the sensitivity of this method of linkage position analysis to the fmol
      level, use of the 7-(1,3-disulfonaphtyl)amino (DSNA-) group instead of the PA
      group as a fluorescent tag was examined. Smith degradation of DSNA-disaccharides
      with a DSNA-hexose, DSNA-N-acetylglucosamine, or DSNA-N-acetylgalactosamine
      reducing-end residue was carried out. HPLC and FAB-MS of the fluorogenic Smith
      degradation products showed that the DSNA-group was stable under the Smith
      degradation reaction conditions, and that the reaction proceeded in a manner
      similar to that using PA-disaccharides to give the predicted products.
      Fluorogenic Smith degradation products specific to the glycosidic linkage
      position were well separated by reversed-phase HPLC, and were easily assignable
      by comparing the HPLC elution positions with those of standard compounds. The
      method was successfully applied to analyzing the structure of an N-linked sugar
      chain.

PMID- 12473200
TI  - Overexpression and functional characterization of a serine carboxypeptidase
      inhibitor (I(C)) from Saccharomyces cerevisiae.
AB  - Carboxypeptidase Y (CPY) inhibitor, I(C), a cytoplasmic inhibitor of vacuolar
      proteinases in yeast, Saccharomyces cerevisiae, was purified by means of a high
      level expression system using a proteinase-deficient strain, BJ2168, and an
      expression vector with the promoter GAL1. The purified I(C) exists as a monomeric
      beta-protein in solution with a mole-cular weight of 24,398.4 as determined by
      gel filtration chromatography, MALDI-TOF mass spectrometry, and far-UV CD
      spectroscopy. The acetylated N-terminal methionine residue is the sole
      posttranslational modification. I(C) specifically inhibits both the peptidase and
      anilidase activities of CPY with inhibitor constants (K(i)) of approximately 1.0
      x 10(-9) M. The chemical modification of I(C) with sulfhydryl reagents indicated
      that it lacks disulfide bonds and has two free SH groups, which are responsible,
      not for the inhibitory function, but, apparently, for the folding of the overall
      structure. The formation of a complex of I(C) with CPY was highly specific, as
      evidenced by no detectable interaction with pro-CPY. Chemical modification
      studies of the CPY-I(C) complex with specific reagents demonstrated that the
      catalytic Ser146 and S1 substrate-binding site of CPY are covered in the complex.

PMID- 12473201
TI  - Affinity selection of DNA-binding proteins from yeast genomic DNA libraries by
      improved lambda phage display vector.
AB  - Phage display is a useful means of identifying and selecting proteins of interest
      that bind specific targets. In order to examine the potential of phage display
      for the genome-wide screening of DNA-binding proteins, we constructed yeast
      genomic libraries using lambda foo-based vectors devised in this work. After
      affinity selection using GAL4 UAS(G) as a probe, phages expressing GAL4 were
      enriched approximately 5 x 10(5)-fold from the library. Approximately 90% of
      polypeptides encoded in correct translation reading frames by the selected phages
      were known or putative polynucleotide-binding proteins. This result clearly
      indicates that the modified lambda phage display vector in combination with our
      enrichment technique has great potential for the enrichment of DNA-binding
      proteins in a sequence-specific manner.

PMID- 12473202
TI  - The ribosome modulation factor (RMF) binding site on the 100S ribosome of
      Escherichia coli.
AB  - During the stationary growth phase, Escherichia coli 70S ribosomes are converted
      to 100S ribosomes, and translational activity is lost. This conversion is caused
      by the binding of the ribosome modulation factor (RMF) to 70S ribosomes. In order
      to elucidate the mechanisms by which 100S ribosomes form and translational
      inactivation occurs, the shape of the 100S ribosome and the RMF ribosomal binding
      site were investigated by electron microscopy and protein-protein cross-linking,
      respectively. We show that (i) the 100S ribosome is formed by the dimerization of
      two 70S ribosomes mediated by face-to-face contacts between their constituent 30S
      subunits, and (ii) RMF binds near the ribosomal proteins S13, L13, and L2. The
      positions of these proteins indicate that the RMF binding site is near the
      peptidyl transferase center or the P site (peptidyl-tRNA binding site). These
      observations are consistent with the translational inactivation of the ribosome
      by RMF binding. After the "Recycling" stage, ribosomes can readily proceed to the
      "Initiation" stage during exponential growth, but during stationary phase, the
      majority of 70S ribosomes are stored as 100S ribosomes and are translationally
      inactive. We suggest that this conversion of 70S to 100S ribosomes represents a
      newly identified stage of the ribosomal cycle in stationary phase cells, and we
      have termed it the "Hibernation" stage.

PMID- 12473203
TI  - Functional tolerance of Streptomyces subtilisin inhibitor toward conformational
      and stability changes caused by single-point mutations in the hydrophobic core.
AB  - Single amino acid mutations of Met103 in the hydrophobic core of a serine
      protease inhibitor, Streptomyces subtilisin inhibitor, caused little change in
      the inhibitory activity, as measured by the inhibitor constant, although some
      altered the thermodynamic stability of the protein considerably. (1)H NMR
      investigations showed that the conformational stress caused by the replacement of
      Met103 with Gly, Ala, Val, and Ile, namely, the effects of the cavities generated
      by replacements with smaller side-chains and of the steric distortions generated
      by beta-branched side-chains, caused considerable changes in the structural
      arrangement of the side-chains within the core. However, these structural changes
      were absorbed within the hydrophobic core, without distorting the structure of
      the reactive site essential for the protein function. These results provide an
      excellent example of the conformational flexibility of a protein core and the
      degree of its tolerance of an amino acid replacement. The results also reveal the
      crucially designed structural relationship between the core of the inhibitor and
      the enzyme-binding segment with the reactive site in a serine protease inhibitor.

PMID- 12473204
TI  - Characterization of an anti-decorin monoclonal antibody, and its utility.
AB  - 6B6 is a monoclonal antibody raised against a purified small dermatan sulfate
      proteoglycan from human ovarian fibroma capsule, has Although it been widely used
      as an anti-decorin monoclonal antibody, its epitope has not yet been
      characterized at the molecular level. Here, we show that 6B6 is specific to
      decorin. The antibody recognized human, mouse, and bovine decorin core protein,
      but not biglycan. Using recombinant decorin domains, we determined that the
      epitope lies within the region of amino acid residues 50-65, termed the cysteine
      cluster region. Cross-reactivity among species further narrowed it down to a
      primary sequence of residues 57-65. We also established the conditions for
      immunostaining. 6B6 stained both frozen and fixed sections. Whereas the
      glycosaminoglycan chain of decorin inhibited access of the antibody in
      immunoblotting, pretreatment of tissue sections with chondrotinase ABC did not
      affect the intensity of staining, suggesting that the glycosaminoglycan chain is
      integrated and the Cys cluster region oriented outside of the collagen fibrils in
      the tissue. When 6B6 was applied to enzyme-linked immunosorbent assay, a
      concentration as low as 0.5 microg/ml of decorin was detectable by either direct
      or sandwich ELISA. 6B6 is thus a sensitive and reliable antibody to study
      functions of decorin from various aspects.

PMID- 12473206
TI  - Optimized clinical-scale culture conditions for ex vivo selective depletion of
      host-reactive donor lymphocytes: a strategy for GvHD prophylaxis in allogeneic
      PBSC transplantation.
AB  - BACKGROUND: Ex vivo selective depletion (SD) is a strategy to prevent GvHD, in
      which host-reactive donor lymphocytes are selectively eliminated from a PBSC
      allograft while conserving useful donor immune function. Prior to testing this
      strategy in patients, our goal was to develop a clinical-scale SD process, which
      involves co-culture of donor lymphocytes and irradiated recipient cells, followed
      by the addition of an immunotoxin (IT) directed against the alpha-chain of the IL
      2 receptor (CD25), expressed on activated donor T cells. METHODS: Stimulator
      cells were generated from immunomagnetically selected and expanded recipient T
      lymphocytes. Donor PBMCs from G-CSF-mobilized peripheral blood were co-cultured
      for 72 h with irradiated stimulator cells. Alloreactive T cells were targeted for
      elimination by the addition of the anti-CD25 IT, RFT5-SMPT-dgA, and the IT
      enhancer, NH(4)Cl. RESULTS: Stimulator-cell selection/expansion yielded > 2 x
      10(10) highly enriched CD3(+) cells (98.9 +/- 2.2%). After SD, cell recovery was
      68.5 +/- 23.3% and viability was 84.6 +/- 6.4%. This permitted a potential T-cell
      dose >/= 1 x 10(8) CD3(+) cells kg(-1) to transplant recipients. Although SD
      donor lymphocytes retained little proliferative capacity against the original
      stimulator cells (2.6 +/- 0.6%), responses were conserved against third party
      cells (107.6 +/- 18.6%), the bacterial superantigen staphylococcus enterotoxin B
      (108.2 +/- 4.2%), and CMV Ag (72.1 +/- 3.8%). DISCUSSION: We have demonstrated
      that ex vivo SD is feasible in clinical-scale culture conditions. The ability of
      this strategy to prevent GvHD is the subject of an ongoing clinical trial, in
      which the SD lymphocyte product is transplanted in conjunction with a T cell
      depleted PBSC allograft.

PMID- 12473207
TI  - CML leukapheresis products can be enriched for CD34+ cells and simultaneously
      depleted of CD15+ cells using a simple Ab cocktail.
AB  - BACKGROUND: CML progenitor-cell studies would be greatly facilitated if samples
      could be repeatedly accessed from a source of well-characterized cells. The
      present study was designed to develop a simple, inexpensive Ab cocktail that
      would provide subpopulations of cells enriched for CD34+ cells and simultaneously
      depleted of CD15+ mature myeloid cells. METHODS: Cells from leukapheresis
      products from CML patients at diagnosis were incubated with each of two Ab
      cocktails. The standard cocktail (debulking, DB), containing 11 Abs, is
      recommended for obtaining a highly enriched population of CD34+ cells. The
      efficacy of an alternative, simpler cocktail (CML custom, CC), containing only
      four Abs was tested. The recoveries of CD34+ cells, CD15+ cells, colony-forming
      unit granulocyte-macrophage, and LTCIC were monitored. The samples were then
      cryopreserved, thawed, and the recoveries remeasured. RESULTS: The purity of
      CD34+ cells was significantly superior using the DB cocktail than with the CC
      cocktail. Conversely, using the CC cocktail, the yield of CD34+ cells was
      significantly higher compared to the DB cocktail. These results were maintained
      even when the amount of Ab was reduced 10-fold. Both Ab cocktails consistently
      removed > 99% of the CD15+ cells. Consistent with the CD34+ cell-enrichment data,
      higher colony-forming cell (CFC) frequencies were obtained with the DB cocktail,
      although superior yields of CFC were obtained with the CC cocktail. After
      cryopreservation and thawing the yield of CD34+ cells remained high, and a
      further reduction in the number of CD15+ cells was obtained. DISCUSSION: A method
      is described that allows the rapid and efficient debulking of large CML samples.
      This strategy will provide a source of well-characterized CML stem/progenitor
      cells that can be repeatedly accessed.

PMID- 12473208
TI  - The basis of the alloimmune response.

PMID- 12473209
TI  - B-cell immunity after allogeneic hematopoietic cell transplantation.

PMID- 12473210
TI  - The contribution of the thymus to immune reconstitution after hematopoietic stem
      cell transplantation.

PMID- 12473211
TI  - Enhancing immune reconstitution after stem cell transplants with cytokines.

PMID- 12473212
TI  - Phase I clinical trial of donor T-helper type-2 cells after immunoablative,
      reduced intensity allogeneic PBSC transplant.

PMID- 12473213
TI  - Immunologic aspects of hematopoietic stem-cell transplantation.

PMID- 12473214
TI  - Immune therapy for EBV infections after hemopoietic stem-cell transplant.

PMID- 12473215
TI  - Immunotherapy for CMV infection.

PMID- 12473216
TI  - Immune therapy of AML.

PMID- 12473217
TI  - Immunotherapy in the B-cell lymphomas.

PMID- 12473218
TI  - T-cell therapy targeting minor histocompatibility Ags for the treatment of
      leukemia and renal-cell carcinoma.

PMID- 12473219
TI  - Targeting malignant B cells of lymphoma and leukemia with genetically engineered
      T-cell clones.

PMID- 12473220
TI  - Natural killer cells: biology and application in stem-cell transplantation.

PMID- 12473221
TI  - What a cell-processing laboratory can and can't do for cellular therapy.

PMID- 12473222
TI  - Adoptive immunotherapy, the Food and Drug Administration and you: a regulatory
      approach to donor lymphocytes.

PMID- 12473223
TI  - Adoptive immunotherapy--the Food and Drug Administration and you: a regulatory
      framework for manipulated cellular products.

PMID- 12473224
TI  - Object relocation task: an exact test of significance with credit for partial
      knowledge.
AB  - The object relocation paradigm is used to assess spatial memory in cognitive,
      developmental and clinical neuropsychological contexts. A number of different
      objects are displayed for a period of time in a particular spatial environment,
      such as a room, a desktop, or a computer screen. The objects are then cleared
      away, and the subject is asked to replace them in their former locations. In this
      paper, a simple measure of individual performance on the task that gives equal
      credit for near misses and correct responses is presented, and an exact small
      sample test of significance for the measure is developed using rook methodology.
      A weighted-credit test of spatial performance is also presented. Computational
      examples are provided to illustrate the methods.

PMID- 12473225
TI  - Asymptotic standard errors of estimated standard errors in structural equation
      modelling.
AB  - Asymptotic standard errors of the estimated asymptotic standard errors for
      parameter estimates in structural equation modelling are derived using the delta
      method with the assumption of multivariate normality for observed variables. The
      derivation covers the cases with and without restrictions on parameters. The
      result can be used to derive the asymptotic standard error of the z score (a
      parameter estimate divided by its estimated standard error), which is frequently
      substantially different from one. The case of standardized observed variables is
      dealt with as a typical example with restrictions on parameters. For actual
      covariance (correlation) structure models, the exploratory factor analysis model
      with factor rotation and the confirmatory factor analysis model are presented
      with numerical examples. Simulations are performed to assess the accuracy of our
      method for normally and non-normally distributed variables.

PMID- 12473226
TI  - Identification of influential cells in the analysis of ordinal square tables.
AB  - For square tables arising from ordinal categorical variables which can be
      considered as manifestations of underlying continuous variables, it is possible
      to model the underlying continuous variables in a form that facilitates the
      comparison of their relative locations and dispersions. An efficient estimation
      method for such a model is available in the literature and the object of this
      paper is to develop an influence analysis procedure to accompany the estimation
      method. The local influence approach is used to obtain the diagnostic measures,
      and real data sets are analysed to illustrate the practicability of the proposed
      measures.

PMID- 12473227
TI  - Estimating the covariance function with functional data.
AB  - This paper describes a two-step procedure for estimating the covariance function
      and its eigenvalues and eigenfunctions in situations where the data are curves or
      functions. The first step produces initial estimates of eigenfunctions using a
      standard principal components analysis. At the second step, these initial
      estimates are smoothed via local polynomial fitting, with the bandwidth in the
      kernel function being selected by a data-driven procedure. The results of a
      simulation study and three real examples are presented to illustrate the
      performance of the proposed methodology.

PMID- 12473228
TI  - A tandem random walk model of the SAT paradigm: response times and accumulation
      of evidence.
AB  - The speed-accuracy trade-off (SAT) paradigm forces participants to trade response
      speed for information accuracy by presenting them with a response signal at
      variable times after the onset of processing to which they must give an immediate
      response (within 300 ms). The processes that underlie the paradigm, especially
      those affecting response times, are not completely understood. Also, the extent
      to which the paradigm might affect the evidence accumulation process is still
      unclear. By testing several different sets of assumptions, we present a random
      walk model for the SAT paradigm that qualitatively explains both accuracy and
      response time data. The model uses a tandem random walk, with two possible
      continuations in a second phase which begins after the response signal. If a
      boundary is not reached during phase one, the walk transfers the current sum
      (relative to the size of the boundaries) from phase one to phase two in the form
      of bias, with drift rate equal to zero. If, however, a boundary is reached in
      phase one, the second phase starts from zero (no bias) with a strong drift rate
      towards the previously reached boundary. The model also incorporates a
      psychological refractory period: a delay in the onset of a second task when two
      tasks are presented in close succession. The model is consistent with the idea
      that information about the evidence accumulation rate is not contaminated by the
      paradigm.

PMID- 12473229
TI  - A mixture model approach to indexing rater agreement.
AB  - Raters are an important potential source of measurement error when assigning
      targets to categories. Therefore, psychologists have devoted considerable
      attention to quantifying the extent to which ratings agree with each other. Two
      main approaches to analysing rater agreement data can be distinguished. While the
      first approach focuses on the development of summary statistics that index rater
      agreement, the second models the association pattern among the observers'
      ratings. With the modelling approach three groups of models can be distinguished:
      latent class models, simple quasisymmetric agreement models, and mixture models.
      This paper discusses a class of mixture models that is defined by its
      characteristic of having a quasi-symmetric log-linear representation. This class
      of models has two interesting properties. First, the simple quasi-symmetric
      agreement models can be shown to be members of this class. Therefore, the results
      of a rater agreement analysis based on a simple quasi-symmetric agreement model
      may be interpreted in the mixture model framework. Second, since the mixture
      models readily provide a familiar measure of rater reliability, it is possible to
      obtain a model-based estimate of rater reliability from the simple quasi
      symmetric agreement models. The suggested class of mixture models will be
      illustrated using data from a persuasive communication study in which three
      raters classified respondents on the basis of their elicited cognitive responses.

PMID- 12473230
TI  - The comparative sensitivity of ordinal multiple regression and least squares
      regression to departures from interval scaling.
AB  - The comparative sensitivity of ordinal multiple regression (OMR) and least
      squares regression (LSR) to criterion variable deviations from interval scaling
      was investigated by way of computer simulation. LSR on raw scores and ranks was
      compared to OMR on raw scores, ranks and dominances. Simulated data sets varied
      on predictor variable correlations, amount of prediction error, weight
      distinctiveness and shape of rating-scale distribution. The results indicated
      that LSR on raw scores was most affected by discretization in all conditions. In
      contrast, the performance of LSR approximated that of OMR when the data were
      first transformed to ranks. The poor performance of LSR on raw scores was most
      pronounced when the data discretization resulted in a symmetrical distribution.
      Predictor variable correlations and amount of prediction error did not affect the
      pattern of results. Weight distinctiveness did not interact with the other
      factors.

PMID- 12473231
TI  - High-breakdown estimation of multivariate mean and covariance with missing
      observations.
AB  - We consider the problem of outliers in incomplete multivariate data when the aim
      is to estimate a measure of mean and covariance, as is the case, for example, in
      factor analysis. The ER algorithm of Little and Smith which combines the EM
      algorithm for missing data and a robust estimation step based on an M-estimator
      could be used in such a situation. However, the ER algorithm as originally
      proposed can fail to be robust in some cases, especially in high dimensions. We
      propose here two alternatives to avoid the problem. One is to combine a small
      modification of the ER algorithm with a so-called high-breakdown estimator as the
      starting point for the iterative procedure, and the other is to base the
      estimation step of the ER algorithm on a high-breakdown estimator. Among the high
      breakdown estimators which are actually built to keep their robustness properties
      even if the number of variables is relatively large, we consider here the minimum
      covariance determinant estimator and the t-biweight S-estimator. Simulated and
      real data are used to compare and illustrate the different procedures.

PMID- 12473232
TI  - Techniques for oblique factor rotation of two or more loading matrices to a
      mixture of simple structure and optimal agreement.
AB  - Three techniques are proposed for oblique rotation of two or more loading
      matrices to a mixture of simple structure and optimal agreement. The three
      techniques, consensus direct oblimin, consensus promin and consensus simple
      target rotation, are compared to existing techniques and to each other, using
      artificial and real data. When agreement between solutions can be expected, the
      new techniques appear to be more useful than oblique rotation of each of the
      loading matrices separately. Consensus direct oblimin achieved the best results
      in terms of 'agreement between simple structures'; consensus promin was the
      technique that best recovered the underlying simple loading matrix; and consensus
      simple target rotation seemed to give an interesting compromise between agreement
      and simple structure, focusing a little more on simplicity than consensus direct
      oblimin.

PMID- 12473233
TI  - Skill set analysis in knowledge structures.
AB  - We extend the theory of knowledge structures by taking into account information
      about the skills a subject has. In the first part of the paper we exhibit some
      structural properties of the skill-problem relationship and consequences for the
      interpretation of concurrent theories in terms of the skill theory. The second
      part of the paper offers a test theory based on skill functions: we present
      measurements for the data consistency of the skill-problem relationship, and
      estimate abilities in terms of lower and/or upper boundaries of problem states
      and skills, given a special instance of the skill-problem relationship. Some
      practical considerations are discussed, which enable the user of a skill-based
      system to optimize a partial theory about the skill-based behaviour of subjects
      based on empirical results.

PMID- 12473234
TI  - Significance-testing the validity of idiographic methods: a little derangement
      goes a long way.
AB  - We present an experimental design for validating idiographic data and the
      mathematical basis for subjecting this to statistical hypothesis testing. The
      method involves matching descriptions of four or more objects to the people from
      which they arose. If four or more can be matched, this is unlikely (p < 0.05) to
      have arisen by chance alone and the null hypothesis that the data communicate no
      information can be rejected. This criterion score of 4 is sufficient for
      statistical significance regardless of the total number of objects on which
      matching was attempted. The mathematics of this somewhat counterintuitive result
      is given, and we argue that this method is of value in validating idiographic
      data. Its relationship with the 'method of mismatched cases' is discussed.

PMID- 12473236
TI  - Genetic relationships among twelve Chinese indigenous goat populations based on
      microsatellite analysis.
AB  - Twelve Chinese indigenous goat populations were genotyped for twenty-six
      microsatellite markers recommended by the EU Sheep and Goat Biodiversity Project.
      A total of 452 goats were tested. Seventeen of the 26 microsatellite markers used
      in this analysis had four or more alleles. The mean expected heterozygosity and
      the mean observed heterozygosity for the population varied from 0.611 to 0.784
      and 0.602 to 0.783 respectively. The mean F<inf>ST</inf> (0.105) demonstrated
      that about 89.5% of the total genetic variation was due to the genetic
      differentiation within each population. A phylogenetic tree based on the Nei
      (1978) standard genetic distance displayed a remarkable degree of consistency
      with their different geographical origins and their presumed migration throughout
      China. The correspondence analysis did not only distinguish population groups,
      but also confirmed the above results, classifying the important populations
      contributing to diversity. Additionally, some specific alleles were shown to be
      important in the construction of the population structure. The study analyzed the
      recent origins of these populations and contributed to the knowledge and genetic
      characterization of Chinese indigenous goat populations. In addition, the
      seventeen microsatellites recommended by the EU Sheep and Goat Biodiversity
      Project proved to be useful for the biodiversity studies in goat breeds.

PMID- 12473237
TI  - Anti-TNF-alpha antibodies suppress the development of experimental autoimmune
      myasthenia gravis.
AB  - To understand the role of TNF-alpha in the induction of experimental autoimmune
      myasthenia gravis (EAMG) and detect a possible effect of anti-TNF-alpha
      antibodies in the treatment of EAMG, anti-TNF-alpha antibodies were administrated
      intraperitoneally to Lewis rats twice per week for 5 weeks from the day of
      immunization with Torpedo AChR and complete Freund's adjuvant (CFA).
      Administration of anti-TNF-alpha antibodies resulted in lower incidence of EAMG,
      and in delayed onset and only mild muscle weakness compared with control EAMG
      rats. These mild clinical signs were accompanied by lower AChR-specific
      lymphocyte proliferation, down-regulated IFN-gamma and IL-10, and up-regulated
      TGF-beta. The lower levels of anti-AChR IgG, Ig2a and IgG2b and decreased anti
      AChR IgG affinity were found in rats treated with anti-TNF-alpha antibodies.
      These results demonstrate that anti-TNF-alpha antibodies can suppress the
      induction and development of EAMG.

PMID- 12473238
TI  - Experimental autoimmune encephalomyelitis: CC chemokine receptor expression by
      trafficking cells.
AB  - Chemokines are chemotactic cytokines, which stimulate migration of inflammatory
      cells towards tissue sites of inflammation. The largest chemokine group, termed
      CC chemokines (CCLs), act primarily on T cells and monocytes, through CC
      chemokine receptors (CCRs) belonging to the superfamily of G-protein coupled
      seven transmembrane domain receptors. CCR expression is a critical determinant of
      cellular responses to CCLs. In this report, we describe the expression pattern of
      mRNA encoding selected CCRs in the spinal cord and spleen of perfused and non
      perfused mice at different stages of chronic-relapsing EAE (ChREAE). We detected
      increased expression of receptors (CCR1, CCR5) associated with T helper-1 (Th1)
      but not those (CCR3, CCR4) associated with Th2 T cells in spinal cord during
      initial attack and relapse of ChREAE. Expression of these CCRs correlated
      temporally and spatially with reported previously expression of corresponding
      CCLs. The principal cells expressing CCR5 were inflammatory cells invading the
      spinal cord. Our results supported the implication of Th1-associated CCRs in the
      CNS-specific inflammatory reaction of ChREAE.

PMID- 12473240
TI  - Identification of the encephalitogenic epitopes of CNS proteolipid protein in
      BALB/c mice.
AB  - It was previously shown that BALB/c mice were susceptible to experimental
      autoimmune encephalomyelitis induced by immunization with proteolipid protein
      (PLP). To determine the encephalitogenic epitopes of PLP in BALB/c mice, mice
      were immunized with successively smaller pools of 20-mer peptides spanning the
      PLP molecule from amino acid 30 to amino acid 206. Immunization with PLP(180-199)
      resulted in clinical EAE in 9/15 mice (mean max clinical score of 3.3), and
      immunization with PLP(185-206) induced clinical EAE in 7/21 BALB/c mice (mean
      maximum score of 3.7). No relapses in disease were observed. No EAE was observed
      in BALB/c mice immunized with PLP(185-199) (n=15), PLP(178-191) (n=13) or other
      regions of PLP (n=15). Passive transfer of PLP(180-199)-primed lymph node cells
      into nai;ve BALB/c mice resulted in EAE (2/2 mice, max score of 4.0). One-micron
      toluidine blue stained sections from the spinal cord of EAE-affected BALB/c mice
      revealed features typical of EAE in other strains, including mononuclear cell
      infiltration, myelin loss, and axonal loss.

PMID- 12473239
TI  - Cross-reactivity and T-cell receptor antagonism of myelin basic protein-reactive
      T cells is modulated by the activation state of the antigen presenting cell.
AB  - The peripheral T-cell population is educated to recognize a maximum of pathogen
      derived epitopes while ignoring self-antigens. As the total number of T-cell
      clones is limited, each T-cell receptor (TCR) needs to be cross-reactive in order
      to achieve a wide repertoire. This opens the possibility for T cells to diverge
      from their defending role and induce auto-aggression by mistake. The factors
      involved in the initiation of such autoimmune responses remain to be fully
      understood. In an attempt to assess the role of antigen presenting cells (APC) in
      the triggering of autoimmunity, we studied the cross-reactivity of TCR transgenic
      Tg4 T cells, reactive to the Ac1-9 peptide of myelin basic protein (MBP). Using
      different APC populations and a range of peptide analogues of Ac1-9, we found
      that the activation of APC enhanced the cross-reactivity of Tg4 cells, and that
      this effect could be mimicked by resting APC supplemented with exogenous co
      stimulation. Further, we observed that the inhibitory effect of an antagonist
      peptide of the Tg4 TCR was greatly reduced when activated APC were used. However,
      when co-stimulation was blocked, TCR antagonism was restored to its normal level.
      Our results show for the first time that the activation of naturally occurring
      APC, namely dendritic cells, B cells and macrophages, can modulate the reactivity
      of T cells, both in terms of cross-reactivity and TCR antagonism, and that this
      effect is most likely due to enhanced levels of co-stimulation.

PMID- 12473241
TI  - Low expression of insulin in the thymus of non-obese diabetic mice.
AB  - Insulin is a predominant autoantigen in IDDM in man and the NOD mouse. Failure of
      negative selection of diabetogenic T cells in thymus may be an important pre
      disposing cause of the disease. To obtain insight into negative selection against
      such T-cell clones the thymic expression of insulin was studied in NOD and Balb/c
      mice by quantitative competitive RT-PCR. We detected RNA for insulin in the
      thymus of 3-week-old Balb/c mice as well as in NOD mice. However, the NOD mice
      expressed only half as many insulin transcripts as the Balb/c mice. Also, insulin
      protein was detected in the thymic medulla of both Balb/c and NOD mice.
      Furthermore, thymic RNA preparations were investigated for the presence of
      insulin transcription factors. None of the known pancreatic transcription factors
      for insulin; Pdx-1, Pax6 or Nkx6.1 were detectable in the thymus of Balb/c mice.
      These results support the idea that low insulin expression in the thymus may be a
      predisposing cause for development of diabetes in NOD mice analogous with what
      has been found in humans with the disease-disposing IDDM2 allele. Furthermore,
      our results suggest that insulin expression in the thymus may be regulated by
      different principles from those in the pancreas.

PMID- 12473242
TI  - TNFalpha inhibition in MRL/lpr mice ameliorates pulmonary but not renal disease.
AB  - TNFalpha inhibition has a clearly beneficial effect in a number of arthritides
      and in Crohn's disease. The exact mechanism of action is uncertain with studies
      showing inhibition of chemokines, inhibition of adhesion molecule expression, and
      improved T-cell function. Unlike most therapeutic interventions for autoimmune
      disease, TNFalpha inhibition appears to act on specific pathologic processes. It
      is not known how wide-spread these TNFalpha-mediated pathologic processes are.
      Efforts to expand the use of TNFalpha inhibition have had notable successes but
      have been disappointing in other disorders. We hypothesized that TNFalpha
      mediated pathologic processes might play a significant role in the end-organ
      effects seen in SLE. We modeled SLE by using MRL/lpr mice and treated with two
      types of TNFalpha inhibitor. Pulmonary disease was significantly improved in the
      treated groups compared to controls. In contrast, renal disease was unaffected
      suggesting that in lupus, where multiple organs are affected, different
      pathologic processes may be mediating the end-organ damage. This has important
      implications for designing therapeutics for SLE.

PMID- 12473243
TI  - alpha4 integrins and L-selectin differently orchestrate T-cell activity during
      diabetes prevention following oral administration of CTB-insulin.
AB  - Oral administration of insulin conjugated to the B chain of cholera toxin (CTB
      insulin) in non-obese diabetic (NOD) mice results in diabetes prevention. We
      investigated the respective contributions of L-selectin (CD62L) and alpha4
      integrin pathways during CTB-driven tolerance. Purified CD62L+CD4+ cells from CTB
      insulin fed mice significantly reduced the capacity of diabetogenic T cells to
      transfer diabetes in syngeneic recipients. In vivo antibody blockade of fed
      animals during adoptive co-transfer experiments indicated that both CD62L and
      alpha4-integrins pathways were necessary to develop a protective response after
      oral tolerance induction. In contrast, when antibodies were given to recipient
      mice, only CD62L was critical for the protection. In vitro stimulated CD62L+CD4+
      cells from the spleen of fed animals secreted lower amounts of IL-4 and IL-10 but
      comparable levels of TGFbeta than CD62L-cells. A reduced IFN-gamma production
      between the two cell subsets was specifically observed in CTB-insulin fed mice.
      Furthermore, antibody treatments induced changes in T-cell migration to the
      spleen, mesenteric and pancreatic lymph nodes. The protective effect was also
      associated with migration of regulatory T cells into pancreatic islets. Taken
      together, our results suggest that L-selectin and alpha4-integrin have distinct
      but complementary roles in the generation and function of regulatory CD4+ T cells
      following CTB-insulin administration.

PMID- 12473244
TI  - Restriction in the usage of variable beta regions in T-cells infiltrating
      valvular tissue from rheumatic heart disease patients.
AB  - Rheumatic Heart Disease (RHD) is a delayed consequence of a pharyngeal infection
      with group A streptococcus (GAS), usually ascribed to a cross-reactive immune
      response to the host's cardiac tissues. Several GAS proteins have been reported
      to be superantigens, also raising the possibility that T cells in RHD could be
      driven by superantigens. We therefore analysed the variable beta (V beta)
      repertoire of T cells infiltrating heart valves from chronic RHD patients
      undergoing elective valvular surgery. We analysed 15 valve specimens from
      patients with longstanding quiescent RHD and control valves from four non
      rheumatic individuals. Total RNA was extracted from fresh valve tissue and
      employed to amplify 22 V beta genes by RT-PCR. In valvular tissue, a restricted
      number of only 2 to 9 V beta regions were detected as opposed to the findings in
      control valves. In 8 RHD valves, the expression of V beta1, 2, 3, 5.1, 7, 8, 9 or
      14 was marked. These V beta regions have been related to GAS superantigens. Our
      results evidence the presence of a restricted set of T lymphocytes in valvular
      tissue from a majority of patients with chronic RHD and suggest that valvular
      sequelae in these patients might be related to a local antigen or superantigen
      driven inflammatory process that persists even many years after the initial
      triggering event.

PMID- 12473245
TI  - Polyreactivity of human IgG Fc-binding phage antibodies constructed from synovial
      fluid CD38+ B cells of patients with rheumatoid arthritis.
AB  - Recent data indicate that rheumatoid factors (RFs) that occur in patients with
      rheumatoid arthritis (RA) are derived from Ig-producing terminally differentiated
      CD20-, CD38+ plasma cells present in synovial fluids (SFs). Phage antibody
      display libraries were constructed using CD38+ plasma cells isolated from SFs of
      two RF-seropositive RA patients. The libraries were enriched for phage antibodies
      (Phabs) binding to human IgG (HuIgG) Fc fragments and the sequences of their V
      genes were analysed. These data provided further evidence for an Ag-driven immune
      response in patients with RA, including expansion of clonally related B cells,
      selection and isotype switching, all hallmarks of a germinal center reaction. In
      the present study, the functional characteristics of these HuIgG Fc-binding
      monoclonal (mo) Phabs were further analysed in order to provide more insight into
      the specificity of HuIgG Fc-binding Phabs. Remarkably, all HuIgG Fc-binding
      moPhabs tested (n=48; derived from four different libraries) displayed
      polyreactivity. Structural analysis of the CDR3 regions revealed characteristic
      features of polyreactive Igs. Most H chain CDR3 regions harboured
      tryptophan/tyrosine-rich parts and approximately 60% of the L chain CDR3 regions
      of both RA patients displayed an identical stretch of amino acids (W/Y-D-S-S).
      Supportive for a dominant role of VH in specificity, exchange of VL regions with
      a single VH region yielded moPhabs with similar specificities. All together, the
      data suggest the presence of an Ag-driven process in the joints of patients with
      RA, including somatic mutation and clonal selection entailing isotype switching,
      resulting in the differentiation of B cells into polyreactive RF-secreting plasma
      cells.

PMID- 12473246
TI  - Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis
      compared with other diseases.
AB  - The molecule SOX13 was initially identified as an autoantigen (ICA12) in Type 1
      diabetes. SOX13 is a member of the SOX family of transcriptional regulatory
      proteins that contain a high mobility group (HMG) motif with structural
      similarity to HMG proteins 1 and 2. Antibodies to HMG 1 and 2 occur in autoimmune
      diseases of the liver and in ulcerative colitis. We measured the occurrence and
      levels of anti-SOX13 by radioimmunoprecipitation in primary biliary cirrhosis
      (PBC) and other diseases, and compared frequencies with anti-HMG measured by
      ELISA. Anti-SOX13 was detected in 18% of patients with PBC, 13% with autoimmune
      hepatitis, 18% with Type 1 diabetes, at lower frequencies in other conditions
      including the multisystem autoimmune diseases, systemic lupus erythematosus and
      rheumatoid arthritis, and in 1% of normal sera. Anti-HMG1 and anti-HMG2 occurred
      at frequencies of 30% and 35% respectively in PBC. Serum levels of anti-SOX13 and
      anti-HMG correlated significantly for PBC although not for Type 1 diabetes. Anti
      SOX13 in PBC may occur merely as an immune response to products of damage to
      parenchymal tissue, or may be illustrative of a general proclivity of
      transcriptional regulatory proteins to elicit autoimmune responses.

PMID- 12473248
TI  - Familial hypercholesterolaemia--screening is effective, but is it cost effective?

PMID- 12473249
TI  - Do statins confer early benefit after acute coronary syndromes? The results from
      FLORIDA.

PMID- 12473250
TI  - Electrical stimulation vs CAB.

PMID- 12473251
TI  - New tricks for an old drug.

PMID- 12473252
TI  - Old and simple tools may do better--sometimes.

PMID- 12473253
TI  - Statins and stroke: evidence for cholesterol-independent effects.

PMID- 12473254
TI  - Cost-effectiveness of a family and DNA based screening programme on familial
      hypercholesterolaemia in The Netherlands.
AB  - AIMS: To estimate the cost-effectiveness of the current screening programme on
      Familial Hypercholesterolaemia (FH) in relatives of diagnosed FH-patients in The
      Netherlands. METHODS AND RESULTS: Data from 2229 screened FH-relatives, including
      age, sex, risk factor status and screening outcome, were combined with the
      Framingham risk function and national disease-specific cost data to arrive at a
      model-based comparison of survival and costs, with and without the screening
      programme. Cost-effectiveness ratios were computed for various treatment
      strategies, with no screening as reference. Costs per life year gained varied
      between 25.5- and 32-thousand Euros, depending upon the precise treatment
      strategy after a positive screen. The costs for screening (tracing the FH
      positive individuals) were much lower than the follow-up costs (treatment), of
      which 80% were costs for statins. Consequently, the costs per life year gained of
      alternative screening programmes are about the same. CONCLUSION: The cost
      effectiveness ratio of FH screening is within the range requiring explicit
      political consideration in The Netherlands. As the costs of statin treatment are
      the single most important determinant of costs, policy decisions reduce to
      decisions on the acceptability of statin treatment for this risk group. Pending
      major changes in statin price, clear guidelines should be developed on how screen
      positive individuals should be treated, since not all of them have an elevated
      cholesterol level.

PMID- 12473255
TI  - Effect of fluvastatin on ischaemia following acute myocardial infarction: a
      randomized trial.
AB  - AIMS: Residual ischaemia following acute myocardial infarction (AMI) is related
      to an adverse outcome, although the effect of early initiation of statin therapy
      is unknown. METHODS: A randomized, placebo-controlled, double-blind, parallel
      study was performed, which compared fluvastatin 80 mg daily with placebo in
      patients with an AMI and total cholesterol of <6.5 mmol.l(-1). Ischaemia was
      measured by ambulatory electrocardiographic (AECG) monitoring over 48-h at
      baseline, after 6 weeks and at 12 months. RESULTS: Five hundred and forty
      patients were included (83% male, age 61+/-11 years); 43% had an anterior AMI and
      50% were treated with fibrinolytics in the acute phase. After 12 months, the
      total cholesterol (TC) level was reduced by 13% and LDL-C (low-density
      lipoprotein cholesterol) by 21% (from 3.5 mmol.l(-1) to 2.7 mmol.l(-1)) in the
      fluvastatin treatment group. Both TC and LDL increased by 9% in the placebo group
      (P<0.001 between groups). At baseline, ischaemia on AECG was present in only 11%
      of patients, and absent in 77%; in the remaining 11%, recordings were technically
      inadequate. After 6 weeks, 32/48 (67%), and 12 months 35/46 (76%) of the patients
      with ischaemia on the baseline AECG, no longer showed signs of ischaemia.
      Nevertheless, ischaemia at baseline was predictive for the occurrence of any
      major clinical event (RR=2.35; 95% CI 1.39-3.2;P <0.001). Fluvastatin treatment
      did not affect ischaemia on AECG, nor the occurrence of any major clinical events
      as compared to placebo. Post-hoc analysis in patients with the most pronounced
      ischaemia at baseline showed a trend for a beneficial effect of fluvastatin on
      major clinical events (P=0.084). CONCLUSION: Residual ischaemia after AMI is
      observed less frequently in the present study, than in earlier studies, although
      it is predictive for future cardiovascular events. As a result, the present study
      was underpowered, and no effect of fluvastatin on AECG ischaemia, or major
      clinical events in the first year after AMI, could be detected. The present data
      do not confirm other reports which support widespread use of statin treatment
      early after AMI.

PMID- 12473256
TI  - Long-term effects of spinal cord stimulation and coronary artery bypass grafting
      on quality of life and survival in the ESBY study.
AB  - AIMS: To assess the long-term outcome regarding quality of life and survival in
      patients who were included in the ESBY study 1992-1995. The ESBY study
      (Electrical Stimulation versus Coronary Artery Bypass Surgery in Severe Angina
      Pectoris) included 104 patients-with severe angina, increased surgical risk and
      no prognostic benefits from revascularization-randomized to coronary artery
      bypass grafting or spinal cord stimulation. METHODS AND RESULTS: The ESBY
      patients' quality of life was analysed using two questionnaires, and 5-year
      mortality was assessed. Quality of life improved significantly 6 months after
      spinal cord stimulation and coronary artery bypass grafting, respectively,
      compared to run-in (P<0.001). The results were consistent after 4.8 years. The 5
      year mortality was 27.9%. There were no significant differences between the
      groups. CONCLUSIONS: Spinal cord stimulation as well as coronary artery bypass
      grafting offered long-lasting improvement in quality of life. Survival up to 5
      years was comparable between the groups. Both methods can be considered as
      effective treatment options for patients with severe angina, increased surgical
      risks and estimated to have no prognostic benefits from coronary artery bypass
      grafting.

PMID- 12473258
TI  - The endothelial nitric oxide synthase (Glu298Asp and -786T>C) gene polymorphisms
      are associated with coronary in-stent restenosis.
AB  - AIMS: Coronary stent deployment is a major advance in percutaneous treatment of
      ischaemic heart disease, but 10-40% of patients still develop angiographic
      restenosis by 6 months due to neointimal hyperplasia. Patient-specific factors,
      including genetic factors, can contribute to this process. We have conducted a
      prospective study to examine the involvement of genetic risk factors (eNOS, ACE,
      MMP-3, IL-6, and PECAM-1) in restenosis following coronary stent deployment.
      METHODS AND RESULTS: A total of 226 patients who underwent elective and
      successful coronary artery stenting to de novo lesions in native coronary
      arteries were studied. Two hundred and five (90.7%) patients were restudied by
      coronary angiogram at 6 months and the stented lesions were assessed using an
      automated quantitative angiography system. Genotype was determined by polymerase
      chain reaction (PCR) and restriction enzyme digestion. Restenosis rate, defined
      as >or=50% diameter stenosis, was 29.3%. The overall genotype frequency
      distributions were in Hardy-Weinberg equilibrium for all variants. Carriers of
      the 298Asp allele of the eNOS Glu298Asp polymorphism showed a higher frequency of
      restenosis with an odds ratio of 1.88 (95%CI: 1.01-3.51, P=0.043) compared to
      298Glu homozygotes. Carriers of the -786C allele of the eNOS -786T>C polymorphism
      also showed a higher frequency of restenosis with odds ratio of 2.06 (95%CI: 1.08
      3.94, P=0.028). These effects were essentially additive and were independent of
      other classical risk factors. Other studied genes did not show significant
      association with coronary in-stent restenosis. CONCLUSION: In patients with
      coronary artery disease, the possession of the 298Asp and -786C variants of the
      eNOS gene are a risk factor for coronary in-stent restenosis, demonstrating the
      importance of the nitric oxide system in restenosis.

PMID- 12473257
TI  - Beneficial clinical effects of perhexiline in patients with stable angina
      pectoris and acute coronary syndromes are associated with potentiation of
      platelet responsiveness to nitric oxide.
AB  - AIMS: To examine whether the prophylactic antianginal agent perhexiline
      potentiates platelet responsiveness to nitric oxide (NO) in patients with stable
      angina pectoris (SAP) and acute coronary syndromes (ACS: unstable angina pectoris
      or non-Q-wave myocardial infarction). METHODS AND RESULTS: Blood samples were
      obtained from patients before and after initiation of treatment with perhexiline.
      ADP-induced platelet aggregation and its inhibition by the NO donor sodium
      nitroprusside (SNP) were determined via impedance aggregometry in whole blood
      (WB) and platelet-rich plasma (PRP). Intraplatelet cGMP content was assayed by
      RIA, and superoxide (O(2)(-)) level by lucigenin-derived chemiluminescence. In
      patients with ACS not receiving perhexiline (n=12), platelet responsiveness to
      SNP did not vary significantly over the first 3 days post admission to hospital.
      Therapy with perhexiline for 3 days was associated with increases in SNP-induced
      inhibition of aggregation from 29+/-2% to 43+/-4% (n=50,P <0.001) in WB and from
      20+/-5% to 42+/-7% (n=12, P<0.01) in PRP. Resolution of symptomatic ischaemia
      (n=39) was associated with significantly greater (P<0.01) increases than non
      resolution (n=11). Similar increases in SNP responsiveness (P<0.001) occurred
      following institution of perhexiline therapy in patients with SAP (n=30),
      associated with a 85% decrease in anginal frequency. Treatment with perhexiline
      potentiated the cGMP-elevating effects of SNP in platelets (n=9,P =0.03).
      Although perhexiline did not alter whole blood O(2)(-) concentration ex vivo, it
      inhibited (P<0.01) O(2)(-) release from neutrophils in vitro. CONCLUSION:
      Perhexiline potentiates platelet responsiveness to NO both in SAP and ACS
      patients; in the latter group this improvement was predictive of resolution of
      ischaemic symptoms. The predominant mechanism of perhexiline effect is an
      increase in platelet cGMP responsiveness. Perhexiline also may reduce the
      potential for NO clearance by neutrophil-derived O(2)(-).

PMID- 12473259
TI  - Electrocardiographic measures of left ventricular hypertrophy show greater
      heritability than echocardiographic left ventricular mass.
AB  - AIMS: To assess the heritability (i.e. relative contribution of genetic factors
      to the variability) of continuous measures of left ventricular hypertrophy
      determined by electrocardiography and echocardiography. METHODS AND RESULTS: We
      studied 955 members of 229 Caucasian families, ascertained through a hypertensive
      proband. Electrocardiographic measurements were performed manually on resting 12
      lead electrocardiograms, and echocardiographic measurements were made on M-mode
      images. Sex-specific residuals for the left ventricular phenotypes were
      calculated, adjusted for age, systolic blood pressure, weight, height, waist-hip
      ratio, and presence of diabetes. Heritability was estimated in two ways: firstly,
      from familial correlations with adjustment for spouse resemblance; and secondly
      by using variance components methods with ascertainment correction for proband
      status. The heritability estimates (given as a range derived from the two
      methods) were higher for Sokolow-Lyon voltage (39-41%) than for echocardiographic
      left ventricular mass (23-29%). Electrocardiographic left ventricular mass,
      Cornell voltage, and Cornell product had heritability estimates of 12-18%, 19
      25%, and 28-32%, respectively. CONCLUSIONS: Genetic factors may explain a
      substantial proportion of variability in quantitative electrocardiographic and
      echocardiographic measures of left ventricular hypertrophy. The greater
      heritability of Sokolow-Lyon voltage suggests that electrocardiographic
      phenotypes may be particularly important for the molecular investigation of the
      genetic susceptibility to cardiac hypertrophy.

PMID- 12473260
TI  - A better control for ICD patients?

PMID- 12473261
TI  - The need for European Registries in inherited cardiomyopathies.

PMID- 12473262
TI  - Gold sodium thiomalate (GSTM) inhibits lipopolysaccharide stimulated tumor
      necrosis factor-alpha through ceramide pathway.
AB  - TNF-alpha has emerged as the major pro-inflammatory cytokine involved in the
      pathogenesis of rheumatoid arthritis (RA). LPS is a potent stimulator of TNF
      alpha production by human monocytes. Ceramide, a structural homolog of LPS and a
      second messenger in the sphingomyelin signal transduction pathway has been shown
      to stimulate TNF-alpha production from murine macrophages. We have previously
      shown that GSTM, an anti-rheumatic drug inhibits LPS stimulated TNF-alpha
      production by normal PBMCs. We studied the ability of ceramide to stimulate TNF
      alpha production by human PBMCs and the mechanism of action of GSTM on ceramide
      and LPS induced TNF-alpha production. LPS induced significant TNF-alpha
      production in PBMCs and THP-1. However, C(2) ceramide stimulated TNF-alpha
      production in 5 of 10 PBMCs (ceramide responder); it did not do so in the other 5
      PBMCs (ceramide non-responder) or the THP-1 cell line. GSTM inhibited LPS
      stimulated TNF-alpha productions in PBMCs of all 5 ceramide responders both at
      protein and mRNA expression level. We also found that GSTM inhibited LPS induced
      NF-kappaB level only in ceramide responder. Thus, we for the first time report
      that GSTM inhibits LPS stimulated TNF-alpha production through ceramide pathway
      and anti-inflammatory activity of GSTM in treatment of RA may depend on its
      ability to inhibit NF-kappaB activation and TNF-alpha production.

PMID- 12473263
TI  - Mechanisms for monocyte activation in co-culture with autologous tumor spheroids.
AB  - Biopsies from carcinoma tissue and benign control mucosa from head and neck
      squamous cell carcinoma patients were used to establish fragment (F)-spheroids in
      vitro. We have previously shown that autologous monocytes co-cultured with F
      spheroids in vitro secrete interleukin (IL)-6 upon 24h in co-culture. Presently,
      the aim was to study the mechanisms of this monocyte secretion. Paraformaldehyde
      (0.1% for 2min) or actinomycin-D (1 microg/ml for 24h) pre-treatment of the F
      spheroids abolished the monocyte IL-6 co-culture response. Addition of glucose
      (100mM) or mannose (100mM), and to some extent galactose (100mM), but not
      fructose (100mM) to the co-cultures, partly inhibited the monocyte IL-6 co
      culture response, but such addition did not inhibit the in vitro monocyte
      lipopolysaccharide (LPS)-generated IL-6 secretion. When mannose was added to the
      co-cultures, monocyte IL-6 mRNA expression was eradicated in malignant co
      cultures and reduced to a low level in benign co-cultures. Addition of mouse anti
      human beta(1)-integrin (anti-CD29) antibody (2 microg/ml) diminished the IL-6 co
      culture response but not the monocyte LPS-generated IL-6 response. In conclusion,
      the monocyte IL-6 co-culture response is dependent on live spheroids and to some
      extent on direct contact with the F-spheroids, possibly via lectin-like
      receptor(s), the mannose receptor and beta(1)-integrin.

PMID- 12473264
TI  - Encapsulated Bifidobacterium bifidum potentiates intestinal IgA production.
AB  - We asked whether Bifidobacterium bifidum regulates the synthesis of IgA by
      mucosal lymphoid cells. B. bifidum alone, but not Clostridium perfringens,
      significantly induced total IgA and IgM synthesis by both mesenteric lymph nodes
      (MLN) and Peyer's patch (PP) cells. We, further, investigated the mucosal
      antibody production following peroral administration of B. bifidum to mice.
      Ingested B. bifidum significantly increased the number of Ig (IgM, IgG, and IgA)
      secreting cells in the culture of both MLN and spleen cells. Nonetheless, B.
      bifidum itself does not induce the own specific antibody responses, implying that
      B. bifidum does not provoke unnecessary immune reaction. Subsequently, it was
      found that encapsulation of B. bifidum further augments the total IgA production
      in the culture of both MLN and spleen cells. Finally, we found that the immuno
      stimulating activity of B. bifidum is due to its cellular components but not due
      to any actively secreting component(s) from bacteria.

PMID- 12473265
TI  - Strong induction of tyrosine phosphorylation, intracellular calcium, nuclear
      transcription factors and interferongamma, but weak induction of IL-2 in naive T
      cells stimulated by bacterial superantigen.
AB  - The outcome of T cell receptor (TCR) engagement is controlled by the differential
      recruitment of a variety of pathways, depending on the nature of the TCR ligand.
      Studies on superantigens (SAGs) were among the first describing such differential
      signaling; however, reported results are inconsistent. We took a quantitative
      approach to reinvestigate this question. Using nai;ve T cells from TCR transgenic
      mice, we found that compared to the antigenic peptide from pigeon cytochrome c,
      the SAG staphylococcal enterotoxin A very efficiently (100-2000-fold more
      sensitive on a weight basis) induced tyrosine kinase activity, intracellular
      calcium increase, and interferon (IFN)gamma production. Up-regulation of CD25 and
      CD69 and proliferation were less efficiently induced (20-30-fold more sensitive),
      and interleukin (IL)-2 production was induced least efficiently (only 2-fold more
      sensitive). This differential activation profile that varies with the activation
      event analyzed is discussed with respect to the propensity for SAG to induce
      anergy.

PMID- 12473266
TI  - Regulation of lymphocyte clustering by CD30-mediated ICAM-1 up-regulation.
AB  - CD30 is expressed transiently on activated B and T lymphocytes and constitutively
      on several B- and T cell lymphomas. CD30 functions include participation in
      negative selection of thymocytes, costimulation of activated T cells, isotype
      switching of B cells, and regulation of the effector activity of cytotoxic
      lymphocytes. Although CD30 is not a marker for T helper 2 (TH2) cells, it may
      participate in the polarization of TH1 and TH2 cells. The pleiotropic functions
      of CD30 are initiated by interaction of CD30-expressing cells with other immune
      competent cells expressing CD30-L and providing the signals for modulation of
      effector cell activity. Here, we report that CD30 signals generated by anti-CD30
      on activated, normal murine T cells strongly up-regulate the expression of
      intercellular adhesion molecule 1 (ICAM-1, CD54), and to a lesser extent, ICAM-2
      (CD102). CD30 signals moreover delay the subsequent decline of ICAM expression.
      CD30 cross-linking did not alter the expression of CD11a/CD18 (LFA-1), the
      counter receptor for ICAM abundant on T cells. CD30-mediated ICAM-1 up-regulation
      is independent of cytokine secretion and appears to be transmitted directly
      through NF-kappaB activation. CD30-mediated up-regulation of ICAM-1 expression
      led to a significant increase in cluster formation of lymph node cells. Increased
      lymphocyte self-aggregation mediated by CD30 may set the stage for fraternal
      signaling to modulate lymphocyte function.

PMID- 12473267
TI  - IP-10 and Mig facilitate accumulation of T cells in the virus-infected liver.
AB  - Viral infection of the liver causes accumulation of T cells in the infected
      organ, raising the question as to the signals that mediate this response.
      Employing an adenovirus induced hepatitis model in mice, we show that IP-10 and
      Mig are essential for T cell recruitment and that induction of the two chemokines
      occurs concomitant to production of IFNgamma. It is shown that while IFNgamma
      induces IP-10 and Mig in hepatocytes, for optimal chemokine induction, a co
      stimulatory signal mediated by cross-linking of Fas on hepatocytes is required.
      Moreover, cross-linking of Fas by injection of anti-Fas antibody into mice
      triggers induction of IP-10 and Mig in the liver. The cells providing the two
      signals are shown to express NK1.1 and AsGM1; elimination of these cells leads to
      inhibition of IFNgamma and chemokine transcript induction. The conclusion is
      drawn that both NK cells and T cells provide the two signals for induction of IP
      10 and Mig in the liver.

PMID- 12473268
TI  - Expression of p58.2 or CD94/NKG2A inhibitory receptors in an NK-like cell line,
      YTINDY, leads to HLA Class I-mediated inhibition of cytotoxicity in the p58.2-
      but not the CD94/NKG2A-expressing transfectant.
AB  - Natural killer cytotoxicity is down-regulated by HLA Class I-specific inhibitory
      receptors classified as killer inhibitory receptors (KIRs) or C-type lectins. The
      regulation of their inhibitory signaling pathways is not completely understood.
      The YTINDY NK-like cell line was transfected to express p58.2 KIR (YT/C143
      transfectant) or CD94/NKG2A C-type lectin (YT/CD94 transfectant); and YT/C143,
      but not YT/CD94, cytotoxicity was down-regulated by Class I. YT/C143 and YT/CD94
      expressed equally low p56(lck) levels, suggesting that p56(lck) is not absolutely
      required for p58.2 signaling but may be required for CD94/NKG2A signaling. Lower
      SHP-1 levels and activity were observed in YT/CD94 compared to YT/C143. However,
      increasing SHP-1 to equivalent levels in YT/C143 did not restore inhibition in
      YT/CD94. Our results suggest that the combination of low p56(lck) and SHP-1
      levels may be responsible for the absent inhibitory signal in YT/CD94. In
      addition, the possible expression of CD94/NKG2C activating receptor may override
      inhibitory signals transduced through CD94/NKG2A.

PMID- 12473269
TI  - Epidemiology of rheumatoid arthritis: determinants of onset, persistence and
      outcome.
AB  - Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease.
      There is some evidence that it may have been brought from North America to Europe
      during the 18th century. Its arrival in rural parts of the developing world is
      still more recent. The incidence and prevalence of RA appear to have fallen in
      Europe, North America and Japan in the last 50 years. During this time the peak
      age of onset has risen. Risk factors for the development of RA include genetic
      factors, an adverse pregnancy outcome, smoking, obesity and recent infections.
      The oral contraceptive pill and some dietary constituents may be protective.
      Older age and female gender are risk factors both for the development of RA and
      for a worse outcome. This risk factor profile offers some opportunities for
      primary and secondary prevention. However, treatment is the greatest determinant
      of RA outcome.

PMID- 12473270
TI  - Seronegative spondyloarthritides.
AB  - Epidemiological studies on the spondyloarthritides have been hindered in the past
      by the lack of adequate classification criteria for the whole group of these
      diseases. Using the Amor and the European Spondyloathropathy Study Group (ESSG)
      criteria the total prevalence of such diseases has been found to be higher than
      estimated in the past. The prevalence of ankylosing spondylitis varies across
      populations, but closely parallels the frequency of HLA B27-associated subtypes.
      The lack of well established criteria for reactive arthritis and the varying
      expression of its clinical manifestations are the principal reasons for the under
      reporting of the true prevalence and incidence of this type of spondyloarthritis.
      Few data exist on the prevalence and incidence of psoriatic arthritis. A recent
      European study on an inception cohort of patients having inflammatory bowel
      disease has evaluated the prevalence of spondyloarthritis using the ESSG
      criteria. Of the patients studied, 18% met these criteria. Undifferentiated
      spondyloarthritis is one of the most frequent spondyloarthritides. It also
      includes a number of different subtypes.

PMID- 12473271
TI  - Osteoarthritis of the peripheral joints.
AB  - Osteoarthritis (OA) is a complex process affecting many different joint areas in
      the body. From a pathophysiological point of view some features are crucial for
      the diagnosis, such as cartilage fibrillation and thinning, subchondral sclerosis
      and the presence of osteophytes. From a clinical perspective, OA is the most
      prevalent rheumatic joint disorder, causing pain and stiffness of the joints and,
      for the individual, impaired function and health status. The aim of this chapter
      is to present current knowledge of definitions of OA, its presence in different
      populations and in different joint areas (the back excluded). Furthermore,
      methods of diagnosing and delineating clinically relevant forms of OA, now and in
      the future, are presented as well as current knowledge of the risk factors for
      developing and the factors for preventing OA.

PMID- 12473272
TI  - Low back pain.
AB  - Low back pain is a major burden to society. Many people will experience an
      episode of low back pain during their life. Some people develop chronic low back
      pain, which can be very disabling. Low back pain is associated with high direct
      and indirect costs. Recent epidemiological data suggest that there is a need to
      revise our views regarding the course of low back pain. Low back pain is not
      simply either acute or chronic but fluctuates over time with frequent recurrences
      or exacerbations. Also, low back pain may frequently be part of a widespread pain
      problem instead of being isolated, regional pain. Although epidemiological
      studies have identified many individual, psychosocial and occupational risk
      factors for the onset of low back pain, their independent prognostic value is
      usually low. Similarly, a number of factors have now been identified that may
      increase the risk of chronic disability but no single factor seems to have a
      strong impact. Consequently, it is still unclear what the most efficient strategy
      is for primary and secondary prevention. In general, multi-modal preventative
      approaches seem better able to reflect the clinical reality than single-modal
      interventions.

PMID- 12473273
TI  - The epidemiology of soft tissue rheumatism.
AB  - Soft tissue rheumatism forms a broad spectrum of health problems, most of them
      poorly defined according to diagnostic criteria and case definitions. In this
      chapter the most prevalent conditions, low back pain, neck pain, shoulder pain,
      arm/wrist/hand conditions and widespread pain, are discussed. A better term for
      referring to these health problems is regional and widespread pain disorders. The
      prevalence and the impact on health care and society of these conditions is high.
      Many physical, psychosocial and work-related factors play a role in aetiology and
      prognosis. A good prevention policy does not exist for most conditions due to the
      lack of knowledge on risk factors, risk groups and trends. To improve the
      epidemiological research on regional and widespread pain disorders, research
      should focus on clear and relevant definitions of cases or pain subgroups and on
      specific risk factors.

PMID- 12473274
TI  - Epidemiology of osteoporosis.
AB  - Osteoporosis is a major public health problem through its association with
      fracture. The problem may be alleviated substantially by appropriate early
      intervention before fracture occurs. This chapter discusses the epidemiology of
      osteoporosis and addresses the following questions: How should osteoporosis be
      defined? What is the incidence and prevalence of osteoporosis and fracture? Is
      there geographical variation in the occurrence of osteoporosis? What are the risk
      factors for osteoporosis and do they explain the occurrence of osteoporosis and
      osteoporotic fracture?

PMID- 12473275
TI  - Systemic sclerosis.
AB  - Systemic sclerosis (SSc) presents with a great deal of variability from patient
      to patient and classification and subset criteria will be analysed and discussed.
      SSc has been reported in people from all over the world. The prevalence and
      incidence, however, varies from country to country and within the same country in
      different ethnic groups. These differences will be elucidated. Genetic and
      environmental factors associated with the disease will be discussed.SSc is
      predominantly a female disease, with the female:male ratio ranging from 3:1 to
      8:1 and being higher in childbearing years. Progenitor cells acquired during
      pregnancy have been suggested to play a role by inducing a graft-versus-host
      disease (microchimerism). Recent epidemiological studies on the relationship
      between SSc and previous pregnancies will be discussed. SSc is associated with a
      significant morbidity and mortality. Survival has improved in the last 15 years.
      Factors associated with such improvement will be analysed.

PMID- 12473276
TI  - Idiopathic inflammatory myopathies - myositis.
AB  - The inflammatory myopathies - myositis - encompass a heterogeneous group of
      chronic muscle disorders of unknown origin and with varying prognoses. New
      clinical phenotypes of myositis have been identified since the most widely used
      classification criteria were proposed in 1975. Based on clinical and
      histopathological features, inclusion body myositis was identified. Furthermore,
      the myositis-specific autoantibodies may also identify different clinical
      phenotypes and serve as prognostic markers. The different classifications and
      inclusion criteria that have been used in different studies make some
      epidemiological data uncertain. In order to improve our knowledge of causative
      factors, as well as of pathogenic mechanisms, there is a need for revision and
      also for an international acceptance of the classification criteria. During
      recent years, our knowledge has increased regarding the role of some genetic and
      environmental factors that could affect susceptibility for developing myositis as
      well as the prognosis. Whether there is an association between myositis and
      malignancies has been a subject of controversy for many years and recent
      epidemiological data have brought some clarification on this issue.

PMID- 12473277
TI  - Systemic vasculitides.
AB  - The vasculitides are a heterogeneous group of diseases that are characterized by
      blood vessel inflammation and necrosis. They have a wide spectrum of
      manifestations due to the involvement of arteries and other vessels of various
      sizes and locations. Classification criteria are useful in improving our
      understanding of the epidemiology of these conditions but they are not diagnostic
      criteria. In recent years a progressive increase in incidence has been reported.
      Both giant cell arteritis and Wegener's granulomatosis are more common in the
      Northern hemisphere. Environmental factors have been implicated in the
      pathogenesis of these syndromes. Recent studies in patients with large and small
      sized vasculitides support a genetic influence in disease susceptibility. They
      have confirmed the association of giant cell arteritis and Henoch-Schonlein
      purpura with HLA-DRB1 alleles. Moreover, the polymorphisms of other genes, such
      as interleukin-1 receptor antagonist, seem to be implicated in disease severity
      in patients with cutaneous vasculitis.

PMID- 12473278
TI  - Epidemiology of systemic lupus erythematosus.
AB  - Several recent studies have suggested that the incidence of systemic lupus
      erythematosus (SLE) is increasing. The female to male ratio varies from 4.3 to
      13.6. SLE is more common in African-Americans, African-Caribbeans, and Asians,
      than in Caucasians. The age at diagnosis is younger in African-Americans than in
      Caucasians. Improvement in survival levelled off in the 1980s; 20-year survival
      is only 53-61%.

PMID- 12473279
TI  - Introduction: Value of epidemiological research for clinical practice.
AB  - Epidemiology is the scientific analysis of the occurrence of diseases in the
      general population in relationship to the characteristics of the individual
      subjects and their environment. Traditional epidemiology is concerned with
      discovering basic truths on the frequencies of diseases and their aetiology;
      clinical epidemiology represents a special field that translates clinical
      practice into quantitative science; public health epidemiology is the basis of
      knowledge, prevention and treatment of diseases in the population. Epidemiology
      has an important clinical impact for it can be used to understand the
      pathogenesis of diseases, improve diagnostic accuracy, help the patient to reduce
      risk factors and the physician to choose the correct therapeutic approach.

PMID- 12473280
TI  - Chlamydia trachomatis - the agent.
AB  - Chlamydiae are obligate intracellular bacteria, parasitizing eukaryotic cells.
      Chlamydia trachomatis, C. psittaci and C. pneumoniae are the three species of
      chlamydiae pathogenic to humans. C. trachomatis shows a tropism for the genital
      and conjunctival epithelia and consists of 19 different serovars which are
      pathogenic predominantly for the urogenital tract.A distinguishing feature of
      chlamydiae is their transition between the infectious elementary body that enters
      the host cell and the non-infectious reticulate body that replicates
      intracellularly within an inclusion that does not fuse with lysosomes. Chlamydiae
      depend for some functions upon the host cell; in particular, chlamydiae have
      little capacity for generating energy. The complete sequence of the 1000-kb
      chromosome of C. trachomatis is known, as are most of the genes located on the
      7.5-kb cryptic plasmid. Recently, several concepts about the biology and the
      metabolic pathways of C. trachomatis have been revised in relation to the genome
      sequence, and different novel proteins have been described.

PMID- 12473281
TI  - Epidemiology of female genital Chlamydia trachomatis infections.
AB  - The World Health Organization (WHO) has estimated that 92 million new cases of C.
      trachomatis (Chlamydia trachomatis) infection occur each year. This chapter
      focuses on the epidemiology of C. trachomatis infection, including the prevalence
      of infection in high- and low-risk groups, the incidence of infection, and data
      on secular trends. The evidence on the transmission of infection is reviewed.
      Risk factors for C. trachomatis infection in women are discussed. The adverse
      sequelae associated with C. trachomatis infection are described. Areas requiring
      further research are highlighted.

PMID- 12473282
TI  - Microbiological aspects of the diagnosis of Chlamydia trachomatis.
AB  - The available diagnostic methods for Chlamydia trachomatis infection comprise
      serology (indirect detection) and culture, antigen detection and nucleic acid
      amplification (direct detection). The rationale, applications, advantages and
      disadvantages of the methods and diagnostic targets are discussed. Compared to
      conventional methods, nucleic acid amplification tests have increased
      sensitivity. This allows samples to be taken at home by the patient herself and
      mailed directly to the laboratory. Public health strategies implying home
      sampling for asymptomatic men and women result in a lower prevalence and a lower
      risk of short-term complications in terms of pelvic inflammatory disease (PID).
      The importance of predictive values and the association with prevalence are
      highlighted.

PMID- 12473283
TI  - The role of serology, antibiotic susceptibility testing and serovar determination
      in genital chlamydial infections.
AB  - Systemic and local antibodies regularly develop in genital infections caused by
      Chlamydia trachomatis. Such antibodies cannot be used as a sign of current
      infection as they often persist for years after the infection has resolved.
      Chlamydial antibodies have, however, been extremely useful for demonstrating
      associations between C. trachomatis and clinical conditions such as ectopic
      pregnancy and tubal factor infertility. In particular, antibodies to the
      chlamydial heat shock protein 60 predict the presence of tubal scarring.C.
      trachomatis has been divided into 15 (or 18) serovars, with many genotypes within
      each serovar. Differences in pathogenicity between serovars have been reported
      but no general pattern has emerged. Genotyping is a powerful epidemiological tool
      but is not yet ready for routine clinical use.C. trachomatis infections can be
      successfully treated by tetracycline or macrolides. Some resistant strains have
      been reported, causing treatment failures, and the problem of emerging antibiotic
      resistance cannot be neglected.

PMID- 12473284
TI  - Chlamydial conjunctivitis (in adults), uveitis, and reactive arthritis, including
      SARA. Sexually acquired reactive arthritis.
AB  - This chapter deals with Chlamydia -induced ocular and rheumatic diseases of the
      adult. All of these may follow a primary urogenital infection with Chlamydia
      trachomatis in genetically predisposed patients. Besides the infection with
      Chlamydia trachomatis, infections with Chlamydia pneumoniae and Chlamydia
      psittaci are also discussed as possible causative agents. Chlamydial
      conjunctivitis is frequently a secondary infection, and the organism is
      transferred from the urogenital tract to the eye by autoinoculation. Uveitis and
      reactive arthritis are believed to be triggered - among other infections - by a
      preceding urogenital infection. Both of them are closely associated with HLA-B27
      positivity. The simultaneous occurrence of uveitis and reactive arthritis is
      termed Reiter's syndrome. We report on clinical characteristics, diagnosis and
      the role of Chlamydia in the pathogenesis of chlamydial conjunctivitis, uveitis
      and reactive arthritis as well as on the currently recommended treatment
      regimens.

PMID- 12473285
TI  - Is the prevention of genital chlamydial infections by community involvement
      possible?
AB  - This chapter presents different means by which community initiatives have been
      undertaken to reduce the prevalence and incidence of genital and allied
      infections caused by Chlamydia trachomatis. As most of these infections in the
      majority of infected individuals do not produce symptoms that are likely to urge
      them to attend any health care unit, screening programmes are mandatory to be
      able to influence the epidemic of infections with this agent. In many societies
      there has been a skewed gender distribution in the number of chlamydia-positive
      persons; this probably indicates that diagnostic service activities have been
      directed more against one gender than the other. The important role of partner
      notification, as in the case of other sexually transmitted infections, has been
      documented. Different means of community initiative have included counselling of
      school children and groups of persons more likely to be infected. Counselling by
      the pharmacy has an important role in many societies. Selected cohorts have been
      offered - via the mass media, Internet, radio and television programmes -
      sampling kits which can be mailed to a laboratory for testing. The establishment
      of youth clinics has been found effective for detecting teenagers harbouring C.
      trachomatis, similarly to screening at antenatal clinics. The offer of free
      consultations, aetiological tests and therapy has been a part of community
      initiatives, mimicking the services offered for some of the classic sexually
      transmitted infections. This chapter considers the usefulness of different test
      methods and stresses the need to retest those found to be positive. Barriers to
      the successful introduction of screening activities and diagnostic services are
      also considered.

PMID- 12473286
TI  - Influence of infection with Chlamydia trachomatis on pregnancy outcome, infant
      health and life-long sequelae in infected offspring.
AB  - This chapter deals with genital chlamydial infections in pregnancy and
      postpartum. There is increasing evidence that Chlamydia trachomatis infection may
      result in a number of adverse pregnancy outcomes, including early and late
      abortion, intrauterine infections of the fetus, stillbirth, prematurity,
      premature rupture of the membranes (PROM) and postpartum endometritis. Ectopic
      pregnancy is commonly associated with a previous tubal chlamydial infection where
      immunological reactions seem to play a role. C. trachomatis infection may be
      acquired as an intrauterine infection, as well as during transit through the
      birth channel, and this may result in neonatal conjunctivitis and/or pneumonia.
      The role of chlamydial infection in the sudden death syndrome has also been
      considered, but evidence so far is minimal. Neonatal chlamydial infection may
      cause life-long sequelae, such as obstructive lung disease. Genital chlamydial
      infections have been associated with problems in insemination and attempts at in
      vitro fertilization. The chapter also deals with screening of pregnant women for
      C. trachomatis and the treatment of infected mothers and their offspring.

PMID- 12473287
TI  - Immunological aspects of genital chlamydia infections.
AB  - Chlamydia trachomatis ascends from the cervix to the Fallopian tubes where it
      forms a persistent infection. The immune response to this infection results in
      tubal occlusion and infertility. In its persistent formC. trachomatis produces
      high levels of a 60-kDa heat shock protein (c-hsp60). There is a human hsp60 (h
      hsp60) which shares a 50% amino acid sequence homology with the c-hsp60.
      Therefore, a chlamydial Fallopian tube infection can induce the development of
      autoantibodies to h-hsp60. H-hsp60 is one of the first proteins synthesized
      following fertilization. It is also expressed by epithelial cells in the decidua.
      Therefore, expression of h-hsp60 in early pregnancy can reactivate the c-hsp60
      sensitized lymphocytes, leading to immune rejection of the embryo. The role of C.
      trachomatis in male infertility requires clarification. Because most C.
      trachomatis infections occur without defined symptoms, only the screening of
      sexually active women will reveal whether a woman is infected with this organism.
      Detection and treatment of a recently acquired infection can prevent development
      of h-hsp60 autoantibodies and tubal occlusion, preserve fertility, and prevent
      complications such as ectopic pregnancy.

PMID- 12473288
TI  - How, and how efficiently, can we treat Chlamydia trachomatis infections in women?
AB  - Several antichlamydial active drugs are available for both non-pregnant and
      pregnant women, potentially allowing effective prevention of the consequences and
      transmission of infection. The choice of treatment regimen not only has to
      consider efficacy, but also side-effects, compliance and the cost of antibiotic
      drugs. In recent years there have been no significant changes to the guidelines
      for treating Chlamydia trachomatis infection as no new antibiotic has been
      included. Inclusion of a new antichlamydial drug in the guidelines must be
      supported by suitable, randomized trials. Furthermore, how much it will be used
      in clinical practice will also depend on considerations of a pharmacoeconomic
      nature.

PMID- 12473289
TI  - Is a Chlamydia vaccine a reality?
AB  - Chlamydia trachomatis is a leading cause of sexually transmitted bacterial
      infections with severe sequelae such as tubal factor infertility and ectopic
      pregnancy; infections can also be asymptomatic. So far no vaccine has been
      developed but studies that may lead to the development of a highly warranted
      vaccine have been performed. The first attempt to vaccinate children with a whole
      cell vaccine initially resulted in protection but the protection was short-lived.
      In animal models whole-cell vaccination resulted in hypersensitivity reactions,
      so that new strategies were devised. The first immunogenic molecule described was
      the major outer membrane protein (MOMP), and this molecule has therefore been
      studied in great detail as a candidate vaccine. Even though complete protection
      was not obtained, reduced shedding was observed and vaccine trials in animal
      models using naked DNA as a vaccine resulted in stimulation of both the humoral
      and cellular immune response, indicating progress in the development of a
      vaccine.

PMID- 12473290
TI  - Chlamydia infection and subfertility.
AB  - In the majority of women chlamydia infections remain asymptomatic but they may
      increase the risk for tubal factor subfertility. Pelvic inflammatory disease
      (PID) and its chronic sequelae are associated with chlamydial IgG antibody
      formation in serum, and a correlation between the height of antibody titres and
      the presence of tubal factor subfertility has been established. The predictive
      value of chlamydia antibody testing (CAT) is limited however. Several factors
      affecting sensitivity and specificity of CAT have been identified. Because it is
      assumed that the presence of chlamydial heat shock proteins (HSPs) may be
      indicative of chronic inflammation, chlamydial HSP60 antibody testing has been
      evaluated in its prediction of tubal factor subfertility.

PMID- 12473291
TI  - Treatment of genital Chlamydia trachomatis infection in pregnancy.
AB  - This chapter gives a systematic review of the literature on treatment of
      Chlamydia trachomatis infections in pregnant women. The benefits of timely
      treatment of chlamydial infections in pregnant women are discussed. Antibiotic
      regimens commonly used for this purpose are identified. A meta-analysis based on
      randomized trials on pregnant women was performed to compare various antibiotic
      regimes in terms of microbiological cure, side-effects and tolerance. Data on
      safety related to the use of these antibiotics during pregnancy are summarized.
      Cost-effectiveness analyses on relevant antibiotic regimes for the treatment of
      uncomplicated chlamydial infection in women are identified. Their relevance and
      their shortcomings regarding the obstetric population are discussed. Treatment
      options for those who failed initial antibiotic treatment, as well as for the
      sexual partners of infected patients, are mentioned.

PMID- 12473293
TI  - Oesophageal disorders: future developments.
AB  - Elicitation of the characteristic symptom patterns remains the primary approach
      to the diagnosis of gastro-oesophageal reflux disease, and this may be enhanced
      by developments in the use of high-resolution endoscopy and oesophageal biopsy.
      For future therapy, proton pump inhibitors and anti-reflux surgery may compete
      with reversible acid pump blockers, reflux inhibitor drugs and diverse luminally
      delivered physical anti-reflux therapies. Short-segment Barrett's oesophagus is
      known to be highly prevalent, but its impact on the risk of adenocarcinoma
      remains poorly defined. Biomarkers for Barrett's oesophagus have been proposed to
      aid in the stratification of cancer risk, and cytology may assume more importance
      in the future. Endoscopic surveillance for Barrett's oesophagus is widely
      practised, but more data are needed to demonstrate cost-effectiveness and a
      positive impact on mortality. Animal and limited human studies suggest that
      chemoprevention may become an important strategy in reducing the risk of
      adenocarcinoma. The ablation of Barrett's epithelium results in a reversal of
      Barrett's epithelium, albeit with an uncertain long-term outcome.

PMID- 12473294
TI  - Current trends in the treatment of upper gastrointestinal disease.
AB  - The past 25 years have seen an amazing improvement in the treatment and
      understanding of acid-related disorders. In particular, the introduction of
      selective histamine receptor antagonists and proton pump inhibitors has made the
      medical control of acid secretion an effective means of therapy. The
      demonstration that infection with Helicobacter pylori is responsible for most
      cases of peptic ulcer disease resulted in another major improvement in therapy in
      these areas as a result of the eradication of the organism. Research continues in
      an attempt to find improved means of acid control and better methods for the
      eradication of H. pylori based on unique proteins expressed by the organism to
      resist gastric acidity.

PMID- 12473295
TI  - Intestinal epithelial pathobiology: past, present and future.
AB  - The intestinal epithelium serves as one of man's primary interfaces with the
      outside world. Its importance is illustrated by the fact that the proper
      functioning of this interface is absolutely essential for human health, and even
      modest perturbations in its function may lead to diarrhoea, constipation,
      malnutrition, dehydration, infectious disease or chronic intestinal inflammatory
      diseases such as Crohn's disease and ulcerative colitis, collectively referred to
      as inflammatory bowel disease. Both pathogen-induced intestinal inflammation and
      the active flares of inflammatory bowel disease are histopathologically defined,
      their sequellae being mediated by neutrophils that migrate across the intestinal
      epithelium, forming a crypt abscess. Classically, the intestinal epithelium has
      been thought of primarily as a barrier, and indeed this is a very important
      aspect of its function, but the intestinal epithelium is also a highly
      interactive barrier. This chapter will summarize some of the basic research
      conducted over the past 15 years that has revealed basic insights into how the
      epithelium participates in the formation of a crypt abscess and how it plays a
      role in causing the characteristic clinical manifestations that ensue. In
      addition, the chapter will discuss how this research has resurrected the 'old',
      yet newly emerging, concept that physiological malfunction of the intestinal
      epithelium can be the primary defect that leads to the innate and adaptive immune
      dysregulation mediating inflammatory bowel disease.

PMID- 12473296
TI  - Evolving concepts in functional gastrointestinal disorders: promising directions
      for novel pharmaceutical treatments.
AB  - In recent years there has been an increasing appreciation of the complexity of
      functional gastrointestinal disorders. These represent a spectrum of conditions
      which may affect any part of the gastrointestinal tract in which there appears to
      be dysregulation of visceral function and afferent sensation and a strong
      association with emotional factors and stress. There is a clear psychological
      dimension, with up to 60% of irritable bowel syndrome (IBS) patients reported to
      have psychological co-morbidities and altered pain perception is also common in
      comparison with control populations. The role of the enteric nervous system, the
      sensory pathways and the brain as well as the influence of the latter on
      sympathetic and parasympathetic outflow have likewise attracted increasing
      interest and have led to exciting new methods to study their complex
      interactions. The concept of low-grade inflammation, such as might occur after
      infection, acting as a trigger for neuromuscular dysfunction has also led to the
      broad integrative hypotheses that help to explain the biopsychosocial dimensions
      seen in functional gastrointestinal disease. The multi-component model places a
      major emphasis on neurogastroenterology and enteric and neuro-immune interactions
      where new approaches to pharmacotherapy lie. Drugs may affect motility, visceral
      sensation and other aspects of gut function such as secretion or absorption. More
      particularly, however, has been the search for and attempts to influence
      important mediators of these primary gut functions. Such targets include
      serotonin and selected 5-HT receptors, which are involved in gut motility,
      visceral sensation and other aspects of gut function, CCK receptors which are
      involved in the mediation of pain in the gut and nociception in the CNS, opioid
      receptors involved in pain in the brain, spinal cord and periphery, muscarinic M3
      receptors, substance P and neurokinin A and B receptors which are involved in
      motor adaptation and pain transmission in association with inflammation, gabba
      receptors involved in nociception and cannabinoid receptors which are involved in
      the control of acetyl choline release in the gut. With a better understanding of
      the structures and pathways involved in visceral perception and hyperalgesia, in
      the CNS, spinal cord and the gut and new pharmacological tools we will be better
      able to elucidate the neuropharmacology of visceral perception and its
      relationship to gut dysfunction. It is likely that there will be multiple
      therapeutic options based on the spectrum of abnormalities capable of causing the
      spectrum of symptoms of functional gastrointestinal disorders in any individual
      patient.

PMID- 12473297
TI  - Perspectives and reflections on integrated digestive surgery.
AB  - The history of the integration of surgery is both extensive and complex involving
      internecine machinations that have, over time, variously encompassed the
      alchemical, religious, technological and biological phases of societal
      development. Thus, the discipline has evolved from a mystic rite through a guild
      phase to its current eristic status as a therapeutic modality considered by some
      as an art form as opposed to a quasi-scientific endeavour of often unpredictable
      beneficial effect. This brief prolepsis provides an exposition of the evolution
      of surgeons and surgical thought proceeding from Galen in 3rd century Rome
      through Pare of Renaissance France, Billroth of fin de siecle Vienna, to Kocher
      and Whipple of Bern and New York respectively. It is apparent that in surgery,
      ontogeny may not readily recapitulate phylogeny and thus the need for a
      contemporary revaluation of integration within a novel educational nexus that
      encompasses the burgeoning matrix of biotechnological, ethical and fiduciary
      revolution is a critical requirement. Such an exercise must embody contemporary
      scientific and educational advance with evolving societal goals that include
      ethical variances, fiduciary issues and alterations in individual perceptions of
      life quality at both the medical and personal level. An incorporation of the
      basic tenets of digestive surgery as well as a delineation of its potential
      direction is both a vital and necessary exercise to ensure the attainment of
      appropriate future goals of medical, ethical, societal, scientific and
      educational validity. Current medical and surgical training programmes and the
      sub-specialization system are archaic, cumbersome, cost ineffective and, for the
      most part, represent endless computations and permutations of intellectually
      antiquated and stultifying processes designed more than a hundred years ago. As
      such, the maieutic skills as well as the clinical vista available for the
      delivery of visceral disease care bear little relation to the needs and desires
      of contemporary society, whether medical or lay. Indeed, the century old notion
      of surgery and medicine as mutually exclusive disciplines that embraced diagnosis
      and therapy as divergent events needs to be cast aside to facilitate the
      development of a new model of disease management (organ specific). Specifically,
      training programmes require to be shortened (educational node) and their focus
      dramatically reconfigured (focus module) to ensure the establishment of a unified
      group of specialists (cluster convergent) each interfaced in delivery of a
      particular skill (component specific) to the resolution of a disease affecting a
      specific organ system. In this fashion, a time sensitive training programme
      producing educationally pre-focused physicians can be implemented to deliver time
      effective care in a cost contained environment with maximization of expertise and
      comprehensive interdisciplinary integration of knowledge, experience and skill
      (cluster care module). As such, digestive surgery itself should cease to be
      regarded as an end in itself or separate entity, but rather as representative of
      one facet in the delivery of a multifaceted integrated health care modality
      focused on the digestive tract.

PMID- 12473298
TI  - The host-microbe interface within the gut.
AB  - Colonization with bacteria is critical for the normal structural and functional
      development and optimal function of the mucosal immune system. Unrestrained
      mucosal immune activation in response to bacterial signals from the lumen is,
      however, a risk factor for inflammatory bowel disease. Therefore, mucosal immune
      responses to indigenous flora require precise control and an immunosensory
      capacity for distinguishing commensals from pathogens. The use of germ-free
      animal models with selective colonization strategies combined with modern
      molecular techniques promises to clarify the molecular signals responsible for
      host-flora interactions in health and disease. At least half of the resident
      flora cannot be cultured by conventional techniques but are identifiable by
      molecular methods. Collectively, the resident flora represent a virtual organ
      with a metabolic activity in excess of the liver and a microbiome in excess of
      the human genome. An improved understanding of this hidden organ holds secrets
      relevant to several infectious, inflammatory and neoplastic disease mechanisms.

PMID- 12473299
TI  - The current future understanding of inflammatory bowel disease.
AB  - Accumulating evidence indicates that the inflammatory bowel diseases result from
      an activation of immune and inflammatory responses initiated by a stimulation of
      the luminal flora or their products. Genetically determined variations in key
      mucosal functions, including cell activation by prototypic bacterial pattern
      molecules, lead to differential susceptibility to the development of these
      disorders, probably reflecting an interrelated activation of the innate and
      adaptive immune responses. The persistence and amplification of inflammation is
      likely to reflect the continuing presence of the driving stimulus and the
      complex, self-reinforcing activation of select T-helper subtypes and macrophages
      and other antigen-presenting cells, mediated by several cytokines. The latter
      include interleukins-2, 12, and 18 as well as interferon and macrophage migration
      inhibitory factors. The production of other broadly pro-inflammatory cytokines,
      most notably tumour necrosis factor and interleukins-1 and 6, enhances related
      inflammatory processes that eventually lead to many of the clinical
      manifestations of inflammatory bowel disease. The overall severity of the
      inflammatory process reflects a balance between leukocyte recruitment and
      downregulatory mucosal repair processes.

PMID- 12473300
TI  - New avenues for the prevention of colorectal cancer: targeting cyclo-oxygenase-2
      activity.
AB  - Carcinoma of the colon and/or rectum represents the second most common
      gastrointestinal malignancy worldwide. Despite this prevalence, current
      therapeutic regimens remain largely ineffectual, particularly when the disease is
      diagnosed at an advanced stage. Recent work in the field of colorectal cancer has
      established that a chronic intake of non steroidal anti-inflammatory drugs can
      reduce the risk of developing colorectal cancer. Although the precise
      mechanism(s) by which these drugs inhibit tumour growth is not completely
      understood, it is likely that at least a part of their anti-tumorigenic effects
      results from an inhibition of the cyclo-oxygenase-2 enzyme. This chapter will
      focus on this emerging research area and the promise it brings for identifying
      new strategies for the prevention of colorectal cancer.

PMID- 12473302
TI  - Amsterdam and Netherlands gastroenterology: a historical perspective.

PMID- 12473301
TI  - Expected developments in hepatology.
AB  - It is very difficult to predict new developments in hepatology so we have decided
      to analyse the most important issues related to three clinical conditions in
      hepatology. The first is chronic hepatitis. Here, we discuss the relevance of
      occult forms of hepatitis B virus infection in the development of cryptogenic
      liver disease and hepatocellular carcinoma. In addition, the role of genotyping
      in hepatitis B is analysed, indicating that patients with genotype A have a
      better prognosis than those with genotype D. The treatment of hepatitis B virus
      infection is also reviewed, and it has been suggested that research should be
      directed towards the development of new anti-viral agents to suppress virus
      replication. The natural history of hepatitis C virus infection is considered,
      emphasizing the need to know the progression of fibrosis in these patients. The
      chapter also suggests that treatment of hepatitis C virus infection with
      pegilated interferon and ribavirin is currently relatively effective. New
      therapeutic strategies will be required in the future, the most important
      challenge being the development of a hepatitis C virus vaccine. The second
      section is on chronic cholestasis. The role of anti-mitochondrial antibodies in
      primary biliary cirrhosis is considered. The possible infectious agents
      implicated as potential triggers of primary biliary cirrhosis are also discussed,
      suggesting that several infections may play a role in the pathogenesis of this
      condition. Other aetiopathogenic factors, for example organic compounds, drugs
      and chemicals, are indicated. It is possible that, in the near future, the
      precise sequence and molecular basis by which infectious agents or xenobiotics
      may initiate the cascade of the autoimmune response will be defined. One of the
      most important challenges in primary sclerosing cholangitis concerns the
      mechanisms that may induce the development of this disease. Up until now, genetic
      factors have been suggested, recent data reporting a clear-cut association
      between primary sclerosing cholangitis and the tumour necrosis factor-alpha(2)
      allele. The third part of this chapter includes recent progress achieved in
      hepatocellular carcinoma, discussing developments in the knowledge of
      hepatocellular carcinogenesis. Hepatocellular carcinomas appear so far to be
      genetically heterogeneous neoplasms, and this heterogeneity may correlate with
      the variety of aetiological factors involved. The risk factors and primary,
      secondary and tertiary prevention of the condition are also analysed. Finally,
      the development of new therapeutic strategies for hepatocellular carcinoma is
      evaluated by evidence-based studies.

PMID- 12473303
TI  - Future developments in endoscopic imaging.
AB  - Flexible gastrointestinal endoscopy was introduced more than 30 years ago; this
      chapter will try to look into its future. Developments are expected in five
      different categories. We will see better with the use of high-resolution
      magnification endoscopy as well as by using other light-tissue interactions (such
      as spectroscopy). We will also be able to look just below the surface with laser
      scanning microscopy and optical coherence tomography with a resolution of 1
      microm (in vivo histology). Computers will assist with the interpretation of what
      we see, and the availability of broadband networks all around the world will
      allow real-time consultation globally. Invisible areas of the gastrointestinal
      tract will be seen with the help of improved endoscopy capsules and virtual
      endoscopy. Finally, we will treat endoscopically, with the help of new
      instruments and accessories, more of the lesions that we see.

PMID- 12473304
TI  - Understanding and controlling the enteric nervous system.
AB  - The enteric nervous system or the 'Little Brain' of the gut controls
      gastrointestinal motility and secretion, and is involved in visceral sensation.
      In this chapter, new developments in understanding the function of the enteric
      nervous system are described. In particular, the interaction of this system with
      the interstitial cells of Cajal, the pacemaker cells of the gut, is highlighted.
      The importance of the interaction between the enteric nervous system and the
      immune system is discussed, especially in relation to functional bowel disorders
      and post-operative ileus. Evidence is also provided that neurones can change
      their function and phenotype, a phenomenon called neuronal plasticity, which
      contributes to the pathogenesis of visceral hypersensitivity. Finally, new
      developments in stem cell transplantation are described. All these new insights
      should lead to a better understanding of the enteric nervous system and hopefully
      to better ways of controlling it.

PMID- 12473305
TI  - Understanding and controlling hepatobiliary function.
AB  - Over the past decade, enormous progress has been made in identifying the
      mechanisms that underlie hepatobiliary excretion. A set of transport proteins
      mediates the canalicular transport of most important bile constituents. With the
      discovery of these transporter genes, the mechanism of bile formation could be
      partly elucidated and genetic defects caused by mutations in these genes
      identified. This progress is crucial not only for paediatric and adult
      hepatology, but also for pharmacology, because the characterization of these
      transport systems provides tools for the prediction of the pharmacokinetics of
      drugs. Indeed, there is a growing interest on the part of the pharmaceutical
      industry for research into transport systems in general and hepatobiliary
      secretion in particular. For all of these transporter genes, knockout mice have
      been bred that allow one to assess the in vivo function of each of these
      transporters with regard to their role in physiology and drug elimination.

PMID- 12473306
TI  - Taming the mucosal immune response in Crohn's disease.
AB  - New effective therapeutic strategies for inflammatory bowel disease are based on
      recent knowledge of the regulation of the immune response. Specific defects of
      innate immunity, such as the NOD2 mutation in a subset of patients with Crohn's
      disease, have been associated with inflammatory bowel disease and provide new
      therapeutic targets. The ultimate therapeutic goal is the complete restoration of
      the mucosal immune balance and healing of all intestinal lesions. This may
      require repair of the underlying genetic mutation, restoration of defects of
      apoptosis, or generation of regulatory T-lymphocytes.

PMID- 12473308
TI  - Two views of self-rated general health status.
AB  - Global self-evaluations of health have proven to be sensitive predictors of
      morbidity and mortality. Yet researchers have only a limited understanding of how
      these self-evaluations are reached. This research compares two interpretations of
      self-rated health, as reflecting either a spontaneous assessment of one's health
      status and related practices, or an aspect of one's enduring self-concept. Using
      longitudinal data from successive waves of the National Population Health Survey
      in Canada (Statistics Canada, 1994-95, 1996-97, NPHS public use microdata
      documentation. Ottawa, Ontario: Statistics Canada; n = 7505), our analysis tests
      a model of change in self-rated health as predicted by respondents' baseline
      physical and mental health symptoms, social support, leisure physical activity,
      smoking, body mass index, and 2-yr changes in these characteristics. As in past
      research, self-rated health was sensitive to improvement or decline in these
      predictors. Much of the explained variance, however, was unique to respondents'
      self-rated health 2 yr earlier. Moreover, the effect of several predictors on
      respondents' self-rated health varied according to whether respondents intended
      to improve specific health-related behaviours in the future. These findings
      suggest that self-rated health is not only a spontaneous assessment of one's
      health status and related practices; like a self-concept, self-rated health may
      be regulated by efforts to achieve one's relatively important health-related
      goals.

PMID- 12473309
TI  - Inherited burden of disease: agricultural dams and the persistence of bloody
      urine (Schistosomiasis hematobium) in the Upper East Region of Ghana, 1959-1997.
AB  - A major agricultural development project was commissioned to celebrate Ghana's
      independence in 1957. In the Upper Region along the border with Upper Volta now
      named Burkina Faso, a total of 185 clay-core dams were constructed in 15 years to
      enhance village water supplies during the 6-month dry season. In a concentrated
      area of N.E. Ghana (now the Upper East Region) no fewer than 104 dams were
      erected in only 3 years. The beneficial impacts of the dams are indisputable, and
      life today would be unthinkable without them, despite severe problems of neglect
      of maintenance. Equally undeniable has been a negative disease impact whereby the
      regional rate of schistosomiasis tripled in 1 or 2 years from 17% to 51%
      prevalence. Thus, an agriculturally induced hyperendemicity of "red water" or
      "bloody urine" disease was established. To test the longevity of community
      disease impact, a survey of hematuria (bloody urine) was conducted in the same
      areas in 1997. It showed a 40-year ecological entrenchment of elevated levels of
      schistosomiasis, that is, seemingly permanent alteration of regional disease
      ecology. The consequences of planning negligence have left a generational impact
      in that hematuria has become a "rite of passage" for young boys and girls.
      Unprepared and overburdened rural health care systems are ill-equipped in the
      face of competing demands to respond to the presence of schistosomiasis. Yet
      excellent medication is available to break the transmission cycle provided that
      there is a sufficiency of political will, accompanied by effective, inter
      sectoral campaign coordination.

PMID- 12473310
TI  - Understanding lesbians' healthcare behaviour: the case of breast self
      examination.
AB  - Lesbians' risk of breast cancer is a much-debated issue in health research
      because lesbians are believed to be at higher risk of the disease than are
      heterosexual women. This belief is based upon particular risk factors for breast
      cancer, which are said to be more prevalent in lesbians; and upon differences in
      preventive health behaviours: in particular, lesbians are said to be less likely
      to practise breast self-examination (BSE). This paper presents data collected as
      part of the UK Lesbians and Healthcare Survey (n = 1066) focusing on lesbians who
      report never practising BSE (n = 218, 20%) and the explanations they offer for
      their healthcare behaviours. It identifies six types of explanation for not
      practising BSE: (i) "I don't know what I'm looking for"; (ii) "I've never got
      into the habit"; (iii) "I'm frightened in case I find something"; (iv) "I don't
      think I'm at much risk"; (v) "I'm uncomfortable with my body"; and (vi) "My
      partner does it for me". These findings are important for increasing
      understanding of lesbians' healthcare behaviour and for developing health
      promotion materials relevant to their needs.

PMID- 12473311
TI  - Social relations and depressive symptoms in older adults with knee
      osteoarthritis.
AB  - Depressive symptoms often occur as a comorbid condition in the context of chronic
      illnesses such as arthritis. However, the role of both social support and social
      strain in relation to depressive symptoms has not been adequately explored. This
      study investigates the association of support and strain with depressive symptoms
      among a sample of older men and women in the USA (N = 298, mean age 71 years) who
      have knee osteoarthritis (OA). Data were collected from a survey mailed to
      residents who had previously participated in the Osteoarthritis Study in Seniors
      (OASIS), a longitudinal observational study of OA progression (survey response
      rate was 77%). Hierarchical regression analyses revealed significant associations
      of both support and strain with depressive symptoms, while statistically
      controlling for a variety of demographic, psychosocial and disease-related
      variables. In addition, social support significantly buffered the relation
      between social strain and depressive symptoms. The interaction effect was not
      significantly different for women and men, nor were the individual associations
      of support and strain with depressive symptoms conditioned by participant gender.
      The results add to the ongoing discussion regarding gender and social relations
      as well as highlight the role of both positive (social support) and negative
      (social strain) aspects of social interactions in relation to the psychological
      functioning of older adults coping with a chronic illness.

PMID- 12473312
TI  - Volunteering and depression: the role of psychological and social resources in
      different age groups.
AB  - There are a number of reasons why volunteering might yield mental health
      benefits, especially to older people. Volunteer work improves access to social
      and psychological resources, which are known to counter negative moods such as
      depression and anxiety. Analysis of three waves of data from the Americans'
      Changing Lives data set (1986, 1989, 1994) reveals that volunteering does lower
      depression levels for those over 65, while prolonged exposure to volunteering
      benefits both populations. Some of the effect of volunteering on depression among
      the elderly is attributable to the social integration it encourages, but the
      mediating effect of psychological resources is very small. Volunteering for
      religious causes is more beneficial for mental health than volunteering for
      secular causes but, again, the effect is confined to the elderly.

PMID- 12473313
TI  - Unraveling the mysteries of timing: women's perceptions about time to treatment
      for cardiac symptoms.
AB  - Women in the USA are at disproportionate risk of dying from a myocardial
      infarction (MI), of suffering disabilities following an MI, and of reinfarcting
      and dying within a year of their initial MI. Various explanations, including
      women's older age at clinical manifestation of coronary heart disease (CHD) and
      higher likelihood of co-morbidities, have been offered for women's heightened
      risk of poor outcomes. Less frequently, research has focused on examining women's
      prolonged time elapse between symptom onset and biomedical treatment, a
      phenomenon that renders women less likely to undergo lifesaving reperfusion
      strategies. [1] To explore factors and circumstances that may shape CHD time to
      treatment, 40 middle age and older women living in Kentucky, USA, half with
      diagnosed CHD and half with chronic conditions considered to be risk factors for
      CHD, participated in a series of in-depth interviews. While much of the existing
      CHD literature implicates individual responsibility as the determining feature in
      time to treatment, these women's narratives suggested that treatment decisions
      inextricably are linked to broader social and structural constraints. Such supra
      individual forces that shape the CHD experiences of women include the social
      construction of "standard" cardiac symptoms based on male norms that ultimately
      confuse symptom detection, women's negative encounters with health care providers
      who discount their knowledge, the competing social demands women face when
      threatened by a serious illness, and structural barriers delimiting women's
      health care choices.

PMID- 12473314
TI  - The feasibility of using ethnicity as a primary tool for antenatal selective
      screening for sickle cell disorders: pointers from the research evidence.
AB  - The Department of Health has announced a linked antenatal and neonatal screening
      programme for haemoglobinopathies by 2004 in a comprehensive national plan for
      the National Health Service in Britain. In response the National Screening
      Committee has commenced development work on how such a programme can best be
      implemented, including investigation of the effectiveness of a question about
      ethnic origin as a basis for selection. In addition, two recent health technology
      assessment reports have assessed alternative options for antenatal and neonatal
      haemoglobinopathy screening programmes in the United Kingdom. Both reports and
      commentators have emphasised the importance of developing a standardised
      instrument for collecting ethnicity data and recommended early development of
      such work. An examination of the evidence base on the use of ethnicity as a
      primary screening tool reveals substantial variability in practice and in the
      quality of data collected, with risk group misclassification as high as 20%
      against a recommended target of under 5.5%. The literature on the conceptual
      basis and structure of ethnicity questions, method of assignment in data
      collection, and level of resolution on categorisation is reviewed to identify the
      most appropriate content and format of a screening question for the
      haemoglobinopathies. Question options are evaluated, including the use of an
      extended 2001 Census classification and a 'non-North European' identifier and a
      candidate question based on 'family origins' is offered for debate. Finally,
      issues relating to the testing of the efficiency of an ethnicity question and the
      operationalising of its use for antenatal sickle cell screening are discussed.

PMID- 12473315
TI  - Subjective experiences of stigma. A focus group study of schizophrenic patients,
      their relatives and mental health professionals.
AB  - Schizophrenia has been found to be one of the most stigmatising conditions. To
      the present, most research on stigma related to mental illness has drawn
      conclusions on the adverse reactions faced by people with schizophrenia from
      studies on public attitudes or analogue behavioural studies. The views of those
      exposed to the stigmatising reactions, however, has largely been absent. Aiming
      to explore stigma from the subjective perspective of people with schizophrenia, a
      focus group study was carried out at the four centres involved in the WPA Global
      Programme against Stigma and Discrimination because of Schizophrenia in Germany.
      In order to get a comprehensive picture of how stigma affects the lives of
      schizophrenic patients, collateral information was sought from relatives and
      mental health professionals. The focus groups enquired about concrete
      stigmatisation experiences of the patients and incidences of stigma witnessed by
      the other two groups. Focus group sessions were tape-recorded and transcripts
      were coded using an inductive method. Results reveal four dimensions of stigma:
      interpersonal interaction, structural discrimination, public images of mental
      illness and access to social roles. Examples are given for the views of patients,
      relatives and mental health professionals on each of the four stigma types. The
      consequences for conceptualisations of stigma and the development of effective
      strategies to reduce stigma and discrimination because of schizophrenia are
      discussed.

PMID- 12473316
TI  - Online commentary during the physical examination: a communication tool for
      avoiding inappropriate antibiotic prescribing?
AB  - A previously identified communication behavior, online commentary, is physician
      talk that describes what he/she is seeing, feeling, or hearing during the
      physical examination of the patient. The investigators who identified this
      communication behavior hypothesized that its use may be associated with
      successful physician resistance to perceived or actual patient expectations for
      inappropriate antibiotic medication. This paper examines the relationship between
      actual and perceived parental expectations for antibiotics and physician use of
      online commentary as well as the relationship between online commentary use and
      the physician's prescribing decision. We conducted a prospective observational
      study in two private pediatric practices. Study procedures included a pre-visit
      parent survey, audiotaping of study consultations, and post-visit surveys of the
      participating physicians. Ten pediatricians participated (participation rate=77%)
      and 306 eligible parents participated (participation rate=86%) who were attending
      sick visits for their children with upper respiratory tract infections between
      October 1996 and March 1997. The main outcomes measured were the proportion of
      consultations with online commentary and the proportion of consultations where
      antibiotics were prescribed. Two primary types of online commentaries were
      observed: (1) online commentary suggestive of a problematic finding on physical
      examination that might require antibiotic treatment ('problem' online
      commentary), e.g., "That cough sounds very chesty"; and (2) online commentary
      that indicated the physical examination findings were not problematic and
      antibiotics were probably not necessary ('no problem' online commentary), e.g.,
      "Her throat is only slightly red". For presumed viral cases where the physician
      thought the parent expected to receive antibiotics, if the physician used at
      least some 'problem' online commentary, he/she prescribed antibiotics in 91%
      (10/11) of cases. Conversely, when the physician exclusively employed 'no
      problem' online commentary, antibiotics were prescribed 27% (4/15) of the time (p
      = 0.07). Use of 'no problem' online commentary did not add significantly to visit
      length. 'No problem' online commentary is a communication technique that may
      provide an effective and efficient method for resisting perceived expectations to
      prescribe antibiotics.

PMID- 12473317
TI  - Disability and a sense of community belonging. A study among tetraplegic spinal
      cord-injured persons in France.
AB  - This article presents a study of the identity of persons with motor impairments
      with regard to the community of disabled persons. The authors used the Tetrafigap
      survey on the long-term outcome of Tetraplegic Spinal-cord-injured (TSCI)
      persons, in France, to study the sense of belonging to the community of disabled
      persons among 1356 TSCI persons in relation to factors of social participation
      (both sociological and disability-related) and subjective factors (subjective
      well-being, social perception of disability, perceived disability). The results
      show that 44% of TSCI persons felt that disabled persons do not constitute a
      community (the "no-community" group). Of those who recognised the existence of
      such a community, 34% said they belonged to it (the "in-community" group) and 22%
      declared they did not (the "out-community" group). People in the "no-community"
      group tended to be more socially integrated, whilst those in the "in-community"
      group tended to have greater social and clinical difficulties. The "out
      community" group was more diverse, being made up of both autonomous persons and
      dependent persons suffering from complications. Factors related to the sense of
      community belonging were identified using bivariate analysis and multiple
      logistic regression. Subjective well-being appeared to be independent of any
      sense of community belonging. However, the authors found a gender difference:
      women in the "in-community" group described themselves as having a poorer level
      of well-being than women in the other two groups. The results are discussed in
      terms of two views on the social treatment of disabilities: universalism and
      assimilation vs. particularism and positive identity and the growth of the
      disability movement.

PMID- 12473318
TI  - The impact of public voluntary health insurance on private health expenditures in
      Vietnam.
AB  - As a financing mechanism with the potential to raise additional funds for health
      services, whilst improving access to services amongst the poor, non-profit health
      insurance has become increasingly attractive to health policy-makers. Using data
      from a household survey in Vietnam, out of pocket health expenditure are compared
      between members and eligible non-members of the government-implemented voluntary
      health insurance scheme. Expenditures are analysed for individuals who sought
      care during their most recent illness. Using an endogenous dummy variable model
      to control for bias resulting from self-selection into the scheme, we find that
      health insurance reduces average out-of-pocket expenditures by approximately
      200%. Whilst income inelastic, health expenditures are found to be significantly
      influenced by an individuals level of income, irrespective of insurance status.
      Despite this, insurance reduces expenditures significantly more for the poor than
      for the rich.

PMID- 12473319
TI  - Technical and cost efficiency of oral health care provision in Finnish health
      centres.
AB  - In this study we measured the productive efficiency of public dental health
      provision across Finland. The analysis was based on data envelopment analysis
      (DEA) using linear programming. In addition, we investigated various factors
      explaining the technical and cost efficiency of public dental care using a
      parametric Tobit model. These analyses revealed substantial variation in
      productive efficiency between health centres in different municipalities. The
      level of cost inefficiency was generally between 20% and 30%. Good dental health
      of the population, high rates of unemployment and high per capita expenditure on
      primary care in the municipality were associated with technical and cost
      inefficiency. According to the results, cost efficiency would not be improved by
      shifting input allocation towards more auxiliary manpower in health centres.
      Individual efficiency scores were clearly sensitive to the choice of output
      specification. Changing the unit of output measurement from visit- to patient
      based measures affected markedly the ranking of dental health centres. However,
      the set of exogenous correlates associated to inefficiency was strikingly similar
      for both types of output specification. More resources are needed if the coverage
      of public dental care is extended to all age groups. The health centre specific
      efficiency scores obtained in this study can be used locally to evaluate, design
      and implement structural changes in the production processes.

PMID- 12473320
TI  - Social mobility and self-reported limiting long-term illness among West Indian
      and South Asian migrants living in England and Wales.
AB  - This study examined the relationship between social mobility and self-reported
      limiting long-term illness (LLTI) in West Indian and South Asian migrants in
      England and Wales present at the 1971, 1981 and 1991 Censuses in the Office for
      National Statistics Longitudinal Study. Most people remained in the same social
      position regardless of migrant status and those who remained most disadvantaged
      reported more LLTI than those who remained least disadvantaged. Amongst those who
      were mobile, upward mobility was more common than downward mobility for South
      Asians and West Indians but not for all other study members. The findings for the
      impact of downward mobility on LLTI were particularly striking. Migrants who were
      downwardly mobile reported more LLTI than all other study members. All other
      study members who were downwardly mobile reported more LLTI than people who
      remained in the least disadvantaged group they left but less than those who
      remained in the most disadvantaged group they joined. Downwardly mobile South
      Asians reported more LLTI than those of the least disadvantaged group but this
      was not significantly different from the most disadvantaged group they joined.
      Downwardly mobile West Indians reported also more LLTI than the least
      disadvantaged group they left but, in contrast, to the South Asians this appeared
      to be more than that of the disadvantaged group they joined. Empirical studies
      are needed to understand the context of social mobility and how this affects
      health-related behaviours and specific diseases among migrants. In a situation
      where migrants do not have established economic or social support, the loss of
      resources or self-esteem could have a disproportionate negative effect on their
      health.

PMID- 12473321
TI  - Gender differences in physical activity in older children and adolescents: the
      central role of organized sport.
AB  - Previous studies have generally had limited success in accounting for gender
      differences in leisure time physical activity. Based on a representative national
      survey of 3270 Icelandic 6th, 8th and 10th grade students, the study found that
      girls' lower enrollment in organized sport clubs fully accounts for gender
      differences in frequency of overall physical activity, and largely accounts for
      gender differences in frequency of strenuous activity, and weekly hours of
      overall and strenuous activity (enrollment hypothesis). Furthermore, girls'
      higher sport club withdrawal rate accounted for a small but significant part of
      the gender difference in weekly hours of overall activity and frequency of
      strenuous activity (withdrawal hypothesis). No evidence was found to suggest that
      different activity levels of boys and girls enrolled in the clubs affected gender
      differences in levels of overall or strenuous physical activity (activity
      differential hypothesis). Other independent variables, i.e., perceived importance
      of sport achievement, sport and exercise related instruction, physical education
      experiences, and social modeling, did not significantly affect observed gender
      differences beyond the sport club variables. The meaning of the results, and
      their implications for gender disparities, health promotion, and future research
      are discussed.

PMID- 12473322
TI  - How can we learn to live with pain? A Q-methodological analysis of the diverse
      understandings of acceptance of chronic pain.
AB  - An analysis is reported of the variety of understandings available in British
      culture to understand acceptance of chronic pain. Q-factor analysis is used
      within a critical framework as Q-methodology. Thirty participants completed the
      procedure. Eight factors or accounts of accepting chronic pain were derived.
      These are reported as taking control, living day to day, acknowledging
      limitations, empowerment, accepting loss of self, more to life than pain, don't
      fight battles that cannot be won, and spiritual strength. Common features of
      accepting chronic pain are (1) the acknowledgement that a cure for pain is
      unlikely, (2) a shift of focus away from pain to non-pain aspects of life, and
      (3) a resistance to any suggestion that pain is a sign of personal weakness.
      Where accounts of chronic pain differ is in the extent to which acceptance of
      pain means a change in core aspects of self. Implications of this study for the
      study of chronic pain are discussed. In particular, how identity is managed in
      the context of threatening chronic pain is suggested as a fruitful area of future
      investigation.

PMID- 12473323
TI  - The influence of attractiveness factors and distance to general practice
      surgeries by level of social disadvantage and global access in Perth, Western
      Australia.
AB  - The impact on attendance of the distance to general practice surgeries, and the
      attributes offered by those surgeries, was investigated. One thousand and forty
      four subjects, selected at random from the metropolitan area of Perth, Western
      Australia, responded to a household interview survey concerning which attributes
      of general practice (GP) surgeries they found attractive and the identity of the
      surgery they preferred to attend. The sample was stratified by different levels
      of social disadvantage and by good and poor global levels of spatial
      accessibility of GP surgeries. In separate fieldwork, interviewers collected
      detailed environmental data from practice staff at 466 GP surgeries available to
      the community survey respondents within metropolitan Perth. Respondents living in
      areas of poor global access were more likely to attend their nearest surgery (25%
      vs. 6%) and to bypass fewer surgeries to attend a preferred surgery (median 2 vs.
      20). Those who were most socially disadvantaged were less likely than those who
      were better off to bypass surgeries where global access was poor, but more likely
      to bypass nearby surgeries and to seek out a surgery that bulk billed in areas
      where global access was good. A number of attractiveness factors had an important
      influence on choice of surgery, including: 'easy to make an appointment';
      'generally sees patients on time'; 'pharmacy nearby'; 'bulk bills' and 'open at
      all on Sundays'. Respondents attending their nearest surgery were more likely to
      have all of their nominated 'very important' attributes satisfied at that surgery
      than non-attenders (40% vs. 16%). A logistic regression model, adjusting for
      distance effects and size of surgery, showed within each level of global access
      and social disadvantage a consistent increase in the odds of attending a surgery
      that satisfied the attributes desired by respondents.

PMID- 12473324
TI  - Mortality after spousal loss: are there socio-demographic differences?
AB  - This study evaluates the effect of spousal death on mortality among Israeli
      adults and examines differences in this effect by duration of bereavement, age,
      sex, education, ethnic origin, household size, and number of children. Data are
      taken from the Israel Longitudinal Mortality Study which is based on a linkage of
      records from a 20% sample of the 1983 census to records of deaths occurring
      during the period 1983-1992. The study population comprised 49,566 men and 41,264
      women, of whom 4,402 (9%) and 11,114 (27%), respectively, were bereaved during
      the follow-up period. Excess mortality among the bereaved was evident among both
      men and women, especially after bereavement of short duration. During the first 6
      months, the excess mortality was about 50% among women and about 40% among men.
      For men, the effect of bereavement on mortality decreased linearly with age, with
      a relative risk of 3 among younger men during early widowhood. Bereavement had a
      greater impact on the more educated men. The effect of bereavement did not vary
      by ethnic origin or household size.

PMID- 12473325
TI  - Concepts of arthritis in India's medical traditions: Ayurvedic and Unani
      perspectives.
AB  - Anthropology and other social sciences have not given detailed attention to
      cultural constructions of arthritic disorders and their place in traditional
      medical systems. Humoral medicine and its numerous crosscultural variants offer
      an important perspective on the conceptualization and treatment of arthritis. The
      present paper provides a descriptive account of rheumatic disorders in India's
      Ayurvedic and Unani medical traditions. Data derive from anthropological
      fieldwork in the New Delhi metropolitan area and from Ayurvedic and Unani texts
      and secondary sources. The discussion explores these two traditions together as a
      polysynthetic field of ideas, practices, and materials, and it highlights their
      congruent concepts of arthritis and related somatic concepts, etiologies, and
      treatments. It reveals parallels in the clinical practices of Ayurvedic and Unani
      practitioners and identifies a broadly shared model of arthritis that circulates
      between these practitioners and their ethnically diverse patient-clienteles. The
      paper suggests that this South Asian humoral model provides a framework that may
      be useful in anthropological studies of arthritis in other humoral traditions.

PMID- 12473339
TI  - Transcriptional regulatory networks and the yeast cell cycle.
AB  - A large amount of microarray gene expression data relevant to the yeast cell
      cycle has been collected, and several hundred genes have been placed into a model
      transcriptional control network. Genome-wide studies of the location of cell
      cycle transcription factors, and a variety of computational approaches, have
      allowed refinement of the model, and at the same time show how other genome-wide
      data sets may be organised into model networks.

PMID- 12473340
TI  - A revised picture of the E2F transcriptional network and RB function.
AB  - New techniques have enhanced our picture of E2F regulation. These studies have
      shed light on the roles played by individual E2F and retinoblastoma family
      members and implicate these proteins in processes extending well beyond the G1/S
      transition. One thorny issue remains: do our current molecular models of E2F and
      retinoblastoma action explain all of the functions of these proteins in vivo?

PMID- 12473341
TI  - Histone mRNA expression: multiple levels of cell cycle regulation and important
      developmental consequences.
AB  - Histone mRNA metabolism is tightly coupled to cell cycle progression and to rates
      of DNA synthesis. The recent identification of several novel proteins involved in
      histone gene transcription and pre-mRNA processing has shed light on the variety
      of mechanisms cells employ to achieve this coupling.

PMID- 12473342
TI  - Centrosomes and tumour suppressors.
AB  - Centrosomes are microtubule organising centres that act as spindle poles during
      mitosis. Recent work implicates centrosomes in many other processes, and shows
      that centrosome defects can cause genetic instability. Many regulators of
      mammalian centrosome function were predicted from studies of model systems.
      Surprisingly, some well-known tumour suppressors have recently been found at
      centrosomes, where they influence centrosome duplication and function, suggesting
      that control of centrosome function is central to genetic stability.

PMID- 12473343
TI  - Regulation of APC-Cdc20 by the spindle checkpoint.
AB  - The spindle checkpoint ensures the fidelity of chromosome segregation in mitosis
      and meiosis. In response to defects in the mitotic apparatus, it blocks the
      activity of the anaphase-promoting complex, a large ubiquitin ligase required for
      chromosome segregation. Recent studies indicate that the spindle checkpoint
      monitors both the attachment of chromosomes to the mitotic spindle and the
      tension across the sister chromatid generated by microtubules. Upon checkpoint
      activation, checkpoint protein complexes containing BubR1(Mad3), Bub3, Mad2 and
      Cdc20 directly bind to the anaphase-promoting complex and inhibit its ligase
      activity. Therefore, the checkpoint proteins form a complex intracellular
      signalling network to inhibit the anaphase-promoting complex.

PMID- 12473344
TI  - Apoptosomes: engines for caspase activation.
AB  - Activation of the caspases that initiate apoptosis typically requires cognate
      scaffold proteins, including CED-4 in Caenorhabditis elegans, Apaf-1 in mammals
      and Dark in Drosophila. Each scaffold protein oligomerizes procaspases into a
      complex called the apoptosome, but the regulation and biological roles of the
      scaffolds differ. Whereas CED-4 is restrained by the Bcl-2 homologue CED-9, Apaf
      1 is inhibited by its WD40 repeat region, until it is activated by cytochrome c,
      derived from damaged mitochondria. Although Dark also has a WD40 region, its
      activation does not seem to involve cytochrome c. CED-4 is essential for
      apoptosis in the worm and Dark for many apoptotic responses in the fly, but the
      Apaf-1/caspase-9 system probably amplifies rather than initiates the mammalian
      caspase cascade.

PMID- 12473345
TI  - Apoptosis-independent functions of killer caspases.
AB  - Caspases are well known for their role in the execution of the apoptotic program
      by cleaving specific target proteins, leading to the dismantling of the cell, as
      well as for mediating cytokine maturation. Recent work has highlighted novel non
      apoptotic activities of apoptotic caspases. These reports indicate that caspases
      are much more versatile enzymes than we originally expected. In addition to
      regulating cell survival and cytokine maturation, caspases may be involved in
      regulating cell differentiation, cell proliferation, spreading and receptor
      internalization.

PMID- 12473346
TI  - Caspase-independent cell deaths.
AB  - A very common and the best understood of the mechanisms of physiological cell
      death is apoptosis, resulting from the activation, through either of two primary
      pathways, of site-specific proteases called caspases. There are, however, many
      other routes to cell death, prominently including autophagy and proteasomal
      degradation of critical constituents of cells. These routes are frequently seen
      in experimental situations in which initiator or effector caspases are inhibited
      or blocked through genetic means, but they are also encountered during normal
      physiological and pathological processes. Most frequently, autophagic or
      proteasomal degradation is used to eliminate massive cytoplasm of very large
      cells, especially post-mitotic cells, and these pathways are prominent even
      though caspase genes, messages, and pro-enzymes are found in the cells. These
      forms of cell death are fully physiological and not simply a default pathway for
      a defective cell; and they are distinct from necrosis. We do not yet understand
      the extent to which the pathways are linked, what mechanisms trigger the caspase
      independent deaths, and how the choices are made.

PMID- 12473347
TI  - Engulfment mechanism of apoptotic cells.
AB  - Apoptotic cells are engulfed and removed by phagocytes. This ensures proper
      development of the organism and can modulate immune responses. Recent studies
      have examined molecules on apoptotic cells, such as phosphatidylserine, which may
      signal for engulfment through multiple receptors. Apoptotic recognition
      mechanisms may vary with the apoptotic and engulfing cell type, and even with the
      age of the corpse.

PMID- 12473349
TI  - Nuclear transplantation: lessons from frogs and mice.
AB  - Nuclear transplantation was developed 50 years ago in frogs to test whether
      nuclei from differentiated cells remain genetically equivalent to zygotic nuclei.
      Results from cloning experiments in frogs and mice indicate that nuclei gradually
      lose potency during development from embryonic to adult cells. However, even
      though adult mature lymphocytes were recently shown to remain genetically
      totipotent, no evidence exists to show that surviving clones originate from the
      nuclei of terminally differentiated cells. Thus, it is equally possible that many
      cloned animals are in fact derived from the nuclei of less differentiated adult
      cells such as adult stem cells. These cells might be more easily reprogrammed
      than terminally differentiated cells and may support development of a clone at a
      higher efficiency. Importantly, irrespective of the donor cell, clones display
      common abnormalities such as foetal and placental overgrowth. Indeed, gene
      expression analyses and extensive phenotypic characterisation of cloned animals
      suggest that most, if not all, clones suffer from at least subtle abnormalities.

PMID- 12473350
TI  - Plasticity revisited.
AB  - Despite some recent setbacks, it remains clear that adult stem cells under
      appropriate experimental conditions can at some frequency exhibit a wider range
      of differentiation potentials than previously appreciated. This is underscored by
      the recent demonstration of the extensive differentiation potential of
      mesenchymal stem cells. In terms of mechanism, it remains unclear in many cases
      to what extent plasticity reflects in vitro adaptation, transdifferentiation/cell
      type switching or the persistence in adult tissues of stem cells with extensive
      endogenous or bona fide developmental potentials. These issues will need to be
      resolved before the full therapeutic potential of adult-derived stem cells can be
      realised.

PMID- 12473351
TI  - Genome-wide histone modifications: gaining specificity by preventing promiscuity.
AB  - More than 20 residues within the four core histone proteins of the nucleosome are
      potential sites of post-translational modifications, such as methylation,
      acetylation, ubiquitination and phosphorylation. It has been hypothesized that
      specific patterns of these modifications on the nucleosome facilitate recruitment
      of non-histone proteins to chromatin. When such modifications are restricted to
      particular regions of the genome, they seem to play an important role in creating
      specific chromatin domains. However, more recent results suggest that some
      histone modifications, particularly those that exist on a genome-wide scale, act
      to reduce nonspecific binding by chromatin proteins involved in silencing. This
      decrease of promiscuous binding ensures that the silent chromatin proteins are
      not titrated away from their normal locations on chromosomes. We suggest that
      preventing such promiscuous binding of chromatin proteins is an important part of
      generating specificity to create chromatin domains and overall chromosome
      organization.

PMID- 12473352
TI  - Signaling chromatin to make muscle.
AB  - Several findings published within the past year have further established key
      roles for chromatin-modifying enzymes in the control of muscle gene expression,
      and have thus refined our thinking of how chromatin structure influences muscle
      differentiation, hypertrophy and fiber type determination. We discuss the
      interface between chromatin-modifying enzymes and myogenic transcription factors,
      signaling mechanisms that impinge on these transcriptional complexes, and how
      these multicomponent regulatory cascades may be exploited in the development of
      novel therapeutics to more effectively treat myopathies in humans.

PMID- 12473353
TI  - Epigenetic inheritance of expression states in plant development: the role of
      Polycomb group proteins.
AB  - Polycomb group (PcG) proteins maintain a repressed state of gene expression over
      many cell divisions. The recent characterisation of several PcG proteins from
      plants revealed a remarkable structural and functional conservation of PcG
      proteins between different kingdoms. In both plants and animals, homeotic genes
      are among the target genes of PcG complexes, although the structure of these
      genes is not conserved. However, not all PcG proteins identified in animals are
      present in plants. Furthermore it becomes clear that PcG-mediated repression in
      plants is more transient compared with the long-lasting effects in animals. This
      may be related to the absence of PcG proteins thought to be involved in long-term
      maintenance of PcG repression, suggesting that the mechanisms underlying PcG
      mediated repression differ between plants and animals.

PMID- 12473354
TI  - The interdependence of nuclear structure and function.
AB  - 2001 was the year of the human genome, but the new information has had little
      immediate impact on the field of nuclear structure. Rather, functional studies -
      especially on transcription - are leading us to a better understanding of how
      genomes might organise themselves into structures we call nuclei.

PMID- 12473355
TI  - Aiming to eliminate tsetse from Africa.
AB  - The problem of tsetse-transmitted trypanosomiasis occurs only in sub-Saharan
      Africa, where it represents a major constraint to socio-economic development. The
      East African form of sleeping sickness, caused by Trypanosoma brucei
      rhodensiense, is an acute and fatal disease, whereas the West African form,
      caused by Trypanosoma brucei gambiense, is generally more chronic and
      debilitating. The African governments have developed a new initiative, known as
      the Pan African Tsetse and Trypanosomiasis Eradication Campaign, which seeks to
      employ an area-wide approach and appropriate fly suppression methods to eradicate
      tsetse from areas of tsetse infestation, at a time, to ultimately create tsetse
      free zones.

PMID- 12473356
TI  - Antimicrobial peptides versus parasitic infections?
AB  - Reports of antimicrobial peptides generally have evaluations of their
      antibacterial and antifungal activities. By contrast, little is known of their
      activities against protozoan and metazoan parasites. In vitro antiparasitic
      assays suggest that antimicrobial peptides could represent a powerful tool for
      the development of novel drugs to fight the parasite in the vertebrate host, or
      to complement current therapeutic strategies.

PMID- 12473357
TI  - Trypanosomiasis and leishmaniasis: novel biology versus practical disease
      control.

PMID- 12473361
TI  - Successful model vaccine against malaria.

PMID- 12473362
TI  - Toxoplasma gondii MAG1 protein expression.

PMID- 12473363
TI  - Abundant proton pumping in Plasmodium falciparum, but why?
AB  - Intraerythrocytic Plasmodium parasites depend on glycolysis for energy
      production. The stoichiometric amounts of lactate and protons produced are
      efficiently removed by a lactate:H(+) symporter. However, inhibition of recently
      identified plasma-membrane proton pumps result in acidification, suggesting
      additional mechanism(s) for proton generation. This article attempts to integrate
      the knowledge on the metabolic generation of protons and their disposal in the
      regulation of parasite cytosolic pH, and suggests additional roles for the
      various proton pumps that act in the parasite membrane.

PMID- 12473364
TI  - Will the real Trypanosoma brucei rhodesiense please step forward?
AB  - The sleeping sickness trypanosomes Trypanosoma brucei rhodesiense and T. brucei
      gambiense are morphologically indistinguishable from each other and from T.
      brucei brucei, which does not infect humans. The relationships between these
      three subspecies have been controversial. Several years ago, the characterization
      of T. brucei gambiense was reviewed in an attempt to clarify and draw together
      the results, and to put them in the context of the biology of the organism. The
      discovery of a gene associated with human-serum resistance in T. brucei
      rhodesiense and the consequent reappraisal of the identity of this trypanosome
      prompt this companion article.

PMID- 12473365
TI  - The kinetoplastida endocytic apparatus. Part I: a dynamic system for nutrition
      and evasion of host defences.
AB  - The endocytic system of kinetoplastid parasites is a highly polarized membrane
      network focused on the flagellar pocket localized at one end of the cell. When
      first characterized, the endosomal network was envisioned as a simple system for
      uptake of extracellular material by fluid-phase or receptor-mediated mechanisms.
      Subsequently, it has become clear that the kinetoplastid endosomal system has an
      active and vital role in avoiding the host immune system and virulence, as well
      as providing the basic functions to fulfil cellular nutritional requirements. In
      two reviews, recent advances in the definition and comprehension of
      kinetoplastida endocytosis are discussed and, in Trypanosoma brucei in particular
      as the more developed experimental system. In Part 1, the endocytic system is
      considered in context of the surface molecules and their potential roles in
      virulence.

PMID- 12473366
TI  - Immune responses to Neospora caninum and prospects for vaccination.
AB  - Developing an effective vaccine against neosporosis presents several interesting
      challenges. The parasite is spread efficiently from mother to foetus over several
      generations, and naturally infected cattle do not appear to develop adequate
      protective immunity. Modulation of the immune response during pregnancy favours
      parasite survival and multiplication. However, induction of pro-inflammatory
      responses that are thought to be protective against Neospora caninum would be
      detrimental to the pregnancy. So, is vaccination a feasible option to control the
      disease? This article discusses some of these issues and reports on the progress
      towards a vaccine for neosporosis.

PMID- 12473367
TI  - Analysis of arthropod bloodmeals using molecular genetic markers.
AB  - Little is known about the transmission dynamics of human malaria and other vector
      borne diseases, partly because of the limited availability and distribution of
      appropriate tools for quantifying human-mosquito contact rates. Recent
      developments in molecular biology have allowed a significant increase in the
      efficacy and reliability of bloodmeal identification, and DNA-based molecular
      markers are now being harnessed for typing arthropod bloodmeals. The extent to
      which these markers have been used for analysis of mosquito bloodmeals and the
      potential they might have for the future is discussed, and the contributions that
      the advent of PCR has made are examined here.

PMID- 12473368
TI  - Reducing malaria by mosquito-proofing houses.
AB  - Sometimes, valuable lessons from history are forgotten, remain unknown, or worse,
      are ignored. This article reminds us of the pioneering work of Angelo Celli at
      the end of the 19th century, who demonstrated that people could be protected from
      malaria by screening their homes against mosquitoes. Since then, public health
      scientists have continued to show that simple changes in house design have the
      potential for protecting people against this life-threatening disease. Yet today,
      this type of intervention remains virtually ignored. The literature reviewed here
      demonstrates the enormous potential of these methods to reduce malaria, in the
      hope that it will stimulate scientific debate and further research.

PMID- 12473372
TI  - Small molecule antagonists of proteins.
AB  - The identification of small molecule antagonists of protein function is at the
      core of the pharmaceutical industry. Successful approaches to this problem,
      including screening and rational design, have been developed over the years to
      identify antagonists of enzymes and cellular receptors. These methods have been
      extended to the search for inhibitors of protein-protein interactions. While the
      very possibility of designing a small molecule inhibitor for such interactions
      was once doubted, there are examples of such inhibitors that are currently
      marketed products and many more inhibitors in various stages of research and
      development. Here we review the progress in identifying and designing small
      molecule protein inhibitors, with particular attention to those that block
      protein-protein interactions. We also discuss the physical character of protein
      protein interfaces, and the resulting implications for small molecule lead
      discovery and design.

PMID- 12473373
TI  - U50,488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2)
      production by human astrocytes.
AB  - Kappa-opioid receptor (KOR) ligands have been reported to alter many cell
      functions and to exert an immunomodulatory role in the CNS. Astrocytes, the
      predominant brain cell type, have been implicated in the neuropathogenesis of
      human immunodeficiency virus type 1 (HIV-1). HIV-1 nuclear protein Tat has been
      reported to induce production of the chemokine monocyte chemoattractant protein-1
      (MCP-1 or CCL2) and to activate nuclear factor kappaB (NF-kappaB) in human
      astrocytes. In the present study, we investigated whether the synthetic KOR
      ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneacetamide
      methanesulfonate (U50,488) would down-regulate MCP-1 production in primary human
      astrocytes stimulated by Tat. Treatment of astrocytes with U50,488 inhibited Tat
      induced MCP-1 production in a concentration-dependent manner. The KOR-selective
      antagonist nor-binaltrophimine (nor-BNI) completely blocked the inhibitory effect
      of U50,488, indicating involvement of KOR. While U50,488 alone had a partial
      inhibitory effect on constituent NF-kappaB activation, it potently suppressed Tat
      induced NF-kappaB activation. These findings suggest that KOR ligands could have
      an anti-inflammatory effect in the CNS and thereby be beneficial in the treatment
      of HIV-1-associated brain disease.

PMID- 12473374
TI  - Altered lymphocyte catecholamine reactivity in mice subjected to chronic mild
      stress.
AB  - There is considerable evidence that the sympathetic nervous system influences the
      immune response via activation and modulation of beta(2)-adrenergic receptors
      (beta(2)R). Furthermore, it has been suggested that stress has effects on the
      sympathetic nervous system. In the present study, we analyzed the influence of
      catecholamines on the reactivity of lymphocytes from mice exposed to a chronic
      mild stress (CMS) model of depression (CMS-animals). The effects of the CMS
      treatment on catecholamine and corticosterone levels and on beta(2)R lymphoid
      expression were also assessed. For this purpose, animals were subjected to CMS
      for 8 weeks. Results showed that catecholamines (epinephrine and norepinephrine)
      exert an inhibitory effect on mitogen-induced normal T-cell proliferation and a
      stimulatory effect on normal B-cell proliferation in response to selective B
      lymphocyte mitogens. Specific beta- and beta(2)-antagonists abolished these
      effects. Lymphocytes from mice subjected to CMS had an increased response to
      catecholamine-mediated inhibition or enhancement of proliferation in T and B
      cells, respectively. Moreover, a significant increase in beta(2)R density was
      observed in animals under CMS compared to normal animals. This was accompanied by
      an increment in cyclic AMP production after beta-adrenergic stimulation. On the
      other hand, neither catecholamine levels, determined in both urine and spleen
      samples, nor serum corticosterone levels showed significant variation between
      normal and CMS-animals. These findings demonstrate that chronic stress is
      associated with an increased sympathetic influence on the immune response and may
      suggest a mechanism through which chronic stress alters immunity.

PMID- 12473376
TI  - Potent inhibitory effect of naturally occurring flavonoids quercetin and
      kaempferol on in vitro osteoclastic bone resorption.
AB  - Several recent studies have suggested that flavonols, a class of phytochemicals
      with many biological activities, might exert a protective effect against post
      menopausal bone loss. In the present study, we investigated the effects of
      quercetin and kaempferol, two of the major naturally occurring flavonols on the
      in vitro bone resorbing activity of osteoclasts. Our results indicate that both
      compounds, at concentrations ranging from 0.1 to 100 microM reduce bone
      resorption in a time and dose-dependent manner. Significant inhibitory effects
      were observed at concentrations as low as 0.1 microM especially with kaempferol.
      The IC(50)s, or concentration inhibitory of 50% of basal resorption, calculated
      for quercetin and kaempferol were 1.6 and 5.3 microM, respectively. Using highly
      purified rabbit osteoclasts, we showed that both flavonols directly induce
      apoptosis of mature osteoclasts in the same dose-range effective for inhibiting
      bone resorption. When osteoclasts were treated with 50 microM of quercetin and
      kaempferol, intracellular reactive oxygen species levels decreased significantly
      by 75 and 25%, respectively, indicating these molecules keep their antioxidant
      properties at this concentration. However, at concentrations below 50 microM,
      neither quercetin nor kaempferol exerted antiradical action, suggesting that
      antioxidant properties cannot fully explain the inhibitory effect on bone
      resorption. Finally, we report that kaempferol-, but not the quercetin-induced
      inhibition of bone resorption was partially abolished by the presence of the pure
      anti-estrogen ICI 182780 suggesting that kaempferol's estrogenic effect could be
      involved in the inhibition of bone resorption. The present study demonstrates
      that flavonols widely distributed in human diet such as quercetin and kaempferol,
      exert a potent inhibitory effect on in vitro bone resorption.

PMID- 12473375
TI  - Plasma stability of two glycosyl indolocarbazole antitumor agents.
AB  - In recent years, several glycosyl indolocarbazole derivatives have been developed
      as antitumor agents targeting the topoisomerase I-DNA complex and a few of them
      were evaluated in clinical trials. The lead drug in the series is compound A
      which bears a formylamino substituent on the N-imide F-ring. This compound has
      shown promising antitumor activities in vivo and was tested clinically but it has
      been recently replaced with a more active analogue, J-107088, bearing a
      (hydroxymethyl-2-hydroxy) ethylamino substituent on the N-imide F-ring. We have
      compared the plasma stability of two molecules in this series, compounds A and D,
      which only differ by the nature of the group on the imide ring. The conversion of
      the compounds into the anhydride species B was studied by HPLC and the resulting
      metabolite, formed both in human plasma ultrafiltrate and in water, was
      characterized by NMR and mass spectrometry. Absorption measurements provided a
      facile method to follow the conversion of compounds A and D into their metabolite
      product B. Altogether, the experimental data demonstrate that the replacement of
      the NHCHO substituent of compound A with a hydrophilic NHCH(CH(2)OH)(2) chain
      preserves the intact imide function that is known to be essential for
      topoisomerase I inhibition and cytotoxicity. The transformation of compound A
      into the anhydride metabolite B (or its diacid open form) occurs much more slowly
      compared to compound D. Half-life parameter t(1/2) of 67 and 245 min(-1) were
      calculated for compounds A and D, respectively. A molecular modeling analysis,
      performed to compare the conformation and electronic properties of compounds A
      and D, offers a rational explanation for the gain of chemical stability of the
      indolocarbazole derivative D. The data provide important information for the
      rational design of antitumor indolocarbazole derivatives.

PMID- 12473377
TI  - Reactive oxygen species are involved in the stimulation of the mitochondrial
      permeability transition by dihydrolipoate.
AB  - Dihydrolipoic acid (DHLA) has been found to stimulate the Ca(2+)-induced
      mitochondrial permeability transition (MPT) in rat liver mitochondria (RLM)
      [Biochem. Mol. Biol. Int. 44 (1998) 127] which could be due to its prooxidant
      properties. We therefore investigated whether DHLA stimulated superoxide anion
      (O(2)(.-)) generation in RLM and in bovine heart submitochondrial particles
      (SMP). In RLM DHLA caused a concentration-dependent O(2)(.-) generation assayed
      by lucigenin chemiluminiscence. The stimulation was seen with the lowest
      concentrations of DHLA (5 microM) with pyruvate as the respiratory substrate,
      with 2-oxoglutarate or especially succinate the stimulation was less pronounced.
      Stimulation of O(2)(.-) production by DHLA was also observed in bovine heart SMP
      using an electron spin-trapping technique. Radical scavengers
      (butylhydroxytoluene and TEMPO) decreased O(2)(.-) generation induced by DHLA and
      inhibited MPT. Slight reduction of the mitochondrial membrane potential by a
      small amount of a protonophorous uncoupling agent also delayed the DHLA-induced
      MPT. These data indicate that the stimulation of MPT by DHLA is due to DHLA
      derived prooxidants, i.e. stimulated production of O(2)(.-) and possibly other
      free radicals.

PMID- 12473378
TI  - Sodium tanshinone IIA sulfonate mediates electron transfer reaction in rat heart
      mitochondria.
AB  - In this paper, an electron transfer reaction mediated by sodium tanshinone IIA
      sulfonate (STS) was studied in rat heart mitochondria. It was found that STS
      could stimulate mitochondrial NADH oxidation dose-dependently and partly restore
      NADH oxidation in the presence of respiratory inhibitor (rotenone or antimycin A
      or KCN). It was likely that STS could accept electrons from complex I similar to
      ferricyanide and could be converted to its semiquinone form that could then
      reduce oxygen molecule. The data also showed that cytochrome c (Cyt c) could be
      reduced by STS in the presence of KCN, or STS could transfer the electron to
      oxygen directly. Free radicals were involved in the process. The results suggest
      that STS may protect ischemia-reperfusion injury through an electron transfer
      reaction in mitochondria against forming reactive oxygen radicals.

PMID- 12473379
TI  - The antioxidant activity of caroverine.
AB  - Caroverine, 1-(2-diethylaminoethyl)-3-(p-methoxy benzyl)-1,2-dihydro-2-quinoxalin
      2-on-hydrochloride, is a class B calcium-channel-blocker and antiglutamatergic
      agent with significant effects on the brain function. Caroverine exhibits
      competitive AMPA antagonism, and at higher concentrations, noncompetitive NMDA
      antagonism. In clinical practice caroverine is used as a spasmolytic and
      otoneuroprotective agent. Since reactive oxygen species are supposed to be
      involved in the pathogenesis of inner ear diseases in which caroverine shows
      beneficial effects, the present study aimed to investigate the antioxidant
      properties of caroverine. Lipid peroxidation of liposomal membranes was
      suppressed in the presence of caroverine. In order to understand the mechanism of
      this antioxidant action of caroverine, we determined the rate constants both for
      a possible reaction with superoxide (O(2)(.-)) radicals from xanthine/xanthine
      oxidase and for a possible reaction with hydroxyl (.OH) radicals in Fenton
      system. Using a defined chemical reaction model O(2)(.-) scavenging was found to
      occur at a rather low rate constant only (3 x 10(2)M(-1)s(-1)). Thus, a reaction
      of caroverine with O(2)(.-) radicals is of marginal significance. In contrast,
      the reaction of caroverine with .OH radicals occurs at an extremely high rate
      constant (k=1.9 x 10(10)M(-1)s(-1)). The strong antioxidant activity of
      caroverine is therefore based both on the partial prevention and highly active
      scavenging of hydroxyl radicals.

PMID- 12473380
TI  - Antioxidant and pro-oxidant properties of pyrroloquinoline quinone (PQQ):
      implications for its function in biological systems.
AB  - Pyrroloquinoline quinone (PQQ) is a novel redox cofactor recently found in human
      milk. It has been reported to function as an essential nutrient, antioxidant and
      redox modulator in cell culture experiments and in animal models of human
      diseases. As mitochondria are particularly susceptible to oxidative damage we
      studied the antioxidant properties of PQQ in isolated rat liver mitochondria. PQQ
      was an effective antioxidant protecting mitochondria against oxidative stress
      induced lipid peroxidation, protein carbonyl formation and inactivation of the
      mitochondrial respiratory chain. In contrast, PQQ caused extensive cell death to
      cells in culture. This surprising effect was inhibited by catalase, and was shown
      to be due to the generation of hydrogen peroxide during the autoxidation of PQQ
      in culture medium. We conclude that the reactivities of PQQ are dependent on its
      environment and that it can act as an antioxidant or a pro-oxidant in different
      biological systems.

PMID- 12473381
TI  - Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg(3).
AB  - Multidrug resistance has been a major problem in cancer chemotherapy. In this
      study, in vitro and in vivo modulations of MDR by ginsenoside Rg(3), a red
      ginseng saponin, were investigated. In flow cytometric analysis using rhodamine
      123 as an artificial substrate, Rg(3) promoted accumulation of rhodamine 123 in
      drug-resistant KBV20C cells in a dose-dependent manner, but it had no effect on
      parental KB cells. Additionally Rg(3) inhibited [3H]vinblastine efflux and
      reversed MDR to doxorubicin, COL, VCR, and VP-16 in KBV20C cells. Reverse
      transcriptase-polymerase chain reaction and immuno-blot analysis after exposure
      of KBV20C cells to Rg(3) showed that inhibition of drug efflux by Rg(3) was due
      to neither repression of MDR1 gene expression nor Pgp level. Photo-affinity
      labeling study with [3H]azidopine, however, revealed that Rg(3) competed with
      [3H]azidopine for binding to the Pgp demonstrating that Rg(3) competed with
      anticancer drug for binding to Pgp thereby blocking drug efflux. Furthermore,
      Rg(3) increased life span in mice implanted with DOX-resistant murine leukemia
      P388 cells in vivo and inhibited body weight increase significantly.

PMID- 12473382
TI  - Inhibition of acetylcholine-mediated effects by borneol.
AB  - We previously reported that the aqueous extract from a medicinal plant
      Dryobalanops aromatica specifically inhibits the nicotinic acetylcholine receptor
      (nAChR) (Oh et al. Pharmacol Res 2000;42(6):559-64). Here, the effect of borneol,
      the main constituent of D. aromatica, on nAChR activity was investigated in
      bovine adrenal chromaffin cells. Borneol inhibited a nAChR agonist 1,1-dimethyl-4
      phenylpiperazinium iodide (DMPP)-induced calcium increase with a half maximal
      inhibitory concentration (IC(50)) of 56+/-9 microM. In contrast, borneol did not
      affect the calcium increases induced by high K+, veratridine, and bradykinin. The
      sodium increase induced by DMPP was also inhibited by borneol with similar
      potency (49+/-12 microM), suggesting that the activity of nAChRs is inhibited by
      borneol. Borneol inhibited DMPP-induced secretion of [3H]norepinephrine with an
      IC(50) of 70+/-12 microM. Carbon-fiber amperometry also confirmed the inhibition
      of DMPP-induced exocytosis by borneol in single chromaffin cells. [3H]nicotine
      binding, however, was not affected by borneol. The inhibitory effect by borneol
      is more potent than the effect by lidocaine, a commonly used local anesthetic.
      The data suggest that borneol specifically inhibits the nAChR-mediated effects in
      a noncompetitive way.

PMID- 12473383
TI  - Modulation by caspases of tumor necrosis factor-stimulated c-Jun N-terminal
      kinase activation but not nuclear factor-kappaB signaling.
AB  - Tumour necrosis factor-alpha (TNF) is capable of activating many downstream
      signaling molecules via its two receptors TNFR1 and TNFR2. TNF can stimulate the
      proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) as well as
      the stress induced kinase c-Jun N-terminal kinase (JNK) through mechanisms that
      are not fully delineated. NF-kappaB becomes activated mainly through TNFR1 while
      JNK can be stimulated by either TNF receptor subtype. TNF can also induce
      apoptosis within cells due to its ability to recruit procaspase-8 to TNFR1, which
      in turn induces the caspase proteolytic cascade. We provide evidence here in
      human cells, that TNF-induced JNK activation is under the influence of caspases
      while NF-kappaB activity is not. By using pharmacological inhibitors of caspases,
      we have shown that JNK activity is reduced following caspase inhibition,
      especially when caspase-3 is targeted. NF-kappaB activity, as assessed by
      IkappaBalpha or IkappaBbeta degradation, electrophoretic mobility shift assay and
      NF-kappaB gene reporter assays, is shown to be unaffected by caspase inhibition.
      Therefore, downstream TNF receptor signaling events are differentially influenced
      by caspases.

PMID- 12473384
TI  - Evaluation of oxidative stress during apoptosis and necrosis caused by D
      galactosamine in rat liver.
AB  - Eighteen and twenty-four hours after intraperitoneal administration of D
      galactosamine (1g/kg body weight) to rats, the activity of caspase-3-like
      protease in the liver increased significantly compared with that in the control
      group given saline. Histological examinations including the in situ terminal
      deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method found
      apoptotic hepatocytes 18 hr after the administration of D-galactosamine. Caspase
      3 activity was barely detectable in the plasma of control rats, but increased
      significantly 24 hr after drug administration along with a dramatic increase in
      glutamate-oxaloacetate transaminase (GOT). These results indicated that D
      galactosamine causes apoptosis in the liver by activating caspase-3, which is
      released to the plasma by secondary necrosis. The concentration of lipid
      hydroperoxides in the liver increased significantly 24 hr after D-galactosamine
      administration. In contrast, the concentration of vitamin C in the liver
      decreased significantly 18 and 24 hr after D-galactosamine administration. These
      results suggest that D-galactosamine induces severe oxidative stress in the
      liver, leading to extensive necrosis.

PMID- 12473385
TI  - Preclinical factors influencing the relative contributions of Phase I and II
      enzymes to the metabolism of the experimental anti-cancer drug 5,6
      dimethylxanthenone-4-acetic acid.
AB  - It is important to determine the relative contribution of each metabolic pathway
      (f(p)) and of enzymes to the net metabolism of a drug. The aim of this study was
      to investigate, using a human liver bank, the f(p) of the anti-cancer drug 5,6
      dimethylxanthenone-4-acetic acid (DMXAA) and the effects of various inhibitors
      and inducers on f(p). The mean apparent K(m) and V(max) values (N=14) were 21+/-5
      microM and 0.04+/-0.02 nmol/min/mg, respectively, for 6-methylhydroxylation, and
      143+/-79 microM and 0.71+/-0.52 nmol/min/mg, respectively, for acyl
      glucuronidation in human liver microsomes. 6-Methylhydroxylation and acyl
      glucuronidation contributed 26 and 74%, respectively, to DMXAA metabolism at 5
      microM; values were 7 and 93% at 350 microM DMXAA. There was a significant
      relationship between the ratio of metabolic activity by Phase II and I reactions
      (R(II/I)) and uridine diphosphate glucuronosyltransferase (UGT2B7) protein level
      (r=0.605, P=0.022), whereas a reverse correlation between R(II/I) and cytochrome
      P450 (CYP1A) protein level was observed (r=-0.540, P=0.046). Various compounds
      inhibited either DMXAA glucuronidation or 6-methylhydroxylation, or both
      pathways. Pretreatment of rats with beta-naphthoflavone, but not phenobarbitone
      and cimetidine, increased the percentage of the contribution by 6
      methylhydroxylation to 17% from 4% of control at 5 microM DMXAA. Our results
      indicate that the f(p) of DMXAA is subject to substrate concentration,
      inhibition, induction, and the protein levels of enzymes that biotransform DMXAA.
      However, clinical studies are important to verify the conclusions drawn from in
      vitro data.

PMID- 12473386
TI  - Influence of p53 and p21(WAF1) expression on sensitivity of cancer cells to
      cladribine.
AB  - The present study was performed to gain insight into the role of p53 and
      p21(WAF1) on the cytotoxicity of the purine analogue cladribine (2-CdA) on cancer
      cells. Drug sensitivity, cell cycle distribution and drug-induced cell death were
      compared in three lines derived from the colorectal carcinoma HCT116: the p53+/+
      cell line containing wild-type p53 and the p53-/- and p21(WAF1)-/- lines, in
      which both alleles of p53 or p21(WAF1) were deleted by homologous recombination,
      respectively. p53-/- and p21(WAF1)-/- cells were significantly more resistant to
      the cytotoxic effects of 2-CdA than the p53+/+ cells. p53+/+ cells and p21(WAF1)
      /-, but not p53-/- cells, displayed wt-p53 protein accumulation and arrested in S
      phase after exposure to 2-CdA. mRNA analysis of the transporter hENT1 and of
      enzymes involved in drug metabolism did not show alterations which might explain
      a drug-resistant phenotype in the p53-/- or p21(WAF1)-/- cells. Exposure of
      p53+/+ cells to 2-CdA resulted in expression of p21(WAF1) mRNA and protein,
      enhanced expression of uncleaved PARP-1, and a higher degree both of apoptosis
      and necrosis than in p53-/- and p21(WAF1)-/- cells exposed to 2-CdA. Addition of
      the specific PARP-1 inhibitor 3-AB to 2-CdA-treated cells rendered p53+/+ cells
      resistant to this drug. Bax levels were reduced in the p53-/- while they
      increased in the p53+/+ line and remained stable in the p21(WAF1)-/- cells. We
      conclude that p53 and p21(WAF1) status of cancer cells influences their
      sensitivity to 2-CdA cytotoxicity. This may involve alterations in the apoptotic
      cascade as well as in PARP-1-dependent cell death.

PMID- 12473387
TI  - Neuronal death signaling by beta-bungarotoxin through the activation of the N
      methyl-D-aspartate (NMDA) receptor and L-type calcium channel.
AB  - The aim of this study was to elucidate the mechanism of the neurotoxic effect of
      beta-bungarotoxin (beta-BuTX, a snake presynaptic neurotoxin isolated from the
      venom of Bungarus multicinctus) on cultured cerebellar granule neurons. beta-BuTX
      exerted a potent, time-dependent, neurotoxic effect on mature granule neurons.
      Mature neurons, with an abundance of neurite outgrowths, were obtained after 7-8
      days in culture. By means of microspectrofluorimetry and fura-2, we measured the
      intracellular Ca(2+) concentration ([Ca(2+)](i)) and found it to be increased
      markedly. BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
      tertrakis(acetoxymethyl ester)], EGTA, MK801 (dizocilpine maleate), and diltiazem
      prevented not only the elevation of [Ca(2+)](i), but also the beta-BuTX-induced
      neurotoxic effect. The signaling pathway involved in the elevation of [Ca(2+)](i)
      in beta-BuTX-induced neurotoxicity was studied. The results obtained indicated
      that beta-BuTX initially increased the production of reactive oxygen species and
      subsequently reduced mitochondrial membrane potential and depleted ATP. All of
      these events in the signaling pathway were blocked by MK801, diltiazem, EGTA, and
      BAPTA-AM. These findings suggest that the neurotoxic effect of beta-BuTX is
      mediated, at least in part, by a cascade of events that include the direct or
      indirect activation of N-methyl-D-aspartate (NMDA) receptors and L-type calcium
      channels that, in turn, lead to Ca(2+) influx, oxidative stress, mitochondrial
      dysfunction, and ATP depletion. Therefore, we suggest that this polypeptide
      neurotoxin, as a result of its high potency and irreversible properties, is a
      useful tool to elucidate the mechanisms of neurodegenerative diseases.

PMID- 12473388
TI  - Pharmacology of vanilloids at recombinant and endogenous rat vanilloid receptors.
AB  - This study compared the actions of members of five different chemical classes of
      vanilloid agonists at the recombinant rat vanilloid VR1 receptor expressed in
      HEK293 cells, and at endogenous vanilloid receptors on dorsal root ganglion cells
      and sensory nerves in the rat isolated mesenteric arterial bed. In mesenteric
      beds, vanilloids elicited dose-dependent vasorelaxation with the rank order of
      potency: resiniferatoxin>>capsaicin=olvanil>phorbol 12-phenyl-acetate 13-acetate
      20-homovanillate (PPAHV)>isovelleral. Scutigeral was inactive. Responses were
      abolished by capsaicin pretreatment and inhibited by ruthenium red. In VR1-HEK293
      cells and dorsal root ganglion neurones, Ca(2+) responses were induced by
      resiniferatoxin>capsaicin=olvanil>PPAHV; all four were full agonists. Isovelleral
      and scutigeral were inactive. The resiniferatoxin-induced Ca(2+) response had a
      distinct kinetic profile. Olvanil had a Hill coefficient of approximately 1
      whilst capsaicin, resiniferatoxin and PPAHV had Hill coefficients of
      approximately 2 in VR1-HEK293 cells. The capsaicin-induced Ca(2+) response was
      inhibited in a concentration-dependent manner by ruthenium
      red>capsazepine>isovelleral. These data show that resiniferatoxin, capsaicin,
      olvanil and PPAHV, but not scutigeral and isovelleral, are agonists at
      recombinant rat VR1 receptors and endogenous vanilloid receptors on dorsal root
      ganglion neurones and in the rat mesenteric arterial bed. The vanilloids display
      the same relative potencies (resiniferatoxin>capsaicin=olvanil>PPAHV) in all of
      the bioassays.

PMID- 12473389
TI  - Evaluation of inherent performance of intelligent medical decision support
      systems: utilising neural networks as an example.
AB  - Researchers who design intelligent systems for medical decision support, are
      aware of the need for response to real clinical issues, in particular the need to
      address the specific ethical problems that the medical domain has in using black
      boxes. This means such intelligent systems have to be thoroughly evaluated, for
      acceptability. Attempts at compliance, however, are hampered by lack of
      guidelines. This paper addresses the issue of inherent performance evaluation,
      which researchers have addressed in part, but a Medline search, using neural
      networks as an example of intelligent systems, indicated that only about 12.5%
      evaluated inherent performance adequately. This paper aims to address this issue
      by concentrating on the possible evaluation methodology, giving a framework and
      specific suggestions for each type of classification problem. This should allow
      the developers of intelligent systems to produce evidence of a sufficiency of
      output performance evaluation.

PMID- 12473390
TI  - A multiple classifier system for early melanoma diagnosis.
AB  - Melanoma is the most dangerous skin cancer and early diagnosis is the key factor
      in its successful treatment. Well-trained dermatologists reach a diagnosis via
      visual inspection, and reach sensitivity and specificity levels of about 80%.
      Several computerised diagnostic systems were reported in the literature using
      different classification algorithms. In this paper, we will illustrate a novel
      approach by which a suitable combination of different classifiers is used in
      order to improve the diagnostic performances of single classifiers. We used three
      different kinds of classifiers, namely linear discriminant analysis (LDA), k
      nearest neighbour (k-NN) and a decision tree, the inputs of which are 38
      geometric and colorimetric features automatically extracted from digital images
      of skin lesions. Multiple classifiers were generated by combining the diagnostic
      outputs of single classifiers with appropriate voting schemata. This approach was
      evaluated on a set of 152 digital skin images. We compared the performances of
      multiple classifiers (2- and 3-classifier groups) between them and with respect
      to single ones (1-classifier group). We further compared the classifiers'
      performances with those of eight dermatologists. Classifiers' performances were
      measured in terms of distance from the ideal classifier. Compared with 1- and 2
      classifier groups, performances of 3-classifier systems were significantly higher
      (P<0.0005 and P<0.001, respectively). No statistically significant differences
      were found between the 1- and 2-classifier groups (P=0.352). While the
      dermatologists group showed a level of performances significantly higher than the
      1-classifier systems (P<0.020), no differences were found between the multiple
      classifier groups and the dermatologists groups, indicating comparable
      performances. This work suggests that a suitable combination of different kinds
      of classifiers can improve the performances of an automatic diagnostic system.

PMID- 12473391
TI  - A combined neural network and decision trees model for prognosis of breast cancer
      relapse.
AB  - The prediction of clinical outcome of patients after breast cancer surgery plays
      an important role in medical tasks such as diagnosis and treatment planning.
      Different prognostic factors for breast cancer outcome appear to be significant
      predictors for overall survival, but probably form part of a bigger picture
      comprising many factors. Survival estimations are currently performed by
      clinicians using the statistical techniques of survival analysis. In this sense,
      artificial neural networks are shown to be a powerful tool for analysing datasets
      where there are complicated non-linear interactions between the input data and
      the information to be predicted. This paper presents a decision support tool for
      the prognosis of breast cancer relapse that combines a novel algorithm TDIDT
      (control of induction by sample division method, CIDIM), to select the most
      relevant prognostic factors for the accurate prognosis of breast cancer, with a
      system composed of different neural networks topologies that takes as input the
      selected variables in order for it to reach good correct classification
      probability. In addition, a new method for the estimate of Bayes' optimal error
      using the neural network paradigm is proposed. Clinical-pathological data were
      obtained from the Medical Oncology Service of the Hospital Clinico Universitario
      of Malaga, Spain. The results show that the proposed system is an useful tool to
      be used by clinicians to search through large datasets seeking subtle patterns in
      prognostic factors, and that may further assist the selection of appropriate
      adjuvant treatments for the individual patient.

PMID- 12473392
TI  - Bagging tree classifiers for laser scanning images: a data- and simulation-based
      strategy.
AB  - Diagnosis based on medical image data is common in medical decision making and
      clinical routine. We discuss a strategy to derive a classifier with good
      performance on clinical image data and to justify the properties of the
      classifier by an adapted simulation model of image data. We focus on the problem
      of classifying eyes as normal or glaucomatous based on 62 routine explanatory
      variables derived from laser scanning images of the optic nerve head. As learning
      sample we use a case-control study of 98 normal and 98 glaucomatous subjects
      matched by age and sex. Aggregating multiple unstable classifiers allows
      substantial reduction of misclassification error in many applications and bench
      mark problems. We investigate the performance of various classifiers for the
      clinical learning sample as well as for a simulation model of eye morphologies.
      Bagged classification trees (bagged-CTREE) are compared to single classification
      trees and linear discriminant analysis (LDA). We additionally compare three
      estimators of misclassification error: 10-fold cross-validation, the 0.632+
      bootstrap and the out-of-bag estimate. In summary, the application of our
      strategy of a knowledge-based decision support shows that bagged classification
      trees perform best for glaucoma classification.

PMID- 12473393
TI  - Midpoints for fuzzy sets and their application in medicine.
AB  - Using Kosko's hypercube, we identify a fuzzy set with a point in a unit
      hypercube. A non-fuzzy or crisp subset of a set is a vertex of the hypercube. We
      introduce some new ideas: the definition of the fuzzy segment joining two given
      fuzzy subsets of a set, the set of midpoints between those two fuzzy subsets, and
      the set of equidistant points from given points. We present some basic properties
      and relations between these concepts and provide a complete description of fuzzy
      segments and midpoints. In the majority of cases, there is no unique midpoint;
      one has an infinite set of possibilities to choose from. This situation is
      totally different from classical Euclidean geometry where, for two given points,
      there is a unique midpoint. We use the obtained results to study two sets of
      medical data and present two applications in medicine: the fuzzy degree of two
      concurrent food and drug addictions, and a fuzzy representation of concomitant
      causal mechanisms of stroke.

PMID- 12473395
TI  - Movement disorders in the tropics.
AB  - The spectrum of movement disorders in the tropics is different from that seen in
      the industrialized nations of the west. This is not surprising given the unique
      combination of environmental and population characteristics in the tropics.
      Infections seldom encountered in the west such as tuberculous meningitis, typhoid
      fever, Japanese encephalitis, malaria, trypanosomiasis or cysticercosis are often
      seen in the tropics and with global patterns of travel and immigration these
      conditions are becoming more common worldwide. Movement disorders associated with
      these infections, HIV, slow virus and prion disease are discussed. Taking into
      account the diverse etiologies of movement disorders in the tropics, movement
      disorders with a nutritional basis such as the infantile tremor syndrome,
      seasonal ataxia and tropical ataxic neuropathy, and manganese neurotoxicity are
      also reviewed. Finally, certain special characteristics of ubiquitous disorders
      such as Parkinson's disease, and disorders with a genetic basis such as Wilson's
      disease and spinocerebellar degeneration are described.

PMID- 12473396
TI  - Adaptation to changes in vertical display gain during handwriting in Parkinson's
      disease patients, elderly and young controls.
AB  - Parkinson's disease (PD) patients, matched elderly controls, and normal young
      subjects were tested using a visuo-motor adaptation paradigm in which the gain of
      the vertical component of the visual feedback of handwriting was manipulated in
      real-time. Handwriting was performed on a digitizer tablet and displayed in real
      time on a computer screen in front of the participant. Vision of the hand and pen
      was occluded. Feedback could be normal (pre- and post-exposure conditions),
      smaller, or larger than the actual handwriting (exposure conditions). All groups
      showed a gradual adaptation that compensated for the distorted visual feedback
      during the exposure conditions. Moreover, all the groups showed significant after
      effects during the post-exposure conditions suggesting that all the participants
      learned to compensate for the novel display gains. Taken together, these data
      suggest that the mechanisms for visuo-motor adaptation to changes in vertical
      display gain during handwriting are robust to aging and early stage of PD. These
      results may have implications for the treatment of micrographia in Parkinsonism.

PMID- 12473397
TI  - H reflex threshold in Parkinson's disease patients for different stimulus
      duration.
AB  - Electrical stimulus, with duration starting at 0.1 ms and gradually increased to
      1.0 ms, was used for eliciting the H reflex in 14 normal subjects and 19 patients
      with Parkinson's disease (PD). In 71.1% of normal subjects and in 13.2% of PD
      patients the H reflex to M response threshold ratio (H/M TR) was <1 and the H
      reflex was obtained before the M response for all duration stimuli. For all
      stimulus durations a significant difference between the H/M TR in normal subjects
      and PD patients was found (t test 0.002-0.007). The duration effect was found to
      be highly significant-H/M TR for short stimulus duration was greater than for
      long stimulus durations (p<0.001). The optimal stimulus duration for evaluating H
      reflex behavior in PD patient was 0.2 ms. These very significant differences in
      behavior of the H reflex in PD patients could be used as another parameter in the
      assessment of extrapyramidal rigidity in PD patients.

PMID- 12473398
TI  - The relationship between knowledge of results and motor learning in Parkinsonian
      patients.
AB  - A simple timing movement was used to investigate augmented feedback on motor
      learning in Parkinson's disease (PD) patients and controls. During acquisition,
      participants received knowledge of results (KR) about their errors after every
      trial (100%) or every fifth trial (20%). Participants then performed a retention
      test without KR. Controls performed better on the retention test after having had
      20% KR during acquisition. PDs showed superior retention with 100% KR. This
      suggests that the PD patients are more reliant on KR for learning motor skills; a
      difference that may be attributable to reduced proprioceptive acuity in PD
      patients.

PMID- 12473399
TI  - The frequency and significance of 'striatal toe' in parkinsonism.
AB  - A striatal toe has been defined as an apparent extensor plantar response, without
      fanning of the toes, in the absence of any other signs suggesting dysfunction of
      the cortico-spinal tract. Little is known about the frequency and significance of
      this sign in parkinsonian syndromes. We prospectively examined 62 patients
      (Parkinson's disease: other akinetic-rigid syndromes=38:24) for the presence or
      absence of striatal toe and extensor plantar responses, as defined by Babinski.
      Details of the history, physical findings and investigations previously
      undertaken were rated and examined for their relevance to the response obtained
      from the hallux. Of the 62 patients, 17 patients showed an upgoing plantar
      response, of whom 13 (Parkinson's disease: other akinetic-rigid syndromes=7:6)
      had striatal toes, either unilateral (10) or bilateral (3). The remaining four
      patients showed a classical Babinski sign (Parkinson's disease: other akinetic
      rigid syndromes=2:2). There was no lateralising relationship between lesions of
      the basal ganglia found on imaging and the side of the striatal toe, or the side
      of dyskinesias found at the time of examination. However, there appeared to be a
      greater frequency of dyskinesias and evidence of lesions involving the basal
      ganglia on imaging in patients with striatal toes compared with those who showed
      a plantar response other than upgoing. The possible relevance of these findings
      is discussed.

PMID- 12473400
TI  - Motor impairment in normal aging, clinically possible Parkinson's disease, and
      clinically probable Parkinson's disease: longitudinal evaluation of a cohort of
      prospective brain donors.
AB  - This study presents data on the antemortem evaluations of a cohort of individuals
      registered in a brain donation program. Clinical evaluation determined that many
      individuals were unaware they had clinical signs of Parkinson's disease (PD)
      (rest tremor, bradykinesia, rigidity). Quantitative motor testing (timed tapping
      test and Purdue pegboard test) revealed a graded reduction in performance in
      those clinically found to have clinically possible and clinically probable PD.
      Longitudinal examinations over 4 years revealed some individuals progressed from
      control to clinically possible PD and clinically possible PD to clinically
      probable PD. This study underscores the importance of longitudinal antemortem
      testing of prospective brain donors as well as the potential value of
      quantitative motor testing.

PMID- 12473401
TI  - Transient movement disorders and multiple sclerosis.
AB  - Movement disorders associated with multiple sclerosis (MS) are uncommon, except
      for tremor. We report two patients with relapsing-remitting MS, who developed
      either dystonia or chorea during clinical exacerbation of their MS. The movement
      disorders resolved during treatment with adrenocorticotropin hormone (ACTH).
      Acute exacerbations of MS may be associated with transient movement disorders,
      which are responsive to ACTH.

PMID- 12473402
TI  - Neuroleptic malignant-like syndrome after rapid switch from bromocriptine to
      pergolide.
AB  - Neuroleptic malignant-like syndrome (NMLS) occurred after rapid switch from
      bromocriptine to pergolide in a Parkinsonian patient. Although the underlying
      mechanisms are as yet obscure, we hypothesize that differences in dopamine
      receptor affinities between bromocriptine and pergolide may be involved. Long
      term treatment with bromocriptine may thus have induced plastic changes in
      intracellular signal processing in the nigrostriatal system, which resulted in
      reduced dopaminergic efficacy of pergolide. We recommend vigilant outpatient
      supervision during performance of rapid switchover from one dopamine agonist to
      another in advanced Parkinson's disease or in subjects with predisposing factors
      for onset of a neuroleptic malignant syndrome.

PMID- 12473403
TI  - Evolving spectrum of movement disorders in extrapontine and central pontine
      myelinolysis.
AB  - Extrapontine (EPM) and central pontine myelinolysis (CPM) are rare and frequently
      related to rapid correction of hyponatremia. We describe a 60-year-old woman who
      developed an unusual evolving spectrum of movement disorders secondary to EPM and
      CPM following intravenous sodium replacement therapy for severe hyponatremia. She
      presented initially with confusion, generalized coarse postural limb tremor,
      myoclonic jerks and quadriparesis. Subsequently her mental state improved and her
      tremor and weakness resolved. Over the following months, she developed
      progressive painful dystonia of her facial musculature and lower limbs. This
      gradually became generalized and associated with choreoathethosis in her limbs.
      In addition, she had increasing bradykinesia and rigidity, which responded poorly
      to levodopa treatment. Our case illustrates that while the myelin destruction
      occurs during the initial insult of the osmotic demyelinating process, its
      delayed clinical effects resulting from ineffective reorganization of neuronal
      structures may be progressive, evolve with time, and difficult to treat.

PMID- 12473404
TI  - A family with a tau P301L mutation presenting with parkinsonism.
AB  - We report a sib-pair with a tau P301L mutation. Unlike most previous cases with
      this mutation, parkinsonism, rather than dementing features were the predominant
      and presenting feature. We have also observed that the P301L mutation has
      occurred on the H1 tau haplotype background. The haplotype background may
      influence the disease phenotype since in many previous Caucasian families with
      the P301L mutation, the haplotype background has been H2.

PMID- 12473405
TI  - Mirtazapine in Parkinsonian tremor.

PMID- 12473407
TI  - Using carcinogenic potency ranking to assign air contaminants to emission
      classes.
AB  - Carcinogenic air contaminants are assigned to emission classes with different
      emission limits on the basis of their inhalation carcinogenic potency within the
      revised form of the German First General Administrative Regulation Pertaining to
      the Federal Emission Control Law (Technical Instructions on Air Quality Control
      TA Luft). Accordingly, compounds with high carcinogenic potency are regulated
      more strictly than less potent substances. The data on carcinogenic properties
      are heterogeneous. Twenty-five substances or substance groups have been
      scrutinized and a procedure has been developed to rank these chemicals according
      to their carcinogenic potency. For 14 substances well-founded unit risk estimates
      were available to allow assignment of these air contaminants to emission classes.
      Unit risk estimates for bromoethane, 2-butanone oxime, and o-toluidine were
      derived using the ED(10)/LED(10) method based on animal studies. For several
      substances no qualified unit risk estimates or carcinogenicity studies were
      available to estimate carcinogenic potency after inhalation. Carcinogenic potency
      of these substances was approximated using two simple methods, T25 and CELmin.

PMID- 12473408
TI  - Physiologically based pharmacokinetic (PBPK) models for nasal tissue dosimetry of
      organic esters: assessing the state-of-knowledge and risk assessment applications
      with methyl methacrylate and vinyl acetate.
AB  - Mathematical models have been developed to describe nasal epithelial tissue
      dosimetry with two compounds, vinyl acetate (VA) and methyl methacrylate (MMA),
      that cause toxicity in these tissues These models couple computational fluid
      dynamics (CFD) calculations that map airflow patterns within the nose with
      physiologically based pharmacokinetic (PBPK) models that integrate diffusion,
      metabolism, and tissue interactions of these compounds. Dose metrics estimated in
      these models for MMA and VA, respectively, were rates of MMA metabolism per
      volume of tissue and alterations in pH in target tissues associated with VA
      hydrolysis and metabolism. In this article, four scientists who have contributed
      significantly to development of these models describe the many similarities and
      relatively few differences between the MMA and VA models. Some differences arise
      naturally because of differences in target tissues, in the calculated measures of
      tissue dose, and in the modes of action for highly extracted vapors (VA) compared
      with poorly extracted vapors (MMA). A difference in the approach used to estimate
      metabolic parameters from human tissues provides insights into interindividual
      extrapolation and identifies opportunities for studies with human nasal tissues
      to enhance current risk assessments. In general, the differences in model
      structure for these two esters were essential for describing the biology of the
      observed responses and in accounting for the different measures of target tissue
      dose. This article is intended to serve as a guide for understanding issues of
      optimum model structure and optimal data sources for these nasal tissue dosimetry
      models. We also hope that it leads to greater international acceptance of these
      hybrid CFD/PBPK modeling approaches for improving risk assessment for many nasal
      toxicants. In general, these models predict either equivalent (VA) or lower (MMA)
      nasal tissue doses in humans compared with tissue doses at equivalent exposure
      concentrations in rats.

PMID- 12473409
TI  - Consumer exposure to fragrance ingredients: providing estimates for safety
      evaluation.
AB  - To fully apply already published procedures for the safety evaluation of
      fragrance ingredients, it is necessary to estimate exposure through different
      routes and leading to different potential endpoints. Worst-case scenario
      calculations indicate that deposition on the surface of the skin following use of
      cosmetics represents the major route of exposure to fragrance ingredients when
      conservative estimates for evaporation, rinsing, and other forms of product
      removal are employed. Hydroalcoholic perfumes and colognes deliver the highest
      dose after single product use. Surveys of formulas used in this type of product
      allow the calculation of average maximum or upper 97.5th percentile concentration
      of the ingredient in formulas. With this type of exaggeration, the use of
      estimates of "typical" cosmetic use can be maximized to take account of excessive
      consumption patterns for both short-term and long-term exposure estimates. In the
      latter case, multiple product use must be considered. Short-term exposure (single
      product doses) of an ingredient found at an average maximum use level of P% in
      fragrances is taken to be 0.2 x P% or 3P microg/cm(2). Using upper 97.5th
      percentile concentrations (P(97.5)) of individual ingredients in fragrances, the
      long-term exposure is taken to be P(97.5) x 2,547 microg/kg body wt/day. The
      estimates of long-term exposure incorporate a number of highly conservative
      assumptions (e.g., over a long period, every product used will contain a
      fragrance with this ingredient at this high (P(97.5)) level).

PMID- 12473410
TI  - Prediction of local irritant effects after repeated dermal and respiratory
      exposure to chemicals.
AB  - Health risks resulting from occupational exposure to chemicals are controlled by
      the establishment of acceptable dermal and respiratory exposure levels. Due to a
      lack of route-specific toxicity data, acceptable levels are frequently
      established by means of route-to-route extrapolation. A pitfall in route-to-route
      extrapolation is the occurrence of local effects. Often, the results of acute
      irritation studies are used to assess the likelihood of the occurrence of local
      effects also following repeated exposure and thereby the validity of route-to
      route extrapolation. We questioned this working practice and considered whether
      local effects observed in a given study are of any predictive value with respect
      to the occurrence of local effects after repeated exposure. Our database analysis
      indicates that substances inducing skin and/or eye irritation frequently induce
      local effects after repeated respiratory exposure. In contrast, observations made
      in any type of study show little or no positive predictive value for the
      occurrence of local effects after repeated dermal exposure. Notably, the absence
      of any indication of local effects in any type of study does not exclude the
      occurrence of local effects on repeated dermal or respiratory exposure. We
      conclude that the presumed reliability of route-to-route extrapolation in the
      absence of route-specific toxicity data can be questioned.

PMID- 12473411
TI  - Scientific criteria used for the development of occupational exposure limits for
      metals and other mining-related chemicals.
AB  - The scientific approaches employed by selected internationally recognized
      organizations in developing occupational exposure limits (OELs) for metals and
      other mining-related chemicals were surveyed, and differences and commonalities
      were identified. The analysis identified an overriding need to increase
      transparency in current OEL documentation. OEL documentation should adhere to
      good risk characterization principles and should identify (1) the methodology
      used and scientific judgments made; (2) the data used as the basis for the OEL
      calculation; and (3) the uncertainties and overall confidence in the OEL
      derivation. At least within a single organization, a consistent approach should
      be used to derive OELs. Opportunities for harmonization of scientific criteria
      were noted, including (1) consideration of severity in identification of the
      point of departure; (2) definition of the minimum data set; (3) approaches for
      interspecies extrapolation; (4) identification of default uncertainty factors for
      developing OELs; and (5) approaches for consideration of speciation and
      essentiality of metals. Potential research approaches to provide the fundamental
      data needed to address each individual scientific criterion are described.
      Increased harmonization of scientific criteria will ultimately lead to OEL
      derivation approaches rooted in the best science and will facilitate greater
      pooling of resources among organizations that establish OELs and improved
      protection of worker health.

PMID- 12473413
TI  - Impact of physiologically based pharmacokinetic modeling on benchmark dose
      calculations for TCDD-induced biochemical responses.
AB  - In risk assessment, noncancer risk is currently estimated using a no observed
      adverse effect level (NOAEL) from an experimental dose-response study, divided by
      uncertainty factors, to estimate a presumably safe level of human exposure. A
      benchmark dose approach, in which an effective dose (ED) resulting in a specified
      percentage increase over background for effects is estimated by empirical
      modeling, has been proposed as a replacement for the NOAEL methodology. The aim
      of this analysis is to compare methods for estimation of body burden resulting in
      a 1 or 10% maximum increase over background (BB(01) or BB(10)) for biochemical
      responses following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in
      female Sprague-Dawley rats. In one method, an ED resulting in a prespecified
      increase in response over background was estimated using average daily doses and
      an empirical Hill model. The ED was then converted to an equivalent body burden
      by a simple kinetic model assuming steady-state conditions, half-life of TCDD in
      the rat, and 100% absorption of TCDD. Alternatively, a mechanistic
      physiologically based pharmacokinetic (PBPK) model of TCDD in the rat was used to
      predict body burdens for administered doses. These PBPK-modeled body burdens were
      then used directly by the Hill model to calculate a BB(01) or BB(10). In general,
      the body burden values derived from EDs were within five-fold of BB(01) or BB(10)
      calculated from the PBPK model. BB(01) and BB(10) values from both methods were
      within two orders of magnitude of current human general population exposure to
      all dioxin-like compounds.

PMID- 12473412
TI  - Acute toxicity of carbonyl iron and sodium iron EDTA compared with ferrous
      sulfate in young rats.
AB  - According to the American Association of Poison Control Centers, exposures to
      excessive doses of iron supplements still occur in children less than 6 years of
      age. Since 1998, there has been one death among U.S. children in this age group.
      Exposures, including adverse events, to iron supplements and iron-containing
      vitamins for the years 1999 and 2000 were 23,215 and 24,249, respectively. To
      reduce the potential seriousness of such exposures, carbonyl iron (Fe(0)) has
      been suggested as a possible replacement for ferrous sulfate (FeSO(4)). Carbonyl
      Fe is a unique form of elemental iron because of its small particle size. It is
      highly bioavailable when used to correct iron deficiency anemia. There is also
      current interest in using sodium iron(III) ethylenediaminetetraacetate (NaFeEDTA)
      for food fortification. In this study both NaFeEDTA and carbonyl Fe were compared
      with FeSO(4), the most common form of iron for dietary supplements, to obtain
      information relevant to the acute toxicological profile in young rats. With
      FeSO(4) and NaFeEDTA, total liver nonheme iron increased with increasing dose,
      but the response was approximately 50% lower with NaFeEDTA compared with FeSO(4).
      Serum iron peaked at approximately 0.5 to 1 h for both FeSO(4) and carbonyl Fe,
      while NaFeEDTA was elevated up to 4 h. FeSO(4) had an LD(50) of 1.1 g Fe/kg and
      was approximately 45 times more toxic than carbonyl Fe, which had an LD(50)
      greater then 50 g Fe/kg. NaFeEDTA had an LD(50) of 1.3 g Fe/kg and, when compared
      with FeSO(4), had approximately the same level of toxicity.

PMID- 12473414
TI  - Population distribution of aldehyde dehydrogenase-2 genetic polymorphism:
      implications for risk assessment.
AB  - The role of genetic polymorphisms in modulating xenobiotic metabolism and
      susceptibility to cancer and other health effects has been suggested in numerous
      studies. However, risk assessments have generally not used this information to
      characterize population variability or adjust risks for susceptible subgroups.
      This paper focuses upon the aldehyde dehydrogenase-2 (ALDH2) system because it
      exemplifies the pivotal role genetic polymorphisms can play in determining enzyme
      function and susceptibility. Allelic variants in ALDH2 cause decreased ability to
      clear acetaldehyde and other aldehyde substrates, with homozygous variants
      (ALDH2*2/2) having no activity and heterozygotes (ALDH2*1/2) having intermediate
      activity relative to the predominant wild type (ALDH2*1/1). These polymorphisms
      are associated with increased buildup of acetaldehyde following ethanol ingestion
      and increased immediate symptoms (flushing syndrome) and long-term cancer risks.
      We have used Monte Carlo simulation to characterize the population distribution
      of ALDH2 allelic variants and inter-individual variability in aldehyde internal
      dose. The nonfunctional allele is rare in most populations, but is common in
      Asians such that 40% are heterozygotes and 5% are homozygote variants. The ratio
      of the 95th or 99th percentiles of the Asian population compared to the median of
      the U.S. population is 14- to 26-fold, a variability factor that is larger than
      the default pharmacokinetic uncertainty factor (3.2-fold) commonly used in risk
      assessment. Approaches are described for using ALDH2 population distributions in
      physiologically based pharmacokinetic-Monte Carlo refinements of risk assessments
      for xenobiotics which are metabolized to aldehyde intermediates (e.g., ethanol,
      toluene, ethylene glycol monomethyl ether).

PMID- 12473415
TI  - Reproductive effects of deltamethrin on male offspring of rats exposed during
      pregnancy and lactation.
AB  - The effects of low doses of deltamethrin administered to female rats on the
      reproductive system of male offspring were examined. The dams (n=10-12/group)
      were treated daily by oral gavage with 0, 1.0, 2.0, and 4.0 mg deltamethrin/kg
      from day 1 of pregnancy to day 21 of lactation. Maternal and reproductive outcome
      data and male sexual development landmarks were assessed. Fertility, sexual
      behavior, and a large number of reproductive endpoints, such as organ weights,
      sperm evaluations, testosterone concentration, and testicular histology were
      examined on adult male offsprings. No signs of maternal toxicity were detected at
      the dose levels tested. Significantly adverse effects were only seen on
      testicular and epididymal absolute weights and the diameter of seminiferous
      tubules in the group treated with the highest dose of deltamethrin (4.0 mg/kg).
      The results indicate that in utero and lactational exposure to deltamethrin may
      induce subtle changes in reproductive behavior and physiology of male offspring
      rats at dose levels that do not cause maternal toxicity.

PMID- 12473416
TI  - Chromate content versus particle size for aircraft paints.
AB  - Many industries rely on the corrosion inhibiting properties of chromate
      containing primer paints to protect metal from oxidation. However, chromate
      contains hexavalent chromium (Cr(6+)), a known human carcinogen. The
      concentration of Cr(6+) as a function of paint particle size has important
      implications to worker health and environmental release from paint facilities.
      This research examines Cr(6+) content as a function of particle size for three
      types of aircraft primer paints: solvent-based epoxy-polyamide, water-based epoxy
      polyamide, and solvent-based polyurethane. Cascade impactors were used to collect
      and separate paint particles based on their aerodynamic diameter, from 0.7 to
      34.1 microm. The mass of the dry paint collected at each stage was determined and
      an atomic absorption spectrometer was used to analyze for Cr(6+) content. For all
      three paints, particles less than 7.0 microm contained disproportionately less
      Cr(6+) per mass of dry paint than larger particles, and the Cr(6+)concentration
      decreased substantially as particle size decreased. The smallest particles, 0.7
      to 1.0 microm, contained approximately 10% of the Cr(6+) content, per mass of dry
      paint, compared to particles larger than 7.0 microm. The paint gun settings of
      air to paint ratio was found to have no influence on the Cr(6+) bias.

PMID- 12473417
TI  - Chromate dissociation from three types of paint particles.
AB  - Chromate-containing primer paints are used to inhibit corrosion on metal
      surfaces. Though chromate contains hexavalent chromium (Cr(6+)), a human
      carcinogen, there is little epidemiological evidence of increased lung cancer
      among spray painters. One reason may be that the paint matrix hinders the release
      of Cr(6+) from the paint particle during the time that the particle is within the
      lungs. This study measures the mass of Cr(6+) released from particles originating
      from three types of paint particles: solvent-borne epoxy, water-borne epoxy, and
      polyurethane. Impingers were used to collect paint particles into water and
      particles were held in the water at rest for 1 and 24 h residence times.
      Particles were then separated from the water by centrifugation. The supernatant
      was tested for dissolved Cr(6+), which was compared to the total Cr(6+)
      (dissolved Cr(6+) plus Cr(6+) in particles). The mean fractions of Cr(6+)
      released into the water after 1 and 24 hours for each primer averaged: 70 and 85
      (solvent epoxy), 74 and 84% (water epoxy), and 94 and 95% (polyurethane).
      Correlations between particle size and the fraction of Cr(6+) released indicate
      that smaller particles (<5 microm) release a larger fraction of Cr(6+) versus
      larger particles (>5 microm).

PMID- 12473418
TI  - Statistical procedures to test for linearity and estimate threshold doses for
      tumor induction with nonlinear dose-response relationships in bioassays for
      carcinogenicity.
AB  - Sublinear shapes of the dose-response curve in the low-dose range of toxicity
      testing are often postulated to be indicative of a no-effect threshold. We
      present statistical procedures to test sublinear dose responses in bioassays for
      carcinogenicity against the hypothesis of linearity and estimate a lower
      confidence limit for the dose at the postulated breakpoint. First, a control
      tumor incidence of 0 is assumed. Tumor incidence at dose 1 is allowed to range
      from 0 to 4 tumor-bearing animals (TBAs) in groups of 50 animals, dose 2 is
      assumed to result in a tumor incidence of 5-25 TBAs. The null hypothesis of a
      linear dose response is tested by (i) the likelihood ratio (LR) test and (ii) the
      minimum chi(2) (MC) method. Validation by simulation showed the MC method to be
      more conservative than the LR test. At the 5% level with MC, the following
      observed numbers of TBAs for the dose sequence 0-1-2 resulted in rejection of the
      hypothesis of linearity: 0-0-6, 0-1-10, 0-2-13, 0-3-16, 0-4-18. Second, the
      analysis was adapted to allow for a control tumor incidence of 0-4 TBAs/50 and a
      tumor incidence of 0-10 TBAs/50 at dose 1, and the minimum number of TBAs at dose
      2 to reject linearity at the 5% level was calculated. Third, a program is made
      available to analyze data derived from protocols that include nonstandard dose
      span and group size. Internet access to the respective statistics software and
      source file is provided. Examples for nasal tumor induction by formaldehyde and
      for the induction of renal adenocarcinoma by ochratoxin A are shown. The proposed
      analysis may be useful to test sublinear sections of the dose response for the
      possibility of a threshold for carcinogens and to define dose levels that could
      be used as a starting point for setting exposure standards.

PMID- 12473419
TI  - Effectiveness of a universal drug abuse prevention approach for youth at high
      risk for substance use initiation.
AB  - BACKGROUND: Universal school-based prevention programs for alcohol, tobacco, and
      other drug use are typically designed for all students within a particular school
      setting. However, it is unclear whether such broad-based programs are effective
      for youth at high risk for substance use initiation. METHOD: The effectiveness of
      a universal drug abuse preventive intervention was examined among youth from 29
      inner-city middle schools participating in a randomized, controlled prevention
      trial. A subsample of youth (21% of full sample) was identified as being at high
      risk for substance use initiation based on exposure to substance-using peers and
      poor academic performance in school. The prevention program taught drug refusal
      skills, antidrug norms, personal self-management skills, and general social
      skills. RESULTS: Findings indicated that youth at high risk who received the
      program (n = 426) reported less smoking, drinking, inhalant use, and polydrug use
      at the one-year follow-up assessment compared to youth at high risk in the
      control condition that did not receive the intervention (n = 332). Results
      indicate that a universal drug abuse prevention program is effective for
      minority, economically disadvantaged, inner-city youth who are at higher than
      average risk for substance use initiation. CONCLUSIONS: Findings suggest that
      universal prevention programs can be effective for a range of youth along a
      continuum of risk.

PMID- 12473420
TI  - The effect of intensified diet counseling on the diet of hypertensive subjects in
      primary health care: a 2-year open randomized controlled trial of lifestyle
      intervention against hypertension in eastern Finland.
AB  - BACKGROUND: Diet is an essential part of the nonpharmacological management of
      hypertension. The aim of this study was to investigate in a primary health care
      setting the effect of intensified diet counseling on the diet of hypertensive
      subjects. METHODS: A total of 715 free-living subjects, ages 25-74 years, with
      systolic blood pressure 140-179 mm Hg and/or diastolic blood pressure 90-109 mm
      Hg and/or drug treatment for hypertension participated in an open randomized
      trial with a 2-year follow-up at health centers in eastern Finland. The
      intervention group (n = 360) was advised to reduce their total fat, saturated
      fat, and salt intake and to increase monounsaturated and polyunsaturated fat
      intake as well as to reduce weight and to use alcohol in moderation if at all.
      The usual care group (n = 355) continued with their usual primary health care.
      The subjects filled out a 4-day food record, and 24-h urine samples were
      collected at baseline and at 1- and 2-year examinations. RESULTS: The 2-year net
      changes (change in intervention minus change occurring in usual care group) in
      total fat intake [-2.7 E% (95% CI -4.0, -1.6; P < 0.0005)], in saturated fatty
      acid intake [-1.7 E% (95% CI -2.3, -1.1; P < 0.0005)], and in body weight [-1.4
      kg (95% CI -2.0, -0.8; P < 0.0005)] were significant. Furthermore, the 2-year net
      change in daily sodium intake was significant, -9 mmol (95% CI -17, -2; P =
      0.021), but the 24-h urinary sodium excretion showed no difference between the
      study groups. CONCLUSION: The intensified diet counseling in primary health care
      resulted in dietary changes interpreted as being of benefit in the long-term
      treatment of hypertension and prevention of atherosclerotic vascular diseases.

PMID- 12473421
TI  - Controlled comparison of retention and adherence in home- vs center-initiated
      exercise interventions in women ages 40-65 years: The S.W.E.A.T. Study (Sedentary
      Women Exercise Adherence Trial).
AB  - BACKGROUND: In an 18-month exercise intervention in previously sedentary older
      women (40-65 years), we examined whether an initial 6 months of supervised
      exercise leads to greater long-term retention and adherence to regular physical
      activity than an unsupervised home-based program and whether these outcomes are
      influenced by the exercise intensity. METHODS: Women (N = 126) were recruited
      from the community and randomly assigned to either center-based or home-based
      exercise three times/week. The center-based group attended supervised sessions
      for 6 months, while after 10 initial sessions the home-based group exercised at
      home. After 6 months both groups were home-based for a further 12 months. Within
      each arm, subjects were further randomized to exercise at either moderate or
      vigorous intensity. RESULTS: The center-based group had higher retention than the
      home-based (97, 94, 81 versus 87, 76, and 61%) at 6, 12, and 18 months,
      respectively (P < 0.05). At 6 months, adherence was higher in the center-based
      group (84 versus 63%, P < 0.001) and energy expenditure was higher at 6 (P <
      0.05) and 12 (P < 0.01) months. At 18 months, retention was higher with moderate
      exercise (P < 0.05), while adherence was similar with both intensities.
      CONCLUSION: An initial 6 months of center-based exercise enhanced retention in
      both the short and the long term and promoted short-term adherence and energy
      expenditure. Long-term, moderate exercise retained more subjects, but had little
      influence on adherence.

PMID- 12473422
TI  - Effects of ethnicity, family income, and education on dietary intake among
      adolescents.
AB  - BACKGROUND: The aim of the study is to describe the overall diet and potential
      effects of gender, ethnicity, family income, and parents' education on dietary
      patterns in adolescents aged 11 to 20 years who participated in a cohort study in
      12 Southern California communities. METHODS: A validated 131-item
      youth/adolescent food frequency questionnaire was administrated among 3,201
      participants in the Children's Health Study at follow-up visits between 1998 and
      2000. Sociodemographic characteristics included ethnicity, family income, and
      parents' education. Stratified analysis and analysis of covariance were used to
      describe the intakes of selected nutrients and food groups. RESULTS: Mean intakes
      for all nutrients except calcium met 100% of the Recommended Dietary Allowances.
      Average daily food intakes were below the minimum recommended number of servings
      for all major food groups. The majority of subjects had an excessive intake of
      added sugar. A gender difference was found in intakes of energy, total fat (TF),
      saturated fat (SF), monounsaturated fat (MUSF), and calcium (P < 0.05). Non
      Hispanic Whites had the lowest intakes of fruits while Blacks and Asians had
      significantly higher intakes of vegetables (P < 0.05). Subjects from higher
      income families had significantly higher intakes of polyunsaturated fat, protein,
      calcium, and folate and more frequently consumed dairy products. Intakes of TF,
      SF, MUSF, and cholesterol decreased as parents' education levels increased.
      Subjects from families with parents who had higher educational attainment were
      more likely to meet the recommendations of dairy products, fruits, and
      vegetables. CONCLUSION: Overall, subjects in our study did not have healthy
      eating habits. Dietary patterns varied by sex, ethnicity, income, and education.

PMID- 12473423
TI  - Does physician weight affect perception of health advice?
AB  - BACKGROUND: Obesity is considered a growing health threat in the United States.
      Although physicians have an important role in counseling their patients for
      obesity prevention and treatment, physicians themselves are often overweight.
      There are few data regarding how physician body weight might affect patient
      receptiveness to obesity counseling. METHODS: A 43-item survey instrument was
      developed that consisted of three scales related to physician characteristics,
      health locus of control, and perceptions on receiving health advice from
      overweight physicians. The survey was administered to 226 patients in five
      physician offices. Two of the physicians were classified as obese using BMI
      calculations, and three were nonobese. The responses from the surveys were
      grouped into those from obese and nonobese physicians. RESULTS: Significant
      differences were found for patient receptiveness to counseling for treatment of
      illness (P = 0.038) and health advice (P = 0.049), with the patients of nonobese
      physicians indicating greater confidence scores. The difference for weight and
      fitness counseling did not reach significance (P = 0.075). Analysis revealed that
      patient BMI was not a significant covariate nor were items related to physician
      characteristics in general or health locus of control. CONCLUSIONS: Patients
      seeking care from nonobese physicians indicated greater confidence in general
      health counseling and treatment of illness than patients seeing obese physicians.
      It is not known if this can be translated into increased success in obesity
      prevention and treatment.

PMID- 12473424
TI  - Evaluation of a healthy-lifestyle approach to weight management.
AB  - BACKGROUND: Obesity and overweight have reached near-epidemic proportions in the
      United States. There is a need to further investigate intervention strategies
      designed to help individuals manage their weight by improving diet and exercise
      behaviors. We designed a multidisciplinary weight management program that
      included healthy eating, regular exercise, and behavioral changes based on the
      Transtheoretical Model. The program focused on a healthy lifestyle rather than
      weight loss. METHODS: Overweight and obese adults (n = 144; BMI = 32.5 +/- 3.8)
      participated in a 6-month clinic-based weight management program. The first 3
      months of the program were intense (twice weekly for 2 h) followed by 3 months of
      reduced clinical contact. Assessments completed at baseline, 3 months, and 6
      months included weight, body composition, BMI, total cholesterol, HDL-C, LDL-C,
      and 24-h diet recalls. VO(2max) was assessed at baseline and at 3 months.
      RESULTS: Subjects experienced significant decreases in weight, percentage body
      fat, BMI, total cholesterol, LDL-C, total caloric intake, and the percentage of
      energy intake from dietary fat as well as a significant increase in VO(2max) (P <
      0.05) at 3 months. Changes were maintained at 6 months, with weight, total
      cholesterol, and LDL-C demonstrating further improvement. CONCLUSIONS: A clinic
      based weight management program that focuses on lifestyle is successful at
      promoting changes in exercise and dietary behaviors. These changes appear to
      promote good health, as evidenced by moderate weight loss, increased
      cardiorespiratory fitness, and improved lipid profiles.

PMID- 12473425
TI  - Child-rearing attitudes and cardiovascular risk among children: moderating
      influence of parental socioeconomic status.
AB  - BACKGROUND: We examined associations of parental socioeconomic status (SES) and
      hostile maternal child-rearing attitudes with the insulin resistance syndrome
      (IRS) precursors in children. METHODS: The participants were 210 randomly
      selected healthy boys and girls who participated in the epidemiological
      Cardiovascular Risk in Young Finns study and who were 3, 6, and 9 years of age at
      the three study phases. Hostile maternal child-rearing attitudes were self-rated
      by the mothers. SES consisted of the years of education of the parents and family
      income. The IRS comprised serum insulin, high-density lipoprotein cholesterol,
      triglycerides, systolic blood pressure, and body mass index. RESULTS: Among boys,
      low parental SES and strict maternal discipline were associated with heightened
      somatic risk. Among girls, parental SES moderated the association between
      maternal child-rearing attitudes and somatic risk so that belonging to a high-SES
      family seemed to protect the girls against the adverse health effects of hostile
      mothering. CONCLUSIONS: The findings indicate that the psychosocial environment
      is differentially related to girls' and boys' somatic risk. It is concluded that
      belonging to high social class may buffer against childhood stress, while
      belonging to low social class may enhance vulnerability to stressors in
      childhood.

PMID- 12473426
TI  - Tea consumption and the prevalence of coronary heart disease in Saudi adults:
      results from a Saudi national study.
AB  - BACKGROUND: The aim of the study was to determine whether there was a
      relationship between tea consumption and the prevalence of coronary heart disease
      (CHD) in Saudi Arabia. METHODS: The relationship between tea consumption and the
      prevalence of CHD was investigated using multiple logistic regression analysis in
      the Saudi Coronary Artery Disease Study. A total of 3,430 men and women aged 30
      70 years was studied. RESULTS: Of the 3,430 subjects who were assigned a
      category, 6.3% were classified as having indications of CHD. Those who did drink
      more than 6 cups of tea (>480 mL) per day had a significantly lower prevalence of
      CHD than the nontea drinkers (P < 0.001). Adjustments for risk factors including
      age, gender, occupation, education, smoking, family history, blood lipids,
      diabetes, blood pressure, BMI, physical activity, and coffee and fat intake did
      not remove the significance (OR = 0.49; 95% CI = 0.24-0.96). There was a positive
      dose-response effect between tea consumption and CHD (P < 0.001) that was
      persistent after adjustment for various risk factors (P = 0.022). CONCLUSIONS:
      These findings support a potential protective effect of tea consumption in
      relation to CHD in this Saudi study in which all tea consumed was black tea.

PMID- 12473427
TI  - Understanding intention to undergo colonoscopy among intermediate-risk siblings
      of colorectal cancer patients: a test of a mediational model.
AB  - BACKGROUND: There is a need for research to identify factors influencing
      intentions to undergo colorectal cancer (CRC) screening among family members at
      risk for CRC. This study tested a mediational model primarily guided by Ronis'
      elaboration of the Health Belief Model in predicting intention to have colorectal
      cancer screening among siblings of individuals diagnosed with colorectal cancer
      prior to age 56 years. METHODS: Data were collected from 534 siblings of
      individuals diagnosed with CRC. A baseline survey was administered by telephone.
      Measures included perceived susceptibility, CRC severity, physician and family
      support for CRC screening, cancer-specific distress, the closeness of the
      relationship with the affected sibling, and future intention to have a
      colonoscopy. Participant age, gender, and number of prior colonoscopies, as well
      as the stage of the affected patient's cancer and time from the patient's
      diagnosis to the interview, were controlled for in the analyses. RESULTS: The
      proposed model was not a good fit to the data. A respecified model was fit to the
      data. In this model, physician support, family support, and sibling closeness
      were significantly associated with both perceived benefits and barriers.
      Perceived severity was associated with barriers. Benefits and barriers, as well
      as cancer-specific distress, were directly associated with colonoscopy
      intentions. Results were consistent with a mediational role for benefits and
      barriers in the associations of sibling closeness and with a mediational role for
      barriers in the association between perceived severity and colonoscopy
      intentions. Family and physician support impacted intentions both directly and
      indirectly through effects on benefits and barriers. Perceived risk was not
      associated with benefits, barriers, or colonoscopy intentions. CONCLUSION:
      Intervention efforts to increase colonoscopy intentions may benefit from
      targeting family influences, particularly the affected proband in the family, as
      well as physician influence, cancer-related distress, perceived CRC severity, and
      perceived benefits and barriers to colonoscopy.

PMID- 12473428
TI  - Correlates of underutilization of colorectal cancer screening among U.S. adults,
      age 50 years and older.
AB  - BACKGROUND: Although effective screening for colorectal cancer (CRC) exists, only
      37% of incident CRC are diagnosed at a localized stage at which treatment is
      effective. We identified demographic and other characteristics of adults (> or =
      50 years old) who reported no CRC screening. METHODS: We calculated the
      prevalence of never having had a fecal occult blood test and/or a sigmoidoscopy
      or colonoscopy by age, sex, and other factors using the 1999 Behavioral Risk
      Factor Surveillance System data. RESULTS: CRC screening tests were underutilized
      across all segments of the population. Underutilization was highest in persons
      aged 50-64 years and those with lower education and a lack of health insurance
      and preventive services. CONCLUSIONS: The data indicate that large proportions of
      average-risk adults across various sociodemographics and behavioral factors are
      not utilizing recommended CRC screening tests. There is a need to increase the
      awareness of the importance of utilizing effective CRC screening tests for the
      early detection of colorectal cancers.

PMID- 12473429
TI  - What smokers believe about light and ultralight cigarettes.
AB  - OBJECTIVES: To assess the knowledge of smokers and ex-smokers about light
      cigarettes and nicotine yields and their perception of the risk of lung cancer,
      and to identify the characteristics of smokers of light cigarettes. METHODS: Mail
      survey in a population sample of 494 smokers and exsmokers in Geneva,
      Switzerland, in 1999. RESULTS: Participants were on average 40 years old, and 49%
      were men. They estimated that one would have to smoke two light cigarettes or
      four ultralight cigarettes in order to inhale the same amount of nicotine as that
      in one regular cigarette. Most participants (60%) answered that the risk of lung
      cancer was the same, but 27% answered that this risk was lower in smokers of
      light cigarettes than in smokers of regular cigarettes. The most frequent answer
      (41% of answers) to an open-ended question on the meaning of the number of
      milligrams of nicotine printed on cigarette packs was that this number indicated
      the nicotine content in cigarettes, rather than a machine-determined yield in
      smoke. In a multivariate model, smoking mild, light, or ultralight (vs regular)
      cigarettes was associated with females, a lower Fagerstrom dependence score, an
      intention to quit smoking, and an intention to decrease cigarette consumption.
      CONCLUSIONS: Many smokers choose light cigarettes because they think that such
      cigarettes are safer or less addictive. The public should be further informed of
      the meaning and purpose of cigarette labels.

PMID- 12473430
TI  - Household smoking bans: which households have them and do they work?
AB  - BACKGROUND: This study characterized Oregon households according to type and
      degree of restrictions on smoking and explored whether smoking restrictions are
      associated with decreased environmental tobacco smoke (ETS) exposure. METHODS: A
      population-based, random-digit-dialed cross-sectional telephone survey of 6,199
      adult Oregonians was performed in 1997 to provide baseline data on tobacco use in
      Oregon. RESULTS: Seventy percent of Oregon households were composed of nonsmokers
      only, and 85% of those had a full ban on smoking inside the home. Of the
      households containing one or more smokers, 38% had a full household ban on
      smoking. Among respondents with a full ban in place, 99% of nonsmoker-only
      households reported that no one smoked in the home in the previous month,
      compared with 91% of households with at least one smoker. In both nonsmoker-only
      households and those with at least one smoker, full bans were strongly associated
      with awareness of the harm of ETS (OR = 12.8, 95% CI 7.3-22.3, and OR = 6.6, 95%
      CI 3.6-12.3, respectively). The presence of children in the household was also
      closely associated with full bans in the two types of households (OR = 4.6, 95%
      CI 2.8-7.6, and OR = 3.0, 95% CI 2.1-4.4, respectively). Nevertheless, 50% of
      households with children and a smoker present did not have a full ban in place.
      CONCLUSIONS: While the prevalence of household smoking restrictions is high in
      Oregon, there remains room for improvement, since 50% of households with a smoker
      and a child present do not have a full ban on indoor smoking. Public health
      messages that focus on household smoking restrictions may help protect nonsmokers
      from exposure to ETS.

PMID- 12473431
TI  - Questionnaire or objective assessment for studying exposure to tobacco smoke
      among asthmatic and healthy children: The French VESTA Study.
AB  - BACKGROUND: The underreporting of environmental tobacco smoke (ETS) exposure by
      parents of study children may depend on the instrument used and population
      studied, underlining the need for questionnaire validation in specific study
      settings. This study explores the validity of parent-reported ETS exposure in a
      French multicenter study on asthma. METHODS: The study population was composed of
      313 children ages 4 to 14 years. Exposure to ETS was evaluated both by
      questionnaires on recent ETS exposure and by assessment of urinary cotinine by an
      enzyme immunoassay. RESULTS: According to parents' reports, about one-third of
      children were exposed to ETS within the past 2 days before cotinine measurement,
      and on average 14.9 +/- 15.4 cigarette-equivalent were smoked in their homes. The
      mean urinary cotinine was 435 +/- 530 nmol/mol creatinine and increased with the
      reported number of cigarette-equivalents smoked at home but it did not differ
      between children registered as being exposed to 1-10 cigarettes and children
      registered as unexposed. Agreement between questionnaire and urinary cotinine was
      moderate to poor according to our correlation coefficient (0.22) and kappa
      coefficient (0.09). CONCLUSION: These results show that our questionnaire is not
      discriminating enough to distinguish between nonexposure and mild exposure, but
      reveals gradients of higher exposure.

PMID- 12473432
TI  - Smoking in Cape Town: community influences on adolescent tobacco use.
AB  - BACKGROUND: This paper examines the effect of pro- and antisocial opinions about
      communities on cigarette use by Black, Colored, and White 8th- and 11th-grade
      students in Cape Town, South Africa. METHODS: This analysis consists of 1,328
      students who completed a questionnaire in 1997 on sociodemographic
      characteristics, substance abuse, adolescent behaviors, and opinions about their
      communities. Structural equation modeling (SEM) was used to assess hypotheses
      related to the social development model positing direct and indirect associations
      between community constructs and smoking within the previous 31 days. RESULTS:
      White students had the highest proportion (36.3%, P < 0.01) of past-31-days
      smokers compared to Colored (29.7%) and Black (9.7%) students. SEM analysis
      showed that among all groups the strongest association (beta = 0.29, Whites, P <
      0.01; beta =.14, Coloreds, P < 0.01; beta = 0.05, Blacks, P < 0.05) with recent
      cigarette smoking was the personal knowledge of adults who engaged in antisocial
      behavior. CONCLUSIONS: Youth smoking behavior may be affected by antisocial adult
      behavior, subjective adult norms, and community affirmation. Thus, in addition to
      other factors, social norms and community influence should be considered in
      preventing adolescent smoking.

PMID- 12473433
TI  - Behavioral, demographic, and prior morbidity risk factors for accidental death
      among men: a case-control study of soldiers.
AB  - BACKGROUND: In the United States, the leading cause of death for young men is
      unintentional injury. The experience of the U.S. Army, because it comprises
      mostly young men, provides insights into factors associated with risk of
      accidental death. Between 1990 and 1998, accidents accounted for more than half
      of all deaths of men on active duty in the U.S. Army. METHODS: All men on active
      duty in the U.S. Army who died in an accident between 1990 and 1998 were included
      in the study. For each accidental death case, four randomly selected controls
      were also included, matched on gender and contemporaneous military service.
      RESULTS: In multivariate analyses, accidental death victims were more likely to
      be unmarried, limited to a high school education, in combat-specific occupations,
      veterans of a recent deployment, and previously hospitalized for an
      "injury/poisoning," "mental disorder," or "sign/symptom/ill-defined condition."
      Of behaviors reported on routine health risk assessments, the strongest predictor
      of a subsequent fatal accident was motorcycle use while the most excess deaths
      were attributable to consuming more than five alcoholic drinks per week.
      CONCLUSIONS: There are characteristics, experiences, and behaviors that predict
      accidental death risk. The findings may inform safety and health promotion
      programs aimed at young adults.

PMID- 12473434
TI  - Evidence for the requirement of T cell costimulation in the pathogenesis of
      natural Pneumocystis carinii pulmonary infection.
AB  - Pneumocystis carinii pneumonia (PCP) is a frequent and serious opportunistic
      infection in immunocompromized patients. Although the pathogenesis of PCP
      mediated lung injury is poorly understood, a central involvement of host
      inflammatory responses has been implicated. We have found that while the loss of
      specific T cell costimulatory signals increases susceptibility to the spontaneous
      pneumocystis infection, PCP-induced pulmonary injury (and subsequent morbidity
      and mortality) involves other intact costimulatory pathways. Mice that are
      genetically deficient for the costimulatory receptor CD154 (CD154 knockout (ko)
      mice) spontaneously developed PCP, consistent with the increased susceptibility
      of X-linked hyper IgM syndrome patients (caused by CD154 gene mutations) to P.
      carinii infection. In these mice PCP was manifested by progressive weight loss,
      dyspnea and death. In contrast, CD154 ko mice also genetically lacking ICAM1
      (CD154 koxICAM1 ko) or CD28 (CD154 koxCD28 ko) costimulatory receptors had later
      onset of weight loss and significantly prolonged survival. Although onset of
      infection and age-matched P. carinii organism burden were equivalent, the CD154
      single knockout mice had evidence of greater pulmonary inflammation vs. the
      double ko's. These findings suggest that costimulation-dependent T cell-mediated
      inflammation plays an important role in both susceptibility to and pathogenesis
      of PCP, and may identify potential molecular targets for novel immunomodulatory
      treatment approaches.

PMID- 12473435
TI  - Acid aspiration induces bacterial pneumonia by enhanced bacterial adherence in
      mice.
AB  - The issue of whether acid aspiration facilitates bacterial pneumonia caused by
      Pseudomonas aeruginosa by enhanced bacterial adherence was examined in mice.
      Survival or the number of bacteria in lung tissues was evaluated after an
      intratracheal challenge of hydrochloric acid (HCl), a sublethal dose of P.
      aeruginosa, or both in mice. Bacterial adherence to the tracheal epithelium after
      acid aspiration was also examined by scanning electron microscopy. A simultaneous
      intratracheal challenge of 50 microl of 10(-1) N HCl, but not 10(-2) to 10(-4) N
      HCl, combined with a sublethal dose of P. aeruginosa significantly increased the
      number of bacteria in the lung tissues and decreased survival, while all mice
      that received either HCl or P. aeruginosa survived. Significantly higher numbers
      of adherent bacteria on the tracheal epithelium were found in mice that received
      10(-1)N HCl, compared with mice that received HCl (10(-2) to 10(-4) N) or saline.
      These data indicate that acid aspiration induced airway epithelial injury and
      enhanced P. aeruginosa adherence to the epithelium, and led to the subsequent
      development of bacterial pneumonia in mice. Enhanced bacterial adherence on the
      acid-injured epithelium may explain fatal bacterial pneumonias in patients with
      respiratory aspiration of gastric contents.

PMID- 12473436
TI  - Signature Tagged Mutagenesis of Haemophilus influenzae identifies genes required
      for in vivo survival.
AB  - The pathogenic bacterium Haemophilus influenzae causes meningitis, epiglottitis,
      pneumonia, otitis media and other infections. To further understand the genetic
      basis of invasive disease and to inform about the bacterium's requirements in an
      in vivo environment, we analysed a library of 1632 insertional Tn1545 -Delta3
      transposon mutants for their capacity to cause systemic infection in an animal
      model. We identified 25 genes that are potentially essential for H. influenzae
      invasive disease, and are candidates for further exploratory research. Seven of
      the genes encode hypothetical proteins, the function of six of which could be
      tentatively assigned on the basis of functional motifs and low homology to other
      bacterial genes. Eleven genes encode central metabolic enzymes or transporters;
      eight encode proteins that interact with DNA or modify other proteins; and four
      encode enzymes involved in the elaboration of classical virulence determinants.
      Two genes have no known function. Independent mutagenesis of six of the 25 genes
      and determination of the competitive index confirmed that these genes are
      important or essential to the organism in an in vivo environment. This genome
      wide analysis has identified metabolic and other genes required during invasive
      disease, and the findings may lead to new interventions to prevent and treat H.
      influenzae infections.

PMID- 12473437
TI  - Membrane sorting during swimming internalization of Brucella is required for
      phagosome trafficking decisions.
AB  - Brucella infects macrophages by swimming internalization, after which it is
      enclosed in macropinosomes. We investigated the role of the uptake pathway in
      phagosome trafficking, which remains unclear. This study found membrane sorting
      during swimming internalization and is essential in intracellular replication of
      Brucella. The B. abortus virB mutant replicated intracellularly when it was in
      the macropinosome established by wild-type B. abortus that retained its ability
      to alter phagosome trafficking. Lipid rafts-associated molecules, such as GM1
      ganglioside, were selectively included into macropinosomes, but Rab5 effector
      early endosome autoantigen (EEA1) and lysosomal glycoprotein LAMP-1 were excluded
      from macropinosomes containing B. abortus induced by swimming internalization. In
      contrast, when the swimming internalization was bypassed by phorbol myristate
      acetate (PMA)-induced macropinocytosis, lipid raft-associated molecules were
      excluded, and EEA1 and LAMP-1 were included into macropinosomes containing
      bacteria. The phosphatidylinositol 3-kinase inhibitor wortmannin that inhibits
      PMA-induced macropinocytosis blocked internalization of virB mutant, but not of
      wild-type of B. abortus and wortmannin treatment did not affect intracellular
      replication. Our results suggest that membrane sorting requires swimming
      internalization of B. abortus and decides the intracellular fate of the
      bacterium, and that Brucella -induced macropinosome formation is a different
      mechanism from PMA-induced macropinocytosis.

PMID- 12473438
TI  - Protein A is a virulence factor in Staphylococcus aureus arthritis and septic
      death.
AB  - Staphylococcal protein A (SpA), a cell wall anchored protein of Staphylococcus
      aureus, has the ability to interact with several host components, possibly
      indicating a role as a virulence factor in S. aureus infections. In this study,
      the contribution of SpA to bacterial virulence was investigated in a murine model
      of S. aureus arthritis. Intravenous inoculation of S. aureus wild-type strain
      Newman gave rise to more severe arthritis and higher mortality than the isogenic
      spa mutant strain DU5873. The wild-type strain caused more in vitro spleen cell
      proliferation than the SpA-deficient strain. However, IL-6 and TNF-alpha levels
      were higher after stimulation with thespa mutant strain compared to the wild-type
      strain. To conclude, our results clearly indicate that SpA is a virulence factor
      of S. aureus in murine septic arthritis.

PMID- 12473439
TI  - Threats to women's human rights?

PMID- 12473440
TI  - Competencies for midwifery teachers.
AB  - Saving women's lives with cost-quality effective midwifery care is based on sound
      pre-service and ongoing education. Effective midwifery education requires
      competent, caring, and compassionate teachers. In this paper, I address the basic
      competencies required of midwives who teach others to be midwives. These
      competencies are important regardless of level of student taught, type of
      educational programme, or number of years of midwifery experience that learners
      bring to the educational setting. The competencies are based on the midwifery
      philosophy, values and model of care. Competent midwifery teachers must be
      competent midwifery clinicians for their primary role is to set the boundaries of
      safety for each level of learner. Formal preparation for teaching, understanding
      how adults learn, understanding how to develop an appropriate plan for learning
      (curriculum), and developing competency in a variety of teaching methods for both
      theory and clinical practice are included in the competencies discussed in this
      paper.

PMID- 12473441
TI  - Evaluation of satisfaction with midwifery care.
AB  - OBJECTIVE: to determine if there were differences in women's satisfaction with
      maternity care given by doctors and midwives. In addition a simple, six-question,
      satisfaction questionnaire was to be tested. DESIGN: a randomised controlled
      trial comparing two models of maternity care. SETTING: a tertiary referral centre
      in Alberta, Canada. PARTICIPANTS: one hundred and ninety four women with a low
      risk pregnancy were randomly assigned to either the midwife care, experimental
      group (n = 101), or the doctor care, control group (n = 93). INTERVENTIONS: a
      pilot midwifery programme was introduced into a maternity services delivery
      system that did not have established midwifery. MEASUREMENTS: women's
      satisfaction was measured, at two weeks postpartum, with the Labour and Delivery
      Satisfaction Index (LADSI), general attitudes toward the birth experience, also
      at two weeks postpartum; with the Attitudes about Labour and Delivery Experience
      (ADLE) questionnaire. Fluctuations in satisfaction were measured with a Six
      Simple Questions (SSQ) questionnaire at 36 weeks gestation and 48 hours, two and
      six weeks postpartum. FINDINGS: women in the midwife group reported significantly
      greater satisfaction and a more positive attitude toward their childbirth
      experience than women in the doctor group (p < 0.001). The SSQ demonstrated
      scores similar to the LADSI. Satisfaction in both groups was lowest at 36 weeks
      gestation and highest immediately postpartum. KEY CONCLUSIONS: women experiencing
      low-risk pregnancies were more satisfied with care by midwives than with care
      provided by doctors. Satisfaction scores were high for both groups and may have
      been lower for women in the doctor group as a result of disappointment with
      caregiver assignment as all women had sought midwifery care. The SSQ measures
      similar dimensions to the LADSI but the agreement is not strong enough to
      recommend its use as a substitute at this time. IMPLICATIONS FOR PRACTICE: the
      significantly higher satisfaction of the women with the care provided by the
      midwives together with better clinical outcomes reported elsewhere suggest that
      the option of midwifery care should be accessible as an option for all women in
      Canada. Further research is suggested to determine the usefulness of the SSQ.

PMID- 12473442
TI  - Violence against pregnant women will remain hidden as long as no direct questions
      are asked.
AB  - OBJECTIVE: to assess the experience, knowledge, attitudes and routines regarding
      violence against pregnant women among midwives working at antenatal clinics in
      the county of Vasterbotten, northern Sweden. DESIGN: five qualitative research
      interviews with midwives were conducted. In addition, questionnaires were sent to
      all midwives working at the antenatal clinics in the county. FINDINGS: the
      midwives, although very knowledgeable about and sensitive to pregnant women and
      their needs, still rarely revealed the occurrence of violence. Symptoms and
      signals of abuse may vary and are not easily recognised by an outsider. Among
      pregnant women registered at the antenatal clinic, the midwives roughly estimated
      that the frequency of known cases of physical and sexual abuse before and during
      the current pregnancy was 2.3 and 0.6%, respectively for the preceding calendar
      year. The local programme for antenatal care provided no guidelines regarding
      response to violence, no instruments for disclosure and no directions about
      support when confronted with an abused pregnant woman. The midwife did not
      usually ask any questions if she was merely suspicious but had no strong
      supporting evidence. In answering the questionnaire however, the midwives were
      positive towards asking every pregnant woman about abuse in approximately the
      same way as they asked about other issues already incorporated in the records.
      CONCLUSION: most likely the midwives in this study were disclosing only a
      fraction of the cases of abuse against women. Violence of this kind will probably
      remain hidden as long as the whole issue of violence is not included in the
      national recommendations or in the local programme for antenatal care.
      IMPLICATIONS FOR PRACTICE: there should be specific written recommendations in
      the national antenatal care programme to guide and support the midwives in
      questioning all pregnant women about violence. To achieve adequate and optimal
      assessment and intervention at the antenatal clinic, the midwives need to be
      given education and training and provided with a supportive professional network
      both for themselves and for the abused women.

PMID- 12473443
TI  - The cultural and social meanings of childbearing for Chinese and Scottish women
      in Scotland.
AB  - OBJECTIVE: to analyse the meanings that women gave to their childbearing
      experiences in order to provide some useful insights as to how their experiences
      might be improved. SETTING: maternity units in Scotland. DESIGN: four semi
      structured interviews with each of ten Chinese and ten Scottish women in their
      own language; and unstructured interviews with 45 health workers, women's
      relatives and their friends. FINDINGS: having children was meaningful to Scottish
      and Chinese women in Scotland in different ways which were related to their
      social positions, beliefs and practices involved and the change in social status
      on the birth of a child. Different meanings demanded different coping strategies
      in healthy childbearing. Scottish women took greater interest in their sense of
      control over their childbearing. Some Chinese women were experiencing more
      extensive cultural conflicts and changes as they tried to identify with the new
      culture, while the others were experiencing gradual changes over a period of time
      consciously or unconsciously. Both Chinese and Scottish women in the study were
      in a struggle between autonomy and control over their childbearing--between the
      mind and the body. CONCLUSION: childbearing is socially shaped and culturally
      specific. Maternity services need to consider ways in which cultural sensitive
      care can be provided to women in a multi-ethnic modern society.

PMID- 12473444
TI  - Hong Kong Chinese women's experiences of vaginal examinations in labour.
AB  - OBJECTIVE: to explore women's experiences during vaginal examinations in labour.
      DESIGN: qualitative with phenomenological approach. Data were collected by tape
      recorded open-ended interviews during the early postnatal period. DATA ANALYSIS:
      phenomenological hermeneutic analysis based upon Riceour's interpretation theory.
      PARTICIPANTS: a purposive sample of eight women post-delivery who had given birth
      vaginally and were able to speak and read Chinese. SETTING: a maternity unit of a
      University affiliated District General Hospital in Hong Kong. KEY FINDINGS: women
      accepted the necessity for vaginal examinations, but expressed the need to be
      able to trust that the examiner would respect them as individuals and try to
      maintain their dignity, perform the examination skillfully and communicate the
      findings to them. Pain and embarrassment were frequently experienced during
      vaginal examination. Women wanted to be supported during the examination by
      someone they knew and trusted; they appreciated practitioners who tried to
      minimise their physical and psychological discomfort. Some women felt embarrassed
      when examined by a male doctor, but the attitude and approach of the examiner was
      generally found to be more important than gender. IMPLICATIONS FOR PRACTICE:
      practitioners should be continuously aware of the need to show respect and
      consideration for the dignity of a woman undergoing vaginal examination in
      labour. Although this seems an obvious statement to make it is reiterated because
      some practitioners display insensitivity in this regard. Each woman should be
      treated with courtesy and respect, and her modesty protected by minimal exposure
      and examiners/examinations. Findings from the examination should be discussed
      with her. Practitioners should be aware of the cultural influences that may lead
      a woman to hide her pain during examination and should be alert for signs of
      this.

PMID- 12473445
TI  - The voices and concerns about prenatal testing of Cambodian, Lao and Vietnamese
      women in Australia.
AB  - OBJECTIVES: to examine how Cambodian, Lao and Vietnamese women experience
      prenatal testing and to examine their knowledge and communication with health
      care providers. SETTING: Melbourne Metropolitan Area, Victoria, Australia.
      DESIGN: an ethnographic study of childbearing and childrearing among women born
      in South-east Asia and now living in Melbourne, Australia reporting in-depth
      interviews with 67 women who had given birth in Australia. FINDINGS: nearly all
      the women had prenatal testing as advised by their doctors and their main
      concerns were about their unborn baby and the need to follow doctors' advice. The
      women felt 'indifferent' towards prenatal testing, perceiving it as a normal part
      of antenatal care in Australia. Despite agreeing to undertake prenatal testing,
      the women did not have adequate understanding of the tests. This may be due to
      lack of information per se or inadequate communication between health providers
      and women. IMPLICATIONS FOR PRACTICE: inevitably, the onus rests with the health
      care provider to ensure that all options available to women are understood, so
      that women can make a positive and informed choice regardless of their social or
      cultural background. This will lead to women's increased satisfaction with care
      during pregnancy.

PMID- 12473446
TI  - A delphi survey of midwives and midwifery students to identify non-midwifery
      duties.
AB  - AIM OF THE STUDY: to explore the skill mix requirements for the potential role of
      an unqualified midwifery assistant in the clinical setting. Using results from
      the study we report the difference between student midwives' and qualified
      midwives' perceptions of what constitute non-midwifery duties. DESIGN: a two
      round Delphi survey. SETTING: large maternity hospital in Ireland. PARTICIPANTS:
      population of midwives (n=194) and midwifery students (n=79). FINDINGS: the non
      midwifery duties identified were wide ranging and could be categorised under the
      headings of clerical, stock, porter, domestic and other basic-care-related
      duties. CONCLUSION: although no agreed definition of non-midwifery duty exists it
      can be seen that, through the process undertaken in this study, a definition is
      created. This suggests that the values and beliefs that qualified midwives and
      students hold regarding their role shapes the role of the care assistant.
      IMPLICATIONS FOR PRACTICE: the inclusion of perceptions from student and staff
      midwives enabled the researchers to compare and contrast similarities and
      differences regarding how these different parties constitute a non-midwifery
      duty. The process also gave respondents a sense of ownership and involvement in
      the development of the midwifery assistant role. In addition, this study has
      demonstrated the need for further clarification of how midwives perceive and
      understand their role.

PMID- 12473447
TI  - A salutogenic perspective could be of practical relevance for the prevention of
      smoking amongst pregnant women.
AB  - OBJECTIVE: to use empirical data to assess the theoretical relevance of using a
      salutogenic, instead of a pathogenic, perspective to prevent smoking during
      pregnancy. DESIGN: quantitative study, a questionnaire was completed during the
      first trimester of pregnancy and an interview was conducted after the baby was
      born. SETTING: a geographically defined area in the south-east of Sweden.
      PARTICIPANTS: all 395 women in the study area who were pregnant during the study
      period 1994-1995. FINDINGS: the women were categorised according to their smoking
      habits. A significant difference in the sense of coherence (SOC) score was shown
      between smoking and non-smoking women in indicators of bad health. Women who
      relapsed to smoking showed a lower level of SOC, particularly in the
      manageability component, than others. The SOC score was higher in the whole study
      group than in other comparable, non-pregnant populations. KEY CONCLUSIONS AND
      IMPLICATIONS FOR PRACTICE: a salutogenic perspective could be used in antenatal
      care as a basis for encouraging pregnant women to stop smoking. This could
      enhance the SOC by making smoking more understandable for the woman, by
      discussing smoking as a way of coping, and by encouraging the woman's own
      capacity and motivation to stop smoking. Starting a dialogue about smoking from
      the woman's point of view could do this, with the midwife and the woman exploring
      together the woman's thoughts about the smoking problem.

PMID- 12473448
TI  - Nucleic acid conformational changes essential for HIV-1 nucleocapsid protein
      mediated inhibition of self-priming in minus-strand transfer.
AB  - Reverse transcription of the HIV-1 genome is a complex multi-step process. HIV-1
      nucleocapsid protein (NC) is a nucleic acid chaperone protein that has been shown
      to greatly facilitate the nucleic acid rearrangements that precede the minus
      strand transfer step in reverse transcription. NC destabilizes the highly
      structured transactivation response region (TAR) present in the R region of the
      RNA genome, as well as a complementary hairpin structure ("TAR DNA") at the 3'
      end of the newly synthesized minus-strand strong-stop DNA ((-) SSDNA). Melting of
      the latter structure inhibits a self-priming (SP) reaction that competes with the
      strand transfer reaction. In an in vitro minus-strand transfer system consisting
      of a (-) SSDNA mimic and a TAR-containing acceptor RNA molecule, we find that
      when both nucleic acids are present, NC facilitates formation of the transfer
      product and the SP reaction is greatly reduced. In contrast, in the absence of
      the acceptor RNA, NC has only a small inhibitory effect on the SP reaction. To
      further investigate NC-mediated inhibition of SP, we developed a FRET-based assay
      that allows us to directly monitor conformational changes in the TAR DNA
      structure upon NC binding. Although the majority ( approximately 71%) of the TAR
      DNA molecules assume a folded hairpin conformation in the absence of NC, two
      minor "semi-folded" and "unfolded" populations are also observed. Upon NC binding
      to the TAR DNA alone, we observe a modest shift in the population towards the
      less-folded states. In the presence of the RNA acceptor molecule, NC binding to
      TAR DNA results in a shift of the majority of molecules to the unfolded state.
      These measurements help to explain why acceptor RNA is required for significant
      inhibition of the SP reaction by NC, and support the hypothesis that NC-mediated
      annealing of nucleic acids is a concerted process wherein the unwinding step
      occurs in synchrony with hybridization.

PMID- 12473449
TI  - Structural studies of bacteriophage alpha3 assembly.
AB  - Bacteriophage alpha3 is a member of the Microviridae, a family of small, single
      stranded, icosahedral phages that include phiX174. These viruses have an ssDNA
      genome associated with approximately 12 copies of an H pilot protein and 60
      copies of a small J DNA-binding protein. The surrounding capsid consists of 60 F
      coat proteins decorated with 12 pentameric spikes of G protein. Assembly proceeds
      via a 108S empty procapsid that requires the external D and internal B
      scaffolding proteins for its formation. The alpha3 "open" procapsid structural
      intermediate was determined to 15A resolution by cryo-electron microscopy (cryo
      EM). Unlike the phiX174 "closed" procapsid and the infectious virion, the alpha3
      open procapsid has 30A wide pores at the 3-fold vertices and 20A wide gaps
      between F pentamers as a result of the disordering of two helices in the F capsid
      protein. The large pores are probably used for DNA entry and internal scaffolding
      protein exit during DNA packaging. Portions of the B scaffolding protein are
      located at the 5-fold axes under the spike and in the hydrophobic pocket on the
      inner surface of the capsid. Protein B appears to have autoproteolytic activity
      that cleaves at an Arg-Phe motif and probably facilitates the removal of the
      protein through the 30A wide pores. The structure of the alpha3 mature virion was
      solved to 3.5A resolution by X-ray crystallography and was used to interpret the
      open procapsid cryo-EM structure. The main differences between the alpha3 and
      phiX174 virion structures are in the spike and the DNA-binding proteins. The
      alpha3 pentameric spikes have a rotation of 3.5 degrees compared to those of
      phiX174. The alpha3 DNA-binding protein, which is shorter by 13 amino acid
      residues at its amino end when compared to the phiX174 J protein, retains its
      carboxy-terminal-binding site on the internal surface of the capsid protein. The
      icosahedrally ordered structural component of the ssDNA appears to be
      substantially increased in alpha3 compared to phiX174, allowing the building of
      about 10% of the ribose-phosphate backbone.

PMID- 12473450
TI  - Functional analysis of the glutathione S-transferase 3 from Onchocerca volvulus
      (Ov-GST-3): a parasite GST confers increased resistance to oxidative stress in
      Caenorhabditis elegans.
AB  - This study examined the genomic organisation of the coding region of the
      glutathione S-transferase 3 (Ov-GST-3) from the human parasitic nematode
      Onchocerca volvulus; alternative splicing leads to three different transcripts
      (Ov-GST-3/1; Ov-GST-3/2 and Ov-GST-3/3). Since the expression of Ov-GST-3 is
      inducible by oxidative stress, it is assumed that it is involved in the defense
      against reactive oxygen species (ROS) resulting from cellular metabolism.
      Furthermore, we suggest that Ov-GST-3 plays an important role in the protection
      of the parasite against ROS derived from the host's immune system. To
      experimentally investigate these speculations, we generated Caenorhabditis
      elegans lines transgenic for Ov-GST-3 (AK1) and examined their resistance to
      artificially generated ROS. The AK1 worms (extrachromosomal and integrated lines)
      were found to be much more resistant to internal (juglone) and external
      (hypoxanthine/xanthine oxidase) oxidative stress than wild-type C.elegans worms.
      RNA interference experiments targeted to the Ov-GST-3 transcripts resulted in
      decreased resistance, confirming that this effect is due to the transgenic
      expression of Ov-GST-3. These results clearly demonstrate that the Ov-GST-3 gene
      confers an increased resistance to oxidative stress. This study also shows the
      applicability of C.elegans as a model organism for the functional
      characterization of genes from (parasitic) nematode species which are not
      accessible to genetic manipulations.

PMID- 12473451
TI  - Interconversion of ATP binding and conformational free energies by tryptophanyl
      tRNA synthetase: structures of ATP bound to open and closed, pre-transition-state
      conformations.
AB  - Binding ATP to tryptophanyl-tRNA synthetase (TrpRS) in a catalytically competent
      configuration for amino acid activation destabilizes the enzyme structure prior
      to forming the transition state. This conclusion follows from monitoring the
      titration of TrpRS with ATP by small angle solution X-ray scattering, enzyme
      activity, and crystal structures. ATP induces a significantly smaller radius of
      gyration at pH=7 with a transition midpoint at approximately 8mM. A non
      reciprocal dependence of Trp and ATP dissociation constants on concentrations of
      the second substrate show that Trp binding enhances affinity for ATP, while the
      affinity for Trp falls with the square of the [ATP] over the same concentration
      range ( approximately 5mM) that induces the more compact conformation. Two
      distinct TrpRS:ATP structures have been solved, a high-affinity complex grown
      with 1mM ATP and a low-affinity complex grown at 10mM ATP. The former is
      isomorphous with unliganded TrpRS and the Trp complex from monoclinic crystals.
      Reacting groups of the two individually-bound substrates are separated by 6.7A.
      Although it lacks tryptophan, the low-affinity complex has a closed conformation
      similar to that observed in the presence of both ATP and Trp analogs such as
      indolmycin, and resembles a complex previously postulated to form in the closely
      related TyrRS upon induced-fit active-site assembly, just prior to catalysis.
      Titration of TrpRS with ATP therefore successively produces structurally distinct
      high- and low-affinity ATP-bound states. The higher quality X-ray data for the
      closed ATP complex (2.2A) provide new structural details likely related to
      catalysis, including an extension of the KMSKS loop that engages the second
      lysine and serine residues, K195 and S196, with the alpha and gamma-phosphates;
      interactions of the K111 side-chain with the gamma-phosphate; and a water
      molecule bridging the consensus sequence residue T15 to the beta-phosphate.
      Induced-fit therefore strengthens active-site interactions with ATP,
      substantially intensifying the interaction of the KMSKS loop with the leaving
      PP(i) group. Formation of this conformation in the absence of a Trp analog
      implies that ATP is a key allosteric effector for TrpRS. The paradoxical
      requirement for high [ATP] implies that Gibbs binding free energy is stored in an
      unfavorable protein conformation and can then be recovered for useful purposes,
      including catalysis in the case of TrpRS.

PMID- 12473452
TI  - The lonepair triloop: a new motif in RNA structure.
AB  - The lonepair triloop (LPTL) is an RNA structural motif that contains a single
      ("lone") base-pair capped by a hairpin loop containing three nucleotides. The two
      nucleotides immediately outside of this motif (5' and 3' to the lonepair) are not
      base-paired to one another, restricting the length of this helix to a single base
      pair. Four examples of this motif, along with three tentative examples, were
      initially identified in the 16S and 23S rRNAs with covariation analysis. An
      evaluation of the recently determined crystal structures of the Thermus
      thermophilus 30S and Haloarcula marismortui 50S ribosomal subunits revealed the
      authenticity for all of these proposed interactions and identified 16 more LPTLs
      in the 5S, 16S and 23S rRNAs. This motif is found in the T loop in the tRNA
      crystal structures. The lonepairs are positioned, in nearly all examples,
      immediately 3' to a regular secondary structure helix and are stabilized by
      coaxial stacking onto this flanking helix. In all but two cases, the nucleotides
      in the triloop are involved in a tertiary interaction with another section of the
      rRNA, establishing an overall three-dimensional function for this motif. Of these
      24 examples, 14 occur in multi-stem loops, seven in hairpin loops and three in
      internal loops. While the most common lonepair, U:A, occurs in ten of the 24
      LPTLs, the remaining 14 LPTLs contain seven different base-pair types. Only a few
      of these lonepairs adopt the standard Watson-Crick base-pair conformations, while
      the majority of the base-pairs have non-standard conformations. While the general
      three-dimensional conformation is similar for all examples of this motif,
      characteristic differences lead to several subtypes present in different
      structural environments. At least one triloop nucleotide in 22 of the 24 LPTLs in
      the rRNAs and tRNAs forms a tertiary interaction with another part of the RNA.
      When a LPTL containing the GNR or UYR triloop sequence forms a tertiary
      interaction with the first (and second) triloop nucleotide, it recruits a fourth
      nucleotide to mediate stacking and mimic the tetraloop conformation.
      Approximately half of the LPTL motifs are in close association with proteins. The
      majority of these LPTLs are positioned at sites in rRNAs that are conserved in
      the three phylogenetic domains; a few of these occur in regions of the rRNA
      associated with ribosomal function, including the presumed site of peptidyl
      transferase activity in the 23S rRNA.

PMID- 12473453
TI  - phi29 DNA polymerase residue Phe128 of the highly conserved (S/T)Lx(2)h motif is
      required for a stable and functional interaction with the terminal protein.
AB  - Bacteriophage phi29 encodes a DNA-dependent DNA polymerase belonging to the
      eukaryotic-type (family B) subgroup of DNA polymerases that use a protein as
      primer for initiation of DNA replication. By multiple sequence alignments of DNA
      polymerases from such a family, we have been able to identify two amino acid
      residues specifically conserved in the protein-priming subgroup of DNA
      polymerases, a phenylalanine contained in the (S/T)Lx(2)h motif, and a glutamate
      belonging to the Exo III motif. Here, we have studied the functional role of
      these residues in reactions that are specific for DNA polymerases that use a
      protein-primed DNA replication mechanism, by site-directed mutagenesis in the
      corresponding amino acid residues, Phe128 and Glu161 of phi29 DNA polymerase.
      Mutations introduced at residue Phe128 severely impaired the protein-primed
      replication capacity of the polymerase, being the interaction with the terminal
      protein (TP) moderately (mutant F128A) or severely (mutant F128Y) diminished. As
      a consequence, very few initiation products were obtained, and essentially no
      transition products were detected. Interestingly, phi29 DNA polymerase mutant
      F128Y showed a decreased binding affinity for short template DNA molecules. These
      results, together with the high degree of conservation of Phe128 residue among
      protein-primed DNA polymerases, suggest a functional role for this amino acid
      residue in making contacts with the TP during the first steps of genome
      replication and with DNA in the further replication steps.

PMID- 12473454
TI  - Quaternary structure of the European spiny lobster (Palinurus elephas) 1x6-mer
      hemocyanin from cryoEM and amino acid sequence data.
AB  - Arthropod hemocyanins are large respiratory proteins that are composed of up to
      48 subunits (8 x 6-mer) in the 75kDa range. A 3D reconstruction of the 1 x 6-mer
      hemocyanin from the European spiny lobster Palinurus elephas has been performed
      from 9970 single particles using cryoelectron microscopy. An 8A resolution of the
      hemocyanin 3D reconstruction has been obtained from about 600 final class
      averages. Visualisation of structural elements such as alpha-helices has been
      achieved. An amino acid sequence alignment shows the high sequence identity
      (>80%) of the hemocyanin subunits from the European spiny lobster P.elephas and
      the American spiny lobster Panulirus interruptus. Comparison of the P.elephas
      hemocyanin electron microscopy (EM) density map with the known P.interruptus X
      ray structure shows a close structural correlation, demonstrating the reliability
      of both methods for reconstructing proteins. By molecular modelling, we have
      found the putative locations for the amino acid sequence (597-605) and the C
      terminal end (654-657), which are absent in the available P.interruptus X-ray
      data.

PMID- 12473455
TI  - Engineering a new C-terminal tail in the H-site of human glutathione transferase
      P1-1: structural and functional consequences.
AB  - We have sought the structural basis for the differing substrate specificities of
      human glutathione transferase P1-1 (class Pi) and human glutathione transferase
      A1-1 (class Alpha) by adding an extra helix (helix 9), found in the electrophilic
      substrate-binding site (H-site) of the human class Alpha enzyme, at the C
      terminus of the human class Pi enzyme. This class Pi-chimera (CODA) was expressed
      in Escherichia coli, purified and characterized by kinetic and crystallographic
      approaches. The presence of the newly engineered tail in the H-site of the human
      Pi enzyme alters its catalytic properties towards those exhibited by the human
      Alpha enzyme, as assessed using cumene hydroperoxide (diagnostic for class Alpha
      enzymes) and ethacrynic acid (diagnostic for class Pi) as co-substrates. There is
      a change of substrate selectivity in the latter case, as the k(cat)/K(m)(EA)
      value decreases about 70-fold, compared to that of class Pi. With 1-chloro-2,4
      dinitrobenzene as co-substrate there is a loss of catalytic activity to about 2%
      with respect to that of the Pi enzyme. Crystallographic and kinetic studies of
      the class Pi-chimera provide important clues to explain these altered catalytic
      properties. The new helix forms many complimentary interactions with the rest of
      the protein and re-models the original electrophilic substrate-binding site
      towards one that is more enclosed, albeit flexible. Of particular note are the
      interactions between Glu205 of the new tail and the catalytic residues, Tyr7 and
      Tyr108, and the thiol moiety of glutathione (GSH). These interactions may provide
      an explanation of the more than one unit increase in the pK(a) value of the GSH
      thiolate and affect both the turnover number and GSH binding, using 1-chloro-2,4
      dinitrobenzene as co-substrate. The data presented are consistent with the
      engineered tail adopting a highly mobile or disordered state in the apo form of
      the enzyme.

PMID- 12473456
TI  - Crystal structure of a hypoallergenic isoform of the major birch pollen allergen
      Bet v 1 and its likely biological function as a plant steroid carrier.
AB  - Bet v 1l is a naturally occurring hypoallergenic isoform of the major birch
      pollen allergen Bet v 1. The Bet v 1 protein belongs to the ubiquitous family of
      pathogenesis-related plant proteins (PR-10), which are produced in defense
      response to various pathogens. Although the allergenic properties of PR-10
      proteins have been extensively studied, their biological function in plants is
      not known. The crystal structure of Bet v 1l in complex with deoxycholate has
      been determined to a resolution of 1.9A using the method of molecular
      replacement. The structure reveals a large hydrophobic Y-shaped cavity that spans
      the protein and is partly occupied by two deoxycholate molecules which are bound
      in tandem and only partially exposed to solvent. This finding indicates that the
      hydrophobic cavity may have a role in facilitating the transfer of apolar
      ligands. The structural similarity of deoxycholate and brassinosteroids (BRs)
      ubiquitous plant steroid hormones, prompted the mass spectrometry (MS) study in
      order to examine whether BRs can bind to Bet v 1l. The MS analysis of a mixture
      of Bet v 1l and BRs revealed a specific non-covalent interaction of Bet v 1l with
      brassinolide and 24-epicastasterone. Together, our findings are consistent with a
      general plant-steroid carrier function for Bet v 1 and related PR-10 proteins.
      The role of BRs transport in PR-10 proteins may be of crucial importance in the
      plant defense response to pathological situations as well as in growth and
      development.

PMID- 12473457
TI  - Assembly of amyloid protofibrils via critical oligomers--a novel pathway of
      amyloid formation.
AB  - The amyloid formation of phosphoglycerate kinase (PGK) was investigated by static
      and dynamic light-scattering. The time-course of the scattering intensity and the
      hydrodynamic radius scale with initial monomer concentration in a linear fashion
      over a range of about 50 in concentration. This sets limits on theories for
      aggregation kinetics that can be used, and points towards irreversible, cascade
      type models. In addition, circular dichroism (CD) was used to monitor the
      transition between a predominantly alpha-helical spectrum to a beta-sheet
      enriched one. The time-course of the CD also proves to scale linearly with
      initial monomer concentration. Electron microscopy shows that small oligomers as
      well as protofibrils are present during aggregation. The found coupling between
      growth of intermediates and acquisition of beta-sheet structure is interpreted in
      terms of a generalized diffusion-collision model, where stabilization of beta
      strands takes place by intermolecular interactions.

PMID- 12473458
TI  - Heat capacities and a snapshot of the energy landscape in protein GB1 from the
      pre-denaturation temperature dependence of backbone NH nanosecond fluctuations.
AB  - Protein stability is usually characterized calorimetrically by a melting
      temperature and related thermodynamic parameters. Despite its importance, the
      microscopic origin of the melting transition and the relationship between
      thermodynamic stability and dynamics remains a mystery. Here, NMR relaxation
      parameters were acquired for backbone 15NH groups of the 56 residue
      immunoglobulin-binding domain of streptococcal protein G over a pre-denaturation
      temperature range of 5-50 degrees C. Relaxation data were analyzed using three
      methods: the standard three-Lorentzian model free approach; the
      F(omega)=2omegaJ(omega) spectral density approach that yields motional
      correlation time distributions, and a new approach that determines frequency
      dependent order parameters. Regardless of the method of analysis, the temperature
      dependence of internal motional correlation times and order parameters is
      essentially the same. Nanosecond time-scale internal motions are found for all
      NHs in the protein, and their temperature dependence yields activation energies
      ranging up to about 33kJ/mol residue. NH motional barrier heights are
      structurally correlated, with the largest energy barriers being found for
      residues in the most "rigid" segments of the fold: beta-strands 1 and 4 and the
      alpha-helix. Trends in this landscape also parallel the free energy of folding
      unfolding derived from hydrogen-deuterium (H-D) exchange measurements, indicating
      that the energetics for internal motions occurring on the nanosecond time-scale
      mirror those occurring on the much slower time-scale of H-D exchange. Residual
      heat capacities, derived from the temperature dependence of order parameters,
      range from near zero to near 100J/mol K residue and correlate with this energy
      landscape. These results provide a unique picture of this protein's energy
      landscape and a relationship between thermodynamic stability and dynamics that
      suggests thermosensitive regions in the fold that could initiate the melting
      process.

PMID- 12473459
TI  - De novo backbone and sequence design of an idealized alpha/beta-barrel protein:
      evidence of stable tertiary structure.
AB  - We have designed, synthesized, and characterized a 216 amino acid residue
      sequence encoding a putative idealized alpha/beta-barrel protein. The design was
      elaborated in two steps. First, the idealized backbone was defined with geometric
      parameters representing our target fold: a central eight parallel-stranded beta
      sheet surrounded by eight parallel alpha-helices, connected together with short
      structural turns on both sides of the barrel. An automated sequence selection
      algorithm, based on the dead-end elimination theorem, was used to find the
      optimal amino acid sequence fitting the target structure. A synthetic gene coding
      for the designed sequence was constructed and the recombinant artificial protein
      was expressed in bacteria, purified and characterized. Far-UV CD spectra with
      prominent bands at 222nm and 208nm revealed the presence of alpha-helix secondary
      structures (50%) in fairly good agreement with the model. A pronounced absorption
      band in the near-UV CD region, arising from immobilized aromatic side-chains,
      showed that the artificial protein is folded in solution. Chemical unfolding
      monitored by tryptophan fluorescence revealed a conformational stability
      (DeltaG(H2O)) of 35kJ/mol. Thermal unfolding monitored by near-UV CD revealed a
      cooperative transition with an apparent T(m) of 65 degrees C. Moreover, the
      artificial protein did not exhibit any affinity for the hydrophobic fluorescent
      probe 1-anilinonaphthalene-8-sulfonic acid (ANS), providing additional evidence
      that the artificial barrel is not in the molten globule state, contrary to
      previously designed artificial alpha/beta-barrels. Finally, 1H NMR spectra of the
      folded and unfolded proteins provided evidence for specific interactions in the
      folded protein. Taken together, the results indicate that the de novo designed
      alpha/beta-barrel protein adopts a stable three-dimensional structure in
      solution. These encouraging results show that de novo design of an idealized
      protein structure of more than 200 amino acid residues is now possible, from
      construction of a particular backbone conformation to determination of an amino
      acid sequence with an automated sequence selection algorithm.

PMID- 12473460
TI  - The three-dimensional solution structure of NaD1, a new floral defensin from
      Nicotiana alata and its application to a homology model of the crop defense
      protein alfAFP.
AB  - NMR spectroscopy and simulated annealing calculations have been used to determine
      the three-dimensional structure of NaD1, a novel antifungal and insecticidal
      protein isolated from the flowers of Nicotiana alata. NaD1 is a basic, cysteine
      rich protein of 47 residues and is the first example of a plant defensin from
      flowers to be characterized structurally. Its three-dimensional structure
      consists of an alpha-helix and a triple-stranded antiparallel beta-sheet that are
      stabilized by four intramolecular disulfide bonds. NaD1 features all the
      characteristics of the cysteine-stabilized alphabeta motif that has been
      described for a variety of proteins of differing functions ranging from
      antibacterial insect defensins and ion channel-perturbing scorpion toxins to an
      elicitor of the sweet taste response. The protein is biologically active against
      insect pests, which makes it a potential candidate for use in crop protection.
      NaD1 shares 31% sequence identity with alfAFP, an antifungal protein from alfalfa
      that confers resistance to a fungal pathogen in transgenic potatoes. The
      structure of NaD1 was used to obtain a homology model of alfAFP, since NaD1 has
      the highest level of sequence identity with alfAFP of any structurally
      characterized antifungal defensin. The structures of NaD1 and alfAFP were used in
      conjunction with structure-activity data for the radish defensin Rs-AFP2 to
      provide an insight into structure-function relationships. In particular, a
      putative effector site was identified in the structure of NaD1 and in the
      corresponding homology model of alfAFP.

PMID- 12473461
TI  - Weak cooperativity in the core causes a switch in folding mechanism between two
      proteins of the cks family.
AB  - The human protein ckshs1 (cks1) is a 79 residue alpha/beta protein with low
      thermodynamic and kinetic stability. Its folding mechanism was probed by mutation
      at sites throughout the structure. Many of the mutations caused changes in the
      slope of the unfolding arm of the chevron plot. The effects can be rationalised
      in terms of either transition-state movement or native-state "breathing", and in
      either case, the magnitude of the effect enables the sequence of events in the
      folding reaction to be determined. Those sites that fold early exhibit a small
      perturbation, whilst those sites that fold late exhibit a large perturbation. The
      results show that cks1 folds sequential pairs of beta-strands first; beta1/beta2
      and beta3/beta4. Subsequently, these pairs pack against each other and onto the
      alpha-helical region to form the core. The folding process of cks1 contrasts with
      that of the homologue, suc1. The 113 residue suc1 has the same beta-sheet core
      structure but, additionally, two large insertions that confer much greater
      thermodynamic and kinetic stability. The more extensive network of tertiary
      interactions in suc1 provides sufficient enthalpic gain to overcome the entropic
      cost of forming the core and thus tips the balance in favour of non-local
      interactions: the non-local, central beta-strand pair, beta2/beta4, forms first
      and the periphery strands pack on later. Moreover, the greater cooperativity of
      the core of suc1 protects its folding from perturbation and consequently the
      slope of the unfolding arm of the chevron plot is much less sensitive to
      mutation.

PMID- 12473462
TI  - Structure of functional single AQP0 channels in phospholipid membranes.
AB  - Aquaporin-0 (AQP0) is the most prevalent intrinsic protein in the plasma membrane
      of lens fiber cells where it functions as a water selective channel and also
      participates in fiber-fiber adhesion. We report the 3D envelope of purified AQP0
      reconstituted with random orientation in phospholipid bilayers as single
      particles. The envelope was obtained by combining freeze-fracture, shadowing and
      random conical tilt electron microscopy followed by single particle image
      processing. Two-dimensional analysis of 2547 untilted images produced eight class
      averages exhibiting "square" and "octagonal" shapes with a continuum of
      variation. We reconstructed in 3D five class averages that best described the
      data set. The reconstructions ("molds") appeared as metal cups exhibiting
      external and internal surfaces. We used the internal surface of the mold to
      calculate the "imprints" that represent the AQP0 particles protruding from the
      hydrophobic core of the phospholipid bilayer. The complete envelope of the
      channel, formed by joining the square and octagonal imprints, described
      accurately the size, shape, oligomeric state, orientation, and molecular weight
      of the AQP0 channel inserted in the phospholipid bilayer. Rigid body docking of
      the atomic model of the aquaporin-1 (AQP1) tetramer showed that the freeze
      fracture envelope accounted for the conserved transmembrane domain (approximately
      73% similarity between AQP0 and AQP1) but not for the amino and carboxyl termini.
      We suggest that the discrepancy might reflect differences in the location of the
      amino and carboxyl termini in the crystal and in the phospholipid bilayer.

PMID- 12473463
TI  - Solution structure of a circular-permuted variant of the potent HIV-inactivating
      protein cyanovirin-N: structural basis for protein stability and oligosaccharide
      interaction.
AB  - The high-resolution solution structure of a monomeric circular permuted (cp)
      variant of the potent HIV-inactivating protein cyanovirin-N (CV-N) was determined
      by NMR. Comparison with the wild-type (wt) structure revealed that the observed
      loss in stability of cpCV-N compared to the wt protein is due to less favorable
      packing of several residues at the pseudo twofold axis that are responsible for
      holding the two halves of the molecule together. In particular, the N and C
      terminal amino acid residues exhibit conformational flexibility, resulting in
      fewer and less favorable contacts between them. The important hydrophobic and
      hydrogen-bonding network between residues W49, D89, H90, Y100 and E101 that was
      observed in wt CV-N is no longer present. For instance, Y100 and E101 are
      flexible and the tryptophan side-chain is in a different conformation compared to
      the wt protein. The stability loss amounts to approximately 2kcal/mol and the
      mobility of the protein is evident by fast amide proton exchange throughout the
      chain. Mutation of the single proline residue to glycine (P52G) did not
      substantially affect the stability of the protein, in contrast to the finding for
      wtCV-N. The binding of high-mannose type oligosaccharides to cpCV-N was also
      investigated. Similar to wtCV-N, two carbohydrate-binding sites were identified
      on the protein and the Man alpha1-->2Man linked moieties on the sugar were
      delineated as binding epitopes. Unlike in wtCV-N, the binding sites on cpCV-N are
      structurally similar and exhibit comparable binding affinities for the respective
      sugars. On the basis of the studies presented here and previous results on high
      mannose binding to wtCV-N, we discuss a model for the interaction between gp120
      and CV-N.

PMID- 12473464
TI  - Retrovirus capsid protein assembly arrangements.
AB  - During retrovirus particle assembly and morphogenesis, the retrovirus structural
      (Gag) proteins organize into two different arrangements: an immature form
      assembled by precursor Gag (PrGag) proteins; and a mature form, composed of
      proteins processed from PrGag. Central to both Gag protein arrangements is the
      capsid (CA) protein, a domain of PrGag, which is cleaved from the precursor to
      yield a mature Gag protein composed of an N-terminal domain (NTD), a flexible
      linker region, and a C-terminal domain (CTD). Because Gag interactions have
      proven difficult to examine in virions, a number of investigations have focused
      on the analysis of structures assembled in vitro. We have used electron
      microscope (EM) image reconstruction techniques to examine assembly products
      formed by two different CA variants of both human immunodeficiency virus type 1
      (HIV-1) and the Moloney murine leukemia virus (M-MuLV). Interestingly, two types
      of hexameric protein arrangements were observed for each virus type. One
      organizational scheme featured hexamers composed of putative NTD dimer subunits,
      with sharing of subunits between neighbor hexamers. The second arrangement used
      apparent NTD monomers to coordinate hexamers, involved no subunit sharing, and
      employed putative CTD interactions to connect hexamers. Conversion between the
      two assembly forms may be achieved by making or breaking the proposed symmetric
      NTD dimer contacts in a process that appears to mimic viral morphogenesis.

PMID- 12473465
TI  - Infection control in Sri Lanka.

PMID- 12473466
TI  - Demolition of a hospital building by controlled explosion: the impact on
      filamentous fungal load in internal and external air.
AB  - The demolition of a maternity building at our institution provided us with the
      opportunity to study the load of filamentous fungi in the air. External (nearby
      streets) and internal (within the hospital buildings) air was sampled with an
      automatic volumetric machine (MAS-100 Air Samplair) at least daily during the
      week before the demolition, at 10, 30, 60, 90,120, 180, 240, 420, 540 and 660 min
      post-demolition, daily during the week after the demolition and weekly during
      weeks 2, 3 and 4 after demolition. Samples were duplicated to analyse
      reproducibility. Three hundred and forty samples were obtained: 115 external air,
      69 'non-protected' internal air and 156 protected internal air [high efficiency
      particulate air (HEPA) filtered air under positive pressure]. A significant
      increase in the colony count of filamentous fungi occurred after the demolition.
      Median colony counts of external air on demolition day were significantly higher
      than from internal air (70.2 cfu/m(3) vs 35.8 cfu/m(3)) (P < 0.001). Mechanical
      demolition on day +4 also produced a significant difference between external and
      internal air (74.5 cfu/m(3) vs 41.7 cfu/m(3)). The counts returned to baseline
      levels on day +11. Most areas with a protected air supply yielded no colonies
      before demolition day and remained negative on demolition day. The
      reproducibility of the count method was good (intra-assay variance: 2.4
      cfu/m(3)). No episodes of invasive filamentous mycosis were detected during the
      three months following the demolition. Demolition work was associated with a
      significant increase in the fungal colony counts of hospital external and non
      protected internal air. Effective protective measures may be taken to avoid the
      emergence of clinical infections.

PMID- 12473467
TI  - An evaluation of the efficacy of Aqualox for microbiological control of
      industrial cooling tower systems.
AB  - A comprehensive sampling protocol was employed to evaluate the efficacy of
      Aqualox, a biocide based on electrochemically activated water, against
      legionellae and heterotrophic bacteria in two industrial cooling tower systems.
      Both of the towers in the study remained free from evidence of Legionella spp.
      contamination throughout a five-month evaluation period, despite the previously
      demonstrated presence of legionellae in one of the test towers, and in two other
      towers on the same site, at levels well in excess of UK Health and Safety
      Commission (HSC) Approved Code of Practice and Guidance (ACOP) upper action
      limits. Levels of heterotrophic bacteria were controlled below 10(4) cfu/mL in
      both towers throughout most of the trial. Results also provided indirect evidence
      of significant activity against biofilm bacteria, with biofilm removal beginning
      almost immediately after commissioning of the Aqualox treatment systems. The
      results were particularly encouraging as the two towers studied had a long
      history of poor microbiological control using conventional bromine-based biocide
      products. Significant differences were observed between laboratory measurements
      of total viable counts on frequent liquid samples and those obtained from dip
      slides following HSC recommendations.

PMID- 12473469
TI  - Environmental contamination during a carbapenem-resistant Acinetobacter baumannii
      outbreak in an intensive care unit.
AB  - During a three-month period in 1999, 25 strains of carbapenem resistant
      Acinetobacter baumannii were isolated from 12 of 170 hospitalized intensive care
      unit (ICU) patients, of which 16 were considered to be clinically significant.
      These strains were indistinguishable by biotyping and antibiograms, but
      genotyping was not performed. Appropriate antibiotic treatment, isolation
      precautions, and infection control education of the staff failed to halt the
      outbreak. Environmental contamination was therefore investigated, and A.
      baumannii was found out in 22 (39.3%) of 56 environmental samples obtained by
      swabbing. Different antibiotic sensitivity patterns were obtained in the majority
      of these isolates, but four (7.1%) of the strains were found to have the same
      sensitivity pattern as the strain causing the outbreak. As a result the ICU was
      closed, equipment and the environment cleaned, with hypochlorite and terminal
      disinfection carried out. No bacteria were grown on repeat environmental
      cultures. Environmental contamination has an important reservoir role in
      outbreaks of A. baumannii in ICUs and must be eradicated in order to overcome
      such outbreaks.

PMID- 12473468
TI  - An outbreak of Legionella longbeachae infection in an intensive care unit?
AB  - During a nine-day period, five patients in a 14-bed intensive care unit (ICU)
      were shown to have seroconverted with a four-fold or greater rise in serum
      antibody titre to Legionella longbeachae serogroup 1. A further two patients were
      observed to have high titres consistent with previous exposure but earlier serum
      samples were not available for comparison. No patients had antibody responses to
      Legionella pneumophila serogroups 1 and 2. L. longbeachae was not cultured from
      respiratory secretions from patients or from the environment within the unit.
      Legionella anisa was recovered from one cooling tower on the ninth floor of the
      tower block. The ICU is located on the first floor of the same tower and receives
      external air from two vents, one on the eastern and the other on the western
      aspect. All patients with serological evidence of L. longbeachae infection were
      concomitantly infected with multiresistant Staphylococcus aureus, and were
      located in bays on the eastern side of the unit. A large pigeon nest was
      discovered within 1-2 m of the eastern vent. Following removal of the birds'
      nest, no further cases were seen on routine screening of all patients within the
      unit over the next eight weeks. Alternatively, seroconversion may have been
      related to demolition of the adjacent nine-storey nurses home. This was begun one
      month before the first case was diagnosed and was completed four months later.
      The periodic northerly winds could have carried legionellae from the demolition
      site directly over the block housing the ICU and may have concentrated them near
      the eastern air vent. All patients had pneumonia, which was probably
      multifactorial in origin. There is some uncertainty whether the serological
      responses seen were an epiphenomenon or were truly indicative of infection with
      L. longbeachae.

PMID- 12473470
TI  - Source, carriers, and management of a Serratia marcescens outbreak on a pulmonary
      unit.
AB  - An outbreak of Serratia marcescens was seen on a pulmonary ward from September
      1999 until September 2000. During this period, there were two distinct clusters
      of S. marcescens isolation. In the first episode, September-October 1999, S.
      marcescens isolates with the same resistance pattern were isolated in 10
      patients. PFGE (pulsed-field gel electrophoresis) following digestion with SpeI
      confirmed that these isolates were identical. After an initial decline in the
      number of isolates, the incidence rose again in March 2000. The resistance
      pattern of these isolates differed from that in 1999. PFGE showed that most of
      the isolates in 2000 were identical and had replaced the previous strain (strain
      1). In the second episode, January-August 2000, 26 patients were colonized with
      the subsequent strain (strain 2). Three of these patients had serious clinical
      problems due to S. marcescens, two had bacteraemia and one empyema. In September
      2000, strain 2 was also detected in stock solutions for inhalation therapy. After
      discontinuation of the use of stock solutions and emphasizing hygienic measures,
      the outbreak resolved. The majority (68%) of the patients positive for S.
      marcescens suffered from COPD (chronic obstructive pulmonary disease). PFGE
      results suggest that several COPD patients were carriers of the same strain of S.
      marcescens for a prolonged time. Re-admission of these patients could have lead
      to re-introduction of the epidemic strains.

PMID- 12473471
TI  - Nosocomial transmission of Saccharomyces cerevisiae in bone marrow transplant
      patients.
AB  - Saccharomyces cerevisiae is an unusual cause of clinical infection. We describe
      three bone marrow transplant patients on a haematology unit who developed
      possible invasive disease with the organism. Two patients died and both these
      patients appeared to have a related strain of S. cerevisiae. Screening for S.
      cerevisiae from throat and stool samples revealed four further patients who were
      carriers. Genotyping of the invasive and carriage strains demonstrated an
      indistinguishable strain from patients who had been on the unit at the same time,
      suggesting cross-infection.

PMID- 12473472
TI  - Infection rates in surgical neonates and infants receiving parenteral nutrition:
      a five-year prospective study.
AB  - We performed a prospective, observational, cohort study on 208 surgical neonates
      and infants between 1992 and 1997. Surveillance cultures of the oropharynx and
      rectum were obtained at the start of parenteral nutrition and thereafter twice
      weekly. Blood cultures were taken on clinical indication only. Microbial
      translocation was diagnosed when the micro-organisms in the blood were not
      distinguishable from those carried in the oropharynx and/or rectum. Liver
      function was monitored weekly and when septicaemia was suspected. The incidence
      of septicaemia was 15%. The predominant micro-organisms (86%) were the low-level
      pathogens, coagulase-negative staphylococci and enterococci. Potential pathogens,
      including aerobic Gram-negative bacilli, were responsible for the remainder.
      Microbial translocation was responsible for 84% of septicaemic episodes in 76% of
      patients. The potential pathogens caused septicaemia significantly later than
      coagulase-negative staphylococci, at a time when liver function was significantly
      more impaired. In neonates and infants receiving parenteral nutrition,
      septicaemia is mainly a gut-derived phenomenon and requires novel strategies for
      prevention.

PMID- 12473473
TI  - A clinical trial of mupirocin in the eradication of methicillin-resistant
      Staphylococcus aureus nasal carriage in a digestive disease unit.
AB  - We assessed the incidence of nasal carriage of methicillin-resistant
      Staphylococcus aureus (MRSA) on admission, the rate of acquisition during the
      hospital stay and the relationship with subsequent infection in a digestive
      disease unit. The efficacy of a program of nasal carriage eradication with
      mupirocin was evaluated simultaneously. Over one year 484 patients were studied
      prospectively on admission for nasal and stool carriage of MRSA, then every week
      for nasal carriage. Nearly 70% (68.8%) of patients had chronic liver diseases.
      Nasal carriers were assigned to a five-day course of intranasal mupirocin
      ointment. One hundred and seventeen (24.2%) patients were MRSA positive, 57
      (11.8%) of which were carriers on admission and 60 (12.4%) acquired carriage. Of
      these, 86 were treated with mupirocin with a success rate of 98.8% and 25.9% of
      them recolonized. Fourteen patients were retreated, to allow eradication in 71.4%
      of cases. Seventy percent of these became carriers again. One high-level
      mupirocin-resistant strain was isolated before treatment and seven during or
      after treatment. Hospital stay and stool carriage were independently associated
      with reacquisition (P = 0.0105 and P = 0.0462, respectively). Molecular analysis
      showed identity between the strains isolated from infection samples and from
      nasal swabs during the same week. For every patient who became recolonized, nasal
      strains isolated before and after eradication were the same in 70% of cases.
      Mortality during hospital stay was independently associated with age (P =
      0.0081), MRSA nasal carriage (P = 0.02631), MRSA infection (P < 0.0001) and liver
      disease (P = 0.0017). This study did not show a change in the prevalence rate of
      infection in the unit during treatment with mupirocin. This treatment should only
      be attempted once due to the risk of emergence of high-level resistant strains.

PMID- 12473474
TI  - MRSA bacteraemia: North/South Study of MRSA in Ireland 1999.
AB  - Retrospective aggregate data on all Staphylococcus aureus isolates recovered from
      blood cultures during 1998 were collected in both jurisdictions on the island of
      Ireland, Northern Ireland (North) and the Republic of Ireland (South), as part of
      the North/South Study of MRSA in Ireland 1999. A postal questionnaire was used to
      gather the data, and all diagnostic microbiology laboratories in the North and
      98% of laboratories in the South participated. S. aureus bacteraemia occurred at
      rates of 20.4 per 100,000 population in the North and 24.5 per 100,000 in the
      South (missing data from one laboratory). In the North, 22% of patients who had
      blood cultures positive for S. aureus had methicillin-resistant S. aureus (MRSA)
      and 25% of S. aureus isolates were MRSA (some patients had more than one
      isolate). In the South, 31% of patients who had blood cultures positive for S.
      aureus had MRSA and 36% of S. aureus isolates were MRSA. There was a marked
      variation in rates between different regions. The percentage of patients with
      blood cultures positive for S. aureus that had MRSA was considerably lower in the
      North (22%) than in the South (31%), and in both jurisdictions was lower than
      that found in England and Wales in 1999 (37%). It is recommended that data on S.
      aureus bacteraemia and methicillin-resistance rates (already available in many
      laboratories) are gathered at regional and national level for the surveillance of
      antimicrobial resistance.

PMID- 12473475
TI  - Emergence of vancomycin-resistant Enterococcus faecium at a tertiary care
      hospital in Karachi, Pakistan.
AB  - Vancomycin-resistant enterococcus (VRE) has not been reported previously in
      Pakistan. This is the first report where in vancomycin-resistant Enterococcus
      faecium was isolated from the clinical specimens of six patients admitted to the
      intensive care unit (ICU) and neonatal intensive care unit (NICU) of the Aga Khan
      University Hospital, Karachi. To identify the extent of the outbreak, rectal
      swabs were obtained from all the patients admitted to the ICU and NICU at that
      time. A total of 10 strains of vancomycin-resistant Enterococcus faecium were
      isolated. All the strains showed high-level resistance to both glycopeptides
      (vancomycin and teicoplanin) with a vancomycin minimum inhibitory concentration
      greater than 256 mg/L. All isolates had the vanA gene detected by polymerase
      chain reaction. The contour-clamped homogeneous electric field (CHEF) pattern
      demonstrated that all but one of the isolates were of a single clone, suggesting
      that they were derived from common source. Use of vancomycin and prolonged
      hospitalization were common features in all cases investigated.

PMID- 12473476
TI  - Dermal tolerance and effect on skin hydration of a new ethanol-based hand gel.
AB  - We studied the dermal tolerance (repetitive occlusive patch test; ROPT) and the
      skin hydrating properties of a new ethanol-based gel [85% (w/w)], Sterillium Gel.
      For the ROPT, 53 participants were studied. Gel was applied to one site on the
      back under an occlusive patch during an induction phase (nine applications over
      three weeks) and two weeks later to a virgin site on the back during a challenge
      phase (one application). Twenty-four hours after the removal of the patches
      (induction phase and challenge phase), then 48 and 72 h later (challenge phase)
      sites were graded for skin reactions using a standardized scale. In the induction
      phase none of the 53 participants had a skin reaction. In the challenge phase one
      participant had a barely perceptible skin reaction, and one had mild erythema at
      one time point. To evaluate skin hydrating properties of the gel, treated skin of
      21 participants was compared to untreated skin. The gel was applied twice a day
      to the forearm for 14 days. Control corneometer values were taken before
      application of the gel (mean: 32.7 +/- 5.0) and after one (36.3 +/- 4.4) and two
      weeks (36.1 +/- 5.4). Relative skin hydration on treated skin in comparison with
      an untreated control field was significantly higher after one week by 6.85% (P =
      0.0031; paired t -test for dependent samples) and after two weeks by 4.47% (P =
      0.0153). Sterillium Gel did not demonstrate a clinically relevant potential for
      dermal irritation or sensitization, and significantly increased skin hydration
      after repetitive use, and so could enhance compliance with hand hygiene among
      healthcare workers.

PMID- 12473477
TI  - Placebo-controlled, double-blind, randomized study of prophylactic antibiotics in
      elective abdominal hysterectomy.
AB  - To assess the efficacy of a single dose of ampicillin or cefazolin in preventing
      fever and infection after elective abdominal hysterectomy, we conducted a
      multicentre, randomized, double-blind, controlled trial at Srinagarind Hospital,
      Faculty of Medicine, Khon Kaen University and Khon Kaen Regional Hospital. Three
      hundred and thirty patients scheduled for elective abdominal hysterectomy were
      randomly allocated into either placebo, ampicillin or cefazolin groups. Patients
      received sterile water (3 mL) or ampicillin (1 g) or cefazolin (1 g)
      intravenously according to random assignment 30 min before the operation. After
      the operation, all patients were assessed by blinded independent evaluators until
      discharged from the hospitals. Our main outcome measures were postoperative fever
      and infectious morbidity. We found that 321 patients (97.3% of recruited
      patients) were available for data analysis, 108 in placebo, 106 in ampicillin and
      107 in cefazolin group. Febrile morbidity occurred in 13/108 (12.0%), 14/106
      (13.2%) and 12/107 (11.2%) of patients in the placebo, ampicillin and cefazolin
      groups, respectively. There was no statistically significant difference in
      febrile morbidity between the three groups. Infectious morbidity was found in
      29/108 (26.9%), 24/106 (22.6%) and 11/107 (10.3%) of patients in the placebo,
      ampicillin and cefazolin groups, respectively. There was a statistically
      significant difference between the placebo and cefazolin groups (P = 0.002).
      Between the placebo and ampicillin groups, the result was not significantly
      different (P = 0.476). There was a statistically significant difference between
      the cefazolin and ampicillin groups (P = 0.015). The common causes of infectious
      morbidity were urinary tract infection, vaginal cuff infection and surgical wound
      infection. We concluded that antibiotic prophylaxis by cefazolin should be
      recommended for elective total abdominal hysterectomy.

PMID- 12473478
TI  - Rapid reduction of Staphylococcus aureus populations on stainless steel surfaces
      by zeolite ceramic coatings containing silver and zinc ions.
AB  - This study demonstrates the anti-Staphylococcus aureus properties of stainless
      steel surfaces coated with zeolite containing 2.5% silver and 14% zinc ions.
      Stainless steel panels with and without the heavy-metal-containing coatings were
      inoculated with S. aureus and incubated at room temperature. Survival of S.
      aureus was significantly reduced by the silver/zinc coatings within 1 h. Many
      hospital surfaces could be constructed of stainless steel with silver/zinc
      zeolite coatings. Such measures may reduce rates of hospital-acquired S. aureus
      infection.

PMID- 12473479
TI  - Comparison of bacterial colonization rates of antiseptic impregnated and pure
      polymer central venous catheters in the critically ill.
AB  - A study was performed on critically ill patients to evaluate the rate of
      colonization and catheter-related sepsis using antiseptic bonded (Arrowguard
      Arrow International) versus smooth pure polymer (Infectguard MedexMedical Ltd)
      central venous catheters. Two hundred and thirty-two catheters were inserted into
      181 patients. Indications for removal included local or systemic infection, the
      catheter was no longer required and patient death. No statistical difference in
      colonization rate was found between the two types of catheter.

PMID- 12473480
TI  - Bacterial contamination of ward-based computer terminals.

PMID- 12473481
TI  - Bacterial penetration vis-a-vis lint generation.

PMID- 12473482
TI  - Management of outbreaks of Gram-negative bacteria in neonatal units.

PMID- 12473483
TI  - An ecomorphological model of the initial hominid dispersal from Africa.
AB  - We use new data on the timing and extent of the early Pleistocene dispersal of
      Homo erectus to estimate diffusion coefficients of early Homo from Africa. These
      diffusion coefficients indicate more rapid and efficient dispersals than those
      calculated for fossil Macaca sp., Theropithecus darti, and Mesopithecus
      pentelicus. Increases in home range size associated with changes in ecology,
      hominid body size, and possibly foraging strategy may underlay these differences
      in dispersal efficiency. Ecological data for extant primates and human foragers
      indicate a close relationship between body size, home range size, and diet
      quality. These data predict that evolutionary changes in body size and foraging
      behavior would have produced a 10-fold increase in the home range size of H.
      erectus compared with that of the australopithecines. These two independent
      datasets provide a means of quantifying aspects of the dispersal of early Homo
      and suggest that rapid rates of dispersal appear to have been promoted by changes
      in foraging strategy and body size in H. erectus facilitated by changes in
      ecosystem structure during the Plio-Pleistocene.

PMID- 12473484
TI  - Morphological affinities of the Sal'a 1 frontal bone.
AB  - The human frontal bone from Sal'a, Slovak Republic, has previously entered into
      discussions of the morphological patterns of Central European Neandertals and the
      origins of early modern humans in that region. A morphological reassessment of
      its supraorbital region and a morphometric analysis of its overall proportions
      indicate that it falls well within expected ranges of variation of Late
      Pleistocene Neandertals and is separate from European earlier Upper Paleolithic
      early modern human crania. It is similar to the Qafzeh-Skhul sample in some
      metrical and supraorbital robusticity measures, but it contrasts with them in mid
      sagittal curvature and supraorbital torus morphology. In the context of its
      probable oxygen isotope stage 5 age based on inferred biostratigraphic
      associations, it should not be employed directly for arguments relating to the
      emergence of modern humans in Central Europe.

PMID- 12473485
TI  - U-Series dating of Liujiang hominid site in Guangxi, Southern China.
AB  - It has been established that modern humans were living in the Levant and Africa
      ca. 100ka ago. Hitherto, this has contrasted with the situation in China where no
      unequivocal specimens of this species have been securely dated to more than 30ka.
      Here we present the results of stratigraphic studies and U-series dating of the
      Tongtianyan Cave, the discovery site of the Liujiang hominid, which represents
      one of the few well-preserved fossils of modern Homo sapiens in China. The human
      fossils are inferred to come from either a refilling breccia or a primarily
      deposited gravel-bearing sandy clay layer. In the former case, which is better
      supported, the fossils would date to at least approximately 68ka, but more likely
      to approximately 111-139ka. Alternatively, they would be older than approximately
      153ka. Both scenarios would make the Liujiang hominid one of the earliest modern
      humans in East Asia, possibly contemporaneous with the earliest known
      representatives from the Levant and Africa. Parallel studies on other Chinese
      localities have provided supporting evidence for the redating of Liujiang, which
      may have important implications for the origin of modern humans.

PMID- 12473486
TI  - Male strategies and Plio-Pleistocene archaeology.
AB  - Archaeological data are frequently cited in support of the idea that big game
      hunting drove the evolution of early Homo, mainly through its role in offspring
      provisioning. This argument has been disputed on two grounds: (1) ethnographic
      observations on modern foragers show that although hunting may contribute a large
      fraction of the overall diet, it is an unreliable day-to-day food source, pursued
      more for status than subsistence; (2) archaeological evidence from the Plio
      Pleistocene, coincident with the emergence of Homo can be read to reflect low
      yield scavenging, not hunting. Our review of the archaeology yields results
      consistent with these critiques: (1) early humans acquired large-bodied ungulates
      primarily by aggressive scavenging, not hunting; (2) meat was consumed at or near
      the point of acquisition, not at home bases, as the hunting hypothesis requires;
      (3) carcasses were taken at highly variable rates and in varying degrees of
      completeness, making meat from big game an even less reliable food source than it
      is among modern foragers. Collectively, Plio-Pleistocene site location and
      assemblage composition are consistent with the hypothesis that large carcasses
      were taken not for purposes of provisioning, but in the context of competitive
      male displays. Even if meat were acquired more reliably than the archaeology
      indicates, its consumption cannot account for the significant changes in life
      history now seen to distinguish early humans from ancestral australopiths. The
      coincidence between the earliest dates for Homo ergaster and an increase in the
      archaeological visibility of meat eating that many find so provocative instead
      reflects: (1) changes in the structure of the environment that concentrated
      scavenging opportunities in space, making evidence of their pursuit more obvious
      to archaeologists; (2) H. ergaster's larger body size (itself a consequence of
      other factors), which improved its ability at interference competition.

PMID- 12473487
TI  - Leopard predation and primate evolution.
AB  - Although predation is an important driving force of natural selection its effects
      on primate evolution are still not well understood, mainly because little is
      known about the hunting behaviour of the primates' various predators. Here, we
      present data on the hunting behaviour of the leopard (Panthera pardus), a major
      primate predator in the Tai; forest of Ivory Coast and elsewhere. Radio-tracking
      data showed that forest leopards primarily hunt for monkeys on the ground during
      the day. Faecal analyses confirmed that primates accounted for a large proportion
      of the leopards' diet and revealed in detail the predation pressure exerted on
      the eight different monkey and one chimpanzee species. We related the species
      specific predation rates to various morphological, behavioural and demographic
      traits that are usually considered adaptations to predation (body size, group
      size, group composition, reproductive behaviour, and use of forest strata).
      Leopard predation was most reliably associated with density, suggesting that
      leopards hunt primates according to abundance. Contrary to predictions, leopard
      predation rates were not negatively, but positively, related to body size, group
      size and the number of males per group, suggesting that predation by leopards did
      not drive the evolution of these traits in the predicted way. We discuss these
      findings in light of some recent experimental data and suggest that the principal
      effect of leopard predation has been on primates' cognitive evolution.

PMID- 12473488
TI  - A new skeleton of Theropithecus brumpti (Primates: Cercopithecidae) from Lomekwi,
      West Turkana, Kenya.
AB  - A relatively complete skeleton of the fossil papionin, Theropithecus brumpti,
      from the site of Lomekwi, west of Lake Turkana, Kenya, is here described. The
      specimen, KNM-WT 39368, was recovered at the site of LO 5 (3 degrees 51'N and 35
      degrees 45'E), from sediments dated to approximately 3.3Ma. The skeleton is that
      of an old adult male and preserves a number of articulated elements, including
      most of the forelimbs and tail. The cranial morphology is that of a large, early
      T. brumpti, exhibiting a deep mandible with a deeply excavated mandibular corpus
      fossa, and mandibular alveoli and cheek teeth arrayed in a reversed Curve of
      Spee. The forelimb skeleton exhibits a unique mixture of characteristics
      generally associated with a terrestrial locomotor habitus, such as a narrow
      scapula and a highly stable elbow joint, combined with those more representative
      of habitual arborealists, such as muscle attachments reflecting a large rotator
      cuff musculature and a flexible shoulder joint. The forelimb of KNM-WT 39368 also
      presents several features, unique toTheropithecus, which represent adaptations
      for manual grasping and fine manipulation. These features include a large,
      retroflexed medial humeral epicondyle (to which large pronator, and carpal and
      digital flexor muscles attached) and proportions of the digital rays that denote
      capabilities for precise opposition between the thumb and index finger. Taken
      together, these features indicate that one of the earliest recognized
      representatives of Theropithecus exhibited the food harvesting and processing
      anatomy that distinguished the genus through time and that contributed to its
      success throughout the later Pliocene and Pleistocene. Based on the anatomy of
      KNM-WT 39368 and the known habitat preference of T. brumpti, the species is
      reconstructed as being a generally terrestrial but highly dexterous, very large
      bodied, sexually dimorphic, and possibly folivorous papionin. T. brumpti was
      adapted for propulsive quadrupedal locomotion over generally even ground, and yet
      was highly adept at manual foraging. The estimate of 43.8kg body mass for KNM-WT
      39368 renders unlikely the possibility that the species, or at least adult males
      of the species, were highly arboreal. T. brumpti, as represented by KNM-WT 39368,
      is seen as a large, colorfully decorated, and basically terrestrial papionin that
      was restricted to riverine forest habitats in the Lake Turkana Basin from the
      middle to latest Pliocene.

PMID- 12473489
TI  - Further research at the Oldowan site of Ain Hanech, North-eastern Algeria.
AB  - Further investigations were carried out at Ain Hanech, Algeria in 1998 and 1999
      to explore its potential for investigating early hominid behavioral patterns and
      adaptation. Research concentrated on the stratigraphy and dating, identifying new
      archaeological deposits, and excavating the Ain Hanech and El-Kherba localities.
      To enhance the chronological control within a biostratigraphic framework, the Ain
      Boucherit fossil-bearing stratum, yielding a Plio-Pleistocene fauna, is
      correlated with the regional stratigraphy. In the stratigraphic sequence, the Ain
      Boucherit stratum, located 13m below the Ain Hanech Oldowan occurrences, is found
      in Unit Q of the Ain Hanech Formation. Unit Q shows a paleomagnetically reversed
      polarity, which may be correlated with an age earlier than the Olduvai normal
      subchron (1.95-1.77Ma). Based on test trenches and stratigraphic analyses,
      additional Oldowan deposits A, B, and C are identified at Ain Hanech. All three
      deposits and the El-Kherba site contain Mode I technology artefacts associated
      with an Early Pleistocene fauna. El-Kherba is stratigraphically equivalent to Ain
      Hanech. These two archaeological sites are estimated to be dated to about 1.8Ma.

PMID- 12473492
TI  - Everything has its price.

PMID- 12473493
TI  - What went wrong with Iressa?

PMID- 12473495
TI  - Concurrent chemotherapy and radiation therapy reduce laryngectomy rates.

PMID- 12473496
TI  - Standard protocol helps improve ALL survival rates in India.

PMID- 12473502
TI  - Curry ingredient protects skin against radiation.

PMID- 12473505
TI  - Prostate-cancer screening targets men with BRCA mutations.

PMID- 12473507
TI  - New approach to targeted prodrug therapy.

PMID- 12473510
TI  - Caution needed in restaging of recurrent cancer: a UK perspective.

PMID- 12473511
TI  - Further interpretation of the PORT meta-analysis.

PMID- 12473512
TI  - Chemotherapy for metastatic breast cancer-report of a European expert panel.
AB  - The anthracyclines doxorubicin and epirubicin, and the taxanes paclitaxel and
      docetaxel, are effective chemotherapeutic agents for the first-line and second
      line treatment of metastatic breast cancer, and their clinical use is widespread.
      However, for women whose disease has progressed despite receiving these drugs,
      treatment options are limited. These women often have a good performance status,
      and may survive for many months or even years, so they should be given the
      opportunity to benefit from further chemotherapy. The goals of chemotherapy in
      these patients are to obtain maximum control of symptoms, prevent serious
      complications, and increase survival without diminishing quality of life. Several
      agents are used for this purpose, including fluorouracil, docetaxel (in patients
      who have already received paclitaxel), vinorelbine, and mitomycin c, but because
      data from controlled trials are limited, a standard regimen has not yet been
      established. Moreover, these agents may be inconvenient to administer and can be
      associated with adverse events requiring hospitalisation. Therefore, there is a
      clear need for additional therapeutic options for patients with metastatic breast
      cancer. Ideally, agents should have a convenient method of administration, eg,
      oral, and should be suitable for home-based rather than hospital-based therapy.
      Treatment should control disease in at least 20-30% of patients with an
      acceptable side-effect profile. Novel oral therapies have now been developed and
      are being used increasingly in patients whose disease has progressed following
      taxane therapy.

PMID- 12473513
TI  - Acquired icthyosis: a paraneoplastic skin manifestation of Hodgkin's disease.

PMID- 12473514
TI  - ARCON: a novel biology-based approach in radiotherapy.
AB  - Two mechanisms of radiotherapy resistance which are of major importance in
      various tumour types are tumour-cell repopulation and hypoxia. ARCON (accelerated
      radiotherapy with carbogen and nicotinamide) is a new therapeutic strategy that
      combines radiation treatment modifications, with the aim of counteracting these
      resistance mechanisms. To limit clonogenic repopulation during therapy, the
      overall duration of the radiotherapy is reduced, generally by delivering several
      fractions per day. This accelerated radiotherapy is combined with inhalation of
      hyperoxic gas to decrease diffusion-limited hypoxia, and nicotinamide, a
      vasoactive agent, to decrease perfusion-limited hypoxia. Preclinical studies have
      been done to test the enhancing effects of these three components of ARCON,
      individually and in combination, in several experimentally induced tumours and
      normal tissues. In a mouse mammary carcinoma, the tumour-control rate obtained
      with ARCON was the same as that with conventional treatment, but with a radiation
      dose almost 50% lower. Phase 1 and 2 clinical trials have shown the feasibility
      and tolerability of ARCON, and have produced promising results in terms of tumour
      control. In particular in cancers of the head and neck and bladder, the local
      tumour-control rates are higher than in other studies, and phase 3 trials for
      these tumour types are underway. In conjunction with these trials, hypoxia
      markers detectable by immunohistochemistry are being tested for their potential
      use in predictive assays to select patients for ARCON and other hypoxia-modifying
      therapies.

PMID- 12473516
TI  - FHIT: from gene discovery to cancer treatment and prevention.
AB  - Chromosomal abnormalities, including homozygous deletions and loss of
      heterozygosity, are among the most common features of human tumours. The short
      arm of human chromosome 3, particularly the region 3p14.2, is a major site of
      such rearrangements. The 3p14.2 region spans the most active common fragile site
      of the human genome, encompassing a familial-kidney-cancer-associated breakpoint
      and a papilloma virus integration site. 6 years ago, the FHIT gene was identified
      in this region. Subsequent studies have shown that FHIT is commonly the target of
      chromosomal aberrations involving the long arm of human chromosome 3 and is
      thereby inactivated in most of the common human malignant diseases, including
      cancers of the lung, oesophagus, stomach, breast, and kidney. During the past 5
      years, evidence has accumulated in support of a tumour-suppressor function for
      FHIT. In this review, we describe the recent findings in the molecular biology of
      FHIT with particular focus on the opportunities for treatment and prevention of
      cancer that have emerged.

PMID- 12473515
TI  - The role of systemic chemotherapy in the management of muscle-invasive bladder
      cancer.
AB  - Patients with localised but muscle-invasive transitional-cell carcinoma (TCC) of
      the bladder are at high risk of relapse and death from metastatic disease after
      local treatment by cystectomy, radiation, or both. Despite improvements in
      treatment, patients with metastatic TCC have a median survival of about a year.
      TCC is quite sensitive to chemotherapy, and patients are able to tolerate newer
      regimens such as gemcitabine plus cisplatin better than older regimens such as
      methotrexate, vinblastine, doxorubicin, and cisplatin. However, the role of
      chemotherapy in the management of locally advanced muscle-invasive TCC remains
      uncertain. Most trials of neoadjuvant or adjuvant chemotherapy have shown no
      significant improvement in survival, but many of these studies had suboptimum
      design, evaluated chemotherapy that was less effective than regimens in current
      use, and had sample sizes that were too small for important changes in survival
      to be detected or ruled out. Recent trials show trends in the direction of
      improved survival when optimum chemotherapy is used. Large trials that recruit
      more than 1000 patients are required to assess the effectiveness of adjunctive
      chemotherapy, and a large intergroup trial is in progress. Other trials should
      address the role of molecular markers in selecting patients for chemotherapy.
      Whenever possible, chemotherapy for locally advanced muscle-invasive TCC should
      be given in the context of a well-designed clinical trial.

PMID- 12473517
TI  - Epigenetics in cancer: implications for early detection and prevention.
AB  - Knowledge of the molecular events that occur during the early stages of cancer
      has advanced rapidly. The initiation and development of cancer involves several
      molecular changes, which include epigenetic alterations. Epigenetics is the study
      of modifications in gene expression that do not involve changes in DNA nucleotide
      sequences. Modifications in gene expression through methylation of DNA and
      remodelling of chromatin via histone proteins are believed to be the most
      important of the epigenetic changes. The study of epigenetics offers great
      potential for the identification of biomarkers that can be used to detect and
      diagnose cancer in its earliest stages and to accurately assess individual risk.
      There has been a recent surge of interest among researchers as variations in the
      methylation of DNA have been shown to be the most consistent molecular changes in
      many neoplasms. An important distinction between a genetic and an epigenetic
      change in cancer is that epigenetic changes can be reversed more easily by use of
      therapeutic interventions. The discovery of these basic premises should stimulate
      much future research on epigenetics.

PMID- 12473518
TI  - Endometrial malignant melanoma rediagnosed as clear-cell "sugar" tumour.

PMID- 12473521
TI  - A festive musing.

PMID- 12473522
TI  - [Frequency of consanguineous unions in the Tlemcen area (West Algeria)].
AB  - In order to describe consanguineous unions and their effects in a sample of the
      Algerian population, we interviewed 3,983 couples in a hospital and from urban
      and rural areas near Tlemcen. We observed that unions between cousins represented
      34.0% of the marriages. The frequency of unions between relatives was lower in
      the urban (30.6%) than in the rural areas (40.5%). This difference can be
      explained by changing custom and family relationships in urban areas, and is
      evidenced by social and anthropologic factors and the attitude towards
      consanguineous unions.

PMID- 12473523
TI  - [Doping practices and behaviours among Ivorian soccer players].
AB  - We have conducted a survey of doping among soccer players in Cote d'Ivoire with a
      representative sample of 150 soccer players who filled out an anonymous
      questionnaire. The aim of this survey was to get a clearer picture of doping in
      Ivorian soccer in order to suggest preventive actions against doping. The results
      of this study showed that doping was known by the Ivorian soccer players; about
      18.7% admitted to the use of doping substances, 42% recognised that they felt
      tempted by doping, while 38% knew another soccer player who had already used a
      doping substance. Government and sports organisations should recognize the
      importance of education and information in the antidoping campaign and agree on
      effective preventive as well as repressive strategies.

PMID- 12473524
TI  - [Impact of algorithms on abusive prescriptions of parental drugs at the health
      post level in the Tambacounda health district, Senegal].
AB  - In order to increase the effectiveness and the efficiency of diagnosis and
      treatment procedures of the most common diseases, algorithmic pathways have been
      developed and applied within the implementation of the "Bamako Initiative
      Strategy" at the health post level in Senegal. Among the many expected advantages
      of these pathways, was a reduction of abusive prescriptions of parental drugs. A
      study comparing the trend of the prescriptions 2 years before (1991) and 2 years
      after (1996) the implementation of the Bamako Initiative strategy, was conducted
      using 810 randomly selected patients in 7 out of the 19 health posts of the
      Tambacounda Health district, one of the 45 health districts of Senegal. In 1991,
      all the oral drugs prescribed (sirup, pills, powder) represented 54.5% against
      45.5% for parental drugs (intramuscular and intravenous drugs). These proportions
      had risen to respectively 78.1% and 21.9% in 1996. The difference thus observed
      is statistically significant with a khi2 test of 47.76 and p<10(-7). This result
      then suggests that the use of pathways had highly reduced the prescription of
      parental drugs among patients treated in the health posts of the Tambacounda
      health district in Senegal.

PMID- 12473525
TI  - [Medical emergencies in the Yalgado Ouedraogo national hospital of Ouagadougou:
      patients' profile and assessment of care practices].
AB  - The Emergency Department, the showcase of the hospital, must be functional at all
      times with sufficient resources for looking after the patients without delay. In
      the Medical Emergency Department of the Yalgado Ouedraogo national hospital of
      Ouagadougou (Burkina Faso), problems such as delays and difficulties to obtain
      medicine, give rise to conflicts thus causing the hospital to be a target for
      public criticism. The aim of this study is to establish the profile of the
      patients and to assess how they are taken care of. A cross-sectional survey was
      carried out for 21 consecutive days spread out over three months, from April 25
      to June 25, 1997 and concerned all of the 551 patients consulting on those days.
      The self referral rate was 50.8%. Patients came mainly from the Kadiogo province
      (90.7%), with their own transport means (85.1%), more often at the beginning of
      the week (31 patients per day on average) than during week ends (21 patients per
      day on average, p<0.001). The age group was 15 to 93 years with a mean of 35.4 (
      14,2) years. Infectious diseases, particularly gastroenteritis (21.3%), malaria
      (12.1%), and pneumonia (10.2%) were the main diagnoses. The median waiting time
      was 8 min (from 0 to 3 h 59 min), the median therapeutic time was 56 min (from 5
      min to 16 h 19 min). Patients were supplied with medicine in 14.5% of cases. Thus
      median medicine acquisition time was significantly reduced from 35 min to 21 min
      (p<0.001) when medicines were bought. Medicine acquisition time significantly
      contributes to increase the therapeutic delay (rs=0.31; p<0.001). The median
      therapeutic time was 56 min (5 min to 16 h 19 min). The diagnostic accuracy rate
      was 77.4%, and the satisfaction index 3.5%. Patients expenditure was 9,002 CFA
      francs on average, including 7,963 CFA francs for medicine. Thus access to
      medicine constitutes a major point of malfunction, increasing the caretaking time
      span as well as patients' expenditure. In addition to quickly and systematically
      supplying medicines to all patients, organizing the reception and providing
      comfortable waiting conditions must be considered in order to offer better care
      delivery services.

PMID- 12473526
TI  - [Validation of a method of blood pressure measurement for a study of hypertension
      in a black African population].
AB  - Hypertension is a major public health issue in Black Africa. It is also an
      important factor of cardiovascular risk. To determine the prevalence of
      hypertension in a large population in Burkina Faso, it is more practicable to use
      an automatic device for the measurement of BP. Before the start of the study, we
      tested the reliability of an automatic technique for the measurement of BP in
      sitting position according to the reference technique. The manometer of reference
      was a manual, aneroid, and calibrated manometer. The automatic manometer was
      oscillometric, validated according to the protocol of the British Hypertension
      Society. The study was held on voluntary healthy persons, or patients
      hospitalized in the cardiology department of the national university hospital of
      Ouagadougou (high blood pressure, valvulopathy, cardiac insufficiency). BP
      measurement was made in a sequential way, with the manual manometer, and with the
      automatic manometer, by a single observer. Measurement by the manual manometer
      was based on the auscultation of Korotkoff's murmurs. Systolic blood pressure
      (SBP) corresponded to phase I, and diastolic blood pressure (DBP) to phase V.
      Measurement by the automatic manometer was made by reading the BP shown on the
      device screen. The 10.0 version of the SPSS software was used for data analysis.
      Statistical tests were concluded with a risk of 0.05. Confidence intervals
      included 95% of the subjects. The percentage comparison of hypertensive subjects
      observed in the population by both methods was made with a paired khi2 test. We
      used Pearson's correlation to quantify the relation between the measures taken
      using the two methods. In order to quantify the degree of agreement of the two
      methods, we used the intraclass correlation coefficient (ICC) for quantitative BP
      measurements, and Kappa's coefficient for qualitative measurements (determination
      of normotensive or hypertensive subjects). The study was held on 50 black African
      subjects, with the average age of 38.54  4.83 (18 years-77 years); 55% were male
      subjects. With the reference method in the sleeping position, the mean SBP and
      DBP values were respectively 122.60   8.52 and 70.36   5.22 mmHg. The minimal and
      maximal SBP observed were 80 and 240 mmHg respectively, and the DBP, 30 and 130
      mmHg respectively. With the automatic method in the sitting position, the mean
      values SBP and DBP was 119.88+7.50 and 74.80   4.36 mmHg. SBP minimal was of 75,
      the maximal of 210 mmHg, and the minimal and maximal DBP was respectively 51 and
      121 mmHg. Pearson's correlation coefficients for SBP and DBP between the two
      methods were statistically different from zero; 0.92 (p<0.001), and of 0.82
      (p<0.001) respectively. The ICC was 0.91 for SBP and 0.78 for DBP. Kappa's
      coefficient was calculated to estimate agreement for the determination of
      normotensive or hypertensive subjects; among the 50 subjects, 36 were classified
      normotensive by the two methods, and eight, hypertensive. The differences of
      classification concerned five hypertensive subjects and one normotensive subject,
      according to the referenced method. Kappa's coefficient was 0.65. The
      distribution of the subjects in hypertensive and normotensive did not differ
      significantly in the two methods (p=0.22). The agreement between the two methods
      was found very good for the measurement of SBP and DBP; it was good for the
      determination of an hypertensive or normotensive subject. It is important to test
      the reliability of a technique of BP measurement before the evaluation of
      hypertension prevalence in a large population. The reliability of the technique
      ensures a good estimation of the disease prevalence. It is also important to use
      statistically adapted tests, to avoid any wrong conclusion as to the reliability
      of the technique.

PMID- 12473527
TI  - [Aspects of antihyperglycemic oral bitherapy in 76 cases of non insulindependent
      diabetes in Dakar].
AB  - Some reasons justify the introduction of the association of sulfonylurea and
      metformine when monotherapy is ineffective. Hereafter a period of monotherapy by
      sulfonylurea or metformine only bitherapy has been instituted. Socio-demography,
      number of consultations, type of monotherapy and of association, duration of
      treatment, body mass index, fasting blood glycemia and post-prandial glycemia,
      blood pressure and type of complication were studied. There were 2.5 times more
      women than men with lower mean age for women. The majority of patients were from
      Dakar (81.6%). More than half of patients were women at home (60.5%). Present
      obesity (plethoric diabetes) or past obesity (metaplethoric diabetes) concerned
      90.3% of patients. Patients have done 9.14   4.39 consultations under bitherapy.
      The gliclazide-metformin association was observed 37 times and the glibenclamide
      metformin association 67 times. The duration of monotherapy was 45.9   39.7
      months and that of bitherapy 92.5   43.7 months. The variations of body mass
      index showed a diminution of 1.26 kg/m2 and for fasting blood glycemia and
      augmentation of 0.011 g/L and post-prandial a diminution of 0.05 g/L. The body
      mass index variations in diabetic patients showed a diminution of weight more in
      plethoric patients in bitherapy compared to monotherapy. This study is
      retrospective and cannot show the optimal efficacy of bitherapy. But the
      combination of enhancement of glucose captation and lowering of hepatic glucose
      production has been shown during this bitherapeutic association. Addition of
      metformine and treatment with sulfonylurea make a combination that
      significatively improves glycemic control but also cholesterol level and allows
      obtation of better weight in type 2 non insulin-dependent diabetes with
      insulinoresistance.

PMID- 12473528
TI  - [An epidemic risk of yellow fever in Burkina Faso despite a rapid immunisation
      riposte: role of a multidisciplinary investigation team].
AB  - On October 8, 1999, one yellow fever (YF) case is confirmed in the South West of
      Burkina Faso by the Centre Muraz' virology unit. Epidemic extension is suspected
      as large movements of population are occurring due to troubles in Cote d'Ivoire
      nearby and as the Aedes vector is endemic in the region. On October 23, the
      Gaoua's Health Regional Head immunizes 1,000 people around the detected YF case,
      i.e. 70% of the estimated population and requests an epidemiological
      investigation. A multidisciplinary team (epidemiologist, entomologist,
      virologist) from the Centre Muraz, a medical research centre based in Bobo
      Dioulasso investigate in order to answer the following questions: are there any
      other or asymptomatic cases of YF? How far is the epidemic risk? Is a paper
      filter a valuable method for collecting blood samples? What benefit can be gained
      from a multidisciplinary team? METHOD: An epidemiological analysis of the
      patient, a research of asymptomatic or ignored patient is performed (Health
      Centre registers, interview of the population). This includes the research of
      people missing the immunisation campaign. Blood samples are collected through 5
      ml EDTA glass tubes or through filter paper in order to measure immunoglobuline
      M. A classical entomological prospecting completes the investigation. RESULTS:
      Two possible cases are suspected in the patient's home. History of the patient's
      is in agreement with a local contamination. In the village 110 people missed the
      immunisation campaign and samples were collected in 58 people including 26
      children. Among them, four (15.3%) were positive with immunoglobuline M, while
      there were none in the adults. Aedes Luteocephalus, a potential vector is
      collected through night-captures but is absent of home-water collection. Paper
      filter assays shows a 100% concordance with classical method. CONCLUSION: The
      team could determine the persistency of a yellow fever epidemic risk in the
      region despite a rapid and adequate immunisation riposte. Due to iterative
      sporadic cases and due to population movement, a routine survey of YF has to be
      promoted as the immune status of the population, particularly in the youth, do
      not protect them. Collection of blood through paper filter will greatly help the
      routine survey and shall be confirmed during the following investigations.

PMID- 12473529
TI  - [Aetiologic factors and clinical features associated with thrombocytopenia in
      Cameroonese adults: the importance of Plasmodium falciparum malaria].
AB  - In order to determine the main aetiologies associated with thrombocytopenia in a
      hospital setting of Cameroon, 180 adults with platelet counts <100x10(9)/L were
      examined and screened for a full blood count, thick and thin blood films, basic
      coagulation tests (activated partial thromboplastine time, a one-stage Quick's
      prothrombin time and a bleeding time), an HIV screening test as well as a bone
      marrow aspirate using standard methods. Other tests were selectively done as
      dictated by the suspected diagnosis. The major clinical findings among 180 cases
      included fever >37.5 C (53.9%), splenomegaly (45.6%) and haemorrhage (30.6%). The
      main laboratory findings were anaemia (defined as haemoglobin (Hb) <11g/dL) in
      80.6% of cases and a positive thick blood film (all confirmed to be P.
      falciparum) in 30.6% of cases. Out of the 18 different aetiologies associated
      with a low platelet count in the group studied, malaria appears as the unique
      cause in 22.2% of cases. Petechial bleeding, bruising and epistaxis were the
      major forms of bleeding involved (69.1%, 27.3%, and 23.6% respectively). However,
      only 3 cases diagnosed with malaria showed any form of bleeding (mean malaria
      parasite densities >15,000/muL of blood in each case). No other haemostatic
      abnormalities were observed. It may be cost-effective for patients with low
      platelet counts in malarial regions to be systematically screened for malaria
      parasites.

PMID- 12473530
TI  - [Monitoring of glycemic balance in diabetics living in Africa: a review of
      glycated hemoglobin measurement methods].
AB  - Diabetes has become a health care problem not only in the first world, but also
      in developing countries, where the majority of diabetics live. The development of
      a diabetes care system that can cater for the chronic management of diabetic
      patients is pivotal to an improvement of this situation. A lack of diagnostic
      facilities has often been made responsible for a lack in appropriate treatment
      and for the prevention of complications. However, while this is certainly the
      case in remote areas with health care available only at the primary or secondary
      level, preventing complications by securing a good diabetic control is possible
      now in many cities and/or highly populated regions in developing countries. A
      prerequisite for this is the ability to monitor retrospectively long-term
      glycemic control, specifically, measuring the level of glycated proteins or
      hemoglobins (HbA1c).

PMID- 12473531
TI  - [Management of priapism in sickle-cell diseases with alpha-adrenergic agonists].
AB  - Priapism is a common complication of sickle cell anemia. Two different patterns
      are described: acute priapism, a prolonged painful erection generally lasting
      more than 6 hours, and stuttering priapism, which consist of brief repeated self
      resolving episodes. Until 1990, priapism in sickle-cell patients has relied on
      measures aimed at lowering blood viscosity and acidosis and reducing the level of
      circulating hemoglobin S (alcalinization, hyperhydration, exsanguinotransfusion).
      But these means are not consistently successful. Surgical cavernous-venous shunt
      was proposed after 12 to 24 hours when conservative treatment failed. These
      therapeutic modalities are based on the pathophysiology of sickle-cell priapism.
      Priapism in sickle-cell disease may be due to sequestered sickled red cells in
      the corpus cavernosum with venous outflow obstruction. For some years, the
      treatment of priapism in sickle-cell anemia was changed by the use of alpha
      adrenergic agonists. These therapeutics (mainly etilefrine and epinephrine) were
      first reserved for priapism resulting from intrapenile injections of vasoactive
      drugs which are used for the treatment of impotence. In acute priapism, alpha
      adrenergic agonists are used in intracavernous injections (ICI). In stuttering
      priapism, treatment consists in an oral administration associated, if necessary,
      with self-administered ICI. ICI results mainly depend on when treatment occurs.
      Detumescence is achieved in patients treated within 30 hours, as opposed to the
      few patients treated beyond this delay. This finding is in agreement with
      experimental findings demonstrating histological evidence of necrosis of
      endothelial cells and cavernous smooth muscle fibers after 24 hours. Surgery is
      only used after failure of ICI. The result of oral treatment is not very
      satisfactory because many patients do not respond well or are dependent on ICI.
      However, self-administered ICI associated with the oral treatment protects
      patients with stuttering priapism against acute strokes. The safety of alpha
      adrenergic agonists is good as both oral and ICI have few side-effects. The
      excellent efficacy of ICI in sickle-cell priapism leads to suggest that the
      pathogenic mechanism could involve a neuromuscular dysfunction.

PMID- 12473534
TI  - Gene structure of urea transporters.
AB  - Urea plays various roles in the biology of diverse organisms. The past decade has
      produced new information on the molecular structure of several urea transporters
      in various species. Availability of DNA probes has revealed that the presence of
      urea transporters is not confined to the mammalian kidney but is also evident in
      testis and brain, raising new questions about the possible physiological role of
      urea in these organs. Cloning of the genes encoding the two closely related
      mammalian urea transporters UT-A and UT-B has helped in identifying molecular
      mechanisms affecting expression of urea transporters in the kidney, such as
      transcriptional control for UT-A abundance. On the basis of analysis of genomic
      sequences of individuals lacking the UT-B transporter, mutations have been found
      that explain deficits in their capacity to concentrate urine. More urea
      transporters are being characterized in marine organisms and lower vertebrates,
      and studying the role and regulation of urea transport from an evolutionary
      perspective can certainly enrich our understanding of renal physiology.

PMID- 12473535
TI  - Loop diuretics: from the Na-K-2Cl transporter to clinical use.
AB  - The diuretic response to loop diuretics in various disease states has
      consistently been found to be subnormal. One of the key determinants of the
      degree of diuretic response is the functional integrity of the sodium-potassium
      chloride transporter in the loop of Henle. Studies in animal models suggest that
      expression/activity of the transporter may be affected by factors such as altered
      natural splicing events of NKCC2 (the gene encoding for the renal transporter),
      renal prostanoids, vasopressin, and other autacoids. We have reviewed the
      pharmacokinetics and pharmacodynamics of loop diuretics in health and in
      edematous disorders for which they are used. On the basis of evidence reviewed in
      this paper, we propose that altered expression or activity of the sodium
      potassium-chloride transporter in the loop of Henle, in conjunction with events
      occurring in other segments of the nephron, possibly accounts for the altered
      diuretic response to these agents. Thus the modulators of this altered
      expression/activity could serve as important therapeutic targets for alternative
      diuretic regimens in these conditions.

PMID- 12473536
TI  - Sp1 and Sp3 transcription factors synergistically regulate HGF receptor gene
      expression in kidney.
AB  - We investigated the expression pattern and underlying mechanism that controls
      hepatocyte growth factor (HGF) receptor (c-met) expression in normal kidney and a
      variety of kidney cells. Immunohistochemical staining showed widespread
      expression of c-met in mouse kidney, a pattern closely correlated with renal
      expression of Sp1 and Sp3 transcription factors. In vitro, all types of kidney
      cells tested expressed different levels of c-met, which was tightly proportional
      to the cellular abundances of Sp1 and Sp3. Both Sp1 and Sp3 bound to the multiple
      GC boxes in the promoter region of the c-met gene. Coimmunoprecipitation
      suggested a physical interaction between Sp1 and Sp3. Functionally, Sp1 markedly
      stimulated c-met promoter activity. Although Sp3 only weakly activated the c-met
      promoter, its combination with Sp1 synergistically stimulated c-met
      transcription. Conversely, deprivation of Sp proteins by transfection of decoy
      Sp1 oligonucleotide or blockade of Sp1 binding with mithramycin A inhibited c-met
      expression. The c-met receptor in all types of kidney cells was functional and
      induced protein kinase B/Akt phosphorylation in a distinctly dynamic pattern
      after HGF stimulation. These results indicate that members of the Sp family of
      transcription factors play an important role in regulating constitutive
      expression of the c-met gene in all types of renal cells. Our findings suggest
      that HGF may have a broader spectrum of target cells and possess wider
      implications in kidney structure and function than originally thought.

PMID- 12473537
TI  - ACE inhibition increases expression of the ETB receptor in kidneys of mice with
      unilateral obstruction.
AB  - Unilateral ureteral obstruction (UUO) is a well-established model for the study
      of interstitial fibrosis in the kidney. It has been shown that the renin
      angiotensin system plays a central role in the progression of interstitial
      fibrosis. Recent studies indicate that endothelin, a powerful vasoconstrictive
      peptide, may play an important role in some types of renal disease. To
      investigate the effects of angiotensin II on endothelin and its receptors in the
      kidney, mice were subjected to UUO and treated with or without enalapril, an
      orally active angiotensin-converting enzyme inhibitor, in their drinking water
      (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR, we
      measured the levels of endothelin-1, endothelin A, and endothelin B (ET(B)) along
      with transforming growth factor-beta, TNF-alpha, and collagen type IV mRNA
      expression in the kidney with UUO and the contralateral kidney along with
      interstitial expansion in the kidney cortex by a standard point counting method.
      We found that enalapril administration ameliorated the increased expression of ET
      1 mRNA in the obstructed kidney by 44% (P < 0.02). Although the level of
      endothelin A mRNA expression was significantly increased in the obstructed
      kidney, it was not affected by enalapril. We found that enalapril treatment
      increased ET(B) mRNA expression by 115% (P < 0.05) and protein expression
      (measured by Western blot) in the kidney with an obstructed ureter. Enalapril
      treatment alone inhibited the expansion of interstitial volume due to UUO by 52%.
      Cotreatment with enalapril and the ET(B) receptor antagonist BQ-788 inhibited the
      expression of interstitial volume by only 19%. This study confirms that enalapril
      inhibits the interstitial fibrosis in UUO kidneys. It also suggests a beneficial
      and unforeseen effect of enalapril on the obstructed kidney by potentially
      stimulating the production of nitric oxide through an increased expression of the
      ET(B) receptor.

PMID- 12473539
TI  - Platelet glycoprotein IIb/IIIa inhibition and atheroembolism during bypass graft
      angioplasty: a cup half full.

PMID- 12473540
TI  - A lifetime of prevention: the case of heart failure.

PMID- 12473541
TI  - Preconditioning and arrhythmias.

PMID- 12473542
TI  - Biological revascularization and the interventional molecular cardiologist:
      bypass for the next generation.

PMID- 12473543
TI  - Percutaneous transcatheter implantation of an aortic valve prosthesis for
      calcific aortic stenosis: first human case description.
AB  - BACKGROUND: The design of a percutaneous implantable prosthetic heart valve has
      become an important area for investigation. A percutaneously implanted heart
      valve (PHV) composed of 3 bovine pericardial leaflets mounted within a balloon
      expandable stent was developed. After ex vivo testing and animal implantation
      studies, the first human implantation was performed in a 57-year-old man with
      calcific aortic stenosis, cardiogenic shock, subacute leg ischemia, and other
      associated noncardiac diseases. Valve replacement had been declined for this
      patient, and balloon valvuloplasty had been performed with nonsustained results.
      METHODS AND RESULTS: With the use of an antegrade transseptal approach, the PHV
      was successfully implanted within the diseased native aortic valve, with accurate
      and stable PHV positioning, no impairment of the coronary artery blood flow or of
      the mitral valve function, and a mild paravalvular aortic regurgitation.
      Immediately and at 48 hours after implantation, valve function was excellent,
      resulting in marked hemodynamic improvement. Over a follow-up period of 4 months,
      the valvular function remained satisfactory as assessed by sequential
      transesophageal echocardiography, and there was no recurrence of heart failure.
      However, severe noncardiac complications occurred, including a progressive
      worsening of the leg ischemia, leading to leg amputation with lack of healing,
      infection, and death 17 weeks after PHV implantation. CONCLUSIONS: Nonsurgical
      implantation of a prosthetic heart valve can be successfully achieved with
      immediate and midterm hemodynamic and clinical improvement. After further device
      modifications, additional durability tests, and confirmatory clinical
      implantations, PHV might become an important therapeutic alternative for the
      treatment of selected patients with nonsurgical aortic stenosis.

PMID- 12473544
TI  - Transplantation of Progenitor Cells and Regeneration Enhancement in Acute
      Myocardial Infarction (TOPCARE-AMI).
AB  - BACKGROUND: Experimental studies suggest that transplantation of blood-derived or
      bone marrow-derived progenitor cells beneficially affects postinfarction
      remodeling. The safety and feasibility of autologous progenitor cell
      transplantation in patients with ischemic heart disease is unknown. METHODS AND
      RESULTS: We randomly allocated 20 patients with reperfused acute myocardial
      infarction (AMI) to receive intracoronary infusion of either bone marrow-derived
      (n=9) or circulating blood-derived progenitor cells (n=11) into the infarct
      artery 4.3+/-1.5 days after AMI. Transplantation of progenitor cells was
      associated with a significant increase in global left ventricular ejection
      fraction from 51.6+/-9.6% to 60.1+/-8.6% (P=0.003), improved regional wall motion
      in the infarct zone (-1.5+/-0.2 to -0.5+/-0.7 SD/chord; P<0.001), and profoundly
      reduced end-systolic left ventricular volumes (56.1+/-20 mL to 42.2+/-15.1 mL;
      P=0.01) at 4-month follow-up. In contrast, in a nonrandomized matched reference
      group, left ventricular ejection fraction only slightly increased from 51+/-10%
      to 53.5+/-7.9%, and end-systolic volumes remained unchanged. Echocardiography
      revealed a profound enhancement of regional contractile function (wall motion
      score index 1.4+/-0.2 at baseline versus 1.19+/-0.2 at follow-up; P<0.001). At 4
      months, coronary blood flow reserve was significantly (P<0.001) increased in the
      infarct artery. Quantitative F-18-fluorodeoxyglucose-positron emission tomography
      analysis revealed a significant (P<0.01) increase in myocardial viability in the
      infarct zone. There were no differences for any measured parameter between blood
      derived or bone marrow-derived progenitor cells. No signs of an inflammatory
      response or malignant arrhythmias were observed. CONCLUSIONS: In patients with
      AMI, intracoronary infusion of autologous progenitor cells appears to be feasible
      and safe and may beneficially affect postinfarction remodeling processes.

PMID- 12473545
TI  - Use of emergency medical services in acute myocardial infarction and subsequent
      quality of care: observations from the National Registry of Myocardial Infarction
      2.
AB  - BACKGROUND: National practice guidelines strongly recommend activation of the 9-1
      1 Emergency Medical Systems (EMS) by patients with symptoms consistent with an
      acute myocardial infarction (MI). We examined use of the EMS in the United States
      and ascertained the factors that may influence its use by patients with acute MI.
      METHODS AND RESULTS: From June 1994 to March 1998, the National Registry of
      Myocardial Infarction 2 enrolled 772 586 patients hospitalized with MI. We
      excluded those who transferred in, arrived at the hospital >6 hours from symptom
      onset, or who were in cardiogenic shock. We compared baseline characteristics and
      initial management for patients who arrived by ambulance versus self-transport.
      EMS was used in 53.4% of patients with MI, a proportion that did not vary
      significantly over the 4-year study period. Nonusers of the EMS were on average
      younger, male, and at relatively lower risk on presentation. In addition, payer
      status was significantly associated with EMS use. Use of EMS was independently
      associated with slightly wider use of acute reperfusion therapies and faster time
      intervals from door to fibrinolytic therapy (12.1 minutes faster, P<0.001) or to
      urgent PTCA (31.2 minutes faster, P<0.001). CONCLUSIONS: Only half of patients
      with MI were transported to the hospital by ambulance, and these patients had
      greater and significantly faster receipt of initial reperfusion therapies. Wider
      use of EMS by patients with suspected MI may offer considerable opportunity for
      improvement in public health.

PMID- 12473546
TI  - Increased expression of membrane type 3-matrix metalloproteinase in human
      atherosclerotic plaque: role of activated macrophages and inflammatory cytokines.
AB  - BACKGROUND: Matrix metalloproteinases (MMPs) are thought to play a prominent role
      in atherogenesis and destabilization of plaque. Pericellularly localized membrane
      type (MT)-MMPs activate secreted MMPs. We investigated the hypothesis that MT3
      MMP is expressed in human atherosclerotic plaques and is regulated by locally
      produced inflammatory cytokines and oxidized low-density lipoprotein (Ox-LDL).
      METHODS AND RESULTS: Expression and cellular localization of MT3-MMP in normal
      and atherosclerotic human coronary arteries were examined using specific
      antibodies. Abundant MT3-MMP expression was noted in medial smooth muscle cells
      (SMCs) of normal arteries. In atherosclerotic arteries, MT3-MMP expression was
      observed within complex plaques and colocalized with SMCs and macrophages (Mphi).
      Cultured human monocyte-derived Mphi constitutively expressed MT3-MMP mRNA and
      proteolytically active protein, as demonstrated by mRNA analyses, immunoblotting,
      and gelatin zymography, respectively. Ox-LDL, tumor necrosis factor-alpha, or
      macrophage colony-stimulating factor caused dose- and time-dependent increases in
      steady-state levels of MT3-MMP mRNA in cultured Mphi. This correlated with a 2-
      to 4-fold increase in levels of MT3-MMP immunoreactive protein and enzymatic
      activity in Mphi membranes. Confocal microscopy and flow cytometry confirmed
      induction and spatial distribution of MT3-MMP protein from intracellular domains
      to the Mphi plasma membrane by Ox-LDL, tumor necrosis factor-alpha, or macrophage
      colony-stimulating factor. CONCLUSIONS: MT3-MMP is expressed by SMCs and Mphi in
      human atherosclerotic plaques. Proinflammatory molecules cause a progressive
      increase in the expression of MT3-MMP in cultured Mphi. Our results suggest a
      mechanism by which inflammatory molecules could promote Mphi-mediated degradation
      of extracellular matrix and thereby contribute to plaque destabilization.

PMID- 12473547
TI  - Low-density lipoprotein receptor gene mutations and cardiovascular risk in a
      large genetic cascade screening population.
AB  - BACKGROUND: A large cohort of patients with familial hypercholesterolemia (FH),
      free from selection for cardiovascular disease (CVD), and their unaffected
      relatives was collected by genetic cascade screening and examined for the
      influence of different mutations of the LDL receptor gene on lipoprotein levels
      and the risk of CVD. Multivariate analyses with adjustment for age, sex, and
      specific family ties were performed. METHODS AND RESULTS: Significant variation
      of LDL levels was observed among 399 patients with FH with different mutations.
      Null alleles were associated with more severely elevated LDL cholesterol, whereas
      the frequent N543H/2393del9 mutation led to less elevated LDL cholesterol. The
      type of mutation did not influence HDL cholesterol levels. Patients with FH had
      CVD 8.5 times more often compared with their unaffected relatives (RR, 8.54; 95%
      CI, 5.29 to 13.80). The N543H/2393del9 mutation was associated with a smaller
      increase of risk compared with other mutations (P<0.0001). After exclusion of
      families with the N543H/2393del9 mutation, null alleles and other allele
      mutations no longer differed with regard to LDL cholesterol levels and CVD risk.
      CONCLUSIONS: LDL receptor mutations only partly contributed to the variation of
      LDL cholesterol levels and cardiovascular burden in FH. Additional, so far
      unidentified, familial risk factors must underlie the differences of CVD risk,
      most likely independent of lipids and lipoproteins.

PMID- 12473548
TI  - Vascular structural and functional changes in type 2 diabetes mellitus: evidence
      for the roles of abnormal myogenic responsiveness and dyslipidemia.
AB  - BACKGROUND: To further investigate vascular morphology and function in type 2
      (non-insulin-dependent) diabetes mellitus (type 2D), small arteries were examined
      in vitro from carefully defined cohorts of patients with or without concomitant
      hypertension and the results compared with those from selected normotensive
      nondiabetic control subjects and a group of untreated patients with essential
      hypertension (EH). METHODS AND RESULTS: Blood vessels were studied through the
      use of pressure myography to determine vascular morphology, mechanics, and
      myogenic responsiveness, together with testing of constrictor and dilator
      function. Small arteries from patients with EH demonstrated eutrophic inward
      remodeling and an increased distensibility. Vessels from type 2D patients
      demonstrated hypertrophy, a further increase in distensibility, and a highly
      significant loss of myogenic responsiveness compared with patients with EH and
      control patients. Vasoconstrictor function to norepinephrine was normal in
      patients with type 2D and type 2D+H and EH. Endothelium-dependent dilation was
      normal in patients with EH but abnormal in patients with type 2D and type 2D+H.
      There was a significant correlation between dilator impairment and the degree of
      dyslipidemia recorded in all groups. CONCLUSIONS: These results demonstrate
      vascular hypertrophy in small arteries from patients with type 2D. This could be
      a consequence of impaired myogenic responsiveness, which will increase wall
      stress for a given intraluminal pressure, which may be a stimulus for vascular
      hypertrophy. A substantial proportion of endothelial dysfunction can be
      attributed to an effect of the abnormal lipid profile seen in such patients.

PMID- 12473549
TI  - Acetylated low-density lipoprotein stimulates human vascular smooth muscle cell
      calcification by promoting osteoblastic differentiation and inhibiting
      phagocytosis.
AB  - BACKGROUND: Vascular smooth muscle cells (VSMCs) in atherosclerotic lesions
      display an osteogenic phenotype, and calcification commonly occurs in association
      with lipid. We therefore tested the hypothesis that lipid components in
      atherosclerotic lesions influenced VSMC phenotype and calcification using an in
      vitro model of calcification. METHODS AND RESULTS: In situ hybridization of human
      atherosclerotic plaques (n=10) collected from patients undergoing carotid
      endarterectomy demonstrated that subsets of lipid-filled VSMCs adjacent to sites
      of calcification expressed alkaline phosphatase, bone Gla protein, and bone
      sialoprotein, suggesting an osteogenic phenotype. Treatment of VSMCs in culture
      with acetylated low-density lipoprotein (acLDL) or lipoprotein-deficient serum
      altered the time course of bone-associated protein gene expression and
      calcification. AcLDL increased nodule calcification 3-fold, whereas lipoprotein
      deficient serum significantly inhibited it. Reverse transcriptase-polymerase
      chain reaction and Western analysis demonstrated the presence of the acLDL
      receptor, SRA1, exclusively in calcifying nodular VSMCs, and blockade of SRA with
      polyinosinic acid inhibited acLDL-induced calcification. Because apoptotic bodies
      can serve as nucleation sites for calcification, we investigated whether acLDL
      could stimulate apoptosis in nodules. Apoptosis of nodular VSMCs was unaltered,
      but the number of apoptotic bodies per nodule increased approximately 3-fold,
      implying a defect in phagocytosis. Consistent with these observations, binding of
      apoptotic bodies to VSMCs was decreased in the presence of acLDL. CONCLUSIONS:
      These studies suggest that modified lipoproteins stimulate calcification by
      enhancing osteogenic differentiation of VSMCs and by a novel mechanism whereby
      acLDL interacts with SRA on VSMCs and blocks phagocytic removal of apoptotic
      bodies.

PMID- 12473550
TI  - Coronary flow velocity pattern immediately after percutaneous coronary
      intervention as a predictor of complications and in-hospital survival after acute
      myocardial infarction.
AB  - BACKGROUND: Recently, it was reported that the degree of microvascular injury and
      left ventricular functional recovery during the chronic period can be predicted
      after treatment of the infarct-related artery based on the coronary flow velocity
      (CFV) pattern assessed using a Doppler guidewire. The aim of this prospective
      study was to examine whether the CFV pattern may predict complications and in
      hospital survival after acute myocardial infarction (AMI). METHODS AND RESULTS:
      The study population consisted of 169 consecutive patients with a first anterior
      AMI successfully treated with percutaneous coronary intervention (PCI). We
      examined the CFV pattern immediately after PCI using a Doppler guidewire. In
      accordance with previous findings, we defined severe microvascular injury as a
      diastolic deceleration time < or =600 ms and the presence of systolic flow
      reversal. Patients were divided into two groups: those without severe
      microvascular injury (n=118; group 1) and those with severe microvascular injury
      (n=51; group 2). All of the patients who had cardiac rupture were in group 2.
      Congestive heart failure (CHF) was observed more frequently in group 2 than in
      group 1 (53% versus 8%, P<0.001). The in-hospital cardiac mortality rate was
      significantly higher in group 2 than in group 1 (18% versus 0%, P<0.001). Nine
      patients in group 2 died, 5 patients because of CHF and 4 patients because of
      cardiac rupture. CONCLUSIONS: These findings suggest that the CFV pattern is an
      accurate predictor of the presence or absence of complications and of in-hospital
      survival after AMI.

PMID- 12473551
TI  - S-nitrosoglutathione reduces asymptomatic embolization after carotid angioplasty.
AB  - BACKGROUND: The major complication of carotid angioplasty is embolic stroke,
      which may occur after balloon inflation and deflation or in the early
      postintervention period. Platelet adhesion and aggregation to the angioplasty
      site with subsequent embolization seems to plays a major role in early
      postangioplasty embolization and stroke. During this period, asymptomatic embolic
      signals can be detected in patients by transcranial Doppler ultrasound despite
      aspirin and heparin treatment. S-nitrosoglutathione (GSNO) is a nitric oxide
      donor that appears to have relative platelet specificity. We evaluated its
      effectiveness in reducing embolization after carotid angioplasty. METHODS AND
      RESULTS: Sixteen patients undergoing carotid angioplasty and stenting for
      symptomatic > or =70% internal carotid artery stenosis were randomized in a
      double-blind manner to GSNO or placebo given after surgery for 90 minutes. All
      patients were pretreated with aspirin and given heparin for 24 hours after the
      procedure. Transcranial Doppler recordings were made from the ipsilateral middle
      cerebral artery for 1 hour before treatment and at 0 to 3, 6, and 24 hours after
      treatment. GSNO resulted in a rapid reduction in the frequency of embolic signals
      of 95% at 0 to 3 hours and 100% at 6 hours (P=0.007 and P=0.01 versus placebo,
      respectively). In the placebo group, 2 patients experienced ipsilateral stroke
      after the angioplasty. No cerebrovascular events occurred in the GSNO group.
      CONCLUSIONS: S-nitrosoglutathione was highly effective in rapidly reducing the
      frequency of embolic signals after endovascular treatment for symptomatic high
      grade carotid stenosis.

PMID- 12473552
TI  - Lack of benefit from intravenous platelet glycoprotein IIb/IIIa receptor
      inhibition as adjunctive treatment for percutaneous interventions of
      aortocoronary bypass grafts: a pooled analysis of five randomized clinical
      trials.
AB  - BACKGROUND: Despite widespread use of platelet glycoprotein (GP) IIb/IIIa
      receptor inhibitors for percutaneous coronary interventions (PCI) of bypass
      grafts, data supporting this strategy are lacking. METHODS AND RESULTS: A pooled
      analysis of 5 randomized intravenous GP IIb/IIIa inhibitor trials (EPIC, EPILOG,
      EPISTENT, IMPACT II, and PURSUIT) was performed, and outcomes of graft
      interventions were assessed at 30 days and 6 months. Compared with PCI of native
      circulation (n=13 158), graft interventions (n=627) were associated with worse
      outcomes and in particular with a doubling of mortality at 30 days (2.1% versus
      1.0%, P=0.006) and 6 months (4.7% versus 2.0%, P<0.001). Revascularization of a
      graft was identified as an independent predictor of death, myocardial infarction,
      or revascularization at 6 months (hazard ratio, 1.42; 95% CI, 1.24 to 1.63;
      P<0.001). Among patients undergoing graft PCI, the incidence of the triple end
      point at 30 days was 16.5% in the platelet GP IIb/IIIa inhibitor group and 12.6%
      in the placebo group (odds ratio, 1.38; 95% CI, 0.85 to 2.24; P=0.18). At 6
      months, 39.4% of patients randomized to GP IIb/IIIa inhibitors and 32.7% of
      patients allocated to placebo had an ischemic event (hazard ratio, 1.29; 95% CI,
      0.97 to 1.72; P=0.07). CONCLUSIONS: Intravenous platelet GP IIb/IIIa receptor
      inhibition does not improve outcomes after PCI of bypass grafts. In the absence
      of mechanical emboli protection, this procedure is associated with high incidence
      of death and nonfatal ischemic events.

PMID- 12473553
TI  - Lifetime risk for developing congestive heart failure: the Framingham Heart
      Study.
AB  - BACKGROUND: Congestive heart failure (CHF) is an increasing public health
      problem. METHODS AND RESULTS: Among Framingham Heart Study subjects who were free
      of CHF at baseline, we determined the lifetime risk for developing overt CHF at
      selected index ages. We followed 3757 men and 4472 women from 1971 to 1996 for
      124 262 person-years; 583 subjects developed CHF and 2002 died without prior CHF.
      At age 40 years, the lifetime risk for CHF was 21.0% (95% CI 18.7% to 23.2%) for
      men and 20.3% (95% CI 18.2% to 22.5%) for women. Remaining lifetime risk did not
      change with advancing index age because of rapidly increasing CHF incidence
      rates. At age 80 years, the lifetime risk was 20.2% (95% CI 16.1% to 24.2%) for
      men and 19.3% (95% CI 16.5% to 22.2%) for women. Lifetime risk for CHF doubled
      for subjects with blood pressure >/=160/100 versus <140/90 mm Hg. In a secondary
      analysis, we only considered those who developed CHF without an antecedent
      myocardial infarction; at age 40 years, the lifetime risk for CHF was 11.4% (95%
      CI 9.6% to 13.2%) for men and 15.4% (95% CI 13.5% to 17.3%) for women.
      CONCLUSIONS: When established clinical criteria are used to define overt CHF, the
      lifetime risk for CHF is 1 in 5 for both men and women. For CHF occurring in the
      absence of myocardial infarction, the lifetime risk is 1 in 9 for men and 1 in 6
      for women, which highlights the risk of CHF that is largely attributable to
      hypertension. These results should assist in predicting the population burden of
      CHF and placing greater emphasis on prevention of CHF through hypertension
      control and prevention of myocardial infarction.

PMID- 12473554
TI  - Vascular oxidative stress and endothelial dysfunction in patients with chronic
      heart failure: role of xanthine-oxidase and extracellular superoxide dismutase.
AB  - BACKGROUND: Impaired flow-dependent, endothelium-mediated vasodilation (FDD) in
      patients with chronic heart failure (CHF) results, at least in part, from
      accelerated degradation of nitric oxide by oxygen radicals. The mechanisms
      leading to increased vascular radical formation, however, remain unclear.
      Therefore, we determined endothelium-bound activities of extracellular superoxide
      dismutase (ecSOD), a major vascular antioxidant enzyme, and xanthine-oxidase, a
      potent radical producing enzyme, and their relation to FDD in patients with CHF.
      METHODS AND RESULTS: ecSOD and xanthine-oxidase activities, released from
      endothelium into plasma by heparin bolus injection, were determined in 14
      patients with CHF and 10 control subjects. FDD of the radial artery was measured
      using high-resolution ultrasound and was assessed before and after administration
      of the antioxidant vitamin C (25 mg/min; IA). In patients with CHF, endothelium
      bound ecSOD activity was substantially reduced (5.0+/-0.7 versus 14.4+/-2.6 U x
      mL(-1) x min(-1); P<0.01) and closely related to FDD (r=0.61). Endothelium-bound
      xanthine-oxidase activity was increased by >200% (38+/-10 versus 12+/-4 nmol O2*-
      x microL(-1); P<0.05) and inversely related to FDD (r=-0.35) in patients with
      CHF. In patients with low ecSOD and high xanthine-oxidase activity, a greater
      benefit of vitamin C on FDD was observed, ie, the portion of FDD inhibited by
      radicals correlated negatively with ecSOD (r=-0.71) but positively with xanthine
      oxidase (r=0.75). CONCLUSIONS: These results demonstrate that both increased
      xanthine-oxidase and reduced ecSOD activity are closely associated with increased
      vascular oxidative stress in patients with CHF. This loss of vascular oxidative
      balance likely represents a novel mechanism contributing to endothelial
      dysfunction in CHF.

PMID- 12473555
TI  - Exercise anaerobic threshold and ventilatory efficiency identify heart failure
      patients for high risk of early death.
AB  - BACKGROUND: The maximal oxygen uptake (peak VO2) is used in risk stratification
      of patients with chronic heart failure (CHF). Peak VO2 might be lower than
      maximally possible if exercise is stopped early because of lack of patient
      motivation or premature cessation by the investigator. In contrast, the anaerobic
      threshold (VO2AT) and the ventilatory efficiency (VE versus VCO2 slope) are less
      subject to these influences. Thus, we compared these parameters with peak VO2 in
      identifying patients with CHF at increased risk for death within 6 months after
      evaluation. METHODS AND RESULTS: We performed cardiopulmonary exercise tests with
      gas exchange measurements in 223 consecutive patients with CHF (114 coronary
      artery disease, 92 dilated cardiomyopathy, 17 others) at the Herzzentrum
      Ludwigshafen between 1995 and 1998. We measured peak VO2, VO2AT and VE versus
      VCO2 slope. We selected peak VO2 of < or =14 mL/kg per minute, VO2AT of <11 mL/kg
      per minute, and VE versus VCO2 slope of >34 as threshold values for high risk of
      death. The median follow-up time was 644 days. Patients with peak VO2 of < or =14
      mL/kg per minute had a >3-fold-increased risk (OR=3.4; CI, 1.3 to 9.1), with
      VO2AT <11 mL/min per kg or VE versus VCO2 slope >34 a 5-fold increased risk for
      early death (OR=5.3; CI, 1.5 to 19.0; OR=4.8; CI, 1.7 to 13.8, respectively). In
      patients with both VO2AT <11 mL/kg per minute and VE versus VCO2 slope >34, the
      risk of early death was 10-fold higher (OR=9.6; CI, 2.1 to 44.7). After
      correction for age, sex, left ventricular ejection fraction, and New York Heart
      Association class in a multivariate analysis, the combination of VO2AT <11 mL/kg
      per minute and VE versus VCO2 slope >34 was the best predictor of 6-month
      mortality (RR=5.1, P=0.001). CONCLUSIONS: VO2AT of <11 mL/kg per minute and slope
      of VE versus VCO2 >34, combined, better identified patients at high risk for
      early death from CHF than did peak VO2 and should therefore be considered when
      prioritizing patients for heart transplantation.

PMID- 12473556
TI  - Prevalence and severity of "benign" mutations in the beta-myosin heavy chain,
      cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.
AB  - BACKGROUND: Genotype-phenotype correlative studies have implicated 8 particular
      mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects,"
      associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and
      L908V of beta-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N
      of alpha-tropomyosin (TPM1). Routine genetic screening of HCM patients for
      specific mutations is anticipated to provide important diagnostic and prognostic
      information. The frequency and associated phenotype of these mutations in a
      large, unselected cohort of HCM is unknown. METHODS AND RESULTS: A total of 293
      unrelated HCM patients were genotyped for the presence of a benign mutation. DNA
      was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments
      were amplified by polymerase chain reaction; and the mutations were detected by
      denaturing high-performance liquid chromatography and automated DNA sequencing.
      Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5
      subjects with an ascribed benign mutation had already manifested clinically
      severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5
      having a family history of sudden cardiac death, and 1 adolescent requiring an
      orthotopic heart transplant. CONCLUSIONS: These findings demonstrate the rarity
      of specific mutations in HCM and challenge the notion of mutation-specific
      clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and
      those patients with a benign mutation experienced a very serious clinical course.

PMID- 12473557
TI  - Ischemic preconditioning suppresses ventricular tachyarrhythmias after myocardial
      revascularization.
AB  - BACKGROUND: Ventricular fibrillation (VF) and tachycardia (VT) are the common and
      potential life-threatening complications after CABG. Ischemic preconditioning
      (IP) has been proved effective in reducing ischemia reperfusion arrhythmia in
      animals and humans. Whether IP is effective in suppressing postoperative VF/VT in
      patients with CABG has not been studied. METHODS AND RESULTS: Eighty-six patients
      with CABG with stable and unstable 3-vessel disease were equally randomly
      assigned into an IP and a control group. The patients who received IP received 2
      periods of 2-minute ischemia followed by 3-minute reperfusion. Twenty-four-hour
      electrocardiographic data were collected. IP resulted in fewer cases of VF after
      declamping (48.8% versus 79.1% in IP and control, P=0.004) and a shorter VF
      period (2.28+/-0.44 versus 4.41+/-0.51 minutes, P=0.002). The episodes of VT were
      significantly reduced in patients in the IP group during early reperfusion and 24
      hours after reperfusion (0.65+/-0.16 versus 3.71+/-0.46, P=0.000 and 0.07+/-0.04
      versus 2.12+/-1.41, P=0.002, respectively). De novo sustained VT occurred in 3
      control patients as against none in the IP group after surgery. As a result, IP
      significantly curtailed the mechanical ventilation period and reduced the need
      for inotropes. CONCLUSIONS: IP significantly reduced postoperative VF/VT in
      patients with CABG with 3-vessel disease. Suppression of VT during early
      reperfusion and 24 hours after reperfusion suggests early and delayed IP
      phenomena in patients undergoing CABG surgery.

PMID- 12473558
TI  - FrzA, a secreted frizzled related protein, induced angiogenic response.
AB  - BACKGROUND: The secreted frizzled related proteins (sFRP) are soluble proteins
      thought to interfere with the Wnt signaling. Our group previously demonstrated
      that one of these members, sFRP-1/FrzA, is strongly expressed during early phases
      of the vascularization process in embryonic vasculature and in the endothelium of
      arteries and capillaries in adults and modulated vascular cell proliferation.
      METHODS AND RESULTS: Analysis of the expression of sFRP-1 during cyclic ovarian
      angiogenesis revealed that sFRP-1 is expressed during the formation of neovessels
      and becomes undetectable when the vasculature is fully maturated. We then studied
      the role of FrzA in several distinct angiogenic models. FrzA induced angiogenesis
      in a chick chorioallantoic membrane model. Moreover, gene transfer of AdFrzA in
      grafted mesenchymal and glioma cells increased vessel density and tumor growth.
      FrzA induced formation of vessels, which were enlarged, longer, and appeared to
      be more mature compared with vessels formed under control treatments. In vitro,
      FrzA increased migration and tube formation of endothelial cells and seemed to
      protect them from apoptosis. FrzA-angiogenic effect in vitro was independent of
      vascular endothelial growth factor, fibroblast growth factor-2, or angiopiotin-1
      induction and Akt activation. In contrast, FrzA decreased glycogen synthase
      kinase-3 phosphorylation. CONCLUSIONS: These results showed that FrzA has
      proangiogenic effects and suggest that Wnt signaling may be involved in normal
      differentiation as well as in the pathological development of vasculature.

PMID- 12473559
TI  - Low-density lipoprotein upregulates low-density lipoprotein receptor-related
      protein expression in vascular smooth muscle cells: possible involvement of
      sterol regulatory element binding protein-2-dependent mechanism.
AB  - BACKGROUND: Low-density lipoprotein (LDL) receptor-related protein (LRP) is
      highly expressed in vascular smooth muscle cells (VSMCs) of both normal and
      atherosclerotic lesions. However, little is known about LRP regulation in the
      vascular wall. METHODS AND RESULTS: We analyzed the regulation of LRP expression
      in vitro in human VSMCs cultured with native LDL (nLDL) or aggregated LDL (agLDL)
      by semiquantitative reverse transcriptase-polymerase chain reaction, real-time
      polymerase chain reaction, and Western blot and in vivo during diet-induced
      hypercholesterolemia by in situ hybridization. LRP expression in human VSMCs is
      increased by nLDL and agLDL in a time- and dose-dependent manner. Maximal
      induction of LRP mRNA expression was observed after 24 hours of exposure to LDL.
      However, agLDL induced higher LRP mRNA expression (3.0-fold) than nLDL (1.76
      fold). LRP mRNA upregulation was associated with an increase on LRP protein
      expression with the greatest induction by agLDL. VSMC-LRP upregulation induced by
      nLDL or agLDL was reduced by an inhibitor of sterol regulatory element binding
      protein (SREBP) catabolism (N-acetyl-leucyl-leucyl-norleucinal). In situ
      hybridization analysis indicates that there is a higher VSMC-LRP expression in
      hypercholesterolemic than in normocholesterolemic pig aortas. CONCLUSIONS: These
      results indicate that LRP expression in VSMCs is upregulated by intravascular and
      systemic LDL.

PMID- 12473560
TI  - Nonselective cation currents regulate membrane potential of rabbit coronary
      arterial cell: modulation by lysophosphatidylcholine.
AB  - BACKGROUND: The effects of lysophosphatidylcholine (LPC) on electrophysiological
      activities and intracellular Ca2+ concentration ([Ca2+]i) were investigated in
      coronary arterial smooth muscle cells (CASMCs). METHODS AND RESULTS: The patch
      clamp techniques and Ca2+ measurements were applied to cultured rabbit CASMCs.
      The membrane potential was -46.0+/-5.0 mV, and LPC depolarized it. Replacement of
      extracellular Na+ with NMDG+ hyperpolarized the membrane and antagonized the
      depolarizing effects of LPC. In Na+-, K+-, or Cs+-containing solution, the
      voltage-independent background current with reversal potential (E(r)) of
      approximately +0 mV was observed. Removal of Cl- failed to affect it. When
      extracellular cations were replaced by NMDG+, E(r) was shifted to negative
      potentials. La3+ and Gd3+ abolished the background current, but nicardipine and
      verapamil did not inhibit it. In Na+-containing solution, LPC induced a voltage
      independent current with E(r) of approximately +0 mV concentration-dependently.
      Similar current was recorded in K+- and Cs+-containing solution. La3+ and Gd3+
      inhibited LPC-induced current, but nicardipine and verapamil did not inhibit it.
      In cell-attached configurations, single-channel activities with single-channel
      conductance of approximately 32pS were observed when patch pipettes were filled
      with LPC. LPC increased [Ca2+]i as the result of Ca2+ influx, and La3+ completely
      antagonized it. CONCLUSIONS: These results suggest that (1) nonselective cation
      current (I(NSC)) contributes to form membrane potentials of CASMCs and (2) LPC
      activates I(NSC), resulting in an increase of [Ca2+]i. Thus, LPC may affect CASMC
      tone under various pathophysiological conditions such as ischemia.

PMID- 12473561
TI  - NCX-4016 (NO-aspirin) inhibits lipopolysaccharide-induced tissue factor
      expression in vivo: role of nitric oxide.
AB  - BACKGROUND: NCX-4016 is an acetylsalicylic acid (ASA) derivative containing a
      nitric oxide-releasing moiety. Compared with ASA, NCX-4016 has a broader spectrum
      of antithrombotic and antiinflammatory activities. We hypothesized that NCX-4016
      might inhibit in vivo lipopolysaccharide (LPS)-induced expression of tissue
      factor (TF). METHODS AND RESULTS: Rats were administered 90 mg/kg NCX-4016 orally
      for 5 days. Placebo, 50 mg/kg ASA, and 80 mg/kg isosorbide-5-mononitrate (ISMN)
      were used in control groups. On day 5, rats were injected intraperitoneally with
      100 microg/kg LPS and killed 6 hours later. The expression of TF in monocytes was
      measured by flow cytometry and Western blot analysis. Reverse transcriptase
      polymerase chain reaction was performed to assess expression of TF and
      cyclooxygenase-2 (COX-2) genes. Plasma concentrations of interleukin-1beta and
      tumor necrosis factor-alpha were measured. Urine samples were collected to
      evaluate the excretion of the thromboxane metabolite 11-dehydro-thromboxane
      (TX)B2. Gastric mucosa was inspected. LPS injection was followed by synthesis TF
      and COX-2 mRNAs in circulating monocytes, which were blunted by NCX-4016 but not
      by ASA or ISMN. Both NCX-4016 and ISMN reduced TF expression on surface of
      circulating monocyte. LPS increased the excretion 11-dehydro-TXB2, and this was
      prevented by NCX-4016 and ASA. Unlike ASA, NCX-4016 reduced plasma interleukin
      1beta and tumor necrosis factor-alpha. In addition, NCX-4016 almost completely
      prevented mucosal damage, whereas ASA increased the extension of gastric lesions
      in LPS-injected rats. CONCLUSIONS: NCX-4016 prevents monocyte TF expression; this
      is accompanied by inhibition of TX and cytokine biosynthesis. These additive
      effects of nitric oxide release and COX inhibition may help explain efficacy and
      tolerability of NCX-4016.

PMID- 12473562
TI  - Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist,
      attenuates left ventricular remodeling and failure after experimental myocardial
      infarction.
AB  - BACKGROUND: Peroxisome proliferator-activated receptor-gamma activators have
      recently been implicated as regulators of cellular proliferation and inflammatory
      response such as cytokine expression. Because proinflammatory cytokines play a
      critical role in left ventricular (LV) remodeling after myocardial infarction
      (MI), we examined the effects of pioglitazone treatment in an experimental model
      of chronic heart failure. METHODS AND RESULTS: Mice with extensive anterior MI
      were treated with placebo or pioglitazone (3 mg x kg(-1) x d(-1)) as a dietary
      supplement for 4 weeks starting 6 hours after surgery. Infarct size and glucose
      levels were similar among all groups. LV cavity dilatation and dysfunction by
      echocardiography were significantly attenuated in MI mice given pioglitazone. LV
      end-diastolic pressure was increased in MI mice and was significantly reduced by
      pioglitazone treatment. Pioglitazone partially normalized LV dP/dt(max) and
      dP/dt(min), indices of LV contractile function, which were significantly reduced
      in MI mice. Improvement of LV function by pioglitazone was accompanied by a
      decrease in myocyte hypertrophy and interstitial fibrosis and a reduced
      expression of tumor necrosis factor-alpha, transforming growth factor-beta, and
      monocyte chemoattractant protein-1 genes in the noninfarcted LV from MI mice. LV
      inducible nitric oxide synthase and gelatinase B protein levels were increased in
      MI and were not altered by pioglitazone treatment. CONCLUSIONS: Pioglitazone
      improved LV remodeling and function in mice with post-MI heart failure. This
      effect was associated with an attenuated LV expression of inflammatory cytokines
      and chemokines. Peroxisome proliferator-activated receptor-gamma ligands have
      promise as preventive and therapeutic agents against heart failure.

PMID- 12473564
TI  - Images in cardiovascular medicine. Unusual form of truncus arteriosus associated
      with 22q11 deletion.

PMID- 12473563
TI  - Thrombosis increases circulatory hepatocyte growth factor by degranulation of
      mast cells.
AB  - BACKGROUND: Plasma concentrations of hepatocyte growth factor (HGF), a powerful
      angiogenic growth factor inducible by heparin, increase in thrombus-associated
      disorders such as myocardial infarction and unstable angina. The mechanism of
      this thrombus-associated HGF release, however, is unknown. METHODS AND RESULTS:
      Wistar rats received through the tail vein (1) normal saline (NS), (2) 50 micro g
      of the mast cell-degranulating agent CP48/80, or (3) 1000 U/kg heparin. Blood
      samples were collected at 10 minutes or 30 minutes after the injections, or from
      untreated rats, for measurements of HGF. The same experiments were performed in
      mast cell-deficient white spotting (Ws) rats. Ws rats have a small deletion of
      the c-kit gene and are deficient in mast cells. Intravenous heparin immediately
      increased plasma HGF in both Wistar (38.02+/-2.08 ng/mL versus 1.11+/-0.70 ng/mL
      in untreated rats, P<0.0001) and Ws rats (36.39+/-4.15 ng/mL versus 0.66+/-0.18
      ng/mL in NS-treated rats, P<0.0001). Injection of CP48/80 also increased plasma
      HGF in Wistar rats (9.12+/-1.11 ng/mL versus 0.65+/-0.24 ng/mL in NS group,
      P=0.004) but not in Ws rats (0.67+/-0.27 ng/mL versus 0.66+/-0.18 ng/mL in NS
      group, P=0.997). In a rat carotid artery microthrombus model, intra-arterial
      thrombus formation increased circulating HGF in Wistar rats (2.12+/-0.70 ng/mL
      versus sham 0.61+/-0.15 ng/mL in sham-operated Wistar rats, P=0.0064) but not in
      Ws rats (0.76+/-0.33 ng/mL versus 0.21+/-0.04 ng/mL in sham-operated Ws rats,
      P=0.29). In addition, in vitro stimulation of rat peritoneal mast cells with
      thrombin rapidly induced degranulation in a dose-dependent manner. CONCLUSIONS:
      These observations indicate that mast cell degranulation stimulated by thrombin
      is necessary for the rapid induction of plasma HGF in intravascular thrombus
      associated disorders.

PMID- 12473565
TI  - Cardiology patient page. Pulmonary hypertension.

PMID- 12473566
TI  - How to select patient candidates for antioxidant treatment?

PMID- 12473567
TI  - Pressor effects of beta-blockers on standing blood pressure may be harmful for
      older patients with orthostatic hypertension.

PMID- 12473568
TI  - Statin attenuates increase in C-reactive protein during estrogen replacement
      therapy in postmenopausal women.

PMID- 12473569
TI  - Aspirin resistance.

PMID- 12473570
TI  - Increased proinsulin concentrations and excess risk of coronary heart disease in
      patients with diabetes and prediabetes.

PMID- 12473571
TI  - One in 5 at risk for congestive heart failure.

PMID- 12473572
TI  - Targeting the mitochondria: an exciting new approach to myeloma therapy.
      Commentary re: N. J. Bahlis et al., Feasibility and correlates of arsenic
      trioxide combined with ascorbic acid-mediated depletion of intracellular
      glutathione for the treatment of relapsed/refractory multiple myeloma. Clin.
      Cancer Res., 8: 3658-3668, 2002.

PMID- 12473573
TI  - Testing of new agents in childhood cancer preclinical models: meeting summary.
AB  - A workshop on pediatric preclinical testing, sponsored by the National Cancer
      Institute and the Children's Oncology Group Phase 1 Consortium, was held on June
      26-27, 2001 in Bethesda, Maryland. Drs. Peter Adamson, Peter Houghton, and
      Malcolm Smith organized and hosted the meeting. There were 20 participants from
      12 institutions. The primary objectives of the workshop included: (a) development
      of a working inventory of available preclinical models (including human tumor
      xenografts in immunodeficient mice, transgenic and syngeneic tumors, and selected
      in vitro models), with a basic understanding of the strengths and weaknesses of
      each as possible components of a preclinical testing program; (b) identification
      of the key scientific issues related to establishment of a program for
      preclinical testing of new agents for their applicability to childhood cancers;
      and (c) identification of the key infrastructure requirements for a program for
      preclinical testing of new agents for their applicability to childhood cancers.
      This report is a synthesis of the workshop's presentations and discussions.

PMID- 12473574
TI  - Feasibility and correlates of arsenic trioxide combined with ascorbic acid
      mediated depletion of intracellular glutathione for the treatment of
      relapsed/refractory multiple myeloma.
AB  - Patients with multiple myeloma (MM) invariably relapse with chemotherapy
      resistant disease, underscoring the need for new agents that bypass these
      resistance mechanisms. We have reported that ascorbic acid (AA) enhances the
      activity of arsenic trioxide (As(2)0(3)) against drug-resistant MM in vitro by
      depleting intracellular glutathione (GSH). These data led us to open a National
      Cancer Institute/Cancer Therapy Evaluation Program-sponsored Phase I/II trial of
      As(2)0(3) + AA for relapsed/refractory MM. We now present the completed Phase I
      component of this trial. The primary objective of the trial's Phase I component
      was to assess whether the addition of AA affected the well-described toxicity
      profile of As(2)0(3) alone. Correlative studies were undertaken of As(2)0(3) and
      AA pharmacokinetics, the ability of AA to deplete intracellular GSH in vivo, and
      the development of arsenic resistance. Six patients with stage IIIA
      relapsed/refractory myeloma were studied. We found that 0.25 mg/kg/day As(2)O(3)
      + 1,000 mg/day AA could be given for 25 days (over a 35-day period) without dose
      limiting toxicity. One episode of grade 3 hematological toxicity (leukopenia) and
      no grade 3 nonhematological toxicities (in particular, cardiac) were observed.
      The coadministration of AA did not alter the pharmacokinetics of As(2)0(3), and
      elevated AA levels were associated with decreased intracellular GSH. Serial in
      vitro studies demonstrated continued sensitivity of patient myeloma cells to
      As(2)0(3) + AA. Two patients (both with thalidomide-refractory disease) had
      partial responses; four patients had stable disease. In conclusion, we have found
      that As(2)0(3) + AA has acceptable toxicity and that there is promising evidence
      of activity in refractory/relapsed myeloma.

PMID- 12473575
TI  - Correlation between insulin-like growth factor-binding protein-3 promoter
      methylation and prognosis of patients with stage I non-small cell lung cancer.
AB  - PURPOSE: The activities of insulin-like growth factors (IGFs) in regulating cell
      proliferation,differentiation, and apoptosis are modulated by a family of high
      affinity specific IGF-binding proteins (IGFBPs), especially IGFBP-3, the most
      abundant IGFBP in circulation. Hypermethylation of the promoter represses the
      expression of the IGFBP-3 gene. The purpose of this study was to determine
      whether the methylation status of IGFBP-3 promoter influences the prognosis of
      non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Eighty-three patients
      with pathological stage I NSCLC who had undergone curative surgery were
      investigated for promoter hypermethylation of IGFBP-3 by methylation-specific
      PCR. Statistical analyses, all two-sided, were performed to determine the
      prognostic effect of methylation status of the IGFBP-3 promoter on various
      clinical parameters. IGFBP-3 was the only molecular parameter tested on these
      tissues in this study. RESULTS: Hypermethylation of the IGFBP-3 promoter was
      found in 51 (61.5%) of the 83 tumors. The clinicopathological factors, such as
      age, histological type, histological grade, gender, and smoking status, of
      corresponding patients, did not exhibit statistically significant association
      with the methylation status of IGFBP-3 promoter. However, patients with a
      hypermethylated IGFBP-3 promoter had a significantly lower 5-year disease
      specific, disease-free, and overall survival rate than did those without a
      methylated IGFBP-3 promoter (53.1% versus 86.1%, P = 0.006; 36.5% versus 76.2%, P
      = 0.007; and 38.9% versus 64.0%, P = 0.022, respectively). Moreover, multivariate
      analysis indicated that hypermethylation of the IGFBP-3 promoter was the only
      independent predictor for disease-free and disease-specific survival among the
      clinical and histological parameters tested. CONCLUSIONS: Hypermethylation of the
      IGFBP-3 promoter, as measured by methylation-specific PCR, is a frequent
      phenomenon and strongly associated with poor prognosis among patients with stage
      I NSCLC.

PMID- 12473576
TI  - Safety and immunogenicity of TA-HPV, a recombinant vaccinia virus expressing
      modified human papillomavirus (HPV)-16 and HPV-18 E6 and E7 genes, in women with
      progressive cervical cancer.
AB  - PURPOSE: Cervical cancer, the second most common malignancy in women worldwide,
      is almost invariably associated with infection by human papillomavirus (HPV). HPV
      16 or -18 is commonly present in 70% of cervical cancers. HPV-positive tumor
      cells present antigens of the viral protein in the context of human leukocyte
      antigen (HLA) class I that can be recognized by CTLs. We have conducted a study
      in patients with early-stage cervical cancer to assess the safety and
      immunological effects of vaccination with TA-HPV, a live recombinant vaccinia
      virus expressing modified forms of the HPV-16 and -18 E6 and E7 proteins.
      EXPERIMENTAL DESIGN: Twenty-nine patients with clinical International Federation
      of Gynecologists and Obstetricians (FIGO) stage Ib or IIa cervical cancer were
      given two vaccinations with TA-HPV at least 4 weeks apart, starting 2 weeks
      before radical hysterectomy. Patients were monitored closely for side effects of
      the vaccination. Serial blood samples were examined for HPV-specific CTLs or
      changes in levels of antibodies to HPV-16 or -18 E6 and E7 proteins and to
      vaccinia virus. RESULTS: Vaccination with recombinant vaccinia was well tolerated
      in all patients with only mild to moderate local toxicity, and no serious adverse
      events were attributable to the vaccine. After a single vaccination, HPV-specific
      CTLs were found in four patients (HLA A1, A3, three patients; HLA A1, A24, one
      patient). Eight patients developed HPV-specific serological responses.
      CONCLUSIONS: This study confirmed the safety and immunogenicity of the vaccine in
      a proportion of those patients vaccinated. Additional clinical studies using TA
      HPV in combination with an additional experimental vaccine for HPV-16 are
      currently under way.

PMID- 12473577
TI  - Phase I study of intraperitoneal recombinant human interleukin 12 in patients
      with Mullerian carcinoma, gastrointestinal primary malignancies, and
      mesothelioma.
AB  - PURPOSE: The purpose is to determine dose-limiting toxicity,
      pharmacokinetics,pharmacodynamics, and immunobiology after i.p. injections of
      recombinant human IL-12 (rhIL-12). EXPERIMENTAL DESIGN: rhIL-12 was administered
      to 29 previously treated patients with peritoneal carcinomatosis from Mullerian
      carcinomas, gastrointestinal tract carcinomas and peritoneal mesothelioma in a
      Phase I trial. rhIL-12 doses were increased from 3 to 600 ng/kg. Three or more
      patients at each level received weekly i.p. injections of rhIL-12. RESULTS: Dose
      limiting toxicity (elevated transaminase) occurred in 2 of 4 patients at the 600
      ng/kg dose. More frequent toxicities included fever, fatigue, abdominal pain,
      nausea, and catheter-related infections. Ten patients received 300 ng/kg with
      acceptable frequency and severity of side effects. Two patients (one with ovarian
      cancer and one with mesothelioma) had no remaining disease at laparoscopy. Eight
      patients had stable disease and 19 progressive disease. At 300 ng/kg i.p., IL-12
      was cleared from peritoneal fluid in a biphasic manner with a terminal-phase half
      life of 18.7 h; peritoneal fluid levels of IL-12 5 min after i.p. injection were
      100-200 pg/ml, and serum levels reached approximately 10 pg/ml between 24 and 36
      h. IL-1-alpha, IL-2, IL-10, tumor necrosis factor alpha, and IFN-gamma were
      determined in serum and peritoneal fluid. IFN-gamma, IL-10, and tumor necrosis
      factor alpha were detected most frequently. Immunobiological effects included
      peritoneal tumor cell apoptosis, decreased tumor cell expression of basic
      fibroblast growth factor and vascular endothelial growth factor, elevated IFN
      gamma and IFN-inducible protein 10 transcripts in peritoneal exudate cells, and
      increased proportions of peritoneal CD3(+) relative to CD14(+) cells.
      CONCLUSIONS: rhIL-12 at 300 ng/kg by weekly i.p. injection is biologically active
      and adequately tolerated for Phase II studies.

PMID- 12473578
TI  - Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and
      interferon alpha.
AB  - PURPOSE: A therapeutic lyophilized melanoma vaccine consisting of two
      mechanically disrupted allogeneic melanoma cell lines and the immunological
      adjuvant Detox-PC (Melacine) has demonstrated encouraging activity in metastatic
      malignant melanoma, often in regimens containing pretreatment with low-dose
      cyclophosphamide. In addition, IFN-alpha2b (INTRON A; Schering-Plough
      Corporation, Kenilworth, NJ) has shown efficacy in melanoma refractory to
      Melacine. In this Phase II trial, the combination of cyclophosphamide, Melacine,
      and IFNalpha was tested in metastatic malignant melanoma. EXPERIMENTAL DESIGN:
      Eligibility criteria included measurable disease, no prior systemic therapy for a
      minimum of 4 weeks, and adequate marrow, renal, and hepatic function.
      Cyclophosphamide was administered once at a dose of 300 mg/m(2) i.v. on day -3
      before the first dose of Melacine. Melacine was administered at a dose of 2 x
      10(7) tumor cell equivalents per dose admixed with 0.25 ml of Detox-PC s.c. once
      a week on weeks 1-4 and week 6. Melacine maintenance was then given monthly from
      the 8th week, until progression or intolerable toxicity. IFN was started in the
      evening after the fourth dose of Melacine at a dose of 5,000,000 units/m(2) 3
      times a week, and continued until progression. RESULTS: Forty-seven patients were
      enrolled, of whom 39 completed the full course and were considered evaluable. The
      toxicity of the regimen was minimal and consisted mainly of pain at injection
      sites and granulomas caused by Detox-PC, and constitutional symptoms attributable
      to IFN. In 39 evaluable patients, the overall objective response rate was 10.2%,
      but 64% of patients had stabilization of their disease for at least 16 weeks. The
      median time to disease progression in evaluable patients was 8 months [95%
      confidence interval (CI), 6-13 months]. Median survival time for all of the 47
      patients enrolled was 12.5 months (95% CI, 8-15 months) with a median time to
      disease progression of 4 months (95% CI, 3-7 months). CONCLUSION: Despite a low
      objective response rate, this combination holds great promise because of its
      tolerability and the high proportion of prolonged durations of remission or
      disease stabilization that it elicited.

PMID- 12473579
TI  - A phase I study of the natural killer T-cell ligand alpha-galactosylceramide
      (KRN7000) in patients with solid tumors.
AB  - PURPOSE: alpha-galactosylceramide (KRN7000) is a glycosphingolipid that has been
      shown to inhibit tumor growth and to prolong survival in inoculated mice through
      activation of natural killer (NK) T cells. We performed a dose escalation study
      of KRN7000 in advanced cancer patients. EXPERIMENTAL DESIGN: Patients with solid
      tumors received i.v. KRN7000 (50-4,800 micro g/m(2)) on days 1, 8, and 15 of a 4
      weekly cycle. Patients were given 1 cycle and, in the absence of dose-limiting
      toxicity or progression, treatment was continued. Pharmacokinetics (PK) and
      immunomonitoring were performed in all patients. RESULTS: Twenty-four patients
      were entered into this study. No dose-limiting toxicity was observed over a wide
      range of doses (50-4,800 micro g/m(2)). PK was linear in the dose range tested.
      Immunomonitoring demonstrated that NKT cells (CD3+Valpha24+Vbeta11+) typically
      disappeared from the blood within 24 h of KRN7000 injection. Additional
      biological effects included increased serum cytokine levels (tumor necrosis
      factor alpha and granulocyte macrophage colony-stimulating factor) in 5 of 24
      patients and a transient decrease in peripheral blood NK cell numbers and
      cytotoxicity in 7 of 24 patients. Importantly, the observed biological effects
      depended on pretreatment NKT-cell numbers rather than on the dose of KRN7000.
      Pretreatment NKT-cell numbers were significantly lower in patients compared with
      healthy controls (P = 0.0001). No clinical responses were recorded and seven
      patients experienced stable disease for a median duration of 123 days.
      CONCLUSION: i.v. KRN7000 is well tolerated in cancer patients over a wide range
      of doses. Biological effects were observed in several patients with relatively
      high pretreatment NKT-cell numbers. Other therapeutic strategies aiming at
      reconstitution of the deficient NKT-cell population in cancer patients may be
      warranted.

PMID- 12473580
TI  - A phase I trial of a potent P-glycoprotein inhibitor, Zosuquidar.3HCl
      trihydrochloride (LY335979), administered orally in combination with doxorubicin
      in patients with advanced malignancies.
AB  - PURPOSE: The purpose of this study was to investigate the safety and tolerability
      of Zosuquidar.3HCl, a potent inhibitor of P-glycoprotein (Pgp), when administered
      p.o. alone and in combination with doxorubicin and to determine whether
      Zosuquidar.3HCl affects doxorubicin pharmacokinetics and inhibits Pgp function in
      peripheral blood natural killer lymphocytes. EXPERIMENTAL DESIGN: Patients with
      advanced nonhematological malignancies were eligible for this Phase I trial.
      Zosuquidar.3HCl and doxorubicin were administered separately during the first
      cycle of therapy and then administered concurrently. Zosuquidar.3HCl was
      administered over 4 days, with doses escalated until the occurrence of dose
      limiting toxicity. Subsequently, doxorubicin doses were increased from 45 to 75
      mg/m(2). Zosuquidar.3HCl, doxorubicin, and doxorubicinol pharmacokinetics were
      analyzed, and dual fluorescence cytometry was used to determine the effects of
      Zosuquidar.3HCl on Pgp function in natural killer cells. RESULTS: A total of 38
      patients were treated at nine dose levels. Neurotoxicity was dose-limiting for
      oral Zosuquidar.3HCl, characterized by cerebellar dysfunction, hallucinations,
      and palinopsia. The maximum-tolerated dose for oral Zosuquidar.3HCl administered
      every 12 h for 4 days is 300 mg/m(2). Zosuquidar.3HCl did not affect doxorubicin
      myelosuppression or pharmacokinetics, and Zosuquidar.3HCl pharmacokinetics were
      similar in the absence and presence of doxorubicin. Higher plasma concentrations
      of Zosuquidar.3HCl were associated with greater Pgp inhibition in natural killer
      cells. CONCLUSION: Zosuquidar.3HCl can be coadministered with doxorubicin using a
      4-day oral dosing schedule, with little effect on doxorubicin toxicity or
      pharmacokinetics. Further refinement in Zosuquidar.3HCl dosing and scheduling
      should be explored to optimize Pgp inhibition while minimizing cerebellar
      toxicity.

PMID- 12473581
TI  - A phase I trial of escalating doses of trastuzumab combined with daily
      subcutaneous interleukin 2: report of cancer and leukemia group B 9661.
AB  - PURPOSE: The purpose of this study was to determine the toxicity of escalating
      doses of trastuzumab when combined with a fixed dose regimen of interleukin (IL)
      2. EXPERIMENTAL DESIGN: Eligible patients had nonhematological malignancies for
      which standard therapy did not exist or was no longer effective and had tumors
      that overexpressed HER2. IL-2 was initially administered at a dose of 1.25
      million IU/m(2) (low dose) s.c. daily except for 3 days every 2 weeks, when it
      was given at a dose of 15 million IU/m(2) (intermediate dose). These doses were
      reduced to 1.0 million and 12 million IU/m(2) after the first 18 patients.
      Trastuzumab was administered i.v. just before the first intermediate IL-2 dose
      and was escalated in cohorts of six or more patients from 1 mg/kg every 2 weeks
      to 8 mg/kg weekly. In vitro cytotoxicity testing was performed with patient
      peripheral blood mononuclear cells and HER2-overexpressing cell lines. RESULTS:
      Forty-five patients were treated. Dose-related toxicity from trastuzumab was not
      observed. IL-2-related toxicities such as fever, chills, and fatigue were less
      common with the reduced doses of IL-2. There were two grade 3 and three grade 4
      pulmonary reactions. Four major responses were observed, all in breast cancer
      patients treated with trastuzumab doses of at least 4.0 mg/kg. Although IL-2
      produced expansion of natural killer cell subsets, there was no correlation
      between in vitro cytotoxicity and clinical response. CONCLUSIONS: A regimen of IL
      2 combined with trastuzumab is feasible, and response numbers are encouraging.
      Further testing of this regimen is warranted if the pulmonary toxicity can be
      ameliorated.

PMID- 12473582
TI  - Mitogen-actived protein kinase activation is an early event in melanoma
      progression.
AB  - PURPOSE: Melanoma is the most common cause of death from cutaneous malignancy,
      and is the cancer that is most rapidly rising in incidence. Because current
      therapeutic methods for metastatic melanoma are poorly efficacious, enhanced
      understanding of signal transduction in melanoma progression is warranted. Prior
      experimental studies in murine models and human tissues have shown a correlation
      among activation of mitogen activated protein kinase (MAPK) signaling,
      angiogenesis, and tumorigenesis. Because of these findings, we wanted to assess
      the role of MAPK signaling in melanoma progression and angiogenesis. EXPERIMENTAL
      DESIGN: We studied expression of phosphorylated (active) MAPK and two target
      genes known to be induced by MAPK signaling, tissue factor and vascular
      endothelial growth factor, in 131 melanocytic lesions, ranging from atypical nevi
      to metastatic melanoma. RESULTS: We observed little staining for activated
      (phosphorylated) MAPK and low amounts of angiogenesis in atypical nevi, but
      angiogenesis and MAPK activation were activated in radial growth melanoma and in
      later stage lesions. CONCLUSIONS: Our findings implicate MAPK activation as an
      early event in melanoma progression, and MAPK may be a potential target for
      pharmacologic intervention.

PMID- 12473583
TI  - Expression of TRAIL and TRAIL receptors in colon carcinoma: TRAIL-R1 is an
      independent prognostic parameter.
AB  - PURPOSE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
      selectively induces apoptosis in cancer cells and may be involved in protection
      from metastases. TRAIL receptor (TRAIL-R) 1 and TRAIL-R2, but not TRAIL-R3 and
      TRAIL-R4, mediate apoptosis. We examined the expression of TRAIL and its
      receptors in normal and neoplastic colon epithelium, and studied its correlation
      with prognosis in colon cancer. EXPERIMENTAL DESIGN: Immunohistochemistry was
      performed on normal colon mucosa (n = 10), colon adenomas (n = 20), and R0
      resected Unio Internationale Contra Cancrum stage II/III colon carcinomas (n =
      129). Disease-free survival was examined by Kaplan-Meier estimates and the log
      rank test. Prognostic factors were determined by multivariate Cox-analysis.
      RESULTS: In normal colon mucosa, TRAIL and TRAIL-R2 were expressed mostly in the
      surface epithelium, whereas TRAIL-R1 and TRAIL-R4 were detected all along the
      crypt axis. In adenomas, this expression pattern was mostly retained, although
      some adenomas also neoexpressed TRAIL-R3. In carcinomas, the expression of TRAIL
      and TRAIL receptors was much more variable. TRAIL, TRAIL-R2, TRAIL-R3, and TRAIL
      R4 expression did not correlate statistically with disease-free survival
      (multivariate analysis: P = 0.54, P = 0.67, P = 0.45, and P = 0.69,
      respectively), but TRAIL-R1 expression was significantly associated with disease
      free survival in colon cancer (multivariate analysis: P = 0.003). CONCLUSIONS:
      TRAIL-R1 is an independent prognostic factor in R0-resected Unio Internationale
      Contra Cancrum stage II/III colon cancer.

PMID- 12473584
TI  - Aberrant promoter methylation in Chinese patients with non-small cell lung
      cancer: patterns in primary tumors and potential diagnostic application in
      bronchoalevolar lavage.
AB  - This study was aimed at defining patterns of aberrant gene methylation in non
      small cell lung cancer (NSCLC) in Chinese patients and its use in detecting
      cancer cells in bronchoalveolar lavage (BAL). The methylation-specific PCR (MSP)
      was used to study methylation of the p16, retinoic acid receptor-beta (RARbeta),
      death-associated protein (DAP) kinase, and O(6)-methylguanine-DNA
      methyltransferase (MGMT) genes in 75 NSCLCs [44 adenocarcinomas and 31 squamous
      cell carcinomas (SCCs)] and 68 BALs from suspected lung cancers. More females had
      adenocarcinoma than SCC (11 of 44 versus 2 of 31, P = 0.04). Aberrant methylation
      in at least one gene was found in 63 of 75 (84%) NSCLCs. p16, RARbeta, DAP
      kinase, and MGMT methylation was similar in adenocarcinoma and SCC. However,
      females with NSCLC showed more frequent p16 methylation than males (12 of 13
      versus 36 of 62, P = 0.02), because of more frequent p16 methylation in female
      adenocarcinomas (10 of 11 versus 17 of 33, P = 0.02). This sexual difference was
      not observed in RARbeta, DAP kinase, and MGMT. At 92%, the frequency of p16
      methylation in Chinese female NSCLC is one of the highest known. For BAL, MSP and
      cytological analysis showed concordant and discordant results in 25 of 68 and 43
      of 68 samples. Of 41 MSP+/cytology- cases, 35 were eventually shown to have
      malignant lung lesions, 4 were at high risk but had no evidence of lung cancer,
      and 2 were lost to follow-up. There were two MSP-/cytology+ cases. Frequent gene
      methylations were seen in Chinese NSCLC patients. More frequent p16 methylation
      was seen in female patients. MSP is a useful molecular adjunct for cancer cell
      detection in BAL samples.

PMID- 12473585
TI  - Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and
      intratumoral fluid.
AB  - PURPOSE: On the basis of the finding of marked overexpression in angiogenic
      microvessels, aminopeptidase N/CD13 has recently been suggested to play a
      prominent role in tumor angiogenesis. A soluble form of CD13 (sCD13) is present
      in human plasma, but its role in cancer has not been addressed. We hypothesized
      that sCD13 would be shed by tumor cells and/or endothelial cells lining tumor
      vessels, giving high levels of sCD13 in intratumoral fluid (TF) deposits and in
      malignant effusions. If so, sCD13 could be a convenient potential marker for
      tumor load and/or activated tumor endothelium. EXPERIMENTAL DESIGN: We have
      measured the specific sCD13 activity in effusions from 90 cancer patients and 12
      patients with a nonmalignant condition, and studied its relationship with other
      major (anti-)angiogenic factors. In a separate group of patients (n = 41), the
      relationship of sCD13 activity in plasma with tumor load was studied. RESULTS:
      The sCD13 activity was highest in plasma from cancer patients 71.9 (fmol/ml/s
      hydrolyzed substrate) versus 42.4 for healthy subjects. In TF, malignant
      effusions, and nonmalignant effusions, the activities were 52.8, 33.5, and 18.6,
      respectively. We further studied the relationship of sCD13 with tumor load as
      well as with vascular endothelial growth factor (VEGF), endostatin, matrix
      metalloproteinase (MMP)-2, MMP-9, urokinase-type plasminogen activator, and
      plasmin. A significant correlation of sCD13 activity in plasma was found with
      tumor load (r = 0.68; P = 0.01), suggesting that plasma sCD13 is, at least,
      partly originating from tumor(-endothelium). The concentrations of VEGF and
      endostatin and the activities of urokinase-type plasminogen activator and MMP-9,
      but not MMP-2, were significantly higher in TF compared with all other effusions.
      In TF, a correlation between sCD13 and VEGF was found (r = 0.67; P = 0.03). No
      correlation of sCD13 with the other protease activities was found. CONCLUSION:
      The sCD13 activity is elevated in plasma and effusions of cancer patients. A
      strong correlation of plasma sCD13 with tumor load was found. On the basis of
      these results, the potential of sCD13 activity as a tumor and/or angiogenesis
      marker warrants further investigation.

PMID- 12473586
TI  - Quantification of macrophage migration inhibitory factor mRNA expression in non
      small cell lung cancer tissues and its clinical significance.
AB  - PURPOSE: Macrophage migration inhibitory factor (MIF) is a proinflammatory
      cytokine derived from T cells and the pituitary gland. However, several types of
      solid cancers also secrete MIF, and this factor has been suggested to play an
      important role in carcinogenesis and the progression of malignancy. In this
      study, we quantified MIF mRNA expression of non-small cell lung cancer tissues
      and examined its relationship with clinicopathological factors. EXPERIMENTAL
      DESIGN: MIF mRNAs of both tumor and normal tissues were quantified by a real-time
      monitoring reverse-transcription PCR in 59 patients with non-small cell lung
      cancer. The relationship between the grade of MIF expression and
      clinicopathological factors such as smoking history, cell type, stage, and
      prognosis was examined to investigate the clinical significance of intratumoral
      expression of MIF. RESULTS: The mean copy number of MIF mRNA per 0.08 micro g of
      total mRNA in tumor tissues was 144,078.00, whereas that of normal lung tissue
      was 25,438.46 (P < 0.0001). The amounts of MIF proteins revealed by a Western
      blot analysis correlated well with those of the corresponding mRNAs. Male
      patients and heavy smokers showed significantly higher expression of MIF.
      Patients with squamous cell carcinomas showed a higher expression of MIF mRNA
      than other subjects. In squamous cell carcinoma patients, higher expression of
      MIF mRNA was significantly associated with unfavorable prognosis (P = 0.0142).
      CONCLUSIONS: The general intratumoral expression and close relation with smoking
      suggested that MIF might contribute to tumorigenesis in the lung.

PMID- 12473587
TI  - Tumor DNA in plasma at diagnosis of breast cancer patients is a valuable
      predictor of disease-free survival.
AB  - PURPOSE: We examine prospectively whether the presence of plasma DNA with tumor
      characteristics before mastectomy is a predictive factor related to recurrence
      and disease-free survival (DFS). EXPERIMENTAL DESIGN: A series of 147 patients
      with breast carcinomas, selected sequentially, was analyzed. The characterization
      of plasma DNA, based on similar alterations in tumor and plasma DNA, was achieved
      with six polymorphic markers (D17S855, D17S654, D16S421, TH(2), D10S197, and
      D9S161) and mutations in the TP53 gene. Recurrence, DFS, overall survival, and 12
      other clinicopathological parameters were obtained. Univariate and Cox's
      multivariate studies were performed. RESULTS: A total of 142 patients were
      eligible for study. A total of 104 tumors (73.2%) showed at least one molecular
      alteration. In 61 patients (42.9%), a similar molecular alteration was detected
      in plasma DNA and tumor DNA. No alterations were found in the plasma DNA of the
      remaining 81 patients (57%). During the follow-up period (median, 22 months;
      range, 1-46 months), we observed 23 recurrences (16%), the distribution of which
      was significantly different (P = 0.005) with regard to plasma DNA [17 patients
      (74%) with circulating tumor DNA and 6 patients (26%) without tumor plasma DNA].
      Univariate statistical analysis confirmed the prognostic significance of the
      already known parameters (tumor size, lymph node metastases, and stage) and
      demonstrated that tumor plasma DNA was a predictor of DFS. In multivariate
      analysis, an independent borderline significance was observed for tumor plasma
      DNA. CONCLUSIONS: Tumor DNA in plasma at diagnosis in breast cancer patients can
      predict DFS, and its determination could be used as a prognostic factor in these
      patients.

PMID- 12473588
TI  - ATP-binding cassette superfamily transporter gene expression in human primary
      ovarian carcinoma.
AB  - PURPOSE: The purpose of this study is to attempt to characterize patients with
      unfavorable clinical outcome by the relative mRNA levels of ABC transporter
      expression in their tumor samples and to examine whether relative mRNA levels of
      each of the ABC transporters can be a useful predictor of progression-free
      survival in advanced ovarian carcinoma. EXPERIMENTAL DESIGN: We examined tumor
      samples taken from 30 patients with primary serous papillary adenocarcinoma of
      the ovary for the expression of MDR1 and MRP1, MRP2, and MRP3 mRNA by using real
      time reverse transcription-PCR, and we evaluated its correlation with clinical
      outcome. All 30 patients were divided into three groups according to clinical
      outcome after debulking surgery and platinum-based chemotherapy: 8 patients were
      classified into the unfavorable group; 11 were classified into the favorable
      group; and 11 were classified into intermediate group. RESULTS: The relative mRNA
      levels of MRP1 and MRP3 were significantly different among the three groups, and
      the mRNA levels of MRP1 and MRP3 in the unfavorable group were significantly
      higher than those in the favorable group by multiple comparison. The relative
      mRNA levels of MRP1 expression were significantly correlated with those of MRP3
      expression. In the 30 patients with serous papillary adenocarcinoma, univariate
      and multivariate analysis demonstrated that the high relative mRNA levels of MRP1
      expression were significantly correlated with a short period of progression-free
      survival. CONCLUSIONS: In patients with advanced ovarian serous papillary
      adenocarcinoma, these results suggest that patients with an unfavorable clinical
      outcome are characterized by increased levels of coordinated MRP1 and MRP3 mRNA
      expression in their tumor samples. Furthermore, a higher level of MRP1 mRNA
      expression can be a candidate for a useful predictor of a shorter period of
      progression-free survival.

PMID- 12473589
TI  - Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.
AB  - PURPOSE: Several studies to date have reported ovarian cancer risk due to
      inherited BRCA1 and BRCA2 mutations using familial data or population-based
      series of probands. Familial aggregation associated with both of these methods
      may result in a substantial ascertainment bias. To address this, we have used a
      case-control design that does not involve familial aggregation to estimate the
      lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations.
      EXPERIMENTAL DESIGN: A total of 382 ovarian cancer cases self-identified as being
      Jewish with no prior diagnosis of breast cancer were derived from two hospital
      based series. In the first series, all 197 invasive epithelial ovarian cancer
      cases self-identified as Jewish and without a prior history of breast cancer,
      diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and
      2000, were identified. In the second series, 185 Jewish invasive epithelial
      ovarian cancer patients without prior breast cancer were identified in a study
      conducted at 11 centers in North America and Israel from 1995 to 1996. Controls
      were 3434 Jewish women without any prior history of breast or ovarian cancer from
      a large study of genotyped volunteers of Jewish origin in the Washington, D. C.
      area recruited by investigators at the National Cancer Institute. The cases and
      controls were genotyped for three Ashkenazi Jewish founder mutations, namely
      185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances
      were estimated using the odds ratios, mutation prevalence in the controls, and
      ovarian cancer incidence rates in the general American population obtained from
      the Surveillance, Epidemiology and End Results database adjusted for the
      incidence of ovarian cancer following breast cancer. RESULTS: Mutations were
      identified in 147 cases and 62 controls. The estimated penetrances at age 70
      years were 37% (95% confidence interval, 25-71%) for a BRCA1 mutation and 21%
      (95% CI, 13-41%) for a BRCA2 mutation. CONCLUSIONS: The lifetime penetrances of
      BRCA1 mutations are lower than estimates obtained using familial data with
      multiple affected members but larger than estimates from some population-based
      proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the
      range reported by some of the studies based on familial data. These results could
      have implications for clinical counseling, surgical interventions, and screening
      recommendations in women carrying these founder mutations.

PMID- 12473590
TI  - p16(INK4A) Hypermethylation detected by fluorescent methylation-specific PCR in
      plasmas from non-small cell lung cancer.
AB  - PURPOSE: The p16(INK4A) tumor suppressor gene is inactivated in many solid
      tumors, including non-small cell lung cancers (NSCLCs), through promoter
      hypermethylation. Presence of p16(INK4A) hypermethylation in precursor lesions of
      NSCLC and in body fluids of individuals at risk makes it a potential candidate
      for early disease detection. However, the current low sensitivity of p16(INK4A)
      hypermethylation detection in plasma limits its consideration in a diagnostic
      grid. EXPERIMENTAL DESIGN: A fluorescent methylation-specific PCR assay (F-MSP)
      was established to evaluate p16(INK4A) promoter hypermethylation in 35 NSCLC and
      paired plasma samples and in 15 plasmas from healthy donors. F-MSP sensitivity
      was investigated in combination with microsatellite alterations on 3p (evaluated
      by fluorescent PCR), K-ras mutations (determined by a mutant-enriched PCR), and
      quantification of circulating DNA. Assay results were analyzed by two-sided
      chi(2) or Fisher's exact tests. RESULTS: p16(INK4A) promoter hypermethylation,
      detectable by F-MSP in 22 of 35 NSLCs (63%) and in 12 of 22 (55%) plasmas from
      patients with methylated tumors, was independent of microsatellite alterations
      (detectable in 57% of tumors and 50% of paired plasmas), K-ras mutations
      (detectable in 31% of tumors but in no paired plasma), or amount of circulating
      DNA. p16(INK4A) methylation in association with microsatellite alterations
      identified 62% (18 of 29) of plasma samples from patients presenting the same
      alteration in their tumors, and its sensitivity increased to 80% when combined
      with the amount of circulating DNA. CONCLUSIONS: The establishment of F-MSP
      remarkably improved p16(INK4A) promoter hypermethylation detection in plasmas
      from NSCLC patients. Microsatellite alterations, circulating DNA quantification,
      and p16(INK4A) hypermethylation might contribute to a diagnostic grid for NSCLC.

PMID- 12473591
TI  - Analysis of gene expression in ductal carcinoma in situ of the breast.
AB  - PURPOSE: The risk of recurrence and progression of ductal carcinoma in situ
      (DCIS) of the breast is best designated by morphological indicators, including
      the presence of necrosis. Our purpose was to identify molecular alterations
      underlying progression of DCIS. EXPERIMENTAL DESIGN: We have compared gene
      expression within a cohort of six cases of DCIS with necrosis (DCIS(necrosis+))
      and four cases without necrosis (DCIS(necrosis-)) using microdissection and cDNA
      microarray. RESULTS: A set of 69 cDNAs from a group of 1,181 was identified that
      were consistently differentially expressed. Among this set, the mRNA for angio
      associated migratory cell protein and a serine threonine protein kinase, nuclear
      Dbf2 related, were consistently higher in DCIS(necrosis+) and were also found to
      be overexpressed in the T47D breast cancer cell line subjected to hypoxia.
      Further study of angio-associated migratory cell protein by quantitative reverse
      transcriptase-PCR and in situ hybridization analysis of 37 cases of DCIS
      confirmed higher mRNA expression in DCIS(necrosis+) (P = 0.0095). CONCLUSIONS:
      This study shows that although levels of gene expression are mostly similar
      between morphologically different DCIS, consistent differences in expression of a
      subset of genes can be identified between DCIS with and without necrosis.

PMID- 12473592
TI  - Clinical significance of insulin-like growth factor-binding protein-3 expression
      in stage I non-small cell lung cancer.
AB  - The activities of insulin-like growth factors (IGFs), including mitogenic and
      antiapoptotic properties, are modulated by a family of high-affinity insulin-like
      growth factor-binding proteins (IGFBPs), of which IGFBP-3 is the major serum
      carrier protein. Even though it is well known that IGFBP-3 plays an important
      role in cell proliferation, the expression of IGFBP-3 and its significance in
      primary non-small cell lung cancer (NSCLC) samples are unknown. This study
      explored IGFBP-3 expression in tumor samples from 74 patients with a diagnosis of
      pathological stage I NSCLC to determine if the expression status of IFGBP-3
      influences the prognosis of patients with NSCLC. Two-sided statistical analyses
      were performed to correlate the clinical parameters and the prognostic effect
      with the IGFBP-3 expression level in this cohort. Reduced IGFBP-3 expression was
      found in 42 (56.8%) of 74 samples, and it was more frequent in large cell
      carcinoma than in squamous cell carcinoma and adenocarcinoma, although this
      difference was not statistically significant. This phenomenon was not associated
      with the other clinicopathological parameters tested, such as age, sex,
      histological grade, and smoking history. Significant statistical correlation
      between IGFBP-3 expression and disease-specific survival was noted (P = 0.019 by
      log-rank test). Although statistically nonsignificant, patients with decreased
      IGFBP-3 expression had shorter overall, disease-free, and event-free survival
      rates than did patients with normal IGFBP-3 expression. In a multivariate
      analysis using IGFBP-3 expression and other clinicopathological parameters, the
      level of IGFBP-3 expression remained as an independent factor for predicting a
      shorter disease-specific survival probability (P = 0.020). Our work demonstrates
      that down-regulation of IGFBP-3 is a frequent event in stage I NSCLC and
      correlates with the disease-specific survival probability of patients with stage
      I NSCLC. These results suggest that IGFBP-3 functions as a tumor suppressor and
      plays an important role in determining biological aggressiveness in early NSCLC.

PMID- 12473593
TI  - RANTES expression is a predictor of survival in stage I lung adenocarcinoma.
AB  - PURPOSE: The presence of an active lymphocytic response (ALR) in non-small cell
      lung cancer (NSCLC) tumors has previously been associated with a more favorable
      prognosis. The purpose of this study was to identify differences in global gene
      expression profiles between stage I NSCLC tumors with ALR (ALR+) and those
      without ALR (ALR-). EXPERIMENTAL DESIGN: Sixty-three stage I lung adenocarcinomas
      were analyzed for gene expression using Affymetrix oligonucleotide microarrays.
      Tumors were stratified into ALR+ and ALR- groups and compared for statistically
      significant differences in gene expression. Identified candidate genes were
      validated using both ELISA and immunohistochemistry. Follow-up data for these
      patients were collected and used to assess patient prognosis. RESULTS: Of the 63
      tumors studied, 27 were ALR+ and 36 were ALR-. A total of 303 genes showed
      significant differences in gene expression between the two populations (t test, P
      < 0.02). Three of the genes overexpressed by ALR+ tumors were the chemokines:
      small inducible cytokine A4 (MIP-1beta), RANTES, and interferon inducible protein
      10 (IP-10). Immunohistochemistry analysis showed that the tumor cells expressed
      these cytokines. ELISA showed that MIP-1beta and RANTES were overexpressed at the
      protein level by ALR+ tumors. Univariate Cox proportional hazards analysis showed
      that RANTES was a predictor of survival in stage I lung adenocarcinomas (P =
      0.002). CONCLUSION: When tested in the Cox univariate proportional hazards model,
      RANTES expression by lung adenocarcinoma cells is a predictor of survival in
      stage I NSCLC patients and may be useful as a prognostic factor in lung cancer.

PMID- 12473595
TI  - A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter
      enhances breast cancer susceptibility.
AB  - PURPOSE: Matrix metalloproteinases (MMPs) are likely to be involved in invasion
      and metastasis of several tumors by degrading the extracellular matrix. A single
      adenine insertion/deletion polymorphism (5A/6A) in the MMP-3 promoter region
      causes the elevation of transcriptional level and local expression of MMP-3. The
      aim of this pilot study was to evaluate the impact of this 5A/6A polymorphism on
      susceptibility and metastasis in breast cancer. EXPERIMENTAL DESIGN: Genotyping
      for 5A/6A polymorphism was performed in 86 Italian women operated on for breast
      cancer and followed for 6-30 months (median follow-up, 21 months). A control
      population of 110 Italian age-matched tumor-free women was also genotyped for the
      same polymorphism. The 1G/2G gene promoter polymorphism for MMP-1 was
      additionally tested. RESULTS: The frequency of 5A allele was higher in the breast
      cancer group than in controls (P = 0.035; odds ratio, 1.53; 95% confidence
      interval, 1.02-2.29). The breast cancer group was divided into a group without
      metastasis (M-) and a group that had developed metastasis (M+). At the time of
      diagnosis, the 5A allele was more prevalent in the M+ group than in controls (P =
      0.010; odds ratio, 1.96; 95% confidence interval, 1.16-3.30). The difference
      between M- patients and controls did not reach statistical significance (P =
      0.37). This study was not able to demonstrate any statistical differences with
      respect to 1G/2G polymorphism between controls and cases and between M+ and M-
      subgroups. CONCLUSIONS: Although this should be considered only as a pilot study,
      our results suggest that the presence of 5A polymorphism at the MMP-3 promoter
      region may represent an unfavorable prognostic feature in breast cancer patients
      associated with more invasive disease.

PMID- 12473594
TI  - Rare variants of ATM and risk for Hodgkin's disease and radiation-associated
      breast cancers.
AB  - PURPOSE: In this study, we first sought to evaluate whether individuals
      heterozygous for ATM mutations may have an increased susceptibility to radiation
      induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next
      sought to determine the frequency of ATM variants in patients with Hodgkin's
      lymphoma, regardless of coexisting BC, compared with healthy volunteers.
      EXPERIMENTAL DESIGN: Full sequence analysis of ATM was performed on cDNA from
      peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation
      therapy for HD and 27 comparison cases with HD and no BC treated during the same
      time period. The frequency of ATM variants was analyzed in the total group of 64
      cases of HD and compared to allele frequencies in 128 ethnically matched controls
      from the same geographical region. RESULTS: No protein-truncating ATM mutations
      were observed in cases with HD with or without BC. Missense mutations were more
      frequent in the cohort with HD compared with patients with BC following HD (P =
      0.02). The median time from HD to the development of BC was 18 years in patients
      with ATM variants compared with 16 years in those with no ATM variants (P =
      0.04). Multiple ATM variants, including one homozygous mutation, were observed in
      9 HD cases. CONCLUSIONS: Heterozygous protein-truncating or missense mutations of
      ATM were not associated with increased radiation-associated risk of BC after HD.
      The observation of multiple germ-line mutations and a homozygote suggests that
      rare ATM variants may constitute cancer-susceptibility alleles in a subset of
      cases.

PMID- 12473596
TI  - Down-regulation of PIK3CG, a catalytic subunit of phosphatidylinositol 3-OH
      kinase, by CpG hypermethylation in human colorectal carcinoma.
AB  - PURPOSE: Premature death associated with colorectal adenocarcinoma occurs in
      PIK3CG(-/-) mice and overexpression of PIK3CG in colon cancer cells suppresses
      cell proliferation. We examined expression levels of PIK3CG, a catalytic subunit
      of phosphatidylinositide 3-OH kinase (PI3K), in colon cancer cells to investigate
      the hypothesis that PIK3CG might contribute to the growth and progression of
      colorectal cancers. EXPERIMENTAL DESIGN: The effects of LY294002, a PI3K
      inhibitor, on cell growth were examined to elucidate the role of the PI3K
      Akt/protein kinase B (PKB) pathway in colon cancer. We used reverse transcription
      PCR, Western blotting, and immunohistochemical analyses to examine PIK3CG mRNA
      and protein expression levels in colon cancer cells and primary colorectal
      cancers. To clarify the mechanism responsible for the silencing of this gene in
      colon cancers, we performed methylation-sensitive PCR analysis of DNA digested
      with HpaII and MspI and analyzed PI3KCG expression in DLD-1 and LoVo cells
      treated with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza). RESULTS:
      LY294002 suppressed growth and decreased expression of Akt (Ser(473)) expression
      in cancer cells. Three (60%) of 5 colon cancer cell lines did not express PIK3CG,
      but hypermethylation at CpG sites of the promoter regions of this gene was
      detected. However, 5-Aza-treated DLD-1 and LoVo cells did express PIK3CG.
      Reduction of PIK3CG expression was detected immunohistochemically in 85% of human
      colorectal cancers and was closely associated with invasion, metastasis, and poor
      differentiation. Down-regulation of PIK3CG expression and hypermethylation of
      promoter regions were also detected in primary colon cancers. CONCLUSIONS: Our
      findings suggest that the silencing of the PIK3CG gene plays an important role in
      inhibiting the PI3K-Akt/PKB signaling system responsible for tumorigenesis and
      the progression of colorectal cancers.

PMID- 12473597
TI  - Preclinical validation of a monochrome real-time multiplex assay for
      translocations in childhood acute lymphoblastic leukemia.
AB  - PURPOSE: The purpose is to develop a real-time multiplex reverse transcription
      PCR assay for detection and quantification of leukemia-specific chimeric
      transcripts that identify the genetic subgroups of acute lymphoblastic leukemias
      (ALLs) proposed by the WHO classification. EXPERIMENTAL DESIGN: Real-time
      multiplex assay for t(12;21), t(4;11), and t(1;19) with hypoxanthine
      phosphoribosyltransferase as internal standard used in tandem with a new real
      time quantitative-RT-PCR assay for the t(9;22). This new strategy was designed to
      yield an amplicon from each translocation with a distinct melting peak allowing
      dependable identification using only Sybr green I, without any need for expensive
      hybridization probes. RESULTS: We validated this method with 92 primary ALLs and
      identified 4 E2A-PBX1, 4 mBCR-ABL and 10 TEL-AML1. When compared with
      conventional RT-PCRs and Southern blot analyses, 100% concordance was obtained.
      During the course of these studies, we found marked variations in the levels of
      the TEL-AML1 transcripts in individual patients. We, therefore, extended the
      study to accurately and reproducibly determine TEL-AML1 mRNA levels in 47
      additional patients with t(12;21). The results indicated that the level of
      expression of TEL-AML1 varied among individual patients, and it was independent
      of the WBC count. CONCLUSIONS: Our new real-time multiplex assay can be used for
      rapid, simple, and reliable classification of pediatric ALL. Its reproducible
      quantification results should also facilitate studies on minimal residual
      disease. The observed variation in TEL-AML1 transcript levels is of interest
      because it could reflect biological and/or clinical heterogeneity in the behavior
      of these leukemias.

PMID- 12473598
TI  - Tissue microarray molecular profiling of early, node-negative adenocarcinoma of
      the rectum: a comprehensive analysis.
AB  - PURPOSE: Early-stage adenocarcinoma of the rectum treated with curative intent
      has a favorable overall prognosis; however, 20%-30% of the patients recur, and
      the majority ultimately die of disease. Recurrence and tumor-related mortality
      may be attributable to molecular abnormalities in primary tumors accounting for
      their more aggressive biological behavior. This study evaluates such molecular
      phenotypes with regard to cell cycle regulation and proliferation and determines
      their significance for patient outcome. EXPERIMENTAL DESIGN: One hundred patients
      with primary T(2-3), N(0) adenocarcinoma of the rectum uniformly treated by
      surgery alone were studied. Core biopsies of pathological specimens were
      assembled on tissue microarrays, and expression of p53, mdm-2, p21, Bcl-2, p27,
      cyclin D1, and Ki-67 was analyzed by immunohistochemistry. Molecular profiles
      were correlated with disease-free (DFS) and disease-specific survival (DSS).
      RESULTS: Despite previously described prognostic relevance of some of the
      investigated molecules in analyses where different stages of colorectal cancer
      were included, none of the cell cycle-regulatory or proliferation-related markers
      was associated with recurrence or survival. However, patients with tumors
      demonstrating down-regulation of p27, a cyclin-dependent kinase inhibitor and
      tumor suppressor gene associated with development of metastases, showed a trend
      toward reduced DFS and DSS (P = 0.06 and P = 0.07, respectively). CONCLUSIONS: In
      this homogeneous group of patients with early-stage, node-negative adenocarcinoma
      of the rectum uniformly treated by surgery alone, the investigated cell cycle
      regulatory and proliferation-associated proteins appear to have no prognostic
      significance. However, down-regulation of p27 appears to be associated with a
      trend toward reduced DFS and DSS, which suggests further investigation of other
      p27-related pathways potentially relevant for metastatic disease.

PMID- 12473599
TI  - Loss of pRb2/p130 expression is associated with unfavorable clinical outcome in
      lung cancer.
AB  - Altered expression of cell cycle regulators represents a frequent event in both
      small cell and non-small cell lung cancer (NSCLC). Despite several studies that
      reported involvement of tumor suppressor genes, such as p53 and pRb, in the
      development and progression of lung cancer, contrasting opinions exist about the
      prognostic role of this protein in this neoplasm. We developed an
      immunohistochemical assay suitable for the detection of pRb2/p130, the last
      discovered member of the retinoblastoma gene family, on formalin-fixed and
      paraffin-embedded sections. We evaluated the immunohistochemical expression of
      pRb2/p130 in 135 lung cancer specimens, and performed Western blot analysis in a
      subset of 30 corresponding tumor lysates. A high correlation between
      immunohistochemical data and Western blot results (P = 0.0004) was found. We
      statistically analyzed the relationship between overall survival (OS) time and
      pRb2/p130 expression according to the different histological types in 105
      patients. We did not find any correlation between pRb2/p130 expression and OS in
      small cell lung cancers, whereas in NSCLCs a direct relationship between pRb2 and
      OS was found in both adenocarcinoma (P = 0.0002) and squamous cell carcinoma (P =
      0.0002) histotypes. According to univariate analysis, pRb2/p130 was a prognostic
      factor of which the lost or reduced expression correlated with a shorter OS (P <
      0.0000). At multivariate analysis, pRb2/p130 expression was an independent
      predictor of OS (P = 0.0001) when considered together with histotype. This study
      demonstrates for the first time the potential independent prognostic value of
      pRb2/p130 expression on formalin-fixed, paraffin-embedded sections from lung
      cancer patients. pRb2/p130 immunoreactivity can be used to predict OS in patients
      with NSCLC and, therefore, may represent a new prognostic marker.

PMID- 12473600
TI  - Microvessel density, expression of estrogen receptor alpha, MIB-1, p53, and c
      erbB-2 in inflammatory breast cancer.
AB  - PURPOSE AND EXPERIMENTAL DESIGN: The purpose is to define intratumoral
      microvessel density (MVD) and potential biological markers that correlate with
      inflammatory breast cancer (IBC), we examined MVD, estrogen receptor a (ER)
      status, MIB-1 proliferation index, p53, and c-erbB-2 by immunohistochemistry in
      archival specimens from 67 women diagnosed with breast cancer with or without the
      inflammatory phenotype at the Institut Salah Azaiz (Tunis, Tunisia). RESULTS: The
      moderate (25-50/x400 field) to high microvessel count (>50/x400 field) was
      observed in 23 (51%) of 45 IBC tumors compared with 3 (14%) of 22 non-IBC tumors
      (P = 0.0031; chi(2) test). The presence of ER was found in 6 (14%) of 44 cases
      versus 7 (32%) of 22 cases in IBC and non-IBC, respectively (P = 0.10). In this
      series of 67 patient tumors, the median MVD count in ER-negative breast tumors
      was 21, whereas the median count was 4 in ER-positive breast tumors (P = 0.08;
      Wilcoxon rank-sum test). However, MIB-1, p53, and c-erbB-2 were not significantly
      different between IBC and non-IBC tumors. The intratumoral MVD between IBC and
      non-IBC was still statistically significant after adjustment for multiple
      comparisons (P = 0.02; Bonferroni test). CONCLUSIONS: These data suggest that
      there is an increased MVD in breast cancer with the inflammatory phenotype as
      compared with breast cancer without the inflammatory phenotype.

PMID- 12473601
TI  - Genomic loss of 18p predicts an adverse clinical outcome in patients with high
      risk breast cancer.
AB  - The impact of the genomic imbalances on the clinical outcome of 34 patients with
      lymph-node positive high-risk breast cancer (HRBC) was investigated using
      comparative genomic hybridization. All of the patients were uniformly treated
      with high-dose chemotherapy and autologous stem cell transplantation. The average
      number of chromosomal imbalances per tumor was 11 (range, 2-24), including DNA
      overrepresentation on chromosomes 1q (59%), 17q (38%), 8q and 16p (35% each), 20q
      (32%), and 19p (26%), and genomic losses involving 9p and 18q (41%), 8p, 11q, and
      18p (38%), 17p (32%), 4p and Xq (29%), and 16q (26%). The most significant
      association among genomic changes and clinical-pathological features was the
      correlation of the loss of 8p with progesterone receptor positivity (P < 0.005).
      With a median follow-up time of 74 months, 15 patients (44%) have relapsed. In
      the univariate analysis, patients with gain/amplification of 17q including the
      HER-2/neu gene locus had a longer disease-free survival (P = 0.02), whereas those
      with genomic loss of 18p had a higher probability of relapse (P = 0.003). In
      multivariate analysis, the loss of 18p was the only parameter correlated with
      shorter disease-free survival (relative risk, 4.8; 95% confidence interval, 1.57
      14.8; P = 0.006). In summary, our data indicate that the tumoral genomic profile
      may represent a valuable marker for predicting the clinical outcome in HRBC.
      Furthermore, the genomic loss of 18p may identify a poor prognostic subgroup of
      patients with HRBC.

PMID- 12473603
TI  - Interleukin 15 promotes antigen-independent in vitro expansion and long-term
      survival of antitumor cytotoxic T lymphocytes.
AB  - The survival and expansion of effector cytotoxic T lymphocytes (CTLs) during an
      immunological response are critical for the successful elimination of life
      threatening attacks by microorganisms, parasites, or malignant cells. Among the
      numerous factors that regulate the immune response, interleukin (IL)-2, and its
      close relative, IL-15 are known to function as growth and survival factors for
      antigen-experienced T cells. However, major differences appear to exist between
      these lymphokines in their capacity to act on various T-cell types such as CD4+
      versus CD8+ or effector versus memory T lymphocytes. Although several studies
      have been done in the mouse system, less information is available regarding the
      function of these lymphokines in the human system. Here, we report that IL-15 or
      high concentrations of IL-2 induced antigen-independent expansion of effector
      CD8+ CTLs. Neither IL-2 nor IL-15 induced the proliferation of CD4+ T cells. In
      the absence of antigen, at least one of these lymphokines was required for the
      long-term survival of the cells in tissue culture. Most significantly, the
      effector cytolytic activity of CTLs expanded and maintained in IL-15 for up to 60
      days remained stable, indicating that these cells do not differentiate into a
      memory functional phenotype. The expression of IL-15Ralpha, which was detected on
      CD8+ CTLs but not on CD4+ helper T cells, suggests that this receptor subunit
      somehow participates in the transduction of the mitogenic signals of IL-15. The
      present findings have practical implications for the propagation of antigen
      specific T-cell lines in vitro and could be useful for expansion of therapeutic T
      cells for adoptive transfer.

PMID- 12473602
TI  - Studies with CWR22 xenografts in nude mice suggest that ZD1839 may have a role in
      the treatment of both androgen-dependent and androgen-independent human prostate
      cancer.
AB  - PURPOSE: These studies examined the effect of the epidermal growth factor
      receptor (EGFR) tyrosine kinase inhibitor ZD1839 ("Iressa")(3) on CWR22 prostate
      tumors in nude mice. The effect of ZD1839 was also examined in combination with
      either bicalutamide ("Casodex") or cytotoxic agents against a hormone-dependent
      or -independent variant of CWR22, respectively. EXPERIMENTAL DESIGN: The
      xenografts were grown for 4-7 days, then tumor measurements were made and therapy
      initiated. ZD1839 and bicalutamide were given p.o. on a once-daily, 5-day
      schedule for 2 successive weeks. Carboplatin and paclitaxel were given every 3-4
      days for a total of four doses. Measurements of tumor volume were made twice
      weekly during treatment and for 2 weeks after treatment. The effect of ZD1839 on
      EGFR function was assessed by Western blotting of EGFR and its phosphorylated
      form in CWR22 and variant tumors before and after treatment with this agent.
      RESULTS: ZD1839 at its maximum tolerated dose (150 mg/kg) inhibited the growth of
      androgen-dependent CWR22 by 54%, and the growth of two variants with different
      degrees of androgen independence and androgen receptor gene expression (CWR22LD1
      and CWR22RV1) by 76%. The effects of ZD1839 were similar to those recorded for
      phosphorylation of EGFR as determined by Western blotting. Coadministration of
      ZD1839 at its maximum tolerated dose markedly increased the antiproliferative
      action of the antiandrogen bicalutamide against CWR22LD1. In fact, combining
      ZD1839 with a suboptimal dose of bicalutamide was more effective than a higher
      dose of bicalutamide alone. Coadministration of ZD1839, which required a 2-3-fold
      attenuation of dose to avoid toxicity, also markedly increased the therapeutic
      activity of carboplatin and paclitaxel against CWR22RV1, bringing about
      regression to a degree not seen with either agent alone. Tumor-free mice were
      seen only with the combination of ZD1839 and paclitaxel. CONCLUSIONS: The results
      obtained in these related and highly relevant models of human prostate cancer
      suggest that ZD1839 may have a role in enhancing existing treatments of androgen
      dependent and -independent forms of this disease in patients.

PMID- 12473604
TI  - Screening of HLA-A24-restricted epitope peptides from prostate-specific membrane
      antigen that induce specific antitumor cytotoxic T lymphocytes.
AB  - PURPOSE: Prostate-specific membrane antigen (PSMA), which is a transmembrane
      glycoprotein predominantly expressed in prostate cancer, is an attractive target
      for tumor-specific immunotherapy. To identify human leukocyte antigen (HLA)-A24
      restricted epitope peptides from PSMA for further application of the dendritic
      cell (DC)-based immunotherapy targeting prostate cancer, we have screened several
      PSMA-encoded HLA-A24-binding peptides for their capabilities to elicit specific
      antitumor CTL response in vitro. EXPERIMENTAL DESIGN: The amino acid sequence of
      PSMA was screened for peptides consisting of 9 or 10 amino acids, which possess
      the known HLA-A24-binding motif. Nine candidate peptides were screened for
      binding to HLA-A24 molecules. Then, each of these nine peptides was studied to
      determine whether CTL responses could be induced by primary in vitro immunization
      of CD8(+) T cells using peptide-pulsed autologous DCs derived from peripheral
      blood mononuclear cells of HLA-A24(+) healthy donor as antigen-presenting cells.
      The antigen specificity of the CTL lines was confirmed using several tumor cell
      lines as target cells, which were genetically modified to express both HLA-A24
      and PSMA. RESULTS: Two peptides, LYSDPADYF and NYARTEDFF, were demonstrated to
      elicit CTL lines that lyse peptide-pulsed, HLA-A24(+) B-lymphoblastoid cells.
      Each of the CTL lines recognized their specific PSMA-expressing target cells in a
      HLA-A24-restricted manner. The capability to release IFN-gamma by the CTL lines
      was specifically inhibited by anti-MHC class I and anti-CD8 monoclonal antibodies
      but not by anti-MHC class II and anti-CD4 monoclonal antibodies. CONCLUSION: Two
      novel HLA-A24-restricted PSMA-derived epitopes were identified in this study.
      These epitopes can be used to further evaluate the clinical utility of DC-based
      immunotherapeutic strategies for treatment of hormone-refractory prostate
      cancers.

PMID- 12473605
TI  - Effectiveness of Ecteinascidin-743 against drug-sensitive and -resistant bone
      tumor cells.
AB  - PURPOSE: The identification of new drugs is strongly needed for bone
      tumors.Ecteinascidin-743 (ET-743), a highly promising antitumor agent isolated
      from the marine tunicate Ecteinascidia turbinata, is currently under Phase II
      clinical investigation in Europe and the United States for treatment of soft
      tissue sarcoma. In this study, we analyzed the preclinical effectiveness of this
      drug in osteosarcoma and Ewing's sarcoma. EXPERIMENTAL DESIGN: The effects of ET
      743 were evaluated against a panel of human osteosarcoma and Ewing's sarcoma cell
      lines characterized by different drug responsiveness and compared with the
      effects of standard anticancer agents. In addition, combination treatments with
      ET-743 and the other standard chemotherapy agents for sarcoma were analyzed to
      highlight the best drug-to-drug interaction RESULTS: A potent activity of ET-743
      was clearly observed against both drug-sensitive and drug-resistant (multidrug
      resistant, methotrexate- and cisplatin-resistant) bone tumor cells at
      concentrations that are easily achievable in patients (pM to nM range). Ewing's
      sarcoma cells appeared to be particularly sensitive to the effects of this drug.
      The analysis of the effects of ET-743 on cell cycle, apoptosis, and
      differentiation indicated that both osteosarcoma and Ewing's sarcoma cells had a
      slower progression through the different phases of the cell cycle after treatment
      with ET-743. However, the drug was able to induce a massive apoptosis in Ewing's
      sarcoma but not in osteosarcoma cells. In the latter neoplasm, ET-743 showed a
      differential effect, as indicated by the significant increase in the expression
      and activity of alkaline phosphatase, a marker of osteoblastic differentiation.
      Concurrent exposure of cells to ET-743 and other chemotherapeutic agents resulted
      in greater than additive interactions when doxorubicin and cisplatin were used,
      whereas subadditive effects were observed with methotrexate, vincristine, and
      actinomycin D. CONCLUSIONS: Overall, these results encourage the inclusion of
      this drug in the treatment of patients with bone tumors, although a careful
      design of new regimens is required to identify the best therapeutic conditions.

PMID- 12473606
TI  - Pattern of antitumor activity of a novel camptothecin, ST1481, in a large panel
      of human tumor xenografts.
AB  - PURPOSE: ST1481 is the lead compound of a novel series of 7-modified
      camptothecins, the 7-oxyimino methyl derivatives, characterized by potent
      topoisomerase I inhibition and cytotoxic activity. Based on its therapeutic
      efficacy in a human non-small cell lung carcinoma model and its favorable
      pharmacological profile, the novel analogue was selected for further preclinical
      development. EXPERIMENTAL DESIGN: We investigated the growth-inhibitory effects
      of ST1481 and topotecan, used as a reference compound, in a panel of human tumor
      cell lines of various tumor types (ovarian carcinoma, glioblastoma, osteosarcoma,
      and melanoma), including sublines with acquired resistance to cisplatin. We
      explored the antitumor efficacy in a large panel of human tumor xenografts, with
      particular reference to intrinsically resistant tumor types, using oral
      administration and an intermittent treatment schedule. RESULTS: ST1481 showed a
      potent antiproliferative activity with comparable effects in all tested cell
      lines. Only U-87-MG glioma cells were less sensitive, presumably as a consequence
      of the efficiency of the S-phase checkpoint. ST1481 produced a remarkable
      antitumor effect (tumor volume inhibition > 85%) in 16 of 18 examined models,
      with an appreciable rate of complete tumor regressions in 11 of 18 models
      (despite the nonoptimal intermittent treatment schedule). The most impressive
      antitumor effects were observed against lung carcinoma, melanoma, and
      osteosarcoma models, as documented by the high rate of complete responses (up to
      100%). The efficacy of ST1481 was significantly superior to that of topotecan in
      9 of 17 tumors. The novel drug was also markedly effective against slowly growing
      tumors (A549 lung carcinoma and HT29 colon carcinoma) when a daily protracted
      treatment was used to fully exploit the therapeutic potential of camptothecins.
      CONCLUSIONS: The unusual potency of ST1481 in a variety of tumor cell lines
      suggests the ability of the drug to overcome several resistance factors. The
      profile of antitumor efficacy further supports the therapeutic interest in the
      novel analogue and provides a rational basis for clinical evaluation in selected
      tumor types.

PMID- 12473607
TI  - Docetaxel induced gene expression patterns in head and neck squamous cell
      carcinoma using cDNA microarray and PowerBlot.
AB  - PURPOSE: The purpose is to identify gene expression patterns induced by
      docetaxelin head and neck squamous carcinoma (HNSCC) cells using high throughput
      techniques. EXPERIMENTAL DESIGN: HNSCC cells were treated with docetaxel or
      solvent. After mRNA extraction, cDNA fluorescent (Cy3 or Cy5)-labeled probes were
      synthesized. Then, Cy3 and Cy5-labeled samples were hybridized onto a microarray
      slide. The fluorescent images were scanned and analyzed for quantification.
      PowerBlot immunoblotting technique was used to measure protein expression level.
      Using this dual approach, we focused on genes in established pathways (cell
      cycle, apoptosis, angiogenesis, and signal transduction) of tumorigenesis and
      confirmed these results with conventional techniques. RESULTS: Using cDNA
      microarray, we found that docetaxel altered the expression of >100 genes in HNSCC
      cells. A total of 153 of 1191 genes was found to have altered expression in
      either HN12 (n = 102), HN30 (n = 72), or both (n = 21) by docetaxel. For the
      PowerBlot analysis, a subset of genes (n = 46) in the cDNA microarray analysis
      and an additional 98 genes in the cell cycle, apoptosis, angiogenesis, and signal
      transduction pathways were chosen. We found that PowerBlot data agreed with cDNA
      microarray in 65% of genes examined. The expression of a cell cycle inhibitor
      (p19) and promoters (cyclin A, cyclin B1, and cyclin E2F) were increased and
      decreased, respectively. Apoptosis induced by docetaxel was independent of p53
      and, in part, related to increased Fas expression. Both vascular endothelial
      growth factor secretion and basic fibroblast growth factor expression were
      inhibited by docetaxel, whereas thrombospondin-1 expression was increased by
      docetaxel. Epidermal growth factor receptor, activated epidermal growth factor
      receptor, and activated c-Jun NH(2)-terminal kinase expression was lowered by
      docetaxel. Activated extracellular signal-regulated kinase was elevated by
      docetaxel, but not total extracellular signal-regulated kinase levels.
      CONCLUSIONS: The identification of altered gene expression induced by docetaxel
      demonstrates additional biological activity in HNSCC cells, and the altered
      expression of these genes may serve as potential biomarkers to both predict
      clinical activity and provide information regarding potential efficacy of adding
      novel agents.

PMID- 12473608
TI  - The novel antimicrotubule agent cryptophycin 52 (LY355703) induces apoptosis via
      multiple pathways in human prostate cancer cells.
AB  - We assessed the ability of cryptophycin 52 (LY355703), a novel antimicrotubule,
      to induce growth arrest and apoptosis in prostate cancer cell lines and
      investigated potential molecular mechanisms of death. LNCaP (androgen-dependent)
      and DU-145 (androgen-independent) cells accumulated in G(2)-M phase of the cell
      cycle and progressively acquired sub-G(0)-G(1) DNA content after 48 h of exposure
      to cryptophycin 52 (1-10 pM). Induction of apoptosis was confirmed by DNA ladder
      formation and detection of cytoplasmic nucleosomes. PC-3 (androgen-independent)
      cells were less responsive to cryptophycin 52-induced death. Apoptosis was
      associated with proteolytic processing and activation of the caspase-3-like
      subfamily proteins caspase-3 and caspase-7 and cleavage of the caspase substrate
      poly(ADP-ribose) polymerase. The pan-caspase inhibitor BOC-Asp(OMe)
      fluoromethylketone effectively reduced cryptophycin 52-induced caspase-3-like
      protease activity and apoptosis in DU-145 cells. In contrast, BOC-Asp(OMe)
      fluoromethylketone did not inhibit apoptosis induction in LNCaP cells by
      cryptophycin 52, even though both cryptophycin 52-induced caspase-3-like activity
      and staurosporine-induced death were blocked under identical conditions.
      Cryptophycin 52 induced phosphorylation of c-raf1 and bcl-2 and/or bcl-x(L) to
      comparable levels in all cell lines studied, and LNCaP cells overexpressing bcl-2
      were more resistant to cryptophycin 52-induced apoptosis. Up-regulation of p53,
      bax, and p21 expression was induced in wild-type p53-expressing LNCaP cells only
      after cryptophycin 52 exposure. A sustained increase in c-Jun NH(2)-terminal
      kinase phosphorylation was also observed, the levels of which strongly correlated
      with apoptosis. We conclude that apoptosis induced by cryptophycin 52 in prostate
      cancer cells is androgen status independent, cell type specific for caspase
      requirement, modulated by the bcl-2 family, linked to but not dependent on p53,
      and strongly correlated with c-Jun NH(2)-terminal kinase phosphorylation.
      Cryptophycin 52-induced apoptosis in prostate cancer cells is therefore
      associated with multiple cell line-specific alterations in apoptosis-associated
      proteins and pathways.

PMID- 12473609
TI  - Neuregulin expression, function, and signaling in human ovarian cancer cells.
AB  - PURPOSE: To investigate the expression and function of neuregulin (NRG) isoforms
      in ovarian cancer cell lines and tumor samples. EXPERIMENTAL DESIGN: Expression
      of NRG-1alpha and NRG-1beta proteins were detected by immunohistochemistry and
      mRNA by RT-PCR. erbB receptor levels and downstream signaling proteins were
      measured by Western blot analysis. RESULTS: Expression of NRG-1alpha and NRG
      1beta proteins were detected by immunohistochemistry in 46 of 53 (87%) and 41 of
      53 (77%) ovarian carcinomas, respectively. Serous carcinomas express higher
      levels of NRG-1alpha than endometrioid carcinomas (P = 0.017). NRG mRNA was
      detected by RT-PCR in 20 of 24 (83%) of ovarian carcinomas and eight of nine
      (89%) ovarian cancer cell lines. NRG-1alpha stimulated the growth of 5 of 14 cell
      lines whereas NRG-1beta stimulated 7 of 14 cell lines. The magnitude of NRG
      growth response was significantly associated with erbB2 expression levels. NRG
      1alpha and -1beta (1 nM) growth-stimulated cell lines PE01 and PE06 demonstrated
      increased tyrosine phosphorylation of erbB2 and elevated tyrosine phosphorylation
      of ERK1 and ERK2. In contrast, the SKOV-3 cell line, the growth of which was
      unaffected, did not show these downstream responses. An anti-erbB3 receptor
      antibody (clone H3.105.5) blocked NRG-1beta growth changes and signaling in these
      cell lines. Conversely, the anti-erbB4 antibody (clone H4.72.8) enhanced NRG
      beta1 growth stimulation. Herceptin also inhibited growth. CONCLUSIONS: With NRG
      expression in the majority of ovarian carcinomas and cell lines, there is the
      potential for autocrine regulation of cell growth. Interfering with ligand
      receptor interactions by receptor blocking antibodies suggests erbB3 is primarily
      involved in NRG-1beta-induced proliferation, with erbB4 having a more complex
      role.

PMID- 12473610
TI  - Effects of glutamate transporter inhibitors on the antitumor activity of
      doxorubicin.
AB  - Dihydrokainate, a glutamate transporter inhibitor, was previously found to be a
      useful modulator of antitumor activity of doxorubicin (DOX). Dihydrokainate
      prevented an efflux of DOX by inhibiting the uptake of glutamate by tumor cells.
      We examined the potential of glutamate transporter inhibitors as modulators of
      DOX activity. We observed a significant reduction in the uptake of glutamate by
      other inhibitors and a similar effect on DOX efflux in M5076 ovarian sarcoma
      cells. However, in vivo, the tissue distribution of each isoform is different,
      and glutamate transporter inhibitors with different affinities for each isoform
      affected tumors and normal tissues differently. L-Serine-O-sulfate, which has
      high affinity to glutamate/aspartate transporter, particularly enhanced the
      antitumor activity of DOX in M5076 tumor-bearing mice. In contrast, L-alpha
      aminoadipate tended to increase the DOX concentration in normal tissues rather
      than tumors. It was shown that the relation between glutamate transporter
      isoforms and the selective affinity of inhibitors could selectively affect the
      antitumor activity and side effects of DOX. Furthermore, the effects of
      inhibitors varied among cells expressing different isoforms. Notably, a low
      concentration of L-serine-O-sulfate actually increased the uptake of glutamate in
      P388 leukemia cells.

PMID- 12473611
TI  - Promising preclinical activity of 2-methoxyestradiol in multiple myeloma.
AB  - PURPOSE: 2-Methoxyestradiol (2ME2), a natural endogenous product of estradiol
      metabolism, has demonstrated activity against tumor cell lines and can inhibit
      angiogenesis. There are limited treatment options for patients with multiple
      myeloma (MM) who relapse after high-dose therapy and stem cell transplantation.
      We studied the preclinical activity of 2ME2 as a therapeutic agent for myeloma.
      EXPERIMENTAL DESIGN: Five established myeloma cell lines as well as primary
      plasma cells from patients with MM were exposed to 2ME2 at various
      concentrations. We evaluated the activity of the drug to inhibit cell replication
      and induction of apoptosis in vitro as well as the ability of the drug to inhibit
      myeloma tumor xenograft growth in severe combined immunodeficient mice. RESULTS:
      2ME2 inhibited tritiated thymidine uptake in all myeloma cell lines tested in a
      dose-dependent fashion and induced G(2)-M phase cell cycle arrest. The drug
      induced apoptosis in all cell lines tested and in half of the primary plasma
      cells evaluated in a dose-response manner. Forty-eight h after drug exposure, a
      large proportion of the cells were dead by propidium iodide staining. Injection
      of the drug i.p. suppressed myeloma tumor xenograft growth, and the effect was
      sustained after cessation of therapy. CONCLUSIONS: 2ME2 has significant activity
      against myeloma cell lines and primary myeloma cells both in vitro and in an
      animal model. Clinical trials are required to evaluate its activity in patients
      with MM.

PMID- 12473613
TI  - Retraction.

PMID- 12473612
TI  - Suradista NSC 651016 inhibits the angiogenic activity of CXCL12-stromal cell
      derived factor 1alpha.
AB  - CXCL12 (stromal cell-derived factor 1alpha), a ligand for CXCR4, has been shown
      to induce endothelial cell chemotaxis and to stimulate angiogenesis, suggesting
      that it may be a significant target for antiangiogenic therapy. Here we have
      tested suradista NSC 651016, a compound known to inhibit CXCL12-induced monocyte
      chemotaxis, for its ability to inhibit CXCL12-induced angiogenic activity. NSC
      651016 inhibited CXCL12-mediated endothelial cell chemotaxis in a dose-dependent
      manner. In addition, new vessel sprouting, by both rat and chick aorta in an
      angiogenesis model, was inhibited. Additionally, in vitro capillary-like
      structure formation induced by CXCL12 was inhibited by NSC 651016. Furthermore,
      NSC 651016 inhibited CXCL12-mediated angiogenesis in an in vivo s.c. assay. These
      data indicate that suradista NSC 651016 possesses in vitro and in vivo
      antiangiogenic activity and has the potential to interfere with neovacularization
      of tumors and their metastases.

PMID- 12473615
TI  - Weapons of mass construction.

PMID- 12473618
TI  - Do reindeer and children know something that we don't? Pediatric inpatients'
      belief in Santa Claus.

PMID- 12473619
TI  - Research of the holiday kind. Audiovisual hyperactivity disorder (AVHD): a peril
      of the desire to excel.

PMID- 12473620
TI  - Research of the holiday kind. Stableford: equitable golf-scoring system or
      quality-of-life measure?

PMID- 12473622
TI  - Diversions. What to expect when you're expecting (residents).

PMID- 12473623
TI  - Diversions. PubMed and me: Why my coughs are more productive than my searches.

PMID- 12473627
TI  - Diversions. Universal medicine - the rejected appendix.

PMID- 12473625
TI  - Diversions. Waiting for Romanow: a play in 17 very similar acts.

PMID- 12473628
TI  - Diversions. Super-cef.

PMID- 12473629
TI  - Diversions. Let's leave the shorts on, shall we?

PMID- 12473630
TI  - Diversions. The doorway physical exam: what every psychiatry resident should
      know.

PMID- 12473631
TI  - Reflections. Some days I just want out.

PMID- 12473634
TI  - Reflections. An old prayer for modern medicine.

PMID- 12473636
TI  - Reflections. Return to Afghanistan.

PMID- 12473637
TI  - Our medical past. Death and the doctor.

PMID- 12473638
TI  - Our medical past. Subacute bacterial endocarditis observed: the illness of Alfred
      S. Reinhart.

PMID- 12473639
TI  - Our medical past. Of mortars and morphine: one physician's D-Day.

PMID- 12473641
TI  - Almost famous: E. Clark Noble, the common thread in the discovery of insulin and
      vinblastine.
AB  - Clark Noble was one of the first members of the University of Toronto insulin
      team and came within a coin toss of replacing Charles Best as Frederick Banting's
      assistant during the summer of 1921. Noble performed important early studies
      helping to characterize insulin's action, and he co-authored many of the original
      papers describing insulin. Because mass production of insulin from livestock
      pancreata had proved elusive throughout 1922, J.J.R. Macleod hired Noble during
      the summer of 1923 to help him test and develop a new method for producing
      commercial quantities of insulin that Macleod believed would revolutionize
      insulin production. However, commercial production of insulin from fish proved
      impractical and was dropped by 1924, as methods to produce large quantities of
      mammalian insulin had improved very rapidly. Noble later played a small but
      critical role in the most important Canadian contribution to cancer chemotherapy
      research: the discovery of vinca alkaloids by his brother Robert Laing Noble.
      Although one might expect that a physician involved in 2 of Canada's most
      important medical discoveries during the 20th century must be famous, such was
      not Clark Noble's fate. He died without so much as an obituary in CMAJ.

PMID- 12473643
TI  - Eighty years after insulin: parallels with modern islet transplantation.

PMID- 12473645
TI  - FEEL-1 and FEEL-2 are endocytic receptors for advanced glycation end products.
AB  - Advanced glycation end products (AGEs) are nonenzymatically glycosylated
      proteins, which accumulate in vascular tissues in aging and diabetes. Receptors
      for AGEs include scavenger receptors, which recognize acetylated low density
      lipoproteins (Ac-LDL) such as scavenger receptor class AI/AII (SR-A), cell
      surface glycoprotein CD36, scavenger receptor class B type I (SR-BI), and lectin
      like oxidized low density lipoprotein receptor-1. The broad ligand repertoire of
      these receptors as well as the diversity of the receptors for AGEs have prompted
      us to examine whether AGEs are also recognized by the novel scavenger receptors,
      which we have recently isolated from a cDNA library prepared from human umbilical
      vein endothelial cells, such as the scavenger receptor expressed by endothelial
      cells-I (SREC-I); the fasciclin EGF-like, laminin-type EGF-like, and link domain
      containing scavenger receptor-1 (FEEL-1); and its paralogous protein, FEEL-2. At
      4 degrees C, (125)I-AGE-bovine serum albumin (BSA) exhibited high affinity
      specific binding to Chinese hamster ovary (CHO) cells overexpressing FEEL-1 (CHO
      FEEL-1) and FEEL-2 (CHO-FEEL-2) with K(d) of 2.55 and 1.68 microg/ml,
      respectively, but not to CHO cells expressing SREC (CHO-SREC) and parent CHO
      cells. At 37 degrees C, (125)I-AGE-BSA was taken up and degraded by CHO-FEEL-1
      and CHO-FEEL-2 cells but not by CHO-SREC and parent CHO cells. Thus, the ability
      to bind Ac-LDL is not necessarily a prerequisite to bind AGEs. The (125)I-AGE-BSA
      binding to CHO-FEEL-1 and CHO-FEEL-2 cells was effectively inhibited by Ac-LDL
      and polyanionic SR-A inhibitors such as fucoidan, polyinosinic acids, and dextran
      sulfate but not by native LDL, oxidized LDL, or HDL. FEEL-1, which is expressed
      by the liver and vascular tissues, may recognize AGEs, thereby contributing to
      the development of diabetic vascular complications and atherosclerosis.

PMID- 12473646
TI  - Cooperative regulation by Rac and Rho of agrin-induced acetylcholine receptor
      clustering in muscle cells.
AB  - A key aspect of neuromuscular synapse formation is the clustering of muscle
      acetylcholine receptors (AChR) at synaptic sites in response to neurally secreted
      agrin. Agrin-induced AChR clustering in cultured myotubes proceeds via the
      initial formation of small microclusters, which then aggregate to form AChR
      clusters. Here we show that the coupling of agrin signaling to AChR clustering is
      dependent on the coordinated activities of Rac and Rho GTPases. The addition of
      agrin induces the sequential activation of Rac and Rho in C2 muscle cells. The
      activation of Rac is rapid and transient and constitutes a prerequisite for the
      subsequent activation of Rho. This temporal pattern of agrin-induced Rac and Rho
      activation reflects their respective roles in AChR cluster formation. Whereas
      agrin-induced activation of Rac is necessary for the initial phase of AChR
      cluster formation, which involves the aggregation of diffuse AChR into
      microclusters, Rho activation is crucial for the subsequent condensation of these
      microclusters into full-size AChR clusters. Co-expression of constitutively
      active forms of Rac and Rho is sufficient to induce the formation of mature AChR
      clusters in the absence of agrin. These results establish that Rac and Rho play
      distinct but complementary roles in the mechanism of agrin-induced AChR
      clustering.

PMID- 12473647
TI  - LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is
      epigenetically regulated in cancer.
AB  - LOT1 is a zinc-finger nuclear transcription factor, which possesses anti
      proliferative effects and is frequently silenced in ovarian and breast cancer
      cells. The LOT1 gene is localized at chromosome 6q24-25, a chromosomal region
      maternally imprinted and linked to growth retardation in several organs and
      progression of disease states such as transient neonatal diabetes mellitus.
      Toward understanding the molecular mechanism underlying the loss of LOT1
      expression in cancer, we have characterized the genomic structure and analyzed
      its epigenetic regulation. Genome mapping of LOT1 in comparison with the other
      splice variants, namely ZAC1 and PLAGL1, revealed that its mRNA ( approximately
      4.7 kb; GenBank accession number U76261) is potentially spliced using six exons
      spanning at least 70 kb of the human genome. 5'-RACE (rapid amplification of cDNA
      ends) data indicate the presence of at least two transcription start sites. We
      found that in vitro methylation of the LOT1 promoter causes a significant loss in
      its ability to drive luciferase transcription. To determine the nature of in vivo
      methylation of LOT1, we used bisulfite-sequencing strategies on genomic DNA. We
      show that in the ovarian and breast cancer cell lines and/or tumors the 5'-CpG
      island of LOT1 is a differentially methylated region. In these cell lines the
      ratio of methylated to unmethylated CpG dinucleotides in this region ranged from
      31 to 99% and the ovarian tumors have relatively higher cytosine methylation than
      normal tissues. Furthermore, we show that trichostatin A, a specific inhibitor of
      histone deacetylase, relieves transcriptional silencing of LOT1 mRNA in
      malignantly transformed cells. It appears that, unlike DNA methylation, histone
      deacetylation does not target the promoter, and rather it is indirect and may be
      elicited by a mechanism upstream of the LOT1 regulatory pathway. Taken together,
      the data suggest that expression of LOT1 is under the control of two epigenetic
      modifications and that, in the absence of loss of heterozygosity, the biallelic
      (two-hit) or maximal silencing of LOT1 requires both processes.

PMID- 12473648
TI  - Transient mechanoactivation of neutral sphingomyelinase in caveolae to generate
      ceramide.
AB  - The vascular endothelium acutely autoregulates blood flow in vivo in part through
      unknown mechanosensing mechanisms. Here, we report the discovery of a new acute
      mechanotransduction pathway. Hemodynamic stressors from increased vascular flow
      and pressure in situ rapidly and transiently induce the activity of neutral
      sphingomyelinase but not that acid sphingomyelinase in a time- and flow rate
      dependent manner, followed by the generation of ceramides. This acute
      mechanoactivation occurs directly at the luminal endothelial cell surface
      primarily in caveolae enriched in sphingomyelin and neutral sphingomyelinase, but
      not acid sphingomyelinase. Scyphostatin, which specifically blocks neutral but
      not acid sphingomyelinase, inhibits mechano-induced neutral sphingomyelinase
      activity as well as downstream activation of extracellular signal-regulated
      kinase 1 and 2 (ERK1 and ERK2) by increased flow in situ. We postulate a novel
      physiological function for neutral sphingomyelinase as a new mechanosensor
      initiating the ERK cascade and possibly other mechanotransduction pathways.

PMID- 12473649
TI  - Tracking the putative biosynthetic precursors of oxygenated mycolates of
      Mycobacterium tuberculosis. Structural analysis of fatty acids of a mutant strain
      deviod of methoxy- and ketomycolates.
AB  - Disruption of the mma4 gene (renamed hma) of Mycobacterium tuberculosis has
      yielded a mutant strain defective in the synthesis of both keto- and
      methoxymycolates, with an altered cell-wall permeability to small molecules and a
      decreased virulence in the mouse model of infection (Dubnau, E., Chan, J.,
      Raynaud, C., Mohan, V. P., Laneelle, M. A., Yu, K., Quemard, A., Smith, I., and
      Daffe, M. (2000) Mol. Microbiol. 36, 630-637). Assuming that the mutant would
      accumulate the putative precursors of the oxygenated mycolates of M.
      tuberculosis, a detailed structural analysis of mycolates from the hma
      inactivated strain was performed using a combination of matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry, proton NMR spectroscopy,
      and chemical degradation techniques. These consisted most exclusively of alpha
      mycolates, composed of equal amounts of C(76)-C(82) dicyclopropanated (alpha(1))
      and of C(77)-C(79) monoethylenic monocyclopropanated (alpha(2)) mycolates, the
      double bond being located at the "distal" position. In addition, small amounts of
      cis-epoxymycolates, structurally related to alpha(2)-mycolates, was produced by
      the mutant strain. Complementation of the hma-inactivated mutant with the wild
      type gene resulted in the disappearance of the newly identified mycolates and the
      production of keto- and methoxymycolates of M. tuberculosis. Introduction of the
      hma gene in Mycobacterium smegmatis led to the lowering of diethylenic alpha
      mycolates of the recipient strain and the production of keto- and
      hydroxymycolates. These data indicate that long-chain ethylenic compounds may be
      the precursors of the oxygenated mycolates of M. tuberculosis. Because the lack
      of production of several methyltransferases involved in the biosynthesis of
      mycolates is known to decrease the virulence of the tubercle bacillus, the
      identification of the substrates of these enzymes should help in the design of
      inhibitors of the growth of M. tuberculosis.

PMID- 12473650
TI  - Mammalian tolloid metalloproteinase, and not matrix metalloprotease 2 or membrane
      type 1 metalloprotease, processes laminin-5 in keratinocytes and skin.
AB  - Laminin-5, a major adhesive ligand for epithelial cells, undergoes processing of
      its gamma2 and alpha3 chains. This study investigated the mechanism of laminin-5
      processing by keratinocytes. BI-1 (BMP-1 isoenzyme inhibitor-1), a selective
      inhibitor of a small group of astacin-like metalloproteinases, which includes
      bone morphogenetic protein 1 (BMP-1), mammalian Tolloid (mTLD), mammalian Tolloid
      like 1 (mTLL-1), and mammalian Tolloid-like 2 (mTLL-2), inhibited the processing
      of laminin-5 gamma2 and alpha3 chains in keratinocyte cultures in a dose
      dependent manner. In a proteinase survey, all BMP-1 isoenzymes processed human
      laminin-5 gamma2 and alpha3 chains to 105- and 165-kDa fragments, respectively.
      In contrast, MT1-MMP and MMP-2 did not cleave the gamma2 chain of human laminin-5
      but processed the rat laminin gamma2 chain to an 80-kDa fragment. An immunoblot
      and quantitative PCR survey of the BMP-1 isoenzymes revealed expression of mTLD
      in primary keratinocyte cultures but little or no expression of BMP-1, mTLL-1, or
      mTLL-2. mTLD was shown to cleave the gamma2 chain at the same site as the
      previously identified BMP-1 cleavage site. In addition, mTLD/BMP-1 null mice were
      shown to have deficient laminin-5 processing. Together, these data identify
      laminin-5 as a substrate for mTLD, suggesting a role for laminin-5 processing by
      mTLD in the skin.

PMID- 12473651
TI  - Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal
      prostatic epithelium and cancer.
AB  - DOC-2/DAB2 is a potent tumor suppressor in many cancer types including prostate
      cancer. In prostate cancer, expression of DOC-2/DAB2 can inhibit its growth. Our
      recent studies demonstrate that DOC-2/DAB2 can suppress both protein kinase C and
      peptide growth factor-elicited signal pathways via the Ras-mitogen-activated
      protein kinase pathway. In this study, we further showed that the proline-rich
      domain of DOC-2/DAB2 could also interact with proteins containing the Src
      homology 3 domain, such as Src and Fgr. The binding of c-Src to DOC-2/DAB2 was
      enhanced in cells treated with growth factor, and this interaction resulted in c
      Src inactivation. The c-Src inactivation was evidenced by the decreased tyrosine
      416 phosphorylation of c-Src and reduced downstream effector activation. It
      appears that DOC-2/DAB2 can bind to Src homology 3 domain of c-Src and maintain
      it in an inactive conformation. Thus, this study provides a new mechanism for
      modulating c-Src in prostatic epithelium and cancer.

PMID- 12473652
TI  - Up-regulated Smad5 mediates apoptosis of gastric epithelial cells induced by
      Helicobacter pylori infection.
AB  - The gastric pathogen Helicobacter pylori activates epithelial cell signaling
      pathways, and its infection induces changes in the expression of several genes in
      infected human gastric tissues. Recent studies have indicated that the ability of
      H. pylori to regulate epithelial cell responses depends on the presence of an
      intact cag pathogenicity island (cagPAI). We investigated altered mRNA expression
      of gastric epithelial cells after infection with H. pylori, both cagPAI-positive
      and cagPAI-negative strains, by cDNA microarray, reverse transcription PCR, and
      Northern blot analysis. Our results indicated that cagPAI-positive H. pylori
      strains (ATCC 43504 and clinical isolated strains) significantly activated Smad5
      mRNA expression of human gastric epithelial cells (AGS, KATOIII, MKN28, and
      MKN45). We further examined whether the up-regulated Smad5 was related to
      apoptosis of gastric epithelial cells induced by H. pylori. Smad5 RNA
      interference completely inhibited H. pylori-induced apoptosis. These results
      suggest that Smad5 is up-regulated in gastric epithelial cells through the
      presence of cagPAI of H. pylori and that Smad5 mediates apoptosis of gastric
      epithelial cells induced by H. pylori infection.

PMID- 12473653
TI  - Voltage-gated mobility of the Ca2+ channel cytoplasmic tails and its regulatory
      role.
AB  - Transient increase in intracellular free Ca(2+) concentration generated by the
      voltage-gated Ca(v)1.2 channels acts as an important intracellular signal. By
      using fluorescence resonance energy transfer combined with patch clamp in living
      cells, we present evidence for voltage-gated mobility of the cytoplasmic tails of
      the Ca(v)1.2 channel and for its regulatory role in intracellular signaling.
      Anchoring of the C-terminal tail to the plasma membrane caused an inhibition of
      its state-dependent mobility, channel inactivation, and CREB-dependent
      transcription. Release of the tail restored these functions suggesting a direct
      role for voltage-gated mobility of the C-terminal tail in Ca(2+) signaling.

PMID- 12473654
TI  - Disruption of focal adhesions by integrin cytoplasmic domain-associated protein-1
      alpha.
AB  - Regulation of integrin affinity and clustering plays a key role in the control of
      cell adhesion and migration. The protein ICAP-1 alpha (integrin cytoplasmic
      domain-associated protein-1 alpha) binds to the cytoplasmic domain of the
      beta(1A) integrin and controls cell spreading on fibronectin. Here, we
      demonstrate that, despite its ability to interact with beta(1A) integrin, ICAP-1
      alpha is not recruited in focal adhesions, whereas it is colocalized with the
      integrin at the ruffling edges of the cells. ICAP-1 alpha induced a rapid
      disruption of focal adhesions, which may result from the ability of ICAP-1 alpha
      to inhibit the association of beta(1A) integrin with talin, which is crucial for
      the assembly of these structures. ICAP-1 alpha-mediated dispersion of beta(1A)
      integrins is not observed with beta(1D) integrins that do not bind ICAP. This
      strongly suggests that ICAP-1 alpha action depends on a direct interaction
      between ICAP-1 alpha and the cytoplasmic domain of the beta(1) chains.
      Altogether, these results suggest that ICAP-1 alpha plays a key role in cell
      adhesion by acting as a negative regulator of beta(1) integrin avidity.

PMID- 12473655
TI  - Human RNase H1 activity is regulated by a unique redox switch formed between
      adjacent cysteines.
AB  - Human RNase H1 is active only under reduced conditions. Oxidation as well as N
      ethylmaleimide (NEM) treatment of human RNase H1 ablates the cleavage activity.
      The oxidized and NEM alkylated forms of human RNase H1 exhibited binding
      affinities for the heteroduplex substrate comparable with the reduced form of the
      enzyme. Mutants of human RNase H1 in which the cysteines were either deleted or
      substituted with alanine exhibited cleavage rates comparable with the reduced
      form of the enzyme, suggesting that the cysteine residues were not required for
      catalysis. The cysteine residues responsible for the observed redox-dependent
      activity of human RNase H1 were determined by site-directed mutagenesis to
      involve Cys(147) and Cys(148). The redox states of the Cys(147) and Cys(148)
      residues were determined by digesting the reduced, oxidized, and NEM-treated
      forms of human RNase H1 with trypsin and analyzing the cysteine containing
      tryptic fragments by micro high performance liquid chromatography-electrospray
      ionization-Fourier transform ion cyclotron mass spectrometry. The tryptic
      fragment Asp(131)-Arg(153) containing Cys(147) and Cys(148) was identified. The
      mass spectra for the Asp(131)-Arg(153) peptides from the oxidized and reduced
      forms of human RNase H1 in the presence and absence of NEM showed peptide masses
      consistent with the formation of a disulfide bond between Cys(147) and Cys(148).
      These data show that the formation of a disulfide bond between adjacent Cys(147)
      and Cys(148) residues results in an inactive enzyme conformation and provides
      further insights into the interaction between human RNase H1 and the heteroduplex
      substrate.

PMID- 12473656
TI  - Limitation in use of heterologous reporter genes for gene promoter analysis.
      Silencer activity associated with the cloramphenicol acetyltransferase reporter
      gene.
AB  - Various heterologous reporter genes have been widely used for the functional
      characterization of gene promoters. Many such studies often found weak to very
      strong silencer activities to be associated with specific parts of the basal
      promoter or further upstream regions. In this study, we carried out a systematic
      study on human blood coagulation factor IX (hFIX) and anti-coagulant protein C
      (hPC) genes, previously shown to have silencer activities associated with their
      5'-flanking regions containing promoter sequences. With newly constructed
      chloramphenicol acetyltransferase (CAT) reporter vectors carrying hFIX or hPC
      gene promoter sequences, we confirmed the strong silencer activities associated
      with the regions nt -1895 through nt -416 of the hFIX gene or with the region nt 
      802 through nt -82 of the hPC gene. However, no such silencer activities
      associated with the specific regions were found when autologous hFIX cDNA, hFIX
      minigenes, or hPC minigenes were used as reporters in the expression vector
      system. Relative levels of CAT, hFIX, and hPC proteins produced in the transient
      assays correlated well with their mRNA levels. Human FIX minigene constructs
      containing a simian virus 40 (SV40) 3'-untranslated region (UTR) taken from the
      CAT reporter gene showed no silencer activity, indicating that SV40 3'-UTR
      sequence of the CAT reporter gene does not contribute to the silencer activity.
      Expression vectors constructed with the beta-galactosidase gene under the control
      of hFIX gene promoter sequences also showed no silencer activity associated with
      the region nt -1895 through nt -416. These findings indicate that silencer
      activities associated with specific regions of promoter sequences as analyzed
      with CAT reporter genes may represent artifacts specific to the CAT reporter
      genes. Our findings strongly suggest a need for re-examination of promoter
      characterizations of many eukaryotic genes, which have been studied to date with
      CAT reporter genes.

PMID- 12473657
TI  - A two-drug model for etoposide action against human topoisomerase IIalpha.
AB  - The widely used anticancer drug etoposide kills cells by increasing levels of
      topoisomerase II-mediated DNA breaks. While it is known that the drug acts by
      inhibiting the ability of topoisomerase II to ligate cleaved DNA molecules, the
      precise mechanism by which it accomplishes this action is not well understood.
      Because there are two scissile bonds per enzyme-mediated double-stranded DNA
      break, it has been assumed that there are two sites for etoposide in every
      cleavage complex. However, it is not known whether the action of etoposide at
      only one scissile bond is sufficient to stabilize a double-stranded DNA break or
      whether both drug sites need to be occupied. An oligonucleotide system was
      utilized to address this important issue. Results of DNA cleavage and ligation
      assays support a two-drug model for the action of etoposide against human
      topoisomerase IIalpha. This model postulates that drug interactions at both
      scissile bonds are required in order to increase enzyme-mediated double-stranded
      DNA breaks. Etoposide actions at either of the two scissile bonds appear to be
      independent of one another, with each individual drug molecule stabilizing a
      strand-specific nick rather than a double-stranded DNA break. This finding
      suggests (at least in the presence of drug) that there is little or no
      communication between the two promoter active sites of topoisomerase II. The two
      drug model has implications for cancer chemotherapy, the cellular processing of
      etoposide-stabilized enzyme-DNA cleavage complexes, and the catalytic mechanism
      of eukaryotic topoisomerase II.

PMID- 12473658
TI  - The COOH terminus of GATE-16, an intra-Golgi transport modulator, is cleaved by
      the human cysteine protease HsApg4A.
AB  - Docking of a vesicle at the appropriate target membrane involves an interaction
      between integral membrane proteins located on the vesicle (v-SNAREs) and those
      located on the target membrane (t-SNAREs). GATE-16 (Golgi-associated ATPase
      enhancer of 16 kDa) was shown to modulate the activity of SNAREs in the Golgi
      apparatus and is therefore an essential component of intra-Golgi transport and
      post-mitotic Golgi re-assembly. GATE-16 contains a ubiquitin fold subdomain,
      which is terminated at the carboxyl end by an additional amino acid after a
      conserved glycine residue. In the present study we tested whether the COOH
      terminus of GATE-16 undergoes post-translational cleavage by a protease which
      exposes the glycine 116 residue. We describe the isolation and characterization
      of HsApg4A as a human protease of GATE-16. We show that GATE-16 undergoes COOH
      terminal cleavage both in vivo and in vitro, only when the conserved glycine 116
      is present. We then utilize an in vitro assay to show that pure HsApg4A is
      sufficient to cleave GATE-16. The characterization of this protease may give new
      insights into the mechanism of action of GATE-16 and its other family members.

PMID- 12473659
TI  - Intracellular localization of keratinocyte Fas ligand explains lack of cytolytic
      activity under physiological conditions.
AB  - Acquired Fas ligand (FasL)-mediated cytolytic activity of human keratinocytes
      causes the massive keratinocyte cell death that occurs during toxic epidermal
      necrolysis, a deadly adverse drug eruption. Under normal conditions keratinocyte
      apoptosis is a rare event in the epidermis although keratinocytes express the
      death receptor Fas and its ligand. Here we have investigated why this is so. We
      show that Fas, FasL, Fas-associated death domain, and caspase-8 mRNA are
      detectable in the epidermis, primary keratinocyte cultures, and keratinocyte cell
      line and that Fas protein is expressed in keratinocytes of all subcorneal layers
      of the epidermis, whereas FasL is only expressed in the basal and first
      suprabasal layers. Coexpression of Fas and FasL therefore occurs in basal and
      suprabasal keratinocytes. In vitro, keratinocytes are killed by recombinant FasL
      in a dose-dependent manner, but they are unable to kill Fas-sensitive target
      cells despite FasL expression. Analysis of keratinocyte culture supernatants and
      treatment of keratinocytes with metalloproteinase inhibitors excluded cell
      surface expression of FasL and rapid metalloproteinase-mediated cleavage of cell
      surface FasL. Fluorescence-activated cell sorter, confocal microscopical, and
      electron microscopical analysis revealed that keratinocyte FasL is localized
      intracellularly predominantly associated to intermediate filaments. These data
      suggest that the observed inability of keratinocyte FasL to induce apoptosis
      under physiological conditions is due to its cellular localization and also
      indicate that intermediate filaments may be involved in regulating the
      subcellular localization of FasL.

PMID- 12473660
TI  - The stability of the G protein-coupled receptor-beta-arrestin interaction
      determines the mechanism and functional consequence of ERK activation.
AB  - By binding to agonist-activated G protein-coupled receptors (GPCRs), beta
      arrestins mediate homologous receptor desensitization and endocytosis via
      clathrin-coated pits. Recent data suggest that beta-arrestins also contribute to
      GPCR signaling by acting as scaffolds for components of the ERK mitogen-activated
      protein kinase cascade. Because of these dual functions, we hypothesized that the
      stability of the receptor-beta-arrestin interaction might affect the mechanism
      and functional consequences of GPCR-stimulated ERK activation. In transfected COS
      7 cells, we found that angiotensin AT1a and vasopressin V2 receptors, which form
      stable receptor-beta-arrestin complexes, activated a beta-arrestin-bound pool of
      ERK2 more efficiently than alpha 1b and beta2 adrenergic receptors, which form
      transient receptor-beta-arrestin complexes. We next studied chimeric receptors in
      which the pattern of beta-arrestin binding was reversed by exchanging the C
      terminal tails of the beta2 and V2 receptors. The ability of the V2 beta 2 and
      beta 2V2 chimeras to activate beta-arrestin-bound ERK2 corresponded to the
      pattern of beta-arrestin binding, suggesting that the stability of the receptor
      beta-arrestin complex determined the mechanism of ERK2 activation. Analysis of
      covalently cross-linked detergent lysates and cellular fractionation revealed
      that wild type V2 receptors generated a larger pool of cytosolic phospho-ERK1/2
      and less nuclear phospho-ERK1/2 than the chimeric V2 beta 2 receptor, consistent
      with the cytosolic retention of beta-arrestin-bound ERK. In stably transfected
      HEK-293 cells, the V2 beta 2 receptor increased ERK1/2-mediated, Elk-1-driven
      transcription of a luciferase reporter to a greater extent than the wild type V2
      receptor. Furthermore, the V2 beta 2, but not the V2 receptor, was capable of
      eliciting a mitogenic response. These data suggest that the C-terminal tail of a
      GPCR, by determining the stability of the receptor-beta-arrestin complex,
      controls the extent of beta-arrestin-bound ERK activation, and influences both
      the subcellular localization of activated ERK and the physiologic consequences of
      ERK activation.

PMID- 12473662
TI  - Induction of DNA replication-mediated double strand breaks by psoralen DNA
      interstrand cross-links.
AB  - The effect of DNA interstrand cross-links (cross-links) on DNA replication was
      examined with a cell-free SV40 origin-dependent DNA replication system. A defined
      template DNA with a single psoralen cross-link and the SV40 origin of replication
      was replicated by HeLa cell-free extract in the presence of SV40 large T antigen.
      The psoralen cross-link inhibited DNA replication by terminating chain elongation
      at 1-50 nucleotides before the cross-linked sites. The termination of DNA
      replication by the cross-links mediated the generation of double strand breaks
      near the cross-linked sites. These results are the first biochemical evidence of
      the generation of double strand breaks by DNA replication.

PMID- 12473661
TI  - The GIT family of proteins forms multimers and associates with the presynaptic
      cytomatrix protein Piccolo.
AB  - The cytoskeletal matrix assembled at active zones (CAZ) is implicated in defining
      neurotransmitter release sites. However, little is known about the molecular
      mechanisms by which the CAZ is organized. Here we report a novel interaction
      between Piccolo, a core component of the CAZ, and GIT proteins, multidomain
      signaling integrators with GTPase-activating protein activity for ADP
      ribosylation factor small GTPases. A small region (approximately 150 amino acid
      residues) in Piccolo, which is not conserved in the closely related CAZ protein
      Bassoon, mediates a direct interaction with the Spa2 homology domain (SHD) domain
      of GIT1. Piccolo and GIT1 colocalize at synaptic sites in cultured neurons. In
      brain, Piccolo forms a complex with GIT1 and various GIT-associated proteins,
      including betaPIX, focal adhesion kinase, liprin-alpha, and paxillin. Point
      mutations in the SHD of GIT1 differentially interfere with the association of
      GIT1 with Piccolo, betaPIX, and focal adhesion kinase, suggesting that these
      proteins bind to the SHD by different mechanisms. Intriguingly, GIT proteins form
      homo- and heteromultimers through their C-terminal G-protein-coupled receptor
      kinase-binding domain in a tail-to-tail fashion. This multimerization enables
      GIT1 to simultaneously interact with multiple SHD-binding proteins including
      Piccolo and betaPIX. These results suggest that, through their multimerization
      and interaction with Piccolo, the GIT family proteins are involved in the
      organization of the CAZ.

PMID- 12473663
TI  - Aqueous access channels in subunit a of rotary ATP synthase.
AB  - The role of subunit a in proton translocation by the Escherichia coli F(1)F(o)
      ATP synthase is poorly understood. In the membrane-bound F(o) sector of the
      enzyme, H(+) binding and release occurs at Asp(61) in the middle of the second
      transmembrane helix (TMH) of subunit c. Protons are thought to reach Asp(61) via
      an aqueous access pathway formed at least in part by one or more of the five TMHs
      of subunit a. In this report, we have substituted Cys into a 19-residue span of
      the fourth TMH of subunit a and used chemical modification to obtain information
      about the aqueous accessibility of residues along this helix. Residues 206, 210,
      and 214 are N-ethylmaleimide-accessible from the cytoplasmic side of the membrane
      and may lie on the H(+) transport route. Residues 215 and 218 on TMH4, as well as
      residue 245 on TMH5, are Ag(+)-accessible but N-ethylmaleimide-inaccessible and
      may form part of an aqueous pocket extending from Asp(61) of subunit c to the
      periplasmic surface.

PMID- 12473664
TI  - Two novel proteins activate superoxide generation by the NADPH oxidase NOX1.
AB  - NOX1, an NADPH oxidase expressed predominantly in colon epithelium, shows a high
      degree of similarity to the phagocyte NADPH oxidase. However, superoxide
      generation by NOX1 has been difficult to demonstrate. Here we show that NOX1
      generates superoxide when co-expressed with the p47(phox) and p67(phox) subunits
      of the phagocyte NADPH oxidase but not when expressed by itself. Since p47(phox)
      and p67(phox) are restricted mainly to myeloid cells, we searched for their
      homologues and identified two novel cDNAs. The mRNAs of both homologues were
      found predominantly in colon epithelium. Differences between the homologues and
      the phagocyte NADPH oxidase subunits included the lack of the autoinhibitory
      domain and the protein kinase C phosphorylation sites in the p47(phox) homologue
      as well as the absence of the first Src homology 3 domain and the presence of a
      hydrophobic stretch in the p67(phox) homologue. Co-expression of NOX1 with the
      two novel proteins led to stimulus-independent high level superoxide generation.
      Stimulus dependence of NOX1 was restored when p47(phox) was used to replace its
      homologue. In conclusion, NOX1 is a superoxide-generating enzyme that is
      activated by two novel proteins, which we propose to name NOXO1 (NOX organizer 1)
      and NOXA1 (NOX activator 1).

PMID- 12473665
TI  - Stimulation of the ERK pathway by GTP-loaded Rap1 requires the concomitant
      activation of Ras, protein kinase C, and protein kinase A in neuronal cells.
AB  - The small GTPases Ras or Rap1 were suggested to mediate the stimulatory effect of
      some G protein-coupled receptors on ERK activity in neuronal cells. Accordingly,
      we reported here that pituitary adenylate cyclase-activating polypeptide (PACAP),
      whose G protein-coupled receptor triggers neuronal differentiation of the PC12
      cell line via ERK1/2 activation, transiently activated Ras and induced the
      sustained GTP loading of Rap1. Ras mediated peak stimulation of ERK by PACAP,
      whereas Rap1 was necessary for the sustained activation phase. However, PACAP
      induced GTP-loading of Rap1 was not sufficient to account for ERK activation by
      PACAP because 1) PACAP-elicited Rap1 GTP-loading depended only on phospholipase
      C, whereas maximal stimulation of ERK by PACAP also required the activity of
      protein kinase A (PKA), protein kinase C (PKC), and calcium-dependent signaling;
      and 2) constitutively active mutants of Rap1, Rap1A-V12, and Rap1B-V12 only
      minimally stimulated the ERK pathway compared with Ras-V12. The effect of Rap1A
      V12 was dramatically potentiated by the concurrent activation of PKC, the cAMP
      pathway, and Ras, and this potentiation was blocked by dominant-negative mutants
      of Ras and Raf. Thus, this set of data indicated that GPCR-elicited GTP loading
      of Rap1 was not sufficient to stimulate efficiently ERK in PC12 cells and
      required the permissive co-stimulation of PKA, PKC, or Ras.

PMID- 12473666
TI  - A role for the cytoplasmic tail of the pre-T cell receptor (TCR) alpha chain in
      promoting constitutive internalization and degradation of the pre-TCR.
AB  - Engagement of the alpha beta T cell receptor (TCR) by its ligand results in the
      down-modulation of TCR cell surface expression, which is thought to be a central
      event in T cell activation. On the other hand, pre-TCR signaling is a key process
      in alpha beta T cell development, which appears to proceed in a constitutive and
      ligand-independent manner. Here, comparative analyses on the dynamics of pre-TCR
      and TCR cell surface expression show that unligated pre-TCR complexes expressed
      on human pre-T cells behave as engaged TCR complexes, i.e. they are rapidly
      internalized and degraded in lysosomes and proteasomes but do not recycle back to
      the cell surface. Thus, pre-TCR down-regulation takes place constitutively
      without the need for extracellular ligation. By using TCR alpha/p Tau alpha chain
      chimeras, we demonstrate that prevention of recycling and induction of
      degradation are unique pre-TCR properties conferred by the cytoplasmic domain of
      the pT alpha chain. Finally, we show that pre-TCR internalization is a protein
      kinase C-independent process that involves the combination of src kinase
      dependent and -independent pathways. These data suggest that constitutive pre-TCR
      down-modulation regulates pre-TCR surface expression levels and hence the extent
      of ligand-independent signaling through the pre-TCR.

PMID- 12473667
TI  - Characterization of alpha 2,6-sialyltransferase cleavage by Alzheimer's beta 
      secretase (BACE1).
AB  - BACE1 is a membrane-bound aspartic protease that cleaves the amyloid precursor
      protein (APP) at the beta-secretase site, a critical step in the Alzheimer
      disease pathogenesis. We previously found that BACE1 also cleaved a membrane
      bound sialyltransferase, ST6Gal I. By BACE1 overexpression in COS cells, the
      secretion of ST6Gal I markedly increased, and the amino terminus of the secreted
      ST6Gal I started at Glu(41). Here we report that BACE1-Fc chimera protein cleaved
      the A-ST6Gal I fusion protein, or ST6Gal I-derived peptide, between Leu(37) and
      Gln(38), suggesting that an initial cleavage product by BACE1 was three amino
      acids longer than the secreted ST6Gal I. The three amino acids, Gln(38)-Ala(39)
      Lys(40), were found to be truncated by exopeptidase activity, which was detected
      in detergent extracts of Golgi-derived membrane fraction. These results suggest
      that ST6Gal I is cleaved initially between Leu(37) and Gln(38) by BACE1, and then
      the three-amino acid sequence at the NH(2) terminus is removed by exopeptidase(s)
      before secretion from the cells.

PMID- 12473668
TI  - Spectroscopic characterization of the electronic changes in the active site of
      Streptomyces antibioticus tyrosinase upon binding of transition state analogue
      inhibitors.
AB  - The dinuclear copper enzyme tyrosinase (Ty) from genetically engineered
      Streptomyces antibioticus has been investigated in its paramagnetic half-met form
      [Cu(I)-Cu(II)]. The cw EPR, pulsed EPR, and hyperfine sublevel correlation
      spectroscopy (HYSCORE) experiments on the half-met-Ty and on its complexes with
      three different types of competitive inhibitor are reported. The first type
      includes p-nitrophenol, a very poor substrate for the monooxygenase activity of
      Ty. The second type comprises hydroxyquinones, such as kojic acid and l-mimosine,
      and the third type of inhibitor is represented by toluic acid. The electronic and
      structural differences of the half-met-Ty form induced at the cupric site by the
      different inhibitors have been determined. Probes of structural effects are the
      hyperfine coupling constants of the non coordinating Ndelta histidyl nitrogens.
      By using the available crystal structures of hemocyanin as a template in
      combination with the spectroscopic results, a structural model for the active
      site of half-met-Ty is obtained and a model for the binding modes of both mono-
      and diphenols could be proposed.

PMID- 12473669
TI  - Zinc binding and dimerization of Streptococcus pyogenes pyrogenic exotoxin C are
      not essential for T-cell stimulation.
AB  - Streptococcal pyrogenic enterotoxin C (Spe-C) is a superantigen virulence factor
      produced by Streptococcus pyogenes that activates T-cells polyclonally. The
      biologically active form of Spe-C is thought to be a homodimer containing an
      essential zinc coordination site on each subunit, consisting of the residues
      His(167), His(201), and Asp(203). Crystallographic data suggested that receptor
      specificity is dependent on contacts between the zinc coordination site of Spe-C
      and the beta-chain of the major histocompatibility complex type II (MHCII)
      molecule. Our results indicate that only a minor fraction of dimer is present at
      T-cell stimulatory concentrations of Spe-C following mutation of the unpaired
      side chain of cysteine at residue 27 to serine. Mutations of amino acid residues
      His(167), His(201), or Asp(203) had only minor effects on protein stability but
      resulted in greatly diminished MHCII binding, as measured by surface plasmon
      resonance with isolated receptor/ligand pairs and flow cytometry with MHCII
      expressing cells. However, with the exception of the mutants D203A and D203N,
      mutation of the zinc-binding site of Spe-C did not significantly impact T-cell
      activation. The mutation Y76A, located in a polar pocket conserved among most
      superantigens, resulted in significant loss of T-cell stimulation, although no
      effect was observed on the overall binding to human MHCII molecules, perhaps
      because of the masking of this lower affinity interaction by the dominant zinc
      dependent binding. To a lesser extent, mutations of side chains found in a second
      conserved MHCII alpha-chain-binding site consisting of a hydrophobic surface loop
      decreased T-cell stimulation. Our results demonstrate that dimerization and zinc
      coordination are not essential for biological activity of Spe-C and suggest the
      contribution of an alternative MHCII binding mode to T-cell activation.

PMID- 12473670
TI  - Osteopontin induces nuclear factor kappa B-mediated promatrix metalloproteinase-2
      activation through I kappa B alpha /IKK signaling pathways, and curcumin
      (diferulolylmethane) down-regulates these pathways.
AB  - We have recently reported that osteopontin (OPN) stimulates tumor growth and
      activation of promatrix metalloproteinase-2 (pro-MMP-2) through nuclear factor
      kappa B (NF kappa B)-mediated induction of membrane type 1 matrix
      metalloproteinase (MT1-MMP) in murine melanoma cells (Philip, S., Bulbule, A.,
      and Kundu, G. C. (2001) J. Biol. Chem. 276, 44926-44935). However, the molecular
      mechanism by which OPN activates NF kappa B and regulates pro-MMP-2 activation in
      murine melanoma (B16F10) cells is not well defined. We also investigated the
      mechanism of action of curcumin (diferulolylmethane) on OPN-induced NF kappa B
      mediated activation of pro-MMP-2 in B16F10 cells. Here we report that OPN induces
      phosphorylation and degradation of the inhibitor of nuclear factor kappa B (I
      kappa B alpha) by inducing the activity of I kappa B kinase (IKK) in these cells.
      OPN also induces the nuclear accumulation of NF kappa B p65, NF kappa B-DNA
      binding, and transactivation. However, curcumin a known anti-inflammatory and
      anticarcinogenic agent suppressed OPN-induced I kappa B alpha phosphorylation and
      degradation by inhibiting the IKK activity. Moreover, our data revealed that
      curcumin inhibited the OPN-induced translocation of p65, NF kappa B-DNA binding,
      and NF kappa B transcriptional activity. The OPN-induced pro-MMP-2 activation and
      MT1-MMP expression were also drastically reduced by curcumin. Curcumin also
      inhibited OPN-induced cell proliferation, cell migration, extracellular matrix
      invasion, and synergistically induced apoptotic morphology with OPN in these
      cells. Most importantly, curcumin suppressed the OPN-induced tumor growth in nude
      mice, and the levels of pro-MMP-2 expression and activation in OPN-induced tumor
      were inhibited by curcumin. To our knowledge, this is the first report that OPN
      induces NF kappa B activity through phosphorylation and degradation of I kappa B
      alpha by activating IKK that ultimately triggers the activation of pro-MMP-2 and
      further demonstrates that curcumin potently suppresses OPN-induced cell
      migration, tumor growth, and NF kappa B-mediated pro-MMP-2 activation by blocking
      the IKK/I kappa B alpha signaling pathways.

PMID- 12473671
TI  - Targeted disruption of the PEPT2 gene markedly reduces dipeptide uptake in
      choroid plexus.
AB  - The presence of multiple oligopeptide transporters in brain has generated
      considerable interest as to their physiological role in neuropeptide homeostasis,
      pharmacologic importance, and potential as a target for drug delivery through the
      blood-brain and blood-cerebrospinal fluid barriers. To understand further the
      purpose of specific peptide transporters in brain, we have generated PEPT2
      deficient mice by targeted gene disruption. Homozygous PepT2 null mice lacked
      expression of PEPT2 mRNA and protein in choroid plexus and kidney, tissues in
      which PepT2 is normally expressed, whereas heterozygous mice displayed PepT2
      expression levels that were intermediate between those of wild-type and
      homozygous null animals. Mutant PepT2 null mice were found to be viable, grew to
      normal size and weight, and were without obvious kidney or brain abnormalities.
      Notwithstanding the lack of apparent biological effects, the proton-stimulated
      uptake of 1.9 microm glycylsarcosine (a model, hydrolysis-resistant dipeptide) in
      isolated choroid plexus was essentially ablated (i.e. residual activity of 10.9
      and 3.9% at 5 and 30 min, respectively). These novel findings provide strong
      evidence that, under the experimental conditions of this study, PEPT2 is the
      primary member of the peptide transporter family responsible for dipeptide uptake
      in choroid plexus tissue.

PMID- 12473672
TI  - Helicase and nuclease activities of hyperthermophile Pyrococcus horikoshii Dna2
      inhibited by substrates with RNA segments at 5'-end.
AB  - Dna2 protein plays an important role in Okazaki fragment maturation on the
      lagging strand and also participates in DNA repair in Eukarya. Herein, we report
      the first biochemical characterization of a Dna2 homologue from Archaea, the
      hyperthermophile Pyrococcus horikoshii (Dna2Pho). Dna2Pho has both a RecB-like
      nuclease motif and seven conserved helicase motifs similar to Dna2 from
      Saccharomyces cerevisiae. Dna2Pho has single-stranded (ss) DNA-stimulated ATPase
      activity, DNA helicase activity (5' to 3' direction) requiring ATP, and nuclease
      activity, which prefers free 5'-ends of ssDNA as substrate. These activities
      depend on MgCl(2) concentrations. Dna2Pho requires a higher concentration of
      MgCl(2) for the nuclease than helicase activity. Both the helicase and nuclease
      activities of Dna2Pho were inhibited by substrates with RNA segments at the 5'
      end of flap DNA, whereas the nuclease activity of Dna2 from S. cerevisiae was
      reported to be stimulated by RNA segments in the 5'-tail (Bae, S.-H., and Seo, Y.
      S. (2000) J. Biol. Chem. 38022-38031).

PMID- 12473673
TI  - Enhancement of scavenger receptor class B type I-mediated selective cholesteryl
      ester uptake from apoA-I(-/-) high density lipoprotein (HDL) by apolipoprotein A
      I requires HDL reorganization by lecithin cholesterol acyltransferase.
AB  - The severe depletion of cholesteryl ester (CE) in adrenocortical cells of apoA-I(
      /-) mice suggests that apolipoprotein (apo) A-I plays an important role in the
      high density lipoprotein (HDL) CE selective uptake process mediated by scavenger
      receptor BI (SR-BI) in vivo. A recent study showed that apoA-I(-/-) HDL binds to
      SR-BI with the same affinity as apoA-I(+/+) HDL, but apoA-I(-/-) HDL has a
      decreased V(max) for CE transfer from the HDL particle to adrenal cells. The
      present study was designed to determine the basis for the reduced selective
      uptake of CE from apoA-I(-/-) HDL. Variations in apoA-I(-/-) HDL particle
      diameter, free cholesterol or phospholipid content, or the apoE or apoA-II
      content of apoA-I(-/-) HDL had little effect on HDL CE selective uptake into Y1
      BS1 adrenal cells. Lecithin cholesterol acyltransferase treatment alone or
      addition of apoA-I to apoA-I(-/-) HDL alone also had little effect. However,
      addition of apoA-I to apoA-I(-/-) HDL in the presence of lecithin cholesterol
      acyltransferase reorganized the large heterogeneous apoA-I(-/-) HDL to a more
      discrete particle with enhanced CE selective uptake activity. These results show
      a unique role for apoA-I in HDL CE selective uptake that is distinct from its
      role as a ligand for HDL binding to SR-BI. These data suggest that the
      conformation of apoA-I at the HDL surface is important for the efficient transfer
      of CE to the cell.

PMID- 12473674
TI  - Protein phosphatase 2A regulates the stability of Pim protein kinases.
AB  - The pim family of proto-oncogenes encodes three serine-threonine kinases that
      have been implicated in the development of malignancies in mice and in humans.
      Expression of the Pim protein kinases is tightly regulated at the
      transcriptional, post-transcriptional, and translational levels. Dysregulation of
      pim transcription and pim mRNA stability have been implicated in Pim-mediated
      transformation. The data presented herein demonstrate that expression of the Pim
      kinases is additionally regulated at the post-translational level, by the serine
      threonine phosphatase protein phosphatase 2A (PP2A). The catalytic subunit of
      PP2A associates with the Pim kinases in vivo, and the Pim kinases are substrates
      of PP2A phosphatase activity in vitro. Furthermore, overexpression of PP2A
      reduces the levels of the Pim proteins, whereas inhibition of PP2A activity by
      the protein phosphatase inhibitor okadaic acid stabilizes the Pim proteins.
      Finally, the effects of PP2A on the expression of the Pim proteins can affect Pim
      function. Taken together, these data suggest that PP2A activity is important for
      the regulation of the stability and function of the Pim kinases.

PMID- 12473675
TI  - The accessory molecules CD5 and CD6 associate on the membrane of lymphoid T
      cells.
AB  - CD5 and CD6 are closely related lymphocyte surface receptors of the scavenger
      receptor cysteine-rich superfamily, which show highly homologous extracellular
      regions but little conserved cytoplasmic tails. Both molecules are expressed on
      the same lymphocyte populations (thymocytes, mature T cells, and B1a cells) and
      share similar co-stimulatory properties on mature T cells. Although several works
      have been reported on the molecular associations and the signaling pathway
      mediated by CD5, very limited information is available for CD6 in this regard.
      Here we show the physical association of CD5 and CD6 at the cell membrane of
      lymphocytes, as well as their localization at the immunological synapse. CD5 and
      CD6 co-immunoprecipitate from Brij 96 but not Nonidet P-40 cell lysates,
      independently of both the co-expression of other lymphocyte surface receptors and
      the integrity of CD5 cytoplasmic region. Fluorescence resonance energy transfer
      analysis, co-capping, and co-modulation experiments demonstrate the physical in
      vivo association of CD5 and CD6. Analysis of T cell/antigen-presenting cells
      conjugates shows the accumulation of both molecules at the immunological synapse.
      These results indicate that CD5 and CD6 are structurally and physically related
      receptors, which may be functionally linked to provide either similar or
      complementary accessory signals during T cell activation and/or differentiation.

PMID- 12473676
TI  - Sequence identification and characterization of human carnosinase and a closely
      related non-specific dipeptidase.
AB  - Carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-aminobutyric acid-L
      histidine) are two naturally occurring dipeptides with potential neuroprotective
      and neurotransmitter functions in the brain. Peptidase activities degrading both
      carnosine and homocarnosine have been described previously, but the genes linked
      to these activities were unknown. Here we present the identification of two novel
      cDNAs named CN1 and CN2 coding for two proteins of 56.8 and 52.7 kDa and their
      classification as members of the M20 metalloprotease family. Whereas human CN1
      mRNA and protein are brain-specific, CN2 codes for a ubiquitous protein. In
      contrast, expression of the mouse and rat CN1 orthologues was detectable only in
      kidney. The recombinant CN1 and CN2 proteins were expressed in Chinese hamster
      ovary cells and purified to homogeneity. CN1 was identified as a homodimeric
      dipeptidase with a narrow substrate specificity for Xaa-His dipeptides including
      those with Xaa = beta Ala (carnosine, K(m) 1.2 mM), N-methyl beta Ala, Ala, Gly,
      and gamma-aminobutyric acid (homocarnosine, K(m) 200 microM), an isoelectric
      point of pH 4.5, and maximal activity at pH 8.5. CN2 protein is a dipeptidase not
      limited to Xaa-His dipeptides, requires Mn(2+) for full activity, and is
      sensitive to inhibition by bestatin (IC(50) 7 nM). This enzyme does not degrade
      homocarnosine and hydrolyzes carnosine only at alkaline pH with an optimum at pH
      9.5. Based on their substrate specificity and biophysical and biochemical
      properties CN1 was identified as human carnosinase (EC ), whereas CN2 corresponds
      to the cytosolic nonspecific dipeptidase (EC ).

PMID- 12473677
TI  - Mcm1 binds replication origins.
AB  - Mcm1 is an essential protein required for the efficient replication of
      minichromosomes and the transcriptional regulation of early cell cycle genes in
      Saccharomyces cerevisiae. In this study, we report that Mcm1 is an abundant
      protein that associates globally with chromatin in a punctate pattern. We show
      that Mcm1 is localized at replication origins and plays an important role in the
      initiation of DNA synthesis at a chromosomal replication origin in vivo. Using
      purified Mcm1 protein, we show that Mcm1 binds cooperatively to multiple sites at
      autonomously replicating sequences. These results suggest that, in addition to
      its role as a transcription factor for the expression of replication genes, Mcm1
      may influence the local structure of replication origins by direct binding.

PMID- 12473678
TI  - Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA
      methyltransferase, Dnmt1.
AB  - During mammalian cell division, DNA methylation patterns are transferred
      accurately to the newly synthesized DNA strand. This depends on maintenance DNA
      methyltransferase activity. DNA methylation can affect chromatin organization and
      gene expression by recruitment of histone deacetylases (HDACs). Here we show that
      the methyl-CpG binding protein, MeCP2, interacts directly with the maintenance
      DNA methyltransferase, Dnmt1. The region of MeCP2 that interacts with Dnmt1
      corresponds to the transcription repressor domain which can also recruit HDACs
      via a corepressor, mSin3A. Dnmt1 can form complexes with HDACs as well as MeCP2.
      Surprisingly, the MeCP2-Dnmt1 complex does not contain the histone deacetylase,
      HDAC1. Thus, Dnmt1 takes the place of the mSin3A-HDAC1 complex, indicating that
      the MeCP2-interacting Dnmt1 does not bind to HDAC1. Further, we demonstrate that
      MeCP2 can form a complex with hemimethylated as well as fully methylated DNA.
      Immunoprecipitated MeCP2 complexes show DNA methyltransferase activity to
      hemimethylated DNA. These results suggest that Dnmt1 associates with MeCP2 in
      order to perform maintenance methylation in vivo. We propose that genome-wide
      and/or -specific local DNA methylation may be maintained by the Dnmt1-MeCP2
      complexes, bound to hemimethylated DNA. Dnmt1 may be recruited to targeted
      regions via multiple steps that may or may not involve histone deacetylases.

PMID- 12473679
TI  - Structural basis of type VI collagen dimer formation.
AB  - We have determined the interactive sites required for dimer formation in type VI
      collagen. Despite the fact that type VI collagen is a heterotrimer composed of
      alpha1(VI), alpha2(VI), and alpha3(VI) chains, the formation of dimers is
      determined principally by interactions of the alpha2(VI) chain. Key components of
      this interaction are the metal ion-dependent adhesion site (MIDAS) motif of the
      alpha2C2 A-domain and the GER sequence in the helical domain of another
      alpha2(VI) chain. Replacement of the alpha2(VI) C2 domain with the alpha3(VI)
      domain abolished dimer formation, whereas alterations in the alpha2(VI) C1 domain
      did not disrupt dimer formation. When the helical sequences were investigated,
      replacement of the alpha2(VI) sequence GSPGERGDQ with the alpha3(VI) sequence
      GEKGERGDV abolished dimer formation. Mutating the Pro-108 to a Lys-108 in this
      alpha2(VI) sequence did not influence dimer formation and suggests that, unlike
      the integrin I-domain/triple-helix interaction, hydroxyproline is not required in
      collagen VI A-domain/helix interaction. These results demonstrate that the
      alpha2(VI) chain position in the assembled triple-helical molecule is critical
      for antiparallel dimer formation and identify the interacting collagenous and
      MIDAS sequences involved. These interactions underpin the subsequent assembly of
      type VI collagen.

PMID- 12473680
TI  - Cleavage of model replication forks by fission yeast Mus81-Eme1 and budding yeast
      Mus81-Mms4.
AB  - The blockage of replication forks can result in the disassembly of the
      replicative apparatus and reversal of the fork to form a DNA junction that must
      be processed in order for replication to restart and sister chromatids to
      segregate at mitosis. Fission yeast Mus81-Eme1 and budding yeast Mus81-Mms4 are
      endonucleases that have been implicated in the processing of aberrant DNA
      junctions formed at stalled replication forks. Here we have investigated the
      activity of purified Mus81-Eme1 and Mus81-Mms4 on substrates that resemble DNA
      junctions that are expected to form when a replication fork reverses. Both
      enzymes cleave Holliday junctions and substrates that resemble normal replication
      forks poorly or not at all. However, forks where the equivalents of either both
      the leading and lagging strands or just the lagging strand are juxtaposed at the
      junction point, or where either the leading or lagging strand has been unwound to
      produce a fork with a single-stranded tail, are cleaved well. Cleavage sites map
      predominantly between 3 and 6 bp 5' of the junction point. For most substrates
      the leading strand template is cleaved. The sole exception is a fork with a 5'
      single-stranded tail, which is cleaved in the lagging strand template.

PMID- 12473681
TI  - Structural basis of protein-bound endogenous aldehydes. Chemical and
      immunochemical characterizations of configurational isomers of a 4-hydroxy-2
      nonenal-histidine adduct.
AB  - 4-Hydroxy-2-nonenal (HNE), a major racemic product of lipid peroxidation, reacts
      with histidine to form a stable HNE-histidine Michael addition-type adduct
      possessing three chiral centers in the cyclic hemiacetal structure. In the
      present study, we characterized configurational isomers of a HNE-N(alpha)
      acetylhistidine adduct by NMR spectroscopy and by molecular orbital calculations.
      In addition, we raised monoclonal antibodies against (R)-HNE-histidine and (S)
      HNE-histidine adducts, characterized their specificities, and examined in vivo
      localizations of each adduct under oxidative stress. To facilitate structural
      characterization of the configurational isomers of an HNE-histidine adduct, we
      prepared the (R)-HNE-histidine and (S)-HNE-histidine adducts by incubating
      N(alpha)-acetylhistidine with each HNE enantiomer, both of which provided two
      peaks (Ra and Rb from (R)-HNE-histidine and Sa and Sb from (S)-HNE-histidine
      adducts) in reversed-phase high-performance liquid chromatography. The NMR
      analysis showed that each peak was a mixture of two diastereomers. In addition,
      the analysis of the nuclear Overhauser effect enabled the determination of
      configurations of the eight isomers. The relative amounts of these isomers in the
      NMR analysis correlated with the relative energies calculated by molecular
      orbital methods. On the other hand, using (R)-HNE-modified and (S)-HNE-modified
      keyhole limpet hemocyanins as the antigens, we raised the monoclonal antibodies,
      mAbR310 and mAbS412, which enantioselectively recognized the (R)-HNE-histidine
      and (S)-HNE-histidine adducts, respectively. Among the mixtures (Ra, Rb, Sa, and
      Sb) of diastereomers, mAbR310 showed the highest immunoreactivity to Rb (the
      mixture of 2R,4S,5R and 2S,4S,5R isomers), whereas mAbS412 preferentially
      recognized Sa (the mixture of 2R,4S,5S and 2S,4S,5S isomers). The presence of (R)
      HNE and (S)-HNE epitopes in vivo was immunohistochemically examined in the kidney
      of rats exposed to the renal carcinogen, ferric nitrilotriacetate, by which
      nuclear and cytosolic stainings with mAbR310 and mAbS412, respectively, were
      detected.

PMID- 12473682
TI  - Lysyl oxidase is required for vascular and diaphragmatic development in mice.
AB  - Lysyl oxidase (LOX) is an enzyme responsible for the cross-linking of collagen
      and elastin both in vitro and in vivo. The unique functions of the individual
      members of this multigene family have been difficult to ascertain because of
      highly conserved catalytic domains and overlapping tissue expression patterns. To
      address this problem of functional and structural redundancy and to determine the
      role of LOX in the development of tissue integrity, Lox gene expression was
      deleted by targeted mutagenesis in mice. Lox-targeted mice (LOX(-/-)) died soon
      after parturition, exhibiting cardiovascular instability with ruptured arterial
      aneurysms and diaphragmatic rupture. Microscopic analysis of the aorta
      demonstrated fragmented elastic fiber architecture in homozygous mutant null
      mice. LOX activity, as assessed by desmosine (elastin cross-link) analysis, was
      reduced by approximately 60% in the aorta and lungs of homozygous mutant animals
      compared with wild type mice. Immature collagen cross-links were decreased but to
      a lesser degree than elastin cross-links in LOX(-/-) mice. Thus, lysyl oxidase
      appears critical during embryogenesis for structural stability of the aorta and
      diaphragm and connective tissue development.

PMID- 12473683
TI  - Microtubule release from the centrosome in migrating cells.
AB  - In migrating cells, force production relies essentially on a polarized actomyosin
      system, whereas the spatial regulation of actomyosin contraction and substrate
      contact turnover involves a complex cooperation between the microtubule (MT) and
      the actin filament networks (Goode, B.L., D.G. Drubin, and G. Barnes. 2000. Curr.
      Opin. Cell Biol., 12:63-71). Targeting and capture of MT plus ends at the cell
      periphery has been described, but whether or not the minus ends of these MTs are
      anchored at the centrosome is not known. Here, we show that release of short MTs
      from the centrosome is frequent in migrating cells and that their transport
      toward the cell periphery is blocked when dynein activity is impaired. We further
      show that MT release, but not MT nucleation or polymerization dynamics, is
      abolished by overexpression of the centrosomal MT-anchoring protein ninein. In
      addition, a dramatic inhibition of cell migration was observed; but, contrary to
      cells treated by drugs inhibiting MT dynamics, polarized membrane ruffling
      activity was not affected in ninein overexpressing cells. We thus propose that
      the balance between MT minus-end capture and release from the centrosome is
      critical for efficient cell migration.

PMID- 12473684
TI  - BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and
      impairs neuronal Cl- extrusion.
AB  - Pathophysiological activity and various kinds of traumatic insults are known to
      have deleterious long-term effects on neuronal Cl- regulation, which can lead to
      a suppression of fast postsynaptic GABAergic responses. Brain-derived
      neurotrophic factor (BDNF) increases neuronal excitability through a conjunction
      of mechanisms that include regulation of the efficacy of GABAergic transmission.
      Here, we show that exposure of rat hippocampal slice cultures and acute slices to
      exogenous BDNF or neurotrophin-4 produces a TrkB-mediated fall in the neuron
      specific K+-Cl- cotransporter KCC2 mRNA and protein, as well as a consequent
      impairment in neuronal Cl- extrusion capacity. After kindling-induced seizures in
      vivo, the expression of KCC2 is down-regulated in the mouse hippocampus with a
      spatiotemporal profile complementary to the up-regulation of TrkB and BDNF. The
      present data demonstrate a novel mechanism whereby BDNF/TrkB signaling suppresses
      chloride-dependent fast GABAergic inhibition, which most likely contributes to
      the well-known role of TrkB-activated signaling cascades in the induction and
      establishment of epileptic activity.

PMID- 12473685
TI  - Gene density and transcription influence the localization of chromatin outside of
      chromosome territories detectable by FISH.
AB  - Genes can be transcribed from within chromosome territories; however, the major
      histocompatibilty complex locus has been reported extending away from chromosome
      territories, and the incidence of this correlates with transcription from the
      region. A similar result has been seen for the epidermal differentiation complex
      region of chromosome 1. These data suggested that chromatin decondensation away
      from the surface of chromosome territories may result from, and/or may
      facilitate, transcription of densely packed genes subject to coordinate
      regulation.To investigate whether localization outside of the visible confines of
      chromosome territories can also occur for regions that are not coordinately
      regulated, we have examined the spatial organization of human 11p15.5 and the
      syntenic region on mouse chromosome 7. This region is gene rich but its genes are
      not coordinately expressed, rather overall high levels of transcription occur in
      several cell types. We found that chromatin from 11p15.5 frequently extends away
      from the chromosome 11 territory. Localization outside of territories was also
      detected for other regions of high gene density and high levels of transcription.
      This is shown to be partly dependent on ongoing transcription. We suggest that
      local gene density and transcription, rather than the activity of individual
      genes, influences the organization of chromosomes in the nucleus.

PMID- 12473686
TI  - The transcription cycle of RNA polymerase II in living cells.
AB  - RNA polymerase II transcribes most eukaryotic genes. Its catalytic subunit was
      tagged with green fluorescent protein and expressed in Chinese hamster cells
      bearing a mutation in the same subunit; it complemented the defect and so was
      functional. Photobleaching revealed two kinetic fractions of polymerase in living
      nuclei: approximately 75% moved rapidly, but approximately 25% was transiently
      immobile (association t1/2 approximately 20 min) and transcriptionally active, as
      incubation with 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole eliminated it.
      No immobile but inactive fraction was detected, providing little support for the
      existence of a stable holoenzyme, or the slow stepwise assembly of a
      preinitiation complex on promoters or the nuclear substructure. Actinomycin D
      decreased the rapidly moving fraction, suggesting that engaged polymerases stall
      at intercalated molecules while others initiate. When wild-type cells containing
      only the endogenous enzyme were incubated with [3H]uridine, nascent transcripts
      became saturated with tritium with similar kinetics (t1/2 approximately 14 min).
      These data are consistent with a polymerase being mobile for one half to five
      sixths of a transcription cycle, and rapid assembly into the preinitiation
      complex. Then, most expressed transcription units would spend significant times
      unassociated with engaged polymerases.

PMID- 12473687
TI  - Lamin A/C speckles mediate spatial organization of splicing factor compartments
      and RNA polymerase II transcription.
AB  - The A-type lamins have been observed to colocalize with RNA splicing factors in
      speckles within the nucleus, in addition to their typical distribution at the
      nuclear periphery. To understand the functions of lamin speckles, the effects of
      transcriptional inhibitors known to modify RNA splicing factor compartments
      (SFCs) were examined. Treatment of HeLa cells with alpha-amanitin or 5,6
      dichlorobenzimidazole riboside (DRB) inhibited RNA polymerase II (pol II)
      transcription and led to the enlargement of lamin speckles as well as SFCs.
      Removal of the reversible inhibitor DRB resulted in the reactivation of
      transcription and a rapid, synchronous redistribution of lamins and splicing
      factors to normal-sized speckles, indicating a close association between lamin
      speckles and SFCs. Conversely, the expression of NH2-terminally modified lamin A
      or C in HeLa cells brought about a loss of lamin speckles, depletion of SFCs, and
      down-regulation of pol II transcription without affecting the peripheral lamina.
      Our results suggest a unique role for lamin speckles in the spatial organization
      of RNA splicing factors and pol II transcription in the nucleus.

PMID- 12473688
TI  - The intranuclear mobility of messenger RNA binding proteins is ATP dependent and
      temperature sensitive.
AB  - After being released from transcription sites, messenger ribonucleoprotein
      particles (mRNPs) must reach the nuclear pore complexes in order to be
      translocated to the cytoplasm. Whether the intranuclear movement of mRNPs results
      largely from Brownian motion or involves molecular motors remains unknown. Here
      we have used quantitative photobleaching techniques to monitor the intranuclear
      mobility of protein components of mRNPs tagged with GFP. The results show that
      the diffusion coefficients of the poly(A)-binding protein II (PABP2) and the
      export factor TAP are significantly reduced when these proteins are bound to mRNP
      complexes, as compared with nonbound proteins. The data further show that the
      mobility of wild-type PABP2 and TAP, but not of a point mutant variant of PABP2
      that fails to bind to RNA, is significantly reduced when cells are ATP depleted
      or incubated at 22 degrees C. Energy depletion has only minor effects on the
      intranuclear mobility of a 2,000-kD dextran (which corresponds approximately in
      size to 40S mRNP particles), suggesting that the reduced mobility of PABP2 and
      TAP is not caused by a general alteration of the nuclear environment. Taken
      together, the data suggest that the mobility of mRNPs in the living cell nucleus
      involves a combination of passive diffusion and ATP-dependent processes.

PMID- 12473689
TI  - The yeast nuclear pore complex functionally interacts with components of the
      spindle assembly checkpoint.
AB  - Aphysical and functional link between the nuclear pore complex (NPC) and the
      spindle checkpoint machinery has been established in the yeast Saccharomyces
      cerevisiae. We show that two proteins required for the execution of the spindle
      checkpoint, Mad1p and Mad2p, reside predominantly at the NPC throughout the cell
      cycle. There they are associated with a subcomplex of nucleoporins containing
      Nup53p, Nup170p, and Nup157p. The association of the Mad1p-Mad2p complex with the
      NPC requires Mad1p and is mediated in part by Nup53p. On activation of the
      spindle checkpoint, we detect changes in the interactions between these proteins,
      including the release of Mad2p (but not Mad1p) from the NPC and the accumulation
      of Mad2p at kinetochores. Accompanying these events is the Nup53p-dependent
      hyperphosphorylation of Mad1p. On the basis of these results and genetic analysis
      of double mutants, we propose a model in which Mad1p bound to a Nup53p-containing
      complex sequesters Mad2p at the NPC until its release by activation of the
      spindle checkpoint. Furthermore, we show that the association of Mad1p with the
      NPC is not passive and that it plays a role in nuclear transport.

PMID- 12473690
TI  - The targeting of the atToc159 preprotein receptor to the chloroplast outer
      membrane is mediated by its GTPase domain and is regulated by GTP.
AB  - The multimeric translocon at the outer envelope membrane of chloroplasts (Toc)
      initiates the recognition and import of nuclear-encoded preproteins into
      chloroplasts. Two Toc GTPases, Toc159 and Toc33/34, mediate preprotein
      recognition and regulate preprotein translocation. Although these two proteins
      account for the requirement of GTP hydrolysis for import, the functional
      significance of GTP binding and hydrolysis by either GTPase has not been defined.
      A recent study indicates that Toc159 is equally distributed between a soluble
      cytoplasmic form and a membrane-inserted form, raising the possibility that it
      might cycle between the cytoplasm and chloroplast as a soluble preprotein
      receptor. In the present study, we examined the mechanism of targeting and
      insertion of the Arabidopsis thaliana orthologue of Toc159, atToc159, to
      chloroplasts. Targeting of atToc159 to the outer envelope membrane is strictly
      dependent only on guanine nucleotides. Although GTP is not required for initial
      binding, the productive insertion and assembly of atToc159 into the Toc complex
      requires its intrinsic GTPase activity. Targeting is mediated by direct binding
      between the GTPase domain of atToc159 and the homologous GTPase domain of
      atToc33, the Arabidopsis Toc33/34 orthologue. Our findings demonstrate a role for
      the coordinate action of the Toc GTPases in assembly of the functional Toc
      complex at the chloroplast outer envelope membrane.

PMID- 12473691
TI  - VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is
      required for Golgi and ER assembly in vivo.
AB  - NSF and p97 are ATPases required for the heterotypic fusion of transport vesicles
      with their target membranes and the homotypic fusion of organelles. NSF uses ATP
      hydrolysis to dissociate NSF/SNAPs/SNAREs complexes, separating the v- and t
      SNAREs, which are then primed for subsequent rounds of fusion. In contrast, p97
      does not dissociate the p97/p47/SNARE complex even in the presence of ATP. Now we
      have identified a novel essential factor for p97/p47-mediated membrane fusion,
      named VCIP135 (valosin-containing protein [VCP][p97]/p47 complex-interacting
      protein, p135), and show that it binds to the p97/p47/syntaxin5 complex and
      dissociates it via p97 catalyzed ATP hydrolysis. In living cells, VCIP135 and p47
      are shown to function in Golgi and ER assembly.

PMID- 12473694
TI  - Urbanization, urbanicity, and health.
AB  - A majority of the world's population will live in urban areas by 2007. The most
      rapidly urbanizing cities are in less-wealthy nations, and the pace of growth
      varies among regions. There are few data linking features of cities to the health
      of populations. We suggest a framework to guide inquiry into features of the
      urban environment that affect health and well-being. We consider two key
      dimensions: urbanization and urbanicity. Urbanization refers to change in size,
      density, and heterogeneity of cities. Urbanicity refers to the impact of living
      in urban areas at a given time. A review of the published literature suggests
      that most of the important factors that affect health can be considered within
      three broad themes: the social environment, the physical environment, and access
      to health and social services. The development of urban health as a discipline
      will need to draw on the strengths of diverse academic areas of study (e.g.,
      ecology, epidemiology, sociology). Cross-national research may provide insights
      about the key features of cities and how urbanization influences population
      health.

PMID- 12473692
TI  - Lineage-specific requirements of beta-catenin in neural crest development.
AB  - Beta-catenin plays a pivotal role in cadherin-mediated cell adhesion. Moreover,
      it is a downstream signaling component of Wnt that controls multiple
      developmental processes such as cell proliferation, apoptosis, and fate
      decisions. To study the role of beta-catenin in neural crest development, we used
      the Cre/loxP system to ablate beta-catenin specifically in neural crest stem
      cells. Although several neural crest-derived structures develop normally, mutant
      animals lack melanocytes and dorsal root ganglia (DRG). In vivo and in vitro
      analyses revealed that mutant neural crest cells emigrate but fail to generate an
      early wave of sensory neurogenesis that is normally marked by the transcription
      factor neurogenin (ngn) 2. This indicates a role of beta-catenin in premigratory
      or early migratory neural crest and points to heterogeneity of neural crest cells
      at the earliest stages of crest development. In addition, migratory neural crest
      cells lateral to the neural tube do not aggregate to form DRG and are unable to
      produce a later wave of sensory neurogenesis usually marked by the transcription
      factor ngn1. We propose that the requirement of beta-catenin for the
      specification of melanocytes and sensory neuronal lineages reflects roles of beta
      catenin both in Wnt signaling and in mediating cell-cell interactions.

PMID- 12473693
TI  - Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to
      matrix adhesion.
AB  - Cell migration involves many steps, including membrane protrusion and the
      development of new adhesions. Here we have investigated whether there is a link
      between actin polymerization and integrin engagement. In response to signals that
      trigger membrane protrusion, the actin-related protein (Arp)2/3 complex
      transiently binds to vinculin, an integrin-associated protein. The interaction is
      regulated, requiring phosphatidylinositol-4,5-bisphosphate and Rac1 activation,
      and is sufficient to recruit the Arp2/3 complex to new sites of integrin
      aggregation. Binding of the Arp2/3 complex to vinculin is direct and does not
      depend on the ability of vinculin to associate with actin. We have mapped the
      binding site for the Arp2/3 complex to the hinge region of vinculin, and a point
      mutation in this region selectively blocks binding to the Arp2/3 complex.
      Compared with WT vinculin, expression of this mutant in vinculin-null cells
      results in diminished lamellipodial protrusion and spreading on fibronectin. The
      recruitment of the Arp2/3 complex to vinculin may be one mechanism through which
      actin polymerization and membrane protrusion are coupled to integrin-mediated
      adhesion.

PMID- 12473695
TI  - A population health framework for inner-city mental health.
AB  - Dealing with mental health problems in the inner city presents a major challenge
      to planners and service providers. Traditional mental health service-oriented
      interventions often prove ineffective due to the complexity of individuals'
      needs. This article argues that a population health framework can be used to
      identify critical risk and protective factors and facilitate more effective,
      upstream, population-based interventions for mental health problems in the inner
      city. A community report card is seen as a useful measure of key indicators at
      any point in time and of changes over time at the community or neighborhood
      level. A number of issues with regard to report card development are identified
      and discussed, as is the process of creating a report card, including key domains
      and the organization of findings.

PMID- 12473696
TI  - Social trust and self-rated health in US communities: a multilevel analysis.
AB  - This study assessed the contextual and individual effects of social trust on
      health. Methods consisted of a multilevel regression analysis of self-rated poor
      health among 21,456 individuals nested within 40 US communities included in the
      2000 Social Capital Community Benchmark Survey. Controlling for demographic
      covariates, a strong income and education gradient was observed for self-rated
      health. Higher levels of community social trust were associated with a lower
      probability of reporting poor health. Individual demographic and socioeconomic
      predictors did not explain the association of community social trust with self
      rated health. Controlling for individual trust perception, however, rendered the
      main effect of community social trust statistically insignificant, but a complex
      interaction effect was observed, such that the health-promoting effect of
      community social trust was significantly greater for high-trust individuals. For
      low-trust individuals, the effect of community social trust on self-rated health
      was the opposite. Using the latest data available on community social trust, we
      conclude that the role of community social trust in explaining average population
      health achievements and health inequalities is complex and is contingent on
      individual perceptions of social trust. Future multilevel investigations of
      social capital and population health should routinely consider the cross-level
      nature of community or neighborhood effects.

PMID- 12473697
TI  - Methodological, practical, and ethical challenges to inner-city health research.
AB  - Inner-city health research can be challenging because it deals with vulnerable
      populations and sometimes puts investigators in difficult situations. Some
      challenges are methodological, including selecting the optimal research design,
      implementing effective methods of recruitment and retention, and determining the
      best approach to data analysis. Other issues are practical, including addressing
      potential biases in social research; dealing with conflicting research agendas
      among investigators, community agencies, and funding agencies; and disseminating
      research findings effectively. Another set of issues relates to the ethical
      conduct of research, including ensuring privacy, maintaining confidentiality, and
      obtaining consent that is informed, not coerced, and not influenced by undue
      inducements. Throughout the research endeavor, the inner-city health researcher
      must carefully balance the roles of investigator, advocate, activist, and
      caregiver.

PMID- 12473698
TI  - Recombinant human bone morphogenetic protein-2 for treatment of open tibial
      fractures: a prospective, controlled, randomized study of four hundred and fifty
      patients.
AB  - BACKGROUND: The treatment of open fractures of the tibial shaft is often
      complicated by delayed union and nonunion. The objective of this study was to
      evaluate the safety and efficacy of the use of recombinant human bone
      morphogenetic protein-2 (rhBMP-2; dibotermin alfa) to accelerate healing of open
      tibial shaft fractures and to reduce the need for secondary intervention.
      METHODS: In a prospective, randomized, controlled, single-blind study, 450
      patients with an open tibial fracture were randomized to receive either the
      standard of care (intramedullary nail fixation and routine soft-tissue management
      [the control group]), the standard of care and an implant containing 0.75 mg/mL
      of rhBMP-2 (total dose of 6 mg), or the standard of care and an implant
      containing 1.50 mg/mL of rhBMP-2 (total dose of 12 mg). The rhBMP-2 implant
      (rhBMP-2 applied to an absorbable collagen sponge) was placed over the fracture
      at the time of definitive wound closure. Randomization was stratified by the
      severity of the open wound. The primary outcome measure was the proportion of
      patients requiring secondary intervention because of delayed union or nonunion
      within twelve months postoperatively. RESULTS: Four hundred and twenty-one (94%)
      of the patients were available for the twelve-month follow-up. The 1.50-mg/mL
      rhBMP-2 group had a 44% reduction in the risk of failure (i.e., secondary
      intervention because of delayed union; relative risk = 0.56; 95% confidence
      interval = 0.40 to 0.78; pairwise p = 0.0005), significantly fewer invasive
      interventions (e.g., bone-grafting and nail exchange; p = 0.0264), and
      significantly faster fracture-healing (p = 0.0022) than did the control patients.
      Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the
      fracture at the postoperative visits from ten weeks through twelve months (p =
      0.0008). Compared with the control patients, those treated with 1.50 mg/mL of
      rhBMP-2 also had significantly fewer hardware failures (p = 0.0174), fewer
      infections (in association with Gustilo-Anderson type-III injuries; p = 0.0219),
      and faster wound-healing (83% compared with 65% had wound-healing at six weeks; p
      =0.0010). CONCLUSIONS: The rhBMP-2 implant was safe and, when 1.50 mg/mL was
      used, significantly superior to the standard of care in reducing the frequency of
      secondary interventions and the overall invasiveness of the procedures,
      accelerating fracture and wound-healing, and reducing the infection rate in
      patients with an open fracture of the tibia.

PMID- 12473699
TI  - Comparison of intra-articular lidocaine and intravenous sedation for reduction of
      shoulder dislocations: a randomized, prospective study.
AB  - BACKGROUND: Acute anterior glenohumeral dislocations have been commonly treated
      with closed reduction and the use of intravenous sedation. Recently, the use of
      intra-articular lidocaine has been advocated as an alternative to sedation, since
      intravenous access and patient monitoring are not required. The purpose of this
      study was to evaluate the value of local anesthesia compared with that of the
      commonly used intravenous sedation during the performance of a standardized
      reduction technique. METHODS: In a prospective, randomized study, skeletally
      mature patients with an isolated glenohumeral joint dislocation and no associated
      fracture were randomized to receive either intravenous sedation or intra
      articular lidocaine to facilitate reduction of the dislocation. Reduction was
      performed with the modified Stimson method. The two groups were compared with
      regard to the rate of successful reduction, pain as rated on a visual analog
      scale, time required for the reduction, time from the reduction until discharge
      from the emergency department, and cost. RESULTS: Thirty patients were enrolled
      in the study. Five (two in the lidocaine group and three in the sedation group)
      required scapular manipulation in addition to the Stimson technique to reduce the
      dislocation. The lidocaine group spent significantly less time in the emergency
      department (average time, seventy-five minutes compared with 185 minutes in the
      sedation group, p < 0.01). There was no significant difference between the two
      groups with regard to pain (p = 0.37), success of the Stimson technique (p =
      1.00), or time required to reduce the shoulder (p = 0.42). The cost of the
      intravenous sedation was $97.64 per patient compared with $0.52 for use of the
      intra-articular lidocaine. CONCLUSIONS: Use of intra-articular lidocaine to
      facilitate reduction with the Stimson technique is a safe and effective method
      for treating acute shoulder dislocations in an emergency room setting. Intra
      articular lidocaine requires less money, time, and nursing resources than does
      intravenous sedation to facilitate reduction with the Stimson technique.

PMID- 12473700
TI  - Ten to fifteen-year follow-up after total hip arthroplasty with a tapered cobalt
      chromium femoral component (tri-lock) inserted without cement.
AB  - BACKGROUND: Fixation of the femoral component of a total hip arthroplasty without
      cement has had variable results. While tapered stems appear to have consistently
      good results, the duration of follow-up in many series has been relatively short.
      The purpose of this study was to present a longer-term (ten to fifteen-year)
      follow-up after total hip arthroplasty with insertion of a tapered femoral
      component without cement. METHODS: Sixty-seven total hip arthroplasties were
      performed with insertion of a tapered, cobalt-chromium femoral component without
      cement in fifty-eight patients from 1983 to 1986. Thirteen patients (fifteen
      hips) died prior to the fifteen-year follow-up examination, and three patients
      (three hips) were lost to follow-up after ten years, leaving forty-two patients
      (forty-nine hips) who were followed clinically for a mean of fifteen years.
      Thirty-seven of the forty-nine hips were followed radiographically for fifteen
      years, and the remaining twelve were followed for a minimum of ten years.
      RESULTS: The mean preoperative Charnley score was 3.0 points for pain, 2.7 points
      for function, and 3.2 points for motion. At the time of the final follow-up, the
      mean scores were 5.6, 5.6, and 5.2 points, respectively. Although no preoperative
      Harris hip scores were available, the mean score at the time of the latest follow
      up was 92 points (range, 78 to 100 points). There were no revisions because of
      isolated aseptic loosening of the femoral component (although revision because of
      aseptic loosening of the acetabular component led to femoral component revision
      in seven hips). Two femoral components showed radiographic evidence of
      instability. At fifteen years, the prevalence of thigh pain was 2%. No femoral
      component that was thought to be stable, with bone ingrowth at two years, lost
      fixation. CONCLUSIONS: The design features of this cobalt-chromium femoral
      component (i.e., the collarless, tapered, wedge fit with circumferential porous
      coating) are thought to be crucial to the achievement of the good-to-excellent
      results seen in this study.

PMID- 12473701
TI  - Osteonecrosis of the femoral head after solid organ transplantation: a
      prospective study.
AB  - BACKGROUND: The reported prevalence of osteonecrosis of the femoral head in
      patients who have undergone a solid organ transplant has ranged from 3% to 41%.
      The wide variation is due to the retrospective nature of most studies and the
      inability to capture data on asymptomatic patients. The primary goals of this
      study were to determine the true prevalence of osteonecrosis of the femoral head
      following solid organ transplantation, the time to the development of the
      osteonecrosis, and whether findings on magnetic resonance imaging precede the
      onset of symptoms. METHODS: Beginning in 1997, patients who had undergone a solid
      organ transplant were asked to participate in a prospective study in which they
      would be screened for osteonecrosis of the femoral head. Inclusion criteria
      included an age of greater than fourteen years, a first-time transplant, and
      magnetic resonance imaging performed within six months after the transplant.
      Exclusion criteria were pre-existing osteonecrosis of the femoral head in the hip
      included in the study, a history of inflammatory arthritis, previous hip surgery,
      any contraindication to magnetic resonance imaging, a prior organ transplant,
      prior systemic corticosteroid treatment, and mental health issues preventing
      adequate follow-up. Screening magnetic resonance imaging was performed every four
      months. Survivorship analysis was used to determine the prevalence of
      osteonecrosis of the femoral head. RESULTS: Fifty-two patients (103 hips) were
      enrolled in the study. Their ages ranged from twenty-four to sixty-five years
      (mean, forty-three years). Sixteen patients were dropped from the study, but the
      data collected on them before they were dropped were included in the analysis.
      Osteonecrosis of the femoral head was diagnosed in eight of the 103 hips.
      Survivorship analysis revealed that, at one year after the transplant, 89% +/- 7%
      of the hips and 80% +/- 13% of the patients were free of osteonecrosis of the
      femoral head; thus the prevalence of osteonecrosis one year after transplantation
      was 11% or 20%, respectively. The mean duration of follow-up of the remaining
      hips was 2.3 years. In two hips the osteonecrosis of the femoral head was seen on
      the initial screening magnetic resonance imaging, and in the other six it
      developed after the initial magnetic resonance imaging revealed negative
      findings. All cases of osteonecrosis of the femoral head developed within ten
      months after the transplant. Seven of the eight hips were asymptomatic at the
      time of diagnosis. There was a significant difference in the one-year
      osteonecrosis-free survival rate between the patients who were less than forty
      years old (78%) and those who were at least forty years old (97%) (p = 0.011).
      Diabetes, smoking, and rejection episodes were not risk factors for osteonecrosis
      of the femoral head. CONCLUSIONS: Our study of patients who had had a solid organ
      transplant revealed that the true prevalence of osteonecrosis of the femoral head
      in such patients is lower than that reported in most previous studies,
      osteonecrosis of the femoral head develops prior to the onset of symptoms, an age
      of less than forty years is a risk factor for osteonecrosis of the femoral head,
      and osteonecrosis of the femoral head develops within one year after
      transplantation. We recommend that magnetic resonance imaging be used to screen
      for osteonecrosis of the femoral head within one year after transplantation. The
      utility of additional magnetic resonance imaging after one year has not been
      established.

PMID- 12473702
TI  - Mechanical strength of arthroscopic rotator cuff repair techniques: an in vitro
      study.
AB  - BACKGROUND: Retears after rotator cuff repairs occur relatively frequently and
      may compromise the functional result. The goal of this study was to analyze the
      mechanical properties following arthroscopic techniques for rotator cuff repair
      and to evaluate possible alternative techniques. METHODS: In the first part, five
      different bone anchors (the Revo screw; Mitek Rotator Cuff anchor, 5.0-mm Statak,
      PANALOK RC absorbable anchor, and 5.0-mm Bio-Statak) were tested in vitro under
      cyclic loading on five pairs of cadaveric shoulders. Then five types of
      arthroscopic tendon suturing instruments were tested on rotator cuff tendons.
      Finally, the arthroscopically performed mattress and modified Mason-Allen
      stitches, fixed with either the Revo screw or the Bio-Statak, were evaluated on
      ten pairs of human cadaveric shoulders. RESULTS: The holding strengths of the
      various anchors were similar, ranging from 130 to 180 N, and approximated the
      holding strength of knotted number-2 suture materials. The fixation of the tested
      anchors yielded comparable values of stiffness except for one anchor, which
      showed significantly greater subsidence under cyclic load (p = 0.003). All
      tested, commercially available arthroscopic suturing devices were unsuitable for
      performing a modified Mason-Allen stitch on normal supraspinatus tendons.
      Modification of a commercially available suture punch with a longer needle
      allowed us to consistently perform a modified Mason-Allen stitch. The modified
      Mason-Allen stitch, which has shown favorable mechanical properties in open
      repairs of the rotator cuff, was not found to be stronger than the mattress
      stitch when performed arthroscopically and used with bone anchors. When the
      modified Mason-Allen stitch was fixed to one anchor, it was even weaker than a
      mattress stitch repaired with another anchor (168 versus 228 N). Unequal loading
      of the two suture branches due to the more rigid modified Mason-Allen stitch may
      be the reason for this difference. CONCLUSIONS: Arthroscopic techniques for
      rotator cuff repair with use of the mattress stitch and bone anchors allow for a
      relatively solid fixation. The holding strength is not improved with use of the
      modified Mason-Allen stitch. Although a direct comparison with previous in vitro
      studies is not possible, the holding strength of open fixation techniques seems
      to be stronger. If rotator cuffs are subjected to high postoperative loading,
      open repair might be preferred to reduce the risk of a retear, until stronger
      arthroscopic fixation techniques are developed.

PMID- 12473703
TI  - Correlation of thrombophilia and hypofibrinolysis with pulmonary embolism
      following total hip arthroplasty: an analysis of genetic factors.
AB  - BACKGROUND: The increased thromboembolic risk associated with total hip
      arthroplasty is multifactorial. We assessed whether the prevalence of
      abnormalities shown by newer genetic screening tests for thrombophilia and
      hypofibrinolysis was higher in patients in whom pulmonary embolism had developed
      after total hip arthroplasty than it was in matched control patients. METHODS:
      Fourteen patients with documented pulmonary embolism after total hip arthroplasty
      and fourteen matched control patients who had undergone total hip arthroplasty
      without any clinical indication of thromboembolism were evaluated for risks of
      thrombophilia and hypofibrinolysis. Functional tests of hemostasis included
      evaluations of prothrombin time; activated partial thromboplastin time; levels of
      fibrinogen, serum homocysteine, protein C and S, and antithrombin III; activated
      protein-C resistance; and dilute Russell viper venom time. Molecular genetic
      testing was performed for factor-V Leiden, prothrombin promoter G20210A,
      methylenetetrahydrofolate reductase C677T, plasminogen activator inhibitor-1
      4G/4G, and platelet glycoprotein IIb/IIIa A1/A2 or A2/A2 mutations. RESULTS: The
      total number of genetic thrombophilic abnormalities identified was higher in the
      pulmonary embolism group (twenty-four abnormalities) than in the control group
      (fifteen abnormalities). Only patients with pulmonary embolism were found to have
      heterozygosity or homozygosity for the prothrombin G20210A mutation (four of
      fourteen patients; p = 0.05 compared with the control group) and a decreased
      antithrombin-III level (three of thirteen patients; p = 0.10 compared with the
      control group). Patients with pulmonary embolism were much more likely than
      control patients to have at least one thrombophilic abnormality: seven of
      fourteen patients with pulmonary embolism had a low antithrombin-III level or the
      prothrombin G20210A gene mutation compared with none of the fourteen in the
      control group (Fisher exact test, p < 0.01). The presence of the prothrombin
      G20210A gene mutation was significantly correlated with pulmonary embolism (r =
      0.41, p = 0.03), as was the presence of least one abnormality (a low antithrombin
      III level or the presence of the prothrombin G20210A gene mutation) (r = 0.58, p
      = 0.001). CONCLUSIONS: Genetic thrombophilia and hypofibrinolysis were more
      frequent in patients who had had pulmonary embolism after total hip arthroplasty
      than in those who had not. The presence of multiple genetic thrombophilic
      polymorphisms, particularly prothrombin G20210A and antithrombin III, rather than
      any single genetic prothrombotic abnormality, appears to signal an increased
      thromboembolic risk in patients undergoing total hip arthroplasty. Future
      refinements and availability of these tests will likely allow preoperative
      identification of patients with an increased genetic predisposition for
      thromboembolism.

PMID- 12473704
TI  - Ulnohumeral arthroplasty for primary degenerative arthritis of the elbow: long
      term outcome and complications.
AB  - BACKGROUND: Primary degenerative arthritis of the elbow is an uncommon disorder
      that recently has been more clearly recognized. The purpose of this study was to
      analyze the long-term results and complications of ulnohumeral arthroplasty as
      treatment of primary osteoarthritis of the elbow and to document any tendency for
      recurrence of the arthritis after the procedure. METHODS: The results of
      ulnohumeral arthroplasties performed at our institution, between 1986 and 1996,
      in forty-six elbows (forty-five patients) with primary osteoarthritis were
      reviewed at an average of eighty months (range, twenty-four to 164 months) after
      the operation. There were forty-four men and one woman with a mean age of forty
      eight years. All patients complained of pain with terminal elbow extension. The
      pain was associated with locking in fourteen elbows and with ulnar nerve symptoms
      in twelve. The surgical procedure involved fenestration of the olecranon fossa
      and excision of olecranon and coronoid osteophytes in all patients, with removal
      of loose bodies in thirty-six elbows. A capsular release was performed in
      nineteen elbows, and an ulnar nerve transposition or neurolysis was done in
      eight. Preoperative and follow-up assessment included evaluation of elbow pain
      and range of motion with the Mayo Elbow Performance Score. RESULTS: The mean arc
      of flexion-extension improved from 79 degrees (range, 10 degrees to 135 degrees)
      preoperatively to 101 degrees (range, 45 degrees to 135 degrees) at the time of
      follow-up (p < 0.05). At the last follow-up examination, thirty-five elbows (76%)
      were not painful or were only mildly painful and eleven were moderately or
      severely painful. According to the Mayo Elbow Performance Score, the result was
      excellent for twenty-six elbows, good for eight, fair for four, and poor for
      eight. Thirteen of the forty-five patients reported some degree of ulnar nerve
      symptoms postoperatively, and six of them required another operation to
      decompress or translocate the nerve. Two other patients underwent additional
      surgery because of persistent symptoms. CONCLUSIONS: The data from this study
      show that ulnohumeral arthroplasty can yield satisfactory long-term pain relief
      and an increase in the range of motion. Patients with severe preoperative
      limitation of elbow extension of >60 degrees and flexion of <100 degrees and
      those who undergo manipulation under anesthesia in the early postoperative period
      to increase motion are at risk for the development of ulnar nerve dysfunction
      postoperatively. One should consider prophylactic ulnar nerve decompression or
      mobilization under these circumstances.

PMID- 12473705
TI  - Synovial entrapment: a complication of posterior stabilized total knee
      arthroplasty.
AB  - BACKGROUND: We observed a complication of posterior stabilized total knee
      arthroplasty involving hypertrophy of tissue proximal to the patella associated
      with pain during active knee extension from 90 degrees of flexion. The purpose of
      this paper was to describe synovial entrapment and to determine if design
      features of the prosthesis predispose patients to the complication. METHODS:
      Between April 1990 and June 1999, we performed 459 consecutive posterior
      stabilized primary total knee arthroplasties using three prosthetic designs with
      different femoral intercondylar geometries. We identified twenty-six patients
      (twenty-seven knees) in whom arthroscopic debridement of the knee or open
      arthrotomy with debridement of the knee had been subsequently performed because
      of a diagnosis of synovial entrapment. We reviewed the records of these patients
      to identify the knee components that had been used and the symptoms and
      conditions that necessitated additional treatment. RESULTS: Symptoms (grating,
      crepitation, and pain with active knee extension from 90 degrees) necessitating
      subsequent debridement occurred in 13.5% (nineteen) of 141 knees treated with the
      Anatomic Modular Knee-Congruency implant, 3.8% (eight) of 212 treated with the
      Anatomic Modular Knee-Posterior Stabilized implant, and none of the 106 treated
      with the Press Fit Condylar Sigma-Posterior Stabilized implant. All patients had
      difficulty rising from a chair and climbing stairs; however, none had symptoms
      when standing or walking. No patient had a patellar clunk. The symptoms occurred
      at a mean of seven months after the arthroplasty in the patients with an Anatomic
      Modular Knee-Congruency implant and at a mean of twenty months after the
      arthroplasty in those with an Anatomic Modular Knee-Posterior Stabilized implant.
      Debridement of the frond-like hypertrophic synovial tissue at the distal aspect
      of the quadriceps tendon alleviated symptoms in all patients. No nodules were
      identified during the arthroscopy. CONCLUSIONS: Synovial entrapment is
      characterized by hypertrophic synovial tissue at the superior pole of the
      patella. Use of a posterior stabilized femoral component with a proximally
      positioned or wide femoral box is more likely to result in this complication.

PMID- 12473706
TI  - Patellar tendinosis: a follow-up study of surgical treatment.
AB  - BACKGROUND: Patellar tendinopathy (jumper's knee) is an overuse syndrome that
      frequently affects athletes. A retrospective study was done to analyze the
      results at a minimum of five years after the performance of a surgical technique
      in competitive athletes. METHODS: From 1985 to 1995, thirty-two patients (thirty
      eight knees) affected by patellar tendinopathy were treated surgically after
      failure of nonoperative treatment. All knees were operated on by the same surgeon
      using the same surgical technique: longitudinal splitting of the tendon, excision
      of any abnormal tissue that was identified, and resection and drilling of the
      inferior pole of the patella. The results in twenty-seven patients (thirty-three
      knees), including twenty-two athletes (twenty-seven knees) who were still
      involved in sports activities (or wished to still be involved) at a competitive
      level at the time of final follow-up, were reviewed at a mean of eight years
      postoperatively. The results were evaluated according to symptoms and the ability
      to return to full sports activities. RESULTS: The result was excellent in twenty
      three knees (70%), good in five, fair in one, and poor in four at the time of the
      long-term follow-up. Eighty-two percent of the patients who tried to pursue
      sports at their preinjury level were able to do so, and 63% of those knees were
      totally symptom-free. CONCLUSIONS: The outcome of the described surgical
      treatment appears to be satisfactory; however, the results are less predictable
      in volleyball players.

PMID- 12473707
TI  - The influence of glenohumeral prosthetic mismatch on glenoid radiolucent lines:
      results of a multicenter study.
AB  - BACKGROUND: In shoulder arthroplasty, mismatch is defined as the difference in
      the radius or diameter of curvature between the humeral head and glenoid
      components. Recommendations for mismatch have not been substantiated
      scientifically. The purpose of this study was to evaluate the effect of mismatch
      on glenoid radiolucent lines. METHODS: The results of 319 total shoulder
      arthroplasties performed for the treatment of primary osteoarthritis were
      evaluated. All of the arthroplasties were performed with a single type of
      prosthesis (Aequalis; Tornier, Montbonnot, France) that included a cemented, all
      polyethylene glenoid component. Three sizes of glenoid components and seven
      humeral head diameters were utilized. Radial mismatch was categorized as < or = 4
      mm, 4.5 to 5.5 mm, 6 to 7 mm, or >7 to 10 mm. Radiographs were evaluated at a
      mean of 53.5 months (range, twenty-four to 110 months) postoperatively. Glenoid
      radiolucent lines were scored with a scale ranging from 0 points for no
      radiolucency to 18 points for radiolucent lines exceeding 2 mm in six zones.
      Variance, linear contrasts polynomial, quadratic polynomial contrast statistical,
      and linear regression analyses were performed to evaluate the relationship
      between radial mismatch and glenoid radiolucent lines. RESULTS: A significant
      linear relationship was found between mismatch and the glenoid radiolucency score
      (p < 0.0001), with significantly lower (better) radiolucency scores associated
      with radial mismatches of >5.5 mm. CONCLUSIONS: In this study of glenohumeral
      prosthetic mismatch ranging from 0 to 10 mm, the mismatch had a significant
      influence on the scores for the glenoid radiolucent lines, which were best when
      the radial mismatch was between 6 and 10 mm. The theoretical risk of prosthetic
      instability with larger mismatch values was not demonstrated within the range of
      mismatch values evaluated in this series.

PMID- 12473708
TI  - Treatment of advanced primary and recurrent diffuse pigmented villonodular
      synovitis of the knee.
AB  - BACKGROUND: Diffuse pigmented villonodular synovitis of the knee is a difficult
      tumor to eradicate. We report our experience with a combined open posterior and
      anterior synovectomy with and without adjuvant postoperative radiation therapy in
      patients with advanced extracapsular disease. METHODS: A single surgeon operated
      on forty patients, with an average age of thirty-five years (range, fourteen to
      sixty-eight years), who had diffuse pigmented villonodular synovitis of the knee.
      All patients had been referred to us after having initially undergone
      arthroscopic or open surgical procedures without eradication of the disease.
      Patients were retrospectively placed into one of three groups: Group I received
      surgery alone (five patients), Group II had surgery and intra-articular radiation
      synovectomy with use of dysprosium-165 (thirty patients), and Group III had
      surgery and external beam radiation (five patients). Adjuvant radiation was
      performed three months postoperatively. Magnetic resonance imaging was used for
      all patients for preoperative staging and postoperative follow-up. RESULTS: The
      average Knee Society score for the entire series improved from 61 points
      preoperatively to 92 points at the time of follow-up, at an average of five years
      (range, 1.5 to eight years) (p < 0.001). There was also a significant (p < 0.001)
      increase in the average range of motion of the knees across all groups. On the
      basis of the Knee Society scores, thirty-seven patients (93%) had a good or
      excellent result, two patients had a fair result, and one patient had a poor
      result. Complications included stiffness requiring manipulation in three knees,
      one case of reflex sympathetic dystrophy, advanced osteoarthritis leading to a
      total knee replacement in four patients, and seven recurrences (a prevalence of
      18%) after operative treatment and radiation therapy. CONCLUSIONS: This surgical
      technique allows excellent visualization and removal of intra-articular and extra
      articular diffuse pigmented villonodular tissue and yields excellent functional
      results and a low prevalence of knee stiffness. However, the rate of recurrence
      detected by magnetic resonance imaging was 18%. Adjuvant intra-articular
      radiation therapy may be beneficial for eradication of small foci of residual
      disease, but complete resection of all pigmented villonodular tissue appears to
      be the key to preventing recurrence. Magnetic resonance imaging was essential for
      accurate preoperative staging of the tumor and for follow-up since the presence
      of residual disease did not reliably correlate with the clinical findings.
      Patients with minimal degenerative arthritis and primary or recurrent extra
      articular disease will benefit most from this approach.

PMID- 12473709
TI  - The influence of elbow position on the range of motion of the wrist following
      transfer of the brachioradialis to the extensor carpi radialis brevis tendon.
AB  - BACKGROUND: In patients who have an injury of the cervical spinal cord, the
      brachioradialis tendon may be transferred to the extensor carpi radialis brevis
      tendon to restore voluntary wrist extension. We hypothesized that the active
      range of motion of the wrist depends on the position of the elbow after this
      transfer because the brachioradialis changes length substantially during elbow
      flexion, which implies the maximum force that the muscle can produce varies with
      elbow position. The objectives of this study were to determine whether the
      position of the elbow influences the range of motion of the wrist following
      transfer of the brachioradialis to the extensor carpi radialis brevis tendon and
      to evaluate the effect of surgical tensioning. METHODS: The range of motion of
      eight wrists was assessed after brachioradialis transfer. Two positions of the
      elbow were tested, the passive limit of elbow extension and 120 degrees of
      flexion. The range of motion of the wrist was also simulated with use of a
      biomechanical model. Using the model, we compared the active range of motion of
      the wrist, with the elbow at 0 degrees and 120 degrees of flexion, following
      three different approaches to surgical tensioning. The simulations were also
      repeated to evaluate how muscle strength influences outcomes. RESULTS: Wrist
      extension decreased and passive flexion increased when the elbow was flexed.
      Maximum wrist extension was significantly correlated with passive flexion in all
      subjects (r = 0.95 and p < 0.001 when the elbow was extended and r = 0.82 and p <
      0.03 when the elbow was flexed). The biomechanical model suggested that
      tensioning the tendon transfer so that the fibers of the brachioradialis do not
      become excessively short when the elbow is flexed may improve outcomes. The
      simulations also revealed that it is more difficult to maintain a consistent
      wrist position with the elbow in different postures when a weaker muscle is
      transferred. CONCLUSIONS: The model suggests that altering the surgical tension
      could improve wrist extension when the elbow is flexed. However, the ultimate
      result is sensitive to the strength of the brachioradialis.

PMID- 12473710
TI  - Mennen plate fixation for the treatment of periprosthetic femoral fractures: a
      multicenter study of thirty-six fractures.
AB  - BACKGROUND: The management of periprosthetic femoral fractures after total hip
      and knee replacement remains difficult and controversial. This study was
      performed to determine the results of Mennen plate fixation for the treatment of
      periprosthetic femoral fractures. METHODS: This retrospective multicenter study
      consists of a review of a consecutive series of thirty-five patients in whom a
      total of thirty-six periprosthetic femoral fractures were treated with Mennen
      plate fixation. The average duration of follow-up was twenty-seven months (range,
      eight to forty-six months). RESULTS: Twenty-six fractures (72%) had united at an
      average of five months (range, three to ten months) after surgery. One of them
      had varus bending (10 degrees) of the plate. The remaining ten fractures had a
      nonunion and varus bending (20 degrees to 30 degrees) of the plate, with a
      fracture of the plate in eight. A revision procedure was successfully performed
      in the eight patients with nonunion. CONCLUSIONS: The treatment of unstable
      periprosthetic femoral fractures with Mennen plate fixation was complicated by
      high rates of mechanical failure (31%) and nonunion (28%). For this reason, we do
      not recommend the use of the Mennen plate for the treatment of periprosthetic
      femoral fractures.

PMID- 12473711
TI  - Treatment of segmental defects of the humerus with an osteoseptocutaneous fibular
      transplant.
AB  - BACKGROUND: There are limited reconstructive options for the treatment of
      segmental bone defects of the upper extremity that are >6 cm in length,
      especially those that are associated with soft-tissue defects. The purpose of the
      present review was to report on our experience with fifteen patients who received
      an osteoseptocutaneous fibular transplant for reconstruction of a humeral defect.
      METHODS: The study cohort included eight male patients and seven female patients
      with an average age of forty-one years. The indications for the procedure
      included segmental nonunion (nine patients), a gunshot wound (three), a defect at
      the site of a tumor resection (two), and failure of an allograft-prosthesis
      reconstruction (one). The fibular graft was fixed by means of intramedullary
      impaction in eleven patients, was used as an onlay graft in three, and was used
      as a strut between the intact diaphysis and the humeral head in one. RESULTS: The
      average length of the segmental humeral defect was 9.3 cm. The average length of
      the fibular graft was 16.1 cm, and the average length and width of the skin
      paddle were 8.1 and 4.5 cm. The average duration of follow-up was twenty-four
      months. Three patients had venous thrombosis and underwent a successful revision
      of the anastomosis. Four patients had early failure of graft fixation. Three
      patients had a fracture of the fibular graft within the first year
      postoperatively. All but one of these latter seven patients were successfully
      treated with open reduction, internal fixation, and additional bone-grafting. One
      patient with an infection at the site of a nonunion and signs of graft resorption
      required a second fibular transplant. CONCLUSIONS: The osteoseptocutaneous
      fibular transplant is an effective treatment for combined segmental osseous and
      soft-tissue defects of the arm. However, the application of this technique to the
      arm is more complex than application to the forearm and is associated with a
      higher rate of complications.

PMID- 12473712
TI  - Osteolysis in failed total knee arthroplasty: a comparison of mobile-bearing and
      fixed-bearing knees.
AB  - BACKGROUND: Osteolysis is an important complication associated with total knee
      arthroplasty. The purpose of this study was to compare the prevalence of
      osteolysis after failed total knee arthroplasty with a mobile-bearing prosthesis
      and after failed arthroplasty with a fixed-bearing prosthesis. METHODS: Eighty
      revision total knee arthroplasties performed between 1995 and 1998 were included
      in this study. All had radiographic evidence of advanced polyethylene wear. The
      mobile-bearing group consisted of thirty-four knees with a Low Contact Stress
      implant, and the fixed-bearing group included forty-six knees. The average time
      (and standard deviation) from the primary operation to the revision was 102.8 +/-
      26.5 months in the mobile-bearing group and 96.0 +/- 30.1 months in the fixed
      bearing group. The prerevision radiographs and operative findings were reviewed.
      RESULTS: The prevalence of osteolysis was significantly higher in the mobile
      bearing group (47%; sixteen of thirty-four knees) than in the fixed-bearing group
      (13%; six of forty-six knees) (p = 0.003). The distal part of the femur was
      involved in thirteen knees in the mobile-bearing group and in four knees in the
      fixed-bearing group. Seventeen knees had osteolysis in the posterior aspect of
      the femoral condyle, which was the most common site of osteolysis; however,
      twelve of them had no evidence of osteolysis on prerevision radiographs.
      CONCLUSIONS: The prevalence of osteolysis was higher in the knees with a mobile
      bearing prosthesis than in those with a fixed-bearing prosthesis. The osteolysis
      was predominantly on the femoral side, adjacent to the posterior aspect of the
      condyle. Radiographic evaluation of osteolysis in the distal part of the femur
      may not be reliable and usually leads to an underestimation of the degree of
      osteolysis.

PMID- 12473713
TI  - Prevalence of neural axis abnormalities in patients with infantile idiopathic
      scoliosis.
AB  - BACKGROUND: Although reports in the literature have demonstrated an approximately
      20% prevalence of neural axis abnormalities in patients with juvenile idiopathic
      scoliosis who have a curve of >20 degrees, the prevalence of neural axis
      abnormalities in patients with infantile idiopathic scoliosis is not well
      documented. In two previous studies involving a total of only ten patients with
      infantile idiopathic scoliosis, five patients were noted to have a neural axis
      abnormality on magnetic resonance images. METHODS: The records of forty-six
      consecutive patients who were seen between 1992 and 2000 at three spinal
      deformity clinics were retrospectively reviewed. The inclusion criteria included
      presumed idiopathic scoliosis at the time of presentation, an age of three years
      or less, a curve magnitude of > or = 20 degrees, normal neurological findings, no
      associated syndromes, and no congenital abnormalities. All patients were
      evaluated with a total spine magnetic resonance imaging protocol for examination
      of neural axis abnormalities from the skull to the coccyx. RESULTS: Ten (21.7%)
      of the forty-six patients were found to have a neural axis abnormality on
      magnetic resonance imaging. This group included five patients with an Arnold
      Chiari malformation and an associated cervicothoracic syrinx, three with
      syringomyelia, one with a low-lying conus, and one with a brainstem tumor. Eight
      of these ten patients needed neurosurgical intervention for treatment of the
      abnormality. CONCLUSIONS: The 21.7% prevalence of neural axis abnormalities in
      this group of patients with infantile idiopathic scoliosis was found to be almost
      identical to that reported in the literature on patients with juvenile idiopathic
      scoliosis. Because of the high prevalence of abnormalities and the fact that
      eight of the ten patients with abnormal findings on magnetic resonance images
      required neurosurgical intervention, a total spine magnetic resonance imaging
      evaluation at the time of presentation is recommended for all patients with
      infantile idiopathic scoliosis who have a curve measuring > or = 20 degrees.

PMID- 12473714
TI  - Modern unicompartmental knee arthroplasty with cement: a three to ten-year follow
      up study.
AB  - BACKGROUND: Unicompartmental arthroplasty is a treatment alternative when only
      one compartment of the knee is affected with arthritis, but the reported results
      of this procedure have been variable. The purpose of the present study was to
      evaluate the results of a modern unicompartmental knee arthroplasty performed
      with use of a cemented metal-backed prosthesis and surgical instrumentation
      comparable with that used for total knee replacement. METHODS: The indications
      for the procedure were osteonecrosis or osteoarthritis associated with full
      thickness loss of cartilage that was limited to one tibiofemoral compartment as
      evaluated on standing and stress radiographs. One hundred and sixty consecutive
      cemented metal-backed Miller-Galante prostheses in 147 patients were evaluated
      after a mean duration of follow-up of sixty-six months (range, thirty-six to 112
      months). The mean age of the patients at the time of the index procedure was
      sixty-six years. RESULTS: Three knees were revised because of progression of
      osteoarthritis in the patellofemoral joint (two knees) or the lateral
      tibiofemoral compartment (one knee). Two knees had revision of the polyethylene
      liner. The average Hospital for Special Surgery knee score improved from 59
      points preoperatively to 96 points at the time of the review. According to Kaplan
      Meier analysis, the ten-year survival rate (with twenty-nine knees at risk) was
      94% +/- 3% with revision for any reason or radiographic loosening as the end
      point. CONCLUSIONS: A modern unicompartmental knee arthroplasty is a valid
      alternative for patients with unicompartmental tibiofemoral noninflammatory
      disease. The patient selection must be strict with regard to the status of the
      patellofemoral joint. The preoperative planning includes stress radiographs to
      assess the correction of the deformity and the status of the uninvolved
      compartment. Continued long-term follow-up is necessary to evaluate long-term
      polyethylene wear.

PMID- 12473715
TI  - The influence of rotator cuff disease on the results of shoulder arthroplasty for
      primary osteoarthritis: results of a multicenter study.
AB  - BACKGROUND: Rotator cuff disease is uncommon in primary glenohumeral
      osteoarthritis. Consequently, the prognostic implications of rotator cuff disease
      in patients undergoing prosthetic replacement for the treatment of primary
      glenohumeral osteoarthritis are uncertain. The purpose of this study was to
      report the effects of the condition of the supraspinatus tendon and the rotator
      cuff musculature on the results of shoulder arthroplasty in the treatment of
      primary osteoarthritis. METHODS: Five hundred and fifty-five shoulders in 514
      patients who had an arthroplasty for the treatment of primary glenohumeral
      osteoarthritis as part of a multicenter study were evaluated. Forty-one shoulders
      had a partial-thickness tear of the supraspinatus, and forty-two had a full
      thickness tear. Ninety shoulders had moderate (stage-2) fatty degeneration of the
      infraspinatus, and nineteen had severe (stage-3 or 4) degeneration. Eighty-four
      shoulders had moderate fatty degeneration of the subscapularis, and fifteen had
      severe degeneration. The influence of the condition of the supraspinatus tendon
      and the infraspinatus and subscapularis musculature on the postoperative outcome
      was evaluated with respect to the scores according to the system of Constant and
      Murley, active mobility, subjective satisfaction, radiographic result, and rate
      of complications. RESULTS: The shoulders were evaluated at a mean of 43.1 months
      postoperatively. With the numbers available, supraspinatus tears were not found
      to influence the postoperative outcome with respect to the total Constant score,
      active mobility, subjective satisfaction, radiographic result, or rate of
      complications. Additionally, the treatment of these tears did not markedly
      influence the outcome parameters. Conversely, both shoulders with moderate fatty
      degeneration and those with severe degeneration of the infraspinatus were
      associated with poorer results than those with no degeneration with respect to
      the total Constant score (p < 0.0005), active external rotation (p < 0.0005),
      active forward flexion (p = 0.001), and subjective satisfaction (p = 0.031).
      Similar although less dramatic results were seen with fatty degeneration of the
      subscapularis. CONCLUSIONS: This study demonstrates that minimally retracted or
      nonretracted rotator cuff tears that are limited to the supraspinatus tendon do
      not appreciably affect most shoulder-specific outcome parameters in shoulder
      arthroplasty performed for the treatment of primary osteoarthritis. Conversely,
      fatty degeneration of the infraspinatus and, less importantly, subscapularis
      musculature adversely affects many of these parameters.

PMID- 12473716
TI  - Morphology of the knee in adult patients with neglected developmental dysplasia
      of the hip.
AB  - BACKGROUND: Although there have been numerous studies on the treatment of
      developmental dysplasia of the hip, few have focused on its natural history into
      adulthood. We observed valgus deformity of the knee in a group of adult patients
      with developmental dysplasia of the hip. To the best of our knowledge, there has
      been no detailed study of that condition. The purpose of this study was to
      investigate structural changes of the knee in patients with neglected
      developmental dysplasia of the hip. METHODS: Thirty-four adult patients with
      neglected developmental dysplasia of the hip and ten healthy adults were
      evaluated. The lower extremities were grouped according to the severity of the
      dysplasia. The morphology of the knees was evaluated with radiographic
      measurements, and the groups were compared. RESULTS: Compared with the control
      group, the patients with severe developmental dysplasia of the hip had
      significant valgus deformity of the knee. This finding was associated with an
      increased vertical dimension of the medial femoral condyle, which led to a valgus
      inclination of the distal femoral articular surface. Although the femoral sulcus
      was shallower in the patients with developmental dysplasia of the hip,
      patellofemoral congruency was not deranged. CONCLUSIONS: The pathologic condition
      of the hip joint in patients with developmental dysplasia of the hip results in
      developmental changes in the osseous anatomy of the knee joint, with the
      development of a valgus deformity of the lower extremity. If any surgical
      intervention is planned in a patient with developmental dysplasia of the hip, the
      whole lower extremity should be carefully analyzed, with special attention to the
      morphology of the knee, to avoid creating problems of malalignment.

PMID- 12473717
TI  - The vascular anatomy of the glenohumeral capsule and ligaments: an anatomic
      study.
AB  - BACKGROUND: A detailed description of the vascular anatomy of the shoulder
      capsule is lacking, yet surgical procedures may put this capsular blood supply at
      risk. We hypothesized that a hypovascular area is present in the capsule. The
      purpose of the present study was to describe the vascular anatomy of the human
      glenohumeral capsule and ligaments and its relevance to surgical treatment of the
      shoulder. METHODS: In twenty-four fresh adult cadaveric shoulders, the axillary
      artery proximal to the thoracoacromial branch and the suprascapular artery were
      injected with India ink. The specimens were sectioned and then cleared with a
      modified Spalteholz technique. RESULTS: The glenohumeral capsule demonstrates
      consistent arterial contributions from the anterior circumflex, posterior
      circumflex, circumflex scapular, and suprascapular arteries. The arterial supply
      is centripetal in nature. The contributing vessels enter the capsule both
      laterally and medially and arborize toward the middle of the capsule. The rotator
      cuff provides additional blood supply to the capsule through perforating vessels.
      The dominant capsular vessels run horizontally and form intracapsular anastomoses
      via vertical branches. The anterior and posterior bands of the inferior
      glenohumeral ligament complex are vascularized by adjacent parallel vessels. In
      five of twelve specimens, a hypovascular zone was located near the humeral
      insertion of the anterior aspect of the capsule. In these five specimens, there
      was an associated hypovascular zone in the underlying capsule. CONCLUSION: The
      glenohumeral capsule is a well-vascularized structure with direct predictable
      contributions from four named arteries. These arteries send branches that enter
      the capsule superficially and from the periphery. These dominant vessels run
      horizontally toward the midcapsule and to deeper layers of the capsule. Vessels
      originating from the rotator cuff provide additional blood supply to the capsule.

PMID- 12473718
TI  - Humeral nonunion associated with metallosis secondary to use of a titanium
      flexible humeral intramedullary nail: a case report.

PMID- 12473719
TI  - Early clinical failure of total joint replacement in association with follicular
      proliferation of B-lymphocytes: a report of two cases.

PMID- 12473720
TI  - A ganglion of the anterior cruciate ligament causing erosion of the lateral
      femoral condyle: a case report.

PMID- 12473721
TI  - Primary pyomyositis.

PMID- 12473723
TI  - Dancing with who brung us: reaffirming our tradition, redefining our trajectory.

PMID- 12473724
TI  - Prophylaxis against venous thromboembolic disease: costs and controversy.

PMID- 12473725
TI  - Complications of evaluating the scientific quality of randomized clinical trials.

PMID- 12473726
TI  - How to pass the american board of orthopaedic surgery certifying examinations.

PMID- 12473727
TI  - What's new in orthopaedic rehabilitation.

PMID- 12473728
TI  - Autosomal mutation in somatic cells of the mouse.
AB  - Tumor suppressor genes are located on autosomal chromosomes. Therefore, an
      understanding of how cancer-related mutations occur in somatic cells requires a
      detailed understanding of spontaneous and induced autosomal mutagenesis. This
      review will present recent advances in the study of how autosomal mutations form
      in somatic cells by focusing on the mouse Aprt and Tk model systems that have
      been developed to examine the formation of autosomal mutations in vivo. These
      loci can detect the entire spectrum of mutations known to inactivate tumor
      suppressor genes. Studies with these models have provided novel information on
      the frequencies and types of spontaneous autosomal mutations that occur in
      different cell types. They also show great promise for the screening of genotoxic
      effects resulting from environmental exposures and for the study of mutation when
      DNA repair pathways are compromised. Continued use of the mouse Aprt and Tk
      models will have a significant impact on our understanding of some of the
      earliest steps in the conversion of normal cells to those with malignant
      phenotypes.

PMID- 12473729
TI  - Mutagenesis and DNA adduct formation in the mouse mammary gland exposed to 2
      hydroxyamino-1-methyl-6-phenylimidazo-[4,5-b]pyridine in whole organ culture.
AB  - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagen and rodent
      mammary gland carcinogen found in the human diet. 2-Hydroxyamino-1-methyl-6
      phenylimidazo[4,5-b]pyridine (N-hydroxy-PhIP) is the proximate reactive
      metabolite of PhIP associated with PhIP-DNA adduct formation and mutagenesis. In
      the current study, whole mammary glands obtained from transgenic C57Bl/6 mice
      carrying the plasmid-lacZ mutational reporter gene were cultured in defined
      medium and exposed to various concentrations of N-hydroxy-PhIP for 24 h. At
      various times after N-hydroxy-PhIP exposure, PhIP-DNA adduct levels were
      determined by the (32)P-post-labeling assay and the lacZ(-) mutant frequency
      determined by the positive selection system. Glands were cultured in either
      medium containing insulin (I medium), necessary for maintenance of the gland, or
      I medium containing prolactin, aldosterone and hydrocortisone (IPAH medium) to
      induce lobuloalveolar development. At 3 and 7 days after exposure to 10 micro M N
      hydroxy-PhIP, mutant frequency was upwards of 9-fold higher in glands incubated
      in IPAH medium than in I medium (15.2 +/- 1.9 and 1.6 +/- 0.7 x 10(-3),
      respectively, 3 day time point). PhIP-DNA adduct levels were 1.7-fold higher in
      glands cultivated in IPAH medium than in I medium immediately after exposure to
      10 micro M N-hydroxy-PhIP. A statistically significant reduction in PhIP-DNA
      adduct levels occurred with time in glands cultivated in IPAH medium but not I
      medium (one-way analysis of variance, P < 0.05). By 7 days after exposure, PhIP
      DNA adduct levels were similar in glands cultured in I and IPAH medium (3.2 +/-
      0.2 and 2.8 +/- 0.29 adducts/10(7) nucleotides, respectively). DNA synthesis as
      measured by [(3)H]thymidine labeling was approximately 2-fold higher in glands
      cultured in IPAH medium than in I medium. The higher mutant frequency in glands
      cultivated in IPAH medium versus I medium appeared to be due to a combination of
      higher initial PhIP-DNA adduct levels and a greater fixation of mutations that
      occurred at higher proliferation rates. The findings indicate that mammotrophic
      hormones influence the mutagenicity of PhIP in the mammary gland in vitro and
      emphasize the importance of hormonal milieu on carcinogen-DNA adduct-induced
      mutations in this organ.

PMID- 12473730
TI  - Repairability during G1 of lesions eliciting sister chromatid exchanges induced
      by methylmethanesulfonate or ethylmethanesulfonate in bromodeoxyuridine
      substituted and unsubstituted DNA strands.
AB  - The repairability during G(1) of DNA lesions eliciting sister chromatid exchanges
      (SCE) induced by methylmethanesulfonate (MMS) and ethylmethanesulfonate (EMS) in
      BrdU-substituted and unsubstituted DNA strands was determined in murine salivary
      gland cells in vivo. The SCE frequency was determined after exposure to MMS or
      EMS during early and late G(1) in the first or second cell division. The
      inducibility and repairability of SCE-eliciting lesions during G(1) in BrdU
      substituted and unsubstituted strands were estimated considering that in the
      first division induction occurs on the unsubstituted strand and during the second
      division in one unsubstituted and one BrdU- substituted DNA strand. The results
      indicate that DNA lesions induced by MMS are 50% repaired in both the BrdU
      substituted and unsubstituted strands and those induced by EMS are 60% repaired
      in the unsubstituted strand but only 20% in the BrdU-substituted strand. The
      increase in sensitivity of the BrdU-substituted strand to SCE induction with
      respect to the unsubstituted strand was 155 and 45% for MMS and EMS,
      respectively. These results imply that SCE-inducing lesions produced by MMS and
      EMS are only partially repaired and that BrdU incorporation could sensitize DNA
      not only to the induction of lesions eliciting SCE, but also to the induction of
      non-repairable lesions.

PMID- 12473731
TI  - Elevated levels of DNA-protein crosslinks and micronuclei in peripheral
      lymphocytes of tannery workers exposed to trivalent chromium.
AB  - DNA-protein crosslinks (DPC) are a promising biomarker of exposure to hexavalent
      chromium, a known human carcinogen. Although trivalent chromium is considered to
      have much lower toxicity, the risk involved in chronic exposure is uncertain. DPC
      may be a useful tool in clarifying this risk, by signaling an exposure of body
      tissues to biologically active forms of chromium. DPC quantification was carried
      out in lymphocytes of a group of tannery workers exposed to trivalent chromium, a
      small group of manual metal arc stainless steel welders exposed to hexavalent
      chromium and a control group. This biomarker was compared with the frequency of
      micronuclei in cytokinesis blocked peripheral lymphocytes as a biomarker of
      cytogenetic lesions and total plasma and urine chromium levels as an index of
      exposure. The results indicate a significant increase in the formation of DPC in
      tannery workers compared with controls (0.88 +/- 0.19 versus 0.57 +/- 0.21%, P <
      0.001, Mann-Whitney test) and an even higher level of DPC in welders (2.22 +/-
      1.12%, P = 0.03). Tanners showed a significant increase in micronucleated cells
      compared with controls (6.35 +/- 2.94 versus 3.58 +/- 1.69 per thousand, P <
      0.01), whereas in welders this increase was not significant (5.40 +/- 1.67 per
      thousand ). Urinary chromium was increased in both groups, with a greater
      increase observed in tanners compared with controls (2.63 +/- 1.62 versus 0.70 +/
      0.38 microg/g creatinine, P < 0.001) than in welders (1.90 +/- 0.37 microg/g
      creatinine, P < 0.005). Plasma chromium was also increased in both groups
      (tanners 2.43 +/- 2.11 microg/l, P < 0.001, welders 1.55 +/- 0.67 microg/l, P <
      0.005 versus controls 0.41 +/- 0.11 microg/l). In summary, chronic occupational
      exposure to trivalent chromium can lead to a detectable increase in lymphocyte
      DNA damage which correlates with a significant exposure of the cells to the
      metal.

PMID- 12473732
TI  - Saccharomyces cerevisiae as an eukaryotic cell model to assess cytotoxicity and
      genotoxicity of three anticancer anthraquinones.
AB  - The toxicity of most drugs is associated with their enzymatic conversion to toxic
      metabolites. Bioactivation reactions occur in a range of cellular organs and
      organelles, including mitochondria. We have investigated different effects (i.e.
      growth inhibition, mortality and genotoxicity) of doxorubicin, epirubicin and
      mitoxantrone on the D7 strain of Saccharomyces cerevisiae and on its petite (rho
      degrees ) respiratory-deficient mutant at various cellular concentrations of
      cytochrome P450 and glutathione (GSH). The data confirmed the importance of
      oxygen production for doxorubicin toxicity. The complete absence, or a very low
      level, of cytochrome oxidase subunit IV conferred some resistance to doxorubicin.
      Low GSH levels decreased resistance to doxorubicin in both strains, suggesting
      that thiol depletion could potentiate membrane lipid peroxidation. Doxorubicin
      induction of petite colonies suggests that the drug is able to select rather than
      induce respiratory-deficient mutants. Epirubicin induced levels of cytotoxicity
      similar to those of doxorubicin. The effects did not appear to be significantly
      dependent on mitochondrial function or GSH levels, whereas cells were strongly
      protected by cytochrome P450. GSH did not induce an evident alteration. Neither
      were genotoxic effects induced. Mitoxantrone had reduced levels of both growth
      inhibition and cytotoxicity in comparison to anthracyclines and induced
      convertants, revertants and aberrants. All the effects considered were amplified
      at high cytochrome P450 cellular concentrations, although the drug was also shown
      to act without previous metabolism via cytochrome P450. Anthracenedione
      effectiveness was increased by metabolism via cytochrome P450 and partially
      reduced by GSH. However, further mechanisms were suggested, which might implicate
      mitochondrial function and/or production of electrophilic cytotoxic and/or
      genotoxic intermediates by means of GSH conjugation. The biological effectiveness
      of doxorubicin, epirubicin and mitoxantrone on S.cerevisiae was shown to be
      strictly dependent on cell-specific physiological/biochemical conditions, such as
      a functional respiratory chain and levels of cytochrome P450 and GSH.

PMID- 12473734
TI  - Recommendations for conducting the in vivo alkaline Comet assay. 4th
      International Comet Assay Workshop.
AB  - The in vivo alkaline single cell gel electrophoresis assay, hereafter the Comet
      assay, can be used to investigate the genotoxicity of industrial chemicals,
      biocides, agrochemicals and pharmaceuticals. The major advantages of this assay
      include the relative ease of application to any tissue of interest, the detection
      of multiple classes of DNA damage and the generation of data at the level of the
      single cell. These features give the Comet assay potential advantages over other
      in vivo test methods, which are limited largely to proliferating cells and/or a
      single tissue. The Comet assay has demonstrated its reliability in many testing
      circumstances and is, in general, considered to be acceptable for regulatory
      purposes. However, despite the considerable data published on the in vivo Comet
      assay and the general agreement within the international scientific community
      over many protocol-related issues, it was felt that a document giving detailed
      practical guidance on the protocol required for regulatory acceptance of the
      assay was required. In a recent meeting held in conjunction with the 4th
      International Comet Assay Workshop (Ulm, Germany, 22-25 July 2001) an expert
      panel reviewed existing data and recent developments of the Comet assay with a
      view to developing such a document. This paper is intended to act as an update to
      the more general guidelines which were published as a result of the International
      Workshop on Genotoxicity Test Procedures. The recommendations are also seen as a
      major step towards gaining more formal regulatory acceptance of the Comet assay.

PMID- 12473733
TI  - Wortmannin enhances the induction of micronuclei by low and high LET radiation.
AB  - In mammalian cells, the repair of DNA double-strand breaks (DSBs) is mainly
      mediated by DNA non-homologous end joining. DNA-dependent protein kinase (DNA
      PK), a nuclear serine-threonine kinase and a member of the phosphaditylinositol-3
      kinase-related kinase family that is activated by DSBs, is a key component of
      this pathway. Wortmannin (WM) is known to be an irreversible and potent inhibitor
      of DNA-PK and has thus been proposed as an effective sensitizer for ionizing
      radiation and for radiomimetic compounds. The present study, using the
      cytokinesis block micronucleus assay, reports on the differential effect of WM on
      the repair of the DNA damage induced by low LET ((60)Co gamma-radiation) and high
      LET radiation by the boron neutron capture reaction (alpha and Li particles) in
      V79 Chinese hamster cells. Significant increases in the number of micronuclei per
      binucleated cell as well as in the frequency of micronucleated binucleated cells
      were observed in the presence of different concentrations of WM for high LET
      radiation from the boron neutron capture reaction. The increases observed reached
      a maximum of approximately 2-fold in comparison with the respective controls. WM,
      however, had a more pronounced effect on (60)Co gamma-radiation-induced
      micronuclei, increasing the genotoxic damage from this radiation by approximately
      3- to 4-fold. These results are in general in agreement with the concept that
      DSBs induced by high LET radiation are not a more suitable substrate for the end
      joining processes mediated by DNA-PK, yet they do not preclude a role for DNA-PK
      in high LET-induced damage repair.

PMID- 12473735
TI  - Induction of sister chromatid exchanges by cypermethrin and carbosulfan in bone
      marrow cells of mice in vivo.
AB  - The public health effects of pesticides cannot be denied. However, the undesired
      effects of chemical pesticides have been recognized as a serious public health
      concern during the past decades. The present study describes the genotoxic
      effects of two pesticides, namely cypermethrin and carbosulfan, in a murine test
      system in vivo. The test parameter used was analysis of sister chromatid
      exchanges (SCE) in bone marrow cells. Both cypermethrin (5, 10 and 20 mg/kg) and
      carbosulfan (1.25, 2.5 and 5 mg/kg) induced significant increases in the
      frequency of SCEs (P < 0.001). However, no significant dose-response correlation
      could be found for either of the pesticides. Carbosulfan induced a cell cycle
      delay, as evidenced by an increase in average generation time accompanied by
      accumulation of cells in the first division cycle, but cypermethrin did not
      induce any such response. The present study indicates that carbosulfan has a
      higher potential to cause genetic alterations than cypermethrin in mice and may
      also pose a mutagenic risk to human beings.

PMID- 12473737
TI  - Sister chromatid exchange induction and the course of DNA duplication, two
      mechanisms of sister chromatid exchange induction by ENU and the role of BrdU.
AB  - The aims of the present study were to establish the following: (i) the course of
      sister chromatid exchange (SCE) induction by ethylnitrosourea (ENU) in the first,
      second and third divisions as a function of the exposure time; (ii) the
      persistence of SCE-inducing lesions and the determination of whether or not they
      are always involved in SCE formation; (iii) the effect of bromodeoxyuridine
      (BrdU) incorporation on the induction and persistence of SCE. Three-way
      differential staining of sister chromatids in murine bone marrow cells in vivo
      was used in the present study. The results indicate the following: (i) SCE
      induction in each cell division depends on the course of DNA duplication,
      suggesting that SCE occurs at the replication fork; (ii) the cell population
      under study could be considered synchronous and had a cell cycle duration of
      nearly 9 h; (iii) in the second and third cell divisions ENU preferentially
      induced SCE in the cycle in which the exposure occurred; (iv) lesions induced by
      exposure to ENU did not cause SCE at the same site in subsequent divisions; (v)
      ENU was also capable of producing a long-lasting induction of SCE in BrdU
      unsubstituted DNA; (vi) the sensitivity to SCE induction by the mutagen increases
      nearly proportionally to BrdU incorporation into DNA.

PMID- 12473736
TI  - Does the bleomycin sensitivity assay express cancer phenotype?
AB  - The bleomycin (BLM) sensitivity assay has been associated with the measuring of
      increased risk of individual susceptibility to cancer, when chromatid breaks per
      cell (b/c) induced by an in vitro treatment of lymphocytes with BLM are elevated.
      The high heritability of BLM sensitivity indicates a genetic background. We
      wished to clarify whether the test characterizes the head and neck cancer
      phenotype as compared not only with healthy individuals, but also with alcoholic
      patients (ALCs) whose exposure to tobacco and alcohol consumption were similar to
      that of head and neck cancer patients (HNCPs), but whose liver diseases were not
      cancerous. If the BLM test quantifies merely cancer susceptibility on an
      inherited basis, the mutagen sensitivity of HNCPs should differ from that of
      ALCs. Conventional chromosome analysis and the BLM assay were carried out on 156
      HNCPs, 51 ALCs, 146 healthy non-smokers and non-drinkers and 149 non-drinking
      smokers. The spontaneous rates of chromosomal aberrations (CAs) in HNCPs, ALCs
      and healthy smokers were identical (2.8%), but differed significantly from the
      non-smoking controls (2.25%). Sporadic CAs were clearly associated with tobacco
      smoking, but not with health status. Mutagen sensitivity measured by the BLM test
      showed significantly (P < 0.04) elevated values not only in HNCPs (1.13 b/c), but
      also in ALCs (1.29 b/c) as compared with the controls (1.01 b/c). The main
      finding of the study was that a considerable proportion (46%) of Hungarian
      controls were mutagen sensitive, twice as many as in those populations reported
      by others so far. Our data suggest that the BLM test does not characterize
      susceptibility to cancer due to insignificant differences between HNCPs and ALCs
      (P = 0.12) under our conditions. However, the assay might be used as a biomarker
      to predict cancer susceptibility under circumstances when aberrant cell frequency
      is >or=2% and b/c is >or=1.

PMID- 12473738
TI  - Application of a sea urchin micronucleus assay to monitoring aquatic pollution:
      influence of sample osmolality.
AB  - We have improved our sea urchin micronucleus assay for aquatic samples and used
      it to evaluate marine pollution. We found that the water samples we had collected
      for 2 years from the Tokyo bay coast near Tokyo, an industrial megalopolis, were
      positive due to the water samples being hypo-osmotic rather than to chemical
      pollutants. The evidence was as follows: (i) the osmolality and salinity of the
      samples were about half that of sea water; (ii) the micronucleus frequency
      induced in the water sample decreased to the control level when the osmolality
      was increased to that of sea water; (iii) artificial sea water diluted with
      distilled water induced micronuclei dilution-dependently. Since micronucleus
      induction in the sea urchin assay is influenced by sample osmolality, the
      osmolality must be adjusted to that of sea water for the assay and osmotic
      pressure must be considered when evaluating water pollution.

PMID- 12473739
TI  - Molecular analysis of Tripterygium hypoglaucum (level) Hutch-induced mutations at
      the HPRT locus in human promyelocytic leukemia cells by multiplex polymerase
      chain reaction.
AB  - The genotoxicity and cytotoxicity of a Chinese medicinal herb, Tripterygium
      hypoglaucum (level) Hutch (THH), was investigated in human promyelocytic leukemia
      (HL-60) cells using the hypoxanthine-guanine phosphoribosyltransferase mutation
      assay. THH showed clear cytotoxicity and mutagenicity in HL-60 cells at
      concentrations between 6.7 and 20.0 mg/ml. When the mutants were characterized by
      techniques based on multiplex PCR, 46.6% of induced mutants were found to have
      deletions, whereas only 7.7% of spontaneous mutants showed deletions. The rest
      were not characterized, but were assumed to be mainly point mutations. Mapping of
      all intragenic deletion breakpoints showed a random distribution of breakpoints
      in nine exons. Deletion of exon 1 appeared as the only whole gene deletion, while
      deletions of exon 7/8 and 9 often occurred concomitantly (71.4%). It is concluded
      that THH is mutagenic in HL-60 cells, predominantly inducing deletions. Since
      this herb is widely used as a traditional medicine, its genotoxicity should be
      assessed in vivo in treated humans.

PMID- 12473740
TI  - A comparison of folic acid and 5-methyltetrahydrofolate for prevention of DNA
      damage and cell death in human lymphocytes in vitro.
AB  - Folic acid (FA), the most oxidized and stable form of folate, is commonly used as
      a dietary supplement and in culture media. FA must be reduced and methylated to
      become the metabolically active form found in blood and utilized by tissues, i.e.
      5-methyltetrahydrofolate (5-MeTHF). 5-MeTHF is the methyl group donor required
      for the conversion of homocysteine to methionine catalyzed by vitamin B(12)
      dependent methionine synthase. It is hypothesized that 5-MeTHF may be more
      effective than FA in reducing spontaneous DNA damage and improving cell
      proliferation because, unlike FA, it can donate a methyl group for methionine
      synthesis, which is required for cell division via polyamine production and for
      maintenance methylation of DNA after its conversion to S-adenosylmethionine. We
      aimed to determine whether FA and 5-MeTHF differed in their capacity to prevent
      genetic damage and cell proliferation of human lymphocytes in vitro. Lymphocytes
      from eight female volunteers (40-48 years) were cultured in RPMI 1640 medium
      containing 12-120 nM FA or 5-MeTHF for 9 days. Mitogenesis was stimulated with
      phytohemagglutinin and the medium changed on days 3 and 6. Cytokinesis was
      inhibited by adding cytochalasin B on day 8 and cells were harvested and
      transferred to microscope slides on day 9. Chromosome damage, cell death and
      cytostasis was measured using the cytokinesis-block micronucleus assay in its
      comprehensive mode. The results showed that the frequency of micronucleated
      binucleate cells was significantly lower at 120 nM FA compared with 120 nM 5
      MeTHF (P < 0.05), however, at 12 nM concentration both forms of folate were
      associated with increased frequency of micronuclei and nuclear buds relative to
      120 nM (P < 0.05). Apoptosis tended to be significantly higher in 5-MeTHF
      cultures compared with FA cultures, however, necrosis and nuclear division were
      similar between cultures. We conclude that 5-MeTHF is not more efficient than FA
      in preventing human lymphocyte genomic instability in this in vitro system.
      Further research is needed to clarify the role of choline and methionine
      concentration and the importance of the reduced folate carrier and the folate
      receptor in determining the relative bioavailability of 5-MeTHF and FA with
      regard to genome stability.

PMID- 12473741
TI  - Effects of cigarette smoke and a heterocyclic amine, MeIQx on cytochrome P-450,
      mutagenic activation of various carcinogens and glucuronidation in rat liver.
AB  - In order to elucidate the mechanism underlying enhancement by cigarette smoke
      (CS) of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced rat
      hepatocarcinogenesis, hepatic levels of cytochrome P-450 (CYP) enzymes, mutagenic
      activation of various carcinogens and UDP-glucuronyltransferase (UDPGT)
      activities were assayed in male F344 rats. Immunoblot analyses for microsomal CYP
      proteins revealed induction of CYP1A1 and constitutive CYP1A2 (2.3- to 2.7-fold),
      but not CYP2B1/2, 2E1 or 3A2, by CS exposure for 1, 12 or 16 weeks using a
      Hamburg type II smoking machine; the enhancement of CYP1A2 was 4.7-5.7 times that
      of CYP1A1. CS exposure also elevated the mutagenic activities of MeIQx and five
      other heterocyclic amines (HCAs) 1.4- to 3.7-fold, but not those of
      benzo[a]pyrene (BP) and aflatoxin B(1) in strain TA98 and N-nitrosodimethylamine,
      N-nitrosopyrrolidine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in strain
      TA100. In contrast, feeding 300 p.p.m. MeIQx in the diet for 1 or 16 weeks
      produced no significant alterations in the levels of these CYP species and
      mutagenic activities. However, i.g. administration of 50 or 100 mg/kg MeIQx in a
      single dose selectively increased CYP1A1 and 1A2 (2.6-fold) levels and mutagenic
      activities of five HCAs (1.7- to 3.3-fold), but not BP. On the other hand,
      feeding of MeIQx for 16 weeks enhanced UDPGT activities towards 4-nitrophenol and
      testosterone (2.9- and 1.5-fold, respectively), but not bilirubin, while CS
      exposure induced that towards 4-nitrophenol (1.6-fold); combined treatment with
      CS and MeIQx showed a summation effect on induction of UDPGT1A6 activity (3.5
      fold). Consequently, these results demonstrate that CS and MeIQx have a
      bifunctional action, with similar induction patterns of specific CYP proteins,
      mutagenic activity and UDPGT activity. In conjunction with the finding of N
      hydroxy-MeIQx being a poor substrate for rat liver UDPGT, our results clearly
      indicate that enhancement by CS of MeIQx-induced hepatocarcinogenesis in F344
      rats can be attributed to an increase in metabolic activation of MeIQx by hepatic
      CYP1A2 during the initiation phase.

PMID- 12473744
TI  - Levy laws in free probability.
AB  - This article and its sequel outline recent developments in the theory of infinite
      divisibility and Levy processes in free probability, a subject area belonging to
      noncommutative (or quantum) probability. The present paper discusses the classes
      of infinitely divisible probability measures in classical and free probability,
      respectively, via a study of the Bercovici-Pata bijection between these classes.

PMID- 12473745
TI  - Levy processes in free probability.
AB  - This is the continuation of a previous article that studied the relationship
      between the classes of infinitely divisible probability measures in classical and
      free probability, respectively, via the Bercovici-Pata bijection. Drawing on the
      results of the preceding article, the present paper outlines recent developments
      in the theory of Levy processes in free probability.

PMID- 12473742
TI  - Modulation of rat liver cytochrome P450 by protein restriction assessed by
      biochemical and bacterial mutagenicity methods [corrected].
AB  - Protein restriction (PR) significantly inhibits spontaneous and chemical
      carcinogenesis. Several factors seem to be involved in this effect, including a
      decrease in body weight, cellular proliferation and DNA damage and an increase in
      antioxidant defenses. The current study was designed to determine modifications
      in some hepatic cytochromes P450 (CYPs) due to a hypoproteic diet and to
      investigate its implications on chemical mutagenesis. Western blot analysis
      showed decreases of 73, 40 and 74% in CYP1A, CYP2B and CYP2E1 protein
      concentrations in hepatic microsomes from animals fed a protein-restricted (6%
      protein) diet for 6 weeks in comparison with microsomes from rats fed a 24%
      protein diet during the same period. In the same way, low protein fed animals
      showed a 3.5-fold decrease in hepatic CYP1A1-associated ethoxyresorufin O
      deethylase activity, a 6-fold decrease in CYP1A2-associated methoxyresorufin O
      demethylase activity, a 1.7-fold decrease in CYP2B1-associated penthoxyresorufin
      O-dealkylase activity, a 9-fold decrease in CYP2B2-associated benzyloxyresorufin
      O-dealkylase and, finally, a 3.4-fold decrease in CYP2E1-associated 4-nitrophenol
      hydroxylase activity. As a result of decreased CYP hepatic protein concentrations
      and enzymatic activities, liver S9 from rats fed a hypoproteic diet was less
      efficient in activating promutagens than S9 prepared from rats fed a 24% protein
      diet in the Ames test. Mutagenic potency obtained with protein-restricted S9 was
      reduced 25-fold for 2-aminoanthracene, 1.5-fold for N-nitrosodipropylamine, 12.5
      fold for N-nitrosodibutylamine, 2-fold for cyclophosphamide and N
      nitrosopyrrolidine and 71-fold for N-nitrosodimethylamine. However, the mutagenic
      potency of benzo[a]pyrene was the same (4 revertants/ microg) with S9 derived
      from rats fed either a 6 or 24% protein diet.

PMID- 12473746
TI  - Air pollution induces heritable DNA mutations.
AB  - Hundreds of thousands of people worldwide live or work in close proximity to
      steel mills. Integrated steel production generates chemical pollution containing
      compounds that can induce genetic damage (1, 2). Previous investigations of
      herring gulls in the Great Lakes demonstrated elevated DNA mutation rates near
      steel mills (3, 4) but could not determine the importance of airborne or aquatic
      routes of contaminant exposure, or eliminate possible confounding factors such as
      nutritional status and disease burden. To address these issues experimentally, we
      exposed laboratory mice in situ to ambient air in a polluted industrial area near
      steel mills. Heritable mutation frequency at tandem-repeat DNA loci in mice
      exposed 1 km downwind from two integrated steel mills was 1.5- to 2.0-fold
      elevated compared with those at a reference site 30 km away. This statistically
      significant elevation was due primarily to an increase in mutations inherited
      through the paternal germline. Our results indicate that human and wildlife
      populations in proximity to integrated steel mills may be at risk of developing
      germline mutations more frequently because of the inhalation of airborne chemical
      mutagens.

PMID- 12473747
TI  - Satellite imagery characterizes local animal reservoir populations of Sin Nombre
      virus in the southwestern United States.
AB  - The relationship between the risk of hantaviral pulmonary syndrome (HPS), as
      estimated from satellite imagery, and local rodent populations was examined. HPS
      risk, predicted before rodent sampling, was highly associated with the abundance
      of Peromyscus maniculatus, the reservoir of Sin Nombre virus (SNV). P.
      maniculatus were common in high-risk sites, and populations in high-risk areas
      were skewed toward adult males, the subclass most frequently infected with SNV.
      In the year after an El Nino Southern Oscillation (ENSO), captures of P.
      maniculatus increased only in high-risk areas. During 1998, few sites had
      infected mice, but by 1999, 1820 of the high-risk sites contained infected mice
      and the crude prevalence was 30.8%. Only 118 of the low-risk sites contained
      infected rodents, and the prevalence of infection was lower (8.3%). Satellite
      imagery identified environmental features associated with SNV transmission within
      its reservoir population, but at least 2 years of high-risk conditions were
      needed for SNV to reach high prevalence. Areas with persistently high-risk
      environmental conditions may serve as refugia for the survival of SNV in local
      mouse populations.

PMID- 12473748
TI  - Identification and cloning of human polynucleotide phosphorylase, hPNPase old-35,
      in the context of terminal differentiation and cellular senescence.
AB  - Terminal differentiation and cellular senescence display common properties
      including irreversible growth arrest. To define the molecular and ultimately the
      biochemical basis of the complex physiological changes associated with terminal
      differentiation and senescence, an overlapping-pathway screen was used to
      identify genes displaying coordinated expression as a consequence of both
      processes. This approach involved screening of a subtracted cDNA library prepared
      from human melanoma cells induced to terminally differentiate by treatment with
      fibroblast IFN and mezerein with mRNA derived from senescent human progeria
      cells. This strategy identified old-35, which encodes an evolutionary conserved
      gene, human polynucleotide phosphorylase (hPNPase(old-35)), that is regulated
      predominantly by type I IFNs. The hPNPase(OLD-35) protein localizes in the
      cytoplasm of human cells and induces RNA degradation in vitro, as does its
      purified bacterial protein homologue. Ectopic expression of hPNPase(old-35) in
      human melanoma cells reduces colony formation, confirming inhibitory activity of
      this RNA-degradation enzyme. Identification of hPNPase(old-35), an IFN-inducible
      3'-5' RNA exonuclease, provides additional support for a relationship between IFN
      action and RNA processing and suggests an important role for this gene in growth
      control associated with terminal differentiation and cellular senescence.

PMID- 12473750
TI  - What's in the serum of seronegative MG and LEMS?: MuSK et al.

PMID- 12473749
TI  - Associations between human disease genes and overlapping gene groups and multiple
      amino acid runs.
AB  - Overlapping gene groups (OGGs) arise when exons of one gene are contained within
      the introns of another. Typically, the two overlapping genes are encoded on
      opposite DNA strands. OGGs are often associated with specific disease phenotypes.
      In this report, we identify genes with OGG architecture and genes encoding
      multiple long amino acid runs and examine their relations to diseases. OGGs
      appear to be susceptible to genomic rearrangements as happens commonly with the
      loci of the DiGeorge syndrome on human chromosome 22. We also examine the degree
      of conservation of OGGs between human and mouse. Our analyses suggest that (i) a
      high proportion of genes in OGG regions are disease-associated, (ii) genomic
      rearrangements are likely to occur within OGGs, possibly as a consequence of
      anomalous sequence features prevalent in these regions, and (iii) multiple amino
      acid runs are also frequently associated with pathologies.

PMID- 12473751
TI  - Sweetening the pot in muscle: genetic defects of protein glycosylation causing
      muscle disease.

PMID- 12473752
TI  - AChR phosphorylation and indirect inhibition of AChR function in seronegative MG.
AB  - BACKGROUND: Approximately 10% to 20% of patients with autoimmune MG do not have
      antibodies to the acetylcholine receptor (AChR), so-called seronegative MG
      (SNMG). IgG antibodies from up to 70% of SNMG patients bind to the muscle
      specific receptor tyrosine kinase, MuSK. The plasmas and non-IgG fractions from
      SNMG patients (and some with AChR antibodies) also contain a factor, perhaps an
      IgM antibody, that inhibits AChR function, but it is not clear how this factor
      acts and whether it is related to the MuSK IgG antibodies. METHODS: The authors
      studied 12 unselected SNMG plasmas and their non-IgG fractions; seven were
      positive for MuSK IgG antibodies. Ion flux assays, electrophysiology,
      phosphorylation, and kinase assays were used to look at mechanisms of action.
      RESULTS: Eight of the 12 plasmas and their non-IgG fractions inhibited AChR
      function, but the inhibitory activity was transient and did not correlate with
      the presence of MuSK IgG antibodies. Two of three plasmas added outside of a cell
      attached patch pipette inhibited AChR function within the patch, and these two
      plasmas also increased AChR phosphorylation. CONCLUSIONS: The authors propose
      that a plasma factor(s) in SNMG patients, distinct from MuSK IgG antibodies,
      binds to a muscle membrane receptor and activates a second messenger pathway
      leading to AChR phosphorylation and reduced AChR function. Identifying the target
      for this factor should lead to improved diagnosis of MG in MuSK antibody-negative
      patients and may provide new insights into the function of the neuromuscular
      junction and pathophysiological mechanisms in MG.

PMID- 12473753
TI  - Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body
      myopathy.
AB  - BACKGROUND: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal-recessive
      disorder with preferential involvement of the tibialis anterior muscle that
      starts in young adulthood and spares quadriceps muscles. The disease locus has
      been mapped to chromosome 9p1-q1, the same region as the hereditary inclusion
      body myopathy (HIBM) locus. HIBM was originally described as rimmed vacuole
      myopathy sparing the quadriceps; therefore, the two diseases have been suspected
      to be allelic. Recently, HIBM was shown to be associated with the mutations in
      the gene encoding the bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N
      acetylmannosamine kinase (GNE). OBJECTIVE: To determine whether DMRV and HIBM are
      allelic. METHODS: The GNE gene was sequenced in 34 patients with DMRV. The
      epimerase activity in lymphocytes from eight DMRV patients was also measured.
      RESULTS: The authors identified 27 unrelated DMRV patients with homozygous or
      compound-heterozygous mutations in the GNE gene. DMRV patients had markedly
      decreased epimerase activity. CONCLUSIONS: DMRV is allelic to HIBM. Various
      mutations are associated with DMRV in Japan. The loss-of-function mutations in
      the GNE gene appear to cause DMRV/HIBM.

PMID- 12473754
TI  - A randomized, double-blind, placebo-controlled trial of a glycine antagonist in
      neuropathic pain.
AB  - BACKGROUND: Nerve injury results in increases in spinal glutamate, which opens
      the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site
      must be occupied for the channel to open. GV196771 is a selective antagonist of
      the glycine-binding site of the NMDA ionophore. OBJECTIVE: To determine the
      efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of
      concept study. METHODS: With informed consent, 63 subjects (31 placebo, 32
      GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia,
      complex regional pain syndrome, or peripheral nerve injury), a visual analogue
      score averaging > or =30 mm during the screening period, and a well-defined
      primary area of mechanical allodynia were recruited for the study. A multicenter,
      randomized, double-blind, placebo-controlled, parallel-group study design was
      utilized. Subjects came to the research center for a total of five visits over a
      21-day period, which consisted of a 14-day treatment period followed by a 7-day
      washout period. Spontaneous and evoked pain scores, mechanical sensory testing,
      quantitative sensory testing, Short Form McGill Pain Questionnaire, patient
      global satisfaction, and safety assessments were made during the study. RESULTS:
      There was no significant effect of GV196771 on spontaneous or evoked pain,
      quantitative sensory testing, or patient global satisfaction. There was a
      significant effect of GV196771 on the area of dynamic and static allodynia on
      days 7 and 14. The overall incidence of adverse events during treatment was
      similar for GV196771 (56%) and placebo (71%). The incidence of drug-related
      adverse events during treatment was higher for placebo (42%) than GV196771 (28%).
      CONCLUSIONS: Although the glycine antagonists show anti-hyperalgesic action in
      animal models of neuropathic pain, GV196771 does not appear to be an effective
      treatment in subjects with chronic neuropathic pain. This may be due to
      insufficient penetration of GV196771 to central sites of action, differences
      between the human and animal glycine receptors, or differences between
      neuropathic pain in animal models and humans.

PMID- 12473755
TI  - Migraine and Meniere's disease: is there a link?
AB  - BACKGROUND: A possible link between Meniere's disease (MD) and migraine was
      originally suggested by Prosper Meniere. Subsequent studies of the prevalence of
      migraine in MD produced conflicting results. OBJECTIVE: To determine the lifetime
      prevalence of migraine in patients with MD compared to sex- and age-matched
      controls. METHODS: The authors studied 78 patients (40 women, 38 men; age range
      29 to 81 years) with idiopathic unilateral or bilateral MD according to the
      criteria of the American Academy of Otolaryngology. Diagnosis of migraine with
      and without aura was made via telephone interviews according to the criteria of
      the International Headache Society. Additional information was obtained
      concerning the concurrence of vertigo and migrainous symptoms during Meniere
      attacks. The authors interviewed sex- and age-matched orthopedic patients (n =
      78) as controls. RESULTS: The lifetime prevalence of migraine with and without
      aura was higher in the MD group (56%) compared to controls (25%; p < 0.001).
      Forty-five percent of the patients with MD always experienced at least one
      migrainous symptom (migrainous headache, photophobia, aura symptoms) with Meniere
      attacks. CONCLUSIONS: The lifetime prevalence of migraine is increased in
      patients with MD when strict diagnostic criteria for both conditions are applied.
      The frequent occurrence of migrainous symptoms during Meniere attacks suggests a
      pathophysiologic link between the two diseases. Alternatively, because migraine
      itself is a frequent cause of audio-vestibular symptoms, current diagnostic
      criteria may not differentiate between MD and migrainous vertigo.

PMID- 12473756
TI  - Transient restless legs syndrome after spinal anesthesia: a prospective study.
AB  - OBJECTIVE: To assess the incidence and time course of new-onset restless legs
      syndrome (RLS) after spinal anesthesia. METHODS: A total of 202 consecutive
      patients undergoing spinal anesthesia for various types of surgery were
      prospectively evaluated regarding the presence and severity of RLS symptoms 48 to
      72 hours post surgery and after 1 week, 1 month, 3 months, and 6 months. A
      diagnosis of RLS was made according to the criteria of the International RLS
      Study Group (IRLSSG), and severity was assessed by the IRLSSG severity scale.
      RESULTS: Of 161 patients without any history of RLS, 8.7% developed first-onset
      RLS after spinal anesthesia. Symptoms were transient, with a mean duration of 33
      +/- 30 days. Low mean corpuscular volume and mean corpuscular hemoglobin were
      associated with the occurrence of new-onset RLS after spinal anesthesia.
      CONCLUSIONS: Transient RLS can be induced by spinal anesthesia. The mechanisms by
      which spinal anesthesia can trigger RLS are unclear but may include deficits in
      spinal sensorimotor integration in susceptible individuals.

PMID- 12473757
TI  - The association of incident dementia with mortality in PD.
AB  - OBJECTIVE: To evaluate the association of incident dementia with mortality in a
      cohort of patients with idiopathic PD who were nondemented at baseline
      evaluation, controlling for extrapyramidal sign (EPS) severity at each study
      visit. BACKGROUND: The development of dementia has been associated with reduced
      survival in PD. Because EPS severity is associated with both dementia and
      mortality in PD, the association of dementia with mortality may be confounded by
      disease severity. METHODS: A cohort of patients with PD was followed annually
      with neurologic and neuropsychological evaluations. The association of incident
      dementia and the total Unified PD Rating Scale (UPDRS) motor score with mortality
      in PD was examined using Cox proportional hazards models with time-dependent
      covariates. All analyses were adjusted for age at baseline, sex, years of
      education, ethnicity, and duration of PD. RESULTS: Of 180 PD patients, 41 (22.8%)
      died during a mean follow-up period of 3.9 +/- 2.2 years. Among those who died
      during the study period, 48.8% (20 of 41) became demented during follow-up, as
      compared to 23.0% (32 of 139) of those who remained alive. Both incident dementia
      (RR: 2.2, 95% CI: 1.1 to 4.5, p = 0.04) and the total UPDRS motor score at each
      study visit (RR: 1.04, 95% CI: 1.02 to 1.07, p = 0.001) were associated with
      mortality in PD when included in the same Cox model. CONCLUSIONS: Incident
      dementia has an independent effect on mortality when controlling for EPS
      severity. The development of dementia is associated with a twofold increased
      mortality risk in PD.

PMID- 12473758
TI  - Fluctuations in attention: PD dementia vs DLB with parkinsonism.
AB  - BACKGROUND: Marked impairments in and fluctuation of attention are characteristic
      of dementia with Lewy bodies (DLB). The comparative impairment of these cognitive
      domains in PD and PD dementia (PD dementia) has not been studied, and is
      important to the conceptual understanding of parkinsonian dementias. METHOD:
      Detailed evaluations of attention and fluctuating attention (Cognitive Drug
      Research computerized battery) were undertaken in 278 subjects (50 DLB, 48 PD
      dementia, 50 PD, 80 AD, 50 elderly controls) from the Newcastle dementia register
      and the Stavanger PD register (controls, PD, and PD dementia patients were
      recruited from both centers). DLB, AD, PD, and PD dementia were diagnosed using
      operationalized criteria. RESULTS: Impairments in reaction time, vigilance, and
      fluctuating attention were comparable in patients with DLB and PD dementia, but
      were less substantially impaired in patients with DLB without parkinsonism.
      Patients with PD had significantly greater impairment of cognitive reaction time
      than elderly controls, and comparable impairments of cognitive reaction time to
      patients with AD. Patients with PD, however, did not exhibit fluctuation of
      attention. CONCLUSION: The profile of attentional impairments and fluctuating
      attention is similar in PD dementia and DLB with parkinsonism. The current
      findings do not support the current arbitrary distinctions between these patient
      groups. Importantly, patients with PD do not experience fluctuating attention.

PMID- 12473759
TI  - The incremental direct costs associated with behavioral symptoms in AD.
AB  - OBJECTIVE: To determine the incremental costs associated with behavioral symptoms
      in patients with AD. METHODS: A total of 128 patients with probable AD were
      enrolled into this study. Cognitive function and extrapyramidal features were
      assessed in patients with AD. Caregivers were interviewed to determine use of
      health care services, receipt of unpaid care, severity of behavioral symptoms
      (Neuropsychiatric Inventory [NPI]), and comorbid medical conditions in patients
      with AD. Healthcare utilization data were multiplied by unit costs to estimate
      direct formal costs. Unpaid caregiving hours were multiplied by an hourly wage to
      estimate direct informal costs. The annual incremental direct costs of additional
      behavioral symptoms were estimated with multiple regression equations. RESULTS:
      Annual, direct costs were significantly higher in patients with AD at or above
      the median score on the NPI (high NPI group), after adjusting for group
      differences in severity of cognitive impairment and comorbid conditions. Patients
      in the high NPI group had formal costs between US$3,162 and US$5,919 higher than
      the low NPI group and total direct costs between US$10,670 and US$16,141 higher,
      depending on the severity of cognitive impairments. Models for the entire sample
      estimated that a one-point increase in the NPI score would result in an annual
      increase of between US$247 and US$409 in total direct costs, depending on the
      value of unpaid caregiving. CONCLUSIONS: Behavioral symptoms in patients with AD
      significantly increase direct costs of care.

PMID- 12473760
TI  - Prognosis for seizure recurrence in patients with newly diagnosed
      neurocysticercosis.
AB  - OBJECTIVE: To determine the risk of seizure recurrence after a first seizure due
      to neurocysticercosis (NC) and to evaluate risk factors for seizure recurrence,
      including the influence of antihelminthic treatment. METHODS: The authors
      prospectively followed 77 patients with a first seizure and active or
      transitional NC for >7 years (median 24 months). RESULTS: Thirty-one patients
      (40.3%) experienced seizure recurrence. Kaplan-Meier estimated recurrence was 22%
      at 6 months, 32% at 12 months, 39% at 24 months, and 49% at 48 and 84 months.
      Treatment with an antihelminthic (albendazole) did not influence recurrence. On
      multivariable analysis, none of the following predicted recurrence: sex,
      presenting seizure type, classification of NC, localization of cysts, Todd
      paralysis, neurologic deficits at presentation, EEG abnormalities. Only change in
      CT predicted recurrence: 22% in patients in whom cysts disappeared and 56% in
      patients with persistent cysts (p < 0.05). In this latter group, recurrence was
      associated with persistence of an active lesion. Of those with two seizures,
      estimated risk of a third seizure was 68% by 6 years after the second seizure.
      CONCLUSIONS: Seizure recurrence is high after a first acute symptomatic seizure
      due to NC, but this seems related to persistence of active brain lesions.
      Recurrence risk is low and in keeping with seizure risk following other brain
      insults leading to a static encephalopathy in those in whom the NC lesion clears.
      Patients with NC should receive antiseizure medications until the acute lesion
      clears on CT. There is no correlation between treatment with antihelminthic
      agents and seizure recurrence.

PMID- 12473761
TI  - Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide.
AB  - BACKGROUND: Epilepsy affects 80% of patients with Sturge-Weber syndrome; the
      majority of seizures begin before the age of 1. When seizures are intractable to
      medications and unihemispheric, hemispherectomy is often advised. OBJECTIVE: To
      examine the natural history of patients who underwent hemispherectomy and
      identify the outcomes in terms of seizure reduction, cognition, and motor
      deficits. METHODS: A questionnaire was mailed to the parents of patients
      identified by the Sturge-Weber Foundation as having had a hemispherectomy between
      1979 and 2001. Forty-six percent (32/70) of the parents responded. RESULTS: The
      mean age at onset of seizures was 4 months, and the median age at surgery was 1.2
      years. Children had failed to respond to 3.7 anticonvulsants prior to surgery and
      averaged 387 seizures/month. Forty-seven percent had complications (e.g.,
      hemorrhage and hypertension) in the perioperative period; however, 81% are
      currently seizure-free, with 53% off anticonvulsants. Hemispherectomy type
      (anatomic versus functional versus hemidecortication) did not influence outcome.
      Age at onset of seizures did not predict seizure freedom; however, an older age
      at hemispherectomy was positively correlated. Postoperative hemiparesis was not
      more severe than before surgery. Cognitive outcome was not related to the age at
      operation, side of operation, or seizure freedom. CONCLUSIONS: Children
      undergoing hemispherectomy presented at a young age and had frequent seizures for
      approximately 1 year but are now mostly seizure-free. Age at surgery did not have
      an adverse effect on either seizure or cognitive outcomes.

PMID- 12473762
TI  - Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic
      analyses.
AB  - BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology.
      Pathophysiologic hypotheses include a hypothalamic dysfunction and abnormalities
      in the central serotonin and dopamine metabolism. Several clinical symptoms also
      suggest an underlying autoimmune process. OBJECTIVE: To systematically
      investigate patients with KLS with reference to the available hypotheses.
      METHODS: The authors collected clinical, polysomnographic, CSF, CT, and MRI
      records and analyzed gene polymorphisms of HLA-DQB1, tryptophan hydroxylase
      (TpH), and catechol-O-methyltransferase (COMT) in 30 unrelated patients with KLS
      and their families. The genotype data were contrasted with data from a normal
      control population. RESULTS: Only human leukocyte antigen (HLA)-DQB1*0201 allele
      frequency was significantly increased in patients with KLS. Three patients with
      KLS but none of the control subjects were DQB1*0201 homozygous. Two affected
      subjects from the same family were DQB1*0201 homozygous. In 17 DQB1*0201
      heterozygous parents, 11 (64.7%) had transmitted this allele, suggesting a
      preferential transmission. CONCLUSION: These findings, together with the young
      age at onset, the recurrence of symptoms, and the frequent infectious
      precipitating factors, suggest an autoimmune etiology for Kleine-Levin syndrome.

PMID- 12473763
TI  - Biochemical markers predicting survival in peroxisome biogenesis disorders.
AB  - OBJECTIVE: To identify prognostic markers reflecting the extent of peroxisome
      dysfunction in primary skin fibroblasts from patients with peroxisome biogenesis
      disorders (PBD). BACKGROUND: PBD are a genetically heterogeneous group of
      disorders due to defects in at least 11 distinct genes. Zellweger syndrome is the
      prototype of this group of disorders, with neonatal adrenoleukodystrophy and
      infantile Refsum disease as milder variants. Common to these three disorders are
      liver disease, variable neurodevelopmental delay, retinopathy, and perceptive
      deafness. Because genotype-phenotype studies are complicated by the genetic
      heterogeneity among patients with PBD, the authors evaluated a series of
      biochemical markers as a measure of peroxisome dysfunction in skin fibroblasts.
      METHODS: Multiple peroxisomal functions including de novo plasmalogen synthesis,
      dihydroxyacetonephosphate acyltransferase (DHAPAT) activity, C26:0/C22:0 ratio,
      C26:0 and pristanic acid beta-oxidation, and phytanic acid alpha-oxidation were
      analyzed in fibroblasts from a series of patients with defined clinical
      phenotypes. RESULTS: A poor correlation with age at death was found for de novo
      plasmalogen synthesis, C26:0/C22:0 ratio, and phytanic acid alpha-oxidation. A
      fairly good correlation was found for pristanic acid beta-oxidation, but the best
      correlation was found for DHAPAT activity and C26:0 beta-oxidation. A mathematic
      combination of DHAPAT activity and C26:0 beta-oxidation showed an even better
      correlation. CONCLUSIONS: DHAPAT activity and C26:0 beta-oxidation are the best
      markers in predicting life expectancy of patients with PBD. Combination of both
      markers gives an even better prediction. These results contribute to the
      management of patients with PBD.

PMID- 12473764
TI  - Global and domain-specific cognitive impairment and outcome after subarachnoid
      hemorrhage.
AB  - BACKGROUND: Cognitive dysfunction is the most common form of neurologic
      impairment after subarachnoid hemorrhage (SAH). OBJECTIVE: To evaluate the impact
      of global and domain-specific cognitive impairment on functional recovery and
      quality of life (QOL) after SAH. METHODS: One hundred thirteen patients (mean age
      49 years; 68% women) were evaluated 3 months after SAH. Three simple tests of
      global mental status and neuropsychological tests to assess seven specific
      cognitive domains were administered. Four aspects of outcome (global handicap,
      disability, emotional status, and QOL) were compared between cognitively impaired
      and unimpaired patients with analysis-of-covariance models controlling for age,
      race/ethnicity, and education. Multiple linear regression was used to evaluate
      the relative contribution of global and domain-specific cognitive status for
      predicting concurrent modified Rankin Scale (mRS) and Sickness Impact Profile
      (SIP) scores. RESULTS: Impairment of global mental status on the Telephone
      Interview of Cognitive Status (TICS) was associated with poor performance in all
      seven cognitive domains (all p < 0.0005) and was the only cognitive measure
      associated with poor recovery in all four aspects of outcome (all p < or =
      0.005). Cognitive impairment in four specific domains was also associated with
      functional disability or reduced QOL. After accounting for global cognitive
      impairment with the TICS, however, neuropsychological testing did not contribute
      additional predictive value for concurrent mRS or SIP total scores. CONCLUSIONS:
      Cognitive impairment impacts broadly on functional status, emotional health, and
      QOL after SAH. The TICS may be a useful alternative to more detailed
      neuropsychological testing for detecting clinically relevant global cognitive
      impairment after SAH.

PMID- 12473765
TI  - Evaluation of clinical diagnostic criteria for neurofibromatosis 2.
AB  - BACKGROUND: Four sets of clinical diagnostic criteria for neurofibromatosis 2
      (NF2) have been developed by groups of expert clinicians, but sensitivity has
      never been formally assessed. The sets of criteria differ for people without
      bilateral vestibular schwannomas, which are pathognomonic for NF2. OBJECTIVE: To
      empirically evaluate the four existing sets of clinical diagnostic criteria for
      NF2. METHODS: The study was based on 163 of 403 people in the United Kingdom NF2
      registry (41%) who presented without bilateral vestibular schwannomas. The
      authors applied the sets of criteria to each person at initial assessment and at
      the most recent clinical evaluation (mean +/- SE length of follow-up, 13 +/- 1
      years). RESULTS: In people with "definite NF2" and a negative family history of
      NF2, the 1987 US NIH and 1991 NIH criteria each identify 78% of people at the
      most recent clinical evaluation but 0% at initial assessment. The National
      Neurofibromatosis Foundation (NNFF) criteria and the Manchester criteria each
      identify higher proportions at both time points (NNFF criteria, 91% and 10%;
      Manchester criteria, 93% and 14%), but the proportions at initial assessment are
      still low. CONCLUSIONS: None of the existing sets of criteria are adequate at
      initial assessment for diagnosing people who present without bilateral vestibular
      schwannomas as having NF2, particularly people with a negative family history of
      NF2. The authors recommend that a single, revised set of diagnostic criteria be
      devised to replace all of the existing sets of criteria.

PMID- 12473766
TI  - Axonal damage in the spinal cord of MS patients occurs largely independent of T2
      MRI lesions.
AB  - OBJECTIVE: To determine the degree of axonal damage in relationship to signal
      abnormalities on T2-weighted high-resolution MRI in spinal cord tissue of
      patients with MS. METHODS: Spinal cord specimens of nine patients with MS and
      four controls were imaged at high resolution (4.7 T) in an axial plane and scored
      for lesions with increased signal intensity (SI). Histopathologic sections were
      cut and immunostained with NE14 (neurofilament marker) and Luxol fast blue
      (myelin stain). For each area, axonal density and diameter were quantified;
      axonal irregularity, NE14 axonal staining intensity, and myelin content were
      semiquantitatively scored. Included were 209 areas from MS cases and 109 areas
      from control cases distributed over lateral, posterior, and anterior columns.
      RESULTS: In control cases, no SI changes were found, average density of axons was
      26,989/mm(2), average diameter was 1.1 micro m, and all scores for axonal
      irregularity, NE14 staining intensity, and myelin were normal. In MS cases, areas
      with increased SI were found, average axonal density was 11,807/mm(2) (p <
      0.0001), and average axonal diameter 2.0 micro m (p = 0.001). Areas with high SI
      on MRI had lowest axonal density (average count: 10,504/mm(2); range: 3,433 to
      26,325/mm(2)), largest diameter (average: 2.3 micro m; range: 1.0 to 4.0 micro
      m), and highest axonal irregularity and NE14 staining intensity compared to
      normal appearing cord tissue (NACT). However, NACT of MS cases also had lower
      axonal density (14,158/mm(2)) and higher average axonal diameter (1.6 micro m)
      than controls. CONCLUSIONS: Marked axonal loss occurs in MS spinal cords, largely
      independent of the degree of signal abnormality on T2-weighted MRI.

PMID- 12473767
TI  - MR angiography in migrainous vasospasm.

PMID- 12473768
TI  - Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients.
AB  - The authors characterized the clinical and immunologic features of 110 patients
      with Lambert-Eaton myasthenic syndrome (LEMS). Anti-P/Q-type voltage-gated
      calcium channels (VGCC) antibodies were detected in 85% of the patients
      (seropositive) but not in the rest (seronegative). Except for the indication that
      small cell lung carcinoma is less common in seronegative patients, no significant
      differences were found in the clinical characteristics of patients who had or did
      not have anti-P/Q-type VGCC antibodies. The results of passive transfer
      experiments suggest that seronegative LEMS is also an autoantibody-mediated
      disorder.

PMID- 12473769
TI  - GNE mutations in an American family with quadriceps-sparing IBM and lack of
      mutations in s-IBM.
AB  - Analysis for GNE mutations was performed in an American, non-Iranian Jewish,
      family with quadriceps-sparing inclusion body myopathy (QS-IBM) and in 11
      patients with sporadic IBM (s-IBM). Two novel nonallosteric site missense
      mutations were found in the QS-IBM kinship. No mutations were identified in s-IBM
      patients. After 8 years of follow-up and severe disease progression, the
      quadriceps muscle in the QS-IBM patient remains strong despite subclinical
      involvement documented with repeat MRI and muscle biopsy.

PMID- 12473770
TI  - Diagnostic criteria for dystonia in DYT1 families.
AB  - Family studies of primary torsion dystonia have used the diagnostic categories of
      definite, probable, and possible dystonia for gene mapping and identification,
      but the validity of this hierarchical classification is not known. The authors
      assessed 147 DYT1 GAG deletion carriers and 113 blood-related noncarriers from 43
      families. Only the category of definite dystonia was 100% specific. Probable
      dystonia, but not possible, was increased in carriers compared with noncarriers.
      The authors recommend that only those with definite signs of dystonia be
      considered affected in linkage and other genetic studies.

PMID- 12473771
TI  - Exon deletions in the GCHI gene in two of four Turkish families with dopa
      responsive dystonia.
AB  - Most cases of dopa-responsive dystonia (DRD) are thought to be caused by
      mutations in the GCHI gene; however, by sequencing, mutations are found in only
      40% to 60%. Recently, a single report identified, via Southern blot analysis, a
      large genomic GCHI deletion in a "mutation-negative" case. This report describes
      four families with DRD, two of which carry large deletions, thus confirming that
      deletions are an important subtype of GCHI mutations. These deletions were
      detected by quantitative duplex PCR that is amenable to DNA diagnostics.

PMID- 12473772
TI  - Driving safety in Parkinson's disease.
AB  - In this study, 39 patients with PD and 25 control subjects without neurologic
      disease completed testing in a driving simulator. PD patients had more total
      collisions on the driving simulator than control subjects (t = -3.7, p < 0.01).
      In PD patients, collisions were associated with Hoehn and Yahr stage (chi(2) =
      12.4, p = 0.006) and correlated with Unified Parkinson's Disease Rating Scale
      score (r = 0.5, p < 0.01).

PMID- 12473773
TI  - Repetitive transcranial magnetic stimulation for Tourette syndrome.
AB  - In a single-blinded, placebo-controlled, crossover repetitive transcranial
      magnetic stimulation (rTMS) trial, 16 patients with Gilles de la Tourette
      syndrome (GTS) received in random sequence 1 Hz motor, premotor, and sham rTMS,
      which each consisted of two 20-minute rTMS sessions applied on 2 consecutive
      days. In the 12 patients who completed the trial, there was no significant
      improvement of symptoms after any of the rTMS conditions as assessed with the
      Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey.

PMID- 12473774
TI  - Clinical and genetic studies of families with the tau N279K mutation (FTDP-17).
AB  - The tau N279K mutation was identified in four separately ascertained families in
      the United States, Japan, and France and in another recently discovered affected
      individual in Japan. The authors analyzed genealogical and clinical records and
      DNA samples. Average age at onset was 43 years; survival time was 7 years. All
      families exhibited similar clinical features, with parkinsonism, dementia, and
      supranuclear palsy uniformly seen. A founder effect indicated by a shared disease
      haplotype was seen only in two Japanese families. The N279K mutation can develop
      independently in different parts of the world.

PMID- 12473775
TI  - Higher attack rates for left motor deficit among men with cerebrovascular events.
AB  - The authors report the findings of a prospectively collected database of stroke
      and TIA recorded from 1998 through 1999 by the 178 family physicians of the
      Belgian sentinel network. The yearly age-adjusted attack rate per 100,000 men was
      estimated as 109 (95% CI = 86 to 137) for left motor deficit and 75 (95% CI = 56
      to 99) for right motor deficit (p = 0.011). This difference was not observed
      among women nor in the entire sample population. The authors suggest that
      handedness should be systematically recorded and compared to both sex and the
      side of the event.

PMID- 12473776
TI  - Carotid artery dissection after the intracarotid amobarbital test.
AB  - A retrospective chart review of 435 consecutive intracarotid amobarbital tests
      (IAT) was performed to determine the frequency of carotid artery dissection (CAD)
      associated with IAT. Three patients with a CAD were found (0.7%). Mean age of
      patients with dissection (51.3 years) was higher than the average age of 432
      patients without dissection (31.7 years) (p < 0.05). All patients had clinical
      symptoms including face or neck pain. Patients undergoing the IAT are at risk of
      CAD. Age may be a risk factor.

PMID- 12473777
TI  - Impaired renal function in progressive multiple sclerosis.
AB  - The authors analyzed renal function in 25 patients with progressive MS. The mean
      glomerular filtration rate (GFR) was 92 mL/min/1.73 m(2), compared to the
      predicted GFR of 110 (p < 0.001). Nine of the 25 (36%) patients had abnormally
      low GFR (<90). The mean serum creatinine for patients with MS was lower than
      predicted normal values and poorly estimated GFR using standard equations. These
      data document impaired renal function in patients with progressive MS and have
      implications for treatment of these patients with potentially nephrotoxic drugs.

PMID- 12473778
TI  - Adult onset glutaric aciduria type I presenting with a leukoencephalopathy.
AB  - Glutaric aciduria type I usually presents with an acute metabolic crisis during
      infancy. The authors report a previously healthy 19-year-old woman who presented
      with recurrent headaches, oculomotor symptoms, and a severe leukoencephalopathy
      on MRI. The diagnosis was made by urinary organic acid analysis and confirmed by
      enzyme studies. Genetic analysis revealed compound heterozygosity with a deletion
      c.219delC in exon 3 and a novel missense mutation R132G in exon 5 of the glutaryl
      CoA dehydrogenase (GCDH) gene.

PMID- 12473779
TI  - Identification of a susceptibility locus for migraine with and without aura on
      6p12.2-p21.1.
AB  - Migraine is the most common type of chronic episodic headache. To find novel
      susceptibility genes for familial migraine with and without aura, a genomewide
      screen was performed in a large family from northern Sweden. Evidence of linkage
      was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of
      5.41 for marker D6S452. The patients with migraine shared a common haplotype of
      10 Mb between markers D6S1650 and D6S1960.

PMID- 12473781
TI  - Ethylene glycol intoxication: electrophysiological studies suggest a
      polyradiculopathy.

PMID- 12473780
TI  - An Italian family with autosomal recessive inclusion-body myopathy and mutations
      in the GNE gene.

PMID- 12473782
TI  - Phrenic nerve paralysis secondary to Lyme neuroborreliosis.

PMID- 12473783
TI  - Meningoradiculitis associated with giant cell arteritis.

PMID- 12473784
TI  - Lonely cowboy's thoughts.

PMID- 12473785
TI  - A sequential bilateral medial medullary infarction separated by 4 months.

PMID- 12473786
TI  - Epilepsia partialis continua as an atypical presentation of cat scratch disease
      in a young adult.

PMID- 12473787
TI  - An autoantibody to GAD65 in sera of patients with juvenile neuronal ceroid
      lipofuscinoses.

PMID- 12473788
TI  - Fiction: Off-label.

PMID- 12473789
TI  - Smoking and PD in twins.

PMID- 12473790
TI  - Recombinant interferon-alpha-induced chorea and frontal subcortical dementia.

PMID- 12473791
TI  - Morbidity and mortality following pallidotomy in PD.

PMID- 12473792
TI  - Chronic inflammatory demyelinating polyneuropathy presenting with features of
      GBS.

PMID- 12473793
TI  - Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation.

PMID- 12473796
TI  - Prevention interventions for HIV positive individuals.

PMID- 12473797
TI  - Chlamydia screening and sexual health.

PMID- 12473798
TI  - Behavioural surveillance: the value of national coordination.
AB  - Behavioural surveillance programmes have enabled the description of population
      patterns of risk behaviours for STI and HIV transmission and aid in the
      understanding of how epidemics of STI are generated. They have been instrumental
      in helping to refine public health interventions and inform the targeting of
      sexual health promotion and disease control strategies. The formalization and
      coordination of behavioural surveillance in England and Wales could optimise our
      ability to measure the impact of interventions and health promotion strategies on
      behaviour. This will be particularly useful for monitoring the progress towards
      specific disease control targets set in the Department of Health's new Sexual
      Health and HIV Strategy.

PMID- 12473799
TI  - Cost effectiveness of screening for Chlamydia trachomatis: a review of published
      studies.
AB  - OBJECTIVE: Screening for Chlamydia trachomatis in the lower genital tract may
      contribute to the prevention of pelvic inflammatory disease in women. The purpose
      of this review was to critically appraise, and summarise studies of the cost
      effectiveness of screening for C trachomatis. METHODS: A literature search was
      conducted on Medline and in Health Star from 1990-2000. Keywords were C
      trachomatis, screening, cost effectiveness. Bibliographies of reviewed articles
      were also searched. The population studied was asymptomatic sexually active women
      under 30 years of age in a primary care setting. The intervention assessed was
      screening for lower genital tract infection with C trachomatis and the outcomes
      studied were cases of C trachomatis detected, cases of PID prevented, and
      associated costs. Studies were assessed using the Drummond criteria for economic
      evaluations. They were assessed qualitatively as they were too heterogeneous to
      allow quantitative analysis. RESULTS: 10 studies were included. All were modelled
      scenarios and all found screening to be more cost effective than simply testing
      symptomatic women, although all were based on probabilities that were assumed.
      Six of the studies focused on DNA based testing, three of them using urine. The
      models showed screening to be cost effective at prevalences of 3.1-10.0%, and
      cost saving (overtesting symptomatic women) at a prevalence as low as 1.1%, if
      age was used as a selection factor and DNA based tests were used in urine
      samples. CONCLUSIONS: At the prevalence of infection expected in the target
      population, all studies suggest screening is cost effective. However, the
      assumptions used in the models have been difficult to confirm and there is a need
      for more data, particularly on the risk of complications in women with
      asymptomatic lower tract infection.

PMID- 12473800
TI  - Validation of a simplified grading of Gram stained vaginal smears for use in
      genitourinary medicine clinics.
AB  - OBJECTIVES: To validate a simplified grading scheme for Gram stained smears of
      vaginal fluid for the diagnosis of bacterial vaginosis (BV) against the accepted
      "gold" standard of Amsel's composite criteria. METHODS: Women attending
      genitourinary medicine (GUM) clinics, as part of a multicentre study, were
      diagnosed as having BV if three or more of the following criteria were present;
      homogeneous discharge, elevated vaginal pH, production of amines, and presence of
      "clue" cells. Women with less than three of the criteria were considered as
      normal. Simultaneously, smears were made of vaginal fluid and Gram stained and
      then assessed qualitatively as normal (grade I), intermediate (grade II), or
      consistent with BV (grade III). Two new grades were used, grade 0, epithelial
      cells only with no bacteria, and grade IV, Gram positive cocci only. RESULTS: BV
      was diagnosed in 83/162 patient visits using the composite criteria, the
      remainder being regarded as normal. The majority of patients with BV had a smear
      assessed as grade III (80/83, 96%) and the majority of normal women had a smear
      assessed as grade I (normal, 48/79, 61%), giving a high sensitivity (97.5%),
      specificity (96%), and predictive value for a positive (94.1%) and negative (96%)
      test, kappa index = 0.91. Smears assessed as grade II were found predominantly
      (12/13) among patients diagnosed as normal, with less than three of the composite
      criteria. Grades 0 and IV were both only found among normal women. CONCLUSION:
      This simplified assessment of Gram stained smears can be used as an alternative
      to Amsel's criteria and is more applicable for use in busy GUM clinics.

PMID- 12473801
TI  - Provision of chlamydia testing in a nationwide service offering termination of
      pregnancy: with data capture to monitor prevalence of infection.
AB  - OBJECTIVES: To establish a methodology by which all women attending for
      termination of pregnancy (TOP) at British Pregnancy Advisory Service (BPAS)
      branches may be approached to participate in Chlamydia trachomatis screening. To
      examine the feasibility of monitoring C trachomatis prevalence and the impact of
      charging for screening on the uptake rate in this population. METHODS: Patients
      attending for TOP at participating BPAS branches were offered a test for
      chlamydia infection and asked to complete a questionnaire. Urine samples from
      participants were tested using a nucleic acid amplification test (NAAT). RESULTS:
      1001 women provided a urine sample, a 77% response rate among those participating
      in the study. Factors significantly associated with taking up chlamydia screening
      included symptoms, previous TOP, parity, and no previous chlamydial test. Overall
      prevalence of genital chlamydial infection was 7.5%, with highest age specific
      prevalences occurring among attendees aged 20-24 years (11.5%) and under 20 years
      (10.8%). In univariate analysis, chlamydia positivity was significantly
      associated with respondent age and previous diagnosis with chlamydia. Only 35% of
      women who had the screening test would have done so had they been asked to pay
      the pound 20 clinical, administrative, and laboratory costs of the examination.
      CONCLUSIONS: We have demonstrated the feasibility of routine chlamydia screening
      and the potential for prospective prevalence monitoring across the nationwide
      BPAS service. In most cases the chlamydia result was available within the
      clinical contact period for the TOP. Charging patients directly for the test
      could reduce uptake of chlamydia screening to levels unsatisfactory for both the
      public health and prevalence monitoring purposes.

PMID- 12473802
TI  - Investigation into the acceptability and effectiveness of a new contact slip in
      the management of Chlamydia trachomatis at a London genitourinary medicine
      clinic.
AB  - OBJECTIVES: To improve contact tracing for chlamydia. To determine (i) the
      acceptability to patients of using a contact slip that named chlamydia as the
      sexually transmissible infection that the contact may have been at risk of
      acquiring, and (ii) whether an augmented contact slip issued for chlamydia
      significantly increased the number of sexual partners attending for treatment.
      METHODS: For a 2 month period, all consecutive heterosexual patients diagnosed
      with chlamydia at the Mortimer Market Centre (MMC) were offered one or more coded
      contact slips (CS1) as per clinic protocol. During this time, and for 1 month
      afterwards, contacts presenting as a result of receiving these contact slips were
      recorded. This was compared to a subsequent 2 month period during which a contact
      slip naming chlamydia as the potential infection, with an information leaflet
      attached (CS2), was issued. Contacts attending as a result of receiving this
      augmented contact slip were recorded over a similar period. For both cohorts the
      number of patients refusing either contact slip, and contacts attending other GUM
      clinics, were recorded. RESULTS: 121 patients were diagnosed with chlamydia and
      were seen by a health adviser in period one and 130 patients were diagnosed and
      seen in period two. There was no significant difference detected between the
      acceptability of CS1 and CS2 (one refusal per cohort). There was a significant
      increase in the number of sexual contacts attending for treatment after being
      given CS2 (160 attending of 190 contact slips issued (84%, 95% CI 79 to 89)),
      compared to CS1 (48 attending of 144 contact slips issued (33%, 95% CI 26 to
      43)). CONCLUSIONS: An infection specific contact slip was equally acceptable to
      patients as the standard contact slip, and it significantly increased the number
      of sexual contacts attending for treatment.

PMID- 12473803
TI  - The potential role of suppressive therapy for sex partners in the prevention of
      neonatal herpes: a health economic analysis.
AB  - BACKGROUND: The development of suppressive therapy and type specific tests for
      herpes infections allow for screening to reduce the risk of neonatal herpes.
      OBJECTIVES: To assess the potential effectiveness, cost effectiveness, and
      benefit of suppressive therapy among herpes simplex virus serodiscordant sex
      partners during pregnancy. METHODS: Decision and economic analyses are used to
      compare the incidence and costs of neonatal herpes in California (2000) for three
      interventions: (1) no management; (2) current guidelines (caesarean delivery for
      women with lesions); (3) screening for women at risk and use of suppressive
      treatment in sex partners. RESULTS: Screening and suppressive therapy are the
      most effective interventions, while current guidelines have limited
      effectiveness, but the latter provide the most cost effective results.
      CONCLUSIONS: While current guidelines are cost saving, they forgo a potential 82%
      decrease in neonatal herpes incidence that would be possible with screening and
      suppressive therapy if society were willing to pay the necessary US$363 000 per
      case prevented. To evaluate HSV screening and drug therapy completely, clinical
      trials and an economic assessment of infant mortality "value" to society are
      required.

PMID- 12473804
TI  - An evidence based approach to testing for antibody to herpes simplex virus type
      2.
AB  - OBJECTIVES: To establish whether a simple risk scoring system, based on limited
      information, can reflect the variation in HSV-2 prevalence in a population, and
      whether a common system can be used across settings. To establish whether
      knowledge of a patient's score can aid the interpretation of the result from one
      of the commercial type specific assays. METHODS: Four previous cross sectional
      studies are considered, with HSV-2 antibody results by western blot or type
      specific ELISA tests. The clinical settings were a blood donor centre (1359
      participants) and STD clinic (808 participants), London, United Kingdom, an
      antenatal clinic, Sydney, Australia (2317 participants), and a family medical
      centre, Seattle, United States (478 participants). We determined the factors
      associated with HSV-2 prevalence, the similarity of associations across settings,
      and the variation in HSV-2 prevalence by risk score. RESULTS: A simple scoring
      captured much variation in HSV-2 prevalence in each population-for example, for
      London blood donors, scoring based on sex, age, and number of lifetime partners,
      prevalence varied from 0.7% (95% CI 0.1 to 2.0) to 47.3% (37.9 to 56.6) across
      five risk groups. For number of lifetime partners, and sex, the association with
      HSV-2 varied significantly across studies. CONCLUSIONS: A scoring system can aid
      test interpretation-for example, in London blood donors the post-test probability
      of infection following a positive result varies from around 25% to 98% across
      risk groups for a typical type specific assay. Further work could address whether
      this theoretical benefit can be realised in practice. A common risk scoring
      probably could not be used across settings.

PMID- 12473805
TI  - Aborted genital herpes simplex virus lesions: findings from a randomised
      controlled trial with valaciclovir.
AB  - OBJECTIVES: In prospective trials, episodic valaciclovir significantly increased
      the chance of preventing or aborting the development of painful vesicular genital
      herpes simplex virus (HSV) lesions compared with placebo. We explored the
      clinical outcome of aborted lesions and its association with early treatment in a
      study designed to compare 3 and 5 days' treatment with valaciclovir. METHODS: In
      a randomised controlled trial, valaciclovir 500 mg twice daily for 3 or 5 days
      was initiated at the first symptoms of a genital herpes outbreak. The primary end
      point was length of episode with pain, HSV shedding, and aborted lesions
      secondary end points. The effect of time from symptom recognition to treatment
      initiation on aborted lesions was assessed in a post hoc analysis. RESULTS: In
      531 patients, no differences were observed between 3 and 5 days' treatment in
      episode duration (median 4.7 v 4.6 days), loss of pain/discomfort (2.8 v 3.0
      days), or lesion healing (4.9 v 4.5 days). Vesicular lesions were aborted in 27%
      of patients treated for 3 days v 21% of patients receiving valaciclovir for 5
      days. The odds of achieving an aborted episode were 1.93 (95% CI: 1.28 to 2.90)
      times higher for those initiating treatment with valaciclovir within 6 hours of
      first sign or symptom. CONCLUSIONS: There was no difference between 3 and 5 days'
      treatment in reducing episode duration or lesion abortion. Prompt treatment with
      valaciclovir can abort genital HSV reactivation episodes, preventing a vesicular
      outbreak. Maximum treatment benefit depends on prompt therapy after recognition
      of symptoms.

PMID- 12473806
TI  - Mutation patterns in gyrA and parC genes of ciprofloxacin resistant isolates of
      Neisseria gonorrhoeae from India.
AB  - AIM: To analyse mutations in the gyrA and parC genes leading to possible increase
      in ciprofloxacin resistance (high MIC values for ciprofloxacin) in clinical
      isolates of Neisseria gonorrhoeae in Delhi, India. METHOD: MIC of ciprofloxacin
      for 63 clinical isolates of N gonorrhoeae were examined by the Etest method.
      Subsequently, gyrA and parC genes of these isolates were amplified and sequenced
      for possible mutations. RESULTS: Out of the 63 clinical isolates tested, only
      five (8%) isolates were found to be susceptible to ciprofloxacin (MIC <0.06 micro
      g/ml). DNA sequence analysis of the gyrA and the parC genes of all these isolates
      (n = 63) revealed that all isolates which were not susceptible to ciprofloxacin
      (n=58) had mutation(s) in gyrA and parC genes. 12 isolates (19%) exhibited high
      resistance with an MIC for ciprofloxacin of 32 micro g/ml. Two out of these 12
      isolates (UD62 and UD63), harboured triple mutations (Ser-91 to Phe, Asp-95 to
      Asn and Val-120 to Leu) in the gyrA gene. The third mutation of Val-120 to Leu,
      lies downstream of the quinolone resistance determining region (QRDR) of the gyrA
      and has not been described before in gonococcus. In addition, both these isolates
      had a Phe-100 to Tyr substitution in the parC, a hitherto unknown mutation.
      CONCLUSIONS: Emergence of ciprofloxacin resistance with high levels of MIC values
      (up to 32 micro g/ml) in India is alarming. Double and triple mutations in gyrA
      alone or together in gyrA and parC could be responsible for such a high
      resistance.

PMID- 12473808
TI  - Characteristics of adenovirus associated urethritis.
AB  - OBJECTIVES: To describe the characteristics of adenovirus urethritis in men.
      METHOD: Cases occurred over a 30 month period among men presenting with
      urethritis to Melbourne Sexual Health Clinic. All cases had a urethral Gram stain
      and underwent testing for chlamydia, gonorrhoea, herpes, and adenovirus. Cases
      were empirically treated with a macrolide or doxycycline. RESULTS: Eight cases of
      adenovirus associated urethritis were identified in whom no other causative
      organism was isolated. Cases were clustered in autumn and winter of each year and
      all reported recent insertive oral sex and seven reported recent insertive
      vaginal sex. All patients complained of dysuria, seven had meatitis and mucoid
      discharge, six had conjunctivitis, and four constitutional symptoms. Three sexual
      contacts were known to be symptomatic. CONCLUSION: Adenovirus is an uncommon
      cause of urethritis in men but it should be considered in all males presenting
      with dysuria, meatitis, and associated conjunctivitis or constitutional symptoms.

PMID- 12473809
TI  - The criminalization of HIV transmission.
AB  - Since Bennett, Draper, and Frith published a paper in the Journal of Medical
      Ethics in 2000 considering the possible criminalization of HIV transmission, an
      important legal development has taken place. February 2001 saw the first
      successful United Kingdom prosecution for the sexual transmission of disease for
      over a century, when Stephen Kelly was convicted in Glasgow of recklessly
      injuring his former girlfriend by infecting her with HIV. Whether English
      criminal law (as opposed to Scots law) can apply criminal penalties in such a
      case, however, still remains uncertain. This paper, in addition to providing some
      background to the Kelly case, briefly explores the current possibilities for
      prosecution under English law. It then proceeds to outline and comment on the
      issues relevant to criminalization, responding in part to points made by Bennett,
      Draper, and Frith and also by Bird and Leigh Brown in a recent article in the
      BMJ.

PMID- 12473811
TI  - Bilateral groove sign with penoscrotal elephantiasis.
AB  - Lymphogranuloma venereum (LGV) is a sexually transmitted disease of the lymph
      channels caused by Chlamydia trachomatis. Esthiomene, a rare late manifestation
      of LGV, is a primary infection affecting the lymphatics of scrotum, penis, or
      vulva. The male genitalia are affected less commonly by esthiomene, but we report
      a male patient who presented with inguinal syndrome, penoscrotal elephantiasis,
      along with enlargement of femoral lymph nodes.

PMID- 12473810
TI  - Donovanosis.
AB  - Donovanosis, a chronic cause of genital ulceration, has recently been the subject
      of renewed interest after a long period of relative obscurity. The causative
      organism, Calymmatobacterium granulomatis, has been cultured for the first time
      in many years and a polymerase chain reaction diagnostic using a colorimetric
      detection system has been developed. Phylogenetic analysis confirms close
      similarities with the genus Klebsiella and a proposal made that C granulomatis be
      reclassified as Klebsiella granulomatis comb nov. Azithromycin has emerged as the
      drug of choice and should be used if the diagnosis is confirmed or suspected. In
      donovanosis endemic areas, syndromic management protocols for genital ulceration
      may need to be adapted locally. A significant donovanosis epidemic was reported
      in Durban from 1988-97 but the current status of this epidemic is unclear. The
      donovanosis elimination programme among Aboriginals in Australia appears
      successful and is a model that could be adopted in other donovanosis endemic
      areas. Overall, the incidence of donovanosis seems to be decreasing. Increased
      attention would undoubtedly be paid to donovanosis if policy makers recognised
      more readily the importance of genital ulcers in fuelling the HIV epidemic.

PMID- 12473812
TI  - A new way to catch hepatitis C.

PMID- 12473813
TI  - Characteristics of gonorrhoea in Kermanshah, Iran.
AB  - OBJECTIVE: To describe the characteristics of gonorrhoea and prostitution in
      Kermanshah, Iran. METHOD: From 1997 through 2000, 100 male gonorrhoea patients
      were followed for a mean of 18 months (range 8-42 months). Diagnosis and follow
      up were made by a combination of history, physical examination, and the Gram
      stained smear. RESULTS: 4% of patients became infected by girlfriends, 24% by
      temporary (sigheh) wives, and 64% by street prostitutes; the remaining 8% denied
      coitus with sex workers. Of 38 married cases, 31 reported unprotected intercourse
      with permanent wives while infected, and only four of 38 gave prescribed drugs to
      their wives. 89% of contacts with prostitutes were unprotected. Most of the
      prostitutes and professional sigheh wives were practising survival sex. Fear of
      stigmatization and presumed severe penalties prevented prostitutes from seeking
      medical care, and 26% of patrons reported self medication. An average 84% of
      prescriptions of standard therapies failed. 31% of the cases remained refractory
      to all available therapies. CONCLUSIONS: The majority of the prostitutes and
      sigheh wives in Iran exchange sex for survival. Being uneducated survival sex
      workers, they accept risky sex behaviours easily. Sigheh wives are an important
      source of infection. The very high rate of persistent infection despite standard
      treatments is disturbing. Our ideal is a world in which nobody is obliged to
      enter commercial sex work. In the meantime, however, there is an urgent need to
      offer medical care and education to sex workers as needy patients in a safe and
      unprejudiced environment. Denying the presence of such realities as prostitution
      and sexually transmitted diseases (STDs) because of their disagreement with cant
      claims and official propaganda, does not eradicate the facts but results in
      catastrophic public health problems.

PMID- 12473814
TI  - Peripheral neuropathy in patients with HIV infection: consider dual pathology.
AB  - Two HIV infected patients presented with peripheral neuropathy, in one patient
      this was originally ascribed to HIV associated mononeuritis multiplex and in the
      other to stavudine. Investigations confirmed these diagnoses and in both cases
      genetic analysis identified a second hereditary aetiology: in the first patient
      hereditary neuropathy with liability to pressure palsies and in the second
      hereditary motor and sensory neuropathy.

PMID- 12473815
TI  - Kaposi's sarcoma infiltrating skeletal muscle.
AB  - An HIV-1 antibody positive black African man with plasma cell variant Castleman's
      disease and cutaneous Kaposi's sarcoma, despite receiving chemotherapy, had
      progressive disease. In addition, he developed pain and swelling behind the right
      knee. Histology of an ultrasound guided biopsy showed Kaposi's sarcoma
      infiltrating the head of gastrocnemius.

PMID- 12473817
TI  - HIV epidemicity in context of STI declines: a telling discordance.

PMID- 12473818
TI  - Vaginal infection by Enterobacter sakazakii.

PMID- 12473819
TI  - Inhibition of Neisseria gonorrhoeae by vaginal lubricants.

PMID- 12473820
TI  - Successful use of valciclovir in a case of recurrent urticaria associated with
      genital herpes.

PMID- 12473821
TI  - Clinical characteristics of Chlamydia trachomatis infections in a general
      outpatient department of obstetrics and gynaecology in the Netherlands.
AB  - OBJECTIVE: Evaluation of prevalence and risk factors of Chlamydia trachomatis
      infections in an outpatient obstetric and gynaecological population. METHODS: A
      prospective, observational study was performed at an inner city hospital in The
      Hague, Netherlands. 1368 women attending the outpatient department of obstetrics
      and gynaecology participated in the study. For detection of C trachomatis
      infections we used amplification of CT rRNA in urine samples (Gen Probe/AMPLIFIED
      CT) and DNA probe for detection of CT rRNA from a urethral, endocervical and anal
      swab (Gen Probe/PACE 2). RESULTS: The overall prevalence of C trachomatis
      infections in our general obstetric and gynaecological population was 4.5%. The
      prevalence in women under 30 years of age was 8. 1%. We found age and postcoital
      bleeding to be significant risk factors. We did not find significant differences
      between women from different ethnic origin or between women using different kinds
      of contraceptives. 12 (19.4%) patients with C trachomatis infections were found
      positive by urine test only, and 15 (24.2%) only by DNA probe. CONCLUSIONS: Age
      is the most important risk factor in our population (overall prevalence 4.5%,
      prevalence in women under 20 years of age 15.8%). Analyses of urine and of
      endocervical specimens are complementary for the determination of the prevalence
      of C trachomatis infections in women. Cost effectiveness analysis is needed to
      determine to what extent age based screening and/or antibiotic prophylaxis before
      intrauterine manipulations is indicated.

PMID- 12473825
TI  - Introduction: occupational health and safety in biomedical research.

PMID- 12473822
TI  - Human T lymphotrophic virus-I (HTLV-I) infection in patients with unclassifiable
      dermatitis in central Kerala, south India: a preliminary study.
AB  - OBJECTIVE: We have conducted a preliminary serostudy to confirm the presence of
      this virus in cases of dermatitis of unknown aetiology and among individuals with
      sexually transmitted infections (STI) in central Kerala. METHODS: 45 consecutive
      patients who attended the dermatology clinic of Medical College Kottayam with
      extensive dermatitis that could not be clinically classified into any known
      clinical entity and 37 consecutive patients who presented to the sexually
      transmitted disease (STD) clinic were enrolled for the study. Serum/plasma
      samples were screened for anti-HTLV-I antibody. Reactive and indeterminate
      samples were confirmed by an immunoblot. RESULTS: Among 37 STD clinic attendants,
      none had antibody to HTLV-I while two individuals (4.44%) among the 45 with
      dermatitis had antibody to HTLV-I. CONCLUSIONS: Our study proves the presence of
      HTLV-I in a subset of individuals with poorly defined dermatitis in Kerala.
      Further larger studies are necessary to assess the extent of this problem and its
      relation to STI in Kerala.

PMID- 12473826
TI  - An ergonomics process for the care and use of research animals.
AB  - Personnel who work with laboratory animals incur potential occupational health
      risks that can lead to the development of musculoskeletal disorders. Demanding
      manual tasks may also result in increased errors, worker fatigue, poor human
      performance, and decreased productivity. Studies have shown that a comprehensive
      ergonomics program that utilizes a systematic risk management approach can reduce
      the likelihood of exposure to musculoskeletal disorder risk factors and remove
      barriers to human performance. Research has characterized the risk factors of
      musculoskeletal disorder exposure in terms of force, frequency, posture, and
      muscle exertion. Ergonomic risk factors for typical animal handling tasks and
      work areas are identified, and a method is suggested for prioritizing
      interventions using interrelated data indicators. An initial review of potential
      control measures is offered to improve the health, safety, and effectiveness of
      people involved in the care and use of research animals.

PMID- 12473827
TI  - Chemical safety in animal care, use, and research.
AB  - Chemical safety is an essential element of an effective occupational health and
      safety program. Controlling exposures to chemical agents requires a careful
      process of hazard recognition, risk assessment, development of control measures,
      communication of the risks and control measures, and training to ensure that the
      indicated controls will be utilized. Managing chemical safety in animal care and
      use presents a unique challenge, in part because research is frequently conducted
      in two very different environments--the research laboratory and the animal care
      facility. The chemical agents specific to each of these environments are
      typically well understood by the employees working there; however, the extent of
      understanding may not be adequate when these individuals, or chemicals, cross
      over into the other environment. In addition, many chemicals utilized in animal
      research are not typically used in the research laboratory, and therefore the
      level of employee knowledge and proficiency may be less compared with more
      routinely used materials. Finally, the research protocol may involve the exposure
      of laboratory animals to either toxic chemicals or chemicals with unknown
      hazards. Such animal protocols require careful review to minimize the potential
      for unanticipated exposures of the research staff or animal care personnel.
      Numerous guidelines and regulations are cited, which define the standard of
      practice for the safe use of chemicals. Key chemical safety issues relevant to
      personnel involved in the care and use of research animals are discussed.

PMID- 12473828
TI  - What's hot in animal biosafety?
AB  - In recent years, the emergence or re-emergence of critical issues in infectious
      disease and public health has presented new challenges and opportunities for
      laboratory animal care professionals. The re-emergence of bioterrorism as a
      threat activity of individuals or small groups has caused a heightened awareness
      of biosecurity and improved biosafety. The need for animal work involving high
      risk or high-consequence pathogens and for arthropod-borne diseases has
      stimulated renewed interest in animal biosafety matters, particularly for work in
      containment. Application of these principles to animals retained in outdoor
      environments has been a consequence of disease eradication programs. The
      anticipated global eradication of wild poliovirus has prompted the promulgation
      of new biosafety guidelines for future laboratory and animal work. Increased
      concern regarding the use of biologically derived toxins and hazardous chemicals
      has stimulated a new categorization of facility containment based on risk
      assessment. Recognition that prion disease agents and other high-consequence
      pathogens require safe handling and thorough destruction during terminal
      decontamination treatment has led to the development of new biosafety guidelines
      and technologies. The implementation of these guidelines and technologies will
      promote state-of-the-art research while minimizing risk to laboratory animals,
      researchers, and the environment.

PMID- 12473829
TI  - Laboratory animal allergy: an update.
AB  - Allergic reactions are among the most common conditions affecting the health of
      workers involved in the care and use of research animals. Between 11 and 44% of
      the individuals working with laboratory animals report work-related allergic
      symptoms. Of those who become symptomatic, 4 to 22% may eventually develop
      occupational asthma that can persist even after exposure ceases. Allergic
      symptoms consist of rashes where animals are in contact with the skin, nasal
      congestion and sneezing, itchy eyes, and asthma (cough, wheezing, and chest
      tightness). The generation of immunoglobulin E (IgE) antibodies is a prerequisite
      for the production of allergic symptoms. The mechanism by which IgE antibodies
      develop is becoming clearer. The propensity to produce IgE is genetically
      determined, and pre-existing allergy may be a risk factor for the development of
      laboratory animal allergy (LAA). However, exposure to animal allergens is the
      major risk factor for the development of LAA. Techniques to measure the airborne
      concentration of laboratory animal allergens have been developed. Research on
      animal allergens themselves indicates that many of the mouse and rat urinary
      proteins belong to a family of proteins called lipocalins, which share sequence
      homology with antigens of the parasitic agent that causes schistosomiasis. The
      fact that parasite infections also trigger IgE antibody responses may account for
      the development of LAA in persons who have never had any previous allergy. The
      prevention of LAA should be a major goal of an effective health and safety
      program in the animal research facility, and it can be accomplished by education
      and training of employees, reduction of exposure (including the use of personal
      protective gear), and changes in facility design. Medical surveillance programs
      can also play a role in improving health of individuals working with laboratory
      research animals. Early recognition of symptoms and evidence of sensitization can
      lead to interventions to reduce exposure and thereby avoid the long-term health
      consequences of LAA.

PMID- 12473830
TI  - Use of personal protective equipment for respiratory protection.
AB  - Management of hazards in biomedical research facilities requires the application
      of the traditional industrial hygiene responsibilities of anticipation,
      recognition, evaluation, and control to characterize the work environment,
      evaluate tasks and equipment, identify hazards, define exposure groups, and
      recommend controls. Generally, the diversity and unique characteristics of
      hazards faced by laboratory and animal facility employees and the short-term and
      low-level nature of the exposures factor into the selection of proper exposure
      control measures in the laboratory. The proper selection of control measures is
      based on a hierarchy of elimination and minimization by engineering controls,
      followed last by personal protective equipment when exposures cannot be
      eliminated. Once it is decided that personal protective equipment is needed,
      specific regulations and guidelines define safety standards for research
      facilities, including the elements of a sound respiratory protection program.
      These elements include respirator selection (including appropriate protection
      factors), medical evaluation, fit testing, training, inspection, maintenance and
      care, quality, quantity and flow of breathing air, and routine and emergency use
      procedures.

PMID- 12473831
TI  - Occupational medicine programs for animal research facilities.
AB  - Occupational medicine is a key component of a comprehensive occupational health
      and safety program in support of laboratory animal research and production
      facilities. The mission of the department is to maximize employee health and
      productivity utilizing a population health management approach, which includes
      measurement and analysis of health benefits utilization. The department works in
      close cooperation with other institutional health and safety professionals to
      identify potential risks from exposure to physical, chemical, and biological
      hazards in the workplace. As soon as exposures are identified, the department is
      responsible for formulating and providing appropriate medical surveillance
      programs. Occupational medicine is also responsible for targeted delivery of
      preventive and wellness services; management of injury, disease, and disability;
      maintenance of medical information; and other clinic services required by the
      institution. Recommendations are provided for the organization and content of
      occupational medicine programs for animal research facilities.

PMID- 12473832
TI  - Rhesus monkey simian immunodeficiency virus infection as a model for assessing
      the role of selenium in AIDS.
AB  - The objective of this study was to determine whether simian immunodeficiency
      virus (SIV) infection of macaques could be used as a model system to assess the
      role of selenium in AIDS. Plasma and serum selenium levels were determined by
      standard assays in monkeys before and after inoculation of SIV. SIV-infected
      cells or cells expressing the HIV Tat protein were labeled with 75Se, and protein
      extracts were prepared and electrophoresed to analyze selenoprotein expression.
      Total tRNA was isolated from CEMx174 cells infected with SIV or from KK1 cells
      infected with HIV, and selenocysteine tRNA isoforms were characterized by reverse
      phase chromatography. SIV-infected monkeys show a decrease in blood selenium
      levels similar to that observed in AIDS with development of SAIDS. Cells infected
      with SIV in vitro exhibit reduced selenoprotein levels and an accumulation of
      small molecular weight selenium compounds relative to uninfected cells.
      Examination of the selenocysteine tRNA isoforms in HIV-infected KK1 cells or SIV
      infected CEMx174 cells reveals an isoform distribution characteristic of selenium
      deficient cells. Furthermore, transfection of Jurkat E6 cells with the Tat gene
      selectively altered selenoprotein synthesis, with GPX4 and Sep15 being the most
      inhibited and TR1 the most enhanced. Taken together, the data show that monkeys
      infected with SIV in vivo and cells infected with SIV in vitro will provide
      appropriate models for investigating the mechanism(s) responsible for reduced
      selenium levels that accompany the progression of AIDS in HIV disease.

PMID- 12473833
TI  - Effect of zidovudine resistance mutations on virologic response to treatment with
      zidovudine or stavudine, each in combination with lamivudine and indinavir.
AB  - The authors studied the effect of zidovudine (ZDV) resistance mutation on
      virologic response to treatment with ZDV or stavudine (d4T) each in combination
      with lamivudine and indinavir. Viral genotyping was performed on plasma HIV-1 RNA
      at study entry and concerned 155 patients previously treated with ZDV,
      didanosine, or zalcitabine and enrolled in the NOVAVIR (Agence National de
      Recherche sur le SIDA [ANRS] 073) trial. Three virologic responses were
      investigated: early response (<50 copies/mL at week 24), late response (<500
      copies/mL at week 80), and virologic failure (two HIV-1 RNA >5000 copies/mL).
      Patients were classified as resistant or susceptible to ZDV according to the ANRS
      algorithm. Plasma viral RNA from 123 of 155 patients had two or more ZDV
      resistance mutations. The number of ZDV resistance mutations was positively
      correlated with the duration of prior antiviral therapy (p <.001). At week 24,
      74% and 77% of patients with virus classified as resistant were responders in the
      d4T and ZDV arm, respectively. Similar results were found at week 80. Virologic
      failure was reached in 7 of 24 patients with virus classified as susceptible and
      in 26 of 131 patients with resistant virus (p =.29). In the ZDV arm, patients
      classified as resistant had longer times to virologic failure than those
      classified as susceptible (p =.003). In conclusion, sustained virologic response
      despite presence of ZDV resistance mutations implies that these mutations do not
      preclude an early and durable response to treatment with a potent three-drug
      regimen in these patients. Patients susceptible to ZDV had lower median mean
      corpuscular volumes and lower random indinavir levels, suggesting that adherence
      was the main reason for failure.

PMID- 12473834
TI  - Effect of long-term highly active antiretroviral therapy in restoring HIV-induced
      abnormal B-lymphocyte function.
AB  - Although highly active antiretroviral therapy (HAART) has been reported to
      restore defects in cell-mediated immunity to a significant degree, little is
      known of its effects in restoring HIV-induced abnormal antibody-mediated
      immunity. We conducted a cross-sectional study of 1) 29 HIV-infected patients on
      chronic HAART whose HIV viral load was undetectable and whose absolute CD4+ T
      lymphocyte count had been consistently sustained by > or =150 cells/microL over
      their pre-HAART nadir value for >1 year; and 2) 29 untreated HIV-infected
      patients with current CD4 counts matching the treated patients' prior nadir CD4
      counts. Serum was tested for total IgG and by protein electrophoresis with
      immunofixation for paraproteins. Although serum IgG levels were significantly
      lower in patients who had received long-term virologically effective HAART than
      in CD4 count-matched untreated patients (1488 +/- 475 mg/dL vs. 1999 +/- 775
      mg/dL, p =.004), serum IgG was still abnormally elevated in 45% of the untreated
      group despite a mean 28 months of HAART-induced HIV suppression and CD4 count
      restoration. Paraprotein spikes were confirmed by immunofixation in 7% of
      patients in each group. This study provides the longest reported observation to
      date of the effect of HAART on HIV-induced abnormal antibody-mediated immunity.
      Larger and longer-term studies of HAART effect on B-cell reconstitution are
      needed.

PMID- 12473835
TI  - Open-label study of a twice-daily indinavir 800-mg/ritonavir 100-mg regimen in
      protease inhibitor-naive HIV-infected adults.
AB  - Low-dose ritonavir can boost plasma levels of indinavir, thereby enhancing its
      antiretroviral activity despite less frequent dosing. In this open-label,
      noncomparative, 24-week trial with a 24-week extension phase, HIV-infected
      protease inhibitor (PI)- and lamivudine-naive adults received indinavir/ritonavir
      800 mg/100 mg plus stavudine and lamivudine every 12 hours. The proportions of
      patients achieving plasma HIV RNA (vRNA) <400 and <50 copies/mL were analyzed
      with data as observed (DAO) and intention-to-treat models using generalized
      estimating equations (GEE) or counting noncompleters as failures (NC = F). Eighty
      nine patients (80% men) with a median age of 36 years and mean baseline vRNA
      levels and CD4 counts of 5.01 log(10) copies/mL and 269 cells/mm(3) were
      enrolled. The proportions (95% confidence interval [CI]) of patients achieving
      vRNA <400 copies/mL were 93% (84%, 98%), 78% (67%, 86%), and 68% (57%, 78%) at
      week 24 for DAO, GEE, and NC = F analyses, respectively; the corresponding
      results at week 48 were 95% (84%, 99%), 65% (53%, 76%), and 45% (35%, 57%). Most
      patients with vRNA <400 had <50 copies/mL. At week 48, baseline vRNA decreased by
      >2 log(10) copies/mL and CD4 counts increased by approximately 200 cells/mm(3).
      Five patients (6%) experienced serious drug-related adverse experiences. Twenty
      patients (23%) discontinued therapy due to adverse experiences. In this study,
      twice-daily indinavir 800 mg/ritonavir 100 mg with two nucleoside reverse
      transcriptase inhibitors provided potent viral suppression and immunologic
      reconstitution in many PI-naive patients.

PMID- 12473836
TI  - Open-label study of a twice-daily indinavir 800-mg/ritonavir 200-mg regimen in
      HIV-infected adults failing a protease inhibitor regimen.
AB  - There is no standard treatment of HIV-infected patients who fail protease
      inhibitor (PI)-containing antiretroviral therapy. This open-label, noncomparative
      24-week study with a 24-week extension evaluated the efficacy, safety, and
      tolerability of twice-daily indinavir/ritonavir 800/200 mg plus 2 nucleoside
      reverse transcriptase inhibitors (NRTIs) in this population. Presented here are
      the results of the 24-week study. Patients were HIV-infected adults who had prior
      viral RNA (vRNA) suppression (<400 copies/mL), subsequent failure (> or =400 and
      < or =100,000 copies/mL) on antiretroviral therapy, and at least one new NRTI
      available for treatment. The proportions of patients achieving plasma vRNA <400
      and <50 copies/mL were analyzed with data as observed (DAO) and intention-to
      treat (ITT) models using generalized estimating equations (GEE) or counting
      noncompleters as failures (NC = F). Mean changes from baseline in vRNA and CD4
      cell count were evaluated using DAO and an ITT mixed-model approach. Sixty-three
      patients (87% male) with a mean age of 42 years and mean baseline vRNA and CD4
      cell counts of 3.8 log(10) copies/mL and 360 cells/mm(3), respectively, were
      enrolled. The proportion (95% confidence interval) of patients achieving vRNA
      <400 and <50 copies/mL at week 24 were 76% (61%, 87%) and 50% (35%, 65%) for DAO,
      64% (50%, 75%) and 43% (30%, 56%) for GEE, and 56% (43%, 68%) and 37% (25%, 50%)
      for NC = F, respectively. At Week 24, baseline vRNA decreased by >1.0 log(10)
      copies/mL and CD4 cell counts increased by approximately 90 cells/mm(3). Three
      patients (5%) experienced serious drug-related adverse events. Seven patients
      (11%) discontinued treatment due to clinical or laboratory adverse events. In
      this study, the enhanced, twice-daily regimen of indinavir/ritonavir 800/200 mg
      plus 2 NRTIs provided suppression of HIV in many patients who had failed a PI
      containing regimen and was generally well tolerated.

PMID- 12473837
TI  - Underevaluation of HIV-1 plasma viral load by a commercially available assay in a
      cluster of patients infected with HIV-1 A/G circulating recombinant form (CRF02).
AB  - The authors studied the correlation and agreement of commercially available
      assays in detection and quantification of the HIV-1 intersubtype A/G circulating
      recombinant form CRF02. The assays under comparison were Bayer Versant HIV-1 RNA,
      version 3.0; Roche Amplicor HIV-1 Monitor, version 1.5 (standard procedure); and
      Organon Teknika NucliSens HIV-1 RNA QT. Plasma samples from 114 patients infected
      with CRF02 were tested by the three assays under standard conditions. Although
      correlation among the assays was high and statistically significant for subtype B
      and CRF02, in the latter instance, NucliSens measured average viral load values
      (3.29 +/- 0.71 log(10) copies/mL) about 4 and >8 times lower than those obtained
      by Versant (3.90 +/- 0.90 log(10) copies/mL) and Amplicor (4.22 +/- 1.05 log(10)
      copies/mL), respectively. Furthermore, in a statistically significant percentage
      of CRF02-harboring samples, NucliSens produced viral load values undetectable or
      1 log(10) lower than those obtained in Versant and Amplicor assays. Altogether,
      these data underline a low performance of NucliSens in detecting and quantifying
      viremia in plasma samples harboring the CRF02. These results are potentially
      important as global distribution of new HIV-1 subtypes is expanding, and
      recombinant strains, particularly CRF02, are emerging and becoming highly
      prevalent.

PMID- 12473838
TI  - HIV type 1 group M clades infecting subjects from rural villages in equatorial
      rain forests of Cameroon.
AB  - Though the HIV-1 subtypes infecting patients living in urban and semi-urban areas
      in Cameroon have been reported, information on the subtypes infecting patients in
      rural villages is lacking. To begin to understand the diversity of the HIV-1
      group M subtypes infecting persons living in rural villages in the equatorial
      rain forest regions of Cameroon, 49 plasma samples from 14 rural villages in four
      provinces of Cameroon were analyzed using heteroduplex mobility analysis (HMA),
      DNA sequencing, and phylogenetic tree analysis on the basis of env C2V5, gag, or
      pol regions. Sixty-one percent of the group M infections were clade A or CRF02_AG
      like as subtyped by env and gag. Of the remaining group M infections, 12% were
      either A or CRF02_AG-like or CRF01_AE-like in recombination with other clades;
      25% were infections that were entirely non-A or non-CRF02_AG-like; and 2% were
      CRF11_cpx. The HIV-1 group M clades identified included A, D, F (F2), G, and H.
      The CRF strains identified were CRF02_AG-like, CRF01_AE-like, and CRF11_cpx. Two
      new intersubtype recombinant infections, H/G and A/F2, were identified. This
      study suggests that the HIV-1 diversity in rural villages in the equatorial rain
      forest of Cameroon is at least as broad as has been observed in major cities of
      Cameroon and that multiple HIV-1 group M subtypes are infecting persons living in
      the countryside of Cameroon.

PMID- 12473839
TI  - HIV infection in rural villages of Cameroon.
AB  - OBJECTIVE: To evaluate HIV-1 antibody seroprevalence and risk factors for HIV
      seropositivity in rural areas of Cameroon. METHOD: The prevalences of HIV
      antibodies in 53 villages in rural Cameroon visited during May-October 2000 were
      determined with an HIV1/2 rapid assay, standard ELISA, and western blot.
      Demographic data and risk factors were elicited via face-to-face interviews with
      a structured questionnaire. RESULTS: HIV seroprevalence was 5.8% (243/4156, 95%
      confidence interval [CI] = 5.1-6.6) overall, 6.3% (151/2394, 95% CI = 5.4-7.4)
      among females and 5.2% (92/1762, 95% CI = 4.3-6.4) among males. HIV
      seroprevalence among persons aged 15 - 70 years did not differ significantly by
      province (5.6% in Center, 4.5% in East, 6.9% in South, and 5.8% in South-West) (
      =.10). Analysis of age- and gender-standardized prevalence by village across
      provinces indicated a near-significant difference (nonparametric Wilcoxon signed
      rank test, =.06), with highest prevalence in South-West, followed by South,
      Center, and East. Multivariate analysis revealed that single women were
      significantly more likely to be HIV seropositive than were married or widowed
      women. Women with a history of sexual relations while traveling were at
      significantly increased risk of HIV seropositivity (OR adjusted for age and
      marital status = 2.4, 95% CI = 1.4-9.7). Among men, those who reported ever
      having a sexually transmitted disease were at significantly increased risk of HIV
      seropositivity (OR adjusted for age = 1.8, 95% CI = 1.1-2.8). CONCLUSION: We have
      documented a wide range of HIV prevalences among rural villages of Cameroon. Age,
      marital status (in women) and sexual risk factors appear to be associated with
      HIV infection in this setting.

PMID- 12473840
TI  - Adiponectin and leptin levels in HIV-infected subjects with insulin resistance
      and body fat redistribution.
AB  - In this study, we sought to determine the relationship between serum levels of
      leptin and adiponectin (Acrp30) in patients with HIV-associated lipodystrophy
      (HIV-LD). Three groups of subjects were studied; HIV-positive subjects with
      lipodystrophy (HIV-LD; n = 22), HIV-positive subjects without lipodystrophy (HIV;
      n = 17), and ethnicity- and body mass index-matched healthy control subjects (n =
      20). Although total body fat from dual energy x-ray absorptiometry was similar in
      all three groups, the HIV-LD group had a significantly lower mean proportion of
      body fat in the limbs +/- SEM (37.2% +/- 2.2%) than either controls (49.8% +/-
      1.5%) or HIV subjects (45.7% +/- 2.0%). The HIV-LD group also had the lowest mean
      insulin sensitivity +/- SEM (5.11 +/- 0.59 mg of glucose/[kg of lean body mass.
      min] vs. 10.2 +/- 0.72 mg of glucose/[kg of lean body mass. min] in controls and
      8.64 +/- 0.69 mg of glucose/[kg of lean body mass. min] in the HIV group). Leptin
      levels were similar in all three groups and were significantly correlated to
      total body fat (r = 0.86; p <.001), but these levels did not correlate with
      either insulin sensitivity or limb fat. Mean Acrp30 levels +/- SEM were lowest in
      the HIV-LD group (5.43 +/- 0.44 microg/mL vs. 11.2 +/- 1.4 microg/mL in the HIV
      group and 14.9 +/- 1.8 microg/mL in control subjects). Further, Acrp30 levels
      were positively correlated with insulin sensitivity (r = 0.610; p <.001) and limb
      fat (r = 0.483; p <.001). However, the correlation between limb fat and insulin
      sensitivity disappeared when Acrp30 level and other potential mediators were
      removed from the association, suggesting that a deficiency in Acrp30 in subjects
      with HIV-LD may be part of the mechanism for the reduced insulin sensitivity.

PMID- 12473841
TI  - Willingness to participate and enroll in a phase 3 preventive HIV-1 vaccine
      trial.
AB  - OBJECTIVES: To assess the extent to which HIV-negative cohort study participants
      would be willing to participate (WTP) in future HIV vaccine trials, to explore
      enrollment into an ongoing phase 3 HIV vaccine trial, and to assess changing WTP
      in such trials over time. METHODS: The Vanguard Project is a prospective study of
      gay and bisexual men in the greater Vancouver region, British Columbia, Canada.
      Sociodemographic characteristics, sexual risk behavior, beliefs around HIV, and
      reasons for not participating in the AIDSVAX B/B trial were collected from self
      administered questionnaires. Contingency table analysis compared subjects who
      were WTP with subjects who were not WTP. Logistic regression analyses identified
      possible predictors of WTP. A subset analysis was conducted to assess changes in
      WTP in 2001 versus 1997. RESULTS: Of 440 respondents, 214 (48.6%) were WTP, and
      97 (22.0%) were not WTP. Those WTP were disadvantaged, sexually risky, and had a
      high-perceived HIV risk (all p <.05). Reasons for not participating in the
      AIDSVAX B/B trial included fear of health problems and having missed the deadline
      for enrollment (all p < 0.05). Multivariate analysis revealed that having had a
      regular sex partner (adjusted odds ratio, 0.48 [confidence interval, 0.25-0.92])
      was a negative predictor whereas having a high-perceived HIV risk (adjusted odds
      ratio, 5.35 [confidence interval, 1.57-18.25]) was a positive predictor of WTP.
      Comparing WTP in 2001 with that in 1997, 24% of 100 participants who had been
      previously WTP were now not WTP. CONCLUSION: Improving community and participant
      knowledge about preventive HIV vaccine trials may help ensure informed consent.
      However, whether informing potential participants will reverse or contribute to
      the declining trend in WTP observed in this cohort warrants further
      investigation.

PMID- 12473842
TI  - Opportunity for prevention of HIV and sexually transmitted infections in Kenyan
      youth: results of a population-based survey.
AB  - BACKGROUND: Data from sentinel serosurveillance are useful to estimate HIV
      infection in populations but may not be representative of the general population.
      General population-based surveys attempt to avoid selection bias and are the most
      appropriate for tracking changes in exposure to risk of HIV infection over time
      and assessing changes in behavior following prevention campaigns. OBJECTIVES: To
      provide baseline data for targeted sexually transmitted infection (STI) and HIV
      infection prevention interventions by studying parameters of sexual behavior and
      knowledge of HIV infection and STIs, measuring health-seeking behavior related to
      STIs, and measuring gonorrhea, Chlamydia, syphilis, and HIV-1 prevalences.
      DESIGN: Population-based survey with stratified sampling by age group from
      randomly selected households in a suburb of Mombasa, Kenya. METHODS: A standard
      questionnaire was administered to 1497 consenting adults between the ages of 15
      and 49 years who lived in randomly selected households. Urine and blood samples
      were obtained for the estimation of gonorrhea, chlamydial infection, syphilis,
      and HIV-1 infection prevalences. RESULTS: Sexual activity in the past 12 months
      was limited to one partner in all age groups for most sexually active men (68%)
      and women (88%). More men than women reported two or more partners in the past 12
      months (23% vs. 5%, respectively). Almost one half of those persons in the 15- to
      19-year-old age group (56% of boys and 48% of girls) were sexually active. Condom
      use was low with all sexual partners, more so for women than for men. Reported
      STI symptoms in the past 12 months were high for both men and women. Knowledge of
      STI symptoms and HIV infection was present but incomplete. Overall HIV
      seroprevalence was 10.8%, with significantly higher rates among women (13.7%)
      than among men (8.0%). HIV seroprevalence in the 15- to 19-year-old age group was
      3.2%. Female gender, Protestant religion, Catholic religion, and being divorced,
      separated, and widowed were significantly associated with HIV seroprevalence.
      Prevalences of gonorrhea, chlamydial infection, and syphilis were 0.9%, 1.5%, and
      1.3%, respectively. CONCLUSIONS: This study emphasizes the vulnerability of young
      adults, in particular young women, to HIV infection and the need for intensive
      interventions in this group. The low use of condoms, incomplete knowledge of HIV
      infection and STIs, the high number of reported STIs, and the relatively low HIV
      1 seroprevalence among the 15- to 19-year-old group indicate a large need for
      intensive STI and HIV infection prevention programs, especially for the 15- to 19
      year-old age group.

PMID- 12473843
TI  - Prevalence of hepatitis C virus infection and risk for hepatocellular carcinoma
      and non-Hodgkin lymphoma in AIDS.
AB  - Hepatitis C virus (HCV) infection is highly prevalent in some subpopulations with
      AIDS. HCV is linked to hepatocellular carcinoma (HCC) and possibly non-Hodgkin
      lymphoma (NHL), but the impact of AIDS on these associations is uncertain. We
      used U.S. registry data to study HCC and NHL risk in 304,411 adults with AIDS,
      comparing cohort subgroups with high prevalence (hemophiliacs and injection drug
      users) or low prevalence (homosexual men, heterosexuals, and others) of HCV
      infection. The ratio of observed to expected cancer cases (standardized incidence
      ratio [SIR]) measured risk relative to the general population. Sixty-one HCC
      cases were observed (SIR, 7.5; 95% confidence interval, 5.7-9.6). Risk for HCC
      was higher in subgroups with high prevalence of HCV infection than in subgroups
      with low prevalence of HCV infection (SIR: 11.4 versus 5.5, respectively; p
      =.004). Subjects developed the following NHL grades: low, 35 cases; intermediate,
      1035 cases; high, 784 cases; and unspecified, 1395 cases. For each NHL grade,
      SIRs were highest in subgroups with low prevalence of HCV infection. These data
      suggest an effect of HCV infection on HCC risk among adults with AIDS. On the
      other hand, NHL risk was not higher for groups in whom HCV infection was
      prevalent.

PMID- 12473844
TI  - Clostridium difficile-associated diarrhea in patients with HIV: a 4-year survey.

PMID- 12473845
TI  - Progression of cervical disease among adolescents infected with HIV with low
      grade squamous intraepithelial lesions.

PMID- 12473846
TI  - Antiapoptotic activity by HIV protease inhibitors either alone or boostered.

PMID- 12473847
TI  - Carotid intima-media thickness, arterial stiffness and risk of cardiovascular
      disease: current evidence.
AB  - AIMS: Over recent decades the interest in cardiovascular epidemiology has
      broadened from studies on causes and consequences of elevated cardiovascular risk
      factors to include research on causes and consequences of atherosclerosis and
      associated arterial wall abnormalities. One of the underlying reasons was that
      established cardiovascular risk factors were insufficiently accurate in
      identifying those individuals who will suffer from cardiovascular disease in the
      future and measures of subclinical atherosclerosis may enhance the precision of
      these predictions and thus enable better-tailored medical care to be provided.
      The usefulness of measuring subclinical atherosclerosis is conditional on
      evidence that presence of subclinical atherosclerosis confers an increased risk
      of cardiovascular disease and that favourable changes in subclinical
      atherosclerosis parallel reductions in risk. We aimed at providing an overview of
      epidemiological data on carotid intima-media thickness (CIMT) and arterial
      stiffness measurements and their relation to risk of cardiovascular disease.
      METHODS: We reviewed the published epidemiological data. RESULTS AND CONCLUSION:
      CIMT is a good indicator of cardiovascular risk and provides a graded measure of
      vascular damage: no clear CIMT level above which the cardiovascular risk appears
      to increase considerably The evidence for arterial stiffness, assessed as carotid
      distensibility or aortic pulse wave velocity, as an indicator for risk of
      cardiovascular disease is restricted to subjects with either hypertension or end
      stage renal disease or based on small studies in renal transplant patients and
      elderly. Evidence to indicate that information on carotid intima-media thickness
      or arterial stiffness, additional to established cardiovascular risk factors,
      helps to distinguish subjects into those with a high and those with a low
      absolute risk of cardiovascular disease is limited, but needed. Also, information
      on the direct comparison of both arterial stiffness measures in their ability to
      predict cardiovascular disease is needed.

PMID- 12473848
TI  - Apolipoprotein E genotype, smoking and cardiovascular disease.

PMID- 12473849
TI  - A new twist on hypertension-causing mutations in the epithelial Na+ channel.

PMID- 12473850
TI  - Are the new single nucleotide polymorphisms (SNPs) relevant for hypertensive
      populations?

PMID- 12473851
TI  - Arterial stiffness and prediction of cardiovascular risk.

PMID- 12473852
TI  - The finger volume pulse and assessment of arterial properties.

PMID- 12473853
TI  - AT1 receptor antagonists: vascular protection beyond blood pressure reduction?

PMID- 12473854
TI  - Is the autonomic dysfunction the missing link between panic disorder,
      hypertension and cardiovascular disease?

PMID- 12473855
TI  - Statins: cholesterol, blood pressure and beyond.

PMID- 12473856
TI  - Inducible nitric oxide synthase and cardiac dysfunction in salt-sensitive
      hypertension.

PMID- 12473857
TI  - The reactive oxidative species-renin-angiotensin system link.

PMID- 12473858
TI  - Risk factors for non-haemorrhagic stroke and the effect of lipid-modifying
      therapy.

PMID- 12473859
TI  - Hypertension prevalence, control and survivorship in an Afro-Caribbean
      population.
AB  - OBJECTIVE: To evaluate the prevalence, distribution, awareness, treatment and
      control of hypertension in an Afro-Caribbean population, and their relationship
      to 4-year survival. DESIGN Population-based prospective cohort study. SETTING AND
      PARTICIPANTS: Simple random sample of Barbados-born citizens (4709 persons; 84%
      participation), with 4-year follow-up. INTERVENTIONS: None. MAIN OUTCOME
      MEASURES: Hypertension prevalence, awareness, treatment and control were
      evaluated at baseline. Four-year cumulative mortality was assessed by the product
      limit method and relative risk of mortality by the Cox proportional hazards
      method. RESULTS: Mean systolic (SBP) and diastolic (DBP) blood pressure were
      higher among black than white participants. In the black population, age-specific
      prevalence of hypertension increased from 32.7% in men and 34.0% in women at 40
      49 years of age to 63.4% in men and 85.5% in women at ages 80 years and older,
      with an overall prevalence of 55.4%. Hypertension awareness, treatment and
      control rates were 62.5, 53.8 and 18.5%, respectively. Compared to DBP 80 mmHg,
      the presence of a DBP between 80 and 84 mmHg, 100-109 mmHg and > or = 110 mmHg
      was associated with adjusted death rate ratios of 1.6, 1.7 and 2.0, respectively.
      Systolic blood pressure was not related to the risk of cardiovascular mortality,
      after adjustment for age or other potential confounders. Hypertensives were at
      modestly increased risk of 4-year cardiovascular mortality [RR = 1.4; 95%
      confidence inteval (CI) (1.0, 2.0)], while treated uncontrolled hypertensives
      were at increased risk of all cause [RR = 1.4; 95% CI (1.0, 1.9)] and
      cardiovascular [RR = 1.6; 95% CI (1.1, 2.5)] mortality. CONCLUSIONS: High rates
      of hypertension in this population coexist with conservative levels of treatment
      and low rates of blood pressure control. In contrast to other reports, elevated
      SBP was not independently associated with increased risk of cardiovascular
      mortality. The modest impact of elevated blood pressure might partly explain the
      comparatively lower hypertension-related mortality rates in populations of
      Caribbean-origin. Treated uncontrolled hypertensives are at increased risk of
      early mortality, signaling the need for strict blood pressure control in this
      group.

PMID- 12473860
TI  - Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking
      hypertensive men.
AB  - OBJECTIVE: Smoking is a risk factor for increased carotid artery intima-media
      thickness (IMT). The apolipoprotein E (apoE) 4 allele has been associated with
      cardiovascular diseases, but the role of apoE in regard to intima-media thickness
      (IMT) has remained controversial. The objective was to investigate whether there
      is some gene-environment interaction between smoking and apoE polymorphism.
      DESIGN Cross-sectional case-control study. METHODS: IMTs of 511 hypertensive and
      control men were measured ultrasonographically and the apoE genotypes were
      determined. Genotypes with the 4 allele were pooled into one group and the
      genotypes without it into another. RESULTS: A significant interaction between the
      4 allele and smoking affecting IMT was observed among the hypertensive smokers,
      as assessed by analysis of covariance. The mean carotid IMT was significantly
      greater (1.01 versus 0.90 mm, P = 0.003) in the 4 carriers than in the subjects
      without 4 among the hypertensive smokers. The number of plaques was also
      significantly higher. No differences were found in the other subjects
      (hypertensive non-smokers or controls). Linear regression analysis indicated that
      the 4 allele was an independent determinant of IMT in the hypertensive smokers
      but not in the other subjects. The estimated average effect of the 4 allele on
      the mean IMT in the hypertensive smokers was 0.088 mm (P < 0.001). In the oldest
      age group, the interaction of smoking and 4 was also seen in the control
      subjects. CONCLUSION: The findings suggest that the 4 carriers are particularly
      susceptible to the atherogenic effects of smoking. This interaction is
      particularly clear in hypertensive subjects.

PMID- 12473861
TI  - A frameshift mutation of beta subunit of epithelial sodium channel in a case of
      isolated Liddle syndrome.
AB  - BACKGROUND: Liddle syndrome is an autosomal dominant form of salt-sensitive
      hypertension caused by mutations in the epithelial sodium channel expressed in
      the distal nephron playing an essential role in Na absorption. All reported
      mutations in Liddle syndrome are either missense mutations or frameshift
      mutations destroying the PY motif closer to the C-terminus of the beta or gamma
      subunits causing the situation that the epithelial sodium channels are not
      degraded and sodium is pooled and thus hypertension and hypokalemia are caused.
      METHODS: We sequenced the C-terminus of the beta or gamma subunits of the
      epithelial sodium channel in a Japanese family of a patient clinically diagnosed
      as having Liddle syndrome. RESULTS: As a result, we found in the proband, a
      frameshift mutation of the beta subunit caused by a single cytosine insertion at
      the codon 595, introducing a new stop codon at 605 and deleting the last 34 amino
      acids from the normally encoded protein. CONCLUSION: This mutation is carried by
      neither parent (with paternity proven) and hence confirms this has occurred as a
      event within this family.

PMID- 12473862
TI  - Liddle's syndrome associated with a point mutation in the extracellular domain of
      the epithelial sodium channel gamma subunit.
AB  - OBJECTIVE: To characterize novel type of mutations of the epithelial sodium
      channel (ENaC) or subunits in patients with Liddle's syndrome, an autosomal
      dominant form of hypertension. PATIENTS AND METHODS: DNA samples from two
      probands with early-onset, treatment-resistant hypertension and suppressed plasma
      renin activity were initially screened for mutations in the C-terminal exons of
      the ENaC or subunit genes, using amplification by polymerase chain reaction and
      direct DNA sequencing. RESULTS: Two novel mutations causing Liddle's syndrome
      were identified. One mutation due to a single nucleotide insertion in the exon 13
      of ENaC results in a frameshift at codon 601 and abrogates the PY motif similar
      to all the previously described ENaC mutations causing Liddle's syndrome. The
      other mutation, substituting serine for asparagine at codon 530 (Asn530Ser) of
      the extracellular loop of ENaC subunit, was found in a 25-year-old man with
      hypertension, hypokalemia, low plasma renin activity and low serum aldosterone
      levels. Hypertension and hypokalemia favorably responded to amiloride or
      triamterene administration both in the proband and his affected mother.
      Expression of the mutant Asn530Ser ENaC subunit in oocytes demonstrated a two
      fold increase in ENaC activity, compared with the wild-type, without a
      significant change in cell surface expression of ENaC. This suggests that the
      gammaENaC Asn530Ser mutation increases the channel open probability, and is
      consistent with an abnormally high sodium reabsorption in the distal nephron.
      CONCLUSIONS: This study describes the first mutation located in the extracellular
      domain of an ENaC subunit associated with an increased ENaC activity and Liddle's
      syndrome.

PMID- 12473863
TI  - Functionality of two new polymorphisms in the human renin gene enhancer region.
AB  - BACKGROUND: The production of renin, which catalyses the rate-limiting step of
      the renin-angiotensin system, is strongly stimulated by a 225 bp enhancer element
      in the distal region of the promoter of the human gene (-5777 to -5552).
      OBJECTIVE: To demonstrate the major role played by this enhancer in decoy
      experiments, to identify variants in this region, and to determine their effects
      on renin gene transcription. METHODS AND RESULTS: We used this element as a decoy
      for transcription factors in human choriodecidual cells. The activity of the
      renin gene promoter was inhibited by 95% in the presence of this 225 bp enhancer
      element. This confirmation of the key role of this element suggested that changes
      in this region would be likely to affect renin gene expression. We therefore
      sequenced 70 genomic DNAs to identify variations in this region. We identified
      two new single nucleotide polymorphisms (SNPs) downstream from the 225 bp
      enhancer element at positions -5434 and -5312. We transfected choriodecidual
      cells with the four variants and found that a 592 bp region (-5870 to -5312)
      including the 225 bp element and the two SNPs had stronger enhancer activity than
      the 225 bp element alone, and that levels of transcription were 45% greater with
      the -5312T variant than with the -5312C variant, whereas none of the -5434
      variants had an effect on renin transcription. Cis-regulatory elements close to
      the -5312 variant were identified in gel mobility shift assays on the basis of
      specific interactions between human choriodecidual cell nuclear extracts and an
      oligonucleotide including this polymorphism. CONCLUSION: This study demonstrates
      that the human renin enhancer not only comprises the 225 bp element, but also
      extends to the region containing the -5312 SNP.

PMID- 12473864
TI  - Identification of blood pressure quantitative trait loci that differentiate two
      hypertensive strains.
AB  - OBJECTIVE: To describe genetic loci that differentiate blood pressures in two
      genetically hypertensive strains, the Dahl salt-sensitive (S) rat and the Albino
      Surgery (AS) rat. METHODS: A genome scan was performed using 222 genetic markers
      on an F2 population derived from two hypertensive strains, S and AS. The F2 rats
      were fed 8% NaCl for 5 weeks before blood pressure measurements were taken.
      RESULTS: Three blood pressure quantitative trait loci (QTL) were detected, one on
      each of rat chromosomes (RNO) 2, 4 and 8. The QTL on RNO4, unlike those on RNO2
      and RNO8, was not detected in any of the previous seven linkage analyses reported
      with the S rat as one of the parental strains. Interactions between genetic loci
      throughout the genome were sought and interactions involving RNO4 with RNO8 and
      RNO4 with RNO14 were found. Including the new RNO4 locus identified in the
      present study, 16 distinct regions of the S rat genome have been demonstrated, by
      linkage analyses, to harbour loci that control blood pressure in the S rat.
      CONCLUSIONS: Increased blood pressure in two hypertensive strains, S and AS, is
      differentially regulated by genetic factors present on RNOs 2, 4 and 8.
      Therefore, of the 16 distinct genomic regions known to harbour blood pressure QTL
      in S rats, 13 are likely to contain blood pressure alleles that function
      similarly in the S rat and the AS rat, whereas three regions differentiate the
      two strains.

PMID- 12473865
TI  - Augmentation index is associated with cardiovascular risk.
AB  - OBJECTIVES: Augmentation index is a parameter measured by pulse wave analysis
      (PWA) and is used as a surrogate measure of arterial stiffness. The aim of this
      study was to assess whether augmentation index is associated with cardiovascular
      risk, as well as to evaluate whether the determinants of augmentation index are
      different in patients with cardiovascular disease compared to healthy subjects.
      DESIGN AND METHODS: We related augmentation index to risk scores in 216 subjects
      with or without a cardiovascular disease. Subjects without cardiovascular disease
      were classified according to the 'coronary risk chart' of the European Society of
      Cardiology (ESC), and those with cardiovascular disease were classified using the
      SMART (Second Manifestations of ARTerial disease) score and the EPOZ
      (Epidemiological Prevention study Of Zoetermeer) function. Augmentation index was
      derived by PWA using carotid applanation tonometry. Augmentation index was also
      correlated to age, blood pressure, heart rate, smoking history, cholesterol,
      height, body mass index and gender in subjects categorized as healthy or with
      cardiovascular disease. RESULTS: Augmentation index significantly increased with
      increasing risk scores (P < 0.0001) and was significantly correlated to
      cardiovascular risk (ESC: P < 0.0001; SMART: P < 0.0001; EPOZ: P < 0.0001). In
      subjects with and without cardiovascular disease, augmentation index was
      correlated with diastolic blood pressure, heart rate, height and gender. Age was
      found to be significantly correlated with augmentation index only in healthy
      subjects but not in those with atherosclerotic disease. CONCLUSIONS: Our findings
      suggest that augmentation index may be a useful marker of cardiovascular risk.
      Further studies are required to investigate the relationship between age and
      augmentation index in subjects with atherosclerotic disease.

PMID- 12473866
TI  - Pulse wave velocity and the second derivative of the finger photoplethysmogram in
      treated hypertensive patients: their relationship and associating factors.
AB  - OBJECTIVES: To clarify the factors influencing two measures of arterial
      stiffness, pulse wave velocity (PWV) and the second derivative of the finger
      photoplethysmogram (SDPTG), and to evaluate their relationship in treated
      hypertensive subjects. SUBJECTS AND METHODS: The subjects were 294 hypertensive
      patients aged 32-91 years (mean, 61.4 +/- 10.5 years). After blood pressure (BP)
      was measured, carotid-femoral PWV and SDPTG were recorded with the subjects in
      the supine position, with the aid of an automatic device. For assessing SDPTG, we
      focused mainly on the ratios of the absolute value of the height of the early
      negative 'b' wave (B) and that of the late re-decreasing 'd' wave (D) to that of
      the initial positive 'a' wave (A), namely the B : A and D : A ratios, and the
      aging index (AGI). Factors influencing PWV and SDPTG indices, and the
      relationship between PWV and SDPTG indices were evaluated by bivariate and
      multivariate analyses. RESULTS: According to multiple linear regression analysis,
      age, systolic blood pressure (SBP), and heart rate (HR) were variables
      independently and positively correlated with PWV. The age and BP were
      significantly and independently related to SDPTG indices; there were positive
      correlations with the D : A ratio and AGI, and negative correlations with the B :
      A ratio. HR was correlated negatively with the D : A ratio and AGI, and
      positively with the B : A ratio. According to multiple logistic regression
      analysis, adjusted-odds ratios of high PWV, low B : A ratio, high D : A ratio,
      and high AGI were significantly elevated among the elderly and among the subjects
      with uncontrolled BP. Although PWV and the SDPTG indices were associated with
      common factors, including age and BP, bivariate analysis revealed that they were
      only weakly correlated with each other. CONCLUSIONS: The results suggest that in
      hypertensive patients, PWV and SDPTG provide different information about arterial
      properties at central and peripheral sites.

PMID- 12473868
TI  - Remodelling of the left anterior descending artery in a porcine model of
      supravalvular aortic stenosis.
AB  - BACKGROUND: Knowledge of the adaptive mechanisms of structure and function of
      coronary arteries in response to physical stress is important in human health and
      disease. OBJECTIVE: To gain a better understanding of the adaptive mechanisms of
      morphology in the zero-stress state of the coronary arteries in a porcine model
      of hypertension and flow overload. METHODS: The effects of simultaneous increases
      in pressure and flow were examined by studying the left anterior decending (LAD)
      artery in supravalvular aortic stenosis (SVAS). In this model, the pressure is
      uniformly increased along the length of the LAD artery trunk, whereas the
      increase in flow is significantly greater in the proximal than in the distal
      artery. The longitudinal variation of vessel dimension, medial and adventitial
      area, opening angle and residual strains were examined in the LAD arteries of
      aortic-banded (n = 5) and control (n = 5) pigs. RESULTS: Our results show that
      the wall shear stress was normalized, whereas the circumferential stress was
      increased, in the proximal portion of the LAD artery after 5 weeks of SVAS. In
      the distal artery, both shear and circumferential stresses were normalized. The
      vessel wall area was also increased in the remodelled vessels as the result of an
      increase in the medial and adventitial area. CONCLUSION: The major conclusion of
      this study is that, in the SVAS model, the remodelling process of the coronary
      artery is consistent with normalization of shear stress despite an increase in
      the circumferential stress. Furthermore, the remodelling of the zero-stress state
      is also dominated by flow overload.

PMID- 12473867
TI  - AT1-receptor blockade improves augmentation index: a double-blind, randomized,
      controlled study.
AB  - OBJECTIVE: Arterial hypertension leads to vascular structural and functional
      adaptive processes that are influenced by angiotensin II. To analyze the effects
      of AT receptor blockade on vascular function we determined augmentation index.
      METHODS AND DESIGN: A total of 60 patients (53 +/- 10 years) with essential
      hypertension mean [blood pressure (BP) 173 +/- 9/102 +/- 3 mmHg] were randomized
      to 6 weeks double-blind therapy with either valsartan 80 mg, hydrochlorothiazide
      (HCTZ) 25 mg or placebo once daily. Radial artery pressure wave was determined by
      applanation tonometry before and after therapy. The central aortic pressure wave
      and augmentation index were derived by a generalized transfer function. RESULTS:
      Active therapy similarly reduced systolic and diastolic blood pressure (SBP, DBP)
      (valsartan: -22 +/- 18/-11 +/- 11 mmHg, HCTZ: -22 +/- 23/-14 +/- 14 mmHg, all P <
      0.001). However, only valsartan, but no HCTZ reduced the augmentation index
      (valsartan: from 148 +/- 18 to 126 +/- 24, < 0.001; HCTZ: from 145 +/- 19 to 142
      +/- 18, NS). Augmentation index reduction was greater with valsartan (-22 +/- 11)
      than with HCTZ (-3 +/- 11) and placebo (0 +/- 13) (P < 0.01 for pairwise
      comparison of valsartan versus HCTZ and placebo after Bonferroni correction).
      Differences remained significant after taking changes in supine BP into account
      (covariance, P < 0.01). CONCLUSIONS: Blood pressure reduction with the AT
      receptor antagonist valsartan but not with hydrochlorothiazide reduced the
      augmentation index in essential hypertension.

PMID- 12473869
TI  - Skin capillary density changes in normal pregnancy and pre-eclampsia.
AB  - BACKGROUND: Many abnormalities are known to occur in the microcirculation in
      essential hypertension, including reduction in capillary density or rarefaction.
      Peripheral vasodilatation and angiogenesis are critical components of the
      physiological adaptation in normal pregnancy. OBJECTIVE: To investigate the
      hypothesis that defective angiogenesis, reflected in capillary rarefaction, may
      be implicated in the clinical syndrome of pre-eclampsia. METHODS: We used
      intravital capillary video-microscopy to study functional (baseline) and
      structural (after maximization with venous congestion) skin capillary density in
      22 healthy normotensive pregnant women and compared our findings with those in 22
      non-pregnant age-matched healthy controls and 11 women whose pregnancies were
      complicated by pre-eclampsia. RESULTS: We found that both functional and
      structural capillary density increased during normal pregnancy. Capillary density
      in pre-eclamptic women was significantly lower both at baseline and after
      maximization. Skin capillary density appeared to be inversely correlated with
      blood pressure during pregnancy and in pre-eclampsia. CONCLUSIONS: A low
      capillary density may account, in part, for the failure of blood pressure to
      decrease in pre-eclamptic pregnancies, and may reflect the maladaptive
      cardiovascular response that is part of the pre-eclampsia syndrome.

PMID- 12473870
TI  - Sympathetic and cardiac baroreflex function in panic disorder.
AB  - BACKGROUND: Recent reports have demonstrated increased cardiac risk, and an
      association with essential hypertension in patients with panic disorder. The
      cause is not known, but possibly involves sympathetic nervous activation. In this
      study, we evaluated the arterial baroreflex control of vascular sympathetic
      nervous outflow and cardiac baroreflex function in panic disorder patients.
      METHODS AND RESULTS: We studied nine patients suffering from panic disorder and
      ten healthy subjects. Microneurographic recording of muscle sympathetic nerve
      activity (MSNA) was made with simultaneous recording of blood pressure (BP) and
      electrocardiogram (ECG). The relationship between MSNA and spontaneous diastolic
      BP (DBP) changes was assessed at rest and was defined as the arterial baroreflex
      control of MSNA. Cardiac baroreflex function was assessed using the sequence
      method. Anxiety was assessed using Spielberger's anxiety state and trait
      inventory. The slopes of the relationship between MSNA and DBP were more negative
      (steeper) in the panic disorder group compared with the control subjects (-5.97
      +/- 0.45 versus -3.06 +/- 0.43 bursts/100 heart beats per mmHg, P < 0.001). Panic
      disorder patients had significantly higher state and trait anxiety scores. The
      slope of the relationship between MSNA and diastolic BP was significantly related
      to the trait anxiety of the subjects. There was no difference between the cardiac
      baroreflex sensitivity between the two groups. CONCLUSION: Patients with panic
      disorder exhibit enhanced reflex gain of the arterial baroreflex control of MSNA
      but no change in the cardiac baroreflex. While any clinical significance this
      observation might have in relation to increased cardiac risk in panic disorder,
      or to concordance with essential hypertension, remains to be elucidated,
      increased reactivity of vasoconstricting sympathetic nerves may be a trait
      characteristic in this cohort.

PMID- 12473871
TI  - Factors influencing acute ischaemia-induced renal hypertension in rats.
AB  - OBJECTIVE: To verify if the acute hypertension that occurs after reversal of
      complete renal ischaemia is related to the duration of ischaemia, is different in
      one-kidney (1K) and two-kidney (2K) rats, and is prevented by angiotensin
      receptor blockade. METHODS: Four groups of Sprague-Dawley rats anaesthetized with
      pentobarbitone were studied before, during and after a reversible, complete renal
      ischaemia achieved by functional right nephrectomy. RESULTS: In 1K rats (group 1,
      n = 21), reopening of right renal hilum after functional right nephrectomy of
      180, 60 and 30 min was followed by peak increases in systolic blood pressure of
      76.0 10.1 mmHg, 36.5 10.0 mmHg and 18.4 4.4 mmHg, respectively (mean SEM). In 2K
      rats (group 2, n = 21), functional right nephrectomy of 180, 60 and 30 min was
      followed by smaller increases in blood pressure of 49.8 7.6 mmHg, 5.9 3.3 mmHg
      and 8.3 2.1 mmHg, respectively. Plasma renin activity was directly related to the
      duration of functional right nephrectomy, and was greater in 1K rats. In group 3,
      irbesartan administered to 1K rats (n = 8) during functional right nephrectomy
      almost completely prevented the development of hypertension upon reopening. In
      group 4, labetalol injected intravenously in 1K rats (n = 3) did not prevent the
      blood pressure surge at reopening (49.2 8.5 mmHg). CONCLUSIONS: An experimental
      acute renal hypertension may be elicited both in 1K and in 2K rats and for
      functional right nephrectomy of 30, 60 and 180 min duration. The increase in
      blood pressure is proportional to the duration of functional right nephrectomy
      and greater in 1K than in 2K rats. The experimental acute renal hypertension is
      due to acute release of renin and generation of endogenous angiotensin II, and is
      specifically prevented by the angiotensin II type 1 receptor blocker, irbesartan,
      but not by labetalol.

PMID- 12473872
TI  - A 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor reduces hypertensive
      nephrosclerosis in stroke-prone spontaneously hypertensive rats.
AB  - BACKGROUND: Recent studies suggest that 3-hydroxy-3-methylglutaryl co-enzyme A
      reductase inhibitors (statins) exert their protective effects against
      cardiovascular diseases independently of their cholesterol-decreasing effects.
      OBJECTIVE: To clarify the effect of a statin on hypertensive nephrosclerosis.
      METHODS: We treated stroke-prone spontaneously hypertensive rats (spSHRs)
      chronically, starting at the age of 4 weeks, with cerivastatin (2 mg/kg per day
      by gavage) or vehicle. Physiological parameters, plasma chemistry and urine
      protein excretion were analysed. At 14 weeks of age, the rats had their kidneys
      removed for use in assays. RESULTS: Compared with vehicle treatment, statin
      treatment reduced proteinuria and renal injury independently of blood pressure
      and cholesterol concentrations in spSHRs. Although expression of adhesion
      molecules and infiltration of inflammatory cells were not different whether or
      not cerivastatin treatment was used, renal fibrosis was significantly reduced in
      statin-treated spSHRs. We also found that expression of transforming growth
      factor-beta1 in kidneys was significantly inhibited in statin-treated spSHRs.
      CONCLUSION: Cerivastatin prevents or retards hypertension-induced renal injury
      via inhibition of renal fibrosis and proteinuria. These results show the
      potential of statins as protective tools against proteinuric renal diseases,
      independent of their cholesterol-decreasing effects.

PMID- 12473873
TI  - Aminoguanidine inhibits mitogen-activated protein kinase and improves cardiac
      performance and cardiovascular remodeling in failing hearts of salt-sensitive
      hypertensive rats.
AB  - OBJECTIVES: Congestive heart failure (CHF) is associated with inducible nitric
      oxide synthase (iNOS) expression in the failing human heart, and recently we have
      also demonstrated that iNOS expression was upregulated in Dahl salt-sensitive
      hypertensive (DS) rats with cardiac dysfunction and vascular remodeling. Thus, we
      evaluated whether aminoguanidine (AG), a selective iNOS inhibitor, protects
      against cardiac dysfunction and vascular remodeling in DS rats receiving a high
      salt diet. METHODS: AG (DSHF-AG, 150 mg/kg per day) or vehicle (DSHF-V) were
      given from left ventricular hypertrophy stage (11 weeks) to CHF stage (18 weeks)
      for 7 weeks. The left ventricular end-systolic pressure-volume relationship
      (contractility: E(es)) was measured by conductance catheter. RESULTS: Decreased
      E(es) in DSHF-V was significantly ameliorated by AG treatment. The iNOS mRNA and
      protein expression and phospho-p42/p44 extracellular signal-regulated kinase
      (ERK) activities in the left ventricle were significantly upregulated in DSHF-V
      compared with control rats, and significantly suppressed in DSHF-AG compared with
      DSHF-V. DSHF-V showed a significant increase of perivascular fibrosis and
      myocardial fibrosis, with all these parameters being significantly improved by AG
      treatment. CONCLUSIONS: We demonstrated that the selective iNOS inhibitor, AG,
      may be at least a potential therapeutic strategy for treating CHF and
      cardiovascular remodeling.

PMID- 12473874
TI  - Long-term angiotensin II inhibition increases mitochondrial nitric oxide synthase
      and not antioxidant enzyme activities in rat heart.
AB  - OBJECTIVE: To provide insight into the subcellular mechanisms involved in the
      improvement of cardiovascular structure and function by long-term inhibition of
      the renin-angiotensin system. DESIGN: The activities of antioxidant enzymes and
      mitochondrial free radical production were determined in the heart of control
      (C), enalapril-treated (E), and losartan-treated (L) rats to test the hypothesis
      of increased antioxidant enzyme activities and participation of mitochondria in
      the effects of chronic treatments with angiotensin II inhibitors. METHODS: At 6
      and 18 months of treatment, superoxide dismutases (SOD), Se-glutathione
      peroxidase, and catalase activities were determined in left ventricle homogenates
      by spectrophotometric methods and nitric oxide (NO) production in
      submitochondrial membranes by the oxyhemoglobin oxidation assay. The maximal rate
      of hydrogen peroxide (H2O2) production by submitochondrial membranes was also
      evaluated at 18 months by the scopoletin-horseradish peroxidase method. RESULTS:
      No significant increase was found in the antioxidant enzymes measured. At 6
      months, Mn-SOD was actually decreased in E and catalase in both E and L, whereas
      at 18 months Se-glutathione peroxidase was decreased in L. Production of NO by
      submitochondrial particles was 64% higher at 6 months in E and 105% higher at 18
      months in E and L. Maximal hydrogen peroxide production was lower at 18 months in
      both groups. CONCLUSIONS: Results do not support the hypothesis of an increase in
      antioxidant enzyme activity by long-term treatment with angiotensin II inhibitors
      as previously suggested and point towards a role for the NO produced by
      mitochondrial nitric oxide synthase (mtNOS) in the protective effect of these
      drugs.

PMID- 12473875
TI  - Regression of ventricular and vascular hypertrophy: are there differences between
      structurally different angiotensin-converting enzyme inhibitors?
AB  - OBJECTIVES: It is well established that angiotensin-converting enzyme (ACE)
      inhibitors (ACEI) reduce blood pressure (BP) and hypertrophy of the left
      ventricle and vessels. The aim of our study was to compare chemically different
      ACEIs regarding their ability to modulate left ventricular and media hypertrophy,
      ACE activity and plasma endothelin-1 concentrations in spontaneously hypertensive
      rats (SHRs). DESIGN: After establishing equi-effective dose regimes, SHRs were
      treated (3 months) with captopril, enalapril, fosinopril or ramipril (2 x 25, 10,
      20 or 1 mg/kg per day or corresponding 1% doses for studying blood pressure
      independent effects). METHODS AND RESULTS: Systolic blood pressure was reduced in
      SHRs receiving high doses of captopril, enalapril, fosinopril or ramipril (-61, 
      54, -35 and -47 mmHg), whereas low doses were ineffective. Left ventricular
      weight was decreased in animals treated with high doses
      (captopril/enalapril/fosinopril/ramipril: -17/-19/-17/-19%), but not low doses of
      agents. Media thickness of thoracal aorta was reduced by administering high doses
      (captopril/enalapril/fosinopril/ramipril: -31/-32/-27/-26%) and low doses (-16/
      22/-22/-19%) of agents. ACE activity was reduced in heart, aorta and kidney of
      rats treated with high and low doses of all ACE inhibitors, whereby high doses
      showed more pronounced effects. Plasma endothelin-1 concentrations were not
      altered. A blood-pressure-ineffective treatment with an AT -antagonist revealed
      similar effects on cardiovascular hypertrophy. CONCLUSIONS: ACEIs reduce
      cardiovascular hypertrophy uniformly via an AT -receptor- mediated mechanism,
      reinforcing the opinion that ACEI effects are indeed class effects. The
      significance of local renin-angiotensin systems was confirmed by antihypertrophic
      effects in the aorta that were apparent in the absence of any blood pressure
      reduction.

PMID- 12473876
TI  - Non-pharmacological treatment of hypertension in primary health care: a 2-year
      open randomized controlled trial of lifestyle intervention against hypertension
      in eastern Finland.
AB  - OBJECTIVE: To assess whether lifestyle counselling is effective in non
      pharmacological treatment of hypertension in primary health care. DESIGN: Open
      randomized controlled trial. SETTING: Ten municipal primary health care centres
      in eastern Finland. PATIENTS: Seven hundred and fifteen subjects aged 25-74 years
      with systolic blood pressure 140-179 mmHg and/or diastolic blood pressure 90-109
      mmHg or antihypertensive drug treatment. INTERVENTIONS: Systematic health
      counselling given by local public health nurses for 2 years. MAIN OUTCOME
      MEASURES: Blood pressure, lipids and lifestyle data were collected annually.
      RESULTS: Among participants with no antihypertensive drug treatment, the net
      reductions after 1 year both in systolic blood pressure [-2.6 mmHg; 95%
      confidence interval (CI), -4.7 to -0.5 mmHg] and in diastolic blood pressure (
      2.7 mmHg; 95% CI, -4.0 to -1.4 mmHg) were significant in favour of the
      intervention group. This difference in blood pressure change was maintained
      during the second year. In participants with antihypertensive drug treatment, no
      significant difference in blood pressure reduction was seen between the groups
      during the study. CONCLUSIONS: A relatively modest, but systematic counselling in
      primary health care can, at least among untreated hypertensive subjects, produce
      reductions in blood pressure levels that are modest for the individual, but very
      important from the public health point of view.

PMID- 12473877
TI  - Risk factors for non-haemorrhagic stroke in patients with coronary heart disease
      and the effect of lipid-modifying therapy with pravastatin.
AB  - OBJECTIVE: To determine the relative importance of recognised risk factors for
      non-haemorrhagic stroke, including serum cholesterol and the effect of
      cholesterol-lowering therapy, on the occurrence of non-haemorrhagic stroke in
      patients enrolled in the LIPID (Long-term Intervention with Pravastatin in
      Ischaemic Disease) study. DESIGN: The LIPID study was a placebo-controlled,
      double-blind trial of the efficacy on coronary heart disease mortality of
      pravastatin therapy over 6 years in 9014 patients with previous acute coronary
      syndromes and baseline total cholesterol of 4-7 mmol/l. Following identification
      of patients who had suffered non-haemorrhagic stroke, a pre-specified secondary
      end point, multivariate Cox regression was used to determine risk in the total
      population. Time-to-event analysis was used to determine the effect of
      pravastatin therapy on the rate of non-haemorrhagic stroke. RESULTS: There were
      388 non-haemorrhagic strokes in 350 patients. Factors conferring risk of future
      non-haemorrhagic stroke were age, atrial fibrillation, prior stroke, diabetes,
      hypertension, systolic blood pressure, cigarette smoking, body mass index, male
      sex and creatinine clearance. Baseline lipids did not predict non-haemorrhagic
      stroke. Treatment with pravastatin reduced non-haemorrhagic stroke by 23% (P =
      0.016) when considered alone, and 21% (P = 0.024) after adjustment for other risk
      factors. CONCLUSIONS: The study confirmed the variety of risk factors for non
      haemorrhagic stroke. From the risk predictors, a simple prognostic index was
      created for non-haemorrhagic stroke to identify a group of patients at high risk.
      Treatment with pravastatin resulted in significant additional benefit after
      allowance for risk factors.

PMID- 12473878
TI  - Amplifier and resisters.

PMID- 12473879
TI  - Primary repair of penetrating colon injuries: a systematic review.
AB  - PURPOSE: Primary repair of penetrating colon injuries is an appealing management
      option; however, uncertainty about its safety persists. This study was conducted
      to compare the morbidity and mortality of primary repair with fecal diversion in
      the management of penetrating colon injuries by use of a meta-analysis of
      randomized, prospective trials. METHODS: We searched for prospective, randomized
      trials in MEDLINE (1966 to November 2001), the Cochrane Library, and EMBase using
      the terms colon, penetrating, injury, colostomy, prospective, and randomized.
      Studies were included if they were randomized, controlled trials that compared
      the outcomes of primary repair with fecal diversion in the management of
      penetrating colon injuries. Five studies were included. Reviewers performed data
      extraction independently. Outcomes evaluated from each trial included mortality,
      total complications, infectious complications, intra-abdominal infections, wound
      complications, penetrating abdominal trauma index, and length of stay. Peto odds
      ratios for combined effect were calculated with a 95 percent confidence interval
      for each outcome. Heterogeneity was also assessed for each outcome. RESULTS: The
      penetrating abdominal trauma index of included subjects did not differ
      significantly between studies. Mortality was not significantly different between
      groups (odds ratio, 1.70; 95 percent confidence interval, 0.51-5.66). However,
      total complications (odds ratio, 0.28; 95 percent confidence interval, 0.18
      0.42), total infectious complications (odds ratio, 0.41; 95 percent confidence
      interval, 0.27-0.63), abdominal infections including dehiscence (odds ratio,
      0.59; 95 percent confidence interval, 0.38-0.94), abdominal infections excluding
      dehiscence (odds ratio, 0.52; 95 percent confidence interval, 0.31-0.86), wound
      complications including dehiscence (odds ratio, 0.55; 95 percent confidence
      interval, 0.34-0.89), and wound complications excluding dehiscence (odds ratio,
      0.43; 95 percent confidence interval, 0.25-0.76) all significantly favored
      primary repair. CONCLUSION: Meta-analysis of currently published randomized,
      controlled trials favors primary repair over fecal diversion for penetrating
      colon injuries.

PMID- 12473881
TI  - Influence of experience on laparoscopic ileocolic resection for Crohn's disease.
AB  - PURPOSE: The technical difficulties that are frequently encountered in surgery
      for Crohn's disease have led some authors to suggest Crohn's cases should not be
      attempted early in one's laparoscopic colorectal surgery experience. This article
      reviews one surgeon's experience with laparoscopic terminal ileal resections for
      Crohn's disease to assess the safety of beginning laparoscopic colorectal
      resections with these procedures. METHODS: A retrospective review of all
      laparoscopic ileocolic resections performed by a single surgeon was performed.
      RESULTS: Sixty-nine (82 percent) of 84 procedures were completed
      laparoscopically. Reasons for conversion were dense adhesions (n = 5) and complex
      masses (n = 10). The mean operating time for the entire group was 145 +/- 39
      (range, 87-289) minutes. Postoperative length of stay was 5.6 +/- 2.4 (range, 2
      21) days. The mean incision length in the laparoscopic group was 4.5 +/- 1.15 cm.
      If the series is examined in three equal intervals, the number of patients with
      multiple difficulties (abscess, fistula, and previous resection or mass)
      increased in the final part of the study, without affecting complication or
      conversion rates. Despite the increased case complexity, average length of stay
      was significantly reduced between the second and third time periods (P = 0.008).
      CONCLUSIONS: Despite its technical demands, laparoscopic ileocolic resection was
      a safe procedure with potential advantages to patients. Laparoscopic resection is
      possible in the vast majority of patients with ileocolic Crohn's disease,
      regardless of the nature of the pathology. Previous resections, abscesses,
      fistulas, and phlegmons do not preclude success, although these cases should
      likely not be the first attempted.

PMID- 12473880
TI  - Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on
      114 families.
AB  - PURPOSE: Hereditary nonpolyposis colorectal cancer is caused by germline
      mutations in DNA mismatch repair genes. Mutation carriers have a 60 to 85 percent
      risk of developing colorectal cancer. In the Netherlands hereditary nonpolyposis
      colorectal cancer families are monitored in an intensive surveillance program.
      The aim of this study was to examine the stage of the screening-detected tumors
      in relation to the surveillance interval and to assess the risk of developing
      colorectal cancer while on the program. METHODS: The Dutch hereditary
      nonpolyposis colorectal cancer family registry was used. A total of 114 families
      had a mismatch repair gene defect and/or met the clinical criteria for hereditary
      nonpolyposis colorectal cancer. The interval between surveillance and colorectal
      cancer was investigated in initially healthy family members who underwent at
      least one surveillance examination without showing evidence for colorectal cancer
      (surveillance group) and in family members who previously underwent partial or
      subtotal colectomy for colorectal cancer. The risk of colorectal cancer was
      calculated for proven mutation carriers (surveillance group) and for putative
      carriers after partial or subtotal colectomy. RESULTS: A total of 35 cancers were
      detected while on the program. With intervals between colorectal cancer and the
      preceding surveillance examination of two years or less, tumors were at Dukes
      Stage A (n = 4), B (n = 11), and C (1). With intervals of more than two years,
      tumors were at Dukes Stage A (n = 3), B (n = 10), and C (n = 6). The 10-year
      cumulative risk of developing colorectal cancer was 10.5 (95 percent confidence
      interval, 3.8-17.2) percent in proven mutation carriers, 15.7 (95 percent
      confidence interval, 4.1-27.3) percent after partial colectomy, and 3.4 percent
      after subtotal colectomy. CONCLUSION: There is a substantial risk of developing
      colorectal cancer while on the program. However, all tumors but one of subjects
      who underwent a surveillance examination two years or less before detection were
      at a local stage. We recommend surveillance for hereditary nonpolyposis
      colorectal cancer with an interval of two years or less.

PMID- 12473882
TI  - Improved physical performance and increased lean tissue and fat mass in patients
      with ulcerative colitis four to six years after ileoanal anastomosis with a J
      pouch.
AB  - PURPOSE: This study was designed to examine the long-term changes in physical
      performance, body composition, and bone mineral density in patients with
      ulcerative colitis undergoing ileoanal anastomosis with J-pouch. Patients were
      also screened for abnormalities in blood biochemistry. METHODS: Maximal isometric
      strength (sum of pinching, hand grip, arm flexion, and knee extension), work
      capacity (ergometer test at 1.5 W/kg), pulmonary function, body composition (dual
      energy x-ray absorptiometry scan), and fatigue level were assessed before surgery
      and four to six years later. RESULTS: Of 24 patients examined preoperatively, 12
      females and 8 males were retested. At follow-up, their mean age +/- standard
      deviation was 38 +/- 9 years, weight was 76 +/- 14 kg, and height was 173 +/- 7
      cm. Compared with preoperative assessments, muscular strength had increased 10.6
      +/- 17.2 percent (P = 0.015), work capacity 10.4 +/- 13.3 percent (P = 0.003),
      total tissue mass 4.6 +/- 5.4 kg (P = 0.001), lean tissue mass 2.3 +/- 2.2 kg (P
      < 0.001), fat mass 2.2 +/- 3.7 kg (P = 0.014), and bone mineral density 1.6 +/-
      2.4 percent (P = 0.008). Seventeen of 20 patients had biochemical abnormalities.
      CONCLUSIONS: After ileoanal anastomosis with J-pouch, muscular strength and work
      capacity improved concomitant with an increase in total tissue mass, lean tissue
      mass, fat mass, and bone mineral density. Biochemical abnormalities were common.

PMID- 12473883
TI  - A randomized, controlled trial of fibrin glue vs. conventional treatment for anal
      fistula.
AB  - PURPOSE: Fibrin glue is a novel treatment for anal fistulas and possesses many
      advantages in the treatment of difficult high fistulas. Fibrin glue treatment is
      simple and repeatable; failure does not compromise further treatment options; and
      sphincter function is preserved. We aimed to compare the outcomes of patients
      with low and high anal fistulas randomly assigned to either fibrin glue or
      conventional treatment. METHODS: Patients with simple fistulas (low fistulas) and
      complex fistulas (high, Crohn's, and low fistulas with compromised sphincters)
      were randomly assigned to either fibrin glue or conventional treatment
      (fistulotomy or loose seton insertion with or without subsequent advancement
      flap). Patients with rectovaginal fistulas and anal fistulas associated with
      chronic cavities, acute sepsis, and side branches were excluded. The primary end
      point was fistula healing. Secondary end points were complications, changes in
      preoperative continence score, changes in maximum resting and squeeze pressure,
      satisfaction scores, and pain scores and time off work (simple fistulas only).
      RESULTS: Patients in the fibrin glue and conventional treatment arms were well
      matched for gender, median age, duration of fistula symptoms, and follow-up.
      Fibrin glue healed three (50 percent) of six and fistulotomy seven (100 percent)
      of seven simple fistulas (difference, 50 percent; confidence interval, 10 to 90
      percent; P= 0.06, Fisher's exact probability test). There was no change in
      baseline incontinence score, maximum resting pressures, or squeeze pressures
      between the study arms. Return to work was quicker in the glue arm, but pain
      scores were similar and satisfaction scores higher in the fistulotomy group.
      Fibrin glue healed 9 (69 percent) of 13 and conventional treatment 2 (13 percent)
      of 16 complex fistulas (difference, 56 percent; 95 percent confidence interval,
      25.9 to 86.1 percent; P= 0.003, Fisher's exact probability test). There was no
      change in baseline incontinence score, maximum resting pressures, or squeeze
      pressures in either study arm. Satisfaction scores were higher in the fibrin glue
      group. CONCLUSIONS: No advantage was found for fibrin glue over fistulotomy for
      simple fistulas, but fibrin glue healed more complex fistulas than conventional
      treatment and with higher patient satisfaction.

PMID- 12473884
TI  - Endorectal advancement flap: are there predictors of failure?
AB  - PURPOSE: The management of complex perianal fistulas with endorectal advancement
      flap is aimed at avoiding the risk of sphincter injury associated with
      traditional surgical methods. Long-term follow-up is required to assess the
      recurrence and continence outcomes of this procedure. The aim of this study was
      to review our experience with endorectal advancement flap in the treatment of
      complex perianal fistulas and to define the predictors of successful healing.
      METHODS: A retrospective chart review of all patients who underwent endorectal
      advancement flap for complex perianal fistulas between 1988 and 2000 was
      performed. Follow-up was established by telephone interview. RESULTS: One hundred
      six consecutive endorectal advancement flap procedures were performed on 94
      patients (94.4 percent). There were 56 females (59.6 percent). Mean age was 41.6
      (range, 18-76) years. Cryptoglandular disease was the most common cause of
      fistula (n = 41, 43.6 percent), followed by Crohn's disease (n = 28, 29.8
      percent). At a mean follow-up of 40.3 (range, 1-149) months, the procedure was
      successful in 56 (59.6 percent) of 94 patients. Twelve patients underwent repeat
      surgery with the same technique because of initial failure, 8 of whom eventually
      healed. Crohn's disease was associated with a significantly higher recurrence
      rate (57.1 percent) when compared with fistulas in patients without Crohn's
      disease (33.3 percent, P< 0.04). Prior attempts at repair of the fistula were not
      associated with less favorable outcome of the procedure (P = 0.5). Recurrence was
      not associated with the type of fistula, origin, preoperative steroid use,
      postoperative bowel confinement, use of postoperative antibiotics, or creation of
      a diverting stoma. The median time to recurrence was 8 (range, 1-156) weeks;
      there was no postoperative mortality. Two patients had postoperative bleeding,
      one requiring resuture of the flap on the first postoperative day. Recurrences
      were observed in 15.7 percent of the patients 3 or more years after the repair.
      In 8 patients (9 percent), continence deteriorated after the endorectal
      advancement flap, a more common finding in patients who had undergone previous
      surgical repairs (P < 0.02). CONCLUSION: The success rate of endorectal
      advancement flap for complex perianal fistulas is modest. Failure is mainly
      correlated with the presence of Crohn's disease.

PMID- 12473885
TI  - Outcomes of primary repair of anorectal and rectovaginal fistulas using the
      endorectal advancement flap.
AB  - PURPOSE: The endorectal advancement flap is a surgical procedure used in the
      treatment of anorectal and rectovaginal fistulas. There is a wide range of
      success rates published in the literature. This study was undertaken to examine
      the success rate of primary endorectal advancement flap in our own institution.
      We attempted to identify factors that influence the rate of healing. METHODS: A
      retrospective review was performed on 105 patients (43 males) who underwent their
      first endorectal advancement flap at our institution between January 1, 1994, and
      June 30, 1999. Ninety-nine patients were available for follow-up. Sixty-two
      patients had anorectal and 37 had rectovaginal fistulas. The causes of fistula
      included cryptoglandular (48 patients), Crohn's disease (44), obstetric injury
      (5), trauma (1), and other (1). RESULTS: The median follow-up was 17.1 (range,
      0.4-66.9) months. The median age was 42 (range, 16-78) years. Recurrence was seen
      in 36 patients (36.4 percent); thus, the primary rate of healing was 63.6
      percent. Factors that were associated with higher rates of success were increased
      age (P = 0.011), greater body surface area (P = 0.012), history of incision and
      drainage of a perianal abscess preceding advancement flap (P = 0.010), previous
      placement of a seton drain (P = 0.025), and short duration of fistula (P =
      0.003). Factors that negatively influenced the healing rate of the flap were the
      diagnoses of Crohn's disease (P = 0.027) and rectovaginal fistula (P = 0.002).
      Length of hospitalization, discharge on oral antibiotics, and the presence of a
      diverting stoma did not influence the rate of healing. Prednisone was associated
      with a distinct trend toward failure, with none of the patients on high-dose
      prednisone (greater than 20 mg/day) having achieved long-term healing. No
      fistulas recurred after a period of 15 months. CONCLUSION: The endorectal
      advancement flap is an effective method of repair for both anorectal and
      rectovaginal fistulas, even though the success rate may not be as optimistic as
      in some other published studies. Patient selection is imperative, realizing that
      a higher rate of failure may be present in Crohn's disease and rectovaginal
      fistulas. Control of sepsis before endorectal advancement flap with drainage of a
      perianal abscess and/or seton placement, whenever possible, is indicated.

PMID- 12473886
TI  - Dynamic magnetic resonance imaging evaluation of the structural and functional
      results of postanal repair for neuropathic fecal incontinence.
AB  - PURPOSE: The aim of this study was to determine whether dynamic magnetic
      resonance imaging of the pelvic floor can discriminate between patients who
      improve after postanal repair for neurogenic fecal incontinence and those who
      remain symptomatic. METHODS: Pelvic floor measurements obtained during dynamic
      magnetic resonance imaging in eight females whose anal incontinence had improved
      after postanal repair were compared with those from nine females who remained
      symptomatic. All subjects also underwent standard anorectal physiology testing.
      RESULTS: There was no significant difference between groups with respect to any
      measurement of anterior or middle pelvic floor compartments. Additionally, there
      was no difference in posterior pelvic floor configuration when symptomatic
      patients were compared with those who had improved. However, dynamic magnetic
      resonance measurements revealed patients who remained symptomatic had
      significantly greater posterior pelvic floor weakness. Anorectal physiology was
      unable to differentiate between groups. CONCLUSIONS: There is no difference in
      static pelvic floor measurements when subjects remaining symptomatic after
      postanal repair are compared with those who have improved. In contrast, dynamic
      measurements may be able to predict failure in those who demonstrate excessive
      posterior pelvic floor mobility.

PMID- 12473887
TI  - Clinical effects of preoperative radiation therapy on anorectal function after
      proctectomy and colonic J-pouch-anal anastomosis.
AB  - PURPOSE: Preoperative radiotherapy is increasingly used for certain rectal
      cancers, although some evidence suggests that it may adversely affect anorectal
      function. Reconstruction with a colonic J-pouch-anal anastomosis after complete
      proctectomy is thought to improve function, but few published data on pouch
      function after radiation exists. The aim of our study was to compare long-term
      bowel habits in patients receiving preoperative radiation for rectal cancer
      followed by colonic J-pouch-anal anastomosis with those of patients having
      similar rectal cancer surgery without radiation. METHODS: Patients (n = 125)
      having undergone colonic J-pouch-anal anastomosis for rectal cancer, of whom 28
      had preoperative radiotherapy and 97 did not, responded to a detailed
      questionnaire about their bowel habits at least 12 months after surgery, with a
      mean (+/- standard deviation) interval of 64 (+/-42) months. Radiation was
      administered preoperatively as a short (25 Gy over 5 days, n = 22) or long (45 Gy
      over 4 weeks, n = 6) course. All patients had colonic J-pouch-anal anastomosis
      with manual anastomosis at or immediately above the dentate line. RESULTS: Except
      for tumor stage, no preoperative difference was observed between the two groups.
      The number of bowel movements per 24 hours in patients with and without radiation
      was 1.8 (+/-0.8) and 1.8 (+/-1.5), respectively (P> 0.05). In the irradiated
      group, diarrhea (39 vs.13 percent, P= 0.005) and nocturnal defecation (36 vs.15
      percent, P= 0.03) were more frequent than in the nonirradiated group. No other
      significant difference existed between groups with regard to stool clustering,
      use of protective pads, ability to defer evacuation >15 minutes, ability to
      evacuate the bowel within 30 minutes, incontinence score, use of medications, or
      dietary restriction. CONCLUSION: Preoperative radiotherapy followed by
      proctectomy and colonic J-pouch-anal anastomosis significantly increased
      nocturnal defecation frequency and diarrhea compared with similar nonirradiated
      patients but had no influence on the other bowel-habit parameters studied.

PMID- 12473888
TI  - Laparoscopic sigmoid resection for cancer: curative resection and preliminary
      medium-term results.
AB  - PURPOSE: Despite reservations about compliance with oncologic radical criteria,
      laparoscopic resection of the sigmoid colon is increasingly being used with
      curative intent in oncologic surgery of the colorectum. The aim of the present
      study was to obtain further information on the perioperative course, the
      oncologic radicalness of the procedure, and medium-term outcome. METHODS: The
      data presented here were obtained from a prospective, multicenter study conducted
      in Germany and Austria. These data were acquired from an analysis of subgroups
      derived from a total of 3,133 recruited patients. RESULTS: A total of 292
      patients from 36 hospitals underwent laparoscopic resection of the sigmoid colon
      with curative intent. The definitive histopathologic work-up of surgical
      specimens revealed the following International Union Against Cancer tumor stages:
      122 Stage I, 86 Stage II, and 84 Stage III. The mean operating time was 172
      minutes, and the mean intraoperative blood loss was 241 ml. The conversion rate
      to open surgery was 5.5 percent, the majority of such conversions being made
      necessary by vascular lesions. Sixty-five of the patients reported at least one
      postoperative problem or complication (22.3 percent); the mortality rate was 2.7
      percent. With a mean of 13.4 recovered lymph nodes and a mean aboral safety
      margin of 72 mm, the formal criteria for the assessment of oncologic radicalness
      were met. Intraoperative cell dissemination occurred in two patients. The long
      term results, which, at a mean follow-up of 2.1 years and a follow-up rate of
      73.3 percent, must be considered preliminary, show a calculated stage-related
      survival rate of 88.8, 90.9, and 64.1 percent, respectively, for the
      International Union Against Cancer Stages I, II, and III. CONCLUSIONS:
      Laparoscopic sigmoid resection can be performed technically reliably-also with
      curative intent-with acceptable complication and mortality rates and, to date,
      with survival rates that are at least comparable with those achieved with open
      surgical procedures.

PMID- 12473889
TI  - Prospective evaluation of laparoscopic surgery for rectosigmoidal and rectal
      carcinoma.
AB  - PURPOSE: This study was designed to examine the short-term results of laparoscopy
      in the treatment of curative cases of rectosigmoidal and rectal carcinoma.
      METHODS: A review was performed of a prospective registry of 70 patients who
      underwent curative laparoscopic resection for rectosigmoidal and rectal carcinoma
      between July 1993 and April 2001. Before 1997, only patients with early (Tis or
      T1) cancers located in the rectosigmoid and upper rectum that required bowel
      resection were candidates for laparoscopy. In 1997, we expanded the application
      of laparoscopy to include T2 cancers located anywhere in the rectum. Mesorectal
      transection was performed at least 5 cm below the tumor for rectosigmoidal and
      upper rectal lesions, and total mesorectal excision was performed for lower
      tumors. Primary anastomosis was performed by a double-stapling technique, or a
      handsewn coloanal anastomosis was performed. Patient demographics and outcomes
      were recorded prospectively. RESULTS: The median follow-up was 23 months. An
      anastomosis was performed in 92.9 percent of the operations. Oral intake was
      started on median postoperative Day 1, and the median length of hospitalization
      was 8 days. Two patients needed conversion to conventional open surgery. A total
      of 15 postoperative complications occurred in 13 patients (18.6 percent),
      including anastomotic leakage in 6 (8.6 percent) and bowel obstruction in 3 (4.3
      percent). Reoperation was required in six patients. Two patients developed
      recurrence of cancer at the anastomotic site. The expected 5-year survival and
      disease-free survival rates were 100 and 92.1 percent, respectively. CONCLUSION:
      The findings of the present study demonstrate the feasibility and safety of
      laparoscopic surgery for selected patients with rectal carcinoma. Morbidity and
      mortality rates and oncologic outcome appear to be comparable with conventional
      surgery.

PMID- 12473891
TI  - Colostomy closure after Hartmann's procedure with fast-track rehabilitation.
AB  - PURPOSE: The aim of this study was to assess the effect of postoperative
      multimodal rehabilitation after colostomy closure after Hartmann's procedure.
      METHODS: Twenty-seven consecutive patients scheduled for colostomy closure after
      Hartmann's procedure received continuous postoperative epidural analgesia,
      laxative, and enforced oral liquids, protein drinks, and mobilization. RESULTS:
      Defecation occurred at a median 2 days postoperatively. Mean and median
      postoperative stay was 3 days, with two readmissions (1 anastomotic dehiscence
      and 1 social) increasing mean total 1-month hospital stay to 4.3 (median, 3)
      days. No other complications occurred except three superficial wound infections.
      CONCLUSION: Postoperative hospital stay and morbidity may be reduced with
      multimodal rehabilitation after open colostomy closure after Hartmann's
      resection.

PMID- 12473890
TI  - The role of endoscopic colon surveillance in the transplant population.
AB  - PURPOSE: Long-term immunosuppression increases the risks of developing certain
      malignancies. This study examines the effects of long-term immunosuppression on
      the development of metachronous adenomatous polyps and attempts to formulate a
      sound surveillance plan for these individuals. METHOD: A retrospective analysis
      was performed of all solid organ transplant patients at Henry Ford Hospital from
      1989 to 1999, with a specific focus on endoscopic evaluation and outcomes after
      three years of surveillance. Comparison was made to an age-matched and gender
      matched control group from the same endoscopic database. Variables were compared
      using the chi-squared test, Fisher's exact probability test, and Hochberg's test.
      RESULTS: A total of 992 solid organ transplants were performed. Two hundred
      twenty-nine (23 percent) of the transplant recipients underwent pretransplant
      colonoscopy, of which 178 patients (78 percent) were age 50 years or older.
      Seventy-four (32 percent) of the prescreened population had polyps, of which 45
      patients (61 percent) had adenomas. Twenty-seven patients (36 percent) had
      synchronous polyps, of which 12 patients (16 percent) had synchronous adenomas.
      At 3-year follow-up 59 patients (80 percent) had metachronous polyps. Twenty
      eight patients (38 percent) had metachronous adenomas. Eleven patients (15
      percent) with hyperplastic polyps on initial colonoscopy developed adenomas. The
      control group consisted of 25 females and 50 males with a mean age of 65.5 +/-
      1.1 years. Fifty-one patients (68 percent) had adenomas on endoscopy. Twenty-four
      patients (32 percent) had synchronous lesions, of which 13 patients (17 percent)
      had synchronous adenomas. Sixty-one patients (84 percent) developed metachronous
      lesions, of which 33 patients (43 percent) had metachronous adenomas at 3 years.
      There was no difference in the polyp size or histology between the two groups.
      There was no statistically significant difference between the transplant patients
      and the control group in all analyses. CONCLUSION: Because of an equivalent
      incidence of adenomatous polyps compared with the general population, current
      screening criteria should be used in patients posttransplant. Transplant patients
      are not more likely to develop metachronous polyps than the general population.
      Therefore, posttransplant polyp surveillance should not be more frequent than
      currently recommended for nontransplant patients with adenomatous polyps.

PMID- 12473892
TI  - Bacterial translocation in patients with Crohn's disease undergoing surgery.
AB  - PURPOSE: Much evidence, derived from experimental studies, suggests that
      bacterial translocation indeed occurs, yet its clinical significance is still a
      matter of controversy in humans. The aims of this study were to determine the
      prevalence of bacterial translocation in patients with Crohn's disease undergoing
      laparotomy and to identify any association with postoperative septic
      complications or systemic inflammatory response syndrome. METHODS: Mesenteric
      lymph node and peripheral blood samples from 42 patients with Crohn's disease
      undergoing laparotomy were collected for bacteriologic assessments. RESULTS:
      Bacterial translocation to mesenteric lymph node was identified in 20 patients
      (48 percent). The most common organism was (27 percent). Blood cultures were
      positive in 2 of 20 patients in whom translocation to lymph node was identified.
      Bacterial translocation was associated with a greater than two-fold increase in
      the incidence of postoperative septic complications (35 14 percent), but this
      difference was not significant. In the analysis of the occurrence of systemic
      inflammatory response syndrome, a significantly higher incidence continued until
      the third postoperative day in patients with those without bacterial
      translocation. In a logistic regression analysis, bacterial translocation had a
      significant effect on the occurrence of systemic inflammatory response syndrome,
      even though septic complications were taken into account. CONCLUSIONS: Bacterial
      translocation to mesenteric lymph node predisposed patients with Crohn's disease
      undergoing laparotomy to systemic inflammatory response syndrome.

PMID- 12473893
TI  - Excision of anal fistula with closure of the internal opening: functional and
      manometric results.
AB  - PURPOSE: The aim of this study was to evaluate the results concerning recurrence
      and continence after sphincter-saving surgery for fistula-in-ano. METHODS: Forty
      two patients with anal fistula traversing the sphincter were operated on with
      fistula excision and closure of the internal opening. Patients answered a
      questionnaire concerning bowel habits and continence before and 3 and 12 months
      after surgery. A subgroup of 19 patients were also examined with anal manometry.
      RESULTS: Twenty-three (55 percent) patients healed primarily after surgery and a
      further 10 (24 percent) after one reoperation, whereas 7 (17 percent) required 2
      to 4 reoperations until healed. In two patients therapy was changed to cutting
      seton treatment. After 1 year 21 of 36 (58 percent) patients reported improved or
      unaffected continence and 11 (31 percent) reported a slight and 4 (11 percent) a
      major decrease in continence. Detailed data on preoperative continence were
      missing for five patients, and one had a colostomy at late follow-up. Anal
      manometry showed a significant decrease in resting pressure after three months
      and a further decrease in both resting and squeeze pressures after one year.
      CONCLUSION: Surgery for anal fistula with excision and advancement flap has a
      fairly high initial recurrence rate but a good final success rate. A decrease in
      continence is seen also after this kind of surgery for anal fistula. Manometric
      results suggest that this is associated with an impaired internal anal sphincter
      function.

PMID- 12473894
TI  - Long-term survival after resection of colonic adenocarcinoma with synchronous
      metastases to the liver, adrenal gland, and aortic-caval lymph nodes: report of a
      case.

PMID- 12473895
TI  - Colonoscopic detection of a malignant melanoma metastatic to a tubular adenoma of
      the colon: report of a case.
AB  - PURPOSE: Metastasis of a malignant neoplasm to a benign tumor is an infrequent
      event. Adenomatous polyps of the colon have only been reported on three occasions
      acting as host tumors. We report the first case where a malignant melanoma
      metastasizing to a tubular adenoma in the colon was detected during colonoscopy.
      METHODS: An 85-year-old male with dementia and right hemiparesis presented to the
      hospital with change of bowel habits, signs and symptoms of anal incontinence,
      and a perianal ulcer. On physical examination, multiple subcutaneous nodules over
      his chest and abdominal wall were detected, and laboratory data revealed iron
      deficiency anemia. A colonoscopy was performed. RESULTS: During colonoscopy, a
      pedunculated, greenish-brown-colored polyp measuring 2 cm in greatest dimension
      located in the transverse colon was identified and snared. Pathology of this
      polyp was consistent with a malignant melanoma infiltrating into a tubular
      adenoma. Subsequently, one of the subcutaneous lesions was biopsied and this
      revealed malignant melanoma cells metastatic in soft tissue. The primary site of
      the malignant melanoma could not be identified. CONCLUSION: Polyp-cancer sequence
      is well documented in colorectal cancer. The vast majority of malignant lesions
      found in adenomatous polyps in the colon are the consequences of malignant
      transformation from benign neoplastic colonic adenomatous tissue. The possibility
      that colonic adenomatous polyps could harbor metastatic tumors should also be
      entertained. This could change the treatment and may require an appropriate
      workup.

PMID- 12473896
TI  - Nested polymerase chain reaction in the diagnosis of negative Ziehl-Neelsen
      stained Mycobacterium tuberculosis fistula-in-ano: report of four cases.
AB  - PURPOSE: Mycobacterium is one of the causes of granulomatous diseases within the
      anorectal region. Early diagnosis of infection is important before the use of
      antituberculosis chemotherapy. Clinical diagnosis is usually dependent on
      microscopic detection using Ziehl-Neelsen stain and mycobacterial culture, but
      the sensitivity and specificity of these two methods are low. In this study
      nested polymerase chain reaction was used to detect mycobacterial infection in
      anal fistulas. METHODS: Paraffin-embedded specimens from three patients and
      discharge from one patient were used. DNA extraction was performed using
      phenol/chloroform techniques. IS6110-based nested polymerase chain reaction,
      yielding a 259-bp amplicon, for the diagnosis of infection was done to facilitate
      treatment. RESULTS: Four cases of suspected fistulas-in-ano presented with
      persistent fistula or unhealed wound. Histopathologic examination revealed
      granulomatous inflammation with failed microscopic detection of acid-fast bacilli
      using Ziehl-Neelsen stain. Nested polymerase chain reaction confirmed the
      presence of in all cases. The anal lesions healed rapidly following a course of
      antituberculosis therapy. CONCLUSION: Molecular diagnosis of fistula-in-ano by
      nested polymerase chain reaction is useful for clinically highly suspected
      infection despite a negative Ziehl-Neelsen stain.

PMID- 12473897
TI  - Telerobotic-assisted laparoscopic right and sigmoid colectomies for benign
      disease.
AB  - PURPOSE: Telerobotic surgical systems attempt to provide technological solutions
      to the inherent limitations of traditional laparoscopic surgery. In this article,
      we present the first two reported cases of telerobotic-assisted laparoscopic
      colectomies performed on March 6 and 8, 2001. METHODS: In the first patient we
      performed a telerobotic-assisted laparoscopic sigmoid colectomy for
      diverticulitis. In the second patient, we accomplished a telerobotic-assisted
      laparoscopic right hemicolectomy for cecal diverticulitis. The Da Vinci
      telerobotic surgical system was used in both cases to mobilize the bowel. The
      mesenteric division, bowel transection, and anastomoses were accomplished with
      standard laparoscopic-assisted techniques. Both operations were completed with a
      three-trocar technique. RESULTS: We found that the Da Vinci system adequately
      replaced the camera holder. The three-dimensional virtual operative field helped
      to maintain the surgeon's orientation during the operation. The combination of
      three-dimensional imaging and the hand-like motions of the telerobotic surgical
      instruments facilitated dissection. The Da Vinci console offered an ergonomically
      comfortable position for the surgeon. Operative times for the sigmoid colectomy
      was 340 minutes and for the right hemicolectomy 228 minutes. Telerobotic-assisted
      laparoscopic colectomy is feasible, but required a longer operative time than our
      standard laparoscopic-assisted technique. CONCLUSION: Telerobotic-assisted
      laparoscopic colectomy is feasible and warrants further investigations in
      controlled trials.

PMID- 12473899
TI  - Excision of the levator muscles with external sphincter preservation in the
      treatment of selected low T4 rectal cancers.
AB  - PURPOSE: The existence of an anatomic and functional separation between the
      puborectalis muscle and external anal sphincter permits the performance of an
      abdominoendoanal excision, instead of an abdominoperineal excision, of the rectum
      and levator muscles, with preservation of a functioning external sphincter, in
      selected patients with very low rectal cancer and limited infiltration of the
      levator muscles. METHODS: Seven patients (4 females; age, 48-69; mean, 60.7 +/-
      7.8 years) with low posterior or posterolateral localized rectal cancers with
      infiltration of the puborectalis muscle (T4) were submitted to preoperative
      chemoradiation and excision of the rectum with the levator muscles, while the
      external sphincter and its innervation were preserved. A coloanal anastomosis was
      performed at the dentate line. RESULTS: At a median follow-up of 58 (range, 42
      102) months, 6 patients (86 percent) were alive and disease free. No local
      recurrence was observed. Anorectal function, at three years from surgery was no
      worse than that of six patients of the same age and gender who had undergone more
      conventional coloanal anastomoses with preservation of the levator muscles.
      CONCLUSION: Selected patients with very low rectal cancers infiltrating the
      levator muscles (T4) and responding to preoperative chemoradiation therapy can
      still be treated with an advanced sphincter-sparing procedure, instead of an
      abdominoperineal excision. Oncologic and functional results seem to be
      satisfactory.

PMID- 12473900
TI  - What they don't teach you in fellowship!

PMID- 12473901
TI  - Obstructive uropathy and pelvic actinomycosis.

PMID- 12473902
TI  - Nursing assessment and management of patients with head injuries.
AB  - There are approximately 500,00 head injuries each year in the United States. Head
      injuries are also the leading cause of death and disability for persons under the
      age of 40. These injuries are frequently treated in intensive care units (ICU)
      around the country.

PMID- 12473903
TI  - Cardiogenic shock: a success story.
AB  - When the body is unable to deliver oxygen and perfuse tissues adequately, shock
      occurs. Cardiogenic shock is the shock syndrome that develops when the heart has
      lost approximately 40% of its pumping ability. This article reviews the
      pathophysiology and management of cardiogenic shock.

PMID- 12473904
TI  - Recognition and prevention of hospital violence.
AB  - Violence is the second leading cause of death in the workplace. Most acts of
      violence in the healthcare setting go unreported. Critical care and emergency
      department nurses must be prepared to deal with these tragedies. This article
      presents vital information on how to recognize and prevent violence in the
      critical care and emergency departments.

PMID- 12473906
TI  - A personal reflection: whose rights are they, anyway?

PMID- 12473905
TI  - Elements of an informed consent.
AB  - Clinical trials are conducted in all healthcare settings, including hospitals,
      university health centers, clinics, physicians' offices, and home care. A patient
      who is interested in participating in a clinical trial must first sign an
      informed consent. This article reviews the elements of an informed consent for
      clinical research.

PMID- 12473907
TI  - Critical care nurses' attitudes and knowledge related to organ donation.
AB  - The need for organ transplant has nearly quadrupled in the past decade, but the
      number of organ donors has remained relatively constant. Critical care nurses are
      the vital link in the organ donation process because they can be responsible for
      referring potential donor cases to an organ procurement organization. This study
      found that the majority of nurses had overwhelmingly positive attitudes toward
      organ donation, but they failed to act on their beliefs. Applications for
      practice include the need to increase critical care nurses' knowledge about
      designated requesters, the organ donation process, and procedures that assure
      ethical standards are met.

PMID- 12473909
TI  - A closing word: I'm glad I'm a nurse.

PMID- 12473911
TI  - Genetics competency: new directions for nursing.
AB  - Imagine nurses caring for several patients. One uses genetic testing results to
      decide about prophylactic surgery to reduce cancer risks. The second nurse
      modifies dietary habits on the basis of a genetic test result and prevents long
      term effects from impaired metabolism of the amino acid phenylalanine. The third
      nurse cares for a patient who recovers from a narcotic overdose after a gene
      alteration that affects drug metabolism. Due to the significant advances of the
      Human Genome Project and related genetics research, clinical applications of
      genetic technology are moving into nursing practice. Resources are available to
      help nurses meet this challenge. The National Coalition for Health Professional
      Education in Genetics has issued a set of competencies that mandates new
      directions for nursing education and practice. To ensure that patients understand
      both the promise and the limitations of genetic discovery, it is imperative to
      ensure the competence of critical care nurses.

PMID- 12473912
TI  - Education for genetics and nursing practice.
AB  - Genetic factors influence the risk for disease, selection of treatments, and
      overall health of persons throughout the life span. Nurses in critical care
      practice participate in assessing genetic risks for disease, implementing
      treatments, educating people about genetic aspects of health and disease,
      supporting the client's abilities to cope with the information, and assisting the
      individual and family to make health-related decisions involving genetic
      information. Opportunities for critical care nurses to become knowledgeable about
      genetic aspects of critical care nursing exist through academic courses,
      continuing education, and summer institutes. Recently, new guidelines for the
      genetic education of nurses have been developed. However, genetic education
      opportunities are not available to all nurses throughout the United States.
      Genetic nursing education programs based on guidelines for integration of genetic
      knowledge into professional nursing practice are needed.

PMID- 12473913
TI  - Recent advances in prenatal screening and diagnosis of genetic disorders.
AB  - In any pregnancy, there is an approximate 3% to 5% chance that a fetal
      complication will occur. The most familiar prenatal diagnostics cannot be
      performed until the fetus is well into gestation, and most involve invasive
      procedures along with their inherent risks. In light of these facts, many
      noninvasive prenatal screening and diagnostic tests have been developed, the
      newest using recombinant deoxyribonucleic acid (DNA) technology in the
      examination of fetal cells. Through these procedures, genetic coding errors and
      chromosomal disruptions may be detected. This article discusses the currently
      available prenatal and screening diagnostic tests for genetic disorders with a
      focus on the latest technology.

PMID- 12473914
TI  - The genetics of substance abuse.
AB  - Substance abuse is among the most prevalent psychiatric disorders in males and
      contributes significantly to the morbidity and mortality nurses see in practice.
      Substance use and abuse disorders were the cause of a half million drug-related
      visits to emergency rooms in 1995, with more than 50% related to drug overdoses.
      Substance abuse and dependency result from a complex interaction of genetics and
      the environment. Various polymorphisms of genes have been demonstrated to have
      either protective effects or increased risk associated with their presence.
      Substance abuse is a chronic disease state that has effective treatments that
      reduce drug use, crime, and psychosocial problems. Nurses can provide targeted
      education and interventions to positively impact substance abuse treatment and by
      applying basic principles of genetic counseling may prevent transmission to
      future generations.

PMID- 12473915
TI  - Hereditary cancer syndromes of the gastrointestinal system.
AB  - Gastrointestinal (GI) malignancies account for a large percentage of the cancer
      burden in the United States. Although the majority of cancer cases are sporadic,
      approximately 5% to 10% of cancer results from inherited genetic mutations. There
      are several hereditary cancer syndromes of the GI tract that have been
      identified. To date, the genetics of colorectal cancer and its associated
      hereditary cancer syndromes have been characterized in detail, and effective
      screening modalities and recommendations have been incorporated into standards of
      care. Today, scientists are beginning to understand the genetic basis of
      pancreatic and gastric cancer, and in some cases have identified a number of
      their associated inherited cancer syndromes. Information about cancer genetics
      and hereditary cancer syndromes not only will provide advanced practice nurses
      with knowledge of these diseases but also, more importantly, will provide
      opportunities to improve patient care by providing patients with treatment
      options and opportunities for the early detection and prevention of cancer.

PMID- 12473916
TI  - Oxidative stress, DNA damage, and breast cancer.
AB  - Oxidative stress is a disturbance in the balance between the production of
      reactive oxygen species (ROS) and antioxidant defenses. It occurs when excessive
      production of ROS overwhelms the antioxidant defense system or when there is a
      significant decrease or lack of antioxidant defenses. Oxidative stress, in turn,
      is known to cause DNA damage and mutations of tumor suppressor genes that are
      critical initial events in carcinogenesis. Interestingly, early findings of the
      studies suggest that environmental factors, such as high psychological stress and
      poor nutritional profile (eg, low antioxidant and high fat intake), increase ROS
      production. Given that breast cancer is a complex disorder in which gene
      environment interactions play a significant role in the development of cancer,
      oxidative stress may be an excellent model for exploring mechanisms mediating
      gene-environment interactions for nurse scientists and advanced practice nurses.
      Such investigations may help to suggest future strategies for nonpharmacological
      interventions for decreasing cancer risk.

PMID- 12473918
TI  - Genetic testing of children: confluence or collision between parents and
      professionals?
AB  - Nursing has been challenged to lead in all areas of knowledge development in
      genetics. In addition to participation in genetic counseling and research, the
      profession must be an advocate for the proper use of new clinical practices in
      genetic care. One of these areas is the largely unregulated practice of genetic
      testing of minor children. Psychological and bioethical concerns have been raised
      about testing children at parental request when no immediate benefit will result.
      Several professional bodies have urged the adoption of guidelines that would
      limit parental choice in the testing process. This article argues that little
      data exists to support the creation of strict regulations, and also notes that
      analysis of this issue through the use of alternative ethical theory can yield
      useful directions for nurses attempting to navigate this controversial topic.

PMID- 12473917
TI  - Allelic variation and environmental lead exposure in urban children.
AB  - The advent of the Human Genome Project has allowed for increased understanding
      and sophistication in diagnosis, treatment methods, and overall care planning on
      the part of healthcare providers for children with genetic disorders. Genetics
      research dealing with polymorphic changes within a genome has opened the door to
      awareness of how dormant genetic alleles may become active when coupled with
      certain environmental insults. Such genetic aberrations may place a child at a
      higher risk for health disparities when exposed to environmental toxins. It has
      been posited that such exposure in children with an arylsulfatase-A (ASA) allelic
      variation is associated with increased risk for neurodevelopmental damage. This
      initial study contributes to this new field and supports development of finer
      tuned methods to prevent ominous outcomes of lead exposure. The purpose of this
      study was to explore the incidence of children in a representative sample from a
      Midwest metropolitan city with positive test results for the ASA allelic
      variation who have been exposed to the environmental toxin lead. In this
      corollary study of 107 children, part of a parent study on the behavior of
      African American children prenatally exposed to cocaine, 45% were found to be
      heterozygous, 11% mutant homozygous, and 44% normal in terms of ASA allele or
      alleles. Further studies on neurodeficiencies, low-level exposure to
      environmental toxins, and allelic variations must be conducted before a relation
      between ASA allelic variance and environmental lead can be determined.

PMID- 12473919
TI  - Evaluating ventilator weaning best practice: a long-term acute care hospital
      system-wide quality initiative.
AB  - Long-term acute care (LTAC) hospitals and units are becoming increasingly
      important to the management of patients who have serious, complex critical
      illnesses and require mechanical ventilation for extended periods of time.
      Kindred Healthcare, Inc., a nation-wide system of LTAC hospitals embarked on a
      quality initiative to establish a Ventilator Management and Weaning Best
      Practice. The process steps included: measurement of performance of all hospitals
      in the system using a risk-adjusted methodology to evaluate clinical outcomes,
      identification of facilities with superior outcomes; structured evaluation of the
      characteristics, practices, and protocols of these Best Practice hospitals; and
      utilization of the information gleaned from these hospitals to establish evidence
      based LTAC best practice ventilator management guidelines. Key characteristics of
      the Best Practice LTAC hospitals were: hospital-wide philosophy that "everybody
      weans"-that is, all disciplines actively participate and all patients are
      expected to wean; collaborative multidisciplinary plans of care; a consistent and
      a 24-hour-a-day approach to ventilator management and weaning; daily
      communication; mutual respect for the contributions of all disciplines to the
      weaning process; early, aggressive nutrition support and intervention by
      rehabilitation services; use of 24-hour in-hospital advance practice nurses,
      hospitalists, or physician assistants; and intervention by physiatrists.

PMID- 12473920
TI  - The nursing shortage in acute and critical care settings.
AB  - The nursing shortage is seriously challenging hospitals to provide safe, quality
      care to acute and critically ill patients. Most frequently reported are the
      registered nurse (RN) shortages in intensive care units (ICUs) and step-down
      units. Issues surrounding the nursing shortage are multifaceted and require
      comprehensive solutions. Although work place conditions are typically cited as
      the leading cause of the shortages, other factors, including a rapidly aging RN
      workforce, have been implicated. Furthermore, fewer young people are choosing
      nursing as a career and graduating classes of RNs are decreasing in size.
      Remedies for the acute and critical care nursing shortage will require highly
      innovative initiatives and multiple long-term strategies focused on forces
      driving the growing nursing shortage. One solution to workplace issues may lie in
      the philosophy of the Magnet Hospital program. The advanced practice nurse can
      play a significant role in providing leadership in addressing factors and
      designing comprehensive and innovative strategies directed at recruitment and
      retention of RNs in acute and critical care settings.

PMID- 12473922
TI  - Patients who self-injure.

PMID- 12473923
TI  - Nursing presence.

PMID- 12473921
TI  - The numbers speak for themselves--will nurses?

PMID- 12473924
TI  - What could the Nurse Reinvestment Act mean for you?

PMID- 12473925
TI  - Is ritalin the answer?

PMID- 12473927
TI  - Magnetic resonance imaging.

PMID- 12473928
TI  - Cardiovascular magnetic resonance imaging.

PMID- 12473929
TI  - Genetic testing for breast and ovarian cancer risk: the psychosocial issues.

PMID- 12473930
TI  - Ebola.

PMID- 12473931
TI  - Solidifying the future.

PMID- 12473932
TI  - Pain assessment in cognitively impaired older adults.

PMID- 12473933
TI  - The use of papaya on pressure ulcers.

PMID- 12473934
TI  - The elusive drug benefit.

PMID- 12473937
TI  - [Decision analysis demythologized. About the pulmonary solitary nodule].

PMID- 12473938
TI  - [New biological markers of lung cancer: toward targeted biotherapies?].

PMID- 12473939
TI  - [The fly, the fish, and the respiratory physician].

PMID- 12473940
TI  - [Treatment of lung cancer in the elderly].

PMID- 12473941
TI  - [Respiratory infections in long term care facilities: a plea for improved
      prevention].

PMID- 12473942
TI  - [Respiratory handicap of neuromuscular origin: a plea for better patient
      information].

PMID- 12473943
TI  - [A diagnostic strategy for isolated pulmonary nodules less than 2 cm in
      diameter].
AB  - The object of this study is to determine the best diagnostic strategy for
      isolated pulmonary nodules less than 2 cm in diameter starting from decision
      analysis. The diagnostic pathway included strategies: 1. Observation with a
      thoracic tomodensitometry (TDM) every 3 months. 2. Percutaneous needle biopsy. 3.
      Video-assisted thoracoscopic surgery (VATS) resection. 4. Resection by
      thoracotomy. Observation was the best strategy for non-smokers in their 40's with
      a cost of 57-69 Francs per year of life gained. Needle biopsy was the best
      strategy for a 1 cm nodule in patients of 50 years, smokers and non-smokers (life
      expectancy 29.38 and 24.44 years). The best strategy for a 2 cm nodule was needle
      biopsy in 40 year old smokers (life expectancy 34.18 years) and in non-smokers
      aged 50-60 years with a life expectancy from 20.0 to 28.2 years. VATS was the
      best strategy for a 1 cm nodule in smokers over the age of 60 for a 2 cm nodule
      over the age of 50. The costs were 1 811, 3 214, 1 873, 1 811 and 6 093 Francs
      respectively per year of life gained. During the sensitivity analysis VATS
      remained the best strategy provided the post-operative mortality remained below
      2%. When the risk of malignancy is only moderate needle biopsy may be recommended
      but when the risk of malignancy is high it is preferable to advise VATS as the
      method of diagnosis.

PMID- 12473944
TI  - [VEGF and survival of patients with lung cancer: a systematic literature review
      and meta-analysis].
AB  - The process of angiogenesis is an important factor in tumour development. One of
      the principal factors implicated in this process is vascular endothelial growth
      factor (VEGF) which induces, among other things, an increase in vascular
      permeability. We have undertaken a systematic review of the English and French
      literature in order to clarify its effect on the survival of patients with small
      cell (SCLC) and non-small cell (NSCLC) lung cancer. To be eligible studies had to
      deal with the the evaluation of VEGF or its receptors in lung cancer and describe
      the relationship of their expression to survival. The survival figures were
      subject to meta-analysis after a methodological evaluation by means of a specific
      numerical scale evaluating the design of the study, the methodology (including
      laboratory techniques), and the analysis of results. Among the 20 studies
      selected 15 identified VEGF expression, using univariate analysis, as a
      statistically significant indicator of poor prognosis. 17 reported sufficient
      data to allow aggregation of the survival figures, of which 15 were devoted to
      NSCLC (1,549 patients). The median overall methodological score was 48.3% (range
      21.8-72.4%), without significant difference (p=0.63) between studies eligible or
      non-eligible for meta-analysis. The meta-analysis, using the authors' threshold
      of positivity for VEGF, showed that VEGF is an unfavourable prognostic factor in
      NSCLC (HR=1.48; 95% confidence interval 1.27-1.72). The data were insufficient to
      determine the prognostic value of VEGF in SCLC and that of its two receptors Flt
      1 and KDR, with 1, 2 and 1 published studies respectively. In conclusion the
      expression of VEGF in MSCLC is a factor indicating a poor prognosis.

PMID- 12473945
TI  - [The AIRE Study: data analysis of 753 European children with asthma].
AB  - PROBLEM: To analyse the paediatric data from the AIRE study (Asthma insights and
      reality in Europe) describing the standard of asthma control in Europe. MATERIAL
      AND METHODS: Among the 73,880 households contacted by telephone in 7 countries
      753 children under the age of 16 were identified. An interview was conducted with
      a close relative to determine the frequency and severity of symptoms during the
      recent month, visits to casualty and hospital admissions during the past year,
      the medications used, the effects on the lives of the children, the opinions of
      the parents on the level of control of asthma and the monitoring methods used.
      RESULTS: 38.2% of children reported diurnal symptoms and 28% disturbance of sleep
      at least once a week. The consequences were important: limitation of sporting
      activities (29.5%) and absence from school (42.7% in the past year). Treatment
      was inadequate: 26% of children used inhaled steroids yet 45.9% had persistent
      asthma. The level of control was overestimated: 61% of parents of children with
      severe persistent asthma considered the asthma to be well controlled. CONCLUSION:
      European asthmatic children are poorly controlled, under-treated and rarely
      followed up. The consequences, particularly absence from school, should stimulate
      an improvement in their therapeutic and educational management.

PMID- 12473946
TI  - [Diaphragmatic weakness in sepsis: the role of oxidant stress].
AB  - In sepsis contractile weakness of the diaphragm is a major cause of the onset of
      respiratory failure. This muscular weakness is the result of haemodynamic and
      metabolic disorders secondary to sepsis and also the damaging effects of
      inflammatory mediators, among which oxygen free radicals play a crucial role.
      This role is demonstrated by the protective effect of various exogenous anti
      oxidants on diaphragmatic contraction. Early in the course of sepsis there is, in
      animal models and in man, an increased production of oxygen free radicals and
      nitric oxide (NO) in the diaphragm, principally within the mitochondria. The
      formation of peroxinitrite as the result of the action of NO on superoxide anions
      impairs mitochondrial respiration and consequently the energy production
      necessary for diaphragmatic contraction. Among the endogenous anti-oxidant
      systems haem oxygenase, which splits haemoglobin into bilirubin, iron and carbon
      monoxide, is an effective system for the protection of diaphragmatic function by
      limiting the damage of oxidant stress. Nevertheless a transient deficiency of
      local anti-oxidant defences during the early stages of sepsis, when the
      production of oxygen free radicals is intense, encourages the onset of
      contractile weakness.

PMID- 12473947
TI  - [Origin and evolution of the respiratory tract in vertebrates].
AB  - The description of the evolution of Vertebrate lung is based on comparative
      anatomy and physiology, combined with phylogenetics. An air-breathing organ
      (ABO), in addition to gill respiration, appeared in fishes about 400 M years ago.
      It consisted of a single primitive lung ventilated by a buccal pump. This
      breathing system was adopted by the first terrestrial tetrapods, and is largely
      preserved in current amphibians. In the Amniotes, the buccal pulsing pump has
      been replaced with a costal aspiration pump. In mammals, this ABO evolved into a
      bronchoalveolar lung. In "Reptiles", the ABO is a partitioned lung with one or
      several cavities. It serves as a gas exchanger but also as an O(2) reserve, which
      allows for long periods of apnoea. In birds, the ABO is a tubular structure
      ventilated by unidirectional airflow. Such a breathing system allows for high
      rates of O(2) consumption. The diversity of structure and function of the
      Vertebrate lung should not be analysed as a progression of increasing complexity
      towards mammal lungs, but rather as diverse responses to varying environmental
      conditions and phylogenic constraints, and to the challenge of acquiring oxygen
      necessary for aerobic metabolism.

PMID- 12473948
TI  - [Treatment of bronchial carcinoma in the elderly].
AB  - Elderly patients form an increasing proportion of the lung cancer population.
      However, they are poorly represented in clinical trials. The published studies
      are generally phase II trials on highly selected small numbers of patients.
      Applying these trials to clinical practice is therefore difficult and this is
      compounded by the fear of increased treatment toxicity in elderly patients. In
      the event of organ failure (respiratory, cardiac or other organ failure), where
      conventional therapy is not possible, there are a number of alternative options:
      radiotherapy for inoperable limited non-small-cell-lung cancer, chemotherapy
      without platinum for those with more extensive disease or with analogues of
      platinum for small-cell-lung-cancer. Finally, adjunctive therapy with
      haematopoietic-cell growth factors or cytoprotectors may allow full doses of
      treatment to be delivered whilst limiting toxicity. More studies in elderly
      patients, with larger numbers, are needed to develop more rational therapeutic
      strategies. We present here some studies of reference and the most recent
      publications on this subject.

PMID- 12473949
TI  - [Respiratory tract infections in the elderly living in institutions: prevention].
AB  - Pneumonia amongst elderly people living in institutions is common and is a
      frequent cause of mortality and hospital admission. It is important to
      distinguish between prevention of viral pneumonia, which primarily consists of
      influenza vaccination programmes, and prevention of bacterial pneumonia.
      Prevention of influenza infection in institutions requires the vaccination of as
      many as possible of both residents and caregivers. In the event of a declared
      epidemic then amantadine can be used to reduce the severity of, and complication
      rate of, influenza infection. The indications for giving this therapy need to be
      balanced against potential side-effects, especially neurological ones. For the
      prevention of bacterial pneumonia risk factors such as immobility or impaired
      swallowing should be first identified and dealt with as necessary. Anti
      pneumoncoccal vaccination may be considered, but on current evidence, the value
      of systematic vaccination of residents has not yet been established.

PMID- 12473950
TI  - [Meta-analysis: a guide to interpretation].
AB  - The article has as purpose to propose a systematic approach for the reading of
      meta-analysis. Using a particular example, a literature search is proposed to
      identify the two types of meta-analyses: those based on individual data of the
      patients and those performed in systematic reviews of the literature. The
      proposed approach for the literature reading is evidence-based.

PMID- 12473951
TI  - [A case of atypical cryptogenic organising pneumonitis during pregnancy].
AB  - Cryptogenic organising pneumonitis (COP) is now a well defined clinico
      pathological entity. It may be idiopathic or secondary to infection, a drug
      reaction or a connective tissue disorder. Corticosteroid treatment is remarkably
      effective. We describe a case of COP occurring during the course of an acute
      respiratory distress syndrome in a pregnant woman. The unusual association of
      blood and pulmonary eosinophilia leads us to envisage a borderline form of COP
      and eosinophilic pneumonitis. Other unusual features were the poor response to
      steroids and the rapid improvement following death of the foetus.

PMID- 12473952
TI  - [Exercise-induced laryngomalacia].
AB  - Exercise-induced laryngomalacia is a rare differential diagnosis of exercise
      induced asthma. We report the case of a previously fit 14-year-old female patient
      who presented with dyspnoea on intense exertion and whose condition had not
      improved with treatment prescribed for a misdiagnosed exercise-induced asthma. A
      diagnosis of exercise-induced laryngomalacia was eventually made when a variable
      extra-thoracic airway obstruction on the flow-volume loops was obtained after an
      incremental exercise test. Flexible fiberoptic rhinolaryngoscopy confirmed this
      abnormality and demonstrated an anterior prolapse of the arytenoid region,
      partially obstructing the airway. The patient therefore underwent laser
      aryepiglottoplasty which produced a satisfactory anatomical outcome in the larynx
      but which only resulted in a partial functional improvement. Laryngomalacia is
      rare and its pathophysiology is not well understood. However, it should be
      considered in patients presenting with exertional dyspnoea, particularly if there
      is inspiratory embarrassment, who fail to improve with beta-2-adrenergic
      agonists. The diagnosis can be made from the flow-volume loop and direct
      laryngoscopy, before and after exercise.

PMID- 12473953
TI  - [Severe interstitial pneumonitis related to Gemcitabine].
AB  - Gemcitabine is used to treat solid tumours such as non small-cell lung cancer. In
      general, it is a well tolerated cytotoxic agent and myelosuppression is the major
      dose limiting side-effect. Pulmonary toxicity has been described and dyspnoea
      occurs in approximately 8% of patients in whom, for the majority, it is mild and
      reversible. But several cases of acute respiratory distress syndrome (ARDS)
      related to Gemcitabine treatment have been reported since 1997 and a few were
      fatal. We present a case of Gemcitabine toxicity in a patient treated for a lung
      cancer. He presented with a respiratory distress syndrome due to acute
      interstitial pneumonitis from which he promptly recovered with corticosteroid
      therapy.

PMID- 12473954
TI  - [Isolated intrapulmonary plasmacytoma; diagnostic and therapeutic difficulties].
AB  - Localised intrapulmonary plasmacytoma represents less than 5% of all
      extramedullary plasmacytomas. Their diagnosis is usually made difficult by a
      radiological presentation and non specific endoscopic findings as well as non
      contributory biochemical and cytological data. This often justifies the recourse
      to more invasive histological investigation aided by immunohistochemical
      techniques. We report the case of a patient who presented with an isolated
      plasmacytoma in the form of two parenchymatous pulmonary masses and who was
      treated by a combination of surgical resection and external radiotherapy. A
      search for multiple intraosseous myeloma remained negative. Unfortunately a
      relapse in the form of mediastinal invasion occurred 6 months after the
      completion of treatment and led to the death of the patient.

PMID- 12473955
TI  - [Enlarged hila and dyspnea].

PMID- 12473956
TI  - [Clinical investigation of the function of nasal fossae].

PMID- 12473957
TI  - [Revision of the 3rd Consensus Conference in Intensive Care and Emergency
      Medicine in 1988: management of acute asthmatic crisis in adults and chidren
      (excluding infants)].
AB  - Experts designated by the "referentiels" committee of the SRLF analyzed the
      numerous articles published after the French consensus conference on the severe
      acute asthma of 1988. From their work, a revision of this consensus conference
      has been performed. The pediatric specificity has been added in this revision.
      There is no severity score able to predict the severity of acute asthma on
      admission. In every case, the nebulization of beta-2 agonists represents the
      priority treatment. The nebulization of anticholinergic associated with the beta
      2 agonists induces a moderate additional effect. In the absence of response to
      nebulizations, the usefulness of the beta-2 agonists associated intravenous.
      Administration is not demonstrated. Corticosteroids should be administered using
      a 1 to 2 mg per kg dosage, but their efficacy is delayed. In adult patients,
      aminophylline should not be prescribe, but it is still used by some
      pediatricians. Other associated treatments (adrenaline, magnesium sulfate, helium
      oxygen mixture) did not demonstrate their efficacy as adjunctive therapies. The
      therapeutic response should be evaluated using the peak flow determination.

PMID- 12473959
TI  - Gamma hydroxybutyrate (Xyrem) for narcolepsy.

PMID- 12473960
TI  - Adefovir (Hepsera) for chronic hepatitis B infection.

PMID- 12473961
TI  - Clinical significance of drug binding, protein binding, and binding displacement
      drug interactions.
AB  - Drugs widely used in clinical psychopharmacology, with few exceptions, are
      hepatically eliminated and circulate in the blood bound to plasma proteins.
      Often, the degree of binding is high (>90%). This fact has led to a widespread
      belief that such drugs may frequently participate in drug-binding interactions.
      The logic is as follows: Coadministration of drugs can result in a highly bound
      drug displacing a less avidly bound drug from its binding sites. This leads to
      greater amounts of free, nonprotein-bound, drug available for distribution to the
      sites of action. As free drug is a major determinant of pharmacologic effects,
      these drug interactions could result in toxicity and/or enhanced efficacy. This
      reasoning simplifies a complex situation where compensatory changes occur in the
      body to buffer the impact of drug-binding interactions. There are few examples
      where the above events have been documented to occur with psychoactive drugs
      leading to substantial clinical consequences. Although protein-binding
      displacement interactions are generally of minimal clinical significance, this is
      an assumption not based on evidence, but rather the lack of it. The purpose of
      this review is to examine some relevant aspects of drug-protein binding and draw
      conclusions for clinical practice about the significance of drug binding and drug
      binding displacement interactions. Psychopharmacology Bulletin.

PMID- 12473962
TI  - Clinical significance of drug binding, protein binding, and binding displacement
      drug interactions.
AB  - In the course of treatment of psychiatric patients, it is often necessary to
      switch antipsychotic medications. In recent years, atypical antipsychotic agents
      have become the first-line therapeutic interventions for treating psychotic
      symptoms. Reasons for switching patients from the typical antipsychotics to the
      atypical agents can include enhanced efficacy against negative symptoms,
      improvement in cognitive capacity, and reduction of risk of extrapyramidal side
      effects. The presumed long-term benefits of switching to the new antipsychotic
      drug should be assessed. Pharmacokinetic and pharmacodynamic properties of
      antipsychotic agents and drug-drug interactions should be considered during the
      switch process. Two methods are employed for the switch process: crossover
      ("crosstitration") and an abrupt switch. With the crossover method, the patient's
      current medication is tapered over a period of several days to several months to
      prevent potential withdrawal symptoms, such as nausea, vomiting, insomnia, muscle
      aches, and diaphoresis. Due to withdrawal symptoms, clozapine is the only
      atypical agent recommended to proceed with a slow dose taper when switching to
      another atypical drug. Sudden cessation could also precipitate the emergence of
      motor symptoms, which can include pseudoparkinsonism, dystonia, akathisia, and
      dyskinesia. The initiation of the new antipychotic occurs concurrently with the
      tapering of the previous drug. In an abrupt switch, the previous antipsychotic is
      discontinued suddenly, independent of its dose, and the new antipsychotic is
      started on the next day. Both methods have been used in clinical practice and
      double-blind studies. To date, only two medications have been studied in large
      multicenter clinical trials. These are olanzapine and ziprasidone. The olanzapine
      study revealed optimal benefits when the previous agents were gradually withdrawn
      and olanzapine was initiated at 10 mg/day. The ziprasidone switch study
      demonstrated both reduced adverse side effects from the previous agents and
      improvements in clinical efficacy. Additional studies are needed to examine the
      optimal methods for switching patients from one atypical agent to another
      atypical antipsychotic.

PMID- 12473963
TI  - Psychosis and delirium following metabolife use.
AB  - Weight gain is a well-known complication of antipsychotic therapy, especially
      when using newer atypical antipsychotic agents. In addition to the risk of
      medical comorbidities associated with weight gain, such as diabetes mellitus and
      cardiovascular disease, a further risk of antipsychotic-induced weight gain is
      that patients may resort to over-the-counter preparations to aid in weight loss.
      We report on a case in which a patient with schizophrenia began using Metabolife,
      an herbal preparation containing ephedra, for weight reduction and subsequently
      developed an exacerbation of his psychosis with superimposed delirium. We mention
      several relatively safe alternatives to herbal supplements for weight loss, as
      well as emphasize the need for clinicians to educate their patients regarding the
      potential risks of over-the-counter weight loss agents.

PMID- 12473964
TI  - Dependence, dementia, cerebellar dysfunction, and myopathy in association with
      chronic isopropanol ingestion.
AB  - Little is known about the chronic sequelae of isopropanol ingestion. Acute
      effects of isopropanol ingestion include central nervous system depression,
      gastrointestinal irritation, impaired gluconeogenesis, delirium, hypotension, and
      coma. We present a case of a patient who preferentially consumed isopropyl
      alcohol for at least 17 years and developed sequelae of alcoholic neuromyopathy,
      recurrent rhabdomyolysis, cerebellar dysfunction, and dementia. Issues related to
      the patient's preferential consumption of isopropanol are discussed, along with
      descriptions of the neurobehavioral, neurophysiologic, and neuropathologic
      studies related to her chronic isopropanol ingestion. The epidemiology of
      nonbeverage alcohol is briefly reviewed, and clinicians are encouraged to inquire
      about nonbeverage-alcohol consumption in patients presenting with alcohol-related
      problems.

PMID- 12473965
TI  - The effect of a novel dietary intervention on weight loss in psychotropic drug
      induced obesity.
AB  - Weight gain associated with the use of psychotropic drugs may be related to their
      blockade of serotonin receptors which mediate satiety. Obese individuals whose
      weight gain followed psychotropic drug use, or control nondrug-treated obese
      subjects, were treated with a 12-week weight loss program that included a
      carbohydrate-rich, protein-poor beverage thought to increase brain serotonin.The
      38 psychotropic drug treated females lost slightly more weight than their 60
      nondrug-treated controls, ie, 13.4-/+1.8 pounds versus 12.1-/+1.1 pounds. The
      eight drug-treated males lost 26-/+4.1 pounds and their 12 nondrug-treated
      controls lost 22.2-/+3.2 pounds. Weight loss was significant in all groups (all
      P<.001). A treatment program that included a high carbohydrate dietary supplement
      caused as much weight loss among patients on psychotropic drugs as among control
      obese patients, without blocking the drugs' therapeutic effects.

PMID- 12473966
TI  - Candidate gene studies in eating disorders.
AB  - It has become increasingly clear that biological factors contribute to the
      etiology of eating disorders. Vulnerability to anorexia and bulimia nervosa is
      due, at least in part, to the effect of genes. The purpose of this paper is to
      review the extant literature on association studies of putative candidate genes
      for eating disorders.

PMID- 12473967
TI  - Antipsychotic medications and sudden cardiac death.
AB  - The objectives of this paper are to: 1) discuss practical aspects of
      antipsychotic induced QT prolongation, torsades de pointes (TdP) and sudden
      cardiac death, 2) discuss its possible mechanisms, 3) review data for each
      antipsychotic medication or class of medications and, 4) present recommendations
      from the literature. We performed computerized searches of the biomedical
      literature utilizing MEDLINE and PsycINFO computer databases (1966-2001), and by
      reviewing bibliographies to identify all pertinent case reports, case series, and
      formal studies using the following search terms: antipsychotics, sudden cardiac
      death, and QT prolongation. QT prolongation is a dynamic phenomena affected by
      various factors (mood, disease states, gender, medication, etc.). Sudden cardiac
      death attributable to antipsychotic medications seems to occurs in a step-wise
      fashion beginning with QT prolongation, leading to TdP, which can progress to
      cardiac arrest. Blocking the rapidly-acting potassium rectifier current appears
      be the primary mechanism of QT prolongation in drugs known to cause TdP and
      sudden cardiac death. All antipsychotic medications have been shown to cause QT
      prolongation, however, the degree to which this occurs and the risk of TdP
      varies. The risk of sudden cardiac death increases with higher doses of
      medications, use of phenothiazines or intravenous butyrophenones, and in patients
      with certain medical illnesses, especially cardiac disease. In order to prevent
      sudden death from antipsychotic medications, we recommend obtaining screening
      electrocardiograms in all at-risk patients, follow-up electrocardiograms after
      the initiation of medication, and using the lowest effective dose of medication.
      If QT prolongation occurs, the risks and benefits of therapy should be considered
      and medication adjustments made if warranted.

PMID- 12473968
TI  - Citalopram for the treatment of adolescent anxiety disorders: a pilot study.
AB  - Charts of 17 adolescent patients treated naturalistically with citalopram for
      various anxiety disorders were reviewed. Patients were retrospectively assessed
      using the Clinical Global Impression (CGI)-Severity scale at the beginning and
      end of treatment. Eighty-two percent (14/17) of patients were rated as much or
      very much improved on the CGI-Improvement scale after treatment with citalopram.
      Patients were treated for an average of 156-/+85.1 days at a mean dose of 32.3
      /+18.5 mg/day of citalopram. Fifty-three percent (9/17) of this sample had
      previous exposure to alternative selective serotonin reuptake inhibitors, and 89%
      (8/9) of those patients responded positively to citalopram. Citalopram appeared
      well tolerated, with only one patient discontinuing treatment due to side
      effects. In this naturalistic setting, citalopram appeared to be a well-tolerated
      and effective treatment for a range of anxiety disorders in adolescents.

PMID- 12473969
TI  - Ginkgo biloba: a smart drug? A systematic review of controlled trials of the
      cognitive effects of ginkgo biloba extracts in healthy people.
AB  - Extracts of Ginkgo biloba are widely used to alleviate or delay the progress of
      age-related cognitive impairment. Its use as a "smart" drug by healthy
      individuals has also been commercially promoted. The aim of this study was to
      systematically review and critically evaluate the trial data to test whether
      Ginkgo biloba enhances cognitive function in healthy subjects. Literatures
      searches of 6 computerised databases were made for placebo-controlled, double
      blind trials of the effect of standardized Ginkgo biloba extracts on cognitive
      function in healthy subjects. Trials published in any language were included and
      data were extracted independently by the authors following a standardized
      protocol. Nine trials were identified, and these were mainly short term. The
      longest had a treatment period of 30 days. Trials were mostly of good intrinsic
      methodological quality, but certain aspects of methodology were inadequately
      reported by all trials. Taken together, these studies indicate no marked or
      consistent positive effects of Ginkgo biloba on any particular objective measure
      of cognitive function. A positive subjective effect was reported only in the
      longest trial. It is concluded that a positive effect of Ginkgo biloba on
      cognitive function is not proven by data from rigorous clinical trials. The use
      of Ginkgo biloba as a "smart" drug cannot be recommended on the basis of the
      evidence available to date, and there is a particular need for further long-term
      trials with healthy subjects.

PMID- 12473970
TI  - Monoamine oxidase inhibitors: a new generation.
AB  - Monoamine oxidase inhibitors (MAOIs), which ushered in the modern era of
      psychopharmacology in the 1950s, have remained useful in the treatment of
      depression despite important safety concerns, such as acute hypertensive episodes
      brought on by ingestion of foods with high-tyramine content. Experience has shown
      that MAOIs are broadly effective in the treatment of depressive disorders,
      including atypical, chronic, and double depressions. Newer selective and
      reversible inhibitors of the two forms of mitochondrial monoamine oxidase (MAO)
      enzymes, MAO-A and MAO-B, have been developed in an effort to improve the safety
      and tolerability of MAOIs. Selegiline, a selective inhibitor of MAO-B has been
      shown to be effective in the treatment of depression at higher oral doses where
      selectivity for MAO-B is lost. Transdermal delivery of selegiline bypasses first
      pass metabolism and avoids impairment of the gastrointestinal barrier provided by
      MAO-A of the gastrointestinal mucosa. Studies have shown that the selegiline
      transdermal system (STS) does not significantly affect sensitivity to ingested
      tyramine, unlike tranylcypromine, which markedly increases sensitivity. STS has
      been found to be efficacious in the treatment of patients with major depression
      in placebo-controlled trials, without the need for dietary precautions. The
      favorable safety profile of STS should allow this MAOI to be a broadly used
      antidepressant drug.

PMID- 12473971
TI  - [The principles of tissue engineering: role of growth factors in the bone
      regeneration].
AB  - In this article the principles of tissue engineering are analyzed. The growth
      factors release from platelets, TGF-beta, PDGF, IGF-I and -II, are accurately
      described and the structure and functions of these growth factors are reported.
      Then a simple model of bone regeneration is proposed. This model is used every
      time that bone grafts are used in oral and maxillofacial surgery. On the basis of
      this model of bone regeneration, the cells and biochemical indicators (pH and
      pO2) of bone wound where the bone graft is placed, and of surrounding tissues,
      are described. Then three phases of bone regeneration are analyzed: the
      beginning, the second (or immature bone), the third or mature bone with lamellar
      architecture. In each phase the importance of growth factors are evaluated. The
      conclusion is drawn that factors influence the bone regeneration and that their
      increased concentration leads to a quick bone formation and quantity. Moreover,
      the techniques of regeneration in vivo with autogenous bone, are better than
      those in vitro, since the bone structure, is also the result of the biomechanical
      environment, where the bone graft grows up.

PMID- 12473972
TI  - Clinical-statistic survey regarding odontogenic keratocysts in a sample of
      population in Eastern Sicily.
AB  - BACKGROUND: The aim of this study is to point out the frequency, histologically
      documented, of the odontogenic keratocysts in Eastern Sicily, through the study
      of a sample of 220 cystic neoformations. Of these, those presenting
      histopathological peculiarities of odontogenic keratocysts have been examined.
      METHODS: Fifteen keratocysts were histologically classified. The following
      characteristics were examined: histological character, age and sex, location of
      the lesion, association to unerupted teeth. RESULTS: Of the 220 cystic
      neoformations observed, at the histological examination, 15 were odontogenic
      keratocysts. The 53% were found in males, against the 47% in females. In the 67%
      of the cases the lesion involved lower-jaw, against the 33% of the jaw-bone. The
      greatest frequency was found in the angle of the mandible, followed by the
      frontal region of the jaw-bone, by the premolar/molar region of the mandible, by
      the lower frontal region and by the premolar/molar region of the jaw-bone. None
      odontogenic keratocysts relapsed following surgical operations. Patients are kept
      under observation and, to this point, elements of release have not emerged.
      CONCLUSIONS: The epidemiologic data found, are in line with those of the
      literature. We confirm the necessity of a precocious diagnosis for programming a
      correct surgical treatment and for reducing the risk of relapse and of
      ameloblastomatouses transformation.

PMID- 12473973
TI  - [In vitro evaluation of chromatic stability in new-generation composites].
AB  - BACKGROUND: Ultraviolet light exposure produces chromatic changes in composites
      used for esthetic restoration. The aim of the study was to compare the chromatic
      changes induced by accelerated aging in two composites of new generation: Tetric
      Ceram and Diamond Crown. METHODS: Five samples were prepared for each composite,
      each divided into two pieces, one exposed to accelerated aging obtained by
      ultraviolet-light exposure for 24 hours, and one maintained in dark. Thereafter,
      the samples were lighted by a light beam and the percentage of reflected light
      was assessed. The distribution of the levels of red, green and blue was assessed
      using a camera connected to a PC with a software for image processing. RESULTS:
      For both the composites, the values of the three colors were significantly lower
      in the samples artificially aged (p<0.0001). The values concerning to the Tetric
      Ceram were significantly lower than those of Diamond Crown (p<0.0001). The latter
      showed aging-induced variation significantly smaller than the former.
      CONCLUSIONS: Both the composites showed significant chromatic variations after 24
      hours artificial aging. Diamond Crown showed significantly better stability.

PMID- 12473974
TI  - [Idiopathic osteosclerosis in jaw bones. Clinical statistic study on a population
      of Sardinian origin].
AB  - BACKGROUND: Idiopathic Osteosclerosis are localized, non-expansive and
      asymptomatic areas of bone radio-opacity, whose aetiology is unknown. The aim of
      this study was to assess its frequency, and distribution according to its
      location and to patients' age and gender, in a sample of patients native in
      Sardinia. METHODS: 697 consecutive clinical records of patients who underwent
      odontological treatment at the Department of Odontostomatologic Sciences at
      Cagliari University, over a 10-year period were studied. The panoramic
      radiographs attached to the clinical records were examined and searched for all
      cases that showed radio-opacity areas in maxillary bones that could be identified
      as idiopathic osteosclerosis (IO). RESULTS: By examining orthopantomographies we
      have located 58 IOs. We found no significant differences between the sexes;
      average age was 37.8 years. The mandible has proved to be the most affected site
      (98.2%) in the first molar tooth region (34.5%), followed by the premolar teeth
      region (25.9%) and of the second molar tooth (15.5%). The lesions examined had an
      average diameter of 8.8 mm. CONCLUSIONS: IO frequency has proved to be slightly
      higher than that reported in other articles, though remaining significantly lower
      than the values reported in Eastern populations. From the clinical point of view,
      IOs have been identified as sporadic radiographic findings without any real
      pathological relevance, except for one case in which the lesion caused nervous
      compression and dental retention, so that it was necessary to administer specific
      treatment.

PMID- 12473975
TI  - Mucoceles of the frontal sinus. Clinical and therapeutical considerations.
AB  - BACKGROUND: Mucocele is an epithelial lined mucus-containing sac completely
      filling a paranasal sinus and capable of expansion by virtue of a dynamic process
      of bone resorption and new bone formation. It is the most common lesion causing
      expansion of the paranasal sinuses. Even though mucoceles of paranasal sinuses
      are increasingly treated by endoscopic surgery, the external approach with or
      without the obliteration of the sinus still remains a useful and sometimes the
      only tool in the treatment of this disease. METHODS: The results obtained in
      seven patients observed at the ENT Department of the University of Ferrara
      (Italy) in the period ranging from 1989 to 1999 are presented; they were affected
      by massive fronto-ethmoidal mucoceles and treated with the external approach
      alone or combined with an endonasal approach and osteoplastic flap. They were
      five males and two females, with a mean age of 56.5 years. Locations were
      bilateral in one mucocele, while in six patients only one side was involved, with
      a prevalence of the left frontal sinus (4:2). RESULTS: No patient showed any
      local or general complication in the postoperative period. The follow-up showed
      no recurrence of the disease. CONCLUSIONS: Since the osteoplastic flap was
      introduced one hundred years ago, it still remains the optimal surgical treatment
      for fronto-ethmoidal mucoceles. Even though, today, endoscopic surgery represents
      the new horizon in the management of the sinonasal disease, mucoceles need a
      surgical treatment which allows the total vision of the cavity to obtain radical
      treatment and any recurrence of disease.

PMID- 12473976
TI  - Von Recklinghausen neurofibromatosis with palatal localization. Diagnostic and
      surgical problems in two clinical cases.
AB  - This paper illustrates the clinical findings and aims at report surgical matters
      observed in 2 patients affected by neurofibromatosis type I with a rare palatal
      localization. By means of retrospective analysis 2 cases of neurofibromatosis
      type I with a palatal mass are selected. Both cases were surgically treated and
      underwent 12 months follow-up. Patients underwent surgical removal of the palatal
      neurofibroma. At 12 months follow-up a good local condition without any
      recurrence was observed. Malignant transformation was very rarely reported in
      oral neurofibromata and can follow incomplete removal. Surgical treatment of
      neurofibromata requires the sacrifice of the nerve trunk from where they
      originate, together with the complete removal of the mass with security margins.
      Therefore, risks and benefits from surgery should be carefully weighted in each
      patient and where surgery is not performed clinical and radiographic trials are
      advisable.

PMID- 12473977
TI  - [Mandibular hyperostosis. A case report].
AB  - A case of hyperostosis of the left hemimandible medial face in a young patient is
      reported. This in an interesting case both for the remarkable size and the
      location of the lesion and because it was unique and asymmetrical; as a matter of
      fact this pathology, frequent on the jaws, is usually symmetrical and bilateral.
      The most probable etiopathogenetic hypothesis for the case presented to our
      observation seems to be an unknown localized stimulation of osteoblastic cells.
      Considering its size, the lesion was removed.

PMID- 12473978
TI  - Burning mouth syndrome (BMS): an open trial of comparative efficacy of alpha
      lipoic acid (thioctic acid) with other therapies.
AB  - BACKGROUND: Alpha-lipoic acid (ALA) is a potent antioxidant mitochondrial
      coenzyme, trometamol salt of thioctic acid, shown in clinical studies to be
      neuroprotective and in a preliminary study to have an effect on the
      symptomatology of Burning Mouth Syndrome (BMS). METHODS: We were interested in
      extending our studies as to whether alpha-lipoic acid might improve the
      symptomatology in BMS and therefore carried out a larger open controlled clinical
      study on the effects of alpha-lipoic acid on BMS symptomatology. RESULTS: We have
      examined the effects on 4 groups of 20 patients with BMS of ALA, compared with
      bethanecol, Biotene and placebo, and found ALA of remarkable benefit with minimal
      adverse effects. CONCLUSIONS: These results suggest that double-blind randomized
      controlled multicenter studies of ALA are indicated.

PMID- 12473979
TI  - Myoblast transplantation for the treatment of heart failure.

PMID- 12473980
TI  - Ischemic preconditioning. Experimental facts and clinical perspective.
AB  - Brief periods of non-lethal ischemia and reperfusion render the myocardium more
      resistant to subsequent ischemia. This adaption occurs in a biphasic pattern: the
      first being active immediately and lasting for 2-3 hrs (early preconditioning),
      the second starting at 24 hrs until 72 hrs after the initial ischemia (delayed
      preconditioning) and requiring genomic activation with de novo protein synthesis.
      Early preconditioning is more potent than delayed preconditioning in reducing
      infarct size; delayed preconditioning also attenuates myocardial stunning. Early
      preconditioning depends on the ischemia-induced release of adenosine and opioids
      and, to a lesser degree, also bradykinin and prostaglandins. These molecules
      activate G-protein coupled receptors, initiate the activation of KATP channels
      and generation of oxygen radicals, and stimulate a series of protein kinases with
      essential roles for protein kinase C, tyrosine kinases and members of the MAP
      kinase family. Delayed preconditioning is triggered by a similar sequence of
      events, but in addition essentially depends on eNOS-derived NO. Both early and
      pharmacological preconditioning can be pharmacologically mimicked by exogenous
      adenosine, opioids, NO and activators of protein kinase C. Newly synthetized
      proteins associated with delayed preconditioning comprise iNOS, COX-2, manganese
      superoxide dismutase and possibly heat shock proteins. The final mechanism of
      protection by preconditioning is yet unknown; energy metabolism, KATP channels,
      the sodium-proton exchanger, stabilisation of the cytoskeleton and volume
      regulation will be discussed. For ethical reasons, evidence for ischemic
      preconditioning in humans is hard to provide. Clinical findings that parallel
      experimental ischemic preconditioning are reduced ST-segment elevation and pain
      during repetitive PTCA or exercise tests, a better prognosis of patients in whom
      myocardial infarction was preceded by angina, and reduced serum markers of
      myocardial necrosis after preconditioning protocols during cardiac surgery with
      cardiac arrest. The most promising approach to apply principles of ischemic
      preconditioning therapeutically appears to be the pharmacological recruitment of
      delayed protection, as recently demonstrated with intravenous nitroglycerine in
      patients undergoing PTCA 24 hrs later.

PMID- 12473981
TI  - Cardiac risk in noncardiac surgery.
AB  - Preoperative risk assessment plays an important role in reducing perioperative
      morbidity and mortality in patients undergoing noncardiac surgery. In general,
      evaluation should reflect the circumstances of the consultation and the nature of
      the surgical illness. If emergent surgery is indicated, it may not allow further
      cardiac assessment or treatment. Perioperative medical management, surveillance
      and postoperative risk stratification is appropriate in these cases and may be
      instrumental to improving long-term outcomes. Successful perioperative evaluation
      is best achieved with an integrated multidisciplinary approach and good
      communication between the patient, primary care physician, anesthesiologist,
      consultant, and surgeon. A thorough history and physical examination is the most
      important component of a comprehensive preoperative evaluation. In general,
      indications for further cardiac testing and treatments are similar to those in
      the nonoperative setting. Coronary revascularization before noncardiac surgery is
      indicated in only a small subgroup of patients at very high cardiac risk.
      Finally, the goal of appropriate preoperative evaluation and therapy should be to
      not only improve immediate periprocedural outcomes but should also be geared
      towards improved long term clinical outcome.

PMID- 12473982
TI  - Interventional procedures in acute myocardial infarction.
AB  - Acute myocardial infarction (AMI) is a leading cause of death in the western
      world. Primary percutaneous intervention (PCI) has emerged as an effective
      therapy that may improve survival and decrease morbidity in patients with AMI.
      Our article discusses the advantages of PCI over thrombolytic therapy and reviews
      currently available techniques. Rescue angioplasty, adjunctive pharmacologic
      therapies, economic and feasibility considerations are also discussed. Emerging
      therapies are also addressed. Evidence supports the first-line use of PCI for
      AMI. Furthermore, primary PCI appears superior to thrombolytic therapy for AMI in
      many patient populations, especially the elderly, patients with prior coronary
      artery bypass surgery, patients with congestive heart failure and in patients
      with cardiogenic shock. Advancements in equipment and techniques and emerging
      adjunctive therapies will continue to enhance this therapy and improve its
      efficacy.

PMID- 12473983
TI  - Troponin in acute coronary syndrome patients. The interventional cardiologist
      perspective.
AB  - Troponin measurement has now become an integral part of the assessment of
      patients with acute coronary syndromes (ACS). Obtaining troponin levels have been
      used effectively as a diagnostic tool with superior sensitivity and specificity
      compared to creatine kinase MB fraction in identifying high-risk ACS patients.
      The adverse prognosis of these high-risk patients can be modified by more
      aggressive treatment strategy including antiplatelet and antithrombotic therapy
      accompanied, if feasible, by early percutaneous intervention. The current review
      summarizes available data on troponin measurement as a clinical tool for
      tailoring therapeutic strategy in non-ST elevation ACS patients. In addition, the
      data on the potential predictive value of postintervention troponin levels is
      discussed.

PMID- 12473984
TI  - Low molecular weight heparins in the treatment of unstable angina.
AB  - Unstable angina is in most cases caused by partial or complete coronary artery
      occlusion due to the disruption of an atherosclerotic plaque and resultant
      thrombus formation. Platelet aggregation and thrombin formation are key events in
      the development of acute coronary syndromes. An immediate antithrombotic approach
      is essential to prevent fatal and non-fatal myocardial infarction, and the
      combination of aspirin and unfractionated heparin has been the treatment of
      choice in the past years. Low molecular weight heparins have improved
      pharmacokinetic and pharmacodynamic properties over unfractionated heparin that
      have resulted in greater efficacy and safety in the field of venous
      thromboembolism. Low molecular weight heparins can be administered by
      subcutaneous injections at fixed, weight adjusted doses without need for
      monitoring. Three low molecular weight heparins have been tested in adequately
      sized clinical trials in patients with unstable angina and non-Q-wave myocardial
      infarction: nadroparin, dalteparin and enoxaparin. The results of the published
      trials have confirmed that the newer compounds are at least as safe and effective
      as unfractionated heparin offering considerable practical and clinical
      advantages. Low molecular weight heparins are currently recommended as
      alternative to unfractionated heparin in the acute management of acute coronary
      syndromes. Nevertheless, the different properties of these compounds and possibly
      the different designs of the clinical trials have resulted in apparent
      differences in clinical outcomes with the different agents. Direct comparisons
      are now required to determine the superiority of one compound over another.

PMID- 12473985
TI  - Inflammatory markers as predictors of clinical outcome in acute coronary
      syndromes.
AB  - Inflammation is a critical pathogenic component in acute coronary syndromes. As a
      consequence the potential use of inflammatory markers as predictors of clinical
      outcome in acute coronary syndromes has been investigated. This review outlines
      the pathology underlying acute coronary syndromes and reviews the published data
      on inflammatory markers in acute coronary syndromes.

PMID- 12473986
TI  - One year temporal pattern of neurohumoral factors and natriuretic peptides
      compared with clinical variables in patients with dilated cardiomyopathy.
AB  - BACKGROUND: Elevated levels of neuroendocrine peptides and hormones are some of
      the compensatory mechanisms activated in patients with congestive heart failure.
      The aim of this study was to describe their time related variability in
      clinically stable patients and to compare hormones and peptides levels to
      clinical variables. METHODS: Nineteen patients with history of congestive heart
      failure due to dilated cardiomyopathy and in sinus rhythm were recruited. At
      baseline, after 3 months, and at 1 year they underwent 6-min walk test, Minnesota
      Living with Heart Failure Questionnaire, and blood measurements of ANP, BNP,
      plasma renin activity, aldosterone, norepinephrine and epinephrine. RESULTS:
      After 1 year, 17 patients remained clinically stable, and did not change their
      therapy and functional class. Also echocardiographic data and neurohormonal
      parameters did not change significantly except for epinephrine that decreased
      significantly after 3 months and returned to a value similar to the basal one at
      1 year. Two outliner values were observed for norepinephrine belonging to the
      only 2 patients that spontaneously withdrew the ace-inhibitor therapy during the
      follow-up. CONCLUSIONS: This study indicates that plasma concentration of
      neurohormones and peptides were fairly stable over 1 year interval in stable
      patients with mild-moderate heart failure due to dilated cardiomyopathy and that
      norepinephrine could be considered as the most sensible parameters to monitor
      therapy compliance.

PMID- 12473987
TI  - [Evaluation of C3c, C4 and C1-esterase inhibitor (C1-INH) during unstable
      angina].
AB  - BACKGROUND: The complement system plays an important role in the physiopathology
      of acute myocardial infarction (AMI) taking part in myocardial damage and
      reperfusion injury. The aim of this study is to investigate the plasmatic levels
      of some complement components (C3c, C4 and C1-INH) during unstable angina (C1
      INH) and their different concentrations in relation to the different myocardial
      areas affected by ischemia. METHODS: The plasmatic levels of C1-INH, C3c and c4
      in 30 patients affected by unstable angina, and those of 22 clinically healthy
      subjects (control group) were evaluated (Nefelometer Behering). The patients were
      divided into four groups according to the different myocardial area affected by
      ischemia (anterior, antero-lateral, lateral or inferior ischemia), RESULTS: No
      statistically significant differences were found in plasmatic levels of C3c, C4
      and C1-INH between the group of patients and the control group. There is a
      statistically significant difference between the C1-INH levels of the patients
      with inferior ischemia and the plasmatic concentrations of the whole patients'
      group (p<0,01), the control group (p<0,01) and the group of patients with lateral
      ischemia (p<0,02). CONCLUSIONS: There seems to be a different activation of the
      complement system during unstable angina, in relation to the different myocardial
      area affected by ischemia.

PMID- 12473988
TI  - Diagnosis of coronary artery disease based on blood pool radioisotope angiography
      at rest.
AB  - BACKGROUND: The author wanted to determine which of 3 parameters (global left
      ventricular ejection, regional left ventricular ejection fraction, or isocontours
      together with peak filling rate and time of peak filling rate) measured with
      blood pool radioisotope angiography at rest was sufficient to permit diagnosis of
      coronary artery disease. METHODS: Thirty-one patients with coronary artery
      disease and 11 hypertensive patients without coronary heart disease were assessed
      with blood pool radioisotope angiography using a computerized large-field gamma
      camera. RESULTS: Of the 3 parameters measured, only assessment of isocontours
      with peak filling rate and time of peak filling rate provided sufficient
      information for establishing a diagnosis of coronary artery disease. In contrast,
      measurement of global left ventricular ejection provided equivocal data, as did
      that of regional left ventricular ejection fraction. CONCLUSIONS: In combination
      with peak filling rate and time of peak filling rate, measurement of isocontours
      by blood pool radioisotope angiography at rest provided sufficient information
      for establishing a diagnosis of coronary artery disease.

PMID- 12473989
TI  - [Treatment of severe intermittent claudication: ORACLE-PGE1 short term study. A
      randomised 40-week study. Evaluation of efficacy and costs].
AB  - BACKGROUND: The efficacy and cost of prostaglandin E1 (PGE1) in severe
      intermittent claudication was studied comparing a long-term protocol (LTP) with a
      short-term protocol (STP) in a randomised 40-week study. METHODS: Phase 1 was a 2
      week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main
      treatment phase. Treatment was performed with 2-hour infusions (60 micro g PGE1,
      5 days each week for 4 weeks. In phase 3 (4-week interval period), PGE1 was
      administered twice a week (same dosage). In phase 4 (40 weeks), no PGE1 were
      used. In STP, phase 2 treatment was performed in two days by a 2-hour infusion
      (60 micro g PGE1 twice a day in 2 days). The same cycle was repeated every 4
      weeks. A treadmill test was performed at inclusion, at the beginning of each
      phase and at the end of weeks 12, 16, 20 32 and 40. A progressive training plan
      (walking) and reduction in risk factors plan was used in both groups. RESULTS:
      Out of the 1276 included patients 1165 completed the study (606 in LTP group; 559
      in the STP). Drop-outs were 111. The two groups were comparable in distribution,
      risk factors and smoking. Intention-to-treat analysis indicated an increase in
      pain free walking distance (PFWD). The absolute and percent increase in pain-free
      walking distance (PFWD) was comparable in both LTP and STP groups with a
      significative increase in TWD at 4 weeks. At 20 and 40 weeks increase was up to
      219% in the LTP and 460% in the STP group (p<0.02). Comparable results concerning
      PFWD were obtained in the two groups. Both treatments were well tolerated. No
      side effect was observed. Local effects were observed in 8.5% of the treated
      subjects in the LTP and 4% in the STP. The average cost of the LTP protocol was
      8786 Euro. For STP the costs was 946 (10.8% of LTP). For both protocols the cost
      of the infusion was 24% of the total for the LTP and 35% in the STP. Therefore
      75% of the cost is not drug-related. CONCLUSIONS: In conclusion between-group
      analysis favours STP considering walking distance and costs. Results indicate
      good efficacy and tolerability of PGE1 treatment particularly STP.

PMID- 12473990
TI  - [Spinal cord electric stimulation. Treatment of serious chronic ischemic
      syndromes of the limbs].
AB  - BACKGROUND: Aim of this study is to estimate the effectiveness of epidural
      electric stimulation of spinal cord for the treatment of patients with severe
      peripheral chronic arteriopathy who can't be surgically treated or when surgical
      therapy failed. METHODS: A retrospective study was carried out on 18 patients
      with peripheral chronic arteriopathy at clinical stage I of Fontaine
      classification; average age was of 60.08 years an they had rest pain and
      dystrophic lesions. Five patients couldn't be surgically treated. Stimulator
      catheter was placed in the epidural space and its action was evaluated studying
      lesion demarcation and pain resolution. RESULTS: In 16 cases there was a good
      pain control and in 14 patients lesion demarcation, while in 4 cases there was
      cases no improvement and amputation was necessary. CONCLUSIONS: Epidural electric
      stimulation of spinal cord is a valid treatment in selected patients for ischemia
      pain control and limb savage.

PMID- 12473991
TI  - Collateral circulation in internal carotid artery occlusion. A study by duplex
      scan and magnetic resonance angiography.
AB  - BACKGROUND: Clinical effects of internal carotid artery (ICA) occlusion may range
      from the absolute absence of symptoms to lethal hemispheric stroke. In this paper
      symptoms of patients with ICA occlusion have been related to the development of
      collateral circulation, different types of developed collateral circulation have
      been assessed, and the degree of sensitivity and specificity of duplex scan has
      been appraised. METHODS: Forty-eight patients with ICA occlusion or subocclusion,
      24 males and 24 females, aged between 50 and 83 years (67.7+/-7.15), underwent
      duplex scan and magnetic resonance (MR) angiography. Nineteen patients were
      completely asymptomatic, 20 patients showed permanent neurological symptoms and 9
      patients had shown transient symptoms. RESULTS: Twelve patients (25%) did not
      show any collateral circulation, 29 patients (60%) showed collateral circulation
      through homolateral external carotid artery branches and 7 patients (15%) showed
      collateral circulation through other circuits. Of the 20 patients with permanent
      symptoms only 8 showed collateral circulation. On the contrary, all the 19
      asymptomatic patients and the 9 patients with transient symptoms showed
      collateral circulation. Eventually, duplex scan showed 78% sensitivity, 100%,
      specificity and 83% diagnostic accuracy. CONCLUSIONS: Our data show: 1) a clear
      cut prevalence of collateral circulation through homolateral external carotid
      artery branches with respect to other possible collateral circulation; 2) an
      inverse relationship between the development of collateral circulation and the
      appearance of permanent symptoms; 3) a good diagnostic accuracy of duplex scan in
      revealing collateral circulation in the case of ICA occlusion.

PMID- 12473992
TI  - Free radical scavenger activity of rutosides.
AB  - BACKGROUND: The O-(beta-hydroxyethyl)-rutosides (HRs) are a standard mixture of
      flavonoid-derivatives that have a clinico-pharmacological activity on peripheral
      circulation, particularly on the endothelial cells of veins and lymphatics.
      Flavonoids are believed to prevent the oxidative damage derived from radical
      oxidative species (ROS), like hydroxyl radicals (HO.) and hypochlorite (-OCl).
      The aim of the study was to investigate the stability and capability of HRs in
      toto and of their single components (7-mo-nohydroxy ethyl rutoside; 7,4'
      dihydroxyethyl rutoside; 7,3',4'-trihydroxyethyl rutoside and the 7,5,3',4'
      tetrahydroxyethyl rutoside) of scavenging ROS and other radicals generated by
      different oxidative systems, and also their anti-lipoperoxidative activity at mM
      concentrations (1.0-10.0 mM). METHODS: The following oxidative systems have been
      employed: Fenton reaction for the hydro-xylation of l-tyrosine to l-DOPA and the
      peroxidation of arachidonic acid; photo-Fenton type reaction for the oxidation of
      toluene in the aqueous UV irradiated TiO2 system; the azocompound 2.2'-azobis(2,
      4-dimethylvaleronitrile (AMVN) to produce peroxy radicals and the daily
      autoxidation of arachidonic acid. Analyses were performed by HPLC, HPLC-MS, GC
      MS, and spectrophotometry. RESULTS: At 5.0 mM concentration, HRs produced the
      following inhibitions: 63+/-5% of the overall formation of cresols, benzaldehyde,
      benzyl alcohol, and biphenyl induced by photo-Fenton reaction; 91.6+/-5% and 59+/
      8% of the synthesis of l-DOPA induced by HO. generated by Fenton reaction; 45+/
      7% and 52+/-6% of the oxidation of arachidonic acid induced by Fenton reaction
      and AMVN; 60+/-4% of the autoxidation of arachidonic acid. These effects were
      strictly concentration dependent. CONCLUSIONS: At mM concentrations, HRs display
      a significant antilipoperoxidative activity due to their notable scanvenging
      activity against HO.; moreover these actions are concentration-dependent.

PMID- 12473993
TI  - Comparison of post-gel shrinkage strains in light-polymerized composite resins.
AB  - STATEMENT OF PROBLEM: Polymerization shrinkage is associated with light
      polymerized and polyacid-modified composites. PURPOSE: This in vitro study
      compared the polymerization shrinkage of a light-polymerized hybrid composite, a
      posterior composite, and a polyacid-modified composite. MATERIAL AND METHODS:
      Five disk-shaped specimens (1 cm in diameter and 2 mm in thickness) were prepared
      in a mold from each of the following test materials: a light-polymerized hybrid
      composite (3M Valux Plus), a posterior composite (Filtek P60), and a polyacid
      modified composite (Dyract AP). The hybrid composite served as the control
      material. A linear strain gauge was placed at the center of each specimen. After
      the specimens were light-polymerized for 60 seconds under 400-mW/cm(2) light
      intensity, microstrains were recorded with the strain indicator continuously
      every 4 seconds for 120 seconds. The data were evaluated with 1-way analysis of
      variance (P<.05) followed by a post hoc least significant difference test.
      RESULTS: During the first 20 seconds of light polymerization, all materials
      exhibited tensile strains between 6 and 55 mu epsilon that quickly converted into
      compressive strains and continued rising after the light source was removed. The
      strains for all materials increased at a declining rate until they reached a
      constant level between 148 and 180 seconds. The polymerization shrinkage recorded
      for Filtek P60 was the lowest (-190.56 mu epsilon), followed by 3M Valux Plus (
      303.94 mu epsilon) and Dyract AP (-345.64 mu epsilon) (P<.05). The dimensional
      change between Filtek P60 and Dyract AP and between Filtek P60 and 3M Valux Plus
      was significant (P=.001). However, the difference between Dyract AP and 3M Valux
      Plus specimens was not significant (P=.208). CONCLUSION: Within the limitations
      of this study, the light-polymerized posterior composite tested demonstrated less
      polymerization shrinkage than the polyacid-modified and hybrid composites tested.
      Polymerization shrinkage velocity significantly affected the magnitude of
      strains.

PMID- 12473994
TI  - Fit of cast commercially pure titanium and Ti-6Al-4V alloy crowns before and
      after marginal refinement by electrical discharge machining.
AB  - STATEMENT OF PROBLEM: Titanium has been suggested as a replacement for alloys
      currently used in single-tooth restorations and fixed partial dentures. However,
      difficulties in casting have resulted in incomplete margins and discrepancies in
      marginal fit. PURPOSE: This study evaluated and compared the marginal fit of
      crowns fabricated from a commercially pure titanium (CP Ti) and from Ti-6Al-4V
      alloy with crowns fabricated from a Pd-Ag alloy that served as a control.
      Evaluations were performed before and after marginal refinement by electrical
      discharge machining (EDM). MATERIAL AND METHODS: Forty-five bovine teeth were
      prepared to receive complete cast crowns. Stone and copper-plated dies were
      obtained from impressions. Fifteen crowns were cast with each alloy (CP Ti, Ti
      6Al-4V, and Pd-Ag). Marginal fit measurements (in micrometers) were recorded at 4
      reference points on each casting with a traveling microscope. Marginal refinement
      with EDM was conducted on the titanium-based crowns, and measurements were
      repeated. Data were analyzed with the Kruskal-Wallis test, paired t test, and
      independent t test at a 1% probability level. RESULTS: The Kruskal-Wallis test
      showed significant differences among mean values of marginal fit for the as-cast
      CP Ti crowns (mean [SD], 83.9 [26.1] microm) and the other groups: Ti-6Al-4V
      (50.8 [17.2] microm) and Pd-Ag (45.2 [10.4] microm). After EDM marginal
      refinement, significant differences were detected among the Ti-6Al-4V crowns
      (24.5 [10.9] microm) and the other 2 groups: CP Ti (50.6 [20.0] microm) and Pd-Ag
      (not modified by EDM). Paired t test results indicated that marginal refinement
      with EDM effectively improved the fit of CP Ti crowns (from 83.9 to 50.6 microm)
      and Ti-6Al-4V crowns (from 50.8 to 24.5 microm). However, the difference in
      improvement between the two groups was not significant by t test. CONCLUSION:
      Within the limitations of this study, despite the superior results for Ti-6Al-4V,
      both groups of titanium-based crowns had clinically acceptable marginal fits.
      After EDM marginal refinement, the fit of cast CP Ti and Ti-6Al-4V crowns
      improved significantly.

PMID- 12473995
TI  - A retrospective study of pulpal response in vital adult teeth prepared for
      complete coverage restorations at ultrahigh speed using only air coolant.
AB  - STATEMENT OF PROBLEM: The dental literature has shown a 3% to 25% pulpal necrosis
      rate as a result of tooth preparation for complete coverage restorations.
      PURPOSE: The purpose of this retrospective study was to examine clinical and
      radiographic records for evidence of pulpal necrosis in teeth prepared for
      complete coverage restorations at ultrahigh speed when air coolant alone was
      used. MATERIAL AND METHODS: The 1847 teeth in this study (182 fixed partial
      denture abutment teeth and 1665 single teeth restored with 21 all-ceramic, 1095
      metal-ceramic, and 731 all-metal restorations) were prepared with diamond
      instruments (burs) in a sweeping or painting motion with the use of light
      pressure (1-3 oz) at ultrahigh speed with air coolant alone from the handpiece.
      New burs were used for each patient and then discarded. Each bur was used on no
      more than 4 teeth. All impressions were made with reversible hydrocolloid.
      Provisional restorations were fabricated on a stone cast and cemented with zinc
      oxide and eugenol cement. Provisional restorations were removed at 3 to 4 weeks
      and definitive restorations placed. Between 1970 and 1989, 6 different luting
      agents (zinc phosphate, resin, glass ionomer, ortho-ethoxybenzoic acid,
      carboxylate, and polycarboxylate) were used to place definitive restorations. All
      patients were questioned about symptoms of tooth sensitivity, tenderness, or pain
      at their regular (4- to 6-month) hygiene recall appointments. Success was defined
      as any definitively restored teeth that remained free of radiographic evidence of
      periapical radiolucency and clinical signs and symptoms of pulpal sensitivity or
      pain recorded in the clinical record. The results were compared with rates of
      pulpal necrosis for teeth prepared with water coolant as reported in the dental
      literature published between 1970 and 1997. RESULTS: Of 638 teeth prepared
      between 1970 and 1979, the pulpal necrosis rate was 2.19% (14 teeth: 12 single
      teeth and 2 fixed partial denture abutment teeth) (97.81% success rate). Of 1209
      teeth prepared between 1980 and 1989, the pulpal necrosis rate was 0.66% (8
      teeth: 7 single crown teeth and 1 partial denture abutment tooth) (99.34% success
      rate). Of 1825 teeth prepared between 1970 and 1989, radiographic evidence of
      pulpal necrosis was found in 0% (100% success rate). No clinical symptoms of pain
      or sensitivity were recorded in the patient records for the surviving teeth
      during the time period of this study, which was conducted in May 2001. No crowns
      were repaired or removed as a result of carious lesions. No higher incidence of
      pulpal necrosis relative to the type of luting agent was observed. CONCLUSION:
      Within the limitations of this retrospective study, it is suggested that tooth
      reduction procedures can be completed with minimal damage to the pulp when only
      air coolant from the dental handpiece is used.

PMID- 12473996
TI  - Depression and somatization in patients with temporomandibular disorders.
AB  - STATEMENT OF PROBLEM: Psychological and behavioral traits may be important for
      the diagnosis and management of orofacial pain. PURPOSE: This study compared the
      levels of depression and somatization in patients in single and multiple research
      diagnostic criteria for temporomandibular disorders (RDC/TMD) diagnostic groups.
      MATERIAL AND METHODS: The RDC/TMD was established to allow standardization and
      replication of research into the most common forms of muscle- and joint-related
      research and is divided into 2 axes: axis I, clinical TMD, and axis II, pain
      related disability and psychological status. One hundred seventeen patients (28
      male and 89 female; mean age, 33.3 +/- 10.3 years) with RDC/TMD-defined clinical
      TMD were selected. The RDC/TMD history questionnaire and examination forms were
      input directly into computers with the use of a software program developed at the
      National University of Singapore (NUS TMDv1.1 software). Axis I and II variables
      were generated online and automatically archived for statistical analysis.
      Patients were subsequently classified into 7 groups based on the presence of the
      various RDC/TMD axis I diagnostic groups: group A, myofascial pain only (group
      I); group B, disk displacement only (group II); group C, other joint conditions
      such as arthralgia, osteoarthritis, and osteoarthrosis only (group III); group D,
      myofascial pain and disk displacement (groups I and II); group E, myofascial pain
      and other joint conditions (groups I and III); group F, disk displacement and
      other joint conditions (groups II and III); and group G, myofascial pain, disk
      displacement, and other joint conditions (groups I, II, and III). Differences in
      mean Symptom Checklist-90 scores between groups were compared by analysis of
      variance/Scheffe tests to contrast depression and somatization levels between the
      various axis I diagnostic groups (alpha=.05). RESULTS: The frequencies of the
      different groups were as follows: group A, 26.5%; group B, 29.9%; group C, 12.8%;
      group D, 6.0%; group E, 13.7%; group F, 4.3%; and group G, 6.8%. Approximately
      39% of patients were clinically depressed, and 55% had moderate to severe
      somatization. Differences in mean depression and somatization with pain item
      scores were significant between groups (P<.05). CONCLUSION: Within the
      limitations of this study, patients diagnosed with myofascial pain and other
      joint conditions (group E) had significantly higher levels of depression (P=.03)
      and somatization (P=.03) than patients diagnosed with only disk displacements
      (group B).

PMID- 12473997
TI  - Influence of fiber type and wetting agent on the flexural properties of an
      indirect fiber reinforced composite.
AB  - STATEMENT OF PROBLEM: Different fiber types are available for reinforcing
      composite restorations. Little information exists regarding optimal fiber
      type/bonding agent combinations. PURPOSE: This in vitro study examined the
      influence of storage time and 2 fiber wetting agents on the flexural properties
      of an indirect dental composite reinforced by 3 fiber types. MATERIAL AND
      METHODS: Three types of fiber (ultra-high molecular weight polyethylene, Kevlar,
      and Glass fiber) were used to reinforce samples of an indirect composite
      (Artglass) prepared to test flexural properties. Each fiber type was used to
      prepare 3 groups of 10 specimens after fiber wetting with an unfilled or a filled
      resin bonding agent. All fibers were weighed to an accuracy of 0.01 mg to
      standardize the amount of fiber placed in the base (tensile side) of the specimen
      preparation mold (2 x 2 x 25 mm). Fiber-reinforced samples wetted with the
      unfilled resin were stored for 24 hours before flexural testing, whereas separate
      groups of fiber-reinforced samples wetted with the filled resin were tested after
      both 24 hours and 6 months storage in water at 37 degrees C. Two additional
      groups of unreinforced composite control specimens (10 samples per group) were
      prepared, one for each of the 2 storage times, resulting in 11 groups total. Mean
      flexural strengths (MPa) and flexural modulus (GPa) values were determined in a 3
      point bend test at a crosshead speed of 1 mm/min by use of a universal testing
      machine. Comparisons between means were performed with 2- and 1-way analysis of
      variance tests (alpha=.01) to demonstrate the influence of storage time, fiber
      wetting agent, and fiber type on the flexural properties of the indirect dental
      composite tested. RESULTS: Significant increases (124% to 490%) in mean flexural
      strength (P<.01) were found for all fiber-reinforced groups in comparison to the
      unreinforced controls at both storage time intervals. The silane containing
      unfilled bonding agent gave the greatest reinforcing effect (364%) when used with
      the glass fiber material. After 6 months storage in water, a significant decline
      (28%) occurred in the mean flexural strength of the glass fiber-reinforced
      specimens (P<.01) when the filled bonding agent was used. CONCLUSION: Within the
      limitations of this study, the choice of fiber type and wetting agent was shown
      to have a significant positive influence on the flexural properties of the fiber
      reinforced composite. When used with the silane containing unfilled bonding
      agent, the glass fiber increased the mean flexural strength of the unreinforced
      indirect composite by 364%.

PMID- 12473998
TI  - Retentive properties of five different luting cements on base and noble metal
      copings.
AB  - STATEMENT OF PROBLEM: The retention of indirectly fabricated restorations can be
      compromised by short or over-tapered tooth preparations. PURPOSE: The aim of this
      study was to evaluate the retentive properties of 5 different luting cements on
      base and noble metal copings to short and over-tapered preparations. MATERIAL AND
      METHODS: Eighty extracted mandibular premolars were prepared to receive full cast
      copings with a flat occlusal surface, 33 degrees taper, and 3-mm axial length.
      Half of the standardized metal copings were cast in an AuAgPd alloy, whereas the
      other half were cast in an NiCr alloy. Cementation was performed with 5 different
      luting cements through use of 5 kg of pressure in 90% relative humidity.
      Specimens were stored in distilled water at 37 degrees C for 24 hours and
      thermocycled between 5 degrees C and 55 degrees C for 5000 cycles, with a dwell
      time of 30 seconds. After thermocycling, vertical tensile force was applied in a
      Zwick universal testing machine with a constant speed of 1 mm/min until
      separation was noted. A 2-factor analysis of variance was used to analyze the
      data, with a significance level of alpha =.05. RESULTS: Mean dislodgement forces
      for AuAgPd crowns and NiCr crowns were 120.88 N and 143.09 N, respectively, for
      zinc phosphate cement; 135.45 N and 150.38 N for Principle; 145.88 N and 220.71 N
      for Meron; 276.85 N and 225.61 N for Avanto; and 300.92 N and 381.02 N for Fuji
      Plus. CONCLUSION: Within the limitations of this study, Fuji Plus and Avanto
      showed significantly higher retentive strengths for AuAgPd copings in comparison
      to the other cements tested (P <.05). The retentive strength of Fuji Plus was
      significantly higher than those of the other cements tested with NiCr copings (P
      <.05).

PMID- 12473999
TI  - Maximum clenching force of patients with moderate loss of posterior tooth
      support: a pilot study.
AB  - STATEMENT OF PROBLEM: Patients who have lost moderate posterior tooth support may
      also lose clenching force as a result of sensitivity to increased loading to the
      remaining teeth and possibly a loss of muscle strength, because clenching forces
      are limited to avoid stress to the remaining teeth. Few studies have correlated
      moderate posterior tooth loss with maximum clenching force. PURPOSE: The purpose
      of this pilot study was to test the hypothesis that moderate loss of posterior
      tooth support will have a significant effect on maximum clenching force. MATERIAL
      AND METHODS: The maximum clenching force of 44 adults, ages 28 to 76 (mean 46),
      with posterior tooth loss was compared with the maximum clenching force of a
      control group of 20 healthy full dentition adults, ages 18 to 55 (mean 30), by
      use of a bilateral strain-gauged transducer. The transducer consisted of 2
      stainless steel plates separated by a steel sphere that balanced occlusal forces
      between right and left sides. Acrylic resin pads were fabricated for each patient
      to protect the cusps of the teeth. The overall accuracy was found to be within
      2.3% of full scale over a range of 0 to 4000 N (0 to 900 lbs). The calibration
      reliability of the system was checked frequently by use of a dead weight of 222 N
      (50 lbs). Clenching forces were supported by first and second molars and second
      premolars when possible. The instrumentation, methods, and operator were the same
      for both groups. A 2-tailed Student t test (alpha=0.01) and a pooled estimate of
      the mean were used to determine possible statistical significance. To test for
      possible correlations between clenching force and lost tooth support and between
      clenching force and age, a linear regression correlation coefficient R was
      calculated. RESULTS: For the 44 subjects with posterior tooth loss, the mean
      clenching force was 462 N (104 lbs), with a range of 98 to 1031 N (22 to 232
      lbs). This compares with a mean of 720 N (162 lbs) with a range of 244 to 1243 N
      (55 to 280 lbs) for the full-dentition subjects. A 2-tailed t test showed that
      the average difference of 258 N (58 lbs) between the 2 groups was significant (P<
      or =.01). There was only a moderate negative association between clenching
      strength and loss of mandibular tooth support (R = -0.35). Clenching force was
      not well correlated with age as indicated by low R values (R = 0.21, missing
      tooth group and R = -0.03, full dentition group). CONCLUSION: Within the
      limitations of this study the maximum clenching force was less (P< or =.01), by
      258 N (58 lbs) on average, in subjects with moderate loss of posterior tooth
      support. Loss of maximum clenching force was associated with a modest negative
      correlation to the number of missing teeth in the mandibular arch (R = -0.35).
      The range of clenching force was surprisingly large for both the missing tooth
      (98 to 1031 N) and full dentition (244 to 1243 N) groups.

PMID- 12474000
TI  - Effect of fluoride application on tensile bond strength of self-etching adhesive
      systems to demineralized dentin.
AB  - STATEMENT OF PROBLEM: It has been reported that the bond strength of composite to
      demineralized dentin is lower than that to sound dentin. This can be a problem in
      the success of so-called sealed restorations. PURPOSE: The aim of this study was
      to evaluate the effect of fluoride application on the tensile bond strength of
      self-etching adhesive systems to demineralized dentin. MATERIAL AND METHODS: One
      hundred twenty extracted bovine incisors were ground flat with 600-grit silicone
      carbide paper. Ninety teeth were then immersed in acetate buffer (pH 4.0) to form
      demineralized dentin. These teeth were randomly divided into 3 groups of 30 each:
      surfaces treated with fluoride solution (Group NF), surfaces treated with
      fluoride solution followed by a water rinse (Group RF), and control surfaces with
      no pretreatment (Group C). The remaining 30 teeth comprised a group with normal
      dentin surfaces (Group S). Each group was further divided into 3 subgroups of 10
      each to test the bond strength test of Clearfil SE Bond, Unifil Bond, and Mac
      Bond II. Tensile bond strengths (in MPa) were measured with a universal testing
      machine at a crosshead speed of 0.5 mm/min. Mean bond strengths were analyzed by
      2-way analysis of variance and Fisher's PLSD (P =.05). SEM observations of the
      surfaces before and after priming and at resin-dentin interfaces in each group
      were performed. Elemental analysis of the dentin surfaces before priming was also
      carried out. RESULTS: The bond strengths of the adhesives to demineralized dentin
      in Groups NF, RF, and C were significantly lower than that of the normal dentin
      in Group S (P <.05). The mean bond strengths of the 3 adhesives in Group NF were
      higher than those in Groups RF and C, but a significant difference was observed
      only when Clearfil SE Bond was used (P <.05). In SEM images the open dentinal
      tubules on the surface and the resin tag formation at the resin-dentin interface
      were apparent in Group NF but were not observed in Groups RF and C. On elemental
      analysis, considerable amounts of fluoride and calcium were detected in the
      surfaces of Group NF. CONCLUSION: Within the limitations of this study, the
      surface treatment with fluoride solution supported the resin tag formation at the
      resin-dentin interface and slightly improved the bond strength of the self
      etching adhesive systems tested to demineralized dentin. This result indicated
      that the fluoride treatment to demineralized dentin might contribute to the
      success of the sealed restoration.

PMID- 12474001
TI  - Comparison of shear bond strength relative to two testing devices.
AB  - STATEMENT OF PROBLEM: Dentin adhesives are characterized on the basis of their
      bond strength to dentin; however, great variation exists within the same material
      depending on the testing apparatus. To realistically compare bond strengths, the
      testing mechanisms must be the same. PURPOSE: The purpose of this investigation
      was to use 2 testing devices to evaluate the shear bond strength of 3 single
      bottle adhesives with their multistep counterparts. MATERIAL AND METHODS: The
      occlusal surfaces of 120 freshly extracted third molars were ground to expose the
      dentin and polished with 600-grit silicon carbide paper. Three single-bottle,
      (Optibond Solo Plus, 3M Single Bond, and Excite) and 3 multistep adhesives
      (Optibond FL, 3M MultiPurpose Plus, and Syntac) were each used to bond a
      composite cylinder (made from a 2.379 +/-.001-mm diameter by 4-mm-high mold) of
      Tetric Ceram to 20 teeth. The specimens were stored in 100% humidity for 24
      hours. The shear bond strength at failure was measured in kilograms and converted
      to megapascals for each material, using a knife (conventional method) and an
      Ultradent testing device on a universal testing machine (Instron) at a loading
      rate of 0.5 mm/min. A 2-way analysis of variance (ANOVA) test was performed
      comparing the 2 testing devices and the materials at P<.05. Where significant, a
      1-way ANOVA test was conducted among the materials for each test group, and a
      Tukey multiple comparison test was used to determine significant differences
      among the materials tested (P<.05). An independent Student t test at P<.05 was
      used to determine significance between testing devices. RESULTS: The results
      showed that Optibond Solo Plus (26.85 +/- 8.76 MPa), Optibond FL (25.40 +/- 4.44
      MPa), 3M Single Bond (28.12 +/- 5.01 MPa), and 3M MultiPurpose Plus (34.40 +/-
      7.90 MPa) had significantly higher bond strengths when tested with the Ultradent
      testing device. The mean values for Excite (19.47 +/- 6.17 MPa) and Syntac (20.20
      +/- 7.07 MPa) were also higher with the Ultradent testing device, but the
      difference was not significant. CONCLUSION: Within the limitations of this study,
      all bonding agents tested resulted in higher mean shear bond strengths when
      tested with the Ultradent testing device compared with the unrestricted knife.
      The single-step bonding agents exhibited mean bond strengths comparable to their
      multistep counterparts.

PMID- 12474002
TI  - Effect of thermocycling on bond strength and elasticity of 4 long-term soft
      denture liners.
AB  - STATEMENT OF PROBLEM: Two problems found in prostheses with soft liners are bond
      failure to the acrylic resin base and loss of elasticity due to material aging.
      PURPOSE: This in vitro study evaluated the effect of thermocycling on the bond
      strength and elasticity of 4 long-term soft denture liners to acrylic resin
      bases. MATERIAL AND METHODS: Four soft lining materials (Molloplast-B, Flexor,
      Permasoft, and Pro Tech) and 2 acrylic resins (Classico and Lucitone 199) were
      processed for testing according to manufacturers' instructions. Twenty
      rectangular specimens (10 x 10-mm(2) cross-sectional area) and twenty cylinder
      specimens (12.7-mm diameter x 19.0-mm height) for each liner/resin combination
      were used for the tensile and deformation tests, respectively. Specimen shape and
      liner thickness were standardized. Samples were divided into a test group that
      was thermocycled 3000 times and a control group that was stored for 24 hours in
      water at 37 degrees C. Mean bond strength, expressed in megapascals (MPa), was
      determined in the tensile test with the use of a universal testing machine at a
      crosshead speed of 5 mm/min. Elasticity, expressed as percent of permanent
      deformation, was calculated with an instrument for measuring permanent
      deformation described in ADA/ANSI specification 18. Data from both tests were
      examined with 1-way analysis of variance and a Tukey test, with calculation of a
      Scheffe interval at a 95% confidence level. RESULTS: In the tensile test under
      control conditions, Molloplast-B (1.51 +/- 0.28 MPa [mean +/- SD]) and Pro Tech
      (1.44 +/- 0.27 MPa) liners had higher bond strength values than the others (P
      <.05). With regard to the permanent deformation test, the lowest values were
      observed for Molloplast-B (0.48% +/- 0.19%) and Flexor (0.44% +/- 0.14%) (P
      <.05). Under thermocycling conditions, the highest bond strength occurred with
      Molloplast-B (1.37 +/- 0.24 MPa) (P <.05). With regard to the deformation test,
      Flexor (0.46% +/- 0.13%) and Molloplast-B (0.44% +/- 0.17%) liners had lower
      deformation values than the others (P <.05). CONCLUSION: The results of this in
      vitro study indicated that bond strength and permanent deformity values of the 4
      soft denture liners tested varied according to their chemical composition. These
      tests are not completely valid for application to dental restorations because the
      forces they encounter are more closely related to shear and tear. However, the
      above protocol serves as a good method of investigation to evaluate differences
      between thermocycled and control groups.

PMID- 12474003
TI  - In vivo and in vitro evaluation of occlusal indicator sensitivity.
AB  - STATEMENT OF PROBLEM: Indicators used to locate and eliminate occlusal
      disharmonies have not demonstrated specific sensitivity and reliability. PURPOSE:
      The sensitivity and reliability of articulating papers, foils, silk strips, and T
      Scan systems used as occlusal indicators were investigated. The effect of saliva
      on the materials also was determined. MATERIAL AND METHODS: In the in vitro part
      of the study, a test model (mounted in an articulator and in a universal testing
      machine) was established with the use of maxillary and mandibular dentate casts.
      Articulating papers, foils, silk strips, and the T-Scan system were used to
      examine the loss of sensitivity of the recording materials after 3 consecutive
      strokes. The differences in the contact points of the test model determined by
      each of the recording materials were evaluated both in the articulator and in a
      universal testing machine. In the in vivo part of the study, occlusal contact
      recordings of 3 subjects were made before and after drying their mouths. The
      significance of the differences between the strokes repeated more than once was
      evaluated with the Friedman 2-way analysis of variance and Kruskal-Wallis tests.
      To examine the effect of the oral environment, the Wilcoxon matched-pairs signed
      ranks test was applied. In all statistical analyses, the level of significance
      was alpha=.05. RESULTS: The results demonstrated significant differences in the
      sensitivity of the recording materials tested (P<.001). The sensitivity of all
      recording materials decreased after multiple use (P<.001), and the loss of
      recording accuracy was significant (P<.001). All recording materials except the T
      Scan were affected by the presence of saliva (P<.01). CONCLUSION: Within the
      limitations of this study, the results indicated that multiple use of the
      recording materials tested may lead to inaccurate occlusal analysis results. It
      is recommended that the recording materials be used only once and that the teeth
      be dry during occlusal analysis.

PMID- 12474004
TI  - The effect of two polishing pastes on the surface roughness of bis-acryl
      composite and methacrylate-based resins.
AB  - STATEMENT OF PROBLEM: A highly polished restoration surface is necessary to
      promote a plaque-free environment. PURPOSE: The purpose of this study was to
      compare the surface roughness of 3 different bis-acryl composite-based and 3
      different methyl methacrylate-based provisional crown and fixed partial denture
      resins after being polished with aluminum oxide and diamond paste. MATERIAL AND
      METHODS: Six different materials were used (Iso-Temp, Protemp II, Structer 2,
      Dentalon Plus, Tab 2000 Kerr, Temdent). A total of 180 specimens were fabricated:
      30 specimens of each material using circular stainless steel molds 10 mm in
      diameter and 2 mm high. Each material was mixed and polymerized according to
      manufacturer's instructions. The bis-acryl composite specimens were polymerized
      with a laboratory light-initiating unit for 30 seconds on each side (400 to 525
      nm, 75 W quartz-halogen light source). All specimens were kept in a water bath at
      37 degrees C for 45 minutes. Ten specimens of each group were left as untreated
      controls, 10 specimens of each group were polished with the aluminum oxide paste
      (Composite Polish), and 10 specimens of each group were polished with the diamond
      paste (Insta glaze). Surface roughness was determined with a profilometer. The
      data were analyzed with one-way analysis of variance (Post Hoc Scheffe's S test)
      (P<.001). In addition, the profilometric evaluations photographic images were
      recorded with a scanning electron microscope to examine the surface roughness
      after polishing. RESULTS: The mean of the surface characteristics of the bis
      acryl composites were 1.33 microm for aluminum oxide and 0.90 microm for diamond
      polishing paste; the mean of the results of the methyl methacrylate resins were 1
      microm for aluminum oxide and 0.50 microm for diamond polishing paste. The
      difference between the mean values of bis-acryl resins groups and methacrylate
      based resin groups were significant (P<.001). The difference between the
      subgroups of bis-acryl resins group (Iso-Temp, Protemp II, Structer 2) were not
      significant (P>.05). The difference between the subgroups of methacrylate-based
      resin group (Dentalon, Tab 2000, Temdent) were not significant (P>.05).
      CONCLUSION: Within the limitations of this study, single-phase polishing of the
      bis-acryl composites tested and the methacrylate resins tested with diamond-based
      paste produced a smoother surface than when polished with aluminum oxide paste.

PMID- 12474005
TI  - Benchmarking the clinical prosthetic dental literature on MEDLINE.
AB  - STATEMENT OF PROBLEM: The utility of evidence-based clinical prosthetic dental
      decision making is, in part, predicated on the availability of high-quality
      clinical trials and the use of current best evidence. With literature or outcomes
      continually evolving, it is difficult to know how much information is available,
      how fast it changes, or where it is located. PURPOSE: This study identified and
      quantified the availability of high-quality prosthetic dental clinical trials,
      determined the dynamics of literature increase, and identified the location of
      relevant literature published within a specific decade. MATERIAL AND METHODS: A
      search strategy based on the Medical Subject Headings (MeSH) vocabulary for
      prosthetic dentistry was developed to examine MEDLINE with use of the Ovid Web
      Gateway search engine between the years 1990-1999. Specific and sensitive
      methodologic search filters identified 4 categories of information: etiology,
      diagnosis, therapy, and prognosis. The identified studies were limited to human
      subjects and to articles written in English. The results were subdivided by year
      to identify trends and location of the literature. This evaluation did not
      include the following: (1) other databases or languages or (2) an evaluation of
      the validity or clinical applicability of the literature. The first factor would
      increase the estimated number of relevant articles, whereas the second factor
      would decrease it. RESULTS: Between 1990 and 1999, MEDLINE identified 10,258
      articles published in English on human prosthodontic issues. When subdivided by
      clinical category, the number of articles per year (mean +/- SD) for specific and
      sensitive searches, respectively, was as follows: etiology, 10 +/- 6 and 95 +/-
      27; diagnosis, 11 +/- 5 and 77 +/- 21; therapy, 6 +/- 2 and 153 +/- 52; and
      prognosis, 13 +/- 6 and 91 +/- 27. For sensitive searches, this amounted to
      approximately 416 articles per year. The time-course analysis indicated that the
      number of articles in each category increased by approximately 7% per year. The
      articles were published in more than 60 different journals: approximately 50% of
      the articles were published in 14 journals, whereas the remaining articles were
      published in 46 journals. CONCLUSION: There appears to be substantial clinical
      prosthetic dental literature upon which to base clinical decisions. With the
      sensitive search strategy used as an estimate, to stay current, one would need to
      read and absorb approximately 8 articles per week, 52 weeks per year, across 60
      different journals. Increases in the volume of literature each year make access
      even more difficult. These trends suggest the need for computer-based clinical
      knowledge systems.

PMID- 12474006
TI  - Use of denture adhesive to retain an extraoral facial prosthetic wax pattern for
      trial placement.
AB  - This article demonstrates the use of denture adhesive to retain a wax pattern
      during trial placement of an extraoral facial prosthesis. Using denture adhesive
      in this manner easily and temporarily retains the wax pattern in place without
      visual obstructions such as hands or instruments holding the pattern in place.
      With the wax pattern held securely in place, the clinician is able to assess it
      from all angles for position, esthetics, margin extension, and tissue movement
      before the wax pattern is finalized and processed.

PMID- 12474007
TI  - A technique for achieving prerestorative minor tooth movement with orthodontic
      separators.
AB  - This article describes 2 patient treatments in which a simple technique was used
      to realign teeth before restorative procedures. Elastic separators were used to
      tip the desired tooth into its original position. This restored a normal crown
      contour and improved the tooth's long-axis alignment. The procedure is simple and
      inexpensive, and treatment time relatively quick compared with other orthodontic
      procedures.

PMID- 12474008
TI  - Development and clinical application of a surgical guide for optimal implant
      placement.
AB  - Implant placement based on careful preoperative planning is critical for
      successful prosthetic rehabilitation. This article describes a system for optimal
      implant placement that uses a surgical guide designed to orient the surgical
      drills to predetermined implant positions and inclinations.

PMID- 12474009
TI  - A method for fabricating a cast post and core that is esthetic when used under an
      all-ceramic crown.
AB  - This article presents a technique to enhance the optic qualities of all-ceramic
      crowns when placed over a cast post and core. An opaque layer is necessary over a
      metal structure, such as a cast core, to reduce light absorption and increase the
      reflectance of the metal. The desired effect is to raise the value of the core in
      order to approach the optic qualities of dentin. However, the problem of
      reflectance is fully eliminated by the use of an opaque layer of ceramic. The
      translucence of a ceramic crown may not be limited by the use of opaque material
      under the crown. This procedure requires the placement of an opaque layer of
      ceramic on the core, thereby moving such a layer 0.3 to 0.5 mm more deeply from
      the surface of the restoration. This allows more depth and translucence to the
      crown, as light penetrates further into the crown.

PMID- 12474010
TI  - Indirect fabrication of multiple post-and-core patterns with a vinyl polysiloxane
      matrix.
AB  - In the described technique, a vinyl polysiloxane material is used as a matrix for
      the indirect fabrication of multiple custom-cast posts and cores. The matrix
      technique enables the clinician to fabricate multiple posts and cores in a short
      period of time. The form, harmony, and common axis of preparation for all cores
      are well controlled before the definitive crown/fixed partial denture
      restorations are fabricated. Oral tissues are not exposed to the heat of
      polymerization or the excess monomer of the resin material when this technique is
      used.

PMID- 12474011
TI  - Advantages of thermoconditioned autopolymerizing resin.

PMID- 12474012
TI  - Part IV. Enteral nutrition support.

PMID- 12474013
TI  - Part I. Malnutrition in the pediatric population.

PMID- 12474014
TI  - Part II. Common nutritional issues in older adults.

PMID- 12474016
TI  - Editorial: Micronutrients supplementation recommendations for the elderly
      suggested by a public committee.

PMID- 12474015
TI  - Part III. Obesity.

PMID- 12474017
TI  - Recommended micronutrient supplementation for institutionalized elderly.
AB  - A committee nominated by the Israel Ministry of Health examined the relevant
      literature and the local recommendations as well as the recommendations from
      other countries and suggested a daily micronutrient supplementation for
      institutionalized elderly living in institutions supervised by the Ministry of
      Health. The micronutrient preparatory, tailored for this population, is designed
      to contain about half the RDA for most of the vitamins and some microelements.
      Biotin and vitamins C, D and B12 as well as zinc, copper, chromium and molybdenum
      are suggested at a level higher than half the RDA, whereas fluorine, at a lower
      level. Major elements (calcium, magnesium and phosphorus) are excluded and should
      be supplied separately. Vitamin K and iron are also excluded. Fat-soluble
      vitamins should be microencapsulated. Micronutrient supplementation for
      institutionalized elderly is part of the Ministry of Health s balanced nutrition
      policy. The committee s recommendations are also applicable to the free-living
      elderly population.

PMID- 12474018
TI  - Enteral nutrition in French institutionalized patients: a multicentric study.
AB  - BACKGROUND: No previous studies have demonstrated either a nutritional
      improvement, or a survival benefit from tube placement in an institutionalized
      population. OBJECTIVE: The aim of this study was to determine current indications
      for tube feeding in French geriatric centers and to evaluate clinical outcome and
      mortality rates in these frail very old patients. DESIGN: Between November 1,
      2000 and April 31, 2001, we prospectively recruited all hospitalized or
      institutionalized patients who received enteral nutrition (EN) in 7 Departments
      of Geriatric Medicine in France. Nutritional parameters and main indications of
      EN were recorded at the time of feeding tube placement. Pneumonia and mortality
      rates were observed over a period of one year. RESULTS: 57 patients of mean age
      81.6   7.8 yrs underwent placement of a feeding tube. Mean BMI value was 20.7  
      4.8 and mean serum albumin level 26.1   6.1 g/L. The most frequent indications
      for EN included stoke (39%) and other neurologic diseases (42%). Fourteen
      patients (25%) died within 30 days, and 27 (47%) died over the 12-month follow-up
      period. During the first month, an episode of pneumonia was noted in 26 cases
      (55%). CONCLUSION: The similarity between rates of early mortality reported in
      our study and those reported in several previous studies involving younger,
      ambulatory subjects is surprising because we might expect poorer survival in our
      frail elderly patients. We can think that French geriatric teams have changed
      their attitudes toward EN in recent years, EN being less frequently used in
      patients with advanced dementia and at the end-stage of life.

PMID- 12474019
TI  - Examining the effect of intervention to nutritional problems of hospitalised
      elderly: a pilot project.
AB  - BACKGROUND: Up to 65% of elderly patients are protein-energy undernourished at
      admission or acquire nutritional deficits while hospitalised. OBJECTIVES: The
      aims of this project were: 1) to assess the quality of care concerning nutrition
      among geriatric units; 2) to assess the impact of implementive nutritional
      interventions on nutritional status and on the length of hospitalisation. DESIGN:
      Two hundred and six patients consecutively admitted in a geriatric unit of a
      general hospital were studied prospectively for 6 months (from January to June
      2001). All patients underwent a comprehensive geriatric assessment. For the first
      3 months the nutritional status of the patients on admission and at discharge
      were assessed without particular recommendations for nutritional intervention. A
      standardised nutritional intervention was proposed for the last 3 months.
      RESULTS: Median value of Mini-Nutritional Assessment was 19 points (ranged from 9
      to 29), mean admission s prealbumin concentration (PAB) was 0.179 g/l, and C
      reactive protein 5.9 2.8 mg/100ml. Hospitalisation stay was significantly lower
      during the interventional period than during the observational period. A higher
      mean PAB variation was observed during the interventional period as compared to
      the observational period. CONCLUSIONS: Nutritional assessment should be part of
      routine clinical practice in elderly hospitalized patients. A comprehensive
      screening tool for assessment of nutritional status is needed that is clinically
      relevant and cost-effective to perform. If malnutrition is suggested by such
      screening tests, implementations of nutritional intervention allow to ameliorate
      discharge nutritional status and to reduce hospitalization stay.

PMID- 12474020
TI  - Energy balance and malnutrition in institutionalized elderly people.
AB  - Screening tools and more extensive assessment methods have signaled that
      malnutrition is common in institutionalized elderly. There are multiple factors -
      physiologic and non-physiologic - which hereby increase the risk of negative
      energy balance leading to weight loss and subsequent undesirable outcomes.
      Addressing this problem a number of controlled intervention studies have shown
      positive effects of 'simple' nutrition interventions in institutionalized older
      persons.

PMID- 12474021
TI  - Increased amyloid-  levels in APPSWE transgenic mice treated chronically with a
      physiological high-fat high-cholesterol diet.
AB  - Although plasma cholesterol levels are not generally associated with Alzheimer
      disease (AD) incidence, in vitro studies have found that increased cellular
      cholesterol levels are associated with increases in  -amyloid (A ) production,
      with a concomitant decrease in sAPPa, the secreted non amyloidogenic fragment of
      the amyloid precursor protein (APP). In two previous studies using a mouse model
      for AD-like pathology, non-physiological high-cholesterol diet has been shown to
      increase plasma and cerebral cholesterol levels, but have resulted in conflicting
      results on cerebral A  levels. In the present study APPSWE male transgenic mice
      were fed either a chow diet or a physiological high-fat high-cholesterol Western
      type diet until the mice reached 1 year of age. Mice fed the Western type diet,
      compared to the low-fat chow diet, had increased body weight, plasma and cerebral
      cholesterol levels, as well as a 50% increase in cerebral A  levels. Cerebral
      levels of total APP were not altered while cerebral apoE levels were increased in
      the mice fed the Western-type diet, versus the chow-fed mice. These data
      demonstrate that chronic intake of a non-toxic high-cholesterol diet, which is
      similar to a human diet in fat and cholesterol content, was effective in
      increasing A  levels and further suggests that dietary cholesterol and/or fat may
      be a risk factor for AD.

PMID- 12474022
TI  - Low cholesterol, cognitive function and Alzheimer s disease in a community
      population with cognitive impairment.
AB  - BACKGROUND: The association between cholesterol levels, cognitive impairment and
      dementia is controversial. OBJECTIVES: To investigate differences in serum total
      cholesterol levels between mild and moderate cognitive impairment and between
      dementia syndromes. To investigate the association between cholesterol level and
      progression of Alzheimer s disease (AD). DESIGN: Non-fasting cholesterol levels
      were measured in two groups: a) 291 participants in a community study in South
      Korea, aged 65 or over, and scoring below 25 on the Mini-Mental State Examination
      (Korean version: MMSE-K); and b) 79 patients with AD attending a local hospital.
      In the community sample, associations were investigated between cholesterol level
      and both cognitive function and dementia (DSM-IV). For the hospital sample,
      associations were investigated between cholesterol level and decline in cognitive
      function (MMSE-K) and/or functional activities of daily living (ADL, Blessed
      Dementia Scale) over one year. RESULTS: Lower serum cholesterol level was
      associated with worse cognitive function in the community sample. Associations
      with dementia were specific to AD rather than other subtypes. No cross-sectional
      association was found between cholesterol levels and cognitive function in AD
      groups from either sample. No prospective associations were found between
      cholesterol level and decline of cognitive function or functional ADL in hospital
      attenders with AD. Adjustment for age, gender, education, past occupation,
      disablement, duration of dementia, and the presence of APOE e4 made little
      difference to the associations in the hospital sample. CONCLUSION: Lower serum
      cholesterol level may be a state marker of AD but does not appear to influence
      its rate of progression.

PMID- 12474023
TI  - HMG-CoA reductase inhibitors (statins) in the treatment of Alzheimer's disease
      and why it would be ill-advise to use one that crosses the blood-brain barrier.
AB  - Increased circulating cholesterol has been long linked to an increased risk of
      coronary artery disease (CAD), and is now linked to an increased risk of
      developing Alzheimer s disease (AD). We first showed the neuropathologic link
      between CAD and AD as increased incidence of cerebral senile plaques in both
      disorders. We then showed that AD-like neuropathology occurred in the brains of
      cholesterol-fed rabbits; including increased  -amyloid (Ab). Currently there are
      a number of transgenic mouse models of AD that exhibit enhanced Ab pathology if
      cholesterol diet is administered. Culture studies clearly show that excess
      cholesterol enhances beta-metabolism of amyloid precursor protein (APP) and
      production of  -amyloidogenic peptides, and that sufficiently reducing
      cholesterol levels by inhibition of synthesis completely inhibits all beta
      metabolism of APP. Our finding that the elevated levels of Ab in rabbits fed
      cholesterol diet could be cleared from the brain by resuming a control diet
      prompted the hypothesis that lowering cholesterol levels in the blood of AD
      patients may be of some clinical benefit. Pilot data suggests that
      therapeutically lowering circulating cholesterol may attenuate Ab production in
      the cholesterol-fed rabbit brain, may stabilize cognitive performance in mildly
      impaired AD patients, and may reduce the risk of developing AD. Accordingly, we
      have initiated a double-blind treatment trial evaluating Atorvastatin Na+ among
      120 mild-to-moderately impaired AD subjects randomized to one of two groups
      receiving placebo or active drug once a day. Atorvastatin is one of a general
      class of HMG-CoA reductase inhibitor drugs called statins that lower cholesterol
      by inhibition of synthesis. We chose to use Atorvastatin in this AD Treatment
      Trial because it does not cross the blood-brain-barrier, and believe it would be
      ill-advised to use a statin that does. This position stems from the observations
      that excess cholesterol inhibits cholesterol synthesis and increases Ab
      production, that Ab kills cells in part by inhibiting cholesterol synthesis, and
      that statins acting at the neuronal level could further exacerbate degeneration
      in AD by further inhibition of necessary cholesterol synthesis.

PMID- 12474024
TI  - Muscle loss with aging: is it reversible?

PMID- 12474025
TI  - Muscle changes in aging.
AB  - This review summarizes the recent studies to understand the mechanisms of
      sarcopenia of aging. A decrease in mitochondrial and nuclear gene transcriptions
      in skeletal muscle is likely to be responsible for reduced synthesis rates of
      muscle mitochondrial protein, myosin heavy chain (MHC) and actin. A decrease in
      muscle mitochondrial protein synthesis could contribute to reduced mitochondrial
      function. A decrease in synthesis rate of MHC and actin, the key contractile
      proteins could be responsible for reduced muscle strength. The MHC synthesis rate
      seems to result from a selective decrease in transcription of MHC isoforms
      (MHCIIa and IIx) responsible for fast-twitch fibers. Resistance training
      increases MHC-I isoform mRNA levels with an overall increase in MHC synthesis
      rate. Aerobic training increases muscle oxidative enzymes equally in young and
      old but its impact on overall mitochondrial function remains to be clearly
      defined. Long-term studies are needed to determine the potential benefits and
      undesirable effects of replacements of various hormones that decline with aging.
      An individualized exercise prescription involving both aerobic and resistance
      training is definitely helpful to overcome many aging-related muscle
      dysfunctions.

PMID- 12474026
TI  - Serum myostatin-immunoreactive protein is increased in 60-92 year old women and
      men with muscle wasting.
AB  - BACKGROUND: Myostatin is a recently discovered member of the TGF-b superfamily of
      genes. It is expressed in skeletal muscle and believed to suppress muscle growth.
      Myostatin-null mice develop skeletal muscles that are 2-3x larger than wild type
      mice. Serum and intramuscular concentrations of myostatin-immunoreactive protein
      are increased in AIDS-muscle wasting and are inversely related with fat-free mass
      (FFM). OBJECTIVE: We hypothesized that increased expression of the myostatin gene
      is associated with the reduction in FFM and muscle mass typical of advancing age.
      DESIGN: A cross-sectional comparison of serum myostatin-immunoreactive protein
      levels, FFM and skeletal muscle mass in 19-35 yr old men and women (young),
      healthy 60-75 yr old men and women (middle-aged), and physically frail 76-92 yr
      old women. RESULTS: Muscle mass declined with advancing age in both men and
      women. Serum myostatin-immunoreactive protein levels were the highest in the 76
      92 yr old women (P<0.05). Middle-aged men and women had higher serum myostatin
      levels than young men and women (P<0.05). FFM and muscle mass, corrected for
      height, were inversely correlated with serum myostatin-immunoreactive protein
      concentrations. CONCLUSIONS: These findings suggest that serum myostatin may be a
      biomarker of age-associated sarcopenia. They are consistent with the hypothesis
      that the human myostatin gene product is a suppressor of skeletal muscle growth
      in advancing age.

PMID- 12474027
TI  - Managing sarcopenia with progressive resistance exercise training.
AB  - Advancing age appears to alter the chemical and physical properties of skeletal
      muscle proteins. Alterations include: reduced contractile, mitochondrial, and
      enzyme protein synthesis rates, altered expression and post-translational
      modifications to muscle proteins, reduced maximum voluntary muscle strength,
      reduced muscle strength per unit muscle mass and muscle power. These age
      associated impairments in muscle protein quantity and quality contribute to
      physical disability and frailty, a loss of independent function, the risk of
      falling and fractures, and contribute to escalating health care costs.
      Progressive resistance exercise training is a potent, non-pharmacologic,
      effective therapy that opposes the impairments in muscle protein quantity and
      quality in middle age and physically frail adults. In the absence of
      contraindications to exercise, muscle proteins adapt to an exercise training
      stimulus despite the depredation of age. The proposed pathogenesis for some of
      these impairments is briefly reviewed. Evidence that supports the use of
      progressive resistance exercise training to restore muscle quality and quantity
      in elderly adults is reviewed.

PMID- 12474028
TI  - [Visceral pain--a neglected phenomenon in pain therapy and research?].
AB  - The topic "visceral pain"is hardly covered in basic research and pain therapy.
      After low back pain, headache and musculosceletal pain is abdominal pain the 4th
      frequent chronic pain syndrome in the general population with considerable direct
      and indirect disease related costs.An interdisciplinary multimodal treatment of
      chronic abdominal pain syndromes is rarely practiced in clinical care.

PMID- 12474029
TI  - [Physiology and pathophysiology of visceral pain].
AB  - Visceral pain is diffusely localized, referred to deep somatic tissues, skin and
      viscera, frequently not correlated with an actual trauma, commonly correlated
      with strong negative affective reactions and accompanied by strong protective
      autonomic and motor reactions. It is correlated with the excitation of spinal
      (thoraco-lumbar, sacral) visceral afferents and (with a few exceptions) not with
      the excitation of vagal afferents. Spinal visceral afferents are polymodal and
      can be excited by physical and chemical stimuli. All groups of visceral afferents
      can be sensitized (e.g.by inflammation). Normally silent (mechanically
      insensitive) visceral afferents are recruited by inflammation. Individual
      visceral afferent neurons project in laminae I and V of the dorsal horn over
      several segments, medio-lateral over the entire width of the dorsal horn and to
      the contralateral side. Their activity is synaptically transmitted, in these and
      deeper laminae, to viscero-somatic convergent neurons which receive additional
      afferent synaptic input from skin and deep somatic tissues of the corresponding
      dermatomes,myotomes and sclerotomes. The mechanism of sensitization of
      viscerosomatic convergent neurons (central sensitization) during sensitization of
      spinal visceral afferents is unclear.Viscero-somatic tract neurons project to
      lower and upper brain stem,hypothalamus and via the thalamus to various cortex
      areas. Visceral nociception and pain is presumably (together with other visceral
      sensations and homeostatic regulations of autonomic body functions) primarily
      represented in the insula in the context of interoception. The insula obtains its
      main peripheral afferent input from lamina I neurons via the Nucleus
      ventromedialis posterior of the thalamus. The transmission of visceral impulses
      in the spinal cord is modulated by the endogenous control systems in the brain
      stem which are in turn under the control of cortex and limbic system.

PMID- 12474030
TI  - [Epidemiology and clinical phenomenology of visceral pain].
AB  - Visceral pain is characterized by a subjectively painful perception located in
      the abdominal area. Distinct structural lesions or biochemical abnormalities
      which could serve as explanation for these painful sensations can be only
      detected in a proportion of patients. In the absence of precise causes for
      visceral pain, the symptoms are attributed to functional disorders. The two major
      single entities among functional disorders of the gut are functional dyspepsia
      and irritable bowel syndrome. Patients with functional dyspepsia
      characteristically localize the symptoms in the upper abdomen. Functional
      gastrointestinal disturbances which are localized in the lower abdomen are
      summarized as irritable bowel syndrome. Interestingly,both functional dyspepsia
      and irritable bowel syndrome may overlap.

PMID- 12474031
TI  - [Psychophysiology of visceral pain].
AB  - This paper reviews the most important research strategies in the context of the
      psychophysiology of visceral pain. These are disturbed gastrointestinal motility,
      visceral hypersensitivity and central nervous system mechanisms such as response
      bias, attentional bias and affective evaluation. The most prominent research
      methods and results are reviewed and methodological problems are discussed. From
      a psychophysiological perspective, visceral pain remains a complex and
      heterogeneous syndrome in which stress and coping may be etiologically as
      important as pathophysiological mechanisms of peripheral origin and central
      nervous system mechanisms like attentional bias.

PMID- 12474032
TI  - [Psychophysiology of visceral pain syndromes].
AB  - Psychosomatics of visceral pain syndromes. From a psychosomatic point of view
      visceral pain syndromes can be classified into nociceptive (somatic and visceral)
      pain syndromes without and with maladaptive pain coping resp.psychic comorbidity,
      functional pain syndromes (typical symptom clusters without biochemical or
      structural abnormalities in clinical routine diagnostics) and psychic disorders
      with pain as main symptom. With regard to the etiology and the course of chronic
      inflammatory bowel diseases (IBD) as representatives of somatic pain syndromes
      and of irritable bowel syndrome/chronic pelvic pain as representatives of
      functional pain syndromes empirically validated psychosocial aspects are
      summarized: Personality traits, illness behavior, daily hassles, life events and
      psychic comorbidity and effects of psychotherapy. Psychosocial factors are
      decisive in the etiology and the course of functional pain syndromes as
      determinants of their severity (psychosomatic disease in a narrow sense).
      Psychosocial factors are not decisive for the etiology, but for the course of IBD
      (psychosomatic disease in a broader sense). Within general pain therapy of
      visceral pain syndromes a biopsychosocial approach should be applied right from
      the beginning (psychosomatic basic care). Within special pain therapy of visceral
      pain syndromes a qualified psychiatric - psychotherapeutic diagnostics and co
      therapy should be mandatory.

PMID- 12474033
TI  - [Clinical characteristics and pathophysiology of pelvic pain in women].
AB  - Chronic pelvic pain is a common and debilitating problem that can significantly
      impair the quality of life of a woman. Patients with chronic pelvic pain are
      usually evaluated and treated by gynecologists, gastroenterologists, urologists,
      and internists. Although these patients seek medical care because they are
      looking for help to alleviate their pelvic discomfort and pain, in many cases the
      only focus is on finding and possibly treating the underlying pelvic
      disease.However, often the examination and work-up remain unrevealing and no
      specific cause of the pain can be identified. At this point patients are
      frequently told, that no etiology for their chronic pain syndrome can be found
      and that nothing can be done. In these cases it is important to recognize that
      pain is not only a symptom of pelvic disease, but that the patient is suffering
      from a chronic pelvic pain syndrome. Knowledge of the clinical characteristics of
      visceral pain will guide the health care provider in making a diagnosis of
      chronic pelvic pain and in sorting it out from the lump diagnosis of idiopathic
      pain. Once the diagnosis of chronic pelvic pain is made, treatment should be
      directed towards symptomatic pain management.This conceptualization of chronic
      pelvic pain is very important, because chronic pelvic pain is a treatable
      condition! Effective treatment modalities are available to lessen the impact of
      pain and offer reasonable expectations of an improved functional status.

PMID- 12474034
TI  - [Diagnostic criteria and therapeutic strategies of abdominal pain syndromes].
AB  - Abdominal pain syndromes can be categorised into acute or chronic manifestations.
      In general, diagnostic work-up is targeted upon identification of structural
      lesions that cause the symptoms and allows therapeutic measures that permanently
      cure the cause of symptoms. If no structural or biochemical abnormality can be
      identified upon utilising the necessary diagnostic measures, a functional
      disorder as the cause of symptoms is assumed. For these disorders no cure is
      currently available and treatment is targeted towards relief of symptoms only.

PMID- 12474035
TI  - [Results of a poll of cancer patients with respect to pain and quality of life].
AB  - AIM: Bernatzky et al. recently published a study on the prescribing practices of
      general practitioners in Austria with respect to the prescribing of opioids in
      cancer patients. The aim of the study was to assess the adequately of pain
      therapy and the resulting quality of life in chronic cancer patients. METHODS: A
      representative sample of patients was taken from the Carinthian tumor register.
      These patient were sent a questionnaire alone with an explanatory letter and at a
      later date a reminder letter by mail. RESULTS: Of the 1.895 returned
      questionnaires 665 (35%) were completed. In this study only the data of the 429
      patients who indicated that they experienced pain were processed. More than one
      fifth of the patients complained of a poor or a very poor quality of life and 80%
      of the patients were limited in their activities of daily living by pain. There
      are still many prejudices and informational gaps with respect to the effects of
      morphine. The main focus of treatment was medication therapy and was generally
      carried out by the family physician. The satisfaction with pain therapy was at
      best moderate. This is insofar of importance, as the satisfaction with pain
      therapy has a massive impact on the quality of life. CONCLUSIONS: More extensive
      information and education are required with respect to the various options and
      possibilities of pain control. Explanations of the mode of action and side
      effects of pain medication in order to deal with the prejudices. Earlier and more
      focused use of pain therapy (long duration of pain), and use of coping aids for
      activities of daily living (limited through pain) and a broadening of the
      spectrum of treatment are all necessary. Patient satisfaction with pain therapy
      should be the main focus, as this is the deciding factor in terms of the quality
      of life.

PMID- 12474036
TI  - Comparison of tests for viable and infectious Cryptosporidium parvum oocysts.
AB  - The purpose of this study was to compare different assays for viable
      Cryptosporidium parvum incubated in water at a temperature commonly found in the
      environment. C. parvum oocysts were stored in sterile water for 9 months at 15
      degrees C. A sample was removed monthly and analyzed by five different assays to
      determine oocyst viability. Mouse infection and cell culture showed that C.
      parvum oocysts remained viable and infectious when stored for 7 months at this
      temperature. Fluorescence in situ hybridization (FISH) using probes directed to
      ribosomal RNA was also applied to these oocysts. The proportion of FISH-positive
      oocysts was 70-80% for the first 2 months of storage, decreased and remained
      nearly constant at 40-50% for 3-7 months, then decreased to 20% by 8 months, and
      to 0% by 9 months. Amylopectin content and mRNA for amyloglucosidase (CPAG), as
      measured by RT-PCR, decreased much more rapidly. By 3 months and for the
      remainder of the incubation period, amylopectin content was 20% of the original
      amount present in the oocysts. The CPAG RT-PCR signal at 3 months was 50% of that
      observed after 1 month storage, 20% at 4 months, and was not detected thereafter.
      Thus, results from cell culture and mouse infection assay exhibited the best
      agreement, the FISH assay showed modest agreement with these assays, and CPAG RT
      PCR and the amylopectin assay displayed marginal agreement with the other three
      assays.

PMID- 12474037
TI  - Distribution of free-living amoebae in James River, Virginia, USA.
AB  - A comprehensive survey to document the presence of free-living amoebae was
      conducted along 58 km of James River, near Richmond, Virginia, USA. Sites
      included tidal and non-tidal freshwater areas, near 40 combined sewer outflows,
      three municipal wastewater treatment plant release sites, and thermal discharge
      from a coal-fired power plant. Amoebae were present on all collection dates,
      spring through autumn, and at all sites ( n=330). Five genera, Naegleria,
      Vannella, Acanthamoeba, Vahlkampfia, and Hartmannella were present in both the
      water column and sediment. The most common isolates from the water column were
      Naegleria and Vannella. Water conditions conducive to the presence of large
      quantities of fecal coliform bacteria were correlated with the prevalence of free
      living amoebae. Some of the amoebae in this complex ecosystem can act as
      opportunistic pathogens, may play a role in diseases of aquatic organisms in this
      heavily urbanized river, and may present a risk to human health.

PMID- 12474038
TI  - Cellular mechanisms involved in the increased contraction of portal veins from
      Schistosoma mansoni-infected mice.
AB  - We previously reported that portal veins from mice infected with male Schistosoma
      mansoni exhibited an increased reactivity to 5-hydroxytryptamine (5-HT). Here, we
      extended our observations to mice infected by both male and female worms and we
      further investigated another constrictor agent and the mechanism(s) responsible
      for the enhanced maximal contraction ( E(max)). Bisexual infection increased the
      E(max) of 5-HT (from 0.66+/-0.06 mN.s to 1.56+/-0.38 mN.s), in a similar way to
      the unisexual (male) infection. Infection with male worms increased portal vein
      reactivity to acetylcholine, as revealed by a higher E(max) (1.03+/-0.2 mN.s) in
      relation to non-infected control animals ( E(max)= 0.54+/-0.08 mN.s).
      Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibition with 100 nM
      thapsigargin reduced the E(max) of 5-HT by 35% in both tissues, discharging a
      deficiency of SERCA pump in infected animals. In contrast, the number of voltage
      dependent Ca(2+) channels (L-type) was higher in portal veins from infected than
      non-infected control mice. Inhibition of Ca(2+)-activated chloride channels
      (Cl(Ca)) with 10 micro M niflumic acid reduced the E(max) of 5-HT in portal veins
      more from infected than non-infected animals (remaining tension = 60.9+/-2.2% and
      70.4+/-2.3%, respectively). Histopathological analysis revealed an increased
      content of collagen and elastin in portal veins from male S. mansoni-infected
      mice, compatible with an increased intraluminal pressure. In conclusion, male S.
      mansoni altered portal vein physiology, increasing the E(max) of two
      vasoconstrictors, possibly by increasing membrane depolarisation through a more
      effective opening of Cl(Ca) channels, with calcium entering through L-type Ca(2+)
      channels.

PMID- 12474039
TI  - Electron microscopical studies on cysts of Sarcocystis arieticanis within cardiac
      muscle of naturally infected sheep.
AB  - Transmission electron microscopy was used to the cysts and their walls of
      Sarcocystis arieticanis within cardiac muscle of naturally infected sheep. The
      general ultrastructural features of the cysts, previously described by other
      authors, were confirmed. The cyst walls of S. arieticanis and the size and shape
      of the protrusions at different locations on the cyst wall were explained in
      detail. The cysts were 35-62.5 micro m x 52.5-162.5 micro m in size and the cyst
      wall had different-shaped protrusions. Aged cysts that were localized in the
      heart and differences in the morphology of their protrusions were noticed.

PMID- 12474040
TI  - Parasite-specific immunoglobulin isotypes during lethal and non-lethal murine
      malaria infections.
AB  - Production of parasite-specific antibodies is an important component of immunity
      to blood stage malaria infection, as shown by several previous studies in rodent
      models. However, no study has addressed the induction of humoral immunity by
      different parasites in a genetically homogeneous host population. Here, levels of
      parasite-specific immunoglobulin isotypes were measured during primary infections
      of Plasmodium chabaudi and of Plasmodium yoelii in inbred NIH mice inoculated
      with cloned lines of either avirulent or virulent erythrocytic parasites. Non
      lethal infections were characterized by early and late significant upregulation
      of IgG2a and IgG1, respectively. In contrast, for lethal infections, a slower,
      reduced IgG2a response correlated with a rapidly fatal outcome prior to any
      significant synthesis of IgG1. It is proposed that the sequential upregulated
      synthesis of parasite-specific IgG2a (cytophilic) and IgG1 (non-cytophilic) is
      associated with protective immunity to blood stage malaria infections in mice.
      This may provide an immunological framework for examining humoral immunity to
      malaria in humans.

PMID- 12474041
TI  - Ultrastructure of spermiogenesis and spermatozoa of Taenia parvaBaer, 1926
      (Cestoda, Cyclophyllidea, Taeniidae), a parasite of the common genet ( Genetta
      genetta).
AB  - We studied the ultrastructure of spermiogenesis and of the mature spermatozoon of
      Taenia parva, an intestinal cestode of the common genet, Genetta genetta.
      Spermiogenesis in T. parva is characterized by the growth of the axoneme
      externally to a cytoplasmic extension. After a slight rotation, the free
      flagellum fuses with the cytoplasmic extension. This pattern corresponds to type
      III spermiogenesis according to the scheme proposed by Ba and Marchand. The zone
      of differentiation lacks both striated roots associated with the centrioles and
      the intercentriolar body between them. Nevertheless, the flagellar rotation of
      about 45 degrees is observed in this species. On the other hand, the mature
      spermatozoon of T. parva, as in other cestodes, is filiform, tapered at both
      extremities and lacks mitochondria. The presence of a single crest-like body,
      periaxonemal sheath, and transverse intracytoplasmic walls are also
      characteristic ultrastructural features. The pattern of spermiogenesis and the
      ultrastructural organization of the spermatozoon of T. parva are compared with
      the available data on cyclophyllideans and, in particular, species of the family
      Taeniidae.

PMID- 12474042
TI  - A new nematode, Soboliphyme ataahai sp. n. (Nematoda: Soboliphymidae) from
      Laxmann's shrew, Sorex caecutiens Laxmann, 1788 in Mongolia.
AB  - This report describes a new species of the soboliphymid nematode, Soboliphyme
      ataahai sp. n. from Laxmann's shrew, Sorex caecutiens. This species is
      distinguished from the previously known congeners by the notched cephalic sucker
      with a thin circumoral membrane, relatively long vagina, cephalic papillae
      arranged in clusters, and bursa possessing papillae on inner and outer surfaces.
      Also, Soboliphyme ataahai differs from the congeners in other characters, such as
      position of vulva, number and distribution of cervical sacs, structure of
      cephalic sucker, body size, and dimensions of organs.

PMID- 12474043
TI  - Serological investigation of canine encephalitozoonosis in Norway.
AB  - Encephalitozoon cuniculi, a microsporidian parasite of vertebrates, is considered
      a health risk to AIDS patients and other immunocompromised human beings. In most
      hosts, infection with the parasite runs a subclinical course. In some carnivore
      species, however, clinical disease affecting whole litters arises from
      intrauterine transmission of the parasite. In both blue foxes ( Alopex lagpus)
      and dogs ( Canis familiaris), outbreaks of encephalitozoonosis can be severe.
      Canine encephalitooonosis has been reported from various parts of the world,
      including South Africa and the United States. In Norway, there have been large
      outbreaks of the disease in blue fox farms, affecting also mink, but there have
      been no reports of encephalitozoonosis in dogs. Infection in dogs would represent
      a zoonotic problem, due to the close social relationship between dog and man. The
      purpose of the present study was to investigate the possible occurrence of E.
      cuniculi infection in Norwegian dogs by serological methods. In the study, 1,104
      canine serum samples, originally submitted for biochemical analysis by veterinary
      practitioners throughout Norway, were screened by enzyme-linked immunosorbent
      assay for antibodies to E. cuniculi. Samples from 237 of the dogs were tested
      also by the indirect fluorescent antibody test. All samples were concluded as
      negative. The results indicate that the likelihood of occurrence of E. cuniculi
      infection in Norwegian dogs is small.

PMID- 12474044
TI  - Fasciola hepatica alters coagulation parameters in sheep plasma in vivo and in
      vitro.
AB  - The blood-sucking activities of the liver fluke, Fasciola hepatica, are likely to
      cause alterations in coagulation during the course of infection; and the effect
      of F. hepatica on various coagulation parameters was studied during the course of
      acute and chronic fasciolosis of sheep over a period of 17 weeks. Whole blood and
      plasma samples from infected sheep (with 800 metacercariae each) and uninfected
      controls were collected weekly until 17 weeks post-infection (w.p.i.) and the
      activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin
      time (TT) were determined. Additionally, adult F. hepatica were recovered from
      bile ducts, incubated for the production of excretory/secretory products (ESP) or
      homogenised and the effect of fluke products on APTT, PT and TT was determined.
      Anaemia was evident in infected sheep from 8 w.p.i. until 17 w.p.i. Plasma APTT
      was accelerated during 8, 9, 12, 14, 16 and 17 w.p.i., while PT was prolonged at
      8-11 w.p.i. and TT at 10, 14 and 17 w.p.i. Addition of worm ESP or homogenate to
      plasma resulted in an enhancement of the intrinsic pathway (APTT) together with a
      prolongation of the extrinsic and common pathways (PT, TT) of coagulation. It was
      concluded that F. hepatica contains and releases substances that may contribute
      to coagulation changes in vivo. Further characterisation of the active
      substance(s) in vitro revealed heat inactivation, a size >30 kDa and inhibition
      by the proteinase inhibitors Complete and EDTA for the APTT-accelerating
      substance(s). The TT-deceleration, in contrast, was increased after heating.

PMID- 12474045
TI  - Is there a potential danger of "swimmer's itch in Poland?
AB  - Tests with cercariae of Trichobilharzia szidati (Neuhaus, 1952) and Bilharziella
      polonica (Kowalewski, 1895) from naturally parasitised host snails from lake
      Jeziorak in north Poland were carried out on human volunteers under laboratory
      conditions. Only T. szidati was capable of causing the symptoms of "swimmer's
      itch". In the experiment with B. polonica no symptoms of dermatitis were observed
      either after the first or second exposure.

PMID- 12474046
TI  - In vitro studies on the effects of flubendazole against Toxocara canis and
      Ascaris suum.
AB  - Adult Toxocara canis and Ascaris suum were incubated in vitro in media containing
      0.1, 1, 10 or 100 micro g/ml flubendazole in order to study drug-derived effects.
      This incubation was done for 8 h and repeated (in some groups) after 24 h for
      another 8 h. The onset and intensity of flubendazole-derived effects were dosage
      dependent and time-dependent, i.e. the same grade of damage was reached when
      incubating for a longer period at a low dosage or for a shorter period in medium
      containing a high amount (10 or 100 micro g/ml) of flubendazole. A repeated
      incubation in drug-containing medium was superior to a single exposure.
      Flubendazole is apparently able to penetrate into the worm's interior via the
      cuticle. This became evident in worms with sealed orifices, which showed
      identical damage to worms which were not sealed. The type of tissue damage due to
      flubendazole was identical in both worm species when exposed to any of the drug
      dosages used. The principal mode of action of flubendazole was based on the
      complete reduction of microtubuli-polymerisation inside the parasite's cells.
      This apparently led to the complete destruction of the hypodermis, muscle layer
      and intestine. Flubendazole also stopped the formation of gametes. Summarising,
      even low concentrations of flubendazole (0.1 micro g/ml) led to significant and
      irreversible damage in all worms studied.

PMID- 12474047
TI  - Helminth fauna of cervids in Belorussian Polesie.
AB  - We report on the examination of 18 elk ( Alces alces), 16 red deer (Cervus
      elaphus)and 16 roe deer ( Capreolus capreolus) from the Belorussian Polesie in
      the period 1981-1998 for helminths. A total of 18 helminth species were found
      including Dictyocaulus eckerti, Fasciola hepatica, Oesophagostomum venulosum,
      Taenia hydatigena larvae and Trichuris ovis, all of which occurred in all host
      species. Sixteen of the species found are known to infect humans, domestic
      animals and/or farm animals.

PMID- 12474048
TI  - Helminth fauna of the red fox (Vulpes vulpes Linnaeus, 1758) in southern Belarus.
AB  - We examined 94 carcasses of and 1,213 faecal samples from red foxes collected
      between 1981 and 2001 in natural and transformed ecosystems in the southern part
      of Belarus. A total of 32 helminth species were found. Of these, the most common
      were Alaria alata, Pearsonema plica, Taenia crassiceps, Toxocara canis,
      Trichinella spp. larvae and Uncinaria stenocephala. All species are significant
      for medical and veterinary health.

PMID- 12474049
TI  - Expression of progastrin-releasing peptide and gastrin-releasing peptide receptor
      mRNA transcripts in tumor cells of patients with small cell lung cancer.
AB  - PURPOSE: Small cell lung cancer (SCLC) is a rapidly growing neoplasm accounting
      for approximately 20% of patients with lung cancer. Progastrin-releasing peptide
      (proGRP) is produced in about two-thirds of SCLC tumors and is used as a specific
      marker for SCLC. Although GRP is known to have a variety of biological functions,
      only limited information is available concerning expression of proGRP mRNA and
      protein, and that of the receptor for GRP (GRPR) in SCLC tumors. METHODS: In
      individuals with SCLC, the levels of serum proGRP(31-98) were measured by enzyme
      linked immunosorbent assay. Expression of proGRP as well as GRPR mRNA in SCLC
      tumor tissues was investigated by reverse transcription-nested polymerase chain
      reaction (PCR) amplification. The proportions of alternatively spliced proGRP
      mRNA transcripts were analyzed in proGRP-producing tumors by nested and
      competitive PCR amplification. Finally, production of proGRP protein in SCLC
      tumor was evaluated by using immunohistochemical staining with a polyclonal human
      anti-proGRP antibody. RESULTS: ProGRP mRNA transcripts could be detected only in
      tumor tissues recovered from individuals with high serum proGRP levels. The
      proportions of mRNA subtypes in each case were nearly the same, revealing type I
      of 55.4+/-7.6%, type II with 21-b deletion of 1.8+/-3.6%, and type III with 19-b
      deletion of 42.8+/-4.3%, respectively. ProGRP protein production was demonstrated
      in tumor tissues exclusively from individuals exhibiting high serum proGRP
      levels. In contrast, GRPR mRNA transcripts were detectable in cancer cells from
      two of five proGRP-expressing tumor tissues. CONCLUSIONS: ProGRP mRNA expression
      is closely related with the synthesis of proGRP protein which is eventually
      released into the blood. It is suggested GRP may function as an autocrine growth
      factor for cancer cells in a subgroup of SCLC patients through, at least in part,
      upregulation of GRPR expression.

PMID- 12474050
TI  - Identification of antigenic peptide recognized by the anti-JL1 leukemia-specific
      monoclonal antibody from combinatorial peptide phage display libraries.
AB  - PURPOSE: In the present study an antigen-mimetic peptide of the anti-JL1 leukemia
      specific monoclonal antibody (mAb) was identified and characterized. METHODS:
      From combinatorial peptide phage display libraries displaying the random linear
      heptapeptides and dodecapeptides, we selected clones with affinity to anti-JL1
      mAb through repeated rounds of panning on a mAb-coated ELISA plate. The
      antigenicity and immunogenicity of the peptide epitopes were then studied using
      chemically synthesized peptides. RESULTS: The selected clones had the LXPSIP
      consensus sequence. Two synthetic peptides LPPSIPFGLTVGGGGS and LLPSIPNQAYLGGGGS
      specifically reacted with anti-JL1 mAb in ELISA. These two peptides were found to
      inhibit the interaction between anti-JL1 mAb and JL1 antigen-positive Molt-4
      cells. Although the immune sera raised against the keyhole limpet hemocyanin
      conjugated peptides failed to react with Molt-4 cells, it showed strong
      reactivity to the peptide epitope. However, one mAb raised by peptide
      immunization successfully bound to Molt-4 cells. CONCLUSION: An epitope-mimetic
      peptide of anti-JL1 mAb was found using combinatorial peptide phage display
      libraries. It induced strong humoral response against itself, but only a limited
      fraction of this humoral response was cross-reactive with the original JL1
      antigen.

PMID- 12474052
TI  - Neutralization by "antineoplastin" of insulin-activated nitric oxide synthase
      antibody and its effects in cancers.
AB  - PURPOSE: The plasma level of nitric oxide (NO), that has been reported to possess
      various antineoplastic properties, was found to be diminished due to the
      impairment of insulin-activated nitric oxide synthase (IANOS) as a result of the
      appearance of a novel antibody (free light chain of IgG, M(r) 44 kD) against the
      enzyme in the circulation in various cancers compared to normal control. METHODS:
      We report here two NO-generating agents, antineoplastin I (a protein, M(r) 5000)
      and antineoplastin II (an inorganic compound), which when applied to the skin of
      cancer patients were capable of neutralizing the antibody in vivo through the
      production of NO in the skin cells due to the stimulation of membrane IANOS of
      these cells and, subsequently, in erythrocytes in the circulation. RESULTS:
      Neither antineoplastin I nor antineoplastin II itself enters into the circulation
      but due to the application of these agents on the skin, the NO synthesis in
      erythrocytes was normalized in these patients through "feedback" activation and
      amplification of IANOS activity by NO itself. CONCLUSION: It was found that the
      resumption of NO synthesis through the neutralization of antibody resulted in
      favorable modifications of various cancer-associated pathophysiologic
      consequences.

PMID- 12474051
TI  - DNA ploidy and S-phase fraction, but not p53 or NM23-H1 expression, predict
      outcome in colorectal cancer patients. Result of a 5-year prospective study.
AB  - PURPOSE: The aim of this study was to determine TP53 and NM23-H1
      immunoreactivity, DNA ploidy, and S-phase fraction (SPF) in a series of 160
      patients undergoing resective surgery for primary operable colorectal cancer
      (CRC) and to establish whether these alterations have any clinical value in
      predicting CRC patients' prognosis. METHODS: TP53 and NM23-H1 expressions were
      evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and
      SPF on frozen tissue by flow-cytometric analysis. RESULTS: The median follow-up
      time in our study group was 71 months (range 34-115 months). P53 protein
      expression was associated with distal tumors (P<0.05) and DNA aneuploid tumors
      (P<0.05) tumors. DNA-aneuploidy was associated with distal tumors (P<0.01),
      histological grade (G3) (P<0.05), advanced Dukes' stage (C and D) (P<0.01), lymph
      node metastases (P<0.01) and high SPF (>18.3%) (P<0.01). The major significant
      predictors for both disease relapse and death were advanced Dukes' stage, DNA
      aneuploidy, and high SPF, while lymphohematic invasion was the only independent
      factor for relapse and non-curative resection for death. CONCLUSIONS: Our results
      indicate that DNA aneuploidy and high SPF are associated in CRC with a poor
      clinical 5-year outcome, while in contrast the prognostic role of TP53 and NM23
      H1 expression is still to be clarified.

PMID- 12474053
TI  - Role of cell surface GM3 ganglioside and sialic acid in the antitumor activity of
      a GM3-based vaccine in the murine B16 melanoma model.
AB  - PURPOSE: To examine the role of GM3 monosialoganglioside and sialic acid in the
      antitumor activity of a vaccine based on GM3, hydrophobically conjugated with the
      outer-membrane-protein complex from Neisseria meningitidis (GM3/VSSP). METHODS:
      In order to evaluate the relationship between antitumor activity and the presence
      of GM3 on the surface of tumor cells, we used two murine tumor cell lines with
      different ganglioside expression. Syngeneic mice were immunized with four i.m.
      doses of GM3/VSSP (120 micro g) at 14-day intervals and challenged subcutaneously
      with tumor cells. RESULTS: B16 melanoma cells showed GM3 on cell surface and GM3
      dependent in vitro growth. As expected, preimmunization with the vaccine
      significantly inhibited tumor formation and prolonged survival in mice challenged
      with B16 cells. In contrast, no antitumor effect was observed in mice challenged
      with GM3-negative F3II mammary carcinoma cells. The reactivity of sera from
      immunized mice against B16 cells was confirmed by flow cytometry and
      immunoperoxidase staining. Depletion of sialic acid residues from the cell
      surface completely abolished antibody response against melanoma cells.
      CONCLUSIONS: These results indicate that the antitumor activity of GM3/VSSP is
      associated with GM3 expression on tumor cell surface and demonstrate a major role
      of sialic acid in the humoral response of vaccinated mice.

PMID- 12474054
TI  - A slow acetylator genotype associated with an increased risk of advanced cervical
      cancer.
AB  - PURPOSE: Human papillomavirus (HPV) is the major etiological agent associated
      with cervical cancer. However, other risk factors have been indicated, including
      carcinogen exposure, oral contraceptive usage, certain nutritional deficiencies,
      and genetic factors. N-acetyltransferase 2 (NAT2) has an important role in the
      metabolism of several carcinogens. NAT2 polymorphism modulates the activity of
      the enzyme, by activation, via O-acetylation, or through detoxification, via N
      acetylation. This case-control study was designed to evaluate the association
      between NAT2 polymorphism and genetic susceptibility to cervical cancer. METHODS:
      Genomic DNA was obtained from 125 women with advanced cervical cancer and 170
      healthy women. PCR-RFLP (polymerase chain reaction-restriction fragment length
      polymorphisms) was used to analyse two common mutant alleles at NAT2 loci.
      RESULTS: The NAT2*6/NAT2*6 genotype, which corresponds to a slow acetylator
      genotype, was found to be associated with a 3.41-fold (95% CI: 1.35-8.94; P=
      0.007) increase in the risk of cervical cancer. For the entire case groups the
      proportion of cervical cancer cases attributable (attributable proportion) to the
      NAT2*6/NAT2*6 genotype was 10.2%. CONCLUSIONS: The results reported in this study
      suggest that NAT2 polymorphism is a genetic susceptibility factor involved in the
      carcinogenesis of cervical cancer, and also that the analysis of the allelic
      profile of populations in different geographic locations may help to understand
      the incidence of cervical cancer worldwide.

PMID- 12474055
TI  - Profiling genes differentially expressed in NGX6 overexpressed nasopharyngeal
      carcinoma cells by cDNA array.
AB  - PURPOSE: To investigate the role of the NGX6 gene in carcinoma proliferation and
      profile the downstream genes regulated by NGX6 in a nasopharyngeal carcinoma
      (NPC) cell line. METHODS: We established a NPC cell line with NGX6 overexpression
      by gene transfection. Subsequently, a high-density cDNA array was used to
      identify differentially expressed genes in NGX6-overxepressed cells. Four
      differentially expressed genes or EST(expressed sequence tags) were examined
      using Northern blot. Furthermore, flow cytometry was employed to analyze the
      percentages of cells in the G(0)-G(1), S, and G(2)-M phase of the cell cycle in a
      NGX6 overexpression cell line. RESULTS: Fifty-five genes and ESTs were
      differentially expressed after NGX6 transfection in a cDNA array assay. Several
      genes related to cell cycle and transcription regulation were identified using
      this technique. Flow cytometry analysis showed NGX6 overexpression can increase
      the length of the G(1) phase of the cell cycle in NPC cells. CONCLUSION: We
      demonstrated the existence of a panel of genes that can be regulated by NGX6.
      Overexpression of NGX6 can influence the distribution of the cell cycle in NPC
      cells. Further studies are necessary to elucidate the exact function of these
      genes and their relationship to NGX6 expression.

PMID- 12474058
TI  - A DNase I hypersensitive site flanks an origin of DNA replication and
      amplification in Sciara.
AB  - In chromosomes of metazoa, the assembly of the genome into chromatin makes an
      important but poorly understood contribution to determining where DNA replication
      will initiate. We addressed this issue by studying the developmental progression
      of the location of the DNA replication origin (ORI) and alterations in chromatin
      structure in one of the best-mapped ORIs in metazoa, that found in DNA puff II/9A
      of the fly Sciara coprophila. We found that DNA synthesis for both normal
      chromosomal endoduplication and DNA amplification initiates within the same 5.5
      kb EcoRI fragment. We showed that irrespective of the mode of ORI function-
      replication or amplification--chromatin over the 1 kb major ORI is never
      remodeled into a conventional DNase I hypersensitive site (DH site). Instead, we
      found that the major site of alterations to chromatin structure at this locus is
      a large (approximately 400 bp) DH site located 600 bp away from the major ORI, at
      a position where the frequency of replication initiation events falls
      dramatically. We describe a tight positive correlation between ORI activity,
      strength of this DH site, and the intranuclear titer of protein factor(s) that
      bind the DH site in a sequence-specific manner. We propose that the Sciara
      replicator in locus II/9A is composed of sequences that reside within the ORI per
      se as well as sequences encompassed by the DH site.

PMID- 12474059
TI  - Evidence that extrachromosomal double-strand break repair can be coupled to the
      repair of chromosomal double-strand breaks in mammalian cells.
AB  - Transfected linear DNA molecules are substrates for double-strand break (DSB)
      repair in mammalian cells. The DSB repair process can involve recombination
      between the transfected DNA molecules, between the transfected molecules and
      chromosomal DNA, or both. In order to determine whether these different types of
      repair events are linked, we devised assays enabling us to follow the fate of
      linear extrachromosomal DNA molecules involved in both interplasmid and
      chromosome-plasmid recombination, in the presence or absence of a pre-defined
      chromosomal DSB. Plasmid-based vectors were designed that could either recombine
      via interplasmid recombination or chromosome-plasmid recombination to produce a
      functional beta-galactosidase (betagal) fusion gene. By measuring the frequency
      of betagal+ cells at 36 h post-transfection versus the frequency of betagal+
      clones after 14 days, we found that the number of cells containing
      extrachromosomal recombinant DNA molecules at 36 h (i.e., betagal+), either
      through interplasmid or chromosome-plasmid recombination, was nearly the same as
      the number of cells integrating these recombinant molecules. Furthermore, when a
      predefined DSB was created at a chromosomal site, the extrachromosomal
      recombinant DNA molecules were shown to integrate preferentially at that site by
      Southern and fiber-FISH (fluorescence in situ hybridization) analysis. Together
      these data indicate that the initial recombination event can potentiate or commit
      extrachromosomal DNA to integration in the genome at the site of a chromosomal
      DSB. The efficiency at which extrachromosomal recombinant molecules are used as
      substrates in chromosomal DSB repair suggests extrachromosomal DSB repair can be
      coupled to the repair of chromosomal DSBs in mammalian cells.

PMID- 12474056
TI  - Clinicopathological significance of pRb2/p130 expression in squamous cell
      carcinoma of the esophagus.
AB  - PURPOSE: The aim of the current study was to find out the significance of the
      immunohistochemical expression of pRb2/p130, which is a member of the
      retinoblastoma gene family, in squamous cell carcinoma of the esophagus. METHODS:
      We analyzed immunohistochemically the expression of pRb2/p130 of 107 squamous
      cell carcinomas (SCCs) of the esophagus and the correlation of pRb2/p130
      expression with clinicopathological features was investigated. RESULTS:
      Expression of pRb2/p130 was observed in 42 SCCs (39.3%). There was a significant
      correlation of pRb2/p130 expression with the histological type of well
      differentiated SCC (P< 0.0001). The survival rate of patients with esophageal
      SCCs expressing pRb2/p130 was significantly better than that of patients with
      tumors without pRb2/p130 expression (P= 0.016). A multivariate analysis
      demonstrated that pRb2/p130 expression (P= 0.026), venous invasion (P= 0.028),
      and TNM stage (P= 0.044) were independent prognostic indicators in patients with
      esophageal SCCs. CONCLUSIONS: Differentiation of esophageal SCC might be
      partially mediated by the pRb2/p130 gene, and pRb2/p130 expression can
      additionally be an indicator of the better prognosis of patients with esophageal
      SCCs.

PMID- 12474060
TI  - Distribution of interstitial telomere-like repeats and their adjacent sequences
      in a dioecious plant, Silene latifolia.
AB  - The dioecious plant Silene latifolia has large, heteromorphic X and Y sex
      chromosomes that are thought to be derived from rearrangements of autosomes. To
      reveal the origin of the sex chromosomes in S. latifolia, we isolated and
      characterized telomere-homologous sequences from intra-chromosomal regions
      (interstitial telomere-like repeats; ITRs) and ITR-adjacent sequences (IASs).
      Nine genomic DNA fragments with degenerate 84- to 175-bp ITRs were isolated from
      a genomic library and total genome of male plants. Comparing the nucleotide
      sequences, the IASs of the nine ITRs were classified into seven elements (IAS-a,
      IAS-b, IAS-c, IAS-d, IAS-e, IAS-f, and IAS-g) by sequence similarity. The ITRs
      were grouped into two classes (class-I and -II ITRs) according to the
      classification of IASs. The class-I ITRs were sub-grouped into three subclasses
      (subclasses-IA, -IB, and -IC ITRs) based on the arrangement of IAS elements. By
      contrast, the class-II ITR was located between two different IASs (IAS-f and IAS
      g). Genomic Southern analyses showed that both the male and female genomes
      contained six (IAS-f) to 153 (IAS-d) copies of each IAS per haploid genome.
      Fluorescence in situ hybridization analyses showed that one IAS element, IAS-d,
      was distributed in the interstitial and proximal regions of the sex chromosomes
      of S. latifolia. The distribution of IAS-d is important evidence for past
      telomere-mediated chromosome rearrangements during the evolution of the sex
      chromosomes of S. latifolia.

PMID- 12474061
TI  - 3D Structure of the human genome: order in randomness.
AB  - A complex study of the spatial arrangement of different genetic elements (genes,
      centromeres and chromosomal domains) in the cell nucleus is presented and the
      principles of this arrangement are discussed. We show that the radial location of
      genetic elements in the three-dimensional (3D) space between the center of the
      nucleus and the nuclear membrane is element specific and dependent on the
      position of the element on the chromosome. In contrast, mutual angular
      positioning of both homologous and heterologous genetic elements is, in the
      majority of cases, random. In several cases, tethering of heterologous genetic
      elements was observed. This close proximity of specific loci may be responsible
      for their mutual rearrangement and the development of cancer. Comparison of our
      results with transcriptome maps shows that the nuclear location of chromosomal
      domains with highly expressed genes is more central when compared with
      chromosomes with low expression. The higher-order chromatin structure is
      strikingly similar in various human cell types, which correlates with the fact
      that the profiles of gene expression are also similar.

PMID- 12474062
TI  - Origin of an apparent B chromosome by mutation, chromosome fragmentation and
      specific DNA sequence amplification.
AB  - The present study documents the de novo origin of an apparent B chromosome in
      Plantago lagopus. The origin was associated with mutation (aneuploidy),
      chromosome fragmentation, specific DNA sequence amplification, addition of
      telomeric repeats, and centromeric misdivision. It originated in the progeny of
      trisome 2, from the excision of 5S rDNA and 18S, 5.8S, 25S rDNA sequences located
      on chromosome 2, and within a few generations acquired many characteristics of an
      apparent B chromosome. The B chromosome has preferential transmission through the
      male (41%, P<0.025) and female gametes (42%, P<0.01) but does not affect plant
      phenotype. The B chromosome is completely heterochromatic, has a functional
      centromere and does not pair at meiosis with any A chromosomes of the standard
      complement. Fluorescence in situ hybridization analysis showed that it arose from
      massive amplification of 5S rDNA sequences, has 18S, 5.8S, 25S rDNA sequences at
      the ends of both arms and telomeric repeats at both termini. Ag-NOR-banding and
      determination of the maximum number of nucleoli in interphase cells indicate that
      the nucleolar organizer regions at the ends of both arms of the B chromosome are
      active in organizing nucleoli. RNA blot analysis showed that the 5S rDNA
      sequences are not transcribed. To our knowledge, this is the first report that
      fully documents one of the mechanisms by which B chromosomes may arise in nature.

PMID- 12474063
TI  - Unusual chromosome cleavage dynamic in rodent neonatal germ cells.
AB  - At the metaphase/anaphase transition in the mouse and rat male germ lines during
      the perinatal period, sister centromeres separate before sister chromatids. This
      gives the chromosomes an unusual appearance that resembles the premature
      centromere division described in some human pathological conditions such as
      Roberts syndrome. At the same period, there is also an unusual pattern of DNA
      methylation, with strongly demethylated heterochromatin and methylated
      euchromatin. This suggests that chromosome DNA methylation may modulate chromatid
      and centromere splitting, without altering normal chromosome segregation.

PMID- 12474064
TI  - Analysis of chromosome conservation in Lemur catta studied by chromosome paints
      and BAC/PAC probes.
AB  - A panel of human chromosome painting probes and bacterial and P1 artificial
      chromosome (BAC/PAC) clones were used in fluorescence in situ hybridization
      (FISH) experiments to investigate the chromosome conservation of the ring-tailed
      lemur (Lemur catta, LCA) with respect to human. Whole chromosome paints specific
      for human chromosomes 7, 9, 11, 13, 14, 17, 18, 20, 21, and X were found to
      identify a single chromosome or an uninterrupted chromosomal region in LCA. A
      large set of partial chromosome paints and BAC/PAC probes were then used to
      refine the characterization of the rearrangements differentiating the two
      karyotypes. The results were also used to reconstruct the ancestral Lemuridae
      karyotype. Lemur catta, indeed, can be used as an outgroup, allowing
      symplesiomorphic (ancestral) rearrangements to be distinguished from apomorphic
      (derived) rearrangements in lemurs. Some LCA chromosomes are difficult to
      distinguish morphologically. The 'anchorage' of most LCA chromosomes to specific
      probes will contribute to the standardization of the karyotype of this species.

PMID- 12474066
TI  - Paraoxonase 1 Q192R (PON1-192) polymorphism is associated with reduced lipid
      peroxidation in R-allele-carrier but not in QQ homozygous elderly subjects on a
      tomato-rich diet.
AB  - BACKGROUND: The oxidative modification of LDL is considered to play a central
      role in the pathogenesis of atherosclerosis and coronary heart disease (CHD).
      Paraoxonase (PON1) protects LDL from oxidation and may therefore retard the
      development of atherosclerosis. The PON1-192 polymorphism is associated with
      diminished PON1 concentrations and an increased risk for CHD in RR-allele
      subjects. AIM OF THE STUDY: To investigate the effect of tomato juice consumption
      on PON1 activity and other parameters related to oxidative stress in healthy
      elderly subjects. Furthermore, the PON1-192 genotype has been determined in the
      volunteers in order to see whether possible treatment effects are related to the
      PON1-192 polymorphism. METHODS: Fifty elderly subjects were randomly assigned to
      control (mineral water) or intervention group (tomato juice). Subjects of the
      tomato juice group consumed daily 330 mL tomato juice for 8 weeks. Antioxidant
      status was measured as LDL oxidation, plasma malondialdehyde, ferric reducing
      ability of plasma (FRAP) and PON1 activity. The PON1-192 polymorphism was
      determined by restriction fragment length polymorphism polymerase chain reaction
      (RFLP-PCR). Plasma carotenoids were analyzed by HPLC. RESULTS: Tomato juice
      consumption reduced LDL-oxidation and improved antioxidant status in R-allele
      carriers, but not in the QQ genotype group. PON1 activity increased irrespective
      of the genotype in both, control and intervention group. CONCLUSIONS: The changes
      in antioxidant status after tomato juice consumption seem to depend on the PON1
      192 genotype. Healthy elderly, carrying the R-allele, could specifically reduce
      their higher cardiovascular risk by changing dietary habits.

PMID- 12474067
TI  - Relationship between lifestyle factors and defecation in a Japanese population.
AB  - BACKGROUND: There is a paucity of accurate data regarding any association in the
      general population between defecation and lifestyle factors such as diet,
      exercise, physique, and childbirth. AIMS OF THE STUDY: To evaluate the effects of
      such lifestyle factors on defecation among regional residents of Japan. METHODS:
      Residents (n = 1,699) of northern Japan, aged over 40 years, were surveyed in
      1995 using a questionnaire to assess their lifestyle factors (diet, beverage
      consumption, exercise, physique, and childbirth), and examining their defecation
      status. We evaluated the relationship between these lifestyle factors and
      defecation using logistic regression analysis. The authors used four measures
      (defecation frequency, subjective defecation state, subjective fecal properties,
      and fecal consistency) and assigned the subjects to a group defined by their
      defecatory status: constipation, diarrhea, or normal, depending on the responses
      of the subjects to all four criteria. RESULTS: The tendency for constipation
      correlated positively with age in males ( p = 0.130), although this trend was not
      observed in females ( p = 0.641). Of the dietary factors examined, only rice,
      which accounts for the largest proportion of daily dietary fiber intake in Japan,
      demonstrated a preventive effect on constipation in both sexes ( p = 0.050 in
      males and 0.003 in females). Walking was a preventive factor for constipation
      among males ( p = 0.049), and alcohol also inhibited constipation among males ( p
      = 0.007). CONCLUSIONS: These results suggest that exercise, such as walking, and
      a high intake of dietary fiber, such as rice, were useful in the maintenance of
      defecation.

PMID- 12474068
TI  - Determinants of the adherence to an "a priori" defined Mediterranean dietary
      pattern.
AB  - BACKGROUND: A prospective cohort study with university level participants was
      initiated to study the effect of Mediterranean diet on health. AIMS: The
      objective of this study was to identify possible lifestyle and socioeconomic
      variables associated with the consumption of a Mediterranean dietary pattern
      (MDP). METHOD: This analysis includes 1587 males and 2260 females. MDP was
      defined "a priori" by summing the standardized residuals of nutrients and foods
      after adjusting a regression model using total energy intake as the independent
      variable. Multiple regression and non-parametric locally weighted regression
      models were adjusted with the relative adherence to the MDP as the dependent
      variable in males and females. RESULTS: Women were more compliant than men with
      the MDP (Coefficient regression (b) = 4.1; Confidence Interval (CI) 95 % = 3.2 to
      4.9). The compliance with the MDP was significantly poorer among younger
      participants both in men and women (p < 0.001 in men and in women). Participants
      who were more physically active were more likely to fulfill the traditional MDP
      (p = 0.01 in men and p < 0.001 in women). CONCLUSIONS: Our findings provide
      evidence supporting the progressive departure from the traditional MDP in younger
      and highly educated subjects of the Mediterranean area. A more active life-style
      is associated with a better compliance with the MDP.

PMID- 12474069
TI  - The effects of calcium supplementation to patients with primary
      hyperparathyroidism and a low calcium intake.
AB  - BACKGROUND: In patients with primary hyperparathyroidism (PHPT) a low calcium
      intake might cause increased bone loss and thus aggravate osteoporosis, and a
      high intake might increase serum calcium level and the risk of nephrolithiasis.
      AIM OF THE STUDY: Generally, guidelines recommend a normal calcium intake, and
      accordingly, those with a low intake might benefit from a modest calcium
      supplementation. This hypothesis was tested in the present study. METHODS: Thirty
      one patients with asymptomatic PHPT were recruited from an epidemiological study
      (The Tromso study 1994/95). Those with a daily calcium intake below 450 mg were
      given calcium supplementation (500 mg Ca(2+)), and those with an intake above 450
      mg were followed without supplementation. The study was open and lasted 1 year.
      Serum levels of calcium, PTH, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D,
      urinary calcium excretion, blood pressure, and bone mineral density (BMD) were
      measured. RESULTS: Three subjects dropped out without reason, 1 developed
      abdominal discomfort from the calcium supplementation, and 3 had an increase in
      serum calcium of more than 0.2 mmol/L and were therefore excluded. The latter
      three did not differ from the rest of the group at baseline. Of the remaining 24
      that completed the study, 17 were given calcium. In this group there was a non
      significant increase in serum calcium and urinary calcium excretion, a
      significant decrease in PTH after 4 weeks (13.2 (6.0) vs 9.4 (3.0) pmol/L, P <
      0.05), and a significant increase in BMD at the femoral neck at the end of the
      study (0.849 (0.139) vs 0.870 (0.153) g/cm(2), P < 0.05). The blood pressure was
      not significantly affected. CONCLUSIONS: Most patients with mild PHPT and a low
      calcium intake tolerate a moderate calcium supplement. This may have beneficial
      effects on the bones, but the patients must be followed carefully.

PMID- 12474070
TI  - Acute intake of moderate amounts of red wine or alcohol has no effect on the
      immune system of healthy men.
AB  - BACKGROUND: A recent prospective cohort study revealed that moderate wine
      consumption but not consumption of other alcoholic beverages is associated with a
      decreased risk of common cold. In contrast, wine constituents such as ethanol and
      polyphenols are known to suppress immunity. AIM OF THE STUDY: We investigated
      whether acute intake of a moderate amount of alcohol modulates immune functions
      in healthy men and whether polyphenols in red wine with antioxidative and
      immunomodulatory potential induce changes in immune functions that differ from
      those induced by the consumption of the 12 % ethanol. METHODS: Six healthy males
      with moderate alcohol consumption patterns randomly consumed a single dose of 500
      ml of red wine (12 % ethanol), a 12 % ethanol dilution, dealcoholized red wine,
      and red grape juice, respectively. The following immune functions were measured
      before beverage consumption and 1, 3, and 24 h later: phagocytic activity and
      intensity of neutrophils and monocytes, production of tumor necrosis factor
      alpha, interleukin-2, and interleukin-4, lymphocyte proliferation, and lytic
      activity of natural killer cells. RESULTS: Acute consumption of a moderate amount
      of red wine and of a 12 % ethanol solution had no effect on immune functions in
      men. Acute consumption of polyphenol-rich beverages (dealcoholized red wine and
      red grape juice) also did not affect immunity. CONCLUSIONS: This study clearly
      shows that moderate consumption of alcohol at doses which inversely correlate
      with cardiovascular disease risk has no short-term effect on human immune cell
      functions. Acute intake of polyphenol-rich beverages such as red grape juice and
      dealcoholized red wine also does not affect immunity.

PMID- 12474071
TI  - Functionality of endogenous folates from rye and orange juice using human in vivo
      model.
AB  - BACKGROUND: Cereals contribute about a quarter of the daily folate intake from a
      typical diet in several European countries. However, studies on bioavailability
      of endogenous folates, in particular of cereal sources, are scarce. AIM OF THE
      STUDY: We aimed to study how well natural folates from rye (different rye breads
      and muesli made of malted rye) and orange juice function in improving folate
      status of human volunteers compared to a diet containing folic acid fortified
      wheat bread. METHODS: Healthy human volunteers aged 20-66 y took part in a four
      week intervention trial in which bread, breakfast cereal and juice were provided.
      The study had a parallel design with two groups, 1) rye and orange juice group
      (33 volunteers) and 2) fortified wheat bread and apple juice group (31
      volunteers). The test foods provided on average 184 microg and 188 microg folate
      per day in rye and wheat groups, respectively. Test foods were consumed as part
      of the subjects' normal diet. RESULTS: In both groups statistically significant
      increases in serum and red cell folates were observed after the intervention
      period. The serum folate increased 26 % and 31 %, and red cell folate levels
      increased 17 % and 15 % in rye and orange juice and wheat and apple juice groups,
      respectively. The effects did not differ between the rye and wheat groups.
      Increases in serum and red cell folate were more profound among subjects with low
      starting folate levels. Decrease in the plasma homocysteine concentrations was
      observed only in the highest tertile of both groups but not in the group means.
      CONCLUSIONS: Endogenous folates incorporated into a healthy diet, even in
      moderate amounts, is an efficient way to improve folate status among healthy
      adults. Folates from different rye products and orange juice showed good
      bioavailability that was similar to folic acid from fortified white bread.

PMID- 12474072
TI  - Study of wheat breakfast rolls fortified with folic acid. The effect on folate
      status in women during a 3-month intervention.
AB  - BACKGROUND: Folate has come into focus due to its protective role against child
      birth defects such as neural tube defects (NTD). Swedish authorities recommend
      all fertile women to increase their folate intake to 400 microg/day by eating
      folate-rich foods. Because not all women follow these recommendations, there is a
      discussion today about whether Sweden should introduce folic acid fortification
      in wheat flour and sifted rye flour. This decision needs knowledge about the
      bioavailability of folic acid from fortified foods. AIM OF THE STUDY: To
      investigate effects of two folic acid fortification levels on folate status in
      healthy female volunteers and to study the folic acid stability during the baking
      procedure and storage of the fortified breakfast rolls. METHOD: Twenty-nine
      healthy women were recruited. Folic acid-fortified wheat breakfast rolls were
      baked with the purpose to contain 200 microg folic acid/roll (roll L) and 400
      microg folic acid/roll (roll H). Fourteen women were given one roll/day of roll L
      (group L) and 15 one roll/day of roll H (group H) during 12 weeks of
      intervention. Fasting venous blood samples were collected on days 0, 30, 60 and
      90. Serum homocysteine concentrations were determined using an immunoassay. Serum
      and erythrocyte folate concentrations were analysed using a protein-binding assay
      with fluorescent quantification. The folic acid concentration in the breakfast
      rolls was analysed by HPLC on days 0, 30, 60 and 90. Total folate concentration
      was measured with microbiological assay on day 45. RESULTS: Group L Group L had
      initially an average erythrocyte folate concentration of 577 +/- 93 nmol/L. After
      90 days of intervention, an increase of 20 % (p < 0.05) was observed. At day 0,
      mean serum folate concentrations were 16.9 +/- 4.3 nmol/L. The mean serum folate
      concentrations increased by 30 % (p < 0.001) after 90 days. At day 0, mean serum
      homocysteine concentrations were 9.1 +/- 2.0 micromol/L, which decreased by 20 %
      (p < 0.01) after 30 days. Group H Group H had an initial erythrocyte folate
      concentration of 784 +/- 238 nmol/L. After 90 days, an increase of 26 % (p <
      0.05) was observed. Serum folate increased at least 22 % after 30 days, from a
      level of 18.7 +/- 4.8 nmol/L at day 0. Thereafter, all women of group H had serum
      concentrations at or above the upper limit of quantification (23 nmol/L). At day
      0, mean serum homocysteine concentrations were 8.4 +/- 1.7 micromol/L, which
      decreased by 16 % (p < 0.05) after 30 days. The baking procedure resulted in 20
      25 % loss of fortified folic acid in the rolls used in the present study. The
      size of the rolls affected the retention of folic acid during baking. No
      significant loss was seen in folic acid concentration in the rolls during the
      intervention period. CONCLUSION: The present study showed that in healthy women,
      subjected to a 12-week intervention with breakfast rolls fortified with either
      166 microg or 355 microg folic acid, serum homocysteine concentration decreased
      (p < 0.05) and erythrocyte folate increased (p < 0.05). The lower level of
      fortification seems to be sufficient to improve the folate status. Together with
      the average daily intake of natural folates, these women reach the recommended
      intake of 400 microg/day. Folic acid is stable in fortified bread for 90 days
      storage at -20 degrees C.

PMID- 12474073
TI  - Mechanisms of Ras protein targeting in mammalian cells.
AB  - Many physiological and oncogenic activities of the "classical" Ras proteins (H
      Ras, N-Ras and K-Ras4A and -4B) require their correct localization to the plasma
      membrane. Nascent Ras proteins, however, initially associate with endomembranes
      (the ER and in some cases the Golgi) to complete the processing of their
      farnesylated carboxyl-termini before they are delivered to the plasma membrane.
      Recent work has revealed the outlines of the intracellular pathways by which Ras
      proteins reach their ultimate plasma membrane destination and has indicated that
      these pathways differ for different Ras species. Other studies have demonstrated
      that mature Ras proteins can transfer between the plasma membrane and
      intracellular membranes, and that Ras proteins may in some cases signal from
      intracellular compartments. This review will describe recent progress and still
      unresolved questions in these areas.

PMID- 12474074
TI  - Structural implications of placing cationic residues at either the NH2- or COOH
      terminus in a pore-forming synthetic peptide.
AB  - Restoration of chloride conductance via introduction of an anion-selective pore,
      formed by a channel-forming peptide, has been hypothesized as a novel treatment
      modality for patients with cystic fibrosis. Delivery of these peptides from an
      aqueous environment in the absence of organic solvents is paramount. M2GlyR
      peptides, designed based on the glycine receptor, insert into lipid bilayers and
      polarized epithelial cells and assemble spontaneously into chloride-conducting
      pores. Addition of 4 lysine residues to either terminus increases the solubility
      of M2GlyR peptides. Both orientations of the helix within the membrane form an
      anion-selective pore, however, differences in solubility, associations and
      channel-forming activity are observed. To determine how the positioning of the
      lysine residues affects these properties, structural characteristics of the lysyl
      modified peptides were explored utilizing chemical cross-linking, NMR and
      molecular modeling. Initial model structures of the a-helical peptides predict
      that lysine residues at the COOH-terminus form a capping structure by folding
      back to form hydrogen bonds with backbone carbonyl groups and hydroxyl side
      chains of residues in the helical segment of the peptide. In contrast, lysine
      residues at the NH2-terminus form fewer H-bonds and extend away from the helical
      backbone. Results from NMR and chemical cross-linking support the model
      structures. The C-cap formed by H-bonding of lysine residues is likely to account
      for the different biophysical properties observed between NH2- and COOH-terminal
      modified M2GlyR peptides.

PMID- 12474075
TI  - Protons activate homomeric Kir6.2 channels by selective suppression of the long
      and intermediate closures.
AB  - The ATP-sensitive K+ channels (KATP) play an important role in regulating
      membrane excitability. These channels are regulated by H+ in addition to ATP,
      ADP, and phospholipids. To understand how protons affect the single-channel
      properties, Kir6.2DeltaC36 currents were studied in excised inside-out patches.
      We chose to study the homomeric Kir6.2 channel with 36 amino acids deleted at the
      C-terminal end, as there are ADP/ATP-binding sites in the SUR subunit, which may
      obscure the understanding of the channel-gating process. In the absence of ATP,
      moderate intracellular acidosis (pH 6.8) augmented P(open) with small suppression
      (by approximately 10%) of the single-channel conductance. The long and
      intermediate closures were selectively inhibited, leading to a shortening of the
      mean closed time without significant changes in the mean open time. Stronger
      acidification (<pH6.2) caused channel rundown. Although similar changes in the
      single-channel properties were observed in the presence of 1 mM ATP, the P(open)
      pH relationship curve was shifted by 0.17 pH units toward lower pH levels. ATP
      had no effect on the inhibition of single-channel conductance during acidosis.
      Mutation of His175 eliminated the pH effect on the single-channel kinetics, while
      the single-channel response to acidic pH was retained in the K185E mutant that
      greatly reduces the ATP sensitivity. These results indicate that Kir6.2DeltaC36
      channel gating by protons and ATP relies on two distinct mechanisms opposite to
      each other, although the pH sensitivity is modulated by ATP.

PMID- 12474076
TI  - Differential role of Na+/H+ exchange isoforms NHE-1 and NHE-2 in a rat cortical
      collecting duct cell line.
AB  - The Na+/H+ exchanger (NHE) constitutes a gene family containing several isoforms
      that display different membrane localization and are involved in specialized
      functions. Although basolateral NHE-1 activity was described in the cortical
      collecting duct (CCD), the localization and function of other NHE isoforms is not
      yet clear, This study examines the expression, localization, and regulation of
      NHE isoforms in a rat cortical collecting duct cell line (RCCD1) that has
      previously been shown to be a good model of CCD cells. Present studies
      demonstrate the presence of NHE-1 and NHE-2 isoforms, but not NHE-3 and NHE-4, in
      RCCD1 cells. Cell monolayers, grown on permeable filters, were placed on special
      holders allowing independent access to apical and basolateral compartments.
      Intracellular pH (pHi) regulation was spectrofluorometrically studied in basal
      conditions and after stimulation by NH4Cl acid load or by a hyperosmotic shock.
      In order to differentiate the roles of NHE-1 and NHE-2, we have used HOE-694, an
      inhibitor more selective for NHE-1 than for NHE-2. The results obtained strongly
      suggest that NHE-1 and NHE-2 are expressed in the basolateral membrane but that
      they have different roles: NHE-1 is responsible for pHi recovery after an acid
      load and NHE-2 is mainly involved in steady-state pHi and cell volume regulation.

PMID- 12474077
TI  - Effect of ibuprofen and rofecoxib transport parameters in the frog corneal
      epithelium.
AB  - Effects of cyclooxygenase (COX) inhibitors on transport parameters of the frog
      corneal epithelium were studied. Epithelial cells of the intact cornea were
      impaled with microelectrodes. Under short-circuit current (I(sc)) conditions, 10(
      4) M ibuprofen (IBU) (non-specific COX inhibitor) or 5 x 10(-5) M rofecoxib (COX
      2 inhibitor) were added to the tear solution. With ibuprofen, I(sc) decreased by
      1.0 from 3.1 microA/cm2; intracellular potential, V(o), depolarized by 14.2 from 
      56.9 mV; IBU did not affect the transepithelial conductance, g(t), or the apical
      membrane fractional resistance, fR(o). With rofecoxib, I(sc) decreased by 0.9
      from 4.3 microA/cm2; V(o) depolarized by 18 from -62.4 mV; g(t) significantly
      increased by 0.03 from 0.37 ms/cm2; and fR(o) decreased by 12 from 50.
      Basolateral membrane K+ and apical membrane Cl- partial conductances were studied
      by the ion substitution method. Depolarization of V(o) by an increase in stromal
      K+ from 4 to 79 mM was smaller with IBU (17.5 mV) or rofecoxib (19.2 mV) than
      without the inhibitors (29.1 and 29.3 mV, respectively). Depolarization of V(o),
      by a decrease in tear Cl- from 81 to 8.1 mM, was abolished by the COX inhibitors.
      Decrease in I(sc) and V(o) can be explained by a decrease in the K+ and Cl-?
      conductances. Experiments with amphotericin B ruled out a major effect of the
      inhibitors on the Na+/K+ ATPase pump.

PMID- 12474078
TI  - Somatic gene transfer of tagged K+ channel fragments to probe trafficking and
      electrical function in epithelial cells and cardiac myocytes.
AB  - To evaluate the roles of the C-termini of K + channels in subcellular targeting
      and protein-protein interactions, we created fusion constructs of the cell
      surface antigen CD8 and the C-termini of Kv4.3, Kv1.4 and KvLQT1. Using a Cre-lox
      recombination system, we made 3 adenoviruses containing a fusion of the N
      terminal-and transmembrane segments of CD8 with the C-termini of each of the 3 K
      + channels. Expression in polarized Opossum Kidney (OK) epithelial cells led to
      localization of CD8-Kv4.3 and CD8-Kv1.4 into the apical and basolateral
      membranes, while CD8-KvLQT1 remained in the endoplasmic reticulum (ER), even when
      co-expressed with MinK. When expressed in rat cardiac myocytes in culture, all
      the 3 constructs were diffusely targeted to the surface membrane. The ER
      retention of CD8-KvLQT1 in OK cells but not in cardiomyocytes thus reveals
      functional differences in trafficking between these two cell types. To probe
      functional roles of C-termini, we studied K + currents in cardiac myocytes
      expressing CD8-Kv4.3. Patch-clamp recordings of transient outward current
      revealed a hyperpolarizing shift of steady-state inactivation, implying that CD8
      Kv4.3 may be disrupting the interaction of Kv4.x channels with one or more as-yet
      undefined regulatory subunits. Thus, expression of tagged ion-channel fragments
      represents a novel, generalizable approach that may help to elucidate assembly,
      localization and function of these important signaling proteins.

PMID- 12474079
TI  - Characterization of the taurine transport pathway in A6 kidney cells.
AB  - We investigated the role of taurine in cell homeostasis and characterized the
      taurine transport pathway in cultured kidney cells (A6). The taurine
      concentration in A6 cells varies with the osmolarity of the culture medium,
      suggesting that taurine participates in cell osmolarity. Under isosmotic
      conditions, 14C-taurine efflux through the apical membranes (aJtaur) was 6-7
      times lower than that through the basolateral membranes (bJtaur). Under
      hyposmotic conditions, aJtaur remained almost unchanged. On the contrary, bJtaur
      increased 8 times in comparison with isosmotic conditions. In hyposmotic
      conditions, bJtaur was inhibited by 500 microM DIDS, 50 microM NPPB, 10 microM of
      the two oxonol derivatives DISBAC(2)3 and WW-791, and 100 microM ketoconazole.
      Conversely, 100 microM 1,9-dideoxyforskolin, 10 microM tamoxifen, 100 microM
      niflumic acid and 50 microM verapamil had no inhibitory effects. Cell volume
      regulation upon hyposmotic stress was also found to be inhibited by DISBAC(2)3
      (K0.5 of 5+/-1 microM) and by ketoconazole. Nystatin was used to permeabilize the
      apical membranes with the aim to further characterize bJtaur. 14C-taurine
      transepithelial fluxes in nystatin-treated cells were found to be linear over
      taurine concentrations ranging from 3.5 microM to 35 mM. Clamping the
      transepithelial voltage at positive values (serosal side) slightly stimulated the
      14C-taurine transport. Similar time courses of 14C-taurine, 36Cl and 86Rb
      transepithelial fluxes were found under osmotic stimulation followed by DIDS
      inhibition in nystatin-treated cells. In whole cell patch-clamp experiments,
      DISBAC(2)3 application resulted in a strong and reversible decrease of the global
      Cl- current which was stimulated by hyposmotic stress. Our study indicates that
      taurine participates in the control of A6 cell osmolarity and that the
      transporting taurine pathway (efflux) is on the basolateral membranes. In
      addition to usual chloride channel blockers, oxonol was found to be a potent
      blocker of the taurine transport and of the swelling-activated chloride current.
      Using a pharmacological approach, we could not distinguish between a common or
      different pathway for Cl- and taurine.

PMID- 12474080
TI  - Identification of the Ca2+ conductance responsible for K+-induced backward
      swimming in Paramecium caudatum.
AB  - Membrane potential responses of Paramecium caudatum to an application of K+-rich
      solution were examined to understand the mechanisms underlying K+-induced
      backward swimming. A wild-type cell impaled by a microelectrode produced action
      potentials followed by a sustained depolarization in response to an application
      of a K+-rich test solution. After termination of the application, a prolongation
      of the depolarization (depolarizing after-potential) took place. Behavioral
      mutants incapable of exhibiting K+-induced backward swimming did not show
      depolarizing afterpotentials. Upon short application of K+-rich solution, the
      timing and duration of the ciliary reversal of the wild-type cell coincided well
      with the K+-induced depolarization. The duration of the depolarizing
      afterpotential decreased as the duration of the application increased. The
      depolarizing afterpotential recovered slowly after it had been suppressed by a
      preceding application of the K+-rich solution. By injection of an outward current
      into the wild-type cell, the action potentials were evoked normally during the
      period when the K+-induced depolarizing afterpotential was suppressed. We
      concluded that the prolongation of the depolarizing membrane potential response
      following the application of the K+-rich solution represents the Ca2+ conductance
      responsible for the K+-induced backward swimming in P. caudatum and that the
      characteristics of the K+-induced Ca2+ conductance are distinct from those of the
      Ca2+ conductance responsible for the action potentials.

PMID- 12474081
TI  - Laser-based double beam absorption detection for aggregation immunoassays using
      gold nanoparticles.
AB  - A laser-based double beam absorption detection system for aggregation
      immunoassays has been developed. The assay was based on the aggregation of gold
      nanoparticles that are coated with protein antigens in the presence of their
      corresponding antibodies. The aggregation of the gold nanoparticles results in an
      absorption change that is monitored at 635 nm using the double beam spectrometer.
      The noise level of the spectrometer is 1x10(-6)arbitrary units. This corresponds
      to a tenfold improvement in comparison to commercial absorption detectors and is
      comparable with previously reported more complicated laser-based absorption
      spectrometers. The dye Nile-Blue-A was used to test the analytical performance of
      the system. A limit of detection of 3x10(-8 )M Nile-Blue-A was observed. The
      relative standard deviation between consecutive measurements was lower than 1.5%.
      The system is suitable for field applications of aggregation-based immunoassays.

PMID- 12474082
TI  - Application of restricted access material (RAM) with precolumn-switching and
      matrix solid-phase dispersion (MSPD) to the study of the metabolism and
      pharmacokinetics of Verapamil.
AB  - In the pharmaceutical industry, studies of the metabolism and pharmacokinetics of
      drugs are important routine applications which require the analysis of the
      precursor drug and its metabolites in various biological matrices, such as
      plasma, serum, urine, cell culture media and tissue samples. In this study, two
      new and simple methods of sample preparation were optimized and validated: on the
      one hand, a column-switching technique with a restricted access material (RAM)
      was used to analyze biological fluids, and on the other hand, matrix solid-phase
      dispersion (MSPD) was applied to the extraction of analytes from tissue samples.
      Identification of the metabolites was done with a LC-MS system (ion trap in the
      MS(n)mode) coupled both on-line (RAM) and off-line (MSPD). Using the common
      calcium antagonist Verapamil, it is shown that these two methods allow rapid
      identification of phase I and phase II metabolites from biological samples and
      are suitable for pharmacokinetic and pharmacodynamic studies of pharmaceuticals
      in biological matrices.

PMID- 12474083
TI  - Determination of lomefloxacin by terbium sensitized chemiluminescence method.
AB  - A simple, rapid and sensitive chemiluminescence (CL) method was proposed for the
      determination of lomefloxacin (LFX). This method is based on the fact that the
      weak CL from the redox reaction of Ce(4+)-Na(2)SO(3) can be greatly enhanced by
      the complex of Tb(3+)-LFX. The CL intensity is directly proportional to the
      concentration of LFX in the range 2.0x10(-9) to 1.0x10(-5) mol L(-1), and the
      detection limit (S/N=3) is 1.1x10(-9) mol L(-1). This method has been applied to
      the detection of LFX in pharmaceutical preparation, urine and serum samples.
      Recoveries were in the range 95-105%. The CL mechanism of Ce(4+)-Na(2)SO(3)
      Tb(3+)-LFX system was proposed to be an intermolecular energy transfer from
      excited SO(2)(*) to LFX and an intramolecular energy transfer from LFX to Tb(3+).

PMID- 12474084
TI  - Development of a robust technique for sampling volatile metal(loid)s in wetlands.
AB  - The formation of volatile organic and inorganic metals and metalloids in aquatic
      environments is a known, but not very intensively investigated, process. Several
      techniques have been developed over the past 10 years to determine these trace
      components. These techniques are of limited use in wetland environments, where
      samples have to be taken from the soil-water interface, and require an immediate
      sample analysis due to thermodynamic instabilities of the volatile metal(loid)s.
      This paper presents an innovative sampling technique for total concentrations of
      volatile metal(loid)s in wetlands, based on an in situ gas-water separation via a
      porous PTFE membrane and stabilising the volatile metal(loid)s in a liquid
      sorbent (NaOCl solution). Samples may thus be collected even at remote sites,
      where longer storage times have to be accounted for. The sampling system was
      tested by means of a laboratory facility simulating the generation of arsine and
      dimethyl arsine under abiotic conditions as well as under field conditions.
      Results for sampling efficiency, reproducibility, and long-term storage are
      presented. Application of the sampling system in the field is shown.

PMID- 12474085
TI  - Determination of azadirachtin and fatty acid methyl esters of Azadirachta indica
      seeds by HPLC and GLC.
AB  - A simple and economical method has been developed to estimate the azadirachtin
      content and fatty acid composition of neem kernels. Neem kernels are crushed and
      soaked overnight in ethanol. The extract obtained is analysed by HPLC after
      filtering through a 0.22 micro m membrane. The peaks are separated using
      acetonitrile-water (40:60) 1 mL min(-1) as the mobile phase on an RP-18 column
      and monitored at 214 nm. For the determination of fatty acid composition, the
      fatty acids are directly transmethylated in the kernel powder by heating with
      methanol-acetyl chloride-benzene (20:1:4, v/v) for 1 h in a water bath. The fatty
      acid methyl esters (FAMEs) obtained are extracted in hexane and analysed using
      GLC. The separation of the FAMEs is achieved using an RH-Wax column using
      temperature programming, 170-200 degrees C at 2 degrees min(-1). The peaks are
      detected using an FID. Both the methods do not require any clean up or defatting
      of seeds. This results in faster, easier and more economical sample preparation.

PMID- 12474086
TI  - Application of headspace-mass spectrometry for differentiating sources of olive
      oil.
AB  - In the present work we propose the use of headspace-mass spectrometry (HS-MS) for
      the characterisation of monovarietal olive oils, an issue of interest when the
      origin of an oil has to be determined. The HS-MS procedure involves the direct
      introduction of the sample into a vial, headspace generation and automatic
      injection of the volatiles into a mass spectrometer. The results were compared
      with those obtained using more conventional approaches, including
      chromatographic, spectrophotometric and other types of analysis. Linear
      Discriminant Analysis (LDA) was applied to the data obtained with both analytical
      methodologies to achieve the differentiation of the three types of samples. The
      proposed method is faster and cheaper than those usually employed for edible oil
      analysis and no sample preparation is required. Additionally, the measuring
      process is simple and the results obtained from chemometric treatment are 100%
      correct as regards classification and prediction, making it an appropriate method
      for routine control.

PMID- 12474087
TI  - A spot test for aqueous phosphate by color band formation.
AB  - Phosphate is generally analyzed by color intensity of phosphoantimonylmolybdenum
      blue (PAMB): especially by a spot test based on spectrophotometric or visual
      determination. Visual determination is one of the simplest and most inexpensive
      methods; however, it is believed to be of low precision. In this work, we have
      developed an alternative phosphate spot test, where phosphate concentration is
      measured by the color band length of PAMB formed in a detection tube similar to a
      gas detection tube. The color band is formed by the entrapment of the hydrophobic
      ion pair of PAMB and quaternary ammonium ions in the column; we demonstrated that
      this color band length correlates quantitatively with the phosphate
      concentration. In order to optimize the measurement performance, systematic
      investigations have been carried out for various experimental parameters such as
      phosphate concentration, preparation conditions of the column packing material,
      the type of support material (either silica-gel or PVC), the solution feeding
      conditions (filtration or penetration), and volume of the sample solution. The
      effects from some co-existing components were also studied for the measurement of
      real samples. Determination of phosphate concentrations in actual wastewaters was
      successfully carried out by this method, indicating that the quantification range
      achievable was of 3-18 mg PO(4) L(-1) without dilution prior to the analysis. No
      interference was observed from suspended solid (SS) and organic pollutants (COD,
      TOC) during the wastewater analysis. Because of the simplicity and rapid
      processing of the samples (not requiring any special instruments) this newly
      developed method can be applied to the on-site analysis of wastewater.

PMID- 12474088
TI  - A new method for determination of hydroperoxides in cellulose.
AB  - A new chromatographic method for determination of hydroperoxides in cellulose is
      described, whereby the sample is dispersed in phosphate buffer solution (pH 7) of
      FeCl(3), EDTA and the hydroxyl radical scavenger, N,N'-(5-nitro,1,3
      phenylene)bisglutaramide. The reaction time, concentration of reagents and
      chromatographic conditions for subsequent separation and quantification of
      hydroxylated products are optimised. The limit of detection is 0.14 micro mol L(
      1) H(2)O(2) which corresponds to 2.1 micro mol hydroperoxides per kg of cellulose
      (mass of sample: 0.4 g). It was shown that in the concentration range of H(2)O(2)
      up to 15 micro mol L(-1) the method gives linear response and that adsorption of
      reaction products on fibres is negligible. For cellulose samples, this
      corresponds to a linear range of 2.1-225 micro mol of hydroperoxides per kg. Due
      to possible side reactions of hydroxyl radicals in the suspension of analyte, it
      is recommended that the standard addition technique is used. In purified cotton
      cellulose, the steady state concentration of hydroperoxides at room conditions
      was found to be 15.1+/-1.5 micro mol kg(-1).

PMID- 12474089
TI  - Multivariate calibration applied to simultaneous chemiluminescence determination
      of cobalt and chromium.
AB  - The simultaneous determination of chromium and cobalt in water samples has been
      studied. Chemiluminescence registers based on the luminol-hydrogen peroxide
      reaction have obtained by a batch procedure. PLS algorithms have employed to
      model the time-response (formation and destruction of emitter). The influence of
      the presence of two metals and the non-linearity relationship between response
      and concentration have been evaluated in the signal. Different experimental
      designs and the selection of variables have been tested. The calibration set has
      been selected based on two criteria: unicomponent and/or bicomponent standard
      solutions and the slope calculated from linear univariate calibration. The
      response has been modelled providing high percentages of explained variance,
      robust models and low prediction errors. The proposed methodology has been
      validated using test standard solutions and a standard reference material of
      fresh water. Accurate results have proved the advantages of this method for the
      simultaneous determination of chromium and cobalt in water samples.

PMID- 12474090
TI  - Determination of As in environmental solid matrix.
AB  - In line with recent European environmental guidelines on biomasses, one of the
      most important parameters to take into account is the As concentration,
      especially when present in biomasses and complex matrices. The goal of the
      present study is to give information about possible technical-analytical problems
      during the determinations of such elements by means of different instrumental
      spectroscopy techniques, in particular inductively coupled plasma atomic emission
      (ICP-AES) and atomic absorption (AAS), using two different wavelengths, 188.98 nm
      and 193.70 nm. In the Laboratory of Hygiene of National Institute of Health in
      Italy, a specific study has been carried out concerning the determination of As
      contents in environmental solid matrices, using as reference material BCR 141 R,
      represented by a calcareous soil. In particular, whereas recovery tests did not
      show particular drawbacks, difficulties were met in the As detection in reference
      material. Spectral interference was seen during determination by ICP-AES and
      matrix interference during determination by AAS, in particular using ETAAS with
      deuterium background correction and HAAS. Using ETAAS with Zeeman background
      correction at 193.70 nm, the As line did not show particular matrix interference
      during the reading of samples.A ring test involving two more laboratories and
      another certified reference material (IAEA-356 in marine sediment matrix)
      produced important information about problems of under/over estimation of data.
      Two different instrumental techniques, ICP-MS and HAAS, confirmed previous data,
      i.e., overestimation for inductively coupled plasma mass spectrometry and that As
      values achieved by HAAS were of the same order as the references, but affected by
      considerable standard deviation. In the light of this study, data achieved on the
      environmental matrices investigated suggest that the critical step in As
      determination is the instrumental reading, rather than the mineralization
      process. Further, each of the methods proposed, apart from ETAAS with Zeeman
      background correction, presents its own peculiar drawbacks and no particular
      advantage over other techniques.

PMID- 12474091
TI  - Analytical investigation of plasma-treated carbon fibres.
AB  - As-grown and heat-treated vapour grown carbon fibres (VGCF) in the as-prepared
      state, washed in HCl/H(2)O, and treated in O(2) plasma for different periods have
      been investigated by means of XPS and scanning electron microscopy (SEM). The
      surface energy of the carbon fibres before and after plasma treatment was
      determined from the wetting contact angle. Washing introduced hydroxyl, carbonyl
      and carboxyl groups onto the fibre surfaces and oxygen plasma treatment increases
      the total atomic concentration of oxygen up to 17%. This is in good agreement
      with the value of the polar component of the surface energy. Plasma treatment
      also enhanced the fibre surface porosity (by etching).

PMID- 12474092
TI  - Comparison of spark OES methods for analysis of inclusions in iron base matters.
AB  - A statistical model for the evaluation of the emission intensities of single
      spark discharge spectra on three different spark OES instruments (ARL 4460, OBLF
      QSN 750, SpectroLab) was developed for the analysis of non-metallic inclusions in
      steel. In total, the raw measurement data consists of several thousand data
      points (intensities), about 2000 per element channel. A histogram (frequency
      distribution of pulse height intensities) of inclusion-forming elements like Al,
      Ti and Mn performed in intensity classes and the related frequencies contain the
      information of the measurement. Measurement of a pure iron sample with slag
      powder rubbed into the surface by single spark emission spectrometry changes the
      originally (nearly) symmetrical histogram for inclusion related element signals
      to higher intensities. Thus, the known asymmetry of the histograms for steel
      samples is explained by the presence of inclusions.A sum of Gaussian fits
      representing the histogram was expected to express the different elemental
      species and inclusion sizes by using the variables mean, standard deviation and
      area of the peak containing the information of the measurement. Even a less
      complex approximation using a sum of two Gaussian fits is not practicable for the
      Al, Ti and Mn channel and the three spectrometers due to too many variables in
      the fitting function resulting in a large scattering. Coincidences of high
      signals in different element channels could be seen only in terms of MnS.A
      further attempt was to form the second differential of the logarithmic normal
      distribution and to compare the resulting partial areas below the functional
      graph to get information about the asymmetry of the fitting function of the
      original histogram. Two different procedures to evaluate the effect of the
      inclusion concentration on the size of the partial areas were applied to
      measurements on a set of synthetic samples with different concentrations of
      aluminium oxide in micro alloy steel. The results of both evaluation procedures
      correlate significantly with the inclusion concentrations. Electronic
      Supplementary Material is available if you access this article at
      http://dx.doi.org/10.1007/s00216-002-1595-1. On that page (frame on the left
      side), a link takes you directly to the supplementary material.

PMID- 12474093
TI  - Polarographic study on poly alpha-L-glutamic acid-Cd2+,Co2+ complexes in the
      helix-coil pH region.
AB  - Interactions between poly alpha- L-glutamic acid (PGA) and metal ions Cd(2+),
      Co(2+) were studied by direct current polarography. The diffusion currents of
      these ions decreased sharply in the presence of PGA in the pH region from 5.0
      through neutral. A corresponding increase in the helix content of the PGA-metal
      ion complex was revealed by CD measurements on the same solutions. Helix contents
      determined by polarography were in good agreement with those by CD in the neutral
      pH region. On the contrary, the decrease of current in lower acidic pH regions
      was independent of helix formation and suggested that metal ions coordinate to
      sporadically-dissociated carboxylate groups to cause aggregation of the intra
      and/or inter polymer chains. The diffusion current of the ions, therefore, is a
      parameter sensitive to the conformational changes of PGA from acidic through
      neutral pH region.

PMID- 12474094
TI  - The online removal of dissolved oxygen from aqueous solutions used in
      voltammetric techniques by the chromatomembrane method.
AB  - The applicability of the chromatomembrane method for the removal of dissolved
      oxygen from solvents used in voltammetric measurements was investigated. The
      chromatomembrane cell combined with a flow-through system allows an online
      deaeration of solutions. These experiments employed a mercury film electrode as
      working electrode and differential pulse anodic stripping voltammetry as the
      measuring method. Different eluents with adequate supporting electrolyte (without
      analyte) were measured to determine the background current, whether any
      contribution of oxygen is detectable. Voltammograms of eluents deaerated with the
      chromatomembrane method are compared to those of eluents purged with nitrogen for
      several minutes immediately before the measurement. No differences in the
      background currents can be observed when defined flow rates of eluent and
      nitrogen are maintained. Determinations of cadmium and lead even indicate the
      high efficiency of this method.

PMID- 12474095
TI  - TiO2 sol-gel derived amperometric biosensor for H2O2 on the electropolymerized
      phenazine methosulfate modified electrode.
AB  - A novel hydrogen peroxide biosensor was developed based on the immobilization of
      horseradish peroxidase (HRP) in a TiO(2) sol-gel matrix on an electropolymerized
      phenazine methosulfate (PMS) modified electrode surface. Such membranes are of
      interest due to their high surface area, biological compatibility, and ease of
      fabrication. HRP entrapped in the TiO(2) matix was stable and retained its
      activity to a large extent. Cyclic voltammetry and amperometric measurements were
      employed to demonstrate the feasibility of electron transfer between immobilized
      HRP and the glassy carbon electrode via electropolymerized PMS. The influence of
      various experimental parameters such as operating potential, pH, temperature, and
      stability was investigated for optimum analytical performance. The biosensor
      provided a wide linear calibration range from 4.0x10(-6) M to 1.0x10(-3) M, with
      a detection limit of 8.0x10(-7) M at a signal-to-noise ratio of 3. The sensor
      retained 80% of its original activity after two months of operation.

PMID- 12474096
TI  - Ruthenium/rhodium modified gold electrodes for the amperometric detection of
      hydrogen peroxide at low potentials.
AB  - Electrodes of ruthenium/rhodium deposited as thin layers on gold foils were
      investigated. Ruthenium layers were radio frequency (r.f.) magnetron sputtered
      and the rhodium layers were made by vacuum evaporation. Hydrogen peroxide could
      be detected using the cathodic reduction at potentials lower than +170 mV or the
      anodic oxidation at higher potentials. Under flow injection conditions, H(2)O(2)
      was detected between 1 and 1000 micro M at a potential of -100 mV and between 2
      and 500 micro M at a potential of +250 mV vs. Ag/AgCl/0.4 M KCl. The electrodes
      also showed high operational stability and selectivity against many electroactive
      substances. The selectivity against dissolved oxygen was investigated.

PMID- 12474097
TI  - A coulometric method for determining substances that interfere with the
      measurement of water in oils and other chemicals by the Karl Fischer method.
AB  - In order to fulfill a need to measure water in crude oils containing materials
      that interfere with the measurement of water by the Karl Fischer method, by
      reacting with iodine or iodide, a coulometric method has been developed and
      validated using 0.1 mol L(-1) Sodium thiosulfate as a calibrant. These
      interfering substances were measured in water-mass-equivalents, which were
      expressed as the mass of water that reacts with an equal mass of iodine in the
      Karl Fischer method. The SO(2)-free reagent that has been modified reacts
      quantitatively with sodium thiosulfate, cysteine and ascorbic acid but does not
      react with vinyl acetate. The level of interfering substances was measured in
      five transformer oils (including Reference Materials RM 8506 and RM 8507), a high
      and a low sulfur crude oil (Standard Reference Materials SRM 2721 and SRM 2722
      respectively), a white oil, a high-vacuum oil and a high-viscosity base-stock
      oil. One oil contained less than 10 mg kg(-1) (water-mass-equivalents of
      interfering substances in oil) and two oils (RM 8507 and Drakeol 35) contained no
      measurable amount of interfering material (<0.2 mg kg(-1)). SRM 2271, a sour
      crude oil contained 834 mg kg(-1) (standard deviation (SD)=25 mg kg(-1)) (water
      mass-equivalents of interfering substances in oil). Approximately 20% of this
      material was volatile and an additional 20% appeared to undergo some degradation
      (possibly oxidation) once the oil was exposed to air. These results indicate that
      this is a general method for measuring substances in oils that react with iodine
      and that it is capable of measuring in a variety of oils, using commercial
      instrumentation, interfering substances that inflate water measurements.

PMID- 12474098
TI  - Influence of experimental parameters on the determination of antimony in seawater
      by atomic absorption spectrometry using a transversely heated graphite furnace
      with Zeeman-effect background correction.
AB  - Spectroscopic and electrothermal conditions for the determination of antimony in
      seawater using a transversely heated graphite furnace with Zeeman-effect
      background correction have been optimized with the use of an a priori calculation
      of the detection limit. The lowest limit of detection was obtained with a 2 nm
      spectral curvatures bandwidth and the use of an electrodeless discharge lamp;
      however, these experimental conditions resulted in strong premature curvature of
      calibration curves. Pd(NO(3))(2) can be recommended as a chemical modifier
      because seawater interference effects are minimized and pretreatment curves up to
      1500 degrees C can be used permitting the removal of the major part of the saline
      matrix before atomization. Under optimized spectroscopic and electrothermal
      conditions the obtained limit of detection of Sb in seawater was about 0.4 microg
      L(-1).

PMID- 12474099
TI  - Silicon determination in milk by electrothermal atomic absorption spectrometry
      using palladium as chemical modifier.
AB  - A direct method for silicon determination in milk samples by Electrothermal
      Atomic Absorption Spectrometry was developed. Palladium was used as chemical
      modifier at a concentration of 610 mg L(-1); with this modifier, silicon was
      stable up to 1800 degrees C. The precision and accuracy of the method were
      investigated. The detection limit was 16.2, 2.7 and 7.2 micro g L(-1) for cows'
      milk, human milk and infant formula, respectively. The method was applied to
      silicon determination in 17 infant formula samples, 13 human milk samples and 12
      cows' milk samples.

PMID- 12474100
TI  - Slurry sampling for the determination of thallium in soils and sediments by
      graphite furnace atomic absorption spectrometry.
AB  - The analytical conditions for thallium determination in soils and sediments by
      slurry sampling graphite furnace atomic absorption spectrometry were studied and
      optimized. Elimination of a strong background for soils rich in organic materials
      by application of tungsten carbides coated graphite tubes/platforms was studied
      in detail. Tungsten carbides increased the maximum permissible pyrolysis
      temperature from 300 to 900 degrees C. The mechanism of tungsten carbide
      formation on different graphite surfaces was proposed. Application of a strong
      basic anion-exchange resin for interference elimination in thallium determination
      in marine sediments was described. Calibration was performed directly using
      aqueous standards both for soil and sediment analysis. Analysis of CRM confirmed
      the reliability of the approach. The precision and accuracy of thallium
      determination by the described method for soils and sediments was acceptable. A
      characteristic mass of 13.8 pg was obtained and the limit of detection for the
      proposed method was around 0.06 microg g(-1) Tl.

PMID- 12474101
TI  - Direct determination of Cr and Cu in urine samples by electrothermal atomic
      absorption spectrometry using ruthenium as permanent modifier (R1).
AB  - In this study Ru, deposited thermally on an integrated platform pyrolytic
      graphite tube, is proposed as a permanent modifier for the determination of Cu
      and Cr in urine samples by electrothermal atomic absorption spectrometry. The
      samples were diluted 1:1 with nitric acid (1% v/v). Pyrolysis and atomization
      temperatures for spiked urine samples were 1,100 degrees C and 1,900 degrees C
      respectively for Cu, and 1,400 degrees C and 2,500 degrees C respectively for Cr.
      For comparison purposes, the conventional modification with Pd+Mg was also
      studied. The sensitivity for Ru as permanent modifier was higher for the two
      analytes. The characteristic masses were 7.3 and 17.7 for Cr and Cu. The
      detection limits (3sigma) were 0.22 and 0.32 microg/L, for Cr and Cu,
      respectively. Good agreement was obtained with certified urine samples for the
      two elements.

PMID- 12474102
TI  - Column preconcentration and FAAS determination of copper, iron, nickel and zinc
      using 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol-tetraphenylborate-naphthalene
      adsorbent.
AB  - A solid co-precipitated material obtained from an ion-pair of 2-(5-bromo-2
      pyridylazo)-5-diethylaminophenol (5-Br-PADAP) and tetraphenylborate (TPB), and
      microcrystals of naphthalene has been tried as an adsorbent for the column
      preconcentration of copper(I), iron(II), nickel(II) and Zn(II). The retention of
      the metal ions was found to be maximum and constant in the pH range 3.0-8.0 for
      Cu, 3.8-7.5 for Fe, 4.5-7.5 for Ni and 8.5-11.0 for Zn. The elements were
      determined by FAAS after dissolving the metal along with the adsorbent in an
      organic solvent (10 mL of DMF). The characteristic concentration for 1%
      absorption was found to be 0.0332, 0.0536, 0.0537 and 0.0142 (aqueous medium
      0.0512, 0.0638, 0.1294 and 0.0216) microg mL(-1) for Cu, Fe, Ni and Zn,
      respectively. The calibration plot was linear in the range 1.5-20.0, 2.0-38.0,
      2.5-25.0 and 0.5-15.0 micro g in the final 10 mL of DMF solution for Cu, Fe, Ni
      and Zn, respectively. Various parameters such as pH, volume of buffer, amount of
      adsorbent, flow rate, preconcentration factor and effect of diverse salts and
      cations were studied. The optimised conditions were utilized for the
      determination of Cu, Fe, Ni and Zn in various water, beverage and human hair
      samples.

PMID- 12474103
TI  - Quantitative analysis of undefined mixtures - "fishing net" algorithm.
AB  - An approach for quantitative analysis of mixtures with unknown individual
      responses of the components is discussed. Although it is based on a resolution of
      overlapping bands technique, the main emphasis is not given to the computational
      facets of curve fitting. A logical procedure is described, allowing estimation of
      the unknown concentrations in the mixture, and both the number of overlapping
      bands and their assignment to the components in the solution to be determined
      automatically. A general conclusion about the precision of the method cannot be
      defined, because it depends on the extent of overlapping of the individual
      spectra of the components and their complexity. Using this procedure a
      complicated three-component acid-base equilibrium of a halochromic dye in
      solution is studied.

PMID- 12474105
TI  - Spectrophotometric determination of silver with 2-(2-quinolylazo)-5
      diethylaminophenol as chromogenic reagent.
AB  - A new chromogenic reagent, 2-(2-quinolylazo)-5-diethylaminophenol (QADEAP) was
      synthesized. A highly sensitive, selective and rapid method for the determination
      of silver based on the rapid reaction of silver(I) with QADEAP has been
      developed. In the presence of citric acid-sodium hydroxide buffer solution
      (pH=5.0) and sodium dodecyl sulfonate (SDS) medium, QADEAP reacts with silver to
      form a violet complex of a molar ratio 1:2 (silver to QADEAP). The molar
      absorptivity of the complex is 1.33x10(5) L mol(-1) cm(-1)at 590 nm. Beer' s law
      is obeyed in the range of 0.01-0.6 micro g mL(-1). The relative standard
      deviations for eleven replicate samples of 0.2 microg mL(-1) is 1.38%. This
      method was applied to the determination of silver in water with satisfactory
      results.

PMID- 12474104
TI  - Study of 2-(2-quinolinylazo)-5-dimethylaminobenzoic acid as a new chromogenic
      reagent for the spectrophotometric determination of cobalt.
AB  - 2-(2-Quinolinylazo)-5-dimethylaminobenzoic acid (QADMAB) is proposed as a new
      sensitive and selective chromogenic reagent for spectrophotometric determination
      of cobalt. The QADMAB reacts with cobalt in the presence of cetyl
      trimethylammonium bromide (CTMAB) medium to form a violet complex of molar ratio
      1:2 (cobalt to QADMAB) in the pH range 3.2-5.2. The molar absorptivity of the
      complex is 1.28x10(5) L mol(-1) cm(-1) at 625 nm. Beer's law is obeyed in range
      0.01-0.32 micro g mL(-1). The relative standard deviation for eleven replicate
      samples of 0.2 micro g mL(-1) is 0.76%. This method was applied to the
      determination of cobalt in biological samples, Vitamin B(12), alloys and water
      with good results.

PMID- 12474106
TI  - Detection of zirconium in organic and aqueous phases using an inductively coupled
      plasma-mass spectrometer and the same aqueous standards.
AB  - Solvent extraction requires measurement of both aqueous and organic phases, and
      common techniques of such measurements are tedious and time consuming. This paper
      outlines an inductively coupled plasma-mass spectrometric technique in which both
      aqueous and organic phases (both contained in a carrier phase, ethanol) can be
      measured using the same calibration curve. The method has proved to be successful
      as long as the organic and aqueous content in the carrier phase is kept below
      10%. The developed technique is a more convenient tool for solvent extraction
      chemists who have often used radioactive tracers within their experimental
      techniques. In addition, this technique may be used in environmental studies
      involving the analysis of organic fractions, such as metal fingerprinting of
      petroleum fluids. In such analyses, the ability to use more available and
      traceable aqueous standards will lead to significantly improved confidence in the
      analytical results.

PMID- 12474107
TI  - Modification of diamond single crystals by chromium ion implantation with
      sacrificial layers.
AB  - Single-crystal diamond surfaces were implanted with chromium ions. Ion energies
      chosen were 120 and 180 keV. Ion doses of 1x10(17) cm(-2) were applied at a
      substrate temperature of 750 degrees C. Reduced lattice damage could be obtained
      by deposition of a titanium sacrificial layer with a thickness of 10 and 50 nm
      before implantation. Depth profiles of the elemental binding states were taken by
      photoelectron spectroscopy. The effect of the sacrificial layer thickness on
      diamond lattice damage was investigated by infrared spectroscopy.

PMID- 12474108
TI  - Simultaneous determination of major, minor and trace elements in biocarbonates by
      inductively coupled plasma mass spectrometry.
AB  - A method was developed for simultaneous determination of major (Ca), minor (Mg
      and Sr) and trace (Ba and U) elements in biocarbonates by inductively coupled
      plasma mass spectrometry (ICP-MS). The method precision (RSD%) is 0.73% for Ca,
      0.77% for Mg, 0.59% for Sr, 2.02% for Ba, 1.13% for U, 0.67% for Mg/Ca, 0.27% for
      Sr/Ca, 2.06% for Ba/Ca and 1.23% for U/Ca. The ratio precision suggests that ICP
      MS is satisfactory for obtaining multi-ratio data from biocarbonates. This
      technique was applied to 67 continuous coral samples.

PMID- 12474109
TI  - Separation and preconcentration of Se(IV)/Se(VI) species by selective adsorption
      onto nanometer-sized titanium dioxide and determination by graphite furnace
      atomic absorption spectrometry.
AB  - A simple and sensitive method for the selective determination of Se(IV) and
      Se(VI) in natural water and sludge samples through an adsorptive process on a
      nanometer-sized TiO(2) (anatase) was developed. The conditions for quantitative
      and reproducible preconcentration, elution, and subsequent GFAAS determination
      were established. The proposed method gave a concentration factor of 50 for a 100
      mL sample volume, characterized by high precision, high reproducibility, and
      direct determination of Se(IV)/Se(VI). The detection limits (3 sigma, n=11) were
      4.7ng L(-1) for Se(IV) and 6.3ng L(-1) for Se(VI); the precision (relative
      standard deviation) was 0.7% for Se(IV) and 0.9% for Se(VI) at the 0.5microg L(
      1) level.

PMID- 12474110
TI  - Discriminative stimulus properties of 1-(2,5-dimethoxy-4-iodophenyl)-2
      aminopropane [(+/-)DOI] in C57BL/6J mice.
AB  - RATIONALE: The drug discrimination procedure has proven to be a valuable tool for
      studying the mechanism of action of psychoactive drugs. Recently, mice with
      targeted gene mutations have been developed that may also prove useful in
      evaluating the role of specific receptors in mediating the actions of drugs. We
      were interested in studying the effects of hallucinogens in genetically modified
      mice using the drug discrimination procedure. OBJECTIVE: To establish the
      training procedures and characterize the stimulus properties of 1-(2,5-dimethoxy
      4-iodophenyl)-2-aminopropane [(+/-)DOI] versus saline in wild-type mice. METHODS:
      Using a two-lever drug discrimination procedure, C57BL/6J mice were trained to
      discriminate (+/-)DOI (2.5 mg/kg) from saline on a VI 30-s schedule of
      reinforcement. RESULTS: The acquisition function was orderly and similar to that
      found previously with rats, although the training dose required for the mice was
      four times higher (2.5 versus 0.75 mg/kg). The dose-response relationship
      indicated that percent drug lever responding was dose-dependent. Two other
      hallucinogens, LSD and (-)DOB, substituted fully for (+/-)DOI. Mice were tested
      for their ability to discriminate (+/-)DOI following pretreatment with the 5
      HT(2A) receptor antagonist MDL 100,907, or with 5-HT(2C) selective antagonists,
      SB 206,553 or SB 242,084. A dose of 0.25 mg/kg MDL 100,907 essentially completely
      blocked the discriminative stimulus effects of 2.5 mg/kg (+/-)DOI. Surprisingly,
      both SB 206,553 and SB 242,084 also attenuated the effect of 2.5 mg/kg (+/-)DOI.
      The effect of SB 206,553 was surmountable at 5.0 mg/kg (+/-)DOI. CONCLUSIONS:
      These data agree with the results from studies with rats indicating a prominent
      role for the 5-HT(2A) receptors in mediating the discriminative stimulus effects
      of (+/-)DOI but in addition, suggest a small but significant role for the 5
      HT(2C) receptor in mice.

PMID- 12474111
TI  - The consequences of beer consumption in rats: acute anxiolytic and ataxic effects
      and withdrawal-induced anxiety.
AB  - RATIONALE: Rats avidly consume standard off-the-shelf beer; however, the
      behavioural consequences of beer consumption in rodents have hardly been studied.
      OBJECTIVES: The present study examined the acute anxiolytic and ataxic effects of
      beer consumption in rats and the anxiogenic effects of withdrawal from free
      access to beer. METHOD: In experiment 1, male Wistar rats received 30 min access
      to "near-beer" each day (a malt beverage that looks and tastes like beer but
      which contains <0.5% ethanol). On the test day, for some rats, ethanol (either 2%
      or 4% v/v) was added to the near-beer to make it resemble standard (ethanol
      containing) beer of "light" (2.5% beer) or full strength (4.5% beer). Immediately
      after this, rats were tested on their response to a predatory cue (a fabric
      collar that had been worn by a cat) and on an accelerating rotarod. In experiment
      2, rats were trained in the same drinking paradigm as above and then tested on a
      further battery of anxiety tests. In experiment 3, rats were given continuous
      home cage access to either 4.5% beer or near-beer for 35 days. Half of the rats
      were then denied access to beer or near-beer for 24 h and then tested on the same
      anxiety test battery as in experiment 2. RESULTS: Rats drinking 4.5% beer
      approached a predatory cue significantly more than those given near-beer,
      indicating an anxiolytic effect. In experiment 2, rats drinking 4.5% beer
      displayed less anxiety-like behaviour in the elevated plus maze and emergence
      tests but not in the social interaction test. Rats given 4.5% beer fell off the
      rotarod significantly faster than rats given near-beer, indicating an ataxic
      effect. Rats previously given 4.5% beer drank significantly less near-beer the
      following day, suggesting a moderate aversion the day after beer consumption. In
      experiment 3, rats denied access to 4.5% beer showed significantly less social
      interaction and took longer to emerge into an open field than controls.
      CONCLUSION: These results are the first to our knowledge to show that rats will
      consume beer at levels that produce clear effects on anxiety and on motor co
      ordination, and that will eventually produce behavioural signs of withdrawal.

PMID- 12474112
TI  - Effects of long-term moderate alcohol consumption on agonistic and affiliative
      behavior of socially housed female cynomolgus monkeys (Macaca fascicularis).
AB  - RATIONALE: The most widely used drug in the US is alcohol. Most people who use
      alcohol are light-to-moderate drinkers. One or two drinks/day is thought to be
      not only safe but potentially health-promoting. However, little is known about
      the chronic effects of moderate alcohol consumption. Alcohol, even in moderate
      doses, has immediate and robust effects on behavior. OBJECTIVE: To determine the
      effects of long-term moderate alcohol consumption on the social interactions of
      adult monkeys. METHODS: Forty-nine adult, ovariectomized monkeys lived in small,
      stable social groups for 31 months and voluntarily consumed a 2-drink/day
      equivalent (0.5 g/kg ethanol), 5 days/week for 24 months. Alcohol was presented
      in a sweet tasting non-nutritive vehicle to half the monkeys, while the other
      half received vehicle plus maltose-dextrin isocalorically substituted for
      alcohol. Social behavior was recorded 1 h before, 1 h after, and 5 h after
      alcohol. RESULTS: Alcohol caused chronic changes in aggressive and affiliative
      behavior that were not dependent upon the presence of circulating alcohol.
      Alcohol increased physical aggression. A subset of the animals was at higher risk
      for alcohol-induced physical aggression. Alcohol decreased positive affiliative
      behaviors, increased time spent alone, and increased the frequency of extragroup
      vigilance. Acutely, alcohol increased the rate of behavioral pathology, i.e.
      stereotypic behaviors, such as hair plucking, which are normally observed only
      under adverse environmental conditions. CONCLUSIONS: Long-term moderate alcohol
      consumption caused chronic deleterious changes in the social interactions of
      primates in small, stable social groups. These data suggest that chronic moderate
      alcohol consumption can compromise optimal social interactions in primate
      species, including human beings.

PMID- 12474113
TI  - Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on
      inter-temporal choice: a quantitative analysis.
AB  - RATIONALE: Lesions of the orbital prefrontal cortex (OPFC) can cause
      pathologically impulsive behaviour in humans. Inter-temporal choice behaviour
      (choice between reinforcers differing in size and delay) has been proposed as a
      model of "impulsive choice" in animals. OBJECTIVE: A quantitative method was used
      to analyse inter-temporal choice in rats with lesions of the OPFC and sham
      lesioned control rats. METHODS: Under halothane anaesthesia, rats received
      injections of the excitotoxin quinolinate into the OPFC (0.1 M, 0.5 micro l; two
      injections in each hemisphere), or sham lesions (injections of the vehicle). They
      were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in
      discrete-trials schedules. In free-choice trials, a press on A resulted in
      delivery of 50 micro l of the sucrose solution after a delay d (A); a press on B
      resulted in delivery of 100 micro l of the same solution after a delay d (B). d
      (B) was increased progressively across successive blocks of six trials in each
      session, while d (A) was manipulated systematically across phases of the
      experiment. The indifference delay, d (B(50)) (value of d (B) corresponding to
      50% choice of B) was estimated for each rat in each phase. Linear functions of d
      (B(50)) versus d (A) were derived, and the parameters of the function compared
      between the groups. The locations of the lesions were verified histologically at
      the end of the experiment. RESULTS: In both groups, d (B(50)) increased linearly
      with d (A) ( r(2)>0.98 in each case). The slope of the function was significantly
      steeper in the lesioned group than the sham-lesioned group, whereas the intercept
      did not differ significantly between the groups. The brains of the lesioned rats
      showed extensive atrophy/gliosis of the OPFC, with sparing of the dorsolateral
      prefrontal cortex. CONCLUSIONS: The results indicate that lesions of the OPFC can
      alter inter-temporal choice, either promoting or suppressing "impulsive choice",
      depending upon the relative sizes and delays of the two choice alternatives.
      Theoretical analysis based on a quantitative model of inter-temporal choice
      indicates that the pattern of effect of the OPFC lesion is likely to reflect two
      actions: (i) an increase in the rate of time discounting; (ii) an increase in
      sensitivity to the ratio of the sizes of two reinforcers.

PMID- 12474114
TI  - Effects of ayahuasca on sensory and sensorimotor gating in humans as measured by
      P50 suppression and prepulse inhibition of the startle reflex, respectively.
AB  - RATIONALE: Ayahuasca, a South American psychotropic plant tea, combines the
      psychedelic agent and 5-HT(2A/2C) agonist N, N-dimethyltryptamine (DMT) with beta
      carboline alkaloids showing monoamine oxidase-inhibiting properties. Current
      human research with psychedelics and entactogens has explored the possibility
      that drugs displaying agonist activity at the 5-HT(2A/2C) sites temporally
      disrupt inhibitory neural mechanisms thought to intervene in the normal filtering
      of information. Suppression of the P50 auditory evoked potential (AEP) and
      prepulse inhibition of startle (PPI) are considered operational measures of
      sensory (P50 suppression) and sensorimotor (PPI) gating. Contrary to findings in
      lower animals, unexpected increases in sensorimotor gating have been found in
      humans following the administration of the serotonergic psychedelic psilocybin
      and the serotonin releaser 3,4-methylenedioxymethamphetamine (MDMA). In addition,
      to our knowledge P50 suppression has not been assessed previously in humans
      following the administration of a 5-HT(2A/2C) agonist. OBJECTIVES: To assess the
      effects of the acute administration of ayahuasca on P50 suppression and PPI in
      humans, in order to evaluate the drug's modulatory actions on these measures of
      sensory and sensorimotor gating. METHODS: Eighteen healthy volunteers with prior
      experience of psychedelic drug use participated in a clinical trial in which
      placebo or ayahuasca doses (0.6 mg and 0.85 mg DMT/kg body weight) were
      administered according to a double-blind, cross-over balanced design. P50 and
      startle reflex (pulse-alone and 60 ms, 120 ms, 240 ms and 2000 ms prepulse-to
      pulse intervals) recordings were undertaken at 1.5 h and 2 h after drug intake,
      respectively. RESULTS: Ayahuasca produced diverging effects on each of the two
      gating measures evaluated. Whereas significant dose-dependent reductions of P50
      suppression were observed after ayahuasca, no significant effects were found on
      the startle response, its habituation rate, or on PPI at any of the prepulse-to
      pulse intervals studied. CONCLUSION: The present findings indicate, at the doses
      tested, a decremental effect of ayahuasca on sensory gating, as measured by P50
      suppression, and no distinct effects on sensorimotor gating, as measured by PPI.

PMID- 12474115
TI  - Effect of bupropion-SR on REM sleep: relationship to antidepressant response.
AB  - RATIONALE: The effects of antidepressant (AD) drugs on sleep in depressed
      patients and their relationship to AD response have been investigated previously.
      However, newer AD agents, which appear to have different effects on sleep, have
      not been evaluated systematically for their usefulness in predicting treatment
      response. OBJECTIVES: To examine the effect of bupropion sustained release (SR)
      (Wellbutrin SR) on sleep macroarchitecture, and to assess whether the observed
      electroencephalographic (EEG) sleep changes in response to a single dose of
      bupropion are associated with treatment response to the AD. METHODS: Twenty
      patients with unipolar major depressive disorder received EEG sleep assessments
      prior to treatment. Subjects were studied twice for 2 consecutive nights, with
      each 2-night session approximately 1 week apart. Baseline EEG sleep and the EEG
      sleep responses to placebo (baseline sleep) and a single dose of bupropion SR
      (150 mg, PO) were measured using a randomized, double-blind, crossover design.
      The participants then received open-label treatment with bupropion SR for about 8
      weeks. RESULTS: No relationship was observed between baseline EEG sleep measures
      and response to treatment with bupropion. However, a statistically significant
      relationship was found between latency to the onset of rapid eye movement (REM)
      sleep following a single dose of bupropion and clinical response to treatment
      with bupropion. Responders showed an increase in REM latency following bupropion
      challenge, whereas non-responders showed a decrease. Moreover, the REM latency
      change in response to bupropion challenge correlated with change in depression
      ratings as a result of treatment. CONCLUSIONS: These findings suggest that
      bupropion's effect on REM latency and its AD action might be linked, possibly via
      dopamine (D(2)) receptor-mediated effects, or by noradrenergic mechanism(s).

PMID- 12474117
TI  - Effect of benzodiazepines on structural and conceptual/lexical priming.
AB  - RATIONALE: Impaired perceptual priming, as assessed by naming reaction times and
      accuracy, for briefly presented contour-deleted pictures under lorazepam has been
      documented in several studies but whether the nature of this impairment is visual
      versus conceptual/lexical is not clear. We used a previously developed paradigm
      to examine whether lorazepam affects visual processes involved in the coding of
      contour information or conceptual/lexical representations. METHOD: Three groups
      were tested (lorazepam, diazepam and placebo). In the study phase, participants
      named line drawings, presented for 500 ms, in which 50% of the contour was
      deleted by removing every other line and vertex from each part. In the test
      phase, participants saw the identical picture, its complement (the other 50% of
      the contour), or a samename/different-shape picture, each presented for 200 ms.
      RESULTS: For all three groups, the magnitude of priming, as assessed by naming
      RTs and error rates, was equivalent in the identical and in the complementary
      conditions and the amount of facilitation was reduced in the same-name condition.
      Perceptual priming occurred both in the lorazepam and in the diazepam groups,
      though reduced, compared to placebo, for RTs. No conceptual priming (i.e.
      facilitated performance in the same-name condition) was observed in the
      benzodiazepine groups. CONCLUSION: Equivalent priming for identical and
      complementary pictures in the three groups suggests that benzodiazepines do not
      affect the activation of the geon structural description. The lack of priming for
      same-name pictures suggests that benzodiazepines affect access, retrieval or
      selection of conceptual/lexical information.

PMID- 12474116
TI  - In vivo drug action of tandospirone at 5-HT1A receptor examined using positron
      emission tomography and neuroendocrine response.
AB  - RATIONALE: Tandospirone is a selective 5-hydroxytryptamine (HT)(1A) receptor
      agonist and is clinically used as an anxiolytic in Japan. However, there are no
      data concerning the occupancy of these receptors by tandospirone in the living
      human brain. OBJECTIVES: The aim of this study was to assess the effect of
      tandospirone on in vivo 5-HT(1A) receptor binding of [(11)C]WAY 100635 using
      positron emission tomography (PET) and the neuroendocrine effect. METHODS: In the
      PET study, seven healthy volunteers were scanned three times following an oral
      dose of placebo or tandospirone (30 mg or 60 mg). The binding potential of
      [(11)C]WAY 100635 was estimated for six regions: prefrontal cortex, temporal
      cortex, anterior cingulate cortex, parietal cortex, hippocampus and dorsal raphe
      nucleus. In the neuroendocrine study, six volunteers received a single oral dose
      of tandospirone (60 mg) or placebo in a randomized double-blind, cross-over
      design, and then the plasma levels of growth hormone and cortisol and the body
      temperature were measured. RESULTS: Tandospirone (60 mg) induced a significant
      decrease in body temperature and an increase in the plasma concentration of
      growth hormone. However, there was no significant reduction of [(11)C]WAY 100635
      binding following the administration of 30 mg or 60 mg tandospirone. CONCLUSION:
      Despite the significant effect on growth hormone and body temperature, a clinical
      dose of tandospirone had a negligible effect on [(11)C]WAY 100635 binding. This
      indicates that the agonist produces a pharmacological effect without measurable
      occupancy, and a new index other than occupancy will be required for the in vivo
      evaluation of agonists.

PMID- 12474118
TI  - Ethanol-stimulated behaviour in mice is modulated by brain catalase activity and
      H2O2 rate of production.
AB  - RATIONALE: Over the last few years, a role for the brain catalase-H(2)O(2)
      enzymatic system has been suggested in the behavioural effects observed in
      rodents after ethanol administration. This role seems to be related to the
      ability of cerebral catalase to metabolise ethanol to acetaldehyde using
      H(2)O(2)as a co-substrate. On the other hand, it has been shown that normobaric
      hyperoxia increases the rate of cerebral H(2)O(2) production in rodents in vivo.
      Thus, substrate-level changes could regulate brain catalase activity, thereby
      modulating the behavioural effects of ethanol. OBJECTIVES: The aim of the present
      study was to assess if the enhancement of cerebral H(2)O(2) production after
      hyperoxia exposure results in a boost of ethanol-induced locomotion in mice.
      METHODS: CD-1 mice were exposed to air or 99.5% O(2) inhalation (for 15, 30, or
      45 min) and 0, 30, 60 or 120 min after this treatment, ethanol-induced locomotion
      was measured. The H(2)O(2)-mediated inactivation of endogenous brain catalase
      activity following an injection of 3-amino-1,2,4-triazole was used as a measure
      of the rate of cerebral H(2)O(2) production. RESULTS: Hyperoxia exposure (30 or
      45 min) potentiated the locomotor-stimulating effects of ethanol (2.5 or 3.0
      g/kg), whereas cocaine (4 mg/kg) or caffeine (15 mg/kg)-induced locomotion and
      blood ethanol levels were unaffected. Moreover, the results also confirmed brain
      H(2)O(2) overproduction in mice. CONCLUSIONS: The present results suggest that an
      increase in brain H(2)O(2) production potentiates ethanol-induced locomotion.
      Therefore, this study provides further support for the notion that the brain
      catalase-H(2)O(2) system, and by implication centrally formed acetaldehyde, plays
      a key role in the mediation of ethanol's psychopharmacological effects.

PMID- 12474119
TI  - Indorenate produces antidepressant-like actions in the rat forced swimming test
      via 5-HT1A receptors.
AB  - RATIONALE: Indorenate has been proposed to possess antihypertensive, anorectic,
      stimulus control and anxiolytic-like actions. This compound has affinity mainly
      for the serotonergic(1A/1B) receptors, hence it could possess antidepressant-like
      activity. OBJECTIVES: The general purpose of this study was to explore the
      possible antidepressant-like effects of the serotonergic compound indorenate in
      the forced swimming test (FST). METHODS: In a first approach, a comparison of the
      actions of several doses of indorenate (2.5, 5.0, 10 mg/kg) with those of other 5
      HT(1A) agonists, buspirone (5.0, 10.0 mg/kg) and 8-OH-DPAT (0.25, 0.50, 1.0
      mg/kg), was performed in the FST. Secondly, in order to determine the
      serotonergic receptors that are participating in indorenate's action, different
      doses of serotonergic antagonists were administered. The compounds used were the
      5-HT(1A/1B) and beta-adrenergic antagonist pindolol (2.5, 5.0 mg/kg), the 5
      HT(1B)receptor antagonist GR 55562 (0.75, 1.5, 3.0 mg/kg), the 5-HT(1A)
      antagonist WAY 100635 (0.25, 0.5, 1.0 mg/kg) and the 5-HT(2) antagonist
      ketanserin (1.0, 2.0, 4.0 mg/kg). RESULTS: Indorenate (10 mg/kg), 8-OH-DPAT (1.0
      mg/kg) and buspirone (5.0 and 10.0 mg/kg) reduced immobility behaviour in the
      FST, considered as an antidepressant-like effect. Both doses of pindolol (2.5 and
      5.0 mg/kg) and WAY 100635 (0.5 and 1.0 mg/kg) antagonised the antidepressant-like
      effect of indorenate. Neither 5-HT(1B) (GR55562) nor 5-HT(2)(ketanserin)
      antagonists produced changes in the effect of indorenate in the FST. CONCLUSIONS:
      Indorenate produces antidepressant-like actions in the FST that are mediated by
      the stimulation of 5-HT(1A) receptors.

PMID- 12474120
TI  - Dose-dependent effect of ethanol on extracellular dopamine in mesolimbic striatum
      of awake rhesus monkeys: comparison with cocaine across individuals.
AB  - RATIONALE: Dependence on both alcohol and cocaine is a widespread example of
      polydrug abuse/dependence. It has been hypothesized that ethanol reward is
      mediated via increased dopaminergic neurotransmission in mesolimbic striatum, as
      is the case for cocaine. However, little is known about the neurobiology of
      ethanol in primates, or how the effects of ethanol compare to those of cocaine
      across individual animals. OBJECTIVES: To determine in animals with a history of
      cocaine exposure whether there is a dopaminergic impact of ethanol in non-human
      primates, and if so, whether the magnitude of that effect correlates with the
      dopaminergic effect of cocaine across individuals. METHODS: Microdialysis studies
      were conducted in rhesus monkeys previously trained to self-administer cocaine.
      The dopaminergic impact of cocaine had been determined in those animals during
      cocaine self-administration sessions. Probes were placed in the ventral
      mesolimbic and associational central striatum. Ethanol was administered non
      contingently by a slow intravenous infusion at doses of 0.5 g/kg (administered
      over 10 min) and 1.0 g/kg (administered over 20 min). RESULTS: The mean
      dopaminergic response to ethanol in four animals (with 2-4 trials in each animal
      at each dose) indicated a small but significant increase in extracellular
      dopamine at each dose (12% above baseline at 0.5 g/kg, 22% above baseline at 1.0
      g/kg). Examining the responses across individual animals indicated substantial
      variability, in that two of the four animals showed no increase at either dose.
      Across individuals, regression analysis of cocaine-induced changes in dopamine
      with 1.0 g/kg ethanol-induced changes indicated a positive correlation between
      the drug effects, with a trend in this direction observed with the 0.5-g/kg dose
      of ethanol. CONCLUSIONS: These results provide support for the ability of ethanol
      to elevate extracellular dopamine in the mesolimbic striatum, though with a
      modest effect size and variability among individuals. Further, they suggest that
      some common mechanism influences the effects of ethanol and cocaine on
      dopaminergic output despite seemingly unrelated pharmacological mechanisms of
      action.

PMID- 12474121
TI  - Role of benzodiazepine and serotonergic mechanisms in conditioned freezing and
      antinociception using electrical stimulation of the dorsal periaqueductal gray as
      unconditioned stimulus in rats.
AB  - RATIONALE: The dorsal periaqueductal gray matter (dPAG) has been implicated in
      the modulation of defensive behavior. Electrical stimulation of this structure
      can be used as an unconditioned stimulus to produce a conditioned fear reaction
      expressed by freezing, antinociception, and autonomic responses. OBJECTIVES: This
      study investigated the influence of benzodiazepine, serotonergic, and opioid
      mechanisms on these conditioned responses. METHODS: Animals implanted with an
      electrode and a guide cannula into the dPAG were submitted to two conditioning
      sessions. Each session consisted of ten pairings of the light in a distinctive
      chamber (CS) with the electrical stimulation of this structure at the escape
      threshold. On the next day, each animal was exposed only to the CS (testing) and
      the duration of freezing, number of rearing and grooming episodes were recorded
      for 5 min. Before and after the testing session, animals were submitted to the
      tail-flick test. Fifteen minutes before the exposure to the CS, animals received
      injections into the dPAG of midazolam (a positive modulator of benzodiazepine
      sites), alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT; an agonist of 5-HT(2)
      receptors), naltrexone (an opioid antagonist), or vehicle. RESULTS: Conditioning
      with dPAG electrical stimulation caused significant increases in the time of
      freezing and conditioned antinociception. Injections of midazolam into the dPAG
      significantly inhibited freezing behavior and antinociception due to
      conditioning. Injections of alpha-Me-5-HT inhibited the effects of conditioning
      on freezing without affecting conditioned antinociception. Injections of
      naltrexone (13 nmol/0.2 micro l) did not change any of the conditioned responses
      studied. CONCLUSIONS: (1) Conditioned freezing and antinociception are modulated
      by benzodiazepine mechanisms into dPAG. (2) 5-HT(2) receptors seem to regulate
      conditioned freezing behavior. However, conditioned antinociception was not
      affected by 13 nmol naltrexone. (3) Opioid mechanisms do not seem to be involved
      in the conditioned responses using electrical stimulation of the dPAG as
      unconditioned stimulus. Further studies with other opioid and 5-HT(2) receptor
      antagonists are still needed to confirm the conclusions drawn from the present
      work.

PMID- 12474122
TI  - The CRF(1) receptor antagonist DMP696 produces anxiolytic effects and inhibits
      the stress-induced hypothalamic-pituitary-adrenal axis activation without
      sedation or ataxia in rats.
AB  - RATIONALE: CRF(1) antagonists may be effective in the treatment of anxiety
      disorders while having fewer side effects compared with classical
      benzodiazepines. OBJECTIVES: The effects of a small molecule selective CRF(1)
      antagonist DMP696 on anxiety-like behaviors and stress-induced increases in
      corticosterone in rats exposed to a novel environment and on locomotor activity
      and motor coordination were determined in rats. These effects of DMP696 were
      compared with those produced by the classical benzodiazepine chlordiazepoxide
      (CDP). METHODS: DMP696 or CDP were administered PO, 60 minutes before behavioral
      testing in rats. Their effects on latency to exit a dark chamber and stress
      induced increase in corticosterone in the Defensive Withdrawal test (an animal
      model of anxiety), locomotor activity, and rotorod performance (measure of
      ataxia) were determined. RESULTS: DMP696 significantly reduced exit latency and
      reversed the stress-induced increase in corticosterone in the Defensive
      Withdrawal test at doses of 3.0-10 mg/kg and higher. In contrast, CDP
      significantly decreased exit latency at 10 and 30 mg/kg, but not at 100 mg/kg,
      due to concurrent non-specific side effects. Unlike DMP696, CDP had no effect on
      the stress-induced increase in corticosterone at lower doses, but resulted in a
      significant increase at higher doses. DMP696 did not reduce locomotor activity or
      impair motor coordination at doses up to 30-fold higher than doses effective in
      the Defensive Withdrawal model. In contrast, CDP produced significant sedation
      and ataxia at the same doses that were effective in reducing exit latency.
      CONCLUSIONS: These data suggest that the CRF(1) antagonist DMP696 might retain
      the therapeutic benefits of classical benzodiazepines but have fewer motoric side
      effects.

PMID- 12474123
TI  - Social users of alcohol and cannabis who detect substance-related changes in a
      change blindness paradigm report higher levels of use than those detecting
      substance-neutral changes.
AB  - RATIONALE: Understanding the cognitions underpinning substance use has stalled
      using the Stroop paradigm. OBJECTIVE: To employ a novel version of the flicker
      paradigm for induced change blindness to independently compare information
      processing biases in social users of alcohol and cannabis. METHOD: Alcohol and
      cannabis experiments were independently run. In both, participants were asked to
      view successively and repeatedly on a monitor two versions of a visual scene (an
      original and a slightly changed version) until the change was detected. In fact,
      in both experiments two simultaneous changes competed for detection: a substance
      neutral and a substance-related change. RESULTS: In both the alcohol and the
      cannabis experiments, participants detecting the substance-related change
      reported higher levels of use than those detecting the substance-neutral change.
      CONCLUSION: A substance-related processing bias was independently revealed for
      both substances. The utility of the flicker paradigm for substance use research
      is demonstrated as sensitive and quick to administer (taking only 1 min).

PMID- 12474124
TI  - [Reconstruction of the upper stapes].

PMID- 12474125
TI  - [Amplitude modulation following responses in audiological diagnostics].
AB  - The registration of brainstem potentials currently represents one of the most
      common methods in objective audiological diagnostics. However, regardless of
      their use, they are still known to possess important disadvantages, such as low
      specificity and validity in the lower frequency range due to broadband stimuli,
      or uncertainties due to the need for subjective evaluation. One potential
      solution to these problems could involve the registration of amplitude modulation
      following responses (AMFR). These potentials are being discussed much more
      regularly within the anglo-american literature due to their known frequency
      specificity within the high frequency range (resulting from a very narrow
      frequency band of stimulation), and also their ability to permit assessment of
      the hearing threshold at lower frequencies. Another additional advantage of AMFR
      results from the simple statistical verification of its presence.Extensive
      studies on the influence of both stimulating and recording parameters have also
      shown that the registration of AMFR could prove to be a very promising
      audiological tool, with past interest being focussed primarily on the optimal
      modulation frequency, the influence of vigilance of the generation of potentials,
      and the precise assessment of an objective threshold.

PMID- 12474126
TI  - [Reconstruction of the superstructure of the stapes in guinea pigs with biovitro
      ceramic and silicone foil].
AB  - BACKGROUND: The reconstruction of the stapes superstructure is still a problem.
      Efforts for the fixation of implants on the footplate did not show satisfying
      results yet. METHODS: In 6 guinea pigs a biovitro ceramic (Bioverit) was placed
      on the stapes footplate after removal of the superstructure. The exclusive bony
      fixation of the implants on the footplate should be achieved by the use of
      silicone foils. For control purposes replantation of autologous ossicles was done
      in one group of 3 animals and a sham operation was performed without any use of
      implants in the other group of 6 guinea pigs. RESULTS: After 21 weeks not only
      bony fixation of the implant with the footplate was observed, but furthermore
      with the wall of the middle ear. Bone formation was detected along the silicone
      foils. In the first control group of animals we found bony fixation of the
      replanted ossicles and even a bow-shaped reconstruction of the stapes
      superstructure in the second. CONCLUSIONS: The guinea pig was not an ideal model
      for questions of middle ear reconstructions due to its enormous potential for
      bone formation. In this animal model bony fixation of glass-ceramic with the
      stapes-footplate could be induced.

PMID- 12474127
TI  - [The incidence of microlaryngoscopy associated complications].
AB  - BACKGROUND: The frequency of local and cardiovascular side effects of
      microlaryngoscopy is generally underestimated. There are no data available in the
      literature from recent and prospective clinical trials. PATIENTS AND METHODS: We
      examined 81 patients between 03/1998 and 03/2000 who underwent microlaryngoscopy
      in our department. This was done following a standard protocol before, during and
      after surgery. Side effects of endotracheal intubation were avoided by using
      supraglottic jet-ventilation. RESULTS: In 79% of our cases we encountered side
      effects due to the microlaryngoscopic procedure.86% of them were reversible
      lesions,hematomas and edemas of the mucous membranes or mild cardiovascular
      dysregulations. In two cases there was a dental complication (one fracture, one
      dislocation), and seven cases of moderate hemodynamic effects were noted.
      CONCLUSIONS: The incidence of tissue damage caused by microlaryngoscopic
      endoscopes is much higher than commonly assumed in clinical practice. This has to
      be explained to the patient when obtaining his written consent to a certain
      microlaryngoscopic procedure and to be considered during the postoperative follow
      up.The consequent use of tooth protection and a good control of muscle relaxation
      and analgesia can be effective in preventing side effects.

PMID- 12474128
TI  - [Recovery of hearing: results of delayed medical treatment in patients with
      idiopathic sudden hearing loss].
AB  - For the treatment of idiopathic sudden sensorineural hearing loss (ISSNHL), a
      variety of studies about intravenous drug administration with the beginning of
      treatment in the early period of less then one week after the onset of hearing
      loss have been performed. In contrast, very little information is available about
      the efficacy of intravenous drug therapy for ISSNHL with the beginning of
      treatment later than four weeks after the onset of hearing loss. In a
      retrospective chart review we studied the treatment results of 57 patients with
      ISSNHL with beginning of treatment later than four weeks after the onset of
      hearing loss with no spontaneous recovery of hearing. Patients received a
      treatment with intravenous administration of Dextran (concentration 40 g/l with
      NaCl 0.9%) and Procain-HCl (a derivative of the local anaesthetic lidocaine,400
      800 mg in a 500 ml rheologic infusion of Dextran 40). 25% of the patients showed
      a significant improvement of 10 dB or more in hearing threshold at 1000 Hz
      measured in bone-conducted pure tone audiometry. In a subjective evaluation 53%
      of the patients noticed a subjective improvement of their individual hearing
      thresholds.

PMID- 12474129
TI  - [Pharyngeal reconstruction after salvage pharyngolaryngectomy in recurrent
      tumors].
AB  - BACKGROUND: Total pharyngeal reconstruction after salvage pharyngolarynectomy in
      recurrent tumors after primary surgery or radiation therapy may be performed by
      ENT surgeons in the oncologic field. PATIENTS: We report on six patients that
      underwent salvage pharyngolaryngectomy and total pharyngeal reconstruction.
      METHODS: In three cases pharyngeal reconstruction was performed as a two-stage
      procedure with deltopectoral flaps. One of these patients died before the
      completion of reconstruction. In three other patients the reconstruction was
      performed with a tubed pectoralis major myocutaneous flap including one patient
      after a failed reconstruction with a jejunum segment. or fistula prevention we
      applied silicon stents in three patients and self-expanding Nitinol stents in
      three other patients. RESULTS: Of five successfully reconstructed patients two
      fed orally, one fed combined orally and via PEG and two fed via PEG. CONCLUSIONS:
      Summarizing our experiences the use of silicon tubes and nitinol stents has
      proved its worth. Experiences with a larger number of patients must be collected
      in the future.

PMID- 12474130
TI  - [Giant Madelung's disease. Report of a case and review of the literature].
AB  - Madelung's disease, also known as benign symmetrical lipomatosis, is a rare
      proliferative disorder of unknown etiology that was first mentioned by Brodie in
      1846. Characterized by multiple symmetrical deposits of unencapsulated fat in the
      head and neck region, the disease is most common in middle-aged men with a
      history of alcohol abuse. The only effective therapy in cases of dyspnea and
      dysphagia, indicating the necessity of treatment, is the surgical resection of
      the adipose tissue. The authors report on the evaluation and therapy in a case of
      giant Madelung's disease.

PMID- 12474131
TI  - [Physical and technical elements of short-interval, color-filtered double strobe
      flash-stroboscopy].
AB  - INTRODUCTION: Quantitative measurement of vocal fold movements can be done either
      with high-speed imaging or with short interval, color-filtered double strobe
      flash-stroboscopy. The physical and technical elements of this new technique are
      described. METHODS: Two special strobe units (KAY Elemetrics RLS 9100) are used
      in a master-slave configuration. In this way an adjustable interval of 0.1-2.0 ms
      between flashes is introduced. The strobe flashes are color filtered and are
      separated by a brief interval. By this means a double exposure is created in each
      video frame.Real-time visualization of opening and closing velocities over the
      entire length of the vocal fold from anterior to posterior is possible.
      Quantification is possible off-line after image calibration. CONCLUSION: Short
      interval, color-filtered double-strobe flash stroboscopy allows quantitative
      measurement of the velocity of vocal fold movements during vibration at different
      pitches and sound pressure levels (SPL). Images gained with this new technique
      provide information about a dynamic property (velocity) of the vocal fold within
      a single image.Therefore, its use could be helpful from the aspect of clinical
      documentation.

PMID- 12474132
TI  - [Driving ability with vestibular lesions].

PMID- 12474133
TI  - [Duties of the physician with regard to advice on driving ability].

PMID- 12474134
TI  - [Modern sociomedical views of dysphonia].

PMID- 12474135
TI  - [What will change and what will stay].

PMID- 12474136
TI  - [Partial hospitalisation -- indication and characteristic aspects of the setting,
      shown by the example of the day clinic in Freiburg/Germany].
AB  - Until now, in comparison to psychiatric day clinics, there is only a limited
      amount of psychotherapeutic day clinics which offer an intense, multimodal
      treatment on a psychodynamic basis comparable to that of inpatient settings. We
      present the example of the day clinic in Freiburg to discuss characteristic
      aspects of the setting and criteria for indication. Preliminary empirical results
      indicate, that even severely disturbed patients can be adequately treated. The
      combination of an intense therapy program with the daily involvement in the
      outside reality has substantial advantages for some groups of patients and eases
      the transition at discharge.

PMID- 12474137
TI  - [Irrational attitudes and social stress in outpatient behavior therapy: changes,
      prognostic and mediating influences].
AB  - Various studies suggest that social stress and cognitive dysfunction contribute
      to the development of psychiatric disorders. Their roles as moderators and
      mediators of recovery have rarely been studied. Aim of the present research was
      to investigate 1. the change of irrational attitudes and perceived social stress
      during outpatient behavioral treatment and their contribution to 2. the
      prediction and 3. mediation of success in patients with heterogeneous diagnoses.
      METHODS: A diagnostically unselected sample of 62 outpatients participated in a
      questionnaire study at the beginning and at the end of treatment. Success of
      treatment was assessed by the Symptom Check-List-90-R. Cognitive dysfunction was
      measured by the Irrational Attitudes Questionnaire (IAQ). Instruments for the
      assessment of perceived social stress were the Scale of Recent Life Events (SRL),
      the Contractual Conditions-Scale (CCS) and the Impact of Event-Scale (IES).
      RESULTS: 1. Psychological symptoms, irrational attitudes and perceived social
      stress decreased during therapy, while the number of life events remained
      constant. 2. Clinically reliably changed patients scored higher in Self-Blame
      (IAQ) than non-responders at the beginning of therapy. 3. The reduction of
      Negative Self-Evaluation (IAQ) was stronger in patients with clinical change than
      in unchanged patients. DISCUSSION: The results were disputed with reference to
      the literature and to limitations of the study.

PMID- 12474138
TI  - [The demand for integrative approaches in psychotherapy research demonstrated in
      an bibliometrical and speech statistic analysis of the PPMP].
AB  - Based upon the recent discussion on integrative approaches in psychotherapy
      research, the last two volumes of the PPmP were bibliometrically analyzed. The
      articles of authors which belong to different disciplines like psychosomatic or
      medical psychology were compared with respect to the word and speech statistic,
      leading representatives and the reception of the international state of research.
      The interdisciplinary standard of the PPmP has proven successful in view of the
      impact of the journal within the Scientific Community and among the flagship
      journals of the field. The study shows that the plurality of methodological
      approaches and interdisciplinarity provides an important criterion for the
      quality of psychotherapy research and for the corresponding publication
      institutions. Related to scientific quality standard the PPmP has found good
      impact in the scientific community but there are points to be changed.

PMID- 12474139
TI  - [Connections between attachment prototypes and relationship patterns].
AB  - Connections between attachment styles and relationship patterns are studied on 32
      female psychotherapy patients. Our study gives first hints to a connection
      between attachment variables, assessed by the German version of the Adult
      Attachment Prototype Rating (AAPR) and predominant relationship patterns,
      assessed by the Core Conflictual Relationship Theme Method (CCRT) developed by
      Luborsky, if both methods are used independently. Subsamples according to the
      attachment styles show differences in CCRT variables.

PMID- 12474140
TI  - A founding locus within the RET proto-oncogene may account for a large proportion
      of apparently sporadic Hirschsprung disease and a subset of cases of sporadic
      medullary thyroid carcinoma.
AB  - Hirschsprung disease (HSCR) is a common congenital disorder characterized by
      aganglionosis of the gut. The seemingly unrelated multiple endocrine neoplasia
      type 2 (MEN 2) is an autosomal dominant disorder characterized by medullary
      thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Yet, germline
      mutations in the RET proto-oncogene are associated with both MEN 2 and HSCR. In
      the former, gain-of-function mutations in a limited set of codons is found,
      whereas, in the latter, loss-of-function mutations are found. However, germline
      RET mutation is associated with only 3% of a population-based series of isolated
      HSCR, and little is known about susceptibility to sporadic MTC. We have found
      previously that specific haplotypes comprising RET coding single-nucleotide
      polymorphisms (SNPs) comprising exon 2 SNP A45A were strongly associated with
      HSCR, whereas haplotypes associated with exon 14 SNP S836S were associated with
      MTC. In this study, we describe three novel intron 1 SNPs, and, together with the
      coding SNP haplotypes, the data suggest the presence of distinct ancestral
      haplotypes for HSCR and sporadic MTC in linkage disequilibrium with a putative
      founding susceptibility locus/loci. The data are consistent with the presence of
      a very ancient, low-penetrance founder locus approximately 20-30 kb upstream of
      SNP A45A, but the failure of the SNPs to span the locus presents challenges in
      modeling mode of transmission or ancestry. We postulate that this founding locus
      is germane to both isolated HSCR and MTC but also that different mutations in
      this locus would predispose to one or the other.

PMID- 12474141
TI  - A locus for migraine without aura maps on chromosome 14q21.2-q22.3.
AB  - Migraine is a common and disabling neurological disease of unknown origin
      characterized by a remarkable clinical variability. It shows strong familial
      aggregation, suggesting that genetic factors are involved in its pathogenesis.
      Different approaches have been used to elucidate this hereditary component, but a
      unique transmission model and causative gene(s) have not yet been identified. We
      report clinical and molecular data from a large Italian pedigree in which
      migraine without aura (MO) segregates as an autosomal dominant trait. After
      exclusion of any association between MO and the known familial hemiplegic
      migraine and migraine with aura loci, we performed a genomewide linkage analysis
      using 482 polymorphic microsatellite markers. We obtained significant evidence of
      linkage between the MO phenotype and the marker D14S978 on 14q22.1 (maximum two
      point LOD score of 3.70, at a recombination fraction of 0.01). Multipoint
      parametric analysis (maximum LOD score of 5.25 between markers D14S976 and
      D14S978) and haplotype construction showed strong evidence of linkage in a region
      of 10 cM flanked by markers D14S1027 and D14S980 on chromosome 14q21.2-q22.3.
      These results indicate the first evidence of a genetic locus associated with MO
      on chromosome 14.

PMID- 12474142
TI  - Two percent of men with early-onset prostate cancer harbor germline mutations in
      the BRCA2 gene.
AB  - Studies of families with breast cancer have indicated that male carriers of BRCA2
      mutations are at increased risk of prostate cancer, particularly at an early age.
      To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer,
      we screened the complete coding sequence of BRCA2 for germline mutations, in 263
      men with diagnoses of prostate cancer who were </=55 years of age. Protein
      truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%
      5.0%), and all of these mutations were clustered outside the ovarian-cancer
      cluster region. The relative risk of developing prostate cancer by age 56 years
      from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with
      mutations did not have a family history of breast or ovarian cancer. Twenty-two
      variants of uncertain significance were also identified. These results confirm
      that BRCA2 is a high-risk prostate-cancer-susceptibility gene and have potential
      implications for the management of early-onset prostate cancer, in both patients
      and their relatives.

PMID- 12474143
TI  - Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic
      pathway, causing early-onset fatal hypertrophic cardiomyopathy.
AB  - Deficiencies in the activity of cytochrome c oxidase (COX), the terminal enzyme
      in the respiratory chain, are a frequent cause of autosomal recessive
      mitochondrial disease in infants. These patients are clinically and genetically
      heterogeneous, and all defects so far identified in this group have been found in
      genes coding for accessory proteins that play important roles in the assembly of
      the COX holoenzyme complex. Many patients, however, remain without a molecular
      diagnosis. We have used a panel of retroviral vectors expressing human COX
      assembly factors in these patients to identify the molecular basis for the COX
      deficiency by functional complementation. Here we show that overexpression of
      COX15, a protein involved in the synthesis of heme A, the heme prosthetic group
      for COX, can functionally complement the isolated COX deficiency in fibroblasts
      from a patient with fatal, infantile hypertrophic cardiomyopathy. Mutation
      analysis of COX15 in the patient identified a missense mutation (C700T) on one
      allele, changing a conserved arginine to tryptophan (R217W), and a splice-site
      mutation in intron 3 on the other allele (C447-3G), resulting in a deletion of
      exon 4. This splicing error introduces a frameshift and a premature stop codon,
      resulting in an unstable mRNA and, likely, a null allele. Mitochondrial heme A
      content was reduced in the patient's heart and fibroblast mitochondria, and
      levels of heme O were increased in the patient's heart. COX activity and the
      total amount of fully assembled enzyme were reduced by 50%-70% in patient
      fibroblasts. Expression of COX15 increased heme A content and rescued COX
      activity. These results suggest that reduced availability of heme A stalls the
      assembly of COX. This study establishes COX15 as an additional cause, along with
      SCO2, of fatal infantile, hypertrophic cardiomyopathy associated with isolated
      COX deficiency.

PMID- 12474144
TI  - Support for association of schizophrenia with genetic variation in the 6p22.3
      gene, dysbindin, in sib-pair families with linkage and in an additional sample of
      triad families.
AB  - Genetic variants in a gene on 6p22.3, dysbindin, have been shown recently to be
      associated with schizophrenia (Straub et al. 2002a). There is no doubt that
      replication in other independent samples would enhance the significance of this
      finding considerably. Since the gene is located in the center of the linkage peak
      on chromosome 6p that we reported earlier, we decided to test six of the most
      positive DNA polymorphisms in a sib-pair sample and in an independently
      ascertained sample of triads comprising 203 families, including the families for
      which we detected linkage on chromosome 6p. Evidence for association was observed
      in the two samples separately as well as in the combined sample (P=.00068 for SNP
      rs760761). Multilocus haplotype analysis increased the significance further to
      .00002 for a two-locus haplotype and to .00001 for a three-locus haplotype.
      Estimation of frequencies for six-locus haplotypes revealed one common haplotype
      with a frequency of 73.4% in transmitted, and only 57.6% in nontransmitted,
      parental haplotypes. All other six-locus haplotypes occurring at a frequency of
      >1% were less often transmitted than nontransmitted. Our results represent a
      first successful replication of linkage disequilibrium in psychiatric genetics
      detected in a region with previous evidence of linkage and will encourage the
      search for causes of schizophrenia by the genetic approach.

PMID- 12474145
TI  - Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish
      families.
AB  - Preeclampsia is a common, pregnancy-specific disorder characterized by reduced
      placental perfusion, endothelial dysfunction, elevated blood pressure, and
      proteinuria. The pathogenesis of this heterogeneous disorder is incompletely
      understood, but it has a familial component, which suggests that one or more
      common alleles may act as susceptibility genes. We hypothesized that, in a
      founder population, the genetic background of preeclampsia might also show
      reduced heterogeneity, and we have performed a genomewide scan in 15 multiplex
      families recruited predominantly in the Kainuu province in central eastern
      Finland. We found two loci that exceeded the threshold for significant linkage:
      chromosome 2p25, near marker D2S168 (nonparametric linkage [NPL] score 3.77;
      P=.000761) at 21.70 cM, and 9p13, near marker D9S169 (NPL score 3.74; P=.000821)
      at 38.90 cM. In addition, there was a locus showing suggestive linkage at
      chromosome 4q32 between D4S413 and D4S3046 (NPL score 3.13; P=.003238) at 163.00
      cM. In the present study the susceptibility locus on chromosome 2p25 is clearly
      different (21.70 cM) from the locus at 2p12 found in an Icelandic study (94.05
      cM) and the locus at 2q23 (144.7 cM) found in an Australian/New Zealand study.
      The locus at 9p13 has been shown to be a candidate region for type 2 diabetes in
      two recently published genomewide scans from Finland and China. The regions on
      chromosomes 2p25 and 9p13 may harbor susceptibility genes for preeclampsia.

PMID- 12474146
TI  - A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence
      for imprinting.
AB  - Several genetic loci have been reported for psoriasis, but none has been
      specifically linked to psoriatic arthritis (PsA), a condition that affects >10%
      of patients with psoriasis. A genetic component for PsA is suggested by
      segregation within families and high concordance among identical twins. We
      performed a linkage scan to map genes contributing to PsA. We identified 178
      patients with PsA out of 906 patients who were included in our genetic study of
      psoriasis. Using a comprehensive genealogy database, we were able to connect 100
      of these into 39 families. We genotyped the patients using a framework marker set
      of 1,000 microsatellite markers, with an average density of 3 cM, and performed
      multipoint, affected-only, allele-sharing linkage analysis using the Allegro
      program. On the basis of the initial results, we genotyped more markers for the
      most prominent loci. A linkage with a LOD score of 2.17 was observed on
      chromosome 16q. The linkage analysis, conditioned on paternal transmission to
      affected individuals, gave a LOD score of 4.19, whereas a LOD score of only 1.03
      was observed when conditioned for maternal transmission. A suggestive locus on
      chromosome 16q has previously been implicated in psoriasis. Our data indicate
      that a gene at this locus may be involved in paternal transmission of PsA.

PMID- 12474147
TI  - Gene therapy as an alternative to liver transplantation.
AB  - Liver transplantation has become a well-recognized therapy for hepatic failure
      resulting from acute or chronic liver disease. It also plays a role in the
      treatment of certain inborn errors of metabolism that do not directly injure the
      liver. In fact, the liver maintains a central role in many inherited and acquired
      genetic disorders. There has been a considerable effort to develop new and more
      effective gene therapy approaches, in part, to overcome the need for
      transplantation as well as the shortage of donor livers. Traditional gene therapy
      involves the delivery of a piece of DNA to replace the faulty gene. More
      recently, there has been a growing interest in the use of gene repair to correct
      certain genetic defects. In fact, targeted gene repair has many advantages over
      conventional replacement strategies. In this review, we will describe a variety
      of viral and nonviral strategies that are now available to the liver. The ever
      growing list includes viral vectors, antisense and ribozyme technology, and the
      Sleeping Beauty transposon system. In addition, targeted gene repair with RNA/DNA
      oligonucleotides, small-fragment homologous replacement, and triplex-forming and
      single-stranded oligonucleotides is a long-awaited and potentially exciting
      approach. Although each method uses different mechanisms for gene repair and
      therapy, they all share a basic requirement for the efficient delivery of DNA.

PMID- 12474148
TI  - Significance of positive cytotoxic cross-match in adult-to-adult living donor
      liver transplantation using small graft volume.
AB  - A positive cross-match in cadaveric liver transplantation is relatively
      acceptable, but its role in living donor liver transplantation (LDLT) is less
      well known. The aim of this study is to examine the significance of cytotoxic
      cross-match in adult-to-adult LDLT using small-for-size grafts. Forty-three adult
      to-adult LDLTs were performed at Seoul National University Hospital (Seoul,
      Korea) from January 1999 to July 2001. Subjects consisted of 27 men and 16 women
      with an average age of 45.4 years. Average liver graft weight was 565.3 +/- 145.7
      g, and average graft-recipient weight ratio (GRWR) was 0.89% +/- 0.20%. HLA cross
      match testing by lymphocytotoxicity and flow cytometry was performed routinely
      preoperatively. Factors that may influence survival, such as age; sex; blood
      group type A, type B, type O compatibility; cytotoxic cross-match; donor age;
      surgical time; cold ischemic time; and GRWR, were analyzed. Nine patients (20.9%)
      died in the hospital. There was a greater in-hospital mortality rate in women
      than men (37.5% v 11.1%; P = .049). The extra-small-graft group (0.54% < or =
      GRWR < 0.8%; n = 14) showed greater in-hospital mortality rates than the small
      graft group (0.8% < or = GRWR < or = 1.42%; n = 29; 42.9% v 10.3%; P = .022). A
      positive cross-match was detected in 4 women transplant recipients, and 3 of
      these patients belonged to the extra-small-graft group. All patients with a
      positive cross-match died of multiorgan failure after early postoperative acute
      rejection episodes. Positive cross-match was the only significant factor in
      multivariate analysis (P = .035). In conclusion, when lymphocytotoxic cross-match
      and flow cytometry are significantly positive, adult-to-adult LDLT using small
      for-size grafts should not be performed.

PMID- 12474149
TI  - One hundred consecutive hepatic biopsies in the workup of living donors for right
      lobe liver transplantation.
AB  - Living donor liver transplantation allows an increasing number of patients with
      end-stage liver disease the opportunity for effective treatment in the face of a
      critical shortage of cadaveric organs. Hepatic steatosis decreases functional
      graft mass and may contribute to graft dysfunction. Screening liver biopsy allows
      accurate quantitation of hepatic fat, but is an invasive procedure that is not
      universally employed in the evaluation of living donors. We studied 100
      consecutive prospective right lobe living donors, all evaluated with liver
      biopsy, imaging studies, and various clinical parameters. The accuracy and
      predictive value of body mass index (BMI) and imaging were compared with biopsy
      in determining the amount of hepatic fat. There were no complications to biopsy,
      with 33% showing some degree of steatosis. BMI correlated only weakly with
      biopsy, with 73% of overweight (BMI > 25) donors having little or no hepatic fat.
      Imaging was only 12% sensitive to small amounts (5% to 10%) of fat, with
      increasing sensitivity to more severe steatosis. Imaging diagnosed steatosis in 2
      donors without hepatic fat and failed to identify a candidate denied with biopsy
      proven 30% steatosis. Conversely, 9% of candidates with BMIs of 25 or less had
      10% or greater steatosis. Moreover, three candidates were denied surgery because
      biopsy detected occult liver disease. Accurate quantification of hepatic fat is
      not afforded by BMI and imaging studies alone. Screening liver biopsy has a low
      complication rate and may serve to increase donor safety. Biopsy is essential in
      identifying donor grafts at risk for poor recipient outcome while maximizing the
      donor pool.

PMID- 12474150
TI  - Liver biopsy in living donors.

PMID- 12474151
TI  - Intraoperative hemodynamics and liver function in adult-to-adult living liver
      donors.
AB  - Indocyanine green (ICG) can be used to measure cardiac output (CO), hepatic
      function, and blood volume. We used ICG to describe the effect of right
      hepatectomy for living liver donation on intraoperative hemodynamics and
      perioperative liver function. ICG disposition was determined in 12 healthy adult
      living liver donors during the dissection phase and immediately after removal of
      the right hepatic lobe. In addition, measurements were repeated postoperative day
      5. After injecting ICG, plasma concentrations were obtained for approximately 10
      minutes by noninvasive pulse dye densitometry. CO was significantly higher and
      systemic vascular resistance was significantly lower immediately after removal of
      the right lobe compared with those obtained before resection (6.02 +/- 1.12 v
      10.28 +/- 3.84 L/min; P < .05; 639 +/- 254 v 1,007 +/- 264 dyn x s x cm(-5); P <
      .05). Heart rate also increased significantly after removal of the right lobe
      from 62 +/- 10 to 83 +/- 9 beats/min (P < .05). Mean arterial pressure and
      central venous pressure were not different between measurements. The average
      elimination rate constant of ICG (K(ICG)) was reduced by more than 50%
      immediately after resection of the right lobe in comparison to baseline (0.25 +/-
      0.096 v 0.12 +/- 0.03; P < .05). Day 5, K(ICG) was still decreased from baseline
      (0.25 +/- 0.096 v 0.16 +/- 0.04; P < .05), but approximately 25% greater than the
      immediate postresection K(ICG) (0.16 +/- 0.04 v 0.12 +/- 0.03; P > .05). Findings
      show profound intraoperative hemodynamic changes during living liver donation. In
      addition, we show that functional recovery of the liver is likely to be slower
      than morphological recovery, and such clinical parameters as coagulation profile
      may not be a good index of fully restored hepatic function.

PMID- 12474152
TI  - Socioeconomic status does not affect the outcome of liver transplantation.
AB  - The outcome of liver transplantation is dependent on many factors. It was
      suggested that racial disparities in outcome may be related to differences in
      socioeconomic status (SES). In this retrospective study, we analyzed the effect
      of SES on graft and patient survival. Two hundred seventy-six adult patients who
      underwent liver transplantation at our institution from July 1988 to June 2001
      were included in the analysis. Educational and occupation statuses were coded
      using established criteria (Hollingshead Index of Social Status [HI]). SES then
      was calculated using the HI formula: SES = education level x 3 + occupation x 5,
      and categorized into four groups: group 1, score less than 29 (n = 71); group 2,
      score of 29 to 42 (n = 82); group 3, score of 42 to 53 (n = 69); and group 4,
      score greater than 53 (n = 54). Kaplan-Meier analysis was used for graft and
      patient survival, and Cox regression analysis was used to determine the effect of
      confounding factors. Demographics of all four groups were similar. One-, 2-, and
      5-year graft and patient survival did not differ significantly across groups by
      Kaplan-Meier and Cox regression survival analysis. In conclusion, SES did not
      predict graft and patient survival after liver transplantation.

PMID- 12474153
TI  - CMV hepatitis after liver transplantation: incidence, clinical course, and long
      term follow-up.
AB  - Cytomegalovirus (CMV) hepatitis is described as the most frequent manifestation
      of CMV tissue invasive disease after liver transplantation. Its correlation with
      HLA-matching, hepatic artery thrombosis, and chronic rejection is still
      controversial. Risk factors, incidence, clinical course, and complications of CMV
      hepatitis were retrospectively analyzed in a 12-year series of 1,146 consecutive
      liver transplantations in 1,054 patients. All patients received only low-dose
      acyclovir but no gancyclovir prophylaxis. CMV infection was diagnosed by viral
      culture, pp65 antigenemia, or by polymerase chain reaction (PCR). CMV hepatitis
      was proven by liver biopsy. Treatment of CMV disease consisted of intravenous
      ganciclovir for a minimum of 14 days. Long-term follow-up of patients included
      monthly routine laboratory values and routine liver biopsies 1, 3 and 5 years
      after transplantation. CMV hepatitis was a rare event after liver
      transplantation, with a total incidence of 2.1% (24 cases). It was significantly
      more frequent in CMV seronegative (5.2%) than in seropositive recipients (0.7%).
      The leading indication in patients with CMV hepatitis was HCV cirrhosis (n = 8).
      The maximum number of pp65 positive white blood cells was 82 +/- 23 per 10,000
      cells. Most courses manifested as isolated hepatitis; only 2 patients had
      disseminated disease. Nine of 24 patients had received OKT3 monoclonal antibodies
      because of steroid-resistant rejection before CMV hepatitis. In seronegative
      patients with CMV hepatitis, 71% revealed 1 or 2 HLA DR matches, in contrast to
      32% in patients without CMV hepatitis. One-, 3-, and 5-year graft survival was
      78%, 65%, and 59% in patients with CMV hepatitis compared with 88%, 81%, and 79%
      in patients without. Chronic rejection was observed in one patient, but already
      before onset of CMV hepatitis. Beneath D+R-constellation and OKT3 treatment as
      risk factors, HLA DR-matched grafts and HCV seem to favor manifestation of CMV
      hepatitis after liver transplantation. Long-term complications of CMV hepatitis
      were not observed, and especially no correlation with chronic rejection was
      found.

PMID- 12474154
TI  - The natural history of acute histologic rejection without biochemical graft
      dysfunction in orthotopic liver transplantation: a systematic review.
AB  - Protocol biopsy results in the first few weeks after liver transplantation
      sometimes display histologic features of acute cellular rejection (ACR), even in
      the absence of significant clinical or biochemical dysfunction. At present there
      is no clear consensus about the need to treat such cases with adjuvant
      immunosuppression. This systematic review describes, from the available evidence,
      the natural history of untreated histologic ACR in the absence of biochemical
      graft dysfunction. An electronic search of the Medline, Embase, and Cochrane
      Library databases was performed to select studies that reported protocol liver
      biopsies in the early posttransplant period from 1983 to 2000. Studies that
      identified patients with ACR on protocol biopsy who were not treated with
      adjuvant immunosuppression formed the basis of the study group. Data from
      individual studies were extracted using standardized pro forma and pooled for
      descriptive analysis. The search identified 3431 studies, of which 516 were cited
      in full. Of these, 15 studies met all of the inclusion criteria. These 15 studies
      reported on 1566 patients who had protocol biopsies performed in the early
      posttransplant period, of which 1048 (67%) had histologic evidence of ACR. Three
      hundred and thirty one (32%) patients with histologic ACR on protocol biopsy had
      no associated biochemical graft dysfunction. Without treatment, only 14% of these
      patients subsequently developed biochemical graft dysfunction requiring adjuvant
      immunosuppression. Steroid-resistant rejection and chronic rejection both had a
      prevalence of 4% in patients with untreated histologic ACR and no biochemical
      graft dysfunction. Withholding adjuvant immunosuppression from patients with
      histologic ACR and no biochemical graft dysfunction seems to be safe, as long as
      graft function is carefully monitored. The rationale for performing protocol
      biopsies in the absence of biochemical graft dysfunction is questionable.

PMID- 12474155
TI  - Is this the end for protocol early posttransplant liver biopsies?

PMID- 12474156
TI  - Transplantation for hepatocellular carcinoma and cirrhosis: sensitivity of
      magnetic resonance imaging.
AB  - The sensitivity of magnetic resonance imaging (MRI) in patients who undergo
      transplantation for hepatocellular carcinoma (HCC) and cirrhosis is not known. We
      prospectively evaluated 24 patients with known HCC who underwent MRI and
      subsequent transplantation within 60 days (mean, 20 days). Using a phased-array
      coil at 1.5T, breath-hold turbo STIR and T2-weighted MR images were performed.
      Dynamic gadolinium-enhanced MRI was performed using a two- or three-dimensional
      gradient echo pulse sequence with images obtained in the hepatic arterial, portal
      venous, and equilibrium phases. The prospective interpretation of the MR study
      was directly compared with thin-section pathology evaluation of the explanted
      livers. All 24 patients had at least one HCC, and MR diagnosed tumor in 21 (88%)
      of these patients. On a lesion-by-lesion basis, MRI depicted 39 of 118 HCC for an
      overall sensitivity of 33%. MRI detected five (100%) of five lesions >5 cm, 20
      (100%) of 20 lesions >2 cm but not exceeding 5 cm, 11 (52%) of 21 lesions between
      1 and 2 cm, and three (4%) of 72 lesions <1 cm. Of the nine patients with
      carcinomatosis (innumerable lesions less than 1 cm), MR detected three lesions in
      one patient. Of the 15 dysplastic nodules found at pathology, MRI depicted a
      single 1.8-cm high-grade lesion, for a sensitivity of 7%. In conclusion, MRI is
      sensitive for the detection of HCC measuring at least 2 cm in diameter but is
      insensitive for the diagnosis of small HCC (<2 cm) and carcinomatosis.

PMID- 12474157
TI  - Percutaneous radiofrequency thermal ablation of hepatocellular carcinoma: a safe
      and effective bridge to liver transplantation.
AB  - The incidence of hepatocellular carcinoma (HCC) is increasing in the United
      States. Although liver transplantation is an effective means of treating selected
      patients, pretransplantation tumor progression may preclude some patients from
      undergoing transplantation. The aim of this study is to determine the safety and
      efficacy of percutaneous radiofrequency thermal ablation (RFA) in 33 consecutive
      patients with nonresectable HCC and advanced cirrhosis. Mean subject age was 57.2
      +/- 10.6 years, mean Child-Turcotte-Pugh score was 7.0 +/- 1.4, and mean maximal
      tumor diameter was 3.6 +/- 1.1 cm. Using contrast-enhanced computed tomography
      and magnetic resonance imaging, 22 patients (66%) had a complete radiological
      response at 3 months post-RFA, whereas 11 patients (33%) had an incomplete
      radiological response. During follow-up, 18 patients (54%) experienced tumor
      progression and 9 subjects underwent repeated ablation for either residual
      disease or tumor progression. The overall actuarial patient survival rate of the
      33 patients was 58% at 2 years, whereas the transplantation-free patient survival
      rate was 34% at 2 years. Fifteen of 23 transplant candidates were successfully
      bridged to liver transplantation after a mean post-RFA follow-up of 7.9 +/- 6.7
      months. The extent of tumor necrosis in the explant varied, but no subjects had
      evidence of tumor seeding on post-RFA imaging, at liver transplantation, or in
      the explant. The 3-year actuarial posttransplantation patient survival rate was
      85%. Two patients have developed posttransplantation recurrence, and both had
      microscopic vascular invasion in their explants. In summary, our data show that
      RFA is a safe and effective treatment modality for patients with advanced
      cirrhosis and nonresectable HCC. Although the ability of RFA to prevent or delay
      tumor progression requires further prospective study, its favorable safety
      profile and promising efficacy make it an attractive treatment option for liver
      transplant candidates with nonresectable HCC.

PMID- 12474159
TI  - Effect of ischemic preconditioning on hepatic microcirculation and function in a
      rat model of ischemia reperfusion injury.
AB  - Ischemic preconditioning (IPC) may protect the liver from ischemia reperfusion
      injury by nitric oxide formation. This study has investigated the effect of
      ischemic preconditioning on hepatic microcirculation (HM), and the relationship
      between nitric oxide metabolism and HM in preconditioning. Rats were allocated to
      5 groups: 1. sham laparotomy; 2. 45 minutes lobar ischemia followed by 2-hour
      reperfusion (IR); 3. IPC with 5 minutes ischemia and 10 minutes reperfusion
      before IR; 4. L-arginine before IR; and 5. L-NAME + IPC before IR. HM was
      monitored by laser Doppler flowmeter. Liver transaminases, adenosine
      triphosphate, nitrites + nitrates, and guanosine 3'5'-cyclic monophosphate (cGMP)
      were measured. Nitric oxide synthase (NOS) distribution was studied using
      nicotinamide adeninine dinucleotide phosphate (NADPH) diaphorase histochemistry.
      At the end of reperfusion phase, in the IR group, flow in the HM recovered
      partially to 25.8% of baseline (P < .05 versus sham), whereas IPC improved HM to
      49.5% of baseline (P < .01 versus IR). With L-arginine treatment, HM was 31.6% of
      baseline (NS versus IR), showing no attenuation of liver injury. In the
      preconditioned group treated with L-NAME, HM declined to 10.2% of baseline,
      suggesting not only a blockade of the preconditioning effect, but also an
      exacerbated liver injury. Hepatocellular injury was reduced by IPC, and L
      arginine and was increased by NO inhibition with L-NAME. IPC also increased
      nitrate + nitrate (NOx) and cGMP concentrations. NOS detected by NADPH diaphorase
      staining was associated with hepatocytes and vascular endothelium, and was
      induced by IPC. IPC induced NOS and attenuated HM impairment and hepatocellular
      injury. These data strongly suggest a role for nitric oxide in IPC.

PMID- 12474158
TI  - Renal failure and abdominal hypertension after liver transplantation:
      determination of critical intra-abdominal pressure.
AB  - There is growing interest in measuring intra-abdominal pressure (IAP) in
      postsurgical and critically ill patients because increased pressure can impair
      various organs and functions. The aim of this study was to evaluate the effect of
      different IAP levels on the postoperative renal function of subjects undergoing
      orthotopic liver transplantation. IAP was measured every 8 hours with the urinary
      bladder pressure method for at least 72 hours after surgery. At the end of the
      study, the patients were classified on the basis of their IAP values: < or = 18
      mm Hg (group A), 19 to 24 mm Hg (group B), > or = 25 mm Hg (group C). The three
      groups were compared in terms of the incidence of acute renal failure (defined as
      blood creatinine > 1.5 mg/dL or an increase in the same of > 1.1 mg/dL within 72
      hours of surgery), hourly diuresis, blood creatinine, the filtration gradient,
      hemodynamic variations, and outcome. The incidence of renal failure was higher
      among the subjects in group C (P < .05 versus group A and < .01 versus group B),
      who also had higher creatinine levels (P < .01), a greater need for diuretics (P
      < .01) and a worse outcome (P < .05). Receiver Operator Characteristic curve
      analysis showed that an abdominal pressure of 25 mm Hg had the best
      sensitivity/specificity ratio for renal failure. An intra-abdominal pressure of >
      or = 25 mm Hg is an important risk factor for renal failure in subjects
      undergoing liver transplant.

PMID- 12474160
TI  - Metastatic leiomyosarcoma mimicking polycystic liver disease.

PMID- 12474161
TI  - Keratin, fas, and cryptogenic liver failure.

PMID- 12474162
TI  - Rhabdomyolytic syndrome during the lamivudine therapy for acute exacerbation of
      chronic type B hepatitis.

PMID- 12474163
TI  - Pitfalls in interpreting liver biopsy results: the story of the blind men and the
      elephant.

PMID- 12474164
TI  - Hemodynamic profile and tissular oxygenation during liver transplantation:
      influence of the order in vascular clamp release.

PMID- 12474165
TI  - Quality of life measurement in rehabilitation medicine: building an agenda for
      the future.
AB  - In November 2001, a conference convened to discuss the state of the science of
      measuring of quality of life (QOL) in rehabilitation medicine. The meeting
      brought together leading researchers in areas of behavioral health and physical
      medicine and rehabilitation to address the fragmentation that exists across
      specialty areas and disciplines. The goal was to bridge terminology, techniques,
      and advances across the fields of behavioral and rehabilitation medicine. The 5
      topic areas included: (1) general versus targeted measurement, (2) QOL in policy
      development, (3) measuring QOL from the patient's perspective, (4) cultural
      aspects of QOL measurement, and (5) the future of QOL research. This introduction
      synthesizes the information presented at the conference and provides context to
      the articles contained in this 2-part supplement.

PMID- 12474166
TI  - Use of the SF-36 and other health-related quality of life measures to assess
      persons with disabilities.
AB  - This article evaluates the appropriateness of existing approaches to the
      assessment of health-related quality of life (HRQOL) for persons with
      disabilities. We compare the conceptual model of HRQOL from the Medical Outcomes
      Study with the World Health Organization's International Classification of
      Functioning, Disability and Health. In addition, we examine the attitudes toward
      disease "burden" that arise from these 2 models. We note how values or the
      importance attached to domains of health can change with fluctuations in physical
      health. Further, we summarize arguments in favor of developing targeted measures
      of persons with disabilities. Finally, we discuss some methodologic issues in
      assessing physical functioning, attributions to health versus disability, and
      mode of administration. We conclude that users of "standard" HRQOL measures need
      to be aware of their limitations for assessing persons with disabilities.

PMID- 12474167
TI  - Measuring quality of life in chronic illness: the functional assessment of
      chronic illness therapy measurement system.
AB  - We focus on quality of life (QOL) measurement as applied to chronic illness.
      There are 2 major types of health-related quality of life (HRQOL) instruments
      generic health status and targeted. Generic instruments offer the opportunity to
      compare results across patient and population cohorts, and some can provide
      normative or benchmark data from which to interpret results. Targeted instruments
      ask questions that focus more on the specific condition or treatment under study
      and, as a result, tend to be more responsive to clinically important changes than
      generic instruments. Each type of instrument has a place in the assessment of
      HRQOL in chronic illness, and consideration of the relative advantages and
      disadvantages of the 2 options best drives choice of instrument. The Functional
      Assessment of Chronic Illness Therapy (FACIT) system of HRQOL measurement is a
      hybrid of the 2 approaches. The FACIT system combines a core general measure with
      supplemental measures targeted toward specific diseases, conditions, or
      treatments. Thus, it capitalizes on the strengths of each type of measure.
      Recently, FACIT questionnaires were administered to a representative sample of
      the general population with results used to derive FACIT norms. These normative
      data can be used for benchmarking and to better understand changes in HRQOL that
      are often seen in clinical trials. Future directions in HRQOL assessment include
      test equating, item banking, and computerized adaptive testing.

PMID- 12474168
TI  - Quality of life issues in individuals with spinal cord injury.
AB  - Assessments of quality of life (QOL) are increasingly used in rehabilitation,
      embracing a number of conceptual approaches and measurement tools. Very few
      studies on QOL have addressed the specific needs of persons with spinal cord
      injury (SCI). Literature reviewed here describes 2 meta-analytical studies on SCI
      as well as several individual studies that focus on predictors and correlates of
      QOL applied to SCI. Results from a unique study on QOL after SCI using a
      qualitative methodology are also discussed. In addition, we describe the findings
      from another study, which used the Medical Outcomes Study 12-Item Short-Form
      Health Survey to assess QOL and relate it to the concept of being disabled.

PMID- 12474169
TI  - Activity-related quality of life in rehabilitation and traumatic brain injury.
AB  - OBJECTIVES: To review approaches to assessment of quality of life (QOL) outcomes
      in rehabilitation, focusing particularly on traumatic brain injury (TBI), and to
      introduce the concept of activity-related QOL. DATA SOURCES: A conceptual review,
      based on extensive searches of MEDLINE, PsychInfo, and other information sources.
      STUDY SELECTION: Studies indexed under QOL and brain injury. DATA EXTRACTION:
      Literature search on key words quality of life and traumatic brain injury. DATA
      SYNTHESIS: Past research in rehabilitation and TBI has concentrated largely on
      assessment of function or activity. Although research on QOL after TBI remains
      limited, many studies have made inferences about QOL without actually assessing
      it. Persons with TBI experience serious long-enduring problems with QOL. Progress
      has been made in measurement of QOL and understanding of predictors of QOL after
      TBI. CONCLUSIONS: Future research in rehabilitation would do well to consider not
      only activity outcomes but also the affective quality of everyday life, and the
      connections between the two. Measures of activity-related QOL may provide a more
      sensitive, valid, and useful evaluation of rehabilitative therapies than other
      approaches. Further research is needed to improve measurement and interpretation
      of QOL assessments. By assessing both objective and subjective features of
      outcomes, outcomes assessment becomes more complete and potentially more useful.

PMID- 12474170
TI  - Measuring health outcomes in stroke survivors.
AB  - Stroke frequently results in psychologic distress and activity limitations across
      multiple domains of functioning. However, most stroke outcome measurement tools
      and clinical trial endpoints are narrowly focused on neurologic symptom status
      and physical aspects of functioning, and rarely assess other important components
      of health. In this article, I discuss the limitations in the measurement of
      nonfatal stroke outcomes; propose a minimum set of fundamental assessment domains
      comprising a comprehensive assessment of health status in stroke survivors; and
      describe the conceptual development of the Burden of Stroke Scale, a
      comprehensive, patient-reported measure of functioning and well-being for stroke
      survivors.

PMID- 12474171
TI  - Quality of life: an outcomes perspective.
AB  - This article compares a traditional biomedical model with an outcomes model for
      evaluating medical and rehabilitation care. The traditional model emphasizes
      diagnosis and disease-specific outcomes. In contrast, the outcomes model
      emphasizes life expectancy and health-related quality of life (QOL). Although the
      models are similar, they lead to different conclusions with regard to some
      interventions. For some conditions, diagnosis and treatment may reduce the impact
      of a particular disease without extending life expectancy or improving QOL. Older
      individuals with multiple comorbidities may not benefit from treatments for a
      particular disease if competing health problems threaten life or reduce QOL.
      Overall outcomes and benefits of treatment can be summarized by using measures of
      life expectancy that adjust for QOL. The quality-adjusted life year (QALY) has
      been proposed as a comprehensive summary index. QALYs have gained widespread
      usage in many areas of medicine. The outcomes model has been applied widely in
      rehabilitation research, but few studies estimate the benefits of treatments
      using QALYs. These methodologies can also serve as a basis for approaches to
      sharing medical decisions between patients and providers. Opportunities to apply
      these new methods are discussed.

PMID- 12474172
TI  - Exercise capacity early after stroke.
AB  - OBJECTIVE: To evaluate exercise capacity of patients with a poststroke interval
      of less than 1 month. DESIGN: Prospective, cohort, observational study. SETTING:
      Exercise testing laboratory in a tertiary care hospital. PARTICIPANTS: Twenty
      nine patients (mean age +/- standard deviation, 64.9+/-13.5 y) with a poststroke
      interval of 26.0+/-8.8 days. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: Peak exercise capacity (VO(2)peak) was measured by open-circuit
      spirometry during maximal effort treadmill walking with 15% body-weight support.
      RESULTS: Mean VO(2)peak was 14.4+/-5.1 mL. kg(-1). min(-1) or 60%+/-16% of age-
      and sex-related normative values for sedentary healthy adults. CONCLUSIONS:
      Exercise capacity approximately 1 month after stroke was compromised. Further
      research is needed to elucidate the physiologic basis of this low capacity.

PMID- 12474173
TI  - Hemiparetic muscle atrophy and increased intramuscular fat in stroke patients.
AB  - OBJECTIVE: To determine if skeletal muscle atrophy and greater fat deposition
      within the muscle are present in the hemiparetic limb of chronic (>6 mo)
      hemiparetic stroke patients. DESIGN: Cross-sectional study. SETTING: Hospital
      based research center. PARTICIPANTS: Sixty patients (47 men, 13 women; mean age
      +/- standard deviation, 65+/-9 y). INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: Patients underwent a total body scan by dual-energy x-ray
      absorptiometry to determine percentage of body fat, total lean mass, fat mass,
      and lean mass of the paretic and nonaffected legs, thighs, and arms. Thirty
      patients received computed tomography (CT) scans of their midthigh to determine
      muscle area, subcutaneous fat, and low-density lean tissue, as a measure of fat
      within the muscle area, of the paretic and nonaffected midthigh. RESULTS:
      Patients were deconditioned (VO(2)peak: 1.2+/-0.3 L/min) with a percentage of
      body fat of 31.4%+/-9.8% and total lean mass of 51.4+/-9.1 kg. Lean mass of the
      paretic leg and thigh were 4% and 3% lower than the nonaffected leg (P<.001), but
      leg fat was not different. Arm lean mass of the paretic side was 7% lower than
      the nonaffected side, whereas arm fat was not different. CT studies showed that
      midthigh muscle area was 20% lower in the paretic limb than in the nonaffected
      leg (P<.001), midthigh subcutaneous fat was similar, and midthigh low-density
      lean tissue showed a trend to be 3% higher in the paretic leg (P=.06). The ratio
      of midthigh low-density lean tissue to muscle area was higher in the paretic leg
      (P<.001), which indicates a greater intramuscular fat relative to muscle area in
      the affected limb. CONCLUSIONS: Our results show hemiparetic skeletal muscle
      atrophy and more fat within the muscle, factors that may contribute to functional
      disability and increased cardiovascular disease risk in chronic hemiparetic
      stroke patients.

PMID- 12474174
TI  - Classification of chronic pain associated with spinal cord injuries.
AB  - OBJECTIVES: To determine interrater reliability of a classification system for
      chronic pain in persons with spinal cord injury (SCI) and to determine the
      frequency and characteristics of various pain types as categorized by this
      system. DESIGN: Independent categorization (based on questionnaires; for 15
      persons, questionnaires plus personal interviews) by 2 investigators. SETTING:
      Community. PARTICIPANTS: A total of 163 individuals aged >or=18 years with SCI
      and pain. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Pain categories,
      Short-Form McGill Pain Questionnaire, and Chronic Pain Grade questionnaire.
      RESULTS: Among 41 (25%) questionnaires categorized independently by 2
      investigators, strength of agreement in categorizing 68 pain problems was
      substantial (kappa=.68). For 15 persons whose pain was categorized in person by 2
      investigators, strength of agreement was also substantial (kappa=.66). Among 163
      survey respondents with pain, the most common worst pain was SCI pain (31.9%).
      Mean characteristic pain intensity +/- standard deviation for worst pain,
      regardless of type, was 61.02+/-18.5 on a scale from 0 to 100. On average, for
      worst pain, respondents reported moderate pain-related disability (43.70+/-29.4;
      scale range, 0-100). Although certain pain descriptors were more often associated
      with a specific type of pain, none was pathognomonic. CONCLUSIONS: Substantial
      interrater reliability was achieved in determining pain categories by use of
      responses to a questionnaire with a classification system based on presumed
      pathology. Adding interviews with patients increased our ability to classify pain
      but did not improve overall interrater reliability.

PMID- 12474175
TI  - Femur bone mineral density is independently associated with functional recovery
      after hip fracture in elderly women.
AB  - OBJECTIVE: To evaluate the association between femur bone mineral density (BMD)
      and functional recovery after hip fracture. DESIGN: Cross-sectional study.
      SETTING: Rehabilitation hospital in Italy. PARTICIPANTS: A total of 233 of 263
      white women with hip fracture consecutively admitted to a rehabilitation
      hospital. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients
      underwent BMD assessment by dual-energy x-ray absorptiometry (DXA) at the
      proximal femur (5 sites) on admission. Functional recovery was evaluated by using
      Barthel Index scores. RESULTS: A positive correlation was found between BMD and
      Barthel Index scores assessed on both admission and discharge (r range,.16-.24,
      depending on the site of BMD measurement). Linear multiple regression showed that
      the association between BMD and Barthel Index score was independent of 10
      confounding variables: age, body mass index, fracture type, pressure ulcers,
      cognitive impairment, neurologic diseases, total lymphocyte count as a
      nutritional index, time between fracture occurrence and DXA assessment,
      comorbidity, and surgical procedure. Conversely, no significant associations were
      found between BMD and the change in Barthel Index score attributable to
      rehabilitation. CONCLUSIONS: In the study population, femur BMD was an
      independent predictor of the functional recovery assessed by Barthel Index score
      after hip fracture, but not of the change in the functional score resulting from
      rehabilitation.

PMID- 12474176
TI  - Intrathecal baclofen therapy in children with cerebral palsy: efficacy and
      complications.
AB  - OBJECTIVES: To describe the efficacy of intrathecal baclofen (ITB) therapy in the
      management of spasticity in young children with cerebral palsy (CP) and to
      identify risk factors for complications. DESIGN: Consecutive case series of 25
      implanted ITB delivery systems during a 48-month period. SETTING: Pediatric
      specialty hospital and outpatient department. PARTICIPANTS: Twenty-three children
      (age range, 4.5-17.4y) with CP (spastic diplegia in 22%; spastic quadriplegia in
      61%; mixed-type diplegia in 4%; mixed-type quadriplegia in 13%). INTERVENTION:
      Intrathecal baclofen therapy in children with cerebral palsy. MAIN OUTCOME
      MEASURES: Ashworth Scale scores before treatment and at 6 and 12 months after ITB
      therapy; frequency and nature of complications; and relation between patient
      characteristics and outcomes. RESULTS: Average Ashworth scores +/- standard
      deviation decreased from 3.26+/-.73 to 2.34+/-.83 (P<or=.01) in the lower
      extremities and from 2.69+/-.79 to 2.00+/-.55 (P<or=.05) in the upper extremities
      6 months after ITB therapy and remained comparably decreased at 12 months.
      Explantation was required in 44% (11/25), with wound complications as the leading
      cause in 73% (8/11). Complications were associated with the diagnosis of mixed
      type CP, as compared with pure spastic types (P<or=.01). Trends suggest that
      children of smaller size and younger age, as well as those with gastrostomy tubes
      and nonambulatory status, were more likely to encounter complications
      necessitating explantation. CONCLUSION: ITB therapy effectively reduced
      spasticity in children with CP. However, complications necessitating explantation
      can occur. Further research is needed to identify criteria describing the ideal
      pediatric candidate for ITB.

PMID- 12474177
TI  - Neurobehavioral aspects of recovery: assessment of the learned nonuse phenomenon
      in hemiparetic adolescents.
AB  - OBJECTIVE: To test the learned nonuse assumption of constraint-induced movement
      therapy (CIMT), through behavioral assessment, that residual movement abilities
      are not used to their fullest extent in persons with chronic hemiparesis. DESIGN:
      Repeated-measures cohort design. SETTING: Rehabilitation clinic in southwest
      Germany. PARTICIPANTS: Twenty-one persons with upper-limb hemiparesis after brain
      injury and 21 age-matched healthy controls. Participants were hospitalized when
      tested. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Spontaneous
      affected hand use for the items of the Motor Activity Log and the Actual Amount
      of Use Test were compared with the subjects' actual ability to perform these
      items with the affected hand. RESULTS: A significant difference between the
      residual movement capability and the spontaneous use was found in both tests.
      Most movements could be performed with moderate to good movement quality with the
      affected hand, but were still performed with the unaffected "good" hand in the
      spontaneous-use condition. This effect was equally strong in right- and left-side
      affected persons. CONCLUSION: Hemiparetic persons do not use their residual
      movement capabilities to the fullest extent. According to the learned nonuse
      model, this behavior reflects a learned suppression of affected arm movements,
      which may be overcome by CIMT.

PMID- 12474178
TI  - Attentional demands for static postural control after stroke.
AB  - OBJECTIVE: To assess the attentional demands associated with postural control
      among people who have had a stroke. DESIGN: Nonrandomized matched case-control
      study. SETTING: University research laboratory in Canada. PARTICIPANTS: Six
      individuals who had suffered a left or right cerebral ischemic attack in the past
      year and a sample of 6 age- and gender-matched controls. Participants in the
      stroke group had a mean age of 64.17+/-13.14 years; control participants had a
      mean age of 64.00+/-13.91 years. Mean National Institute of Health Stroke Scale
      scores for these patients were 7.67+/-4.92 at the time of stroke and 1.66+/-1.36
      at the time of testing. None of the patients were taking medications that would
      alter cognitive status or balance abilities. INTERVENTION: Participants performed
      a verbal reaction-time test while engaged in 3 postural tasks (sitting, standing,
      standing with feet together). MAIN OUTCOME MEASURE: Reaction time: latency
      between visual stimulus and verbal response. RESULTS: Reaction times in the
      stroke group differed significantly in all conditions from the controls (410+/-72
      ms vs 320+/-54 ms, P<.01). A significant interaction was found between group and
      postural task (P=.05), with reaction-time scores showing a progressive increase
      in postural task difficulty among participants who had suffered a stroke. Post
      hoc comparisons revealed that sitting reaction-time scores were significantly
      slower than reaction-time scores for feet together standing (P=.008) among
      participants in the stroke group. CONCLUSION: Individuals who have suffered a
      stroke showed increased attentional demands for tasks of static postural control
      compared with healthy, age-matched participants.

PMID- 12474179
TI  - The prevalence of postural asymmetry in people with and without chronic low back
      pain.
AB  - OBJECTIVE: To determine the extent of pelvic obliquity and lateral sacral base
      angle in subjects with and without chronic low back pain (LBP) by using postural
      radiographs. DESIGN: Cross-sectional, controlled. SETTING: A Veterans
      Administration hospital. PARTICIPANTS: Veterans and employees with (n=93) and
      without (n=76) chronic LBP. INTERVENTION: Postural radiographs. MAIN OUTCOME
      MEASURE: Differences between the mean extent of pelvic obliquity and the lateral
      sacral base angle in subjects with and without chronic LBP. RESULTS: The z scores
      showed no significant statistical differences in the extent of pelvic obliquity
      or lateral sacral angle in subjects with and without chronic LBP. CONCLUSION:
      Correction of pelvic obliquity by the use of heel lifts has been used as a
      modality of treatment for patients with chronic LBP. The majority of the patients
      in our clinics for whom this modality is used report at least some improvement in
      their pain symptoms. Because the extent of pelvic obliquity is similar in the
      subjects with and without chronic LBP, other factors must account for those who
      benefit from correction of their pelvic obliquity.

PMID- 12474180
TI  - Static trunk posture in sitting and standing during pregnancy and early
      postpartum.
AB  - OBJECTIVE: To investigate the postural alignment of the upper body in the
      sagittal plane during sitting and standing postures as pregnancy progressed and
      then in the postpartum period. DESIGN: Longitudinal, repeated-measures design.
      SETTING: Biomechanics laboratory in an Australian university. PARTICIPANTS: A
      volunteer convenience sample of 9 primiparous and multiparous women and 12
      nulliparous women serving as a control group. INTERVENTIONS: Not applicable. MAIN
      OUTCOME MEASURES: Subjects were filmed while sitting and during quiet standing at
      intervals throughout pregnancy and at 8 weeks postpartum. A repeated-measures
      analysis of variance was used to assess systematic changes in the alignment of
      the pelvic, thoracic, and head segments, and the thoracolumbar and
      cervicothoracic spines. Student t tests were used to compare the postpartum and
      nulliparous control groups. RESULTS: There was no significant effect of pregnancy
      on the upper-body posture, although there was a tendency in some subjects for a
      flatter thoracolumbar spinal curve in sitting as pregnancy progressed. Postpartum
      during standing, the pelvic segment had a reduced sagittal plane anterior
      orientation, and the thoracolumbar spine was less extended, indicating a flatter
      spinal curve compared with the control group. CONCLUSIONS: There was no
      significant effect of pregnancy on upper-body posture during sitting and
      standing, although individuals varied in their postural response. A flatter
      spinal curve was found during standing postpartum.

PMID- 12474181
TI  - Impact of quality scales on levels of evidence inferred from a systematic review
      of exercise therapy and low back pain.
AB  - OBJECTIVE: To assess whether the scale used affects levels of evidence inferred
      from a systematic review of studies on exercise therapy and chronic low back pain
      (LBP). DESIGN: Twenty trials previously analyzed in a systematic review were
      assessed by 2 readers using 16 different scales. SETTING: Tertiary care teaching
      hospital in France. PARTICIPANTS: Chronic LBP patients. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURE: For the scales allowing classification into
      high- and low-quality trials, a rating system with 4 levels of evidence was used
      to summarize conclusions drawn. The Spearman rank correlation coefficient was
      used to assess correlations between the scores obtained with the different
      scales. Interrater reliability of the scales was assessed with the intraclass
      correlation coefficient and the Bland and Altman method, and the degree of
      agreement between the readers was calculated using the kappa coefficient.
      RESULTS: Two of the 3 main results of the systematic review (conflicting evidence
      on the effectiveness of exercise therapy compared with inactive treatments;
      strong evidence that exercise therapy is more effective than usual care by a
      general practitioner) were influenced by the scale used. The range of the
      Spearman rank correlation coefficients between the different scales was wide
      (range,.49-.94), the interreader reliability of the scales was heterogeneous, and
      the interreader agreement was often low (kappa<or=.60 for 7/10 tests).
      CONCLUSIONS: The use of summary scores to identify physical therapy trials of
      high quality is questionable. Different quality assessment scales should probably
      be used to assess pharmacologic interventions and physical therapies. Development
      and validation of quality scales specific to physical treatments are needed.

PMID- 12474182
TI  - Functional deficits in athletes with a history of low back pain: a pilot study.
AB  - OBJECTIVE: To evaluate whether athletes with a history of low back pain (LBP)
      would, on average, perform slower on a timed 20-m shuttle run as compared with a
      normal athletic population. DESIGN: A timed shuttle run to evaluate residual
      functional limitations in college athletes with resolved LBP. SETTING: National
      College Athletic Association (NCAA) division I college. PARTICIPANTS: NCAA
      division I athletes (161 men, 50 women). INTERVENTION: A timed 20-m shuttle run.
      MAIN OUTCOME MEASURE: Each athlete was timed in a divided 20 m (66 ft) run in
      which 2 taped lines were positioned 6.7 m (22 ft) apart. RESULTS: Of 211 athletes
      evaluated, 27 had been treated for LBP during the previous year. Currently
      asymptomatic athletes with a recent history of LBP were slower (6.3s vs 5.8s)
      during performance of the timed 20-m shuttle run than athletes without LBP
      (P=.0002). CONCLUSIONS: Athletes with resolved LBP were slower than a matched
      group of normal athletes without LBP in the timed 20-m shuttle run. Further
      research is needed to support these findings and to understand fully the
      influence of the kinetic chain and the effects of both gender and sport on the
      observed findings.

PMID- 12474183
TI  - Characteristics of successful and unsuccessful completers of 3 postacute brain
      injury rehabilitation pathways.
AB  - OBJECTIVE: To determine whether successful participants along different postacute
      brain injury rehabilitation pathways differ on demographic, injury-related,
      disability, and outcome variables. DESIGN: Secondary analysis of pre- and
      posttreatment, and 1-year follow-up data obtained in a previous study of
      specialized vocational services (SVS) for persons with brain injury. SETTING:
      Outpatient brain injury rehabilitation clinic. PARTICIPANTS: One hundred fourteen
      persons with acquired brain injury. INTERVENTIONS: Participants in 3 distinct
      rehabilitation pathways were studied: SVS only; SVS and a 3-h/wk community
      reintegration outpatient group; and SVS and 6-h/d comprehensive day treatment
      (CDT). MAIN OUTCOME MEASURES: Mayo-Portland Adaptability Inventory (MPAI);
      Vocational Independence Scale; and "success," as defined by community-based
      employment (CBE) at 1-year follow-up. RESULTS: The percentage (77%-85%) of
      participants in CBE at 1-year follow-up did not differ among the 3 pathways. CDT
      participants had more limited educational backgrounds, were less recently
      injured, and showed greater disability and more impaired self-awareness than
      those receiving limited intervention (ie, SVS or community reintegration
      outpatient group). MPAI scores for limited-intervention participants who were
      unsuccessful were similar in level to successful participants in CDT. Logistic
      regression models were developed to predict the probability of success with
      limited intervention and CDT. CONCLUSION: Different rehabilitation pathways
      result in CBE for a large percentage of persons with brain injury if the
      intensity of service is appropriately matched to the severity of the disability,
      the time since injury, and other participant characteristics.

PMID- 12474184
TI  - The magnitude and correlates of alcohol and drug use before traumatic brain
      injury.
AB  - OBJECTIVE: To describe preinjury alcohol and drug use and opportunities for
      secondary prevention among persons with recent traumatic brain injury (TBI).
      DESIGN: Survey. SETTING: Acute inpatient rehabilitation program. PARTICIPANTS: A
      total of 142 (91%) of 156 consecutive admissions who met inclusion criteria and
      were screened. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Alcohol and
      drug use questionnaires, alcohol problem questions, toxicology results, readiness
      to change, and treatment preference questions. RESULTS: Subjects were on average
      37 years old, 80% were men, and 80% were white. Fifty-nine percent of the sample
      was considered "at-risk" drinkers and, as a group, subjects reported a high
      degree of preinjury alcohol-related problems. Thirty-four percent reported recent
      illicit drug use, and 42 (37%) of 114 cases with toxicology results were positive
      for illicit drugs. Motivation to change alcohol use correlated positively with
      greater self-reported alcohol consumption and problem severity. Most at-risk
      drinkers wanted to change on their own, whereas a minority were interested in
      treatment or Alcoholics Anonymous. CONCLUSION: Both alcohol abuse and drug use
      are common before TBI. Inpatient brain injury rehabilitation represents an
      important opportunity to identify and intervene in substance abuse problems.

PMID- 12474185
TI  - Silent autonomic dysreflexia during a routine bowel program in persons with
      traumatic spinal cord injury: a preliminary study.
AB  - OBJECTIVE: To determine the existence and frequency of silent autonomic
      dysreflexia in subjects with a complete spinal cord injury (SCI) above the
      neurologic level of T6. DESIGN: Prospective design. SETTING: Blood pressure
      monitoring of subjects during a routine bowel program. PARTICIPANTS: Ten subjects
      with chronic (>1 y), complete (American Spinal Injury Association Impairment
      Scale class A) SCI with a neurologic level of injury above T6. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURES: An increase in systolic blood pressure (SBP)
      of greater than 20 to 40 mmHg above baseline or an SBP greater than 150 mmHg.
      RESULTS: The mean resting blood pressure for the subject group was 104/65 mmHg.
      During the bowel program, no subject reported experiencing any of the classic
      symptoms of autonomic dysreflexia. The mean maximum blood pressure recorded
      during the bowel program was 160/90 mmHg. All of the patients had an increase in
      SBP greater than 20 mmHg above baseline, and 70% had an increase in SBP greater
      than 40 mmHg above baseline. Sixty percent of subjects had an increase in SBP
      greater than 150 mmHg, with 40% of subjects reaching an SBP greater than 170 mmHg
      at least once during their bowel program. CONCLUSION: Silent autonomic
      dysreflexia occurs frequently in SCI during bowel programs. Further study is
      recommended to determine whether preventative measures or treatment is needed.

PMID- 12474186
TI  - Feasibility of the physiological cost index as an outcome measure for the
      assessment of energy expenditure during walking.
AB  - OBJECTIVE: To determine if the Physiological Cost Index (PCI) can be recommended
      as an outcome measure in clinical trials. DESIGN: Three assessments were
      performed, 2 with shoes, 1 without. The difference between walking with shoes and
      walking barefoot was used to study the ability of the PCI to detect a change in
      the criterion standard. SETTING: A research department affiliated with a
      rehabilitation hospital in the Netherlands. PARTICIPANTS: Twelve children with
      cerebral palsy. INTERVENTIONS: During the first and third assessments, the
      children walked with shoes. During the intermediate assessment, the children
      walked without shoes. MAIN OUTCOME MEASURE: Breath-by-breath oxygen uptake, heart
      rate (HR), and walking speed were measured at a self-selected comfortable speed.
      Oxygen cost (EO(2)) and the PCI were subsequently calculated offline. Feasibility
      judgments were made regarding the ability of the PCI to detect changes in a
      criterion standard and the statistical power of the outcome measure. RESULTS:
      Pearson correlation coefficients were.66 and.62 for HR(walking)-HR(baseline) and
      HR(walking), respectively. The smallest detectable difference of the PCI and
      EO(2) were 69% and 32%, respectively. A difference of at least 69% or 32% should
      be found before one can conclude a difference with a certainty of 95%.
      CONCLUSIONS: The reproducibility of the PCI and the ability to show small
      differences in EO(2) were moderate. Subtracting HR(baseline) when calculating the
      PCI is probably not useful because it only increased within-subject variability.
      With respect to statistical power of a new clinical trial, we recommend using
      EO(2) instead of the PCI.

PMID- 12474187
TI  - The wheelchair circuit: reliability of a test to assess mobility in persons with
      spinal cord injuries.
AB  - OBJECTIVE: To assess the reliability of a 9-task wheelchair circuit. DESIGN:
      Three test trials per subject were conducted by 2 raters. Inter- and intrarater
      reliability were examined. SETTING: Eight rehabilitation centers in the
      Netherlands. PARTICIPANTS: Convenience sample of 27 patients (age, >or=18 y) with
      spinal cord injury (SCI), all of whom were in the final stage of their inpatient
      rehabilitation. INTERVENTION: A wheelchair circuit was developed to assess
      mobility in subjects with SCI. The circuit consisted of 9 tasks: figure-of-8
      shape, doorstep crossing, mounting a platform, sprint, walking, driving up
      treadmill slopes of 3% and 6%, wheelchair driving and transfer. MAIN OUTCOME
      MEASURE: Task feasibility, task performance time, and peak heart rates. RESULTS:
      The number of tasks that subjects could perform varied from 3 to 9. Feasibility
      intrarater reliability was.98, and the interrater reliability intraclass
      correlation coefficient (ICC) was.97. Performance time ICCs ranged from.70 to.99
      (mean,.88) for intrarater reliability and from.76 to.98 (mean,.92) for interrater
      reliability. Heart rate ICCs ranged from.64 to.96 (mean,.81) for intrarater
      reliability and from.82 to.99 (mean,.89) for interrater reliability. CONCLUSIONS:
      The reliability of the wheelchair circuit was good. More research is needed to
      assess test validity and responsiveness.

PMID- 12474188
TI  - Fluoroscopically guided aspiration of a symptomatic lumbar zygapophyseal joint
      cyst: a case report.
AB  - Lumbar zygapophyseal joint cysts are potential pain generators in patients with
      axial pain and/or lower-limb radicular pain. The traditional treatment of
      symptomatic cysts that do not respond to conservative measures is surgical
      decompression. Percutaneous needle aspiration under fluoroscopic guidance is a
      potential minimally invasive treatment option. We present a patient with a large
      symptomatic L4-5 zygapophyseal joint cyst and right L5 radiculopathy who
      responded well to percutaneous aspiration.

PMID- 12474189
TI  - The effects of a new foot-toe orthosis in treating painful hallux valgus.
AB  - OBJECTIVE: To assess the effects of a new foot-toe orthosis on painful hallux
      valgus. DESIGN: Uncontrolled intervention study. SETTING: An outpatient clinic in
      a tertiary medical center with an orthotic laboratory in Taiwan. PARTICIPANTS:
      Seventeen patients with painful hallux valgus. INTERVENTION: Application of a new
      total contact insole with fixed toe separator. MAIN OUTCOME MEASURES: The hallux
      valgus angle, an 11-point numeric rating scale (NRS-11) for pain assessment, and
      walking ability scale. RESULTS: The average hallux valgus angle reduction +/-
      standard deviation was 6.5 degrees +/-3.8 degrees after insole application
      (P<.001). An improvement on the NRS-11 pain scale from 4.06+/-2.8 to 0.88+/-1.17
      (P<.001) was noted after immediate insole application and was.42+/-.67 (P=.002) 3
      months later for the 12 patients who completed the study. The walking ability
      scale improved at least 1 grade or more after the insole was worn for 3 months
      (P=.002). All patients tolerated the insole well without any clinical evidence of
      skin ulcers or blisters. CONCLUSION: Our new total contact insole with fixed toe
      separator reduced pain, and improved walking ability and the hallux valgus angle.
      It is an effective alternative treatment for patients with painful hallux valgus.

PMID- 12474190
TI  - Plantar tissue stiffness in patients with diabetes mellitus and peripheral
      neuropathy.
AB  - OBJECTIVE: To determine if a difference exists in the plantar soft tissue of
      patients with diabetes mellitus (DM) and peripheral neuropathy (PN) compared with
      age-matched controls. DESIGN: Case-control study with a parallel 3-element 1
      dimensional viscoelastic model developed to characterize indentation data.
      SETTING: Data collection performed in an academic physical therapy laboratory.
      PARTICIPANTS: Forty subjects were recruited into 2 groups (20 subjects with DM,
      PN, and history of plantar ulcers; 20 control subjects), matched for age (DM:
      55.22+/-9.39 y; control: 55.91+/-10.97 y), gender (DM: 14 men, 6 women; control:
      14 men, 6 women), and body mass index (DM: 32.96+/-8.39 kg/m(2); control: 32.58+/
      7.69 kg/m(2)). INTERVENTIONS: The plantar soft tissue stiffness was measured over
      the first, third, and fifth metatarsals, and heel of each subject using an
      indentor system that accurately measures force/displacement (F/D) data. A
      parallel 3-element viscoelastic mechanical model was then used to transform the
      F/D data into values that were used to make stiffness assessments. MAIN OUTCOME
      MEASURE: The element coefficients of our model indicated the stiffness of the
      plantar tissue. RESULTS: The plantar tissue of the subjects with DM over the
      metatarsal heads was stiffer than the control population as indicated by one of
      the spring constants in the parallel 3-element model (first: 1.13+/-0.55 N/mm
      vs.72+/-.32 N/mm; third:.96+/-.32 N/mm vs.79+/-.17 N/mm; fifth:.90+/-.31 N/mm
      vs.69+/-.28 N/mm; P<.05). CONCLUSIONS: The plantar tissue of subjects with DM,
      PN, and a history of ulcers was stiffer than control subjects. However,
      additional research is needed to determine the relationship among increased soft
      tissue stiffness, plantar pressures, and skin breakdown.

PMID- 12474192
TI  - Treating carpal tunnel syndrome with lasers and TENS.

PMID- 12474191
TI  - Prospective payment, prospective challenge.
AB  - The Centers for Medicare and Medicaid Services has implemented an inpatient
      rehabilitation facility prospective payment system (IRF-PPS) based on case-mix
      groups (CMGs). The CMGs, now almost identical in structure to the Functional
      Independence Measure-Function-Related Groups (FIM-FRGs), will measure patients'
      functional severity by the FIM trade mark instrument, rather than by the Minimum
      Data Set for Post-Acute Care, as was initially planned. Although this late change
      in plans is a major triumph for physical medicine and rehabilitation and for the
      patients we serve, economic incentives inherent in the IRF-PPS may still
      transform inpatient rehabilitation as it is currently practiced in the United
      States. This commentary compares the CMGs with the FIM-FRGs; addresses the
      implications of the CMGs' implementation for patients, researchers, and
      clinicians; and highlights ways of adapting previous FIM-FRG applications and
      research to help meet the challenges presented by the new IRF-PPS.

PMID- 12474194
TI  - Child and adolescent predictors for eating disorders in a community population of
      young adult women.
AB  - OBJECTIVE: This study investigated early predictors for developing eating
      disorders by young adulthood in a community sample of women participating in a 22
      year longitudinal study. METHOD: Twenty-one women were identified at age 27 with
      lifetime full or partial eating disorders. These women were compared with 47
      women with no history of eating disorders on predictive factors from three broad
      domains. RESULTS: The women with eating disorders had more serious health
      problems before age 5 and mother-reported anxiety-depression at age 9. At 15,
      mothers described them as having more behavior problems. Before age 15, families
      of the eating disorder group had more histories of depression, eating problems
      and changes in family financial circumstances. DISCUSSION: This study identifies
      early predictors distinguishing girls who develop eating disorders. Findings
      point to the need for continued research in the area of early health to
      comprehensively examine the biologic, behavioral, and environmental risks for
      eating disorders.

PMID- 12474195
TI  - Healthy weight control and dissonance-based eating disorder prevention programs:
      results from a controlled trial.
AB  - OBJECTIVE: Because universal psychoeducational eating disorder prevention
      programs have had little success, we developed and evaluated two interventions
      for high-risk populations: a healthy weight control intervention and a dissonance
      based intervention. METHOD: Adolescent girls (N = 148) with body image concerns
      were randomized to one of these interventions or to a waitlist control group.
      Participants completed baseline, termination, and 1, 3, and 6-month follow-up
      surveys. RESULTS: Participants in both interventions reported decreased thin
      ideal internalization, negative affect, and bulimic symptoms at termination and
      follow-up relative to controls. However, no effects were observed for body
      dissatisfaction or dieting and effects diminished over time. DISCUSSION: Results
      provide evidence that both interventions effectively reduce bulimic pathology and
      risk factors for eating disturbances.

PMID- 12474196
TI  - "Knowing one's self" anorexic: implications for therapeutic practice.
AB  - OBJECTIVE: Recent postmodernist studies of anorexia nervosa (AN) challenge
      current clinical understandings and therapies by illuminating not what AN is but
      how what it is known to be by clinicians helps construct the disorder and therapy
      for it. This study points to the equal if not greater importance of how patients
      know AN. METHODS: Using a deconstructive approach, the discourses of a group of
      women diagnosed with severe AN were analyzed to reveal radically different
      versions of "knowing one's self" anorexic. RESULTS: These versions of "self" have
      strategically different implications for, and meanings of, any therapeutic
      endeavour. DISCUSSION: Postmodernist approaches point to the need for social
      reconstruction of lay and community understandings of AN. They also have
      implications at the level of individual therapy, and could be deployed with
      patients to establish individual but authentic bases for therapy.

PMID- 12474197
TI  - Brain tissue volume segmentation in patients with anorexia nervosa before and
      after weight normalization.
AB  - OBJECTIVE: To examine whether gray and white matter volumes are preferentially
      reduced and cerebral spinal fluid (CSF) increased with starvation in patients
      with anorexia nervosa compared with healthy controls and to determine what
      changes occur with weight normalization. METHOD: Whole intracranial volumes of
      patients and controls were segmented into gray matter, white matter, and CSF
      volumes and results compared. A subgroup of patients were rescanned after weight
      normalization. RESULTS: Total white matter and several regional white matter
      volumes were significantly reduced and total and regional CSF volumes were
      significantly increased in patients versus controls whereas gray matter was not
      significantly reduced. Total and regional CSF volumes were significantly
      decreased in patients upon weight normalization whereas white and gray matter
      volumes increased. DISCUSSION: These changes in brain tissue may be related to a
      variety of pathophysiologic mechanisms. We hypothesize that insulin-like growth
      factor-1 may be involved.

PMID- 12474198
TI  - Assessment of eating disorders in adolescents with anorexia nervosa: self-report
      questionnaire versus interview.
AB  - OBJECTIVE: To compare the Eating Disorder Examination (EDE) with the self-report
      version (EDE-Q) in a population of adolescents with anorexia nervosa. METHOD:
      Twenty-eight adolescent women meeting criteria for anorexia nervosa were assessed
      using both measures. The self-report version (EDE-Q) was given both before and
      (Time 1) after (Time 2) administration of the interview-based version (EDE).
      RESULTS: The results comparing the EDE with the EDE-Q at Time 1 were consistent
      with previous studies. Specifically, high correlations were generated on each of
      the four subscales (Dietary Restraint, Eating Concern, Shape Concern, Weight
      Concern) where the EDE-Q consistently overestimated the EDE. However, significant
      differences between the two measures were found on all subscales except Dietary
      Restraint. Agreement was best for the Weight Concern subscale and worst for the
      Eating Concern subscales. Comparing the EDE with the EDE-Q at Time 2, agreement
      improved for all subscales whereas significant differences were found on only two
      of the four subscales (Eating Concern and Shape Concern). DISCUSSION: Adolescents
      with anorexia nervosa report information on the EDE-Q as well as any of the other
      populations that have been studied. The results suggest that providing
      information to participants before they complete the self-report measure could
      improve scores on the EDE-Q.

PMID- 12474199
TI  - Substance use and weight loss tactics among middle school youth.
AB  - OBJECTIVE: Diet pills (DP) and vomiting or laxative (VL) use as weight loss
      tactics are associated with substance use in older adolescent populations. This
      study examined the association of weight loss tactics and substance use among
      middle school students. METHODS: A Youth Risk Behavior Survey was administered to
      6,957 middle school students in eastern North Carolina. Multiple logistic
      regression examined substance use as predictors of DP and VL use. RESULTS: DP and
      VL use was reported by 6.0% and 7.1% of students, respectively, with each
      reported more frequently by females and White students. Regression analysis
      demonstrated alcohol, cigarette, or marijuana use as predictors for individual
      race/gender groups whereas steroid use was a predictor for all race/gender
      groups. We found a clustering effect of alcohol and cigarette use with both DP
      and VL use. DISCUSSION: Substance use is associated with weight loss tactics as
      early as middle school. More research in the areas of clustering of behaviors and
      age at onset is needed.

PMID- 12474200
TI  - Neuropsychological functioning pretreatment and posttreatment in an inpatient
      eating disorders program.
AB  - OBJECTIVE: This study was conducted to determine whether neuropsychological
      dysfunction associated with anorexia nervosa resolves with inpatient treatment.
      METHOD: Subjects were 28 women being treated for anorexia nervosa. Main study
      variables included body mass index (BMI), Beck Depression Inventory-II, and
      neuropsychological test scores. Subjects were tested at admission and discharge.
      RESULTS: Neuropsychological functioning improved across the course of treatment,
      with significant changes on tests of memory and psychomotor speed. This
      improvement was not significantly associated with change in BMI or with the other
      variables that were studied. DISCUSSION: Patients with anorexia nervosa exhibit
      subtle neuropsychological dysfunction, which resolves at least partially during
      treatment. This improvement does not appear to be associated with an increase in
      BMI. However, it is possible that BMI is not a sufficiently sensitive indicator
      of nutritional status or that longer-term follow-up is necessary to reveal the
      nutrition-cognition relationship that we were seeking.

PMID- 12474201
TI  - Seasonal variations in eating disorder subtypes in Japan.
AB  - OBJECTIVE: This study estimated the degree of seasonal changes in eating disorder
      subtypes in Japan. METHOD: A Japanese version of the Seasonal Pattern Assessment
      Questionnaire (SPAQ) was mailed to 228 outpatients with eating disorders in Kyoto
      (latitude 35 degrees 01' N). Ninety responses were analyzed. The mean of the
      global seasonality score (GSS) in the SPAQ and the comorbidity rate of seasonal
      affective disorder (SAD) and subsyndromal-SAD in each subtype were used as
      indices of seasonality. RESULTS: The mean (8.2) of the GSS of the bulimia nervosa
      (BN) group and the sum (43%) of the comorbidity rates of SAD and subsyndromal-SAD
      in the BN group were significantly higher than those in the nonclinical
      comparison group. DISCUSSION: The seasonality of BN in Kyoto is the highest among
      eating disorder subtypes, although lower than that in North America. This finding
      suggests that light therapy could be useful for Japanese BN patients.

PMID- 12474202
TI  - Binge eating in obese children and adolescents.
AB  - OBJECTIVE: The first goal of the current study was to examine the extent to which
      a population of obese children and adolescents have developed binge eating
      problems. The second goal was to generate variables that would distinguish obese
      binge eaters from obese non-binge eaters. METHOD: A group of 126 children and
      adolescents seeking residential care because of their obesity was selected. A
      self-report version of the Eating Disorder Examination was administered. RESULTS:
      Binge eating episodes were reported by 36.5% of the obese youngsters. Six percent
      reported two or more episodes of binge eating a week. Obese binge eaters differed
      significantly from obese non-binge eaters in self-esteem and in a broad range of
      eating-related characteristics. Compared with obese non-binge eaters, the obese
      binge eaters were slightly younger. Obese binge eaters did not differ from obese
      non-binge eaters in degree of overweight or depression. DISCUSSION: Results
      suggest that binge eating is a prevalent problem among obese children and
      adolescents seeking help for their obesity. The marked difference between obese
      children with and without binge eating suggests the need for special treatment to
      focus on the problems of obese binge eaters.

PMID- 12474203
TI  - Diabetes and eating disorders in primary care.
AB  - OBJECTIVE: To determine the relationship between diabetes and eating disorders
      among primary care patients. METHOD: Data on 3,000 patients were obtained from
      eight primary care and family practice settings, including the PRIME-MD Patient
      Health Questionnaire (PHQ), self-reported physical illness, and social
      functioning information. Multivariate logistic regression analyses were used to
      determine the association between diabetes and eating disorders. RESULTS:
      Diabetes was associated with an increased likelihood of eating disorders [OR =
      2.3 (1.4, 3.9)], after adjusting for differences in demographic characteristics
      and comorbid mental disorders. This effect was specific to diabetes. Eating
      disorder was the only mental disorder associated with a significantly increased
      risk of diabetes, odds ratio (OR) = 2.4 (1.4, 4.0), after adjusting for
      demographic characteristics and comorbid mental and physical disorders. Patients
      with both diabetes and eating disorders had significantly higher levels of
      comorbid anxiety, panic attacks, and alcohol use disorders, compared with those
      with one but not both. DISCUSSION: Consistent with reports from community-based
      samples, these data suggest that diabetes may be associated with an increased
      likelihood of eating disorders among patients in primary care. Clinicians who
      treat patients with diabetes, a common condition in primary care, should screen
      for eating disorders. In addition, patients with eating disorders may be at risk
      for the development of diabetes. Further work is needed to determine the
      generalizability of these findings and to understand the mechanism of this
      association.

PMID- 12474204
TI  - Laxative misuse and behavioral disinhibition in bulimia nervosa.
AB  - OBJECTIVE: Various reports suggest that purging with laxatives is associated with
      greater behavioral impulsivity in bulimia nervosa (BN) patients. We investigated
      the extent to which laxative misuse corresponds to specific impulse-control
      problems. METHOD: Participants included bulimic women who misuse laxatives (BNL+;
      n = 12), bulimic women who do not misuse laxatives (BNL-; n = 33), and healthy
      normal eaters (NE; n = 26). Participants completed the Go/No-Go discrimination
      task (a well-validated computerized measure of response disinhibition), as well
      as self-report questionnaires of impulsivity, eating symptoms, and general
      psychopathology. RESULTS: Compared with the other groups, the BNL+ group made
      more commission errors on the Go/No-Go under cues for punishment, indicating they
      were more disinhibited when faced with possible negative outcomes. Compared with
      the BNL- group, the BNL+ group was also more likely to differ from the NE group
      on self-reported impulsivity. There were no differences between the two bulimic
      groups on eating symptoms and the three groups did not differ in terms of general
      psychopathology. DISCUSSION: Findings suggest that, controlling for eating
      symptoms and psychopathology, laxative misuse among BN patients is associated
      with difficulty inhibiting incorrect responses in the face of perceived threats.

PMID- 12474205
TI  - Olanzapine use as an adjunctive treatment for hospitalized children with anorexia
      nervosa: case reports.
AB  - OBJECTIVE: A recent case report suggested that olanzapine resulted in improved
      weight gain and maintenance, as well as decreased anxiety and agitation, for two
      hospitalized inpatients with anorexia nervosa (AN). However, a subsequent larger
      case study did not show a relationship between the use of olanzapine and rate of
      weight gain among a primarily adult population. The aim of this case report was
      to clinically examine the therapeutic benefit and tolerability of olanzapine as
      an adjunctive treatment for four children with AN in a pediatric inpatient
      setting. RESULTS: Olanzapine use was associated with considerable weight gain and
      maintenance, with an average rate of weight gain during hospitalization of 0.99
      kg per week. In addition to weight gain, olanzapine was associated with a
      clinically notable decrease in levels of agitation and premeal anxiety and almost
      immediate improvement in sleep, general functioning, and overall compliance with
      treatment. Olanzapine was also well tolerated in these young patients.
      DISCUSSION: These case report findings warrant more controlled research,
      including randomized controlled studies, to better determine the therapeutic
      benefits and safety of olanzapine use in children with AN.

PMID- 12474206
TI  - Pneumomediastinum simulating a panic attack in a patient with anorexia nervosa.
AB  - OBJECTIVE: Pneumomediastinum is a rare complication of anorexia nervosa. Although
      the mechanism is unknown, severe malnutrition may affect lung mechanics by
      altering the connective tissue, predisposing to pneumomediastinum. METHOD: We
      describe a young male with anorexia nervosa and panic disorder who presented with
      symptoms similar to those of a panic attack and was diagnosed with spontaneous
      pneumomediastinum. RESULTS: This case illustrates the importance of considering
      pneumomediastinum in the differential diagnosis of panic attack in patients with
      eating disorders. DISCUSSION: Although spontaneous pneumomediastinum has a
      generally benign course, it must be differentiated from the potentially life
      threatening secondary pneumomediastinum due to an esophageal tear.

PMID- 12474209
TI  - Degradation of imazosulfuron in different soils-HPLC determination.
AB  - Imazosulfuron, 1-(2-chloroimidazo [1,2-a] pyridin-3-ylsulfonyl)-3-(4,6
      dimethoxypyrimidin-2-yl)urea, is a new sulfonylurea herbicide applied once per
      growing season. It is highly active at low application levels and is used to
      control most annual and perennial broad-leaf weeds and some grasses in cereal
      crop. In this work the degradation of imazosulfuron in four different soils was
      investigated under aerobic laboratory conditions to evaluate its environmental
      fate. Test soils were treated with this herbicide in acetonitrile to obtain a
      final concentration of 0.2 mg kg(-1) (100 g ha(-1)), extracted with methylene
      chloride and analyzed by reversed-phase liquid chromatography (RP-HPLC) using a
      C(18) column coupled with UV detection. Recoveries of spiked soils ranged from
      84.3 to 99.8% (RDS 0.0-4.9%; n = 4). The limits of quantitation ranged from 0.002
      to 0.004 mg kg(-1). Imazosulfuron half-life, t(1/2), was calculated in each of
      the investigated soil. In aerobic conditions it ranged between 1 and 50 days.

PMID- 12474210
TI  - Quantitative determination of ragaglitazar in rat plasma by HPLC: validation and
      application in pharmacokinetic study.
AB  - A specific, accurate, precise and reproducible high-performance liquid
      chromatography (HPLC) method was developed for the estimation of ragaglitazar [(
      ) DRF 2725, NNC 61-0029], a novel anti-diabetic agent, in rat plasma. The assay
      procedure involved simple liquid/liquid extraction of ragaglitazar and internal
      standard (IS, troglitazone) from plasma into ethyl acetate. The organic layer was
      separated and evaporated under a gentle stream of nitrogen at 40 degrees C. The
      residue was reconstituted in the mobile phase and injected onto a Kromasil KR 100
      - 5C(18) column (4.6 x 250 mm, 5 micro m). Mobile phase consisting of 0.01 M
      potassium dihydorgen ortho phosphate (pH 3.2) and acetonitrile (30:70, v/v) was
      used at a flow rate of 1.0 mL/min. The eluate was monitored using an UV detector
      set at 240 nm. Ratio of peak area of analyte to IS was used for quantification of
      plasma samples. Nominal retention times of IS and ragaglitazar were 6.9 and 12.2
      min, respectively. The standard curve for ragaglitazar was linear (r(2) > 0.999)
      in the concentration range 0.2-100 micro g/mL. Absolute recovery was >87% from
      rat plasma for both analyte and IS. The lower limit of quantification (LLOQ) of
      ragaglitazar was 0.2 micro g/mL. The inter- and intra-day precision in the
      measurement of quality control (QC) samples, 0.2, 1.0, 5.0 and 50 micro g/mL,
      were in the range 1.32-3.70% relative standard deviation (RSD) and 1.19-9.39%
      RSD, respectively. Accuracy in the measurement of QC samples was in the range
      94.28-107.45%. Analyte and IS were stable in the battery of stability studies,
      viz. benchtop, autosampler and freeze/thaw cycles. Stability of ragaglitazar was
      established for 1 month at -20 degrees C. The application of the assay to a
      pharmacokinetic study in rats is described.

PMID- 12474211
TI  - Analysis of lipoprotein lipase activity using high-performance liquid
      chromatography.
AB  - Lipoprotein lipase (LPL) is a key enzyme which regulates the plasma triglyceride
      concentration by hydrolyzing triglycerides in chylomicrons and very-low-density
      lipoprotein (VLDL). The activity of LPL was conventionally analyzed using radio
      labeled residues or direct sandwich-ELISA. An assay for lipoprotein lipase
      activity which used a nonradioactive substrate, tri-olein, is described. In this
      method, LPL activity was detected fluorometrically by reacting 9
      anthryldiazomethane (ADAM) with the oleic acid generated from tri-olein by enzyme
      activity and separated by reversed-phase HPLC. This method has been optimized and
      the optimum enzyme incubation time and reaction time of the generated oleic acid
      with ADAM were both at 20 min. The method correlated well with the conventional
      method.

PMID- 12474212
TI  - Simultaneous determination of nicotinamide, pyridoxine hydrochloride, thiamine
      mononitrate and riboflavin in multivitamin with minerals tablets by reversed
      phase ion-pair high performance liquid chromatography.
AB  - A reversed-phase ion-pair high performance liquid chromatographic method (HPLC)
      has been developed and validated for the routine analysis of nicotinamide,
      pyridoxine hydrochloride, thiamine mononitrate and riboflavin in multivitamin
      with minerals tablets. HPLC separation of the vitamins was performed on a
      Hypersil C(18) column and detected by ultraviolet absorbance at 280 nm. The use
      of methanol-aqueous 0.5% acetic acid solution (18:82, v/v; containing 2.5 mM
      sodium hexanesulfonate, pH = 2.8) as the mobile phase at a flow-rate of 1.2
      mL/min enables the baseline separation of the four analytes free from
      interferences with isocratic elution at 30 degrees C. The analysis time was 17
      min per injection. The method was linear in the ranges of 5-90, 2.5-90, 5-95 and
      25-450 micro g/mL for thiamine mononitrate, riboflavin, pyridoxine hydrochloride
      and nicotinamide, respectively. The average coefficients of variation of within-
      and between-day assays were 2.2 and 3.6% for thiamine mononitrate, 1.8 and 2.4%
      for riboflavin, 1.3 and 1.7% for pyridoxine hydrochloride and 1.0 and 1.5% for
      nicotinamide, respectively. The average recoveries of thiamine mononitrate,
      riboflavin, pyridoxine hydrochloride and nicotinamide were 97.0, 97.2, 98.9 and
      100.4% for the tablets, respectively. The method has been successfully applied to
      the simultaneous determination of nicotinamide, pyridoxine hydrochloride,
      thiamine mononitrate and riboflavin in multivitamin with minerals tablets.

PMID- 12474213
TI  - Testing for nandrolone metabolites in urine samples of professional athletes and
      sedentary subjects by GC/MS/MS analysis.
AB  - The concentrations of nandrolone metabolites, 19-norandrosterone (19-NA) and 19
      noretiocholanolone (19-NE) were analysed in urine samples of professional
      athletes doing intense physical activity and sedentary subjects to verify if
      there was endogenous production of nandrolone and if there was any link between
      physical effort and the urinary metabolites of the steroid. We collected 18 urine
      samples from professional footballers age range 20-30 years, all from the same
      team, and 18 urine samples from males not doing any physical activity, age range
      20-30 years. Neither group used nandrolone. Qualitative and quantitative analyses
      of urinary nandrolone metabolites were carried out by GC/MS followed by GC/MS/MS
      to confirm positive samples. This technique has been demonstrated to be an
      excellent analytical approach for the determination of anabolic steroids at very
      low detection limits in complex matrices such as urine. In five urine samples
      from professional footballers traces of 19-NA were detected. No trace of 19-NA
      was found in the group of sedentary subjects and no trace of 19-NE was found in
      any urine sample. The absence of nandrolone metabolites in sedentary subjects
      supports the hypothesis that the presence of 19-NA and 19-NE could be linked to
      physical effort even though the origin is not yet clear.

PMID- 12474214
TI  - Detection of inhaled salbutamol in equine urine by ELISA and GC/MS2.
AB  - Salbutamol is a beta-adrenergic agonist that is used in the treatment of asthma
      in humans and chronic obstructive pulmonary disease in horses. Because of its
      stimulating and growth promoting properties, it is prohibited by horse racing
      authorities. Recently a number of adapters (eg Equinehaler) have been designed,
      allowing the use of metered dose inhalers (MDI) approved for human use. However,
      information on detection times of salbutamol after administration of salbutamol
      in therapeutic doses by inhalation is lacking. In this study, 2 mg salbutamol
      (Ventolin) was administered to four standardbred mares via an MDI with an
      Equinehaler and urine was collected during 48 h. Quantification of salbutamol in
      horse urine was done via an overnight beta-agonist ELISA kit. Salbutamol was
      detected between 1 and 48 h post-administration. Relatively large interindividual
      variations in the total amount excreted during the first 12 h were noticed. The
      maximum urinary concentrations varied between 4.6 and 8.1 ng/mL. The total amount
      excreted within the first 12 h varied between 0.2 and 0.7% of the administered
      dose. For confirmatory analysis in doping control, a GC/MS(2) method was
      developed and validated. Analysis was performed on an ion trap instrument after
      solid phase extraction. The limit of detection was 0.25 ng/mL and was lower than
      in previously reported methods in human urine.

PMID- 12474215
TI  - Development, validation and analytical error function of two chromatographic
      methods with fluorimetric detection for the determination of bisoprolol and
      metoprolol in human plasma.
AB  - This work describes two high-performance liquid chromatographic methods for the
      individual determination of bisoprolol and metoprolol in human plasma. Analytical
      methods involve two different liquid-liquid extractions of human plasma, with
      diethyl ether for bisoprolol and with dichloromethane for metoprolol, coupled
      with a similar Nucleosil C(18) reversed-phase HPLC column. Fluorimetric detection
      was used to identify both beta-blockers. Retention times for bisoprolol and
      metoprolol were 8.7 and 3.2 min, respectively. Linear regressions for the
      calibration curves were linear at a concentration range of 6.25-200 ng/mL. Intra-
      and inter-day precision coefficients of variations and accuracy bias were
      acceptable (within 15%) over the entire range for both drugs. Average recovery
      was 89% for metoprolol and 98% for bisoprolol. Once the methods had been
      validated, analytical error functions were established as standard deviation (SD;
      ng/mL) = 2.216 + 3.608 x 10(-4)C(2) (C = theoretical concentration value) and SD
      (ng/mL) = 0.408 + 0.378 x 10(-1)C for bisoprolol and metoprolol, respectively.
      The methods developed and their associated analytical error functions will be
      suitable for pharmacokinetic studies and for determination of plasma
      concentration if posology individualization of these drugs is needed.

PMID- 12474216
TI  - Design and synthesis of a hydrophilic fluorescent derivatization reagent for
      carboxylic acids, 4-N-(4-N-aminoethyl)piperazino-7-nitro-2,1,3-benzoxadiazole
      (NBD-PZ-NH2), and its application to capillary electrophoresis with laser-induced
      fluorescence detection.
AB  - A hydrophilic fluorescent derivatization reagent for fatty acids, 4-N-(4-N
      aminoethyl)piperazino-7-nitro-2,1,3-benzoxadiazole (NBD-PZ-NH(2)), was designed
      and synthesized. NBD-PZ-NH(2) possesses not only a fluorophore and a reacting
      group but also a positive charge group and, thus, was hydrophilic and suitable
      for application to capillary electrophoresis. NBD-PZ-NH(2) reacted with fatty
      acids in the presence of triphenylphosphine (TPP) and 2,2'-dipyridyl disulfide
      (DPDS) at room temperature within 10 min. The derivatives were strongly
      fluoresced and were positively charged at pH below 3. The derivatives of C4-C20
      fatty acids were separated within 10 min in 50% acetonitrile in water containing
      30 mM ammonium acetate and 1.0 M acetic acid by capillary electrophoresis with
      laser-induced fluorescence (CE-LIF) detection. The detection limits attained were
      6.5 nM (signal-to-noise ratio of 3). It is proposed that NBD-PZ-NH(2) is a
      prominent derivatization reagent for fatty acids which is suitable for CE-LIF
      application.

PMID- 12474217
TI  - Screening for 18 diuretics and probenecid in doping analysis by liquid
      chromatography-tandem mass spectrometry.
AB  - A fast and selective liquid chromatography-tandem mass spectrometric (LC/MS/MS)
      method for the screening of 18 diuretics and probenecid in human urine is
      presented. Analyses were performed on a LCQ-Deca instrument equipped with ESI
      interface using scan by scan polarity changing. All diuretics and probenecid were
      separated in less than 20 min after liquid-liquid extraction with ethyl acetate.
      The LOD for all substances was 100 ng/mL or better. The method was applied to
      detect diuretics after the oral administration of several drugs including
      hydrochlorothiazide, bumetanide, spironolactone, furosemide, amiloride,
      triamterene, chlortalidone and epithizide. All diuretics could be detected for
      periods up to 96 h after the intake of therapeutic amounts.

PMID- 12474218
TI  - Rat liver and kidney catechol-O-methyltransferase activity measured by high
      performance liquid chromatography with fluorescence detection.
AB  - We have previously reported a highly sensitive method for the measurement of
      catechol-O-methyltransferase (COMT) activities in rat erythrocytes with
      norepinephrine (NE), an endogenous native substrate, using high-performance
      liquid chromatography (HPLC)-fluorescence or peroxyoxalate chemiluminescence
      reaction detection. Applying this method to COMT activities in rat liver and
      kidney, known to have the highest activities of all organs, the optimum reaction
      conditions were investigated. Under the optimum conditions, soluble (S)-COMT and
      membrane-bound (MB)-COMT activities in rat liver, with NE as a substrate, were
      2.17 +/- 0.33 and 0.16 +/- 0.02 nmol/min/mg protein (n = 5), respectively. In rat
      kidney, S-COMT and MB-COMT activities were 1.81 +/- 0.20 and 0.079 +/- 0.009
      nmol/min/mg protein (n = 5), respectively. Since liver and kidney play important
      roles in inactivating catecholamines, using the proposed method would yield
      critical information to delineate the role of metabolism of catecholamines in rat
      tissues.

PMID- 12474219
TI  - Stages on the way to breast cancer.
AB  - Pathways to breast cancer have been difficult to define using morphology alone.
      Although epithelial hyperplasia of usual type (HUT) is associated with moderately
      elevated breast cancer risk, molecular evidence placing it in a cancer precursor
      pathway is not clear-cut. Recent evidence suggests that small numbers of
      cytokeratin 5/6 positive cells are precursors of separate lineages which acquire
      either cytokeratin 8/18/19 or smooth muscle actin (SMA) and cytokeratin 14 on
      separate pathways to fully differentiated epithelial and myoepithelial phenotypes
      (and may ultimately lose cytokeratin 5/6 expression). Immunohistochemistry shows
      that most HUT have a mixed precursor phenotype resembling normal breast with co
      expression of cytokeratin 5/6, 8/18/19 and SMA, in contrast to atypical ductal
      hyperplasia (ADH) and ductal carcinoma in situ which typically have a 'mature'
      luminal phenotype positive for cytokeratin 8/18/19 but lacking cytokeratin 5/6
      expression. While this supports the idea of a biological discontinuity between
      HUT and ADH/DCIS, caution is called for in the diagnostic use of these reagents
      until greater experience has been accumulated, and other published data do show
      features of HUT intermediate between normal breast lobules and ADH.

PMID- 12474220
TI  - The yeast two-hybrid system for identifying protein-protein interactions.
AB  - The yeast two-hybrid assay is a system for identifying and analysing protein
      protein interactions. Since the original description in 1989, the technique has
      provided insight into many biological pathways. A variety of adaptations to the
      technique have been developed that allow analysis of protein-DNA, protein-RNA, or
      small molecule-protein interactions. Recent developments now allow the use of
      these technologies to perform global analyses of all such interactions that occur
      in cells. The information gained from these approaches is uncovering many aspects
      of the complex networks that underlie normal cellular processes and how they are
      perturbed in disease states.

PMID- 12474221
TI  - Protective role of endothelial nitric oxide synthase.
AB  - Nitric oxide is a versatile molecule, with its actions ranging from haemodynamic
      regulation to anti-proliferative effects on vascular smooth muscle cells. Nitric
      oxide is produced by the nitric oxide synthases, endothelial NOS (eNOS), neural
      NOS (nNOS), and inducible NOS (iNOS). Constitutively expressed eNOS produces low
      concentrations of NO, which is necessary for a good endothelial function and
      integrity. Endothelial derived NO is often seen as a protective agent in a
      variety of diseases. This review will focus on the potential protective role of
      eNOS. We will discuss recent data derived from studies in eNOS knockout mice and
      other experimental models. Furthermore, the role of eNOS in human diseases is
      described and possible therapeutic intervention strategies will be discussed.

PMID- 12474222
TI  - The proliferation marker pKi-67 organizes the nucleolus during the cell cycle
      depending on Ran and cyclin B.
AB  - The proliferation marker pKi-67 ('Ki-67 antigen') is commonly used in clinical
      and research pathology to detect proliferating cells, as it is only expressed
      during cell-cycle progression. Despite the fact that this antigen has been known
      for nearly two decades, there is still no adequate understanding of its function.
      This study has therefore identified proteins that interact with pKi-67, using a
      yeast two-hybrid system. A mammalian two-hybrid system and immunoprecipitation
      studies were used to verify these interactions. Among other cell-cycle regulatory
      proteins, two binding partners associated with the small GTPase Ran were
      identified. In addition, DNA-structural and nucleolus-associated proteins binding
      to pKi-67 were found. Moreover, it was demonstrated that the N-terminal domain of
      pKi-67 is capable of self-binding to its own repeat region encoded by exon 13.
      Since RanBP, a protein involved in the transport of macromolecules over the
      nuclear lamina, was found to be a binding partner, a possible effect of pKi-67 on
      the localization of cell-cycle regulatory proteins was proposed. To test this
      hypothesis, a tetracycline-responsive gene expression system was used to induce
      the pKi-67 fragments previously used for the two-hybrid screens in HeLa cells.
      Subsequent immunostaining revealed the translocation of cyclin B1 from cytoplasm
      to nucleoli in response to this expression. It is suggested that pKi-67 is a Ran
      associated protein with a role in the disintegration and reformation of the
      nucleolus and thereby in entry into and exit from the M-phase.

PMID- 12474223
TI  - Chemokine expression in IBD. Mucosal chemokine expression is unselectively
      increased in both ulcerative colitis and Crohn's disease.
AB  - Mucosal changes in inflammatory bowel disease (IBD) are characterized by
      ulcerative lesions accompanied by prominent cellular infiltrates in the bowel
      wall. Chemokines are chemotactic cytokines that are able to promote leukocyte
      migration to areas of inflammation and are also able to initiate cell activation
      events. They have recently been implicated in the pathophysiology of many disease
      states. The aim of this study was to detail the degree and distribution of
      specific chemokines, interleukin (IL)-8, monocyte chemoattractant protein (MCP)
      1, -2, and -3, and macrophage inflammatory protein (MIP)-1alpha and -1beta, in
      IBD mucosa. Thirty-nine patients were included, ten controls, 20 ulcerative
      colitis (UC), and nine Crohn's disease (CD), with a range of disease activity.
      Colonic mucosal biopsies were collected from UC, CD, and control patients and
      embedded in glycol methacrylate. Two-micrometre-thick sections were cut and
      stained using immunohistochemistry for chemokine protein expression. Sections
      were analysed using a light microscope. Expression of all types of chemokine
      protein was detected in colonic mucosa from both control and IBD patients.
      Patterns of staining between IBD patients and controls differed significantly,
      but CD and UC patients demonstrated similar patterns of staining. Individual
      chemokine expression was found to be significantly up-regulated in IBD when
      patients were compared with the non-diseased group in all areas of the mucosal
      sections. Up-regulated chemokine expression correlated with increasing activity
      of the disease. It is concluded that human colonic chemokine expression is non
      selectively up-regulated in IBD. The results supported the hypothesis that the
      degree of local inflammation and tissue damage in UC and CD is dependent on local
      expression of specific chemokines within IBD tissues.

PMID- 12474224
TI  - Expression of intestine-specific transcription factors, CDX1 and CDX2, in
      intestinal metaplasia and gastric carcinomas.
AB  - Intestinal metaplasia (IM) is part of a stepwise sequence of alterations of the
      gastric mucosa, leading ultimately to gastric cancer, and is strongly associated
      with chronic Helicobacter pylori infection. The molecular mechanisms underlying
      the onset of IM remain elusive. The aim of this study was to assess the putative
      involvement of two intestine-specific transcription factors, CDX1 and CDX2, in
      the pathogenesis of gastric IM and gastric carcinoma. Eighteen foci of IM and 46
      cases of gastric carcinoma were evaluated by immunohistochemistry for CDX1 and
      CDX2 expression. CDX1 was expressed in all foci of IM and in 41% of gastric
      carcinomas; CDX2 was expressed in 17/18 foci of IM and in 54% of gastric
      carcinomas. In gastric carcinomas, a strong association was observed between the
      expression of CDX1 and CDX2, as well as between the intestinal mucin MUC2 and
      CDX1 and CDX2. No association was observed between the expression of CDX1 and
      CDX2 and the histological type of gastric carcinoma. In conclusion, these results
      show that aberrant expression of CDX1 and CDX2 is consistently observed in IM and
      in a subset of gastric carcinomas. The association of CDX1 and CDX2 with
      expression of the intestinal mucin MUC2, both in IM and in gastric carcinoma,
      indirectly implies that CDX1 and CDX2 may be involved in intestinal
      differentiation along the gastric carcinogenesis pathway.

PMID- 12474225
TI  - Uroplakin gene expression in normal human tissues and locally advanced bladder
      cancer.
AB  - The uroplakins are widely regarded as urothelium-specific markers of terminal
      urothelial cytodifferentiation. This study investigated the expression of the
      four uroplakin genes, UPIa, UPIb, UPII and UPIII, in a wide range of normal human
      tissues to determine tissue specificity and in advanced transitional cell
      carcinoma (TCC) to examine gene expression in primary and metastatic disease. In
      the urinary tract, all four uroplakins were expressed by urothelium and UPIII was
      also expressed by prostatic glandular epithelium. UPIa and UPII appeared to be
      urothelium-specific, but UPIb was detected in several non-urothelial tissues,
      including the respiratory tract, where it was associated with squamous metaplasia
      of tracheal and bronchial epithelia. The ten cases of primary TCC and
      corresponding lymph node metastases demonstrated that each uroplakin gene could
      be expressed at the mRNA level. No single uroplakin gene was expressed in all
      primary tumours or metastases, but 80% of the primary tumours and 70% of the
      lymph node metastases expressed at least one uroplakin gene. UPIII mRNA was often
      expressed in the absence of UPIII protein. These results confirm that in human
      tissues the expression of UPIa and UPII genes is highly specific to urothelium
      and suggest that the tight differentiation-restricted expression of uroplakin
      genes in normal urothelium is lost following malignant transformation.

PMID- 12474226
TI  - Frequent genetic alterations in flat urothelial hyperplasias and concomitant
      papillary bladder cancer as detected by CGH, LOH, and FISH analyses.
AB  - Flat urothelial hyperplasia, defined as markedly thickened urothelium without
      cytological atypia, is regarded in the new WHO classification as a urothelial
      lesion without malignant potential. Frequent deletions of chromosome 9 detected
      by fluorescence in situ hybridization (FISH) have been previously reported in
      flat urothelial hyperplasias found in patients with papillary bladder cancer.
      Using comparative genomic hybridization (CGH) and microsatellite analysis, these
      hyperplasias and concomitant papillary tumours of the same patients were screened
      for other genetic alterations to validate and extend the previous findings.
      Eleven flat hyperplasias detected by 5-ALA-induced fluorescence endoscopy and ten
      papillary urothelial carcinomas (pTaG1-G2) from ten patients were investigated.
      After microdissection, the DNA of the lesions was pre-amplified using whole
      genome amplification (I-PEP-PCR). Loss of heterozygosity (LOH) analyses were
      performed with five microsatellite markers at chromosomes 9p, 9q, and 17p. CGH
      was performed using standard protocols. In 6 of 11 hyperplasias and 7 of 10
      papillary tumours, deletions at chromosome 9 were simultaneously shown by FISH,
      LOH, and CGH analyses. There was a good correlation between FISH, LOH, and CGH
      analyses, with identical results in 6 of 10 patients. In addition to deletions at
      chromosome 9, further genetic alterations were detected by CGH in 9 of 10
      investigated hyperplasias, including changes frequently found in invasive
      papillary bladder cancer (loss of chromosomes 2q, 4, 8p, and 11p; gain of
      chromosome 17; and amplification at 11q12q13). There was considerable genetic
      heterogeneity between hyperplasias and papillary tumours, but a clonal
      relationship was suggested by LOH and/or CGH analyses in 5 of 10 cases. These
      data support the hypothesis that flat urothelial hyperplasias can display many
      genetic alterations commonly found in bladder cancer and could therefore be an
      early neoplastic lesion in the multistep development of invasive urothelial
      carcinoma.

PMID- 12474227
TI  - Cribriform-morular variant of papillary thyroid carcinoma: a pathological and
      molecular genetic study with evidence of frequent somatic mutations in exon 3 of
      the beta-catenin gene.
AB  - The cribriform-morular variant (C-MV), an unusual and peculiar subtype of
      papillary thyroid carcinoma (PTC), has been observed frequently in familial
      adenomatous polyposis (FAP)-associated thyroid carcinoma and also in sporadic
      thyroid carcinoma. In this paper, five young women with the C-MV of PTC, aged 22
      34 years at cancer diagnosis, are reported; two of them had attenuated FAP.
      Grossly, one FAP-associated tumour and one sporadic tumour were multicentric and
      the others were solitary. Histologically, the tumours were encapsulated and
      exhibited a combination of cribriform, follicular, trabecular, solid, and
      papillary patterns of growth, with morular areas. Immunohistochemically, the
      tumour cells showed cytoplasmic expression of thyroglobulin, neuron-specific
      enolase, epithelial membrane antigen, high- and low-molecular-weight
      cytokeratins, vimentin, and bcl-2 protein; nuclear expression of oestrogen and
      progesterone receptors, and retinoblastoma protein; and cytoplasmic and nuclear
      accumulation of beta-catenin. Germline mutations of the adenomatous polyposis
      coli (APC) gene were investigated using the protein truncation test in four
      subjects, including two FAP individuals. Germline APC mutation was identified in
      only one FAP patient with the multicentric C-MV of PTC, who had a thymidine
      deletion at codon 512, resulting in a frameshift leading to a premature stop
      codon. No loss of heterozygosity of loci close to the APC gene was detected in
      tumour tissues from these four patients. Somatic mutation analysis of exon 3 of
      the beta-catenin gene (CTNNB1) revealed alterations in seven tumours from all
      five individuals: one at a serine residue (codon 29), three at amino acids
      adjacent to serine or threonine residues (codons 22, 39, and 44), and three at
      other amino acids (codons 49, 54, and 56). Moreover, each of two different
      tumours examined from two patients with the multicentric C-MV of PTC, had
      different somatic mutations of the CTNNB1 gene. Taken together, these data
      suggest that accumulation of mutant beta-catenin contributes to the development
      of the C-MV of PTC.

PMID- 12474228
TI  - Nuclear accumulation of beta-catenin protein in Wilms' tumours.
AB  - The wnt-signalling pathway plays an important role during both normal kidney
      development and Wilms' tumourigenesis. Activation of this pathway involves
      stabilization, intracellular accumulation, and nuclear translocation of the beta
      catenin protein and may be caused by specific mutations in the beta-catenin gene
      itself. Such mutations have been found in about 15% of Wilms' tumours. This study
      has analysed the intracellular levels and subcellular distribution of beta
      catenin protein in 36 primary Wilms' tumour specimens and has correlated these
      results with the mutational status of the beta-catenin gene. Immunohistochemistry
      detected faint cytoplasmic and strong membranous expression of beta-catenin
      protein in the epithelial compartment of all tumours examined. In contrast,
      nuclear immunoreactivity for beta-catenin was detected in 9 of 9 Wilms' tumours
      containing a mutation of the beta-catenin gene and in 15 of 27 Wilms' tumours
      without detectable beta-catenin mutation. Nuclear positivity, in each case, was
      found to be very strong, but was usually present only in a fraction of cells
      ranging from 5% to 10%. Among the different histological subcompartments,
      blastemal and mesenchymal cell nuclei preferentially stained positive, whereas
      cells of epithelial differentiation displayed nuclear localization of beta
      catenin protein in only a single case. Furthermore, nuclear positive cells were
      found in Wilms' tumours of all stages and in tumours of both favourable and
      unfavourable histology. These data support the idea that activation of the wnt
      signalling pathway is a key oncogenic step in Wilms' tumourigenesis and that it
      probably involves transcriptional activation of critical target genes, carried
      out by beta-catenin protein in the nucleus. The fact that nuclear
      immunoreactivity specific for beta-catenin was detected in a significant number
      of Wilms' tumours in the absence of beta-catenin mutations suggests that genetic
      defects affecting other members of the wnt-signalling pathway may contribute to
      the development of Wilms' tumours in those cases.

PMID- 12474229
TI  - Killer cell immunoglobulin-like receptor expression delineates in situ Sezary
      syndrome lymphocytes.
AB  - p140/KIR3DL2 has been identified in malignant cell lines isolated from the skin
      and blood of patients with transformed mycosis fungoides (MF) and Sezary's
      syndrome (SS). For the first time, the expression of a cell membrane structure
      appeared to be able to distinguish CD4+ tumour lymphocytes from reactive
      lymphocytes in these small cutaneous T-cell lymphomas (CTCLs). This study has
      examined the in vivo expression of this receptor in various CTCL subtypes, which
      constituted a heterogeneous group. Tumour cells diffusely expressed KIR in SS, in
      lymphomatoid papulosis (LyP) and in CD4+CD30+ as well as CD8+ large cell
      pleomorphic CTCL. In contrast, the infiltrating lymphocytes did not express KIR
      in MF at the patch/plaque stage or in CD4+CD30- large cell pleomorphic CTCL,
      except for scattered small cells. One quarter of the transformed MF tested
      exhibited KIR+ tumour cells, suggesting heterogeneity in this subtype. KIR
      expression was also examined in inflammatory lesions characterized by a dense
      infiltrate of T cells, such as lupus erythematosus and lichen planus. Only
      scattered CD8+ cells in lichen planus expressed a significant amount of KIR3DL2.
      Taken together, these results show for the first time that KIR molecules are
      expressed in distinct subtypes of malignant CTCL. It is also shown for the first
      time that SS and MF, which are frequent variants of CTCL with similar
      histological features, can be distinguished by their KIR3DL2 expression analysis.
      The identification of this KIR also differentiates between lupus erythematosus
      and lichen planus, which are both diseases with dense benign lymphocytic
      infiltrates.

PMID- 12474230
TI  - Expression of STAT3 and its phosphorylated forms in mantle cell lymphoma cell
      lines and tumours.
AB  - The pathogenesis of mantle cell lymphoma (MCL) is incompletely understood,
      although cyclin D1 overexpression leading to deregulated cell proliferation is
      probably important. Recent data suggest that interleukin (IL)-10 can increase the
      proliferative activity of MCL cells. STAT3 (signal transducer and activator of
      transcription 3) is the signal transducer of IL-10, and STAT3 is activated by
      phosphorylation. The hypothesis of this study is that STAT3 is activated in MCL.
      The expression of the two phosphorylated (i.e. active) forms of STAT3, pSTAT3-tyr
      (phosphorylated at the tyrosine(705) residue) and pSTAT3-ser (phosphorylated at
      the serine(727) residue), was assessed in four MCL cell lines and 12 MCL tumours
      using western blots and/or immunofluorescence staining techniques. All MCL cell
      lines expressed STAT3, but only one had detectable pSTAT3-tyr and none had pSTAT3
      ser. Addition of IL-10 rapidly resulted in expression of pSTAT3-tyr but not
      pSTAT3-ser. All eight cases of frozen MCL tumours examined had detectable pSTAT3
      tyr and pSTAT3-ser. Immunofluorescence studies using four formalin-fixed,
      paraffin wax-embedded MCL tumours demonstrated cytoplasmic localization of STAT3,
      as opposed to the nuclear localization of the pSTAT3 species. In conclusion,
      these findings provide evidence that STAT3 is constitutively activated in MCL,
      supporting the concept that STAT3 signalling may be important in the pathogenesis
      of these tumours.

PMID- 12474231
TI  - Expression of Mcl-1 in mantle cell lymphoma is associated with high-grade
      morphology, a high proliferative state, and p53 overexpression.
AB  - Mantle cell lymphoma (MCL) is a distinct type of B-cell non-Hodgkin's lymphoma
      characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. Defects in
      apoptosis may contribute to pathogenesis. This study evaluated the expression of
      the anti-apoptotic protein Mcl-1 in two MCL cell lines and five frozen MCL
      tumours (four small-cell, one blastoid/large-cell) using western blot analysis.
      Mcl-1 expression was also assessed in 36 formalin-fixed, paraffin wax-embedded
      MCL tumours (24 small-cell, 12 blastoid/large-cell) by immunohistochemistry.
      Western blot analysis revealed the expected 37 kD protein product in both MCL
      cell lines and in five frozen tumours, with the blastoid case having the highest
      expression level. Using a cut-off of >10% immunolabelled cells for Mcl-1, it was
      found that 12 of 36 MCL tumours were positive. Mcl-1-positive tumours had a
      higher frequency of blastoid/large-cell morphology (8/12 versus 4/24, p = 0.009),
      p53 overexpression (3/10 versus 1/23, p = 0.04), and higher Ki67 immuno-labelling
      (p = 0.002). It is concluded that expression of Mcl-1 in MCL is heterogeneous. A
      relatively high level of Mcl-1 expression correlates with high-grade morphology,
      a high proliferative state, and p53 overexpression.

PMID- 12474232
TI  - Differential expression of CCL19 by DC-Lamp+ mature dendritic cells in human
      lymph node versus chronically inflamed skin.
AB  - De novo formation of lymphoid tissue is one of the characteristic features of
      chronic inflammation. The formation of T cell-mature dendritic cell (DC) clusters
      has been previously demonstrated in chronically inflamed skin infected with
      Candida albicans. A functional similarity was also found between chronic
      inflammation and the T-cell zone of lymph nodes (LNs), since a substantial
      fraction of phenotypically mature DCs in both tissues expressed CCL22 (macrophage
      derived chemokine; MDC) and were closely surrounded by memory-type T cells
      expressing its receptor, CCR4. To analyse the nature of T cell-mature DC
      interactions further in chronically inflamed skin and LNs, the present study
      focuses on another chemokine system, namely CCL19 (EBI1 ligand chemokine; ELC),
      CCL21 (secondary lymphoid tissue chemokine; SLC) and their shared receptor, CCR7.
      RT-PCR analysis revealed expression of CCL19, CCL21, and CCR7 at high levels in
      LNs and at low levels in inflamed skin. Using immunohistochemistry, the majority
      of DC-Lamp(+) mature DCs in the T-cell area of LNs expressed CCL19 and were
      surrounded by CCR7(+) naive-type lymphocytes, while CCL21 was expressed in
      reticular stromal cells and vascular endothelial cells. Very few mature DCs in
      LNs were found to express CCR7. In contrast, the majority of DC-Lamp(+) mature
      DCs in inflamed skin were totally negative for CCL19 and were surrounded by CCR7(
      ) memory-type T cells. Furthermore, CCL21 expression in the inflamed skin was
      detected in dermal lymphatic endothelial cells and rare CCR7(+) mature DCs were
      mostly seen within the lymphatic vessels. In normal skin, on the other hand, no
      cells immunoreactive for CCL19, CCL21, or CCR7 were found. The present study thus
      reveals a striking difference in the function of mature DCs between LNs and
      chronically inflamed skin.

PMID- 12474233
TI  - Psoriatic lesional skin exhibits an aberrant expression pattern of interferon
      regulatory factor-2 (IRF-2).
AB  - Psoriasis is a T-cell-mediated inflammatory skin disease. A Th1 cytokine profile
      with increased levels of interferon-gamma (IFN-gamma) is predominant in skin and
      peripheral blood mononuclear cells (PBMCs) from psoriasis patients. Furthermore,
      psoriatic keratinocytes exhibit an aberrant sensitivity and response to IFN
      gamma. The transcriptional activator interferon regulatory factor-1 (IRF-1) plays
      a crucial role in the activation of IFN-gamma-induced gene expression. Recently
      it was shown that mice deficient in IRF-2, a transcriptional repressor of IFN
      signalling and thereby acting as an IRF-1 antagonist, display psoriasis-like skin
      abnormalities. It was therefore hypothesized that a dysbalance between IRF-1 and
      IRF-2, the activator and repressor of IFN responses, respectively, contributes to
      the altered IFN-gamma signalling observed in patients with psoriasis. In the
      epidermis of patients with psoriasis and healthy controls, similar IRF-1 and IRF
      2 mRNA expression levels were observed. Furthermore, it was not possible to
      detect any differences in IRF-1 and IRF-2 protein levels in nuclear extracts from
      the epidermis of controls and psoriasis patients by electrophoretic mobility
      shift assay and western blot analysis. Using double immunofluorescence labelling,
      it was observed that in normal skin IRF-1 was expressed in keratinocytes
      throughout the epidermis, whereas IRF-2 was restricted to the basal cell layer.
      In psoriatic skin, IRF-1 expression was comparable to normal skin, whereas IRF-2
      was expressed in both basal and suprabasal cell layers. This altered IRF-2
      expression in suprabasal cell layers may therefore result in a dysbalance between
      the activator and repressor of IFN responses in these cell layers, putatively
      contributing to aberrant responses to IFN-gamma and eventually to the psoriatic
      skin phenotype.

PMID- 12474234
TI  - Expression of lymphotoxin-beta (LT-beta) in chronic inflammatory conditions.
AB  - Functional studies in gene-knockout and transgenic mice systems have shown that
      lymphotoxin-alpha and lymphotoxin-beta (LT-alpha and LT-beta) are of fundamental
      importance in peripheral lymphoid organ development, but it remains unclear what
      role these cytokines have to play in the adult immune response and in the
      pathogenesis of disease. In this study, a polyclonal anti-serum to human LT-beta
      was used to investigate the distribution of LT-beta by immunohistochemistry in
      normal and diseased tissues. In the gut, lymph nodes, spleen, and tonsil, there
      was some LT-beta present on a variety of lymphoid cell types. In contrast, strong
      staining for LT-beta was observed on plasma cells and a subpopulation of CD4+ T
      cells in tissues affected by chronic inflammatory disease or infection, for
      example in inflammatory bowel disease, and in lymph nodes obtained from patients
      with sarcoidosis and tuberculosis. In tuberculous and sarcoid lymph nodes, LT
      beta expression also occurred on some but not all epithelioid histiocytes within
      granulomas and on multi-nucleated giant cells. These findings support a role for
      LT-beta in human disease and suggest that it might represent a therapeutic target
      in a variety of common infective or inflammatory disorders.

PMID- 12474235
TI  - Type 2 nitric oxide synthase and protein nitration in chronic lung infection.
AB  - Inflammation in the lung can lead to increased expression of inducible nitric
      oxide synthase (iNOS) and enhanced NO production. It has been postulated that the
      resultant highly reactive NO metabolites may have an important role in host
      defence, although they might also contribute to tissue damage. However, in a
      number of inflammatory lung diseases, including bronchiectasis, iNOS expression
      is increased but no elevation of airway NO can be detected. A potential
      explanation for this finding is that NO is rapidly scavenged by reaction with
      superoxide radicals, forming peroxynitrite, which is preferentially metabolized
      via nitration and nitrosation reactions. To test this hypothesis, anaesthetized,
      specific pathogen-free rats were inoculated with Pseudomonas aeruginosa
      incorporated into agar beads (chronically infected group) or sterile agar beads
      (control group). Ten to 15 days later, the lungs were isolated and fixed.
      Pseudomonas organisms were isolated from the lungs of the chronically infected
      group. These lungs showed extensive inflammatory cell infiltration and tissue
      damage, which were not observed in control lungs. Expression of iNOS was
      increased in the chronically infected group when compared with the control group.
      However, the mean number of cells staining for nitrotyrosine in the chronically
      infected group was not significantly different from that in the controls, nor was
      there an excess of nitrotyrosine, nitrate, nitrite or nitrosothiol concentrations
      in the infected lungs. Thus, no evidence was found of increased NO metabolites in
      chronically infected lungs, including products of the peroxynitrite pathway.
      These findings suggest that chronic infection does not cause increased iNOS
      activity in the lung, despite increased expression of iNOS.

PMID- 12474236
TI  - Re: Skliris et al. Evaluation of seven oestrogen receptor beta antibodies for
      immunohistochemistry, western blotting, and flow cytometry in human breast
      tissue. J Pathol 2002; 196: 155-162.

PMID- 12474238
TI  - Re: Cook et al. Identification of histological features associated with
      metastatic potential in thin (<1.0 mm) cutaneous melanoma with metastases. A
      study on behalf of the EORTC Melanoma Group. J Pathol 2002; 197: 188-193.

PMID- 12474240
TI  - The release of gentamicin from acrylic bone cements in a simulated prosthesis
      related interfacial gap.
AB  - Gentamicin is added to polymethylmethacrylate bone cements in orthopedics as a
      measure against infection in total joint arthroplasties. Numerous studies have
      been published on gentamicin release from bone cements, but none have been able
      to estimate the local concentrations in the prosthesis-related interfacial gap,
      present after implantation. The aim of this study was to develop a method
      allowing determination of antibiotic release in such a gap. Two-hundred
      micrometer-wide gaps with a volume of 6 microl and a surface area of 0.6 cm2 were
      created by inserting stainless-steel strips in gentamicin-loaded bone cement
      plugs prior to polymerization. After hardening, the gap surface was exposed to 6
      microl or 10 ml of phosphate-buffered saline. Within 2 h, gentamicin
      concentrations in the gaps reached around 4000 microg/ml for 4 different CMW and
      Palamed cements and 2500 microg/ml for Palacos R. Concentrations measured in the
      larger volume were several hundred times lower than in the gaps. This simulated
      prosthesis-related interfacial gap model offers new insights in the clinical
      efficacy of antibiotic-loaded bone cements. It is demonstrated that
      concentrations up to 1000-fold the antibiotic resistance levels for most
      bacterial strains causing implant infection can be achieved in a realistic in
      vitro model.

PMID- 12474241
TI  - Analysis of a retrieved Isola spinal system fractured in service.
AB  - A 1/4-in.diameter two-column Isola spinal system implanted in a 13-year-old girl
      suffering from cerebral palsy and a severe neuromuscular scoliosis of 120
      degrees, was replaced 22 months after primary implantation. The system was
      removed due to fracture of the lower left (concave) bar, between its two cross
      connectors (i.e., the distal bypass connector and a transverse cross link), as a
      result of a postoperative infection and a subsequently developed pseudarthrosis.
      The retrieved implants were analyzed with the use of a multitechnique
      characterization procedure involving macroscopic and microscopic examination,
      micro-multiple internal reflectance FTIR spectroscopy, X-ray fluorescence (XRF)
      spectrometry, roughness measurement, and mechanical testing of the constituent
      material and components. Findings suggest that the spinal system failed due to in
      vivo loosening of a two-set screw tandem connector and subsequent overloading of
      the contralateral bar.

PMID- 12474242
TI  - Biocompatibility investigation and urea removal from blood by urease-immobilized
      HEMA incorporated poly(ethyleneglycol dimethacrylate) microbeads.
AB  - The biocompatibility of modified and urease-immobilized poly(ethyleneglycol
      dimethacrylate/2-hydroxyethylmetacrylate) [poly(EGDMA/HEMA)] microbeads was
      tested through blood compatibility tests. Twelve percent HEMA incorporated
      nonporous particles of 105-125 microm were used in the research. Hydroxyl groups
      on microbeads were chemically modified by following a three-step procedure that
      is composed of activation, spacer-arm incorporation (hexamethylene diamine) and,
      finally, glutaraldehyde bounding. Enzyme urease was immobilized on microbead
      surfaces, and adsorption of blood proteins in serum and plasma, blood coagulation
      time, and leukocyte and platelet adhesion were tested. Incubation of 1.5 cc of
      biological fluid with 100 mg of urease-immobilized poly(EGDMA/HEMA) microbeads at
      room temperature shows that protein adsorption on surfaces occurs, but protein
      content after treatment was in the range of healthy people. Adsorbed albumin and
      total globulin amounts per gram of microbeads is much greater than fibrinogen.
      Immobilization of urease reduced the protein adsorption and blood coagulation
      times compared with those of modified microbeads. Prothrombin time (PT) was not
      altered much, whereas poly(EGDMA/HEMA) microbeads induced a significant increase
      of activated partial thromboplastin time (APTT). The platelet and leukocyte
      adhesion slightly increased with the modification of poly(EGDMA/HEMA) and
      decreased with the introduction of urease. When blood samples were treated with
      urease-immobilized microbeads, BUN values of patients were lowered to almost
      acceptable amounts.

PMID- 12474243
TI  - Enhancement of bone growth in titanium fiber mesh by surface modification with
      hydrogen peroxide solution containing tantalum chloride.
AB  - A tight fixation between bone and implant materials is of great importance for a
      successful outcome of procedures such as total knee arthroplasty (TKA) and total
      hip arthroplasty (THA). Surface modification of titanium metal and titanium alloy
      is one of the attractive methods to improve the biological affinity of orthopedic
      prostheses. Recent studies reported that titanium substrates were provided with
      bone-bonding ability, that is, osteoconductivity, through a chemical treatment
      with hydrogen peroxide solution containing tantalum chloride. The present study
      investigated the histological and mechanical effects of such treatment of the
      surface of titanium fiber mesh. Titanium alloy rods of 7.6 x 7.6 x 20 mm that had
      a titanium fiber mesh of 250 microm were implanted bilaterally into the distal
      aspect of the femur of adult beagle dogs. At 3, 5, and 8 weeks after
      implantation, the rods were removed to examine their bonding strength and
      histological compatibility with bone. Bonding strength was evaluated by the pull
      out test. The bonding strength of the treated specimen with bone increased with
      time, and was faster than that of untreated specimens. At 8 weeks postoperative,
      the bonding strength of both the treated and untreated specimens became almost
      equal. The amount of newly formed bone on and in the titanium fiber mesh was
      significantly increased by the chemical treatment (p<0.05). The rate of bone
      formation in the fiber mesh was accelerated after chemical treatment. These
      results indicated that the surface treatment enhanced bone formation in the
      initial stage thank to the osteoconductive property of the titanium fiber mesh
      conferred by the chemical treatment so that faster bonding strength was achieved.
      Surface treatment providing titanium mesh with osteoconductivity has the
      advantages of the fast healing and tight bonding for prostheses in TKA and THA.

PMID- 12474244
TI  - Comparative study of bone cements prepared with either HA or alpha-TCP and
      functionalized methacrylates.
AB  - The properties of bone cements prepared with both hydroxyapatite (HA) and alpha
      tricalcium phosphate (alpha-TCP) and methacrylates containing acidic or basic
      groups are the main interest of this article. The presence of methacrylic acid or
      diethyl amino ethyl methacrylate as comonomers in the bone cement and both
      ceramic types as filler were found not to affect the amount of residual monomer,
      which was generally less than 4.5 wt%. In contrast, setting times, maximum
      temperature, and glass transition temperature were found to be composition
      dependent. For samples with acidic comonomer, a faster setting time, a higher
      maximum temperature, and higher glass transition temperatures were observed
      compared to those with the basic comonomer. The presence of the fillers slightly
      increased the setting time but did not affect the other parameters. The
      mechanical properties of the filled bone cements depended mainly on composition
      and type of testing. Both HA or alpha-TCP filled systems fulfilled the minimum
      compressive strength required for bone cement application, although a
      significantly lower value was observed for the alkaline comonomer systems. The
      minimum bending strength was not satisfied by any of these formulations. The
      tensile and shear strength of these composites ranged from 20 to 37.9 and from 18
      to 27 MPa, respectively. In all cases it was higher for bone cements containing
      methacrylic acid. The results of this study suggest that the properties of dry
      unfilled bone cements prepared with MAA are comparable to CMW 3 in mechanical
      terms but inferior in their setting properties.

PMID- 12474245
TI  - Shear bond strength between titanium alloys and composite resin: sandblasting
      versus fluoride-gel treatment.
AB  - The aim of this study was to investigate the effect of fluoride gel treatment on
      the bond strength between titanium alloys and composite resin, and the effect of
      NaF solution on the bond strength of titanium alloys. Five titanium alloys and
      one Co-Cr-Mo alloy were tested. Surface of the alloys were treated with three
      different methods; SiC polishing paper (No. 2000), sandblasting (50-microm
      Al2O3), and commercially available acidulated phosphate fluoride gel (F-=1.23%,
      pH 3.0). After treatment, surfaces of alloy were analyzed by SEM/EDXA. A
      cylindrical gelatin capsule was filled with a light-curable composite resin. The
      composite resin capsule was placed on the alloy surface after the application of
      bonding agent, and the composite resin was light cured for 30 s in four different
      directions. Shear bond strength was measured with the use of an Instron. Fluoride
      gel did not affect the surface properties of Co-Cr-Mo alloy and Ni-Ti alloy, but
      other titanium alloys were strongly affected. Alloys treated with the fluoride
      gel showed similar bond strengths to the alloys treated with sandblasting. Shear
      bond strength did not show a significant difference (p<0.05) regardless of
      treatment time (5, 10, and 20 min) of fluoride gel. After the ultrasonic cleaning
      subsequent to the fluoride-gel treatment, residues of fluoride ion or any other
      titanium-fluoride complexes were not detected. NaF solution did not reduce the
      shear bond strength of titanium alloys. To enhance the bond strength of composite
      resin to titanium alloys, fluoride-gel treatment may be used as an alternative
      technique to the sandblasting treatment.

PMID- 12474246
TI  - A radiopaque polymeric matrix for acrylic bone cements.
AB  - As part of the search for an alternative to inorganic radiopaque agents, this
      work studies the possibility of modifying bone cement formulations by
      incorporating a radiopaque monomer, that is, 4-iodophenol methacrylate (IPMA), in
      the liquid phase. The monomer was synthesized in the laboratory, and cements were
      prepared by the standard method. The influence on the different cement
      characteristics of various monomer concentrations was studied. It was seen that
      the setting time decreased as the percentage of monomer increased. The
      radiopacity attained in the 15 vol.% IPMA formulations was about the same as that
      for a cement containing 10 wt.% barium sulphate. Dynamic and static mechanical
      properties were measured. The materials did not show significant differences in
      the glass transition temperature. However, static mechanical properties showed
      enhanced compressive strength, tensile strength, and elastic modulus with respect
      to conventional cements formulated with barium sulphate. Histological studies
      showed a good response of muscular tissue to implanted specimens.

PMID- 12474247
TI  - Substrate and product inhibition of hydrogen production by the extreme
      thermophile, Caldicellulosiruptor saccharolyticus.
AB  - Substrate and product inhibition of hydrogen production during sucrose
      fermentation by the extremely thermophilic bacterium Caldicellulosiruptor
      saccharolyticus was studied. The inhibition kinetics were analyzed with a
      noncompetitive, nonlinear inhibition model. Hydrogen was the most severe
      inhibitor when allowed to accumulate in the culture. Concentrations of 5-10 mM
      H(2) in the gas phase (identical with partial hydrogen pressure (pH(2)) of (1-2)
      x 10(4) Pa) initiated a metabolic shift to lactate formation. The extent of
      inhibition by hydrogen was dependent on the density of the culture. The highest
      tolerance for hydrogen was found at low volumetric hydrogen production rates, as
      occurred in cultures with low cell densities. Under those conditions the critical
      hydrogen concentration in the gas phase was 27.7 mM H(2) (identical with pH(2) of
      5.6 x 10(4) Pa); above this value hydrogen production ceased completely. With an
      efficient removal of hydrogen sucrose fermentation was mainly inhibited by sodium
      acetate. The critical concentrations of sucrose and acetate, at which growth and
      hydrogen production was completely inhibited (at neutral pH and 70 degrees C),
      were 292 and 365 mM, respectively. Inorganic salts, such as sodium chloride,
      mimicked the effect of sodium acetate, implying that ionic strength was
      responsible for inhibition. Undissociated acetate did not contribute to
      inhibition of cultures at neutral or slightly acidic pH. Exposure of
      exponentially growing cultures to concentrations of sodium acetate or sodium
      chloride higher than ca. 175 mM caused cell lysis, probably due to activation of
      autolysins.

PMID- 12474248
TI  - Overexpression of a heterologous protein, haloalkane dehalogenase, in a poly-beta
      hydroxybutyrate-deficient strain of the facultative methylotroph Methylobacterium
      extorquens AM1.
AB  - Using an expression vector containing p(mxaF'), a strong native promoter,
      expression of a model heterologous protein, haloalkane dehalogenase, from
      Xanthobacter autotrophicus GJ10 was achieved in the methylotrophic bacterium,
      Methylobacterium extorquens AM1. Although expression using the wild-type strain
      was <5% of total cell protein, expression at a level of 10% of the total cell
      protein was achieved in a mutant unable to synthesize poly-beta-hydroxybutyrate
      granules. Two other tested heterologous proteins, catechol dioxygenase and green
      fluorescent protein, were expressed at moderate levels in both wild-type and the
      PHB-negative strain. These results suggest that the M. extorquens PHB-negative
      strain is a possible platform for overexpression of heterologous proteins with
      labeled or unlabeled methanol as a starting material.

PMID- 12474249
TI  - Optimization of a feed medium for fed-batch culture of insect cells using a
      genetic algorithm.
AB  - Insect cells have been cultured for over 30 years, but their application is still
      hampered by low cell densities in batch fermentations and expensive culture
      media. With respect to the culture method, the fed-batch culture mode is often
      found to give the best yields. However, optimization of the feed composition is
      usually a laborious task. In this report, the successful use of genetic
      algorithms (GAs) to optimize the growth of insect cells is described. A feed was
      developed from 11 different medium components, each used at a wide range of
      concentrations. The feed was optimized within four sets of 20 experiments. The
      optimized feed was tested in bioreactors and the addition scheme was further
      improved. The viable-cell density of HzAm1 (Helicoverpa zea) insect cells
      improved 550% to 19.5 x 10(6) cells/mL compared to a control fermentation in an
      optimized commercial medium. No accumulation of waste products was found, and
      none of the amino acids was depleted. Glucose was depleted, which suggests that
      even further improvement is possible. We show that GAs are a successful method to
      optimize a complex fermentation in a relatively short time frame and without the
      need of detailed information concerning the cellular physiology or metabolism.

PMID- 12474250
TI  - Bcl-xL expression interferes with the effects of L-glutamine supplementation on
      hybridoma cultures.
AB  - While feeding protocols and ectopic expression of anti-apoptotic genes have been
      used to improve the viability of hybridoma cell lines, the effect of the
      expression levels of survival genes on the behavior of hybridomas following
      nutrient supplementation is unknown. In this study, we compared the behavior of
      the Sp2/0-Ag14 hybridoma (Bcl-xL(low)) and the P3x63-Ag8.653 myeloma (Bcl
      xL(high)) following culture supplementation with the amino acid L-glutamine (L
      Gln). Our data revealed that L-Gln addition substantially increased Sp2/0-Ag14
      cell viability and total cell density, concomitant with a decrease in the rate of
      cell death. This effect was not seen when other amino acids or D-glucose (D-Glc)
      replaced L-Gln. The improvement in the culture behavior of Sp2/0-Ag14 cells was
      attributed to a reduction in the rate of accumulation of apoptotic cells. On the
      other hand, L-Gln supplementation had only a limited effect on the growth of the
      P3x63-Ag8.653 cells. Interestingly, Sp2/0-Ag14 cells over-expressing Bcl-xL
      showed a culture behavior upon L-Gln complementation that was similar to the
      P3x63-Ag8.653 myeloma. These results suggest that the anti-apoptotic gene
      expression profile of hybridoma cells can markedly impact on the beneficial
      effects afforded by nutrient supplementation.

PMID- 12474251
TI  - Effects of methanol concentration on expression levels of recombinant protein in
      fed-batch cultures of Pichia methanolica.
AB  - The methylotrophic yeast Pichia methanolica can be used to express recombinant
      genes at high levels under the control of the methanol-inducible alcohol oxidase
      (AUG1) promoter. Methanol concentrations during the induction phase directly
      affect cellular growth and protein yield. Various methanol concentrations
      controlled by an on-line monitoring and control system were investigated in mixed
      glucose/methanol fed-batch cultures of P. methanolica expressing the human
      transferrin N-lobe protein. The PMAD18 P. methanolica strain utilized is a knock
      out for the chromosomal AUG1 gene locus, resulting in a slow methanol utilization
      phenotype. Maximum growth of 100 g of dry cell weight per liter of culture was
      observed in cultures grown at 1.0% (v/v) methanol concentration. Maximum
      recombinant gene expression was observed for cultures controlled at 0.7% (v/v)
      methanol concentration, resulting in maximum volumetric production of 450 mg of
      transferrin per liter after 72 h of elapsed fermentation time.

PMID- 12474252
TI  - Preparation of a colored conductive paint electrode for electrochemical
      inactivation of bacteria.
AB  - In this study we describe the preparation of a colored conductive paint electrode
      containing In(2)O(3), SnO(2), or TiO(2) for the electrochemical inactivation of
      marine bacteria. When each colored conductive paint electrode was immersed in
      seawater containing 10(6) cells/mL for 90 min, marine microbe attachment to the
      TiO(2)/SnO(2)/Sb electrode surface was minimal. Preparation of electrodes coated
      with 40% particles is shown to be more cost-effective, and because of their more
      translucent coatings they can be painted over with bright colors. When a
      potential of 1.0 V was applied for 30 min to the colored conductive paint
      electrode (40 wt% TiO(2)/SnO(2)/Sb) in sterile seawater, the survival ratio
      decreased to 55%. When 1.5 V vs. saturated calomel electrode (SCE) was applied,
      all attached cells were inactivated. Chlorine was not detected below an applied
      potential of 1.5 V. A change in pH was not observed in the range of 0 to 1.5 V.
      This method might be effective for preventing bacterial cell accumulation and the
      formation of biofilms.

PMID- 12474253
TI  - Dilution of solar radiation through "culture" lamination in photobioreactor rows
      facing south-north: a way to improve the efficiency of light utilization by
      cyanobacteria (Arthrospira platensis).
AB  - Efficient utilization of solar radiation for the photoautotrophic production of
      cyanobacterium biomass was achieved, using small pipes (ID = 0.01 m) arranged in
      rows in two photobioreactors facing south-north. A high Arthrospira yield of 47.7
      g m(-2) (installation area) d(-1) was attained under outdoor conditions in a
      tubular undulating row photobioreactor (TURP-10r). During the summer, under a
      semicontinuous culture regime, the optimal biomass concentration (OBC) in TURP-5r
      was 6.0 g L(-1): it was 5.0 g L(-1) in TURP-10r. These OBCs made it possible to
      produce a biomass output rate of 2.7 +/- 0.2 g L(-1) d(-1) in the former and 2.1
      +/- 0.1 g L(-1) d(-1) in the latter. When Arthrospira was grown at a preset
      dilution rate (0.3 d(-1)), sunrise cell density (SrCD) variations were not
      proportional to the drop of solar radiation. The SrCD was comparatively high at
      high solar radiation and decreased abruptly with decreasing solar radiation.
      There was a tendency to stabilize at low solar radiation. In both
      photobioreactors, the chlorophyll content of the Arthrospira biomass (% of the
      dry weight) was higher at sunrise than at sunset. A comparison of the chlorophyll
      biomass content in the TURPs showed no significant differences. Night biomass
      losses were very high (> 30% of the daylight productivity) when the culture
      temperature was kept constant at 31 +/- 1.0 degrees C: these losses fell to < 20%
      of the daylight productivity, when the night temperature of the cultures
      decreased according to the environmental temperature. Dilution of solar radiation
      was carried out using two quasi-laminated bioreactors. The rows of S-N facing
      bioreactors showed a very high growth yield in TURP-10r [about 2.1g (d.w.) MJ(
      1)]. In TURP-10r, the high photic ratio (R(f) = 6), the high surface-to-volume
      ratio (S(ill)/V = 400 m(-1)) and the S-N facing of the rows (better than an E-W
      orientation) allowed for good results.

PMID- 12474254
TI  - Physicochemical characterization and antimicrobial properties of rhamnolipids
      produced by Pseudomonas aeruginosa 47T2 NCBIM 40044.
AB  - Pseudomonas aeruginosa 47T2, grown in submerged culture with waste frying oil as
      a carbon source, produced a mixture of rhamnolipids with surface activity. Up to
      11 rhamnolipid homologs (Rha-Rha-C(8)-C(10); Rha-C(10)-C(8)/Rha-C(8)-C(10);Rha
      Rha-C(8)-C(12:1); Rha-Rha-C(10)-C(10); Rha-Rha-C(10)-C(12:1); Rha-C(10)-C(10);
      Rha-Rha-C(10)-C(12)/Rha-Rha-C(12)-C(10); Rha-C(10)-C(12:1)/Rha-C(12:1)-C(10); Rha
      Rha-C(12:1)-C(12); Rha-Rha-C(10)-C(14:1); Rha-C(10)-C(12)/Rha-C(12)-C(10)) were
      isolated from cultures of P. aeruginosa 47T2 from waste frying oil and identified
      by HPLC-MS analysis. This article deals with the production, isolation, and
      chemical characterization of the rhamnolipid mixture RL(47T2). The
      physicochemical and biological properties of RL(47T2) as a new product were also
      studied. Its surface tension decreased to 32.8 mN/m; and the interfacial tension
      against kerosene to 1 mN/m. The critical micellar concentration for RL(47T2) was
      108.8 mg/mL. The product showed excellent antimicrobial properties. Antimicrobial
      activity was evaluated according to the minimum inhibitory concentration (MIC),
      the lowest concentration of an antimicrobial agent that inhibits development of
      visible microbial growth. Low MIC values were found for bacteria Serratia
      marcescens (4 microg/mL), Enterobacter aerogenes (8 microg/mL), Klebsiella
      pneumoniae (0.5 microg/mL), Staphylococcus aureus and Staphylococcus epidermidis
      (32 microg/mL), Bacillus subtilis (16 microg/mL), and phytopathogenic fungal
      species: Chaetonium globosum (64 microg/mL), Penicillium funiculosum (16
      microg/mL), Gliocadium virens (32 microg/mL) and Fusarium solani (75 microg/mL).

PMID- 12474256
TI  - Study of caspase inhibitors for limiting death in mammalian cell culture.
AB  - Apoptosis in mammalian cell culture is associated with decreased bioproduct
      yields and can be inhibited through altering the intracellular signaling pathways
      mediating programmed cell death. In this study, we evaluated the capacity to
      inhibit caspases to maintain high viable cell numbers in CHO and 293 cultures.
      Two genetic caspase inhibitors, XIAP and CrmA, were examined along with a mutant
      of each, XIAP-BIR123NC, which contains three BIR domains but lacks the RING
      finger, and CrmA-DQMD, which has CrmA's pseudosubstrate site replaced with that
      of another caspase inhibitor, p35. Stable CHO pooled and 293 clonal cell lines
      expressing each protein were exposed to apoptotic insults, including spent
      medium, Sindbis virus, and etoposide. For each insult the mutated protein
      resulted in higher viabilities than its wild-type counterpart. However, the
      mutants provided different levels of protection, depending on the insult
      considered. CrmA-DQMD was the preferred inhibitor for spent medium-induced
      apoptosis, whereas XIAP-BIR123NC conferred better protection for etoposide
      induced death. Addition of Z-VAD.fmk to the genetically engineered cells enhanced
      viabilities in the presence of spent medium or etoposide; however, the largest
      increases in viability were experienced by the control cells, indicating an
      overlap in caspase inhibition between the genetic and chemical inhibitors.
      Finally, parental 293 cells were treated with caspase-8 and -9 inhibitors, Z
      IETD.fmk and Z-LEHD.fmk, in concert with spent medium or etoposide exposure.
      Spent medium-induced death was delayed more readily with the caspase-8
      inhibitors, CrmA-DQMD and Z-IETD.fmk, and etoposide-induced death was stalled
      more so with XIAP-BIR123NC and Z-LEHD.fmk. These results suggest that the
      apoptosis pathways induced and the level of protection afforded by a particular
      caspase inhibitor may vary with the insult considered.

PMID- 12474255
TI  - Water-in-oil macroemulsions sustain long-term viability of microbial cells in
      organic solvents.
AB  - Extremely stable water-in-oil macroemulsions have been obtained by dispersing
      water in isooctane in the presence of lecithin. Either prokaryotic (Escherichia
      coli) and eukaryotic (Saccharomyces cerevisiae and Rhodotorula minuta) cells
      hosted in these water-in-oil macroemulsions are viable for weeks despite the
      consistent excess of organic solvent (ranging from 70 to 84%, v/v) in these
      ternary systems. Conjugation occurs upon mixing macroemulsions containing F(+) or
      F(-) Escherichia coli strains, indicating consistent mass transfer between the
      water droplets. Populations of yeasts hosted in water-in-oil macroemulsion
      feature a higher frequency of cells aggregation when compared with the
      corresponding populations suspended in homogeneous aqueous media.

PMID- 12474258
TI  - Improved fuel cell and electrode designs for producing electricity from microbial
      degradation.
AB  - A new one-compartment fuel cell was composed of a rubber bunged bottle with a
      center-inserted anode and a window-mounted cathode containing an internal, proton
      permeable porcelain layer. This fuel cell design was less expensive and more
      practical than the conventional two-compartment system, which requires aeration
      and a ferricyanide solution in the cathode compartment. Three new electrodes
      containing bound electron mediators including a Mn(4+)-graphite anode, a neutral
      red (NR) covalently linked woven graphite anode, and an Fe(3+)-graphite cathode
      were developed that greatly enhanced electrical energy production (i.e.,
      microbial electron transfer) over conventional graphite electrodes. The
      potentials of these electrodes measured by cyclic voltametry at pH 7.0 were (in
      volts): +0.493 (Fe(3+)-graphite); +0.15 (Mn(4+)-graphite); and -0.53 (NR-woven
      graphite). The maximal electrical productivities obtained with sewage sludge as
      the biocatalyst and using a Mn(4+)-graphite anode and a Fe(3+)-graphite cathode
      were 14 mA current, 0.45 V potential, 1,750 mA/m(2) current density, and 788
      mW/m(2) of power density. With Escherichia coli as the biocatalyst and using a
      Mn(4+)-graphite anode and a Fe(3+)-graphite cathode, the maximal electrical
      productivities obtained were 2.6 mA current, 0.28 V potential, 325 mA/m(2)
      current density, and 91 mW/m(2) of power density. These results show that the
      amount of electrical energy produced by microbial fuel cells can be increased
      1,000-fold by incorporating electron mediators into graphite electrodes. These
      results also imply that sewage sludge may contain unique electrophilic microbes
      that transfer electrons more readily than E. coli and that microbial fuel cells
      using the new Mn(4+)-graphite anode and Fe(3+)-graphite cathode may have
      commercial utility for producing low amounts of electrical power needed in remote
      locations.

PMID- 12474257
TI  - Pulsed feeding during fed-batch fungal fermentation leads to reduced viscosity
      without detrimentally affecting protein expression.
AB  - The goal in this study was to determine if pulsed addition of substrate could be
      used to alter filamentous fungal morphology during fermentation, to result in
      reduced broth viscosity. In all experiments, an industrially relevant strain of
      Aspergillus oryzae was grown in 20-liter fermentors. As a control, cultures were
      fed limiting substrate (glucose) continuously. Tests were performed by altering
      the feeding strategy so that the same total amount of glucose was fed in repeated
      300-s cycles, with the feed pump on for either 30 or 150 s during each cycle.
      Variables indicative of cellular metabolic activity (biomass concentration,
      oxygen uptake rate, base consumed for pH control) showed no significant
      difference between continuous and pulse-fed fermentations. In addition, there was
      no significant difference between total extracellular protein expression or the
      apparent distribution of these proteins. In contrast, fungal mycelia during the
      second half of pulse-fed fermentations were approximately half the size (average
      projected area) of fungi during fermentations with continuous addition of
      glucose. As a result, broth viscosity during the second half of pulse-fed
      fermentations was approximately half that during the second half of continuous
      fermentations. If these results prove to be applicable for other fungal strains
      and processes, then this method will represent a simple and inexpensive means to
      reduce viscosity during filamentous fungal fermentation.

PMID- 12474259
TI  - Kinetic locking-on and auxiliary tactics for bioaffinity purification of NADP+
      dependent dehydrogenases using N6-linked immobilized NADP+ derivatives: Studies
      with mammalian and microbial glutamate dehydrogenases.
AB  - This study is concerned with the development and application of kinetic locking
      on and auxiliary tactics for bioaffinity purification of NADP(+)-dependent
      dehydrogenases, specifically (1) the synthesis and characterization of highly
      substituted N(6)-linked immobilized NADP(+) derivatives using a rapid solid-phase
      modular approach; (2) the evaluation of the N(6)-linked immobilized NADP(+)
      derivatives for use with the kinetic locking-on strategy for bioaffinity
      purification of NADP(+)-dependent dehydrogenases: Model bioaffinity
      chromatographic studies with glutamate dehydrogenase from bovine liver (GDH with
      dual cofactor specificity, EC 1.4.1.3) and glutamate dehydrogenase from Candida
      utilis (GDH which is NADP(+)-specific, EC 1.4.1.4); (3) the selection of an
      effective "stripping ligand" for NADP(+)-dehydrogenase bioaffinity purifications
      using N(6)-linked immobilized NADP(+) derivatives in the locking-on mode; and (4)
      the application of the developed bioaffinity chromatographic system to the
      purification of C. utilis GDH from a crude cellular extract. Results confirm that
      the newly developed N(6)-linked immobilized NADP(+) derivatives are suitable for
      the one-step bioaffinity purification of NADP(+)-dependent GDH provided that they
      are used in the locking-on mode, steps are taken to inhibit alkaline phosphatase
      activity in crude cellular extracts, and 2',5'-ADP is used as the stripping
      ligand during chromatography. The general principles described here are supported
      by a specific sample enzyme purification; the purification of C. utilis GDH to
      electrophoretic homogeneity in a single bioaffinity chromatographic step
      (specific activity, 9.12 micromol/min/mg; purification factor, 83.7; yield 88%).
      The potential for development of analogous bioaffinity systems for other NADP(+)
      dependent dehydrogenases is also discussed.

PMID- 12474260
TI  - Kinetic analysis of bacterial bioluminescence.
AB  - Bioluminescence from the lux-based bacterial reporter Pseudomonas fluorescens
      HK44 was experimentally investigated under growth substrate-rich and limiting
      conditions in batch, continuous stirred tank (CSTR), and turbidostat reactors. A
      mechanistically based, mathematical model was developed to describe
      bioluminescence based on 1) production and decay of catalytic enzymes, and 2)
      reactant cofactor availability. In the model, bioluminescence was a function of
      inducer, growth substrate, and biomass concentration. A saturational dependence
      on growth substrate concentration accommodated dependence on cofactor
      availability and inducer concentration to accommodate enzyme production was
      incorporated in the model. Under growth substrate and inducer limiting conditions
      in the batch reactor and CSTR, bioluminescence was found to decrease in response
      to cellular energy limitations. The effective lux system enzyme decay rate was
      determined in independent measurements to be 0.35 hr(-1) and the model captured
      most of the bioluminescent behavior, except at long growth times and high cell
      density.

PMID- 12474262
TI  - Further structures in the jaw apparatus of Limnognathia maerski (Micrognathozoa),
      with notes on the phylogeny of the Gnathifera.
AB  - The jaws of Limnognathia maerski, Micrognathozoa, were investigated with light-
      and scanning electron microscopy. The study yielded several new structures and
      sclerites, including the ventral part of main jaw, the pharyngeal lamellae, the
      manus, the dorsal and ventral fibularium teeth, and a reinterpretation of the
      fibularium compartmentalization. Furthermore, it was shown that several jaw
      elements are composed of densely packed rods. Comparison with Rotifera and
      Gnathostomulida suggested that the micrognathozoan main jaw is homologous with
      the rotifer incus and the gnathostomulid articularium and that the
      pseudophalangids (the ventral jaws) and their associated sclerites correspond to
      the rotifer mallei. These results imply that Micrognathozoa is more closely
      related to Rotifera than to Gnathostomulida.

PMID- 12474263
TI  - Embryonic integument and "molts" in Manduca sexta (Insecta, Lepidoptera).
AB  - In Manduca sexta the germ band is formed 12 h post-oviposition (p.o.) (=10%
      development completed) and is located above the yolk at the egg surface. The
      cells show a polar organization. They are engaged in the uptake and degradation
      of yolk globules, pinched off from the yolk cells. This process can be observed
      in the integumental cells during the first growth phase of the embryo that lasts
      until "katatrepsis," an embryonic movement that takes place at 40% development
      completed. At 37% development completed, the ectoderm deposits a thin membrane at
      its apical surface, the first embryonic membrane, which detaches immediately
      before katatrepsis. The second period of embryonic growth--from katatrepsis to 84
      h p.o. (70% development completed)--starts with the deposition of a second
      embryonic membrane that is somewhat thicker than the first one and shows a
      trilaminar, cuticulin-like structure. Whereas the apical cell surface is largely
      smooth during the deposition of the first embryonic membrane, it forms microvilli
      during deposition of the second one. At the same time, uptake of formed yolk
      material ceases and the epidermal cells now contain clusters of mitochondria
      below the apical surface. Rough endoplasmic reticulum (RER) increases in the
      perinuclear region. The second embryonic membrane detaches about 63 h p.o. At 69
      h p.o., a new generation of microvilli forms and islands of a typical cuticulin
      layer indicate the onset of the deposition of the larval cuticle. The third
      growth phase is characterized by a steady increase in the embryo length, the
      deposition of the larval procuticle, and by cuticular tanning at about 100 h p.o.
      Beginning at that stage, electron-lucent vesicles aggregate below the epidermal
      surface and are apparently released below the larval cuticle. Manduca sexta is
      the first holometabolous insect in which the deposition of embryonic membranes
      and cuticles has been examined by electron microscopy. In correspondence with
      hemimetabolous insects, the embryo of M. sexta secretes three covers at
      approximately the same developmental stage. A marked difference: the second
      embryonic cover, which in Hemimetabola clearly exhibits a cuticular organization,
      has instead a membranous, cuticulin-like structure. We see the difference as the
      result of an evolutionary reductional process promoted by the redundancy of
      embryonic covers in the egg shell. Embryonic "molts" also occur in noninsect
      arthropods; their phylogenetical aspects are discussed.

PMID- 12474265
TI  - Ultrastructure of the placentae of the natricine snake, Virginia striatula
      (Reptilia: Squamata).
AB  - Virginia striatula is a viviparous snake with a complex pattern of embryonic
      nutrition. Nutrients for embryonic development are provided by large, yolked
      eggs, supplemented by placental transfer. Placentation in this species is
      surprisingly elaborate for a predominantly lecithotrophic squamate reptile. The
      embryonic-maternal interface consists of three structurally distinct areas, an
      omphalallantoic placenta and a regionally diversified chorioallantoic placenta.
      The chorioallantoic placenta over the embryonic hemisphere (paramesometrial
      region) of the egg, features close apposition of embryonic and uterine blood
      vessels because of the attenuate form of the interceding epithelial cells. The
      periphery of the chorioallantoic placenta, which is adjacent to the
      omphalallantoic placenta, is characterized by a simple cuboidal uterine
      epithelium apposed to a stratified cuboidal chorionic epithelium. There are no
      sites with attenuate epithelial cells and close vascular apposition. The
      morphology of the omphalallantoic placenta is similar to that of the peripheral
      chorioallantoic placenta, except that the height of uterine epithelial cells is
      greater and allantoic blood vessels are not associated with the embryonic
      epithelium. The functional capabilities of the three placental regions are not
      known, but structural characteristics suggest that the omphalallantoic placenta
      and peripheral zone of the chorioallantoic placenta are sites of nutritional
      provision via histotrophy. The paramesometrial region of the chorioallantoic
      placenta is also nutritive, in addition to functioning as the primary embryonic
      respiratory system. The structure of the chorioallantoic placenta of V. striatula
      is a new placental morphotype for squamate reptiles that is not represented by a
      classic model for the evolution of reptilian placentation.

PMID- 12474264
TI  - Embryonic and larval staging of summer flounder (Paralichthys dentatus).
AB  - Early development of flatfishes such as the summer flounder Paralichthys dentatus
      (Pleuronectiformes) has not been extensively documented, largely because of a
      dearth of material; however, the recent expansion of flatfish aquaculture has
      made embryos of P. dentatus readily available for developmental studies. We
      divide development of P. dentatus embryos and larvae into two main periods, pre-
      and posthatching, and assign stages within each of those primary divisions.
      Stages from fertilization to hatching loosely follow the general teleost staging
      scheme suggested by Shardo ([1995] J Morphol 225:125-167); stages from hatching
      through metamorphosis are aligned with the series used for Japanese flounder, P.
      olivaceus (Minami [1982] Nippon Suisan Gakkaishi 48:1581-1588; Fukuhara [1986]
      Nippon Suisan Gakkaishi 52:81-91). Although length, width, and age may serve as
      approximate indicators of developmental progression in summer flounder, these
      characteristics are too variable to form the sole basis of a staging table.
      Therefore, we define stages by morphological criteria drawn from the development
      of the jaw apparatus and digestive system, eye migration, and notochord tip
      flexion. Examination of these morphological features in hatched larvae allows
      accurate and consistent assessment of developmental stage despite variation in
      timing and size. The staging scheme for flounder embryonic and larval development
      presented here should facilitate both experimental and comparative research on
      summer flounder and other flatfish species.

PMID- 12474266
TI  - Functional morphology of feeding and gill irrigation in the anuran tadpole:
      electromyography and muscle function in larval Rana catesbeiana.
AB  - This study provides the first data on muscle activity patterns during active
      feeding in a larval anuran. Data regarding muscle function during gill irrigation
      and hyperexpiration are also provided. Electromyographic and kinematic data were
      recorded from six mandibular and hyoid muscles in unanesthetized, unrestrained
      larvae of Rana catesbeiana. Only three (hyoangularis, orbitohyoideus, anterior
      interhyoideus) of the six muscles examined are active during gill irrigation.
      Feeding cycles are characterized by the recruitment of three additional muscles:
      intermandibularis, suspensorioangularis, and levator mandibulae longus
      superficialis. The latter two contribute, respectively, to wide opening and
      forceful closing of the mouth during feeding. Hyperexpiration is characterized by
      a reversal of water flow anteriorly out of the mouth. This hydrodynamic change
      occurs due to modulation of the timing of firing of the anterior interhyoideus,
      as well as recruitment of the posterior interhyoideus, which is only active
      during hyperexpiration. Both regions of the interhyoideus, which are responsible
      for evacuation of the buccal cavity, are active during the opening phase of
      hyperexpiration. Kinematically, transitioning from gill irrigation to feeding
      involves both an overall shortening of the gape cycle and a shift in the relative
      length of opening phase vs. closing phase. Our results corroborate many of the
      findings of Gradwell ([1972] Can J Zool 50:501-521) regarding muscle function
      during gill irrigation and hyperexpiration. Furthermore, we demonstrate that in
      larval anurans the transition from gill irrigation to feeding involves modulation
      of gape cycle kinematics, changes in the level of activity of muscles, and
      recruitment of muscles that are not active during irrigation. In light of new
      data presented here, a review of muscle function in tadpoles is also provided.

PMID- 12474268
TI  - Anatomy of a hemiramphid pharyngeal mill with reference to Arrhamphus sclerolepis
      krefftii (Steindachner) (Teleostei: Hemiramphidae).
AB  - The structure and function of the pharyngeal jaw apparatus (PJA) and
      postpharyngeal alimentary tract of Arrhamphus sclerolepis krefftii, an
      herbivorous hemiramphid, were investigated by dissection, light and scanning
      electron microscopy, and X-ray analysis of live specimens. A simple model of PJA
      operation is proposed, consisting of an adductive power stroke of the third
      pharyngobranchial that draws it posteriorly while the fifth ceratobranchial is
      adducted, and a return stroke in which the third pharyngobranchial bone is drawn
      anteriorly during abduction of the fifth ceratobranchial. Teeth in the
      posteromedial region of the PJA are eroded into an occlusion zone where the teeth
      of the third pharyngobranchial are spatulate incisiform and face posteriorly in
      opposition to the rostrally oriented spatulate incisiform teeth in the wear zone
      of the fifth ceratobranchial. The shape of the teeth and their pedestals (bone of
      attachment) is consistent with the model and with the forces likely to operate on
      the elements of the PJA during mastication. The role of pharyngeal tooth
      replacement in maintaining the occlusal surfaces in the PJA during growth is
      described. The postpharyngeal alimentary tract of A. sclerolepis krefftii
      comprises a stomachless cylinder that attenuates gradually as it passes straight
      to the anus, interrupted only by a rectal valve. The ratio of gut length to
      standard length is about 0.5. Despite superficial similarities to the cichlid PJA
      (Stiassny and Jensen [1987] Bull Mus Comp Zool 151:269-319), the hemiramphid PJA
      differs in the fusion of the third pharyngobranchial bones, teeth in the second
      pharyngobranchials and the fifth ceratobranchial face anteriorly, the presence of
      a slide-like diarthroses between the heads of the fourth epibranchials and the
      third pharyngobranchial, the occlusion zone of constantly wearing teeth, and the
      unusual form of the muscularis craniopharyngobranchialis. The functional
      relationship between these structures is explained and the consequence for the
      fish of a complex PJA and a simple gut is discussed.

PMID- 12474267
TI  - Kinematic model of tyrannosaurid (Dinosauria: Theropoda) arctometatarsus
      function.
AB  - We present a hypothesis of tyrannosaurid foot function termed the "tensile
      keystone model," in which the triangular central metatarsal and elastic ligaments
      dynamically strengthened the foot. The tyrannosaurid arctometatarsus, in which
      the central metatarsal is proximally constricted, displays osteological
      correlates of distal intermetatarsal ligaments. The distal wedge-like imbrication
      of tyrannosaurid metatarsals indicates that rebounding ligaments drew the outer
      elements towards the middle digit early in the stance phase, unifying the
      arctometatarsus under high loadings. This suggests increased stability and
      resistance to dissociation and implies, but does not demonstrate, greater agility
      than in large theropods without an arctometatarsus.

PMID- 12474269
TI  - Development of the basement membrane and formation of collagen fibrils below the
      placodes in the head of anuran larvae.
AB  - The development of the basement membrane and collagen fibrils below placodes,
      including the corneal region of the ectoderm, lens epithelium, nasal plate, and
      auditory vesicle in anuran larvae was observed by transmission electron
      microscopy and compared with that in nonplacodal regions such as the epidermis,
      neural tube, and optic vesicle. In the corneal region the lamina densa becomes
      thick concomitantly with the development of the connecting apparatuses such as
      hemidesmosomes and anchoring fibrils. The collagen fibrils increase in number and
      form a multilayered structure, showing similar morphology to the connective
      tissues below the epidermis. These two areas, i.e., the corneal region and
      epidermis, possess much collagenous connective tissue below them. On the other
      hand, the neural tube and ophthalmic vesicle that originated from the neural tube
      each have a thin lamina densa and a small number of underlying collagen fibrils.
      The lamina densa does not thicken and the number of collagen fibrils do not
      significantly increase during development. These two areas possess little
      extracellular matrix. The nasal plate and auditory vesicle show intermediate
      characteristics between the epidermis-type and the neural tube-type areas. In
      these areas, the lamina densa becomes thick and hemidesmosomes and anchoring
      fibrils develop. The number of collagen fibrils increases during development, but
      does not show an orderly arrangement; rather, they are randomly distributed. It
      is thought that the difference in the arrangement of collagen fibrils in
      different tissues is due to differences in the extracellular matrix around the
      collagen fibrils. Placodal epithelia have the same origin as epidermis, but
      during development their morphological characteristics differ and they are not
      associated with the pattern of extracellular matrix with characteristics of
      epidermal and corneal multilayered collagen fibril areas.

PMID- 12474270
TI  - Microampullary organs of a freshwater eel-tailed catfish, Plotosus (tandanus)
      tandanus.
AB  - Whole body studies of Plotosus tandanus revealed that ampullary pores occur over
      the entire body of the fish, but are in higher concentrations in the head region.
      These pores give rise to a short canal (50-60 microm) produced by columnar
      epithelial cells bound together by tight junctions and desmosomes. At the
      junction of the canal and the ampulla, cuboidal epithelial cells make up the
      wall. The ampulla consists of layers of collagen fibers that surround flattened
      epithelial cells in the lateral regions and give rise to supportive cells that
      encase a small number of receptor cells (10-15). The ampullary wall comprises
      several types of cells that are adjoined via tight junctions and desmosomes
      between cell types. The ovoid receptor cells possess microvilli along the luminar
      apical area. Beneath this area, the cells are rich in mitochondria and rough
      endoplasmic reticulum. An unmyelinated neuron adjoins with each receptor cell
      opposite multiple presynaptic bodies. This form of microampulla has not been
      previously described within the Family Plotosidae.

PMID- 12474271
TI  - [Health preservation for coal industry workers and its role in correcting
      demographic situation in the Kemerovo region].

PMID- 12474272
TI  - [Actual problems of occupational and environmental hygiene in coal miner towns].
AB  - The authors present priority directions of occupational diseases prevention
      nowadays in Kouzbass.

PMID- 12474273
TI  - [Research in basic science for health protection of coal miners in Kuzbass].
AB  - The article covers results of studies in occupational hygiene and physiology,
      occupational traumatism, morbidity among coal miners of Kouzbass; evaluation of
      occupational morbidity risks and environmental state in coal miner towns.

PMID- 12474274
TI  - [Occupational morbidity and traumatism in coal mining industry of Kuzbass].
AB  - The article covers problems concerning prevalence of occupational morbidity and
      traumatism, their cause-effect relation with work conditions and organization,
      prognosis for oncoming 10-15 years.

PMID- 12474275
TI  - [Health problems of coal miners in Kuzbass].
AB  - The materials presented characterize state of medical service of coal miners and
      ways to optimize it.

PMID- 12474276
TI  - [A concept of prophylaxis for occupational diseases in the Kemerovo region].
AB  - The authors represented integral evaluation of sanitary and epidemiologic well
      being of people residing in coal miner towns. This evaluation plays an important
      role in formation of general including children's, occupational and infectious
      morbidity.

PMID- 12474277
TI  - [System of education and certification in work safety for coal industry managers
      in Kuzbass].
AB  - The article covers idea on creation and functions of a system concerning
      education and certification in work safety for coal industry managers in
      Kouzbass.

PMID- 12474278
TI  - [Organization of occupational health services in the Kemerovo region].
AB  - The article covers organizational structure of occupational medical service in
      Kemerovo region.

PMID- 12474279
TI  - [System of provision of quality of health care and evaluation of temporary
      disability in fuel industry workers].
AB  - The article covers materials on improvement of system evaluating, controlling
      quality of medical care, providing medical examination of temporary disability
      within medical and sanitary security of workers.

PMID- 12474280
TI  - [Experience of Health Protection Center on organization of medical care for coal
      miners in Kuzbass].
AB  - The authors present materials on activities of medical and sanitary center on
      contemporary phase of economic development under reforms of health care and coal
      industry.

PMID- 12474281
TI  - [Coronary heart disease, its risk factors and somatic types in coal miners having
      chronic dust-related diseases of lungs].
AB  - Studies covered incidence of coronary heart disease, its risk factors and
      features of constitutional types among Kouzbass coal miners suffering from
      anthracosilicosis and chronic dust bronchitis. Findings are reliably higher
      incidence of coronary heart disease among coal miners having lung diseases caused
      by dust. Coronary heart disease among the miners with anthracosilicosis is
      favored by arterial hypertension, overweight and hypersthenic constitutional
      type, that among those with dust bronchitis is favored only by overweight.

PMID- 12474282
TI  - [Constitutional-morphologic features of coal miners exposed to vibration and
      suffering from coronary heart disease].
AB  - Occurrence of coronary heart disease and its risk factors are studied in
      individuals working with vibration instruments--in drift miners, miners of
      breakage face--and in 390 reference group miners who never faced occupational
      vibration. Findings are higher incidence of coronary heart disease, arterial
      hypertension and hypercholesterole mia in the miners working with vibration
      instruments. The main group miners suffering from coronary heart disease
      demonstrated more frequent hypersthenic constitutional type.

PMID- 12474283
TI  - [Occupational and environmental hygiene on motor vehicle depots at the coal
      mining sites of Kuzbass].

PMID- 12474284
TI  - [Occupational hygiene and health state of workers in coal mining of Southern
      Kuzbass].

PMID- 12474285
TI  - [Hygienic advantages of mechanized method of coal mining in Kuzbass].

PMID- 12474286
TI  - [Work conditions of bulldozer operators with 12-hour working shift on open-cast
      mines in Kuzbass].

PMID- 12474287
TI  - [Overlap syndrome of systemic lupus erythematosus and dermatomyositis presented a
      large demyelinating subcortical lesion mimicking brain tumor and high level of
      CSF antineuronal and serum anti-ribosomal P antibodies].
AB  - We reported a 50-year-old man with an overlap syndrome of dermatomyositis and
      SLE, whose magnetic resonance image of the brain showed a rapidly increasing
      large tumor-like focal lesion unequally enhanced by Gd-DTPA in the left frontal
      lobe. Its pathological finding by the brain biopsy was fibrinoid necrosis,
      inflammatory cell aggregation around blood vessels and many myelin-laden
      macrophages with central necrosis. Although many cases of blood vessel injury are
      reported in CNS lupus, in this case the brain lesion partly took reversible
      course and neural symptoms such as paresis were slight and the lesion well
      responded to steroid. Moreover we considered that the measurement of serum anti
      ribosomal P and CSF antineuronal antibodies are useful to diagnose cases as CNS
      lupus.

PMID- 12474288
TI  - [A case of slowly progressive unilateral spastic hemiparasis, hand clumsiness,
      limb ataxia and constructional apraxia].
AB  - A 65-year-old woman was seen in our clinic because of a 4-year history of slowly
      progressive left hand clumsiness and left limping. Neurologically, she had left
      side spastic hemiparasis including her tongue, hand clumsiness, limb ataxia,
      constructional apraxia, and memory impairment. Dementia, parkinsonism and lower
      motor neuron sign were not confirmed. MRI study showed diffuse cerebral atrophy
      and shrinkage of the right cerebral peduncle and pontine base. SPECT (99mTc-ECD)
      study revealed hypoperfusion of the right fronto-parietal cortex. This is a rare
      case presented with slowly progressive left-side spastic hemiparasis, mimicking
      Mills' syndrome. In addition this case had other cortical signs, such as
      ipsilateral hand clumsiness, limb ataxia, constructional apraxia. Neuroimaging
      study suspects that the right front-parietal cortex is the primary lesion.
      Etiologically atypical motor neuron disease with adjacent cortical involvement is
      suspected rather than corticobasal degeneration with severe unilateral pyramidal
      tract degeneration.

PMID- 12474289
TI  - [Cerebrovascular accidents with familial antithrombin III deficiency--gene
      analysis study].
AB  - We report two cases of the cerebral infarction with familial antithrombin III
      type I deficiency. Case 1 is a 47-year-old woman presenting deep cerebral vein
      thrombosis. Case 2 is a 20-year-old man presenting the top of the basilar
      syndrome. Beside them, substantial number of members had cerebral infarction in
      this pedigree. We measured AT III activity and quantity for 18 persons in this
      pedigree. As a consequence, 6 of 18 persons in this pedigree had AT III type I
      deficiency. Analysis of PCR products of AT III gene derived from the case 1's
      leukocyte DNA revealed a novel frame shift insertion was demonstrated as mutant
      alleles with 4-base CTTT in nt 2,420 or nt 2,424 in exon 2 domain on the AT III
      gene. AT III type I deficiency caused by frame shift insertion has been reported
      only twelve pedigrees. This is the first case report of AT III type I deficiency
      caused by frame shift insertion in Japan.

PMID- 12474290
TI  - [A case of carbon monoxide intoxication presenting subacute dementia as the
      initial symptom].
AB  - We reported a 67-year-old woman who had developed abnormal behavior and dementia
      from January 21, 2001 and deteriorated to akinetic mutism on February 15. T2
      weighted magnetic resonance imaging showed high intensity in bilateral globus
      pallidus and a rapid spreading of diffuse high intensity in bilateral deep white
      matter. Later on, we got an important information that she had used a little coal
      stove three times about three weeks before presenting the initial symptom. She
      was diagnosed as carbon monoxide intoxication and treated with hyperbaric oxygen
      from March 1. A remarkable improvement on dementia and motor disability was
      observed. We conclude that this case is the first reported example of a case of
      intermittent carbon monoxide intoxication presenting subacute dementia as an
      initial symptom.

PMID- 12474291
TI  - [A patient with primary Sjogren's syndrome featuring polyneuropathy and
      oculomotor paralysis and associated with asymptomatic left middle cerebral artery
      stenosis].
AB  - We report a case of primary Sjogren's syndrome (primary SjS) with polyneuropathy
      and right oculomotor paralysis associated with middle cerebral artery stenosis. A
      39-year-old woman developed progressive numbness and clumsiness of the limbs. Two
      months later, right third cranial palsy manifested itself and she was admitted to
      our hospital. A cranial MRA showed left middle cerebral artery stenosis confirmed
      by transcranial color doppler sonography. A nerve conduction study showed a
      decrease in the NCV and reduced CMAP, while sural nerve biopsy showed axonal
      degeneration and infiltration of inflammatory cells around the small blood vessel
      walls. The patient complained of dry mouth and a salivary gland biopsy revealed
      inflammatory changes, while salivary gland scintigraphy showed diminished
      secretion. These findings led to the diagnosis of Sjogren's syndrome. Reports of
      primary SjS with involvement of large cerebral arteries are rare. In our case,
      polyneuropathy and oculomotor paralysis were the manifest symptoms, but middle
      cerebral artery stenosis was also observed. This indicates that, even in the
      absence of CNS symptoms, cerebral artery involvement may be present in primary
      SjS.

PMID- 12474292
TI  - [A case of CIDP with horizontal gaze-evoked nystagmus and ataxia].
AB  - A 46-year-old man developed mild to moderate weakness in the distal muscles of
      lower limbs and then had gradually progressive weakness and sensory loss in four
      limbs. He subsequently developed difficulty in walking over a few months.
      Examination showed severe distal muscle weakness and atrophy, but mild proximal
      weakness in four limbs. Superficial sensation was decreased in both distal limbs
      and his vibratory sense was mildly decreased in bilateral feet. All tendon
      reflexes were absent. Furthermore, he showed four-limb and truncal ataxia with
      bilateral horizontal gaze-evoked nystagmus in both directions. Nerve conduction
      study revealed sensorimotor neuropathy, and sural nerve biopsy showed mixed
      axonal damage and demyelination. Cerebrospinal fluid protein levels were raised
      212 mg/dl. Lumbar spine MRI showed marked cauda equina enhancement with
      gadolinium. Anti-ganglioside antibodies were negative but serum antineuronal
      antibodies without known antigen specificity were found. Neurootological findings
      indicated bilateral horizontal gaze-evoked nystagmus was caused by
      spinocerebellar damage. We diagnosed this case was CIDP with cerebellar ataxia.
      After administration of high dose steroid therapy, intravenous methylprednisolone
      1000 mg/day, his symptoms including ataxia and polyneuropathy were apparently
      improved.

PMID- 12474293
TI  - [A young patient with endometrioid adenocarcinoma who suffered Trousseau's
      syndrome associated with vasculitis].
AB  - A 27-year-old woman was admitted to our hospital because of headache, fever and
      right neck pain. Neurological examination revealed mild meningeal signs, and
      hyper-reflexia in all extremities. In the laboratory tests, white-cell count was
      13,000/mm3, rheumatoid factor(RF) and C-reactive protein(CRP) were positive. The
      cerebro-spinal fluid showed pleocytosis (56/mm3, neutorophils and lymphocytes
      were 26 and 28, respectively). Thus, she was diagnosed as aseptic meningitis. A
      few days later, she had weakness and dysesthesia of the right face and the left
      extremities. Pulse therapy with intravenous methylprednisolone was started. A
      magnetic resonance imaging (MRI) of the brain showed a hemorrhagic infarction in
      the right parietal lobe. In hemostatic markers, thrombin-antithrombin III
      complex(TAT; 106 ng/dl), D-dimer 1234 ng/dl, prothrombin fragment 1 + 2(F1 + 2;
      2.36 nmol/L), beta-thromboglobulin (beta TG; 4,300 ng/dl) and platelet factor 4
      (PF-4; 1,770 ng/dl) were extremely elevated. On duplex ultrasonography, a low
      echo lucent plaque was observed at the right internal carotid artery and the mean
      blood flow velocity in the right carotid artery was decreased. She was placed on
      oral prednisolone and warfarin for suspected stroke due to hypercoagulability
      associated with vasculitis. Afterwards, she discharged from our hospital. Two
      months later, she was readmitted to our hospital because of irregular menses and
      vaginal bleeding. Endometrial uterus biopsy was conducted, which revealed a grade
      I endometrioid adenocarcinoma. She was under total uterectomy without tumor
      recurrence. After the radical operation, white-cell count, RF, CRP, TAT, D-dimer,
      F1 + 2, and beta TG were normalized, and the mean flow velocity of the right
      common carotid artery was increased. Thereafter, she did not experience stroke
      recurrence. Therefore, we speculated that she had stroke due to
      hypercoagulability in association with malignancy, that is Trousseau's syndrome.
      We also assumed that aseptic meningitis, brainstem encephalitis associated with
      vasculitis in this patient are other clinical variants of paraneoplastic syndrome
      through immunological mechanisms associated with malignancy. We emphasize that
      patients with Trousseau's syndrome can be associated with other paraneoplastic
      manifestations such as vasculitis as seen in this patient.

PMID- 12474294
TI  - [Nacrolepsy manifesting initially as cataplexy and sleep paralysis: usefulness of
      CSF hypocretin-1 examination for early diagnosis].
AB  - We report a 24-year-old man with narcolepsy initially suffered from cataplexy and
      sleep paralysis. From May 2000, at age 23 he experienced two kinds of recurrent
      episodes of weakness without altered consciousness; one was provoked by emotion
      and excitement, the other occurred spontaneously on onset of sleep without
      hallucination. He denied having daytime sleepiness and did not experience
      hypnagogic hallucinations. In July 2000, at our hospital he received the first
      medical examinations, of which physical and neurological results were
      unremarkable. A magnetic resonance imaging scan of the brain also gave
      unremarkable results. The initial diagnosis was epilepsy, and anti-convulsant
      drugs were begun in August 2000. The weakness episodes were not lessened by the
      treatment with carbamazepine, sodium valproate or clonazepam, and he was admitted
      to our clinic in April 2001 for further examinations. Human leukocyte antigen
      testing was positive for DR15 (DR2) and DQ6 (DQ1). The routine
      electroencephalographam detected no epileptic discharge or paradoxical alpha
      blocking. A polysomnogram showed a sleep onset REM sleep period and sleep
      fragmentation, but there was no apnea or periodic leg movements. A multiple sleep
      latency test showed a mean sleep latency of 1.8 min and REM sleep in three of
      five naps. These findings suggested probable narcolepsy, so we examined the
      hypocretin-1 (orexin A) concentration in his cerebrospinal fluid (CSF). It was
      below the detection limit of the assay (< 40 pg/mL). The final diagnosis in April
      2001 was narcolepsy. Making an initial diagnosis of incomplete or atypical
      narcolepsy is difficult for clinicians. A delay in diagnosis, however, may
      produce personal and social problems for narcoleptic patients. We believe that an
      examination of CSF hypocretin-1 aids in the early diagnosis of narcolepsy.

PMID- 12474295
TI  - [A patient of ADEM with central and peripheral conduction block improved with
      ultra-high-dose methylprednisolone].
AB  - A patient with exanthem and fever showed progressive disturbance of consciousness
      and flaccid quadriplegia predominantly in the lower extremities. Antibiotics,
      aciclovir, high-dose methylprednisolone (1 g/day for 3 consecutive days) and IVIG
      (400 mg/kg/day for 5 consecutive days) were not effective. Nerve conduction study
      and SEP in the lower extremities showed peripheral and central conduction block.
      EEG showed irregular sharp and slow waves predominantly in the left hemisphere.
      ABR and SEP in the upper extremities were normal. Consecutive studies of cranial
      and spinal MRIs showed no abnormalities. A diagnosis of acute disseminated
      encephalomyelitis (ADEM) was made. We started administration of ultra-high-dose
      methylprednisolone (5.4 mg/kg/h for 47 hours), the dose for acute spinal cord
      injury based on the randomized controlled trial of The Third National Acute
      Spinal Cord Injury Study in the USA. After this, she regained consciousness and
      the quadriplegia improved. The abnormalities in the electrophysiological studies
      also normalized. It is thought that the neuroprotective mechanism of ultra-high
      dose methylprednisolone could be attributed to its inhibition of lipid
      peroxidation, secondary, ischemia, energy failure and so on. If the usual
      treatment is not effective for severe encephalomyelitis cases, we can consider
      the administration of ultra-high-dose methylprednisolone as one of the new
      treatment options.

PMID- 12474296
TI  - [ACE inhibitors and its usefulness in the prevention of aspiration pneumonia in
      chronic cerebrovascular disease patients with asymptomatic swallowing
      dysfunction].
AB  - The double contrast pharyngogram by use of computed radiography (DCP-CR) has been
      found to be useful in detection of asymptomatic swallowing dysfunction. Following
      the DCP-CR examination, we investigated the incidence of aspiration pneumonia in
      143 patients with chronic cerebrovascular disease (CVD) for 3 years and the
      effects of ACE inhibitors on the prevention of pneumonia. Aspiration pneumonia
      occurred in 29 out of 143 patients, and more frequently in the elderly chronic
      CVD patients with multiple brain lesions. Aspiration pneumonia was confirmed in
      26 out of 85 patients (30.6%) with abnormal barium adhesion to the pharyngeal
      wall on the double contrast pharyngogram image by DCP-CR; whereas pneumonia
      occurred in 3 out of 58 patients (5.2%) with normal findings of DCP-CR
      pharyngogram. Among chronic CVD patients with abnormal findings of DCP-CR
      pharyngogram, the incidence of aspiration pneumonia was significantly lower in
      the patients treated with ACE inhibitors than in those treated with other
      antihypertensive agents or without antihypertensive agents (chi 2 value = 7.163,
      p < 0.05). Accordingly, ACE inhibitors may prevent the aspiration pneumonia and
      reduce the incidence of aspiration pneumonia in the chronic CVD patients with
      abnormal DCP-CR pharyngogram images.

PMID- 12474297
TI  - [Intracranial hypertrophic pachymeningitis with high perinuclear anti-neutrophil
      cytoplasmic antibody (p-ANCA) occurred in a patient on hemodialysis].
AB  - We present a 66-year-old woman undergoing hemodialysis who developed intracranial
      hypertrophic pachymeningitis. Neurological examinations revealed a loss of
      bilateral visual acuity with optic atrophy, headache, and markedly restricted
      bilateral extraocular movement. MRI examinations demonstrated homogenous
      hypertrophic dural enhancement compatible with hypertrophic cranial
      pachymeningitis, and biopsied dural specimen revealed chronic inflammatory
      changes with proliferation of dense collagen fibers. There was no direct evidence
      of vasculitis and specific infections including tuberculosis and troponema
      pallidum. Most of the inflammatory infiltrates were demonstrated to be T
      lymphocytes. Intriguingly, p-ANCA was found to be highly elevated at x 220 and
      decreased to x 110 after steroid treatment. Neurological manifestations and
      radiological findings also improved in accordance with the lowering of p-ANCA.
      Although a few reports have described similar conditions such as chronic renal
      failure accompanying hemodialysis and pachymeningitis, and though vasculitis was
      not depicted histologically in this patient, we considered that immunological
      mechanisms probably provoked the patient's glomerulonephritis and
      pachymeningitis. Additionally, positive reaction against hepatitis c virus might
      have influenced the immunological system leading to the occurrence of the
      pachymeningitis.

PMID- 12474298
TI  - [Dide-Botcazo syndrome associated with Anton's syndrome after a cardioembolic
      infarction in the distribution of the bilateral posterior cerebral arteries].
AB  - Dide-Botcazo syndrome (Rev Neurol, 1902) is a unique neuropsychological syndrome,
      characterized by combinations of cortical blindness, amnesia, and topographical
      disorientation. We report 82-year-old right-handed man manifesting such syndrome
      associated with Anton's syndrome after a cardioembolic infarction in the
      distribution of the bilateral posterior cerebral arteries. The MRI study
      demonstrated recent extensive infarctions bilaterally in the occipital lobes and
      the medial temporal lobes, and thalamus. Following the resolution of
      unconsciousness and tetraparesis, the patient persistently presented with denial
      of cortical blindness (Anton's syndrome), profound anterograde amnesia and
      retrograde amnesia of about 50 years, severe topographical disorientation, and
      partial impairment of the tactile and auditory naming for objects. The bilateral
      extensive damages to the visual area, the memory area, and the connecting areas
      including the occipital lobe of the non-dominant hemisphere possibly responsible
      for topographical disorientation, may account for producing Dide-Botcazo
      syndrome. The syndrome may clinically occur following the "top of the basilar"
      syndrome.

PMID- 12474299
TI  - [Comprehensive use of newly-developed ophthalmic instruments].

PMID- 12474300
TI  - [Effect of ultraviolet-B irradiation pretreatment on a second-set rejection model
      of orthotopic corneal grafts].
AB  - PURPOSE: To investigate the effect of ultraviolet-B irradiation (UV-B) on the
      donor cornea in a second-set rejection model of rat orthotopic corneal
      transplantation. MATERIALS AND METHODS: Three patterns of fully mismatched
      allogeneic bilateral orthotopic corneal transplantations (DA to AO) after 10-week
      interval were studied: Untreated primary corneal grafts into the right eyes
      followed by untreated secondary grafts into the left eyes, UV-B treated primary
      corneal grafts into the right eyes followed by untreated secondary grafts into
      the left eyes, and untreated primary corneal grafts into the right eyes followed
      by UV-B treated secondary grafts into the left eyes. RESULTS: The rejection of
      untreated secondary grafts was hastened in recipients who had previously rejected
      untreated primary grafts (p = 0.00507). Recipients bearing long-surviving UV-B
      pretreated corneal grafts rejected secondary untreated corneal grafts at the
      first-set tempo. Recipients who had previously rejected untreated primary grafts
      rejected UV-B pretreated secondary grafts at the first-set tempo. CONCLUSIONS:
      The UV-B pretreatment to donor corneas may induce dysfunction of antigen
      presentation so that the recipients' immune system fails to be sensitized in
      second-set phenomena.

PMID- 12474301
TI  - [Functional MRI activation in area V4 alpha during a hue arrangement test].
AB  - BACKGROUND: Recent studies of cerebral information processing have shown that
      area V4 alpha, the area anterior to area V4, which is known as the human color
      center, is also associated with color. However, our clinical study has shown that
      lesions associated with hue arrangement test failures are more anterior than
      those associated with pseudoisochromatic plate test failure. PURPOSE AND METHODS:
      We studied area V4 alpha, and planned two functional magnetic resonance
      experiments for V4 alpha activity during the hue arrangement test. The task in
      the first experiment was virtual simulation of the hue arrangement test. The
      second experiment involved a task more specific to color information processing.
      RESULTS: We found significant activity in area V4 alpha in healthy subjects.
      CONCLUSIONS: We have reported that one of our patients with a more anterior
      lesion excluding area V4 had dyschromatopsia, as revealed by a panel D-15 test.
      Our experimental data and the clinical findings suggest that area V4 alpha plays
      an important role in processing during the hue arrangement test.

PMID- 12474302
TI  - [Vitreous surgery for macular edema in branch retinal vein occlusion].
AB  - PURPOSE: To examine the efficacy of vitreous surgery for macular edema in branch
      retinal vein occlusion (BRVO). PATIENTS AND METHODS: This study included 183
      patients (183 eyes) that underwent vitreous surgery for macular edema in BRVO.
      They were 77 males and 106 females. The average age of the patients was 65 years
      (range, 35-87 years). The average duration of macular edema was 18 weeks (range,
      1-161 weeks). Mean preoperative visual acuity was 0.32 (0.01-1.2). Preoperative
      visual acuity was less than 0.1 in 27% and more than 0.5 in 26% of the cases. The
      average follow-up period was 24 months (range, 12-83 months). RESULTS: Macular
      edema was absorbed in 21% at 1 month, 54% at 3 months, 81% at 6 months, and 95%
      at 12 months postoperatively. The mean absorption period of macular edema was 4.5
      months. Postoperative visual acuity improved to 0.68, which was statistically
      significant. Postoperative visual acuity was less than 0.1 in 9% of the cases,
      more than 0.5 in 68%, and more than 0.8 in 47%. CONCLUSION: After vitreous
      surgery for macular edema in BRVO, macular edema was absorbed rapidly and visual
      acuity improved. Vitreous surgery may be an effective treatment.

PMID- 12474303
TI  - [Long-term enlargement of laser photocoagulation scars after treatment of
      choroidal neovascularization].
AB  - PURPOSE: To investigate long-term enlargement of laser photocoagulation scars
      after treatment of choroidal new vessels (CNV) in age-related macular
      degeneration or myopic neovascular maculopathy. OBJECTS AND METHOD: Twenty-four
      eyes of 24 patients aged between 45 and 77 years were treated with laser
      photocoagulation for juxtafoveal or extrafoveal choroidal neovascularization in
      Yodogawa Christian Hospital. There was no recurrence in any of the eyes and the
      mean follow-up period was 31.0 +/- 13.7 (mean +/- standard deviation) months (13
      60 months). The laser photocoagulation scar was measured with an image analyzer
      immediately and once a year after the treatment. We investigated the relationship
      between scar expansion rate and visual axis measured by A-mode ultrasonography.
      RESULTS: Expansion of the coagulation scars (atrophic creep) was observed in 19
      eyes (79.2%). The coagulation scar expanded with the length of the period after
      treatment in most of the patients. The expansion rate was significantly
      correlated with the length of the eye at two years after treatment in all 24 eyes
      and even in 21 of the eyes without high myopia (p < 0.05). A decrease in visual
      acuity was observed in only one eye (4.2%). Remarkable pigmentation around the
      scar was found in three eyes of five that did not have atrophic creep.
      CONCLUSION: Although atrophic creep occurs in approximately 80% of eyes after
      successful laser treatment, visual acuity deterioration is rarely encountered.
      The rate of expansion is significantly correlated with the axial length among the
      eyes both with and without high myopia. Heavy pigmentation around scars may be
      one sign which indicates a low expansion rate of atrophic creep.

PMID- 12474304
TI  - [Transdifferentiation of conjunctival epithelium after ocular surface
      rehabilitation through deep lamellar sclerokeratoplasty].
AB  - PURPOSE: The quality of the postoperative corneal epithelia of patients with
      severe ocular surface disorders, whose ocular surface had been reconstructed
      through deep lamellar sclerokeratoplasty (DLSKP) using allografts, was examined.
      PATIENTS AND METHODS: Six eyes with ocular surface disorders in 6 patients who
      had received DLSKP were observed for periods of 2 years or longer (average: 3
      years and 10 months). The rehabilitated corneal epithelium cells of some of these
      patients were analyzed with impression cytology and fluorescence in situ
      hybridization (FISH) analysis methods. RESULTS: All 3 cases analyzed using the
      impression cytology method showed normal corneal epithelium cell forms. In the 2
      cases analyzed also with the FISH analysis method, in which the hosts and donors
      were of the opposite gender, the cells were host-derived (99.3% and 98.8%).
      CONCLUSION: It is considered that rehabilitation of severe ocular surface
      disorders using allograft epithelial transplantation procedures, including DL
      SKP, is eventually concluded by transdifferentiation of the conjunctival
      epithelium cells derived from the host.

PMID- 12474305
TI  - [A case of choroidal rupture due to blunt ocular trauma healed with proliferative
      tissue protruding into the vitreous cavity].
AB  - BACKGROUND: Indirect choroidal rupture due to blunt ocular trauma involves
      rupture of the choriocapillaris or the full thickness of the choroid and Bruch's
      membrane. The overlying retinal pigment epithelium and the sensory retina are
      usually intact or atrophic, but rarely ruptured. We report a case of choroidal
      rupture healed with proliferative tissue protruding through the sensory retina
      into the vitreous cavity. CASE: A 22-year-old man was punched in the left eye.
      Hypotony maculopathy and choroidal rupture passing through the macula were noted.
      RESULTS: The intraocular pressure was normalized after suturing of the dialyzed
      ciliary body to the sclera and hypotony maculopathy was cured. Proliferative
      tissue formation protruding through the sensory retina into the vitreous cavity
      was observed 1 month after the injury. Corrected visual acuity was improved from
      0.09 to 0.6. Optical coherence tomography showed that the site of the
      proliferative tissue was located immediately temporal to the fovea and that the
      fovea kept its normal form. CONCLUSION: Optical coherence tomography was useful
      in monitoring the morphological change in the macula and predicting visual acuity
      in a case of blunt ocular trauma involving the macular area.

PMID- 12474306
TI  - [Editorial].

PMID- 12474307
TI  - [Schizophrenia in childhood and adolescence. Symptomatology, clinical course,
      etiological and therapeutic aspects].
AB  - Schizophrenic psychosis is rare in patients below 15 years of age. Early
      diagnosis is crucial as the illness is likely to have a poor outcome: indeed,
      duration of untreated psychosis may exert a negative influence on the prognosis.
      Thus, it may be highly relevant to recognise premorbid changes of character
      traits, behaviour and cognitive problems which are reflected in worsening school
      performance. For example, some 40 to 50% of the children who later develop a
      psychosis will show social withdrawal, loss of interest in age-appropriate
      activities, peculiar or immature responsiveness, increasingly suspicious, fearful
      or depressive states, baseless despair, unusual somatic complaints, concentration
      problems, cognitive and linguistic disabilities, and peculiar motor movement
      disorders such as bizarre, ritualistic behaviour, mannerisms, stereotypies,
      echopraxia. These features are non-specific: they can but need not represent the
      early signs indicating later development of schizophrenia. They should be
      evaluated in terms of potential psychosocial, genetic and somatic pre-, peri- and
      postnatal risk categories. During the child's development these features may
      build up to constitute vulnerability and stress factors that may lead to
      psychotic breakdown. Early age of onset correlates with high social disability
      scores. Complete remission is an extremely rare event in patients with gradual
      insidious onset of psychosis.

PMID- 12474308
TI  - [Early detection and intervention in childhood and adolescent psychoses].
AB  - Research into schizophrenic disorders increasingly focusses on the early stage of
      the disease (prodrome). Experience in rehabilitation treatment and relapse
      prevention have led to new diagnostic and treatment strategies before the onset
      of schizophrenia that could contribute to disease prevention. The present article
      reports on the latest research results. From the point of view of medical
      practice negative symptoms and cognitive dysfunctions play a major role in the
      assessment of prodromal signs. Psychosocial and psychotherapeutic interventions
      are available for treating patients in the prodromal phase. But so far, there has
      not been sufficient data to recommend the use of antipsychotics before the onset
      of schizophrenia.

PMID- 12474309
TI  - [Cooperation between office-based medical practices and hospitals in the
      treatment of schizophrenia in children and adolescents].
AB  - Starting from needs assessment and actual situation of child and adolescent
      psychiatric care the following article describes priorities, gateways, interfaces
      and problems related to the co-operation of parents, children and adolescents
      with office- and hospital-based physicians and institutions in the early
      diagnosis, hospital admission, in-patient treatment and outpatient follow-up of
      children and adolescents with psychotic disorders. Data from a sample of 100
      children and adolescents with psychotic disorders, who have been treated in the
      Department of Child and Adolescent Psychiatry, Rheinische Kliniken Duesseldorf,
      are provided to illustrate the possibility of and need for co-operation between
      office-based medical practices and hospitals. Finally co-operative activities
      will be specified between: 1. nation-wide quality circles and regional working
      groups, 2. the schizophrenia research network, 3. the professional bodies and 4.
      public relations as important opportunities for the improvement of
      psychoeducation, early diagnosis and treatment.

PMID- 12474310
TI  - [Specific features and problems in the pharmacotherapy of schizophrenic psychoses
      in children and adolescents].
AB  - The present article reviews the specific problems of the off-label use of
      atypical and typical neuroleptics in the treatment of adolescent patients with
      schizophrenia. There is a considerable gap in the empirical knowledge of
      treatment efficacy and long term safety in adult populations as compared to
      children and adolescents. This means that in most in-patients with early onset
      schizophrenia some sort of typical or atypical neuroleptic drug is currently used
      beyond license. From a legal point of view there is no protection for treated
      children or adolescents and their parents as the manufacturer of these
      pharmaceutical products does not assume liability for off-label use. Whether the
      doctor can be held liable in these cases, depends on the quality of the
      information he provides to his patients and the patients' consent. Legal changes
      such as the Food and Drug Administration Modernization Act (FDAMA) and Pediatric
      Rule in the USA have brought forward more research to the benefit of children and
      adolescents. In 2002 a trend has been noticed in both the European and the German
      Parliament to improve the general conditions for using drugs that are well
      established in adult medicine for the treatment of children.

PMID- 12474311
TI  - [Barriers and need for support in the primary care of depressive patients].
AB  - The aim of the study was to record the difficulties and barriers in the
      management of depressive patients faced by primary care physicians, their self
      reported competence and need for support. In this study a questionnaire was sent
      out to 960 physicians, of whom 180 replied (response rate: 19%). This sample
      matches the total sample in essential dimensions such as age, sex and special
      field. From the results retrieved it can be concluded that apart from
      organisational structural factors the greatest barriers in the treatment of
      depressive patients are created by the patients' behaviour, i.e. mainly
      scepticism and reluctance towards treatment. The physicians rated their own
      competence in treating depression highly, especially concerning diagnostics and
      primary care. Accordingly, physicians reported they required support in more
      specific areas (mainly in the management of suicidality). The results are
      discussed with respect to their implications for professional development
      programs. Two central aspects were identified: a) the development of practice
      oriented measures that can be used to improve guideline-based health care and b)
      the explicit involvement of patients into treatment processes.

PMID- 12474312
TI  - [Mapping of HbA1c as a quality measure in the primary care of diabetic patients
      in Thuringia, Germany].
AB  - BACKGROUND: In order to improve quality and outcome in the primary care for
      patients with diabetes mellitus it is necessary to recognise districts with
      poorer supply of structured diabetes care. Hba1c is an evaluated surrogate
      parameter which indicates the long-term control of diabetes therapy. The aim of
      the study was to create a map with all Hba1c-values of every district of the Free
      State of Thuringia, Germany. METHODS: Medical laboratories working for general
      practitioners were used as a new data source. All hba1c-values which were
      measured in Thuringia within the 4th quarter of 1997 were collected. A
      corresponding postal code was registered for each hba1c-value for identification
      purposes. Thuringia consists of 23 districts, and this geographic structure was
      used as a basis for the hba1c-map. RESULTS: 6 laboratories sent 23,214 hba1c
      values. 16,591 values belonged to the territory of Thuringia: The medium relative
      hba1c (hba1c/mean normal of healthy people) for Thuringia was 1.44, two-fold
      increased hba1c was found in 7.9% of all hba1c values. The proportion of two-fold
      increased hba1c-values varied up to 100%. CONCLUSION: This pilot study disclosed
      significant differences in the outcome of regional ambulatory care for patients
      with diabetes mellitus in Thuringia. An intervention in districts with poorer
      study outcomes might result in direct benefits for patients and providers of
      health care services. Since hba1c-values could not be collected for all districts
      the first hba1c-map remains incomplete.

PMID- 12474313
TI  - [Trend-based medicine--a satire that is yet to be topped].

PMID- 12474314
TI  - [Honesty in science].

PMID- 12474315
TI  - [Psychological symptoms in children of alcoholic fathers].
AB  - OBJECTIVES: In spite of a growing interest in recent years in epidemiological
      research on behavior problems of children of alcoholics (COAs), few prospective
      longitudinal child psychiatric studies have been conducted up to now. METHODS: In
      the Mannheim Study of Risk Children, an ongoing prospective study of high risks,
      the data of 219 children (26 COAs and 193 non-COAs) were analyzed from birth to
      the age of 11 years. Sociodemographic data, organic and psychosocial risk
      factors, the number and severity of behavior problems, and the rate of expansive
      and introversive disorders have been investigated. RESULTS: The family status of
      the COAs was characterized by the father's lower level of education as well as by
      socioeconomic difficulties and more numerous adverse life events. Other
      psychosocial problems such as marital conflict and a lack of coping mechanisms
      were also more frequent in COA families. A significantly higher rate of expansive
      symptoms and disorders was found in children of alcoholic fathers from the age of
      two years on. CONCLUSIONS: Children of alcoholic fathers represent a group at
      risk for the early onset of psychiatric problems and are deserving of more
      attention in prevention and early intervention programs.

PMID- 12474316
TI  - [Subjective family image in anorexia nervosa and bulimia nervosa in adolescence:
      a controlled study].
AB  - OBJECTIVES: The family environments of patients with eating disorders have been
      studied extensively in recent decades. The "Subjective Family Image Test" is an
      instrument developed especially to measure differential perceptions by family
      members. Assessments of subjective family image in families of adolescents by
      means of this test have been carried out in only a few samples. METHODS: We aimed
      first to investigate subjective perceptions by adolescents of their family
      relations in a larger clinical sample of female adolescents (n = 118) suffering
      from anorexia nervosa of either subtype or from bulimia nervosa and to compare
      these perceptions with those of healthy controls (n = 96). Second we investigated
      intra-familial differences in perception. RESULTS: The main findings were that
      bulimia nervosa patients perceived lower individual autonomy and lower emotional
      connectedness than all other groups, the adolescents with bulimia perceived
      significantly lower autonomy and emotional connectedness within the family than
      their fathers, and the restrictive anorexia nervosa patients perceived higher
      connectedness than their fathers. The relevance of these findings for
      understanding family dynamics are discussed.

PMID- 12474317
TI  - [Reliability, trainability and stability of auditory discrimination performance
      in 2 computer-assisted assessment and training methods].
AB  - OBJECTIVES: The present study focuses on the possibilities and effects of
      training dyslexic children in tone and phoneme discrimination tasks. METHODS: A
      computer program was developed to train dyslexic children to discriminate between
      tone and speech stimuli. The correlation between auditory discrimination and
      reading and orthography performance was then tested in a preliminary study of n =
      63 children. In a prospective study 44 children were assigned to one of three
      paralyzed groups: tone training, phoneme training or a control group. Upon
      completion of the initial diagnostics for all groups, the two training groups
      received four weeks of discrimination training, after which all three groups were
      immediately re-tested for the first time. Parallel thereto all children underwent
      specific training in reading and orthography at their school. Six months later
      all were re-tested a second time. RESULTS: Both test methods showed a high
      reliability (rn = .94; .95). Significant correlations between auditory
      discrimination and reading and orthography performance were confirmed. Auditory
      discrimination was significantly trainable. Specific training effects, as well as
      independent developmental effects were found. While the training effects of
      phoneme discrimination were stable over six months, those of tone discrimination
      were not. CONCLUSION: The central auditory discrimination between tone and
      phoneme stimuli can be trained successfully in dyslexic children and might also
      affect their reading and orthography performance.

PMID- 12474318
TI  - [Intervention in autistic disorders: status quo, evidence-based, questionable and
      doubtful techniques].
AB  - OBJECTIVE: We describe and critically discuss intervention methods that have been
      used to modify autistic behaviors. METHODS: Early intervention methods, training
      of social skills, pharmacological treatment and alternative approaches are
      reviewed in the light of the empirical evidence. RESULTS: Autism is a persistent
      and phenotypically heterogeneous disorder for which no cure has been found to
      date. However, individually composed care and therapies can lead to remarkable
      quantitative improvement. CONCLUSIONS: Further research is needed to evaluate the
      true impact of psychological and biological intervention techniques in autistic
      disorders. Among other things, the therapy studies carried out up to now often
      lack an adequate diagnostic assessment.

PMID- 12474319
TI  - [Headache in children: also a problem for child and adolescent psychiatry?
      Pathogenesis, comorbidity, therapy].
AB  - Headache is a recurrent somatic complaint in childhood and adolescence. In recent
      decades headache prevalence has increased while the age of onset has decreased.
      In most cases headache can be categorized as migraine or tension-type headache
      without significant organic pathology, i.e. head trauma, structural lesion, etc.
      Diagnosis according to the criteria of the International Headache Society is
      based on subjective reports by patients and their parents. The basic tools of
      clinical assessment are history, physical examination and a headache diary.
      Laboratory tests, including electroencephalography and imaging studies should
      not, as a rule, be undertaken routinely. Pathophysiological models with an impact
      on therapeutic interventions will be discussed. Childhood headache is often
      treated inappropriately in daily practice despite the availability of various
      options (including environmental, drug, and psychological therapy). Psychological
      therapy (relaxation training, biofeedback, stress management, etc.) as well as
      medication can be applied for prophylaxis. Minimal therapeutic interventions have
      been shown to be equally effective in a remarkable number of patients. Chronic
      Headache shows relevant comorbidity with anxiety and depression and is associated
      with somatization and school disorders. A careful investigation and an adequate
      therapy of eventual psychiatric comorbidity is therefore strongly recommended.

PMID- 12474320
TI  - [Waived EEG diagnosis before administration and during drug therapy with
      methylphenidate: dangerous or justifiable?].
AB  - OBJECTIVES: The issue of whether or not to perform an EEG before or during
      therapy with psychostimulants currently is a topic of controversial discussion.
      Only a few studies have described the types of EEG alterations that occur in
      patients without epilepsy who are being treated with psychostimulants. The aim of
      our study was to assess the types of change in the EEG that occur before and
      during this treatment so as to be able to formulate recommendations for EEGs in
      children with ADHD. METHODS: The EEGs of 124 children and adolescents with ADHD
      before and during treatment with methylphenidate were analyzed retrospectively.
      RESULTS: In summary the rate of hypersynchronous activity (HSA) during therapy
      with methylphenidate does not increase. Patients on antiepileptic medication did
      not show any increased rates of seizures or HSA. CONCLUSIONS: Whether or not
      methylphenidate medication influences the occurrence of epileptic seizures
      remains unsettled. Given the data from this study, we would conclude that an EEG
      during therapy with methylphenidate is not necessary. Before commencing a planned
      methylphenidate therapy, however, an EEG should be performed.

PMID- 12474321
TI  - [The law on patients' rights: a revolution of morals or mummification of
      rights?].

PMID- 12474322
TI  - [Diagnosis and treatment of depression in the advanced stage of cancer].
AB  - The diagnosis of depression in patients with advanced cancer is a particularly
      complex task. The lack of diagnostic tools specifically developed for this
      patient population, the difficulty of interpreting neurovegetative symptoms of
      depression--which can result from the neoplastic disease--and the "normal and
      understandable" nature of many symptoms or signs of psychological distress are
      among the main obstacles to a clear-cut diagnosis of depression. Things go even
      more complex when it comes about to discuss whether one should treat patients
      displaying psychological distress that does not meet established criteria for the
      diagnosis of a depressive illness. When the indication to treat is finally
      acknowledged, the choice of the optimal antidepressant will depend upon a series
      of parameters including survival expectancy, tolerance profile and drug
      interactions. Though we currently lack prospective data about the efficacy and
      safety of antidepressants in depressed patients with advanced cancer,
      extrapolation of data available from other patient populations with severe
      medical conditions and clinical experience allow to draw guidelines aimed at
      helping healthcare professionals faced with those problems to improve the quality
      of life of their patients. These elements are presented and discussed in this
      paper in the light of the recent developments resulting from the growing interest
      of the medical community to the care to patients with terminal illness.

PMID- 12474323
TI  - [Serotonin syndrome].
AB  - The serotonin syndrome is a hyperserotoninergic state resulting from an excess of
      intrasynaptic 5-hydroxytryptamine, induced by multiple psychotropic agents, but
      also non psychiatric drugs. It is a potentially dangerous and sometimes lethal
      condition. The clinical manifestations usually include cognitive, neuromuscular
      and autonomic features and are mediated by the action of serotonin on various
      subtypes of receptors. The main differential diagnosis is the neuroleptic
      malignant syndrome. Treatment is mainly supportive. No pharmacological agent has
      been definitely demonstrated really effective. However, reports of cases treated
      with the 5-HT2 blockers, including cyproheptadine or chlorpromazine have
      suggested that these agents could have some efficacy. Serotonin syndrome is a
      toxic condition which requires heightened clinical awareness among physicians in
      order to prevent, recognize, and treat the condition promptly.

PMID- 12474324
TI  - [Role of transesophageal echocardiography in infectious endocarditis].
AB  - The role of transoesophageal echocardiography in infective endocarditis is
      detailed after concisely restating the precautions required by this examination.
      The diagnosis is nowadays based on the Duke University criteria, the major
      echocardiographic criteria being a typical image of vegetation, of abscess or of
      prosthetic valve dehiscence. The assessment of the complications includes the
      evaluation of the extent of destruction of the valvar or intracardiac structures
      and its hemodynamic consequences, the occurrence of a pericarditis and the
      assessment of the embolic risk. The different pitfalls and limitations of the
      examination are considered. The indications for repeating transoesophageal
      echocardiography during follow-up are considered, based on recently published
      recommendations. The respective advantages of the transthoracic and the
      transoesophageal approach are discussed, with a special focus on right heart
      endocarditis.

PMID- 12474325
TI  - [Embolization of uterine fibroids].
AB  - Uterine artery embolization (UAE) for symptomatic leiomyomas is a new attractive
      treatment in patients who don't desire pregnancy and for which conventional
      therapy has failed. Uterine fibroid embolization can also be considered for
      patients who desire pregnancy when myomectomy is technically difficult or
      impossible and in case of recurrence after myomectomy. 90% improvements are
      commonly reported in abnormal bleeding, pelvic pains, and in bulk-related
      symptoms. Although numerous pregnancies have been reported after UAE, the
      fertility rate after UAE remains to be compared to myomectomy. Absolute contra
      indications are pregnancy, endometrial carcinoma, gynaecologic infections,
      adnexal masses, and rapid growth of uterine leiomyomas (considered as a
      significant sign of sarcoma). Besides procedure related risks of angiography some
      specific complications are reported: deep pelvic vein thrombosis with exceptional
      pulmonary embolus, vaginal discharges with sometime transcervical expulsion of
      fibroid (5%), transient or permanent amenorrhea (4-5%) and extensive necrosis (1
      2%) with possible perforation and infection. A hysterectomy is needed to manage
      this complication in 0.9 to 0.3% of case. The mortality rate of embolisation is
      evaluated to 1/3.000 against 6/10.000 for the hysterectomy. UAE is proposed as a
      less invasive alternative to hysterectomy and myomectomy for the treatment of
      symptomatic leiomyomas. This technique allows reducing the hospital stay, the
      convalescence period, the morbidity and the mortality rate compared to
      conventional surgical treatment.

PMID- 12474326
TI  - [Results of the third medical doctorate at the Brussels Free University:
      relationship with the first three years in the first generation students].
AB  - The aim of our study was to assess the relationships between the end-of-year
      results in the 1st session across 4 study years (the first 3 years and the 6th
      year) of medical school at the "Universite libre de Bruxelles" in a group of 102
      students, before initiation of the numerus clausus selection. In particular, we
      wanted to evaluate whether success in the 6th year was significantly related to
      the results in the preceding years, notwithstanding other non-academic factors,
      in two cohorts of students (1994-2000 and 1995-2001). Results showed that success
      in the 3rd doctorate was only slightly correlated to results in the first three
      years of study. The 3rd year final percentage was the only variable allowing to
      significantly predict a very good grade in the 6th year, but its actual
      contribution was very weak. On the other hand, based on their percentage, the
      ordering of students each year showed poor stability: three quarter of the
      students did either progress or regress in the 6th year compared to their rank in
      the first 3 years of study. These results are discussed with a special emphasis
      on the particular study sample, selected on the basis of a yearly success in 2
      sessions maximum and in the context of the issue of students selection.

PMID- 12474327
TI  - [Partial androgenic deficit in the aging male].
AB  - It is possible to observe in the aging male an hypotestosteronemia below 3 ng/ml.
      The indications of an androgenic treatment are discussed with their benefits,
      risks, contra-indications and choices of molecules. Testosterone-gel seems to be
      now the first choice for this type of patient. In case of normal testosteronemia
      and erectile dysfunction, the benefits/risks ratio of sildenafil is very
      favorable, except when contra-indicated.

PMID- 12474329
TI  - [Second meeting on severe emergencies and complications in cancer patients].

PMID- 12474328
TI  - [Acute interstitial pneumonia and bronchial cancer].
AB  - A 64 year-old woman with a lung cancer metastatic to the bone was admitted to the
      Intensive Care Unit for a hypoxemic interstitial diffuse pneumonia. The diagnosis
      was obtained with a further complementary investigation. The differential
      diagnosis of intestitial pneumonia is discussed.

PMID- 12474330
TI  - [Albin Lambotte, a great surgeon and artists' friend].

PMID- 12474331
TI  - Research and publication in scientific journals in Spain.

PMID- 12474332
TI  - Assessing rectal sensitivity in irritable bowel syndrome: a positive diagnosis at
      last?

PMID- 12474333
TI  - Prevalence of rectal hypersensitivity in patients with irritable bowel syndrome
      and its clinical subgroups.
AB  - AIM: To evaluate the prevalence of rectal hypersensitivity in our irritable bowel
      syndrome (IBS) patients, the relationship of hypersensitivity to rectal
      distensibility and the differences in sensitivity among clinical subgroups of
      IBS. MATERIAL AND METHODS: 18 healthy subjects and 56 IBS patients (Rome-II
      criteria; 22 diarrhea-predominant, 15 constipation-predominant and 19
      alternating). Rectal sensitivity and distensibility were studied by isobaric
      phasic distension of a poliethilene bag with a barostat. RESULTS: IBS patients
      showed a lower threshold for discomfort, pain and maximum tolerate distension,
      without any differences in rectal distensibility. 64% of IBS patients were
      hypersensitive. 89% of patients with alternating IBS were hypersensitive while
      only 68% and 26% of patients with diarrhea-predominant IBS and constipation
      predominant IBS, respectively, were. There were no differences in rectal
      distensibility between hypersensitive and normosensitive patients. CONCLUSION:
      64% of our IBS patients show rectal hypersensitivity, apparently not related to
      rectal distensibility. Hypersensitivity is mostly found in alternating IBS
      patients, and rare in constipation-predominant IBS.

PMID- 12474334
TI  - Push-enteroscopy series: diagnostic and therapeutic efficacy.
AB  - OBJECTIVE: To analyse the diagnostic efficacy of oral push-type enteroscopy (PE)
      according to indications. To assess evolution in patients with occult
      gastrointestinal bleeding (OGIB) according to findings and endoscopic therapy.
      METHODS: 204 PE performed in 167 patients: OGIB: 117, Crohn's disease: 34,
      radiological abnormalities: 21; chronic diarrhoea: 12; intestinal sub-occlusion:
      11; polyposis: 7; other: 2. We followed clinical outcome in 72 patients after PE
      for OGIB. They were separated according to findings and endoscopic therapy: no
      findings: 32; no treated angiodysplasia: 10; treated angiodysplasia: 20; other
      lesions: 10. We evaluated the number of admissions and transfusional requirements
      before and after PE, re-bleeding and surgical treatment. Statistics were
      performed using Student's t test and Chi-square test (statistical significance p
      < 0.05). RESULTS: We diagnosed lesions in 65.8% PE for OGIB, angiodysplasia being
      the more frequent finding (33.3%). We found lesions before Treitz in 15.4% A
      higher diagnostic efficacy was seen in active bleeding (83.4%) versus anaemia
      (52.2%), p < 0.05. After PE both admissions and transfusional requirements
      decreased in all subgroups specially in treated angiodysplasias and other
      lesions, nearly reaching statistical significance (p = 0.07). Re-bleeding
      occurred in 50% of non-treated lesions versus 20-25% in treated lesions. We found
      lesions in 47% of PE for Crohn's disease, in 52.4% for radiological
      abnormalities, in 41.6% for chronic diarrhoea and in 0% for intestinal sub
      occlusion. CONCLUSIONS: PE is efficient in the diagnosis and therapy of patients
      with OGIB, Crohn's disease and radiological abnormalities. Its usefulness is
      controversial in the study of chronic diarrhoea and intestinal sub-occlusion.

PMID- 12474335
TI  - Infliximab treatment and prognostic factors for response in patients with Crohn's
      disease.
AB  - OBJECTIVE: The aim of this study is to report our experience with infliximab and
      analyse prognostic factors for response in Crohn's disease (CD). MATERIAL AND
      METHODS: Consecutive patients were prospectively enrolled in the study when
      referred for infliximab infusion. Data collected included indication for
      infusion, patient epidemiological characteristics, Vienna classification,
      previous surgery, previous medications and extra-intestinal manifestations.
      Adverse events and clinical response were tabulated separately for patients with
      luminal or fistulous Crohn's disease. RESULTS: 28 patients were treated (7 with
      inflammatory and 21 with fistulizing disease). Patients received a total of 116
      infusions of infliximab: 57.1% (4 of 7) of patients with luminal disease had
      complete response within a median of 17.5 days (range 15-28 days), and 62% (13 of
      21) of patients with fistulizing disease had complete response within a median of
      9 days (range 6-51 days). All patients (5) without relapse received concomitant
      treatment with immune modifiers. The group of patients with previous resection or
      perianal fistula repair had complete response more frequently p = 0.03 (OR = 30;
      IC 95% = 1.47-119.8). CONCLUSIONS: Infliximab is safe and beneficial in clinical
      practice for Crohn's disease. The re-treatment regimen of infliximab is effective
      in maintaining clinical response. Immunosuppressant therapy may have a role in
      the duration of maintained clinical remission in patients with fistulizing
      disease. In patients with perianal fistulizing disease infliximab treatment is
      more effective when previous resection or fistula repair is present.

PMID- 12474337
TI  - Agenesis of the gallbladder confirmed by nuclear magnetic resonance
      cholangiogram.
AB  - We present a case of gallbladder agenesis, an uncommon bile duct malformation,
      which was found on attempting to perform a laparoscopic cholecystectomy. The
      diagnosis was confirmed postoperatively on a nuclear magnetic resonance
      cholangiogram.

PMID- 12474336
TI  - Small dose of recombinant factor VIIa (rFVIIa) to perform percutaneous liver
      biopsies in cirrhotic patients.
AB  - Low levels of vitamin K-dependent coagulation factors, synthesized in the liver,
      play a key role in the hypocoagulable state of end-stage liver disease patients.
      Recombinant factor VII (rFVIIa) has been developed for, and currently is used in
      the treatment of patients with hemophilia A and B with inhibitors. Some
      experience was gained with rFVIIa in liver diseases since 1995. We used a low
      dose of rFVIIa to perform percutaneous liver biopsy in three patients, all of
      them with abnormal coagulation, impeditive of the percutaneous liver biopsy. The
      first one was a 29 years old man with alcoholic cirrhosis and a liver nodule; the
      second was a 32 years old man with post hepatitis C cirrhosis and excessive
      alcohol intake; the third was a 53 years old man with chronic hepatitis C and a
      congenital deficit of factor VII. A single dose of 5 micrograms/Kg of rFVII
      administered before liver biopsies raised levels of factor VII to acceptable
      values during more than 5 hours in the first two patients. We conclude that a
      small dose of rFVIIa can be enough to correct the abnormal coagulation of
      cirrhotic patients, permits percutaneous liver biopsy, and is cost-effective,
      compared to transjugular access.

PMID- 12474338
TI  - [Chronic cough in gastroesophageal reflux].

PMID- 12474339
TI  - [Upper digestive hemorrhage and hepatic artery aneurysm].

PMID- 12474340
TI  - [Dysphagia lusoria caused by aberrant left subclavian artery and Kommerell
      diverticulum].

PMID- 12474341
TI  - [Secondary splenic cyst as infrequent cause of splenomegaly].

PMID- 12474342
TI  - [Schwachman-Diamond syndrome as a cause of chronic diarrhea].

PMID- 12474343
TI  - [Medical applications of dronabinol].

PMID- 12474344
TI  - [Adjuvants for vaccines].

PMID- 12474345
TI  - [Expectorants. Help for acute cold bronchitis?].

PMID- 12474346
TI  - [Inhalation therapy. Forms and indications for use].

PMID- 12474347
TI  - [Medications for type-2 diabetes and high blood pressure].

PMID- 12474348
TI  - [Weight gain from drugs].

PMID- 12474349
TI  - [Shedding light on teeth. Which procedures work for lightening teeth and which
      can be recommended?].

PMID- 12474350
TI  - [Emergency mushroom poisoning. When gourmets risk liver and life].

PMID- 12474352
TI  - [Severe pain in the behind but nothing to be seen. A fantasy or abscess?].

PMID- 12474351
TI  - [Meeting Patch Adams. Laughter against stress. Interview].

PMID- 12474353
TI  - [A type 1 diabetes mellitus patient becomes pregnant. To what do you have to pay
      attention].

PMID- 12474354
TI  - [Chronic constipation. So the intestine has to move!].

PMID- 12474355
TI  - [Hazardous natural products. Are there carcinogens in herbal teas?].

PMID- 12474356
TI  - [Discussion on acrylamide in food products. Hysteria or real danger? Interview].

PMID- 12474357
TI  - [Treatment monitoring, recurrence detection, prognosis. Here's where tumor
      markers make good sense].
AB  - Of the growing group of cancer biomarkers, circulating humoral tumour markers
      (TM) are the longest-known subgroup of substances with protein, lipid, glycolipid
      or carbohydrate structure, that can be used as probes for identifying the origin,
      growth and therapy-related debulking of a tumor. Relevant TM are well-defined and
      easy to determine, and disturbing factors and statistical characteristics well
      known. They are most commonly used not so much for early detection, localization
      and diagnosis, but for treatment monitoring, detection of recurrence and,
      latterly, also for outcome prediction. Their particular value lies in their
      supporting role in invasive imaging or endoscopic procedures. In some cases, they
      may also prolong the intervals between for such procedures.

PMID- 12474358
TI  - [Vitamin supplements in oncology -- necessary, useful or superfluous?].
AB  - Vitamins are essential components of a normal diet, and sufficient amounts are
      always needed. Occasionally, multivitamin supplements may make sense in cancer
      patients. However, because of the balance of (antioxidant) vitamins, coenzymes,
      trace elements and secondary phytochemicals it offers, a varied diet of fresh
      fruits and vegetables is--wherever possible--to be preferred to supplements of
      single or combinations of vitamins. Although preclinical studies have confirmed
      the positive effects of high-dose vitamins on cancer, there is currently no
      evidence that increased consumption of vitamins benefits cancer patients--nor is
      the dose necessary to achieve a possible therapeutic impact known. Since a number
      of clinical and epidemiological studies fail to show any benefit, and adverse
      effects have even been reported, high-dose vitamins can at present be recommended
      only for short-term substitution in known vitamin deficiencies. Before a
      definitive pronouncement can be made, therefore, further clinical studies of
      megavitamins in cancer patients are needed.

PMID- 12474359
TI  - [Detection of disseminated tumor cells in bone marrow--currently of no practical
      therapeutic value].
AB  - Development of metastases in cancer patients is usually due to tumour cells
      seeding from the primary. These disseminated cells can be detected in blood or
      bone marrow with the aid of immunocytochemical methods. The clinical significance
      of this is, however, still controversial. With the aim of determining the
      prognostic value of disseminated tumour cells, a meta-analysis of 20 publications
      reporting results based on data collected from a total of 2494 breast cancer
      patients, was carried out. The outcome of the meta-analysis was that 14 of the 20
      studies provided evidence suggesting positive bone marrow findings to be an
      unfavorable prognostic factor. Five out of twelve studies provided multivariate
      analytic evidence of an impact of bone marrow status on recurrence-free survival.
      In five out of twelve studies, a univariate analysis showed a positive bone
      marrow finding to correlate significantly with overall survival, while a
      multivariate analysis found such a correlation in only two out of six studies.
      Owing to a lack of standardization, the results of the individual studies are not
      directly comparable. Against this background it is too early to say whether the
      detection of disseminated tumour cells in the bone marrow can be used as a
      prognostic factor with an impact on therapeutic strategies.

PMID- 12474360
TI  - [Recall of the herbal anxiolytic kava. Underestimation of its value or
      overestimation of its risks?].

PMID- 12474361
TI  - [Microorganisms and coronary heart disease. Do antibiotics protect against
      cardiac events?].

PMID- 12474362
TI  - [Evidence-based guidelines on Internet. Hot line between science and everyday
      practice].

PMID- 12474363
TI  - [In small steps to far ahead. Diminished risk of interactions as definite
      advantage].

PMID- 12474364
TI  - [Everybody is annoyed about the health care system. Only the patients are
      satisfied!].

PMID- 12474366
TI  - [A modern device without FCKW. A simple handling helps the compliance].

PMID- 12474365
TI  - [A new initiative to inform the patients. Education optimizes asthma therapy].

PMID- 12474367
TI  - [Neuraminidase inhibitor permitted. The first pill against influenza].

PMID- 12474368
TI  - [Beta blockade plus NO release. Patients with heart failure can be loaded more].

PMID- 12474369
TI  - [The patient suffers from rheumatism for many years. It also makes the bones
      brittle].

PMID- 12474370
TI  - [Thanks to cardioprotective omega-3 fatty acids. To live longer with cod-liver
      oil].

PMID- 12474371
TI  - [Therapy of severe pain. Cannabinoid acts not only as an analgesic].

PMID- 12474372
TI  - [80,000 patients with arthrosis treated. Coxib gets through a practice test,
      too].

PMID- 12474373
TI  - [Depression therapy in family practice. To limit to fewer substances].

PMID- 12474374
TI  - [Gleaning from the American Oncology Congress. A new standard in colorectal
      carcinoma].

PMID- 12474375
TI  - Use of plant and insect hosts to model bacterial pathogenesis.

PMID- 12474376
TI  - Identification of host and pathogen factors involved in virulence using
      Caenorhabditis elegans.

PMID- 12474377
TI  - Goldfish as an animal model system for mycobacterial infection.

PMID- 12474378
TI  - Green fluorescent protein as a marker for conditional gene expression in
      bacterial cells.
AB  - To date, the majority of studies of bacterial gene expression have been carried
      out on large communities, as techniques for analysis of expression in individual
      cells have not been available. Recent developments now allow us to use reporter
      genes to monitor gene expression in individual bacterial cells. Conventional
      reporters are not suitable for studies of living single cells. However, variants
      of GFP have proved to be ideal for the study of development, cell biology, and
      pathogenesis and are now the reporters of choice for microbial studies. In
      combination with techniques such as DFI and IVET and the use of flow cytometry
      and advanced fluorescence microscopy, the latest generation of GFP reporters
      allows the investigation of gene expression in individual bacterial cells within
      particular environments. These studies promise to bring a new level of
      understanding to the fields of bacterial pathogenesis and environmental
      microbiology.

PMID- 12474379
TI  - Genetic methods for deciphering virulence determinants of Mycobacterium
      tuberculosis.

PMID- 12474380
TI  - Analysis of gene function in bacterial pathogens by GAMBIT.

PMID- 12474381
TI  - Microbial gene expression elucidated by selective capture of transcribed
      sequences (SCOTS).

PMID- 12474382
TI  - Identification of essential genes in Staphylococcus aureus using inducible
      antisense RNA.

PMID- 12474383
TI  - Transposomes: a system for identifying genes involved in bacterial pathogenesis.

PMID- 12474384
TI  - Functional screening of bacterial genome for virulence genes by transposon
      footprinting.

PMID- 12474385
TI  - Use of LexA-based system to identify protein-protein interactions in vivo.

PMID- 12474386
TI  - Borrelia burgdorferi gene expression profiling with membrane-based arrays.

PMID- 12474387
TI  - Transcript profiling of Escherichia coli using high-density DNA microarrays.

PMID- 12474388
TI  - Neisseria microarrays.

PMID- 12474389
TI  - Acquisition and archiving of information for bacterial proteomics: from sample
      preparation to database.

PMID- 12474390
TI  - Proteomic analysis of pH-dependent stress responses in Escherichia coli and
      Helicobacter pylori using two-dimensional gel electrophoresis.

PMID- 12474391
TI  - Mycobacterial proteomes.

PMID- 12474392
TI  - Proteomic analysis of response to acid in Listeria monocytogenes.

PMID- 12474393
TI  - Proteome analysis of Chlamydia pneumoniae.

PMID- 12474394
TI  - Enrichment and proteomic analysis of low-abundance bacterial proteins.

PMID- 12474395
TI  - Immunoproteome of Helicobacter pylori.

PMID- 12474396
TI  - Helicobacter pylori and apoptosis.

PMID- 12474397
TI  - Modulation of apoptosis during infection with Chlamydia.

PMID- 12474398
TI  - Measurement of pore formation by contact-dependent type III protein secretion
      systems.

PMID- 12474399
TI  - Interaction of enteropathogenic Escherichia coli with red blood cell monolayers.

PMID- 12474400
TI  - GAP activity of Yersinia YopE.

PMID- 12474401
TI  - Tyrosine phosphorylation of eukaryotic proteins and translocated intimin receptor
      by enteropathogenic Escherichia coli.

PMID- 12474402
TI  - Purification and detection of Shigella type III secretion needle complex.

PMID- 12474403
TI  - Analysis of Salmonella invasion protein-peptidoglycan interactions.

PMID- 12474404
TI  - RP4-based plasmids for conjugation between Escherichia coli and members of the
      Vibrionaceae.

PMID- 12474405
TI  - Role of autoinducers in gene regulation and virulence of Pseudomonas aeruginosa.

PMID- 12474406
TI  - Quorum-sensing system of Agrobacterium plasmids: analysis and utility.

PMID- 12474407
TI  - [Health reason for firefighters to leave their job].
AB  - The objective of this study was to identify major pathologies among firefighters,
      being the cause of leaving the job. The study was based on the analysis of
      temporary work disability and disability certificates, taking account of age and
      duration of employment in the capacity of a firefighter. The study was performed
      on a representative sample of 1503 firefighters, employed between 1994 and 1997
      in 29 fire stations. During that period, 214 firefighters left their job (40% of
      them got retired and 38% of persons were given the right to receive disability
      pension). The analysis revealed the average annual frequency of leaving the job
      by firefighters that accounted for about 43/1000 persons (including 17 retired
      and 16 persons on disability pension per 1000 firefighters, respectively). Among
      firefighters, the frequency of leaving the job because of retirement or permanent
      disability was by 60% higher than among workers employed in different branches of
      the national economy. The analysis of the relationship between leaving the job
      and the duration of employment (adjusted for age) showed that the majority of
      those retired left job after 15 years and those on disability pension after 22
      years. Sick absence among firefighters who left the job because of disability and
      retirement was respectively 13 and 4 times higher than that observed among
      firefighters in active service. Diseases of the musculoskeletal and circulatory
      systems and mental disorders were the most common causes of disability. Diseases
      of the circulatory system (26%), diseases of musculoskeletal system (25%) and
      mental disorders (16%) were the main causes of sick absence among those disabled,
      whereas diseases of the musculoskeletal system (26%), nervous system and sense
      organs (24%) and digestive system (13%) among those getting retired. The study
      indicated an interchangeable nature of two main reasons why firefighters leave
      their job (retirement and disability), which results from the right to get
      retired after 15 years of employment, regardless of the age. The aforesaid
      pathologies, being the major causes of disability certification and temporary
      disability for work should be the basis for developing an enlarged program of
      compulsory preplacement medical examinations addressed to candidates for
      employment in a fire-brigade.

PMID- 12474408
TI  - [Hearing disorders among private farmers in Poland].
AB  - The studies of the state of hearing were conducted among a selected group of 128
      farmers, aged 28-65 years with employment ranging from 11 to 40 years. The study
      design covered physical laryngologic examinations, detailed otologic medical
      history and proper audiometric tests (air and bone conduction). The results of
      the study showed that the highest mean values of hearing loss remained mostly
      within two high frequencies of 4 and 6 kHz and were 34.9-39.7 d B. These
      frequencies are typical of acoustic trauma. A highly statistically significant
      correlation (p < 0.001) was observed between hearing loss and age (r = 0.32-0.53
      for 3-8 kHz), while a slightly weaker correlation was noted between hearing loss
      and employment duration (r = 0.20-0.27 for 3-8 kHz; p < 0.01). The mean values of
      hearing loss obtained among farmers were considerably enhanced, compared to the
      control group (42 people aged 29-59 years), the difference being very high
      statistically (p < 0.001). The studies of the state of private farmers' hearing
      clearly confirm the hypothesis that an excessive exposure to noise present in the
      farming equipment, is the major cause of the decreased hearing among farmers.

PMID- 12474409
TI  - [Mammography in Lodz--doses and conditions of diagnostic devices].
AB  - Mammography is a radiodiagnostic technique that has been long recognized and
      highly praised, nevertheless it should be remembered that it is beneficial only
      if the X-ray picture quality ensures correct diagnosis and the dose received by
      patients is reasonably low. The authors present the results of dose measurements
      in patients. The study covered 12 mammographs used in the Lodz radiological
      laboratories. Thermoluminescent dosimeters placed directly on the patient's
      breast during the examination in cranio-caudal projection were used for dose
      measurements. Although the measurements were taken only in patients with the
      compressed breast thickness close to 5 cm--a standard adopted for accreditation
      phantom--a sixfold difference between extreme dose values was observed (ranging
      from 4 to 24 mGy). Nine mammographs were also tested for quality control
      according to the protocol consistent with the recommendations of the European
      Commission, and elaborated by the Department of Radiological Protection of the
      Nofer Institute of Occupational Medicine in Lodz. An improper functioning of the
      automatic exposure control, especially with respect to the selection of the
      amount of emitted radiation in relation to the thickness of the object examined,
      was found to be the most frequent defect (in 7 of the 9 mammographs). Regarding
      that so called automatic option of the apparatus is used in a large majority of
      examinations, this may denote poor picture quality or too high dose received by
      patients, and even wrong diagnosis. In addition, the unsatisfactory quality of
      accredited phantom picture was found in three mammographs, which was equal to
      rather poor quality of clinical picture, and consequently a very limited
      legibility of anatomic details. The results of the measurements show that a
      certain part of mammographic examinations is performed in a way far from being
      perfect. But an actual improvement of the present situation depends on ensuring
      permanent quality control and, even more important, on providing funds necessary
      to cover all costs involved in remedial interventions.

PMID- 12474410
TI  - [Effect of electromagnetic field produced by mobile phones on the activity of
      superoxide dismutase (SOD-1) and the level of malonyldialdehyde (MDA)--in vitro
      study].
AB  - The aim of the study was to assess in vitro the effect of electromagnetic field
      produced by mobile phones on the activity of superoxide dismutase (SOD-1) and the
      level of malonyldialdehyde (MDA) in human blood platelets. The suspension of
      blood platelets was exposed to the electromagnetic field with the frequency of
      900 MHz for 1, 3, 5, and 7 min. Our studies demonstrated that microwaves produced
      by mobile phones significantly depleted SOD-1 activity after 1, 5, and 7 min of
      exposure and increased after 3 min in comparison with the control test. There was
      a significant increase in the concentration of MDA after 1, 5, and 7 min and
      decrease after 3 min of exposure as compared with the control test. On the
      grounds of our results we conclude that oxidative stress after exposure to
      microwaves may be the reason for many adverse changes in cells and may cause a
      number of systemic disturbances in the human body.

PMID- 12474411
TI  - [Occupational acute mercury intoxication--a case report].
AB  - The aim of this paper is to present a case of acute occupational mercury
      poisoning treated at the Clinical Department of Occupational Diseases. A welder,
      forty years old was employed at a large chemical plant in the dissembling
      department involved in the production of acetaldehyde. The patient was referred
      to the hospital by an occupational physician. During his shift; dissembling
      mercury-covered tubes a nausea, abdominal pain and elevated temperature occurred.
      He was also complaining of headache and symptoms of gingivitis, which lasted two
      weeks before hospitalization. Before admission to the Clinical Department,
      mercury concentrations in urine were measured twice. The urine mercury levels
      were very high, impossible to determine precisely. During hospitalization, the
      patient was complaining of head and gingiva pains. Since the symptoms persisted
      and high urine mercury levels (830 micrograms/l) were determined--DMPS--Heyl was
      administered. After treatment symptoms subsided and the concentration of mercury
      in urine was gradually returning to normal. The results of laboratory tests did
      not reveal any impairment of internal organs. Consultant in neurology found the
      presence of nystagmus and positive Romberg test in the patient. Neurological
      signs disappeared after a month. The measurements performed by the Department of
      Work Safety revealed high exceeded hygiene permissible limits of mercury vapors
      in the air. The information provided by the employer's technical services also
      showed that the patient was working with the face mask, but its absorber was not
      readjusted to mercury vapors. A control ambulatory examination (one and a half
      year later) did not reveal health effects of acute exposure to mercury vapors.

PMID- 12474412
TI  - [Efficiency assessment of investment in workers' health--economic issues].
AB  - The economic analysis of efficiency of investment in health care and health at
      large by means of cost-benefit or cost-effectiveness techniques is the subject of
      implementation work in a number of countries. Poland's integration with the
      countries of the European Union justifies the need to understand and to use
      economic analyses. Unfortunately, these activities encounter many methodological
      and executive barriers. The investments in workers' health are not only
      investments in health care and the improvement of working conditions, but also in
      compensations, including financial ones, resulting from adverse effects of
      factors influencing the health of working population. The financial reporting
      system that exists in Poland does not ensure the possibility of full presentation
      of the aggregated data on the financing of activities for workers' health and
      diminishing of the adverse effects of factors present in the work environment.
      The information on the outcome of the investments in workers' health come from
      different sources, which means that it applies to different groups subjected to
      the analysis. The problem lies not only in the assessment of profitability of
      health investments but also in the social problem of the division of the
      resultant costs and benefits among various branches of the national economy.
      Therefore, the analyses involving mutual relations between individual sectors
      that invest in workers' health and those that bear consequences is essential in
      the terms of economic analyses. The authors present the determinants of economic
      evaluation in regard to health of working population in Poland.

PMID- 12474413
TI  - [Economic prerequisites of active influenza prevention].
AB  - Influenza and other acute infections of the upper respiratory tract are
      characterized by a high morbidity and mortality. As a result, they entail not
      only human but also economic consequences. A typical treatment is nonspecific and
      conservative. It consists of treatment with nonsteroid antiinflammatory drugs,
      antitussive drugs, hydratation, etc. Influenza is very often associated with
      complications especially in high risk groups (children, the elderly, chronically
      ill people). The cost of treatment increases because of raising costs of
      pharmacotherapy and the increased absence from work. Vaccination is a safe and
      morbidity-diminishing method.

PMID- 12474414
TI  - [The role of Helicobacter pyroli in the development of skin diseases].
AB  - The paper presents the current state-of-the-art concerning the effect of
      Helicobacter pyroli infection on the progress of some skin diseases (Raynaud's
      disease, purpura hyperergica, rosacea, prurigo nodularis, atopic dermatitis,
      chronic urticaria). The attention was turned to the lack of unanimity among
      authors respective to the effect of Helicobacter pylori on the progress of some
      skin diseases, especially those of allergic etiology. The methods of bacteria
      identification were discussed. The methods are as follows: invasive tests
      involving endoscopy of the upper segment of the alimentary tract--a traumatic
      test, histologic examination and bacteria culture as well as noninvasive tests:
      respiratory test and serological tests able to detect the humoral response to
      infection or examination of the bacteria genetic material by means of PCR. The
      therapeutic methods used to eradicate effectively the infection, recommended by
      the Working Group of the Polish Association of Gastroenterology (a three
      component treatment for seven days--a drug able to diminish gastric secretion and
      two antibiotics) are also discussed.

PMID- 12474415
TI  - [Could a health service worker with viral hepatitis be a danger to patients? An
      attempt to assess the problem in Poland].
AB  - The paper presents current problems regarding the risk for viral hepatitis
      transmission to patients by health service workers infected with this disease. In
      Poland, the scientific assessment of this problem has not as yet been undertaken.
      Moreover, there is a lack of preventive measures and legal regulations in this
      area. In our country, the stay in a hospital is accompanied by a high risk of
      viral hepatitis infection (hospital infections make 60% of all HBV cases). In
      view of the HBV and HCV preventive programs carried out in many countries, the
      Polish specialists should turned attention to the virus carriers among health
      service workers. The authors propose to establish a legal framework aimed at
      reducing the risk of patient' infection with viral hepatitis by a health service
      worker. The experience of other countries presented in this paper may prove to be
      a useful guide in taking appropriate steps.

PMID- 12474416
TI  - [Yersinia pestis as a dangerous biological weapon].
AB  - Plague is an infectious disease caused by the Yersinia pestis microorganism,
      which is transmitted to the human host from a natural reservoir (different rodent
      species) by a flea bite. Plague is still encountered in humans in the areas of
      its enzootic prevalence in local rodent populations. Infection by flea bite
      results in a bubonic or septicemic plague, possibly complicated by secondary
      pneumonia. The person with pneumonic symptoms may be a source of a droplet-borne
      inhalatory infection for other people who consequently develop primary pneumonic
      plague. Despite a clinical form, plague is a severe infection characterized by a
      short incubation period, rapid onset and quick progress with mortality exceeding
      50% if not treated properly. The pneumonic plague is associated with a
      particularly rapid progress and the mortality rate of almost 100% if not treated
      properly. As Yersinia pestis can be easily obtained and cultured and is highly
      pathogenic for humans, it poses a serious threat of being used for bioterrorism
      purposes. Artificially created aerosol containing plague bacilli can cause
      numerous and almost simultaneous cases of primary pulmonic plague in an exposed
      population. Persons exposed would most likely develop severe pneumonia with
      rapidly progressing respiratory and circulatory failure. The use of the Yersinia
      pestis strains resistant to antibiotics typically applied cannot be excluded.

PMID- 12474417
TI  - [Professional cooperation between occupational medicine practitioners and general
      practitioners].

PMID- 12474418
TI  - Even in California, capitation no longer one-size-fits-all.

PMID- 12474419
TI  - Evolution of risk in California portends future trends.

PMID- 12474420
TI  - Ancillary, outpatient costs driving commercial premium increases.

PMID- 12474421
TI  - Losses mount for medical groups in face of competition, regulations.

PMID- 12474422
TI  - Evolutionary partial differential equations for biomedical image processing.
AB  - We are presenting here a model for processing space-time image sequences and
      applying them to 3D echo-cardiography. The non-linear evolutionary equations
      filter the sequence with keeping space-time coherent structures. They have been
      developed using ideas of regularized Perona-Malik an-isotropic diffusion and
      geometrical diffusion of mean curvature flow type (Malladi-Sethian), combined
      with Galilean invariant movie multi-scale analysis of Alvarez et al. A
      discretization of space-time filtering equations by means of finite volume method
      is discussed in detail. Computational results in processing of 3D echo
      cardiographic sequences obtained by rotational acquisition technique and by real
      time 3D echo volumetrics acquisition technique are presented. Quantitative error
      estimation is also provided.

PMID- 12474423
TI  - Cancerous nuclei detection on digitized pathological lung color images.
AB  - In this paper, we propose a methodology (in the form of a software package) for
      automatic extraction of the cancerous nuclei in lung pathological color images.
      We first segment the images using an unsupervised Hopfield artificial neural
      network classifier and we label the segmented image based on chromaticity
      features and histogram analysis of the RGB color space components of the raw
      image. Then, we fill the holes inside the extracted nuclei regions based on the
      maximum drawable circle algorithm. All corrected nuclei regions are then
      classified into normal and cancerous using diagnostic rules formulated with
      respect to the rules used by experimented pathologist. The proposed method
      provides quantitative results in diagnosing a lung pathological image set of 16
      cases that are comparable to an expert's diagnosis.

PMID- 12474424
TI  - Measuring agreement in medical informatics reliability studies.
AB  - Agreement measures are used frequently in reliability studies that involve
      categorical data. Simple measures like observed agreement and specific agreement
      can reveal a good deal about the sample. Chance-corrected agreement in the form
      of the kappa statistic is used frequently based on its correspondence to an
      intraclass correlation coefficient and the ease of calculating it, but its
      magnitude depends on the tasks and categories in the experiment. It is helpful to
      separate the components of disagreement when the goal is to improve the
      reliability of an instrument or of the raters. Approaches based on modeling the
      decision making process can be helpful here, including tetrachoric correlation,
      polychoric correlation, latent trait models, and latent class models. Decision
      making models can also be used to better understand the behavior of different
      agreement metrics. For example, if the observed prevalence of responses in one of
      two available categories is low, then there is insufficient information in the
      sample to judge raters' ability to discriminate cases, and kappa may
      underestimate the true agreement and observed agreement may overestimate it.

PMID- 12474425
TI  - Characteristic attributes in cancer microarrays.
AB  - Rapid advances in genome sequencing and gene expression microarray technologies
      are providing unprecedented opportunities to identify specific genes involved in
      complex biological processes, such as development, signal transduction, and
      disease. The vast amount of data generated by these technologies has presented
      new challenges in bioinformatics. To help organize and interpret microarray data,
      new and efficient computational methods are needed to: (1) distinguish accurately
      between different biological or clinical categories (e.g., malignant vs. benign),
      and (2) identify specific genes that play a role in determining those categories.
      Here we present a novel and simple method that exhaustively scans microarray data
      for unambiguous gene expression patterns. Such patterns of data can be used as
      the basis for classification into biological or clinical categories. The method,
      termed the Characteristic Attribute Organization System (CAOS), is derived from
      fundamental precepts in systematic biology. In CAOS we define two types of
      characteristic attributes ('pure' and 'private') that may exist in gene
      expression microarray data. We also consider additional attributes ('compound')
      that are composed of expression states of more than one gene that are not
      characteristic on their own. CAOS was tested on three well-known cancer DNA
      microarray data sets for its ability to classify new microarray samples. We found
      CAOS to be a highly accurate and robust class prediction technique. In addition,
      CAOS identified specific genes, not emphasized in other analyses, that may be
      crucial to the biology of certain types of cancer. The success of CAOS in this
      study has significant implications for basic research and the future development
      of reliable methods for clinical diagnostic tools.

PMID- 12474426
TI  - Evidence-based careflow management systems: the case of post-stroke
      rehabilitation.
AB  - The activities of a care providers' team need to be coordinated within a process
      properly designed on the basis of available best practice medical knowledge. It
      requires a rethinking of the management of care processes within health care
      organizations. The current workflow technology seems to offer the most convenient
      solution to build such cooperative systems. However, some of its present
      weaknesses still require an intense research effort to find solutions allowing
      its exploitation in real medical practice. This paper presents an approach to
      design and build evidence-based careflow management systems, which can be viewed
      as components of a knowledge management infrastructure each health care
      organization should be provided with to increase its performance in delivering
      high quality care by efficiently exploiting the available knowledge resources.
      The post-stroke rehabilitation process has been taken as a challenging care
      problem to assess our methodology for designing and developing careflow
      management systems. Then a system was co-developed with a team of rehabilitation
      professionals who will be committed to use it in their daily work. The system's
      main goal is to deliver a full array of rehabilitation services provided by an
      interdisciplinary team. They are related to identify which patients are most
      likely to benefit from rehabilitation, manage a rehabilitation treatment plan,
      and monitor progress both during rehabilitation and after return to a community
      residence. A model of the rehabilitation process was derived from an
      international guideline and adapted to the local organization of work. It
      involves different organizational units, such as wards, rehabilitation units,
      clinical laboratories, and imaging services. Several organizational agents work
      within them and play one or more roles. Each role is defined by the goals' set
      that she/he must fulfill. Special effort has been given to the design and
      development of a knowledge-based system for managing exceptions, which may occur
      in daily medical work as any deviation from the normal flow of activities. It
      allows either avoiding or recovering automatically from expected exceptions. When
      they are not expected, organizational agents, with enough power to do that, are
      allowed to modify the scheduled flow of activities for an individual patient
      under the only constraint of justifying their decision. After an intensive
      testing in a research laboratory, the system is now in the process of being
      transferred in a real working setting with the full support of its future users.

PMID- 12474427
TI  - Comparative genomics approaches to study organism similarities and differences.
AB  - Comparative genomics is a large-scale, holistic approach that compares two or
      more genomes to discover the similarities and differences between the genomes and
      to study the biology of the individual genomes. Comparative studies can be
      performed at different levels of the genomes to obtain multiple perspectives
      about the organisms. We discuss in detail the type of analyses that offer
      significant biological insights in the comparisons of (1) genome structure
      including overall genome statistics, repeats, genome rearrangement at both DNA
      and gene level, synteny, and breakpoints; (2) coding regions including gene
      content, protein content, orthologs, and paralogs; and (3) noncoding regions
      including the prediction of regulatory elements. We also briefly review the
      currently available computational tools in comparative genomics such as
      algorithms for genome-scale sequence alignment, gene identification, and
      nonhomology-based function prediction.

PMID- 12474428
TI  - Calculating costs for an episode of care.

PMID- 12474429
TI  - Successes and challenges in treating obesity.

PMID- 12474430
TI  - The hypercoagulable state as a risk factor for venous thromboembolism. Part 1.

PMID- 12474432
TI  - Drainage for an acute paronychia.

PMID- 12474431
TI  - A cost analysis of physician assistants in primary care.
AB  - Acute medical conditions commonly seen by physician assistants (PAs) or
      physicians were assigned costs for all resources used to treat an episode of
      illness. Included in the analysis were data on the provider of record for the
      episode, patient characteristics, health status, diagnosis, treatment, referrals,
      medication, imaging, laboratory studies, and return visits. In every medical
      condition managed by PAs, the total episode cost was less than a similar episode
      managed by a physician, regardless of patient age, gender, health status, and
      department. Few differences emerged in the use of resources and the rate of
      return visits for a diagnosis between physicians and PAs. In this setting PAs
      appear to be cost-effective from an employment standpoint.

PMID- 12474433
TI  - [Past, present, and future therapeutically options in age related macular
      degeneration].
AB  - Age related macular degeneration is the most common cause of blindness in
      patients older than 65 years of age and it ranks second after diabetic
      retinopathy as the leading cause of blindness in the 45 to 64 years age group.
      Along the time, an important number of therapeutical options was developed, in
      association with the pathogenic hypothesis: medication, laser treatment,
      photodynamic therapy, surgical methods, etc. The goal of this paper is to
      summarize the evolution of the main therapeutical approaches in age related
      macular degeneration.

PMID- 12474434
TI  - [Ocular injuries due to allergic mechanism].
AB  - The paper presents the main ocular injuries due to allergic mechanism and it
      point out the actual data about etiopathogenesis of type 1 hypersensitivity and
      immunologic mechanism involved in allergic keratoconjunctivitis. Then are exposed
      the classification of ocular allergy, the main signs and symptoms, the
      paraclinical methods of diagnosis and the actual agents of therapy.

PMID- 12474435
TI  - [Cataract surgery. Anterior capsulorrhexis technique].
AB  - The cataract surgery is in a continuous dynamic because of the technological
      progress. The last years the surgical technique for cataract has changed and the
      most important progresses are the use of small incisions that don't require
      sutures, the realise of the anterior capsulotomy with smooth margins (continuous
      circular capsulorrhexis) and the extracapsular extraction of the cataract by
      phacoemulsification. The authors described the most usual techniques of the
      anterior capsulotomy with the advantages offered by capsulorrhexis, an important
      surgical step from the manual extracapsular extraction of the cataract to
      phacoemulsification.

PMID- 12474436
TI  - [Syphilitic uveitis].
AB  - The authors show that syphilis can affect the anterior and posterior ocular
      segment and present history, symptoms, clinical forms, laboratory tests,
      prognosis and treatment.

PMID- 12474437
TI  - [Macular cystoid edema in eyes with secondary glaucoma after surgery].
AB  - The authors a case of a 53 year old patient who has been under observation of the
      Ophthalmologic Department from lassy Railway Hospital since September 2000. The
      the diagnosis was on both eyes: Operate Inflammatory Secondary Glaucoma.
      Incipient Cataract. Anterior Uveiti Sechelae. Cicatricial Corioretinitis. In
      January 2001 this patient came in our clinic on the right eye with acute decrease
      of visual acuity from 1/6 to 1/25 on white, unpainful eye, with marked ocular
      hipotony. The suspected etiologic diagnosis was initially RE: Intermediate
      Uveitis. After local and general treatment with corticosteroid antiinflammatory
      agents the inflammatory phenomena was decreased but the visual acuity remained
      unchanged. After that we suspected macular cystoid edema. The cause of the visual
      acuity decrease remains obscure and this case underlines the difficulties meeting
      on the therapeutic management of the glaucoma on an eye with numerous associated
      diseases.

PMID- 12474438
TI  - [Complications of palpebral epitheliomas: diagnostic, therapeutic, and prognostic
      implications].
AB  - PURPOSE: To illustrate two cases of palpebral tumors that determined local
      complications, with consequences on the preoperative diagnosis and the surgical
      treatment (case 1) and on the functional prognosis of the eye (case 2). METHOD:
      The history and evolution of the cases, the surgical techniques, the
      histopathological reports and the anatomical and functional results are described
      and analyzed. RESULTS: In case 1, the extension of the tumor led to a
      considerable tissular defect that claimed for a long and hard surgery for the
      anatomical and functional repair of the region. In case 2, the vegetant evolution
      of the tumor determined the irritation of the cornea and consecutive corneal
      ulcer that perforated, with the functional loss of the eye. CONCLUSIONS: The two
      cases are revealing aspects that are less frequent in the ophthalmic practice.
      They signalize, besides the deffisient adresability of the patient, the problem
      of the "territorial dispute" over the palpebral surgery between different
      specialties.

PMID- 12474439
TI  - [Secondary glaucoma in iridocorneal syndromes; difficulties in therapeutical
      approaches].
AB  - The authors present a case of a 29 year old patient who has been diagnosed on the
      right eye with Cogen-Reese syndrome and secondary glaucoma in 1997. This case
      came in the Ophtalmologic department from the lassy Railway Hospital in August
      2000. For the treatment of the glaucoma and other associated complications it was
      realised on this eye: Cairns trabeculectomy with 5 FU, perforated keratoplasty,
      Laserphaco with PC-IOL, Laser selerostomy, goniotrepanation, explant of the IOL.
      Despite of the best cooperation of the patient and the numerous applicated
      therapeutical methods this case has a harm evolution and the obtaining of a
      morpho-functional balance on this eye seems to be a purpose impossible to reach.

PMID- 12474440
TI  - [Therapeutical, and evolutive particular aspects in cataract surgery].
AB  - Even if the ophthalmic surgeons are concentrated, most of the time, on the
      surgery, they have to remember all other aspects related with the general status
      of the patient, because these could influence the ultimate visual outcome. The
      paper presents some cases of cataract operated in our Clinic, having particular
      aspects: clinical, therapeutical and evolutive aspects. In these cases, the
      coexisting diseases of the patients have requested special diagnostic procedures,
      anti-infectious prophylaxis, special postoperative management or laser
      treatments.

PMID- 12474441
TI  - [Visual evoked potentials and ultrasonography in ischemic optic neuropathy].
AB  - THE AIM OF THE PAPER: To emphasize the importance of the examination VEP and
      Doppler ultrasonography for ION diagnostic establishment and their monitoring.
      MATERIALS AND METHODS: There have been taken into VEP examination 43 patients,
      simple stimuli (flash) having used. For Doppler ultrasonography there have been
      taken into examination 38 patients whose extracerebral carotidian arterial system
      and ophthalmic artery have been examined. RESULTS AND DEBATES: The VEP
      examination at the beginning of NOI have emphasized a depress of the amplitude of
      the VEP with normal VEP latency in 65.1% of cases and a depress of the amplitude
      with prolonged latency time in 4.7% of cases. VEP examination after 7-14 days
      from the ION beginning have emphasized only the depress of the amplitude in 48.8%
      of cases. Doppler ultrasonography examination have emphasized diffuse
      atherosclerotic lesions in 81.6% of cases and local carotidian stenosis in 7.9%
      of cases. CONCLUSIONS: VEP and Doppler ultrasonography examinations complete in
      an efficient way the range of clinical examinations and permit the getting of
      useful results in ION diagnosis. The examinations are complementary allowing the
      estimation of the nervous conductibility degree of deterioration and of the
      vascular pathway of the illness. VEP and Doppler ultrasonography are easy
      reproducible and non-aggressive methods which bring important diagnosis elements
      and allow ION monitoring.

PMID- 12474442
TI  - [Clinical aspects in ischemic optic neuropathy].
AB  - THE PURPOSE OF THE PAPER: Clinical evaluation of the patients suffering of
      Ischaemic Optic Neuropathy (ION) for the establishment of a quick and accurate
      diagnosis and a therapeutical strategy. MATERIAL AND METHOD: There have been
      taken into study 56 patients whose epidemiological, aetiological aspects and
      clinical manifestations were followed up from the beginning and during the
      evolution. RESULTS AND DEBATES: In ION aetiology there have been found:
      atherosclerosis + systemic hypertension (87.4%); giant cell arteritis (7.2%);
      normal-tension glaucoma (3.6%) and systemic hypotension (1.8%). Diabetes mellitus
      and dislipidemia have been found in 21.4% of cases. In most of the cases the
      visual acuity was quickly reduced affecting only one eye, in two of the cases it
      was bilaterally affected. CONCLUSIONS: ION affects old people, without any
      differences between sexes, whose predominant aetiology is atherosclerosis
      associated with hypertension. ION are serious illnesses, the visual deficit
      persists or get worse even if an appropriate treatment is made. The establishment
      of the aetiology, arteritical or atherosclerotical, has a great clinical
      importance for the therapeutics strategy.

PMID- 12474443
TI  - [Arterial hypotension-risk factor in nonarteritic anterior ischemic optic
      neuropathy].
AB  - PURPOSE: To determine whether a decrease a arterial blood pressure may be a risk
      factor in occurrence of non-arteritic anterior ischemic optic neuropathy (NAION).
      METHODS: Two groups of patients were followed up: group I--with arterial
      hypertension treated with hypotensive therapy and without NAION.; group II--with
      arterial hypertension treated with hypotensive drugs and NAION previously
      diagnosticated--Ophthalmologic evaluation (including visual acuity, visual
      fields, intraocular pressure, slit lamp and ophthalmoscopic evaluation, relative
      afferent pupillary defect) was performed. Systemic evaluation consist in blood
      tests (including erythrocyte sedimentation rate and Creative protein),
      echocardiography and 24-hours blood pressure monitoring. RESULTS: A significant
      low blood pressure was found at the patients with affected eyes (with NAION) in
      comparison to the patients with unaffected eyes. CONCLUSIONS: Decrease of blood
      pressure may be considered a characteristic risk factor of NAION, leading to a
      vascular insufficiency in the optic nerve head.

PMID- 12474444
TI  - [Diagnosis and treatment of orbital inflammations].
AB  - The purpose of this study is to describe current investigations and treatment in
      orbital inflammations. It usually occurs complications of maxillary sinuses,
      although it also be caused by dental infections or oculo-facial trauma. Diagnosis
      of orbital cellulitis is necessary to be early and will be clinically with
      radiologic or CT-scan confirmation. Treatment is medical in conjunction with
      ocular, dental and sinus surgery.

PMID- 12474445
TI  - [Unilateral myelinated nerve fibers associated with myopia or amblyopia].
AB  - There are described a number of 9 clinical cases with unilateral myelinated nerve
      fibers, associated with myopia or amblyopia. Four cases developed extended
      myelinated areas, anisometropia with increased values, accentuated amblyopia and
      macular changes. Patients underwent treatment for amblyopia through correction
      with spectacles lenses and the occlusion of the congenerous eye. The obtained
      functional results differentiated the casemix in two groups: with therapeutic
      failure, 4 cases, characterized by extended myelination, anisometropia with an
      average of over -10 diopters and macular changes. with therapeutic success, 5
      cases, characterized by reduced myelination, anisometropia with an average of
      over -4 diopters and normal maculae. It has been found a significantly
      statistical difference between the two groups as regarding the value of the
      anisometropia. However, the macular aspect has been an important factor in order
      the therapeutic effect to succeed. This clinical syndrome is differentiated from
      the unilateral simple myopia with amblyopia and from the myelinated nerve fibers
      without myopia or amblyopia.

PMID- 12474446
TI  - [Secondary cataract; correlations concerning lens surgery and pseudophakia type.
      Therapeutic aspects].
AB  - The study presents the correlations concerning the advent of the secondary
      cataract depending on the surgical technique and pseudofak type (PMMA, acrylic,
      siliconic), as well the safety and efficacy of the YAG: Nd capsulotomy. A 3 years
      clinical retrospective trial was done on 320 eyes operated for senile cataract.
      The incidence of the secondary cataract was 11.4%, usually after 12 months, (the
      lower in phacoemulsification using acrylic IOL). Nd: YAG capsulotomy being done
      in cases with visual acuity lower than 0.6.

PMID- 12474447
TI  - [Noninfectious uveitis after extracapsular lens extraction].
AB  - PURPOSE: To reveal the etiopathogenic features of the noninfectious uveitis after
      extracapsular lens extraction, with or without artificial lens implantation.
      METHOD: A retrospective study including 33 patients with noninfectious uveitis
      after extracapsular lens extraction with or without artificial lens implantation
      has been performed. The patients have been selected exclusively according to
      clinical criteria. RESULT: In 27 patients (80.80%), risk factors for the
      postoperative uveitis have been identified. Among these, the most frequently
      incriminated has been the operation itself (14 cases--42.42%), with the
      persistence of cortical material on the first place: 10 cases (30.30%).
      CONCLUSION: The unfavourable evolution of the uveitis has been associated with
      the following risk factors: previous uveitis, the incorrect position of the
      artificial lens, rheumatoid arthritis, diabetes mellitus.

PMID- 12474448
TI  - [Management of intra-vitreous hemorrhage in diabetics].

PMID- 12474449
TI  - [Filtering bleb failure of open angle glaucoma].
AB  - PURPOSE: To analyze the frequency and the causes of trabeculectomy failure in
      primary and secondary open angle glaucoma and the results of the individual
      treatment in these cases. METHOD: Retrospective study that includes 69
      trabeculectomy failures. Filtering bleb failure was recorded in 49 cases of
      primary open glaucoma and 21 cases of secondary open angle glaucoma. The slit
      lamp examination and the gonioscopy clarify the causing mechanism of the failure.
      The treatment has been established in an individual manner in order to achieve
      stable control of intraocular pressure (under 21 mmHg) RESULTS: The cause of the
      early failure (15 cases) was the obstruction of the internal ostium of the
      trabeculectomy in 10 cases, episcleral and conjunctival fibrosis in 4 cases and
      encapsulated bleb in 1 case. Episcleral and conjunctival fibrosis in 46 cases and
      encapsulated bleb in 6 cases have caused the late failure. The most effective
      option in early failure of trabeculectomy was internal de-sobstruction. In late
      failures, additional medical therapy and a second filtering surgery combined with
      antifibrotic agents were the most effective and commonly techniques. CONCLUSIONS:
      Immediate recognition of the failure, the ascertaining of the etiology and of the
      appropriate treatment allows a high rate therapeutic success achievement.

PMID- 12474450
TI  - [Efficacity of diode laser photocoagulation in retinal neovascularization
      treatment in diabetic retinopathy].
AB  - Retinal neovascularization (NVR) is a common complication of diabetes, which can
      cause legal blindness. This article presents the results of a study on 32
      diabetic patients with NVR treated by DIODE LASER panretinal fotocoagulation.

PMID- 12474451
TI  - [Clinical and therapy features of ocular toxoplasmosis in patients with HIV-AIDS
      infection].
AB  - The paper presents clinical and therapy features of the ocular Toxoplasmosis in
      patients with HIV-AIDS infection. Four cases of AIDS have been observed in witch
      has been recognized the ocular toxoplasmosis (two at children and two at adults).
      It was watched the evolution under treatment of the lesions caused by the
      parasite and it was appreciated the efficiency of the therapy. CONCLUSION: The
      antitoxoplasmosis therapy is made in the same way as at the immunocompetents
      patients, but it must be followed by a maintenance treatment all the patience's
      life.

PMID- 12474452
TI  - [Age related macular degeneration surgery].
AB  - Age related macular degeneration (ARMD) is a disease in which the retinal pigment
      epithelium (RPE) is damaged in the central retinal area. In the exudative form,
      the vision loss is due to choroidal neovascularization, while in the nonexudative
      or atrophic form, there is a vision loss because of the retinal pigment
      epithelium atrophy. Treatment which proved to be efficient in lowering the risk
      of severe vision loss in the exudative form includes laser photocoagulation,
      photodynamic therapy, transpupilary thermotherapy and as surgical treatment, the
      controversial subretinal membrane extraction. In all these situations the RPE is
      damaged by the disease itself and by the therapeutic procedure too. Retinal
      translocation is a surgical procedure that intends to remove the neurosensory
      retina from an area with damaged RPE to an healthy RPE area, through a 360
      degrees retinotomy or through a limited one. This paper present some ARMD cases
      treated by subretinal membrane extraction and one by limited retinal
      translocation. The question which is still remaining is which are the risks and
      benefits for the following treatment procedures: laser photocoagulation,
      photodynamic therapy, transpupilary thermotherapy and surgical approach?

PMID- 12474453
TI  - [Interpretation of visual field with Humphrey Zeiss Analyser].
AB  - In the beginning of the article where are defined the notions of the soft of
      automated perimetry: threshold, kind of tests, the strategy of automated
      perimetry. Then are shown the steps of automated perimetry interpretation: kind
      of test and strategy, evaluation of patient reliability, interpretation of the
      visual field defects (artifacts or no) and statistical analysis.

PMID- 12474455
TI  - [Causes of disabling forms of tuberculous spondylitis].
AB  - To define the causes of disabling forms of tuberculous spondylitis, 218 patients
      with advanced complicated forms of tuberculosis of the vertebral column were
      examined. Their specific process was complicated by abscesses, fistulas,
      deformity, and instability of the affected portion of the vertebral column, and
      neurological disorders. Analysis of clinical findings has indicated that the main
      causes of complications are late diagnosis of the disease and general
      practitioners' poor special knowledge. Diagnostic errors may be also caused by a
      larger number of asymptomatic and atypical forms of tuberculous spondylitis.
      Diagnosis and differential diagnosis should be improved in order to prevent
      complications due to spinal tuberculous and as a result its disabling forms.

PMID- 12474454
TI  - [On grouping the contingents of tuberculosis dispensaries].
AB  - The contingents followed up at the dispensaries in the Ukraine are analyzed.
      These include as high as 15.42% of patients with tuberculosis, 5.03% with
      questionable tuberculosis, 67.13% with inactive tuberculosis or infections, and
      12.42% of persons contacting with patients. A total of 4.84% of the
      appropriations are used to follow up the contingents. A new procedure for
      grouping TB dispensary contingents is proposed.

PMID- 12474456
TI  - [Risk factors for tuberculosis, specific features of its detection and course].
AB  - Risk factors for tuberculosis were ranged in 112 new cases. Under the present
      conditions, the tuberculous process were shown to run by manifesting significant
      symptoms associated with the predominance of exudative inflammation, with
      considerable extension of the process, and a high frequency of lung tissue
      destruction. Bacterial isolation was massive, accompanied by primary drug
      resistance in 35%. The author shows it necessary to activate work on the
      detection and prevention of tuberculosis.

PMID- 12474457
TI  - [Characterization of life quality in patients with respiratory tuberculosis
      treated in the outpatient setting].
AB  - The overall Life Quality-100 questionnaire recommended by the World Health
      Organization was used to survey 29 patients with active respiratory tuberculosis
      and 19 healthy persons. Life quality (LQ) was assessed by 24 items pooled to form
      6 categories. There were significant differences in the overall life quality and
      in the mental health scale. The activity, mobility, physical status of the
      patients were impaired. The survey revealed the aspects lowering LQ in patients
      with active respiratory tuberculosis. It is concluded that individual
      psychosocial correction of the status of a patient with tuberculosis is promising
      in making his/her life quality normal.

PMID- 12474458
TI  - [Clinical and functional comparisons in patients with tuberculous pleurisy].
AB  - Forty four patients with tuberculous pleurisy or pulmonary tuberculosis
      complicated by pleurisy were examined. The examination was made before or in the
      first days after antituberculous chemotherapy. Along with routine methods used to
      examine patients with tuberculosis, a complex study of external respiration
      function involved spirometry, air flow/volume on forced expiration, body
      plethismography, esophageal probing of respiratory mechanics. Analysis indicated
      that RD was significantly more frequently observed in tuberculous pleurisy
      concurrent with infiltrative tuberculosis (81%) than in the former alone (50%).
      Restrictive disorders were diagnosed significantly more commonly in encysted
      pleurisy than in free one. Obstruction was significantly more frequently
      encountered in tuberculous changes in the lung (80%) than in pleurisy alone
      (46%). Statistical analysis demonstrated a significant contingency of the
      incidence and severity of restrictive disorders and bronchial obstruction, which
      is likely to suggest of the common tuberculous nature of these ventilatory
      disturbances. The dynamic and static compliance of the lung significantly
      decreased as the severity of restriction increased. The spirometric indices, such
      as total lung capacity (TLC) and forced expiratory volume (FEVI), and the indices
      of dynamic and static compliance of the lung (Cdyn, Cst) (the correlation
      coefficient (r) with the degree of restrictive disorders was -0.78, -0.76, -0.48,
      and -0.45, respectively; p < 0.05) are of the greatest informative value in
      evaluating restrictive disorders. At the same time, the severity of obstructing
      lesions correlated with the air flow indices IVS25, IVS50, IVS75, and the
      Tiffeneau index (r = -0.74, -0.82, -0.81, and -0.75, respectively; p < 0.05).

PMID- 12474459
TI  - [Efficiency of supra-venous blood laser radiation used in the treatment of
      disseminated pulmonary tuberculosis in adolescents].
AB  - In 19 of 40 adolescent patients with disseminated pulmonary tuberculosis,
      supravenous blood laser radiation was used in the complex treatment 2-3 weeks
      after the initiation of chemotherapy. The use of this type of laser therapy
      enhanced the efficiency of the treatment, accelerated positive changes of
      tuberculosis by 2.5-3.5 months, as evidenced by clinical and laboratory
      parameters, led to a smooth course of tuberculosis to develop less pronounced
      residual changes in the lung.

PMID- 12474460
TI  - [Unipolar endoprosthesis of the hip joint in fracture of the neck of the femur in
      elderly patients with different forms of pulmonary tuberculosis].

PMID- 12474462
TI  - [Biochemical characteristics of fluid and cells of bronchoalveolar washings in
      patients with extrinsic allergic alveolitis].
AB  - In 43 patients with exogenous allergic alveolitis (EAA), including 30 and 13 in
      its acute and chronic disease, bronchoalveolar lavage was performed,
      bronchoalveolar washing fluid (BAWF), isolated alveolar macrophages (AM) and
      unfractionated cellular sediment (NFCS) were separately studied. The BAWF showed
      high rates of lipid peroxidation (LPO), decreased antiproteolytic defense, and
      activated local synthesis of haptoglobin (Hp), fibronectin (FN), platelet
      activation factor (PAF), and enzymes of antioxidative defense (AOD). There was a
      rise in FN and PAF concentrations in the acute phase of the disease and higher
      PLO rates and elevated Hp levels in chronic EAA. The rate of oxidative metabolism
      in AMs was much higher in acute EAA than that in chronic EAA and accompanied by
      imbalance in the PLO-AOD system. AM levels of PAF was high in patients in both
      groups. The rate of LPO was higher in NFCS than in AM and was also followed by
      simultaneous AOD mobilization with preserved imbalance. A particularly
      significant AOD insufficiency in the NFCS was noted in chronic EAA, which was
      accompanied by decreased PAF. Thus, local pathochemical processes are of
      significance in developing the pattern of the process in EAA.

PMID- 12474461
TI  - [Alveolar macrophage section of cytokines and levels of phospholipids in the
      bronchoalveolar washing in pulmonary sarcoidosis and tuberculosis].
AB  - Sixty seven patients with sarcoidosis and 12 patients with pulmonary tuberculosis
      were examined. A control group comprised 9 apparently healthy individuals. The
      alveolar macrophages (AM) isolated from the bronchoalveolar washing (BAW) of
      patients with both sarcoidosis and tuberculosis secreted elevated amounts of IL-6
      (by 11 and 5.6 times, respectively) as compared to the controls. However,
      patients with no BAW lymphocytosis there were no great differences in the level
      of IL-6 production between sarcoidosis and tuberculosis. In this connection, it
      is not advisable to determine the production of AM cytokines for differential
      diagnosis of pulmonary sarcoidosis and tuberculosis. There were significant
      differences in the BAW concentrations of phospholipids in sarcoidosis and
      tuberculosis. Tests for total lipid phosphorus and cumulative phosphatidylcholine
      were found to be of the highest sensitivity and may be used for differential
      diagnosis. In questionable cases if the level of total lipid phosphorus is
      greater than 21.36 (M P/L (M + 26, there will be 98.3% probability for no
      tuberculosis in such a patient.

PMID- 12474463
TI  - [Research in accordance with the Phthisio-pulmonary research program in 2001].

PMID- 12474464
TI  - [Current aspects of teaching phthisiopulmonology to senior students of a medical
      university].

PMID- 12474465
TI  - [Commemorating A. I. Abrikosov].

PMID- 12474466
TI  - [Informatics networks of phthisiopediatric services].

PMID- 12474467
TI  - [Report of the Minister of Health of the Russian Federation at the Summary
      Collegium Conference on March 19-20, 2002 (continued)].

PMID- 12474468
TI  - Resistance of Schistosoma mansoni to praziquantel: is there a problem?
AB  - Evidence for resistance to praziquantel (PZQ) in Schistosoma mansoni has been
      sought in parasites taken from treated, but uncured human patients, and in a
      laboratory isolate of S. mansoni subjected to successive passages under drug
      pressure. Patients from villages in Egypt and Senegal have yielded isolates that
      can tolerate higher dosages of PZQ than other ostensible control isolates when
      passaged and subjected to drug treatment in mice. In vitro tests on these and the
      laboratory-selected isolate support the conclusion that a degree of resistance to
      PZQ can occur in S. mansoni, but the levels of drug resistance found so far are
      low. Preliminary studies have begun on these isolates to identify genetic,
      physiological and morphological characteristics associated with PZQ resistance
      and some of these may find use as markers for monitoring whether or not
      resistance is developing in endemic areas where the drug is used. More intensive
      application of PZQ can be expected in future, particularly in other parts of
      Africa, and vigilance will be needed to ensure that it continues to be useful as
      a drug for treatment of schistosomiasis. Further work is needed to elucidate the
      mode of action of PZQ and there is already a need for alternative drugs to treat
      PZQ-resistant schistosomiasis, such as already exists in northern Senegal.

PMID- 12474469
TI  - New insights into the transmission biology of urinary schistosomiasis in
      Zanzibar.
AB  - A better understanding of the transmission biology of urinary schistosomiasis in
      Zanzibar, Tanzania was only possible after the development of molecular DNA
      markers for identification of Bulinus africanus group snails, the potential
      intermediate hosts of Schistosoma haematobium. Hitherto, identification of
      natural populations of B. globosus and B. nasutus was problematic and the
      intermediate host status and distribution of either species remained speculative.
      By recourse to molecular markers, snail distribution maps could be drawn,
      revealing an allopatric distribution and, more importantly, leading to the
      discovery that B. nasutus played no role in transmission. Indeed, in Unguja the
      area of active transmission of S. haematobium to humans is confined within the
      distribution of B. globosus. This strong relationship may prove useful for
      predicting the distribution of urinary schistosomiasis within Zanzibar and, if
      snail schistosome compatibilities persist, in other areas nearby, e.g. coastal
      Tanzania and Kenya. The transmission biology of urinary schistosomiasis in
      Zanzibar is reviewed, the paper reports on ongoing malacological studies in
      Zanzibar and Kenya and finally closes by posing the question whether medical
      malacology forms an essential component associated with mass-scale chemotherapy
      control programmes.

PMID- 12474470
TI  - Irrigated crop production is associated with less malaria than traditional
      agricultural practices in Tanzania.
AB  - There is concern that crop irrigation that results in increased numbers of vector
      mosquitoes will lead to a rise in malaria in local communities. We evaluated the
      level of malaria experienced in 3 communities in northern Tanzania with different
      agricultural practices: rice irrigation, sugar-cane irrigation and traditional
      maize cultivation. Five cross-sectional surveys were used to measure the
      prevalence of infection with falciparum malaria in 1-4 years old children in each
      community over a period of 12 months. Active case detection was also carried out
      to record clinical episodes of malaria during the study period. Information on
      antimalarial measures was also recorded. Results from the cross-sectional surveys
      showed that the overall prevalence of malaria parasites was less near the rice
      irrigation (12.5%) and sugar-cane (16.9%) schemes than the savannah village
      (29.4%). There were also significantly fewer clinical episodes of malaria in the
      rice village (15 cases/1000 child-weeks at risk [cwar]) than either the sugar
      cane (36 cases/1000 cwar) or savannah (40 cases/1000 cwar) villages. Overall,
      rice irrigation was associated with less malaria than alternative agricultural
      practices, despite the considerable numbers of vectors produced in the paddies.
      This finding supports other studies that indicate that irrigation in much of sub
      Saharan Africa will not lead to increased malaria. Nonetheless, African
      governments planning irrigation projects need effective policies to encourage
      local communities to use personal protection measures, such as insecticide
      treated bednets, and to ensure that these communities have access to effective
      antimalarial drugs and efficient health services.

PMID- 12474471
TI  - Malaria during a multinational military deployment: the comparative experience of
      the Italian, British and Australian Armed Forces in East Timor.
AB  - Although their efficacy has been shown to be similar in south-east Asia,
      doxycycline was less effective than mefloquine for malaria chemoprophylaxis in
      East Timor. Lower adherence, higher incidence of adverse effects and reduced
      bioavailability of doxycycline may have been possible causes. Mefloquine seems
      therefore preferable in arduous and prolonged field conditions.

PMID- 12474472
TI  - Evaluation of a prototype long-lasting insecticide-treated mosquito net under
      field conditions in rural Burkina Faso.
AB  - Insecticide measurements and standard World Health Organization bioassays on
      random samples of new unwashed, traditionally washed and up to 18 months field
      used 'long-lasting' deltamethrin treated mosquito nets demonstrated a rapid
      reduction of efficacy under field conditions. The technology of 'long-lasting'
      insecticide-treatment needs much improvement.

PMID- 12474473
TI  - Geophagy and its association with geohelminth infection in rural schoolchildren
      from northern KwaZulu-Natal, South Africa.
AB  - The social pattern of geophagy (soil-eating) and its possible role in the
      transmission of Ascaris lumbricoides, Trichuris trichiura and hookworm were
      investigated in a rural area of South Africa between March 1998 and July 1999.
      Schoolchildren (median age = 10.7 years; interquartile range 8.3-14.8 years) were
      examined for geohelminth infection at baseline and re-examined 3 and 29 weeks
      after treatment with albendazole. Interviews were conducted with the pupils in
      order to find out about their socio-economic background and their behaviour
      regarding geophagy. Soil-eating was less frequent in boys (39%), where it
      decreased with age, than in girls (53%), where no such age trend was apparent.
      The habit was more common in children from families of higher socio-economic
      status. The baseline prevalence of A. lumbricoides infection was higher in pupils
      who regularly ate soil from termite mounds (28%) when compared with non
      geophageous pupils (19%; prevalence ratio (PR) = 1.46; 95% confidence interval
      (95% CI) 1.04-2.03). In contrast it was markedly lower in the groups who
      preferred eating tree termite soil (13%; PR = 0.67; 95% CI 0.43-1.04) or soil
      from other sources (8%; PR = 0.40; 95% CI 0.15-1.04). This pattern was still
      apparent after adjusting for possible confounders and was also found when
      analysing A. lumbricoides reinfection. In contrast, differences in prevalence of
      T. trichiura and hookworm infection between groups with different soil preference
      were small.

PMID- 12474474
TI  - Outbreak of cutaneous larva migrans in Naples, southern Italy.
AB  - An outbreak of cutaneous larva migrans occurring in Naples, southern Italy, and
      involving 6 people is described. The infection was contracted in the area of
      Naples, through contact with material for dried floral arrangements most probably
      contaminated with dog or cat faeces. The factors that contributed to creating
      ideal conditions for the development and spread of this infection in this area
      are discussed.

PMID- 12474475
TI  - Laboratory vector competence experiments with yellow fever virus and five South
      African mosquito species including Aedes aegypti.
AB  - Three domestic and peridomestic mosquito species, selected because their
      prevalence, distribution and ecology favoured them as potential urban vectors of
      yellow fever (YF) in South Africa, were submitted to numerous tests for
      infectivity [measured as dose needed to infect 50% of the mosquitoes (MID50)],
      mainly with a Kenyan strain (BC7914) of the virus. Use of a Nigerian virus strain
      (TVP1617) did not significantly alter infectivity. After artificial infective
      blood meals with titres of 7.0-8.0 log10MID50/mL, head squash infection rates
      (HSIRs) determined by the indirect fluorescent antibody test were 0-4%
      (Eretmapodites quinquevittatus), 0-29% (Aedes simpsoni s. s.) and 0-21% (5
      populations of Aedes aegypti). For some populations of Ae. aegypti tests were
      repeated with blood meals incorporating freshly prepared rather than frozen mouse
      brain but HSIRs did not increase. HSIRs did increase when a high infecting titre
      of 9.0 log10MID50/mL was used with the Richards Bay population (67-90%). It is
      concluded that these 3 mosquito species are potentially poor YF vectors but that
      Ae. simpsoni and Richards Bay Ae. aegypti are the most susceptible to the virus.
      However, the latter 2 species could support person-to-person transmission only if
      they were present at very high densities. This rarely occurs with Ae. simpsoni in
      South Africa but Ae. aegypti may occur at high densities although only in
      discrete foci. The feral Ae. furcifer and Ae. cordellieri had HSIRs of 29% and 3%
      respectively and Ae. furcifer 'transmitted' the virus in vitro at a transmission
      rate of 25%. This suggests that Ae. furcifer would be more important than Ae.
      cordellieri in transmission between monkeys in West Africa.

PMID- 12474476
TI  - Risk of malaria attacks in Gambian children is greater away from malaria vector
      breeding sites.
AB  - The causes of local variation in the prevalence of malaria were investigated in
      rural Gambia. Cross-sectional prevalence surveys were carried out among 1184
      young children (aged 6 months-5 years) in 48 villages, at the end of the
      transmission season in 1996. Villages were categorized according to distance from
      the nearest vector breeding sites, and the patterns of malaria transmission,
      infection and disease compared. Children living in villages within 3 km of
      breeding sites experienced more infective bites, and higher prevalences of
      parasitaemia and spleen enlargement than less-exposed children living further
      away. Clinical illness, in contrast, was more common among infected children who
      were less exposed. Infected children living 3 km or more from breeding sites were
      more likely to have high-density parasitaemia (odds ratio [OR] = 1.98), fever (OR
      = 2.60) and high-density parasitaemia together with fever (OR = 3.17). Clinical
      attacks did not decline in older children, as seen amongst children who were more
      exposed. These findings show that significant differences in the risk of
      infection and clinical attacks can occur over very short distances. The age at
      which protective immunity is acquired may be delayed in villages where
      transmission intensity is lower, thus increasing the risk of a clinical attack
      following infection. Communities with the lowest vector densities may be those at
      greatest risk of disease.

PMID- 12474477
TI  - Urinary schistosomiasis in schoolchildren on Zanzibar Island (Unguja), Tanzania:
      a parasitological survey supplemented with questionnaires.
AB  - The distribution of urinary schistosomiasis in schoolchildren on Zanzibar Island
      (Unguja) was surveyed in May 2001 to test a potential correlation with the
      distribution of snail species of the Bulinus africanus group and to record
      contemporary baseline epidemiological data. Quasi-random samples of 40
      schoolchildren of mixed sexes were selected from each of 10 schools. Schistosoma
      haematobium infections were detected upon the basis of micro-haematuria with
      subsequent confirmation by microscopy examination for schistosome eggs. At the
      time of urine collection, each child was interviewed with a suite of 12 questions
      prepared as a standardized questionnaire. Total prevalence of urinary
      schistosomiasis (known locally as kichocho) was 12% although schistosome
      infections were absent in 5 schools. Schools located west of 39 degrees 19'E and
      north of 6 degrees 10'S harboured nearly all of the infections; the highest
      prevalence (55%) was found at Kinyasini where many B. globosus habitats occur
      nearby. The general level of understanding of kichocho was low (24%) and
      individual self-diagnosis was poor (sensitivity, 8.5%; specificity, 85%). Grouped
      freshwater-contact patterns of schoolchildren differed significantly between
      schools and correlated well with prevalence of infections within schools. Across
      the island the area of active transmission of S. haematobium to humans appears
      confined within the distribution of B. globosus. There was no epidemiological
      evidence to suggest any involvement of B. nasutus in local transmission,
      confirming previous laboratory findings. In areas where B. globosus occurs,
      targeted snail control should be considered, to reduce schistosome transmission.

PMID- 12474478
TI  - Human and porcine Taenia solium infection in rural north India.
AB  - 72 members of a pig farming community and 50 slaughtered pigs in Uttar Pradesh,
      India, were examined between November 2000 and June 2001 for Taenia solium
      infection. 27 of the human subjects (38%) had intestinal taeniasis and 7 (9.7%)
      had reported seizures. All 3 of the latter who were examined had
      neurocysticercosis. 13 of the pigs (26%) had cysticercosis. Such high prevalences
      indicate the need for detailed assessment of the disease burden in this
      community.

PMID- 12474479
TI  - Seroepidemiology of Helicobacter pylori infection in Guadeloupe.
AB  - 854 sera collected from blood donors in Guadeloupe were screened for Helicobacter
      pylori immunoglobulin G antibodies by a commercial enzyme-linked immunosorbent
      assay kit. The overall prevalence was 55.2%; it increased significantly with age
      from 36.1% at 18-19 years to 63.7% at 50-59 years (P = 0.003).

PMID- 12474480
TI  - Species-specific field testing of Entamoeba spp. in an area of high endemicity.
AB  - Entamoeba histolytica has been separated in recent years into 2 morphologically
      identical species: the apathogenic E. dispar and the pathogenic E. histolytica,
      only the latter being pathogenic. Although various laboratory techniques allow
      discrimination between the 2 species there is a lack of field data about the
      suitability of available diagnostic tests for use in epidemiological studies and
      few epidemiological studies using species-specific diagnosis have been performed
      at community level in endemic areas, especially in sub-Saharan Africa. We
      conducted a repeated cross-sectional study of 967 schoolchildren in central Cote
      d'Ivoire to compare and evaluate light microscopy, 2 different antigen detection
      assays, and one polymerase chain reaction (PCR) assay. Microscopy and a non
      specific antigen capture Entamoeba enzyme-linked immunosorbent assay (ELISA) were
      used for the primary screening of all children (time t0). The prevalence of the
      E. histolytica/E. dispar species complex at t0 was 18.8% by single microscopical
      examination and 31.4% using the non-specific ELISA. Approximately 2 months after
      the initial screening, fresh stool specimens were collected on 2 consecutive days
      (t1 and t2) from (i) all the children who were positive by microscopy at t0 (n =
      182) and (ii) 155 randomly selected children who were negative at the primary
      screening. These samples were tested with a second antigen detection ELISA
      specific for E. histolytica (n = 238) and with a species-specific PCR assay (n =
      193). The second and third examinations (t1 and t2) revealed an additional 43
      infections with the species complex E. histolytica/E. dispar, so that the
      cumulative microscopical prevalence for t1 and t2 was 27.7%. The overall
      prevalence of E. histolytica by species-specific ELISA antigen detection was low
      (0.83%), while the prevalence of E. dispar was 15%. When analysing only
      microscopically positive samples by PCR (n = 129), the ratio E. histolytica: E.
      dispar was very low (1:46), suggesting that the vast majority of Entamoeba
      infections in this area were apathogenic. Both species-specific tests performed
      well but the ELISA was easier to use for large-scale field screening.

PMID- 12474481
TI  - Co-infection by Leishmania amazonensis and L. infantum/L. chagasi in a case of
      diffuse cutaneous leishmaniasis in Bolivia.
AB  - We present the first report of a co-infection by Leishmania amazonensis and L.
      infantum/L. chagasi isolated in 1993 from a patient with diffuse cutaneous
      leishmaniasis (DCL), living in the sub-Andean region of Bolivia. This is the
      third reported case of DCL in Bolivia, but the first one with isoenzymatic
      identification of the aetiological agents involved and the first one giving
      evidence for a mixed infection by 2 Leishmania parasites in the same lesion.

PMID- 12474482
TI  - Compassionate use of sitamaquine in an HIV-positive patient with visceral
      leishmaniasis.

PMID- 12474483
TI  - Entamoeba dispar in a terminal case of acquired immune deficiency syndrome
      compared with Brumpt's (1925) original cat material.
AB  - A rectal biopsy from a terminal case of acquired immune deficiency syndrome is
      compared with a similar biopsy taken by Brumpt in 1925 from a cat which he had
      infected with what he named Entamoeba dispar.

PMID- 12474484
TI  - Relationship between onchocerciasis and epilepsy: a matched case-control study in
      the Mbam Valley, Republic of Cameroon.
AB  - Studies conducted during the past 10 years to investigate the possible
      relationship between onchocerciasis and epilepsy have led to contradictory
      results. In 1991-92 and 2001 we investigated 14 villages in central Cameroon to
      evaluate the relationship, at the community level, between the prevalence of
      epilepsy and the endemicity level of onchocerciasis. A case-control study
      compared the microfilarial loads of 72 epileptic and 72 non-epileptic
      individuals, matched according to sex, age, and village of residence. The
      prevalence of epilepsy and the community microfilarial load (CMFL) were closely
      related (P < 0.02), and the case-control study demonstrated that the
      microfilarial loads (microfilariae per snip) in the epileptic group (arithmetic
      mean = 288, median = 216) were significantly higher (P < 10(-4)) than in the
      control group (arithmetic mean = 141, median = 63). The results strongly support
      the existence of a link between onchocerciasis and epilepsy. The fact that such a
      relationship has not been found recently in some other West and Central African
      areas is probably due to the lowered endemicity of onchocerciasis following
      vector- and ivermectin-related control measures applied over the past 5-25 years.
      The socio-economic and demographic impact of onchocerciasis-related epilepsy
      should be evaluated, and taken into account as part of all onchocerciasis control
      programmes.

PMID- 12474485
TI  - Onchocerciasis-associated morbidity: hypothesis.
AB  - Tissue concentrations of vitamin A in Onchocerca volvulus are about 8 times
      higher than those of the host. About 100,000 microfilariae (mf) die every day in
      heavily infected persons. Onchocerciasis-associated morbidity may be due in part
      to the release of retinoids from dying mf and their gradual accumulation to toxic
      concentrations in affected tissues.

PMID- 12474486
TI  - Evaluation of the Integrated Management of Childhood Illness guidelines for
      treatment of intestinal helminth infections among sick children aged 2-4 years in
      western Kenya.
AB  - Anthelmintic treatment of sick preschool-age children at health facilities is a
      potentially effective strategy for intestinal helminth control in this age-group.
      We conducted a study from July 1998 to February 1999 in western Kenya to
      determine whether the Integrated Management of Childhood Illness (IMCI)
      guidelines' clinical assessment can be used to identify helminth-infected
      children, and to evaluate the nutritional benefit of treating sick children
      without pallor with an anthelmintic (mebendazole is already part of IMCI
      treatment for sick children aged 2-4 years with palmar pallor in areas where
      hookworm and Trichuris trichiura infections are endemic). Sick children aged 2-4
      years seen at 3 rural health facilities were clinically evaluated and tested for
      haemoglobin concentration, malaria parasites, and intestinal helminths. Children
      without pallor were randomly assigned to receive a single dose of 500 mg of
      mebendazole or a placebo and re-examined 6 months later. Among the 574 children
      enrolled, 11% had one or more intestinal helminths. Most infections were of light
      intensity. Selected clinical signs and symptoms available from the IMCI
      assessment, including palmar pallor and low weight-for-age, were not associated
      with helminth infection. Six months after enrollment, no differences in growth of
      children without pallor were observed between the mebendazole (n = 166) and
      placebo (n = 181) groups. However, there was a significantly greater mean
      increase in weight, height, and weight-for-age Z score among the helminth
      infected children in the mebendazole group (n = 22) as compared with helminth
      infected children in the placebo group (n = 20). We conclude that even lightly
      infected preschool-age children without palmar pallor benefit from anthelmintic
      treatment; however, in this study setting of low helminth prevalence and
      intensity, helminth-infected children could not be identified using the IMCI
      guidelines. Cost-effectiveness studies are needed to help define helminth
      prevalence thresholds for routine anthelmintic treatment of sick preschool-age
      children seen at first-level health facilities.

PMID- 12474487
TI  - High rate of Bartonella henselae infection in HIV-positive outpatients in
      Johannesburg, South Africa.
AB  - The emerging opportunistic pathogen Bartonella henselae has a wide range of
      clinical presentation, which includes, particularly, bacillary angiomatosis. This
      non-random pilot survey of outpatients attending HIV clinics in Johannesburg,
      South Africa, sampled 188 patients, in whom there was a 10% prevalence of
      Bartonella bacteraemia, as determined by nested polymerase chain reaction.

PMID- 12474488
TI  - Role of the pfcrt codon 76 mutation as a molecular marker for population-based
      surveillance of chloroquine (CQ)-resistant Plasmodium falciparum malaria in
      Ugandan sentinel sites with high CQ resistance.
AB  - The mutant genotype at codon 76 of the pfcrt gene (T76) has been proposed as a
      molecular marker for surveillance of chloroquine (CQ)-resistant Plasmodium
      falciparum malaria but this proposal has not been validated by population-based
      surveys. In 1998-99, in 6 Ugandan sentinel sites, the prevalence of P. falciparum
      infections with the T76 genotype and the level of CQ use were measured by
      community surveys, and CQ resistance was determined by in-vivo tests on 6-59
      month-old children with clinical malaria. The prevalence of T76 was not related
      to the overall clinical (early and late treatment failure: ETF + LTF; r = 0.14, P
      = 0.78) or parasitological (RI + RII + RIII; r = 0.17, P = 0.73) CQ resistance.
      However, the percentage of individuals carrying only infections with the T76
      genotype (T76 alone) increased with increasing ETF (r = 0.76, P = 0.07) and type
      RIII parasitological failure (r = 0.69, P = 0.12). Similarly, the ratio between
      T76 and K76 (the wild type) prevalences (T76/K76) was strongly and positively
      correlated with ETF (r = 0.85, P = 0.03) and RIII (r = 0.82, P = 0.04). Moreover,
      T76 alone (r = 0.90, P = 0.01) as well as T76/K76 (r = 0.90, P = 0.01)
      significantly increased with increasing community CQ use. T76 alone and T76/K76
      can be useful markers to estimate the ETF and RIII prevalence as well as the
      amount of CQ use in the community.

PMID- 12474489
TI  - Current absence of pyrimethamine resistance of Plasmodium falciparum in
      Madagascar.
AB  - Reported are (i) the in vitro sensitivities to pyrimethamine of 58 primary
      Plasmodium falciparum isolates collected from the foothill and coastal areas in
      Madagascar, and (ii) the results of the amplification of the dhfr gene followed
      by restriction enzyme digestion of codon 108. Testing took place between March
      1999 and February 2000 and all the isolates were sensitive to pyrimethamine. The
      50% inhibitory concentration (IC50) ranged from 0.1 nM to 242.9 nM (mean IC50 =
      30.5 nM, median IC50 = 4.8 nM, 95% confidence interval 17.6-43.4 nM). None of the
      58 isolates yielded digestion products after polymerase chain reaction product
      treatment with BsrI or ScrFI. The results indicate the absence of the dhfr
      encoding Asn108 and Thr108 among tested clinical isolates. The sensitivity of P.
      falciparum to pyrimethamine-based antimalarial drugs in Madagascar is discussed.

PMID- 12474490
TI  - Seroprevalence of antibodies to repetitive domains of Plasmodium vivax
      circumsporozoite protein in United Arab Emirates children.
AB  - The aim of this study was to determine the exposure of child citizens of the
      United Arab Emirates (UAE) to Plasmodium vivax, and to elucidate if it was
      related to place of residence or previous international travel to malaria-endemic
      areas. Blood samples were collected from 1010 primary schoolchildren resident in
      7 out of 9 districts of the UAE during October and November 1999. Plasma samples
      were tested for antibodies against MAP4 (DGQPAGDR)3P2P30, a multiple antigen
      peptide containing the repeat amino acid sequences of P. vivax circumsporozoite
      protein (CSP), conjugated to 2 T-helper epitopes, P2 (QYIKANSKFIGITE) and P30
      (FNNFTVSFWLRVPKVSASHLE) from tetanus toxin. For confirmation of P. vivax-specific
      reactivity, positive samples were further tested against (AGDR)6, a synthetic
      peptide containing 6 copies of a protective epitope within the CSP, and against a
      recombinant CSP, designated as NS1(81)V20. Results indicated that 3.3% of the
      children were seropositive. The seropositivity rates differed significantly in
      relation to place of residence, whereas travel outside the UAE did not
      significantly affect the exposure rates to P. vivax.

PMID- 12474491
TI  - The effect of repeated leishmanin skin testing on the immune responses to
      Leishmania antigen in healthy volunteers.
AB  - The leishmanin skin test (LST) is used in immunogenicity studies. The effect of
      multiple LSTs on immune responses was assessed. None of the volunteers converted
      to LST positive. IFN-gamma and IL-10 levels remained unchanged. Repetition of LST
      does not modulate the in vivo or in vitro immune responses to Leishmania antigen.

PMID- 12474492
TI  - Critical comparison of molecular genotyping methods for detection of drug
      resistant Plasmodium falciparum.
AB  - We have critically evaluated 3 techniques for the detection of mutations
      conferring drug resistance of Plasmodium falciparum, using samples containing
      known numbers of well-characterized parasites and artificial mixtures of these
      parasites at known proportions. We compared the sensitivity and specificity of
      mutation-specific polymerase chain reaction (MS-PCR), polymerase chain reaction
      followed by restriction enzyme digestion at polymorphic sites (PCR/RFLP), and a
      dot-blot/probe hybridization technique, for detection of point mutations at
      nucleotide 323 of the P. falciparum dihydrofolate reductase gene (dhfr) that
      confer resistance to the antimalarial drug pyrimethamine. We have also
      investigated the benefits in terms of sensitivity and reproducibility of the
      incorporation of radiolabelled nucleotides into the PCR/RFLP assay. We found that
      MS-PCR was very sensitive--at least 10 parasites could be detected in a sample-
      but non-specific amplification resulted in erroneous typing of some samples.
      PCR/RFLP was less sensitive; 10 parasites per sample could not always be
      detected, but the technique was specific. The addition of radiolabelled
      nucleotides to the assay did not markedly improve the sensitivity but the results
      were easier to read and there was less subjectivity in scoring the results. The
      dot-blot/probe hybridization technique was specific and sensitive, with similar
      levels of specificity and sensitivity to PCR/RFLP. On balance, the dot-blot/probe
      hybridization technique seems best suited to large-scale epidemiological surveys
      of genes associated with antimalarial drug resistance.

PMID- 12474493
TI  - Treatment of uncomplicated malaria.

PMID- 12474494
TI  - Antimalarial use during pregnancy and its effect on birthweight.

PMID- 12474495
TI  - Reading ICT filariasis rapid diagnostic card tests under field conditions and
      issues of good clinical practice in clinical trials.

PMID- 12474496
TI  - Plasmodium falciparum PCR in pregnant females and their infants.

PMID- 12474498
TI  - Trends in hospital service provision.
AB  - In this paper, trends in hospital service provision are measured using data on
      the numbers and nature of hospitals, on hospital expenditure and on hospital
      activity over recent years. The number of public acute care hospitals was fairly
      stable, however, bed numbers decreased. Hospital numbers rose for private
      hospitals, as did numbers of beds, particularly for group for-profit private
      hospitals. Recurrent health expenditure on hospitals as a proportion of all
      recurrent health expenditure fell, although it rose for private hospitals, and
      real increases in expenditure occurred for both public acute and private
      hospitals. Population rates for separations and patient days rose for private
      hospitals and were stable and fell, respectively, for public acute hospitals.
      Average length of stay decreased for both public acute and private hospitals,
      with increasing numbers of separations occurring on a same day basis. Increasing
      proportions of procedures were undertaken during same day stays, and in private
      hospitals. Separation rates varied geographically, with highest rates overall,
      and for public hospitals and overnight separations, for patients resident in
      remote centres and other remote areas. Highest rates for private hospitals were
      for patients resident in capital cities, other metropolitan centres and large
      rural centres.

PMID- 12474497
TI  - A plea to continue the search for an Onchocerca volvulus macrofilaricide.

PMID- 12474499
TI  - Innovation in Australian hospitals.
AB  - This paper examines the challenge of innovation, and reports on innovation in the
      Australian hospital sector. Through review of both published and 'grey'
      literature, the analysis of the innovative record of Australian hospitals is
      focused on two key questions: How has the hospital sector made use of
      opportunities for renewal and improved effectiveness in its ongoing response to
      the challenges it faces? And are the conditions for effective innovation in
      place? To be truly innovative, the Australian hospital sector requires greater
      supporting mechanisms including: a consistent policy and funding framework,
      greater ability to harness the power of information, and development of
      innovation skills. The government has an important role to play in stimulating
      the creative capacities of hospitals and their staff.

PMID- 12474500
TI  - The future of hospitals.
AB  - In 2100, hospitals will focus on care of the sick, but the nature of health,
      sickness, treatment and care will be very different. Current hospital-based
      diagnostic services will be automated and deliverable in the home, resulting in a
      major shift of the burden of caring. This shift will eliminate today's community
      hospital. Work of low to medium complexity will be undertaken, usually by
      machines, in the home. Ambulatory centres, highly automated, highly accessible,
      will be customer friendly one-stop health shops of tomorrow. Machines will
      substantially replace human labour. Hospitals will remain cherished icons and
      centres of health knowledge, but will be a lesser component of the health care
      system than they are today, there will be less of them, and they will lose their
      dominance as the focus of health care training, policy and activity. The four
      major factors driving these changes are science & technology, demography, the
      economy and the environment. The "chaos factor" will be society's response to
      moral questions such as the diffusion of genetic technology. By 2100 we will be
      spending twice as much on health care as we are today and there will be less
      doctors relative to other health care workers, continuations of well-established
      twentieth century trends.

PMID- 12474501
TI  - Capital investment in public hospitals.
AB  - Capital investment is a major concern for public hospitals. Relative to operating
      expenditures, it has been almost constant for 40 years, despite great changes in
      technology and patient throughputs. Research studies during the last decade
      suggest that over that time almost all investment has been on simply replacing
      existing assets. Per person, the total capital stock has actually declined.
      However most replacement outlays are predictable. Although major building outlays
      may still need some central supervision, equipment replacement can be projected
      with enough confidence to fund it through operating grants. Using data from
      several surveys, some capital-weighted DRGs have been developed and a funding
      system suggested.

PMID- 12474502
TI  - Planning Australia's hospital workforce.
AB  - Growing government support has been evident during the past decade for macro
      level workforce planning to ensure that future populations have access to
      appropriate health care services. Population ageing is impacting on workforce
      requirements and on workforce supply within Australia and internationally.
      Changes in financing and the organisation of health services are impacting on the
      availability of training and on the quality of working life. The age and gender
      profile and career expectations of young Australians are changing. These factors
      are all adding to the importance and complexity of workforce planning. This paper
      draws on data from various sources to describe Australia's hospital workforce, to
      explore supply-side workforce trends and to discuss some contemporary issues of
      concern to policy makers and workforce planners. The paper finds that in recent
      years there has been a 3 per cent decline in the number of full time equivalent
      staff in public hospitals, while the number in the private hospital workforce has
      increased by 28 per cent. The paper concludes that, nationally, there are serious
      limitations in the data available to describe and monitor the hospital workforce
      and that there is a need to remedy this situation.

PMID- 12474503
TI  - Safety and quality.
AB  - Safe and high quality health care is an objective that everybody supports. With
      so much written about it and everybody committed to it, why are we still
      struggling to achieve it? The successful acceptance and adoption of casemix
      provides some clues as to the answer. This paper examines the factors that
      assisted casemix and the obstacles to achieving progress with safety and quality.
      It concludes that both the health industry and community's tolerance of risk in
      health is too high. The lessons from the casemix story can be applied to advance
      the safety and quality agenda. A good place to start is a determined campaign
      focussing on improving safety.

PMID- 12474504
TI  - Toward greater integration of the health system.
AB  - As demand for hospital and emergency services grows there will be pressure to
      improve the integration of primary, acute and continuing care services. Research
      on ambulatory sensitive care conditions suggests that a significant proportion of
      hospital use is potentially preventable by primary health and community care
      services. The desire for better health outcomes and reduced use of acute care
      suggests a greater focus on primary health and community care. Reforms have
      generally emphasised planning, funding and regulatory mechanisms including
      brokered management of services for an enrolled population, capitation payments
      and pooled funding across primary, acute and continuing care, the development of
      coordinated service pathways and the consolidation of responsibility for costs
      and outcomes. Australia's division of funding, regulatory and planning
      responsibilities across jurisdictions introduces a unique set of challenges to
      address these issues. Nevertheless, there are a number of options better aligning
      Commonwealth and State initiatives through the Australian Health Agreements and
      funding for range of primary health and community care finding programs.

PMID- 12474505
TI  - Issues and challenges facing rural hospitals.
AB  - Australia's rural hospitals face most of the same issues and challenges faced by
      metropolitan hospitals. However they also face additional challenges around
      geographic isolation, their iconic status and role as major employers in local
      communities, and their close relationship with community based health services.
      Future opportunities include more formal integration with community service
      through multipurpose service arrangements, regional networking with urban
      centers, expanded us of IT linkages, and with the expanding rural academic
      networks. Rural hospitals' roles as key aged care providers in the country is a
      particular challenge.

PMID- 12474506
TI  - Conflicting interests in private hospital care.
AB  - This article looks at key changes impacting on private hospital care: the
      increasing corporate ownership of private hospitals; the Commonwealth
      Government's support for private health; the significant increase in health fund
      membership; and the contracting arrangements between health funds and private
      hospitals. The changes highlight the often conflicting interests of hospitals,
      doctors, Government, health funds and patients in the provision of private
      hospital care. These conflicts surfaced in the debate around allegations of
      'cherry picking' by private hospitals of more profitable patients. This is also a
      good illustration of the increasing entanglement of the Government in the
      fortunes of the private health industry.

PMID- 12474507
TI  - Linking acute care to a strategy for improving Aboriginal health.
AB  - In this paper we consider the extent to which strategies to improve access to
      acute care services have been integrated with national strategies to improve
      Aboriginal health outcomes. To do this we review the primary and secondary
      sources and provide an overview of current national strategy in Aboriginal health
      and identify where policy and strategic issues relevant to acute care have been
      developed. In particular we consider the extent to which national policy
      processes have focussed on the interface between the primary and acute sectors.
      It is our contention that nationally integrated strategies to improve access to
      the acute care sector require the development of an Aboriginal health focus in
      hospital based quality assurance processes and a comprehensive engagement with
      Aboriginal issues across the acute care sector.

PMID- 12474508
TI  - Aged care symposium: overview.

PMID- 12474509
TI  - The interface between hospital and residential aged care.
AB  - The last 15 years have seen substantial changes in both the aged care and the
      acute hospital sectors. This article focuses on the impact of those changes on
      the interface between hospital and residential care. It examines trends in
      expenditure, supply and patterns of service use in the two sectors. Despite good
      national databases on hospitals and aged care services, there is little national
      information on the interface of the two sectors. The material presented here is
      based on work being undertaken at the Australian Institute of Health and Welfare,
      as part of a project aimed at developing a national database linking residential
      aged care and hospital morbidity data.

PMID- 12474510
TI  - Clinical issues in aged care: managing the interface between acute, subacute,
      community and residential care.
AB  - Although there is considerable evidence for the use of geriatric assessment and
      rehabilitation in many clinical settings, there exists relatively poor access in
      various regions of Australia. There has been considerable growth of community
      support services to assist in personal care of older people. Unfortunately, a
      lack of uniform assessment has hindered prioritization of clients, with the
      resultant need, and delivery, of post-acute hospital care services. In addition,
      there has been considerable progress in the clinical management of the age
      dependent disabling problems, such as dementia, osteoporosis, incontinence and
      falls, but the appropriate mix of funding between primary, secondary and tertiary
      interventions has not been determined. The health care needs of older people in
      residential care have been totally neglected, placing the sector at considerable
      risk. There need to be a fundamental rethink in managing the interface between
      acute, subacute, community and residential care.

PMID- 12474511
TI  - Subacute care and rehabilitation.
AB  - Subacute and rehabilitation services are likely to play an increasingly important
      role in the health and long-term care systems, as population ageing increases the
      prevalence of chronic disease and disability. The role and scope of these
      services is difficult to assess in the Australian context due to the paucity of
      standardised definitions and administrative reporting systems. This paper
      appraises the role of these services and reflects on principles and evidence that
      might underpin their future development.

PMID- 12474512
TI  - [Results of ventral hernia repair: comparison of suture repair with mesh
      implantation (onlay vs sublay) using open and laparoscopic approach--prospective,
      randomized, multicenter study].
AB  - Incisional hernias is a frequent complication following abdominal surgery, it
      develops in 11-20% of patients who had laparotomies. Different operative
      techniques are used for repair but results are often poor. In the absence of
      valid scientific data, there is no general agreement on the best surgical
      treatment. To provide evidence based surgery a nation-wide multi-center,
      prospective, randomized study is set up. The present study compares suture and
      mesh repairs in different positions, using open and laparoscopic approach to
      define standard indication for the treatment of incisional hernias. The study was
      started in March, 2002, with 23 surgical departments participating. Each report
      about 100 patients with incisional hernia repair. The 2300 consecutive patients
      (who are 18 to 70 years old) with primary incisional hernia or first recurrent
      umbilical hernia are randomized. Patients are divided in two groups. If the
      hernia is between 5-25 cm2 (Group I) they are selected at random either for
      prosthetic (sublay) or suture repair. In patients with a hernia larger than 25
      cm2 (Group II) mesh is implanted at random as either sublay or onlay position
      using a computer randomization program. After a short learning period, in Group
      II the laparoscopic approach will also be randomized. Postoperative outcome,
      complications and recurrence are recorded. The study will run for five years. All
      collected data are sent to the coordinating center via internet to be entered
      into database.

PMID- 12474513
TI  - [Results of laparoscopic repair of ventral hernias--a case-control study].
AB  - The surgical treatment of ventral hernias has changed in the last decade.
      Conventional methods involve tightening of the abdominal fascias is the reason
      for high recurrence rate. While the use of mesh reduces the recurrence rate, it
      does not change the rate of other complications, in particular, the risk of
      infection. We report the results of laparoscopic repair of ventral hernias
      performed in 15 patients (10 female, 5 male). The average age of patients was
      59.5 years (39-79). Indications included 7 recurrent incisional hernias (3
      patients had second recurrence, 4 patients had first recurrence operated on
      without mesh in the first operation); 5 patients with primary incisional hernias;
      and 3 primary umbilical hernias. The mean size of the defect was 66.2 cm2 (16-130
      cm2). Average operation time was 101 minutes (64-190 min). In the postoperative
      period 1 patient developed seroma, and 4 patients developed ileus each was
      successfully treated conservatively. In one patient a second-look laparoscopy was
      performed because of neuralgia. Length of hospital stay varied between 3 and 10
      days (median: 6 days); the length of follow-up period was 5-22 months (median:
      12.4 months). We believe that laparoscopic treatment of ventral hernias reduces
      the complication rate, and reduces hospital stay.

PMID- 12474514
TI  - [Secondary aorto-enteral fistula--material of 22 years and literature review].
AB  - INTRODUCTION: Aorto-enteral fistula is a pathological communication between the
      aorta and the bowel lumen. In its secondary form is a dreaded, often fatal
      complication of the aorto-iliac operations. METHODS: We report 34 secondary
      fistulas, a great number of patients treated in the last 22 years. One can rarely
      find such a number in the literature. RESULTS: The incidence of secondary
      fistulas is 0.42% following aorto-iliac operations. We give a detailed
      description of diagnostics. We prefer in situ solutions (graft change, aorto
      aortic interposition, iliac desobliteration, homograft or deep venous bypass,
      aorto-bifemoral bypass) to extra-anatomical bypasses. We emphasize the importance
      of the postoperative care, and the necessity of adequate antibiotic therapy.
      CONCLUSION: Despite improved operations and intensive care mortality is still
      high (55.88%). We find that prevention is of great importance.

PMID- 12474515
TI  - [15 years experience in the surgical treatment of decubitus ulcers of the pelvic
      region].
AB  - We summarize our 15 year experience in the surgical treatment of pressure ulcers
      of the pelvic region. The technique of suggested operations is described (sacral
      defect--gluteus maximus musculocutaneous V-Y advancement flap, trochanteric
      defect--tensor fascia lata musculofasciocutaneous transpositional flap, ischial
      defect--biceps femoris musculocutaneous V-Y advancement flap). In recent years we
      cover defects in all these regions using the principle of Emmett's hatchet flap-
      i.e. with musculocutaneous hatchet flap. We performed 105 operations, 3 patients
      had recurrence.

PMID- 12474516
TI  - [Intestinal endometriosis causing subacute ileus. Experience in three cases].
AB  - We present three rare cases of intestinal endometriosis. The patients were
      treated at the Endometriosis Clinic of the 1st Dept. of Obstetrics and Gynecology
      of the Semmelweis University, Budapest. Their main symptom besides the classic
      symptoms of endometriosis (dysmenorrhea, dyspareunia, pelvic pain) was the
      catamenial haematochesia--a subacute obstruction which became more intensive in
      the perimenstrum and needed medical treatment but no surgical intervention.
      Because of the recurrent complaints, after detailed check-up and biopsy of the
      obstructing intestinal endometriosis, anterior resection of the rectum was
      performed with endocoagulation or extirpation of other endometriosis implants of
      the pelvis. Depending on the severity of pre or postoperative complaints patients
      underwent a GnRH-analogue therapy for six months. In one patient because of the
      patient's age, and extensive retrocervical-deep endometriosis causing serious
      dyspareunia--the resection was performed with additional hysterectomy and
      adnexectomy (TAH). Recently the patient is on monophasic hormone replacement
      therapy. In the two other patients after a second-look laparoscopy with testing
      the lumen of the tubes treatment was started for the induction--because of
      infertility. We give an overview of the frequency, incidence and possible
      pathomechanism of pelvic endometriosis. We describe the modern diagnostic and
      therapeutic tools of pelvic endometriosis.

PMID- 12474517
TI  - [Transdiaphragmatic pericardial fenestration: laparoscopic modification of the
      procedure].
AB  - We present a modification of the laparoscopic pericardial fenestration, an
      already accepted method for the treatment of the pericardial effusion caused by
      intrathoracic malignancies. We used this new technique in 5 patients. Laparoscopy
      was performed with three ports standard technique and dissection with
      Ultrascision was used for the fenestration of the pericardium. The mean operation
      time was 26 minutes (8-49). No complications developed. The average length of
      hospital stay was 2.8 days (2-5).

PMID- 12474518
TI  - [Neoadjuvant chemotherapy in advanced stomach cancer--a case of complete
      response].
AB  - In the treatment of gastric cancer R0 surgical resection is the only hope for
      cure. Unfortunately most patients are first seen when they are in an advanced
      stage, when the possibility of R0 resection is very poor. In these cases
      administration of other therapies is justified. In the last decade neoadjuvant
      combination chemotherapy had been introduced with promising results. ECF
      neoadjuvant chemotherapy has 60% response rate in irresectable cases. We report
      about a patient with locally advanced gastric cancer treated with neoadjuvant ECF
      chemotherapy. The patient reacted with complete response, so following
      chemotherapy R0 resection could be carried out. We describe different therapies
      used for patients with locally advanced gastric cancer. Neoadjuvant chemotherapy
      is a recommended therapeutic modality in locally advanced gastric cancer, because
      it may have the effect of irresectable disease becoming resectable.

PMID- 12474519
TI  - [Pancreas head resection combined with resection of the superior mesenteric vein:
      extensive procedure for tumors of the pancreas head].
AB  - Surgical treatment for locally advanced cancer of the pancreas head with vascular
      invasion is controversial. It is regarded as a contraindication for resection by
      most surgeons, others perform resection involving the vessel. We performed
      pancreaticoduodenectomy with vascular resection in a 61 year old patient. The
      vascular reconstruction was performed using reversed saphenous vein. We review
      and analyse clinical, and operative data and results.

PMID- 12474520
TI  - [Left-sided gallbladder].
AB  - Transposition of the gallbladder to the left side without situs inversus viscerum
      is rare. These gallbladders are almost always situated under the left lobe of the
      liver between the IV and III segments or on the III segment to the left of the
      falciform ligament. One left positioned gallbladder was found in a consecutive
      series of 2536 patients undergoing microlaparotomy cholecystectomy for
      symptomatic gallstone disease in the "Moritz Kaposi" Teaching Hospital between
      1990 and 2000, a prevalence of 0.04 per cent. Despite of the abnormal position of
      the gallbladder, the biliary pain experienced by the patient was on the right
      side. Preoperative diagnosis of this anomaly was not made in this patient despite
      preoperative sonography. The cystic duct may open in the common hepatic duct
      either side. In this anomaly safe microlaparotomy cholecystectomy or laparoscopic
      cholecystectomy can be performed.

PMID- 12474521
TI  - [Effects of ischemic preconditioning on the oxidative stress in small bowel
      autotransplantation].
AB  - One determining factor in intestinal transplantation is the bowel's extreme
      sensitivity to ischemia-reperfusion injury. This study was meant to investigate
      the effect of ischemic preconditioning prior to autotransplantation. Total
      orthotopic intestinal autotransplantation was performed in 40 mongrel dogs. Four
      groups (GI-GIV) were established. In GI and GII grafts were stored in 4 degrees C
      Euro Collins and University of Wisconsin solutions. In GIII and GIV before
      preservation IPC was induced by 4 cycles (5-min ischemia + 10-min reperfusion).
      Three hours of preservation was followed by 1 hour of reperfusion. We determined
      oxidative stress markers in bowel tissue [reduced glutathione (GSH), superoxide
      dismutase (SOD)], oxygen free radicals (OFRs) (confocal microscopy), NF-kappa B
      (gel electrophoretic mobility shift assay), DNA damage (TUNEL). Cold preservation
      could not prevented against oxidative stress and resulted decrease of SOD
      activity significantly during reperfusion. In the preconditioned groups the
      elevated GSH and better preserved SOD activity indicated development of
      protection. Production of OFRs increased during reperfusion in non-preconditioned
      groups. Activation of NF-kappa beta was peaking by 1-3 hours following
      preconditioning. We detected more cells suffered DNA strand breaks in
      preconditioned groups. Our findings confirm that ischemic preconditioning prior
      to preservation can moderate the severity of oxidative stress and activate the
      endogenous celluar adaptation in bowel tissue.

PMID- 12474522
TI  - Immunotherapy of urologic tumors: principles and progress.
AB  - Immunotherapy is receiving interest as an alternative or adjuvant approach to the
      treatment of many malignancies. The potential for immune modulation as a
      treatment of solid tumors is the focus of cancer researchers throughout the
      world. Though not a novel idea, increasing technological sophistication and
      continued advancement in the understanding of the immune system have increased
      the number of novel therapeutic approaches. In urology, BCG is an excellent
      example of how modulation of the immune system can be used to treat malignancy,
      and we are only now beginning to understand its immune mechanisms. Numerous other
      immunotherapeutic approaches have been and are being developed and evaluated. We
      provide a brief overview of immunology and its relation to tumor development and
      growth, and focus on some of the immunotherapeutic approaches to renal cell
      carcinoma, prostate adenocarcinoma, and transitional cell carcinoma of the
      bladder.

PMID- 12474523
TI  - Identification of two genes differentially expressed upon different spatial
      configuration of the MGH-U3 human bladder cancer cells.
AB  - By using mRNA differential display technology, we have compared gene expression
      in neoconfluent (actively proliferating) and 14-day confluent (non-proliferative)
      MGH-U3 cells. Two clones (6.17.6 and 10.9.2) displayed significantly increased
      expression in the 14-day confluent MGH-U3 cells, as confirmed by Northern blot
      analysis. Nucleotide sequence showed that clone 6.17.6 was part of the human
      insulin-like growth factor binding protein-5 (IGFBP-5) cDNA, while clone 10.9.2
      was part of a human gene with unknown function (clone HSI12602). The differential
      IGFBP-5 expression in this model system was also evidenced by Western analysis.
      The possible anti-proliferative role of IGFBP-5 in this model system is briefly
      discussed.

PMID- 12474524
TI  - p21 gene codon 31 polymorphism is associated with bladder cancer.
AB  - The function of p21 is related to cell apoptosis, progression and malignancies.
      It is thought that p21 is related to cancer formation but is not related to tumor
      grade. We aimed to investigative the polymorphism of p21 codon 31 as a candidate
      for the genetic marker of bladder cancer and its progression. The distribution
      was analyzed in 53 bladder cancer patients, 119 healthy controls in Taiwanese
      patients. Polymerase chain reaction based restriction analysis was used for the
      study of the association of p21 codon 31 polymorphism with bladder cancer. There
      was a significant difference in p21 codon 31 polymorphism between the control and
      the cancer patients (p < 0.01). The arginine form was prominent in the cancer
      patient (per copy of the A allele, odds ratio = 2.03, 95% confidence interval =
      1.23-3.37). Furthermore, the distribution of this polymorphism was significantly
      different from non-invasive to invasive bladder cancer (p < 0.05). Serine
      heterozygote was more prominent in the invasive group with 25 to 1% respectively
      when compared with the non-invasive group. The polymorphism of p21 codon 31 is
      associated with bladder cancer. An individual possessing one allele of arginine
      form in p21 codon 31 has a higher risk of developing bladder cancer than the
      serine form. Although the mechanism is unclear, our results show p21 gene is
      associated with tumor grade.

PMID- 12474525
TI  - Differential C-erbB-2 and VEGF expression following BCG immunotherapy in
      superficial papillary transitional cell carcinoma of the bladder.
AB  - Bacillus Calmette Guerin (BCG) is generally regarded as an effective
      immunotherapy for superficially invasive papillary transitional cell carcinoma of
      the bladder. The exact mechanism(s) which underlie its efficacy are unknown. As C
      erbB-2 oncoprotein and vascular endothelial growth factor (VEGF) have been shown
      to be over-expressed in TCC of the bladder, it has been postulated that they may
      be important in its pathogenesis. The purpose of this study was to 1.)
      differentially evaluate the effect of BCG immunotherapy in treated and untreated
      cohorts on the immunohistochemical expression of C-erbB-2 and VEGF in formalin
      fixed paraffin-embedded sections of superficial and superficially invasive (Stage
      Ta-T1) transitional cell carcinoma of the bladder. Immunolabeling intensity was
      assessed independently by two pathologists and reported as a mean labeling index.
      The results confirm previous studies that 1.) both c-erbB-2 and VEGF are over
      expressed in these tumors MLI = 90.1 and 45.7 respectively, 2.) that VEGF is an
      early and sensitive indicator of TCC, and 3.) that BCG has a salutary effect on
      papillary TCC, 66% vs. 89% recurrence rate, P = .04. Our findings show that 1.) C
      erbB-2 expression is decreased in patients tumors which show response to BCG
      (45.7 to 38.5), P = 0.15, 2.) that BCG administration has no effect on the
      expression of VEGF. While the decrement in c-erbB-2 immunostaining observed in
      those patients who received BCG contrasts with the increase in c-erbB-2
      immunolabeling observed in patients who did not receive BCG, the differences were
      not statistically significant and could reflect tumor grade or stage regression
      associated with BCG therapy. However, this study suggests that BCG differentially
      influences the expression of C-erbB-2 and VEGF.

PMID- 12474526
TI  - Association between American Urologic Association (AUA) urinary symptom score and
      disease stage in men with localized prostate cancer.
AB  - We assessed the relationship of American Urological Association (AUA) urinary
      symptom score and tumor stage in men treated for localized prostate cancer.
      METHODS: Participants in our study were found through urology and radiation
      oncology clinics, and all eligible patients were asked to take part. All patients
      had been initially diagnosed on the basis of rising PSA or abnormal physical
      examination. Histological confirmation of diagnosis was obtained for all
      subjects. Tumor stage was determined by digital rectal examination. 265 men with
      prostate cancer were studied. RESULTS: There was a significant difference in AUA
      symptom score in the three disease stages (p = 0.035, one way anova). Tukey's
      multiple range B test showed a significant difference between the AUA symptom
      scores of patients with t3 disease, when compared to patients with t1 and t2
      disease (p = 0.05). The range test showed no significant difference between the
      AUA symptom scores of patients with t1 and t2 disease (p = 0.897). There was a
      significant difference in mean age of men with t1, t2, and t3 disease (p <
      0.001). Men with t2 disease had a mean age of 69 years, as opposed to men with t1
      and t3 disease (mean ages 66 and 64, respectively). Tukey's multiple range B test
      showed a significant difference (p = 0.05) between the ages of the men with t2
      disease and the men with t1 or t3 disease. But there was no significant
      difference between the ages of the men with t1 and t3 disease. There was no
      relationship between age and AUA symptom score (r = 0.008, P = 0.89). The AUA
      symptom score index classifies the symptoms of men with a score of 0 to 7 as
      mild, 8 to 19 moderate, and 20 and above as severe. According to this
      classification, 55.6% of the prostate cancer patients we studied had mild
      symptoms, 37.1% had intermediate symptoms, and 7.3% had severe symptoms.
      CONCLUSIONS: The majority (approximately 80%) of prostate cancers are found in
      the peripheral zone. But prostate cancers associated with urinary symptoms might
      arise in the periurethral transition zone, where almost all symptomatic benign
      prostatic hypertrophy originates. We hypothesize that symptomatic and non
      symptomatic prostate cancer may be two distinct disease entities, each with its
      own characteristic genetic complement. In addition, urologists are actively
      seeking additional indicators of prostate cancer aggressiveness. Many prostate
      cancers are quite indolent and may never cause a problem, but it is impossible to
      identify such tumors with certainty. Further studies of AUA symptom score and
      outcome would be worthwhile. If AUA symptom score is a predictor of outcome that
      is independent of t stage, AUA score might be clinically valuable in disease
      management.

PMID- 12474527
TI  - The case for early androgen deprivation: the data should not be ignored.

PMID- 12474528
TI  - Mode of presentation of renal cell carcinoma provides prognostic information.
AB  - PURPOSE: Broadened applications of imaging modalities have increased the
      incidental detection of renal cell carcinoma (RCC) over the past decade. Previous
      small series have suggested a prognostic benefit for incidental presentation.
      This study utilizes a large contemporary patient cohort to examine patterns of
      RCC presentation and their clinical implications. MATERIALS AND METHODS:
      Retrospective analysis was performed on 721 patients (260 women, 461 men) who
      underwent 750 nephrectomies for treatment of RCC between 7/1/89 and 12/31/97; 29
      patients required two operations for bilateral RCC. Median age and follow-up were
      63 years and 41 months, respectively. Indicators of symptomatic presentation
      included flank pain, flank mass, hematuria, varicocele, constitutional symptoms,
      paraneoplastic syndromes, and bone pain related to metastatic disease. Mode of
      presentation was compared with clinicopathologic parameters using Chi-square and
      t-test analyses. Survival analysis was performed using Kaplan-Meier estimates
      (log-rank test) and Cox regression modeling. RESULTS: Incidental and symptomatic
      presentation occurred in 57% and 42% of cases, respectively. When compared to
      incidental cases, symptomatic presentation was predominantly detected in younger
      patients (mean age, 59 years; P < .001), in males (P < .04), and in tumors with
      conventional (clear cell) histology (P < .001), larger size (mean, 8 cm; P <
      .001), and non-organ confined pathology (P < .001). In univariate analysis,
      symptomatic cases had a more adverse disease-free (P < .0001) and disease
      specific (P < .0001) survival. In multivariate analysis, mode of presentation was
      an independent predictor of disease-free (P < 0.0001) and disease-specific
      survival (P < 0.005). CONCLUSIONS: Symptomatic presentation correlates with an
      aggressive histology and advanced disease. Incidental tumors may be frequently
      detected in female and elderly patients, as these groups traditionally seek
      general medical care more regularly. Mode of presentation can independently
      predict an adverse patient outcome and should be included in RCC-specific
      modeling systems.

PMID- 12474529
TI  - A validation of two preoperative nomograms predicting recurrence following
      radical prostatectomy in a cohort of European men.
AB  - Kattan et al. at Baylor College of Medicine and D'Amico et al. at Harvard Medical
      School have each developed preoperative nomograms for prostate cancer recurrence
      after radical prostatectomy based on readily available clinical variables.
      Calibration and validation of those tools was achieved using North American
      patient cohorts, and their validity has not yet been shown in patients from other
      continents. We investigated the predictive accuracy of these nomograms when
      applied to European men with localized prostate cancer. Clinical data from
      patients who underwent radical prostatectomy at the University-Hospital Hamburg
      and fitted the respective derivation criteria were used for external validation
      (n = 1003 for the Kattan-Nomogram, n = 932 men for the D'Amico-Nomogram).
      Nomogram predictions of the probability for 2-years and 5-years freedom from
      recurrence predicted by the D'Amico-Nomogram and the Kattan-Nomogram respectively
      were compared with actual follow-up. The predictive accuracy of the nomograms was
      tested using areas under the receiver-operating-characteristic curves (AUC). The
      D'Amico-Nomogram AUC predicting 2-years probability of freedom from PSA
      recurrence was 0.80 vs. Kattan-Nomogram 5-years prediction with an AUC of 0.83.
      Using the 932 patients who exactly fit the derivation criteria of both nomograms,
      the predictive accuracy of the Kattan-Nomogram was 0.81. The superiority in
      predictive accuracy of the Kattan-Nomogram was statistically significant (p =
      0.0274) but of unclear clinical significance. The two nomograms predicted
      recurrence with similar accuracy when applied to men diagnosed with localized
      prostate cancer in Germany. The high predictive accuracy of both nomograms
      demonstrates that these predictive tools derived in the U.S. can be applied to
      non-U.S. patients.

PMID- 12474530
TI  - Presence of circulating prostate cancer cells in African American males adversely
      affects survival.
AB  - African-Americans (AAM) with prostate cancer are more likely to relapse than
      Caucasian-Americans (CAM) despite controlling for known prognostic factors. One
      explanation may be that micrometastatic disease in AAM behaves more aggressively
      than in CAM. We tested this hypothesis by comparing the reverse transcriptase
      polymerase chain reaction amplification of the Prostatic Specific Antigen-mRNA
      (RTPCR PSA-mRNA) results from peripheral blood samples of AAM and CAM with
      respect to disease outcome. We evaluated the peripheral blood of 246 consecutive
      patients at the time of radical prostatectomy. The RTPCR PSA-mRNA test for
      determination of circulating prostate cancer cells was performed. The results
      were stratified by races and correlated with standard clinico-pathological
      variables and disease free survival. 27% and 23% of AAM and CAM patients were
      RTPCR PSA-mRNA positive, respectively. The RTPCR PSA-mRNA status correlated with
      the pathologic stage in CAM but not in AAM, (p = 0.05). There was no association
      with Gleason score, PSA level, or clinical stage with the RTPCR PSA-mRNA status
      in either group. AAM with organ-confined prostate cancer were marginally more
      likely to have circulating prostate cells than similarly staged CAM (24% vs.
      17%). In AAM but not CAM who had prostate cancer, the RTPCR PSA-mRNA status
      correlated with and was an independent predictor of disease-free survival. Our
      data suggests that, though the likelihood of having circulating prostate cells is
      the same in AAM and CAM, the presence of circulating prostate cells in AAM is
      predictive of a worse outcome. This may partially explain the worse prognosis in
      AAM vs. CAM with clinically localized prostate cancer.

PMID- 12474531
TI  - Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced
      transitional cell cancer.
AB  - PURPOSE: To assess long-term survival and prognostic indicators of survival in
      patients with advanced urothelial cancer treated with gemcitabine and cisplatin.
      MATERIALS AND METHODS: Survival data from three previously published phase II
      trials of gemcitabine/cisplatin were updated. Baseline hemoglobin, performance
      status, and presence of visceral metastases, which are known prognostic factors
      with other regimens, were examined. Survival curves were constructed by the
      Kaplan-Meier method and significance assessed using the log-rank statistic. Cox's
      Proportional Hazards Model was used to construct univariate and multivariate
      survival models. RESULTS AND CONCLUSIONS: Overall median survival of 121 included
      patients was 13.2 (11.0 to 14.9) months and estimated 4 year survival was 13 +/-
      6%. In a univariate analysis, the presence of visceral metastases and a
      hemoglobin < 12.5 mg/dl had significant adverse prognostic implications (P <
      0.001 and P = 0.02, respectively). Performance status was not a significant
      predictor of survival, perhaps due to the fact that only 14% of patients had a
      performance status of 2. In a multivariate analysis, only the absence of visceral
      metastases retained its prognostic importance with an estimated 24% 4-year
      survival in such patients. These results lend further evidence for the clinical
      benefit of this regimen in advanced transitional cell cancer.

PMID- 12474532
TI  - Higher antitumor activity of vinflunine than vinorelbine against an orthotopic
      murine model of transitional cell carcinoma of the bladder.
AB  - The aim of this report was to investigate the feasibility of systemic treatment
      of transitional cell carcinoma of the bladder with vinflunine (VFL), and to
      compare its activity in respect to vinorelbine (VRL). Exposure of MB49 murine
      bladder cancer cells to both drugs showed a higher chemosensitivity of the cells
      to VRL than to VFL (IC50 values of 60 nM and 400 nM, respectively). Pretreatment
      of MB49 cells with non-cytotoxic drug concentrations revealed an inhibition of
      control in vitro invasiveness of 40 to 70% (1-25 nM VRL) and 22 to 80% (1-100 nM
      VFL) (P < 0.0001, ANOVA). The intraperitoneal administration of the drugs twice a
      week for 4 weeks in C57B1/6 female mice revealed that VFL was very well
      tolerated, with a 8-fold increase in the maximum tolerated dose in respect to VRL
      (40 mg/kg and 4.8 mg/kg, respectively). The administration schedule was evaluated
      in C57B1/6 female mice inoculated transurethraly with 5 x 10(4) MB49 cells.
      Intravesical tumor incidence on day 21 was 0% and 17% in mice treated
      intraperitoneally with 20 and 10 mg/kg VFL respectively (P = 0.0017 and P =
      0.0001, Fischer's Exact Test), contrasting with 75-83% obtained in all VRL
      treated groups and Controls. All mice treated with 20 mg/kg VFL were still alive
      60 days after intravesical MB49 tumor implantation, as well as 50% of those
      treated with 10 mg/kg VFL, while most of the remaining mice (Control and VRL
      treated) died before day 32. These studies clearly demonstrate the activity of
      VFL against a murine bladder cancer model, with a favorable toxicity profile.

PMID- 12474533
TI  - The role of radical prostatectomy in patients with pretreatment prostate-specific
      antigen > or = 40 ng/mL.
AB  - OBJECTIVE: To assess the efficacy of radical prostatectomy (RP) in men presenting
      with markedly elevated prostate-specific antigen (PSA) levels, the records of 17
      patients presenting with serum PSA values > or = 40 ng/mL, who underwent RP at
      Walter Reed Army Medical Center (WRAMC) between 1990 and 1995, were reviewed.
      METHODS: Pathologic and clinical data (staging, Gleason score, recurrences,
      adjuvant and neo-adjuvant treatment, most recent PSA value, urinary continence,
      and sexual function) for each patient was examined. The Kaplan-Meier method was
      used to analyze the disease-free survival (DFS) for PSA and clinical recurrence.
      Urinary continence and potency were also assessed. RESULTS: With a mean follow-up
      of 6.21 years (median 5.28 y), all 17 patients are alive. Five patients have no
      evidence of disease (NED), and 12 are alive with prostate cancer. Fifteen
      patients have PSA values between 0.1 and 3.0 ng/mL, and two patients have PSA
      values that have returned to pretreatment levels. Eleven patients received neo
      adjuvant and/or adjuvant therapy. Fourteen men (82.3%) are continent and seven
      (41.1%) are potent. Survival analysis demonstrates a PSA DFS of 52.9% at five
      years and 26.5% at nine years; while, clinical DFS was 92.3% at five years and
      58.0% at nine years. CONCLUSIONS: This study suggests a possible surgical role in
      treating patients presenting with significantly elevated PSA values. While
      surgery alone is unlikely to cure prostate cancer in these patients, surgery in
      conjunction with hormonal or radiation therapy may prolong survival with
      acceptable effects on urinary continence and potency.

PMID- 12474534
TI  - A comparison of hospital-based charges following partial and radical nephrectomy.
AB  - OBJECTIVE: Recent studies demonstrate similar survival rates in patients treated
      with either partial or radical nephrectomy for renal tumors less than 4 cm. We
      retrospectively compared the hospital based charges for these two procedures in a
      similar cohort of patients treated at Memorial Sloan-Kettering Cancer Center.
      PATIENTS AND METHODS: A retrospective review of 103 consecutive cases of renal
      tumors less than 4 cm treated by either radical or partial nephrectomy from 1996
      to 1999 was conducted. Overall hospital charges were calculated by analyzing 18
      separate departmental charge categories including room and board, pharmacy,
      radiologic tests, operating room charges, and laboratory services. RESULTS: A
      total of 66 partial and 37 radical nephrectomies were analyzed. No difference was
      found in the mean charge per procedure ($16,660, partial and $16,545, radical);
      (p > .05). The major cost drivers for partial and radical nephrectomy
      respectively were: 1) room and board, 42% and 44%; 2) operating room charges, 28%
      and 25%; 3) pathology, 6% and 6%; 4) recovery room, 6% and 7%; and 5)
      biochemistry, 5% and 5%. Significant increases in charges for partial nephrectomy
      were noted from the blood bank services and intraoperative surgical supplies. The
      median length of stay (5 days) was identical for partial and radical nephrectomy.
      No difference was found in the complication rate for these procedures (p > .05).
      CONCLUSION: Hospital-based charges for radical and partial nephrectomy are
      similar at when performed at a tertiary care referral center.

PMID- 12474535
TI  - The clinical role of prostate-specific membrane antigen (PSMA).
AB  - Prostate cancer remains the most common cancer type in men in the United States.
      Efforts are increasing to evaluate and to discover diagnostic and therapeutic
      markers for prostate cancer patients. One of these, prostate-specific membrane
      antigen (PSMA), is a transmembrane protein highly expressed in all types of
      prostatic tissue, especially cancer. The radio-immunoconjugate form of the anti
      PSMA monoclonal antibody (mAb) 7E11, known as the ProstaScint scan, is currently
      being used to diagnose prostate cancer metastasis and recurrence. Early promising
      results from various Phase I and II trials have utilized PSMA as a therapeutic
      target. Recently, PSMA expression in endothelial cells of tumor-associated
      neovasculature has been described. PSMA's possible role in malignant angiogenesis
      newly expands the realm of its possible beneficial uses, especially as new anti
      PSMA mAbs continue to be developed and refined.

PMID- 12474536
TI  - Expression of CD44 protein in renal cell carcinomas: association with p53
      expression.
AB  - CD44 is an adhesion molecule involved in cell-to-cell and cell-to-matrix
      interactions. Recent evidence indicates a role of CD44 in tumor growth and
      metastatic potential of tumor cells. Moreover, it is widely known that the p53
      tumor suppressor gene controls cell proliferation and loss of its normal function
      may lead to carcinogenesis. To investigate the role of these biomarkers in renal
      cancer, we analyzed the immunohistochemical distribution of CD44's expression on
      formalin fixed paraffin embedded tissue from 67 renal cell carcinomas and
      correlated with clinicopathologic parameters as well as with p53 suppressor gene
      expression. The monoclonal antibodies CD44 and p53 were applied to the tissues
      using the streptavidin biotin peroxidase method after microwave antigen
      retrieval. For CD44 and p53 more than 10% membranous and 5% nuclear staining,
      respectively, were estimated as positive. CD44's membranous immunoreactivity was
      detected in 24/67 tumors (35%) and mostly in carcinomas of clear/granular cell
      type. Nine tumors expressed nuclear immunoexpression of p53 protein (13.4%).
      Statistically significant correlation was noted between CD44 expression and
      nuclear grade (P < 0.001), tumor stage (P < 0.001), vascular invasion (P < 0.05)
      and p53 expression (P < 0.01). These results suggest that CD44s and p53 are
      markers of tumor progression in renal cell cancer.

PMID- 12474537
TI  - Genetic fieldwork for hereditary prostate cancer studies.
AB  - The success of a genetic family study depends on the recruitment of a sufficient
      number of unaffected family members. We present our experiences from interviews
      performed in two family studies, a genetic family study of prostate cancer (PC)
      and a medical, anthropological, qualitative study. In the genetic family study,
      949 PC patients were contacted, and 29% responded. Response rates were higher
      (44%) among subjects contacted by health providers participating in the study,
      compared to only 18% of those contacted by letter. Thirty-six pedigrees were
      ascertained. On average, each family had 3.3 affected relatives. Average age at
      time of diagnosis was 61.9 years in the probands. 58% of the families reported
      additional cancers. Breast cancer was reported in 12 families; colon cancer was
      the second most reported cancer, followed by lung, stomach, and throat cancers.
      Beliefs about the inheritance of PC were explored with 20 participants. The
      parental origin of the proband's PC in each family did not significantly affect
      participants' beliefs about the inheritance of PC. 95% agreed that PC could be
      inherited from a father to a son. Participants thought that a mother (n = 12) or
      daughter of a patient (n = 11) could not give PC to their sons. This
      misperception of the inheritance of PC can result in (1) an underreporting of PC
      cases in a kindred, and (2) healthy men underestimating their risk of developing
      PC when the disease runs in the mother's family. Thus health educators and
      genetic counselors might consider these findings when teaching patients and their
      relatives about hereditary PC.

PMID- 12474538
TI  - The use of the marker tumor concept in Ta, T1 bladder cancer: is it justified?
AB  - Adjuvant instillations with chemo- or immunotherapy agents after transurethral
      resection of Ta, T1 bladder tumors are administered on non-measurable non-visible
      disease. To know whether adjuvant therapies are efficacious the marker tumor
      concept has been developed. The use of marker lesions has been questioned by many
      as dangerous and/or unethical because a deliberately left-behind tumor might be
      invasive or become invasive if the adjuvant therapy is not effective. However, 4
      EORTC, 2 British, and one Japanese study using different drugs have shown that it
      is safe and ethically justified to use the marker tumor concept in clinical phase
      II studies. Data from six trials indicate the the risk of leaving an invasive
      tumor behind or that a tumor might progress while being treated with
      instillations is 0.8% (3/383). Marker lesion studies should be limited to
      intermediate risk patients. Expensive and inefficient long term phase III trials
      may be avoided by marker tumor trials. Exposing patients to ineffective drugs in
      prophylactic trials also jeopardizes the patient with regard to recurrence and/or
      progression of their bladder tumors.

PMID- 12474539
TI  - Ethical issues in the use of tumor markers in clinical investigation of the
      management of bladder cancer.
AB  - The use of marker tumors in clinical research on bladder cancer raises three
      significant ethical issues. The first concerns the management of risk in the
      design and conduct of clinical investigation. The use of tumor markers meets
      recognized ethical requirements for identifying and managing such risk and also
      meets the condition of equipoise. The second concerns the informed consent
      process, which should include provision to potential subjects of information
      about why a tumor marker is being used, risk of progression, and how subjects
      will be monitored to manage risk of progression. The third concerns monitoring of
      clinical trials. The use of a Data and Safety Monitoring Bord adds an important,
      additional level of protection for research subjects.

PMID- 12474540
TI  - Outcome research: prostate cancer databases.

PMID- 12474541
TI  - Localization and mRNA expression of somatostatin receptor subtypes in human
      prostatic tissue and prostate cancer cell lines.
AB  - Somatostatin (SST) plays an important regulatory role in the physiological
      control of various organs including the prostate. Somatostatin receptors (SSTRs)
      and SST analogs are potential targets for prostate cancer treatment, especially
      since it has been shown that SST analogues are clinically effective in the
      treatment of advanced prostate cancer. The presence of SST containing
      neuroendocrine (NE) cells in the epithelium of the human prostate and their
      suggested role in the paracrine regulation of this gland prompted us to study the
      potential expression of somatostatin receptors (SSTRs) in human prostatic tissue
      and prostate cancer cell lines. Using the reverse transcriptase polymerase chain
      reaction (RT-PCR), we found the SSTR subtypes 1-3 in stromal cells and in
      prostate cancer cell lines LNCaP, PC-3 and DU 145. Immunohistochemical analysis
      of 27 radical prostatectomy specimens demonstrated the presence of hSSTR1 in a
      subpopulation of cancerous and NE cells, whereas hSSTR2 was found in the stroma,
      peritumoral blood vessels and tumor cells. Receptor subtype 3 was demonstrated to
      be present on the cell membrane of BPH and malignant areas. A strong
      immunoreaction (IR) of hSSTR4 was found in tumor cells, as compared with a less
      intense IR in adjacent BPH areas. Somatostatin receptor subtype 5 was not
      detectable. Western blot analysis revealed immunoreactive bands of molecular
      weight between 44-60 kDa. In summary, the present study clearly demonstrates the
      presence of hSSTR1-3 in tumoral and nontumoral epithelial cells as well as in the
      stromal compartment, whereas hSSTR4 was found to be confined to epithelial cells,
      and SSTR5 was not detectable.

PMID- 12474542
TI  - Relationship between expression of KAI1 metastasis suppressor gene, mRNA levels
      and p53 in human bladder and prostate cancer cell lines.
AB  - The molecular basis for the loss of KAI1 expression in invasive and metastatic
      tumors and tumor cell lines is not understood. Recently, identification of a
      sequence with homology to the consensus p53-binding motif in the promoter of the
      KAI1 metastasis suppressor gene, has led to a proposal that transcriptional
      regulation by p53 controls expression of KAI1, and that a dramatic down
      regulation of KAI1 mRNA levels in invasive tumors and many tumor cell lines, is
      directly due to loss of p53 function. We have tested this hypothesis by assessing
      KAI1 mRNA levels in a series of 22 cell lines derived from bladder and prostate
      cancers, in which we confirmed the p53 gene sequence and characterized the
      functional status of the endogenous p53 protein. We anticipated that cell lines
      expressing p53 capable of transactivation should express high levels of KAI1 mRNA
      compared with cell lines expressing defective p53, or which were p53-null. KAI1
      mRNA levels were determined by northern analysis using a full-length KAI1 cDNA
      probe, and varied widely between cell lines examined. However, there was no
      association between these levels and p53 status. Furthermore, transfection of
      representative cell lines with wild-type p53, or exposure to DNA damaging agents,
      had no effect on KAI1 mRNA levels. Our data suggest that p53 is not a major
      factor regulating levels of KAI1 mRNA in bladder and prostate cancer cell lines.

PMID- 12474543
TI  - Age, lifestyle, health risk indicators, and prostate-specific antigen scores in
      men participating in the world senior games.
AB  - BACKGROUND: A number of risk factors have been implicated for prostate cancer,
      with dietary fat intake the most commonly accepted modifiable risk. OBJECTIVE: To
      assess the relationship between health risk indicators (e.g., cholesterol, blood
      pressure, blood sugar, and percent body fat), which are related to dietary fat
      intake, and prostate-specific antigen (PSA) scores. Relationships between
      demographics and select behaviors (e.g., cigarette smoking and physical activity)
      with PSA scores are also considered. The setting was the 1999 Huntsman World
      Senior Games in St. George, Utah. Subjects' analysis is based on 536 men aged 50
      years and older completing a questionnaire and receiving free screening,
      including a PSA. METHODS: Frequency distributions, multiple regression
      techniques, and the Spearman correlation coefficients. RESULTS: A positive
      relationship was observed between increasing age groups and mean PSA scores
      (Cochran-Mantel-Haenszel Chi-Square: 53.8, p < 0.0001). After adjusting for age,
      none of the personal risk factor indicators (i.e., cholesterol, blood pressure,
      blood sugar, and percent body fat) were related to PSA scores. Other factors not
      related to PSA scores after adjusting for age were race, marital status,
      education, history of chronic disease, cigarette smoking, alcohol use, and
      physical activity. CONCLUSION: Because risk indicators such as cholesterol, blood
      pressure, blood sugar, and percent body fat are associated with dietary fat
      intake, their failure to be related with PSA scores makes it further unclear how
      this commonly accepted modifiable risk factor for prostate cancer may influence
      the disease.

PMID- 12474544
TI  - Derivation of MPR and TRAMP models of prostate cancer and prostate cancer
      metastasis for evaluation of therapeutic strategies.
AB  - Pre-clinical models of primary and metastatic prostate cancer are increasingly
      needed to evaluate efficacy of the new therapeutic strategies currently under
      investigation. The androgen-independent RM1 and androgen-dependent TR cell lines
      derived from transgenic mouse models of prostate cancer were examined in this
      regard. Following implantation in immune competent mice, the RM1 cell line was
      able to generate extremely fast growing s.c. and iprost tumors and metastatic
      lung lesions providing a time period of approximately 14-17 days from the time of
      tumor establishment to animal sacrifice to assess therapies. Implantation of TR
      cell lines resulted in more slowly growing s.c. and iprost tumors and metastatic
      lung lesions that exhibited highly variable incidence and growth. These models
      represent the best available means to evaluate therapeutics in primary and
      metastatic prostate cancer variants in an intact immune system.

PMID- 12474546
TI  - Interstitial photodynamic therapy in subcutaneously implanted urologic tumors in
      rats after intravenous administration of 5-aminolevulinic acid.
AB  - Photodynamic therapy (PDT) may be an attractive option for treatment of early
      stage prostate cancer. Aminolevulinic acid (ALA) acts as a prodrug leading to a
      selective accumulation of a photosensitizer, protoporphyrin IX (PpIX), in
      epithelial cells. We investigated the efficacy of ALA-mediated PDT for rat R3327
      H prostate cancer, compared with the AY-27 bladder tumor. Rats bearing either AY
      27 or R3327-H tumors were randomized to different groups when their tumors
      reached approximately 1000 mm3. At the day of PDT, animals were administered 500
      mg/kg ALA intravenously 4 hours prior to laser therapy. The argon-pumped dye
      laser light (630 nm) was coupled to multiple quartz fibers with cylindrical
      diffusing tips, which were inserted into the tumor in icosahedral pattern. Light
      exposure was varied to yield doses of 1000 to 3000 J/tumor. Animals bearing R3327
      H tumors were imaged with 99mTc-HMPAO scintigraphy to evaluate tumor perfusion
      changes induced by PDT. There was a light-dose dependent tumor response in both
      tumor models. The mean time for R3327-H tumor to re-grow to 4 x treatment volume
      was 79.7 days in the control group (light only), 159 days in 1000 J group, and
      169 days in 2000 J group (P < 0.05). Tumors treated with 3000 J were clinically
      cured (P < 0.01). Likewise, for AY-27 tumors, the average time to re-grow to 4 x
      treatment volume was 13.7 days in the control group, 179.3, 183.3, and 185.7 days
      in groups of 1000, 1500, and 2000 J (P < 0.05), respectively. Tumors treated with
      3000 J were clinically cured (P < 0.01). 99mTc-HMPAO scintigraphy demonstrated a
      mild perfusion impairment following PDT. Interstitial PDT with ALA/PpIX is
      equally effective in treating prostate cancer and TCC in these heterotopic rat
      models.

PMID- 12474545
TI  - Quality of life in patients with metastatic renal cell carcinoma participating in
      a phase I trial of an autologous tumor-derived vaccine.
AB  - BACKGROUND: We prospectively examined quality of life (QOL) in patients with
      metastatic renal cell carcinoma treated with nephrectomy followed by heat shock
      protein peptide complex 96 (HSPPC-96) vaccine, a nontoxic, active, specific
      immunotherapy. MATERIALS AND METHODS: QOL and intrusive thoughts were measured in
      36 patients with newly diagnosed stage IV renal cell carcinoma at the start of
      treatment, 3 weeks later on the final day of treatment, and at follow-up 1 month
      later. At each assessment, patients completed the RAND 36-Item Health Survey and
      the Impact of Event Scale (IES). RESULTS: Mixed model analyses revealed a
      significant improvement over time in the Physical Component Summary score (p <
      0.0001) and no significant change over time in the Mental Component Summary score
      or the IES scores. In comparisons with other populations, at the 1-month follow
      up assessment, patients reported significantly worse QOL than the general
      population on the physical dimensions and similar QOL on the psychosocial and
      emotional dimensions, a similar QOL to that in patients with type II diabetes,
      and a significantly better QOL on four dimensions than that in patients with
      congestive heart failure. CONCLUSION: QOL remained stable or improved during
      treatment with the HSPPC-96 vaccine.

PMID- 12474547
TI  - [Chronic radiation enteritis after irradiation of the lesser pelvis: surgical
      (im)possibilities].
AB  - Three women aged 74, 59 and 36 years, had chronic complaints of abdominal pain,
      nausea, vomiting and diarrhoea, 1 to 8 years after radiotherapy for pelvic
      malignancies. Mechanical ileus due to fibrotic adhesions was found to be the
      cause; all three patients recovered after one or more operations. The prevalence
      of chronic radiation injury correlates with both radiation factors (volume) and
      patient characteristics. If possible, tumour recurrence needs to be excluded.
      Chronic intermittent ileus is the predominant symptom of chronic radiation
      injury. It often occurs within 2 years, but sometimes as long as 10 to 20 years
      after radiotherapy. Resection is warranted when short segments are affected. In
      other cases an intestinal bypass or stoma is the treatment of choice.

PMID- 12474548
TI  - [Dutch Institute for Healthcare Improvement guideline, "Treatment of breast
      carcinoma": important document but an open attitude to new "evidence" is
      necessary].
AB  - In addition to the many international guidelines on the treatment of breast
      cancer, the Dutch Institute for Healthcare Improvement [Dutch acronym: CBO] has
      issued a Dutch national guideline on this subject, aided by representatives from
      the various medical professions involved and the patient advocacy group. A
      potential problem in reaching consensus on a practice guideline is the masking of
      controversies, which may hamper participation in new and innovative studies.
      Examples are the manner in which local and systemic treatments are combined and
      the consequences of new diagnostic modalities, for example the histopathologic
      presence of micrometastases in the sentinel node. The abridged version of the
      guideline published in this issue of the journal, scarcely allows space for
      specific problems such as the very young or old, pregnancy, hormonal
      substitution, male breast cancer and the patient with hereditary breast cancer.
      The authors of this guideline propose a nationwide registration of all patients
      plus follow-up to monitor the adherence to the guideline. The best way to study
      the quality of care and compliance with guidelines is still being debated in the
      medical literature. The money required for a nationwide registration of data on
      all patients including follow-up, might be better spent on measuring a number of
      indicators in a limited group of patients on the one hand and on devising new
      (randomised) trials on the other. This would result in the collection of better
      evidence for the many unanswered questions in the treatment of this common
      malignancy.

PMID- 12474549
TI  - [Adverse cardiovascular effects of postmenopausal hormone replacement therapy].
AB  - The views on the effects of postmenopausal hormone-replacement therapy (HRT) on
      cardiovascular disease have moved from one end of the spectrum to the other over
      the past decades. The presumed beneficial effects of HRT on arterial
      cardiovascular disease were based on observational findings and have led to the
      widespread use of these agents. However, recent large-scale randomised, placebo
      controlled trials have demonstrated that HRT in women with a history of arterial
      diseases initially increases the risk of recurrent disease, while offering no
      benefit in the long term. Healthy postmenopausal women on HRT have an increased
      risk of arterial cardiovascular events compared with those taking placebo
      (relative risk 1.29; 95% CI: 1.02-1.63). Finally, the risk of venous thrombosis
      and pulmonary embolism is increased with the use of HRT. These results
      demonstrate that bias and confounding can play an important role in observational
      research and underscore the importance of randomised, placebo-controlled trials
      when studying the efficacy of drugs.

PMID- 12474550
TI  - [Postmenopausal hormone-replacement therapy discredited, except in healthy women
      shortly after menopause].
AB  - Results from the Women's Health Initiative randomized trial in 16,608 healthy
      postmenopausal women have revealed more risks than benefits in terms of invasive
      breast cancer and cardiovascular disease rates in patients treated for more than
      5 years with a combination of conjugated oestrogens and progestin compared with
      placebo. Hormone-replacement therapy (HRT) is more effective in healthy women
      (maintaining vascular health) than in older women with atherosclerosis (restoring
      endothelial dysfunction). The initiation of HRT in patients at risk of a
      cardiovascular event results in an increased rate of cardiovascular complications
      and has not been proven beneficial in the long term. The point at which HRT is
      started after menopause plays a crucial role in the effectiveness of hormones on
      the vascular system: it is uncertain whether HRT initiated shortly after
      menopause can delay clinical signs of atherosclerotic disease.

PMID- 12474551
TI  - [The Dutch College of General Practitioners' practice guidelines, "Examination of
      the neonate": response from the perspective of pediatrics].
AB  - The practice guideline on routine neonatal examination of the Dutch College of
      General Practitioners describes the examination of the newborn directly after
      birth, whether at home or in the hospital. It is proposed that examination be
      limited to inspection, without auscultation and palpation. If conducted strictly
      according to the guidelines given, this may be sufficient. However, auscultation
      of the heart is the most reliable way to determine the heart rate. Including
      auscultation and palpation in the routine examination after birth would
      contribute to the experience of general practitioners with these techniques in
      babies. This is of importance, since general practitioners are the first to be
      consulted in case of any health problems in this patient category. Previously, it
      was recommended that the general practitioner visit mother and child on the
      third, fourth or fifth day after delivery and examine the baby. In the new
      standard, this second examination is considered to be redundant, based on data in
      the literature. However, it remains the duty of the general practitioner to
      inform the parents about (non-specific) early signs of disease in newborns.
      Furthermore, the threshold for consultation of the general practitioner should be
      low for the early diagnosis and management of serious conditions, such as
      septicaemia or congenital heart disease.

PMID- 12474552
TI  - [The Dutch College of General Practitioners' practice guidelines, "Examination of
      the neonate": response from the perspective of general practice medicine].
AB  - With the publication of the Dutch College of General Practitioners' practice
      guideline 'Examination of the neonate', a discussion which has lasted several
      decades has been brought to an end. Up to now a second neonatal examination by
      the general practitioner on the third, fourth or fifth day after a midwife
      assisted birth was recommended. The arguments in support of this recommendation
      were based on the following: (a) the limited expertise of midwives in the past,
      (b) the experience that general practitioners had in examining children, although
      this experience was not specifically related to the defects for which neonates
      should be checked, and (c) the government bodies' wish to restrict the number of
      hospital deliveries by giving greater structure to the organisation of midwife
      care, which in practice, did not lead to large changes. Based on three studies,
      the practice guideline recommends that a second examination is of no added value.

PMID- 12474553
TI  - [Refractive surgery: most commonly used techniques, results and complications].
AB  - Refractive surgery is gaining enormous popularity. It is estimated that in 2001,
      refractive surgery was performed on 1 in 8000 persons in the Netherlands.
      Photorefractive keratectomy and laser in-situ keratomileusis are effective and
      predictable for the correction of myopia up to 10.0 D and hypermetropia up to
      +4.5 D. There is rarely any significant loss of best-corrected visual acuity
      postoperatively. For the correction of higher levels of myopia and hypermetropia,
      phakic intraocular lenses can be implanted in the anterior or posterior eye
      chamber, in other words in front of the natural lens. The magnification effect of
      these lenses often results in improved vision at higher levels of myopia. Good
      preoperative selection of refractive surgery candidates is essential and patients
      should be properly informed about the results, potential complications and
      adverse effects of refractive surgery techniques.

PMID- 12474554
TI  - [Summary of the Dutch College of General Practitioners' practice guideline,
      "Examination of the neonate"].
AB  - The routine examination of the neonate by the general practitioner directly after
      birth provides a first impression of the state and vitality of the newborn, gives
      base values that may be relevant for later occurring illnesses or problems, and
      is a first orientation on the presence of congenital malformations. Inspection of
      the newborn is the most important. Four possible malformations receive special
      attention: congenital malformations of the heart and eye, developmental hip
      dysplasia, and undescended testes. If the first examination was properly
      performed, a second routine examination by the general practitioner during the
      maternity visit has no proven added value. A specific physical examination should
      take place if indicated. It is recommended that all involved parties (health
      centre physicians, obstetricians, general practitioners, paediatricians and
      midwives) reach agreement as to the content and reporting of the first
      examination.

PMID- 12474555
TI  - [Dutch Institute for Healthcare Improvement guideline, "Treatment of breast
      cancer"].
AB  - The first Dutch evidence-based guideline for the treatment of breast cancer has
      been developed to realise the optimal care of breast cancer patients in the
      Netherlands. This was possible due to the close cooperation of the Dutch
      Institute for Healthcare Improvement [Dutch acronym: CBO] and the Dutch
      Consultative Committee on Breast Cancer [Dutch acronym: NABON]. A broad,
      multidisciplinary working group was appointed to develop the guideline. This
      group consisted of surgeons, radiotherapists, internists, pathologists, a
      radiologist, a nuclear medicine specialist, a plastic surgeon and a clinical
      geneticist, all of whom had been given a mandate to represent their respective
      professional societies. In addition to these medical specialists, there were
      physiotherapists, oncology nurses, psychologists, staff from comprehensive cancer
      centres and the Dutch Institute for Healthcare Improvement and representatives
      from the Dutch Breast Cancer Association. This CBO guideline is divided into
      seven chapters: local treatment of operable breast cancer, systemic adjuvant
      treatment, locoregionally advanced disease, follow-up, locoregional recurrence,
      metastasised disease, and the psychosocial aspects of breast cancer. Although the
      guideline is not intended as a set of instructions that must be rigidly adhered
      to, deviations from the guideline must be motivated, principally on the basis of
      published scientific information. To obtain insight into the actual use of the
      guidelines 'Screening and diagnostics' and 'Treatment of breast cancer' the work
      group advocates a nationwide prospective registration of all breast cancer
      patients, including follow-up. Steps to this end have been undertaken. In this
      way, the CBO guideline will contribute to a further optimisation of breast cancer
      care in the Netherlands.

PMID- 12474556
TI  - [Diagnostic image (113). A neonate blowing bubbles. Esophageal atresia with
      tracheoesophageal fistula, Hirschsprung disease and suspected Down's syndrome].
AB  - In a male neonate 'blowing bubbles', three diagnoses were seen on a combined
      thoracic and abdominal X-ray: esophageal atresia with tracheoesophageal fistula,
      Hirschsprung's disease, and suspected Down's syndrome (because of the presence of
      II pairs of ribs).

PMID- 12474557
TI  - [Manic state during the addition of lithium in the case of depression resistant
      to imipramine].
AB  - Two women, aged 65 and 43 years, who were suffering from tricyclic-resistant
      depressions, developed a (hypo)manic state after a few days of lithium addition.
      In both cases the lithium plasma level was fairly low. For the first woman an
      increase in the lithium dosage combined with a substitution of the antidepressant
      resulted in a complete recovery and for the second woman, an increase in the
      lithium dosage combined with the continued use of the same antidepressant
      resulted in a recovery to a large extent. In animal experiments lithium addition
      resulted in a rapid increase in serotonergic neurotransmission, due to an
      increase in serotonin synthesis and release. This may explain a rapid
      amelioration of depression as well as the development of (hypo)manic symptoms.
      Depending on the severity and the persistence of hypomanic symptoms, the
      antidepressant can be either continued or withdrawn but the lithium dose must be
      adjusted in order to reach an adequate plasma level of lithium.

PMID- 12474558
TI  - [Clinical reasoning and decision making in practice. Fever, purpura and
      hemiparesis in a 29-year old female].

PMID- 12474560
TI  - The European Health Report 2002. Introduction.

PMID- 12474559
TI  - [The effect of comedication with folic or folinic acid on the toxicity and
      efficacy of methotrexate in rheumatoid arthritis: a randomized, double blind,
      placebo controlled study of 48 weeks].

PMID- 12474562
TI  - The major determinants of health. Part Two.

PMID- 12474561
TI  - The health situation in the European Region. Part One.

PMID- 12474563
TI  - Health systems policies and reforms. Part Three.

PMID- 12474564
TI  - [Adhesion molecules in patients with chronic renal failure treated with
      haemodialysis].
AB  - Patients with chronic haemodialysis present with a number of symptoms resulting
      from immunoincompetence observed in this group. Many of these alterations may be
      the effect of an interaction of blood with a dialyzer membrane. When blood cells
      and plasma proteins contact artificial surface of the dialyzer, neutropenia,
      creation of platelet-leukocyte aggregates and leukocyte degranulation occur.
      These processes are reflected by changing expressions of adhesion molecules'
      membrane-bound receptors and levels of their circulating forms. Since the
      intensity of the above mentioned reactions depends on the type of the dialyzer
      membrane that is used. Adhesins' receptors may serve as markers of haemodialysis
      related bioincompatibility. Meanwhile, further investigation on soluble adhesion
      molecules should evaluate their usefulness in assessing haemodialysis influence
      on patients' immunity.

PMID- 12474565
TI  - [Evaluation of the effect of obesity on selected haemostatic and fibrinolytic
      parameters in peri- and postmenopausal women].
AB  - Localization of adipose tissue influence on obesity-dependent diseases. In obese
      people many abnormalities are observed connected with coagulation factors and
      fibrinolysis. We studied 47 peri- and postmenopausal female patients, who were
      operated on for benign changes within the pelvis minor. The patients were divided
      according to BMI (group I--BMI < 25 kg/m2, group II--BMI > 29 kg/m2). In obese
      women lower SHBG concentration, higher insulin and glucose fasting blood levels,
      higher LDL, higher total fatty tissue content, higher fibrinogen level and
      elevated PAI-1 activity were found. A positive correlation between area under
      insulin curve and PAI-1 activity and a negative correlation between fasting
      insulin levels and tPA were also observed. Based on the studies performed it can
      be said that: 1. Fatty tissue content in postmenopausal women exerts an influence
      on PAI-1 activity. 2. Obesity influences coagulation and fibrinolysis system in
      peri- and postmenopausal women. 3. Carbohydrate metabolism disturbances have
      influence on PAI-1 activity in peri- and postmenopausal women.

PMID- 12474566
TI  - [Frequency of Bordetella pertussis antibodies in serum of patients with
      Parkinson's disease].
AB  - The assessment of the levels of IgG antibodies against Bordetella pertussis in
      serum using ELISA test was performed in 59 patients (including 30 patients with
      Parkinson's disease--PD, 15 patients with other non-inflammatory neurological
      diseases, and 14 controls). The average age in the groups was 64.0, 64.4, and
      58.7 years, respectively. Positive results were found in 17/30 patients with PD,
      8/15 subjects with other non-inflammatory neurological diseases and in 7/14
      controls. The above results are surprising and demonstrate a high incidence of
      subclinical whooping cough among the adult population. No statistically
      significant difference has been found between patients with Parkinson's disease
      and patients with other neurological diseases. A tendency is observed for a
      higher percentage of negative results among controls in comparison with patients
      with Parkinson's disease and other non-inflammatory neurological diseases.

PMID- 12474567
TI  - [Autopsy evaluation of the extent of degeneration of the lumbar intervertebral
      discs].
AB  - The aim of study was to evaluate the degree of lumbar intervertebral disc
      degeneration during post-mortem studies, and its relation to the age and gender
      of cadavers. The changes of intervertebral disc were classified according to
      Nachemson [13]. The study included 308 lumbar intervertebral discs taken during
      autopsy from 57 females (mean age 41.83) and 79 males (mean age 42.06). Two
      hundred and forty discs showed degenerative changes. The statistic analysis
      revealed that the degeneration is more pronounced with age (ANOVA p < 0.05). The
      study demonstrated that in males degeneration occurs a decade earlier than in
      females, and could be observed in the second decade of life. Similarly, the
      degeneration of 3rd or 4th grade could be observed a decade earlier in men than
      in women. The statistical analysis revealed the differences (p < 0.05) in
      degeneration between upper (levels L2 and L3), and lower (levels L4 and L5)
      lumbar spine. Analysing the discs as single levels, no statistical differences in
      degeneration were observed.

PMID- 12474568
TI  - [The effect of recombinant human growth hormone on urea and creatinine kinetics
      and selected dialysis adequacy parameters in children with end-stage renal
      failure treated with peritoneal dialysis].
AB  - The aim of this work was to assess the effect of recombinant human growth hormone
      (rhGH) on the kinetics of urea and creatinine and selected indices of dialysis
      adequacy in children with end-stage renal failure treated with peritoneal
      dialysis. We studied 24 children on peritoneal dialysis, including 10 children
      aged 9-15.7 years (mean age 12.5 years) treated with 1-1.1 IU/kg/week of rhGH
      administered daily for 6 months. The control group included 14 patients aged 5.4
      18.3 years (mean age 12.6 years). Kinetic modelling of urea and creatinine using
      Adequest was performed in all patients at baseline and after 3 and 6 months of
      follow-up. Total dialysate and urinary excretion of urea and creatinine (tUE and
      tCE, mg/min), total urea and creatinine clearance (tUC and tCC, L/week), weekly
      Kt/V, normalized total weekly creatinine clearance (ntCC, L/week/1.73 m2), total
      body water (TBW, kg), and absolute and percent change of TBW (DTBW, kg, and
      D%TBW, respectively) were calculated. Albumin level was measured and diet
      composition was analysed in all patients. Insignificant decrease in Kt/V was
      found after 3 and 6 months of rhGH treatment despite stable values of tUC (45.3
      +/- 15 L/week vs 45.6 +/- 15 L/week, p = NS). Serum creatinine increased from
      7.38 +/- 1.52 to 9.26 +/- 2.98 mg/dL after 6 months of rhGH treatment.
      Significantly higher values of delta %TBW were found among treated patients
      compared to the control group (1.23 +/- 0.7 kh vs 0.57 +/- 0.7 kg, P < 0.05).
      delta TBW in patients treated with rhGH was significantly higher during months 0
      3 compared to months 3-6 (0.85 +/- 0.6 kg and 0.38 +/- 0.17 kg, respectively, p <
      0.05). No significant changes in ntCC, albumin concentration and diet composition
      were found. CONCLUSIONS: 1. A trend to lower urea values in children treated with
      peritoneal dialysis was found after 3 months of rhGH treatment. Concomitant
      decrease in Kt/V may have resulted from increased TBW. 2. An increase in
      creatinine level was observed during rhGH treatment in children treated with
      peritoneal dialysis. Decrease in normalized total creatinine clearance (ntCC) and
      normalized dialysate creatinine clearance (ndCC) during rhGH treatment may have
      resulted from increased serum creatinine and not from decreased creatinine
      excretion. 3. Treatment with rhGH in children on peritoneal dialysis makes it
      difficult to interpret commonly used indices of dialysis adequacy such as Kt/V
      and ntCC.

PMID- 12474569
TI  - [Thyrotropin receptor antibodies (TRAb) as a test of surgical treatment
      effectiveness in Graves-Basedow's diseases].
AB  - The aim of the study was to assess the relations between the concentration of
      antibodies against TSH receptors (TRAb) and the outcome of the surgical treatment
      in Graves-Basedow's disease. The studies were performed in 30 patients (age range
      -18-50, mean -37) operated on for Graves-Basedow's disease and in 20 healthy
      controls. In control group, the TRAb concentration was mean -2.75 +/- 2.06 U/l,
      the TSH mean -1.06 +/- 0.53 mlU/l, and FT4 mean -14.71 +/- 2.15 pmol/l. The
      thyroid volume was mean -14.45 +/- 2.37 ml. In the group operated on antibody
      concentration was determined before and 12 months after the surgery. The TSH and
      FT4 concentrations were also determined before and 12 months after the operation.
      Moreover, the size of the thyroid remnant was assessed ultrasonographically 12
      months after the procedure. The results showed the effectiveness of the surgical
      treatment, i.e. hyperthyroidism was not observed in 22 out of 30 patients. Among
      these 22 patients, euthyreosis was found in 14 cases (46%) and hypothyreosis was
      observed in 8 cases (27%). In the euthyreosis group, the pre-operative TRAb
      concentration was mean -24.00 +/- 11.04 U/l. 12 months after the operation, the
      decreased levels of antibodies were found in 13 patients (mean -6.14 +/- 5.71
      U/l). In the hypothyreosis group, the pre-operative TRAb concentration was mean 
      24.50 +/- 10.43 U/l. After the surgical procedure, TRAb levels were normal in all
      patients, the average values being 2.13 +/- 1.34 U/l. In 8 patients with
      recurrent hyperthyroidism (27%), TRAb concentration before the surgery was
      higher, mean -107.25 +/- 56.69 U/l. 12 months after subtotal strumectomy, the
      patients in this group still did not show normal TRAb levels (mean -54.25 +/-
      51.61 U/l). Moreover, the relations between the size of the thyroid remnant and
      the TRAb level were evaluated. In the group with recurrent hyperthyroidism and
      high TRAb levels, the thyroid size (volume) left was mean -12.10 +/- 6.25 ml, in
      the euthyreosis group mean -5.54 +/- 2.23 ml, while in the hypothyreosis group it
      was mean -4.86 +/- 1.14 ml.

PMID- 12474570
TI  - [Effect of methylprednisolone on emotional functioning of patients with multiple
      sclerosis].
AB  - The effects were examined of high doses of intravenous methylprednisolone (MP; 1
      g daily, administered for 5 days) on emotional functions in multiple sclerosis
      (MS) patients with clinical relapse. Thirty two patients with relapsing-remitting
      disease were included. The mean age was 39.4 (20-56) years, mean disease duration
      and mean Expanded Disability Status Scale scores were 6.6 (0.8-28) years and 4.1
      (2-6.5), respectively. MS patients were subjected twice to psychological tests:
      immediately after MP treatment and 6 months later. Hamilton Rating Scale for
      Depression (HRSD) and Hopkins Symptom Check List (HSCL) were used. Thirty two
      control subjects (mean age 37.2 years) with ischialgia, not receiving steroids,
      underwent the same testing procedure. On the basis of their results in learning
      tests (Nonverbal Learning Test and Rey Auditory Verbal Learning Test) upon
      admission, MS subjects were allocated into 2 different subgroups: 20 patients
      were included into cognitively preserved group (cpMS) and 12 patient into the
      group with cognitive decline (cdMS). Immediately after MP treatment, MS patients
      (total group) achieved significantly higher scores than controls on the HRSD and
      two subclasses of the HSCL: depression with inhibition and phobic anxiety. There
      were no significant differences between cpMS and control subjects in HRSD and
      HSCL tests. CdMS patients, as compared with controls and cpMS subjects upon
      admission showed depressed mood, obsessive-compulsive disorder, increased anxiety
      and interpersonal hypersensitivity. Therapy with MP did not markedly change
      emotional functions in all MS patients (total group, cpMS, cdMS). CONCLUSIONS: 1.
      Only cdMS patients show emotional disturbances. 2. Therapy with MP does not
      significantly change the emotional profile of MS patients.

PMID- 12474571
TI  - [Effect of antibiotic therapy on phagocytosis and oxidative metabolism of
      polymorphonuclear leukocytes in patients with Lyme arthritis].
AB  - The purpose of this work was to evaluate phagocytosis and oxidative burst changes
      in neutrophils of patients with Lyme arthritis before and after antibiotic
      treatment. The examined patients were divided into three groups: group 1-18
      patients with diagnosed Lyme arthritis, group 2-12 patients with Lyme arthritis
      after 14-day treatment with cefuroxime and control group--25 healthy individuals.
      The phagocytic activity of peripheral blood neutrophils (percentage of phagocytic
      cells and fluorescence) was measured using standard cytometric flow assay
      (Phagotest-kit, Orpegen Pharma). The oxidative metabolism (percentage of bursting
      cells and fluorescence stimulated by Escherichia coli and PMA) was measured using
      cytometric flow assay (Burst-test, Orpegen Pharma). The results were
      statistically analysed using Mann-Whitney test. Evaluation of phagocytosis
      demonstrated no changes in the percentage of phagocytic cells. But fluorescence
      increased significantly after treatment. The comparison of oxidative metabolism
      activity showed no changes despite E. coli and PMA stimulation. Parameters of
      phagocytosis and oxidative metabolism did not correlate with neutrophil count in
      analysed groups of patients.

PMID- 12474572
TI  - [Effect of minoxidil on hair growth in androgenic alopecia in women].
AB  - The aim of the study was to carry out clinical and trichological examination
      (trichogram and assessment of hair loss) before and after treatment in 17 women
      aged 41-50 years with androgenic alopecia. Minoxidil (Loxon) was topically
      applied twice a day massaging the solution into the scalp over 6-12 months. It
      was revealed on the ground of clinical and trichological examination that the
      medication containing 2% solution of minoxidil externally applied on the scalp
      with androgenic alopecia over a few months caused normalization of hair root
      condition and decrease of hair loss in some patients of the observed group. The
      drug has a stimulating influence on hair growth and should be administered as an
      adjuvant therapy in androgenic alopecia in women.

PMID- 12474573
TI  - [Evaluation of renal function in children undergoing surgery under general
      anaesthesia].
AB  - 47 children (29 boys and 18 girls) aged from 3 to 13 years were examined. The
      children were operated under general anaesthesia. All children were in good
      general condition, belonged to anaesthesia risk groups ASA 1 and ASA 2, had no
      metabolic, endocrinological, haematological diseases nor had renal or hepatic
      dysfunction. The examined children were divided into two groups with regard to
      anaesthesia method. 24 healthy children aged 2-16 years were included into
      control group. Urinary excretion of N-acetyl-beta-D-glucosaminidase (U-NAG), Tamm
      Horsfall protein (U-THP), beta 2-microglobulin (U-beta 2-m) and albumins (U-Alb)
      as indicators of functions of the following nephron structures: glomerular,
      proximal and distal tubular were assessed. The studies were carried out directly
      before and on the first day after surgery. RESULTS: Statistically significant
      differences between values of examined indicators before and after surgery have
      not been observed. CONCLUSION: The administered methods of anaesthesia have not
      negatively influenced renal function in children.

PMID- 12474575
TI  - [Imaging diagnosis of alveolar echinococcosis].
AB  - Alveolar echinococcosis, a parasitic disease caused in humans by the larval stage
      of Echinococcus granulosus tapeworm is a rare disease in Poland There are about
      16 officially registered cases and further 8 cases described before creation of
      the European Registration system. This disease still causes significant
      diagnostic difficulties. Presently available radiological imaging techniques
      which can be applied in the alveolar echinococcosis diagnosis are presented.
      Ultrasound, CT and MRI images of patient with recurrent liver alveococcosis are
      presented against the background of literature data.

PMID- 12474574
TI  - [Helicobacter pylori CagA(+) infection in gastric cancer patients].
AB  - STUDY AIM: The aim of the study was to evaluate the role of Helicobacter pylori
      CagA(+) infection in gastric cancer. MATERIAL AND METHODS: 475 patients were
      included into the study (270 gastric cancer patients and 205 control subjects).
      Helicobacter pylori CagA status was determined by enzyme-linked immunoabsorbent
      assay (ELISA). The frequency of H. pylori CagA infection in gastric cancer
      patients and control group was compared. The relationship between presence of
      anti-H. pylori CagA antibodies and selected clinical and pathomorphological
      parameters was analysed. RESULTS: Gastric cancer patients and controls had the
      same prevalence of H. pylori CagA antibodies (54.4 vs 52.5%; p = 0.078). The
      persons with H. pylori CagA(+) and CagA(-) were at the same risk for developing
      gastric cancer (OR = 1.08; 95%CI = 0.66-1.49). However subgroup analysis showed
      that the risk of gastric cancer development in H. pylori CagA(+) depended on age
      being 2 times higher for young people (15-40 years) (OR = 2.0; 95% CI = 0-4.25)
      and four times higher for those under the age of 30 years (OR = 4.0; 95%CI = 0
      15.9). There was a positive relationship between H. pylori CagA(+) infection and
      age (p = 0.043). H. pylori CagA(+) infection was independent of sex, family
      history of cancers, duration of symptoms, ABO blood group, tumour site, stage,
      histology and p53 accumulation in cancer gastric tissue. CONCLUSION: Our study
      shows that H. pylori CagA(+) infection increases the risk for developing gastric
      cancer in young persons and does not protect the host against cardia cancer. The
      results suggest also that infection by H. pylori CagA(+) in gastric cancer has no
      influence on p53 gene mutation development.

PMID- 12474576
TI  - [Neoplasms and angiogenesis].
AB  - Angiogenesis is a process of new blood vessels formation in many physiological
      and pathological conditions such as wound healing, cancer, ischaemic diseases (of
      heart or limb) and chronic inflammations. Neoplastic angiogenesis plays an
      important role in progression of the disease and development of metastases. The
      angiogenic process may be initiated by hypoxia in cancerous cells, mutations in
      suppressor genes or oncogenes. Cancer cells activate specific angiogenic factors
      mainly vasoendothelial growth factor (VEGF) that stimulate migration and division
      of vascular endothelial cells. The studies of several pro- and antiangiogenic
      molecules and factors, and mechanism of vessel growth, have revealed that
      therapeutic interferences with these processes offers a tool for clinical
      applications in various pathologies. Inhibition of angiogenesis can prevent
      diseases with excessive vessel growth such as, particularly, cancers. Stimulation
      of angiogenesis can be beneficial in the treatment of diseases such as coronary
      disease and limb ischaemia. In this article some aspects are presented of current
      knowledge of angiogenesis and its regulation.

PMID- 12474577
TI  - [Chromosome Y microdeletions in the pathogenesis of male infertility].
AB  - Since over 10 years the Y chromosome has been the subject of interest of
      geneticists. Until now its role has been proven in in male sex determination and
      development but the function of the remaining genes located on it is still within
      the sphere of intense research. Studies for identification of location of
      sequences responsible for normal course of spermatogenesis process in men have
      been performed since 1970s. It is believed that the factor responsible for these
      disorders is the gene conventionally called AZF (azoospermia factor) located
      probably in the euchromatic part of the long arm in Yq11.23 locus. The incidence
      of Y microdeletion in infertile males ranges from 1 to 55%, according to various
      authors. Estimated data demonstrate that about 10-15% of cases of azoospermia and
      about 5-10% of cases of severe oligospermia are caused by Y chromosome
      microdeletion.

PMID- 12474578
TI  - [Ageing and degeneration of human lumbar intervertebral discs].
AB  - Intervertebral discs undergo serious age-related changes. It is generally
      accepted that degeneration of discs begins during the second decade of life, and
      it is well known that other structures of spine do not change as fast as the
      intervertebral discs. The most extensive degenerative changes occur in the
      nucleus pulposus, including degradation of proteoglycans aggregates with its
      fragmentation, dehydration, and loss of viable cells. Data available in
      literature, suggests that the most critical factor contributing to the
      degeneration, is increasing volume of the disc due to its growth, resulting in
      longer nutritional pathways and insufficient nutrition.

PMID- 12474579
TI  - [The role of monocytes/macrophages and their cytokines in the development of
      immunosuppression after severe injury].
AB  - Despite new generations of antibiotics and great improvement in the fields of
      rescue and modern intensive care medicine, sepsis remains one of the most
      frequent causes of complications and death in severely injured patients. Shock,
      bacterial colonization, invasive methods of treatment and immune mechanisms are
      reported to be responsible for the increased susceptibility of patients to sepsis
      after trauma. Posttraumatic immune abnormalities consist of two mechanistic
      entities: inappropriately hyperactive inflammatory processes and profound
      depression of cell-mediated immune function. Monocytes/macrophages carry out the
      fundamental protective functions of ingesting and killing invading
      microorganisms. Macrophages play a central role in the immune response by
      presenting antigens to lymphocytes, modulating T cell functions and by secreting
      a large number of inflammatory mediators. Macrophage-derived cytokines play key
      roles in the amplification of both humoral and cell-mediated immune responses.
      Depression of macrophage function appears to have serious deleterious effects in
      critically injured patients and has been associated with increased mortality.
      Phagocytosis, oxidative burst activity and cytokine secretion are impaired in
      macrophages early after traumatic injury. However, a widely accepted clinical
      treatment for post-injury immunosuppression does not currently exist. As our
      understanding of the pathogenesis of injury-induced immunosuppression progresses,
      our treatment approaches will likely improve.

PMID- 12474581
TI  - [Pharmacological justification for the use of new antidepressant drugs].
AB  - This review compares a new generation of antidepressants with standard tricyclic
      antidepressants. It is now believed that an ideal antidepressant should be
      characterised by high therapeutic efficacy, good tolerance, safety of use related
      to low incidence of adverse effects, little potential for interactions and low
      cost of use. Mirtazapine, nefazodone and venlafaxine have therapeutic efficacy
      which is comparable with that of tricyclic antidepressants and their lack of (or
      insignificant) receptor effect as well as double mechanism of action makes them a
      safer therapeutic option.

PMID- 12474582
TI  - [Surgical complications of trabeculectomy and methods of their treatment].
AB  - The author presents the review of new literature concerning advances in
      conservative and surgical treatment of the most common postoperative
      complications after trabeculectomy--the most popular antiglaucoma operation.

PMID- 12474580
TI  - [Drugs against human cytomegalovirus].
AB  - Human cytomegalovirus (HCMV) infects about 60% of adults in developed world and
      more than 90% of developing countries population. In the immunocompetent host,
      initial infection and reactivation of latent infection are usually asymptomatic.
      However, in hosts with impaired cellular immune functions, such as transplant
      recipients, patients infected with human immunodeficiency virus (HIV) or
      undergoing anticancer chemo- and/or radiotherapy, the full pathogenic potential
      of the virus may be realized. HCMV is also among the most common causes of viral
      intrauterine infection affecting from 0.4 to 2.3% of live-born infants. Though in
      pregnant, immunocompetent women infections with HCMV are usually asymptomatic,
      severe infections may occur among congenitally infected fetuses and infants due
      to immaturity of their immune system. Approximately 40% of mothers with primary
      HCMV infections during gestation transmit virus to their infants. Although only
      10% of infected infants are symptomatic at birth, 20 to 30% of these die. In
      addition, 5 to 15% of asymptomatic neonates are at risk of developing congenital
      anomalies later. In this outline we present anti-CMV drugs currently in clinical
      use and give examples of new molecules under laboratory and clinical development.

PMID- 12474583
TI  - [Is dehydration an ethical problem?].
AB  - In the paper, issues connected with chronic dehydration were discussed from the
      point of view of medical ethics. Rudimentary definitions concerning the issues
      were mentioned. An attempt was made at analysing critically the views on chronic
      voluntary dehydration as a possible form of causing death. Some
      pathophysiological and psychopathological aspects were discussed. "The pyramid"
      of physician doubts were presented.

PMID- 12474584
TI  - [SEN virus--novel hepatotropic agent causing hepatitis?].
AB  - The author presents the review of world literature on infection of novel
      discovered SEN virus (SENV) after the initials of the infected patients, a human
      immunodeficiency virus-infected injection drug user. This single-stranded DNA
      virus, distantly related to the TT virus (TTV) has been announced as a major
      cause of non-A-E hepatitis. Genotypes SENV-D and SENV-H were more prevalent in
      the serum samples of patients with transfusion-associated hepatitis and were of
      lesser prevalence in serum samples from healthy blood donors.

PMID- 12474586
TI  - [Disorders of thermoregulatory mechanisms of the organism and their metabolic
      consequences. Part I. Hypothermia].
AB  - The maintenance of thermal equilibrium depends on the normal functioning of
      numerous body systems and their appropriate interaction with the environment. Man
      has a complicated neural and neuroendocrine control system that is designed to
      maintain a constant core temperature despite changes in environmental temperature
      or level of activity. Heat exchange is a bidirectional process involving the
      transfer of heat between an object and its environment. There are four mechanisms
      of heat dissipation: evaporation, conduction, convection, and radiation. Heat
      production is the sum of basal metabolism and shivering and non-shivering
      thermogenesis. The hypothalamus is the central control centre that ensures
      thermal homeostasis. Although many schemes exist for the classification of
      hypothermia, from the clinical point of view it is recommended to consider any
      temperature below 35 degrees C significant. Accurate temperature measurement and
      core temperature monitoring are essential for diagnosing hypothermia.

PMID- 12474585
TI  - [Review of current etiopathogenic data of Buerger disease].
AB  - Although 75 years have passed since Buerger's disease was described as a separate
      nosological, its etiology and pathogenesis are not sufficiently elucidated.
      According to many authors the disease origin is significantly connected to
      genetic and environmental factors. Exposure of some patients with special
      genotype, mainly HLA-A9 and HLA-B5, to environmental factors, mainly nicotine,
      may be the base of etiology and pathogenesis of Buerger's disease. Discovery of
      antielastin, anticollagen I and III antibodies, antinicotine and antivascular
      antigen antibodies in blood of patients, allowed to put forward a theory of
      immunological character of TO. In Buerger's disease, defined in recent years as
      an inactive collagenosis, immunological complexes, cell toxins developing during
      phagocytosis, found in smokers, constitute the main agents responsible for
      vascular wall damage. Disturbance of prostacyclin I2/thromboxane A2 balance and
      accelerated platelet aggregation cause spasm of arterioles and in effect lead to
      higher procoagulant readiness. Some adhesive molecules, for example P and L
      selectins, play an important role in vascular endothelium damage. Prostaglandin
      treatment induces an improvement of vascular wall (endothelium) status, and
      simultaneously improvement of tissue perfusion, expressed by a decrease of
      selectin and vWF concentrations and of the number of desquamated endothelial
      cells.

PMID- 12474587
TI  - [Doctor Mikolaj Witczak's life and work].
AB  - On the grounds of conducted research, the life and activities of Dr Mikolaj
      Witczak (1857-1918) have been reconstructed. The history of Jastrzebie Zdroj Spa
      has also been presented as one of the most remarkable European health resorts of
      the turn of the 19th century.

PMID- 12474588
TI  - The tetraplegic upper limb. Introduction.

PMID- 12474589
TI  - History of surgery in the rehabilitation of the tetraplegic upper limb.
AB  - Surgery in the tetraplegic upper limb made tremendous strides during the last
      half of the 20th century, inspiring the motivation and creativity of hand
      surgeons to restore upper limb functions in one of the most unfortunate
      complications of trauma. Undoubtedly, the future will provide new tools to
      improve the surgeons' challenge. Meanwhile, they must proceed with meticulous
      clinical examinations, determine the level of the spinal cord lesion and the
      muscles available for transfer, and select the most appropriate and proven
      surgical procedures for each patient.

PMID- 12474590
TI  - Tetraplegia: update on assessment.
AB  - The overall assessment in the tetraplegic patient should be comprehensive and
      detailed. This paper discusses aspects of the medical and physical assessment
      that normally may go unrecognized but are extremely important in the outcome of
      the tetraplegic patient. A comprehensive classification also is provided as a new
      guideline for rehabilitation and surgery. Additionally, the power of [figure: see
      text] cultural, social, and personal dimensions of disability are illustrated and
      the importance of these dimensions as they relate to assessment is examined.
      Finally, the COPM is introduced as an outcome measure capable of crossing
      cultural [table: see text] boundaries and allowing for the comparison of
      interventions.

PMID- 12474591
TI  - The unoperated hand: the role of passive forces in hand function after
      tetraplegia.
AB  - Passive forces play a large role in hand function after tetraplegia. Most
      individuals with tetraplegia choose not to undergo surgical reconstruction of
      hand function and, therefore, depend on the passive properties of their
      musculoskeletal system to perform functional tasks. Knowledge of the levels of
      force needed to perform many of these tasks is lacking. Understanding the
      mechanics of producing passive force is important for designing adaptive tools
      and other devices for tetraplegic individuals. Knowledge of the passive
      properties of the upper extremity is important in forming treatment strategies.
      The passive forces produced for change to the tenodesis grasp are small but
      useful to the individual. Since these forces arise from basic anatomy and muscle
      function, they are important even after surgical restoration of hand function.
      Compensatory strategies for the unoperated hand probably play a role in the
      operated hand. The approach to surgical restoration of grasp must consider how
      passive forces contribute to functional outcome.

PMID- 12474592
TI  - Injured metamere and functional surgery of the tetraplegic upper limb.
AB  - The size of injured metamere (IM) in tetraplegia exhibits a high variability that
      explains the different clinical presentations in patients who have the same
      neurologic level. Even when functional electrical stimulation is not planned, the
      lower motor neuron (LMN) integrity of paralyzed muscles must be evaluated,
      especially in patients with high-level tetraplegia. During the acute phase,
      detecting the size of the IM is important to prevent supination contracture and
      stiffness of the thumb and finger joints. When planning functional surgery, the
      LMN integrity of intrinsic muscles helps the surgeon adapt his surgical
      procedures. Assessing IM size must be integrated systematically into the
      evaluation of tetraplegic patients.

PMID- 12474593
TI  - General indications for functional surgery of the hand in tetraplegic patients.
AB  - General indications for surgery of the upper limb cannot be codified and do not
      follow any general rules. Each case is different, and a successful outcome
      depends on the experience acquired by a specialized surgeon, the team that
      surrounds the patient, and the customization of treatment to the personality and
      wishes of the patient. In addition, direct and caring human contract between the
      surgeon and his patient are fundamental. Today, many tetraplegic patients who are
      confined to their wheelchairs spend much of their time on the computer, eager to
      obtain as much information as possible about their condition from the Internet.
      One must stress, however, the risks of the false and partial information they
      might find. Surgical indications should be assessed only after a clinical
      evaluation and a long and personal discussion between the surgeon and the
      patient, who in this way establish a covenant between them. In the 21st century,
      patients will continue to become better informed, but the surgeon will maintain
      his role as mediator between the patient and surgery.

PMID- 12474594
TI  - Tendon transfers as applied to tetraplegia.
AB  - The techniques of the tendon transfers that are used primarily for the functional
      rehabilitation of upper limbs in tetraplegia are described in this article. The
      restoration of active elbow extension can be obtained either by biceps-to-triceps
      or by deltoid-to-triceps transfers. Grasp and key grip can be restored either by
      active or by passive tendon transfers. The usual motors of active transfer are
      the BR and ECRL. The usual tenodesis involve the FDS (via lassos), EDC, EPL, FPL,
      and APL.

PMID- 12474595
TI  - Cervical epidural anesthesia in tetraplegia.
AB  - The primary result of this series is that each patient participated actively
      during his or her procedures. The concept of selective sensory block, therefore,
      which was the authors' overriding reason for using CEA in secondary tendon
      surgery, also may be beneficial to tetraplegic patients. Nystrom and Nystrom [2]
      also came to this conclusion. The use of CEA in tetraplegia is and must be used
      only in exceptional cases. If the usual surgical techniques seem to be inadequate
      for a given patient, and if the surgeon wishes to assess muscle tonicity and the
      effect of tenodesis in vivo, CEA may be used. The patients in the authors' series
      have been so satisfied with the technique that this dynamic approach to the
      tetraplegic upper leg may be as advantageous for the patient as it is for the
      surgeon.

PMID- 12474596
TI  - Elbow extension.
AB  - Reconstruction of elbow extension is an established treatment with a high degree
      of patient satisfaction. The D-T transfer is the most common method and has the
      advantage of inducing no serious complications; however, it necessitates a long
      period of healing and recovery. The Bi-T transfer is used much less frequently
      and, in the author's opinion, has few advantages compared with the D-T transfer.
      It is somewhat less time consuming to perform, and the rehabilitation period is a
      few weeks shorter. This method, however, has several drawbacks, including
      difficulties in learning to use the muscle as an extensor and a reduction of
      elbow flexion strength, which might result in a subjective functional loss. What
      is the best treatment for patients with a posterior deltoid that has a strength
      grade of 2 or 3: a D-T or Bi-T transfer or functional electrical stimulation?
      Today, this question is impossible to answer. The author is convinced that the
      optimal postoperative regimen for a reconstructed elbow extension has not been
      found yet.

PMID- 12474597
TI  - Surgical rehabilitation for the weaker patients (groups 1 and 2 of the
      International Classification).
AB  - We have benefited from having had an initial large experience with the
      straightforward and predictable FPL tenodesis procedure and, after gaining
      experience, have continually modified it with the goal of customizing procedures
      to particular patients. We have moved toward reconstructing a dynamic pinch by
      tendon transfer when the brachioradialis is not needed to augment wrist
      extension. In any case, any patient and any hand are different. There is no such
      thing as a "standard procedure" when dealing with tetraplegic patients, and
      available procedures must be discussed in view of each patient's needs, desires,
      and specific circumstances.

PMID- 12474598
TI  - Midcervical tetraplegia with strong wrist extension: a two-stage synergistic
      reconstruction of the hand.
AB  - Reconstructive surgery can restore appreciable function of the upper limb in
      tetraplegic patients. The magnitude of the function regained depends on several
      factors: (1) the level of the spinal cord lesion, (2) careful patient selection,
      (3) thoughtful application of the basic principles of tendon transfer, (4)
      absence of severe spasticity, (5) the remaining sensory function of the hand, and
      (6) the surgical program and the surgeon's expertise with this type of patient.
      Reconstructive surgery offers patients not only greater physical independence but
      also psychological benefits. This article refers to cases with midcervical spinal
      cord lesion where wrist extension is complete and strong (MRC grading 5). It
      describes the author's strategy and technical choices in these patients, based on
      an ever evolving experience of more than 30 years.

PMID- 12474599
TI  - Strategy for improving hand opening in the tetraplegic upper limb.
AB  - In the tetraplegic patient, restoring an adequate grip requires primary
      restoration of proper hand opening. This opening (or "extensor") surgical stage
      is performed 3 or 4 months before the closing (or "flexor") stage. Surgical
      strategy is based on group 5 of the IC, which represents a turning point. Above
      this group (i.e., in IC groups 2-4), opening is essentially based on passive
      procedures (such as tenodesis and arthrodesis). Starting at group 5, restoration
      of active digital extension is [table: see text] feasible, as well as active
      stabilization of the thumb ray in lower groups. In those lower groups, all
      efforts should aim at re-establishing an intrinsic balance, keeping in mind the
      difference between supple and rigid claw deformities, which require different
      corrective procedures (Table 1).

PMID- 12474600
TI  - Surgical strategy: matching the patient with the procedure.
AB  - The general indications, timing, and choice of procedure can be determined by
      asking and answering the following questions appropriately: 1. Has the patient
      achieved neurologic, emotional, and social stability? 2. What is the patient's
      current level of motor and sensory resources and function? The number and
      strength of muscles remaining under good voluntary control are the most important
      variables. 3. Are the patient's expectations realistic? 4. Does the patient
      possess the necessary intelligence and motivation? Some procedures, such as
      arthrodesis of a specific joint, require little motivation to succeed; however, a
      complex set of muscle-tendon transfers requires a great deal of motor reeducation
      for the patient to achieve an optimal result. 5. Does the patient have the
      necessary time to invest in achieving a good result? The patient must be able to
      set aside the time necessary for postoperative immobilization in a cast or splint
      and for therapy and reeducation. 6. Are the necessary support services and
      personnel available and committed? 7. Have all preoperative obstacles to success
      been considered and has a plan developed to overcome any remaining obstacles? 8.
      Does the patient understand the potential complications and benefits? 9. Can the
      patient and professional team tolerate a complication, failure, or suboptimal
      result? Both the medical staff and the patient must be prepared for complications
      that may lead to a suboptimal outcome or frank failure. 10. Are the patient's
      current health and well-being ideal? 11. Is the surgical plan consistent with the
      patient's physical resources, goals, and expectations? 12. Does an alternate plan
      exist? 13. Does the surgeon understand the scope of the complications and how to
      salvage an acceptable result should a complication occur?

PMID- 12474601
TI  - Indications and future directions for upper limb neuroprostheses in tetraplegic
      patients: a review.
AB  - The development of the upper extremity neuroprosthesis has been a challenging and
      rewarding contribution to the management of the SCI patient. The authors'
      experience and that of their clinical trial teams has verified that this
      technology is a strong alternative to conventional reconstruction and
      conservative management. In the future, even more powerful tools will emerge from
      the laboratory as these devices and collaborative surgical procedures evolve.

PMID- 12474602
TI  - Reconstruction of the upper extremity in the child with tetraplegia.
AB  - According to Howard H. Steel, the orthopedic surgeon who first recognized the
      need for special care for children with spinal cord injury (SCI), and who
      persuaded Shriners Hospitals to establish specialized programs for these children
      over 20 years ago, no field of the health sciences is the statement "a child is
      not a small adult" more apropos than in the arena of trauma to the spinal cord.
      Children and adolescents with tetraplegia differ in many ways from adults with
      the disease. The dissimilarities that influence the outcome of surgical
      reconstruction of the upper extremity are the focus of this article.

PMID- 12474603
TI  - Evolution of surgery for tetraplegic hands in Japan.
AB  - In Japan, reconstructive surgery for the tetraplegic hand has developed mainly
      with Tsuge, Yabe, and their students for a little more than 30 years. They mostly
      used Zancolli's classification and, consequently, followed his treatment
      guidelines. Some unique procedures and techniques, however, have been devised
      based on their own experiences, including a static opponens tenodesis using FCR
      tendon, a modified lasso procedure to anchor a paralyzed flexor superficialis
      tendon through A2 pulley rather than A1 pulley, one-stage reconstruction of both
      extensor and flexor tendons, and the percutaneous functional electrical
      stimulation (FES) system.

PMID- 12474604
TI  - The future: surgery of the spinal cord?
AB  - Surgery of the spinal cord is still experimental, and outcomes must be confirmed
      by more cases. In this field, knowledge and research are still figuratively in
      the Stone Age. Nevertheless, the author is confident that in the future, with the
      improvement of surgical and resuscitation techniques and with the introduction of
      new biotechnologic drugs and molecules that favor axon regeneration and inhibitor
      blocking, CNS-peripheral nerve connections can be performed with some functional
      improvement, even in tetraplegia.

PMID- 12474605
TI  - Unfinished business: an opportunity for change.

PMID- 12474606
TI  - Appropriateness ratings for coronary revascularization.

PMID- 12474607
TI  - The epidemiology of atopic dermatitis.
AB  - Atopic dermatitis is the most common chronic inflammatory skin disease and is a
      major cause of morbidity and suffering. This review examines its differing
      prevalence worldwide, its aetiology, and genetics.

PMID- 12474608
TI  - The pathogenesis of atopic eczema.
AB  - Atopic eczema is associated with a genetic predisposition to dysregulation of the
      immune system. T lymphocytes differentiate towards the Th2 type with promotion of
      immunoglobulin E antibodies. Allergic responses to environmental allergens
      develop and microbes, including staphylococci and pityrosporum yeasts, may
      contribute to the inflammatory process.

PMID- 12474609
TI  - Phototherapy and systemic treatments.
AB  - A proportion of children and adults with moderate to severe atopic eczema are not
      adequately controlled with emollients and topical steroids, resulting in
      significant morbidity and disability. Studies indicate a significant placebo
      response, so randomized controlled trials of new treatments are vital. This
      article reviews the evidence for phototherapy and systemic treatments in atopic
      eczema.

PMID- 12474610
TI  - Functional imaging in stroke.
AB  - Recent advances in magnetic resonance techniques make it possible to image
      physiological parameters such as molecular diffusion, tissue perfusion and
      cortical activation. These techniques greatly contribute to the early detection
      and to the understanding of the pathophysiological evolution and recovery from
      ischaemic stroke.

PMID- 12474611
TI  - Escitalopram: efficacy and tolerability in the treatment of depression.
AB  - Escitalopram is a new antidepressant drug, available for clinical use in many
      countries. This review describes the properties of escitalopram, summarizes the
      results of randomized controlled trials, and suggests that escitalopram has
      advantages over citalopram in the treatment of depression.

PMID- 12474612
TI  - The implantable cardioverter defibrillator.
AB  - The implantable cardioverter defibrillator is the optimal treatment for both
      primary and secondary prevention in patients with previous aborted sudden death
      and with life-threatening cardiac arrhythmias. This article will review the
      indications and the evidence supporting implantable cardioverter defibrillator
      use.

PMID- 12474613
TI  - X-linked severe combined immunodeficiency.
AB  - Severe combined immunodeficiency is one of the most common causes of primary
      immunodeficiencies in humans. Molecular biological techniques have allowed new,
      therapeutically useful treatments for these diseases to be introduced into
      clinical practice. This review will focus on the molecular basis and new
      treatments for X-linked severe combined immunodeficiency.

PMID- 12474614
TI  - Common injuries of the shoulder.

PMID- 12474615
TI  - Outcomes of specialist registrar assessments.
AB  - The present study analyses the record of in-training assessment grades of 12,822
      specialist registrars in the UK over a 12-month period and the outcome of further
      assessments during the subsequent year.

PMID- 12474616
TI  - Somatoform disorder: how good are we at diagnosis?

PMID- 12474617
TI  - The first reported presentation of rickets with metabolic seizures.

PMID- 12474619
TI  - A case of Bannwarth syndrome.

PMID- 12474620
TI  - Setting priorities in waiting lists.

PMID- 12474621
TI  - Intestinal ischaemia.

PMID- 12474622
TI  - What are you going to do about the base deficit?

PMID- 12474623
TI  - Fluoridation and social equity.
AB  - The overall reduction in caries prevalence and severity in the United States over
      recent decades is largely due to widespread exposure to fluoride, most notably
      from the fluoridation of drinking waters. Despite this overall reduction,
      however, caries distribution today remains skewed, with the poor and deprived
      carrying a disproportionate share of the disease burden. Dental caries, like many
      other diseases, is directly related to low socioeconomic status (SES). In some
      communities, however, caries experience has now diminished to the point where the
      need for continuing water fluoridation is being questioned. This paper argues
      that water fluoridation is still needed because it is the most effective and
      practical method of reducing the SES-based disparities in the burden of dental
      caries. There is no practical alternative to water fluoridation for reducing
      these disparities in the United States. For example, a school dental service,
      like those in many other high-income countries, would require the allocation of
      substantial public resources, and as such is not likely to occur soon. But
      studies in the United States, Britain, Australia, and New Zealand have
      demonstrated that fluoridation not only reduces the overall prevalence and
      severity of caries, but also reduces the disparities between SES groups. Water
      fluoridation has been named as one of the 10 major public health achievements of
      the 20th century by the Centers for Disease Control and Prevention, and promoting
      it is a Healthy People objective for the year 2010. Within the social context of
      the United States, water fluoridation is probably the most significant step we
      can take toward reducing the disparities in dental caries. It therefore should
      remain as a public health priority.

PMID- 12474624
TI  - A systematic review of the performance of methods for identifying carious
      lesions.
AB  - This systematic review evaluates evidence describing histologically validated
      performance of methods for identifying carious lesions. A search identified 1,407
      articles, of which 39 were included that described 126 assessment of visual,
      visual/tactile, radiographic (film and digital), fiber optic transillumination,
      electrical conductance, and laser fluorescence methods. A subsequent update added
      four studies contributing 10 assessments. The strength of the evidence was judged
      to be poor for all applications, signifying that the available information is
      insufficient to support generalizable estimates of the sensitivity and
      specificity of any given application of a diagnostic method. The literature is
      problematic with respect to complete reporting of methods, variations in
      histological validation methods, the small number of in vivo studies, selection
      of teeth, small numbers of examiners, and other factors threatening both internal
      and external validity. Future research must address these problems as well as
      expand the range of assessments to include primary teeth and root surfaces.

PMID- 12474626
TI  - AAPHD 2002 Distinguished Service Award: Myron Allukian, Jr., DDS, MPH.

PMID- 12474625
TI  - Predictors of chewing difficulty onset among dentate adults: 24-month incidence.
AB  - OBJECTIVES: Chewing ability is an important measure of health-related quality of
      life, yet few studies have examined predictors of chewing difficulty in community
      based samples. This study describes longitudinal patterns of chewing difficulty
      and identifies predictors of chewing difficulty onset. METHODS: The Florida
      Dental Care Study (FDCS) was a longitudinal study of oral health and related
      behaviors. Interviews and a clinical exam were conducted with a sample that
      included persons who had at least one tooth and were aged 45 years or older (n =
      873). The five-item chewing index of Leake (1990), with minor revision, was the
      outcome of interest. RESULTS: Approximately 21 percent of baseline participants
      reported chewing difficulty and about 34 percent reported difficulty during the
      study. Having infected or sore gums, loose tooth, loose crown or bridge,
      toothache pain, lower numbers of opposing pairs of teeth, dry mouth, and being
      female were significant predictors of incident chewing difficulty. CONCLUSIONS:
      Self-reported oral disease and tissue damage and toothache pain were strong
      predictors of decline in chewing ability. Additionally, women were identified as
      a high-risk group for incident chewing difficulty. Future research should
      elaborate further the pathways through which these factors affect oral function.

PMID- 12474627
TI  - AAPHD 2002 Public Service Award: Senator Jeff Bingaman.

PMID- 12474628
TI  - AAPHD 2002 Special Merit Award: Robert J. Weyant, DMD, DrPH.

PMID- 12474629
TI  - AAPHD 2002 Special Merit Award for Outstanding Achievement in Community Dentistry
      -International: Patricia Main, DDS, DDPH, MSc.

PMID- 12474630
TI  - All systems go.

PMID- 12474631
TI  - Leave it out!

PMID- 12474632
TI  - Workforce development. Strong-arm tactics.

PMID- 12474633
TI  - Consultant appraisals. Appraise where due.
AB  - A study of consultant appraisal in Welsh trusts revealed concerns about lack of
      protected time and uncertainty about how issues raised should be handled. The
      research showed it is important to ensure that issues raised are addressed by the
      organisation. Resources must be made available to trusts to offer protected time
      for the process, and adequate training.

PMID- 12474634
TI  - Clinical implications of physicochemistry of stone formation.
AB  - Measuring crystallization processes for assessing the risk of stone formation or
      the effect of treatment on that risk. In summary, crystallization processes are
      involved in the risk for stone formation at several levels. Several tests are
      available for assessing if crystalization is disturbed. It is important to first
      establish for which part of the urinary tract the information is sought and then
      adapt the experimental conditions to that site [53]. This information helps in
      visualizing what is happening inside the urinary tract of a SF and what the
      treatment measures prescribed may do to change that situation.

PMID- 12474635
TI  - Pathogenesis of hypercalciuric nephrolithiasis.
AB  - The major contribution of hypercalciuria in raising urinary state of saturation
      with respect to calcium salts and subsequent risk of nephrolithiasis is
      appreciated. Derangements in the physiological mechanisms that regulate calcium
      homeostasis and contribute to hypercalciuria have also been identified. New
      avenues of research are beginning to explore the specific defects that may
      contribute to hypercalciuria. From such studies, an understanding of the role of
      certain dietary excesses as contributors to the development of hypercalciuria
      and, in some cases, attendant bone loss, is beginning. The contribution of
      genetics to hypercalciuria has provided a powerful means of identifying genes
      that contribute to the hypercalciuric phenotype in a number of hypercalciuric
      conditions. Such studies have disclosed that hypercalciuria is probably polygenic
      in nature and will require a concerted effort to better understand the defects
      while attempting to develop gene-specific countermeasures.

PMID- 12474636
TI  - Pathophysiology of hypocitraturic nephrolithiasis.
AB  - Urinary citrate inhibits calcium stone formation by complexing calcium in a
      soluble form and by effects on urinary crystals to prevent growth to stones. Low
      urinary citrate has been recognized for several decades as a contributing factor
      in some stone forming patients, but recent studies have elucidated the mechanisms
      and derangements of the renal handling of citrate in various conditions. In
      addition, oral citrate as an alkalinizing agent can not only increase urinary
      citrate, but also favorably impact other stone-promoting conditions. This review
      will focus on the understanding of these concepts.

PMID- 12474637
TI  - Pathophysiology of uric acid nephrolithiasis.
AB  - Humans although a predominantly ureotylic organism, has preserved the ability to
      excrete nitrogen as uric acid and ammonia. An imbalance between these two
      secondary modes of nitrogen excretion has resulted in uric acid precipitation in
      human urine. Uric acid nephrolithiasis can arise from diverse etiologies all with
      distinct underlying defects converging to one or more of three defects of
      hyperuricosuria, acidic urine pH, and low urinary volume, originating from
      secondary, genetic or heretofore undefined (idiopathic) causes. A subset of
      idiopathic uric acid nephrolithiasis (gouty diathesis) may be the "tip of the
      icebergp" of a broader systemic illness characterized by insulin resistance. A
      novel renal manifestation of insulin resistance is a mild defect in ammonium
      excretion, which is not severe enough to disturb acid-base homeostasis, but is
      sufficient to set up the chemical milieu for uric acid nephrolithiasis.

PMID- 12474638
TI  - Hyperuricosuric calcium nephrolithiasis.
AB  - Since the findings of Yu and Gutman [1], the hyperuricosuric calcium stone former
      is a unique clinical entity. While an impressive number of clinical and
      epidemiologic studies implicate hyperuricosuria in calcium stone formation, the
      exact physicochemical mechanism by which uric acid affects calcium oxalate
      crystallization has not been proven. Allopurinol decreases stone recurrences and
      is the drug of choice for patients with isolated HCN.

PMID- 12474639
TI  - Hyperoxaluric calcium nephrolithiasis.
AB  - Hyperoxaluria leads to increased calcium oxalate supersaturation and calcium
      oxalate stone formation. Excess oxalate can arise from endogenous overproduction
      as in primary hyperoxaluria or from dietary sources. In the last 15 years great
      strides have been made in the diagnosis and treatment of primary hyperoxaluria.
      However options still seem limited in treating the mild hyperoxaluria found in
      many stone formers. Inadequate knowledge of food oxalate content, the effect of
      dietary oxalate precursors on oxalate excretion, and the factors affecting
      handling of oxalate by the intestine prevent development of rational therapies
      for treatment of hyperoxaluria. Recent studies of oxalate degrading bacteria and
      renewed interest in the role of diet calcium in oxalate absorption may lead to
      better therapeutic strategies for hyperoxaluric calcium nephrolithiasis.

PMID- 12474640
TI  - Cystinuria and other noncalcareous calculi.
AB  - Urinary stone disease is the only clinical presentation in patients with
      cystinuria. Two genes have been associated with type I (SLC3A1) and non-type I
      (SLC7A9) cystinuria and multiple mutations of these genes have been identified.
      The type I form is completely recessive while the non-type I form is incompletely
      recessive. Clinically, heterozygotes with type I mutations are silent while
      heterozygotes with non-type I (types II and III) present with a wide range of
      urinary cystine levels and some even have symptomatic urolithiasis. Although the
      exact molecular basis for these differences needs additional investigations, the
      future of medical management of cystinuria is based on molecular and gene
      therapy. Minimally invasive surgery using percutaneous and ureteroscopic
      techniques is the cornerstone of surgical management. Both cystine and struvite
      calculi can form staghorn configuration with propensity for rapid growth and
      frequent recurrences after surgical treatment. While urinary alkalinization for
      cystine calculi is an integral part of medical management, the effect of oral
      alkalinizing agents is limited because of the high pKa (8.3) of cystine.
      Chelating agents, therefore, are frequently used to decrease cystine solubility
      and stone recurrences. Similarly, urinary acidification for struvite calculi may
      dissolve existing stones and prevent recurrences. However, no effective oral
      agent is available today. A future challenge will be to introduce reliable oral
      agents for urinary acidification.

PMID- 12474641
TI  - Stones from bowel disease.
AB  - Kidney stones are increased in patients with bowel disease, particularly those
      who have had resection of part of their gastrointestinal tract. These stones are
      usually CaOx, but there is a marked increase in the tendency to form uric acid
      stones, as well, particularly in patients with colon resection. These patients
      all share a tendency to chronic volume contraction due to loss of water and salt
      in diarrheal stool, which leads to decreased urine volumes. They also have
      decreased absorption, and therefore diminished urinary excretion, of citrate and
      magnesium, which normally act as inhibitors of CaOx crystallization. Patients
      with colon resection and ileostomy form uric acid stones, as loss of bicarbonate
      in the ileostomy effluent leads to formation of an acid urine. This, coupled with
      low urine volume, decreases the solubility of uric acid, causing crystallization
      and stone formation. Prevention of stones requires treatment with alkalinizing
      agents to raise urine pH to about 6.5, and attempts to increase urine volume,
      which increases the solubility of uric acid and prevents crystallization.
      Patients with small bowel resection may develop steatorrhea; if the colon is
      present, they are at risk of hyperoxaluria due to increased permeability of the
      colon to oxalate in the presence of fatty acids, and increased concentrations of
      free oxalate in the bowel lumen due to fatty acid binding of luminal calcium. EH
      leads to supersaturation of urine with respect to CaOx, in conjunction with low
      volume, hypocitraturia and hypomagnesuria. Therapy involves a low-fat, low
      oxalate diet, attempts to increase urine volume, and agents such as calcium given
      to bind oxalate in the gut lumen. Correction of hypocitraturia and hypomagnesuria
      are also helpful.

PMID- 12474642
TI  - Childhood stones.
AB  - Urinary stones in children are usually genetic and most commonly due to
      hypercalciuria. Symptoms of urolithiasis in children differ among age groups.
      Isolated hematuria in children may be caused by hypercalciuria and precede
      calculus formation. Careful evaluation successfully identifies the cause of
      urinary stones in most children, although diagnostic criteria may vary in
      different age groups. Therapies should be targeted to the underlying diagnosis.

PMID- 12474643
TI  - Nutritional aspects of stone disease.
AB  - Kidney stones can form during a state of urinary supersaturation. Because urine
      often is supersaturated with respect to various salts, crystal formation is very
      common in nonstone formers and stone formers alike, and it may even be absent in
      kidney stone formers. Thus, uncomplicated crystalluria does not distinguish
      between stone formers and healthy people. Landmark clinical studies, however,
      have shown that under identical conditions of dietary and fluid intake, healthy
      controls almost exclusively excrete single calcium oxalate crystals 3 to 4
      microns in diameter, whereas recurrent calcium stone formers pass larger
      crystals, 10 to 12 microns in diameter, often fused into polycrystalline
      aggregates 20 to 300 microns in diameter. Thus, those who form stones appear to
      be more "sensitive" to a given diet than nonstone formers. It is in these
      subjects that "bad dietary habits" induce nephrolithiasis, making nutritional
      aspects important. This article reviews the current evidence-based knowledge of
      the impact of nutrition on the recurrence of a kidney stone.

PMID- 12474644
TI  - Medical evaluation of nephrolithiasis.
AB  - A careful and individualized evaluation of risk factors is a fundamental part of
      the management of patients with urinary tract stone disease. Identification and
      correction of important abnormalities provide the basis for designing an
      efficient and rational treatment program, aiming at an arrest or at least
      reduction of recurrent stone formation. It is beyond doubt that appropriate
      therapeutic steps in this regard are of great benefit for the patient. It needs
      to be emphasized, however, that no success will be obtained unless the patient is
      willing and able to follow the ensuing dietary recommendations and medical
      advice.

PMID- 12474645
TI  - Medical treatment of nephrolithiasis.
AB  - The medical treatment of nephrolithiasis is aimed in particular at the prevention
      of relapses, even though in some cases, such as cystine or uric acid lithiasis,
      the calculi also can be dissolved on site. When the diagnosis and metabolic
      profile have been performed correctly, medical treatment is effective in a large
      number of patients. The greatest difficulty is the patient's compliance with the
      most suitable prevention measures and the frequency of follow-up controls. This
      compliance can be influenced significantly by the amount of time that the doctor
      spends to explain the origin of the disease. This article reviews the main
      methods available for the medical treatment of various nephrolithiasis types,
      namely water intake, diet, and drugs, supplying the relevant information about
      the mechanism of action, metabolic consequences, indications, evidence provided
      from studies, dosage, efficacy, and side-effects. Finally, brief simplified
      guidelines are given for the medical treatment of stone disease caused by calcium
      oxalate or calcium phosphate, uric acid, cystine, and struvite.

PMID- 12474646
TI  - Surgical management of urolithiasis.
AB  - The surgical management of urinary calculus disease has changed dramatically in
      the past two decades. Minimally invasive options have made open stone surgery
      nearly obsolete. The development of shock wave lithotripsy, percutaneous
      nephrostolithotomy techniques and intracorporeal lithotripsy devices has
      conferred unprecedented management tools for upper tract stones. Moreover,
      transfusion rates, hospital costs, and convalescence periods have been markedly
      reduced when compared to open surgery. Likewise, the advent of fiberoptic
      technology has resulted in miniaturization of ureteroscopes making access to the
      entire collecting system possible from either a retrograde or antegrade approach.
      With experience, successful stone retrieval has occurred in upwards of 90% of
      cases, again with minimal complications. The subspecialty of Endourology has
      emerged over the past 20 years and significantly changed the management of
      urinary tract calculi within this short period of time. Further advancements in
      shock wave and laser technology, training modules and the development of more
      durable endoscopes may prove beneficial in providing even better stone treatments
      with a reduction in morbidity.

PMID- 12474647
TI  - Ethical obligations for the psychiatrist: confidentiality, privilege, and privacy
      in psychiatric treatment.

PMID- 12474648
TI  - The case of the confidential confession: psychiatry.

PMID- 12474649
TI  - Personhood, discrimination, and the new genetics.

PMID- 12474650
TI  - Evidence-based practice in pediatric rehabilitation.
AB  - EBP is not a new concept. To practice using the newest and best research
      evidence, clinicians must have the knowledge and skills to find and appraise the
      quality of the evidence. This process starts with the formulation of a focused
      question, followed by an effective search for the best evidence, critical
      appraisal of the evidence retrieved, and integration of that best evidence into
      practice. There are an increasing number of resources that can provide clinicians
      with the best evidence and that can assist clinicians with enhancement of their
      EBP skills. Unique challenges exist in practicing in an evidence-based manner in
      the field of pediatric rehabilitation, but through the collaboration of
      clinicians and researchers, these challenges can be overcome.

PMID- 12474651
TI  - [The problems of migraine headache treatment].
AB  - The acute treatment and prophylaxis of migraine headache are discussed in this
      article. The medications for acute treatment, their doses, indications,
      contraindications and adverse effects are compared. The special attention for
      migraine headache prophylaxis is paid. The migraine diagnostic criteria and
      triggers of migraine headache are noted.

PMID- 12474652
TI  - [Multiple trauma: evaluation of patient's condition and local injuries by trauma
      classification systems].
AB  - Evaluation of polytrauma patient's status by using scoring system is very
      important for selection of patient's placement and management, prophylaxis and
      diagnosis of early complications. In the article trauma classification systems
      are presented and discussed. Clinical evidences of Kaunas Medical University
      Hospital are presented as well. There are suggestive recommendations on
      evaluation of polytrauma patient's status and proper separation of severely
      injured.

PMID- 12474653
TI  - [Use of magnesium sulfate in anesthesiology].
AB  - The objective of this study was to evaluate usage possibilities of magnesium
      sulfate in anesthesiology. METHODOLOGY: In Clinic of Cardiac Surgery, Kaunas
      University of Medicine magnesium sulfate was started for use as an adjuvant to
      anesthetics. For anesthesia it was used in 20 cases. This review article presents
      the methodology based on which the magnesium sulfate anesthesia was given.
      Methodology was created using the data of international clinical trials. After
      anesthesia induction with thiopental (5 mg/kg) and fentanyl (2 mg/kg), patients
      were given shock-dose injection (30-50 mg/kg) of MgSO4; also continual infusion
      through syringe pump at 500 mg/h was given for total duration of 20 hours. The
      state of patients during anesthesia was evaluated based on hemodynamic readings:
      arterial blood pressure, heart rate and functional oxygen saturation in the
      arterial blood (SpO2). RESULTS: Data on importance of magnesium sulfate for
      anesthesia is currently in process, however it was determined that when magnesium
      sulfate is used for anesthesia, the smaller doses of fentanyl and myorelaxants
      are needed. The last dose of fentanyl before the end of anesthesia is injected at
      the similar interval as in cases when magnesium is not used. CONCLUSIONS: Even
      though the precise data is not available yet, we can conclude that when magnesium
      sulfate is used as an adjuvant for anesthesia, the reduced doses of painkiller
      medicines are needed and their action is strengthened. In addition, magnesium
      does not prolong the activity of painkiller substances.

PMID- 12474654
TI  - [Typical and atypical symptoms of laryngopharyngeal reflux disease].
AB  - The aim of the study was to evaluate and compare intensity and incidence of both,
      typical (heartburn, acid regurgitation) and atypical (hoarseness, throat
      clearing, globus pharyngeus) symptoms of laryngopharyngeal reflux disease among
      72 patients and 123 healthy persons. Diagnosis of laryngopharyngeal reflux
      disease in 58 cases (80.6%) was confirmed by endoscopic and histological findings
      of esophagitis and in 14 cases (19.4%) by Omeprasol test. The intensity of the
      symptom was calculated by multiplication of the intensity and frequency of the
      symptom. According to the data obtained laryngopharyngeal reflux disease
      manifested more frequently with atypical symptoms. In the patients' group mean
      intensity of hoarseness was 5.29 +/- 0.74 points, mean index of hoarseness 7.06
      +/- 1.35 points. Typical symptoms were found only in 14-22% of patients. The mean
      intensity of heartburn was 2.6 +/- 0.66 points, mean index of heartburn was 4.73
      +/- 1.02 points. The incidence of atypical symptoms was three times higher than
      the incidence of typical symptoms (p < 0.05). According to the multinomial
      logistic regression analysis the combination of three atypical symptoms
      (hoarseness, throat clearing and globus pharyngeus) separated groups of the
      patients and healthy persons. The combination of these symptoms increases the
      odds ratio for laryngopharyngeal reflux disease 59.7 times. Idiopathic hoarseness
      as a single symptom increases the odds ratio for laryngopharyngeal reflux disease
      85 times.

PMID- 12474655
TI  - [Adrenogenital syndrome: feminizing genital reconstruction].
AB  - Adrenogenital syndrome, or so called congenital adrenal hyperplasia, is caused by
      a congenital insufficiency of the enzyme 21-hydroxylase, which is responsible for
      converting cortisol into cholesterol. Because of virilizing effect of androgens
      overproduction girls develop clitoral hypertrophy and persistent urogenital sinus
      (common channel for urethra and vagina). Surgical treatment is recommended in
      order to repair those developmental faults. The aim of this study was to employ
      the contemporary surgical techniques and to evaluate the postoperative results.
      Forty-seven patients affected by adrenogenital syndrome were investigated and
      treated at two institutions: Departments of Pediatric Surgery of Copenhagen
      University Hospital and Kaunas Medical University Hospital. Forty-three patients
      have been operated and underwent genitoplasty. Surgical method was chosen
      individually depending on the height of the urogenital sinus. In a case of low
      sinus a simple cut-back procedure was performed. In a case of high sinus the more
      complex procedure such as total urogenital mobilization or vaginal pull through
      would be involved. All patients underwent vaginal dilatations for 6-12 months
      postoperatively. Twenty-eight patients underwent clitoroplasty while the glans
      and the neurovascular bundle were preserved and clitoral skin used for plasty of
      the labia minora. Postoperatively the patients were observed for 0.5-5 years, the
      close results showed to be good. There were 4 cases of vaginal stenosis and 2
      cases of urethrovaginal fistula (all successfully repaired later). Early one
      staged genitoplasty and postoperative vaginal dilatations for the period of 6-12
      months is recommended.

PMID- 12474656
TI  - [Results of levothyroxine therapy in thyroid nodules].
AB  - The aim of this study--to investigate the effect of Levothyroxine on thyroid
      nodules avoiding the growth of nodules. We have compared results with studies,
      had evaluated this treatment method and discuss about guidelines of
      endocrinologist's-practitioner's consensus on this subject. MATERIALS AND
      METHODS: Sixty-two patients (all female) were evaluated. The mean age of the
      group was 47.89 +/- 13.73 year. Plasma thyroid-stimulating hormone (TSH)
      concentration was measured in all patients before therapy initiation and after 6
      months, some of them were observed during 24 months (20 (32.3%)) and were
      examined every 6 months. Nodules evaluation was made by ultrasound. Therapy with
      Levothyroxine was prescribed for 37 (59.68%) patients. The data was compared with
      25 (40.32%) cases of control group not treated with Levothyroxine. RESULTS: There
      was reached mild TSH suppression in 11 (29.7%) cases, moderate--in 4 (10.8%),
      strong in 2 (5.4%) prescribing 54.39 +/- 26.71 micrograms of Levothyroxine.
      Thirteen women's TSH significantly decreased, while was > 1 mIU/L. Seven (18.9%)
      patients failed suppression. CONCLUSIONS: The treatment with little-moderate
      doses decreased TSH significantly and TSH suppression mild to strong was achieved
      in a half of treated investigative; furthermore, the size of thyroid nodules have
      changed statistically significant after 6 months of therapy and positive effect
      was reached for 89.2% of treated patients.

PMID- 12474657
TI  - [Treatment of joint surface pathology by Pridie drilling].
AB  - This is an article of two homogenic groups treatment comparison, with 25 patients
      in each. Between 1998 and 2001 twenty-five patients underwent osteochondral or
      chondral fragment excision with Pridie tunelisations and 25 patients (controls)-
      osteochondral/chondral fragment excision alone (O-CFE). Average follow-up was
      12.4 (range 10-14 months) and 23.6 months (range 22-25 months). All patients were
      younger than 30 years of age. Patients were evaluated through ICRS and modified
      HSS scales, arthroscopically, histologically and with x-rays. A blinded research
      assistant performed all follow-up evaluations. Sixteen of 25 (64%) tunelised
      (Pridie) results were good and 9 (36%)--fair at the time of last follow-up.
      Twelve of 25 (48%) in O-CFE group results were good and 12 (48%)--fair 23.6
      months post operations. Final modified HSS evaluation showed statistically
      significantly better results in the Pridie group at the 12.4 and 23.6 months (p =
      0.005). Last follow-up showed deterioration in both groups (p < 0.05). At an
      average 23.6 months follow-up x-rays showed initial osteoarthritis signs in the
      knees. Consequently, we recommend Pridie tunelisation procedure until final
      indications of cartilage grafting techniques will be established.

PMID- 12474658
TI  - [Unusual revascularization in acute mesenteric ischemia (a case report and review
      of the literature)].
AB  - Acute-on-chronic mesenteric ischemia is rare, symptomatic manifestation of
      arteriosclerosis, and there are important gaps in our knowledge and recognition
      of this potentially lethal condition. Careful exploration of anamnestic history
      and angiography remain cornerstones of early diagnosis. Prognosis crucially
      depends on rapid diagnosis and surgical management, to prevent, or at least to
      minimize bowel infarction. Delay in surgical intervention is associated with
      increasing mortality that is still high and varies from 60 to 100%. The prognosis
      dramatically improves if revascularization can be achieved prior to intestinal
      infarction. Patients surviving extended intestinal resection may develop short
      gut syndrome. Case rapport of acute-on-chronic mesenteric ischemia with
      extraordinary approach for superior mesenteric artery revascularisation is
      described. Literature review is presented.

PMID- 12474659
TI  - [Effects of aluminum ions on the mouse protein synthesis in vivo and in vitro].
AB  - Impact of aluminium ions on the translation process in mice liver, kidney,
      skeletal muscle and heart was investigated in vivo as well as on the protein
      synthesis in liver cell-free translation system in vitro. We find that at early
      stages of intoxication the effect of aluminium ions on protein synthesis in
      muscle tissues differs qualitatively from that one in liver or kidneys. Most
      noticeable aluminium-induced changes of protein synthesis in organs in vivo occur
      within the first 15-20 h after intoxication. We show that aluminium ions
      activates protein synthesis in liver and kidneys (at 8-16 h) while in skeletal
      muscle and heart does not. These results indirectly are supported by the data of
      experiments in vitro, which demonstrate that at low concentration aluminium ions
      activates protein synthesis in the cell-free translation system prepared from
      liver.

PMID- 12474660
TI  - [Synthesis of hydroxamic acids and study of their complexes with iron (II) and
      (III) ions].
AB  - Hydroxamic acids are widespread in the tissues of plants, in metabolites of
      bacteria and fungi, including complex compounds with metal ions. These acids have
      wide spectrum of biological activity and therefore are perspective reagents for
      analysis of chemical elements. Fourteen aliphatic and aromatic derivatives of
      hydroxamic acids have been synthesized from esters of carboxylic acids.
      Photometric reactions of hydroxamic acids with iron (II) and (III) were
      investigated. Complex formation of iron (II) and (III) depending on pH was
      studied with series of synthesized hydroxamic acids: octanohydroxamic, maleic
      hydroxamic, 2-hydroxybenzoxydroxamic, benzoxydroxamic, phthalmonoxydroxamic and 3
      metoxybenzohydroxamic acids. Composition of iron (III) complexes with 2
      hydroxybenzohydroxamic, octanoxydroxamic, 3-metoxybenzohydroxamic acids and iron
      (II) with 2-hydroxybenzohydroxamic acid was studied by methods of mole ratio and
      isomolar solutions. Sensitivity of reagents was evaluated by values of absorption
      coefficients (epsilon). Stability of complexes in water and organic solvents was
      investigated. Interaction between iron (III) and hydroxamic acids
      (octanoxydroxamic, 2-hydroxybenzohydroxamic, 3-metoxybenzohydroxamic) have been
      applied for quantitative photometric analysis of iron (III) salts. Color reaction
      of iron (II) with 2-hydroxybenzohydroxamic acid was applied for quantitative
      photometric determination of iron (II) salts. 3-Metoxybenzohydroxamic acid was
      proposed as a new indicator for complexonometric analysis of iron (III).
      Chelatometric titration of iron (III) using this indicator is not influenced by
      copper, cobalt, zinc, manganese, so this methods is recommended for iron quantity
      detection in antianemic drugs, which are composed of latter microelements.
      Synthesis procedure of 2-benzoylamino-3-arylacrylhydroxamic acids from saturated
      azlactones was created. Color and precipitate reactions of iron (II) and (III),
      copper (II), nickel (II) and cobalt (II) ions with four newly synthesized acids
      (with and without substitutes in aromatic ring) were studied. Sensitivities of
      reactions between 2-benzoylamino-3-arylacrylhydroxamic acids and iron (II) and
      (III) were evaluated and compared with 2-hydroxybenzohydroxamic acid.

PMID- 12474661
TI  - [The psychosocial factors associated with preschoolers' wellbeing in a
      kindergarten].
AB  - The aim of our investigation was to find out how do pre-school aged children felt
      themselves in kindergarten and what factors their well-being depended on. The
      survey was carried out in 1999 and 2000. A sample of 631 children aged 6-7 years
      was interviewed in 12 randomly selected kindergartens of Kaunas. The children
      were divided into two groups. The children who said that they liked to be in
      kindergarten more than at home belonged to the first group (n = 361 or 57.3%).
      They answered that they liked their group mates, like to speak with their
      teacher, to learn, to sing, to play quiet games, they heard good words about
      themselves in kindergarten more often. The children who enjoyed to be at home
      more than in kindergarten belonged to the second group (n = 269 or 42.7%). They
      said that they did not like to obey the tasks of their teacher, to sleep after
      dinner more often in comparison with the first group. Factorial analysis of the
      data indicated that children with positive factor of well-being through they were
      better than their group friends, thought they could do things better than their
      group mates, they had less complaints of various pains. A statistically
      significant correlation between the common factors of well-being and self-esteem
      was estimated.

PMID- 12474662
TI  - [The development of mixed emotional and behavioral disorders in children raised
      in foster care institutions].
AB  - The aim of the work was to evaluate the changes brought by time in the
      psychoemotional state of neglected and abandoned children (exhibiting disturbed
      social relations), which were displayed in childrens' behavior. The longitudinal
      research has been carried out by the epidemiological case-control scheme. Two
      groups of children were examined. During the first test the study group was
      formed by 70 (44 boys and 26 girls) neglected and abandoned children drew up from
      foster care institutions. The control group was adequate in age and sex to the
      study group. It included 70 (44 boys and 26 girls) children from traditional
      families. The second test was carried out two was years later. It was applied to
      the same groups of children, only this time 50 (32 boys and 18 girls) children
      from the study and from the control group were tested. Mixed psychoemotional and
      behavioral disorders were evaluated by experts (teachers from foster care
      institutions, nurseries and schools) who applied the scale of indicators. The
      results gave evidence of psychoemotional problems in the neglected and abandoned
      children growing up in foster care institutions: they were nervous, exhibited
      aggression, difficulties in their education emerge. The behavior and emotions
      shape themselves in frustration and depression. These disorders tend to grow and
      become more serious in the course of time, social behavior deviations and social
      health development disorders emerged. The psychoemotional health development of
      neglected and abandoned children evoked difficulties in their psychological
      adaptation.

PMID- 12474663
TI  - [Acute adrenocortical insufficiency].
AB  - Severe acute adrenocortical insufficiency or adrenal crisis are often elusive
      diagnoses that may result in severe morbidity and mortality when undiagnosed or
      ineffectively treated. Although more than 50 steroids are produced within the
      adrenal cortex, cortisol and aldosterone are far the most abundant and
      physiologically active. In primary adrenocortical insufficiency, glucocorticoid
      and mineral-corticoid properties are lost; however, in secondary adrenocortical
      insufficiency (i.e., secondary to disease or suppression of the hypothalamic
      pituitary axis), mineralocorticoid function is preserved. Every emergency
      physician should be familiar with adrenocortical insufficiency--a potentially
      life-threatening entity. The initial diagnosis and decision to treat are
      presumptive and are based on history, physical examination, and, occasionally,
      laboratory findings. Delay in treatment while attempting to confirm this
      diagnosis can result in poor patient outcomes. This article review data about
      physiology, pathophysiology of the adrenal cortex, physiologic effects of
      glucocorticoids, aldosterone, causes of primary and secondary adrenal
      insufficiency, frequency, clinical picture, laboratory and imaging studies of
      adrenal crisis, laboratory evaluation of adrenal function and emergency therapy,
      replacement therapy, mortality/morbidity of this pathology.

PMID- 12474664
TI  - [Transmyocardial laser revascularization: a past or future treatment method?
      (review of the literature)].
AB  - Despite the success of current medical and surgical management of ischemic heart
      disease, a growing number of patients have diffuse obstructive coronary artery
      disease that is not amenable to coronary artery bypass grafting or catheter based
      interventions. This problem has stimulated interest in developing alternative
      therapeutic approaches. The construction of subendocardial channels to perfuse
      ischemic areas of the myocardium has been investigated since the 1950s. Before
      coronary artery bypass grafting, PTCA, and transmyocardial laser
      revascularization, mechanical methods to create transmural channels and thereby
      to revascularize the myocardium were reported. Early attempts at indirect
      myocardial revascularization had limited success. Transmyocardial laser
      revascularization is a new procedure for the treatment of angina pectoris. This
      article reviews the historical background of transmyocardial laser
      revascularization and possible mechanisms by which it may work, and discusses
      existing evidences for and against the procedure and how it may be applied in the
      future. The most important experimental studies and randomized prospective
      clinical trials from 1996 to 2001 were examined. The literature review concluded
      that transmyocardial laser revascularization does not have a life-saving effect,
      nor does it improve myocardial function. However, the method has a considerable
      short-term symptomatic effects, the mechanism of which is not understood.
      Neoangiogenesis, myocardial inflammation, denervation and placebo may play a
      role. Therefore, transmyocardial laser revascularization is potentially indicated
      for patients with severe angina that is refractory to medical therapy and who
      have contraindications for more traditional therapies (coronary artery bypass
      grafting, PTCA and heart transplantation). More expert groups recommend further
      research to clarify the mechanisms of transmyocardial laser revascularization
      treatment.

PMID- 12474665
TI  - [Anesthesia used in minimally invasive myocardial revascularization surgery].
AB  - As myocardial revascularisation operations without cardiopulmonary bypass are
      getting more popular, more facts are found about their surgical techniques.
      However, the questions considering their anesthesia, the protection of myocardium
      and other are not widely analyzed. The specific features of anesthesia in
      cardiosurgery, such as methods of ventilation, combination of induction and
      general anesthesia with epidural anesthesia, usage of cardiac protection and
      ischemic preconditioning, monitoring, heparin management, usage of drugs,
      postoperative pain management are given in this article. As anesthesiological and
      surgical techniques are getting better and the professional skills of surgeons
      and anesthesiologists are improving, given data should improve the perspectives
      of minimally invasive cardio surgery operations and anesthesia in Lithuania.

PMID- 12474666
TI  - [Evaluation of diagnostic methods and characteristics of patients operated on for
      cervical cancer in Lithuania, 1998-2000].
AB  - The total number of new cases of cervical cancer for the three-year period was
      1392 patients. The number of cases was fairly evenly distributed among the years
      of the study period 1998-2000. The total number of new cases of Stages I and II
      of cervical cancer was 713 (51.2%) cases, and that of Stages III and IV was 623
      (44.8%) cases. The number of the new cases with an unknown stage of the disease
      was found to be 56 (4.0%) cases. The number of patients with Stage IIIB disease
      was the highest (69 cases) among all the stages of cervical cancer for the study
      period 1998-2000. The second most common stage was Stage IB disease with 52
      patients belonging to this category. One-half (50.0%) of all operated patients
      because of cervical cancer during the study period 1998-2000 were women of 44
      years of age and younger. Therefore, major considerations are to be given for
      women of reproductive age where effective screening and early detection of
      cervical pathology could help to avoid a lot of invasive cases of the disease and
      thus decrease mortality due to it. Generally, the diagnostic work-up and
      examinations of cervical cancer patients were insufficient, especially in cases
      of advanced stage disease. Stages III and IV were diagnosed in 44.8% of all
      cases. Overall, cystoscopy was performed in 39.4% (42 cases) of the total number
      of cases in Stages IIB through IVA of cervical cancer. Overall,
      rectosigmoidoscopy was performed in 6.4% (7 cases) of the total number of cases
      in Stages IIB through IVA of the disease. Finally, the proportion of CT that was
      performed in cases of Stages IIB through IVB of cervical cancer was 8.4% only.
      Clinical staging correlates well with pathologic staging in Stage I, particularly
      Stage IA (88.91%). The data also indicates that parametrial involvement would
      seem to be the most difficult problem, as 28.59% of Stage IIB and 32.3% of Stage
      IIIB were down-staged on the basis of pathological findings. This would suggest
      that in some cases the basic clinical staging rules are not being followed, or
      clearly understood. Kappa statistics (p = 0.05), diagnostic agreement 86.9% +/-
      8%.

PMID- 12474667
TI  - [Demographic and clinical characteristics of patients with myasthenia gravis].
AB  - THE AIM OF THE STUDY: To evaluate demographic and clinical features of the
      patients with myasthenia gravis. MATERIAL AND METHODS: Retrospective analysis of
      medical data on 82 patients with myasthenia gravis, referred to the University
      Hospital of Kaunas during 1992 to 2001. RESULTS AND CONCLUSIONS: More than a half
      of all patients with myasthenia gravis were female, and almost four fifths fell
      ill before the age of 50 years. The most common first sign of myasthenia gravis
      was unilateral or bilateral ptosis and diplopia. The Osserman-Genkins grade at
      onset was I in 34.1%, IIA in 35.4% and IIB in 30.5% of cases. Among thymectomised
      patients, the percentage of thymomas in late-onset group (> or = 50 years) was
      higher than in the early-onset group (< 50 years). Mortality rate was 7.3%.
      Myasthenic crisis was the main cause of death in all cases. Overall, 99% of
      patients were treated with acethylcholinesterase inhibitors and 92% with
      prednisolone at some time. Pharmacological remission was observed in more than
      40% of patients. Prospective design of the study is recommended for the research
      of chronic noncommunicable diseases since it allows to evaluate the course and
      progression of the disease, effectiveness and side-effects of the treatment in
      more precise way. We used retrospective data in this study, therefore the results
      should be considered keeping in mind the possibility of bias and as the basis of
      prospective autoimmune myasthenia gravis studies in future.

PMID- 12474668
TI  - [Atherosclerosis-related stroke: risk factors, location, outcome].
AB  - We compared the characteristics of 1114 patients with first stroke caused by
      atherosclerosis with characteristics of 2159 patients with stroke due to other
      etiology. Stroke due to atherosclerosis with stenosis more often than stroke due
      to atherosclerosis unthout stenosis and stroke due to other etiology occurred in
      the caroted territory (respectively 66.9%, 55.2% and 61.7%, p < 0.001) and border
      zone (respectively 7.2%, 0.5% and 1.1%, p < 0.001). Stroke due to atheroscerosis
      unthout stenosis more often than strokes caused by other etiologies occurred in
      the vertebrobasilar territory (respectively 40.1%, 20.2% and 29%, p < 0.001). The
      proportion of patients with death or major disability was greater in the group
      atherosclerosis with stenosis (18%) than in the group atherosclerosis without
      stenosis (9.4%, p < 0.001).

PMID- 12474669
TI  - [Coloanal anastomosis in rectal cancer surgery].
AB  - PURPOSE: To determine the efficacy of proctectomy with coloanal anastomosis for
      adenocarcinoma of the lower third of the rectum, and to compare quality of life
      after colonal anatomosis with low anterior rectal resection. MATERIAL AND
      METHODS: Twenty coloanal anatomosies were performed on 1996-2001 in Kaunas
      Medical University Hospital. Coloanal anatomosis was performed due to 1 villous
      adenoma and 19 adenocarcinomas. Postoperative functional results and quality of
      life were assessed by questionnaire, which was sent by mail to 17 patients after
      coloanal anatomosis and randomly assigned to 35 patients after low anterior
      rectal resection. Questionnaire was answered by 10 patients (59%) after coloanal
      anatomosis and 23 patients (66%) after low anterior rectal resection. RESULTS:
      Four general and 7 surgical complications occurred after coloanal anatomosis.
      Postoperative mortality was 15% (3 cases). Symptomatic anastomotic strictures
      revealed in 2 patients. The frequency of defecation 6 and more times per day
      after coloanal anatomosis were in 2 cases (20%) and after low anterior rectal
      resection in 3 cases (13%). In coloanal anatomosis group normal continence
      occurred in 40% of cases and after low anterior rectal resection--in 65%. One
      patient had incontinence of solids after low anterior rectal resection. In 4
      cases after low anterior rectal resection occurred stable urine dysfunction. In
      coloanal anatomosis group sexual dysfunction occurred in 30% of cases, after low
      anterior rectal resection--in 22%. After both operations about 50% patients felt
      better. Hard social, emotional problems had only one patient with incontinence of
      solids. In other aspects quality of life was similar in both groups. CONCLUSIONS:
      Proctectomy with coloanal anastomosis is suitable and safe procedure to treat
      lower third rectal cancer, with functional results and quality of life similar to
      low anterior rectal resection.

PMID- 12474670
TI  - [A rare clinical case: myocardial infarction caused by coronary artery occlusion
      by cancer cells].
AB  - Rare clinical case of myocardial infarction, conditioned by neoplasmal obturation
      of coronary artery, is presented in the article. Primary nidus of the neoplasmal
      growth was in 3 and 4 segments of the lung. Tumor penetrated pleura, pericardium,
      epicardium and infiltrated wall of the circumflex branch and formed neoplasmal
      thrombus.

PMID- 12474671
TI  - [A rare complication of chronic pancreatitis: pancreatic ascites].
AB  - Case report of successful treatment of pancreatic ascitis is presented.
      Pancreatic ascitis is a rare complication of chronic pancreatitis. A local
      inflammation of pancreas ducts-system is a cause of pancreatic duct stenosis,
      later--of pancreatic duct obstruction. That causes dilatation and rupture of
      pancreatic duct, then pancreatic juice comes to peritoneal cavity and there
      collects exudate, rich of protein. Diagnosis of pancreatic ascitis is possible
      after investigation of evacuated peritoneal fluid. Conservative treatment is
      insufficient in 40-60% cases. Operative technique must be chosen concerning
      pathology of pancreatic duct. Most important point in pancreatic ascitis
      treatment is to preserve pancreatic functions. Investigation and correct
      treatment are necessary conditions of successful treatment of pancreatic ascitis.

PMID- 12474672
TI  - [Influence of temperature on the recovery of muscle function after performing
      maximal intensity exercise].
AB  - The purpose of this study was to establish the influence of temperature on
      quadriceps femoris muscle force, contraction and relaxation time, low frequency
      fatigue and muscle recovery after performing high-intensity exercise. Healthy
      untrained men (age 21-30 years, n = 9) gave their informed consent to take part
      in all experiments within the study. A high voltage stimulator (MG 440, Medicor,
      Hungary) was used for electrical stimulation; quadriceps muscle was stimulated
      through surface electrodes (9 x 18 cm) padded with cotton cloth and soaked in
      saline solution. The following data were measured: the force of quadriceps
      muscle, aroused by electrical stimulation under 1 Hz (Pt), 20 Hz (P20) and 50 Hz
      (P50) frequencies (the duration of each electrical stimulation series was 1
      second) and maximal voluntary contraction force (MVCF). Hot water (44-45 degrees
      C) bath was used for muscle heating. Blood lactate concentration was measured
      before exercise and after 5 min. and 1 hour after performing high-intensity
      exercise. Two experiments with two months recreation time were carried out. The
      following conclusions were received: even though muscle heating increases the
      speed of dominating lactate in blood and increases the muscle force caused by low
      and high stimulation frequency, it does not influence the recovery properties of
      muscle contraction and relaxation during 24 hours after performing high-intensity
      exercise.

PMID- 12474673
TI  - [Changes of A and V waves in transesophageal electrogram].
AB  - The transesophageal electrogram is registered in case of complicated setting up
      by means of surface electrocardiogram the relation of the atrial complex and
      electric activity. Various biophysical factors, including the electric conduction
      of the electrode environment in the esophagus, influence the quality or the
      transesophageal electrogram (amplitude, interval of frequency, phase). The
      objective of the research is to show the conduction of the electrode environment
      in the esophagus of the persons under investigation who were asked to swallow
      some big gulps of drinking water. The analysis of the monopolar and bipolar
      transesophageal electrogram of thirty volunteers showed a steady statistic growth
      of the amplitude of a and v waves and the spectral force of the signal. The
      setoff components of high frequency high frequency reflect the process of the
      depolarization of the atrium.

PMID- 12474674
TI  - [Effects of mercury on the course of Listeria monocytogenes infection in mice].
AB  - Effects of mercury ions on the colonization of mice organs by Listeria
      monocytogenes were investigated. It was found that single injection of 0.05 LD50
      mercury ions has little effect on listeria spreading in mice internal organs.
      Dissemination of bacteria in the liver of mice, which received 0.5 LD50, was
      similar to that one in control animals, which received physiologic solution,
      while higher numbers of bacteria were found in spleen of experimental animals at
      later stages of infection (after 24 and 48 h), when inflammation processes begin
      to take place. Chronic exposure to 0.05 LD50 mercury ions for 6 weeks caused
      decrease in body weight and survival of mice as well as increase in the infection
      degree of their internal organs. In addition, we demonstrate the mercury ions
      results in decreased synthesis of specific antibodies against listeria proteins.

PMID- 12474675
TI  - [Development of intranasal lactocin (oxytocin) drops technology].
AB  - Pure oxytocin substance was obtained from posterior part of cattle pituitary
      gland by high pressure liquid chromatography. Biological activity of the
      substance--450-500 IU/mg. Chromatographically pure Oxytocin substance was used in
      developing two different compositions of Lactocin intranasal drops (40 IU/ml).
      Stability evaluation was performed for 2 year period. The technical documentation
      was prepared on the basis of the research results. Lactocin is active preparation
      helping lactation and is indicated for lactostasis treatment and its prophylaxis
      after delivery.

PMID- 12474676
TI  - [Social status, psychological stress and myocardial infarction risk among 35-64
      year-old women].
AB  - We examined the association between social status, assessed by education and
      occupational categories and risk of myocardial infarction. We conducted a case
      control study among 35-64 year-old women of Kaunas. Cases were 191 women with
      first myocardial infarction treated in hospitals in 1997-2000, and controls were
      482 women in the same age group, randomly selected, without ischemic heart
      disease. We used multiple logistic regression to estimate the adjusted odds
      ratios of developing myocardial infarction in relation to social status and
      psychological stress. The study results indicated that stress, arterial
      hypertension, smoking, overweight and low education increased the risk of first
      myocardial infarction among 35-64 years old women. Managers and service, market
      sales workers had about twice higher risk for myocardial infarction than
      associate professionals (OR = 2.64; 95% CI 1.17-6.62 and OR = 2.18; 95% CI 1.03
      4.63 correspondingly).

PMID- 12474677
TI  - [Diabetic ketoacidosis].
AB  - Diabetic ketoacidosis is an emergency medical condition that can be life
      threatening if not treated properly. Diabetic ketoacidosis occurs most often in
      patients with type 1 diabetes (formerly called insulin-dependent diabetes
      mellitus); however, its occurrence in patients with type 2 diabetes (formerly
      called noninsulin-dependent diabetes mellitus) is not as rare as was once
      thought. This article reviews data about precipitating events, pathogenesis,
      carbohydrate, lipid and ketone, water and electrolyte metabolism in this
      hyperglycemic crisis. The review discusses diagnostic procedures, laboratory
      evaluation, differential diagnosis and treatment: replacement of fluid and
      electrolytes, low-dose insulin therapy and recommendations for use of
      bicarbonate. A discussion of complications management of diabetic ketoacidosis
      (hypoglycemia, hypokalemia, cerebral edema, hyperchloremic metabolic acidosis,
      pulmonary edema, adult respiratory distress syndrome), mortality rate and
      prevention are included in this review.

PMID- 12474678
TI  - [Good drug distribution practice and its implementation in drug distribution
      companies].
AB  - Good Distribution Practice is based on the Directive of the Board of the European
      Community 92/25/EEC regarding the wholesale distribution of drugs for human
      consumption. It is stated in the Directive that the whole drug distribution
      channel is to be controlled from the point of drug production or import down to
      the supplies to the end user. In order to reach the goal, the drug distribution
      company must create the quality assurance system and facilitate its correct
      functioning. This aim requires development of the rules of the Good Distribution
      Practice. Those rules set the general requirements of the Good Distribution
      Practice for distribution companies that they must conduct. The article explains
      main requirements postulated in the rules of the Good Distribution Practice and
      implementation of the Good Distribution Practice requirements in drug
      distribution companies.

PMID- 12474679
TI  - [Procalcitonin: a new infection marker. Its use in intensive care].
AB  - In daily routine diagnosis, there are few parameters available to monitor
      critically ill patients and to control the course of therapy in severe
      inflammations. There are also few reliable parameters differentiating acute
      bacterial infection from other types of inflammation. Most of the presently used
      indicators of the inflammatory response, like body temperature, white cell count,
      erythrocyte sedimentation rate or C reactive protein are unspecific parameters
      with changing reliability. Procalcitonin is a diagnostic parameter of bacterial
      infections with systemic reaction of the organism. It is an innovative diagnostic
      parameter with feature different from other presently available indicators of the
      inflammatory response. The incidence of noninfectious systemic inflammatory
      response syndrome associated with coronary artery bypass surgery and the
      potential role of several inflammatory parameters as early markers of pulmonary
      dysfunction induced by cardiopulmonary bypass were investigated. Procalcitonin
      seems to be appropriate parameter indicating the early development of severe
      noninfectious systemic inflammatory response syndrome and for predicting
      pulmonary dysfunction secondary to cardiopulmonary bypass. Hence, the review of
      the data of different authors may lead to the conclusion that because of wide
      spectrum of indications procalcitonin concentration can be used for differential
      diagnosis of bacterial versus non-bacterial inflammation, as monitoring parameter
      in critically ill patients, the course of disease, treatment control evaluating
      the effectiveness of antibacterial treatment, for evaluation of high risk
      patients to see if there are no postoperative bacterial complications as a
      prognostic indicator.

PMID- 12474680
TI  - [Prevalence of papillomavirus infection among patients with laryngeal
      papillomatosis and the effects of some risk factors on the persistence of
      papillomaviruses in the upper respiratory tract].
AB  - Infection with high-risk human papillomaviruses is a significant risk factor of
      various benign and malignant human lesions in the upper respiratory tract, skin
      and the genital tract. The identification of particular human papillomaviruses
      types is important for identifying patients with premalignant lesions who are at
      risk of progression to malignancy. Our aim was to establish the prevalence of
      human papillomaviruses infection in the upper respiratory tract of patients with
      laryngeal papillomatosis, to identify viral types, to evaluate the relationship
      between some risk factors and persistence of human papillomaviruses in the upper
      respiratory tract and to determine the pattern of human papillomaviruses
      infection. MATERIAL AND METHODS: The group of 36 patients with laryngeal
      papillomatosis and control group of 108 persons without any complains of
      respiratory system was examined. Epidemiologic characteristics and objective data
      were analyzed and routine laryngological examination was performed. Pharyngeal
      swabs of all persons and laryngeal biopsies of 17 patients were taken and
      analyzed for the presence of human papillomaviruses DNA. Viral typing using the
      polymerase chain reaction was performed. RESULTS: Human papillomaviruses DNA was
      detected in all except one case of laryngeal papillomatosis; then only 23.15% of
      persons without complaints of respiratory system were found human
      papillomaviruses positive. Human papillomaviruses 6, 11 types were predominant
      (in 88.9% of patients and 19.4% of persons from control group). High-risk human
      papillomaviruses were detected in 52.78% of laryngeal papillomatosis cases and in
      9.26% of control cases. Risk factors were noted statistically significantly more
      often in human papillomaviruses positive cases. CONCLUSIONS: The prevalence of
      human papillomaviruses infection in the upper respiratory tract of patients with
      laryngeal papillomatosis is high; human papillomaviruses 6, 11 types are
      predominant. High-risk human papillomaviruses were noted statistically
      significantly more often in the group of patients with laryngeal papillomatosis.
      Inclination to diseases of respiratory system, dental caries, smoking, low living
      standard are statistically significantly related to human papillomaviruses
      persistence in the upper respiratory tract.

PMID- 12474681
TI  - [Treatment outcome in femoral neck fractures].
AB  - Retrospective study of 372 patients with Garden III-IV type intracapsular femoral
      neck fractures performed in Clinic of Orthopedics and Traumatology, Kaunas
      University of Medicine, Kaunas Red Cross hospital. Ninety eight percent of them
      were operated: osteosynthesis for 302 patients, and arthroplasty for 63 patients.
      Evaluating results of treatment we paid attention on walking ability, pain in hip
      joint. Mean follow-up time was 1.5 years. Satisfactory results we received for
      41.8%. The best results we received after total hip replacement and after
      osteosynthesis with modern fixation devices. Delayed surgery worsens results.
      Type of anesthesia did not influence results of osteosynthesis.

PMID- 12474682
TI  - [Knee joint evaluation after anterior cruciate ligament plasty].
AB  - AIM OF THE STUDY: To make certain how the patients themselves evaluate the state
      of their knee joint and check-up the state objectively after 3, 6, 12 months
      period after the anterior cruciate ligament reconstruction. MATERIALS AND
      METHODS: In 1996-2001 there were performed 78 anterior cruciate ligament
      reconstruction operations. Twenty one patient was chosen. The patients were
      questioned according to subjective IKDC (International Knee Documentation
      Committee) form, 12 months after the anterior cruciate ligament reconstruction.
      To have an objective evaluation, the patients had to come to the control check-up
      in 3, 6 and 12 months after the operation. During the clinical check-up the
      objective IKDC form was being used. RESULTS: According to subjective IKDC
      formula: for six patients (29%) the results were very good; for seven patients
      (33%)--good; for seven patients (33%)--satisfactory; for one patient (5%)--bad.
      The objective data showed that the state of the knee joint before the operation
      was bad or satisfactory. Now to 90% of the patients the state of the knee joint
      is very good; 10% evaluate it as good. For all patients (100%) the instability of
      the knee joint disappeared. CONCLUSIONS: For all questioned patients the
      instability of the knee joint after the anterior cruciate ligament reconstruction
      disappeared; 95% patients are satisfied with the results of the operation.

PMID- 12474683
TI  - [Arrhythmias and heart rate variability in Duchenne and Becker muscular
      dystrophy].
AB  - The myocardial damage is common in the Duchenne and Becker muscular dystrophy.
      The rhythm and conduction disorders, associated with these diseases and treatment
      are analyzed in this publication. Heart rate variability is a sensitive,
      noninvasive measurement of autonomic input to the heart and can provide valuable
      information about autonomic function. We investigated the changes in sympatovagal
      control of heart rate in patients with Duchenne and Backer disease in comparison
      with the same age healthy children.

PMID- 12474684
TI  - [Clinical information system and its significance in intensive care].
AB  - The increasing number of the patients requiring admission to the intensive care
      unit and growing demand for the outcome analysis was noted over the last decade.
      The goal of this study was to evaluate the characteristics of the patients, to
      compare the outcome of surgical and medical patients, and to demonstrate the
      importance of the clinical information system in the intensive care. During 12
      month period 1031 patients were enrolled for the study. Data were collected on
      forms and then entered into a computer program specifically designed for this
      study. For the overall population mean age was 63 years, Simplified Acute
      Physiology Score II (SAPS II)--31, and stay in the intensive care unit--4 days.
      The most frequent site of the intensive care unit acquired infection was
      respiratory, mainly pneumonia. The overall mortality in the intensive care unit
      was 19.4% and hospital mortality--24.8%. The mortality was directly associated
      with advanced age, increased SAPS II sore, and the occurrence of organ
      dysfunction. Medical patients in comparison with surgical patients had higher
      SAPS II scores (p < 0.001) and number of organ dysfunctions (p < 0.001), longer
      intensive care unit stay (p < 0.001) and higher mortality rate (p < 0.001). The
      underprediction of actual mortality by the SAPS II system was predetermined by
      this value of the neurological patients. The outcome of the surgical patients was
      good compared to the results of the studies from other countries. Clinical
      information system is necessary for comprehensive and objective evaluation of the
      intensive care unit data and quality of therapy.

PMID- 12474685
TI  - [Complications of carotid endarterectomy].
AB  - BACKGROUND AND PURPOSE: Carotid endarterectomy has been shown to be beneficial in
      patients with high-grade carotid stenosis. This benefit will be realized only if
      the operation is performed safely. We determined the ratio of operative
      complications and sought to identify the risk factors for operative stroke and
      death from carotid endarterectomy. METHODS: Two hundred fifty seven patients
      underwent carotid endarterectomy during 1995-1999 years in Vilnius emergency
      hospital. Nineteen potential risk factors for operative complications were
      examined. RESULTS: Mortality of endarterectomy was 2.7%, the overall risk of
      stroke and/or death was 4.3%. In multivariate logistic-regression models a
      symptom status (recent history of stroke) and angiographic features
      (contralateral stenosis 70% and more) were as independent risk factors for
      operative stroke and death. CONCLUSIONS: The risk of stroke and death from
      carotid endarterectomy is related to clinical and angiographic characteristics.
      These observations may help clinicians to estimate operative risks for individual
      patients.

PMID- 12474686
TI  - [Cocaine-induced myocardial infarction (clinical case report)].
AB  - Cocaine abuse has been associated with various cardiovascular complications,
      including angina pectoris, myocardial infarction, and sudden cardiac death. The
      first report of myocardial infarction temporally related to the recreational use
      of cocaine appeared in 1982. This article discusses the possible pathological
      mechanisms underlying the pathogenesis of myocardial ischemia and infarction
      secondary to cocaine abuse, and current ideas on the management of cocaine
      induced myocardial infarction. We report a case of acute myocardial ischemia in a
      young healthy male patient and his 5-year follow-up.

PMID- 12474687
TI  - [Histological analysis of electrochemotherapy influence in Lewis lung carcinoma].
AB  - Under the influence of strong electric fields the permeability of tumor cell
      membranes to poor permeating drugs increases and as a result the tumor growth is
      inhibited. This new tumor treatment method is named electrochemotherapy. We
      investigated the electrochemotherapy influence of bleomycin upon mice Lewis Lung
      Carcinoma by using optical histological and electron microscopic tumor analysis.
      It was shown that due to electrochemotherapy tumor necrosis area is significantly
      increased, intercellular gaps enlarge, and a big amount of cells is destroyed.
      Cell and nucleus membranes break as well as hemorrhage are very often. The
      observable histological tumor change was noted when electrical pulses of 1300
      V/cm and 0.1 ms duration were applied. Pulses of 1700 V/cm and 0.1 ms duration
      induce total tumor destruction.

PMID- 12474688
TI  - [Development of formulations of desmopressin intranasal drops].
AB  - In recent years synthetic vasopressin analogues (particularly desmopressin)
      emerged as safe and effective representatives of this class of drugs for same
      clinical indications as natural hormone. It was imperative to create intranasal
      drug form using synthetic desmopressin compound. The purpose of this work was to
      develop formulations of intranasal desmopressin drug using synthetic active
      compound with optimal composition. Aquatic desmopressin intranasal solution was
      prepared in 0.05 mg/ml concentration using phosphate buffer (pH 4.5-5.5) and
      following preservatives: nipagin-nipazol 7:3--0.1% or benzalkonium chloride
      0.01%. Sterility is the main condition for intranasal drops and hormones as a raw
      material are thermolabile so it is not possible to apply a thermic sterilisation.
      Polymeric membrane filters of 0.22 micron pore size were employed as sterilizing
      filters. In order to control the quality, to determine the stability of
      desmopressin intranasal drops at long-lasting storage (24 months) and to evaluate
      the influence of the technological factors we have developed the analytical
      methods of quality control. According to our quality control data, desmopressin
      intranasal drops are stable for two years and remain sterile during storage and
      administration of the drug.

PMID- 12474689
TI  - [Poisonings with psychotropic drug mixtures: analysis using the thin-layer
      chromatography method].
AB  - It is observed increase in number of remedy intoxications in Lithuania,
      especially important is intoxication with psychotropic drugs and their mixtures.
      The thin-layer chromatography (TLC) method was proposed for separation and
      identification of drugs in mixture aminazine: nitrazepam: barbamylum. The mixture
      of these drugs excreted from body fluids (blood and urine) was investigated by
      TLC. Most acceptable these mobile phases: 1. Diethyl ether: dioxane--40:60. Rf
      values for drugs: aminazine 0.23-0.25; barbamylum 0.85-0.9; nitrazepam 0.75-0.8.
      2. Diethyl ether: NH3 (25%): benzenum--80:10:10. Rf values for drugs: aminazine
      0.55-0.58; barbamylum 0.32-0.35; nitrazepam 0.17-0.2.

PMID- 12474690
TI  - [Representation of the pulse wave of blood pressure by the series of impulses of
      the pulse-rhythmic neurons in the nucleus tractus solitarii].
AB  - Baroreceptor afferent fibers from the aortic arch and carotid sinus project to
      the nucleus of solitary tract in the medulla. The aim of this study was to define
      the relation between the activity of neurons in this nucleus and changes of the
      blood pressure in the aorta during the pulse wave. Impulses of 74 pulse-rhythmic
      neurons, i.e. neurons discharging in bursts of impulses synchronously with the
      pulse wave, were recorded in acute experiments on 30 rabbits. Impulse histograms
      triggered by the R wave of the ECG and the averaged pulse wave over 250
      consecutive R-R intervals were compared. These post-R histograms showed a close
      correlation of impulse activity with the pulse wave for most (74%) neurons. The
      beginning of the burst of impulses corresponded to the beginning of the pulse
      wave and the highest frequency of discharges coincided with the steepest rise in
      blood pressure of the pulse wave. The similarity of the histograms to the pulse
      wave shows that the pulse-rhythmic neurons integrate mostly the afferent input
      received from the arterial baroreceptors.

PMID- 12474691
TI  - [Patient satisfaction with the work of the hospital medical personnel].
AB  - The article presents the data of patient's satisfaction with the work of nurses
      and physicians in the hospitals, which belong to Lithuanian Health promotion
      hospitals network. All nine hospitals of the Lithuanian health promotion
      hospitals network took part in this study. Altogether 1300 questionnaires were
      handed out. They have been completed and returned by 1271 patients, i.e. 97.8%.
      Patients were asked to complete uniform anonymous questionnaire and evaluate the
      work, behavior and educational activity of nurses and physicians. The majority of
      respondents assessed the work of nurses and physicians positively, respectively
      96.1% and 95.5%. The evaluation of nurses' work depended on patients' sex and the
      size of the hospital in which they were treated. Male patients and the ones who
      were treated in big hospitals assessed the work of nurses better than females and
      patients in smaller hospitals. The evaluation of physicians' work was related to
      the patients' education and extra payment for health services. Patients, who had
      higher education and indicated that they had paid additionally, assessed the work
      of physicians more critically. The majority of patients assessed the behavior of
      nurses and physicians as very good or excellent, respectively 86.0% and 90.5%.
      The work of nurses was better evaluated by elderly people and patients treated in
      big hospitals and as well as in the departments of internal medicine. Patients'
      satisfaction with the behavior of physicians was associated with patients'
      education. Better-educated people were more critical in assessing the behavior of
      physicians. The results of this study have shown that patients' satisfaction
      depends on many factors. To improve the quality of health care services in
      hospitals it is necessary to study patients' needs, expectations and factors
      associated with patients' satisfaction.

PMID- 12474692
TI  - [Long-term risk of stroke after acute myocardial infarction].
AB  - PURPOSE: To examine the incidence of stroke during the first three years after a
      first-ever myocardial infarction. MATERIAL AND METHODS: Both Kaunas community
      based ischemic heart disease register and stroke register were used as the
      primary source of data. The methods used for data collection were those applied
      by the WHO for the international MONICA project. During 1986 to 1996, 4201
      persons aged 25 to 61 years with a first-ever myocardial infarction were included
      into Kaunas community-based ischemic heart disease register and followed-up for
      three years against first-ever stroke or death from any cause. Actuarial life
      tables were used to analyze risk of stroke. RESULTS: During the study period, 82
      (2.0%) patients with the first-ever stroke that occurred among survivors of
      myocardial infarction were identified: 68 (82.9%) men and 14 (17.1%) women. The
      cumulative risk of stroke was 3.19% (95% CI 2.50 to 3.88%) by 3 years: among male
      myocardial infarction survivors this risk was accounted for 3.37% (95% CI 2.54 to
      4.17%) and that among female--for 2.51% (95% CI 1.22 to 3.80%). The risk was
      identified as the highest one early after ictus among the myocardial infarction
      survivors: 0.43% (95% CI 0.21-0.65%) by 3 months (men--0.51% (95% CI 0.24 to
      0.78%), women--0.12% (95% CI 0 to 0.38%)) and 0.23% (95% CI 0.05 to 0.41%) by 6
      months (men--0.25% (95% CI 0.03 to 0.47%), women--0.18% (95% CI 0 to 0.53%)).
      CONCLUSION: The risk of stroke is identified as the highest one early after the
      myocardial infarction.

PMID- 12474693
TI  - [Diagnosis and therapy of systemic Candida infection].
AB  - Over the past three decades, the significant morbidity and mortality associated
      with candidemia and invasive candidiasis have been well established.
      Technological and scientific advancement had led to an increase in the incidence
      of serious Candida infections. With the introduction of the azoles and other
      antifungal agents, our ability to treat these infections has improved; however,
      our ability to diagnose these infections in a timely fashion remains limited, and
      patient outcomes remain poor. This review article discusses these problems, the
      role of antifungal prophylaxis, risk factors for invasive Candida infection and
      treatment of systemic Candida infection.

PMID- 12474694
TI  - [Brain contusion: morphology, pathogenesis and treatment].
AB  - Focal cerebral contusions can be dynamic and expansive, leading to a delayed
      neurological deterioration. In head--injured patients, the rise in intracranial
      pressure (ICP), subsequent to uncontrollable swelling, is the only and the most
      frequent cause of death. Studies show that brain swelling, after traumatic brain
      injury (TBI), is caused by brain edema rather than cerebral blood volume (CBV).
      CBV is reduced in proportion to cerebral blood flow (CBF) reduction, following a
      severe TBI. Cerebrovascular damages, leading to subsequent reductions in regional
      CBF, may play an important role in secondary cell damages following TBI. The
      histological examination revealed the formation of microthrombosis in the
      contused area, extending from the center to the peripheral areas within 6 hours
      after injury. In the pericontusional zone and surrounding parenchyma,
      vasoresponsivity may be nearly three times normal, which suggests
      hypersensitivity to hyperventilation and other phenomena. Glutamate is the most
      widely distributed excitatory neurotransmitter in the mammalian brain. However,
      when glutamate is present in excessive quantities, it may overactivate specific
      ion channels, especially the N-methyl-D-aspartate channel. A shift of potassium
      into the extracellular space will result in rapid swelling of astrocytes, which
      absorb quantities of potassium to preserve ionic homeostasis. This process may
      cause rapid cytotoxic edema, which is probably, a major factor in causation of
      posttraumatic raised ICP. The presence of a focal contusion and primary or
      secondary ischemic events were the clinical features most strongly correlated
      with high dialysate of glutamate. Raised ICP was significantly more common, and
      outcome was worse in patients with high levels of glutamate. Contusion is a key
      factor in the development of blood brain barrier (BBB) permeability. BBB endures
      at least 7 days post TBI. Biphasing opening of the BBB, following head trauma and
      a possible second wave of secondary brain damage, was confirmed. Brain tissue pO2
      monitoring might become an important tool in the treatment regime for TBI
      patients. Histologically the loss of CA3 pyramidal cells in the hippocampus was
      observed ipsilaterally in the cortical contusion and bilaterally in diffuse
      axonal injury. Aggressive, early hyperventilation after TBI augments neuronal
      death in CA3 hippocampus. Due to high mortality associated with such cerebral
      contusions, a standard practice has evolved into evacuating contusions in
      patients who had deterioration in the level of consciousness, lesions more than
      30 sec and CT suggestion of raised ICP.

PMID- 12474695
TI  - [Ischemic stroke and its risk factors after cardiac surgery].
AB  - The modern reparative procedures are highly successful in terms of the cardiac
      outcome; they can be detrimental in regard to the central nervous system (CNS).
      Perioperative stroke is one of the most serious complications of cardiac surgery.
      Refinements and advances in surgical techniques, myocardial preservation and
      anesthesia have led to a decline in morbidity and mortality for cardiac surgical
      patients. Adverse cerebral outcomes, however, are increasing, largely because of
      a trebling of deaths caused by neurologic injury. Complications involving the
      brain are increasing substantially because older patients with advanced
      atherosclerotic vascular disease now have surgery, suggesting that advances in
      surgical and anesthetic techniques proven to provide better myocardial protection
      have not had an impact on reducing the incidence of ischemic brain injury.
      Careful preoperative evaluation process must be undertaken to identify patients
      who are at the highest risk of having perioperative stroke. This article provides
      a concise summary of a very important problem in contemporary cardiac surgery.
      The authors have concentrated on review of the predictive factors for
      perioperative stroke, identified by multivariate analysis in the recent studies.
      These factors taken together can identify patients, who are at high risk for
      perioperative focal cerebral ischaemic injury. Recognition of the high-risk group
      will facilitate prevention of stroke by modification of surgical procedures or
      pharmacologic intervention. Prevention is the most effective way of managing
      neurologic disorders.

PMID- 12474696
TI  - [Use of adenosine and high-energy phosphates in cardiac anesthesiology].
AB  - Usage of adenosine and high-energy phosphates in cardiac anesthesiology is widely
      discussed. Implementation of above substances can be achieved via three possible
      ways: during the preparation of patients for cardiac surgery, during surgery and
      after the surgery during intensive postoperative care. Optimum methods for
      cardiac protection, which could guarantee safe, lasting heart function
      preservation after the surgery are investigated till now. Advantages and
      disadvantages of adenosine application during preoperative and postoperative
      periods as well as in cardiac surgery are presented. Possibilities to use
      phosphocreatine for cardioprotection will be discussed as well.

PMID- 12474697
TI  - [Tracheostomy and prolonged artificial ventilation of patients after heart
      surgery].
AB  - Dysfunction of respiratory system after open heart surgery is one of the main
      problems in postoperative period. When mechanical ventilation is prolonged
      because of different causes, tracheostomy is usually performed, but the optimal
      time is still being discussed. In order to elucidate the influence of
      tracheostomy to subsequent course of disease we reviewed the indications,
      frequency and complications of postoperative tracheostomies performed in 1998
      2000 in Cardiosurgical clinic after open heart surgery. The survey of our
      experience (only 15 tracheostomy procedures have been performed) showed that
      ventilation through tracheostomy tube is safe and comfortable way of application
      of prolonged mechanical ventilation: it is easier to stabilize, suction, and
      attach respiratory equipment. The patient can eat and, with some adjustments, can
      talk. Complications of tracheostomy are not often. If tracheostomy was well
      timed, the risk of trachea stenosis, infection of respiratory tract and other
      possible complications would decrease.

PMID- 12474698
TI  - [Acute and chronic facial pain due to injured neural plexus of the upper teeth].
AB  - The general causes of upper dental plexus injury are tooth disturbances and the
      periodontal tissues diseases, the pathology of maxillary sinus, various
      traumatically manipulations in the area of tooth and maxilla as well. The main
      symptom of upper tooth neural plexus injury is acute and chronic pain in the
      alveolar sprout of maxilla, gums or in the area of singly tooth, which rarely
      spreads into neighboring maxillofacial areas. The authors recommend that the
      acute pain syndrome would be called the inflammation of upper tooth plexus, and
      the chronic pain syndrome--plexopathia of upper tooth. Study presents the
      differential diagnosis according to character of facial pain syndrome and the
      data of sensority disorders research and investigation of pain thresholds as
      well. The recommendations for treatment tactic and methods of analyzed
      indispositions are suggested.

PMID- 12474699
TI  - [Malocclusion and upper airway obstruction].
AB  - After more than a century of conjecture and heated argument, the orthodontic
      relevance of nasal obstruction and its assumed effect on facial growth continues
      to be debated. Oral respiration disrupts those muscle forces exerted by tongue,
      cheeks and lips upon the maxillary arch. The main characteristics of the
      respiratory obstruction syndrome are presence of hypertrophied tonsils or
      adenoids, mouth breathing, open-bite, cross-bite, excessive anterior face height,
      incompetent lip posture, excessive appearance of maxillary anterior teeth, narrow
      external nares, "V" shaped maxillary arch. The purpose of this study is to
      evaluate relationship between nasal obstruction and severity of malocclusion. The
      sample analyzed in this article consisted of 49 children aged from 7 to 15 years,
      who pronounced difficulty in breathing through the nose. Patients and their
      parents were interviewed, clinical examination was performed, and measurements
      from dental casts and panoramic radiograph were obtained. All patients were
      examined by otorhinolaryngologist, and the nasal obstruction was confirmed by
      posterior rhinomanometry test. This study showed the significant association
      between nasal resistance and increased overjet (p = 0.042), open bite (p = 0.033)
      and maxillary crowding (p = 0.037). The tendency of greater nasal resistance was
      observed for the patients with the first permanent molars relationship Angle II
      and posterior cross-bite.

PMID- 12474700
TI  - [Long-term follow-up of osteochondritis dissecans].
AB  - Fifty-two patients with osteochondritis dissecans lesions were evaluated after 7
      25 years after excision of a partially detached (grade III) fragment or loose
      (grade IV) fragment from the medial femoral condyles. Average follow-up time was
      17.2 (range 7-25 years). Two homogenic groups based on special inclusion criteria
      were formed; 31 patient was in the first and 21--in the second group. The only
      difference between the groups was the age; the age average in the first group was
      -25.6 years (range 15-35 years), and -45.2 years (range 35-55 years) in the
      second group. Patients were evaluated through ICRS (International Cartilage
      Repair Society), modified HSS and KOOS (Knee injury and osteoarthritis Outcome
      score) scales, and with X-rays. Evaluation with the ICRS, modified HSS and KOOS
      rating scales for osteochondritis dissecans revealed in 9 cases (17%) good
      results, 32 cases (62%)--fair, and 11 cases (21%)--failure results. Final ICRS
      and modified HSS evaluation showed statistically significantly better results in
      the younger patient group at the 21 years (p < 0.04). At an average 17.2 year
      follow-up X-rays and KOOS evaluation form showed initial and second-degree
      (according to Ahlback) osteoarthritis signs in the knees. The long-term results
      of the natural history of osteochondritis dissecans are extremely poor.
      Consequently, we recommend autologous osteochondral grafting for the replacement
      of the osteochondritis dissecans defects in the knee joint.

PMID- 12474701
TI  - [Analysis of the outcome of the treatment of small bowel obstruction and factors
      which determine the outcome (10-year experience at the Kaunas Medical University
      Clinic)].
AB  - AIM: To evaluate the results of the treatment of small bowel obstruction in the
      Surgical clinic of Kaunas University of Medicine in 1990-1999, the changes of the
      results of the treatment, to evaluate the factors, which determine these changes.
      PATIENTS AND METHODS: 489 patients with small bowel obstruction (SBO) were
      treated during 10-year period. Acute SBO was found in 433 (88.5%) cases; 322
      (65.8%) patients underwent surgery. The patients were divided into two groups:
      1990-1995 year group (A) and 1996-1999 year group (B) according to the newly
      implemented methods of diagnostics and treatment (computer-aided diagnosis,
      laparoscopic cutting of adhesions, conservative small bowel decompression with
      long intestinal tube and etc.). Both groups were statistically similar. By means
      of statistical methods factors, which determine the results of the treatment of
      SBO, were found and the differences of distribution of these factors in both
      groups were evaluated. RESULTS: The mortality rate was 10.3% in group A and 1.8%-
      in group B. The most significant factors, which determine the outcome of the
      treatment of SBO, were: the time period of making diagnosis, adjacent illnesses,
      small bowel necrosis and its length, acute SBO, SBO due to multiple adhesions,
      surgical methods. In comparing both groups, they differed according to the time
      of making diagnosis (18.6 h and 9.6 h), the frequency of small bowel necrosis
      (14.2% and 5.7% cases); the methods of surgery also differed. CONCLUSION: The
      results of the treatment of SBO improved. The short-cut of the time period to
      make diagnosis, the more rare cases of bowel necrosis and new surgical methods
      influenced these changes.

PMID- 12474702
TI  - [Effectiveness of tolfenamic acid in the prevention of migraine].
AB  - The migraine prophylactic effect of tolfenamic acid 300 mg versus pizotifen 1.5
      was evaluated in a prospective, randomized, double-blind, parallel group study.
      192 patients were included with a frequency of 4-8 moderate to severe migraine
      attacks monthly, with or without aura, fulfilling the diagnostic criteria for
      migraine as defined by the International Headache Society. A four-week baseline
      period without medication was followed by 12 weeks of treatment with tolfenamic
      acid 300 mg or pizotifen 1.5 mg. In both periods patients were allowed to take
      escape medication (paracetamol and codeine) if the treatment was inefficient. All
      the patients had a headache diary before and during treatment. The primary
      criterion of efficacy was reduction in attack frequency per 4 weeks. Also
      reduction in intensity or duration of migraine attacks in hours at the end of 12
      weeks treatment compared to the baseline period was measured. Both groups
      exhibited significant reduction in attack frequency (p < 0.001). Tolfenamic acid
      significantly reduced severity compared to the run-in period (p = 0.009).
      Patients treated with pizotifen needed more escape medication when compared to
      the run-in period (p < 0.01). Tolerance, especially weight gain, was a major
      drawback with pizotifen. Because of its high efficacy, excellent tolerability and
      low cost, tolfenamic acid is an interesting option for migraine prophylaxis.

PMID- 12474703
TI  - [Foreign bodies in the heart].
AB  - During 1987-2000, in Clinic of Thoracic Surgery, Kaunas Medical University
      Hospital 30 patients with cardiac injuries and foreign bodies in the heart were
      treated. Average age of patients--37 years. Eighteen patients were extra operated
      with symptoms of acute pericardial tamponade and shock. We found right
      ventricular involvement for 5 patients; 9 patients had left ventricular injury, 2
      had right atrium injury and 1 patient had left atrium injury. Two patients had
      foreign bodies in the heart (one--needles, one--bullet). We present two rare
      cases of foreign bodies in the heart.

PMID- 12474704
TI  - [Anti-arrhythmic action of N-(aminoalkylene) derivatives of indoline-2,3-diones
      and 1,2-benzene-dicarboxiamides].
AB  - The aim of study was to modify the structure of indoline-2,3-diones and 1,2
      benzenedicarboximides using the pharmacophores of new generation antiarrhythmics
      and to assess the impact of their structure upon the acute toxicity and
      antiarrhythmic action. The quaternary derivatives of N-aminoalkylindoline-2,3
      diones and N-aminoalkyl-1,2-benzenedicarboximides were synthesized. The acute
      toxicity of compounds for white mice was tested. Using the calcium chloride- and
      aconitine-induced arrhythmia models in rats the antiarrhythmic action of
      derivatives was assessed. It was shown, that the antiarrhythmic action of N
      aminoalkyl-1,2-benzenedicarboximides increases by lengthening of alkylene chain
      from one methylene group to two or by the presence of methanesulfonamide group in
      benzene ring. These structural changes, especially the presence of
      methanesulfonamido group, cause the decrease of acute toxicity. Among the N
      aminoalkylindoline-2,3-diones the most antiarrhythmic action and minimal toxicity
      demonstrates the compound containing the bromo-substituted benzene ring.

PMID- 12474705
TI  - [Analysis of benzodiazepine derivative mixture by gas-liquid chromatography].
AB  - The analysis of mixture of benzodiazepine derivates (chlordiazepoxide,
      flunitrazepam, medazepam, nitrazepam, oxazepam and tetrazepam) by gas--liquid
      chromatography (GLC) in purpose to separate and identify these psychotropic drugs
      in mixture is presented in this article. The experiment was carried out in vitro,
      accommodating this method for identification and separation of drugs, isolated
      from biological objects (blood and urine). Referring to data of annual reports of
      chemical investigations (1) above-mentioned psychotropic drugs are very frequent
      among drug intoxication. In most cases they are detected in the mixture of the
      same or different pharmacological group, and this causes difficulty for
      separation and identification. The analysis of the mixture was carried out by
      GLC, which is widely used in practice of forensic-chemical examination.
      Adsorbents and stationery phases were changed; the conditions and parameters of
      chromatography were modified, in purpose totally separate preparations in the
      mixture. For the separation and identification of all three preparation the
      column packed with Inerton Super with stationary phase 3% OV-17 is suitable. The
      column temperature-290 degrees C. The mixture of these drugs was excreted from
      body fluids (blood and urine) in vitro and investigated by GLC under these
      conditions. The results of investigation were similar.

PMID- 12474706
TI  - [Do maternal social factors, health behavior and work conditions during pregnancy
      increase the risk of low birth weight in Lithuania?].
AB  - The objective of the paper was to evaluate the importance of maternal social
      factors, health behavior (smoking, alcohol drinking and drug abuse) and working
      conditions on incidence of low birth weight (LBW). MATERIAL AND METHODS:
      Statistical analysis was performed utilizing database of Medical Birth Registry
      for the years 1995-1998 using the indicators of maternal social factors, health
      behavior and working conditions. Statistical analysis was carried out using
      statistical package SPSS 10.0. RESULTS: During 1995-1998 the incidence of LBW (<
      2500 g) was 3.6 per cent. Young (< 20 years) and older (> or = 35 years) maternal
      age, low (primary or basic) education and "lone mother" status (single, divorced
      or widowed) increased the risk of delivering LBW baby. The odds ratio of smoking
      mothers to deliver LBW baby was 3.3. Odds ratios of LBW newborns associated with
      alcohol drinking and drug abuse were 10.3 and 6.1 respectively. The odds ratio of
      mothers physically abused during pregnancy to deliver LBW baby was 2.7. However,
      the harmful working conditions were not associated with the higher odds of LBW.
      Young and older age was attributable for 22.2 and 49.3 per cent LBW cases in the
      exposed group respectively. While attributable fraction in exposed due to the low
      educational level and unfavourable marital status accounted to 38.9 and 52.9 per
      cent LBW cases respectively. Smoking was attributable for 68 per cent LBW cases,
      alcohol drinking--87.2 per cent, drug abuse--80.5 per cent LBW cases among
      exposed mothers. Preventable population attributable risk for unfavourable
      marital status was 11.7 per cent, low education--9 per cent, smoking--8 per cent,
      older age--6.9 per cent. Drug abuse and hard manual work had minimal association
      while harmful working conditions were not associated with higher risk to deliver
      the LBW baby in the total population. CONCLUSIONS: Maternal health behavior
      peculiarities and hard manual work are related to newborns' birth weight, and
      medical professionals should encourage quitting the hazardous habits and
      regulation of workload for expectant mothers. Adverse social factors contribute
      to the higher incidence of LBW. The solution of social problems should become the
      priority of State health policy.

PMID- 12474707
TI  - [Trends in the development of atherosclerosis in Kaunas population].
AB  - The trends of development of atherosclerosis were evaluated by comparing the
      epidemiological morphological data from the seventh decade (first study, 1962
      1965) and the tenth decade (second study, 1991-1993) of the 20th century. The
      first study included arteries from 818 patients (422 men and 396 women); whereas
      the second study included arteries from 1252 patients (958 men and 294 women). We
      have observed an age-independent increase in frequency and extent of the raised
      atherosclerotic lesions in aortas and coronary arteries of Kaunas men in the
      second study. Thus, the atherosclerosis has become more severe. The trends of
      development of atherosclerosis in aortas of Kaunas women were similar to those of
      men, but the atherosclerosis of coronary arteries did not progress until the
      fifth decade of life (the frequency of fibrous plaques in the left anterior
      descending artery was even lower, p < 0.05), and the area of raised lesions
      became larger only in the sixth-seventh decades. During the latter 20-30 years,
      the area of raised atherosclerotic lesions of abdominal aortas also increased in
      men in Riga, Tallinn, Tartu, Yalta, and elder men in Malmo as well as in Kaunas
      and Malmo women, aged 40-59.

PMID- 12474708
TI  - [Prevalence of congenital heart defects in the newborn and infants: mortality in
      the City of Kaunas, 1995-1998].
AB  - This study presents the results of analysis of congenital heart malformations
      (CHM) prevalence, lethality and mortality of newborns with CHM in 1995-1998 in
      Kaunas city. According to official data, 131 CHM cases were registered in
      delivery hospitals using statistical forms 066. We conducted a validated registry
      in all children outpatient hospitals and in Neonatology division of Kaunas
      University of Medicine. We registered additional 53 CHM cases, which made up an
      increase by 28.8 percent. The prevalence of CHM increased from 7.5 to 10.6 per
      1000 livebirths. Mortality of infants, born with CHM was 2.36 per 1000
      livebirths, while lethality was 22.3 percent per year.

PMID- 12474709
TI  - [Albumin and its use].
AB  - Although albumin (A) may be considered an ideal natural colloid, the clinical
      importance efficacy of A administration in the treatment of critical illness have
      changed considerably of late years. This article reviews data about the use of A
      at present. It is obvious that, routine administration of A on the basis of
      reduced plasma albumin levels cannot be recommended. There are at the present
      time no clear indications for A administration. Albumin can be used only as a
      second-choice infusion solution when other products are not indicated, are
      contraindicated or have been used up their maximum dose.

PMID- 12474710
TI  - [Neuroleptic malignant syndrome].
AB  - The neuroleptic malignant syndrome (NMS) is a rare but potentially lethal form of
      neuroleptic drug-induced hyperthermia, altered level of consciousness,
      extrapyramidal effects, autonomic instability and muscle rigidity. The present
      review describes pathophysiology, frequency, course, outcome, mortality and
      management of NMS in prehospital care and emergency department care. Review
      discusses clinical features, diagnosis differentiation of this hyperpyretic
      rigidity syndrome from other disorders and prevention of this serious iatrogenic
      condition as life-threatening disorder.

PMID- 12474711
TI  - [The value and adaptability of glomerular filtration rate and reserve test
      (review of the literature)].
AB  - In normal conditions only 75% of kidney function capability are in use. Resting
      part of kidney function is called renal functional reserve. It is a very
      important indicator for prediction of renal insufficiency in chronic renal
      diseases, morphological changes or reduced mass of kidney parenchyma. More common
      test to estimate renal functional reserve is a method of measurement of
      glomerular filtration rate (clearance) before and after provocation of renal
      filtration by acute peroral protein load. The value and the possibilities to put
      in practice this test as well the factors influencing the results of glomerular
      filtration rate were estimated in this review.

PMID- 12474713
TI  - [Impact of the effectiveness of myocardial reperfusion after thrombolytic and
      spontaneous recanalization of infarct related artery on myocardial recovery in
      the future].
AB  - OBJECTIVE: To assess the efficiency of myocardial reperfusion after thrombolytic
      and spontaneous recanalization of infarct related artery (IRA) by the serial 12
      lead ECG data and its impact on subsequent myocardial recovery. MATERIAL AND
      METHODS: We examined 25 patients with a first Q wave myocardial infarction at
      hospital and after 1 and 3 years from discharge (13 treated with intravenous
      thrombolysis, 12 treated conservatively). Four patients treated using
      thrombolysis and 3 patients treated conservatively were excluded from the
      analysis due to reocclusion or another myocardial infarction and coronary bypass
      surgery. The efficiency of myocardial reperfusion was assessed by our original
      method, based on the intensity of changes in ECG stages. The myocardial recovery
      was analyzed by quantitative changes in clinical, radiographic, echocardiographic
      and ECG (the Selvester-Wagner QRS score) data. RESULTS: Clinical and radiographic
      signs of heart failure decreased in cases of sufficient myocardial reperfusion
      after thrombolytic and spontaneous recanalization, but increased--in cases of
      insufficient myocardial reperfusion. Echocardiographic dyssynergic score
      decreased after 3 years from discharge (79, 67 after 1 and 3 yrs/at discharge
      (%), respectively, p < 0.00005) in cases of thrombolysis with sufficient
      myocardial reperfusion but the tendency for increasing (113, 183 after 1 and 3
      yrs/at discharge (%), respectively, p = 0.07) was shown in cases of insufficient
      myocardial reperfusion; although, the QRS score decreased in both subgroups of
      thrombolysis (89, 36 after 1 and 3 yrs/at discharge (%), respectively, p < 0.01,-
      with sufficient myocardial reperfusion; 73, 62 after 1 and 3 yrs/at discharge
      (%), respectively, p < 0.005,--with insufficient myocardial reperfusion).
      CONCLUSIONS: The QRS score normalization after myocardial infarction predicts
      myocardial functional recovery only in patients with sufficient myocardial
      reperfusion. Thrombolysis gives positive impact on subsequent myocardial
      functional recovery only in cases of sufficient myocardial reperfusion;
      spontaneous recanalization of IRA may give positive impact on myocardial
      functional recovery in cases of sufficient myocardial reperfusion. Our method of
      serial ECG interpretation provides the possibility to detect insufficient
      myocardial reperfusion after thrombolytic and spontaneous recanalization and then
      the additional mechanical methods of recanalization should be applied.

PMID- 12474712
TI  - [Results of the surgical treatment of periampullary cancer at the Kaunas Medical
      University Hospital].
AB  - During 1998-2000 (till October 1) 55 radical operations on the pancreas because
      of periampullary carcinoma were performed in Kaunas Medical University Hospital.
      There were 50 pancreatoduodenal resections (PDR) and 5 total pancreatectomies
      (PE). Age of patients ranged from 28 to 78 years, mean age was 61.9 years. Thirty
      six percent (36.4%) of patients were older than 70 years. Carcinoma of the head
      of the pancreas was diagnosed in 48 (87.3%) cases, common bile duct carcinoma in
      3 (5.5%) cases, carcinoma of p. Vateri in 2 (3.6%) cases and carcinoma of
      duodenum in 2 (3.6%) cases. Twenty five (45.5%) patients were suffering from
      first or second stage cancer, 28 (50.9%)--from third stage. Stage IV was
      diagnosed for 2 (3.6%) patients, due to invasion to the portal, mesenteric or
      splenic veins. For those patients resection of portal, mesenteric or splenic
      veins was performed. Malignant invasion to the resection margin of the pancreas
      was found in 4 (7.3%) patients. Regional lymphadenectomies (D1) were performed in
      23 cases and radical lymphadenectomies (D2) in 32 cases. There was no
      statistically significant difference in overall morbidity after the operations
      between those two groups. Hospital mortality in PDR group was 8% (4 pts.) and 20%
      (1pt.) in PE group. Actuarial survival was estimated based on data of February 1,
      2001. Survival function was compared between patients who underwent radical (n =
      50) and palliative (n = 43) operations. Median survival time after radical
      operations was 382 days, whereas after palliative operations--128 days. As
      postoperative morbidity is not influenced by the extent of lymphadenectomy, D2
      dissection should be performed. The pancreatic resection during PDR should be
      performed through macroscopically normal pancreatic tissue. PE is recommended if
      the macroscopical invasion to distal part of the pancreas is present.

PMID- 12474714
TI  - [Morphogenesis of thoracic aorta aneurysms: investigation of matrix
      metalloproteinases and their tissue inhibitors].
AB  - The matrix metalloproteinases are a large group of proteases with a central role
      of the degradation of all types of extracellular matrix. The present study
      investigated expression of matrix metalloproteinases (MMP-1, -2, -9) and their
      inhibitors (TIMP-1, -2) in chronic Aneurysm of the Thoracic Aorta (ATA) and Post
      Stenotic Dilatation of the ascending aorta due to valvular aortic stenosis (PSD).
      Fragments of the ascending aorta that had been taken from the patients during
      coronary by-pass surgery were used as controls. Immunohistochemical investigation
      showed that medical SMC in the samples taken from aortas with ATA and PDS
      expressed a stronger immunoreactivity for MMP-1, -2, -9 and TIMP-1, -2 as
      compared to controls. It can be suggested that during formation of ATA and PSD,
      production of MMPs and TIMPS by medial smooth muscle cells is of great
      importance.

PMID- 12474715
TI  - [Dependence of peripheral blood lymphocyte subpopulations on causative
      microorganisms able to produce superantigens].
AB  - A retrospective study of 176 immunologically tested patients admitted to Kaunas
      Medical University Hospital during 1997-2000 was performed. All patients had
      positive bacteriological culture test result confirming an infectious etiology of
      the disease. Our results showed that majority of immunological parameters were
      dependent on such non-specific factors as intensity and localization of the
      inflammatory process, an overall functional status of the patient, and the number
      of the disease exacerbation episodes during the last year before admission. In
      contrast to this, the absolute number of CD4 lymphocytes, the relative amount of
      HLA-DR positive lymphocytes and the index of neutrophil latex phagocytosis were
      exceptionally dependent on the species of the causative microorganism, in
      particular on superantigen producing cocci. In this case, the HLA-DR positive
      lymphocyte amount and the neutrophil phagocytosis index were significantly
      higher. In addition, the CD4/CD8 lymphocyte ratio (the immunoregulatory index)
      was significantly lower in this group. As much as those findings are concordant
      with the signs of excessive immune activation, we conclude that they reflect a
      possible superantigenic action of the disease causing bacteria. Therefore, a need
      for immunomodulating therapy during the infections caused by species able to
      produce superantigens is confirmed.

PMID- 12474716
TI  - [Atrioventricular conduction and permanent atrial pacing].
AB  - The goal of the report was to evaluate changes of atrioventricular conduction in
      patients with sick sinus syndrome treated with permanent atrial pacing. METHODS
      AND RESULTS: 150 patients (82 women and 68 men) with implanted permanent atrial
      AAI and AAIR pacemakers were followed for 5.9 +/- 3.6 years (maximum 15 yrs).
      After mean 5.9 years of follow up incidence of III degrees AVB was 0.7%, II
      degrees AVB--2.7%, and I degree AVB--2.74%; twenty six of 150 patients showed
      nonphysiological increase of the SQ interval at pacing rate 120 imp/min.
      CONCLUSIONS: 1. Atrioventricular conduction in elderly patients with sick sinus
      syndrome is decreasing. 2. Continuous observation of the atrioventricular
      conduction is obligatory in patients with single chamber AAI pacing. 3. Upper
      heart rate limit in patients with single chamber atrial pacing must be programmed
      taking into account changes of atrioventricular conduction.

PMID- 12474717
TI  - [Post-traumatic infraorbital nerve neuropathy].
AB  - The authors have investigated functional state of infraorbital nerve of 479
      patients with zygomatic fractures. The degree of nerve damage was evaluated
      according to changes of pain threshold during damaged nerve stimulation. It was
      estimated that in 64.3% of zygomatic fractures the infraorbital nerve was
      affected. The nerve damage degree could be mild, moderate and severe. In 43.18%
      of moderate and severe nerve damage cases the neuropathy develops. The symptoms,
      signs and treatment of neuropathy have been described. The neuropathy with
      clinical symptoms as permanent soreness and paresthesias (itch, "running ant",
      fibrillations of cheek tissues etc.) in the infraorbital nerve innervation zone
      occur to 43.18% of the patients after moderate and severe damage of the nerve.
      The treatment of neuropathy was analysed. In cases of moderate and severe nerve
      damages, authors recommend to perform decompression of the nerve, because if not
      applied, the function of nerve does not recover.

PMID- 12474718
TI  - [Autologous osteochondral transplantation (mosaicplasty) in the treatment of
      femoral condyle defects].
AB  - Adult articular cartilage lacks the capacity for self-repair. Cartilage defects
      change articular biomechanics and lead to eventual osteoarthritis and joint
      destruction. During the past decade, several competing techniques have evolved to
      stimulate articular cartilage repair. Micro-fracture can successfully treat small
      lesions of non weigh-bearing surfaces. When the damaged area is more extensive,
      osteochondral cylinder grafting (mosaicplasty) should be considered. Our
      experience includes 5 cases with follow-up of 6 months to 1 year. Between 1999
      and 2000 an osteochondral transplantation (mosaicplasty) was performed in 5
      patients. The defect-size in these 5 patients (2 males and 3 females) ranged
      between 12 mm and 23 mm in diameter and had an average-size of 15 mm. In the all
      of cases an average of 7.2 grafts was needed. Preoperative complaints of pain,
      crepitation and locking disappear. The short outcome in the modified HSS-score
      has shown excellent and good results. The average score value during follow-up
      was 93.8 (range 92-96). This outcome forms prerequisite for likewise middle-term
      results. Mosaicplasty can be recommended for the treatment of chondral and
      osteochondral defects in the weight-bearing area of the knee as a safe procedure
      for transplantation of hyaline cartilage.

PMID- 12474719
TI  - [Simultaneous myocardial revascularization and abdominal aortic aneurysm repair
      (report of a fatal case)].
AB  - Patients with coronary disease associated with abdominal aortic aneurysm or
      aortoiliac occlusive disease often raise problems of operative strategy. In
      particular, the order in which these lesions should be treated is a frequent
      source of controversy. Our approach for the past two years has been a combined
      myocardial revascularization with abdominal aortic reconstruction in patients
      with both lesions. From 1999 through 2001 seven patients underwent combined
      abdominal aortic reconstruction with coronary artery bypass grafting. We report
      here the fatal case of combined coronary artery bypass grafting and abdominal
      aortic aneurysm repair. Partial heparinization and operation without
      extracorporeal circulation caused acute thrombosis of abdominal aortic aneurysm
      and femoral arteries. Our first experience advocates using total heparinisation
      and cardiopulmonary bypass for combined cardiac-aortic procedures.

PMID- 12474720
TI  - [Preparation, analysis and anti-anemic action of peroral powders with ferrous
      oxalate. Ferosol-1].
AB  - Investigation of new stable iron (II) compounds is still an actual problem of
      today. Therefore we synthesized ferrous oxalate and prepared a stable antianaemic
      powder Ferosol-1 including copper, zinc and cobalt. We used colour tests,
      precipitation reactions and paper chromatography for identification of components
      of this powder. Quantitative analysis of iron and other elements was performed
      using atomic absorption spectroscopy. We used Lichfield and Wilkinson method
      modificated by Roth to detect acute Ferosol-1 toxicity. To estimate a local
      action of this powder we used guinea pigs which were grouped into control and
      trial ones. We determined bioavailability of Ferosol-1 by giving it to rabbits
      with experimental posthemorrhagic anemia. Iron resorption was tested on 20-25
      days old piglets. We also tried this drug on newborn piglets while atching their
      weight gain and calculation daily weight gain. This data was used to estimate
      indirect impact of Ferosol-1 on metabolism of piglets. According to our data
      Ferosol-1 is of low toxicity (LD50 = 2.25 g/kg), it does not irritate mucosa of
      duodenum and ventriculus and could be used orally. Iron from Ferosol-1 was found
      to be well assimilated and to take place in hemopoetic processes of rabbit. After
      administration of Ferosol-1 to piglets iron concentration in their serum
      increased from 35.03 +/- 0.66 to 54.88 +/- 6.63 mumol/l, hemoglobin concentration
      increased to 96.4 +/- 2.5 g/l, erythrocyte number increased to 4.4 +/- 0.14 x
      10(12)/l. The same data of control piglets were respectively 83.7 +/- 3.1 g/l and
      3.52 +/- 0.3 x 10(12)/l. According to our results Ferosol-1 is an effective drug
      for prevention of iron-deficiency anemia and causes slight weight gain of
      piglets.

PMID- 12474721
TI  - [Preparation, analysis and anti-anemic action of peroral powders with ferrous
      oxalate. Ferosol. 2].
AB  - Experiments with piglets showed good assimilation and metabolism of iron (II) in
      antianaemic powder Ferosol-1. In order to improve this drug, manganese, calcium
      (Ferosol-2, 1 composition) and ascorbic acid (Ferosol-2, 2 composition) were
      added. Manganese and ascorbic acid stimulate erythropoiesis and being strong
      reductants stabilize iron (II) on storage and in gastrointestinal tract.
      Components of Ferosol-2 were identified using colour, precipitation- and
      extraction tests, as well as paper chromatography and absorption spectroscopy.
      Quantitative analysis of microelements and ascorbic acid was performed using
      absorption spectroscopy, extraction photometry and iodometric titration methods.
      Ferosol-2 proved to be more stable than Ferosol-1. Lichfield and Wilkinson method
      modificated by Roth was used for detection of acute toxicity of Ferosol-2. A
      local action was estimated on quine pigs. Iron resorption was on 20 days old
      piglets. Antianaemic effectiveness of Ferosol-2 was evaluated on newborn piglets
      watching their weight. Experiments with white mice showed low toxicity of Ferosol
      2 (LD50 = 4.3 g/kg, for 1 composition and 4.6 g/kg for 2 composition). It does
      not irritate mucosa of duodenum and ventriculus. Iron in Ferosol-2 was found to
      be well assimilated in gastrointestinal tract of piglets, easily gets into blood
      and joins albumen of plasma. After administration of Ferosol-2 to piglets
      increased iron concentration in blood serum was observed for 3 hours (1
      composition) and 6 hours (2 composition). Experimental data showed increased
      resorption of iron in Ferosol-2, 2 composition due to ascorbic acid. Components
      of Ferosol-2 are well assimilated and join erythropoetic processes. Ferosol-2
      leads to quicker weight gain as well as significantly higher amount of hemoglobin
      and red blood cells in piglets.

PMID- 12474723
TI  - [Myocardial infarct morbidity and mortality trends in the Kaunas population 25-64
      years of age during 1983-1998].
AB  - The aim of the present study was to evaluate the trends in attack rate,
      incidence, recurrence and 28-day case-fatality of myocardial infarction (MI) in
      Kaunas population aged 25-64 during 1983-1998, according to ischemic heart
      disease register data. The source of data--Kaunas population-based ischemic heart
      disease register. Trends were analyzed using method of linear regression on
      logarithms of the age-standardized annual morbidity and lethality rates. The
      regression coefficient multiplied by 100 is given as an average yearly change.
      The age-standardized rates were calculated by the direct method and the world
      standard population was used as the standard. During the study period attack
      rates of MI remained stable in men. Among Kaunas men aged 25-64 years incidence
      rates of MI decreased statistically significantly, while MI recurrence rates had
      a tendency to increase during the study period. Among Kaunas women, both attack
      rates of MI and recurrence rates of MI were increasing statistically
      significantly, although MI incidence rates remained stable during 1983-1998. The
      MI 28-day case-fatality rates tended to decrease among both men and women.
      Further efforts of the primary prevention of the ischemic heart disease are
      required in order to achieve stable decreasing trends in both attack rate and
      incidence of MI in the middle-aged Kaunas population.

PMID- 12474722
TI  - [Trends in the prevalence of risk factors of noncommunicable diseases during 1987
      1999].
AB  - The trends in the prevalence of hypertension, hypercholesterolemia, overweight
      and smoking among Lithuanian rural population were assessed from 1987 to 1999.
      Three independent surveys in 1987, 1993 and 1999 were carried out in five rural
      regions of Lithuania in random samples of men and women aged 25-64 involving
      2695, 1550 and 1838 persons respectively. The risk factors were defined according
      to the WHO criteria. During the 13 years the prevalence of hypercholesterolemia
      and overweight has significantly decreased among men (by 23.2% and 4.9%
      respectively) as well as among women (by 19.9% and 10.7% respectively). The
      prevalence of hypertension among women has decreased by 9.1%, with no significant
      changes among men. The prevalence of smoking has increased by 8.9% among women
      and has not changed among men. Age was positively correlated with the prevalence
      of all risk factors, except smoking. Younger persons smoked more often than
      elderly did. Prevalence of risk factors varied by educational level. Hypertension
      and overweight have been more prevalent among women with incomplete secondary
      education, than among those with university education. The prevalence of
      overweight and hypercholesterolaemia has been higher among highly educated men
      compared to low educated. The inverse relationship between smoking and education
      has been observed in men. In conclusion, the decreasing trends in the prevalence
      of some risk factors have been estimated in Lithuania within last decade.
      Sociodemographic differences in the prevalence of risk factors should be taken
      into account while developing health promotion and diseases prevention
      programmes.

PMID- 12474724
TI  - [Accessibility of health care: evaluation of the performance of the city of
      Vilnius Seskines outpatient clinic].
AB  - INTRODUCTION: The purpose of this study was to determine the reasons of the
      queues, which patients meet in clinic and to determine the spent time of patients
      in different places of clinic. We wanted to figure out the opinion of patients
      about the work of the personnel, to find the ways of reducing the queues in the
      clinic. METHODS: Study was done in November 2000-January 2001. Total or 1000
      questionnaires were given to every third visitor over the age of 16. After return
      of 67.8% of questionnaires, 222 new questionnaires were sent to people, who
      didn't answer the first time. The overall response rate was 77.8%; 40
      questionnaires were inapplicable for study, therefore a sample of 738 respondents
      was studied. Statistic data analysis was made using SPSS for Windows. The
      differences between respective indexes were assumed as statistically significant,
      then the mistake probability was p < or = 0.05. RESULTS: The aim of our study--to
      determine the time spent in different places of clinic, and to figure out
      patient's opinion about work of the personnel. In registry office every patient
      spent on average 16 minutes. Every patient spends on average 30 minutes waiting
      to doctor. Consultations via telephone different groups of respondents evaluated
      differently: the older the patient, the worse his attitude towards consultation.
      Besides the fact, that 40% of elderly respondents are benevolent to consultations
      by the telephone, they assume, that they wouldn't use such kind of service.
      Waiting time for procedures, is on average 17 minutes. In all cases we can say,
      that the more patients face the queues, the more they think, that those queues
      should not exist. But the majority of respondents meet the queues very rarely,
      and most of them think, that the queues are imperative, or at least short waiting
      is inevitable.

PMID- 12474725
TI  - [The 150th anniversary of the birth of Dr. Jonas Basanavicius: a great
      Humanitarian and a great Physician, faithful servant of Aesculapius and
      Lithuania].
AB  - On the occasion of the 150th birth anniversary of Doctor Jonas Basanavicius (1851
      1927), the most significant figure of the national renaissance of Lithuanians at
      the end of 19th century, the focus is laid once more on the academic heritage of
      this distinguished personality. Jonas Basanavicius interests embraced a wide
      spectrum of academic fields, and his doctor's achievements were relevant for
      people in medical profession. Dr. Jonas Basanavicius is well known for his
      contribution to medicine. He is considered the founder of sanitation science in
      Bulgaria, the promoter of public health, the originator of Lithuanian medical
      terminology, the author of scientific and educational works "Materials on
      Sanitation Ethnography in Bulgaria. Lomskijat District (1880-1889)" ("Materiali
      za sanitarnata etnografija na Bulgarija. Lomskijat okrug (1880-1889)") published
      in 1891, "Materials for Our National Medicine" ("Medega musu tautiskai
      vaistininkystai") published in 1898, and articles.

PMID- 12474726
TI  - [Diagnosis and treatment of rheumatoid arthritis].
AB  - The paper describes the typical clinical features of rheumatoid arthritis and
      principles of its treatment. It includes an overview of the universally accepted
      diagnostic criteria and discusses the diagnostic value of laboratory and
      instrumental investigations. The significance of correct diagnosis in an early
      stage of the disease is emphasized with regard to the difficulties related to
      differential diagnosis. Appropriate evaluation of the inflammatory activity of
      rheumatoid arthritis and of the functional state of the patient is discussed.
      Contemporary principles of complex and individual treatment of rheumatoid
      arthritis, depending on the course of disease are presented, placing special
      emphasis on the importance of disease--modifying treatment. Possible side effects
      of NSAIDs and glucocorticosteroids and methods of their prevention are discussed,
      as well as indications for new biological medications.

PMID- 12474727
TI  - [Staging of rectal cancer by endorectal ultrasound].
AB  - The aim of the present study was to compare the accuracy of transrectal
      ultrasound in staging rectal carcinoma. 30 consecutive patients with rectal
      carcinoma proven pathomorphological were staged transrectal ultrasound and
      computed tomography imaging, and then underwent radical surgery. The data of
      preoperative staging were compared with pathomorphological findings of the
      specimens according to Surgical excised the TNM classification system.
      Transrectal ultrasound showed better results than computed tomography in
      evaluating N (sensitivity 45.2%, specificity 45.2%), because the parameters of
      sensitivity and specificity were high enough (76.6%). Computed tomography has
      limited usefulness in staging rectal tumors because the layers of the rectal wall
      are not resolved by computed tomography. In T staging transrectal ultrasound
      sensitivity and specificity ranges 87.54% and 94.82% respectively and that
      enables to perform adequate surgical procedure.

PMID- 12474728
TI  - [Usefulness of ultrasonography in the diagnosis of rotator cuff tears].
AB  - The purpose of this study was to determine the diagnostic performance of high
      resolution ultrasonography compared with arthroscopy examination for the
      detection and characterization of rotator cuff tears. 31 patients with shoulder
      pain who had undergone preoperative ultrasonography and subsequent arthroscopy
      were identified. RESULTS: Ultrasonography for full-thickness rotator cuff tears
      has sensitivity of 80%, specificity of 100%, PPV of 100%, NPV of 82%.
      Ultrasonography for partial-thickness rotator cuff tears has sensitivity of
      78.5%, specificity of 82%, PPV of 85%, NPV of 75%. CONCLUSION: Ultrasonography
      was highly accurate for detecting full-thickness rotator cuff tears; it was less
      sensitive and specific for detecting partial-thickness rotator cuff tears.
      Because of its low cost ultrasonography could be the first diagnostic tool for
      the rotator cuff tears.

PMID- 12474729
TI  - [Hemorrhage within pituitary adenomas: possibilities of computed tomography and
      magnetic resonance imaging methods].
AB  - The purpose of this study was to determine the character of MR findings in the
      cases of intratumoral hemorrhage within pituitary adenomas, and to correlate them
      with surgery and CT. In our study we included 86 patients with pituitary
      adenomas, who underwent surgery at the Clinic of Neurosurgery at Kaunas Medical
      University Hospital. In 23% (n = 20) of cases with MR evidence of intratumoral
      hemorrhage the variety of focal MR signal changes was observed in dependence of
      hemoglobin degradation process and accumulation of blood products. CT
      demonstrated only 10% (n = 2) of cases with acute intratumoral hemorrhage. The
      nonspecific hypodensities within pituitary adenomas were observed in 35% (n = 7)
      cases. Fifty-five percent (n = 11) of cases demonstrated no focal changes. All
      surgically discovered hemorrhages within pituitary adenomas were clinically
      asymptomatic.

PMID- 12474730
TI  - [Brain computed tomography angiography in case of subarachnoid hemorrhage].
AB  - Objective was to evaluate sensitivity, specificity and diagnostic accuracy of
      brain computed tomography (CTA) in patients with subarachnoid hemorrhage (SAH).
      MATERIALS: In the period of January-September, 2001 CTA was performed in 46
      patients (with SAH on initial CT) of Clinic of Neurosurgery and Clinic of
      Neurology clinics, Kaunas University Hospital. METHODS: CTA was performed at
      different time from the onset (from several hours to one year). Each patient
      underwent care bolus procedure (slice thickness 5 mm, rotation time 1.0 s,
      voltage 140 kV, delay time 11 s, scan plane suspected aneurysm or cavernous
      sinus, number of scans 15 (each 2 s), volume 20 ml, flow rate 2.8 ml/s) and CTA
      (slice thickness 1 mm, rotation 2.0, rotation time 1.0 s, voltage 120 kV,
      increment 1.0, delay time individual, volume 80 ml, flow rate 2.8 ml/s). Axial
      and 3D (maximum intensity projection (MIP), volume rendering technique (VRT) and
      surface shaded display (SSD) images were evaluated. Before or after CTA
      procedure, digital subarachnoid angiography (DSA) was performed in 44 patients.
      RESULTS: Twenty-three aneurysms of various localization and size were found.
      There were no findings in 21 patients. One false negative and one false positive
      result was present. Specificity and sensitivity was 95.8% (23/24), and diagnostic
      accuracy--95.6% (44/46). Two patients were operated according to CTA results. Two
      patients had repeat-DSA (according to CTA results), and the aneurysms were
      finally found. CONCLUSIONS: CTA is a quick, noninvasive method to be performed in
      outpatient and inpatient basis. It gives information about vessels and
      surrounding tissues. In some cases it can replace DSA. CTA must not be considered
      as replacement of DSA, instead, it should be considered as method providing more
      additional information.

PMID- 12474731
TI  - [Diagnosis of angiographically negative spontaneous subarachnoid hemorrhage].
AB  - Objective of the study was to review patients with angiographically negative
      spontaneous subarachnoid hemorrhage (SAH) and to compare with aneurysmal SAH, as
      well as to discuss, which patients need repeat-angiography and what imaging
      method should be used. MATERIALS AND METHODS: All patients, who were admitted to
      Department of Neuroangiosurgery of Kaunas University Hospital after spontaneous
      SAH in 1994-2000 were evaluated. Neurological status, complications, outcome,
      radiological findings were investigated and evaluated. RESULTS: Study showed that
      the main reason of spontaneous SAH is ruptured intracranial aneurysm. Rare causes
      of SAH are also possible; also ones of unknown etiology. It was found that
      patients with angiographically negative SAH were in better neurological status,
      had a small number of complications and better outcome. It was discussed, which
      patients need repeat-angiography and what method of imaging should be used.
      CONCLUSIONS: Angiographically negative SAH course is better than aneurysmal SAH;
      not all patients need angiography to be repeated. It is proposed to perform
      angiography in the group of patients with increased risk.

PMID- 12474732
TI  - [Scintigraphy of lymphomatous masses using 99mTc-MIBI].
AB  - Tc 99m sestamibi imaging is used in nuclear oncology, cardiology, but its role in
      detecting lymphomas has not been widely investigated. During 1998-2001 at the
      Department of Nuclear medicine, Kaunas University Hospital 68 patients with
      lymphomas (50 patients with Hodgkins disease (HD), 18 with non-Hodgkins (NHL))
      underwent Tc 99m MIBI whole-body imaging. Of the 47 lymphoma lesions showed
      abnormal MIBI uptake. The accuracy of MIBI scintigraphy in patients with Hodgkins
      disease was lower (78%) compared to that of patients with non-Hodgkins lymphomas
      (94%). However, this difference was not related to tumor type, but to lesion
      size. Tumor size was significantly (p = 0.01) higher in lesions NHL with
      increased MIBI uptake (3.9 +/- 2.5 cm) compared with those with no uptake (1.5 +/
      0.5 cm).

PMID- 12474733
TI  - [Role of computed tomography and ultrasonography in the diagnosis of renal
      lymphoma].
AB  - Renal lymphoma is most often seen in conjunction with multisystemic, disseminated
      lymphoma. Renal lymphoma may also be seen as primary disease. Computed tomography
      (CT) is the most sensitive, and comprehensive examination for evaluation of the
      kidneys in patients with suspected renal lymphoma. Helical CT in particular
      improves detection and characterization of lymphomatous renal involvement by
      optimizing contrast dynamics and data acquisition and is the current modality of
      choice for accurate staging of lymphoma. Typical CT patterns in renal lymphoma
      include single or multiple masses, invasion from contiguous retroperitoneal
      disease, perirenal disease, and diffuse renal infiltration. Atypical CT patterns
      may also be encountered and provide a diagnostic challenge. These include
      spontaneous hemorrhage, necrosis, heterogeneous attenuation and calcification.
      Solid renal masses including renal cell carcinoma and metastases are the most
      commonly encountered entities that mimic renal lymphoma at CT and require biopsy
      for definitive diagnosis. Helical CT is useful in the evaluation of patients with
      suspected renal lymphoma; and familiarity with the spectrum of findings in renal
      lymphoma is important for accurate diagnosis.

PMID- 12474734
TI  - [Radiographic diagnosis of gastrointestinal lymphoma].
AB  - The gastrointestinal tract is very infrequently involved by malignant lymphoma.
      Primary lymphoma accounts for 1-4% of all gastrointestinal tumors. The stomach is
      the most common site of primary non-Hodgkin lymphoma. Esophagus is least likely
      site of lymphoma of the gastrointestinal tract. Hodgkin disease is almost
      exclusively a nodal disease, and the involvement of gastrointestinal tract
      usually is the result of disseminated disease that began in nodal sites.
      Gastrointestinal lymphomas have a wide array of appearances, which can be
      explained by the nature of lymphocytes and the variety of ways in which their
      malignant counterparts can develop and spread. The radiographic appearance of
      gastrointestinal lymphoma varies. Frequently, an appearance is indistinguishable
      from a primary adenocarcinoma, from other primary mural masses, such as smooth
      muscle tumors. The radiograph double-contrast barium study remains the screening
      procedure. Computed tomography plays a pivotal role in management of the process
      of staging in patient with lymphoma. CT is comparable in its ability to detect
      retroperitoneal and pelvic lymph nodes. Also 99mTc-MIBI scintigraphy and 99mTc
      MIBI uptake within the lymphomatous tumors are helpful. During 1991-2000, 63
      patients with suspected lymphoma of gastrointestinal tract were examined in
      Clinic of Radiology of Kaunas University Hospital. Contrast-enhanced CT had shown
      79.3 percent involvement in mesenterial lymph nodes, X-ray double-barium study-
      14.2 percent in stomach, 3 percent in small intestine, 1.5 percent in colon.

PMID- 12474735
TI  - [Diagnosis of malignant lymphoma of the stomach].
AB  - There were 2385 (1236 female, 1149 male) cases of malignant lymphoma diagnosed in
      Kaunas region. Forty-five cases of histologically confirmed malignant gastric
      lymphoma diagnosed throughout 1981-2000 period are discussed. The disease was
      diagnosed to 37 patients only after surgery and to other eight by means of
      endoscopical investigation. Before establishing the correct diagnosis, gastric
      carcinoma was supposed to 27 patients, gastric ulcer to 12 patients, gastropathia
      erosiva to 6 patients. Histologically primary non-Hodgkin gastric lymphoma was
      diagnosed to 29 patients. That consisted 78.3 per cent of all surgically treated
      patients, 64.4 per cent of histologically confirmed cases and 1.2 per cent of all
      diagnosed malignant lymphomas. Gastric lymphogranulomatosis was diagnosed to 16
      patients. Primary lymphogranulomatosis three cases. After supposed stomach
      cancer, three patients were operated. All patients were examined by X-ray, CT and
      endoscopy. Biopsy was taken from pathological or not pathological mucous
      membrane.

PMID- 12474736
TI  - [Evaluation of lung perfusion scintigraphy without ventilation scintigraphy in
      the diagnosis of pulmonary thromboembolism].
AB  - The role of perfusion lung scintigraphy in the diagnosis of pulmonary embolism
      (PE) is reviewed. During the study 227 perfusion lung scans were obtained. The
      scans were grouped according to the PIOPED criteria into 5 groups: normal scans,
      very low, low, intermediate and high PE probability. The perfusion scans were
      analyzed according to the original PIOPED criteria, without ventilation scans.
      Evidence is provided that a normal perfusion scan excludes pulmonary embolism,
      and that a high probability lung scan, defined as a segmental perfusion defect
      with locally normal chest X-ray or findings in X-ray are smaller, sufficiently
      confirms the presence of pulmonary embolism in the majority of these patients
      (92.2%).

PMID- 12474737
TI  - [Radiographic methods in the diagnosis of tuberculous spondylitis].
AB  - During one year period (from May 2000 to June 2001) 136 radiographic examinations
      were performed in Kulautuva tuberculosis hospital due to suspision of skeletal
      tuberculosis. Tuberculous spondilitis being most frequent presentation of
      skeletal tuberculosis, showed radiographic signs in 31 cases (22.8%). The role of
      conventional X-rays and computed tomography diagnosis of tuberculous spondilitis
      is reviewed. Early changes on plain films are non-specific making early diagnosis
      of spine tuberculosis a challenging task. In such cases spinal computed
      tomography may be helpful. Must frequently pathologic changes include high
      spectrum varying from osteoporosis to destruction of vertebrae and two or three
      vertebraes and intervertebrae disks are always involved.

PMID- 12474738
TI  - [Gammadynamic treatment in advanced malignant tumors].
AB  - Since 1989 the total of 97 patients (173 tumours) have got gammadynamic treatment
      in Lithuanian oncology center. The treatment modality, when the sensitizer
      delivered to malignant tissue was activated by low dose (6-9 Gy) gammaradiation,
      which caused death of malignant tissues, was given the name of Gammadynamic
      treatment (GDT). Providing GDT Hematoporphyrin was injected i/v for patients and
      following 24, 48 and 72 hours after the injection tumours were irradiated with
      gamma rays 2-3 Gy at a time from the radioactive Co 60. As the immediate results
      of such treatment, 40 tumours completely disappeared; significant necrosis of 37
      tumours and partial necrosis of 42 tumours was noticed.

PMID- 12474739
TI  - [Changes in bone mineral density in rheumatoid arthritis].
AB  - Rheumatoid arthritis (RA) is one of the causes of secondary osteoporosis. One
      hundred eighty eight patients with RA (27 males and 161 females) were examined;
      the historical, clinical data and bone mineral mass of the spine and of the hip
      were evaluated. Osteoporosis was found more frequently in the spine than in the
      hip (27.7% and 17.9% respectively, p = 0.04). Bone mineral density (BMD) in the
      spine was less in women than in men (p = 0.04). The number of swollen joints, the
      mean of erythrocyte sedimentation rate (ESR) and rheumatoid factor (as indicators
      of inflammation) are correlated significantly with BMD of the hip. The age,
      hypogonadism and RA specific factors such as the duration and stage of the
      disease, and the long use of glucocorticosteroids were associated with
      osteoporosis. The relation between osteoporosis and history of a prior fracture
      in patients or in closest relatives, low weight, smoking, and RA specific factor
      such as the mean daily dose of glucocorticosteroids was not significant.

PMID- 12474740
TI  - [Comparison of electrocardiographic parameters during pneumoperitoneum in
      patients without cardiovascular diseases and in patients with ischemic heart
      disease].
AB  - Pneumoperitoneum induces significant pathophysiological changes. Changes in
      performance of cardiovascular system can be severe in patients with compromised
      cardiac function. Groups of patients to whom these changes may be deleterious are
      yet to be identified. Aim of the study was to elucidate the influence of
      pneumoperitoneum on the electrocardiographic recording. PATIENTS AND METHODS: 35
      cardiovascular healthy (ASA I-II) patients (group 1) and 34 patients with
      underlying moderate ischemic heart disease (ASA II-IV, Goldman's cardiac risk
      class II-III) (group 2), scheduled for elective laparoscopic cholecystectomy,
      were included in the study. Premedication included sedatives for all patients and
      the group 2 received their usual cardiovascular treatment one hour before
      operation. A standardized protocol of monitoring and anesthesia was followed in
      the operating room. 12 lead electrocardiograms (ECG) were obtained before and
      after induction of anesthesia, every 10 minutes during pneumoperitoneum, after
      the peritoneal desufflation and after extubation. The ECGs were recorded and
      analysed by the means of computerized system for ECG record and analysis "Kaunas"
      (UAB "Kardiosignalas", Kaunas, Lithuania). The analysis was performed
      postoperatively. RESULTS: During pneumoperitoneum a deviation of cardiac
      electrical axis to the left was observed. There were no marked changes in
      duration of P wave, P-Q interval, and QRS complex. Following abdominal
      insufflation a tendency to flattening of T wave was observed returning to the
      initial position after desufflation. No significant dislocation of ST segment was
      recorded. CONCLUSIONS: The pneumoperitoneum induced changes of cardiac electrical
      axis can affect the interpretation of ECG seen on a cardiac monitor during
      anesthesia. Pneumoperitoneum does not pose patients with moderate ischemic heart
      disease at additional risk of developing myocardial ischemia.

PMID- 12474741
TI  - [The possibility of the investigation of portal vein thrombosis by means of
      ultrasonography].
AB  - Doppler-based sonography investigation of liver blood circulation plays major
      role in the modern diagnosis of portal hypertension that is frequently caused by
      portal vein thrombosis. Eight patients with portal vein thrombosis have been
      investigated. During the sonographic investigation we evaluated the size of
      liver, focal changes in liver, the diameters of the portal vein and its both
      branches, of the spleen vein, of the superior mesenteric vein, the direction and
      the characteristics of the blood flow, portaportic and portasystemic collaterals,
      and the size of spleen. The thrombosis of the trunk and both branches of the
      portal vein was detected in 4 patients, out of which there was one case of
      additional thrombosis of the spleen and the superior mesenteric veins, while in
      another case there was partial thrombosis of the spleen vein. A separate thrombus
      of the portal vein trunk was noticed in 1 patient. The thrombosis of the portal
      vein trunk and the right branch was diagnosed in 1 case. There were 2 cases of
      thrombosis of only left branch of the portal vein. The cause of the portal vein
      thrombosis remained undetected in 6 cases. The thrombosis of the portal vein
      developed as a consequence of pancreatitis in one patient, the cause of another
      case was hepatocellular carcinoma. In comparison to CT, sonography is able to
      determine additionally the direction of the blood flow and to record a variety of
      different sections in detecting the above-mentioned pathology. Doppler-based
      sonography investigation of liver blood circulation, especially the color-coded,
      is non-invasive, it can be carried out quickly and does not need expensive
      contrast medium.

PMID- 12474742
TI  - [Statistical study of the wavelet-based lossy medical image compression
      technique].
AB  - Medical digital images have informational redundancy. Both the amount of memory
      for image storage and their transmission time could be reduced if image
      compression techniques are applied. The techniques are divided into two groups:
      lossless (compression ratio does not exceed 3 times) and lossy ones. Compression
      ratio of lossy techniques depends on visibility of distortions. It is a variable
      parameter and it can exceed 20 times. A compression study was performed to
      evaluate the compression schemes, which were based on the wavelet transform. The
      goal was to develop a set of recommendations for an acceptable compression ratio
      for different medical image modalities: ultrasound cardiac images and X-ray
      angiographic images. The acceptable image quality after compression was evaluated
      by physicians. Statistical analysis of the evaluation results was used to form a
      set of recommendations.

PMID- 12474743
TI  - [Prevalence of health affecting behavior factors among the population of Northern
      Lithuania].
AB  - The paper presents data on the prevalence of health affecting behavior factors-
      tobacco smoking and alcohol consumption in the region of Northern Lithuania (the
      districts of Birzai, Pasvalys and Pakruojis). In 1997-98, 1580 residents of this
      region were surveyed using the questionnaire prepared according to the
      recommendations of the WHO experts. Analysis of the study--patterns in tobacco
      smoking and consumption of alcoholic beverages--showed that 51.3% of males and
      12.5% of females smoked every day. More male smokers were found in the
      countryside, while more female smokers--in towns. Most smokers were found in 30
      39 year--old group (14.6% and 6.1%, respectively). Single women smoked more often
      than married ones or widows (p < 0.05). Irrespective of the marital status, the
      greatest proportion was of those who consumed alcohol at least once a month.
      There were 3.6 times more married women who never consumed alcoholic beverages
      compared to married men (p < 0.05). The prevalence rate of risk factors depended
      on education: men with higher education smoked more seldom than those with lower
      education; there were no men consuming alcohol every day among those with higher
      education; women with higher education smoked more often than those with lower
      education; with education getting higher, the number of women who never consumed
      alcohol was decreasing. In all age groups the highest proportion was of those who
      consumed alcohol once a month; somewhat lower was the proportion of those who
      consumed alcohol once a week.

PMID- 12474744
TI  - [Cervical cancer: recent trends of incidence and mortality in Lithuania].
AB  - Time trends of the cervical cancer in Lithuanian population were analysed.
      Changes in age standardised cancer incidence rates (World standard) in Lithuania
      were analysed between 1978 and 1999. Incidence rates were calculated by periods-
      1978-1982, 1983-1987, 1988-1992, 1993-1997 and 1998-1999. Incidence was analysed
      among 15-34, 35-49, 50-64, 65-74 and 75+ age groups. From 1978-1982 cervical
      cancer incidence decreased from 15.4 to 12.9 per 100,000 in 1993-1997. Increase
      was observed from 1993-1997 up to 17.4 per 100,000 in 1998-1999. In 1998-1999
      only 49.2 of all cervical cancer cases were diagnosed at stages I and II. During
      1978-1992 cervical cancer mortality rates were not decreasing despite the
      reduction of incidence (6.8, 7.0 and 6.8 cases per 100,000 in 1978-1982, 1983
      1987 and 1988-1992 respectively). Starting from 1993 the increasing number of new
      incidence cases is being registered, but mortality rates are not subjected to
      changes (7.6 and 7.7 cases per 100,000 in 1993-1997 and 1998-1999 metais
      respectively). The higher increasing rates in incidence and mortality were
      observed among women below 50 years. The causes of increase of cervical cancer
      incidence are demanding detailed studies. The incidence and mortality of cervical
      cancer can be reduced by the implementation of national-wide screening program
      for cervical cancer.

PMID- 12474745
TI  - [Academician Vladas Lasas -- distinguished Lithuanian scientist, organizer and
      educator].
AB  - The material of this publication is dedicated to the memory of Professor Vladas
      Lasas, honored scientist of Lithuania, member of Lithuanian Academy of Sciences
      and corresponding member of the Academy of Medicine of the USSR. V. Lasas was
      born on January 13th, 1892, on a farmstead in Rokiskis region, Lithuania. He died
      on January 2nd, 1966 in Kaunas. V. Lasas studied medicine at the Faculty of
      Medicine of Tartu (Dorpat) University and graduated from it in 1918. In 1921 he
      was invited to deliver lectures on physiology at the newly organized Higher
      Courses in Kaunas. During 1920-1924 he attended higher educational establishments
      of Prague, Berlin, Lausanne and Paris. In 1924 V. Lasas worked on probation in
      Lausanne under supervision of famous scientist M. Arthus, the founder of
      experimental allergy--anaphylaxis, in the field of experimental anaphylaxis,
      desensibilization, enteral sensibilization and resorption of native albumins,
      transfer of allergic state from mother to fetus, the role of interoceptors and
      biologically active substances in the formation and development of anaphylaxis.
      Over 40 scientific papers were published and 12 doctoral these were maintained,
      dealing with these problems. From 1924 to 1940 and from 1944 to 1946 V. Lasas
      acted as dean of the Faculty of Medicine at Kaunas University. During this period
      he displayed great organizational talent, and on his initiative three basic
      clinical buildings were built for the Faculty of Medicine. In 1946 V. Lasas was
      elected as academician and appointed as secretary-in-charge of natural
      mathematical and applied science of the Academy of Sciences of Lithuania. V.
      Lasas was the founder and longstanding chairman of the Lithuanian Physiological
      Society. Alone and with coauthors he has published 16 original textbooks. The
      list of his bibliography accounts to 229 publications.

PMID- 12474746
TI  - [Osteoporosis: diagnosis, prevention and treatment].
AB  - The paper describes prevalence, mechanisms of development, clinical features of
      osteoporosis, its complications and the principles of treatment. It includes an
      overview of the universally accepted diagnostic methods and criteria and
      discusses the diagnostic value of laboratory and instrumental investigations. The
      significance of radiological methods of the diagnosis is emphasized with regard
      to the problems related to differential diagnosis and appropriate evaluation of
      the risk factors for osteoporosis and fractures. Contemporary methods of both,
      prevention and treatment of osteoporosis, depending on the bone mineral density
      and risk factors for osteoporosis, are presented. Possible problems of tolerance
      and common adverse drug reactions are discussed.

PMID- 12474747
TI  - [Hormonal anti-inflammatory and anti-allergic ocular drugs and their use (review
      of the literature)].
AB  - Recent reports have shown a worldwide increase of allergic diseases during the
      past 10-20 years. One of the risk factors of allergic diseases is atmospheric
      pollution. Ocular allergic disorders contain 2-15 percents of all allergic
      diseases. Corticosteroids have been useful in control of inflammatory and
      immunologic diseases of the eye. The anti-inflammatory effects of corticosteroids
      are nonspecific and they inhibit inflammation without regard to cause. Topical
      therapy is effective in anterior segment of eye. New modes of delivering a drug
      to the eyes are being actively explored. Formulation characteristics markedly
      increase drug residence time in the eye and absorption. The difficulty for drugs
      to penetrate through the cornea is combined with their rapid removal through the
      tear system and their dilution by reflex tearing.

PMID- 12474748
TI  - [Rehabilitation possibilities of the post-resection defects of facial bones and
      surrounding soft tissues in cancer patients (review of the literature)].
AB  - The review of the scientific literature, concerning contemporary treatment
      methods and materials of the post-resection defects of facial bones and
      surrounding soft tissues in cancer patients is presented in this article. The
      aloplastic endoprostheses, removable post-resection intraoral prostheses, fixed
      on implants and ectoprostheses, which are reconstructing the defects of soft
      facial tissues, are analysed more broadly. The advantages and leaks of these
      treatment methods are discussed, taking into account the problems, which are
      faced by the patients after the surgical and radiological treatment of malignant
      tumours of face and jaws. According to the data of Institute of Oncology, Vilnius
      University and Kaunas Medical University Clinics, from the beginning of the 1999
      till the end of the 2000, 63 patients needed the rehabilitation after the
      treatment of the malignant tumours of face and jaws.

PMID- 12474749
TI  - [Brain death determination algorithm].
AB  - The article overviews the summarized published data concerning determination of
      brain death in different countries. The paper is based on some foreign
      guidelines, as well as recent literature. Brain death has been discussed
      extensively for the last 30 years. Brain death is defined as cessation and
      irreversibility of all brains function, including brain stem. Brain death is
      equivalent to death of the individual, even though the heart continues to beat
      and spinal cord functions may persist. There are no internationally accepted
      guidelines for diagnosis of brain death. Different sets of criteria, based on the
      Harvard Medical School criteria (1968), are used in different countries, and have
      been revised and updated in the recent years. The exact identification of the
      preconditions is among the most important requirements. The cause of coma has to
      be known and sufficient to account for the irreversible loss of all brain
      functions. Coma and apnea must coexist as well as absence of brainstem function.
      Cultural differences can lead to fundamentally different approaches to brain
      death determination. Moral, ethical, religious as well as educational factors,
      including mass media are important in the determination brain death in different
      countries. Brain death is both a medically and legally important event. In some
      Western countries, the legal and medical systems have cooperated, while in others
      only the medical system is working. There are no medical criteria and no legal
      support in Egypt, many Islamic and African countries. Brain death can usually be
      diagnosed reliably by clinical criteria alone. However, there are special
      circumstances when these are not suitable and cannot be applied and confirmatory
      instrumental test is required for the diagnosis of brain death. In the paper is
      presented algorithm of the brain death determination developed according to the
      some foreign guidelines, as well as literature.

PMID- 12474751
TI  - [Ruptured abdominal aortic aneurysm].
AB  - Rupture of the abdominal aortic aneurysm is a high lethal risk pathology, which
      requires precise diagnosis and urgent and efficient surgical treatment. Despite
      improved diagnostic capabilities (echoscopy, in specialized departments-
      angiography, computed tomography, magnetic nucleus resonance), mortality related
      to this pathology remains high in intensive care units. In the present article
      data concerning prevalence and clinical outcomes of the rupture of the abdominal
      aortic aneurysm for 1999-2001 is presented in detail. During this period 22
      patients have undergone surgery due to abdominal aortic aneurysm rupture.
      Described are most prevalent complications, mortality rates and causes, analyzed
      are treatment strategy and tactics.

PMID- 12474750
TI  - [Myocardial protection: which method of cardioplegia is better?].
AB  - The remarkable advances in cardiac surgery over the last 50 years have led to the
      concept of "routine" open heart surgery. The introduction of novel surgical
      technologies, methods of anesthesiology and intensive care allowing for a
      reduction morbidity and mortality at perioperative period. The development of
      intraoperative myocardial protection has been impressive too. A tremendous body
      of literature has documented the physiologic basis of current cardioprotective
      methods and debate over the optimal technique. We tried to review current trends
      and future perspectives of myocardial protection in this article.

PMID- 12474752
TI  - [Pain in failed back surgery syndrome].
AB  - The problems of diagnosis and treatment of Failed Back Surgery Syndrome are
      briefly analyzed in this article. Literature overview and analysis is
      supplemented by the data collected at the Spinal Neurosurgery Department in
      Kaunas University of Medicine Hospital during the study in which clinical
      findings and data were analyzed and compared to the answers of patients in the
      special questionnaires about pain specially designed for the patients with low
      back pain and the Failed Back Surgery Syndrome. During this study specially
      designed questionnaire was introduced for the detailed pain evaluation, McGill
      pain questionnaire and visual analogical scales were included in this diagnostic
      tool. The most important clinical aspects of diagnosis and treatment of Failed
      Back Surgery Syndrome are discussed in this article and compared to the clinical
      trial in order to point out the real their value, effectiveness and long term
      results. In addition, the clinical value and use of special pain questionnaires
      is discussed and their auxiliary role is established.

PMID- 12474754
TI  - [Prognostication of acute intraoperative bleeding in children with burn wounds
      undergoing tangential necrectomy and auto-dermatoplasty].
AB  - The aim of this study was to estimate the blood loss of children undergoing
      tangential necrectomies and skin grafting by using gravimetric methods. Also we
      had to estimate the influence of age upon the quantity of blood loss. We examined
      50 cases. The body surface from which the intraoperative bleeding took place
      included the areas of tangential necrectomy and skin harvesting. The bleeding was
      controlled by electrocoagulation and wound dressing, soaked with epinephrine
      solution 1:50,000. The blood loss was estimated by weighing the material before
      and after the operation, excluding from the amount the quantity of the
      epinephrine solution. We divided the children into 3 groups according to their
      age: first--up to 1 year, second--1-3 year old, third--3-15 year old. By using
      the gravimetric method we found out that the mean blood loss from the areas of
      necrectomy and harvesting is 0.47 +/- 0.1 ml/cm2. The age of children does not
      influence the intensiveness of bleeding per square measure site of the necrectomy
      and harvesting area. The blood loss is a constant quantity and is equal to 0.47
      +/- 0.1 ml/cm2. The blood loss that takes place from one percent of the
      necrectomy and harvesting areas is approximately equal to 2.05% of the
      circulating blood volume.

PMID- 12474753
TI  - [Analysis of treatment outcomes after electric injuries (1991-2000)].
AB  - During the 1991-2000 year period 1728 children and 1967 adults have been treated
      in the Unit of Plastic Surgery and Burns of Kaunas Medical University Hospital. A
      retrospective analysis of patients who sustained electric injuries during these
      years period was carried out. Among all patients 93 (2.517%) were injured by
      electricity. 38 (40.86%) of them were children and 55 (59.14%)--adult patients.
      Seven (18.42%) children and 13 (23.64%) adults underwent high voltage electrical
      injury, 29 (76.32%) children and 22(40%) adult underwent low voltage injury and 2
      (5.26%) children and 20(36.36%) adult were injured by Voltaic arc. Twenty two
      patients were treated conservatively, 55 necrectomies, 74 skin grafts, 5
      microvascular flap transplantations were performed. During this study we find
      that severity of injury depends on current voltage. Tissue damage and rate of
      complications were much larger for patients who underwent high voltage electric
      injury than for patients who sustained low voltage or Voltaic arc injury. For 6
      (of 7) children who underwent high voltage injury amputations were performed. For
      one child amputation of upper arm was performed, for 3 patients--amputation of
      forearm, for all the rest amputations of fingers were performed. These patients
      had more severe injuries with deep necrosis of muscular tissue, tendons and bone.
      Three patients who underwent low voltage injury needed amputation of digits. For
      other 2 patients from this group was necrosis of tendons and they required
      transplantation of microvascular flap. Five patients of adult high voltage injury
      group needed amputation. Three of them needed amputation of forearm, one--of
      upper arm and one--of the calf. From low voltage injury group 3 patients needed
      amputations of one or two fingers and only one patient needed amputation of upper
      arm.

PMID- 12474755
TI  - [Localization of impacted maxillary canines by palpation and orthopantomography].
AB  - In orthodontic practice occurred problems associated with labio-palatal
      localization of impacted permanent maxillary canines. Not always is possible to
      determinate labio-palatal location of these teeth on the basis of palpation,
      therefore clinical examination aided by radiographic investigation.
      Orthopantomogram is the most widely used radiograph in orthodontics. The purpose
      of present study-test diagnostic value of palpation and orthopantomography in
      cases of maxillary canines impaction on the basis of evaluation of migration and
      inclination of impacted teeth. Thirty nine patients of Clinic of Orthodontics,
      Kaunas University of Medicine, orthopantomograms were available for analysis.
      Forty two impacted canines were investigated. Only 64% of canines could be
      palpated. It depended on the vertical position of the tooth. Distribution of the
      values of canine inclination to the middle of upper jaw was too big for more
      precise statistical analysis. Canines, which were medial to the 3th horizontal
      sector (these canines overlapped longitudinal axis of the lateral incisor), were
      located palatally.

PMID- 12474756
TI  - [Poisoning by chromium and its long lasting detoxication].
AB  - Long lasting influence of cumulated Cr provide irreversible damages of vascular
      walls, organs and their systems. During long lasting treatment most of Cr is
      removed during the first 20 days through bileric tract and at the same time
      through the renal tract the Cr amounts decreases because chromium-d-penicilamin
      complex in hepatocytes induces synthesis of specific chromium-d-penicilamin
      binding labile protein and they are removed with bile. The levels of essential
      microelements (Cu and Zn) are maintained at the level of the physiological
      tolerance during treatment. Cr removes very slowly (about a year) from human
      body, and after treatment patients health do not improve because Cr-inducted
      damages of vascullars, organs and their systems are not recovered. The treatment
      must be evaluated continuously by controlling concentrations' of Cr, Cu, Zn and
      other microelements in the blood, plasma and urine by electrothermal atomic
      absorbtion spectrophotometry methods.

PMID- 12474757
TI  - [Application of methods for hemodynamic monitoring in critical cardiac pathology
      (an experimental model for assessment of hemodynamics)].
AB  - Hemodynamic assessment of critically compromised patients with cardiac pathology
      is one of the goals of recent diagnostics and treatment strategies. Different
      methods for assessment of hemodynamics are applied in clinical practice. However,
      applied methods (invasive and noninvasive) have specific advantages and
      disadvantages. These are discussed in the article. First experience of
      experimental model for assessment of hemodynamics in laboratory conditions is
      analyzed in the article. In the year 2002 it was explored a possibility to use
      standard procedure to evaluate hemodynamics for laboratory animals in Kaunas
      University of Medicine. It were selected 6 laboratory animals of different weight
      and sex. 7 measurements of hemodynamics were performed. Standard methodics was
      successfully applied in the experimental model. Results, method limitations and
      recommendations for further studies are presented in the article.

PMID- 12474758
TI  - [Characteristics of general anesthesia in the investigation of heart
      electrophysiology].
AB  - Investigating electrophysiological properties of the heart under acute
      experimental conditions, dogs are affected by operative stress because of
      traumatic surgical manipulations, so investigations are performed under general
      anaesthesia. Many anaesthetics together with their main function have
      desintegrating influence on autonomic regulation mechanisms. That is why
      anaesthetics used during experiments must fullfil such requirement--have minimal
      influence on autonomic nervous system (ANS) and heart conductivity system (HCS)
      interaction parameters or to make this influence insignificant. We did not found
      common anaesthesia methodics that can fullfil that requirements, so we decided to
      prepare new common anaesthesia methodics, which could fullfil requirements
      mentioned above. We choose medicaments according to their pharmacokinetics and
      pharmacodynamics action. For methodics optimization we've used 2 groups of dogs
      (mongrel dogs males weight 7-15 kg) (n = 10). We've applied different anaesthesia
      schemas on each group. Premedication in the I-st group was performed with
      intramuscle (i.m.) combination of diazepam, ketamine and phentanyl and for
      anaesthesia continuous intravenous (i.v.) infusion of thiopental and ketamine. In
      II-nd group premedication was performed with i.m. injection of ketamine/phentanyl
      combination and for anaesthesia--continuous i.v. infusion of thiopental.
      Induction in both groups was performed with i.v. thiopental injection.
      Suitability of premedication and anaesthesia was valued by adequativity of
      haemodynamics (heart rate 1/min) and surgical manipulations during experiments.
      Our conclusion is: investigating interaction of ANS and HCS methodics used in the
      I-st group of dogs is more suitable.

PMID- 12474759
TI  - [Ultraviolet spectrophotometric determination of psychotropic drug mixtures].
AB  - The mixture of psychotropic drugs aminazine, barbamylum and nitrazepam using
      ultraviolet (UV) spectrophotometric method was researched. As the solvent, most
      acceptable for identification and differentiation of these preparation was found
      0.1N solution of sulphuric acid. By measuring the optical density of the
      solutions in different concentration the calibration diagrams for all
      preparations were made. The standard deviation, by determining the quantity of
      aminazine is 2.8; 4.0; 4.3; barbamylum--1.0; 2.5; 1.15; nitrazepam--2.64; 1.0;
      1.35.

PMID- 12474760
TI  - [Ecological monitoring of population mortality in Kaunas micro-districts, 1992
      1997].
AB  - In Lithuania, the mortality rate is constantly increasing. However, regional
      differences of mortality rates in a large industrial town were unexplored. The
      study was carried out in Kaunas, second biggest town of Lithuania with a well
      developed industry, as well as high atmospheric air pollution. Harmful effects of
      the regional environmental complex (dustiness, carbon monoxide, sulfur and
      nitrogen dioxides) were evaluated by summarized pollution index. Causes of death
      were taken from certificates of death for 1992-1997. In the study, the 9th
      revision of International Classification of Diseases and the European age
      standard were used. Mortality was studied in three microdistricts with threefold
      differences in levels of air pollution. The age-adjusted death rate (SMR) from
      all causes in a relatively clean microdistrict--D3 (SMR = 1720.5 +/- 60.4) is
      higher than the same indicator of microdistricts with developed industry--D1 (SMR
      = 1446.5 +/- 102.1) or heavy traffic--D2 (SMR = 1402.7 +/- 86.2). In terms of
      cause-specific mortalities, there is a prevalence of cardiovascular diseases and
      neoplasms. The SMR from circulatory system disorders (ICD-9 390-459) in D3 is
      equal 562 +/- 56.1, compared to D2--509.7 +/- 63.9 and D1--479.7 +/- 79.2.
      Neoplasms (ICD-9 140-239) are ranked second in the list of causes of deaths. They
      account for 244.8 +/- 32.0 per 100,000 population in D3, 184.4 +/- 40.8 in D2 and
      221.1 +/- 47.6 in D1, respectively. The overall mortality of the population did
      not relate to the levels of outdoor pollution. Circulatory disorders and
      neoplasms are the main cause of death. In a polluted micro district risk of death
      for a young person is higher, irrespective of accidents, injuries and poisonings.

PMID- 12474761
TI  - [Osteoporosis: diagnosis and treatment of vertebral fractures].
AB  - This review article calls attention of clinicians to under-diagnosed and
      untreated complication of osteoporosis-osteoporotic vertebral fractures. Usually
      without clinically significant symptoms, vertebral fractures are very important
      as an unfavorable prognostic factor of development of osteoporosis. Significant
      rise of risk of new fractures is observed already in a first year after the
      fracture. The newest results of the clinical trials of medications for
      osteoporosis treatment are presented.

PMID- 12474762
TI  - High apoptosis-inducing and antitumor activities of the products of biological
      but not chemical cyclophosphamide activation.

PMID- 12474763
TI  - The synthesis and degradation of juvenile hormone in Drosophila are under common
      control.

PMID- 12474764
TI  - A population of the common shrew Sorex araneus L. (Insectivora, Mammalia) of the
      Sok race inhabiting a patch of forest at the southern boundary of the species
      range.

PMID- 12474765
TI  - Preliminary note on the treatment of gonorrhoea with heated bougies. 1913.

PMID- 12474766
TI  - The presence of the transposable element ISBsu2 from a cryptic plasmid in
      chromosomes of some Bacillus subtilis strains.

PMID- 12474767
TI  - Laser correlation spectroscopy as an effective method of detection of DNA
      containing and other macromolecular complexes in blood serum of patients with
      diabetes mellitus.

PMID- 12474768
TI  - Effect of allicin on Ca2+ responses of human lymphocytes.

PMID- 12474769
TI  - [Programmed cell death: molecular mechanisms and detection].
AB  - Apoptosis or programmed cell death is genetically determined process to destroy
      cells for the maintaining of cellular homeostasis in the tissue. This paper
      reviews the current knowledge on the molecular mechanisms of apoptosis.
      Activation of cysteine proteases called caspases plays a major role in the
      execution of apoptosis. These activated caspases selectively cleave cellular
      proteins, which result in apoptotic morphology (internucleosomal fragmentation of
      DNA into 180-200 base pair pieces, shrinkage of the cell and the nucleus as well
      and fragmentation of the cell into apoptotic bodies) and death of the cell. Now
      two pathways of caspase activation are reported. The first through triggering of
      cellular death-receptor superfamily. The second is mitochondrial pathway induced
      by the changes of the expression of pro- and anti-apoptotic genes in the cell. It
      leads to release of cytochrome c and apoptosis inducing factor from mitochondria.
      The paper reviews also currently used methods of detection of apoptotic cells in
      tissue samples, causes of false-positive or false-negative results of ISEL and
      TUNEL in situ reactions.

PMID- 12474770
TI  - [Some aspects of diagnosis and treatment of cervical intraepithelial neoplasia
      (review of the literature)].
AB  - Cervical cancer has remained close to the forefront of oncologic studies even in
      our days. The incidence of the disease has changed little, except in those
      countries with effective screening programs. The morbidity in Lithuania reached
      23.9/100,000 in the 2000's, while in comparison the morbidity in the 1994's was
      20.4/100,000. The mortality was 13.2 and 11.3/100,000, respectively. Over the
      last 50 years our understanding of the etiology and pathogenesis of lower genital
      tract squamous neoplasia has increased enormously and, particularly in the last
      15 years, progress in our understanding of the molecular events associated with
      lower anogenital tract neoplasia has developed rapidly. Cervical cancer is the
      second most common type of cancer in women worldwide, after breast cancer. Since
      1978 it is known that Human Papillomavirus is closely related to genital
      neoplasia--cervical, vulva, vagina, penis, anus intraepithelial neoplasia and
      invasive carcinoma. It is also known that cytologic smear is one of the most
      important way to diagnose cervical intraepithelial neoplasia and cancer as well,
      because we can not evaluate cervical lesion visually. Cytologic smear remains the
      main principle of cancer screening because of its simplicity and accessibility,
      while colposcopy remains the method of examination in choice, when pathologic
      cytologic findings are determined.

PMID- 12474772
TI  - [Blood plasma potassium, sodium and magnesium levels in chronic alcoholism during
      alcohol withdrawal].
AB  - Blood plasma potassium, sodium and magnesium levels were studied in 114 chronic
      alcoholic patients (pts) during alcohol withdrawal. They were abnormal in 88.6%
      cases. Hypokalemia was observed in 28.9%, hyperkalemia--in 4.4%, hypomagnesemia
      in 29.8%, hypermagnesemia in 5.4%, hyponatremia in 72.8%, hypernatremia in 3.5%
      pts. In 23.7% cases disorders of two electrolytes and in 14% cases disorders of
      all three electrolytes for the same patient were established. Our data shows,
      that during alcohol withdrawal hyponatremia, hypomagnesemia and hypokalemia are
      not uncommon.

PMID- 12474771
TI  - [Transcatheter renal arterial embolization in malignant renal neoplasms: clinical
      results and indications for use of the method in multi-profile hospitals].
AB  - The authors analyse the long-term and in-hospital results of treatment 29
      patients with renal neoplasms, who underwent transcatheter renal arterial
      embolization and also discuss the benefits of transcatheter renal arterial
      embolization in other clinical situations. Transcatheter renal arterial
      embolization was performed with embosil for 23 patients (79.3%) and with
      concentrated alcohol for 6 patients (20.7%) before nephrectomy of advance renal
      tumour in 21 patients. Transcatheter renal arterial embolization was performed as
      palliative treatment in 8 patients. Complete embolization was achieved in 27
      patients (93.1%), incomplete--in 2 patients (6.9%). Nephrectomy was performed
      after 22.14 +/- 9.28 days. The most evident post procedural reactions were
      moderately elevated temperature in 22 patients (75.9%), highly elevated
      temperature (> 38 degrees) in 7 patients (24.1%) and pain. Only 6 patients
      (20.7%) didn't feel pain. One hematoma was noticed in puncture region. After 5
      years, 4 patients of 10 analysed patients are still alive (all-pT3, size of tumor
      6.5-9 cm.). Two patients were not operated due to very big tumor and technical
      inoperability. Remaining 4 patients died during 2-3 years. As exclusion was one
      patient with inoperable renal tumor and lung metastases. After transcatheter
      renal arterial embolization he was alive 4 years. In conclusion, transcatheter
      renal arterial embolization was effective in diminishing the technical
      difficulties to remove advance tumors and in treatment of inoperable patients.
      It's rational to supply transcatheter renal arterial embolization with
      embolization and chemoembolization of primary and metastatic lesions.

PMID- 12474773
TI  - [Effects of periodontitis and opsonized zymosan on chemiluminescence of blood
      neutrophils].
AB  - The objective of the present investigation was to explore oxidative function of
      parodontitis patient's blood neutrophils stimulated with opsonized zymosan by
      method of luminol- and lucigenin-dependent chemiluminescence. The leukocytes for
      this study were obtained from peripheral venous blood of 16 parodontitis patients
      and 10 healthy subjects. The luminol-dependent chemiluminescence of stimulated
      neutrophils of parodontitis patients did not differ (p > 0.05) from control
      subjects (66,849 +/- 6372 cpm and 61,243 +/- 5240 cpm, respectively). Lucigenin
      dependent chemiluminescence of stimulated neutrophils of parodontitis patients
      was increased (p < or = 0.001) comparing with control subjects (1361 +/- 169 cpm
      and 492 +/- 56 cpm respectively). The luminol- and lucigenin-dependent
      chemiluminescence (381 +/- 63 cpm, and 389 +/- 52 cpm, respectively) of
      nonstimulated neutrophils of parodontitis patients was significantly higher (p <
      or = 0.001) than analogous Cl (134 +/- 22 cpm and 138 +/- 16 cpm respectively) of
      control subjects. The results indicate that increased oxidative function of
      neutrophils of parodontitis patients possibly can affect parodontal health.

PMID- 12474774
TI  - [Hypotensive effects of telmisartan on blood pressure during rest and exercise in
      patients with mild and moderate arterial hypertension].
AB  - The aim of the study was to evaluate an antihypertensive effect of AT1-receptor
      blocker telmisartan on the rest and exercise blood pressure (BP) in patients
      suffering from mild and moderate arterial hypertension. Twenty males (mean age
      50.9 +/- 6.9) following a 3-week placebo run-in phase were treated by telmisartan
      80 mg q.d. Bicycle exercise test and echocardiography was performed at the end of
      placebo run-in phase and following 12 weeks of treatment. The workload on the
      bicycle exercise test has been increased by 25 watts every 2 min and stopped at
      systolic BP (SDP) 240 or diastolic BP (DBP) 130 mmHg. The maximal workload was
      the same, prior and after 12 weeks of the treatment. Antihypertensive therapy
      with telmisartan had a favorable effect, i.e. significantly decreased the rest BP
      -both SBP (152.5 +/- 11.4 mmHg vs. 139.2 +/- 12.3 mmHg, p < 0.001) and DBP (100.0
      +/- 4.6 mmHg vs. 88.7 +/- 6.2 mmHg, p < 0.001). There were no significant changes
      in the heart rate (HR) at rest prior and after telmisartan treatment (71.4 +/-
      9.1 b/min vs. 72.2 +/- 10.4 b/min). When repeating the exercise test after 12
      weeks of telmisartan treatment we detected the significant decrease of BP at
      maximal workload, i.e. SBP decreased from 230.9 +/- 11.4 mmHg to 211.3 +/- 12.7
      mmHg, p < 0.05 and DBP decreased from 124.6 +/- 7.5 mmHg to 109.7 +/- 9.7 mmHg, p
      < 0.05. There was a significant decrease in HR (140.6 +/- 13.2 b/min vs. 130.1 +/
      14.2 b/min, p < 0.05) and significant increase in JT interval at maximal
      workload after telmisartan treatment (0.193 +/- 0.014 sec vs. 0.201 +/- 0.014
      sec, p < 0.05). Telmisartan decreased the double product at rest and maximal
      workload (diff. of 16 x 10(2) mmHg x b/min and 48 mmHg x 10(2) b/min,
      respectively, p < 0.05). CONCLUSIONS: Twelve weeks of the telmisartan treatment
      showed a significant decrease of blood pressure at rest and exercise with no
      effect on the heart rate at rest in patients with mild and moderate arterial
      hypertension. There was statistically significant decrease in HR at maximal
      workload after the treatment by telmisartan.

PMID- 12474775
TI  - [Effects of aluminum ions on the resistance of mice to experimental Listeria
      monocytogenes infection].
AB  - This study presents evaluation of effects of aluminium ions on the development of
      experimental infection induced by the injection of Listeria monocytogenes
      bacteria into growing mice. We show that single exposure of mice to 0.05 LD50 or
      0.5 LD50 of aluminium ions does not affect the accumulation of bacteria in liver
      and spleen of experimental animals. Long-term exposure of mice to aluminium ions
      (injection of 0.05 LD50 Al3+ every 3 days for totally 6 weeks) did not slow down
      the increase in weight of animals while in the infected animals aluminium
      significantly reduced their growth. Animals subjected to chronic aluminium
      exposure have shown lower accumulation of bacteria in liver 24 h after the
      initiation of experimental infection as compared to the mice after single
      injection of 0.05 LD50 Al3+. Also, long-term exposure to aluminium causes more
      complicated development of experimental infection, which was evidenced by the
      decreased survival of aluminium-treated animals (77% compared to 83% in control
      group) as well as by the increase in the fraction of animals carrying infection
      after 6 weeks (36% versus 5% in control group). In addition, aluminium-exposed
      animals had significantly lower blood serum agglutination titer to the listeria,
      and decrease in the delayed type of hypersensitivity to the listeria antigens.
      Results, presented here, indicate that the long-term exposure to low aluminium
      doses activates the antibacterial defence in experimental animals while the
      specific immunity becomes suppressed.

PMID- 12474776
TI  - [The quantitative changes of bioelements (Ca, Zn, Mg, Cu, Mn) in crystalline
      lenses under the influence of hypodynamic stress and zinc].
AB  - The aim of the study was to investigate and estimate quantitative changes of
      bioelements (Ca, Zn, Mg, Cu, Mn) in the lenses on the influence of hypodynamic
      stress and zinc (Zn). Hypodynamic stress of 48 days duration was provoked for
      Chinchilla rabbits (n = 20) by placing them in metal hutches. Every day (48 days)
      10 rabbits, which had intervention received 0.3 mg/kg body wt. doses of Zn (in
      form of Zn acetate). The rabbits (n = 10) of the control group, which had no
      intervention were kept in vivarium conditions. Concentration of bioelements in
      the lenses of rabbits was detected by atomic absorption spectrophotometry 503
      "Perkin-Elmer" (USA). The investigation revealed that hypodynamic stress of 48
      days duration caused the increase in amount of Ca, Zn, Mn in lenses as compared
      with that in control rabbits and in rabbits receiving Zn. The concentration of
      bioelements (Ca, Zn, Mg, Cu, Mn) in lenses of rabbits receiving Zn in case of
      hypodynamic stress did not change significantly.

PMID- 12474777
TI  - [The prevalence of type I diabetes mellitus among adult population of towns and
      regions of Lithuania].
AB  - OBJECTIVE, MATERIAL AND METHODS: The goal of study was to analyze the prevalence
      rates in > 15-year-aged patients with Type 1 (insulin-dependent) diabetes
      mellitus in different provinces, cites, and regions of Lithuania. The data on >
      16-year-aged patients were collected with the help of endocrinologists and
      physicians-internists working in the diabetes care in all towns and regions in
      Lithuania. The data on > 14 and < 16-year-aged patients we have received from the
      National children Insulin-dependent diabetes mellitus Register. RESULTS: On 31
      December 1998 there were 1, 744 > or = 15-year-aged and adult Type 1 diabetic
      patients or 140.97 per 100,000 (95% uneven Poisson confidence interval was 134.97
      143.43) living in 12 cities of national jurisdiction and 1,609 or 112.22 (107.10
      117.57) living in 44 country-side regions, p > 0.05. Male/female ratio of
      prevalence rates in cities was 1.48, and in country-side regions--1.44. The
      prevalence rates of Type 1 diabetes mellitus in cities with > or = 100,000
      inhabitants vary from 123.70 (107.73-142.04) in Klaipeda city to 173.34 (159.85
      187.97) (p > 0.05) in Kaunas city. The prevalence rate of Type 1 diabetes
      mellitus in localities with < 70,000 inhabitants vary from 61.31 (37.56-100.08)
      in Lazdijai region to 184.25 (130.30-260.55) in Druskininkai health-resort or
      228.53 (109.09-480.00) in Birstonas health-resort. The prevalence rate of Type 1
      diabetes mellitus was 118.47 (102.73-136.62) in Alytus province, 152.95 (143.39
      163.215) in Kaunas province, 121.04 (109.66-133.60) in Klaipeda province, 115.07
      (96.00-137.93) in Marijampole province, 125.30 (112.28-139.83) in Panevezys
      province, 114.46 (105.10-129.04) in Siauliai province, 115.12 (95.89-138.21) in
      Taurage province, 137.01 (118.85-157.95) in Telsiai province, 98.23 (84.05
      114.81) in Utena province and 117.75 (110.10-125.93) in Vilnius province. The
      male/female ratios of rates were 1.71, 1.35, 1.39, 1.14, 1.87, 1.67, 1.72, 1.12,
      1.31 and 1.51. CONCLUSION: There were no statistical significant differences
      between Type 1 diabetes mellitus prevalence rates in different localities in
      Lithuania.

PMID- 12474778
TI  - [Nutritional status evaluation of elderly patients with prostatic cancer: a mini
      questionnaire on nutrition].
AB  - Mini Nutritional Assessment has been specifically designed to assess the
      nutritional status of elderly patients and preoperative nutritional evaluation.
      It can be used for nutritional evaluation in patients receiving treatment for
      advanced prostate cancer. We assessed 80 patients 65 year age and over. Forty
      patients were with prostate cancer and 40 patients with benign prostatic
      hyperplasia. The Mini Nutritional Assessment is a clinical score consisting of
      four items: anthropometric assessment, global evaluation, dietetic assessment and
      subjective assessment. The Mini Nutritional Assessment stratifies patients in the
      three categories: well--nourished patients (24 < or = MNA < or = 30), at risk of
      malnutrition (17 < or = MNA < 23.5) and undernutrition (MNA < 17). Patients
      suffering from prostate cancer were more likely to be overweight and they had
      rapid lost of weight. The Mini Nutritional Assessment was found to be well-suited
      for nutritional evaluation in patients receiving treatment for advanced prostate
      cancer. Mini Nutritional Assessment requires no complex analysis and can be
      easily used in hospitals and should be routinely performed.

PMID- 12474779
TI  - [Trends in health care expenditures in Lithuania].
AB  - The aim of the study was to analyze the tendencies of public and private health
      care expenditure in Lithuania during 1994-1999. Crude examination of statistical
      data show, that the growth rate of health care spending per capital is largely
      determined by growth of national gross domestic product (GDP). We have estimated
      that health care spending in Lithuania have risen twice faster than GDP during
      1994-1999. (Percentage of rise in health care spending, divided by percentage
      rise of GDP, is +2.26). The introduction of compulsory health insurance in 1997,
      and the development of private health care sector in Lithuania, led to increase
      health care expenditure in total, and has influenced changes in public-private
      spending proportions. A source of private spending in national health account has
      increased from 15 per cent in 1994-1995 to 24 percent in 1996-1999. The tendency
      of increasing private spending shows, the evidence, that households are facing
      more financial risk of purchasing health care. This should be an implication for
      health care policy makers. Further decisions to increase private payments have to
      be based on evidence after detailed analysis of impact of consequences on health
      care access for various social economic groups of population.

PMID- 12474780
TI  - [Work cycle "Human growth hormone (isolation, research, manufacturing, treatment,
      studies) 1971-2001" annotation].

PMID- 12474781
TI  - [Opioid overdose].
AB  - The dangers of opioid overdose have been recognized for as long as the use of
      opium itself. When used correctly for medical purposes, opioids are remarkably
      safe and effective agents. However, excessive dosing, whether with therapeutic,
      suicidal, or euphoric intent, may results in significant toxicity. In a number of
      countries the use of heroin and other opioids in nonmedical contexts in
      associated with on increasing rate of overdose and often of fatal opioid
      overdose. This review article discusses opioid-receptor pharmacology, which is
      necessary for understanding of the signs and symptoms of opioid ingestion and
      management principles, clinical and toxic effects mediated with the opioids, the
      diagnosis and management guidelines in opioid intoxication, a clinical prediction
      rule to identify patients who can be safely discharge from hospital, the problems
      of the significant morbidity and mortality associated with opioid overdose.

PMID- 12474782
TI  - [Dopaminergic modulation of cerebral activity and cognitive functions].
AB  - Alterations in dopaminergic system are known to lie in the basis of such diseases
      as Parkinson's disease, Huntington's disease, Attention Deficit/Hyperactivity
      Disorder, Tourette syndrome, schizophrenia and drug abuse. This induced broad
      investigations of dopaminergic system in nearly all the areas of neuroscience.
      New insights into the pathogenesis of neuropsychiatric diseases have emerged.
      Research in the field of dopaminergic neurotransmission and memory was awarded
      Nobel prize in the year 2000. New avenues for the development of more selective
      drugs have been opened. In their daily practice clinicians are often prescribing
      medications acting on presynaptic or postsynaptic sites of dopaminergic units.
      Thus the aim of this review was to renew some knowledge on the architecture of
      dopaminergic system and also to glance through some of the studies implying its
      modulating effect on cognitive functions.

PMID- 12474783
TI  - [Development of child mental health services in Lithuania: achievements and
      obstacles].
AB  - In 1990, political, economic and social changes in Lithuania introduced the
      possibility to develop for the first time in nations's history an effective and
      modern system of child mental health services. During the period between 1990 and
      1995 a new model of services was developed in the Department of Social pediatrics
      and child psychiatry of Vilnius University. The model included development of
      child and adolescent psychiatric services, as well as early intervention services
      for infants and preschool children with developmental disabilities. The emphasis,
      following recommendations of WHO and existing international standards, was made
      on deinstitutionalization and development of family-oriented and community-based
      services, which have been ignored by previous system. In the first half of 90's
      of 20th century, new training programs for professionals were introduced, more
      than 50 methods of assessment, treatment and rehabilitation, new for Lithuanian
      clinical practice, were implemented, and a new model of services, including
      primary, secondary and tertiary level of prevention, was introduced in
      demonstration sites. However, during next phase of development, in 1997-2001,
      serious obstacles for replicating new approaches across the country, have been
      identified, which threatened successful implementation of the new model of
      services into everyday clinical practice. Analysis of obstacles, which are
      blocking development of new approaches in the field of child mental health, is
      presented in the article. The main obstacles, identified during analysis of
      socioeconomic context, planning and utilization of resources, running of the
      system of services and evaluation of outcomes, are as follows: lack of
      intersectorial cooperation between health, education and social welfare systems;
      strong tradition of discrimination of psychosocial interventions in funding
      schemes of health services; societal attitudes, which tend to discriminate and
      stigmatize marginal groups, including disabled children and dysfunctional
      families; lack of evidence-based decision making in the process of health care
      reform and reform of social infrastructure.

PMID- 12474784
TI  - [Play therapy in social work with children].
AB  - This article introduces the results of scientific research performed in 1995-1997
      in Kaunas primary school with 1st and 2nd grade children exhibiting behavioral
      disorders. Play therapy, a quite novel method in the country, seeks better
      improvement and an achievement of a better relationship for disadvantaged
      children in educational process. Play group counseling, or play media counseling,
      is shown as an important method in working with early primary grade children,
      especially those who present behavioral problems in the classroom. Another
      important aspect of group play therapy is the concentrated relationship with the
      counselor. Primary school children, especially those who are disadvantaged
      respond more to warmth than to praise for being right and doing well. Data
      analysis allow us to assume that behavioral difficulties of primary school
      children are connected with a low rate of self-esteem and dissatisfaction with
      their vital activities. Main conclusions to correspond with hypothesis held for
      the research are: a) children exhibiting behavioral problems are less active in
      educational process; b) by means of systematic use of play group counseling
      method in school, problematic children are able to solve their difficulties and
      to optimize their academic improvement; c) there is a complementary relationship
      between child's self-esteem and his/her satisfaction with his/her vital activity.

PMID- 12474785
TI  - [Relationships between social factors and suicidal attempts of adolescent girls].
AB  - This study presents a comparative analysis of family and school situation among
      adolescent girls, who attempted a suicide and those who did not. The control
      group was represented by normative sample of school girls of Lithuania. The
      results indicate that most of the attempters live in incomplete families, with
      step-father, step-sisters and step-brothers. The results showed that there were
      more conflicts within families of the attempters than within the other groups of
      the study. The girls, who completed a suicide attempt more often reported about
      arguing with their parents. They also appeared to brake the law more frequently
      and also they experienced abuse more often than girls in the control group. The
      attempters more frequently reported about financial difficulties of their
      families. Those girls also reported more problems at school such as truancy. The
      attempters also evaluated their academic achievements much lower than girls in
      the control group.

PMID- 12474786
TI  - [Relationship between the suicidal attempts of adolescent girls and risk factors
      in the family].
AB  - The same factors in the family are described as risk factors for the suicidal
      behavior of adolescents by some authors and as risk factors for the development
      of depression by others. The goal of the study is to learn, if incomplete family,
      parental alcohol abuse, mentally ill member of the family, suicidal behavior in
      the family, sexual, physical or emotional abuse experienced in the family are
      directly related with the suicidal attempts of adolescent girls or relates to it
      just by causing depression. The results of the study suggest that 57.4% of the
      female adolescent suicide attempters and 9.3% of their non-suicidal peers in the
      comparison group were diagnosed clinical depression. Incomplete family, parental
      alcohol abuse, suicidal behavior in the family, sexual, physical or emotional
      abuse experienced in the family were statistically more frequent among the
      depressed and not depressed suicide attempters than among their non-suicidal
      peers. This allows the conclusion, that these risk factors in the family have a
      relationship with the suicide attempts of adolescent girls independently from
      clinical depression and require attention of the specialists, involved in the
      treatment and prevention of adolescents suicidal behavior.

PMID- 12474787
TI  - [Depression and suicidal risk of the adolescents (comparative analysis in the
      cities of Klaipeda, Kaunas and Siauliai)].
AB  - The aim of this research is to explain frequency of depressivity and suicidal
      risk among the adolescents and the ratio between depressivity and suicidal risk,
      to compare the level of depressivity and suicidal risk of the adolescents between
      the cities of Kaunas, Klaipeda and Siauliai, to compare the level of depressivity
      and suicidal risk of adolescents of schools and gymnasiums. 2573 adolescents aged
      12-18 participated in research in Klaipeda (794 in gymnasiums and 1779 in
      schools), 1525 in Kaunas (822 in gymnasiums, 703 in schools) and 1072 in Siauliai
      (in schools). Depressivity of adolescents was found in Siauliai 47.9%, in Kaunas
      58.8%, in Klaipeda 51.5%, suicidal risk among the adolescents in all investigated
      cities was: 13.2% in Kaunas, 14.2% in Siauliai, 15.4% in Klaipeda. The suicidal
      risk is higher among girls. The attempts of suicides was more frequent among
      adolescents in Klaipeda (7.1%), suicidal attempts of girls were more frequent
      than those of boys (2:1) in all investigated cities. The ratio of depressivity
      and suicidal attempters was 8.4:1 in Siauliai, 10.3:1 in Kaunas and 7.2:1 in
      Klaipeda. The research demonstrated that depressivity is the factor for suicidal
      risk. The data of these researches were used to improve the suicidal prevention,
      involving the teachers and the parents.

PMID- 12474788
TI  - [Externalizing and internalizing problems of adolescent suicide attempters].
AB  - This study aims at comparative analysis between externalized and internalized
      behavior of adolescents. The girls were grouped into a group of suicide
      attempters and non-attempters. The group of attempters was patients taken to
      child departments of Psychiatry clinics after attempting a suicide. Lithuanian
      students formed the control group of the study. The groups were similar in
      respect of age, gender and place of living. Suicide attempters demonstrated more
      evident problems of internalized behavior. Their depressiveness was found to be
      at the higher levels, also they presented more somatic complaints. There was a
      statistically important difference on scales of depressiveness (p < or = 0.001)
      and somatic complaints (p < or = 0.001). The suicide attempters also reported a
      bigger number of other problems than girls of control group did. The values of
      subscales of aggression and delinquency were much higher than ones in the control
      group (p < or = 0.001). The research shows that the attempters often have not
      only emotional problems, but also are more aggressive and demonstrate more
      behavioral problems than the rest of children. Disobedience in relationships with
      adults and breaking of existing rules are those symptoms of conduct disorder,
      which have the strongest relationship with suicidal attempts among adolescent
      girls. Depression symptoms of sad mood and suicidal thinking had the strongest
      relation to suicidal attempts of the adolescents.

PMID- 12474789
TI  - [Aspects of the development of autistic children].
AB  - Autism is attributed to a complex developmental disability. Child development is
      pervasively impaired in many mental functioning spheres. This study aims to
      investigate the impact of the autistic features to the physical development of
      the autistic children. Most attention was paid to the nutrition and sleeping
      habits of the autistic children including communicational and behavioral aspects
      related to the mentioned functions. The results were compared with the healthy
      controls. Differences between the groups were analysed. Low appetite, narrow
      range of assortment of preferable dishes, digestive autonomic nervous system
      reactions were significantly more common in the autistic group. Sleep of the
      autistic children was significantly more often disrupted by waking up caused not
      by physiological needs when comparing with the control group. Tallness and weight
      of the autistic children were compared with the Lithuanian norms, physical growth
      autistic children was delayed and not harmonious. Further investigations in the
      field are needed.

PMID- 12474790
TI  - [Features of nursing of the autistic children].
AB  - Due to the behavioral and communication difficulties autistic children need
      individualized approaches providing them medical help. Aspects of nursing of
      autistic children were not investigated in our country. Thirty seven mothers of
      autistic children and 74 mothers of children without developmental disorders
      (control group) were interviewed orally and filled the questionnaire. The age of
      children was 3-12 years old. The aim of the research was to analyze peculiarities
      of behavior, communication and social adaptation of children with autism disorder
      together with troubles they face in medical services (outpatient and inpatient),
      and prepare practical recommendations to the pediatric and mental health nurses.
      It appeared that families with autistic children come across the great
      difficulties in various areas of the daily life. Autistic children tended to have
      severe behavioral and emotional difficulties while being examined by the medical
      staff. Adaptation difficulties in medical services were very prominent,
      especially at the in-patient departments (unpredictable and impulsive behavior,
      anxiety, decrease of appetite, sleep disturbances). Possibilities of home visit
      of the nurses are underestimated and could provide more useful and constructive
      help to the families. The data showed existing difficulties for the pediatric
      nurses and medical staff to establish good contact with the autistic children and
      their parents and lack of knowledge about the children with pervasive
      developmental disorders and their needs. Practical recommendations are provided.

PMID- 12474791
TI  - [The role of nurses in early rehabilitation of children with developmental
      disorders].
AB  - The role of nurse in early rehabilitation of children with developmental
      disorders in our country is still not clear and little investigated. The main
      purpose of the study was to analyze the needs of nursing at the department of
      Early Rehabilitation, describe appropriate activity spheres for the nurses, and
      prepare methodical recommendations for the nurse's work with developmentally
      disabled children. The study was carried out at the in-patient department of
      Early Rehabilitation, Child Development Center, Vilnius University Hospital.
      Eighty six mothers of developmentally disabled children were interviewed and
      filled the questionnaire developed by the authors. Aspects of mothers' views,
      opinions, suggestions and needs were investigated. The data revealed an
      interesting overview of the current situation in the field from the patient's
      perspective. The need for the adequate nurse and care was obvious. The role of
      the nurses is underestimated and functions could be broader expanded regarding
      the specific needs of the disabled children and their families. Organizational
      and practical recommendations are provided.

PMID- 12474792
TI  - [Psychological adjustment of children with phenylketonuria].
AB  - INTRODUCTION: Phenylketonuria is an inherited disorder, which prevents the normal
      use of protein food and causes changes in body chemistry, which, if left
      uncontrolled can lead to severe learning disabilities. By following a strict low
      protein diet early from birth phenylketonuria children can avoid mental
      retardation, other somatic as well as psychiatric disorders. However, early
      treated children with phenylketonuria are found to have more emotional and
      behavioral problems. Because of the lack of correlation between elevated
      phenylalanine (Phe) levels and psychological adjustment recent studies strongly
      indicate a psychological perspective for the development of emotional and
      behavioral problems in phenylketonuria patients. THE AIM OF PRESENT STUDY: To
      evaluate psychological adjustment of Lithuanian phenylketonuria children and to
      find out possible reasons for psychological problems of phenylketonuria children.
      METHODS: Parents of 45 phenylketonuria children and 45 normal controls aged 2 to
      14 years old were asked to fill in Lithuanian version of Child Behavior Checklist
      (CBCL, Achenbach, 1991) and a questionnaire on reactions to child's disease. The
      mean Phe level and IQ of some phenylketonuria children were considered as well.
      RESULTS AND CONCLUSIONS: Older phenylketonuria children have significantly more
      psychological problems than healthy peers. There were no such considerable
      differences found in younger groups. Parental maladjustment to child's chronic
      illness is related to higher levels of internalizing and other problems of
      phenylketonuria children.

PMID- 12474793
TI  - [The impact of children with externalizing difficulties on their families].
AB  - This study examined the impact on families of children with externalizing
      behaviors (e.g. hyperactive, aggressive, non-compliant; n = 22), and no
      significant problem behaviors (n = 40) on several measures of family functioning.
      Compared to parents with normally developing children, parents with externalizing
      children reported more negative feelings about child and parenting (p < or =
      0.001), more negative impact on social life (p < or = 0.01). Parents of children
      with externalizing behaviors have not used many of the coping strategies
      necessary to deal with stresses they encounter. Scores of emotional empathy index
      of parents with externalizing children were significantly lower in comprising
      with control (p < or = 0.001). We suggest that this parental characteristic
      contributes significantly to parent-child relationship problems.

PMID- 12474794
TI  - [Behavioral and emotional problems of children with learning disabilities].
AB  - The aim of research is to compare behavior and emotional problems of children
      with learning disabilities to problems of children without learning disabilities.
      Parents of 67 children with learning disabilities and of 60 children without
      learning disabilities were asked to fill in Child Behavior Checklist (CBCL 4/18;
      Achenbach, 1991). Children with learning disabilities had significantly more
      internal (somatic complaints, isolation, anxiety/depression) and external
      problems (aggression and delinquency) as well as attention and social problems.
      The research showed that children with learning disabilities are at greater risk
      for psychosocial adjustment difficulties. Limitations of the study are discussed.

PMID- 12474795
TI  - [The attitude of the 11th grade school girls to their bodies and weight control].
AB  - OBJECTIVE: Of the study was to detect the girls of 11th grade attitude towards
      their bodies and weight control. METHODS: The girls attitude towards their bodies
      and weight control was determined by anonymous 48-item questionnaire. The
      percentage of body fat (Durnin & Womersley, 1974) of each girl was estimated as
      well. RESULTS: Showed that a large part of the normal weight girls (58.5%)
      considered their weight too high. The girls with higher body fat and those who
      considered their weight to be too high judged their bodies and separate body
      parts more negative; their weight control behavior was more negative as well. The
      bigger difference between actual and desirable body weight was related with more
      negative weight control behavior and higher fear of weight gain. The attitude of
      the girls involved and not involved in leisure sports activities towards their
      bodies showed no significant difference while more dieting cases in sport
      involved group was determined. CONCLUSIONS: Attitude towards body weight was a
      higher predictor of negative weight control aspects than the actual percentage of
      body fat. The problem needs future examination.

PMID- 12474797
TI  - [Complexity of help to children with developmental disabilities in the context of
      the establishment of Early Rehabilitation Services].
AB  - During of the years of restoration of independence of Lithuania a new model of
      services for children with developmental disorders was designed by Vilnius Child
      Development Center and Clinic of Social Pediatrics and Child Psychiatry, Vilnius
      University, and started to be implemented throughout all the country. Analysis of
      current situation of early intervention services in Lithuania is presented. The
      study was carried at the four randomly selected early intervention services.
      Patients and specialists of early intervention services together with patients
      and specialists of polyclinics where the services are located were interviewed
      using the questionnaires developed by the authors. Complexity of views of
      services providers and consumers together with the aspects of distribution of the
      information about the early intervention services and cooperation of early
      intervention services with other professionals was analysed. Data of the focus
      groups discussions with the specialists of early intervention services and
      analysis of the case histories are also presented. The data reflected the
      problems of the process of establishing the new services, period of creation and
      difficulties of working with children having severe disturbances and their
      families. Diagnosing and treatment of motor disabilities were dominating while
      emotional and behavioral disorders were underdiagnosed, case histories lacked
      complexity of the biopsychosocial view. Recommendations for the ways for future
      development are provided stressing the importance of seeking more complex
      interventions including psychosocial aspects of child development and family
      counseling.

PMID- 12474796
TI  - [The assessment of infant motor development disorders in primary health care
      institutions].
AB  - OBJECTIVE: The delay or disorders of infant motor development require early
      screening and treatment. The objective of this study was to investigate the
      possibilities to assess infant motor development disorders in primary health care
      institutions of central part of Lithuania. MATERIALS AND METHODS: The original
      questionnaires were sent to primary health care institutions of Kaunas district.
      One-hundred-forty-eight questionnaires with answers of General Practitioners and
      Pediatricians returned to investigators. RESULTS: Analysing the data we found
      that one physician in average takes care of 28.8 +/- 18.4 infants, among these
      infants 3.55 +/- 4.2 have disorders of motor development. Most of the doctors
      (92.6%) evaluate the infant motor development, but use only the method of routine
      clinical assessment. Very few physicians (4.8%) use very precise methods of
      assessment (Munich diagnostic scheme or Bobath method). Among all doctors 66.9%
      expressed the will to asses infant motor development by themselves in primary
      health care clinic. CONCLUSIONS: We conclude, that General Practitioners and
      Pediatricians feel the lack of competence and assistant aids for the assessment
      of motor development disorders in infants.

PMID- 12474798
TI  - [Anxiety disorders in children and adolescents. Psychotherapeutic interventions].
AB  - Anxiety disorders are among the most prevalent mental health problems in
      childhood and adolescence. In this article authors share their experience working
      with anxiety disorders in inpatient department. Fifty four case histories were
      analyzed. Authors present, which part of psychiatric disorders takes the anxiety
      disorders and how they distribute according to ICD-10 diagnostic categories.
      Anxiety disorders' risk factors, main clinical symptoms and psychotherapeutic
      methods are discussed.

PMID- 12474799
TI  - [Antipsychotic agents and pharmacotherapy of psychoses].
AB  - Antipsychotic drugs have been used clinically for approximately 50 years.
      Reserpine and chlorpromazine were first drugs found be useful in schizophrenia.
      The term "antipsychotic" is used to describe a group of drugs that has been used
      mainly for treating of schizophrenia, but also is effective in some other
      psychoses and agitated states. The dopamine hypothesis is the most fully
      developed of several hypothesis and is the basis for rational drug therapy.
      However, the dopamine hypothesis is far from complete. Typical antipsychotic
      drugs have a wide spectrum of central nervous system, autonomic and endocrine
      effects. The most recently introduced antipsychotics are at least as potent in
      inhibiting 5-HT receptors as they are in inhibiting D receptors. A rational
      choice of antipsychotic drugs may be based on differences between chemical
      structures and pharmacological differences. No basis exists for choosing drugs
      for the use against selected target symptoms, as there is no evidence of
      specificity in their effects.

PMID- 12474800
TI  - Superoxide generation and bioelectrogenesis in wheat root cells with modified ion
      conductance of plasmalemma.

PMID- 12474801
TI  - The effects of immunomodulating peptides on the preimplantation development of
      mouse embryos.

PMID- 12474802
TI  - The molecular chain of electron transfer in the primary act of bacterial
      photosynthesis as determined using femtosecond spectroscopy.

PMID- 12474803
TI  - Effects of pineal-gland peptides on the electric activity of pinealocytes in
      rats.

PMID- 12474804
TI  - Assessment of 241Am accumulation rate by samples of algobacterial community of
      the Yenisei River.

PMID- 12474805
TI  - New data on the content of tritium in a tributary of the Yenisei River.

PMID- 12474806
TI  - Correlation between the concentrations of alkaloids and chemical elements as
      estimated in the seeds of Lupinus polyphyllus Lindl. Using mathematical
      simulation.

PMID- 12474807
TI  - Mechanisms of natural protection of plant ecosystems against radiation.

PMID- 12474808
TI  - [The life achievements of Jaroslav Pojer, professor of internal medicine].

PMID- 12474810
TI  - Lack of expertise and funding are hampering prostate cancer screening and
      treatment.

PMID- 12474812
TI  - Companies refuse to deliver drugs as hospital debts soar.

PMID- 12474813
TI  - A pilot test of WebOSCE: a system for assessing trainees' clinical skills via
      teleconference.
AB  - WebOSCE is a computer-based system that allows a student at an affiliate site to
      participate in a 10-station standardized patient-based exam using a
      videoconference interface, while nine other students take the exam on-site. We
      pilot-tested this system during a required year-end objective structured clinical
      exam. We compared performance data between the 26 distance students taking the
      exam via WebOSCE with 221 on-site students. We also compared both student groups'
      responses on a post-exam questionnaire, and conducted a post-exam structured
      interview to elicit the Pittsburgh students' perspectives on the WebOSCE
      experience. Students taking the exam via WebOSCE scored significantly lower in
      most categories except for physical exam and information-giving skills, on which
      the groups did not differ. There were no differences between groups in students'
      overall evaluation of the exam experiences. In general, Pittsburgh students rated
      WebOSCE highly and offered many helpful comments to improve the technology and
      the experience.

PMID- 12474815
TI  - Community-oriented medical emergency programme: development and evaluation
      issues.
AB  - A community-oriented medical emergency programme for multidisciplinary healthcare
      professionals on the Higher Professional Diploma in International Healthcare
      Studies, at the United Medical Education College, London is described. The main
      aim of the course is to introduce students to the clinical skills of dealing with
      medical emergency problems and situations. Students are also exposed to how
      medical emergency is practised in the community. The four-week programme consists
      of 16 sessions of clinical skills teaching where students are attached to various
      community clinics, 10 sessions of college teaching, consisting of talks,
      workshops and interactive small-group work and four sessions encouraging students
      to learn independently in a self-directed learning format. Student and tutor
      evaluations of the programme demonstrate that its aims are being met. However,
      further adaptation of the module to increase the range and quantity of clinical
      cases for student learning is being planned.

PMID- 12474816
TI  - Copying letters to patients. Policy should be implemented as soon as possible.

PMID- 12474817
TI  - Copying letters to patients. No one really cares.

PMID- 12474818
TI  - Comparison of different measures of blood pressure. Study was not first or only
      one.

PMID- 12474819
TI  - Comparison of different measures of blood pressure. Agreement is not same as
      correlation.

PMID- 12474820
TI  - Comparison of different measures of blood pressure. Ambulatory blood pressure may
      not be gold standard.

PMID- 12474821
TI  - Comparison of different measures of blood pressure. Blood pressure measurement
      causes problems in clinical practice.

PMID- 12474822
TI  - Benefiting from 'evil': an incipient moral problem in human stem cell research.
AB  - When does benefiting from others' wrongdoing effectively make one a moral
      accomplice in their evil deeds? If stem cell research lives up to its therapeutic
      promise, this question (which has previously cropped up in debates over fetal
      tissue research or the use of Nazi research data) is likely to become a central
      one for opponents of embryo destruction. I argue that benefiting from wrongdoing
      is prima facie morally wrong under any of three conditions: (1) when the
      wrongdoing is one's agent; (2) when acceptance of benefit directly encourages the
      repetition of the wrongful deed (even though no agency relationship is involved);
      and (3) when acceptance of a benefit legitimates a wrongful practice. I conclude
      by showing that, because of the ways in which most embryonic stem cell lines come
      into being, people who oppose embryo destruction may use human embryonic stem
      cells without incurring moral blame.

PMID- 12474823
TI  - Retaining nurses in the NHS. People starting nurse training should think again.

PMID- 12474824
TI  - Retaining nurses in the NHS. Poor pay is not the only reason.

PMID- 12474825
TI  - Retaining nurses in the NHS. Nurses' loyalty may be underestimated.

PMID- 12474826
TI  - The ins and outs of organic farming.

PMID- 12474827
TI  - Embryonic stem cell research and therapy: the need for a common European legal
      framework.
AB  - The possibility of obtaining stem cells from human embryos has given rise to an
      intensive legal and ethical debate. In this paper, attention is paid to the
      normative disparity and ambiguity in Europe. An argument for the need for a
      minimum legal harmonization is made; and a prudent and flexible way to reach this
      successfully is suggested. Establishing a common legal framework seems to be the
      only way to guarantee true competitiveness for the European scientific community.

PMID- 12474828
TI  - Thrombolysis for acute ischaemic stroke. Good quality research that addresses
      patients' needs is required.

PMID- 12474829
TI  - Organic farming and energy efficiency.

PMID- 12474830
TI  - When medical students go off the rails. In New York standards are set and tools
      for help given at start of medical school.

PMID- 12474831
TI  - Doctors question use of dead or dying patients for training.

PMID- 12474832
TI  - Review boards pose threat to tough work by social scientists.

PMID- 12474833
TI  - Would Title IX help women in science?

PMID- 12474834
TI  - Court upholds state access to abortion clinic records.

PMID- 12474835
TI  - Nepal legalizes abortion, bans child abuse.

PMID- 12474836
TI  - Drug industry is told to stop gifts to doctors.

PMID- 12474837
TI  - Trials are halted on gene therapy: child in experiment falls ill--new setback for
      research.

PMID- 12474839
TI  - Would Title IX help women in science?

PMID- 12474838
TI  - On medicine's frontier: the last journey of James Quinn: an experimental
      artificial heart gave him a few more months of life, but he regretted his
      decision to accept it.

PMID- 12474840
TI  - U.S. troops were subjected to a wider toxic testing.

PMID- 12474841
TI  - Panel advises resuming genetic studies: U.S. agency halted trials after boy fell
      ill in French experiment.

PMID- 12474842
TI  - Atacamite in jaws and printed wiring boards.

PMID- 12474843
TI  - Court ruling limits prosecutors' access to patient records.

PMID- 12474844
TI  - U.S. tested a nerve gas in Hawaii.

PMID- 12474845
TI  - Persons of lesser values--moral argument and the "final solution".
AB  - For many persons, 'Holocaust-abomination' is a fixed point on their moral
      compass: if anything can be evil, it was. Yet at least one of the justifications
      deployed by its perpetrators (the eugenics argument) involves widely-held values
      concerning human health and procreation. Hence persons endorsing many current
      activities based on those values (e.g. genetic counselling) have been charged
      with being on a morally deplorable slippery slope. This paper sketches the
      necessary structure of a moral position capable of consistently embracing those
      values without placing its occupants on that slippery slope.

PMID- 12474846
TI  - A National Ecological Observatory Network.

PMID- 12474847
TI  - Sacrificing one to save many.
AB  - Attempts to solve the Trolley Problem by means of a single principle have proved
      unpersuasive. Nor can the intuition about Transplant be adequately grounded in
      the hypothetical dissent of rational contractors. It is explained by the initial
      liability principle, that loss should lie where it falls unless there is
      sufficient reason to shift it. If we did not think we should accept misfortune in
      such cases and thought that minimising loss of life was sufficient reason to
      shift the loss we should not be according others the minimum respect and
      treatment we feel is their due. The intuition about Trolley is explained by the
      affinity of that case to the pure case where the choice is between saving many
      and saving fewer, where minimising misfortune is the only credible option. But
      these considerations are not yet enough to accommodate the cases that lie between
      the extremes of Trolley and Transplant. We can handle the intermediate cases by
      attempting to assimilate them to one or other paradigm and to one another with a
      sensitivity to morally relevant and irrelevant differences that seeks initially
      to be faithful to the values reflected by our moral intuitions. Those intuitive
      judgements are unlikely to survive such an examination wholly unmodified.

PMID- 12474848
TI  - Blocked exchanges revisited.
AB  - This paper reconsiders the topic of blocked exchanges. It has been argued by some
      philosophers and social theorists that in order to encourage people to make
      donations of, e.g., blood, the sale of such items should be banned by law or
      public policy. In this paper I argue that (a) donations made without the option
      of selling are morally diminished and (2) selling such items isn't morally wrong
      or even insignificant in all cases since prudence (which is a moral virtue, pace
      Kant) may require that one sell them.

PMID- 12474849
TI  - Coherence and applied ethics.
AB  - In order for a moral theory to support application it must be able to provide
      determinate answers to actual moral problems or, at the least, to significantly
      narrow acceptable options. It must also support the development of a genuine
      consensus, one that is disinterested, reasonable, and unbiased. I argue that
      theories concentrating on principles, or on rules, or on particular cases fail to
      meet these standards. A full coherence theory, taking into account principles,
      rules, practices, and judgments holds the greatest promise for successful
      application. I present a detailed outline of a full coherence theory that is
      principled, pluralistic, and comprehensive. This coherence theory includes three
      basic principles (expressed both negatively and positively), but binds these, in
      terms of their explication and application, to rules and practices. This theory
      respects current practices but also directs us to change practices and
      institutions and even the interpretations of basic moral principles. The theory
      includes ways to determine which aspect of moral experience should take
      precedence in given circumstances, ways to determine who has particular
      obligations, and how--by means of a mutuality principle--value may be enhanced
      under conditions of value conflict.

PMID- 12474850
TI  - The numbers game.

PMID- 12474851
TI  - The animal health market.

PMID- 12474852
TI  - Start small, think big--the art of process R&D.

PMID- 12474853
TI  - [History and development of research in cardiorespiratory and pulmonary
      circulation in the Czech Republic].

PMID- 12474854
TI  - Joint European Conference on Reproduction. Tours, France, December 2002.
      Abstracts.

PMID- 12474855
TI  - Orthopaedic proceedings, 2001-2002.

PMID- 12474856
TI  - A 32-year-old Brazilian woman with severe headache and fever.

PMID- 12474857
TI  - Pieter W. Postma 1942-2002.

PMID- 12474858
TI  - Criteria for chemical selection for programs on human milk surveillance and
      research for environmental chemicals.
AB  - The people of the United States is exposed to a large number of chemicals in
      their daily lives. In order to prioritize chemicals that should be considered for
      surveillance of and/or research in human milk, criteria were developed at the
      Technical Workshop on Human Milk Surveillance and Research on Environmental
      Chemicals in the United States. The criteria include (1) lipid solubility and/or
      persistence in the environment; (2) extensive exposure (e.g., high-production
      volume chemicals and chemicals in personal care products); (3) known or suspected
      toxicity in a biological system; (4) historical interest, trend information; (5)
      chemicals of emerging concern; and (6) chemicals for medicinal use and chemicals
      in occupational settings. A working list of chemicals was developed for each of
      the criteria. It should be noted that more than one criterion may be applicable
      to a selected chemical, but the selected chemical should possess at least one of
      these designated criteria. It is hoped that by following a cohort of nursing
      women through their lactational cycle for a group of these chemicals, data
      generated will indicate the extent of infant exposure and may suggest methods for
      risk management to decrease inadvertent exposure for breast-feeding mothers and
      infants. While not the focus of this article, certain endogenous chemicals in
      human milk beneficial to the health of the infant warrant study as well.

PMID- 12474859
TI  - Abstracts of the 7th ESMO (European Society for Medical Oncology) Congress. 18-22
      October 2002, Nice, France.

PMID- 12474860
TI  - Abstracts of the XX Brazilian Congress of Neurology. 28 September-3 October 2002,
      Florianopolis, Santa Catarina, Brazil.

PMID- 12474862
TI  - Abstracts of The Movement Disorder Society's 7th International Congress of
      Parkinson's Disease and Movement Disorders. November 10-14, 2002. Miami, Florida,
      USA.

PMID- 12474861
TI  - 75th Scientific Sessions of the American Heart Association.

PMID- 12474863
TI  - The target animal safety test--is it still relevant?
AB  - In Europe, the target animal safety test (TAST) is stipulated by 52 European
      Pharmacopoeia monographs, by three European Union (EU) Directives and a number of
      EU guidelines as a routine test for veterinary immunologicals, to be carried out
      on the finished product. TAST data from seven European Official Member States
      Control Laboratories (OMCLs) and 14 manufacturers were retrospectively analysed.
      During 1994-1997, 11185 vaccine batches had been submitted for batch release, and
      the OMCLshad tested 670 batches in the TAST (665 passed, 4 passed after
      retesting, 1 failed). In total, 82 of these batches were not released; however,
      in only one case this was due to failure in the TAST. The data received from the
      14 manufacturers covered the years from 1997 to 1999. 11386 batches were tested
      in the TAST,of which 215 passed after retesting and 7 failed. Although only 30%
      of the OMCLs provided data and the data of the manufacturers are not complete
      they clearly indicate that the TAST does not contribute to the safety of
      veterinary vaccines and should therefore not be required as a routine batch test.
      In cases, where it appears to be necessary, detailed guidance on the test design
      and evaluation should be given.

PMID- 12474864
TI  - Assay parameters and methods of data analysis for the comparison of complement
      sources in the Neisseria meningitidis serogroup C serum bactericidal assay.

PMID- 12474866
TI  - [26th Annual meeting of the Austrian Society of Diabetes. 19-21 November 1998.
      Vienna, Austria. Abstracts].

PMID- 12474865
TI  - Abstracts of the American Academy of Optometry annual meeting. December 12-15,
      2002. San Diego, California, USA.

PMID- 12474867
TI  - Neural sites and pathways regulating food intake in birds: a comparative analysis
      to mammalian systems.
AB  - The paper reviews hypotheses explaining the regulation of food intake in mammals
      that have addressed specific anatomical structures in the brain. An hypothesis,
      poikilostasis, is introduced to describe multiple, homeostatic states whereby the
      regulation of metabolism and feeding occur in birds. Examples are given for both
      wild and domestic avian species, illustrating dynamic shifts in homeostasis
      responsible for the changes in body weights that are seen during the course of an
      annual cycle or by a particular strain of bird. The following neural structures
      are reviewed as each has been shown to affect food intake in birds or in mammals:
      ventromedial hypothalamic nucleus (n.), lateral hypothalamic area,
      paraventricular hypothalamic n., n. tractus solitarius and area postrema,
      amygdala, parabrachial n., arcuate n. and bed n. of the stria terminalis. Two
      neural pathways are described which have been proposed to regulate feeding. The
      trigeminal sensorimotor pathway is the most complete neural pathway characterized
      for this behavior and encompasses the mechanics of pecking, grasping and
      mandibulating food particles from the tip of the bill to the back of the buccal
      cavity. A second pathway, the visceral forebrain system (VFS), affects feeding by
      regulating metabolism and the balance of the autonomic nervous system. Wild,
      migratory birds are shown to exhibit marked changes in body weight which are
      hypothesized to occur due to shifts in balance between the sympathetic and
      parasympathetic nervous systems. Domestic avian species, selected for a rapid
      growth rate, are shown to display a dominance of the parasympathetic nervous
      system. The VFS is the neural system proposed to effect poikilostasis by altering
      the steady state of the autonomic nervous system in aves and perhaps is
      applicable to other classes of vertebrates as well.

PMID- 12474868
TI  - Molecular Medicine 2002. XXVIII Nordic Congress in Clinical Chemistry and XXXV
      Nordic Conference on Coagulation. Reykjavik, Iceland, 10-13 August 2002.
      Abstracts.

PMID- 12474869
TI  - Blood pressure and secondary prevention of strokes. How low should we go?
      Randomised trial of a perindopril-based blood-pressure-lowering regimen among
      6,105 individuals with previous stroke or transient ischaemic attack.

PMID- 12474870
TI  - Society for Reproductive Biology 33rd Annual Conference. Adelaide, Australia. 22
      25 September 2002. Abstracts.

PMID- 12474871
TI  - Abstracts of the General Meeting of the NASA Astrobiology Institute. April 10-12,
      2001. Washington, D.C., USA.

PMID- 12474872
TI  - HUPO (Human Proteome Organization) 1st World Congress. 21-24 November 2002,
      Versailles, France. Abstracts.

PMID- 12474873
TI  - Abstracts of the VIII Polish Conference on Cell Biology. Wroclaw, 23-25 September
      2002.

PMID- 12474875
TI  - Cumulative author and subject index for volumes 195 to 205 (2002).

PMID- 12474874
TI  - Interpretation of analysis.

PMID- 12474877
TI  - [75th Meeting of the Association of Ophthalmologists of the Rhine-Main Region. 26
      October 2002, Wiesbaden. Abstracts].

PMID- 12474876
TI  - Gene expression levels in different stages of progression in oral squamous cell
      carcinoma.
AB  - Oral squamous cell carcinoma (OSCC) is one of the most common cancer types
      worldwide. The prognosis for patients with this disease is generally poor and
      little is known about its progression. Gene expression studies may provide
      important insights to the molecular mechanisms of this disease. We analyzed gene
      expression data from a small panel of patients diagnosed with OSCC. Even with
      only 13 patient samples we were able to find genes with significant differences
      in expression levels between normal, dysplasia, and cancer samples. The largest
      differences in expression were generally found between normal and cancer samples,
      but significant differences were also found for several genes between dysplasia
      and the other two sample types. We also represent the significance levels of
      differentially expressed genes on the chromosome domain. The genes and genetic
      features we examine are potentially important factors on the molecular level in
      the progression of OSCC.

PMID- 12474878
TI  - Abstracts of the 3rd International Symposium on Silica, Silicosis, Cancer and
      other Diseases. S Margherita Ligure, Italy, 21-25 October 2002.

PMID- 12474880
TI  - Abstracts of the 13th Annual Meeting of the American Society of Echocardiography.
      Orlando, Florida, USA. June 9-12, 2002.

PMID- 12474879
TI  - Labeling of diphenhydramine-containing drug products for over-the-counter human
      use. Final rule.
AB  - The Food and Drug Administration (FDA) is issuing a final rule amending the final
      monographs for over-the-counter (OTC) antiemetic, antihistamine, antitussive, and
      nighttime sleep-aid drug products to add a warning statement for oral products
      containing diphenhydramine citrate or diphenhydramine hydrochloride. The warning
      advises consumers not to use oral OTC diphenhydramine products with any other
      product containing diphenhydramine, including products used topically. This final
      rule also includes the agency's conclusions on additional warning statements and
      a direction statement for OTC external analgesic drug products containing
      diphenhydramine hydrochloride. These conclusions will be incorporated into the
      final monograph for OTC external analgesic drug products in a future issue of the
      Federal Register. FDA is issuing this final rule after considering public
      comments on the agency's proposed regulation and all new data and information on
      drug products containing diphenhydramine that have come to the agency's attention

PMID- 12474881
TI  - Bibliography current world literature.

PMID- 12474883
TI  - Abstracts of the 5th Congress of the European Society for Sexual and Impotence
      Research. Hamburg, Germany, December 1-4, 2002.

PMID- 12474882
TI  - The Chronus II temporal database mediator.
AB  - Clinical databases typically contain a significant amount of temporal
      information. This information is often crucial in medical decision-support
      systems. Although temporal queries are common in clinical systems, the medical
      informatics field has no standard means for representing or querying temporal
      data. Over the past decade, the temporal database community has made a
      significant amount of progress in temporal systems. Much of this research can be
      applied to clinical database systems. This paper outlines a temporal database
      mediator called Chronus II. Chronus II extends the standard relational model and
      the SQL query language to support temporal queries. It provides an expressive
      general-purpose temporal query language that is tuned to the querying
      requirements of clinical decision support systems. This paper describes how we
      have used Chronus II to tackle a variety of clinical problems in decision support
      systems developed by our group.

PMID- 12474884
TI  - Abstracts of the Swedish Association of Urology annual meeting. Stockholm,
      Sweden, 28-29 November 2001.

PMID- 12474885
TI  - Abstracts for the 11th National Conference of the Inflammation Research
      Association. 6-10 October 2002, New York, USA.

PMID- 12474886
TI  - Abstracts of The Physiological Society scientific meeting held at University of
      Leeds, 10-12 September 2002.

PMID- 12474887
TI  - Bibliography. Current world literature. Nutrition and physiological function.

PMID- 12474889
TI  - Bibliography. Current world literature. Nutrition and the gastrointestinal tract.

PMID- 12474888
TI  - Bibliography. Current world literature. Micronutrients and nutraceutics.

PMID- 12474890
TI  - Cued in: advances and opportunities in freshwater chemical ecology.
AB  - We focus this mini-review on how naturally occurring chemical cues mediate
      ecological interactions, especially interspecific competition and predation in
      freshwater communities. Although freshwater chemical ecology lags behind
      terrestrial and marine chemical ecology, we identify recent progress toward: (1)
      identifying the chemical composition of cues important in food web interactions,
      e.g., specific glucosinolates, benzyl succinoates, and lignoids as deterrents to
      herbivory on freshwater macrophytes; (2) employing a nonreductionist approach
      that tests for emergent responses to suites of multiple chemical cues, e.g.,
      trade-offs in snail refuge-seeking behavior in the presence of chemical cues from
      both fish and crayfish; (3) investigating how abiotic forces, such as
      hydrodynamics, impact chemical communication across a broad spatial and temporal
      scale, e.g., drift responses of mayfly nymphs to whole-stream additions of trout
      cue; and (4) quantifying the importance of genetic variability, e.g., how
      chemical cues change selective pressures of local environments. The questions of
      interest in freshwater chemical ecology cross taxonomic boundaries; traverse
      broad spatial and temporal scales; demonstrate nonlinear, unpredictable results;
      and necessitate a multidisciplinary approach for adequate understanding.

PMID- 12474891
TI  - Marine tannins: the importance of a mechanistic framework for predicting
      ecological roles.
AB  - Since chemical ecology emerged as a field of marine science, it has been strongly
      influenced by studies of chemically mediated interactions in land-based systems.
      Marine chemical ecologists, like their terrestrial counterparts, initially
      focused on identifying natural products and evaluating the potential ecological
      roles of these products as defenses, attractants, or other cues. Now, like our
      land-based colleagues, we must increase our focus on the physiological and
      biochemical mechanisms that underlie the chemical interactions, paying particular
      attention to regulation of biosynthetic pathways, within-plant and between-plant
      signaling cues, and comparative and functional genomics. Here, we review the
      current state of knowledge regarding a heterogenous group of macrophyte natural
      products, the marine tannins and simple phenolics, to illustrate how such
      information is critical to future attempts to predict their ecological roles.

PMID- 12474892
TI  - Chemical cues for surface colonization.
AB  - Colonization of surfaces in marine benthic environments is often one of the most
      significant moments in the life history of benthic organisms, representing, for
      example, a change from a planktonic to a benthic existence, a shift from a mobile
      to a sessile life form, or the initiation of pathogenesis. Many of the surfaces
      that are colonized are, in fact, other marine organisms, and in a general sense
      there is widespread evidence that specific chemical cues derived from marine
      organisms affect colonization by both marine prokaryotes and eukaryotes. However,
      detailed information for any one system on the nature of such cues, their
      distribution in situ, and their effects on the demography of colonizers is rare.
      Here, we selectively review the literature on chemical cues for colonization in
      the sea, focussing on contrasts between positive (inducers) and negative
      (inhibitors, deterrents) cues and on prokaryote/eukaryote interactions. We also
      consider whether generalized life history or natural history characteristics of
      colonizers (i.e., the mobility of a propagule, the extent to which a species is a
      habitat generalist or specialist, etc.) affect their response to chemical cues,
      and we touch briefly on some recent highlights relevant to the critical interplay
      between hydrodynamics and chemistry. A number of important methodological
      concerns are now being addressed through the introduction of field assays and
      analyses for chemical cues, and through molecular techniques for the
      characterization of microbial biofilms. These developments are encouraging, as is
      the increasingly multidisciplinary and cross-taxonomic approach to research in
      this area.

PMID- 12474893
TI  - Ecological consequences of chemically mediated prey perception.
AB  - To locate food, mobile consumers in aquatic habitats perceive and move towards
      sources of attractive chemicals. There has been much progress in understanding
      how consumers use chemicals to identify and locate prey despite the elusive
      identity of odor signals and the complex effects of turbulence on chemical
      dispersion. This review highlights how integrative studies on behavior, fluid
      physics, and chemical isolation can be fundamental in elucidating mechanisms that
      regulate species composition and distribution. We suggest three areas where
      further research may yield important ecological insights. First, although basic
      aspects of stimulatory molecules are known, our understanding of how consumers
      identify prey from a distance remains poor, and the lack of studies examining the
      influence of distance perception on food preference may result in inaccurate
      estimation of foraging behavior in the field. Second, the ability of many animals
      to find prey is greatest in unidirectional, low turbulence flow environments,
      although recent evidence indicates a trade-off in movement speed versus tracking
      ability in turbulent conditions. This suggests that predator foraging mode may
      affect competitive interactions among consumers, and that turbulence provides a
      hydrodynamic refuge in space or time, leading to particular associations between
      predator success, prey distributions, and flow. Third, studies have been biased
      towards examining predator tracking. Current data suggest a variety of mechanisms
      prey may use to disguise their presence and avoid predation; these mechanisms
      also may produce associations between prey distributions and flow environments.
      These examples of how chemical attraction may mediate interactions between
      consumers and their resources suggest that the ecology of chemically mediated
      prey perception may be as fundamental to the organization of aquatic communities
      as the ecology of chemical deterrence.

PMID- 12474894
TI  - Chemical ecology of marine microbial defense.
AB  - Because marine animals and plants are continuously exposed to a large diversity
      of potentially harmful microorganisms, it seems reasonable to hypothesize that
      potential hosts might produce bioactive compounds to deter microbial attack.
      However, little is known about how host metabolites may defend against harmful
      microbes or facilitate the growth or colonization of helpful symbionts. While
      there is a large body of literature describing the antimicrobial activities of
      marine secondary metabolites, we are only now beginning to understand how these
      compounds function in an ecological context. For example, there is mounting
      evidence that nontoxic concentrations of secondary metabolites can have
      significant effects on microbial behavior, suggesting that certain host-microbe
      interactions are chemically mediated. Herein, we discuss the importance of
      employing ecologically relevant assays to elucidate microbiological effects and
      the need to develop a better understanding of host-microbe associations within an
      ecologically realistic context. Continued research in this field along with
      improved techniques will certainly provide further insight into how microbes have
      influenced the evolution of secondary metabolite production in marine organisms.

PMID- 12474895
TI  - Chemical defense of early life stages of benthic marine invertebrates.
AB  - Accurate knowledge of factors affecting the survival of early life stages of
      marine invertebrates is critically important for understanding their population
      dynamics and the evolution of their diverse reproductive and life-history
      characteristics. Chemical defense is an important determinant of survival for
      adult stages of many sessile benthic invertebrates, yet relatively little
      consideration has been given to chemical defenses at the early life stages. This
      review examines the taxonomic breadth of early life-stage chemical defense in
      relation to various life-history and reproductive characteristics, as well as
      possible constraints on the expression of chemical defense at certain life
      stages. Data on the localization of defensive secondary metabolites in larvae and
      the fitness-related consequences of consuming even a small amount of toxic
      secondary metabolites underpin proposals regarding the potential for Mullerian
      and Batesian mimicry to occur among marine larvae. The involvement of microbial
      symbionts in the chemical defense of early life stages illustrates its complexity
      for some species. As our knowledge of chemical defenses in early life stages
      grows, we will be able to more rigorously examine connections among phylogeny,
      chemical defenses, and the evolution of reproductive and life-history
      characteristics among marine invertebrates.

PMID- 12474896
TI  - Community and ecosystem level consequences of chemical cues in the plankton.
AB  - Aquatic organisms produce compounds that deter consumers, alter prey behavior,
      suppress or kill target and nontarget species, and dramatically affect food-web
      structure, community composition, and the rates and pathways of biogeochemical
      cycles. Toxins from marine and freshwater phytoplankton create health hazards for
      both aquatic and terrestrial species and can significantly affect human
      activities and the economic vitality of local communities. A reasonable case can
      be made that phytoplankton metabolites such as dimethyl sulfide (DMS) link
      interaction webs that span hundreds to thousands of kilometers and connect
      production from oceanic phytoplankton to desert cacti and coyotes via
      zooplankton, fishes, and sea birds. The possible role of DMS in global heat
      budgets expands this effect even further. The ecosystem-wide and potentially
      global consequences of aquatic chemical cues is an underappreciated topic that
      warrants additional attention.

PMID- 12474897
TI  - Influence of age and body size on alarm responses in a freshwater snail Pomacea
      canaliculata.
AB  - A hypothesis that size selection of prey by predators elicits size-specific
      responses from prey was examined. Freshwater snails, Pomacea canaliculata, ages
      1, 3, 7, 15, 30, or 60 days, were given an extract of 3-day-old snails, and 3-day
      old snails were given extracts of snails of the otherages oreggs. Snails 15 days
      or younger crawled out of the water in response to the 3-day-old snail extract,
      but older ones did not. The 3-day-old snails responded to the extracts of snails
      of all examined ages, but not to the extract of eggs. Snails of four size
      classes, 3-days-old, small (shell lengths 8-12 mm), medium (13-20 mm), and large
      (>28 mm) were given extracts of snails of each of these four classes. The 3-day
      old snails crawled out of the water in response to the extract of 3-day-old
      snails, but showed a lower or no response to other extracts. Larger snails buried
      themselves in the soil in response to the extract of snails of similar sizes.
      These responses are discussed in the context of the evolution of the snail's
      avoidance behavior in response to the size-dependent prey choice by the predator.

PMID- 12474898
TI  - Isolation of bacterial metabolites as natural inducers for larval settlement in
      the marine polychaete Hydroides elegans (Haswell).
AB  - The bacterial component of marine biofilms plays an important role in the
      induction of larval settlement in the polychaete Hydroides elegans. In this
      study, we provide experimental evidence that bacterial metabolites comprise the
      chemical signal for larval settlement. Bacteria were isolated from biofilms,
      purified and cultured according to standard procedures. Bacterial metabolites
      were isolated from spent culture broth by chloroform extraction as well as by
      closed-loop stripping and adsorption of volatile components on surface-modified
      silica gel. A pronounced biological activity was exclusively observed when
      concentrated metabolites were adsorbed on activated charcoal. Larvae did not
      respond to waterbome metabolites when prevented from contacting the bacterial
      film surface. These results indicate that an association of the chemical signal
      with a sorbent-like substratum may be an essential cofactor for the expression of
      biological activity. The functional role of bacterial exopolymers as an
      adsorptive matrix for larval settlement signals is discussed.

PMID- 12474899
TI  - Influence of Myriophyllum spicatum-derived tannins on gut microbiota of its
      herbivore Acentria ephemerella.
AB  - The submerged living larvae of Acentria ephemerella were fed in the laboratory
      with either M. spicatum or Potamogeton perfoliatus, two of their host plants.
      Larvae exhibited a reduced growth when fed M. spicatum, a freshwater angiosperm
      that contains high concentrations of tannins, secondary metabolites known for
      their herbivore-deterrent and antimicrobial properties. In this study, we
      investigated the influence of food-derived tannins on gut microbiota. Bacterial
      densities in the guts did not differ between the food regimes, ranging from 2.8
      to 13.3 x 10(6) cells per gut. Gut bacteria were characterized with cultivation
      techniques and subsequent identification of the strains by molecular methods. We
      isolated 17 bacterial strains belonging to all subdivisions, i.e., we identified
      alpha-, beta-, and gamma-proteobacteria, Cytophyaga/Flavobacteria (CF) and
      several Gram-positive bacteria. All except one Gram-positive strain were found in
      the guts of larvae fed with P. perfoliatus. Gram-positive bacteria and bacteria
      of the CF cluster were more sensitive to polyphenol-containing extracts of M.
      spicatum in an agar diffusion assay than strains of the alpha- or gamma
      proteobacteria subdivision. Our results suggest an influence of food-derived
      tannins on gut microbiota in A. ephemerella.

PMID- 12474900
TI  - Oligoalginate recognition and oxidative burst play a key role in natural and
      induced resistance of sporophytes of laminariales.
AB  - Forty-five species of brown algae (Phaeophyceae) were surveyed for their capacity
      to respond by an oxidative burst to challenges with alginate oligosaccharides.
      Intertidal frondose brown algae (Fucales) constitutively released high quantities
      of peroxide. The capacity to recognize oligoguluronates and to react with an
      oxidative burst was confined to alginate-rich taxa with complex thallus
      morphology, epitomized by the sporophytes of Laminariales. When kelp sporophytes
      were impaired in their capacity to perform an oxidative burst by the NAD(P)H
      oxidase inhibitor diphenylene iodonium, they were readily degraded by their
      bacterial epiflora. Thus, in these algae, the oxidative response is an essential
      element of natural resistance. We also report on the establishment of a well
      defined experimental system for investigations on kelp immunity, with Laminaria
      digitata as the host and its phaeophycean endophyte, Laminariocolax
      tomentosoides, as the pathogen. We found that an alginate-triggered oxidative
      burst significantly induces resistance in Laminaria digitata against infection.
      From these findings we infer that oligoalginate signals are important cues in the
      interaction between laminarialean kelps and potential pathogens.

PMID- 12474901
TI  - Induction of pseudopterosin biosynthesis in the gorgonian Pseudopterogorgia
      elisabethae.
AB  - A number of biological and physical stimuli have been evaluated as inducers of
      pseudopterosin biosynthesis in the sea whip Pseudopterogorgia elisabethae. Data
      indicate that the production of pseudopterosins can be significantly increased in
      response to high levels of predation by the mollusk Cyphoma gibbosum and in
      response to decreased levels of UV/visible radiation. High levels of feeding by
      Chaetodon capistratus and an artificial wounding of the sea whip did not result
      in increased pseudopterosin levels.

PMID- 12474902
TI  - Comparison of the wound-activated transformation of caulerpenyne by invasive and
      noninvasive Caulerpa species of the Mediterranean.
AB  - The invasive green alga, Caulerpa taxifolia, that has spread rapidly after its
      introduction into the Mediterranean and the North American Pacific, reacts to
      wounding by transforming its major metabolite caulerpenyne. This wound-activated
      reaction involves the transformation of the bis-enol acetate moiety of 1,
      releasing reactive 1,4-dialdehydes. The ability to perform this transformation is
      found also in both the noninvasive Mediterranean C. prolifera and the invasive C.
      racemosa. Trapping experiments, as well as transformation of the model substrate
      geranyl acetate, suggest that all three investigated Caulerpa spp. rely on
      esterases that act upon wounding of the algae by subsequently removing the three
      acetate residues of caulerpenyne. The resulting reactive 1,4-dialdehyde oxytoxin
      2 can be identified by liquid chromatography-mass spectrometry and is unstable in
      the wounded tissue. Caulerpenyne transformation occurs rapidly, and severe tissue
      damage caused degradation of more than 50% of the stored caulerpenyne within 1
      min in all three algae. Prevention of the enzymatic reaction before extraction,
      by shock freezing the tissue with liquid nitrogen, was used for the determination
      of the caulerpenyne content in intact algae. It gives about twofold higher values
      compared to an established methanol extraction protocol. The speed and mechanism
      of the wound-activated transformation, as well as the caulerpenyne content in
      intact tissue of invasive and noninvasive Caulerpa spp., are comparable. Thus,
      this enzymatic transformation, despite being fast and efficient, is likely not
      the key for the success of the investigated invasive species.

PMID- 12474903
TI  - Role of semiochemicals in mate location by parasitic sea louse, Lepeophtheirus
      salmonis.
AB  - The role of olfaction and diffusible pheromones in mate location behavior of sea
      lice, Lepeophtheirus salmonis, was assessed with Y-tube behavioral bioassays. The
      pheromone "emitting" animals were located in a chamber in one arm of a Y-tube
      arena, with artificial seawater flowing through both arms. Adult male sea lice
      displayed both activation and directional responses to seawater conditioned with
      preadult II virgin females, but were only activated by mated adult female
      conditioned water. Further, when males were given the choice of preadult II
      virgin females or mated adult females, a significant number of males chose the
      arm with the preadult II virgin females. Adult males showed activation responses
      when presented with water conditioned with adult males but were not attracted to
      them. When presented with adult males, preadult II virgin females showed only
      directional responses, but not activation responses. Preadult II virgin female
      conditioned water was extracted using solid-phase extraction (SPE) protocols
      pioneered for semiochemical isolation. Adult male sea lice showed significant
      directional responses to the preadult II virgin female SPE extract. Distillation
      under vacuum was performed on the extract to give a distillate comprising
      components with a molecular weight range and physical properties comparable to
      those of compounds utilized as volatile semiochemicals by terrestrial organisms
      and a residue comprising components with higher molecular weight range comparable
      to those utilized as involatile semiochemicals. Adult males were found to be both
      significantly activated and attracted to the distillate, but not to the residue.
      This research provides evidence that small, lipophilic organic molecules are used
      by sea lice as sex pheromone signals to locate a member of the opposite sex.

PMID- 12474904
TI  - Myth #53: Qualitative research is cheap.

PMID- 12474905
TI  - Reconciling incompatibilities: a grounded theory of HIV medication adherence and
      symptom management.
AB  - The purpose of this grounded theory study was to explain how ethnically diverse
      men and women living with HIV manage their interacting illness symptoms,
      medication side effects, and treatment adherence choices. The authors used the
      constant comparative method to analyze textual data from in-depth interviews with
      66 HIV-infected people representing the changing HIV demographic profile in the
      San Francisco Bay area and generate a theory of Reconciling Incompatibilities.
      Adherence options of complying, not complying, or self-tailoring occurred in a
      context of attributional uncertainty as to whether distress was illness- or
      treatment-related, a sometimes silent virus, and perceived fickle medical
      markers. Conditions, including self-identity, illness ideology, concurrent
      treatment regimens, the meaning of time, medication burden and side effects, and
      lifestyle, coalesced to produce a state of mind that shaped adherence choices on
      a dose-by-dose basis. This theory offers a basis for interventions designed to
      promote optimal adherence choices concerning HIV therapies.

PMID- 12474906
TI  - In invisibility and isolation: the experience of HIV-affected families in German
      speaking Switzerland.
AB  - Based on critical hermeneutics, the author presents insights about caregiving
      experiences of HIV-affected families in Switzerland. Using a qualitative
      approach, she interviewed 11 families and conducted 3 group discussions with
      members of different families. Two main themes emerged--Caught In Between: Family
      Changes Forced by HIV/AIDS and No Request for Support: Family Caregiving in the
      Context of Invisibility. The former portrays the families' struggle with new
      family constellations. Members felt close to, ambivalent toward, or distant from
      the infected member and built subgroups representing these connections and
      values. The latter portrays the families' withdrawal from their environment,
      whereby one or two close family members almost invisibly provided caregiving
      without outside support. These behaviors were reinforced by the Swiss health care
      system, which focuses on individuals. Suggestions for interventions are
      introduced.

PMID- 12474907
TI  - Cognitive representations of AIDS: a phenomenological study.
AB  - Cognitive representations of illness determine behavior. How persons living with
      AIDS image their disease might be key to understanding medication adherence and
      other health behaviors. The authors' purpose was to describe AIDS patients'
      cognitive representations of their illness. A purposive sample of 58 men and
      women with AIDS were interviewed. Using Colaizzi's (1978) phenomenological
      method, rigor was established through application of verification, validation,
      and validity. From 175 significant statements, 11 themes emerged. Cognitive
      representations included imaging AIDS as death, bodily destruction, and just a
      disease. Coping focused on wiping AIDS out of the mind, hoping for the right
      drug, and caring for oneself. Inquiring about a patient's image of AIDS might
      help nurses assess coping processes and enhance nurse-patient relationships.

PMID- 12474908
TI  - To work or not to work: combination therapies and HIV.
AB  - The authors describe the labor force experiences of people living with HIV and
      AIDS (PHAs) who are taking combination therapies using information from in-depth
      interviews conducted in 1999 and 2000 in the Windsor and Essex County region of
      Canada with 35 PHAs. They analyze labor force experience contextually, setting it
      within the contexts of personal illness experience (including disease trajectory
      and treatment history), workplace structure and discrimination, the labor market,
      and the structure of health and social service systems. Barriers to returning to
      or remaining in the labor force are numerous and require a specific commitment to
      overcome. Existing workplace and government policies and programs and labor
      market conditions impede labor force participation for PHAs who have recovered
      from serious illness and are now able and willing to work.

PMID- 12474909
TI  - The social construction of sexually transmitted infections (STIs) in South
      African communities.
AB  - Since the medical link between sexually transmitted infections (STIs) and
      HIV/AIDS was established, there has been an increased focus on the spread of STIs
      in South Africa. The aim of this study was to provide an in-depth picture of the
      dynamics involved in sexuality and the spread of STIs and HIV/AIDS. The authors
      present the findings of a focus group study, which was a part of a larger,
      national project addressing the broad question of health-care seeking behavior
      for STIs. A discourse analysis carried out on 10 focus groups reveals complex and
      rich narratives on the way in which STIs are constructed in South African
      communities. The dominant discourses focused on the continuing stigmatization of
      STIs, causal explanations, and prevention strategies. The analysis raises
      important recommendations for both educational interventions and health services
      toward the challenge of halting the spread of STIs and HIV/AIDS.

PMID- 12474910
TI  - Malnutrition, dehydration, and starvation in the midst of plenty: the political
      impact of qualitative inquiry.
AB  - The author presents findings from studies investigating the factors that
      influence the quality of care in nursing homes. The findings disclose that
      multiple factors, such as lack of individualized care, inattention to problems
      such as dysphagia and oral health care, and especially inadequate staffing and
      lack of professional supervision contribute to malnutrition, dehydration, and
      weight loss among nursing home residents. She describes how these qualitative
      studies had a significant impact on long-term health care policy. She urges
      investigators to publish research in the public realm accessible to those who can
      effect change and thus prevent pain and suffering among nursing home residents.
      Furthermore, she emphasizes the importance of publishing qualitative findings in
      a language understandable by the media, policy makers, governmental agencies,
      politicians, and the lay public.

PMID- 12474911
TI  - Human body parts as therapeutic tools: contradictory discourses and transformed
      subjectivities.

PMID- 12474912
TI  - Enhancing the usefulness of qualitative inquiry: gaps, directions, and
      responsibilities.
AB  - Although qualitative researchers have often complained that our research is not
      funded, that our articles receive unfair reviews, and that our findings are not
      implemented, as a discipline we have been slow to develop criteria for review of
      articles, are just beginning to develop criteria for review of proposals, and
      have not yet suggested mechanisms for the transference of qualitative findings
      into practice. In this keynote address, using the example of a project conducted
      at a summer camp for ventilator-dependent children, the author examines these
      issues of review and utilization and explores the responsibility of qualitative
      researchers. She argues that by meeting these needs, qualitative researchers will
      expedite qualitative inquiry and hence will legitimize the discipline.

PMID- 12474913
TI  - How do we talk to each other? Writing qualitative research for quantitative
      readers.
AB  - The growth of qualitative research holds the potential for vastly enriching our
      understanding of phenomena in the health sciences. However, the potential of this
      trend is hampered by a widespread inability of quantitative and qualitative
      researchers to talk to each other. The authors' concern in this area grows out of
      our experience reviewing small grant applications for the National Institute on
      Aging, where they frequently find qualitative research proposals scoring worse
      than do those using quantitative approaches. This article addresses practical
      problems in communicating qualitative research to readers whose training and
      experience is primarily quantitative. Two themes running through the discussion
      are the need for detail and the explicit tying of methodological strategies to
      research goals.

PMID- 12474914
TI  - Abnormalities of orbital volume.
AB  - New information on the physiopathology and treatment of orbital volumes
      pathologies is described: 1) In post-enucleation or evisceration socket syndrome
      placing of synthetic material (HA-TCP) directly in the intraconal orbital fat can
      correct most of the symptoms. However the best approach is to prevent orbital
      volume deficiencies during first surgery using an implant large enough to allow a
      future prosthesis of a volume less than 2 mL. New procedures for placing the
      implant after enucleation or evisceration are described. 2) In proptosis related
      to Graves' orbitopathy relative indications are given for orbital decompression
      by removal of fat or bone.

PMID- 12474915
TI  - Ultrasound measurement of the horizontal external eye muscles in patients with
      thyroid disease. Is orbital involvement associated with thyroid autoantibodies?
AB  - PURPOSE: To describe ophthalmic findings with emphasis on exophthalmometry and
      ultrasonic assessment of extraocular eye muscle diameter in a consecutive group
      of females with Graves' disease (GD), compared with healthy controls and patients
      with other thyroid diseases. We also investigated the relationship with
      biochemical markers of thyroid autoimmunity such as TSH receptor antibodies
      (TRAb) and anti-thyroid peroxidase antibodies (anti-TPO). METHODS: Seventy adult
      women (age 26-74 years) with various types of thyroid disease consecutively
      entered the study at a tertiary referral center for thyroid-associated
      ophthalmopathy (TAO). Twenty-three had long-standing GD with TAO. Clinically, TAO
      was mainly absent in 22 with newly diagnosed GD and in seven with relapse of GD.
      Nine with Hashimoto's thyrolditis and nine with multinodular goiter were included
      for comparison and 18 healthy females served as controls. A full ophthalmic
      status included B-scan ultrasonic assessment of the four horizontal rectus muscle
      thicknesses, and a clinical NOSPECS score was attempted for each. RESULTS AND
      CONCLUSIONS: Besides higher NOSPECS scores, the TAO subgroup had higher
      exophthalmometry and muscle thickness. The GD groups without significant TAO also
      scored higher in these ratings compared to controls. Hertel recordings, NOSPECS
      and muscle thicknesses were all correlated in GD but showed no correlation to
      thyroid antibodies (TRAb and anti-TPO). Thus, the muscle thickness did not
      correlate with thyroid autoimmune activity. Nevertheless, we found extraocular
      muscle assessment useful since a) thicker muscles were usually found in patients
      with GD, with or without evidence of TAO, and b) other space-occupying orbital
      lesions could be excluded, thereby reducing the need for the more elaborate
      imaging techniques (CT, MRI, etc.).

PMID- 12474916
TI  - Fluorescein dye disappearance test in patients with different degrees of
      epiphora.
AB  - PURPOSE: To assess the diagnostic efficacy of a modification of the fluorescein
      dye disappearance test (DDT) in patients with different degrees of epiphora.
      METHODS: DDT was performed by instilling a drop of 2% fluorescein in the eye.
      Schirmer tear test strips were placed in the lower conjunctival fornix, after 3
      and 10 minutes. The colour dilution on the strips was compared to a scale with
      known standards and the most closely comparable colour dilution was chosen and
      recorded as the visual scale test (VST) grade of the strip. The grey-scale value
      (GV) of each strip was calculated by computer image analysis. The control group
      comprised 44 patients, mean age 44.8 years (SD 7.5, range 30-60). There were 13
      patients in group 1 with moderate epiphora; mean age was 44.2 years (SD 9.5,
      range 30-60). There were 17 patients in group 2 with severe epiphora; mean age
      was 48.3 years (SD 7.7, range 37- 60). RESULTS: VST and GV differed significantly
      between controls and group 1 patients at 3 minutes (p=0.002, p=0.001), and
      between controls and group 2 patients at 3 minutes (p<0.001, p<0.001). There was
      no difference between groups 1 and 2 patients in VST and GV at 3 minutes. The
      differences were highly significant between controls and group 1 at 10 minutes
      (p=0.001, p=0.007), and between controls and group 2 at 10 minutes (p<0.001,
      p<0.001). The differences in GV and VST between groups 1 and 2 were significant
      at 10 minutes (p=0.026, p=0.018). CONCLUSIONS: This modified DDT permits
      identification of different degrees of epiphora in a non-invasive manner, it can
      therefore be used to evaluate the outcome of different treatment strategies.

PMID- 12474917
TI  - Topical allopurinol or corticosteroids and acetylcysteine in the early treatment
      of experimental corneal alkali burns: a pilot study.
AB  - PURPOSE: To investigate the effect of topical allopurinol on experimental corneal
      burns and to compare this to established treatment modalities such as topical
      prednisolone and acetylcysteine. METHODS: Twenty Wistar rats were randomly
      assigned to four groups (n=5 each). The groups were controls (normal saline),
      allopurinol 0.4% eye drops, prednisolone acetate 1% eye drops and acetylcysteine
      8% eyedrops. Corneal burn was induced using a 3 mm paper disc soaked in 1N NaOH
      for 60 seconds. Drops were instilled 6 times per day. In addition, one drop/day
      ofloxacine was given to prevent secondary infections. Eyes were enucleated 50
      hours later and fixed in 4.5% formaldehyde. Three histological levels of each
      globe were stained with hematoxylin-eosin and examined by two independent masked
      investigators using a 0 to 4+ inflammatory score. All pair-wise multiple
      comparison procedures (Student-Newman-Keuls method) were applied for statistical
      work-up. RESULTS: All three substances significantly reduced the number of
      histologically visible inflammatory cells compared to the control group (p<0.05).
      CONCLUSIONS: In the present study, topical allopurinol was as effective as
      established drugs, namely steroids and acetylcysteine, in the early treatment of
      experimental alkali corneal burns.

PMID- 12474918
TI  - Corneal complications following abuse of topical anesthetics.
AB  - PURPOSE: To describe corneal complications in three patients following abuse of
      topical anesthetics. MATERIALS AND METHODS: We describe one case with bilateral
      corneal perforation, another with unilateral corneal perforation and a third case
      of chronic keratitis following excessive use of topical anesthetics. RESULTS: Two
      patients continued to instill topical anesthetic drops despite all
      recommendations to stop. The result was a bilateral corneal perforation in the
      first case and a large unilateral descemetocele in the second. The third patient
      who had chronic toxic keratitis discontinued the anesthetic drops and after the
      appropriate treatment the cornea returned to normal. Corneal grafting and
      conjunctival flaps were used to seal the corneal perforation but the long-term
      anatomical and functional results were very poor. CONCLUSIONS: The initial
      presentation of this rare clinical entity creates difficulties in reaching a
      correct diagnosis. A presumed acanthamoeba keratitis is the first choice among
      many similar conditions. Thus abuse of topical ocular anesthetic drops should be
      included in the differential diagnosis of cases of chronic keratitis as it may
      masquerade as acanthamoeba keratitis. A current or past history of psychiatric
      and mental disorders or psychoactive substance abuse is important in the
      diagnosis. Functional and anatomical results after appropriate treatment are
      usually poor. Psychiatric counselling is extremely helpful and is in fact
      mandatory in the management of these patients.

PMID- 12474919
TI  - Photorefractive keratectomy for compound myopic astigmatism with the MEL-70 G
      Scan excimer laser.
AB  - PURPOSE: To assess the safety, efficacy, predictability and stability of
      photorefractive keratectomy in compound myopic astigmatism with a moderate and
      high cylinder component. METHODS: Photorefractive keratectomy was done in 42 eyes
      with compound myopic astigmatism with the spherocylindrical algorithm of the MEL
      70 excimer laser, with wide ablation zones. RESULTS: Spherical equivalent
      refraction changed from -4.19 +/- 1.65D to -0.05 +/- 0.31D, refractive cylinder
      from -2.01 +/- 0.71D to -0.09 +/- 0.20D and mean sphere from -3.22 +/- 1.76D to 
      0.02 +/- 0.26D. Mean uncorrected visual acuity rose from 0.12 +/- 0.17 to 0.91 +/
      0.10. No eye lost lines of spectacle-corrected visual acuity. The safety index
      was 1.03 and the efficacy index 0.98. Six months from the treatment all eyes were
      within +/- 1D, 8.9% of eyes were within 0.50D and 44% were plano of target
      refraction. Refractive and topographical stability were achieved between one and
      three months after treatment. Transient haze was observed between one and three
      months after PRK. CONCLUSIONS: Photorefractive keratectomy with the MEL-70
      excimer laser to correct myopic astigmatism was a safe and effective procedure
      with good stability at six months' follow-up. Refractive and visual outcome
      confirmed that excellent predictability can be expected.

PMID- 12474920
TI  - Refractive lens exchange for correction of high myopia.
AB  - PURPOSE: To evaluate the efficiency and safety of refractive lens exchange for
      the correction of high myopia. METHODS: We made a prospective study of the
      results of refractive lens exchange in 72 eyes that had undergone this surgical
      procedure between January 1996 and January 2001. Lens extraction by
      phacoemulsification was done by one surgeon on 34 patients. Follow-up was five
      months to five years (mean 48 months). The postoperative refractive target was
      emmetropia or a low degree of myopia. We compared pre- and postoperative
      uncorrected visual acuity, and preoperative best-corrected visual acuity with
      postoperative uncorrected visual acuity. Intra- and postoperative complications
      were recorded. RESULTS: In 72.2% of the eyes best-corrected visual acuity (BCVA)
      was > or = 0.5 before surgery. Four years after refractive lens exchange,
      uncorrected visual acuity (UCVA) was > or = 0.5 in 58.3% of eyes, and the
      proportion of eyes with BCVA > or = 0.5 increased to 83.3%. The sphere was fully
      corrected in 70.8% of cases, remained within 1.0 D of emmetropia in 87.5% and
      within 2.0 D of emmetropia in 95.8%. Posterior capsule opacification developed in
      22 eyes (30.5%) and was treated with neodymium:YAG (Nd:YAG) laser capsulotomy.
      Cystoid macular edema with retinal detachment occurred in one eye. No wound
      leakage or eye infections were observed during five years' follow-up.
      CONCLUSIONS: Refractive lens exchange seems to be an effective alternative for
      the correction of high myopia, helping people over 40 years of age regain their
      distant vision.

PMID- 12474922
TI  - A comparison of endophthalmitis after phacoemulsification or extracapsular
      cataract extraction in a socio-economically deprived environment: a retrospective
      analysis of 2446 patients.
AB  - PURPOSE: To assess which cataract operation technique involves least risk of
      postoperative endophthalmitis, when performed in a population living in poor
      hygiene conditions. METHODS: This retrospective clinical study evaluated 2446
      cases at the Eye Clinic of the Komotini General Hospital, Greece, between January
      1998 and January 2001. RESULTS: Endophthalmitis arose in 12/1055 patients (1.13%)
      after extracapsular cataract extraction (ECCE) and in 8/1391 after
      phacoemulsification (0.57%). The mean time to onset of endophthalmitis was 23 and
      73 days respectively after phacoemulsification and ECCE. This difference was
      statistically significant. CONCLUSIONS: Endophthalmitis develops considerably
      later after ECCE than phacoemulsification. Thus it would appear that hygiene
      conditions have a stronger effect in patients operated with the ECCE technique.
      In order to reduce the risk of endophthalmitis after cataract extraction in
      patients living in substandard conditions, phacoemulsification is proposed as
      preferable to ECCE.

PMID- 12474921
TI  - Posterior capsule opacification and Nd:YAG capsulotomy rates after implantation
      of silicone, hydrogel and soft acrylic intraocular lenses: a two-year follow-up
      study.
AB  - PURPOSE: To compare the posterior capsule opacification (PCO) and neodymium:YAG
      (Nd:YAG) laser posterior capsulotomy rates associated with three different
      posterior chamber foldable intraocular lenses (IOL). METHODS: We retrospectively
      evaluated the rates of PCO and Nd:YAG laser capsulotomy in 1150 eyes two years
      after standard phacoemulsification with a no-stitch 3.5mm clear corneal incision
      (CCI) and in-the-bag implantation of one of three types of IOL: 190 eyes received
      a one-piece round-edged hydrogel IOL (Hydroview H60M, Bausch & Lomb); 475 eyes a
      three-piece round-edged silicone IOL (AMO PhacoFlex SI-40NB, Allergan); 485 eyes
      a three-piece square-edged soft acrylic lens (AcrySof MA60MA, Alcon). RESULTS:
      The PCO and Nd:YAG laser capsulotomy rates were respectively 43.15% and 20.5% in
      the Hydroview H60M group, 27.57% and 9.68% in the AMO PhacoFlex SI-40NB group,
      10.5% and 2.47% in the AcrySof MA60MA group. CONCLUSIONS: PCO and Nd:YAG laser
      capsulotomy rates were significantly higher in the Hydroview H60M group and
      significantly lower with the AcrySof MA60MA lenses, which combine a bioactive
      constitutive material with the square-edged optic design.

PMID- 12474923
TI  - Ab-interno trabeculo-canalectomy: surgical approach and histological examination.
AB  - PURPOSE: To evaluate, on eye bank eyes, a new surgical approach aimed at removing
      a quadrant of the trabecular meshwork (TM), with an ab interno approach. METHODS:
      Gonioscopically controlled ab interno removal of the TM was done with a
      subretinal forcep on six human bank eyes. Serial histological sections were
      obtained from the treated and untreated part of each globe to assess the effect
      of the technique on intraocular tissues. RESULTS: Under the gonioscope, the TM
      was easily removed in strings of varying length. Histological examination showed,
      unexpectedly, that this resulted in a well-defined deep furrow in the middle of
      the trabecular region involving both the TM and the inner wall of Schlemm's
      canal. The operation created a direct communication between the anterior chamber
      and Schlemm's canal lumen without any evident damage to the outer canal wall and
      adjacent ocular structures such as the iris base and corneal endothelium.
      CONCLUSIONS: Our small series on human bank eyes showed that the procedure
      involves both the TM and the inner wall of Schlemm's canal and is therefore
      called ab interno trabeculocanalectomy (AITC). The intraoperative findings and
      the histological evidence are encouraging, and suggest that the procecedure could
      have potential clinical application.

PMID- 12474924
TI  - Scanning laser polarimetric analysis of retinal nerve fiber layer thickness in
      Turkish patients with glaucoma and ocular hypertension.
AB  - PURPOSE: To assess the thickness of the retinal nerve fiber layer (RNFL) in
      patients with different stages of glaucoma, in comparison with ocular
      hypertensive (OHT) and healthy subjects in a Turkish population. METHODS:
      Scanning laser polarimetry was done with a GDx Nerve Fiber Analyzer (NFA, GDx
      version, 1.0.08) on 270 eyes with glaucoma, 52 OHT eyes, and 81 normal eyes. The
      eyes were classified as having early (146 eyes), moderate (66 eyes) and severe
      (58 eyes) glaucoma based on the Humphrey Visual Field indices. We compared 14 NFA
      parameters by analysis of variance (ANOVA) and Scheffe multiple comparison
      analysis. Receiver operator characteristic curves (ROC) and Fisher linear
      discriminant analysis (LDF) were used to measure the sensitivity and specificity
      of the NFA parameters. RESULTS: Except for symmetry, all NFA parameters showed
      significant differences between the groups (p<0.05). The eyes with glaucoma had
      significantly thinner RNFL than healthy eyes (p<0.01). The RNFL retardation
      measurements of OHT eyes were lower than controls, but higher than the early
      glaucoma group. The sensitivity and specificity of the GDx System were 87% and
      72.8%, respectively. Applying LDF, the group with the highest sensitivity and
      specificity (85.9% and 74.1%) was determined as inferior ratio, superior/nasal
      ratio, superior maximum and the Number. CONCLUSIONS: Assessment of RNFL thickness
      with scanning laser polarimetry can distinguish glaucoma, OHT and normal subjects
      with relatively high sensitivity and specificity.

PMID- 12474925
TI  - Usefulness of systematic ophthalmologic investigations in neurofibromatosis 1: a
      cross-sectional study of 211 patients.
AB  - PURPOSE: To evaluate the usefulness of ophthalmologic examination for diagnosis
      and for detection of complications in adult patients with neurofibromatosis 1.
      METHODS: PATIENTS with at least one criterion of neurofibromatosis 1 (excluding
      ophthalmologic criteria) seen at a referral centre had a systematic
      ophthalmologic examination including best-corrected visual acuity, slit-lamp
      examination and dilated funduscopy. The ophthalmologist was unaware of all other
      anamnestic data. RESULTS:  PATIENTS: 211 patients with NF1 were included (mean
      age: 32 +/- 14 yr.). Ophthalmologic examination in neurofibromatosis 1 patients:
      Lisch nodules (n = 185) (87.7%); choroidal hamartomas (n = 61) (29%); enlarged
      corneal nerves (n = 1); 3 plexiform neurofibromas (n = 3); symptomatic optic
      pathway gliomas (n = 5). Diagnostic contribution of presence of Lisch nodules: 6
      (3%) of 211 patients. Detection of complications: none. CONCLUSIONS: In adult
      patients with neurofibromatosis 1, the contribution of ophthalmologic examination
      to diagnosis and to the detection of complications is low. Ophthalmologic
      examination should be performed in patients for whom questioning and clinical
      examination failed to give evidence of NF1 or to determine the NF subtypes.

PMID- 12474926
TI  - Electro-oculographic abnormality in eyes with uveal melanoma.
AB  - PURPOSE: To seek out correlations between preoperative electro-oculogram (EOG)
      recordings with different types of uveal melanomas, after surgery. METHODS: We
      analysed the EOG recordings of 120 patients with uveal melanomas, histologically
      verified, 100 in the choroid and 20 in the iris and ciliary body. The EOG data
      were correlated with the site, size and histological type of the tumor. RESULTS:
      In 100 eyes with choroidal melanoma the Arden Index (AI) was less than in fellow
      eyes (mean 126.6, SD +/- 23.8 and 202.9, SD +/- 47.0; p=0.01). The EOG values
      were not different with respect to the histological type, site and size of tumor.
      In cases with iris and ciliary body melanomas the AI were not significantly
      different from the fellow eyes (mean 180.6, SD +/- 23.6 and 203.2, SD +/- 38.7;
      p=0.07). CONCLUSIONS: Since the EOG is abnormal in eyes with choroidal melanoma,
      it can be considered a powerful auxiliary for diagnosing these tumors.

PMID- 12474927
TI  - Posterior segment involvement in ocular Behcet's disease.
AB  - PURPOSE: Posterior segment involvement, which can lead to blindness with
      recurrent inflammatory attacks, has a very important prognostic value in ocular
      Behcet's disease (BD). This study evaluated the frequency and characteristics of
      posterior segment involvement and the causes of visual impairment in patients
      with ocular BD. METHODS: We retrospectively evaluated 257 eyes of the 131
      patients who were followed from 1993 to 2001 in the Uveitis and BD division of
      SSK Ankara Eye Hospital, Turkey. RESULTS: The mean follow-up was 49.2 +/- 27.4
      months. Thirty-one of the palents were female (23.6%) and 100 male (76.4%). The
      mean age was 25.1 +/- 7.9. Fundus changes were observed in 213 (82.9%) eyes and
      were bilateral in 87%, and vitritis was present in 239 (93%) eyes. The most
      frequent fundus changes were vascular sheathing in 61 eyes (23.7%), optic atrophy
      in 46 (17.9%), macular edema in 29 (11.3%), retinal hemorrhage in 23 (9%),
      macular scar in 21 (8.2%), optic disc paleness in 19 (7.4%), retinal edema in 17
      (6.6%), branch retinal vein occlusion in 15 (5.8%). The most common fluorescein
      angiography findings were diffuse vascular leakage in 98 (38%), hyperfluorescence
      of the optic disc in 38 (14.8%) and hyperfluorescence of the macula in 29 eyes
      (11.3%). Visual acuity was <1/10 in 85 (33%) of the eyes. Optic atrophy was the
      main cause (54.1%) of permanent visual impairment. CONCLUSIONS: Posterior segment
      involvement is the most serious ocular complication of BD, leading to blindness
      with recurrent attacks. Following patients closely, performing fluorescein
      angiography in all patients diagnosed as BD even they have no clinical ocular
      involvement, and early treatment are very important in the prognosis of the
      disease.

PMID- 12474928
TI  - Eyelid verrucous carcinoma.
AB  - PURPOSE: To report a case of verrucous carcinoma (VC) that presented as an eyelid
      mass on the right eye. CASE REPORT: A 66-year-old man developed a slow-growing
      eyelid lesion on the lateral canthus of the right eye. The tumor was firm, well
      defined, sessile, acuminate, and exuded foul-smelling fluid. RESULTS: Excisional
      biopsy revealed a VC. The patient remains asymptomatic. CONCLUSIONS: VCs are
      extremely rare eyelid tumors. This clinicopathological entity is a low-grade
      variant of squamous cell carcinoma that occurs mainly in the intraoral,
      genitogluteal, and plantar areas. A role of human papillomavirus (HPV) in these
      tumors has been recently identified. VCs characteristically show locally
      aggresive growth. This is the second case reported in the literature on the
      eyelid. VC should be considered in the differential diagnosis of eyelid tumors.

PMID- 12474929
TI  - Conjunctival ulcer--mucocutaneous or ocular manifestation of Behcet's disease? A
      case report.
AB  - PURPOSE: To report the rare occurrence of conjunctival ulceration in a patient
      with Behcet's disease. METHODS: Case report. A 35 year old "Behcet's suspect" on
      azathioprine presented to the ophthalmic emergency room with a painful ulceration
      involving the inferior palpebral conjunctiva of her left eye. RESULTS: The ulcer
      responded to treatment with topical steroids and healed without scarring.
      CONCLUSIONS: Conjunctival ulceration is not a common manifestation of Behcet's
      disease. Its occurrence during maintenance therapy with azathioprine in a patient
      with Behcets could be either incidental or indicate inadequate immunosuppression.

PMID- 12474930
TI  - Escherichia coli endophthalmitis after trans-scleral resection of uveal melanoma.
AB  - PURPOSE: To report a case of Escherichia coli endophthalmitis after trans-scleral
      resection of an uveal melanoma. METHODS: A large ciliary body melanoma was
      treated by trans-scleral resection and full-thickness sclerectomy because of
      epibulbar tumor extrusion, followed by adjuvant ruthenium plaque therapy.
      RESULTS: Two months after treatment the patient developed wound dehiscence and
      consecutive endophthalmitis. Cultures of the involved sclera yielded Escherichia
      coil. The infection resolved after systemic intravenous ciprofloxacin and
      ceftriaxone, with aggressive topical ciprofloxacin and tobramycin. Final visual
      acuity was light perception. CONCLUSIONS: We assume that the ruthenium plaque
      placed over the scleral patch was responsible for the delay in scleral healing,
      with consequent wound dehiscence and E. coli endophthalmitis.

PMID- 12474931
TI  - Self-inflicted repetitive optic nerve injury: a case report.
AB  - PURPOSE: To describe an obsessive-compulsive patient who developed blindness
      after self-inflicted repetitive optic nerve injury. METHODS: Case report.
      RESULTS: A myopic 46-year-old male became blind as a result of intermittent
      rubbing of his eyes, causing stretching of the optic nerves. Extensive ocular,
      neurologic and systemic work-ups were negative. Cerebral and orbital MR studies
      showed severe bilateral optic nerve atrophy. Psychiatric evaluation confirmed
      obsessive-compulsive personality. CONCLUSIONS: Self-inflicted optic nerve injury
      should be included in the differential diagnosis of progressive optic neuropathy
      in a young adult.

PMID- 12474932
TI  - The Bologna Primary Care Liaison Service: first year evaluation.
AB  - Primary care and mental health were recently integrated by the Italian health
      authorities. The Bologna Primary Care Liaison Service (PCLS) is ideally suited to
      the Italian National Health Care System, because most primary care physicians
      practice individually and mental health services provide first level care. The
      distinctive features of the program are: 1) location within a mental health
      center; 2) comprehensive mental health assessment and intervention; 3)
      collaboration between primary care physicians and mental health services which is
      facilitated through committees and communication. First year results met
      expectations. Integrating a PCLS program within a mental health center can be a
      viable means of implementing national policy.

PMID- 12474933
TI  - Residential environment and quality of life among seriously mentally ill
      residents of board and care homes.
AB  - This study examined the relationship between residential environment of seriously
      mentally ill patients living in board and care homes and quality of life.
      Participants included 162 seriously mentally ill veteran patients living in 26
      board and care homes in Los Angeles. Data from structured interviews were used to
      assess subjective quality of life (satisfaction with living situation and general
      well-being) and objective quality of life (social functioning and daily
      activities). Independent variables examined in multivariate analyses included
      individual socio-demographic and clinical characteristics, objective
      characteristics of the home, and subjective resident assessments of social
      climate within the home. Adjusting for individual characteristics, social climate
      was significantly and positively associated with both satisfaction with current
      living situation and with general well-being. Interpersonal conflict was
      negatively associated with general well-being. Number of beds within the home and
      median income in the neighborhood were significantly associated (positively and
      negatively, respectively) with social functioning outside the home. Living
      environment characteristics explained between 3 and 9% of the total variation in
      three of four quality of life measures, and 27% of the variation in the fourth,
      satisfaction with living situation. Satisfaction with living situation among
      seriously mentally ill residents of board and care homes may be enhanced by
      making the social climate more positive, and reducing conflict within the home.
      Social functioning outside of the home may be enhanced by placing patients into a
      home with more beds, and/or a home located in a lower income neighborhood.

PMID- 12474934
TI  - Effects of prior trauma and age on posttraumatic stress symptoms in Asian and
      Middle Eastern immigrants after terrorism in the community.
AB  - Forty-five adult Asian and Middle Eastern immigrants living in Oklahoma City at
      the time of the 1995 bombing were surveyed 114 to 2 years later as part of a
      disaster mental health outreach program. Demographic variables, physical and
      interpersonal exposure, initial physiologic and emotional responses to the
      bombing, and posttraumatic stress symptoms associated with this disaster and with
      earlier trauma were measured. Most participants had experienced prior trauma in
      their homeland. PTSD symptomatology from prior trauma was most predictive of
      initial physiologic and emotional response and of later bomb-related PTSD
      symptoms. Bomb-related PTSD symptoms increased with current age and were
      inversely related to age at the time of prior trauma. Results underscore the
      importance of providing long-term disaster assistance to immigrants with prior
      trauma.

PMID- 12474935
TI  - The Trauma Recovery and Empowerment Model (TREM): conceptual and practical issues
      in a group intervention for women.
AB  - This article describes the Trauma Recovery and Empowerment Model (TREM), a
      manualized group intervention designed for women trauma survivors with severe
      mental disorders, and discusses key issues in its conceptualization and
      implementation. TREM recognizes the complexity of long-term adaptation to trauma
      and addresses a range of difficulties common among survivors of sexual and
      physical abuse. Focusing primarily on the development of specific recovery skills
      and current functioning, TREM utilizes techniques shown to be effective in trauma
      recovery services. The group's content and structure are also informed by the
      role of gender in the ways women experience and cope with trauma.

PMID- 12474936
TI  - Development and implementation of a spiritual issues psychoeducational group for
      those with serious mental illness.
AB  - Recent research has suggested that religion and spirituality can be a resource or
      a burden for those with serious mental illness (SMI). Investigators have begun to
      explore the nature and impact of interventions that focus on spiritual issues in
      this population. This study describes an innovative program for people with SMI
      who are dealing with spiritual/religious issues. The program was a seven-week
      semistructured, psychoeducational intervention in which participants discussed
      religious resources, spiritual struggles, forgiveness, and hope. This paper also
      reviews participants' feedback about the group intervention. Suggestions are made
      that may add to the clinical utility of this program in the future.

PMID- 12474937
TI  - Adapted cognitive behavioral group therapy for depressed low-income African
      American women.
AB  - In this study we examine the degree to which a manualized cognitive-behavioral
      therapy intervention can be adapted to be culturally sensitive in treating
      depressed low-income African American women with multiple stressors. We describe
      the adaptations we made to an existing intervention, a group treatment developed
      for depressed low-income medical patients. We also describe our evaluation of the
      adapted treatment in which outcomes of African American women treated in the
      culturally adapted group were compared to African American women treated in the
      non-adapted group. Following treatment, women in the adapted group exhibited a
      larger drop in average BDI scores. Implications are discussed in terms of
      challenges related to the development and evaluation of culturally adapted
      treatment.

PMID- 12474938
TI  - The challenge of implementing and sustaining integrated dual disorders treatment
      programs.
AB  - Integrated dual disorders treatment programs for people with severe mental
      illness and co-occurring substance use disorder have been implemented in a
      variety of community mental health center sites across the U.S. and in several
      other countries over the past 15 years. Consumers who receive services from
      programs that offer integrated dual diagnosis treatments that are faithful to
      evidence-based principles achieve significant improvements in their outcomes.
      Unfortunately, not all programs that attempt implementation are successful, and
      the quality of high-fidelity programs sometimes erodes over time. This article
      outlines implementation strategies that have been used by successful programs. As
      a general rule, success is achieved by involving all major participants
      (consumers, family members, clinicians, program leaders, and state or county
      mental health authorities) in the process and attending to the three phases of
      change: motivating, enacting, and sustaining implementation.

PMID- 12474939
TI  - The unified interaction model applied to LiF:Mg,Ti (TLD-100): properties of the
      luminescent and competitive centres during sensitisation.
AB  - An attempt is made to predict/interpret theoretically the experimentally measured
      values of f(D) and S(Ds)/So for composite peak 5 in TLD-100. using the Unified
      Interaction Model (UNIM) with identical values of the UNIM parameters for both
      sets of experimental data. Although an excellent fit can be obtained to the
      experimental f(D) data over the entire dose region where f(D) is greater than
      unity. i.e. from 5 Gy to several thousand Gy, a satisfactory fit to both sets of
      data is found to require different values for at least one of the parameters. The
      lack of success in fining f(D) and S(Ds)/So with the same values of all the
      parameters, suggests that the sensitisation anneal (particularly the duration of
      the anneal) may somehow change the structure (S(LC)) and/or the total number of
      available LCs in an unknown manner.

PMID- 12474940
TI  - Study of the dosimetric characteristics of cosmic radiation at civil aviation
      altitudes.
AB  - The dependence of the doses on solar activity for intermediate levels of the
      solar modulation parameter has been studied by means of simulations carried out
      by the Monte Carlo transport code FLUKA. The vertical cut-off rigidities
      investigated lie between 0.4 and 6.1 GV. The calculated results show that the
      linear dependence proposed in a previous work, for the effective dose rate as a
      function of the solar modulation parameter, can be considered as an acceptable
      approximation. In addition, some dosimetric characteristics of cosmic radiation
      and some properties of the dosemeters in use for monitoring in the cosmic ray
      environment have been analysed with a view to simplifying measurements. The depth
      dose curves in the ICRU sphere and the response of a tissue-equivalent ionisation
      chamber have been determined by the FLUKA code for a number of cosmic ray spectra
      On the basis of the calculated results, it is concluded that a value of the
      depth. d, which would make the ambient dose equivalent a conservative predictor
      of the effective dose, cannot be specified for cosmic radiation. However, the
      operational quantity can be useful in order to verify the predictions of Monte
      Carlo calculations. It is demonstrated that a crude approximation of the ambient
      dose equivalent could be obtained by multiplying by 2 the absorbed dose measured
      by a tissue-equivalent ionisation chamber with wall thickness of 10 mm.

PMID- 12474941
TI  - Latin american and Caribbean intercomparison of radiation protection area
      monitoring instruments.
AB  - In December 2000 the International Atomic Energy Agency sponsored an
      intercomparison of radiation protection area monitoring instruments which was
      held at the Instituto de Radioprotecao e Dosimetria--IRD/CNEN, Rio de Janeiro.
      Brazil. This intercomparison exercise was aimed at evaluating the ability of some
      Latin American and Caribbean countries to perform calibrations or such
      instruments, or have them properly performed by a third party. Nine countries
      participated in the exercise with 13 portable gamma dose rate monitors. The
      quantity of interest for the intercomparison was the ambient dose equivalent,
      H*(10), although some instruments were not designed or calibrated in this
      quantity. Results were converted to H*(10), whenever necessary. according to the
      information supplied by each participant. All results for the quantity of
      interest agree well within 10% of the reference values and the quoted
      uncertainties.

PMID- 12474942
TI  - Comparison of the 1st, 2nd and 3rd generation Lawrence Livermore National
      Laboratory Torso phantoms.
AB  - The Lawrence Livermore National Laboratory (LLNL) Torso phantom, which is the de
      facto standard for lung counter calibration for low energy photon emitters, has
      undergone a number of revisions since its development. The first generation used
      real human bone: the second generation used synthetic bone and had a major design
      change; the third generation had more subtle material and mould changes. This
      work has compared a first generation, two second generation, and two third
      generation LLNL phantoms to see if there are any differences between the
      phantoms. The comparison of five LLNL phantoms using the same counting regions
      has shown that the second and third generation phantoms are essentially
      equivalent at low photon energies, but the first generation phantom shows an
      increased counting efficiency at low photon energies due to a design flaw. It is
      also apparent that these phantoms have maintained their performance
      characteristics over an extended period of time.

PMID- 12474943
TI  - Effect of uncertainty in transfer rates for the ICPR publication 67 biokinetic
      model on dose estimation for 239Pu from results of individual monitoring.
      International Commission on Radiological Protection.
AB  - The radiation dose due to internal exposures from 239Pu is mainly estimated by
      measuring actual urinary or faecal excretion of activity and comparing those
      values with the standard excretion rates calculated from the models of the
      International Commission on Radiological Protection (ICRP). Recently, on the
      other hand, uncertainties in the ICRP's models and parameters are under
      consideration because of the paucity of human data. In addition, there is a
      possibility of variation between individuals. A code has been developed to
      reproduce the ICRP's dose coefficients and excretion rates for 239Pu, which is
      one of the most important elements for occupational exposure. By using this code,
      the respective transfer rates for the ICRP Publication 67 biokinetic model were
      modified, and the effect owing to these changes on present hazard assessment was
      investigated. As a result, it was shown that dose estimates for workers exposed
      to 239Pu were not very sensitive to changes in these transfer rates.

PMID- 12474944
TI  - Experimental determination of the absorption rate of unattached radon progeny
      from respiratory tract to blood.
AB  - An exposure methodology was developed for the determination of the absorption
      rate of unattached radon progeny deposited in the human respiratory tract to
      blood. Twenty-one volunteers were exposed in a radon chamber during well
      controlled aerosol and radon progeny conditions, with predominantly unattached
      radon daughters. Special efforts were made to restrict the dose to the volunteers
      to an absolute maximum of 0.08 mSv. Measurements of radon gas and radon progeny
      in blood samples of these volunteers indicated absorption half times of 20 min to
      60 min. Former determinations, mainly performed with much larger aerosol
      particles of diameters between 100 nm and 1,000 nm, implied absorption half times
      around 10 h. This indicates that the absorption of radon decay products from
      ciliated airways into blood is dependent upon particle size and particle
      composition.

PMID- 12474945
TI  - Thermal neutron equivalent dose assessment around the KFUPM neutron source
      storage area using NTDs. King Fahd University of Petroleum and Minerals.
AB  - Area passive neutron dosemeters based on nuclear track detectors (NTDs) have been
      used for 13 days to assess accumulated low doses of thermal neutrons around
      neutron source storage area of the King Fahd University of Petroleum and Minerals
      (KFUPM). Moreover, the aim of this study is to check the effectiveness of
      shielding of the storage area. NTDs were mounted with the boron converter on
      their surface as one compressed unit. The converter is a lithium tetraborate
      (Li2B4O7) layer for thermal neutron detection via 10B(n,alpha)7Li and
      6Li(n,alpha)3H nuclear reactions. The area passive dosemeters were installed on
      26 different locations around the source storage area and adjacent rooms. The
      calibration factor for NTD-based area passive neutron dosemeters was found to be
      8.3 alpha tracks x cm(-2) x microSv(-1) using active snoopy neutron dosemeters in
      the KFUPM neutron irradiation facility. The results show the variation of
      accumulated dose with locations around the storage area. The range of dose rates
      varied from as low as 40 nSvx h(-1) up to 11 microSv x h(-1). The study indicates
      that the area passive neutron dosemeter was able to detect accumulated doses as
      low as 40 nSv x h(-1), which could not be detected with the available active
      neutron dosemeters. The results of the study also indicate that an additional
      shielding is required to bring the dose rates down to background level. The
      present investigation suggests extending this study to find the contribution of
      doses from fast neutrons around the neutron source storage area using NTDs
      through proton recoil. The significance of this passive technique is that it is
      highly sensitive and does not require any electronics or power supplies, as is
      the case in active systems.

PMID- 12474946
TI  - Measurements of X ray absorbed doses to dental patients in two dental X ray units
      in Nigeria.
AB  - Measurements of absorbed doses from radiographic examinations to various
      anatomical sites in the head and neck of patients with an average age of 45 years
      using intra-oral dental radiography have been carried out. LiF (TLD-100)
      dosemeters were used for the measurements of the absorbed dose. The measured
      absorbed doses to the various anatomical sites in the two units are reported,
      discussed and compared with results from the literature. Quality control
      measurements were also performed using a Victoreen quality control test device on
      the X ray units. The tube voltage accuracies for the two units were found to be
      within acceptable limits (less than +/- 10%). On the other hand the exposure time
      accuracies for these units have large deviations (>20%). These results and those
      that have been reported in the literature may be an indication that high patient
      doses are common in most dental X ray centres and countries. As a result of this,
      regular compliance and performance checks of dental diagnostic X ray equipment
      are essential in order to ensure proper performance and to minimise unnecessary
      patient and operator doses.

PMID- 12474947
TI  - Effect of soil parameters on radon entry into a building by means of the transrad
      numerical model.
AB  - High indoor radon concentration means an increased risk of developing lung
      cancer. When high radon levels are present in a dwelling, the major source is
      normally the soil. Therefore, it is useful to know the radon concentration field
      in the soil underneath a building. A steady-state two-dimensional radon transport
      model has been used to calculate the effect of a reference building on the soil
      radon concentration, and the influence of soil parameters on radon entry through
      a single crack in the basement. Both advective and diffusive flows are
      considered. Away from the building, the well-known undisturbed soil radon
      concentration profile has been obtained, while under the house the radon level is
      increased. A variability analysis around the reference site has shown that the
      most relevant soil parameters on the radon flux at the top of the crack are, in
      this case, effective diffusion coefficient, soil gas-permeability and deep soil
      radon concentration.

PMID- 12474948
TI  - Calculation of the average solid angle subtended by a detector to source in a
      parallel plane by a Monte Carlo method.
AB  - A short computer program is described for a PC which uses a Monte Carlo method to
      calculate the average solid angle subtended by a rectangular or circular detector
      window to a coaxial or non-coaxial rectangular, circular or point source. The
      advantage of the Monte Carlo method is that it allows the calculation of average
      solid angle for source-detector geometries that are difficult to analyse by
      analytical methods. The values of solid angle are calculated to accuracies of
      typically better than 0.1%. The calculated values from the Monte Carlo method
      agree closely with those produced by polygon approximation and numerical
      integration by Gardner and Verghese, and others.

PMID- 12474949
TI  - Projection of residential radon lung cancer risks: the Beir VI risk models.

PMID- 12474950
TI  - Wear resistance of hybrid composite resin for crown material by the two-body
      sliding test.
AB  - Comparative studies on two-body sliding wear resistance were performed between a
      hybrid composite resin and conventional light-curing composite veneering
      materials. This study investigated the wear resistance of hybrid composite resins
      compared with three composite resin veneering materials for 12%Au-Ag-Pd alloy,
      the wear resistance of four restorative materials opposed to hybrid composite
      resin, and the influence of surface characteristics on hybrid composite resins.
      Hybrid composite resin without heat-curing, which was compared with other
      composite resin materials exhibited inferior wear resistance, but hybrid
      composite resin mechanically polished after heat-curing exhibited the most
      superior wear resistance.

PMID- 12474951
TI  - A study of cavity preparation by Er:YAG laser. Effects on the marginal leakage of
      composite resin restoration.
AB  - The purpose of this study was to evaluate marginal leakage of composite resin
      restoration from cavities prepared by Er:YAG laser. The observation of the dentin
      surface after the application of laser irradiation was performed by LSM, the
      cutting surface showed a rough surface similar to scales, and exposed dentinal
      tubules were observed without striations or a smeared layer formation that were
      observed when using a rotary cutting device. Leakage tests revealed no
      significant differences in the marginal seal for both enamel and dentin between
      cavities prepared by Er:YAG laser irradiation and when using an air-turbine. In
      this study, the usefulness of cavity preparation by Er:YAG laser irradiation in
      composite resin restoration was suggested.

PMID- 12474952
TI  - In vitro study of collagen coating of titanium implants for initial cell
      attachment.
AB  - The aim of this study was to examine the influence of collagen coating on
      titanium on the initial attachment of human gingival fibroblasts for the
      development of the implant with periimplant soft tissue attachment. The
      morphological changes of cultured human gingival fibroblasts were investigated by
      scanning electron microcopy (SEM). Four different surfaces, i.e. non-coated
      mirror-polished titanium, collagen-coated titanium, non-coated tissue-culture
      polystyrene, and collagen-coated polystyrene were examined. Collagen coating of
      titanium was effective for enhancing the initial cell attachment. It is expected
      that collagen coating of titanium implants will improve the attachment of the
      peri-implant soft tissue to titanium at early stages after the implantation. SEM
      observation revealed the morphological effect of collagen coating on both
      titanium and polystyrene surfaces. Many lamellipodia and filopodia were
      recognized on collagen-coated titanium or polystyrene. Collagen coating improved
      the activity of human gingival fibroblasts.

PMID- 12474953
TI  - Mechanical properties of reinforced denture base resin: the effect of position
      and the number of woven glass fibers.
AB  - This study examined the effects of the position and the number of woven glass
      fibers on the flexural strength, flexural modulus, and toughness of reinforced
      denture base resin. The woven glass fiber consisted of 1-4 laminated sheets.
      Chemical curing was used to polymerize three types of 4-mm-thick test specimens:
      fibers in compresrion, fibers in the center, and fibers in tension. Unreinforced
      specimens were produced as controls. A three-point flexural test was performed
      and the woven glass fiber content was calculated after the woven glass fiber was
      fired. The best results were obtained when the woven glass fiber was incorporated
      outside the base resin under tension, thereby increasing the flexural strength
      and flexural modulus. Furthermore, the denture base resin reinforced with woven
      glass fiber was made tougher by increasing the number of woven glass fibers
      incorporated into the portion under tension.

PMID- 12474954
TI  - Mechanical properties and microstructures of dental cast Ti-Ag and Ti-Cu alloys.
AB  - In this study, experimental Ti-Ag alloys (5, 10, and 20 mass% Ag) and Ti-Cu
      alloys (2, 5, and 10 mass% Cu) were made in an argon-arc melting furnace. The
      alloys were cast into magnesia molds using an argon gas-pressure dental casting
      machine, and the mechanical properties and microstructures of the castings were
      investigated. As the concentration of silver or copper in the alloys increased,
      the tensile strength, yield strength, and hardness of the alloys became higher
      than those of CP Ti, and the elongation of the alloys became lower than that of
      CP Ti. Changes in the mechanical properties by alloying were considered to be
      caused by solid-solution strengthening of the a-phases and by precipitation of
      intermetallic compounds.

PMID- 12474955
TI  - The Florida reef tract and the 'one third rule'.

PMID- 12474956
TI  - Application of the luciferase cell culture bioassay for the detection of refined
      petroleum products.
AB  - A luciferase cell culture-based bioassay, developed to detect 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD)-like activity of halo-genated and polycyclic
      aromatic hydrocarbons, was optimized to detect refined petroleum products and to
      determine their relative inducing potency. Quality control standards from 32
      refined products (gasolines and diesels, jet fuels, lubricating oils, fuel oils
      and weathered products) and three commercial products were evaluated. Induction
      equivalents (I-EQs) were determined by direct comparison of the EC50 and EC20
      values (based on the median and 20% TCDD maximal response, respectively) from
      dose-response curves for each product to those obtained with TCDD. Most petroleum
      products were active in the luciferase bioassay, with those products composed of
      fractions produced later in the distillation process (i.e. fuel oils) inducing
      higher levels. Additionally, weathering of products reduced their induction
      potency. Based on the high I-EQ estimates of many products, biological effects
      associated with exposure may have been previously underestimated using other
      diagnostic methods.

PMID- 12474957
TI  - Increase of nitrous oxide flux to the atmosphere upon nitrogen addition to red
      mangroves sediments.
AB  - Response of nitrous oxide N20 sediment/air flux to nitrogen addition was assessed
      in mangrove (Rhizophora mangle) sediments. Fluxes were enhanced with both
      ammonium and nitrate loading. Greatest fluxes (52 micromol m(-2) h(-1)) were
      obtained with ammonium addition and saturation was achieved with additions of 0.9
      mol m(-2). Maximum flux following ammonium addition was 2785 times greater than
      control plots and 4.5 times greater during low tide than with equivalent ammonium
      addition at high tide. Nitrate enrichment resulted in exponential growth, with
      maximal mean flux of 36.7 micromolm(-2) h(-1) at 1.9 molm(-2); saturation was not
      achieved. Differential response to ammonium and nitrate, and to tide and
      elevation, indicate that microbial nitrification is responsible for most of the
      observed gas flux. Mangrove sediments constitute an important source of global
      atmospheric N20 and increases in nitrogen loading will lead to significant
      increases in the flux of this atmospherically active gas.

PMID- 12474958
TI  - Concentration and distribution of 210Po in the tissues of the scallop Chlamys
      varia and the mussel Mytilus edulis from the coasts of Charente-Maritime
      (France).
AB  - Polonium-210 (210Po) has been analysed in the soft parts of two bivalves species,
      the scallop Chlamys varia and the common mussel Mytilus edulis, from the Bay of
      La Rochelle and Re Island, on the French Atlantic coast. Between those sites, the
      highest 210Po concentrations have been found in whole scallop soft parts from La
      Rochelle, reaching 1,181 +/- 29 Bq kg(-1) dry weight (dwt), a size effect being
      related to the highest 210Po concentration in the smallest scallops. The results
      show a significant difference in concentrations for similar size individuals
      between species in each site (C. varia > M. edulis) and between sites for each
      species (Re Island > Bay of La Rochelle). Very high 210Po concentrations have
      been found in the digestive gland of C varia, ranging 3,150-4,637 Bq kg(-1) dwt.
      Thus, the digestive gland contains up to 60% of the radionuclide. Subcellular
      investigations have shown that approximately 40% of the 210Po contained in the
      digestive gland is in the cytosolic fraction, suggesting a high bioavailability
      of the 210Po from this fraction to the trophic upper level. Calculations will
      show that approximately 4 kg of scallops flesh intake would be necessary to reach
      the annual incorporation limit of 1 mSv.

PMID- 12474959
TI  - Transfer and distribution of lead in the asteroid Asterias rubens following
      ingestion of contaminated food: a radiotracer study.
AB  - A radiotracer technique using 210Pb was applied to quantify the transfer and
      distribution of lead in the asteroid Asterias rubens following a single ingestion
      of radio-labelled mussels under controlled laboratory conditions. Approximately
      50% of the 210Pb accumulated by mussels in their soft tissues from seawater was
      transferred to the asteroid through the food pathway resulting in a transfer
      factor less than unity. Loss kinetics of 210Pb in the asteroid were best
      described by a two-component exponential model. A. rubens eliminated 56% +/- 5%
      of the ingested 210Pb in a few days while the remaining fraction (42% +/- 5%),
      was absorbed and eliminated very slowly. Following ingestion, 210Pb was
      accumulated in the pyloric caeca and the body wall with little radioisotope found
      in the coelomic fluid. Lead-210 was then transferred to the organic matrix of the
      body wall through the general body cavity via the coelomic fluid, and then to the
      skeleton. In this way, lead appears to be progressively eliminated from the
      organic matrix of the body wall while it is efficiently trapped in the calcite
      skeleton. The sequestration and retention of lead in the skeleton is considered
      as a detoxification process, but it also prevents lead transfer to higher trophic
      levels of the marine food chain since the skeleton is not digested by higher
      consumers. In addition, the skeleton of asteroids can be regarded as a
      bioindicator of long-term dietary lead contamination.

PMID- 12474960
TI  - An evaluation of hemolymph cholinesterase activities in the tropical scallop,
      Euvola (Pecten) ziczac, for the rapid assessment of pesticide exposure.
AB  - The use of sequential measurements of hemolymph cholinesterase activities as a
      non-invasive biomarker of seasonal organophosphate/carbamate exposure was
      investigated for the tropical scallop, Euvola (Pecten) ziczac. Overall activities
      of both acetylcholinesterase and butyrylcholinesterase were relatively high
      compared to studies with bivalve tissues. Acute in vivo experiments showed
      inhibition of hemolymph acetylcholinesterase activity at concentrations of the
      organophosphate insecticide chlorpyrifos of 0.1, 1 and 10 ng l(-1). Monthly
      sampling of hemolymph from scallops at two sites in Bermuda over a 15 month
      period showed seasonal acetylcholinesterase and butyrylcholinesterase inhibition.
      Direct and indirect evidence suggests that this inhibition did not relate to
      biochemical or physiological changes associated with gonad maturation and
      spawning, but rather reflected diffuse contamination of the marine environment by
      cholinesterase inhibitors or increased bioavailability of such inhibitors at
      these times. Repetitive sampling of scallop hemolymph for cholinesterase
      activities represents a rapid, sensitive and non-invasive method for assessing
      seasonal, sublethal pesticide exposure in these commercially important bivalves
      and suggests a wider use in marine pollution monitoring.

PMID- 12474961
TI  - Total and methylmercury in a Brazilian estuary, Rio de Janeiro.
AB  - Guanabara Bay, in Rio de Janeiro state, is impacted by organic matter, oil and
      heavy metals. The present study evaluated the total mercury (THg) and
      methylmercury (MeHg) concentrations and the MeHg to THg ratio (%MeHg) in water
      samples from different points of the bay and in 245 organisms of three different
      trophic levels sampled between 1990 and 2000. Dissolved mercury concentration in
      estuarine water samples ranged from 0.72 to 5.23 ngl(-1). THg and MeHg in mussel,
      ranging from 11.6 to 53.5 microg THg kg(-1) wet wt. and 4.5-21.0 microg MeHg kg(
      1) wet wt., varied according to sampling point and water quality. Planktivorous
      fish and mussel presented similar MeHg concentrations, meanwhile THg in
      planktivorous fish were lower than in mussel. Carnivorous fish showed higher THg
      and MeHg concentrations (199.5 +/- 119.3, 194.7 +/- 112.7 microg kg(-1) wet wt.
      respectively) than organisms from other feeding habits and lower trophic levels.
      There was a significant difference in the %MeHg among trophic levels: mussel
      presented lower MeHg percentage (33%) than planktivorous fish (54%) and
      carnivorous fish (98%).

PMID- 12474962
TI  - Spatial aspects of organochlorine contamination in northern fur seal tissues.
AB  - Northern fur seals from the Pribilof Islands, Alaska (St. George Is. and St. Paul
      Is.) were examined for organochlorine contamination (OC) and whether the
      organochlorine levels differed between the populations and were at levels that
      may adversely affect their health. Fur seal blubber and milk samples were
      obtained from pups, sub-adult males, and adult females on both Pribilof Islands.
      These samples were analyzed for organochlorine contaminants including dioxin-like
      PCBs and other selected PCBs and pesticides by high performance liquid
      chromatography/photodiode array. Results showed that there are clear differences
      between the two islands in the patterns of fur seal OC distribution. Generally,
      these differences are confined to the PCBs with only minimal differences in the
      DDTs. There are also clear biological differences in the levels shown between
      milk, pup blubber, and sub-adult male blubber. When considering blubber, St.
      George Is. fur seals show higher OC levels than St. Paul Is., for both pups and
      sub-adults. On the other hand, milk samples from St. Paul Is. showed higher PCB
      levels than St. George Is. For the milk, the overall OC levels may impact the
      immune function of the pups, but are probably of only minimal impact to humans.
      However, for blubber, the overall toxic equivalency shows levels exceeding those
      levels recommended for human consumption at St. George Is. and approaching those
      levels at St. Paul Is. The concentration curves suggest that the movement of OC
      in and out of milk follows a complex set of reactions dependent on how the OC
      compounds on a congener level are associated with lipid. In fact, there is some
      evidence that they may not follow the lipid as closely as we had thought and that
      lipid levels can vary without impacting the total OC level in the milk.

PMID- 12474963
TI  - A comparison of neustonic plastic and zooplankton abundance in southern
      California's coastal waters.
AB  - The density of neustonic plastic particles was compared to that of zooplankton in
      the coastal ocean near Long Beach, California. Two trawl surveys were conducted,
      one after an extended dry period when there was little land-based runoff, the
      second shortly after a storm when runoff was extensive. On each survey, neuston
      samples were collected at five sites along a transect parallel to shore using a
      manta trawl lined with 333 micro mesh. Average plastic density during the study
      was 8 pieces per cubic meter, though density after the storm was seven times that
      prior to the storm. The mass of plastics was also higher after the storm, though
      the storm effect on mass was less than it was for density, reflecting a smaller
      average size of plastic particles after the storm. The average mass of plastic
      was two and a half times greater than that of plankton, and even greater after
      the storm. The spatial pattern of the ratio also differed before and after a
      storm. Before the storm, greatest plastic to plankton ratios were observed at two
      stations closest to shore, whereas after the storm these had the lowest ratios.

PMID- 12474964
TI  - Trace metals in striped mojarra fish (Diapterus plumieri) from Puerto Rico.

PMID- 12474965
TI  - Mercury uptake by the estuarine species Palaemonetes pugio and Fundulus
      heteroclitus compared with their parasites, Probopyrus pandalicola and
      Eustrongylides sp.
AB  - When exposed to methylmercury in the laboratory, grass shrimp, Palaemonetes
      pugio, parasitized by the isopod Probopyrus pandalicola, accumulated lower
      concentrations of mercury than their unparasitized counterparts. The parasitic
      isopod accumulated far less mercury than the grass shrimp. When exposed to
      mercury in a contaminated field site, mummichogs, Fundulus heteroclitus,
      parasitized with the nematode Eustrongylides, similarly accumulated lower
      concentrations of mercury than unparasitized fish, and the parasite similarly
      accumulated less than the host. The lower uptake by the parasites compared to
      their hosts is counter to the general view of biomagnification of methylmercury,
      since parasites are a trophic level above their hosts. The mechanism whereby
      parasitized animals accumulate less toxicant than unparasitized ones is unknown,
      but may be partially due to lower metabolic rate.

PMID- 12474966
TI  - The use of transplanted cultured tropical oysters (Saccostrea commercialis) to
      monitor Cd levels in North Queensland coastal waters (Australia).
AB  - Bivalves are commonly used to detect metal pollution in the marine environment.
      Commercially cultured Milky oysters (Saccostrea commercialis) were transplanted
      in various sites along the North Queensland coast and analyzed for two metals of
      potentially anthropogenic origin (Cd, Zn). To provide additional information,
      naturally occurring Black Lip oysters (Saccostrea echinata) were also collected
      at the transplantation sites. The study demonstrated that the oysters species
      transplanted are good bioindicators of these metal concentrations in tropical
      waters, sensitive to variations in the environment at concentrations which are
      much smaller than pollution signals commonly reported for temperate waters. Three
      transplant experiments were carried out from May 1999 to February 2000. Milky
      oysters transplanted to offshore areas (Orpheus Is., Kelso Reef) accumulated Cd
      in the soft parts whereas oysters sampled from cages placed in Ross Creek and the
      Herbert River estuaries showed a decrease in Cd concentration, which resulted
      from an increase in dry weight. Dry weight appeared to be an important covariant
      affecting Cd concentration in the oysters whereas it does not unambiguously
      affect Zn concentrations. For the duration of the experiments, oysters sampled
      from the Magnetic Is. reference site showed effectively constant Cd
      concentrations and total Cd contents which indicates that any seasonal cycle
      affecting metal concentration is weak. It was found that Cd accumulation in
      oysters increased as ambient dissolved Cd concentration decreased, from which it
      was concluded that for these oysters, the predominant source of Cd was from the
      particulate phase rather than the dissolved phase.

PMID- 12474967
TI  - The effect of the new Massachusetts Bay sewage outfall on the concentrations of
      metals and bacterial spores in nearby bottom and suspended sediments.
AB  - Since the new outfall for Boston's treated sewage effluent began operation on
      September 6, 2000, no change has been observed in concentrations of silver or
      Clostridium perfringens spores (an ecologically benign tracer of sewage), in
      bottom sediments at a site 2.5 km west of the outfall. In suspended sediment
      samples collected with a time-series sediment trap located 1.3 km south of the
      outfall, silver and C. perfringens spores increased by 38% and 103%,
      respectively, in post-outfall samples while chromium, copper, and zinc showed no
      change. All metal concentrations in sediments are <50% of warning levels
      established by the Massachusetts Water Resources Authority. An 11-year data set
      of bottom sediment characteristics collected three times per year prior to
      outfall startup provides perspective for the interpretation of post-outfall data.
      A greater than twofold increase in concentrations of sewage tracers (silver and
      C. perfringens) was observed in muddy sediments following the exceptional storm
      of December 11-16, 1992 that presumably moved contaminated inshore sediment
      offshore.

PMID- 12474968
TI  - Mercury exposure and elimination rates in captive bottlenose dolphins.
AB  - Mercury concentrations in fish, faeces and exhaled air were investigated in order
      to evaluate total mercury exposure through the gut in captive bottlenose dolphin
      and excretion via intestine and pulmonary routes. Results showed that faeces
      account for elimination of 34-48% of dietary mercury; while only 0.9-1.2% of
      alimentary mercury is eliminated through exhaled air. The remaining 51.2-65.3% of
      ingested mercury, ranging approximately between 266 and 339 microg per day, is
      retained within the organism. The complexation of mercury with selenium, forming
      insoluble tiemannite granules, is discussed as an important mechanism,
      complementary to excretion, by which odontocetes are able to cope with elevated
      alimentary exposure to mercury.

PMID- 12474969
TI  - Modelling of hydrodynamics and cohesive sediment transport in Tanshui River
      estuarine system, Taiwan.
AB  - A laterally averaged two-dimensional numerical model is used to simulate
      hydrodynamics and cohesive sediment transport in the Tanshui River estuarine
      system. The model handles tributaries as well as the main stem of the estuarine
      system. Observed time series of salinity data and tidally averaged salinity
      distributions have been compared with model results to calibrate the turbulent
      diffusion coefficients. The overall model verification is achieved with
      comparisons of residual currents and salinity distribution. The model reproduces
      the prototype water surface elevation, currents and salinity distributions.
      Comparisons of the suspended cohesive sediment concentrations calculated by the
      numerical model and the field data at various stations show good agreement. The
      validated model is applied to investigate the tidally averaged salinity
      distributions, residual circulation and suspended sediment concentration under
      low flow conditions in the Tanshui River estuarine system. The model results show
      that the limit of salt intrusion in the mainstem estuary is located at Hsin-Hai
      bridge in Tahan Stream, 26 km from the River mouth under Q75 flow. The null point
      is located at the head of salt intrusion, using 1 ppt isohaline as an indicator.
      The tidally averaged sediment concentration distribution exhibits a local maximum
      around the null point.

PMID- 12474970
TI  - Specific accumulation and temporal trends of organochlorine contaminants in
      Dall's porpoises (Phocoenoides dalli) from Japanese coastal waters.
AB  - Organochlorine compounds (OCs) such as polychlorinated biphenyls (PCBs),
      dichlorodiphenyltrichloroethane and its metabolites (DDTs), chlordane related
      compounds, hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), tris(4
      chlorophenyl) methane (TCPMe) and tris(4-chlorophenyl) methanol were determined
      in the blubber of Dall's porpoises (Phocoenoides dalli) collected from Japanese
      coastal waters in 1998/1999. Among OCs analyzed, PCBs were the predominant
      contaminants with concentrations ranging from 1.5 to 39 microg/g on a wet weight
      basis. OCs concentrations were relatively low and less variable in mature females
      possibly due to the lactational excretion from their bodies, while in males the
      concentrations were increased with body length. Concentrations and compositions
      of DDTs and HCHs showed significant differences between the truei-type population
      off the Pacific coast of northern Japan and dalli-type from the Sea of
      Japan/Okhotsk, suggesting its usefulness to discriminate different populations.
      OCs levels detected in truei-type porpoises collected in 1998/1999 were lower
      than those collected in 1984, except TCPMe. On the other hand, except DDTs, the
      residue levels of other organochlorines in dalli-type porpoises showed no
      significant decrease since 1984.

PMID- 12474971
TI  - Comparison of benthic invertebrate assemblages at Spartina alterniflora marshes
      reestablished after an oil spill and existing marshes in the Arthur Kill (NY/NJ).
AB  - In January 1990, an oil spill damaged salt marshes along the banks of the Arthur
      Kill (New York and New Jersey, USA). In the years following the spill, Spartina
      alterniflora seedlings were planted at a number of the oil damaged sites and
      successfully reestablished at these sites. In 1996, the National Marine Fisheries
      Service began a study to compare the benthic invertebrate assemblages at the
      reestablished S. alterniflora marshes to those at nearby existing marshes in the
      Arthur Kill. Oligochaetes, nematodes, and the small tube-building polychaete,
      Manayunkia aestuarina were the dominant taxa in the study. Significant
      differences were found in the abundances of all invertebrate individuals,
      oligochaetes, and nematodes between the September and May sampling times but not
      between reestablished and existing marshes. Although benthic invertebrate
      community structure was similar at reestablished and existing marshes three to
      four years after planting, the functional similarity of these marshes was not
      assessed in this study.

PMID- 12474972
TI  - Estuarine phytoplankton group-specific responses to sublethal concentrations of
      the agricultural herbicide, atrazine.
AB  - Atrazine is a common agricultural herbicide that is readily transported into
      estuaries through surface water runoff. In this study, we determined the short
      term (24-48 h) sublethal effects of atrazine on estuarine phytoplankton biomass
      and community composition. Phytoplankton group-specific responses to atrazine
      exposure (25 microgh(-1)) were measured using natural water samples collected
      from two locations in Galveston Bay, Texas. Addition bioassays, coupled with HPLC
      pigment analysis, were used to quantify changes in the relative abundances of
      algal groups. For all algal groups except prasinophytes, the addition of atrazine
      in combination with nitrate was not significantly different from nitrate
      additions alone. These results suggest no significant negative effect of atrazine
      on phytoplankton under the specified environmental conditions for the bioassays.
      Although low concentrations of atrazine may have minimal impacts on
      phytoplankton, herbicide loadings need to be further characterized before
      generalizations can be applied to estuarine and coastal ecosystems.

PMID- 12474973
TI  - Contaminant concentrations in sport fish from San Francisco Bay, 1997.
AB  - In 1997, seven sport fish species were sampled from seven popular fishing areas
      in San Francisco Bay. Mercury exceeded a human health screening value in 44 of 84
      (52%) samples. All collected samples of leopard shark and striped bass exceeded
      the mercury screening value of 0.23 microg/g wet weight. PCBs exceeded the
      screening value in 51 of 72 (71%) samples. DDT, chlordane, and dieldrin, had
      lower numbers of samples above screening values: 16 of 72 (22%) for DDT, 11 of 72
      (15%) for chlordanes, and 27 of 72 (37%) for dieldrin. Concentrations of PCBs and
      other trace organics were highest in white croaker and shiner surfperch, the two
      species with the highest fat content in their muscle tissue. Fish from one
      location, Oakland Harbor, had significantly elevated wet weight concentrations of
      mercury, PCBs, DDTs, and chlordanes compared to other locations. Removal of skin
      from white croaker fillets reduced lipid concentrations by 27-49% and
      concentrations of trace organics by 33-40%.

PMID- 12474974
TI  - Mercury concentrations in the fur of steller sea lions and northern fur seals
      from Alaska.
AB  - We compared total mercury (THg) concentrations in the fur of northern fur seals
      (Callorhinus ursinus) from the depleted Pribilof Islands population with those of
      both declining and thriving populations of Steller sea lions (Eumetopias jubatus)
      from Prince William Sound (PWS) and Southeast Alaska (SEA), respectively.
      Relatively low wet weight concentrations (ranges) of THg were detected in the fur
      of Steller sea lion (SSL) pups (0.90-3.14 microg/g) and juveniles (0.56-6.75
      microg/g) from both areas in 1998 and 2000 compared to northern fur seal (NFS)
      pups (3.15-8.14 microg/g) in 2000. The mean concentration +/- SD for SSLs sampled
      were 1.46 +/- 0.64 microg/g for pups (n = 22) and 2.74 +/- 2.89 microg/g for
      juveniles (n = 6). Analyses indicated higher THg concentrations from SSL pups
      from PWS compared to the SEA. Mean +/- SD. THg in the NFS pups was 4.90 +/- 1.42
      microg/g (n = 34) and for post-partum dams was 7.84 +/- 1.78 microg/g (n = 12).

PMID- 12474975
TI  - Bioconcentration of heavy metals in aquatic environments: the importance of
      bioavailability.
AB  - The importance of heavy metal bioavailability on the bioconcentration in aquatic
      biota is examined. To this purpose, mono- and multivariate statistical techniques
      are applied to develop correlations between heavy metal bioconcentration factor
      and sediment characteristics, that are expected to affect bioavailability, using
      a database of heavy metal concentrations in biota and sediment along with the
      available physicochemical characteristics. The statistical analysis shows that
      satisfactory correlations are obtained only when factors that affect
      bioavailability, such as metal oxides concentration and organic carbon content in
      the sediment, are taken into account.

PMID- 12474976
TI  - Effects of antifouling paint components (TBTO, copper and triazine) on the early
      development of embryos in cod (Gadus morhua L.).
AB  - To assess the risk of antifoulant use to the commercially important cod (Gadus
      morhua L.), fertilised cod eggs were exposed to triazine, copper and TBTO singly
      or combined in laboratory tests with running seawater. At the highest tested
      concentrations (11.5 microg Cu l(-1); 5 microg TBTO l(-1)) larval mortality was
      increased. The highest concentration of triazine (40 microg l(-1)) did not cause
      any significant mortality. Fertilised eggs that had been exposed to all the three
      chemicals singly for five days showed a higher buoyancy than the controls. No
      synergistic or antagonistic effects were indicated. Embryos/larvae exposed to
      0.004-0.8 microg TBTO l(-1) did not show any changed respiration compared to the
      controls after hatching. It is concluded that existing known field concentrations
      of the three antifoulants are hardly expected to cause detectable effects on fish
      embryonic/larval development.

PMID- 12474977
TI  - Plastic debris collars on juvenile carcharhinid sharks (Rhizoprionodon lalandii)
      in southwest Atlantic.
AB  - Three juvenile Brazilian sharpnose sharks (Rhizoprionodon lalandii) caught in
      gillnets in southeast Brazil, southwest Atlantic, were found with plastic debris
      rings around their gill or mouth region. The rings caused severe abrasion on the
      sharks' tissues as the animal grew, the collars probably hampering normal feeding
      and/or ventilation since two of the collared individuals were emaciated. The
      rings were identified as detachable lid parts from plastic bottles, likely thrown
      overboard by fishery and/or recreation boats. As several carcharhinid shark
      species dwells and reproduce in shallow waters, the impact of discarded plastic
      debris likely is greater on this shark type.

PMID- 12474978
TI  - A comparison of anthropogenic mercury pollution in Kastela Bay (Croatia) with
      pristine estuaries in Ore (Sweden) and Krka (Croatia).
AB  - Anthropogenic mercury pollution was studied in Kastela Bay (Croatia), 10 years
      after chloralkaline plant (PVC) stopped production. The concentration of total
      mercury determined in sediments which are composed mainly of calcite and quartz,
      are in the range 14,280-30,400 ng/g. The values are higher than reported in the
      literature for Elbe and Seine estuaries and also above 25,000 ng/g used for
      criterion in remediation project in Minamata Bay. The concentration of
      methylmercury 6.05-36.74 ng/g are typical for slightly to highly contaminated
      estuarine sediments. The low ratio of methylmercury to total mercury found in
      sediments of Kastela Bay is in the range 0.04-0.18%. It can be explained that in
      this region predominate conditions which do not promote in-situ methylation.
      Sediments were found to be highly anoxic. Concentrations of total mercury in
      unfiltered surface waters are in the range 69-145 ng/l and in unfiltered bottom
      waters in the range 230-1,418 ngl(-1). High concentrations found in bottom waters
      suggest that either resuspension or partial dissolution of sediments takes place.
      An experiment performed on filtered and unfiltered waters showed that about 85%
      of total mercury in surface water and almost 100% in bottom water was retained on
      45 microm filters. To demonstrate contrasts, two pristine estuaries from norths
      and south Europe were studied. Silicious sediments of Ore estuary (Sweden) and
      calcareous sediments of Krka estuary (Croatia) have total mercury concentrations
      close to accepted background level. The ratio of methylmercury to total mercury
      is < or = 1% in all samples with one exception. The highest observed ratio
      (2.70%) was in the surface sediment from E2 station in Krka estuary measured in
      March 2000. This location is suitable for studying methylmercury formation in
      pristine environment.

PMID- 12474979
TI  - Determination of organohalogenated contaminants in liver of harbour porpoises
      (Phocoena phocoena) stranded on the Belgian North Sea coast.

PMID- 12474980
TI  - Natural levels of dissolved/dispersed petroleum hydrocarbons in the South West
      Atlantic.

PMID- 12474981
TI  - TACE mRNA expression in peripheral mononudear cells precedes new lesions on MRI
      in multiple sclerosis.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of
      multiple sclerosis (MS). It has to be released from its cell membrane-bound
      precursor by proteolytic cleavage. This is mainly performed by a member of the
      ADAM (a disintegrin and metalloproteinase) family of enzymes, TNF-alpha
      converting enzyme (TACE, ADAM 17). In a longitudinal study on 11 relapsing
      remitting MS patients, we qualitatively determined mRNA expression of TNF-alpha
      and TACE in peripheral blood mononuclear cells (PBMCs) without ex vivo
      stimulation. mRNA expression was related to disease activity as assessed by
      monthly gadolinium (Gd)-enhanced brain magnetic resonance imaging (MRI). Patients
      found positive for TACE mRNA in PBMCs showed a significantly higher mean number
      of new Gd-enhancing lesions per scan one month following PBMC sampling.

PMID- 12474982
TI  - Retinol measurements and retinoid receptor gene expression in patients with
      multiple sclerosis.
AB  - Treatment with interferon (IFN)-beta1a has been associated with decreased disease
      activity in patients with multiple sclerosis (MS). In several biological systems,
      type 1 IFNs and retinoids have been demonstrated to have synergistic effects. In
      these studies, we measured blood and cerebrospinal fluid (CSF) retinol levels and
      naive and memory T-helper cell subset percentages in samples from a group of
      patients with MS. We also examined retinol receptor expression in peripheral
      blood cells from MS patients with or without a history of prior treatment with
      IFN-beta1a. The mean plasma retinol level for untreated relapsing-remitting (RR)
      MS patients was lower than for patients with noninflammatory neurological
      disease. Among IFN-beta1a-treated RR patients, mean levels were slightly higher
      than for RR patients not on treatment Lower plasma retinol levels among the MS
      patents studied were associated with higher CSF retinol index measurements--a
      measure that was calculated to correct for nonspecific leakage of retinol from
      blood into CSF. Far the MS samples examined, there was a borderline statstically
      significant direct correlation between CSF retinol index measurements and CSF
      memory T-helper cell percentages. Examination of peripheral blood from untreated
      RR patents for retinoid receptor mRNA expression revealed the expression of the
      retinoic add receptor (RAR)-alpha, RAR-gamma, and retinoic X receptor (RXR)-alpha
      receptor subtypes. For RR patients on IFN-beta1a therapy, expression of the some
      RAR subtypes was noted as well as expression of RXR-beta and RXR-gamma. These
      studies suggest an association between plasma retinol levels and clincal disease
      activity in patents with MS and that treatment with IFN-beta1a may be associated
      with activation of specific retnoid receptor subtypes.

PMID- 12474983
TI  - A comparative study of Japanese multiple sclerosis patients with and without
      oligoclonal IgG bands.
AB  - The cerebrospinal fluid oligodonal IgG bands (OB) are less frequently observed in
      Japanese multiple sclerosis (MS) patients compared with Caucasian patients. We
      studied 40 consecutive Japanese MS patients to investigate the differences in the
      clinical and magnetic resonance imaging (MRI) features of MS between OB-positive
      patients and OB-negative ones. Among the 40 patients, 22 (55%) patients were OB
      positive by either agarose gel electrophoresis (AGE) or isoelectric focusing
      (IEF), and 18 (45%) patients were OB-negative by both AGE and IEF. There were
      differences between the two groups only in the clincal forms of MS, but not in
      terms of gender, onset age, disease duration, or disease severity. In the OB
      negative group, nine (50%) of the patients had the optic-spinal form of MS (OS
      MS), but only one patient (4.5%) in the OB-positive group had OS-MS. Although
      most OB-positive patients showed brain MRI lesions typical of MS, 13 (72%) of the
      OB-negative patients showed no or few brain MRI lesions and the rest of the OB
      negative patients showed atypical MS lesions, such as diffuse white matter
      lesions or large ring-enhanced lesions. Our results suggest that the majority of
      OB-negative Japanese MS patents show either no or few brain MRI lesions or
      atypical brain MRI lesions.

PMID- 12474985
TI  - Susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating
      disease in BALB/cAnNCr mice is related to absence of a CD4+ T-cell subset.
AB  - Two histocompatible substrains of BALB/c mice (BALB/cByJ, BALB/cAnNCr) are
      resistant and susceptible, respectively, to Theiler's murine encephalomyelitis
      virus-induced demyelinating disease (TMEV-1DD)--a model for viral etiology of
      human multiple sclerosis. BALB/cByJ mice become susceptible following low-dose
      irradiation given prior to infection. Resistance is restored by adoptive transfer
      of CD8+ (but not CD4+) splenic T cells from infected, unirradiated BALB/cByJ
      donors. In contrast resistance is conferred to BALB/cAnNCr mice by adoptive
      transfer of either CD4+ or CD8+ T cells from resistant BALB/cByJ donors. T cells
      from BALB/cAnNCr mice cannot confer protection. To integrate these two
      observations, we hypothesized that the BALB/cAnNCr mice possess precursors of the
      regulatory CD8+ T cells, but fail to activate them because they lack a critical
      CD4+ T-cell subpopulation. We tested this model using serial transfers. The
      transfer of CD4+ T cells from the BALB/cByJ to the BALB/cAnNCr mice permitted
      development of BALB/cAnNCr CD8+ T cells that in turn, provided resistance when
      transferred into susceptible recipients. The BALB/cByJ CD4+ T cells, which
      activated the CD8+ cells, were sensitive to low-dose irradiation, unlike CD4+ T
      cells involved in the later inflammatory demyelination. Thus, susceptibility of
      BALB/cAnNCr mice is due to a defective/absent CD4+ T-cell subset acting
      immediately after infection.

PMID- 12474984
TI  - Mature bone marrow-derived dendritic cells polarize Th2 response and suppress
      experimental autoimmune encephalomyelitis.
AB  - Distinct subsets of dendritic cells (DCs) based on the origin, phenotypes, and
      the nature of the signals that promote DC maturation can determine polarized
      immune responses of T cells. In this study, DCs were cultured from mouse bone
      marrow (BM) progenitors in granulocyte-macrophage colony-stimulating factor (GM
      CSF). To generate mature DCs (mDCs), lipopolysaccharide (LPS) was used in the
      culture for 24 h. LPS-stimulated DCs were phenotypically mature, which exhibited
      strongly upregulated CD40, B7.1, and B7.2 compared to non-LPS-stimulated immature
      DCs (imDCs). Both mDCs and imDCs expressed high levels of MHC class II but low
      level of CD54. mDCs produced higher levels of IL-10 and lower IL-12 compared to
      imDCs. No IFN-gamma or IL-4 was found in both groups. When mDCs were injected
      intraperitoneally (i.p.) to the mice with experimental autoimmune
      encephalomyelitis (EAE), the severity of clinical signs and inflammation in the
      CNS was significantly suppressed compared to imDC-injected mice (p<0.01) and PBS
      injected mice (p<0.02). Moreover, lymphocytes from mDC-injected mice produced
      lower level of IL-12, IFN-gamma, but higher level of IL-10, compared to imDC
      injected and non-DC-injected mice. We conclude that BM-mDCs, but not BM-imDCs,
      promote Th2 differentiation and have the potential for suppression of
      inflammatory demyelination.

PMID- 12474986
TI  - An examination of the association between beta2 adrenergic receptor polymorphisms
      and multiple sclerosis.
AB  - In multiple sclerosis (MS), beta-adrenergic receptor densities on peripheral
      blood mononuclear cells are enhanced, while the astrocytes present in plaques
      lack beta2 adrenergic receptor (beta2AR) expression. This differentially altered
      expression suggests that beta2ARs may influence the pathogenesis of MS. In the
      present study, we investigated the association of polymorphisms of the beta2AR
      gene with the occurrence of MS. Our results showed no significant differences in
      the distribution of the polymorphisms between MS patients overall and control
      subjects. Furthermore, no association was observed between the presence of
      beta2AR gene polymorphisms and clinical characteristics, such as age at disease
      onset and disease severity. While a trend towards an increase of the Gly allele
      frequency in codon 16 was observed in the secondary-progressive MS, this result
      was not significantly different from that observed in relapsing-remitting MS
      patients or control subjects. Together, our findings suggest that the presence of
      beta2AR gene polymorphisms may be inconclusive in the susceptibility to MS or in
      the clinical characteristics of Japanese patients with MS and, therefore, need
      further studies.

PMID- 12474987
TI  - Quantitative magnetization transfer imaging of pre-lesional white-matter changes
      in multiple sclerosis.
AB  - OBJECTIVE: Previous magnetization transfer (MT) studies in multiple sclerosis
      (MS) suggest a reduction of the MT ratio (MTR) precedes new lesion development.
      To gain further insight into pre-lesional tissue abnormalities, we investigated
      the time course of additional quantitative MT parameters. METHODS: Serial
      magnetic resonance imaging (MRI), including a gadolinium-enhanced T1 scan and MT
      imaging by means of a FastPACE sequence, was performed on 12 patients (4 males, 8
      females) with relapsing-remitting MS. Quantitative MT values including the
      magnetization exchange rate (kfor) and the native relaxation time (T1free were
      analysed in the six months prior to the appearance of 44 enhancing lesions and in
      88 control regions of persistently normal-appearing white matter (NAWM). RESULTS:
      Appearance of new active lesions was preceded by a significant decrease of the
      MTR (F7,166=91.5; p<0.0001) and of kfor (F7,166=105.2; p<0.0001), and by an
      increase of T1free (F7,166=57.3; p<0.0001). The drop of kfor was the most
      pronounced pre-lesional change and together with the MTR was statistically
      significant already four months before the appearance of new lesion. The observed
      increase of T1free was relatively small. MT variables of reactivated lesions were
      always different from NAWM but showed no characteristic time course. CONCLUSIONS:
      Multiparametric MT measurements suggest both a reduction of macromolecular
      material and a focal increase of free water to occur several months before the
      appearance of an active lesion. Reduction of the magnetization exchange rate,
      which may result from primary damage to myelin, appears to be the leading event

PMID- 12474988
TI  - Effect of combined IFNbeta-1a and glatiramer acetate therapy on GA-specific T
      cell responses in multiple sclerosis.
AB  - The combined treatment with interferon beta (IFNbeta) and glatiramer acetate (GA)
      is of current interest in multiple sclerosis (MS). The therapeutic effect of GA
      in MS is believed to be mediated by GA-specific Th2 cells. IFNbeta has a
      significant anti-proliferative effect on GA-induced lymphoproliferation in vitro.
      Therefore, we examined the possibility that IFNbeta may interfere with the
      generation and phenotype of GA T-cell responses in MS patients receiving combined
      therapy. Sixty-six GA-specific T-cell lines (TCL) were generated ex vivo from
      five MS patients enrolled in an open-label dinical trial of combined IFNbeta/GA
      treatment. Controls included 83 pretreatment and 131 on-treatment GA-TCL from 11
      MS patients treated with GA only, and five GA-TCL generated from four patients
      receiving IFNbeta-1a monotherapy. IFNgamma and IL-5 (markers of Th1 and Th2
      responses, respectively) were assayed by ELISA in GA-TCL supematants. Th1/Th2
      bias was defined by the IFNgamma/IL-5 level ratio ( >2 = Th1 bias, <0.5 = Th2
      bias, and 0.5-2 = Th0 bias). The frequency with which GA-reactive TCL were
      generated was 37.0% for the patients in the combination trial compared to 33.3%
      in the patients receiving GA alone. The mean stimulation index of the GA-TCL was
      8.41 (range 2-42) for the combination compared to a mean of 6.29 (range 2-37) for
      the GA-treated group--a nonsignificant difference. Mean GA-TCL IFNgamma
      production was significantly lower in all treatment groups compared to
      pretreatment IL-5 levels were enhanced in all treatment groups compared to
      pretreatment levels, but the change was not statistically significant. The
      Th1/Th0/Th2 distribution of GA-TCL was 7%/30%/63% for the GA+IFNbeta group,
      8%/9%/83% for the GA group, compared to 48%/21%/31% pre-GA treatment. All five GA
      TCL from the IFNbeta-1a monotherapy patients were Th2-biased. We conclude that
      IFNbeta-1a does not affect the generation of GA-reactive T cells in vivo.
      Although more Th0 G4-TCL occurred with combination therapy than with G4 treatment
      alone, both groups shared an overall Th2 bias. Therefore, we speculate that
      combined therapy is unlikely to reduce the efficacy of GA treatment in MS.

PMID- 12474989
TI  - Low interferon gamma producers are better treatment responders: a two-year follow
      up of interferon beta-treated multiple sclerosis patients.
AB  - As response to interferon beta (IFNB) treatment, a 50% reduction of the mean
      relapse rate compared to pretreatment values has been reported. However,
      individual responses vary considerably, ranging from no reduction in exacerbation
      frequency to complete suppression of relapses for at least two years. At the
      moment, valid predictors for IFNB response are lacking. Here we present a
      prospective evaluation of 33 patients with primary relapsing multiple sclerosis
      who were followed for two years of IFNB treatment A low interferon gamma (IFG)
      production before treatment predicted a two-year term without exacerbations in
      68.8% of cases correctly, whereas a high pretreatment IFG production implied the
      risk of at least one relapse in the first two years in 70.6%. These preliminary
      results encourage further evaluation of IFG as predictor of an IFNB treatment
      response.

PMID- 12474990
TI  - Epileptic seizures, cranial neuralgias and paroxysmal symptoms in remitting and
      progressive multiple sclerosis.
AB  - The occurrence of a first epileptic seizure, spinal or brainstem paroxysmal
      symptom and cranial neuralgia during 25 years after onset was studied in a
      population-based multiple sclerosis (MS) cohort of 255 patients. Epileptic
      seizures occurred in 20, paroxysmal symptoms in 11 and cranial (trigeminal,
      intermedius, retroauricular or occipital) neuralgia in 11 patients. The yearly
      incidence of epileptic seizures in MS was estimated to be 349(+/-153)/100,000,
      approximately seven times higher than in the general population. The yearly
      incidence of a first paroxysmal symptom in the present material was calculated to
      be 190 cases in 100,000 MS patients, and the yearly incidence of cranial
      neuralgia was 189 cases in 100,000 MS patients. The epileptic seizures were more
      frequent during the progressive course than in the relapsing-remitting (RR)
      course. The frequencies of paroxysmal symptoms and cranial neuralgia did not
      differ between these two disease courses. A coincidence of epileptic seizures and
      a decline in cognitive functioning not seen among patients with paroxysmal
      symptoms was found The relatively late occurrence of epileptic seizures indicates
      that the frequency of epileptogenesis, known to involve neuronal damage,
      increases in the later stages of MS.

PMID- 12474991
TI  - The roles of blink reflex and sympathetic skin response in multiple sclerosis
      diagnosis.
AB  - The neurological history and examination are important in multiple sclerosis (MS)
      diagnosis, but early and accurate diagnosis of MS often requires judicious use of
      paraclinical information. Electrophysiologic techniques have an important role in
      demonstrating lesions that are clincally silent but magnetic resonance imaging
      (MRI) is accepted as the most sensitive paraclincal test for detecting
      asymptomatic dissemination in space for MS patients. In order to test the
      sensitivity of electrophysiologic techniques in diagnosing asymptomatic MS
      lesions, we performed blink reflex (BR) and sympathetic skin response (SSR)
      studies on 13 female (mean age 39 -/+ 9 years) and 8 male (mean age 35 -/+ 14
      years) patients with a diagnosis of definite MS who do not have any clinical
      symptoms nor signs referable to brainstem or autonomic system dysfunction. Forty
      three percent of patients on SSR testing and 40% of patients on BR testing
      demonstrated abnormal results. In countries with unfavorable economic conditions,
      diagnosis, especially the follow-up evaluation of MS patients, poses a major
      dilemma. The role of diagnostic techniques in MS diagnosis when MRI is available
      is an economic problem. Diagnostic evaluation adds to the cost of health
      expenses. We usually choose to perform MRI only at the initial diagnosis of MS
      and perform follow-up evaluations during remissions and exacerbations with the
      aid of electrophysiologic techniques. We stress the importance of
      electrophysiologic screenings in MS patients because they provide data that
      cannot be obtained through clinical evaluations only with a little cost.

PMID- 12474992
TI  - Central hyperacusis with phonophobia in multiple sclerosis.
AB  - Hearing disorders are a well-described symptom in patients with multiple
      sclerosis (MS). Unilateral or bilateral hyperacusis or deafness in patients with
      normal sound audiometry is often attributed to demyelinating lesions in the
      central auditory pathway. Less known in MS is a central phonophobia, whereby
      acoustic stimuli provoke unpleasant and painful paresthesia and lead to the
      corresponding avoidance behaviour. In our comparison collective, patient 1
      described acute shooting pain attacks in his right cheek each time set off by the
      ringing of the telephone. Patient 2 complained of intensified, unbearable noise
      sensations when hearing nonlanguage acoustic stimuli. Patient 3 noticed hearing
      unpleasant echoes and disorders of the directional hearing. All patients had a
      clinical brainstem syndrome. ENT inspection, sound audiometry and stapedius
      reflex were normal. All three patients had pathologically changed auditory evoked
      potentials (AEPs) with indications of a brainstem lesion, and in magnetic
      resonance imaging (MRI) demyelinating lesions in the ipsilateral pons and in the
      central auditory pathway. The origin we presume in case 1 is an abnormal impulse
      conduction from the leminiscus lateralis to the central trigeminus pathway and,
      in the other cases, a disturbance in the central sensory modulation. All patients
      developed in the further course a clinically definite MS. Having excluded
      peripheral causes for a hyperacusis, such as, e.g., an idiopathic facial nerve
      palsy or myasthenia gravis, one should always consider the possibility of MS in a
      case of central phonophobia. Therapeutic possibilities include the giving of
      serotonin reuptake inhibitors or acoustic lenses for clearly definable disturbing
      frequencies.

PMID- 12474993
TI  - Simple phonic tic in multiple sclerosis.
AB  - Movement disorders occurring in association with multiple sclerosis (MS) are
      rare. Among them paroxysmal dystonia is the most common, although chorea,
      ballism, palatal myoclonia, spasmodic torticollis, writer's cramp and generalized
      dystonia have been reported. We describe a 34-year old woman with MS who
      developed simple phonic tic characterized by throat-clearing sounds. Magnetic
      resonance imaging showed demyelinating lesions involving the thalamus and basal
      ganglia. This is the first report of tic disorder occurring as a manifestation of
      MS.

PMID- 12474995
TI  - Fatigue in multiple sclerosis: a comparison of different rating scales and
      correlation to clinical parameters.
AB  - OBJECTIVES: Fatigue is one of the most common, yet poorly defined, disabling
      symptoms in patients with multiple sclerosis (MS). To delineate more clearly the
      frequency and type of fatigue, we first compared four widely used fatigue scales
      in consecutive MS patients. Secondly, to further clarify the nature of fatigue,
      we investigated its relation to physical disability, course of the disease,
      immunotherapy, and depression. PATIENTS AND METHODS: Between February and
      September 2000, 151 consecutive MS patients entering our outpatient clinic (94
      relapsing-remitting, 50 secondary progressive, and 7 primary progressive
      patients; mean age 29.0 +/- 7.3 years, mean disease duration 9.9 +/- 6.7 years,
      median EDSS 3.5) filled in a standardized questionnaire induding four fatigue
      scales--Fatigue Severity Scale (FSS), MS-specific FSS (MFSS), Modified Fatigue
      Impact Scale (MFIS), and Visual Analogue Scale (VAS). Patients were included in
      the 'MS-related fatigue group' (MS-F) when they stated in the questionnaire that
      fatigue: 1) is one of their three most disabling symptoms; 2) occurs daily or on
      most of the days; and 3) limits their activities at home or at work Patients
      fulfilling none of these criteria were classified as 'MS-related nonfatigue
      group' (MS-NF). Depression was measured by Beck's Depression Inventory (BDI).
      RESULTS: Although all scales showed significant differences between MS-F and MS
      NF, correlation between these scales was, at best moderate (correlation
      coeffcients ranging from 0.06 to 0.56). The most discriminative scales were FSS
      and MFIS, showing no overlap of the 10th and 90th percentiles for the MS-F and MS
      NF groups, with cut-off values of 4.6 and 38, respectively. Depression (BDI > or
      = 18) was present in 24 of 148 patients who filled in the BDI (16%). FSS was
      significantly correlated with physical disability (r=0.33, p<0.0001) and BDI
      (r=0.41, p<0.0001), but not with age, disease duration, clinical activity, and
      treatment with interferon-beta. In multivariate analysis, however, only BDI
      independently predicted fatigue. CONCLUSIONS: The association of fatigue and
      depression suggests that there might be either common underlying mechanisms or
      interdependence by a cause-and-effect relationship that requires further
      investigation. The weak correlation within various fatigue scales is best
      explained by the fact that fatigue is a multidimensional symptom and, therefore,
      the available tests measure and weight different aspects of fatigue. Our findings
      underline the necessity for a more exact definition of fatigue and the
      development of more valid tools if these are to be used to evaluate treatments.

PMID- 12474994
TI  - Analyses of the minimum data set: comparisons of nursing home residents with
      multiple sclerosis to other nursing home residents.
AB  - This research compares nursing home residents with multiple sclerosis (MS) at
      admission to other nursing home residents using the minimum data set (MDS). These
      comparisons include sociodemographic characteristics and health status measures,
      as well as treatments and procedures received. We analysed 14,009 admission
      assessments in the MDS for residents with MS between June 22, 1998 and December
      31, 2000. We also analysed 440,642 MDS admission assessments for all residents
      admitted to nursing homes during the year 2000, with any admission assessments
      for residents with MS excluded from this comparison group. Residents with MS were
      significantly younger at admission than other recently admitted residents. In
      addition, residents with MS tended to be significantly more physically disabled
      and also less cognitively impaired than other residents at admission, based on
      analyses of several measures of physical disability and cognitive performance.
      Nursing homes caring for residents with MS should provide services and programs,
      including mental health care, that address the needs of these younger, more
      physically disabled, and more cognitvely intact residents.

PMID- 12474996
TI  - Quality of life in multiple sclerosis patients in Spain.
AB  - OBJECTIVE: The cross-sectional study evaluated the psychometric properties of the
      Functional Assessment of Multiple Sclerosis (FAMS) Spanish version and its use in
      measuring quality of life (QOL) of multiple sclerosis (MS) patients in Spain.
      METHODS: The FAMS is a factorially derived self-report scale designed to assess
      six primary aspects of QOL of patients with MS: Mobility, Symptoms, Emotional
      Well-Being, General Contentment, Thinking and Fatigue, and Family/Social Well
      Being. Its Spanish translated version was used to assess QOL of 625 MS patients
      recruited in an outpatient clinic setting from 58 hospitals in Spain. Internal
      consistency of the Spanish FAMS was evaluated Multiple regression analyses were
      performed to identify significant predictors from demographic, clinical and
      treatment characteristics, and Kurtzke Expanded Disability Status Scale (EDSS)
      scores in predicting FAMS scale scores. RESULTS: Most of the patients are females
      (66%), and 74% were of the relapsing-remitting (RR) clinical subtype. Cronbach's
      alpha coefficients were high (range=0.78-0.96), indicating subscale homogeneity
      comparable to that of the original English version. Linear multivariate
      regression analyses revealed that the EDSS is a dominant variable in predicting
      all the FAMS subscales, especially mobility (R2=0.51) and the total scores.
      CONCLUSIONS: The Spanish FAMS is a psychometrically valid instrument that allows
      clinicians and clinical researchers the ability to measure the QOL concerns of MS
      patients in Spain.

PMID- 12474997
TI  - The effect of the neuroprotective agent riluzole on MRI parameters in primary
      progressive multiple sclerosis: a pilot study.
AB  - Progressive axonal loss is the most likely pathologic correlate of irreversible
      neurologic impairment in primary progressive multiple sclerosis. In a run-in
      versus treatment trial, we show that the neuroprotective agent riluzole seems to
      reduce the rate of cervical cord atrophy and the development of hypointense T1
      brain lesions on magnetic resonance imaging.

PMID- 12474998
TI  - Arthritis during interferon beta-1b treatment in multiple sclerosis.
AB  - Interferon beta (IFN-beta) is the most widely prescribed disease-modifying drug
      for multiple sclerosis (MS). Therapy with IFN-beta may be associated with a
      number of adverse reactions The development or exacerbation of other autoimmune
      diseases is a rare but reported side effect of IFN-beta therapy. In this case
      report, we present clinical and laboratory findings of two MS patients who
      developed arthritis during IFN-beta1b treatment, probably of autoimmune origin.

PMID- 12474999
TI  - Goldblatt's kidney, Hughes syndrome and hypertension.

PMID- 12475000
TI  - The autoimmune response to chromatin antigens in systemic lupus erythematosus:
      autoantibodies against histone H1 are a highly specific marker for SLE associated
      with increased disease activity.
AB  - This study investigates specificity, sensitivity and concomitant presence of
      antibodies against histone H1 (H1), nucleosomes (NUC), chromatin (CHR) and dsDNA
      in patients with systemic lupus erythematosus (SLE), analyses their association
      with SLE disease activity and characterizes the immunodominant epitope reactivity
      of anti-H1 antibodies and its relation to SLE disease activity. In a cross
      sectional study 394 sera of patients with various rheumatic diseases and healthy
      subjects were analysed by ELISA for antibodies against H1, NUC, CHR and dsDNA. In
      addition, a longitudinal analysis was performed that included 121 sequential
      serum samples derived from 16 SLE patients to assess the relation of these
      antibodies as well as antibodies to histone H2B to SLE disease activity. To
      assess epitope reactivity of anti-H1 antibodies overlapping synthetic peptides
      covering the entire H1 sequence were used. Anti-H1 antibodies yielded a
      sensitivity of approximately 45% and a specificity of over 98% for SLE, which was
      comparable to that found for anti-dsDNA antibodies. Anti-CHR and anti-NUC
      antibodies were of similar sensitivity but slightly (anti-CHR) or considerably
      (anti-NUC) less specific for SLE (95 and 85%, respectively). The sequential
      analysis revealed a strong correlation of anti-H1 antibodies with SLE disease
      activity that was better than the correlation of anti-dsDNA and anti-NUC
      antibodies, while only weak correlation was found for anti-CHR and anti-H2B
      antibodies. The immunodominant epitope for anti-HI was localised between amino
      acids 204 and 218 (pp204-218) and immune reactivity to this epitope also
      correlated with disease activity. Anti-H1 is a highly specific marker for SLE
      with a diagnostic value comparable to anti-dsDNA. A positive testing for anti-H1
      indicates increased disease activity, as does the appearance of antibodies to its
      immunodominant epitope pp204-218.

PMID- 12475001
TI  - Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA
      antibodies: a prospective controlled study.
AB  - Anti-Ro/SSA antibodies are associated with neonatal lupus but are also considered
      a possible cause for unexplained pregnancy loss and adverse pregnancy outcome. In
      a large multicentres cohort study we have prospectively followed 100 anti-Ro/SSA
      positive women (53 systemic lupus erythematosus (SLE)) during their 122
      pregnancies and 107 anti-Ro/SSA negative women (58 SLE) (140 pregnancies). Anti
      Ro/SSA antibodies were tested by immunoblot and counterimunoelectrophoresis. Mean
      gestational age at delivery (38 vs 37.9 weeks), prevalence of pregnancy loss (9.9
      vs 18.6%), preterm birth (21.3 vs 13.9%), cesarean sections (49.2 vs 53.4%),
      premature rupture of membranes (4.9 vs 8.1%), preeclampsia (6.6 vs 8%),
      intrauterine growth retardation (0 vs 2.3%)and newborns small for gestational age
      (11.5 vs 5.8%) were similar in anti-Ro/SSA positive and negative SLE mothers;
      findings were similar in non-SLE women. Two cases of congenital heart block were
      observed out of 100 anti-Ro/SSA positive women. In conclusion, anti-Ro/SSA
      antibodies are responsible for congenital heart block but do not affect other
      pregnancy outcomes, both in SLE and in non-SLE women. The general outcome of
      these pregnancies is now very good, ifprospectively followed by multidisciplinary
      teams with ample experience in this field.

PMID- 12475002
TI  - Gender and age differences in systemic lupus erythematosus. A study of 489 Greek
      patients with a review of the literature.
AB  - We investigated whether gender and age influence the clinical course and outcome
      in systemic lupus erythematosus (SLE) patients. Thus, we analyzed the clinical
      and laboratory data of 489 SLE patients at presentation and during follow-up. In
      addition, disease activity score (using the European Consensus Lupus Activity
      Measure, ECLAM) and organ damage index (using the Systemic Lupus International
      Collaboration Clinics/American College of Rheumatology Damage Index, DI) were
      measured. Furthermore, data from both sexes were analyzed according to the
      following age groups: < 55 years(younger group) and > 55 years (older group).
      There were 68 men and 421 women, giving a ratio of 1:7. We found no differences
      in the mean age, mean age at diagnosis, disease duration as well as duration of
      follow-up between men and women. Young men presented more frequently with
      serositis and discoid lesions, while women presented with Raynaud's phenomenon
      (RP) and malar rash. Regarding the laboratory findings, young women presented
      more often with anti-Ro(SSA) and anti-La(SSB) antibodies, while increased levels
      of erythrocyte sedimentation rate (ESR) were found in old women. During follow
      up, men had serositis and renal disease more frequently, while the women's group
      were found to complain of RP, photosensitivity and mucosal ulcers more
      frequently, especially in young women.Anemia, leukopenia, thrombocytopenia and
      elevated levels of ESR were also found more frequently in young women during
      follow-up. However, there were no significant differences concerning ECLAM and DI
      scores between the two gender groups. Using multiple logistic regression
      analysis, a statistically significant association of malar rash, discoid lesions,
      serositis, RP, anti-Ro(SSA)/ La(SSB) and increased ESR with sex was found
      independently of age, while only malar rash showed a statistically significant
      association with age independently of sex. Thus, we conclude that gender
      influences the clinical expresion of the disease independently of age, while both
      gender and age do not affect the overall damage score.

PMID- 12475003
TI  - Clinical significance of acquired activated protein C resistance in patients with
      systemic lupus erythematosus.
AB  - Antiphospholipid antibodies (aPL) may induce acquired activated protein C
      resistance (acquired APCR). The role of acquired APCR in patients with systemic
      lupus erythematosus (SLE) is not well known. To evaluate the prevalence of
      acquired APCR and its association with clinical manifestations we studied 103
      consecutive SLE patients and 103 matched controls. APCR in the undiluted test and
      after dilution in factor V deficient plasma, factor V Leiden, protein C and S,
      lupus anticoagulant, and anti-cardiolipin, anti-beta2-glycoprotein I and anti
      prothrombin antibodies were determined. Factor V Leiden was found in 4% in both
      patients and controls. The prevalence of acquired APCR was 22% for the undiluted
      assay and 17% in the diluted test. In SLE patients, acquired APCR was associated
      with aPL (39 vs 13% in undiluted assay, P = 0.007; and 33 vs 7% in the diluted
      test, P = 0.001). Arterial thromboses were found in 24% of patients with acquired
      APCR and in 6% of patients without (P = 0.04). However, no relationship was found
      with venous thrombosis. Acquired APCR was also associated with pregnancy losses:
      miscarriages in 70% of women with acquired APCR vs 32% in those without (P=0.03).
      Thus, in SLE patients acquired APCR seems to be associated with increased
      prevalence of arterial thrombosis and pregnancy losses.

PMID- 12475004
TI  - Behavioral and cognitive deficits occur only after prolonged exposure of mice to
      antiphospholipid antibodies.
AB  - The antiphospholipid (Hughes) syndrome (APS) includes systemic and central
      nervous system (CNS) pathology associated with antibodies to a complex of
      phospholipids and beta2-glycoprotein I (beta2-GPI). Beta2-GPI immunized mice
      develop systemic manifestations of APS and we presently examined CNS
      manifestations in this APS model. Female BALB/c mice were immunized once with
      beta2-GPI in complete Freund's adjuvant (CFA) or with CFA alone (controls). A
      staircase test and a T-maze alternation test were performed to test behavior and
      cognition in independent groups of mice 6, 12 and 18 weeks following the
      immunization. The APS mice developed elevated levels of antibodies against
      negatively charged phospholipids and beta2-GPI. Neurological impairment was
      detected only 18 weeks after the induction of the APS and consisted of both
      cognitive (53 +/- 4 vs 71 +/- 3% correct choices in the T-maze alternation for
      APS vs control mice, P < 0.001) and behavioral changes (higher number of rears
      (18 +/- 2 vs 11 +/- 1, P < 0.006) and higher number of stairs climbed (12 +/- 2
      vs 7 +/- 1, P < 0.02). This is the first report of cognitive deficits in this APS
      model and demonstrates the time course for the development of previously
      described behavioral changes. The mechanism involved in these CNS manifestations
      remains to be elucidated.

PMID- 12475005
TI  - Cardiac valvular abnormalities are frequent in systemic lupus erythematosus
      patients with manifest arterial disease.
AB  - The objective of this study was to study cardiac valve morphology and function
      and ventricular function in systemic lupus erythematosus (SLE) patients with and
      without co-existing cardiovascular disease (CVD) and in population controls.
      Twenty-six women (52 +/- 8.2 years) with SLE (SLE cases) and a history of CVD
      (angina pectoris, myocardial infarction, cerebral infarction or intermittent
      claudication) were compared with 26age-matched women with SLE but without
      manifest CVD (SLE controls) and 26 age-matched control women (population
      controls). Echocardiographywas performed to assess valvular abnormalities and
      manifestations of ischaemic heart disease. Thirteen of the 26 SLE cases but only
      one of the SLE controls and one of the population controls had cardiac valvular
      abnormalities. Three of the SLE cases had already undergone valve replacement and
      another had significant aortic insufficiency; the other nine had thickening of
      mainly mitral leaflets without hemodynamic significance. Among SLE cases,
      patients with valvular abnormalities had higher homocysteine (P < 0.001) and
      triglyceride (P = 0.02) concentrations than patients without valvular disease. In
      contrast atherosclerosis as determined by IMT, oxidized LDL as measured by the
      monoclonal antibody E06, autoantibodies against epitopes of OxLDL (aOxLDL) or
      phospholipids (aPL), disease duration or activity, or acute phase reactants did
      not differ between SLE cases with or without valvular abnormalities. Valvular
      abnormalities were not more common in SLE cases with stroke as compared to those
      with myocardial infarction, angina or claudication. In conclusion, valvular
      abnormalities are strongly associated with CVD in SLE. Raised levels of
      homocysteine and triglycerides characterize patients with cardiac valve
      abnormalities.

PMID- 12475006
TI  - Drug-induced lupus following treatment with infliximab in rheumatoid arthritis.
AB  - After introduction of infliximab for the treatment of rheumatoid arthritis (RA),
      there have been many reports of patients developing asymptomatic higher rate of
      antinuclear antibodies and anti-dsDNA antibodies than in non-infliximab-treated
      patients. However, only five clinical drug-induced lupus (DIL) cases have been
      documented following treatment with infliximab, in RA and in Crohn's diseases. We
      report a case of a 69-year-old female with a 5 year history of RA, whowas
      successfully treated with low-dose methotrexate (MTX) and infliximab (initially 3
      mg/kg and from the fourth infusion 5 mg/kg) for 23 weeks. Before the sixth
      infusion, she was diagnosed with DIL by both clinical features (fever > 38
      degrees C, recurrence of active synovitis, myalgia, erythematous rash and general
      malaise) and laboratory findings (antinuclear antibodies 1:160, anti-double
      stranded DNA positive by ELISA assay, decreased serum complement C3 andC4,
      hypergammaglobulinaemia, increased erythrocyte sedimentation rate). After
      discontinuation of treatment and therapy with oral prednisone, lupus resolved
      within 8 weeks.

PMID- 12475007
TI  - Antiphospholipid syndrome in a patient with sarcoidosis: a case report.
AB  - We report the case of a 72-year-old female with sarcoidosis who developed a
      central retinal artery occlusion in her left eye in association with persistently
      high titers of IgG anti-cardiolipin antibodies. Only two previous cases of
      antiphospholipid antibody syndrome in association with sarcoidosis have been
      reported. Our patient's vision stabilized on anti-coagulant therapy along with
      concomitant treatment of sarcoidosis-related uveitis with methotrexate.

PMID- 12475008
TI  - Practice patterns of antiphospholipid syndrome at a tertiary teaching hospital in
      Lebanon.
AB  - The objective of the study was to describe the practice patterns of the
      antiphospholipid syndrome (APS) as compared with consensus guidelines for
      diagnosis and to determine whether practice patterns correlate with patient
      demographics and physician specialty. A retrospective medical chart review was
      conducted at the American University Hospital, in Beirut, Lebanon. All adult and
      pediatric patients admitted to the hospital between 1 January and 31 December
      1998 who underwent either anticardiolipin antibodies (aCL) or lupus anticoagulant
      (LA) testing were included in the study. Work-up of APS syndrome was compared
      with: (a) the consensus guidelines for clinical diagnosis; (b) physician
      specialty; and (c) patient demographics (age, gender, ethnicity, health insurance
      status). Eighty-seven patients fulfilled at least one clinical criterion for APS;
      92% were for work-up of thrombosis and 8% for pregnancy morbidities. Fifty-one
      percent underwent both aCL and LA. Overall 38% (33) of patients had an abnormal
      test result, however only 18% (6) underwent retesting, of whom only two satisfied
      a minimum of 6 weeks between test and retest TheAPS diagnostic work-up was
      requested by 11 different specialties. Rheumatologists were the most consistent
      in asking for both tests. APS is seen and diagnosed by a variety of medical
      specialties. Practice patterns as compared with the latest consensus are sub
      optimal, and need to be improved. Interventions to help improve this have been
      discussed and are being implemented.

PMID- 12475010
TI  - Volume threshold for micturition. Influence of filling rate on sensory and motor
      bladder function.
AB  - Filling at physiological rates (natural filling) is the specific stimulus for
      activation of the micturition reflex. In urodynamic studies this has rarely been
      taken into consideration. In the vast majority of clinical urodynamic studies 50
      ml/min has been the preferred filling rate. A comparative study in 17 healthy
      volunteers of cystometry at 50 and 100 ml/min (CMG) and ambulatory monitoring
      (AM) during natural filling has been performed by other authors (3). It was found
      that CMG increases volume threshold for micturition, impairs detrusor
      contractility and has lower sensitivity for detecting spontaneous phasic detrusor
      activity. These results are discussed in the present article. The nearest
      explanation is at the cellular level. Filling rates above physiological range (>
      15 HD (Hour-Diuresis units)) are a mechanical trauma to receptors, nerve endings,
      cells and cell junctions, which are temporarily functionally disturbed.

PMID- 12475009
TI  - Churg-Strauss syndrome complicated by endomyocardial fibrosis and
      intraventricular thrombus. Importance of the echocardiography for the diagnosis
      of asymptomatic phases of potentially severe cardiac complications.

PMID- 12475011
TI  - Brain control of the lower urinary tract.
AB  - The knowledge on neural pathways involved in micturition and continence has been
      expanded greatly the last ten years. The aim of the present review is to
      summarize results obtained from animal and human experiments and to discuss the
      pathophysiology of relevant urological dysfunction. Four specific parts of the
      mammalian neural system are important for the control of micturition and
      continence: 1) ganglion cells in the bladder wall and sympathetic chain
      (autonomic) and dorsal root chain (sensory); 2) motoneurons and sensory
      interneurons in the caudal spinal cord; 3) the caudal brainstem; and 4) the
      cortical and subcortical areas. The parts 1) to 3) comprise the basic components
      of the micturition reflex and are interconnected via peripheral nerves and
      central fiber tracts. Normally, we are continent for urine continuously, except
      for the necessary emptying of the bladder five to eight times a day. Specific
      lesions of the neural pathways can result in distinct types of urological
      dysfunction: hypoactivity or hyperactivity of the micturition or continence
      pathways, and a loss of control of the beginning of micturition.

PMID- 12475012
TI  - Possible pathways for cerebellar modulation of autonomic responses: micturition.
AB  - Experimental and clinical studies have shown that the cerebellum participates in
      the regulation of various visceral responses, including micturition. It is not
      yet clear through which parts of the central nervous system such cerebellar
      influences are mediated. However, a series of investigations have shown that the
      cerebellum is directly or indirectly connected to various centres that appear to
      be involved in autonomic control. These include parts of the cerebral cortex, the
      hypothalamus, the periaquaductal grey, nuclei in and around the pontine
      micturition centre, the dorsal vagal nucleus and nucleus of the solitary tract,
      and the medullary reticular formation. This article examines some of the circuits
      that may be involved in cerebellar modulation of visceral reflexes, especially
      the micturition reflex.

PMID- 12475013
TI  - The pontine micturition centres.
AB  - OBJECTIVE: To review recent literature on the function of the two postulated
      pontine regions (the M- and L-regions) concerned with lower urinary tract
      control. MATERIAL AND METHODS: The work reviewed is based on stimulation and
      lesion experiments and post-operative follow-up in the cat, supported by acute
      chemical stimulation and blocking experiments in the rat and PET functional brain
      scanning in humans. RESULTS AND CONCLUSIONS: The M-region in the cat, homologous
      to Barrington's micturition centre and to a similar area in humans, is a small
      region both specific and necessary to voiding, the origin of the final common
      pathway to bladder and urethra, and the locus of co-ordination of the bladder and
      the striated sphincter. The L-region in the cat is part of a larger, less
      specific area that probably serves sphincter control in various circumstances,
      not exclusively micturition. The homolog of this region in the human or in the
      rat has not been adequately established.

PMID- 12475014
TI  - Efferent control of different visceral pelvic organs by spinal and supraspinal
      centres.
AB  - A growing number of patients with pelvic organ dysfunction and failing response
      to standard treatment concepts are referred to special neuro-urology services.
      New therapeutic options are available, such as unilateral and bilateral sacral
      nerve stimulation, and the use of different neurotoxins for the overactive
      bladder. However, a lack of knowledge and understanding in central innervation
      and modulation of pelvic organ function prevents a striking progress in this
      clinical area. A concept of efferent innervation of pelvic organs based on
      experimental animal studies, using the retrograde, transneuronal and self
      amplifying tracer Pseudorabiesvirus, is discussed in a clinical context.

PMID- 12475015
TI  - Bladder and urethral responses to pelvic nerve stimulation in the pig.
AB  - OBJECTIVE: The aim of our study of the pig was to investigate the responses of
      smooth muscle of the bladder and the urethral sphincter to preganglionic
      parasympathetic stimulation, and to assess the effect on the lower urinary tract
      of IV administration of alpha,beta-methylene-ATP. MATERIALS AND METHODS: In seven
      anaesthetised female pigs, the responses to repeated 20 s pelvic nerve
      stimulations before and after IV administration of 0.02 mg/kg alpha-beta
      methylene-ATP, and the responses to the drug itself, were recorded in the bladder
      and the urethra separately. RESULTS: In the urethral high-pressure zone, pre
      stimulation pressure was a mean of 61+/-11 cmH2O. During pelvic nerve
      stimulation, urethral pressure declined by 48+/-9 cmH2O, while the bladder
      pressure increased to 30+/-18 cmH2O. The rate of pressure changes during the
      first 3 s of stimulation (initiation of voiding) was larger in the urethra than
      in the bladder (urethral pressure decrease: 13.0+/-3.1 cmH2O/s, bladder pressure
      increase: 3.2+/-2.5 cmH2O/s). Administration of alpha,beta-methylene-ATP was
      followed by a significant but temporary enlargement in the bladder response to
      pelvic nerve stimulation to 36+/-20 cmH2O, p = 0.028, n = 7, but no change in
      urethral response. CONCLUSIONS: At least 80% of the urethral pre-stimulation
      pressure was exerted by the smooth muscle. The synergic activation of the
      detrusor and the urethral smooth muscle in response to preganglionic
      parasympathetic nerve stimulation was controlled by the peripheral nerves or by
      the neuromuscular transmission. Administration of alpha,beta-methylene-ATP
      increased the bladder response to pelvic nerve stimulation without changing the
      urethral response.

PMID- 12475016
TI  - Voiding and the sacral reflex arc: lessons from capsaicin instillation.

PMID- 12475017
TI  - Mictunrition and the sacral reflex arc: lessons from electrophysiological
      techniques.
AB  - Electrophysiological techniques applied either for diagnostic or therapeutic
      reasons have contributed to elucidation of the neurocontrol of micturition. But
      the ability of electrophysiological diagnostic tests to reveal neurogenic
      involvement in patients suffering from lower urinary tract dysfunction is
      limited, and has been overestimated. Furthermore, the correlation between a
      proven neurogenic deficit and the consecutive dysfunction is complex. The
      electrophysiological tests, however, may also be applied for testing the central
      nervous system integrative function, such as in testing reflex thresholds,
      excitability levels of motor nuclei, etc. The use of electrical stimulation for
      therapeutic purposes has instigated much physiological research. Insights related
      to micturition neurocontrol, as for instance that afferent inputs from
      lumbosacral and vesical sensory fibres modulate the micturition threshold, are
      being therapeutically exploited. It is expected that further use of
      electrophysiological techniques, being complementary to functional neuroimaging,
      will clarify particularly the temporal aspects of neurocontrol mechanisms
      involved in micturition.

PMID- 12475018
TI  - Electromyography in urinary retention and obstructed voiding in women.

PMID- 12475019
TI  - Overactive bladder--experimental aspects.
AB  - Supra-pontine lesions resulting from neurological disorders such as vascular
      disease, Parkinson's disease, or Alzheimer type senile dementia lead to an
      increase in bladder activity. This is due in part to the removal at the cortical
      inhibitory control of the micturition center in the brain stem - i.e. the pontine
      micturition center (PMC) - and in part to facilitation of excitatory control.
      These inhibitory or excitatory controls consist of several neurotransmitter
      systems, including glutamate, dopamine, gamma-aminobutyric acid (GABA), and
      acetylcholine. Bladder overactivity caused by cerebral infarction is mediated by
      upregulation of N-methyl-D-aspartate (NMDA) glutamatergic and D2 dopaminergic
      excitatory mechanisms, and by downregulation of NMDA glutamatergic and Ml
      muscarinic inhibitory mechanisms in the brain. Bladder overactivity associated
      with Parkinson's disease is reportedly induced by a loss of input to the D1
      dopaminergic receptor. Furthermore, bladder overactivity caused by Alzheimer type
      dementia is thought to be mediated by downregulation of M1 muscarinic inhibitory
      mechanisms. Development of bladder overactivity following cerebral infarction is
      mediated by activation of the NMDA receptor and accompanied by an increase in c
      fos, zif268 and COX-2 mRNA expression in the dorsal pontine tegmentum.

PMID- 12475020
TI  - Clinical aspects of the overactive bladder and detrusor overactivity.
AB  - OBJECTIVE: The overactive bladder is a widespread medical condition with
      significant quality of life and financial impact. Despite this much remains
      unknown about the epidemiology and pathophysiology of this condition. This review
      gives an overview of the current knowledge base and the recent terminology
      changes approved by the international continence society. METHODS: Critical
      review of the literature regarding aetiology, epidemiology, urodynamic and
      clinical aspects of detrusor overactivity. Explanation of the recently adopted
      terminology. RESULTS: The term "overactive bladder" has replaced the term
      "unstable bladder", which held no intuitive meaning. "Detrusor overactivity" is
      the corresponding urodynamic term, replacing "detrusor instability" and "detrusor
      hyperreflexia". Knowledge regarding the epidemiology of the overactive bladder is
      limited. The myogenic and neurogenic theories of pathophysiology require further
      evidence. CONCLUSION: Massive research efforts are required into all aspects of
      this common chronic disease. The adoption of new ICS terminology will aid
      consistency in research.

PMID- 12475021
TI  - Overactive bladder--pharmacological aspects.
AB  - The micturition reflex can be initiated by contraction or distension of detrusor
      smooth muscle cells, or by signals from the urothelium. It has been shown that
      bladder distension causes release of ATP from the urothelium, and that ATP can
      activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a
      neural discharge. However, most probably the activation of afferent fibres during
      bladder filling involves not only ATP, but a cascade of inhibitory and
      stimulatory transmitters/mediators. These mechanisms may be targets for future
      drugs. Both in the normal and functionally disturbed bladder, muscarinic receptor
      stimulation produces the main part of detrusor contraction, but evidence is
      accumulating that in disease states, such as neurogenic bladders, outflow
      obstruction, idiopathic detrusor instability, interstitial cystitis, and also in
      the ageing bladder, a non-cholinergic activation via purinergic receptors may
      occur. If this component of activation is responsible not only for part of the
      bladder contractions, but also for the symptoms of the overactive bladder, it
      should be considered an important target for therapeutic interventions. Drags
      blocking different P2X receptor subtypes, or counteracting bladder contraction
      via other mechanisms, e.g. beta3-adrenoceptor stimulation, may be developed for
      treatment of the overactive bladder.

PMID- 12475022
TI  - Neuromodulation and other electrostimulatory techniques.

PMID- 12475023
TI  - Sacral neuromodulation in Norway: clinical experience of the first three years.
AB  - We present our first three years' experience of sacral neromodulation as first
      line therapy in patients with a non-neurogenic refractory urge incontinence. In
      53 patients, 45 women and 8 men with a mean age of 54 years (range 17-76 years),
      tested by subacute percutan nerve evaluation, 19 patients were declared as
      responders according to our programme. Fourteen patients, twelve women and two
      men with a mean age of 47 years (range 33-73 years), agreed to implantation of a
      neuroprosthesis (Medtronic Interstim Model 3031), which was placed in a
      subcutaneous buttock pocket in 12 patients. In the first two patients, the device
      was implanted subcutaneously corresponding to the lower quadrants of the
      abdominal wall. In two patients, the lead was repositioned from S:4 to S:3 six to
      twelve months after the primary implantation. In one woman with sensory urgency,
      the neuroprosthesis was removed six months after it was implanted because of
      failure. The patients were followed every six months using voiding diary,
      uroflowmetry, residual urine and cystometry. Eight patients reported total
      continence, and five declared >50% improvement. One woman has chronic bacteriuria
      and intermittently symptomatic urinary tract infection, which reduce the response
      to the chronic sacral nerve stimulation. Because of residual urine, four women
      are following an individual self-catheterisation programme. In conclusion, we
      have documented that sacral neuromodulation is an effective and safe procedure in
      patients with refractory urge incontinence depending on detrusor overactivity. We
      confirm the clinical results reported by other centres with long experience of
      sacral neuromodulation.

PMID- 12475024
TI  - The use of FTICR-MS to detect chemical tags from a combinatorial library.
AB  - The use of tagging in combinatorial chemistry permits tracking of the solid phase
      as it is taken through iterative split and mix cycles. Several analytical
      approaches to the identification of tags (and hence the chemical history of the
      support) have been described. We describe herein a novel chemical tagging
      strategy for combinatorial solid phase chemistry. The identities of the tags
      attached to a single bead are discovered by the high resolution, accurate mass
      technique of Fourier transform ion cyclotron resonance mass spectrometry (FTICR
      MS).

PMID- 12475025
TI  - Post-oxidative conversion of thiol residue to sulfonic acid in the binding sites
      of molecularly imprinted polymers: disulfide based covalent molecular imprinting
      for basic compounds.
AB  - An imprinted polymer using a disulfide derivative as a template was treated with
      NaBH4 to yield the polymer with thiol groups in the binding sites. The thiol
      groups were then oxidized with H2O2/AcOH to yield the molecularly imprinted
      polymer with sulfo groups in the binding sites. This site conversion can provide
      amine-imprinted polymers, in which amine is retained to the imprinted polymer by
      the strong electrostatic interaction between the amino group and the sulfo group
      in the binding sites.

PMID- 12475026
TI  - Selective determination of hydrogen peroxide by adduct formation with a dinuclear
      iron(III) complex and flow injection analysis/tandem mass spectrometry.
AB  - A highly selective method for the determination of hydrogen peroxide is
      presented. In a flow injection analysis (FIA) instrument, the analyte is brought
      into contact with a dinuclear heptadentate iron(III) complex. The formation of
      the peroxide adduct is quantified using electrospray tandem mass spectrometry
      (ESI-MS/MS). Selected reaction monitoring (SRM) based on the transition from the
      triply charged peroxide adduct with m/z = 251.2 to the triply charged fragment
      ion of m/z = 240.5 is performed. The limit of detection for hydrogen peroxide is
      10(-7) mol dm(-3), limit of quantification is 3 x 10(-7) mol dm(-3), and a linear
      range of 2.5 decades starting at the limit of quantification is observed.

PMID- 12475027
TI  - Bidirectional isotachophoresis on a planar chip with integrated conductivity
      detection.
AB  - The use of a miniaturised planar separation device with integrated conductivity
      detection for performing bidirectional isotachophoresis (ITP) is described. The
      chips were produced in poly(methyl methacrylate) (PMMA) using a milling
      procedure. To enable bidirectional ITP the devices were designed to inject
      samples into the centre of the section channel and incorporated two integrated on
      column conductivity detectors, positioned at opposite ends of this channel. When
      used with a hydrodynamic sample transport system the devices were used for the
      analysis of a range of small ions: NH4+; Na+; Mg2+; Ca2+; Li+; NO3-; ClO4-; SO4(2
      ); F-. Results sucessfully achieved included the simultaneous separation of three
      anions and three cations.

PMID- 12475028
TI  - Retention equilibrium and mass transfer characteristics in reversed-phase liquid
      chromatography using methanol-water mixtures.
AB  - Pulse response experiments (i.e., elution chromatography) were made in reversed
      phase liquid chromatography (RPLC) using a C18 silica gel column and methanol
      water mixtures of different compositions (phi). The moment analysis of the
      elution peak profiles measured in the RPLC system provided some items of
      information about four parameters characterizing the retention equilibrium and
      the mass transfer kinetics in the column, i.e., adsorption equilibrium constant,
      isosteric heat of adsorption, surface diffusion coefficient and activation energy
      of surface diffusion. Characteristics of the chromatographic behavior were
      studied by analyzing the dependence of the four parameters on phi and the
      correlation between them. It was found that surface diffusion was one of the
      important processes of molecular migration having a significant contribution to
      the mass transfer kinetics in the column. Both the adsorption equilibrium
      constant and the surface diffusion coefficient varied depending on phi. The
      direction of their changes was approximately opposite, suggesting that the mass
      transfer in the manner of surface diffusion was restricted owing to the retention
      of the sample molecules on the stationary phase.

PMID- 12475029
TI  - Separation of ephedrine stereoisomers by molecularly imprinted polymers-
      influence of synthetic conditions and mobile phase compositions on the
      chromatographic performance.
AB  - Separation of ephedrine stereoisomers by molecularly imprinted polymers was
      performed to study the factors that affect the selectivity and column efficiency.
      The polymer synthesized with pentaerythritol triacrylate as the cross-linker and
      chloroform as the porogen was found to have the best overall separation
      performance. Investigation of the recognition mechanism by NMR and
      chromatographic analysis revealed that the major binding forces between the
      polymer stationary phase and ephedrine are the ionic and hydrogen bonding
      interactions. Studies of the influence of mobile phase compositions on the HPLC
      analysis have shown that a methanol-aqueous buffer was the suitable mobile phase
      for the separation in which pH, ionic strength and water content can be adjusted
      to optimize the chromatographic analysis.

PMID- 12475030
TI  - Sensitive determination of low molecular mass phenols by liquid chromatography
      with chemiluminescence detection for the determination of phenol and 4
      methylphenol in urine.
AB  - A rapid, reliable method for the routine determination of phenol and 4
      methylphenol in urine samples by liquid chromatography with peroxyoxalate
      chemiluminescence detection was developed. Phenols were first cleaned up by
      passing the sample through a LiChrolut EN sorbent column and then derivatized
      straightforwardly with dansyl chloride (15 min at room temperature) thanks to the
      micellar catalytic effect provided by Triton X-100 micelles. The derivatives were
      successfully separated in 15 min on a C18 analytical column and determined using
      an integrated derivatization chemiluminescence detection unit based on the
      bis(2,4,6-trichlorophenyl) oxalate-hydrogen peroxide system. Linear ranges from 3
      to 500 microg L(-1), limits of detection at a signal-to-noise ratio of 3 from 0.3
      to 0.5 microg L(-1) and relative standard deviations from 2.8 to 4.7% were
      obtained. The proposed method was applied to the assay of different human urine
      samples (healthy, smoker and petrol station worker volunteers) and free and total
      phenol and 4-methylphenol were determined. The proposed method surpasses other
      chromatographic alternatives for the determination of these phenols in terms of
      limit of detection and sample requirements for the analysis.

PMID- 12475031
TI  - Determination of ethane, pentane and isoprene in exhaled air using a multi-bed
      adsorbent and end-cut gas-solid chromatography.
AB  - A method for the determination of exhaled ethane, pentane and isoprene was
      developed and validated. The method was based on pre-concentration of the
      analytes on a multi-bed solid adsorbent tube containing Tenax TA, Carboxen 569
      and Carboxen 1000, thermal desorption and gas chromatography (GC) with flame
      ionisation detection (FID). A pre-column in an end-cut GC system was used to
      avoid problems with water and strongly retained substances. The detection limits
      were 5, 2 and 6 pmol per sample for ethane, pentane and isoprene, respectively,
      using a sample volume of 500 ml. The linearity was good for all analytes with
      correlation coefficients exceeding 0.999. The repeatability for exhaled air
      samples was 7, 10 and 12% for ethane, pentane and isoprene, respectively.
      Analysis of a certified reference material of ethane and pentane did not differ
      significantly from the certified values. Ethane and pentane levels were stable up
      to six days of storage in sample tubes. Isoprene levels were not stable during
      storage in the sample tubes used here, but using Carbopack X instead of Carboxen
      569, levels were stable up to two days. The levels of exhaled ethane, pentane and
      isoprene in healthy subjects (n = 4) were 8.1+/-5.8 pmol l(-1), 11+/-5.8 pmol l(
      1) and 2.4+/-0.90 mnol l(-1), respectively. The method could, with minor
      modifications, be used to determine other low-molecular hydrocarbons in exhaled
      air as well.

PMID- 12475032
TI  - Simultaneous determination of cyanide and carbonyls in cyanogenic plants by gas
      chromatography-electron capture/photoionization detection.
AB  - A new method to simultaneously detect cyanide and carbonyl compounds arising from
      cyanogenic glycosides in plants is described. A portable gas
      chromatograph.housing two detectors using a single carrier gas is employed to
      measure the carbonyl compounds (photoionization detector) and cyanide as its
      cyanogen chloride derivative (electron capture detector) from the headspace of a
      plant sample. This method affords in-field, rapid screening of plants to
      determine cyanogenicity. Good agreement was seen between this method for cyanide
      determination and two traditional field cyanide test kits. Detection of both the
      cyanide and the carbonyl compound(s) allows for confirmation of the presence of
      cyanogenic glycosides and eliminates the problem of false positives often seen in
      traditional cyanide test kits. Gas phase limits of detection for cyanide,
      acetone, butanone, and benzaldehyde were 69, 41, 105, and 0.39 parts per billion
      by volume (ppbv), respectively, allowing sensitive detection of cyanogenic
      glycoside breakdown products. The method's utility for screening cyanogenic
      plants is demonstrated, and it should be useful for screening cyanogenic
      foodstuffs to determine suitability for consumption.

PMID- 12475033
TI  - Reconstructed protein arrays from 3D HPLC/tandem mass spectrometry and 2D gels:
      complementary approaches to Porphyromonas gingivalis protein expression.
AB  - We compare typical qualitative protein identification data from two-dimensional
      (2D) polyacrylamide gel electrophoresis and reconstructed protein arrays, in the
      context of measuring protein expression by the Gram-negative periodontal pathogen
      Porphyromonas gingivalis. The arrays were assembled computationally from genome
      annotations and tandem mass spectrometry data from an off-line HPLC fractionation
      combined with 2D capillary HPLC analysis of whole proteome enzymatic digests. The
      2D separation was carried out with a standard binary gradient HPLC system,
      modified only slightly with readily available components. Compared to 2D gels,
      the number of annotated open reading frames identified using the 3D HPLC approach
      was typically larger by at least a factor of 30. However, the newer technology is
      currently limited in its ability to reflect the many protein variants derived
      from posttranscriptional and posttranslational processing.

PMID- 12475034
TI  - Metabolic profiling using direct infusion electrospray ionisation mass
      spectrometry for the characterisation of olive oils.
AB  - There is a continuing need for improved methods for assessing the adulteration of
      foodstuffs. We report some highly encouraging data, where we have developed
      direct infusion electrospray ionisation mass spectrometry (ESI-MS) together with
      chemometrics as a novel, rapid (1 min per sample) and powerful technique to
      elucidate key metabolite differences in vegetable and nut oils. Principal
      components analysis of these ESI-MS spectra show that the reproducibility of this
      approach is high and that olive oil can be discriminated from oils which are
      commonly used as adulterants. These adulterants include refined hazelnut oil,
      which is particularly challenging given its chemical similarity to olive oils.

PMID- 12475035
TI  - Determination of pentachlorophenol by negative ion chemical ionization with
      membrane introduction mass spectrometry.
AB  - Pentachlorophenol (PCP) was used as a model compound to explore the potential of
      desorption chemical ionization (DCI) in the determination of polychlorinated
      pesticides using membrane introduction mass spectrometry (MIMS). A direct
      insertion membrane probe was modified so that a chemical ionization plasma could
      be established at the membrane surface. Using selected ion monitoring (SIM) in a
      tandem triple quadrupole mass spectrometer with isobutane chemical ionization
      (CI), the PCP detection limit under positive chemical ionization is 20 ppb
      whereas negative CI gives detection limits in the low ppb range. This performance
      is achieved without any pre-treatment or derivatization of the sample. Negative
      ion CI gives a signal that is linear over a concentration range of 2-1000 ppb.
      Comparison of data obtained with low ppb samples of 2,4,6-trichlorophenol,
      2,3,4,6-tetrachlorophenol and pentachlorophenol suggests that the sensitivity of
      this analytical procedure increases with increase in the number of
      electronegative substituents in the molecule.

PMID- 12475036
TI  - Development and evaluation of a nano-electrospray ionisation source for
      atmospheric pressure ion mobility spectrometry.
AB  - A nano-electrospray ionisation source has been designed and constructed for a
      high temperature ion mobility spectrometer. The drift cell was modified by
      replacement of the 63Ni atmospheric pressure chemical ionisation source with a
      tube lens/desolvation region and operated using commercial nano-electrospray
      capillaries. Ions were introduced into the drift region via a Bradbury-Nielson
      gate (pulse width 50 micros, repetition period 20 ms). A unidirectional flow of
      nitrogen was used as the drift gas at temperatures in the range 100-150 degrees C
      to aid desolvation. The performance of the nano-electrospray ion source has been
      demonstrated for analytes including crown ethers, amino acids and peptides.
      Reduced mobilities determined by nano-ESI were consistent with those reported
      using a 63Ni ion source.

PMID- 12475037
TI  - Fluorescent nano-PEBBLE sensors designed for intracellular glucose imaging.
AB  - Polyacrylamide-based, ratiometric, spherical, optical nanosensors, or
      polyacrylamide PEBBLEs (Probes Encapsulated By Biologically Localized Embedding),
      have been fabricated, aimed at real-time glucose imaging in intact biological
      systems, i.e. living cells. These nanosensors are prepared using a microemulsion
      polymerization process, and their average size is about 45 nm in diameter. The
      sensors incorporate glucose oxidase (GOx), an oxygen sensitive fluorescent
      indicator (Ru[dpp(SO3Na)2]3)Cl2, and an oxygen insensitive fluorescent dye,
      Oregon Green 488-dextran or Texas Red-dextran, as a reference for the purpose of
      ratiometric intensity measurements. The enzymatic oxidation of glucose to
      gluconic acid results in the local depletion of oxygen, which is measured by the
      oxygen sensitive ruthenium dye. The small size and inert matrix of these sensors
      allows them to be inserted into living cells with minimal physical and chemical
      perturbations to their biological functions. The PEBBLE matrix protects the
      enzyme and fluorescent dyes from interference by proteins in cells, enabling
      reliable in vivo chemical analysis. Conversely, the matrix also significantly
      reduces the toxicity of the indicator and reference dyes to the cells, so that a
      larger variety of dyes can be used in optimal fashion. Furthermore, the PEBBLE
      matrix enables the synergistic approach in which there is a steady state of local
      oxygen consumption, and this cannot be achieved by separately introducing free
      enzyme and dyes into a cell. The work presented here describes the production and
      characterization of glucose sensitive PEBBLEs, and their potential for
      intracellular glucose measurements. The sensor response is determined in terms of
      the linear range, ratiometric operation, response time, sensor stability,
      reversibility and immunity to interferences.

PMID- 12475038
TI  - Sol-gel based optical carbon dioxide sensor employing dual luminophore
      referencing for application in food packaging technology.
AB  - An optical sensor for the measurement of carbon dioxide in Modified Atmosphere
      Packaging (MAP) applications has been developed. It is based on the fluorescent
      pH indicator 1-hydroxypyrene-3,6,8-trisulfonate (HPTS) immobilised in a
      hydrophobic organically modified silica (ormosil) matrix. Cetyltrimethylammonium
      hydroxide was used as an internal buffer system. Fluorescence is measured in the
      phase domain by means of the Dual Luminophore Referencing (DLR) sensing scheme
      which provides many of the advantages of lifetime-based fluorometric sensors and
      makes it compatible with established optical oxygen sensor technology. The long
      term stability of the sensor membranes has been investigated. The sensor displays
      13.5 degrees phase shift between 0 and 100% CO2 with a resolution of better than
      1% and a limit of detection of 0.08%. Oxygen cross-sensitivity is minimised (0.6%
      quenching in air) by immobilising the reference luminophore in polymer nano
      beads. Cross-sensitivity towards chloride and pH was found to be negligible.
      Temperature effects were studied, and a linear Arrhenius correlation between ln k
      and 1/T was found. The sensor is stable over a period of at least seven months
      and its output is in excellent agreement with a standard reference method for
      carbon dioxide analysis.

PMID- 12475039
TI  - Selective sensing of triazine herbicides in imprinted membranes using ion
      sensitive field-effect transistors and microgravimetric quartz crystal
      microbalance measurements.
AB  - A series of triazine herbicides consisting of the chlorotriazine atranex
      (atrazine), (1), prozinex, (2), tyllanex, (3), simanex, (4) and the
      methylthiolated triazines ametrex, (5), prometrex, (6) and terbutex, (7), were
      imprinted in an acrylamide-methacrylate copolymer. The polymer was deposited on
      the gate surface of ion-sensitive field-effect transistors (ISFETs) and
      piezoelectric Au-quartz crystals. Selective sensing of the imprinted substrates
      was accomplished by the imprinted polymer membrane associated with the ISFETs and
      Au-quartz crystals. Binding of the substrates onto the imprinted polymer
      associated with the gate of the ISFET alters the electrical charge and potential
      of the gate interface, thus allowing the potentiometric transduction of the
      binding events. The association of the substrates with the imprinted membrane
      linked to the Au-quartz crystal results in the membrane swelling, thus enabling
      the microgravimetric quartz crystal microbalance assay of the substrate binding
      events. The specificity of the imprinted recognition sites is attributed to
      complementary H-bond and electrostatic interactions between the substrates and
      the acrylamide-methacrylic acid copolymer.

PMID- 12475040
TI  - Electrochemiluminescence in aqueous solution of a ruthenium(II) bipyridyl complex
      containing a crown ether moiety in the presence of metal ions.
AB  - Changes in electrochemiluminescence (ECL) properties of a ruthenium polyazine
      compound containing a crown-ether moiety have been investigated in aqueous
      buffered solution. The electrochemistry, photophysics and ECL of (bpy)2Ru(AZA
      bpy)2+ [bpy = 2,2'-bipyridine; AZA-bpy = 4-(N-aza-18-crown-6-methyl-2,2'
      bipyridine)] in the presence of Pb2+, Hg2+, Cu2+ and Ag+ are reported. Oxidation
      of (bpy)2Ru(AZA-bpy)2+ produces ECL in the presence of tri-n-propylamine (TPrA;
      0.2 M KH2PO4). Increases in ECL efficiency (photons generated per redox event)
      greater than 2-fold have been observed that depend on both the concentration and
      nature of the metal ion, allowing the determination of ions not directly involved
      in the ECL reaction sequence.

PMID- 12475041
TI  - The membrane free sonoelectroanalytical determination of trace levels of lead and
      cadmium in human saliva.
AB  - In this paper, square wave anodic stripping voltammetry (SWASV), synergistically
      coupled with an ultrasonically enhanced preconcentration step has been shown to
      yield a quantitative determination of lead and cadmium in human saliva at a
      membrane free in situ plated mercury thin film glassy carbon electrode. The
      sensitivity was facilitated by acoustic streaming which promoted efficient mass
      transport to the electrode thus reducing sampling times. Cavitation was
      responsible for cleaning and activating the electrode surface, this was essential
      in order to obtain a reproducible and representative signal. In silent conditions
      electrode fouling leading to fluctuations in the baseline current and signal
      depression, precluded accurate quantitative analyses. The results presented
      herein provide an extension to the proof of concept given in the authors' earlier
      work, with the analysis of lead in human saliva as opposed to artificial saliva
      reported. We also address the hitherto unreported detection and determination of
      cadmium in this medium. Results for both were independently verified by
      inductively coupled plasma-mass spectroscopy (ICP-MS). Close agreement between
      lead concentration determined by sono-SWASV and independent and blind ICP-MS is
      reported for human saliva samples having a total lead content of 0.92 microg L(
      1) and 5 microg L(-1) with a detection limit of 0.5 microg L(-1). Microaddition
      calibration data for cadmium additions of 0.0125 microg L(-1) to samples spiked
      with 2.5 microg L(-1) and 5.0 microg L(-1) (reflecting levels in workers
      occupationally exposed) exhibited close agreement with the known total cadmium in
      the samples. A detection limit of 1 microg L(-1) cadmium in saliva has been
      established.

PMID- 12475042
TI  - Electrochemical behavior of the bis(2,2'-bipyridyl)copper(II) complex immobilized
      on a self-assembled monolayer modified electrode for L-ascorbic acid detection.
AB  - Modification of a gold electrode has been achieved by immobilizing a bis(2,2'
      bipyridyl)copper(II) complex in a self-assembled monolayer (SAM) of 3
      mercaptopropionic acid. The electrostatic interaction of the negatively charged
      SAM with a di-positive copper complex allowed the attachment. The modified
      electrode exhibited excellent redox behavior. The dependence of the modified
      electrode response was investigated in terms of pH, supporting electrolyte and
      ionic strength. Moreover, it showed good electrocatalytic activity for ascorbic
      acid oxidation, allowing convenient quantification at levels down to 8.1 x 10(-8)
      mol l(-1). The [Cu(bipy)2]/SAM modified electrode under optimized operational
      conditions (PIPES buffer 0.01 mol l(-1) at pH 6.8 and 200 mV vs. SCE) presented a
      linear response range between 1.0 micromol l(-1) and 100.0 micromol l(-1) for
      ascorbic acid. This modified electrode also presented an excellent repeatability,
      showing a relative standard deviation of 2.1% for a series of 12 successive
      measurements of a 5.0 micromol l(-1) ascorbic acid solution. Furthermore, the
      electroactivity was maintained over a long period (e.g., 92% after 100
      determinations).

PMID- 12475043
TI  - Co-immobilization of polymeric luminol, iron(II) tris(5-aminophenanthroline) and
      glucose oxidase at an electrode surface, and its application as a glucose
      optrode.
AB  - The anodic polymerization of 3-aminophthalhydrazide (luminol) and iron(II) tris 5
      aminophenanthroline (Fe(phen-NH2)3(2+)) has been reported in this paper. A
      bilayer electrode was developed based on these polymers and the ITO conductive
      glass (denoted ITO[Fe(phen-NH2)3(2+)]luminol electrode). This electrode emitted
      light (lambdaem: 430 nm) as it was brought into contact with H2O2. At pH 10, the
      resulting electrochemiluminescence (ECL) showed a linear relationship with the
      concentration of H2O2 in the range of 10 microM(-1) mM. This bilayer electrode
      also showed an application potential for the detection of glucose after being
      further modified with glucose oxidase (denoted ITO[Fe(phen-NH2)3(2+)]luminol]GOx
      electrode). Although the resulting ECL decayed more rapidly in concentrated
      glucose solutions (e.g., I M) because of the consumption of luminol during use,
      the decay became less severe in diluted glucose solutions (e.g., 10 mM).
      According to the flow injection analysis, a linear relationship existed between
      the ECL and the concentration of glucose from 10(-5)-10(-3) M at pH 9. The
      detection limit could reach a level of 5 x 10(-5) M at this pH.

PMID- 12475044
TI  - Carbon composite electrodes: surface and electrochemical properties.
AB  - Electrodes based on particulate carbon-epoxy or silicone composites have been
      formed and characterised using electrochemical methods, scanning electron
      microscopy and scanning electrochemical microscopy. These composites are rigid,
      exhibit high electrical conductivity and are stable in organic solvents for
      prolonged periods. The bulk resistance of the Araldite-M and Araldite-CW2215
      based electrodes is low, 130+/-12 and 185+/-15 ohms, respectively. In contrast,
      the bulk resistance of the silicone based electrodes is 1480+/-112 ohms. The
      uncompensated resistance of electrochemical cells where the composites act as
      working electrodes is significantly larger than that expected on the basis of
      solution resistance alone, i.e., up to 7.5 kohms in the case of the silicone
      composites. These results are interpreted in terms of the presence of pores
      within the composite material. The response times of the composite electrodes to
      changes in the applied potential is between 3.1 and 7.2 ms which, although almost
      an order of magnitude longer than a comparable glassy carbon electrode, is
      sufficiently rapid to give useful voltammetric data for scan rates of several V
      s(-1). Close to ideal reversible cyclic voltammetry is observed for ferrocene
      under semi-infinite diffusion control for scan rates between 0.01 and 0.1 V s(-1)
      at the Araldite composites. In contrast, the large resistance associated with the
      silicone based materials causes quasi-reversible responses to be observed over
      this range of scan rate. Scan rate dependent cyclic voltammetry and time resolved
      chronoamperometry responses observed for ferrocene in solution are consistent
      with those expected for a random array of microelectrodes. Scanning electron
      microscopy and scanning electrochemical microscopy has been used to image the
      shape, size and electrochemical activity of the electroactive zones. In the case
      of Araldite-M, the quality of the electrode surface has been probed by comparing
      the rate of heterogeneous electron transfer at a composite microelectrode with
      that found for a carbon fibre electrode. The standard heterogeneous electron
      transfer rate constant, k degrees , is 6.0+/-0.1 x 10(-3) cm s(-1) for the
      composite compared to 1.5+/-0.1 x 10(-1) cm s(-1) for the carbon fibre electrode.
      While the smaller rate constant found for the composite suggests a less pristine
      surface, k degrees is sufficiently large to support reversible, electron transfer
      under typical electroanalytical conditions. These fundamental measurements will
      underpin the development of enzyme based biosensors for use in organic solvents.

PMID- 12475045
TI  - Analytical curve or standard addition method: how to elect and design--a strategy
      applied to copper determination in sugarcane spirits using AAS.
AB  - In most instrumental analysis, the analyte concentration is usually obtained the
      by Analytical Curve Method (ACM) or Standard Addition Method (SAM). Thus, it is
      important for the analyst to select the most appropriate method, to seek the best
      conditions of analysis, and to provide parameters of analytical performance. A
      strategy to do so is proposed in this paper in conjunction with MATLAB software
      to implement it. The proposed strategy was applied to copper determination by
      atomic absorption spectrometry in Brazilian sugarcane spirits termed 'Cachaca'
      and SAM was chosen as the most appropriate method. To select the best
      experimental design for SAM, the influence of some factors, such as the number of
      standard additions and concentration levels, the location of the levels and the
      average concentration of the standard additions were demonstrated. The design
      with six standard additions, four concentration levels located near the inferior
      and superior levels and the average concentration of the standard additions
      closer to zero yielded SAM with an adequate compromise between precision, cost
      and time of analysis. The uniform distribution of concentration levels, usually
      used in routine analysis, is not a good design regarding precision. On the other
      hand, it is adequate when the linear range is unknown. Generally, the proposed
      strategy can be applied to different instrumental techniques and samples, which
      aim to improve their analytical performance.

PMID- 12475046
TI  - Chemiluminescence determination of carbofuran and promecarb by flow injection
      analysis using two photochemical reactions.
AB  - A flow injection-chemiluminescent method for the determination of carbofuran and
      promecarb is proposed. The assay was based on the on-line conversion of the
      pesticides into methylamine by irradiation with UV light. The methylamine
      generated was subsequently reacted with tris(2,2'-bipyridine)ruthenium(III),
      which was generated through the on-line photo-oxidation of tris(2,2'
      bipyridine)ruthenium(II) with peroxydisulfate. The emitted light showed a linear
      relationship with the concentration of the pesticide over the ranges 0.22-11.2
      microg ml(-1) for carbofuran and 0.41-16.6 microg ml(-1) for promecarb. The
      repeatability was 1.6% expressed as relative standard deviation (n = 10) and the
      reproducibility, studied on five different days, was 2%. The sample throughput
      was 200 injections per h. The reliability of the method for routine analysis of
      these pesticides in water, soil and grains is demonstrated.

PMID- 12475047
TI  - Fluorescence for the determination of protein with functionalized nano-ZnS.
AB  - ZnS nanoparticles have been prepared and modified with sodium thioglycolate. The
      functionalized nanoparticles are water-soluble. They were used as fluorescence
      probes in the determination of proteins, which was proved to be a simple, rapid
      and specific method. In comparison with single organic fluorophores, these
      nanoparticle probes are brighter, more stable against photobleaching, and do not
      suffer from blinking. Under optimum conditions, linear relationships were found
      between the enhanced intensity of fluorescence at 441 nm and the concentration of
      protein in the range 0.1-4.0 microg mL(-1) for human serum albumin (HSA), 0.2-3.0
      microg mL(-1) for bovine serum albumin (BSA) and 0.1-4.5 microg mL(-1) for gamma
      globulin (gamma-G). The limits of detection were 0.015 microg mL(-1) for HSA,
      0.024 microg mL(-1) and 0.017 microg mL(-1) for BSA and gamma-G, respectively.
      The method has been applied to the analysis of human serum samples collected from
      the hospital and the results were in good agreement with those reported by a
      hospital, indicating that the method presented here is not only sensitive and
      simple, but also reliable and suitable for practical application.

PMID- 12475048
TI  - In situ Fourier transform infrared spectroscopy as an efficient tool for
      determination of reaction kinetics.
AB  - The performance of new FTIR-based monitoring technology to representatively
      determine reaction kinetics has been demonstrated on an example of homogeneously
      catalyzed liquid-phase sucrose hydrolysis to fructose and glucose. The reaction
      kinetics were investigated by using the ReactIR 1000 reaction analysis system,
      which enables determination of the component concentration from its
      characteristic FTIR spectrum. During the sucrose inversion, the ReactIR 1000
      instrument connected to a computer controlled standard glass batch reactor
      provided the required operating conditions and information about the component
      concentration in real-time. We have studied the influence of hydrogen ion
      concentration, temperature and initial concentration of sucrose on the sucrose
      disappearance rate. It was found out that the inversion of sucrose is an
      irreversible reaction, which is not affected by the formation of fructose and
      glucose in the liquid-phase. Then, the parameters of the kinetic model (i.e.,
      reaction rate constant and activation energy) were calculated. A comparison of
      the model output and the measured data showed that the kinetics of the sucrose
      inversion could be well described by means of the pseudo first-order kinetic
      model. Finally, the method of determining the kinetic model by FTIR spectroscopy
      was verified by comparing the results obtained in the batch reactor with the
      results obtained in the continuously stirred tank reactor.

PMID- 12475049
TI  - Determination of mercury by continuous flow cold vapor atomic fluorescence
      spectrometry using micromolar concentration of sodium tetrahydroborate as
      reductant solution.
AB  - Systematic experiments were conducted to evaluate and compare the analytical
      figures of merit of two reducing agents (SnCl2 and NaBH4) in a continuous flow
      cold vapor atomic fluorescence mercury analyzer. It was found that sodium
      tetrahydroborate can efficiently reduce Hg2+ in various environmental samples at
      a concentration as low as 10 microM (ca. 3.8 x 10(-5)% w/v). Most commonly
      encountered transition metals (Fe2+, Fe3+, Zn2+, Cu2+, Ni2+, Pb2+ and Cr3+) did
      not interfere with total Hg determination. No interference from hydride-forming
      elements (Se4+, Sb3+ and As3+) was observed. Interference caused by Mn2+ and Ag+
      could be readily removed by dilution and by using appropriate modification of the
      reaction matrix. A higher concentration of NaBH4 (0.1 M) is stable for I month
      when stored in the NaOH matrix (0.2 M) and at low temperature (4 degrees C). A
      working solution of NaBH4 can be freshly prepared by dilution. With NaBH4, the
      whole continuous flow system is kept clean much more easily as no precipitate is
      formed, which in turn considerably reduces memory effects, simplifies analytical
      operation and reduces the chemical cost six-fold.

PMID- 12475050
TI  - Nutrition in terrestrial isopods (Isopoda: Oniscidea): an evolutionary-ecological
      approach.
AB  - The nutritional morphology, physiology and ecology of terrestrial isopods
      (Isopoda: Oniscidea) is significant in two respects. (1) Most oniscid isopods are
      truly terrestrial in terms of being totally independent of the aquatic
      environment. Thus, they have evolved adaptations to terrestrial food sources. (2)
      In many terrestrial ecosystems, isopods play an important role in decomposition
      processes through mechanical and chemical breakdown of plant litter and by
      enhancing microbial activity. While the latter aspect of nutrition is discussed
      only briefly in this review, I focus on the evolutionary ecology of feeding in
      terrestrial isopods. Due to their possessing chewing mouthparts, leaf litter is
      comminuted prior to being ingested, facilitating both enzymatic degradation
      during gut passage and microbial colonization of egested faeces. Digestion of
      food through endogenous enzymes produced in the caeca of the midgut glands
      (hepatopancreas) and through microbial enzymes, either ingested along with
      microbially colonized food or secreted by microbial endosymbionts, mainly takes
      place in the anterior part of the hindgut. Digestive processes include the
      activity of carbohydrases, proteases, dehydrogenases, esterases, lipases,
      arylamidases and oxidases, as well as the nutritional utilization of microbial
      cells. Absorption of nutrients is brought about by the hepatopancreas and/or the
      hindgut epithelium, the latter being also involved in osmoregulation and water
      balance. Minerals and metal cations are effectively extracted from the food,
      while overall assimilation efficiencies may be low. Heavy metals are stored in
      special organelles of the hepatopancreatic tissue. Nitrogenous waste products are
      excreted via ammonia in its gaseous form, with only little egested along with the
      faeces. Nonetheless, faeces are characterized by high nitrogen content and
      provide a favourable substrate for microbial colonization and growth. The
      presence of a dense microbial population on faecal material is one reason for the
      coprophagous behaviour of terrestrial isopods. For the same reason, terrestrial
      isopods prefer feeding on decaying rather than fresh leaf litter, the former also
      being more palatable and easier to digest. Acceptable food sources are detected
      through distance and contact chemoreceptors. The 'quality' of the food source
      determines individual growth, fecundity and mortality, and thus maintenance at
      the population level. Due to their physiological adaptations to feeding on and
      digesting leaf litter, terrestrial isopods contribute strongly to nutrient
      recycling during decomposition processes. Yet, many of these adaptations are
      still not well understood.

PMID- 12475052
TI  - Nitric oxide and changes of iron metabolism in exercise.
AB  - Accumulated data imply that exercise itself might not lead to a true iron
      deficiency or 'sport anaemia' in a healthy athlete who has adequate iron intake.
      The higher prevalence of iron deficiency anaemia in younger female athletes might
      be not due to exercise itself, but probably results from dietary choices,
      inadequate iron intake and menstruation. These factors can also induce iron
      deficiency or anaemia in the general population. However, exercise does affect
      iron metabolism, leading to low or sub-optimal iron status. The underlying
      mechanism is unknown. In this review, recent advances in the study of the effect
      of exercise on iron metabolism and nitric oxide, and the relationship between
      nitric oxide and iron status in exercise are discussed. A hypothesis that
      increased production of nitric oxide might contribute to sub-optimal iron status
      in exercise is proposed.

PMID- 12475051
TI  - Haeckel's ABC of evolution and development.
AB  - One of the central, unresolved controversies in biology concerns the distribution
      of primitive versus advanced characters at different stages of vertebrate
      development. This controversy has major implications for evolutionary
      developmental biology and phylogenetics. Ernst Haeckel addressed the issue with
      his Biogenetic Law, and his embryo drawings functioned as supporting data. We re
      examine Haeckel's work and its significance for modern efforts to develop a
      rigorous comparative framework for developmental studies. Haeckel's comparative
      embryology was evolutionary but non-quantitative. It was based on developmental
      sequences, and treated heterochrony as a sequence change. It is not always clear
      whether he believed in recapitulation of single characters or entire stages. The
      Biogenetic Law is supported by several recent studies -- if applied to single
      characters only. Haeckel's important but overlooked alphabetical analogy of
      evolution and development is an advance on von Baer. Haeckel recognized the
      evolutionary diversity in early embryonic stages, in line with modern thinking.
      He did not necessarily advocate the strict form of recapitulation and terminal
      addition commonly attributed to him. Haeckel's much-criticized embryo drawings
      are important as phylogenetic hypotheses, teaching aids, and evidence for
      evolution. While some criticisms of the drawings are legitimate, others are more
      tendentious. In opposition to Haeckel and his embryo drawings, Wilhelm His made
      major advances towards developing a quantitative comparative embryology based on
      morphometrics. Unfortunately His's work in this area is largely forgotten.
      Despite his obvious flaws, Haeckel can be seen as the father of a sequence-based
      phylogenetic embryology.

PMID- 12475053
TI  - Sexual selection: an evolutionary force in plants?
AB  - Sexual selection has traditionally been used to explain exaggerated sexual traits
      in male animals. Today the concept has been developed and various other sexually
      related traits have been suggested to evolve in the same manner. In nearly all
      new areas where the theory of sexual selection has been applied, there has been
      an intense debate as to whether the application is justified. Is it the case that
      some scientists are all too ready to employ fashionable ideas? Or are there too
      many dogmatic researchers refusing to accept that science develops and old ideas
      are transformed? Maybe the controversies are simply a reflection of the
      difficulty of defining a theory under constant re-evaluation. Thus, we begin by
      summarizing the theory of sexual selection in order to assess the influence of
      sexual selection on the evolution of plant morphology. We discuss empirical
      findings concerning potentially affected traits. Although we have tried to
      address criticisms fairly, we still conclude that sexual selection can be a
      useful tool when studying the evolution of reproductive traits in plants.
      Furthermore, by including the evidence from an additional kingdom, a fuller
      understanding of the processes involved in sexual selection can be gained.

PMID- 12475054
TI  - Memory trace in prefrontal cortex: theory for the cognitive switch.
AB  - The dorsolateral prefrontal cortex in human and non-human primates functions as
      the highest-order executor for the perception-action cycle. According to this
      view, when perceptual stimuli from the environment are novel or complex, the
      dorsolateral prefrontal cortex serves to set consciously a goal-directed scheme
      which broadly determines an action repertory to meet the particular demand from
      the environment. In this respect, the dorsolateral prefrontal cortex is a short
      term activation device with the properties of a cognitive switch', because it
      couples a particular set of perceptual stimuli to a particular set of actions.
      Here, I suggest that, in order for the organism to react systematically to the
      environment, neural traces for the switch function must be stored in the brain.
      Thus, the highest-order, perception-action interface function of the dorsolateral
      prefrontal cortex per se depends on permanently stored neural traces in the
      dorsolateral prefrontal cortex and related structures. Such a memory system may
      be located functionally between two of the well-documented memory systems in the
      brain: the declarative memory system and the procedural memory system. Finally,
      based on available neurophysiological data, the possible mechanisms underlying
      the formation of cognitive switch traces are proposed.

PMID- 12475055
TI  - Density fluctuations of the leafminer Phyllonorycter strigulatella (Lepidoptera:
      Gracillariidae) in the impact zone of a power plant.
AB  - Populations of a tiny moth Phyllonorycter strigulatella, whose larvae develop in
      leaves of Alnus incana, were monitored around a coal fired power plant (annually
      emitting 11-29 Kt of SO2) near Apatity, northwestern Russia, during 1991-2001.
      The periodicity in density fluctuation was not affected by pollution; the peak
      densities of the leafminer in both polluted and clean localities were observed in
      1993 and 1999. Densities of P. strigulatella showed no correlation with pollution
      between the outbreaks but strongly increased near the power plant during the
      outbreaks. In polluted localities the density increased by a factor of 15-20,
      whereas in clean localities it increased by a factor of 3-4, relative to the
      latent density. Mine distribution among individual leaves was more aggregated
      near the power plant. P. strigulatella demonstrated higher preference of long
      shoots in the contaminated sites, but mine distributions within a shoot and
      within a leaf did not change with the distance from the polluter. Thus, moderate
      contamination by SO2 favoured P. strigulatella, leading to an increase in the
      intensity of outbreaks (the ratio between outbreak and latent densities) by a
      factor of five, but did not change either frequency of outbreaks or timing of
      density increase.

PMID- 12475056
TI  - Anthropogenic metal enrichment of snow and soil in north-eastern European Russia.
AB  - Trace metal composition of winter snowpack, snow-melt filter residues and top
      soil samples were determined along three transects through industrial towns in
      the Usa basin, North-East Russia: Inta, Usinsk and Vorkuta. Snow was analysed for
      Ag, Al, As, Ba, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sr and Zn using ICP-MS (Ca and K by F
      AAS for Vorkuta only), pH and acidity/alkalinity. Filter residues were analysed
      for: Al, Ba, Ca, Cd, Cu, K, Mg, Mn, Ni, Pb, Sr and Zn using F-AAS and GF-AAS; top
      soil samples were analysed for Ba, Cu, Mg, Mn, Na, Ni, Pb, Sr, Zn using F-AAS.
      Results indicate elevated concentrations of elements associated with alkaline
      combustion ash around the coal mining towns of Vorkuta and Inta. There is little
      evidence of deposition around the gas and oil town of Usinsk. Atmospheric
      deposition in the vicinity of Vorkuta, and to a lesser extent Inta, added
      significantly to the soil contaminant loading as a result of ash fallout. Acid
      deposition was associated with pristine areas whereas alkaline combustion ash
      near to emission sources more than compensated for the acidity caused by SO2.

PMID- 12475057
TI  - Chloride/bromide ratios in leachate derived from farm-animal waste.
AB  - Ratios of conservative chemicals have been used to identify sources of
      groundwater contamination. While chloride/bromide ratios have been reported for
      several common sources of groundwater contamination, little work has been done on
      leachate derived from farm-animal waste. In this study, chloride/bromide ratios
      were measured in leachate derived from longhorn-cattle, quarterhorse, and pygme
      goat waste at a farm in Abilene, Texas, USA. (Minimum, median, and maximum)
      chloride/bromide ratios of (66.5, 85.6, and 167), (119, 146, and 156), and (35.4,
      57.8, and 165) were observed for cattle, horses, and goats, respectively. These
      ratios are below typical values for domestic wastewater and within the range
      commonly observed for oilfield brine. Results of this study have important
      implications for identifying sources of contaminated groundwater in settings with
      significant livestock and/or oil production.

PMID- 12475058
TI  - Recolonization and succession of subtidal macrobenthic infauna in sediments
      contaminated with cadmium.
AB  - Recolonization and succession of macrobenthic infauna in defaunated sediment
      contaminated with Cd were studied over a period of 14 months. Trays with
      defaunated sediment contaminated with cadmium, and trays with defaunated
      (control) sediment, were exposed at the subtidal in a subtropical environment.
      Macrobenthic succession exhibited different patterns in Cd-contaminated and
      control sediments. Abundance and species number were significantly higher in Cd
      contaminated sediment during early succession, suggesting that cadmium may
      facilitate recolonization of certain species of macrobenthos. Cadmium also led to
      a significant change in species composition in initial colonization and
      subsequent succession. No significant difference in abundance, species number,
      diversity and species composition was found between Cd-contaminated and control
      sediments at the end of experiment, suggesting a stable benthic community was
      arrived within 14 months.

PMID- 12475059
TI  - Uptake of 207Pb and 111Cd through bark of mature sugar maple, white ash and white
      pine: a field experiment.
AB  - A field study was undertaken to determine whether 207Pb and 111Cd, applied to the
      exterior bark of sugar maple (Acer saccharum Marsh.), white ash (Fraxinus
      americana L.) and white pine (Pinus strobus L.), could enter xylem tissue. Stable
      isotope tracers (3 microg Pb ml(-1); 2 microg Cd ml(-1)) were applied separately
      to bark in simulated rainfall, acidified to pH 4.5, in multiple doses over a 4
      month (July-October) period. Tree cores were extracted from the region of
      application in the following March, and Pb and Cd isotopes were measured in bark
      and the outer tree rings using inductively coupled plasma mass spectrometry. The
      majority of the applied stable isotope tracer recovered (over 94%) was present in
      bark tissue, although a small amount of each metal tracer entered the outer (1-3)
      tree rings in all trees. Despite high concentrations of excess 207Pb in bark (up
      to 50 microg g(-1)), the maximum concentration of excess 207Pb measured in tree
      rings was only around 50 ng g(-1), which represents less than 30% of the
      background Pb concentration in wood at the study site. High excess 111Cd
      concentrations in bark (up to 35 microg g(-1)) also resulted in small increases
      in 111Cd in wood (up to 50 ng g(-1)), but due to lower background Cd
      concentrations in wood, such increases more than doubled the amount of Cd in wood
      compared with background levels. However, at sites where such high bark Cd
      concentrations are found, uptake from Cd-contaminated soil would probably be much
      greater than found at our study site. It appears that Cd and Pb applied to bark
      can enter woody tissue, but that this route of uptake is likely to be a minor
      contributor to the metal burden in wood.

PMID- 12475060
TI  - Is the OECD acute worm toxicity test environmentally relevant? The effect of
      mineral form on calculated lead toxicity.
AB  - In a series of experiments the toxicity of lead to worms in soil was determined
      following the draft OECD earthworm reproduction toxicity protocol except that
      lead was added as solid lead nitrate, carbonate and sulphide rather than as lead
      nitrate solution as would normally be the case. The compounds were added to the
      test soil to give lead concentrations of 625-12 500 microg Pb g(-1) of soil.
      Calculated toxicities of the lead decreased in the order nitrate> carbonate>
      sulphide, the same order as the decrease in the solubility of the metal compounds
      used. The 7-day LC50 (lethal concentration when 50% of the population is killed)
      for the nitrate was 5321+/-275 microg Pb g(-1) of soil and this did not change
      with time. The LC50 values for carbonate and sulphide could not be determined at
      the concentration ranges used. The only parameter sensitive enough to distinguish
      the toxicities of the three compounds was cocoon (egg) production. The EC50s for
      cocoon production (the concentration to produce a 50% reduction in cocoon
      production) were 993, 8604 and 10246 pg Pb g(-1) of soil for lead nitrate,
      carbonate and sulphide, respectively. Standard toxicity tests need to take into
      account the form in which the contaminant is present in the soil to be of
      environmental relevance.

PMID- 12475061
TI  - The influence of time on lead toxicity and bioaccumulation determined by the OECD
      earthworm toxicity test.
AB  - Internationally agreed standard protocols for assessing chemical toxicity of
      contaminants in soil to worms assume that the test soil does not need to
      equilibrate with the chemical to be tested prior to the addition of the test
      organisms and that the chemical will exert any toxic effect upon the test
      organism within 28 days. Three experiments were carried out to investigate these
      assumptions. The first experiment was a standard toxicity test where lead nitrate
      was added to a soil in solution to give a range of concentrations. The mortality
      of the worms and the concentration of lead in the survivors were determined. The
      LC50s for 14 and 28 days were 5311 and 5395 microgPb g(-1)soil respectively. The
      second experiment was a timed lead accumulation study with worms cultivated in
      soil containing either 3000 or 5000 microgPb g(-1)soil. The concentration of lead
      in the worms was determined at various sampling times. Uptake at both
      concentrations was linear with time. Worms in the 5000 microg g(-1) soil
      accumulated lead at a faster rate (3.16 microg Pb g(-1)tissue day(-1)) than those
      in the 3000 microg g(-1) soil (2.21 microg Pb g(-1)tissue day(-1)). The third
      experiment was a timed experiment with worms cultivated in soil containing 7000
      microgPb g(-1)soil. Soil and lead nitrate solution were mixed and stored at 20
      degrees C. Worms were added at various times over a 35-day period. The time to
      death increased from 23 h, when worms were added directly after the lead was
      added to the soil, to 67 h when worms were added after the soil had equilibrated
      with the lead for 35 days. In artificially Pb-amended soils the worms accumulate
      Pb over the duration of their exposure to the Pb. Thus time limited toxicity
      tests may be terminated before worm body load has reached a toxic level. This
      could result in under-estimates of the toxicity of Pb to worms. As the
      equilibration time of artificially amended Pb-bearing soils increases the
      bioavailability of Pb decreases. Thus addition of worms shortly after addition of
      Pb to soils may result in the over-estimate of Pb toxicity to worms. The current
      OECD acute worm toxicity test fails to take these two phenomena into account
      thereby reducing the environmental relevance of the contaminant toxicities it is
      used to calculate.

PMID- 12475062
TI  - Preliminary estimation of the rainfall chemical composition evaluated through the
      scavenging modeling for north-eastern Amazonian region (Amapa state, Brazil).
AB  - Numerical modeling of scavenging processes has been compared with data obtained
      for rainwater and aerosol chemistry at Serra do Navio, in the state of Amapa in
      the Brazilian Amazon region. Sulfate, nitrate and ammonium concentrations were
      determined in rainwater samples collected from May 1995 until June 1997. The
      levels of these same chemicals were also determined in aerosols for the same
      period and region. Scavenging processes have been evaluated on a rainfall event
      basis, via numerical modeling, in order to simulate the rainwater concentrations
      and compare them with the observed data. RAMS (Regional Atmospheric Modeling
      System) was used to simulate cloud structures. A model of below-cloud scavenging
      was evaluated, as well. The determinations made from the results of the
      scavenging model are the following: a) aerosol vertical profiles are quite
      important to rainwater concentrations; b) modeled sulfate in rainwater is a
      better fit to the observed data values than ammonium and nitrate; c) the obtained
      sulfate aerosol concentrations samples are similar to ones found in the
      literature, although the sulfate concentrations in rainwater are much lower than
      other studies in the literature; d) the in-cloud scavenging process dominates, e)
      our modeled results, using an input gas vertical profile extracted from the
      ABLE2B experimental data set, present a smaller ratio between gas and aerosol
      scavenging than found in other studies in the literature, other studies may have
      had larger rainfall times, which increase the importance of gas phase scavenging.

PMID- 12475063
TI  - The global re-cycling of persistent organic pollutants is strongly retarded by
      soils.
AB  - 'Persistent organic pollutants' (POPs) are semi-volatile, mobile in the
      environment and bioaccumulate. Their toxicity and propensity for long-range
      atmospheric transport (LRAT) has led to international bans/restrictions on their
      use/release. LRAT of POPs may occur by a 'single hop' or repeated temperature
      driven air-surface exchange. It has been hypothesised that this will result in
      global fractionation and distillation-with condensation and accumulation in polar
      regions. Polychlorinated biphenyls (PCBs)--industrial chemicals banned/restricted
      in the 1970s--provide a classic illustration of POP behaviour. A latitudinally
      segmented global PCB inventory has been produced, which shows that approximately
      86% of the 1.3 x 10(6) tonnes produced was used in the temperate industrial zone
      of the northern hemisphere. A global survey of background surface soils gives
      evidence for 'fractionation' of PCBs. More significantly, however, very little of
      the total inventory has 'made the journey' via primary emission and/or air
      surface exchange and LRAT out of the heavily populated source regions, in the 70
      years since PCBs were first produced. Soils generally occlude PCBs, especially
      soils with dynamic turnover of C/bioturbation/burial mechanisms. This limits the
      fraction of PCBs available for repeated air-soil exchange. The forested soils of
      the northern hemisphere, and other C-rich soils, appear to be playing an
      important role in 'protecting' the Arctic from the advective supply of POPs.
      Whilst investigations on POPs in remote environments are important, it is
      imperative that researchers also seek to better understand their release from
      sources, persistence in source regions, and the significant loss
      mechanisms/global sinks of these compounds, if they wish to predict future
      trends.

PMID- 12475064
TI  - Polychlorinated naphthalenes in sediments from the industrial region of
      Bitterfeld.
AB  - Bitterfeld (Germany) was a major site of chemical production in the former German
      Democratic Republic with chloralkali electrolysis as the basic process. Effluents
      were dumped via the creek Spittelwasser into the rivers Mulde and Elbe. Despite
      the fact that the chloralkali industry is known as a possible source of
      polychlorinated naphthalenes (PCNs), to date no data about PCN pollution in the
      region of Bitterfeld and downstream regions are available. Therefore, sediments
      of the creek Spittelwasser were isomer-specifically analysed for penta-, hexa-
      and heptachlorinated naphthalenes using GC/MS. Concentrations of 880, 543 and
      1120 ng/g dry weight were found, respectively. The isomer pattern suggests
      chloralkali industry as the major source of PCN contamination. Because of their
      toxicological relevance we suggest to include PCNs into monitoring and risk
      assessment programs of the rivers Mulde and Elbe downstream of Bitterfeld.

PMID- 12475065
TI  - Storage mediums affect metal concentration in woodlice (Isopoda).
AB  - Terrestrial invertebrates are becoming widely established as tools to assess
      heavy metal pollution at contaminated sites. A practical and time saving method
      to sample terrestrial invertebrates consist of pitfall traps, often filled with a
      4% formaldehyde solution and some detergent. The reliability of metal
      concentrations based on organisms captured and stored in this solution might
      however be questioned and we therefore tested the effect of formaldehyde on Zn,
      Cu, Cd and Pb concentration experimentally in three isopod species. Our results
      showed that in many cases, significant decreases in Cu concentrations compared to
      animals stored in a freezer were observed that could be as high as 40%, while Zn,
      Cd and Pb concentrations increased. A regression analysis of individual dry
      weight on individual size revealed that formaldehyde decreases the dry weight
      substantially and in that way causes increased measurements of Zn, Cd and Pb
      concentrations. We conclude that pitfall traps with formaldehyde should better
      not be used to collect animals in which concentrations of heavy metals or other
      toxic substances will be determined.

PMID- 12475066
TI  - Histological examination of sublethal effects of diazinon on ovary of bluegill,
      Lepomis macrochirus.
AB  - The effects of the insecticide, diazinon (an organophosphorous compound), on the
      ovaries of bluegill (Lepomis macrohirus) were studied. Histological preparations
      of bluegill ovarian tissue was examined at 24, 48, 72 and 96 h and 1, 2 and 3
      weeks following exposure to sublethal doses of diazinon (60 microg/l). The
      control contained primary follicles with an intact ovigerous lamellae and tunica
      albuginea. The control also revealed well developed stage IV oocytes with
      properly distributed provitelline nucleoli. After 24 h of exposure to diazinon,
      primary follicles began to show adhesion and cytoplasmic retraction in oocyte II
      occured. Cytoplasmic degeneration and additional adhesion and more retraction
      were visible at 48 h in oocyte II; 72 h brought forth adhesion, retraction and
      cytoplamic expulsion from oocyte IV. The number of atretic oocytes increased.
      Damages to the oocyte IV started to occur after 72 h of exposure. Cytoplasmic
      retraction and clumping was more visible at 96 h in oocyte IV. Partial
      destruction of the ovigerous lamellae and vitellogenic membrane occurred after 1
      week. Two weeks continued to reveal destruction of follicles. Severe damage of
      the ovigerous lamellae, increased intrafollicular spaces, vacuolated cytoplasm,
      extrusion of karyoplasm and necrosis in the cytoplasm were most evident following
      3 weeks of exposure. The ovarian wall became frayed and broken. Additionally, a
      marked increase of atretic follicles, shrinkage, and embedded nucleoli into the
      surrounding cytoplasm in oocyte II, III and IV were observed at week 3. This
      study revealed that oocytes at their different stages of maturation get affected
      differently at various exposure. Based on observations of the ovarian tissue
      compositional and structural changes following given exposure times, it becomes
      evident that consistent sublethal doses of diazinon can and will alter
      microscopic anatomy of the fish ovary.

PMID- 12475067
TI  - Ecotoxicological evaluation of in situ bioremediation of soils contaminated by
      the explosive 2,4,6-trinitrotoluene (TNT).
AB  - To evaluate the environmental relevance of in situ bioremediation of contaminated
      soils, effective and reliable monitoring approaches are of special importance.
      The presented study was conducted as part of a research project investigating in
      situ bioremediation of topsoils contaminated by the explosive 2,4,6
      trinitrotoluene (TNT). Changes in soil toxicity within different experimental
      fields at a former ordnance factory were evaluated using a battery of five
      bioassays (plant growth, Collembola reproduction, soil respiration, luminescent
      bacteria acute toxicity and mutagenicity test) in combination to chemical
      contaminant analysis. Resulting data reveal clear differences in sensitivities
      between methods with the luminescent bacteria assay performed with soil leachates
      as most sensitive toxicity indicator. Complete test battery results are presented
      in so-called soil toxicity profiles to visualise and facilitate the
      interpretation of data. Both biological and chemical monitoring results indicate
      a reduction of soil toxicity within 17 months of remediation.

PMID- 12475068
TI  - Influence of particle characteristics and organic matter content on the
      bioavailability and bioaccumulation of pyrene by clams.
AB  - Hydrophobic chemicals are known to associate with sediment particles including
      those from both suspended particulate matter and bottom deposits. The complex and
      variable composition of natural particles makes it very difficult therefore, to
      predict the bioavailability of sediment-bound contaminants. To overcome these
      problems we have previously devised a test system using artificial particles,
      with or without humic acids, for use as an experimental model of natural
      sediments. In the present work we have applied this experimental technique to
      investigate the bioavailability and bioaccumulation of pyrene by the freshwater
      fingernail clam Sphaerium corneum. The uptake and accumulation of pyrene in clams
      exposed to the chemical in the presence of a sample of natural sediment was also
      investigated. According to the results obtained, particle surface properties and
      organic matter content are the key factors for assessing the bioavailability and
      bioaccumulation of pyrene by clams.

PMID- 12475069
TI  - Effect of new soil metal immobilizing agents on metal toxicity to terrestrial
      invertebrates.
AB  - Application of 5% (w:w) novel metal immobilizing agent reduced the water soluble,
      the calcium chloride extracted as well as the pore water concentration of zinc in
      soils from Maatheide, a metal contaminated site in the northeast of Belgium.
      Addition of the metal immobilizing agents also eliminated acute toxicity to the
      potworm Enchytraeus albidus and the earthworm Eisenia fetida and chronic toxicity
      to the springtail Folsomia candida. Cocoon production by E. fetida, however, was
      still adversely affected. These differences may be explained by the species
      dependent routes of metal uptake: F. candida is probably mainly exposed via pore
      water while in E. fetida dietary exposure is probably also important. From these
      results it is clear that organisms with different exposure routes should be used
      simultaneously to assess the environmental risk of metal contaminated soils.

PMID- 12475070
TI  - The relationships between heavy metal (Cd, Cr, Cu, Fe, Pb, Zn) levels and the
      size of six Mediterranean fish species.
AB  - Heavy metal (Cd, Cr, Cu, Fe, Pb, Zn) concentrations in the muscle, gill and liver
      of six fish species (Sparus auratus, Atherina hepsetus, Mugil cephalus, Trigla
      cuculus, Sardina pilchardus and Scomberesox saurus) from the northeast
      Mediterranean Sea were measured and the relationships between fish size (length
      and weight) and metal concentrations in the tissues were investigated by linear
      regression analysis. Metal concentrations (as microg/g d.w.) were highest in the
      liver, except for iron in the gill of Scomberesox sauris and lowest in the muscle
      of all the fish species. Highest concentrations of Cd (4.50), Cr (17.1) and Pb
      (41.2) were measured in liver tissues of T. cuculus, Sardina pilchardus and A.
      hepsetus, respectively. The liver of M. cephalus showed strikingly high Cu
      concentrations (202.8). The gill of Scomberesox saurus was the only tissue that
      showed highest (885.5) iron concentrations. Results of linear regression analysis
      showed that, except in a few cases, significant relationships between metal
      concentrations and fish size were negative. Highly significant (P<0.001) negative
      relationships were found between fish length and Cr concentrations in the liver
      of A. hepsetus and M. cephalus, and Cr concentrations in the gill of T. cuculus.
      Cr and Pb concentrations in the liver and Cu concentrations in all the tissues of
      Scomberesox saurus also showed very significant (P<0.001) negative relationships.
      Negative relationships found here were discussed.

PMID- 12475071
TI  - Foliar response of an Ailanthus altissima clone in two sites with different
      levels of ozone-pollution.
AB  - Potted plants of Ailanthus altissima, produced by root suckers coming from a
      single symptomatic mother tree, were placed in two sites in the vicinity of
      Florence (central Italy), with different levels of ozone pollution. These plants
      were kept in well watered conditions during the period May-September 1999. In the
      high pollution site (Settignano-SET) the level of ozone exposure (AOT40) reached
      at the end of the season a value of 31 ppm h, whereas in the "low pollution" site
      (Cascine-CAS) the exposure to ozone was 11 ppm h. A. altissima showed foliar
      symptoms in early July at SET and in the second half of July at CAS when exposure
      values reached 5 ppm h at both sites. However, at the end of August the
      conditions of the plantlets were rather similar in both sites. Microscopic and
      ultrastructural analysis were performed at the first onset of symptoms at SET
      (the CAS leaflets were asymptomatic). Observing the upper leaf surface where the
      brown stipples were visible, it was found that the cells of the palisade
      mesophyll displayed loss of chlorophyll and the organelles in the cytoplasm were
      damaged. Swelling of thylacoids was observed in the CAS leaflets, thus indicating
      the possible onset of a pre-visual damage. The injured cells were separated from
      the healthy ones by a layer of callose. We conclude that the sensitivity to ozone
      of A. altissima leaves is related to its leaf structure, with low leaf density
      and large intercellular spaces. Cell walls, as well as acting as mechanical
      barriers against the spread of ozone within the cell, also provide important
      detoxifying processes.

PMID- 12475072
TI  - Effect of soil aggregation on the biodegradation of phenanthrene aged in soil.
AB  - A study was conducted to determine the possible role of soil aggregates in the
      sequestration of phenanthrene and thus in the declined biodegradation of the
      hydrocarbon. Phenanthrene aged in Lima loam (2-mm aggregates) showed declined
      biodegradation with time of aging to the test bacterium P5-2 capable of using
      sorbed phenanthrene. In contrast, the compound aged in a soil reconstructed with
      68% clay-silt and 32% sand that had been separated from the Lima loam was readily
      mineralized. The percentages of each fraction used were the same as those of the
      original soil. Biodegradation of aged phenanthrene was not affected significantly
      by varying the ratios of each fraction in reconstructed mixtures. In experiments
      with Lima loam, its clay-silt fraction, and its sand fraction, mineralization
      extent was much lower in soil aggregates compared with the other samples while
      all had similar organic carbon content of ca. 1.51%. This suggests that
      aggregation may be another important determinant in the reduced biodegradation of
      aged phenanthrene.

PMID- 12475073
TI  - Overwintering sites and winter mortality of Euseius finlandicus (Acari:
      Phytoseiidae) in a peach orchard in northern Greece.
AB  - In peach orchards of northern Greece Euseius finlandicus Oudemans overwinters in
      various sites on the trees, usually in groups of 5-15 females. Overwintering
      females were mostly found in bark crevices near the hibernation cocoons of the
      peach moth Adoxophyes orana (Fischer von Rosslerstamm), and also in small
      crevices of the bark and in pedicels left after fruit harvesting. Empty scales of
      dead diaspidids and dead coccids, cocoons of lacewings and mummies of parasitized
      aphids sporadically found on trees, were less common overwintering sites for
      females of the mite. In two successive years, mortality of overwintering females
      was very low, approximately 4 and 4.5% which could be due to the mild climate of
      northern Greece and the high cold tolerance of the mite.

PMID- 12475074
TI  - Predatory behaviors of Neoseiulus californicus and Galendromus helveolus (Acari:
      Phytoseiidae) attacking Oligonychus perseae (Acari: Tetranychidae).
AB  - Predatory behaviors of Neosieulus californicus (McGregor) and Galendromus
      helveolus (Chant) attacking Oligonychus perseae Tuttle, Baker and Abbatiello on
      avocado leaves were videotaped and analyzed. Behaviors were recorded for "fresh"
      predators that were used < or = 48 hr post receipt from a commercial insectary
      and "cold stored" predators that were maintained at 12 degrees C for
      approximately 14 days. Fresh and cold stored G. helveolus were observed to attack
      O. perseae only after invading webbed nests. Conversely. fresh and cold stored N.
      californicus employed three different modes of predatory attack: (1) intercepting
      and attacking migrant O. perseae outside of web nests: (2) attacking prey through
      nest webbing; or (3) invading and attacking O. perseae inside nests. Predatory
      efficacy of both N. californicus and G. helveolus was reduced following cold
      storage. as both species engaged in certain predatory behaviors less frequently
      in comparison to predators that were not stored at low temperatures. Our observed
      results for N. californicus and G. helveolus attacking O. perseae are interpreted
      in relation to the chaetotaxy hypothesis, which proposes that phytoseiid invasion
      efficiency and propensity of webbed nests is facilitated by dorsal setal lengths.

PMID- 12475075
TI  - Interactions in a tritrophic acarine predator-prey metapopulation system III:
      effects of Tetranychus urticae (Acari: Tetranychidae) on host plant condition.
AB  - Spider mites are serious pests on many economically important plant species,
      because they may reduce plant productivity and, at high mite densities,
      overexploit and even kill the host plants. We have conducted a series of
      greenhouse experiments to quantify the effects of two-spotted spider mites
      (Tetranychus urticae) on host plants (Phaseolus vulgaris). The average amount of
      chlorophyll per cm2 leaf area was used as a measure of plant condition. It was
      shown that chlorophyll concentration decreases with plant age and intensity of
      spider mite feeding. Damage caused by spider mites was assessed visually, using
      the Leaf Damage Index (LDI) defined by Hussey and Parr (1963b), and a
      mathematical relationship between the visual measurements and the amount of
      chlorophyIV cm2 was fitted to data. The relationship may serve as a short-cut to
      estimate overall plant injury, expressed as the relative loss of chlorophyll/cm2
      leaf area caused by spider mites (D). D takes values between 0 (no injury) and I
      (all leaves dead). A highly significant positive relationship between the
      instantaneous spider mite density and D was found, even though D is expected to
      reflect the cumulated density of mites (mite-days). A model of plant growth
      incorporating information about plant age and D predicts that plant area has a
      maximum when plant age is about 60 days, and that plant area decreases
      exponentially with an increase in D.

PMID- 12475076
TI  - Interactions in a tritrophic acarine predator-prey metapopulation system IV:
      effects of host plant condition on Tetranychus urticae (Acari: Tetranychidae).
AB  - Feeding by spider mites can cause severe injury to a host plant and lead to a
      decreasing per capita growth rate and an increasing per capita emigration rate.
      Such density-dependent responses to local conditions are important in a
      metapopulation context because they allow the herbivores to colonize new host
      plants and thereby prolong the time until regional (metapopulation) extinction.
      In order to include density-dependent responses of the two-spotted spider mite
      (Tetranychus urticae) in a realistic metapopulation model, a series of greenhouse
      experiments was conducted with the purpose to quantify how the condition of bean
      plants (Phaseolus vulgaris) influences the demographic parameters of T. urticae.
      Plant age per se reduced the growth rate of the spider mites only slightly,
      whereas the growth rate declined significantly as the plants were injured by the
      mites. The relationships between plant condition (expressed by the plant injury
      index D) and the birth and loss (death + emigration) rates of the mites were
      quantified so as to predict population growth as a function of D. Maximum per
      capita growth rate (r) was estimated to be c. 0.21 day(-1). The growth rate is
      expected to be negative when D exceeds 0.8. When mites were allowed to emigrate
      to neighbouring plants via bridges, the per capita emigration rate increased
      almost exponentially with D. The proportion of eggs in the population decreased
      with D while the numerical ratio between immatures to adults and the sex ratio
      did not change with D. Overall, immatures and adults constituted 74% and 26%,
      respectively, of the active mites and c. 46% of the adults were males. The
      bridges that connected a donor plant with the surrounding recipient plants were
      responsible for the majority of the emigrations from donor plants. Most mites
      stopped after having crossed a single bridge, but a few crossed two bridges while
      none crossed three bridges within 24 h. The significance of the results for
      biological control is discussed.

PMID- 12475077
TI  - Effects of triflumuron on the two-spotted spider mite, Tetranychus urticae
      (Acari: Tetranichydae).
AB  - The effects of triflumuron on the mortality, fecundity, and fertility of the two
      spotted spider mite, Tetranychus urticae, were evaluated in the laboratory. No
      differences in toxicity for larvae, protonymphs and deutonymphs were observed,
      but immature stages were 3.8-times more susceptible than adults at the LC50. The
      compound exhibited a direct contact ovicidal activity influenced by eggs age. 48
      72 h old eggs were significantly more sensitive than eggs of the other age
      classes. No hatch inhibition was observed in eggs laid by treated adult females
      using a sublethal dose at two physiological times (<12 and 48-72 h old). However.
      fecundity decreased in younger treated females, but it increased in the older
      ones. The toxicity for immatures and eggs, and the sublethal effects described
      suggest that triflumuron could be an interesting incorporation in integrated pest
      programs of T. urticae.

PMID- 12475078
TI  - Mating and fecundity of Dermatophagoides farinae.
AB  - Studies of the life cycle of cultured Dermatophagoides farinae found that after
      an initial mating D. farinae females lived for 63.3+/-64.6 (SD) d after their egg
      production period ended (Arlian and Dippold 1996). The long period after
      cessation of egg production for D. farinae suggested D. farinae females could
      mate multiple times and produce eggs continuously for a longer period. The
      purpose of this study was to determine if female D. farinae could mate at least
      two times, and subsequently increase the production of viable eggs over a longer
      period of time compared to a single mating. Female D. farinae were randomly
      selected from thriving cultures and isolated in cages. When the females had
      ceased to lay eggs a male was added to the cage. Fifty-seven percent of the
      isolated females mated again and produced a second batch of viable eggs. In
      natural or culture populations, females have continuous availability of males.
      Therefore, in another experiment, females that emerged from the tritonymphal
      stages were continuously exposed to fresh males and fecundity and lengths of the
      reproductive and post reproductive periods were determined. These females had a
      11 d longer reproductive period and produced 30.7% more eggs compared to females
      that only mated one time after they emerged from the tritonymphal stage. However,
      the post reproductive period was still long (58.6+/-11.4 [SE] d) the significance
      of which is not clear. In conclusion, this study revealed that D. farinae females
      are capable of more than one successful mating that results in increased egg
      production compared to that of a single mating. It is likely that females mate
      multiple times in natural and culture populations. It was observed that females
      actively attract males during the reproductive period but not afterward even
      though she continues to live a long time.

PMID- 12475079
TI  - Detection of serine proteases in extracts of the domestic mite Blomia tropicalis.
AB  - Previous studies have shown that the domestic mites Dennatophagoides
      pteronyssinus and D. farinae contain allergens with serine protease activity.
      These proteolytic allergens include trypsin, chymotrypsin, elastase, kallikrein,
      and C3/C5 convertase. However, it is not known whether the domestic mite Blomia
      tropicalis shares with other mite species the serine protease activities. The
      enzymatic activity present in extracts obtained from food-free B. tropicalis was
      investigated using specific substrates and inhibitors. Based upon the
      concentration response and inhibition profiles, and the digestion of specific
      substrates our data demonstrate that extracts from B. tropicalis exhibit several
      serine-protease-like activities. The enzyme activities detected in the B.
      tropicalis extracts are trypsin, elastase, chymotrypsin, kallikrein, C3/C5
      convertase, and mast cell protease. Our results also demonstrate that kallikrein
      and C3/C5 convertase-like activities were not significantly affected by the
      alpha1-antiprotease, a naturally occurring serine protease inhibitor which
      protects lung mucosa from the enzymatic action. These data strongly suggest that
      the Echymyopodidae mite B. tropicalis shares at least five serine proteases with
      members of other mite families, the Glycyphagidae and Pyroglyphidae. In addition,
      our data demonstrate the potential use of biochemical methods to detect serine
      proteases for evaluation of mite growth in viitro, or to detect environmental
      exposures to these enzymes.

PMID- 12475080
TI  - Characterization of protective antigens from the midgut of Amblyomma variegatum
      ticks.
AB  - Separation of midgut membrane proteins from the tick, Ambylomma variegatum, using
      a nonionic detergent (Triton X-114), resulted in two protein fractions, namely
      DET (detergent) and AQ (aqueous). In immunoblotting analysis with polyclonal
      antibodies against these fractions, 4 proteins (Mr approximately 27,000, 67,000,
      86,000 and 95,000,) and 2 proteins (M, approximately 54,000 and 67,000) were
      detected in the DET and AQ fractions, respectively. Three of the DET fraction
      proteins Mr approximately 27,000, 67,000 and 95,000 were glycosylated since they
      bound to the lectin, concanavalin A. In 2-dimensional gel electrophoresis, the AQ
      and DET fraction proteins were found to be acidic in nature. In a series of
      bioassay experiments, rabbits were first immunised with both DET and AQ fractions
      and then infested with ticks. The egg batch weights of these ticks were reduced
      by 50% compared to control ticks. Furthermore, there was a significant reduction
      in the hatchability of eggs laid by ticks fed on rabbits previously immunised
      with both DET (14%) and AQ (33%) fractions. Based on the egg hatchability, the
      reproductive capacity of ticks was reduced by 77 and 48% by DET and AQ fractions,
      respectively.

PMID- 12475081
TI  - Life-cycle and host specificity of Amblyomma tigrinum (Acari: Ixodidae) under
      laboratory conditions.
AB  - Biological data of three generations of Amblyomma tigrinum in the laboratory are
      reported and the suitability of different host species for immature ticks are
      compared. Grouping the three generations, infestations by both the larval and
      nymphal stages were performed on chickens (Gallus gallus), wistar rats (Rattus
      norvegicus), rabbits (Orytolagus cuniculus), wild mice (Calomys callosus), dogs
      (Canis familiaris) and opossums (Didelphis albiventris). Only dogs were used for
      infestations by adult ticks. Tick developmental periods were observed in an
      incubator at 27 degrees C and RH 90%. The proportion of engorged larvae recovered
      from chickens (21.7% of the exposed larvae) was significantly larger (p<0.001)
      than those from the five mammal species used in the infestations (maximum of
      3.1%). A significant larger (p<0.01) proportion of engorged larvae successfully
      molted after being fed on chickens than on mammal hosts. The proportion of
      engorged nymphs recovered from chickens (28.8% of the exposed nymphs) was
      significantly larger (p0.001) than those from mammal hosts (range: 0-2.1%).
      Larvae showed similar feeding periods on exposure to different host species,
      except for those larvae fed on C. callosus, which showed significantly longer
      (p<0.001) feeding periods. Engorged larvae detachment peaked on the 5th feeding
      day, followed by the 6th day, on all hosts except for C. callosus. Larval premolt
      periods were similar for engorged ticks exposed to different host species, except
      for larvae fed on dogs, which showed significantly longer (p<0.001) premolt
      periods. Host detachment of engorged nymphs peaked on the 6th feeding day on
      chickens. Although nymphal detachment on rats peaked on the 8th day, only 15
      nymphs were recovered from this host species. In a sample of 144 F3 nymphs fed on
      chickens no significant difference (p>0.10) was found between the feeding or
      premolt periods of 82 males and 62 females, but female nymphs were significantly
      heavier (p<0.005) than male nymphs. Sixteen engorged females (61.5% of the
      exposed ticks) were recovered after being fed on dogs. and all these females laid
      viable eggs. Chickens, the only avian host, were the most suitable host when
      compared with the five mammal species. Dogs were demonstrated to be a suitable
      host for adults of A. tigrinum, which is consistent with, several reports of
      adult A. tigrinum ticks parasitizing dogs in different areas of South America.
      Our results reinforce that in these same areas avian species are the major hosts
      for immature stages of this tick species.

PMID- 12475082
TI  - Relative importance of lizards and mammals as hosts for ixodid ticks in northern
      California.
AB  - Abstract Lizards and mammals were trapped and examined for ticks from August 1992
      to June 1993 in two habitat types, chaparral and woodland-grass, in northern
      California. Five tick species were collected from mammals (Dermacentor
      occidentalis, Haemaphysalis leporispalustris, Ixodes pacificus, I. spinipalpis,
      I. woodi), but only I. pacificus was found on lizards. Dermacentor occidentalis,
      I. pacificus, and I. woodi occurred in both habitats, whereas H. leporispalustris
      and I. spinipalpis were found only on animals trapped in chaparral. The tick
      species most commonly encountered on mammals was D. occidentalis in chaparral and
      I. pacificus in woodland-grass. Peak infestation of mammals occurred in spring
      for I. pacificus immatures and H. leporispalustris, summer for D. occidentalis
      immatures, fall through spring for I. woodi immatures, and fall through winter
      for I. spinipalpis. The primary aim of the study was to quantify the relative
      importance of the western fence lizard (Sceloporus occidentalis), which is
      reservoir-incompetent for Borrelia burgdorferi sensu lato (s.l.), and mammalian
      B. burgdorferi s.l.-reservoirs as hosts for the immature stages of I. pacificus
      in spring. The estimated relative utilization by I. pacificus of the western
      fence lizard versus mammals was 88% for larvae and 99% for nymphs in chaparral in
      May. When tick infestation data were corrected for a two-fold lower efficiency of
      field examinations for rodents than for lizards, the western fence lizard still
      accounted for 78% of larval and 98% of nymphal feedings. In woodland-grass, 46%
      of 100 I. pacificus larvae and 100% of 52 nymphs recovered from mammals or
      western fence lizards during May-June were collected from the lizards. However,
      this may represent an underestimate of the importance of the western fence lizard
      as a larval host in this habitat because inclement weather during the late May
      sampling period doubtless resulted in significantly decreased lizard activity. In
      conclusion, the western fence lizard was more heavily utilized by I. pacificus
      immatures, especially nymphs, than were rodents.

PMID- 12475083
TI  - Tick-borne encephalitis virus prevalence in Ixodes ricinus ticks collected in
      high risk habitats of the south-Bohemian region of the Czech Republic.
AB  - A survey for tick-borne encephalitis virus in trades ricinus ticks was conducted
      in May 2000 in two districts of the South-Bohemian region of the Czech Republic
      with a high occurrence of tick-borne encephalitis (TBE) in humans. Homogenized
      ticks were tested on PS cells, which were examined for any cytopathic effect,
      plaque assay and indirect fluorescent antibody test (IFT). The IFT has proved to
      be the most sensitive and most rapid test to demonstrate the virus in ticks. TBE
      virus was found in 17 of 187 pooled samples. consisting of a total of 2,968
      ticks. The mean minimum infection rate was 0.6% for all tick stages combined.
      Infection rates in nymphs collected in different locations varied between 0.2 and
      1.3% and between 5.9 and 11.1% in adult ticks. The observed TBE prevalence in
      ticks was compared with data obtained elsewhere in the Czech Republic. It is
      concluded that screening of ticks for TBE virus prevalence using IFT is a
      valuable indicator for the degree of risk to contract TBE in as particular
      habitat.

PMID- 12475084
TI  - Delirium and dying.

PMID- 12475085
TI  - Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer's
      disease: a population-based study of the oldest old.
AB  - BACKGROUND: The purpose of this study was to examine if Type 2 diabetes mellitus
      is a risk factor for dementia in very old age, specifically for Alzheimer's
      disease (AD) and vascular dementia (VaD). METHODS: We evaluated the risk of
      dementia in relation to Type 2 diabetes using a population-based sample of 702
      individuals aged 80 years and older (mean age 83 years). A total of 187 persons
      received a dementia diagnosis. Thirty-one individuals had a diabetes diagnosis
      prior to onset of the dementia. RESULTS: Cox proportional hazard analyses,
      adjusted for age, gender, education, smoking habits, and circulatory diseases,
      indicated an elevated risk to develop VaD (relative risk = 2.54, 95% confidence
      interval 1.354.78) in individuals with diabetes mellitus. No association was
      found between diabetes and AD. CONCLUSION: Type 2 diabetes is selectively related
      to the different subtypes of dementia. There is no increased risk of AD but more
      than a twofold risk of VaD in persons with diabetes.

PMID- 12475086
TI  - Describing cognitive decline of patients at the mild or moderate stages of
      Alzheimer's disease using the Standardized MMSE.
AB  - OBJECTIVE: To describe the progression of patients with mild or moderate
      Alzheimer's disease (AD) to a severe stage using the Standardized Mini-Mental
      State Examination (SMMSE). METHODS: A cohort of 206 patients was stratified
      according to their baseline SMMSE scores: mild (19-24) and moderate (10-18).
      Proportional hazards analyses were used to determine the hazard of switching into
      a severe stage, defined as SMMSE score < 10. RESULTS: Among patients at the mild
      stage, 25% reached the severe stage within 2.6 years, and in the moderate group
      within 1.5 years. Patients with hallucinations at the mild stage experienced more
      rapid decline. The previous rate of decline was also found to be an important
      predictor. At the moderate stage, key predictors were lower SMMSE score and
      longer time since onset. CONCLUSIONS: Current SMMSE scores with other clinical
      details can be used to advise patients and caregivers about the expected
      progression of AD.

PMID- 12475087
TI  - Accuracy of the clock drawing test for detecting dementia in a multicultural
      sample of elderly Australian patients.
AB  - OBJECTIVE: To assess the accuracy of clock drawing for detecting dementia in a
      multicultural, non-English-speaking-background population. DESIGN: A prospective
      cohort study. SETTING: A general geriatric medical outpatient clinic in southwest
      Sydney, Australia. PARTICIPANTS: Ninety-three consecutive new patients to the
      clinic who had a non-English-speaking-background country of birth (mean age 78.0
      years). MEASUREMENTS: The clock drawing test was conducted at the beginning of
      each clinic visit by a blinded investigator. Each patient was then assessed by a
      geriatrician who collected demographic data, administered the Modified Barthel
      Index, the Geriatric Depression Scale, and the Folstein Mini-Mental State
      Examination, and categorized each patient as normal or demented, according to DSM
      IV criteria. Interpreters were used for participants who spoke a language other
      than English or who requested them. Each clock drawing was scored according to
      the 4-point CERAD scale and the previously published methods of Mendez, Shulman,
      Sunderland, Watson, and Wolf-Klein. Scoring was evaluated for reliability and
      predictive accuracy, using receiver operating characteristic (ROC) curve
      analysis. Logistic regression analysis was used to assess the potential
      interaction between level of education and each of the clock scoring methods.
      RESULTS: Using ROC curve analysis, there was no significant difference between
      the clock scoring methods (area under the curve varied from 0.60 to 0.72). The
      most sensitive was the Mendez scoring method (98%), with a specificity of 16%.
      Specificity above 50% was found only for the Wolf-Klein method, with an
      intermediate sensitivity of 78%. CONCLUSIONS: There were no significant
      differences in the clock scoring methods used to detect dementia. Performance of
      the clock drawing test was modest at best with low levels of specificity across
      all methods. Scored according to these methods, clock drawing was not a useful
      predictor of dementia in our multicultural population.

PMID- 12475088
TI  - Telephone screening to identify potential dementia cases in a population-based
      sample of older adults.
AB  - This study examined the utility of the TELE, a telephone assessment for dementia,
      in a sample of 269 individuals that was not selected on the basis of previous
      dementia diagnosis. Thus, the conditions of the study reflect the actual
      situation in which a screening instrument might be employed. Scores on TELE were
      compared to dementia diagnoses. Using the best cutoff score, sensitivity was .86
      and specificity was .90. Longitudinal follow-up established that false positives
      primarily included those who subsequently developed dementia. Telephone screening
      for dementia has both clinical and research applications. One recommendation
      based on our experience is that longitudinal studies should include a telephone
      interview component for anyone who drops out of the study, to enable
      characterizing the cognitive status of dropouts.

PMID- 12475089
TI  - Apolipoprotein E genotypes in a group of elderly subjects of Spanish descent
      living in Mexico City.
AB  - The association between the APOE gene and Alzheimer's disease and other forms of
      dementia has been widely documented, but its relevance as a genetic risk factor
      in specific ethnic groups other than Caucasians in the United States and Europe
      is limited. The aim of this work was to describe the distribution of the APOE
      genotype in 80 subjects of Spanish origin, over 60 years old, who were
      institutionalized in the Spanish Hospital of Mexico City. Thirty-eight subjects
      who met the DSM-IV and ICD-10 criteria for Alzheimer's disease or vascular
      dementia and 42 controls without dementia underwent genotyping. APOE epsilon
      allele frequencies were as follows: for affected individuals, epsilon2, 7.9%,
      epsilon3, 69.7%, and epsilon4, 22.4%; for controls, epsilon2, 4.8%, epsilon3,
      91.6%, and epsilon4, 3.6%. The higher frequency of the epsilon4 allele in the
      affected group (chi2 = 14.5; df = 4, p = .006) confirms an association between
      this APOE molecular variant and dementia in elderly Spaniards.

PMID- 12475090
TI  - Confusion/delirium following cataract surgery: an incidence study of 1-year
      duration.
AB  - BACKGROUND: Delirium is frequently observed in clinical practice, particularly in
      medical and surgical wards and more so among patients at risk, especially elderly
      with preexisting central nervous system impairments. OBJECTIVE: Despite the
      severe consequences of delirium, epidemiological data relating to incidence of
      delirium following "minor" surgery are lacking. The aim of the present study was
      to evaluate the incidence of delirium following cataract surgery in community
      dwelling patients. OUTCOME: For purposes of the present study, the Confusion
      Rating Scale was used. RESULTS: Of 296 patients fulfilling the inclusion
      criteria, 13 (4.4%) had had immediate postoperative delirium. The two variables
      that significantly differentiated between delirious and nondelirious patients
      were older age (82.1 vs. 73.06 years; p < .001) and more frequent use of
      benzodiazepine premedication (69% vs. 39.9%; p < .002). CONCLUSION: These
      findings suggest that the incidence of delirium following cataract surgery
      requires greater awareness, possibly changes in premedication, and a longer
      observation period in the very old.

PMID- 12475091
TI  - Anticholinergic burden and the risk of falls among elderly psychiatric
      inpatients: a 4-year case-control study.
AB  - OBJECTIVE: Falls are an everyday risk for the elderly and their etiology is
      multifactorial. Because there are little data focusing on falls among elderly
      psychiatric inpatients, we aimed to retrospectively assess the characteristics of
      inpatients that had sustained a fall during hospitalization. METHODS: Over 4
      years, all adverse-event reports of falls were reviewed. Inclusion criteria were
      age >65 years and intact cognition. The control group consisted of the previous
      and next admission of an elderly patient to the same ward. Anticholinergic score
      was calculated for each patient. RESULTS: Of 414 admissions of elderly patients,
      34 (8.2%) patients had had a fall. The control group (n = 68) did not differ in
      mean age, distribution of diagnoses, or use of benzodiazepines, antidepressants,
      or antipsychotics. Two variables were significantly associated with falls: female
      gender (68% vs. 39%, p < .05) and anticholinergic burden score (ABS) (mean: 3.7
      vs. 2.1, p < .05). CONCLUSIONS: Our results support reported findings of higher
      rates of falls among elderly women and suggest that ABS may be a risk factor for
      falls.

PMID- 12475092
TI  - Bipolar disorder: similarities and differences between patients with illness
      onset before and after 65 years of age.
AB  - BACKGROUND: Recent reports have suggested that bipolar disorder beginning in late
      life is strongly associated with organic brain disease whereas early-onset cases
      are more likely to be associated with a family history of mood disorder. It is
      not yet clear whether late-onset bipolar disorder is therefore a "phenocopy" of
      the classic early-onset disorder, sharing symptoms but having a different
      etiology, or whether people with early- and late-onset bipolar disorder have a
      common underlying vulnerability that interacts with age-specific triggering
      factors. AIM: The present study examines the administrative records of patients
      treated for bipolar disorder, to establish whether differences between early- and
      late-onset cases might be consistent with their having distinct etiological
      processes. METHODS: We used a file containing administrative data for all
      patients with a diagnosis of bipolar disorder who were in contact with the health
      services of Western Australia between 1980 and 1998. For each contact with
      psychiatric services, the file provided the patient's age, gender, marital
      status, educational achievement, employment, ethnic origin, postcode of
      residence, primary and secondary diagnoses, and the duration of the
      (administrative) episode. Subjects were designated "late-onset" when their first
      contact with psychiatric services occurred at or after 65 years of age. RESULTS:
      Between 1980 and 1998 there were 33,004 service contacts involving 6,182
      individuals whose primary or secondary clinical diagnosis was bipolar disorder.
      This indicates that the prevalence of bipolar disorder in Western Australia is
      approximately 0.4%. Most patients had an onset of illness between 15 and 45 years
      of age, but 492 patients (8%) were aged 65 years or over at the time of first
      contact with mental health services. We observed that the relative frequency of
      late-onset bipolar disorder increased between 1980 and 1998 (1% to 11%). There
      was an excess of women in our cohort (3:2), but no difference in the age of onset
      between males and females. Early onset was associated with a subsequently lower
      socioeconomic status, aboriginal ethnicity, and a higher frequency of mixed
      affective episodes, other mood disorders, schizophrenia, and schizoaffective
      disorder. Patients with late-onset bipolar disorder were more likely to have a
      diagnosis of organic mental disorder recorded (2.8% vs. 1.2%). There was no
      evidence of a bimodal pattern of age-specific incidence. CONCLUSION: The observed
      differences between early- and late-onset bipolar disorders are small and most
      likely attributable to differences in the duration of illness. Only a small
      proportion of patients with bipolar disorder were ever diagnosed with an organic
      mental disorder, which suggests that the reported association between late onset
      of illness and organic factors may be of limited clinical relevance.

PMID- 12475094
TI  - Catheter ablation of atrial fibrillation: fact and controversy.

PMID- 12475093
TI  - Irrigated-tip catheter ablation of pulmonary veins for treatment of atrial
      fibrillation.
AB  - INTRODUCTION: Catheter ablation of pulmonary veins (PV) for treatment of atrial
      fibrillation (AF) is limited by the disparate requirements of sufficient energy
      delivery to achieve PV isolation while avoiding PV stenosis. The aim of the
      present study was to evaluate the safety and efficacy of using an irrigated-tip
      catheter for systematic isolation of PV. METHODS AND RESULTS: The study
      population consisted of 136 consecutive patients (109 men, mean age 52 +/- 10
      years) with symptomatic, drug-refractory paroxysmal (122) or persistent (14) AF.
      Cavotricuspid isthmus ablation and systematic radiofrequency isolation of all
      four PVs (guided by a circumferential mapping catheter) was performed in all
      patients with a protocol using an irrigated-tip catheter. PV diameter was
      assessed by selective angiography. The electrophysiologic endpoint of PV
      isolation was achieved in 100% of patients. Bidirectional cavotricuspid isthmus
      block was achieved in 99% of patients. Moderate PV stenosis (50% narrowing) was
      observed in one patient (0.7%) without clinical consequence. No other
      complications were observed. Reablation procedures were required in 67 patients
      (49%). After a mean follow-up of 8.8 +/- 5.3 months, 81% of patients were free of
      AF clinical recurrence, including 66% not taking any antiarrhythmic drugs.
      CONCLUSION: Systematic radiofrequency ablation of PV using an irrigated-tip
      catheter in patients with atrial fibrillation allows complete isolation of all
      four PVs with a very low incidence of stenosis.

PMID- 12475095
TI  - Intracardiac Doppler echocardiographic quantification of pulmonary vein flow
      velocity: an effective technique for monitoring pulmonary vein ostia narrowing
      during focal atrial fibrillation ablation.
AB  - INTRODUCTION: Ablation at the pulmonary vein (PV) ostium to isolate triggers for
      atrial fibrillation (AF) may induce PV narrowing. The AcuNav ultrasound catheter
      can image PV flow and quantify peak velocity and may be useful in assessing the
      degree of narrowing of PV ostia. METHODS AND RESULTS: In 93 patients with AF
      undergoing PV ostial ablation (up to 40 W, 52 degrees C, 90 sec), the ultrasound
      catheter was placed in the right atrium and PV peak flow velocities were measured
      during systole and diastole before and after ablation. Ostial PV electrical
      isolation was achieved in 216 of the 219 targeted PVs. The ultrasound catheter
      provided flow imaging of all PVs. The ostial peak flow velocities measured 56 +/-
      12 cm/sec before ablation and increased to 101 +/- 22 cm/sec after ablation (P <
      0.001). Peak velocity >100 cm/sec was detected in 103 (47%) of 219 and > or = 158
      cm/sec (estimated pressure gradient 10 mmHg) with turbulent flow features, in 7
      (3.2%) of 219 PVs. The highest velocity detected in one PV was 211 cm/sec (17.7
      mmHg). Follow-up ultrasound catheter measurements were obtained in 13 patients
      (30 previously ablated PVs) during repeat ablations. The ostial peak velocity had
      decreased by 22 +/- 14 cm/sec and in 25 (83%) of 30 PVs was within the baseline
      range (<100 cm/sec) at a mean follow-up of 4.9 +/- 2.2 months. Follow-up magnetic
      resonance imaging (MRI) or contrast-enhanced CT was obtained at 7.0 +/- 3.8
      months in seven patients with PV velocity > 158 cm/sec after initial ablation. No
      significant stenosis (<30%) was identified, and no patient suffered clinical
      symptoms (follow-up 6-18 months) related to the described acute changes in PV
      flow after an initial ablation procedure. Of 13 patients with repeat ablation,
      two had PV velocities >100 cm/sec before repeat ablation, and three PVs in two
      patients had flow velocity >158 cm/sec after repeat ablation. One of these
      patients developed symptoms of exertional dyspnea; MRI at 4 months showed 50% to
      60% ostial narrowing. CONCLUSION: Ostial ablation for PV isolation may induce a
      mild-to-moderate increase in PV flow velocity, which can be identified using an
      ultrasound catheter with Doppler color flow imaging. Increases in PV flow
      velocity (<158 cm/sec) after a primary ablation procedure appear to be well
      tolerated, and a return toward baseline flow characteristics should be
      anticipated by 3 months. A more cautious approach may be required for patients
      undergoing repeat PV isolation.

PMID- 12475096
TI  - Acute results of transvenous cryoablation of supraventricular tachycardia (atrial
      fibrillation, atrial flutter, Wolff-Parkinson-White syndrome, atrioventricular
      nodal reentry tachycardia).
AB  - INTRODUCTION: Radiofrequency (RF) catheter ablation currently is used for
      treatment of cardiac arrhythmias. Although the success rate is high for almost
      all supraventricular tachycardias (SVT), this technique has some drawbacks,
      especially when pulmonary veins (PV) are targeted for treatment of atrial
      fibrillation (AF). Additionally, new techniques for isolation of the PVs have the
      drawback that they can be used only for PV isolation and not for routine
      treatment of other SVTs. The aim of this study was to report on the safety and
      efficacy of a new cryoablation system for treatment of all SVTs. METHODS AND
      RESULTS: Forty-nine patients with SVT (38 men; age 48 years, range 23-76) were
      enrolled in the study. Five patients were withdrawn from the study before they
      underwent cryoablation. The remaining 44 patients were treated with cryoablation
      (22 AF, 15 atrial flutter, 3 accessory pathway, 2 AV nodal reentrant tachycardia,
      1 AV junction ablation for permanent AF, 1 atrial tachycardia). Cryoablation was
      performed with the CryoCor cryoablation system, which uses a precooling system
      and N2O as a refrigerant. The number of freezes applied varied according to the
      index arrhythmia treated. Successful isolation of PVs was performed in 20 of
      (96%) 21 AF patients and 53 of 55 veins. The overall acute success was 98%
      (43/44). Fifty-three PVs were isolated (2.5/patient). The success rate was 100%
      (23/23) for right-sided procedures. The average and nadir temperatures reached in
      right-sided and left-sided procedures were -77 degrees C and -80 degrees C and 
      75 degrees C and -78 degrees C, respectively. No acute PV stenosis was seen.
      CONCLUSION: This novel cryoablation system appears to be safe and can
      successfully treat different types of SVTs, including AF. Isolation of PVs is
      possible without producing stenosis. Despite the high blood flow in the right
      atrial isthmus and PVs, bidirectional conduction block can be achieved.

PMID- 12475097
TI  - Transvenous cryoablation of supraventricular tachycardias: it works but is it
      better?

PMID- 12475098
TI  - Advanced rhythm discrimination for implantable cardioverter defibrillators using
      electrogram vector timing and correlation.
AB  - INTRODUCTION: Discrimination of ventricular and supraventricular arrhythmias
      remains one of the major challenges for appropriate implantable defibrillator
      (ICD) therapy delivery. The electrogram vector timing and correlation (VTC)
      algorithm was developed for such rhythm discrimination. The VTC algorithm
      differentiates normally conducted supraventricular beats from abnormally
      conducted ventricular beats by comparing the timing and correlation of rate and
      shock channel electrograms. METHODS AND RESULTS: Rate and shock channel
      electrograms of sinus rhythm and induced arrhythmias were collected from 93
      patients during ICD placement. The algorithm was developed using data from 50
      patients and prospectively tested in a software model with the remaining 43
      patients. A sinus rhythm reference was formed by averaging complexes of the shock
      channel signal aligned by the peak amplitude of the rate channel. Eight features
      measuring the amplitude and timing of shock channel signal characteristics were
      extracted from the reference for comparison. When a high-rate rhythm was
      detected, the VTC algorithm computed the correlation of the arrhythmia complex
      features with the reference. Rhythms with a sufficient number of uncorrelated
      beats were classified as ventricular tachycardia (VT). In a dual-chamber
      implementation, the VTC algorithm is integrated with ventricular and atrial rate
      comparison (V>A) and stability above an atrial fibrillation rate threshold. The
      test set consisted of 117 arrhythmias. Dual-chamber sensitivity was 100% (81/81
      VT) and specificity was 97% (35/36 supraventricular tachycardia). Single-chamber
      analysis demonstrated 99% sensitivity and 97% specificity. CONCLUSION: The VTC
      algorithm demonstrated high sensitivity and specificity in discriminating between
      ventricular and supraventricular arrhythmias.

PMID- 12475099
TI  - Unidirectional conduction block at cavotricuspid isthmus created by
      radiofrequency catheter ablation in patients with typical atrial flutter.
AB  - INTRODUCTION: Although unidirectional conduction block at the cavotricuspid
      isthmus can be created by radiofrequency ablation for atrial flutter, its
      underlying mechanism has not been elucidated. METHODS AND RESULTS: Twenty-seven
      patients (22 men and 5 women; mean age 59 +/- 11 years) who met the following
      criteria were studied: (1) bidirectional isthmus conduction demonstrable at
      baseline; (2) at least one linear lesion attempted on the cavotricuspid isthmus
      with radiofrequency catheter ablation; and (3) conduction times at anterolateral
      and posteromedial portions of the isthmus measured for both clockwise and
      counterclockwise directions before the ablation procedure. Unidirectional
      conduction block was observed before achieving bidirectional block in 9 patients
      (group I); the remaining 18 patients did not exhibit unidirectional conduction
      block (group II). All unidirectional conduction blocks were demonstrated in the
      counterclockwise direction. Anterolateral isthmus conduction time in group I was
      significantly longer than that in group II in both directions. However, there
      were no significant differences in posteromedial isthmus conduction time between
      groups I and II in either direction. Anterolateral isthmus conduction time was
      significantly longer than posteromedial conduction time in group I but not in
      group II. CONCLUSION: There were significant differences in conduction properties
      at the cavotricuspid isthmus between patients who developed unidirectional
      conduction block and those who did not. Our results support the notion that
      anisotropy contributes to the genesis of unidirectional conduction block at the
      cavotricuspid isthmus during the radiofrequency ablation procedure.

PMID- 12475100
TI  - Inducible ventricular flutter and fibrillation predict for arrhythmia occurrence
      in coronary artery disease patients presenting with syncope of unknown origin.
AB  - INTRODUCTION: Ventricular fibrillation and ventricular flutter (cycle length < or
      = 230 msec) induced at electrophysiologic studies are thought to be nonspecific
      findings in patients presenting with syncope of unknown origin. However, there
      are limited data on the prognosis of these patients in long-term follow-up.
      METHODS AND RESULTS: We followed 274 consecutive patients with coronary artery
      disease presenting with syncope or presyncope who underwent electrophysiologic
      studies from January 1992 to June 1999 and assessed the risk of subsequent
      arrhythmias stratified by the electrophysiologic result at the time of their
      presentation with syncope. Ventricular fibrillation was induced in 23 patients
      (8%); ventricular flutter in 24 (9%), sustained ventricular tachycardia in 41
      (15%); and nonsustained ventricular tachycardia 42 (15%). In 37 +/- 25 months of
      follow-up, there have been ventricular arrhythmias in 34 patients, including 3
      (13%) of 23 who had induced ventricular fibrillation, and 7 (30%) of 24 with
      induced ventricular flutter, compared to 13 (32%) of 41 with sustained
      ventricular tachycardia, 7 (17%) of 42 with nonsustained ventricular tachycardia,
      and only 4 (3%) of 144 noninducible patients (P < 0.001 for induced ventricular
      fibrillation and ventricular flutter vs noninducible patients). The inducibility
      of ventricular fibrillation and ventricular flutter were independent risk factors
      for arrhythmia occurrence in follow-up. CONCLUSION: Ventricular fibrillation and
      ventricular flutter induced at electrophysiologic studies have prognostic
      significance for arrhythmia occurrence in patients presenting with syncope. These
      induced arrhythmias may not be as nonspecific as previously thought and treatment
      should be considered for these patients.

PMID- 12475101
TI  - Programmed ventricular stimulation in patients with syncope: does it really help?

PMID- 12475102
TI  - Interatrial transseptal electrical conduction: comparison of patients with atrial
      fibrillation and normal controls.
AB  - INTRODUCTION: This study analyzed the electrophysiologic properties of
      interatrial transseptal electrical conduction at Bachmann's bundle and the ostium
      of the coronary sinus (CS os) in response to pulmonary vein (PV) stimuli, which
      mimicked spontaneous ectopy. METHODS AND RESULTS: Forty patients with atrial
      fibrillation (AF) referred for ablation (15 persistent AF and 25 paroxysmal AF)
      and 15 control patients were enrolled in the study. During decremental extra
      stimulus pacing from the PVs, right atrial activation was analyzed using
      noncontact mapping and multipolar catheters. The refractory periods and
      conduction times were calculated for Bachmann's bundle, CS os, and left atrium.
      The dispersion of refractoriness was calculated as the difference between the
      refractory periods of Bachmann's bundle and the CS os. The refractory period at
      Bachmann's bundle was 244 msec in the persistent AF group, 213 msec in the
      paroxysmal AF group, and 199 msec for controls. The refractory period at the CS
      os was 220 msec in the persistent AF group, 201 msec in the paroxysmal AF group,
      and 193 msec for controls. The dispersion of refractoriness was 54 msec in the
      persistent AF group; this was significantly greater than in paroxysmal AF at 32
      msec (P < 0.05) and controls at 13 msec (P < 0.01). During decremental pacing,
      lengthening of conduction times at both Bachmann's bundle and the CS os were
      significantly greater in the persistent AF group compared with paroxysmal AF or
      control groups. A higher dispersion of refractoriness was associated with a
      higher incidence of inducible AF and a lower rate of ablation success.
      CONCLUSION: There are differences between the left to right interatrial
      electrical connections between patients with persistent AF, paroxysmal AF and
      controls.

PMID- 12475103
TI  - Effect of shock-induced changes in transmembrane potential on reentrant waves and
      outcome during cardioversion of isolated rabbit hearts.
AB  - INTRODUCTION: Although numerous theories exist for the mechanisms of
      defibrillation, experimental data directly relating these mechanisms to the
      termination of reentry in whole hearts are lacking. METHODS AND RESULTS: Using
      video imaging technology, we recorded approximately 5,000 optical action
      potentials simultaneously from the anterior and posterior ventricular epicardium
      of rabbit hearts during cardioversion of stable reentrant arrhythmias. Monophasic
      shocks at three strengths for each polarity were delivered between electrodes
      inside the right ventricle (RV) and above the left atrium. Cardioversion efficacy
      at the three strengths was 21%, 42%, and 92% for RV + shocks, which primarily
      depolarized the epicardium, and 10%, 15%, and 33% for RV- shocks, which primarily
      hyperpolarized the epicardium. The mechanism of cardioversion for RV+ shocks was
      elimination of excitable gaps and reentry via excitation ahead of wavefronts and
      action potential prolongation at wavetails, both of which increased with shock
      strength. Partial elimination of these gaps resulted in resetting of preshock
      reentry and/or induction of new reentry. RV- shocks cardioverted primarily via
      deexcitation, which terminated reentry by creating new postshock wavefronts via
      break excitation that rapidly activated excitable gaps. Outcome was dependent on
      the preshock state for both polarities at strengths near the 50% success level.
      Before successful shocks, more epicardium was recovered, resulting in more
      excitation and longer postshock depolarization (RV+ shocks) and faster postshock
      elimination of excitable gaps (RV- shocks). CONCLUSION: These findings provide a
      direct mechanistic link between shock-induced changes in Vm and the effect of
      polarity, strength, and timing on cardioversion efficacy.

PMID- 12475104
TI  - Are we closer to understanding defibrillation in the whole heart?

PMID- 12475105
TI  - Mathematical model of the rapidly activating delayed rectifier potassium current
      I(Kr) in rabbit sinoatrial node.
AB  - INTRODUCTION: A rapidly activating delayed rectifier potassium current (I(Kr)) is
      known to have an important role in determining the properties of spontaneous
      pacing in enzymatically isolated rabbit sinoatrial node (SAN) cells. The
      functional characteristics of I(Kr) are conferred by its dependence on time,
      voltage, and external potassium. The aim of this study was to develop a rigorous
      mathematical representation for I(Kr) based on experimental findings and to
      investigate the role of I(Kr) in the automaticity and intercellular communication
      of SAN cells. METHODS AND RESULTS: A Markov model was developed using available
      experimental data for I(Kr) in rabbit SAN. The dependence of I(Kr) on external
      potassium, [K+]o, was incorporated using data from both in vitro preparations and
      results from heterologous expression experiments for this ether-a-go-go related
      gene product. Our simulation results show the following. (1) I(Kr) is the
      dominant repolarizing current in rabbit SAN cells. (2) Deactivation of I(Kr)
      contributes to the net current change during the early diastolic depolarization
      phase. (3) Inward rectification of I(Kr) results in a decrease in membrane
      resistance during repolarization relative to plateau. (4) The complex [K+]o
      dependence of I(Kr) confers [K+]o insensitivity on isolated cells, which may
      account for the sensitivity of pacing rate to elevated [K+]o at the tissue level.
      CONCLUSION: Model results show that I(Kr) mediates diastolic depolarization by
      the kinetics of its decay and by lowering resistance during late repolarization.
      In elevated [K+]o, increased chord conductance is balanced by the changes in
      kinetics and voltage dependence of I(Kr) so that the pacing rate of single cells
      may be more [K+]o insensitive than expected. In addition, elevated [K+]o
      increases I(Kr) magnitude during repolarization but lowers resistance, so current
      flow through gap junctions is less able to hyperpolarize pacing cells.

PMID- 12475106
TI  - Effect of action potential duration and conduction velocity restitution and their
      spatial dispersion on alternans and the stability of arrhythmias.
AB  - INTRODUCTION: The slope of the action potential duration (APD) restitution curve
      has been used to explain wavebreaks during arrhythmia initiation and maintenance.
      This hypothesis remains incomplete to fully describe the experimental data. Other
      factors contributing to wavebreaks must be studied to further understand
      arrhythmia dynamics. METHODS AND RESULTS: Control APDs were measured from
      isolated rabbit hearts using a monophasic action potential probe. APD and
      conduction velocity (CV) restitution were quantified over the heart surface for
      two drugs, diacetyl monoxime (DAM) and cytochalasin D (CytoD), using a dual
      camera video imaging system. For all pacing intervals: (1) control APDs were
      shorter than for CytoD but longer than for DAM; and (2) CV was greater for CytoD
      compared with DAM. APD dispersion increased as pacing interval decreased for both
      drugs. For DAM, increased dispersion was due to a difference in APD restitution
      between the right and left ventricle. For CytoD, increased dispersion was due to
      discordant alternans, with no significant spatial variation in restitution.
      Fibrillation was sustained only in the control hearts; with DAM, stable reentry
      was sustained with shorter APD and cycle length compared with CytoD for which
      only nonsustained unstable reentry occurred. CONCLUSION: Alternans and arrhythmia
      dynamics are affected by the spatial dispersion of APD restitution as well as CV
      restitution, not simply the slope of APD restitution. Therefore, a direct link of
      the APD restitution slope to alternans and arrhythmia dynamics in rabbit heart
      does not exist. Designing antiarrhythmic drugs to alter only the restitution
      slope may not be appropriate.

PMID- 12475107
TI  - Electrical restitution and ventricular fibrillation: negotiating a slippery
      slope.

PMID- 12475108
TI  - Three-dimensional mapping of right atrial activation during sinus rhythm and its
      relationship to endocardial architecture.
AB  - INTRODUCTION: Previous mapping studies of right atrial (RA) activation during
      sinus rhythm have been limited by the use of epicardial electrode plaques in open
      chest subjects or microelectrodes in the excised heart. This study describes
      global RA endocardial activation patterns using high-density mapping and compares
      the results with underlying endocardial architecture. METHODS AND RESULTS:
      Noncontact mapping of the RA was performed in 21 anesthetized swine. Isopotential
      and isochronal maps were superimposed upon three-dimensional reconstructions of
      RA geometry. Hearts were excised and endocardial dissection performed. Two
      patterns of RA activation were recorded. The site of earliest endocardial
      activation occurred either laterally at a position consistent with the terminal
      crest or superiorly at the junction between the superior caval vein and RA
      appendage. The subsequent spread of depolarization followed the longitudinal
      orientation of muscle fibers. Areas of conduction delay and block were seen at
      the junction between the terminal crest and posterior wall, the cavotricuspid
      isthmus, and around the margins of the triangle of Koch. Endocardial dissection
      at these sites demonstrated complex fiber orientation. A lateral site of earliest
      activation demonstrated a more prominent display of conduction delay or block.
      CONCLUSION: The spread of the sinus impulse follows endocardial myofiber
      orientation and is dictated by the site of earliest activation. Even during sinus
      rhythm, anisotropic conduction results in areas of conduction block or delay.
      These findings have implications in the development of reentrant arrhythmias and
      may influence surgical or electrophysiologic procedures.

PMID- 12475109
TI  - Cryothermic ablation within the coronary sinus of an epicardial posterolateral
      pathway.
AB  - Radiofrequency ablation inside the coronary sinus (CS) is associated with the
      risk of vein stenosis, or perforation or damage to the circumflex artery.
      Cryothermic ablation has proved less harmful, but there are no data on its use
      within a venous structure. A patient with a posterolateral accessory pathway
      underwent several unsuccessful attempts at endocardial ablation. Ablation then
      was performed with cool energy within the CS, where the shortest VA interval and
      a possible Kent potential were recorded. Selective left coronary angiography
      showed a normal circumflex artery and the absence of lesions of the CS. Six
      months later, the patient was asymptomatic without taking antiarrhythmic drugs.
      We conclude that cryoablation within the CS may be effective and safe.

PMID- 12475110
TI  - Ablation of epicardial macroreentrant ventricular tachycardia associated with
      idiopathic nonischemic dilated cardiomyopathy by a percutaneous transthoracic
      approach.
AB  - Characterization of the substrate and mechanism of epicardial ventricular
      tachycardia (VT) associated with idiopathic nonischemic dilated cardiomyopathy is
      limited. We report a case of successful mapping and ablation of an epicardial VT
      by a percutaneous transthoracic approach in a patient with idiopathic dilated
      cardiomyopathy, frequent VT, and previously unsuccessful endocardial ablation.
      Evidence of myocardial scar was limited to the epicardium. Electroanatomic and
      entrainment mapping defined a figure-of-eight macroreentrant circuit within the
      epicardial scar. VT terminated at the onset of low-power radiofrequency
      application to the central isthmus of the circuit. VT was no longer induced and
      did not recur during long-term follow-up.

PMID- 12475111
TI  - Is it safe to program a long tachycardia detection interval?
AB  - Implantable cardioverter defibrillator (ICD) therapy is used frequently in
      patients with "slow" ventricular tachycardia (VT). Hence, the tachycardia
      detection interval is programmed within the range of the physiologic heart rate,
      but this may cause serious problems. If a fast VT is converted to sinus
      tachycardia with a cycle length shorter than the tachycardia detection interval,
      the episode is not terminated and the success counter is not reset. If this
      happens repeatedly, therapies will be exhausted without termination of the
      episode. If VT recurs within such an episode, it will not be treated. This report
      describes a patient who died suddenly in a scenario similar to the one described.
      Although all documented VT/ventricular fibrillation episodes were terminated by
      the device, the episode was not terminated because of the ongoing
      supraventricular tachycardia. Therefore, no further therapies were available and
      the patient probably died of fast untreated VT. Programming of a long tachycardia
      detection interval is dangerous in currently available ICDs.

PMID- 12475112
TI  - Steepness of the restitution curve: a slippery slope?

PMID- 12475113
TI  - Recurrent syncope in a patient with an implantable loop recorder: what is the
      diagnosis?

PMID- 12475114
TI  - Inappropriate defibrillator discharges caused by an unusual interaction between
      an implantable cardioverter defibrillator and a pacemaker.

PMID- 12475115
TI  - Magnetic resonance imaging of arrhythmogenic right ventricular dysplasia.

PMID- 12475116
TI  - Sinus node inhibition during ventricular stimulation.

PMID- 12475118
TI  - Updating the guidelines for pacemaker/defibrillator device implantation: an
      historical perspective and a guide to their interpretation.

PMID- 12475117
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- 12475119
TI  - How liability law affects medical productivity.
AB  - Previous research suggests that "direct" reforms to the liability system-reforms
      designed to reduce the level of compensation to potential claimants-reduce
      medical expenditures without important consequences for patient health outcomes.
      We extend this research by identifying the mechanisms through which reforms
      affect the behavior of health care providers. Although we find that direct
      reforms improve medical productivity primarily by reducing malpractice claims
      rates and compensation conditional on a claim, our results suggest that other
      policies that reduce the time spent and the amount of conflict involved in
      defending against a claim can also reduce defensive practices substantially. In
      addition, we find that "malpractice pressure" has a more significant impact on
      diagnostic rather than therapeutic treatment decisions. Our results provide an
      empirical foundation for simulating the effects of untried malpractice reforms on
      health care expenditures and outcomes, based on their predicted effects on the
      malpractice pressure facing medical providers.

PMID- 12475120
TI  - Why do transplant surgeons turn down organs? A model of the accept/reject
      decision.
AB  - Despite the scarcity of transplantable organs, 45% of livers are rejected by the
      first surgeon to whom they are offered. I present a model in which a surgeon
      decides to accept or reject an organ for a patient based on the patient's current
      health level. Using data on transplanted patients, I show that surgeons' behavior
      is consistent with the solution to an optimal stopping problem in which they
      reject low quality organs for relatively healthy patients in the hope that they
      will receive a better organ offer in the future. I discuss trends in organ
      procurement in light of this finding.

PMID- 12475121
TI  - Should we use willingness to pay to elicit community preferences for health care?
      New evidence from using a 'marginal' approach.
AB  - We describe a willingness to pay (WTP) survey in which values were elicited from
      the public for three disparate health care programmes. Previous applications of
      WTP in this context have revealed a high proportion of preference reversals
      between WTP values and ordinal ranking of the programmes. In view of the doubts
      these findings raise over the use of WTP in this context, our aim was to develop
      a method of eliciting WTP values which we considered would improve consistency
      between respondents' explicit ranking of the programmes and their WTP values.
      Compared to the standard approach, the structure of the new design (the marginal
      approach) reduced the number of possible preference reversals, thus encouraging a
      degree of consistency among respondents. Despite this, the marginal approach did
      not result in fewer preference reversal being observed in actuality, thus casting
      doubt on the application of WTP in this context.

PMID- 12475122
TI  - A lifetime portfolio of risky and risk-free sexual behaviour and the prevalence
      of AIDS.
AB  - A lifetime portfolio of risky and risk-free sexual activities is conceptually
      constructed in this paper. People's time allocation between risky and risk-free
      sexual activities affects, and is affected by, the prevalence of AIDS. A small
      satisfaction differential between risky and risk-free sex can lead to a
      significant prevalence of AIDS. Numerical simulations suggest that the reduction
      in the prevalence of AIDS generated by a 1% improvement in the sensual quality of
      freely distributed condoms can be 0.855% when the initial satisfaction
      differential between risky and risk-free sex is 50% or 0.464% when the initial
      satisfaction differential is 100%.

PMID- 12475123
TI  - Managed competition and consumer price sensitivity in social health insurance.
AB  - This paper examines whether the introduction of managed competition in Dutch
      social health insurance has resulted in effective price competition among
      insurance funds. We find evidence of limited price competition, which may be
      caused by low consumer price sensitivity. Using aggregate panel data from all
      insurance funds over the period 1996-1998, estimated premium elasticities of
      market share are -0.3 for compulsory coverage and -0.8 for supplementary
      coverage. These elasticities are much smaller than in managed competition
      settings in US group insurance. This may be explained by differences in switching
      experience and higher search costs associated with individual insurance.

PMID- 12475124
TI  - The effect of report cards on consumer choice in the health insurance market.
AB  - We test the effect of report cards on consumer choice in the HMO market. Federal
      employees were provided with report cards on a limited basis in 1995 and then on
      a widespread basis in 1996. Exploiting this natural experiment, we find that
      subjective measures of quality and coverage influence plan choices, after
      controlling for plan premiums, expected out of pocket expenses and service
      coverages. The effect is stronger within a small sample of new hires compared to
      a larger sample of existing federal employees. We also find evidence that report
      cards increase the price elasticity of demand for health insurance.

PMID- 12475125
TI  - Multiple payers, commonality and free-riding in health care: Medicare and private
      payers.
AB  - Managed health care plans and providers in the US and elsewhere sell their
      services to multiple payers. For example, the three largest groups of purchasers
      from health plans in the US are employers, Medicaid plans, and Medicare, with the
      first two accounting for over 90% of the total enrollees. In the case of
      hospitals, Medicare is the largest buyer, but it alone only accounts for 40% of
      the total payments. While payers have different objectives and use different
      contracting practices, the plans and providers set some elements of the quality
      in common for all payers. In this paper, we study the interactions between a
      public payer, modeled on Medicare, which sets a price and takes any willing
      provider, a private payer, which limits providers and pays a price on the basis
      of quality, and a provider/plan, in the presence of shared elements of quality.
      The provider compromises in response to divergent incentives from payers. The
      private sector dilutes Medicare payment initiatives, and may, under some
      circumstances, repair Medicare payment policy mistakes. If Medicare behaves
      strategically in the presence of private payers, it can free-ride on the private
      payer and set its prices too low. Our paper has many testable implications,
      including a new hypothesis for why Medicare has failed to gain acceptance of
      health plans in the US.

PMID- 12475126
TI  - Economic implications of antibiotic resistance in a global economy.
AB  - This paper concerns the economic implications of antibiotic resistance in a
      global economy. The global economy consists of several countries, where
      antibiotic consumption creates a stock of bacteria which is resistant to
      antibiotics. This stock affects the welfare in all countries because of the risk
      that resistant bacterial strains may be transmitted. The main purpose of the
      paper is to compare the socially optimal resource allocation with the allocation
      brought forward by the decentralized market economy. In addition, a dynamic
      Pigouvian tax designed to implement the globally optimal resource allocation is
      presented.

PMID- 12475127
TI  - Does alcohol-use increase the risk of sexual intercourse among adolescents?
      Evidence from the NLSY97.
AB  - This study investigates the causal link between alcohol-use and adolescent sexual
      activity. In a recent paper, using data from the 1995 wave of the National
      Longitudinal Study of Adolescent Health, Rees et al. [Journal of Health Economics
      20 (5) (2001)] found little evidence of such a link. The data used here are from
      the National Longitudinal Study of Youth, 1997 (NLSY97), and results indicate
      that alcohol-use increases the probability of sexual intercourse, even after
      accounting for the potential endogeneity. However, consistent with Rees et al.,
      there is less evidence that heavy drinking has a significant effect on sexual
      intercourse.

PMID- 12475128
TI  - Design, material and methods in the NORA study. Nordic Research on Ageing.
AB  - This paper describes the research design of the NORA (Nordic Research on Ageing)
      study carried out in three Nordic localities. Response and participation rates in
      the baseline (age 75) and follow-up (age 80) studies are shown for each locality;
      in addition, the number of dead and censored cases are presented. In Goteborg,
      450 persons were randomly sampled for invitation to the baseline study among all
      persons aged 75 years; in Glostrup, 571 persons aged 75 were selected, and in
      Jyvaskyla all 388 persons aged 75 were selected. Baseline measurements were
      conducted in Jyvaskyla and Glostrup in 1989, and in Goteborg in 1990. The
      participants were first interviewed at home, and afterwards went through tests
      and examinations in a standardized laboratory environment. The follow-up study
      was carried out five years after the baseline study. In Jyvaskyla 92.9% (N=355),
      in Goteborg 82.5% (N=368), and in Glostrup 84.5% (N=480) of the eligible subjects
      took part in the baseline interview; corresponding figures for taking a test at
      the laboratory/clinic of the study center were 77.2% (N=295), 72.4% (N=323) and
      72.4% (N=411). For the follow-up interview, those subjects who took part in the
      baseline interview were considered eligible. The participation rate was 93.6%
      (N=250) in Jyvaskyla, 76.6% (N=226) in Goteborg, and 79.1% (N=277) in Glostrup.
      Corresponding figures for the tests at the study center were 71.5% (N=191), 71.9%
      (N=212) and 59.7% (N=209). The mortality rate was lowest in Goteborg (19.0%), and
      highest in Glostrup (27.2%). The data of the NORA study enables various types of
      descriptions and comparisons to be made across localities and measurement
      occasions.

PMID- 12475129
TI  - Muscle strength as a predictor of onset of ADL dependence in people aged 75
      years.
AB  - The aim of this prospective study over 5 years was to examine maximal isometric
      strength of multiple muscle groups as a predictor of losing independence in
      activities of daily living (ADL). The participants were from the Nordic Research
      on Aging (NORA75). These analyses are restricted to 567 people who at baseline
      were independent in ADL and participated in strength tests, and who five years
      later participated in follow-up ADL assessments. Tests on maximal isometric
      strength of hand grip, elbow flexion, knee extension and trunk flexion and
      extension were done using adjustable dynamometers. For each muscle group tested,
      three equal groups were formed for men and women separately based on
      distributions of results. Those who reported being unable or needing help for
      eating, dressing, bathing, toileting, walking indoors or transferring from a bed
      or a chair were rated as ADL dependent. Of the 227 initially ADL independent men,
      21 (9.3%) became dependent in ADL. In women, the figures were 30 (8.8%) of 340.
      Multiple logistic regression models were used to predict the risk of ADL
      dependence in groups based on strength tertiles. After confirming that the
      association of muscle strength and incident ADL-dependence was similar in men and
      women, both genders were included in the same analyses adjusted for body weight
      and height, gender and research locality. Gender specific cut-offs were used for
      strength tertiles. All the strength tests predicted ADL dependence, with those
      being in the lowest tertile having two to three times greater risks than those in
      the highest tertile of strength. Further adjustments for chronic diseases did not
      materially change the results. Strength tests could be used to identify people
      who are still independent in ADL but who are at increased risk of becoming
      dependent because of poor muscle strength, and who could reduce their risk by
      strengthening exercises.

PMID- 12475130
TI  - Depressed mood: changes during a five-year follow-up in 75-year-old men and women
      in three Nordic localities.
AB  - The aim of the study was to look firstly at the changes that occurred in
      depressive symptomatology over a 5-year period among originally 75-year-old
      residents in three Nordic localities: Glostrup in Denmark, Goteborg in Sweden and
      Jyvaskyla in Finland, and secondly, at some selected variables if they predicted
      depressed mood in this study. The study is a part of a 5-year follow-up of the
      Nordic comparative NORA study on functional capacity. A 5-year follow-up was
      carried out with the survivors in 1994. Depressive symptomatology was assessed by
      the Center for Epidemiologic Studies Depression Scale (CES-D). The number of
      survivors was 277 in Glostrup, 226 In Goteborg and 250 in Jyvaskyla. The
      proportion of respondents with depressive symptoms was highest in Jyvaskyla; this
      was true for both men and women at baseline and at the follow-up. In the baseline
      study, minor depression was more common among women than men in all three
      localities, and at the follow-up in Goteborg and Glostrup. In the follow-up
      study, men and women in Jyvaskyla scored higher means on the CES-D scale than did
      the groups in Goteborg and Glostrup. During the follow-up, there was no
      significant change in the mean score describing depressed mood (CES-D total
      scale) in any locality in either men or women. The mean score of those who died
      during the follow-up period differed significantly from the score of survivors
      among women in Goteborg and in Glostrup. The most clear predictors for depressed
      mood in this Nordic 5-year follow-up study were chronic diseases, feelings of
      loneliness, and self-rated health.

PMID- 12475131
TI  - Changes in cognitive functioning from 75 to 80 years of age: a 5-year follow-up
      in two Nordic localities.
AB  - The purpose of the study was to analyze changes and stability in cognitive
      functions among older persons aged from 75 to 80 years, as well as differences in
      this development between two Nordic localities. The number of subjects taking
      part in the follow-up phase was 188 in Jyvaskyla, Finland, and 184 in Goteborg,
      Sweden. Cognitive functions were assessed using conventional memory tests (Digit
      Span Forward and Backward for assessing primary working memory; Visual
      Reproduction for visual memory) and intelligence tests (Digit Symbol for
      assessing psychomotor speed; Word Fluency for verbal ability; Raven's Matrices
      for non-verbal reasoning). With few exceptions, the mean test scores declined
      significantly among the retested men and women in both localities. Analyses
      showed that generally over half of the subjects maintained their level of
      performance over the 5-year period, while a part of the deteriorating minority
      had a steep decline. There were significant differences in the test performance
      between the localities both at the baseline and follow-up assessments, but few
      differences between women and men. On the whole, however, the groups of older
      women and men from the two Nordic localities had a similar pattern of cognitive
      development from 75 to 80 years of age.

PMID- 12475132
TI  - Postural balance in elderly people: changes over a five-year follow-up and its
      predictive value for survival.
AB  - Postural balance in three test conditions (normal standing with eyes open, normal
      standing with eyes closed, and tandem standing with eyes open) was measured in
      samples of 75-year-old men and women (N=757) living in three Nordic localities
      (Glostrup in Denmark, Goteborg in Sweden, and Jyvaskyla in Finland). The subjects
      were re-tested five years later when they had reached the age of 80 years
      (N=434). The results showed a highly significant longitudinal decline in
      balancing abilities in all localities and in both sexes. The longitudinal change
      was larger than suggested by cross-sectional comparisons. On both occasions women
      showed better results in the balance tests than men in all three localities.
      Inter-locality differences observed at baseline (somewhat poorer performance
      among the subjects from Goteborg) largely remained during the follow-up. The
      simplest balance test, normal standing with eyes open, was also a significant
      predictor for survival over the 5-year follow-up: the results at baseline were
      poorer in those subjects who died during the follow-up than in the survivors. It
      is concluded that postural balance deteriorates markedly from 75 to 80 years of
      age; at high ages a poor performance in balance tests may also indicate below
      average survival.

PMID- 12475133
TI  - The incidence of mobility restrictions among elderly people in two Nordic
      localities. A five-year follow-up.
AB  - The aim of this study was to investigate the incidence of limitations in self
      reported mobility as well as the decline in measured walking speed and stair
      mounting ability over five years among men and women aged 75 at baseline in two
      Nordic localities. Another purpose was to analyze the relationship and its
      consistency over time between self-reports and performance-based measures in the
      decline of mobility. Identical Interviews and performance tests were carried out
      in Jyaskyla, Finland (N=244) and Glostrup, Denmark (N=275) at baseline and five
      years later. The subjects were asked about their ability to manage with
      transferring from chair or bed, walking indoors and outdoors and climbing stairs.
      The occurrence of new limitations in these tasks was analyzed among those who did
      not report limitations in the same task at baseline. Maximal walking speed and
      step-mounting height were measured in the laboratory. The decline in walking
      speed below 1.2 m/s and stair-mounting height below 30 cm was analyzed among
      those whose results were, initially, above these limits. Most frequently, new
      limitations occurred in walking outdoors and in climbing stairs (44-60%). Walking
      speed and stair-mounting ability deteriorated below the thresholds mentioned in 4
      36% of the participants, depending on gender and locality. There were only minor
      differences between the two Nordic localities in the decline in mobility
      functions. A substantial proportion of those whose performance had declined had
      developed limitations in self-reported mobility as well. However, the
      relationship between different methods of measurement was not straightforward.
      This indicates that multiple approaches are needed to obtain thorough knowledge
      about mobility and its decline among elderly people.

PMID- 12475134
TI  - Changes in social relations in old age. Are they influenced by functional
      ability?
AB  - The aims of this article were to describe changes in social relations from ages
      75 to 80, and analyze whether changes in social relations are influenced by
      functional ability at age 75. The study includes data from the NORA follow-up
      study of 75-80 year-old men and women in Jyvaskyla (Finland), Goteborg (Sweden)
      and Glostrup (Denmark). The present analyses include the 743 persons who
      participated in both studies and who answered the questions about social
      relations. The structure of social relations was measured by: 1) frequency of
      contacts with children, grand/greatgrandchildren, relatives, close friends,
      acquaintances, and neighbors; 2) diversity of social relations (number of types
      of social contacts); 3) telephone contacts; and 4) social participation. The
      function of social relations was measured by instrumental social support.
      Functional ability was measured by tiredness and need for help in Physical
      Activities of Daily Living (PADL). Depressive symptoms, living alone and locality
      were included as covariates in the multivariate analyses. There were large
      changes in social relations in old age, but the changes included widely varying
      patterns of losses and gains among the participants. Women who felt tired in
      their daily activities had more sustained little contact with children [OR=4.2
      (1.4-12.1)] and more sustained little diversity in social relations [OR=2.2 (0.95
      5.3)]. Both men and women in need of help had more sustained little diversity in
      social relations compared to the well-functioning persons [men: OR=4.4 (1.3
      15.0); women: OR=3.0 (0.93-9.6)].

PMID- 12475135
TI  - Changes in household composition as determinant of changes in functional ability
      among old men and women.
AB  - The aims of this article were 1) to describe changes in functional ability from
      ages 75 to 80 among men and women in three Nordic localities, and 2) to analyze
      whether these changes are determined by changes in household composition from
      ages 70 to 75. The present analyses include the persons who participated in the
      NORA follow-up study of 75-80 year-old men and women in Jyvaskyla, Finland
      (N=243), Goteborg, Sweden (N=226), and Glostrup, Denmark (N=274). Functional
      ability was measured by tiredness and need for help in Physical and Instrumental
      Activities of Daily Living (PADL and IADL). Changes in functional ability are
      described as 1) sustained good, 2) decreased, 3) improved, and 4) sustained poor,
      and changes in household composition as 1) sustained living alone, 2) from living
      with others to living alone, and 3) sustained living with others. Number of
      chronic diseases and home help were included as covariates in the multivariate
      analyses. A large proportion of men and women had sustained good functional
      ability from age 75 to 80, but we observed both improvement and deterioration
      over time. For example, with regard to need for help in PADL: 64/59% of the
      mer/women had sustained good function, 19/21% deteriorated, 3/6% improved, and
      14/14% had sustained poor function. Among the women in need of help at age 75,
      those who lived alone/became alone had a higher risk of sustained need for help
      from age 75 to 80 compared to women who lived with others [adjusted OR=4.0 (1.3
      12.2/4.4 (0.7-26.9)]. This was not seen among the poor-functioning men. It is
      concluded that poor-functioning, single-living women are at higher risk of not
      regaining functional ability compared to cohabiting women.

PMID- 12475136
TI  - Health behaviors in elderly people. A 5-year follow-up of 75-year-old people
      living in three Nordic localities. Smoking, physical activity, alcohol
      consumption, and healthy eating, and attitudes to their importance.
AB  - Few studies about health behavior among elderly persons in the Nordic countries
      are available, and our knowledge about longitudinal changes is especially
      limited. The purpose of this study was to assess the prevalence of selected
      health behaviors as reported at age 75 years in Finland, Sweden and Denmark
      together with answers regarding attitudes to such habits, and study longitudinal
      changes between 75 and 80 years. The study population included 499 men and 704
      women born in 1914/15 and examined in 1989/90 in Jyvaskyla (Finland), Goteborg
      (Sweden), and Glostrup (Denmark). Survivors were re-examined in 1994/95. A self
      administered validated questionnaire developed from the Danish Nationwide Health
      Surveys was given to the participants during a home visit and checked when the
      subjects came to the laboratory examination. The Danes had the highest proportion
      of smokers and persons with daily alcoholic beverage consumption and the smallest
      proportion of healthy eaters, but the Swedes had the most sedentary life-style.
      Women had the healthiest life-style. Between ages 75 and 80 years, the proportion
      of participants who tried to improve their health decreased, but there was no
      change in believing the importance of one's own effort in maintaining health. The
      free-time physical activity decreased, but there was no change in the attitude
      towards physical activity. There were major cross-national differences among the
      three Nordic localities, but the health behaviors were rather stable, though the
      proportion of participants who tried to improve their health decreased. Not more
      than 60 to 70% of the subjects believed that their own efforts are important to
      health.

PMID- 12475137
TI  - Physical activity and mortality of 75-year-old people in three Nordic localities:
      a five-year follow-up.
AB  - The purpose of this 5-year follow-up study was to investigate the relationship
      between physical activity and mortality in persons aged 75 in three Nordic
      localities. The study is part of the common NOrdic Research project on Ageing
      (NORA). The samples consisted of 221 men and 259 women in Glostrup, Denmark, 159
      men and 209 women in Goteborg, Sweden, and 119 men and 236 women in Jyvaskyla,
      Finland. Physical activity was measured with a self-report questionnaire, from
      which a dichotomous explanatory variable was created for the subsequent analysis.
      Covariates examined in this study were smoking, use of alcohol and the presence
      of cardiovascular diseases. Baseline measurements were conducted in Glostrup and
      Jyvaskyla in 1989, and a year later in Goteborg. Mortality data was collected
      from the mortality registry in each country. The follow-up period was 5 years.
      Fisher's exact test, Cox regression and Kaplan-Meier survival analysis were used
      in the statistical analysis of the data. The results showed that when physical
      activity alone was considered, inactivity was associated with an increased
      mortality risk in all groups except for the men in Jyvaskyla. Of the covariates,
      only smoking and cardiovascular diseases were found to be associated with
      increased mortality risk and only among the women in Goteborg and Jyvaskyla,
      respectively. When the effect of physical activity on mortality was analyzed
      together with the covariates, the relationship between physical inactivity and
      increased mortality risk remained significant in all groups except for the men in
      Jyvaskyla. In addition to this, smoking remained a significant predictor of
      mortality for women in Goteborg, and the effect of cardiovascular diseases for
      women in Jyvaskyla was nearly significant. The results showed that being
      physically active predicted survival for persons aged 75 during the follow-up
      period in all three localities.

PMID- 12475138
TI  - Leo Tolstoy, TB in Russia, and American perceptions.

PMID- 12475139
TI  - Smoking and tuberculosis: an association overlooked.
AB  - OBJECTIVES: This article discusses the role of smoking as a risk factor for
      tuberculosis. A review of the evidence that has been documented is presented.
      DATA SOURCES: Relevant articles in the medical literature derived from searching
      the Medline database (1966 to present) with key terms 'smoking' and
      'tuberculosis'. The bibliographies of all papers thus located were searched for
      further relevant articles. RESULTS: On searching the database, a total of 12
      studies were found. A search of the bibliographies yielded four more articles.
      Sixteen studies published between 1956 to the present were included in this
      review. The evidence suggests that smoking could be considered as an important
      risk factor for the development of tuberculosis. Not only does active smoking
      appear to heighten the chances of contracting pulmonary tuberculosis, smokers
      also seem to be at an increased risk for extrapulmonary tuberculosis. Exposure to
      environmental tobacco smoke in children seems to enhance the hazards of acquiring
      tuberculosis. Increased tuberculin reactivity, in a dose-dependent manner, was
      recorded in smokers as compared to non-smokers. CONCLUSIONS: Although an
      association between smoking and tuberculosis appears evident, prospective studies
      would help to confirm the evidence and to highlight this noxious association.
      Nevertheless, smoking should be considered as an important risk factor for
      tuberculosis.

PMID- 12475140
TI  - Treatment of isoniazid-resistant tuberculosis with isoniazid, rifampin,
      ethambutol, and pyrazinamide for 6 months.
AB  - SETTING: In 1992 the Seattle-King County Department of Public Health Tuberculosis
      Clinic began to treat patients with isoniazid-resistant tuberculosis with a
      regimen of isoniazid, rifampin, pyrazinamide, and ethambutol daily for 6 months.
      OBJECTIVE: To conduct a review of clinical and bacteriological outcomes of
      treatment for patients who received the four-drug, 6-month regimen for isoniazid
      resistant tuberculosis. DESIGN: A retrospective review of medical records of TB
      cases meeting the study criteria, a Mycobacterium tuberculosis isolate resistant
      to isoniazid, and intent to treat with a 6-month course of isoniazid, rifampin,
      pyrazinamide, and ethambutol. RESULTS: Through December 1999, 44 consecutive
      patients with isoniazid-resistant, rifampin-susceptible tuberculosis were started
      on the four-drug, 6-month daily regimen. Among 42 patients followed until
      completion of therapy, three required changes in the regimen due to side effects.
      There was one case of drug-induced hepatotoxicity. Among 39 patients with
      pulmonary involvement, 37 converted sputum cultures from positive to negative
      within 2 months of starting treatment. There were no treatment failures. On
      passive follow-up of at least 2 years on all patients, two patients relapsed. The
      single patient with bacteriological relapse did not develop further drug
      resistance. CONCLUSION: The regimen of isoniazid, rifampin, pyrazinamide, and
      ethambutol given daily for 6 months produced successful outcomes when used in a
      public health tuberculosis clinic as routine therapy for isoniazid-resistant
      tuberculosis.

PMID- 12475141
TI  - A low cost, home-made, reverse-line blot hybridisation assay for rapid detection
      of rifampicin resistance in Mycobacterium tuberculosis.
AB  - SETTING: Cetrangolo Hospital, Vicente Lopez, Argentina, 1995-1999. OBJECTIVE: To
      describe a home-made reverse-line blot hybridisation assay for the detection of
      rifampicin resistance-associated mutations in the rpoB gene of Mycobacterium
      tuberculosis, and to evaluate the usefulness of this rifampicin oligonucleotide,
      or 'RIFO' assay, to predict rifampicin resistance. DESIGN: A total of 135 M.
      tuberculosis isolates from the Cetrangolo Hospital were tested using the RIFO
      assay, the proportion method and the Mycobacterial Growth Indicator Tube (MGIT
      960). In addition, 120 drug-susceptible isolates from the Netherlands were
      included. RESULTS: The results obtained with the proportion method and the MGIT
      960 system were in full agreement. In the RIFO assay, 90 of the 97 rifampicin
      resistant isolates were correctly identified (sensitivity 92.8%, positive
      predictive value 100%). All of the drug-susceptible isolates were correctly
      predicted by the RIFO assay. CONCLUSIONS: With this home-made molecular test,
      rifampicin resistance in M. tuberculosis can be predicted in colonies isolated in
      culture in only 1 day, and can therefore shorten the laboratory turn around time
      for rifampicin susceptibility testing by weeks. In principle the test can also be
      applied directly to Zichl-Neelsen slides and clinical material, as has been
      demonstrated for another reverse-line blot-based assay for M. tuberculosis,
      spoligotyping.

PMID- 12475142
TI  - Analysis of tuberculosis surveillance in Hungary in 2000.
AB  - SETTING: Hungary, Central Europe, with a population of 10.3 million living in 20
      administrative districts (19 counties and the capital). OBJECTIVE: To summarize
      the results of the first year of the revised National Tuberculosis Surveillance
      System. DESIGN: Retrospective survey of the National Tuberculosis Surveillance
      Center (NTSC) database. METHODS: Analysis of data on all tuberculosis cases
      reported to the NTSC in 2000. Drug susceptibility results were evaluated in line
      with WHO and IUATLD definitions. RESULTS: During 2000, a total of 3598 patients
      with tuberculosis were reported. Only 40% of these were bacteriologically
      confirmed. Although susceptibility testing has been required for previously
      untreated culture-positive cases, only 801 (67.8% of the bacteriologically
      confirmed cases) were tested in 2000. Drug resistance was detected in 10.7% of
      previously untreated and in 23.5% of previously treated patients. Multidrug
      resistant (MDR) cases were not common: only 1.5% of the isolates from previously
      untreated patients and 4.9% of those from previously treated patients were MDR.
      CONCLUSIONS: The results suggest that the NTSC should work towards increasing the
      numbers of cases that are bacteriologically confirmed. In addition, some form of
      surveillance system should be instituted to ensure that mandatory susceptibility
      testing is performed on all isolates from previously untreated tuberculosis
      patients.

PMID- 12475143
TI  - The impact of national health insurance on the notification of tuberculosis in
      Taiwan.
AB  - SETTING: General notification of tuberculosis in Taiwan. OBJECTIVES: To ensure
      the completeness of notification of tuberculosis (TB) in Taiwan, the Bureau of
      National Health Insurance (NHI) introduced two policies in 1997: 1) the no
      notification-no-reimbursement (NNNR) policy, and 2) the notification-fee (NF)
      policy. The goals of this study were to investigate the impact of the NNNR and NF
      policies on notification of TB. DESIGN: Review of all cases notified to the
      National TB Register from 1995 to 1999 to determine calendar trend, type of case
      and source of notification. RESULTS: There were 11,453 and 13,612 reported cases
      in 1995 and 1996, respectively. Following the implementation of the NHI policies,
      there was a 47% increase in 1997, with 20 021 reported cases. Quarterly reporting
      of cases reached a historic peak in the third quarter of 1997. The increase in
      reported cases was mainly from general hospitals/clinics. Since 1998, the number
      of reported cases has declined steadily, at a rate of 7% and 3% in 1998 and 1999,
      respectively. CONCLUSIONS: The NNNR and NF policies had a significant impact on
      notification of TB in Taiwan. These policies substantially improved completeness
      of reporting, an observation with implications for surveillance of other reported
      diseases.

PMID- 12475144
TI  - Tuberculosis in east timorese refugees: implications for health care needs in
      East Timor.
AB  - SETTING: East Timorese refugees evacuated to Darwin, Australia, September 1999.
      OBJECTIVE: Presentation of the process and results of tuberculosis (TB) screening
      in a previously unscreened refugee population. DESIGN: Screening for TB by
      clinical examination (all persons) and chest X-ray (CXR) (persons over 12 years
      of age and those of any age with respiratory symptoms) and sputum microscopy and
      mycobacterial culture (abnormal CXR). RESULTS: Seventy-six patients were
      diagnosed with TB (38 culture-positive for Mycobacterium tuberculosis, including
      11 sputum smear-positive). Of 89 positive mycobacterial cultures, 51 were non
      tuberculous mycobacteria (NTM). Of the M. tuberculosis isolates, 82.2% were fully
      sensitive, 17.2% were resistant to isoniazid and 8.6% were resistant to isoniazid
      and streptomycin. Fifty-three consecutively diagnosed patients with TB were HIV
      negative. The TB burden in this population was very high (point prevalence of
      542/100,000 for smear-positive and 2,060/100,000 for culture-positive cases).
      Rates of culture for NTM were also high. Information from this study assisted the
      implementation of a National TB Control Programme for East Timor in February
      2000. CONCLUSION: The challenges for public health authorities in East Timor to
      provide a successful TB control programme are enormous. The apparently low
      prevalence of drug resistance and HIV co-infection in the population is
      encouraging.

PMID- 12475145
TI  - Prevalence of pulmonary tuberculosis among HIV-infected persons in a home care
      program in Phnom Penh, Cambodia.
AB  - SETTING: Phnom Penh, Cambodia. OBJECTIVE: To determine the burden of active
      pulmonary tuberculosis among an HIV-infected cohort and the proportion of drug
      resistant strains, using active case-finding adapted to a home care setting.
      DESIGN: Cross-sectional study. Measures include the prevalence of culture
      confirmed Mycobacterium tuberculosis, utilizing a single spot sputum specimen;
      the proportion of pulmonary TB, detected and undetected; proportion of cases
      resistant to isoniazid, rifampicin, ethambutol, streptomycin; and the diagnostic
      value of symptoms. RESULTS: Of 441 persons surveyed, 41 (9%) had active pulmonary
      TB by culture; 29 were smear-positive (71%), and only one case was on treatment.
      The total burden of pulmonary TB was 12% (54/441), with a ratio of undetected to
      detected cases of 3:1. Primary isoniazid resistance was detected in six new cases
      (15%); no MDR-TB was identified. Symptoms were not predictive of active pulmonary
      disease. Mortality was high among those not surveyed (20%) and those found to
      have TB (49%). CONCLUSIONS: Tuberculosis is epidemic in this HIV-infected
      population. Active case-finding yielded three times the number of cases already
      detected and should be considered where resources allow. However, effective
      passive case detection and improved coordination of TB and HIV care programs are
      required to address HIV-associated TB morbidity and mortality.

PMID- 12475146
TI  - Risk factors for hepatotoxicity associated with rifampin and pyrazinamide for the
      treatment of latent tuberculosis infection: experience from three public health
      tuberculosis clinics.
AB  - SETTING: Three municipal tuberculosis (TB) clinics. OBJECTIVES: Reports of liver
      injury in patients treated with a 2-month regimen of daily rifampin and
      pyrazinamide (2RZ) for latent TB infection have raised concern about its safety.
      We aimed to evaluate the safety and tolerability of 2RZ and identify risk factors
      for hepatotoxicity. METHODS: We reviewed charts of adults started on 2RZ between
      1999 and 2001. Cases with grade 3 hepatotoxicity (AST or ALT >5.0-20.0 x upper
      limit of normal) and grade 4 hepatotoxicity (AST or ALT >20.0 x upper limit of
      normal) were identified. RESULTS: Of 148 patients prescribed 2RZ, 85 (57.4%)
      completed therapy. Grade 3 or 4 hepatotoxicity occurred in 14 patients (eight
      grade 4 cases). In multivariate analysis, hepatotoxicity was associated with
      female sex (odds ratio [OR] 4.1; 95% confidence interval [CI] 1.2-14.3) and with
      presumed recent infection (recent tuberculin skin test conversion or contact with
      a TB case) (OR 14.3; 95%CI 1.8-115), but not with alcohol use, illicit drug use,
      age, race, or pyrazinamide dose. CONCLUSIONS: Hepatotoxicity occurred in a high
      proportion of patients prescribed 2RZ, and was more common among females and
      those with recent infection. Caution is warranted in using 2RZ in populations
      where its safety has not been established.

PMID- 12475147
TI  - Historic and recent events contribute to the disease dynamics of Beijing-like
      Mycobacterium tuberculosis isolates in a high incidence region.
AB  - SETTING: A retrospective study in an urban setting with a high tuberculosis
      incidence. OBJECTIVE: To study the molecular epidemiology and disease dynamics of
      a prevalent Mycobacterium tuberculosis strain family, F29, a subset of the
      Beijing strains. DESIGN: Multi-locus DNA fingerprinting and genomic analysis was
      used to characterise F29 isolates. Demographic and molecular epidemiologic data
      were correlated with those of other isolates from the setting. The geographic
      locations of five F29 strain clusters were plotted using a geographic information
      system (GIS) and an index for geographic distribution was calculated. Their
      cumulative temporal occurrence was also plotted. RESULTS: The genomic similarity
      of F29 to the Beijing-strains was confirmed. A high degree of clustering
      predicted high disease transmission. Spatial distribution was mostly widespread
      except for one cluster. Smaller foci of transmission were observed. The temporal
      spread showed ongoing transmission. CONCLUSION: F29 belongs to the Beijing strain
      group. The prevalence and high degree of strain clustering, with limited
      geographic clustering, indicates that F29 strains are endemic in the study
      community. However, recent epidemiologic events also contributed to the disease
      spread. The combination of molecular epidemiologic, spatial and temporal data has
      enhanced our understanding of the disease dynamics of Beijing strains in our
      study community.

PMID- 12475148
TI  - Is there a value of mantoux test and erythrocyte sedimentation rate in pre
      employment screening of health care workers for tuberculosis in a high prevalence
      country?
AB  - SETTING: Pre-employment screening of health care workers (HCWs) is practiced
      widely. Research needs to be carried out to evaluate the screening procedure in
      developing countries. OBJECTIVE: To evaluate the efficacy of Mantoux test and
      erythrocyte sedimentation rate (ESR) for the diagnosis of active tuberculosis
      (TB), in pre-employment screening of HCWs, in a high prevalence country. DESIGN:
      Pre-employment screening of all new employees was reviewed from June to September
      2000. The screening consisted of history, physical examination, blood and urine
      tests, Mantoux test and a chest radiograph. Patients with clinical, laboratory or
      radiological features suggestive of active TB were referred to a specialist.
      RESULTS: Out of 207 employees, a Mantoux reaction of > or = 10 mm and ESR of > or
      = 25 mm/first hour was noted in 90 (43.5%) and 21 (10.1%), respectively. One
      person had symptoms suggestive of TB and was already on anti-tuberculosis therapy
      at the time of screening. All other employees were asymptomatic. Based on
      radiographic findings, four (2%) cases were referred and one was given anti
      tuberculosis therapy. An additional 48 (23.1%) employees were referred on the
      basis of positive Mantoux or elevated ESR; none were found to have active TB.
      CONCLUSION: In high prevalence countries use of Mantoux test and ESR in pre
      employment screening of HCWs is not recommended for detection of active TB.

PMID- 12475149
TI  - Dose related pharmacokinetics of ofloxacin in healthy volunteers.
AB  - OBJECTIVE: To evaluate the pharmacokinetic profile of ofloxacin in healthy
      volunteers after single oral doses of 600 and 800 mg. DESIGN: Seven healthy
      volunteers were administered 600 and 800 mg of ofloxacin on two occasions with an
      interval of one week. Paired samples of blood and saliva were collected after 1,
      2, 3, 6, 9, 12, 24, 32 and 48 hours post-dose. Urine samples were collected over
      a period of 0-6, 6-12 and 12-24 hours. Concentrations of ofloxacin in plasma,
      saliva and urine were assayed by high performance liquid chromatography. RESULTS:
      Increases of 22% in peak plasma concentration (Cmax) and 40% in area under the
      concentration-time curve (AUC0-24) were observed with the 800 mg dose. The other
      parameters, namely time to attain Cmax, half-life, the apparent volume of
      distribution, plasma and renal clearance and percentage of dose excreted in urine
      over 24 hours were independent of doses. The mean ratios of the concentration in
      saliva to the concentration in plasma ranged from 0.4-0.6, and the correlation
      coefficient was 0.94. CONCLUSIONS: Dose proportionality was observed in Cmax and
      AUC0-24 when 600 and 800 mg doses of ofloxacin were given. Ofloxacin determined
      in saliva seems to be suitable for therapeutic drug monitoring.

PMID- 12475150
TI  - Humoral immune response against 38-kDa and 16-kDa mycobacterial antigens in bone
      and joint tuberculosis.
AB  - SETTING: The diagnosis of bone and joint tuberculosis (BTB) is difficult, and
      diagnostic delays often occur. A reliable serological test detecting anti
      mycobacterial antibodies would thus be of some use in this form of the disease.
      OBJECTIVE: To evaluate the diagnostic accuracy of an assay detecting IgG against
      38-kDa and 16-kDa recombinant mycobacterial antigens in BTB. MATERIALS AND
      METHODS: In a prospective study, serum samples from 124 subjects were examined:
      30 BTB cases, 40 non-specific bone and joint infection patients (NSBI), 30 lung
      cancer patients (LC), and 24 healthy volunteers (HC). An ELISA-based test
      (Pathozyme TB complex plus) was used. RESULTS: The cut-off level was established
      at 150 U/ml according to receiver operating characteristic (ROC) curves. The
      quantified level of sensitivity of the test detecting BTB was 56%, at a
      specificity of 99%. The positive and negative predictive values were respectively
      94% and 88%. Mean IgG level in the BTB group was 470 +/- 761 U/ml (mean +/- SD),
      and was significantly higher than the antibody level in the control groups (NSBI
      58 +/- 42 U/ml, LC 43 +/- 38 U/ml, HC 40 +/- 29 U/ml). CONCLUSION: The test
      presents an acceptable level of sensitivity and very good specificity in the
      diagnosis of BTB, and can be used in combination with other methods to increase
      diagnostic accuracy in this disease.

PMID- 12475151
TI  - Fixed-dose combination chemotherapy (Rifater/Rifinah) for active pulmonary
      tuberculosis in Taiwan: a two-year follow-up.
AB  - SETTING: Veterans General Hospital-Taipei, Taiwan. OBJECTIVE: To assess the
      efficacy and safety of a fixed-dose combination (FDC) of Rifater (RFT)/Rifinah
      (RFN) in the treatment of newly diagnosed smear-positive pulmonary tuberculosis.
      DESIGN: Patients were randomly assigned to two 6-month short-course chemotherapy
      regimens. One group of patients was treated with FDCs and another was given the
      four component drugs (INH, RMP, EMB and PZA) as separate formulations. RESULTS:
      The 105 patients enrolled in the study were divided into two treatment groups.
      Fifty-one patients who had completed treatment without interruption, 26 in the
      FDC group and 25 in the separate regimen, were eligible for analysis at the end
      of 2 years. Among the patients with a drug susceptibility test result available,
      four in the FDC group had bacilli resistant to pyrazinamide. In the separate
      regimen group, two patients had bacilli resistant to ethambutol and six had
      bacilli resistant to pyrazinamide. The two regimens were of similar effectiveness
      with regard to sputum conversion, compliance and radiological improvement. No
      patient with FDC treatment developed gastointestinal symptoms, visual disturbance
      or peripheral neuropathy (P < 0.05). However, FDC treatment resulted in drug
      induced fever in one patient. One patient (3.8%) in the FDC group relapsed 5
      months after completing treatment. CONCLUSION: This study suggests that the two
      regimens had similar effectiveness in the treatment of smear-positive pulmonary
      tuberculosis. However, the fewer adverse drug events among those patients treated
      with the FDC regimen suggests that it has a better safety profile.

PMID- 12475152
TI  - Drug-resistant tuberculosis in India.

PMID- 12475153
TI  - Cardiac hydatid cyst in a patient with pulmonary tuberculosis.

PMID- 12475154
TI  - Prosthodontics in the third millennium.

PMID- 12475155
TI  - Finite element analysis studies of a metal-ceramic crown on a first premolar
      tooth.
AB  - PURPOSE: This study examined the stresses developed during loading in a first
      premolar metal-ceramic crown made of different metal cores, and used them to
      anticipate the locations and form of the most likely failure modes. The maximum
      principal stresses in the porcelain are indicators of fracture, and the von Mises
      stresses in the metal core are indicators of the location of yielding. MATERIALS
      AND METHODS: Two-dimensional axisymmetric models with different core metals were
      analyzed using finite element analyses. An axial load of 600 N was applied
      vertically downward, over a circular area around the crown's fissure. RESULTS:
      The peak maximum principal tensile stress in the porcelain existed on the surface
      of the crown, partially outside the cusp, with the greatest peak in the gold
      porcelain system (15.8 MPa). An inverse relationship between the peak maximum
      principal tensile stress of each system and the elastic modulus of each core
      material was found. According to evaluation of the critical flaw size for each
      system, even a crack completely through the thickness of the porcelain was not
      critical. The maximum von Mises stress existed in the metal coping, on the radial
      edge at the axial/occlusal line angle, with the highest maximum in the nickel
      chromium system (143.9 MPa). There existed a proportional relationship between
      the maximum von Mises stress in each metal and their respective elastic moduli.
      All maximums were well below the yield strength of the metal alloys used.
      CONCLUSION: A greater understanding of the influence of an axial load on the
      resulting stresses has been achieved, showing that the phenomena of fracture and
      yielding are unlikely for the crown experiencing this axial load.

PMID- 12475156
TI  - Evaluation of a newly developed visual shade-matching apparatus.
AB  - PURPOSE: This study evaluated a newly developed visual shade-matching apparatus,
      Shademat Visual+, as well as the influence of tab arrangement, clinician gender,
      and years in practice on shade-matching quality. MATERIALS AND METHODS: A group
      of 129 color-normal evaluators-dental students and general dentists-matched the
      shade of four ceramometal crowns using the Vitapan Classical shade guide. Crowns
      were positioned onto the upper member of an artificial head and fastened to the
      headrest of the dental chair or Shademat Visual+. Shade tabs were arranged
      according to the manufacturer's suggestion or according to deltaE* in relation to
      the "lightest" tab and divided into groups (alternative arrangement). The
      evaluators matched the shade of four ceramometal crowns both in daylight and
      using the Shademat Visual+ artificial light source. The color coordinates were
      determined using digital image analysis. Based on deltaE* values, each shade
      matching result was ranked from 1 (the worst match) to 16 (the best match)
      points. RESULTS: The evaluators achieved a better result in Shademat Visual+
      trials than in daylight trials (13.2 points vs 12.4 points; P < .001). For the
      same ceramometal crown, 12.7 points were recorded in daylight trials with the
      manufacturer-suggested arrangement, and 13.7 were recorded with the alternative
      arrangement (P< .001). Corresponding values for Shademat Visual+ trials were 13.6
      points and 14.6 points, respectively (P< .001). Female-male and student-dentist
      evaluator differences were not significant. CONCLUSION: The Shademat Visual+
      apparatus enabled better shade-matching results than daylight. The alternative
      tab arrangement enabled better results than the manufacturer-suggested one.
      Gender and years in practice did not influence shade-matching quality.

PMID- 12475157
TI  - Bonding of silicone prosthetic elastomers to three different denture resins.
AB  - PURPOSE: The aim of this study was to evaluate the interfacial bond strength
      between different types of silicone facial elastomers and denture resins.
      MATERIALS AND METHODS: The facial materials studied were Cosmesil and Ideal,
      whereas SR 3/60, SR 3/60 Quick, and Triad were included in the denture resins
      group. The "overlap-joint" model was used to evaluate the bond strength, and the
      samples were placed in tension until failure. The bonding surfaces were treated
      with a primer. Ten samples for each silicone/resin group were tested. The results
      were subjected to two-way analysis of variance and Tukey's test for comparison.
      RESULTS: The bond strength was affected by the type of silicone elastomer and
      denture resin. An interaction between them was also noted. The bond strength
      ranged from 0.03 to 0.23 MPa. CONCLUSION: Cosmesil condensation-type silicone
      always showed higher bond strength with the three different types of denture
      resins compared to Ideal addition silicone, keeping other variables associated
      with the silicone-resin bond fixed.

PMID- 12475158
TI  - A 5-year follow-up of occlusal status and radiographic findings in mandibular
      condyles of the elderly.
AB  - PURPOSE: The aim of the present 5-year follow-up was to clarify the nature of
      occlusal support status and radiographic changes in condyles of the elderly, and
      the association between these two variables. MATERIALS AND METHODS: The present
      study is part of a comprehensive medical survey of a random sample born in 1904,
      1909, and 1914. A total of 364 subjects living in Helsinki participated in the
      dental part of the examination during 1990 to 1991, and after 5 years a total of
      103 were reexamined. Comprehensive data on occlusal support status were available
      for 94 subjects, and radiographic data were available for 88 subjects. Occlusal
      support status was assessed on the basis of the Eichner index, radiographic
      changes were assessed from panoramic radiographs, and symptoms of
      temporomandibular disorders were assessed using Helkimo's anamnestic index.
      RESULTS: The most frequent radiographic finding in the mandibular joint was
      flattening of the articular surface of the condyle associated with
      osteoarthrosis, found at baseline in 17% and during follow-up in 13% of the
      subjects. During the 5-year follow-up, Eichner index for natural dentition
      remained unaltered in 94% of the subjects and in 85% of the subjects when
      removable dentures were included. There were no radiographic changes in 92% of
      the cases. No differences based on age or gender were found. A logistic
      regression model revealed associations between the selected baseline factors. The
      odds ratio for baseline Helkimo's anamnestic index was 4.1, 5.7 for Eichner index
      with the support of removable dentures, and 356 for radiographic findings.
      CONCLUSION: Radiographic changes in condyles of elderly people were small during
      the 5-year follow-up, but baseline radiographic findings, Helkimo's anamnestic
      index, and Eichner index with removable dentures were risk factors for
      radiographic findings at the end of the follow-up.

PMID- 12475159
TI  - Implant-supported welded titanium frameworks in the edentulous maxilla: a 5-year
      prospective multicenter study.
AB  - PURPOSE: This study evaluated the 5-year clinical and radiographic performance of
      fixed implant-supported maxillary prostheses with either welded titanium or
      conventional cast-gold alloy frameworks. MATERIALS AND METHODS: Fifty-eight
      consecutive patients were provided with 349 osseointegrated Branemark system
      implants in the edentulous maxilla at six different implant centers. Twenty-eight
      of the patients received, at random, prostheses with laser-welded titanium
      frameworks, and the remaining 30 patients had prostheses with conventional cast
      gold alloy frameworks. Clinical and radiographic data were collected for 5 years
      after prosthesis placement. RESULTS: The titanium and cast-gold framework groups
      exhibited similar cumulative survival and success rates (CSR). The 5-year implant
      CSR from time of placement was 91.4% and 94.0%, respectively, and from prosthesis
      delivery the rate was 94.9% and 95.6%, respectively. The corresponding 5-year
      prosthesis CSRs were 96.4% and 93.3%. One patient from each group lost all the
      implants and turned to complete dentures within the first year of function.
      Another patient with a cast-gold framework had the prosthesis replaced after 4
      years, basically because of problems with the veneering material. No fractures of
      implant components were observed during the follow-up period. Bone loss was on
      average 0.59 mm (SD 0.97 mm) during 5 years, with no statistical difference
      between the two groups. CONCLUSION: Welded titanium frameworks presented a
      similar favorable clinical performance as conventional cast-gold alloy frameworks
      in fixed implant-supported prostheses in the edentulous maxilla after 5 years in
      function. Implant failures were concentrated in only a few patients in each study
      group.

PMID- 12475160
TI  - The effectiveness of seven denture cleansers on tea stain removal from PMMA
      acrylic resin.
AB  - PURPOSE: In this study, seven denture cleansers were evaluated for their mode of
      action of tea stain removal from Perspex acrylic resin material. MATERIALS AND
      METHODS: Perspex acrylic resin specimens were stained using a combination of
      chlorhexidine and tea solution. The specimens were also treated with saliva to
      form an initial pellicle layer and facilitate the uptake of the stain. The
      capacity for stain removal was determined by measuring the optical density of the
      treated specimens by using a spectrophotometer. These were then exposed, for 5
      minutes, to seven denture cleansers to demonstrate the percentage stain-removal
      ability of each cleanser. The same procedure was applied for roughened Perspex
      acrylic resin specimens. Water was used as a control in the two parts of the
      experiment. RESULTS: The products containing alkaline hypochlorite had the
      highest ability for removing stain from the acrylic resin material together with
      a bleaching effect. The results varied when the same denture cleansers were used
      on the roughened Perspex surface, and this was attributed to the presence of
      irregularities and porosities on the blocks. CONCLUSION: Denture cleansing agents
      containing hypochlorite and Boots Denture Cleaning Powder (constituents not
      stated by the manufacturer) exhibited the ability to remove stain from the
      denture base materials most effectively. Irregularities and porosities present on
      the denture surface played a major role in reducing the activity of denture
      cleaning agents and hence increased stain and plaque retention.

PMID- 12475161
TI  - Modulation of mastication during experimental loosening of complete dentures.
AB  - PURPOSE: Suction is achieved when complete dentures are first fitted, but it
      fades during the months following insertion, when it is increasingly complemented
      by muscular denture control. The aim of this study was therefore to investigate
      the extent to which patterns of mastication are altered by experimental failure
      of physical retention. MATERIALS AND METHODS: Seven edentulous volunteers had
      maxillary replica dentures made, with fine tubes incorporated so that alternating
      positive and negative air pressure could be generated under the fitting surface.
      Mandibular movements, EMG, and pressure under the denture base were recorded
      during unilateral chewing. RESULTS: The change of physical retention passed
      undetected by all subjects; they continued chewing apparently undisturbed.
      However, during air injection, the mandibular excursions were slightly slower
      (nonsignificant) and demonstrated a reduced variance (P < or = .05). The muscle
      activity showed significantly longer bursts (P < or = .05), and peak activity
      occurred later in the cycle (nonsignificant). CONCLUSION: Sudden failure of
      denture retention seems to initiate an immediate and effective modulation of
      centrally generated muscular activity patterns.

PMID- 12475162
TI  - A survey of cusp fractures in a population of general dental practices.
AB  - PURPOSE: This study was conducted to expand the knowledge on the incidence of
      complete cusp fractures of posterior teeth in Dutch general practices. MATERIALS
      AND METHODS: During a 3-month period, data were obtained from 28 general
      practitioners, representing 46,394 patients. For each new case of complete cusp
      fracture, clinicians recorded information using a standard form with questions
      relating to location of the fracture, cause of fracture, and restorative status
      of the tooth prior to the cusp fracture. RESULTS: There were 238 cases of
      complete cusp fracture recorded. The results of this study indicate an incidence
      rate of cusp fractures of 20.5 per 1,000 person-years at risk. Molars were more
      frequently registered with cusp fractures than premolars (79% vs 21%). Maxillary
      molars presented more fractures of buccal cusps (66% vs 34%), while mandibular
      molars presented more fractures of lingual cusps (75% vs 25%). Almost 77% of the
      cases had been restored on three or more surfaces. Statistical analysis revealed
      a positive correlation between history of endodontic treatment and subgingival
      fracture location. Mastication was most frequently reported as the cause for
      fracture (54%), although one can argue whether the occlusal force was the cause
      or the immediate reason. CONCLUSION: This study revealed that complete cusp
      fracture is a common phenomenon in dental practice and has shown differences in
      cusp fracture with respect to tooth type and restorative status of the tooth.
      Teeth with a history of endodontic treatment are susceptible to unfavorable
      subgingival fracture locations.

PMID- 12475163
TI  - A 6- and 12-month follow-up of appliance therapy in TMD patients: a follow-up of
      a controlled trial.
AB  - PURPOSE: This study compared the long-term effects of treatment with a
      stabilization appliance and treatment with a control appliance in patients with
      temporomandibular disorders (TMD). MATERIALS AND METHODS: In a controlled trial,
      60 TMD patients with temporomandibular joint (TMJ) pain were evaluated after 10
      weeks of treatment with either a stabilization appliance or a control appliance.
      At the 10-week follow-up, the 60 patients were assigned to one of three groups
      according to their demand for treatment. Group T, the treatment group, comprised
      30 patients treated with a stabilization appliance; group C, the control group,
      comprised nine patients treated with a control appliance; and group M, the mixed
      treatment group, comprised 21 patients treated with first a control appliance and
      then a stabilization appliance. Signs and symptoms were evaluated in all three
      groups at 6- and 12-month follow-ups. RESULTS: At the 6- and 12-month follow-ups,
      a significant reduction in TMJ pain as measured on a visual analogue scale was
      found in all three groups, and a significant decrease in signs and symptoms was
      found in groups T and M. CONCLUSION: After 6 and 12 months of use, the
      stabilization appliance was found to still be effective in the alleviation of
      signs and symptoms in patients with TMD. Many patients in group C changed to a
      stabilization appliance at the 1 0-week follow-up, which significantly reduced
      the number of patients in this group. Most patients reported positive change in
      overall subjective symptoms in this trial. The stabilization appliance can
      therefore be recommended for patients with TMD.

PMID- 12475164
TI  - Fracture resistance of five different metal framework designs for metal-ceramic
      restorations.
AB  - PURPOSE: This study evaluated fracture resistance of five different metal
      framework designs for metal-ceramic restorations. MATERIALS AND METHODS: Twenty
      five artificial crowns were fabricated with different degrees of facial metal
      reduction: metal collar (group 1), and 0, 0.5, 1, and 1.5 mm (groups 2 to 5,
      respectively). All of the crowns were thermocycled in two different baths of 5
      and 60 degrees C for 20 seconds and had a dwell time of 10 seconds in a resting
      bath at 37 degrees C for 510 cycles. The artificial crowns were then subjected to
      vertical loading until fracture with a Shimadzu testing machine at a cross-head
      speed of 1 mm/min. The load at fracture was recorded. RESULTS: There were no
      statistically significant differences between mean fracture strength of groups 1
      and 2 or between groups 4 and 5. There were significant differences between group
      3 and groups 1, 2, 4, and 5. CONCLUSION: As the amount of metal reduction
      increased, the vertical fracture resistance decreased. Failure loads for all test
      groups exceeded normal biting forces.

PMID- 12475165
TI  - Masticatory function and patient satisfaction with implant-supported mandibular
      overdentures: a prospective 5-year study.
AB  - PURPOSE: The aim of this study was to assess the outcome of treatment with
      implant-supported mandibular overdentures in terms of biting and chewing, in
      entirely satisfied and not fully satisfied patients. MATERIALS AND METHODS:
      Twelve edentulous patients who had worn dentures for at least 5 years
      participated. They were in good health but had retention problems with their
      mandibular dentures. First, all patients received new dentures. After 3 months,
      two Astra Tech implants were placed in the anterior part of the mandible, and 6
      months later the abutments were connected. Patient assessment (questionnaire) and
      functional recordings (chewing ability, bite force, electromyographic activity)
      were performed with the new dentures, and again 3 months, 1 year, and 5 years
      after overdenture treatment. RESULTS: After treatment, all patients were able to
      comminute hard and tough food, the maximum bite force and the chewing activity
      increased in parallel, and the duration of the chewing cycle was reduced. Every
      patient felt improved function and reduction of chewing pain. However, the seven
      patients not fully satisfied with the function of the implant-supported
      mandibular overdentures were characterized by lower muscle activity, even before
      implant placement, than the entirely satisfied patients. CONCLUSION: Implant
      supported mandibular overdenture treatment permits better biting and chewing
      function than conventional complete dentures.

PMID- 12475166
TI  - Temperature changes at the implant-bone interface during simulated surface
      decontamination with an Er:YAG laser.
AB  - PURPOSE: This study investigated temperature changes at the implant-bone
      interface during simulated implant surface decontamination with an Er:YAG laser.
      MATERIALS AND METHODS: Stepped cylinder implants with three different surfaces
      (titanium plasma sprayed, sandblasted and acid etched, and hydroxyapatite coated)
      were placed in bone blocks cut from freshly resected pig femurs. An artificial
      periimplant bone defect with a size of 6 mm2 provided access for laser
      irradiation in the coronal third of the implant. A 540-pm periimplantitis
      application tip was used at a distance of 0.5 mm from the implant surface. Pulse
      energy was varied between 60 and 120 mJ at 10 pps. The bone block was placed into
      a 37 degrees C water bath to simulate in vivo thermal conductivity and
      diffusitivity of heat. K-type thermocouples connected to a digital meter were
      used to register temperature changes at three levels of the periimplant bone.
      RESULTS: The temperature at the implant-bone interface did not exceed 47 degrees
      C after 120 seconds of continuing laser irradiation. Temperature elevations were
      significantly higher at the hydroxyapatite-coated implants than in the two
      titanium surface groups (P < .001). CONCLUSION: Decontamination of implant
      surfaces by means of the Er:YAG laser did not excessively heat the periimplant
      bone within the energy range investigated. This technique therefore seems
      clinically safe, at least when used with the surfaces studied.

PMID- 12475167
TI  - Introduction: the cellular protein folding machinery.

PMID- 12475168
TI  - Structure and function of the GroE chaperone.
AB  - The Escherichia coli proteins GroEL and GroES were the first chaperones to be
      studied in detail and have thus become a role model for assisted protein folding
      in general. A wealth of both structural and functional data on the GroE system
      has been accumulated over the past years, enabling us now to understand the basic
      principles of how this fascinating protein-folding machine accomplishes its task.
      According to the current model, GroE processes a nonnative polypeptide in a cycle
      consisting of three steps. First, the polypeptide substrate is captured by GroEL.
      Upon binding of the co-chaperone GroES and ATP, the substrate is then discharged
      into a unique microenvironment inside of the chaperone, which promotes productive
      folding. After hydrolysis of ATP, the polypeptide is released into solution.
      Moreover, GroE may actively increase the folding efficiency, e.g. by unfolding of
      misfolded protein molecules. The mechanisms underlying these features, however,
      are yet not well characterized.

PMID- 12475169
TI  - The DnaK/ClpB chaperone system from Thermus thermophilus.
AB  - Proteins of thermophilic organisms are adapted to remain well structured and
      functional at elevated temperatures. Nevertheless like their 'cousins' that
      reside at medium temperatures, they require the assistance of molecular
      chaperones to fold properly and prevent aggregation. This review compares
      structural and functional properties of the DnaK/ClpB systems of Thermus
      thermophilus and, mainly, Escherichia coli (DnaK(Tth) and DnaK(Eco)). Many
      elemental properties of these systems remain conserved. However, in addition to a
      general increase of the thermal stability of its components, the DnaK(Tth) system
      shows profound differences in its regulation, and genetic as well as oligomeric
      organization. Whether these differences are unique or represent general
      strategies of adaptation to life at elevated temperatures remains to be
      clarified.

PMID- 12475170
TI  - Protein folding and degradation in bacteria: to degrade or not to degrade? That
      is the question.
AB  - In Escherichia coli protein quality control is carried out by a protein network,
      comprising chaperones and proteases. Central to this network are two protein
      families, the AAA+ and the Hsp70 family. The major Hsp70 chaperone. DnaK,
      efficiently prevents protein aggregation and supports the refolding of damaged
      proteins. In a special case, DnaK, together with the assistance of the AAA+
      protein ClpB, can also refold aggregated proteins. Other Hsp70 systems have more
      specialized functions in the cell, for instance HscA appears to be involved in
      the assembly of Fe/S proteins. In contrast to ClpB, many AAA+ proteins associate
      with a peptidase to form proteolytic machines which remove irreversibly damaged
      proteins from the cellular pool. The AAA+ component of these proteolytic machines
      drives protein degradation. They are required not only for recognition of the
      substrate but also for substrate unfolding and translocation into the proteolytic
      chamber. In many cases, specific adaptor proteins modify the substrate binding
      properties of AAA+ proteins. While chaperones and proteases do not appear to
      directly cooperate with each other, both systems appear to be necessary for
      proper functioning of the cell and can, at least in part, substitute for one
      another.

PMID- 12475171
TI  - SecB, one small chaperone in the complex milieu of the cell.
AB  - SecB is only one of a plethora of cytosolic chaperones in E. coli whose common
      property is that they bind nonnative proteins. It plays a crucial role during
      protein export via the general secretory pathway by modulating the partitioning
      of precursors between folding or aggregation and delivery to the membrane-bound
      translocation apparatus. In this latter role SecB demonstrates specific binding
      to a unique partner, SecA. SecB has the potential to participate in functions
      outside of export acting as a general nonspecific chaperone to provide buffering
      capacity of the nonnative state of proteins in the cytosolic pool. We discuss the
      interactions of SecB with its many binding partners in light of its recently
      determined structure, emphasizing both kinetic and thermodynamic parameters.

PMID- 12475172
TI  - Redox-regulated molecular chaperones.
AB  - The conserved heat shock protein Hsp33 functions as a potent molecular chaperone
      with a highly sophisticated regulation. On transcriptional level, the Hsp33 gene
      is under heat shock control; on posttranslational level, the Hsp33 protein is
      under oxidative stress control. This dual regulation appears to reflect the close
      but rather neglected connection between heat shock and oxidative stress. The
      redox sensor in Hsp33 is a cysteine center that coordinates zinc under reducing,
      inactivating conditions and that forms two intramolecular disulfide bonds under
      oxidizing, activating conditions. Hsp33's redox-regulated chaperone activity
      appears to specifically protect proteins and cells from the otherwise deleterious
      effects of reactive oxygen species. That redox regulation of chaperone activity
      is not restricted to Hsp33 became evident when the chaperone activity of protein
      disulfide isomerase was recently also shown to cycle between a low- and high
      affinity substrate binding state, depending on the redox state of its cysteines.

PMID- 12475173
TI  - Nascent-polypeptide-associated complex.
AB  - Nascent-polypeptide-associated complex (NAC) is a heterodimeric complex which can
      reversibly bind to eukaryotic ribosomes. NAC is located in direct proximity to
      newly synthesized polypeptide chains as they emerge from the ribosome. Although
      its function is thought to be conserved from yeast to humans our current
      knowledge about what NAC actually does in a living cell is incomplete. It has
      been suggested that NAC is a (i) dynamic component of the ribosomal exit tunnel,
      providing a shield for nascent polypeptides, (ii) negative regulator of
      translocation into the endoplasmic reticulum and (iii) positive regulator of
      translocation into the mitochondria. However, none of these hypotheses is
      generally accepted. Moreover, the individual subunits of NAC have been implicated
      in processes related to transcription rather than translation, and it is
      currently under debate whether NAC might be a protein of dual function. This
      review attempts to summarize the data from different fields and to discuss the
      partly controversial results in a common context.

PMID- 12475174
TI  - Heat-shock protein 90, a chaperone for folding and regulation.
AB  - Heat-shock protein 90 (Hsp90) is an abundant and highly conserved molecular
      chaperone that is essential for viability in eukaryotes. Hsp90 fulfills a
      housekeeping function in contributing to the folding, maintenance of structural
      integrity and proper regulation of a subset of cytosolic proteins. A remarkable
      proportion of its substrates are proteins involved in cell cycle control and
      signal transduction. Hsp90 acts with a cohort of Hsp90 co-chaperones that
      modulate its substrate recognition, ATPase cycle and chaperone function. The
      large conformational flexibility of Hsp90 and a multitude of dynamic co-chaperone
      complexes contribute to generating functional diversity, and allow Hsp90 to
      assist a wide range of substrates.

PMID- 12475175
TI  - sHsps and their role in the chaperone network.
AB  - Small Hsps (sHsps) encompass a widespread but diverse class of proteins. These
      low molecular mass proteins (15-42 kDa) form dynamic oligomeric structures
      ranging from 9 to 50 subunits. sHsps display chaperone function in vitro, and in
      addition they have been suggested to be involved in the inhibition of apoptosis,
      organisation of the cytoskeleton and establishing the refractive properties of
      the eye lens in the case of a-crystallin. How these different functions can be
      explained by a common mechanism is unclear at present. However, as most of the
      observed phenomena involve nonnative protein, the repeatedly reported chaperone
      properties of sHsps seem to be of key importance for understanding their
      function. In contrast to other chaperone families, sHsps bind several nonnative
      proteins per oligomeric complex, thus representing the most efficient chaperone
      family in terms of the quantity of substrate binding. In some cases, the release
      of substrate proteins from the sHsp complex is achieved in cooperation with Hsp70
      in an ATP-dependent reaction, suggesting that the role of sHsps in the network of
      chaperones is to create a reservoir of nonnative refoldable protein.

PMID- 12475176
TI  - A specialized mitochondrial molecular chaperone system: a role in formation of
      Fe/S centers.
AB  - Mitochondria contain a specialized system of molecular chaperones that plays a
      critical role in the biogenesis of Fe/S centers. This Hsp70:J-protein system
      shows many similarities to the system found in bacteria, but the precise role of
      neither chaperone system has been defined. However, evidence to date suggests an
      interaction with the scaffold protein on which a transient Fe/S center is
      assembled, and thus implies a role in either assembly of the center or its
      transfer to recipient proteins.

PMID- 12475177
TI  - A bright future for anti-adhesion therapy of infectious diseases.

PMID- 12475178
TI  - Functions and malfunctions of the tau proteins.
AB  - The tau proteins belong to the family of microtubule-associated proteins. They
      are mainly expressed in neurons where they play major regulatory roles in the
      organization and integrity of the cytoskeleton network. Neurofibrillary changes
      of abnormally hyperphosphorylated tau are a key lesion in Alzheimer's disease and
      a number of other tauopathies. However, despite an ever-increasing body of data
      on the changes which tau undergoes in disease, its role regarding the fundamental
      disease process is still unclear. Moreover, conceptions of tau functions continue
      to evolve, which complicates an understanding of its role in the disease process.
      This review attempts to summarize data on the role of tau proteins in the context
      of both normal cellular function and dysfunction. Furthermore, we try to develop
      a mechanistic framework for the involvement of tau during the disease process.
      The review closes with a look towards various approaches to elucidate the
      functions and malfunctions of tau.

PMID- 12475179
TI  - Physicochemical profiling in drug research: a brief survey of the state-of-the
      art of experimental techniques.
AB  - This review begins with a general presentation of the new paradigm of drug
      discovery, with its emphasis on the rapid identification and elimination of
      compounds with unsuitable physicochemical and pharmacokinetic properties. The
      focus of the paper is on the various experimental methods used to determine such
      key physicochemical properties as ionization, lipophilicity and distribution in
      isotropic and anisotropic systems, solubility, and permeability across artificial
      membranes. Both traditional and high-throughput methods are presented and their
      limits highlighted. The text concludes with the trade-off between quantity/speed
      in high-throughput screening techniques versus greater data quality in the more
      labor-intensive methods.

PMID- 12475180
TI  - Differential effects of v-Jun and c-Jun proteins on v-myb-transformed monoblasts.
AB  - The v-myb oncogene of avian myeloblastosis virus transforms myelomonocytic cells
      in vitro. The line of v-myb-transformed chicken monoblasts BM2 can be induced to
      terminal differentiation using phorbol esters. The fact that Jun proteins are up
      regulated in the phorbol ester-treated BM2 cells prompted us to investigate the
      role of the Jun proteins in regulation of myeloid differentiation. We ectopically
      expressed v-jun and c-jun in BM2 cells and evaluated their effects on
      differentiation and proliferation. c-Jun up-regulated the transactivation
      activity of v-Myb and induced a proliferation block and differentiation of BM2
      cells. In contrast, v-Jun down-regulated v-Myb transactivation causing no
      dramatic effects on BM2 cells. This confirms that there is no strong correlation
      between transcriptional activation and strength of oncogenic transformation by v
      Myb. Both c-Jun and v-Jun proteins affected sensitivity of BM2 cells to retinoic
      acid and phorbol ester. Sensitivity of BM2 cells to retinoic acid was enhanced by
      both Jun proteins, while sensitivity to phorbol 12-myristate 13-acetate was
      reduced by v-Jun. These data suggest thate Jun plays a major role in macrophage
      differentiation.

PMID- 12475181
TI  - Melatonin regulation of antioxidant enzyme gene expression.
AB  - Antioxidant enzymes (AOEs) are part of the primary cellular defense against free
      radicals induced by toxins and/or spontaneously formed in cells. Melatonin (MLT)
      has received much attention in recent years due to its direct free radical
      scavenging and antioxidant properties. In the present work we report that MLT, at
      physiological serum concentrations (1 nM), increases the mRNA of both superoxide
      dismutases (SODs) and glutathione peroxidase (GPx) in two neuronal cell lines.
      The MLT effect on both SODs and GPx mRNA was mediated by a de novo synthesized
      protein. MLT alters mRNA stability for Cu-Zn SOD and GPx. Experiments with a
      short time treatment (pulse action) of MLT suggest that the regulation of AOE
      gene expression is likely to be receptor mediated, because 1-h treatment with MLT
      results in the same response as a 24-h treatment.

PMID- 12475183
TI  - Glycoconjugates of the intestinal goblet cells of four cyprinids.
AB  - The aim of this work was to show differences in the terminal and subterminal
      sugar composition of carbohydrate chains of glycoconjugates produced by the
      goblet cells of the intestines of four cyprinids. We analysed intestines of two
      herbivorous species--sneep and grass carp--and two omnivorous ones--chub and
      common carp. We compared four intestinal regions of every studied species. In
      every region, the presence of neutral and acidic glycoconjugates was confirmed.
      The smallest amount of acidic glycoconjugates was present in the second region of
      sneep intestine. Sulphated glycoconjugates were absent in the third and fourth
      region of chub intestine. Lectin histochemistry provided evidence for the
      presence of beta-D-galactose, a-N-acetylgalactosamine, beta-N-acetylglucosamine
      and sialic acids. Additionally, the occurrence of alpha-L-fucose in the goblet
      cells of chub, grass carp and sneep was confirmed. We tried to correlate the
      pattern of glycoconjugate glycosylation with feeding habits of the studied
      fishes.

PMID- 12475182
TI  - Opposite actions of testosterone and progesterone on UCP1 mRNA expression in
      cultured brown adipocytes.
AB  - The brown adipose tissue (BAT) thermogenic response to diet-induced obesity and
      cold has been found to be gender dependent. In the present work, we aimed to
      investigate the effects of the main physiological male and female sex hormones,
      i.e. testosterone, progesterone and 17-beta-estradiol, on the expression of
      uncoupling protein I (UCP1)--the main mediator of BAT thermogenesis--and on UCP2
      and lipid accumulation in rodent brown adipocytes differentiated in culture.
      Testosterone-treated cells showed fewer and smaller lipid droplets than control
      cells and a dose-dependent inhibition of UCP1 mRNA expression, under adrenergic
      stimulation by norepinephrine (NE). These effects were reverted by the androgen
      receptor antagonist flutamide, suggesting they are dependent, at least in part,
      on the androgen receptor. Progesterone- and 17-beta-estradiol-treated cells
      showed more and larger lipid droplets and progesterone stimulated NE-induced UCP1
      mRNA expression at the lower concentration tested, but not at higher
      concentrations, suggesting that for brown adipocytes, this hormone is dose
      dependent. 17-beta-Estradiol did not have any remarkable effect either on UCP1 or
      UCP2 mRNA expression. Interestingly, the specific progesterone receptor
      antagonist RU486 induced UCP1 and UCP2 mRNAs, including UCP1 mRNA expression in
      non-NE-treated brown adipocytes, suggesting a profound effect of this
      antiprogestagen on brown adipocyte thermogenic capacity. Thus, are conclude that
      testosterone, 17-beta-estradiol, progesterone and RU486 have distinct actions on
      brown adipocytes, thus modulating UCP1 and UCP2 mRNA expression and/or lipid
      accumulation, and that sex hormones are factors that may explain in part the
      gender-dependent BAT thermogenic response.

PMID- 12475185
TI  - Epithelial supporting cells can differentiate into outer hair cells and Deiters'
      cells in the cultured organ of Corti.
AB  - The organ of Corti is a complex structure containing a single row of inner hair
      cells (IHCs) and three rows of outer hair cells (OHCs), supported respectively by
      one row of inner phalangeal cells and three rows of Deiters' cells. When fetal
      rat organ of Corti explants are cultured, supernumerary OHCs and supernumerary
      Deiters' cells are produced, without any additional cell proliferation. Analysis
      of semi- and ultrathin sections revealed that supernumerary OHCs are produced at
      the distal edge of the organ of Corti. Quantitative analysis of cell types
      present in the organ of Corti demonstrates that when the number of OHCs
      increases: (i) the total number of cells remains constant; (ii) the number of
      Deiters' cells increases; (iii) the number of tectal cells decreases and of
      Hensen's cells decreases. Using specific HC markers, i.e. jagged2 (Jag2) and
      Math1, we showed that in addition to existing OHCs, supernumerary OHCs, tectal
      cells and Hensen's cells expressed these markers in embryonic day 19 organ of
      Corti explants after 5 days in vitro. The results of this study suggest that
      Hensen's cells retain the capacity to differentiate into either tectal cells,
      which differentiate into OHCs, or into undertectal cells which differentiate into
      Deiters' cells.

PMID- 12475184
TI  - Glioma cell activation by Alzheimer's peptide Abeta1-42, alpha1-antichymotrypsin,
      and their mixture.
AB  - We compared the effects ofAlzheimer's peptide (Abeta1-42), a,-antichymotrypsin
      (ACT) and an ACT/Abeta1-42 mixture on human glioma DK-MG cells. The solution of
      Abeta (5 microM) formed by 2-h incubation at room temperature induced tumour
      necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 levels by 55 and 45%,
      respectively, and increased gelatinase B activity by 67%, while exposure of cells
      to the ACT/Abeta1-42 mixture (1:10 molar ratio ACT: Abeta1-42) under the same
      experimental conditions showed no effect on IL-6 levels or gelatinase B activity,
      but strongly induced TNF-alpha (by 190%), compared to the controls. Stimulation
      of the cells with Abeta1-42 alone, but not with ACT, increased by about 20% low
      density lipoprotein (LDL) uptake and mRNA levels for LDL receptor and HMG-CoA
      reductase, while the ACT/Abeta1-42 mixture significantly increased LDL uptake (by
      50%), up-regulated mRNA levels for LDL receptor and HMG-CoA reductase by 48 and
      63%, respectively, and increased lipid accumulation by about 20-fold. These data
      suggest a possible new role for Abeta in Alzheimer's disease through its
      interaction with the inflammatory reactant, ACT.

PMID- 12475186
TI  - Retinoic acid modulates gap junctional intercellular communication in hepatocytes
      and hepatoma cells.
AB  - Gap junctional communication permits the direct exchange of small molecules and
      ions and has been implicated in tissue homeostasis/metabolite exchange. The lack
      of gap junctional intercellular communication (GJIC) plays important roles in the
      promotion and progression of carcinogenesis. In the present study, we demonstrate
      that treatment of human hepatoma Hep G2 cells with retinoic acid (RA) results in
      increased amounts and phosphorylation of connexins, their stabilisation in plasma
      membrane plaques and enhanced GJIC. In cultured fetal hepatocytes, which
      represent a non-transformed, proliferating and incompletely differentiated liver
      system, the effects of RA are limited to the establishment of connexin in areas
      of cell-cell contact and the improvement of GJIC. This suggests that modulation
      of cell-cell channel communication by RA occurs differently in these two
      experimental models: while RA is able to revert cell transformation in Hep G2
      cells, in fetal hepatocytes it may induce the expression of a more differentiated
      phenotype.

PMID- 12475187
TI  - Treatment of amatoxin poisoning: 20-year retrospective analysis.
AB  - BACKGROUND: Amatoxin poisoning is a medical emergency characterized by a long
      incubation time lag, gastrointestinal and hepatotoxic phases, coma, and death.
      This mushroom intoxication is ascribed to 35 amatoxin-containing species
      belonging to three genera: Amanita, Galerina, and Lepiota. The major amatoxins,
      the alpha-, beta-, and gamma-amanitins, are bicyclic octapeptide derivatives that
      damage the liver and kidney via irreversible binding to RNA polymerase II.
      METHODS: The mycology and clinical syndrome of amatoxin poisoning are reviewed.
      Clinical data from 2108 hospitalized amatoxin poisoning exposures as reported in
      the medical literature from North America and Europe over the last 20 years were
      compiled. Preliminary medical care, supportive measures, specific treatments used
      singly or in combination, and liver transplantation were characterized. Specific
      treatments consisted of detoxication procedures (e.g., toxin removal from bile
      and urine, and extracorporeal purification) and administration of drugs.
      Chemotherapy included benzylpenicillin or other beta-lactam antibiotics,
      silymarin complex, thioctic acid, antioxidant drugs, hormones and steroids
      administered singly, or more usually, in combination. Supportive measures alone
      and 10 specific treatment regimens were analyzed relative to mortality. RESULTS:
      Benzylpenicillin (Penicillin G) alone and in association was the mostfrequently
      utilized chemotherapy but showed little efficacy. No benefit was found for the
      use of thioctic acid or steroids. Chi-square statistical comparison of survivors
      and dead vs. treated individuals supported silybin, administered either as mono
      chemotherapy or in drug combination and N-acetylcysteine as mono-chemotherapy as
      the most effective therapeutic modes. Future clinical research should focus on
      confirming the efficacy of silybin, N-acetylcysteine, and detoxication
      procedures.

PMID- 12475188
TI  - Carbamazepine poisoning: elimination kinetics and quantitative relationship with
      carbamazepine 10,11-epoxide.
AB  - Carbamazepine (amizepine) is a widely used psychotropic agent. A much easier
      accessibility of this drug, observed during the recent years, may account for an
      increasing number of acute intoxications with carbamazepine. The aim of this
      study was to determine the elimination kinetics of carbamazepine and its
      metabolite carbamazepine 10,11-epoxide, and to identify the quantitative
      relationship between concentrations of these compounds, in serum. The subjects
      were 41 patients with acute carbamazepine intoxication. Serum carbamazepine and
      carbamazepine 10,11-epoxide concentrations were determined every 6 hours during
      thefirst 24 hours of hospitalization, and then every 12 hours. At the same time,
      urinalyses were performed for each patient to confirm or exclude homogeneity of
      poisoning. Depending on the type of intoxication (homogenous or combined), three
      groups of patients, and on the method of treatment (symptomatic, charcoal
      administration), two groups of patients were distinguished. The statistical
      analysis of the results revealed that among the investigated parameters (time
      integrated concentrations of carbamazepine and carbamazepine 10,11-epoxide in
      serum, the presence of drugs, and/or ethanol, charcoal treatment) only
      carbamazepine concentrations had statistically significant effect on the duration
      of coma regarded as a critical effect. The kinetics of carbamazepine elimination
      was determined on the basis of the mean carbamazepine concentrations at the same
      timing of sampling for each patient in all the three groups; the mean
      carbamazepine elimination in serum followed zero-order kinetics. In individual
      groups, the decrease in serum carbamazepine concentrations ranged from 0.5 to 0.8
      mg L(-1) hour(-1). Contrary to the suggestions found in the literature,
      carbamazepine 10,11-epoxide determination does not seem to enhance the
      possibility of anticipating the course of intoxication or the time of recovery.

PMID- 12475189
TI  - Regional variation in the incidence of symptomatic pesticide exposures:
      applications of geographic information systems.
AB  - OBJECTIVE: To evaluate the epidemiology of symptomatic human pesticide exposures
      using poison control center data and geographic information systems. METHODS: All
      symptomatic human pesticide exposures reported to the poison center during the
      period from January 1 to December 31, 2000 were included for analysis using
      geographic information systems. A space-time scan statistic was utilized to
      evaluate for clustering of symptomatic human exposures. RESULTS: Of 322
      symptomatic pesticide exposures, 297 (92%) contained spatial identifiers that
      could be further analyzed using geographic information systems. A spatial and
      temporal cluster of symptomatic pesticide exposures was identified during the
      periodfrom April 1 to August 31, 2000, covering a large geographic area of
      eastern and predominantly rural regions of the state. The relative risk of
      reporting a symptomatic pesticide exposure among individuals living within this
      geographic area was 1.8 (log likelihood ratio = 18.5, P = 0.0005). CONCLUSIONS:
      Geographic information systems can be effectively utilized by poison control
      centers to study regional and temporal variation in the incidence of human
      pesticide exposures. With the collection of more specific spatial identifiers,
      geographic information systems may have many additional applications in the
      surveillance and prevention of pesticide and other sentinel event exposures.

PMID- 12475190
TI  - Acupressure for prevention of emesis in patients receiving activated charcoal.
AB  - OBJECTIVE: Vomiting after activated charcoal decontamination is problematic.
      Acupressure (traditional Chinese medicine) is an effective treatment for emesis,
      but has not been tested in overdose patients. We sought to determine (1) the
      incidence of emesis after activated charcoal and (2) the ability of acupressure
      to prevent emesis due to activated charcoal. METHODS: Consecutive overdose
      patients were enrolled in a preliminary, prospective study to determine the
      incidence of emesis after activated charcoal. Awake patients, > 18 years,
      received 1 g/kg activated charcoal orally or via nasogastric tube, and then
      observedfor 1 hour. These patients served as controls forpart 2 of the study,
      where acupressure bands were placed on overdose patients at the Nei-Guan P-6
      point of both wrists prior to activated charcoal, followed by 1 hour observation.
      Exclusion criteria included: ipecac decontamination, antiemetic drug ingestion,
      antiemetic drug therapy within 1 hour of activated charcoal, or intubation.
      RESULTS: Eighty-one patients were included in the control group and 106 patients
      in the acupressure treatment group. Demographics and ingested substances were
      similar in both groups. 21/81 (25.9%) in the control group vomited and 15/106
      (14.2%) in the acupressure group vomited. Acupressure reduced emesis by 46% (p =
      0.043; chi2). Within the acupressure group, the median duration of prophylactic
      acupressure was 5 minutes in those patients without vomiting compared to 4
      minutes in those patients with vomiting (NS; Wilcoxon rank sum test). CONCLUSION:
      The incidence of emesis after activated charcoal at our institution was 26%.
      Prophylactic acupressure reduced activated charcoal-induced vomiting by 46%.
      Investigators suggest 5 minutes of acupressure prior to activated charcoal.

PMID- 12475191
TI  - Physostigmine as a treatment for gamma-hydroxybutyrate toxicity: a review.
AB  - INTRODUCTION: Gamma-hydroxybutyrate is a potent sedative-hypnotic agent and a
      popular drug of abuse. In the United States, gamma-hydroxybutyrate is a Schedule
      I controlled substance (sodium oxybate) with orphan drug status for the treatment
      of narcolepsy within approved clinical studies. Physostigmine is a carbamate
      inhibitor of acetylcholinesterase that is reported to attenuate the sedative
      effects of a number of drugs, including gamma-hydroxybutyrate. We reviewed the
      literature that pertains to the use of physostigmine to treat gamma
      hydroxybutyrate-induced sedation. METHODS: A structured literature search was
      performed to identify articles in which physostigmine and gamma-hydroxybutyrate
      were mentioned. Keywords were used to identify relevant articles in the Medline
      database, and the reference sections of articles identified by this method were
      hand-checked to identify additional articles. Those articles that presented
      original evidence pertaining to the use of physostigmine to treat gamma
      hydroxybutyrate-induced sedation were included in this review; those that did not
      were rejected. RESULTS: The literature search identified 22 articles, six of
      which did not pertain to the subject matter. Of the 16 articles which remained,
      12 were rejected because they offered opinions without presenting original
      evidence. Of the four articles that presented original evidence, there were no in
      vitro studies and no animal studies. There were two small case series in which
      physostigmine was given to treat acute gamma-hydroxybutyrate toxicity in an
      emergency department setting, and two larger series in which physostigmine was
      given to attenuate the sedation induced by gamma-hydroxybutyrate in a more
      structured anesthesia setting. Although these references report that
      physostigmine attenuates gamma-hydroxybutyrate-induced sedation, there are
      methodological flaws and confounding factors that limit the scope of the
      conclusions that can be drawn from them. CONCLUSIONS: There is currently
      insufficient scientific evidence to support the routine use of physostigmine in
      the treatment of gamma-hydroxybutyrate toxicity. Further studies are needed to
      determine the role, if any, for physostigmine in this setting.

PMID- 12475192
TI  - Valproic acid toxicity: overview and management.
AB  - Acute valproic acid intoxication is an increasing problem, accounting for more
      than 5000 calls to the American Association of Poison Control Centers in 2000.
      The purpose of this paper is to review the pharmacology and toxicology of
      valproic acid toxicity. Unlike earlier antiepileptic agents, valproic acid
      appears to function neither through sodium channel inhibition nor through direct
      gamma-aminobutyric acid agonism, but through an indirect increase in regional
      brain gamma-aminobutyric acid levels. Manifestations of acute valproic acid
      toxicity are myriad, and reflect both exaggerated therapeutic effect and impaired
      intermediary metabolism. Central nervous system depression is the most common
      finding noted in overdose, and may progress to coma and respiratory depression.
      Cerebral edema has also been observed. Although hepatotoxicity is rare in the
      acute overdose setting, pancreatitis and hyperammonemia have been reported.
      Metabolic and hematologic derangements have also been described. Management of
      acute valproic acid ingestion requires supportive care and close attention to the
      airway. The use of controversial adjunctive therapies, including extracorporeal
      drug elimination and L-carnitine supplementation, will be discussed.

PMID- 12475193
TI  - Review of oximes in the antidotal treatment of poisoning by organophosphorus
      nerve agents.
AB  - The cholinesterase-inhibiting organophosphorus compounds referred to as nerve
      agents (soman, sarin, tabun, GF agent, and VX) are particularly toxic and are
      considered to be among the most dangerous chemical warfare agents. Included in
      antidotal medical countermeasures are oximes to reactivate the inhibited
      cholinesterase. Much experimental work has been done to better understand the
      properties of the oxime antidotal candidates including the currently available
      pralidoxime and obidoxime, the H oximes HI-6 and Hlo-7, and methoxime. There is
      no single, broad-spectrum oxime suitablefor the antidotal treatment of poisoning
      with all organophosphorus agents. If more than one oxime is available, the choice
      depends primarily on the identity of the responsible organophosphorus compound.
      The H oximes appear to be very promising antidotes against nerve agents because
      they are able to protect experimental animals from toxic effects and improve
      survival of animals poisoned with supralethal doses. They appear more effective
      against nerve agent poisoning than the currently used oximes pralidoxime and
      obidoxime, especially in the case of soman poisoning. On the other hand,
      pralidoxime and especially obidoxime seem sufficiently effective to treat
      poisonings with organophosphorus insecticides that have relatively less toxicity
      than nerve agents.

PMID- 12475194
TI  - An unusual case of methyl bromide poisoning.
AB  - A nonlethal poisoning case by methyl bromide in a young woman due to leakage of
      old fire extinguishers is described. The patient developed major action and
      intention myoclonus the day following exposure. Inorganic bromide concentrations
      in plasma were determined by inductively coupled plasma mass spectrometry. The
      initial plasma bromide level was 202 mg/L, 40-fold in excess than the commonly
      accepted tolerance limit, and decreased slowly to normal levels within 2 months.
      Although plasma inorganic bromide concentration is known not to be directly
      correlated to the severity of organic bromide poisoning, its determination was,
      in the present case, particularly useful to confirm the diagnosis. One year post
      exposure, the patient showed no sign of central nervous system toxicity. While
      such a case of poisoning is particularly rare today, it illustrates, however,
      that the danger still exists in France although the destruction

PMID- 12475196
TI  - Structure and mechanism of the pepsin-like family of aspartic peptidases.

PMID- 12475197
TI  - Human and parasitic papain-like cysteine proteases: their role in physiology and
      pathology and recent developments in inhibitor design.

PMID- 12475198
TI  - Caspases: keys in the ignition of cell death.

PMID- 12475199
TI  - Serine protease mechanism and specificity.

PMID- 12475200
TI  - Precursor processing by kex2/furin proteases.

PMID- 12475201
TI  - Signal peptidases.

PMID- 12475202
TI  - Metalloaminopeptidases: common functional themes in disparate structural
      surroundings.

PMID- 12475203
TI  - Viral proteases.

PMID- 12475204
TI  - Protein ectodomain shedding.

PMID- 12475205
TI  - Irreversible inhibitors of serine, cysteine, and threonine proteases.

PMID- 12475206
TI  - Serpin structure, mechanism, and function.

PMID- 12475207
TI  - Prodomains and protein folding catalysis.

PMID- 12475208
TI  - Proteases in organic synthesis.

PMID- 12475209
TI  - Mechanistic and kinetic considerations of protein splicing.

PMID- 12475210
TI  - Catalytic antibodies as designer proteases and esterases.

PMID- 12475211
TI  - Chemically gated electron transfer. A means of accelerating and regulating rates
      of biological electron transfer.
AB  - Long-range protein electron transfer [ET] reactions may be relatively slow
      because of long ET distance and low driving force. It is possible to dramatically
      increase the rate of such nonadiabatic reactions by using an adiabatic chemical
      reaction to activate the system for rapid ET. Three such examples are discussed;
      nitrogenase, pyruvate:ferredoxin oxidoreductase, and the methylamine
      dehydrogenase-amicyanin complex. In each example, the faster activated ET
      reaction is gated (i.e., rate-limited) by the chemical reaction. However, the
      reaction rate is still orders of magnitude greater than that of the ungated true
      ET reaction in the absence of chemical activation. Models are presented to
      describe the mechanisms of activation in the context of ET theory, and the
      relevance of such chemically gated ET to the regulation of metabolism is
      discussed.

PMID- 12475212
TI  - Proline cis-trans isomerization and protein folding.
AB  - Proline cis-trans isomerization plays a key role in the rate-determining steps of
      protein folding. The energetic origin of this isomerization process is
      summarized, and the folding and unfolding of disulfide-intact bovine pancreatic
      ribonuclease A is used as an example to illustrate the kinetics and structural
      features of conformational changes from the heterogeneous unfolded state
      (consisting of cis and trans isomers of X-Pro peptide groups) to the native
      structure in which only one set of proline isomers is present.

PMID- 12475213
TI  - S-methylated cysteines in human lens gamma S-crystallins.
AB  - The proteins of the eye lens, which do not turn over throughout life, undergo
      many modifications, some of which lead to senile cataract. We describe a
      modification, S-methylation of cysteine, that may serve to protect the lens from
      detrimental modifications. The modification was detected as a +14 Da peak in
      electrospray ionization mass spectra of human lens gammaS-crystallins.
      Derivatization of gammaS-crystallin with iodoacetamide showed reaction at only
      six of the seven cysteines, indicating the modification blocked reaction at one
      cysteine. Further analysis of the modified gammaS-crystallin as tryptic peptides
      located the modification primarily at Cys 26, with smaller amounts at Cys 24.
      Tandem mass spectrometry and exact mass measurements showed that the modification
      was S-methylation. Methylation of proteins has been documented at several other
      amino acid residues, but S-methylation of cysteine residues has previously been
      detected only as part of a methyltransferase DNA repair mechanism or at trace
      amounts in hemoglobin. The high levels of S-methylated cysteines in lens nuclei
      and the specificity for Cys 26 and Cys 24 suggest the reaction is enzymatically
      mediated. This modification is particularly important because it blocks disulfide
      bonding of gammaS-crystallins and, thereby, inhibits formation of the high
      molecular weight assemblies associated with cataract. Evidence of more S
      methylation in soluble than in insoluble gammaS-crystallins supports the
      contention that S-methylation of gammaS-crystallin inhibits protein
      insolubilization and may offer protection against cataract.

PMID- 12475214
TI  - Electron transfer from plastocyanin to the photosystem I reaction center in
      mutants with increased potential of the primary donor in Chlamydomonas
      reinhardtii.
AB  - The dependence of the P(700)(+)/P(700) midpoint potential on kinetics of
      reduction of P(700)(+) in vivo has been examined in a series of site-directed
      mutants of Chlamydomonas reinhardtii in which the histidyl axial ligand to the
      Mg(2+) of the P(700) chlorophyll a has been changed to several different amino
      acids. In wild-type photosystem I, the potential of P(700)(+)/P(700) is 447 mV
      and the in vivo half-time of P(700)(+) reduction by its natural donor,
      plastocyanin, is 4 micros. Substitution of the axial histidine ligand with
      cysteine increases the potential of P(700)(+)/P(700) to 583 mV and changes the
      rate of P(700)(+) reduction to 0.8 micros. Mutants with a range of potentials
      between 447 and 583 mV show a strong correlation of the P(700)(+)/P(700)
      potential to the rate of reduction of P(700)(+) by plastocyanin. There is also an
      increase in the rate of photosystem I-mediated electron transfer from the
      artificial electron donor DCPIP to methyl viologen in thylakoid membranes. The
      results indicate that the overall rate constant of P(700)(+) reduction is
      determined by the rate of electron transfer between the copper and P(700)(+) and
      confirmed that in vivo there is a preformed complex between plastocyanin and
      photosystem I. Using approximations of the Marcus electron transfer theory, it is
      possible to estimate that the distance between the copper of plastocyanin and
      P(700)(+) is approximately 15 A. On the basis of this distance, the plastocyanin
      docking site should lie in a 10 A hollow formed by the lumenal exposed loops
      between transmembrane helices i and j of PsaA and PsaB.

PMID- 12475215
TI  - Structure of bacterial 3beta/17beta-hydroxysteroid dehydrogenase at 1.2 A
      resolution: a model for multiple steroid recognition.
AB  - The enzyme 3beta/17beta-hydroxysteroid dehydrogenase (3beta/17beta-HSD) is a
      steroid-inducible component of the Gram-negative bacterium Comamonas
      testosteroni. It catalyzes the reversible reduction/dehydrogenation of the
      oxo/beta-hydroxy groups at positions 3 and 17 of steroid compounds, including
      hormones and isobile acids. Crystallographic analysis at 1.2 A resolution reveals
      the enzyme to have nearly identical subunits that form a tetramer with 222
      symmetry. This is one of the largest oligomeric structures refined at this
      resolution. The subunit consists of a monomer with a single-domain structure
      built around a seven-stranded beta-sheet flanked by six alpha-helices. The active
      site contains a Ser-Tyr-Lys triad, typical for short-chain
      dehydrogenases/reductases (SDR). Despite their highly diverse substrate
      specificities, SDR members show a close to identical folding pattern
      architectures and a common catalytic mechanism. In contrast to other SDR
      apostructures determined, the substrate binding loop is well-defined. Analysis of
      structure-activity relationships of catalytic cleft residues, docking analysis of
      substrates and inhibitors, and accessible surface analysis explains how
      3beta/17beta-HSD accommodates steroid substrates of different conformations.

PMID- 12475216
TI  - Structure of the complex of calmodulin with the target sequence of calmodulin
      dependent protein kinase I: studies of the kinase activation mechanism.
AB  - Calcium-saturated calmodulin (CaM) directly activates CaM-dependent protein
      kinase I (CaMKI) by binding to a region in the C-terminal regulatory sequence of
      the enzyme to relieve autoinhibition. The structure of CaM in a high-affinity
      complex with a 25-residue peptide of CaMKI (residues 294-318) has been determined
      by X-ray crystallography at 1.7 A resolution. Upon complex formation, the CaMKI
      peptide adopts an alpha-helical conformation, while changes in the CaM domain
      linker enable both its N- and C-domains to wrap around the peptide helix. Target
      peptide residues Trp-303 (interacting with the CaM C-domain) and Met-316 (with
      the CaM N-domain) define the mode of binding as 1-14. In addition, two basic
      patches on the peptide form complementary charge interactions with CaM. The CaM
      peptide affinity is approximately 1 pM, compared with 30 nM for the CaM-kinase
      complex, indicating that activation of autoinhibited CaMKI by CaM requires a
      costly energetic disruption of the interactions between the CaM-binding sequence
      and the rest of the enzyme. We present biochemical and structural evidence
      indicating the involvement of both CaM domains in the activation process: while
      the C-domain exhibits tight binding toward the regulatory sequence, the N-domain
      is necessary for activation. Our crystal structure also enables us to identify
      the full CaM-binding sequence. Residues Lys-296 and Phe-298 from the target
      peptide interact directly with CaM, demonstrating overlap between the
      autoinhibitory and CaM-binding sequences. Thus, the kinase activation mechanism
      involves the binding of CaM to residues associated with the inhibitory
      pseudosubstrate sequence.

PMID- 12475217
TI  - The pH dependence of CD2 domain 1 self-association and 15N chemical exchange
      broadening is correlated with the anomalous pKa of Glu41.
AB  - We have previously shown using (15)N nuclear relaxation measurements that the
      concentration-dependent rotational correlation time and chemical exchange
      broadening for selected resonances of rat CD2 domain 1 (CD2d1) are consistent
      with a model of low-affinity self-association of the protein molecules. The
      exchange broadening data, which at high protein concentrations highlight selected
      nuclei in the major C'-C-F-G beta-sheet face of the immunoglobulin fold,
      implicate a surface reminiscent of the major lattice contact within crystals of
      the intact CD2 ectodomain. In a separate study, we have also demonstrated that
      the beta-strand C' surface-exposed residue Glu41 possesses an anomalously
      elevated acidity constant (pK(a) = 6.7 at a protein concentration of 1.2 mM).
      Mutagenesis studies showed that the close contact of residue Glu41 with Glu29
      (beta-strand C) is the primary cause of the high pK(a). However, the measured
      pK(a) of Glu41 also shows a weak dependence on protein concentration, implicating
      Glu41 in the mechanism of CD2d1 self-association. In the study presented here, we
      demonstrate a correlation of the pH dependence of the chemical shift and (15)N
      nuclear relaxation parameters measured for wild-type and mutant forms of CD2d1
      with pH and the protonation state of Glu41. Self-association of CD2d1 molecules
      is promoted whenever the side chain charge of residue 41 is neutralized. These
      observations are consistent with a model for CD2d1 self-association that
      corresponds to the crystal structure lattice contact where the interatomic
      distances are consistent with Glu41 being in the protonated state. This study
      reinforces the conclusion that residue-specific chemical exchange broadening of
      protein resonances can arise from weak self-association phenomena. In addition,
      the electrostatic profile of rat CD2 interfacial residues parallels that of the
      homologous human CD2 in a manner that suggests a rationalization of similar
      exchange broadening observations.

PMID- 12475218
TI  - Structural basis for the molecular properties of cytochrome c6.
AB  - This is a thorough biochemical, spectroscopic, electrochemical, and structural
      study of a cytochrome c(6) isolated from the filamentous green alga Cladophora
      glomerata. The protein sequence, elucidated using chemical and mass spectrometric
      techniques, features 91 amino acids and the characteristic CXXCH heme-binding
      motif found in c-type cytochromes. The protein is monomeric in both oxidation
      forms, thereby putting in question a functional role for protein dimerization.
      Direct electrochemical measurements established, for the first time, the kinetic
      and thermodynamic data for the redox process in a cytochrome c(6). In particular,
      the quasi-reversible and diffusion-controlled redox process is accompanied by
      negative enthalpy and entropy changes, resulting in an E degrees ' value of 0.352
      V at 298 K. The pH-dependent properties of the oxidized protein, detected by UV
      visible, NMR, and direct cyclic voltammetry, indicate the presence of two acid
      base equilibria occurring in the acidic (pK(a) = 4.5) and alkaline regions (pK(a)
      = 9.0). NMR and electronic spectra allowed the assignment of these equilibria to
      deprotonation of heme propionate-7 and to replacement of the axial methionine
      with another ligand, respectively. The 1.3 A resolution X-ray structure of the
      oxidized protein, revealing a fold typical for class I cytochromes, suggests that
      the conserved Lys60 replaces the axial methionine at pH >9. The heme solvent
      accessibility is low, and no water molecules were found in the vicinity of the
      axial ligands of the heme Fe. A structure-based alignment of cytochromes c(6),
      and the direct comparison of their structures, indicate a substantial degree of
      identity between the tertiary structures and suggest patches involved in protein
      protein interaction. In particular, the surface electrostatic potential of
      cytochromes c(6) features a hydrophobic region around the heme cofactor, and a
      backside surface rich in negative charges.

PMID- 12475219
TI  - A protein caught in a kinetic trap: structures and stabilities of insulin
      disulfide isomers.
AB  - Proinsulin contains six cysteines whose specific pairing (A6-A11, A7-B7, and A20
      B19) is a defining feature of the insulin fold. Pairing information is contained
      within A and B domains as demonstrated by studies of insulin chain recombination.
      Two insulin isomers containing non-native disulfide bridges ([A7-A11,A6-B7,A20
      B19] and [A6-A7,A11-B7,A20-B19]), previously prepared by directed chemical
      synthesis, are metastable and biologically active. Remarkably, the same two
      isomers are preferentially formed from native insulin or proinsulin following
      disulfide reassortment in guanidine hydrochloride. The absence of other disulfide
      isomers suggests that the observed species exhibit greater relative stability
      and/or kinetic accessibility. The structure of the first isomer ([A7-A11,A6
      B7,A20-B19], insulin-swap) has been described [Hua, Q. X., Gozani, S. N., Chance,
      R. E., Hoffmann, J. A., Frank, B. H., and Weiss, M. A. (1995) Nat. Struct. Biol.
      2, 129-138]. Here, we demonstrate that the second isomer (insulin-swap2) is less
      ordered than the first. Nativelike elements of structure are retained in the B
      chain, whereas the A chain is largely disordered. Thermodynamic studies of
      guanidine denaturation demonstrate the instability of the isomers relative to
      native insulin (DeltaDeltaG(u) > 3 kcal/mol). In contrast, insulin-like growth
      factor I (IGF-I) and the corresponding isomer IGF-swap, formed as alternative
      products of a bifurcating folding pathway, exhibit similar cooperative unfolding
      transitions. The insulin isomers are similar in structure and stability to two
      disulfide analogues whose partial folds provide models of oxidative folding
      intermediates. Each exhibits a nativelike B chain and less-ordered A chain. This
      general asymmetry is consistent with a hierarchical disulfide pathway in which
      nascent structure in the B chain provides a template for folding of the A chain.
      Structures of metastable disulfide isomers provide probes of the topography of an
      energy landscape.

PMID- 12475220
TI  - Determination of proton transfer rates by chemical rescue: application to
      bacterial reaction centers.
AB  - The bacterial reaction center (RC) converts light into chemical energy through
      the reduction of an internal quinone molecule Q(B) to Q(B)H(2). In the native RC,
      proton transfer is coupled to electron transfer and is not rate-controlling.
      Consequently, proton transfer is not directly observable, and its rate was
      unknown. In this work, we present a method for making proton transfer rate
      controlling, which enabled us to determine its rate. The imidazole groups of the
      His-H126 and His-H128 proton donors, located at the entrance of the transfer
      pathways, were removed by site-directed mutagenesis (His --> Ala). This resulted
      in a reduction in the observed proton-coupled electron transfer rate [(Q(A)(
      )(*)Q(B))Glu(-) + H(+) --> (Q(A)Q(B)(-)(*))GluH], which became rate-controlled by
      proton uptake to Glu-L212 [Adelroth, P., et al. (2001) Biochemistry 40, 14538
      14546]. The proton uptake rate was enhanced (rescued) in a controlled fashion by
      the addition of imidazole or other amine-containing acids. From the dependence of
      the observed rate on acid concentration, an apparent second-order rate constant
      k((2)) for the "rescue" of the rate was determined. k((2)) is a function of the
      proton transfer rate and the binding of the acid. The dependence of k((2)) on the
      acid pK(a) (i.e., the proton driving force) was measured over 9 pK(a) units,
      resulting in a Bronsted plot that was characteristic of general acid catalysis.
      The results were fitted to a model that includes the binding (facilitated by
      electrostatic attraction) of the cationic acid to the RC surface, proton transfer
      to an intermediate proton acceptor group, and subsequent proton transfer to Glu
      L212. A proton transfer rate constant of approximately 10(5) s(-)(1) was
      determined for transfer from the bound imidazole group to Glu-L212 (over a
      distance of approximately 20 A). The same method was used to determine a proton
      transfer rate constant of 2 x 10(4) s(-)(1) for transfer to Q(B)(-)(*). The
      relatively fast proton transfer rates are explained by the presence of an
      intermediate acceptor group that breaks the process into sequential proton
      transfer steps over shorter distances. This study illustrates an approach that
      could be generally applied to obtain information about the individual rates and
      energies for proton transfer processes, as well as the pK(a)s of transfer
      components, in a variety of proton translocating systems.

PMID- 12475221
TI  - Suppression of interleukin-1 beta-induced nitric oxide production in RINm5F cells
      by inhibition of glucose-6-phosphate dehydrogenase.
AB  - In rat pancreatic islets and insulin-producing cell lines, IL-1beta induces
      expression of inducible nitric oxide synthase and NO production leading to
      impairment of glucose-stimulated insulin release and decreased cell survival.
      NADPH is an obligatory cosubstrate for iNOS synthesis of NO. We hypothesized that
      IL-1beta stimulates an increase in activity of NADPH-producing enzyme(s) prior to
      NO production and that this increase is necessary for NO production. Using rat
      insulin-secreting RINm5F cells, we found that (1) IL-1beta caused a biphasic
      change in the NADPH level (increased by 6 h and decreased after prolonged
      incubation in the presence of 2 ng/mL IL-1beta); (2) IL-1beta stimulated
      increased activity of glucose-6-phosphate dehydrogenase (G6PD) in a time- and
      dose-dependent manner, and G6PD expression was increased by about 80% after
      exposure to 2 ng/mL IL-1beta for 18 h: (3) IL-1beta-stimulated NO production was
      positively correlated with increased G6PD activity; (4) IL-1beta did not cause
      any significant change in enzyme activity of another NADPH-producing enzyme,
      malic enzyme; (5) IL-1beta-induced NO production was significantly reduced either
      by inhibiting G6PD activity using an inhibitor of G6PD (dehydroepiandrosterone)
      or by inhibiting G6PD expression using an antisense oligonucleotide to G6PD mRNA;
      and (6) IL-1beta stimulated a decrease in the cAMP level. 8-Bromo-cAMP caused
      decreased G6PD activity, and the protein kinase A inhibitor H89 led to a increase
      in G6PD activity in RINm5F cells. In conclusion, our data show that IL-1beta
      stimulated G6PD activity and expression level, providing NADPH that is required
      by iNOS for NO production in RINm5F cells. Also, inhibition of the cAMP-dependent
      PKA signal pathway is involved in an IL-1beta-stimulated increase in G6PD
      activity.

PMID- 12475222
TI  - Two tarantula peptides inhibit activation of multiple sodium channels.
AB  - Two peptides, ProTx-I and ProTx-II, from the venom of the tarantula Thrixopelma
      pruriens, have been isolated and characterized. These peptides were purified on
      the basis of their ability to reversibly inhibit the tetrodotoxin-resistant Na
      channel, Na(V) 1.8, and are shown to belong to the inhibitory cystine knot (ICK)
      family of peptide toxins interacting with voltage-gated ion channels. The family
      has several hallmarks: cystine bridge connectivity, mechanism of channel
      inhibition, and promiscuity across channels within and across channel families.
      The cystine bridge connectivity of ProTx-II is very similar to that of other
      members of this family, i.e., C(2) to C(16), C(9) to C(21), and C(15) to C(25).
      These peptides are the first high-affinity ligands for tetrodotoxin-resistant
      peripheral nerve Na(V) channels, but also inhibit other Na(V) channels (IC(50)'s
      < 100 nM). ProTx-I and ProTx-II shift the voltage dependence of activation of
      Na(V) 1.5 to more positive voltages, similar to other gating-modifier ICK family
      members. ProTx-I also shifts the voltage dependence of activation of Ca(V) 3.1
      (alpha(1G), T-type, IC(50) = 50 nM) without affecting the voltage dependence of
      inactivation. To enable further structural and functional studies, synthetic
      ProTx-II was made; it adopts the same structure and has the same functional
      properties as the native peptide. Synthetic ProTx-I was also made and exhibits
      the same potency as the native peptide. Synthetic ProTx-I, but not ProTx-II, also
      inhibits K(V) 2.1 channels with 10-fold less potency than its potency on Na(V)
      channels. These peptides represent novel tools for exploring the gating
      mechanisms of several Na(V) and Ca(V) channels.

PMID- 12475223
TI  - Subtype-specific regulation of receptor internalization and recycling by the
      carboxyl-terminal domains of the human A1 and rat A3 adenosine receptors:
      consequences for agonist-stimulated translocation of arrestin3.
AB  - In this study, we have characterized the differential effects on inhibitory
      adenosine receptor (AR) trafficking of disrupting predicted sites for
      palmitoylation and phosphorylation within each receptor's carboxyl terminus.
      While a Cys(302,305)Ala-mutated rat A(3)AR mutant internalizes significantly
      faster than the wild-type (WT) receptor in response to agonist exposure,
      analogous mutation of the human A(1)AR (Cys(309)Ala) had no effect on receptor
      internalization. Moreover, unlike the WT A(3)AR, the entire pool of internalized
      mutant A(3)AR is able to recycle back to the plasma membrane following agonist
      removal. These properties do not reflect utilization of an alternative
      trafficking pathway, as internalized WT and mutant A(3)ARs both accumulate into
      transferrin receptor-positive endosomal compartments. However, receptor
      accumulation into endosomes is dependent upon prior G-protein-coupled receptor
      kinase (GRK)-mediated phosphorylation of the receptor's carboxyl terminus, as
      replacement of the carboxyl-terminal domain of the human A(1)AR with the 14 GRK
      phosphorylated amino acids of the rat A(3)AR confers rapid agonist-mediated
      endosomal accumulation of the resulting chimeric A(1)CT3AR. Sensitivity to GRK
      mediated phosphorylation also dictates the distinct redistribution of arrestin3
      observed upon agonist exposure. Thus, while the nonphosphorylated A(1)AR
      redistributes arrestin3 from the cytoplasm to punctate clusters at the plasma
      membrane, GRK-phosphorylated WT and Cys(302,305)Ala-mutated A(3)ARs, as well as
      the A(1)CT3AR chimera, each induce the redistribution of arrestin3 into punctate
      accumulations both at the plasma membrane and within the cytoplasm. Neither the
      human A(1)AR nor the rat A(3)AR colocalized with arrestin3 under basal or agonist
      stimulated conditions. Together, these results demonstrate that inhibitory AR
      mediated changes in arrestin3 distribution are subtype-specific, with specificity
      correlating with the sensitivity of the receptor's carboxyl-terminal domain to
      GRK phosphorylation. In the case of the rat A(3)AR, sensitivity to GRK-mediated
      internalization appears to be regulated in part by the integrity of putative
      palmitate attachment sites upstream of its GRK phosphoacceptor sites.

PMID- 12475224
TI  - Mechanism of nucleocapsid protein catalyzed structural isomerization of the
      dimerization initiation site of HIV-1.
AB  - Dimerization of two homologous strands of genomic RNA is an essential feature of
      retroviral replication. In the human immunodeficiency virus type 1 (HIV-1), a
      conserved stem-loop sequence, the dimerization initiation site (DIS), has been
      identified as the domain primarily responsible for initiation of this aspect of
      viral assembly. The DIS loop contains an autocomplementary hexanucleotide
      sequence flanked by highly conserved 5' and 3' purines and can form a homodimer
      through a loop-loop kissing interaction. In a structural rearrangement activated
      by the HIV-1 nucleocapsid protein (NCp7) and considered to be associated with
      viral particle maturation, the DIS dimer converts from an intermediate kissing to
      an extended duplex isoform. Using 2-aminopurine (2-AP) labeled sequences derived
      from the DIS(Mal) variant and fluorescence methods, the two DIS dimer isoforms
      have been unambiguously distinguished, allowing a detailed examination of the
      kinetics of this RNA structural isomerization and a characterization of the role
      of NCp7 in the reaction. In the presence of divalent cations, the DIS kissing
      dimer is found to be kinetically trapped and converts to the extended duplex
      isoform only upon addition of NCp7. NCp7 is demonstrated to act catalytically in
      inducing the structural isomerization by accelerating the rate of strand exchange
      between the two hairpin stem helices, without disruption of the loop-loop helix.
      Observation of an apparent maximum conversion rate for NCp7-activated DIS
      isomerization, however, requires protein concentrations in excess of the 2:1
      stoichiometry estimated for high-affinity NCp7 binding to the DIS kissing dimer,
      indicating that transient interactions with additional NCp7(s) may be required
      for catalysis.

PMID- 12475225
TI  - Structure and dynamics of the modular halves of Escherichia coli cyclic AMP
      receptor protein.
AB  - E. coli cyclic AMP receptor protein, CRP, is a modular protein that consists of a
      covalent linkage of two common structural domains. To probe the mechanism for
      intramolecular communications and to define the unique properties acquired by
      covalent linkage, the structural, and functional properties of the cAMP- and DNA
      binding domains of CRP were studied separately as two independent polypeptides.
      The N-terminal cAMP-binding domain (alpha-CRP), including S-CRP and CH-CRP, which
      were generated by digestion of CRP by subtilisin and chymotrypsin, respectively,
      are mainly populated by beta-sheets. The C-terminal DNA-binding domain,
      designated as beta-CRP, consists of mostly alpha-helices. The residues of S-CRP
      and CH-CRP are from 1 to 116 and 1 to 136 of intact wild-type CRP, and those of
      beta-CRP are from 108 to 209. The secondary structures of alpha-CRP and beta-CRP
      were monitored by FT-IR, and they are similar to those of the corresponding parts
      in intact wild-type CRP. Results from hydrogen-deuterium exchange experiments
      indicated that beta-CRP is more dynamic than alpha-CRP. In an earlier study, it
      was shown that alpha-CRP retains the function of binding cAMP [Heyduk, E., et al.
      (1992) Biochemistry 31, 3682-3688]. beta-CRP was able to bind to DNA, although
      only weakly, and was not sequence specific. Thus, a covalent linkage between the
      two domains is essential for the realization of the intramolecular signal
      transmission between the domains triggered by ligand binding. The acquisition of
      this unique property is intimately associated with the dynamics of the molecule.

PMID- 12475226
TI  - A kinetics and modeling study of RANTES(9-68) binding to heparin reveals a
      mechanism of cooperative oligomerization.
AB  - Heparan sulfate (HS) and heparin bind to virtually all chemokines and have been
      shown to play critical roles in the regulation of their activities. However, both
      binding mechanisms and structural features involved in chemokine-HS interactions
      remain poorly defined. In the study presented here, we analyzed the binding of
      heparin to RANTES(9-68), a N-terminally truncated form of the CC-chemokine
      RANTES. Using biochemical and surface plasmon resonance (BIAcore system)
      approaches, we showed that the RANTES(9-68)-heparin interaction was characterized
      by a complex binding model that involved dimerization of the chemokine through a
      mechanism of positive cooperativity. Since RANTES(9-68) remains monomeric in
      solution, we concluded that heparin induced chemokine dimerization. The structure
      of a complex involving a RANTES dimer and a heparin heptadecasaccharide was
      proposed by molecular modeling. This model was used to design a dimer of "head to
      head" coupled octasaccharides that would fit the internal symmetry of the
      chemokine dimer. This engineered oligosaccharide bound RANTES(9-68) much better
      than a natural heparin fragment of the same length, further supporting the
      interaction process and the proposed structural model. Altogether, the data
      reported here provide a basis for understanding the mechanisms by which HS
      modulates RANTES functions.

PMID- 12475227
TI  - Crystal structure of phospholipase A2 complex with the hydrolysis products of
      platelet activating factor: equilibrium binding of fatty acid and
      lysophospholipid-ether at the active site may be mutually exclusive.
AB  - We have solved the 1.55 A crystal structure of the anion-assisted dimer of
      porcine pancreatic group IB phospholipase A2 (PLA2), complexed with the products
      of hydrolysis of the substrate platelet activating factor. The dimer contains
      five coplanar phosphate anions bound at the contact surface between the two PLA2
      subunits. This structure parallels a previously reported anion-assisted dimer
      that mimics the tetrahedral intermediate of PLA2 bound to a substrate interface
      [Pan, Y. H., et al. (2001) Biochemistry 40, 609-617]. The dimer structure has a
      molecule of the product acetate bound in subunit A and the other product 1
      octadecyl-sn-glycero-3-phosphocholine (LPC-ether) to subunit B. Therefore, this
      structure is of the two individual product binary complexes and not of a ternary
      complex with both products in one active site of PLA2. Protein crystals with
      bound products were only obtained by cocrystallization starting from the initial
      substrate. In contrast, an alternate crystal form was obtained when PLA2 was
      cocrystallized with LPC-ether and succinate, and this crystal form did not
      contain bound products. The product bound structure has acetate positioned in the
      catalytic site of subunit A such that one of its oxygen atoms is located 3.5 A
      from the catalytic calcium. Likewise, a longer than typical Ca-to-Gly(32)
      carbonyl distance of 3.4 A results in a final Ca coordination that is four
      coordinate and has distorted geometry. The other oxygen of acetate makes hydrogen
      bonds with N(delta)(1)-His(48), O(delta)(1)-Asp(49), and the catalytic assisting
      water (w7). In contrast, the glycerophosphocholine headgroup of LPC-ether in
      subunit B makes no contacts with calcium or with the catalytic residues His(48)
      or Asp(49). The tail of the LPC-ether is located near the active site pocket with
      the last nine carbons of the sn-1- acyl chain refined in two alternate
      conformations. The remaining atoms of the LPC-ether product have been modeled
      into the solvent channel but have their occupancies set to zero in the refined
      model due to disorder. Together, the crystallographic and equilibrium binding
      results with the two products show that the simultaneous binding of both the
      products in a single active site is not favored.

PMID- 12475228
TI  - Estrone 3-sulfate mimics, inhibitors of estrone sulfatase activity: homology
      model construction and docking studies.
AB  - Steroid sulfatase (STS) is a new target for the endocrine therapy of breast
      cancer. To ascertain some of the requirements for inhibition of estrone sulfatase
      activity, a number of novel analogues of estrone 3-O-sulfate possessing sulfate
      surrogates were synthesized and evaluated as inhibitors of estrone sulfatase
      (STS) in comparison to a lead inhibitor, estrone-3-O-methylthiophosphonate (E1-3
      MTP). Using a selective enzyme digestion, one of the diastereoisomers of this
      compound, (R(p))-E1-3-MTP, could be prepared and evaluated. From structure
      activity studies, we show that chirality at the phosphorus atom, hydrophobicity,
      basicity, size, and charge all influence the ability of a compound to inhibit
      estrone sulfatase activity. Of these, hydrophobicity seems to be the most
      important since simple, active nonsteroidal inhibitors, based on 5,6,7,8
      tetrahydronaphth-2-ol (THN), can be prepared, provided that they are lipophilic
      enough to partition into a nonpolar environment. Also, a negatively charged group
      is favorable for optimal binding, although it appears that the presence of a
      potentially cleavable group can compensate for lack of charge in certain cases. A
      homology model of STS has been constructed from the STS sequence, and molecular
      docking studies of inhibitors have been performed to broaden the understanding of
      enzyme/inhibitor interactions. This model clearly shows the positions of the key
      amino acid residues His136, His290, Lys134, and Lys368 in the putative catalytic
      region of the formylglycine at position 75, with residues Asp35, Asp36, Asp342,
      and Gln343 as ligands in the coordination sphere of the magnesium ion. Docking
      studies using the substrate and estrone-3-sulfate mimics that are active
      inhibitors indicate they are positioned in the area of proposed catalysis,
      confirming the predictive power of the model.

PMID- 12475229
TI  - Interactions that favor the native over the non-native disulfide bond among
      residues 58-72 in the oxidative folding of bovine pancreatic ribonuclease A.
AB  - In the initial stages of the oxidative folding of both bovine pancreatic
      ribonuclease A (RNase A) and a 58-72 fragment thereof from the fully reduced,
      denatured state, the 65-72 correctly paired disulfide bond forms in preponderance
      over the incorrectly paired 58-65 disulfide bond. Since both disulfide-bonded
      loops contain the same number of amino acid residues, the question arises as to
      whether the native pairing results from interactions within the 58-72 segment
      that lead to a nativelike structure even in its fully reduced form. To answer
      this question, the chain buildup procedure, based on ECEPP, including a solvation
      treatment, was used to generate the low-energy structures for the 58-72 RNase
      segment, beginning with residue 72 and building back to residue 58; in this
      fragment, all three Cys residues (at positions 58, 65, and 72) initially exist in
      the reduced (CysH) state. After the open-chain energy minima of the 65-72 peptide
      were generated, these conformations were allowed to form the 65-72 disulfide
      bond, and the energies of the resulting oxidized conformations were reminimized
      and rehydrated. The global minimum of the loop-closed 65-72 structure and many of
      the low-lying loop-closed minima could be superimposed on the energy-minimized X
      ray structure for residues 65-72. The low-energy structures for the full open
      chain 58-72 peptide were then computed and were allowed to form disulfide bonds
      either between residues 65 and 72 (native) or between residues 58 and 65 (non
      native), and their energies were reminimized and rehydrated in the loop-closed
      state. Although the overall fold of the 65-72 loop-closed global minimum was the
      same as for the energy-minimized X-ray structure of these residues, the overall
      rms deviation was 3.9 A because of local deviations among residues 58-64. In
      contrast, the 65-72 segment of the global minimum of the 58-72 fragment could be
      superimposed on the corresponding residues of the energy-minimized X-ray
      structure. The lowest-energy structure for the 58-65 non-native paired 58-72
      sequence was 6 kcal/mol higher in energy than that for the 58-72 peptide with the
      65-72 disulfide bond formed. These results suggest that the native pairing of the
      65-72 peptide arises from energetic determinants (adoption of left-handed single
      residue conformations by Gly 68, and side chain interactions involving Gln 69)
      contained within this peptide sequence.

PMID- 12475230
TI  - Affinity and sequence specificity of DNA binding and site selection for primer
      synthesis by Escherichia coli primase.
AB  - Primase is an essential DNA replication enzyme in Escherichia coli and
      responsible for primer synthesis during lagging strand DNA replication. Although
      the interaction of primase with single-stranded DNA plays an important role in
      primer RNA and Okazaki fragment synthesis, the mechanism of DNA binding and site
      selection for primer synthesis remains unknown. We have analyzed the energetics
      of DNA binding and the mechanism of site selection for the initiation of primer
      RNA synthesis on the lagging strand of the replication fork. Quantitative
      analysis of DNA binding by primase was carried out using a number of
      oligonucleotide sequences: oligo(dT)(25) and a 30 bp oligonucleotide derived from
      bacteriophage G4 origin (G4ori-wt). Primase bound both sequences with moderate
      affinity (K(d) = 1.2-1.4 x 10(-)(7) M); however, binding was stronger for G4ori
      wt. G4ori-wt contained a CTG trinucleotide, which is a preferred site for
      initiation of primer synthesis. Analysis of DNA binding isotherms derived from
      primase binding to the oligonucleotide sequences by fluorescence anisotropy
      indicated that primase bound to DNA as a dimer, and this finding was further
      substantiated by electrophoretic mobility shift assays (EMSAs) and UV cross
      linking of the primase-DNA complex. Dissection of the energetics involved in the
      primase-DNA interaction revealed a higher affinity of primase for DNA sequences
      containing the CTG triplet. This sequence preference of primase may likely be
      responsible for the initiation of primer synthesis in the CTG triplet sites in
      the E. coli lagging strand as well as in the origin of replication of
      bacteriophage G4.

PMID- 12475231
TI  - Lysine 152 of MuLV reverse transcriptase is required for the integrity of the
      active site.
AB  - Comparison of the three-dimensional structure of the active sites of MuLV and HIV
      1 reverse transcriptases shows the presence of a lysine residue (K152) in the
      substrate-binding region in MuLV RT, while its equivalent position in HIV-1 RT is
      occupied by a glycine (G112). To investigate the role of K152 in the mechanism of
      the polymerase reaction catalyzed by MuLV RT, four mutant RTs, namely, K152A,
      K152R, K152E, and K152G, were generated and biochemically characterized. All
      muteins exhibited reduced polymerase activity on both RNA and DNA template
      primers with K152E being the most defective. The template-primer binding affinity
      and the processivity of DNA synthesis, however, remained unchanged. The steady
      state kinetic characterization showed little change in K(m.dNTP) (except for that
      of K152E) and an approximately 3-10-fold decrease in k(cat) depending upon the
      template-primer and mutational substitutions. The ddNTP resistance patterns were
      unchanged for all muteins, suggesting no participation of K152 in ddNTP
      recognition. The ability of individual muteins to add dNTP on the covalently
      cross-linked enzyme-template-primer complex was significantly decreased. These
      results together with the analysis of the ion pairs in the catalytic apparatus of
      MuLV RT suggest that K152 participates in maintaining the integrity of the active
      site of MuLV RT. Examination of the prepolymerase ternary complex formation
      showed that neither the wild type nor any of the K152 muteins of MuLV RT are
      capable of forming stable ternary complexes. This property is in contrast to that
      of HIV-1 RT, which readily forms stable ternary complexes under similar
      conditions. These results further indicate that the catalytic mechanism of MuLV
      RT is significantly different from that of HIV-1 RT, despite the presence of a
      number of conserved motifs and amino acid residues.

PMID- 12475232
TI  - Electron paramagnetic resonance dynamic signatures of TAR RNA-small molecule
      complexes provide insight into RNA structure and recognition.
AB  - Electron paramagnetic resonance (EPR) spectroscopy was utilized to investigate
      the correlation between RNA structure and RNA internal dynamics in complexes of
      HIV-1 TAR RNA with small molecules. TAR RNAs containing single nitroxide spin
      labels in the 2'-position of U23, U25, U38, or U40 were incubated with compounds
      known to inhibit TAR-Tat complex formation. The combined changes in nucleotide
      mobility at all four sites, as monitored by their EPR spectral width, yield a
      dynamic signature for each compound. The multicyclic dyes Hoechst 33258, DAPI,
      and berenil bind to TAR RNA in a similar manner and gave nearly identical
      signatures. Different signatures were obtained for the acridine derivative CGP
      40336A and the aminoglycoside antibiotic neomycin, which bind to different
      regions of the RNA. The dynamic signature for guanidinoneomycin was remarkably
      similar to that obtained for argininamide and is evidence for guanidinoneomycin
      binding to the same site as arginine 52 of the Tat protein, rather than to the
      neomycin binding site. The data presented here show that the dynamic signatures
      provide strong insights into RNA structure and recognition and demonstrate the
      value of EPR spectroscopy for the investigation of small molecule binding to RNA.

PMID- 12475233
TI  - Multiple metal ions drive DNA association by PvuII endonuclease.
AB  - Restriction enzymes serve as important model systems for understanding the role
      of metal ions in phosphodiester hydrolysis. To this end, a number of laboratories
      have reported dramatic differences between the metal ion-dependent and metal ion
      independent DNA binding behaviors of these systems. In an effort to illuminate
      the underlying mechanistic details which give rise to these differences, we have
      quantitatively dissected these equilibrium behaviors into component association
      and dissociation rates for the representative PvuII endonuclease and use these
      data to assess the stoichiometry of metal ion involvement in the binding process.
      The dependence of PvuII cognate DNA on Ca(II) concentration binding appears to be
      cooperative, exhibiting half-saturation at 0.6 mM metal ion and yielding an n(H)
      of 3.5 +/- 0.2 per enzyme homodimer. Using both nitrocellulose filter binding and
      fluorescence assays, we observe that the cognate DNA dissociation rate (k(-)(1)
      or k(off)) is very slow (10(-)(3) s(-)(1)) and exhibits a shallow dependence on
      metal ion concentration. DNA trap cleavage experiments with Mg(II) confirm the
      general irreversibility of DNA binding relative to cleavage, even at low metal
      ion concentrations. More dramatically, the association rate (k(1) or k(on)) also
      appears to be cooperative, increasing more than 100-fold between 0.2 and 10 mM
      Ca(II), with an optimum value of 2.7 x 10(7) M(-)(1) s (-)(1). Hill analysis of
      the metal ion dependence of k(on) indicates an n(H) of 3.6 +/- 0.2 per enzyme
      dimer. This value is consistent with the involvement in DNA association of two
      metal ions per subunit active site, a result which lends new strength to
      arguments for two-metal ion mechanisms in restriction enzymes.

PMID- 12475234
TI  - Crucial role of conserved lysine 277 in the fidelity of tRNA aminoacylation by
      Escherichia coli valyl-tRNA synthetase.
AB  - Valyl-tRNA synthetase (ValRS) from Escherichia coli undergoes covalent valylation
      by a donor valyl adenylate synthesized by the enzyme itself. ValRS could also be
      modified, although to a lesser extent, by the noncognate isosteric substrate L
      threonine from a donor threonyl adenylate synthesized by the synthetase itself,
      or by the nonsubstrate methionine from methionyl adenylate produced by catalytic
      amounts of methionyl-tRNA synthetase. MALDI mass spectrometry analysis designated
      lysines 154, 162, 170, 533, 554, 593, 894, 930, and 940 of ValRS as the target
      residues for the attachment of valine. Following autothreonylation, lysines 162,
      170, 178, 277, 291, 554, 580, 593, 861, 894, and 930 were found to be modified.
      Finally, L-Met-labeled residues were lysines 118, 162, 170, 178, 277, and 938.
      Alignment of the available ValRS amino acid sequences showed that lysines 277 and
      554 are strictly conserved (with the exception concerning replacement of Lys-277
      with a methionine or a tyrosine in archaebacteria), suggesting that these
      residues might be functionally significant. Indeed, lysine 554 of ValRS is the
      first lysine of the Lys-Met-Ser-Lys-Ser signature of the catalytic site of class
      I aminoacyl-tRNA synthetases. Lys-277 which is labeled by L-threonine or L
      methionine, and not by L-valine, is located at or near the editing site, in the
      three-dimensional structure of ValRS. The role of lysine 277 was evaluated by
      site-directed mutagenesis. The Lys277Ala mutant (K277A) exhibited a posttransfer
      Thr-tRNA(Val) editing rate that was significantly lower than that observed for
      the wild-type enzyme. In addition, the K277A substitution altered amino acid
      discrimination in the editing site, resulting in hydrolysis of the correctly
      charged cognate Val-tRNA(Val). Finally, significant amounts of mischarged Thr
      tRNA(Val) were produced by the K277A mutant, and not by wild-type ValRS.
      Altogether, our results designate Lys-277 as a likely candidate for nucleophilic
      attack of misacylated tRNA in the editing site of ValRS.

PMID- 12475235
TI  - Trp repressor-operator binding: NMR and electrophoretic mobility shift studies of
      the effect of DNA sequence and corepressor binding on two Trp repressor-operator
      complexes.
AB  - In Trp repressor-DNA complexes, most interactions either occur with phosphate
      groups or are water-mediated hydrogen bonds to bases. To examine the factors
      involved in DNA selectivity, we have studied Trp repressor binding to two
      operator sequences, trpR(S)() and trpO(M)(), with L-tryptophan or 5
      methyltryptophan as corepressor. These operators contain all the consensus bases
      but differ at base pairs contacted by their phosphate groups. In electrophoretic
      mobility shift assays (EMSAs) the trpR(S)() sequence gives solely 1:1 protein-DNA
      complexes with either corepressor. The trpO(M )()sequence binds more weakly than
      trpR(S)(). It gives dissociating 2:1 complexes in EMSAs with L-tryptophan, but
      both 1:1 and 2:1 complexes are observed with 5-methyltryptophan or if glycerol is
      present in the gel. The backbone resonances of the TrpR-L-tryptophan-DNA
      complexes were assigned using triple-resonance experiments and selectively (15)N
      labeled protein. On changing the DNA sequence, the largest differences in the NMR
      spectra are at residues 78-81, at the turn of the helix-turn-helix motif and the
      tip of the recognition helix. I79 and A80 interact with the conserved bases of
      the operators, while G78 and T81 interact with phosphate groups at bases that
      differ between the two sequences. Changing the corepressor from L-tryptophan to 5
      methyltryptophan causes effects at residues 52, 60, 61, and 85, which do not
      interact with the DNA. The spectra suggest that there is mutual induced fit
      between protein and DNA so that sequence changes at bases contacted only by the
      phosphate groups affect the environment of the protein at residues that bind to
      conserved bases elsewhere in the DNA.

PMID- 12475236
TI  - Fusidic and helvolic acid inhibition of elongation factor 2 from the archaeon
      Sulfolobus solfataricus.
AB  - Fusidic acid (FA) and helvolic acid (HA) belong to a small family of naturally
      occurring steroidal antibiotics known as fusidanes. FA was studied for its
      ability to alter the biochemical properties supported by elongation factor 2
      isolated from the archaeon Sulfolobus solfataricus (SsEF-2). Both poly(Phe)
      synthesis and ribosome-dependent GTPase (GTPase(r)) were progressively impaired
      by increasing concentrations of FA up to 1 mM, whereas no effect was measured in
      the intrinsic GTPase of SsEF-2 triggered by ethylene glycol in the presence of
      barium chloride (GTPase(g)). The highest antibiotic concentration caused
      inhibition of either poly(Phe) synthesis or GTPase(r) only slightly above 50%. A
      greater response of SsEF-2 was observed when HA was used instead of FA. HA caused
      even a weak impairment of GTPase(g). A mutated form of SsEF-2 carrying the L452R
      substitution exhibited an increased sensitivity to fusidane inhibition in either
      poly(Phe) synthesis or GTPase(r). Furthermore, both FA and HA were able to cause
      impairment of GTPase(g). The antibiotic concentrations leading to 50% inhibition
      (IC(50)) indicate that increased fusidane responsiveness due to the use of HA or
      the L452R amino acid replacement is mutually independent. However, their combined
      effect decreased the IC(50) up to 0.1 mM. Despite the difficulties in reaching
      complete inhibition of the translocation process in S. solfataricus, these
      findings suggest that fusidane sensibility is partially maintained in the
      archaeon S. solfataricus. Therefore, it is likely that SsEF-2 harbors the
      structural requirements for forming complexes with fusidane antibiotics. This
      hypothesis is further evidenced by the observed low level of impairment of
      GTPase(g), a finding suggesting a weak direct interaction between the archaeal
      factor and fusidanes even in the absence of the ribosome. However, the ribosome
      remains essential for the sensitivity of SsEF-2 toward fusidane antibiotics.

PMID- 12475237
TI  - Toward a unified scheme for the aggregation of tau into Alzheimer paired helical
      filaments.
AB  - Alzheimer's disease is characterized by aggregates of tau protein. Attempts to
      study the conditions for aggregation in vitro have led to different experimental
      systems, some of which appear mutually exclusive (e.g., oxidative vs reductive
      conditions, induction by polyanions vs fatty acids). We show here that different
      approaches and pathways can be viewed in a common framework, and that apparent
      differences can be explained by variations in the kinetics of subreactions. A
      unified view of PHF aggregation should help to analyze the causes of PHF
      aggregation and devise methods to prevent it.

PMID- 12475238
TI  - Proximity of cytoplasmic and periplasmic loops in NhaA Na+/H+ antiporter of
      Escherichia coli as determined by site-directed thiol cross-linking.
AB  - The unique trypsin cleavable site of NhaA, the Na(+)/H(+) antiporter of
      Escherichia coli, was exploited to detect a change in mobility of cross-linked
      products of NhaA by polyacrylamide gel electrophoresis. Double-Cys replacements
      were introduced into loops, one on each side of the trypsin cleavage site (Lys
      249). The proximity of paired Cys residues was assessed by disulfide cross
      linking of the two tryptic fragments, using three homobifunctional cross-linking
      agents: 1,6-bis(maleimido)hexane (BMH), N,N'-o-phenylenedimaleimide (o-PDM), and
      N,N'-p-phenylenedimaleimide (p-PDM). The interloop cross-linking was found to be
      very specific, indicating that the loops are not merely random coils that
      interact randomly. In the periplasmic side of NhaA, two patterns of cross-linking
      are observed: (a) all three cross-linking reagents cross-link very efficiently
      between the double-Cys replacements A118C/S286C, N177C/S352C, and H225C/S352C;
      (b) only BMH cross-links the double-Cys replacements A118C/S352C, N177C/S286C,
      and H225C/S286C. In the cytoplasmic side of NhaA, three patterns of cross-linking
      are observed: (a) all three cross-linking reagents cross-link very efficiently
      the pairs of Cys replacements L4C/E252C, S146C/L316C, S146C/R383C, and
      E241C/E252C; (b) BMH and p-PDM cross-link efficiently the pairs of Cys
      replacements S87C/E252C, S87C/L316C, and S146C/E252C; (c) none of the reagents
      cross-links the double-Cys replacements L4C/L316C, L4C/R383C, S87C/R383C,
      A202C/E252C, A202C/L316C, A202C/R383C, E241C/L316C, and E241C/R383C. The data
      reveal that the N-terminus and loop VIII-IX that have previously been shown to
      change conformation with pH are in close proximity within the NhaA protein. The
      data also suggest close proximity between N-terminal and C-terminal helices at
      both the cytoplasmic and the periplasmic face of NhaA.

PMID- 12475239
TI  - The heavy chain of conventional kinesin interacts with the SNARE proteins SNAP25
      and SNAP23.
AB  - Recent studies on the conventional motor protein kinesin have identified a
      putative cargo-binding domain (residues 827-906) within the heavy chain. To
      identify possible cargo proteins which bind to this kinesin domain, we employed a
      yeast two-hybrid assay. A human brain cDNA library was screened, using as bait
      residues 814-963 of human ubiquitous kinesin heavy chain. This screen initially
      identified synaptosome-associated protein of 25 kDa (SNAP25) as a kinesin-binding
      protein. Subsequently, synaptosome-associated protein of 23 kDa (SNAP23), the
      nonneuronal homologue of SNAP25, was also confirmed to interact with kinesin. The
      sites of interaction, determined from in vivo and in vitro assays, are the N
      terminus of SNAP25 (residues 1-84) and the cargo-binding domain of kinesin heavy
      chain (residues 814-907). Both regions are composed almost entirely of heptad
      repeats, suggesting the interaction between heavy chain and SNAP25 is that of a
      coiled-coil. The observation that SNAP23 also binds to residues 814-907 of heavy
      chain would indicate that the minimal kinesin-binding domain of SNAP23 and SNAP25
      is most likely residues 45-84 (SNAP25 numbering), a heptad-repeat region in both
      proteins. The major binding site for kinesin light chain in kinesin heavy chain
      was mapped to residues 789-813 at the C-terminal end of the heavy chain stalk
      domain. Weak binding of light chain was also detected at the N-terminus of the
      heavy chain tail domain (residues 814-854). In support of separate binding sites
      on heavy chain for light chain and SNAPs, a complex of heavy and light chains was
      observed to interact with SNAP25 and SNAP23.

PMID- 12475240
TI  - Identification of a region of the ileal-type sodium/bile acid cotransporter
      interacting with a competitive bile acid transport inhibitor.
AB  - Drug intervention that prevents reabsorption of circulating bile acids by the
      apical (ileal) sodium/bile acid cotransporter (ASBT) may be a promising new
      therapy for lowering of plasma cholesterol. 2164U90 is a benzothiazepine-based
      competitive inhibitor of bile acid transport with K(i) values of approximately 10
      and 0.068 microM for the homologous human and mouse apical transporters,
      respectively. Hybrid human-mouse and mouse-human transporters were engineered to
      identify regions involved in this 150-fold difference in the inhibition constant
      for 2164U90. A mouse-human chimera with only the most C-terminal hydrophobic
      domain and the C-terminus of the transporter originating from the human variant
      was found to have a sensitivity to 2164U90 inhibition similar to that of the
      human transporter. Conversely, a human-mouse hybrid transporter encompassing the
      same C-terminal region from the mouse sequence but now inserted into the human
      sequence demonstrated the greater inhibition seen with the mouse wild type ASBT.
      Amino acid substitutions, individually or in combinations, of six candidate
      nonconserved residues between mouse and human transporters in this C-terminal
      domain showed replacements of Thr294 by Ser and Val295 by Ile to be responsible
      for the difference in the sensitivity toward 2164U90 seen between the species.
      The hamster apical SBAT encompassing Ser/Ile in these positions shared the lower
      sensitivity to 2164U90, as seen with the human ASBT, even though it is identical
      to the mouse SBAT in the remaining four positions of this region. In addition,
      the rat ASBT which is identical to the mouse ASBT in this domain also had the
      high sensitivity to 2164U90 inhibition found for the mouse ASBT.
      Methanethiosulfonates (MTS) are known to inactivate the sodium/bile acid
      transporters through alkylation of a cysteine in the most C-terminal hydrophobic
      domain (1). Inactivation of the human ASBT due to MTS modification of cysteine
      270 was shown to be largely abolished when the transporter was preincubated with
      2164U90, suggesting that the binding of this benzothiazepine is in the vicinity
      of position 270. Thus, the domain containing the two most C-terminal putative
      transmembrane regions of the SBATs, H8-H9, previously shown to constitute part of
      the binding pocket for bile acids, interacts also with the bile acid transport
      competitive inhibitor, 2164U90.

PMID- 12475241
TI  - VSV transmembrane domain (TMD) peptide promotes PEG-mediated fusion of liposomes
      in a conformationally sensitive fashion.
AB  - Helical instability induced by gly residues in the transmembrane domain (TMD) of
      G protein, the fusion protein of vesicular stomatitis virus (VSV), was speculated
      to aid in the later steps of the fusion process, because G protein with ala's
      substituted for the two TMD gly's was inactive (Cleverley, D. Z., and Lenard, J.
      (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 3425-30). Here we examine the
      conformations of synthetic peptides corresponding to fusion-active (GGpep) and
      inactive (AApep; G's replaced by A's) TMDs by CD spectroscopy, and then their
      effects on the kinetics of poly (ethyleneglycol) (PEG)-mediated fusion of small
      unilamellar vesicles. GGpep and AApep both assumed history-dependent, non
      interconvertible ordered structures. Both peptides were largely helical under all
      conditions if derived from trifluoroethanol solutions, and aggregated in a beta
      sheet form if derived from acetonitrile solutions. In solvent, detergents or
      lipid bilayers, GGpep showed a greater range of secondary structural features
      than did AApep. The two peptides had large but different effects on PEG-mediated
      fusion. Both enhanced the rate but not the extent of lipid mixing. AApep
      significantly inhibited the extent of fusion pore formation while GGpep had no
      effect. The initial rate of fusion was enhanced 6-fold by GGpep and less than 2
      fold by AApep. Addition of 5 mol % hexadecane overrode all peptide-induced
      effects. We suggest that both GGpep and hexadecane promote pore formation by
      stabilizing the nonlamellar structures in fusion intermediates or initial small
      pores. AApep, which had fewer nonhelical features in its CD spectrum than GGpep,
      actually inhibited fusion pore formation.

PMID- 12475242
TI  - Linkage of multiequilibria in DNA recognition by the D53H Escherichia coli cAMP
      receptor protein.
AB  - The transcription factor cyclic AMP receptor protein, CRP, regulates the operons
      that encode proteins involved in translocation and metabolism of carbohydrates in
      Escherichia coli. The structure of the CRP-cAMP complex reveals the presence of
      two sets of cAMP binding sites. Solution biophysical studies show that there are
      two high-affinity and two low-affinity binding sites, to which the binding of
      cAMP is characterized by varying degrees of cooperativity. A stoichiometry of
      four implies that potentially CRP can exist in five conformers with different
      numbers of bound cAMP. These conformers may exhibit differential affinities for
      specific DNA sequences. In this study, the affinity between DNA and each
      conformer of D53H CRP was defined through a dissection of the thermodynamic
      linkage scheme that included all the conformers. Loading of the high- and low
      affinity sites with cAMP leads to high and low affinity for DNA, respectively.
      The specific magnitude of the binding constants of these conformers is DNA
      sequence dependent. The various association constants defined by the present
      study provide a solution to address an enigma of the CRP system, namely, the 3
      orders of magnitude difference between the cAMP binding constants determined by
      in vitro studies and the cAMP concentration regime to which the bacteria respond.
      Under physiological conditions, the apo-CRP-DNA complex is the dominant species.
      As a consequence of the 1000-fold stronger affinity of cAMP to the apo-CRP-DNA
      complex than that to CRP, the relevant reaction is the binding of cAMP to this
      DNA-protein complex. The binding constant is of the order of 10(7) M(-)(1), the
      same concentration regime as that of cellular concentration of cAMP. In addition,
      under physiological conditions the species that binds to the lac and gal operons
      is predicted to be CRP-(cAMP)(1). A comparison of parameters between the wild
      type and the mutant CRP shows that the mutation apparently shifts the various
      thermodynamically linked equilibria without a change in the basic mechanism that
      governs CRP activities. Thus, the conclusions derived from a study of the mutant
      are relevant to wild-type CRP. A dissection of the individual binding constants
      in this multiequilibria reaction scheme leads to a definition of the mechanism of
      action of this transcription factor.

PMID- 12475243
TI  - Conformation transition in silk protein films monitored by time-resolved Fourier
      transform infrared spectroscopy: effect of potassium ions on Nephila spidroin
      films.
AB  - We used time-resolved Fourier transform infrared spectroscopy (FTIR) to follow a
      conformation transition in Nephila spidroin film from random coil and/or helical
      structures to beta-sheet induced by the addition of KCl from 0.01 to 1.0 mol/L in
      D(2)O. Time series difference spectra showed parallel increases in absorption at
      1620 and 1691 cm(-)(1), indicating formation of beta-sheet, together with a
      coincident loss of intensity of approximately 1650 cm(-)(1), indicating decrease
      of random coil and/or helical structures. Increase in KCl concentration produced
      an increased rate of the conformation transition that may attributable to
      weakening of hydrogen bonds within spidroin macromolecules. The conformation
      transition was a biphasic process with [KCl] > or = 0.3 mol/L but monophasic with
      [KCl] < or = 0.1 mol/L. This suggests that, at high KCl concentrations, segments
      of the molecular chain are adjusted first and then the whole molecule undergoes
      rearrangement. We discuss the possible significance of these findings to an
      understanding of the way that spiders spin silk.

PMID- 12475244
TI  - The effect of salts on the stability of the H2A-H2B histone dimer.
AB  - The core nucleosome, which comprises an H3-H4 tetramer and two H2A-H2B dimers, is
      not a static DNA packaging structure. The nucleosome is a dynamic protein-DNA
      complex, and the modulation of its structure is an important component of
      transcriptional regulation. To begin to understand the molecular details of
      nucleosome dynamics, we have investigated the stability of the isolated H2A-H2B
      dimer. The urea-induced equilibrium responses of the heterodimer have been
      examined by far-UV circular dichroism and intrinsic tyrosine fluorescence. The
      two spectroscopic probes yielded coincident transitions, and global fitting of
      the reversible urea-induced unfolding further demonstrated that H2A-H2B unfolds
      by a two-state equilibrium response. At physiological ionic strengths, the free
      energy of unfolding in the absence of urea of H2A-H2B is 11.8 +/- 0.3 kcal mol(
      )(1), moderate stability for a dimer of 26.4 kDa. The m value, or sensitivity of
      the unfolding to urea, is 2.9 +/- 0.1 kcal mol(-)(1) M(-)(1). This value is
      significantly larger than would be predicted for the unfolding of the
      dimerization motif alone ( approximately 2 kcal mol(-)(1) M(-)(1)), suggesting
      that the N-terminal tails may adopt a collapsed, solvent-excluding structure that
      undergoes an unfolding transition. The efficacies of several potassium salts and
      three chloride salts to stabilize the H2A-H2B dimer were determined. The salt
      dependent stabilization of the H2A-H2B dimer shows that the Hofmeister effect is
      the predominant mode of stabilization. However, studies employing multiple salts
      suggest that there is a component of stabilization that must arise from screening
      of electrostatic repulsion in the highly basic heterodimer. The most highly
      charged regions of the dimer are the N-terminal tails, sites of posttranslational
      modifications such as acetylation and phosphorylation. These modifications, which
      alter the charge density of the tails, are involved in regulation of nucleosome
      dynamics.

PMID- 12475245
TI  - The N-terminal tails of the H2A-H2B histones affect dimer structure and
      stability.
AB  - The histone proteins of the core nucleosome are highly basic and form
      heterodimers in a "handshake motif." The N-terminal tails of the histones extend
      beyond the canonical histone fold of the hand-shake motif and are the sites of
      posttranslational modifications, including lysine acetylations and serine
      phosphorylations, which influence chromatin structure and activity as well as
      alter the charge state of the tails. However, it is not well understood if these
      modifications are signals for recruitment of other cellular factors or if the
      removal of net positive charge from the N-terminal tail plays a role in the
      overall structure of chromatin. To elucidate the effects of the N-terminal tails
      on the structure and stability of histones, the highly charged N-terminal tails
      were truncated from the H2A and H2B histones. Three mutant dimers were studied:
      DeltaN-H2A/WT H2B; WT H2A/DeltaN-H2B, and DeltaN-H2A/DeltaN-H2B. The CD spectra,
      stabilities to urea-denaturation, and the salt-dependent stabilization of the
      three truncated dimers were compared with those of the wild-type dimer. The data
      support four conclusions regarding the effects of the N-terminal tails of H2A and
      H2B: (1) Removal of the N-terminal tails of H2A and H2B enhance the helical
      structure of the mutant heterodimers. (2) Relative to the full-length WT
      heterodimer, the DeltaN-H2A/WT H2B dimer is destabilized, while the WT H2A/DeltaN
      H2B and DeltaN-H2A/DeltaN-H2B dimers are slightly stabilized. (3) The truncated
      dimers exhibit decreased m values, relative to the WT dimer, supporting the
      hypothesis that the N-terminal tails in the isolated dimer adopt a collapsed
      structure. (4) Electrostatic repulsion in the N-terminal tails decreases the
      stability of the H2A-H2B dimer.

PMID- 12475246
TI  - Sheared Aanti.Aanti base pairs in a destabilizing 2 x 2 internal loop: the NMR
      structure of 5'(rGGCAAGCCU)2.
AB  - The 5'(rGGCAAGCCU)(2) duplex contains tandem A.A pairs. The three-dimensional
      structure of the 5'(rGGCAAGCCU)(2) duplex was modeled by molecular dynamics and
      energy minimization with NMR-derived distance and dihedral angle restraints.
      Although the 5'(rCAAG)(2) loop is thermodynamically destabilizing by 1.1
      kcal/mol, the tandem A.A pairs adopt a predominant conformation: a sheared anti
      anti (A.A trans Hoogsteen/Sugar-edge) alignment similar to that observed in the
      crystal structure of the P4-P6 domain of the Tetrahymena thermophila intron
      [Cate, J. H., Gooding, A. R., Podell, E., Zhou, K., Golden, B. L., Kundrot, C.
      E., Cech, T. R., and Doudna, J. A. (1996) Science 273, 1678-1685]. The NMR
      derived structure of the 5'(rGGCAAGCCU)(2) duplex exhibits cross-strand hydrogen
      bonds from N3 of A4 to an amino hydrogen of A5 and from the 2' oxygen of the A4
      sugar to the other amino hydrogen of A5. An intrastrand hydrogen bond is formed
      from the 2' OH hydrogen of A4 to O5' of A5. The cross-strand A5 bases are
      stacked. The Watson-Crick G-C regions are essentially A-form. The sheared anti
      anti (A.A trans Hoogsteen/Sugar-edge) alignment provides potential contact sites
      for tertiary interactions and, therefore, is a possible target site for
      therapeutics. Thus, thermodynamically destabilizing internal loops can be
      preorganized for tertiary interactions or ligand binding.

PMID- 12475247
TI  - Molecular recognition in purine-rich internal loops: thermodynamic, structural,
      and dynamic consequences of purine for adenine substitutions in 5'(rGGCAAGCCU)2.
AB  - The contribution of amino groups to the thermodynamics, structure, and dynamics
      of tandem A.A mismatches is investigated by substitution of purine (P) for
      adenine (A) within the RNA duplex, 5'(rGGCAAGCCU)(2), to give 5'(rGGCPAGCCU)(2),
      5'(rGGCAPGCCU)(2), and 5'(rGGCPPGCCU)(2). The 5'(rGGCAAGCCU)(2) duplex has
      sheared A(anti).A(anti) (A.A trans Hoogsteen/Sugar-edge) pairs in which the A5
      amino group is involved in hydrogen bonds but the A4 amino group is not [Znosko,
      B. M., Burkard, M. E., Schroeder, S. J., Krugh, T. R., and Turner, D. H. (2002)
      Biochemistry 41, 14969-14977]. In comparison to 5'(rGGCAAGCCU)(2), replacing the
      amino group of A4 with a hydrogen stabilizes the duplex by 1.3 kcal/mol,
      replacement of the A5 amino group destabilizes the duplex by 0.6 kcal/mol, and
      replacement of both A4 and A5 amino groups destabilizes the duplex by 0.8
      kcal/mol. In NMR structures, the P.A noncanonical pairs of the 5'(rGGCPAGCCU)(2)
      duplex have a sheared anti-anti structure (P.A trans Hoogsteen/Sugar-edge) with
      P4.A5 interstrand hydrogen bonding and A5 bases that interstrand stack, similar
      to the structure of 5'(rGGCAAGCCU)(2). In contrast, the A.P pairs of the
      5'(rGGCAPGCCU)(2) duplex have a face-to-face conformation (A.P trans Watson
      Crick/Watson-Crick) with intrastrand stacking resembling typical A-form geometry.
      Although the P5 bases in 5'(rGGCPPGCCU)(2) are involved in an interstrand stack,
      the loop region is largely undefined. The results illustrate that both hydrogen
      bonded and non-hydrogen-bonded amino groups play important roles in determining
      the thermodynamic, structural, and dynamic characteristics of purine rich
      internal loops.

PMID- 12475248
TI  - Kinetic analysis of R67 dihydrofolate reductase folding: from the unfolded
      monomer to the native tetramer.
AB  - R67 dihydrofolate reductase (DHFR) is a homotetrameric enzyme. Its subunit has a
      core structure consisting of five antiparallel beta-strands that form a compact
      beta-barrel. Our interest was to describe the molecular mechanism of the complete
      folding pathway of this beta-sheet protein, focusing on how the oligomerization
      steps are coordinated with the formation of secondary and tertiary structures all
      along the folding process. The folding kinetics of R67 dihydrofolate reductase
      into dimers at pH 5.0 were first examined by intrinsic tryptophan fluorescence,
      fluorescence energy transfer, and circular dichroism spectroscopy. The process
      was shown to consist of at least four steps, including a burst, a rapid, a
      medium, and a slow phase. Measurements of the ellipticity at 222 nm indicated
      that about 50% of the total change associated with refolding occurred during the
      4 ms dead time of the stopped-flow instrument, indicating a substantial burst of
      secondary structure. The bimolecular association step was detected using
      fluorescence energy transfer and corresponded to the rapid phase. The slow phase
      was attributed to a rate-limiting isomerization of peptidyl-prolyl bonds
      involving 15% of the unfolded population. A complete folding pathway from the
      unfolded monomer to the native tetramer was proposed and an original model based
      upon the existence of early partially folded monomeric intermediates, rapidly
      stabilized in a dimeric form able to self-associate into the native homotetramer
      was formulated. The rate constants of these various steps were determined by
      fitting the kinetic traces to this model and supported our mechanistic
      assumptions.

PMID- 12475249
TI  - Iron-sulfur clusters of biotin synthase in vivo: a Mossbauer study.
AB  - Biotin synthase, the enzyme that catalyzes the last step of the biosynthesis of
      biotin, contains only [2Fe-2S](2+) clusters when isolated under aerobic
      conditions. Previous results showed that reconstitution with an excess of FeCl(3)
      and Na(2)S under reducing and anaerobic conditions leads to either [4Fe-4S](2+),
      [4Fe-4S](+), or a mixture of [4Fe-4S](2+) and [2Fe-2S](2+) clusters. To determine
      whether any of these possibilities or other different cluster configuration could
      correspond to the physiological in vivo state, we have used (57)Fe Mossbauer
      spectroscopy to investigate the clusters of biotin synthase in whole cells. The
      results show that, in aerobically grown cells, biotin synthase contains a mixture
      of [4Fe-4S](2+) and [2Fe-2S](2+) clusters. A mixed [4Fe-4S](2+):[2Fe-2S](2+)
      cluster form has already been observed under certain in vitro conditions, and it
      has been proposed that both clusters might each play a significant role in the
      mechanism of biotin synthase. Their presence in vivo is now another argument in
      favor of this mixed cluster form.

PMID- 12475250
TI  - Effects of cholesterol on surface activity and surface topography of spread
      surfactant films.
AB  - Pulmonary surfactant forms a monolayer of lipids and proteins at the alveolar
      air/liquid interface. Although cholesterol is a natural component of surfactant,
      its function in surface dynamics is unclear. To further elucidate the role of
      cholesterol in surfactant, we used a captive bubble surfactometer (CBS) to
      measure surface activity of spread films containing
      dipalmitoylphosphatidylcholine/1-palmitoyl-2-oleoylphosphatidylcholine/1
      palmitoyl-2-oleoylphosphatidylglycerol (DPPC/POPC/POPG, 50/30/20 molar
      percentages), surfactant protein B (SP-B, 0.75 mol %), and/or surfactant protein
      C (SP-C, 3 mol %) with up to 20 mol % cholesterol. A cholesterol concentration of
      10 mol % was optimal for reaching and maintaining low surface tensions in SP-B
      containing films but led to an increase in maximum surface tension in films
      containing SP-C. No effect of cholesterol on surface activity was found in films
      containing both SP-B and SP-C. Atomic force microscopy (AFM) was used, for the
      first time, to visualize the effect of cholesterol on topography of SP-B- and/or
      SP-C-containing films compressed to a surface tension of 22 mN/m. The protrusions
      found in the presence of cholesterol were homogeneously dispersed over the film,
      whereas in the absence of cholesterol the protrusions tended to be more clustered
      into network structures. A more homogeneous dispersion of surfactant lipid
      components may facilitate lipid insertion into the surfactant monolayer. Our data
      provide additional evidence that natural surfactant, containing SP-B and SP-C, is
      superior to surfactants lacking one of the components, and furthermore, this
      raises the possibility that the cholesterol found in surfactant of warm-blooded
      mammals does not have a function in surface activity.

PMID- 12475251
TI  - Molecular crowding regulates the structural switch of the DNA G-quadruplex.
AB  - Almost all biochemical reactions in vitro have been investigated through numerous
      experiments conducted in dilute solutions containing low concentrations of
      solutes. However, biomacromolecules such as nucleic acids, proteins, and
      polysaccharides are designed to function and/or form their native structures in a
      living cell containing high concentrations of biomacromolecules, substrates,
      cofactors, salts, and so on. In the present study, we have demonstrated
      quantitatively the effect of molecular crowding on structures and stabilities of
      the G-quadruplex of d(G(4)T(4)G(4)). Molecular crowding with poly(ethylene
      glycol) (PEG) induced a structural transition from the antiparallel to the
      parallel G-quadruplex of d(G(4)T(4)G(4)), while molecular crowding with
      polycations did not alter the structure of the antiparallel G-quadruplex. The
      binding constants of putrescine, one of the polycations, for d(G(4)T(4)G(4)) in
      the absence and presence of Na(+) are calculated to be 277 and 2.5 M(-)(1),
      respectively. This indicates that the polycations coordinate to d(G(4)T(4)G(4))
      with electrostatic interactions. The thermodynamic parameters of the antiparallel
      G-quadruplex formation under the crowding and noncrowding conditions induced by
      putrescine were also estimated. The stability of the antiparallel G-quadruplex
      decreased (-DeltaG degrees (25) decreased from 28 to 22 kcal mol(-)(1)) with
      molecular crowding by putrescine. Also, enthalpy and entropy changes in the
      structural formation under crowding and noncrowding conditions clearly showed
      that destabilization was entropy-driven. These quantitative parameters indicated
      that both the volume excluded by PEG and chemical interactions such as
      electrostatic interaction with solute polycations are critical for determining
      how molecular crowding affects the structure and stability of highly ordered DNA
      structures.

PMID- 12475252
TI  - E. coli expression of TIMP-4 and comparative kinetic studies with TIMP-1 and TIMP
      2: insights into the interactions of TIMPs and matrix metalloproteinase 2
      (gelatinase A).
AB  - The inhibitory properties of TIMP-4 for matrix metalloproteinases (MMPs) were
      compared to those of TIMP-1 and TIMP-2. Full-length human TIMP-4 was expressed in
      E. coli, folded from inclusion bodies, and the active component was purified by
      MMP-1 affinity chromatography. Progress curve analysis of MMP inhibition by TIMP
      4 indicated that association rate constants (k(on)) and inhibition constants
      (K(i)) were similar to those for other TIMPs ( approximately 10(5) M(-)(1) s(
      )(1) and 10(-)(9)-10(-)(12) M, respectively). Dissociation rate constants
      (k(off)) for MMP-1 and MMP-3 determined using alpha(2)-macroglobulin to capture
      MMP dissociating from MMP-TIMP complexes were in good agreement with values
      deduced from progress curves ( approximately 10(-)(4) s(-)(1)). K(i) and k(on)
      for the interactions of TIMP-1, -2, and -4 with MMP-1 and -3 were shown to be pH
      dependent. TIMP-4 retained higher reactivity with MMPs at more acidic conditions
      than either TIMP-1 or TIMP-2. Molecular interactions of TIMPs and MMPs
      investigated by IAsys biosensor analysis highlighted different modes of
      interaction between proMMP-2-TIMP-2 (or TIMP-4) and active MMP-2-TIMP-2 (or TIMP
      4) complexes. The observation that both active MMP-2 and inactive MMP-2 (with the
      active site blocked either by the propeptide or a hydroxamate inhibitor) have
      essentially identical affinities for TIMP-2 suggests that there are two TIMP
      binding sites on the hemopexin domain of MMP-2: one with high affinity that is
      involved in proMMP-2 or hydroxamate-inhibited MMP-2; and the other with low
      affinity involved in formation of the complex of active MMP-2 and TIMP-2. Similar
      models of interaction may apply to TIMP-4. The latter low-affinity site functions
      in conjunction with the active site of MMP-2 to generate a tight enzyme-inhibitor
      complex.

PMID- 12475253
TI  - Functions of tropomyosin's periodic repeats.
AB  - Tropomyosin binds along actin filaments and regulates actin-myosin interaction in
      muscle and nonmuscle cells. Seven periodic amino acid repeats are proposed to
      correspond to actin binding sites, and the middle periods are important for
      cooperative activation of actin by myosin. The functional contributions of
      individual periods were studied in mutants in which periods 2-6 were individually
      deleted from rat striated muscle alphaalpha-tropomyosin or replaced with a
      leucine zipper sequence. Unacetylated recombinant tropomyosins were assayed for
      actin binding, regulation of the actomyosin ATPase with troponin, cooperative
      myosin S1-induced binding to actin, and thermal stability. Tropomyosin function
      is relatively insensitive to deletion of period 2, but loss increases as the
      deletion is shifted toward the C-terminus. Retention of function upon deletion of
      the periodic repeats is in the order of 2 > 3 approximately 4 approximately 6 >>
      5. Internal periods are important for specific functions and are not
      quasiequivalent. Deletion of period 5 (residues 166-207), and especially deletion
      or replacement of residues 166-188, a constitutively expressed region encoded by
      exon 5, had severe consequences on actin affinity and cooperative myosin S1
      induced binding to actin. Period 6, residues 208-242, part of the troponin
      binding site, is required for full inhibition of the actomyosin ATPase in the
      absence of calcium. The effect of the deletion can depend on its context,
      suggesting that sequence alone is not the only factor important for function. We
      propose that the local structure and stability, and consequent flexibility, of
      the coiled coil are major determinants of actin affinity.

PMID- 12475254
TI  - Carboxylase overexpression effects full carboxylation but poor release and
      secretion of factor IX: implications for the release of vitamin K-dependent
      proteins.
AB  - Vitamin K-dependent (VKD) proteins are modified by the VKD carboxylase as they
      transit through the endoplasmic reticulum. In a reaction required for their
      activity, clusters of Glu's are converted to Gla's, and fully carboxylated VKD
      proteins are normally secreted. In mammalian cell lines expressing high levels of
      r-VKD proteins, however, under- and uncarboxylated VKD forms are observed.
      Overexpression of r-carboxylase does not improve carboxylation, but the lack of
      effect is not understood, and the intracellular events that occur during VKD
      protein carboxylation have not been investigated. We analyzed carboxylation in
      293- and BHK cell lines expressing r-factor IX (fIX) and endogenous carboxylase
      or overexpressed r-carboxylase. The fIX secreted from the four cell lines was
      highly carboxylated, indicating fIX-carboxylase engagement during intracellular
      trafficking. The r-carboxylase was functional for carboxylation: overexpression
      resulted in a proportional increase in fIX-carboxylase complexes that yielded
      full fIX carboxylation. Interestingly, the carboxylated fIX product was not
      efficiently released from the carboxylase in r-fIX/r-carboxylase cells, resulting
      in decreased fIX secretion. r-Carboxylase overexpression changed the ratios of
      intracellular fIX to carboxylase, and we therefore developed an in vitro assay to
      test whether fIX levels affect release. FIX-carboxylase complexes were in vitro
      carboxylated with or without excess VKD substrate or propeptide. These analyses
      are the first to dissect the rates of release versus carboxylation and showed
      that release was much slower than carboxylation. In the absence of excess VKD
      substrate/propeptide, fIX in the fIX-carboxylase complex was fully carboxylated
      by 10 min, but 95% was still complexed with carboxylase after 30 min. The
      presence of excess VKD substrate/propeptide, however, led to a significant
      increase in VKD product release, possibly through a second propeptide binding
      site in the carboxylase. The intracellular analyses also showed that the fIX
      carboxylation rate was slow in vivo and was similar in r-fIX versus r-fIX/r
      carboxylase cells, despite the large differences in carboxylase levels. The
      results suggest that the vitamin K cofactor may be limiting for carboxylation in
      the cell lines.

PMID- 12475255
TI  - Interleukin-1 beta folding between pH 5 and 7: experimental evidence for three
      state folding behavior and robust transition state positions late in folding.
AB  - The thermodynamic stability and folding kinetics of the all beta-sheet protein
      interleukin-1beta were measured between 0 and 4 M GdmCl concentrations and pH 5
      7. Native interleukin-1beta undergoes a 3.5 kcal/mol decrease in thermodynamic
      stability, Delta, as pH is increased from 5 to 7. The native state parameter
      m(NU), measuring protein destabilization/[GdmCl], remains constant between pH 5
      and 7, indicating that the solvent-exposed surface area difference between the
      native state and unfolded ensemble is unchanged across this pH range. Similarly,
      pH changes between 5 and 7 decrease only the thermodynamic stability,
      DeltaG(H)2(O), and not the m-values, of the kinetic intermediate and transition
      states. This finding is shown to be consistent with transition state
      configurations which continue to be the high-energy configurations of the
      transition state in the face of changing stability conditions. A three-state
      folding mechanism U right arrow over left arrow I right arrow over left arrow N
      is shown to be sufficient in characterizing IL-1beta folding under all conditions
      studied. The m-values of refolding transitions are much larger than the m-values
      of unfolding transitions, indicating that that the fast, T(2) (U right arrow over
      left arrow I), and slow, T(1) (I right arrow over left arrow N), transition
      states are highly similar to the intermediate I and native state N, respectively.
      Many of the folding properties of interleukin-1beta are shared among other
      members of the beta-trefoil protein family, although clear differences can exist.

PMID- 12475256
TI  - Structure-based thermodynamic analysis of a coupled metal binding-protein folding
      reaction involving a zinc finger peptide.
AB  - The thermodynamics of metal binding by the prototypical Cys(2)His(2) zinc finger
      peptide CP-1 has been examined through the use of isothermal titration
      calorimetry. In cholamine buffer at pH 7.0, the binding of zinc(II) to CP-1 shows
      an enthalpy change of DeltaH degrees (obs) = -33.7 +/- 0.8 kcal/mol. Between one
      and two protons appear to be released accompanying the metal binding process. The
      heat of protonation of the cholamine buffer used is quite large (-11.5 kcal/mol),
      indicating that a portion of the observed metal binding enthalpy is due to buffer
      protonation. Structure-based thermodynamic analysis including the effect of water
      release from zinc(II) appears to account for the entropy associated with the
      coupled metal binding-protein folding process semiquantitatively. The strongest
      driving force for the reaction is the enthalpy associated with the four bonds
      from zinc(II) to cysteinate and histidine residues, compared with the bonds from
      zinc(II) to water. The binding of cobalt(II) to CP-1 is less enthalpically driven
      than the binding of zinc(II) by -7.6 kcal/mol. This value is approximately equal
      to, but slightly larger than, the expectation based on considerations of ligand
      field stabilization energy.

PMID- 12475258
TI  - A light-dependent mechanism for massive accumulation of manganese in the
      photosynthetic bacterium Synechocystis sp. PCC 6803.
AB  - Manganese is an essential micronutrient for many organisms. Because of its unique
      role in the water oxidizing activity of photosystem II, manganese is required for
      photosynthetic growth in plants and cyanobacteria. Here we report on the
      mechanism of manganese uptake in the cyanobacterium Synechocystis sp. PCC 6803.
      Cells grown in 9 microM manganese-containing medium accumulate up to 1 x 10(8)
      manganese atoms/cell, bound to the outer membrane (pool A). This pool could be
      released by EDTA treatment. Accumulation of manganese in pool A was energized by
      photosynthetic electron flow. Moreover, collapsing the membrane potential
      resulted in the immediate release of this manganese pool. The manganese in this
      pool is mainly Mn(II) in a six-coordinate distorted environment. A distinctly
      different pool of manganese, pool B ( approximately 1.5 x 10(6) atoms/cell),
      could not be extracted by EDTA. Transport into pool B was light-independent and
      could be detected only under limiting manganese concentrations (1 nM). Evidently,
      manganese uptake in Synechocystis 6803 cells occurs in two steps. First,
      manganese accumulates in the outer membrane (pool A) in a membrane potential
      dependent process. Next, manganese is transported through the inner membrane into
      pool B. We propose that pool A serves as a store that allows the cells to
      overcome transient limitations in manganese in the environment.

PMID- 12475257
TI  - A member of a new class of GTP cyclohydrolases produces formylaminopyrimidine
      nucleotide monophosphates.
AB  - The hyperthermophilic euryarchaeon Methanococcus jannaschii has no recognizable
      homologues of the canonical GTP cyclohydrolase enzymes that are required for
      riboflavin and pteridine biosyntheses. Instead, it uses a new type of
      thermostable GTP cyclohydrolase enzyme that produces 2-amino-5-formylamino-6
      ribofuranosylamino-4(3H)-pyrimidinone ribonucleotide monophosphate and inorganic
      phosphate. Whereas canonical GTP cyclohydrolases produce this formylamino
      pyrimidine nucleotide as a reaction intermediate, this compound is shown to be an
      end product of the purified recombinant M.jannaschii enzyme. Unlike other enzymes
      that hydrolyze the alpha-beta phosphate anhydride bond of GTP, this new enzyme
      completely hydrolyzes pyrophosphate to inorganic phosphate. As a result, the
      enzyme has a steady-state turnover of 21 min(-)(1), which is much faster than
      those of canonical GTP cyclohydrolase enzymes. The effects of substrate analogues
      and inhibitors suggest that the GTP cyclohydrolase and pyrophosphate
      phosphohydrolase activities occur at independent sites, although both activities
      depend on Mg(2+).

PMID- 12475260
TI  - Detection of giant myofibrillar proteins connectin and nebulin in fish meat by
      electrophoresis in 3-5 gradient sodium dodecyl sulfate polyacrylamide slab gels.
AB  - An improved method was investigated for sodium dodecyl sulfate polyacrylamide
      slab gel electrophoresis (SDS-PAGE) to facilitate the analysis of the giant
      myofibrillar proteins, connectin and nebulin, in fish meat by using jack mackerel
      (Trachurus japonicus) as the sample fish. It was established that separation of
      the alpha-connectin band from the beta-connectin band by SDS-PAGE could be
      achieved by using 3-5% gradient gels with glycerol to facilitate the formation of
      a gradient with polymerization at 35 degrees C. SDS-PAGE samples of white dorsal
      muscle from the jack mackerel were homogenized with a 2% SDS solution containing
      an inhibitor mixture (1 microg/mL of phenylmethanesulfonyl fluoride, 1 microg/mL
      of leupeptin, and 1 microg/mL of E-64) and heated at 50 degrees C for 20 min.
      Heating these samples at 100 degrees C for 2 min resulted in the disintegration
      of connectin but did not affect nebulin. A purified myofibril sample and a whole
      muscle sample showed similar changes in the overall rate of degradation of whole
      connectin and nebulin during the postmortem storage period, but it was clear that
      beta-connectin was cleaved from alpha-connectin during the preparation of
      myofibrils at the early stage postmortem. Storage of the SDS-PAGE samples at -85
      degrees C was preferable to storage at -18 degrees C for a long period.

PMID- 12475259
TI  - Engineering the protein N-glycosylation pathway in insect cells for production of
      biantennary, complex N-glycans.
AB  - Insect cells, like other eucaryotic cells, modify many of their proteins by N
      glycosylation. However, the endogenous insect cell N-glycan processing machinery
      generally does not produce complex, terminally sialylated N-glycans such as those
      found in mammalian systems. This difference in the N-glycan processing pathways
      of insect cells and higher eucaryotes imposes a significant limitation on their
      use as hosts for baculovirus-mediated recombinant glycoprotein production. To
      address this problem, we previously isolated two transgenic insect cell lines
      that have mammalian beta1,4-galactosyltransferase or beta1,4
      galactosyltransferase and alpha2,6-sialyltransferase genes. Unlike the parental
      insect cell line, both transgenic cell lines expressed the mammalian
      glycosyltransferases and were able to produce terminally galactosylated or
      sialylated N-glycans. The purpose of the present study was to investigate the
      structures of the N-glycans produced by these transgenic insect cell lines in
      further detail. Direct structural analyses revealed that the most extensively
      processed N-glycans produced by the transgenic insect cell lines were novel,
      monoantennary structures with elongation of only the alpha1,3 branch. This led to
      the hypothesis that the transgenic insect cell lines lacked adequate endogenous N
      acetylglucosaminyltransferase II activity for biantennary N-glycan production. To
      test this hypothesis and further extend the N-glycan processing pathway in Sf9
      cells, we produced a new transgenic line designed to constitutively express a
      more complete array of mammalian glycosyltransferases, including N
      acetylglucosaminyltransferase II. This new transgenic insect cell line,
      designated SfSWT-1, has higher levels of five glycosyltransferase activities than
      the parental cells and supports baculovirus replication at normal levels. In
      addition, direct structural analyses showed that SfSWT-1 cells could produce
      biantennary, terminally sialylated N-glycans. Thus, this study provides new
      insight on the glycobiology of insect cells and describes a new transgenic insect
      cell line that will be widely useful for the production of more authentic
      recombinant glycoproteins by baculovirus expression vectors.

PMID- 12475261
TI  - Evaluation of antioxidant activity of some natural polyphenolic compounds using
      the Briggs-Rauscher reaction method.
AB  - A new method based on the inhibitory effects of antioxidants on the oscillations
      of the hydrogen peroxide, acidic iodate, malonic acid, and Mn(II)-catalyzed
      system (known as the Briggs-Rauscher reaction), was used for the evaluation of
      antioxidative capacity. With this method, which works near the pH of the fluids
      in the stomach (pH approximately 2), a group of natural compounds present in
      fruits and vegetables or in medicinal plants assumed to have antioxidant
      capacity, was tested successfully. The aim of the present study is to evaluate
      the antioxidative properties of some active principles contained in vegetables
      and aromatic plants, namely, cynarin (from Cynara scolymus), rosmarinic acid
      (from Rosmarinus officinalis), echinacoside (from Echinacea species), puerarin
      (from Pueraria lobata), and oleuropein (from Olea europea). Also studied with the
      Briggs-Rauscher reaction method was the antioxidant activity of cyanidin 3-O-beta
      glucopyranoside (from Citrus aurantium) in order to compare the results with
      those obtained by other methods. The conclusions on the dependency of the
      antioxidative activity on the pH of the testing system are given.

PMID- 12475262
TI  - Characterization of lycopene nanoparticles combining solid-state and suspended
      state NMR spectroscopy.
AB  - The core-shell structure of lycopene micronizates can be verified by employing a
      combination of solid-state and suspended-state NMR spectroscopy. The type of
      molecular aggregation of carotenoid nanoparticles can be clearly determined from
      their characteristic fingerprint pattern in the solid-state NMR spectra.

PMID- 12475263
TI  - New method for ethephon ((2-chloroethyl)phosphonic acid) residue analysis, and
      detection of residual levels in the fruit and vegetables of Western Japan.
AB  - A new method for the detection and quantification of ethephon residues in fruit
      and vegetables was developed. The present study indicates that fruit and
      vegetables require a rapid and simple cleanup step before using gas
      chromatograph/mass spectrometry. The recovery and precision of the new method
      were evaluated by spiking the fruit and vegetable samples with 0.01-0.1 microg/g
      of ethephon. The amount of ethephon residue can be determined with good accuracy
      (recovery, 78.6-109%; coefficient variation, 2.65-6.41%), and the detection
      limit, defined as the amount of ethephon equivalent to three standard deviations
      (SD) of the noise level in observations at the baseline level of the selected ion
      (m/z 110), was 4 pg. The determination limit, defined as the equivalent to 8 SD
      of the noise level, was 11 pg. The working range was between 10 and 1000 ng/mL,
      and the correlation coefficient was 0.999 in the five experiments. Ethephon
      residues were determined between <2 and 97 ng/g in commercial pineapples from
      Western Japan.

PMID- 12475264
TI  - Tequila authenticity assessment by headspace SPME-HRGC-IRMS analysis of 13C/12C
      and 18O/16O ratios of ethanol.
AB  - By use of headspace SPME sampling and a PLOT column, on-line capillary gas
      chromatography-isotope ratio mass spectrometry was employed in the combustion (C)
      and the pyrolysis (P) modes (HRGC-C/P-IRMS) to determine the delta(13)C(VPDB) and
      delta(18)O(VSMOW) values of ethanol in authentic (n = 14) and commercial tequila
      samples (n = 15) as well as a number of other spirits (n = 23). Whereas with
      delta(13)C(VPDB) values ranging from -12.1 to -13.2 per thousand and from -12.5
      to -14.8 per thousand similar variations were found for 100% agave and mixed
      tequilas, respectively, the delta(18)O(VSMOW) data differed slightly within these
      categories: ranges from +22.1 to +22.8 per thousand and +20.8 to +21.7 per
      thousand were determined for both the authentic 100% agave and mixed products,
      respectively. The data recorded for commercial tequilas were less homogeneous;
      delta(13)C(VPDB) data from -10.6 to -13.9 per thousand and delta(18)O(VSMOW)
      values from +15.5 to +22.7 per thousand were determined in tequilas of both
      categories. Owing to overlapping data, attempts to differentiate between white,
      rested, and aged tequilas within each of the two categories failed. In addition,
      discrimination of tequila samples from other spirits by means of delta(13)C(VPDB)
      and delta(18)O(VSMOW) data of ethanol was restricted to the products originating
      from C(3) as well as C(4)/CAM raw materials.

PMID- 12475265
TI  - Polymeric procyanidins as radical-scavenging components in red-hulled rice.
AB  - The extracts from white-, black-, and red-hulled rice were prepared by sequential
      extraction with six different polar solvents, and their radical-scavenging
      activities were measured by methods using 1,1-diphenyl-2-picrylhydrazyl radical
      (DPPH*) and tert-butyl hydroperoxyl radical (t-BuOO*). The extracts prepared with
      highly polar solvents, methanol and deionized water, exhibited higher DPPH* and t
      BuOO* scavenging activities in all three cultivars. In addition, the acetone
      extract from red-hulled rice exhibited a high DPPH* and t-BuOO* scavenging
      activity, while no such activity was detected for the acetone extracts from white
      and black-hulled rice. The major components responsible for the radical
      scavenging in the acetone extract from red-hulled rice were identified as
      procyanidins by acidic hydrolysis, vanillin assay, and Sephadex LH-20
      chromatography. GPC analysis of the acetylated procyanidins revealed that the
      average molecular weight is about 5000, in a range of about 500-18,000.

PMID- 12475266
TI  - Characterization of antioxidants present in bitter tea (Ligustrum pedunculare).
AB  - The present study examined the antioxidants present in bitter tea (Ligustrum
      pedunculare). It was found that the crude glycoside fraction strongly protected
      human low-density lipoprotein (LDL) from oxidation. Further column chromatography
      led to purification of eight phenylethanoid or monoterpene glycosides: lipedoside
      A-I, lipedoside A-II, lipedoside B-I, lipedoside B-III, lipedoside B-V,
      lipedoside B-VI, osmanthuside B, and anatolioside. It was found that lipedoside A
      I, lipedoside A-II, lipedoside B-V, and lipedoside B-VI were protective, whereas
      the other four compounds did not protect human LDL from Cu(2+)-medicated
      oxidation. Lipedoside A-I, lipedoside A-II, lipedoside B-V, and lipedoside B-VI
      also had a scavenging effect on 2,2-diphenyl-1-picrylhydrazyl free radical
      (DPPH), comparable to that of alpha-tocopherol. The inhibitory effect of these
      four phenylethanoid or monoterpene glycosides on oxidation of human LDL and alpha
      tocopherol was dose-dependent at concentrations of 5-40 microM. The present
      results demonstrate that bitter tea as a beverage contains effective antioxidants
      that may have benefits similar to those of green tea in terms of antioxidant
      activity.

PMID- 12475267
TI  - Antioxidant capacity of lettuce leaf tissue increases after wounding.
AB  - Wounding induced the accumulation of phenolic compounds in Iceberg and Romaine
      lettuce leaf tissue. Phenolic concentrations were quantified after holding the
      leaf tissue at 10 degrees C for 48 h as the absorbance of a methanol extract at
      320 nm, and by the Folin-Ciocalteu method. Heat-shock treatments applied by
      immersing tissue in 45 degrees C water for 2.5 min before or after wounding
      reduced the accumulation of phenolic compounds. Compared to the nonwounded,
      nonheat-shocked controls, these and other wounding and heat-shock treatments
      produced leaf tissue with a 4-fold range in phenolic content. The antioxidant
      capacity of the tissue, measured as DPPH (alpha,alpha-diphenyl-beta
      picrylhydrazyl)-radical scavenging activity, or as ferric-reducing antioxidant
      power (FRAP), increased after wounding. The increase was linearly correlated with
      the increase in phenolic compounds in Iceberg (R(2) > 0.97) and in Romaine (R(2)
      > 0.95) lettuce leaf tissue. Increased consumption of diets rich in phenolic
      antioxidants may contribute to reducing human diseases. Treatments that reduce
      the browning of wounded lettuce leaf tissue by preventing the oxidation of the
      accumulated wound-induced phenolic compounds may produce a healthier fresh-cut
      product than treatments that prevent the wound-induced synthesis and accumulation
      of phenolic compounds with antioxidant properties.

PMID- 12475268
TI  - Juice and phenolic fractions of the berry Aristotelia chilensis inhibit LDL
      oxidation in vitro and protect human endothelial cells against oxidative stress.
AB  - Oxidative modification of low-density lipoprotein (LDL) particles is a key event
      in the development of atherosclerosis. Oxidized LDL induces oxidative stress and
      modifies gene expression in endothelial cells. Berries constitute a rich dietary
      source of phenolic antioxidants. We found that the endemic Chilean berry
      Aristotelia chilensis (ach) has higher phenol content and scores better for total
      radical-trapping potential and total antioxidant reactivity in in vitro
      antioxidant capacity tests, when compared to different commercial berries. The
      juice of ach is also effective in inhibiting copper-induced LDL oxidation. In
      human endothelial cell cultures, the addition of ach juice significantly protects
      from hydrogen peroxide-induced intracellular oxidative stress and is dose
      dependent. The aqueous, anthocyanin-rich fraction of ach juice accounts for most
      of ach's antioxidant properties. These results show that ach is a rich source of
      phenolics with high antioxidant capacity and suggest that it may have
      antiatherogenic properties.

PMID- 12475269
TI  - Valorization of grape (Vitis vinifera) byproducts. Antioxidant and biological
      properties of polyphenolic fractions differing in procyanidin composition and
      flavonol content.
AB  - Many byproducts and wastes generated by agroindustries contain polyphenols with
      potential application as food antioxidants and preventive agents against skin
      cancer and other diseases. The performance of polyphenolic fractions from
      Parellada grape (Vitis vinifera) pomace as antioxidants in different
      physicochemical environments was tested. Fractions containing oligomers with mean
      degree of polymerization between 3 and 4 and percentage galloylation ca. 30% were
      the most potent free radical scavengers and efficient antioxidants in an oil-in
      water emulsion. A fraction including glycosylated flavonols was also efficient in
      the emulsion. All the fractions showed low aquatic toxicity and weak influence on
      proliferation of human melanoma cells.

PMID- 12475270
TI  - Comparison of the evolution of low molecular weight phenolic compounds in typical
      Sherry wines: Fino, Amontillado, and Oloroso.
AB  - Changes in the content of low molecular weight phenolic compounds (hydroxybenzoic
      and hydroxycinnamic acids, aldehydes, and their esterified derivatives, tyrosol
      and 5-(hydroxymethyl)-2-furaldehyde) during the aging of three different classes
      of Sherry wine, Fino, Oloroso, and Amontillado, have been studied. The samples
      studied were taken from each of the scales of the particular aging system applied
      to the three classes of wine. Clear differences were observed in the behavior of
      the low molecular weight phenolic in the three classes of wine. The wines
      subjected to oxidative aging presented a higher phenolic content overall, with
      the exception of the esterified derivatives of phenolic compounds that are mainly
      found in the samples that have not undergone any process of oxidation. MANOVA
      results confirmed that there are significant differences between all of the
      samples of the three types of wines. Using LDA, a classification of 100% of the
      samples has been made.

PMID- 12475271
TI  - High CO2 atmosphere modulating the phenolic response associated with cell
      adhesion and hardening of Annona cherimola fruit stored at chilling temperature.
AB  - Phenylalanine ammonia-lyase (PAL, EC 4.3.1.5.) activity, tanning ability, and
      polyphenols levels were measured in cherimoya (Annona cherimola Mill.) fruit
      treated with 20% CO(2) + 20% O(2) + 60% N(2) for 1, 3, or 6 days during chilling
      temperature (6 degrees C) storage. The residual effect of CO(2) after transfer to
      air was also studied. These observations were correlated with texture and
      cellular characteristics, visualized by cryo-SEM. Tanning ability and the early
      increase in tannin polyphenols induced by chilling temperature were reduced by
      CO(2) treatment. Conversely, high CO(2) atmosphere enhanced the nontannin
      polyphenol fraction as compared with fruit stored in air. Lignin accumulation and
      PAL activation observed in untreated fruit after prolonged storage at chilling
      temperature were prevented by high CO(2). Moreover, the restraining effect on
      lignification was less effective when the CO(2) treatment was prolonged for 6
      days. In addition, fruits held at these conditions had greater firmness and the
      histological characterization of the separation between cells was similar to that
      in untreated fruits. We conclude that CO(2) treatment modulates the phenolic
      response that seems to regulate the strength of cell adhesion and so to prevent
      hardening caused by chilling temperature storage.

PMID- 12475272
TI  - Transformation of the fungicide chlorothalonil by Fenton reagent.
AB  - A modified Fenton reagent (Fe(3+)/H(2)O(2)) transformed the fungicide
      chlorothalonil within 60 min in aqueous solution at unadjusted pH. Transformation
      varied with ferric salt. Transformation was greatest with ferric nitrate and
      least when ferric sulfate was used. UV irradiation enhanced the transformation of
      chlorothalonil. The transformation of chlorothalonil was enhanced, which
      increased with ferric ion or hydrogen peroxide concentration. Maximum
      transformation was achieved at 2 mM ferric ion and 100 mM hydrogen peroxide.
      Additionally, chlorothalonil was more dechlorinated in the UV irradiation
      condition. The proposed reaction pathway includes reduction of chlorothalonil to
      trichloroisophthalonitrile, dichloroisophthalonitrile, and
      monochloroisophthalonitrile; oxidation of trichloroisophthalonitrile to trichloro
      3-cyanobenzoic acid and 3-carbamyltrichlorobenzoic acid; and oxidation of
      hydroxychlorothalonil to trichloro-3-cyanohydroxybenzoic acid and
      trichlorocyanophenol.

PMID- 12475273
TI  - Analysis of fiber content in flax stems by near-infrared spectroscopy.
AB  - The conventional means of measuring the fiber content of flax is time-consuming
      and laborious, and the results obtained vary with the analysis technique used.
      The plant tissues must first be "retted", a process by which the fibers are
      separated from the rest of the stem, either by indigenous organisms in the soil
      when the stems are left in the field or by water (anerobic bacteria) or enzymatic
      retting. The fiber content is then determined by mechanical or manual separation.
      In this study, fiber content of flax stems was measured rapidly and objectively
      by near-infrared spectroscopy (NIRS) using whole pieces of stem in a large cell,
      in reflectance mode. Compared to the conventional method, the standard error of
      performance of the NIRS method was between 0.96 and 1.45% (dry matter basis),
      depending on the model and data processing used. NIRS calibrations were generated
      by hand separation of fiber from water-retted specimens. The water retting
      procedure takes several days to complete and requires considerable trained labor
      to complete the hand separation step. The NIRS procedure was conducted on pieces
      of stem to simulate measurement in the field.

PMID- 12475274
TI  - Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the
      edible mushroom Grifola frondosa.
AB  - The bioassay-guided isolation and purification of the hexane extract of the
      cultured mycelia of Grifola frondosa led to the characterization of a fatty acid
      fraction and three compounds, ergosterol (1), ergostra-4,6,8(14),22-tetraen-3-one
      (2), and 1-oleoyl-2-linoleoyl-3-palmitoylglycerol (3). The composition of fatty
      acid fraction was confirmed as palmitic, oleic, and linoleic acids by GC-MS and
      by comparison with the retention values of authentic samples. The structures of
      compounds 1-3 were established by spectroscopic methods. The fatty acid fraction
      and compounds 1-3 showed cyclooxygenase (COX) enzyme inhibitory and antioxidant
      activities. The inhibition of COX-1 enzyme by the fatty acid fraction and
      compounds 1-3 at 250 microg/mL were 98, 37, 55, and 67%, respectively. Similarly,
      COX-2 enzyme activity was reduced by fatty acid fraction and compounds 1-3 at 250
      microg/mL by 99, 37, 70, and 4%, respectively. The inhibitions of liposome
      peroxidation by the fatty acid fraction and compounds 1 and 2 at 100 microg/mL
      were 79, 48, and 42%, respectively. This is the first report of compounds 2 and 3
      from the cultured mycelia of G. frondosa. The COX inhibitory activities of
      compounds 1-3 are reported here for the first time.

PMID- 12475275
TI  - Differential characteristics in the chemical composition of bananas from Tenerife
      (Canary Islands) and Ecuador.
AB  - The contents of moisture, protein, ash, ascorbic acid, glucose, fructose, total
      sugars, and total and insoluble fiber were determined in cultivars of bananas
      (Gran Enana and Pequena Enana) harvested in Tenerife and in bananas (Gran Enana)
      from Ecuador. The chemical compositions in the bananas from Tenerife and from
      Ecuador were clearly different. The cultivar did not influence the chemical
      composition, except for insoluble fiber content. Variations of the chemical
      composition were observed in the bananas from Tenerife according to cultivation
      method (greenhouse and outdoors), farming style (conventional and organic), and
      region of production (north and south). A highly significant (r = 0.995)
      correlation between glucose and fructose was observed. Correlations of ash and
      protein contents tend to separate the banana samples according to origin. A
      higher content of protein, ash, and ascorbic acid was observed as the length of
      the banana decreased. Applying factor analysis, the bananas from Ecuador were
      well separated from the bananas produced in Tenerife. An almost total
      differentiation (91.7%) between bananas from Tenerife and bananas from Ecuador
      was obtained by selecting protein, ash, and ascorbic acid content and applying
      stepwise discriminant analysis. By selecting the bananas Pequena Enana and using
      discriminant analysis, a clear separation of the samples according to the region
      of production and farming style was observed.

PMID- 12475276
TI  - Production of trichothecenes and other secondary metabolites by Fusarium culmorum
      and Fusarium equiseti on common laboratory media and a soil organic matter agar:
      an ecological interpretation.
AB  - Fusarium culmorum and F. equiseti were characterized with regard to production of
      trichothecenes and other secondary metabolites. Results following growth on
      laboratory media are interpreted with the aim of increasing the understanding of
      fungal metabolism in the field environment. While trichothecene production was
      detected for 94 of 102 F. culmorum isolates, only 8 of 57 F. equiseti isolates
      were positive. Profiles of secondary metabolites were compared by following
      growth on yeast extract sucrose agar (YES), potato sucrose agar (PSA), and an
      agar medium, prepared from soil organic matter (SOM), which was included to
      simulate growth conditions in soil. SOM supported the production of chrysogine by
      F. culmorum. The two species utilized the media differently. F. culmorumproduced
      zearalenone (ZEA) on YES, whereas some F. equiseti isolates produced ZEA on PSA.
      Other F. equiseti isolates produced equisetin. These differences may reflect that
      F. culmorum depends on a pathogenic life style while F. equiseti has a more
      saprotrophic mode of existence.

PMID- 12475277
TI  - Studies on water transport through the sweet cherry fruit surface. 7. Fe3+ and
      Al3+ reduce conductance for water uptake.
AB  - The effects of the chloride salts LiCl, CaCl(2), MgCl(2), AlCl(3), EuCl(3), and
      FeCl(3) and the iron salts FeCl(2), FeCl(3), Fe(NO(3))(3), FeSO(4), and
      Fe(2)(SO(4))(3) on water conductance of exocarp segments (ES) and rates of water
      uptake into detached sweet cherry fruit (Prunus avium L. cv. Adriana, Early
      Rivers, Namare, Namosa, and Sam) were studied. ES were excised from the cheek of
      mature fruit and mounted in stainless steel diffusion cell; water penetration was
      monitored gravimetrically from donor solutions containing the above mineral salts
      into a PEG 6000 (osmolality = 1.14 osM, pH 4.8, 25 degrees C) receiver solution.
      Conductance of ES was calculated from the amount of water taken up per unit of
      surface area and time by dividing by the gradient in water activity across ES.
      LiCl, CaCl(2), MgCl(2), FeCl(2), and FeSO(4) had no significant effect on
      conductance, but AlCl(3), FeCl(3), Fe(NO(3))(3), and Fe(2)(SO(4))(3)
      significantly reduced conductance compared to water only as a donor. Also,
      EuCl(3) lowered conductance; however, this effect was not always significant.
      Effects of salts on water conductance of ES and rates of water uptake into
      detached fruit were closely related (R 2 = 0.97***). Upon application of an
      FeCl(3)-containing donor conductance decreased instantaneously. FeCl(3)
      concentrations of <6.6 x 10(-)(4) M had no effect on conductance, but
      concentrations at or above this threshold decreased conductance. FeCl(3) lowered
      water conductance at a receiver pH of 4.8, but not at pH < or =2.6. The effect of
      FeCl(3) on conductance was largest in cv. Namare and smallest in cv. Adriana.
      There was no significant effect of FeCl(3) on conductance for transpiration.
      Formation of aluminum and iron oxides and hydroxides in the exocarp as a result
      of a pH gradient between donor and receiver solution is discussed as the
      potential mechanism for Fe(3+) and Al(3+) reducing conductance for water uptake.

PMID- 12475278
TI  - Characterization of commercial iron chelates and their behavior in an alkaline
      and calcareous soil.
AB  - Iron deficiency is a common problem for many plants grown in alkaline and
      calcareous soils. To correct this problem, iron is supplied to plants as
      chelates. Several iron chelates are sold under diverse trademarks with different
      characteristics. This work evaluated 18 commercial products containing the most
      representative chelated iron sources used in agricultural practice in Spain when
      the study was done, namely the ferric chelates of EDDHA, EDDHMA, EDDCHA, EDDHSA,
      EDTA, and DTPA. The chelates were comprehensively characterized and quantitated
      by several techniques, including several chromatographic methods. Iron and
      chelate dynamics in soil were also studied in a model alkaline and calcareous
      soil. Results indicate that, in this model soil, among the different iron
      compounds studied only FeEDDHA and analogues have the capacity to maintain
      soluble iron in soil solution over time. These results are in agreement with
      general experience under field conditions. Furthermore, among the different ortho
      ortho isomers of FeEDDHA's, FeEDDHSA and FeEDDCHA showed greater capacity than
      FeEDDHA and FeEDDHMA to maintain the chelated iron in soil solution over time.

PMID- 12475279
TI  - Flavor composition of cashew (Anacardium occidentale) and marmeleiro (Croton
      species) honeys.
AB  - The aim of this work was to characterize the volatile fractions of two Brazilian
      honeys known as caju and marmeleiro. The volatile components were isolated by a
      column extraction technique using acetone as the extraction solvent. Totals of 59
      and 36 volatile compounds were definitely or tentatively identified in the caju
      and marmeleiro honeys, respectively, using reference substances, mass spectral
      libraries, and the odor qualities of the compounds eluted from the GC column.
      Aroma extraction dilution analysis allowed the tentative identification of
      furfuryl mercaptan, benzyl alcohol, delta-octalactone, gamma-decalactone,
      eugenol, benzoic acid, isovaleric acid, phenylethyl alcohol, and 2-methoxyphenol
      as impact volatile compounds in the caju honey. In the marmeleiro honey, only
      isovaleric acid, gamma-decalactone, benzoic acid, and vanillin were considered to
      be potent odorants. This study showed that the medium- to high-boiling volatile
      compounds are important contributors to the characteristic aroma of these honeys.

PMID- 12475280
TI  - Changes in volatile compounds of gamma-irradiated fresh cilantro leaves during
      cold storage.
AB  - Consumption of salsas and dishes containing cilantro has been linked to several
      recent outbreaks of food-borne illness due to contamination with human pathogens.
      Ionizing irradiation can effectively eliminate food-borne pathogens from various
      vegetables including cilantro. However, the effect of irradiation on aroma of
      fresh cilantro is unknown. This study was conducted to investigate the effect of
      irradiation on volatile compounds of fresh cilantro leaves. Fresh cilantro leaves
      (Coriandrum sativum L) were irradiated with 0, 1, 2, or 3 kGy gamma radiation and
      then stored at 3 degrees C up to 14 days. Volatile compounds were extracted using
      solid-phase microextraction (SPME), followed by gas chromatographic separation
      and mass spectra detection at 0, 3, 7, and 14 days after irradiation. Most of the
      volatile compounds identified were aldehydes. Decanal and (E)-2-decenal were the
      most abundant compounds, accounting for more than 80% of the total amount of
      identified compounds. The amounts of linalool, dodecanal, and (E)-2-dodecenal in
      irradiated samples were significantly lower than those in nonirradiated samples
      at day 14. However, the most abundant compounds [decanal and (E)-2-decenal] were
      not consistently affected by irradiation. During storage at 3 degrees C, the
      amount of most aldehydes peaked at 3 days and then decreased afterward. Our
      results suggest irradiation of fresh cilantro for safety enhancement at doses up
      to 3 kGy had minimal effect on volatile compounds compared with the losses that
      occurred during storage.

PMID- 12475281
TI  - Changes in the volatile compounds and in the chemical and physical properties of
      snake fruit (Salacca edulis Reinw) Cv. Pondoh during maturation.
AB  - During the maturation of snake fruit (Salacca edulis Reinw) Pondoh, the contents
      of sucrose, glucose, fructose, and volatile compounds changed drastically. The
      glucose, fructose, and volatile compounds contents showed their maximum levels at
      the end of maturation; however, the sucrose content decreased. During maturation,
      the flesh firmness tended to increase; however, at the end of maturation (6
      months), the flesh became soft. The major volatile aroma in solvent-assisted
      flavor evaporation (SAFE) and solvent extracts were identified to be methyl
      esters of butanoic acids, 2-methylbutanoic acids, hexanoic acids, pentanoic
      acids, and the corresponding carboxylic acids. Furaneol (4-hydroxy-2,5-dimethyl
      3(2H)-furanone) was also identified as a minor aroma constituent in the SAFE
      residue. The methyl esters were found to increase dramatically during stages 4-6
      (5-6 months after the pollination) to exceed the amounts of carboxylic acids,
      whereas the acid amount increased gradually until stage 5 (5.5 months after the
      pollination) to reach the maximum at stage 6 (6 months after the pollination).

PMID- 12475282
TI  - Release of deuterated (E)-2-nonenal during beer aging from labeled precursors
      synthesized before boiling.
AB  - Although lipid autoxidation in the boiling kettle is a key determinant of the
      cardboard flavor of aged beers, recent results show that mashing is another
      significant source of wort nonenal potential, the well-known indicator of how a
      beer will release (E)-2-nonenal during storage. Although unstable, deuterated (E)
      2-nonenal nitrogen adducts created during mashing can in some cases partially
      persist in the pitching wort, to release deuterated (E)-2-nonenal during beer
      aging. In the experiment described here, the relative contributions of mashing
      and boiling were estimated at 30 and 70%, respectively. The presence of oxygen
      during mashing and, to a lesser extent, high lipoxygenase activity can intensify
      the stale cardboard flavor.

PMID- 12475283
TI  - Green-leaf-derived C6-aroma compounds with potent antibacterial action that act
      on both Gram-negative and Gram-positive bacteria.
AB  - All eight C6-aliphatic alcohol and aldehyde compounds in naturally occurring
      green leaves showed bacteriostatic effects against Staphylococcus aureus IFO
      12732, methicillin-resistant S. aureus, Escherichia coli IFO 3301, E. coli
      O157:H7, and Salmonella enteritidis, with bacteriostatic activities of less than
      12.5 microg mL(-1). In this study, the susceptibility of Gram-positive bacteria
      tested was observed to be greater than that of Gram-negative bacteria. The
      bactericidal action of the aldehyde compounds was found to be much stronger than
      that of the alcohol compounds under both liquid and gaseous conditions. The most
      effective compound was (3E)-hexenal at concentrations of 0.1 and 1 microg mL(-1),
      which killed 2.1 x 10(5) cfu mL(-1) of S. aureus IFO 12732 and 1.4 x 10(5) cfu
      mL(-1) of E. coli IFO 3301, respectively, by direct contact with the compound.
      Lethality of (3E)-hexenal against S. aureus IFO 12732 and E. coli IFO 3301 was
      also observed as a result of gaseous contact at concentrations of 3 and 30 microg
      mL(-1), respectively. The bactericidal effects of 30 microg mL(-1) (3E)-hexenal
      were thoroughly maintained throughout periods of 2 days and 1 day against S.
      aureus IFO 12732 and E. coli IFO 3301, respectively, by a complex formation with
      alpha-cyclodextrin.

PMID- 12475284
TI  - Role of beer lipid-binding proteins in preventing lipid destabilization of foam.
AB  - The negative effect of fatty acids on the foam stability of beer has been
      assessed. Long-chain fatty acids are far more damaging than short-chain fatty
      acids on the foam stability of beer at the concentrations employed. Polypeptides
      have been isolated from an all malt beer by hydrophobic interaction
      chromatography. Using this technique five groups of polypeptides were isolated,
      group 1 being the least hydrophobic and group 5 the most hydrophobic, all of
      which exhibited similar polypeptide compositions by SDS-PAGE. All five
      hydrophobic polypeptide groups bound [(14)C]linoleic acid; however, group 5, the
      most hydrophobic group, bound the most linoleic acid. Groups 1 and 5 were
      titrated with cis-parinaric acid (CPA) to produce binding curves, which were
      compared with a binding curve obtained for bovine serum albumin (BSA). Groups 1
      and 5 both produced binding curves that saturated at approximately 5.5 microM and
      4 microM CPA and had association constants (K(a)) of 6.27 x 10(7) and 1.62 x
      10(7) M(-1), respectively. In comparison, BSA produced a binding curve that
      saturated at 6 microM CPA and had a K(a) of 3.95 x 10(7) M(-1). Further
      investigation has shown that group 1 is pH sensitive and group 5 pH insensitive
      with respect to lipid binding. The lipid-binding activity of group 5 was also
      shown to be unaffected by ethanol concentration. Linoleic acid (5 microM) when
      added to beer resulted in unstable foam. Group 5 was added to the lipid-damaged
      beer and was shown to restore the foam stability to values that were obtained for
      the control beer. It has therefore been demonstrated that proteins isolated from
      beer have a lipid-binding capacity and that they can convey a degree of
      protection against lipid-induced foam destabilization.

PMID- 12475285
TI  - Formation and stability of foam made with various potato protein preparations.
AB  - In the present study, foam-forming and -stabilizing properties of potato proteins
      were studied using whipping and sparging tests. The soluble potato proteins are
      mainly composed of patatin and protease inhibitors. The whipping tests showed
      that less foam was formed from untreated patatin than from the protease
      inhibitors, but patatin foam was much more stable. The foam-forming properties of
      patatin could be strongly improved by partial unfolding of the protein. Whipping
      tests, at both low (0.5 mg/mL) and high (10 mg/mL) protein concentration, also
      indicated that foams made with an ethanol-precipitated protein isolate were more
      stable than those made with beta-casein and beta-lactoglobulin. More generally,
      it can be concluded that when proteins are used as a foaming agent, a high
      concentration is required, because the protein available is inefficiently used.
      Also, there are several variables that may all, in different ways, affect both
      foam formation (amount of foam, bubbles size distribution) and foam stability.
      These variables include the type and concentration of protein, solvent conditions
      (pH, I), and the method used to make the foam.

PMID- 12475286
TI  - Volatile response of four apple varieties with different coatings during
      marketing at room temperature.
AB  - Five experimental coatings with different resistance to gas exchange were used
      with freshly harvested and 20-week commercially stored apples of Delicious, Fuji,
      Braeburn, and Granny Smith varieties. The coated or noncoated apples were held at
      20 degrees C for up to 4 weeks. The gas partial pressures inside the fruits with
      the various coatings ranged from 1 to 25 kPa CO(2) and from 20 to 1 kPa O(2).
      Volatile evaporation rates were measured, as also were the volatiles compositions
      in the fruit. The coatings with intermediate gas resistance (carnauba-shellac
      mixture and candelilla) gave intermediate values of CO(2) and O(2) in the
      internal atmosphere in Delicious, Fuji, and Braeburn apples and the highest
      concentrations of butyl acetate and 2-methylbutyl acetate in the fruits. The
      coatings with the highest gas resistance (shellac and shellac-protein) caused
      high internal CO(2) and low O(2), resulting in anaerobic fermentation in Braeburn
      and Granny Smith apples and relatively high amounts of low-molecular-weight ethyl
      esters trapped within the fruit. A small portion of the alcohols were evaporated
      from fruits compared to esters, this attributed to their high Henry's law
      coefficients.

PMID- 12475287
TI  - Acid-induced unfolding of flounder hemoglobin: evidence for a molten globular
      state with enhanced pro-oxidative activity.
AB  - The acid-induced unfolding of flounder oxyhemoglobin was investigated and the
      effect on pro-oxidative activity assessed. Hemoglobin exhibited multistep
      unfolding transitions as pH was lowered, with the major transition between pH 3.5
      and 4 5. The protein was maximally acid-unfolded (but not fully unfolded) at
      approximately pH 2.5, and further titration with HCl led to a partially refolded
      protein due to a stabilizing effect of Cl(-) anions. At low pH, the protein
      retained a sizable amount of secondary structure and had increased ANS binding,
      suggesting a molten globular form at low pH. Dramatic changes in the heme
      environment occurred concurrently with the changes in protein conformation. These
      changes resulted in an enhancement in the pro-oxidative activity of the protein.
      The results show that an increase in flounder hemoglobin pro-oxidation was
      correlated with the extent of its unfolding, and they provide useful insight into
      what may occur with hemoglobin in processes where highly acidic conditions are
      employed.

PMID- 12475288
TI  - Cross-polarization/magic angle spinning NMR to study glucose mobility in a model
      intermediate-moisture food system.
AB  - Theories for the chemical stability of foods cite the role of moisture content or
      water activity in reactant mobility, though mobility has been variously defined.
      One theory, based on plasticization by moisture, is limited by a lack of research
      directly linking the mobility of a matrix to the mobility and reactivity of small
      solute molecules in foods. A cross-polarization/magic angle spinning technique
      was developed to study glucose rotational mobility in the solid state over a
      range of water activities and in matrixes with different glass transition
      temperatures. Data analysis stressed the significance of separating molecular
      mobility from relaxation time. Results showed that, in a caseinate matrix,
      compared to a control, adding glycerol yielded the highest glucose mobility and
      lowest glass transition temperature (T(g)), while adding sorbitol also increased
      mobility and lowered T(g). Consequently, plasticization by either moisture or
      these humectants increases the mobility of small solute molecules such as
      glucose.

PMID- 12475289
TI  - A model system study of the inhibition of heterocyclic aromatic amine formation
      by organosulfur compounds.
AB  - Organosulfur compounds and sodium bisulfite significantly inhibited (P < 0.05)
      heterocyclic aromatic amine (HAA) formation in model systems containing
      phenylalanine, creatinine, and glucose. There was, however, no inhibition by the
      same compounds in a model system containing only phenylalanine and creatinine.
      Diallyl disulfide (DAD) and dipropyl disulfide (DPD) concentrations in the model
      systems were significantly decreased (P < 0.05) after heating for 10 min at 180
      degrees C. Only very low concentrations of sulfhydryl groups (4.19 and 4.00
      micromol) were produced on heating DAD and DPD for 30 min. Reaction of glucose
      and DAD produced several sulfur-containing compounds. After 10 min of heating at
      180 degrees C, HAA formation in the control model systems was increased
      significantly, and DAD was an effective inhibitor during this heating period.
      Tetrahydrothiophene-3-one (THT) and tetrahydrothiophene (THP); two products
      resulting from the interaction of glucose and DAD, had no direct influence on HAA
      formation in the model systems.

PMID- 12475290
TI  - Specific fluctuations in the composition of lipoxygenase- and glycosidase
      generated flavors in some cultivated teas of Assam.
AB  - Variations of fatty acid compositions, glycosides precursors, and lipoxygenase
      and glycosidase enzymatic activities were used simultaneously to differentiate
      for nine genetically different cultivated teas, four seasonal changes, and the
      affect of leaf maturity. The muscatel flavor of second-flush teas was associated
      with increased activities of glycosidase and several terpenes, phenolics, and
      aliphatic compounds bound to glycosides, whereas high levels of fatty acids and
      lipoxygenase activity biosynthesized more green volatiles in monsoon teas.
      Sequential hydrolysis of lipids and lipoxygenase-mediated reactions, during
      withering and rolling, showed a 3-fold increase of hexenol, hexenal, and related
      volatiles, but they decreased to the levels of fresh leaf during drying. However,
      a 4-fold increase of the floral bend of volatiles found in black tea developed
      due to the hydrolysis of the glycoside precursors throughout processing stages.
      About 45 key volatiles were monitored for flavor superiority among different
      clones. Various parameters affecting yield of volatiles were optimized and
      recommended.

PMID- 12475291
TI  - Suppression effect of Cinnamomum cassia bark-derived component on nitric oxide
      synthase.
AB  - The inhibitory effects of Cinnamomum cassia bark-derived material on nitric oxide
      (NO) production in RAW 264.7 cells was determined through the evaluation of NO
      production and expression of inducible nitric oxide and compared to the effects
      of three commercially available compounds, cinnamyl alcohol, cinnamic acid, and
      eugenol. The biologically active constituents of C. cassia extract were
      characterized as trans-cinnamaldehyde by spectral analysis. The inhibitory
      effects varied with both chemical and concentration used. Potent inhibitory
      effects of cinnamaldehyde against NO production were 81.5 and 71.7% at 1.0 and
      0.5 microg/microL, respectively, and a 41.2% inhibitory effect was revealed at
      0.1 microg/microL. However, little or no activity was observed for cinnamic acid
      and eugenol. Suppression effects of cinnamaldehyde on inducible nitric oxide
      synthase expression were revealed by Western blot analysis. As a naturally
      occurring therapeutic agent, trans-cinnamaldehyde could be useful for developing
      new types of NO inhibitors.

PMID- 12475292
TI  - Comparison of the antioxidant activities of extra virgin olive oils.
AB  - The phenol content and antioxidant activity of extra virgin olive oils (EVOOs)
      differing in their origins and degradation degrees were studied. The o-diphenolic
      compounds typical of olive oil, namely, the oleuropein derivatives hydroxytyrosol
      (3',4'-dihydroxyphenylethanol, 3',4'-DHPEA), the dialdehydic form of elenolic
      acid linked to 3',4'-DHPEA (3',4'-DHPEA-EDA), and an isomer of oleuropein aglycon
      (3',4'-DHPEA-EA), were analyzed by HPLC. The antioxidant activity was studied by
      (a) the xanthine oxidase (XOD)/xanthine system, which generates superoxide
      radical and hydrogen peroxide; (b) the diaphorase (DIA)/NADH/juglone system,
      which generates superoxide radical and semiquinonic radical; and (c) the 2,2
      diphenyl-1-picrylhydrazyl radical (DPPH) test. Results showed that EVOOs with a
      low degradation level (as evaluated by acidity, peroxide number, and
      spectroscopic indices K(232), K(270), and deltaK according to the EU Regulation)
      had a higher content of 3',4'-DHPEA-EDA and a lower content of 3',4'-DHPEA than
      oils having intermediate and advanced degradation levels. EVOOs with a low
      degradation degree were 3-5 times more efficient as DPPH scavengers and 2 times
      more efficient as inhibitors of the XOD-catalyzed reaction than oils with
      intermediate and advanced degradation levels. The DIA-catalyzed reaction was
      inhibited by EVOOs having low or intermediate degradation levels but not by the
      most degraded oils.

PMID- 12475293
TI  - Synthesis of sildenafil analogues from anacardic acid and their phosphodiesterase
      5 inhibition.
AB  - Anacardic acid (6-pentadecylsalicylic acid), a major component of cashew nut
      shell liquid, consists of a heterogeneous mixture of monoenes, dienes, and
      trienes. The enes mixture of anacardic acid was hydrogenated to a saturated
      compound. Using saturated anacardic acid as a starting material, analogues of
      sildenafil [a potent phosphodiesterase-5 (PDE(5)) inhibitor and an orally active
      drug for the treatment of erectile dysfunction] were synthesized, to observe the
      effect of the pentadecyl side chain on PDE(5) inhibition. The synthesized
      compounds were characterized by spectral studies and tested for PDE(5)
      inhibition, and the results were compared with those obtained with sildenafil.

PMID- 12475294
TI  - Topoisomerase I and II enzyme inhibitory aqueous extract of Ardisia compressa and
      ardisin protect against benomyl oxidation of hepatocytes.
AB  - Tea preparations of Ardisia compressa (AC) have been used in folk medicine
      against liver disorders. The objective of this study was to evaluate the in vitro
      topoisomerase I and II enzyme inhibition and the antioxidant effect of an aqueous
      extract from dry leaves of AC and a pure component (ardisin) purified from AC on
      benomyl (Be)-induced cytotoxicity in primary culture rat hepatocytes. Lipid
      peroxidation (malondialdehyde), antioxidant enzyme activities of glutathione
      reductase, glutathione peroxidase, and superoxide dismutase, and glutathione
      levels were studied. Topoisomerase I and II enzyme inhibition was used to guide
      purification of ardisin, which was purified using TLC, MPLC, and preparative and
      analytical HPLC methods. Benomyl increased malondialdehyde (58% change in
      comparison to the control) and glutathione peroxidase (10%), producing a
      significant consumption of endogenous antioxidant glutathione (65%, P < 0.05). A
      94% hepatocyte protection was observed when cells were first exposed to ardisin
      (0.27 microg/mL), followed by Be (35 microg/mL). Cell protection by the tea
      extract of AC (AE) was greater than that by (-)-epigallocatechin 3-gallate
      (EGCG). Ardisin showed a clear inhibition of topoisomerases I and II catalytic
      activity in Saccharomyces cerevisiae mutant cells JN 394, JN394t(-)(1), and
      JN394t-(2)(-)(5). The potency of ardisin was superior to that of AE and EGCG as
      an antioxidant, protecting rat hepatocytes when exposed to Be. On the basis of
      the effective concentrations of equivalents to [+]catechin found in the present
      study, it can be estimated that, in order to gain antioxidative protection, a
      person would need to ingest approximately 1 L of AC tea per day, with a total
      content of 10.8 g of plant material.

PMID- 12475295
TI  - Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in
      humans.
AB  - Postprandial hyperlipemia is a well-defined risk factor for atherosclerosis. A
      reasonable contributing mechanism could involve the postprandial increase of
      plasma lipid hydroperoxides (LPO) affecting the oxidant/antioxidant balance and
      increasing the susceptibility of LDL to oxidation. Wine has been shown to prevent
      both these events. The present study was designed to investigate the effect of
      supplementing a meal with grape seed proanthocyanidins (the main phenolic
      antioxidant of red wine) on plasma postprandial oxidative stress. In two
      different sessions, 8 healthy volunteers consumed the same test meal rich in
      oxidized and oxidizable lipids without (control) or with 300 mg of a
      proanthocyanidin-rich grape seeds extract (GSE). Lipid hydroperoxide
      concentration, antioxidant status, and LDL resistance to oxidative modification
      were measured in postprandial plasma. The content of LPO in chylomicrons was 1.5
      fold higher after the control meal than after the GSE-supplemented meal. Plasma
      LPO increased only after consumption of the control meal. The plasma antioxidant
      capacity increased in the postprandial phase only following the GSE supplemented
      meal. LDL isolated 3 h after the control meal tended to be more susceptible to
      oxidative modification (but the difference did not reach statistical
      significance). An opposite trend was observed following the GSE supplemented
      meal. In conclusion, the supplementation of a meal with GSE minimizes the
      postprandial oxidative stress by decreasing the oxidants and increasing the
      antioxidant levels in plasma, and, as a consequence, enhancing the resistance to
      oxidative modification of LDL.

PMID- 12475296
TI  - Stability of ingested methylcellulose in the rat determined by polymer molar mass
      measurements by light scattering.
AB  - Methylcellulose (MC) is ingested by humans in food and pharmaceutical
      formulations. The functional properties of MC like those of other linear polymers
      depend primarily on polymer length or molar mass for largely linear polymers.
      Although many studies in animals and humans have shown complete excretion of MC,
      in vitro human fecal fermentation studies indicate that MC can be degraded and
      presumably lose some of its functionality. In this study, MC polymer distribution
      in the feces from rats fed a diet containing 8% methylcellulose were compared to
      the fed MC. The water-soluble polymers in the feces were separated by a size
      exclusion chromatography (SEC) and the polymer distributions determined by
      multiple angle laser light scattering (MALLS). Detection of the fluorescent MC
      calcofluor complex was used to confirm the identity of the eluting MC peak. All
      dietary MC was recovered in the feces. There is a small shift (P < 0.06) in the
      weight-averaged molecular weight of polymer distribution of MC extracted from the
      feces to 2.71 +/- 0.15 x 10(5) g/mol from 3.15 +/- 0.02 x 10(5) g/mol in the
      standard. There is also an increase in the polydispersity from 1.21 in the
      standard to 1.8 in the fecal extract. The distribution of the substituted
      methoxylated glucose monomers by gas chromatography also confirms the stability
      of MC fed to rats. The amount of actual hydrolysis is estimated to be about 0.1
      glycosidic linkage/molecule. MC is not easily determined by standard dietary
      fiber methods, and SEC with MALLS and/or fluorescence may be a useful
      alternative.

PMID- 12475297
TI  - Absorption of anthocyanins from blueberries and serum antioxidant status in human
      subjects.
AB  - In recent years, numerous studies have shown that the polyphenolics present in
      fruit and vegetable products exhibit a wide range of biological effects. However,
      there is little reliable information on the absorption of glycosylated and
      acylated anthocyanins in humans. In the present study, the absorption of
      anthocyanins in humans was investigated after the consumption of a high-fat meal
      with a freeze-dried blueberry powder containing 25 individual anthocyanins
      including 6 acylated structures. Nineteen of the 25 anthocyanins present in the
      blueberries were detected in human blood serum. Furthermore, the appearance of
      total anthocyanins in the serum was directly correlated with an increase in serum
      antioxidant capacity (ORAC(acetone), P < 0.01). These results show that
      anthocyanins can be absorbed in their intact glycosylated and possibly acylated
      forms in human subjects and that consumption of blueberries, a food source with
      high in vitro antioxidant properties, is associated with a diet-induced increase
      in ex vivo serum antioxidant status.

PMID- 12475298
TI  - Immunoassay to quantify the major peach allergen Pru p 3 in foodstuffs.
      Differential allergen release and stability under physiological conditions.
AB  - Pru p 3 is a lipid transfer protein (LTP) that has been identified as the major
      peach (Prunus persica) allergen. However, little is known about the amount
      present in both raw and processed foodstuffs. Moreover, the in vivo release upon
      consumption of peach-containing foods remains unclear. We have developed a
      sensitive monoclonal antibody-based ELISA for Pru p 3. The method has been
      applied to measure the allergen levels in foodstuffs and the allergen release
      under different physiological conditions. A significant variability in all raw
      peaches and peach-containing foods tested has been detected. The allergen was
      extracted more efficiently at a low pH, and it was highly resistant to pepsin.
      This ELISA will be very useful in controlling the allergen concentration in
      diagnostics, in evaluating threshold levels in provocation tests, and in
      detecting hidden allergens in processed foods and cosmetics.

PMID- 12475299
TI  - [2 + 2] cross coupling of benzene and tropylium ligands in reductively activated
      piano stool complexes of Mn, Cr, and W.
AB  - We have established cation/anion coupling reactions between the tropylium ligand
      in [M(eta7-C7H7)(CO)3]+ (M = Cr, W) and the reductively activated eta4-benzene
      ligand in [Mn(eta4-C6H6)(CO)3]- (3-) to form [M(CO)3(mu2-eta6:eta5-C7H7
      C6H6)Mn(CO)3]; [Cr(CO)3(mu2-eta6:eta5-C7H7-C6H6)Mn(CO)3] can be further reduced
      to [Cr(CO)3(mu2-eta5:eta4-C7H7-C6H6)Mn(CO)3]2-, in which the tropylium and
      benzene ligands have undergone a [2 + 2] cross coupling reaction.

PMID- 12475300
TI  - Structure-performance relations in homogeneous Pd catalysis by in situ EXAFS
      spectroscopy.
AB  - X-ray absorption fine structure (XAFS) spectroscopy is used to unravel the
      structure of homogeneous catalysts in their catalytically active phase
      (solution), for which other characterization techniques failed in providing
      detailed structural information. Application of in situ EXAFS shows that the
      conformation of the allylic fragment of (P-P)Pd(1,1-dimethylallyl) catalytic
      intermediate complexes in solution (i.e., reaction medium) differs from that in
      the solid state, dependent on the bidentate ligand. The change in orientation
      directly explains differences in regioselectivity in the allylic alkylation
      reaction, displayed by the distinct complexes.

PMID- 12475301
TI  - Theoretical evidence that Cu(I) complexation promotes degradation of S
      nitrosothiols.
AB  - The degradation of S-nitrosothiols (RSNOs) to release NO is believed to be
      catalyzed by CuI ions, but the mechanism remains unclear. Kinetic experiments
      have shown that decomposition rates vary significantly with the chemical nature
      of the RSNO considered. On the basis of first-principles calculations, the
      catalytic role of CuI ion is investigated for the decomposition of S
      nitrosocysteine and its N-acetylated and ethyl ester derivatives, and for S
      nitrosohomocysteine. This preliminary study focuses on the CuI-RSNO intermediates
      involved in the decomposition pathway. The model chemistry has been validated by
      comparing calculated CuI-ligand binding energies and S-N bond homolysis energies
      with available experimental data. Calculations show that the formation of CuI
      RSNO intermediates results in weakening of the S-N bond and strengthening of the
      N-O bond, which would promote S-N bond breaking and NO release from S
      nitrosothiols.

PMID- 12475302
TI  - Raman spectroscopic evidence for cooperative C-H...O interactions in the
      acetaldehyde-CO2 complex.
AB  - In carbonyl compounds having a hydrogen atom attached to the alpha-carbon or
      directly to the carbonyl carbon, our recent ab initio and solvation studies have
      predicted the presence of a weak C-H...O interaction with CO2. This
      intermolecular interaction acts cooperatively with the Lewis acid-Lewis base
      interaction that exists between CO2 and the carbonyl group. This communication
      provides the first experimental evidence for this cooperative interaction in the
      acetaldehyde-CO2 complex using Raman spectroscopy at 25.0 degrees C in the gas
      phase. The implications of these interactions in the solvation of carbonyl-based
      CO2-philes are also discussed.

PMID- 12475303
TI  - The ene reactions of nitroso compounds involve polarized diradical intermediates.
AB  - The ene reactions of nitroso compounds were studied with B3LYP/6-31G* geometry
      optimizations and energy calculations, along with single point energy evaluations
      using CASPT2/6-31G** and UCCSD(T)/6-311+G* methods. Reactions of HNO with propene
      and of MeNO and p-NO2C6H4NO with propene or substituted alkenes were also
      studied. The reaction mechanism is stepwise and involves a polarized diradical
      intermediate. The electronic structure of this intermediate is between that of a
      closed shell polar species and that of a pure diradical, and it is stabilized by
      polar solvents. A weak C-N bonding interaction combined with a CH-O hydrogen bond
      leads to heightened barriers to rotation about formally single bonds compared to
      conventional diradicals. Consequently, rotation is slower than hydrogen
      abstraction and cyclization to form an aziridine N-oxide. This aziridine N-oxide
      does not lead to ene products without subsequent ring opening but provides a
      mechanism for the RNO moiety to translate from one end of the alkene to the
      other. B3LYP calculations are also able to reproduce kinetic isotope effects and
      regioselectivity.

PMID- 12475304
TI  - The first silastannene >si=sn<: a new doubly-bonded system of heavier group 14
      elements.
AB  - The reaction of bis[di-tert-butyl(methyl)silyl]dilithiosilane 1 with
      dichlorobis(2,4,6-triisopropylphenyl)stannane in THF at room temperature yielded
      highly air- and moisture-sensitive deep violet crystals of 1,1-bis[di-tert
      butyl(methyl)silyl]-2,2-bis(2,4,6-triisopropylphenyl)-1-sila-2-stannaethene 2
      with a Si=Sn double bond. The molecular structure of 2 was established by X-ray
      crystallography, which showed a trans-bent structure (bending angles of 26.2
      degrees for the sp2 Si atom and 9.6 degrees for the sp2 Sn atom) with a >Si=Sn<
      bond length of 2.4188(14) A and a twisting angle of 34.6 degrees . The geometry
      and regioselectivity of the addition reaction of PhEH (E = O and S) corresponds
      to the polarity of the double bond Sidelta-=Sndelta+, which is also supported by
      theoretical calculations on the model silastannene (H3Si)2Si=SnPh2.

PMID- 12475305
TI  - Electroauxiliary-assisted sequential introduction of two carbon nucleophiles on
      the same alpha-carbon of nitrogen: application to the synthesis of spiro
      compounds.
AB  - The sequential introduction of two carbon nucleophiles on the same alpha-carbon
      of nitrogen by using selective oxidative cleavage of two silyl groups as
      electroauxilialies has been accomplished. The combination of this expedient
      transformation and ring-closing metathesis enables reliable and straightforward
      syntheses of nitrogen-containing spiro compounds, such as cephalotaxine.

PMID- 12475306
TI  - First total synthesis of (+/-)-strychnofoline via a highly selective ring
      expansion reaction.
AB  - An efficient synthesis of the antitumor alkaloid (+/-)-strychnofoline is
      documented. Key to the development of the highly convergent strategy delineated
      is the coupling of a cyclic imine with spiro[cyclopropan-1,3'-oxindole], which
      takes place in a highly diastereoselective manner. The ability to conduct
      annulation reactions of spirocyclopropyloxindoles with functionalized cyclic
      imines provides new avenues for the preparation of this important class of
      biologically active structures.

PMID- 12475307
TI  - Bis-cyclometalated Ir(III) complexes as efficient singlet oxygen sensitizers.
AB  - We report the singlet oxygen sensitization properties of a series of bis
      cyclometalated Ir(III) complexes (i.e., (bt)2Ir(acac), (bsn)2Ir(acac), and
      (pq)2Ir(acac); bt = 2-phenylbenzothiazole, bsn = 2-(1-naphthyl)benzothiazole, pq
      = 2-phenylquinoline, and acac = acetylacetonate). Complexes with acetylacetonate
      ancillary ligands give singlet oxygen quantum yields near unity (PhiDelta = (0.7
      1.0) +/- 0.1), whether exciting the ligand-based state or the lowest energy
      excited state (MLCT + 3LC). The singlet oxygen quenching rates for these beta
      diketonate complexes were found to be small [(5 +/- 2) x 105 to (6 +/- 0.2) x 106
      M-1 s-1], roughly 3 orders of magnitude slower than the corresponding
      phosphorescence quenching rate. Similar complexes were prepared with glycine or
      pyridine tethered to the Ir(III) center (i.e., (bsn)2Ir(gly) and (bt)2Ir(py)Cl;
      gly = glycine and py = pyridine). The glycine and pyridine derivatives give high
      singlet oxygen yields (PhiDelta = (0.7-1.0) +/- 0.1).

PMID- 12475308
TI  - Synthesis, structure, and redox properties of the extremely crowded
      triarylpnictogens: tris(2,4,6-triisopropylphenyl)phosphine, arsine, stibine, and
      bismuthine.
AB  - A series of the extremely crowded triarylpnitogens, tris(2,4,6
      triisopropylphenyl)phosphine (1), arsine (2), stibine (3), and bismuthine (4),
      were synthesized by the reaction of 2,4,6-triisopropylphenylcopper(I) with the
      corresponding pnictogen trichlorides. Introduction [corrected] of the three bulky
      aryl groups resulted in the unusual structures and redox properties, which were
      studied by X-ray crystallography and cyclic voltammetry. The triarylpnictogens 1,
      2, and 3 had extremely large bond angles around pnictogen atoms (1: 111.5 degrees
      , 2: 109.2 degrees , 3: 106.7 degrees ), and not only 1 and 2, but also stibine 3
      displayed a reversible redox wave in the cyclic voltammograms at very low
      potentials (1: 0.16 V, 2: 0.50 V, 3: 0.57 V vs Ag/Ag+), which suggests
      considerable stability of the corresponding cation radicals.

PMID- 12475309
TI  - A remarkably efficient synthesis of pure cis-stilbenoid hydrocarbons using trans
      dibromoalkenes via palladium catalysis.
AB  - A remarkably versatile synthesis of cis-stilbenoid hydrocarbons containing highly
      functionalized phenyl groups is developed via an efficient palladium-catalyzed
      coupling of aryl Grignard reagents with trans-1,2-dibromoalkenes (generally
      obtained via bromination of the corresponding dialkylacetylenes) in
      tetrahydrofuran.

PMID- 12475310
TI  - The use of polymer heteronuclei for crystalline polymorph selection.
AB  - A method for the production of crystalline polymorphs from solution is described
      which utilizes a diverse set of polymer heteronuclei. Application to crystalline
      polymorph selection for the important pharmaceuticals acetaminophen and
      carbamazepine is demonstrated. This method provides a new paradigm for polymorph
      selection, where solvent and temperature conditions can be chosen on the basis of
      process considerations and the polymer heteronucleus can be varied for specific
      polymorph production.

PMID- 12475311
TI  - Highly enantioselective 1,3-dipolar cycloaddition reactions of 2-benzopyrylium-4
      olate catalyzed by chiral Lewis acids.
AB  - We have found that significant levels of enantioselectivity are obtained in the
      1,3-dipolar cycloadditions of 2-benzopyrylium-4-olate using chiral 2,6
      bis(oxazolinyl)pyridine (Pybox)-rare earth metal triflate complexes as chiral
      Lewis acid catalysts. The reactions with benzyloxyacetaldehyde derivatives
      catalyzed by Sc(III)-Pybox-i-Pr (10 mol %) proceeded to give endo-adducts
      selectively with high enantioselectivity (up to 93% ee). The reaction with benzyl
      pyruvate under similar conditions gave an exo-adduct selectively with 87% ee. In
      the reaction with 3-acryloyl-2-oxazolidinone, Yb(III)-Pybox-Ph was found to be
      effective in providing an exo-adduct with extremely high enantioselectivity (98%
      ee).

PMID- 12475312
TI  - The use of a thermally reversible bond for molecular imprinting of silica
      spheres.
AB  - A silica monomer-estrone complex (EstSi) having a thermally cleavable urethane
      bond and a cross-linkable triethoxysilane group was synthesized. From EstSi and
      TEOS, spherical silica particles with sizes of 1.5-3 mum were prepared. The
      template molecules were removed from the silica matrix by heating at 180 degrees
      C in DMSO in the presence of water, generating a cavity with an amino group. The
      control silica particles that had the same sizes and shapes were obtained with
      aminopropyl triethoxysilane and TEOS. When ethylene glycol was added in place of
      H2O, an ethyl alcoholic group was formed in the cavity. Their recognition ability
      and specific binding for estrone were characterized by uptake experiments. The
      estrone-imprinted silica particles showed a much higher recognition ability than
      the control silica particles and higher selectivity for estrone than testosterone
      propionate.

PMID- 12475313
TI  - Structural features of the cytochrome C molten globule revealed by fluorescence
      energy transfer kinetics.
AB  - Nonnative states of proteins are involved in a variety of cellular processes,
      including translocation of proteins across membranes and formation of amyloid
      fibrils. Probes that report on the structural heterogeneity of a polypeptide
      ensemble could resolve ambiguities in the classification of these states.
      Employing fluorescence energy transfer kinetics, we have shown that added anions
      shift the equilibrium between the compact and extended polypeptide structures
      that are present during refolding of Saccaromyces cerevisiae iso-1 cytochrome c.
      Specifically, at high salt concentrations (>/=700 mM), all of the polypeptides
      are compact with a mean C-terminal fluorophore-heme separation quite close to
      that in the native protein (25 A).

PMID- 12475314
TI  - Cluster synthesis via ligand-arrested solid growth: triethylphosphine-capped
      fragments of binary metal chalcogenides.
AB  - A new and potentially highly generalizable technique for synthesizing molecular
      fragments of binary solids is demonstrated through application to selected
      transition metal chalcogenides. Employing a metal atom reactor, the solids are
      evaporated with a tungsten heating boat, and the resulting vapor is co-condensed
      with triethylphosphine. Major cluster products identified from a survey of first
      row transition metal sulfides include the known species Cr6S8(PEt3)6,
      Co6S8(PEt3)6, and Cu12S6(PEt3)8, as well as the unprecedented species
      Fe4S4(PBun3)4, Ni4S4(PEt3)8, and Cu6S4(PEt3)4. Reactions utilizing Cu2Se resulted
      in the much larger clusters Cu26Se13(PEt3)14 and Cu70Se35(PEt3)21. The core of
      the former has a Th-symmetry structure featuring a body-centered icosahedron of
      Se2- anions, while the latter adopts a triangular structure based on three
      hexagonal closest packed layers of Se2- anions. In both cases, the Cu+ cations
      occupy distorted tetrahedral or trigonal planar sites similar to those
      encountered in Cu2Se; however, emergence of the face-centered cubic anion lattice
      of the bulk solid is not yet apparent at these cluster sizes.

PMID- 12475315
TI  - Copper-catalyzed halogen exchange in aryl halides: an aromatic Finkelstein
      reaction.
AB  - A mild and general method for the conversion of aryl, heteroaryl, and vinyl
      bromides into the corresponding iodides was developed utilizing a catalyst system
      comprising 5 mol % of CuI and 10 mol % of a 1,2- or 1,3-diamine ligand. A variety
      of polar functional groups are tolerated, and even N-H containing substrates such
      as sulfonamides, amides, and indoles are compatible with the reaction conditions.
      Both the reaction rate and the equilibrium conversion of the aryl bromide depend
      on the choice of the halide salt and the solvent. The best results were obtained
      using NaI as the halide salt and dioxane, n-butanol, or n-pentanol as the
      solvents.

PMID- 12475316
TI  - Hydrophobic interaction and hydrogen bonding cooperatively confer a vancomycin
      hydrogel: a potential candidate for biomaterials.
AB  - Antibiotic hydrogels based on a vancomycin (Van) derivative, formed by self
      assembling Van-pyrene (1) in water, using the pi-pi interaction of pyrene
      moieties and hydrogen bonding of Vans, promise a new way to make novel
      biomaterials.

PMID- 12475317
TI  - Total synthesis of (-)-tuberostemonine.
AB  - The first total synthesis of the complex pentacyclic Stemona alkaloid
      tuberostemonine was accomplished in 24 steps and in 1.4% overall yield from a
      hydroindole intermediate which is readily obtained in three steps from Cbz-l
      tyrosine. An innovative synthetic strategy was applied that relays the single
      stereocenter of the amino acid precursor into nine of the ten stereogenic carbons
      of the target molecule. Among the highlights of the synthetic methodology are the
      3-fold use of ruthenium catalysis, first in an azepine ring-closing metathesis
      and then in an alkene isomerization followed by a cross-metathesis propenyl-vinyl
      exchange, as well as the stereoselective attachment of the gamma-butyrolactone
      moiety to the core tetracycle by use of a lithiated ortho ester.

PMID- 12475318
TI  - Catalyzed asymmetric aryl transfer reactions to aldehydes with boronic acids as
      aryl source.
AB  - Chiral diaryl methanols are important intermediates for the synthesis of
      biologically active compounds. Here, we describe a flexible method for their
      catalyzed asymmetric synthesis from readily available starting materials.
      Noteworthy is the fact that with a single catalyst both enantiomers of the
      product are accessible simply by choosing the appropriate combination of aryl
      boronic acid or aldehyde as aryl donor and acceptor, respectively. The catalysis
      with a planar-chiral ferrocene is easy to perform and yields a broad range of
      products with excellent enantioselectivities (up to 98% ee).

PMID- 12475319
TI  - Evidence for a new ferroelectric switching liquid crystalline phase formed by a
      carbosilane based dendrimer with banana-shaped mesogenic units.
AB  - The first carbosilane dendrimer with peripheral bent-core mesogenic units is
      reported. This material forms a liquid crystalline phase which is stable over a
      wide temperature range and forms an LC glass on cooling. Polarizing microscopy, X
      ray diffraction, and dielectric and electrooptic investigations reveal the
      presence of a novel liquid crystalline phase, in which the molecules are tilted
      and adapt a polar order within the layers, but without long-range correlation
      between the layers. By applying external electric fields, switching into a
      ferroelectric organization can be achieved. Once formed the ferroelectric states
      are stable and can be switched between the different polarization states.

PMID- 12475320
TI  - B4CO2: a new, observable sigma-pi diradical.
AB  - A new sigma-pi diradical, B4(CO)2, prepared in matrix isolation, was
      characterized unambiguously by isotopic-substitution infrared spectroscopy and by
      theoretical computations. Both open-shell singlet and triplet states have three
      pi electrons but are aromatic with moderately large NICS values. Quantum chemical
      calculations at various levels indicate that the open-shell singlet is slightly
      more stable than the triplet state. However, the singlet and triplet are computed
      to have very similar IR features which do not allow experimental differentiation.

PMID- 12475321
TI  - Templating effect of hydrogen-passivated silicon nanowires in the production of
      hydrocarbon nanotubes and nanoonions via sonochemical reactions with common
      organic solvents under ambient conditions.
AB  - A new type of well-structured, hydrocarbon nanomaterial including nanotubes and
      onions, with interlayer spacing ranging from 3.4 to 5.8 A, was discovered by
      reacting SiNWs with common organic solvents in a laboratory sonicator under
      ambient conditions (room temperature and atmospheric pressure).

PMID- 12475322
TI  - Reactivity of intermediates in benzoylformate decarboxylase: avoiding the path to
      destruction.
AB  - Benzoylformate decarboxylase forms a covalent intermediate from thiamin
      diphosphate (TDP) and benzoylformate, alpha-mandelylTDP. This loses carbon
      dioxide to form a carbanion (enamine). Protonation of the carbanion and
      elimination of benzaldehyde regenerate enzyme-bound TDP. We synthesized alpha
      mandelylthiamin and found that the rate of the loss of carbon dioxide is one
      millionth that of the enzymic reaction. Thus, the enzyme provides an environment
      that facilitates the unimolecular decarboxylation process. However, the resulting
      nonenzymic carbanion reacts very rapidly to give products that lead to the
      irreversible destruction of the cofactor. This contrasts with the normal process
      on the enzyme. Bronsted acids on the enzyme may divert the reaction to the
      benzaldehyde precursor, or the enzyme may block access to the pathway that leads
      to destruction of the cofactor.

PMID- 12475323
TI  - An altered mechanism of hydrolysis for a metal-complexed phosphate diester.
AB  - Isotope effects in the nucleophile and in the leaving group were measured to gain
      information about the mechanism and transition state of the hydrolysis of methyl
      p-nitrophenyl phosphate complexed to a dinuclear cobalt complex. The complexed
      diester undergoes hydrolysis about 1011 times faster than the corresponding
      uncomplexed diester. The kinetic isotope effects indicate that this rate
      acceleration is accompanied by a change in mechanism. A large inverse 18O isotope
      effect in the bridging hydroxide nucleophile (0.937 +/- 0.002) suggests that
      nucleophilic attack occurs before the rate-determining step. Large isotope
      effects in the nitrophenyl leaving group (18Olg = 1.029 +/- 0.002, 15N = 1.0026
      +/- 0.0002) indicate significant fission of the P-O ester bond in the transition
      state of the rate-determining step. The data indicate that in contrast to
      uncomplexed diesters, which undergo hydrolysis by a concerted mechanism, the
      reaction of the complexed diester likely proceeds via an addition-elimination
      mechanism. The rate-limiting step is expulsion of the p-nitrophenyl leaving group
      from the intermediate, which proceeds by a late transition state with extensive
      bond fission to the leaving group. This represents a substantial change in
      mechanism from the hydrolysis of uncomplexed aryl phosphate diesters.

PMID- 12475324
TI  - Sensitive through-space dipolar correlations between nuclei of small organic
      molecules by partial alignment in a deuterated liquid solvent.
AB  - Through-space residual dipolar correlations in NMR spectra can be measured
      between nuclei of small organic molecules by partially aligning them with respect
      to the magnetic field in a pure deuterated liquid solvent, 4-pentyl-4'
      cyanobiphenyl. A simple temperature change of this liquid phase enables spectra
      to be compared between samples under isotropic tumbling conditions and weakly
      oriented anisotropic states. This should provide access of a number of small
      nonpolar molecules to more sensitive through-space nuclear correlations than
      possible through NOE experiments, depending on the net orientation of specific
      nuclear pairs with respect to the magnetic field and the specific coherence
      transfers employed.

PMID- 12475325
TI  - Regularly shaped, single-crystalline ZnO nanorods with Wurtzite structure.
AB  - A convenient route at ambient conditions was employed to prepare narrow-dispersed
      ZnO nanorods in terms of size and morphology. Transmission electron microscopy
      and X-ray diffraction were used to characterize the structurally uniform and well
      proportioned products. The as-prepared specimen exhibits strong ultraviolet
      exciton emission at 385 nm and disappearance of visible defect emission.

PMID- 12475326
TI  - To probe the origin of activation effect of carboxylic acid and (+)-NLE in
      tridentated titanium catalyst systems.
AB  - The activation effect of carboxylic acid and positive nonlinear effect ((+)-NLE)
      in tridentated titanium catalyst systems for hetero Diels-Alder reaction and
      aldol-type reactions has been first elucidated on the basis of X-ray crystal
      structural analysis of homochiral (pseudo-octahedral coordination geometry with
      C2 symmetry) and heterochiral (pseudo-octahedral coordination geometry with C1
      symmetry) titanium complexes and the observation of their different reactivities
      with carboxylic acid additive.

PMID- 12475327
TI  - Peptide microarrays for the determination of protease substrate specificity.
AB  - A method is described for the preparation of substrate microarrays that allow for
      the rapid determination of protease substrate specificity. Peptidyl coumarin
      substrates, synthesized on solid support using standard techniques, are printed
      onto glass slides using DNA microarraying equipment. The linkage from the peptide
      to the slide is formed through a chemoselective reaction, resulting in an array
      of uniformly displayed fluorogenic substrates. The arrays can be treated with
      proteases to yield substrate specificity profiles. Standard instrumentation for
      visualization of microarrays can be used to obtain comparisons of the specificity
      constants for all of the prepared substrates. The utility of these arrays is
      demonstrated by the selective cleavage of preferred substrates with trypsin,
      thrombin, and granzyme B, and by assessing the extended substrate specificity of
      thrombin using a microarray of 361 different peptidyl coumarin substrates.

PMID- 12475328
TI  - Functional specificities of methylglyoxal synthase and triosephosphate isomerase:
      a combined QM/MM analysis.
AB  - Combined SCC-DFTB/CHARMM calculations were carried out to analyze the origin for
      the functional specificities of triosephosphate isomerase (TIM) and methylglyoxal
      synthase (MGS). The two enzymes bind to the same substrate, dihydroxyacetone
      phosphate (DHAP), and have rather similar active sites. However, they catalyze
      different reactions; TIM catalyzes the isomerization of DHAP to glyceraldehyde 3
      phosphate (GAP), while MGS catalyzes the elimination of phosphate from DHAP.
      Similar to previous suggestions, the calculations confirmed that GAP formation is
      prohibited in MGS due primarily to the reduced flexibility of the catalytic base
      (Asp 71) compared to that in TIM (Glu 165). For the suppression of phosphate
      elimination in TIM, the calculations show that the widely accepted
      stereoelectronic argument that invokes the different phosphoryl torsion angles
      observed in the X-ray structures of inhibitor complexes of the two enzymes is not
      as important as electrostatic contributions from the protein and water molecules
      surrounding the phosphoryl.

PMID- 12475329
TI  - Oxidation of heme to beta- and delta-biliverdin by Pseudomonas aeruginosa heme
      oxygenase as a consequence of an unusual seating of the heme.
AB  - The origin of the unusual regioselectivity of heme oxygenation, i.e. the
      oxidation of heme to delta-biliverdin (70%) and beta-biliverdin (30%), that is
      exhibited by heme oxygenase from Pseudomonas aeruginosa (pa-HO) has been studied
      by (1)H NMR, (13)C NMR, and resonance Raman spectroscopies. Whereas resonance
      Raman indicates that the heme-iron ligation in pa-HO is homologous to that
      observed in previously studied alpha-hydroxylating heme oxygenases, the NMR
      spectroscopic studies suggest that the heme in this enzyme is seated in a manner
      that is distinct from that observed for all other alpha-hydroxylating heme
      oxygenase enzymes for which a structure is known. In pa-HO, the heme is rotated
      in-plane approximately 110 degrees, so the delta-meso-carbon of the major
      orientational isomer is located within the HO-fold in the place where the alpha
      hydroxylating enzymes typically place the alpha-meso-carbon. The unusual heme
      seating displayed by pa-HO places the heme propionates so that these groups point
      in the direction of the solvent-exposed heme edge and appears to originate in
      large part from the absence of stabilizing interactions between the polypeptide
      and the heme propionates, which are typically found in alpha-hydroxylating heme
      oxygenase enzymes. These interactions typically involve Lys-16 and Tyr-112, in
      Neisseriae meningitidis HO, and Lys-16 and Tyr-134, in human and rat HO-1. The
      corresponding residues in pa-HO are Asn-19 and Phe-117, respectively. In
      agreement with this hypothesis, we found that the Asn-19 Lys/Phe-117 Tyr double
      mutant of pa-HO exists as a mixture of molecules exhibiting two distinct heme
      seatings; one seating is identical to that exhibited by wild-type pa-HO, whereas
      the alternative seating is very similar to that typical of alpha-hydroxylating
      heme oxygenase enzymes and is related to the wild-type seating by approximately
      110 degrees in-plane rotation of the heme. Furthermore, each of these heme
      seatings in the pa-HO double mutant gives rise to a subset of two heme isomeric
      orientations that are related to each other by 180 degrees rotation about the
      alpha-gamma-meso-axis. The coexistence of these molecules in solution, in the
      proportions suggested by the corresponding area under the peaks in the (1)H NMR
      spectrum, explains the unusual regioselectivity of heme oxygenation observed with
      the double mutant, which we found produces alpha- (55%), delta- (35%), and beta
      biliverdin (10%). Alpha-biliverdin is obtained by oxidation of the heme seated
      similar to that of alpha-hydroxylating enzymes, whereas beta- and delta
      biliverdin are formed from the oxidation of heme seated as in wild-type pa-HO.

PMID- 12475330
TI  - Investigating cellular metabolism of synthetic azidosugars with the Staudinger
      ligation.
AB  - The structure of sialic acid on living cells can be modulated by metabolism of
      unnatural biosynthetic precursors. Here we investigate the conversion of a panel
      of azide-functionalized mannosamine and glucosamine derivatives into cell-surface
      sialosides. A key tool in this study is the Staudinger ligation, a highly
      selective reaction between modified triarylphosphines and azides that produces an
      amide-linked product. A preliminary study of the mechanism of this reaction, and
      refined conditions for its in vivo execution, are reported. The reaction provided
      a means to label the glycoconjugate-bound azidosugars with biochemical probes.
      Finally, we demonstrate that the cell-surface Staudinger ligation is compatible
      with hydrazone formation from metabolically introduced ketones. These two
      strategies provide a means to selectively modify cell-surface glycans with
      exogenous probes.

PMID- 12475331
TI  - Thermodynamic analysis of beta-hairpin-forming peptides from the thermal
      dependence of (1)H NMR chemical shifts.
AB  - The temperature dependence of the (1)H chemical shifts of six designed peptides
      previously shown to adopt beta-hairpin structures in aqueous solution has been
      analyzed in terms of two-state (beta-hairpin left arrow over right arrow coil)
      equilibrium. The stability of the beta-hairpins formed by these peptides, as
      derived from their T(m) (midpoint transition temperature) values, parallels in
      general their ability to adopt those structures as deduced from independent NMR
      parameters: NOEs, Deltadelta(C)(alpha)(H), Deltadelta(C)(alpha), and
      Deltadelta(C)(beta) values. The observed T(m) values are dependent on the
      particular position within the beta-hairpin that is probed, indicating that their
      folding to a beta-hairpin conformation deviates from a "true" two-state
      transition. To obtain individual T(m) values for each hairpin region in each
      peptide, a simplified model of a successive uncoupled two-state equilibrium
      covering the entire process has been applied. The distribution of T(m) values
      obtained for the different beta-hairpin regions (turn, strands, backbone, side
      chains) in the six analyzed peptides reveals a similar pattern. A model for beta
      hairpin folding is proposed on the basis of this pattern and the reasonable
      assumption that regions showing higher T(m) values are the last ones to unfold
      and, presumably, the first to form. With this assumption, the analysis suggests
      that turn formation is the first event in beta-hairpin folding. This is
      consistent with previous results on the essential role of the turn sequence in
      beta-hairpin folding.

PMID- 12475332
TI  - Selenium-assisted nucleic acid crystallography: use of phosphoroselenoates for
      MAD phasing of a DNA structure.
AB  - The combination of synchrotron radiation and a variety of atoms or ions (either
      covalently attached to the biomolecule prior to crystallization or soaked into
      crystals) that serve as anomalous scatterers constitutes a powerful tool in the X
      ray crystallographer's repertoire of structure determination techniques.
      Phosphoroselenoates in which one of the nonbridging phosphate oxygens in the
      backbone is replaced by selenium offer a simplified means for introducing an
      anomalous scatterer into oligonucleotides by conventional solid-phase synthesis.
      Unlike other methods that are used to derivatize DNA or RNA by covalent
      attachment of a heavy atom (i.e., bromine at the C5 position of pyrimidines),
      tedious synthesis of specialized nucleosides is not required. Introduction of
      selenium is readily accomplished in solid-phase oligonucleotide synthesis by
      replacing the standard oxidation agent with a solution of potassium
      selenocyanide. This results in a diastereomeric mixture of phosphoroselenoates
      that can be separated by strong anion-exchange HPLC. As a test case, all 10 DNA
      hexamers of the sequence CGCGCG containing a single phosphoroselenoate linkage
      (PSe) were prepared. Crystals were grown for a subset of them, and the structure
      of [d(C(PSe)GCGCG)](2) was determined by the multiwavelength anomalous dispersion
      technique and refined to 1.1 A resolution.

PMID- 12475333
TI  - Simple cation-pi interaction between a phenyl ring and a protonated amine
      stabilizes an alpha-helix in water.
AB  - Cation-pi interactions have been proposed to be important contributors to protein
      structure and function. In particular, these interactions have been suggested to
      provide significant stability at the solvent-exposed surface of a protein. We
      have investigated the magnitude of cation-pi interactions between phenylalanine
      (Phe) and lysine (Lys), ornithine (Orn), and diaminobutanoic acid (Dab) in the
      context of an alpha-helix and have found that only the Phe...Orn interaction
      provides significant stability to the helix, stabilizing it by -0.4 kcal/mol.
      This interaction energy is in the same range as a salt bridge in an alpha-helix,
      and equivalent to the recently reported Trp...Arg interaction in an alpha-helix,
      despite the fact that Trp...guanidinium interactions have been proposed to be
      stronger than Phe...ammonium interactions. These results indicate that even the
      simplest cation-pi interaction can provide significant stability to protein
      structure and demonstrate the subtle factors that can influence the observed
      interaction energies in designed systems.

PMID- 12475334
TI  - Influencing receptor-ligand binding mechanisms with multivalent ligand
      architecture.
AB  - Multivalent ligands can function as inhibitors or effectors of biological
      processes. Potent inhibitory activity can arise from the high functional
      affinities of multivalent ligand-receptor interactions. Effector functions,
      however, are influenced not only by apparent affinities but also by alternate
      factors, including the ability of a ligand to cluster receptors. Little is known
      about the molecular features of a multivalent ligand that determine whether it
      will function as an inhibitor or effector. We envisioned that, by altering
      multivalent ligand architecture, ligands with preferences for different binding
      mechanisms would be generated. To this end, a series of 28 ligands possessing
      structural diversity was synthesized. This series provides the means to explore
      the effects of ligand architecture on the inhibition and clustering of a model
      protein, the lectin concanavalin A (Con A). The structural parameters that were
      varied include scaffold shape, size, valency, and density of binding elements. We
      found that ligands with certain architectures are effective inhibitors, but
      others mediate receptor clustering. Specifically, high molecular weight,
      polydisperse polyvalent ligands are effective inhibitors of Con A binding,
      whereas linear oligomeric ligands generated by the ring-opening metathesis
      polymerization have structural properties that favor clustering. The shape of a
      multivalent ligand also influences specific aspects of receptor clustering. These
      include the rate at which the receptor is clustered, the number of receptors in
      the clusters, and the average interreceptor distance. Our results indicate that
      the architecture of a multivalent ligand is a key parameter in determining its
      activity as an inhibitor or effector. Diversity-oriented syntheses of multivalent
      ligands coupled with effective assays that can be used to compare the
      contributions of different binding parameters may afford ligands that function by
      specific mechanisms.

PMID- 12475335
TI  - Displacement of Mn2+ from RNA by K+, Mg2+, neomycin B, and an arginine-rich
      peptide: indirect detection of nucleic acid/ligand interactions using phosphorus
      relaxation enhancement.
AB  - We have developed a novel method to study the interactions of nucleic acids with
      cationic species. The method, called phosphorus relaxation enhancement (PhoRE),
      uses (1)H-detected (31)P NMR of exogenous probe ions to monitor changes in the
      equilibrium between free Mn(2+) and Mn(2+) bound to the RNA. To demonstrate the
      technique, we describe the interactions of four RNA molecules with metal ions
      (K(+) and Mg(2+)), a small molecule drug (neomycin b), and a cationic peptide
      (RSG1.2). In each case, cationic ligand binding caused Mn(2+) to be displaced
      from the RNA. Free Mn(2+) was determined from its effect on the T(2) NMR
      relaxation rate of either phosphite (HPO(3)(2-)) or methyl phosphite (MeOPH,
      CH(3)OP(H)O(2-)). Using this method, the effects of [RNA] as low as 1 microM
      could be measured in 20 min of accumulation using a low field (200 MHz)
      instrument without pulsed field gradients. Cation association behavior was
      sequence and [RNA] dependent. At low [K(+)], Mn(2+) association with each of the
      RNAs decreased with increasing [K(+)] until approximately 40 mM, where saturation
      was reached. While saturating K(+) displaced all the bound Mn(2+) from a 31
      nucleotide poly-uridine (U(31)), Mn(2+) remained bound to each of three hairpin
      forming sequences (A-site, RRE1, and RRE2), even at 150 mM K(+). Bound Mn(2+) was
      displaced from each of the hairpins by Mg(2+), allowing determination of Mg(2+)
      dissociation constants (K(d,Mg)) ranging from 50 to 500 microM, depending on the
      RNA sequence and [K(+)]. Both neomycin b and RSG1.2 displaced Mn(2+) upon binding
      the hairpins. At [RNA] approximately 3 microM, RRE1 bound a single equivalent of
      RSG1.2, whereas neither RRE2 nor A-site bound the peptide. These behaviors were
      confirmed by fluorescence polarization using TAMRA-labeled peptide. At 2.7 microM
      RNA, the A-site hairpin bound a single neomycin b molecule. The selectivity of
      RSG1.2 binding was greatly diminished at higher [RNA]. Similarly, each hairpin
      bound multiple equivalents of neomycin at the higher [RNA]. These results
      demonstrate the utility of the PhoRE method for characterizing metal binding
      behaviors of nucleic acids and for studying RNA/ligand interactions.

PMID- 12475336
TI  - Conformation of glycomimetics in the free and protein-bound state: structural and
      binding features of the C-glycosyl analogue of the core trisaccharide alpha-D-Man
      (1 --> 3)-[alpha-D-Man-(1 --> 6)]-D-Man.
AB  - The conformational properties of the C-glycosyl analogue of the core
      trisaccharide alpha-D-Man-(1 --> 3)-[alpha-D-Man-(1 --> 6)]-D-Man in solution
      have been carefully analyzed by a combination of NMR spectroscopy and time
      averaged restrained molecular dynamics. It has been found that both the alpha-1,3
      and the alpha-1,6-glycosidic linkages show a major conformational averaging.
      Unusual Phi ca. 60 degrees orientations for both Phi torsion angles are found.
      Moreover, a major conformational distinction between the natural compound and the
      glycomimetic affects to the behavior of the omega(16) torsion angle around the
      alpha-1 --> 6-linkage. Despite this increased flexibility, the C-glycosyl
      analogue is recognized by three mannose binding lectins, as shown by NMR (line
      broadening, TR-NOE, and STD) and surface plasmon resonance (SPR) methods.
      Moreover, a process of conformational selection takes place, so that these
      lectins probably bind the glycomimetic similarly to the way they recognize the
      natural analogue. Depending upon the architecture and extension of the binding
      site of the lectin, loss or gain of binding affinity with respect to the natural
      analogue is found.

PMID- 12475337
TI  - Probing the reactivity of photoinitiators for free radical polymerization: time
      resolved infrared spectroscopic study of benzoyl radicals.
AB  - A series of substituted benzoyl radicals has been generated by laser flash
      photolysis of alpha-hydroxy ketones, alpha-amino ketones, and acyl and
      bis(acyl)phosphine oxides, all of which are used commercially as photoinitiators
      in free radical polymerizations. The benzoyl radicals have been studied by fast
      time-resolved infrared spectroscopy. The absolute rate constants for their
      reaction with n-butylacrylate, thiophenol, bromotrichloromethane and oxygen were
      measured in acetonitrile solution. The rate constants of benzoyl radical addition
      to n-butylacrylate range from 1.3 x 10(5) to 5.5 x 10(5) M(-1) s(-1) and are
      about 2 orders of magnitude lower than for the n-butylacrylate addition to the
      counterradicals that are produced by alpha-cleavage of the investigated ketones.
      Density functional theoretical calculations have been performed in order to
      rationalize the observed reactivities of the initiating radicals. Calculations of
      the phosphorus-centered radicals generated by photolysis of an acyl and
      bis(acyl)phosphine oxide suggest that P atom Mulliken spin populations are an
      indicator of the relative reactivities of the phosphorus-centered radicals. The
      alpha-cleavage of (2,4,6-trimethylbenzoyl)phosphine oxide was studied by
      picosecond pump-probe and nanosecond step-scan time-resolved infrared
      spectroscopy. The results support a mechanism in which the alpha-cleavage occurs
      from the triplet excited state that has a lifetime less than or equal to the
      singlet excited state.

PMID- 12475338
TI  - Ion-pairing molecular recognition in water: aggregation at low concentrations
      that is entropy-driven.
AB  - Investigations into the thermodynamic parameters that characterize the binding of
      citrate to tris-guanidinium host 1 in water are reported. The parameters K(a),
      DeltaH degrees, DeltaS degrees, and DeltaG degrees for the binding event were
      quantified using isothermal titration calorimetry (ITC) techniques. The 1:1
      binding stoichiometry was verified by a Job plot derived from NMR data, and the
      microcalorimetry data was collected for solutions of 1 and citrate ranging from 1
      to 100 mM using phosphate buffer concentrations of 5 and 103 mM. At low buffer
      concentrations (low ionic strength) complexes with greater than 1:1
      stoichiometries were observed by ITC, and K(1) was determined to range from 2.0 x
      10(3) to 3.0 x 10(3) M(-1). At higher buffer concentrations (high ionic strength)
      the higher-order complexes were not detected, and K(1) was determined to be 409
      M(-1). The 1:1 association of host 1 and citrate is characterized by a large
      favorable entropy component and negative enthalpy. However, the complexes with
      higher-order stoichiometry arise from desolvation processes that result from the
      association of polyions in aqueous media and is entirely entropy driven. This
      leads to an unusual observation: the dilution of one component of the host/guest
      complex leads to the formation of the higher-order complexes. The reason for this
      observation is discussed.

PMID- 12475339
TI  - Physical organic chemistry of transition metal carbene complexes. 25. Kinetic and
      thermodynamic acidities of substituted (methylthiophenylcarbene)pentacarbonyl
      tungsten(0) and (Benzoxymethylcarbene)pentacarbonyl tungsten(0) in aqueous
      acetonitrile. Evidence for transition state imbalances.
AB  - A kinetic study of the reversible deprotonation of substituted
      (methylthiophenylcarbene)pentacarbonyltungsten(0) ((CO)(5)W=C(SC(6)H(4)Z)CH(3))
      and of substituted (benzoxymethylcarbene)pentacarbonyltungsten(0)
      ((CO)(5)W=C(OCH(2)C(6)H(4)Z)CH(3)) by primary aliphatic and secondary alicyclic
      amines in 50% MeCN-50% water (v/v) at 25 degrees C is reported. From the
      dependence of the deprotonation rate constants on amine basicity and on carbene
      complex acidity (variation of Z), Bronsted beta(B) and alpha(CH) values,
      respectively, were obtained. The alpha(CH) values were found to be smaller than
      the beta(B) values. These results indicate a transition state imbalance in which
      the loss of the carbene complex stabilizing pi-donor effect of the OCH(2)Ar and
      SAr groups lags behind the proton transfer. These findings confirm a previously
      formulated hypothesis as to how pi-donor groups attached to the carbene carbon of
      carbene complexes can affect transition state imbalances and mask the
      experimental manifestation of such imbalances. It is also shown that the
      transition state structure of the reactions examined in this work is subject to
      changes with changing amine basicity and carbene complex acidity; these changes
      can be expressed by p(xy)() cross correlation coefficients, which are positive.

PMID- 12475340
TI  - Are 1,5-disubstituted semibullvalenes that have C2v equilibrium geometries
      necessarily bishomoaromatic?
AB  - Unrestricted density functional theory (UB3LYP), CASSCF, and CASPT2 calculations
      have been employed to compute the relative energies of the C(s) and C(2v)
      geometries of several 1,5-disubstituted semibullvalenes. Substitution at these
      positions with R = F, -CH(2)-, or -O- affords semibullvalenes that are predicted
      to have C(2v) equilibrium geometries. Calculated singlet-triplet energy
      splittings and the energies of isodesmic reactions are used to assess the amount
      of bishomoaromatic character at these geometries. The results of these
      calculations show that employing strain to destabilize the C(s) geometries of
      semibullvalenes can lead to a significant decrease in the amount of
      bishomoaromatic stabilization of the C(2v) geometries, due to reduced through
      space interaction between the two allyl groups. However, the C(2v) equilibrium
      geometries of the 1,5-disubstituted semibullvalenes with R = F and -RR- = -O- do
      benefit from stabilizing through-bond interactions between the two allyl groups.
      These interactions involve mixing of the bisallyl HOMO with the low-lying C-F or
      C-O sigma orbital combinations of the same symmetry. In contrast, for -RR- = 
      CH(2)-, through-bond interactions destabilize the bisallyl HOMO and are predicted
      to make the ground state of this semibullvalene a triplet.

PMID- 12475341
TI  - Total synthesis of (-)-gambierol.
AB  - The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin,
      has been achieved. Key features of the successful synthesis include (1) a
      convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via
      our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the
      octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive
      triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling. The
      ABC ring fragment 5 was synthesized in a linear manner (B --> AB --> ABC),
      wherein the A ring was formed by intramolecular hetero-Michael reaction and the C
      ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved
      synthetic entry to the EFGH ring fragment 6 is also described, in which SmI(2)
      induced reductive cyclization methodology was applied to the stereoselective
      construction of the F and H rings, leading to 6 with remarkable overall
      efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura
      coupling with 6 provided endocyclic enol ether 45 in high yield, which was then
      converted to octacyclic polyether core 4. Careful choice of the global
      deprotection stage was a key element for the successful total synthesis.
      Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2.
      Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's
      Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis
      of (-)-gambierol (1).

PMID- 12475342
TI  - Relative rates and approximate rate constants for inter- and intramolecular
      hydrogen transfer reactions of polymer-bound radicals.
AB  - Measurements of relative rates and rate constants for inter- and intramolecular
      hydrogen transfer reactions of polymer-bound radicals are reported. The relative
      rate of reaction of resin-bound primary alkyl radical with tributyltin hydride is
      about 2 times slower than that of the benchmark reaction in solution. The data do
      not reveal whether this is due to a reduced rate constant or a lower
      concentration of tin hydride in the resin phase. Yet the difference between solid
      and solution reactions is small enough to be neglected, and it appears that rate
      constants measured in solution can be applied directly to resin-bound radicals. A
      resin-bound aryl radical abstracts a hydrogen atom rapidly (k = 3 x 10(6) s(-1))
      from its own polymer backbone and linker, and a simplified view of the resin as a
      "solvent" is suggested for predicting such effects with other polymers and
      linkers. Rapid cyclizations of resin-bound aryl radicals will be possible, but
      slower cyclizations and most bimolecular reactions will be difficult due to the
      competing polymer/linker hydrogen transfer.

PMID- 12475343
TI  - Total synthesis of desferrisalmycin B.
AB  - The first total synthesis of a naturally occurring siderophore antibiotic,
      desferrisalmycin B, is described, and the configuration of the unknown
      stereocenter is assigned. The synthesis features a synthetic strategy of
      constructing the novel amino-heptopyranoside component by stereoselective
      dihydroxylation followed by a Bose-modified Mitsunobu reaction. Through this
      convergent approach, other members of salmycins should also be synthetically
      accessible.

PMID- 12475344
TI  - Could ionic gamma-elimination be concerted: clocking the internal displacement
      across a cyclobutane ring.
AB  - Carbanion 1, obtained by a nucleophilic attack of PhSe- on 3-chlorobicyclobutane
      carbonitrile in DME undergoes both protonation and elimination as shown in eq 1.
      Alcohols of increasing acidity in the following order: t-BuOH, i-PrOH, MeOH,
      trifluoroethanol (TFE), and hexafluoro2-propanol (HFIP) were used as proton
      donors. An Eigen-type plot of the log of the product ratio
      (protonation/elimination) vs the pK(a) of the alcohols, levels off for the two
      most acidic alcohols, TFE and HFIP which react at a diffusion-controlled rate.
      The partitioning of the products between protonation and elimination enables,
      therefore, the determination of the rate constant for the internal elimination as
      approximately 3 x 10(10) s(-1). Ab initio calculations at the B3LYP/6-31G level
      show that the elimination from a model carbanion (4, eq 4) occurs in a
      barrierless process. Simulation of the experimental reaction by including
      solvation effects using the Onsager model, shows that using the dielectric
      constant of DME (7.2) stabilizes, as expected, the carbanion and prevents a
      spontaneous elimination. In the absence of solvation effects, using Me- as a
      base, a complete elimination of HCl (proton removal and leaving-group expulsion)
      took place from 3-chlorocyclobutanecarbonitrile in a barrierless process without
      the formation of any discrete intermediate.

PMID- 12475345
TI  - Reactivity differences of indomethacin solid forms with ammonia gas.
AB  - The present study deals with the acid-base reaction of three solid-state forms of
      the nonsteroidal antiinflammatory drug indomethacin with ammonia gas. X-ray
      powder diffraction, optical microscopy, gravimetry, and spectroscopic methods
      were employed to establish the extent of the reaction as well as the lattice
      changes of the crystal forms. The glassy amorphous form readily reacts with
      ammonia gas to yield a corresponding amorphous ammonium salt. In addition, the
      metastable crystal form of indomethacin (the alpha-form) also reacts with ammonia
      gas, but produces the corresponding microcrystalline ammonium salt. This reaction
      is anisotropic and propagates along the a-axis of the crystals. The stable
      crystal form (the gamma-form), however, is inert to ammonia gas. Amorphous
      indomethacin can react with ammonia gas because it has more molecular mobility
      and free volume. The reactivity differences between the alpha- and gamma-forms
      are dictated by the arrangement of the molecules within the respective crystal
      lattices. The recently determined crystal structure of the metastable alpha-form
      of indomethacin (monoclinic P2(1) with Z = 6, V = 2501.8 A(3), D(c) = 1.42 g.cm(
      3)) has three molecules of indomethacin in the asymmetric unit. Two molecules
      form a mutually hydrogen-bonded carboxylic acid dimer, while the carboxylic acid
      of the third molecule is hydrogen bonded to one of the amide carbonyls of the
      dimer. The carboxylic acid groups of the alpha-form are exposed on the [100]
      faces and are accessible to attack by ammonia gas. After one layer of molecules
      reacts, the reactive groups in the subsequent layer are accessible to the ammonia
      gas. This process proceeds along the a-axis until the ammonia gas has penetrated
      the entire crystal. In contrast to the alpha-form, the gamma-form has a
      centrosymmetric crystal structure in which the hydrogen-bonded carboxylic acid
      dimers are not accessible to ammonia gas because they are caged inside a
      hydrophobic shield comprising the remainder of the indomethacin molecule. In view
      of the significantly lower density of the stable gamma-form as compared to the
      metastable alpha-form (1.37 and 1.42 g cm(-3), respectively), it became apparent
      that the reactivity of the crystal forms depends exclusively on the molecular
      arrangement and not on the packing density of the indomethacin crystals.

PMID- 12475346
TI  - Effects of surface morphology on the anchoring and electrooptical dynamics of
      confined nanoscale liquid crystalline films.
AB  - The orientation and dynamics of two 40-nm thick films of 4-n-pentyl-4'
      cyanobiphenyl (5CB), a nematic liquid crystal, have been studied using step-scan
      Fourier transform infrared spectroscopy (FTIR). The films are confined in
      nanocavities bounded by an interdigitated electrode array (IDA) patterned on a
      zinc selenide (ZnSe) substrate. The effects of the ZnSe surface morphology
      (specifically, two variations of nanometer-scale corrugations obtained by
      mechanical polishing) on the initial ordering and reorientation dynamics of the
      electric-field-induced Freedericksz transition are presented here. The
      interaction of the 5CB with ZnSe surfaces bearing a spicular corrugation induces
      a homeotropic (surface normal) alignment of the film confined in the cavity.
      Alternately, when ZnSe is polished to generate fine grooves along the surface, a
      planar alignment is promoted in the liquid crystalline film. Time-resolved FTIR
      studies that enable the direct measurement of the rate constants for the electric
      field-induced orientation and thermal relaxation reveal that the dynamic
      transitions of the two film structures are significantly different. These
      measurements quantitatively demonstrate the strong effects of surface morphology
      on the anchoring, order, and dynamics of liquid crystalline thin films.

PMID- 12475347
TI  - Responsive hydrogels from the intramolecular folding and self-assembly of a
      designed peptide.
AB  - A general peptide design is presented that links the pH-dependent intramolecular
      folding of beta-hairpin peptides to their propensity to self-assemble, affording
      hydrogels rich in beta-sheet. Chemical responsiveness has been specifically
      engineered into the material by linking intramolecular folding to changes in
      solution pH, and mechanical responsiveness, by linking hydrogelation to self
      assembly. Circular dichroic and infrared spectroscopies show that at low pH
      individual peptides are unstructured, affording a low-viscosity aqueous solution.
      Under basic conditions, intramolecular folding takes place, affording amphiphilic
      beta-hairpins that intermolecularly self-assemble. Rheology shows that the
      resulting hydrogel is rigid but is shear-thinning. However, quick mechanical
      strength recovery after cessation of shear is observed due to the inherent self
      assembled nature of the scaffold. Characterization of the gelation process, from
      the molecular level up through the macroscopic properties of the material,
      suggests that by linking the intramolecular folding of small designed peptides to
      their ability to self-assemble, responsive materials can be prepared. Cryo
      transmission electron and laser scanning confocal microscopies reveal a water
      filled porous scaffold on both the nano- and microscale. The environmental
      responsiveness, morphology, and peptidic nature make this hydrogel a possible
      material candidate for biomedical and engineering technology.

PMID- 12475348
TI  - 1,2-dithiin annelated with bicyclo[2.2.2]octene frameworks. One-electron and two
      electron oxidations and formation of a novel 2,3,5,6-tetrathiabicyclo[2.2.2]oct-7
      ene radical cation with remarkable stability owing to a strong transannular
      interaction.
AB  - A stable derivative of 1,2-dithiin annelated with bicyclo[2.2.2]octene frameworks
      4 was synthesized as red crystals by the reaction of a dilithiated dimer of
      bicyclo[2.2.2]octene with elemental sulfur in 59% yield. The cyclic voltammetry
      of 4 in CH(2)Cl(2) at -78 degrees C showed two reversible oxidation waves at
      E(1/2) +0.18 V and +0.72 V versus Fc/Fc(+), indicating that the radical cation
      and dication of 4 are stable under these conditions. Upon chemical one-electron
      oxidation of 4 in a rather low concentration (4.0 x 10(-4) M) with a 1.5 equiv of
      SbCl(5) in CH(2)Cl(2), a radical cation 4.+ was formed, whose spin distribution
      was determined by ESR spectroscopy and by the results of theoretical calculations
      (UB3LYP/6-31G). The electronic absorption spectrum of 4.+ in CH(2)Cl(2) exhibited
      a maximum absorption at 428 nm (epsilon = 2.3 x 10(3)), which was
      hypsochromically shifted from that of neutral 4 (469 nm). When the radical cation
      4.+ was produced in higher concentration (0.06 M) in CH(2)Cl(2), a
      disproportionation was found to take place to give a SbCl(6)(-) salt of
      remarkably stable radical cation 5.+ having a novel 2,3,5,6
      tetrathiabicyclo[2.2.2]oct-7-ene structure. In the X-ray structure of 5.+SbCl(6)(
      ), the transannular distance (2.794(3) A) between the sulfur atoms was found to
      be less than the sum of the van der Waals radii of a sulfur atom (3.70 A),
      suggesting the existence of a bonding interaction between the two disulfide
      linkages. The theoretical calculations (UB3LYP/6-31G) suggested that this
      transannular interaction could be described as the resonance between the limiting
      structures, each of them having a two-center three-electron bond between two
      sulfur atoms belonging to two different disulfide linkages: thus, both the spin
      and positive charge are equally delocalized to the four sulfur atoms, causing a
      great stabilization of 5.+. On the other hand, the 1,2-dithiin radical cation 4.+
      was found to readily react with triplet oxygen with subsequent rearrangement to
      give the 1,2-dithiolium derivative 6+ having a carboxyl group. Finally, the
      reaction of 4 with an excess amount of SbF(5) gave the corresponding dication
      4(2+), which was found to be a 6pi aromatic system on the basis of the results of
      NMR measurement and theoretical calculations.

PMID- 12475349
TI  - Tuning intermolecular attraction to create polar order and one-dimensional
      nanostructures on surfaces.
AB  - This study utilizes atomic force microscopy and electrostatic force microscopy to
      investigate the orientation of overcrowded aromatics in films with submonolayer
      coverage. The results demonstrate that the side chains in the molecules can be
      used as a tool to control the molecular order and orientation in thin films. For
      molecules that do not self-associate well, the interaction with the substrate
      dominates, and the molecules orient with their aromatic planes parallel to the
      surface. These monolayers have measurable polar order. For molecules that self
      associate well, the opposite orientation is observed. These films are comprised
      of isolated stacks of molecules parallel to the surface.

PMID- 12475350
TI  - Creating new supramolecular materials by architecture of three-dimensional
      nanocrystal fiber networks.
AB  - The architecture of three-dimensional interconnecting self-organized nanofiber
      networks from separate needlelike crystals of L-DHL (lanosta-8,24-dien-3beta
      ol:24,25-dihydrolanosterol = 56:44) in di-isooctylphthalate has been achieved for
      the first time, on the basis of the completely new concept of branching creation
      by additives (branching promoters). [In this work, an additive, ethylene/vinyl
      acetate copolymer (EVACP), is used at a concentration of several 10 ppm.] We
      demonstrate that this novel technique enables us to produce previously unknown
      self-supporting supramolecular functional materials with tailormade micro- or
      nanostructures, possessing significantly modified macroscopic properties, by
      utilizing materials thus far considered to be "useless". In addition, both the
      self-organized structure and the properties of the new materials can be fine
      tuned by altering the processing conditions. Our results show that the formation
      of the interconnecting 3D self-organized network structure is controlled by a new
      mechanism, so-called crystallographic mismatch branching mechanism, as opposed to
      the conventionally adopted molecular self-assembly mechanism. The principles and
      criteria for the selection of branching promoters are also discussed from the
      point of view of molecular structures.

PMID- 12475351
TI  - Comparison and contrasts between the active site PKs of Mn-superoxide dismutase
      and those of Fe-superoxide dismutase.
AB  - The Fe- and Mn-containing superoxide dismutases catalize the same reaction and
      have almost superimposable active sites. Therefore, the details of their
      mechanisms have been assumed to be similar. However, we now show that the pH
      dependence of Escherichia coli MnSOD activity reflects a different active site
      proton equilibrium in (oxidized) Mn(3+)SOD than the event that affects the active
      site pK of oxidized FeSOD. We find that the universally conserved Tyr34 that has
      a pK above 11.5 in Fe(3+)SOD is responsible for the pK near 9.5 of Mn(3+)SOD and,
      thus, that the oxidized state pK of Mn(3+)SOD corresponds to an outer-sphere
      event whereas that of Fe(3+)SOD corresponds to an inner sphere event [Bull, C.;
      Fee, J. A. J. Am. Chem. Soc. 1985, 107, 3295-3304]. We also present the first
      description of a reduced-state pK for MnSOD. Mn(2+)SOD's pK involves
      deprotonation of Tyr34, as does Fe(2+)SOD's pK [Sorkin, D. L.; Miller A.-F.
      Biochemistry 1997, 36, 4916-4924]. However, the values of the pKs, 10.5 and 8.5
      respectively, are quite different and Mn(2+)SOD's pK affects the coordination
      geometry of Mn(2+), most likely via polarization of the conserved Gln146 that
      hydrogen bonds to axially coordinated H(2)O. Our findings are consistent with the
      different electronic configurations of Mn(2+/3+) vs Fe(2+/3+), such as the
      stronger hydrogen bonding between Gln146 and coordinated solvent in MnSOD than
      that between the analogous Gln69 and coordinated solvent in FeSOD, and the
      existence of weakly localized H(2)O near the sixth coordination site of Mn(2+) in
      Mn(2+)SOD [Borgstahl et al. J. Mol. Biol. 2000, 296, 951-959].

PMID- 12475352
TI  - Dimensional changes as a function of charge injection in single-walled carbon
      nanotubes.
AB  - Motivated by the central importance of charge-induced dimensional changes for
      carbon nanotube electromechanical actuators, we here predict changes in nanotube
      length and diameter as a function of charge injection for armchair and zigzag
      nanotubes having different diameters. Density functional theory with periodic
      boundary conditions is used, which we show provides results consistent with
      experimental observations for intercalated graphites. Strain-versus-charge
      relationships are predicted from dimensional changes calculated with a uniform
      background charge ("jellium") for representing the counterions. These jellium
      calculations are consistent with presented calculations that include specific
      counterions for intercalated graphite, showing that hybridization between the
      ions and the graphite sheets is unimportant. The charge-strain relationships
      calculated with the jellium approximation for graphite and isolated single-walled
      nanotubes are asymmetric with respect to the sign of charge transfer. The
      dependence of nanotube strain on charge approaches that for a graphite sheet for
      intermediate-sized metallic nanotubes and for larger diameter semiconducting
      nanotubes. However, the strain-charge curves strongly depend on nanotube type
      when the nanotube diameter is small. This reflects both the dependence of the
      frontier orbitals for the semiconducting nanotubes on the nanotube type and the
      pi-sigma mixing when the nanotube diameter is small.

PMID- 12475353
TI  - Binding to an RNA aptamer changes the charge distribution and conformation of
      malachite green.
AB  - RNA plays a central role in many biological processes and is therefore an
      important target for drug development. In recent years an increasing wealth of
      structural and functional information about RNA-ligand complexes has been
      obtained using in vitro selected RNAs (aptamers). However, all those studies
      focused on structure and changes of the nucleic acid and mostly considered the
      ligand as a rigid target. To develop a detailed picture of ligand structure and
      dynamics in RNA-small molecule complexes, the malachite green binding aptamer was
      studied. Isotopically labeled ligand in complex with RNA was analyzed by NMR
      spectroscopy in solution. The surprisingly asymmetric changes in the (13)C
      chemical shift of the ligand methyl groups indicate that the dye undergoes
      changes in its conformation and charge distribution upon binding. The role of the
      RNA electrostatic field in this interaction was explored using ab initio
      calculations of the ligand structure and charge distribution. The results
      indicate that the uneven charge distribution in the RNA binding pocket provides a
      major contribution to the driving force of the ligand structural changes. The
      observation that not only the RNA adapts to the ligand, in what is called
      adaptive binding, but that the ligand itself also undergoes conformational
      changes ("induced fit") is crucial for the rational design of RNA ligands and for
      understanding the properties of RNA-ligand complexes.

PMID- 12475354
TI  - Structures of neat and hydrated 1-octanol from computer simulations.
AB  - Molecular dynamics computer simulations of 1-octanol and its mixtures with water
      have been performed. The liquid is composed of regions enriched in either
      hydrocarbons or hydroxyl groups. In neat octanol, the hydroxyl groups form
      clusters of long, thin chains. Upon the addition of water, the clusters become
      longer and more spherical, forming a structure that can be described as
      consisting of "overlapping elongated inverse micelles". The structures of the
      mixtures obtained at different hydration levels are consistent with those of
      experimental diffraction studies of water/octanol mixtures and previous computer
      simulations of neat and water-saturated octanol. The saturation point of the
      model has been calculated using the cavity-bias particle insertion method. The
      solubility of water in octanol is slightly too low compared to experimental
      results, and suggestions for possible improvements to the force field are made.

PMID- 12475355
TI  - Turning the [Ru(bpy)2dppz]2+ light-switch on and off with temperature.
AB  - We report temperature-dependent excited-state lifetime measurements on
      [Ru(bpy)(2)dppz](2+) in both protic and aprotic solvents. These experiments yield
      a unifying picture of the excited-state photophysics that accounts for
      observations in both types of solvent. Our measurements support the notion of bpy
      like and phz-like states associated with the dppz ligand and show that the ligand
      orbital associated with the bright state is similar in size to the corresponding
      orbital in the (3)MLCT state of [Ru(bpy)(3)](2+). In contrast to the current
      thinking, the experiments presented here indicate that the light-switch effect is
      not driven by a state reversal. Rather, they suggest that the dark state is
      always lowest in energy, even in aprotic solvents, and that the light-switch
      behavior is the result of a competition between energetic factors that favor the
      dark state and entropic factors that favor the bright (bpy) state.

PMID- 12475356
TI  - Strategy for the resolution of a chiral dearomatization agent:[TpRe(CO)(1
      methylimidazole)] coordination of alpha-pinene (Tp =
      hydridotris(pyrazolyl)borate).
AB  - A methodology for resolving TpRe(CO)(1-methylimidazole)(eta(2)-benzene) has been
      developed utilizing (R)-alpha-pinene. Each enantiomer of the [TpRe(CO)(MeIm)]
      system can be obtained with the enantiomer ratio (er) = 97:3 by taking advantage
      of differing rates of pinene substitution for the two diastereomers of
      TpRe(CO)(MeIm)(eta(2)-(R)-alpha-pinene).

PMID- 12475357
TI  - Mechanism of the hydrogenation of ketones catalyzed by trans
      dihydrido(diamine)ruthenium II complexes.
AB  - The complexes trans-RuH(Cl)(tmen)(R-binap) (1) and (OC-6-43)
      RuH(Cl)(tmen)(PPh(3))(2) (2) are prepared by the reaction of the diamine
      NH(2)CMe(2)CMe(2)NH(2) (tmen) with RuH(Cl)(PPh(3))(R-binap) and
      RuH(Cl)(PPh(3))(3), respectively. Reaction of KHB(sec)Bu(3) with 1 yields trans
      Ru(H)(2)(R-binap)(tmen) (5) while reaction of KHB(sec)Bu(3) or KO(t)Bu with 2
      under Ar yields the new hydridoamido complex RuH(PPh(3))(2)(NH(2)CMe(2)CMe(2)NH)
      (4). Complex 4 has a distorted trigonal bipyramidal geometry with the amido
      nitrogen in the equatorial plane. Loss of H(2) from 5 results in the related
      complex RuH(R-binap)(NH(2)CMe(2)CMe(2)NH) (3). Reaction of H(2) with 4 yields the
      trans-dihydride (OC-6-22)-Ru(H)(2)(PPh(3))(2)(tmen)(6). Calculations support the
      assignment of the structures. The hydrogenation of acetophenone is catalyzed by 5
      or 4 in benzene or 2-propanol without the need for added base. For 5 in benzene
      at 293 K over the ranges of concentrations [5] = 10(-)(4) to 10(-)(3) M, [ketone]
      = 0.1 to 0.5 M, and of pressures of H(2) = 8 to 23 atm, the rate law is rate =
      k[5][H(2)] with k = 3.3 M(-1) s(1), DeltaH++ = 8.5 +/- 0.5 kcal mol(-1), DeltaS++
      = -28 +/- 2 cal mol(-1) K(-1). For 4 in benzene at 293 K over the ranges of
      concentrations [4] = 10(-4) to 10(-3) M, [ketone] 0.1 to 0.7 M, and of pressures
      of H(2) = 1 to 6 atm, the preliminary rate law is rate = k[4][H(2)] with k = 1.1
      x 10(2) M(-1) s(-1), DeltaH++ = 7.6 +/- 0.3 kcal mol(-1), DeltaS++ = -23 +/- 1
      cal mol(-1) K(-1). Both theory and experiment suggest that the intramolecular
      heterolytic splitting of dihydrogen across the polar Ru=N bond of the amido
      complexes 3 and 4 is the turn-over limiting step. A transition state structure
      and reaction energy profile is calculated. The transfer of H(delta+)/H(delta-) to
      the ketone from the RuH and NH groups of 5 in a Noyori metal-ligand bifunctional
      mechanism is a fast process and it sets the chirality as (R)-1-phenylethanol (62
      68% ee) in the hydrogenation of acetophenone. The rate of hydrogenation of
      acetophenone catalyzed by 5 is slower and the ee of the product is low (14% S)
      when 2-propanol is used as the solvent, but both the rate and ee (up to 55% R)
      increase when excess KO(t)Bu is added. The formation of ruthenium alkoxide
      complexes in 2-propanol might explain these observations. Alkoxide complexes
      [RuP(2)]H(OR)(tmen), [RuP(2)] = Ru(R-binap) or Ru(PPh(3))(2), R= (i) Pr, CHPhMe,
      (t)Bu, are observed by reacting the alcohols (i)PrOH, phenylethanol, and (t)BuOH
      with the dihydrides 5 and 6, respectively, under Ar. In the absence of H(2), the
      amido complexes 3 and 4 react with acetophenone to give the ketone adducts
      [RuP(2)]H(O=CPhMe)(NH(2)CMe(2)CMe(2)NH) in equilibrium with the enolate complexes
      trans- [RuP(2)](H)(OCPh=CH(2))(tmen) and eventually the decomposition products
      [RuP(2)]H(eta(5)-CH(2)CPhCHCPhO), with the binap complex characterized
      crystallographically. In general, proton transfer from the weakly acidic
      molecules dihydrogen, alcohol, or acetophenone to the amido nitrogen of complexes
      3 and 4 is favored in two ways when the molecule coordinates to ruthenium: (1) an
      increase in acidity of the molecule by the Lewis acidic metal and (2) an increase
      in the basicity of the amido nitrogen caused by its pyramidalization. The formato
      complexes trans-[RuP(2)]H(OCHO)(tmen) were prepared by reacting the respective
      complex 4 or 5 with formic acid. The crystal structure of
      RuH(OCHO)(PPh(3))(2)(tmen) displays similar features to the calculated transition
      state for H(delta+)/H(delta-) transfer to the ketone in the catalytic cycle.

PMID- 12475358
TI  - Hydrogen adsorption on the indium-rich indium phosphide (001) surface: a novel
      way to produce bridging In-H-In bonds.
AB  - The indium phosphide (001) surface provides a unique chemical environment for
      studying the reactivity of hydrogen toward the electron-deficient group IIIA
      element, indium. Hydrogen adsorption on the In-rich delta(2 x 4) reconstruction
      produced a neutral, covalently bound bridging indium hydride. Using vibrational
      spectroscopy and ab initio cluster calculations, two types of bridging hydrides
      were identified, a (mu-H)In(2) and a (mu-H)(2)In(3) "butterfly-like" structure.
      These structures were formed owing to the large thermodynamic driving force for
      adsorption of H atoms on solid-state indium dimers.

PMID- 12475359
TI  - Direct detection by atomic force microscopy of single bond forces associated with
      the rupture of discrete charge-transfer complexes.
AB  - Atomic force microscopy (AFM) was used to measure the chemical binding force of
      discrete electron donor-acceptor complexes formed at the interface between
      proximal self-assembled monolayers (SAMs). Derivatives of the well-known electron
      donor N,N,N',N'-tetramethylphenylenediamine (TMPD) and the electron acceptor
      7,7,8,8-tetracyanoquinodimethane (TCNQ) were immobilized on Au-coated AFM tips
      and substrates by formation of SAMs of N,N,N'-trimethyl-N'-(10-thiodecyl)-1,4
      phenylenediamine (I) and bis(10-(2-((2,5-cyclohexadiene-1,4
      diylidene)dimalonitrile))decyl) disulfide (II), respectively. Pull-off forces
      between modified tips and substrates were measured under CHCl(3) solvent. The
      mean pull-off forces associated with TMPD/TCNQ microcontacts were more than an
      order of magnitude larger than the pull-off forces for TMPD/TMPD and TCNQ/TCNQ
      microcontacts, consistent with the presence of specific charge-transfer
      interactions between proximal TMPD donors and TCNQ acceptors. Furthermore,
      histograms of pull-off forces for TMPD/TCNQ contacts displayed 70 +/- 15 pN
      periodicity, assigned to the rupture of individual TMPD-TCNQ donor-acceptor
      (charge-transfer) complexes. Both the mean pull-off force and the 70 pN force
      quantum compare favorably with a contact mechanics model that incorporates the
      effects of discrete chemical bonds, solvent surface tensions, and random contact
      area variations in consecutive pull-offs. From the 70 pN force quantum, we
      estimate the single bond energy to be approximately 4-5 kJ/mol, in reasonable
      agreement with thermodynamic data. These experiments establish that binding
      forces due to discrete chemical bonds can be detected directly in AFM pull-off
      measurements employing SAM modified probes and substrates. Because SAMs can be
      prepared with a wide range of exposed functional groups, pull-off measurements
      between SAM-coated tips and substrates may provide a general strategy for
      directly measuring binding forces associated with a variety of simple, discrete
      chemical bonds, e.g., single hydrogen bonds.

PMID- 12475360
TI  - Electron delocalization in mixed-valence Keggin polyoxometalates. Ab initio
      calculation of the local effective transfer integrals and its consequences on the
      spin coupling.
AB  - We present a quantitative evaluation of the influence of the electron transfer on
      the magnetic properties of mixed-valence polyoxometalates reduced by two
      electrons. For that purpose, we extract from valence-spectroscopy ab initio
      calculations on embedded fragments the value of the transfer integrals between W
      nearest-neighbor atoms in a mixed-valence alphaPW(12)O(40) polyoxowolframate
      Keggin anion. In contradiction with what is usually assumed, we show that the
      electron transfer between edge-sharing and corner-sharing WO(6) octahedra have
      very close values. Considering fragments of various ranges, we analyze the
      accuracy of calculations on fragments based on only two WO(5) pyramids which
      should allow a low cost general study of transfer parameters in polyoxometalates.
      Finally, these parameters are introduced in an extended Hubbard Hamiltonian that
      models the whole anion. It permits to prove that electron transfers induce a
      large energy gap between the singlet ground state and the lowest triplet states
      providing a clear explanation of the diamagnetic properties of the mixed-valence
      Keggin ions reduced by two electrons.

PMID- 12475362
TI  - Towards a behavioral phenotype for Rett syndrome.
AB  - Despite considerable interest in Rett syndrome, there have been few studies of
      associated behavioral and emotional problems. In the present study, 143 girls
      with Rett syndrome were compared on the Developmental Behavior Checklist with 85
      girls with severe to profound mental retardation of mixed etiologies. After
      controlling for the effects of physical disabilities, we found that the girls
      with Rett syndrome presented more "autistic-relating" and fewer antisocial
      behaviors. A subsample of children with autism was also compared to the girls
      with Rett syndrome on autistic-relating behaviors, revealing that the Rett
      syndrome group did not present with classic autistic behavioral features The
      implications of these results for the identification of a Rett syndrome
      behavioral phenotype are discussed.

PMID- 12475363
TI  - Altered diurnal pattern of salivary substance P in adults with developmental
      disabilities and chronic self-injury.
AB  - Morning and afternoon salivary substance P and cortisol levels were measured in
      26 adults with chronic self-injurious behavior (SIB) and severe developmental
      disabilities and compared with matched controls without SIB. Chronic SIB was
      associated with an altered diurnal pattern of salivary substance P relative to
      matched controls, characterized primarily by lower levels of morning substance P,
      which were significantly correlated with overall severity of SIB. There was a
      trend for SIB subjects to exhibit higher levels of cortisol, which was
      significantly correlated with overall severity of SIB. These results support a
      model of altered nociception and possible stress-induced analgesia among
      individuals with developmental disability and chronic SIB.

PMID- 12475364
TI  - Temporal changes in incidence and prevalence of intellectual disability between
      two birth cohorts in Northern Finland.
AB  - We followed two separate, genetically homogeneous cohorts of children born in
      1966 (n = 11,965) and 1985-1986 (n = 9,432) in Northern Finland to determine
      temporal changes in the incidence and prevalence of subcategories of intellectual
      disability within the same geographic area. The children were followed up to the
      age of 11.5 years. Similar study design, data ascertainment methods, and
      definition of intellectual disability were used. There was no change in the total
      incidence (12.62/1,000 in each) or in total prevalence (11.03/1,000 vs.
      11.23/1,000) of intellectual disability. However, in the subcategories of
      intellectual disability, there was a shift from severe and moderate towards mild;
      whereas profound intellectual disability remained at the same level. The temporal
      changes followed generally similar patterns by gender.

PMID- 12475365
TI  - Using mood ratings and mood induction in assessment and intervention for severe
      problem behavior.
AB  - The literature on problem behavior documents the need for developing methods for
      assessing the impact of broad contextual variables. It has been suggested that
      the impact of some of these variables can be captured in mood ratings. We
      examined this possibility by observing whether there was a correlation between
      mood ratings and subsequent display of problem behavior. Further, we developed an
      intervention based on mood induction for altering these ratings and observed
      whether these alterations were correlated with changes in the likelihood of
      problem behavior. Our data demonstrated that bad mood ratings were highly
      predictive of problem behavior. Further, when we implemented our induction
      procedure to improve mood ratings, we subsequently observed dramatic decreases in
      problem behavior.

PMID- 12475366
TI  - Implicit and explicit learning in young adults with mental retardation.
AB  - We examined intelligence-related differences in explicit and implicit learning
      using an artificial grammar paradigm. Young adults with and without mental
      retardation completed a sequence-learning and identification task. For some
      participants, sequences were constructed following an artificial grammar; for
      others, sequences were random. Explicit learning was determined by ability to
      learn and later identify random sequences. Implicit learning was determined by
      the tendency to incorrectly identify new grammatical sequences as seen before,
      relative to new nongrammatical sequences. Participants with mental retardation
      did more poorly than participants without mental retardation on explicit learning
      but just as well on implicit learning. Results suggest that learning of complex
      materials, when accomplished through implicit processing, is functionally
      equivalent in individuals with and without mental retardation.

PMID- 12475367
TI  - Insight into the physiological actions of thyroid hormone receptors from
      genetically modified mice.
AB  - Thyroid hormones exert a range of developmental and physiological actions in all
      vertebrates. Serum concentrations of L-thyroxine (T4) and 3,5,3 -L
      triiodothyronine (T3) are maintained by a negative feedback loop involving T3
      inhibition of hypothalamic thyrotrophin releasing hormone (TRH) and pituitary
      thyroid stimulating hormone (TSH) secretion, and by tissue specific and hormone
      regulated expression of the three iodothyronine deiodinase enzymes that activate
      or metabolise thyroid hormones. T3 actions are mediated by two T3-receptors,
      TRalpha and TRbeta, which act as hormone-inducible transcription factors. The
      TRalpha (NR1A1) and TRbeta (NR1A2) genes encode mRNAs that are alternatively
      spliced to generate 9 mRNA isoforms (TRalpha1, alpha2, alpha3, Deltaalpha1,
      Deltaalpha2, beta1, beta2, beta3 and Deltabeta3), of which four (TRalpha1,
      alpha2, beta1 and beta2) are known to be expressed at the protein level in vivo.
      The numerous TR mRNAs are expressed widely in tissue- and developmental stage
      specific patterns, although it is important to note that levels of mRNA
      expression may not correlate with receptor protein concentrations in individual
      tissues. The TRalpha2, alpha3, Deltaalpha1 and Deltaalpha2 transcripts encode
      proteins that fail to bind T3 in vitro. These  non-binding  isoforms, in addition
      to TRDeltabeta3 which does bind hormone, may act as dominant negative antagonists
      of the true T3-binding receptors in vitro, but their physiological functions and
      those of the TRbeta3 isoform have not been determined. In order to obtain a new
      understanding of the complexities of T3 action in vivo and the role of TRs during
      development, many mouse models of disrupted or augmented thyroid hormone
      signalling have been generated. The aim of this review is to provide a picture of
      the physiological actions of thyroid hormones by considering the phenotypes of
      these genetically modified mice.

PMID- 12475368
TI  - High occurrence of thyroid multinodularity and low occurrence of subclinical
      hypothyroidism among tobacco smokers in a large population study.
AB  - Tobacco smoking increases the risk of goitre and Graves' disease, but the
      association with thyroid nodularity and hypothyroidism has not been settled. We
      investigated 4649 subjects from the general population with questionnaires,
      thyroid ultrasonography and blood tests. The results were analysed in
      multivariate regression models. Tobacco smoking was associated with an increased
      prevalence of thyroid multinodularity (odds ratio (OR) 1.9; 95% confidence
      interval (CI) 1.4-2.5), but not with increased prevalence of solitary thyroid
      nodules. The tendency was for a stronger association in the area with the most
      pronounced iodine deficiency (P for interaction=0.08). Lower levels of serum TSH
      were found among tobacco smokers (P<0.001), but this association disappeared when
      adjustment was made for thyroid nodularity and thyroid Volume. The prevalence of
      elevated TSH levels was markedly reduced among smokers (OR 0.47; 95% CI 0.33
      0.67). No association was found between smoking and hyperthyroidism. The observed
      associations seem to be explainable by the blocking of iodine uptake and
      organification in the thyroid by thiocyanate, a degradation product of cyanide in
      tobacco smoke.

PMID- 12475369
TI  - Is the low tri-iodothyronine state a crucial factor in determining the outcome of
      coronary artery bypass patients? Evidence from a clinical pilot study.
AB  - The cardiovascular system is an important target for thyroid hormones. The
      present study evaluates the changes affecting thyroid hormone metabolism during
      and 6 days after coronary artery bypass and their relationship with the post
      operative outcome of the patients. Thirty-three patients were enrolled in the
      study; their thyroid hormone profiles were determined at 13 sampling points
      during surgery and for 6 days afterwards. Serum total tri-iodothyronine (T3) and
      free T3 (FT3) concentrations decreased significantly after surgery (P<0.001) and
      they remained significantly low until the end of the study. Free thyroxine (FT4)
      and T4 declined significantly immediately after surgery (P<0.05 for FT4, P<0.001
      for T4) but they returned to baseline values (24 h and 96 h post-surgery
      respectively). Serum reverse T3 increased remarkably 36 h after surgery (P<0.001)
      and remained significantly higher than the baseline value throughout the study. A
      relevant finding was that the days of post-operative hospitalization (10+/-3
      days, means+/-S.D.) was inversely correlated with the slope of the recovery of T3
      concentration (P<0.001) or with the area under the plasma curves of T3 (P=0.024,
      time range 72-144 h) and the FT3/FT4 ratio (P=0.037, time range 72-144 h) during
      the post-operative period. Our data suggest a prolonged reduction of T4 to T3
      conversion in patients undergoing cardiac surgery and indicate that the recovery
      period is the most critical in the evaluation of a possibly successful approach
      for T3 substitutive therapy.

PMID- 12475370
TI  - Uptake of tri-iodothyronine and thyroxine in myoblasts and myotubes of the
      embryonic heart cell line H9c2(2-1).
AB  - Uptake of tri-iodothyronine (T(3)) was compared with that of thyroxine (T(4)) in
      the embryonic heart cell line H9c2 (2-1). These cells propagate as myoblasts and
      form differentiated myotubes upon reduction of the serum concentration, as
      indicated by a 31-fold increase in creatine kinase activity. Protein and DNA
      content per well were around 2-fold higher in myotubes than in myoblasts. When
      expressed per well, T(3) and T(4) uptake were, compared with myoblasts, 1.9- to 2
      fold and 3.1- to 4-fold higher in myotubes respectively. On the other hand, the
      characteristics of T(3) and T(4) uptake were similar in myoblasts and myotubes.
      At any time-point, T(4) uptake was 2-fold higher than that of T(3), and both
      uptakes were energy but not Na(+) dependent. T(3) and T(4) uptake exhibited
      mutual inhibition in myoblasts and myotubes: 10 microM unlabeled T(3) reduced
      T(4) uptake by 51-60% (P<0.001), while 10 microM T(4) inhibited T(3) uptake by 48
      51% (P<0.001). Furthermore, T(3) and T(4) uptake in myoblasts was dose
      dependently inhibited by tryptophan (maximum inhibition around 70%; P<0.001).
      Exposure of the cells to T(3) or T(4) during differentiation significantly
      increased the fusion index (35 and 40%; P < 0.01). Finally, both myoblasts and
      myotubes showed a small deiodinase type I activity, while deiodinase type II
      activity was undetectable. In conclusion, T(3) and T(4) share a common energy
      dependent transport system in H9c2(2-1) cells, that may be important for the
      availability of thyroid hormone during differentiation.

PMID- 12475371
TI  - Influence of maternal hyperthyroidism in the rat on the expression of neuronal
      and astrocytic cytoskeletal proteins in fetal brain.
AB  - Maternal hypothyroidism during pregnancy impairs brain function in human and rat
      offspring, but little is known regarding the influence of maternal
      hyperthyroidism on neurodevelopment. We have previously shown that the expression
      of neuronal and glial differentiation markers in fetal brain is compromised in
      hypothyroid rat dam pregnancies and have now therefore extended this
      investigation to hyperthyroid rat dams. Study groups comprised partially
      thyroidectomised dams, implanted with osmotic pumps infusing either vehicle (TX
      dams) or a supraphysiological dose of thyroxine (T4) (HYPER dams), and euthyroid
      dams infused with vehicle (N dams). Cytoskeletal protein abundance was determined
      in fetal brain at 21 days of gestation by immunoblot analysis. Relative to N
      dams, circulating total T4 levels were reduced to around one-third in TX dams but
      were doubled in HYPER dams. Fetal brain weight was increased in HYPER dams,
      whereas litter size and fetal body weight were reduced in TX dams. Glial
      fibrillary acidic protein expression was similar in HYPER and TX dams, being
      reduced in both cases relative to N dams. alpha-Internexin (INX) abundance was
      reduced in HYPER dams and increased in TX dams, whereas neurofilament 68 (NF68)
      exhibited increased abundance in HYPER dams. Furthermore, INX was inversely
      related to - and NF68 directly related to - maternal serum total T4 levels,
      independently of fetal brain weight. In conclusion, maternal hyperthyroidism
      compromises the expression of neuronal cytoskeletal proteins in late fetal brain,
      suggestive of a pattern of accelerated neuronal differentiation.

PMID- 12475372
TI  - Evidence for a negative feedback in the control of eel growth hormone by thyroid
      hormones.
AB  - The regulation of growth hormone (GH) by thyroid hormones (THs) has been shown to
      present species variation. We investigated the regulation of GH in the eel, a
      representative of an ancient group of teleosts. In vivo administration of
      triiodothyronine (T(3)) or thyroxine (T(4)) significantly reduced pituitary and
      serum GH levels, as measured by homologous RIA. In order to investigate the
      ability of THs to regulate GH production directly at the pituitary level, we used
      a long-term, serum-free primary culture of eel pituitary cells. Both T(3) and
      T(4) inhibited GH release in a concentration-dependent manner, producing up to
      50% inhibition at 10 nM, with an ED(50) of <0.2 nM, within the range of their
      physiological circulating levels. Other hormones also acting via the nuclear
      receptor superfamily, such as sex steroids (testosterone, estradiol and
      progesterone) and corticosteroid (cortisol), had no effect on GH release in
      vitro, underlining the specificity of the regulatory effect of THs on GH.
      Measurement of both GH release and cellular content for calculation of GH
      production in vitro indicated that THs not only inhibited GH release but also GH
      synthesis. Dot-blot assay of GH messenger RNA (mRNA) using an homologous eel cDNA
      probe showed a decrease in GH mRNA levels in cells cultured in the presence of
      T(3), as compared with control cells. This demonstrated that the inhibition of
      T(3) on GH synthesis was mediated by a decrease in GH mRNA steady state levels.
      In conclusion, we demonstrate inhibitory regulation of eel GH synthesis and
      release by THs, exerted directly at the pituitary level. These data contrast with
      the rat, where THs are known to have a stimulatory effect and suggest that the
      pattern observed here in an early vertebrate and also found in birds, reptiles
      and some mammals including humans, may represent an ancestral and more
      generalized vertebrate pattern of TH regulation of pituitary GH.

PMID- 12475373
TI  - Adult growth hormone treatment reduces hypertension and obesity induced by an
      adverse prenatal environment.
AB  - The discovery of a link between an adverse in utero environment and the
      propensity to develop metabolic and cardiovascular disease in adult life is one
      of the most important advances in epidemiological research of recent Years.
      Increasing experimental evidence suggests that alterations in the fetal
      environment may have long-term consequences for the development of metabolic
      disorders in adult life. This process has been termed 'fetal programming' and we
      have shown that undernutrition of the mother during gestation leads to
      development of the metabolic syndrome X during adult life. Striking metabolic
      similarities exist between syndrome X and untreated GH deficiency (GHD). In the
      present study we have investigated the effects of GH treatment on blood pressure
      and metabolic parameters. Virgin Wistar rats (age 75+/-5 days, n=20 per group)
      were time-mated and randomly assigned to receive food either ad libitum (AD) or
      30% of AD intake (UN) throughout pregnancy. At weaning, male offspring were
      assigned to one of two diets (control or hypercaloric (30% fat)). Systolic blood
      pressure was measured at day 100 and following twice daily treatment with
      recombinant bovine GH for 21 days. GH treatment increased body weights in all
      treated animals but significantly reduced retroperitoneal and gonadal fat pad
      weights. Following GH treatment, systolic blood pressure was markedly decreased
      in all UN offspring. Saline-treated animals showed no change in systolic blood
      pressure over the treatment period. GH treatment increased heart-to-body weight
      ratio in all GH-treated animals. Our data demonstrated that GH treatment reduces
      hypertension and improves cardiovascular function in animals exposed to adverse
      environmental conditions during fetal or postnatal life.

PMID- 12475374
TI  - Mechanism of action of the growth hormone secretagogue, L-692,585, on isolated
      porcine somatotropes.
AB  - The effects of a GH secretagogue, L-692,585 (L-585), and human GH-releasing
      hormone (hGHRH) on calcium transient and GH release were investigated in isolated
      porcine pituitary cells using calcium imaging and the reverse hemolytic plaque
      assay (RHPA). Somatotropes were functionally identified by the application of
      hGHRH. All cells that responded to hGHRH responded to L-585 application.
      Perfusion application of 10 microM hGHRH and L-585 for 2 min resulted in an
      increase in intracellular calcium concentrations ([Ca(2+)](i)) of 53+/-1 nM
      (mean+/-S.E.M.) (P < 0.01) and 68+/-2 nM (P < 0.01) respectively. The L-585
      response was characterized by an initial increase in [Ca(2+)](i) followed by a
      decline to a plateau level above the baseline. Concurrent calcium imaging with
      RHPA indicated that the L-585-evoked increase in [Ca(2+)](i) coincided with GH
      release. L-585 significantly increased the percentage of plaque-forming cells
      (24+/-3 vs 40+/-6%; P < 0.05) and mean area of plaques (1892+/-177 vs 3641+/-189
      micro m(2); P < 0.01) indicating increased GH release. Substance P (SP) analogue
      ([d -Arg(1),d -Phe(5),d -Trp(7,11)]-SP) blocked, and the hGHRH receptor
      antagonist ((Phenylac-Tyr(1),d -Arg(2), p-chloro-Phe(6), Homoarg(9), Tyr
      (Me)(10), Abu(15), Nle(27),d -Arg(28), Homoarg(29))-GRF (1-29) amide) decreased
      the stimulatory effect of hGHRH. These failed to block the stimulatory effect of
      L-585, suggesting a different receptor for L-585 from the GHRH receptor. The
      hGHRH-induced calcium transients and initial peak increase induced by L-585 were
      significantly decreased by removal of calcium from the bathing medium or the
      addition of nifedipine, an L-calcium channel blocker. The plateau component of L
      585-induced calcium change was abolished by removal of calcium and nifedipine.
      These results suggest an involvement of calcium channels in GH release. Either SQ
      22536, an adenylate cyclase inhibitor, or U73122, a phospholipase C (PLC)
      inhibitor, blocked the stimulatory effects of hGHRH and L-585 on [Ca(2+)](i)
      transient, indicating the involvement of adenylate cyclase-cAMP and PLC-inositol
      triphosphate pathways. These results further suggested that calcium mobilization
      from internal stores during the first phase of the L-585 response induced an
      increase in [Ca(2+)](i) whereas calcium influx during the second phase is a
      consequence of somatotrope depolarization.

PMID- 12475376
TI  - Distribution and characterization of plasmalemma vesicle protein-1 in rat
      endocrine glands.
AB  - Plasmalemma vesicle protein-1 (PV-1) is an integral membrane protein associated
      with endothelial cell caveolae and fenestrae. Since endocrine glands are enriched
      with fenestrated endothelium, we examined the distribution of PV-1 mRNA and
      protein in endocrine glands and determined its cellular localization. A single
      transcript was detected by RT-PCR in all endocrine glands examined. A synthetic
      peptide was used to generate antibodies for Western blotting and
      immunohistochemistry (IHC). Western blotting of membrane fractions from lung,
      pituitary, adrenal, testis and PV-1-transfected Cos-1 cells revealed a major 65
      kDa protein. This protein binds to heparin with high affinity. Using IHC, PV-1
      was localized to both endothelial cells of the adrenal zona reticularis and
      chromaffin cells of the medulla. In the pancreas, PV-1 expression was restricted
      to a few cells in the islets of Langerhans that partially overlap with
      somatostatin-positive delta-cells. In both neonatal and adult pituitaries, strong
      PV-1 immunoreactivity was detected in neural lobe pituicytes in a pattern similar
      to that of glial fibrillary acidic protein (GFAP). PV-1 and GFAP expression was
      seen in the adult, but not neonatal, intermediate lobe. Endothelial cells
      throughout the neonatal anterior lobe were PV-1 positive, but PV-1 in the adult
      was restricted to some endothelial and endocrine cells localized near the margins
      of lobe. In the adult testis, strong PV-1 expression was seen in germ cells
      within the seminiferous tubules that varied with the stage of spermatogenesis. In
      contrast, PV-1 in the neonatal testis was localized to the interstitial cells but
      not seminiferous tubules. In the ovary, PV-1 was expressed in stromal endothelial
      cells as well as the thecal layer of developing follicles. Over half the corpus
      luteal cells were positive for PV-1. Our data have shown that PV-1 is not
      restricted to endothelial cells but is localized in many types of endocrine and
      non-endocrine cells. Furthermore, PV-1 expression in the pituitary and testis is
      developmentally regulated.

PMID- 12475375
TI  - Proinsulin processing in the diabetic Goto-Kakizaki rat.
AB  - The biosynthesis and processing of proinsulin was investigated in the diabetic
      Goto-Kakizaki (GK) rat. Immunofluorescence microscopy comparing GK and Wistar
      control rat pancreata revealed marked changes in the distribution of alpha-cells
      and pronounced beta-cell heterogeneity in the expression patterns of insulin,
      prohormone convertases PC1, PC2, carboxypeptidase E (CPE) and the PC-binding
      proteins 7B2 and ProSAAS. Western blot analyses of isolated islets revealed
      little difference in PC1 and CPE expression but PC2 immunoreactivity was markedly
      lower in the GK islets. The processing of the PC2-dependent substrate
      chromogranin A was reduced as evidenced by the appearance of intermediates. No
      differences were seen in the biosynthesis and post-translational modification of
      PC1, PC2 or CPE following incubation of islets in 16.7 mM glucose, but incubation
      in 3.3 mM glucose resulted in decreased PC2 biosynthesis in the GK islets. The
      rates of biosynthesis, processing and secretion of newly synthesized (pro)insulin
      were comparable. Circulating insulin immunoreactivity in both Wistar and GK rats
      was predominantly insulin 1 and 2 in the expected ratios with no (pro)insulin
      evident. Thus, the marked changes in islet morphology and PC2 expression did not
      impact the rate or extent of proinsulin processing either in vitro or in vivo in
      this experimental model.

PMID- 12475377
TI  - Effect of estrogen on scavenger receptor BI expression in the rat.
AB  - High-dose 17alpha-ethinyl estradiol treatment is associated with increased
      adrenal and decreased hepatic levels of scavenger receptor class B type 1 (SR-BI)
      in rats. In this paper we explored the mechanisms responsible for the
      differential regulation of SR-BI by estrogen in these two tIssues. Previously it
      was shown that estrogen-treated rats are profoundly hypolipidemic due to
      increased hepatic low density lipoprotein receptor (LDLR) activity, and that this
      effect is not maintained with hypophysectomy. To determine if the reduction in
      hepatic SR-BI was a direct or indirect effect of estrogen, we treated
      hypophysectomized rats with high-dose estrogen; the levels of SR-BI expression
      did not change in the livers or adrenals of these animals. To determine if the
      absence of response to estrogen in the adrenals of hypophysectomized animals was
      due to the absence of adrenocorticotropic hormone (ACTH), we examined the effect
      of estrogen treatment on SR-BI expression in animals treated with dexamethasone,
      which inhibits endogenous ACTH production. The administration of dexamethasone
      completely inhibited the increase in SR-BI expression in the adrenals of estrogen
      treated rats. From these studies we conclude that estrogen does not have a direct
      effect on SR-BI expression in either the liver or the adrenals. In the liver, the
      decrease in SR-BI is dependent on the estrogen-induced increase in LDLR activity,
      and in the adrenal glands, ACTH is required for the estrogen-associated increase
      in expression of SR-BI.

PMID- 12475378
TI  - The effect of long-term treatment with steroid hormones or tamoxifen on oestrogen
      receptors (alpha and beta) in the endometrium of ovariectomized cynomolgus
      macaques.
AB  - The effects of oestrogen are mediated by two specific intracellular receptors,
      oestrogen receptors (ER) alpha and beta, which function as ligand-activated
      transcriptional regulators. Ovariectomized macaques (Macaca fascicularis) were
      used to study the regulation of ERalpha and ERbeta in the endometrium by
      immunohistochemistry and in situ hybridization after long-term hormone treatment.
      Animals were treated continuously for 35 Months with either conjugated equine
      oestrogen (CEE), medroxyprogesterone acetate (MPA), combined CEE/MPA, or
      tamoxifen (TAM). Treatment with CEE/MPA down-regulated ERalpha in the superficial
      glands. In the superficial stroma the ERalpha level was lower in the CEE/MPA
      group than in the CEE and MPA groups. ERbeta immunostaining was faint with minor
      variation in response to treatment, but increased in the superficial stroma after
      MPA treatment. The ratio of ERbeta/ERalpha increased in superficial stroma and
      gland after CEE/MPA treatment, and also in stroma after MPA and TAM. Cystic
      endometrial hyperplasia was observed in TAM-treated animals, in combination with
      a high level of ERalpha protein expression. The present data show that long-term
      hormone treatment affects the ERalpha and ERbeta protein levels in the
      endometrium. The balance between ERalpha and ERbeta seems to be important for the
      proliferative response to oestrogen.

PMID- 12475379
TI  - Osteoblast differentiation influences androgen and estrogen receptor-alpha and 
      beta expression.
AB  - Significant levels of estrogen and androgens circulate in men and women, and both
      play an important role in bone metabolism. While it is well established that
      either estrogen or androgen replacement therapy is effective at ameliorating bone
      loss associated with hypogonadism, recent evidence nevertheless suggests that
      estrogen and androgens have distinct molecular actions on the skeleton. In this
      study, we have employed normal rat calvarial osteoblast cultures to characterize
      relative expression profiles of estrogen (ERalpha and ERbeta) and androgen
      receptors (AR) during osteoblast differentiation. Normal osteoblast cultures can
      proceed through in vitro differentiation with distinct stages of proliferation,
      matrix maturation and mineralization in the appropriate differentiation medium
      containing ascorbic acid. Expression profiles of AR, ERalpha and ERbeta in
      primary cultures during osteoblast differentiation were characterized both by
      semi-quantitative relative RT-PCR and by Western analysis. In cultures induced to
      differentiate by growth in the presence of ascorbic acid, the expression profile
      for each receptor was unique during the course of differentiation. ERalpha levels
      were elevated during matrix maturation and then declined during mineralization.
      ERbeta expression was relatively constant throughout differentiation, exhibiting
      more constitutive expression. In contrast, AR levels were lowest during
      proliferation, and then increased throughout differentiation with highest levels
      in the most mature mineralizing cultures. Since steroid hormone action is
      generally mediated by specific cognate receptors, these results suggest that
      androgen actions may target cells during the mineralization stage of osteoblast
      differentiation, while estrogen action through either receptor isoform is more
      likely to affect osteoblasts earlier during matrix maturation. Interestingly, sex
      steroid receptor expression profiles did not exhibit the same patterns of
      regulation if osteoblast cultures were grown without ascorbic acid in medium that
      did not support extracellular matrix deposition. Thus, sex steroids may
      distinctly influence skeletal health by differential modulation of function
      during osteoblast differentiation.

PMID- 12475380
TI  - Drug-induced prevention of gastrectomy- and ovariectomy-induced osteopaenia in
      the young female rat.
AB  - Both ovariectomy (Ovx) and gastrectomy (Gx) induce osteopaenia in rats and
      humans. While the effect of Ovx has been ascribed to oestrogen deficiency, the
      underlying mechanism behind Gx is poorly understood. Alendronate, oestrogen and
      parathyroid hormone (PTH) are known to prevent the osteopaenia induced by Ovx in
      rats. The purpose of the present study was to determine whether alendronate,
      oestrogen or PTH could also prevent Gx-evoked osteopaenia. Rats were Ovx-, Gx-,
      or were sham-operated (Sham) and were then treated with alendronate (50 micro
      g/kg/day), oestrogen (10 micro g/kg/day) or PTH(1-84) (75 micro g/kg/day) for
      eight weeks. At sacrifice, serum PTH was unaffected by surgery (Ovx, 64+/-8
      pg/ml; Gx, 75+/-13 pg/ml; Sham, 58+/-11 pg/ml). The bone mineral density (BMD) of
      the fifth lumbar vertebra (L5) was analysed. Ovx and Gx reduced the BMD (ash
      weight/Volume) of the L5 by 15+/-4% and 22+/-3% respectively. Trabecular BMD and
      the cortical bone mineral content (BMC) of the femur were assessed using
      peripheral computed tomography. Both Ovx and Gx markedly reduced trabecular BMD
      in the metaphyseal area of the distal femur (Ovx, -37+/-7%; Gx, -49+/-7%). The
      cortical BMC of the femur was only slightly reduced. Alendronate prevented
      trabecular bone loss after both Ovx and Gx, while oestrogen and PTH prevented
      trabecular bone loss after Ovx but not after Gx. In conclusion, the
      bisphosphonate alendronate prevented both Ovx- and Gx-induced trabecular bone
      loss. In contrast, PTH and oestrogen prevented Ovx-induced but not Gx-induced
      trabecular bone loss, suggesting that the mechanism behind the trabecular bone
      loss in Ovx rats differs from that in Gx rats. The results support the notion
      that the mechanism of action for the bone-sparing effect of these drugs differs.
      The ability of alendronate, and probably also other bisphosphonates, to prevent
      Gx-evoked osteopaenia in the rat might be of potential clinical interest when
      dealing with post-Gx osteopaenia in humans.

PMID- 12475381
TI  - Glucocorticoid effects on chondrogenesis, differentiation and apoptosis in the
      murine ATDC5 chondrocyte cell line.
AB  - Glucocorticoids (GC) are used extensively in children and may cause growth
      retardation, which is in part due to the direct effects of GC on the growth
      plate. We characterised the ATDC5 chondrocyte cell line, which mimics the in vivo
      process of longitudinal bone growth, to examine the effects of dexamethasone
      (Dex) and prednisolone (Pred) during two key time points in the chondrocyte life
      cycle - chondrogenesis and terminal differentiation. Additionally, we studied the
      potential for recovery following Dex exposure. During chondrogenesis, Dex and
      Pred exposure at 10(-8) M, 10(-7) M and 10(-6) M resulted in a significant mean
      reduction in cell number (28% vs 20%), cell proliferation (27% vs 24%) and
      proteoglycan synthesis (47% vs 43%) and increased alkaline phosphatase (ALP)
      activity (106% vs 62%), whereas the incidence of apoptosis was unaltered. Minimal
      effects were noted during terminal differentiation with both GC although all
      concentrations of Dex lowered apoptotic cell number. To assess catch-up growth
      the cells were incubated for a total of 14 days which included 1, 3, 7, 10 or 14
      days exposure to 10(-6) M Dex, prior to the recovery period. Recovery of
      proteoglycan synthesis was irreversibly impaired following just one day exposure
      to Dex. Although cell number showed a similar pattern, significant impairment was
      only achieved following 14 days exposure. Irreversible changes in ALP activity
      were only noticed following 10 days exposure to Dex. In conclusion, GC have
      maximal effects during chondrogenesis; Dex is more potent than Pred and cells
      exposed to Dex recover but this may be restricted due to differential effects of
      GC on specific chondrocyte phenotypes.

PMID- 12475382
TI  - Calcitonin decreases the adherence and survival of HEK-293 cells by a caspase
      independent mechanism.
AB  - We recently reported that calcitonin (CT) can profoundly inhibit the growth of
      HEK-293 cells transfected with the human calcitonin receptor (hCTR). We also
      obtained preliminary evidence that suggested a role for CT in cell survival, and
      in the present study we have investigated the pro-apoptotic action of CT, which
      we observe in conditions of low serum concentration. Under these conditions, we
      have found that CT treatment of HEK-293 cells stably transfected with the insert
      negative form of the human CTR (HR12 cells) caused a time-dependent decrease in
      cell number associated with loss of cellular attachment. Loss of cellular
      adherence in CT-treated cultures caused programmed cell death, as shown by
      Annexin V staining of cells, failure of cells to exclude Trypan Blue dye,
      condensation and cleavage of nuclear DNA, and appearance of hypodiploid cells in
      fluorescence-activated cell sorting (FACS) analysis. The accumulation of non
      adherent cells and cell death was concomitant with increased intracellular
      activity of caspase-3. However, inhibition of caspase activation in HR12 cells
      did not prevent CT-mediated loss of attachment and did not maintain the viability
      of non-adherent cells, indicating that caspase activation accompanied, but was
      probably not the cause of, the loss of cell viability. Neither the effects of CT
      on cell survival nor the activation of caspase-3 were observed in serum-replete
      conditions, suggesting that serum-derived factors provide protection of cells
      from CT-induced apoptosis. The inhibitory effects of CT on cell growth were found
      previously to be related to activation of Erk1/2 MAP kinase. In the present
      experiments, it was found that the Erk1/2 inhibitor, PD 98059, inhibited the CT
      induced loss of cellular adherence and the consequent reduction in cell numbers.
      These results demonstrate that CT can negatively affect cell survival and they
      identify roles for cell adherence and MAP kinase activation in this process.

PMID- 12475383
TI  - Isoproterenol is a positive regulator of the suppressor of cytokine signaling-3
      gene expression in 3T3-L1 adipocytes.
AB  - SOCS (suppressor of cytokine signaling)-3 has recently been shown to be an
      insulin- and tumor necrosis factor (TNF)-alpha-induced negative regulator of
      insulin signaling. To further clarify a potential involvement of SOCS-3 in the
      development of insulin resistance, we measured differentiation-dependent SOCS-3
      mRNA expression in 3T3-L1 adipocytes and studied its regulation by various
      hormones known to impair insulin signaling using quantitative real-time RT-PCR.
      There was a differentiation-dependent downregulation of SOCS-3 mRNA by 50% over
      the 9 day adipocyte differentiation course. Interestingly, besides insulin and
      TNF-alpha, chronic treatment of differentiated 3T3-L1 cells with 10 microM
      isoproterenol for 16 h stimulated SOCS-3 gene expression by about 3.5-fold.
      Furthermore, isoproterenol stimulated SOCS-3 mRNA expression in a dose-dependent
      manner with significant activation detectable at concentrations as low as 10 nM
      isoproterenol. Moreover, a strong 27- and 47-fold activation of SOCS-3 mRNA
      expression could be seen after 1 h of isoproterenol and GH treatment
      respectively. The stimulatory effect of isoproterenol could be almost completely
      reversed by pretreatment of 3T3-L1 cells with the beta-adrenergic antagonist
      propranolol. Finally, isoproterenol's action could be mimicked by stimulation of
      G(S)-proteins with cholera toxin and of adenylyl cyclase with forskolin and
      dibutyryl cAMP. Taken together, our results demonstrate a differentiation
      dependent downregulation of SOCS-3 in adipocytes and suggest that SOCS-3 gene
      expression is stimulated by beta-adrenergic agents via activation of a G(S)
      protein-adenylyl cyclase-dependent pathway. As SOCS-3 is a novel inhibitor of
      insulin signaling, the data support a possible role of this protein as a
      selectively regulated mediator of catecholamine-induced insulin resistance.

PMID- 12475384
TI  - Leptin controls the fate of fatty acids in isolated rat white adipocytes.
AB  - Leptin directly increases the rate of exogenous glucose and fatty acids oxidation
      in isolated adipocytes. However, the effects of leptin on fatty acid metabolism
      in white adipose tIssue have not been examined in detail. Here, we report that in
      adipocytes incubated for 6 h in the presence of leptin (10 ng/ml), the insulin
      stimulated de novo fatty acid synthesis was inhibited by 36% (P<0.05), while the
      exogenous oxidation of acetic and oleic acids was increased by 50% and 76%
      respectively. Interestingly, leptin did not alter the oxidation of intracellular
      fatty acids. Leptin-incubated cells presented a 16-fold increase in the
      incorporation of oleic acid into triglyceride (TG) and a 123% increase in the
      intracellular TG hydrolysis (as measured by free fatty acids release). Fatty acid
      TG cycling was not affected by leptin. By employing fatty acids radiolabeled with
      (3)H and (14)C, we could determine the concomitant influx of fatty acids
      (incorporation of fatty acids into TG) and efflux of fatty acids (intracellular
      fatty acids oxidation and free fatty acids release) in the incubated cells.
      Leptin increased by 30% the net efflux of fatty acids from adipocytes. We
      conclude that leptin directly inhibits de novo synthesis of fatty acids and
      increases the release and oxidation of fatty acids in isolated rat adipocytes.
      These direct energy-dissipating effects of leptin may play an important role in
      reducing accumulation of fatty acids into TG of rat adipose cells.

PMID- 12475385
TI  - Definition and characterization of relative hypo- and hyperleptinemia in a large
      Caucasian population.
AB  - The adipocyte-derived hormone, leptin, has been implicated in the regulation of
      appetite, weight gain and glucose homeostasis as well as in liver fibrogenesis,
      hematopoiesis and immune function. No previous reports have clearly defined
      pathologically elevated or decreased serum leptin levels for Caucasian adults.
      The aim of this study was to define and characterize subjects with relative hyper
      and hypoleptinemia in a large population-based German cohort. Percentiles of
      leptin levels by body mass index (BMI) were calculated from 4971 adult Germans,
      and the participants with leptin levels above the 95th and below the 5th
      percentile were defined as relatively hyperleptinemic and relatively
      hypoleptinemic, respectively, for their BMI. These participants were compared
      with the intermediate group with respect to anthropometric and clinical data and
      parameters of glucose and iron metabolism, lipid status, renal, adrenal and
      reproductive function. Relatively hyperleptinemic participants (HL) showed higher
      insulin, c-peptide, and total cholesterol levels than the hypoleptinemic
      subjects; in males, ferritin levels were higher and testosterone levels lower in
      the HL group. In conclusion, we report the first percentile curves for serum
      leptin by BMI in a large Caucasian population. Relatively low leptin values may
      be associated with a lower metabolic risk than relatively high serum leptin
      values.

PMID- 12475386
TI  - Gender-specific programming of insulin secretion and action.
AB  - Insulin secretion and glucose tolerance were studied in 20-week-old male and
      female offspring of rat dams maintained on an isocaloric 20% or 8% protein diet
      during pregnancy and lactation after transfer to the same diet at weaning.
      Protein-restricted male and female offspring were also weaned onto a 20% protein
      diet. In males, post-absorptive insulin concentrations were suppressed by protein
      restriction from conception to adulthood (by 41%; P<0.001); however, basal
      insulin levels were 2.6-fold higher (P<0.001) if protein restriction was limited
      to gestation and lactation. Post-absorptive insulinaemia in females was
      unaffected by early or sustained protein restriction, but was lower than for
      males in the control group and the group exposed to protein restriction during
      early life alone (by 40% (P<0.001) and 52% (P<0.001) respectively). Plasma
      insulin/blood glucose ratios were higher in males compared with females in both
      control and early protein-restricted groups (1.6-fold (P<0.05) and 2.3-fold
      (P<0.001) respectively). A positive linear relationship existed between mean
      ambient insulin and glucose concentrations in males (r=1.0) and females (r=0.9),
      but the gradient was 12.4-fold greater (P<0.01) in males. beta-Cell function was
      evaluated after intravenous glucose challenge. In males, the acute insulin
      response and the suprabasal 30-min area under the insulin curve were dramatically
      higher in rats exposed to protein restriction during gestation and lactation
      alone (2.6- and 2.8-fold respectively; P<0.001). In contrast, these parameters
      were lowered by extending the exposure to protein restriction to adulthood in
      males, and by either early or prolonged exposure to protein restriction in
      females. The insulin resistance index was increased (2.5-fold; P<0.001) in male,
      but not female, rats exposed to protein restriction during gestation and
      lactation alone, and was not increased by extending the period of protein
      restriction to adulthood in either sex. Thus the data have demonstrated gender
      specific lowering of insulin sensitivity due to protein restriction during early
      life only. The insulinogenic index (insulin response in relation to prevailing
      glycaemia) was increased in male, but not female, rats exposed to protein
      restriction during gestation and lactation alone (3.0-fold; P<0.001). A modest
      decline in insulin secretion in the female groups exposed to protein restriction
      until either the end of lactation or adulthood was compensated by increased
      insulin sensitivity, as demonstrated by significant decreases in the insulin
      resistance index in both groups (by 48% and 52% respectively; P<0.05). Glucose
      disappearance rates did not differ between the male and female control or early
      protein-restricted groups but were higher in both male (31%; P<0.05) and female
      groups (46%; P<0.001) exposed to protein restriction from conception to
      adulthood. Marked gender differences in glucose-stimulated insulin secretion were
      not associated with gender differences with respect to glucose tolerance. Our
      data therefore demonstrated that exposure to protein restriction during early
      life alone leads to relative insulin resistance and hyperinsulinaemia in
      adulthood, but this relationship is gender specific, observed only in males, and
      glucose tolerance is maintained.

PMID- 12475387
TI  - Comparative peptidomics of the endocrine pancreas: islet hormones from the clawed
      frog Xenopus laevis and the red-bellied newt Cynops pyrrhogaster.
AB  - Electrospray mass spectrometry coupled with reverse-phase HPLC was used to
      identify peptides in the molecular mass range 3000-6000 Da in extracts of the
      pancreata of the clawed frog Xenopus laevis (Anura: Pipidae) and the red-bellied
      newt Cynops pyrrhogaster (Caudata: Salamandridae). Amino acid sequences of
      insulins, peptides derived from the post-translational processing of proglucagons
      and pancreatic polypeptide were determined by automated Edman degradation. Three
      molecular forms of insulin were isolated from the tetraploid organism X. laevis
      that represent insulin-1 and insulin-2, as deduced from the nucleotide sequences
      of previously characterized cDNAs, and a third form which differed from insulin-2
      by the single amino acid substitution Asp(21)-->Glu in the B-chain. The amino
      acid sequence of Xenopus preproglucagons (genes 1 and 2 ) may be deduced from the
      nucleotide sequences of cDNAs but the pathways of post-translation processing of
      the precursors are not known. Two molecular forms of glucagon with 36 amino
      acids, derived from genes 1 and 2 and representing glucagon-29 extended from its
      C terminus by different heptapeptides, and five molecular forms of glucagon-like
      peptide 1 (GLP-1) were isolated. The GLPs represent proglucagon-(77-113), -(122
      158) and -(160-191) from gene 1, and proglucagon-(77-113) and -(160-191) from
      gene 2. A single molecular form of insulin, glucagon-36, a C-terminally alpha
      amidated GLP-1 with 30 amino acid residues, a 33 amino acid residue GLP-2 and
      pancreatic polypeptide were isolated from the pancreatic extract of the diploid
      organism C. pyrrhogaster. This study has illustrated the power of electrospray
      mass spectrometry for the rapid and reliable identification of peptides in
      chromatographic fractions without the need to use radioimmunoassay, radioreceptor
      assay or bioassay.

PMID- 12475388
TI  - Modulation of the peroxisomal gene expression pattern by dehydroepiandrosterone
      and vitamin D: therapeutic implications.
AB  - Peroxisomes are ubiquitous organelles required for several metabolic functions.
      Their dysfunction is responsible for a group of human inherited disorders. In the
      search for endogenous factors regulating the peroxisomal compartment in normal
      liver, we treated female rats with dehydroepiandrosterone (DHEA) and 25
      hydroxycholecalciferol for 1 and 6 days. Relative transcription levels of 39
      selected genes were evaluated by real-time quantitative RT-PCR analysis. Catalase
      (peroxisomal marker)-specific activity was assayed in total liver homogenate and
      peroxisomes were visualized by catalase localization. DHEA induced peroxisome
      proliferation and raised catalase specific activity. Expression levels of 16 (of
      which 11 were peroxisomal) genes were altered. Pex 11, acyl-CoA oxidase,l - andd 
      multifunctional enzyme, thiolase 1, phytanoyl-CoA hydroxylase, 70 kDa peroxisomal
      membrane protein and very long chain acyl-CoA synthetase were upregulated, three
      others were downregulated. Vitamin D caused downregulation of six genes.
      Administration of vitamin D to peroxisomal disorder patients may be
      contraindicated. The adrenocortical hormone DHEA is a potential natural regulator
      of the peroxisomal compartment. Its therapeutic use in X-linked
      adrenoleukodystrophy, some other beta-oxidation defects and classical Refsum
      should be considered.

PMID- 12475389
TI  - Protein tyrosine phosphatases are involved in LH/chorionic gonadotropin and 8Br
      cAMP regulation of steroidogenesis and StAR protein levels in MA-10 Leydig cells.
AB  - The LH signal transduction pathway features the activation of protein tyrosine
      phosphatases (PTPs) as one of the components of a cascade that includes other
      well characterized events such as cAMP-dependent protein kinase A (PKA)
      activation. Moreover, the action of PTPs is required to increase the rate
      limiting step in steroid biosynthesis, namely the cAMP-regulated transfer of
      cholesterol to the inner mitochondrial membrane. Since both PKA activity and
      steroidogenic acute regulatory (StAR) protein induction are obligatory steps in
      this transfer of cholesterol, the present study was performed to investigate the
      role of PTPs in the regulation of PKA activity and StAR expression in response to
      LH/chorionic gonadotropin (CG) and 8Br-cAMP in MA-10 cells. While the exposure of
      MA-10 cells to the PTP inhibitor, phenylarsine oxide (PAO), did not modify PKA
      activity, it partially inhibited the effect of human CG and cAMP analog on StAR
      protein levels. Time-course studies demonstrated that PAO inhibited cAMP
      induction of StAR protein and mRNA. At 30 min, the effect on cAMP-stimulated StAR
      protein levels was a 35% inhibition, progressing to up to 90% inhibition at 120
      min of stimulation. The maximal inhibitory effect on cAMP-induced StAR mRNA level
      was obtained at 60 min (85%). In summary, these results demonstrate that
      inhibition of PTP activity affected both StAR protein and mRNA synthesis and
      suggest that the activity of hormone-regulated PTPs is a requirement in the LH
      signaling cascade that results in the up-regulation of StAR protein and,
      subsequently, increased steroid synthesis.

PMID- 12475390
TI  - Tumor necrosis factor-alpha inhibits glutathione S-transferase-alpha expression
      in cultured porcine Sertoli cells.
AB  - Glutathione S-transferases (GSTs) are a family of soluble enzymes of
      detoxification that use reduced glutathione in conjugation and reduction
      reactions. Toxic electrophiles are substrates for the GSTs. GSTalpha is expressed
      at high levels in different tIssues such as the testis. Among the different GSTs
      present in the testis, GSTalpha is specifically expressed in Leydig and Sertoli
      cells known to be under the control of hormonal and local regulatory factors. The
      present study investigated the regulatory action of tumor necrosis factor-alpha
      (TNFalpha) on basal and hormone (FSH and testosterone)-stimulated GSTalpha
      expression in cultured Sertoli cells. Treatment with TNFalpha (0-20 ng/ml, 48 h)
      induced a decrease in basal GSTalpha mRNA levels in a dose-dependent manner
      (fivefold decrease; P<0.001). The maximal and half maximal effects were observed
      at 20 ng/ml and 7 ng/ml respectively. The inhibitory effect of TNFalpha was also
      time-dependent with a maximal inhibitory effect (threefold decrease; P<0.001)
      observed at 48 h. The inhibitory effect of the cytokine was also observed on
      basal GSTalpha protein (28 kDa) levels. TNFalpha also inhibited the hormone
      stimulated GSTalpha expression in Sertoli cells. The treatment of cultured
      Sertoli cells with both FSH and TNFalpha (100 ng/ml and 10 ng/ml respectively, 48
      h) resulted in a complete suppression of the stimulatory action of FSH on
      GSTalpha mRNA levels. Similarly, in Sertoli cells treated with testosterone or
      its non-aromatizable metabolite dihydrotestosterone (100 ng/ml, 24 h), TNFalpha
      reduced the hormone-stimulated GSTalpha mRNA and protein levels. TNFalpha
      inhibited basal GSTalpha expression without affecting mRNA stability. Indeed, the
      decay curves (mRNA half-life time=18 h) for the GSTalpha basal mRNA levels in
      Sertoli cells was similar in the absence or presence of TNFalpha (10 ng/ml, 48
      h). Testosterone increased GSTalpha mRNA without affecting the enzyme mRNA
      stability. TNFalpha antagonized the androgen-stimulated GSTalpha mRNA levels
      without affecting the enzyme mRNA stability, suggesting that the interaction
      between the androgen and the cytokine is mostly exerted at a transcriptional
      level. FSH increased GSTalpha mRNA levels through an increase in mRNA stability
      (increased mRNA half-life times to 119 h). TNFalpha antagonized the stimulatory
      effect of FSH on GSTalpha mRNA levels by antagonizing the stabilizing effect
      exerted by the hormone on GSTalpha mRNA. Together, these results suggest that the
      increase in the cytokine levels within the testis would alter the detoxification
      processes against genotoxic products during spermatogenesis.

PMID- 12475391
TI  - Pharmacokinetics, safety and tolerability of three dosage regimens of buccal
      adhesive testosterone tablets in healthy men suppressed with leuprorelin.
AB  - We used a randomised, double-blind, crossover design to evaluate the
      pharmacokinetics, safety and tolerability of three doses of buccal adhesive
      testosterone tablets (BATT). Twenty-four healthy men, whose endogenous
      testosterone was suppressed to </=5.38 nmol/l with leuprorelin acetate, took BATT
      (10, 20 or 30 mg) daily for 10 days. There was a 4-day washout between
      treatments. Substantial testosterone absorption occurred from BATT, and mean
      serum testosterone, free testosterone and dihydrotestosterone (DHT)
      concentrations over 24 h showed circadian variation. Steady state was reached by
      day 5. Average 24-h concentrations for the three BATT doses were within the
      normal range for eugonadal men: testosterone 11.67-14.57 nmol/l, free
      testosterone 0.026-0.33 nmol/l and DHT 1.66-2.03 nmol/l. On all three doses, peak
      testosterone and free testosterone was reached 8-9 h after tablet application;
      DHT peaked about 1-2 h later, and declined more slowly. Hormone concentrations
      increased with BATT dose, but increases were less than dose-proportional. There
      was no evidence of testosterone accumulation. BATT was well tolerated.

PMID- 12475392
TI  - 16K prolactin induces NF-kappaB activation in pulmonary fibroblasts.
AB  - The amino-terminal 16 kDa fragment of prolactin (16K PRL) promotes the expression
      of the inducible isoform of nitric oxide synthase (iNOS) accompanied by the
      production of nitric oxide (NO) by rat pulmonary fibroblasts. The present study
      was designed to elucidate whether the mechanism by which 16K PRL promotes iNOS
      expression involves the activation of nuclear factor-kappa B (NF-kappaB), a key
      transcription factor for iNOS induction. 16K PRL stimulated DNA-binding activity
      of NF-kappaB in pulmonary fibroblasts as demonstrated by gel shift assays.
      Likewise, fluorescence immunocytochemistry showed that 16K PRL promotes nuclear
      translocation of the p65 subunit of NF-kappaB. Finally, treatment with 16K PRL
      induced the degradation of the NF-kappaB inhibitor kappaB-beta (IkappaB-beta),
      and such degradation was prevented by blocking IkappaB-beta phosphorylation.
      Altogether, these results show that 16K PRL activates NF-kappaB nuclear
      translocation via the phosphorylation and degradation of IkappaB-beta. These
      findings are consistent with NF-kappaB being part of the signal transduction
      pathway activated by 16K PRL to induce iNOS expression.

PMID- 12475393
TI  - Cbl-ArgBP2 complex mediates ubiquitination and degradation of c-Abl.
AB  - The mechanisms leading to the ubiquitination and degradation of the activated c
      Abl kinase have not yet been identified. We found that the multi-adaptor protein
      ArgBP2 links c-Abl to the ubiquitin ligase Cbl. Phosphorylation of Cbl and ArgBP2
      by c-Abl resulted in the stabilization of their interactions, thus facilitating
      Cbl-induced ubiquitination and subsequent degradation of c-Abl and ArgBP2.

PMID- 12475394
TI  - Evidence for a direct interaction between the Thr11 residue of vasoactive
      intestinal polypeptide and Tyr184 located in the first extracellular loop of the
      VPAC2 receptor.
AB  - We developed previously VPAC(1) [vasoactive intestinal peptide (VIP)/pituitary
      adenylate cyclase-activating peptide (PACAP) receptor]>VPAC(2) receptor selective
      ligands. Replacement of the VIP-Thr(11) by an Arg(11) in these ligands
      contributed to their selectivity: Arg(11)-VIP had a 200-fold lower affinity when
      compared with VIP at VPAC(2) receptors as opposed to 3- to 5-fold higher affinity
      at VPAC(1) receptors. Comparison of the binding and functional properties of
      related VIP analogues suggested that the VPAC(1) selectivity of Arg(11)-VIP was
      due to the loss of a hydrogen bond between the hydroxy group of Thr residue and
      the VPAC(2) receptor, steric hindrance between the Arg side chain and the VPAC(2)
      receptor and charge attraction by the VPAC(1) receptor. Comparison of the ability
      of VIP analogues to activate adenylate cyclase through chimaeric VPAC(1)/VPAC(2)
      and VPAC(2)/VPAC(1) receptors indicated that the first extracellular receptor
      loop carried most of the VPAC(2) receptors' ability to discriminate VIP from
      Arg(11)-VIP. Based on results obtained for a truncated VPAC(2) receptor and the
      closely related PACAP-preferring receptor (PAC(1)) and secretin receptors, we
      hypothesized that Thr(11) interacted with the VPAC(2) receptor Tyr(184) (similar
      to the VPAC(1) receptor Phe(200) residue). The Y184F (Tyr(184)-->Phe) VPAC(2)
      mutant lost the ability to discriminate VIP from Val(11)-VIP, and the F200Y
      VPAC(1) mutant acquired the ability to discriminate the natural peptide from
      Val(11)-VIP. These results support the hypothesis that the hydroxy group of the
      native VIP-Thr(11) side chain can indeed form a hydrogen bond with the Tyr side
      chain in the VPAC(2) receptor.

PMID- 12475395
TI  - Sarcomere length-dependence of activity-dependent twitch potentiation in mouse
      skeletal muscle.
AB  - BACKGROUND: It has been reported that potentiation of a skeletal muscle twitch
      response is proportional to muscle length with a negative slope during staircase,
      and a positive slope during posttetanic potentiation. This study was done to
      directly compare staircase and posttetanic responses with measurement of
      sarcomere length to compare their length-dependence. METHODS: Mouse extensor
      digitorum longus (EDL) muscles were dissected to small bundles of fibers, which
      permit measurement of sarcomere length (SL), by laser diffraction. In vitro fixed
      end contractions of EDL fiber bundles were elicited at 22 degrees C and 35
      degrees C at sarcomere lengths ranging from 2.35 microm to 3.85 microm. Twitch
      contractions were assessed before and after 1.5 s of 75 Hz stimulation at 22
      degrees C or during 10 s of 10 Hz stimulation at 22 degrees C or 35 degrees C.
      RESULTS: Staircase potentiation was greater at 35 degrees C than 22 degrees C,
      and the relative magnitude of the twitch contraction (Pt*/Pt) was proportional to
      sarcomere length with a negative slope, over the range 2.3 microm - 3.7 microm.
      Linear regression yielded the following: Pt*/Pt = -0.59 x SL+3.27 (r2 = 0.74);
      Pt*/Pt = -0.39 x SL+2.34 (r2 = 0.48); and Pt*/Pt = -0.50 x SL+2.45 (r2 = 0.80)
      for staircase at 35 degrees C, and 22 degrees C and posttetanic response
      respectively. Posttetanic depression rather than potentiation was present at long
      SL. This indicates that there may be two processes operating in these muscles to
      modulate the force: one that enhances and a second that depresses the force.
      Either or both of these processes may have a length-dependence of its mechanism.
      CONCLUSION: There is no evidence that posttetanic potentiation is fundamentally
      different from staircase in these muscles.

PMID- 12475396
TI  - Increased expression of AP2 and Sp1 transcription factors in human thyroid
      tumors: a role in NIS expression regulation?
AB  - BACKGROUND: Sodium/iodide symporter (NIS) is a key protein in iodide transport by
      thyroid cells and this activity is a prerequisite for effective radioiodide
      treatment of thyroid cancer. In the majority of thyroid cancers, however, iodide
      uptake is reduced, probably as a result of decreased NIS protein expression.
      METHODS: To identify the mechanisms that negatively affect NIS expression in
      thyroid tumors, we performed electrophoresis mobility shift assays and immunoblot
      analysis of nuclear protein extracts from normal and tumoral thyroid tissues from
      14 unrelated patients. RESULTS: Two proteins closely related to the transcription
      factors AP2 and Sp1 were identified in the nuclear extracts. Expression of both
      AP2 and Sp1 in nuclear extracts from thyroid tumors was significantly higher than
      that observed in corresponding normal tissues. CONCLUSION: These observations
      raise the possibility that NIS expression, and subsequently iodide transport, are
      reduced in thyroid tumors at least in part owing to alterations in the binding
      activity of AP2 and Sp1 transcription factors to NIS promoter.

PMID- 12475397
TI  - Effect of treating periodontitis on C-reactive protein levels: a pilot study.
AB  - BACKGROUND: Periodontitis is associated with elevated levels of C-reactive
      protein and fibrinogen and it may be a coronary heart disease risk factor. We
      wanted to study if treatment of periodontitis can decrease the levels of these
      inflammatory markers. METHODS: C-reactive protein and fibrinogen levels were
      measured in 35 patients (21 M, 14 F, mean age 50 years) with adult periodontitis,
      before and after treatment. RESULTS: The median baseline C-reactive protein level
      in the patients was 1.05 mg/l and it decreased to 0.7 mg/l (p = 0.05) after
      periodontal treatment. Of the 30 patients who could be included in the analyses,
      24 patients had a baseline level below 2 mg/l (the 95th percentile limit in
      Finland); 6 patients had levels higher than this. Elevation of the baseline C
      reactive protein level or the magnitude of its decrease were not associated with
      severe form of periodontitis. The decrease in C-reactive protein levels was at
      least 50 % in 4/6 of those with elevated baseline levels, as compared with 3/24
      of the rest of the patients (p = 0.016). No corresponding effect was observed in
      fibrinogen levels. CONCLUSIONS: Periodontitis seems to increase C-reactive
      protein only in some individuals, presumably the ones reacting to it with a
      systemic inflammatory reaction. Periodontal treatment decreases C-reactive
      protein levels in these individuals and it may thus decrease their risk of
      coronary heart disease.

PMID- 12475398
TI  - A stable aberrant immunophenotype characterizes nearly all cases of cutaneous T
      cell lymphoma in blood and can be used to monitor response to therapy.
AB  - BACKGROUND: Abnormal variations in the expression level of some commonly
      expressed T-cell antigens are a feature of many T-cell malignancies. METHODS: We
      sought to assess the frequency of such abnormal antigen expression by flow
      cytometry in peripheral blood (PB) samples from patients with mycosis fungoides
      (MF) and Sezary syndrome (SS). We correlated presence of morphologically
      identifiable tumor cells on PB smear with the frequency of abnormalities in the
      level of expression of CD3, CD4, CD7, CD8 and CD26. We also examined the degree
      of stability of these abnormal findings in tumor cells over the course of
      disease. The flow cytometric findings in 100 PB samples from 44 patients,
      including 38 who had multiple sequential PB samples (2-8 samples each), were
      assessed. RESULTS: Abnormalities were seen in the expression level of one or more
      T-cell markers in 41 cases (93%) including CD3 in 34% of patients, CD4 in 54%,
      CD26 in 86% and CD 45 in 40% (10 cases tested). In all but 2 cases, the abnormal
      T-cell immunophenotype remained similar over the course of treatment and
      correlated with the relative numbers of tumor cells counted on PB smear.
      CONCLUSIONS: Using a standard T-cell panel, stable phenotypically aberrant T-cell
      populations representing the tumor are detected in the vast majority of involved
      PB samples in MF/SS and can be used to monitor response to therapy.

PMID- 12475399
TI  - [The randomized controlled trial of isosorbide mononitrate plus propranolol
      compared with propranolol alone for the prevention of variceal rebleeding].
AB  - OBJECTIVE: The aim of this study was to test the effectiveness of isosorbide-5
      mononitrate (IM) as an adjunct to propranolol (PR) in the prevention of variceal
      rebleeding. METHODS: Seventy-six cirrhotic patients with variceal bleeding were
      randomly assigned to treatment with PR + IM (34 patients) or PR alone (32
      patients). RESULTS: Seven patients in the PR + IM group and 13 in the PR group
      had rebleeding during the 1 year after randomization. The actuarial probability
      of rebleeding 1 years after randomization was lower in the PR + IM group but the
      difference was not significant (P = 0.09). However, by adding an additional 8
      months of follow-up, the decrease in the risk of rebleeding reached statistical
      significance (P = 0.05). No significant difference was found in rebleeding index
      and survival. The multivariate Cox analysis indicated both treatment (P = 0.04),
      severity of liver disease (P = 0.03) and age (P = 0.045) were factors predictive
      of rebleeding and second, that PR + MI reduced the risk of rebleeding by half
      (relative risk: 0.54). CONCLUSION: These results suggest that the addition of IM
      improves the efficacy of PR alone in the prevention of variceal rebleeding in
      cirrhotic patients. However no beneficial effects were observed on other
      parameters reflecting the efficacy of treatment.

PMID- 12475401
TI  - [Retrospective comparative analysis of intranasal endoscopic resection of
      sinonasal tumors].
AB  - OBJECTIVE: To investigate the effectiveness and indication of intranasal
      endoscopic resection of sinonasal benign tumors. METHODS: A retrospective
      comparative study was made of intranasal endoscopy among twelve patients with
      benign tumors and twelve patients with inverting papilloma of the nose and
      paranasal sinuses between October 1996 and June 2001. A follow-up was made for
      ten months to five years. RESULTS: Of the twelve cases of benign tumors, five
      cases of hemangioma including one case of nasopharyngeal angiofibroma, one case
      of fibroma and one case of neurofibroma as well as one case of benign
      fibromatosis of nasal ethmoid sinus were completely excised without any evidence
      of recurrence so far. Of the four patients with ossifying fibromas, two cases
      with ethmoid sinus invasion underwent successful total removal without any
      recurrence three years after operation, one case was completely ablated after
      second procedure and another case had her tumor subtotally resected with symptom
      remission. Of the twelve cases of inverting papilloma among which two patients
      had cancerated, eight achieved complete resection at first attempt, and the
      remaining four cases having either persistence or recurrence of tumor also got
      cured via endoscopic YAG laser or revision procedure. All these 12 patients
      except one were followed up for two to five years without any recurrence.
      CONCLUSION: With excellent visualization, a less operative invasiveness and no
      scar on face the endoscopic approach appears to be the method of choice for the
      treatment of some benign tumors including inverting papilloma of nose and
      paranasal sinuses.

PMID- 12475400
TI  - [Effects of antisense transforming growth factor beta receptor-I expressing
      plasmid on pig serum-induced rat liver fibrosis].
AB  - OBJECTIVE: To observe the effects of antisense transforming growth factor beta
      receptor-I (TbetaRI) expressing plasmid on rat liver fibrosis. METHODS: RT-nested
      PCR and gene recombinant techniques were used to construct the rat antisense
      TbetaRI recombinant plasmid which can be expressed in eucaryotic cells. The
      recombinant plasmid and blanx vector (pcDNA3) were encapsulated by glycosyl-poly
      L-lysine and then transducted into rats of pig serum-induced liver fibrosis model
      respectively. Expression of exogenous transfected plasmid was assessed by
      Northern blot, RT-PCR, Western blot and immunohistochemistry. Serum TGF-beta(1)
      was determined by ELISA. The content of hepatic hydroxyproline was tested.
      Immunohistochemistry was used to test type I and III collagen. VG staining was
      used for pathological study. RESULTS: The exogenous antisense TbetaRI could be
      expressed in vivo, and could block the mRNA and protein expression of TbetaRI in
      the fibrotic liver induced by pig serum. Its expression also reduced the level of
      TGF-beta(1) (P < 0.05) and decreased the the contents of hepatic hydroxyproline
      and the deposition of collagens type I and type III (P < 0.01). And its
      expression also improved the pathologic classification of liver fibrosis models
      (P < 0.01). CONCLUSIONS: The results demonstrate that the antisense TbetaRI
      recombinant plasmid has certain extern reverse effect on liver fibrosis and make
      it as a possible candidate for use in future gene therapy.

PMID- 12475402
TI  - [Expression of receptors for advanced glycation end products at surface of
      peripheral blood monocytes and relationship thereof to plasma proinflammatory
      cytokines in patients undergoing hemodialysis].
AB  - OBJECTIVE: To elucidate the relationship between the expression of receptors for
      AGE (RAGE) at the surface of monocyte and the plasma levels of tumor necrosis
      factor alpha (TNFalpha) and interleukin-1beta (IL-1beta), proinflammatory
      cytokines in patients with chronic renal failure (CRF) undergoing hemodialysis
      (HD). METHODS: Human serum albumin modified with AGE (AGE-HSA) was prepared in
      vitro and was radiolabeled with (125)I. Human peripheral blood monocytes were
      isolated from 59 CRF patients (37 of which underwent hemodialysis) and 30 normal
      volunteers by Ficoll-hypaque centrifugation technique. Specific binding of AGE
      HSA to monocytes was analyzed by radioactive ligand-receptor binding assay. The
      degradation to AGE-HSA by monocytes was measured by trichloroacetic acid
      precipitation method. The expression of REGE in monocytes was determined by flow
      cytometry. The levels of TNFalpha and IL-1beta were detected by a sandwich enzyme
      immunoassay. RESULTS: The specific binding of (125)I-AGE-HSA to monocytes was
      41.4 fmol/10(5) cells +/- 2.2 fmol/10(5) cells, significantly higher than that in
      normal controls (31.6 fmol/10(5) cells +/- 4.1 fmol/10(5) cells, P < 0.05). The
      number of AGE conjugated protein at the monocytes' surface of CRF patients
      undergoing HD was 2.42 +/- 0.21 x 10(5)/cells, significantly higher than that in
      normal controls (1.74 +/- 0.29 x 10(5)/cells, P < 0.001), and the affinity
      constant (Kd) of the monocytes of CRF patients undergoing HD was 228 nmol/L +/-
      100 nmol/L, not significantly different from that in normal controls (262 nmol/L
      +/- 108 nmol/L, P > 0.05). The degration rate of AGE-HAS by monocytes in CRF
      patients undergoing HD was 25.24% +/- 4.35%, significantly higher than that in
      normal controls (18% +/- 0.6%, P < 0.05). The fluorescent intensity of RAGE at
      the surface of monocytes in CRF patients undergoing HD was 3.68 +/- 0.42,
      significantly higher than that in normal controls (1.09 +/- 0.37, P < 0.05), When
      the monocytes were incubated in vitro with 50 microgram/ml of AGE-HSA, the levels
      of TNFalpha and IL-1beta in the supernatants of CRF patients undergoing HD were
      197 +/- 98 ng/L and 357.0 +/- 140.1 ng/L respectively, both significantly higher
      than those in the normal controls (111 +/- 77 ng/L and 184 +/- 118 ng/L
      respectively, both P < 0.05). The secretion of proinflammatory cytokines was
      inhibited when the monocytes were preincubated with anti-RAGE. Increased RAGE
      level was accompanied by higher plasma levels of TNFalpha and IL-1beta.
      CONCLUSION: The expression of AGE receptors in monocytes is up-regulated in
      patients with CRF. This may contribute to the enhanced plasma level of
      proinflammatory cytokines seen in HD patients.

PMID- 12475403
TI  - [Association of 5-HT(2A) receptor polymorphism and attention deficit
      hyperactivity disorder in children].
AB  - OBJECTIVE: To stude the association of 5-HT(2A) receptor polymorphism and
      attention deficit hyperactivity disorder (ADHD) in children. METHODS: Blood
      samples were taken from 323 6 approximately 17.5-year-old children with ADHD
      disgnosed based on the DSM-IV criteria, 182 healthy 18 approximately 49-year-old
      controls, and 195 pairs of parents of affected children, all of Han nationality.
      DNA was extracted. PCR was performed to examine the 5-hydroxytryptamine (5
      HT)(2A) receptor T102C polymorphism. Transmission disequilibrium test (TDT) was
      used to test the association of alleles of 5-HT(2A) T102C polymorphic sites and
      AFDHD. RESULTS: The frequency of T102T in patients with ADHD combined subtype was
      lower than that in the controls (22.35 vs 33.5%, OR = 0.569, P = 0.028, 95% CI
      0.344 - 0.943), and the frequency of T102C in patients with ADHD combined subtype
      was higher than that in the controls (64.0% vs 47.3%, OR = 1.987, P = 0.003, 95%
      CI 1.264 approximately 3.124). TDT showed biased transmission of the alleles of
      T102C polymorphism among families of girl patients with ADHD combined subtype (P
      = 0.031). CONCLUSION: For the ADHD combined subtype, the T102T genotype is a
      protective factor and the T102C genotype is a risk factor. For the girl with ADHD
      combined subtype, the allele C102 is a disease-predisposing gene.

PMID- 12475404
TI  - [Correlation of expression levels of multidrug resistance gene 1 (mdr1) mRNA,
      multidrug resistance-associated protein (MRP), amd P-glycoprotein (P-gp) with
      chemotherapy efficacy in malignant lymphomas].
AB  - OBJECTIVE: To explore the correlation of chemotherapy efficacy in malignant
      lymphomas with the expression level of multidrug resistance gene 1 (mdr1) mRNA,
      multidrug resistance-associated protein (MRP), and P-glycoprotein (P-gp).
      METHODS: Using the methods of semi quantitative reverse transcriptase polymerase
      chain reaction (RT-PCR) and flow cytometry (FCM), a prospective research was
      performed to detect the expression levels of molrl gene, MRP gene, and p-gp in
      the lymph nodes of 23 untreated first visit (HD1, NHL 22) and 23 recurrent (HD 5,
      NHL 18) lymphoma patients. Eight normal human lymph nooles were used as controls.
      RESULTS: The expression levels and positive rates of mdr1 and P-gp in recurrent
      patients were higher than those in untreated patients (P < 0.001). There was no
      difference in MRP gene expression level and positive rate between recurrent and
      untreated patients (P > 0.05). The chemotherapy effective rates were lower in
      mdr1 gene and P-gp positive expression patients (33.33% and 26.67%) than in
      negative expression patients (85.71% and 83.87%) (P < 0.001). Relevant analysis
      showed that there was a significant relevance in expression level between mdr1
      gene and P-gp (r = 0.296 3, P < 0.05), but there was no correlation between mdr1
      and MRP or between MRP and P-gp (r = 0.072 3, P > 0.05; r = 0.081 8, P > 0.05).
      CONCLUSION: mdr1 gene and P-gp expression levels are dominant mechanisms of
      clinical drug resistance of lymphomas, whereas, MRP gene appears to play no role
      in that course. mdr1 gene and P-gp expression levels are relevant to chemotherapy
      efficacy, however, MRP gene expression level seems to have no impact on it.

PMID- 12475405
TI  - [Solid and cystic tumor of pancreas, analysis of 14 pediatric cases].
AB  - OBJECTIVE: To study the clinical manifestations, diagnosis, and treatment of
      solid and cystic tumor of pancreas (SCTP). METHODS: The clinical data, including
      clinical manifestations, imaging examination, pathology, and methodology and
      effect of surgical treatment, of 14 children with SCTP, one boy and 13 girls,
      aged 9 approximately 14, admitted to Beijing Children's Hospital November 1985
      approximately March 2002 were collected and analyzed. RESULTS: The symptoms
      included abdominal pain (64.3%, 9/14), abdominal mass (50%, 7/14), and jaundice
      (21.4%, 3/14). The levels of alpha-fetoprotein, carcinoembryonic antigen, and
      CA199 were normal. Test of neuron specific enolase (NSE) made in 2 patients (a 10
      year girl and a 13-year girl) showed increased levels (267.4 micro g/ml and 124
      micro g/ml). Test of estrogen (E(2)) made in these 2 patients showed increased
      levels (0.3 ng/ml and 42.7 ng/ml) too. Test of lactate dehydrogenase (LDH) was
      made in one case and showed an increased level. Ultrasonography and CT scanning
      showed a round and well-circumscribed mass in the pancreas, 3 approximately 15 cm
      in diameter and with a little calcification, 7 masses in the head of pancreas, 3
      in the body, and 2 in the tail. Local resection was performed on 2 patients and
      the other 12 underwent radical surgery with total splenectomy (4 cases) or
      partial splenectomy (1 case). Local infiltration was seen in only one case. One
      week after the operation the NSE level decreased to normal (9.5 micro g/ml and
      8.7 micro g/ml) and the E(2) level decreased by more than 50% (17.5 ng/ml and
      20.7 ng/ml) in the 2 patients. Follow-up of one month to 16 years showed that all
      patients survived without recurrence and metastasis. CONCLUSION: SCTP, a rare
      tumor with low malignancy or a bordering tumor, is mostly seen in teenage girls.
      Imaging examination is helpful in diagnosis. Radical surgery is the best choice.

PMID- 12475406
TI  - [Relationship between insulin resistance and cardiovascular risk factors
      clustering: an epidemiological study].
AB  - OBJECTIVE: To study the relationship between insulin resistance and
      cardiovascular risk factor clustering. METHODS: The height, body weight, waist
      circumference, and hip circumference were measured, and fasting venous blood was
      drawn among 1 196 rural residents, 533 males (44.57%) and 663 females (55.43%),
      aged 35 approximately 59 with the average age of 46.69, in Pizhou City, Jiangsu
      Province, selected by random sampling. Fasting serum true insulin (TI) was
      determined by ELISA. Blood lipids were measured by completely automatic
      biochemical analyzer. Homeostasis model assessment (HOMA) index was calculated
      and used as the indicator to evaluate insulin resistance. The statistic methods,
      such as Spearman correlation, partial correlation and multivariate Logistic
      regression were used to study the relationship between insulin resistance and
      hypertension, overweight, visceral obesity, dyslipidemia and cardiovascular risk
      factors clustering. RESULTS: The median (Q(R)) of TI and HOMA index were 4.89
      (3.02 approximately 7.09) mIU/L and 0.98 (0.57 approximately 1.44) respectively,
      and TI and HOMA index of the female subjects were significantly higher than those
      of the male subjects (P < 0.01). The correlation coefficient between HOMA index
      and cardiovascular risk factors number was 0.290 (P < 0.01) by Spearman
      correlation analysis and 0.177 6 (P < 0.01) by partial correlation analysis after
      adjustment by age, sex, body mass index and waist circumference respectively. The
      results of non-conditional multivariate stepwise Logistic regression indicated
      that insulin resistance associated with cardiovascular risk factors aggregation
      and was independent of age, sex, body mass index and waist circumference, and the
      odds ratio (95% CI) was 1.250 (1.089 approximately 1.434). CONCLUSION: Insulin
      resistance may be a common pathogenetic mechanism of cardiovascular risk factor
      dustering.

PMID- 12475407
TI  - [The effect of basic fibroblast growth factor on myofibroblasts and its
      significance on wound healing].
AB  - OBJECTIVE: To observe the effect of basic fibroblast growth factor (bFGF) on the
      outcome of myofibroblasts in burn wounds, and to further explore the mechanism of
      bFGF on wound healing. METHODS: Seventy-two Wistar rats were anaesthetized and
      put into hot water at the temperature of 98 degrees C with their back hair cut so
      as to cause full-thickness scald injury with an area of 30% of the total body
      surface. Then the rats were randomly divided into two groups of 36 mice: pure
      thermal injury group (administered with sterilization and dressing every other
      day for three times) and bFGF treatment group (administered locally with bFGF
      every other day in addition to the routine dressing). Three hours, six hours, one
      day, three days, seven days, and fourteen days after scalding samples of skin
      wound was taken, six rats for each time-point. Six rats were put into water at
      the temperature of 37 degrees C as controls and their skin samples were taken 8s
      after. In situ hybridization and immunohistochemical techniques were employed to
      detect the expression of caspase mRNA and proteins. alpha-smooth muscle actin
      (ASMA), and transforming growth factor-beta1 (TGF-beta1) were detected by
      immunohistochemical staining at different time points after scalding. RESULTS: No
      obvious difference of ASMA expression in dermal tissues was seen at the early
      stage of injury. The number of cells with positive ASMA expression began to
      increase 1 approximately 3 days after and reached the peak by the 7th day after
      scalding, and then decreased gradually. The ASMA expression in bFGF group was
      remarkably increased by the 7th day, significantly higher than that in the pure
      thermal injury group (P < 0.05). By the 14th day, the ASMA expression in the bFGF
      group was still significantly higher than that in pure thermal injury group (P <
      0.01), however, it was much lower than that in the bFGF group by the 7th day. By
      the 14th days after scald injury. The number of TGF-beta1 positive cells began to
      increase since the 3rd hour after scald injury and began to decrease by the 14th
      day in both experimental groups. However, the TGF-beta1 expression in bFGF group
      was stronger than that in pure thermal injury group. The expressions of caspase-3
      mRNA and protein in bFGF group changed in the same way as in the simple injured
      group. Three hours after injury, the expression of caspase-3 mRNA was lower in
      bFGF group than in pure injury group (P < 0.05). Then the expression decreased
      till the 3rd day. Six hours after injury, no difference in the expression of
      caspase-3 mRNA was found between the two experimental groups. The expression of
      caspase-3 reached its second peak by the 7th day and then decreased again.
      However, the first expression peak of the bFGF group was lower than that of the
      pure thermal injury group, however, the second peak of the bFGF group was higher.
      CONCLUSION: Myofibroblasts may play a critical role in wound closure and healing.
      bFGF treatment may increase the expression of TGF-beta1 and have a potential
      synergistic effect with other growth factors to stimulate the apoptosis of
      myofibroblasts during wound healing.

PMID- 12475408
TI  - [Protective and rescue effects of transgenic bFGF/GFP expression mediated by
      cationic liposome on gentamicin-induced guinea pig cochlear toxicity].
AB  - OBJECTIVE: To observe the expression of cationic stearylamine (SA) liposome
      mediated basic fibroblast growth factor/green fluorescence protein (bFGF/GFP)
      gene in the cochlea of guinea pig, and evaluate the protection and rescue action
      of bFGF against the damage caused by gentamicin. METHODS: Thirty-six guinea pigs
      were divided into 3 experimental groups. Prevention group with inoculation of SA
      bFGF/GFP complexes through the round window of right ear and injection of
      gentamicin 150 mg.kg(-1).d(-1) one day after for 8 days and rescue group with
      injection of gentamicin for 8 days and infusion of SA-bFGF/GFP complexes in the
      same way on the ninth day, and control group with only injection of gentamicin
      for 8 days. Auditory brainstem responses (ABR) was measured prior to and after
      the administration and before the animals were killed respectively. The animals
      were killed after the experiment and ABR test, and specimens and slices of
      chochleae were made to examine the absence of outer and inner hair cells. The
      expression of GFP in cochlea shown by green fluorescence was observed with
      fluorescent microscopy. RESULTS: Fluorescent microscopy showed green fluorescence
      in the cochleae of guinea pigs in prevention and rescue groups. There was no
      significant difference in ABR threshold between the left and right ears of
      animals in each group before and after experiment, among both ears of animals in
      the 3 groups before experiment, and between prevention and rescue group groups
      before killing (all P > 0.05). However, the ABR thresholds in prevention group
      and rescue group were significantly lower than that in control group before the
      animals were killed (P < 0.01 and P < 0.05). The average number of lost outer
      hair cells was 5 106 +/- 299 cells and 5 605 +/- 109 cells in prevention group
      and rescue group respectively, without a significant difference between them (P >
      0.05). The average amount of missing inner hair cells was 301 +/- 64 cells and
      487 +/- 92 cells in prevention group and rescue group respectively, without a
      significant difference between them (P > 0.05), and significantly lower than that
      in control group (1 062 +/- 67, P < 0.01 and P < 0.05). The average amount of
      missing outer hair cells in control group was 6 248 +/- 119 cells, significantly
      higher than that in prevention group (5 106 +/- 299, P < 0.01) and that in rescue
      group (5 605 +/- 109, P < 0.05). CONCLUSION: SA-liposome mediated bFGF/GFP gene,
      which was perfused in one ear, can be expressed highly in both cochleae of the
      guinea pig, and may protect and rescue cochlea against gentamicin ototoxicity.

PMID- 12475409
TI  - [The functional and phenotypic analysis of T lymphocytes under stimulation of
      THANK].
AB  - OBJECTIVE: To study the function of THANK in T lymphocyte immune regulation.
      METHODS: On the basis of THANK gene cloning and expression, isolated T and B
      lymphocytes were stimulated by purified THANK protein and its function in immune
      regulation was investigated by (3)HTdR incorperation and flow cytometric
      analysis. RESULTS: In addition to the costimulation on B cell growth, THANK
      promoted CD3-mediated T cells proliferation, activated resting peripheral blood T
      lymphocytes and induced apoptosis and the phenotypic change of activated T
      lymphocytes. CONCLUSION: THANK is involved in the modulation of T cells phenotype
      and function.

PMID- 12475410
TI  - [Influence of high-frequency electric surgical knife on healing of abdominal
      incision, experimental and clinical studies].
AB  - OBJECTIVE: To study the influence of high-frequency electric surgical knife on
      abdominal incision healing. METHODS: Two hundred and forty Wistar rats were
      randomly divided into two groups of 120 rats to undergo abdominal incision by
      high-frequency electric knife or common lancet respectively. Each of these two
      groups was redivided into four subgroups that were injected hypodermically with
      0.2 ml of quantitative mixture of Escherichia coli, Staphylococcus aureus and
      Pseudomonas aeruginosa at the concentrations of 0.24 x 10(2) bacteria (10(2)
      group), 4.49 x 10(4) bacteria (10(5) group), and 4.11 x 10(7) bacteria (10(8)
      group) respectively, and normal saline of the same volume (10(0) group). Eight
      days after the operation, the rats were killed. The infection rate of the
      operational wound was observed and the tissues around the wounds were examined
      pathologically. On the basis of the animal experiment, 220 patients undergoing
      abdominal operation above type II were randomly allocated into one of following
      three groups: high-frequency electric knife (EK) group (93 cases, high-frequency
      electric knife was used to cut the abdominal tissues and electro-coagulation was
      used for hemostasis), electro-coagulation (EC) group (55 cases, the abdominal
      tissues were cut with common lancet and electro-coagulation was used for
      hemostasis) and control group (72 cases, common lancet and silk thread suture
      were used). The healing of wound was observed after operation. RESULTS: Four rats
      died of anesthetic accident; the other 236 rats were killed 8 days after. The
      wound infection rates were 23.33% and 6.60% in the experimental 10(0) group and
      the control 10(0) group respectively (chi(2) = 3.28, P > 0.05); 37.04% and 13.33%
      in the experimental 10(2) group and the control 10(2) group respectively (chi(2)
      = 4.31, P > 0.05), 50.00% and 24.14% in the experimental 10(5) group and the
      control 10(5) group respectively (chi(2) = 4.22, P > 0.05); and 63.33% and 36.67%
      in the experimental 10(8) group and the control 10(8) group respectively (chi(2)
      = 4.27, P > 0.05). Clinical observation showed a delayed wound healing rate of
      17.20% (16 cases) in EK group, 16.36% (11 cases) in EC group, and 2.86% (2 cases)
      in the control group. There was a statistically significant difference in delayed
      wound healing rate between the EK and control groups (chi(2) = 8.57, P < 0.01)
      and between the EC and control groups (chi(2) = 5.66, P < 0.05). However, no
      significant difference in the delayed wound healing rate was seen between the EK
      and EC groups (chi(2) = 0.017, P > 0.05). CONCLUSION: High-frequency electric
      knife remarkably delays the healing of abdominal incision. Its application should
      be minimized so as to reduce the possibility of postoperative complications.

PMID- 12475411
TI  - [Effect of propofol on protecting Rhesus macaques from reperfusion lung injury
      during hemorrhagic shock and resuscitation].
AB  - OBJECTIVE: To investigate the protective efficacy of propofol against lung injury
      during hemorrhagic shock and resuscitation among Rhesus macaques. METHODS: Two
      healthy rhesus monkeys (Rhesus macaques) were killed and their lungs were taken
      out as samples of normal lung. Two healthy rhesus monkeys were made animal models
      of hemorrhagic shock and then were killed with their lungs taken out as samples
      of hemorrhagic shock lung. Another 12 healthy rhesus monkeys were randomly
      divided into two groups of six animals: propofol group (administered with
      propofol to a plasma concentration of 8 mg/L by target control infusion with
      computer before hemorrhagic shock) and control group. The monkeys were bled
      through the right femoral vein till the mean arterial pressure remained at the
      shock level of 40 mm Hg +/- 5 mm Hg. Two hours later, the total amount of bled
      blood and normal saline of the volume 2 times the volume of blood loss were
      reinfused into the animals quickly. Another 2 hours later hemodynamic parameters
      were measured, and blood samples were taken for measurement of malondialdehyde
      (MDA), superoxidedismutase (SOD) and lactate before bleeding, two hours after
      shock appeared, and 2 hours after resuscitation. The monkeys were killed 2 hours
      after resuscitation; their lungs were taken for pathologic examination and
      determination of water-to-dry weight ratio. RESULTS: The lungs of the 2 normal
      rhesus monkeys were normal with the W/D of 5.545 +/- 0.191. There is not
      remarkable change in the lung constitution of the 2 shock rhesus monkeys with a
      W/D ratio of 5.655 +/- 0.474. The mean pulmonary arterial pressure (MPA) and
      pulmonary vascular resistance index (PVRI) of the control group 2 hours after
      hemorrhagic shock and 2 hours after resuscitation were 17.00 +/- 4.42 and 22.83
      +/- 5.11 respectively, both significantly higher than those of the propofol group
      (10.83 +/- 2.71 and 18.66 +/- 3.38, both P < 0.05). The pulmonary vascular
      resistance index (PVRI) of the control group 2 hours after hemorrhagic shock and
      2 hours after resuscitation were 458.67 +/- 91.92 and 260.17 +/- 57.85
      respectively, both significantly higher than those of the propofol group (258.67
      +/- 63.02 and 159.17 +/- 47.98 respectively, both P < 0.05). The W/D ratio of the
      control group 2 hours after resuscitation was significantly higher than that of
      the propofol group (P < 0.05). The pulmonary edema of the control group was more
      serious than that of the propofol group by light microscopy and electron
      microscopy. CONCLUSION: Propofol remarkably relieves the lung injury occurring
      during hemorrhagic shock and resuscitation stage by ameliorating pulmonary
      circulation.

PMID- 12475412
TI  - [Anti-tumor effect of lentivirus-mediated MUCI antibody-targeted gene therapy
      with VP22-TK system on MUC1(+) human ovarian cancer transplanted
      intraperitoneally in nude mice].
AB  - OBJECTIVE: To investigate the anti-tumor effect of anti-MUCI single-chain
      variable fragment (ScFv)-targeted and lentivirus-mediated herpes simplex virus
      structural protein VP22 and thymidinre kinase (TK) therapy on MUC1(+) human
      ovarian epithelial carcinoma tumor in mice transplanted intraperitoneally.
      METHODS: Lentiviruses scFv-VP22-TK and VP22-TK were constorted Ten female BABL/c
      mice were injected intraperitoneally with MUC1+ human ovarian epithelial
      carcinoma cells line 3AO and then pathological examination was done to those mice
      that died of tumor. A human ovarian epithelial carcinoma model was established in
      another 30 female mice and they were randomly divided into 6 groups of 5 mice: NS
      (normal saline) + NS group (injected intraperitoneally with NS once per day for 3
      days and then with NS 24 h after once a day for 5 days), VP22-TK + NS group
      (injected with herpes simplex virus structural protein VP22 and TK once a day for
      three days and then with NS 24 h after once a day for 5 days), scFv-VP22-TK + NS
      group (injected with scFv-VP22-TK and then NS in the same way), NS + ganciclovir
      (GCV) group (injected with NS and then with GCV), VP22-TK + GCV group (injected
      with VP22-TK and then GCV), and scFv-VP22-TK + GCV group (injected with scFv-VP22
      TK and then GCV). The survival time was observed. Ten female nude mice without
      injection of tumor cells were injected with scFv-VP22-TK or VP22-TK, each for 5
      mice; 3 weeks later their abdominal organs were examined to observe the effects
      of lentivirus on organs. RESULTS: All of the first ten mice injected with human
      ovarian epithelial carcinoma cells died of tumor. The mean survival times of the
      six experimental groups were 18.4 d +/- 2.9 d, 18.8 d +/- 1.5 d, 17.6 d +/- 1.1
      d, 18.5 d +/- 1.6 d, 24 d +/- 5 d, and 46 d +/- 22 d respectively with
      significant differences between the VP22-TK + GCV group and NS + GCV group
      (chi(2) = 6.71, P = 0.009), between the scFv-VP22-TK + GCV group and NS + GCV
      group (chi(2) = 9.7, P = 0.002), and between the scFv-VP22-TK + GCV group and the
      VP22-TK + GCV group (chi(2) = 7.43, P = 0.006). Necrosis and apoptosis could be
      seen in the tumors in the VP22-TK + GCV group and scFV-VP22-TK + GCV group. No
      toxicity was observed in the mice injected with only scFv-VP22-TK or VP22-TK.
      CONCLUSION: The anti-MUCI ScFv-targeted and lentivirus-mediated herpes simplex
      virus VP22 and thymidinre kinase (TK) gene therapy has a significant anti-tumor
      effect on MUC1+ human ovarian epithelial carcinoma.

PMID- 12475413
TI  - [Influence of HPV16 on expression of Rb, p16 and cyclin D1 in oral epithelial
      cell].
AB  - OBJECTIVE: To investigate the role of HPV16E6 and E7 during the transformation of
      oral epithelial cells. METHODS: An human immortalized oral epithelial cell line
      (HIOEC) was established by transfecting HPV16E6, E7 open reading frames using
      recombinant retroviral system plxsn to human normal oral epithelial cells.
      Expression of HPV16E6, E7, Rb, P16 and Cycin D1 were analyzed by Western blot in
      HIOEC and human normal oral epithelial cells. Formation of complex of HPV16E7 and
      Rb were analyzed by Immunoprecipitation-western blot. Human normal oral
      epithelial cells and the oral epithelial cells transfected with plxsn were used
      as control groups. RESULTS: HIOEC expressed HPV16 E6 and E7; HIOEC expressed both
      hyperphosphorylated and underphosphorylated Rb while oral epithelial cells in two
      control groups only expressed hyperphosphorylated Rb. HPV16 E7 formed complex
      with underphosphorylated Rb; the level of P16 and Cyclin D1 had no remarkable
      change. CONCLUSIONS: HPV16E7 plays an important role in the immortalization of
      oral epithelial cells induced by HPV16.

PMID- 12475414
TI  - [An antimetastatic study of Arg-Asp (RD) on salivary adenoid cystic carcinoma in
      vivo].
AB  - OBJECTIVE: To test the antimetastatic effects of Arg-Asp (RD) on salivary adenoid
      cystic carcinoma (SACC-LM) in vivo. METHODS: RD was administered orally to
      experimental metastasized nude mice. The pulmonary metastatic foci number and
      survival were determined to assay the antimetastatic effects of RD. RESULTS: 30
      mg/kg, 120 mg/kg of RD demonstrated an inhibitory effect on the pulmonary
      metastatic foci formation. All of the tested dosages (7.5 mg/kg, 30 mg/kg, 120
      mg/kg) of RD prolonged the survival. CONCLUSIONS: Oral administration of RD has a
      antimetastatic effect on SACC-LM. RD is low toxicity.

PMID- 12475415
TI  - [Relation between the expression of P-gp and GST-pi in oral and maxillofacial
      squamous carcinoma and chemoresistance].
AB  - OBJECTIVE: To investigating the relation between the expression of P-glycoprotein
      and Glutathione transferase-pi and the chemoresistance. METHODS: The expressions
      of these two proteins in patients with oral and maxillofacial squamous carcinoma
      and normal oral tissues were detected by immunohistochemistry. RESULTS: The
      positive expression rate of P-gp and GST-pi in oral and maxillofacial malignant
      tumor was 57.1% and 53.6% respectively, and no expression in normal oral tissues;
      the expression of GST-pi was relevant to the resistance to cisplatin, while the
      expression of P-gp was relevant to the resistance to chemotherapeutic drug in
      general. CONCLUSIONS: The method of immunohistochemistry combining MTT assay in
      vitro may become an efficient way to predict the sensitivity to chemotherapeutic
      drug.

PMID- 12475416
TI  - [Paclitaxel-induced apoptosis in ACC-2 cells is associated with the arrest of
      G(2)/M].
AB  - OBJECTIVE: To investigate whether paclitaxel (Taxel) can efficiently induce
      apoptosis of ACC-2 or not, and to study the relation of apoptosis and arrest of
      cell mitosis. METHODS: Paclitaxel-induced arrest of cell mitosis and apoptosis of
      ACC-2 cells in various concentration and different treat time were determined
      using transmission electron microscope (TEM), fluorescence microscope, flow
      cytometry and DNA agarose gel electrophoresis technique. RESULTS: Under
      fluorescence microscope, apoptotic cells were green with irregular clumping of
      nucleus chromatin, or even nuclear chromatin segregation. The typical ultra
      structural changes of apoptosis observed by TEM were cell compaction, margination
      of nuclear chromatin, condensation of cytoplasm, protuberances and apoptotic
      body. "DNA Ladder" was absent in agarose gel electrophoresis of DNA extracted
      from culture of ACC-2 cells and paclitaxel-induced ACC-2 cells. "Sub-G(1)" phase
      peak of ACC-2 cells induced by 50 nmol/L paclitaxel in 48 h and 72 h was 17.13%
      and 16.26%, respectively. The percentage of G(2)/M phase increased in accordance
      with raise of the paclitaxel concentration and prolongation of treatment. The
      typical ultra-structural changes of apoptosis were observed in case that G(2)/M
      phase was arrested. CONCLUSIONS: Paclitaxel could induce apoptosis of ACC-2
      cells. Arrest of G(2)/M phase might induce apoptosis of ACC-2 cells.

PMID- 12475417
TI  - [The role of mitogen-activated protein kinase (MAPK) pathway in the action
      mechanism of PYM-induced KB cells apoptosis].
AB  - OBJECTIVE: To study the role of mitogen-activated protein kinase (MAPK) pathway
      in the action mechanism of PYM-induced KB cell apoptosis. METHODS: Western blot
      analysis was used to investigate the expression of the mitogen-activated protein
      kinase. RESULTS: When treated with PYM in cultured KB cells, the extracellular
      signal-regulated kinase (ERKl/2) showed a dose-and time-dependent decreasing in
      phosphorylation status of these proteins through a western blot analysis, whereas
      protein levels of p38 MAPK remained unchanged. CONCLUSIONS: The mitogen-activated
      protein kinase (MAPK) pathway may play an important ro1e in PYM-induced apoptosis
      of KB cells.

PMID- 12475418
TI  - [Expression of VEGF, EGFR, p16 in lip cancers and oral squamous cell carcinomas
      and their clinic significance].
AB  - OBJECTIVE: To detect the expression of vascular endothelial growth factor (VEGF),
      epidermal growth factor receptor (EGFR), p16 protein in lip cancers and oral
      squamous cell carcinoma (OSCC) as well as their clinicopathological significance.
      METHODS: Immunohistochemisty for expression VEGF, EGFR, P16 were carried out in
      69 cases of lip cancers and OSCC. RESULTS: Expression of VEGF, EGFR, p16 protein
      in OSCC and lip cancers was respectively 71.01%, 46.37%, 28.98% and there were no
      significance between their positive expressions (P > 0.05) as well as in
      different sites of them (P > 0.05). Expression of VEGF was respectively 71.01% in
      cancers and 10.00% in non-tumor tissues, there was statistic significance among
      those (P < 0.05). CONCLUSIONS: The results show that there is no correlation to
      the expression of VEGF, EGFR and P16 protein in OSCC and lip cancers. It is
      suggests that the expression of VEGF might become one of the useful markers for
      OSCC.

PMID- 12475419
TI  - [Isolation, culture and identification of bovine cementum-derived cells].
AB  - OBJECTIVE: To isolate and culture bovine cementum-derived cells and investigate
      their biological properties. METHODS: Culture of primary bovine cementoblast (CB)
      were established from new-born bovine teeth. Cementum was manually dissected,
      fragmented, and digested twice with collagenase. Following a thorough wash to
      remove liberated cells, the remaining cementum fragments were plated and cultured
      in RPMI1640 containing 10% FCS and 1.5% Hepes. The cells in culture were
      identified using immunocytochemistry by expression of cementum attachment protein
      (CAP), osteocalcin (OCN) and alkaline phosphatase (ALP). ALP activity was
      measured by modified Gomori staining. RESULTS: (1) The cells in culture possessed
      the typical morphology of CB and there were no obvious change of the cell
      morphology up to 5th passage; (2) Cells in culture exhibited alkaline phosphatase
      activity and were also positive to CAP, OPN and ALP immunohistochemistry
      staining. CONCLUSION: The cells isolated and cultured in this experiment possess
      the properties of CB. This enables us to further observe its biological
      characteristics during cementogenesis and periodontal regeneration.

PMID- 12475420
TI  - [Transforming growth factor beta(1) and bone morphogenetic protein 2 induce the
      differentiation of odontoblasts in vitro].
AB  - OBJECTIVE: To investigate the effects of transforming growth factor beta(1) (TGF
      beta(1)) and bone morphogenetic protein 2 (BMP2) combined with heparin on
      odontoblast differentiation. METHODS: Trypsin-isolated dental papillae from day
      17 mandibular first molar were cultured in semisolid-agar medium for 6d.
      Recombinant human TGF-beta(1) and BMP2 combined with heparin were added to the
      medium. RESULTS: TGF-beta(1) and BMP2 combined with heparin induced
      differentiation of odontoblasts and promoted matrix secretion. Odontoblast
      differentiation never occurred when TGF-beta(1) or BMP2 were added alone to the
      medium, whereas an increase in extracellular matrix production was observed.
      CONCLUSION: These results demonstrate that both TGF-beta(1) and BMP2 stimulate
      the cytological and functional differentiation of preodontoblasts, and that
      heparin might play important role as a substrate.

PMID- 12475421
TI  - [Investigation on the relationship of occlusal force to formation of wedge-shaped
      defects].
AB  - OBJECTIVE: To clinically investigate and identify the occlusal force as one of
      factors relative to formation of wedge-shaped defects. METHODS: 123 subjects,
      selected from a group of middle-aged and elderly people in an urban area were
      divided into four groups: control, light, middle and severe group according to
      the severity of wedge-shaped defects. Cuspid, first and second premolars, and
      first molar in maxilla were examined for occlusal force by occlusometer, and the
      peak value of occlusal contact strain on every maxillary tooth was studied by
      photocclusion. RESULTS: Significant reduce of occlusive force in the defected
      teeth was found than that of in the control teeth. The occlusal contact strain of
      first premolars with defects by photocclusion was statistically increased. The
      relative occlusal contact strain of first premolars and first molar of defects
      was higher than that of their proximate teeth. CONCLUSION: Occlusal force could
      have relation to the formation of wedge-shaped defects.

PMID- 12475422
TI  - [Evaluation of inferior alveolar nerve function with trigeminal somatosensory
      evoked potential during mandibular distraction osteogenesis in monkeys].
AB  - OBJECTIVE: To assess sensory function of inferior alveolar nerve in monkeys with
      mandibular distraction osteogenesis by use of trigeminal somatosensory evoked
      potential (TSEP). METHOD: Seven young monkeys, 4 approximately 6 kg, were
      undergone a 13.5 mm bilateral or right-side mandibular lengthening with
      mandibular angle osteotomy and intraoral bone-born appliance. The inferior
      alveolar nerve function was assessed with TSEP before surgery, at the completion
      of distraction, and after four weeks of fixation. RESULTS: No significant
      differences in latencies and amplitudes of TSEP between the left and right
      inferior alveolar nerves before surgery. At the completion of distraction,
      latencies of TSEP showed significant elongation (P < 0.01, P < 0.001) and
      amplitudes also significantly decreased (P < 0.001). After four weeks of
      fixation, various degrees of TSEP recovery were identified. The latencies and the
      amplitude were slightly improved. CONCLUSIONS: Mandibular distraction
      osteogenesis affects sensory function of inferior alveolar nerves in studied
      monkeys evaluated with SEP, but recovery is observed four weeks after surgery.

PMID- 12475423
TI  - [Trace features of the mandibular condylar kinematic center during jaw protrusive
      and open-closing movements in healthy subjects].
AB  - OBJECTIVE: To investigate the variation in movement traces of different condylar
      reference points. METHODS: In 30 healthy subjects, mandibular movements were
      recorded during protrusion and open-closing of the jaw. The kinematic center and
      terminal hinge axis point of the condyle were used as reference points. RESULTS:
      The kinematic center was located anteriorly and superiorly with respect to the
      terminal hinge axis point. The trace distance of the kinematic center was longer
      than that of the terminal hinge axis point of the condyle during opening. In
      contrast to differences in trace distances of the left and right condylar
      terminal hinge axis points, no such left-right differences were found for the
      kinematic centers. The ratio between the distance of opening trace and the
      distance of protrusion trace of the kinematic center was above 1.5. CONCLUSIONS:
      In comparison to the terminal hinge axis, the kinematic center shows fewer
      variations in the movement traces.

PMID- 12475424
TI  - [Effects of hexamethylene bisacetamide on related genes expression of apoptosis
      and cell proliferating in human mucoepidermoid carcinoma cell line MEC-1].
AB  - OBJECTIVE: To investigate the effects of hexamethylene bisacetamide (HMBA) on
      related genes expression of apoptosis and cell proliferating in human
      mucoepidermoid carcinoma cell line MEC-1. METHODS: MEC-1 was induced 72 hours by
      0.002 mol/L HMBA in vitro. The morphologic observation and the expression of
      PCNA, bcl-2, bax protein and bcl-2 mRNA were determined by microscope,
      immunohistochemistry, in situ hybridization and image analysis. RESULTS: The
      expression of bax, bcl-2 protein and bcl-2 mRNA were higher than control group (P
      < 0.01). The related genes of cell proliferating PCNA were decreased in control
      group. CONCLUSIONS: HMBA could inhibit the MEC-1 cell proliferation by down
      regulation of PCNA expression, it could also induce apoptosis effectively that
      might be through the way of up-regulation of bax and bcl-2 gene expression.

PMID- 12475425
TI  - [The activity of M-phase promoting factor in oral normal tissue and tumor].
AB  - OBJECTIVE: To investigate the content and activity of M-phase promoting factor
      (MPF) in pleomorphic adenoma, mucoepidermoid carcinoma, buccal carcinoma and
      normal tissue, in order to evaluate the role of MPF in the development of tumor
      and the relationship between MPF and malignant degree. METHODS: The content and
      activity of MPF were assessed by immunobloting and Gollicano method. RESULTS: The
      cdc2 and cyclinB (two subunits of MPF) were found both in normal and tumor
      tissues, and their content in tumor was higher than normal tissues. Buccal
      carcinoma was 64% higher than normal tissues. The activity of MPF in carcinoma
      was higher than normal tissue and had positive relation with the malignant
      extent. CONCLUSIONS: The content and activity of MPF in tumor are higher than
      normal tissue. PKC can activate MPF. These results show PKC may promote tumor
      proliferation by activating MPF and also, the activity of MPF has some relation
      with malignant extent.

PMID- 12475426
TI  - [The relationship between tumor necrosis factor A-308 gene polymorphism and
      susceptibility of severe periodontitis in adults].
AB  - OBJECTIVE: To investigate the relationship between tumor necrosis factor A-308
      gene polymorphism and susceptibility of severe periodontitis in adults. METHODS:
      Buccal swabs from 65 adult patients with severe periodontitis and 96 periodontal
      healthy adult controls were obtained. DNA was extracted from each sample using
      Chelex-100 method, then PCR-RFLP was performed to determine the TNFA-308
      genotype. Data were analyzed by statistics software. RESULTS: A significant
      difference of genotype distribution was found between the patients and controls.
      The percentage of 1/1 type of the patients was much higher (P < 0.001). Risk
      Analysis showed odds ratio for allele 1 was 4.64. CONCLUSION: This study
      suggested that TNFA-308 allele 1 maybe a marker of susceptibility to severe
      periodontitis.

PMID- 12475427
TI  - [The effects of indomethcin rinse on the periodontal inflammation].
AB  - OBJECTIVE: To observe the clinical results and the changes of gingival crevicular
      fluid prostaglandins E(2) (GCF-PGE(2)) levels three months after indomethcin
      rinsing. METHODS: Nineteen periodontal patients who had received periodontal
      treatment before were chosen and divided into two groups randomly: indomethcin
      test group and placebo control group. The clinical parameters and gingival
      crevicular fluid (GCF) samples were obtained respectively at 0, 1, 3 month. The
      levels of GCF-PGE(2) were measured by radioimmunoassay (RIA). RESULTS: After 3
      months' rinse treatment, the bleeding index and the amounts of GCF in test group
      decreased significantly than those of the control group. Attachment level
      improved in test group as well. The levels of GCF-PGE(2) significantly decreased
      in test group, which not changed in control group. The percentage value of plaque
      reduced considerably in both test group and control group after rinsing, but no
      significant difference was found between these two groups. CONCLUSION: Gingival
      inflammation and the levels of GCF-PGE(2) are reduced after topical indomethcin
      administration. The effect is related to the decrease of local PGE(2) levels.

PMID- 12475428
TI  - [The study of calcification of autogenous bone marrow stem cell transplantation
      on alveolar bone defect in dogs].
AB  - OBJECTIVE: To evaluate the effect of calcification of autogenous bone marrow stem
      cell transplantation in periodontal tissue regeneration. METHODS: Bone marrow
      stem cells derived from the same dog were cultured with alpha-MEM. 1 x 10(7)
      cells of first passage were allowed to attach to the collagen membrane for 24
      hours. The membrane-cells were transplanted into periodontal defect in the same
      dog. Then the defects were covered with e-pTFE membranes. The defects covered
      only with e-pTFE without membrane-cells were served as control. Eighteen teeth of
      6 dogs for every group were studied. The dogs were sacrificed after 6 weeks.
      RESULTS: The results showed that new bone formation in test group was
      significantly higher than that of control group. The calcification of new bone in
      test group was better than control group. CONCLUSIONS: The results suggested that
      autogenous bone marrow stem cell transplantation with guided tissue regeneration
      technique could enhance periodontal tissue regeneration and could form new bone
      tissue fast and could shorten times of periodontal tissue regeneration in dogs.

PMID- 12475429
TI  - [Effects of mechanical stretching force on osteoblast-like function of human
      periodontal ligament cells in vitro].
AB  - OBJECTIVE: To investigate the osteoblast-like functional characteristics
      exhibited by human periodontal ligament cells (hPDLCs) under mechanical force.
      METHODS: Human PDLCs cultured in vitro were stretched by mechanical force.
      Radioimmunoassay (RIA) was used to measure the expression of secreting alkaline
      phosphotase (ALP) and osteocalcin (OCN). The non-secreting ALP, OCN and
      osteopontin (OPN) in cells were determined by immunohistochemistry. RESULTS: It
      exhibited increasing of ALP secreted into conditional media, and in the 24 hour
      period there were two peaks which appeared at the 2nd and 4th hour and the 24th
      hour (P < 0.01). While in the late of the 24 hours, expression of OCN in
      conditional media increased (P < 0.05). CONCLUSION: Mechanical force induces
      hPDLCs to differentiate into functional osteoblast-like cells and plays a role in
      bone remodeling.

PMID- 12475430
TI  - [Anterior open bite: surgically or orthodontically treated].
AB  - OBJECTIVE: To study the boundary between orthodontic and surgical treatment in
      correction of anterior open bite. METHODS: 70 cases (18.0 ages in average)
      treated orthodontically and 14 cases (25.1 ages in average) treated surgically
      were chosen. 154 hard and soft tissue measurements were analyzed by statistical
      software. RESULTS: A diagnostic index, L1MP, was gained with simple factorial
      analysis. L1MP </= 89.5 was bound to be treated with surgery. A discriminate
      function, Z = -0.80188 L1MP + 0.91401 Age + 0.671111 Antigonial notch-MP +
      0.599992 SNPg, was produced by multiple factorial discriminate analysis. Z < O is
      an indication of orthodontic treatment. CONCLUSION: The diagnostic index and
      discriminate function were both useful in determining which method to be chosen
      in treatment of anterior open bite. The discriminate function was tested to be
      more efficient than the diagnostic index.

PMID- 12475431
TI  - [The preliminary study on creating the differential templates of the skeletal
      profiles for Shanghainese with normal occlusion in early permanent dentition].
AB  - OBJECTIVE: To establish the differential templates of the skeletal profiles for
      Shanghainese with normal occlusion in early permanent dentition. METHODS: 71
      lateral cephalometric radiographs of subjects with normal occlusion in early
      permanent dentition, aged from 11 - 15 years (37 females and 34 males) were
      traced. 23 skeletal landmarks were identified on the tracings, which afterwards
      were scanned on the computer. An x-y coordinate system was established: the
      tracing superimposed on sella rotated 7 degrees down from the sella-nasion line
      as the x axis and the vertical line through sella perpendicular to the x axis as
      the y axis. A special length/depth ratio was designed. The length/depth ratio of
      each graph were calculated. Steiner analysis was applied to check the difference
      between genders. RESULTS: There was no difference between genders. The tracings
      were divided into three categories: short face, normal face and long face
      according to the mean and standard deviation of the ratio. The three types of
      tracings were superimposed on the x axis with sella registered. Three templates
      were created. CONCLUSIONS: The differences were apparent when the three templates
      were superimposed.

PMID- 12475432
TI  - [Development of internal distractors for jaws: experimental and clinical
      studies].
AB  - OBJECTIVE: To introduce a series of internal distractors developed by the authors
      and results of experimental study and clinical trials. METHODS: Based on the
      demand of clinical use and experimental studies, 7 kinds and 17 types of internal
      distractors were developed. Required biomechanics were evaluated and animal
      studies were undertaken in 16 Rhesus monkeys and 12 goats with 40 distractors.
      Clinically, 68 Patients with 7 kinds of severe dento-gratho-facial deformities
      were treated with 82 distractors and the histocompatibility, stability, influence
      on new bone formation were evaluated. RESULTS: The 7 kinds of distractors were
      State-approved products made of Titanium alloy and permitted for use in human.
      The pull and twist force tests demonstrated that the loading capability of them
      were larger than 7.8 kgf and 5.0 kgf respectively. The domestic made Grade II
      screw was used to transmit the moving, it was nimble, without dead point, and
      with a forward-backward space of < 0.1 mm. The horizontal space in between the
      two fixing parts was < 0.1 mm. The parallel degree of the two direction-guide
      rods was within 0.05 mm. Animal and clinical studies demonstrated that there was
      no rejection response of the tissues. There were fractures of the direction-guide
      rods in two early cases, the design was improved then. Other results both
      experimentally and clinically were satisfactory with good osteogenesis.
      CONCLUSIONS: This series of domestic made internal distractors can be used
      satisfactorily in distraction osteogenesis for various kinds of jaw deformities.
      The successful production of these distractors will provide a good foundation to
      popularize the internal distraction osteogenesis of the jaws.

PMID- 12475433
TI  - [Development and property test of synthetic macromolecular resin class of comfort
      denture adhesive].
AB  - OBJECTIVE: To prepare a new synthetic macromolecular resin class of denture
      adhesive (named Comfort-DA). METHODS: Twelve different formulae for denture
      adhesive were designed by orthogonal design. Each factor affecting tensile bond
      strength of adhesive was analyzed by ANNOVA to select the best formula. Then the
      chemical and physical properties, such as tensile bond strength, pH value, and
      viscosity, were evaluated and compared with Fittydent in vitro also. RESULTS: The
      effect of content of polyvinyl acetate and cellulose ether on tensile bond
      strength exhibited no statistical significance (P > 0.05), while ethyl alcohol
      and CMC-Na showed statistical significance and mutual action (P < 0.05). Results
      of testing viscosity and shearing stress showed that there was no significant
      difference between Fittydent and Comfort-DA (P > 0.05), while Fittydent exhibited
      a significantly lower tensile bond strength than the prepared one (P < 0.05). The
      prepared adhesive demonstrated a neutral or slightly basic pH. CONCLUSIONS: The
      generally favorable in vitro performance of the prepared adhesive (Comfort-DA)
      formulation indicated that it might be efficacious denture adhesive.

PMID- 12475434
TI  - Study of gastrointestinal stromal tumors by light microscopy, electron microscopy
      and immunohistochemistry.
AB  - OBJECTIVE: To investigate the morphological features, immunohistochemical
      speciality of the gastrointestinal stromal tumors (GISTs), and its histogenesis
      as well. METHODS: The morphologic characteristics of GISTs were studied in 65
      cases using light microscopy and 17 cases by electron microscopy. The expression
      of c-kit (CD117), CD34, vimentin, SMA, actin, desmin, S-100 and MBP were detected
      in all the cases with EnVision trade mark staining. RESULTS: Among 65 cases of
      GISTs, 46 were spindle cell type, 6 epithelioid cell type and 13 mixture type,
      equivalent to 85.5% (65 of 76) of all of the mesenchymal tumors of
      gastrointestinal tract admitted in the same period. The epithelioid cell type
      tumors composed of mainly the epithelioid cells, predominantly short spindle,
      oval or round in pattern, with an overall eosinophilic cytoplasm by hematoxylin
      eosin stain. Focal cytoplasmic vacuolization was often seen. Sometimes signet
      ring like cells and cells with a clear cytoplasm were seen in the epithelioid
      stromal tumor. The tumor cells arranged in interlacing fascicles forming whorls
      or sometimes cell clusters. Electronic microscopy showed the presence of
      interdigitating cell processes, in some areas, synapse-like structure and
      numerous desmosome-like junctions as well as a few gap junctions and small round
      neurosecretory granules. There were also abundant intermediate filaments and thin
      filaments of actin-type with longitudinal condensations (dense bodies). All of
      the 65 stromal tumors were strongly positive for vimentin (100%), 61 out of 65
      tumors positive for CD117 (c-kit) (93.8%) and 51 out of 65 positive for CD34
      (78.5%). Some cases also expressed SMA, actin, S-100 and MBP. CONCLUSIONS: GISTs
      were the most frequent mesenchymal tumor seen in the gastrointestinal tract.
      Under light microscope, the morphology of stromal tumors looks sometimes like a
      leiomyoma and Schwannoma. The application of immunohistochemical markers
      (particularly CD117 and CD34) and ultrastructural study are considered necessary
      for the differential diagnosis. GISTs may originate from the pluripotential
      precursor cells like the interstitial cells of Cajal.

PMID- 12475435
TI  - Clinicopathological observation of renal adenomas.
AB  - OBJECTIVE: To investigate the morphologic features and diagnostic criteria of
      various types pf renal adenomas of the kidney. METHODS: In addition to light
      microscopy, electron microscopy, histochemical and immunohistochemical assays
      were applied. All 19 cases of adenomas were followed up. RESULTS: Three (3) cases
      of papillary adenoma were featured as papillary or tubulopapillary growth in
      patterns consisting of tumor cells with basophilic or acidophilic cytoplasm and
      were positive for both epithelial membrane antigen (EMA) and cytokeratin (CK7).
      Thirteen (13) cases of oncocytoma were characterized by the diversity of the
      structures including to be nest, tubular and papillary in pattern; a mixture of
      cell types including the classic oncocytes, oncoblasts and clear cells which were
      negative for vimentin and CK7 but positive for EMA. Enormous large mitochondria
      were obtained in 4 cases of oncocytoma by electronic microscopy. Three (3) cases
      of metanephric adenoma consisted of closely packed, round tubules lined by small
      bland cells with solid, glomeruloid constructure. Branching, elongated tubules
      and polypoid fronds were also detected. Tumor cells were negative for EMA,
      negative or only focally positive for CK7. Eighteen (18) patients were alive
      except one oncocytoma patient died 5 years after the diagnosis convinced. All the
      cases reported in this article had been followed up of 3 - 5 years. CONCLUSIONS:
      There are 3 kinds of renal adenomas, namely, the papillary adenoma, oncocytoma,
      and metanephric adenoma and each kind has its own clincopathological features.
      The latter two can be recognized by their distinctive morphology, and the former
      can only be diagnosed according to the size of the tumor as the reference.
      Histochemical and immohistochemical assays are helpful in differential diagnosis.

PMID- 12475436
TI  - Clinicopathological study on phyllodes tumor of the breast.
AB  - OBJECTIVE: To study the relationship between pathological features and
      classification criteria of the breast Phyllodes tumor. METHODS: 203 cases of
      breast phyllodes tumor diagnosed in 22 hospitals since 1956 were analyzed and
      reappraised by a retrospective study. RESULTS: 133 cases were benign, 42 cases
      were borderline and 28 were malignant. The follow-up (6 to 372 months) showed
      that 28/133 benign, 19/42 borderline and 18/28 malignant cases recurred, and 17
      patients (2 borderline and 15 malignant) died. The statistic cluster analysis
      demonstrated that stromal cellar atypia, margin involvement, mitotic activity and
      tumor necrosis were retained in the variable group, and no error distinguish were
      showed. CONCLUSIONS: The breast phyllodes tumor can be classified as the
      following three types: benign, borderline and malignant. It is important to
      diagnose and classify the breast phyllodes tumor according to the involvement of
      tumor margin, stromal cellar atypia, mitotic activity, stromal overgrowth and
      tumor necrosis. There are significant differences of 5 years survival rates,
      recurrent rates and death rates between the benign, borderline and malignant
      breast phyllodes tumor. With wide excision the recurrence of the tumor decreased
      suggesting that broad excision is preferred for the benign phyllodes tumor and
      mastectomy is indicated for recurred borderline and malignant tumors.

PMID- 12475437
TI  - Telangiectatic osteosarcoma: a clinicopathologic analysis of 14 cases.
AB  - OBJECTIVE: To investigate the clinicopathologic characteritics and prognosis of
      telangiectatic osteosarcoma. METHODS: The clinical and pathological data of 14
      cases of telangiectatic osteosarcoma were reviewed. RESULTS: Most of these
      patients were male (9/14). The mean age was 23 years. Most tumors were located in
      the lower extremities (10/14). The roentgenograms showed a large purely
      osteolytic lesion. Both medullar and cortical bone were extensively destroyed.
      The gross specimen showed cystic cavities separated by septa, similar to an
      aneurismal bone cyst. Microscopically, the septa contained anaplastic cells. A
      few fine, lace-like osteoid were scattered among these sarcomatous cells. 12
      patients were followed-up from 6 months to 84 months. Of seven patients who had
      developed pulmonary metastasis, six patients died and one alive with lung
      metastasis. The remaining five patients survived after operation. CONCLUSIONS:
      Difficulties in making an early diagnosis and highly malignant of this disease
      might be the important factors that affect the prognosis of telangiectatic
      osteosarcoma.

PMID- 12475438
TI  - Clinicopathologic significance of structural alterations of p53 protein in
      papillary thyroid carcinoma.
AB  - OBJECTIVE: To make a thorough study on the clinicopathologic significance of the
      three-dimensional structural alteration of the p53 protein in papillary thyroid
      carcinomas and to provide an objective criterion for the evaluation of PTC
      prognosis. METHODS: A total of 41 PTC cases were enrolled. Techniques including
      polymerase chain reaction with single strand conformational polymorphism (PCR
      SSCP), DNA sequencing, computerized three-dimensional protein modeling by means
      of international shared resources and related software analysis were used.
      RESULTS: 15 cases with p53 gene mutation defined as Group I were detected in
      totally 41 PTC cases. No p53 gene mutation was found in the rest 26 cases which
      were classified as Group II. The differences in lymph node metastatic rate,
      distant metastatic rate, age, sex, size of the lesion between Group I and Group
      II were not significant (P > 0.05). The alterations of the amino acid residues of
      9 PTC cases out of the 15 p53-gene mutated patients (Group I) were either located
      in the p53-protein domains, mainly the core domain and the non-specific DNA
      binding basic domain, or the severely defect cases with the formation of widely
      divergent structures. It was found that the alterations of the structure of the
      core domain could directly check the binding of p53 protein to its target DNA
      molecules. In addition, the alterations of the structure of the basic domain
      could indirectly prohibit the binding. The ones mentioned above were classified
      as Group Ib. The rest of six cases with their p53 protein amino acid residues
      mutated beyond the domains were grouped as Group Ia. The differences in lymph
      node metastatic rate, distant metastatic rate between Group Ib and Group Ia were
      statistically significant (P < 0.01, P < 0.05) respectively. CONCLUSIONS: The
      alterations of the three-dimensional structure of p53-protein is considered as
      one of the morphological basis of the progression and heterogeneity of PTC. They
      render an authentic evidence for the selection of the clinical cases with a poor
      risk for metastasis.

PMID- 12475439
TI  - Expression of vascular endothelial growth factor and E26 transformation-specific
      1 in breast carcinoma.
AB  - OBJECTIVE: To study the expression of vascular endothelial growth factor (VEGF)
      and transcription factor E26 transformation-specific-1 (ETS-1) in breast
      carcinoma and its effect on angiogenesis, tumor invasion and metastasis. METHODS:
      In situ hybridization and immunohistochemistry (streptomycin avidin-biotin
      peroxidase complex, SP) were used to detect the mRNA and protein expression of
      VEGF and ETS-1 in breast carcinoma. RESULTS: VEGF mRNA and its protein were
      highly expressed in tumor cells of breast carcinoma. The positive rate was 75%
      (36/48) and 70.8% (34/48) respectively. There was almost no expression of VEGF in
      vascular endothelial cells. Over expression of ETS-1 was seen in both breast
      carcinoma and endothelial cells. The positive rate of ETS-1 mRNA and protein in
      carcinoma cells was 85.4% (41/48) and 79.2% (38/48) respectively. The microvessel
      density was significantly higher in VEGF and ETS-1 highly expressed groups than
      that in the low expressed groups (P < 0.01). Both VEGF and ETS-1 expressions were
      well correlated with the histological grade and lymph node metastasis.
      CONCLUSIONS: VEGF and ETS-1 can promote angiogenesis in breast carcinoma and
      correlate with tumor invasion and lymph node metastasis. The expression of VEGF
      and ETS-1 might be considered to be a reference indicator for determining the
      angiogenesis and invasion of breast carcinoma.

PMID- 12475440
TI  - Diagnosis and differential diagnosis of nodular lymphocyte-predominant Hodgkin's
      lymphoma.
AB  - OBJECTIVE: To study the diagnosis and the differential diagnosis of nodular
      lymphocyte-predominant Hodgkin's lymphoma (NLPHL). METHODS: 245 cases of
      Hodgkin's lymphoma (HL) diagnosed between 1980 and 2000 from 3 hospitals in
      Guangzhou were reviewed. Four cases of NLPHL were confirmed according to the WHO
      classification of lymphoid neoplasms. Among the other 3 cases of NLPHL, 2
      collected from other clinical centers and 1 from Fudan University Cancer
      Hospital. Immunohistochemistry (IHC) were performed on paraffin sections through
      SP technique using a panel of markers to define the large neoplastic cells (CD45,
      CD20, CD15, CD30 and vimentin) as well as the non-neoplastic background cells
      (CD3, CD20, CD45RO, CD57, CD68 and TIA-1). RESULTS: Seven patients with NLPHL
      were 4 males and 3 females, age 29 to 70 years, average 43.8 years. All patients
      had lymphadenopathy. Histologically, in NLPHL, instead of the structure of normal
      lymph nodes, the tumor tissue became nodular in architecture. Characteristic
      lymphocytic and histiocytic (L&H) cells with scant cytoplasm and large
      multilobulated nuclei distributed among a predominant population of small
      lymphoid cells. The large cells exhibited a CD45+, CD20+, but CD15-, CD30- and
      vimentin-phenotype. The background cellularity was relatively rich in B cells and
      the majority of T-cells infiltrated were CD57(+) cells. TIA-1+ cells were few.
      CONCLUSIONS: NLPHL can be diagnosed according to the morphologic and
      immunophenotypic features rather than by morphology alone. It is important to
      distinguish this tumor from its morphologic mimics, such as lymphocyte-rich
      classical Hodgkin's lymphoma (LRCHL) and T-cell rich B-cell lymphoma (TCRBCL).
      The immunophenotype of neoplastic cells and background cells are the helpful
      criteria for the differential diagnosis.

PMID- 12475441
TI  - Expression of antisense thrombin receptor gene inhibits intimal hyperplasia of
      rat carotid artery after balloon injury.
AB  - OBJECTIVE: To study the mechanism of restenosis after angioplasty and to clarify
      the effect of thrombin and its receptor on restenosis development. METHODS:
      Balloon catheter-induced injury was adopted to induce intimal hyperplasia of the
      carotid arteries in rats. Antisense thrombin receptor (ATR) cDNA was transfected
      by perfusing recombinant LXSN ATR plasmid/nanoparticle complex into the segment
      of the injured carotid artery. RESULTS: PCR result showed integration of the
      recombined gene. Dot blot showed the expression of antisense TR mediated by
      recombinant LXSN ATR plasmid/nanoparticle complex in the wall of common carotid
      arteries of the experimental group rats, which enabled to inhibit TR gene
      expression and intimal hyperplasia of the injured arteries. CONCLUSIONS: Thrombin
      and its receptor play an important role in the formation of neointima after the
      injury, which provides a potential clue in developing a new approach for
      prevention and treatment of restenosis after angioplasty.

PMID- 12475442
TI  - Effect of retinoblastoma gene on human osteosarcoma cell line OS732.
AB  - OBJECTIVE: To investigate the effect of growth suppression and gap junctional
      intercellular communication (GJIC) on osteosarcoma cell line OS732 transduced
      with the exogenous N-terminal truncated retinoblastoma (Rb) gene. METHODS:
      Recombinant eukaryotic expression plasmid harbouring 1.65 kb Rb gene was
      constructed and transduced into OS732 cells. Rb mRNA expression was detected by
      RT-PCR and Northern blot. The cell count, cell cycle analysis and soft agar
      colony formation test were used to observe growth features. RT-PCR and Lucifer
      yellow dye transfer were carried out to measure GJIC. RESULTS: Both exogenous and
      endogenous Rb gene could be detected in OS732 cell transduced with the N-terminal
      truncated Rb gene. Compared with the parental cells, change in morphology of Rb
      transduced cells were found; growth rate decreased; amount of colony formation
      reduced; cell cycle arrested at G(0)/G(1) checkpoint; Connexin43 expression and
      GJIC enhanced. CONCLUSIONS: The malignant phenotype of OS732 is inhibited and
      GJIC is increased by transduction of N-terminal truncated Rb gene.

PMID- 12475443
TI  - The expression, characterization and roles of macrophage colony-stimulating
      factor receptor in human leukemia cell lines.
AB  - OBJECTIVE: To explore the expression, characteristics and roles of macrophage
      colony-stimulating factor receptor (M-CSF-R) in human leukemia cell lines.
      METHODS: Peripheral blood mononuclear cells (PBMCs) collected from 3 healthy
      persons, cord blood mononuclear cells (CBMCs) collected from 5 healthy persons
      and 4 human myelomonocytic leukemia cell lines including J6-1, J6-2, K562 and HL
      60 were studied by using ABC immunoperoxidaes assay, indirect immunofluorescene
      staining, flow cytometry, and Western blot. RESULTS: M-CSF-R was noticed to be
      localized in the cytoplasm, nucleus and at the membrane in 4 human leukemia cell
      lines; expression of M-CSF-R was not detected in normal human PBMCs without PHA
      stimulation. Human PBMCs stimulated by PHA expressed a low level of M-CSF-R.
      Frequencies of membrane bound M-CSF-R (M-CSF-mR) expression in J6-1, J6-2, K562
      and HL-60 were 78.9%, 72.6%, 54.9% and 58.0% respectively. Frequencies of
      cytoplasm and nucleus associated M-CSF-R (M-CSF-cnR) were 52.3%, 44.3%, 28.0% and
      65.3% respectively. One form of M-CSF-R with a molecular weight of 120 000 was
      detected both in the cytoplasm and nucleus of HL-60 cells. The half-life of M-CSF
      cnR in leukemia cells mentioned above was longer than that of corresponding M-CSF
      R in stimulated CBMCs, and the half-life of M-CSF-mR in leukemia cells was
      extended except that of M-CSF-mR in K562 cells. Both anti-M-CSF-R monoclonal
      antibody and recombinant human M-CSF soluble receptor could cause the growth
      arrest of HL-60 cell in G(0)/G(1) phase, and could inhibit the formation of
      colony of HL-60 cell in soft agarose. CONCLUSIONS: Expression of M-CSF-R in
      leukemia cells is heterogeneous. The accumulation of cellular M-CSF-R results in
      the low degradation rate of cellular M-CSF-R in leukemia cells, which could be a
      potential mitotic signal. Signal mediated by M-CSF-R is important and necessary
      for the growth of HL-60 cell.

PMID- 12475444
TI  - Effects of selenium and iodine on the expression of c-fos and c-jun mRNA and
      their proteins in cultured rat hippocampus neurons.
AB  - OBJECTIVE: To study the effect of selenium (Se) and iodine (I) and the compound
      of both on the proto-oncogenes c-fos and c-jun mRNA and their protein expression
      in the cultured rat hippocampus neurons. METHODS: Using the technique of serum
      free hippocampus neuron culture, different doses of Se and I and Se + I compound
      were added into the medium. The expression of the mRNA of c-fos, c-jun in
      hippocampus neurons cultured for 1, 3, 5, 7 and 10 d were studied using both in
      situ hybridization and SABC immunohistochemical technique. RESULTS: Both Se and I
      could enhance the expression of c-fos, c-jun mRNA and their proteins, especially
      the combination of I and Se able to give a remarkable effect on c-jun mRNA
      expression. CONCLUSIONS: Se and I may effect the expression of both c-fos and c
      jun mRNA, especially the c-jun mRNA and its protein of hippocampus neurons, and
      thus may effect the differentiation and development of neurons.

PMID- 12475445
TI  - The expression of TNF-alpha mRNA and its significance in murine viral
      myocarditis.
AB  - OBJECTIVE: To study the change of serum tumor necrosis factor-alpha (TNF-alpha)
      and its mRNA in viral myocarditis (VMC) and its role in VMC. METHODS: The
      expression of TNF-alpha mRNA in VMC mice was studied by the way of RT-PCR.
      Changes of serum TNF-alpha on day 3, 5, 7, 9, 15 and 35 after virus inoculation
      in VMC mice were assayed using ELISA. The possible relationship of TNF-alpha and
      VMC was analysed. RESULTS: The expression of TNF-alpha mRNA in VMC mice increased
      apparently. The level of TNF-alpha mRNA expressed on the 7th day after virus
      inoculation (1.94) was higher than that on the 3rd day (1.09). Serum TNF-alpha of
      the VMC mice was higher than that of the control mice (127.2 +/- 13.8) from the
      3rd to 35th day after virus inoculation (3rd day group 159.7 +/- 40.8, 5th day
      group 212.7 +/- 40.0, 7th day group 296.7 +/- 34.3, 9th day group 267.3 +/- 41.4,
      15th day groups 187.8 +/- 49.6, and 35th day groups 155.4 +/- 35.9) and the peak
      expression was on the 7th day after the inoculation (P < 0.01 compared with the
      control group). CONCLUSIONS: Both serum TNF-alpha and its mRNA increased in
      murine VMC, which may take part in the pathogenesis of VMC.

PMID- 12475446
TI  - Significance of HER-2/neu expression in ovarian epithelial tumours.
AB  - OBJECTIVE: To investigate expression of Her-2/neu (c-erbB-2) and its significance
      in ovarian epithelial tumors. METHODS: 106 specimens and clinical history of
      ovarian epithelial tumors were collected including 54 cases of malignant, 33
      cases of borderline and 19 benign cases. There were 19 cases of stages I and II
      and 35 cases of stages III and IV in ovarian carcinoma and all borderline
      malignant cases were stage I according to FIGO's standard. Immunohistochemical
      staining for Her-2/neu was performed by LSAB method. RESULTS: The positives rates
      of Her-2/neu of benign, borderline and malignant tumors were 47.4% (9/19), 84.8%
      (28/33,), and 85.2% (46/54), respectively. Both borderline and malignant cases
      were found to have higher expression of Her-2/neu than those of benign cases (P <
      0.02 and P < 0.01) respectively. Overexpression of Her-2/neu showed in 14/54
      (25.9%) of malignant cases, 3/33 (9.1%) of borderline, and none of benign cases.
      Overexpression of Her-2/neu in malignant tumors cases with metastasis was higher
      than those without metastasis (P < 0.001). CONCLUSION: Overexpression of Her
      2/neu is associated with biological aggressiveness of ovarian cancer.

PMID- 12475447
TI  - Integrating quality into the cycle of therapeutic development.
AB  - The quality of healthcare, particularly as reflected in current practice versus
      the available evidence, has become a major focus of national health policy
      discussions. Key components needed to provide quality care include: 1)
      development of quality indicators and performance measures from specific practice
      guidelines, 2) better ways to disseminate such guidelines and measures, and 3)
      development of support tools to promote standardized practice. Although rational
      decision-making and development of practice guidelines have relied upon results
      of randomized trials and outcomes studies, not all questions can be answered by
      randomized trials, and many treatment decisions necessarily reflect physiology,
      intuition, and experience when treating individuals. Debate about the role of
      "evidence-based medicine" also has raised questions about the value of applying
      trial results in practice, and some skepticism has arisen about whether advocated
      measures of clinical effectiveness, the basic definition of quality, truly
      reflect a worthwhile approach to improving medical practice. We provide a
      perspective on this issue by describing a model that integrates quantitative
      measurements of quality and performance into the development cycle of existing
      and future therapeutics. Such a model would serve as a basic approach to
      cardiovascular medicine that is necessary, but not sufficient, to those wishing
      to provide the best care for their patients.

PMID- 12475448
TI  - A long-term perspective on the protective effects of an early invasive strategy
      in unstable coronary artery disease: two-year follow-up of the FRISC-II invasive
      study.
AB  - OBJECTIVES: We sought to report the first and repeat events and to separate
      spontaneous and procedure-related events over two years in the Fast
      Revascularization during InStability in Coronary artery disease (FRISC-II)
      invasive trial. BACKGROUND: The FRISC-II invasive trial compared the long-term
      effects of an early invasive versus noninvasive strategy, in terms of death and
      myocardial infarction (MI) and the need for repeat hospital admissions and late
      revascularization procedures in patients with coronary artery disease (UCAD).
      METHODS: In the FRISC-II trial, 2,457 patients with UCAD were randomized to an
      early invasive or noninvasive strategy. RESULTS: At 24 month follow-up, there
      were reductions in mortality (n = 45 [3.7%] vs. 67 [5.4%]; risk ratio 0.68 [95%
      confidence interval (CI) 0.47 to 0.98]; p = 0.038), MI (n = 111 [9.2%] vs. 156
      [12.7%]; risk ratio 0.72 [95% CI 0.57 to 0.91]; p = 0.005), and the composite end
      point of death or MI (n = 146 [12.1%] vs. 200 [16.3%]; risk ratio 0.74 [95% CI
      0.61 to 0.90]; p = 0.003) in the invasive compared with the noninvasive group.
      Procedure-related MIs were two to three times more common, but spontaneous ones
      were three times less common in the invasive than in the noninvasive group. After
      the first year, there was no difference in mortality (n = 20 [1.7%]) between the
      two groups and fewer MIs in the invasive group (p = 0.031). CONCLUSIONS: In UCAD,
      the early invasive approach leads to a sustained reduction in mortality, cardiac
      morbidity, and the need for repeat hospital admissions and late revascularization
      procedures. Although the benefits are greatest during the first months, during
      the second year, cardiac morbidity is lower and the need for hospital care is
      less in the invasive group.

PMID- 12475449
TI  - Cardioprotective effects of an early invasive strategy for non-ST-segment
      elevation acute coronary syndromes: are we all becoming "interventional"
      cardiologists?

PMID- 12475450
TI  - Increased ubiquitin immunoreactivity in unstable atherosclerotic plaques
      associated with acute coronary syndromes.
AB  - OBJECTIVES: The current study was designed to examine whether ubiquitin
      expression is higher in unstable than in stable lesions of patients with acute
      coronary syndrome (ACS). BACKGROUND: The ubiquitin system has been identified as
      the nonlysosomal pathway of protein degradation; it is involved in a number of
      biologic processes crucial to cell and tissue integrity and therefore, might be
      potentially involved in the rupture of unstable coronary plaques. METHODS: We
      conducted an autopsy-based study of 25 consecutive patients with fatal ACS.
      Lesions of both infarct-related and noninfarct-related segments from the same
      patients were examined for the expression and localization of ubiquitin by use of
      immunohistochemistry and a semiquantitative grading scale. RESULTS: Ubiquitin
      immunoreactivity was higher in infarct-related than in noninfarct-related lesions
      (1.4 +/- 0.5 vs. 1.1 +/- 0.6, p = 0.03). Compared with areas adjacent to the
      plaque (0.6 +/- 0.7), ubiquitin immunoreactivity was higher in areas around the
      lipid core (2.5 +/- 0.8, p < 0.001), plaque shoulders (1.6 +/- 1.1, p < 0.001),
      and fibrous cap regions (1.6 +/- 1.1, p < 0.001). Within the plaque area, co
      localization of ubiquitin immunoreactivity with T cells and macrophages was
      found. In areas adjacent to the plaque, ubiquitin immunoreactivity co-localized
      with neointima cells and media smooth muscle cells. CONCLUSIONS: In patients with
      ACS, ubiquitin immunoreactivity is enhanced in unstable, infarct-related lesions,
      predominantly in plaque regions of tissue degradation. Based on these findings,
      this study suggests a role for the ubiquitin system in the destabilization and
      rupture of coronary atherosclerotic plaques in humans.

PMID- 12475451
TI  - Induction of mild systemic hypothermia with endovascular cooling during primary
      percutaneous coronary intervention for acute myocardial infarction.
AB  - OBJECTIVES: The purpose of this study was to evaluate the safety and feasibility
      of endovascular cooling during primary percutaneous coronary intervention (PCI)
      for acute myocardial infarction (AMI). BACKGROUND: In experimental models of AMI,
      mild systemic hypothermia has been shown to reduce metabolic demand and limit
      infarct size. METHODS: In a multi-center study, 42 patients with AMI (<6 h from
      symptom onset) were randomized to primary PCI with or without endovascular
      cooling (target core temperature 33 degrees C). Cooling was maintained for 3 h
      after reperfusion. Skin warming, oral buspirone, and intravenous meperidine were
      used to reduce the shivering threshold. The primary end point was major adverse
      cardiac events at 30 days. Infarct size at 30 days was measured using (99m)Tc
      sestamibi SPECT imaging. RESULTS: Endovascular cooling was performed successfully
      in 20 patients (95%). All achieved a core temperature below 34 degrees C (mean
      target temperature 33.2 +/- 0.9 degrees C). The mean temperature at reperfusion
      was 34.7 +/- 0.9 degrees C. Cooling was well tolerated, with no hemodynamic
      instability or increase in arrhythmia. Nine patients experienced mild episodic
      shivering. Major adverse cardiac events occurred in 0% vs. 10% (p = NS) of
      treated versus control patients. The median infarct size was non-significantly
      smaller in patients who received cooling compared with the control group (2% vs.
      8% of the left ventricle, p = 0.80). CONCLUSIONS: Endovascular cooling can be
      performed safely as an adjunct to primary PCI for AMI. Further clinical trials
      are required to determine whether induction of mild systemic hypothermia with
      endovascular cooling will limit infarct size in patients undergoing reperfusion
      therapy.

PMID- 12475452
TI  - Immunosuppressive Therapy for the Prevention of Restenosis after Coronary Artery
      Stent Implantation (IMPRESS Study).
AB  - OBJECTIVES: This study tested the effect of oral prednisone on clinical and
      angiographic restenosis rate after successful stent implantation in patients with
      persistent elevation of systemic markers of inflammation after the procedure.
      BACKGROUND: Experimental studies have shown that corticosteroids have the
      potential to reduce the inflammatory response associated with stent implantation.
      METHODS: Eighty-three patients undergoing successful stenting with C-reactive
      protein (CRP) levels >0.5 mg/dl 72 h after the procedure were randomized to
      receive oral prednisone or placebo for 45 days. The primary clinical end point
      was 12-month event-free survival rate (defined as freedom from death, from
      myocardial infarction, and from recurrence of symptoms requiring additional
      revascularization). The angiographic end points were restenosis rate and late
      loss at six months. RESULTS: Twelve-month event-free survival rates were 93% and
      65% in patients treated with prednisone and placebo, respectively (relative risk
      [RR] 0.18, 95% confidence intervals [CI], 0.05 to 0.61, p = 0.0063). Six-month
      restenosis rate and late loss were lower in prednisone-treated than in placebo
      treated patients (7% vs. 33%, p = 0.001, and 0.39 +/- 0.6 mm vs. 0.85 +/- 0.6 mm,
      p = 0.001, respectively). CONCLUSIONS: In patients with persistently high CRP
      levels after successful coronary artery stent implantation, oral
      immunosuppressive therapy with prednisone results in a striking reduction of
      clinical events and angiographic restenosis rate.

PMID- 12475453
TI  - A unique, low dose of intravenous enoxaparin in elective percutaneous coronary
      intervention.
AB  - OBJECTIVES: This study was designed to examine a unique and low dose of
      intravenous enoxaparin in elective percutaneous coronary intervention (PCI) that
      would be applicable to an unselected population regardless of age, weight, renal
      function, or use of glycoprotein IIb/IIIa inhibitors. BACKGROUND: There is
      limited experience of anticoagulation using intravenous (IV) low-molecular-weight
      heparin in PCI, which has been obtained with high doses causing elevated
      anticoagulation levels and delayed sheath withdrawal. METHODS: A total of 242
      consecutive patients undergoing elective PCI were treated with a single IV bolus
      of enoxaparin (0.5 mg/kg), and 26% of patients (n = 64) also received
      eptifibatide. Sheaths were removed immediately after the procedure in patients
      treated with enoxaparin only, and 4 h after the procedure in those also treated
      with eptifibatide. RESULTS: A peak anti-Xa >0.5 IU/ml was obtained in 97.5% of
      the population, and 94.6% of patients had their peak anti-Xa level in the
      predefined target range of 0.5 to 1.5 IU/ml. Advanced age, renal failure, being
      overweight, and eptifibatide use did not alter the anticoagulation profile. At
      one-month follow-up, six patients (2.5%) had died, had a myocardial infarction,
      or undergone an urgent revascularization; all the patients had an anti-Xa level
      >0.5 IU/ml during PCI. Patients without an ischemic event and without a creatine
      kinase rise, but with a detectable troponin release in the next 24 h of PCI (>2
      microg/ml, n = 21), had similar anti-Xa levels as those without troponin
      elevation. There were one major and three minor bleeding events that were not
      associated with anti-Xa overshoot. CONCLUSIONS: Low-dose (0.5 mg/kg) IV
      enoxaparin allows a prespecified target level of anticoagulation (anti-Xa >0.5
      IU/ml) in the vast majority of patients undergoing PCI, appears to be safe and
      effective, allows immediate sheath removal when used alone, and does not require
      dose adjustment when used with eptifibatide.

PMID- 12475454
TI  - Percutaneous coronary intervention versus repeat bypass surgery for patients with
      medically refractory myocardial ischemia: AWESOME randomized trial and registry
      experience with post-CABG patients.
AB  - OBJECTIVES: This report compares long-term percutaneous coronary intervention
      (PCI) and coronary artery bypass graft (CABG) survival among post-CABG patients
      included in the Angina With Extremely Serious Operative Mortality Evaluation
      (AWESOME) randomized trial and prospective registry. BACKGROUND: Repeat CABG
      surgery is associated with a higher risk of mortality than first-time CABG. The
      AWESOME is the first randomized trial comparing CABG with PCI to include post
      CABG patients. METHODS: Over a five-year period (1995 to 2000), patients at 16
      hospitals were screened to identify a cohort of 2,431 individuals who had
      medically refractory myocardial ischemia and at least one of five high-risk
      factors. There were 454 patients in the randomized trial, of whom 142 had prior
      CABG. In the physician-directed registry of 1,650 patients, 719 had prior CABG.
      Of the 327 patient-choice registry patients, 119 had at least one prior CABG. The
      CABG and PCI survivals for the three groups were compared using Kaplan-Meier
      curves and log-rank tests. RESULTS: The CABG and PCI three-year survival rates
      were 73% and 76% respectively for the 142 randomized patients (75 and 67
      patients) (log-rank = NS). In the physician-directed registry, 155 patients were
      assigned to reoperation and 357 to PCI (207 received medical therapy); 36-month
      survivals were 71% and 77% respectively (log-rank = NS). In the patient-choice
      registry, 32 patients chose reoperation and 74 chose PCI (13 received medical
      therapy); 36-month survivals were 65% and 86% respectively (log-rank test p =
      0.01). CONCLUSIONS: Percutaneous coronary intervention is preferable to CABG for
      many post-CABG patients.

PMID- 12475455
TI  - A prospective randomized trial comparing stenting with off-pump coronary surgery
      for high-grade stenosis in the proximal left anterior descending coronary artery:
      three-year follow-up.
AB  - OBJECTIVES: This study was done to identify the best treatment for an isolated
      high-grade stenosis of the proximal left anterior descending coronary artery
      (LAD). BACKGROUND: Percutaneous transluminal coronary angioplasty with stenting
      (PCI) and off-pump coronary artery bypass grafting (surgery) are used to treat
      single-vessel disease of a high-grade stenosis of the proximal LAD. Midterm
      results of both treatments are compared in this prospective randomized study.
      METHODS: In a single-center prospective trial, we randomly assigned 102 patients
      with a high-grade stenosis of the proximal LAD (American College of
      Cardiology/American Heart Association classification type B2 or C) to PCI (n =
      51) or surgery (n = 51). Primary composite end point was freedom from Major
      Adverse Cardiac and Cerebrovascular Events (MACCE) at follow-up, including death,
      myocardial infarction, cerebrovascular accident, and repeat target vessel
      revascularization (TVR). Secondary end points were angina pectoris class and need
      for antianginal medication at follow-up. Analysis was by intention-to-treat (ITT)
      and received treatment (RT). RESULTS: Mean follow-up time was three years (90%
      midrange, two to four years). Incidence of MACCE was 23.5% after PCI and 9.8%
      after surgery; p = 0.07 ITT (24.1% vs. 8.3%; p = 0.04 RT). After surgery a
      significantly lower angina pectoris class (p = 0.02) and need for antianginal
      medication (p = 0.01) was found compared to PCI. Target vessel revascularization
      was 15.7% after PCI and 4.1% after surgery (p = 0.09). CONCLUSIONS: At three-year
      follow-up (range, two to four years), a trend in favor of surgery is observed in
      regard to MACCE-free survival with a significantly lower angina pectoris status
      and significantly lower need for antianginal medication.

PMID- 12475456
TI  - Association between CK-MB elevation after percutaneous or surgical
      revascularization and three-year mortality.
AB  - OBJECTIVES: The goal of this study was to assess the long-term impact of creatine
      kinase-MB isoform (CK-MB) elevation after percutaneous or surgical
      revascularization. BACKGROUND: The long-term impact of CK-MB elevation after
      coronary artery bypass grafting (CABG) is not as well characterized as that
      following percutaneous coronary intervention (PCI). METHODS: The three-year
      cumulative survival of consecutive patients who underwent their first
      percutaneous or surgical revascularization procedure between January 1, 1995 and
      August 31, 2000 and had CK-MB determination was assessed using the Social
      Security Death Index. RESULTS: The 3,812 patients undergoing CABG had a less
      favorable coronary risk profile than the 3,573 patients undergoing PCI. The
      incidence of CK-MB elevation above normal range was 90% and 38% for the CABG and
      PCI groups (p < 0.001). In 6% and 5%, respectively, the elevation surpassed 10x
      the upper limit of normal (ULN). At an average follow-up of three years, there
      were 712 deaths, 83 of which occurred within 30 days of procedure. The cumulative
      survival was 92% and 90% for CABG and PCI, respectively (p = 0.003). Chronic
      renal insufficiency (adjusted hazard ratio [HR] 3.8, [95% confidence interval 3.1
      to 4.6]), age (HR 1.5 per decade [1.3 to 1.6]), ejection fraction <40% (HR 1.3
      [1.1 to 1.5] and PCI (HR 1.6 [1.3 to 1.9]) were the main predictors of increased
      mortality. Creatine kinase-MB isoform elevation only above 10 x ULN was
      independently predictive of mortality in the CABG (HR 1.3 [1.1 to 1.5]) and PCI
      (HR 1.1 [1.0 to 1.2]) groups, p < 0.001. CONCLUSIONS: Creatine kinase MB isoform
      elevation after revascularization is very common, particularly in CABG patients.
      When extensive, it is independently correlated with increased mortality over a
      three-year period. Identification and aggressive management of patients with high
      levels of CK-MB after revascularization may improve their outcome.

PMID- 12475457
TI  - Outcomes of repeat revascularization in diabetic patients with prior coronary
      surgery.
AB  - OBJECTIVES: This study evaluated both short- and long-term outcomes of diabetic
      patients who underwent repeat coronary artery bypass graft surgery (CABG) or
      percutaneous coronary intervention (PCI) after initial CABG. BACKGROUND: Although
      diabetic patients who have multivessel coronary disease and require initial
      revascularization may benefit from CABG as compared with PCI, the uncertainty
      concerning the choice of revascularization may be greater for diabetic patients
      who have had previous CABG. METHODS: Data were obtained over 15 years for
      diabetic patients undergoing PCI procedures or repeat CABG after previous
      coronary surgery. Baseline characteristics were compared between groups, and in
      hospital, 5-year, and 10-year mortality rates were calculated. Multivariate
      correlates of in-hospital and long-term mortality were determined. RESULTS: Both
      PCI (n = 1,123) and CABG (n = 598) patients were similar in age, gender, years of
      diabetes, and insulin dependence, but they varied in presence of hypertension,
      prior myocardial infarction, angina severity, heart failure, ejection fraction,
      and left main disease. In-hospital mortality was greater for CABG, but
      differences in long-term mortality were not significant (10 year mortality, 68%
      PCI vs. 74% CABG, p = 0.14). Multivariate correlates of long-term mortality were
      older age, hypertension, low ejection fraction, and an interaction between heart
      failure and choice of PCI. The PCI itself did not correlate with mortality.
      CONCLUSIONS: The increased initial risk of redo CABG in diabetic patients and the
      comparable high long-term mortality regardless of type of intervention suggest
      that, except for patients with severe heart failure, PCI be strongly considered
      in all patients for whom there is a percutaneous alternative.

PMID- 12475458
TI  - Absence of postprandial surge in coronary blood flow distal to significant
      stenosis: a possible mechanism of postprandial angina.
AB  - OBJECTIVES: This study was designed to investigate a possible mechanism of
      postprandial angina. BACKGROUND: Postprandial angina has been recognized for more
      than two centuries; however, its mechanism is still controversial. The most
      widely accepted mechanism involves increased myocardial oxygen demand after food
      intake. Recently, the redistribution in coronary blood flow (CBF) was suggested
      as a possible mechanism. METHODS: Twenty young, healthy volunteer controls and 20
      patients with significant stenosis in the left anterior descending (LAD) or left
      main coronary artery were enrolled in the study. Coronary blood flow was
      evaluated in the distal LAD by using transthoracic Doppler echocardiography
      before and 15, 30, 45, and 60 min after food intake. In the CBF curve, the time
      velocity integral of diastolic flow (Dtvi) and the product of Dtvi and heart rate
      (HR) were measured. In six patients, these measurements were repeated after
      successful coronary intervention. RESULTS: In the healthy volunteer controls,
      Dtvi and Dtvi x HR increased after food intake with a peak value at 15 min, which
      indicates the presence of postprandial surge in the CBF. Fasting values and peak
      values at 15 min were significantly different (Dtvi: 15.1 +/- 4.9 cm/s vs. 18.9
      +/- 5.9 cm/s, p = 0.04, Dtvi x HR: 862.2 +/- 261.5 cm/min vs. 1,174.2 +/- 307.5,
      p = 0.002). In contrast with the controls, despite postprandial increase in
      double product (HR x blood pressure), Dtvi and Dtvi x HR in the patient group
      decreased after food intake, with a nadir value at 45 min. Fasting values and
      nadir values at 45 min were significantly different (Dtvi: 24.0 +/- 19.6 cm/s vs.
      19.3 +/- 17.1 cm/s, p < 0.001, Dtvi x HR: 1,449.6 +/- 1,044.0 cm/min vs. 1,273.4
      +/- 1,000.9 cm/min, p = 0.002). In six patients, the CBF pattern resumed the
      normal pattern of postprandial surge in the CBF after successful coronary
      intervention. CONCLUSIONS: Results of our study suggest that "steal phenomenon"
      may play a role in the mechanism of postprandial angina.

PMID- 12475459
TI  - Haptoglobin phenotype is an independent risk factor for cardiovascular disease in
      individuals with diabetes: The Strong Heart Study.
AB  - OBJECTIVES: The goal of this study was to determine if the haptoglobin phenotype
      was predictive of cardiovascular disease (CVD) in diabetic mellitus (DM).
      BACKGROUND: Cardiovascular disease is the most frequent, severe, and costly
      complication of type 2 DM. There are clear geographic and ethnic differences in
      the risk of CVD among diabetic patients that cannot be fully explained by
      differences in conventional CVD risk factors. We have demonstrated that a
      functional allelic polymorphism in the haptoglobin gene acts as a major
      determinant of susceptibility for the development of diabetic microvascular
      complications. METHODS: We sought to determine if this paradigm concerning the
      haptoglobin gene could be extended to CVD in DM. We tested this hypothesis in a
      case-control sample from the Strong Heart study, a population-based longitudinal
      study of CVD in American Indians. Haptoglobin phenotype was determined by
      polyacrylamide gel electrophoresis in 206 CVD cases and 206 matched controls age
      45 to 74 years. Median follow-up was six years. RESULTS: In multivariate analyses
      controlling for conventional CVD risk factors, haptoglobin phenotype was a highly
      statistically significant, independent predictor of CVD in DM. The odds ratio of
      having CVD in DM with the haptoglobin 2-2 phenotype was 5.0 times greater than in
      DM with the haptoglobin 1-1 phenotype (p = 0.002). An intermediate risk of CVD
      was associated with the haptoglobin 2-1 phenotype. CONCLUSIONS: This study
      suggests that determination of haptoglobin phenotype may contribute to the
      algorithm used in CVD risk stratification, and in evaluation of new therapies to
      prevent CVD in the diabetic patient.

PMID- 12475460
TI  - Oral conjugated equine estrogen increases plasma von Willebrand factor in
      postmenopausal women.
AB  - OBJECTIVES: We sought to test whether one month of daily oral conjugated equine
      estrogen (CEE) or transdermal estradiol alters hemostatic factors in
      postmenopausal subjects. BACKGROUND: Estrogen replacement therapy and hormonal
      replacement therapy (HRT) effect an early increase in cardiovascular events in
      postmenopausal women. Circulating plasma von Willebrand factor (vWF) antigen is a
      marker of generalized endothelial dysfunction and atherothrombosis. METHODS:
      Thirty-eight healthy postmenopausal women (average 59 +/- 7 years) were
      randomized to receive daily oral CEE, 0.625 mg (n = 21); transdermal estradiol,
      0.1 mg/day (n = 7); or oral placebo (n = 10) for one month. Blood samples were
      collected at baseline and after two weeks and four weeks of therapy for
      measurement of circulating plasma hormones, lipid concentrations, and hemostatic
      factors. RESULTS: Oral CEE decreased total cholesterol (p < 0.01) and low-density
      lipoprotein cholesterol (p < 0.01), although it increased both triglycerides (p <
      0.05) and high-density lipoprotein cholesterol (p < 0.01). Transdermal estradiol
      had no significant effect on lipids. Plasminogen activator inhibitor-1 antigen
      declined in both oral CEE and transdermal estradiol users, but did not achieve
      statistical significance. Fibrin D-dimer antigen did not vary significantly in
      any group. However, oral CEE users had a significant increase in vWF from
      baseline to four weeks (p < 0.03) and a decrease in tissue-type plasminogen
      activator antigen from baseline to four weeks (p < 0.004), which was
      significantly different from the change observed in the transdermal estradiol
      group (p < 0.05). CONCLUSIONS: These data suggest that the oral CEE-mediated
      increase in plasma vWF may have clinical relevance given the early
      atherothrombotic effects of HRT in postmenopausal women.

PMID- 12475461
TI  - Effects of nitroglycerin treatment on baroreflex sensitivity and short-term heart
      rate variability in humans.
AB  - OBJECTIVES: We set out to determine the effect of sustained treatment with
      nitroglycerin (GTN) on neural modulation of heart rate in humans. BACKGROUND:
      Acutely, exogenous and endogenous nitric oxide reduces sympathetic, while
      increasing vagal, outflow. An animal study showed loss of these effects during
      nitrate tolerance. METHODS: A total of 29 healthy men (age range, 18 to 32 years)
      received transdermal GTN (0.6 mg/h/24 h) or no therapy for six days in a parallel
      controlled trial. The reflex regulation of heart rate was assessed with the
      spontaneous baroreflex sensitivity (BRS) method. Heart rate variability was
      calculated both in time (standard deviation of mean RR interval [RRSD]) and
      frequency domains (Fast Fourier Transformation) over 10-min intervals. RESULTS:
      Systolic blood pressure was unchanged after continuous GTN, whereas mean RR
      interval decreased significantly (from 839 to 781 ms, p < 0.05). Nitroglycerin
      blunted BRS (p < 0.05). When compared with untreated subjects, RRSD was
      significantly lower after GTN, whereas the ratio of low to high frequencies was
      increased (all p < 0.05). CONCLUSIONS: Chronic GTN reduces tonic and reflex vagal
      heart rate modulation, resulting in greater relative sympathetic influence.
      Importantly, such changes in the regulation of chronotropic oscillations might
      have negative prognostic implications in both heart failure and coronary artery
      disease. Furthermore, because chronic GTN alters the blood pressure/heart rate
      relationship, our data suggest caution when using these variables as
      pharmacodynamic markers for the development of nitrate tolerance.

PMID- 12475462
TI  - The effect of vardenafil, a potent and highly selective phosphodiesterase-5
      inhibitor for the treatment of erectile dysfunction, on the cardiovascular
      response to exercise in patients with coronary artery disease.
AB  - OBJECTIVES: The effect of vardenafil, a potent and highly selective
      phosphodiesterase-5 (PDE5) inhibitor, on symptom-limited exercise time, time to
      first awareness of angina, and time to ischemic threshold (ST-segment depression
      > or =1 mm from baseline) during exercise tolerance testing (ETT) was examined in
      patients with stable coronary artery disease (CAD). BACKGROUND: Erectile
      dysfunction (ED) is common among men with CAD. PDE5 inhibition is increasingly
      the preferred treatment option for ED. However, the effect of PDE5 inhibition on
      exercise-induced ischemia in CAD patients has received limited prospective
      evaluation. METHODS: In this double-blind, crossover, single-dose multicenter
      study, 41 men with reproducible stable exertional angina due to ischemic CAD
      received vardenafil 10 mg or placebo, followed by ETT (5 to 10 metabolic
      equivalents [METS], Bruce protocol) 1 h postdose. Sublingual nitrate use was
      prohibited for > or =24 h pre- and postexercise study days. End points included
      symptom-limited treadmill exercise time, time to first awareness of angina, time
      to ischemic threshold, and safety. RESULTS: Relative to placebo, vardenafil 10 mg
      did not alter exercise treadmill time (427 +/- 105 s vs. 433 +/- 109 s, p =
      0.39), or time to first awareness of angina (292 +/- 110 s vs. 291 +/- 123 s, p =
      0.59), but significantly prolonged time to ischemic threshold (334 +/- 108 s vs.
      381 +/- 108, p = 0.0004). At peak exercise, vardenafil 10 mg did not alter blood
      pressure, heart rate, or rate-pressure product relative to placebo. The most
      common adverse events (facial flushing and headache) were of mild or moderate
      intensity, and short-lived. CONCLUSIONS: Vardenafil 10 mg did not impair the
      ability of patients with stable CAD to exercise at levels equivalent or greater
      than that attained during sexual intercourse (average of 2.5 to 3.3 METS).

PMID- 12475463
TI  - QRST subtraction combined with a pacemap catalogue for the prediction of ectopy
      source by surface electrocardiogram in patients with paroxysmal atrial
      fibrillation.
AB  - OBJECTIVES: This study evaluated the use of ectopic P-wave morphology to localize
      pulmonary vein (PV) and non-PV sources of atrial ectopics in patients with
      paroxysmal atrial fibrillation (PAF). BACKGROUND: The vectorial information
      embodied in the morphology of ectopic P waves is concealed by overlying T waves.
      METHODS: The P-wave morphology of 56 ectopics was prospectively analyzed in 44
      patients with PAF (age, 52 +/- 12 years; 36 male) by subtracting the adjacent
      QRST from the QRST-ectopic P-wave complex using custom-designed software.
      Subtraction fidelity was validated in 15 other patients (55 +/- 19 years, 11
      male) by comparing drive beats with simulated ectopics (S2 from the same site)
      unmasked by subtracting overlying QRST. An algorithm combined with PV pacemaps
      was used to predict PV sources. Subtracted ectopic P-wave morphologies after PV
      disconnection were compared with PV and non-PV site pacemaps. Localization was
      confirmed by mapping and successful ablation. RESULTS: A > or =10-lead
      electrocardiogram (ECG) match was observed in 92% of 644 simulated ectopics
      (coupling intervals: 190 to 520 ms). In PAF patients, 37 spontaneous ectopics
      originated from the PV, while 19 were noted after PV disconnection. Using the P
      wave algorithm alone, correct prediction of PV origin was achieved in 30/37
      ectopics (81%). Combination with PV pacemaps allowed correct prediction in 34/37
      (92%). After PV disconnection, ECG localization predicted successful ablation
      sites in 16/19 (84%). CONCLUSIONS: Comparison of subtracted ectopic P waves with
      a pacemap catalogue provides a simple and accurate 12-lead ECG-based method for
      localization, which can facilitate ablation of arrhythmia triggers irrespective
      of origin from the PV or elsewhere.

PMID- 12475464
TI  - Interventricular and intraventricular dyssynchrony in idiopathic dilated
      cardiomyopathy: a prognostic study with fourier phase analysis of radionuclide
      angioscintigraphy.
AB  - OBJECTIVES: The study evaluated the prognostic value of interventricular and
      intraventricular dyssynchrony in idiopathic dilated cardiomyopathy (IDC).
      BACKGROUND: Biventricular pacing is an emerging treatment for patients with
      dilated cardiomyopathy and ventricular dyssynchrony. The prognostic values of
      interventricular and intraventricular dyssynchrony have not been previously
      compared. METHODS: A total of 103 patients with IDC were studied. Left bundle
      branch block was present in 25% of patients. Equilibrium radionuclide angiography
      was performed and Fourier phase analyses were examined in both ventricles.
      Difference between the mean phase of left ventricle (LV) and right ventricle (RV)
      assessed interventricular dyssynchrony, and standard deviations (SDs) of the mean
      phase in each ventricle assessed intraventricular dyssynchrony. RESULTS: The QRS
      duration was related to both interventricular and intraventricular dyssynchrony.
      A degradation of the hemodynamic status was associated with an increase in
      intraventricular dyssynchrony but not in interventricular dyssynchrony. With a
      follow-up of 27 +/- 23 months, 18 patients had a major cardiac event (7 cardiac
      deaths; 11 worsening, leading to heart transplantation). The SDs of the LV and RV
      mean phase and QRS duration were predictors of cardiac event (all p < 0.0001),
      but interventricular dyssynchrony was not. Among 13 univariate predictors of
      cardiac event, the only independent predictors were an increased SD of LV mean
      phase (p = 0.0004) and an increased pulmonary capillary wedge pressure (p =
      0.009). CONCLUSIONS: Intraventricular dyssynchrony evaluated with phase analysis
      of radionuclide angiography is an independent predictor of cardiac event in IDC.
      The prognosis is related to intraventricular rather than to interventricular
      dyssynchrony in IDC.

PMID- 12475465
TI  - The importance of being synchronous: on the prognostic value of ventricular
      conduction delay in heart failure.

PMID- 12475466
TI  - Delisting of infants and children from the heart transplantation waiting list
      after carvedilol treatment.
AB  - OBJECTIVES: We performed a prospective, randomized, double-blind, placebo
      controlled study of carvedilol effects in children with severe, chronic heart
      failure (HF), despite the use of conventional therapy. BACKGROUND: Little is
      known about the effects of carvedilol in youngsters with chronic HF and severe
      left ventricular (LV) dysfunction. METHODS: We conducted a double-blind, placebo
      controlled study of 22 consecutive children with severe LV dysfunction. The
      children had chronic HF and left ventricular ejection fraction (LVEF) <30%.
      Patients were randomly assigned to receive either placebo (8 patients) or the
      beta-blocker carvedilol (14 patients) at 0.01 mg/kg/day titrated up to 0.2
      mg/kg/day, followed-up for six months. RESULTS: During the follow-up and the up
      titration period in the carvedilol group, four patients died and one underwent
      heart transplantation. In patients receiving carvedilol evaluated after six
      months, a significant increase occurred in LVEF, from 17.8% (95% confidence
      interval [CI], 14.1 to 21.4%) to 34.6% (95% CI, 25.2 to 44.0%); p = 0.001.
      Modified New York Heart Association (NYHA) functional class improved in nine
      patients taken off the transplant waiting list. All nine patients were alive at
      follow-up. In the placebo group, during the six-month follow-up, two patients
      died, and two underwent heart transplantation. Four patients persisted with HF
      symptoms (NYHA functional class IV). No significant change occurred in LVEF or
      fractional shortening. CONCLUSIONS: Carvedilol added to standard therapy may
      reduce HF progression and improve cardiac function, allowing some youngsters to
      be removed from the heart transplantation waiting list.

PMID- 12475467
TI  - Circadian variation of blood pressure and endothelial function in patients with
      essential hypertension:a comparison of dippers and non-dippers.
AB  - OBJECTIVES: The purpose of this study was to evaluate the relationship between
      the circadian blood pressure (BP) rhythm and endothelial function in patients
      with essential hypertension. BACKGROUND: Hypertension is associated with
      alterations in resistance artery endothelial function. Patients with a non-dipper
      circadian pattern of BP have a greater risk of cerebrovascular and cardiovascular
      complications than do patients with a dipper circadian pattern. METHODS: We
      evaluated the forearm blood flow (FBF) response to intra-arterial acetylcholine
      (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an
      endothelium-independent vasodilator, infusion in 20 patients with non-dipper
      hypertension and 20 age- and gender-matched patients with dipper hypertension.
      The FBF was measured using a mercury-filled Silastic strain-gauge plethysmograph.
      RESULTS: The 24-h systolic BP, as well as nocturnal systolic and diastolic BPs
      were higher in non-dipper patients than in dipper patients. The 24-h urinary
      excretion of nitrite/nitrate and cyclic guanosine monophosphate was lower in non
      dippers than in dippers. The response of FBF to ACh was smaller in non-dippers
      than in dippers (25.1 +/- 3.1 vs. 20.2 +/- 3.0 ml/min/100 ml tissue, p < 0.05).
      The FBF response to ISDN was similar in dippers and non-dippers. The FBF response
      to ACh was similar in the two groups following intra-arterial infusion of the
      nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine. CONCLUSIONS:
      These findings suggest that endothelium-dependent vasodilation is blunted through
      a decrease in NO release in non-dippers compared with patients who have dipper
      hypertension.

PMID- 12475469
TI  - Isometric arm counter-pressure maneuvers to abort impending vasovagal syncope.
AB  - OBJECTIVES: We hypothesized that isometric arm exercises were able to increase
      blood pressure (BP) during the phase of impending vasovagal syncope and allow the
      patient to avoid losing consciousness. BACKGROUND: Hypotension is always present
      during the prodromal phase of vasovagal syncope. METHODS: We evaluated the effect
      of handgrip (HG) and arm-tensing in 19 patients affected by tilt-induced
      vasovagal syncope. The study consisted of an acute single-blind, placebo
      controlled, randomized, cross-over tilt-table efficacy study and a clinical
      follow-up feasibility study. RESULTS: In the acute tilt study, HG was
      administered for 2 min, starting at the time of onset of symptoms of impending
      syncope. In the active arm, HG caused an increase in systolic blood pressure
      (SBP) from 92 +/- 10 mm Hg to 105 +/- 38 mm Hg, whereas in the placebo arm SBP
      decreased from 91 +/- 11 mm Hg to 73 +/- 21 mm Hg (p = 0.008). Heart rate
      behavior was similar in the two arms. In the active arm, 63% of patients became
      asymptomatic, versus 11% in the control arm (p = 0.02); conversely, only 5% of
      patients developed syncope, versus 47% in the control arm (p = 0.01). The
      patients were trained to self-administer arm-tensing treatment as soon as
      symptoms of impending syncope occurred. During 9 +/- 3 months of follow-up, the
      treatment was actually performed in 95/97 episodes of impending syncope (98%) and
      was successful in 94/95 (99%). No patients suffered injury or other adverse
      morbidity related to the relapses. CONCLUSIONS: Isometric arm contraction is able
      to abort impending vasovagal syncope by increasing systemic BP. Arm counter
      pressure maneuvers can be proposed as a new, feasible, safe, and well accepted
      first-line treatment for vasovagal syncope.

PMID- 12475468
TI  - Right ventricular function in adults with repaired tetralogy of Fallot assessed
      with cardiovascular magnetic resonance imaging: detrimental role of right
      ventricular outflow aneurysms or akinesia and adverse right-to-left ventricular
      interaction.
AB  - OBJECTIVES: We examined the relationship among biventricular hemodynamics,
      pulmonary regurgitant fraction (PRF), right ventricular outflow tract (RVOT)
      aneurysm or akinesia, and baseline and surgical characteristics in adults with
      repaired tetralogy of Fallot (rTOF). BACKGROUND: The precise relationship of
      pulmonary regurgitation with biventricular hemodynamics has been hampered by
      limitations of right ventricular (RV) imaging. METHODS: We assessed 85
      consecutive adults with rTOF and 26 matched healthy controls using cardiovascular
      magnetic resonance imaging. RESULTS: Patients had higher right ventricular end
      diastolic volume index (RVEDVi) (p < 0.001), right ventricular end-systolic
      volume index (RVESVi) (p < 0.001), right ventricular mass index (RVMi) (p <
      0.001), and lower right ventricular ejection fraction (RVEF) (p < 0.001) and left
      ventricular ejection fraction (LVEF) (p = 0.002) compared to controls. The PRF
      (range 0% to 55%) independently predicted RVEDVi (p < 0.01) and the latter
      predicted RVESVi (p < 0.01) and RVMi (p < 0.01). The RVOT aneurysm/akinesia was
      present in 48/85 (56.9%) of patients and predicted RV volumes (RVEDVi, p = 0.01,
      and RVESVi, p = 0.03). There was a negative effect of RVOT aneurysm/akinesia and
      RVMi on RVEF (p < 0.01 and p = 0.02, respectively). There was only a tendency
      among patients with transannular or RVOT patching toward RVOT aneurysm/akinesia
      (p = 0.09). The LVEF correlated with RVEF (r = 0.67, p < 0.001). CONCLUSIONS:
      Pulmonary regurgitation and RVOT aneurysm/akinesia were independently associated
      with RV dilation and the latter with RV hypertrophy late after rTOF. The RVOT
      aneurysm/akinesia was common but related only in part to RVOT or transannular
      patching. Both RV hypertrophy and RVOT aneurysm/akinesia were associated with
      lower RVEF. Left ventricular systolic dysfunction correlated with RV dysfunction,
      suggesting an unfavorable ventricular-ventricular interaction. Measures to
      maintain or restore pulmonary valve function and avoid RVOT aneurysm/akinesia are
      mandatory for preserving biventricular function late after rTOF.

PMID- 12475470
TI  - The commercial promotion of medicine.

PMID- 12475472
TI  - Percutaneous laser revascularization in patients with chronic total occlusions.

PMID- 12475473
TI  - Stented angioplasty or coronary artery bypass graft surgery for multivessel
      disease?

PMID- 12475475
TI  - Relationship of chlorine decay and THMs formation to NOM size.
AB  - Because of increasing concern about balancing health risks for pathogen control
      and disinfection by-product (DBP) formation in water supplies, utilities are
      forced to closely examine and optimize their disinfection practices. A better
      understanding of the relationship between the molecular weights of the natural
      organic matter (NOM), chlorine decay kinetics and THMs formation can help the
      utilities to minimize the DBP concentrations, providing healthier and microbially
      safer water. The authors present data on chlorine decay kinetics and total
      trihalomethanes (TTHM) formation kinetics and modeling with different molecular
      weights NOM fractions of Mississippi River water. TTHM modeling results indicated
      that the TTHM formation in fractionated NOM was a function of chlorine
      consumption. TTHM yield coefficients ranged from 31 to 42 microg-TTHM/mg-Cl2. As
      the molecular weight of the fractions decreased, TTHM yield coefficients
      increased.

PMID- 12475476
TI  - Solubilization and mineralization of polycyclic aromatic hydrocarbons by
      Pseudomonas putida in the presence of surfactant.
AB  - The solubilization and mineralization of polycyclic aromatic hydrocarbons (PAHs)
      in a soil system amended with different surfactants was examined. Mineralization
      experiments were conducted with the addition of [14C]pyrene. An inoculum of the
      PAH-degrading microorganism, Pseudomonas putida, was investigated for its
      sensitivity towards four non-ionic and one anionic surfactants with different
      polyoxyethylene (POE) chain lengths. The addition of surfactant was found to
      enhance the bioavailability of naphthalene, phenanthrene and pyrene with
      efficiencies ranging from 21.1 to 60.6%, 33.3 to 62.8% and 26.8 to 70.9%,
      respectively. The enhanced efficiency followed the order of Brij 30, Triton X
      100, Tween 80, and Brij 35, which is correlated with the polyoxyethylene chain of
      the surfactants. Brij 35 and Tween 80 inhibited the growth of P. putida. However,
      microorganisms can utilize Triton X-100 and Brij 30 as the sole carbon and energy
      sources at concentrations above CMC values. In the aqueous system without the
      addition of surfactants, microorganisms could mineralize [14C]pyrene to 14CO(2)
      which corresponds to 28% of mineralization. The addition of surfactants decreased
      the mineralization rate of pyrene. Also, the fraction of the micellar-phase
      pyrene that can be directly biodegraded decreased as the concentration of micelle
      increases. However, the mineralization rate can be enhanced by the amendment of
      Brij 30 when soil was applied to the cultures. This suggests that biodegradable
      surfactants can be applicable for increasing the bioavailability and
      mineralization of PAHs in soil systems.

PMID- 12475477
TI  - Chemical oxidation of chlorinated non-aqueous phase liquid by hydrogen peroxide
      in natural sand systems.
AB  - This study explored the Fenton-like oxidation of trichloroethylene (TCE) existing
      as dense non-aqueous phase liquid (DNAPL) in natural silica sand (iron=0.04 g/kg)
      and the sand from an aquifer (iron=2.01 g/kg). Glass bead containing no iron
      mineral was used as the control. Batch oxidation experiments were conducted to
      assess interactions between oxidant and TCE DNAPL. Column experiments were
      performed to evaluate dynamics of TCE and H(2)O(2) during oxidation. The pH was
      not altered. In the batch system, a single application of 3% H(2)O(2) to the
      aquifer sand oxidized 40% of the added TCE DNAPL in 1 h, which was four times of
      that by dissolution with the gas purge procedure. This demonstrated the ability
      of mineral-catalyzed Fenton-like reaction to directly oxidize TCE in non-aqueous
      liquid. In the column experiments, after passing 7 pore volumes (PVs) of 1.5 and
      3% H(2)O(2) solution, the residual TCE in aquifer sand column was 12.0 and 2.6%
      of the initial added, respectively. On the other hand, 28.4% of the added TCE
      still remained in the silica sand column by 7 PVs of 3% H(2)O(2). The
      distribution of TCE in column and effluent indicated the occurring of direct
      oxidation of TCE DNAPL and the increased solubilization, which probably due to
      size reduction of DNAPL droplets, followed by water-phased TCE oxidation.

PMID- 12475478
TI  - Influence of raw materials and distillation equipment on the heavy metal content
      of waste from an alcoholic anis-type beverage.
AB  - This study focused on the heavy metal content waste resulting from the production
      of an anis-type beverage. Although natural ingredients were used in the
      production process, the waste contains heavy metals and is considered hazardous.
      Several metals were found in the waste (Fe, Cu, Ni, Zn, Cr and Cd), with
      concentrations of Fe to 157.5, Cu to 82.5, Zn to 31 and Ni to 8.5mg/l. To collect
      information on the source of these metals, the residues of the herbs used for
      flavoring were examined for processes employing metallic and non-metallic pot
      stills. Herbs distillation residues were found to contain metals in non-metallic
      stills, e.g. aniseed residues from glass stills contained Cu up to 1.02 and Ni up
      to 0.9 mg/l. Fennel residues contained Ni up to 1.2 and Zn up to 6.6mg/l. The
      main source for the metals was the bronze pot stills. The metals were in
      complexed form in the solution. The existence of metals in the amorphous phase as
      shown by a SEM micrograph indicates forming of metal-organic complexes, also
      verified by HPLC. Complexation data can be used for selecting the proper wash
      treatment method. The formation of large molecules favors precipitation and chemi
      sorption treatment methods.

PMID- 12475479
TI  - Degradation of perchloroethylene in cosolvent solutions by zero-valent iron.
AB  - Remediation of sites contaminated by chlorinated organic compounds is a
      significant priority in the environmental field. Subsequently, the addition of
      cosolvent solutions for in situ flushing of contaminated source zones has been
      successfully field tested. However, the treatment of effluent fluids in such
      cleanup efforts is an often overlooked component of this technology
      implementation. The purpose of this research was to evaluate the effectiveness of
      zero-valent iron (Fe(0)) in treating perchloroethylene (PCE) in an aqueous
      solution, and how the presence of a cosolvent (ethanol) and modification of the
      iron surface altered dechlorination. The modified iron surfaces included in this
      study were nickel-plated iron, acid-treated iron, and untreated iron surfaces.
      PCE dechlorination in the presence of each of the iron surfaces displayed pseudo
      first-order kinetics. The highest degradation rate of PCE occurred on the nickel
      plated iron surface, 5.83 x 10(-3)h(-1), followed by the acid-treated iron, 4.92
      x 10(-3)h(-1), and the untreated iron, 3.34 x 10(-3)h(-1). Dechlorination on each
      of the surfaces decreased with increasing cosolvent fractions. It was shown that
      as cosolvent fractions increased, PCE adsorption decreased and resulted in a
      concomitant decrease in PCE degradation rates.

PMID- 12475480
TI  - Biological treatment of mixed industrial wastewaters in a fluidised bed reactor.
AB  - A study has been carried out on the operating parameters that influence the
      biodegradation of petroleum and brewery wastewaters, with a low-density biomass
      support. The biodegradation rate of a mixture of two wastes was compared with
      that of the separate wastes. A low aspect ratio reactor was employed, and this
      made it possible to operate at low superficial gas and liquid velocities. The gas
      distributor used created a fluid flow pattern similar to that of a draft tube,
      which enhanced axial mixing. At a particles loading of 12% (v/v), the optimum
      superficial gas velocity was 2.5 cm/s for the mixture. The interstice structure
      of the biomass-support particles, improved microbial attachment due to the
      resulting large surface area. There was a low biomass concentration when
      petroleum wastewater was treated alone, however, for a mixture of petroleum and
      brewery wastewaters, an increase in the concentration was observed. There was a
      higher gas hold up in the mixture than in the petroleum wastewater, but lower
      than in the brewery wastewater. An improved biodegradation was achieved when a
      mixture of brewery and petroleum wastewaters was treated, and this gave an
      indication that nutrient deficient wastes can be treated together with phosphate
      and nitrate rich food industry wastewaters.

PMID- 12475481
TI  - Sorption and permeability of gasoline hydrocarbons in organobentonite porous
      media.
AB  - We investigate the use of organobentonites as liners for underground gasoline
      storage tanks to reduce the risk of subsurface contamination. A series of
      permeability measurements were conducted on two types of organobentonites:
      benzyltriethylammonium-bentonite (BTEA-bentonite) and hexadecyltrimethylammonium
      bentonite (HDTMA-bentonite). Both water and commercial unleaded gasoline were
      used as the permeant liquids. Results of these measurements indicate that the
      intrinsic permeability of the organobentonite decreases by one to two orders of
      magnitude when the permeant liquid is changed from water to gasoline. Results of
      batch sorption measurements reveal that benzene sorption to both organobentonites
      from water is greater than benzene sorption to conventional bentonite. The
      magnitude of benzene sorption is related to the loading of the organic quaternary
      ammonium cation on the clay. As the HDTMA cation loading increases from 25% of
      cation exchange capacity (CEC) to 120% of CEC, benzene sorption increases.
      However, as the BTEA cation loading increases from 40 to 120% of CEC, benzene
      sorption decreases. Collectively, these results suggest that organobentonites can
      be used effectively to reduce hydrocarbon migration rates beneath leaking
      underground gasoline storage tanks, and that the optimal organic cation loading
      with respect to pollutant sorption may be less than 50% of cation exchange
      capacity for some organobentonite-solute combinations.

PMID- 12475484
TI  - Physical education - new technologies for mapping plant genomes.

PMID- 12475491
TI  - Early diversification of plant aquaporins.

PMID- 12475492
TI  - Transcription factors do it together: the hows and whys of studying protein
      protein interactions.
AB  - Protein-protein interactions are intrinsic to virtually every cellular process.
      Recent breakthroughs in techniques to study protein-interaction and the
      availability of fully sequenced plant genomes have attracted many plant
      scientists to undertake the first steps in the field of protein interactions.
      High-throughput screening systems allow the discovery of protein functions. Even
      without performing laborious functional assays, in planta functional homologues
      and redundant proteins can be accurately predicted based on protein-interaction
      maps. Therefore, protein-protein-interaction screenings are an essential
      supplement to the current functional-genomics toolbox.

PMID- 12475493
TI  - Moss transcriptome and beyond.
AB  - The ancient land plant Physcomitrella patens is a model system that is becoming
      increasingly important for plant functional genomics because gene knockouts can
      be produced with relative ease. Recently, several EST-sequencing projects have
      been launched as a first step towards a thorough functional characterization of
      the moss. However, for careful comparison with other plant model systems, the
      complete genomic sequence is needed as well as the transcriptome.

PMID- 12475494
TI  - Obtaining the sequence of the rice genome and lessons learned along the way.
AB  - Rice holds the record for the largest number of separate genome projects and for
      having the genome of two subspecies sequenced. This might be a short-lived record
      in the genomics era, but it highlights the significance of rice as a food staple
      and as a model plant for cereal species. Clearly, obtaining the genome sequence
      four times seems redundant, yet the rationale and motivation for each of these
      projects is valid; whether it is serving corporate shareholders or the general
      scientific community. Although the multiple projects resulted in some duplicated
      efforts, the value of data sharing was obvious and the winner in the end will be
      the global public.

PMID- 12475495
TI  - Universal inheritable barcodes for identifying organisms.
AB  - The needs for recognition of novel conventional or transgenic organisms include
      protection of patented or Identity Preserved lines, detecting transgenics and
      tracing dispersal. We propose simple 'Biobarcodes' using universal PCR primers to
      recognize the universal 'nonsense' recognition site of all biobarcodes, followed
      by a variable nonsense sequence. The proposed sequences are long enough to allow
      recognition in spite of mutations, have stop codons to prevent coding, and will
      not self anneal. Sequences of PCR-amplified biobarcodes can be compared to a
      universal database.

PMID- 12475496
TI  - Domains as functional building blocks of plant proteins.
AB  - Emerging evidence in eukaryotic systems suggests that many proteins of diverse
      cellular processes are made up of protein domains that are well defined in both
      sequence and structure. This article updates the identification of many 'classic'
      eukaryotic protein domains in various plant cellular processes, with particular
      emphasis on the non-catalytic categories. We discuss the importance of domains to
      plant-protein functions and cellular networking, and the emergence of plant
      specific domains.

PMID- 12475497
TI  - Deciding among green plants for whole genome studies.
AB  - Recent comparative DNA-sequencing studies of chloroplast, mitochondrial and
      ribosomal genes have produced an evolutionary tree relating the diversity of
      green-plant lineages. By coupling this phylogenetic framework to the explosion of
      information on genome content, plant-genomic efforts can and should be extended
      beyond angiosperm crop and model systems. Including plant species representative
      of other crucial evolutionary nodes would produce the comparative information
      necessary to understand fully the organization, function and evolution of plant
      genomes. The simultaneous development of genomic tools for green algae,
      bryophytes, 'seed-free' vascular plants and gymnosperms should provide insights
      into the bases of the complex morphological, physiological, reproductive and
      biochemical innovations that have characterized the successful transition of
      green plants to land.

PMID- 12475498
TI  - The Dof family of plant transcription factors.
AB  - Dof proteins are members of a major family of plant transcription factors. The
      proteins have similar DNA-binding properties because of the highly conserved DNA
      binding domain. However, recent studies are disclosing their diverse roles in
      gene expression when associated with plant-specific phenomena including light,
      phytohormone and defense responses, seed development and germination. Based on
      the structural diversity indicated by the complete catalog of Arabidopsis Dof
      proteins, Dof genes appear to have evolved multiple times, preceding and
      paralleling the diversification of angiosperms. Such gene multiplication might
      have led to the functional diversification of Dof proteins proceeding differently
      in distinct plant species.

PMID- 12475503
TI  - Acute dorsal trans-scaphoid perilunate fracture-dislocations: medium-term
      results.
AB  - The purpose of this study was to investigate the medium-term results (mean follow
      up, 8 years) of a series of 14 trans-scaphoid dorsal perilunate fracture
      dislocations treated operatively at an average of 6 days following injury. Eleven
      underwent open reduction and internal fixation through a dorsal approach.
      Combined palmar and dorsal approaches were used in only three cases, for open
      reduction and internal fixation in two and proximal row carpectomy in one. The
      Mayo wrist score revealed five excellent, three good, five fair and one poor
      result. The average score was 79% (range 55-95%). All internally fixed scaphoids
      healed and no lunate or scaphoid fragment avascular necrosis with collapse was
      observed. Carpal alignment was satisfactory in most cases. Post-traumatic
      radiological midcarpal and/or radiocarpal arthritis were almost always observed
      at follow-up, but this did not correlate with the Mayo wrist score.

PMID- 12475504
TI  - Synovial cyst of the pulp of the little finger--origin from the wrist joint.
AB  - Synovial cysts of the pulp of the little finger in three elderly patients were
      shown by arthrography to arise from leakage of synovial fluid from the wrist
      joint into the ulnar bursa and thence into the flexor synovial sheath in the
      digit. Distant as well as local sources of the contents of synovial cysts should
      be considered when the local anatomy permits communication between a degenerate
      joint and an adjacent tendon sheath.

PMID- 12475505
TI  - Primary flexor tendon repair--operative repair, pulley management and
      rehabilitation.

PMID- 12475506
TI  - Hand-arm-vibration syndrome (HAVS): is there a central nervous component? An fMRI
      study.
AB  - Hand-held vibrating tools may result in neuromuscular dysfunction and vasospastic
      problems of the hand. Sensory and motor dysfunction can be explained by injury to
      peripheral structures, but could also be due to changes in cortical somatotopic
      mapping of the hand in the brain. The purpose of the present study was to use
      functional magnetic resonance imaging (fMRI) to assess the somatotopic cortical
      representation of the hands of workers subjected to occupational vibration. The
      study included six men with severe vibration exposures who were suffering from
      hand-arm-vibration syndrome (HAVS) and six controls. The analysis focused on the
      pattern and degree of activation of contra- and ipsilateral hemispheres of the
      brain with tactile stimulation and motor activation of the hand. These
      stimulations resulted in well-defined activation of the contralateral, and to a
      lesser extent the ipsilateral hemisphere. Statistical analysis of this limited
      patient material did not indicate any significant somatotopic cortical changes
      following long-term exposure to vibrating hand-held tools, although there was a
      tendency to a shift of activation towards the more cranial parts of the cortex in
      the patient group.

PMID- 12475507
TI  - Hand muscle weakness in long-term vibration exposure.
AB  - Hand muscle strength was compared between workers regularly exposed to hand-held
      vibrating tools (n=81) and a non-exposed control group (n=45). Maximal voluntary
      strengths of hand grip, thumb pinch, thumb palmar abduction and index and little
      finger abduction were measured. The exposed workers had significantly weaker
      extrinsic (7%, P<0.01) and intrinsic (19%, P<0.0001) muscles than the controls.
      Reduced vibration perception was noted in nine vibration-exposed workers who
      presented with symptoms of hand muscle weakness (P<0.01). Cold intolerance
      following vibration exposure was found to precede sensorineural and vasospastic
      symptoms. We therefore postulate that cold intolerance may be a valuable marker
      for early detection of the adverse effects of vibration. This study emphasizes
      the need for tests of intrinsic muscle strength in order to evaluate the
      impairment of hand function observed in vibration-exposed workers.

PMID- 12475508
TI  - Dominances in finger arteries.
AB  - We studied the patterns of dominance in the palmar digital arteries of the
      fingers in 39 fresh cadaver arms which had been injected with coloured latex
      solution. We also performed photoplethysmographic studies in 20 hands. The ulnar
      digital artery in the index finger and the radial digital artery of the little
      finger were usually dominant, and their counterparts were slim and often
      hypoplastic. The findings are relevant to digit revascularization and might
      influence the planning of digital island-flaps or toe transfers.

PMID- 12475509
TI  - A prospective review of open central slip laceration repair and rehabilitation.
AB  - A prospective review was carried out to evaluate the outcome of surgically
      repaired open central slip (zone III) injuries which were treated with 3 weeks of
      proximal interphalangeal joint immobilization within a cylinder splint and then
      with 3 weeks of controlled mobilization within a Capener coil splint. Thirty-one
      fingers in 27 patients were assessed by the same independent therapist. All
      fingers achieved an excellent or good recovery with a mean proximal
      interphalangeal joint flexion of 94 degrees (range 70-110 degrees) and a mean
      distal interphalangeal joint flexion of 57 degrees (range 30-81 degrees).
      Extension deficits of the proximal interphalangeal joint were noted in five
      fingers (mean 6 degrees, range 3-15 degrees). The results show that a combination
      of immobilization and controlled mobilization is an effective rehabilitation
      regime for surgically repaired open central slip injuries.

PMID- 12475510
TI  - Posterior interosseous nerve palsy due to parosteal lipoma.
AB  - Lipomas are extremely common benign soft tissue tumours that are usually
      subcutaneous and asymptomatic. Occasionally, lipomas can occur in deeper soft
      tissue planes and when adjacent to the neck of the radius they can cause
      compression of the posterior interosseous nerve. Five such cases are described.
      An anterior approach to excision of the lipoma is recommended.

PMID- 12475511
TI  - Norian SRS versus functional treatment in redisplaced distal radial fractures: a
      randomized study in 20 patients.
AB  - We compared the use of Norian SRS, an injectable calcium phosphate bone cement,
      with functional treatment of redisplaced distal radial fractures in a prospective
      randomized study of 20 patients. The redisplaced fractures were either rereduced
      and stabilized by Norian SRS, or the displaced position was accepted and was not
      rereduced. All wrists were immobilized in a short-arm dorsal splint for 1 week,
      followed by a removable splint for another 3 weeks. The chosen primary effect
      variable was grip strength at 7 weeks, and this did not differ between the two
      treatment groups. The clinical results at 6 months in both groups were similar.
      We conclude that aggressive treatment of redisplaced fractures of the distal
      radius may be unnecessary in most women aged 50 years or more.

PMID- 12475512
TI  - Treatment of "Gamekeeper's Thumb" by reconstruction of the ulnar collateral
      ligament.
AB  - This study examines the treatment of 22 thumbs with symptomatic laxity of the
      ulnar collateral ligament of the metacarpophalangeal joint by ligament
      reconstruction 1 week to 10 years after injury. The existing ligament remnants
      were repaired in 13 thumbs and were re-attached to bone, using a bone anchor, in
      seven cases. Two ligaments were reconstructed using the extensor pollicis brevis
      tendon. Patients were reviewed at a mean of 16 months. Functional stability was
      regained in all patients, but two thumbs had ongoing pain in the
      metacarpophalangeal joint. All but one patient returned to their original work
      and recreational pastimes. This study suggests that ligament reconstruction for
      chronic laxity of the ulnar collateral ligament is likely to achieve painless
      stability of the metacarpophalangeal joint even when reconstruction is delayed.
      This makes joint fusion unnecessary in most instances.

PMID- 12475513
TI  - Radiographic assessment of the relative lengths of the bones of the fingers of
      the human hand.
AB  - The study assessed whether a relationship existed between the lengths of the
      phalanges of the fingers of the hand. The centres of rotation of the joints in
      each finger were determined by dissection of cadaveric hands. Using these data,
      the distances between the joint centres was determined on anteroposterior hand X
      rays taken for clinical purposes. The study has shown that, for all the fingers,
      there is a ratio of 1 for the distance between the metacarpophalangeal and
      proximal interphalangeal joint and the distance between the proximal
      interphalangeal joint and the finger tip. The ratio for the distances between the
      interphalangeal joints and the distal joint and the tip approximates to 1.3 for
      the index, middle and ring fingers and to 1.0 for the little finger. No evidence
      was found to support Littler's hypothesis that the interarticular distances of
      the finger follow the Fibonacci sequence.

PMID- 12475514
TI  - Acquired periungual fibrokeratoma with accessory germinal matrix.
AB  - Five cases of acquired periungual fibrokeratoma involving the proximal nail fold
      were treated surgically. Clinically, all five patients regained normal nail
      contours postoperatively, but one patient developed a local recurrence 1 year
      after operation. Histologically, an accessory germinal matrix was observed at the
      distal end of the lesion in all five cases. Change in pressure around the lesion
      seemed to have induced the formation of this accessory germinal matrix.

PMID- 12475515
TI  - Granuloma annulare in the hand.
AB  - A review of our cases of granuloma annulare in the hand revealed that it
      presented as either an annular or subcutaneous lesion, most commonly on the
      dorsum of the metacarpophalangeal joint of the middle or ring fingers. Lesions
      were approximately 10 mm in diameter and the diagnosis was confirmed by surgical
      biopsy. The majority of cases resolved spontaneously within 1 year, and
      recurrence, though common, did not necessitate a further biopsy.

PMID- 12475516
TI  - Simple decompression with small skin incision for cubital tunnel syndrome.
AB  - Eighteen elbows in 17 patients with cubital tunnel syndrome were treated by
      simple decompression using only a 1.5-2.5 cm skin incision with no endoscopic
      assistance. According to McGowan's criteria, three elbows were classified
      preoperatively as grade I, six as grade II and nine as grade III. The mean follow
      up period was 14 months (range 3-25). Clinical results were evaluated as
      excellent for four elbows, good for ten and fair for four. Improvement of
      symptoms occurred in all patients and dislocation of the ulnar nerve was not
      observed. Simple decompression through a small skin incision can be recommended
      for the treatment of cubital tunnel syndrome, if the indication is appropriate.

PMID- 12475517
TI  - Arthrodesis of the wrist with bioabsorbable fixation in patients with rheumatoid
      arthritis.
AB  - Twenty-four wrist arthrodeses were performed on 18 patients with rheumatoid
      arthritis using a bioabsorbable self-reinforced poly-L-lactide rod as the
      fixation device. There was one nonunion which required a re-operation and two
      nonunions which did not need further treatment. The position of the arthrodesis
      was ulnar deviation and extension in most patients, and there was high patient
      satisfaction with 21 of the 24 wrists and satisfactory pain relief in 22 of the
      24 wrists. This method for fusing the wrist in patients with rheumatoid arthritis
      appears reliable and simple to perform.

PMID- 12475518
TI  - Wrist arthrodesis: modified Gill's technique.
AB  - Twenty-five wrist arthrodesis procedures were performed on 24 patients, applying
      a modification of Gill's technique, which used a corticocancellous strut graft
      from the distal radius. Patients were followed up until solid bony fusion was
      established. Union was achieved in 21 of 25 wrists and was subsequently achieved
      with a further procedure in the remaining four wrists. We have found that the
      modified Gill's technique is a reliable, simple procedure with a low complication
      rate which does not require the harvest of a distant bone graft.

PMID- 12475519
TI  - Fibulo-scapho-lunate arthrodesis as a motion-preserving procedure after tumour
      resection of the distal radius.
AB  - Free microvascular fibula transfer is an established method for reconstruction of
      the distal radius following tumour resection. If the radial articular surface is
      resected, fixation of the fibula to the carpus is either performed as a complete
      wrist fusion, or the fibular head is transferred together with the shaft to
      replace the radial joint surface, thus allowing some wrist mobility but providing
      only limited wrist stability. Fibulo-scapho-lunate fusion represents an
      alternative. This reconstruction in two patients provided excellent wrist
      stability and a functional range of midcarpal motion.

PMID- 12475520
TI  - An anatomical study of the dorsal cutaneous branches of the digital arteries.
AB  - This study describes the anatomy of the dorsal digital arteries in the 144
      fingers of 18 pairs of fresh human cadaver hands. Previous studies have shown two
      constant branches in the proximal and middle pulp spaces from each proper digital
      artery. We have shown that these branches have consistent sites of origin at
      predictable distances from the proximal interphalangeal joint. Thus cutaneous
      flaps can be safely planned on these dorsal vessels.

PMID- 12475521
TI  - High bifurcation of median nerve at the wrist causing common digital nerve injury
      in endoscopic carpal tunnel release.
AB  - A 45-year-old right-handed woman was treated by endoscopic carpal tunnel release
      under local anaesthetic. When cutting the proximal half of the flexor retinaculum
      with the retrograde blade, she complained of an electric shock-like pain in her
      middle and ring fingers. Open exploration of the carpal tunnel was performed and
      a laceration of the middle/ring common digital nerve, which bifurcated at the
      unusually high level of the wrist crease, was found.

PMID- 12475522
TI  - Entrapment neuropathy of the palmar cutaneous branch of the median nerve
      concomitant with carpal tunnel syndrome: a case report.
AB  - A case of the entrapment neuropathy of the palmar cutaneous branch of the median
      nerve, concomitant with carpal tunnel syndrome is presented. This report
      demonstrates that the Semmes-Weinstein monofilament test and nerve conduction
      studies can identify entrapment of the palmar cutaneous branch of the median
      nerve concomitant with carpal tunnel syndrome.

PMID- 12475523
TI  - Isolated injury to a major branch of the posterior interosseous nerve--a rare
      occurrence?

PMID- 12475527
TI  - MnDPDP enhanced magnetic resonance imaging of focal liver lesions.
AB  - Mangafodipir trisodium (MnDPDP) is a contrast agent for use in magnetic resonance
      imaging (MRI) of the liver. The agent is taken up by normal hepatocytes resulting
      in increased signal on T1-weighted imaging, and is excreted in the biliary
      system. Hepatocyte-containing liver neoplasms such as hepatomas or focal nodular
      hyperplasia (FNH), take up MnDPDP and demonstrate varying degrees of enhancement.
      Metastatic liver deposits and primary liver tumours of non-hepatocyte origin do
      not typically enhance with MnDPDP thus increasing their conspicuity compared with
      pre-contrast T1-weighted images. Metastases may demonstrate rim enhancement
      particularly on delayed imaging at 24 h, which can increase their conspicuity,
      thus allowing better visualization of small lesions. Functional biliary
      obstruction due to liver metastases can also result in wedge shaped areas of
      parenchymal enhancement. The MRI features of various focal liver after
      continuance with lesions following MnDPDP are discussed and illustrated including
      primary lesions such as hepatoma and secondary metastases.

PMID- 12475528
TI  - The imaging features of post-traumatic myositis ossificans, with emphasis on MRI.
AB  - Post-traumatic myositis ossificans is a benign condition of heterotopic bone
      formation, which can mimic soft-tissue and bone malignancies. This pictorial
      review describes the specific imaging features of myositis ossificans using
      different imaging techniques, but with emphasis on MRI.

PMID- 12475529
TI  - A survey of current practice in out of hours percutaneous nephrostomy insertion
      in the United Kingdom.
AB  - AIM: To establish the current out of hours service provided in the United Kingdom
      for nephrostomy insertion. MATERIALS AND METHODS: Using the Royal College of
      Radiologists' (RCR) database a questionnaire was sent to all the current clinical
      directors. RESULTS: Questionnaires were sent to 246 hospitals, with replies
      received from 178 (72.3%). The number of consultants doing nephrostomies as part
      of their routine work was 476; this increased to 625 including those who perform
      nephrostomies out of hours. Therefore 24% of consultants only perform
      nephrostomies out of hours. For the times when there was no formal out of hours
      nephrostomy service, the arrangements varied and included calling a consultant
      who was not on call (52%), or transferring the patient (37%). Only 19 hospitals
      (11%) had a separate interventional on call rota, the majority of these being
      teaching hospitals (68%). The availability of assistance was limited, with
      nursing staff available only 43% of the time. In institutions with specialist
      registrars, the registrars were involved with the nephrostomies 75% of the time.
      CONCLUSIONS: There is a wide variation in the out of hours service provided by
      radiology departments for nephrostomy insertion. A large percentage of out of
      hours nephrostomies are done by consultants who do not perform do the procedure
      as part of their routine clinical practice, which is contrary to the advice of
      the Royal College of Radiologists for out of hours working. In addition the
      provision of nursing assistance for the procedure is inadequate.

PMID- 12475530
TI  - Trends in radiological anatomy teaching in the U.K. and Ireland.
AB  - AIM: To determine the prevalence of radiological anatomy teaching in modern
      medical curricula. MATERIALS AND METHODS: The present paper details a survey
      carried out amongst 21 medical schools in the U.K. and Ireland to determine the
      variability of the inclusion of radiological anatomy in their different
      curricula. RESULTS: In all the institutions surveyed teaching of anatomy as
      revealed by radiological techniques was delivered by anatomy departments. There
      was considerable variation, however, in the way in which it was delivered, by
      whom and in the range of radiological material available. Most anatomy
      departments had links with radiology departments, though the precise arrangements
      of these also varied. CONCLUSION: This study highlights the need for
      standardization between anatomy departments with regard to the content and level
      of radiological anatomy taught to ensure that an appropriate basis for clinical
      undergraduate training is provided.

PMID- 12475531
TI  - Hepatic metastases from an unknown primary neoplasm (UPN): survival, prognostic
      indicators and value of extensive investigations.
AB  - AIM: The objectives of this study were to identify prognostic features for
      patients with hepatic metastases and unknown primary neoplasms (UPN), determine
      the common primary tumours, assess the value of diagnostic tests in finding these
      tumours, and evaluate the impact of therapy and knowledge of the primary tumour
      on patient survival. MATERIALS AND METHODS: Eighty-eight patients with UPN and
      liver biopsy proven hepatic metastases over a 10-year period were reviewed (M:F,
      58:30; age range 27-91 years, median 64.5 years). Histopathology, diagnostic
      investigations and success at identifying the primary neoplasm were recorded. In
      addition, in 70 patients with adenocarcinoma histology (M:F, 48:22; age range 27
      91 years, median 65 years), treatment and survival data from the date of biopsy
      were recorded. RESULTS: The histological spectrum included adenocarcinoma in 70,
      neuroendocrine in four, squamous cell carcinoma in four, small cell carcinoma in
      four, carcinoid in two, hepatoma in one and three others. Extensive investigation
      identified a primary neoplasm in 16/88 patients (18%) including colorectal in
      six, gastric in two, lung in four, oesophageal in two, prostate in one and
      carcinoid in one. In the adenocarcinoma group survival data were available for
      62/70 patients. Sixteen of 62 patients received active treatment with either
      surgery, chemotherapy, radiotherapy or a combination protocol. Forty-six of 62
      patients received palliative care alone. Median survival for the adenocarcinoma
      group overall was 49 days. The median survival for treated patients (49 days)
      versus untreated patients (52 days) was not significantly different (P=0.128).
      Patients <65 years were more likely to receive active treatment than those >65
      years (P=0.006). Age with a hazard ratio (HR) of 1.01 (P=0.178), active treatment
      (HR=0.65;P=0.194), knowledge of the primary neoplasm (HR=0.60;P=0.213) and male
      gender (HR=0.88;P=0.642) had no significant effect on survival. CONCLUSION:
      Although hepatic metastases are associated with poor prognosis, it is essential
      that a liver biopsy be performed to obtain a histological diagnosis.
      Adenocarcinoma metastases carry a dismal prognosis, and no prognostic factors,
      including knowledge of the primary tumour, are significant for patient survival.
      Extensive investigation is not warranted in patients with adenocarcinoma liver
      metastases.

PMID- 12475532
TI  - High-resolution CT features of severe asthma and bronchiolitis obliterans.
AB  - AIM: To evaluate the high-resolution CT findings of severe asthma (SA) and
      bronchiolitis obliterans (BO) and determine whether any reliable discriminating
      HRCT features exist. MATERIALS AND METHODS: HRCT examinations of the chest of 30
      patients with SA and 14 patients with BO were analysed. Images were scored for
      the presence and extent of 21 CT findings. RESULTS: The most consistent HRCT
      features in SA were bronchial wall thickening in 30 (100%), expiratory air
      trapping in 19 of 22 examinations with expiratory images (87%), inspiratory
      decreased attenuation in 18 (60%), and bronchial luminal narrowing in 12 (40%).
      The most consistent HRCT features in BO were expiratory air trapping in 10 of 10
      examinations with expiratory images (100%), bronchial wall thickening in 13
      (93%), inspiratory decreased attenuation in 11 (79%), ground glass opacity in
      seven (50%), and mosaic pattern of attenuation in seven (50%). Decreased
      attenuation was more extensive in BO than in SA on both inspiratory and
      expiratory images. The mosaic pattern of attenuation was present in seven (50%)
      BO patients but in only one (3%) SA patients (P=0.0006). CONCLUSIONS: Mosaic
      pattern of attenuation, when present, is highly suggestive of BO, but SA and BO
      may be indistinguishable.

PMID- 12475533
TI  - Should breast screening programmes limit their detection of ductal carcinoma in
      situ?
AB  - OBJECTIVE: Previous research has shown that the detection of ductal carcinoma in
      situ (DCIS) aids the detection of small invasive cancers at mammographic
      screening. A correlation may therefore exist between a screening unit's DCIS
      detection rate and their small invasive cancer detection rate. We have therefore
      investigated the effect of DCIS detection rate on the detection of small (<15 mm)
      invasive cancers in the 95 units of the U.K. NHS Breast Screening Programme
      (NHSBSP). MATERIALS AND METHODS: DCIS detection rates were examined against large
      (> or =15 mm) and small (<15 mm) invasive cancer detection rates in women aged 50
      64 years at prevalent and incident screens over a 3-year period. RESULTS: After
      adjusting for background incidence, screening units with the highest DCIS
      detection of > or =1.3/1000 detected over 20% more small invasive cancers than
      units with DCIS detection rates within the NHSBSP guidelines of 0.5-1/1000
      (P<0.001). Sixty percent of units had DCIS detection rates above the guidelines.
      There was no correlation between DCIS detection and > or =15 mm invasive cancer
      detection. The results suggest that over the range of DCIS rates studied, that
      for every two extra DCIS cancers detected, an additional small invasive cancer
      (<15 mm) is detected that may otherwise not have been. The results therefore
      provide supporting evidence that the detection of DCIS aids the detection of
      small invasive cancers. CONCLUSION: Units with DCIS detection above the NHSBSP
      guidelines have significantly better small invasive cancer detection rates. The
      existence of an upper limit for DCIS detection within the NHSBSP may be
      preventing the detection of small invasive cancers, because units are not
      recalling some small clusters of calcification in order to keep DCIS detection
      rates down. The upper limit may therefore be inappropriate.

PMID- 12475534
TI  - Is breast MRI ever useful in a mammographic screening programme?
AB  - OBJECTIVE: To establish the diagnostic impact of breast magnetic resonance
      imaging (MRI), on the management of cases in our mammographic screening
      programme. METHODS AND MATERIALS: We analysed the cases examined from July 1997
      to December 2000 during which time 44,000 population screening mammograms and 85
      MRI studies were undertaken on women identified by computer overlap. The studies
      were reviewed to find the reason for the MRI study and its diagnostic impact.
      RESULTS: Of 83 studies analysed, 31 were for recurrence of tumour, 33 in newly
      diagnosed cancer, 22 to assess extent, 11 to monitor primary chemotherapy. In a
      small diagnostic subset of 19 cases MRI was used to find or characterize a
      lesion. The 11 cases in which MRI results caused a measurable beneficial change
      in management were from the query recurrence and diagnostic groups. In 52 cases
      from all groups, MR increased diagnostic confidence. In 11 cases MRI results were
      indeterminate, and in six of these stimulated more studies. CONCLUSION: MRI is an
      expensive investigation and its use must be justified. There is a limited, but
      valuable role for breast MRI in selected cases from screening assessment.
      Misinterpretation of enhancing lesions may generate additional procedures.
      Diagnostic impact was greatest for the detection of tumour recurrence.

PMID- 12475535
TI  - Subvoxel image registration of multislice (2D) magnetic resonance images in
      patients with high-grade gliomas of the brain.
AB  - AIMS: To implement a multislice two-dimensional (2D) T2-weighted sequence
      suitable for subvoxel image registration and to assess its usefulness in
      detecting change in high-grade intracranial gliomas. MATERIALS AND METHODS:
      Twenty patients with high-grade gliomas were studied on two or more occasions. T2
      weighted multislice pulse sequences with a Gaussian slice profile, 50%
      overlapping slices and nearly isotropic voxels were acquired. The images were
      registered and subtraction images were produced. The images were compared with
      three-dimensional (3D) T1-weighted registered images and conventional
      unregistered T2-weighted images. All images were scored for changes in the
      lesions and ventricular system. RESULTS: The 2D and 3D registered subtraction
      images were the most sensitive for detecting changes in both the lesions and
      other regions in the brain. The mean rank scores were significantly higher for
      the lesions (chi2=86.742; df=5, n=38, P<0.0001) and for the ventricles
      (chi2=63.837; df=5, n=35, P<0.0001) compared with the unregistered and registered
      anatomical images. The subtraction images were also most sensitive for detecting
      signal intensity changes irrespective of the direction of change. CONCLUSION:
      Rigid body subvoxel registration can be successfully performed with both
      multislice 2D and 3D imaging. In principle, virtually all forms of clinical MR
      images of the brain can be accurately registered and subtracted.

PMID- 12475536
TI  - Back pain in pregnancy--magnetic resonance imaging correlation.
AB  - AIM: To study the relationship of disk abnormality and signal changes of the
      uterine cervix on magnetic resonance imaging (MRI) with back pain in pregnancy at
      36-39 weeks of gestation. MATERIAL AND METHODS: One hundred and five pregnant
      Chinese women with previous Caesarean section at 36-39 weeks gestation undergoing
      magnetic resonance pelvimetry performed for a study for trial of vaginal delivery
      were questionnaired for back pain. Sagittal T2-weighted images were analysed for
      intervertebral disk abnormality, and signal intensity of the uterine cervix on
      the same sagittal images. The findings on MRI were correlated with back pain.
      RESULTS: Seventy-three (70%) of the pregnant women had back pain. Disk bulge or
      prolapse were infrequent but correlated significantly with the presence of back
      pain (P=0.02). Women with back pain in the current pregnancy tended to have a
      higher signal intensity of the uterine cervix compared with those without
      (P=0.006). Women with a history of back pain also had higher cervical signal
      intensity compared with those without (P=0.02). CONCLUSION: Disk bulge or
      prolapse was associated with back pain in pregnancy but were relatively
      infrequent. The significant correlation of high signal intensity in the uterine
      cervix and back pain suggested that soft tissue laxity may be a more important
      cause of back pain in pregnancy than disk bulge or prolapse.

PMID- 12475537
TI  - Displacement of occluded plastic endoprostheses into the duodenum during
      percutaneous biliary drainage: description of an under-reported technique.
AB  - AIM: Percutaneous transhepatic biliary drainage (PTBD) is occasionally requested
      in patients with an occluded plastic stent in situ. We describe a technique for
      dislodging the stent into the duodenum during PTBD. MATERIALS AND METHODS: Twelve
      patients (M:F, 9:3 mean age 70 years) with plastic stents in the common bile duct
      (CBD) underwent PTBD. Eleven patients had malignant obstruction and one patient
      had Mirizzi's syndrome and a large duodenal diverticulum. PTBD was performed
      using right lobe access in nine patients and a left hepatic access in three
      patients. The level of biliary obstruction was at the lower CBD in five patients,
      mid-CBD in four patients and upper CBD in three patients. After standard
      percutaneous biliary access was established, an 8mm by 4 cm balloon catheter was
      gently inflated alongside the upper end of the plastic stent and advanced over a
      stiff guidewire, towards the duodenum, to dislodge the plastic stent. RESULTS:
      Plastic stents were successfully dislodged in all 11 patients with malignancy and
      metallic stents were deployed for palliation. In nine of 11 patients with
      malignant lesions the PTBD dislodgement of the plastic stent and insertion of a
      metallic stent was carried out as a single-step procedure. In two patients with
      biliary sepsis, a two-step procedure was necessary. In the patient with Mirizzi's
      syndrome the plastic stent could not be dislodged. No complications were
      observed. CONCLUSION: Plastic stents, inserted at ERCP, can be dislodged in the
      majority of cases at PTBD using a balloon catheter inserted alongside the failed
      stent without complication.

PMID- 12475538
TI  - The management of ureteric obstruction secondary to malignant pelvic disease.
AB  - AIM: Management of upper-tract obstruction secondary to a malignant pelvic
      process is a difficult problem and is best dealt with by a multi-disciplinary
      team. In the present audit, we address the question: is staged antegrade stenting
      better than retrograde ureteric stenting? MATERIALS AND METHODS: We reviewed our
      present management of upper-tract obstruction secondary to malignant pelvic
      disease in 65 patients treated over a period of 2 years. Fifty-eight patients had
      urological cancer and seven patients had non-urological cancers; 70% of all cases
      had renal impairment. Twenty-four of 65 patients had an attempt at endoscopic
      retrograde ureteric stenting as a primary method of decompression while
      percutaneous nephrostomy followed by antegrade ureteric stenting was performed in
      41/65 patients. RESULTS: Endoscopic retrograde stenting had a success rate of 21%
      whereas two-stage antegrade stenting was successful in 98% of patients. The
      antegrade approach had minimal morbidity. CONCLUSION: Obstruction of the pelvic
      ureter secondary to any pelvic malignancy is best managed by two-stage antegrade
      ureteric stenting. This approach has a high success rate with minimal morbidity,
      and should be preferred to an endoscopic approach. This highlights the important
      role of an interventional uroradiologist in the management of these patients.

PMID- 12475539
TI  - Review of readmissions due to complications from uterine fibroid embolization.
AB  - AIM: To determine the frequency, nature and outcome of complications resulting in
      readmission to hospital following uterine artery embolization (UAE). MATERIAL AND
      METHODS: A retrospective review of the medical notes and available imaging of 42
      consecutive patients who had undergone elective uterine artery embolization for
      the treatment of fibroid disease was performed. RESULTS: The mean age of the
      patients was 42 years (range 31--54 years) and seven patients (17%) were
      readmitted to hospital. The median time to readmission was 3 weeks (range 1-29
      weeks). All seven patients were admitted with signs and symptoms of infection. In
      four patients an organism was isolated from high vaginal swabs, and in one
      patient the midstream urine sample was confirmed as the source of infection. In
      the other two patients no definite source of infection was identified. All
      patients were treated with intravenous antibiotics. Six of the seven patients
      responded to treatment. The remaining patient required hysterectomy for
      uncontrolled uterine sepsis. CONCLUSION: Readmission following UAE is common and
      arises secondary to infection. Infection can occur several months after the
      procedure.

PMID- 12475540
TI  - Case report. Tumour-induced osteomalacia in a patient with osseous haemangioma.

PMID- 12475541
TI  - Data analysis.

PMID- 12475543
TI  - Clinical proceduress in prenatal diagnosis.
AB  - The prenatal diagnosis of fetal genetic disease has become a routine part of
      obstetric care. Pregnancies at risk are identified by a number of factors,
      including maternal age, positive serum screening, a history of a previous
      affected child, a parental chromosome rearrangement or an ultrasound-identified
      anomaly. Invasive diagnostic testing can be performed in the first trimester by
      chorionic villus sampling or in the second trimester by amniocentesis. Both
      procedures are safe, with an equivalent 0.5% risk of procedure-induced pregnancy
      loss. When performed prior to the routine sampling window of 15 weeks,
      amniocentesis may increase the risk of talipes equinovarus, the highest risk
      being encountered prior to 13 weeks' gestation. When chorionic villus sampling is
      performed prior to 9 weeks' gestation, there may be an increased risk of limb
      reduction defects. The laboratory analysis of both procedures is reliable.
      Chorionic villus sampling has a 1-2% incidence of confined placental mosaicism,
      requiring additional evaluation in some cases.

PMID- 12475544
TI  - Prenatal diagnosis: molecular genetics and cytogenetics.
AB  - The technologies developed for the Human Genome Project, the recent surge of
      available DNA sequences resulting from it and the increasing pace of gene
      discoveries and characterization have all contributed to new technical platforms
      that have enhanced the spectrum of disorders that can be diagnosed prenatally.
      The importance of determining the disease-causing mutation or the informativeness
      of linked genetic markers before embarking upon a DNA-based prenatal diagnosis
      is, however, still emphasized. Different fluorescence in situ hybridization
      (FISH) technologies provide increased resolution for the elucidation of
      structural chromosome abnormalities that cannot be resolved by more conventional
      cytogenetic analyses, including microdeletion syndromes, cryptic or subtle
      duplications and translocations, complex rearrangements involving many
      chromosomes, and marker chromosomes. Interphase FISH and the quantitative
      fluorescence polymerase chain reaction are efficient tools for the rapid prenatal
      diagnosis of selected aneuploidies, the latter being considered to be most cost
      effective if analyses are performed on a large scale. There is some debate
      surrounding whether this approach should be employed as an adjunct to karyotyping
      or whether it should be used as a stand-alone test in selected groups of women.

PMID- 12475545
TI  - Screening.
AB  - Historically, obstetrician/gynaecologists have utilized screening procedures as a
      major component of their routine clinical practice. The Papanicolaou (Pap) smear
      technique for cervical cancer is more than 50 years old and has saved countless
      lives by identifying who among the supposedly low-risk group of patients is in
      fact at high risk of cervical cancer. The introduction of alpha-fetoprotein
      screening for neural tube defects in the 1970s, low alpha-fetoprotein level for
      Down syndrome in the 80s, multiple markers in the 90s and now, after the
      millennium combined ultrasound and biochemistry for a more precise risk
      identification, has radically changed our approach towards optimizing the
      sensitivity, specificity and positive and negative predictive values of
      screening. As these techniques improve, old mainstays of attributable risks such
      as advanced maternal age will probably fade into oblivion as stand-alone
      criteria. The specifics of screening techniques will vary by disorder, but the
      general principles are important and can be applied to all new technologies as
      they come on line. In fact, the real 'take-home message' is that one must use
      these principles when looking at new technologies to understand their role in
      emerging practice.

PMID- 12475546
TI  - Pre-implantation genetic diagnosis.
AB  - Pre-implantation genetic diagnosis is an alternative to prenatal diagnosis for a
      select group of patients. Patients have to go through in vitro fertilization in
      order to produce embryos in vitro, from which one or two cells are removed at the
      8-cell stage. A fluorescence in situ hybridization or polymerase chain reaction
      is carried out for the genetic diagnosis. Fluorescence in situ hybridization is
      used for the analysis of chromosomes for sexing for X-linked disease, chromosome
      abnormalities and aneuploidy screening. Aneuploidy screening is performed for
      infertile patients going through in vitro fertilization to try to improve their
      pregnancy rate. A polymerase chain reaction is used for the diagnosis of single
      gene disorders. Since the risk of contamination and allele dropout is high with a
      polymerase chain reaction, linked or unlinked markers are usually used in a
      fluorescent multiplex polymerase chain reaction. New techniques, for example
      comparative genomic hybridization, allow the analysis of all of the chromosomes
      from one cell at one time. The ethical implications of pre-implantation genetic
      diagnosis are immense as the technique has already been used for social sexing
      and human leukocyte antigen matching.

PMID- 12475547
TI  - Fetal therapy.
AB  - Over the past 40 years, a small but increasing number of fetal genetic and
      congenital anomalies has become amenable to in utero treatment. Successful fetal
      therapies have included open procedures for congenital diaphragmatic hernia,
      cystadenomatoid malformation of the lung and saccrococygeal teratoma, shunts for
      uropathies and thoracic fluids, pharmacological therapies for congenital adrenal
      hyperplasia and neural tube defect prevention, and the stem cell treatment of
      severe combined immunodeficiency disorder.

PMID- 12475548
TI  - Molecular approach to common causes of female infertility.
AB  - Pivotal genetic information has been derived for a host of rare genetic
      disorders, but progress has been much slower in relation to the common causes of
      female infertility. In this chapter, we shall illustrate the approaches being
      applied in elucidating conditions causing infertility that are inherited in a
      polygenic/multifactorial fashion. The task is to determine the number of genes
      responsible and their chromosomal location(s). The first approach is to use
      genome-wide quantitative linkage analysis, searching throughout the genome with
      no prior expectation that a given gene or chromosomal region is casually
      involved. A second approach is to search across the genome for altered gene
      expression, for example comparing endometriosis and normal (non
      endometriosis)cells. The third approach is less indiscriminate and more focused,
      depending upon identifying specific candidate genes. Aromatase, calhedrin,
      oestrogen receptor, galactose-1-phosphate uridyl transferase (GALT) and tumour
      suppressor genes such as p53 are attractive candidate genes for endometriosis.
      Endometriosis, which has long been suspected to possess a familial tendency, has
      been subjected to genome-wide linkage analysis in Oxford, UK, where sib-pair
      analysis uses polymorphic DNA markers and fluorescence-based automated analysis.
      Several regions of exclusion have been found, but no linkages have so far been
      reported. A candidate gene approach focuses on the presence of chromosomal
      aberrations, the assumption being that endometriosis parallels neoplasia. At
      Baylor College of Medicine, we thus began by showing chromosome alterations
      involving trisomy 11, monosomy 16 and monosomy 17 in late-stage endometriosis. A
      loss of only the p53 tumour suppressor gene, rather than a loss (monosomy) of
      chromosome 17 per se, however, seems to be the pivotal event. A second
      representative polygenic/multifactorial disorder causing female infertility is
      polycystic ovarian syndrome. Both quantitative linkage analysis and candidate
      gene approaches are being pursued. In the far more commonly observed 'idiopathic'
      variety (non-adrenal polycystic ovarian syndrome and hirsutism), consensus has
      long existed that one or more dominant genes causes the condition. Although the
      mode of inheritance in 'essential' polycystic ovarian syndrome remains uncertain,
      dominant tendencies are clearly more pertinent than recessive ones. Genes for
      adrenal biosynthetic enzymes, insulin receptors, leptin and leptin receptors,
      follistatin, activin and inhibins are attractive candidates for polycystic
      ovarian disease. A linkage to 37 candidate genes was sought using affected sib
      pair analysis and transmission/disequilibrium methods.

PMID- 12475549
TI  - Hereditary risk of women's cancers.
AB  - The characterization of specific genes responsible for the hereditary risk of
      common cancers has enabled the development of clinical tests designed to identify
      at-risk individuals and to significantly improve the clinical outcome of such
      individuals. Two of the most important syndromes associated with a hereditary
      risk of cancer in women are hereditary breast and ovarian cancer, resulting from
      the BRCA1 and BRCA2 genes, and hereditary non-polyposis colorectal cancer, caused
      primarily by the MLH1 and MSH2 genes. As testing for the hereditary risk of
      breast, ovarian, endometrial and colorectal cancer enters the clinical
      mainstream, physicians responsible for the health care of women are increasingly
      required to assess and provide guidance to healthy patients with a strong family
      history, cancer survivors who may be at risk of a second cancer and women who
      discover that a family member carries a specific mutation identified through
      genetic testing. Obstetricians and gynaecologists must therefore become familiar
      with the principles of assessing the family history for specific hereditary
      cancer syndromes, with the appropriate use of tests to confirm such syndromes and
      with the management options for women who have inherited a greatly increased risk
      of cancer.

PMID- 12475550
TI  - Mitochondrial diseases.
AB  - Mitochondrial disorders are caused by deficient respiratory chain function,
      resulting in a complex series of pathophysiological events. Genetic counselling
      is complicated because the respiratory chain subunits are encoded by both nuclear
      and mitochondrial DNA genes. Only a minority of the nuclear genes involved in
      mitochondrial function have been identified, and even fewer are associated with
      human mitochondrial disease. Mutations in mitochondrial DNA are particularly
      challenging because of the complexities of mitochondrial genetics: the
      mitochondrial DNA is strictly maternally inherited; there are 10(3)-10(4) copies
      of mitochondrial DNA in somatic cells; affected individuals often have a mixture
      of normal and mutated mitochondrial DNA (mitochondrial DNA heteroplasmy), the
      level of mutated mitochondrial DNA (the mitochondrial DNA mutation load) may vary
      widely between different maternally related individuals, between tissues and with
      time; a particular minimal threshold of mutated mitochondrial DNA is required to
      impair respiratory chain function; and there is not always a good correlation
      between mutant load and phenotype.

PMID- 12475551
TI  - The genomic revolution and the obstetrician/gynaecologist: from societal trends
      to patient sessions.
AB  - A major aspect of reaping the benefits of the genome revolution in women's health
      relates to questions of how we are going to handle this scientific manna of
      information and potential treatment options while minimizing social exclusion
      along the lines of race, class and gender. Four society-level scenarios or
      patterns of diffusion of genomic access are discussed, each with its own set of
      assumptions and outcomes in terms of equity. Like it or not, the front-line
      obstetrician/gynaecologist will play a critical role in whether such new
      information helps either to reduce or to exacerbate discrepancies in health-care
      status along the lines of race and socio-economic status. Patients must not be
      denied access to knowledge and information within the genetic counselling
      session, or to the opportunity to make an informed autonomous decision because of
      the use of unfamiliar language and conventions of conversation that support power
      differentials and discourage rapport and empathy. Aspects of communication that
      are critical to the outcome of the genetic counselling session, such as the level
      of directness of counselling, physician interruptions of the patient and the
      power implications of the rhetorical question, are explored. In addition, the
      special challenges to counsellor neutrality and patient autonomy offered by the
      longitudinal primary obstetrician/gynaecologist relationship are discussed.
      Strategies encouraging more effective collaboration and communication between
      generalist and patient in the counselling session are offered.

PMID- 12475552
TI  - The genetic revolution: new ethical issues for obstetrics and gynaecology.
AB  - The genomic revolution inherently changes the paradigms that have informed the
      interactions between patient and physician. These changes obligate physicians
      both to continually learn about the advances occurring in genetic testing and to
      review their interactions in light of the changing ethical issues these advances
      uncover. Particular areas for concern are the use of genetic testing for
      predisposition genes. The issues differ between uses for adults, for children and
      for pre-implantation genetics. Furthermore, there are issues of justice raised by
      limited access to these technologies, research confidentiality, potential
      discrimination and the meaning of individuality in an era of potential genetic
      cloning. These changes require obstetrician/gynaecologists to advocate for the
      best interests of both their patients and those who may not be able to voice
      their interests, for example children-to-be and research subjects in developing
      countries.

PMID- 12475553
TI  - Future directions.

PMID- 12475555
TI  - Hierarchical structures in fibrillar collagens.
AB  - The collagen family includes several large transcripts, usually exceeding 1000
      amino acid residues per single chain. As a group, they make up 1/3 of all the
      protein of the body and are responsible for modelling the framework of connective
      tissues; individually, they show both a wide variety and a complex hierarchy of
      mutual interactions, and form a range of functional aggregates including a
      variety of fibrils, microfibrils and basal membranes. Of the collagens, the
      fibril-forming types (i.e. the types I, II III, V and XI) are the most abundant
      and the most extensively studied. At the primary structure level, the amino acid
      sequence of all collagens is now known in detail and it shows a distinctive
      domain organization, its composition being dominated by the amino acid glycine
      (roughly 1/3 of all residues) and by post-translational hydroxylation of proline
      and lysine residues. Collagen secondary and tertiary structure, which together
      give origin to a classic triple helix, were painstakingly determined in the 1950s
      and 1960s. In contrast with the primary, secondary and tertiary structure, the
      supramolecular arrangement within collagen fibres seems to be far more elusive,
      and none of the models so far advanced can be said to be universally accepted.
      Half a century of research and debate spawned numerous mutually incompatible
      models, most of them focussing either on a quasi-crystalline supramolecular array
      or on several forms of microfibrillar aggregates, while radial fibrils, epitaxial
      fibrils and other structural models have almost been ignored. In many cases, data
      gained with a single technique from a single tissue were arbitrarily given a
      general legitimacy, whilst other well-documented morphological evidence went
      virtually unnoticed by the scientific community.Moreover, in recent years there
      has been a growing interest in the multiple interactions of collagens with the
      other macromolecules of the extra-cellular matrix, as their structure and their
      functional role become known. It is now indisputable that collagen interacts and
      forms functional entities with several other macromolecules of the extracellual
      matrix. This paper will succinctly review some current concepts on the structural
      biology of collagen higher-order structures.

PMID- 12475556
TI  - Light elements quantification in stimulated cells cryosections studied by
      electron probe microanalysis.
AB  - The quantification of intracellular light elements such as carbon, nitrogen and
      oxygen may be useful in understanding the biological mechanisms, for example the
      generation of nitric oxide which is involved in apoptosis and inflammatory
      reaction. Electron energy loss spectroscopy (EELS) coupled with scanning
      transmission electron microscopy is a useful method to detect light elements in
      thin cryosections. Recent developments of X-ray detectors with ultra-thin
      protection windows allows the detection of such elements by energy dispersive X
      ray spectroscopy. In the present study, we have demonstrated using both methods
      that the stimulation of BV-2 murine microglial cell line by gamma-interferon and
      lipopolysaccharide leads to the increase of intracellular oxygen concentration
      and no change in the intracellular nitrogen concentration. This indicates the use
      of exogeneous molecular oxygen in response to the stimulation. But the increase
      of oxygen concentration detected could not be only due to NO expression because
      the NO production was 1000 times less than the oxygen concentration increase
      observed.

PMID- 12475557
TI  - Evaluation of argyrophilic nucleolar organizer regions in oral tumor progression.
AB  - The aim of this study was to compare the presence of nucleolar organizer regions
      (NORs) in normal oral mucosa, dysplasia and microinvasive carcinoma. All
      histological specimens were reviewed according to the modified classification and
      staging system for oral leukoplakia described by van-der-Waal et al. [Oral Oncol.
      36 (2000) 264]. NOR quantification was performed with an image analyzer after
      staining by the argyrophilic nucleolar region technique. The morphometric results
      were statistically different for normal mucosa, dysplasia and microinvasive
      carcinoma. It was concluded that an increase of NOR activity follows the disease
      progression and may reflect the degree of cellular proliferation and malignancy.

PMID- 12475558
TI  - In vitro fibrillogenesis of the amyloid beta 1-42 peptide: cholesterol
      potentiation and aspirin inhibition.
AB  - Understanding the formation of extracellular amyloid neurofibrillar
      bundles/senile plaques and their role in the development of Alzheimer's disease
      is of considerable interest to neuroscientists and clinicians. Major components
      of the extracellular neurofibrillar bundles are polymerized amyloid beta (Abeta)
      peptides (1-40), (1-42) and (1-43), derived in vivo from the soluble amyloid
      precursor protein (sAPP) by proteolytic (beta- and gamma-secretase) cleavage. The
      Abeta(1-42) peptide is widely considered to be of greatest significance in
      relation to the pathogenesis of Alzheimer's disease. A well-defined
      ultrastructural characteristic within Alzheimer dense plaques is the presence of
      helical fibrils that are believed to consist of polymerized amyloid beta,
      together with other associated proteins such as the serum amyloid P protein,
      apolipoprotein E isoform epsilon 4, alpha1-anti-chymotrypsin, catalase,
      glycoproteins, proteoglycans, cholesterol and other lipids. The spontaneous in
      vitro fibrillogenesis of chemically synthesized Abeta(1-42) peptide (rat
      sequence), following 20h incubation at 37 degrees C, has been assessed from
      uranyl acetate negatively stained specimens studied by transmission electron
      microscopy (TEM). Amyloid beta(1-42) peptide fibrillogenesis in the presence of
      cholesterol has been investigated using aqueous suspensions of microcrystalline
      cholesterol and cholesteryl acetate, globular particles of cholesteryl oleate, a
      soluble (micellar) cholesterol derivative (polyoxyethyl cholesteryl
      sebacate/cholesteryl PEG 600 sebacate), cholesterol-sphingomyelin liposomes and
      sphingomyelin liposomes. In all these cases, with the exception of cholesteryl
      oleate, considerable potentiation of long smooth helical fibril formation
      occurred, compared to 20h 37 degrees C control samples containing the Abeta(1-42)
      peptide alone. The binding of polyoxyethyl cholesteryl sebacate micelles to
      helical Abeta fibrils/filaments and the binding of fibrils to the surface of
      cholesterol and cholesteryl acetate microcrystals, and to a lesser extent on
      cholesteryl oleate globules, indicates an affinity of the Abeta peptide for
      cholesterol. This potentiation of Abeta(1-42) polymerization is likely to be
      mediated at the molecular level via hydrophobic interaction between the amino
      acid side chains of the peptide and the tetracyclic sterol nucleus. Addition of
      cupric sulphate (0.1mM) to the Abeta solution produced large disorganized fibril
      aggregates. Inclusion of 1mM aspirin (sodium acetylsalicylate) in the Abeta
      peptide alone and as an addition to Abeta peptide solution containing
      cholesterol, cholesteryl acetate, soluble cholesterol, sphingomyelin and
      sphingomyelin-cholesterol liposomes, and to 0.1mM cupric sulphate solution,
      completely inhibited fibrillogenesis. Instead, only non-crystalline diffuse, non
      filamentous microaggregates of insoluble Abeta particles were found, free and
      attached to the sterol particles. The in vitro system presented here provides a
      way to rapidly monitor at the structural/TEM level other compounds (e.g.
      chelating agents, drugs, beta-sheet breaking peptides and anti-oxidants) for
      their effects on amyloid beta peptide fibrillogenesis (and on preformed fibril
      disassembly) in parallel with in vitro biochemical studies and in vivo studies
      using animal models of Alzheimer's disease as well as studies on man.

PMID- 12475560
TI  - Methods for atom probe analysis of microgradients in functionally graded cemented
      carbides.
AB  - Methods to prepare needle-shaped specimens for atom probe field ion microscopy
      from near surface regions have been developed. The material used was a cemented
      carbide with a composition gradient towards the surface, but the method is
      equally applicable for other materials. The preparation technique involves dimple
      grinding, electropolishing and focused ion beam (FIB) milling. The use of FIB
      milling allows for specimen preparation of materials which due to the
      preferential etching of different phases are difficult to electropolish. The
      technique also allows for preparation of specimens at well defined depth from the
      sample surface, selection of phase to be analysed, and to sharpen and re-use
      already analysed specimens. Atom probe analyses of the near surface zone region
      in a gradient sintered WC-Ti(C,N)-TaC-Co cemented carbide are presented.

PMID- 12475559
TI  - Ultrastructural study of first and second order neurons in the visual system of
      the crab Ucides cordatus following exposure to ultraviolet radiation.
AB  - The visual system as an interface between the environment and the living organism
      can serve as a sensitive indicator especially in studies that deal with effects
      of radiation. The crab retina as the seat of the photoreceptors and the lamina
      ganglionaris as the place of second order neurons were the targets of our study.
      Conventional specimen preparation techniques for transmission electron microscopy
      (TEM) are adequate to preserve any modifications that may occur as a consequence
      of the experimental treatment. In this study we analyzed by TEM how retinal and
      lamina ganglionaris cells of the crab Ucides cordatus responded to a 30 min
      exposure to ultraviolet C (UV-C) and ultraviolet B (UV-B) radiation with doses of
      7200 and 590J/cm(2), respectively. The results show that damaged cells occurred
      in both retina and lamina ganglionaris, but that the retinal cells were affected
      to a greater extent. Morphological alterations of the pigment granules and an
      increase in the quantity of lipid droplets of the retinal cells were also
      observed. Additional changes include an increase in heterochromatin, nuclear
      karyolyses and karyorrhexes, distention of rough endoplasmic reticulum and
      mitochondrial disruptions. The observed morphological changes are indicative of
      apoptotic processes and show that an exposure to light of wavelengths of 254 and
      312 nm may be injurious to the visual system of invertebrates.

PMID- 12475561
TI  - Seasonal- and age-dependent changes of the structure and chemical composition of
      the spherites in the midgut gland of the harvestmen Gyas annulatus (Opiliones).
AB  - Spherites--round laminated membrane bound structures--are located in the
      cytoplasm of all cell types of the midgut gland in the harvestmen Gyas annulatus.
      The spherites consist of an organic matrix composed of glycoproteins and
      proteoglycans whose sugar portion are carboxylated glycosaminoglycans. Different
      elements are embedded in this matrix, and their presence varies during the life
      cycle. All spherites in juveniles are composed of alternating concentrically
      arranged electron dense and electron lucent layers of organic matrix material
      before overwintering (December). At that time, spherites contain calcium,
      phosphorus and silicon. Calcium and phosphorus are located in their electron
      dense layers, and silicon spotwise, mainly peripheral. Material seems to be lost
      during overwintering of Gyas as electron lucent "empty" layers appear in
      spherites in March. The "lost" material could be used as energy supply and/or to
      provide molecules for synthesis processes during non-nourishing overwintering.
      Spherites do not contain calcium and phosphorus in July and October. These
      elements seem to have important biological relevance in the formation and
      hardening of the cuticle during the moultings in spring. In contrast to calcium
      and phosphorus, silicon is still stored in spherites in July and October but in
      decreasing concentration, therefore it could be involved in metabolic processes
      in adult Gyas. In the period from July to the end of their adult life in late
      autumn, an increasing number of spherites disintegrate and their remnant organic
      matrix material progressively aggregates with other cellular waste material in
      one or more huge vacuoles of glandular cells.

PMID- 12475562
TI  - Automated microaxial tomography of cell nuclei after specific labelling by
      fluorescence in situ hybridisation.
AB  - Microaxial tomography provides a good means for microscopic image acquisition of
      cells or sub-cellular components like cell nuclei with an improved resolution,
      because shortcomings of spatial resolution anisotropy in optical microscopy can
      be overcome. Thus, spatial information of the object can be obtained without the
      necessity of confocal imaging. Since the very early developments of microaxial
      tomography, a considerable drawback of this method was a complicated image
      acquisition and processing procedure that requires much operator time. In order
      to solve this problem the Heidelberg 2pi-tilting device has been mounted on the
      Brno high-resolution cytometer as an attempt to bring together advanced
      microscopy and fast automated computer image acquisition and analysis. A special
      software module that drives all hardware components required for automated
      microaxial tomography and performs image acquisition and processing has been
      developed. First, a general image acquisition strategy is presented. Then the
      procedure for automation of axial tomography and the developed software module
      are described. The rotation precision has been experimentally proved followed by
      experiments with a specific biological example. For this application, also a
      method for the preparation of cell nuclei attached to glass fibres has been
      developed that allows for the first time imaging of three-dimensionally
      conserved, fluorescence in situ hybridisation-stained cell nuclei fixed to a
      glass fibre.

PMID- 12475563
TI  - Temperature induced alterations in the liver of wall lizard (Hemidactylus
      frenatus): morphological and biochemical parameters.
AB  - Wall lizards (Hemidactylus frenatus) were adapted to 20, 25, and 30 degrees C,
      and the liver was examined using standard transmission electron microscopy (TEM)
      and biochemical analysis. Peroxisomes were visualized after using the 3,3'
      diaminobenzidine (DAB) technique. Catalase, uricase and protein content were
      determined biochemically. The hepatocytes of animals adapted to higher
      temperature displayed larger lipid inclusions than those of animals adapted to
      lower temperature. Rough endoplasmic reticulum was better developed in the
      animals kept at low temperature (20 and 25 degrees C) than in the animals held at
      30 degrees C. Cytoplasmic crystalline structures were visualized, and better
      developed in the hepatocytes at 25 degrees C. Peroxisomes varied with the
      temperature, being more frequent in the animals kept at 20 degrees C, while the
      bigger ones prevailed in the animals kept at 30 degrees C. The higher catalase
      activity at higher temperature was correlated to an increase in staining
      intensity of DAB-incubated peroxisomes as visualized cytochemically in TEM. The
      biochemical results confirmed the cytochemical reaction observed by TEM. The
      hepatocytes of the animals at 30 degrees C showed a reduction in the number of
      peroxisomes, however, at this temperature the largest peroxisomes with a stronger
      reaction to DAB and a higher activity of catalase predominate. In contrast, the
      uricase activity showed no significant variation in relation to adaptation
      temperature. Overall, these data show the morphological and functional plasticity
      of hepatocytes to temperature adaptation of H. frenatus.

PMID- 12475565
TI  - Cytological modifications in maize plants infected by barley yellow dwarf virus
      and maize dwarf mosaic virus.
AB  - Three inbred lines of maize (33-16, MO17 and B73) differing in their
      susceptibility to Barley yellow dwarf virus and Maize dwarf mosaic virus were
      studied to compare the ultrastructural modifications induced by the two viruses
      in leaf tissues of different age. The results demonstrate that the alterations
      induced by the two viruses in the different maize lines could depend on the
      particular line tested.

PMID- 12475564
TI  - Bidder's organ of Bufo ictericus: a light and electron microscopy analysis.
AB  - Male toads of the Bufonidae Family have rudimentary ovaries designated Bidder's
      organs, and if the testes are removed this organ develops into a functional
      ovary, representing a morphological strategy for the reproduction of the species.
      The Bidder's organ of Bufo ictericus was examined using routine and histochemical
      techniques by light microscopy and transmission electron microscopy. Each
      Bidder's organ presented a typical ovarian morphology, being composed of a cortex
      and a medulla. Bidderian follicles in different stages of development were
      visualized in the cortex, where they are better developed. The germ cells exhibit
      a large oocyte with a round-shaped nucleus. The Bidderian follicles are supported
      by a loose net of reticular fibers. In the medullar region, collagen fibers were
      immersed in the matrix rich in blood vessels that also contained a small quantity
      of neutral glycoproteins rich in hexose and/or sialic acid and carboxylated
      polymers with a characteristic distribution of glycosaminoglycans. The oocyte and
      the follicular cells were separated by a narrow space containing microvilli. The
      oocyte exhibit a well developed smooth endoplasmic reticulum, a poorly developed
      Golgi apparatus, and occasional lysosomes. Concentric cisternal complexes are
      often visualized; however, their morphological significance remains unclear. The
      peroxisomes display a fine granular matrix without a crystalline core, with a
      weak 3,3'-diaminobenzidine-reaction. Intimate association between peroxisomes,
      peroxisomes and lipid inclusions was observed in the oocyte, suggesting its
      participation in yolk metabolism.

PMID- 12475566
TI  - Measuring the aspect ratios of ZnO nanobelts.
AB  - Nanobelts are new materials that have a rectangular cross-section and are
      characterized by widths and width-to-thickness aspect ratios. In this paper, the
      thickness and aspect ratios of ZnO nanobelts are measured by a conjunction
      application of convergent beam electron diffraction (CBED) and electron energy
      loss spectroscopy (EELS). The thicknesses of thicker nanobelts are first
      determined by CBED under two-beam diffracting condition, then they are used to
      determine the electron inelastic mean-free-path (MFP) length, which is 161+/-15nm
      for ZnO at 200kV. The thicknesses of the thinner nanobelts are then determined by
      EELS using the calibrated MFP. The results show that the aspect ratio depends on
      conditions under which the sample was synthesized.

PMID- 12475568
TI  - Tight junction proteins.
AB  - A fundamental function of epithelia and endothelia is to separate different
      compartments within the organism and to regulate the exchange of substances
      between them. The tight junction (TJ) constitutes the barrier both to the passage
      of ions and molecules through the paracellular pathway and to the movement of
      proteins and lipids between the apical and the basolateral domains of the plasma
      membrane. In recent years more than 40 different proteins have been discovered to
      be located at the TJs of epithelia, endothelia and myelinated cells. This
      unprecedented expansion of information has changed our view of TJs from merely a
      paracellular barrier to a complex structure involved in signaling cascades that
      control cell growth and differentiation. Both cortical and transmembrane proteins
      integrate TJs. Among the former are scaffolding proteins containing PDZ domains,
      tumor suppressors, transcription factors and proteins involved in vesicle
      transport. To date two components of the TJ filaments have been identified:
      occludin and claudin. The latter is a protein family with more than 20 members.
      Both occludin and claudins are integral proteins capable of interacting
      adhesively with complementary molecules on adjacent cells and of co-polymerizing
      laterally. These advancements in the knowledge of the molecular structure of TJ
      support previous physiological models that exhibited TJ as dynamic structures
      that present distinct permeability and morphological characteristics in different
      tissues and in response to changing natural, pathological or experimental
      conditions.

PMID- 12475569
TI  - Understanding complex signaling networks through models and metaphors.
AB  - Signaling networks are complex both in terms of the chemical and biophysical
      events that underlie them, and in the sheer number of interactions. Computer
      models are powerful tools to deal with both aspects of complexity, but their
      utility goes beyond simply replicating signaling events in silicon. Their great
      advantage is as a tool to understanding. The completeness of the description
      demanded by computer models highlights gaps in knowledge. The quantitative
      description in models facilitates a mapping between different kinds of analysis
      methods for complex systems. Systems analysis methods can highlight stable states
      of signaling networks and describe the transitions between them. Modeling also
      reveals functional similarities between signaling network properties and other
      well-understood systems such as electronic devices and neural networks. These
      suggest various metaphors as a tool to understanding. Based on such descriptions,
      it is possible to regard signaling networks as systems that decode complex inputs
      in time, space and chemistry into combinatorial output patterns of signaling
      activity. This would provide a natural interface to the combinatorial input
      patterns required by genetic circuits. Thus, a combination of computer modeling
      methods to capture the complexity and details, and useful abstractions revealed
      by these models, is necessary to achieve both rigorous description as well as
      human understanding.

PMID- 12475570
TI  - Regulation of cardiac inwardly rectifying potassium channels by membrane lipid
      metabolism.
AB  - Types and distributions of inwardly rectifying potassium (Kir) channels are one
      of the major determinants of the electrophysiological properties of cardiac
      myocytes. Kir2.1 (classical inward rectifier K(+) channel), Kir6.2/SUR2A (ATP
      sensitive K(+) channel) and Kir3.1/3.4 (muscarinic K(+) channels) in cardiac
      myocytes are commonly upregulated by a membrane lipid, phosphatidylinositol 4,5
      bisphosphates (PIP(2)). PIP(2) interaction sites appear to be conserved by
      positively charged amino acid residues and the putative alpha-helix in the C
      terminals of Kir channels. PIP(2) level in the plasma membrane is regulated by
      the agonist stimulation. Kir channels in the cardiac myocytes seem to be actively
      regulated by means of the change in PIP(2) level rather than by downstream signal
      transduction pathways.

PMID- 12475572
TI  - Treatment of imperforate hymen by application of Foley catheter.

PMID- 12475573
TI  - Route of delivery of fetuses with structural anomalies.
AB  - Our ability to diagnose fetuses with congenital anomalies has dramatically
      increased over the past two decades and with improved surgical treatment for some
      defects, more women may choose to continue their pregnancies. Antenatal
      management is thus of increasing relevance. The literature on route of delivery
      suggests the following conclusions. Babies with neural tube defects presenting by
      the breech benefit from caesarean section but there is no clear evidence that
      cesarean improves outcome in those with a vertex presentation. When the size of
      the sac exceeds 6 cm, cesarean section may be justified to decrease the risk of
      disruption. Vaginal delivery is desirable in all other cases to reduce maternal
      morbidity. Cystic hygroma: cesarean section offers optimal conditions for
      management of large anterior lymphangiomas that can obstruct the airway.
      Sacrococcygeal teratoma: the current approach is based on the size of the tumor.
      In a fetus with a tumor of less than 5 cm, vaginal delivery may be attempted.
      Ventral wall defects: there is no conclusive evidence that cesarean section is
      beneficial for fetuses with omphalocele. Gastroschisis: because of the
      heterogeneity of the studies, it is difficult to assess the net impact of mode of
      delivery. There is no evidence of significant differences in outcome among
      fetuses delivered by the vaginal versus the abdominal route. Trauma to the
      abdominal viscera can occur during either route, and careful delivery is thus
      mandated.

PMID- 12475574
TI  - Maternal morbidity after elective repeat caesarean section after two or more
      previous procedures.
AB  - OBJECTIVES: To determine the incidence of maternal morbidity following elective
      caesarean section in women with a history of at least two previous caesarean
      sections, and to determine if the incidence of morbidity correlates with the
      number of previous sections. STUDY DESIGN: We conducted an individual chart
      review of all women who had an elective caesarean section because of a history of
      two previous sections from 1990 to 1999. RESULTS: There were 67,097 deliveries of
      babies weighing 500 g or more. The total number of cases eligible for the study
      was 250. There were 12 cases (4.8%) of placenta praevia of which four required a
      transfusion and two a hysterectomy. The incidence of wound infection was 6.3% and
      urinary tract infection was 11.2%. There were no cases of thromboembolism
      recorded. CONCLUSIONS: Maternal morbidity with elective repeat caesarean section
      is low. The major morbidity is associated with placenta praevia. We found no
      correlation between the incidence of maternal morbidity and the number of
      previous sections.

PMID- 12475575
TI  - Maternal and fetal side effects of tocolysis using transdermal nitroglycerin or
      intravenous fenoterol combined with magnesium sulfate.
AB  - OBJECTIVE: To compare the maternal and fetal side effects of transdermal
      nitroglycerin and intravenous fenoterol combined with magnesium sulfate in a
      prospective randomised study. STUDY DESIGN: Fifty pregnant women between 27 and
      35 weeks of gestation with preterm labour were treated with either nitroglycerin
      (0.4-0.8 mg/h) or fenoterol (60 - 120 microg/h). Outcome parameters were (1) the
      effects on fetal and maternal heart frequency (FHF/MHF) and blood pressure, and
      (2) subjective experiences of adverse effects assessed by utilising a
      questionnaire. RESULTS: In the fenoterol group, elevated mean MHF, FHF and
      systolic blood pressure were recorded compared to nitroglycerin. Fewer maternal
      side effects were reported in the nitroglycerin group. Palpitations (82%), tremor
      (68%) and restlessness (64%) were most common in the fenoterol group (two drop
      outs), whereas nitroglycerin caused headaches in 71% of the cases (four drop
      outs). CONCLUSION: Transdermal nitroglycerin appears to be a safe therapy for the
      mother and fetus and is a promising new option for the treatment of preterm
      labour.

PMID- 12475576
TI  - Misoprostol and dinoprostone therapy for labor induction: a Doppler comparison of
      uterine and fetal hemodynamic effects.
AB  - OBJECTIVE: To compare the effect of misoprostol (PGE(1)) versus dinoprostone
      (PGE(2)) on blood flow in uteroplacental circulation during labor induction.
      STUDY DESIGN: Eighty-four women with indications for induction of labor were
      assigned to receive either misoprostol 50 microg per vagina every 4 h as needed
      or 0.5 mg doses of dinoprostone given intra-cervically every 6 h by means of a
      randomization table generated by computer. Doppler velocimetry of umbilical,
      uterine and arcuate arteries was performed immediately before and 2-3 h after the
      administration of misoprostol or dinoprostone. The SAS system was used to perform
      statistical analysis. RESULTS: There were no significant changes of pulsatility
      index (PI), resistance index (RI) and systolic/diastolic (S/D) ratio in umbilical
      arteries after both prostaglandin compounds. Vaginal application of misoprostol
      significantly increased all ratios in arcuate artery and S/D ratio in uterine
      artery. Intra-cervically dinoprostone significantly increased PI, RI and S/D
      ratio in arcuate and uterine arteries. CONCLUSIONS: Our results indicate that
      vaginal misoprostol and cervical dinoprostone administration increases
      uteroplacental resistance but does not affect umbilical blood flow. Misoprostol
      would be as safe and effective agent as dinoprostone for cervical ripening and
      labor induction.

PMID- 12475577
TI  - Short-term low-dose heparin plus bedrest impairs bone metabolism in pregnant
      women.
AB  - OBJECTIVE: To assess the osteoporotic risk of short-term low-dose heparin plus
      bedrest in pregnancy. STUDY DESIGN: In a prospective case-control study, 10
      pregnant women on bedrest receiving prophylactic unfractionated heparin 10,000 IU
      per day for 7-46 days pre-study and 28 days per-study were compared with 6 normal
      pregnant controls of similar maternal and gestational age and 10 nonpregnant
      women of similar age. Serum ionised calcium, 1,25-dihydroxyvitamin D(3),
      osteocalcin, and urinary calcium/creatinine ratio were determined three times at
      2-week intervals. RESULTS: 1,25-Dihydroxyvitamin D(3) was lower in the treated
      group than in pregnant controls throughout (P<0.03). Osteocalcin was lower at
      study start than end in both pregnant groups (P<0.05), and lower in the treated
      group than in either pregnant (n.s.) or nonpregnant controls (P<0.005).
      Calcium/creatinine ratio differences were non significant (n.s.). CONCLUSION:
      Short-term low-dose heparin plus bedrest suppresses 1,25-dihydroxyvitamin D(3)
      and osteocalcin levels in pregnancy.

PMID- 12475578
TI  - Antigenic and functional levels of alpha-1-antitrypsin in serum during normal and
      diabetic pregnancy.
AB  - OBJECTIVES: Serum alpha-1-antitrypsin (AAT) concentration may not be
      representative of the functional capacity of this inhibitor. The aim of this
      study was to determine the antigenic and functional serum levels of AAT during
      normal and diabetic pregnancy. METHODS: Serum AAT concentration was measured on
      NOR-Partigen plates (Dade Behring). Trypsin inhibitory capacity (TIC) in the
      serum was determined with N-benzoyl-DL-arginine-p-nitroaniline (BAPNA, Sigma) as
      substrate. The examined material included pregnant women with type 1 diabetes
      mellitus (n=16) studied prospectively in successive stages of pregnancy, healthy
      pregnant women in the first trimester (n=12), second trimester (n=15), third
      trimester (n=15) and healthy non-pregnant women (n=14). RESULTS: Serum
      concentration of AAT in all consecutive phases of diabetic pregnancy is higher as
      compared to normal pregnancy (P<0.0001). Serum TIC is significantly lower in the
      first and third trimesters in diabetic pregnancy (P<0.05, 0.001, respectively).
      Specific activity of serum AAT (mg of trypsin inhibited by 1mg of AAT) does not
      change between subsequent trimesters both in normal and diabetic pregnancy and in
      diabetic pregnancy is two times lower as compared to normal pregnancy.
      CONCLUSION: In spite of the higher level of AAT in the serum in diabetic
      pregnancy, the ability of this inhibitor to inhibit trypsin is two times lower as
      compared to normal pregnancy.

PMID- 12475579
TI  - The critical period of non-reassuring fetal heart rate patterns in preterm
      gestation.
AB  - OBJECTIVE: Our purpose was to determine the critical period for non-reassuring
      fetal heart rate (FHR) patterns in preterm gestation in predicting fetal acidosis
      (umbilical arterial pH <7.1) at birth. STUDY DESIGN: A prospective descriptive
      study was performed. We reviewed the FHR pattern and umbilical blood gas level
      measurements, and investigated the correlations between non-reassuring FHR
      patterns and umbilical arterial pH. RESULTS: There was a significant difference
      in the frequency of fetal acidosis between the neonatal death and survival groups
      (5/13 versus 30/759, P=0.0001). Umbilical pH values in fetuses with persistent
      late deceleration with loss of variability (7.15+/-0.11, P<0.01) and in those
      with prolonged deceleration (7.17+/-0.16, P<0.01) were significantly lower than
      in fetuses with reassuring FHR patterns (7.29+/-0.06). Fetal acidosis also
      occurred more often in these two groups. The critical periods for late
      deceleration with loss of variability and for prolonged deceleration were 60 and
      30 min, respectively. CONCLUSION: These data indicate that a critical period for
      non-reassuring FHR patterns in preterm gestation exists. Prompt delivery is
      required within that short critical period.

PMID- 12475580
TI  - Antenatal visits and adverse perinatal outcomes: results from a British
      population-based study.
AB  - OBJECTIVE: The objective of this study was to explore the relationship between
      the number of antenatal visits made by a representative sample of British women
      and adverse perinatal outcomes. STUDY DESIGN: A total of 20,771 women with a
      singleton pregnancy were recruited from nine representative maternity units in
      Northern England and North Wales. A record of each woman's antenatal care and the
      adverse perinatal outcomes of interest were extracted retrospectively from their
      case notes. Multivariate binomial regression was used to model the probability of
      adverse outcomes with respect to the absolute number of antenatal visits, after
      controlling for potentially confounding factors. Separate analyses were performed
      for primiparae and multiparae, and for low- and high-risk women within each
      parous group. RESULTS: The study revealed an inverse association between the
      number of antenatal visits and delivery of a low birthweight infant, infant
      admission to a special care baby unit and perinatal mortality over the 4-14
      antenatal visit range, which dissipated at higher levels of antenatal visits. The
      study also revealed a significant positive association between the number of
      antenatal visits and delivery by caesarean section (P<0.01). Similar trends in
      the probabilities of adverse outcomes were observed for low- and high-risk women
      within each parous group. CONCLUSION: Further experimental research is required
      to ascertain whether a causal relationship exists between antenatal visiting
      schedules and adverse perinatal outcomes.

PMID- 12475582
TI  - Should all sexually active young women in Hungary be screened for Chlamydia
      trachomatis?
AB  - OBJECTIVE: Cost-effectiveness analysis was carried out to develop screening
      strategy for Chlamydia trachomatis to assess the possibility of preventing pelvic
      inflammatory disease and its sequelae. STUDY DESIGN: An 18 months epidemiological
      study of prevalence of chlamydial infection among pregnant women was carried out
      in Hungary. RESULTS: The policy of testing and treating was less cost-effective
      than neither testing nor treating, unless the cost of the diagnostic test were
      less than or equal to US$ 10, or the prevalence of infection in women were
      greater than 8.3. CONCLUSIONS: Since the prevalence of chlamydial infection
      amongst 15-24 years old women in this study was 8.0%, the cost of screening in
      Hungary only barely outweighs the benefit in economic terms. Given the
      undesirable potential consequences of the infection, it is thus recommended that
      Hungarian clinicians should screen all young, sexually active women for C.
      trachomatis at the same time as they perform routine pelvic examinations.

PMID- 12475581
TI  - Diphenhydramine and hyaluronic acid derivatives reduce adnexal adhesions and
      prevent tubal obstructions in rats.
AB  - OBJECTIVE: The purpose of this study is to investigate the effects of
      diphenhydramine-HCl and Na-hyaluronate derivatives on the development of
      postoperative peritoneal adhesion and tubal obstruction. STUDY DESIGN: Forty
      female rats of Sprague-Dawley type were used in the study. The rats were divided
      into four groups, each comprising 10 subjects. After all the rats were
      anaesthetized with 50mg/kg ketamine HCl, their abdomens were opened with a lower
      midline incision. Injury was induced on the right pelvic peritoneum and on the
      peritoneal surface of left uterine tube. No additional procedure was applied to
      the first group. 10 mg/kg diphenhydramine-HCl was given to the second group
      intravenously. In the third group, 0.25 mg/kg Orthovisc, a Na-hyaluronate
      derivative was diluted with 2 ml physiological saline and poured into the
      abdomen. For the fourth group, Seprafilm, a Na-hyaluronate derivative was covered
      in a layer of 0.7 cm x 3 cm over the left uterine tube. After 14 days, the rats
      were anaesthetized with ketamine HCl again, and 5 cm(3) blood sample was taken
      with cardiac puncture. The abdomen was opened with an incision transverse to the
      upper end of the midline incision, and the presence of adhesions was
      investigated. Detected adhesions were staged according to the Mazuji
      classification. Tubal patencies were inspected by injecting methylene blue from
      the uterine corpus into the lumen using an injector. A piece of abdominal wall of
      4 cm x 4 cm was removed by extending the incision in the reverse U shape. The
      tensile strength and bursting pressure of the suture line were determined using
      the Peacock method. One gram of tissue was taken from the incision line, and
      hydroxyproline levels were determined by the Bergman-Loxley method. Aspartate
      aminotransferase (AST) levels were measured. RESULTS: All of the rats completed
      the study. AST levels, tissue hydroxyproline levels and tensile strength and
      bursting pressure test results were found to be similar in all groups. While
      adhesion rates in the groups were 100, 40, 40 and 30%, respectively, adhesion
      stages were found to be, respectively as 2.1+/-1.7, 0.6+/-0.67, 0.6+/-0.67 and
      0.5+/-0.85. Adhesion stages in the study groups were significantly lower
      (P<0.05). Tubal obstruction rates were found to be 70, 30, 30 and 20%,
      respectively. CONCLUSION: Diphenhydramine, Orthovisc and Seprafilm significantly
      reduce postoperative peritoneal adhesion development, and they allow the uterine
      tubes to remain open.

PMID- 12475583
TI  - Information contained in miscarriage-related websites and the predictive value of
      website scoring systems.
AB  - OBJECTIVES: To identify websites providing information about early pregnancy loss
      and compare this information with published guidelines from the Royal College of
      Obstetricians and Gynaecologists (RCOG). The value of 'Silberg' and 'Health on
      the net (HON)' website scoring systems in predicting the information provided via
      websites identified was assessed. STUDY DESIGN: A cross-sectional survey. SAMPLE:
      Nineteen websites identified via two search engines (http://www.lycos.co.uk and
      http://www.msn.co.uk). METHODS: Websites were searched for specific information
      in a structured manner and then scored by two independent observers against the
      website scoring systems and against a scoring system derived from guidelines
      published by the RCOG. MAIN OUTCOME MEASURES: Website scores against the scoring
      systems and against RCOG guidelines. RESULTS: Information concerning miscarriage
      contained within these websites was poor and scored accordingly against the RCOG
      guidelines (median score, 4.5/8). The website scoring systems did not predict the
      RCOG scores for a website (HON score R(S)=0.193 (95% confidence interval from 
      0.286 to 0.595), Silberg score, R(S)=0.035 (95% confidence interval from -0.426
      to 0.482)). CONCLUSIONS: Few relevant websites were identified despite searching
      a large number via two search engines. The websites found did not answer our
      specific questions and consequently scored poorly against the RCOG guidelines.
      RCOG scores did not correlate with either scoring system. Web-based information
      for women attending with early pregnancy complications needs to be easily
      accessed and comprehensive. Written information given to women when seen with
      early pregnancy complications should include details of available comprehensive
      websites. Professional organisations, colleges or Government agencies should
      provide this type of information.

PMID- 12475584
TI  - Vaginal intraepithelial neoplasia: treatment by carbon dioxide laser and risk
      factors for failure.
AB  - OBJECTIVE: To evaluate the effectiveness of CO(2) laser ablation of vaginal
      intraepithelial neoplasia (VAIN) and to define prognostic factors. STUDY DESIGN:
      Medical records of 24 patients with VAIN II or III, treated by CO(2) laser
      ablation from 1990 to 1998 were reviewed. The grade, location, and focality of
      the lesions, the age, follow-up period and menopausal status of the patients, the
      power and duration of laser ablation, the presence of concurrent cervical or
      vulvar neoplasia or previous hysterectomy were evaluated as possible prognostic
      factors. RESULTS: Ablations of the VAIN were successfully accomplished in all of
      the patients with a mean period of 25.2+10.2 min, including additional
      simultaneous ablations of the cervix or vulva in eight (33.3%) patients. There
      was no early or late major complication. VAIN was completely eliminated in 17
      (70.8%) patients after the first and in 19 (79.2%) patients after multiple
      episodes of ablation with a mean follow-up of 26.7+19.6 months. VAIN progressed
      to invasive vaginal carcinoma in one woman. None of the evaluated prognostic
      factors was found to be related to the persistence or recurrence. CONCLUSION:
      CO(2) laser ablation was a safe and effective method for the treatment of VAIN.
      However, since no prognostic factor was defined, all patients should be closely
      evaluated for persistence, recurrence or progression to invasion.

PMID- 12475585
TI  - Simple one-step catheter placement for the treatment of infected lymphocele.
AB  - OBJECTIVE: A pelvic lymphocele is a cystic collection of lymph fluid in the
      pelvis following pelvic lymphadenectomy. This retrospective study was undertaken
      to show the efficacy and safety of simple one-step catheter placement for the
      treatment of infected lymphocele. STUDY DESIGN: Ten infected lymphoceles were
      treated in nine patients. The percutaneous drainage procedures were performed
      using simple one-step trocar technique under sonographical guidance. The one-step
      pig tail catheter system consists of an 18-gauge needle, stylet, and 7F drainage
      tube. A 33% povidone-iodine solution was instilled and left in the cavity for 30
      min twice daily. RESULTS: Overall, 9 of the 10 infected lymphoceles were
      successfully treated with one-step catheter drainage. Percutaneous catheter
      drainage was maintained for 2-17 days. One of the patients required open surgery
      for the persistence of infected lymphocele due to the catheter dislodgment. No
      patients encountered sepsis, bowel perforation, and neurovascular injury.
      CONCLUSION: Simple one-step procedure enables long-term drainage and is a well
      tolerated, safe, and effective technique in the management of infected
      lymphocele.

PMID- 12475586
TI  - Treatment of imperforate hymen by application of Foley catheter.
AB  - OBJECTIVE: To treatment of patients with imperforate hymen without damaging the
      structure of hymen. MATERIALS AND METHODS: Foley catheter was applied to 15
      patients with the history of pelvic pain and diagnosed as imperforate hymen in
      Department of Obstetric and Gynecology, Faculty of Medicine, Selcuk University,
      between 1 January 1996 and 25 December 2000. After performed oval-centralize
      closure on imperforate hymen membranes, Foley catheter was inserted through
      closure of hymen and then balloon of Foley catheter was insufflated 10 cm(3).
      Catheter was removed after 2 weeks. RESULTS: Mean age of patients was 14.3+/-2.6.
      After procedure, closure of hymen was open. Hymen was seen annular and intact.
      Following the patients, closing of the closure of hymen was not seen. After
      marriage of six patients, hymeneal bleeding and defloration was seen in all of
      them. Ceftriaxon (Rocephin, Roche, Istanbul) 1g was given to all patients only
      one dose as prophylactic antibiotheraphy. Any pelvic and vaginal infection were
      not seen due to this procedure during follow up. CONCLUSION: This new technique
      is less invasive than other methods and prevents many social problem by
      preventing destruction of the architecture of hymen and providing annular-intact
      hymeneal ring.

PMID- 12475587
TI  - Uterine lipoleiomyoma containing metastatic breast carcinoma: a case with two
      unusual pathologies.
AB  - Uterine lipoleiomyoma is a rare benign tumor. Besides this, metastasis to this
      tumor from breast carcinoma is extremely rare without any case reported in the
      literature. We report one such case of metastatic carcinoma in uterine
      lipoleiomyoma from primary breast cancer.

PMID- 12475588
TI  - Heterotopic pregnancy in a natural conception cycle presenting with tubal
      rupture: a case report and review of the literature.
AB  - BACKGROUND: Heterotopic pregnancy is a potentially fatal condition, rarely
      occurring in natural conception cycles. CASE: We report such a case in a 28-year
      old para 0, gravida 1 woman with no known risk factors. The ectopic pregnancy was
      diagnosed after rupturing at 11 weeks, 4 weeks after diagnosis of the
      intrauterine pregnancy, and resected via laparotomy. A healthy baby was delivered
      without complications at 40 weeks gestation. CONCLUSION: Heterotopic pregnancy is
      possible with natural conception and the survival of the intrauterine fetus is
      feasible.

PMID- 12475589
TI  - Benign multiple diffuse neonatal hemangiomatosis after a pregnancy complicated by
      polyhydramnios and a placental chorioangioma.
AB  - A male newborn with multiple cutaneous hemangiomatosis is described. Pregnancy
      was complicated by polyhydramnios and a large placental chorioangioma. After an
      initial outburst of the hemangiomas in the first two weeks of life, spontaneous
      and almost complete regression occurred before the age of 3 months. The
      relationship between hemangiomas and placental chorioangioma is briefly
      discussed.

PMID- 12475590
TI  - Increase in birthweight: a unique biological event and an obstetrical problem.

PMID- 12475591
TI  - How can chemical compounds alter human fertility?

PMID- 12475593
TI  - Successful termination of a cervical pregnancy with misoprostol.

PMID- 12475597
TI  - What is the biblical attitude towards personal hygiene during vaginal bleeding?
AB  - OBJECTIVE: To analyze biblical passages associated with personal hygiene during
      vaginal bleeding. According to the Bible, a woman who is menstruating or who has
      pathological vaginal bleeding is unclean. Anybody who touches such a woman's bed
      or her personal things is also regarded as unclean and should therefore, wash
      carefully. Sexual relations are forbidden within 7 days from the beginning of
      menstruation and during pathological vaginal bleeding. Seven days after the
      cessation of vaginal bleeding, a woman is considered as clean, and therefore,
      sexual contacts are permitted. From a modern perspective sexual contacts during
      menses are associated with the development of chlamydial and gonococcal diseases,
      the risk of transmission of the human immunodeficiency virus infection,
      endometriosis and subsequent infertility. This report indicates that the roots of
      contemporary obstetric preventive medicine can be traced to Biblical times.

PMID- 12475598
TI  - EBCOG hospital visiting, a step forward in the quality assessment of training in
      obstetrics and gynaecology.
AB  - Since the start in 1996, over 30 hospital visits have been successfully conducted
      by the European Board and College of Obstetrics and Gynaecology (EBCOG) in more
      than 12 European countries. Hospital visiting is an important tool for raising
      training standards. EBCOG hospital visiting is voluntary, but its ultimate goal
      is a National Hospital Visiting Programme in each country within Europe. Some
      countries, following the initial process of visits by EBCOG have introduced their
      own hospital visiting system successfully, e.g. Norway and Portugal.

PMID- 12475601
TI  - Backtalk in neurons.
AB  - A recent paper investigates retrograde transmission from dendrites of the
      oxytocin neurons of the supraoptic nucleus. Dendrites appear to have release
      properties different from those of axon terminals, and release appears to be
      enhanced if intracellular Ca2+ has been previously elevated, suggesting that
      cells can be 'primed'.

PMID- 12475602
TI  - CGRP receptor heterogeneity: a role for receptor component protein?

PMID- 12475606
TI  - Secretory granule biogenesis and chromogranin A: master gene, on/off switch or
      assembly factor?
AB  - Secretory granules are found in specialized cell types, including endocrine
      cells, suggesting that a coordinated programme of gene expression is involved in
      their biogenesis. Indeed, it has been proposed that chromogranin A (CgA) acts as
      an on/off switch for secretory granule biogenesis. However, this proposed
      function is difficult to reconcile with the large body of evidence suggesting
      that secretory granules exist in the absence of CgA and that cells can synthesize
      CgA in the absence of secretory granules. Indeed, recent evidence suggests that,
      rather than a master gene or universal on/off switch, a series of on/off switches
      combines to induce expression of subsets of secretory granule-associated genes.
      The assembly of newly synthesized proteins and the inclusion of existing granule
      proteins would produce functional secretory granules. CgA and related proteins
      might act as assembly factors in this process.

PMID- 12475607
TI  - Emerging functions for tuberoinfundibular peptide of 39 residues.
AB  - Tuberoinfundibular peptide of 39 residues (TIP39), a neuropeptide recently
      purified from the hypothalamus, appears to be an endogenous ligand for the
      parathyroid hormone 2 (PTH2) receptor. PTH2 receptors are present in several
      central nervous system and peripheral areas and are particularly concentrated in
      the hypothalamus, limbic areas and the outer layers of the spinal cord dorsal
      horn. TIP39-containing neuronal cell bodies have been identified in the
      subparafascicular area and the medial paralemniscal nucleus, two brainstem
      regions that project widely through the entire neuraxis. Treatment of
      hypothalamic explants with TIP39, and intraventricular injection of the peptide,
      suggest that it might stimulate hypothalamic-releasing factor secretion.
      Injection of TIP39, and sequestration of endogenous TIP39 by intrathecal
      injection of an antibody to TIP39, have provided evidence that it is involved in
      some aspects of pain sensitivity. Thus, TIP39 might be a new neuromodulator.

PMID- 12475608
TI  - Pain in the brain: are hormones to blame?
AB  - Pain is a multi-dimensional process involving the physical, emotional and
      perceptual integration of noxious information. The physical component is relayed
      via the spinal cord to several brain areas to initiate the detection of pain. The
      emotional aspect is encoded by the limbic system and encapsulates the
      relationship between pain and mood. Within the limbic system, the hypothalamus
      undertakes a diversity of separate and interrelated functions. Dysfunction of the
      hypothalamo-pituitary-adrenal axis has been implicated in a variety of chronic
      pain conditions and might also be associated with increased risk of developing
      mood disorders. Experimental and clinical evidence also exists to implicate the
      effects of other hormonal modulators in the manifestation of chronic pain.
      Specific targeting of hormonal cascade and effector mechanisms could provide an
      alternative strategy for the treatment of various chronic pain conditions.

PMID- 12475609
TI  - The GH-IGF-I axis and breast cancer.
AB  - The growth hormone-insulin-like growth factor-I (GH-IGF-I) axis plays a
      fundamental role in the development of the breast. The maintenance of breast
      tissue architecture is aided by its effect on proliferation, differentiation and
      apoptosis. There has been increasing recognition of its role as a major
      determinant of breast cancer and, more recently, its involvement in the
      development of resistance to both tamoxifen and an important novel therapy for
      advanced disease, trastuzumab (Herceptin). Here, we discuss the influence of the
      GH-IGF-I axis in normal mammary development and homeostasis, its putative role in
      breast tumorigenesis and its interactions with estrogen signalling.

PMID- 12475610
TI  - GnRH II and type II GnRH receptors.
AB  - Hypothalamic gonadotrophin-releasing hormone (GnRH I), which is of a variable
      structure in vertebrates, is the central regulator of the reproductive system
      through its stimulation of gonadotrophin release from the pituitary. A second
      form of GnRH (GnRH II) is ubiquitous and conserved in structure from fish to
      humans, suggesting that it has important functions and a discriminating receptor
      that selects against structural change. GnRH II is distributed in discrete
      regions of the central and peripheral nervous systems and in nonneural tissues.
      The cognate receptor for GnRH II has recently been cloned from amphibians and
      mammals. It is highly selective for GnRH II, has a similar distribution to GnRH
      II in the nervous system and, notably, in areas associated with sexual behaviour.
      It is also found in reproductive tissues. An established function of GnRH II is
      in the inhibition of M currents (K(+) channels) through the GnRH II receptor in
      the amphibian sympathetic ganglion, and it might act through this mechanism as a
      neuromodulator in the central nervous system. The conservation of structure over
      500 million years and the wide tissue distribution of GnRH II suggest that it has
      a variety of reproductive and nonreproductive functions and will be a productive
      area of research.

PMID- 12475611
TI  - Emerging role of endothelin-1 in tumor angiogenesis.
AB  - Tumor vessels express distinct molecular markers that are functionally relevant
      in the angiogenic process. Although tyrosine kinase receptor agonists are the
      major mediators of angiogenesis, several G-protein-coupled receptor agonists have
      also been shown to have a role. Among these, endothelin-1 (ET-1), by acting
      directly on endothelial cells via the ET(B) receptor, modulates different stages
      of neovascularization, including proliferation, migration, invasion, protease
      production and morphogenesis, and also stimulates neovascularization in vivo. ET
      1 can also modulate tumor angiogenesis indirectly through the induction of
      vascular endothelial growth factor (VEGF). Engagement of the ET(A) receptor by ET
      1 induces VEGF production by increasing levels of hypoxia-inducible factor 1
      alpha. Moreover, tumor cells themselves, predominantly expressing the ET(A)
      receptor, might form vessel-like channels within the tumors. The role of ET-1 and
      its signaling network in tumor angiogenesis suggests that new therapeutic
      strategies using specific ET(A)-receptor antagonists could improve antitumor
      treatment by inhibiting both neovascularization and tumor cell growth.

PMID- 12475612
TI  - Saponins in cereals.
AB  - Saponins are a diverse family of secondary metabolites that are produced by many
      plant species, particularly dicots. These molecules commonly have potent
      antifungal activity and their natural role in plants is likely to be in
      protection against attack by pathogenic microbes. They also have a variety of
      commercial applications including use as drugs and medicines. The enzymes, genes
      and biochemical pathways involved in the synthesis of these complex molecules are
      largely uncharacterized for any plant species. Cereals and grasses appear to be
      generally deficient in saponins with the exception of oats, which produce both
      steroidal and triterpenoid saponins. The isolation of genes for saponin
      biosynthesis from oats is now providing tools for the analysis of the evolution
      and regulation of saponin biosynthesis in monocots. These genes may also have
      potential for the development of improved disease resistance in cultivated
      cereals.

PMID- 12475613
TI  - Monosaccharide composition and properties of a deglycosylated turnip peroxidase
      isozyme.
AB  - A neutral peroxidase isozyme (TP) purified from turnip (Brassica napus L. var.
      purple top white globe) was partially deglycosylated, using chemical and
      enzymatic treatment. A 32% carbohydrate removal was achieved by exposing TP to a
      mixture of PNGase F, O-glycosidase, NANase, GALase III and HEXase I, while m
      periodate treatment removed about 88% of TP carbohydrate moiety. The glycoprotein
      fraction of the TP contained a relatively high mannose and fucose content (37 and
      31%, w/w, respectively), 16% (w/w) galactose, and 15% (w/w) GlcNAc. Thus, the
      carbohydrate moiety was classified as a hybrid type. Partially deglycosylated TP
      had reduced activity (by 50-85%), was more susceptible to proteolysis, and showed
      a slight decrease in thermostability compared to the native enzyme. Circular
      dichroism studies strongly suggested that although the carbohydrate moiety of TP
      did not influence the conformation of the polypeptide backbone, its presence
      considerably enhanced protein conformational stability toward heat. Removal of
      oligosaccharide chains from TP caused a decrease in K(m) and V(max) for hydrogen
      peroxide. Native and chemically deglycosylated TP were similarly immunodetected
      by rabbit polyclonal antibodies raised against TP. The results suggest that the
      carbohydrate moiety of TP is important for peroxidase activity and stability.

PMID- 12475614
TI  - Biochemical characterization of sap (latex) of a few Indian mango varieties.
AB  - Mango sap (latex) from four Indian varieties was studied for its composition. Sap
      was separated into non-aqueous and aqueous phases. Earlier, we reported that the
      non-aqueous phase contained mainly mono-terpenes having raw mango aroma
      (Phytochemistry 52 (1999) 891). In the present study biochemical composition of
      the aqueous phase was studied. Aqueous phase contained little amount of protein
      (2.0-3.5 mg/ml) but showed high polyphenol oxidase (147-214 U/mg protein) and
      peroxidase (401-561 U/mg protein) activities. It contained low amounts of
      polyphenols and protease activities. On native PAGE, all the major protein bands
      exhibited both polyphenol oxidase and peroxidase activities. Both polyphenol
      oxidase and peroxidase activities were found to be stable in the aqueous phase of
      sap at 4 degrees C. Sap contained large amount of non-dialyzable and non-starchy
      carbohydrate (260-343 mg/ml sap) which may be responsible for maintaining a
      considerable pressure of fluid in the ducts. Thus, the mango sap could be a
      valuable by-product in the mango industry as it contains some of the valuable
      enzymes and aroma components.

PMID- 12475615
TI  - Three alpha-amylases from malted finger millet (Ragi, Eleusine coracana, Indaf
      15)--purification and partial characterization.
AB  - Three alpha-amylases (E.C. 3.2.1.1) were purified to apparent homogeneity from 72
      h finger millet malt by three step purification via fractional acetone
      precipitation, DEAE-Sephacel ion exchange and Sephacryl S-200 gel permeation
      chromatographies with a recovery of 6.5, 2.9, 9.6% and fold purification of 26,
      17 and 31, respectively. alpha-Nature of these amylases was identified by their
      ability to rapidly reduce the viscosity of starch solution and also in liberating
      oligosaccharides of higher D.P. and were accordingly designated as amylases alpha
      1((b)), alpha-2 and alpha-3, respectively. These amylases, having a molecular
      weight of 45+/-2 kDa were found to be monomeric. The pH and temperature optima of
      these alpha-amylases were found to be in the range of 5.0-5.5 and 45-50 degrees
      C, respectively. K(m) values of these amylases for various cereal starches varied
      between 0.59 and 1.43%. Carbodiimide (50 mM) and metal ions such as Al(3+),
      Fe(2+), and Hg(2+) (5 mM) have completely inhibited these enzymes at 45 degrees
      C. Amino acid analysis of these enzymes indicated high amounts of glycine which
      is an unusual feature of these enzymes.

PMID- 12475616
TI  - Reduced levels of cadinane sesquiterpenoids in cotton plants expressing antisense
      (+)-delta-cadinene synthase.
AB  - Cotton plants were transformed with an antisense construct of cdn1-Cl, a member
      of a complex gene family of delta-(+)cadinene (CDN) synthase. This synthase
      catalyzes the cyclization of (E,E)-farnesyl diphosphate to form CDN, and in
      cotton, it occupies the committed step in the biosynthesis of cadinane
      sesquiterpenoids and heliocides (sesterterpenoids). Southern analyses of the
      digestion of leaf DNA from R(o), T(o), and T(1) plants with Hind III, Pst I and
      Kpn I restriction enzymes show the integration of antisense cdn1-C1 cDNA driven
      by the CaMV 35S promoter into the cotton genome. Northern blots demonstrate the
      appearance of cdn synthase mRNA preceding CDN synthase activity and the formation
      of gossypol in developing cottonseed. T(2) cottonseed show a reduced CDN synthase
      activity and up to a 70% reduction in gossypol. In T(1) leaves the accumulated
      amounts of gossypol, hemigossypolone and heliocides are reduced 92.4, 83.3 and
      68.4%, respectively. These data demonstrate that the integration of antisense
      cdn1-C1 cDNA into the cotton genome leads to a reduction of CDN synthase activity
      and negatively impacts on the biosynthesis of cadinane sesquiterpenoids and
      heliocides in cotton plants.

PMID- 12475617
TI  - Expression of a Streptomyces 3-hydroxysteroid oxidase gene in oilseeds for
      converting phytosterols to phytostanols.
AB  - Plant sterols and their hydrogenated forms, stanols, have attracted much
      attention because of their benefits to human health in reducing serum and LDL
      cholesterol levels, with vegetable oil processing being their major source in
      several food products currently sold. The predominant forms of plant sterol end
      products are sitosterol, stigmasterol, campesterol and brassicasterol (in
      brassica). In this study, 3-hydroxysteroid oxidase from Streptomyces
      hygroscopicus was utilized to engineer oilseeds from rapeseed (Brassica napus)
      and soybean (Glycine max), respectively, to modify the relative amounts of
      specific sterols to stanols. Each of the major phytosterols had its C-5 double
      bond selectively reduced to the corresponding phytostanol without affecting other
      functionalities, such as the C-22 double bond of stigmasterol in soybean seed and
      of brassicasterol in rapeseed. Additionally, several novel phytostanols were
      obtained that are not produced by chemical hydrogenation of phytosterols normally
      present in plants.

PMID- 12475618
TI  - Isolation and characterization of two fructokinase cDNA clones from rice.
AB  - Two cDNA clones, OsFKI and OsFKII, encoding fructokinase (EC 2.7.1.4) were
      isolated from immature seeds of rice (Oryza sativa L.) by PCR. OsFKI cDNA encoded
      a deduced protein of 323 amino acids that was 59-71% identical to previously
      characterized plant fructokinases. In contrast, OsFKII cDNA encoded a deduced
      protein of 336 amino acids that shared only 64% amino acid identity with OsFKI.
      The deduced proteins both possessed an ATP-binding motif and putative substrate
      recognition site sequences that were previously identified in bacterial
      fructokinases. Genomic DNA blot analysis also revealed that each fructokinase
      gene exists as a single copy in the rice genome. The identity of OsFKI and OsFKII
      as fructokinases was confirmed by the expression of enzyme activity in E. coli.
      Although both OsFKI and OsFKII utilized fructose as substrate, only OsFKII
      activity was strongly inhibited at a high fructose concentration. The mRNA
      corresponding to OsFKII accumulated at high levels in developing rice grains,
      whereas there were only low levels of OsFKI transcripts in immature seeds. These
      results indicate that fructokinase in rice endosperm is encoded by two divergent
      genes, which play different roles in rice grains for starch storage based on
      their sensitivity to substrate inhibition and level of transcripts in endosperm.

PMID- 12475619
TI  - Structural and compositional modifications in lignin of transgenic alfalfa down
      regulated in caffeic acid 3-O-methyltransferase and caffeoyl coenzyme A 3-O
      methyltransferase.
AB  - Isolated lignins from alfalfa deficient in caffeic acid 3-O-methyltransferase
      contained benzodioxanes resulting from the incorporation of the novel monomer, 5
      hydroxyconiferyl alcohol. Due to the high level incorporated into the soluble
      lignin fraction and the use of sensitive NMR instrumentation, unique structural
      features were revealed. A new type of end-unit, the 5-hydroxyguaiacyl glycerol
      unit, was identified. It was possible to establish that coniferyl alcohol,
      sinapyl alcohol, and the novel 5-hydroxyconiferyl alcohol can cross-couple with
      the 5-hydroxyguaiacyl units that are formed in the lignin, the latter giving rise
      to extended chains of benzodioxane units. There is also evidence that 5
      hydroxyconiferyl alcohol couples with normal (guaiacyl or syringyl) lignin units.
      Lignin in the alfalfa deficient in caffeoyl CoA 3-O-methyltransferase was
      structurally similar to the control lignin but the transgenic exhibited a
      dramatic decrease in lignin content (approximately 20%) and modest increase in
      cellulose (approximately 10%) reflecting a 30% increase in cellulose:lignin
      ratio. The compositional changes in both transgenics potentially allow enhanced
      utilization of alfalfa as a major forage crop by increasing the digestibility of
      its stem fraction.

PMID- 12475620
TI  - The biotransformation of the diterpene 2beta-hydroxy-ent-13-epi-manoyl oxide by
      Gibberella fujikuroi.
AB  - Incubation of the diterpene 2beta-hydroxy-ent-13-epi-manoyl oxide with Gibberella
      fujikuroi afforded in good yield 2beta,6beta-dihydroxy-ent-13-epi-manoyl oxide,
      2beta,12beta-dihydroxy-ent-13-epi-manoyl oxide and 2beta,20-dihydroxy-ent-13-epi
      manoyl oxide, confirming that although ent-13-epi-manoyl oxide is a final
      metabolite of a biosynthetic branch in this fungus, more polar derivatives of
      this compound can be transformed by this micro-organism.

PMID- 12475621
TI  - 6H-dibenzo[b,d]pyran-6-one derivatives from the cultured lichen mycobionts of
      Graphis spp. and their biosynthetic origin.
AB  - The spore-derived mycobionts of the lichen Graphis prunicola, G. cognata and G.
      scripta were cultivated on a malt-yeast extract medium supplemented with 10%
      sucrose and their metabolites were investigated. Graphislactones A-D were
      isolated from the cultures of G. prunicola, while alternariol and graphislactones
      A and C were isolated from those of G. cognata. From the cultured mycobionts of
      G. scripta, a new 6H-dibenzo[b,d]pyran-6-one derivative, graphislactone E with
      graphislactones A and C was obtained. On the other hand, cultivation of the
      mycobionts of G. prunicola on a malt-yeast extract medium supplemented with 2.5%
      sucrose and 0.25% sodium acetate produced two new metabolites, graphislactones E
      and F. Their structures were determined by spectroscopic methods. The biogenetic
      origin of the carbon skeleton in both compounds was verified by administering
      sodium [1-13C]-acetate and sodium [1,2-13C(2)]-acetate.

PMID- 12475622
TI  - Synthesis of gibberellin GA6 and its role in flowering of Lolium temulentum.
AB  - The induction of flowering by one long day (LD) in the grass Lolium temulentum is
      most closely mimicked by application of the gibberellins (GAs) GA(5) or GA(6),
      both of which occur naturally. These gibberellins promote floral development but
      have little effect on stem elongation. Endogenous GA(5) and GA(6) contents in the
      shoot apex double on the day after the LD and, for GA(5) (and we presume for
      GA(6) as well) reach a concentration known to be inductive for the excised shoot
      apex in vitro. They are, therefore, strong candidates as LD floral stimuli in
      this grass. The synthesis of GA(6) and an examination of its florigenic
      properties in L. temulentum are described.

PMID- 12475623
TI  - Bacterial resistance modifying agents from Lycopus europaeus.
AB  - As part of an ongoing project to identify plant natural products which modulate
      bacterial multidrug resistance (MDR), bioassay-guided isolation of an extract of
      Lycopus europaeus yielded two new isopimarane diterpenes, namely methyl-1alpha
      acetoxy-7alpha 14alpha-dihydroxy-8,15-isopimaradien-18-oate (1) and methyl
      1alpha,14alpha-diacetoxy-7alpha-hydroxy-8,15-isopimaradien-18-oate (2). The
      structures were established by spectroscopic methods. These compounds and several
      known diterpenes were tested for in vitro antibacterial and resistance modifying
      activity against strains of Staphylococcus aureus possessing the Tet(K), Msr(A),
      and Nor(A) multidrug resistance efflux mechanisms. At 512 microg/ml none of the
      compounds displayed any antibacterial activity but individually in combination
      with tetracycline and erythromycin, a two-fold potentiation of the activities of
      these antibiotics was observed against two strains of S. aureus that were highly
      resistant to these agents due to the presence of the multidrug efflux mechanisms
      Tet(K) (tetracycline resistance) and Msr(A) (macrolide resistance).

PMID- 12475624
TI  - Inhibition of LDL oxidation by flavonoids in relation to their structure and
      calculated enthalpy.
AB  - Twenty flavonoid compounds of five different subclasses were selected, and the
      relationship of their structure to the inhibition of low-density lipoprotein
      (LDL) oxidation in vitro was investigated. The most effective inhibitors, by
      either copper ion or 2,2'-azobis (2-amidino-propane) dihydrochloride (AAPH)
      induction, were flavonols and/or flavonoids with two adjacent hydroxyl groups at
      ring B. In the presence of the later catechol group, the contribution of the
      double bond and the carbonyl group at ring C was negligible. Isoflavonoids were
      more effective inhibitors than other flavonoid subclasses with similar structure.
      Substituting ring B with hydroxyl group(s) at 2' position resulted in a
      significantly higher inhibitory effect than by substituting ring A or ring B at
      other positions. The type of LDL inducer had no effect in flavonoids with
      catechol structure. Calculated heat of formation data (deltadeltaH(f)) revealed
      that the donation of a hydrogen atom from position 3 was the most likely result,
      followed by that of a hydroxyl from ring B. Position 3 was favored only in the
      presence of conjugated double bonds between ring A to ring B. This study makes it
      possible to assign the contribution of different functional groups among the
      flavonoid subclasses to in vitro inhibition of LDL oxidation.

PMID- 12475625
TI  - Benzoquinone, the substance essential for antibacterial activity in aqueous
      extracts from succulent young shoots of the pear Pyrus spp.
AB  - Aqueous extracts of the tissue of succulent young shoots of the pear Pyrus spp.
      exhibited strong antibacterial activity against the bacterium Erwinia amylovora
      bv. 4. This activity was investigated quantitatively by a newly developed
      bioassay method. It was found that the activity changed with the age of the
      tissue. Extracts of the youngest leaves and stems from the shoot tops showed the
      strongest activity, and the activity decreased with age of the leaves and stems.
      The activity also changed with increase in time after preparation of the extract,
      increasing rapidly in the first hour after preparation, reaching a maximum at
      about 4 h, and then decreasing slowly. The substance essential for the
      antibacterial activity was isolated from the extract by steam distillation in
      vacuo and through charcoal powder column chromatography. It was identified as
      benzoquinone (2,5-cyclohexadiene-1,4-dione) by NMR-spectra, mass spectra and HPLC
      analysis. The phenolic metabolism from arbutin to hydroquinone and then to
      benzoquinone in the aqueous extracts was analyzed quantitatively by HPLC. The
      changes in the contents of benzoquinone in the extracts of leaves and stems with
      tissue aging and with increase in time after preparation of the extracts
      paralleled the changes in antibacterial activity as determined by the
      quantitative bioassay.

PMID- 12475626
TI  - Thelephantins A, B and C: three benzoyl p-terphenyl derivatives from the inedible
      mushroom Thelephora aurantiotincta.
AB  - Three benzoyl p-terphenyl derivatives named thelephantins A, B and C were
      isolated from the ethyl acetate extract of fruit bodies of the Thelephoraceous
      Basidiomycete Thelephora aurantiotincta. Their structures were elucidated by
      analysis of high-resolution 2D NMR, MS, IR and UV spectra.

PMID- 12475627
TI  - Glycosides of 2-C-methyl-D-erythritol from the fruits of anise, coriander and
      cumin.
AB  - Eight glycosides of 2-C-methyl-D-erythritol (1) were isolated from the fruit of
      anise, and their structures were clarified as 1-O-beta-D-glucopyranoside, 3-O
      beta-D-glucopyranoside, 4-O-beta-D-glucopyranoside, 1-O-beta-D-fructofuranoside,
      3-O-beta-D-fructofuranoside, 4-O-beta-D-fructofuranoside, 1-O-beta-D-(6-O-4
      hydroxybenzoyl)-glucopyranoside and 1-O-beta-D-(6-O-4-methoxybenzoyl)
      glucopyranoside of 2-C-methyl-D-erythritol (2-9), respectively. Furthermore, 2
      and 4 were isolated from the fruit of coriander, and 2, 3 and 4 were isolated
      from the fruit of cumin. Though the phosphate of 1 was known to be one of the
      first precursors of isoprenoids in the non-mevalonate pathway, and 1 is
      considered to be a common constituent in Umbelliferous plants, the glycosides of
      1 are found for the first time.

PMID- 12475628
TI  - Polymorphonuclear leukocyte migration across model intestinal epithelia enhances
      Salmonella typhimurium killing via the epithelial derived cytokine, IL-6.
AB  - The host response to Salmonella typhimurium involves movement of
      polymorphonuclear leukocytes (PMN) across the epithelium and into the intestinal
      lumen. Following their arrival in the lumen, the PMN attempt to combat bacterial
      infection by activating antimicrobial defenses such as granule release, oxidative
      burst, phagocytosis, and cell signaling. We sought to examine PMN-S. typhimurium
      interaction following PMN arrival in the lumenal compartment. Here, for the first
      time, we demonstrate that PMN that have transmigrated across model intestinal
      epithelia have an enhanced ability to kill S. typhimurium. Our data provide
      evidence to indicate that the extracellular release of the primary and secondary
      granules of PMN, myeloperoxidase and lactoferrin, respectively, is correlated
      with enhanced bacterial killing. Furthermore, epithelial cells, during PMN
      transmigration, release the cytokine IL-6. IL-6 is known to increase
      intracellular stores of Ca(2+), and we have determined that this epithelial
      released cytokine is not only responsible for priming the PMN to release their
      granules, but also stimulating the PMN to kill S. typhimurium. These results
      substantiate the pathway in which PMN transmigration activates the epithelial
      release of IL-6, which in turn increases intracellular Ca(2+) storage. Our
      results, herein, extend this pathway to include an enhanced PMN granule release
      and an enhanced killing of S. typhimurium.

PMID- 12475629
TI  - Tyrosine residues at the immunoglobulin-C-type lectin inter-domain boundary of
      intimin are not involved in Tir-binding but implicated in colonisation of the
      host.
AB  - Intimin is an outer membrane adhesion molecule involved in bacterial adhesion to
      intestinal epithelium by several human and animal enteric pathogens, including
      enteropathogenic and enterohaemorrhagic Escherichia coli and Citrobacter
      rodentium. Intimin binds to the translocated intimin receptor, Tir, which is
      delivered to the plasma membrane of the host cell by a type III protein
      translocation system. Intimin is also implicated in binding to a host cell
      encoded intimin receptor (Hir). The receptor-binding activity of intimin resides
      within the carboxy terminus 280 amino acids (Int280) of the polypeptide.
      Structural analysis of this region revealed two immunoglobulin-like domains, the
      second of which forms a number of contacts with the distal C-type lectin-like
      module. Specific orientation differences at this inter-domain boundary, which
      consists of several tyrosine residues, were detected between the crystal and
      solution structures. In this study, we determined the influence of site-directed
      mutagenesis of each of four tyrosine residues on intimin-Tir interactions and on
      intimin-mediated intimate attachment. The mutant intimins were also studied using
      a variety of in vitro and in vivo infection models. The results show that three
      of the four Tyr, although not essential for A/E lesion formation in vitro, are
      required for efficient colonisation of the mouse host following oral challenge.

PMID- 12475630
TI  - Human cytomegalovirus infection reduces surface CCR5 expression in human
      microglial cells, astrocytes and monocyte-derived macrophages.
AB  - Within the brain, glial cells are target cells for human cytomegalovirus (HCMV)
      and HIV. We infected cultures of unstimulated human microglial cells and
      astrocytes of embryonic origin and of monocyte-derived macrophages (MDM) with
      HCMV strain AD169 and observed down-regulation of the plasma membrane expression
      of CCR5 in the three cell types, and of CXCR4 and CD4 in microglial cells only.
      Cells were then coinfected simultaneously or at a 24-h interval with both AD169
      and two different HIV-1 monocytotropic strains. HCMV late antigens and HIV-1 tat
      protein colocalized in the cytoplasm of 5-10% of microglia and MDM. p24 antigen
      levels decreased 10- to 40-fold in supernatants of MDM and the reduction was
      greater when HCMV infection was performed 24 h before HIV-1 infection. These data
      suggest that HCMV-induced reduction in the cell-surface expression of the primary
      co-receptor of HIV-1 monocytotropic strains may impair the ability of HIV to
      infect these cells.

PMID- 12475631
TI  - Co-localization of quantitative trait loci regulating resistance to Salmonella
      typhimurium infection and specific antibody production phenotypes.
AB  - Salmonella enterica serotype typhimurium is a facultative intracellular bacteria
      that induces systemic infection in mice. Resistance to this pathogen is under
      polygenic control in which Nramp1 is the major gene involved. Lines of mice
      obtained by selective breeding for high (HIII) or low (LIII) antibody response to
      flagellar antigens of salmonellae showed significant susceptibility differences,
      although both the lines display Nramp1(R) alleles. The HIII line was extremely
      susceptible to infection, while the LIII line was resistant. In order to examine
      the cellular and genetic mechanisms involved in this distinct pattern of
      resistance, HIII and LIII mice were analyzed for IFNgamma and IL4 production and
      screened for quantitative trait loci involved in S. typhimurium infection, using
      several polymorphic microsatellites. In the present work, HIII mice showed an
      IFNgamma downregulation in the early phase of infection when compared with LIII
      animals. No interline differences in IL4 production were verified. The loci
      screening was performed on immunized F2 intercrosses obtained from HIII and LIII
      mice. Three antibody-controlling chromosomal regions were coincident, and another
      was mapped near one of the four loci known to affect susceptibility to S.
      typhimurium. These results indicate a major role of IFNgamma in our model, and
      suggest the co-localization of quantitative trait loci modulating both infection
      and antibody production phenotypes.

PMID- 12475632
TI  - Protective immunity against Taenia crassiceps murine cysticercosis induced by DNA
      vaccination with a Taenia saginata tegument antigen.
AB  - This study investigated the protective capacity of the recombinant Taenia
      saginata Tso18 antigen administered as a DNA vaccine in the Taenia crassiceps
      murine model of cysticercosis. This Tso18 DNA sequence, isolated from a T.
      saginata oncosphere cDNA library, has homologies with Taenia solium and
      Echinococcus sp. It was cloned in the pcDNA3.1 plasmid and injected once
      intramuscularly into mice. Compared to saline-vaccinated control mice,
      immunization reduced the parasite burden by 57.3-81.4%, while lower levels of non
      specific protection were induced in control mice injected with the plasmid
      pcDNA3.1 (18.8-33.1%) or a plasmid with irrelevant construct, pcDNA3.1/3D15 (33.4
      38.8%). Importantly, significant levels of protection were observed between the
      pcDNA3.1/Tso18 plasmid and pcDNA3.1/3D15 plasmid immunized mice. Mice immunized
      with pTso18 synthesized low levels of, primarily IgG1 sub-class, antibodies.
      These antibodies were shown to recognize a 66 kDa antigen fraction of T.
      crassiceps and T. solium. Splenocytes enriched in both CD4+CD8- and CD4-CD8+ T
      cells from these vaccinated mice proliferated in vitro when exposed to antigens
      from both T. solium and T. crassiceps cestodes. Immunolocalization studies
      revealed the Tso18 antigen in oncospheres of T. saginata and T. solium, in the
      adult tapeworm and in the tegument of T. solium cysticerci. The protective
      capacity of this antigen and its extensive distribution in different stages,
      species and genera of cestodes points to the potential of Tso18 antigen for the
      possible design of a vaccine against cestodes.

PMID- 12475633
TI  - Metabolites released by Cryptococcus neoformans var. neoformans and var. gattii
      differentially affect human neutrophil function.
AB  - Differences in the ability of Cryptococcus neoformans var. neoformans (CNVN) and
      var. gattii (CNVG) to establish localized lesions in the lungs of healthy humans
      remain unexplained. In this study, CNVG infection in a rat model was
      characterized by early neutrophil invasion into lung tissue, but phagocytosis of
      cryptococci was not observed. The chemical composition of non-enzymic components
      secreted by one strain of each variety (heat-inactivated supernatants from CNVN
      and CNVG, termed vns and vgs, respectively) were compared, using magnetic
      resonance spectroscopy. Effects on human neutrophil viability and functions at
      both pH 5.5 and 7.0 were investigated, as the pH of cryptococcomas was found to
      be 5.4-5.6 in vivo. The supernatants were similar in composition, although
      metabolites in vns were generally present in higher concentrations. In addition,
      vgs contained two novel metabolites-acetoin and dihydroxyacetone. Polyphosphate
      was observed in cells from both varieties and may be a source of extracellular
      inorganic phosphate. Superoxide production in the presence of phorbol ester was
      enhanced by treatment with vns and decreased by vgs. At pH 5.5, vns caused high
      levels of necrosis in neutrophils, as well as increased adhesion/migration
      through A549 lung epithelial cell monolayers. Individual supernatant components
      such as polyols, acetoin, dihydroxyacetone, and gamma-aminobutyric acid exhibited
      both pro- and anti-inflammatory properties. Overall, we found that vgs was
      potentially less pro-inflammatory than vns. Inhibition of neutrophil function by
      products of CNVG may promote survival of extracellular organisms, and local
      multiplication to form cryptococcomas.

PMID- 12475634
TI  - Epidemiology of visceral leishmaniasis in Atbara River area, eastern Sudan: the
      outbreak of Barbar El Fugara village (1996-1997).
AB  - An outbreak of visceral leishmaniasis (VL) started in 1995 in the Atbara River
      area in eastern Sudan. This article reports on this outbreak and on the clinical
      and immunological studies that were carried out in a village, with the highest
      incidence of VL cases, from 1996 to 1997. A significant increase in VL incidence
      was recorded in a dozen villages in this area; one village, Barbar El Fugara
      accounted for half of the total number of cases recorded at the regional
      hospital. A total of 152 VL and 61 post kala-azar dermal lesion (PKDL) cases were
      diagnosed and treated in Barbar. Household (n = 671) and school (n = 276) surveys
      were performed using the leishmanin skin test (LST) and the direct agglutination
      test (DAT). LST positivity was 23.1 and 15.7%, whereas DAT positivity was 8.9 and
      26.4% in both surveys, respectively. No gender differences were observed in
      either test. Unlike DAT, LST positivity was predominant in the higher age groups
      that also exhibited lower prevalence of VL. Few individuals were positive by both
      tests (1.3%, 5.2%) while the majority (68.8%, 64.8%) had no evidence of acquired
      immune response, suggesting either a role of innate immunity in preventing
      parasite establishment or, unexpectedly, lack of exposure to Leishmania.
      Subclinical parasitism was also demonstrated, as evidence of both acquired
      humoral and cellular immune responses was observed in individuals with no past
      history of the disease. The wide spectrum of L. donovani/human interactions may
      be explained by differential exposure to environmental risk factors, parasite
      strain polymorphisms or host genetic makeup.

PMID- 12475635
TI  - The interplay between environmental and host factors during an outbreak of
      visceral leishmaniasis in eastern Sudan.
AB  - Parasitic diseases, including human visceral leishmaniasis, are multifactorial.
      Factors that are expected to play an important role in the parasite-human
      interaction are exposure, parasite "virulence" and host resistance factors. In
      populations exposed to Leishmania donovani most subjects do not allow the
      parasites to establish themselves or remain asymptomatic. Some individuals,
      however, fail to control parasite expansion and dissemination and develop a
      visceral disease. We report here the results of a longitudinal survey whose aims
      were to identify risk factors underlying visceral leishmaniasis (VL)
      susceptibility during an outbreak that occurred in a Sudanese village between
      1995 and 1999. Most of the 660 subjects (90%) living in the central district were
      exposed to Leishmania and 20.9% (n = 138), mostly teenagers, developed VL. VL
      cases increased markedly in adults late in the outbreak, suggesting some changes
      in adult resistance status or in Leishmania "virulence" during the epidemic. Age
      and ethnic origin of the patients were the most important critical risk factors
      to account for the distribution of the VL cases that were recorded during the
      whole epidemic. This and the high frequency of VL in certain families suggest
      that host genetic factors played an important role in shaping the outbreak in
      this village. However, environmental factors (the presence of cows and neems in
      the households) that increase/decrease exposure to the parasite had significant
      effects on the distribution of VL cases in the village in the first phase of the
      outbreak.

PMID- 12475636
TI  - The epidemiology of yellow fever in Africa.
AB  - Yellow fever (YF) is still a major public heath problem, particularly in Africa,
      despite the availability of a very efficacious vaccine. The World Health
      Organization estimates that there are 200,000 cases of YF annually, including
      30,000 deaths, of which over 90% occur in Africa. In the past 15 years, the
      number of YF cases has increased tremendously, with most of the YF activity in
      West Africa. This increase in YF activity is in part due to a breakdown in YF
      vaccination and mosquito control programs. Five genotypes of YF virus have been
      found in Africa, and each genotype circulates in a distinct geographical region.
      West Africa genotype I, found in Nigeria and surrounding areas, is associated
      with frequent epidemics, whereas the three genotypes in East and Central Africa
      are in regions where YF outbreaks are rare. Other factors, including genetic and
      behavioral variation among vector species, are also thought to play a role in the
      epidemiology of YF in Africa.

PMID- 12475637
TI  - Zebrafish as an immunological model system.
AB  - Two decades of research have established the zebrafish (Danio rerio) as a
      significant model system for studying vertebrate development and gene structure
      function relationships. Recent advances in mutation screening, the creation of
      genomic resources, including the Zebrafish Genome Project and the development of
      efficient transgenesis procedures, make this model increasingly attractive for
      immunological study.

PMID- 12475638
TI  - Molecular mechanical understanding of how integrins work as bi-directional
      communication devices between cells and surrounding extracellular matrix.

PMID- 12475639
TI  - Rhodocetin antagonizes stromal tumor invasion in vitro and other alpha2beta1
      integrin-mediated cell functions.
AB  - The pleiotropic effects of Calloselasma rhodostoma venom is caused by various
      toxins, among them kistrin and ancrod, which block platelet activation triggered
      by RGD-dependent integrins and the blood clotting cascade, respectively. Here, we
      demonstrate that rhodocetin, another component of this venom, acts as alpha2beta1
      integrin inhibiting disintegrin and antagonizes important cellular responses to
      type I collagen. Cell adhesion, migration, and collagen lattice contraction in
      vitro were specifically inhibited by rhodocetin, whereas expression of collagen
      degrading matrix metalloproteases was differently modulated. Moreover, cell
      invasion of HT1080 fibrosarcoma cells into a type I collagen matrix, but not into
      a fibrin gel or a basement membrane-extracted matrigel was efficiently blocked by
      rhodocetin. Unlike its natural ligand collagen, rhodocetin failed to cluster
      alpha2beta1 integrin, despite similar binding affinities. Hence, in the absence
      of focal adhesions cells do not attach firmly to rhodocetin and do not respond
      with any of alpha2beta1-triggered cell reactions, except for MMP-1 production.
      Therefore, this disintegrin may be a valuable tool to specifically target stromal
      tumor invasion and to manipulate other alpha2beta1 integrin-mediated functions,
      such as excessive scar contraction and fibrosis. Rhodocetin might be
      therapeutically useful because of its lack of interference with RGD-dependent
      integrins, low molecular mass, high solubility, and biochemical stability.

PMID- 12475640
TI  - The third activity for lysyl hydroxylase 3: galactosylation of hydroxylysyl
      residues in collagens in vitro.
AB  - Lysyl hydroxylase (LH, EC 1.14.11.4), galactosyltransferase (EC 2.4.1.50) and
      glucosyltransferase (EC 2.4.1.66) are enzymes involved in posttranslational
      modifications of collagens. They sequentially modify lysyl residues in specific
      positions to hydroxylysyl, galactosylhydroxylysyl and glucosylgalactosyl
      hydroxylysyl residues. These structures are unique to collagens and essential for
      their functional activity. Lysines and hydroxylysines form collagen cross-links.
      Hydroxylysine derived cross-links, usually as glycosylated forms, occur
      especially in weight-bearing and mineralized tissues. The detailed functions of
      the hydroxylysyl and hydroxylysyl linked carbohydrate structures are not known,
      however. Hydroxylysine linked carbohydrates are found mainly in collagens, but
      recent reports indicate that these structures are also present and probably have
      an important function in other proteins. Earlier we have shown that human LH3,
      but not isoforms LH1, LH2a and LH2b, possesses both LH and glucosyltransferase
      activity (J. Biol. Chem. 275 (2000) 36158). In this paper we demonstrate that
      galactosyltransferase activity is also associated with the same gene product,
      thus indicating that one gene product can catalyze all three consecutive steps in
      hydroxylysine linked carbohydrate formation. In vitro mutagenesis experiments
      indicate that Cys(144) and aspartates in positions 187-191 of LH3 are important
      for the galactosyltransferase activity. Our results suggest that manipulation of
      the gene for LH3 can be used to selectively alter the glycosylation and
      hydroxylation reactions, and provides a new tool to clarify the functions of the
      unique hydroxylysine linked carbohydrates in collagens and other proteins.

PMID- 12475641
TI  - Following matrix metalloproteinases activity near the cell boundary by infrared
      micro-spectroscopy.
AB  - Matrix Metalloproteinases (MMPs) are cell-secreted soluble and membrane-tethered
      enzymes that degrade extracellular matrix (ECM) proteins. These proteases play a
      key role in diverse physiological and pathological processes, including embryonic
      development, wound repair, inflammatory diseases and cancer. Yet, there is
      insufficient knowledge on the mode by which cell-produced MMPs conduct their
      action on the ECM. Specifically, the localization and the mode of the degradation
      within the pericellular space are of great interest. To provide new insights to
      these questions we utilized Fourier transform infrared (FTIR) micro-spectroscopy
      to follow proteolytic processes, induced by invasive cancer cells, on insoluble
      collagen-based matrices. Here we show that FTIR micro-spectroscopy have a great
      potential for monitoring degradation events near cells. Using this tool we
      demonstrate that the net proteolysis is unevenly distributed around the cell
      boundary. The degradation patterns show different levels of proteolytic activity
      by MMPs within the pericellular space. In addition, our spectral analysis
      suggests that the enzymatic proteolysis of the collagen-based matrices induces
      unwinding of the triple helical structures of the macromolecules within the
      collagen network.

PMID- 12475642
TI  - Distribution of newly synthesized aggrecan in explant cultures of bovine
      cartilage treated with retinoic acid.
AB  - This paper describes temporal changes in the metabolism and distribution of newly
      synthesized aggrecan and the organization of the extracellular matrix when
      explant cultures of articular cartilage maintained in the presence of fetal calf
      serum were exposed to retinoic acid for varying periods of time. Explant cultures
      of articular cartilage were incubated with radiolabeled sulfate prior to exposure
      to retinoic acid. The radiolabeled and chemical aggrecan present in the tissue
      and appearing in the culture medium was studied kinetically. Changes in the
      localization of radiolabeled aggrecan within the extracellular matrix were
      monitored by autoradiography in relation to type VI collagen distribution in the
      extracellular matrix. In control cultures where tissue levels of aggrecan remain
      constant the newly synthesized aggrecan remained closely associated with the
      territorial matrix surrounding the chondrocytes. Exposure of cultures to retinoic
      acid for the duration of the experiment, resulted in the extensive loss of
      aggrecan from the tissue and the redistribution of the remaining radiolabeled
      aggrecan from the chondron and territorial matrix into the inter-territorial
      matrix. These changes preceded alterations in the organization of type VI
      collagen in the extracellular matrix that involved the remodeling of the chondron
      and the appearance of type VI collagen in the inter-territorial matrix; there was
      also evidence of chondrocyte proliferation and clustering. In cartilage explant
      cultures exposed to retinoic acid for 24 h there was no loss of aggrecan from the
      matrix but there was an extensive redistribution of the radiolabeled aggrecan
      into the inter-territorial matrix. This work shows that maintenance of the
      structure and organization of the extracellular matrix that comprises the
      chondron and pericellular microenvironment of chondrocytes in articular cartilage
      is important for the regulation of the distribution of newly synthesized aggrecan
      monomers within the tissue.

PMID- 12475643
TI  - Immunolocalisation and expression of proteoglycan 4 (cartilage superficial zone
      proteoglycan) in tendon.
AB  - Cartilage superficial zone protein/proteoglycan (SZP) or proteoglycan 4 (PRG4),
      has been demonstrated to have the potential for several distinct biological
      functions including cytoprotection, lubrication and matrix binding. In the
      present study, we have examined both the immunolocalisation and the mRNA
      expression pattern of PRG4 in tissue harvested from the compressed and tensional
      regions of young and mature bovine tendons. Immunohistochemical analyses,
      utilizing monoclonal antibody 3-A-4 which recognizes a conformational-dependent
      epitope on native PRG4, demonstrated that PRG4 is present predominantly at the
      surface of fibrocartilaginous regions of tendon, with the intensity of
      immunoreactivity in this region increasing with age. RT-PCR analyses revealed
      that the expression of PRG4 mRNA can be modulated by exposure to cytokines and
      growth factors. In addition, analyses of human pathological tendon revealed that
      PRG4 may also be expressed as an alternatively spliced form lacking exons which
      encode part of the N-terminal matrix-binding and cell-proliferative domain;
      however, it remains to be determined whether such splice variants are a feature
      of human tendon, regardless of disease state. Taken together, these data indicate
      that PRG4 may play an important cytoprotective role by preventing cellular
      adhesion to the tendon surface as well as providing lubrication during normal
      tendon function, in a manner complimentary to cartilage PRG4. Structural
      modifications to SZP, together with a reduction in synthesis during tendon
      inflammation with injury and disease may account for the formation of tendon
      adhesions and contribute to the overall dysfunction of the tissue.

PMID- 12475644
TI  - Expression of the EMILIN-1 gene during mouse development.
AB  - Expression of EMILIN-1, the first member of a newly discovered family of
      extracellular matrix genes, has been investigated during mouse development.
      EMILIN-1 mRNA is detectable in morula and blastocyst by RT-PCR. First expression
      of the gene is found by in situ hybridization in ectoplacental cone in embryos of
      6.5 days and in extraembryonic visceral endoderm at 7.5 days. The allantois is
      also labeled. Staining of ectoplacental cone-derived secondary trophoblast giant
      cells and spongiotrophoblast is strong up to 11.5 days and then declines. In the
      embryo, high levels of mRNA are initially expressed in blood vessels, perineural
      mesenchyme and somites at 8.5 days. Later on, intense labeling is identified in
      the mesenchymal component of organs anlage (i.e. lung and liver) and different
      mesenchymal condensations (i.e. limb bud and branchial arches). At late gestation
      staining is widely distributed in interstitial connective tissue and smooth
      muscle cell-rich tissues. The data suggest that EMILIN-1 may have a function in
      placenta formation and initial organogenesis and a later role in interstitial
      connective tissue.

PMID- 12475645
TI  - Evidence of nidogen-2 compensation for nidogen-1 deficiency in transgenic mice.
AB  - Previous studies have shown that inhibition of nidogen-laminin binding interferes
      with basement membrane stabilization in various mouse organ cultures while no
      overt phenotype has been observed following inactivation of the nidogen-1 gene in
      mice. We have now used recombinant mouse nidogen-1 and nidogen-2 in order to
      evaluate a possible compensation between the two isoforms in the knock-out mice.
      Essentially, a comparable in vitro binding of nidogens-1 and -2 to the same
      laminin gamma1 chain structure and to several other basement membrane proteins
      has been revealed. Quantitative radioimmuno-assays have demonstrated high
      concentrations of nidogen-1 exceeding those of laminin gamma1 and nidogen-2 by
      factors of 5 and 20-50, respectively, in tissue extracts of wild-type mice. A
      three- to sevenfold increase in nidogen-2 was observed in heart and muscle of
      mice with nidogen-1 deficiency and confirmed by a similar increase in the
      intensity of immunogold staining of these tissues. However, a few of the tissues
      from mice with the gene knock-out still contained some nidogen-1-like
      immunoreactivity (1% of wild-type). Furthermore, both nidogen isoforms showed a
      similar distribution in various organs during embryonic development which,
      however, as shown previously, changed in some adult tissues. The data support the
      nidogen-2 compensation hypothesis to explain the limited phenotype observed
      following elimination of the nidogen-1 gene.

PMID- 12475646
TI  - Molecular genetics and histopathologic features of adult distal nephron tumors.

PMID- 12475647
TI  - Current trends in the management of posterior urethral valves in the pediatric
      population.

PMID- 12475648
TI  - Percutaneous radiofrequency ablation of renal tumors: technique, limitations, and
      morbidity.
AB  - OBJECTIVES: To evaluate our evolving experience with percutaneous radiofrequency
      (RF) renal tumor ablation and focus on our technique to ensure maximal treatment
      efficacy and reduce the possibility of complications. METHODS: Fifteen patients
      with small (less than 4 cm) posterior or lateral contrast-enhancing (more than 10
      Hounsfield units) renal tumors were candidates for RF treatment. Of these
      patients, 12 (13 tumors) received computed tomography-guided percutaneous RF
      ablation. General anesthesia was administered in all but our first 2 patients,
      who received intravenous sedation. After treatment, patients were closely
      followed up with computed tomography scans at 6 weeks and 3, 6, and 12 months,
      and every 6 months thereafter. Successful ablation was defined as a lesion along
      with a margin of normal parenchyma that no longer enhanced (less than 10
      Hounsfield units) on follow-up contrast imaging. RESULTS: The mean tumor size was
      2.4 +/- 0.6 cm. The average procedure time was 95 minutes (range 60 to 150) and
      length of stay 0.9 days. All patients underwent the procedure without any major
      complications. At a mean follow-up of 4.9 months, 12 (93%) of 13 tumors were
      successfully ablated. In 3 patients, the procedure was not performed because of
      intervening bowel or lung parenchyma when positioned in the prone position before
      the procedure. Computed tomography-guided percutaneous RF ablation of small renal
      tumors is a viable minimally invasive treatment option with a high short-term
      success rate and low morbidity. This new technology must be uniformly applied to
      assess its long-term efficacy.

PMID- 12475649
TI  - Symptoms and inflammation in chronic prostatitis/chronic pelvic pain syndrome.
AB  - OBJECTIVES: To evaluate the possibility that patients with inflammatory and
      noninflammatory chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) might
      present with different symptoms. Patients with CP/CPPS present with
      characteristic symptoms without bacteriuria. The new National Institutes of
      Health consensus suggests that CP/CPPS can be divided into inflammatory and
      noninflammatory categories. METHODS: Standardized symptom surveys were completed
      by 130 subjects who met the criteria for CP/CPPS after clinical examination and
      urethral, urine, expressed prostatic secretion (EPS), and seminal fluid analysis
      evaluations. RESULTS: When classified by either EPS or postprostatic massage
      urine (VB3) findings, subjects with and without inflammation had similar
      symptoms. However, when classified using the combination of EPS, VB3, and seminal
      fluid analysis, subjects with inflammatory CP/CPPS had more severe (P <0.02) and
      more frequent symptoms, in particular, difficulty reaching erection (P <0.01),
      weak urinary stream (P <0.01), urinary frequency (P = 0.03), and penile pain (P =
      0.04). CONCLUSIONS: The increased severity and frequency of symptoms among
      patients with inflammatory CP/CPPS provide empirical support for the new
      consensus classification on the basis of the combination of EPS, VB3, and seminal
      fluid analysis findings.

PMID- 12475650
TI  - Major postoperative complications secondary to use of the Bookwalter self
      retaining retractor.
AB  - OBJECTIVES: To report on five serious intraoperative damages to nonprocedure
      related organs during 10 years of experience with the Bookwalter device. Self
      retaining retractors are helpful devices, particularly during major
      transperitoneal and retroperitoneal operations. Various retractors are available
      and allow the use of all combinations of blades to maintain exposure during each
      step of an operation. Furthermore, by using these devices, most operations can be
      performed by two surgeons only. METHODS: With the help of the operation
      protocols, more than 4000 applications of the Bookwalter device between January
      1992 and December 2001 were retrospectively reviewed. Four cases with damage to
      the large bowel and one of femoral neuropathy were documented. RESULTS: In one
      transperitoneal and three retroperitoneal approaches, serious damage to the large
      bowel occurred. None was recognized before postoperative days 2 and 7. One
      femoral neuropathy was noted. CONCLUSIONS: The Bookwalter self-retaining
      retractor is a helpful and safe device in exposing the intraoperative situs.
      However, care must be taken in patients with risk factors, such as
      immunosuppression and diverticulitis, and particularly in retroperitoneal
      operations when tightening the blades. When the intra-abdominal cavity is not
      exposed, damage to other organs may not be directly noted, which could explain
      the delay of several days to the onset of symptoms.

PMID- 12475651
TI  - Endoscopic antegrade laser incision in the treatment of urethral stricture.
AB  - OBJECTIVES: To examine the possibility of antegrade incisions at varying
      stricture lengths. We have developed a new method of using a ureteroscope and
      holmium:yttrium-aluminum-garnet (YAG) laser to make an antegrade incision without
      using a guidewire. Endoscopic internal urethrotomy involves the use of a
      guidewire or ureteral catheter that is passed through the stricture as an
      indicator for retrograde incision. METHODS: An antegrade incision was performed
      in 31 procedures for 28 patients with urethral strictures. We used a semirigid
      ureteroscope with an outer diameter of 6F at the tip. The ureteroscope was
      inserted into the urethra and passed through the stricture into the bladder under
      direct vision. The ureteroscope was pulled distally while an incision was made
      using the holmium:YAG laser at the 10-o'clock and 2-o'clock positions to a
      diameter of 17F. The endoscope was then replaced by a 17F panendoscope and an
      antegrade incision was similarly made up to 21F to 22F. RESULTS: An antegrade
      incision without the use of a guidewire was possible in all cases. Of the 31
      incisions, restenosis appeared in 11 (35%). Of the 11 cases, re-incision was
      performed in 4 cases, and urethral sounding was conducted in the other 7 cases.
      Of the 4 re-incision cases, restenosis recurred in only 1 case. Of the 31
      incisions, 23 (74%) were eventually successful. CONCLUSIONS: Antegrade incision
      using the narrow-diameter ureteroscope and holmium:YAG laser is a safe and easy
      method. This method is especially effective in cases of long strictures.

PMID- 12475652
TI  - Laparoscopic treatment for ureteropelvic junction obstruction.
AB  - OBJECTIVES: To assess retrospectively the subjective and objective outcomes
      achieved after laparoscopic treatment for ureteropelvic junction obstruction at
      our institutions. METHODS: Between August 1999 and July 2001, 19 patients (11
      women and 8 men), with a mean age of 31.2 years (range 17 to 67), underwent
      laparoscopic treatment for ureteropelvic junction obstruction. Of these, 17
      patients were eligible for postoperative analysis. Nine of these patients had a
      history of prior surgical intervention on the affected side. The patients were
      subjectively assessed by an analog pain scale performed before and at least 6
      months after surgery. Preoperatively, patients had a diuretic renal scan to
      confirm the presence of obstruction. Helical computed tomography was also
      performed preoperatively to assess for the presence of crossing vessels. The
      renal scan was repeated at least 12 weeks after surgery to document the relief of
      obstruction objectively. RESULTS: Helical computed tomography correctly predicted
      the presence of crossing vessels in 12 patients (63%). The Anderson-Hynes and
      Fenger pyeloplasty techniques were performed in 16 and 2 patients, respectively.
      In 1 patient, a small crossing vein over the ureteropelvic junction was
      identified and divided without complications. The average operative time was 240
      minutes (range 128 to 470). The blood loss was minimal, and no open conversions
      were required. The mean hospital stay was 2.9 days (range 2 to 7). Two
      postoperative complications occurred (11.7%). The average subjective follow-up
      was 14.4 months (range 6 to 27), and the average objective follow-up was 7.8
      months (range 3 to 12). Of 17 assessable patients, 16 (94%) had subjective and
      objective success (postoperative improvement in analog pain score and half-life
      of radiotracer washout). The average split renal function improved from 34.1% to
      38.5% (P <0.01). CONCLUSIONS: On the basis of our data, laparoscopic pyeloplasty
      has a similar success rate compared with the traditional open approach and better
      results than other minimally invasive techniques. Longer follow-up and further
      experience are needed to validate these data.

PMID- 12475653
TI  - Pregnancy in women with ureterosigmoidostomy.
AB  - OBJECTIVES: To review our experience with four pregnancies during the past 5
      years with special attention to the diagnostic and therapeutic aspects of
      ureterosigmoidostomy. Pregnancy in women with ureterosigmoidostomy is a rare
      condition that differs in many ways from pregnancies in women with other forms of
      urinary diversion. METHODS: From 1995 to 2000, we observed four pregnancies in 3
      women with ureterosigmoidostomy. Two women had had bladder exstrophy, and one had
      had interstitial cystitis. During pregnancy, we performed urologic examinations
      every 4 weeks with renal ultrasonography, calculation of the resistive index, and
      tests of serum electrolytes, urea, creatinine, and blood gas analysis. In all
      pregnancies, antibiotic prophylaxis was performed. RESULTS: All women had
      recurring urinary tract infections before pregnancy. In all cases, reversible
      dilation of the upper urinary tract was observed during pregnancy. The resistive
      index never increased to a pathologic range (greater than 0.7). With
      administration of sodium-potassium-hydrogen citrate, no acidosis was observed.
      With antibiotic prophylaxis, the women only had one episode each of urinary tract
      infection during pregnancy. One patient developed preeclampsia that led to a
      cesarean section at week 36 of gestation. Delivery was achieved by cesarean
      section in two more cases and vaginally in 1 case. We did not observe any
      postpartum or neonatal complications related to pregnancy. CONCLUSIONS: Under
      regular urologic and gynecologic control, there is no contraindication to
      pregnancy in patients with ureterosigmoidostomy. Antibiotic prophylaxis seems to
      be recommended.

PMID- 12475654
TI  - Surgical management of the urinary tract in patients with locally advanced
      colorectal cancer.
AB  - OBJECTIVES: To review cases of colorectal cancer requiring urologic management to
      clarify the role the urologist should play in the surgical procedures. A
      deterrent to radical surgery for advanced colorectal carcinoma with urinary
      involvement is the technical complexity and associated morbidity and mortality of
      this procedure. METHODS: Thirty-six tumors in 35 patients, including 19 sigmoid
      cancers (Stage II, 17; Stage III, 2), 12 rectal cancers (Stage II, 11; Stage III,
      1), and 5 local recurrences of colorectal carcinoma in the pelvis were reviewed.
      All tumors had invaded the bladder, prostate, or ureter. The demographic and
      clinical characteristics, type of operative procedure, and postoperative
      complications were analyzed. RESULTS: Of the patients with a sigmoid tumor,
      partial cystectomy was performed in 15 patients who underwent a bladder-sparing
      procedure; an ileal conduit and ileal neobladder were created in 2 patients each
      who required cystectomy. Four patients with rectal cancer underwent a bladder
      sparing procedure: partial cystectomy in 1, partial cystectomy with ileal ureter
      in 1, and prostatectomy in 2. The remaining 8 patients underwent cystectomy with
      the following types of reconstruction: colonic neobladder in 1, ileal neobladder
      in 4, Indiana pouch in 1, ileal conduit in 1, and ureterocutaneostomy in 1
      patient. The bladder was spared in a greater percentage of patients with sigmoid
      cancer than in those with rectal cancer. The incidence of complications was
      greater in patients with rectal cancer and local recurrence than in those with
      sigmoid tumors. The complication rate was especially low in patients who
      underwent a bladder-sparing procedure (10.5%) compared with patients who required
      cystectomy (58.3%). The survival in patients with sigmoid cancer who underwent
      bladder-sparing surgery also was better than in those who underwent cystectomy.
      CONCLUSIONS: The treatment of advanced colorectal cancer is best managed by a
      committed team that includes an experienced urologist. Urologists play a critical
      role in determining the surgical options and creating appropriate urinary
      diversions to achieve curative resection with the highest quality of life.

PMID- 12475655
TI  - Comparison study on two different accessing methods for retroperitoneoscopic
      adrenalectomy.
AB  - OBJECTIVES: To compare, in a retrospective nonrandomized study, two
      retroperitoneal laparoscopic access methods for treatment of adrenal tumors:
      direct needle insufflation with balloon dissection and finger-assisted dissection
      without balloon dissection. METHODS: The operative data from 120 consecutive
      patients undergoing retroperitoneoscopic adrenalectomy (RA) for benign adrenal
      tumors were reviewed. The operative outcomes of 70 RAs accessed by direct needle
      insufflation and balloon dissection were compared with another 50 RAs accessed by
      finger dissection without balloon dissection. The RA surgical parameters for
      tumors with different laterality, pathologic features, and size were also
      analyzed. RESULTS: The operative time in the finger dissection group was shorter
      (118 +/- 11 minutes) compared with that in the balloon dissection group (143 +/-
      21 minutes; P = 0.03). The surgical parameters, including incidence of peritoneal
      perforation, intraoperative blood loss, time to oral intake, analgesic
      requirement, postoperative hospital stay, and convalescence, did not differ
      between the groups. For tumors greater than 5 cm, the operative time increased to
      220 +/- 30 minutes compared with 132 +/- 31 minutes for tumors 5 cm or less (P =
      0.02). The finger and balloon dissection methods had similar operative times for
      tumors larger than 5 cm (218 +/- 10 versus 224 +/- 15 minutes). No additional
      morbidity regarding the recovery time was noted in the finger dissection group
      compared with the balloon dissection group. CONCLUSIONS: Finger dissection
      appears to be a more efficient and equally effective access method for RA
      compared with balloon dissection. We suggest that balloon dissection may not be
      required for RA in patients not excessively obese.

PMID- 12475656
TI  - Prognostic importance of resection margin width after nephron-sparing surgery for
      renal cell carcinoma.
AB  - OBJECTIVES: To examine the relationship between the width of the resection margin
      and disease progression in renal cell carcinoma (RCC) after nephron-sparing
      surgery (NSS). During NSS for RCC, it is standard practice to excise the tumor
      along with a surrounding margin of normal parenchyma (margin of resection) to
      ensure complete resection of the neoplasm. However, no agreement has been reached
      on how wide the margin of resection should be. METHODS: We retrospectively
      reviewed the histopathologic sections and medical records of 69 patients with
      localized RCC who had undergone NSS between 1976 and 1988 to determine whether
      the resection margin, tumor size, TNM stage, and Fuhrman nuclear grade were
      associated with disease progression (defined as local tumor recurrence or
      metastasis). The mean postoperative follow-up interval was 8.5 years. RESULTS: No
      association was found between the width of the resection margin and disease
      progression (P = 0.98, log-rank test). Both TNM stage and Fuhrman nuclear grade
      correlated with disease progression. Patients with T1-T2 tumors had lower
      progression (P <0.001, log-rank test), and increased Fuhrman nuclear grade
      correlated with more disease progression (P <0.001, log-rank test). CONCLUSIONS:
      The width of the resection margin after NSS for RCC does not correlate with long
      term disease progression. A histologic tumor-free margin of resection,
      irrespective of the width of the margin is sufficient to achieve complete local
      excision of RCC.

PMID- 12475657
TI  - Nephron-sparing surgery for localized renal cell carcinoma with a normal
      contralateral kidney: a European three-center experience.
AB  - OBJECTIVES: To assess the long-term effectiveness and safety of nephron-sparing
      surgery for the treatment of localized renal cell carcinoma with a normal
      contralateral kidney. METHODS: Since 1973, 118 patients have undergone nephron
      sparing surgery for renal cell carcinoma on an elective basis at our
      institutions. The vast majority of these tumors were incidental findings, with a
      mean tumor diameter of 3.35 cm (range 0.7 to 5.6). The median follow-up was 8.5
      years (range 0.5 to 18), and of those patients alive, 27 (28%) were followed up
      for more than 10 years. RESULTS: The pathologic stage was pT1N0M0 in 110 cases
      (93.2%) and pT3aN0M0 in 8 (6.7%); 59 were grade 1, 52 were grade 2, and 7 were
      grade 3. Complications occurred in 4 patients, including retroperitoneal bleeding
      in 1 treated by reoperation, urinomas in 2, and ureteral stricture in 1 treated
      conservatively. Renal function remained normal during the whole follow-up period,
      and slight proteinuria was observed in 13 patients. The 10-year distant and local
      recurrence rate was 4% and 3.9%, respectively. The cancer-specific 5, 10, and 15
      year survival rate was 97.3%, 96.4%, and 96.4%, respectively. CONCLUSIONS: Our
      experience, based on a long median follow-up, suggests that nephron-sparing
      surgery on an elective basis can achieve long-term survival for the treatment of
      incidental and low-stage renal cell carcinomas without compromising the efficacy
      of cancer treatment.

PMID- 12475658
TI  - Partial nephrectomy for renal cortical tumors: pathologic findings and impact on
      outcome.
AB  - OBJECTIVES: To review the experience with partial nephrectomy for the diagnosis
      and treatment of renal cortical tumors at the Memorial Sloan-Kettering Cancer
      Center with a particular focus on the histologic findings at the time of surgery.
      METHODS: The results of 292 consecutive partial nephrectomies were reviewed.
      Demographic data, perioperative complications, and disease status were recorded.
      The specimens were reviewed for histologic subtyping in accordance with the
      Heidelberg classification for renal cortical tumors. The probabilities of
      recurrence and disease-specific death were assessed with the cumulative incidence
      estimate. RESULTS: The median follow-up was 25.3 months (range 1 to 155). A total
      of 246 patients (87%) were diagnosed with a renal cortical tumor, 1 patient (less
      than 1%) was diagnosed with another cancer, and 34 (12%) were diagnosed with
      benign lesions. The most frequent histologic finding among the renal cortical
      tumor subgroup was conventional clear cell carcinoma in 148 cases (51%), followed
      by papillary carcinoma in 54 (18%), oncocytoma in 32 (11%), and chromophobe
      carcinoma in 21 (7%). Bilateral disease and multifocality were most prevalent in
      the conventional and papillary subtypes, respectively. The 5-year probability of
      recurrence and disease-specific death was 12% and 8%, respectively, for the
      conventional clear cell type. No local or distant disease recurrence was observed
      in any other renal cortical tumor subtypes. CONCLUSIONS: Partial nephrectomy
      should be considered a diagnostic and therapeutic surgical approach for renal
      cortical masses. Conventional clear cell carcinoma is the most frequent
      histologic subtype and is associated with a less favorable outcome compared with
      papillary carcinoma and chromophobe carcinoma. Radical nephrectomy for renal
      lesions that could be removed by partial nephrectomy will risk renal impairment
      in a substantial proportion of patients with benign disease.

PMID- 12475659
TI  - Retroperitoneoscopy-assisted total nephroureterectomy for upper urinary tract
      transitional cell carcinoma.
AB  - OBJECTIVES: To apply retroperitoneoscopy-assisted nephroureterectomy (RTN) and
      examine its benefit compared with traditional open nephroureterectomy. The
      reference standard of treatment for upper urinary tract transitional cell
      carcinoma is standard total nephroureterectomy (STN) with excision of a bladder
      cuff. METHODS: Retroperitoneoscopic radical nephrectomy was performed, followed
      by open distal ureterectomy with excision of a bladder cuff. The specimen was
      removed en bloc from the lower pararectal incision that was used during distal
      ureterectomy. From January 1999, 17 patients with upper urinary tract
      transitional cell carcinoma underwent this procedure at our institution. For
      comparison, the most recent 17 STNs were also reviewed. RESULTS: The operative
      time was longer in the RTN group than in the STN group but not to a significant
      extent (239.5 versus 286.8 minutes; P = 0.2663). On the other hand, the estimated
      blood loss, duration to potential discharge, and recovery to normal activities
      were significantly reduced in the RTN group (151.1 versus 299.6 minutes, 2.7
      versus 4.2 days, and 15.9 versus 19.3 days; P = 0.0262, 0.0479, and 0.0363,
      respectively). From an oncologic standpoint, local recurrence occurred in 1
      patient of the RTN group and 4 patients of the STN group (median follow-up of 8.8
      and 23.0 months, respectively). No significant difference was detected in the
      disease-free survival rate between the two groups (P = 0.6775). CONCLUSIONS: RTN
      can make total nephroureterectomy less invasive. From an oncologic standpoint,
      although it revealed a disease-free survival rate comparable with the standard
      open procedure with limited follow-up, further follow-up of additional cases with
      simultaneous extended lymphadenectomy is necessary to evaluate the effectiveness
      of this procedure.

PMID- 12475660
TI  - Endoscopic silicone injection for female stress urinary incontinence due to
      intrinsic sphincter deficiency: impact of coexisting urethral mobility on
      treatment outcome.
AB  - OBJECTIVES: To evaluate periurethral silicone injection in the treatment of
      female stress urinary incontinence due to intrinsic sphincter deficiency (ISD)
      and assess whether coexisting urethral hypermobility has an impact on treatment
      outcome. METHODS: A total of 29 female patients with stress urinary incontinence
      underwent endoscopic periurethral silicone injection. Using abdominal leak point
      pressure measurement, ISD was shown preoperatively in all cases. In addition,
      urethral hypermobility was demonstrated in 14 cases by cotton-swab testing.
      Treatment outcome was assessed at 3 and 24 months by questionnaire and classified
      as cure, improvement, or failure. RESULTS: The morbidity of the procedure was
      minimal. The median follow-up was 29 months (range 24 to 36). For the entire
      group, the cure rate was 55% and 45% at 3 and 24 months, respectively. Depending
      on the existence of urethral hypermobility, the treatment outcome differed
      significantly. At 3 months, cure was achieved in 73% of the patients with pure
      ISD and in 36% with urethral hypermobility (P = 0.04). At 24 months, 67% with
      pure ISD remained continent, but only 21% with urethral hypermobility (P = 0.02).
      CONCLUSIONS: In our experience, periurethral silicone injection was a safe
      treatment for female stress urinary incontinence and provided a moderately
      successful and durable therapeutic effect in those with sphincter deficiency and
      good anatomic support. Unsatisfactory results in those with both anatomic
      incontinence and sphincter deficiency highlight the need for careful preoperative
      assessment of urethral mobility to exclude such patients from injection therapy.

PMID- 12475661
TI  - Increase in pelvic floor muscle activity after 12 weeks' training: a randomized
      prospective pilot study.
AB  - OBJECTIVES: To compare electromyography-assisted biofeedback training to pelvic
      floor muscle training (PFMT) alone in patients with female stress urinary
      incontinence. METHODS: A prospective randomized pilot study was conducted between
      March 1998 and February 2000 at the university hospital for outpatient care.
      Participants were women with urodynamically tested stress incontinence aged 31 to
      69 years without previous incontinence operations, 30 volunteers altogether. The
      biofeedback group received an electromyography-guided biofeedback device for home
      training and the PFMT-alone group trained without any device at home. All
      patients were advised to practice for 20 minutes per day five times a week for 12
      weeks. RESULTS: According to the data analysis, muscle forces increased
      significantly in both supine (P <0.001) and standing (P <0.001) positions. In the
      supine position, the increase was significantly higher in the biofeedback group
      (P = 0.024). The results showed close to a significant decrease in the leakage
      index in the biofeedback group (P = 0.068), but in the PFMT-alone group, no
      change occurred. With respect to the pad test, the decrease was significant, but
      it was the same for both groups (P = 0.907). CONCLUSIONS: The findings of this
      study show that pelvic floor muscle activity is increased and the amount of
      leaked urine is decreased after 3 months of PFMT. These preliminary results show
      a significant improvement compared with the PFMT-alone group in PFMT outcome
      measures in patients using electromyography-assisted biofeedback training.

PMID- 12475663
TI  - Do patients profit from 5-aminolevulinic acid-induced fluorescence diagnosis in
      transurethral resection of bladder carcinoma?
AB  - OBJECTIVES: To evaluate in a prospective study the influence of fluorescence
      diagnosis (FD) controlled transurethral resection of bladder tumors on
      therapeutic consequences. The aim was to determine in how many patients FD led to
      a change in treatment strategy compared with conventional white light (WL)
      cystoscopy. METHODS: A total of 279 patients with suspected bladder tumors
      underwent transurethral resection using FD in addition to WL cystoscopy. The
      number of additional tumor-positive patients, staging change, number of
      multilocular tumors exclusively detected by FD, and resulting therapeutic
      consequences compared with the results after WL cystoscopy were investigated. In
      addition a biopsy-based evaluation was performed. RESULTS: Tumor or dysplasia II
      degrees (moderate dysplasia) was detected in 177 patients. In 168 patients, tumor
      was detected by WL cystoscopy, and in 9 (5.1%) of the patients, tumor was
      completely overlooked by WL cystoscopy and diagnosed exclusively by FD (n = 3
      TaG1-G2, n = 2 carcinoma in situ, n = 1 greater than T1, and n = 3 dysplasia II
      degrees ). Multilocular tumor involvement was detected in 10 cases using FD, and
      a change in the stage by detection of coexisting dysplasia II degrees and
      carcinoma in situ occurred in 8 patients. In 27 patients (15.3%), additional
      information was obtained by exclusive detection of tumors by FD. This resulted in
      a change in the treatment strategy for 16 patients (9%). CONCLUSIONS: FD leads to
      an improvement in the diagnosis of bladder carcinoma. It allows the early
      selection of the best treatment option and thus has a potentially positive effect
      on the prognosis of the affected patients.

PMID- 12475664
TI  - Ultraviolet-excited (308 nm) autofluorescence for bladder cancer detection.
AB  - OBJECTIVES: To assess the ability of ultraviolet laser-induced autofluorescence
      for the diagnosis of transitional cell carcinoma of the bladder. METHODS: We
      studied 43 patients undergoing transurethral resection with recurrent
      transitional cell carcinoma of the bladder. Guided through 5-aminolevulinic acid
      induced fluorescence endoscopy, the autofluorescence of the red fluorescing areas
      and the adjacent tissue and inconspicuous-appearing mucosa were measured
      spectroscopically. The autofluorescence excitation was carried out with a xenon
      chloride excimer laser operating at 308 nm (AF308). For the evaluation of the
      autofluorescence spectra, an intensity ratio (335/430 nm) was calculated and
      correlated with the histologic results of the biopsies taken. RESULTS: We
      analyzed the AF308 spectra of 114 biopsies (21 malignant, 93 benign). The
      autofluorescence intensity ratios for the benign lesions were a factor of 2 to 7
      higher than carcinoma in situ and neoplastic tissue. Therefore, 20 of 21
      neoplastic lesions were detected as true positive by AF308. A sensitivity and
      specificity for AF308 of 95% and 77%, respectively, could be calculated. The
      sensitivity and specificity for 5-aminolevulinic acid-induced fluorescence
      endoscopy was 90% and 61%, respectively. By combining the two methods, we
      calculated a sensitivity of 90% and a specificity of 84%. CONCLUSIONS: The
      combination of a sensitive imaging technique such as 5-aminolevulinic acid
      induced fluorescence endoscopy and a more specific spectral fluorescence probe
      technique with autofluorescence at 308 nm is a very efficient procedure in the
      detection of transitional cell carcinoma of the bladder.

PMID- 12475665
TI  - Substratification of stage T1C prostate cancer based on the probability of
      biochemical recurrence.
AB  - OBJECTIVES: To evaluate the influence of preoperative prostate-specific antigen
      (PSA), biopsy Gleason sum, and prostate biopsy quantitative histologic findings
      on the probability of biochemical failure in an attempt to identify criteria to
      substratify Stage T1c prostate cancer more accurately. METHODS: We reviewed the
      records of 1149 patients who underwent prostatectomy for T1c disease between 1988
      and 2000. Biochemical recurrence (PSA 0.2 ng/mL or greater) defined the endpoint
      in this study. Recursive partitioning analysis was used to establish cutpoints
      for preoperative PSA level, biopsy Gleason sum, number of positive biopsy cores,
      and maximal percentage of any single biopsy core involved with cancer. These
      cutoff values were then evaluated using Kaplan-Meier estimations to determine the
      probability of remaining biochemically recurrence free. RESULTS: Using a PSA
      cutpoint of 10 ng/mL or a biopsy Gleason sum of 7, two groups of patients were
      identified (T1cI and T1cII). The rate of freedom from PSA recurrence at 3, 5, and
      10 years after surgery for T1cI was 98%, 96%, and 96%, respectively, and for
      T1cII was 86%, 83%, and 73%, respectively (P <0.001). For T1cII patients, the
      greatest percentage of cancer in a single biopsy core was found to be a predictor
      of biochemical failure on multivariate analysis and, using a cutoff value of 50%,
      further stratified the PSA recurrence-free rates for the men in group T1cII (90%
      and 85% versus 75% and 56% at 5 and 10 years after surgery, respectively, P =
      0.03). CONCLUSIONS: The results of this study demonstrate that within Stage T1c
      there are two populations of patients with significantly different recurrence
      probabilities: T1cI (Gleason sum less than 7 and PSA 10 ng/mL or less) and T1cII
      (Gleason sum 7 or greater or PSA greater than 10 ng/mL). Furthermore, using a
      cutpoint of 50% of cancer in a single core of biopsy tissue, additional risk
      stratification is afforded to men with higher risk "T1cII" cancer.

PMID- 12475666
TI  - Long-term (7 to 8-year) experience with finasteride in men with benign prostatic
      hyperplasia.
AB  - OBJECTIVES: To evaluate the effects of finasteride, a specific type II 5-alpha
      reductase inhibitor, on symptoms of benign prostatic hyperplasia, prostate
      volume, and urinary flow during a 7 to 8-year period. METHODS: A total of 190 men
      with symptomatic benign prostatic hyperplasia and enlarged prostates entered one
      of two Phase II double-blind 3 to 6-month studies. Of these, 156 patients
      continued taking open-label finasteride, and more than 70 patients completed 7 to
      8 years of treatment. The symptoms were scored using a patient self-administered
      modified Boyarsky symptom questionnaire. Prostate volume was measured by magnetic
      resonance imaging or ultrasonography, and the maximal urinary flow rate was
      assessed noninvasively. RESULTS: Treatment with finasteride for 7 to 8 years led
      to sustained improvement in symptoms, reduction in prostate volume (28% from
      baseline), and increased urinary flow (median 2.5 mL/s from baseline). Decreases
      in dihydrotestosterone (86%) and prostate-specific antigen (54%) levels were also
      maintained. Long-term finasteride treatment was safe and generally well
      tolerated. CONCLUSIONS: Long-term treatment with finasteride was well tolerated
      and resulted in durable symptom relief and improvement in prostate volume and
      urinary flow.

PMID- 12475667
TI  - Sequential transurethral resection of the prostate and laparoscopic bladder
      diverticulectomy: comparison with open surgery.
AB  - OBJECTIVES: To compare our experience with transurethral resection of the
      prostate and sequential laparoscopic bladder diverticulectomy with a previous
      series of combined open bladder diverticulectomy and transvesical prostatectomy.
      METHODS: We compared the data of 10 consecutive patients (group 1) who underwent
      sequential transurethral resection of the prostate and transperitoneal
      laparoscopic bladder diverticulectomy and 13 consecutive patients (group 2) who
      underwent traditional combined open bladder diverticulectomy and transvesical
      prostatectomy. The following parameters were considered: size and position of the
      diverticulum, transrectal ultrasound adenoma volume, operative time,
      postoperative hemoglobin variations, analgesic requirement, complications,
      postoperative hospital stay, and urinary flowmetry. RESULTS: No statistically
      significant differences existed between the two groups either for diverticulum
      size (6.8 versus 7.2 cm) or diverticula position. A significant difference was
      observed in the operative time (247 minutes for group 1 versus 136 minutes for
      group 2, P <0.0001), mean postoperative hemoglobin decrease (2.6 g/dL for group 1
      and 3.9 g/dL for group 2, P = 0.001), analgesic requirement (1.3 ampoules of
      buprenorphine cloritrate for group 1 versus 1.8 ampoules for group 2, P = 0.45),
      and postoperative hospital stay (3 days for group 1 versus 9.6 days for group 2,
      P <0.0001). No statistically significant difference was recorded for control
      flowmetry. No intraoperative complications were recorded for the two groups.
      CONCLUSIONS: In our series, sequential transurethral resection of the prostate
      and transperitoneal laparoscopic diverticulectomy for large diverticula proved to
      be a safe, effective, and minimally invasive procedure, despite the longer
      operative times compared with transvesical prostatectomy and open bladder
      diverticulectomy.

PMID- 12475668
TI  - An active regimen of weekly paclitaxel and estramustine in metastatic androgen
      independent prostate cancer.
AB  - OBJECTIVES: The efficacy of weekly high-dose paclitaxel in androgen-independent
      prostate carcinoma and its cytotoxic synergy with estramustine led to the
      evaluation of a weekly schedule of paclitaxel and estramustine in this Phase II
      trial. METHODS: Patients were eligible if they had metastatic prostate
      adenocarcinoma with objective progression or rising prostate-specific antigen
      (PSA) levels despite androgen deprivation therapy and antiandrogen withdrawal.
      Prior radiation and/or one prior chemotherapy regimen was permitted. A Zubrod
      performance status of 2 or less and adequate bone marrow and hepatic and renal
      function were required. Estramustine was administered orally at a dose of 280 mg
      three times daily on days 1 to 3, 8 to 10, and 15 to 17. Paclitaxel (150 mg/m2)
      was administered as a 1-hour intravenous infusion on days 2, 9, and 16. Therapy
      was repeated every 28 days (one cycle). RESULTS: Twenty-eight patients were
      enrolled (median age 71.5 years). Fifteen patients had measurable disease (nine
      nodal and seven visceral) and 13 had bone-only metastases. A total of 116 cycles
      of therapy were delivered (median 4 cycles per patient, range 1 to 12). Nine
      patients required dose reduction. The predominant toxicities consisted of grade 3
      neuropathy in 6 patients and grade 3 and 4 neutropenia in 4 patients, with one
      hospitalization for febrile neutropenia. Three patients had thrombotic
      manifestations: one deep venous thrombosis and two non-Q wave myocardial
      infarctions. Of the 28 patients, 26 were assessable for response. Of 13 patients
      with measurable disease, 5 demonstrated a partial response (1 in the liver and 4
      in the lymph nodes), and 8 of 13 patients with bone-only metastases had a 50% or
      greater decrease in PSA level. Three patients had a 90% or greater decline in
      PSA. The overall PSA response rate was 61.53% (95% confidence interval 38.1% to
      74.2%). The median time to progression was 4.64 months, and the median survival
      was 13 months. CONCLUSIONS: The combination of weekly estramustine and paclitaxel
      is active in metastatic androgen-independent prostate cancer.

PMID- 12475669
TI  - Questionnaire-based outcomes of urinary incontinence and satisfaction rates after
      radical prostatectomy in a national study population.
AB  - OBJECTIVES: To assess the incidence of incontinence and the associated quality of
      life in men younger than 65 years of age after radical prostatectomy. METHODS:
      The TRICARE/CHAMPUS database was searched to identify 1000 patients who underwent
      radical prostatectomy within 2 years before study initiation. All patients were
      younger than 65 years of age at the time of surgery and had at least 18 months of
      postoperative follow-up. An eight-part questionnaire focusing on continence after
      surgery was mailed to the study population. Respondents reported on voiding
      dysfunction, degree of incontinence, satisfaction with continence, and lifestyle
      impact of incontinence. RESULTS: A total of 674 eligible patients (78%) completed
      the survey. Any amount of pad use or changing of underwear to keep dry was
      reported by 31.7%, leakage once per day occurred in 16.8%, and leakage more than
      once per day in 9.2%. Severe urgency or urge incontinence occurred in 17.4% and
      was the primary cause of incontinence in one third of patients with incontinence.
      Only 8.9% of patients used two or more pads per day, and severe incontinence
      (more than four pads per day) occurred in 2.7%. Incontinence-corrective surgery
      was used by 4.9% of patients. Overall, 83.3% of patients reported satisfaction
      with their continence after surgery, and 12% considered postoperative
      incontinence to be a problem. CONCLUSIONS: The results of this questionnaire
      based outcomes evaluation of a large national sample of prostatectomy patients
      younger than 65 years of age demonstrate that incontinence rates in this younger
      population are similar to those in the Medicare population and may be more
      representative of the national experience than single-center reports.

PMID- 12475670
TI  - Hypospadias in adults.
AB  - OBJECTIVES: To review the follow-up data and complications of adult patients who
      underwent hypospadias surgery. METHODS: The records of 88 male patients with an
      average age of 21.9 years (range 20 to 27) who were operated on for hypospadias
      from 1996 to 2001 were reviewed in two groups: primary cases and all others (at
      least one unsuccessful attempt to correct the hypospadias). The primary cases
      consisted of 48 anterior, 9 middle, and 2 proximal hypospadias; the second group
      consisted of 16 urethrocutaneal fistula, 8 hypospadias, and 5 cripple cases.
      RESULTS: The complication rate was 10.1% for the first group and 27.5% for the
      second group. After the second intervention in groups 1 and 2, the overall
      success rate was 100% and 89.6%, respectively. CONCLUSIONS: Adult hypospadias is
      repaired with the techniques used in pediatric cases. However, the postoperative
      complication rate is higher, and these patients more often require multiple
      interventions.

PMID- 12475671
TI  - Correlation between fluorescence in situ hybridization and testicular biopsy for
      the prediction of spermatogenesis in 37 patients with nonobstructive azoospermia.
AB  - OBJECTIVES: We applied interphase fluorescence in situ hybridization (FISH) to
      testis sections to examine the evidence of spermatogenesis in patients with
      nonobstructive azoospermia. This technique was evaluated and compared with
      conventional testicular histopathologic findings for the possibility of
      additional clinical applications. METHODS: Thirty-seven consecutive patients with
      nonobstructive azoospermia were carefully evaluated clinically. Testes were
      biopsied for both sperm extraction and histopathologic examination. FISH staining
      was performed with a CEP 18 SpectrumAqua/CEP X SpectrumGreen/CEP Y SpectrumOrange
      probe. RESULTS: Eight of 11 cases (sensitivity 73%) that were found to have
      spermatids on the histopathologic slides also were proven to produce haploid
      cells by FISH staining. On the other hand, 21 of the 26 cases (specificity 81%)
      for which no spermatids could be found on the histopathologic slides also had
      only diploid cells by FISH staining. On the basis of the good correlation between
      the FISH staining and conventional histopathologic findings, we could confirm the
      diagnosis of spermatogenesis using both methods. CONCLUSIONS: FISH staining of
      testicular sections allows more reliable prediction of spermatogenesis and
      provides benefits for a patient's decision regarding fertility counseling.

PMID- 12475672
TI  - Prevalence of abnormal sperm DNA denaturation in fertile and infertile men.
AB  - OBJECTIVES: To examine the prevalence of abnormal sperm DNA denaturation (DD), a
      marker of sperm DNA integrity, in a group of fertile and infertile men. METHODS:
      Eighty-eight nonazoospermic, infertile men and 13 fertile men underwent standard
      semen analysis and acridine orange sperm DNA integrity studies. Standard semen
      parameters (sperm concentration, motility, and morphology) and sperm DNA
      integrity (expressed as the percentage of spermatozoa with DD) were measured.
      RESULTS: Of the 88 infertile men, 13 had completely normal semen parameters and
      the remaining 75 had at least one abnormal semen parameter. The mean (+/-SE)
      sperm DD level was significantly lower in the population of infertile men with
      normal semen parameters compared with those having abnormal parameters (11.1% +/-
      3.7% versus 23.1% +/- 1.8%, respectively, P <0.001). Only 1 (8%) of the 13 men
      with normal semen parameters had elevated sperm DD (greater than 30%, verified on
      two separate analyses) compared with 13 (17%) of the 75 infertile men with
      abnormal semen parameters (P >0.05). None of the fertile controls had elevated
      sperm DD. We observed significant inverse correlations between the sperm DD and
      sperm motility, morphology, and concentration (P <0.001). CONCLUSIONS: Our data
      show that sperm DD negatively correlates with standard semen parameters and that
      an isolated abnormality of sperm DD, a marker of sperm DNA integrity, is uncommon
      in infertile men. Additional studies are needed to support the notion that
      isolated abnormalities of sperm DNA integrity may represent a new diagnosis for
      men with unexplained infertility.

PMID- 12475673
TI  - Clinical and genetic features of patients with congenital unilateral absence of
      the vas deferens.
AB  - OBJECTIVES: To review the clinical and genetic findings in men with congenital
      unilateral absence of the vas deferens (CUAVD). CUAVD is important because of its
      association with renal anomalies and cystic fibrosis transmembrane conductance
      regulator gene mutations. METHODS: A retrospective review of two urologic
      practices, both with subspecialty interest in male infertility, was performed.
      Renal imaging and cystic fibrosis (CF) testing were recommended to all men found
      to have CUAVD. RESULTS: Fifteen men with CUAVD were identified. Only the 12 men
      with sufficient clinical data were selected for this study. Three patients had CF
      mutations, and all had obstruction of the contralateral vas deferens in either
      the pelvis or retroperitoneum. One patient had obstruction of the contralateral
      pelvic vas deferens and was negative for all CF mutations tested. Four patients
      (33%) had renal agenesis. Three patients had ipsilateral renal agenesis, and one
      had contralateral renal agenesis. No patient with CF mutations had renal
      agenesis. One had polycystic kidney disease, which was considered an incidental
      finding. CONCLUSIONS: Patients with CUAVD may have CF mutations and renal
      agenesis. Renal ultrasonography and CF testing are therefore recommended for
      these patients. Patients of reproductive age found to have CUAVD should be
      counseled about the potential risk of transmission of renal anomalies and CF
      mutations.

PMID- 12475674
TI  - Topical alprostadil cream for the treatment of erectile dysfunction: a combined
      analysis of the phase II program.
AB  - OBJECTIVES: To present a meta-analysis of the efficacy and safety data of two
      recently completed Phase II studies examining a novel alprostadil topical cream
      for the treatment of erectile dysfunction (ED). METHODS: Patients (n = 303) with
      ED of at least 3 months' duration were randomized to receive placebo or 50, 100,
      200, or 300 microg alprostadil in two nearly identical 11-dose, multicenter, at
      home studies of a novel topical cream containing alprostadil and a proprietary
      skin permeation enhancer. The primary efficacy endpoint was the change in
      erectile function domain score from baseline to the final visit. Secondary
      endpoints included changes in scores for questions 3 and 4 of the International
      Index of Erectile Function and standard diary analyses. Safety was assessed by
      analysis of adverse events, changes in laboratory test results, and physical
      examination findings. RESULTS: The mean baseline parameters for the erectile
      function score, ED history, and secondary diagnoses suggested no significant
      differences among the treatment groups. The changes from baseline to the final
      visit erectile function scores were 0.98 +/- 0.84, 3.4 +/- 1.3, 3.4 +/- 0.88 (P
      <0.05), 5.3 +/- 0.92 (P <0.001), and 9.4 +/- 1.43 (P <0.001) for the ascending
      dose groups. Most secondary efficacy endpoints were significant for the 200 and
      300-microg dose groups. Dose-related trends in efficacy were observed. Adverse
      events were localized to the application site, were of mild or moderate
      intensity, and were of short duration. CONCLUSIONS: These results suggest topical
      alprostadil cream, when combined with a novel dermal permeation-enhancer, to be a
      potentially useful agent for the treatment of ED.

PMID- 12475675
TI  - Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic
      analysis with pathogenetic implications.
AB  - OBJECTIVES: To investigate the pathologic, clinical, and genetic features of
      renal medullary carcinomas (RMCs) in search of clues to their pathogenesis.
      METHODS: We analyzed 40 RMCs for clinical features, for immunohistochemical
      expression using a panel of markers, and for genetic changes using comparative
      genomic hybridization. RESULTS: Patients presented at 5 to 32 years of age, and
      82% were African American. All patients tested had sickle cell trait or disease.
      Seven patients presented with suspected renal abscess or urinary track infection
      without a clinically recognizable mass. Of the 15 tumors able to be analyzed, all
      were positive for epithelial markers CAM 5.2 and epithelial membrane antigen. All
      were negative for high-molecular-weight cytokeratin 34betaE12. Cytokeratins 7 and
      20 and carcinoembryonic antigen were heterogeneous and variable. Ulex was focally
      positive in a minority of cases. Eight of 12 tumors showed significant positivity
      for TP53 protein (greater than 25% nuclear positivity). All tumor tested (n = 8)
      were strongly positive for vascular endothelial growth factor and hypoxia
      inducible factor. Of nine tumors analyzed for genetic gains and losses using
      comparative genomic hybridization, eight showed no changes and one showed loss of
      chromosome 22. Survival ranged from 2 weeks to 15 months (mean 4 months).
      CONCLUSIONS: These findings suggest that RMC is clinically and pathologically
      distinct from collecting duct carcinoma. The hypothesis that chronic medullary
      hypoxia secondary to hemoglobinopathy may be involved in the pathogenesis of RMC
      is suggested by strong vascular endothelial growth factor and hypoxia inducible
      factor expression and positivity for TP53.

PMID- 12475676
TI  - Value of increase in bladder capacity in treatment of refractory monosymptomatic
      nocturnal enuresis in children.
AB  - OBJECTIVES: To evaluate children with refractory monosymptomatic nocturnal
      enuresis to determine whether detrusor overactivity (DOA) plays a role in 4 weeks
      of unsuccessful treatment with retention control training (RCT); whether an
      increase in bladder capacity can eventually be obtained by RCT plus oxybutynin;
      and whether the increase in capacity is the primary key to success. METHODS:
      Sixty-eight children with refractory monosymptomatic nocturnal enuresis were
      included. They all had a maximal cystometric capacity less than the age-expected
      value. RCT was done by water loading and retention to the point of urgency once
      daily. During training, changes in bladder capacity were evaluated by voiding
      charts. If after 4 weeks of RCT, less than a 10% increase in bladder capacity was
      noted, oral oxybutynin was added. RESULTS: The incidence of DOA was 66%. After 4
      weeks of RCT, the bladder capacity increased in 20.6%. Combining RCT with
      oxybutynin led in the end to normalization of the bladder capacity in 79.4%.
      Older age and high-pressure DOA negatively influenced the ability to increase the
      bladder capacity. Fifteen children became completely dry, mainly by converting
      enuresis to nocturia. CONCLUSIONS: Unsuccessful RCT is often caused by DOA,
      especially if a bladder capacity rise of at least 10% cannot be achieved within 4
      weeks. If oxybutynin is added to the treatment, normalization of bladder capacity
      can be obtained in most. This increased bladder capacity cures enuresis only in a
      minority by sharpening their arousal and provoking nocturia.

PMID- 12475677
TI  - Shortened pull-string simplifies office-based ureteral stent removal.
AB  - A disadvantage of stent use after ureteroscopy is the need to remove the stent
      cystoscopically. We describe a modification that avoids the discomfort of a
      transurethral suture and allows easy cystoscopic extraction. This modification
      may also facilitate repositioning or removal of a migrated stent.

PMID- 12475678
TI  - Oops we got in the chest: fluoroscopic chest tube insertion for hydrothorax after
      percutaneous nephrostolithotomy.
AB  - Percutaneous supracostal renal puncture provides ideal access to the collecting
      system or proximal ureter but is associated with an increased risk of pleural
      injury. We describe a simplified approach to intraoperative thoracostomy tube
      placement that uses urologic techniques and protects against recurrent
      hydrothoraces at second-look nephroscopy, without increasing patient morbidity or
      length of hospital stay.

PMID- 12475679
TI  - Laparoscopic bilateral partial adrenalectomy for pheochromocytoma.
AB  - INTRODUCTION: To describe the technique of transperitoneal laparoscopic bilateral
      synchronous partial adrenalectomy in a patient with bilateral adrenal
      pheochromocytoma. TECHNICAL CONSIDERATIONS: An 81-year-old woman with bilateral
      adrenal pheochromocytoma underwent bilateral laparoscopic partial adrenalectomy.
      A three-port transperitoneal approach was used for each side, with an additional
      port for liver retraction during right partial adrenalectomy. Laparoscopic
      flexible ultrasonography was invaluable for localizing the adrenal tumor and for
      precise planning of the line of excision. The right main adrenal vein was
      preserved. Dissection and enucleation of the adrenal tumor and parenchymal
      hemostasis was achieved effectively using a harmonic scalpel. The total operative
      time was 2 and 2.5 hours for the left and right adrenal gland, respectively. No
      major intraoperative hemodynamic instability was noted. The total blood loss was
      150 mL, and the hospital stay was 4 days. Pathologic examination confirmed
      bilateral adrenal pheochromocytoma. CONCLUSIONS: Laparoscopic partial
      adrenalectomy for pheochromocytoma is safe and technically feasible.
      Intraoperative ultrasonography is helpful to accurately plan resection of the
      tumor. If tumor location permits, the main adrenal vein should be preserved to
      ensure adequate vascularity for the adrenal remnant.

PMID- 12475680
TI  - Robotic-assisted laparoscopic adrenalectomy.
AB  - INTRODUCTION: Remote robotic telemanipulators have been recently used in
      performing laparoscopic urologic procedures, both in the laboratory and in
      clinical practice. We present, to our knowledge, the initial 2 cases of robotic
      assisted laparoscopic adrenalectomy in humans. TECHNICAL CONSIDERATIONS: Robotic
      assisted laparoscopic adrenalectomy (one right, one left) was performed in 2
      patients with an adrenal tumor (one nonfunctional, one pheochromocytoma). Patient
      age was 81 and 47 years, and tumor size was 4.5 and 3 cm, respectively. Both
      cases were performed transperitoneally using the da Vinci Robotic Surgical
      System. Robotic-assisted laparoscopic adrenalectomy was successful in both cases
      without conversion to conventional laparoscopy or open surgery. The operative
      time was 110 and 165 minutes, the blood loss was 50 and 100 mL, and the hospital
      stay was 2 and 3 days. No intraoperative or postoperative complications occurred.
      CONCLUSIONS: Robotic-assisted laparoscopic adrenalectomy is technically feasible.
      With increasing experience and refinement in the technology, the role of robotics
      in urologic laparoscopy is likely to expand.

PMID- 12475681
TI  - Ruptured abdominal aortic aneurysm complicated by horseshoe kidney and renal cell
      carcinoma.

PMID- 12475682
TI  - Spontaneous nephrocutaneous fistula.

PMID- 12475683
TI  - Primary neuroendocrine carcinoma of the urethra.
AB  - We present a rare case of a primary neuroendocrine carcinoma of the urethra after
      radical cystectomy and orthotopic urinary reconstruction for transitional cell
      carcinoma of the urinary bladder.

PMID- 12475684
TI  - Recurrence of prostate adenocarcinoma presenting with multiple myeloma simulating
      skeletal metastases of prostate adenocarcinoma.
AB  - We present the case of a 77-year-old man with recurrence of prostate
      adenocarcinoma and widespread skeletal lesions. The skeletal lesions were found
      to be caused by multiple myeloma rather than metastatic spread of prostate
      adenocarcinoma. Various aspects of the radiographic imaging, evaluation of
      elevated prostate-specific antigen, and treatment of prostate adenocarcinoma are
      discussed.

PMID- 12475685
TI  - Renal cell carcinoma in pregnancy.
AB  - Renal cell carcinoma is a rarely reported neoplasm in pregnancy. The pregnancy
      demands special consideration in terms of the diagnostic evaluation and
      management. Two patients with renal cell carcinoma who presented during the
      second trimester of pregnancy and underwent radical nephrectomy are reported with
      a review of published studies. It seems that because the mother's welfare is the
      primary concern, surgical management need not be delayed.

PMID- 12475687
TI  - Prolapsed ureterocele after upper pole heminephrectomy.
AB  - Prolapse of a ureterocele through the external meatus is uncommon, and a
      prolapsed ureterocele occurring after upper pole heminephrectomy is extremely
      rare. We describe such a case, occurring 2 months after surgery. The ureterocele
      was excised with the upper pole ureteral stump, and the lower pole ureter was
      reimplanted with a good outcome.

PMID- 12475686
TI  - Fatal respiratory failure associated with treatment of prostate cancer using
      docetaxel and estramustine.
AB  - Chemotherapy that targets microtubular trafficking induces responses in most
      patients with prostate cancer. One regimen under investigation is the combination
      of docetaxel and estramustine. We report on 2 patients with androgen-independent
      disease who received continuous weekly docetaxel and estramustine and who died of
      irreversible respiratory failure. The clinical, pathologic, and radiographic data
      support drug toxicity as the likely etiology. Inclusive of these patients, only
      17 cases (10 fatal) of acute pulmonary toxicity using docetaxel have been
      reported, despite its wide use. We recommend that patients receiving weekly
      docetaxel, with or without estramustine, have frequent treatment breaks and be
      evaluated with computed tomography of the chest every 8 weeks.

PMID- 12475688
TI  - Acute pancreatitis after extracorporeal shock wave lithotripsy for a renal
      calculus.
AB  - Extracorporeal shock wave lithotripsy (ESWL) is currently considered the standard
      treatment for most renal and upper ureteral calculi. The complication rates with
      ESWL have been reported to be low, resulting in its widespread acceptance and
      use. However, as the technique has become more widely available, serious
      complications as a result of injury to the kidney and the surrounding organs have
      been recognized. We report on the development of severe acute pancreatitis in a
      patient after ESWL for a right-sided renal calculus. The patient history and
      chronologic clinical course strongly suggest a causal association between the
      ESWL and the development of pancreatitis.

PMID- 12475689
TI  - Recurrent bleeding from intercostal arterial pseudoaneurysm after retroperitoneal
      laparoscopic radical nephrectomy.
AB  - We report a case of a 59-year-old man with recurrent bleeding after
      retroperitoneal laparoscopic nephrectomy. Computed tomography and Doppler
      ultrasonography confirmed an intercostal artery pseudoaneurysm as the source.
      Angiography 1 month later demonstrated resolution after conservative management.

PMID- 12475690
TI  - Testicular extrusion due to scrotoschisis.
AB  - We present the eighth case of testicular extrusion through a congenital defect in
      the scrotal wall, along with a review of the published reports and a discussion
      of its possible embryogenesis.

PMID- 12475691
TI  - Paratesticular leiomyosarcoma in an elderly man.
AB  - Soft tissue tumors, both benign and malignant, of the testes are relatively
      uncommon. Primary leiomyosarcoma of the testis is rare, and its clinical behavior
      is difficult to predict. We report a case of paratesticular leiomyosarcoma in a
      71-year-old man. Routine histologic examination and immunohistochemical staining
      were performed. The tumor was composed of interlacing fascicles of smooth muscle
      cells with marked nuclear pleomorphism and three to four mitoses per high power
      field, with few atypical mitoses. On the basis of the microscopic examination and
      immunohistochemical studies, the tumor was identified as a paratesticular
      leiomyosarcoma. The published studies on this entity are reviewed.

PMID- 12475692
TI  - Huge scrotal, flank, and retroperitoneal lymphangioma successfully treated by OK
      432 sclerotherapy.
AB  - Retroperitoneal lymphangioma is extremely rare. It may obstruct or invade
      surrounding vital organs, which may result in lethal effects to the host.
      Although surgical excision has been suggested as the first choice for treatment,
      complete extirpation is often impossible. Moreover, the rates of postoperative
      morbidity and disease recurrence remain high. We report a case of a huge
      retroperitoneal lymphangioma extending to the flank and scrotum that was
      successfully treated by intralesional OK-432 sclerotherapy without any serious
      complications.

PMID- 12475693
TI  - High expression of the Met receptor in prostate cancer metastasis to bone.
AB  - OBJECTIVES: Expression of the active Met receptor tyrosine kinase causes tumor
      metastasis in animal models. To begin to analyze whether Met expression might be
      related to the spread of prostate cancer cells, we investigated whether its
      expression correlates with prostate-specific antigen recurrence and whether its
      expression depends on the site of metastasis. METHODS: Ninety radical
      prostatectomy specimens with a Gleason sum of 6 or 7 and 86 specimens of bone,
      lymph node, and soft-tissue metastasis were immunohistochemically stained for
      Met, and a semiquantitative scoring system for Met in heterogeneously positive
      prostate cancers was applied. Met protein in prostate cancer cell lines was
      measured by Western blotting. RESULTS: With the exception of two lymph node
      metastases, all metastases and 51% of the primary prostate cancers expressed Met.
      Moreover, the bone metastases expressed significantly more Met than did the lymph
      node metastases. However, in prostate cancer with a Gleason sum of 6 or 7, Met
      was not a prognostic marker for prostate-specific antigen recurrence. In prostate
      cancer cell lines, Met expression correlated inversely with expression of the
      androgen receptor. CONCLUSIONS: The high expression of the Met receptor tyrosine
      kinase in bone metastasis renders Met a promising target for nuclear imaging and
      treatment of metastatic prostate cancer.

PMID- 12475694
TI  - Calcium intake and prostate cancer risk in a long-term aging study: the Baltimore
      Longitudinal Study of Aging.
AB  - OBJECTIVE: To investigate the association between prostate cancer and calcium and
      other nutrients thought to influence the synthesis of 1,25-dihydroxyvitamin D
      [1,25(OH)2D]. METHODS: We included in the analysis 454 male participants in the
      Baltimore Longitudinal Study of Aging who were 46 to 92 years old at the time of
      completion of a food frequency questionnaire. Among them, 69 men were diagnosed
      with prostate cancer during their lifetime. In 68% of the cases, the food
      frequency questionnaire was completed after the diagnosis of cancer. Multiple
      logistic regression analysis was used to calculate the odds ratio and 95%
      confidence interval of prostate cancer. RESULTS: The median calcium intake was
      788 mg/day. The adjusted odds ratio of prostate cancer for the highest tertile
      compared with the lowest tertile of calcium intake was 0.92 (95% confidence
      interval 0.48 to 1.77; P(trend) = 0.89). Likewise, no significant trends were
      found for phosphorus, vitamin D, fructose, or animal protein intake. Dairy
      products, including milk, were not associated with an increased risk of prostate
      cancer. The adjusted odds ratio of prostate cancer was 1.26 (95% confidence
      interval 0.57 to 2.79; P(trend) = 0.73) for men with high dairy intakes compared
      with those with low dairy intakes. CONCLUSIONS: The results of this study suggest
      that calcium intake within moderate limits is not associated with a notably
      increased risk of prostate cancer.

PMID- 12475695
TI  - Prognostic value of proliferative activity and nuclear morphometry for
      progression in TaT1 urothelial cell carcinomas of the urinary bladder.
AB  - OBJECTIVES: To analyze the predictive power of Ki67 area% (Ki67), mitotic
      activity index (MAI), p53 area% (p53), and the mean area of the 10 largest nuclei
      (MNA10) for progression of stage in 195 primary consecutive TaT1 urothelial cell
      carcinomas of the urinary bladder. METHODS: Ki67- and p53-positive versus
      negative nuclei, MAI, and MNA10 using motorized systematic random sampling
      morphometry were determined. Kaplan-Meier curves and multivariate survival
      analysis (Cox model) were used to assess the prognostic value of the quantitative
      and classic clinicopathologic risk factors (age, sex, stage, grade, carcinoma in
      situ, multicentricity). RESULTS: Thirteen (6.7%) of the 195 patients had
      progression (0 [0%] of 36 low-risk, 1 [1.1%] of 85 intermediate-risk, and 12
      [16.2%] of 74 high-risk patients). In univariate analysis (all variables), the
      strongest predictors with the highest hazard ratios were Ki67 (threshold 25.0%),
      MAI (threshold 30), and MNA10 (threshold 170 microm2). In multivariate analysis,
      the strongest independent combinations for progression--MNA10 (170 microm2) plus
      MAI (threshold 30) and MNA10 (threshold 170 microm2) plus Ki67 (threshold 25.0%)-
      overshadowed all other features. p53 was weaker but, combined with Ki67, still
      predicted progression fairly well. In the total group, the sensitivity,
      specificity, and positive and negative predictive values of MNA10-MAI and MNA10
      Ki67 at the thresholds mentioned were 100%, 89%, 38%, and 100%, respectively.
      These feature combinations were also strongest prognostically in the high-risk
      treatment group. CONCLUSIONS: The combined biomarkers MNA10-MAI or MNA10-Ki67 are
      accurate, well reproducible, and easy to assess progression predictors in all
      patients with TaT1 urothelial cell carcinomas, as well as in high-risk (bacille
      Calmette-Guerin-treated) patients.

PMID- 12475697
TI  - Microcirculation of the urinary bladder in a rat model of ischemia-reperfusion
      induced cystitis.
AB  - OBJECTIVES: To determine the microcirculatory disturbances in a rat model of
      ischemia-reperfusion-induced cystitis using intravital fluorescence
      videomicroscopy. METHODS: Twenty male Sprague-Dawley rats were used for the
      experiments. In 10 animals, warm ischemia of the bladder was induced for 60
      minutes. After 30 minutes of reperfusion, microvascular macromolecular leakage,
      leukocyte-endothelial cell interactions, venular red blood cell velocity,
      functional capillary density, and the arteriolar and venular diameters were
      determined by intravital videomicroscopy. In addition, the intravesical pressure
      and macrohemodynamic parameters were assessed during the experiments. Sham
      operated animals served as the controls (n = 10). RESULTS: After ischemia
      reperfusion, the numbers of rolling and firmly adherent leukocytes in the
      postcapillary venules were significantly increased. Venular red blood cell
      velocity and functional capillary density, as well as the arteriolar and venular
      diameters, were significantly decreased. The macromolecular leakage had increased
      in both arterioles and venules. CONCLUSIONS: After ischemia-reperfusion,
      inflammatory reactions and microcirculatory failure were observed in the urinary
      bladder. This study targeted the microcirculatory consequences of cystitis using
      intravital videomicroscopy. Because the parameters investigated are relevant not
      only for ischemia-reperfusion of the urinary bladder but also for cystitis caused
      by other stimuli, this model represents a novel tool in the field of inflammation
      research in urology.

PMID- 12475698
TI  - Neural codes for conscious vision.
AB  - What makes cerebral activity conscious - is it the location of the activity or
      the type of processing taking place? A recent study of binocular fusion adds to
      the increasing evidence in favour of processing, not location, as the crucial
      factor. It also provides evidence for the co-localization of perceptual and non
      perceptual activity within individual cortical areas.

PMID- 12475696
TI  - Quantitative GSTP1 hypermethylation in bodily fluids of patients with prostate
      cancer.
AB  - OBJECTIVES: To further determine the value of real-time quantitative methylation
      specific polymerase chain reaction (MSP) of GSTP1 as a molecular tool for the
      detection of prostate adenocarcinoma. Recent studies have shown a high frequency
      (more than 90%) of GSTP1 gene promotor methylation in prostate adenocarcinoma and
      a lower frequency in DNA from serum and urine. METHODS: Tissue samples from 69
      patients with early-stage prostate adenocarcinoma and 31 patients with benign
      prostatic hyperplasia were collected. Matched urine and plasma specimens were
      obtained preoperatively. After sodium-bisulfite treatment, extracted DNA was
      analyzed for GSTP1 promoter hypermethylation both by conventional and real-time
      quantitative MSP. RESULTS: In tissue samples, GSTP1 hypermethylation was detected
      in 63 (91.3%) of the 69 patients with cancer and in 9 (29%) of the 31 patients
      with benign prostatic hyperplasia. Conventional MSP detected GSTP1
      hypermethylation in a larger number of urine and plasma samples than did real
      time quantitative MSP (53.6% versus 31.9%, overall). In all positive bodily
      fluids, the paired tumor was also confirmed to be methylated. GSTP1
      hypermethylation was detected by both MSP methods in only one urine sample (3.2%)
      from a patient with benign prostatic hyperplasia. CONCLUSIONS: Although not
      quantitative, conventional MSP is currently more sensitive than real-time
      quantitative MSP in the detection of GSTP1 hypermethylation in bodily fluids from
      patients with prostate cancer with clinically localized disease. The value of
      quantitative determinations in monitoring and risk assessment remains to be
      further explored.

PMID- 12475699
TI  - The skill of seeing: beyond the sensorimotor account?
AB  - How crucial a role do reason, memory and planning play alongside lower-level
      sensorimotor skills in our visual activity? Andy Clark has recently proposed a
      new skill-based account of seeing. This suggests there is more to perception than
      only the mastery of sensorimotor contingencies, as O'Regan, Noe and others have
      stressed in recent influential papers.

PMID- 12475700
TI  - More to 3-D vision than meets the eye.
AB  - Does self-motion affect object recognition? Researchers have long studied how 3-D
      objects are recognized from different points of view, but have disregarded the
      observers' own movement by keeping them motionless. A recent study by Simons et
      al. shows that self-motion cannot be ignored, as it changes the way that objects
      are recognized.

PMID- 12475701
TI  - Do chess and GO need 'g'?

PMID- 12475702
TI  - Imitation: on the dot.

PMID- 12475703
TI  - Interpreting visual images, individually.

PMID- 12475704
TI  - Looking to improve haptic performance.

PMID- 12475706
TI  - No need for repression.

PMID- 12475707
TI  - Repression can (and should) be studied empirically.

PMID- 12475709
TI  - Conception, perception and the control of action.

PMID- 12475708
TI  - Frames of reference and language concepts.

PMID- 12475710
TI  - Hippocampal and neocortical contributions to memory: advances in the
      complementary learning systems framework.
AB  - The complementary learning systems framework provides a simple set of principles,
      derived from converging biological, psychological and computational constraints,
      for understanding the differential contributions of the neocortex and hippocampus
      to learning and memory. The central principles are that the neocortex has a low
      learning rate and uses overlapping distributed representations to extract the
      general statistical structure of the environment, whereas the hippocampus learns
      rapidly using separated representations to encode the details of specific events
      while minimizing interference. In recent years, we have instantiated these
      principles in working computational models, and have used these models to address
      human and animal learning and memory findings, across a wide range of domains and
      paradigms. Here, we review a few representative applications of our models,
      focusing on two domains: recognition memory and animal learning in the fear
      conditioning paradigm. In both domains, the models have generated novel
      predictions that have been tested and confirmed.

PMID- 12475711
TI  - Atypical trajectories of number development: a neuroconstructivist perspective.
AB  - Despite the fact that number deficits are as prevalent as literacy deficits,
      research on basic numerical skills lags seriously behind the successful studies
      identifying low-level deficits in dyslexia. We review current debates on number,
      discussing how the competing theories pertain to mathematical disabilities in
      normal children and numeracy deficits in genetic disorders. We stress the need to
      consider these issues within the framework of a developing system rather than
      from the neuropsychological perspective of focal damage. The earlier the
      exploration of atypical trajectories in very basic numerical skills, the better
      we will be able to chart their developmental impact on subsequent, higher-level
      arithmetic abilities.

PMID- 12475712
TI  - How (and where) does moral judgment work?
AB  - Moral psychology has long focused on reasoning, but recent evidence suggests that
      moral judgment is more a matter of emotion and affective intuition than
      deliberate reasoning. Here we discuss recent findings in psychology and cognitive
      neuroscience, including several studies that specifically investigate moral
      judgment. These findings indicate the importance of affect, although they allow
      that reasoning can play a restricted but significant role in moral judgment. They
      also point towards a preliminary account of the functional neuroanatomy of moral
      judgment, according to which many brain areas make important contributions to
      moral judgment although none is devoted specifically to it.

PMID- 12475713
TI  - Classical conditioning, awareness, and brain systems.
AB  - Memory is composed of several different abilities that are supported by different
      brain systems. The distinction between declarative (conscious) and nondeclarative
      (non-conscious) memory has proved useful in understanding the nature of eyeblink
      classical conditioning - the best understood example of classical conditioning in
      vertebrates. In delay conditioning, the standard procedure, conditioning depends
      on the cerebellum and brainstem and is intact in amnesia. Trace conditioning, a
      variant of the standard procedure, depends additionally on the hippocampus and
      neocortex and is impaired in amnesia. Recent studies have sharpened the contrast
      between delay and trace conditioning by exploring the importance of awareness. We
      discuss these new findings in relation to the brain systems supporting eyeblink
      conditioning and suggest why awareness is important for trace conditioning but
      not for delay conditioning.

PMID- 12475714
TI  - The dynamics of standing balance.
AB  - The control of standing is a complicated task that involves the action of muscles
      distributed over the whole body. Forces arising from gravity, external events or
      our own actions all tend to disturb the unstable equilibrium that preserves
      posture. For the central nervous system the problem of standing can be cast in
      terms of finding appropriate relations among body segments to maintain the
      desired position of the body as a whole with respect to the environment. In this
      review we evaluate some recent discoveries on the effects of predictable and
      unpredictable perturbations, and the role of perceptual information, attention
      and cognitive processes in the control of upright stance.

PMID- 12475715
TI  - A window to the structure of the mind.

PMID- 12475716
TI  - Opposing associationism.

PMID- 12475717
TI  - Back to nature.

PMID- 12475718
TI  - Estrogen receptor phosphorylation.
AB  - Estrogen receptor alpha (ERalpha) is phosphorylated on multiple amino acid
      residues. For example, in response to estradiol binding, human ERalpha is
      predominately phosphorylated on Ser-118 and to a lesser extent on Ser-104 and Ser
      106. In response to activation of the mitogen-activated protein kinase pathway,
      phosphorylation occurs on Ser-118 and Ser-167. These serine residues are all
      located within the activation function 1 region of the N-terminal domain of
      ERalpha. In contrast, activation of protein kinase A increases the
      phosphorylation of Ser-236, which is located in the DNA-binding domain. The in
      vivo phosphorylation status of Tyr-537, located in the ligand-binding domain,
      remains controversial. In this review, I present evidence that these
      phosphorylations occur, and identify the kinases thought to be responsible.
      Additionally, the functional importance of ERalpha phosphorylation is discussed.

PMID- 12475719
TI  - Expression of estrogen receptor alpha and beta in myometrium of premenopausal and
      postmenopausal women.
AB  - Although a clear role for estrogen receptor (ER) alpha has been established, the
      contribution of ERbeta in estrogen-dependent development, growth and functions of
      the myometrium is not understood. As a first step towards understanding the role
      of ERbeta, we have examined the expression of ERalpha and ERbeta in the human
      myometrium. With competitive RT-PCR assays, the level of ERbeta mRNA was 10-200
      times lower than that of ERalpha mRNA in both premenopausal and postmenopausal
      myometrium. In premenopausal myometrium, the expression pattern of ERbeta mRNA
      during the menstrual cycle was similar to that of ERalpha mRNA, with highest
      levels in peri-ovulatory phase. In postmenopausal myometrium, ERbeta mRNA was
      significantly higher than it was in premenopausal myometrium, while the level of
      ERalpha mRNA was lower. The net result was a change in the ratio of ERbeta to
      ERalpha mRNA expression. The ratio changed from 0.6-1.5 in premenopausal to 2.5
      7.6 in postmenopausal myometrium. In premenopausal women, the gonadotropin
      releasing hormone analogue, leuprorelin acetate, elicited a decrease in ERalpha
      and an increase in ERbeta mRNA expression to cause a postmenopausal receptor
      phenotype. Estradiol, on the other hand, reversed ERalpha and ERbeta mRNA
      expression and their ratio in postmenopausal myometrium to those of premenopausal
      myometrium. Immunohistochemical staining and Western blot analysis of ERalpha and
      ERbeta with semiquantitative analysis showed good agreement between mRNA and
      protein levels. The data indicate that coordinated expression of ERalpha and
      ERbeta might be necessary for normal estrogen action in myometrium. Furthermore,
      estrogen appears a dominant regulator of both receptors in the myometrium.

PMID- 12475721
TI  - Chemical synthesis of 7- and 8-dehydro derivatives of pregnane-3,17alpha,20
      triols, potential steroid metabolites in Smith-Lemli-Opitz syndrome.
AB  - Pregnane-3,17 alpha,20-triols bearing unsaturation at delta(7), delta(8),
      delta(5,7), or delta(5,8) have been tentatively identified as steroid metabolites
      in Smith-Lemli-Opitz syndrome (SLOS). Starting with 17 alpha-hydroxypregnenolone
      diacetate, we have synthesized 13 unsaturated C(21) triols by four different
      routes in one to four steps. These multifunctional steroids were prepared by a
      series of regio- and stereoselective transformations chosen to minimize facile
      olefin isomerization and 17-deoxygenation. The results include a study of
      stereoselectivity in the reduction of 17 alpha-hydroxy-20-ketosteroids, an
      alternative method for reducing diethyl azodicarboxylate adducts of delta(5,7)
      steroids, and an efficient oxidation-isomerization of a delta(5,7) steroid using
      cholesterol oxidase. The 13 triols and their synthetic precursors were fully
      characterized by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The
      NMR data, together with molecular modeling, indicated unanticipated
      conformational heterogeneity for two synthetic intermediates, 17 alpha
      hydroxypregna-4,7-diene-3,20-dione and 17 alpha-hydroxy-5 beta-pregn-7-ene-3,20
      dione. The unsaturated C(21) triols are useful as reference standards to study
      adrenal steroid production in SLOS and to develop methods for pre- and postnatal
      diagnosis of this congenital disorder.

PMID- 12475720
TI  - Receptor profiling and endocrine interactions of tibolone.
AB  - The receptor profiles and in vivo activity of tibolone, and its primary
      metabolites, Delta(4)-isomer, and 3alpha- and 3beta-hydroxytibolone, were studied
      and compared to those of structurally related compounds. The Delta(4)-isomer was
      the strongest binder and activator of the progesterone receptor (PR); tibolone
      was 10 times weaker in binding and half as potent in transactivation of PR;
      3alpha- and 3beta-hydroxytibolone did not bind or activate PR. In rabbits oral
      tibolone produced a minor progestagenic effect in the endometrium, whereas co
      administration of tibolone and the anti-estrogen ICI 164,384 unmasked tibolone's
      progestagenic effect. 3-Hydroxytibolones were the strongest binders and
      activators of the estrogen receptors (ERs), with greater affinity for ERalpha
      than for ERbeta. Tibolone showed weaker binding and activation of both ERs and
      the Delta(4)-isomer has a binding and activation activity of less than 0.1% of E2
      for ERalpha or ERbeta. Tamoxifen and 4-hydroxytamoxifen showed partial ERalpha
      agonistic effects with a maximal response of 12% and raloxifene of 3-5%. Oral
      administration of 1mg tibolone to ovariectomized rats induced an estrogenic
      effect on vaginal epithelium. The Delta(4)-isomer was a stronger binder and
      activator of the androgen receptor (AR) than tibolone; both 3-hydroxytibolones
      did not bind or activate AR. Introducing a 7alpha-methyl group decreased
      progestagenic and increased androgenic activity. We conclude that the
      progestagenic and androgenic activities of tibolone are mediated by the Delta(4)
      isomer, and the estrogenic activity, by the 3-hydroxytibolones. The estrogenic
      activity of the 3-hydroxytibolones masked the progestagenic activity of tibolone
      in rabbit endometrium. Full estrogenic response was observed in rat vaginal
      tissue after oral administration of tibolone.

PMID- 12475722
TI  - Determination of second-order association constants by global analysis of 1H and
      13C NMR chemical shifts. Application to the complexation of sodium fusidate and
      potassium helvolate by beta- and gamma-cyclodextrin.
AB  - The host-guest interaction between the steroid antibiotics sodium fusidate and
      potassium helvolate as guests and the hosts beta- and gamma-cyclodextrin was
      studied by 13C and 1H NMR techniques. The analysis of chemical shifts of
      individual nuclei leads to inconsistent values of the association constants and
      fails generally in the case of mixtures of 1:1 and 1:2 stoichiometries. The
      problem of parameter correlation is identified and the global analysis of two or
      more nuclei is proposed as a very effective method for the detection of complexes
      of higher stoichiometries and for the precise determination of the involved
      association constants. A matrix formulation of global analysis and the
      determination of confidence intervals is described. An analytical solution of the
      cubic equation, necessary for the description of higher order complexes, is
      presented in detail and its use together with commercial fitting software is
      compared with dedicated implementations. gamma-Cyclodextrin forms with both
      studied steroids, sodium fusidate and potassium helvolate, 1:1 complexes with
      high values of the association constants, K(1)=(60+/-24)x10(3)lmol(-1), and
      K(2)=(22+/-9)x10(3)lmol(-1), respectively. To the contrary, beta-cyclodextrin
      forms 1:1 and 1:2 (guest:host) complexes with both steroids, with moderate K(1)
      and low K(2) values (K(1)=(0.74+/-0.13)x10(3)lmol(-1), K(2)=(0.210+/
      0.075)x10(3)lmol(-1)), and (K(1)=(2.42+/-0.87)x10(3)lmol(-1), K(2)=(0.06+/
      0.09)x10(3)lmol(-1)), respectively.

PMID- 12475723
TI  - Spectra and structure of complexes formed by sodium fusidate and potassium
      helvolate with beta- and gamma-cyclodextrin.
AB  - The complexation of two steroid antibiotics of the fusidane family, sodium
      fusidate and potassium helvolate, by beta-CD and gamma-CD has been studied by
      using 1D and 2D-NMR techniques. Both guests form 1:1 complexes with gamma-CD and
      1:2 (guest:cyclodextrin) complexes with beta-CD. Thus, both antibiotics behave as
      monotopic and ditopic guests when they are complexed by gamma-CD and beta-CD,
      respectively. Both steroids enter into the cavity of the gamma-CD by the side
      chain, reaching the central region of the steroid (rings C and D), whereas the A
      and B (partially) rings remain outside. For beta-CD complexes, ROESY spectra show
      a remarkable absence of interactions of the protons of the C and D rings, whereas
      clear interactions corresponding to the side chain, and A and B rings are
      observed. The obtained equilibrium constants (see previous paper) are discussed
      in terms of the structures proposed for the complexes. NMR spectra of sodium
      fusidate are revised, and a full assignment of the 1H and 13C NMR spectra is
      presented for potassium helvolate.

PMID- 12475724
TI  - Urinary estrogen metabolites and breast cancer: differential pattern of risk
      found with pre- versus post-treatment collection.
AB  - INTRODUCTION: The products of estrogen metabolism may affect breast
      carcinogenesis. The 16alpha-hydroxyestrone (16-OHE) metabolite has a higher
      affinity for the estrogen receptor (ER) than the 2-hydroxyestrone (2-OHE)
      metabolite, while conjugated 2-OHE metabolite may inhibit angiogenesis. We
      investigated the association between the relative concentrations of these
      metabolites in urine (2-OHE/16-OHE) and breast cancer in a case-control study of
      Chinese women living in Shanghai. METHODS: Incident breast cancer cases between
      25 and 65 years of age (n=110) were identified from hospital or population tumor
      registries in Shanghai, China. Controls (n=110) were randomly selected from a
      complete registry of the Shanghai population, and individually matched to cases
      by menopausal status, age, and pre-treatment or post-treatment urine collection
      time. Urine samples were collected prior to any breast cancer treatment or
      surgery among 78 case-control pairs, while urine was collected after surgery, and
      perhaps other treatments, among 32 case-control pairs. A commercial enzyme
      immunoassay kit was used to measure urinary estrogen metabolite concentrations.
      Conditional logistic regression was used to calculate odds ratios summarizing the
      2-OHE/16-OHE and breast cancer association within subjects providing either pre
      treatment or post-treatment urine samples. RESULTS: Subjects with a higher
      urinary 2-OHE/16-OHE ratio were less likely to be diagnosed with breast cancer,
      but only when urine samples were collected prior to breast cancer treatment
      (OR(Tertile3(T3)versusTertile1(T1))=0.5, 95% CI (0.2, 1.1)). In contrast, a
      higher 2-OHE/16-OHE ratio was significantly associated with breast cancer among
      subjects providing urine specimens after treatment initiation
      (OR(T3versusT1)=8.7, 95% CI (1.6, 47.1)). This observed cross-over modification
      occurred within both pre-menopausal and post-menopausal women, and independent of
      body mass index or recent dietary intake. CONCLUSION: Cross-study differences in
      urine collection protocols may explain observed inconsistencies in the 2-OHE/16
      OHE and breast cancer association. Our case-control analysis using pre-treatment
      urine samples suggested that a lower 2-OHE/16-OHE ratio was associated with an
      increased risk of pre-menopausal and post-menopausal breast cancer diagnosis
      among Chinese women.

PMID- 12475725
TI  - Anti-proliferative action of endogenous dehydroepiandrosterone metabolites on
      human cancer cell lines.
AB  - Dehydroepiandrosterone (DHEA) is a naturally occurring steroid synthesized in the
      adrenal cortex, gonads, brain, and gastrointestinal tract, and it is known to
      have chemopreventive and anti-proliferative actions on tumors. These effects are
      considered to be induced by the inhibition of glucose-6-phosphate dehydrogenase
      (G6PD) and/or HMG-CoA reductase (HMGR) activities. The present study was
      undertaken to investigate whether endogenous DHEA metabolites, i.e. DHEA-sulfate,
      7-oxygenated DHEA derivatives, androsterone, epiandrosterone, and
      etiocholanolone, have anti-proliferative effects on cancer cells and to clarify
      which enzyme, G6PD or HMGR, is responsible for growth inhibition. Growth of Hep
      G2, Caco-2, and HT-29 cells, evaluated by 3-[4,5-dimethylthiazol]-2yl-2,5
      diphenyl tetrazolium bromide (MTT) and bromodeoxyuridine incorporation assays,
      was time- and dose-dependently inhibited by addition of all DHEA-related steroids
      we tested. In particular, the growth inhibition due to etiocholanolone was
      considerably greater than that caused by DHEA in all cell lines. The suppression
      of growth of the incubated steroids was not correlated with the inhibition of
      G6PD (r=-0.031, n=9, NS) or HMGR (r=0.219, n=9, NS) activities. The addition of
      deoxyribonucleosides or mevalonolactone to the medium did not overcome the
      inhibition of growth induced by DHEA or etiocholanolone, while growth suppression
      by DHEA was partially prevented by the addition of ribonucleosides. These results
      demonstrate that endogenous DHEA metabolites also have an anti-proliferative
      action that is not induced by inhibiting G6PD or HMGR activity alone. These non
      androgenic DHEA metabolites may serve as chemopreventive or anti-proliferative
      therapies.

PMID- 12475726
TI  - Steroidal oxathiazine inhibitors of estrone sulfatase.
AB  - The presence of estrone sulfatase in breast tumors and the high levels of
      circulating estrone sulfate may contribute the major portion of estrogen
      synthesized locally in breast tissues through conversion of estrone sulfate to
      estrone by the enzyme. Using inhibitors of estrone sulfatase for the treatment of
      estrogen-dependent (estrogen receptor positive, ER(+)) breast cancer could be a
      very effective therapeutic strategy for the treatment of estrogen-dependent
      breast tumors in postmenopausal women. Therefore, we designed and synthesized
      several steroidal 2',3'-oxathiazines that inhibit estrone sulfatase and have
      greatly reduced estrogenic side effects. Our in vitro studies indicate that the
      oxathiazine compounds have inhibitory activity on estrone sulfatase in MCF-7
      human breast cancer cells. These estrone sulfatase inhibitors (ESIs) also inhibit
      the growth of MCF-7 cells induced by estrone sulfate. In addition, our in vivo
      experiments demonstrate that our ESIs have moderate antitumor activity against
      MCF-7 breast cancer xenografts in Balb/c athymic nude mice. The synthesis and
      biological activity of a number of these unique steroidal ESIs are described.

PMID- 12475727
TI  - Stress, gender and motherhood (II).

PMID- 12475728
TI  - Peripheral and central sex steroids have differential effects on the HPA axis of
      male and female rats.
AB  - Sex differences in hypothalamic-pituitary-adrenal (HPA) function were examined in
      gonadectomized male and female rats given equivalent sex hormone replacement
      regimens either using subcutaneous silastic implants (Experiment 1) or cannula
      implants in the medial preoptic area (MPOA) (Experiment 2) containing either
      dihydrotestosterone (DHT), testosterone propionate (TP), estradiol benzoate (EB),
      or left empty (control). Plasma was obtained before and after 20 min of restraint
      stress to determine plasma ACTH, corticosterone, and CBG levels as measures of
      HPA function. Consistent with the literature, androgens decreased, and estrogen
      increased these measures of HPA function, although peripheral implants were more
      effective than MPOA implants. Gonadectomy and sex hormone treatment did not
      eliminate sex differences; overall, females had higher levels than males on
      measures of HPA function. Analyses of variance (ANOVA) indicated interactions of
      sex and sex hormone treatment on CBG levels and post-stress corticosterone levels
      in Expt. 1. The results suggest that sexual dimorphisms influence HPA function
      even when males and females are given equivalent physiological doses of gonadal
      steroids, and that the relevant sexual dimorphisms involve both the periphery and
      the CNS.

PMID- 12475729
TI  - The brain prolactin system: involvement in stress response adaptations in
      lactation.
AB  - This review focuses on prolactin as a potential candidate for the regulation of
      emotional and neuroendocrine stress responses in the brain. In particular, we
      summarise evidence for a brain prolactin receptor-mediated anxiolytic action both
      in female and male rats, and for inhibitory actions on the reactivity of the
      hypothalamic-pituitary-adrenal (HPA) axis and the neurohypophysial oxytocin
      system. These physiological functions of the brain prolactin system are
      especially relevant in the peripartum period, as an attenuation of behavioural
      and neuroendocrine stress responses has been described during pregnancy and
      lactation. At this time, there is an increase in brain prolactin receptor
      expression and binding, and an increase in hypothalamic prolactin gene
      expression. In the absence of a selective prolactin receptor antagonist,
      complementary approaches including chronic intracerebral infusion of prolactin,
      and antisense targeting of the long form of the brain prolactin receptor were
      used to investigate the actions of prolactin. The hypothesis of a brain prolactin
      system activated in the peripartum period which contributes to the adaptive
      changes in stress responsiveness in order to support reproductive functions is
      strongly emphasised.

PMID- 12475730
TI  - Oxytocin links mothering received, mothering bestowed and adult stress responses.
AB  - We review recent discoveries that implicate oxytocin in the intergenerational
      transmission of similar levels of maternal behavior and acute stress responses in
      female rats. First, ICV-infused oxytocin antagonist decreased the display by
      nursing dams of pup-licking (PL) and arched-back nursing (ABN), but not other
      components of maternal behavior, and increased maternal self-grooming suggesting
      that oxytocin may shift the balance of oral grooming by dams away from themselves
      and toward pups. Second, oxytocin receptor concentrations in areas of the adult
      brain where oxytocin stimulates maternal behavior or diminishes anxiety and
      adrenal axis responses to acute stress were positively related to PL-ABN received
      during infancy. Third, oxytocin and oxytocin antagonist treatments of pups on
      postnatal days 2-10, respectively increased and decreased PL by the treated rats
      when adult and themselves nursing dams. This indicates that oxytocin activity in
      female pups, which may be regulated by PL-ABN received from their mothers,
      influences their adult levels of PL. These three lines of evidence suggest that
      oxytocin selectively enhances PL-ABN by rat dams, which then increases oxytocin
      activity in female pups and, thereby, facilitates their expression of central
      oxytocin receptors (and perhaps other aspects of central oxytocin systems) and,
      consequently, their adult PL-ABN frequencies and acute stress responses.

PMID- 12475731
TI  - Effects of emotion on oxytocin, prolactin, and ACTH in women.
AB  - Research on both non-human mammals and humans has raised interest in the role
      that oxytocin may play in human attachment and attachment-related emotions. This
      study examined changes in plasma oxytocin, prolactin, and ACTH concentrations in
      response to laboratory-induced positive and negative emotions related to close,
      interpersonal relationships. Participants were 32 female volunteers recruited
      from university communities. During positive emotion induction, oxytocin
      decreased over time (F(1,3) = 4.41, p < 0.007), prolactin increased (F(1,3) =
      4.80, p < 0.004) and ACTH remained constant. During negative emotion induction,
      prolactin levels increased (F(1,3) = 2.81, p < 0.05), ACTH decreased only after
      the induction terminated (F(1,3) = 4.02, p < 0.01) and oxytocin remained
      constant. While oxytocin decreased during positive emotion, this finding
      contrasted previous research that showed decreases in response to negative
      emotion. In conclusion, plasma oxytocin levels were not reliably altered by
      positive or negative emotion induction. While prolactin and ACTH were expected to
      decrease over time due to diurnal variation, they instead either increased or
      remained level during emotion induction, or decreased only after the induction.
      Overall, the degree of change in circulating hormones in response to happy and
      sad emotions was very small and possibly not functionally significant.

PMID- 12475732
TI  - Effect of chronic intermittent immobilization stress on Fos-like immunoreactivity
      in rat brain and adrenal medulla.
AB  - The present study examined the influence of short- and long-term chronic
      intermittent immobilization stress throughout the brain and on the adrenal
      medulla of intact rats using Fos-like immunoreactivity (Fos-LI) as a marker of
      cellular activation. The effect of adreno-medullectomy on the central nervous
      system (CNS) response to chronic immobilization stress was also examined. It was
      found that control unoperated, unstressed rats had no Fos-LI cells in the brain
      or in the adrenal medulla. In intact rats, neither short term (1 week) nor long
      term (4 weeks) chronic intermittent immobilization stress produced significant
      increases in Fos-LI in the CNS compared with control animals. However, marked
      increase in the number of Fos-LI cells was observed in the adrenal medulla of
      animals stressed for 4 weeks compared with control, unstressed animals or those
      stressed for 1 or 2 weeks. In adreno-medullectomised rats, 4 weeks, but not 1
      week, chronic immobilization stress produced significant increases in numbers of
      Fos-LI neurons in the paraventricular hypothalamic and supraoptic nuclei and the
      medial amygdala compared with intact animals stressed for a similar period of
      time. It is concluded that long term stress produces chronic Fos-LI in the
      adrenal medulla and that adreno-medullectomy increases the Fos response of the
      PVN, supraoptic nucleus and medial amygdala to long term stress.

PMID- 12475733
TI  - Immediate-early Fos protein levels in brainstem neurons of male and female
      gonadectomized mice subjected to cold exposure.
AB  - The expression of the immediate early gene c-fos has been used extensively as a
      marker for neural activation in response to acute and chronic stressful stimuli
      in brain and spinal cord. The present study examined the expression of Fos
      protein in the brainstem nuclei of male and female gonadectomized mice in
      response to cold stress. Free-floating sections were processed
      immunohistochemically for Fos protein using standard avidin-biotin complex
      methods. The number of Fos-positive neurons in each nucleus was determined.
      Although the experiment was designed to look for gender differences, results were
      equivalent between females and males. After mice were exposed to a cold ambient
      temperature (4 degrees C) for 2 h, elevated numbers of Fos-positive neurons were
      counted in the medullary gigantocellular reticular nucleus, medullary raphe
      nucleus, nucleus of the solitary tract and in locus coeruleus. However, no
      elevated expression was found in nucleus ambiguus, nor in neurons of the A1
      group, nor the C2 or C3 group. Similar to rats, these results with mice reveal a
      widespread arousal system in the lower brainstem activated by cold stress in both
      genders. These findings in gonadectomized mice have set the stage for
      investigations following hormonal and genetic manipulations.

PMID- 12475734
TI  - Oral concentration of volatile sulphur compounds in stressed rats.
AB  - Stress has been identified as a halitosis-inducing factor. Halitosis may be
      measured by the determination of oral volatile sulphur compound levels (VSC).
      Since immobilization and swimming are two experimental protocols widely used to
      induce stress in laboratory animals, the aim of this work was to investigate the
      influence of stress on VSC in rats. Male Wistar rats were submitted to three
      swimming or immobilization sessions over consecutive days. The oral VSC increased
      3 h after the first and third swimming or immobilization sessions. The results in
      the present study support the hypothesis that stress may be an etiological factor
      in halitosis. Also, the animal experimental design may represent a new approach
      to research concerning the relationship between halitosis and stress.

PMID- 12475735
TI  - Hypothalamic and hippocampal release of serotonin in rats bred for hyper- or hypo
      anxiety.
AB  - Microdialysis for measurement of serotonin in the paraventricular nucleus of the
      hypothalamus (PVN) and the dorsal hippocampus was performed under both basal and
      stimulated conditions, known to elicit differential behavioral and neuroendocrine
      responses in rats with inborn high (HAB) or low (LAB) anxiety-related behavior.
      We studied the release of hypothalamic and hippocampal serotonin in response to
      elevated platform exposure and forced swim stress, a mild emotional and a
      combined emotional and physical stressor, respectively. The data suggest that
      serotonin release patterns may depend on the inborn level of anxiety, the brain
      area dialyzed, and the stressor the animals were exposed to. Under basal
      conditions, no differences in serotonin release in either the PVN or dorsal
      hippocampus were observed between HAB and LAB rats. While in the PVN open
      platform exposure failed to change the release of serotonin, forced swim stress
      induced an increase in both HAB (p = 0.0001) and LAB (p = 0.01) rats with a
      significantly greater effect in the former (p = 0.027). In the dorsal
      hippocampus, only LABs, but not HABs, responded to the elevated platform exposure
      by enhancing the release of serotonin (p = 0.01). Also, forced swim stress
      increased hippocampal serotonin only in LAB (p = 0.002), but not HAB, rats
      probably indicating an involvement of hippocampal serotonin in locomotion and
      active stress coping. It remains to be shown to what extent the differences in
      serotonin release contribute to neuroendocrine and behavioral differences between
      HAB and LAB rats.

PMID- 12475736
TI  - Essential thrombocythemia (ET): moving from palliation to cure.
AB  - Essential thrombocythemia (ET) is a clonal hematopoietic stem cell
      myeloproliferative disorder characterized by megakaryocytic hyperplasia and
      persistent thrombocytosis. The clinical presentation and evolution of ET are
      heterogeneous. This review highlights the current treatment options in the
      management of ET, including hydroxyurea, anagrelide and both regular and
      pegylated interferons. Anagrelide, while very effective at controlling counts and
      symptoms in most patients, may not consistently reduce the bone marrow
      megakaryocyte mass. Interferon is very effective and not associated with
      leukemogenesis, but has not been proven to restore polyclonal hematopoiesis and
      has significant dose-related adverse events. Pegylated interferon represents a
      significant improvement over the unmodified interferon preparations. Novel
      therapeutic options directed towards eradication of the malignant ET clone are
      required.

PMID- 12475737
TI  - Myelodysplasia and the acute myeloid leukaemias.
AB  - The myelodysplastic syndromes are increasingly recognised clinical entities
      reflecting a stem cell defect that gives rise to ineffective clonal
      haematopoiesis. The spectrum extends from relatively indolent refractory anaemia
      through varying combinations of leucopoenia and thrombocytopenia to acute
      leukaemia. Diagnosis rests on marrow hypercellularity with dysplastic morphology,
      apoptosis and, often distinctive cytogenetic defects. Stratification to risk
      related protocols range from occasional blood transfusions or erythropoietin
      through innovative options including thalidomide or amifostine to haematopoietic
      stem cell transplantation in selected individuals. Acute myeloid leukaemia,
      conceptually segregated from preleukaemia, is treated differently although
      accumulating cellular and molecular data favour a more integrated approach.
      Morphology and immunophenotyping are complemented by molecular genetics. On this
      basis chemotherapy alone is sufficient in defined sub-groups whereas others
      benefit by autologous or allogeneic grafting. Attention to demonstrating minimal
      residual disease is the basis for more specific intervention exemplified by
      monoclonal antibodies or maturation-inducing agents as with retinoic acid in
      acute progranulocytic leukaemia

PMID- 12475738
TI  - Molecular biology of gastric MALT lymphoma: application in clinical management.
AB  - The development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma
      depends critically on Helicobacter pylori infection. The bacterial infection
      stimulates the lymphoma B-cells through both direct (auto-antigen) and indirect
      (H. pylori specific intra-tumour T-cells) immunological stimulation. It also
      promotes the acquisition of genetic abnormality through activated neutrophils,
      which release oxygen reactive species. Malignant clones bearing t(11;18)(q21;q21)
      form lymphomas that are H. pylori growth independent. Those without
      t(11;18)(q21;q21) but with other genetic abnormality such as trisomy 3 depend
      critically on H. pylori mediated immune response at early stages and are
      therefore responsive to H. pylori eradication. However, at late stages when
      additional genetic defects such as t(1;14)(p22;q32) accumulate, the tumour may
      escape its growth dependence on H. pylori mediated immune response. Detection of
      these chromosomal translocations has significant implication in clinical
      management of patients with gastric MALT lymphoma.

PMID- 12475739
TI  - Is there a role for reduced-intensity haematopoietic stem cell transplantation
      for indolent non-Hodgkin's lymphoma?
AB  - The therapeutic options for the indolent non-Hodgkin's lymphomas have evolved
      significantly over the years. However, at present, allogeneic haematopoietic stem
      cell transplantation (HSCT), despite its significant transplant associated
      complications, is still the only option which may be delivered with curative
      potential. The debut of reduced-intensity conditioning regimens has extended the
      applicability of allogeneic transplants to groups of patients ineligible for
      conventional myeloablative allografts. However, there are still substantial
      hurdles to overcome, namely that of relapse, graft-versus-host disease and
      infection. Whilst follow-up is still relatively limited for a disease group with
      a median survival of up to 10 years, early results are extremely encouraging and
      further studies are warranted.

PMID- 12475740
TI  - Autologous hematopoietic stem cell transplantation for refractory lymphomatoid
      granulomatosis.
AB  - Lymphomatoid granulomatosis (LG) is a rare lymphoproliferative disorder. There is
      no standard therapy for refractory patient. Here we present the case of a patient
      with LG of the lung and the brain who was refractory to polychemotherapy. An
      autologous hematopoietic stem cell transplantation was done and the patient
      achieved a complete remission. This represents the first case of high-dose
      chemotherapy with hematopoietic stem cell support in this disease.

PMID- 12475741
TI  - Thrombus formation with rehydrated, lyophilized platelets.
AB  - Stored human platelets are frequently used in hemorrhagic emergencies, but have
      limited immediate utility for controlling bleeding due to storage lesion and are
      frequently contaminated with microorganisms. The development of paraformaldehyde
      treated, lyophilized and rehydrated (RL) platelets, which are sterile and have a
      prolonged shelf life (years), ameliorate the efficacy and sterility problems with
      stored platelets. RL platelets have been shown to have many native functions of
      fresh platelets in vitro and to mediate hemostasis in vivo in large animal models
      of hemorrhagic shock and cardiopulmonary bypass induced platelet dysfunction. To
      further evaluate the functional properties of this transfusion product, we
      studied the role of RL platelets in three aspects of thrombus formation and
      lysis. First, the interaction between RL platelets and fibrinogen was
      investigated. The surface density of unligated GPIIb-IIIa on RL and fresh
      platelets were, respectively 30000 and 70000 molecules per cell as detected with
      the monoclonal antibody 10E-5. Freezing, lyophilization and rehydration steps in
      the preparation of RL platelets resulted in the surface presentation of 120000
      molecules of fibrinogen per cell from alpha granule sources. After ADP
      activation, RL platelets bound exogenous 125I-labeled fibrinogen in a dose
      dependent manner with an affinity that is similar to that of fresh platelets and
      was inhibited by RGD peptides. 125I-Labeled fibrinogen binding to RL and fresh
      platelets, respectively, saturated at 14000 and 32000 molecules per cell.
      Scanning electron microscopic ultrastructural analysis showed that fibrin strands
      interacted with the surface of RL platelets in a normal manner. The second set of
      studies investigated the ability of RL platelets to catalyze and amplify the clot
      formation process in an activation-dependent manner. We showed that RL platelets
      undergo degranulation in fibrin in clots and functioned as thrombogenic surfaces
      for the generation of activated coagulation factors and fibrin generation. A
      final set of studies was performed to investigate fibrin of clots that contained
      RL platelets. RL platelet clots were lysed in the presence of tissue plasminogen
      activator with a similar time course as clots without platelets, and lysis
      occurred faster than when fresh platelets were included in the fibrin mass. The
      results of these three studies demonstrate that RL platelets are capable of
      mediating thrombus formation and do not inhibit lysis. Our results help explain
      how RL platelets restore hemostasis in vivo, and indicate that these cells might
      be a viable alternative to fresh stored platelets in transfusion medicine.

PMID- 12475743
TI  - Differential regulation of glomerular arginine transporters (CAT-1 and CAT-2) in
      lipopolysaccharide-treated rats.
AB  - The decrease in glomerular filtration rate (GFR) that is characteristic of sepsis
      has been shown to result from inhibition of glomerular endothelial nitric oxide
      synthase (eNOS) by nitric oxide (NO) generated from the inducible isoform of NOS
      (iNOS). Although l-arginine is the sole precursor for NO biosynthesis, its
      intracellular availability in glomeruli from septic animals has never been
      investigated. Arginine uptake was measured in freshly harvested glomeruli from
      the following experimental groups: 1) untreated rats; 2) rats pretreated with LPS
      (4 mg/kg body wt, 4 h before experiments); 3) rats treated with LPS as above with
      either l-N(6)-(1-iminoethyl)lysine hydrochloride (l-NIL), a selective iNOS
      antagonist, or 7-nitroindazole, a selective neuronal NOS antagonist; and 4) rats
      treated with l-NIL only. Both glomeular and mesangial arginine transport
      characteristics were found compatible with a y(+) system. Arginine uptake was
      augmented in glomeruli from LPS-treated rats. Treatment with l-NIL completely
      abolished this effect whereas l-NIL alone had no effect. Similar results were
      obtained when primary cultures of rat mesangial cells were preincubated with LPS
      (10 microg/ml for 24 h) with or without l-NIL. Using RT-PCR, we found that in
      vivo administration of LPS resulted in a significant increase in glomerular
      cationic amino acid transporter-2 (CAT-2) mRNA expression whereas CAT-1 mRNA was
      undetected. Northern blotting further confirmed a significant increase in
      glomerular CAT-2 by LPS. In mesangial cells, the expression of both CAT-1 and CAT
      2 mRNA was augmented after incubation with LPS. In conclusion, in vivo
      administration of LPS augments glomerular arginine transport through upregulation
      of steady-state CAT-2 mRNA while downregulating CAT-1 mRNA. These results may
      correspond to the changes in glomerular iNOS and eNOS activity in sepsis.

PMID- 12475744
TI  - CFTR null mutation altered cAMP-sensitive and swelling-activated Cl- currents in
      primary cultures of mouse nephron.
AB  - The role of cystic fibrosis transmembrane conductance regulator (CFTR) in the
      control of Cl(-) currents was studied in mouse kidney. Whole cell clamp was used
      to analyze Cl(-) currents in primary cultures of proximal and distal convoluted
      and cortical collecting tubules from wild-type (WT) and cftr knockout (KO) mice.
      In WT mice, forskolin activated a linear Cl(-) current only in distal convoluted
      and cortical collecting tubule cells. This current was not recorded in KO mice.
      In both mice, Ca(2+)-dependent Cl(-) currents were recorded in all segments. In
      WT mice, volume-sensitive Cl(-) currents were implicated in regulatory volume
      decrease during hypotonicity. In KO mice, regulatory volume decrease and swelling
      activated Cl(-) current were impaired but were restored by adenosine perfusion.
      Extracellular ATP also restored swelling-activated Cl(-) currents. The effect of
      ATP or adenosine was blocked by 8-cyclopentyl-1,3-diproxylxanthine. The ecto
      ATPase inhibitor ARL-67156 inhibited the effect of hypotonicity and ATP. Finally,
      in KO mice, volume-sensitive Cl(-) currents are potentially functional, but the
      absence of CFTR precludes their activation by extracellular nucleosides. This
      observation strengthens the hypothesis that CFTR is a modulator of ATP release in
      epithelia.

PMID- 12475745
TI  - CFTR-dependent and -independent swelling-activated K+ currents in primary
      cultures of mouse nephron.
AB  - The role of CFTR in the control of K(+) currents was studied in mouse kidney.
      Whole cell clamp was used to identify K(+) currents on the basis of
      pharmacological sensitivities in primary cultures of proximal (PCT) and distal
      convoluted tubule (DCT) and cortical collecting tubule (CCT) from wild-type (WT)
      and CFTR knockout (KO) mice. In DCT and CCT cells, forskolin activated a 293B
      sensitive K(+) current in WT, but not in KO, mice. In these cells, a hypotonic
      shock induced K(+) currents blocked by charybdotoxin in WT, but not in KO, mice.
      In PCT cells from WT and KO mice, the hypotonicity-induced K(+) currents were
      insensitive to these toxins and were activated at extracellular pH 8.0 and
      inhibited at pH 6.0, suggesting that the corresponding channel was TASK2. In
      conclusion, CFTR is implicated in the control of KCNQ1 and Ca(2+)-sensitive
      swelling-activated K(+) conductances in DCT and CCT, but not in proximal
      convoluted tubule, cells. In KO mice, impairment of the regulatory volume
      decrease process in DCT and CCT could be due to the loss of an autocrine
      mechanism, implicating ATP and adenosine, which controls swelling-activated Cl(-)
      and K(+) channels.

PMID- 12475746
TI  - Arginase inhibition slows the progression of renal failure in rats with renal
      ablation.
AB  - Exogenous arginine slows the progression of chronic renal failure (CRF) in
      remnant rats through a nitric oxide (NO)-dependent mechanism. We tested whether
      the inhibition of arginase could induce similar results through the increased
      availability of endogenous arginine. Three groups of remnant rats were studied
      for 8 wk: 1) untreated rats (REM); 2) remnant rats treated with 1% l-arginine
      (ARG); and 3) remnant rats administered a Mn(2+)-free diet to inhibit arginase
      (MNF). Normal rats (NOR) were used as controls. Liver arginase activity was
      depressed in MNF rats (-35% vs. REM, P < 0.01). No difference in metabolic data
      was detected among the groups throughout the study; blood pressure was
      significantly lower in MNF vs. ARG and REM rats after 6 wk (P < 0.001). The
      glomerular filtration rate (GFR) was greatly depressed in REM rats (-47% vs. NOR,
      P < 0.03) but was higher in ARG and MNF rats (+40 and +43% vs. REM, respectively,
      P < 0.05), with comparable changes in renal hemodynamics. Despite the better GFR,
      proteinuria was decreased in both ARG and MNF rats (-42%, P < 0.05, and -57%, P <
      0.01, respectively, vs. REM rats). Arginine plasma levels, significantly reduced
      in REM rats (-41% vs. NOR, P < 0.01), were partially restored in MNF rats (+38%
      vs. REM), and urinary nitrite excretion, greatly depressed in REM rats (-76% vs.
      NOR, P < 0.01), was significantly increased in MNF rats (+209% vs. REM, P <
      0.05). At the renal level, arginase activity was only slightly depressed in MNF
      rats (-18% vs. REM), but intrarenal concentrations of arginine were lower in this
      latter group (P < 0.05 vs. other groups). Beyond the hemodynamic modifications,
      MNF rats showed a lower glomerular sclerosis index (P < 0.05 vs. REM and ARG).
      Inhibition of arginase slows the progression of CRF in remnant rats similarly to
      arginine-treated rats; the better histological protection in MNF rats, however,
      suggests that additional factors are involved in these modifications.

PMID- 12475747
TI  - Preserved macula densa-dependent renin secretion in A1 adenosine receptor
      knockout mice.
AB  - Recent studies demonstrated that the influence of the macula densa on glomerular
      filtration is abolished in adenosine A(1) receptor (A(1)AR) knockout mice.
      Inasmuch as the macula densa not only regulates glomerular filtration but also
      controls the activity of the renin system, the present study aimed to determine
      the role of the A(1)AR in macula densa control of renin synthesis and secretion.
      Although a high-salt diet over 1 wk suppressed renin mRNA expression and renal
      renin content to similar degrees in A(1)AR(+/+), A(1)AR(+/-), and A(1)AR(-/-)
      mice, stimulation of Ren-1 mRNA expression and renal renin content by salt
      restriction was markedly enhanced in A(1)AR(-/-) compared with wild-type mice.
      Pharmacological blockade of macula densa salt transport with loop diuretics
      stimulated renin expression in vivo (treatment with furosemide at 1.2 mg/day for
      6 days) and renin secretion in isolated perfused mouse kidneys (treatment with
      100 microM bumetanide) in all three genotypes to the same extent. Taken together,
      our data are consistent with the concept of a tonic inhibitory role of the A(1)AR
      in the renin system, whereas they indicate that the A(1)AR is not indispensable
      in macula densa control of the renin system.

PMID- 12475748
TI  - Characterization of cis-acting element in renal NaPi-2 cotransporter mRNA that
      determines mRNA stability.
AB  - Hypophosphatemia leads to an increase in Na(+)-P(i) cotransporter (NaPi-2) mRNA
      levels. This increase is posttranscriptional and correlates with a more stable
      transcript mediated by the terminal 698 nt of the NaPi-2 mRNA. A 71-nt binding
      element was identified with renal proteins from rats fed control and low-P(i) (
      P(i)) diet. The binding of -P(i) renal proteins to this transcript was increased
      compared with control proteins. The functionality of the cis element was
      demonstrated by an in vitro degradation assay. -P(i) renal proteins stabilized
      transcripts that included the cis element compared with control renal extracts.
      The full-length NaPi-2 transcript, but not control transcripts, was stabilized by
      -P(i) extracts. Insertion of the binding element into green fluorescent protein
      (GFP) as a reporter gene decreased chimeric GFP mRNA levels in transfection
      experiments. Our results suggest that the protein-binding region of the NaPi-2
      mRNA functions as a cis-acting instability element. In hypophosphatemia there is
      increased binding to the cis-acting element and subsequent stabilization of NaPi
      2 mRNA.

PMID- 12475749
TI  - CNP gene expression is activated by Wnt signaling and correlates with Wnt4
      expression during renal injury.
AB  - C-type natriuretic peptide (CNP) regulates salt excretion, vascular tone, and
      fibroblast proliferation and activation. CNP inhibits fibroblast activation in
      vitro and fibrosis in vivo, but endogenous CNP gene (Nppc) expression during
      tissue fibrosis has not been reported. We determined that Nppc is induced in
      renal tubular epithelia and then in interstitial myofibroblasts after unilateral
      ureteral obstruction (UUO). Induction of Nppc occurred in identical cell
      populations to those in which Wnt4 is induced after renal injury. In addition,
      Nppc was activated in Wnt4-expressing cells during nephrogenesis. Wnt signaling
      components beta-catenin and T cell factor/lymphoid enhancer binding factor
      (TCF/LEF) specifically bound to cognate elements in the Nppc proximal promoter.
      Wnt-4, beta-catenin, and LEF-1 activated an Nppc transgene in cultured cells, and
      transgene activation by Wnt-4 and LEF-1 was dependent on the presence of intact
      cognate elements. These findings suggest that Wnt-4 stimulates Nppc in a TCF/LEF
      dependent manner after renal injury and thus may contribute to limiting renal
      fibrosis.

PMID- 12475750
TI  - Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2
      diabetes.
AB  - A gut insulinotropic peptide, glucagon-like peptide-1 (GLP-1), when given
      continuously subcutaneously, has been shown to be an effective agent to treat
      type 2 diabetes. Because of inactivation by dipeptidyl peptidase IV (DPP IV), it
      has a very short half-life (90-120 s), hence the need for continuous
      administration. Exendin-4 is an agonist of the GLP-1 receptor. It is not a
      substrate for DPP IV, and we previously demonstrated that intravenous
      administration has potent insulinotropic properties in type 2 diabetic
      volunteers. We evaluated the efficacy of bolus subcutaneous exendin-4 in insulin
      naive type 2 diabetic volunteers. Ten patients aged 44-72 yr with mean fasting
      glucose levels of 11.4 +/- 0.9 mmol/l were enrolled, and daily or twice-daily
      bolus subcutaneous exendin-4 was self-administered for 1 mo. Glycosylated
      hemoglobin, multiple daily capillary blood glucose, beta-cell sensitivity to
      glucose, and peripheral tissue sensitivity to insulin were compared before and
      after treatment. The greatest decline in capillary blood glucose was seen before
      bed, with a drop from 15.5 to 9.2 mmol/l (P < 0.0001). Glycosylated hemoglobin
      improved significantly with treatment, from 9.1 to 8.3% (P = 0.009). beta-Cell
      sensitivity to glucose was improved, as assessed by C-peptide levels during a
      hyperglycemic clamp. No significant adverse effects were noted or reported. Our
      data suggest that, even with this short duration of therapy, exendin-4 treatment
      had a significant effect on glucose homeostasis.

PMID- 12475751
TI  - Creatine supplementation has no effect on human muscle protein turnover at rest
      in the postabsorptive or fed states.
AB  - Dietary creatine supplementation is associated with increases in muscle mass, but
      the mechanism is unknown. We tested the hypothesis that creatine supplementation
      enhanced myofibrillar protein synthesis (MPS) and diminished muscle protein
      breakdown (MPB) in the fed state. Six healthy men (26 +/- 7 yr, body mass index
      22 +/- 4 kg/m(2)) were studied twice, 2-4 wk apart, before and after ingestion of
      creatine (21 g/day, 5 days). We carried out two sets of measurements within 5.5 h
      of both MPS (by incorporation of [1-(13)C]leucine in quadriceps muscle) and MPB
      (as dilution of [1-(13)C]leucine or [(2)H(5)]phenylalanine across the forearm);
      for the first 3 h, the subjects were postabsorptive but thereafter were fed
      orally (0.3 g maltodextrin and 0.083 g protein. kg body wt(-1) x h(-1)). Creatine
      supplementation increased muscle total creatine by approximately 30% (P < 0.01).
      Feeding had significant effects, doubling MPS (P < 0.001) and depressing MPB by
      approximately 40% (P < 0.026), but creatine had no effect on turnover in the
      postabsorptive or fed states. Thus any increase in muscle mass accompanying
      creatine supplementation must be associated with increased physical activity.

PMID- 12475752
TI  - Dual PPARalpha /gamma activation provides enhanced improvement of insulin
      sensitivity and glycemic control in ZDF rats.
AB  - Improvement of insulin sensitivity and lipid and glucose metabolism by
      coactivation of both nuclear peroxisome proliferator-activated receptor
      (PPAR)gamma and PPARalpha potentially provides beneficial effects over existing
      PPARgamma and alpha preferential drugs, respectively, in treatment of type 2
      diabetes. We examined the effects of the dual PPARalpha/gamma agonist
      ragaglitazar on hyperglycemia and whole body insulin sensitivity in early and
      late diabetes stages in Zucker diabetic fatty (ZDF) rats and compared them with
      treatment with the PPARgamma preferential agonist rosiglitazone. Despite
      normalization of hyperglycemia and Hb A(1c) and reduction of plasma triglycerides
      by both compounds in both prevention and early intervention studies, ragaglitazar
      treatment resulted in overall reduced circulating insulin and improved insulin
      sensitivity to a greater extent than after treatment with rosiglitazone. In late
      intervention therapy, ragaglitazar reduced Hb A(1c) by 2.3% compared with 1.1% by
      rosiglitazone. Improvement of insulin sensitivity caused by the dual
      PPARalpha/gamma agonist ragaglitazar seemed to have beneficial impact over that
      of the PPARgamma-preferential activator rosiglitazone on glycemic control in
      frankly diabetic ZDF rats.

PMID- 12475753
TI  - Pathways for glucose disposal after meal ingestion in humans.
AB  - To characterize postprandial glucose disposal more completely, we used the
      tritiated water technique, a triple-isotope approach (intravenous [3-H(3)]glucose
      and [(14)C]bicarbonate and oral [6,6-(2)H(2)]glucose) and indirect calorimetry to
      assess splanchnic and peripheral glucose disposal, direct and indirect glucose
      storage, oxidative and nonoxidative glycolysis, and the glucose entering plasma
      via gluconeogenesis after ingestion of a meal in 11 normal volunteers. During a 6
      h postprandial period, a total of approximately 98 g of glucose were disposed of.
      This was more than the glucose contained in the meal ( approximately 78 g) due to
      persistent endogenous glucose release ( approximately 21 g): splanchnic tissues
      initially took up approximately 23 g, and an additional approximately 75 g were
      removed from the systemic circulation. Direct glucose storage accounted for
      approximately 32 g and glycolysis for approximately 66 g (oxidative approximately
      43 g and nonoxidative approximately 23 g). About 11 g of glucose appeared in
      plasma as a result of gluconeogenesis. If these carbons were wholly from glucose
      undergoing glycolysis, only approximately 12 g would be available for indirect
      pathway glycogen formation. Our results thus indicate that glycolysis is the main
      initial postprandial fate of glucose, accounting for approximately 66% of overall
      disposal; oxidation and storage each account for approximately 45%. The majority
      of glycogen is formed via the direct pathway ( approximately 73%).

PMID- 12475754
TI  - Effect of weight loss on VLDL-triglyceride and apoB-100 kinetics in women with
      abdominal obesity.
AB  - The effects of obesity and weight loss on lipoprotein kinetics were evaluated in
      six lean women [body mass index (BMI): 21 +/- 1 kg/m(2)] and seven women with
      abdominal obesity (BMI: 36 +/- 1 kg/m(2)). Stable isotope tracer techniques, in
      conjunction with compartmental modeling, were used to determine VLDL-triglyceride
      (TG) and apolipoprotein B-100 (apoB-100) secretion rates in lean women and in
      obese women before and after 10% weight loss. VLDL-TG and VLDL-apoB-100 secretion
      rates were similar in lean and obese women. Weight loss decreased the rate of
      VLDL-TG secretion by approximately 40% (from 0.41 +/- 0.05 to 0.23 +/- 0.03
      micromol x kg fat-free mass(-1) x min(-1); P < 0.05). The relative decline in
      VLDL-TG produced from nonsystemic fatty acids, derived from intraperitoneal and
      intrahepatic TG, was greater (61 +/- 7%) than the decline in VLDL-TG produced
      from systemic fatty acids, predominantly derived from subcutaneous TG (25 +/- 8%;
      P < 0.05). Weight loss did not affect VLDL-apoB-100 secretion rate. We conclude
      that weight loss decreases the rate of VLDL-TG secretion in women with abdominal
      obesity, primarily by decreasing the availability of nonsystemic fatty acids.
      There is a dissociation in the effect of weight loss on VLDL-TG and apoB-100
      metabolic pathways that may affect VLDL particle size.

PMID- 12475755
TI  - Interorgan exchange of aminothiols in humans.
AB  - In the present study, we used organ balance across the kidney, splanchnic organs,
      and lower limb in subjects undergoing diagnostic central venous catheterizations
      to gain insight into the renal and extrarenal exchange of aminothiols in humans.
      Although Hcy was released only in low amounts from leg tissues, Cys-Gly (a
      peptide derived from GSH hydrolysis) was released by both the leg and splanchnic
      organs, whereas Cys was released by the kidney and taken up by splanchnic organs.
      The kidney removed approximately 90% of the Cys-Gly released into the
      circulation. Removal of Cys-Gly by the kidney depended on Cys-Gly arterial levels
      and showed a high fractional extraction ( approximately 26%), with clearance
      rates slightly higher than the glomerular filtration rate (GFR). Although the
      average kidney removal of Hcy was not statistically significant, the fractional
      extraction of Hcy across the kidney varied directly with renal plasma flow. Our
      data show that thiol metabolism in humans is a compartmentalized interorgan
      process involving fluxes of individual aminothiols that are parallel and of
      opposite sign among peripheral tissues, splanchnic organs, and kidney. Cys-Gly is
      released by peripheral tissue and splanchnic organs from GSH hydrolysis and is
      taken up by the kidney by GFR; the kidney returns Cys to the circulation to
      preserve substrate availability for GSH synthesis. On the other hand, Hcy is
      released by peripheral tissues in low amounts, and its removal by the kidney
      seems to depend on blood supply. These findings may help explain several
      alterations in aminothiol metabolism observed in patients with chronic diseases.

PMID- 12475756
TI  - VLDL-triglyceride kinetics during hyperglycemia-hyperinsulinemia: effects of sex
      and obesity.
AB  - We have previously shown that sex and obesity independently affect basal very low
      density lipoprotein (VLDL)-triglyceride (TG) kinetics. In the present study, we
      investigated the effect of hyperglycemia-hyperinsulinemia on VLDL-TG kinetics in
      lean and obese men and women (n = 6 in each group). VLDL-TG kinetics were
      measured during basal, postabsorptive conditions and during glucose infusion (5.5
      mg x kg FFM(-1) x min(-1)) by using [(2)H(5)]glycerol bolus injection in
      conjunction with compartmental modeling analysis. Basal VLDL-TG secretion in
      plasma was greater in obese than in lean men (7.8 +/- 0.6 and 2.9 +/- 0.4
      micromol x l plasma(-1) x min(-1); P < 0.001) but was not different in lean and
      obese women (5.0 +/- 1.1 and 5.9 +/- 1.1 micromol x l plasma(-1) x min(-1)).
      Glucose infusion decreased the VLDL-TG secretion rate by approximately 50% in
      lean and obese men and in lean women (to 1.5 +/- 0.4, 4.0 +/- 0.6, and 2.2 +/-
      0.4 micromol x l plasma(-1) x min(-1), respectively; all P < 0.05) but had no
      effect on the VLDL-TG secretion rate in obese women (4.9 +/- 1.0 micromol x l
      plasma(-1) x min(-1)). These results demonstrate that both sex and adiposity
      affect the regulation of VLDL-TG metabolism. Glucose and insulin decrease VLDL-TG
      production in both lean men and lean women; obesity is associated with resistance
      to the glucose- and insulin-mediated suppression of VLDL-TG secretion in women,
      but not in men.

PMID- 12475757
TI  - Thyroid status, but not insulin status, affects expression of avian uncoupling
      protein mRNA in chicken.
AB  - The aim of this study was to investigate the hormonal regulation of the avian
      homolog of mammalian uncoupling protein (avUCP) by studying the impact of thyroid
      hormones and insulin on avUCP mRNA expression in chickens (Gallus gallus). For 3
      wk, chicks received either a standard diet (control group), or a standard diet
      supplemented with triiodothyronine (T(3); T3 group) or with the thyroid gland
      inhibitor methimazole (MMI group). A fourth group received injections of the
      deiodinase inhibitor iopanoic acid (IOP group). During the 4th wk of age, all
      animals received two daily injections of either human insulin or saline solution.
      The results indicate a twofold overexpression of avUCP mRNA in gastrocnemius
      muscle of T3 birds and a clear downregulation (-74%) in MMI chickens compared
      with control chickens. Insulin injections had no significant effect on avUCP mRNA
      expression in chickens. This study describes for the first time induction of
      avUCP mRNA expression by the thermogenic hormone T(3) in chickens and supports a
      possible involvement of avUCP in avian thermogenesis.

PMID- 12475759
TI  - Role of airway surface liquid and submucosal glands in cystic fibrosis lung
      disease.
AB  - Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance
      regulator (CFTR) protein, an epithelial chloride channel expressed in the
      airways, pancreas, testis, and other tissues. A central question is how defective
      CFTR function in CF leads to chronic lung infection and deterioration of lung
      function. Several mechanisms have been proposed to explain lung disease in CF,
      including abnormal airway surface liquid (ASL) properties, defective airway
      submucosal gland function, altered inflammatory response, defective organellar
      acidification, loss of CFTR regulation of plasma membrane ion transporters, and
      others. This review focuses on the physiology of the ASL and submucosal glands
      with regard to their proposed role in CF lung disease. Experimental evidence for
      defective ASL properties and gland function in CF is reviewed, and deficiencies
      in understanding ASL/gland physiology are identified as areas for further
      investigation. New model systems and measurement technologies are being developed
      to make progress in establishing lung disease mechanisms in CF, which should
      facilitate mechanism-based design of therapies for CF.

PMID- 12475760
TI  - Cytoskeletal modulation of sodium current in human jejunal circular smooth muscle
      cells.
AB  - A Na(+) current is present in human jejunal circular smooth muscle cells. The aim
      of the present study was to determine the role of the cytoskeleton in the
      regulation of the Na(+) current. Whole cell currents were recorded by using
      standard patch-clamp techniques with Cs(+) in the pipette to block K(+) currents.
      Cytochalasin D and gelsolin were used to disrupt the actin cytoskeleton and
      phalloidin to stabilize it. Colchicine was used to disassemble the microtubule
      cytoskeleton (and intermediate filaments) and paclitaxel to stabilize it.
      Acrylamide was used to disrupt the intermediate filament cytoskeleton. Perfusion
      of the recording chamber at 10 ml/min increased peak Na(+) current recorded from
      jejunal smooth muscle cells by 27 +/- 3%. Cytochalasin D and gelsolin abolished
      the perfusion-induced increase in Na(+) current, whereas incubation with
      phalloidin, colchicine, paclitaxel, or acrylamide had no effect. In conclusion,
      the Na(+) current expressed in human jejunal circular smooth muscle cells appears
      to be regulated by the cytoskeleton. An intact actin cytoskeleton is required for
      perfusion-induced activation of the Na(+) current.

PMID- 12475762
TI  - Inhibition of interferon-gamma expression by osmotic shrinkage of peripheral
      blood lymphocytes.
AB  - A hypertonic environment, as it prevails in renal medulla or in hyperosmolar
      states such as hyperglycemia of diabetes mellitus, has been shown to impair the
      immune response, thus facilitating the development of infection. The present
      experiments were performed to test whether hypertonicity influences activation of
      T lymphocytes. To this end, peripheral blood lymphocytes (PBL) of cytomegalovirus
      (CMV)-positive donors were stimulated by human leukocyte antigen (HLA)-A2
      restricted CMV epitope NLVPMVATV to produce interferon (IFN)-gamma at varying
      extracellular osmolarity. As a result, increasing extracellular osmolarity during
      exposure to the CMV antigen indeed decreased IFN-gamma formation. Addition of
      NaCl was more effective than urea. A 50% inhibition was observed at 350 mosM by
      addition of NaCl. The combined application of the Ca(2+) ionophore ionomycin (1
      microg/ml) and the phorbol ester phorbol 12-myristate 13-acetate (PMA; 5
      microg/ml) stimulated IFN-gamma production, an effect again reversed by
      hyperosmolarity. Moreover, hyperosmolarity abrogated the stimulating effect of
      ionomycin (1 microg/ml) and PMA (5 microg/ml) on the transcription factors
      activator protein (AP)-1, nuclear factor of activated T cells (NFAT), and NF
      kappaB but not Sp1. In conclusion, osmotic cell shrinkage blunts the stimulatory
      action of antigen exposure on IFN-gamma production, an effect explained at least
      partially by suppression of transcription factor activation.

PMID- 12475761
TI  - PDGF upregulates delayed rectifier via Src family kinases and sphingosine kinase
      in oligodendroglial progenitors.
AB  - An increase in the expression of the delayed rectifier current (I(K)) has been
      shown to correlate with mitogenesis in many cell types. However, pathways
      involved in the upregulation of I(K) by growth factors in oligodendroglial
      progenitors (OPs) have not been well-elucidated. In this study, we found that
      treatment with platelet-derived growth factor (PDGF) and basic fibroblast growth
      factor but not ciliary neurotrophic factor resulted in increased I(K) density and
      upregulation of Kv1.5 and Kv1.6 mRNA transcripts. The effect of PDGF on I(K) was
      blocked by mimosine, a cell cycle inhibitor, and by genistein, a tyrosine kinase
      inhibitor. Using inhibitors of PDGF-activated pathways, we found that PDGF
      induced upregulation of Kv1.5 and I(K) density involves Src family tyrosine
      kinases, sphingosine kinase, and intracellular Ca(2+) but not ERK1/2 or
      phosphatidylinositol 3-kinase pathways. Furthermore, agents that were effective
      inhibitors of PDGF-induced I(K) upregulation also attenuated OP proliferation,
      supporting the concept that I(K) is an important link between PDGF-activated
      signaling cascades and cell cycle progression.

PMID- 12475763
TI  - Detection of ClC-3 and ClC-5 in epididymal epithelium: immunofluorescence and RT
      PCR after LCM.
AB  - Epithelial cells of the epididymis and vas deferens establish an optimum luminal
      environment in which spermatozoa mature and are stored. This is achieved by
      active transepithelial transport of various ions including Cl(-) and H(+). We
      investigated the localization of three closely related members of the ClC family,
      ClC-3, ClC-4, and ClC-5, in the epididymis and vas deferens. RT-PCR using mRNA
      isolated by laser capture microdissection (LCM)-detected ClC-3 and ClC-5
      transcripts but did not detect any ClC-4-specific transcript. Western blot and
      immunofluorescence analysis demonstrated that ClC-3 and ClC-5 proteins are
      present in all regions of the epididymis and in the vas deferens. ClC-5 is
      expressed exclusively in H(+)-ATPase-rich cells (narrow and clear cells).
      Confocal microscopy showed that ClC-5 partially colocalizes with the H(+)-ATPase
      in the subapical pole of clear cells. ClC-3 is strongly expressed in the apical
      membrane of principal cells of the caput epididymidis and the vas deferens and is
      less abundant in principal cells of the body and cauda epididymidis. These
      findings are consistent with a potential role for ClC-3 in transepithelial
      chloride transport by principal cells and for ClC-5 in the acidification of H(+)
      ATPase-containing vesicles in narrow and clear cells. ClC-5 might facilitate
      endosome trafficking in the epididymis, as has been proposed in the kidney.

PMID- 12475764
TI  - Regulation of insulin production: in search of therapeutic targets. Proceedings
      of the 3rd Servier-IGIS Symposium. St Jean Cap Ferrrat, France, 21-24 March 2002.

PMID- 12475765
TI  - Challenges and strategies for investigating the genetic complexity of common
      human diseases.
AB  - There is substantial interest in the identification of genes underlying
      susceptibility to complex human diseases because of the potential utility of such
      genes in disease prediction or therapy. Type 1 diabetes is an example of one such
      disorder and is presumed to arise from the effect of multiple genes and
      environmental factors. One identified locus has a major effect on type 1 diabetes
      susceptibility (IDDM1), whereas other loci have significant, yet small,
      individual effects (IDDM2, IDDM15). It is unclear whether susceptibility for type
      1 diabetes arises because of the effects of loci acting independently or whether
      there are important interactions between loci. Although genetic tools are
      continuing to be developed to enable examination of candidate regions, the means
      to identify and narrow "true" susceptibility regions continues to be limited by
      the lack of statistical power resulting from inadequately sized collections of
      families. This report provides an evaluation of the approaches for identification
      of regions harboring type 1 diabetes genes, methods to identify the gene regions
      that interact to define the risk for type 1 diabetes, and efforts to fine-map the
      variants responsible.

PMID- 12475766
TI  - Genetics of obesity and type 2 diabetes: tracking pathogenic traits during the
      predisease period.
AB  - The modern generalization of sedentary life and caloric abundance has created new
      physiological conditions capable of changing the level of expression of a number
      of genes involved in fuel metabolism and body weight regulation. It is likely
      that the genetic variants or alleles of these genes have in the past participated
      in the adaptation of human physiology to its evolutionary constraints. The nature
      and prevalence of polymorphisms responsible for the quantitative variation of
      complex metabolic traits may have been different among human populations,
      depending on their environment and ancestral genetic background. These
      polymorphisms could likely explain differences in disease susceptibility and
      prevalence among groups of humans. From complex traits to potentially complex
      alleles, understanding the molecular genetic basis underlying quantitative
      variation will continue to be a growing concern among geneticists dealing with
      obesity and type 2 diabetes, the main fuel disorders of the modern era. Genomics
      and genetic epidemiology now allow high-level linkage and association studies to
      be designed. But the pooling of large trans-geographic cohorts may in fact
      increase the genetic heterogeneity of studied traits and dilute genotype
      phenotype associations. In this article, we underscore the importance of
      selecting the traits to be subjected to quantitative genetic analysis. Although
      this is not possible for most other multifactorial diseases, obesity and type 2
      diabetes can be subjected to a pregenetic dissection of complexity into simpler
      quantitative traits (QTs). This dissection is based on the pathogenic mechanisms,
      and the time course of the traits, and the individuals' age, within the
      predisease period rather than on descriptive parameters after disease diagnosis.
      We defend that this approach of phenotypes may ease future associations to be
      established between QTs of intermediate complexity and genetic polymorphisms.

PMID- 12475767
TI  - Increased insulin resistance in obese children who have both 972 IRS-1 and 1057
      IRS-2 polymorphisms.
AB  - In two cohorts of 174 and 165 obese Caucasian children, we measured insulin
      sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for
      the Arg972Gly and the Asp1057Gly variants, respectively. Because IRS-1 and IRS-2
      have complementary roles in insulin signaling, we classified the genotypes in
      three categories: those with none of the variants in IRS-1 or IRS-2, those with
      one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2
      proteins. The obese children with either the IRS-1 or IRS-2 variant had a mean
      insulin sensitivity index (2.9 +/- 0.2 in cohort 1, 2.7 +/- 0.1 in cohort 2) only
      slightly lower than the children having no variant in either gene (3.1 +/- 0.2
      and 3.5 +/- 0.3, respectively). However, patients having variant alleles in both
      IRS-1 and IRS-2 genes showed a 25-35% decrease in sensitivity (2.3 +/- 0.2 and
      2.0 +/- 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001).
      These observations are reminiscent of the insulin sensitivity phenotypes in
      double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. Our results stress the
      need for combined genotype analysis when candidate genes are functionally
      involved in the same pathway.

PMID- 12475768
TI  - Searching for type 2 diabetes genes on chromosome 20.
AB  - Genome scans in families with type 2 diabetes identified a putative locus on
      chromosome 20q. For this study, linkage disequilibrium mapping was used in an
      effort to narrow a 7.3-Mb region in an Ashkenazi type 2 diabetic population. The
      region encompassed a 1-logarithm of odds (LOD) interval around the microsatellite
      marker D20S107, which gave a LOD score of >3 in linkage analysis of a combined
      Caucasian population. This 7.3-Mb region contained 25 known and 99 predicted
      genes. Predicted single nucleotide polymorphisms (SNPs) were chosen from public
      databases and validated. Two SNPs were unique to the Ashkenazi. Here, 91 SNPs
      with a minor allele frequency of >or=10% were genotyped in pooled DNA from 150
      case subjects and 150 control subjects of Ashkenazi Jewish descent. The SNP
      association study showed that SNP rs2664537 in the TIX1 gene had a significant P
      value of 0.035, but the finding did not replicate in an additional case pool. In
      addition, HNF4a and Mybl2 were screened for mutations and new polymorphisms. No
      mutations were identified, and a new nonsynonymous SNP (R687C in exon 14 of
      Mybl2) was found. The limits to this type of association study are discussed.

PMID- 12475769
TI  - Evidence for a novel type 1 diabetes susceptibility locus on chromosome 8.
AB  - Type 1 diabetes results from a combination of genetic susceptibility and
      environmental exposures. Susceptibility loci other than HLA and the insulin gene
      remain to be identified to account for the degree of familial clustering observed
      in this disorder. Early genome-wide scans provided suggestive evidence of linkage
      on chromosome 8q, prompting detailed analysis of this region. A total of 20
      microsatellite markers spanning an 88-cM region of 8q11-24 were genotyped in 24
      type 1 diabetes pedigrees from Wisconsin that contained 39 affected sib-pairs.
      Multipoint linkage analyses provided close to suggestive evidence of linkage,
      with a multipoint logarithm of odds score (MLS) of 2.4 and Genehunter
      nonparametric logarithm of odds score (NPL) of 2.7 (P = 0.003). There is also
      evidence of linkage disequilibrium at peak marker D8S1823 for the 217bp allele (P
      = 0.037) using the pedigree disequilibrium test. Although our sample size was
      small, the multiple tests were consistent and our preliminary results suggested
      that 8q24 may harbor a novel population-specific type 1 diabetes susceptibility
      gene. Continued investigation of this region for a novel type 1 diabetes
      susceptibility gene appears justified.

PMID- 12475770
TI  - Regulation of pdx-1 gene expression.
AB  - The homeodomain-containing transcription factor pancreatic duodenal homeobox 1
      (PDX-1) plays a key role in pancreas development and in beta-cell function.
      Upstream sequences of the gene up to about -6 kb show islet-specific activity in
      transgenic mice. Attempts to identify functional regulatory elements involved in
      the controlled expression of the pdx-1 gene led to the identification of distinct
      distal beta-cell-specific enhancers in human and rat genes. Three additional
      sequences, conserved between the mouse and the human 5'-flanking regions, two of
      which are also found in the chicken gene, conferred beta-cell-specific expression
      on a reporter gene, albeit to different extents. A number of transcription
      factors binding to and modulating the transcriptional activity of the regulatory
      elements were identified, such as hepatocyte nuclear factor (HNF)-3beta, HNF
      1alpha, SP1/3, and, interestingly, PDX-1 itself. A fourth conserved region was
      localized to the proximal promoter around an E-box motif and was found to bind
      members of the upstream stimulatory factor (USF) family of transcription factors.
      We postulate that disruption of pdx-1 cis-acting regulatory sequences and/or
      mutations or functional impairment of transcription factors controlling the
      expression of the gene can lead to diabetes.

PMID- 12475771
TI  - Glucose-regulated gene expression maintaining the glucose-responsive state of
      beta-cells.
AB  - The mammalian beta-cell has particular properties that synthesize, store, and
      secrete insulin in quantities that are matched to the physiological demands of
      the organism. To achieve this task, beta-cells are regulated both acutely and
      chronically by the extracellular glucose concentration. Several in vivo and in
      vitro studies indicate that preservation of the glucose-responsive state of beta
      cells is lost when the extracellular glucose concentration chronically deviates
      from the normal physiological condition. Experiments with the protein synthesis
      inhibitor cycloheximide suggest that the maintenance of the functional state of
      beta-cells depends on protein(s) with rapid turnover. Analysis of newly
      synthesized proteins via two-dimensional gel electrophoresis and high-density
      gene expression microarrays demonstrates that the glucose-dependent preservation
      of beta-cell function is correlated with glucose regulation of a large number of
      beta-cell genes. Two different microarray analyses of glucose regulation of the
      mRNA profile in beta-cells show that the sugar influences expression of multiple
      genes involved in energy metabolism, the regulated insulin biosynthetic/secretory
      pathway, membrane transport, intracellular signaling, gene transcription, and
      protein synthesis/degradation. Functional analysis of some of these regulated
      gene clusters has provided new evidence for the concept that cataplerosis, the
      conversion of mitochondrial metabolites into lipid intermediates, is a major
      metabolic pathway that allows beta-cell activation independently of closure of
      ATP-sensitive potassium channels.

PMID- 12475772
TI  - Experimental models of transcription factor-associated maturity-onset diabetes of
      the young.
AB  - Six monogenic forms of maturity-onset diabetes of the young (MODY) have been
      identified to date. Except for MODY2 (glucokinase), all other MODY subtypes have
      been linked to transcription factors. We have established a MODY3 transgenic
      model through the beta-cell-targeted expression of dominant-negative HNF-1alpha
      either constitutively (rat insulin II promoter) or conditionally (Tet-On system).
      The animals display either overt diabetes or glucose intolerance. Decreased
      insulin secretion and reduced pancreatic insulin content contribute to the
      hyperglycemic state. The conditional approach in INS-1 cells helped to define new
      molecular targets of hepatocyte nuclear factor (HNF)-1alpha. In the cellular
      system, nutrient-induced insulin secretion was abolished because of impaired
      glucose metabolism. Conditional suppression of HNF-4alpha, the MODY1 gene, showed
      a similar phenotype in INS-1 cells to HNF-1alpha. The existence of a regulatory
      circuit between HNF-4alpha and HNF-1alpha is confirmed in these cell models. The
      MODY4 gene, IPF-1 (insulin promoter factor-1)/PDX-1 (pancreas duodenum homeobox
      1), controls not only the transcription of insulin but also expression of enzymes
      involved in its processing. Suppression of Pdx-1 function in INS-1 cells does not
      alter glucose metabolism but rather inhibits insulin release by impairing steps
      distal to the generation of mitochondrial coupling factors. The presented
      experimental models are important tools for the elucidation of the beta-cell
      pathogenesis in MODY syndromes.

PMID- 12475773
TI  - Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1alpha
      deficient mice: a mechanism for hypersensitivity to sulfonylurea therapy in
      patients with maturity-onset diabetes of the young, type 3 (MODY3).
AB  - Diabetes in subjects with hepatocyte nuclear factor (HNF)-1alpha gene mutations
      (maturity-onset diabetes of the young [MODY]-3) is characterized by impaired
      insulin secretion. Surprisingly, MODY3 patients exhibit hypersensitivity to the
      hypoglycemic actions of sulfonylurea therapy. To study the pharmacogenetic
      mechanism(s), we have investigated glibenclamide-induced insulin secretion,
      glibenclamide clearance from the blood, and glibenclamide metabolism in wild-type
      and Hnf-1alpha-deficient mice. We show that despite a profound defect in glucose
      stimulated insulin secretion, diabetic Hnf-1alpha(-/-) mice have a robust
      glibenclamide-induced insulin secretory response. We demonstrate that the half
      life (t(1/2)) of glibenclamide in the blood is increased in Hnf-1alpha(-/-) mice
      compared with wild-type littermates (3.9 +/- 1.3 vs. 1.5 +/- 1.8 min, P <or=
      0.05). The clearance of glibenclamide from the blood during the first hours after
      intravenous administration was reduced approximately fourfold in Hnf-1alpha(-/-)
      mice compared with Hnf-1alpha(+/+) littermates. Glibenclamide uptake into
      hepatocytes was dramatically decreased in vivo and in vitro. To study the
      metabolism of glibenclamide in Hnf-1alpha(-/-) animals, we analyzed liver
      extracts from [(3)H]glibenclamide-injected animals by reverse-phase
      chromatography. We found that the ratio of the concentrations of glibenclamide
      and its metabolites was moderately increased in livers of Hnf-1alpha(-/-) mice,
      suggesting that hepatic glibenclamide metabolism was not impaired in animals with
      Hnf-1alpha deficiency. Our data demonstrate that high serum glibenclamide
      concentrations and an increased t(1/2) of glibenclamide in the blood of Hnf
      1alpha(-/-) mice are caused by a defect in hepatic uptake of glibenclamide. This
      suggests that hypersensitivity to sulfonylureas in MODY3 patients may be due to
      impaired hepatic clearance and elevated plasma concentrations of the drug.

PMID- 12475774
TI  - Regulation of intracellular Ca2+ stores by multiple Ca2+-releasing messengers.
AB  - Although glucose-elicited insulin secretion depends on Ca(2+) entry through
      voltage-gated Ca(2+) channels in the surface cell membrane of the pancreatic beta
      cell, there is also ample evidence for an important role of intracellular Ca(2+)
      stores, particularly in relation to hormone- or neurotransmitter-induced insulin
      secretion. There is now direct evidence for Ca(2+) entry-induced release of
      Ca(2+) from the endoplasmic reticulum in neurons, but with regard to glucose
      stimulation of beta-cells, there is conflicting evidence about the operation of
      such a process. This finding suggests that the sensitivity of the Ca(2+) release
      channels in the endoplasmic reticulum membrane varies under different conditions
      and therefore is regulated. Recent evidence from studies of pancreatic acinar
      cells has revealed combinatorial roles of multiple messengers in setting the
      sensitivity of the endoplasmic reticulum for Ca(2+) release. Here we focus on the
      possible combinatorial roles of inositol 1,4,5-trisphosphate, cyclic ADP-ribose,
      and nicotinic acid adenine dinucleotide phosphate in beta-cell function.

PMID- 12475775
TI  - Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2
      diabetes.
AB  - Type 2 diabetes is generally perceived as a polygenic disorder, with disease
      development being influenced by both hereditary and environmental factors.
      However, despite intensive investigations, little progress has been made in
      identifying the genes that impart susceptibility to the common late-onset forms
      of the disease. E23K, a common single nucleotide polymorphism in K(IR)6.2, the
      pore-forming subunit of pancreatic beta-cell ATP-sensitive K(+) (K(ATP))
      channels, significantly enhances the spontaneous open probability of these
      channels, and thus modulates sensitivities toward inhibitory and activatory
      adenine nucleotides. Based on previous association studies, we present evidence
      that with an estimated attributable proportion of 15% in Caucasians, E23K in
      K(IR)6.2 appears to be the most important genetic risk factor for type 2 diabetes
      yet identified.

PMID- 12475776
TI  - The common single nucleotide polymorphism E23K in K(IR)6.2 sensitizes pancreatic
      beta-cell ATP-sensitive potassium channels toward activation through nucleoside
      diphosphates.
AB  - E23K, a common polymorphism in the pore-forming subunit K(IR)6.2 of pancreatic
      beta-cell ATP-sensitive K(+) (K(ATP)) channels, is functionally relevant and thus
      might play a major role in the pathophysiology of common type 2 diabetes. In this
      study, we show that in the simultaneous presence of activatory and inhibitory
      nucleotides, the polymorphism exerts opposite effects on the potencies of these
      modulators: channel opening through nucleoside diphosphates is facilitated,
      whereas sensitivity toward inhibition through ATP is slightly decreased. The
      results support the conclusion that E23K predisposes to type 2 diabetes by
      changing the channel's response to physiological variation of cytosolic
      nucleotides, resulting in K(ATP) overactivity and discrete inhibition of insulin
      release.

PMID- 12475777
TI  - Sulfonylurea stimulation of insulin secretion.
AB  - Sulfonylureas are widely used to treat type 2 diabetes because they stimulate
      insulin secretion from pancreatic beta-cells. They primarily act by binding to
      the SUR subunit of the ATP-sensitive potassium (K(ATP)) channel and inducing
      channel closure. However, the channel is still able to open to a limited extent
      when the drug is bound, so that high-affinity sulfonylurea inhibition is not
      complete, even at saturating drug concentrations. K(ATP) channels are also found
      in cardiac, skeletal, and smooth muscle, but in these tissues are composed of
      different SUR subunits that confer different drug sensitivities. Thus tolbutamide
      and gliclazide block channels containing SUR1 (beta-cell type), but not SUR2
      (cardiac, smooth muscle types), whereas glibenclamide, glimepiride, repaglinide,
      and meglitinide block both types of channels. This difference has been exploited
      to determine residues contributing to the sulfonylurea-binding site. Sulfonylurea
      block is decreased by mutations or agents (e.g., phosphatidylinositol
      bisphosphate) that increase K(ATP) channel open probability. We now propose a
      kinetic model that explains this effect in terms of changes in the channel open
      probability and in the transduction between the drug-binding site and the channel
      gate. We also clarify the mechanism by which MgADP produces an apparent increase
      of sulfonylurea efficacy on channels containing SUR1 (but not SUR2).

PMID- 12475778
TI  - Interaction of the cytosolic domains of the Kir6.2 subunit of the K(ATP) channel
      is modulated by sulfonylureas.
AB  - The NH(2)- and COOH-termini of the ATP-sensitive potassium (K(ATP)) channel pore
      forming subunit, Kir6.2, both lie intracellularly and interact with one another.
      To study this interaction, cyan fluorescent protein (CFP) and yellow fluorescent
      protein (YFP) were fused to the NH(2)- and COOH-termini of Kir6.2, respectively
      (CFP-Kir6.2-YFP). These fluorescent proteins have sufficient spectral overlap to
      allow distance-dependent fluorescence resonance energy transfer (FRET). When CFP
      Kir6.2-YFP was expressed in human embryonic kidney cells and illuminated at 440
      nm to excite CFP, significant fluorescence was recorded at 535 nm, the peak of
      the YFP emission spectrum. This indicated that FRET was occurring and thus that
      the NH(2)- and COOH-termini of Kir6.2 lie in close proximity to one another. The
      emission ratio, F(535)/F(480), was increased by co-expression of SUR2A, but not
      SUR1, suggesting that SUR2A but not SUR1 influences the Kir6.2 NH(2)- and COOH
      terminal interaction. This interaction was reduced by the sulfonylureas
      tolbutamide and gliclazide, but not by the pore blocker barium. The properties of
      the tolbutamide response indicate that the drug disrupts the interaction between
      the NH(2)- and COOH-termini of Kir6.2 by binding to a low-affinity site on
      Kir6.2.

PMID- 12475779
TI  - Gliclazide directly inhibits arginine-induced glucagon release.
AB  - Arginine-stimulated insulin and somatostatin release is enhanced by the
      sulfonylurea gliclazide. In contrast, gliclazide inhibits the glucagon response.
      The aim of the present study was to investigate whether this inhibition of
      glucagon release was mediated by a direct suppressive effect of gliclazide or was
      secondary to the paracrine effect of released somatostatin. To eliminate the
      paracrine effects of somatostatin, we first perfused isolated rat pancreata with
      a medium supplemented with 23% of the standard calcium content. Second, we
      perifused isolated rat islets with a novel and highly specific antagonist of type
      2 somatostatin receptor, DC-41-33 (2 micro mol/l), which fully antagonizes the
      suppressive somatostatin effect on rat A cells. Gliclazide (30 micro mol/l)
      inhibited glucagon release by 54% in the perfusion experiments, whereas the
      somatostatin response was nearly abolished. In islet perifusions with DC-41-33,
      arginine-induced glucagon release was inhibited by 66%. We therefore concluded
      that gliclazide inhibits glucagon release by a direct action on the pancreatic A
      cell.

PMID- 12475780
TI  - Intracellular targeting of protein kinases and phosphatases.
AB  - Compartmentalization of kinases and phosphatases is a key determinant in the
      specificity of second messenger-mediated signaling events. Localization of the
      cAMP-dependent protein kinase (PKA) and other signaling enzymes is mediated by
      interaction with A-kinase anchoring proteins (AKAPs). This study focused on
      recent advances that further our understanding of AKAPs, with particular emphasis
      on the bidirectional regulation of signaling events by AKAP signaling complexes
      and their contribution to the control of actin reorganization events.

PMID- 12475781
TI  - Stimulus/secretion coupling factors in glucose-stimulated insulin secretion:
      insights gained from a multidisciplinary approach.
AB  - There is a growing appreciation for the complexity of the pathways involved in
      glucose-stimulated insulin secretion (GSIS) from pancreatic islet beta-cells. In
      our laboratory, this has stimulated the development of an interdisciplinary
      approach to the problem. In this study, we review recent studies combining the
      tools of recombinant adenovirus for gene delivery, the development of novel cell
      lines that exhibit either robust or weak GSIS, and nuclear magnetic resonance
      imaging for metabolic fingerprinting of glucose-stimulated cells. Using these
      tools, we demonstrate a potentially important role for pyruvate carboxylase
      mediated pyruvate cycling pathways in the control of GSIS, and discuss potential
      coupling factors produced by such pathways.

PMID- 12475782
TI  - Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics.
AB  - Glucokinase (GK) serves as glucose sensor in pancreatic beta-cells and in other
      glucose sensor cells in the body. Biochemical genetic studies have characterized
      many activating and inactivating GK mutants that have been discovered in patients
      with hyperinsulinemic hypoglycemia or diabetes, all inherited as autosomal
      dominant traits. Mathematical modeling of the kinetic data of recombinant human
      wild-type and mutant GK accurately predicts the effects of GK mutations on the
      threshold of glucose-stimulated insulin release and glucose homeostasis.
      Structure/function studies of the enzyme suggest the existence of a hitherto
      unknown allosteric activator site of the enzyme that has significant implications
      for the physiological chemistry of GK-containing cells, particularly the
      pancreatic beta-cells. Glucose is the preeminent positive regulator of beta-cell
      GK expression and involves molecular mechanisms that are still to be elucidated
      in detail, but seem to have a specific requirement for increased glucose
      metabolism. Pharmaceutical chemists, motivated by the clear tenets of the GK
      glucose-sensor paradigm, have searched for and have discovered a novel class of
      GK activator molecules. The therapeutic application of this basic discovery
      offers a new principle for drug therapy of diabetes.

PMID- 12475783
TI  - Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta
      cell adaptation and failure in the etiology of diabetes.
AB  - Beta-cells possess inherent mechanisms to adapt to overnutrition and the
      prevailing concentrations of glucose, fatty acids, and other fuels to maintain
      glucose homeostasis. However, this is balanced by potentially harmful actions of
      the same nutrients. Both glucose and fatty acids may cause good/adaptive or
      evil/toxic actions on the beta-cell, depending on their concentrations and the
      time during which they are elevated. Chronic high glucose dramatically influences
      beta-cell lipid metabolism via substrate availability, changes in the activity
      and expression of enzymes of glucose and lipid metabolism, and modifications in
      the expression level of key transcription factors. We discuss here the emerging
      view that beta-cell "glucotoxicity" is in part indirectly caused by
      "lipotoxicity," and that beta-cell abnormalities will become particularly
      apparent when both glucose and circulating fatty acids are high. We support the
      concept that elevated glucose and fatty acids synergize in causing toxicity in
      islets and other organs, a process that may be instrumental in the pleiotropic
      defects associated with the metabolic syndrome and type 1 and type 2 diabetes.
      The mechanisms by which hyperglycemia and hyperlipidemia alter insulin secretion
      are discussed and a model of beta-cell "glucolipotoxicity" that implicates
      alterations in beta-cell malonyl-CoA concentrations; peroxisome proliferator
      activated receptor-alpha and -gamma and sterol regulatory element binding protein
      1c expression; and lipid partitioning is proposed.

PMID- 12475784
TI  - Genetic manipulations of fatty acid metabolism in beta-cells are associated with
      dysregulated insulin secretion.
AB  - Triacylglyceride (TG) accumulation in pancreatic beta-cells is associated with
      impaired insulin secretion, which is called lipotoxicity. To gain a better
      understanding of the pathophysiology of lipotoxicity, we generated three models
      of dysregulated fatty acid metabolism in beta-cells. The overexpression of sterol
      regulatory element binding protein-1c induced lipogenic genes and TG
      accumulation. Under these conditions, we observed a decrease in glucose oxidation
      and upregulation of uncoupling protein-2, which might be causally related to the
      decreased glucose-stimulated insulin secretion. The overexpression of AMP
      activated protein kinase was accompanied by decreased lipogenesis, increased
      fatty acid oxidation, and decreased glucose oxidation; insulin secretions to
      glucose and depolarization stimuli were decreased, probably because of the
      decrease in glucose oxidation and cellular insulin content. It was notable that
      the secretory response to palmitate was blunted, which would suggest a role of
      the fatty acid synthesis pathway, but not its oxidative pathway in palmitate
      stimulated insulin secretion. Finally, we studied islets of PPAR-gamma(+/-) mice
      that had increased insulin sensitivity and low TG content in white adipose
      tissue, skeletal muscle, and liver. On a high-fat diet, glucose-stimulated
      insulin secretion was decreased in association with increased TG content in the
      islets, which might be mediated through the elevated serum free fatty acid levels
      and their passive transport into beta-cells. These results revealed some aspects
      about the mechanisms by which alterations of fatty acid metabolism affect beta
      cell functions.

PMID- 12475785
TI  - Glutaminolysis and insulin secretion: from bedside to bench and back.
AB  - Identification of regulatory mutations of glutamate dehydrogenase (GDH) in a form
      of congenital hyperinsulinism (GDH-HI) is providing a model for basal insulin
      secretion (IS) and amino acid (AA)-stimulated insulin secretion (AASIS) in which
      glutaminolysis plays a key role. Leucine and ADP are activators and GTP is an
      inhibitor of GDH. GDH-HI mutations impair GDH sensitivity to GTP inhibition,
      leading to fasting hypoglycemia, leucine hypersensitivity, and protein-induced
      hypoglycemia, indicating the importance of GDH in basal secretion and AASIS. The
      proposed model for glutaminolysis in IS is based on GDH providing NADH and alpha
      ketoglutarate (alpha-KG) to the Krebs cycle, hence increasing the beta-cell ATP
      to-ADP ratio to effect insulin release. The process operates with 1) sufficient
      lowering of beta-cell phosphate potential (i.e., fasting) and when 2) AAs provide
      leucine for allosteric activation and glutamate from transaminations. To test
      this hypothesis, IS studies were performed in rat and GDH-HI mouse models. In the
      rat study, rat islets were isolated, cultured, and then perifused in Krebs-Ringer
      bicarbonate buffer with 2 mmol/l glutamine using 10 mmol/l 2-aminobicyclo[2,2,1]
      heptane-2-carboxylic acid (BCH) or a BCH ramp after 50 or 120 min of glucose
      deprivation. In the GDH-HI mouse study, the H454Y GDH-HI mutation driven by the
      rat insulin promoter was created for H454Y beta-cell-specific expression.
      Cultured, isolated islets were perifused in leucine 0-10 mmol/l with 2 mmol/l
      glutamine 0-25 mmol/l, AA 0-10 mmol/l, or glucose 0-25 mmol/l. Rat islets
      displayed enhanced BCH-stimulated IS after 120 min of glucose deprivation, but
      not when energized by fuel. H454Y and control islets had similar glucose
      stimulated IS, but H454Y mice had lower random blood glucose. Leucine-stimulated
      IS and AASIS occurred at lower thresholds and were greater in H454Y versus
      control islets. Glutamine stimulated IS in H454Y but not control islets. The
      clinical manifestations of GDH-HI and related animal studies suggest that GDH
      regulates basal IS and AASIS. Energy deprivation enhanced GDH-mediated IS, and
      H454Y mice were hypoglycemic, substantiating roles for GDH and its regulation by
      the phosphate potential in basal IS. Excessive IS from H454Y islets upon exposure
      to GDH substrates or stimuli indicate that regulation of GDH by the beta-cell
      phosphate potential plays a critical role in AASIS. These findings provide a
      foundation for defining pathways of basal secretion and AASIS, augmenting our
      understanding of beta-cell function.

PMID- 12475786
TI  - Insulin receptor signaling and sarco/endoplasmic reticulum calcium ATPase in beta
      cells.
AB  - Glucose is the main physiological secretagogue for insulin secretion by
      pancreatic beta-cells, and the major biochemical mechanisms involved have been
      elucidated. In particular, an increase in intracellular calcium is important for
      insulin exocytosis. More recently, it has become apparent that the beta-cell also
      has many of the elements of the insulin receptor signal transduction pathway,
      including the insulin receptor and insulin receptor substrate (IRS) proteins 1
      and 2. Studies with transgenic models have shown that the beta-cell-selective
      insulin receptor knockout and the IRS-1 knockout lead to reduced glucose-induced
      insulin secretion. Overexpression of the insulin receptor and IRS-1 in beta-cells
      results in increased insulin secretion and increased cytosolic Ca(2+). We have
      thus postulated the existence of a novel autocrine-positive feedback loop of
      insulin on its own secretion involving interaction with the insulin receptor
      signal transduction pathway and regulation of intracellular calcium homeostasis.
      Our current working hypothesis is that this glucose-dependent interaction occurs
      at the level of IRS-1 and the sarco(endo)plasmic reticulum calcium ATPase, the
      calcium pump of the endoplasmic reticulum.

PMID- 12475787
TI  - The multiple actions of GLP-1 on the process of glucose-stimulated insulin
      secretion.
AB  - The physiological effects of glucagon-like peptide-1 (GLP-1) are of immense
      interest because of the potential clinical relevance of this peptide. Produced in
      intestinal L-cells through posttranslational processing of the proglucagon gene,
      GLP-1 is released from the gut in response to nutrient ingestion. Peripherally,
      GLP-1 is known to affect gut motility, inhibit gastric acid secretion, and
      inhibit glucagon secretion. In the central nervous system, GLP-1 induces satiety,
      leading to reduced weight gain. In the pancreas, GLP-1 is now known to induce
      expansion of insulin-secreting beta-cell mass, in addition to its most well
      characterized effect: the augmentation of glucose-stimulated insulin secretion.
      GLP-1 is believed to enhance insulin secretion through mechanisms involving the
      regulation of ion channels (including ATP-sensitive K(+) channels, voltage
      dependent Ca(2+) channels, voltage-dependent K(+) channels, and nonselective
      cation channels) and by the regulation of intracellular energy homeostasis and
      exocytosis. The present article will focus principally on the mechanisms proposed
      to underlie the glucose dependence of GLP-1's insulinotropic effect.

PMID- 12475788
TI  - Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent
      repolarizing K(+) currents in beta-cells: a possible glucose-dependent
      insulinotropic mechanism.
AB  - Glucagon-like peptide-1 (GLP-1) acts through its G-protein-coupled receptor to
      enhance glucose-stimulated insulin secretion from pancreatic beta-cells. This is
      believed to result from modulation of at least two ion channels: ATP-sensitive
      K(+) (K(ATP)) channels and voltage-dependent Ca(2+) channels. Here, we report
      that GLP-1 receptor signaling also regulates the activity of beta-cell voltage
      dependent K(+) (K(V)) channels, themselves potent glucose-dependent regulators of
      insulin secretion. GLP-1 receptor activation with exendin 4 (10(-8) mol/l) in rat
      beta-cells antagonized K(V) currents by 43.3 +/- 6.3%, whereas the GLP-1 receptor
      antagonist exendin 9-39 had no effect. The effect of GLP-1 receptor activation on
      K(V) currents could be replicated (current reduction of 55.7 +/- 6.0%) by G
      protein activation with GMP-PNP (10 nmol/l). The cAMP pathway antagonist Rp-cAMPS
      (100 micro mol/l) prevented current inhibition by exendin 4, implicating cAMP
      signaling in GLP-1 receptor modulation of beta-cell K(V) currents. Finally,
      exendin 4 (10(-8) mol/l) increased the amplitude (130 +/- 5.7%) and duration (285
      +/- 15.9%) of the beta-cell depolarization response to current injection,
      independent of any effect on K(ATP) or Ca(2+) channels. The present results
      demonstrate that GLP-1 receptor signaling can antagonize beta-cell repolarization
      by reducing voltage-dependent K(+) currents, an effect likely to contribute to
      GLP-1's glucose-dependent insulinotropic effect.

PMID- 12475789
TI  - Two generations of insulinotropic imidazoline compounds.
AB  - The imidazoline RX871024 increased basal- and glucose-stimulated insulin release
      in vitro and in vivo. The compound inhibited activity of ATP-sensitive K(+)
      channels as well as voltage-gated K(+) channels, which led to membrane
      depolarization, an increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)),
      and insulin release. Importantly, RX871024 also enhanced the insulinotropic
      effect of glucose in cells with clamped [Ca(2+)](i) but in the presence of high
      ATP and Ca(2+)concentration inside the cell. We believe that the latter effect on
      insulin exocytosis was at least in part mediated by a rise in diacylglycerol,
      which then activated protein kinase C (PKC) and increased the generation of
      arachidonic acid (AA) metabolites. Activation of both the PKC and AA pathways
      resulted in potentiation of glucose effects on insulin secretion. Unlike
      RX871024, the novel imidazoline BL11282 did not block ATP-dependent K(+)
      channels, but similarly to RX871024, it stimulated insulin secretion in
      depolarized or permeabilized islets. Accordingly, BL11282 did not influence
      glucose and insulin levels under basal conditions either in vitro or in vivo, but
      it markedly enhanced the insulinotropic effects of glucose. BL11282 restored the
      impaired insulin response to glucose in islets from spontaneously diabetic GK
      rats. We conclude that BL11282 belongs to a new class of insulinotropic compounds
      that demonstrate a strong glucose-dependent effect on insulin exocytosis.

PMID- 12475790
TI  - Endoplasmic reticulum stress and the development of diabetes: a review.
AB  - The early steps of insulin biosynthesis occur in the endoplasmic reticulum (ER),
      and the beta-cell has a highly developed and active ER. All cells regulate the
      capacity of their ER to fold and process client proteins and they adapt to an
      imbalance between client protein load and folding capacity (so-called ER stress).
      Mutations affecting the ER stress-activated pancreatic ER kinase (PERK) and its
      downstream effector, the translation initiation complex eukaryotic initiation
      factor 2 (eIF2), have a profound impact on islet cell development, function, and
      survival. PERK mutations are associated with the Wolcott-Rallison syndrome of
      infantile diabetes and mutations that prevent the alpha-subunit of eIF2 from
      being phosphorylated by PERK, block beta-cell development, and impair
      gluconeogenesis. We will review this and other rare forms of clinical and
      experimental diabetes and consider the role of ER stress in the development of
      more common forms of the disease.

PMID- 12475791
TI  - Recent advances in the Okamoto model: the CD38-cyclic ADP-ribose signal system
      and the regenerating gene protein (Reg)-Reg receptor system in beta-cells.
AB  - Twenty years ago, we first proposed our hypothesis on beta-cell damage and its
      prevention (the Okamoto model), according to which poly(ADP-ribose)
      synthetase/polymerase (PARP) activation is critically involved in the consumption
      of NAD(+), leading to energy depletion and cell death by necrosis. Recently, the
      model was reconfirmed by results using PARP knockout mice and has been recognized
      as providing the basis for necrotic death of various cells and tissues. Based on
      the model, we proposed two signal systems in beta-cells: one is the CD38-cyclic
      ADP-ribose (cADPR) signal system for insulin secretion, and the other is the
      regenerating gene protein (Reg)-Reg receptor system for beta-cell regeneration.
      The physiological and pathological significance of the two signal systems in a
      variety of cells and tissues as well as in pancreatic beta-cells has recently
      been recognized. Here, we describe the Okamoto model and its descendents, the
      CD38-cADPR signal system and the Reg-Reg receptor system, focusing on recent
      advances and how their significance came to light. Because PARP is involved in
      Reg gene transcription to induce beta-cell regeneration, and the PARP activation
      reduces the cellular NAD(+) to decrease the formation of cADPR (a second
      messenger for insulin secretion) and further to cause necrotic beta-cell death,
      PARP and its inhibitors have key roles in the induction of beta-cell
      regeneration, the maintenance of insulin secretion, and the prevention of beta
      cell death.

PMID- 12475792
TI  - Prolonged in vitro exposure to autoantibodies against CD38 impairs the function
      and survival of human pancreatic islets.
AB  - Autoantibodies against CD38 (adenosine-5'-diphosphate[ADP]-ribosyl cyclase/cyclic
      ADP-ribose hydrolase) have been described in 10-12% of patients with type 2
      diabetes. In human islets, anti-CD38 autoantibodies (CD38Abs) acutely stimulate
      insulin release (IR) and increase the cytosolic calcium concentration
      ([Ca(2+)](i)). Whether CD38Abs affect human islet cell function and survival upon
      prolonged in vitro exposure is not known. We cultured human islets for up to 7
      days in the presence of sera from 10 patients with type 2 diabetes that had
      neither CD38Ab- nor [Ca(2+)](i)-mobilizing activity (-/-), sera from 6 patients
      with type 2 diabetes that was CD38Ab-positive and had [Ca(2+)](i)-mobilizing
      activity (+/+), or no sera (control). At baseline, +/+ sera caused a significant
      (P < 0.002) acute stimulation of IR (IR at 3.3 mmol/l glucose was 45 +/- 19, 84
      +/- 24, and 34 +/- 12 micro U/ml in control, +/+, and -/- sera, respectively; the
      corresponding IR at 16.7 mmol/l glucose was 72 +/- 25, 204 +/- 56, and 80 +/- 32
      micro U/ml). At 3 days, IR at 3.3 mmol/l glucose was 42 +/- 18, 27 +/- 11, and 43
      +/- 24 micro U/ml (P = 0.0003) for control, +/+, and -/- sera, respectively,
      whereas at 16.7 mmol/l glucose, it was 95 +/- 76, 45 +/- 35, and 76 +/- 42 micro
      U/ml, respectively. After 7 days of exposure, the corresponding IR at 3.3 mmol/l
      glucose was 40 +/- 11, 28 +/- 12, and 35 +/- 15 micro U/ml, respectively, whereas
      at 16.7 mmol/l glucose it was 79 +/- 39, 39 +/- 17, and 62 +/- 39 micro U/ml. At
      both 3 and 7 days, IR still increased when switching from 3.3 to 16.7 mmol/l
      glucose (P < 0.0003), and incubation with +/+ sera induced a significant decrease
      in the insulin response (P < 0.002). At 7 days, the number of dead cells (as
      evaluated by an enzyme-linked immunosorbent assay technique) differed
      significantly between control (1.2 +/- 0.3 OD units) cells, islets exposed to -/-
      sera (1.4 +/- 0.1), and islets coincubated with +/+ sera (1.9 +/- 0.4, P < 0.01).
      We conclude that prolonged exposure of human islets to sera positive for the
      presence of CD38Abs with [Ca(2+)](i)-mobilizing activity impairs beta-cell
      function and viability in cultured human pancreatic islets.

PMID- 12475793
TI  - Production and characterization of Reg knockout mice: reduced proliferation of
      pancreatic beta-cells in Reg knockout mice.
AB  - Reg (regenerating gene) was isolated as a gene specifically expressed in
      regenerating islets. We have demonstrated in vitro and in vivo that the exogenous
      addition of rat and human Reg gene products, Reg/REG proteins, induced beta-cell
      replication via the Reg receptor and thereby ameliorated experimental diabetes.
      In the present study, we produced Reg knockout mice by homologous recombination.
      The Reg gene disruption resulted in a null mutation. Knockout mice developed
      normally. Islets from the Reg knockout mice appeared morphologically
      indistinguishable from those of normal controls. However, [(3)H]thymidine
      incorporation in isolated islets from Reg knockout mice was decreased. When
      hyperplastic islets were induced by the injection of goldthioglucose, the average
      islet size in Reg knockout mice was significantly smaller than that of control
      Reg(+/+) mice. We then produced transgenic mice carrying the Reg gene under the
      control of the rat insulin II promoter (Ins-Reg) to express Reg in beta-cells.
      Isolated islets from the Ins-Reg transgenic mice showed increased [(3)H]thymidine
      incorporation. By intercrossing, we produced NOD mice carrying the Ins-Reg
      transgene and found that development of diabetes in the resultant Ins-Reg
      transgenic NOD mice was significantly retarded, coinciding with an increase in
      the pancreatic beta-cell mass. These results indicate that Reg plays an important
      role in beta-cell growth/regeneration.

PMID- 12475794
TI  - Activation of nuclear factor-kappaB by depolarization and Ca(2+) influx in MIN6
      insulinoma cells.
AB  - The purpose of the current study was to determine whether nuclear factor-kappaB
      (NF-kappaB) activation is a component of the depolarization/Ca(2+)-dependent
      signaling in beta-cells. MIN6 cells were transfected with a plasmid containing
      five tandem repeats of NF-kappaB binding sites linked to a luciferase reporter.
      The results of these experiments showed that KCl induced depolarization-activated
      NF-kappaB-dependent transcription (3.8-fold at 45 mmol/l, P < 0.01) in a
      concentration-dependent manner. Tumor necrosis factor-alpha (TNF-alpha), a known
      inducer of NF-kappaB signaling, activated this construct by 3.4-fold (P < 0.01).
      The response of NF-kappaB to depolarization was inhibited by the Ca(2+)-channel
      blocker verapamil and by the mitogen-activated protein kinase kinase (MEK)
      inhibitor PD98059 (70 and 62%, respectively). TNF-alpha, glucose, and KCl
      treatment resulted in inhibitory kappaBalpha degradation by Western blot
      analysis. TNF-alpha treatment and depolarization activation of NF-kappaB differed
      significantly in that TNF-alpha activation was not blocked by PD98059.
      Transfection with PKA, MEK, and MEK kinase induced NF-kappaB-dependent
      transcription by 20-, 90-, and 300-fold, respectively, suggesting that these
      pathways contribute to the activation in the depolarization response. These
      findings demonstrate that depolarization/Ca(2+) influx, as well as TNF-alpha
      treatment, can activate NF-kappaB-dependent transcription in pancreatic beta
      cells, but by different signaling pathways. The current studies show that Ca(2+)
      signals in pancreatic beta-cells can activate transcription factors involved in
      the regulation of cell cycle and apoptosis. These findings now add NF-kappaB to
      the list of depolarization-induced transcription factors in pancreatic beta
      cells.

PMID- 12475795
TI  - Proinsulin 2 knockout NOD mice: a model for genetic variation of insulin gene
      expression in type 1 diabetes.
AB  - Insulin is a major disease determinant in type 1 diabetes, type 2 diabetes, and
      related disorders. The role of variations in the expression of the insulin gene
      has been proposed in genetic susceptibility to the three pathological conditions
      in humans. In contrast to humans, rodents express two proinsulin isoforms. One
      isoform, proinsulin 1, is expressed exclusively in islets. The second, proinsulin
      2, is expressed in islets and in other tissues, especially the thymus. We took
      advantage of the expression of these two isoforms to introduce a null proinsulin
      2 allele in NOD mice and to evaluate the consequence of a variation of proinsulin
      2 gene expression on the development of type 1 diabetes on the NOD genetic
      background. Heterozygote NOD mutant mice carrying a null proinsulin 2 mutation
      showed an increased incidence of type 1 diabetes at successive backcross
      generations. Plasma glucose and insulin levels were identical in prediabetic
      mutant and in wild-type mice at 4 weeks of age. Variation in insulin gene
      expression is hypothesized to interfere with diabetes development at both the
      islet and the thymus level.

PMID- 12475796
TI  - Quantitative assessment of airway remodeling using high-resolution CT.
AB  - Asthma and COPD are the most prevalent of lung diseases and contribute an
      enormous burden of morbidity in North America and globally. In both conditions,
      inflammation leads to airway remodeling, which contributes to airway narrowing.
      To date, airway remodeling has only been assessed using histological examination
      of airways. However, it may now be possible to assess and quantify the extent of
      airway remodeling in vivo using high-resolution CT (HRCT). The aim of this
      article is to review the use of HRCT in the investigation of airway remodeling. A
      number of investigators have reported techniques to make measurements of airway
      dimensions using CT and an increasing number of quantitative methods are being
      developed. Using these techniques, airway dimensions have been examined in
      patients with asthma and COPD. In patients with asthma, the airway wall area was
      increased without a decrease in luminal area, whereas in patients with COPD, the
      airway luminal area was decreased and airway wall area was increased. The
      different pattern of remodeling may reflect fundamental differences in the
      inflammatory processes in asthma and COPD and could influence the reversibility
      of the narrowing. It has also been shown that, by quantifying both the extent of
      emphysema and of airway remodeling, CT is useful in differentiating COPD patients
      who have primarily parenchymal disease from those who have primarily airway
      pathology. With additional advances in technology, it is likely that quantitative
      assessment of airway wall dimensions will ultimately provide a valuable tool for
      the study of airway disease.

PMID- 12475797
TI  - Remodeling and Repair in Respiratory Diseases. Santa Fe, New Mexico, USA. October
      14-17, 2001. Proceedings of a meeting.

PMID- 12475798
TI  - Fibronectin matrix deposition and cell contractility: implications for airway
      remodeling in asthma.
AB  - The adhesion of cells to the extracellular matrix (ECM) protein, fibronectin, is
      important in the regulation and coordination of such complex processes as cell
      growth, migration, differentiation, and ECM organization. The deposition of
      fibronectin into the ECM is a cell-dependent process that is normally tightly
      regulated to ensure controlled matrix deposition. Increased deposition of
      fibronectin and collagen into the subepithelial space of the airways is observed
      in all forms of asthma and occurs early in the progression of the disease.
      Experimental evidence suggests a model in which fibronectin matrix accumulation
      contributes to the progression of asthma by altering both the structural
      properties of the airways and the functional properties of cells of the airway
      wall.

PMID- 12475799
TI  - Corticosteroid-induced apoptosis of airway epithelium: a potential mechanism for
      chronic airway epithelial damage in asthma.
AB  - Damage to the airway epithelium is one prominent feature of chronic asthma.
      Mucosal damage includes gap openings, partial denudation, and loss of ciliated
      cells. Apoptosis of the airway epithelium is increasingly recognized as a
      potential mechanism by which damage may occur. Corticosteroids (CSs) induce
      apoptosis in inflammatory cells, which in part explains their ability to suppress
      airway inflammation. However, CS therapy does not necessarily reverse epithelial
      damage. We examined whether CS therapy actually could induce airway epithelial
      apoptosis using culture models of primary airway epithelial cells and cell lines.
      The administration of CSs in low-micromolar concentrations induces apoptosis that
      involves the disruption of mitochondrial polarity, the activation of caspases,
      and the involvement of Bcl-2. Clear differences exist between CS-induced
      apoptosis in the cultured epithelium vs cultured hematopoietic cells in regard to
      time course and resistance to apoptosis. Our data suggest that the use of CSs, in
      concentrations that could be attained in vivo with the inhalation of potent
      preparations or with systemic administration, may be one factor in the airways
      remodeling and epithelial damage that is seen in many patients with chronic,
      persistent asthma.

PMID- 12475800
TI  - Genetics and pulmonary hypertension.
AB  - Primary pulmonary hypertension (PPH) is a serious pulmonary vascular disease
      occurring mostly in adult women. Although its occurrence in families was reported
      within a few years after the original clinical report, PPH was formerly believed
      rarely to have a genetic basis. Recent progress has not only clarified a basic
      molecular mechanism for PPH in families, but has also identified mutations of the
      same gene in many sporadic PPH patients, suggesting that its basis is commonly
      genetic. Extensive investigations in many centers are now in progress to provide
      a complete dissection of all the pathogenetic mechanisms of PPH.

PMID- 12475801
TI  - The myofibroblast in pulmonary fibrosis.
AB  - The pathogenesis of pulmonary fibrosis remains incompletely understood. Studies
      of associated inflammation have led to the discovery of a number of cytokines and
      chemokines that are found to be important either directly or indirectly for the
      fibrotic process. However, the importance of inflammation in pulmonary fibrosis
      is unclear, and at the time of diagnosis the inflammatory component is variable
      and usually not responsive to anti-inflammatory therapeutic agents. Patients
      usually exhibit evidence of active fibrosis with increased numbers of activated
      fibroblasts, many of which have the phenotypic characteristics of myofibroblasts.
      At these sites, increased amounts of extracellular matrix deposition are evident
      with effacement of the normal alveolar architecture. Animal model studies show
      the myofibroblast to be the primary source of type I collagen gene expression in
      active fibrotic sites. In vitro studies show differentiation of these cells from
      fibroblasts under the influence of certain cytokines but indicate their
      susceptibility to nitric oxide-mediated apoptosis. In addition to promoting
      myofibroblast differentiation, transforming growth factor-beta1 provides
      protection against apoptosis. Thus, this well-known fibrogenic cytokine is
      important both for the emergence of the myofibroblast and its survival against
      apoptotic stimuli. This is consistent with the critical importance of this
      cytokine in diverse models of fibrosis in various tissues. In view of these
      properties, the persistence or prolonged survival of the myofibroblast may be key
      to understanding why certain forms of lung injury may result in progressive
      disease, terminating in end-stage disease.

PMID- 12475802
TI  - Roles for insulin-like growth factor I and transforming growth factor-beta in
      fibrotic lung disease.
AB  - Idiopathic pulmonary fibrosis (IPF) is a lung disease that is characterized by
      epithelial cell damage and areas of denuded basement membrane resulting in
      inflammation, fibroblast proliferation, excessive extracellular matrix (ECM)
      deposition, and remodeling of alveolar gas exchange units. The progressive loss
      of lung gas exchange units in patients with IPF leads to respiratory failure and
      eventually to death. While the etiology of this disease is unknown, for many
      years studies suggested that chronic inflammation was the underlying factor that
      caused fibroproliferation and structural alterations of the lung. Recent data
      show that fibroproliferation and fibrosis can occur independently of
      inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather
      than an immune disorder. Mesenchymal growth factors, including transforming
      growth factor (TGF)-beta, insulin-like growth factor (IGF)-I, platelet-derived
      growth factor, connective tissue growth factor, fibroblast growth factors, and
      keratinocyte growth factors, as well as proinflammatory cytokines such as tumor
      necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in
      several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and
      bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic
      diseases such as rheumatoid arthritis or progressive systemic sclerosis
      (scleroderma). We argue that inflammation is required to initiate growth factor
      production and repair of the damaged alveolar epithelial lining in fibrotic lung
      diseases and that exaggerated TGF-beta production may be responsible for the
      fibrotic response seen in diseases such as IPF. We recognize the potential role
      of several growth factors in the fibroproliferative process in the lung, and in
      this brief report we focus on the possible roles of the growth factors IGF-I and
      TGF-beta in cell migration, proliferation, and ECM synthesis in patients with
      IPF.

PMID- 12475803
TI  - Apoptosis in lung fibrosis and repair.
AB  - Cell death by apoptosis has fundamental significance in both normal lung
      homeostasis and a variety of pathologic processes, and for this reason apoptosis
      in the lung is a rapidly growing area of investigation. Evidence from human lung
      biopsy specimens and from animal models of lung fibrosis points to important
      roles for apoptosis in both the pathogenesis and resolution of fibrotic lesions.
      As more evidence accumulates, the more apparent becomes the paucity of
      information on the regulation of this mode of cell death in the many different
      cell types of the lung parenchyma. This discussion will review the current state
      of knowledge regarding the roles of apoptosis in lung fibrosis and will focus on
      its role in pathogenesis.

PMID- 12475804
TI  - CXC chemokines in angiogenesis related to pulmonary fibrosis.
AB  - Angiogenesis, defined as the growth of new capillaries from preexisting vessels,
      is a pervasive biological phenomenon that is at the core of many physiologic and
      pathologic processes. An opposing balance of angiogenic and angiostatic factors
      regulates angiogenesis. Examples of physiologic processes that depend on
      angiogenesis include embryogenesis, wound repair, and the ovarian/menstrual
      cycle. In contrast, chronic inflammation associated with chronic
      fibroproliferative disorders as well as growth and metastasis of solid tumors are
      associated with aberrant angiogenesis. CXC chemokines comprise a unique cytokine
      family that contains members that exhibit on a structural/functional basis either
      angiogenic or angiostatic biological activity. In this review, we will discuss
      the role of CXC chemokines and angiogenesis in pulmonary fibrosis.

PMID- 12475805
TI  - Animal models of cigarette smoke-induced COPD.
AB  - OBJECTIVES: To review the animal models of COPD, and to compare these data to
      those found in humans. RESULTS: Smoke-induced animal models can produce
      emphysema, although the lesions are not generally close mimics of human
      emphysema, as well as increases in mucous-secreting cells and vascular changes
      including pulmonary hypertension. There is considerable species-to-species
      variation in the degree and/or presence of these different abnormalities, so that
      care has to be used in selecting a species to study. Remarkably little
      information is available about the biochemical and molecular changes induced by
      cigarette smoke in animal models. CONCLUSIONS: Great insights into the pathology
      of chronic obstructive lung disease have been made using various animal models.

PMID- 12475806
TI  - Airway wall remodeling induced by occupational mineral dusts and air pollutant
      particles.
AB  - OBJECTIVES: COPD has been reported in workers exposed to particulates, and there
      is increasing evidence that high levels of ambient particulate pollutants may
      also be associated with COPD. The studies here investigate the hypothesis that
      particulates, including air pollution particles, can induce airway wall fibrosis,
      a process that can lead to COPD. DESIGN: Rat tracheal explants were exposed to
      various occupationally encountered dusts, air pollution particles, and model air
      pollution particles. In some experiments, iron was loaded onto the particle
      surface. Gene expression and nuclear factor (NF)-kappaB activation were measured
      after 7 days of air culture. Adhesion to and uptake of dusts by the tracheal
      epithelium were also evaluated. RESULTS: Known fibrogenic dusts such as amosite
      asbestos produced increased gene expression of procollagen, transforming growth
      factor-beta, and platelet-derived growth factor, and increased hydroxyproline in
      the explants, and the addition of iron increased these effects. The addition of
      iron also converted nonfibrogenic TiO2 into a fibrogenic dust. Dusts with surface
      complexed iron activated NF-kappaB via an oxidant mechanism. However, an
      ultrafine TiO2 with very low iron was also fibrogenic. In separate experiments,
      exogenous tumor necrosis factor-alpha increased dust adhesion to, and exogenous
      ozone increased dust uptake by, tracheal epithelial cells. CONCLUSIONS: Mineral
      dusts can directly induce fibrosis in the airway wall. Exogenous inflammatory
      cells and exogenous agents are not required, but they probably exaggerate the
      fibrogenic effects. An iron-mediated oxidant mechanism underlies the fibrogenic
      effects of some, but not all, of these dusts. Particle-induced airway wall
      fibrosis may lead to COPD.

PMID- 12475807
TI  - Chronic ethanol ingestion increases susceptibility to acute lung injury: role of
      oxidative stress and tissue remodeling.
AB  - Clinical studies have demonstrated that chronic alcohol abuse is an independent
      outcome variable in acute lung injury. The Emory Center for the Study of Acute
      Lung Injury is determining the mechanisms by which ethanol increases
      susceptibility to acute lung injury. We developed a rat model of chronic ethanol
      ingestion and demonstrated that ethanol predisposes rats to edematous lung injury
      elicited by endotoxemia or sepsis. Chronic ethanol ingestion in rats led to
      decreased levels of glutathione, an important antioxidant in the lung, and this
      defect was associated with alterations in epithelial cell permeability, decreased
      alveolar liquid clearance, decreased cell viability, and decreased surfactant
      production. Chronic ethanol ingestion also led to the activation of lung tissue
      remodeling as demonstrated by the increased expression of profibrotic growth
      factors, matrix components, and metalloproteases. In cultured fibroblasts, the
      induction of the matrix glycoprotein fibronectin by ethanol was mediated via
      nicotinic acetylcholine receptor-dependent signal transduction. We speculate that
      these alterations render the host susceptible to acute lung injury by diminishing
      the protective mechanisms of the lung and promoting exaggerated inflammatory and
      tissue repair responses elicited against injurious agents.

PMID- 12475808
TI  - Oxidant-antioxidant balance in acute lung injury.
AB  - ARDS is a disease process that is characterized by diffuse inflammation in the
      lung parenchyma. The involvement of inflammatory mediators in ARDS has been the
      subject of intense investigation, and oxidant-mediated tissue injury is likely to
      be important in the pathogenesis of ARDS. In response to various inflammatory
      stimuli, lung endothelial cells, alveolar cells, and airway epithelial cells, as
      well as activated alveolar macrophages, produce both nitric oxide and superoxide,
      which may react to form peroxynitrite, which can nitrate and oxidize key amino
      acids in various lung proteins, such as surfactant protein A, and inhibit their
      functions. The nitration and oxidation of a variety of crucial proteins present
      in the alveolar space have been shown to be associated with diminished function
      in vitro and also have been identified ex vivo in proteins sampled from patients
      with acute lung injury (ALI)/ARDS. Various enzymes and low-molecular-weight
      scavengers that are present in the lung tissue and alveolar lining fluid
      decreased the concentration of these toxic species. The purpose of this brief
      chapter is to review the results from various studies demonstrating increased
      levels of reactive oxygen-nitrogen intermediates in the alveolar spaces of
      patients with ALI/ARDS.

PMID- 12475809
TI  - Goblet cell and mucin gene abnormalities in asthma.
AB  - Goblet cell hyperplasia (GCH) has been established as a pathologic characteristic
      of mild, moderate, and severe asthma. Abnormalities in goblet cell number are
      accompanied by changes in stored and secreted mucin (MUC). The functional
      consequences of these changes in MUC stores and secretion can contribute to the
      pathophysiologic mechanisms for multiple clinical abnormalities in patients with
      asthma, including sputum production, airway narrowing, exacerbations, and
      accelerated loss in lung function. CD4(+) T cells and their T-helper type-2
      cytokine products are important mediators of GCH, and MUC5AC is the dominant MUC
      gene that is expressed in goblet cells. The mechanism of cytokine-induced GCH,
      the relationships between MUC gene up-regulation and GCH, and the role of ion
      channels are all currently being explored. The process of working out the
      molecular mechanisms of GCH and goblet cell degranulation should provide new
      targets for novel therapeutic interventions. Such new treatments are urgently
      needed, because mucus hypersecretion is an important cause of morbidity and
      mortality in patients with asthma, and no specific treatments are available.

PMID- 12475810
TI  - Hypoxic activation of adventitial fibroblasts: role in vascular remodeling.
AB  - Substantial experimental evidence supports the idea that the fibroblast may play
      a significant role in the vascular response to injury, especially under hypoxic
      conditions. Fibroblasts have the ability to rapidly respond to hypoxic stress and
      to modulate their function to adapt rapidly to local vascular needs. Fibroblasts
      appear to be uniquely equipped to proliferate, transdifferentiate, and migrate
      under hypoxic conditions. Proliferative responses to hypoxia depend on the
      activation of Galpha(i) and Gq kinase family members, and on the subsequent
      stimulation of protein kinase C and mitogen-activated protein kinase family
      members. Extracellular nucleotides (eg, adenosine triphosphate [ATP]) are likely
      to be increased in the hypoxic adventitial compartment and can act as
      autocrine/paracrine modifiers of the hypoxia-induced proliferative response. The
      proliferative effects of ATP appear to be mediated largely through G-protein
      coupled P2Y receptors in fetal and neonatal fibroblasts. Hypoxia, acting through
      Galpha(iota)-coupled pathways, also can directly up-regulate alpha-smooth muscle
      actin expression in fibroblast subpopulations, suggesting that hypoxia may play a
      direct role in mediating the "transdifferentiation" of fibroblasts into
      myofibroblasts in the vessel wall. In addition, chronic hypoxia causes stable (at
      least in vitro) phenotypic changes in fibroblasts that appear to be associated
      with changes in the signaling pathways used to elicit proliferation. However, it
      is also becoming clear that, similar to the heterogeneity described for vascular
      smooth muscle cells, numerous fibroblast subtypes exist in the vessel wall, and
      that each may respond in unique ways to hypoxia and other stimuli and thus serve
      special functions in response to injury. In fact, adventitia may be considered to
      be compartments in which cells with "stem-cell-like" characteristics reside.
      Future work is needed to determine more precisely the role of the fibroblast in
      the wide variety of vascular complications observed in many humans diseases, and
      in the genes and gene products that confer unique properties to this important
      vascular cell.

PMID- 12475811
TI  - Overview of pulmonary fibrosis.
AB  - Pulmonary fibrosis is a component of over 200 interstitial lung diseases. Some
      have known etiologies, however, for many diseases, the etiology remains unknown
      or obscure. This brief review examines the prevalence and classification of these
      diseases, the approach to be taken for the investigation of a patient suspected
      of having pulmonary fibrosis, the indications for the performance of lung biopsy,
      and current thoughts concerning the pathogenesis of the idiopathic forms of
      fibrotic lung disease. A brief review of established and emerging therapeutic
      strategies is included.

PMID- 12475812
TI  - Alveolar fluid clearance in patients with ARDS: does it make a difference?
AB  - Experimental methods to quantify alveolar fluid clearance have been adapted for
      our studies in patients with acute lung injury (ALI) or ARDS. We recently
      completed a study of 79 patients with ALI/ARDS that was designed to examine
      alveolar fluid clearance in the setting of alveolar epithelial injury from
      ALI/ARDS. Pulmonary edema fluid and plasma were sampled serially in the first 4 h
      after endotracheal intubation and the initiation of positive-pressure
      ventilation. Net alveolar fluid clearance was calculated from sequential edema
      fluid protein measurements. Patients with maximal alveolar fluid clearance had a
      significantly lower mortality rate and a shorter duration of mechanical
      ventilation. Several mechanisms may account for the decrease in the rate of
      alveolar fluid clearance in ALI/ARDS patients, including hypoxia, reactive oxygen
      species, reactive nitrogen species, and the loss of an intact epithelial barrier
      in the distal airspaces of the lung. Despite the epithelial injury in patients
      with ALI/ARDS, some experimental studies have suggested that alveolar fluid
      clearance could be increased with therapy using cyclic adenosine monophosphate
      agonists or other pharmacologic agents.

PMID- 12475813
TI  - Weaning parameters: read the methodology before proceeding.

PMID- 12475814
TI  - Endobronchial ultrasound and peripheral pulmonary lesions: localization and
      histopathologic correlates using a miniature probe and the flexible bronchoscope.

PMID- 12475815
TI  - A pulmonary myth unmasked?

PMID- 12475816
TI  - Clinical measurement of pulmonary edema.

PMID- 12475817
TI  - Radiographic assessment of intravascular volume.

PMID- 12475818
TI  - Would Euclid approve of how we select mechanical ventilators?

PMID- 12475819
TI  - Ventilator-associated pneumonia: is there any gold in these standards?

PMID- 12475820
TI  - Women and mesothelioma.

PMID- 12475821
TI  - Analysis of the internal structure of peripheral pulmonary lesions using
      endobronchial ultrasonography.
AB  - STUDY OBJECTIVE: To correlate the internal structure of peripheral pulmonary
      lesions, as visualized by endobronchial ultrasonography (EBUS), and the histology
      of the surgical specimen to develop a classification system for distinguishing
      benign from malignant lesions by EBUS. DESIGN: Retrospective review. SETTING: A
      national hospital. PATIENTS: One hundred twenty-four patients with peripheral
      pulmonary lesions who had undergone EBUS in whom a definitive histologic
      diagnosis was made. In 69 patients, EBUS findings were correlated with the
      histology of a surgical specimen. INTERVENTION: EBUS was performed by a miniature
      probe (20-MHz) introduced up to the lesion through a channel in a bronchoscope.
      RESULTS: Three classes and six subclasses of lesions were identified by EBUS
      based on the internal structure of the lesion, focusing on internal echoes,
      vascular and bronchial patency, and the morphology of the hyperechoic areas,
      reflecting air in the alveoli and bronchioles. The classes of lesions are as
      follows: type I, homogeneous pattern (type Ia, with patent vessels and patent
      bronchioles; type Ib, without vessels and bronchioles); type II, hyperechoic dots
      and linear arcs pattern (type IIa, without vessels; type IIb, with patent
      vessels); and type III, heterogeneous pattern (type IIIa, with hyperechoic dots
      and short lines; type IIIb, without hyperechoic dots and short lines). Twenty
      three of 25 type I lesions (92.0%) were benign, while 98 of 99 type II and III
      lesions (99.0%) were malignant. Twenty-one of 24 type II lesions (87.5%) were
      well-differentiated adenocarcinomas, and all type IIIb lesions were malignant,
      including 18 poorly differentiated adenocarcinomas (81.8%). CONCLUSIONS: EBUS
      permits the visualization of the internal structure of peripheral pulmonary
      lesions, and this information suggests the histology of the lesion.

PMID- 12475823
TI  - Clinical significance of myocardial magnetic resonance abnormalities in patients
      with sarcoidosis: a 1-year follow-up study.
AB  - PURPOSE: To assess the follow-up of patients with sarcoidosis and myocardial MRI
      abnormalities. MATERIALS AND METHODS: Twelve patients with histologically proven
      sarcoidosis and highly suspected cardiac involvement underwent initial and 12
      month follow-up cardiac assessment including cardiac MRI (T2-weighted, functional
      gradient echo, and T1-weighted gadolinium-diethylenetriamine penta-acetic acid
      enhanced sequences). MRI abnormalities and clinical and MRI progression were
      scored by two observers. RESULTS: Six patients receiving corticosteroid therapy
      (including three patients with clinical cardiac involvement) were scored as
      having cleared or improved at MRI follow-up, while others were seen to have
      worsened or remained stable. The stability, improvement, or clearing of MRI
      findings were correlated with clinically stable, improved or cleared sarcoidosis,
      while a worsening at MRI follow-up was correlated with a worsening of sarcoidosis
      and, in one patient, was predictive of clinical cardiac involvement. CONCLUSION:
      Cardiac MRI is a useful noninvasive method for the early diagnosis and follow-up
      of cardiac sarcoidosis.

PMID- 12475824
TI  - Cigarette smoking, preinvasive bronchial lesions, and autofluorescence
      bronchoscopy.
AB  - STUDY OBJECTIVES: Autofluorescence bronchoscopy (AFB), when used as an adjunct to
      standard white light bronchoscopy (WLB), enhances the bronchoscopist's ability to
      localize small neoplastic lesions, especially intraepithelial lesions. The
      current study was undertaken in order to define the population in which the rate
      of detection is higher using AFB. DESIGN AND PATIENTS: Two hundred forty-four
      consecutive patients, who were symptomatic smokers or patients who previously had
      been treated for lung cancer or head and neck cancers, underwent WLB and AFB. All
      patients with endoscopic abnormalities underwent biopsies. Data concerning
      smoking history were prospectively registered. RESULTS: We report the prevalence
      of high-grade or invasive lesions at the time of examination. On a lesion-by
      lesion analysis, 92 low-grade lesions, 42 high-grade lesions (ie, moderate
      dysplasia, severe dysplasia, and carcinoma in situ), and 39 invasive carcinomas
      were diagnosed. There was no effect of age, gender, and age at smoking initiation
      on the prevalence of preinvasive or invasive lesions. The 10 patients who
      previously had undergone surgery for lung cancer and exhibited high-grade
      preinvasive lesions had a history of carcinoma of the epidermoid histologic type
      (p = 0.01). These 10 patients displayed multiple lesions in the bronchial tree
      (mean No. of lesions, 1.8 per patient). In current smokers, the prevalence of
      high-grade or invasive lesions were both related to the number of pack-years
      smoking had occurred (p = 0.01) and to the duration of smoking (p = 0.01). In
      contrast, the prevalence of preinvasive lesions in former smokers was related to
      a history of epidermoid carcinoma. CONCLUSIONS: AFB should be recommended in
      patients with a history of epidermoid carcinomas of the lung. Current smokers
      with a prolonged smoking history appear to comprise a population in which the
      rate of detection of preneoplastic lesions is high with AFB.

PMID- 12475825
TI  - Safety of bronchoscopy, biopsy, and BAL in research patients with COPD.
AB  - BACKGROUND: Bronchoscopy with biopsy and BAL is being performed increasingly in
      patients with COPD as a research tool. Previous reports have shown these
      procedures to be safe in asthmatic patients, but there is little safety data
      specific to COPD. METHODS: We studied 57 patients with COPD (11 women and 46 men;
      median FEV(1), 1.2 L [range, 0.64 to 2.69 L]; percent predicted FEV(1), 44.5%
      [range, 25 to 74.8%]). Eleven patients had mild disease, 28 patients had moderate
      disease, and 18 patients had severe disease according to British Thoracic Society
      classification. Ninety-eight bronchoscopies were performed according to American
      Thoracic Society guidelines: 68 procedures with endobronchial biopsy and BAL and
      30 procedures with biopsy alone. Controlled oxygen was administered via nasal
      cannula, and pulse oximetry and vital signs were monitored. RESULTS: Five adverse
      events occurred. One patient in the moderate-disease group had severe
      bronchospasm requiring 4 days of inpatient treatment. One patient in the severe
      disease group had a pneumothorax requiring 7 days of inpatient treatment. There
      were three episodes of hemoptysis, two with pleuritic pain (in the BAL group)
      that settled without intervention. No deaths or prolonged morbidity were
      observed. We found a 2.0% incidence of adverse events requiring hospital
      treatment and a 3.1% incidence of minor hemoptysis requiring no intervention.
      CONCLUSIONS: Bronchoscopy, biopsy, and BAL can be performed safely in patients
      with COPD, including those with severe disease, provided careful assessment is
      performed and guidelines are adhered to.

PMID- 12475826
TI  - Volume of pleural fluid required for diagnosis of pleural malignancy.
AB  - STUDY OBJECTIVES: To determine if the diagnosis of pleural malignancy is
      dependent on the volume of pleural fluid sampled. DESIGN AND SETTING: Single
      center retrospective chart review. PATIENTS: Two hundred eighty-two patients who
      underwent diagnostic thoracentesis between October 1, 1998, and June 30, 1999.
      INTERVENTIONS: Charts were analyzed for volume of fluid, pathologic and clinical
      diagnoses, and demographics. Patients were classified into quartiles based on the
      volume of pleural fluid collected. Sensitivity and negative predictive value
      (NPV) were calculated for each quartile for diagnosis of pleural malignancy by
      cytology of pleural fluid. Further analyses were done regarding the effect of
      sex, race, age, smoking history, and personal history of malignancy on diagnosis.
      RESULTS: In total, 374 samples from 282 patients were identified (140 men and 142
      women). Pleural malignancy within 6 months of initial thoracentesis was diagnosed
      in 99 patients (35.1%). No differences were detected for sensitivity and NPV for
      diagnosis of pleural malignancy between any two quartiles (p > 0.05). Samples
      collected from women had a higher sensitivity for predicting pleural malignancy
      (p = 0.0011), and those collected from nonsmokers had a slightly higher but not
      statistically significant sensitivity for predicting pleural malignancy (p =
      0.057). Samples collected from subjects with no history of malignancy had a
      significantly higher NPV than samples collected from subjects with a history of
      malignancy (p < 0.001). After adjusting for these demographic and medical history
      factors, the associations of the pleural fluid volume quartiles with sensitivity
      and NPV did not change. CONCLUSION: The sensitivity for diagnosis of pleural
      malignancy is not dependent on the volume of pleural fluid extracted during
      thoracentesis.

PMID- 12475827
TI  - Clinical role of F-18 fluorodeoxyglucose positron emission tomography imaging in
      patients with lung cancer and suspected malignant pleural effusion.
AB  - STUDY OBJECTIVES: The goals of this study were to determine the sensitivity,
      specificity, and predictive accuracy of F-18 fluorodeoxyglucose positron emission
      tomography (PET-FDG) imaging in detecting metastatic disease involvement of
      pleura and/or presence of malignant pleural effusion in patients with proven lung
      cancer. We wanted to compare efficacy of PET-FDG imaging to CT scanning in
      differentiating benign pleural effusion from malignant effusion and/or pleural
      involvement in patients with lung cancer. METHODS: We studied 35 patients with
      biopsy-proven lung cancer and abnormal findings on CT scanning for presence of
      pleural effusion (n = 34) and/or pleural thickening or nodular involvement (n =
      4). The results of positron emission tomography and CT scanning were compared to
      pleural cytology (n = 31), histologic findings of pleural biopsy (n = 3), and/or
      clinical follow-up (n = 3) for at least 1 year for presence or absence of
      malignant pleural effusion. RESULTS: PET-FDG imaging correctly detected the
      presence of malignant pleural effusion and malignant pleural involvement in 16 of
      18 patients and excluded malignant effusion or pleural metastatic involvement in
      16 of 17 patients (sensitivity, specificity, and accuracy of 88.8%, 94.1%, and
      91.4% respectively). CONCLUSION: PET-FDG imaging is a highly accurate and
      reliable noninvasive test to differentiate malignant from benign pleural effusion
      and/or pleural involvement in patients with lung cancer and findings of suspected
      malignant pleural effusion on CT scanning.

PMID- 12475828
TI  - Effect of heavy-ion radiotherapy on pulmonary function in stage I non-small cell
      lung cancer patients.
AB  - STUDY OBJECTIVES: The purpose of this study was to investigate the effect of
      heavy-ion radiotherapy on pulmonary function in patients with clinical stage I
      non-small cell lung cancer (NSCLC) patients. DESIGN: Retrospective study.
      SETTING: Research Center Hospital for Charged Particle Therapy, National
      Institute of Radiological Sciences, Chiba, Japan. PATIENTS: From a total of 81
      patients who were not candidates for surgical resection due to medical reasons or
      patient refusal, and who were treated with carbon beam radiotherapy from October
      1994 to February 1999, the 52 patients who had completed the repeat overall
      pulmonary function tests at 6 and 12 months after undergoing heavy-ion
      radiotherapy were examined. The total heavy-ion irradiation dose ranged from 59.4
      to 95.4 photon gray equivalents (GyE), with a mean dose of 76.2 GyE.
      INTERVENTIONS AND MEASUREMENT: Pulmonary function was evaluated prior to heavy
      ion radiotherapy and at 6 and 12 months after heavy-ion radiotherapy. Comparisons
      of all pulmonary function indexes between, before, and at 6 and 12 months after
      heavy-ion radiotherapy were made using repeated-measures analysis of variance
      using the Dunnett test for post hoc comparison. RESULTS: A statistically
      significant decrease in FEV(1) and total lung capacity was detected at both 6 and
      12 months after the patient had undergone heavy-ion radiotherapy. No significant
      decreases in other pulmonary function indexes in patients were observed at either
      6 or 12 months after heavy-ion radiotherapy. The magnitude of the decrease in all
      pulmonary function indexes was < 8% at both 6 and 12 months after heavy-ion
      radiotherapy. CONCLUSIONS: These findings suggest that heavy-ion radiotherapy is
      feasible for stage I NSCLC patients without a severe loss of pulmonary function.

PMID- 12475829
TI  - Low rate of venous thromboembolism after craniotomy for brain tumor using
      multimodality prophylaxis.
AB  - CONTEXT: Venous thromboembolism (VTE) is the most frequent complication following
      craniotomy for brain tumors. At Brigham and Women's Hospital, VTE after
      craniotomy for brain tumor is the leading cause of deep vein thrombosis (DVT) and
      pulmonary embolism (PE) among patients hospitalized for conditions other than
      VTE. OBJECTIVE: To minimize VTE among patients undergoing craniotomy for brain
      tumor. DESIGN: Randomized, prospective, double-blind clinical trial. SETTING:
      Brigham and Women's Hospital. PATIENTS: One hundred fifty patients undergoing
      craniotomy for brain tumor randomized to enoxaparin, 40 mg/d, vs heparin, 5,000 U
      bid, with all patients receiving graduated compression stockings and intermittent
      pneumatic compression. MAIN OUTCOME MEASURES: The rate of DVT detected by venous
      ultrasonography prior to hospital discharge. RESULTS: Symptomatic DVT or PE
      developed in none of the patients. The overall rate of asymptomatic VTE was 9.3%,
      with no significant difference in the rates between the two prophylaxis groups.
      Ten of the 14 patients identified with VTE had thrombus limited to the deep veins
      of the calf. CONCLUSIONS: Enoxaparin, 40 mg/d, or unfractionated heparin, 5,000 U
      bid, in combination with graduated compression stockings, intermittent pneumatic
      compression, and predischarge surveillance venous ultrasonography of the legs,
      resulted in 150 consecutive patients without symptomatic VTE. The low 9.3%
      frequency of asymptomatic VTE comprised mostly isolated calf DVT. Therefore, this
      comprehensive, multimodality approach to VTE prophylaxis achieved excellent
      efficacy and safety.

PMID- 12475830
TI  - Advanced presentation of lung cancer in Asian immigrants: a case-control study.
AB  - STUDY OBJECTIVES: To determine if Asian immigrants to the United States present
      with more advanced lung cancer compared to non-Asians. DESIGN: A 5-year
      retrospective case-control study (January 1, 1992, to December 31, 1996) of
      patients with lung cancer identified using the New England Medical Center cancer
      center database. A 2-year follow up was obtained in all subjects. SETTING: A
      tertiary level care hospital providing all levels of medical care to the local
      Asian population in the Boston area. PATIENTS: Forty-two Asian immigrants with
      lung cancer diagnosed over the study period were matched for age and sex with 42
      non-Asian control subjects. RESULTS: Asians presented more frequently with
      advanced stage (stage III or IV) and less frequently with early stage (stage I or
      II) lung cancer compared with the non-Asian control group (p < 0.05). Asians were
      more likely to present with hemoptysis or constitutional symptoms (p < 0.01) and
      had a longer duration of symptoms prior to presentation (p < 0.01) compared with
      non-Asians. There was no difference in the length of time elapsed between
      diagnosis and start of treatment (approximation of workup time) between the two
      groups. The utilization of tests and procedures for clinical disease staging was
      not significantly different between the two groups. The incidence of large cell
      carcinoma (p < 0.05) was higher in Asians compared with non-Asians. Asians were
      more likely to receive radiotherapy and less likely to receive combination
      therapy compared with non-Asians (p < 0.05). The treatment of stage I and II lung
      cancer did not differ between the two groups. The median 2-year survival was
      significantly reduced in Asians compared with non-Asians: Asians, 7 months (95%
      confidence interval [CI], 3.1 to 10.9); non-Asians, 15 months (95% CI, 12.0 to
      17.5) [p < 0.001]. CONCLUSIONS: Asian immigrants with lung cancer appear to
      present with more advanced stage of disease, have more prolonged symptomatology,
      and have reduced survival compared with non-Asians. These data suggest that
      ethnicity may play a role in the presentation and outcome of lung cancer in the
      Asian immigrant population.

PMID- 12475831
TI  - Lung function decline in bronchial asthma.
AB  - STUDY OBJECTIVE: We evaluated the longitudinal changes in lung function and the
      factors associated with FEV(1) changes over time in a sample of asthmatic
      subjects. SETTING: FEV(1) measures were recorded every 3 months over a 5-year
      follow-up period. To compare all subjects independently of body size, FEV(1)
      values were normalized for the subject's height at the third power. We evaluated
      the possible effect of age, baseline FEV(1), disease duration, and FEV(1)
      variability on the rate of change of FEV(1). PATIENTS: We studied 142 subjects
      with asthma diagnosed on the basis of validated clinical and functional criteria.
      RESULTS: FEV(1) showed a linear decay with aging in each subject. For a subject
      1.65 m in height, the median overall FEV(1) decay was 40.9 mL/yr. FEV(1) decay
      slopes were significantly influenced by age and sex, being steeper in younger
      male subjects. A significant interaction was found between age and baseline
      FEV(1): the FEV(1) decay was significantly higher among younger asthmatics with a
      poorer baseline functional condition. A longer disease duration was associated
      with a lower FEV(1) slope. FEV(1) variability was strongly associated with an
      increased rate of FEV(1) decline. CONCLUSIONS: FEV(1) decline in patients with
      bronchial asthma is significantly influenced by baseline FEV(1), disease
      duration, and FEV(1) variability. Moreover, the rate of FEV(1) decline seems to
      increase in younger subjects only when the baseline function is poorer.

PMID- 12475832
TI  - A comparison of bone mineral density in elderly female patients with COPD and
      bronchial asthma.
AB  - BACKGROUND: A recent study has shown that osteoporosis and vertebral fractures
      are quite common in patients with advanced COPD and showed a significant
      relationship to the mortality of these patients. These results suggested that
      management of osteoporosis in advanced COPD is an important intervention. But
      whether patients with COPD who had never received chronic systemic
      corticosteroids have a high incidence of osteoporosis and whether these patients
      require treatment strategies to decrease osteoporotic fracture is not yet known.
      Furthermore, it is unclear whether there are differences in terms of the degree
      of osteoporosis between patients with COPD and patients with bronchial asthma.
      OBJECTIVES: To compare the degree of osteoporosis and bone metabolism markers
      between elderly women with COPD and those with bronchial asthma who had never
      received chronic systemic corticosteroids, and to determine the factors
      influencing bone metabolism in these patients. DESIGN: Cross-sectional medical
      survey. PATIENTS: A total of 44 elderly female patients with COPD (n = 20) or
      bronchial asthma (n = 24) who had not received chronic systemic corticosteroids
      were enrolled (mean +/- SEM age, 74.6 +/- 1.0 years). MEASUREMENTS: Total body
      and lumbar bone mineral density (BMD) were measured by dual-energy x-ray
      absorptiometry, and the data were compared between the two groups. In addition,
      the association between bone mass and clinical variables was determined. RESULTS:
      When lumbar BMD was expressed as a Z score, the Z scores of patients with COPD
      were significantly lower than those of patients with bronchial asthma (p < 0.01).
      The prevalence of osteoporosis was also significantly higher in patients with
      COPD (50% vs 21%, p < 0.05). In patients with COPD, body mass index was
      positively correlated with BMD in the lumbar spine (r = 0.55, p = 0.02) and total
      body (r = 0.49, p = 0.03). Other clinical, biochemical, and anthropometric
      variables were not correlated with BMD. CONCLUSIONS: In elderly female patients,
      osteoporosis is more common in cases of COPD than in bronchial asthma, even if
      these patients had not received long-term systemic corticosteroids. The
      explanation for the higher prevalence of osteoporosis in COPD is still not known,
      but preventive strategies to decrease osteoporotic fractures should be added to
      the management of elderly patients with COPD.

PMID- 12475833
TI  - Efficacy and safety of beclomethasone dipropionate extrafine aerosol in childhood
      asthma: a 12-week, randomized, double-blind, placebo-controlled study.
AB  - BACKGROUND: Beclomethasone dipropionate (BDP) has been formulated as an extrafine
      aerosol (hydrofluoroalkane-134a [HFA]-BDP) [QVAR; 3M Pharmaceuticals; St Paul,
      MN], which gives improved lung deposition compared with chlorofluorocarbon (CFC)
      BDP. The clinical efficacy of HFA-BDP has been established in adult asthma at a
      required dose below that of CFC-BDP, but has not been evaluated in children.
      OBJECTIVE: To examine the efficacy and safety of HFA-BDP in childhood asthma.
      DESIGN: A 12-week, multicenter, randomized, double-blind, placebo-controlled,
      parallel-group study involving 353 children aged 5 to 12 years with moderate,
      symptomatic asthma. After a 2-week run-in period, patients were randomized to HFA
      BDP, 80 micro g/d (n = 120); HFA-BDP, 160 micro g/d (n = 117); or HFA-placebo (n
      = 116) administered twice daily. SETTING: Hospital outpatient. RESULTS: HFA-BDP,
      80 micro g/d and 160 micro g/d, produced a significant, dose-related increase
      from baseline in FEV(1) percent predicted compared with placebo. At week 12, mean
      changes from baseline in FEV(1) percent predicted were 9.2% (p < or = 0.01 vs
      placebo), 10% (p < or = 0.01 vs placebo), and 3.9% for the HFA-BDP 80 micro g/d,
      HFA-BDP 160 micro g/d, and placebo groups, respectively. There was also a
      significant decrease in daily beta-agonist use, improvement in peak expiratory
      flow, and increase [correction] in the percentage of days free from asthma
      symptoms (p < or = 0.05 for HFA-BDP, 160 micro g/d, vs placebo at weeks 11 to
      12). HFA-BDP was well tolerated, with no significant differences in the incidence
      or nature of adverse events between HFA-BDP and placebo groups. Neither were
      there significant differences between groups in mean percentage change from
      baseline in the morning plasma cortisol level at week 12 or in the percentage of
      patients with morning plasma cortisol levels below the reference range at
      baseline and week 12. In a subgroup tested, the percentage of patients with an
      abnormal response to low-dose adrenocorticotropic hormone stimulation at week 12
      was low and similar among all groups. CONCLUSIONS: HFA-BDP, 80 to 160 micro g/d,
      is effective and safe in childhood asthma.

PMID- 12475834
TI  - Effects of varying doses of fluticasone propionate on the physiology and
      bronchial wall immunopathology in mild-to-moderate asthma.
AB  - OBJECTIVES: Inhaled corticosteroids (ICS) are typically associated with a flat
      dose-response curve when traditional efficacy values are examined (eg, FEV(1)).
      The aim of the present study was to investigate if a dose-response relationship
      exists for lung function and inflammatory cell numbers in bronchial biopsy
      specimens. METHODS: Bronchial biopsy specimens were obtained from 36 patients
      randomized to receive 100 micro g, 500 microg, or 2,000 microg/d of fluticasone
      propionate (FP). Lung physiology and bronchial biopsies were performed at
      baseline and after 2 weeks of treatment. RESULTS: Improvement in lung function
      and suppression of airway inflammation were optimal at a dose of 500 microg/d of
      FP. Significant changes from baseline following treatment were documented in
      FEV(1) (p = 0.02), forced expiratory flow (p = 0.002), FEV(1)/FVC (p = 0.007),
      provocative concentration of histamine causing a 20% fall in FEV(1) (PC(20)) [p =
      0.02], T-cell numbers (p = 0.0005), activated eosinophils (p = 0.01), and numbers
      of macrophages (p = 0.01) in the group treated with 500 microg/d of FP.
      Comparison between groups administered different doses of FP failed to
      demonstrate a dose-response relationship for change from baseline in PC(20) (p =
      0.43), any of the lung function parameters, T-cell numbers (p = 0.64), activated
      T cells (p = 0.46), eosinophils (p = 0.53), activated eosinophils (p = 0.48), or
      macrophage numbers (p = 0.68). CONCLUSION: The apparent lack of a dose-response
      for ICS treatment in patients with asthma further validates the preferential use
      of add-on therapy over increasing the dose of ICS.

PMID- 12475835
TI  - Patterns of inhaled asthma medication use: a 3-year longitudinal analysis of
      prescription claims data from British Columbia, Canada.
AB  - STUDY OBJECTIVES: To assess trends in asthma management and to identify factors
      associated with increasing short-acting (SA) beta-agonist utilization in British
      Columbia using administrative prescription data. DESIGN: A retrospective cohort
      analysis. SETTING: All patients between 13 and 50 years of age who had received
      at least one prescription for a SA beta-agonist covered by BC Pharmacare between
      January 1, 1996, and December 31, 1998. METHODS: Cross-sectional analysis of all
      patients, and longitudinal analyses only of patients who had received at least
      one SA beta-agonist prescription in each of the 3 years. Trends in asthma
      medication use over time were evaluated using repeated-measures Mantel-Haenszel
      tests. Multiple logistic regression was used to identify factors associated with
      increasing SA beta-agonist use. RESULTS: A total of 78,758 patients were included
      in the cohort. No decrease in the annual prevalence of receiving more than four
      canisters per year of a SA beta-agonist was identified between 1996 and 1998. A
      total of 12,844 patients filled at least one SA beta-agonist prescription each
      year. Time-trend analysis showed an overall increasing probability of not
      receiving an inhaled corticosteroid (ICS) agent in this population (p = 0.002).
      In patients exhibiting low SA beta-agonist use, > 18 years of age (adjusted odds
      ratio [OR], 1.5), male gender (adjusted OR, 1.7), and in receipt of social
      assistance (adjusted OR, 2.3) were associated with receiving increasing amounts
      of SA beta-agonist agents over the 3 years. In patients with a high degree of use
      of SA beta-agonists, only the receipt of social assistance (adjusted OR, 1.3) was
      significantly associated with increasing use. CONCLUSIONS: Despite the
      development and dissemination of asthma management guidelines, there was no trend
      toward decreasing SA beta-agonist use. An unexpected trend toward decreasing ICS
      utilization was identified. Receiving social assistance was a risk factor for
      increasing SA beta-agonist use, independent of baseline utilization.

PMID- 12475836
TI  - Comparison of single 7.5-mg dose treatment vs sequential multidose 2.5-mg
      treatments with nebulized albuterol in the treatment of acute asthma.
AB  - STUDY OBJECTIVE: s: The purpose of the current trial was to compare the relief of
      airway obstruction from treatment with a single dose of albuterol,7.5 mg (single
      dose group), with that from three sequential doses of albuterol, 2.5 mg, spaced
      20 min apart (multidose group). DESIGN: Randomized clinical trial designed to
      test equivalence. SETTING: Urban county hospital emergency department. PATIENTS
      OR PARTICIPANTS: Adult patients between the ages of 18 and 60 years presenting to
      the emergency department with acute asthma, as defined by the American Thoracic
      Society criteria, with FEV (1) on presentation to the emergency department of <
      or = 75% of predicted were included in the study. INTERVENTIONS: After the
      initial evaluation, patients were administered either albuterol, 2.5 mg via
      nebulizer every 20 min for a total of three doses, or albuterol 7.5 mg via
      nebulizer in a single dose. MEASUREMENTS AND RESULTS: Ninety-four patients
      participated, 46 in the single-dose group and 48 in the multidose group. Patients
      in both groups had severe obstruction on presentation to the emergency department
      (single-dose group pretreatment FEV(1), 45% of predicted [SD, 16% of predicted];
      multidose group pretreatment FEV(1), 47% of predicted [SD, 17% of predicted]; p =
      0.62). The primary outcome measure was the change in FEV(1) percent predicted
      over time. The secondary outcome measures were disposition after treatment (ie,
      hospitalization or discharge to home) and the incidence of side effects. We noted
      a 44.5% improvement (SD, 56.2%) in pretreatment to posttreatment FEV(1) values in
      the single-dose group and a 38.1% improvement (SD, 37.3%) in the multidose group
      (p = 0.52). A similar proportion of patients in both groups required
      hospitalization (single-dose group, 48%; multidose group, 41%; p = 0.51). There
      was a trend for the patients in the single-dose group to experience more side
      effects than patients in the multidose group (patients in the single-dose group
      patients, 40% [SD, 19%]; multidose group patients, 22% [SD, 10%]; p = 0.06).
      CONCLUSION: A single dose of 7.5 mg nebulized albuterol and sequential doses of
      2.5 mg nebulized albuterol are clinically equivalent in the treatment of patients
      with moderate-to-severe acute asthma and result in similar dispositions from the
      emergency department.

PMID- 12475837
TI  - Vocal cord dysfunction induced by methacholine challenge testing.
AB  - STUDY OBJECTIVES: To determine whether methacholine challenge testing (MCT)
      provokes vocal cord dysfunction (VCD), as evidenced by inspiratory vocal cord
      closure on direct laryngoscopy, and whether spirometry and flow-volume loops
      (FVLs) demonstrate any changes that are suggestive of VCD. DESIGN: Prospective,
      controlled study. SETTING: Army medical center. PATIENTS: Thirty-four subjects
      all with normal baseline spirometry. Ten subjects had documented evidence of VCD,
      12 subjects had exercise-induced asthma (EIA) and reactive MCT, and 12 subjects
      served as healthy asymptomatic control subjects. METHODS: Measurement of
      spirometry with FVLs and direct laryngoscopy of the vocal cords performed
      immediately before and after subjects had undergone MCT. RESULTS: Evidence of
      inspiratory vocal cord adduction was found in four VCD patients. Two patients had
      adducted vocal cords at baseline, and their conditions were unchanged after
      undergoing MCT. Two other patients had normal conditions at baseline and
      demonstrated acute inspiratory vocal cord adduction after undergoing MCT. None of
      the patients in the EIA or control groups had evidence of VCD at baseline or
      after undergoing MCT. Truncation of the inspiratory limb of the FVL after MCT was
      noted in five patients, which correlated with evidence of VCD in 60% of these
      patients. One EIA patient had truncation of the inspiratory FVL after MCT, and no
      changes were found in the control group. A comparison of spirometry between EIA
      patients and VCD patients with and without evidence of inspiratory vocal cord
      adduction during MCT showed no significant differences. CONCLUSIONS: The findings
      suggest that MCT may cause an acute episode of vocal cord adduction and that
      positive results may not reflect underlying reactive airways disease. However, a
      flattening or truncation of the inspiratory FVL after the patient undergoes MCT
      is not diagnostic for the presence of inspiratory vocal cord adduction.

PMID- 12475838
TI  - Costs of COPD in Sweden according to disease severity.
AB  - OBJECTIVES: COPD is a common and disabling disease that entails high costs for
      society. The objectives of this study were to measure the societal costs of COPD
      in Sweden, and to examine the relationship between severity of illness and costs.
      METHODS: The costs of COPD were examined using a well-defined and representative
      cohort of subjects with mild, moderate, and severe COPD. Regular telephone
      interviews regarding resource utilization were made to a cohort of 212 subjects
      with COPD derived from studies of the general population in Northern Sweden.
      RESULTS: The annual per capita cost for COPD in Swedish crowns (SEK) was
      estimated at SEK 13,418 (1,284 US dollars (USD); 1,448 euros (EUR). The direct
      and indirect costs were SEK 5,592 (42%) and SEK 7,828 (58%), respectively. A
      highly significant relationship was found between severity of disease and costs.
      Costs for severe disease were 3 times as high as costs for moderate disease and >
      10 times as high as for mild disease. Large individual variations in the level of
      costs were found. CONCLUSION: Assuming that the prevalence and treatment patterns
      are representative of Sweden as a whole, the total costs of COPD to society in
      1999 were estimated at SEK 9.1 billion (USD 871 million; EUR 982 million).
      Subjects with mild disease (83%) accounted for 29%, while subjects with moderate
      disease (13%) accounted for 41% of the total costs. The subjects with severe
      disease (4%) accounted for the remainder (30%). Prevention, early diagnosis, and
      postponement of disease progression should have large monetary and policy
      implications.

PMID- 12475839
TI  - Characteristics of adults dying with COPD.
AB  - STUDY OBJECTIVE: To describe factors associated with COPD deaths in the United
      States. DESIGN: Cross-sectional survey. PARTICIPANTS: A total of 12,803 decedents
      in the National Mortality Followback Survey, a nationally representative sample
      of US deaths in 1993. METHODS: We compared the characteristics of adults > or =
      35 years of age who died with COPD (bronchitis, emphysema, chronic airway
      obstruction) with those dying without COPD listed on their death certificates.
      RESULTS: Of the estimated 225,400 adults who died with COPD in 1993, 16.7% had
      never smoked. People dying with COPD were more likely than those dying without
      COPD to be current smokers (odds ratio [OR], 6.5; 95% confidence interval [CI],
      4.3 to 9.9) or former smokers (OR, 3.7; 95% CI, 2.5 to 5.3), have a history of
      asthma (OR, 5.0; 95% CI, 3.2 to 7.8), be underweight (OR, 4.5; 95% CI, 2.8 to
      7.2), and be of the white race (OR, 3.1; 95% CI, 2.4 to 4.0), after controlling
      for age group and sex. CONCLUSIONS: A significant proportion of COPD-related
      deaths occurs in never-smokers. Factors such as a history of asthma and being
      underweight are associated with COPD mortality and may provide additional
      opportunities for intervention.

PMID- 12475841
TI  - Nebulized 3% hypertonic saline solution treatment in ambulatory children with
      viral bronchiolitis decreases symptoms.
AB  - OBJECTIVE: To determine the utility of inhaled hypertonic saline solution to
      treat ambulatory infants with viral bronchiolitis. DESIGN: Randomized, double
      blind, controlled trial. Sixty-five ambulatory infants (mean +/- SD age, 12.5 +/-
      6 months) with viral bronchiolitis received either of the following: inhalation
      of 0.5 mL (5 mg) terbutaline added to 2 mL of 0.9% saline solution as a wet
      nebulized aerosol (control; group 1; n = 32) or 0.5 mL (5 mg) terbutaline added
      to 2 mL of 3% saline solution administered in the same manner as above
      (treatment; group 2; n = 33). This therapy was repeated three times every day for
      5 days. RESULTS: The clinical severity (CS) scores at baseline on the first day
      of treatment were 6.4 +/- 1.8 in group 1 and 6.6 +/- 1.5 in group 2 (not
      significant). After the first day, the CS score was significantly lower (better)
      in group 2 as compared to group 1 on each of the treatment days (p < 0.005; Fig 1
      ). On the first day, the percentage decrease in the CS score after inhalation
      therapy was significantly better for group 2 (33%) than for group 1 (13%) [p <
      0.005; Fig 1 ]. On the second day, the percentage improvement was better in the
      hypertonic saline solution-treated patients (group 2) as compared to the 0.9%
      saline solution-treated patients (group 1) [p = 0.01; Fig 1 ]. CONCLUSIONS: We
      conclude that in nonasthmatic, nonseverely ill ambulatory infants with viral
      bronchiolitis, aerosolized 3% saline solution plus 5 mg terbutaline is effective
      in decreasing symptoms as compared to 0.9% saline solution plus 5 mg terbutaline.

PMID- 12475840
TI  - Inspiratory capacity and decrease in lung hyperinflation with albuterol in COPD.
AB  - STUDY OBJECTIVES: Inspiratory capacity (IC) has been proposed as a simple method
      to assess acute changes in functional residual capacity (FRC) with
      bronchodilation, assuming that total lung capacity (TLC) is unchanged. This
      assumption is based on studies using body plethysmography, which may not
      accurately measure TLC in severely obstructed subjects. The aim of this study is
      to validate the use of IC measured by optoelectronic plethysmography (OEP)
      [ICOEP], a noninvasive technique capable of computing changes in absolute lung
      volumes with great accuracy. MEWTHODS AND MEASUREMENTS: We studied 13 subjects
      with COPD in clinically stable condition at baseline and after 200 microg of
      inhaled albuterol. Changes in lung volumes were obtained from changes in chest
      wall volume (Vcw) measured by OEP and were compared with those measured by
      standard techniques. RESULTS: Albuterol treatment caused a small but significant
      increase in FEV(1) and FVC, a significant decrease of Vcw at FRC (VcwFRC), but no
      changes of Vcw at TLC (VcwTLC) and breathing pattern variables. The reduction of
      VcwFRC was not correlated with either spirometric or breathing-pattern variables.
      IC measured with a pneumotachograph was highly correlated with and not
      significantly different from ICOEP (p < 0.001). CONCLUSIONS: A single dose of
      inhaled albuterol does not significantly modify VcwTLC in subjects with COPD,
      thus validating the use of IC to measure changes of FRC in the assessment of
      reversibility of airway obstruction.

PMID- 12475842
TI  - Improved sputum expectoration following a single dose of INS316 in patients with
      chronic bronchitis.
AB  - Uridine 5'-triphosphate (UTP) is a naturally occurring agonist for P2Y(2)
      receptors on the apical surface of ciliated respiratory epithelium. UTP
      stimulates salt and water transport and cilia beat frequency in human airway
      epithelium in vitro. Single, inhaled doses of UTP stimulate mucociliary clearance
      in conscious, intubated sheep and in patients with mild chronic bronchitis
      (smokers and former smokers), suggesting that UTP may be useful for obtaining
      deep-lung sputum specimens suitable for diagnostic purposes. STUDY OBJECTIVE: UTP
      is being developed for the cytologic diagnosis of lung cancer under the compound
      number INS316 Solution for Inhalation (Inspire Pharmaceuticals; Durham, NC). Its
      ability to improve the quality of expectorated sputum was tested in the current
      study. DESIGN: Placebo-controlled, double-blind, escalating two-period cross-over
      study. SETTING: Outpatient volunteers. PATIENTS OR PARTICIPANTS: Twenty-six
      patients with mild chronic bronchitis. INTERVENTION: Patients attempted to
      expectorate a specimen spontaneously, following a single inhaled dose of INS316
      (10 to 180 mg), and following placebo. MEASUREMENTS AND RESULTS: Sputum weight,
      sputum cell content, spirometry, and oxyhemoglobin saturation. Only 28% of these
      patients were able to expectorate a macrophage-containing, deep-lung specimen
      spontaneously or following inhalation of placebo. In contrast, 85% of the
      patients were able to produce a specimen following inhalation of INS316. The
      average weight of the sputum expectorated was increased fourfold by placebo and
      10-fold by INS316. A mild transient decrease in pulmonary function was observed
      following INS316 administration. CONCLUSION: A single dose of INS316 safely
      improves the ability of patients with mild chronic bronchitis to expectorate a
      deep-lung sputum specimen suitable for cytologic evaluation.

PMID- 12475843
TI  - Validation of the Hong Kong Chinese version of the St. George Respiratory
      Questionnaire in patients with bronchiectasis.
AB  - STUDY OBJECTIVES: To validate the Hong Kong Chinese version of the St. George
      Respiratory Questionnaire (SGRQ-HK) in patients with bronchiectasis. DESIGN AND
      SETTING: Outpatients (93 patients; 61 women; mean age [+/- SD], 59.0 +/- 14.2
      years) were assessed at baseline by the SGRQ-HK, the Hong Kong Chinese version of
      the 36-item short form health survey (SF-36-HK), and the hospital anxiety and
      depression scale (HADS). Forty randomly selected patients also were reassessed at
      2 weeks for repeatability. Seventy-two patients were further reassessed at 6
      months for responsiveness. MEASUREMENTS AND RESULTS: Cronbach alpha coefficients,
      which reflected internal consistency, were > 0.7 for all SGRQ-HK components
      except for symptoms (alpha = 0.59), and the intraclass correlation coefficients
      between baseline and the 2-week follow-up visits were between 0.80 and 0.94 (p >
      0.05). SGRQ-HK component scores and total scores correlated with all the
      component scores of the SF-36-HK and the HADS (p < 0.02). SGRQ-HK component
      scores and total scores correlated with the scores of the SF-36-HK and the HADS,
      confirming the concurrent validity. All SGRQ-HK scores correlated negatively with
      FEV(1), FVC, and arterial oxygen saturation (p < 0.005), while the activity score
      correlated with the Karnofsky performance scale and the number of bronchiectatic
      lobes (p < 0.001). SGRQ-HK scores positively correlated with Borg scale scores,
      exacerbation frequency, and 24-h sputum volumes (p < 0.03). Patients with 24-h
      sputum volumes of > or = 10 mL or < 10 mL had significantly different SQRG-HK
      component scores and total scores (p < 0.002), although this sensitivity was not
      displayed by scores on the HADS or the SF-36-HK. Patients with 25% reductions in
      24-h sputum volumes had significant improvements in SGRQ-HK activity scores,
      impact scores, and total scores (p < 0.02), but not in other quality-of-life
      measures or clinical parameters, indicating the responsiveness of the SGRQ-HK.
      CONCLUSION: The SGRQ-HK is a valid and sensitive instrument for determining
      quality of life in bronchiectasis patients.

PMID- 12475844
TI  - Measurement of gastric emptying in gastroesophageal reflux-related chronic cough.
AB  - STUDY OBJECTIVES: Gastroesophageal reflux (GER) is one of the most common causes
      of chronic cough, but the mechanisms of GER-related cough are not well
      understood. We tested the hypothesis that gastric emptying is delayed in patients
      with GER-related chronic cough. DESIGN: We studied 12 patients (7 women; mean
      age, 53 years; age range, 37 to 68 years) with GER-related chronic cough and a
      control group of 27 asymptomatic healthy volunteers (16 women; mean age, 37
      years; age range, 18 to 62 years). Gastric emptying scintigraphy was performed,
      and the time at which 50% of the radiolabeled material had left the stomach
      (T(1/2)) was calculated. RESULTS: There was no statistically significant
      difference in T(1/2) values between healthy volunteers and subjects with GER
      related cough (99 +/- 26 min vs 86 +/- 20 min, respectively; difference between
      the means, 13 min [95% confidence interval, -4 to 30 min]; p = 0.13).
      CONCLUSIONS: Gastric emptying was not delayed in patients with GER-related
      chronic cough. The measurement of gastric emptying did not therefore provide
      further insights into the mechanisms of GER-related cough or clinically relevant
      information that would assist in patient management.

PMID- 12475845
TI  - Immunostimulation with OM-85 in children with recurrent infections of the upper
      respiratory tract: a double-blind, placebo-controlled multicenter study.
AB  - OBJECTIVE: Recurrent upper respiratory tract infections (URTIs) are common
      illnesses in young children. As the immunoactive bacterial extract OM-85 has been
      shown to prevent these infections in both adults and children, the aim of the
      present trial was to investigate further its efficacy and safety in infection
      prone children. METHODS: This is a randomized, double-blind, placebo-controlled,
      multicenter study with OM-85 in 232 patients aged 36 to 96 months with recurrent
      URTIs. Treatment was one capsule daily during month 1 and during 10 days in
      months 3 to 5. URTI was defined by the presence of at least two of the following:
      rhinitis, pharyngitis, cough, hoarseness, temperature > or = 38.5 degrees C, or
      URTI-related prescription of an antibiotic. RESULTS: OM-85-treated patients had a
      lower rate of URTIs (p < 0.05). The cumulated difference in URTIs between the two
      groups reached - 0.40 URTIs per patient in 6 months, corresponding to a 16%
      reduction in the active-treatment group with respect to placebo. The largest
      difference was observed in the patients having had three or more URTIs during the
      study period; odds ratios for three or more URTIs were 0.51 (95% confidence
      interval, 0.29 to 0.91) and 0.65 (95% confidence interval, 0.37 to 1.11) after 5
      months and 6 months, respectively. The difference between OM-85 and placebo was
      independent of age but was more important in patients reporting a larger number
      of URTIs in the previous year. Patients' global assessment showed improvement in
      comparison to the previous season in the majority of the cases (OM-85, 78.4% of
      cases; placebo, 75.5%); however, there were more cases reporting worsening with
      placebo (6.4% vs 0.9%; p = 0.05). CONCLUSIONS: OM-85 treatment significantly
      reduced the rate of URTIs, particularly in children with a history of frequent
      URTIs. Safety and tolerance of test medication were good, comparable to placebo.

PMID- 12475846
TI  - Cardiac troponin T and cardiac enzymes after external transthoracic cardioversion
      of ventricular arrhythmias in patients with coronary artery disease.
AB  - BACKGROUND: Serum levels of cardiac troponins after external cardioversion (ECV)
      for atrial fibrillation and atrial flutter are widely investigated, and no
      increases in cardiac troponin T (cTnT) levels have been reported. However, the
      effect of ECV on cardiac enzyme release may depend on the type of arrhythmias.
      Furthermore, ventricular tachycardia (VT) or ventricular fibrillation (VF) could
      cause release of cardiac enzymes after ECV due to underlying myocardial ischemia,
      myocardial dysfunction, or more pronounced hemodynamic deterioration during
      arrhythmia. AIM: The purpose of this study was to determine whether direct
      current (DC) shock may increase cardiac enzyme levels in patients with coronary
      artery disease undergoing ECV for VT or VF, so that diagnosis of acute myocardial
      infarction, which initially presents with VT or VF, can be excluded. METHOD AND
      RESULTS: We obtained measurement of cTnT, total creatine kinase (CK), and CK MB
      isoenzyme (CK-MB) activity before and after ECV in 27 patients (mean +/- SD age,
      62 +/- 13 years) with induced VT or VF (22 patients) who required ECV during
      provocative electrophysiologic testing and who underwent ECV due to VT (5
      patients) in the cardiology department. Blood samples were drawn before, and 4 h,
      8 h, and 24 h after ECV. The total energy used was 630 +/- 375 J (range, 200 to
      1,280 J). CK levels rose to the upper limit of reference range in seven patients
      (26%), and CK-MB activity was higher than the normal reference range in five
      patients (19%) after ECV. In contrast, cTnT concentrations remained within the
      normal range (< 0.1 micro g/L) in all patients. Peak CK and CK-MB activity levels
      strongly correlated with the total energy delivered. CONCLUSION: Elevation of
      cTnT level after an urgent DC shock strongly indicates the diagnosis of acute
      myocardial infarction presented with life-threatening arrhythmias, rather than
      myocardial damage caused by ECV.

PMID- 12475847
TI  - Ventricular arrhythmias in patients with COPD are associated with QT dispersion.
AB  - STUDY OBJECTIVE: QT dispersion (QTd) and late potentials derived from signal
      averaged ECG (SAECG) have been proposed as noninvasive predictors of cardiac
      arrhythmias that occur in patients with COPD. In this study, we aimed to
      investigate QTd and SAECG in patients with COPD. DESIGN: Cross-sectional study.
      SETTING: Teaching chest disease hospital and cardiology center in a university
      hospital. PATIENTS: Thirty patients with COPD (28 men and 2 women; mean +/- SD
      age, 60 +/- 9 years) and 31 age- and sex-matched control subjects (28 men and 3
      women; mean age, 57 +/- 7 years) were included. MEASUREMENTS AND RESULTS:
      Respiratory function tests, arterial blood gas analyses, echocardiographic
      examinations, rhythm Holter recordings, and heart rate variability (HRV) analyses
      were performed in addition to the measurements of QT intervals and SAECG.
      Patients with COPD had higher rate of ventricular premature beats (VPBs) as
      compared to control subjects (924 +/- 493 beats vs 35 +/- 23 beats, p = 0.009).
      Eight patients with COPD (27%) had nonsustained runs of ventricular tachycardia
      (VT). QTd rates were significantly increased in patients with COPD as compared to
      control subjects (57.7 +/- 9.9 ms vs 37.5 +/- 8.2 ms, p < 0.001). On comparing
      patients with COPD with and without runs of VT, patients with VT had longer QTd
      (67 +/- 10 ms vs 55 +/- 8 ms, p = 0.001). However no difference in any HRV and
      late potential parameters were found between patients with COPD with and without
      runs of VT. VPB rates were strongly correlated with QTd in patients with COPD (r
      = 0.61, p < 0.001). On SAECG analysis, patients with COPD had significantly
      increased total QRS duration as compared to control subjects. Nine of the 30
      patients with COPD (30%) had positive late potentials. However, QTd and VPB rates
      were also similar between patients with COPD with and without late potentials.
      CONCLUSIONS: The development of ventricular arrhythmia in patients with COPD was
      associated with increased QTd. Increased QTd may be associated with autonomic
      changes seen in patients with COPD.

PMID- 12475848
TI  - Carvedilol reduces the inappropriate increase of ventilation during exercise in
      heart failure patients.
AB  - STUDY OBJECTIVE: To evaluate the effects of beta-blockers on ventilation in heart
      failure patients. Indeed, beta-blockers ameliorate the clinical condition and
      cardiac function of heart failure patients, but not exercise capacity. Because
      ventilation is inappropriately elevated in heart failure patients due to
      overactive reflexes from ergoreceptors and chemoreceptors, we hypothesized that
      beta-blockers can elicit their positive clinical effects through a reduction of
      ventilation. DESIGN: This was a double-blind, randomized, placebo-controlled
      study. SETTING: University hospital heart failure unit. PATIENTS AND
      INTERVENTIONS: While receiving placebo (2 months) and a full dosage of carvedilol
      (4 months), 15 chronic heart failure patients were evaluated by quality-of-life
      questionnaire, pulmonary function tests, cardiopulmonary exercise tests with
      constant workload, and a ramp protocol. RESULTS: Therapy with carvedilol did not
      affect resting pulmonary function and exercise capacity. However, carvedilol
      improved the results of the quality-of-life questionnaire, reduced the mean (+/-
      SD) slope of the minute ventilation (E)/carbon dioxide output (CO(2)) ratio (from
      36.4 +/- 8.9 to 31.7 +/- 3.8; p < 0.01) and reduced ventilation at the following
      times: at peak exercise (from 60 +/- 14 to 48 +/- 15 L/min; p < 0.05); during the
      intermediate phases of a ramp-protocol exercise; and during the steady-state
      phase of a constant-workload exercise (from 42 +/- 14 to 34 +/- 13 L/min; p <
      0.05, at third min). The end-expiratory pressure for carbon dioxide increased as
      ventilation decreased. The reduction in the E/CO(2) ratio was correlated with
      improvement in quality of life (r = 0.603; p < 0.02). CONCLUSIONS: Improvement in
      the clinical conditions of heart failure patients treated with carvedilol is
      associated with reductions in the inappropriately elevated ventilation levels
      observed during exercise.

PMID- 12475849
TI  - Clinical features and outcome of patients with direct percutaneous coronary
      intervention for acute myocardial infarction resulting from left circumflex
      artery occlusion.
AB  - BACKGROUND: Little is known about the clinical features and outcome of patients
      with left circumflex artery (LCX) infarct-related acute myocardial infarction
      (AMI). This study was conducted to investigate the clinical features and outcome
      of patients who underwent direct percutaneous coronary intervention (d-PCI) for
      AMI caused by LCX occlusion, and to discover prognostic determinants in this
      clinical setting. METHODS AND RESULTS: Between May 1993 and October 2000, a total
      of 819 patients with AMI underwent d-PCI in our hospital. Sixty-seven patients
      (8.2%) who had LCX infarct-related AMI constituted the population of this study.
      Ten of 67 patients (14.9%) were in cardiogenic shock. Angiographic findings
      demonstrated that the incidences of triple-vessel disease, reference lumen
      diameter (RLD) of the LCX > or = 4.0 mm, and LCX as the dominant artery in these
      patients were 26.9%, 22.4%, and 34.3%, respectively. Sixteen patients (23.9%) had
      unsuccessful reperfusion (defined as Thrombolysis in Myocardial Infarction flow <
      or = 2). Univariate analysis showed that dominant LCX, RLD of the LCX > or = 4.0
      mm, cardiogenic shock, precordial ST-segment depression, and complete
      atrioventricular block were significantly related to unsuccessful reperfusion.
      Multiple stepwise logistic regression analysis demonstrated that dominant LCX and
      cardiogenic shock were significant independent predictors of unsuccessful
      reperfusion. The 30-day mortality rate in the 67 patients was 14.9%. Univariate
      analysis demonstrated that triple-vessel disease, dominant LCX, cardiogenic
      shock, poor left ventricular ejection fraction, and unsuccessful reperfusion were
      significantly associated with 30-day mortality. By multiple stepwise logistic
      regression analysis, dominant LCX, cardiogenic shock, and triple-vessel disease
      were significant independent predictors of increased 30-day mortality.
      CONCLUSIONS: LCX infarct-related AMI has its unique clinical features. The
      presence of dominant LCX and cardiogenic shock were independent determinants of
      unsuccessful reperfusion, and the presence of dominant LCX, cardiogenic shock,
      and triple-vessel disease were independent determinants of increased 30-day
      mortality in this clinical setting.

PMID- 12475850
TI  - Midterm clinical results in myocardial revascularization using the radial artery.
AB  - STUDY OBJECTIVES: The aim of this study was to evaluate the immediate and midterm
      results of coronary artery bypass grafting with the radial artery (RA) as a
      conduit. PATIENTS: Two hundred forty-one patients underwent myocardial
      revascularization using the RA. In 78.5% of patients, three coronary vessels were
      involved, and in 25% of patients, the left main coronary artery was involved. The
      mean (+/- SD) preoperative ejection fraction was 58 +/- 13%. INTERVENTIONS: The
      RA was implanted on branches of the circumflex artery in 81% of the cases, and
      the left internal mammary artery was implanted on the left anterior descending
      artery in 94% of patients. Total arterial myocardial revascularization was
      performed in 58% of patients. MEASUREMENTS AND RESULTS: The in-hospital mortality
      rate was 0.8%. Two patients had acute myocardial infarction, and three patients
      experienced a transient low-cardiac output syndrome. We reviewed the records of
      all 171 patients who had undergone at least 6 months of follow-up after surgery.
      The late mortality rate in this group was 0.6% (one patient died 2 months after
      surgery because of cardiocirculatory arrest due to untreatable ventricular
      fibrillation). At a mean follow-up time of 545 +/- 253 days, two patients showed
      class 3 residual angina according to the Canadian Cardiovascular Society (CCS)
      guidelines. One patient required another hospital admission 6 months after
      undergoing surgery for PTCA/stenting on a circumflex artery that had not
      previously undergone bypass. The second patient, 8 months after undergoing
      coronary artery bypass grafting, underwent angiography and stenting on a stenosed
      anastomosis of a posterolateral branch of the circumflex artery that previously
      had been bypassed with the right internal mammary artery. CONCLUSIONS: The
      routine use of the RA for coronary bypass grafting is a safe surgical technique,
      providing excellent clinical mid-term results in terms of cardiac event-free
      expectancy.

PMID- 12475851
TI  - Prognostic value of extravascular lung water in critically ill patients.
AB  - OBJECTIVE: Measurement of extravascular lung water (EVLW) as a clinical tool for
      the assessment of pulmonary function has been found to be more appropriate than
      oxygenation parameters or radiographic techniques. In this study, we analyzed the
      prognostic value of EVLW in critically ill patients. DESIGN: Retrospective
      analysis. SETTING: Operative ICU of a university hospital. MEASUREMENTS AND
      RESULTS: We retrospectively analyzed 373 critically ill patients (133 female and
      240 male patients; 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 infradiaphragmatic aorta. EVLW was calculated using a computer system.
      For each measurement, 15 to 17 mL of cooled 2% indocyanine green were injected
      central venously. In our results, maximum EVLW was significantly higher in
      nonsurvivors (n = 186) than in survivors (n = 187) [median, 14.3 mL/kg vs 10.2
      mL/kg, respectively; p < 0.001]. In univariate logistic regression models, EVLW
      (r(2) = 0.024, p = 0.003) at baseline as well as simplified acute physiology
      score (SAPS) II (r(2) = 0.135, p < 0.0001) and APACHE (acute physiology and
      chronic health evaluation) II scores (r(2) = 0.050, p < 0.0001) were significant
      predictors of mortality. If SAPS II and APACHE II scores are combined, r(2)
      increases to 0.136, but the improvement over SAPS II alone is not significant.
      The addition of baseline EVLW further increases r(2) to 0.149 (p = 0.021 for the
      improvement), indicating that EVLW contributes independently to prognosis.
      CONCLUSION: EVLW correlated well with survival (ie, nonsurvivors had
      significantly higher EVLW values than survivors) and is an independent predictor
      of prognosis.

PMID- 12475852
TI  - Findings on the portable chest radiograph correlate with fluid balance in
      critically ill patients.
AB  - STUDY OBJECTIVES: Fluid balance concerns occur daily in critically ill patients,
      complicated by difficulties assessing intravascular volume. Chest radiographs
      (CXRs) quantify pulmonary edema in acute lung injury (ALI) and total blood volume
      in normal subjects. We hypothesized that CXRs would reflect temporal changes in
      fluid balance in critically ill patients. DESIGN: Standardized scoring of 133
      supine, portable, anteroposterior CXRs. Outcomes included subjective and
      objective measures of intravascular volume and pulmonary edema. SETTING: Academic
      university medical center and affiliated Veterans Affairs hospital. PATIENTS:
      Thirty-seven patients with ALI receiving mechanical ventilation blindly
      randomized to treatment with diuretics and colloids or dual placebo for 5 days.
      MEASUREMENTS AND RESULTS: Treated patients experienced a 3.3-L diuresis and 10-kg
      weight loss during the 5-day period. A significant correlation was observed in
      all patients between changes in vascular pedicle width (VPW) and net
      intake/output (r = 0.50, p = 0.01) or weight (r = 0.51, p = 0.01). The
      correlation between VPW and fluid balance was greatest for weight changes in the
      treatment group alone (r = 0.71, p = 0.005). Pulmonary artery occlusion pressure
      correlated highly with changes in VPW (r = 0.70, p < 0.001). After day 1, CXRs
      revealed significant between-group differences in VPW without changes in
      cardiothoracic ratio or subjective measures of edema. The proportion of patients
      with VPW < 70 mm did not differ at baseline but was significantly more in the
      treatment group on all subsequent days (p < 0.05). CONCLUSIONS: We conclude that
      temporal fluid balance changes are reflected on commonly utilized portable CXRs.
      Objective radiographic measures of intravascular volume may be more appropriate
      indicators of fluid balance than subjective measures, with VPW appearing most
      sensitive. If systematically quantitated, serial CXRs provide a substantial
      supplement to other clinically available data for the purpose of fluid management
      in critically ill patients.

PMID- 12475853
TI  - Effects of inspiratory flow waveforms on lung mechanics, gas exchange, and
      respiratory metabolism in COPD patients during mechanical ventilation.
AB  - STUDY OBJECTIVE: The clinical usefulness of varying inspiratory flow waveforms
      during mechanical ventilation has not been adequately studied. The aim of this
      study was to compare the effects of three different respiratory waveforms on the
      pulmonary mechanics, gas exchange, and respiratory metabolism of ventilated
      patients with COPD. DESIGN: A randomized and comparative trial of consecutive
      patients. SETTING: Medical ICUs of a 2,000-bed university hospital. PATIENTS:
      Fifty-four patients with COPD were enrolled. INTERVENTIONS: Constant,
      decelerating, and sine waveforms were applied to each patient in a random order.
      MEASUREMENTS AND RESULTS: With tidal volume, inspiratory time, and inspiratory
      frequency being kept constant, the decelerating waveform produced statistically
      significant reductions of peak inspiratory pressure, mean airway resistance,
      physiologic dead space ventilation (VD/VT), PaCO(2), and symptom score. There was
      also a significant increase in alveolar-arterial oxygen pressure difference with
      the decelerating flow waveform, but there were no significant changes in mean
      airway pressure, arterial oxygenation, heart rate, mean BP, and other hemodynamic
      measurements. In addition, assessment on the work of breathing (WOB) revealed
      that ventilator WOB values were reduced with the decelerating waveform. Oxygen
      consumption and carbon dioxide output were virtually not affected by changing
      inspiratory flow waveforms. Except for VD/VT, the effects of constant square and
      sine waveforms were similar to each other and could not be separated
      statistically. CONCLUSIONS: The most favorable flow pattern for ventilated
      patients with COPD appeared to be the decelerating waveform. There are
      possibilities for the improvement of ventilation in these patients by selecting
      an appropriate inspiratory flow.

PMID- 12475854
TI  - Comparison of five bilevel pressure ventilators in patients with chronic
      ventilatory failure: a physiologic study.
AB  - OBJECTIVE: To compare patient-ventilator interaction and comfort in patients with
      chronic ventilatory failure (CVF) who are undergoing noninvasive positive
      pressure ventilation with five different commercial bilevel pressure home
      ventilators. Also, we wanted to evaluate the short-term effects of the five
      ventilators on physiologic variables, namely, breathing patterns and inspiratory
      muscles. DESIGN: Randomized, controlled physiologic study. SETTING: Pulmonary
      division of a rehabilitation institution. PATIENTS: Twenty-eight patients with
      CVF due to COPD (17 patients) and restrictive chest wall diseases (11 patients).
      MEASUREMENTS: Sensation of comfort, breathing patterns and minute ventilation
      (E), respiratory muscles and mechanics, and patient-ventilator interaction during
      both unassisted and assisted ventilation with the five ventilators applied
      randomly. RESULTS: The five ventilators showed different flow and pressure
      waveforms. The level of comfort was somehow different among the studied
      ventilators. When compared to unassisted ventilation, all ventilators induced a
      significant increase in E (p < 0.01) without any significant difference among
      ventilators. Use of the five ventilators resulted in significant differences in
      peak airway opening pressure (Pao,peak) but not in mean airway opening pressure
      computed over a period of 1 min (PTPao,min), and in a duty cycle. Ineffective
      efforts (IEs) were similar among the studied ventilators. In comparison with
      unassisted ventilation, all ventilators induced significant reductions in
      inspiratory muscle effort (p < 0.001). No significant relationship was found
      between level of comfort and PTPao,min, Pao,peak, or the number of IEs.
      CONCLUSIONS: In stable, awake patients with CVF, all of the studied ventilators
      were well-tolerated, although with a great intersubject variability in comfort,
      and performed well in terms of improvement in E and inspiratory muscle unloading,
      thus fulfilling the aims of mechanical ventilation. This effect was obtained with
      similar levels of PTPao,min, despite the fact that Pao,peak was different among
      some ventilators. The number of IEs was similar among the studied ventilators.

PMID- 12475855
TI  - Epidemiology and outcomes of ventilator-associated pneumonia in a large US
      database.
AB  - OBJECTIVES: To evaluate risk factors for ventilator-associated pneumonia (VAP),
      as well as its influence on in-hospital mortality, resource utilization, and
      hospital charges. DESIGN: Retrospective matched cohort study using data from a
      large US inpatient database. PATIENTS: Patients admitted to an ICU between
      January 1998 and June 1999 who received mechanical ventilation for > 24 h.
      MEASUREMENTS: Risk factors for VAP were examined using crude and adjusted odds
      ratios (AORs). Cases of VAP were matched on duration of mechanical ventilation,
      severity of illness on admission (predicted mortality), type of admission
      (medical, surgical, trauma), and age with up to three control subjects.
      Mortality, resource utilization, and billed hospital charges were then compared
      between cases and control subjects. RESULTS: Of the 9,080 patients meeting study
      entry criteria, VAP developed in 842 patients (9.3%). The mean interval between
      intubation, admission to the ICU, hospital admission, and the identification of
      VAP was 3.3 days, 4.5 days, and 5.4 days, respectively. Identified independent
      risk factors for the development of VAP were male gender, trauma admission, and
      intermediate deciles of underlying illness severity (on admission) [AOR, 1.58,
      1.75, and 1.47 to 1.70, respectively]. Patients with VAP were matched with 2,243
      control subjects without VAP. Hospital mortality did not differ significantly
      between cases and matched control subjects (30.5% vs 30.4%, p = 0.713).
      Nevertheless, patients with VAP had a significantly longer duration of mechanical
      ventilation (14.3 +/- 15.5 days vs 4.7 +/- 7.0 days, p < 0.001), ICU stay (11.7
      +/- 11.0 days vs 5.6 +/- 6.1 days, p < 0.001), and hospital stay (25.5 +/- 22.8
      days vs 14.0 +/- 14.6 days, p < 0.001). Development of VAP was also associated
      with an increase of > $40,000 USD in mean hospital charges per patient ($104,983
      USD +/- $91,080 USD vs $63,689 USD+/- $75,030 USD, p < 0.001). CONCLUSIONS: This
      retrospective matched cohort study, the largest of its kind, demonstrates that
      VAP is a common nosocomial infection that is associated with poor clinical and
      economic outcomes. While strategies to prevent the occurrence of VAP may not
      reduce mortality, they may yield other important benefits to patients, their
      families, and hospital systems.

PMID- 12475856
TI  - Lung damage in experimental pleurodesis induced by silver nitrate or talc: 1-year
      follow-up.
AB  - STUDY OBJECTIVE: To compare the lung damage caused by intrapleural silver nitrate
      (SN) with that caused by talc over a 12-month period. DESIGN: One hundred forty
      rabbits received an intrapleural injection of 0.5% SN or 400 mg/kg talc slurry in
      2 mL saline solution. Groups of 10 rabbits were killed after 1, 2, 4, 6, 8, 10,
      or 12 months. The macroscopic pleurodesis, microscopic lung changes (ie,
      collapse, hemorrhage, and edema), and cellular infiltrates (number and proportion
      of cells) were graded on a scale of 0 to 4. RESULTS: The mean (+/- SEM) adhesion
      score after SN injection (3.3 +/- 0.1) was higher (p < 0.001) than that after
      talc injection (2.3 +/- 0.1). The mean alveolar collapse score was greater (p <
      0.001) 1 month after SN injection (2.2 +/- 0.3) than after talc injection (0.2 +/
      0.1) and was similar from the second month on. The degree of parenchymal
      hemorrhage, by alveolar collapse score, (SN injection, 0.2 +/- 0.1; talc
      injection, 0.2 +/- 0.0) and edema (SN injection, 0.4 +/- 0.1; talc injection, 0.3
      +/- 0.1) was minimal in both groups (p > 0.05). One month after the injection,
      the total number of inflammatory cells was greater (p < 0.001) in rabbits that
      had received SN injections (2.7 +/- 0.3) than in those that had received talc
      injections (1.2 +/- 0.1). From the second month on, cellularity decreased and
      became similar in both groups. The cellular profile was different, with a
      predominantly neutrophilic reaction after talc injection and a predominantly
      eosinophilic reaction after SN injection. CONCLUSIONS: Rabbits injected with
      intrapleural 0.5% SN had significantly higher scores for adhesions than did those
      that had received talc injections, with mild and reversible alveolar collapse and
      an eosinophilic responses, conditions showing a clear tendency to normalize with
      time.

PMID- 12475857
TI  - Effects of nebulized diethylenetetraamine-NONOate in a mouse model of acute
      Pseudomonas aeruginosa pneumonia.
AB  - OBJECTIVE: Endogenous and exogenous nitric oxide (NO) may have important
      antibacterial effects in patients with pneumonia. NO administration has been
      limited to the continuous inhalation of gas-phase NO (ie, inhaled NO [iNO]).
      Intermittent nebulization of NONOates, novel NO donors, may permit the continuous
      intrapulmonary delivery of NO. Thus, we assessed the effects of nebulized
      diethylenetetraamine-NONOate (DETA-NO) in a model of acute Pseudomonas aeruginosa
      pneumonia. DESIGN: Randomized, controlled study. SUBJECTS: Male C57Bl/6 mice.
      INTERVENTIONS: Pneumonia was induced by intratracheal instillation of P
      aeruginosa (3 x 10(7) CFU in 50 microL). Pneumonia and sham mice were randomized
      to receive no treatment, nebulized DETA-NO (12.5 or 125 micromol) at 4 h and 12
      h, or continuous iNO for 24 h (10 or 40 ppm) until they were killed at 24 h. MAIN
      RESULTS: The nebulization of DETA-NO was associated with a marked increase in
      mean (+/- SEM) exhaled NO levels (after nebulization, 484 +/- 34 parts per
      billion [ppb]; baseline, 13.4 +/- 0.4 ppb; p < 0.01) and plasma levels of
      nitrites/nitrates (after nebulization, 73 +/- 28 microM; at baseline, 14 +/- 3
      microM; p < 0.05). Nebulized DETA-NO decreased the pulmonary bacterial load in
      mice with pneumonia by 65 +/- 19% (p < 0.05 vs untreated mice) but had no effect
      on pulmonary leukocyte infiltration. Although the growth of P aeruginosa colonies
      in vitro was impaired on exposure to DETA-NO, growth was similarly impaired by
      exposure to DETA nucleophile/backbone alone. CONCLUSIONS: The nebulization of
      DETA-NO provides a method for the prolonged intrapulmonary delivery of NO. The
      antibacterial effect of DETA-NO in vivo and in vitro is due, in large part, to
      the DETA nucleophile moiety and is independent of NO, suggesting a limited
      therapeutic role for exogenous NO in pneumonia.

PMID- 12475858
TI  - Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1
      messenger RNA induction and leukocyte migration: role in preventing lung injury
      and fibrosis in bleomycin-challenged mice.
AB  - BACKGROUND AND OBJECTIVE: Although the pathogenesis of interstitial pneumonia and
      pulmonary fibrosis are not well understood, it has been reported that
      inflammatory cells, especially neutrophils, and the injurious substances produced
      by them play important roles in the progression of interstitial pneumonia and
      subsequent fibrosis. Erythromycin and other 14-membered ring macrolides (14
      MRMLs) have been reported to improve the survival of patients with diffuse
      panbronchiolitis by antineutrophil and several other anti-inflammatory
      mechanisms. The present study was undertaken to investigate the effects of 14
      MRMLs on an experimental model of bleomycin-induced acute lung injury and
      subsequent fibrosis in mice. METHODS: Bleomycin was administered IV to ICR mice.
      At 28 days after bleomycin injection, fibrotic foci were histologically observed
      in left lung tissues, and hydroxyproline content in right lung tissues was
      chemically analyzed. The inhibitory effects of 14-MRMLs were assessed by overall
      comparison between control (normal saline solution [NS] alone), untreated
      (bleomycin alone), and treated (bleomycin plus 14-MRMLs) groups. For evaluation
      of early-phase inflammation, cell populations in BAL fluid and induction of
      messenger RNA (mRNA) of adhesion molecules (E-selectin, P-selectin, intercellular
      adhesion molecule 1 [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) in
      lung tissues were examined at 0 to 13 days after bleomycin treatment. These
      parameters were also compared with those for the control (NS alone), 14-MRML
      untreated (bleomycin alone), and 14-MRML pretreated (bleomycin plus 14-MRML
      pretreated) groups. RESULTS: Bleomycin-induced pulmonary fibrosis was inhibited
      by erythromycin and other 14-MRMLs on day 28 after bleomycin injection in ICR
      mice, especially those pretreated with 14-MRMLs. Hydroxyproline content in lung
      tissues was also decreased in the 14-MRML-pretreated groups. The number of
      neutrophils in BAL fluid significantly increased, with two peaks at 1 day and 9
      days (from 6 to 11 days) after bleomycin administration. 14-MRMLs significantly
      inhibited both peaks of neutrophil infiltration into the airspace. Changes in
      mRNA expression of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1)
      were associated with leukocyte migration into the airspace. 14-MRMLs clearly
      inhibited the induction of VCAM-1 mRNA, and tended to attenuate that of ICAM-1
      mRNA, but inhibited the induction of neither E-selectin mRNA nor P-selectin mRNA.
      CONCLUSION: These findings indicate that attenuation of inflammatory cell
      migration into the airspace by 14-MRMLs, especially of neutrophils and
      macrophages, resulted in inhibition of lung injury and subsequent fibrosis. 14
      MRMLs clearly attenuated the expression of VCAM-1 mRNA during the early phase of
      bleomycin-induced lung injury, and this might be one mechanism of inhibition of
      neutrophil and macrophage migration into the airspace by 14-MRMLs. This may be
      one mechanism of the anti-inflammatory and antifibrotic effects of 14-MRMLs.
      These findings suggest that prophylactic administration of 14-MRMLs may be
      clinically efficacious in preventing acute exacerbation of interstitial pneumonia
      and acute lung injury.

PMID- 12475859
TI  - The influence of pulmonary staple line reinforcement on air leaks.
AB  - OBJECTIVES: Although uncommon, prolonged postoperative air leaks are a
      troublesome complication of lung surgery. This study was performed to determine
      if buttressing pulmonary staple lines would reduce air leakage at varying airway
      pressures, and if there was a difference between buttressing materials. METHODS:
      Using cadaver lungs, the development of air leak from staple lines was evaluated
      at incremental airway pressures. Unreinforced staples were compared to staples
      reinforced with bovine pericardium and staples reinforced with expanded
      polytetrafluorethylene (ePTFE). RESULTS: Unreinforced staple lines began to leak
      air at an airway pressure of 20 mm Hg, and > 90% leaked at a pressure of 35 mm
      Hg. Both bovine pericardium and ePTFE significantly reduced the incidence of air
      leak at these airway pressures. At higher airway pressures, ePTFE was superior to
      bovine pericardium. CONCLUSION: Staple line reinforcement with either material
      protects against air leak. Patients at risk for elevated airway pressures and/or
      postoperative ventilator support should be considered for utilization of these
      staple reinforcing materials.

PMID- 12475860
TI  - Lymphoid interstitial pneumonia: a narrative review.
AB  - Lymphoid interstitial pneumonia (LIP) is regarded as both a disease and a
      nonneoplastic, inflammatory pulmonary reaction to various external stimuli or
      systemic diseases. It is an uncommon condition with incidence and prevalence
      rates that are largely unknown. Liebow and Carrington originally classified LIP
      as an idiopathic interstitial pneumonia in 1969. Although LIP had since been
      removed from that category, the most recent consensus classification sponsored by
      the American Thoracic Society and the European Respiratory Society recognizes
      that some cases remain idiopathic in origin, and its clinical, radiographic, and
      pathologic features warrant the return of LIP to its original classification
      among the idiopathic interstitial pneumonias. LIP also belongs within a spectrum
      of pulmonary lymphoproliferative disorders that range in severity from benign,
      small, airway-centered cellular aggregates to malignant lymphomas. It is
      characterized by diffuse hyperplasia of bronchus-associated lymphoid tissue. The
      dominant microscopic feature of LIP is a diffuse, polyclonal lymphoid cell
      infiltrate surrounding airways and expanding the lung interstitium. Classically,
      LIP occurs in association with autoimmune diseases, most often Sjogren syndrome.
      This has led to consideration of an autoimmune etiology for LIP, but its
      pathogenesis remains poorly understood. Persons who are seropositive for HIV, and
      children in particular, are at increased risk of acquiring LIP. Some studies
      suggest causal roles for both HIV and Epstein-Barr virus. The incidence of LIP is
      approximately twofold greater in women than men. The average age at diagnosis is
      between 52 years and 56 years. Symptoms of progressive cough and dyspnea
      predominate. There is great variability in the clinical course of LIP, from
      resolution without treatment to progressive respiratory failure and death.
      Although LIP is often regarded as a steroid-responsive condition, and oral
      corticosteroids continue to be the mainstay of therapy, response is
      unpredictable. Approximately 33 to 50% of patients die within 5 years of
      diagnosis, and approximately 5% of cases of LIP transform to lymphoma.

PMID- 12475861
TI  - Hormones and breathing.
AB  - A number of hormones, including hypothalamic neuropeptides acting as
      neurotransmitters and neuromodulators in the CNS, are involved in the physiologic
      regulation of breathing and participate in adjustment of breathing in disease. In
      addition to central effects, some hormones also control breathing at peripheral
      chemoreceptors or have local effects on the lungs and airways. Estrogen and
      progesterone seem to protect from sleep-disordered breathing, whereas
      testosterone may predispose to it. Progesterone and thyroxine have long been
      known to stimulate respiration. More recently, several hormones such as
      corticotropin-releasing hormone and leptin have been suggested to act as
      respiratory stimulants. Somatostatin, dopamine, and neuropeptide Y have a
      depressing effect on breathing. Animal models and experimental human studies
      suggest that also many other hormones may be involved in respiratory control.

PMID- 12475862
TI  - Nosocomial pneumonia: the importance of a de-escalating strategy for antibiotic
      treatment of pneumonia in the ICU.
AB  - Nosocomial pneumonia is the second most frequent nosocomial infection and
      represents the leading cause of death from infections that are acquired in the
      hospital. In the last decade, a large body of data has accumulated that points to
      the substantial impact of inadequate antibiotic treatment as a major risk factor
      for infection-attributed mortality in ventilator-associated pneumonia (VAP)
      patients. In most instances, high-risk pathogens (eg, highly resistant Gram
      negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp, as well
      as methicillin-resistant staphylococci) are the predominant microorganisms
      causing excess mortality. Among various risk factors for mortality from VAP,
      which include the severity of the underlying disease and the degree of functional
      physiologic impairment caused by the pulmonary infectious process, only
      inappropriate antibiotic therapy is directly amenable to modification by
      clinicians. Secondary modifications of an initially failing antibiotic regimen do
      not substantially improve the outcome for these critically ill patients.
      Therefore, the best approach for reducing infection-related mortality seems to be
      the initial institution of an adequate and broad-spectrum antibiotic regimen in
      severely ill patients, which should be modified in a de-escalating strategy when
      the results from microbiologic testing become available. To circumvent the
      inherent danger of the emergence of resistance in ICU patients, additional
      measures have to be implemented and tested in clinical trials to reduce
      antibiotic consumption, shorten the duration of antibiotic treatment, and reduce
      the selection pressure on the ICU flora. This latter goal could be met by new
      antibiotic strategies including scheduled changes of recommended empiric
      antibiotic regimens at fixed intervals on a rotating basis.

PMID- 12475864
TI  - Family member presence during cardiopulmonary resuscitation: a survey of US and
      international critical care professionals.
AB  - OBJECTIVE: Recent international emergency cardiovascular care (ECC) and
      cardiopulmonary resuscitation (CPR) guidelines have recommended that health-care
      professionals allow family members to be present during resuscitation attempts.
      To assess whether critical care professionals support these recommendations, we
      surveyed health-care professionals for their opinions regarding family-witnessed
      resuscitation (FWR). METHODS: We surveyed health-care professionals attending the
      International Meeting of the American College of Chest Physicians in San
      Francisco, CA, from October 23 to 26, 2000, about their CPR experience, their
      opinions on FWR, and demographic characteristics. The opinions of physicians,
      nurses, and other allied health professionals were compared, and differences in
      opinions based on demographics were examined. RESULTS: Five hundred ninety-two
      professionals were surveyed. Fewer physicians (20%) than nurses and allied health
      care workers combined (39%) would allow family member presence during adult CPR
      (p = 0.0037 [chi(2) test]). Fourteen percent of physicians and 17% of nurses
      would allow a family presence during pediatric CPR. There was a significant
      difference among the opinions of US professionals, based on regional location.
      Professionals practicing in the northeastern states were less likely than other
      US professionals to allow FWR during adult or pediatric resuscitations (p = 0.016
      and p < 0.001, respectively [chi(2) test]). Midwestern professionals were more
      likely than others to allow family members to be present during an adult
      resuscitation, when compared to professional in the rest of the nation (p = 0.002
      [chi(2) test]). Health-care professionals disapproving of family member presence
      during CPR did so because of the fear of psychological trauma to family members,
      performance anxiety affecting the CPR team, medicolegal concerns, and a fear of
      distraction to the resuscitation team. CONCLUSIONS: Our evaluation indicated that
      the majority of critical care professionals surveyed do not support the current
      recommendations provided by the ECC and CPR guidelines of 2000.

PMID- 12475863
TI  - Informal caregiving for chronic lung disease among older Americans.
AB  - STUDY OBJECTIVE: To obtain nationally representative estimates of the additional
      time, and related cost, of unpaid family caregiving (informal caregiving)
      associated with chronic lung disease among older Americans. DESIGN: Multivariable
      regression models using data from the 1993 Asset and Health Dynamics Study, a
      nationally representative survey of people > or = 70 years old (n = 7,443).
      PARTICIPANTS: National population-based sample of the community-dwelling elderly.
      MEASUREMENTS: Weekly hours of informal caregiving, and imputed cost of caregiver
      time, for community-dwelling elderly who reported the following: (1) no lung
      disease, (2) lung disease without associated activity limitations, or (3) lung
      disease with associated activity limitations. RESULTS: After adjusting for
      sociodemographic variables, potential caregiver network, and comorbid conditions,
      individuals with chronic lung disease and associated activity limitations (n =
      403) received an additional 5.1 h/wk of informal care when compared to those with
      no lung disease (n = 6,593; p < 0.001). The associated additional yearly cost of
      informal care per case was $2,200 USD. This represents a national annual cost of
      informal caregiving for chronic lung disease of > $2 billion USD. CONCLUSIONS:
      The quantity and associated economic cost of informal caregiving for elderly
      individuals with chronic lung disease are substantial. These costs to families
      and society must be accounted for if the full societal costs of chronic lung
      disease are to be calculated. Pulmonary physicians caring for elderly individuals
      with chronic lung disease should be mindful of the importance of informal care
      for the well-being of their patients, as well as the potential for significant
      burden on those (often elderly) individuals providing the care.

PMID- 12475865
TI  - Evaluation of the polymerase chain reaction method for detection of Streptococcus
      pneumoniae DNA in pleural fluid samples.
AB  - STUDY OBJECTIVE: Streptococcus pneumoniae is the most frequent causative agent of
      community-acquired pneumonia (CAP); however, an etiologic diagnosis by
      traditional techniques can be accomplished in only a small percentage of patients
      with CAP. Pleural fluid is present in approximately 40% of patients with CAP;
      therefore, we hypothesized that detection of S pneumoniae DNA in pleural fluid by
      polymerase chain reaction (PCR) may help to increase the rate of diagnosis of
      pneumococcal pneumonia. DESIGN: A prospective study of cases. SETTING: A
      university hospital in Lleida, Spain. PATIENTS AND METHODS: One hundred two
      samples of pleural fluid (51 samples from consecutive adult patients with
      pneumonia and 51 samples from unselected control subjects) were tested by the
      nested-PCR method to detect selected pneumolysin gene of S pneumoniae, and the
      results were compared with those provided by alternative diagnostic methods.
      RESULTS: PCR in pleural fluid had a diagnostic sensitivity of 78% in patients
      with pneumococcal pneumonia, with positive results in 2 of 2 patients (100%) and
      5 of 7 patients (71%) who had positive or negative pleural fluid culture
      findings, respectively. PCR results were also positive in 3 of 24 patients (12%)
      with pneumonia of unknown etiology and negative in all patients with pneumonia
      due to microorganisms other than S pneumoniae. Thus, the calculated specificity
      was 93%. Among control subjects, PCR gave positive results in two cases (4%).
      CONCLUSION: The nested-PCR test, applied to pleural fluid samples from patients
      with CAP, showed a sensitivity of 78% and a specificity of 93% in the diagnosis
      of pneumococcal pneumonia.

PMID- 12475866
TI  - How should we quantify asthma control? A proposal.
AB  - BACKGROUND: Current asthma guidelines suggest a series of criteria to assess if
      asthma is controlled. However, there is a need to develop a simple and practical
      method to quantify the degree of such control, both in clinical practice and
      research. STUDY OBJECTIVES: This report describes a new method to quantify asthma
      control based on a percentage score. It also aims at comparing the percentage
      scores obtained with patient's self-evaluation of asthma control and a current
      validated Mini Asthma Quality of Life (MAQOL) questionnaire. SETTING AND
      SUBJECTS: Forty-two subjects (25 female and 17 male patients) with asthma of
      different severity recruited from a tertiary center asthma clinic. METHODS: The
      asthma scoring method provided a percentage control for symptoms, baseline
      expiratory flows and, an optional parameter, for airway inflammation assessed
      from induced-sputum eosinophil count. These control parameters were compared to
      an overall assessment of asthma control by the patient (also on a 100% scale) and
      the score obtained from a validated MAQOL questionnaire. RESULTS: Mean +/- SEM
      scores for symptoms, expiratory flows, and airway eosinophilia (last 2 weeks)
      were 87.8 +/- 1.4%, 88.6 +/- 1.8%, and 66.2 +/- 3.9%, respectively. No
      significant correlation was found between these three parameters (p > 0.05). The
      mean global asthma control score and the score estimated by the patient were 80.9
      +/- 1.5% and 91.7 +/- 1.5%, respectively (not significantly different). There was
      a significant correlation between asthma control score (percentage) and
      percentage symptom score (p < 0.001), while it almost achieved significance for
      FEV(1) (p = 0.05). Only symptom scores correlated with the MAQOL questionnaire.
      CONCLUSIONS: We developed a simple easy-to-use asthma control scoring system
      based on a percentage of optimal control. The percentage symptom score but not
      the global control score of this new method correlated with patient's global
      assessment of asthma control. This could be a simple tool that is potentially
      useful both for the clinician and for research purposes, to quantify global or
      specific aspects of asthma control.

PMID- 12475867
TI  - Malignant mesothelioma due to environmental exposure to asbestos: follow-up of a
      Turkish cohort living in a rural area.
AB  - STUDY OBJECTIVES: This study examines the incidence of malignant pleural
      mesothelioma (MPM) in a rural population of Turkey with environmental exposure to
      asbestos-contaminated soil mixtures (white soil). DESIGN: A field-based
      epidemiologic study. SETTING AND SUBJECTS: A cohort of villagers (the "Eskisehir"
      cohort) from 11 villages around Eskisehir in central Anatolia, who had been
      environmentally exposed to asbestos due to the use of white soil. MEASUREMENTS:
      The mineral content and asbestos contamination of the white soil used in these
      villages was determined, as well as airborne fiber concentrations. Cohort
      members' details of age, sex, ambient exposure data, duration of residence in the
      villages, and hospital records, including pathologic diagnosis, were recorded.
      RESULTS: The Eskisehir cohort consisted of 1,886 villagers. During the
      observation time, 377 deaths occurred and 24 MPM cases were diagnosed. Average
      annual mesothelioma incidence rates were 114.8/100,000 for men and 159.8/100,000
      for women. CONCLUSIONS: These data indicate that the risk of mesothelioma is 88.3
      times greater in men and 799 times greater in women, respectively, in comparison
      to world background incidence rates.

PMID- 12475868
TI  - Unilateral pulmonary edema in a 29-year-old man visiting high altitude.

PMID- 12475869
TI  - Bilateral video-assisted thoracoscopic surgery for bilateral spontaneous
      pneumothorax.
AB  - OBJECTIVE: To review our experience with bilateral video-assisted thoracoscopic
      surgery (VATS) for the treatment of bilateral spontaneous pneumothorax (SP).
      DESIGN: Retrospective study followed by a telephone interview for follow-up.
      SETTING: Thoracic Surgery Department, Chest Diseases Hospital, Kuwait. PATIENTS
      AND INTERVENTIONS: Fifteen patients undergoing bilateral VATS for bilateral SP
      from 1994 to 1999. RESULTS: The mean age of the patients was 22.9 years (range,
      17 to 34 years), and 14 were men. All patients were successfully treated using
      the bilateral video-assisted technique. Operative indications included
      simultaneous bilateral pneumothorax (n = 7) and contralateral recurrence of SP (n
      = 8). Twelve patients had primary SP. In the three remaining patients,
      simultaneous bilateral SP was secondary to sarcoidosis in two patients and
      histiocytosis X in one patient. Eleven patients had multiple blebs or bullae
      located in the upper lobes, and 4 patients had no blebs. All blebs or bullae were
      resected. All patients had gauze pleurodesis. The mean +/- SD operative time was
      133.6 +/- 9.1 min. There were no perioperative complications and no deaths
      attributable to the procedure. Postoperative prolonged air leak occurred in three
      patients (20%). The mean drainage time was 3 days (range, 2 to 8 days). The mean
      postoperative hospital stay was 5 +/- 1.7 days. Mean follow-up was 3.3 years
      (range, 2 to 5 years) for all patients. Pneumothorax recurred in one patient with
      histiocytosis X after 1 month and required a reoperation on the right side.
      CONCLUSIONS: Bilateral VATS is a safe procedure in the treatment of simultaneous
      and nonsimultaneous bilateral SP. This avoids the need for subsequent operations.

PMID- 12475870
TI  - Bilateral alveolar infiltrates in a 29-year-old man with chronic myelogenous
      leukemia.

PMID- 12475871
TI  - Knee discomfort in a 38-year-old man.

PMID- 12475872
TI  - Diagnosis of vocal cord dysfunction: the utility of spirometry and
      plethysmography.

PMID- 12475873
TI  - Multidisciplinary therapy including high-dose chemotherapy followed by peripheral
      blood stem cell transplantation for invasive thymoma.
AB  - We describe two patients with invasive thymomas who responded to high-dose
      chemotherapy followed by peripheral blood stem cell transplantation (PBSCT)
      combined with surgery and radiotherapy. The first patient was a 42-year-old man
      admitted to the hospital with chest pain, and the second patient was a 45-year
      old man admitted with myasthenia gravis. Both patients had nonresectable thymomas
      (stage IVa) because of invasion of the aorta, pulmonary artery, or both, and
      dissemination to the pericardium. They initially received two cycles of
      chemotherapy consisting of adriamycin (40 mg/m(2), day 1), cisplatin (50 mg/m(2),
      day 1), vincristine (0.6 mg/m(2), day 3), and cyclophosphamide (700 mg/m(2), day
      4) at 3-week intervals. Four weeks later, they were administered high-dose
      etoposide (300 mg/m(2), days 1 to 5) followed by granulocyte colony-stimulating
      factor (G-CSF) [50 micro g/m(2)/d] subcutaneously to mobilize stem cells into the
      blood. After two additional cycles of adriamycin, cisplatin, vincristine, and
      cyclophosphamide (ADOC), the patients received high-dose ifosfamide (1.5 g/m(2),
      days 1 to 4), carboplatin (400 mg/m(2), days 3 to 5), and etoposide (200 mg/m(2),
      days 1 to 5) followed by PBSCT. They were administered G-CSF (50 micro g/m(2)/d)
      after PBSCT, with subsequent rapid recovery of neutrophil and platelet level. The
      tumors shrank remarkably, and could be excised completely in both patients.
      Postoperatively, 50 Gy of irradiation was administered. Disease-free status has
      been maintained for 5 years in the first patient and 2 years in the second
      patient. Our findings suggest that high-dose ifosfamide, carboplatin, and
      etoposide followed by PBSCT in combination with an ADOC regimen, surgery, and
      radiotherapy is very effective and well tolerated in patients with advanced
      nonresectable thymoma.

PMID- 12475874
TI  - Subarachnoid pleural fistula due to penetrating trauma: case report and review of
      the literature.
AB  - We describe a case of a 30-year-old man who developed a recurrent pleural
      effusion after sustaining a gunshot wound to the left side of his chest with
      subsequent complete paralysis at the T2 level. Subarachnoid-pleural fistulas have
      rarely been reported as complications of penetrating and blunt trauma, thoracic
      surgery, as well as spinal surgery. Concomitant injuries may overshadow or
      complicate the diagnosis of subarachnoid-pleural fistulas. The diagnosis should
      be considered in any patient with a pleural effusion that is associated with
      severe neurologic injury, as the fistula rarely heals without surgical
      intervention and may lead to CNS infection or pneumocephalus.

PMID- 12475875
TI  - Cardiac decortication (epicardiectomy) for occult constrictive cardiac physiology
      after left extrapleural pneumonectomy.
AB  - Constrictive cardiac physiology typically does not occur in the absence of
      parietal pericardium. However, we report eight patients who, after left
      extrapleural pneumonectomy and removal of the parietal pericardium for
      malignancy, presented with dyspnea, jugular venous distension, and peripheral or
      generalized edema unresponsive to diuretics. Cardiac decortication
      (epicardiectomy) was performed whereby a thickened peel encasing the heart was
      surgically excised, resulting in vigorous contraction and expansion of the heart.
      In one patient, decortication occurred early after pneumonectomy and was
      incomplete. Acute signs of inflammation were present, and recurrence necessitated
      repeat decortication. When patients present with dyspnea, hepatojugular reflux,
      and peripheral edema refractory to diuretics, constrictive cardiac physiology
      should be considered in the differential diagnosis, even in the absence of
      parietal pericardium.

PMID- 12475876
TI  - Bacterial endocarditis and functional mitral stenosis: a report of two cases and
      brief literature review.
AB  - Mitral valve endocarditis typically results in mitral regurgitation. However,
      endocarditis leading to functional mitral stenosis is uncommon and, when present,
      fungal organisms are typically implicated. Thus, obstructive-type bacterial
      endocarditis due to large vegetations blocking the mitral valve orifice is a rare
      occurrence, with approximately 20 reported cases in the literature. We report on
      two patients with bacterial endocarditis and severe functional mitral stenosis
      requiring emergent surgery. Additionally, this is the first report of vancomycin
      resistant enterococcus causing endocarditis and functional mitral stenosis. The
      discussion emphasizes the hemodynamic instability of these patients and need for
      early surgical intervention.

PMID- 12475877
TI  - Criteria for bronchodilator response.

PMID- 12475878
TI  - Cardiac troponins in acute pulmonary embolism.

PMID- 12475879
TI  - Acute myocardial infarction in a young male patient with combined hormonal
      disorder.

PMID- 12475880
TI  - Nocturnal gastroesophageal reflux: symptom of obstructive sleep apnea syndrome in
      association with impaired swallowing.

PMID- 12475881
TI  - Fluticasone vs placebo in toddlers with asthma: good science or questionable
      ethics?

PMID- 12475882
TI  - Metal stenting as first-line therapy for tracheal compression after gastric pull
      up.

PMID- 12475885
TI  - General anesthetic actions in vivo strongly attenuated by a point mutation in the
      GABA(A) receptor beta3 subunit.
AB  - General anesthetics are widely used in clinical practice. On the molecular level,
      these compounds have been shown to modulate the activity of various neuronal ion
      channels. However, the functional relevance of identified sites in mediating
      essential components of the general anesthetic state, such as immobility and
      hypnosis, is still unknown. Using gene-targeting technology, we generated mice
      harboring a subtle point mutation (N265M) in the second transmembrane region of
      the beta3 subunit of the GABA(A) receptor. In these mice, the suppression of
      noxious-evoked movements in response to the intravenous anesthetics etomidate and
      propofol is completely abolished, while only slightly decreased with the volatile
      anesthetics enflurane and halothane. beta3(N265M) mice also display a profound
      reduction in the loss of righting reflex duration in response to intravenous but
      not volatile anesthetics. In addition, electrophysiological recordings revealed
      that anesthetic agents were significantly less effective in enhancing GABA(A)
      receptor-mediated currents, and in decreasing spontaneous action potential firing
      in cortical brain slices derived from mutant mice. Taken together, our results
      demonstrate that a single molecular target, and indeed a specific residue (N265)
      located within the GABA(A) receptor beta3 subunit, is a major determinant of
      behavioral responses evoked by the intravenous anesthetics etomidate and
      propofol, whereas volatile anesthetics appear to act via a broader spectrum of
      molecular targets.

PMID- 12475886
TI  - Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect.
AB  - Megalin is an endocytic receptor highly expressed in the proximal tubules of the
      kidney. Recently, we demonstrated that this receptor is essential for the renal
      uptake and conversion of 25-OH vitamin D3 to 1,25-(OH)2 vitamin D3, a central
      step in vitamin D and bone metabolism. Unfortunately, the perinatal lethality of
      the conventional megalin knockout mouse model precluded the detailed analysis of
      the significance of megalin for calcium homeostasis and bone turnover in vivo.
      Here, we have generated a new mouse model with conditional inactivation of the
      megalin gene in the kidney by using Cre recombinase. Animals with a renal
      specific receptor gene defect were viable and fertile. However, lack of receptor
      expression in the kidney results in plasma vitamin D deficiency, in hypocalcemia
      and in severe bone disease, characterized by a decrease in bone mineral content,
      an increase in osteoid surfaces, and a lack of mineralizing activity. These
      features are consistent with osteomalacia (softening of the bones) as a
      consequence of hypovitaminosis D and demonstrate the crucial importance of the
      megalin pathway for systemic calcium homeostasis and bone metabolism.

PMID- 12475887
TI  - Betacellulin induces angiogenesis through activation of mitogen-activated protein
      kinase and phosphatidylinositol 3'-kinase in endothelial cell.
AB  - Betacellulin (BTC) is a member of the epidermal growth factor (EGF) family, and
      it acts through EGF receptors. We asked whether BTC could be an angiogenic
      factor. Using human umbilical vein endothelial cells (HUVECs), we examined the
      effect of BTC on kinases and angiogenic processes. BTC induced ERK1/2 and Akt
      phosphorylation in a dose- and time-dependent manner. BTC induced phosphorylation
      of all three EGF receptors present on HUVECs: ErbB2, ErbB3, and ErbB4.
      Pretreatment with effective concentrations of ErbB1 inhibitor did not suppress
      BTC-induced kinase phosphorylation. BTC, EGF, VEGF (all at 10 ng/ml) produced
      similar increases in DNA synthesis. BTC, EGF, and VEGF all significantly
      increased endothelial cell migration. In addition, BTC promoted survival in a
      dose-dependent manner, and its effect was inhibited by pretreatment with PtdIns
      3'-kinase inhibitor wortmannin or MEK1/2 inhibitor PD98059. Both BTC and EGF
      produced similar increases in tube formation in collagen gels. BTC-induced tube
      formation was suppressed by PD98059, wortmannin, and LY294002. In the mouse
      Matrigel plug assay, BTC (100 ng/ml) promoted neovessel formation, and its effect
      was suppressed by a combination of wortmannin and PD98059. Taken together, these
      data show that BTC exerts potent angiogenic activity through activation of EGF
      receptors, mitogen-activated protein kinase, and PtdIns 3'-kinase/Akt in
      endothelial cells.

PMID- 12475888
TI  - Stochastic resonance in osteogenic response to mechanical loading.
AB  - Stochastic resonance, in which noise enhances the response of a nonlinear system
      to a weak signal, has been observed in various biological sensory systems. We
      speculated that bone formation in response to mechanical loading could be
      enhanced by adding noise (vibration) to a standard exercise regimen. To test this
      hypothesis, three different loading regimens were applied to the ulnae of mice:
      (1) high amplitude, low frequency sinusoidal loading at 2 Hz with an amplitude of
      3 N to simulate exercise; (2) low amplitude, broad frequency vibration with
      frequency components 0-50 Hz and 0.3 N of mean amplitude; (3) the sinusoidal wave
      combined with vibration (S+V) to invoke stochastic resonance. The simulated
      exercise regimen induced new bone formation on the periosteal surface of the
      ulna, however the addition of vibration noise with exercise enhanced the
      osteogenic response by almost 4-fold. Vibration by itself had no effect on bone
      formation. It was concluded that adding low magnitude vibration greatly enhanced
      bone formation in response to loading, suggesting a contribution of stochastic
      resonance in the osteogenic response.

PMID- 12475889
TI  - Changes of peripheral A2A adenosine receptors in chronic heart failure and
      cardiac transplantation.
AB  - Peripheral blood mononuclear cells of chronic heart failure (CHF) patients
      produce great amounts of pro-inflammatory cytokines, indicating that circulating
      cells are activated and could mirror changes occurring in inflammatory cells
      infiltrating the failing heart. Adenosine is a regulatory metabolite acting
      through four membrane receptors that are linked to adenylyl cyclase: activation
      of the A2A receptor subtype has been reported to inhibit cytokine release.
      Changes of the adenosinergic system may play a role in CHF development. Here we
      report an increase of A2A receptor expression, density, and coupling to adenylyl
      cyclase in blood circulating cells of CHF patients. A2A receptor up-regulation
      was also found in the explanted hearts of these patients, suggesting that changes
      of peripheral adenosine receptors mirror changes occurring in the disease target
      organ. In a cohort of patients followed longitudinally after heart
      transplantation, alterations of peripheral A2A adenosine receptor progressively
      normalized to control values within 6 months, suggesting that improvement of
      cardiac performance is accompanied by progressive restoration of a normal
      adenosinergic system. These results validate the importance of the A2A receptor
      in human diseases characterized by a marked inflammatory/immune component and
      suggest that the evaluation of this receptor in peripheral blood cells may be
      useful for monitoring hemodynamic changes and the efficacy of pharmacological and
      non-pharmacological treatments in CHF patients.

PMID- 12475890
TI  - Cyclic ADP-ribose generation by CD38 improves human hemopoietic stem cell
      engraftment into NOD/SCID mice.
AB  - Cyclic ADP-ribose (cADPR) is a potent and universal intracellular calcium
      mobilizer, recently shown to behave as a new hemopoietic cytokine stimulating the
      in vitro proliferation of both committed and uncommitted human hemopoietic
      progenitors (HP). Here, we investigated the effects of cADPR on engraftment of
      hemopoietic stem cells (HSC) into irradiated NOD/SCID mice. Two different
      protocols were used: i) a 24 h in vitro priming of cord blood-derived mononuclear
      cells (MNC) with micromolar cADPR, followed by their infusion into irradiated
      mice (both primary and secondary transplants); and ii) co-infusion of MNC with
      CD38-transfected, cADPR-generating, irradiated murine 3T3 fibroblasts. We
      demonstrated a dual effect of cADPR on human HP in vivo: i) enhanced
      proliferation of committed progenitors, responsible for improvement of short-term
      engraftment; ii) expansion of HSC, with increased long-term human engraftment
      into secondary recipients and a significantly higher expansion factor of CD34+
      progenitors in mice co-infused with MNC and CD38+ 3T3 fibroblasts. These results
      hold promise for the possible therapeutic use of cADPR, and of cADPR-producing
      stroma, to achieve long-term expansion of human HSC, that is, those HP capable of
      self-renewal and responsible for repopulation of the bone marrow.

PMID- 12475891
TI  - Distinct palindromic extensions of the 5'-TTC...GAA-3' motif allow STAT6 binding
      in vivo.
AB  - STATs (signal transducers and activators of transcription) are transcription
      factors downstream of cytokine and growth factor signals. All of the seven
      different STATs bind to regulatory promoter elements with the common core motif
      5'-TTC(N)2-4GAA-3'. A key question is how the different STAT factors recognize
      "their" response elements, that is, what distinguishes for example STAT1 from
      STAT6 binding sites. In vivo, binding of the different STATs to DNA elements is
      highly specific and disruption of the genes for the different STAT factors is
      accompanied with distinct, non-overlaping phenotypical effects. As a first step
      towards discrimination of target sequences for the various STATs, we determined
      requirements for binding sites for STAT6. In functional assays, six sequences
      were identified. These have palindromic extensions of the core motif in common
      (underlined): 5'-TTTCNNNGAAA-3', 5'-CTTCNNNGAAG-3', 5'-TTTCNNNNGAAA-3', 5'
      CTTCNNNNGAAG-3', 5'-TTCCNNGGAA-3' and 5'-TTCANNTGAA-3'. Different approaches and
      mutational analysis demonstrated the functionality of these sequences and high
      specific binding to STAT6. (I) These elements mediate transcriptional induction
      by interleukin-(IL)-4, IL-13, IL-15, and platelet-derived growth factor. (II)
      When used as "decoy" oligonucleotides, they bind STAT6 and disrupt its function
      in vivo, attenuating (a) STAT6/IL-4-mediated reporter gene transcription and (b)
      STAT6/IL-4-mediated induction of mu-opioid receptor mRNA of Raji cells.

PMID- 12475892
TI  - Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent
      signal for insulin secretion.
AB  - The ryanodine (RY) receptors in beta-cells amplify signals by Ca2+-induced Ca2+
      release (CICR). The role of CICR in insulin secretion remains unclear in spite of
      the fact that caffeine is known to stimulate secretion. This effect of caffeine
      is attributed solely to the inhibition of cAMP-phosphodiesterases (cAMP-PDEs). We
      demonstrate that stimulation of insulin secretion by caffeine is due to a
      sensitization of the RY receptors. The dose-response relationship of caffeine
      induced inhibition of cAMP-PDEs was not correlated with the stimulation of
      insulin secretion. Sensitization of the RY receptors stimulated insulin secretion
      in a context-dependent manner, that is, only in the presence of a high
      concentration of glucose. This effect of caffeine depended on an increase in
      [Ca2+]i. Confocal images of beta-cells demonstrated an increase in [Ca2+]i
      induced by caffeine but not by forskolin. 9-Methyl-7-bromoeudistomin D (MBED),
      which sensitizes RY receptors, did not inhibit cAMP-PDEs, but it stimulated
      secretion in a glucose-dependent manner. The stimulation of secretion by caffeine
      and MBED involved both the first and the second phases of secretion. We conclude
      that the RY receptors of beta-cells mediate a distinct glucose-dependent signal
      for insulin secretion and may be a target for developing drugs that will
      stimulate insulin secretion only in a glucose-dependent manner.

PMID- 12475893
TI  - Hepatocyte growth factor counteracts transforming growth factor-beta1, through
      attenuation of connective tissue growth factor induction, and prevents renal
      fibrogenesis in 5/6 nephrectomized mice.
AB  - We investigated the mechanism of the anti-fibrotic effects of hepatocyte growth
      factor (HGF) in the kidney, with respect to its effect on connective tissue
      growth factor (CTGF), a down-stream, profibrotic mediator of transforming growth
      factor-beta1 (TGF-beta1). In wild-type (WT) mice with 5/6 nephrectomy (Nx), HGF
      and TGF-beta1 mRNAs increased transiently in the remnant kidney by week 1 after
      the Nx, returned to baseline levels, and increased again at weeks 4 to 12. In
      contrast, CTGF and alpha1(I) procollagen (COLI) mRNAs increased in parallel with
      HGF and TGF-beta1 during the early stage, but did not re-increase during the late
      stage. In the case of TGF-beta1 transgenic (TG) mice with 5/6 Nx, excess TGF
      beta1 derived from the transgene enhanced CTGF expression significantly in the
      remnant kidney, accordingly accelerating renal fibrogenesis. Administration of
      dHGF (5.0 mg/kg/day) to TG mice with 5/6 Nx for 4 weeks from weeks 2 to 6
      suppressed CTGF expression in the remnant kidney, attenuating renal fibrosis and
      improving the survival rate. In an experiment in vitro, renal tubulointerstitial
      fibroblasts (TFB) were co-cultured with proximal tubular epithelial cells (PTEC).
      Pretreatment with HGF reduced significantly CTGF induction in PTEC by TGF-beta1,
      consequently suppressing COLI synthesis in TFB. In conclusion, HGF can block, at
      least partially, renal fibrogenesis promoted by TGF-beta1 in the remnant kidney,
      via attenuation of CTGF induction.

PMID- 12475894
TI  - ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in
      released membrane vesicles.
AB  - Cells can release membrane components in a soluble form and as membrane vesicles.
      L1, an important molecule for cell migration of neural and tumor cells, is
      released by membrane-proximal cleavage, and soluble L1 promotes cell migration.
      Release of L1 is enhanced by shedding inducers such as phorbol ester and
      pervanadate, but it is also enhanced by depletion of cellular cholesterol with
      methyl-beta-cyclodextrin (MCD). How such different compounds can induce shedding
      is presently unknown. We show here that ADAM10 is involved in L1 cleavage, which
      occurs at the cell surface and in the Golgi apparatus. MCD and pervanadate
      treatment induced the release of microvesicles containing full-length L1 and the
      active form of ADAM10. L1 cleavage occurred in isolated vesicles. L1-containing
      microvesicles could trigger haptotactic cell migration. Only the neural L1 form
      carrying the RSLE signal for clathrin-dependent endocytosis was recruited and
      cleaved in vesicles. Phorbol ester treatment activated L1 cleavage predominantly
      at the cell surface. Our results provide evidence for two pathways of L1
      cleavage, based on ADAM10 localization, that can be activated differentially: 1)
      direct cleavage at the cell surface, and 2) release and cleavage in secretory
      vesicles most likely derived from the Golgi apparatus. The findings establish a
      novel role for ADAM10 as a vesicle-based protease.

PMID- 12475895
TI  - The structural nature of chromosomal instability in colon cancer cells.
AB  - Biological and genetic cell heterogeneity is a landmark of most colorectal
      cancers and provides a frame for tumor progression as an evolutional process.
      Classical models have hypothesized that increased genetic instability may
      contribute to modulating and shaping malignant transformation. This is true for
      the small subset of colorectal cancers displaying microsatellite instability. For
      the rest of colorectal tumors, numerical and/or structural chromosomal
      alterations are the most prominent outcome of genetic disruption. These
      observations have prompted some investigators to hypothesize about the presence
      of chromosomal instability in these cells. To characterize chromosomal
      instability in cancer cells, we have analyzed genetic clonal divergence in three
      colorectal cancer cell lines considered to be archetypes in cancer research
      (HCT116, LoVo, and SW480). A dynamic setting was designed to allow the
      calculation of mutation rates. Comprehensive analyses at the chromosomal level
      revealed distinctive patterns of genetic divergence. Aneuploid SW480 cells
      displayed high rates of structural alterations (>100-fold) as compared with near
      diploid LoVo cells. Numerical alterations also occurred more frequently in SW480
      cells but at low rates as compared with rearrangements in the chromosomically
      unstable SW480 cells. These results strengthen the role of structural instability
      in the generation of genetic heterogeneity in colorectal cancer.

PMID- 12475896
TI  - A variable fold change threshold determines significance for expression
      microarrays.
AB  - The use of expression microarrays to determine bona fide changes in gene
      expression between experimental paradigms is confounded by noise due to
      variability in measurement. To assess the variability associated with transcript
      hybridization to commercial oligonucleotide-based microarrays, we generated a
      data set consisting of five replicate hybridizations of a single labeled cRNA
      target from three distinct experimental paradigms, using the Affymetrix human U95
      GeneChip set. We found that the variability of expression level in our data set
      is intensity-specific. We quantified the observed variability in our data set in
      order to determine significant changes in gene expression. LOESS fitting to a
      plot of the standard deviation of replicates assigned a variability associated
      with a specific intensity. This allowed for the calculation of a "variable fold
      change" threshold for any absolute intensity at any level of statistical
      confidence. Testing of this method indicates that it removes intensity-specific
      bias and results in a 5- to 10-fold reduction in the number of false-positive
      changes. We suggest that this approach can be widely used to improve prediction
      of significant changes in gene expression for oligonucleotide-based microarray
      experiments and reduce false leads, even in the absence of replicates.

PMID- 12475897
TI  - Pharmacological interference with intestinal bile acid transport reduces plasma
      cholesterol in LDL receptor/apoE deficiency.
AB  - Reduction of plasma cholesterol by statins is fundamental to prevent coronary
      heart disease. Such therapy is often sub-optimal, however, particularly in
      patients with reduced LDL receptors (familial hypercholesterolemia), and novel or
      adjuvant therapies are therefore warranted. Cholesterol elimination is profoundly
      influenced by the rate of its conversion to bile acids (BA), regulated by the
      enzyme Cyp7a1. Induced fecal loss of BA by resin treatment reduces plasma
      cholesterol, presumably through induction of hepatic LDL receptors (LDLR). We
      here describe the effect of PR835, a drug belonging to a new class of lipid
      lowering agents that inhibit the Slc10a2 protein, the intestinal transporter
      responsible for active uptake of BA. Treatment reduced plasma cholesterol by 40%
      in mice devoid of both the LDLR and its ligand, apoE, while triglycerides and HDL
      cholesterol were unchanged. Cyp7a1 enzyme activity and mRNA were induced several
      fold, and hepatic HMG CoA reductase mRNA increased, mirroring an induced
      synthesis of BA and cholesterol. The addition of a statin potentiated the effect,
      leading to reductions of plasma total and LDL cholesterol by 64% and 70%,
      respectively. These effects could not be attributed to induction of other known
      hepatic lipoprotein receptors and indicate the presence of new points of
      targeting in lipid-lowering therapy.

PMID- 12475899
TI  - Epidermal growth factor receptor trans-activation mediates the tonic and
      fibrogenic effects of endothelin in the aortic wall of transgenic mice.
AB  - Vascular remodeling and rearrangement of the extracellular matrix formation are
      among the major adaptive mechanisms in response to a chronic blood pressure
      increase. Vasoactive peptides, such as endothelin, participate in hypertension
      associated vascular fibrosis by stimulating collagen I formation and increasing
      contractility of arterial wall. In the present study, we tested the hypothesis
      that activation of the epidermal growth factor (EGF) receptor pathway mediates
      these events. Experiments were performed in transgenic mice harboring the
      luciferase gene under the control of the collagen I-alpha2 chain promoter.
      Endothelin induced a rapid phosphorylation of the mitogen-activated protein
      kinase (MAPK)/ERK and increased collagen I gene activity in freshly isolated
      aortas. This effect of endothelin was totally inhibited by an endothelin receptor
      antagonist, an EGF receptor phosphorylation inhibitor, and a blocker of the
      MAPK/ERK cascade. In parallel experiments, inhibition of EGF receptor
      phosphorylation decreased the endothelin-induced pressor effect in isolated
      aortic rings and in anesthetized animals in vivo. In addition, the endothelin
      induced increase of blood pressure was blunted in the waved-2 mice, a strain
      expressing functionally impaired EGF receptors. Our results provide the first
      evidence that the EGF receptor mediates at least two of the major actions of
      endothelin in the vascular tissue: contractility and fibrogenesis.

PMID- 12475898
TI  - Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse.
AB  - The 37-kDa protein annexin 1 (Anx-1; lipocortin 1) has been implicated in the
      regulation of phagocytosis, cell signaling, and proliferation and is postulated
      to be a mediator of glucocorticoid action in inflammation and in the control of
      anterior pituitary hormone release. Here, we report that mice lacking the Anx-1
      gene exhibit a complex phenotype that includes an altered expression of other
      annexins as well as of COX-2 and cPLA2. In carrageenin- or zymosan-induced
      inflammation, Anx-1-/- mice exhibit an exaggerated response to the stimuli
      characterized by an increase in leukocyte emigration and IL-1beta generation and
      a partial or complete resistance to the antiinflammatory effects of
      glucocorticoids. Anx-1-/- polymorphonuclear leucocytes exhibited increased
      spontaneous migratory behavior in vivo whereas in vitro, leukocytes from Anx-1-/-
      mice had reduced cell surface CD 11b (MAC-1) but enhanced CD62L (L-selectin)
      expression and Anx-1-/- macrophages exhibited anomalies in phagocytosis. There
      are also gender differences in activated leukocyte behavior in the Anx-1-/- mice
      that are not seen in the wild-type animals, suggesting an interaction between sex
      hormones and inflammation in Anx-1-/- animals.

PMID- 12475900
TI  - Delayed rejection of porcine cartilage is averted by transgenic expression of
      alpha1,2-fucosyltransferase.
AB  - The use of xenogeneic cells or tissues for tissue engineering applications may
      lead to advances in biomedical research. Hyperacute and delayed rejection are
      immunologic hurdles that must be addressed to achieve xenograft survival in the
      pig-to-primate setting. Expression of human alpha1,2-fucosyltransferase (HT) in
      the donor cell or tissue protects from hyperacute rejection (HAR) by reducing
      expression of Galalpha1,3-Gal epitope, the major xenoantigen recognized by human
      natural antibodies. We hypothesized that Galalpha1,3-Gal antigen contributes to
      delayed tissue rejection. To test this hypothesis, we transplanted control or HT
      transgenic engineered porcine cartilage s.c. into alpha1,3-galactosyltransferase
      knockout (Gal KO) mice. Control porcine cartilage grafted in Gal KO mice was not
      susceptible to HAR but was rejected in several wk by a prominent cellular immune
      infiltrate and elevated antibody titers. In contrast, Gal KO mice receiving the
      HT engineered cartilage showed a markedly reduced anti-pig antibody response and
      no anti-Galalpha1,3-Gal-elicited antibody response. The HT implants had a mild
      cellular infiltrate that was confined to the graft periphery. Our study
      demonstrates that a marked reduction of Galalpha1,3-Gal antigen in HT-transgenic
      porcine cartilage confers resistance to a process of delayed rejection. Further
      development of tissue engineering applications that use genetically modified
      porcine tissues is encouraged.

PMID- 12475901
TI  - Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct
      signaling microdomains.
AB  - Intracellular targets of the ubiquitous second messenger cAMP are located at
      great distances from the most widely studied source of cAMP, the G protein
      responsive transmembrane adenylyl cyclases. We previously identified an
      alternative source of cAMP in mammalian cells lacking transmembrane spanning
      domains, the "soluble" adenylyl cyclase (sAC). We now demonstrate that sAC is
      distributed in specific subcellular compartments: mitochondria, centrioles,
      mitotic spindles, mid-bodies, and nuclei, all of which contain cAMP targets.
      Distribution at these intracellular sites proves that adenylyl cyclases are in
      close proximity to all cAMP effectors, suggesting a model in which local
      concentrations of cAMP are regulated by individual adenylyl cyclases targeted to
      specific microdomains throughout the cell.

PMID- 12475902
TI  - Involvement of TRAIL and its receptors in viral hepatitis.
AB  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill a
      broad spectrum of tumor cells but appears to be nontoxic to most normal cells.
      Because there are conflicting data about the hepatotoxicity of TRAIL, we
      investigated the physiological function of TRAIL and its receptors in the liver.
      Hepatocytes are sensitive for FasL- and TRAIL-mediated apoptosis in vitro, but
      TRAIL induces no apoptosis in healthy livers in vivo. Using mouse models of
      adenoviral hepatitis and livers of patients with hepatitis infection, we could
      demonstrate that apoptosis in virally infected hepatocytes is mediated by TRAIL
      receptor DR5 and TRAIL. In contrast to FasL, TRAIL-mediated apoptosis of
      hepatocytes in vivo is triggered through viral infection. The TRAIL
      receptor/ligand system enables the organisms to specifically kill virus-infected
      hepatocytes, whereas normal uninfected hepatocytes in vivo are resistant to TRAIL
      mediated apoptosis. Overexpression of TRAIL in the liver after viral infection is
      not dependent on lymphocytes, natural killer, or Kupffer cells, which indicates
      that the TRAIL receptor/ligand system is a paracrine mechanism of hepatocytes
      against virally infected cells. Our results suggest that TRAIL might be used not
      only for cancer therapy but also for therapy of patients with viral hepatitis to
      selectively eliminate infected hepatocytes and limit viral replication.

PMID- 12475903
TI  - Mutation in collagen-1 that confers resistance to the action of collagenase
      results in failure of recovery from CCl4-induced liver fibrosis, persistence of
      activated hepatic stellate cells, and diminished hepatocyte regeneration.
AB  - Collagen-I, which predominates in the neomatrix of fibrotic liver, regulates
      hepatocyte and hepatic stellate cell (HSC) phenotypes. Recovery from liver
      fibrosis is accompanied by hepatocyte regeneration, matrix degradation, and HSC
      apoptosis. Using mice bearing a mutated collagen-I gene (r/r mice), which confers
      resistance to collagenase degradation, we have investigated the hypothesis that
      collagen-I degradation is critical to HSC apoptosis and hepatocyte regeneration
      during recovery from liver fibrosis. During a 28-day recovery period after 8 wk
      of CCl4 treatment, wild-type (WT) livers had significantly (43%) decreased
      hydroxyproline (OHP) content. In r/r livers, however, OHP content remained
      elevated at peak fibrosis levels. Expressed markers of activated HSC (alpha
      smooth muscle actin, collagen-I), elevated at peak fibrosis, dropped to control
      levels in WT livers after 28 days but remained raised in the r/r livers.
      Moreover, relative to WT livers, r/r livers had significantly reduced stellate
      cell apoptosis and hepatocyte regeneration during the recovery period. Using
      extracted collagen-I from each genotype as culture substrata, relative to r/r, we
      show that WT collagen-I promotes hepatocyte proliferation via stimulation of
      integrin alpha(v)beta3. Failure to degrade collagen-I critically impairs HSC
      apoptosis and may prevent the effective restoration of hepatocyte mass in liver
      fibrosis.

PMID- 12475904
TI  - Impaired cardiac contraction and relaxation and decreased expression of
      sarcoplasmic Ca2+-ATPase in mice lacking the CREM gene.
AB  - Congestive heart failure is the common endpoint of various cardiac diseases
      representing a leading cause of cardiovascular mortality in Western countries.
      Characteristic functional alterations of the failing heart are explained by
      expressional changes of myocardial regulatory proteins; however, little is known
      about underlying mechanisms regulating cardiac gene expression in the failing
      heart. Here, we address the specific role of transcription factor CREM for
      cardiac function in CREM mutant mice with complete inactivation of the CREM gene.
      We show that CREM mutant mice display distinct alterations of cardiac function
      resembling characteristic functional defects of the failing heart. Left
      ventricular hemodynamic assessment of CREM mutant mice revealed impairment of
      both cardiac contraction and relaxation in basal state, as well as a decreased
      responsiveness to beta-adrenergic stimulation. The diminished cardiac contractile
      performance was associated with a selective down-regulation of beta1-adrenergic
      receptors and a decreased ventricular expression of SERCA, the Ca2+-ATPase of the
      sarcoplasmic reticulum. The cardiac phenotype of CREM mutant mice provides the
      first evidence that CREM represents an important key regulator of cardiac gene
      expression, which is essential for normal left ventricular contractile
      performance and response to beta-adrenoreceptor stimulation.

PMID- 12475905
TI  - Art v 1, the major allergen of mugwort pollen, is a modular glycoprotein with a
      defensin-like and a hydroxyproline-rich domain.
AB  - In late summer, pollen grains originating from Compositae weeds (e.g., mugwort,
      ragweed) are a major source of allergens worldwide. Here, we report the isolation
      of a cDNA clone coding for Art v 1, the major allergen of mugwort pollen.
      Sequence analysis showed that Art v 1 is a secreted allergen with an N-terminal
      cysteine-rich domain homologous to plant defensins and a C-terminal proline-rich
      region containing several (Ser/Ala)(Pro)2-4 repeats. Structural analysis showed
      that some of the proline residues in the C-terminal domain of Art v 1 are
      posttranslationally modified by hydroxylation and O-glycosylation. The O-glycans
      are composed of 3 galactoses and 9-16 arabinoses linked to a hydroxyproline and
      represent a new type of plant O-glycan. A 3-D structural model of Art v 1 was
      generated showing a characteristic "head and tail" structure. Evaluation of the
      antibody binding properties of natural and recombinant Art v 1 produced in
      Escherichia coli revealed the involvement of the defensin fold and
      posttranslational modifications in the formation of epitopes recognized by IgE
      antibodies from allergic patients. However, posttranslational modifications did
      not influence T-cell recognition. Thus, recombinant nonglycosylated Art v 1 is a
      good starting template for engineering hypoallergenic vaccines for weed-pollen
      therapy.

PMID- 12475906
TI  - Cord-like mosaic patches in the adrenal cortex are fractal: implications for
      growth and development.
AB  - Organogenesis proceeds rapidly and faithfully during fetal development. The
      process includes generation of parenchyma, followed by organization into
      functional tissues. The method by which the growth of organ parenchyma is
      regulated is not known, but insight into this regulation has been obtained by
      studying mosaic tissues of experimental chimeras and transgenic mosaics. The
      patterns revealed by this procedure offer an indication of how the parenchyma was
      generated. In the liver, the pattern appears as islands of one cell type in a sea
      of the other cell type, while in the adrenal cortex the pattern is one of
      alternating cords of one cell type adjacent to the other cell type. We have
      established previously that mosaic patches in the liver are fractal. The fractal
      dimensions of patches in the liver are consistent with an iterative, recursive
      growth model with simple stereotypical division rules. Here we report that the
      patches in mosaic adrenal cortex of the mouse and rat are also fractal and that
      the fractal dimension of the surface of the patches is lower than that in the
      liver. Fetal development and fractal dimensions of adrenal cortical mosaic
      patches are consistent with an algorithmic cell division model in which
      parenchymal growth is constrained to edges of growth centers forcing cord
      structures to form. Fractal analysis of the geometry of mosaic patches in tissues
      of experimental chimeras is helpful in constructing hypotheses of organ growth.

PMID- 12475907
TI  - Cognition impairment in the genetic model of aging klotho gene mutant mice: a
      role of oxidative stress.
AB  - A new gene, termed klotho, is associated with the suppression of several aging
      phenotypes. Because high expression of klotho gene was detected in the brain, it
      would be plausible that klotho gene is involved in the regulation of brain aging.
      We investigated the changes in mnemonic function accompanying aging in klotho
      mutant mice. Cognitive function measured by novel-object recognition and
      conditioned-fear tests in klotho mutant mice was normal at the age of 6 wk, but
      markedly impaired at the age of 7 wk. Lipid (malondialdehyde) and DNA (8-hydroxy
      2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice
      increased at the age of 5 wk, 2 wk before the development of cognition deficits.
      Pro-death Bax increased, whereas anti-death Bcl-2 and Bcl-XL decreased, and
      apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant
      mice at the age of 7 wk. A potent antioxidant, a-tocopherol, prevented cognition
      impairment and lipid peroxide accumulation and decreased the number of apoptotic
      cells in klotho mutant mice. These results suggest that oxidative stress has a
      crucial role in the aging-associated cognition impairment in klotho mutant mice.
      Klotho protein may be involved in the regulation of antioxidative defense.

PMID- 12475908
TI  - Fibroblast growth factor 4 induces vascular permeability, angiogenesis and
      arteriogenesis in a rabbit hindlimb ischemia model.
AB  - Previous studies have shown that fibroblast growth factor (FGF)-1, FGF-2, and FGF
      5 induce therapeutic angiogenesis. Here, we investigated the potential of FGF-4
      for therapeutic neovascularization in comparison to vascular endothelial growth
      factor (VEGF), using adenoviral gene transfer in a novel rabbit hind limb
      ischemia model, with ischemia restricted to the calf. Magnetic resonance imaging
      and a modified Miles assay showed that both AdFGF-4 and AdVEGF given
      intramuscularly (i.m.) resulted in increases in vascular permeability and edema
      in transduced muscles 6 days after the gene transfer. In contrast, recombinant
      FGF-4 protein injected in the rabbit skin did not induce acute vascular
      permeability. Injections (i.m.) of AdFGF-4 and AdVEGF, but not intra-arterially
      administered AdVEGF, increased collateral growth, popliteal blood flow, and
      muscle perfusion compared with controls. The angiogenesis response consisted
      mainly of the enlargement of pre-existing vessels rather than an increase in
      capillary density. Adenoviral FGF-4 overexpression up-regulated endogenous VEGF,
      which may explain many of the effects thought to be specific for VEGF such as the
      increase in vascular permeability. This study demonstrates for the first time
      that FGF-4 induces vascular permeability, therapeutic angiogenesis, and
      arteriogenesis comparable to that of VEGF and could be useful for the treatment
      of peripheral vascular disease.

PMID- 12475909
TI  - Mildly oxidized LDL particle subspecies are distinct in their capacity to induce
      apoptosis in endothelial cells: role of lipid hydroperoxides.
AB  - The risk of atherosclerosis is intimately related to the heterogeneity of low
      density lipoprotein (LDL) particles. The potential relationship between oxidative
      modification of distinct LDL subspecies and induction of apoptosis in arterial
      wall cells is indeterminate. The capacity of light LDL3 versus dense LDL5 to
      induce cytotoxicity in endothelial cells as a function of the degree of copper
      mediated oxidation was compared. Mildly oxidized LDL3 (oxLDL3) exerted potent
      cytotoxicity, which was intimately related to both the degree of oxidation and
      the oxLDL3 concentration based on either cholesterol content or particle number.
      In contrast, dense LDL5 particles exerted a minor effect on cell viability. Cells
      incubated with oxLDL3 exhibited apoptotic features, with cytoplasmic
      condensation, cell or nuclear fragmentation, and accumulation of DNA fragments.
      OxLDL3-induced apoptosis involved cytoplasmic release of cytochrome c, with a
      concomitant increase in caspase-3-like protease activity. OxLDL3 particles were
      uniquely distinct from oxLDL5 particles in their elevated content of lipid
      hydroperoxides. Hydroperoxide removal by NaBH4 markedly reduced oxLDL3-induced
      cytotoxicity, leading to an increase in cell viability. Lipid hydroperoxide
      content of oxidatively modified LDL subclasses is therefore a major determinant
      of the induction of apoptosis in endothelial cells. These data are highly
      relevant to atherogenic hypercholesterolemia, in which the LDL phenotype is
      dominated by elevated concentrations of light LDL3.

PMID- 12475910
TI  - Differential activation of AP-1 in human bladder epithelial cells by inorganic
      and methylated arsenicals.
AB  - Chronic exposures to inorganic arsenic (iAs) have been linked to increased
      incidences of various cancers, including cancer of the urinary bladder.
      Mechanisms by which iAs promotes cancer may include stimulation of activator
      protein-1 (AP-1) DNA binding through increased expression and/or phosphorylation
      of the AP-1 constituents. However, the role of methylated metabolites of iAs in
      AP-1 activation has not been thoroughly examined. In this study, we show that
      short-time exposures to 0.1-5 microM arsenite (iAsIII) or the methylated
      trivalent arsenicals methylarsine oxide (MAsIIIO), or iododimethylarsine
      (DMAsIIII) induce phosphorylation of c-Jun and increase AP-1 DNA binding activity
      in human bladder epithelial cells. DMAsIIII and especially MAsIIIO are
      considerably more potent than iAsIII as inducers of c-Jun phosphorylation and AP
      1 activation. Phosphorylated c-Jun, JunB, JunD, and Fra-1, but not c-Fos, FosB,
      or ATF-2, are detected in the AP-1-DNA binding complex in cells exposed to
      trivalent arsenicals. In cells transiently transfected with an AP-1-dependent
      promoter-reporter construct, MAsIIIO was more potent than iAsIII in inducing the
      AP-1-dependent gene transcription. Exposures to trivalent arsenicals induce
      phosphorylation of extracellular signal-regulated kinase (ERK), but not c-Jun N
      terminal kinases or p38 kinases. These results indicate that an ERK-dependent
      signal transduction pathway is at least partially responsible for c-Jun
      phosphorylation and AP-1 activation in UROtsa cells exposed to inorganic or
      methylated trivalent arsenicals.

PMID- 12475911
TI  - Visualization of the compartmentalization of glutathione and protein-glutathione
      mixed disulfides in cultured cells.
AB  - Fluorescence microscopy of A549 cells stained with a glutathione (L-gamma
      glutamyl-L-cysteinylglycine, GSH)-specific polyclonal antibody displayed uniform
      staining of the peri-nuclear cytosol, with the nuclear region apparently lacking
      GSH staining. This discontinuous staining was confirmed in other cell types and
      also corroborated in A549 cells stained with the thiol-reactive dye mercury
      orange. The selectivity of antibody binding was confirmed by buthionine
      sulfoximine (BSO)-dependent inhibition of GSH synthesis. However, confocal
      visualization of antibody-stained A549 cells in the z-plane revealed the majority
      of the peri-nuclear staining intensity in the upper half of the cell to be
      associated with mitochondria, as confirmed by double staining for cytochrome
      oxidase. Integration of the confocal signals from the nuclear and cytosolic
      regions halfway down the z-plane showed that the GSH concentrations of these
      compartments are close to equilibrium. Confirmation of the relatively high levels
      of mitochondrial glutathione was provided in cells treated with BSO and
      visualized in z-section, revealing the mitochondrial GSH content of these cells
      to be well preserved in apposition to near-complete depletion of
      cytosolic/nuclear GSH. Localized gradients within the cytosolic compartment were
      also visible, particularly in the z-plane. The antibody also provided initial
      visualization of the compartmentalization of protein-GSH mixed disulfides formed
      in A549 cells exposed to diamide. Discontinuous staining was again evident, with
      heavy staining in membrane blebs and in the nuclear region. Using FACS analysis
      of anti-GSH antibody-stained Jurkat T lymphocytes, we also demonstrated
      population variations in the cellular compliment of GSH and protein-GSH mixed
      disulfides, formed in response to diamide. In addition, we showed cell-cycle
      variation in GSH content of the cells, with the highest levels of GSH associated
      with the G2/M mitotic phase of the cell cycle, using double staining with
      propidium iodide. Similar FACS analyses performed in isolated mitochondria
      presented a considerable variation in GSH content within mitochondria of uniform
      granularity from the same preparation.

PMID- 12475912
TI  - Genomic analysis of smooth muscle cells in 3-dimensional collagen matrix.
AB  - The proliferation, differentiation, and protein synthesis of vascular smooth
      muscle cells (SMCs) play important roles in vascular remodeling. Here, we
      compared the genetic programming and signaling of SMCs in collagen matrix as a
      three-dimensional (3-D) environment and on a two-dimensional (2-D) surface. By
      using DNA microarrays with 9600 genes, we showed that 77 genes were expressed
      more than twofold and 22 genes were less than one-half in 3-D matrix, when
      compared with the 2-D condition. The higher expression level of cyclin-dependent
      kinase inhibitor 1 (p21) in 3-D matrix suggests that p21 may be responsible for
      the lower proliferation rate in 3-D matrix. The expression level of collagen I
      was higher in 3-D matrix, suggesting that SMCs in 3-D matrix have increased
      matrix synthesis. In addition, SMCs in 3-D matrix had less stress fibers and
      focal adhesions, and a lower level of tyrosine phosphorylation of focal adhesion
      kinase (FAK). Overexpression of FAK attenuated the expression of p21 and collagen
      I in 3-D matrix, suggesting that FAK functions as a molecular switch for cell
      cycle regulation and matrix synthesis. The information generated in this study
      helps to elucidate the molecular basis of the modulation of SMC phenotypes by the
      extracellular matrix.

PMID- 12475913
TI  - A novel pathway for regulation of glucose-dependent insulinotropic polypeptide
      (GIP) receptor expression in beta cells.
AB  - Glucose-dependent insulinotropic polypeptide (GIP) is secreted postprandially and
      acts in concert with glucose to stimulate insulin secretion from the pancreas.
      Here, we describe a novel pathway for the regulation of GIP receptor (GIPR)
      expression within clonal beta-cell lines, pancreatic islets, and in vivo. High
      (25 mM) glucose was able to significantly reduce GIPR mRNA levels in INS(832/13)
      cells after only 6 h. In contrast, palmitic acid (2 mM) and WY 14643 (100 microM)
      stimulated approximate doublings of GIPR expression in INS(832/13) cells under
      low (5.5 mM), but not high (25 mM), glucose conditions, suggesting that fat can
      regulate GIPR expression via PPARalpha in a glucose-dependent manner. Both MK
      886, an antagonist of PPARalpha, and a dominant negative form of PPARalpha
      transfected into INS(832/13) cells caused a significant reduction in GIPR
      expression in low, but not high, glucose conditions. Finally, in hyperglycemic
      clamped rats, there was a 70% reduction in GIPR expression in the islets and a
      71% reduction in GIP-stimulated insulin secretion from the perfused pancreas.
      Thus, evidence is presented that the GIPR is controlled at normoglycemia by the
      fatty acid load on the islet; however, when exposed to hyperglycemic conditions,
      the GIPR is down-regulated, which may contribute to the decreased responsiveness
      to GIP that is observed in type 2 diabetes.

PMID- 12475915
TI  - Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic
      blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes.
AB  - Diabetic macular edema, resulting from increased microvascular permeability, is
      the most prevalent cause of vision loss in diabetes. The mechanisms underlying
      this complication remain poorly understood. In the current study, diabetic
      vascular permeability (blood-retinal barrier breakdown) is demonstrated to result
      from a leukocyte-mediated Fas-FasL-dependent apoptosis of the retinal
      vasculature. Following the onset of streptozotocin-induced diabetes, FasL
      expression was increased in rat neutrophils (P<0.005) and was accompanied by a
      simultaneous increase in Fas expression in the retinal vasculature. Static
      adhesion assays demonstrated that neutrophils from diabetic, but not control,
      rats induced endothelial cell apoptosis in vitro (P<0.005). The latter was
      inhibited via an antibody-based FasL blockade (P<0.005). In vivo, the inhibition
      of FasL potently reduced retinal vascular endothelial cell injury, apoptosis, and
      blood-retinal barrier breakdown (P<0.0001) but did not diminish leukocyte
      adhesion to the diabetic retinal vasculature. Taken together, these data are the
      first to identify leukocyte-mediated Fas-FasL-dependent retinal endothelial cell
      apoptosis as a major cause of blood-retinal barrier breakdown in early diabetes.
      These data imply that the targeting of the Fas-FasL pathway may prove beneficial
      in the treatment of diabetic retinopathy.

PMID- 12475916
TI  - The role of indigenous microflora in the development of murine intestinal fucosyl
      and sialyltransferases.
AB  - Most enteric bacteria use intestinal brushborder glycoconjugates as their target
      host cell receptors. It has been postulated that resident microbes regulate
      specific glycosyltransferases that are responsible for synthesizing brushborder
      glycoconjugates. To investigate this hypothesis, we measured glycosyltransferase
      enzyme activities in intestine from different regions of maturing conventional
      (CONV), germ-free (GF), and ex-germ-free (XGF) mice and compared them to general
      enzyme markers of gut development, for example, disaccharidases. High alpha2,3/6
      Sialyltransferase (ST) activity and low alpha1,2-fucosyltransferase (FT)
      activities were detected from duodenum to colon in suckling CONV mice, but the
      relative levels of these activities reversed during the third postnatal wk,
      rapidly reaching adult levels by the fourth wk. These age-related enzyme changes
      were significantly attenuated in GF mice, maintaining an immature pattern well
      past 3 wk. Introduction of gut microflora in GF mice rapidly initiated maturation
      of glycosyltransferase activity but had no significant affect on developmental
      programming of dissacharidases. Therefore, in mice, intestinal
      glycosyltransferase activities are under tissue and developmental control and
      microflora play a major role in their specific ontogeny but not in overall
      development. These findings may help explain the regional specificity of
      commensal bacteria and of enteric pathogens and may also relate age-related
      changes in microflora to susceptibility to enteropathogens.

PMID- 12475917
TI  - The Max factor.

PMID- 12475918
TI  - Commentary on Samuel Broder's, Stephen Hoffman's and Peter Hotez's article in
      EMBO reports, September 2002.

PMID- 12475919
TI  - Commentary on Samuel Broder's, Stephen Hoffman's and Peter Hotez's article in
      EMBO reports, September 2002.

PMID- 12475920
TI  - A new partnership between science and politics. European scientists ought to
      adapt to new research policy paradigms.

PMID- 12475921
TI  - Turning manure into gold. The potential of methane-producing bacteria to meet
      future energy needs.

PMID- 12475922
TI  - Mad deer. The North American version of prion disease.

PMID- 12475923
TI  - Patents and public health. European institutions are challenging Myriad
      Genetics's patent monopoly on the brca1 gene.

PMID- 12475924
TI  - Grand ideas floating freely. Conference on the new prion biology: basic science,
      diagnosis and therapy.

PMID- 12475925
TI  - Healthy ageing: a question of stress, damage and repair. Meeting on mechanisms of
      biological ageing.

PMID- 12475926
TI  - Attraction within the membrane. Forces behind transmembrane protein folding and
      supramolecular complex assembly.
AB  - Biological membranes are fascinating two-dimensional microenvironments that
      exhibit unique solvent behaviours due to their varying lipid composition.
      Although many important bioenergetic and signalling events involve the transient
      or permanent assembly of membrane protein complexes, the characterization of the
      thermodynamic and kinetic properties behind this assembly is just beginning. In
      particular, the molecular forces that govern protein association within these
      structures remain poorly understood. An understanding of the docking of
      transmembrane proteins to supramolecular complexes, which will make possible the
      development of predictive computational tools, will require detailed knowledge of
      interaction forces at the atomistic or residue level. Here, I review current data
      on supramolecular complexes in membrane environments and make a tentative
      comparison between assembly processes in membranes and those driven by the
      hydrophobic effect in water. This comparison suggests that, in addition to being
      controlled by specific characteristics of the lipid molecules themselves,
      molecular assembly in the membrane milieu also depends more generally on the
      entropy of the lipid fraction.

PMID- 12475927
TI  - Telomere architecture.
AB  - Telomeres are protein-DNA complexes that cap chromosome ends and protect them
      from being recognized and processed as DNA breaks. Loss of capping function
      results in genetic instability and loss of cellular viability. The emerging view
      is that maintenance of an appropriate telomere structure is essential for
      function. Structural information on telomeric proteins that bind to double and
      single-stranded telomeric DNA shows that, despite a lack of extensive amino-acid
      sequence conservation, telomeric DNA recognition occurs via conserved DNA-binding
      domains. Furthermore, telomeric proteins have multidomain structures and hence
      are conformationally flexible. A possibility is that telomeric proteins take up
      different conformations when bound to different partners, providing a simple
      mechanism for modulating telomere architecture.

PMID- 12475928
TI  - Neuroglobin and cytoglobin. Fresh blood for the vertebrate globin family.
AB  - Neuroglobin and cytoglobin are two recently discovered members of the vertebrate
      globin family. Both are intracellular proteins endowed with hexacoordinated heme
      Fe atoms, in their ferrous and ferric forms, and display O2 affinities comparable
      with that of myoglobin. Neuroglobin, which is predominantly expressed in nerve
      cells, is thought to protect neurons from hypoxic-ischemic injury. It is of
      ancient evolutionary origin, and is homologous to nerve globins of invertebrates.
      Cytoglobin is expressed in many different tissues, although at varying levels. It
      shares common ancestry with myoglobin, and can be traced to early vertebrate
      evolution. The physiological roles of neuroglobin and cytoglobin are not
      completely understood. Although supplying cells with O2 is the likely function,
      it is also possible that both globins act as O2-consuming enzymes or as O2
      sensors. Here, we review what is currently known about neuroglobin and cytoglobin
      in terms of their function, tissue distribution and relatedness to the well-known
      hemoglobin and myoglobin. Strikingly, the data reveal that O2 metabolism in cells
      is more complicated than was thought before, requiring unexpected O2-binding
      proteins with potentially novel functional features.

PMID- 12475929
TI  - Orthologs of a novel archaeal and of the bacterial peptidyl-tRNA hydrolase are
      nonessential in yeast.
AB  - Peptidyl-tRNA hydrolase (encoded by pth) is an essential enzyme in all bacteria,
      where it releases tRNA from the premature translation termination product
      peptidyl-tRNA. Archaeal genomes lack a recognizable peptidyl-tRNA hydrolase (Pth)
      ortholog, although it is present in most eukaryotes. However, we detected Pth
      like activity in extracts of the archaeon Methanocaldococcus jannaschii. The
      uncharacterized MJ0051 ORF was shown to correspond to a protein with Pth
      activity. Heterologously expressed MJ0051 enzyme catalyzed in vitro the cleavage
      of the Pth substrates diacetyl-[14C]lysyl-tRNA and acetyl-[14C]phenylalanyl-tRNA.
      On transformation of an Escherichia coli pth(ts) mutant, the MJ0051 gene (named
      pth2) rescued the temperature-sensitive phenotype of the strain. Analysis of
      known genomes revealed the presence of highly conserved orthologs of the archaeal
      pth2 gene in all archaea and eukaryotes but not in bacteria. The phylogeny of
      pth2 homologs suggests that the gene has been vertically inherited throughout the
      archaeal and eukaryal domains. Deletions in Saccharomyces cerevisiae of the pth2
      (YBL057c) or pth (YHR189w) orthologs were viable, as was the double deletion
      strain, implying that the canonical Pth and Pth2 enzymes are not essential for
      yeast viability.

PMID- 12475930
TI  - Direct inhibition by nitric oxide of the transcriptional ferric uptake regulation
      protein via nitrosylation of the iron.
AB  - Ferric uptake regulation protein (Fur) is a bacterial global regulator that uses
      iron as a cofactor to bind to specific DNA sequences. The function of Fur is not
      limited to iron homeostasis. A wide variety of genes involved in various
      mechanisms such as oxidative and acid stresses are under Fur control.
      Flavohemoglobin (Hmp) is an NO-detoxifying enzyme induced by NO and nitrosothiol
      compounds. Fur recently was found to regulate hmp in Salmonella typhimurium, and
      in Escherichia coli, the iron-chelating agent 2,2'-dipyridyl induces hmp
      expression. We now establish direct inhibition of E. coli Fur activity by NO. By
      using chromosomal Fur-regulated lacZ reporter fusion in E. coli, Fur activity is
      switched off by NO at micromolar concentration. In vitro Fur DNA-binding
      activity, as measured by protection of restriction site in aerobactin promoter,
      is directly sensitive to NO. NO reacts with Fe(II) in purified FeFur protein to
      form a S = 12 low-spin FeFur-NO complex with a g = 2.03 EPR signal. Appearance of
      the same EPR signal in NO-treated cells links nitrosylation of the iron with Fur
      inhibition. The nitrosylated Fur protein is still a dimer and is stable in
      anaerobiosis but slowly decays in air. This inhibition probably arises from a
      conformational switch, leading to an inactive dimeric protein. These data
      establish a link between control of iron metabolism and the response to NO
      effects.

PMID- 12475931
TI  - Noninvasive real-time imaging of apoptosis.
AB  - Strict coordination of proliferation and programmed cell death (apoptosis) is
      essential for normal physiology. An imbalance in these two opposing processes
      results in various diseases including AIDS, neurodegenerative disorders,
      myelodysplastic syndromes, ischemiareperfusion injury, cancer, autoimmune
      disease, among others. Objective and quantitative noninvasive imaging of
      apoptosis would be a significant advance for rapid and dynamic screening as well
      as validation of experimental therapeutic agents. Here, we report the development
      of a recombinant luciferase reporter molecule that when expressed in mammalian
      cells has attenuated levels of reporter activity. In cells undergoing apoptosis,
      a caspase-3-specific cleavage of the recombinant product occurs, resulting in the
      restoration of luciferase activity that can be detected in living animals with
      bioluminescence imaging. The ability to image apoptosis noninvasively and
      dynamically over time provides an opportunity for high-throughput screening of
      proapoptotic and antiapoptotic compounds and for target validation in vivo in
      both cell lines and transgenic animals.

PMID- 12475932
TI  - Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation
      of toxic recombination intermediates from single-stranded gaps created by DNA
      replication.
AB  - Toxic recombination events are detected in vegetative Saccharomyces cerevisiae
      cells through negative growth interactions between certain combinations of
      mutations. For example, mutations affecting both the Srs2 and Sgs1 helicases
      result in extremely poor growth, a phenotype suppressed by mutations in genes
      that govern early stages of recombination. Here, we identify a similar
      interaction involving double mutations affecting Sgs1 or Top3 and Mus81 or Mms4.
      We also find that the primary DNA structures that initiate these toxic
      recombination events cannot be double-strand breaks and thus are likely to be
      single-stranded DNA. We interpret our results in the context of the idea that
      replication stalling leaves single-stranded DNA, which can then be processed by
      two competing mechanisms: recombination and nonrecombination gap-filling.
      Functions involved in preventing toxic recombination would either avoid
      replicative defects or act on recombination intermediates. Our results suggest
      that Srs2 channels recombination intermediates back into the gap-filling route,
      whereas Sgs1Top3 and Mus81Mms4 are involved in recombination andor in replication
      to allow replication restart.

PMID- 12475933
TI  - Protection against ischemic brain injury by protein therapeutics.
AB  - Preventing massive cell death is an important therapeutic strategy for various
      injuries and disorders. Protein therapeutics have the advantage of delivering
      proteins in a short period. We have engineered the antiapoptotic bcl-x gene to
      generate the super antiapoptotic factor, FNK, with a more powerful cytoprotective
      activity. In this study, we fused the protein transduction domain (PTD) of the
      HIVTat protein to FNK and used the construct in an animal model of ischemic brain
      injury. When added into culture media of human neuroblastoma cells and rat
      neocortical neurons, PTD-FNK rapidly transduced into cells and localized to
      mitochondria within 1 h. It protected the neuroblastomas and neurons against
      staurosporine-induced apoptosis and glutamate-induced excitotoxicity,
      respectively. The cytoprotective activity of PTD-FNK was found at concentrations
      as low as 0.3 pM. Additionally, PTD-FNK affected the cytosolic movement of
      calcium ions, which may relate to its neuroprotective action. Immunohistochemical
      analysis revealed that myc-tagged PTD-FNK (PTD-myc-FNK) injected i.p. into mice
      can have access into brain neurons. When injected i.p. into gerbils, PTD-FNK
      prevented delayed neuronal death in the hippocampus caused by transient global
      ischemia. These results suggest that PTD-FNK has a potential for clinical utility
      as a protein therapeutic strategy to prevent cell death in the brain.

PMID- 12475934
TI  - Excision of misincorporated ribonucleotides in DNA by RNase H (type 2) and FEN-1
      in cell-free extracts.
AB  - Misincorporated ribonucleotides in DNA will cause DNA backbone distortion and may
      be targeted by DNA repair enzymes. Using double-stranded oligonucleotide probes
      containing a single ribose, we demonstrate a robust activity in human, yeast, and
      Escherichia coli cell-free extracts that nicks 5' of the ribose. The human and
      yeast extracts also make a subsequent cut 3' of the ribonucleotide releasing a
      ribonucleotide monophosphate. The resulting 1-nt gap is an ideal substrate for
      polymerase and ligase to complete a proposed repair sequence that effectively
      replaces the ribose with deoxyribose. Screening of yeast deletion mutant cells
      reveals that the initial nick is made by RNase H(35), a RNase H type 2 enzyme,
      and the second cut is made by Rad27p, the yeast homologue of human FEN-1 protein.
      RNase H type 2 enzymes are present in all kingdoms of life and are evolutionarily
      well conserved. We knocked out the corresponding rnhb gene in E. coli and show
      that extracts from this strain lack the nicking activity. Conversely, a highly
      purified archaeal RNase HII type 2 protein has a pronounced activity. To study
      substrate specificity, extracts were made from a yeast double mutant lacking the
      other main RNase H enzymes [RNase H1 and RNase H(70)], while maintaining RNase
      H(35). It was found that a single ribose is preferred as substrate over a stretch
      of riboses, further strengthening a proposed role of this enzyme in the repair of
      misincorporated ribonucleotides rather than (or in addition to) processing RNADNA
      hybrid molecules.

PMID- 12475935
TI  - POTE, a highly homologous gene family located on numerous chromosomes and
      expressed in prostate, ovary, testis, placenta, and prostate cancer.
AB  - We have identified a gene located on chromosomes 21 that is expressed in normal
      and neoplastic prostate, and in normal testis, ovary, and placenta. We name this
      gene POTE (expressed in prostate, ovary, testis, and placenta). The POTE gene has
      11 exons and 10 introns and spans approximately equal 32 kb of chromosome 21q11.2
      region. The 1.83-kb mRNA of POTE encodes a protein of 66 kDa. Ten paralogs of the
      gene have been found dispersed among eight different chromosomes (2, 8, 13, 14,
      15, 18, 21, and 22) with preservation of ORFs and splice junctions. The
      synonymous:nonsynonymous ratio indicates that the genes were duplicated rather
      recently but are diverging at a rate faster than the average for other paralogous
      genes. In prostate and in testis, at least five different paralogs are expressed.
      In situ hybridization shows that POTE is expressed in basal and terminal cells of
      normal prostate epithelium. It is also expressed in some prostate cancers and in
      the LnCAP prostate cancer cell line. The POTE protein contains seven ankyrin
      repeats between amino acids 140 and 380. Expression of POTE in prostate cancer
      and its undetectable expression in normal essential tissues make POTE a candidate
      for the immunotherapy of prostate cancer. The existence of a large number of
      closely related but rapidly diverging members, their location on multiple
      chromosomes and their limited expression pattern suggest an important role for
      the POTE gene family in reproductive processes.

PMID- 12475936
TI  - The structure of Escherichia coli BtuF and binding to its cognate ATP binding
      cassette transporter.
AB  - Bacterial binding protein-dependent ATP binding cassette (ABC) transporters
      facilitate uptake of essential nutrients. The crystal structure of Escherichia
      coli BtuF, the protein that binds vitamin B12 and delivers it to the periplasmic
      surface of the ABC transporter BtuCD, reveals a bi-lobed fold resembling that of
      the ferrichrome binding protein FhuD. B12 is bound in the "base-on" conformation
      in a deep cleft formed at the interface between the two lobes of BtuF. A stable
      complex between BtuF and BtuCD (with the stoichiometry BtuC2D2F) is demonstrated
      to form in vitro and was modeled using the individual crystal structures. Two
      surface glutamates from BtuF may interact with arginine residues on the
      periplasmic surface of the BtuCD transporter. These glutamate and arginine
      residues are conserved among binding proteins and ABC transporters mediating iron
      and B12 uptake, suggesting that they may have a role in docking and the
      transmission of conformational changes.

PMID- 12475937
TI  - Association testing by DNA pooling: an effective initial screen.
AB  - With an ever-increasing resource of validated single-nucleotide polymorphisms
      (SNPs), the limiting factors in genome-wide association analysis have become
      genotyping capacity and the availability of DNA. We provide a proof of concept of
      the use of pooled DNA as a means of efficiently screening SNPs and prioritizing
      them for further study. This approach reduces the final number of SNPs that
      undergo full, sample-by-sample genotyping as well as the quantity of DNA used
      overall. We have examined 15 SNPs in the cholesteryl ester transfer protein
      (CETP) gene, a gene previously demonstrated to be associated with serum high
      density lipoprotein cholesterol levels. The SNPs were amplified in two pools of
      DNA derived from groups of individuals with extremely high and extremely low
      serum high-density lipoprotein cholesterol levels, respectively. P values <0.05
      were obtained for 14 SNPs, supporting the described association. Genotyping of
      the individual samples showed that the average margin of error in frequency
      estimate was approximately 4% when pools were used. These findings clearly
      demonstrate the potential of pooling techniques and their associated technologies
      as an initial screen in the search for genetic associations.

PMID- 12475938
TI  - Mammalian septins nomenclature.
AB  - There are 10 known mammalian septin genes, some of which produce multiple splice
      variants. The current nomenclature for the genes and gene products is very
      confusing, with several different names having been given to the same gene
      product and distinct names given to splice variants of the same gene. Moreover,
      some names are based on those of yeast or Drosophila septins that are not the
      closest homologues. Therefore, we suggest that the mammalian septin field adopt a
      common nomenclature system, based on that adopted by the Mouse Genomic
      Nomenclature Committee and accepted by the Human Genome Organization Gene
      Nomenclature Committee. The human and mouse septin genes will be named SEPT1
      SEPT10 and Sept1-Sept10, respectively. Splice variants will be designated by an
      underscore followed by a lowercase "v" and a number, e.g., SEPT4_v1.

PMID- 12475939
TI  - Different transmembrane domains associate with distinct endoplasmic reticulum
      components during membrane integration of a polytopic protein.
AB  - We have been studying the insertion of the seven transmembrane domain (TM)
      protein opsin to gain insights into how the multiple TMs of polytopic proteins
      are integrated at the endoplasmic reticulum (ER). We find that the ER components
      associated with the first and second TMs of the nascent opsin polypeptide chain
      are clearly distinct. The first TM (TM1) is adjacent to the alpha and beta
      subunits of the Sec61 complex, and a novel component, a protein associated with
      the ER translocon of 10 kDa (PAT-10). The most striking characteristic of PAT-10
      is that it remains adjacent to TM1 throughout the biogenesis and membrane
      integration of the full-length opsin polypeptide. TM2 is also found to be
      adjacent to Sec61alpha and Sec61beta during its membrane integration. However,
      TM2 does not form any adducts with PAT-10; rather, a transient association with
      the TRAM protein is observed. We show that the association of PAT-10 with opsin
      TM1 does not require the N-glycosylation of the nascent chain and occurs
      irrespective of the amino acid sequence and transmembrane topology of TM1. We
      conclude that the precise makeup of the ER membrane insertion site can be
      distinct for the different transmembrane domains of a polytopic protein. We find
      that the environment of a particular TM can be influenced by both the "stage" of
      nascent chain biosynthesis reached, and the TM's relative location within the
      polypeptide.

PMID- 12475941
TI  - Kar9p-independent microtubule capture at Bud6p cortical sites primes spindle
      polarity before bud emergence in Saccharomyces cerevisiae.
AB  - Spindle orientation is critical for accurate chromosomal segregation in
      eukaryotic cells. In the yeast Saccharomyces cerevisiae, orientation of the
      mitotic spindle is achieved by a program of microtubule-cortex interactions
      coupled to spindle morphogenesis. We previously implicated Bud6p in directing
      microtubule capture throughout this program. Herein, we have analyzed cells
      coexpressing GFP:Bud6 and GFP:Tub1 fusions, providing a kinetic view of Bud6p
      microtubule interactions in live cells. Surprisingly, even during the G1 phase,
      microtubule capture at the recent division site and the incipient bud is dictated
      by Bud6p. These contacts are eliminated in bud6 delta cells but are proficient in
      kar9 delta cells. Thus, Bud6p cues microtubule capture, as soon as a new cell
      polarity axis is established independent of Kar9p. Bud6p increases the duration
      of interactions and promotes distinct modes of cortical association within the
      bud and neck regions. In particular, microtubule shrinkage and growth at the
      cortex rarely occur away from Bud6p sites. These are the interactions selectively
      impaired at the bud cortex in bud6 delta cells. Finally, interactions away from
      Bud6p sites within the bud differ from those occurring at the mother cell cortex,
      pointing to the existence of an independent factor controlling cortical contacts
      in mother cells after bud emergence.

PMID- 12475940
TI  - Selective protein exit from yeast endoplasmic reticulum in absence of functional
      COPII coat component Sec13p.
AB  - Sec13p has been thought to be an essential component of the COPII coat, required
      for exit of proteins from the yeast endoplasmic reticulum (ER). We show herein
      that normal function of Sec13p was not required for ER exit of the Hsp150
      glycoprotein. Hsp150 was secreted to the medium under restrictive conditions in a
      sec13-1 mutant. The COPII components Sec23p and Sec31p and the GTP/GDP exchange
      factor Sec12p were required in functional form for secretion of Hsp150. Hsp150
      leaves the ER in the absence of retrograde COPI traffic, and the responsible
      determinant is a peptide repeated 11 times in the middle of the Hsp150 sequence.
      Herein, we localized the sorting determinant for Sec13p-independent ER exit to
      the C-terminal domain. Sec13p-dependent invertase left the ER in the absence of
      normal Sec13p function, when fused to the C-terminal domain of Hsp150,
      demonstrating that this domain contained an active mediator of Sec13p-independent
      secretion. Thus, Hsp150 harbors two different signatures that regulate its ER
      exit. Our data show that transport vesicles lacking functional Sec13p can carry
      out ER-to-Golgi transport, but select only specific cargo protein(s) for ER exit.

PMID- 12475942
TI  - Characterization of an A-kinase anchoring protein in human ciliary axonemes.
AB  - Although protein kinase A (PKA) activation is known to increase ciliary beat
      frequency in humans the molecular mechanisms involved are unknown. We demonstrate
      that PKA is associated with ciliary axonemes where it specifically phosphorylates
      a 23-kDa protein. Because PKA is often localized to subcellular compartments in
      proximity to its substrate(s) via interactions with A-kinase-anchoring proteins
      (AKAPs), we investigated whether an AKAP was also associated with ciliary
      axonemes. This study has identified a novel 28 kDa AKAP (AKAP28)that is highly
      enriched in airway axonemes. The mRNA for AKAP28 is up-regulated as primary
      airway cells differentiate and is specifically expressed in tissues containing
      cilia and/or flagella. Additionally, both Western blot and immunostaining data
      show that AKAP28 is enriched in airway cilia. These data demonstrate that we have
      identified the first human axonemal AKAP, a protein that likely plays a role in
      the signaling necessary for efficient modulation of ciliary beat frequency.

PMID- 12475943
TI  - Mutant actins demonstrate a role for unpolymerized actin in control of
      transcription by serum response factor.
AB  - Signal-induced activation of the transcription factor serum response factor (SRF)
      requires alterations in actin dynamics. SRF activity can be inhibited by ectopic
      expression of beta-actin, either because actin itself participates in SRF
      regulation or as a consequence of cytoskeletal perturbations. To distinguish
      between these possibilities, we studied actin mutants. Three mutant actins, G13R,
      R62D, and a C-terminal VP16 fusion protein, were shown not to polymerize in vivo,
      as judged by two-hybrid, immunofluorescence, and cell fractionation studies.
      These actins effectively inhibited SRF activation, as did wild-type actin, which
      increased the G-actin level without altering the F:G-actin ratio. Physical
      interaction between SRF and actin was not detectable by mammalian or yeast two
      hybrid assays, suggesting that SRF regulation involves an unidentified cofactor.
      SRF activity was not blocked upon inhibition of CRM1-mediated nuclear export by
      leptomycin B. Two actin mutants were identified, V159N and S14C, whose expression
      favored F-actin formation and which strongly activated SRF in the absence of
      external signals. These mutants seemed unable to inhibit SRF activity, because
      their expression did not reduce the absolute level of G-actin as assessed by
      DNase I binding. Taken together, these results provide strong evidence that G
      actin, or a subpopulation of it, plays a direct role in signal transduction to
      SRF.

PMID- 12475944
TI  - Regulation of IkappaBbeta expression in testis.
AB  - IkappaBalpha and IkappaBbeta are regulators of the nuclear factor-kappaB (NF
      kappaB) transcription factor family. Both IkappaBs bind to the same NF-kappaB
      dimers and are widely expressed in different cells and tissues. To better
      understand how these two IkappaB isoforms differ biologically, we have
      characterized the expression of IkappaBbeta in testis, a tissue in which
      IkappaBalpha is only minimally expressed. We have found that IkappaBbeta
      expression is localized within the haploid spermatid stages of spermatogenesis
      and follows the expression of nuclear NF-kappaB. IkappaBbeta expression in
      haploid spermatids is likely regulated by Sox family proteins, members of which
      are also expressed within spermatids. We have shown that both SRY and Sox-5 can
      bind to multiple Sox binding sites found within the IkappaBbeta promoter and can
      enhance transcription of a reporter gene in transient transfection assays. We
      also demonstrate that IkappaBbeta mRNA is strongly expressed in developing male
      gonads. These results therefore suggest that IkappaBbeta may be a novel target
      for transcription factors of the HMG-box SRY/Sox family and imply a potential
      role for NF-kappaB/IkappaBbeta in spermatogenesis.

PMID- 12475945
TI  - Characterization of human alpha-dystrobrevin isoforms in HL-60 human
      promyelocytic leukemia cells undergoing granulocytic differentiation.
AB  - The biochemical properties and spatial localization of the protein alpha
      dystrobrevin and other isoforms were investigated in cells of the human
      promyelocytic leukemia line HL-60 granulocytic differentiation as induced by
      retinoic acid (RA). Alpha-dystrobrevin was detected both in the cytosol and the
      nuclei of these cells, and a short isoform (gamma-dystrobrevin) was modified by
      tyrosine phosphorylation soon after the onset of the RA-triggered
      differentiation. Varying patterns of distribution of alpha-dystrobrevin and its
      isoforms could be discerned in HL-60 promyelocytes, RA-differentiated mature
      granulocytes, and human neutrophils. Moreover, the gamma-dystrobrevin isoform was
      found in association with actin and myosin light chain. The results provide new
      information about potential involvement of alpha-dystrobrevin and its splice
      isoforms in signal transduction in myeloid cells during induction of granulocytic
      differentiation and/or at the commitment stage of differentiation or phagocytic
      cells.

PMID- 12475946
TI  - Pink-eyed dilution protein modulates arsenic sensitivity and intracellular
      glutathione metabolism.
AB  - Mutations in the mouse p (pink-eyed dilution) and human P genes lead to
      melanosomal defects and ocular developmental abnormalities. Despite the critical
      role played by the p gene product in controlling tyrosinase processing and
      melanosome biogenesis, its precise biological function is still not defined. We
      have expressed p heterologously in the yeast Saccharomyces cerevisiae to study
      its function in greater detail. Immunofluorescence studies revealed that p
      reaches the yeast vacuolar membrane via the prevacuolar compartment. Yeast cells
      expressing p exhibited increased sensitivity to a number of toxic compounds,
      including arsenicals. Similarly, cultured murine melanocytes expressing a
      functional p gene were also found to be more sensitive to arsenical compounds
      compared with p-null cell lines. Intracellular glutathione, known to play a role
      in detoxification of arsenicals, was diminished by 50% in p-expressing yeast. By
      using the glutathione-conjugating dye monochlorobimane, in combination with
      acivicin, an inhibitor of vacuolar gamma-glutamyl cysteine transpeptidase,
      involved in the breakdown of glutathione, we found that p facilitates the
      vacuolar accumulation of glutathione. Our data demonstrate that the pink-eyed
      dilution protein increases cellular sensitivity to arsenicals and other
      metalloids and can modulate intracellular glutathione metabolism.

PMID- 12475947
TI  - Specific heterodimer formation is a prerequisite for uroplakins to exit from the
      endoplasmic reticulum.
AB  - Much of the lower urinary tract, including the bladder, is lined by a stratified
      urothelium forming a highly differentiated, superficial umbrella cell layer. The
      apical plasma membrane as well as abundant cytoplasmic fusiform vesicles of the
      umbrella cells is covered by two-dimensional crystals that are formed by four
      membrane proteins named uroplakins (UPs) Ia, Ib, II, and III. UPs are synthesized
      on membrane-bound polysomes, and after several co- and posttranslational
      modifications they assemble into planar crystals in a post-Golgi vesicular
      compartment. Distension of the bladder may cause fusiform vesicles to fuse with
      the apical plasma membrane. We have investigated the early stages of uroplakin
      assembly by expressing the four uroplakins in 293T cells. Transfection
      experiments showed that, when expressed individually, only UPIb can exit from the
      endoplasmic reticulum (ER) and move to the plasma membrane, whereas UPII and
      UPIII reach the plasma membrane only when they form heterodimeric complexes with
      UPIa and UPIb, respectively. Heterodimer formation in the ER was confirmed by
      pulse-chase experiment followed by coimmunoprecipitation. Our results indicate
      that the initial building blocks for the assembly of crystalline uroplakin
      plaques are heterodimeric uroplakin complexes that form in the ER.

PMID- 12475948
TI  - Adaptor protein Crk is required for ephrin-B1-induced membrane ruffling and focal
      complex assembly of human aortic endothelial cells.
AB  - Endothelial cell migration is an essential step in vasculogenesis and
      angiogenesis, in which receptor tyrosine kinases play a pivotal role. We
      investigated the mechanism by which ephrin-B1 promotes membrane ruffling in human
      aortic endothelial cells, because membrane ruffling heralds cell body migration.
      We especially focused on the role of Crk adaptor protein in EphB-mediated
      signaling. Using DsRed-tagged Crk and a fluorescent time-lapse microscope, we
      showed that Crk was recruited to the nascent focal complex after ephrin-B1
      stimulation. Furthermore, we found that p130(Cas), but not paxillin, recruited
      Crk to the nascent focal complex. The necessity of Crk in ephrin-B1-induced
      membrane ruffling was shown both by the overexpression of dominant negative Crk
      mutants and by the depletion of Crk by using RNA interference. Then, we examined
      the role of two major downstream molecules of Crk, Rac1 and Rap1. The dominant
      negative mutant of Rac1 completely inhibited ephrin-B1-induced membrane ruffling
      and focal complex assembly. In contrast, rap1GAPII, a negative regulator of Rap1,
      did not inhibit ephrin-B1-induced membrane ruffling. However, in rap1GAPII
      expressing cells, ephrin-B1 did not induce membrane spreading, probably due to
      instability of the focal complex. These results indicated that Crk plays a
      critical role in Rac1-induced membrane ruffling and Rap1-mediated nascent focal
      complex stabilization contributing to ephrin-B1-induced human aortic endothelial
      cells migration.

PMID- 12475949
TI  - Peroxisome senescence in human fibroblasts.
AB  - The molecular mechanisms of peroxisome biogenesis have begun to emerge; in
      contrast, relatively little is known about how the organelle functions as cells
      age. In this report, we characterize age-related changes in peroxisomes of human
      cells. We show that aging compromises peroxisomal targeting signal 1 (PTS1)
      protein import, affecting in particular the critical antioxidant enzyme catalase.
      The number and appearance of peroxisomes are altered in these cells, and the
      organelles accumulate the PTS1-import receptor, Pex5p, on their membranes.
      Concomitantly, cells produce increasing amounts of the toxic metabolite hydrogen
      peroxide, and we present evidence that this increased load of reactive oxygen
      species may further reduce peroxisomal protein import and exacerbate the effects
      of aging.

PMID- 12475950
TI  - Entamoeba histolytica expressing a dominant negative N-truncated light subunit of
      its gal-lectin are less virulent.
AB  - The 260-kDa heterodimeric Gal/GalNAc-specific Lectin (Gal-lectin) of Entamoeba
      histolytica dissociates under reducing conditions into a heavy (hgl, 170 kDa) and
      a light subunit (lgl, 35 kDa). We have previously shown that inhibition of
      expression of the 35-kDa subunit by antisense RNA causes a decrease in virulence.
      To further understand the role of the light subunit of the Gal-lectin in
      pathogenesis, amoebae were transfected with plasmids encoding intact, mutated,
      and truncated forms of the light subunit lgl1 gene. A transfectant in which the
      55 N-terminal amino acids of the lgl were removed, overproduced an N-truncated
      lgl protein (32 kDa), which replaced most of the native 35-kDa lgl in the
      formation of the Gal-lectin heterodimeric complex and exerted a dominant negative
      effect. Amoebae transfected with this construct showed a significant decrease in
      their ability to adhere to and kill mammalian cells as well as in their capacity
      to form rosettes with and to phagocytose erythrocytes. In addition,
      immunofluorescence confocal microscopy of this transfectant with anti-Gal-lectin
      antibodies showed an impaired ability to cap. These results indicate that the
      light subunit has a role in enabling the clustering of Gal-lectin complexes and
      that its N-truncation affects this function, which is required for virulence.

PMID- 12475951
TI  - Role of secretory carrier membrane protein SCAMP2 in granule exocytosis.
AB  - In secretory carrier membrane proteins (SCAMPs), the most conserved structural
      segment is between transmembrane spans 2 and 3, facing the cytosol. A synthetic
      peptide, CWYRPIYKAFR (E peptide), from this segment of SCAMP2 potently inhibits
      exocytosis in permeabilized neuroendocrine (PC12) cells. E peptide blocked
      discharge of (35)S-labeled secretogranin with the same structural selectivity and
      potency as observed for hexosaminidase secretion in mast cells. SCAMPs 1 and 2
      are concentrated primarily on intracellular membranes in PC12 cells. Both,
      however, are found on plasma membranes, but neither is present on large dense
      core vesicles. Yet, large dense-core vesicles marked by secretogranin attach to
      plasma membranes at foci containing SCAMP2 along with syntaxin1 and complexin at
      putative cell-surface docking/fusion sites. Regulated overexpression of SCAMP2
      with point mutations in its E peptide but not of normal SCAMP2 caused dose
      dependent inhibition of depolarization-induced secretion. The SCAMP2 mutants also
      inhibited secretion stimulated by elevated calcium. Inhibition was largely
      overcome by adding lysophosphatidylcholine to the medium at concentrations that
      do not otherwise affect secretion. Although overexpression of normal or mutant
      SCAMP2 slightly inhibits endocytosis, this effect does not appear to be related
      to the specific effect of the mutant SCAMP on stimulated exocytosis. Thus, SCAMP2
      not only colocalizes with fusion sites but also appears to have an essential
      function in granule exocytosis through actions mediated by its E peptide
      containing domain.

PMID- 12475952
TI  - Human adipose tissue is a source of multipotent stem cells.
AB  - Much of the work conducted on adult stem cells has focused on mesenchymal stem
      cells (MSCs) found within the bone marrow stroma. Adipose tissue, like bone
      marrow, is derived from the embryonic mesenchyme and contains a stroma that is
      easily isolated. Preliminary studies have recently identified a putative stem
      cell population within the adipose stromal compartment. This cell population,
      termed processed lipoaspirate (PLA) cells, can be isolated from human
      lipoaspirates and, like MSCs, differentiate toward the osteogenic, adipogenic,
      myogenic, and chondrogenic lineages. To confirm whether adipose tissue contains
      stem cells, the PLA population and multiple clonal isolates were analyzed using
      several molecular and biochemical approaches. PLA cells expressed multiple CD
      marker antigens similar to those observed on MSCs. Mesodermal lineage induction
      of PLA cells and clones resulted in the expression of multiple lineage-specific
      genes and proteins. Furthermore, biochemical analysis also confirmed lineage
      specific activity. In addition to mesodermal capacity, PLA cells and clones
      differentiated into putative neurogenic cells, exhibiting a neuronal-like
      morphology and expressing several proteins consistent with the neuronal
      phenotype. Finally, PLA cells exhibited unique characteristics distinct from
      those seen in MSCs, including differences in CD marker profile and gene
      expression.

PMID- 12475953
TI  - Vps10p cycles between the TGN and the late endosome via the plasma membrane in
      clathrin mutants.
AB  - Clathrin-coated vesicles mediate the transport of the soluble vacuolar protein
      CPY from the TGN to the endosomal/prevacuolar compartment. Surprisingly, CPY
      sorting is not affected in clathrin deletion mutant cells. Here, we have
      investigated the clathrin-independent pathway that allows CPY transport to the
      vacuole. We find that CPY transport is mediated by the endosome and requires
      normal trafficking of its sorting receptor, Vps10p, the steady state distribution
      of which is not altered in chc1 cells. In contrast, Vps10p accumulates at the
      cell surface in a chc1/end3 double mutant, suggesting that Vps10p is rerouted to
      the cell surface in the absence of clathrin. We used a chimeric protein
      containing the first 50 amino acids of CPY fused to a green fluorescent protein
      (CPY-GFP) to mimic CPY transport in chc1. In the absence of clathrin, CPY-GFP
      resides in the lumen of the vacuole as in wild-type cells. However, in chc1/sec6
      double mutants, CPY-GFP is present in internal structures, possibly endosomal
      membranes, that do not colocalize with the vacuole. We propose that Vps10p must
      be transported to and retrieved from the plasma membrane to mediate CPY sorting
      to the vacuole in the absence of clathrin-coated vesicles. In this circumstance,
      precursor CPY may be captured by retrieved Vps10p in an early or late endosome,
      rather than as it normally is in the trans-Golgi, and delivered to the vacuole by
      the normal VPS gene-dependent process. Once relieved of cargo protein, Vps10p
      would be recycled to the trans-Golgi and then to the cell surface for further
      rounds of sorting.

PMID- 12475954
TI  - EB1 targets to kinetochores with attached, polymerizing microtubules.
AB  - Microtubule polymerization dynamics at kinetochores is coupled to chromosome
      movements, but its regulation there is poorly understood. The plus end tracking
      protein EB1 is required both for regulating microtubule dynamics and for
      maintaining a euploid genome. To address the role of EB1 in aneuploidy, we
      visualized its targeting in mitotic PtK1 cells. Fluorescent EB1, which localized
      to polymerizing ends of astral and spindle microtubules, was used to track their
      polymerization. EB1 also associated with a subset of attached kinetochores in
      late prometaphase and metaphase, and rarely in anaphase. Localization occurred in
      a narrow crescent, concave toward the centromere, consistent with targeting to
      the microtubule plus end-kinetochore interface. EB1 did not localize to
      kinetochores lacking attached kinetochore microtubules in prophase or early
      prometaphase, or upon nocodazole treatment. By time lapse, EB1 specifically
      targeted to kinetochores moving antipoleward, coupled to microtubule plus end
      polymerization, and not during plus end depolymerization. It localized
      independently of spindle bipolarity, the spindle checkpoint, and dynein/dynactin
      function. EB1 is the first protein whose targeting reflects kinetochore
      directionality, unlike other plus end tracking proteins that show enhanced
      kinetochore binding in the absence of microtubules. Our results suggest EB1 may
      modulate kinetochore microtubule polymerization and/or attachment.

PMID- 12475955
TI  - Interorganellar regulation of lysosome positioning by the Golgi apparatus through
      Rab34 interaction with Rab-interacting lysosomal protein.
AB  - We present evidence to suggest the existence of a regulatory pathway for the
      Golgi apparatus to modulate the spatial positioning of otherwise distantly
      located lysosomes. Rab34, a new member of the Rab GTPase family, is associated
      primarily with the Golgi apparatus. Expression of wild-type or GTP-restricted but
      not GDP-restricted versions of Rab34 causes spatial redistribution of lysosomes
      from the periphery to the peri-Golgi region. The regulation of lysosomal
      positioning by Rab34 depends on its association with the membrane mediated by
      prenylation and its direct interaction with Rab-interacting lysosomal protein
      (RILP). This biological activity, mediated by Rab34-RILP interaction, is
      dependent on Lys82 in the switch I region. Our results have uncovered a novel
      mechanism for the Golgi apparatus to regulate the spatial distribution of another
      organelle.

PMID- 12475956
TI  - Novel myosin heavy chain kinase involved in disassembly of myosin II filaments
      and efficient cleavage in mitotic dictyostelium cells.
AB  - We have cloned a full-length cDNA encoding a novel myosin II heavy chain kinase
      (mhckC) from Dictyostelium. Like other members of the myosin heavy chain kinase
      family, the mhckC gene product, MHCK C, has a kinase domain in its N-terminal
      half and six WD repeats in the C-terminal half. GFP-MHCK C fusion protein
      localized to the cortex of interphase cells, to the cleavage furrow of mitotic
      cells, and to the posterior of migrating cells. These distributions of GFP-MHCK C
      always corresponded with that of myosin II filaments and were not observed in
      myosin II-null cells, where GFP-MHCK C was diffusely distributed in the
      cytoplasm. Thus, localization of MHCK C seems to be myosin II-dependent. Cells
      lacking the mhckC gene exhibited excessive aggregation of myosin II filaments in
      the cleavage furrows and in the posteriors of the daughter cells once cleavage
      was complete. The cleavage process of these cells took longer than that of wild
      type cells. Taken together, these findings suggest MHCK C drives the disassembly
      of myosin II filaments for efficient cytokinesis and recycling of myosin II that
      occurs during cytokinesis.

PMID- 12475957
TI  - Mitochondrial fusion in human cells is efficient, requires the inner membrane
      potential, and is mediated by mitofusins.
AB  - Mitochondrial fusion remains a largely unknown process despite its observation by
      live microscopy and the identification of few implicated proteins. Using green
      and red fluorescent proteins targeted to the mitochondrial matrix, we show that
      mitochondrial fusion in human cells is efficient and achieves complete mixing of
      matrix contents within 12 h. This process is maintained in the absence of a
      functional respiratory chain, despite disruption of microtubules or after
      significant reduction of cellular ATP levels. In contrast, mitochondrial fusion
      is completely inhibited by protonophores that dissipate the inner membrane
      potential. This inhibition, which results in rapid fragmentation of mitochondrial
      filaments, is reversible: small and punctate mitochondria fuse to reform
      elongated and interconnected ones upon withdrawal of protonophores. Expression of
      wild-type or dominant-negative dynamin-related protein 1 showed that
      fragmentation is due to dynamin-related protein 1-mediated mitochondrial
      division. On the other hand, expression of mitofusin 1 (Mfn1), one of the human
      Fzo homologues, increased mitochondrial length and interconnectivity. This
      process, but not Mfn1 targeting, was dependent on the inner membrane potential,
      indicating that overexpressed Mfn1 stimulates fusion. These results show that
      human mitochondria represent a single cellular compartment whose exchanges and
      interconnectivity are dynamically regulated by the balance between continuous
      fusion and fission reactions.

PMID- 12475958
TI  - Ran GTPase cycle and importins alpha and beta are essential for spindle formation
      and nuclear envelope assembly in living Caenorhabditis elegans embryos.
AB  - The small GTPase Ran has been found to play pivotal roles in several aspects of
      cell function. We have investigated the role of the Ran GTPase cycle in spindle
      formation and nuclear envelope assembly in dividing Caenorhabditis elegans
      embryos in real time. We found that Ran and its cofactors RanBP2, RanGAP, and
      RCC1 are all essential for reformation of the nuclear envelope after cell
      division. Reducing the expression of any of these components of the Ran GTPase
      cycle by RNAi leads to strong extranuclear clustering of integral nuclear
      envelope proteins and nucleoporins. Ran, RanBP2, and RanGAP are also required for
      building a mitotic spindle, whereas astral microtubules are normal in the absence
      of these proteins. RCC1(RNAi) embryos have similar abnormalities in the initial
      phase of spindle formation but eventually recover to form a bipolar spindle.
      Irregular chromatin structures and chromatin bridges due to spindle failure were
      frequently observed in embryos where the Ran cycle was perturbed. In addition,
      connection between the centrosomes and the male pronucleus, and thus centrosome
      positioning, depends upon the Ran cycle components. Finally, we have demonstrated
      that both IMA-2 and IMB-1, the homologues of vertebrate importin alpha and beta,
      are essential for both spindle assembly and nuclear formation in early embryos.

PMID- 12475959
TI  - Alternative splicing regulates the subcellular localization of divalent metal
      transporter 1 isoforms.
AB  - Divalent metal transporter 1 (DMT1) is responsible for dietary-iron absorption
      from apical plasma membrane in the duodenum and iron acquisition from the
      transferrin cycle endosomes in peripheral tissues. Two isoforms of the DMT1
      transcript generated by alternative splicing of the 3' exons have been identified
      in mouse, rat, and human. These isoforms can be distinguished by the different C
      terminal amino acid sequences and by the presence (DMT1A) or absence (DMT1B) of
      an iron response element located in the 3' untranslated region of the mRNA.
      However, it has been still unknown whether the structural differences between the
      two DMT1 isoforms is functionally important. Here, we report that each DMT1
      isoform exhibits a differential cell type-specific expression patterns and
      distinct subcellular localizations. DMT1A is predominantly expressed by
      epithelial cell lines, whereas DMT1B is expressed by the blood cell lines. In HEp
      2 cells, GFP-tagged DMT1A is localized in late endosomes and lysosomes, whereas
      GFP-tagged DMT1B is localized in early endosomes. Using site-directed
      mutagenesis, a Y(555)XLXX sequence in the cytoplasmic tail of DMT1B has been
      identified as an important signal sequence for the early endosomal-targeting of
      DMT1B. In polarized MDCK cells, GFP-tagged DMT1A and DMT1B are localized in the
      apical plasma membrane and their respective specific endosomes. Disruption of the
      N-glycosylation sites in each of the DMT1 isoforms affects their polarized
      distribution into the apical plasma membrane but not their correct endosomal
      localization. Our data indicate that the cell type-specific expression patterns
      and the distinct subcellular localizations of two DMT1 isoforms may be involved
      in the different iron acquisition steps from the subcellular membranes in various
      cell types.

PMID- 12475960
TI  - Identification of the nuclear localization signal in Xenopus cyclin E and
      analysis of its role in replication and mitosis.
AB  - Cyclin-dependent kinase (Cdk)2/cyclin E is imported into nuclei assembled in
      Xenopus egg extracts by a pathway that requires importin-alpha and -beta. Here,
      we identify a basic nuclear localization sequence (NLS) in the N-terminus of
      Xenopus cyclin E. Mutation of the NLS eliminated nuclear accumulation of both
      cyclin E and Cdk2, and such versions of cyclin E were unable to trigger DNA
      replication. Addition of a heterologous NLS from SV40 large T antigen restored
      both nuclear targeting of Cdk2/cyclin E and DNA replication. We present evidence
      indicating that Cdk2/cyclin E complexes must become highly concentrated within
      nuclei to support replication and find that cyclin A can trigger replication at
      much lower intranuclear concentrations. We confirmed that depletion of endogenous
      cyclin E increases the concentration of cyclin B necessary to promote entry into
      mitosis. In contrast to its inability to promote DNA replication, cyclin E
      lacking its NLS was able to cooperate with cyclin B in promoting mitotic entry.

PMID- 12475961
TI  - Lamin A/C binding protein LAP2alpha is required for nuclear anchorage of
      retinoblastoma protein.
AB  - The phosphorylation-dependent anchorage of retinoblastoma protein Rb in the
      nucleus is essential for its function. We show that its pocket C domain is both
      necessary and sufficient for nuclear anchorage by transiently expressing green
      fluorescent protein (GFP) chimeras of Rb fragments in tissue culture cells and by
      extracting the cells with hypotonic solutions. Solid phase binding assays using
      glutathione S-transferase-fusion of Rb pockets A, B, and C revealed a direct
      association of lamin C exclusively to pocket C. Lamina-associated polypeptide
      (LAP) 2alpha, a binding partner of lamins A/C, bound strongly to pocket C and
      weakly to pocket B. When LAP2alpha was immunoprecipitated from soluble nuclear
      fractions, lamins A/C and hypophosphorylated Rb were coprecipitated efficiently.
      Similarly, immunoprecipitation of expressed GFP-Rb fragments by using anti-GFP
      antibodies coprecipitated LAP2alpha, provided that pocket C was present in the
      GFP chimeras. On redistribution of endogenous lamin A/C and LAP2alpha into
      nuclear aggregates by overexpressing dominant negative lamin mutants in tissue
      culture cells, Rb was also sequestered into these aggregates. In primary skin
      fibroblasts, LAP2alpha is expressed in a growth-dependent manner. Anchorage of
      hypophosphorylated Rb in the nucleus was weakened significantly in the absence of
      LAP2alpha. Together, these data suggest that hypophosphorylated Rb is anchored in
      the nucleus by the interaction of pocket C with LAP2alpha-lamin A/C complexes.

PMID- 12475962
TI  - A specific structural requirement for ergosterol in long-chain fatty acid
      synthesis mutants important for maintaining raft domains in yeast.
AB  - Fungal sphingolipids contain ceramide with a very-long-chain fatty acid (C26). To
      investigate the physiological significance of the C26-substitution on this lipid,
      we performed a screen for mutants that are synthetically lethal with ELO3. Elo3p
      is a component of the ER-associated fatty acid elongase and is required for the
      final elongation cycle to produce C26 from C22/C24 fatty acids. elo3delta mutant
      cells thus contain C22/C24- instead of the natural C26-substituted ceramide. We
      now report that under these conditions, an otherwise nonessential, but also
      fungal-specific, structural modification of the major sterol of yeast,
      ergosterol, becomes essential, because mutations in ELO3 are synthetically lethal
      with mutations in ERG6. Erg6p catalyzes the methylation of carbon atom 24 in the
      aliphatic side chain of sterol. The lethality of an elo3delta erg6delta double
      mutant is rescued by supplementation with ergosterol but not with cholesterol,
      indicating a vital structural requirement for the ergosterol-specific methyl
      group. To characterize this structural requirement in more detail, we generated a
      strain that is temperature sensitive for the function of Erg6p in an elo3delta
      mutant background. Examination of raft association of the GPI-anchored Gas1p and
      plasma membrane ATPase, Pma1p, in the conditional elo3delta erg6(ts) double
      mutant, revealed a specific defect of the mutant to maintain raft association of
      preexisting Pma1p. Interestingly, in an elo3delta mutant at 37 degrees C, newly
      synthesized Pma1p failed to enter raft domains early in the biosynthetic pathway,
      and upon arrival at the plasma membrane was rerouted to the vacuole for
      degradation. These observations indicate that the C26 fatty acid substitution on
      lipids is important for establishing raft association of Pma1p and stabilizing
      the protein at the cell surface. Analysis of raft lipids in the conditional
      mutant strain revealed a selective enrichment of ergosterol in detergent
      resistant membrane domains, indicating that specific structural determinants on
      both sterols and sphingolipids are required for their association into raft
      domains.

PMID- 12475963
TI  - Lipid-dependent subcellular relocalization of the acyl chain desaturase in yeast.
AB  - The degree of acyl chain desaturation of membrane lipids is a critical
      determinant of membrane fluidity. Temperature-sensitive mutants of the single
      essential acyl chain desaturase, Ole1p, of yeast have previously been isolated in
      screens for mitochondrial inheritance mutants (Stewart, L.C. and Yaffe, M.P.
      (1991). J. Cell Biol. 115, 1249-1257). We now report that the mutant desaturase
      relocalizes from its uniform ER distribution to a more punctuate localization at
      the cell periphery upon inactivation of the enzyme. This relocalization takes
      place within minutes at nonpermissive conditions, a time scale at which
      mitochondrial morphology and inheritance is not yet affected. Relocalization of
      the desaturase is fully reversible and does not affect the steady state
      localization of other ER resident proteins or the kinetic and fidelity of the
      secretory pathway, indicating a high degree of selectivity for the desaturase.
      Relocalization of the desaturase is energy independent but is lipid dependent
      because it is rescued by supplementation with unsaturated fatty acids.
      Relocalization of the desaturase is also observed in cells treated with
      inhibitors of the enzyme, indicating that it is independent of temperature
      induced alterations of the enzyme. In the absence of desaturase function, lipid
      synthesis continues, resulting in the generation of lipids with saturated acyl
      chains. A model is discussed in which the accumulation of saturated lipids in a
      microdomain around the desaturase could induce the observed segregation and
      relocalization of the enzyme.

PMID- 12475964
TI  - Requirement of the N-terminal extension for vacuolar trafficking and transport
      activity of yeast Ycf1p, an ATP-binding cassette transporter.
AB  - Ycf1p is the prototypical member of the yeast multidrug resistance-associated
      protein (MRP) subfamily of ATP-binding cassette (ABC) transporters. Ycf1p resides
      in the vacuolar membrane and mediates glutathione-dependent transport processes
      that result in resistance to cadmium and other xenobiotics. A feature common to
      many MRP proteins that distinguishes them from other ABC transporters is the
      presence of a hydrophobic N-terminal extension (NTE), whose function is not
      clearly established. The NTE contains a membrane spanning domain (MSD0) with five
      transmembrane spans and a cytosolic linker region (L0). The goal of this study
      was to determine the functional significance of the NTE of Ycf1p by examining the
      localization and functional properties of Ycf1p partial molecules, expressed
      either singly or together. We show that MSD0 plays a critical role in the
      vacuolar membrane trafficking of Ycf1p, whereas L0 is dispensable for
      localization. On the other hand, L0 is required for transport function, as
      determined by monitoring cadmium resistance. We also examine an unusual aspect of
      Ycf1p biology, namely, the posttranslational proteolytic processing that occurs
      within a lumenal loop of Ycf1p. Processing is shown to be Pep4p dependent and
      thus serves as a convenient marker for proper vacuolar localization. The
      processed fragments associate with each other, suggesting that these natural
      cleavage products contribute together to Ycf1p function.

PMID- 12475965
TI  - A subset of chaperones and folding enzymes form multiprotein complexes in
      endoplasmic reticulum to bind nascent proteins.
AB  - We demonstrate the existence of a large endoplasmic reticulum (ER)-localized
      multiprotein complex that is comprised of the molecular chaperones BiP; GRP94;
      CaBP1; protein disulfide isomerase (PDI); ERdj3, a recently identified ER Hsp40
      cochaperone; cyclophilin B; ERp72; GRP170; UDP-glucosyltransferase; and SDF2-L1.
      This complex is associated with unassembled, incompletely folded immunoglobulin
      heavy chains. Except for ERdj3, and to a lesser extent PDI, this complex also
      forms in the absence of nascent protein synthesis and is found in a variety of
      cell types. Cross-linking studies reveal that the majority of these chaperones
      are included in the complex. Our data suggest that this subset of ER chaperones
      forms an ER network that can bind to unfolded protein substrates instead of
      existing as free pools that assembled onto substrate proteins. It is noticeable
      that most of the components of the calnexin/calreticulin system, which include
      some of the most abundant chaperones inside the ER, are either not detected in
      this complex or only very poorly represented. This study demonstrates an
      organization of ER chaperones and folding enzymes that has not been previously
      appreciated and suggests a spatial separation of the two chaperone systems that
      may account for the temporal interactions observed in other studies.

PMID- 12475966
TI  - Microtubule asymmetry during neutrophil polarization and migration.
AB  - The development of cell polarity in response to chemoattractant stimulation in
      human polymorphonuclear neutrophils (PMNs) is characterized by the rapid
      conversion from round to polarized morphology with a leading lamellipod at the
      front and a uropod at the rear. During PMN polarization, the microtubule (MT)
      array undergoes a dramatic reorientation toward the uropod that is maintained
      during motility and does not require large-scale MT disassembly or cell adhesion
      to the substratum. MTs are excluded from the leading lamella during polarization
      and motility, but treatment with a myosin light chain kinase inhibitor (ML-7) or
      the actin-disrupting drug cytochalasin D causes an expansion of the MT array and
      penetration of MTs into the lamellipod. Depolymerization of the MT array before
      stimulation caused 10% of the cells to lose their polarity by extending two
      opposing lateral lamellipodia. These multipolar cells showed altered localization
      of a leading lamella-specific marker, talin, and a uropod-specific marker, CD44.
      In summary, these results indicate that F-actin- and myosin II-dependent forces
      lead to the development and maintenance of MT asymmetry that may act to reinforce
      cell polarity during PMN migration.

PMID- 12475968
TI  - Calcium regulation of GM-CSF by calmodulin-dependent kinase II phosphorylation of
      Ets1.
AB  - The multipotent cytokine granulocyte macrophage-colony stimulating factor (GM
      CSF) is involved in particular in the physiological response to infection and in
      inflammatory responses. GM-CSF is produced by many cell types, including T
      lymphocytes responding to T-cell receptor activation and mantle zone B
      lymphocytes. B-cell receptor and T-cell receptor activation generates two major
      signals: an increase in intracellular Ca(2+) concentration and a protein kinase
      cascade. Previous studies have shown that the Ca(2+)/calmodulin-dependent
      phosphatase calcineurin mediates stimulation of GM-CSF transcription in response
      to Ca(2+). In this study, we show that Ca(2+) signaling also regulates GM-CSF
      transcription negatively through Ca(2+)/calmodulin-dependent kinase II (CaMK II)
      phosphorylation of serines in the autoinhibitory domain for DNA binding of the
      transcription factor Ets1. Wild-type Ets1 negatively affects GM-CSF transcription
      on Ca(2+) stimulation in the presence of cyclosporin A, which inhibits
      calcineurin. Conversely, Ets1 with mutated CaMK II target serines showed an
      increase in transactivation of the GM-CSF promoter/enhancer. Moreover,
      constitutively active CaMK II inhibited transactivation of GM-CSF by wild-type
      Ets1 but not by Ets1 with mutated CaMK II sites. Mutation of CaMK II target
      serines in Ets1 also relieves inhibition of cooperative transactivation of GM-CSF
      with the Runx1/AML1 transcription factor. In addition, the Ca(2+)-dependent
      phosphorylation of Ets1 reduces the binding of Ets1 to the GM-CSF promoter in
      vivo.

PMID- 12475969
TI  - Protection of cap-dependent protein synthesis in vivo and in vitro with an eIF4G
      1 variant highly resistant to cleavage by Coxsackievirus 2A protease.
AB  - The shutoff of host protein synthesis by certain picornaviruses is mediated, at
      least in part, by proteolytic cleavage of eIF4G-1. Previously, we developed a
      cleavage site variant of eIF4G-1, termed eIF4G-1(SM), that was 100-fold more
      resistant to in vitro cleavage by Coxsackievirus 2A protease (2A(Pro)) than wild
      type eIF4G-1 (eIF4G-1(WT)), but it was still digested at high protease
      concentrations. Here we identified a secondary cleavage site upstream of the
      primary site. We changed Gly at the P1'-position of the secondary site to Ala to
      produce eIF4G-1(DM). eIF4G-1(DM) was 1,000-10,000-fold more resistant to cleavage
      in vitro than eIF4G-1(WT). Full functional activity of eIF4G-1(DM) was
      demonstrated in vitro by its ability to restore cap-dependent translation to a
      2A(Pro)-pretreated rabbit reticulocyte system. An isoform containing the binding
      site for poly(A)-binding protein, eIF4G-1e(DM), was more active in this assay
      than an isoform lacking it, eIF4G-1a(DM), but only with polyadenylated mRNA.
      Functional activity was also demonstrated in vivo with stably transfected HeLa
      cells expressing eIF4G-1(DM) from a tetracycline-regulated promoter. Cap
      dependent green fluorescent protein synthesis was drastically inhibited by
      2A(Pro) expression, but synthesis was almost fully restored by induction of
      either eIF4G-1a(DM) or eIF4G-1e(DM). By contrast, encephalomyocarditis virus
      internal ribosome entry site-dependent green fluorescent protein synthesis was
      stimulated by 2A(Pro); stimulation was suppressed by eIF4G-1e(DM) but not eIF4G
      1a(DM).

PMID- 12475967
TI  - A novel transforming growth factor-beta receptor-interacting protein that is also
      a light chain of the motor protein dynein.
AB  - The phosphorylated, activated cytoplasmic domains of the transforming growth
      factor-beta (TGFbeta) receptors were used as probes to screen an expression
      library that was prepared from a highly TGFbeta-responsive intestinal epithelial
      cell line. One of the TGFbeta receptor-interacting proteins isolated was
      identified to be the mammalian homologue of the LC7 family (mLC7) of dynein light
      chains (DLCs). This 11-kDa cytoplasmic protein interacts with the TGFbeta
      receptor complex intracellularly and is phosphorylated on serine residues after
      ligand-receptor engagement. Forced expression of mLC7-1 induces specific TGFbeta
      responses, including an activation of Jun N-terminal kinase (JNK), a
      phosphorylation of c-Jun, and an inhibition of cell growth. Furthermore, TGFbeta
      induces the recruitment of mLC7-1 to the intermediate chain of dynein. A kinase
      deficient form of TGFbeta RII prevents both mLC7-1 phosphorylation and
      interaction with the dynein intermediate chain (DIC). This is the first
      demonstration of a link between cytoplasmic dynein and a natural growth
      inhibitory cytokine. Furthermore, our results suggest that TGFbeta pathway
      components may use a motor protein light chain as a receptor for the recruitment
      and transport of specific cargo along microtublules.

PMID- 12475970
TI  - Analysis of the catalytic and binding residues of the diadenosine tetraphosphate
      pyrophosphohydrolase from Caenorhabditis elegans by site-directed mutagenesis.
AB  - The contributions to substrate binding and catalysis of 13 amino acid residues of
      the Caenorhabditis elegans diadenosine tetraphosphate pyrophosphohydrolase
      (Ap(4)A hydrolase) predicted from the crystal structure of an enzyme-inhibitor
      complex have been investigated by site-directed mutagenesis. Sixteen glutathione
      S-transferase-Ap(4)A hydrolase fusion proteins were expressed and their k(cat)
      and K(m) values determined after removal of the glutathione S-transferase domain.
      As expected for a Nudix hydrolase, the wild type k(cat) of 23 s(-1) was reduced
      by 10(5)-, 10(3)-, and 30-fold, respectively, by replacement of the conserved
      P(4)-phosphate-binding catalytic residues Glu(56), Glu(52), and Glu(103) by Gln.
      K(m) values were not affected, indicating a lack of importance for substrate
      binding. In contrast, mutating His(31) to Val or Ala and Lys(83) to Met produced
      10- and 16-fold increases in K(m) compared with the wild type value of 8.8
      microm. These residues stabilize the P(1)-phosphate. H31V and H31A had a normal
      k(cat) but K83M showed a 37-fold reduction in k(cat). Lys(36) also stabilizes the
      P(1)-phosphate and a K36M mutant had a 10-fold reduced k(cat) but a relatively
      normal K(m). Thus both Lys(36) and Lys(83) may play a role in catalysis. The
      previously suggested roles of Tyr(27), His(38), Lys(79), and Lys(81) in
      stabilizing the P(2) and P(3)-phosphates were not confirmed by mutagenesis,
      indicating the absence of phosphate-specific binding contacts in this region.
      Also, mutating both Tyr(76) and Tyr(121), which clamp one substrate adenosine
      moiety between them in the crystal structure, to Ala only increased K(m) 4-fold.
      It is concluded that interactions with the P(1)- and P(4)-phosphates are minimum
      and sufficient requirements for substrate binding by this class of enzyme,
      indicating that it may have a much wider substrate range then previously
      believed.

PMID- 12475971
TI  - Glucose conjugation of anthranilate by the Arabidopsis UGT74F2
      glucosyltransferase is required for tryptophan mutant blue fluorescence.
AB  - Plant mutants with defects in intermediate enzymes of the tryptophan biosynthetic
      pathway often display a blue fluorescent phenotype. This phenotype results from
      the accumulation of the fluorescent tryptophan precursor anthranilate, the bulk
      of which is found in a glucose-conjugated form. To elucidate factors that control
      fluorescent tryptophan metabolites, we conducted a genetic screen for suppressors
      of blue fluorescence in the Arabidopsis trp1-100 mutant, which has a defect in
      the second enzymatic step of the tryptophan pathway. This screen yielded loss-of
      function mutations in the UDP-glucosyltransferase gene UGT74F2. The bacterially
      expressed UGT74F2 enzyme catalyzed a conjugation reaction, with free anthranilate
      and UDP-glucose as substrates, that yielded the same fluorescent glucose ester
      compound as extracted from the trp1-100 mutant. These results indicate that sugar
      conjugation of anthranilate by UGT74F2 allows its stable accumulation in plant
      tissues. A highly related Arabidopsis enzyme UGT74F1 could also catalyze this
      reaction in vitro and could complement the ugt74F2 mutation when overexpressed in
      vivo. However, the UGT74F1 gene is expressed at a lower level than the UGT74F2
      gene. Therefore, even though UGT74F1 and UGT74F2 have redundant conjugating
      activities toward anthranilate, UGT74F2 is the major source of this activity in
      the plant.

PMID- 12475972
TI  - Carbohydrate-induced differential gene expression patterns in the
      hyperthermophilic bacterium Thermotoga maritima.
AB  - The hyperthermophilic bacterium Thermotoga maritima MSB8 was grown on a variety
      of carbohydrates to determine the influence of carbon and energy source on
      differential gene expression. Despite the fact that T. maritima has been
      phylogenetically characterized as a primitive microorganism from an evolutionary
      perspective, results here suggest that it has versatile and discriminating
      mechanisms for regulating and effecting complex carbohydrate utilization. Growth
      of T. maritima on monosaccharides was found to be slower than growth on
      polysaccharides, although growth to cell densities of 10(8) to 10(9) cells/ml was
      observed on all carbohydrates tested. Differential expression of genes encoding
      carbohydrate-active proteins encoded in the T. maritima genome was followed using
      a targeted cDNA microarray in conjunction with mixed model statistical analysis.
      Coordinated regulation of genes responding to specific carbohydrates was noted.
      Although glucose generally repressed expression of all glycoside hydrolase genes,
      other sugars induced or repressed these genes to varying extents. Expression
      profiles of most endo-acting glycoside hydrolase genes correlated well with their
      reported biochemical properties, although exo-acting glycoside hydrolase genes
      displayed less specific expression patterns. Genes encoding selected putative ABC
      sugar transporters were found to respond to specific carbohydrates, and in some
      cases putative oligopeptide transporter genes were also found to respond to
      specific sugar substrates. Several genes encoding putative transcriptional
      regulators were expressed during growth on specific sugars, thus suggesting
      functional assignments. The transcriptional response of T. maritima to specific
      carbohydrate growth substrates indicated that sugar backbone- and linkage
      specific regulatory networks are operational in this organism during the uptake
      and utilization of carbohydrate substrates. Furthermore, the wide ranging
      collection of such networks in T. maritima suggests that this organism is capable
      of adapting to a variety of growth environments containing carbohydrate growth
      substrates.

PMID- 12475973
TI  - Interactions between fission yeast Cdk9, its cyclin partner Pch1, and mRNA
      capping enzyme Pct1 suggest an elongation checkpoint for mRNA quality control.
AB  - RNA polymerase II (pol II) is subject to an early elongation delay induced by
      negative factors Spt5/Spt4 and NELF, which is overcome by the positive factor P
      TEFb (Cdk9/cyclin T), a protein kinase that phosphorylates the pol II C-terminal
      domain (CTD) and the transcription elongation factor Spt5. Although the rationale
      for this arrest and restart is unclear, recent studies suggest a connection to
      mRNA capping, which is coupled to transcription elongation via physical and
      functional interactions between the cap-forming enzymes, the CTD-PO(4), and Spt5.
      Here we identify a novel interaction between fission yeast RNA triphosphatase
      Pct1, the enzyme that initiates cap formation, and Schizosaccharomyces pombe
      Cdk9. The C-terminal segment of SpCdk9 comprises a Pct1-binding domain distinct
      from the N-terminal Cdk domain. We show that the Cdk domain interacts with S.
      pombe Pch1, a homolog of cyclin T, and that the purified recombinant SpCdk9/Pch1
      heterodimer can phosphorylate both the pol II CTD and the C-terminal domain of S.
      pombe Spt5. We provide genetic evidence that SpCdk9 and Pch1 are functional
      orthologs of the Saccharomyces cerevisiae CTD kinase Bur1/Bur2, a putative yeast
      P-TEFb. Mutations of the kinase active site and the regulatory T-loop of SpCdk9
      abolish its activity in vivo. Deleting the C-terminal domain of SpCdk9 causes a
      severe growth defect. We suggest a model whereby Spt5-induced arrest of early
      elongation ensures a temporal window for recruitment of the capping enzymes,
      which in turn attract Cdk9 to alleviate the arrest. This elongation checkpoint
      may avoid wasteful rounds of transcription of uncapped pre-mRNAs.

PMID- 12475974
TI  - Electrostatic contribution in the catalysis of O2*- dismutation by superoxide
      dismutase mimics. MnIIITE-2-PyP5+ versus MnIIIBr8T-2-PyP+.
AB  - The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (Mn(III)TE-2-PyP(5+))
      is a potent superoxide dismutase (SOD) mimic in vitro and was beneficial in
      rodent models of oxidative stress pathologies. Its high activity has been
      ascribed to both the favorable redox potential of its metal center and to the
      electrostatic facilitation assured by the four positive charges encircling the
      metal center. Its comparison with the non-alkylated, singly charged analogue
      Mn(III) beta-octabromo meso-tetrakis(2-pyridyl)porphyrin (Mn(III)Br(8)T-2-PyP(+))
      enabled us to evaluate the electrostatic contribution to the catalysis of O(2)()
      dismutation. Both compounds exhibit nearly identical metal-centered redox
      potential for Mn(III)/Mn(II) redox couple: +228 mV for Mn(III)TE-2-PyP(5+) and
      +219 mV versus NHE for Mn(III)Br(8)T-2-PyP(+). The eight electron-withdrawing
      beta pyrrolic bromines contribute equally to the redox properties of the parent
      Mn(III)T-2-PyP(+) as do four quaternized cationic meso ortho pyridyl nitrogens.
      However, the SOD-like activity of the highly charged Mn(III)TE-2-PyP(5+) is >100
      fold higher (log k(cat) = 7.76) than that of the singly charged Mn(III)Br(8)T-2
      PyP(+) (log k(cat) = 5.63). The kinetic salt effect showed that the catalytic
      rate constants of the Mn(III)TE-2-PyP(5+) and of its methyl analogue, Mn(III)TM-2
      PyP(5+), are exactly 5-fold more sensitive to ionic strength than is the k(cat)
      of Mn(III)Br(8)T-2-PyP(+), which parallels the charge ratio of these compounds.
      Interestingly, only a small effect of ionic strength on the rate constant was
      found in the case of penta-charged para (Mn(III)TM-4-PyP(5+)) and meta isomers
      (Mn(III)TM-3-PyP(5+)), indicating that the placement of the positive charges in
      the close proximity of the metal center (ortho position) is essential for the
      electrostatic facilitation of O(2)() dismutation.

PMID- 12475975
TI  - Lack of tyrosine nitration by hypochlorous acid in the presence of physiological
      concentrations of nitrite. Implications for the role of nitryl chloride in
      tyrosine nitration in vivo.
AB  - Elevated levels of reactive nitrogen species (RNS) such as peroxynitrite have
      been implicated in over 50 diverse human diseases as measured by the formation of
      the RNS biomarker 3-nitrotyrosine. Recently, an additional RNS was postulated to
      contribute to 3-nitrotyrosine formation in vivo; nitryl chloride formed from the
      reaction of nitrite and neutrophil myeloperoxidase-derived hypochlorous acid
      (HOCl). Whether nitryl chloride nitrates intracellular protein is unknown.
      Therefore, we exposed intact human HepG2 and SW1353 cells or cell lysates to HOCl
      and nitrite and examined each for 3-nitrotyrosine formation by: 1) Western
      blotting, 2) using a commercial 3-nitrotyrosine enzyme-linked immunosorbent assay
      kit, 3) flow cytometric analysis, and 4) confocal microscopic analysis. With each
      approach, no significant 3-nitrotyrosine formation was observed in either whole
      cells or cell lysates. However, substantial 3-nitrotyrosine was observed when
      peroxynitrite (100 microm) was added to cells or cell lysates. These data suggest
      that nitryl chloride formed from the reaction of nitrite with HOCl does not
      contribute to the elevated levels of 3-nitrotyrosine observed in human diseases.

PMID- 12475976
TI  - The guanine nucleotide exchange factor trio activates the phagocyte NADPH oxidase
      in the absence of GDP to GTP exchange on Rac. "The emperor's nw clothes".
AB  - The superoxide-generating NADPH oxidase complex of phagocytes consists of a
      membrane-associated flavocytochrome b(559) and four cytosolic components as
      follows: p47(phox), p67(phox), p40(phox), and the small GTPase Rac (1 or 2).
      Activation of the oxidase is the result of assembly of the cytosolic components
      with cytochrome b(559) and can be mimicked in vitro by mixtures of membrane and
      cytosolic components exposed to an anionic amphiphile, serving as activator. We
      reported that prenylation of Rac1 endows it with the ability to support oxidase
      activation in conjunction with p67(phox) but in the absence of amphiphile and
      p47(phox). We now show the following 6 points. 1) The Rac guanine nucleotide
      exchange factor Trio markedly potentiates oxidase activation by prenylated Rac1
      GDP. 2) This occurs in the absence of exogenous GTP or any other source of GTP
      generation, demonstrating that the effect of Trio does not involve GDP to GTP
      exchange on Rac1. 3) Trio does not potentiate oxidase activation by prenylated
      Rac1-GTP, by nonprenylated Rac1-GDP in the presence or absence of amphiphile, and
      by a prenylated [p67(phox)-Rac1] chimera in GDP-bound form. 4) Rac1 mutants
      defective in the ability to bind Trio or to respond to Trio by nucleotide
      exchange fail to respond to Trio by enhanced oxidase activation. 5) A Trio mutant
      with conserved Rac1-binding ability but lacking nucleotide exchange activity
      fails to enhance oxidase activation. 6) The effect of Trio is mimicked by
      displacement of Mg(2+) from Rac1-GDP. These results reveal the existence of a
      novel mechanism of Rac activation by a guanine nucleotide exchange factor and
      suggest that the induction by Trio of a conformational change in Rac1, in the
      absence of nucleotide exchange, is sufficient for enhancing its effector
      function.

PMID- 12475977
TI  - NFBD1, a novel nuclear protein with signature motifs of FHA and BRCT, and an
      internal 41-amino acid repeat sequence, is an early participant in DNA damage
      response.
AB  - Efficient repair of DNA double-strand breaks depends on the intact signaling
      cascade, comprising molecules involved in DNA damage signal pathways and
      checkpoints. Budding yeast Rad9 (scRad9) is required for activation of scRad53
      (mammalian homolog Chk2) and transduction of the signal further downstream in
      this pathway. In the search for a mammalian homolog, three proteins in the human
      data base, including BRCA1, 53BP1, and nuclear factor with BRCT domains protein 1
      (NFBD1), were found to share significant homology with the BRCT motifs of scRad9.
      Because BRCA1 and 53BP1 are involved in DNA damage responses, a similar role for
      NFBD1 was tested. We show that NFBD1 is a 250-kDa nuclear protein containing a
      forkhead-associated motif at its N terminus, two BRCT motifs at its C terminus,
      and 13 internal repetitions of a 41-amino acid sequence. Five minutes after gamma
      irradiation, NFBD1 formed nuclear foci that colocalized with the phosphorylated
      form of H2AX and Chk2, two phosphorylation events known to be involved in early
      DNA damage response. NFBD1 foci are also detected in response to camptothecin,
      etoposide, and methylmethanesulfonate treatments. Deletion of the forkhead
      associated motif or the internal repeats of NFBD1 has no effect on DNA damage
      induced NFBD1 foci formation. Conversely, deletion of the BRCT motifs abrogates
      damage-induced NFBD1 foci. Ectopic expression of the BRCT motifs reduced damage
      induced NFBD1 foci and compromised phosphorylated Chk2- and phosphorylated H2AX
      containing foci. These results suggest that NFBD1, like BRCA1 and 53BP1,
      participates in the early response to DNA damage.

PMID- 12475978
TI  - Differential regulation of the actomyosin interaction by skeletal and cardiac
      troponin isoforms.
AB  - There are significant isoform differences between the skeletal and cardiac
      troponin complexes. Studies of the regulatory properties of these proteins have
      previously shown only significant differences in the calcium dependence of their
      regulation. Using a sensitive myosin subfragment 1 (S1) binding assay we show
      that in the presence of calcium, thin filaments reconstituted with either
      skeletal or cardiac troponin produce virtually identical S1 binding curves.
      However in the absence of calcium the S1 binding curves differ considerably.
      Combined with kinetic measurements, curve fitting to the three-state thin
      filament regulatory model shows the main difference is that calcium produces a 4
      fold change in K(T) (the closed-open equilibrium) for the skeletal system but
      little change in the cardiac system. The results show a significant difference in
      the range of regulatory effect between the cardiac and skeletal systems that we
      interpret as effects upon actin-troponin (Tn)I-TnC binding equilibria. As
      structural data show that the Ca(2+)-bound TnC structures differ, the additional
      counter-intuitive result here is that with respect to myosin binding the +Ca(2+)
      state of the two systems is similar whereas the -Ca(2+) state differs. This shows
      the regulatory tuning of the troponin complex produced by isoform variation is
      the net result of a complex series of interactions among all the troponin
      components.

PMID- 12475979
TI  - Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the
      receptor protein-tyrosine phosphatase DEP-1.
AB  - The receptor protein-tyrosine phosphatase (PTP) DEP-1 (CD148/PTP-eta) has been
      implicated in the regulation of cell growth, differentiation, and transformation,
      and most recently has been identified as a potential tumor suppressor gene
      mutated in colon, lung, and breast cancers. We have generated constructs
      comprising the cytoplasmic segment of DEP-1 fused to the maltose-binding protein
      to identify potential substrates and thereby suggest a physiological function for
      DEP-1. We have shown that the substrate-trapping mutant form of DEP-1 interacted
      with a small subset of tyrosine-phosphorylated proteins from lysates of the human
      breast tumor cell lines MDA-MB-231, T-47D, and T-47D/Met and have identified the
      hepatocyte growth factor/scatter factor receptor Met, the adapter protein Gab1,
      and the junctional component p120 catenin as potential substrates. Following
      ligand stimulation, phosphorylation of specific tyrosyl residues in Met induces
      mitogenic, motogenic, and morphogenic responses. When co-expressed in 293 cells,
      the full-length substrate-trapping mutant form of DEP-1 formed a stable complex
      with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type
      DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1
      preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH
      terminal tyrosine implicated in morphogenesis (Tyr(1365)), whereas tyrosine
      residues in the activation loop of Met (Tyr(1230), Tyr(1234), and Tyr(1235)) were
      not preferred targets of the PTP. The ability of DEP-1 preferentially to
      dephosphorylate particular tyrosine residues that are required for Met-induced
      signaling suggests that DEP-1 may function in controlling the specificity of
      signals induced by this PTK, rather than as a simple "off-switch" to counteract
      PTK activity.

PMID- 12475980
TI  - Analysis of the cytosolic proteome in a cell culture model of familial
      amyotrophic lateral sclerosis reveals alterations to the proteasome, antioxidant
      defenses, and nitric oxide synthetic pathways.
AB  - Injury to motor neurons associated with mutant Cu,Zn-superoxide dismutase (SOD1)
      related familial amyotrophic lateral sclerosis (FALS) results from a toxic gain
      of-function of the enzyme. The mechanisms by which alterations to SOD1 elicit
      neuronal death remain uncertain despite intensive research effort. Analysis of
      the cellular proteins that are differentially expressed in the presence of mutant
      SOD1 represents a novel approach to investigate further this toxic gain-of
      function. By using the motor neuron-like cell line NSC34 stably transfected with
      wild-type, G93A, or G37R mutant human SOD1, we investigated the effects of mutant
      human SOD1 on protein expression using proteomic approaches. Seven up-regulated
      proteins were identified as argininosuccinate synthase, argininosuccinate lyase,
      neuronal nitric-oxide synthase, RNA-binding motif protein 3, peroxiredoxin I,
      proteasome subunit beta 5 (X), and glutathione S-transferase (GST) Alpha 2. Seven
      down-regulated proteins were identified as GST Mu 1, GST Mu 2, GST Mu 5, a
      hypothetical GST Mu, GST Pi B, leukotriene B(4) 12-hydroxydehydrogenase, and
      proteasome subunit beta5i (LMP7). GST assays demonstrated a significant reduction
      in the total GST activity of cells expressing mutant human SOD1. Proteasome
      assays demonstrated significant reductions in chymotrypsin-like, trypsin-like,
      and post-glutamylhydrolase proteasome activities. Laser capture microdissection
      of spinal cord motor neurons from human FALS cases, in conjunction with reverse
      transcriptase-PCR, demonstrated decreased levels of mRNA encoding GST Mu 1,
      leukotriene B(4) 12-hydroxydehydrogenase, and LMP7. These combined approaches
      provide further evidence for involvement of alterations in antioxidant defenses,
      proteasome function, and nitric oxide metabolism in the pathophysiology of FALS.

PMID- 12475981
TI  - Characterization of general transcription factor 3, a transcription factor
      involved in slow muscle-specific gene expression.
AB  - General transcription factor 3 (GTF3) binds specifically to the bicoid-like motif
      of the troponin I(slow) upstream enhancer. This motif is part of a sequence that
      restricts enhancer activity to slow muscle fibers. GTF3 contains multiple helix
      loop-helix domains and an amino-terminal leucine zipper motif. Here we show that
      helix-loop-helix domain 4 is necessary and sufficient for binding the bicoid-like
      motif. Moreover, the affinity of this interaction is enhanced upon removal of
      amino-terminal sequences including domains 1 and 2, suggesting that an unmasking
      of the DNA binding surface may be a precondition for GTF3 to bind DNA in vivo. We
      have also investigated the interactions of six GTF3 splice variants of the mouse,
      three of which were identified in this study, with the troponin enhancer. The
      gamma-isoform lacking exon 23, and exons 26-28 that encode domain 6, interacted
      most avidly with the bicoid-like motif; the alpha- and beta- isoforms that
      include these exons fail to bind in gel retardation assays. We also show that
      GTF3 polypeptides associate with each other via the leucine zipper. We speculate
      that cells can generate a large number of GTF3 proteins with distinct DNA binding
      properties by alternative splicing and combinatorial association of GTF3
      polypeptides.

PMID- 12475982
TI  - The Src-selective kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine
      kinases.
AB  - 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]- pyrimidine (PP1) was
      identified as an Src-selective tyrosine kinase inhibitor and has been used
      extensively to investigate signaling pathways involving Src kinases, including
      events downstream of the stem cell factor (SCF) receptor c-Kit. While
      investigating the role of Src kinases in SCF signaling, we found that PP1
      completely abrogated the proliferation of M07e cells in response to SCF. PP1
      inhibited SCF-induced c-Kit autophosphorylation in intact cells and blocked the
      activation of mitogen-activated protein kinase and Akt. In vitro kinase assays
      using immunoprecipitated c-Kit confirmed direct inhibition by PP1. SCF-induced c
      Kit phosphorylation was also inhibited by the related inhibitor 4-amino-5- (4
      chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP2) and by STI571 but not
      by the Src inhibitor SU6656. PP1 inhibited the activity of mutant constitutively
      active forms of c-Kit (D814V and D814Y) found in mast cell disorders, and
      triggered apoptosis in the rat basophilic leukemia cell line RBL-2H3 that
      expresses mutant c-Kit. In addition, PP1 (and PP2) inhibited the in vitro kinase
      activity and autophosphorylation in whole cells of p210 Bcr-Abl. PP1 reduced the
      constitutive activation of signal transducer and activators of transcription 5
      and mitogen-activated protein kinase and triggered apoptosis in FDCP1 cells
      expressing Bcr-Abl. These results have implications for the use of PP1 in
      investigating intracellular signaling and suggest that PP1 or related compounds
      may be useful in the treatment of malignant diseases associated with dysregulated
      c-Kit or Abl tyrosine kinase activity.

PMID- 12475983
TI  - Molecular visualization of immunoglobulin switch region RNA/DNA complex by atomic
      force microscope.
AB  - Immunoglobulin heavy-chain (IgH) class switch recombination (CSR) is initiated by
      DNA breakage in the switch (S) region featuring tandem repetitive nucleotide
      sequences. Various studies have demonstrated that S-region transcription and
      splicing proceed to genomic recombination and are indispensable for CSR in vivo,
      although the precise molecular mechanism is largely unknown. Here, we show the
      novel physical property of the in vitro transcribed S-region RNA by direct
      visualization using an atomic force microscope (AFM). The S-region sense RNA, but
      not the antisense RNA, forms a persistent hybrid with the template plasmid DNA
      and changes the plasmid conformation from supercoil to open circle in the
      presence of spermidine. In addition, the S-region transcripts generate globular
      forms and are assembled on the template DNA into a large aggregate that may stall
      replication and increase the recombinogenicity of the S-region DNA.

PMID- 12475984
TI  - The TAR RNA-binding protein, TRBP, stimulates the expression of TAR-containing
      RNAs in vitro and in vivo independently of its ability to inhibit the dsRNA
      dependent kinase PKR.
AB  - TRBP (HIV-1 transactivating response (TAR) RNA-binding protein) and PKR, the
      interferon-induced dsRNA-regulated protein kinase, contain two dsRNA binding
      domains. They both bind to HIV-1 TAR RNAs through different sites. Binding to
      dsRNA activates PKR that phosphorylates the eukaryotic initiation factor eIF
      2alpha leading to protein synthesis inhibition. TRBP and PKR can heterodimerize,
      which inhibits the kinase function of PKR and has a positive effect on HIV-1
      expression. In this study, an in vitro reticulocyte assay revealed the poor
      expression of TAR containing CAT RNAs compared with CAT RNAs. Addition of TRBP
      restored translation efficiency of TAR-CAT RNA and decreased the phosphorylation
      status of eIF-2alpha, confirming its role as a PKR inhibitor. Unexpectedly, eIF
      2alpha was phosphorylated in the presence of TAR-CAT as well as CAT RNA devoid of
      the TAR structure. TRBP inhibited eIF-2alpha phosphorylation in both cases,
      suggesting that it restores the translation of TAR-CAT RNA independently and in
      addition to its ability to inhibit PKR. TRBP activity on gene expression was then
      analyzed in a PKR-free environment using PKR-deficient murine embryo fibroblasts.
      In a transient reporter gene assay, TRBP stimulated the expression of a TAR
      containing luciferase 3.8-fold whereas the reporter gene with mutated TAR
      structures or devoid of TAR was stimulated 1.5- to 2.4-fold. Overall, the
      activity of TRBP2 was higher when the 5'-end of the mRNA was structured and was
      mediated independently by each dsRBD in TRBP. Increasing concentrations of TRBP
      showed no significant modification of the luciferase RNA levels, suggesting that
      TRBP stimulates translation of TAR-containing RNAs. Therefore, TRBP is an
      important cellular factor for efficient translation of dsRNA containing
      transcripts, both by inhibiting PKR and in a PKR-independent pathway.

PMID- 12475985
TI  - Inhibition of cdk2 activating phosphorylation by mevastatin.
AB  - Phosphorylation of cdk2 on threonine 160 is essential for kinase activity.
      Mevastatin, an inhibitor of cholesterol synthesis, inhibits cell growth through
      inhibition of cdk2 and this has been suggested to be due to enhancement of p21
      levels. In a prostate cancer cell line, PC3, mevastatin treatment led to elevated
      levels of p21 and caused a small increase in the p21 associated with cdk2.
      However, this increase in the associated p21 appeared out of proportion with the
      resulting dramatic inhibition of kinase activity. Using RNA interference we show
      that mevastatin inhibits cdk2 activity despite lack of induction of p21, p27, and
      p57. Instead the kinase was inhibited due to a decrease in activating
      phosphorylation. Phosphorylation of cdk2 from mevastatin-treated cells with
      exogenous cyclin-dependent kinase (cdk)-activating enzymes restored its
      functional activity. The only known mammalian cyclin H.cdk7.mat1 complex (cdk2
      activating kinase, Cak), was not inhibited by mevastatin, suggesting either that
      a different CAK is responsible for cdk2 phosphorylation in vivo or that the
      regulation is at the level of substrate accessibility or of cdk2
      dephosphorylation. These results suggest that mevastatin inhibits cdk2 activity
      in PC3 cells through the inhibition of Thr-160 phosphorylation of cdk2, providing
      a novel example of regulation of cdk2 at this level.

PMID- 12475987
TI  - Crystal structure of Bacillus sp. GL1 xanthan lyase, which acts on the side
      chains of xanthan.
AB  - Xanthan lyase, a member of polysaccharide lyase family 8, is a key enzyme for
      complete depolymerization of a bacterial heteropolysaccharide, xanthan, in
      Bacillus sp. GL1. The enzyme acts exolytically on the side chains of the
      polysaccharide. The x-ray crystallographic structure of xanthan lyase was
      determined by the multiple isomorphous replacement method. The crystal structures
      of xanthan lyase and its complex with the product (pyruvylated mannose) were
      refined at 2.3 and 2.4 A resolution with final R-factors of 17.5 and 16.9%,
      respectively. The refined structure of the product-free enzyme comprises 752
      amino acid residues, 248 water molecules, and one calcium ion. The enzyme
      consists of N-terminal alpha-helical and C-terminal beta-sheet domains, which
      constitute incomplete alpha(5)/alpha(5)-barrel and anti-parallel beta-sheet
      structures, respectively. A deep cleft is located in the N-terminal alpha-helical
      domain facing the interface between the two domains. Although the overall
      structure of the enzyme is basically the same as that of the family 8 lyases for
      hyaluronate and chondroitin AC, significant differences were observed in the loop
      structure over the cleft. The crystal structure of the xanthan lyase complexed
      with pyruvylated mannose indicates that the sugar-binding site is located in the
      deep cleft, where aromatic and positively charged amino acid residues are
      involved in the binding. The Arg(313) and Tyr(315) residues in the loop from the
      N-terminal domain and the Arg(612) residue in the loop from the C-terminal domain
      directly bind to the pyruvate moiety of the product through the formation of
      hydrogen bonds, thus determining the substrate specificity of the enzyme.

PMID- 12475986
TI  - Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma )
      ligand, selectively induces the early growth response-1 gene independently of
      PPAR gamma. A novel mechanism for its anti-tumorigenic activity.
AB  - Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma (PPAR
      gamma) ligand that has pro-apoptotic activity in human colon cancer. Although TGZ
      binds to PPAR gamma transcription factors as an agonist, emerging evidence
      suggests that TGZ acts independently of PPAR gamma in many functions, including
      apoptosis. Early growth response-1 (Egr-1) transcription factor has been linked
      to apoptosis and shown to be activated by extracellular signal-regulated kinase
      (ERK). We investigated whether TGZ-induced apoptosis may be related to Egr-1
      induction, because TGZ has been known to induce ERK activity. Our results show
      that Egr-1 is induced dramatically by TGZ but not by other PPAR gamma ligands.
      TGZ affects Egr-1 induction at least by two mechanisms; TGZ increases Egr-1
      promoter activity by 2-fold and prolongs Egr-1 mRNA stability by 3-fold.
      Inhibition of ERK phosphorylation in HCT-116 cells abolishes the Egr-1 induction
      by TGZ, suggesting its ERK-dependent manner. Further, the TGZ-induced Egr-1
      expression results in increased promoter activity using a reporter system
      containing four copies of Egr-1 binding sites, and TGZ induces Egr-1 binding
      activity to Egr-1 consensus sites as assessed by gel shift assay. In addition,
      TGZ induces ERK-dependent phosphorylation of PPAR gamma, resulting in the down
      regulation of PPAR gamma activity. The fact that TGZ-induced apoptosis is
      accompanied by the biosynthesis of Egr-1 suggests that Egr-1 plays a pivotal role
      in TGZ-induced apoptosis in HCT-116 cells. Our results suggest that Egr-1
      induction is a unique property of TGZ compared with other PPAR gamma ligands and
      is independent of PPAR gamma activation. Thus, the up-regulation of Egr-1 may
      provide an explanation for the anti-tumorigenic properties of TGZ.

PMID- 12475988
TI  - Extracellular superoxide dismutase is a major antioxidant in human fibroblasts
      and slows telomere shortening.
AB  - There is good evidence that telomere shortening acts as a biological clock in
      human fibroblasts, limiting the number of population doublings a culture can
      achieve. Oxidative stress also limits the growth potential of human cells, and
      recent data show that the effect of mild oxidative stress is mediated by a stress
      related increased rate of telomere shortening. Thus, fibroblast strains have
      donor-specific antioxidant defense, telomere shortening rate, and growth
      potential. We used low-density gene expression array analysis of fibroblast
      strains with different antioxidant potentials and telomere shortening rates to
      identify gene products responsible for these differences. Extracellular
      superoxide dismutase was identified as the strongest candidate, a correlation
      that was confirmed by Northern blotting. Over-expression of this gene in human
      fibroblasts with low antioxidant capacity increased total cellular superoxide
      dismutase activity, decreased the intracellular peroxide content, slowed the
      telomere shortening rate, and elongated the life span of these cells under
      normoxia and hyperoxia. These results identify extracellular superoxide dismutase
      as an important antioxidant gene product in human fibroblasts, confirm the causal
      role of oxidative stress for telomere shortening, and strongly suggest that the
      senescence-like arrest under mild oxidative stress is telomere-driven.

PMID- 12475989
TI  - p38 isoforms have opposite effects on AP-1-dependent transcription through
      regulation of c-Jun. The determinant roles of the isoforms in the p38 MAPK signal
      specificity.
AB  - p38 MAPK pathway signaling is known to participate in cell proliferation,
      apoptosis, and differentiation, in a manner dependent on the cellular context.
      The factors that determine the specific biological response in a given cell type,
      however, remain largely unknown. We report opposite effects of the p38 isoforms
      on regulation of AP-1-dependent activities by p38 activators MAPK kinase 6 (MKK6)
      and/or arsenite in human breast cancer cells. The p38beta isoform increases the
      activation of AP-1 transcriptional activities by MKK6 and/or arsenite, whereas
      p38gamma/p38delta inhibits or has no effect on the stimulation. The p38beta does
      so by increasing the levels of phosphorylated c-Jun, whereas the p38gamma and 
      delta isoforms may act by regulating the c-jun transcription. AP-1-dependent
      processes such as vitamin D receptor gene promoter activation and cellular
      proliferation were similarly activated by the p38beta or inhibited by the
      p38gamma and/or -delta isoforms. Whereas the human breast cancer cells express
      all four isoforms, mouse NIH 3T3 and EMT-6 cells express only some of the p38
      family members, with p38beta higher in 3T3 cells but p38delta only detected in
      the EMT-6 line. Consistent with the positive and negative roles of p38beta and
      p38delta in AP-1 regulation, MKK6 stimulates AP-1-dependent transcription in NIH
      3T3 but not EMT-6 cells. In support of a role of c-Jun regulation by p38 isoforms
      in determining AP-1 activity, the levels of endogenous c-Jun and its
      phosphorylated form on p38 activation are higher in NIH 3T3 cells. These results
      demonstrate the contrasting activities of the different p38 isoforms in
      transmitting the upstream signal to AP-1 and show that the expression profile of
      p38 isoforms determines whether the p38 signal pathway activates or inhibits AP-1
      dependent processes.

PMID- 12475990
TI  - Loss of Igf2 imprinting in monoclonal mouse hepatic tumor cells is not associated
      with abnormal methylation patterns for the H19, Igf2, and Kvlqt1 differentially
      methylated regions.
AB  - IGFII, the peptide encoded by the Igf2 gene, is a broad spectrum mitogen with
      important roles in prenatal growth as well as cancer progression. Igf2 is
      transcribed from the paternally inherited allele, whereas the linked H19 is
      transcribed from the maternal allele. Igf2 imprinting is thought to be maintained
      by differentially methylated regions (DMRs) located at multiple sites such as
      upstream of H19 and Igf2 and within Kvlqt1 loci. Biallelic expression (loss of
      imprinting (LOI)) of Igf2 is frequently observed in cancers, and a subset of
      Wilms' and intestinal tumors have been shown to exhibit abnormal methylation at
      H19DMR associated with loss of maternal H19 expression, but it is not known
      whether such changes are common in other neoplasms. Because cancers consist of
      diverse cell populations with and without Igf2 LOI, we established four
      independent monoclonal cell lines with Igf2 LOI from mouse hepatic tumors. We
      here demonstrate retention of normal differential methylation at H19, Igf2, or
      Kvlqt1 DMR by all of the cell lines. Furthermore, H19 was found to be expressed
      exclusively from the maternal allele, and levels of CTCF, a multifunctional
      nuclear factor that has an important role in the Igf2 imprinting, were comparable
      with those in normal hepatic tissues with no mutational changes detected. These
      data indicate that Igf2 LOI in tumor cells is not necessarily linked to abnormal
      methylation at H19, Igf2, or Kvlqt1 loci.

PMID- 12475991
TI  - The structure of a cold-adapted family 8 xylanase at 1.3 A resolution. Structural
      adaptations to cold and investgation of the active site.
AB  - Enzymes from psychrophilic organisms differ from their mesophilic counterparts in
      having a lower thermostability and a higher specific activity at low and moderate
      temperatures. The current consensus is that they have an increased flexibility,
      enhancing accommodation and transformation of the substrates at low energy costs.
      Here we describe the structure of the xylanase from the Antarctic bacterium
      Pseudoalteromonas haloplanktis at 1.3 A resolution. Xylanases are usually grouped
      into glycosyl hydrolase families 10 and 11, but this enzyme belongs to family 8.
      The fold differs from that of other known xylanases and can be described as an
      (alpha/alpha)(6) barrel. Various parameters that may explain the cold-adapted
      properties were examined and indicated that the protein has a reduced number of
      salt bridges and an increased exposure of hydrophobic residues. The crystal
      structures of a complex with xylobiose and of mutant D144N were obtained at 1.2
      and 1.5 A resolution, respectively. Analysis of the various substrate binding
      sites shows that the +3 and -3 subsites are rearranged as compared to those of a
      family 8 homolog, while the xylobiose complex suggests the existence of a +4
      subsite. A decreased acidity of the substrate binding cleft and an increased
      flexibility of aromatic residues lining the subsites may enhance the rate at
      which substrate is bound.

PMID- 12475993
TI  - Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of
      apoptosis.
AB  - Mcl-1L (myeloid cell leukemia-1 long) is an antiapoptotic Bcl-2 family protein
      discovered as an early induction gene during leukemia cell differentiation.
      Previously, we identified Mcl-1S (short) as a short splicing variant of the Mcl-1
      gene with proapoptotic activity. To identify Mcl-1-interacting proteins, we
      performed yeast two-hybrid screening and found cDNAs encoding tankyrase 1. This
      protein possesses poly(ADP-ribose) polymerase activity and presumably facilitates
      the turnover of substrates following ADP-ribosylation. In yeast and mammalian
      cells, tankyrase 1 interacts with both Mcl-1L and Mcl-1S, but does not bind to
      other Bcl-2 family proteins tested. Analysis of truncated tankyrase 1 mutants
      indicated that the first 10 ankyrin repeats are involved in interaction with Mcl
      1. In the N terminus of Mcl-1, a stretch of 25 amino acids is sufficient for
      binding to tankyrase 1. Overexpression of tankyrase 1 antagonizes both Mcl-1L
      mediated cell survival and Mcl-1S-induced cell death. Furthermore, coexpression
      of tankyrase 1 with Mcl-1L or Mcl-1S decreased the levels of Mcl-1 proteins.
      Although tankyrase 1 down-regulates Mcl-1 protein expression, no ADP-ribosylation
      of Mcl-1 was detected. In contrast, overexpression of Mcl-1 proteins suppressed
      the ADP-ribosylation of the telomeric repeat binding factor 1, another tankyrase
      1-interacting protein. Thus, interaction of Mcl-1L and Mcl-1S with tankyrase 1
      could serve as a unique mechanism to decrease the expression of these Bcl-2
      family proteins, thereby leading to the modulation of the apoptosis pathway.

PMID- 12475992
TI  - Constitutive DNase I hypersensitivity of p53-regulated promoters.
AB  - The ability of p53 to alter, at the transcriptional level, the gene expression of
      downstream targets is critical for its role as a tumor suppressor. Most models of
      p53 activation postulate the stepwise recruitment by p53 of coactivators, histone
      acetyltransferases, and/or chromatin remodeling factors to a promoter region to
      facilitate the subsequent access of the general transcriptional machinery
      required for transcriptional induction. We demonstrate here, however, that the
      promoter regions for the p53 target genes, p21, 14-3-3sigma, and KARP-1, exist in
      a constitutively open conformation that is readily accessible to DNase I. This
      conformation was not altered by DNA damage or by whether p53 was present or
      absent in the cell. In contrast, p53 response elements, which resided outside the
      immediate promoter regions, existed within DNase I-resistant chromatin domains.
      Thus, p53 activation of downstream target genes occurs without p53 inducing
      chromatin alterations detectable by DNase I accessibility at either the promoter
      or the response element. As such, these data support models of p53 activation
      that do not require extensive chromatin alterations to support cognate gene
      expression.

PMID- 12475994
TI  - Self-perpetuating structural states in biology, disease, and genetics.

PMID- 12475995
TI  - Catalysis at a dinuclear [CuSMo(==O)OH] cluster in a CO dehydrogenase resolved at
      1.1-A resolution.
AB  - The CO dehydrogenase of the eubacterium Oligotropha carboxidovorans is a 277-kDa
      Mo- and Cu-containing iron-sulfur flavoprotein. Here, the enzyme's active site in
      the oxidized or reduced state, after inactivation with potassium cyanide or with
      n-butylisocyanide bound to the active site, has been reinvestigated by multiple
      wavelength anomalous dispersion measurements at atomic resolution, electron spin
      resonance spectroscopy, and chemical analyses. We present evidence for a
      dinuclear heterometal [CuSMoO)OH] cluster in the active site of the oxidized or
      reduced enzyme, which is prone to cyanolysis. The cluster is coordinated through
      interactions of the Mo with the dithiolate pyran ring of molybdopterin cytosine
      dinucleotide and of the Cu with the Sgamma of Cys-388, which is part of the
      active-site loop VAYRC(388)SFR. The previously reported active-site structure
      [Dobbek, H., Gremer, L., Meyer, O. & Huber, R. (1999) Proc. Natl. Acad. Sci. USA
      96, 8884-8889] of an Mo with three oxygen ligands and an SeH-group bound to the
      Sgamma atom of Cys-388 could not be confirmed. The structure of CO dehydrogenase
      with the inhibitor n-butylisocyanide bound has led to a model for the catalytic
      mechanism of CO oxidation which involves a thiocarbonate-like intermediate state.
      The dinuclear [CuSMo(O)OH] cluster of CO dehydrogenase establishes a previously
      uncharacterized class of dinuclear molybdoenzymes containing the pterin cofactor.

PMID- 12475998
TI  - Aurora-A in cell fate control.
AB  - Key cells divide asymmetrically during the development of multicellular organisms
      to give rise to offspring with different fates. In the Drosophila external
      sensory organ, asymmetrical division depends on polarization of the precursor
      cells during interphase and the consequent unequal distribution during mitosis of
      the protein Numb, which determines cell fate. Gonzalez discusses recent research
      implicating the mitotic kinase Aurora-A in the asymmetric localization of Numb in
      sensory organ pI precursor cells, a new function that appears to be independent
      of Aurora-A's known roles in regulating centrosomal maturation and the
      organization of mitotic spindle microtubules.

PMID- 12475999
TI  - Hitting the target: emerging technologies in the search for kinase substrates.
AB  - Through phosphorylation, protein kinases can alter the activity, localization,
      protein association, and stability of their targets. Despite the importance to
      our understanding of all aspects of cell biology, progress toward identifying
      bona fide substrates of specific protein kinases has been slow. Traditionally
      used techniques to identify true kinase substrates, such as genetics, yeast two
      hybrid screens, and biochemical purification, are often laborious and unreliable.
      However, several new approaches have recently been developed and used
      successfully to identify genuine in vivo substrates of certain protein kinases.
      These methods include screening for phosphorylation of proteins from phage
      expression libraries, peptide library screens to determine optimal motifs favored
      by specific kinases, the use of phospho-motif antibodies, and an approach that
      uses structurally altered kinases and allele-specific adenosine triphosphate
      analogs and kinase inhibitors. We describe these approaches and discuss their
      utility and inherent caveats.

PMID- 12476000
TI  - Plasticity of the kinomes in monkey and rat tissues.
AB  - The Kinetworks KPKS 1.0 immunoblotting screen was used to investigate the
      differential expression of 58 protein serine-threonine kinases, five protein
      threonine-tyrosine kinases, and 15 other nonreceptor protein tyrosine kinases in
      three types of human blood cells, 14 monkey organs, and six rat organs. The
      results demonstrate striking differences in the kineome profiles of diverse
      organs and even between the same organs in different species.

PMID- 12476001
TI  - Pulsating ion fluxes and growth at the pollen tube tip.
AB  - Reproduction in higher plants requires the directed growth of pollen tubes in
      order to transmit sperm cells to the ovules at the base of the style. Many
      signaling processes have been implicated in polarized pollen tube growth. Here,
      changes in the concentration of calcium, potassium, hydrogen (pH), and chloride
      are discussed, as they may all contribute to the process of oscillatory growth
      and guidance observed in pollen tubes.

PMID- 12476002
TI  - Creating asymmetric cell divisions by skewing endocytosis.
AB  - How can one cell divide to form two cells, which are genetically identical to the
      mother cell, with different cell fates? That is the question discussed by Shen
      and Temple. Specifically, they address how Notch signaling is attenuated in one
      daughter cell through the asymmetric inheritance of the protein Numb, which may
      be responsible for mediating the endocytosis of the receptor Notch in the Numb
      enriched cell.

PMID- 12476003
TI  - Design and use of a mammalian protein-protein interaction trap (MAPPIT).
AB  - Identifying the interaction partners of a protein is a straightforward way to
      gain insight into the protein's function and to position it in an interaction
      network such as a signal transduction pathway. Various techniques have been
      developed to serve this purpose, and some are specifically designed to study
      posttranslational modifications in mammalian proteins and to clarify their normal
      physiological context. However, several intrinsic constraints limit the use of
      these technologies, and most are not suitable for screening for new interacting
      partners. In the Mammalian Protein-Protein Interaction Trap (MAPPIT) Protocol
      described here, knowledge of cytokine receptor signaling has been used to design
      a versatile genetic tool that can be used analytically and for detection of new
      protein-protein interactions in mammalian cells.

PMID- 12476004
TI  - The use of standardized human skin models for cutaneous pharmacotoxicology
      studies.
AB  - Reconstructed skin and epidermis models are finding increasingly numerous
      applications in cosmetology and dermatology. In particular, they are currently
      employed to assess the tolerability and efficacy of raw materials and
      formulations, in conditions approaching those of normal use. Importantly, the use
      of such models greatly reduces the need for animal testing. Various models of
      reconstructed skin and epidermis have been developed [1-4] and some are now
      produced industrially [5-8]. They are used for the prediction of cutaneous
      irritancy and, to a lesser extent, percutaneous absorption and cutaneous
      metabolism. However, before being officially recognized as valid alternative
      methods and entering routine use, standard protocols must be developed to assess
      their reproducibility and performance as compared with in situ human studies.

PMID- 12476005
TI  - Characterization of reconstructed skin models.
AB  - The aim of the present study was to evaluate tissue architecture and lipid
      composition of commercially available reconstructed human skin models; EpiDerm,
      SkinEthic and Episkin in comparison to in-house reconstructed epidermis on a de
      epidermized dermis (RE-DED) model and native tissue. For this purpose, the tissue
      architecture was examined using light microscopy, electron microscopy and
      immunohistochemistry; epidermal lipid composition was analyzed by HPTLC.
      Histological examination showed a completely stratified epithelium in all skin
      models closely resembling normal human epidermis. Low intra-batch variation in
      tissue architecture was observed in all skin models, but moderate to considerable
      inter-batch variation was noticed. In the stratum corneum extracellular space,
      lipid lamellae consisting of multiple alternating electron-dense and electron
      lucent bands were present. Lipid analyses revealed the presence of all major
      epidermal lipid classes. Compared with native epidermis and RE-DED in EpiDerm,
      SkinEthic and Episkin models, the content of polar ceramides 5 and 6 was lower,
      ceramide 7 was absent, and the content of free fatty acids was very low.
      Evaluation of the expression and localization of a number of differentiation
      specific protein markers revealed that all skin models showed an aberrant
      expression of keratin 6, skin-derived antileukoproteinase, small-proline-rich
      proteins, involucrin and transglutaminase. Although variation within batches was
      low, in particular keratin 6, involucrin and skin-derived antileukoproteinase
      expression demonstrated some inter-batch variation. In conclusion, all skin
      models provide a promising means for studying the effects of topically applied
      chemicals, although the observed deviations in tissue homeostasis and barrier
      properties need to be diminished. All skin models tested reproduced many of the
      characteristics of normal human epidermis and therefore provide a morphologically
      relevant in vitro means to assess skin irritation and perform other skin-related
      studies.

PMID- 12476006
TI  - Permeation and skin absorption: reproducibility of various industrial
      reconstructed human skin models.
AB  - Human reconstructed skin models could be very useful tools to quantify
      percutaneous permeation and absorption. Before using such models, the
      reproducibility in the same batch and/or various batches, i.e. the relevance of
      the results obtained, must be verified. The reproducibility of 3 industrial
      models--EpiDerm, Episkin and SkinEthic--was tested regarding the permeation and
      skin absorption of 3 topically applied compounds (with a large range of
      physicochemical properties): lauric acid, caffeine and mannitol. For all the
      models, the intrabatch reproducibility was greater than the interbatch
      reproducibility. According to the batches tested, the larger difference in terms
      of reproducibility between the 3 models was observed in the case of mannitol, a
      very poor permeant. In this case, the best reproducibility was observed with
      EpiDerm and Episkin. Moreover, the rank order of the 3 compounds applied, in
      terms of permeation and skin absorption, was the same as that expected from ex
      vivo human skin. Such results revealed human skin models as a promising means to
      test in vitro permeation and percutaneous absorption of topical products.

PMID- 12476007
TI  - Improvement of the experimental setup to assess cutaneous bioavailability on
      human skin models: dynamic protocol.
AB  - Human skin models, such as EpiDerm and Episkin, are not easily mounted into
      static or dynamic diffusion cells that are commonly used to perform
      bioavailability studies with human skin ex vivo. For various reasons, such as
      fragility, small sample size, and other morphological constraints, skin
      absorption studies with human skin models are often carried out on the delimited
      skin surface obtained by gluing a ring onto the reconstituted epidermis and
      manually exchanging the receptor solution. However, such an experimental setup is
      prone to artifacts. Discontinuous removal of the receptor fluid leads to
      alternating sink conditions, and an area of application smaller than the area in
      contact with the receptor fluid, as well as imperfect seal of the glued ring, may
      result in inaccurate penetration rates. Human skin models were shown to be
      relatively easily mounted into In-Line cells (PermeGear Inc.), vertical diffusion
      cells which appear to be appropriately designed for such a purpose. In-Line cells
      allowed accurate determination of solute penetration as well as automated
      sampling of receptor fluid. Excised human skin can be mounted into these cells as
      well, making it possible to compare penetration rates through different types of
      skin samples under identical conditions. Using mannitol as a reference compound,
      penetration profiles and epidermal distribution similar to those obtained with
      human skin ex vivo were obtained both with EpiDerm and Episkin. Under the present
      conditions, human skin models were more permeable to mannitol than excised human
      skin, which was only slightly permeable to mannitol. Due to these experimental
      innovations and to the good agreement with the absorption characteristics through
      human skin ex vivo, EpiDerm and Episkin seem to be promising human skin models
      for testing the cutaneous bioavailability of topical products in vitro.

PMID- 12476008
TI  - Comparison of cutaneous bioavailability of cosmetic preparations containing
      caffeine or alpha-tocopherol applied on human skin models or human skin ex vivo
      at finite doses.
AB  - The use of human skin models for performing cutaneous bioavailability studies has
      been little investigated. For instance, only few studies have been reported on
      human skin models dealing with vehicle effects on percutaneous penetration. The
      present study aimed at evaluating the influence on caffeine's and alpha
      tocopherol's cutaneous bioavailability of cosmetic vehicles such as a water-in
      oil emulsion, an oil-in-water emulsion, a liposome dispersion and a hydrogel
      applied at finite dose using the reconstructed human skin models EpiDerm and
      Episkin. The results were compared with those obtained in human skin ex vivo
      using similar experimental conditions. It was demonstrated that the rank order of
      solute permeability could be correctly predicted when the preparation was applied
      at a finite dose in human skin models, at least when solutes with far different
      physicochemical properties such as caffeine and alpha-tocopherol were used. If
      only slight effects of cosmetic vehicle on skin bioavailability were observed in
      human skin ex vivo, they were less predictable using skin models. Especially,
      alcohol-containing vehicles seemed to behave differently in EpiDerm as well as in
      Episkin than on human skin ex vivo. Stratum corneum intercellular lipid
      composition and organization of human skin models differ to some extent from that
      of human stratum corneum ex vivo, which contributes to less pronounced barrier
      properties, together with the increased hydration of the outermost stratum
      corneum layers of the models. These features, as well as still unknown factors,
      may explain the differences observed in vehicle effects in human skin ex vivo
      versus human skin models.

PMID- 12476009
TI  - Comparison of activities dependent on glutathione S-transferase and cytochrome P
      450 IA1 in cultured keratinocytes and reconstructed epidermal models.
AB  - There is an increasing need for in vitro testing of compounds for topical
      application. Reconstructed epidermal models may provide a suitable and relevant
      model for screening compounds that may affect the activities of phase I and II
      enzymes involved in epidermal detoxification. In this study, we measured the
      activity of a phase I enzyme, cytochrome P450 IA1, i.e. 7-ethoxyresorufin-O
      deethylase (EROD) and 7-ethoxycoumarin-O-deethylase (ECOD) activities, and that
      of a phase II enzyme, glutathione S-transferase (GST). The enzyme activities were
      determined in cultured keratinocytes, reconstructed epidermal models and samples
      of human epidermis or hair follicle. EROD activity was detected in cultured
      keratinocytes and was induced by 3-methylcholanthrene (3-MC) and beta
      naphthoflavone. The level of induction increased with increasing confluence.
      Induced EROD activity could be inhibited by clotrimazole in a dose-dependent
      manner. However, EROD activity was not detected in either hair follicles or
      untreated epidermal models but could be induced by 3-MC. The ability to induce
      EROD activity in epidermal models was batch dependent, and clotrimazole was able
      to inhibit the induced EROD activity. ECOD activity was detected in untreated
      models and paralleled EROD activity. GST activity was detected in cultured
      keratinocytes and all epidermal models. GST activity in models was equal or
      higher than the activity in epidermal samples. Reconstructed skin models may be
      useful to study the effects of non-water-soluble topical formulations on
      xenobiotic metabolism.

PMID- 12476010
TI  - NAD(P)H:quinone reductase activity in human epidermal keratinocytes and
      reconstructed epidermal models.
AB  - Reconstructed epidermal models may provide a suitable and relevant model for
      screening compounds such as quinones, which affect the activities of phase I and
      II enzymes involved in epidermal detoxification. Reconstructed epidermis may also
      allow the study of the metabolism of topically applied compounds by the phase I
      and II enzymes. We demonstrate that NAD(P)H:quinone reductase (NQR) activity is
      present in three different types of reconstructed epidermal models and that
      levels vary depending on the type of model. We also determined the inter- and
      intrabatch variability and demonstrate that NQR activity can be significantly
      inhibited by dicumarol treatment. The NQR activity in reconstructed epidermis is
      similar to that in human epidermis and lower than in cultured keratinocytes.
      Therefore reconstructed epidermis is a more suitable model for testing the
      effects of topically applied compounds on NQR activity or the metabolism of the
      compound by NQR.

PMID- 12476011
TI  - Reconstructed skin kits: reproducibility of cutaneous irritancy testing.
AB  - The aim of this study was to determine the reproducibility of data obtained from
      in vitro irritation testing using three industrial reconstructed human epidermis
      models, EpiDerm, Episkin and SkinEthic, and one in-house model developed at
      Wella/Cosmital. A common protocol was established based on the measurement of
      cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
      (MTT) assay and of extracellular release of proinflammatory mediators and
      cytosolic enzymes after a range of exposure times to sodium lauryl sulfate (SLS).
      This time course protocol was applied to 6 different batches of each skin model
      using triplicate tissue cultures per test condition. The parameters analyzed for
      intra- and inter-batch reproducibility were the cell viability determined as MTT
      reduction capacity and the ET-50 values in the 6 batches, as well as the release
      of the cytokine IL-1alpha and of the cellular enzymes LDH and GOT in 3 batches
      only. The MTT viability results showed that EpiDerm was the most resistant to the
      SLS treatment and at the same time the most reproducible model, SkinEthic was the
      most sensitive to SLS and the least reproducible, and Episkin and the Cosmital
      model were intermediate. Measurements of IL-1alpha release showed a relatively
      high intra- and inter-batch variability in all the skin models. It was not
      possible to detect the extracellular release of the enzymes LDH and GOT in the
      Episkin assay medium. With the 3 other models, the release of LDH and GOT varied
      in about the same range as that of IL-1alpha. For all the parameters in this
      study, the inter-batch variability was generally greater than the intra-batch
      variability. A possible reduction in the number of batches and replicates for
      future applications in routine irritancy testing is discussed on the basis of the
      results obtained using 6 batches in triplicate.

PMID- 12476012
TI  - The response of uninvolved skin of patients with psoriasis to single and repeated
      applications of dithranol cream: an immunohistochemical assessment.
AB  - Dithranol is one of the most effective topical treatments for patients with
      psoriasis. The well-known irritation is a serious limitation. In an earlier study
      we investigated the inflammatory response to single and repeated applications
      with dithranol 2% cream in skin from healthy volunteers. In the present study, we
      assessed the clinical and cell-biological response of single and repeated
      challenges with dithranol 2% cream in uninvolved skin of patients with psoriasis.
      A striking difference between the two studies is the late phase in the single
      challenge group after 8 days, showing a longer-lasting response in the uninvolved
      skin compared to normal skin with respect to proliferation and inflammation
      markers. A controlled and synchronised irritation by dithranol might induce anti
      inflammatory processes and as such constitute an antipsoriatic principle. It is
      attractive to speculate that in psoriasis the induction of anti-inflammatory
      responses is defective. Following repeated applications of dithranol, a more
      uniform course of proliferation, differentiation and inflammation markers was
      observed in the uninvolved psoriatic skin as compared to the skin of healthy
      volunteers. Again a defect in the induction of anti-inflammatory responses might
      account for this event. In view of these differences between normal skin and
      psoriatic uninvolved skin, it may be advisable to use the uninvolved skin of
      patients with psoriasis in further studies on the interference between dithranol
      irritancy and various anti-inflammatory agents.

PMID- 12476013
TI  - An immunohistochemical assessment of the response of the psoriatic lesion to
      single and repeated applications of high-dose dithranol cream.
AB  - Dithranol, although a time-honoured treatment and from the beginning of the
      previous century still going strong, remains an empirical treatment. There is
      growing evidence that the biochemical basis for the mechanism of action of
      dithranol at the molecular level is related to the redox activity leading to the
      production of active oxygen species, which include singlet oxygen, superoxide
      anion radical and hydroxyl radical. Some authors suggest that epidermal
      proliferation and/or keratinisation may be the target for dithranol, while others
      refer to aspects of cutaneous inflammation as crucial in the antipsoriatic effect
      of dithranol. The present study aims to analyse the effect of single and repeated
      applications of dithranol on aspects of epidermal proliferation, keratinisation
      and inflammation in the psoriatic plaque. The most marked effect of dithranol
      proved to be that on epidermal proliferation (the number of Ki-67-positive
      nuclei) with an early reduction already 1 day following the single application.
      This reduction lasted for 16 days. However, such an application induced only a
      modest clinical improvement. Repeated challenges, resulting in a decrease in the
      number of Ki-67-positive nuclei of 66%, led to a substantial clinical improvement
      after 12 days. Repeated challenges resulted in a significant reduction of the
      number of polymorphonuclear leucocytes. However, this reduction was less
      pronounced as compared to the effect on epidermal proliferation. It is concluded
      that epidermal proliferation is a sensitive marker to demonstrate an early effect
      of dithranol. The dynamics of the cell-biological responses suggest that
      intermittent applications might be a promising new approach. As dithranol does
      not reduce the number of T lymphocytes, it is attractive to speculate that the
      combination of dithranol with immunosuppressive treatments might be a very
      effective combination.

PMID- 12476014
TI  - The potential of the essential fatty acid-deficient hairless rat as a psoriasis
      screening model for topical anti-proliferative drugs.
AB  - The objective of this study was to establish essential fatty acid deficiency
      (EFAD) in hairless rats and investigate the potential of this model as a
      psoriasis screening model by testing the effects of calcipotriol and dithranol on
      differentiation and proliferation in the epidermis. Hairless rats were fed with a
      fat-free diet lacking linoleic acid. The EFAD condition was established within 8
      weeks. In order to ensure that this condition had been established, several
      parameters were measured and observed, i.e. animal weight, water consumption,
      transepidermal water loss, clinical skin symptoms, histology of the epidermis and
      fatty acid analysis of serum and skin. Immediately after the EFAD condition had
      been established, the animals were treated with dithranol ointment or different
      concentrations of calcipotriol solution. A reduction in epidermal thickness of 15
      20% was seen after the treatment with calcipotriol. Dithranol and its coal tar
      containing vehicle also showed a reductive effect on epidermal thickness. EFAD
      hairless rats possess various histological changes resembling psoriasis. These
      histological changes normalise during treatment with anti-psoriatic drugs as
      calcipotriol, dithranol and coal tar. The results of the present study indicate
      that the EFAD rat may be a useful model for studies of anti-psoriatic drugs
      affecting cell proliferation.

PMID- 12476015
TI  - Development of an in vivo animal model for skin penetration in hairless rats
      assessed by mass balance.
AB  - The aim of the study was to develop an in vivo animal model for studies of the
      penetration of topically applied drugs into the skin of hairless rats. Protective
      appliances were designed for non-occluded and finite-dose application of topical
      formulations. The design allowed 2 test sites for each rat and free mobility
      throughout the test period. By consecutive tape stripping, monitored by
      measurements of transepidermal water loss and confirmed by histological
      examination of skin biopsies, 10 tape strippings were found to remove the stratum
      corneum completely. For assessment of the model, (14)C-salicylic acid and (14)C
      butyl salicylate were topically applied. Rapid and differentiated percutaneous
      absorption of both compounds were shown by urinary excretion data. For (14)C
      salicylic acid the amount on the skin surface, in the stratum corneum and in the
      viable skin was determined. Total mass balance on the applied radioactivity was
      performed and a recovery of 90 +/- 2% was achieved. The radioactivity found in
      the protective appliances (<10%) was explained by lateral skin diffusion of the
      model compounds into the dressings.

PMID- 12476016
TI  - Diffusion of E and Z urocanic amphiphiles through skin and their insertion in a
      membrane model.
AB  - The incorporation of synthetic urocanic amphiphiles into a membrane model is
      described. A monomolecular film of dipalmitoyl phosphatidylcholine (DPPC) and
      cholesterol was formed at the air-water interface and used as a model. In
      parallel, diffusion of these derivatives through the skin was studied using rat
      skin on flow-through diffusion cells. The flux and the cumulative amount were
      determined. Although the structure and the composition of the DPPC/cholesterol
      monolayer differed greatly from multilayers of epidermal lipids, the results
      obtained in the incorporation and diffusion studies were similar. The structure
      of the urocanic amphiphiles was very close, but the membranes led to the
      following flux or insertion classification: Ester E > Ester Z >> Amide E. From
      the results obtained and for simplicity, the technique of Langmuir monolayers
      seems to be highly suited to the primary screening of amphiphilic compounds.

PMID- 12476017
TI  - A multicenter randomized trial of ketoconazole 2% and zinc pyrithione 1% shampoos
      in severe dandruff and seborrheic dermatitis.
AB  - Ketoconazole (KET) and zinc pyrithione (ZPT) are compounds active against the
      Malassezia spp. yeasts, which are believed to play a major role in dandruff and
      seborrheic dermatitis. We compared the efficacy and safety of KET 2% and ZPT 1%
      in shampoo formulations for the alleviation of severe dandruff and seborrheic
      dermatitis. This open randomized, parallel-group trial began with a 2-week run-in
      phase during which subjects applied a neutral non-antidandruff shampoo. It was
      followed by a 4-week randomized treatment phase and a subsequent 4-week follow-up
      phase without treatment. Shampooing during the treatment period was carried out
      twice weekly for the KET group and at least twice weekly for the ZPT group in
      accordance with the label instructions. A total of 343 subjects were recruited to
      enter the trial. Of the 331 eligible volunteers, 171 were randomized to KET 2%
      and 160 to ZPT 1%. Clinical assessments were performed. Beneficial effects were
      evidenced for both medicated shampoos, but the effect was significantly better
      for KET 2%, which achieved a 73% improvement in the total dandruff severity score
      compared with 67% for ZPT 1% at week 4 (p < 0.02). The recurrence rate of the
      disease was also significantly lower following KET 2% treatment than following
      ZPT 1% treatment. As a consequence, the overall clearing of the skin condition at
      the end of treatment and follow-up phase was in favor of the KET 2% formulation
      (p = 0.004). Side effects were minimal. It is concluded that after a 4-week
      treatment, KET 2% shampoo was significantly superior to ZPT 1% shampoo in the
      treatment of subjects with severe dandruff or seborrheic dermatitis of the scalp.
      It is our assumption that this difference is noticeable for the patient and as a
      consequence relevant. Both formulations were well tolerated.

PMID- 12476018
TI  - EEMCO guidance for the measurement of skin microcirculation.
AB  - The blood supply to the skin is provided by a network of arterioles, capillaries
      and venules organized into a superficial and a deep plexus. The assessment of
      skin microcirculation is of valuable interest in cosmetology in the
      quantification of the sun protection factor, skin irritation and efficacy of
      antiredness treatments. Skin microcirculation can be measured by means of
      different techniques, based mainly on the quantification of optical and thermal
      properties of the skin which are modified by the amount of blood perfusion.
      Relevant and reproducible data can be obtained only through the understanding of
      the biophysical background of the technique(s) utilized. Standardization of
      measuring conditions and procedures is particularly required for blood flow
      assessment. In this paper, the advantages and disadvantages of the main
      techniques in use are discussed, and optimization of measurements for laser
      Doppler techniques is described.

PMID- 12476020
TI  - Pediatric skull base surgery. 1. Embryology and developmental anatomy.
AB  - Surgical pathology of the pediatric cranial base is uncommon, but in affected
      children, traditional operative techniques and management philosophies
      predominate. While the creation of multidisciplinary skull base teams
      synergistically pools the talents of individual specialties, a better
      understanding of the developmental anatomy of the cranial base becomes essential
      in order for such teams to safely implement these approaches in children. The
      extant neurosurgical literature lacks a comprehensive review of this anatomy.
      This report discusses the developmental anatomy and embryology of the cranial
      base within the context of specific surgical approaches. Detailed development of
      the calvaria, midface skeleton and orbit is excluded.

PMID- 12476021
TI  - Pediatric skull base surgery. 2. Experience and outcomes in 55 patients.
AB  - In the second of these two articles, we will discuss our clinical experience with
      skull base surgery in the pediatric population. We present a retrospective
      analysis of 55 patients less than 16 years of age who underwent skull base
      surgical approaches at the Primary Children's Medical Center or the University of
      Utah Medical Center between January 1992 and April 1999. There were 30 boys and
      25 girls (mean age 9.8 years). Patient follow-up averaged 58 months. Most
      patients had pathology that required either an anterior or anterolateral
      approach; 6 patients underwent a far-lateral or a transpetrosal exposure. Thirty
      five procedures were performed by a neurosurgeon, a pediatric otolaryngologist
      performed 11 procedures, and 10 procedures were performed by both services
      together. Ninety-six percent of patients (n = 53) had a Glasgow Outcome Score of
      4 or 5. Complications included 4 sustained cranial nerve palsies and 2
      hemipareses. There were no CSF leaks, infections or deaths. Patients with sellar
      region pathology had a disproportionately higher incidence of postoperative
      morbidity. We conclude that in selected pediatric cases, skull base surgical
      techniques can be performed effectively and safely with the use of
      multidisciplinary teams. To implement these techniques, knowledge of their
      limitations and of the anatomical differences between the adult and pediatric
      cranial base is essential.

PMID- 12476022
TI  - Vertebrobasilar thrombosis in children: report of two cases and recommendations
      for treatment.
AB  - Two consecutive cases of children with vertebrobasilar thrombosis (VBT) were
      treated with high-dose intra-arterial urokinase within 4 h of presenting to the
      emergency room, after full evaluation by CT scan, MRI and MR angiography.
      Complete resolution of neurologic symptoms was achieved in both cases. Based on
      our limited pediatric experience, previous treatment of VBT at our institution
      and a review of the relevant literature, the authors suggest that VBT be
      specifically ruled out at initial diagnosis, and if present, full consideration
      be given to immediate treatment with intra-arterial thrombolytic therapy. This
      may lead to a significant reduction in the morbidity and mortality associated
      with VBT in children. A large prospective multi-institution study is needed to
      further evaluate the efficacy of this approach to childhood stroke.

PMID- 12476023
TI  - Efficacy of sequential chemotherapy including methotrexate and doxorubicin in an
      infant with partially resected choroid plexus carcinoma.
AB  - This report refers to a 3-month-old male, with a residual choroid plexus
      carcinoma following partial resection, who was successfully treated with
      sequential chemotherapy without any postoperative radiation therapy. Along with
      carboplatin, we also used doxorubicin and methotrexate, hypothesizing that, given
      the patient's age, the blood-brain barrier should not hamper drug delivery to the
      tumor. According to this hypothesis, the treatment achieved complete remission of
      the disease, which lasts 27 months after the diagnosis. This result deserves
      further studies to assess the possible curative role of chemotherapy in very
      young patients suffering from choroid plexus carcinoma.

PMID- 12476025
TI  - Comparison of total versus partial revision of initial ventriculoperitoneal shunt
      failures.
AB  - BACKGROUND: Optimal surgical management of patients presenting with shunt failure
      in the age of neuroendoscopy remains complex. The value of replacing the entire
      shunt system as opposed to a single shunt component has not been assessed.
      METHODS: We reviewed the records of all pediatric patients who underwent their
      first shunt revision between January 1992 and December 1998. Patients with
      primary shunt failure attributed solely to proximal catheter obstruction or
      distal catheter obstruction were included for analysis. Shunt revisions were
      classified as total (entire shunt replaced) or partial (only malfunctioning
      component replaced). Kaplan-Meier (shunt survival curves) and log rank analysis
      were used to compare failure rates between partially and totally revised shunts
      according to the underlying diagnosis and failed shunt part. Significant
      differences in univariate analysis were confirmed with a multivariate
      proportional hazards regression model. RESULTS: 301 pediatric patients underwent
      primary shunt revision (183 total, 118 partial revisions). All shunts utilized
      distal slit peritoneal catheters. In shunt failures attributed to proximal
      obstruction, reutilization of the distal catheter was associated with a 57%
      increased risk of subsequent shunt failure (hazard ratio 1.57, 95% confidence
      interval 1.19-3.49). In shunt failures attributed to distal obstruction,
      subsequent shunt survival was not affected by reutilization of the proximal
      catheter (p = 0.581). When stratified according to the etiology of hydrocephalus,
      only patients with intraventricular hemorrhage (IVH) failed to demonstrate
      greater survival of totally revised shunts. CONCLUSIONS: In this series, in the
      setting of proximal shunt catheter obstruction, reutilizing the functional distal
      catheter was associated with an increase in subsequent shunt failure rates
      compared to revising the entire shunt system. Total revision was not associated
      with improved shunt survival in patients with IVH.

PMID- 12476024
TI  - The effect of intrauterine myelomeningocele repair on the incidence of shunt
      dependent hydrocephalus.
AB  - BACKGROUND: Intrauterine myelomeningocele repair (IUMR) was first successfully
      performed in 1997. Preliminary reports suggest that this procedure reduces the
      incidence of shunt-dependent hydrocephalus when compared to conventional
      postnatal therapy. However, the existing cohort of IUMR patients has not yet been
      systematically compared to a comparable group of conventionally treated controls.
      METHODS: Patients 1 year old or greater who had undergone IUMR at either
      Vanderbilt University or the Children's Hospital of Philadelphia (CHOP) were
      compared to a group of conventionally treated historical controls treated and
      followed at CHOP. In order to measure any differences between the groups,
      patients were stratified according to the level of the myelomeningocele lesion
      and the gestational age at the time of IUMR. RESULTS: One hundred and four IUMR
      patients were compared to 189 conventionally treated controls. IUMR resulted in
      statistically significant reductions in the incidence of shunt-dependent
      hydrocephalus at both lumbar and sacral lesion levels. When lumbar lesion levels
      were further stratified, from L1 to L5, it appeared that the benefit of IUMR was
      statistically significant only at levels below L2. Other factors with a
      significant impact on hydrocephalus were estimated gestational age and
      ventricular size at the time of surgery. In particular, statistically significant
      differences compared to controls were seen in the younger (< or =25 weeks) group
      but not in the older (>25 weeks) group. CONCLUSIONS: IUMR appears to
      substantially reduce the incidence of shunt-dependent hydrocephalus when compared
      to conventional treatment even when lesion level is taken into account. Patients
      with lesions above L3 may not share in this benefit. IUMR cannot be justified in
      fetuses older than 25 weeks of gestation. Additional improvements might be
      obtained by further reducing the average age at which fetuses are operated upon.
      It remains to be determined whether this benefit outweighs the potential risks of
      intrauterine surgery.

PMID- 12476026
TI  - Lumboperitoneal shunts in children.
AB  - OBJECTIVE: To determine the safety and efficacy of lumboperitoneal (LP) shunts in
      carefully selected children with abnormalities of the absorption of cerebrospinal
      fluid. METHODS: Magnetic resonance imaging studies, indications for treatment and
      pre- and postoperative symptoms of 25 patients (mean age 9.6 years) who had
      undergone LP shunting in the past 10 years in a single pediatric neurosurgical
      practice were analyzed retrospectively. RESULTS: Indications for treatment
      included postoperative pseudomeningocele, pseudotumor cerebri and a severe form
      of slit ventricle syndrome. Preoperative symptoms resolved completely in all 25
      patients as a result of the shunt, and no patient developed symptomatic or
      radiographic hindbrain herniation. Twenty-one shunts incorporated valve
      mechanisms. CONCLUSION: LP shunts may be used for specific indications without
      excessive risk of hindbrain herniation.

PMID- 12476027
TI  - Complications of invasive monitoring used in intractable pediatric epilepsy.
AB  - Invasive monitoring for intractable epilepsy is useful when the epileptogenic
      focus is in question even after an extensive noninvasive presurgical evaluation,
      or when the epileptogenic focus is located in or near eloquent cortex. From June
      1989 to June 2001 at the Children's Hospital of Philadelphia, 64 children with
      intractable epilepsy underwent 67 invasive monitoring procedures as part of their
      presurgical evaluation. The average age at implantation was 10 years. In all but
      two cases, subdural strips and grids were used. Depth electrodes, when used, were
      placed stereotactically or under direct vision. The average duration of the
      monitoring period was 5.87 days. Every patient had intradural cultures sent
      during removal of the electrodes, and lumbar punctures were performed in 15
      patients. Twenty-one patients had at least one episode of a CSF leak. Of the 67
      patients, 10 had positive intradural cultures, only 1 of whom had a positive
      lumbar puncture and none of whom developed clinically significant meningitis. No
      clinically relevant hemorrhages occurred as a result of the invasive monitoring.
      One patient did have a transient visual field loss after placement of an
      occipital grid. While CSF leaks are common after invasive monitoring despite
      precautions, clinically significant CSF infections are uncommon and appear to be
      unrelated to the duration of monitoring, the occurrence of a CSF leak or the
      length of time the patient is on perioperative antibiotics. We conclude that
      invasive monitoring for intractable epilepsy is generally safe.

PMID- 12476028
TI  - Chorda dorsalis.

PMID- 12476029
TI  - Gun injuries: are we doing enough?

PMID- 12476030
TI  - Peyer's patches: organized lymphoid structures for the induction of mucosal
      immune responses in the intestine.
AB  - Peyer's patches (PP) comprise transmucosal clusters of lymphoid follicles
      overlaid with a specialized lympho-epithelium and consequently play a central
      role in the induction of mucosal immune responses in the gut. Despite
      considerable achievements in the last 3 decades, in our understanding of how PP
      are involved in the induction of immune responses, much remains to be learned
      about these major organized lymphoid organs. The history and current status of PP
      termed 'the major inductive site of immune responses' is reviewed. The present
      understanding of PP biology and function, taking into account their preferential
      and unique retention of immune competent cells at specific sites, is discussed.

PMID- 12476031
TI  - Trypanosoma cruzi Infection Impairs the Endocytosis of Zymosan A by
      Cardiomyocytes.
AB  - OBJECTIVE: We have previously reported that mannose receptors participate and are
      regulated during Trypanosoma cruzi cardiomyocyte (CM) infection. Our present aim
      is to characterize the endocytosis of mannosylated ligands like zymosan A (Zy) in
      uninfected and T. cruzi-infected CM. METHODS: CM infected or not by T. cruzi were
      incubated with Zy for different periods of time and their internalization was
      analyzed at light microscopy level. Fluorescent approaches were performed by
      treating Zy with concanavalin-A-TRITC and washing it exhaustively prior to
      incubation with CM. The cultures were further stained with phalloidin-FITC and
      DAPI for actin and DNA visualization, respectively. RESULTS: CM internalized Zy
      particles in a time-dependent fashion. The ligand specificity was confirmed by
      the addition of mannan, which efficiently blocked the Zy endocytosis. Designed
      fluorescent approaches extended and confirmed the Zy internalization by striated
      cells. Infected cultures displayed impairment in Zy endocytosis, which seems to
      be directly related to host infection rates. CONCLUSIONS: Altogether, our results
      show the ability of CM to ingest large particles such as the mannosylated ligand
      Zy. During their infection with T. cruzi, there is a loss in Zy internalization
      possibly due to the negative modulation of mannose receptors.

PMID- 12476032
TI  - In vitro autoreactivity against skin and synovial cells in patients with juvenile
      idiopathic and rheumatoid arthritis.
AB  - In the present study we compared specific lysis of various autologous target
      cells in patients with juvenile idiopathic arthritis JIA; n = 8) or rheumatoid
      arthritis RA; n = 17) with those of healthy controls (n = 15). (51)Cr-release
      cytotoxic assay with autologous peripheral blood mononuclear cells as effector
      cells was used. When compared with controls, effector cells of patients with JIA
      or RA were found to lyse significantly autologous synovial cells (p < 0.0005) and
      epidermal keratinocytes (p < 0.0005), however, no difference was found for
      autologous dermal fibroblasts.

PMID- 12476033
TI  - Expression of 60-kD heat shock protein increases during carcinogenesis in the
      uterine exocervix.
AB  - OBJECTIVES: The aim of the present study was to determine the presence and
      expression of the 60-kD heat shock protein (HSP60) in the dysplasia-carcinoma
      sequence in the uterine exocervix and to evaluate its diagnostic and prognostic
      significance. METHODS AND RESULTS: We performed Western blot and
      immunohistochemical analyses on biopsies from 40 cases, consisting of 10 normal
      exocervical biopsies, 10 low-grade squamous intraepithelial lesions (L-SIL), 10
      high-grade squamous intraepithelial lesions (H-SIL) and 10 cancerous exocervices
      (G2 grade). The immunohistochemical results were quantified by computer-assisted
      image analysis. Western blot analysis showed that HSP60 was undetectable in
      normal tissues and that there was a gradual increase of protein expression from L
      SIL to carcinoma. Immunostaining for HSP60 was negative in normal tissue and
      positive in basal and parabasal layers of L-SIL epithelium; H-SIL were markedly
      stained in all layers of epithelium, and carcinomas showed an even stronger
      positivity. The increasing expression correlated with the malignancy grade.
      Finally, koilocytes were mostly negative in L-SIL and positive in H-SIL.
      CONCLUSIONS: The increasing degree of expression of HSP60 from L-SIL to carcinoma
      and the different intraepithelial distribution between L-SIL and H-SIL could be
      used as a new diagnostic tool. Moreover, HSP60 could have a role in cervical
      carcinogenesis.

PMID- 12476035
TI  - Elution of IgA from kidney tissues exhibiting glomerular IgA deposition and
      analysis of antibody specificity.
AB  - Glomerular IgA deposits were eluted from renal biopsy specimens exhibiting IgA
      nephropathy (IgAN) by using a combination of citrate buffer and collagenase.
      Collagenase predigestion of the kidney tissues resulted in increased amounts of
      IgA eluted by citrate buffer, and the elusion procedure did not attenuate the
      antigen-binding ability of IgA antibody. When reactivity of the eluted IgA with
      bacteria components was examined by Western blotting, the most notable reaction
      was observed for Haemophilus influenzae lysates in the form of a 34 kD-band. The
      reactivity of IgA eluted from the kidney tissues against the H. influenzae 34 kD
      antigen was evident in 3 of 5 IgAN cases. However, similar reactivity was also
      evident in 2 of 6 non-IgAN hepatic diseases exhibiting a glomerular IgA
      deposition. These findings suggest that antibody specificity of IgA against H.
      influenzae itself may not be directly associated with glomerular injury, although
      anti-H. influenzae 34 kD IgA was deposited in the kidney, at least in part, by
      IgAN. Further investigations into the properties of IgA deposited in the
      glomerulus are needed. Our improved method for IgA elution from kidney tissues
      would be useful for analysing the pathogenesis of IgAN.

PMID- 12476034
TI  - Residual cftr expression varies with age in cftr(tm1Hgu) cystic fibrosis mice:
      impact on morphology and physiology.
AB  - Mouse models for cystic fibrosis (CF) mimic intestinal manifestations of the
      human disease, but the lung disease phenotypes are lacking in most strains. In
      this work, the issue was addressed whether aging of the respiratory tract leads
      to lung pathophysiology in the exon 10 insertional mutant cftr(tm1Hgu) mouse.
      Weight gain, body weight and life-span of cftr(tm1Hgu) mice were significantly
      reduced compared with control mice. cftr(tm1Hgu) mice expressed 20, 21 or 37%
      (median) of wild-type cystic fibrosis conductance transmembrane regulator (cftr)
      mRNA transcript in lungs, intestine and kidney. Wild-type cftr mRNA in renal and
      respiratory epithelia varied with age from levels similar to Ztm:MF1 controls at
      the age of 2 and 4 months to levels seen in patients with CFTR splice mutations
      beyond the age of 6 months. The morphology of the bronchi and more distal airways
      was apparently normal in cftr(tm1Hgu) mice during their first year of life. The
      alveolar surfactant phospholipid pool was increased in cftr(tm1Hgu) mice by 1.5-
      to 2-fold compared with Ztm:MF1 controls. Alveolar clearance of gamma-labelled
      scandium oxide - the first report of lung clearance measurement in living mice -
      was reduced in cftr(tm1Hgu) mice compared with littermate controls. Although no
      progressive lung pathology was seen in the cftr expression of cftr(tm1Hgu) mice,
      surfactant phospholipid homeostasis, and alveolar and mucociliary clearance were
      abnormal. Therefore, the described model is useful for studying the initial CF
      lung pathophysiology.

PMID- 12476036
TI  - Mouse soluble CD14 truncated at amino acid 71 in transgenic mice: preventive
      effect on endotoxin-mediated toxic shock.
AB  - Mouse soluble CD14 truncated at amino acid 71 (N71) contains the
      lipopolysaccharide (LPS)-binding sequence. Transgenic mice carrying alpha1
      antitrypsin (AT) promoter-N71 fusion genes, designated AT363-1 and AT363-2, were
      produced. These mice constitutively produced elevated levels of N71. The
      concentration of LPS in sera after intraperitoneal LPS injection was lower in
      AT363-1 mice than in nontransgenic mice. The expression of N71 mRNA was enhanced
      by subcutaneous turpentine oil injection. The levels of serum LPS and tumor
      necrosis factor-alpha (TNF-alpha) after intraperitoneal LPS injections were lower
      in AT363-1 mice than in nontransgenic mice. Cell surface TNF-alpha and CD14
      expression in exudate peritoneal macrophages prepared by intraperitoneal
      injection of proteose peptone and then LPS were higher in AT363-1 mice than in
      nontransgenic mice. Neutrophil infiltration in the liver after induction of the
      generalized Shwartzman reaction was lower in AT363-1 mice than in nontransgenic
      mice. Lethality of the Shwartzman reaction was significantly lower in AT363-1
      than in nontransgenic mice. These findings suggest that the endotoxin-binding
      protein (N71) from CD14 prevents endotoxin-mediated toxic shock.

PMID- 12476037
TI  - Pharmacokinetics and absolute oral bioavailability of an 800-mg oral dose of
      telithromycin in healthy young and elderly volunteers.
AB  - BACKGROUND: This two-way, randomized, single-dose, crossover study determined the
      pharmacokinetics and absolute oral bioavailability of telithromycin in young and
      elderly healthy subjects. METHODS: Twelve young (18-40 years) and 12 elderly (>65
      years and </=85 years) subjects received a single 800-mg oral dose of
      telithromycin or an intravenous infusion of 400 mg (young subjects) or 480 mg
      (elderly subjects) of telithromycin over 2.5 h in two treatment periods,
      separated by a 1-week washout period. The plasma concentrations and
      pharmacokinetic parameters of telithromycin and its major metabolite, RU 76363,
      were determined. Absolute oral bioavailability was calculated using the area
      under the plasma concentration-time curve (AUC) from zero hours to infinity.
      RESULTS: The absolute oral bioavailability of telithromycin was 57% in both young
      and elderly subjects. The AUC for the metabolite was lower after intravenous
      infusion of telithromycin, indicating first-pass loss following oral
      administration. Telithromycin was well tolerated in both groups of subjects.
      CONCLUSIONS: Telithromycin has an absolute oral bioavailability of 57% in young
      and elderly subjects and is well tolerated.

PMID- 12476038
TI  - Comparison of in vitro antifungal activities of amphotericin B lipid complex with
      itraconazole against 708 clinical yeast isolates and opportunistic moulds
      determined by National Committee for Clinical Laboratory Standards methods M27-A
      and M38-P.
AB  - We compared the in vitro antifungal activity of amphotericin B lipid complex
      (ABLC) with that of itraconazole (ITZ) against 535 yeast strains and 173
      opportunistic filamentous fungi by using a microdilution method (National
      Committee for Clinical Laboratory Standards M27-A and M38-P). The overall
      geometric mean MIC was 0.13 microg/ml and 0.177 microg/ml for ITZ and ABLC,
      respectively, and the MIC(50) was 0.125 microg/ml for both agents against yeast
      isolates. ITZ had a similar or slightly superior efficacy compared to ABLC when
      tested against Candida albicans, Candida parapsilosis, Cryptococcus neoformans,
      Candida krusei, Candida glabrata and Candida tropicalis. Effectiveness against C.
      glabrata was lower for ITZ (MIC(90) 2 microg/ml, and for ABLC, 0.5 microg/ml).
      For Aspergillus fumigatus, activity of ITZ was superior in comparison with ABLC
      (MIC(90) 1 and 16 microg/ml, respectively); MIC(90) for Aspergillus niger was 4
      and 2 microg/ml for ABLC and ITZ, respectively. Scedosporium spp. showed a low
      susceptibility to both ABLC and ITZ. In conclusion, ABLC and ITZ are useful
      alternatives for the treatment of severe fungal infections. The selection of an
      antifungal agent should be made considering the toxicological and pharmacological
      properties and cost/benefit relationship and be supported by the susceptibility
      of the isolate.

PMID- 12476039
TI  - The activity of levofloxacin and comparator agents against clinical isolates of
      Streptococcus pneumoniae collected worldwide during 1999 and 2000.
AB  - BACKGROUND: Increases in penicillin-resistant Streptococcus pneumoniae have been
      documented worldwide. METHODS: During 1999 and 2000, 5,015 S. pneumoniae isolates
      were collected from 13 countries on five continents and tested for antimicrobial
      susceptibility. RESULTS: Penicillin resistance rates were as follows: South
      Korea, 70.1%; Hong Kong, 50.3%; Thailand, 39.3%; France, 28.7%; Spain, 24.8%;
      Mexico, 18.1%; Ireland, 11.8%; South Africa, 11.1%; Italy, 9.4%; United Kingdom,
      3.1%; Brazil, 2.9%; China, 2.3%, and Germany, 0.7%. Resistance to azithromycin,
      clarithromycin and trimethoprim-sulfamethoxazole was commonly associated with
      penicillin resistance. Levofloxacin-resistant isolates were detected in 8 of 13
      countries: Germany (0.2%), France (0.4%), Thailand (0.5%), South Korea (0.9%),
      Mexico (1.5%), Spain (1.6%), China (3.3%) and Hong Kong (8.0%). Multidrug
      resistance (resistance to >/=3 antimicrobial classes) occurred in 626/5,015
      isolates (12.5%). Levofloxacin was active against 96.0% (601/626) of the
      multidrug-resistant (MDR) isolates and 99.7% (4,374/4,389) of the non-MDR
      isolates. CONCLUSION: Although relatively high levels of levofloxacin resistance
      were detected in China and Hong Kong, overall, levofloxacin remained active
      against >99% of clinical isolates of S. pneumoniae despite their resistance to
      other agents. Continued surveillance of S. pneumoniae will track any changes in
      levofloxacin activity, should they occur.

PMID- 12476040
TI  - Antiproliferative properties of toremifene on AIDS-related Kaposi's sarcoma
      cells.
AB  - BACKGROUND: Kaposi's sarcoma (KS) is the most common neoplastic apoptosis
      manifestation of acquired immunodeficiency syndrome. Toremifene is known to
      upregulate transforming growth factor beta-1 (TGF-beta1), which is a growth
      inhibitory factor for KS. We investigated the in vitro effect of toremifene on KS
      cells. METHODS: MTT assay was used to measure the growth of four KS cell lines
      and a human umbilical vein endothelial (HUVE) cell line after incubation with
      toremifene. Reverse transcription polymerase chain reaction and ELISA were used
      to measure the level of TGF-beta1. RESULTS: The IC(50) for the KS cells ranged
      from 2.2 to 3.2 microM, and 80% of the growth inhibition occurred within 24 h.
      Toremifene enhanced TGF-beta1 mRNA expression, and the level of TGF-beta1
      increased from 103 to 473 pg/ml after 48 h of incubation. Toremifene had no
      effect on the growth of HUVE cells. CONCLUSION: Toremifene has a specific
      antiproliferative effect on KS cells. The stimulation of TGF-beta1 production may
      play a role in the antiproliferative process.

PMID- 12476041
TI  - Possible modulatory role of nitric oxide in lung toxicity induced in rats by
      chronic administration of bleomycin.
AB  - BACKGROUND: The present study was undertaken to evaluate whether stimulation or
      inhibition of nitric oxide (NO) synthesis could affect lung toxicity induced by
      chronic administration of bleomycin (BLM). L-arginine (ARG) and N(G)-nitro-L
      arginine methyl ester (L-NAME) were employed as NO precursor and NO synthesis
      inhibitor, respectively. METHODS: BLM was administered intraperitoneally to male
      Wistar rats at a dose of 15 mg/kg, 3 times a week, for a total period of 4 weeks.
      ARG (500 mg/kg/day) and L-NAME (100 mg/kg/day) were given in drinking water, the
      treatments commenced with BLM and continued up to the end of the experiment.
      Appropriate controls were performed. RESULTS: BLM treatment resulted in a
      pronounced fall in the average body weight of animals, together with a rise in
      the lung weight/body weight ratio. In the lung tissue, elevated levels of
      hydroxyproline (HP) and lipid peroxides (LP) as well as decreased activity of
      angiotensin converting enzyme (ACE) further evidenced the toxicity. Pulmonary
      level of NO end products, nitrite and nitrate, tended to rise but did not reach a
      significant level. Glutathione (GSH) content and GSH-peroxidase activity measured
      in the lung remained unaltered. In animals given concurrent treatment of BLM and
      ARG, a remarkable rise in the pulmonary level of nitrite and nitrate was
      observed. Average body weight was still decreased when compared with the
      untreated control group, but the decrease was significantly less than that
      observed in the BLM group. In addition, ARG decreased the extent of BLM-induced
      elevations of lung HP and LP levels. Meanwhile, ARG failed to significantly
      affect the BLM-evoked decrease in pulmonary ACE activity and increase in lung
      weight/body weight ratio. In animals given simultaneous treatment of BLM and L
      NAME, noticeable reductions in the pulmonary levels of nitrite/nitrate and GSH
      were detected. BLM-induced decrease in body weight and increase in lung
      weight/body weight ratio were accentuated by L-NAME co-treatment. Furthermore,
      administration of L-NAME led to more profound elevations in lung HP and LP
      levels, without affecting the decrease in pulmonary ACE activity elicited by BLM.
      CONCLUSION: In principle, the present findings indicate that the lung toxicity
      exerted by chronic administration of BLM is alleviated by ARG, but exacerbated by
      L-NAME supplementation. This could indicate a possible protective role of NO.

PMID- 12476042
TI  - Modified ESHAP as salvage chemotherapy for recurrent or refractory non-Hodgkin's
      lymphoma: results of a single-center study of 32 patients. Modified etoposide,
      methylprednisolone, cytarabine and cisplatin.
AB  - BACKGROUND: We have evaluated the clinical efficacy and toxicity of a modified
      etoposide, methylprednisolone, cytarabine and cisplatin (ESHAP) chemotherapy
      regimen that has been used by the Hacettepe University Department of Medical
      Oncology (Ankara, Turkey) since 1993. METHODS: Thirty-two patients (18 men and 14
      women) with refractory or recurrent non-Hodgkin's lymphoma (NHL) were treated
      with this protocol. The median age of the patients was 39 years (range 21-66
      years). Patients were hospitalized during therapy. On the first day, 2 g/m(2)
      cytarabine was given, followed on days 2-5 by 60 mg/m(2) etoposide, 500 mg of
      methylprednisolone and 25 mg/m(2) cisplatin. After two cycles of chemotherapy,
      clinical efficacy was assessed by clinical examination, chest radiography,
      ultrasonography and/or computed tomography. The complications were assessed on
      the basis of the World Health Organization criteria. RESULTS: Nine patients (28%)
      had a complete response and 8 patients (25%) had a partial response. In
      responders, the median duration of remission was 6 months. By the end of the
      first year, 27% of the patients were still disease free and 66% were alive. High
      serum levels of lactate dehydrogenase had an adverse effect on disease-free
      survival, but no effect on overall survival (OS). The only unfavorable prognostic
      factor for OS was the presence of bulky disease. Neutropenia developed in 59% of
      patients, and febrile neutropenia developed in 74% of these patients, requiring
      hospitalization for an average of 8 days. Three patients died of neutropenia
      associated sepsis despite broad-spectrum antibacterial and antifungal treatment.
      Thrombocytopenia was detected in 10 patients and anemia in 3 patients; among
      these, 7 patients with thrombocytopenia and 1 patient with anemia required
      transfusions. CONCLUSIONS: The modified ESHAP regimen induced remission in more
      than half of the patients with refractory or recurrent NHL. However, the duration
      of remission was brief. Moreover, significant myelotoxicity was common, and the
      risk of treatment-related death was 9%.

PMID- 12476043
TI  - Esberitox N as supportive therapy when providing standard antibiotic treatment in
      subjects with a severe bacterial infection (acute exacerbation of chronic
      bronchitis). A multicentric, prospective, double-blind, placebo-controlled study.
AB  - 53 patients with planned antibiotic therapy for the treatment of acute
      exacerbation of chronic bronchitis as an example of a severe bacterial infection
      requiring antibiotics were included in a prospective, multicentre, double-blind,
      placebo-controlled study. The chronic bronchitis was staged by forced expiratory
      volume of the 1st second (FEV(1)) measured in the infection-free interval prior
      to the current episode and had to be between 35 and 75% for the predicted value.
      Patients were randomly assigned to receive newer macrolide antibiotics plus
      either Esberitox N or placebo. Antibiotic therapy was administered according to
      generally accepted guidelines and Esberitox N or placebo was given for 28 days.
      The baseline-adjusted means for FEV(1) (%) on day 10 were 68.7 points for the
      Esberitox N group and 59.2 points for the placebo group (p = 0.0303). For FEV(1)
      the difference between the two treatment groups was 267 ml (p = 0.0499). The time
      to half maximal improvement was 5.7 days in the Esberitox N group compared to
      12.8 days in the placebo group. The treatment was well tolerated; no serious
      adverse events were documented. In conclusion, comedication of antibiotics with
      Esberitox N in subjects with acute exacerbation of chronic bronchitis seems to be
      of benefit for the patient. Apparently, therapy with Esberitox N leads to a
      faster recovery from this severe bacterial infection, possibly via preventing an
      impairment of the host's immune system which might otherwise occur as a
      consequence of aggressive antimicrobial therapeutics.

PMID- 12476045
TI  - Junctional adhesion molecules and interendothelial junctions.
AB  - Similar to epithelia, endothelial cells are linked to each other via
      intercellular junctional complexes including gap junctions, adherens junctions
      and tight junctions. While polarized epithelial cells show a high degree of
      spatial sorting of junctional complexes, endothelia organize their junctions
      randomly. For this reason the nature of endothelial contacts may be highly
      adaptable to the need of permeability and leukocyte transmigration. For instance,
      high endothelial venules (HEVs) in lymphoid organs, where lymphocytes
      continuously exit the bloodstream, generally show more leaky contacts than brain
      with its impermeable blood-brain barrier. We recently identified an Ig
      superfamily molecule named JAM-2 which is specifically expressed in junctions of
      lymphatic endothelial cells and HEVs. We showed that JAM-2 belongs to the novel
      CTX molecular family and we now cloned the human equivalent of JAM-2. The
      presence of JAM-2 at sites of constitutive lymphocyte circulation argues for a
      role of this molecule in facilitating transmigration. This is supported by the
      increased transmigration in vitro across endothelial cells overexpressing JAM-2
      at intercellular contacts.

PMID- 12476046
TI  - Leukocyte adhesion deficiency II: therapy and genetic defect.
AB  - Leukocyte adhesion deficiency II (LAD II) is a rare congenital disease which is
      caused by a defect in fucosylation of glycoconjugates. Hypofucosylated structures
      include ligands for the selectin family of adhesion molecules. This results in a
      leukocyte adhesion defect causing an immunodeficiency. In addition, LAD II
      patients show severe mental and growth retardations suggesting a role of fucose
      in development. Recently, a LAD II patient was treated with oral supplementation
      of fucose. This simple therapy restored selectin ligands and corrected the
      immunodeficiency. However, in another patient the treatment protocol had no
      effect indicating that the biochemical defect in the latter patient is somewhat
      different. The genetic defect in LAD II has now been located to a gene encoding a
      GDP-fucose transporter which gates GDP-fucose into the Golgi where fucose is
      transferred onto glycoconjugates. Point mutations have been detected in this gene
      in several LAD II patients, which inactivate the transporter function. Thus, LAD
      II represents the first developmental and immune defect that is based on a
      malfunctioning nucleotide sugar transporter.

PMID- 12476047
TI  - Measuring cell adhesion forces with the atomic force microscope at the molecular
      level.
AB  - In the past 25 years many techniques have been developed to characterize cell
      adhesion and to quantify adhesion forces. Atomic force microscopy (AFM) has been
      used to measure forces in the pico-newton range, an experimental technique known
      as force spectroscopy. We modified such an AFM to measure adhesion forces between
      live cells or between cells and surfaces. This strategy required functionalizing
      the surface of the sensors for immobilizing the cell. We used Dictyostelium
      discoideum cells which respond to starvation by surface expression of the
      adhesion molecule csA and consequent aggregation to measure the adhesion force of
      a single csA-csA bond. Relevant experimental parameters include the duration of
      contact between the interacting surfaces, the force against which this contact is
      maintained, the number and specificity of interacting adhesion molecules and the
      constituents of the medium in which the interaction occurs. This technology also
      permits the measurement of the viscoelastic properties of single cells or cell
      layers.

PMID- 12476048
TI  - Integrin-mediated adhesion and signaling during blastocyst implantation.
AB  - Blastocyst implantation in rodents and primates depends on adhesive interactions
      between trophoblast cells and the endometrial extracellular matrix. As the
      blastocyst contacts the uterine basal lamina, cells of the trophectoderm become
      adhesion-competent and conclude their phenotypic conversion from a polarized
      epithelium to invasive trophoblast cells that anchor the embryo in the uterine
      wall and eventually infiltrate the endometrium. Trophoblast cells become capable
      of adhesion to fibronectin as alpha(5)beta(1) integrins traffick to their apical
      surfaces. While integrin trafficking may be required for trophoblast adhesion to
      the endometrium, accumulating evidence indicates that, in response to contact
      with the extracellular matrix, additional molecules must be recruited to the
      apical surface before strong adhesion is attained. Based on the known
      interactions of integrins with cytoplasmic regulatory proteins, we propose that
      extracellular matrix-bound integrins mediate intracellular signaling cascades
      that strengthen their adhesive activity. We will review some of the known
      integrin signaling pathways that could regulate trophoblast adhesion and
      differentiation.

PMID- 12476049
TI  - Integrins and extracellular matrix proteins at the maternal-fetal interface in
      domestic animals.
AB  - Establishment of pregnancy in mammals requires coordinated conceptus-maternal
      interactions involving numerous hormones, growth factors and cytokines acting via
      specific receptors in the uterus. Uterine secretions play an important role in
      establishing synchrony between development of the conceptus and uterine
      receptivity, as well as in conceptus remodeling, adhesion, implantation and
      placentation in domestic species. Studies of non-invasive implantation in
      domestic livestock provide valuable opportunities to investigate fundamental
      processes of the initial events of apposition, attachment and adhesive
      interactions that are shared among species. In pigs and sheep, it appears that
      integrins play a dominant role in these fundamental processes via interactions
      with extracellular matrix molecules and other ligands to transduce cellular
      signals in uterine epithelial cells and conceptus trophectoderm. This review
      considers several of the potential integrin-binding ligands involved in the
      complex implantation adhesion cascade in pigs and sheep along with in vitro
      evidence for the transduction of cytoplasmic signals that may be required to
      sustain fetal and maternal contributions to the formation of the epitheliochorial
      placenta.

PMID- 12476050
TI  - Experimental modulation of cell-cell adhesion, invasiveness and differentiation
      in trophoblast cells.
AB  - The establishment of pregnancy in the human decisively depends on the competence
      of the early trophoblast to interact during implantation with (1). the uterine
      epithelium and subsequently (2). with the endometrial stroma and blood vessels.
      In the interaction with uterine epithelium cell-to-cell adhesion appears to be a
      critical element, involving initially (and astonishingly) apical cell poles of
      both epithelia. The subsequent invasion of the stroma includes both adhesive
      interactions with and degradation of extracellular matrix. How these different
      processes are regulated in detail remains largely unknown. While the invasiveness
      of the trophoblast is known to be regulated in local and temporal terms it has
      remained unclear so far whether trophoblast adhesiveness to cells and/or matrix
      is subject to a coupled regulation or whether both properties involve different,
      maybe sequentially effective, control mechanisms. It is also not known how the
      regulation of these activities is related to the differentiation pathways leading
      to the formation of noninvasive villous trophoblast serving endocrine as well as
      nutritive functions. This communication reviews experiments using normal
      cytotrophoblast cells isolated from first trimester or term placentae as well as
      malignant trophoblast (choriocarcinoma) cells treated with a panel of compounds
      known to modulate cell differentiation [retinoic acid, methotrexate, dibutyryl
      cAMP, phorbol-(12-myristoyl-13-acetyl)-diester]. Parameters indicative of
      trophoblast differentiation [in particular chorionic gonadotrophin (hCG)
      secretion] as well as adhesion to uterine epithelial cells and invasion into
      extracellular matrix in vitro were monitored. While expression of differentiation
      parameters was increased by all drug treatments, adhesion to uterine epithelial
      cells in vitro was reduced. Modulation of invasiveness, however, followed a
      different pattern: while it was reduced in normal trophoblast cells it was even
      increased in choriocarcinoma cells with various substances. The response of cells
      with respect to production of extracellular matrix proteins or matrix-degrading
      proteinases showed a complex pattern that again lacked a stringent correlation
      with hCG production and adhesion, and in addition also with invasive behavior.
      These results suggest that adhesiveness of trophoblast to uterine epithelial
      cells and invasiveness into the uterine stroma (extracellular matrix) are subject
      to different control mechanisms. They support the view that trophoblast
      endometrium interactions involve a cascade of various adhesion and migration
      processes whose cellular and molecular basis is complex but accessible to
      experimental investigation using a variety of available in vitro systems.

PMID- 12476051
TI  - In vitro studies on endometrial adhesiveness for trophoblast: cellular dynamics
      in uterine epithelial cells.
AB  - Initiation of embryo implantation involves adhesion of trophoblast cells to the
      epithelial lining of the endometrium. The mechanisms regulating the adhesive
      properties of the uterine epithelium for trophoblast during initiation of human
      embryo implantation, however, are still incompletely understood. We report here
      on model studies that we have performed in our laboratory, and in particular on
      certain methodological approaches that seem to yield new insight into basic
      mechanisms involved. Of central interest is the ability of the uterine epithelium
      to develop an adhesion competence at its apical cell pole. This confronts us with
      a cell biological paradox in that adhesion must be established at the pole which
      in simple epithelia is typically specialized to resist adhesion. Gain of apical
      adhesion competence by uterine epithelial cells should be related to cellular
      rearrangements, i.e. a modulation of their apicobasal cell polarity. Here, we
      used monolayer-cultured uterine epithelial RL95-2 cells as an in vitro model for
      the human receptive uterine epithelium. We demonstrated that formation of stable
      cell-to-cell bonds between the free (apical) pole of these cells and attaching
      trophoblast (modelled by JAr cells) depends on a number of structural and
      functional peculiarities that RL95-2 cells have in contrast to other uterine
      epithelial cells (HEC-1-A cells) which resist attachment via this cell pole. RL95
      2 cells were shown to lack tight junctions and to exhibit only rudimentary
      adherens junctions and a non-polar organization of the actin cytoskeleton. Using
      the atomic force microscope in a force spectroscopy mode, we exactly defined the
      time dependence of adhesive interactions between RL95-2 cells and trophoblast,
      measured the pressure force needed to initiate this process, and screened the
      buildup of the adhesive forces between the binding partners. A dynamic
      interaction between the actin cytoskeleton and integrins (a prerequisite for
      functional activity of integrins) was shown to be an important aspect of the
      adhesive properties of RL95-2 cells. In addition, at least two types of calcium
      channels in the plasma membrane of RL95-2 cells seem to play a role in activation
      of a variety of calcium-sensitive response mechanisms including adhesiveness for
      trophoblast, i.e. diltiazem-sensitive channels seem to contribute to the
      initiation of JAr cell binding and SKF-96365-sensitive channels to participate in
      a feedback loop that controls the balance of bonds. By extrapolation, these data
      suggest an active role of the uterine epithelium in the process of embryo
      implantation which we are just beginning to understand in terms of its cell
      biology.

PMID- 12476052
TI  - The retina of five atherinomorph teleosts: photoreceptors, patterns and spectral
      sensitivities.
AB  - We investigated the spectral and morphological features of the photoreceptors of
      five atherinomorph teleosts, representing two different orders, and with
      different life styles and habitats, the Beloniformes and Atheriniformes. The
      retinae of Belone belone (Belonidae), Dermogenys pusillus (Hemiramphidae),
      Atherina boyeri (Atherinidae), Marosatherina ladigesi (Telmatherinidae), and
      Melanotaenia maccullochi (Melanotaeniidae) were examined by light and electron
      microscopy and microspectrophotometry. In addition to rods, five morphologically
      different cone types were identified: short, intermediary and long single cones,
      and double cones which are arranged in distinct specific mosaics. Sporadically,
      triple cones were also found. Double cones were longer-wave-sensitive, but no
      general correlation between single cone morphology and spectral sensitivity could
      be demonstrated. The rods had lambda(max) close to 506-509 nm. The lambda(max) of
      cone visual pigments ranged from about 368 nm to 578 nm. Ultraviolet-sensitive
      single cones were present in the three freshwater species, M. ladigesi, M.
      maccullochi and D. pusillus and three spectrally distinct short-wave-sensitive
      single cone classes were identified in M. maccullochi. In M. ladigesi, spectral
      sensitivity varied among individuals due to varying rhodopsin/porphyropsin
      mixtures. In D. pusillus and M. maccullochi polymorphism of the longer-wave cone
      pigments might occur. These findings are discussed with respect to phylogeny,
      photic habitat, behavior and feeding habits.

PMID- 12476053
TI  - Asymmetry and symmetry in brain waves from dolphin left and right hemispheres:
      some observations after anesthesia, during quiescent hanging behavior, and during
      visual obstruction.
AB  - Studies of sleep in cetaceans (whales, dolphins, and porpoises), substantiated by
      electrophysiological data, are rare with the great majority of observations
      having been made by one group from Russia. This group employed hard-wired
      recording with low-noise cables for their EEG observations, whereas our report
      describes behavioral and EEG observations of dolphin sleep using telemetry.
      Marked asymmetry of the EEG was observed during behavioral sleep posture. At
      different times synchronized slow waves appeared in both left and right brain
      hemispheres concurrently with lower voltage, faster, desynchronized EEG activity
      in the opposite hemisphere. On the other hand, during one brief period of sleep
      behavior, sleep-like EEG activity appeared on leads from both hemispheres. When
      the animal was exposed to a loud sound, it woke with lower voltage, faster,
      relatively symmetrical, desynchronized EEG activity appearing from both
      hemispheres. Additionally, the EEG appeared relatively desynchronized and
      symmetrical between the two hemispheres when the animal was awake during recovery
      from pentothal-halothane anesthesia as well as during waking periods when one or
      both of the animal's eyes were covered by an opaque rubber suction cup.

PMID- 12476054
TI  - The distribution and morphological characteristics of cholinergic cells in the
      brain of monotremes as revealed by ChAT immunohistochemistry.
AB  - The present study employs choline acetyltransferase (ChAT) immunohistochemistry
      to identify the cholinergic neuronal population in the central nervous system of
      the monotremes. Two of the three extant species of monotreme were studied: the
      platypus (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus
      aculeatus). The distribution of cholinergic cells in the brain of these two
      species was virtually identical. Distinct groups of cholinergic cells were
      observed in the striatum, basal forebrain, habenula, pontomesencephalon, cranial
      nerve motor nuclei, and spinal cord. In contrast to other tetrapods studied with
      this technique, we failed to find evidence for cholinergic cells in the
      hypothalamus, the parabigeminal nucleus (or nucleus isthmus), or the cerebral
      cortex. The lack of hypothalamic cholinergic neurons creates a hiatus in the
      continuous antero-posterior aggregation of cholinergic neurons seen in other
      tetrapods. This hiatus might be functionally related to the phenomenology of
      monotreme sleep and to the ontogeny of sleep in mammals, as juvenile placental
      mammals exhibit a similar combination of sleep elements to that found in adult
      monotremes.

PMID- 12476055
TI  - The distribution and morphological characteristics of catecholaminergic cells in
      the brain of monotremes as revealed by tyrosine hydroxylase immunohistochemistry.
AB  - The present study describes the distribution and cellular morphology of
      catecholaminergic neurons in the CNS of two species of monotreme, the platypus
      (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus aculeatus).
      Tyrosine hydroxylase immunohistochemistry was used to visualize these neurons.
      The standard A1-A17, C1-C3 nomenclature was used for expediency, but the
      neuroanatomical names of the various nuclei have also been given. Monotremes
      exhibit catecholaminergic neurons in the diencephalon (A11, A12, A13, A14, A15),
      midbrain (A8, A9, A10), rostral rhombencephalon (A5, A6, A7), and medulla (A1,
      A2, C1, C2). The subdivisions of these neurons are in general agreement with
      those of other mammals, and indeed other amniotes. Apart from minor differences,
      those being a lack of A4, A3, and C3 groups, the catecholaminergic system of
      monotremes is very similar to that of other mammals. Catecholaminergic neurons
      outside these nuclei, such as those reported for other mammals, were not numerous
      with occasional cells observed in the striatum. It seems unlikely that
      differences in the sleep phenomenology of monotremes, as compared to other
      mammals, can be explained by these differences. The similarity of this system
      across mammalian and amniote species underlines the evolutionary conservatism of
      the catecholaminergic system.

PMID- 12476056
TI  - The distribution and morphological characteristics of serotonergic cells in the
      brain of monotremes.
AB  - The distribution and cellular morphology of serotonergic neurons in the brain of
      two species of monotremes are described. Three clusters of serotonergic neurons
      were found: a hypothalamic cluster, a cluster in the rostral brainstem and a
      cluster in the caudal brainstem. Those in the hypothalamus consisted of two
      groups, the periventricular hypothalamic organ and the infundibular recess, that
      were intimately associated with the ependymal wall of the third ventricle. Within
      the rostral brainstem cluster, three distinct divisions were found: the dorsal
      raphe nucleus (with four subdivisions), the median raphe nucleus and the cells of
      the supralemniscal region. The dorsal raphe was within and adjacent to the
      periaqueductal gray matter, the median raphe was associated with the midline
      ventral to the dorsal raphe, and the cells of the supralemniscal region were in
      the tegmentum lateral to the median raphe and ventral to the dorsal raphe. The
      caudal cluster consisted of three divisions: the raphe obscurus nucleus, the
      raphe pallidus nucleus and the raphe magnus nucleus. The raphe obscurus nucleus
      was associated with the dorsal midline at the caudal-most part of the medulla
      oblongata. The raphe pallidus nucleus was found at the ventral midline of the
      medulla around the inferior olive. Raphe magnus was associated with the midline
      of the medulla and was found rostral to both the raphe obscurus and raphe
      pallidus. The results of our study are compared in an evolutionary context with
      those reported for other mammals and reptiles.

PMID- 12476057
TI  - STAR Day: one hospital's solution to educational challenges.
AB  - To answer the challenge of 24-hour staffing coupled with required contact hour
      requirements, an all-day educational program is offered to all 1,300 employees of
      this suburban Level II trauma center. Providing flexible session attendance
      options while retaining the advantages of interpersonal adult learning make this
      a useful option for the continuing education of hospital staff.

PMID- 12476059
TI  - Educational support during organizational transition: half-day workshops for
      nurses and leaders.
AB  - The integration of the Intensive Care Unit and Coronary Care Unit at the Brant
      Community Healthcare System (Brantford General Site) in Brantford, Ontario,
      Canada, was carefully planned. As part of the planning efforts, much attention
      was given to effective transition management. An educational program was designed
      to assist the nurses from these units to begin to disengage from old ways of
      planning and delivering care, provide support to help them through the period of
      uncertainty (neutral zone) associated with this type of transition, and help them
      adapt to the new realities that the integrated Critical Care Unit demanded. This
      article describes the workshops designed to assist nurses and leaders through
      this transition.

PMID- 12476058
TI  - Efficacy of a teaching intervention on nurses' knowledge regarding diabetes.
AB  - The absence of a diabetic nurse educator and continuing education opportunities
      regarding diabetes management was the impetus for one staff nurse's research.
      Subjects' (N = 72) current knowledge about diabetes mellitus was tested before
      and after a peer-developed diabetes management presentation. Results reflected a
      need for improving diabetes knowledge. The teaching intervention positively
      influenced postintervention scores (p =.000).

PMID- 12476060
TI  - Identifying performance criteria for staff development competencies.
AB  - Performance criteria for specific staff development competencies need to be
      developed. The primary investigator (PI) surveyed the literature and developed
      specific performance criteria for objective staff development competencies. A
      survey was sent to a random stratified sample of 300 nurses certified in nursing
      continuing education and staff development asking them to rank the performance
      criteria for the objective statements and provide suggestions for an additional
      five subjective competencies. The PI reviewed the data and developed criteria for
      the subjective competencies. A survey with performance criteria for all 10
      competencies was sent to National Nursing Staff Development Organization (NNSDO)
      affiliate groups for validation. Performance criteria were identified for all 10
      competency statements. The mean scores for the national and regional samples were
      very similar in most areas. The data will provide a mechanism to promote and
      advance evidence-based practice in staff development. Instructors, individual
      staff development specialists, or organizations can use these performance
      criteria to determine if staff development personnel are meeting specified
      competencies.

PMID- 12476061
TI  - Lightening the burden for preceptors: consider adding a "Faculty Model" week to
      orientation.
AB  - The physical and emotional stress on preceptors creates a conundrum as hospitals
      expand and/or experience higher rates of nursing staff turnover. When chosen
      well, preceptors are an excellent way to integrate and teach new nurses. However,
      being a preceptor can often be an added burden in a busy hospital climate.
      Creating innovative systems, within new nurse orientation, that respect the
      preceptor role and provide some relief have much merit in today's bustling
      hospital environment. The creation of such a system in a large tertiary care
      hospital in Boston, MA, entitled the Faculty Model Pilot Program, seems to be
      both supporting the overworked preceptors and providing a comprehensive
      standardized practice week for newly hired medical/surgical nurses. The pilot
      program appeared to increase not only their knowledge of the hospital itself but
      also the standards of patient care throughout the hospital. This added week
      seemed to provide a good understanding of general nursing practice prior to the
      acquisition of the unit-based, specific knowledge; thus, lightening the burden
      for unit preceptors.

PMID- 12476062
TI  - Nursing care of patients with gastrointestinal cancer: a staff development
      approach.
AB  - This article discusses how staff development educators can conduct an innovative
      class for nurses caring for patients with gastrointestinal cancer. The nurse's
      role in caring for these patients includes knowledge of the pathophysiology, risk
      factors, detection methods, signs and symptoms, treatments, conventional and
      integrative holistic nursing interventions, and community resources. However,
      consideration should be given to the total learning experience rather than
      technical skills alone.

PMID- 12476063
TI  - Staff development stories: a new staff development director's story.

PMID- 12476064
TI  - Changes.

PMID- 12476065
TI  - Effective communication skills: the key to preventing and resolving ethical
      situations.

PMID- 12476066
TI  - Future challenges.

PMID- 12476067
TI  - Gene therapy in the post-Gelsinger era.
AB  - As gene therapy research races to a first cure of a genetic-based disease, the
      research community has struggled with the aftermath of the well-publicized death
      of Jesse Gelsinger from complications of an experimental treatment. In a wrongful
      death lawsuit against the University of Pennsylvania and its researchers, Jesse
      Gelsinger's family alleged violations of federal regulations and research ethics.
      This article reviews gene therapy research, examines the role of the key players
      in this tragedy, and provides suggestions for preventing future misfortunes.

PMID- 12476068
TI  - The culture of patient safety.
AB  - Hospital patient safety culture is examined as a critical component of quality
      where preventable and identifiable adverse and sentinel events should not occur.
      The author, a former hospital executive, illustrates how culture helps illuminate
      patient safety practices using examples from hospital situations he encountered
      as a consultant. These cases demonstrate the hospital nurses' focuses on job
      requirements and training as opposed to actually doing the "right thing" at the
      "right time." The nurse hospitalist, an advanced practice nurse, is proposed as a
      daily teacher and facilitator for hospital nurses based on a curriculum of day-to
      day examples of good patient care through training and observation of patient
      care as it is being given.

PMID- 12476069
TI  - Experiences of Dutch families who parent an adopted Romanian child.
AB  - The pilot phase of a longitudinal study of 83 children (response 86%) adopted
      from Romania is reported; the present status of the children is compared with the
      past status on the basis of parental recollection. At placement, the average age
      of the children was 2.9 years; at the time of the interview of the adoptive
      parents, the average age of the children was 6.8 years. At placement, 67% of the
      adoptive parents needed professional help, and 10% of the children were infected
      with Hepatitis B. Only 13% did not show any important psychosocial problems. The
      number of psychosocial problems reported by the parents at placement predicts 69%
      of the lag of development observed 4 years later; the age of arrival adds up to
      72%. Most problems still exist 4 years after placement; however, no disruptions
      of the adoption have taken place yet.

PMID- 12476070
TI  - Massage therapy by mothers enhances the adjustment of circadian rhythms to the
      nocturnal period in full-term infants.
AB  - The objective of this study was to investigate the effect of massage therapy on
      phase adjustment of rest-activity and melatonin secretion rhythms to the
      nocturnal period in full-term infants. Rest-activity cycles of infants
      (measurement 1, n = 16) were measured by actigraphy before and after 14 days of
      massage therapy (starting at age 10 [+/-4] d) and subsequently at 6 and 8 weeks
      of age. 6-Sulphatoxymelatonin excretion was assessed in urine samples at 6, 8,
      and 12 weeks of age (measurement 2, n = 21). At 8 weeks the controls revealed one
      peak of activity at approximately 12 midnight (11 p.m.-3 a.m.) and another one at
      approximately 12 noon (11 a.m.-3 p.m.), whereas in the treated group, a major
      peak was early in the morning (3 a.m.-7 a.m.) and a secondary peak in the late
      afternoon (3 p.m.-7 p.m.). At 12 weeks, nocturnal 6-sulphatoxymelatonin
      excretions were significantly higher in the treated infants (1346.38 +/- 209.40
      microg/night vs 823.25 +/- 121.25 microg/night, respectively; <.05). It is
      concluded that massage therapy by mothers in the perinatal period serves as a
      strong time cue, enhancing coordination of the developing circadian system with
      environmental cues.

PMID- 12476071
TI  - Effect of the deficits of fragile X mental retardation protein on cognitive
      status of fragile x males and females assessed by robust pedigree analysis.
AB  - The effect of the fragile X mental retardation 1 (FMR1) gene product (fragile X
      mental retardation protein [FMRP]) deficits on Full-Scale IQ (FSIQ) and FSIQ
      adjusted Wechsler subtests and index scores in fragile X disorder were assessed
      using a robust modification of the maximum likelihood estimators for pedigree
      data. The results from 144 extended families have demonstrated a linear effect of
      progressively reduced levels of FMRP on the FSIQ and all subtest and summary
      scores in either gender. The effect of FMRP in decreasing FSIQ-adjusted subtest
      scores was highly significant for Digit Span, Symbol Search, Object Assembly, and
      Picture Arrangement, with a consistent trend in both genders. Heritability for
      FSIQ and unadjusted subtest scores estimated from the covariance model did not
      exceed 50% and varied widely from the highest for Verbal score to the lowest for
      Picture Completion score. Possible mechanisms by which FMRP deficit impacts on
      specific weaknesses in fragile X are considered on the basis of present data.

PMID- 12476072
TI  - Toilet training in primary care: current practice and recommendations from
      behavioral pediatrics.
AB  - This article is the first to evaluate pediatricians' (1). current practices
      regarding recommendations for toilet training typically developing first-time
      learners and (2). opinions on an intensive procedure for rapid toilet training.
      Results of surveys obtained from 103 pediatricians indicate that physicians'
      recommendations lean toward a gradual, passive approach to toilet training with
      72% endorsing "child interest" in the toilet as one of the top criteria children
      must exhibit before beginning training. Respondents had a somewhat unfavorable
      view of intensive toilet training for first-time learners with 29% endorsing the
      use of such a procedure, although in most cases without all of the components. It
      is recommended that some components of the intensive procedure could easily "fit"
      with physicians' current practices to increase toilet-training effectiveness
      within a shorter training interval. These recommendations, including compliance
      training as a part of teaching, increased fluid intake to promote toileting
      trials, and multiple training sits, are described.

PMID- 12476073
TI  - Temperament characteristics of premature infants in the first year of life.
AB  - Parenting preterm infants in the first months after hospital discharge is
      challenging. Although preterm infants are considered to be difficult, preterm
      temperament at less than 3 months is unknown empirically. The purpose of this
      analysis was to investigate the 6-week temperament characteristics of preterm
      infants in comparison with standardized norms of full-term infants. The sample of
      74 infants with gestational ages at birth between 24 and 32 weeks were enrolled
      in a study of preterm infant neurobehavioral outcomes. Mothers rated temperament
      at 6 weeks, 6 months, and 12 months of age (adjusted for prematurity). At 6 weeks
      the premature infants were significantly less rhythmic (regular), more
      distractible (soothable), less approaching (more withdrawing), and less intense
      than standardized norms for full-term infants. From these data we conclude that
      premature infants may be initially more challenging to parent. Temperament
      moderated over time but remained significantly lower in persistence at 12 months.
      Considerable change in temperament in the first 12 months of life may be
      influenced by biological and environmental factors common to the premature birth
      experience.

PMID- 12476074
TI  - Promoting the resiliency of children and families amidst chaos and uncertainty.

PMID- 12476075
TI  - Parental concerns about extended breastfeeding in a toddler.

PMID- 12476076
TI  - Unintentional injury prevention efforts for young children: levels, methods,
      types, and targets.
AB  - Unintentional injury is the leading killer of children in the United States.
      Although many may consider such injuries to be accidents, the majority of
      unintentional injuries are preventable. This article reviews research on programs
      intended to prevent injuries in young children. The article examines levels of
      intervention (e.g., national, community, family, and individual), methods of
      intervention (e.g., legislation, education, and behavioral training), types of
      intervention (e.g., passive and active), and targets of intervention (e.g.,
      families, caregivers, and children). The paper also suggests a means of
      categorizing types of interventions along a numerical continuum from most passive
      to most active.

PMID- 12476077
TI  - Dose response and therapeutic index of inhaled corticosteroids in asthma.
AB  - Inhaled glucocorticoids play an indispensable role in the therapy of asthma.
      Development of new compounds was initially directed to increase the potency of
      the individual corticosteroid; thereafter, pharmacokinetic characteristics were
      modified to reduce unwanted systemic effects. Target of the present development
      is to attain compounds with the most favorable risk-to-benefit ratios. Since
      then, there has been substantial discussion about how to rank and weigh the
      different glucocorticoids. This article provides an evaluation of the relevant
      clinical studies published between May 2001 and June 2002, identifying the main
      determinants of the therapeutic value of inhaled glucocorticoids.

PMID- 12476078
TI  - Airway remodeling and long-term decline in lung function in asthma.
AB  - Asthma is a heterogeneous disease that frequently shows progression of airway
      obstruction. There are indications that ongoing airway inflammation is
      responsible for the more severe hyperresponsiveness, lower lung function, and
      accelerated loss of forced expiratory volume in 1 second. At this moment, we are
      not well informed about the contributing factors to and the exact relation
      between airway inflammation and airway remodeling. Exciting new findings during
      the past years are the potential role of interleukin-13, the further exploration
      of the epithelial-mesenchymal trophic unit, and the presence of degranulated mast
      cells in smooth muscle bundles from the bronchi.

PMID- 12476079
TI  - Asthma remission: does it exist?
AB  - Subjects believed to have grown out of asthma often develop symptoms again later
      in life. Ongoing airway inflammation may determine the risk of relapse, although
      the mechanisms involved are still misunderstood. Additionally, patients with
      asthma during childhood may develop irreversible airflow obstruction ( airway
      remodeling) as a result of chronic airway inflammation. Recently, airway
      inflammation and remodeling could be demonstrated in bronchial biopsy specimens
      from young adults who considered themselves grown out of asthma. It is also shown
      that evidence of airway inflammation and remodeling can be obtained
      noninvasively, thereby providing the opportunity to monitor disease activity. If
      chronic airway inflammation and/or remodeling are consistent findings in
      asymptomatic subjects with a history of atopic asthma, the question arises
      whether natural history can be positively altered with prolonged antiinflammatory
      therapy. Benefits of long-term prognosis are, however, not yet shown. Since
      epidemiologic work has demonstrated that a certain percentage of subjects with
      apparently outgrown atopic asthma remains asymptomatic without needing therapy
      for the rest of their lives, it can be argued that "asthma remission does exist."
      The question is whether this percentage can be increased with prolonged
      antiinflammatory therapy and regular control.

PMID- 12476080
TI  - Interleukin-13 in asthma.
AB  - Some time ago, the Th2 cytokine, interleukin (IL)-13, was identified as a
      critical regulator of the allergic response. Initial studies in animal models of
      disease provided compelling evidence that IL-13, independent from other Th2
      cytokines, was necessary and sufficient to induce all features of allergic
      asthma. This contention was supported in human disease when strong associations
      between IL-13 levels and genetic polymorphisms in the IL-13 gene and disease
      correlates were found. With the preponderance of evidence continuing to support
      the importance of IL-13 in allergic disorders, attention is now turned towards
      understanding the mechanisms by which this cytokine may mediate the
      pathophysiologic features of allergic disease. The emerging paradigm is that IL
      13 induces features of the allergic response via its actions on epithelial and
      smooth muscle cells not through traditional effector pathways involving
      eosinophils and IgE-mediated events. In light of recent developments, this review
      will explore our current understanding of the role of IL-13 in the pathogenesis
      of allergy and asthma with a particular focus on new insights into the mechanisms
      by which IL-13 induces the features of asthma.

PMID- 12476081
TI  - Role of matrix metalloproteinases in asthma.
AB  - Airway inflammation and remodeling are key features of asthma. Matrix
      metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of
      metalloproteinases (TIMPs) are thought to contribute to the pathogenesis of
      asthma via their influence on the function and migration of inflammatory cells as
      well as matrix deposition and degradation. TIMPs bind MMPs in a 1:1 fashion.
      Thus, an increase in the molar ratio of MMP/TIMP may favor tissue injury, while
      the reverse could be associated with increased fibrosis. MMP-9 is the predominant
      MMP in asthma, and its expression is enhanced when patients have spontaneous
      exacerbations or in response to local instillation of allergen in the airway. As
      acute inflammation resolves, MMP-9 levels return toward normal. Interestingly,
      corticosteroids downregulate MMP and enhance TIMPs. Even though it is clear that
      enhanced airway inflammation in asthma is associated with increased expression of
      MMPs, whether specific inhibitors of MMP could reduce airway injury and
      facilitate orderly healing in asthma is still unknown.

PMID- 12476082
TI  - The other cells in asthma: dendritic cell and epithelial cell crosstalk.
AB  - Dendritic cells (DCs) and epithelial cells are the first cells to encounter
      inhaled allergens. The response of these cell types to allergens is fundamentally
      different in asthmatics compared with nonasthmatics. DCs and epithelial cells
      interact through cell-cell interactions and through release of soluble mediators.
      The response of epithelial cells to allergens can profoundly modify the behavior
      of intramucosal DCs. Upon migration to the draining nodes, mucosal DCs undergo
      functional maturation and induce proliferation in naive T cells and primed Th2
      cells. The implications of the DC-epithelial interaction for the pathogenesis of
      asthma is becoming increasingly clear by the use of mouse models and culture
      systems of human cells.

PMID- 12476083
TI  - Acid reflux and asthma.
AB  - The association between asthma and gastroesophageal reflux (GER) has been further
      delineated with recent clinical investigations. The prevalence of GER development
      in asthmatics is higher than in control populations. Furthermore, asthmatics with
      GER have a higher risk of asthma hospitalization. Asthma medications may be one
      of the promoting factors for GER development in asthmatics. Inhaled albuterol
      decreases lower esophageal sphincter (LES) pressure and esophageal contraction
      amplitude. Furthermore, oral prednisone results in increased esophageal acid
      contact times. Respiratory symptoms also correlate with esophageal acid events.
      The role of neurogenic inflammation in asthma-induced bronchoconstriction is also
      being further developed. Therapy of GER may improve asthma outcomes in selected
      asthmatics. Currently, there are no double-blind, placebo-controlled, multicenter
      trials reporting asthma outcomes with antireflux therapy.

PMID- 12476084
TI  - Allergic rhinitis and asthma: the link further unraveled.
AB  - Allergic asthma and rhinitis are manifestations of the atopic syndrome. Although
      the diseases commonly occur together, it is still unclear why some allergic
      patients develop only asthma and others only rhinitis. The reason for the variety
      in clinical expression of allergic airway disease is not known. Besides a genetic
      predisposition, environmental factors contribute to the development of the
      allergic phenotype. Local and systemic inflammatory processes also seem to be
      involved, however, their exact contribution to the clinical picture of airway
      allergy still remains to be elucidated. Although it is clear that the condition
      of the upper airways has an impact on lower airway physiology, the mechanisms
      underlying this relation are far from being resolved. To date, most data point
      towards a systemic link between upper and lower airways, involving bloodstream
      and bone marrow. In this article, the latest developments with regard to
      nasobronchial interaction in allergic airway disease will be reviewed.
      Epidemiologic, experimental and clinical data underline the importance of a
      global approach in allergic rhinitis and asthma.

PMID- 12476085
TI  - Inhaled corticosteroids and leukotriene modifiers in the acute treatment of
      asthma exacerbations.
AB  - Asthma exacerbation has a considerable impact on patients' quality of life and
      constitutes a challenging condition for primary health-care providers. Severe
      exacerbations are also an important cause of hospital admissions and require high
      costs. Despite this, a widely accepted definition is still lacking; etiologic and
      pathogenetic mechanisms are still incompletely defined. Although the efficacy of
      inhaled corticosteroids (ICS) and leukotriene modifiers in preventing mild to
      moderate asthma exacerbation is well recognized, their role within the context of
      an asthma action plan in general practice and in home-based early intervention
      for acute exacerbations is still controversial. Although systemic corticosteroids
      (CS) are standard care for severe exacerbation in the emergency department's (ED)
      management of asthma, published evidence suggests that high doses of ICS may be
      beneficial in the ED. The additive benefit of ICS when used with systemic CS is
      still debated. Data on leukotriene modifiers in the management of asthma
      exacerbation are limited. However, therapeutic strategies of this emergency
      including ICS and leukotriene modifiers seem logical and may be suitable, at
      least in certain patient groups. The availability of different drugs, active on
      different targets, can potentially contribute to a better management of asthma
      exacerbations.

PMID- 12476086
TI  - Theophylline and PDE4 inhibitors in asthma.
AB  - Over the past three decades, beta -adrenoceptor agonists and glucocorticosteroids
      have formed the mainstay of treatment for patients with asthma; during this time,
      only one new drug class, leukotriene receptor antagonists, have been introduced.
      Theophylline has also been used in the treatment of patients with asthma,
      although there is a perception that this drug does not offer the patient any
      advantages over conventional therapeutic strategies. However, a number of
      clinical studies have documented the efficacy of this orally active drug. The
      mechanism by which theophylline exerts its well recognized antiinflammatory
      activity remains to be established but, if explained, could lead to newer drug
      development with greater efficacy. The development of phosphodiesterase (PDE)4
      inhibitors is one such approach, and recent studies have demonstrated the
      potential utility of this new drug class for the treatment of patients with
      asthma.(2)

PMID- 12476088
TI  - Neurophysiology of cochlear implant users I: effects of stimulus current level
      and electrode site on the electrical ABR, MLR, and N1-P2 response.
AB  - OBJECTIVE: As the need for objective measures with cochlear implant users
      increases, it is critical to understand how electrical potentials behave when
      stimulus parameters are systematically varied. The purpose of this study was to
      record and evaluate the effects of implanted electrode site and stimulus current
      level on latency, amplitude, and threshold measures of electrically evoked
      auditory potentials, representing brainstem and cortical levels of the auditory
      system. DESIGN: The electrical auditory brainstem response (EABR), electrical
      auditory middle latency response (EAMLR), and the electrical late auditory
      response (ELAR) were recorded from the same experimental subjects, 11 adult
      Clarion cochlear implant users. The Waves II, III, and V of the EABR, the Na-Pa
      complex of the EAMLR and the N1-P2 complex of the ELAR were investigated relative
      to electrode site (along the intra-cochlear electrode array) and stimulus current
      level. Evoked potential measures were examined for statistical significance using
      analysis of variance (ANOVA) for repeated measures. RESULTS: For the EABR, Wave V
      latency was significantly longer for the basal electrode (7) compared with the
      mid (4) and apical (1) electrodes. For the EAMLR and ELAR, there were no
      significant differences in latency by electrode site. For all subjects and each
      of the evoked potentials, the apical electrodes tended to have the largest
      amplitude and the basal electrodes the smallest amplitude, although amplitude
      differences did not reach statistical significance. In general, decreases in
      stimulus current level resulted in statistically significant decreases in the
      amplitude of Wave V, Na-Pa and N1-P2. The evoked potential thresholds for Wave V,
      Na-Pa, and N1-P2 were significantly higher for the basal Electrode 7 than for
      Electrodes 4 and 1. CONCLUSIONS: Electrophysiologic responses of Waves II, III,
      and V of the EABR, Na-Pa of the EAMLR, and N1-P2 of the ELAR were characterized
      as functions of current level and electrode site. Data from this study may serve
      as a normative reference for expected latency, amplitude and threshold values for
      the recording of electrically evoked auditory brainstem and cortical potentials.
      Responses recorded from cochlear implant users show many similar patterns, yet
      important distinctions, compared with auditory potentials elicited with acoustic
      signals.

PMID- 12476089
TI  - Neurophysiology of cochlear implant users II: comparison among speech perception,
      dynamic range, and physiological measures.
AB  - OBJECTIVE: The overall objective of this study was to relate electrically evoked
      potentials recorded from different levels of the auditory pathway with behavioral
      measures obtained from adult cochlear implant subjects. The hypothesis was that
      adult recipients of cochlear implants who have open-set speech perception and
      those recipients with no open-set speech perception would differ in their
      neurophysiologic responses recorded at one or more levels of the auditory
      pathway. DESIGN: The subjects were 11 adults implanted with the Clarion cochlear
      implant. The electrical auditory brainstem response (EABR, Wave V), electrical
      auditory middle latency response (EAMLR, Na-Pa complex), and the electrical late
      auditory response (ELAR, N1-P2 complex), were recorded from three intra-cochlear
      electrodes. The stimuli used to record the evoked potentials varied in rate and
      amplitude. Behavioral measures (between threshold and upper limit of comfortable
      loudness) were used to define the subject's dynamic range at the different
      stimulus rates. Word and sentence recognition tests evaluated subjects' speech
      perception in quiet and noise. Evoked potential and behavioral measures were
      examined for statistical significance using analysis of variance for repeated
      measures and correlational analyses. RESULTS: Subjects without open-set speech
      recognition demonstrated 1) poorly formed or absent evoked potential responses,
      2) reduced behavioral dynamic ranges, 3) lack of change in the size of the
      dynamic range with a change in stimulus rate, and 4) longer periods of auditory
      deprivation. The variables that differentiated the best performers included 1)
      presence of responses at all three levels of the auditory pathway, with large
      normalized amplitudes for the EAMLR, 2) lower evoked potential thresholds for the
      Na-Pa complex, 3) relatively large dynamic ranges, and 4) changes in the size of
      the dynamic range with changes in stimulus rate. CONCLUSIONS: In this study, the
      inability to follow changes in the temporal characteristics of the stimulus was
      associated with poor speech perception performance. Results also illustrate that
      variability in speech perception scores of cochlear implant recipients relates to
      neurophysiologic responses at higher cortical levels of the auditory pathway.
      Presumably, limited neural synchrony for elicitation of electrophysiologic
      responses underlies limited speech perception. Results confirm that neural
      encoding with electrical stimulation must provide sufficient physiologic
      responses of the central nervous system to perceive speech through a cochlear
      implant.

PMID- 12476090
TI  - A sensitive period for the development of the central auditory system in children
      with cochlear implants: implications for age of implantation.
AB  - OBJECTIVE: The aim of the present experiment was to assess the consequences of
      cochlear implantation at different ages on the development of the human central
      auditory system. DESIGN: Our measure of the maturity of central auditory pathways
      was the latency of the P1 cortical auditory evoked potential. Because P1
      latencies vary as a function of chronological age, they can be used to infer the
      maturational status of auditory pathways in congenitally deafened children who
      regain hearing after being fit with a cochlear implant. We examined the
      development of P1 response latencies in 104 congenitally deaf children who had
      been fit with cochlear implants at ages ranging from 1.3 yr to 17.5 yr and three
      congenitally deaf adults. The independent variable was the duration of deafness
      before cochlear implantation. The dependent variable was the latency of the P1
      cortical auditory evoked potential. RESULTS: A comparison of P1 latencies in
      implanted children with those of age-matched normal-hearing peers revealed that
      implanted children with the longest period of auditory deprivation before
      implantation-7 or more yr-had abnormal cortical response latencies to speech.
      Implanted children with the shortest period of auditory deprivation-approximately
      3.5 yr or less-evidenced age-appropriate latency responses within 6 mo after the
      onset of electrical stimulation. CONCLUSIONS: Our data suggest that in the
      absence of normal stimulation there is a sensitive period of about 3.5 yr during
      which the human central auditory system remains maximally plastic. Plasticity
      remains in some, but not all children until approximately age 7. After age 7,
      plasticity is greatly reduced. These data may be relevant to the issue of when
      best to place a cochlear implant in a congenitally deaf child.

PMID- 12476091
TI  - Speech understanding in noise with a Med-El COMBI 40+ cochlear implant using
      reduced channel sets.
AB  - OBJECTIVE: The objective of the investigation described in this paper was the
      determination of the number of (widely spaced) active electrodes needed for users
      of a COMBI 40+ cochlear implant to achieve asymptotic performance in the
      recognition of speech against a background of wideband noise. DESIGN: This study
      measured the performance in speech tests of patients using the Med-El
      implementation of continuous interleaved sampling with widely spaced electrode
      pair subsets of 2, 3, 4, 6, 8, and 10 out of a possible maximum of 12. An eight
      vowel test, a 16-consonant test, and BKB sentences were presented against a
      background of pink noise. Additionally, AB monosyllabic words were presented both
      in quiet and in noise to processors with 6, 8, and 11 widely spaced electrodes.
      11 subjects participated in the study. RESULTS: Using moderate signal-to-noise
      ratios, for these patients the curve relating percentage score to increasing
      numbers of active channels approached an asymptote before the 10-channel data
      point was reached. Asymptotic performance was achieved using four channels for
      consonants, and eight channels for sentences. Understanding of monosyllabic words
      reached a maximum value at a similar number of channels for both quiet conditions
      and against a background of pink noise, and the mean increase in test score
      between 6 and 11 channels was only 7%. CONCLUSIONS: These results are similar to
      those of previous experiments carried out in quiet listening conditions. The data
      suggest that 12 frequency channels (the number implemented by the COMBI 40+
      cochlear implant) are more than adequate for users to achieve asymptotic
      performance levels in clinical speech tests applied in the presence of wideband
      noise at moderate signal-to-noise ratios.

PMID- 12476092
TI  - Variability in fluorescein angiography interpretation for photodynamic therapy in
      age-related macular degeneration.
AB  - OBJECTIVES: To investigate the variability in fluorescein angiography
      interpretation for photodynamic therapy in age-related macular degeneration.
      METHODS: Eight graders, who included two TAP-certified ophthalmologists, three
      other retinal specialists, two fellows in vitreoretinal diseases, and a senior
      fundus photograph grader, evaluated fluorescein angiograms of six patients
      treated according to the Treatment for ARMD With Verteporfin (TAP) protocol at a
      single center. Each patient's baseline angiogram was evaluated to determine
      whether the CNV lesion was predominantly (> or =50%) classic. For each follow-up
      angiogram, at 3, 6, 12, and 24 months, the grader was required to determine
      whether fluorescein leakage was present. Six months after the initial gradings,
      each reader was again presented with the baseline angiogram for each patient and
      once again asked to determine whether the CNV lesion was predominantly classic
      without knowledge of the previous grading. All gradings were performed without
      knowledge of the clinical course. RESULTS: In grading initial visit and follow-up
      visit angiograms, the overall concordance rates were 81% and 82%, respectively.
      Concordance rates were not statistically different between the group as a whole
      when compared with the gradings of the two TAP-certified ophthalmologists. When
      initial visit angiograms were regraded, an intraobserver variability of 17% was
      noted. Overall, gradings were discordant with the majority opinion in
      approximately 19% of decisions. CONCLUSIONS: Considerable variability can be
      expected in fluorescein angiography interpretation as the results of the TAP
      investigation are applied to clinical practice.

PMID- 12476093
TI  - Duration of skin photosensitivity and incidence of photosensitivity reactions
      after administration of verteporfin.
AB  - BACKGROUND: Verteporfin (Visudyne, Novartis AG) is a light-activated drug that
      reduces the risk of vision loss in patients with certain types of choroidal
      neovascularization (CNV). Because photosensitivity can occur with
      photosensitizers, it is important for ophthalmologists providing verteporfin
      therapy to understand its time course and duration, as well as the incidence of
      photosensitivity reactions. METHODS: Data were obtained from three sources: 1)
      the time course of skin photosensitivity in 17 volunteers by measuring
      erythema/edema over time after verteporfin, using red light exposure; 2) the
      duration of skin photosensitivity in 30 patients with skin cancer by exposing
      skin to simulated solar light and calculating the daily minimal erythematous
      dose; and 3) the incidences of photosensitivity reactions as recorded in three
      phase III trials in patients with CNV secondary to age-related macular
      degeneration or pathologic myopia who received the regimen of verteporfin therapy
      currently approved by regulatory authorities (infusion of 6 mg/m(2) body surface
      area). RESULTS: 1) Skin photosensitivity was high at the first timepoint of 1.5
      hours after dosing and decreased rapidly thereafter; 2) the duration of skin
      photosensitivity was dose dependent, ranging from 2.0 to 6.7 days at 6 to 20
      mg/m(2), respectively (mean of 2 days at a dose of 6 mg/m(2)); and 3)
      photosensitivity reactions occurred in only 2.2% of patients in the phase III
      trials, including two severe events, one secondary to extravasation. All
      treatment-related reactions in the phase III trials occurred within the first 2
      days after dosing, with the exception of two mild reactions and one moderate
      reaction that occurred 3 days after treatment. CONCLUSIONS: Verteporfin is
      associated with short-lived photosensitivity and a low incidence of
      photosensitivity reactions in clinical trials, most of which could probably have
      been avoided by adherence to protocol instructions for skin protection.

PMID- 12476094
TI  - Ring melanoma of the ciliary body: report on twenty-three patients.
AB  - BACKGROUND: Ring melanoma of the ciliary body is a rare variant of uveal melanoma
      that has a poor prognosis. Only isolated cases have been reported in the
      literature. METHODS: A retrospective review of the clinical features, management,
      histopathology, and prognosis of 23 consecutive patients with ring melanoma of
      the ciliary body was performed. RESULTS: Of 8,800 patients with uveal melanoma
      treated on the Oncology Service at Wills Eye Hospital over a 25-year period, only
      23 patients (0.3%) were found to have ring melanoma of the ciliary body. The mean
      patient age was 59 years (median, 63 years; range, 8-81 years). The only visual
      symptom was blurred vision in 17 patients (74%), and the other six patients (26%)
      were asymptomatic. At the initial presentation elsewhere, melanoma was recognized
      in 13 cases (57%). In the remaining 10 cases (43%), the initial clinical
      diagnosis was glaucoma in three (13%), iris nevus in three (13%), cataract in two
      (9%), ciliary body detachment in one (4%), and iridocyclitis in one (4%). The
      patients were observed elsewhere for a mean of 3 months before the diagnosis of
      melanoma was suspected and referral to Oncology Service was made. On examination,
      the tumor involved a mean of eight clock hours of the ciliary body. Seven
      patients (30%) had complete circumferential (360 degrees) involvement of the
      ciliary body, and 16 (70%) had incomplete (180-360 degrees) ring involvement. The
      mean tumor thickness was 8 mm. Associated findings included neovascularization of
      the iris in one case (4%), shallow anterior chamber in 11 (48%), anterior chamber
      inflammation in five (22%), cataract in nine (39%), lens indentation in eight
      (35%), and lens subluxation in three (13%). A prominent episcleral (sentinel)
      vessel (17 cases, 74%), multilobulation of the mass (19 cases, 83%), blockage of
      light on transillumination (23 cases, 100%), and ultrasonographic hollowness with
      intrinsic pulsations (23 cases, 100%) were important features differentiating
      this tumor from simulating conditions. The tumor was managed with enucleation in
      all 23 patients. Histopathologic studies revealed epithelioid cell-type melanoma
      in two patients (9%), mixed cell-type in 17 (74%), and spindle cell-type in four
      (17%). Extraocular extension was present in eight patients (35%). Metastasis
      developed in 12 of 23 patients (52%) after a mean follow-up of 55 months.
      CONCLUSIONS: Ring melanoma of the ciliary body is a rare tumor that can remain
      hidden from ophthalmoscopic examination. Certain features, such as prominent
      episcleral sentinel vessels, multilobulation of the mass, light blockage on
      transillumination, and ultrasonographic hollowness with intrinsic vascular
      pulsations, suggest the diagnosis. The life prognosis is poor.

PMID- 12476095
TI  - Fine needle aspiration biopsy (FNAB) for retinoblastoma.
AB  - PURPOSE: To determine the incidence of diagnostic fine needle aspiration biopsy
      (FNAB) in eyes with retinoblastoma (RB) as well as its indications and potential
      complications. METHODS: A retrospective study by survey was designed and a
      questionnaire inquiring on FNAB use in RB diagnosis during the past 15 years was
      submitted to 12 high-volume ocular oncology clinics. RESULTS: A total of 3,651
      patients with RB have been diagnosed and treated in 12 clinics since 1985. During
      the same period, eight biopsies were obtained for diagnostic purposes and six of
      these proved to be RB by cytology; the other two showed inflammatory cells and
      benign retinal cells. The median age for the biopsied patients was 46 months; 6
      of the biopsied children were older than 4 years of age. The average age at the
      time of biopsy was 46 months. Most of the cases were biopsied with clinical
      diagnosis of uveitis/endophthalmitis through the limbus and pars plana with 25-
      and 27-gauge needles. Five of six cases of RB had enucleation and one patient had
      cryotherapy and I-125 brachytherapy after FNAB. The average follow-up time for
      biopsy-proven RB cases was 10.8 years with no recurrent disease. CONCLUSION: The
      results of this survey suggest that FNAB indication for RB diagnosis is rare; the
      majority of cases can be diagnosed and treated by ocular oncologists without
      invasive procedures.

PMID- 12476096
TI  - Iatrogenic choroidal neovascularization occurring in patients undergoing macular
      surgery.
AB  - PURPOSE: To report three cases of choroidal neovascularization (CNV) that
      occurred following surgical disruption of Bruch membrane during macular surgery.
      METHODS: A retrospective case series was compiled. Macular translocation surgery
      with punctate retinotomy was performed in two patients for subfoveal CNV, and
      pars plana vitrectomy with epiretinal membrane (ERM) peeling was performed in one
      patient for idiopathic ERM. RESULTS: CNV developed at a site of subretinal
      cannulation in two cases of macular translocation, and at a site of inadvertent
      injury to Bruch membrane with a vitreoretinal pick in the one case that underwent
      ERM peeling. CONCLUSIONS: These cases underscore the need to monitor breaks in
      Bruch membrane for CNV following macular surgery.

PMID- 12476097
TI  - Peripheral retinoschisis and exudative retinal detachment in pars planitis.
AB  - PURPOSE: To review and describe bullous retinoschisis and exudative retinal
      detachment in patients with pars planitis. METHODS: Retrospective, multicenter
      study of patients with pars planitis who presented with retinoschisis and
      exudative retinal detachments. RESULTS: The authors describe 13 eyes of 9
      patients with pars planitis who presented with inferior peripheral retinoschisis
      and/or exudative retinal detachment. Four patients were male; five were female.
      Patients' ages ranged from 8 years to 35 years (median, 12 years). The follow-up
      interval ranged from 1 month to 10 years (median, 4 years). These peripheral
      retinal elevations had a tendency to remain stable, although those with
      telangiectatic vessels or vasoproliferative tumors occasionally demonstrated an
      increase in accumulation of exudate. Treatment of such eyes with cryotherapy, or
      low-dose plaque radiotherapy, resulted in vasoproliferative tumor and
      telangiectatic vessel regression, absorption of the hard exudate, and resolution
      of the retinal elevation in four of five eyes. One patient had spontaneous
      regression of the retinoschisis cavity over a 4-year period. CONCLUSION: Patients
      with pars planitis may present with bullous retinoschisis and/or exudative
      retinal detachment. These findings may be related to a Coats disease-like
      vascular response (telangiectatic vessels and vasoproliferative tumors) secondary
      to chronic inflammation. Treatment of the vascular leakage tended to result in
      resolution of the detachment and/or schisis.

PMID- 12476098
TI  - Office-based sutureless transconjunctival pars plana vitrectomy.
AB  - PURPOSE: This is a preliminary report to describe our technique of office-based
      vitrectomy (OVIT) and to report the incidence of complications over a 6-year
      period. METHODS: In a retrospective, noncomparative case series, OVIT was
      performed on 225 patients in four participating offices. Each patient was
      operated on with a 23-gauge vitreous cutter that the authors have developed. They
      have also developed a 23-gauge transconjunctival infusion needle device.
      Diagnoses included endophthalmitis, uveitis, intravitreal lens fragments, ghost
      cell glaucoma, and rhegmatogenous retinal detachment. RESULTS: The surgical goal
      was accomplished in all cases, but supplemental office procedures were required
      for two eyes, and a scleral buckle was necessary in one eye. There were 15
      complications in 14 eyes: "fish-egg" gas bubbles (one eye), intraocular
      hemorrhage (nine eyes), choroidal detachment (two eyes), new retinal breaks (one
      eye), retinal detachment (one eye), and temporary elevation of intraocular
      pressure (one eye). The hemorrhages, choroidal detachments, and fish-egg bubbles
      all resolved spontaneously. CONCLUSION: Office-based sutureless transconjunctival
      pars plana vitrectomy, with infusion when needed, is an effective operation for
      selected diseases of the posterior segment. In a multicenter series of 225 eyes,
      there were 15 complications in 14 (6%) eyes. Two of the complications were
      successfully managed with additional office procedures; one was managed in the
      operating room; and 12 resolved spontaneously.

PMID- 12476099
TI  - Postoperative laser coagulation as retinopexy in patients with rhegmatogenous
      retinal detachment treated with scleral buckling surgery: a prospective clinical
      study.
AB  - PURPOSE: To evaluate postoperative laser photocoagulation as retinopexy mode in
      patients with rhegmatogenous retinal detachment treated with scleral buckling
      surgery. METHODS: The authors conducted a prospective feasibility study of
      consecutive patients with rhegmatogenous retinal detachment treated with scleral
      buckling surgery and postoperative laser during an 18-month period with a minimal
      follow-up of 6 months. Outcome measures were total retinal reattachment and the
      occurrence of proliferative vitreoretinopathy (PVR). RESULTS: A total of 123
      patients (124 eyes) were included in this study. Seventy-six percent were phakic
      and 24% were pseudophakic. Fifty percent presented with one horseshoe tear, 15%
      with multiple tears, 30% with round breaks, and 5% with no identifiable break.
      Ten percent presented with a vitreous hemorrhage and 25% with three or four
      quadrants of detached retina. Six patients had PVR C1. Twelve patients required a
      postoperative gas injection, five patients received an additional buckle, and
      five patients underwent a vitrectomy, in four because of PVR. In all patients the
      retina was fully reattached at the end of follow-up. Planned postoperative laser
      coagulation took place 1 day to 10 weeks (median 3(1/2) weeks) after buckling
      surgery. Buckling material was removed in three patients without redetachment.
      CONCLUSION: Postoperative laser coagulation is a feasible alternative retinopexy
      mode in scleral buckling surgery, with encouraging anatomical results and a low
      incidence of PVR.

PMID- 12476100
TI  - Vitrectomy with arteriovenous decompression and internal limiting membrane
      dissection in branch retinal vein occlusion.
AB  - PURPOSE: The therapeutic armamentarium for functional improvement after branch
      retinal vein occlusion (BRVO) is limited with uncertain efficacy. Some surgeons
      have proposed surgical decompression of the vein at the arteriovenous (AV)
      crossing. METHODS: Forty-three patients with BRVO were treated in the authors'
      department from August 1999 to April 2001 with AV decompression. Twenty-five
      patients with comparable BRVO who refused this surgical intervention served as a
      control group. All 68 patients received an isovolemic hemodilution therapy for 10
      days. The surgical procedure consisted of a standard pars plana vitrectomy and
      separation of the overlying artery from the vein using microscissors. In 16 cases
      dissection of the internal limiting membrane (ILM) in the macular area and around
      the AV crossing was also performed. Assessment of visual acuity, fluorescein
      angiography, and multifocal electroretinography were performed preoperatively and
      6 weeks after surgery in seven patients. RESULTS: Surgical procedure and
      postoperative course were uneventful. In most of the treated eyes visual acuity
      improved and fluorescein angiography revealed capillary reperfusion. Functional
      results in patients with AV decompression were highly significantly better than
      in the control group. Furthermore, removal of the ILM seems to have an additional
      beneficial effect on the functional outcome. CONCLUSION: These results
      demonstrate the therapeutic effect of surgical AV decompression in BRVO.
      Additional removal of the ILM seems to improve the functional results. Further
      experience may answer some open questions.

PMID- 12476101
TI  - Evaluating outpatient versus inpatient costs in endophthalmitis management.
AB  - PURPOSE: To assess the cost savings that would result from 1) implementing the
      treatment guidelines of the Endophthalmitis Vitrectomy Study (EVS) and 2)
      performing procedures on an outpatient rather than an inpatient basis, and to
      compare the savings to the cost of conducting the EVS. METHODS: The coding
      algorithms for four endophthalmitis treatment groups were obtained from Patient
      Financial Services at the Anne Bates Leach Eye Hospital (ABLEH) and national
      Medicare averages were consulted for reimbursements in 2000 dollars. The four
      groups were: 1) inpatient pars plana vitrectomy (PPV) with intravenous
      antibiotics; 2) outpatient PPV; 3) inpatient vitreous tap with intravenous
      antibiotics; and 4) outpatient vitreous tap. Physician reimbursements were
      calculated using International Classification of Diseases-9 (ICD-9) diagnoses and
      Current Procedural Terminology (CPT) codes. Facility reimbursements were
      calculated using ICD-9 diagnoses and Diagnosis-Related Group codes for inpatient
      procedures versus Ambulatory Payment Classification codes for outpatient
      procedures. The annual savings in reimbursements were estimated for a range of
      annual incidence rates of endophthalmitis assuming ABLEH financial data across
      all patients in the United States, and the savings into the future as well as the
      total expenses of conducting the EVS from 1989 to 1995 were summed in 2000
      dollars using a net present value analysis based on the Bureau of Labor
      Statistics consumer price indices. RESULTS: Facility reimbursements are
      significantly higher for procedures performed on an inpatient compared to an
      outpatient basis (P < 0.001). Treating endophthalmitis according to the EVS
      guidelines on an outpatient basis would be associated with an estimated $1.5 to
      $7.8 million reduction in reimbursements per year. The cost of the EVS in 2000
      dollars was $4.0 million. CONCLUSIONS: Implementing the treatment guidelines of
      the EVS on an outpatient basis may result in significant cost savings--savings
      that may cover the entire cost of the EVS in 3 years.

PMID- 12476102
TI  - Diabetic papillopathy in type II diabetic patients.
AB  - PURPOSE: To evaluate the patient characteristics and fundus findings of patients
      with type II diabetes presenting with diabetic papillopathy. METHODS: The authors
      retrospectively reviewed the medical records of 3,235 patients with diabetes
      followed in their institution since 1986 and identified the patients with
      unilateral or bilateral transient disk swelling and without significant
      deterioration of best-corrected visual acuity. The authors investigated patient
      demographics, symptoms, fundus findings, ancillary test results, and clinical
      course of those patients. RESULTS: Twenty-four eyes of 16 patients with type II
      diabetes mellitus met the criteria. Patients had a mean age of 57.1 (+/-8.8)
      years and had diabetes mellitus of long duration (mean 10.0 +/- 8.6 years).
      Approximately half of the patients had poor metabolic control. Disk swelling was
      bilateral in 8 (50%) patients and resolved in an average of 7.8 +/- 3.7 months. A
      total of 13 (54%) eyes had nonproliferative and 2 (8%) eyes had proliferative
      diabetic retinopathy at presentation. In 4 (17%) eyes retinopathy progression
      into the proliferative stage occurred and panretinal photocoagulation was
      performed. CONCLUSIONS: Diabetic papillopathy may be found in older patients with
      type II diabetes. Nonproliferative or proliferative diabetic retinopathy as well
      as macular edema may also be associated with this disorder.

PMID- 12476103
TI  - Retinal thickness in diabetic retinopathy: a study using optical coherence
      tomography (OCT).
AB  - BACKGROUND AND OBJECTIVE: The authors conducted a controlled study to quantify
      macular retinal thickness in diabetic retinopathy using optical coherence
      tomography (OCT) as an objective and noninvasive tool. The relationship between
      retinal thickness and standard methods of evaluating macular edema was
      investigated. PATIENTS AND METHODS: A total of 136 patients in different stages
      of diabetic retinopathy were examined with OCT. In addition, fluorescein
      angiograms as well as standard eye examinations were conducted. The control group
      consisted of 30 individuals with a normal macula. RESULTS: In the controls,
      retinal thickness was 153 +/- 15 microm in the fovea, 249 +/- 19 microm in the
      temporal parafoveal region, and 268 +/- 20 microm in the nasal parafoveal region.
      In diabetic patients, retinal thickness was increased to 307 +/- 136 microm in
      the fovea, 337 +/- 88 microm in the temporal retina, and 353 +/- 95 microm in the
      nasal retina, respectively. The differences between diabetics and controls were
      highly significant (P < 0.001). Retinal thickening correlated with fluorescein
      leakage in the angiograms to some extent. There was an intermediate correlation
      between retinal thickness and visual acuity, particularly in patients without
      macular ischemia. Sensitivity of detecting clinically significant macular edema
      by measuring foveal retinal thickness was 89% and specificity was 96%.
      CONCLUSION: Optical coherence tomography allows us to quantify retinal thickness
      in diabetic retinopathy with excellent reproducibility. OCT is able to detect
      sight-threatening macular edema with great reliability.

PMID- 12476104
TI  - Retinal thickness analysis(RTA): an objective method to assess and quantify the
      retinal thickness in healthy controls and in diabetics without diabetic
      retinopathy.
AB  - BACKGROUND: Since it has been shown that photocoagulation is indicated in
      patients with diabetic macular edema, quantitative and objective assessment of
      retinal thickness is of clinical importance. METHODS: A laser slit beam was
      projected on the retina and scanned across a 2 x 2 mm retinal area in 200 msec.
      Nine type 1 and 2 diabetic patients without funduscopically and photographically
      visible diabetic retinopathy and 10 healthy controls were scanned with the RTA.
      The intraindividual and interindividual variabilities of the RTA were determined.
      RESULTS: The intraindividual and interindividual variability was 5 microm and 15
      microm, respectively. The mean value of the mean foveal thickness (MFT) and
      perifoveal retinal thickness (PFT) in the 10 healthy controls was 152 +/- 15
      microm and 175 +/- 14 microm, respectively, and 181 +/- 26 microm and 191 +/- 27
      microm, respectively, in the group of nine diabetics without signs of diabetic
      retinopathy. The MFT in the group of diabetic patients was significantly (P <
      0.001) larger than in the control groups. CONCLUSION: Retinal thickness in
      diabetic patients without diabetic retinopathy was increased in all measurements
      in comparison with the findings in healthy subjects. Retinal thickness
      measurements with the RTA could possibly detect early signs of diabetic
      retinopathy before funduscopic and photographic signs are visible and may be
      helpful in guiding treatment.

PMID- 12476105
TI  - Effect of squalamine on iris neovascularization in monkeys.
AB  - PURPOSE: To investigate the effect of squalamine, an antiangiogenic aminosterol,
      in an experimental model of iris neovascularization. METHODS: Iris
      neovascularization was created in cynomolgus monkeys by occluding retinal veins
      with an argon laser and inducing persistent hypotony with a central corneal
      suture. Twenty-four eyes were treated in three groups. In Group 1, four eyes were
      injected intravitreally with 3 microg/0.1 mL squalamine and four eyes with
      balanced saline solution (controls) immediately after vein occlusion (day 1);
      injections were repeated every 3 days for 3 weeks. In Group 2, 1 mg/kg squalamine
      was administered with intravenous infusion in dextrose 5% in four animals; four
      control animals received only dextrose. Infusions began on day 1 and were
      repeated every 3 days for 3 weeks. In Group 3, after development of iris
      neovascularization on day 7, 1 mg/kg squalamine was injected systemically in four
      animals; four control animals received dextrose 5%. Monkeys were examined by slit
      lamp biomicroscopy and underwent color photography and fluorescein angiography.
      RESULTS: Group 1: All eyes, treated and control, developed intense and persistent
      rubeosis iridis. Group 2: Two of the four treated eyes in this group developed
      minimal iris neovascularization; the other two had no iris neovascularization.
      All four control eyes developed intense, persistent iris neovascularization.
      Group 3: All eyes developed extensive rubeosis iridis; iris neovascularization
      regressed in all four treated eyes after squalamine injections. Two of four
      treated eyes retained minimal iris neovascularization; two showed complete
      regression of rubeosis iridis. Rubeosis iridis completely regressed in two of the
      four control eyes; the remaining two control eyes had intense, persistent iris
      neovascularization. CONCLUSIONS: Intravitreally injected squalamine did not
      affect the development of iris neovascularization; however, systemic squalamine
      injection inhibited the development of iris neovascularization and caused partial
      regression of new vessels in a primate model.

PMID- 12476106
TI  - Diagnostic and therapeutic challenges.

PMID- 12476107
TI  - Consecutive central retinal artery and vein occlusions in primary
      antiphospholipid syndrome.

PMID- 12476108
TI  - Macular translocation in nonexudative age-related macular degeneration.

PMID- 12476109
TI  - Retinal pigment epithelial changes after indocyanine green-assisted vitrectomy.

PMID- 12476110
TI  - Raman spectroscopy: noninvasive determination of silicone oil in the eye:
      potential applications for intraocular determination of biomaterials.

PMID- 12476111
TI  - Successful treatment of fungal retinitis and retinal vasculitis with oral
      itraconazole.

PMID- 12476112
TI  - PCR-aided diagnosis of fungal chorioretinitis following ingestion of traditional
      Chinese medication.

PMID- 12476113
TI  - Spontaneous regression of metastatic cutaneous melanoma to the choroid.

PMID- 12476114
TI  - Ocular manifestations of remote lightning strike.

PMID- 12476116
TI  - Metastatic breast carcinoma to the retina: optical coherence tomography findings.

PMID- 12476115
TI  - Mushroom-shaped choroidal metastasis simulating a choroidal melanoma.

PMID- 12476117
TI  - Needle drainage of subretinal fluid under ophthalmoscopic visualization.

PMID- 12476118
TI  - Retinal translocation and photodynamic therapy for age-related macular
      degeneration with classic choroidal neovascularization: a clinicopathologic case
      report.

PMID- 12476119
TI  - Visual improvement after pars plana vitrectomy and membrane peeling for
      vitreoretinal traction associated with combined hamartoma of the retina and
      retinal pigment epithelium.

PMID- 12476121
TI  - Radial optic neurotomy for central retinal vein occlusion.

PMID- 12476120
TI  - Intraocular metastasis of pancreatic cancer: report of two cases.

PMID- 12476122
TI  - Combined vitrectomy lens and contact electrode for erg recording during surgery.

PMID- 12476123
TI  - Retinal hemorrhages following indirect ocular trauma in a patient with angioid
      streaks.

PMID- 12476124
TI  - One in three people concerned about draft mental health Bill.

PMID- 12476125
TI  - If nursing's profile is to be raised it must be assertive.

PMID- 12476126
TI  - Research nurse who falsified the results of research.

PMID- 12476127
TI  - The appropriate use of gloves to reduce allergies and infection.
AB  - Twenty years ago, the wearing of gloves for non-sterile procedures was viewed as
      insulting to the patient as it made him/her feel 'unclean'. Today, gloves are
      worn for all procedures and are often wastefully used. There must be a fine
      balance between inappropriate and appropriate use of gloves and between the use
      of latex gloves for comfort and fine movements vs the potential for latex
      allergies. This article will review the use of synthetic and latex gloves and
      examine some of the related issues.

PMID- 12476128
TI  - Statutory duties under the Occupiers' Liability Act 1957.
AB  - Case Scenario: Aubretia was a community nurse working for the Roger Park Hospital
      and her list of patients included some who lived on a very deprived estate. She
      was visiting one elderly person when she fell through a rotten floorboard and
      sustained severe injuries to her leg. She was admitted to hospital and was off
      work for several weeks. She is anxious to obtain compensation and seeks legal
      advice.

PMID- 12476129
TI  - Establishing breach of the duty of care in the tort of negligence.
AB  - This article, the third in a series on clinical negligence, looks at the law
      surrounding breach of the duty of care in negligence. It shows some of the
      principles that judges and lawyers use in order to decide whether a person has
      broken his/her duty of care in the tort of negligence. It will be seen that the
      principles are contained in decided court cases, some of which are quite old but
      are still relevant today. The focus of this article is on the rule that courts,
      in deciding the issue of a breach of duty of care, would judge the defendant's
      conduct by the standard of what the hypothetical, 'reasonable person' would have
      done in the circumstances of the case.

PMID- 12476130
TI  - Ethics and children's rights: learning from past mistakes.
AB  - The primary aim of this article is to examine, within the context of recent
      controversial child health practice and research, the underlying philosophy of
      the aspect of the Nursing and Midwifery Council's Code of Professional Conduct
      which states that: 'You are personally accountable for ensuring that you promote
      and protect the interests and dignity of patients and clients, irrespective of
      gender, age, race, ability, sexuality, economic status, lifestyle, culture and
      religious or political belief.' A description of the Nuremberg Code, the Helsinki
      Declaration, the United Nations Convention on the Rights of the Child, and the
      Human Rights Act 1998 will form the backdrop to this article and a range of
      contemporary examples will be used to illuminate the ethical dilemmas facing
      children's nurses in their day-to-day work. Within this context the four major
      principles that underpin healthcare this will be investigated and the legacy of
      historical unethical practice and research acknowledged. The vulnerability of
      children and their families to potential coercion, and the role of local research
      ethics committees, will be discussed.

PMID- 12476131
TI  - Attitudes of registered nurses and student nurses to disabled children.
AB  - The purpose of this study was to examine and compare the attitudes of registered
      nurses and student nurses towards disabled children. A convenience sample
      consisting of 99 registered nurses employed in paediatric hospitals and 189
      student nurses was selected. The instrument used for data collection was the
      'Attitudes Towards Disabled Persons' (ATDP) scale. Descriptive statistics and one
      way analysis of variance were performed to test for significant differences. On
      the whole subjects' attitudes appeared to be poor. Student nurses had more
      positive attitudes in comparison to registered nurses; however, the difference
      was not statistically significant. There were significant differences between the
      different age groups and between student groups within different education
      settings. There were no significant differences in gender. Actions to improve
      subjects' attitudes towards disabled children are discussed and suggested.

PMID- 12476132
TI  - The concept of hope in nursing 4: hope and gerontological nursing.
AB  - This article is the fourth in a series of six that explores the nature of hope,
      reviews the existing theoretical and empirical work in several discrete areas of
      nursing and provides case studies to illustrate the role that hope plays in
      clinical situations. This article focuses on hope within the specialty of
      gerontological nursing. To date, most of the hope research, using qualitative and
      quantitative methodologies, has focused on well and chronically ill young or
      middle-aged adults; very few studies have examined hope in the older adult and
      specifically how older adults maintain hope in spite of multiple losses and/or
      changes. Hope has been studied in several elderly populations, including grieving
      widow(er)s, community-based older persons, persons living in long term care
      facilities and elders recruited from senior citizen centres. Research findings
      provide initial direction for the assessment of hope, and a reference for
      evaluating the effectiveness of these strategies. There remains, however, a need
      for continuing research in the area of hope in the older adult that is
      multifaceted and applicable to both practice and education.

PMID- 12476133
TI  - Secondary wound dressings: an evaluation of Alldress.
AB  - Nurses are increasingly faced with the need to balance clinical efficacy with
      economic advantages when selecting wound management products. Compared to 20 or
      30 years ago the money spent by the NHS in the UK on wound dressings has risen
      dramatically. It is also true that the rise in costs has, for the most part, been
      matched by an improvement in product performance. It is, however, important that
      claimed advances in wound management products are assessed critically to ensure
      they provide both clinical and economic benefits. In this article the authors
      explore the use of a secondary wound dressing. Using a case study methodology,
      the authors have conducted an evaluation aimed at identifying possible economic
      benefits associated with the study dressing as opposed to more expensive
      alternatives. In the case studies observed the dressing has been found to provide
      the required level of clinical performance at a considerable saving when compared
      to other modern wound management dressings. The authors conclude that these
      initial findings merit further investigation as they could, if replicated on a
      larger scale, result in considerable cost savings for the NHS without sacrificing
      clinical standards.

PMID- 12476134
TI  - Higher level practice is in fact advanced practice.

PMID- 12476135
TI  - Nurses should be united if they want to be taken seriously.

PMID- 12476136
TI  - The future direction of nurse education is being debated.

PMID- 12476137
TI  - Nurse who left a physically disabled patient on a bedpan.

PMID- 12476138
TI  - Management of people with diabetes during Ramadan.
AB  - In the UK, Islam is the second largest religion after Christianity and there are
      about 2.5 million Muslims living in the UK. Fasting is obligatory for all healthy
      adult Muslims during the holy month of Ramadan. During Ramadan, no food, drink,
      or medication is allowed between dawn and sunset. As a result of different
      research results there is no agreement on whether it is safe for Muslim diabetics
      to fast. Through dialogue between health professionals and patients, it is
      usually possible to facilitate at least some safe fasting for those who wish to
      observe this annual ritual. In this article some key pointers will be given for
      health professionals to consider with the aim of improving the quality of care of
      Muslim patients with diabetes during Ramadan.

PMID- 12476139
TI  - Clinical negligence and the need to keep professionally updated.
AB  - Nurses and doctors are under a legal duty to keep reasonably up to date; this is
      a fundamental aspect of their legal duty of care to their patients. A nurse or
      doctor could be negligent if a patient is harmed because of ignorance of well
      accepted and known published nursing and medical research findings. It is all a
      question of fact and degree and cases will turn on their own circumstances. There
      are a number of reported court cases which explore this issue and which contain
      useful guidance. These cases are discussed within the context of the new NHS and
      the Government's emphasis on health quality, and increasing healthcare
      litigation.

PMID- 12476140
TI  - Whistle-blowing and the Public Interest Disclosure Act 1998.
AB  - Dave worked in the intensive care unit and was concerned at the staffing levels.
      On several occasions over a weekend he had been compelled to look after more than
      one ventilated patient at the same time and he feared that a serious tragedy was
      imminent. What action could he take?

PMID- 12476141
TI  - Nurses' perceptions of their role and skills in a medium secure unit.
AB  - This descriptive study investigated the perceptions - in relation to their own
      role and skills - of 25 qualified nurses who work in a medium secure unit. Data
      were collected by means of semi-structured interviews and analysed by thematic
      content analysis. The findings suggest that nurses in this environment had a
      broad role and possessed a range of skills and personal qualities. Similarities
      with colleagues in generic psychiatric settings were identified, but further
      specialist skills and knowledge were perceived to be required within the medium
      secure environment. Preregistration training was seen not to prepare nurses for
      the secure environment; after registration, there was a perceived lack of
      structure. Various factors were believed to affect the nursing role, which was
      also perceived as being complementary to that of other disciplines. Nurses were
      viewed as making a unique contribution to the multidisciplinary team. The
      provision of a therapeutic and secure environment was perceived to present a
      challenge.

PMID- 12476142
TI  - Developing continuing care: towards a teaching nursing home.
AB  - This article describes a partnership between staff, residents and relatives of a
      nursing home for older people with mental health problems, and lecturers within
      an academic department of nursing. The aim of the partnership is to develop
      practice and to improve the setting of the care home as an environment for
      living, working and learning. In our attempts to create a teaching nursing home,
      we recognize the need to ensure that all participants - residents, relative and
      staff - feel that they are valued members of the team. We describe our progress
      to date, together with some of the challenges of working together.

PMID- 12476143
TI  - Safer handling practice: influence of staff education on older people.
AB  - The purpose of this small-scale survey was to explore the level of moving and
      handling training undertaken by nurses within private sector continuing care
      environments and the potential this training had to influence the care of older
      people. This study uses a definition of safer handling practice derived from
      existing literature to examine how nurses report the application of this training
      and whether they observe changes to the mobility of older people within their
      care. The limitations of this study indicate that generalizations must be made
      cautiously. However, this study tentatively suggests that potential exists to
      influence positively the use of safer handling practice as defined within this
      study. Recommendations for further study are made.

PMID- 12476144
TI  - Evaluation of Acti-Wrap: a new cohesive retention bandage.
AB  - Retention bandages are designed to keep dressings, devices and creams in place
      without causing discomfort to the patient. They should be lightweight, soft and
      comfortable and should not cause unwanted compression. Acti-Wrap retention
      bandage (Activa Healthcare) is a new, conforming bandage which is easy to apply
      and because of its cohesive nature stays in place. This product focus looks at
      the ways in which the bandage can be used effectively and the cost-effectiveness
      of using this type of bandage. The simple evaluation described in this article
      compares Acti-Wrap with two other frequently used retention bandages.

PMID- 12476145
TI  - New initiative to provide evidence-based IV care.

PMID- 12476147
TI  - What is the evidence for specific pressure-reducing mattresses?

PMID- 12476148
TI  - Teaching nurses psychological support of patients with wounds.
AB  - Concerns about lack of professional empathy with psychological aspects of wound
      care provided the springboard for this study. Forty-three qualified nurses who
      regularly care for patients with wounds recorded in research diaries how they
      supported patients holistically before and after attending a counselling skills
      workshop. Thirty-nine nurses then attended focus groups to share their
      experiences. Participants represented varied practice settings, with 581 patient
      situations recorded in the diaries. Data analysis identified four themes:
      reflection sharpens the focus on practice; complex situations; emotional labour;
      and knowing the patient. While patients' feelings were identified in the first
      diary period, and reflection sharpened the focus on practice, patients'
      psychological needs were not attended to fully. Following the workshop there was
      a major shift in the understanding and provision of psychological support for
      patients with wounds by some of the nurses. Others were unable or unwilling to
      embrace counselling skills into care. This highlights the need to address nurses'
      attitudes and beliefs that might interfere with psychological support for
      patients with wounds.

PMID- 12476149
TI  - Teaching bandaging and Doppler usage for venous ulcer treatment.
AB  - This article describes how an assessor's guide and a student learning contract
      about compression and Doppler therapy was presented to community nurses and
      practice nurses in an NHS acute and community trust. The objectives were to
      provide potential assessors with standardized practice in the application of
      compression bandaging and the use of Doppler-assisted diagnosis in the treatment
      of venous leg ulceration. This was achieved by a teaching session using two
      checklists, one for the assessor and the other for the 'student'. Role play was
      used to allow experience of assessing or being assessed in a classroom setting.
      References to key pertinent articles were provided to support the learning
      contract, and the development of a resource file was proposed. In recognizing
      their own limited knowledge and experience, a small number of practitioners felt
      unable to assess 'officially' other members of their staff.

PMID- 12476150
TI  - The management of a pilonidal sinus and its follow-up care.
AB  - This article describes the care of a young man following surgery for a pilonidal
      sinus and the follow-up care after removal of the sutures from the wound.
      Unfortunately, the wound became infected and dehisced on removal of the sutures,
      causing the patient to have problems with both wound healing and body image.

PMID- 12476151
TI  - Clinical and scientific data of a hydropolymer range of dressings.
AB  - The Tielle trade mark family (Johnson and Johnson Medical) is a range of
      hydropolymer foam dressings that come in a variety of shapes and sizes, and are
      designed to fit the different types and locations of wounds that occur in
      practice. There are three types: Tielle, Tielle Lite and Tielle Plus. Each can be
      based on the characteristics of the primary dressing, if any, and on the degree
      of exudate that the wound is producing. This article aims to give an overview of
      the range and a summary of research-based clinical and scientific evidence to
      support clinical practice.

PMID- 12476152
TI  - Deep Cell Prime: preventing and healing pressure ulcers.
AB  - One method of pressure ulcer prevention is the use of alternating pressure air
      mattresses. This article outlines the Talley Medical Deep Cell Prime trade mark
      mattress replacement system, which is used in conjunction with Trinity HR Dynamic
      trade mark cushion in order to provide 24-hour pressure relief.

PMID- 12476153
TI  - Mepore Ultra and Alldress: primary and secondary dressings.
AB  - Expenditure on wound care continues to rise in the UK as new products and
      innovations are introduced. Nurse specialists in tissue viability are at the
      forefront of many of these advances and therefore it is vital that they consider
      both the clinical and economic benefits of each new treatment. In this article,
      the authors use a case study methodology to evaluate primary and secondary wound
      dressings. The aim was to focus on the opportunity for reducing overall costs in
      wound management without compromising clinical outcomes. Given the initial
      results observed there appears to be ample scope for a debate within the tissue
      viability specialty with regard to achieving best value for money in wound care.
      The authors suggest that the time has come to consider this area in greater
      detail and depth.

PMID- 12476229
TI  - Current issues in trauma.

PMID- 12476230
TI  - Carotid endarterectomy in octogenarians with symptomatic high-grade internal
      carotid artery stenosis: long-term clinical and duplex follow-up.
AB  - The objective of this study was to evaluate the clinical and duplex outcome after
      carotid endarterectomy (CEA) in recently symptomatic patients aged 80 years or
      older. Information was assembled from a prospective data collection of all CEAs
      performed from January 1986 to December 1999. Included were all patients with
      recently symptomatic carotid artery stenosis who were aged 80 years or older at
      time of operation. Thirty-two patients, with a mean age of 82 years, were
      included. Outcome events were stroke, death, and restenosis (more than 50%
      diameter reduction) during routine duplex scan follow-up. Conventional surgical
      technique was used regarding anesthesia and selective shunting or patching. None
      of the operated-on patients suffered a stroke at any time during follow-up. One
      patient (3.1%) died in the early postoperative phase (<30 days). An additional 8
      patients died during follow-up. None of these deaths were of cerebrovascular
      origin. Survival at 3 years was 73% (life table analysis). Routine duplex scan
      follow-up showed 2 patients with a diameter reduction of more than 50%, both 3
      months after CEA. Restenosis rate on duplex scan was 7.4% after 1 year. The
      authors conclude that there seems to be no reason to deny the very elderly the
      benefits of CEA. Stroke-free survival and survival rates show that carotid
      surgery is a safe procedure in patients aged 80 and over who are in apparently
      good health. These findings are supported by a low incidence of restenosis on
      duplex scan follow-up, indicating a durable repair.

PMID- 12476231
TI  - Ophthalmologic findings as predictors of carotid artery disease.
AB  - Vascular events that occur in the brain also occur in the eye, giving rise to
      different ophthalmologic manifestations that range from amaurosis fugax to
      complete blindness due to central retinal artery occlusion. The objective of this
      study was to ascertain the relative frequency and predictive value of ocular
      findings suggestive of carotid occlusive disease in patients being investigated
      for carotid endarterectomy. The charts of 366 patients undergoing carotid
      angiography for evaluation of cerebrovascular or visual symptoms over a 5-year
      period were reviewed. The presence of eye symptoms, neurologic symptoms, cervical
      bruits, and ophthalmologic findings on admission was recorded and correlated with
      the presence of significant carotid artery stenosis (>or=50%). Positive eye
      findings included retinal plaques, rubeosis iridis, neovascular glaucoma, venous
      stasis retinopathy, central and branch retinal artery occlusion, ischemic optic
      neuropathy, and asymmetric hypertensive retinopathy. Seventy-five patients (21%)
      presented with amaurosis fugax; 41 patients (11%) were found to have one or more
      ocular findings consistent with carotid artery disease. All patients with
      positive eye findings were diagnosed by ophthalmologists, who were consulted in
      94 cases. Of these 41 patients, 29 (70.3%) were subsequently shown to have
      greater than 50% stenosis of the common or internal carotid artery. Ten patients
      had amaurosis fugax, a carotid bruit, and positive eye findings. All were shown
      to have a significant carotid stenosis. This study shows that ocular pathology,
      if diagnosed, is correlated with carotid stenosis, especially if other
      contributing history and physical findings are also considered.

PMID- 12476232
TI  - Factors related to short length of stay after carotid endarterectomy.
AB  - In the past decade, expected in-hospital length of stay (LOS) after carotid
      endarterectomy (CEA) has decreased from 4 days to 1. Long LOS is associated with
      known complications and factors affecting severity of the patient's condition.
      Factors affecting an intermediate stay of 2 to 4 days need further clarification.
      The vascular registry at Jobst Vascular Center includes data on manifestation of
      disease; cardiovascular history; operation and discharge dates; surgeon; surgical
      details such as patching, shunting, and completion arteriography; and
      complications. Univariate chi-square and ANOVA and multivariate logistic
      regression were applied to analyze 635 CEAs performed in 1998, 1999, and 2000.
      Statistical significance was at a p value less than 0.05 (two-sided). Overall
      morbidity rate was 8.2% with three (0.5%) in-hospital neurologic complications
      and one death for a 0.16% mortality rate. Fifty-eight percent of the patients
      were discharged in 1 day. Patients staying 1 day were 3 years younger. Female
      gender and prior cerebrovascular accident were factors extending LOS to 2 and 3
      days. History of angina, heart failure, valve disease, and vein patch or no patch
      contributed to LOS of 3 or 4 days. Completion arteriography had an association
      with LOS of 2 days. The relative percentage of patients with complications
      increased with LOS. No significant relationship was found for symptoms, smoking,
      myocardial infarction, atrial fibrillation, cardiac revascularization, or
      surgeon. Insulin-treated diabetes mellitus, cardiac risk factors, cerebrovascular
      accident, and vein patch or no patch correlated with prolonged hospitalization.
      Factors were identified that may alter a clinical pathway designed for discharge
      1 day after CEA. Focused management of patients with cardiac and cerebrovascular
      accident history or requiring vein patch and a better understanding of CEA in
      women may further increase the percentage of patients discharged 1 day after CEA.

PMID- 12476233
TI  - Complication rates of diagnostic angiography performed by vascular surgeons.
AB  - The objective of this study was to compare the complication rates of diagnostic
      angiography performed by vascular surgeons to those previously published by
      interventional radiologists. From May 1999 through August 2000, 3 board-certified
      vascular surgeons performed 224 endovascular procedures in a modern endovascular
      suite. Of these 224 procedures, 144 were diagnostic angiographies. A
      retrospective chart review was conducted to identify periprocedural complications
      of these angiographies. The patients were classified into 3 groups according to
      the indication for angiography, and the major and overall complication rates were
      tabulated. The complication rates for the initial 25 and subsequent 119
      arteriographies were compared to evaluate the presence of a learning curve.
      Thirty-eight percent of angiographies were performed to define aneurysmal anatomy
      (type I), 51% to define peripheral arterial stenosis or occlusion (type II), and
      12% to assess symptomatic carotid artery disease or mesenteric ischemia (type
      III). The major complication rates for these 3 types were 0%, 2.7%, and 5.9%,
      respectively, and showed no statistical difference (Fischer's exact test)
      compared to published rates of 0.7%, 2.9%, and 9.1%. Major complications included
      an external iliac artery dissection, a cerebral air embolus, and a deep venous
      thrombosis. The overall major complication rate was 2.1%, which compares to
      published rates of 1.9-2.9%. The major complication rates for the initial 25 and
      final 119 were 8% and 0.8%, respectively. Vascular surgeons can perform
      diagnostic angiography with acceptable complication rates. The complication rate
      is reduced with angiographic experience.

PMID- 12476234
TI  - Noninvasive measurement of shear rate in autologous and prosthetic bypass grafts.
AB  - There is a major difference in thrombogenicity between lower extremity prosthetic
      and autologous vein bypass grafts, and arterial blood flow shear rate is known to
      influence thrombus formation. Despite this association, there has been little
      direct clinical observation of shear rates in bypass grafts. The authors
      developed a new noninvasive method to quantitate human arterial shear rate and
      used it in a pilot study to characterize differences in lower extremity bypasses.
      Shear rates were measured in 10 prosthetic and 14 autologous vein femoropopliteal
      bypass grafts. With CVI-M-mode color flow ultrasonography in resting supine
      patients, a velocity profile was recorded from a midgraft longitudinal section in
      the ultrasound beam direction. Shear rates were calculated by using a
      mathematical-graphic computer program at the anteromedial (near) and
      posterolateral (far) graft walls by averaging values immediately before and after
      peak systolic velocity (PSV). Comparison between prosthetic and autologous graft
      groups respectively revealed that differences in age (67 +/- 12 [SD] vs 71 +/- 10
      yr), male gender (60% vs 43%), prevalence of hypertension (50% vs 71%), diabetes
      (40% vs 64%), smoking (50% vs 50%), hypercholesterolemia (30% vs 29%), coronary
      artery disease (60% vs 50%), and critical ischemia (60% vs 86%) did not reach
      statistical significance (p>0.19). Median PSVs were significantly less in
      prosthetic than in autologous vein bypasses (37 +/- 13 vs 57 +/- 22 cm/s,
      p=0.018). Prosthetic and autologous graft diameters were not statistically
      significantly different (6.3 +/- 1.1 vs 5.6 +/- 1.3 mm, p = 0.18). Shear rates
      were significantly less in prosthetic than in autologous vein bypasses both at
      the near wall (382 +/- 146 vs 698 +/- 271 s(-1), p=0.003) and at the far wall
      (551+/-235 vs 827+/-339 s(-1), p-0.037). This mathematical model can be used to
      calculate shear rate from observed ultrasound flow patterns. Prosthetic bypass
      grafts had lower shear rates than autologous vein grafts.

PMID- 12476235
TI  - Congenital absence of internal carotid artery associated with hypogonadotropic
      hypogonadism--a case report.
AB  - Congenital absence of internal carotid artery is a relatively rare disorder. It
      may be an isolated entity or combined with other organ or system anomalies.
      Investigations of a 19-year-old male patient with hypogonadotropic hypogonadism
      and hypothyroidism suffering from intracerebral and subarachnoid hemorrhages
      showed absence of the left internal carotid artery. The association of
      endocrinologic disorders and congenital absence of internal carotid artery is
      discussed with the pertinent literature. In conclusion, association of the
      absence of internal carotid artery and hypogonadism is extremely rare. Patients
      with absence of internal carotid artery may also have intracerebral and
      subarachnoid hemorrhages and should be followed up closely.

PMID- 12476236
TI  - Pseudoaneurysm of the subclavian-vertebral artery junction--case report and
      review of the literature.
AB  - Pseudoaneurysm of the subclavian-vertebral artery junction (SVJ) is a rare
      complication of internal jugular vein catheter placement. Because of its
      retroclavicular location, arterial injury at the SVJ poses a significant
      therapeutic challenge. A case report and review of the literature are presented.

PMID- 12476237
TI  - Fractured aorta--a case report.
AB  - A 66-year-old, restrained driver involved in a high-speed motor vehicle crash
      sustained a transmural infrarenal fracture of a circumferentially calcified
      aorta. Blunt abdominal aortic injury is exceedingly rare, about twenty times less
      common than its thoracic counterpart, and the current case report is therefore
      unusual. A high index of suspicion in combination with a suggestive clinical
      history or examination should prompt diagnostic intervention, as both morbidity
      and mortality are high.

PMID- 12476238
TI  - Distal venous arterialization for limb salvage--a case report.
AB  - The reperfusion of an ischemic limb in the absence of suitable target artery
      remains a formidable task. The authors report a case of an ischemic limb in
      patient whose distal arteries were identified intraoperatively as unsuitable for
      conventional revascularization. A distal arteriovenous fistula was created
      between the already arterialized in situ greater saphenous vein conduit and the
      inframalleolar superficial venous system of the foot. The flow through the
      superficial venous system salvaged the limb and continues to perfuse the foot 4
      years post-operatively with resolution of rest pain.

PMID- 12476239
TI  - Enhanced platelet force development despite drug-induced inhibition of platelet
      aggregation in patients with thromboangiitis obliterans--two case reports.
AB  - Thromboangiitis obliterans (TAO) is a nonatherosclerotic, nonnecrotizing,
      nonspecific, segmental inflammatory obliterative vasculitis, characterized by
      decreased flow to the distal extremities and increased risk of amputation. While
      smoking cessation is viewed as critical to successful treatment, various
      therapeutic options have been employed. While many treatment regimens seek to
      diminish platelet function, there are relatively few studies of platelet function
      in this disease entity and even fewer that have offered evidence of increased
      platelet activity. The authors report here 2 cases of TAO in which evaluations
      for hypercoagulable states and of platelet function were performed. Platelet
      contractile force (PCF) was found to be 82% higher than a normal control in 1 TAO
      patient and 340% higher than normal in the second patient. This was true despite
      the fact that platelet aggregations confirmed suppression of aggregation by
      antiplatelet medications. Elevated PCF has been seen in a variety of conditions,
      such as coronary artery disease and diabetes mellitus, in which endothelial
      function is abnormal. Whether high PCF values play a role in the pathogenesis of
      these diseases or simply serve as markers of enhanced platelet function and/or
      endothelial dysfunction awaits additional evaluations.

PMID- 12476240
TI  - Sexual offenders' perceptions of their early interpersonal relationships: an
      attachment perspective.
AB  - The present study examined the perceptions of early interpersonal experiences of
      sexual offenders (child molesters and rapists) and two criminal comparison
      groups. A grounded theory approach was applied to a comprehensive list of
      responses provided by the participants to questions about their early
      interpersonal experiences. The raw data was collapsed into 14 basic categories by
      grouping together responses of similar meanings. The categories were
      responsiveness, consistency, acceptance, boundaries, emotional regulation,
      autonomy, self-evaluation, developmental trauma, sexual abuse and deviation,
      physical abuse, loss, conflict, safety, and positive mediating interactions. In
      the second part of the study, the four groups were compared using the categories
      and the differences noted. All four groups experienced significantly negative
      early interpersonal experiences.

PMID- 12476241
TI  - Psychological factors and the sexuality of pregnant and postpartum women.
AB  - This study examined the influence of role quality, relationship satisfaction,
      fatigue, and depression on women s sexuality during pregnancy and after
      childbirth. Questionnaire data were obtained from 138 women pregnant with their
      first child, of whom 104 responded at 12 weeks postpartum, and 70 responded at 6
      months postpartum. Women reported significant reductions in sexuality during
      pregnancy and postpartum. Relationship satisfaction explained levels of sexual
      satisfaction during pregnancy, and was a predictor of sexual desire in the
      postpartum. Depression was an important predictor of reduced sexual desire and
      sexual satisfaction during pregnancy, and of reduced frequency of intercourse at
      12 weeks postpartum. At 6 months postpartum, the quality of the mother role
      strongly related to measures of sexuality. Throughout the perinatal period,
      fatigue impacted on measures of sexuality, either directly or/and indirectly. The
      implications of these results in terms of the impact of pregnancy and childbirth
      on relationships and sexuality are discussed.

PMID- 12476242
TI  - Do all orgasms feel alike? Evaluating a two-dimensional model of the orgasm
      experience across gender and sexual context.
AB  - The characteristics common to all human orgasm experiences and potential gender
      and contextual factors affecting these experiences were investigated in two
      studies. A two-dimensional descriptive model of the orgasm experience was
      evaluated by testing hypotheses concerning (a) fit of the model to adjective
      ratings data describing male and female orgasm experiences, and (b) sexual
      context effects on the importance of model components. In the first model
      evaluation study, 888 university students (523 women) provided adjective ratings
      to convey orgasm experiences attained through both solitary masturbation and sex
      with a partner. In a cross-validation study, 798 university students (503 women)
      provided similar ratings to convey orgasm experiences attained either through
      solitary masturbation or through sex with a partner. Overall, findings supported
      the utility of a two-dimensional model of the orgasm experience, an adjective
      rating approach in comparing male and female orgasm, and the importance of
      examining sexual context effects on the orgasm experience.

PMID- 12476243
TI  - The Sexual Inhibition (SIS) and Sexual Excitation (SES) Scales: I. Measuring
      sexual inhibition and excitation proneness in men.
AB  - This study involves the development and initial validation of a questionnaire
      measuring the propensity for sexual inhibition and excitation in men: the Sexual
      Inhibition Sexual Excitation Scales (SIS/SES). The underlying theoretical model
      postulates that sexual response and associated behavior depend on dual control
      mechanisms, involving excitatory and inhibitory neurophysiological systems. The
      scales and their discriminant and convergent validity and test-retest reliability
      are described. In a sample of 408 sexually functional men (mean age = 22.8
      years), factor analyses identified three higher-level factors: two related to
      sexual inhibition and one to sexual excitation. Multigroup Confirmatory Factor
      Analyses revealed that the factor structure provided an acceptable fit to the
      data obtained in a second (N = 459; mean age = 20.9 years) and third (N = 313;
      mean age = 46.2 years) sample of men, with similar distributions and
      relationships with other measures. Theoretical issues and areas for further
      research, including male sexual dysfunction and risk taking, are discussed.

PMID- 12476244
TI  - The Sexual Inhibition (SIS) and Sexual Excitation (SES) Scales: II. Predicting
      psychophysiological response pattens.
AB  - This study evaluated the predictive value of a newly developed measure of the
      propensity for sexual inhibition and excitation; the Sexual Inhibition Sexual
      Excitation Scales (SIS/SES). Sexual, cardiovascular, and startle responses were
      measured in a group of 40 sexually functional men during the presentation of
      threatening and nonthreatening erotic films. Two levels of performance demand
      were created and two films were combined with a distraction task. Participants
      were assigned to high and low groups for each of the three SIS/SES scales. As
      predicted, men with high SES scores showed generally higher sexual responses.
      High and low SIS1 groups did not differ in their responses. Men with high and low
      SIS2 scores did not differ in their responses to nonthreatening stimuli; however,
      low SIS2 men showed greater genital response to the threatening stimuli. The
      findings provide support for the value of the SIS/SES scales in predicting sexual
      responses.

PMID- 12476245
TI  - Seven tenths incorrect: heterogeneity and change in the waist-to-hip ratios of
      Playboy centerfold models and Miss America pageant winners.
AB  - Drawing on an article by Singh (1993), many discussions of the evolutionary
      psychology of heterosexual male preferences have reported a remarkable
      consistency in the waist-to-hip ratios of Playboy centerfold models and Miss
      America pageant winners over time. We reexamine the measurement data on these
      American beauty icons and show that these reports are false in several ways.
      First, the variation in waist-to-hip ratios among these women is greater than
      reported. Second, the center of the distribution of waist-to-hip ratios is not
      0.70, but less than this. Third, the average waist-to-hip ratio within both
      samples has changed over time in a manner that is statistically significant and
      can be regarded as mutually consistent. Taken together, the findings undermine
      some of the evidence given for the repeated suggestion that there is something
      special--evolutionarily hard-wired or otherwise--about a specific female waist-to
      hip ratio of 0.70 as a preference of American heterosexual males.

PMID- 12476246
TI  - A brief telephone interview to identify lesbian and bisexual women in random
      digit dialing sampling.
AB  - Lesbian health research has most often relied on nonprobability samples that are
      biased and restrict generalizability. Random sampling could reduce bias, but
      requires development of a method for fast and reliable screening of a large
      number of women. We tested the feasibility of using a brief telephone interview
      to assess sexual attraction, behavior, and identity. Using Random Digit Dialing
      in a neighborhood of Boston with a high density of lesbian residents, we
      interviewed 202 women aged 18 to 59. Of the respondents, 33% reported some sexual
      attraction to other women, 20% reported sex with women since age 18, and 14%
      identified as a lesbian. The high level of cooperation with the study among
      eligible women (94%) and the high proportion of women who disclosed homosexual
      attraction, behavior, or identity show that it is feasible to use a brief
      screening questionnaire about sexuality of women over the telephone even without
      building special rapport with the respondents.

PMID- 12476247
TI  - Expectancies specific to condom use mediate the alcohol and sexual risk
      relationship.
AB  - The present study tested the role of alcohol expectancies for condom use in
      mediating the alcohol and risky sex relationship. Expectancies for condom use are
      specific anticipations for alcohol's effect on one's ability to use a condom.
      College students (N = 563) reported on beliefs, intentions and actual sexual and
      drinking behavior. Among the sexually active, alcohol was directly related to
      future intention to use a condom in drinking situations for men, but not for
      women. In the men, alcohol expectancies for condom use mediated the relationship
      between drinking and condom intention. Beliefs that alcohol negatively impacts
      one's ability to use condoms were associated with more drinking and lower
      intentions to use a condom. These expectancies may help explain how alcohol
      affects risky sex in men. Gender differences and implications are discussed.

PMID- 12476248
TI  - Promoting sexual health and responsible sexual behavior: an introduction.
AB  - Facing a myriad of sexual health problems today, health ministries are being
      compelled to develop comprehensive approaches to sexual health promotion.
      Recently, there have been several attempts to develop these strategies at
      national, regional, and global levels. One of the challenges of articulating
      strategies has been arriving at basic definitions of sex, sexuality, sexual
      health, and responsible sexual behavior. However, there is remarkable consistency
      throughout these recent documents. These documents call for leadership of the
      health sector to create better climates for discussion of sexuality, access to
      information and education about sexuality, prevention strategies, access to care,
      and more research in human sexuality and evaluation of programs designed to
      promote sexual health and responsible sexual behavior.

PMID- 12476249
TI  - Sexuality and health challenges: responding to a public health imperative.
AB  - Sexuality is associated with a number of public health imperatives to prevent
      disease or disability or, if prevention is not possible, to treat and reduce the
      burden of disease as expeditiously as possible. With the advent of modern testing
      technology and better sampling of populations, the burden of sexually
      transmissible infections, sexual assault, and sexual disability have become more
      apparent. Presented here are U.S. data on the public health dimensions of human
      sexuality and the evidence for the urgent need to address the magnitude of
      sexually related public health problems.

PMID- 12476250
TI  - Human sexual development.
AB  - Empirical research by scholars from several disciplines provides the basis for an
      outline of the process of sexual development. The process of achieving sexual
      maturity begins at conception and ends at death. It is influenced by biological
      maturation/aging, by progression through the socially-defined stages of
      childhood, adolescence, adulthood, and later life, and by the person s
      relationships with others, including family members, intimate partners, and
      friends. These forces shape the person's gender and sexual identities, sexual
      attitudes and sexual behavior. Adults display their sexuality in a variety of
      lifestyles, with heterosexual marriage being the most common. This diversity
      contributes to the vitality of society. Although changes in sexual functioning in
      later life are common, sexual interest and desire may continue until death.

PMID- 12476251
TI  - Biological factors in human sexuality.
AB  - This paper considers a number of key concepts relevant to biological determinants
      of human sexuality, including sexual differentiation, brain mechanisms involved
      in sexual response, the role of sex hormones, and the sexual effects of drugs.
      The paper concludes with consideration of how little is known about the
      interaction between biology and culture in shaping human sexuality, and the need
      for research in this area.

PMID- 12476252
TI  - Family influences on adolescent sexual and contraceptive behavior.
AB  - Studies of adolescent pregnancy risk are relevant to understanding responsible
      adolescent sexual behavior because most investigators have focused on the key
      proximal determinants of pregnancy--sexual intercourse and contraceptive use-
      rather than analyzing pregnancy status per se. Lesser pregnancy risk is
      associated with teens remaining sexually abstinent, postponing onset of
      intercourse, and having intercourse less often or with fewer partners, as well as
      by using contraception at first or most recent intercourse and by using
      contraception consistently over time. Living with a single parent, in a lower SES
      family, having older sexually active siblings or pregnant/parenting teenage
      sisters, being a victim of sexual abuse, and residing in disorganized/dangerous
      neighborhoods all place teens at elevated risk of adolescent pregnancy. Parent
      child closeness or connectedness, and parental supervision or regulation of
      children, in combination with parents values against teen intercourse (or
      unprotected intercourse), decrease the risk of adolescent pregnancy. Studies
      about parent-child sexual communication and adolescent pregnancy risk are less
      conclusive, largely because of methodological complexities.

PMID- 12476253
TI  - The impact of schools and school programs upon adolescent sexual behavior.
AB  - Because most youth are enrolled in school for many years before they initiate sex
      and when they initiate sex, schools have the potential for reducing adolescent
      sexual risk-taking. This paper reviews studies which examine the impact upon
      sexual risk-taking of school involvement, school characteristics, specific
      programs in school that do not address sexual behavior, and specific programs
      that do address sexual risk-taking. Multiple studies support several conclusions.
      First, involvement in and attachment to school and plans to attend higher
      education are all related to less sexual risk-taking and lower pregnancy rates.
      Second, students in schools with manifestations of poverty and disorganization
      are more likely to become pregnant. Third, some school programs specifically
      designed to increase attachment to school or reduce school dropout effectively
      delayed sex or reduced pregnancy rate, even when they did not address sexuality.
      Fourth, sex and HIV education programs do not increase sexual behavior, and some
      programs decrease sexual activity and increase condom or contraceptive use.
      Fifth, school-based clinics and school condom-availability programs do not
      increase sexual activity, and either may or may not increase condom or
      contraceptive use. Other studies reveal that there is very broad support for
      comprehensive sex- and HIV-education programs, and accordingly, most youth
      receive some amount of sex or HIV education. However, important topics are not
      covered in many schools.

PMID- 12476254
TI  - Influences of culture on Asian Americans' sexuality.
AB  - Asian Americans comprise a population group that is characterized by an enormous
      demographic, historical, and cultural heterogeneity, yet Asian Americans also
      share many Asian cultural characteristics such as the primacy of the family and
      the collective's goals over individual wishes, emphasis on propriety and social
      codes, the appropriation of sexuality only within the context of marriage, and
      sexual restraint and modesty. Although there are significant gaps in the
      scientific literature concerning Asian Americans sexuality, the existing data
      point to notable differences between Asian Americans and other ethnic groups on
      major aspects of sexual behavior. For example, relative to other U.S. ethnic
      group cohorts, Asian American adolescents and young adults tend to show more
      sexually conservative attitudes and behavior and initiate sexual intercourse at a
      later age. There are indications that as Asian Americans become more acculturated
      to the mainstream American culture, their attitudes and behavior become more
      consistent with the White American norm. Consistent with their more sexually
      conservative tendencies in normative sexual behavior, Asian American women also
      appear more reluctant to obtain sexual and reproductive care, which in turn
      places them at a greater risk for delay in treatment for breast and cervical
      cancer as well as other gynecological problems. Available data suggest that the
      prevalence rate of sexual abuse in Asian American communities appear lower than
      those of other groups, although it is not clear to what extent the low rates are
      due to cultural reluctance to report shameful experiences.

PMID- 12476255
TI  - Mass media influences on sexuality.
AB  - The mainstream mass media (television, magazines, movies, music, and the
      Internet) provide increasingly frequent portrayals of sexuality. We still know
      relatively little about how this content is used and how it affects sexual
      beliefs and behaviors. The few available studies suggest that the media do have
      an impact because the media keep sexual behavior on public and personal agendas,
      media portrayals reinforce a relatively consistent set of sexual and relationship
      norms, and the media rarely depict sexually responsible models. More longitudinal
      research, especially with early adolescents is needed to learn more about how
      media content is attended to, interpreted, and incorporated into developing
      sexual lives.

PMID- 12476256
TI  - The roles and rules of law in sexual development.
AB  - This article provides an overview of the diverse sources of law that regulate
      sexual development and its resulting behaviors, dispositions, and outcomes. After
      exploring how the law influences sexuality by regulating families, schools,
      media, and social service delivery, the article examines the role of criminal and
      civil law in regulating partners  influences on sexual relationships. The article
      then briefly analyses how the law influences the manner individuals themselves
      influence their intimate relationships and social environments. The article
      emphasizes that the necessary brevity of the overview masks many complexities but
      that existing laws and trends highlight how the law plays a dominant role in our
      lives, how the law seeks to promote certain dispositions, that the law must be
      harnessed to foster healthy relationships, and that contending with the law s
      dictates provides social scientists with important opportunities to foster social
      reform and structure healthy, supportive social environments conducive to
      responsible behaviors, attitudes, and dispositions.

PMID- 12476257
TI  - Effective approaches to reducing adolescent unprotected sex, pregnancy, and
      childbearing.
AB  - In the United States, there exist a multitude of different approaches to reducing
      adolescent sexual risk-taking, unintended pregnancy, childbearing, and sexually
      transmitted disease, including HIV. While many of these approaches have some
      positive effects upon some outcomes (such as greater knowledge), only some of
      these programs actually delay the initiation of sex, increase condom or
      contraceptive use, and reduce unprotected sex among youth. This article
      summarizes a review of 73 studies and their respective programs, and describes
      four groups of programs which have reasonably strong evidence that they delay
      sex, increase condom or contraceptive use, or reduce teen pregnancy or
      childbearing. These four groups of programs include (a) sex and HIV education
      curricula with specified characteristics, (b) one-on-one clinician-patient
      protocols in health settings with some common qualities, (c) service learning
      programs, and (d) a particular intensive youth development program with multiple
      components.

PMID- 12476258
TI  - Effective targeted and community HIV/STD prevention programs.
AB  - Community interventions and interventions targeting specific groups at risk of
      STDs/HIV have demonstrated significant impacts on sexual behavior, particularly
      condom use and safer sex. The scientific evidence suggests the factors that make
      these interventions particularly effective include the establishment of
      community, including business and CBO partnerships; maintainance of the
      intervention post-research funding; and buy-in by the community or target group.
      The modification of risky normative beliefs through the use of opinion leaders
      and role models, and through intervention delivery by peer educators, is an
      important facet of such interventions. Interventions delivered by health
      professionals, absent a community base, appear to be unsuccessful. Where cultures
      or subcultures are targeted, the close involvement of such groups in the design
      and delivery of messages is critical to their success. Diffusion of interventions
      through existing social networks further extends the intervention into the
      community and acts to reinforce and maintain changes in peer norms toward safer
      sexual behavior. The available data confirm that community or medical
      infrastructure-based interventions are effective in changing sexual behavior and
      can reach a wider range of the population than face-to-face programs if they
      incorporate peer educators as role models in modifying norms, and if diffusion of
      the intervention is integral to the design.

PMID- 12476259
TI  - Clinic-based service programs for increasing responsible sexual behavior.
AB  - Three general classes of clinic-based programs to increase responsible sexual
      behavior are considered: (a) clinic-based educational/counseling programs, (b)
      school clinic-based condom distribution programs, and (c) clinic-based STD/HIV
      screening programs. Consistent condom use may double in response to clinic-based
      counseling. However, consistent use seldom exceeds 50% of coital exposures.
      Extensive and personalized counseling interventions reduce incident sexually
      transmitted infections by 5% to 10%. Increases in responsible sexual behavior
      following school-based condom distribution programs is reported in some but not
      in all studies. Screening programs for sexually transmitted infections are
      associated with decreases in rates of some infections. STD/HIV screening should
      be considered an important aspect of healthy sexuality and an adjunct to other
      counseling efforts.

PMID- 12476260
TI  - Media interventions to promote responsible sexual behavior.
AB  - While the media have been used effectively to promote sexual responsibility in
      other countries for decades, few such opportunities have been seized in the
      United States. Mass media may be especially useful for teaching young people
      about reproductive health because elements of popular culture can be used to
      articulate messages in young people s terms, in language that won t embarrass
      them and may even make safe sex more attractive. Media can potentially change the
      way people think about sex, amidst cultural pressures to have sex at a young age,
      to have sex forcefully, or to have unsafe sex. Information can be communicated
      through a variety of channels--small media (e.g., pamphlets, brochures, and the
      Internet) and mass media--and in a variety of formats--campaigns, news coverage,
      and educational messages inserted into regular entertainment programming. Several
      international studies show that exposure to family planning messages through
      television, radio, and print media are strongly associated with contraceptive
      use. Domestically, safe sex media campaigns have been associated with increased
      teen condom use with casual partners, and reductions in the numbers of teenagers
      reporting sexual activity. Due to private ownership and First Amendment concerns,
      U.S. sexual health advocates have been working with the commercial media to
      incorporate subtle health messages into existing entertainment programming.

PMID- 12476261
TI  - Sexual dysfunction: overview of prevalence, etiological factors, and treatments.
AB  - Sexual dysfunctions and sexual problems are reviewed from the perspective of
      prevalence, broad etiological factors, and available treatments. Although a large
      percentage of individuals experience sexual problems, with estimates between 10
      and 52% of men and 25 and 63% of women, the prevalence of sexual dysfunctions
      that meet diagnostic criteria is lower and less well established by large scale
      population-based studies. Sexual problems and dysfunctions are correlated with
      other health conditions, including cardiovascular disorders, common diseases such
      a s diabetes, health habits, and mental health. Adequate sexual functioning also
      appears to be associated with personal well-being and relationship stability,
      although this may be more accurate for men than women. Efficacious and effective
      treatments exist for some of the sexual disorders, and there is an increasing
      focus on medical (particularly pharmacological) treatments being tested by the
      pharmaceutical industry. Sexual problems and dysfunctions have been notably under
      researched, particularly from the perspective on consequences to individual
      mental health, relationships, and family functioning.

PMID- 12476262
TI  - Sexual health policies in other industrialized countries: are there lessons for
      the United States?
AB  - Health professionals have been concerned about the high rates of unwanted and
      unplanned pregnancy, teenage pregnancy, abortion, and sexually transmitted
      diseases in the U.S. A major concern has been why these rates in the U.S. are so
      much higher than in most other western industrialized countries. In this article
      I summarize major national and comparative studies that have attempted to
      understand how the U.S. can do better in providing for the sexual health of its
      citizens. I also discuss approaches to sexual health in countries that do
      substantially better on the aforementioned indicators of sexual health. This
      review indicates that the recommendations of health and social science experts in
      the U.S. are consistent with approaches in countries where programs have done a
      better job in meeting the sexual health needs of their populations.

PMID- 12476263
TI  - Childhood sexual experiences and the perception of abuse among Latino men who
      have sex with men.
AB  - There is a lack of consensus on how to define childhood sexual abuse (CSA). In
      this study we explore the perceptions of CSA among men who had such experiences.
      One hundred Latino men (predominately gay) who had childhood sexual experiences
      with an older partner (CSEOP) were asked whether they considered their
      experiences sexual abuse (41 said no; 59 said yes). Those who felt abused were
      younger when the events happened and were more likely to have been physically
      forced, physically hurt, threatened, and emotionally hurt. Negative correlates of
      CSEOP in adulthood were also explored. Men who considered themselves the victims
      of CSA differed from those without CSEOP in having more alcohol use, unprotected
      anal sex, and male sex partners.

PMID- 12476264
TI  - How common is intersex? a response to Anne Fausto-Sterling.
AB  - Anne Fausto-Sterling s suggestion that the prevalence of intersex might be as
      high as 1.7% has attracted wide attention in both the scholarly press and the
      popular media. Many reviewers are not aware that this figure includes conditions
      which most clinicians do not recognize as intersex, such as Klinefelter syndrome,
      Turner syndrome, and late-onset adrenal hyperplasia. If the term intersex is to
      retain any meaning, the term should be restricted to those conditions in which
      chromosomal sex is inconsistent with phenotypic sex, or in which the phenotype is
      not classifiable as either male or female. Applying this more precise definition,
      the true prevalence of intersex is seen to be about 0.018%, almost 100 times
      lower than Fausto-Sterling s estimate of 1.7%.

PMID- 12476265
TI  - The influence of dual-identity development on the psychosocial functioning of
      African-American gay and bisexual men.
AB  - To examine the influence of racial-ethnic and sexual identity development on the
      psychosocial functioning of African-American gay and bisexual men (AAGBM), 174
      AAGBM completed questionnaire packets designed to assess their levels of racial
      ethnic and sexual identity development, self-esteem, social support, male gender
      role stress, HIV prevention self-efficacy, psychological distress, and life
      satisfaction. The results indicate that AAGBM who possess more positive (i.e.,
      integrated) self-identification as being African American and gay reported higher
      levels of self-esteem, HIV prevention self-efficacy, stronger social support
      networks, greater levels of life satisfaction, and lower levels of male gender
      role and psychological distress than their counterparts who reported less
      positive (i.e., less well integrated) African American and gay identity
      development. Although higher levels of racial-ethnic identity development were
      associated with greater levels of life satisfaction, sexual identity development
      was not.

PMID- 12476266
TI  - Sexual satisfaction in premarital relationships: associations with satisfaction,
      love, commitment, and stability.
AB  - This investigation focused on how sexual satisfaction is associated with
      relationship quality and stability in premarital couples. With data collected at
      multiple times over several years from a sample of heterosexual couples (who were
      all dating at Time 1), we examined how sexual satisfaction was associated with
      relationship satisfaction, love, commitment, and stability. At each wave of the
      study, sexual satisfaction was associated positively with relationship
      satisfaction, love, and commitment for both men and women. In addition, change in
      sexual satisfaction between Time 1 and Time 2 was associated with change over the
      same period in relationship satisfaction, love, and commitment. Furthermore, some
      evidence was found that sexual satisfaction was associated with relationship
      stability. Overall, sexual satisfaction had stronger links with relationship
      quality for men than for women.

PMID- 12476267
TI  - Inconsistencies in reporting the occurence and timing of first intercourse among
      adolescents.
AB  - Two types of reporting inconsistency for sexual initiation were analyzed--event
      occurrence and its timing--using data from two waves of the National Longitudinal
      Study of Adolescent Health (Add Health). Overall, 11.1% of those who reported
      they were sexually active at the time of first interview denied this at the
      subsequent one. Males of each race/ethnic group had higher percentages of
      inconsistency than their female counterparts. Being older, not living with
      parents, or having a highly educated mother was negatively associated with
      rescinding. Among those reporting sexual experience at both interviews, only
      22.2% reported the same date of first sex. On average, teens revised their age at
      first sex to older ages, and boys, especially African American boys, had large
      variability in reporting dates, as did teens with lower verbal ability. Seven
      strategies for resolving inconsistent reports are presented and implications for
      substantive findings are discussed.

PMID- 12476268
TI  - Age, religious beliefs, and sexual attitudes.
AB  - Age effects on sexual attitudes were examined using the Hendrick and Hendrick
      (1987a) Sexual Attitude Scale. The study was cross-sectional, including people
      from various age groups, from young adults to older adults. The religious beliefs
      variable, which covaries substantially both with age and sexual attitudes, was
      controlled. Three main questions guided the study: (a) Is the four-factor
      structure (Permissiveness, Instrumentality, Communion, and Sexual Practices)
      previously identified in a sample of young students able to accurately account
      for data gathered over a full range of adult ages, (b) are older adults much less
      permissive and less instrumentalist than young people, and (c) to what extent are
      believers less permissive and instrumentalist than young people when age is taken
      into account? Factor analyses showed that at least five correlated factors were
      needed to account for the data; the fourth factor, Sexual Practices, divided
      itself into two distinct factors: Pleasure and Responsibility. Older adults and
      believers were shown to be less permissive than young people and nonbelievers,
      and this result held regardless of the participants  educational level. As
      regards to instrumentality, however, the pattern of differences was extremely
      complex.

PMID- 12476269
TI  - Sexual coercion reported by women in three midwestern prisons.
AB  - The study was an anonymous self-report survey of coercive sexual experiences of
      women incarcerated in three Midwestern prisons. Inmate populations were 295
      (Facility 1), 113 (Facility 2) and 60 (Facility 3). Return rates were over 50%.
      Some prison staff were also surveyed. The 150 inmates in Facility 1 reported
      relatively high rates of sexual coercion: 27% had been coerced in the state
      system and 19% in their present facility. The 80 inmates in Facility 1 and 36
      inmates in Facility 3 reported lower rates: 8% to 9% for prisons statewide and 6%
      to 8% for their present facility. One half of the perpetrators were females. Most
      incidents involved genital touching. About one fifth of the incidents were
      classifiable as rape. We concluded that the prison environment potentially
      fosters female sexual aggression among inmates and sexual exploitation by staff.

PMID- 12476270
TI  - Gender, relationship stage, and sexual behavior: the importance of partner
      emotional investment within specific situations.
AB  - This study examined the relationship of type of sexually instigating situation
      (partner behavior conveying emotional investment or not), relationship stage, and
      gender to self-reported likelihood of engaging in sexual behavior. Participants
      (200 female and 122 male college students) read scenarios describing partner
      behavior in eight hypothetical sexual situations. Five of the sexual situations
      were proposed to explicitly communicate a sense of emotional investment in the
      relationship, and three other scenarios were conceived as not explicitly
      conveying emotional investment. Emotional investment situations were hypothesized
      to influence likelihood ratings as a function of imagined relationship stage
      (dating or in a serious relationship), manipulated across participants.
      Situations not conveying investment were hypothesized to influence ratings as a
      function of both relationship stage and gender. In large part, hypotheses were
      confirmed. The few exceptions were consistent with other gender-role
      considerations related to trust and power.

PMID- 12476271
TI  - Alemtuzumab (Campath-1H) for treatment of lymphoid malignancies in the age of
      nonmyeloablative conditioning?
AB  - The anti-CD52 (Campath-1) monoclonal antibodies (Mabs) have a substantial history
      of use for controlling graft-versus-host disease in allogeneic bone marrow
      transplantation. Now, with the availability of a humanised form, alemtuzumab
      (Campath-1H), and the demonstration that this agent can reduce the tumour burden
      in B-CLL, a new niche may be found - as a potentially curative agent in which its
      tumour purging ability in vivo combines with its role as a conditioning agent in
      nonmyeloablative transplantation. Review of the literature shows that alemtuzumab
      has unique advantages as a method of depleting malignant lymphocytes, including
      those in patients resistant to conventional chemotherapy. Alemtuzumab can also be
      used in BMT for depletion of normal T and B lymphocytes of both the recipient and
      donor for prevention of graft rejection and GVHD. It allows good stem cell
      recovery with resultant rapid engraftment, has a low risk of EBV-triggered
      secondary malignancy and does not interfere with blood stem cell mobilisation. As
      a method of eliminating the malignant clone in B-CLL, alemtuzumab has shown
      remarkable efficacy in heavily pre-treated patients, a number of whom have
      progressed to autologous or allogeneic transplantation. Efficacy data are shown
      within the context of other transplantation data for B-CLL. These results
      indicate that the combination of tumour-depleting and immunosuppressive
      properties of alemtuzumab should be explored, with the hope of providing improved
      treatment options for elderly patients with advanced B-CLL or indolent lymphoma
      whose prognosis is too poor currently to allow treatment with traditional
      regimens of high-dose myeloablative chemotherapy.

PMID- 12476272
TI  - Nonablative hematopoietic cell transplantation for the treatment of metastatic
      renal cell carcinoma.
AB  - Nonablative hematopoietic cell transplantation (HCT) is becoming a preferred
      treatment for those recipients in whom the potential toxicity risk of standard
      ablative allogeneic therapy may be unacceptable. Graft-versus-malignancy effects
      may be generated against epithelial malignancies which are similar to the graft
      versus-leukemia activity that is well documented in human hematological
      malignancies. Renal cell carcinoma has been shown to be responsive to
      immunotherapy with recombinant human cytokines and may be an ideal model for
      exploring this novel therapy. Clinical investigations have demonstrated
      regression of metastatic renal cell carcinoma occurs in some patients following
      nonablative allogeneic HCT. However, graft-versus-host disease remains a
      significant toxicity of nonablative transplantation, and further investigations
      are warranted to further evaluate this promising approach and to improve its
      safety.

PMID- 12476273
TI  - Increasing use of reduced intensity conditioning transplants: report of the 2001
      EBMT activity survey.
AB  - Since 1990, the EBMT has annually collected numbers of HSCT by disease
      indication, donor type and stem cell source. The 2001 survey concentrates on the
      use of reduced intensity conditioning (RIC) transplants and its dissemination in
      Europe. In 2001, there were 19576 HSCT for new patients, 6413 with allogeneic
      HSCT (33%), 13163 with autologous HSCT (67%) and 3256 additional re- or multiple
      transplants, 868 (667/201) allogeneic and 2658 (537/2121) autologous, collected
      from 596 centers in 35 European countries. The main indications in 2001 were
      leukemias (32%; 73% of them allogeneic); lymphomas (53%; 92% of them autologous);
      solid tumors (11%; 93% of them autologous) and non-malignant disorders (4%; 90%
      of them allogeneic). Compared to 2000, there was a drop in allogeneic HSCT of
      over 20% for chronic myeloid leukemia and an increase of 2% in autologous HSCT. A
      total of 1759 or 27% of allogeneic transplants were reported as RIC HSCT. These
      have risen in number in 3 years from <1% in 1998. There are wide variations from
      0 to 71% RIC HSCT in European countries with no obvious explanation. These data
      document the current status of blood and marrow transplantation in Europe and
      indicate a marked change towards RIC HSCT in allogeneic transplantation.

PMID- 12476274
TI  - A phase II trial of liposomal busulphan as an intravenous myeloablative agent
      prior to stem cell transplantation: 500 mg/m(2) as a optimal total dose for
      conditioning.
AB  - We conducted a phase I/II trial, to evaluate the efficacy and safety of an
      intravenous liposomal formulation of busulphan (LBu) as a myeloablative agent for
      stem cell transplantation (SCT). The liposomal busulphan was administered as a 3
      h infusion twice daily over 4 consecutive days. Six adults received 1.6-2
      mg/kg/dose and 18 children received 1.8-3 mg/kg/dose. Pharmacokinetic parameters
      were studied after the first and the last dose of busulphan. No significant
      difference in clearance, AUC, elimination half-lives or distribution volume
      between the first and the last dose was found in either groups. A significantly
      (P < 0.005) higher clearance was observed in children after the first and the
      last dose (3.61 and 3.79 ml/min/kg, respectively) compared to adults (2.40 and
      2.33 ml/min/kg, respectively). The elimination half-lives after the first and the
      last dose were significantly (P < 0.005) shorter in children (2.59 and 2.72 h,
      respectively) compared to adults (3.35 and 3.61 h, respectively). Clearance
      correlated significantly with age. However, no significant correlation with age
      was observed when clearance was adjusted to the body surface area. Two cases of
      VOD following a total dose of 24 mg/kg were observed. Six patients experienced
      mucositis. No other organ toxicity was observed. We conclude that intravenous
      liposomal busulphan pharmacokinetics is age dependent. A dosage schedule based on
      body surface area should be used especially in young children to reduce the age
      dependent difference in kinetics. An intravenous liposomal dose of busulphan of
      500 mg/m(2) is suggested to reach a similar systemic exposure and myeloablative
      effect in both children and adults. Moreover, the novel liposomal form of
      busulphan showed a favorable toxicity profile and seems safe as a part of the
      high-dose therapy prior to SCT.

PMID- 12476275
TI  - Optimal protocol for total body irradiation for allogeneic bone marrow
      transplantation in mice.
AB  - We have previously demonstrated, using chimeric resistant MRL/lpr mice, that a
      fractionated total body irradiation (FTBI) (5 Gy x 2 with a 4 h interval on the
      day before allogeneic bone marrow transplantation (BMT)) is the best conditioning
      regimen for the treatment of autoimmune diseases in radiosensitive MRL/lpr mice.
      In the present study, using various standard strains of mice (not radiosensitive
      mice), we explore the best protocol for irradiation (doses and intervals) as the
      conditioning regimen for allogeneic BMT. Recipient mice were exposed to various
      irradiation regimens: a single total body irradiation (TBI) of 9.5 or 12 Gy and
      FTBI of (5+5) Gy to (7+7) Gy with a 1 to 24 h interval. The method generally
      utilized for humans ((2+2) Gy with a 4 h interval for 3 days (total 12 Gy)) was
      also used. One day after the last irradiation, donor BMCs from BALB/c, C3H, or
      C57BL/6 (B6) mice were transplanted into C3H or B6 mice. The irradiation protocol
      of (2+2) Gy for 3 days was found to be insufficient to enable the complete
      removal of recipient immunocompetent cells, since donor-reactive T cells were
      observed in the recipient spleens and many recipient-type NK and CD4(+) cells
      were also detected in the recipient hematolymphoid tissues. In all the
      combinations, the highest survival rate was achieved in the recipients irradiated
      with (6+6) or (6.5+6.5) Gy with a 4 h interval. In the surviving mice, the
      hematolymphoid tissues had been fully reconstituted with donor cells.

PMID- 12476276
TI  - Optimising parameters for peripheral blood leukapheresis after r-metHuG-CSF
      (filgrastim) and r-metHuSCF (ancestim) in patients with multiple myeloma: a
      temporal analysis of CD34(+) absolute counts and subsets.
AB  - Patients (n = 69) with multiple myeloma undergoing peripheral blood stem cell
      collection (PBSC) were treated with cyclophosphamide and a combination of
      recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF,
      filgrastim) and recombinant methionyl human stem cell factor (r-metHuSCF,
      ancestim). The objectives of this study were to determine: (1) The proportion of
      patients reaching a target yield of >or=5 x 10(6) CD34(+) cells/kg in one or two
      successive large-volume (20 liter) leukapheresis procedures; (2) the optimal
      collection time for leukapheresis; (3) mobilization kinetics of CD34(+) subsets
      in response to G-CSF/SCF. All patients were mobilized with cyclophosphamide (2.5
      g/m(2)) on day 0 followed by filgrastim (10 microg/kg ) plus ancestim (20
      microg/kg) commencing day 1 and continuing to day 11 or 12. Of the 65 evaluable
      patients, 57 were considered not heavily pretreated and 96.5% obtained a target
      of >or=5 x 10(6)/kg in one collection. The median CD34(+) cells/kg was 39.5 x
      10(6) (range: 5.2-221.2 x 10(6)). Subset analysis demonstrated the number of
      CD38(-), CD33(-), and CD133(+) peaked at day 11; and CD34(+), CD90(+) cells
      peaked at day 10. The optimum day for leukapheresis was determined to be day 11.
      The median absolute peripheral blood CD34(+) cell numbers on day 11 was 665 x
      10(6)/l (range: 76-1481 x 10(6)/l). Eight of the 10 heavily pretreated patients
      were evaluable: three achieved the target dose in one leukapheresis (37.5%) and
      three (37.5%) achieved the target dose with two leukaphereses. Use of this
      mobilization strategy allowed the collection of high numbers of CD34(+) cells and
      early progenitors and the ability to predictably schedule leukapheresis.

PMID- 12476277
TI  - G-CSF-primed haploidentical marrow transplantation without ex vivo T cell
      depletion: an excellent alternative for high-risk leukemia.
AB  - Based on our encouraging results of G-CSF-primed HLA-matched related marrow
      transplants for high-risk leukemia, we extended the study from matched related to
      haploidentical transplants using G-CSF primed marrow and sequential
      immunosuppressants to prevent both graft-versus-host disease (GVHD) and host
      versus-graft rejection (HVGR). Fifteen high-risk leukemia patients, who needed
      urgent transplantation but lacked an HLA-matched donor, underwent G-CSF-primed
      haploidentical marrow transplantation without ex vivo T cell depletion. Donors
      were given G-CSF (Lenograstim) at 3-4 microg/kg/day for 7 days prior to marrow
      harvest. GVHD and HVGR prophylaxis were combined in the sequential usage of
      cyclosporin A, methotrexate, anti-thymocyte globulin and mycophenolate mofetil.
      All patients established sustained trilineage engraftment at a median of 19 days
      and 21 days for neutrophil and platelets respectively. G-CSF priming
      significantly increased CD34(+) and CFU-GM cells, reduced total lymphocytes and
      reversed the CD4(+)/CD8(+) ratio in the donor marrow. The incidence of grade II
      IV acute GVHD was 33.3%. Nine patients survived more than a year with a Karnofsky
      performance status of 100%. Estimated overall disease-free survival at 2 years
      was 60 +/- 7%. In conclusion, using G-CSF priming marrow grafts along with
      sequential immunosuppressants provided an excellent alternative for the treatment
      of high-risk hematological malignancy in patients who lack matched donors.

PMID- 12476278
TI  - W/Wv marrow stromal cells engraft and enhance early erythropoietic progenitors in
      unconditioned Sl/Sld murine recipients.
AB  - Transplantation of marrow stromal cells may provide a means of modulating
      hematopoiesis and serve as a form of cell therapy. We employed a murine
      transplant model using Sl/Sl(d) mice, which have macrocytic anemia due to
      defective expression of stem cell factor (SCF) on bone marrow stromal cells.
      Donor cells were derived from the complementary mutant strain W/W(v), which also
      exhibit anemia, due to mutations in c-kit, the SCF receptor expressed on
      hematopoietic stem cells. The strength of this model is that any correction of
      the Sl/Sl(d) anemia from the infusion of W/W(v) stromal cells can be attributed
      to the effect of the stromal cells and not to contaminating W/W(v) hematopoietic
      stem cells, a major concern in experiments involving wild-type animals. Cultured
      stromal cells were infused into unconditioned non-splenectomized Sl/Sl(d) mice.
      Engraftment of donor stromal cells reached levels of up to 1.0% of total marrow
      cells 4 months post transplant. However, stromal engraftment was not detectable
      in the spleen. Recipients of W/W(v) stroma showed a significant increase in the
      committed erythroid progenitors compared with those receiving Sl/Sl(d) stromal
      cells: 109 +/- 26 vs 68 +/- 5 CFU-E per 10(5) BMC, P = 0.002; 25 +/- 10 vs 15 +/-
      5 BFU-E per 10(5) BMC, P = 0.037, for W/W(v) and Sl/Sl(d) stroma recipients,
      respectively. Despite this increase in erythroid progenitors, the anemia was not
      corrected. Our data suggest that in this murine model, splenic erythropoiesis may
      influence stromal cell therapy, and that higher levels of marrow engraftment may
      be necessary to obtain a clinically significant effect.

PMID- 12476280
TI  - Intensive sequential dose dense chemotherapy with stem cell support as first-line
      treatment in advanced ovarian carcinoma: a phase II study.
AB  - From August 1995 to December 1997, 15 patients with stage III-IV ovarian cancer
      were treated with outpatient intensive chemotherapy with G-CSF and stem cell
      support. The first cycle consisted of cyclophophamide IV 6 g/m(2); second, third,
      fourth and fifth paclitaxel 250 mg/m(2) and the sixth and seventh carboplatin AUC
      18. CD34(+) cells were collected after the first cycle and reinfused after
      completion of cycles 6 and 7. Fourteen patients had stage IIIc and one patient
      had stage IV disease with liver metastases. All patients underwent laparotomy to
      maximize tumor debulking. This was optimal in eight patients and suboptimal in
      seven patients. Second-look surgery was performed in 14 patients. All patients
      had macroscopic complete responses and 10 patients had complete histologic
      response. Median follow-up was 48 months (range, 20 to 62). Twelve patients had
      further progression at a median of 27 months (range, 9 to 42) and nine are alive,
      three without evidence of disease progression. This pilot study shows that dose
      dense chemotherapy with paclitaxel and carboplatin is associated with low
      toxicity and may improve the outcome of patients with poor prognosis ovarian
      cancer.

PMID- 12476279
TI  - Transplantation as salvage therapy for high-risk patients with myeloma in
      relapse.
AB  - Patients with myeloma relapsing after tandem transplant have a poor survival and
      treatment options are limited. The role of additional salvage transplant
      procedures for these patients is unknown. To evaluate the benefit and identify
      prognostic factors, the outcome of 76 consecutive patients with recurrent myeloma
      after tandem transplant receiving salvage transplants (ST) was analyzed. Prior to
      ST, 23 patients (30%) had shown chemosensitive response to preceding salvage
      chemotherapy: two complete remissions (CR); eight near CRs (nCR: only
      immunofixation positive); 13 partial remissions (PR >or=75% reduction in M
      protein). Fifty received an autologous transplant, 22 a sibling-matched
      allogeneic transplant, and four a matched-unrelated allogeneic transplant.
      Overall response after ST was 59%: eight CRs (11%); 14 nCRs (18%); 23 PRs (30%).
      Overall survival (OS) at 2 years was 19%; 2 year event-free survival rate (EFS)
      7%. On univariate analysis for survival, only pre-transplant chemosensitive
      relapse (P < 0.05), serum albumin >3 g/dl (P = 0.001), normal LDH (P = 0.04), and
      long interval between the second transplant and relapse/progression were
      significant beneficial factors. In a Cox proportional hazard model,
      chemosensitive relapse, and albumin >3 g/dl were significant for better OS:
      hazard ratio (HR) 1.4, 1.7, respectively, while normal LDH, and absence of CA13
      were significant for better EFS: HR 1.8, 1.7, respectively. Patients with albumin
      >3 g/dl who had chemosensitive disease before ST (n = 16) had a median survival
      of 16 months, compared to 7 months (n = 34) and 2 months (n = 26) for patients
      with only one (n = 34) or no favorable prognostic factors (n = 28), respectively
      (P < 0.001). Their survival at 2 years post-ST was 43%, 17% and 11%,
      respectively. Our study suggests further transplantation should only be
      considered in the setting of a clinical trial in patients with favorable
      prognostic factors.

PMID- 12476281
TI  - 'Relative' chemotherapy sensitivity: the impact of number of salvage regimens
      prior to autologous stem cell transplant for relapsed and refractory aggressive
      non-Hodgkin's lymphoma.
AB  - The purpose of the study was to assess the impact of number of salvage regimens
      needed to demonstrate chemotherapy sensitivity on relapse rates, survival, and
      toxicity following high-dose therapy and autologous bone marrow transplantation
      (ABMT) in relapsed or refractory non-Hodgkin's lymphoma. We retrospectively
      reviewed 136 patients with intermediate-grade lymphoma who underwent ABMT. All
      patients were treated with salvage therapy to maximum tumor reduction. Three
      quarters (102/136) of the patients received one salvage regimen, while 31 (23%)
      patients received two or more regimens. When compared to patients requiring >or=
      two regimens, patients requiring only one salvage regimen to demonstrate
      chemosensitivity were more likely to have a longer previous CR from initial
      therapy (CR >or=12 months in 47% vs 26%; P = 0.04) and to have attained CR with
      salvage (54% vs 16%; P = 0.001). Both median relapse-free survival (RFS) and
      overall survival (OS) have not yet been reached in patients receiving one salvage
      regimen (median follow-up 50.6 months). This is superior to the median RFS of 9.1
      months (P = 0.004) and OS of 11.1 months in patients requiring >or=two regimens
      to demonstrate chemosensitivity (P = 0.002). Time to engraftment, toxic deaths
      and incidence of myelodysplasia were similar in the groups. The survival rate
      observed in patients requiring >or=two salvage regimens, although inferior to
      that of patients receiving a single salvage regimen, are still generally superior
      to results in the literature for patients treated with chemotherapy alone without
      ABMT. We conclude that high-dose therapy with ABMT is appropriate for lymphoma
      patients even when disease reduction requires repeated numbers of salvage
      regimens.

PMID- 12476282
TI  - High-dose chemotherapy with autologous stem cell rescue in children with
      nephroblastoma.
AB  - Children with Wilms tumor who have a particular risk of failure at relapse or at
      primary diagnosis were treated with high-dose chemotherapy (HDC) and autologous
      peripheral blood stem cell rescue in order to improve their probability of
      survival. From April 1992 to December 1998, 23 evaluable patients received HDC
      within the German Cooperative Wilms Tumor Studies. Nineteen were given melphalan,
      etoposide and carboplatin (MEC); the others received different regimens. The dose
      of carboplatin was adjusted according to renal function. Indications for HDC were
      high-risk relapse in 20 patients, bone metastases in two patients and no response
      in one patient. Fourteen of 23 patients are alive after a median observation time
      of 41 months, 11 of 14 in continuous complete remission, three in CR after
      relapse post HDC. The estimated survival and event-free survival for these
      patients are 60.9% and 48.2%. Twelve children relapsed after HDC; nine of them
      died within 12 months and three are surviving from 20 to 33 months after relapse.
      The main toxicities were hematologic, mucositis and renal (tubular dysfunction;
      intermittent hemodialysis in one patient). There were no toxic deaths. About half
      of the children suffering from Wilms tumor with very unfavorable prognostic
      factors survive disease-free after HDC for over 3 years. Besides hematological
      toxicity, mucositis and infections, renal function is at risk during HDC. With
      dose adjustment on glomerular filtration rate, however, no permanent renal
      failure was observed.

PMID- 12476283
TI  - Basiliximab is well tolerated and effective in the treatment of steroid
      refractory acute graft-versus-host disease after allogeneic stem cell
      transplantation.
AB  - Basiliximab, a chimeric interleukin-2 receptor (IL-2-R) antagonist, was evaluated
      in 17 patients with steroid-refractory acute graft-versus-host disease (GVHD)
      after allogeneic stem cell transplantation (SCT). Patients were transplanted from
      a related (n = 6) or unrelated (n = 11) HLA-identical donor because of acute
      lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 3), chronic myeloid
      leukemia (n = 7), myelodysplastic syndrome (n = 1), non-Hodgkin's lymphoma (n =
      1), and multiple myeloma (n = 1). Basiliximab was given at a dose of 2 x 20 mg on
      2 consecutive days after steroid-refractory acute GVHD had developed. Basiliximab
      was repeated on day 8 in cases of persistent GVHD. A median of four basiliximab
      infusions (range 1-12) were given to these patients. None had infusion-associated
      or cytokine-related side-effects after basiliximab. Twelve of 17 patients (71%)
      responded to basiliximab, 9/17 (53%) had a complete response (CR) of acute GVHD
      and 3/17 (18%) had a partial response (PR). Five of 17 patients (29%) did not
      respond. Chronic GVHD developed in 8/13 evaluable patients and only 2/8 had
      responded to basiliximab before. Five of 13 evaluable patients have no signs of
      chronic GVHD and all five had a CR or PR after basiliximab. This is the first
      report on the safety of basiliximab in patients with steroid-refractory acute
      GVHD. Our data suggest that basiliximab is effective in a substantial proportion
      of these patients.

PMID- 12476284
TI  - Evaluation for synergistic suppression of T cell responses to minor
      histocompatibility antigens by chloroquine in combination with tacrolimus and a
      rapamycin derivative, SDZ-RAD.
AB  - The 4-aminoquinolines, chloroquine and hydroxychloroquine, can suppress chronic
      graft-versus-host disease (GVHD) following blood and marrow transplantation (BMT)
      in mice and humans, respectively. We hypothesized that chloroquine in combination
      with tacrolimus and the rapamycin derivative SDZ-RAD can synergistically suppress
      T cell responses and antigen-presenting cell (APC) function in vitro. We used the
      APC-dependent C57BL/6 anti-BALB.B T cell response and APC-independent anti
      CD3epsilon antibody-induced response to evaluate the role of synergism between
      chloroquine and tacrolimus or SDZ-RAD on each component of a T cell response to
      minor histocompatibility antigens. We found that chloroquine with tacrolimus had
      a greater synergistic suppression of APC-dependent compared to the APC
      independent T cell responses, with a combination index (CIx) for 50% inhibition
      by mean effect analysis of 0.16 and 0.50, respectively (a lower number indicates
      greater suppression). By contrast, chloroquine with SDZ-RAD had a similar CIx
      between the two responsed 0.50 vs0.45) suggesting only T cell suppression.
      Synergy between chloroquine and SDZ-RAD involved a direct effect on T cell
      cytokine production, whereas synergism between chloroquine and tacrolimus was due
      to an effect on both T cells and APCs. We conclude that the renal-sparing 4
      aminoquinolines may be used syneristically with immunosuppressive drugs currently
      used for BMT.

PMID- 12476285
TI  - Distinct TCRAV and TCRBV repertoire and CDR3 sequence of T lymphocytes clonally
      expanded in blood and GVHD lesions after human allogeneic bone marrow
      transplantation.
AB  - Acute graft-versus-host disease (GVHD) is a disorder involving the skin, gut and
      liver that is caused by mismatches of major and/or minor histocompatibility
      antigens between the HLA-identical donor and recipient. If T lymphocytes
      infiltrating GVHD lesions recognize antigens expressed in these organs, T cell
      clones should expand in inflammatory tissues. We previously reported that
      recipients of allogeneic bone marrow grafts have clonally expanded
      TCRalphabeta(+) T lymphocytes soon after transplantation, which leads to a skew
      of TCR repertoires. To establish whether or not the same antigens cause clonal
      expansion of T lymphocytes in both blood and GVHD tissues, we examined the usage
      of TCR alpha and beta chain variable regions (TCRAV and TCRBV) and determined the
      complementarity-determining region 3 (CDR3) of T lymphocytes clonally expanded in
      circulating blood and GVHD lesions. We found that the repertoires and CDR3
      diversity of TCRAV and TCRBV differed between the GVHD lesions and circulating
      blood, suggesting the selective recruitment of antigen-specific T cells into GVHD
      tissues. We also found that the usage of TCRAV and TCRBV by the clonally expanded
      T lymphocytes and their CDR3 sequences differed between the GVHD tissues and
      blood. These results suggest that the antigen specificity of TCRalphabeta(+) T
      lymphocytes clonally expanded in blood and GVHD lesions is different.

PMID- 12476286
TI  - Aspergillus infections in allogeneic stem cell transplant recipients: have we
      made any progress?
AB  - Invasive aspergillosis (IA) is common in allogeneic SCT recipients, with an
      incidence of 4-10%. The majority of these infections are diagnosed several months
      after SCT and they are frequently associated with GVHD. The diagnosis is
      difficult and often delayed. Established IA is notoriously difficult to treat
      with a death rate of 80-90%. This review summarises recent data on this problem
      to assess whether there has been any progress. Effective prophylactic measures
      are still lacking. Severe immunosuppression is the main obstacle to the success
      of therapy. Recent and ongoing developments in diagnostic measures and new
      antifungal agents may improve treatment results to some extent, but Aspergillus
      infections still remain a formidable problem in allogeneic transplantation.
      Further studies in this field will focus on the role of various cytokines and
      combinations of antifungal agents.

PMID- 12476287
TI  - Prospective evaluation of Candida species colonization in hospitalized cancer
      patients: impact on short-term survival in recipients of marrow transplantation
      and patients with hematological malignancies.
AB  - Most hematogenous candidiasis originates from endogenous host flora. The impact
      of clinically prominent Candida colonization on short-term mortality (<or=14
      weeks) was prospectively studied in 193 hospitalized patients from 1998 to 1999.
      Clinically prominent colonization included yeasts isolated from all sterile body
      sites and >50 colonies of Candida from non-sterile sites. Fourteen (7.1%)
      patients were granulocytopenic (ANC <or=100/microl). Nineteen (9.8%) had
      undergone marrow transplantation, 26 (13.5%) had a hematologic malignancy and 129
      (66.5) had non-hematologic cancer. Candida isolates (216) were collected form 210
      specimens. Fifty-three (27.5%) patients died; 25 (19.4%) with solid tumors,
      compared to 16 (61.5%) with hematological malignancy, and 11 (57.9%) BMT
      recipients (P < 0.001). No deaths were seen in patients with AIDS, and one (7.7%)
      in a patient with a benign condition (P < 0.001). Twenty-six (29.2%) patients
      with respiratory tract, 13 (23.2%) with gastrointestinal tract, and three (14.3%)
      with genitourinary tract colonization died. In patients with multiple-site
      colonization, mortality was significantly higher (45.5%) (P < 0.05). Mortality
      was higher in patients with C. glabrata (52.9%) and C. krusei (75%) colonization
      than with C. albicans (24.1%) (P < 0.025). This study shows that patients with
      hematologic cancer and recipients of marrow transplant with Candida colonization
      of multiple body sites, and colonization with C. glabata or C. krusei have poor
      survival.

PMID- 12476288
TI  - Early infections in adult patients undergoing unrelated donor cord blood
      transplantation.
AB  - Early transplant-related mortality after cord blood transplantation from
      unrelated donors (UD-CBT) is close to 50%, mainly due to infectious
      complications. We have studied the incidence and characteristics of early
      infections (before day 100) in a series of 27 adult patients (median age 30
      years, range 16-46) undergoing UD-CBT at a single institution. All 27 patients
      experienced at least one infectious episode and 18 (66%) suffered a severe
      infection. Bacteremia occurred in 55% of patients (13 with Gram-positive and 11
      with Gram-negative microorganisms). Eleven of 19 CMV-seropositive patients (58%)
      developed CMV antigenemia and one patient had CMV disease. Fungal infections were
      documented in three patients (11%), comprising invasive fungal infections in two
      cases and a localized esophagitis in one. Ten patients (37%) died before day 100
      after transplantation. Infection was considered the primary cause of death in
      four patients (sepsis by Acinetobacter spp. bacteremia in three cases) and
      contributed to death in another four. The most striking findings in this series
      were the high incidence of, and mortality due to multiresistant Acinetobacter
      spp. and the low incidence of and lack of mortality due to CMV disease. This
      report confirms that infection is a major complication in adults undergoing UD
      CBT.

PMID- 12476289
TI  - Randomized clinical trial of ganciclovir vs acyclovir for prevention of
      cytomegalovirus antigenemia after allogeneic transplantation.
AB  - Cytomegalovirus (CMV) disease remains a major cause of morbidity following
      allogeneic stem cell transplantation (SCT). In a prospective randomized trial, we
      tested prophylactic therapy with ganciclovir or acyclovir for patients at high
      risk of disease. Ninety-one CMV seropositive recipients of related (n = 53) and
      unrelated (n = 38) donor transplants were enrolled. All patients received
      intravenous (i.v.) ganciclovir 5 mg/kg every 12 h days -7 to -2, followed by
      acyclovir 10 mg/kg i.v. every 8 h from day -1 until neutrophil engraftment.
      Patients were then randomly assigned to either ganciclovir (n = 45) or acyclovir
      (n = 46) until day 100 post transplant. Any degree of antigenemia was treated
      with ganciclovir 5 mg/kg i.v. twice a day for 2 weeks, followed by 5 mg/kg i.v.
      each weekday for 6 weeks. At day 100, the cumulative incidence of antigenemia was
      31% (95% CI 17-45%) for ganciclovir and 41% (95% CI 26-56%) (P = 0.22) for
      acyclovir prophylaxis, respectively. The assigned prophylaxis cohort did not
      predict for CMV antigenemia. The cumulative incidence of CMV disease at 12 months
      was 13% (95% CI 3-23%) and 17% (95% CI 6-28%) (P = 0.59) for the ganciclovir- and
      acyclovir-treated groups, respectively. An absolute neutrophil count (ANC)
      <or=1500 x 10(6)/l at randomization (P < 0.01) and grade II-IV acute graft-versus
      host-disease (P = 0.01), but not the assigned prophylaxis cohort (P = 0.62), were
      independent risk factors for CMV disease. The incidence of fungal infections and
      renal insufficiency was similar across treatment groups; however, bacterial
      infections and secondary neutropenia occurred more frequently in the ganciclovir
      group. With our study powered to detect a 60% reduction in antigenemia with
      ganciclovir prophylaxis, we did not find a statistically significant difference
      between ganciclovir and acyclovir when used as part of an overall strategy for
      prevention of CMV antigenemia and disease in SCT, although fewer side-effects
      occurred with acyclovir treatment.

PMID- 12476290
TI  - Standardized parenteral alanyl-glutamine dipeptide supplementation is not
      beneficial in autologous transplant patients: a randomized, double-blind, placebo
      controlled study.
AB  - We conducted a controlled, double-blind study of parenteral glutamine
      supplementation in an unselected group of consecutive autologous transplant
      patients. Patients received 30 g of alanyl-glutamine dipeptide (Dipeptiven;
      Fresenius-Kabi, Bad Homburg, Germany) or glutamine-free amino acid solution i.v.
      from day +1 to day +14 or to discharge. All patients were assessed for clinical
      status, mucositis, blood counts, oral intake and immune reconstitution.
      Parenteral nutrition was administered according to predefined guidelines. Forty
      patients were randomized; 21 into the glutamine and 19 into the placebo arm.
      Glutamine patients had less days with diarrhoea (3.3 +/- 4.0 vs 4.3 +/- 3.0, P =
      0.03), but they had more severe oral mucositis (mean 4 +/- 4.7 vs 1.4 +/- 2.3
      days of mucositis score >13, P = 0.04), spent more days on opioids (mean 3.5 +/-
      4.2 vs 1.2 +/- 2.2 days, P = 0.03) and left hospital later than placebo patients
      (mean 13.5 +/- 3.1 vs 11.7 +/- 2.4 days after transplant, P = 0.06). There were
      more relapses (P = 0.02) and deaths (P = 0.05) in the glutamine group. The cost
      of supportive care (mean 2960 +/- 1694 vs 1534 +/- 513 Euro, P = 0.002) was also
      greater for glutamine patients, mainly due to the cost of glutamine dipeptide
      itself. The described mode and dosage of glutamine administration did not produce
      meaningful benefit in our autologous transplant patients and it was certainly not
      cost-effective.

PMID- 12476291
TI  - Progressive multifocal leukoencephalopathy after stem cell transplantation,
      unsuccessfully treated with cidofovir.
AB  - We report a patient with progressive multifocal leukoencephalopathy (PML) after
      autologous stem cell transplantation (SCT) for non-Hodgkin's lymphoma (NHL). This
      is an unusual association, and to date only seven cases have been reported. This
      is the first case of PML after SCT treated with cidofovir, and the fifth case
      treated with this drug in a patient without human immunodeficiency virus (HIV)
      infection. In the previous four patients treated with cidofovir the outcome was
      discouraging, as was the case in this patient.

PMID- 12476292
TI  - Voriconazole in the management of invasive aspergillosis in two patients with
      acute myeloid leukemia undergoing stem cell transplantation.
AB  - The management of invasive aspergillosis in patients with hematological
      malignancies remains controversial. A major problem is how to manage patients who
      had invasive aspergillosis during remission induction and consolidation therapy
      and then undergo SCT. Indeed in these patients the mortality rate related to
      invasive aspergillosis recurrence remains unacceptably high. We report two cases
      of patients who underwent remission induction for AML, developed invasive
      aspergillosis during antifungal prophylaxis with itraconazole, failed
      amphotericin B deoxycholate and liposomal amphotericin B treatment, were
      successfully treated with voriconazole and eventually underwent SCT with
      voriconazole prophylaxis without reactivation of invasive aspergillosis.

PMID- 12476293
TI  - Favorable outcome with STI571 (imatinib mesylate) and allogeneic stem cell
      transplantation in a case of Ph+ chemorefractory acute lymphocytic leukaemia.
AB  - We present a patient with a Philadelphia chromosome positive (Ph+) acute
      lymphocytic leukaemia (ALL) refractory to standard induction chemotherapy.
      Treatment with the ABL-specific tyrosine kinase inhibitor STI571 (Glivec,
      Gleevec, imatinib mesylate) resulted in a complete haematologic and cytogenetic
      remission. Allogeneic stem cell transplantation from an unrelated donor could be
      undertaken while the patient was in STI571-induced complete remission from the
      leukaemia. At present, the patient has a 15-month post-transplantation follow-up
      and is in stable molecular remission as evaluated by quantitative reverse
      transcriptase polymerase chain reaction (qRT-PCR) for the BCR/ABL fusion gene
      transcript. Our case demonstrates that STI571 can act as a bridge to potentially
      curative allogeneic stem cell transplant in otherwise poor prognosis Ph+ ALL.

PMID- 12476295
TI  - Unrelated bone marrow transplantation for leukocyte adhesion deficiency.
AB  - The severe form of leukocyte adhesion deficiency type I (LAD-I) usually leads to
      death early in life. Allogeneic haematopoietic transplantation is the only cure.
      Unrelated transplantation has been reported only once. We describe three children
      with LAD-I transplanted with T cell non-depleted bone marrow from unrelated HLA
      matched donors. All patients engrafted, one of them at second transplant. One
      patient developed grade I and one grade II acute GVHD. Two patients are alive,
      one of them with a decrease in CD11/CD18 expression. Early referral for HLA
      matched unrelated BMT is a reasonable option for patients with LAD-I lacking an
      HLA-matched related donor.

PMID- 12476294
TI  - Treatment of diffuse alveolar hemorrhage after allogeneic bone marrow transplant
      with recombinant factor VIIa.
AB  - Diffuse alveolar hemorrhage (DAH) is a potentially life-threatening pulmonary
      toxicity that occurs in 1-21% of patients following bone marrow transplantation.
      The syndrome is associated with a high mortality rate; and current treatment
      options are limited. Recombinant factor VIIa (rFVIIa, Novoseven) has recently
      been approved for the treatment of bleeding in patients with hemophilia A/B with
      inhibitors. A greater understanding of the mechanism by which rFVIIa restores
      hemostasis has recently become available; with in vitro evidence supporting that
      the thrombin burst achieved by rFVIIa is independent of the presence or binding
      to tissue factor. This insight has suggested a range of other potential clinical
      uses for the drug; including the setting of pulmonary hemorrhage. We review our
      experience with using rFVIIa for treatment of DAH in a patient with acute
      myelogenous leukemia following a matched unrelated donor bone marrow transplant.
      Boluses of 90 microg/kg rFVIIa were given every 3 h x 4 doses/day, concurrently
      with high-dose corticosteroids and maintenance of a platelet count >50 000/mm(3).
      Rapid clinical and radiological improvement was noted within several doses of
      rFVIIa, with discontinuation of the drug after eight doses. However, the
      patient's clinical condition began to rapidly deteriorate following cessation of
      rVIIa, resulting in reinstitution of therapy 24 h later. The patient again
      exhibited rapid clinical improvement; and rFVIIa was continued for an additional
      16 doses with no further evidence of pulmonary hemorrhage noted. No toxicity or
      adverse events were observed with rFVIIa treatment. Our experience indicates that
      rFVIIa may be an effective treatment option for DAH post bone marrow transplant;
      although further clinical studies are needed before recommendations can be made
      regarding off label use of rFVIIa in this clinical setting.

PMID- 12476296
TI  - Human herpesvirus-7 infection of the CNS with acute myelitis in an adult bone
      marrow recipient.
AB  - The beta-herpesviruses, human herpesviruses-6 and -7 (HHV-6 and HHV-7), are
      closely related and have very similar biological behaviour. While HHV-6 is
      associated with encephalitis in immunosuppressed adults, HHV-7 is not recognised
      as a cause of neurological disease in such patients. This report describes the
      identification of a reactivated HHV-7 infection in the cerebrospinal fluid of an
      adult who presented with an acute myelitis 11 months after unrelated donor bone
      marrow transplant.

PMID- 12476297
TI  - Safety and efficacy of high-dose G-CSF (24 microg/kg) alone for PBSC moblization
      in children.

PMID- 12476299
TI  - Philadelphia-positive leukemia: a personal perspective.

PMID- 12476300
TI  - Inhibition of the Bcr-Abl tyrosine kinase as a therapeutic strategy for CML.

PMID- 12476301
TI  - BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic
      myelogenous leukemia.

PMID- 12476302
TI  - Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia.
AB  - The fusion of 5' parts of the BCR gene to the ABL gene at the second exon yields
      several forms of an oncogenic Bcr-Abl oncoprotein observed in several types of
      Philadelphia chromosome positive leukemia patients. The first exon of the BCR
      gene is a critical part of this fusion, as the coiled-coil domain at the amino
      terminal domain of the Bcr protein causes oligomerization of the Bcr-Abl
      oncoprotein forming tetramers, thereby activating the tyrosine kinase activity of
      the normally silent c-Abl protein. Another consequence of this Bcr-Abl fusion is
      the extensive autophosphorylation of the cis Bcr protein sequences on tyrosine
      residues. This review will summarize the effects of Bcr-Abl autophosphorylation
      on tyrosines as they relate to the oncogenic activity of Bcr-Abl, and as a means
      to inactivate the serine/threonine kinase activity of the Bcr protein. The review
      also discusses our findings that show that phosphoserine Bcr by means of a unique
      structure, binds to the Abl SH2 domain of the Bcr-Abl oncoprotein, and as a
      result this SH2 binding inhibits the oncogenic effects of the oncoprotein. Our
      results indicate that one effect of this binding is inhibition of the Bcr-Abl
      tyrosine kinase. Serine 354 of Bcr plays a major role in this inhibition. In the
      case of Bcr(64-413), serine 354 is required for the formation of the unique Bcr
      structure that binds to the Abl SH2 domain.

PMID- 12476303
TI  - Transforming pathways activated by the v-Abl tyrosine kinase.
AB  - The Abelson Murine Leukemia Virus (A-MuLV) is the acute transforming retrovirus
      encoding the v-abl oncogene. Two isolates of the virus encoding proteins of p120
      Kd and 160 Kd have been extensively studied. These viral isolates have been found
      to transform both hematopoietic and fibroblastic cells in vitro, while inducing
      predominantly pre-B cell leukemias in vivo. Both p120(v-Abl) and p160(v-Abl) are
      plasma membrane-associated non-receptor tyrosine kinases and the transforming
      activity of these proteins requires their tyrosine kinase activity. A-MuLV
      infection of hematopoietic cells has often been found to result in the abrogation
      of their cytokine-dependence for growth. In addition, v-Abl expressing
      hematopoietic cells often lose their ability to differentiate in response to
      appropriate cytokines. This review discusses some of the early transformation
      studies of A-MuLV, as well as some of the findings concerning the structure and
      biochemical activity of the v-Abl protein. Finally, we discuss the mechanisms
      associated with v-Abl mediated transformation through examination of the various
      signal transduction pathways activated by this oncogene.

PMID- 12476304
TI  - Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA
      binding proteins.
AB  - Shuttling hnRNPs control the fate of eukaryotic mRNAs throughout their journey
      from the active site of transcription to that of translation; thus, gain or loss
      of their function in hematopoietic cells might result in altered hematopoiesis
      and/or be associated with the process of leukemogenesis. In BCR/ABL-expressing
      cells, there is a marked increase in the protein levels FUS, hnRNP A1 and hnRNP
      E2, three RNA-binding proteins involved in the regulation of mRNA processing,
      nucleocytoplasmic export, and translation. Ectopic expression and/or inhibition
      of the activity of these RNA-binding proteins affects proliferation, survival,
      and differentiation of normal and BCR/ABL-expressing cells, suggesting that
      enhanced expression/activity of certain RNA-binding proteins plays an important,
      but as yet unrecognized, role in BCR/ABL leukemogenesis. The identification of
      the mRNA subsets associated with RNA-binding proteins upregulated in BCR/ABL
      expressing cells should functionally link the process of leukemogenesis with
      alteration of mRNA metabolism.

PMID- 12476305
TI  - Novel targeted therapies for Bcr-Abl positive acute leukemias: beyond STI571.
AB  - In the pathophysiology of CML, the constitutive activity of the Bcr-Abl tyrosine
      kinase (TK) is, most likely, the sole molecular abnormality of the chronic phase.
      It also remains a critical molecular determinant of malignant behavior of the
      leukemic progenitors in the accelerated and blastic phase of CML. Therefore,
      downregulation of the levels and activity of Bcr-Abl is clearly the lynchpin of a
      rational therapeutic strategy against all phases of CML. Support for this has
      only been strengthened by the observations that resistance to imatinib mesylate
      (imatinib) commonly involves a breakthrough and the persistent activity of Bcr
      Abl TK. This is due to either mutations that inhibit imatinib action on Bcr-Abl
      TK or amplification of the bcr-abl gene. Recent studies have demonstrated that
      other small molecule tyrosine kinase inhibitors that also inhibit Bcr-Abl TK may
      be highly active in inducing differentiation and apoptosis of CML progenitors,
      regardless of their sensitivity to imatinib. Small molecule inhibitors that
      downregulate the levels of Bcr-Abl by inhibiting its translation, e.g., arsenic
      trioxide, or promoting its proteasomal degradation, e.g., geldanamycin analogues,
      have also been identified. Finally the identification of other potent survival
      and antiapoptotic signaling pathways in imatinib-resistant CML progenitors
      indicates that inhibitors of these pathways will eventually be treatment
      strategies for advanced phases of CML.

PMID- 12476306
TI  - BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic
      treatment and in genomic instability.
AB  - BCR/ABL regulates cell proliferation, apoptosis, differentiation and adhesion. In
      addition, BCR/ABL can induce resistance to cytostatic drugs and irradiation by
      modulation of DNA repair mechanisms, cell cycle checkpoints and Bcl-2 protein
      family members. Upon DNA damage BCR/ABL not only enhances reparation of DNA
      lesions (e.g. homologous recombination repair), but also prolongs activation of
      cell cycle checkpoints (e.g. G2/M) providing more time for repair of otherwise
      lethal lesions. Moreover, by modification of anti-apoptotic members of the Bcl-2
      family (e.g. upregulation of Bcl-x(L)) BCR/ABL provides a cytoplasmic 'umbrella'
      protecting mitochondria from the 'rain' of apoptotic signals coming from the
      damaged DNA in the nucleus, thus preventing release of cytochrome c and
      activation of caspases. The unrepaired and/or aberrantly repaired (but not
      lethal) DNA lesions resulting from spontaneous and/or drug-induced damage can
      accumulate in BCR/ABL-transformed cells leading to genomic instability and
      malignant progression of the disease. Inhibition of BCR/ABL kinase activity by
      STI571 (Gleevec, imatinib mesylate) reverses drug resistance and, in combination
      with standard chemotherapeutics can exert strong anti-leukemia effect.

PMID- 12476307
TI  - Mechanisms underlying abnormal trafficking and expansion of malignant progenitors
      in CML: BCR/ABL-induced defects in integrin function in CML.

PMID- 12476308
TI  - The biology of chronic myelogenous leukemia:mouse models and cell adhesion.
AB  - Chronic myelogenous leukemia (CML) is a biphasic neoplasm of the bone marrow that
      is precipitated by the Philadelphia chromosome, a t(9;22) balanced translocation
      that encodes a constitutively activated nonreceptor tyrosine kinase termed
      P210(BCR-ABL). This oncoprotein has several intracellular functions; however, the
      most important effect of P210(BCR-ABL) leading to cell transformation is
      phosphorylation of signaling molecules through a constitutively active tyrosine
      kinase domain. Despite extensive knowledge of the structure and functional
      domains of BCR-ABL, its precise function in transformation is not known. Progress
      has been hampered, in part, by the lack of relevant CML models, as cell culture
      and in vitro assays do not mimic the pathogenesis of CML. Recently, there has
      been significant progress toward improving murine models that closely resemble
      human CML. This has allowed researchers to evaluate critical functions of BCR-ABL
      and has provided a model to test the efficacy of therapeutic medications that
      block these pathways. Our laboratory has developed two intersecting research
      programs to better understand the functioning of P210(BCR-ABL) in leukemogenesis.
      In one approach, we have developed a murine CML model by transferring HSCs that
      express BCR-ABL from a retroviral vector. All recipients develop a rapidly fatal
      MPD that shares several important features with CML. This model has been
      extremely useful for studying the function of BCR-ABL in the pathogenesis of CML.
      A second approach utilizes a quantitative cell detachment apparatus capable of
      measuring small changes in cell adhesion to investigate the mechanism by which
      P210(BCR-ABL) causes abnormal cell binding. Altered cell adhesion may contribute
      to the imbalance between proliferation and self-renewal in the hematopoietic
      progenitor compartment. To better understand the role abnormal adhesion may play
      in the development of leukemia, we have attempted to correlate the effects of
      functional P210(BCR-ABL) mutants in regulating adhesion and oncogenicity.

PMID- 12476309
TI  - The molecular mechanism of chronic myelogenous leukemia and its therapeutic
      implications: studies in a murine model.
AB  - Chronic myelogenous leukemia (CML) is a malignant disease resulting from the
      neoplastic transformation of a hematopoietic stem cell. Generation of the BCR-ABL
      fusion gene plays an essential role in causing the vast majority of CML. Clinical
      and laboratory studies have indicated that development of CML involves both the
      effects of BCR-ABL within its correct target cells and interactions of BCR-ABL
      target cells with the rest of the in vivo environment, and that the progression
      of the disease to blast crisis involves multiple genetic alterations. An
      efficient mouse bone marrow transduction and transplantation model for CML has
      recently been developed. This review summarizes the analysis of the roles of
      functional domains and downstream signaling pathways of BCR-ABL, of altered
      cytokine production, of interferon signaling pathways and of oncogene cooperation
      in the pathogenesis of CML using this murine model. The in vivo studies of
      leukemogenesis will help to advance mechanism-based therapies for CML, as well as
      to understand fundamental rules of leukemogenesis and hematopoiesis.

PMID- 12476310
TI  - Studying the pathogenesis of BCR-ABL+ leukemia in mice.
AB  - Animal models of BCR-ABL+ leukemias have provided important new knowledge about
      the molecular pathophysiology of these diseases, and answered questions that are
      difficult or impossible to address using BCR-ABL-expressing cell lines or primary
      Ph+ leukemia samples from patients. The power of mouse models lies in their
      ability to recapitulate precisely the phenotypes of BCR-ABL+ leukemias in vivo,
      but this comes at the price of significant complexity. Here I review recent
      studies of leukemias induced in mice by BCR-ABL with an emphasis on the intricate
      nature of these diseases and the need for careful pathological and molecular
      analysis.

PMID- 12476311
TI  - BCR/ABL genes and leukemic phenotype: from molecular mechanisms to clinical
      correlations.
AB  - The Philadelphia chromosome (Ph), a minute chromosome that derives from the
      balanced translocation between chromosomes 9 and 22, was first described in 1960
      and was for a long time the only genetic lesion consistently associated with
      human cancer. This chromosomal translocation results in the fusion between the 5'
      part of BCR gene, normally located on chromosome 22, and the 3' part of the ABL
      gene on chromosome 9 giving origin to a BCR/ABL fusion gene which is transcribed
      and then translated into a hybrid protein. Three main variants of the BCR/ABL
      gene have been described, that, depending on the length of the sequence of the
      BCR gene included, encode for the p190(BCR/ABL), P210(BCR/ABL), and P230(BCR/ABL)
      proteins. These three main variants are associated with distinct clinical types
      of human leukemias. Herein we review the data on the correlations between the
      type of BCR/ABL gene and the corresponding leukemic clinical features. Lastly,
      drawing on experimental data, we provide insight into the different transforming
      power of the three hybrid BCR/ABL proteins.

PMID- 12476312
TI  - The basis of T-cell-mediated immunity to chronic myelogenous leukemia.

PMID- 12476313
TI  - Depression and cardiovascular disease: co-occurrence or shared genetic
      substrates?

PMID- 12476316
TI  - Association of WKL1/MLC1 with catatonic schizophrenia.

PMID- 12476318
TI  - Mouse genetic models for prepulse inhibition: an early review.
AB  - Prepulse inhibition (PPI) is the phenomenon in which a weak prepulse stimulus
      attenuates the response to a subsequent startling stimulus. Patients with
      schizophrenia and some other neuropsychiatric disorders have impaired PPI.
      Impaired PPI in these patient populations is thought to reflect dysfunctional
      sensorimotor gating mechanisms. Recently, various inbred mouse strains and
      genetically modified mouse lines have been examined to investigate the potential
      genetic basis of sensorimotor gating. This review provides a synopsis of the use
      of mouse models to explore genetic and neurochemical influences on PPI. Studies
      describing the PPI responses of various inbred strains of mice, mice with genetic
      mutations, and mice treated with various drugs prior to July 2001 are reviewed.
      The continuous nature of the distribution of PPI responses among inbred strains
      of mice indicates that PPI is a polygenic trait. Findings from spontaneous and
      gene-targeted mutants suggest that mutant mice are important tools for dissecting
      and studying the role of single genes and their products, and chromosomal regions
      in regulating PPI. Pharmacological studies of PPI have typically confirmed
      effects in mice that are similar to those reported previously in rats, with some
      important exceptions. The use of mice to study PPI is increasing at a dramatic
      rate and is helping to increase our understanding of the biological basis for
      sensorimotor gating.

PMID- 12476319
TI  - 5-HT2A promoter polymorphism -1438G/A in children and adolescents with obsessive
      compulsive disorders.
AB  - Positive association between obsessive compulsive disorder (OCD) and the A-allele
      of the 5-HT(2A)-receptor promoter polymorphism -1438G/A has recently been
      reported in adults. We performed an association analysis of this polymorphism in
      55 children and adolescents with OCD and in 223 controls consisting of unrelated
      students. We detected statistically significant differences in genotype (P <
      0.05) and allele frequencies (P < 0.05) between individuals with OCD and
      controls. In this, to our knowledge, first association study based on children
      and adolescents with OCD, we confirm an association of the A-allele of the 5-HT2A
      receptor gene with OCD.

PMID- 12476320
TI  - Serotonin transporter gene polymorphism, differential early rearing, and behavior
      in rhesus monkey neonates.
AB  - A polymorphism in the serotonin (5-HT) transporter gene regulatory region (5
      HTTLPR) is associated with measures of 5-HT transporter (5-HTT) expression and 5
      HT-mediated behaviors in humans. An analogous length variation of the 5-HTTLPR
      has been reported in rhesus monkeys (rh5-HTTLPR). A retrospective association
      study was conducted on 115 rhesus macaque infants either homozygous for the long
      5HTTLPR variant (l/l) or heterozygous for the short and long form (l/s). To
      assess contributions of genotype and early rearing environment, 36 mother-reared
      monkeys (l/l = 26, l/s = 10) and 79 nursery-reared monkeys (l/l = 54, l/s = 25)
      were assessed on days 7, 14, 21, and 30 of life on a standardized primate
      neurobehavioral test designed to measure orienting, motor maturity, reflex
      functioning, and temperament. Both mother-reared and nursery-reared heterozygote
      animals demonstrated increased affective responding relative to l/l homozygotes.
      Nursery-reared, but not mother-reared, l/s infants exhibited lower orientation
      scores than their l/l counterparts. These results demonstrate the contributions
      of rearing environment and genetic background, and their interaction, in a
      nonhuman primate model of behavioral development.

PMID- 12476321
TI  - Tau negative frontal lobe dementia at 17q21: significant finemapping of the
      candidate region to a 4.8 cM interval.
AB  - We report the results of a genome-wide search in a four-generation pedigree with
      autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53-79
      years). In this family we previously excluded the known Alzheimer's disease genes
      based on linkage analysis and mutation screening of the amyloid precursor protein
      gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded
      mutations in the prion protein gene and exons 9-13 of the microtubule associated
      protein tau (MAPT) gene. We obtained conclusive linkage with chromosome 17q21
      markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a
      candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Recent
      clinical and neuropathological follow-up of the family showed that the phenotype
      most closely resembled frontotemporal dementia (FTD) characterized by dense
      ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation
      analysis of MAPT identified 38 sequence variations in exons, introns,
      untranslated regions and the 5' regulatory sequence, however none was comprised
      within the disease haplotype. Although our findings do not entirely exclude a
      mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT
      mutations combined with the lack of tau pathology is highly suggestive for
      another defective gene at 17q21 responsible for FTD in this family.

PMID- 12476323
TI  - Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects
      with schizophrenia.
AB  - To test the hypothesis that muscarinic receptors are involved in the pathology of
      schizophrenia, we measured muscarinic(1) (M1R) and muscarinic(4)(M4R) protein and
      mRNA as well as [(3)H]pirenzepine binding in Brodmann's areas (BA) 9 and 40
      obtained postmortem from 20 schizophrenic and 20 age/sex-matched control
      subjects. There was a significant decrease in [(3)H]pirenzepine binding to BA 9
      (mean +/- SEM: 151 +/- 15 vs 195 +/- 10 fmol mg(-1) ETE; P< 0.02), but not BA 40
      (143 +/- 13 vs 166 +/- 11 fmol mg(-1) ETE), from subjects with schizophrenia. The
      level of M1R protein (0.11 +/- 0.007 vs 0.15 +/- 0.008 OD; P < 0.01), but not M4R
      protein, was decreased in BA9 from schizophrenic subjects with neither receptor
      protein being altered in BA 40. The level of M1R mRNA was decreased in BA 9 (30
      +/- 7.0 vs 79 +/- 14 dpm x 10(3) mg(-1) ETE, P < 0.01) and BA 40 (28 +/- 5.9 vs
      99 +/- 14, P < 0.01) with schizophrenia but M4R mRNA was only decreased in BA 40
      (48 +/- 6.6 vs 89 +/- 9.9, P < 0.005). These data suggest that the M1R, at least
      in the dorsolateral prefrontal cortex, may have a role in the pathology of
      schizophrenia.

PMID- 12476322
TI  - Dopamine D2S and D2L receptors may differentially contribute to the actions of
      antipsychotic and psychotic agents in mice.
AB  - Regulation of dopamine D2 receptor (D2) function plays an important role in
      alleviating either the motor deficits of Parkinson's disease or psychotic
      symptoms of schizophrenia. D2 also plays a critical role in sensorimotor gating
      which can be measured by monitoring the prepulse inhibition of the startle
      response. Alternative splicing of the D2 gene generates two isoforms, D2S and
      D2L. Here we investigated the role of D2S and D2L in the mechanisms of action of
      dopaminergic drugs, using mice lacking D2L (D2L(-/-)) but expressing D2S as a
      model system. We found that the typical antipsychotic raclopride was much less
      potent in inhibiting locomotor activity and eliciting catalepsy (or parkinsonism)
      in D2L(-/-) mice, whereas the atypical antipsychotic clozapine was equally
      effective in D2L(-/-) and wild-type mice. These suggest that the deletion of D2L
      diminishes drug-induced parkinsonism. Furthermore, two dopamine agonists,
      amphetamine and apomorphine, reduced prepulse inhibition to a similar degree in
      D2L(-/-) and wild-type mice. These results together suggest that D2S alone can
      mediate the action of clozapine and the dopamine agonist-induced disruption of
      prepulse inhibition. The differential binding affinities of these agents for D2S
      vs D2L were not sufficient to explain the divergent effects of typical vs
      atypical antipsychotics in D2L(-/-) mice. These findings suggest that D2S and D2L
      may differentially contribute to the therapeutic actions and side effects of
      antipsychotic agents, and may have implications for developing better
      antipsychotic agents.

PMID- 12476324
TI  - Mutation screening and LD mapping in the VCFS deleted region of chromosome 22q11
      in schizophrenia using a novel DNA pooling approach.
AB  - We examined whether variation within six genes from the VCFS critical region at
      22q11 (DGSC, Stk22A1, DGSI, Gscl, Slc25A1 and Znf74) confers susceptibility to
      schizophrenia. We screened the exons and flanking intronic sequence of each gene
      for mutations in 14 individuals with DSM-IV schizophrenia using DHPLC. All
      polymorphisms identified were characterised and genotyped in a sample of 184
      schizophrenics and matched controls, using novel DNA pooling methods. Of the
      polymorphisms identified, 17 were located within exons, six were within coding
      sequence, and two were non-synonymous. Pooled genotyping revealed no differences
      in the allele frequencies for any polymorphism between cases and controls that
      met our pre-defined criterion (P < or = 0.1). In a complementary approach we also
      attempted to define the location of a schizophrenia susceptibility locus more
      precisely by performing association mapping using seven microsatellites spanning
      the VCFS region with an average inter-marker distance of 450 kb. Conventional
      chi(2) analysis of genotypes in 368 cases and 368 controls revealed that none of
      the markers was significantly associated (P < 0.05) with schizophrenia. However,
      evidence for significant association (P = 0.003) was obtained for D22S944 when
      alleles were combined. TDT analysis of D22S944 genotyped in a further 278 cases
      of schizophrenia and their parents failed to find any overall allele-wise
      significant transmission disequilibrium (chi(2) = 18.3, P = 0.17). However,
      individual analysis of the alleles revealed that allele 12 was excessively non
      transmitted and that this almost reached significance when corrected for multiple
      alleles (chi(2) = 7.35, P = 0.006, P = 0.078 corrected for 13 alleles).

PMID- 12476325
TI  - Identification of a novel variant of the human NR2B gene promoter region and its
      possible association with schizophrenia.
AB  - N-methyl-D-aspartate (NMDA) receptor dysfunction is involved in the pathogenesis
      of schizophrenia. We determined the nucleotide sequence of the 5'-upstream region
      of the human NMDA receptor 2B (NR2B) subunit gene and identified a novel T-200G
      variant located in one of the Sp1 binding sites. To investigate the effect of
      this variant on the transcriptional activity of the hNR2B gene, we performed gene
      reporter assays using PC12 pheochromocytoma cells transiently transfected with
      luciferase reporter plasmids. In the absence of nerve growth factor (NGF),
      luciferase activities did not significantly differ between the two alleles and
      the control plasmid. However, luciferase reporter activity of the T allele was
      significantly up-regulated compared to that of the G allele in the presence of
      NGF (P = 0.0013), indicating that this polymorphic site is a critical region for
      NR2B gene regulation through NGF-induced Sp1-binding. A case control study showed
      that the frequency of the G allele (P = 0.0164) was significantly higher in 100
      schizophrenics than in 100 controls. These findings suggest that the T-200G
      variant causes dysfunction of NMDA receptors consisting of the NR2B subunit and
      may be involved in the development of schizophrenia. Replication studies of
      independent samples and family-based association studies are necessary to further
      evaluate the significance of our findings.

PMID- 12476326
TI  - The plasma levels of interleukin-12 in schizophrenia, major depression, and
      bipolar mania: effects of psychotropic drugs.
AB  - Interleukin-12 (IL-12) plays a key role in promoting T helper 1 (Th1) responses
      and subsequent cell-mediated immunity. Given the role of cytokines in the
      pathogenesis of psychiatric disorders, the dysregulation of IL-12 in these
      illnesses would be expected. We measured the plasma levels of IL-12 in 102
      psychiatric patients (43 schizophrenia, 34 major depression and 25 bipolar
      disorder) and 85 normal controls. In addition, IL-12 levels of the patients were
      measured after an 8-week treatment to assess whether the levels were affected by
      medication. The IL-12 levels of the patient group with major depression were
      significantly higher than that of the control group, whereas no differences were
      found among the other groups. IL-12 values of the three patient groups decreased
      significantly after 8 weeks of treatment. These findings support the hypothesis
      that activation of the inflammatory response system and in particular of Th-1
      like cells, is involved in the pathophysiology of major depression and that
      repeated administration of antidepressive and antipsychotic drugs may suppress IL
      12 plasma concentrations in psychiatric patients.

PMID- 12476327
TI  - Association study of the serotonin transporter promoter polymorphism and
      symptomatology and antidepressant response in major depressive disorders.
AB  - The serotonin transporter (5-HTT) is the site of primary action for the selective
      serotonin reuptake inhibitors (SSRIs). Previous Western reports have demonstrated
      that the lallele of the 5-HTT gene-linked polymorphic-region (5-HTTLPR)
      polymorphism is associated with better SSRI antidepressive effects than the s
      allele, however, another study of a Korean population has produced a contrasting
      finding. The present study tested the hypothesis that the 5-HTTLPR genetic
      polymorphism is associated with SSRI antidepressant response by evaluating total
      and cluster depressive symptoms for 121 Chinese patients diagnosed with major
      depression. Analysis of the results reveals that patients with the l/l genotype
      had a significantly better response to SSRI (fluoxetine) when compared with s
      allele carriers, as evaluated on the basis of total (P = 0.013), core (P =
      0.011), and psychic-anxiety (P = 0.005) and somatic-anxiety (P = 0.002) Hamilton
      Depression Rating Scale-score percentage change. Our findings confirm reports
      that the l allele is associated with better SSRI response.

PMID- 12476328
TI  - Combined action of the ACE D- and the G-protein beta3 T-allele in major
      depression: a possible link to cardiovascular disease?
AB  - Although it is well established that depression is a major risk factor for the
      development of coronary artery disease and that cerebrovascular disease can be a
      major contributing factor for the development of depression, the information
      about the interplay between the central nervous system and cardiovascular disease
      is still limited. We investigated the angiotensin I converting enzyme (ACE) ID
      and the G-protein beta3-subunit (Gbeta3) C825T polymorphism in 201 patients with
      unipolar major depression and 161 ethnically and age-matched controls. Both gene
      variants have earlier been associated with either cardiovascular disease or
      affective disorders, making them good candidates for a combined analysis. We
      found a significant increase in the Gbeta3 T allele (OR = 1.61, 95% CI 1.17-2.2,
      P = 0.0035) and a marginal altered genotype distribution of the ACE ID
      polymorphism with decrease in the II genotypes (chi(2) = 6.43, df=3, P = 0.04) in
      the patients' group. Analysing the data for both genes we found that the combined
      actions of ACE and Gbeta3 genotypes accumulate in carriers of the ACE D allele
      (ID and DD) and Gbeta3 TT homozygotes with ID/DD-TT carriers showing a more than
      five-fold increase in risk for major depression (crude OR = 5.83, 95% CI 1.99
      17.08, P = 0.0002). As our study was carried out with depressive patients without
      serious cardiac impairment at the time of the investigation, we are presently
      unable to predict whether this combined action of the ACE ID/DD-Gbeta3 TT
      genotype is increasing the risk for both disorders. Nevertheless our study
      reports for the first time that the same allelic combination of two genes that
      have been shown to increase the risk for myocardial infarction (Naber et al,
      2000) increase the vulnerability for depressive disorder.

PMID- 12476332
TI  - A Systematic Review of the Congruence Between People's Needs and Nurses'
      Interventions for Supporting Hope.
AB  - PURPOSE: This systematic review of nursing research from 1987 to 1999 was
      conducted to explore the factors people identify as supportive of hope, the
      interventions nurses use to support hope, and the congruence between these two
      sets of studies. CONCLUSIONS: The factors supporting hope for patients and
      families found most frequently were social and professional support, cognitive
      strategies, spiritual or religious activities, relying on inner resources, and
      setting goals. Nurses used interventions to support families, assist with goal
      setting and distraction, affirm patient worth, and provide symptom relief. There
      was substantial congruence between people's needs and nursing actions. The main
      incongruence was the lack of interventions supporting spiritual practices.
      IMPLICATIONS: Nurses should continue current practices to nurture hope in their
      patients and clients. In addition, nurses need to provide spiritual care as an
      intervention that supports hope. There is a need for further research on nursing
      interventions to stimulate hope as well as research to understand the differences
      and relationships among hope, hopelessness, coping, courage, well-being, and
      spirituality. Research to understand hope in cultures outside of the mainstream
      United States culture is also needed.

PMID- 12476329
TI  - Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in
      postmortem brain samples of both suicide victims and controls.
AB  - Several lines of evidence suggest that a partly genetically controlled
      serotonergic dysfunction is involved in the biological pathogenesis of suicide.
      In this study, we measured tryptophan hydroxylase (TPH) immunoreactivity as a pre
      synaptic marker, and serotonin receptor 2A (5HT2A receptor) density as a post
      synaptic marker in the serotonergic system in 10 postmortem brains of suicide
      victims. We also examined whether TPH gene polymorphisms (A218C and A-6526G
      polymorphisms) could affect TPH immunoreactivity and 5HT2A receptor gene
      polymorphism (A-1438G polymorphism) could affect 5HT2A receptor density in 28
      postmortem brain samples. No significant differences were found in TPH
      immunoreactivity or 5HT2A receptor density between suicide victims and controls.
      The AA genotype of the A218C polymorphism of the TPH gene showed higher TPH
      immunoreactivity along with lower 5HT2A receptor density than did any other
      genotypes in the postmortem brains of both suicide victims and controls. Our
      findings suggest that the A218C polymorphism of the TPH gene can be expected to
      provide new insights not only for neurobiological studies of suicide, but also
      for research into the behavioral characteristics that may be associated with
      serotonergic dysfunction.

PMID- 12476333
TI  - Mother-Infant Interaction and Maternal Substance Use/Abuse: An Integrative Review
      of Research Literature in the 1990s.
AB  - PURPOSE: Mother-infant interaction is crucial for optimal infant development and
      parenting. In the environment of prenatal substance use/abuse there is potential
      for both mother and child to present negative interactive behaviors. Recent
      increased incidence of substance use/abuse by pregnant women in the United States
      has provoked concern for the infant's outcome in these circumstances. Recent
      literature does not indicate a uniformly dismal outlook for infants born exposed
      to drugs. In this paper, published research from the 1990s that specifically
      addressed the relationship between prenatal substance use/abuse and the mother
      infant interaction was examined utilizing the Barnard model of parent-infant
      interaction as a guide. Twenty-three articles matched search criteria and were
      included in the review. CONCLUSIONS: The majority of studies (14/23) showed that
      maternal substance abuse was associated with a recognizably detrimental impact on
      mother-child interaction. Six studies did not confirm an adverse effect. Negative
      impact on the interaction was related to the degree of maternal substance abuse
      in three studies and to its continuation postnatally in two. Postnatal
      environment correlated strongly with the quality of mother-child interaction in
      the substance-exposed dyads. IMPLICATIONS: Clinical and research implications are
      described.

PMID- 12476334
TI  - A Program of Research Evaluating the Effects of a Collaborative Research
      Utilization Model.
AB  - Advances in research are meaningless unless they reach clinicians at the point of
      care. This article describes a program of research in which a collaborative
      research utilization (CRU) model was developed and tested in four clinical
      studies in the context of pain management. The overall aim of the research
      program was to decrease the long lag time from when research innovations are
      developed to when they appear in clinicians' day-to-day caregiving activities. In
      the model, partnerships are formed between researchers, undergraduate and
      graduate students, and clinicians in academic and practice settings. The
      developmental process, structure, and steps of the model are described as well as
      outcomes that have been achieved in the student, scientist, clinician, nursing
      practice, and most importantly, the patient.

PMID- 12476335
TI  - Incorporating Research Application Into Nurse Practitioner Education.

PMID- 12476336
TI  - Adolescent Sexual Decision-Making: An Integrative Review.
AB  - PURPOSE: The purpose of this integrative review was to summarize the present
      literature to identify factors associated with adolescent sexual decision-making.
      Thirty-eight salient research studies were selected as a basis of this review
      from the databases of Medline, CINAHL, and Psychinfo using the Cooper
      methodology. CONCLUSIONS: Two categories of decision-making were identified: 1)
      The research on factors related to the decisions that adolescents make to become
      sexually active or to abstain from sexual activity; 2) The research on factors
      related to contraceptive decision-making. The most consistent findings were that
      the factors of gender differences, cognitive development, perception of benefits,
      parental influences, social influences, and sexual knowledge were important
      variables in the decision-making processes of adolescents. IMPLICATIONS: Practice
      implications for nursing suggest that clinicians should assess adolescent sexual
      decision-making in greater detail and address the social and psychological
      context in which sexual experiences occur. Nurses must be aware of the
      differences between adolescent and adult decision-making processes and
      incorporate knowledge of growth and development into intervention strategies.
      Moreover, to the degree that adolescent sexual decision-making proves to be less
      than rational, interventions designed to improve competent sexual decision-making
      are needed.

PMID- 12476337
TI  - Evaluation of Selected Behavior Change Theoretical Models Used in Weight
      Management Interventions.
AB  - Purpose: This paper evaluates selected behavior change theoretical models used in
      weight reduction interventions and presents recommendations for the use of theory
      in weight reduction research. Overweight and obesity are complex problems,
      requiring long-term behavioral change. Behavioral treatments for overweight and
      obesity are as varied as the elements of behavior, and the long-term efficacy of
      most approaches is poor. Because of the complexity of both the problem and its
      treatment, investigations must target the development of cause-effect
      explanations. CONCLUSIONS: Many of the behavioral change intervention studies
      reviewed lacked external validity, primarily due to the failure to consider
      salient moderators. The theoretical models reviewed in this paper were primarily
      tested on white, employed populations. These and other data suggest that extant
      theoretical approaches may not be salient in certain groups. IMPLICATIONS:
      Practice implications include: 1) assess indicators for readiness to engage in
      weight reduction efforts; 2) base interventions on multiple theories; and 3)
      develop context-based interventions. Future research should include a focus on
      innovative methods in theory development, development of theory acknowledging
      mediator/moderator interactions, development of theory in context, and
      development of theory reflecting cultural meaning and diversity.

PMID- 12476338
TI  - Psychoneuroimmunological Outcomes in Dementia Caregiver Intervention Studies: An
      Idea Whose Time Has Come? 
AB  - PURPOSE: Mounting evidence indicates that the chronic stress of family caregiving
      has physiological effects and that caregiver stress may be associated with
      changes in the caregiver's physical health. Existing caregiver behavioral
      intervention studies have focused on caregiver stress and psychological distress
      outcomes. To date, no known caregiver intervention studies have included
      psychoneuroimmunological (PNI) outcome measures. Two bodies of literature were
      reviewed to determine if the current state-of-the-science supports the
      development of caregiver intervention studies that examine PNI outcomes--first,
      dementia caregiver PNI studies; and second, cognitive behavioral PNI intervention
      studies conducted with other clinical populations. CONCLUSIONS: If this line of
      research is pursued, the following issues need to be addressed: a) sampling
      strategies and study designs; b) measurement issues; and c) the need for
      multidisciplinary collaborative research teams. IMPLICATIONS: Nurses' preparation
      in the biomedical and behavioral sciences establishes a knowledge base that
      enables nurses to apply a PNI model in clinical situations. Their preparation and
      access to family caregivers put them in a unique position to design and implement
      improved caregiver interventions that focus on caregiver psychological,
      physiological, and physical health outcomes.

PMID- 12476339
TI  - The Truth, the Whole Truth.about EBP and RCTs.

PMID- 12476340
TI  - Incorporating Evidence Based Practice into Nursing Practice.

PMID- 12476342
TI  - Neural immunity: Friend or foe?
AB  - The articles compiled in this special edition of Journal of NeuroVirology target
      a developing field of investigation seeking to uncover how the immune system
      affects both the pathogenic process and protection against the ravages of
      neurodegenerative processes. Whether caused by a microbe, trauma, toxic
      metabolite, autoimmunity, or part of a wide degenerative process, immune
      dysfunction commonly affects central nervous system (CNS) disease. All together,
      the work presented here proved to be a unique undertaking with contributing
      scientists outside the field of neurovirology. Indeed, multiple disciplines
      including molecular neuroscience, neuroimmunology, virology, cellular immunology,
      receptor pharmacology, neuronal electrophysiology, neurochemistry, clinical
      neurology, and development neurobiology were joined. The basis of this work rests
      with the hypothesis that brain mononuclear phagocytes (MP; perivascular and brain
      macrophages and microglia) act as inducers of disease by engaging the immune
      system to protect, defend, or induce neural injury. Indeed, it is the brain MP
      that act as scavengers killing microblial pathogens, regulate immune responses
      through antigen presentation and mobilization of adaptive immune activities, and
      affect the production of neurotrophic or toxic secretory factors that incite
      disease processes. For many years, these responses were thought to be reactive to
      ongoing disease mechanisms with little effects on disease itself, let alone
      repair. The works compiled in this issue demonstrate quite clearly this is no
      longer true. Immune responses cannot be directed only against a microbe but also
      against self-antigens that are expressed in damaged CNS, leading to innate
      neurotoxic or adaptive anti-self immunity that commonly follow viral infections.
      Importantly, therapeutic modalities may take advantage of CNS immune responses
      through vaccination generating neuroprotection. Together, these articles serve to
      bring together common neuroimmune links between highly divergent diseases (for
      example, Parkinson's and Alzheimer's disease and human immunodeficiency virus
      type-one dementia). In the end, I hope this work will serve as discussion points
      for future collaborations and began to break down the barriers of disease,
      enabling targeted research activities toward what we have in common.

PMID- 12476343
TI  - Autoimmunity as the body's defense mechanism against the enemy within:
      Development of therapeutic vaccines for neurodegenerative disorders.
AB  - Insults to the central nervous system (CNS), whether of microbial or microbe-free
      origin, result in tissue damage. Until recently, it was generally believed that
      only microbe-related damage elicits an adaptive immune response, the purpose of
      which is to eliminate the offending microorganisms. Recent studies in the
      author's laboratory suggest, however, that the body exhibits an adaptive immune
      response to microbe-free injuries as well. The immune response in this case is
      directed against dominant self-antigens residing in the damaged site, where such
      an adaptive anti-self immune response reinforces the protective activity of local
      resident cells by providing them with factors that can augment and regulate their
      capacity for buffering troublemakers such as destructive self-compounds emerging
      from the injured neural tissue. Because the specificity of this autoimmune
      response apparently depends not on the type but on the site of lesion, the
      response can be boosted by therapeutic vaccination for acute and chronic
      neurodegenerative conditions irrespective of their primary etiology. The results
      have far-reaching implications, both for microbial infections and for
      neurodegenerative diseases of the CNS.

PMID- 12476344
TI  - Slit proteins, potential endogenous modulators of inflammation.
AB  - Recent studies suggest that molecules important for guiding neuronal migration
      and axon path-finding also play a role in modulating leukocyte chemotaxis.
      Neuronal migration and leukocyte chemotaxis may share some common regulatory
      mechanisms. Intracellular signal transduction mechanisms guiding neuronal
      migration and leukocyte chemotaxis are beginning to be elucidated. Studying
      molecular mechanisms modulating cell migration may provide new insights into
      understanding of endogenous inhibitors of inflammation.

PMID- 12476345
TI  - Regulation and function of class II major histocompatibility complex, CD40, and
      B7 expression in macrophages and microglia: Implications in neurological
      diseases.
AB  - The ability of microglia, the brain's resident macrophage, to present antigen
      through the class II major histocompatibility complex (MHC) to T cells allows
      these normally quiescent cells to play a critical role in shaping the outcome of
      many neurological diseases. The expression of class II MHC antigens and the
      costimulatory molecules CD40 and B7 on microglia and infiltrating macrophages is
      regulated through a complex network of cytokines in the inflamed brain. In this
      review, we describe the molecular mechanisms underlying class II MHC, CD40 and B7
      regulation in microglia and macrophages. Our focus is on the cis-elements in the
      promoters of their genes and the transcription factors activated by cytokines
      that bind them. The functional implications of aberrant class II MHC, CD40 and B7
      expression by microglia and macrophages as related to the diseases of Multiple
      Sclerosis and Alzheimer's Disease are discussed.

PMID- 12476347
TI  - Local neuroinflammation and the progression of Alzheimer's disease.
AB  - Postmortem immunohistochemical studies have revealed a state of chronic
      inflammation limited to lesioned areas of brain in Alzheimer's disease. Some key
      actors in this inflammation are activated microglia (brain macrophages), proteins
      of the classical complement cascade, the pentraxins, cytokines, and chemokines.
      The inflammation does not involve the adaptive immune system or peripheral
      organs, but is rather due to the phylogenetically much older innate immune
      system, which appears to operate in most tissues of the body. Chronic
      inflammation can damage host tissue and the brain may be particularly vulnerable
      because of the postmitotic nature of neurons. Many of the inflammatory mediators
      have been shown to be locally produced and selectively elevated in affected
      regions of Alzheimer's brain. Moreover, studies of tissue in such degenerative
      processes as atherosclerosis and infarcted heart suggest a similar local innate
      immune reaction may be important in such conditions. Much epidemiological and
      limited clinical evidence suggests that nonsteroidal anti-inflammatory drugs may
      impede the onset and slow the progression of Alzheimer's disease. But these drugs
      strike at the periphery of the inflammatory reaction. Much better results might
      be obtained if drugs were found that could inhibit the activation of microglia or
      the complement system in brain, and combinations of drugs aimed at different
      inflammatory targets might be much more effective than single agents.

PMID- 12476346
TI  - Glucocorticoids and central nervous system inflammation.
AB  - Glucocorticoids (GCs) are well known for their anti-inflammatory and
      immunosuppressive properties in the periphery and are therefore widely and
      successfully used in the treatment of autoimmune diseases, chronic inflammation,
      or transplant rejection. This led to the assumption that GCs are uniformly anti
      inflammatory in the periphery and the central nervous system (CNS). As a
      consequence, GCs are also used in the treatment of CNS inflammation. There is
      abundant evidence that an inflammatory reaction is mounted within the CNS
      following trauma, stroke, infection, and seizure, which can augment the brain
      damage. However an increasing number of studies indicate that the concept of GCs
      being universally immunosuppressive might be oversimplified. This article
      provides a review of the current literature, showing that under certain
      circumstances GCs might fail to have anti-inflammatory effects and sometimes even
      enhance inflammation.

PMID- 12476348
TI  - Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in
      Alzheimer's disease.
AB  - Although Alzheimer's disease (AD) may not involve a transmissible agent, it does
      involve a pathogenic process similar to that of transmissible prion disorders
      (both involve a protein that adopts an abnormal pathogenic conformation in which
      it self-aggregates, forming amyloid deposits in and surrounding neurons) and
      viral dementias such as human immunodeficiency virus (HIV) encephalitis. The
      clinical presentation of patients with AD is dominated by cognitive deficits and
      emotional disturbances that result from dysfunction and degeneration of neurons
      in the limbic system and cerebral cortex. The pathogenic process in the brain
      involves deposition of insoluble aggregates of amyloid beta-peptide, oxidative
      stress and calcium dysregulation in neurons, and activation of inflammatory
      cytokine cascades involving microglia. However, AD patients also exhibit
      alterations in immune function. Studies of lymphocytes and lymphoblast cell lines
      from AD patients and age-matched normal control patients have documented
      alterations in cytokine and calcium signaling and increased levels of oxidative
      stress in immune cells from the AD patients. Studies of the pathogenic actions of
      mutations in presenilins and amyloid precursor protein that cause early-onset
      familial AD have established central roles for perturbed cellular calcium
      homeostasis and oxidative stress in the neurodegenerative process. Presenilin and
      amyloid precursor protein (APP) mutations also increase oxidative stress and
      perturb calcium signaling in lymphocytes in ways that alter their production of
      cytokines that are critical for proper immune responses. Immune dysfunction
      occurs prior to clinical symptoms in mouse models of AD, and brain cytokine
      responses to immune challenge are altered in presenilin mutant mice, suggesting a
      causal role for altered immune function in the disease process. Interestingly,
      immunization of AD mice with amyloid beta-peptide can stimulate the immune system
      to remove amyloid from the brain and can ameliorate memory deficits, suggesting
      that it may be possible to prevent AD by bolstering immune function.

PMID- 12476349
TI  - Glial cell response: A pathogenic factor in Parkinson's disease.
AB  - Parkinson's disease (PD) is a common neurodegenerative disorder characterized by
      the progressive loss of dopaminergic neurons in the substantia nigra pars
      compacta (SNpc). The loss of these neurons is associated with a glial response
      composed mainly of activated microglial cells and, to a lesser extent, of
      reactive astrocytes. This glial response may be the source of trophic factors and
      can protect against reactive oxygen species and glutamate. Alternatively, this
      glial response can also mediate a variety of deleterious events related to the
      production of pro-oxidant reactive species, proinflammatory prostaglandin, and
      cytokines. In this review, the authors discuss the potential protective and
      deleterious effects of glial cells in the SNpc of PD and examine how these
      factors may contribute to the pathogenesis of this disease.

PMID- 12476350
TI  - CXC chemokine receptors in the central nervous system: Role in cerebellar
      neuromodulation and development.
AB  - Chemokines and their receptors are constitutively present in the central nervous
      system (CNS), expressed in neurons and glial cells. Much evidence suggests that,
      beyond their involvement in neuroinflammation, these proteins play a role in
      neurodevelopment and neurophysiological signaling. The goal of this review is to
      summarize recent information concerning expression, signaling, and function of
      CXC chemokine receptor in the CNS, with the main focus on the developmental and
      neuromodulatory actions of chemokines in the cerebellum.

PMID- 12476351
TI  - Chemokine receptors and neural function.
AB  - Numerous studies have demonstrated that chemokines play an integral role in
      diseases marked by inflammation. Recently, it has also been shown that chemokines
      and their receptors are widely expressed in the central nervous system by all
      types of cells, including neurons. The functions of neuronal chemokine receptors
      have yet to be fully defined. However, there are indications that neuronal
      chemokine receptors play an integral role in the development of the nervous
      system, in the regulation of neuronal excitability and in the signal transduction
      pathways that regulate neuronal survival. This review explores these topics and
      discusses the overall impact that chemokines may have on neuronal function.

PMID- 12476352
TI  - Fractalkine (CX3CL1) and brain inflammation: Implications for HIV-1-associated
      dementia.
AB  - Leukocyte migration and activation play an important role in immune surveillance
      and the pathogenesis of a variety of neurodegenerative disorders, including human
      immunodeficiency virus (HIV)-1-associated dementia (HAD). A novel chemokine named
      fractalkine (FKN, CX3CL1), which exists in both membrane-anchored and soluble
      isoforms, has been proposed to participate in the generation and progression of
      inflammatory brain disorders. Upon binding to the CX3C receptor one (CX3CR1), FKN
      induces adhesion, chemoattraction, and activation of leukocytes, including brain
      macrophages and microglia (MP). Constitutively expressed in the central nervous
      system (CNS), mainly by neurons, FKN is up-regulated and released in response to
      proinflammatory stimuli. Importantly, FKN is up-regulated in the brain tissue and
      cerebrospinal fluid (CSF) of HAD patients. Together, these observations suggest
      that FKN and its receptor have a unique role in regulating the neuroinflammatory
      events underlying disease. This review will examine how FKN contributes to the
      recruitment and activation of CX3CR1-expressing MP, which are critical events in
      the neuropathogenesis of HAD.

PMID- 12476353
TI  - The macrophage response to HIV-1: Intracellular control of X4 virus replication
      accompanied by activation of chemokine and cytokine synthesis.
AB  - During human immunodeficiency virus (HIV)-1 infection, T lymphocytes and
      macrophages play dual roles. They are the primary targets for virus replication,
      but they are also primary effector cells in acquired and innate immunity,
      respectively. The authors are now investigating how these roles come together in
      the response of human monocyte-derived macrophages (MDM) to certain HIV-1. The
      authors and others have previously shown that MDM permit entry of some X4 virus
      strains, but control viral replication intracellularly. In the present study,
      viral DNA synthesis, entry into the nucleus, and transcription to RNA were all
      observed in X4 virus-infected MDM. MDM arrested HIV-1 replication prior to
      expression of mature capsid antigen p24 and production of cell-free infectious
      viral particles. Cell-associated transmissible HIV-1 was detected by
      cocultivation of infected MDM and susceptible T lymphocytes. A second protective
      response of MDM to specific R5 as well as X4 HIV-1 was identified in rapid and
      extensive secretion of tumor necrosis factor-alpha, macrophage inflammatory
      protein-1alpha, and RANTES. These findings support the view that MDM act
      aggressively to control HIV-1 replication: X4 strains by severely limiting the
      progeny virus production and R5 strains by producing beta-chemokines competent to
      block virus entry into target cells. Optimizing these innate immune responses
      offers another means to control HIV-1 infection in the human host.

PMID- 12476354
TI  - Tumor necrosis factor-alpha in normal and diseased brain: Conflicting effects via
      intraneuronal receptor crosstalk?
AB  - Tumor necrosis factor-alpha (TNF-alpha) is pleiotropic mediator of a diverse
      array of physiological and neurological functions, including both normal
      regulatory functions and immune responses to infectious agents. Its role in the
      nervous system is prominent but paradoxical. Studies on uninflamed or "normal"
      brain have generally attributed TNF-alpha a neuromodulatory effect. In contrast,
      in inflamed or diseased brain, the abundance of evidence suggests that TNF-alpha
      has an overall neurotoxic effect, which may be particularly pronounced for
      virally mediated neurological disease. Still others have found TNF-alpha to be
      protective under some conditions of neurological insult. It is still uncertain
      exactly how TNF-alpha is able to induce these opposing effects through receptor
      activation of only a limited set of cell signaling pathways. In this paper, we
      provide support from the literature to advance our hypothesis that one mechanism
      by which TNF-alpha can exert its paradoxical effects in the brain is via
      crosstalk with signaling pathways of growth factors or other cytokines.

PMID- 12476357
TI  - Analysis of lobar differences in particle deposition in the human lung.
AB  - Lung diseases caused by the inhalation of various particulate pollutants have
      often been reported to occur at specific sites in the lung with some diseases
      preferentially occurring in one of the lobes. Models for the dosimetry of
      particulate matter in the lung, therefore, need to be developed at a level of
      resolution that allows for the study of lobar- and airway-specific patterns of
      deposition. Using an approach best described as a combination of asymmetric and
      symmetric approaches to modeling lung geometry, we calculated deposition of
      particulate matter (PM) ranging from ultrafine to coarse particles in each airway
      down to the level of the lobar bronchi. Further down the airway tree, we
      calculated deposition averaged over an airway generation in each lung lobe. We
      compared our results for regional and lobar deposition with various experimental
      data as well as with results from other models. The calculated results compared
      reasonably well with experimental data. Significant variations in deposition were
      observed among the lobar bronchi as well as among the five lobes. The differences
      among the lobes were accentuated as one examined generation-specific deposition.
      Deposition per unit surface area of each lobar bronchus was considerably elevated
      relative to that calculated for the whole lung. The relative distribution of
      aerosol deposited per unit surface area among the lobar bronchi was altered by
      breathing condition and aerosol size. Our observations suggest that a multiple
      path model that incorporates the heterogeneous structure of airways in the lung
      is likely to reduce uncertainties in PM health risk assessments.

PMID- 12476358
TI  - Inflammatory and cytotoxic potential of the airborne particle material assessed
      by nasal lavage and cell exposure methods.
AB  - Exposure to bioaerosols in moisture-damaged indoor environments has been shown to
      be a potential health risk. The aim of the present study was to evaluate the
      inflammatory and cytotoxic potential of airborne particle material using both the
      nasal lavage (NAL) method and a cell exposure study. A 24-h sample collection for
      airborne particles was performed using personal sampling and microenvironmental
      measurements in homes and an 8-h sample collection in the working places of the
      studied subjects. At the end of the sampling period, the production of nitric
      oxide, tumor necrosis factor alpha, interleukin (IL)-1 beta, IL-4, and IL-6 was
      analyzed in the NAL samples of the subjects. The same mediators, excluding IL-4,
      were measured in the cell culture medium of mouse RAW264.7 macrophages, which
      were exposed to the pooled filter extracts representing personal, home, and
      workplace exposure of each individual during the 24 h before the NAL. Samplings
      were repeated after 2 wk. The subjects were divided into groups of "low exposure"
      and "high exposure" according to the concentrations of viable fungi, viable
      bacteria, or total microbial amount in the pooled extract. Cytokine levels in the
      NAL samples of subjects with high microbial exposure were slightly increased
      compared to the corresponding values of the subjects with low exposure. Filter
      samples collected from the subjects with high microbial exposure induced a
      significant increase in the production of cytokines in the RAW264.7 macrophages,
      as compared to those from the subjects with low exposure. The within-subject
      variation was low in all of the cytokine measurements, but the correlation
      between the studied methods was poor. In conclusion, both of the methods
      discriminate at the group level between subjects with high and low microbial
      exposure. Sampling of airborne particle material and exposure of the mammalian
      cells to the obtained samples seems to be highly applicable in the environmental
      monitoring, whereas examination of the exposed subjects directly, for example by
      using the NAL method, is essential when association between exposure and health
      effects is evaluated.

PMID- 12476359
TI  - The role of free radicals in the toxic and inflammatory effects of four different
      ultrafine particle types.
AB  - PM10 contains an ultrafine component, which is generally derived from combustion
      processes. This ultrafine fraction may be a factor in the increases in
      exacerbations of respiratory disease and deaths from cardiorespiratory causes
      associated with transient increases in levels of PM10. By using four different
      ultrafine particles (carbon black, cobalt, nickel, and titanium dioxide), we set
      out to determine the attributes of the ultrafine particle (surface area, chemical
      composition, particle number, or surface reactivity) that contribute most to its
      toxicity and proinflammatory effects both in vivo and in vitro. Instillation of
      125 micro g ultrafine carbon black (UFCB) and ultrafine cobalt (UFCo) particles
      induced a significant influx of neutrophils at both 4 and 18 h postinstillation.
      Accompanying the influx of neutrophils was an increase in macrophage inflammatory
      protein-2 (MIP-2) (at 4 h) and an increase in gamma-glutamyl transpeptidase (at
      18 h) in bronchoalveolar lavage fluid (BAL). Ultrafine nickel (UFNi) did not
      induce a significant increase in neutrophil influx until 18 h postinstillation.
      The increase in neutrophils induced by UFNi at this timepoint was comparable to
      that induced by UFCo and UFCB. UFTi did not induce a significant increase in
      neutrophils following instillation into the rat lung. The levels of MIP-2
      observed at 4 h and neutrophil influx at 18 h induced by the particle samples
      were consistent with the pattern of surface free radical generation (as measured
      by the plasmid scission assay) whereby UFCo, UFCB, and UFNi all cause significant
      increases in inflammatory markers, as well as inducing a significant depletion of
      supercoiled plasmid DNA, indicative of hydroxyl radical generation. A role for
      free radicals and reactive oxygen species (ROS) in mediating ultrafine
      inflammation is further strengthened by the ability of the antioxidants N
      acetylcysteine (NAC) and glutathione monoethyl ester (GSHme) to block the
      particle induced release of tumour necrosis factor-alpha (TNF-alpha) from
      alveolar macrophages in vitro. The ultrafine particles in PM10 may cause adverse
      effects via oxidative stress, and this could have implications for susceptible
      individuals. Susceptible individuals, such as those with COPD or asthma, already
      exhibit preexisting oxidative stress and hence are in a primed state for further
      oxidative stress induced by occupational or environmental particles.

PMID- 12476355
TI  - Role of trophic factors on neuroimmunity in neurodegenerative infectious
      diseases.
AB  - Viral infection of the central nervous system elicits a myriad of cellular,
      vascular, and neuroimmune factors that contribute to acute, subacute, and chronic
      damage to the brain. In response to cellular damage, the host is capable of
      producing trophic factors that may protect neuronal, glial, and endothelial cell
      populations. Both neurotrophic and angiotrophic factors can also operate by
      modulating the neuroimmune response, which plays a central role in the
      pathogenesis of the neurodegenerative process. In this regard, crosstalk
      signaling among host cells, components of the neuroimmune response, and virus
      could influence cell fate by production of trophic factors that protect or rescue
      neurons vulnerable to viral damage. In this context, the main objective of this
      review is to provide an overview of evidence in support of the role of trophic
      factors in regulating the neuroimmune response in chronic viral infections of the
      central nervous system. Special emphasis is placed on the interaction of the
      human immunodeficiency virus (HIV) Tat protein with endothelial, astroglial,
      microglial, and neuronal cells, resulting in altered expression of vascular
      endothelial growth factor, fibroblast growth factor, interleukin-8, and
      regulation of calcium flux via CXCR2, which directly influences neuronal cell
      fitness.

PMID- 12476360
TI  - Biopersistence of graphite whiskers deposited in rat lungs by 4-week inhalation.
AB  - Rats were exposed to a new graphite whisker for 4 wk by inhalation. Mass and
      fiber concentrations were 8.3 +/- 2.2 mg/m3 and 151.7 +/- 78.8 fibers (F)/ml,
      respectively, and mass median aerodynamic diameter was 3.0 micro m. Geometric
      mean sizes of the original whiskers were 0.86 micro m diameter and 6.8 micro m
      length. Size distributions, numbers, and mass of deposited whiskers in rat lungs
      were measured at 4 days, 7 mo, and 12 mo after the end of the exposure. Lungs
      including the whiskers were digested with acids by microwaves, then filtered onto
      polycarbonate filters. The number of whiskers on the filters was counted and
      sizes were measured based on scanning electron microphotos, and the mass was
      analyzed by an x-ray diffractometer. Change in the number of whiskers in the lung
      was expressed as an exponential decay with time, and the longer whiskers (>20
      micro m) tended to remain selectively in the lung after the 12-mo clearance. Mass
      of graphite whisker also decreased exponentially. Count median diameters and
      lengths (CMDs and CMLs) decreased gradually during clearance time, although CMDs
      did not decrease linearly. Morphological change of this whisker was very unique
      and characteristic; that is, the surface of the whiskers peeled away in the lung
      as a result of their stratified crystalline structure.

PMID- 12476361
TI  - Exposure of human lung cells to inhalable substances: a novel test strategy
      involving clean air exposure periods using whole diluted cigarette mainstream
      smoke.
AB  - An experimental approach was established for the validation of an in vitro test
      system for complex environmental test atmospheres consisting of both gaseous
      substances and particulates. Smoke from two different cigarette types (generated
      by an automatic cigarette-smoking machine) was employed to assess both the
      sensitivity and the specificity of the system. The smoke was diluted with
      synthetic air and used to expose human lung cells grown on microporous membranes.
      Cells were exposed alternately to diluted cigarette smoke and pure synthetic air.
      The effect of diluted smoke was assessed without humidification, addition of CO2,
      or any other physical or chemical modification of the smoke. The experimental
      setup included online monitoring of the gas phase (by analysis of CO
      concentration) and particulate phase (by light-scattering photometry). Replicate
      experiments confirmed a reproducible generation and dilution of the smoke and a
      smoke age of about 7 s at the time it came into contact with the cells.
      Experiments using human lung cells revealed that smoke from the two different
      cigarette types induced different levels of dose-dependent toxicity. A cell
      exposure of 6 min using 6 alternating smoke and synthetic air periods was
      sufficient to cause different effects as measured by intracellular glutathione
      content. The fact that the system could differentiate between two different types
      of cigarette smoke demonstrated its high sensitivity and specificity. The system
      offers new ways to test native complex gaseous and aerosol mixtures in vitro
      using short exposure times and very small amounts of test substances.

PMID- 12476362
TI  - Glutaraldehyde inhalation exposure of rats: effects on lung morphology, Clara
      cell protein, and hyaluronic acid levels in BAL.
AB  - Glutaraldehyde (GA) is a biocide widely used in hospital and laboratory practice.
      GA is a volatile substance and, under certain circumstances, significant airborne
      concentrations may be generated at room temperature. Occupational exposure to GA
      by inhalation is suspected of causing delayed irritating effects. In recent
      years, GA has emerged as the main cause of occupational asthma among health-care
      workers. The aim of the present study was to evaluate effects of GA inhalatory
      exposure (0.025 ppm or 0.1 ppm, for 28 days) in rats exposed corresponding to the
      occupational shift cycle, at time point 24 h, 48 h, and 7 days postexposure (PE).
      Numerous vacuoles and dilated spaces in epithelial cells in bronchioles showing a
      destructive effect of GA on the cellular membrane were observed at 24 h PE in 0.1
      ppm exposed rats. Lipid vacuoles observed after 48 h PE in higher GA exposure, in
      the Clara cells of the bronchial epithelium, and in endothelial cells of the
      alveolar capillaries are probably attributable to disturbed lipid metabolism.
      Many foci of collagen fibers were observed already after 7 days postexposure.
      Monitoring of inflammatory response and repair was made possible by using two
      biomarkers: Clara-cell protein (CC16) and hyaluronic acid (HA). Our results show
      that the inflammatory repair response contributed to progenitor Clara cells and
      HA plays a role in the development of fibrotic changes in the lung of rats.
      Glutaraldehyde in rats causes fibrotic effects at the actual threshold limit
      value-time weighted average (TLV-TWA) level for GA as specified by current Polish
      and other national regulations.

PMID- 12476363
TI  - [Pouchitis--pathophysiology and therapy].
AB  - Ulcerative colitis can be cured with a reasonable quality of life by the complete
      excision of the colorectum and construction of an ileoanal pouch. The cure is
      incomplete since there is a certain incidence of a so called pouchitis. Pouchitis
      occurs with a frequency of 36 %. A single episode of a pouchitis can be cured
      easily, but in 8-32 % the concerned patients develop a chronic pouchitis. There
      are many signs that pouchitis might be a remanifestation of ulcerative colitis.
      This article gives an overview on the actual state of pathophysiology,
      pathogenesis and therapy of this disease. Apart of that the surgical aspects of
      the disease are described.

PMID- 12476364
TI  - [Resection of the trachea for cicatrical stenosis].
AB  - Tracheal stenosis represents a serious complication of tracheostomy or of
      endotracheal intubation. The objective of this article was to evaluate the
      results of resective therapy of patients with tracheal stenosis. METHODS: In 41
      patients treated by tracheal resection for tracheal stenosis the diagnosis was
      established by bronchoscopy, tracheal tomography or CT. The following parameters
      were evaluated: the reasons for artificial pulmonary ventilation, basic
      parameters of stenosis (site of stenosis, length, diameter), the relationship
      between the duration of cannulation and asymptomatic interval, and postoperative
      complications. RESULTS: The most frequent reason for cannulation was trauma (n =
      23), most patients were cannulated for 4-5 weeks (n = 16), the symptoms of
      stenosis appeared mostly within 4-5 weeks (n = 11) after decannulation. The
      asymptomatic interval was longer in patients with longer periods of cannulation
      (p < 0.01) than in patients with a shorter cannulation period. The most frequent
      site of stenoses was the medium third of the trachea (n = 22). The longest
      resected section measured 60 mm. In 3 patients (7.3 %) a tracheoesophageal
      fistula was found together with the stenosis. In 3 patients (7.3 %) restenosis
      appeared. Tracheocutaneous fistula with osteomyelitis of the sternum developed in
      one patient. Granulation tissue on the anastomosis site (n = 4, 9.7 %) was
      treated by laser or disappeared spontaneously. None of the patients died within
      30 days after operation. CONCLUSION: Resection is the optimum therapeutic method
      for tracheal stenosis with low postoperative mortality and a small number of
      postoperative complications. Successful tracheal resection is a definitive
      solution in comparison with stent placement.

PMID- 12476365
TI  - [Follow-up results and learning curve in laparoscopic gastrofundoplications].
AB  - AIM OF THE STUDY: To analyze the postoperative results and the learning curve of
      laparoscopic gastrofundoplications by postoperative clinical monitoring of
      consequences and self-evaluation of complaints 12 months after surgery. METHODS:
      One hundred patients (58 female and 42 male) were operated at the Department of
      Surgery, Hospital of Kaunas University of Medicine, from April 1998 to January
      2001 because of hiatal hernias, complicated with gastroesophageal reflux (in 59
      cases sliding axial non-fixed, in 38 cases sliding axial fixed, and in 3 cases
      paraesophageal hernias were found). 89 Nissen and 11 Toupet fundoplications were
      performed. Patients were distributed into five groups (20 patients in each).
      Operation time, number of postoperative complications, postoperative hospital
      stay were analyzed. RESULTS: The mean operation time was 198 min in the 1 st
      group, 105 min in the 2 nd group, 110 min in the 3 rd group, 124 min in the 4 th
      group and 120 min in the 5 th group. Conversion to laparotomy was necessary in
      two cases (the 1 st and the 2 nd groups). The number of postoperative
      complications decreased from 5 in the 1 st group to 2 in the 2 nd group, and to 1
      in the 3 rd and 4 th groups; no complications were noted in the 5 th group.
      According patient's opinion, successful results were received in 87 %.
      CONCLUSIONS: Laparoscopy is a good approach for surgical management of hiatal
      hernias complicated with gastroesophageal reflux, but laparoscopic
      gastrofundoplication needs advanced skills to be performed safely. The learning
      curve in terms of operation time covered initial 20 procedures and remained
      stable afterwards, the number of postoperative complications decreased after
      initial 20 operations, but dangerous complications occurred until the 60 th
      procedure. Other conventional elective surgical procedures of medium extent can
      be successfully performed simultaneously with laparoscopic fundoplication without
      affecting the outcome. The true learning curve of laparoscopic fundoplication can
      be drawn by careful follow-up and analysis of long-term postoperative results;
      this enables to improve operative techniques.

PMID- 12476366
TI  - [Venous stasis and deep vein thrombosis prophylaxis during laparoscopic
      fundoplication].
AB  - AIMS OF THE STUDY: first, to study the effect of a pneumoperitoneum (12 mm Hg) on
      femoral venous outflow, second, to evaluate the efficacy of mechanical antistasis
      devices: intermittent pneumatic compression (IPC), intermittent electric calf
      muscle stimulation (IECS) and graded compression leg bandages (LB) in reducing
      venous stasis, third, to determinate the incidence of deep venous thrombosis
      (DVT) after laparoscopic fundoplications using venous occlusion plethysmography
      method. PATIENTS AND METHODS: 54 patients undergoing elective laparoscopic
      fundoplications were studied. They were randomized into three groups - 18
      patients in each group. The first group received LB, the second group received
      IECS and the third group IPC during operations. Lower extremity venous blood
      velocity was evaluated using Doppler ultrasonography during operation. In all 54
      patients leg venous outflow was measured 1 day before and 1 day after operation
      using venous occlusion plethysmography method, in order to detect possible DVT
      after operation. The blood velocity in the femoral vein without pneumoperitoneum
      was 20.1 +/- 2.4 cm/s in the IPC group, 20.3 +/- 1.4 cm/s in the IECS group, and
      23.9 +/- 1.2 cm/s in the LB group. With the introduction of a pneumoperitoneum
      (12 mm Hg) and the reverse Trendelenburg position the femoral venous blood
      velocity was significantly reduced in all groups: 9.3 +/- 0.9 cm/s in IPC group,
      9.4 +/- 0.9 cm/s in IECS group, and 9.2 +/- 1.1 cm/s in LB group (p < 0.05). The
      maximum blood velocity generated by the IPC when a pneumoperitoneum (12 mm Hg)
      was present was 17.4 +/- 1.9 cm/s, and in the IECS group 14.0 +/- 1.1 cm/s,
      whereas in the LB group the blood velocity remained the same (9.2 +/- 1.1 cm/s).
      Calf DVT and pulmonary artery microembolization developed in one patient of the
      LB group, detected by venous occlusion plethysmography and lung perfusion
      scintigraphy methods one day after operation. CONCLUSIONS: The femoral vein
      stasis which appears in laparoscopic fundoplications can be minimized by reducing
      the intraabdominal pressure during operation, and avoiding reverse Trendelenburg
      position as much as possible. IPC is more effective than IECS in reducing venous
      stasis induced by the pneumoperitoneum and the reverse Trendelenburg position.
      Graded compression by leg bandages is ineffective in patients undergoing
      laparoscopic gastrofundoplication. With a pneumoperitoneum in place, neither
      device was able to return the depressed blood flow velocity to the values
      recorded without a pneumoperitoneum. The incidence of DVT and pulmonary embolism
      after laparoscopic fundoplications was 1.8 % in our study.

PMID- 12476367
TI  - [Factors determining morbidity and effectiveness in videothoracoscopic
      splanchnicectomy].

PMID- 12476368
TI  - [Transhiatal esophagectomy for carcinoma of the esophagus--our ten years
      experience].
AB  - During the past 10 years, at University Surgical Clinic Rijeka, 107 patients
      underwent operation for carcinoma of the esophagus and cardia. Transhiatal
      esophagectomy was performed in 29 patients; in 28 of them an esophagogastrostomy
      was performed, and in one patient a pharingogastrostomy. Of the 29 patients,
      there were 24 men (82.8 %) and 5 women (17.2 %), with an average age of 60.7
      years. Histologically, 26 lesions (89.7 %) were squamous cell carcinomas, and 3
      (10.3 %) were adenocarcinomas. According to the prognostic stage as defined by
      the UICC, 15 patients (51.7 %) were stage II A, and 14 (48.3 %) stage III. The
      lesion was located in the cervical esophagus in two, the thoracic esophagus in
      thirteen and the lower esophagus in fourteen patients. Six patients died, for a
      hospital mortality rate of 20.7 %; the most common cause of death was respiratory
      failure. Pulmonary complications occurred in 14 patients (48.3 %). Anastomotic
      leak with all clinical manifestations occurred in one patient, while in two
      patients the radiological diagnosis of anastomotic leakage was made without
      clinical manifestations. Five patients (17.2 %) developed anastomotic stenosis,
      which was satisfactory treated by endoscopic dilatation. Mean survival after
      surgery was 21 months. One-year survival was 65.5 %, two and three-year survival
      was 37.9 and 17.2 % respectively. Younger patients and patients with lower stage
      of disease survived significantly longer (p < 0.05).

PMID- 12476369
TI  - [Patients with non-advanced pancreatic cancer benefit from extended
      lymphadenectomy].
AB  - BACKGROUND: Despite improvements in surgical technique and adjuvant therapy
      models, the overall outcome for patients with pancreatic cancer has not
      significantly improved over the recent decades. The aim of the study was to
      assess the value of extended lymphadenectomy for pancreatic cancer. STUDY DESIGN:
      We performed a retrospective analysis of 136 patients with pancreatic cancer who
      underwent pancreatectomy and standard or extended lymph node dissection, to
      compare the rate of perioperative complications and 5-year survival. RESULTS: Of
      136 patients treated, 43 (32 %) underwent standard (group I) and 93 (68 %)
      extended (group II) lymphadenectomy. Both groups were comparable with regard to
      various clinicopathological factors including patients' age, gender, tumour
      location, advancement and radicality of performed resection. The mean operative
      time in the extended group was longer (385 +/- 78 min) than in the standard group
      (359 +/- 62 min) but observed difference was insignificant. Similarly, there were
      no significant differences with respect to transfused blood and plasma units. The
      mean number of resected lymph nodes was significantly (p < 0.001) higher in group
      II (29.0 +/- 17.7) compared to I (13.0 +/- 7.4). The overall morbidity and
      mortality rates were 43 % and 6 %, respectively, without significant differences
      between both groups. The overall 5-year survival was 16.7 % and was similar
      regardless the type of performed lymphadenectomy. However, patients with node
      negative pancreatic cancer following extended lymphadenectomy had significantly
      higher (p < 0.01) 5-year survival (48 %) compared to the standard resection (22
      %). CONCLUSION: Extended pancreatoduodenectomy can be performed with similar
      morbidity and mortality rates as the standard procedure. However, only patients
      with non-advanced pancreatic cancer are likely to benefit of 5-year survival.

PMID- 12476370
TI  - [Surgical palliation for pancreatic cancer. The 25-year experience of a single
      reference centre].
AB  - BACKGROUND: In spite of dynamic development of modern diagnostic and therapeutic
      methods, the long-term results of surgical therapy in pancreatic cancer are still
      unsatisfying. The aim of this study was to analyse long-term results of surgical
      palliation for pancreatic cancer in a pancreatic surgery centre. METHODS: We
      performed a retrospective analysis of 418 patients who underwent non-resective,
      palliative procedures for pancreatic cancer between 1975 and 1999. In order to
      compare two consecutive periods of time, the patients were divided in 2 groups;
      group I treated from 1975 to 1990 (n = 204), and group II from 1991 to 1999 (n =
      214). RESULTS: Of all patients qualified for surgery, 281 (67.2 %) underwent
      surgical bypass, 107 (25.6 %) laparotomy, and in 30 cases surgical intervention
      was limited to implantation of endoprosthesis. A significant tendency towards
      double (i. e. biliary and gastric) anastomosis was observed (32.3 % vs. 74.8 %; p
      < 0.01) in patients who underwent bypass procedures. The postoperative morbidity
      was 16.3 %. The postoperative mortality rate was 5.7 % and significantly (p <
      0.01) decreased from 10.3 % (group I) to 1.4 % (group II). No differences neither
      in mortality nor morbidity related to the type of performed surgery were found.
      The mean time of hospital stay was 15.5 +/- 6.9 days and showed no differences
      related to the type of intervention. Jaundice or symptoms of gastric outlet
      obstruction were observed in 16 % of patients in the follow-up period and
      concomitantly performed biliary and gastric bypasses were associated with the
      lowest rate of the late gastrointestinal obstruction (4 %). The median survival
      time was 169 days and only 4 % of patients survived 12 months. The univariate
      analysis of prognostic factors showed that location and stage of the tumour, the
      type of surgical intervention and bypass procedure influenced 1-year survival.
      The multivariate analysis using Cox proportional hazard model proved that only
      stage and location of the tumour had independent prognostic value. CONCLUSION:
      Surgical palliation for pancreatic cancer can be performed with acceptable
      morbidity and mortality rates. For tumours located in the head and body of the
      pancreas combined biliary and gastric bypass should be preferred. For cancers
      located in the tail of the pancreas gastric bypass should be performed routinely.
      Because surgical palliation can prevent gastric outlet obstruction by
      gastroenterostomy, endoscopic biliary stenting should be only performed in
      patients with pancreatic head cancers and simultaneous evidence of distal
      metastases as well as in older patients with high comorbidity.

PMID- 12476371
TI  - [Portasystemic shunt--our twenty years experience].
AB  - OBJECTIVE: It was the aim of this study to demonstrate our experiences over
      twenty years with portasystemic shunt surgery in patients with chronic liver
      disease and variceal bleeding. PATIENTS AND METHODS: From January 1 st, 1980 to
      December 31 st, 2000 we performed 90 portasystemic shunt operations (PSO). The
      patients were divided in two groups. The patients of the first group were
      operated upon between 1980-1988 (n = 58), patients of the second group (n = 32)
      between 1988-1998. Both groups did not differ in age, gender and cause of hepatic
      disease. In the first group the most performed type of shunt was the portacaval
      shunt, in group II the splenorenal shunt. RESULTS: We observed an improved early
      and late mortality rate, encephalopathy rate and reduction of recurrent variceal
      bleeding in the second group: the early mortality rate decreased from 16 to 9 %
      (p < 0.01), the late mortality rate from 35 to 6 % (p < 0.05), the encephalopathy
      rate from 43 to 12 % and the variceal rebleeding rate from 10 to 6 %. CONCLUSION:
      Selective shunts, such as the distal splenorenal shunt are significantly superior
      to the standard (end-to-side or side-to-side) portasystemic shunt. In countries
      where acute treatment of recurrent variceal hemorrhage with sclerotherapy is not
      available in remote areas or in countries where transplantation procedures are in
      the very beginning and where TIPPS operations are too expensive, portasystemic
      shunt operations are the only possibility to save the patients life when
      sclerotherapy fails.

PMID- 12476372
TI  - [Importance of a clinical protocol in the treatment of severe acute
      pancreatitis].
AB  - BACKGROUND: Selection of the optimal treatment strategy in severe acute
      pancreatitis (SAP) is a serious clinical challenge largely due to difficult
      differential diagnosis of patients with early SAP. The aim of this study is a
      retrospective evaluation of the first experiences in the treatment of patients
      with SAP and early SAP according to a new complex clinical protocol (CCP).
      METHODS: A total of 210 patients complied with Atlanta recommendations for SAP
      and were included in the retrospective study. Patients were stratified into two
      groups according to the diagnostic and treatment strategy. Non-protocol (NP)
      group comprised 154 patients who had received their treatment based on previous
      clinical routine and subjective decision of physicians in charge. 56 patients who
      were managed according to the new CCP developed for SAP comprised the CCP group.
      CCP included:- Early assessment of the severity of acute pancreatitis (APACHE II
      score, presence of SIRS and/or organ dysfunction); - Immediate ICU monitoring
      including routine measurement of the intraabdominal pressure; - Conservative
      treatment including early enteral nutrition, colloids, antibacterial prophylaxis
      and early continuous venovenous hemofiltration (CVVHF) when indicated; - Surgical
      treatment when conservative treatment was not effective (progression of the organ
      dysfunction) or presence of infection was evident. Hospital, ICU stays and
      outcomes were analysed. Statistical comparison was done by Mann-Whitney U-test
      and Chi-square test. RESULTS: The age structure and severity of the disease were
      similar in both groups with mean of 51.3 (15.6) vs. 46.8 (15.2) years and 9.7
      (5.1) vs. 9.8 (4.4) APACHE II points in groups NP and CCP, respectively.
      Male/female ratio was 2 : 1, and alcohol was the main etiologic factor in about
      55 % of cases in both groups. Early SAP was diagnosed in 33 % to 46 % of patients
      according to the results of the SOFA scoring. The results of the conservative
      therapy considerably improved after implementation of the CCP treatment. Surgical
      intervention was done in 46-52 % of patients. MODS was the main cause of death in
      both groups. Remarkable decrease in early mortality (within the first week from
      admission) was a real advantage of CCP treatment comprising 1.8 % vs. 22.1 % in
      NP patients, p < 0.01. Mortality from early SAP was reduced by CCP treatment to
      3.8 % compared to 33 % in NP group, p < 0.01. There was a considerable reduction
      in postoperative mortality with CCP treatment comprising 10.3 % vs. 32.7 % in
      patients who did not receive CCP treatment, p < 0.05. Overall mortality
      associated with CCP treatment ranged to 5 %, compared to 34 % mortality in the NP
      treatment group, p < 0.01. Due to the considerable number of early deaths among
      NP patients, there was statistically longer ICU and hospital stay in CP group
      with mean of 14.1 (14.1) vs. 9.6 (15.2) days and 37.9 (26.7) vs. 23.4 (21.8)
      days, compared to NP group, p < 0.01. CONCLUSIONS: Timely recognition and complex
      therapy of SAP including ICU monitoring, colloids, antibacterial prophylaxis,
      early enteral nutrition, and CVVHF is the most effective way how to manage this
      category of patients. Implementation of a specialised treatment protocol
      considerably improves outcome and reduces the number of deaths associated with
      surgery and early SAP.

PMID- 12476373
TI  - [Increased intra-abdominal pressure--an important risk factor of early organ
      dysfunction in severe acute pancreatitis].
AB  - BACKGROUND: Sustained increase of the intra- abdominal pressure is recently
      recognized as a potential risk factor of early organ dysfunction in patients with
      severe acute pancreatitis. Assessment of the possible mutual relevance between
      increased intra-abdominal pressure and early organ dysfunction is important for
      optimisation of the treatment strategy in this category of patients. PATIENTS AND
      METHODS: 71 patients with severe acute pancreatitis were entered in this
      prospective study. Clinical routine, sequential organ failure assessment score
      (SOFA), and intra-abdominal pressure were registered, considering 25 cm H 2 O a
      critical value for the grouping in high-risk (n = 18) and low-risk (n = 53)
      patients according to whether they experienced the critical level during their
      treatment course. RESULTS: The age structure and the initial presentation of the
      organ dysfunction were similar between both groups. Progression of the organ
      dysfunction was observed in 61 % of the high-risk patients, compared to 32 % of
      low-risk patients, p < 0.05. Organ function improved after three to four day
      treatment only in survivors. Peak intra-abdominal pressure was greater in high
      risk patients, p < 0.01, but declined after three to five day treatment period in
      all survivors, remaining critical in nonsurvivors. 78 % of high-risk and 32 % of
      low-risk patients were operated, p < 0.05. The overall mortality was 8.5 %,
      consisting of 2 % mortality in the low-risk group and 28 % mortality in the high
      risk group, p < 0.01. CONCLUSION: Increased intra-abdominal pressure could be an
      important risk factor of early organ dysfunction in patients with severe acute
      pancreatitis. Critical increase of the intra-abdominal pressure and persisting
      organ dysfunction are an indication for reassessment of the treatment strategy.

PMID- 12476374
TI  - [Diagnostic and therapeutic management of symptomatic cholecystolithiasis and pre
      operatively suspected choledocholithiasis].
AB  - The goal of this study was to examine the effectiveness of endoscopic retrograde
      choledocho-pancreatography (ERCP) at the Unfallkrankenhaus Berlin in the setting
      of pre-operative suspicion of choledocholithiasis. The predictive value of
      various pathologic findings with regard to choledocholithiasis was to be
      determined in this patient population.All patients treated operatively for
      symptomatic cholecystolithiasis between August 2000 and August 2001 were
      evaluated retrospectively for the following variables: age, gender, operative
      strategy, intra-operative cholangiography, sonographic findings, occurrence of
      choledocholithiasis. In 21.4 % of 196 patients who underwent cholecystectomy (n =
      42) a pre-operative ERCP was performed. In 19 of these 42 patients, no pathology
      was found on ERCP. The percentage of therapeutic pre-operative investigations was
      47.6 % (n = 20). In 3 patients, a juxtapapillary diverticulum was seen.69.9 % of
      the operations (n = 137) were performed laparoscopically. 167 patients (85.2 %)
      underwent intra-operative cholangiography. In 4 patients, the ERCP was performed
      post-operatively. The indication for 3 of those 4 examinations was an abnormal
      intra-operative cholangiogram. Complications occurred in 4 of the 46 patients who
      underwent ERCP (8.7 %). Choledocholithiasis was found in 12.2 % (n = 24) of all
      196 patients. The pathologic finding with the highest positive predictive value
      for the diagnosis of choledocholithiasis was the finding of a dilated common bile
      duct to more than 8 mm diameter (PPV 75 %). Among laboratory variables
      investigated in this study, the elevation of serum bilirubin level exhibited the
      highest positive predictive value (PPV 39.2 %).

PMID- 12476375
TI  - [Continuous single-layer technique in turnable and nonturnable gastrointestinal
      anastomoses. A prospective observational study of emergency and elective
      operations].
AB  - First reports about the continuous single-layer technique for gastrointestinal
      anastomosis have shown advantages regarding shorter time for construction and
      lower costs without a higher complication rate. This prospective observational
      study was conducted to prove the safety of routine use of the continuous single
      layer technique for gastrointestinal anastomosis. All consecutive patients
      operated upon in the abdomino-surgical department of a community hospital in a
      period of 5 years with resections of the stomach, small and large bowel or upper
      third of the rectum were included in this study. All gastrointestinal anastomoses
      were performed by continuous single-layer technique using 3/0 or 4/0 absorbable
      PDS suture. Follow-up was until hospital discharge. 344 patients received 405
      anastomoses, 30 % were emergency and 70 % elective operations. 6 anastomotic
      leaks (1.7 %) and 1 stenosis (0.2 %) occurred, two patients died after
      reoperation followed by multiple organ failure. 30-day-mortality was 12 % due to
      a high percentage of emergency operations, of patients with late stage
      malignancy, and multimorbidity or old age. The continuous single-layer technique
      for gastrointestinal anastomosis is safe in routine clinical practice and should
      receive broader attention due to its advantages.

PMID- 12476376
TI  - [Orthotopic liver transplantation in case of TIPS stent dislocation].
AB  - Transjugular intrahepatic portosystemic shunts (TIPS) are indicated in patients
      with liver cirrhosis and portal hypertension for treatment of variceal bleeding
      or refractory ascites. Additionally implantation of stents may lead to stent
      dislocation or thrombosis in up to 20 % of cases. Detailed information about
      stent dislocation and its impact on subsequent orthotopic liver transplantation
      (OLT) is rare regarding the literature. We report on a patient suffering from
      ethyltoxic liver cirrhosis in which OLT was technically complicated by a
      thrombosed TIPS stent, dislocated in the portal vein. This stent was implanted
      prior to OLT due to refractory ascites and partial portal vein thrombosis. We
      conclude that TIPS stent insertion, especially in liver transplant candidates,
      should only be performed by radiologists in centers with expertise and
      experience.

PMID- 12476377
TI  - [The history of kidney transplantation in Germany].
AB  - In 1910 Ernst Unger started kidney transplantation in Germany, when he tried to
      cure an uremic patient in Berlin by transplanting a monkey kidney. But it was not
      until 1963 that the urologists Brosig and Nagel - again in Berlin - began
      relevant clinical renal transplantation. In the late sixties the teams in Munich
      and Heidelberg took over the main initiative. In the seventies the method was
      widely accepted as therapy in chronic renal failure. But the quantitative
      development in both parts of Germany was very slow. In 1977 less than 100
      transplantations were carried out in East Germany and less than 300 in the West.
      But then the numbers reached 2 015 in 1990 in the BRD and 343 in the DDR, resp.
      Unfortunately after the reunification there was no further increase, the numbers
      rather fluctuated between 2 000 and 2 300. While the former difference between
      East and West may well be explained by different forms of organisation, the
      situation after the reunification might be due to the emotional discussions on
      legislation and necessary structural alterations, the roots of which are
      disclosed.

PMID- 12476379
TI  - [Primary hip- and knee arthroplasty--comparison of the actual costs with the
      Australian diagnosis related groups (DRG)-].
AB  - AIM: With the introduction of the Australian DRG system in Germany the question
      arises which current procedures remain reasonable in cost. The present study
      compares the actual costs with the expected DRG reimbursement. PATIENTS AND
      METHODS: Prospective analysis of 23 patients with primary hip and 26 with knee
      arthroplasty was performed to identify all cost factors during the
      hospitalization period including all applied measures. Retrospective analysis was
      carried out of the additional costs of relevant concomitant diseases (liver
      transplantation, haemophilia). RESULTS: Expenses of 6231 euro; for hip and 6453
      euro; for knee implants were covered by the DRG reimbursement. Although a special
      reimbursement was paid, the additional costs of the concomitant diseases resulted
      in a financial loss. CONCLUSION: To cover the current costs for patients free of
      complications, an enormous reduction of the length of stay is required. Otherwise
      complicated cases may result in a loss of quality or selection of patients. The
      present cost analysis outlines a guideline for an individual calculation and
      assessment of the necessary DRG reimbursement.

PMID- 12476380
TI  - [Revision total hip arthroplasty: how do metaphyseal onset, diaphyseal fill and a
      three-point-stem-fixation influence the postoperative subsidence of a revision
      straight-stem?].
AB  - AIM: It was the purpose of this study to determine the postoperative subsidence
      of a cementless hip revision stem in regard to the degree of metaphyseal onset,
      diaphyseal fit and a three-point contact of the stem in the femur. METHODS: Data
      of 50 revision total hip replacements using a cementless revision straight stem
      (PFM-R) could be investigated. The degree of subsidence was measured on pelvic X
      rays 6 and 12 months postoperatively. The degree of metaphyseal onset, diaphyseal
      fit and a three-point contact of the stem in the femur was determined on the
      immediate postoperative X-rays. RESULTS: The amount of subsidence was strongly
      related to the degree of metaphyseal onset. With minor onset (up to 25 % of the
      possible) stems subsided 9.4 (6 months), respectively, 13.2 millimeters (12
      months) in average within the investigation periods. If there was a large degree
      of metaphyseal onset (more than 75 % of the possible) the average subsidence was
      only 1.6 (6 months) or 0.9 millimeters, respectively (12 months). Neither the
      amount of diaphyseal fit nor the presence of three-point contact of the stem in
      the femur influenced the subsidence significantly. Conclusion The amount of the
      postoperative subsidence of stems in cementless revision total hip arthroplasty
      is predominantly influenced by the degree of the metaphyseal onset of the
      prosthesis.

PMID- 12476381
TI  - [Vacuum mixing systems for bone cement completion - comparison of different
      systems].
AB  - INTRODUCTION: The use of vacuum mixing systems when mixing bone cement reduces
      its porosity and hereby significantly improves the features of the material. The
      currently available mixing systems are compared with regard to handling,
      mechanical properties and economical aspects. METHODS: In 8 vacuum mixing systems
      the handling, pump performance, system tightness, the used air volume, the filter
      efficiency, the remaining amounts in the mixing system and the porosity of the
      cements are shown in comparison. RESULTS: All vacuum mixing systems reduce the
      porosity of the cement in comparison to hand mixed cements significantly if used
      correctly. The individual examinations, though, show enormous differences, which
      can be of significance to the user in the individual choice of system and,
      depending on the individual circumstances, can influence the quality of the mixed
      cement. CONCLUSION: The results enable the user to choose and handle a vacuum
      mixing system which is optimally suitable for the individual circumstances in
      respect to the characteristics examined.

PMID- 12476382
TI  - [Results of uncemented revision arthroplasty of the hip with the MRP-stem using
      an intrafemoral approach with vascularized distal fenestration].
AB  - AIM: THR is one of the most successful principles in orthopaedics. With the
      increasing number of primary THR more and more revision arthroplasties of the hip
      are necessary. Many factors including loss of bone stock, instability of the
      joint, infection, fractures, removal of the implant or cement mantles are a
      challenging condition for the surgeon. Many approaches and techniques for the
      removal of cement mantles are published. We prefer the intrafemoral approach with
      an distal vascularized femoral window. METHOD: We want to describe our surgical
      technique and report the short term results of 45 revision arthroplasties of the
      hip using the uncemented modular titanium MRP stem. Mean follow-up was 2.6 years
      (min:1 year, max: 7 years). RESULTS: Mean Harris hip score increased from
      preoperative 53,2 (16 - 89) to postoperative 90.4 (35 - 100) points. We could
      find remodelling of the bone and spontaneous refill of bony defects in all cases.
      After 14 weeks we could find bony consolidation of the femoral window. The
      Trendelenburg sign was positive preoperatively in 26 cases, postoperatively in 11
      cases. Just one single dislocation of the revised hip occurred postoperatively.
      CONCLUSION: The intrafemoral approach with distal vascularized femoral
      fenestration is a mild approach without further weakening of the
      pelvitrochanteric muscles. Removal of cement mantles is possible without any
      problems. Using the vascularized technique of the femoral fenestration prompt
      bony consolidation can be achieved.

PMID- 12476383
TI  - [The KIL-system for qualitative and quantitative evaluation of posture in lateral
      view].
AB  - AIM: To register also minor variations of posture sa simple and economic
      procedure should be worked out to categorize posture types concerning quality as
      well quantity. METHOD: On the Image of the lateral body profile three reference
      points were determined which allow us to measure two distances and two angles.
      RESULTS: The relation of the two distances reflects the degree of kyphosis, the
      angles indicate on the one hand the inclination of the spinal sagittal
      configuration and on the other hand the degree of lordosis. The measured values
      are shown in the Kyphosis-Inclination-Lordosis system (KIL system). The
      components of measurement have proved successful also for static as well as for
      dynamic posture assessments. The method was simple and economic as postulated.
      CONCLUSION: The method allowed us to analyse reliably the effect of active
      primary Intervention also for minor variations in posture on pupils at the age of
      11 to 15 over a period of three years. The quantitative analyse made it possible 
      contrarily to the usual postural types going by what Staffel said - to define
      subcategories and with it a precise selection of individuals who need a secondary
      intervention. The method has been set up for check-ups in school, but an
      application to other groups should be possible.

PMID- 12476384
TI  - [Use of peridural catheters in the treatment of postoperative pain after spinal
      instrumentated fusion--an experience report].
AB  - AIM: In a prospective randomized clinical study we investigated in a group of 20
      patients after spinal instrumentation surgery the analgesic efficacy and the
      safety of epidural analgesia. Intraoperatively an epidural catheter was placed by
      the orthopedic surgeons for postoperative pain control. METHOD: For epidural
      catheter analgesia a mixture of the local anesthetic ropivacaine and the opioid
      sufentanil was used with an initial bolus, followed by a continuous infusion and
      the possibility of patient-controlled bolus administration (PCEA). Pain-scores
      (VAS) were measured pre- and postoperatively at rest, and during active
      mobilization maneuvers like turning around in bed and standing. The neurological
      status, side effects, and complications were evaluated. RESULTS: Mean pain-scores
      (VAS) were 3.8 pre-operatively at rest, after initiation of epidural analgesia
      0.3 at rest, 1.6 at turning around in bed and 0.8 at standing (6.8 pre
      operatively). Transient sensible or motoric deficits, due to the local
      anesthetics' effect, occurred in 8 respectively in 3 of the patients. Drug
      induced typical side-effects were pruritus, nausea and emesis. No cardiopulmonary
      complications happened. CONCLUSION: The epidural lumbal analgesia is an effective
      and safe method to control postoperative pain after spinal instrumentation
      surgery. Precondition is the knowledge about the safe and standardized technique
      of intraoperative catheter placement by the orthopedic surgeon, the choice of the
      appropriate analgesic drugs and a good cooperation between the departments of
      anesthesiology and orthopedic surgery and nursing staff.

PMID- 12476385
TI  - [Spinal cord stimulation (SCS) using an 8-pole electrode and double-electrode
      system as minimally invasive therapy of the post-discotomy and post-fusion
      syndrome--prospective study results in 34 patients].
AB  - AIM: Therapy of a pronounced post-discotomy (PDS) and post-fusion syndrome (PFS)
      is often unsatisfactory because of the complexity and multifactorial pain
      genesis. If surgical interventions cannot promise relief and if the entire
      interdisciplinary spectrum of conservative treatment measures is inadequate, the
      area of neuromodulative procedures offers spinal cord stimulation (SCS). The
      objective of this study was to examine the therapeutic possibilities of SCS using
      an 8-pole electrode and double electrode system in PDS and PFS with extensive
      back-leg pain areas. METHOD: An appropriate SCS system was implanted in 34
      patients with PDS and PFS. Follow-up examinations were made prospectively over a
      period of 24 months using general criteria and psychometric test measuring
      instruments validated for German-language use. RESULTS: An 8-pole double
      electrode system was implanted 23 times, a single electrode sufficed in 11 cases.
      The area of pain was covered in all patients. This required special technical
      capabilities of the SCS system. The results remained constant over 24 months. The
      morphine dose could be reduced by at least 50 %. All measuring instruments
      confirmed a clear reduction in pain and improvement in quality of life as a
      result of SCS implantation. CONCLUSION: The SCS is an minimally invasive surgical
      procedure which can enlarge the therapeutical possibilities of pronounced PDS and
      PFS resistant to other modes of treatment. Special technical possibilities of
      parameter setting are required to cover the pain areas.

PMID- 12476386
TI  - [Anthropometric 3D-body scanning in idiopathic scoliosis].
AB  - PURPOSE: A new, non-invasive method of 3D-measurement is presented which allows
      the spatial recording of the entire body surface in scoliotic deformities. The
      application of the system is examined to raise automatically anthropometric data
      of patients with scoliosis. METHOD: 32 patients with idiopathic scoliosis were
      examined (average age 15.3 years, 25 girls and 7 boys, Cobb angles between 11 and
      72 degrees). The whole body recording is carried out with a 3D laser scanner.
      During the measuring process the patient is standing in a frame. Within the
      measuring time of 15 seconds the body surface is registered by lasers and four
      cameras. The measured values are converted to a digital 3D model. The resolution
      is up to 1 mm. On the digital 3D model an automatic calculation of defined
      anthropometric parameters were carried out. Each patient was measured twice.
      RESULTS: In all patients a virtual 3D model with a high surface accuracy was
      obtained. Was the model the typical body asymmetries in scoliotic deformities
      were visible. The automatic calculation shows a mean deviation of the second
      measurements between 0.23 and 0.71 cm. The reproducibility depended on the type
      of the measured parameters. CONCLUSIONS: The laser scanning system allows a
      rapid, touchless and accurate 3D measurement of the whole body in scoliotic
      deformities. To determine anthropometric parameters the reproducibility of the
      automatic calculation is sufficient in most parameters.

PMID- 12476387
TI  - [Paleopathology of the lumbar spine in the early medieval period].
AB  - AIM: The lumbar spine of people from ancient civilizations can provide a large
      amount of information about these individuals and their physical condition
      through paleopathological investigation. METHOD: This study was conducted on a
      sample of 185 lumbar spines from southwestern Germany dating back in the early
      medieval period. The skeletons came from the row graves from Nusplingen,
      Schretzheim, Neresheim, and Pleidelsheim. RESULTS: Examples of congenital
      malformations, degenerative processes, infections and traumatic diseases were
      discovered. The most common pathological findings were degenerative changes of
      the lumbar spine in 24 %. Congenital anomalies and spondylolysis were relatively
      common in this population. Examples of traumatic injuries and infections of the
      spine were rare. Metastatic lesions on the vertebral bodies were identified in no
      case. CONCLUSION: Most diseases of the lumbar column in the ancient inhabitants
      of southwestern Germany were similar to those that affect the present-day
      population of that area.

PMID- 12476388
TI  - [Experiences with lumbar disc herniations in adolescents].
AB  - AIM: Lumbar disc herniation is rare in adolescents and often misread. The
      difference of etiology, symptoms and therapy in comparison to adults were
      investigated and the long-term outcome of conservative and surgically treatment
      evaluated. METHOD: We analysed informations obtained from the medical records of
      51 patients younger than 20 years with 79 lumbar disc herniations. For the long
      term follow-up we prepared a questionnaire composed of general questions about
      the patient's lifestyle, pain level and remaining symptoms. RESULTS: The average
      period from the beginning of the symptoms to the finding of the right diagnosis
      took about 14,3 months. We compared disc herniations in adolescents with the
      current literature of disc herniations in adults and found differences in
      etiology and symptoms. In 16 % of our patients the beginning of the pain was
      associated with a trauma, in 12 % the pain began during sports activity
      (microtrauma). In 49 % we found radiological signs of spinal aberrations. Low
      back pain and monoradicular sciatica were the main complaints, but findings of
      neurological deficits were rare. 27 patients were managed conservatively and 24
      surgically. On the day of discharge 94 % of patients reported excellent or good
      results. The outcomes of the follow-up period were similar in both treatment
      groups. Almost all patients were able to attain a normal activity level and few
      reported restrictions of their daily life. The success rate of the pain frequency
      was 85 % and pain intensity was 81 %. CONCLUSION: The etiology of lumbal disc
      herniations in adolescents has a multifactoral basis. Conservative treatment
      should be pursued as a mainstay of treatment. Only if conservative treatment
      fails, surgical treatment should be considered.

PMID- 12476389
TI  - [Osteosarcoma and Ewing's sarcoma--The most frequent malignant bone tumors in
      children--therapy and outcome].
AB  - BACKGROUND: Osteosarcoma and Ewing's sarcoma are the most frequent malignant bone
      tumors in children and young adults with relatively poor overall survival rates.
      METHODS: Between January 1980 and December 1994, 175 children with osteosarcoma
      and 64 children with Ewing's sarcoma were treated at the author's institution. 22
      children had synchronous metastases, 19 patients had a pathologic fracture. Both
      groups were treated systemically with chemotherapy regimens (COSS and CESS).
      Local therapy was amputation or tumor resection and endoprosthetic replacement or
      biological reconstruction with wide or radical resection margins. In case of
      Ewing's sarcoma in 35 patients postoperative radiation therapy was done. RESULTS:
      Five-year overall survival rate for osteosarcoma and Ewing's sarcoma patients is
      about 63 %, ten-year survival rate for osteosarcoma patients is 60.2 %, for
      Ewing's sarcoma patients 54.5 %. Prognostic factors significantly influencing
      overall survival rates are tumor response to chemotherapy (p values = 0.0056 and
      0.013, respectively), surgical treatment with adequate resection margins (p value
      = 0.0001 for osteosarcoma patients) and development of postoperative metastases
      (p value = 0.0001 for both groups). CONCLUSION: For both groups of malignant bone
      tumors systemic chemotherapy as well as adequate surgical therapy are necessary
      to reduce the rates of local recurrences and to achieve better survival rates.

PMID- 12476390
TI  - [Open surgical procedures in calcifying tendinitis of the shoulder - concomitant
      pathologies affect clinical outcome].
AB  - AIM OF THE STUDY: Open surgical removal of calcifications in chronic courses of
      calcifying tendinitis of the shoulder can be combined with acromioplasty.
      Independent of the surgical procedure not all patients achieve satisfactory
      surgical results. The aim of the study was to investigate whether preoperatively
      known epidemiologic, social, clinical and radiologic factors or intraoperative
      findings might influence the therapeutic outcome. METHODS: Following diagnostic
      arthroscopy, open removal of the calcifications was done as an isolated procedure
      (group A, n = 12) or combined with open acromioplasty (group/B, n = 24). Follow
      up was 33 months for both groups. RESULTS: Clinical outcomes were comparable in
      both groups (Group A, 74.9 points; Group B 73.4 points, Constant-Murley score)
      and independent of gender, age, profession, duration of anamnesis, hospital-stay
      period, follow-up period, dominance of arm, preoperative Constant-Murley score,
      calcification morphology and size and acromial type. 20 patients in total
      achieved a clinical outcome of </= 75 points (Constant-Murley score). 12 of these
      demonstrated lesions of the rotator cuff and joint cartilage combined with
      synovialitis. In 6 patients an adverse preoperative Constant-Murley score or the
      wish to receive a pension was recorded. CONCLUSION: Both surgical procedures lead
      to overall good and satisfactory clinical results. Below average clinical
      outcomes are associated with pathologic findings of the glenohumeral joints,
      adverse preoperative clinical situation or the wish to receive a pension.

PMID- 12476391
TI  - [Shoulder arthrodesis with plate fixation. Special features in cases of resection
      and defects].
AB  - AIM: Shoulder arthrodesis following prosthesis explantation or resection of the
      acromion has not often been described in the literature. The presented article
      analyses the special features and problems of these preoperative circumstances in
      4 cases and discusses them within the entire group. PATIENTS AND METHOD: Between
      06/1987 and 02/2001, a total of 30 shoulder arthrodeses using plate fixation were
      performed in our clinic and then analysed after an average of 2.7 (0.5 - 8.7)
      years. Surgery was carried out on 5 (17 %) females and 25 (83 %) males with a
      mean age of 37 (17 - 82) years. Two patients underwent shoulder arthrodesis as a
      salvage operation following unsatisfactory arthroplasty, or after trapezius
      transfer with corresponding reduced bony conditions, respectively. RESULTS: The
      active extent of movement following arthrodesis was 56 degrees (20 degrees - 90
      degrees ) abduction, and 60 degrees (20 degrees - 105 degrees ) anteversion. The
      most frequent complications following arthrodesis included pseudarthroses (3/10
      %), infections (4/13 %), and fractures of the humerus (4/13 %). The rate of
      complications was especially high in the cases after explantation of a shoulder
      prosthesis and resection of the acromion. In two of the four patients, three or
      five revision operations, respectively, were necessary. Two of the three
      pseudarthroses of the entire group occurred in these two cases. CONCLUSION:
      Complications of shoulder arthrodesis after resection of the acromion or the
      proximal humerus are especially frequent. To avoid pseudarthrosis in such cases,
      primary spongioplasty is advantageous. A fixation with plates is superior to a
      simple screw arthrodesis. For postoperative immobilization a plaster cast instead
      of an orthotic device should be taken into consideration.

PMID- 12476392
TI  - [Striated muscle microvascular response to implants with sol-gel calcium
      phosphate coating. A comparative in vivo study].
AB  - AIM: Local microvascular perfusion plays an important role in reparative
      processes and the pathogenesis of infection. The impairment of skeletal muscle
      microcirculation by a biomaterial may therefore have profound consequences. The
      aim of our study was to determine whether the biological acceptance of the widely
      utilised implant material stainless steel can be improved by a coating of sol-gel
      calcium phosphate. METHODS: Using the hamster dorsal skinfold chamber preparation
      and intravital microscopy, we quantified nutritive perfusion and leukocyte
      endothelium interaction in skeletal muscle after implantation of sol-gel calcium
      phosphate-coated stainless steel- and commercial pure titanium implants, and
      compared these results to those obtained with uncoated stainless steel and
      titanium. RESULTS: Within the first 24 h after implantation, animals with calcium
      phosphate coated stainless steel showed a significantly lower inflammatory
      response than did those with an uncoated stainless steel implant. After 24 h the
      quantified microcirculatory parameters deteriorated for animals with a calcium
      phosphate-coated stainless steel plate, indicating that, for as yet unknown
      reasons, the shielding mechanism of the calcium phosphate seems to deteriorate.
      Although not as inert as pure titanium, we found a relatively low inflammatory
      response for calcium phosphate coated titanium over the whole observation period,
      suggesting that the coating as such is well tolerated by the skeletal muscle
      microcirculation. CONCLUSIONS: Our in vivo results suggest that the biological
      acceptance of a conventional stainless steel implant can be improved over a short
      term by a sol-gel coating of calcium phosphate. Concerning tolerance by the local
      vascular system, commercially pure titanium currently remains unsurpassed.

PMID- 12476393
TI  - [Advantages of biomatrices in chondrogenesis of pluripotent mesenchymal stem].
AB  - AIM: The autologous in vitro expansion of chondrocytes is a new method for the
      treatment of localized cartilage defect zones in humans. In the past several
      investigators have shown the occurrence of mesenchymal stem cells (MSC) in human
      bone marrow, periosteum and somite mesoderm. Moreover it has been shown that
      these progenitor cells are able to differentiate into chondral tissue under
      special in vitro conditions. The following study shows current possibilities and
      borders of a chondrogenetic stem cell therapy. Furthermore advantages and
      disadvantages of different cellular biomatrix carriers are described, cartilage
      tissue engineering-related problems are discussed and possible solutions were
      pointed out. METHODS: A literature investigation served for evaluation of the
      present clinical and experimental data. Furthermore our own cell culture
      experiences were considered. RESULTS: Until now there exists no clinical concept
      using the potential of MSC for cartilage tissue engineering. Reasons are the lack
      of biomechanical and histological stability and handling problems of the
      cultivated cartilage tissue, especially the difficulties to fix and secure the
      transplant in the cartilage defect zones in situ. CONCLUSION: The systematic
      investigation of biomatrices by chondrogenic progenitor cell culture systems may
      lead to important data for the evaluation of the chondrogenic potency
      biomatrices.

PMID- 12476394
TI  - [Fetal hyperechogenic and cystic pulmonary masses: sonographic findings,
      antenatal management and outcome of 12 cases].
AB  - OBJECTIVE: Presentation of prenatal findings and postnatal outcome of cases with
      echogenic or cystic lesions of the lungs. Discussion of the prenatal diagnostic
      and clinical management. PATIENTS AND METHODS: Retrospective analysis of the
      antenatal sonographic findings, the management and outcome of 12 cases of fetal
      chest masses. RESULTS: The postnatal findings included cystic adenomatoid
      malformation of the lungs (CAML) (nine cases) and lung sequestration (LS) (one
      case). Five fetuses were observed up to term. Two of them underwent postnatal
      surgery and three fetuses revealed an antenatal decrease of the lesion. None of
      these surviving fetuses developed hydrops, but in three of them a mediastinal
      shift was seen. The other fetuses did not survive (termination of pregnancy: six
      cases, spontaneous fetal loss: one case). Four of them had bilateral solid
      lesions, hydrops or additional malformations. CONCLUSIONS: 1. Ultrasound
      evaluation of chest masses is useful in diagnosing of the type and the extent of
      the lesion, recognition of secondary alterations and exclusion of additional
      malformations. 2. Termination of pregnancy should be recommended in cases of
      hydrops that develops early in gestation, bilateral lesions with expected
      unfavourable outcome or life-threatening additional malformations. 3. Mediastinal
      shift does not seem to predict a poor perinatal outcome. 4. Spontaneous decrease
      of the size of the lesion is associated with a favourable outcome.

PMID- 12476395
TI  - [Obstetrical care in Berlin: possibilities for delivery from the gynaecologists'
      point of view].
AB  - BACKGROUND: Berlin offers a variety of delivery facilities: maternity clinics,
      birth centres, obstetrical practices and ambulant working midwives for the
      various options and kinds of delivery. To select an individual service is a
      difficult task for most women. In this process of decision-making the
      gynaecologist plays an important part. This raised the question as to how
      established gynaecologists appraise the available services, which delivery sites
      they recommend, and what criteria are decisive for their recommendation. METHODS:
      A postal survey of all the 523 gynaecologists of Berlin was conducted
      anonymously, 273 (52.2 %) of whom completed the questionnaire. RESULTS: The
      results of the study demonstrated that the most important aspects for the
      recommendation of a delivery place are the technological equipment and
      qualification of the staff. However, characteristics of good care and support and
      an atmosphere of kindness and mutual trust are equally important. According to
      these goals, criticism has been expressed especially in the area of care and
      kindness, larger obstetrical divisions having more defaults in this regard.
      CONCLUSIONS: Future developments in delivery units of hospitals should take into
      consideration that both safety and optimal care are expected.

PMID- 12476396
TI  - [The probability of spontaneous delivery -- possibility and limits of obstetric
      risk scores].
AB  - QUESTION: For a sound consultation of pregnant women e. g. regarding the choice
      of delivery place, a simple, reliable prepartal risk estimation system would be
      desirable. METHODS: After exclusion of all "hospital required" risk cases, out of
      203,111 records from the Berlin Clinical Perinatal Data 1993 - 1999 176,734
      births remained, for which all risks already discernible before delivery
      (catalogues of the German Maternity Guidelines) were retrospectively valued and
      weighted by means of a logistic regression analysis on their real importance for
      the prediction of a spontaneous birth. On the basis of logarithms of the odds
      ratio for the individual risk factors a point system was developed. RESULTS:
      There is a clearly higher risk for a surgical delivery in primiparae compared
      with multiparae. For multiparae 27, for primiparae 26 statistically significant
      (p < 0.01) risk factors could be identified. After conversion of the odds ratio
      values into the point system of the score, for the group of primiparae the cut
      off value was > 1 point (with a specificity of 0.5 and a sensitivity of 0.5), in
      the multiparae > 3 points (sensitivity 0.7, specificity 0.7). CONCLUSIONS: As for
      primiparae the resulting prognosis of birth mode (spontaneous vs. surgical birth)
      using the described score is false at 46 %, in multiparae at 33 %, the prognosis
      power of the risk score can therefore only be classified as relatively poor. The
      risk assessment system is therefore not suitable e. g. as aid to decision-making
      for or against an extra-clinical delivery place where no obstetrical operations
      are possible.

PMID- 12476398
TI  - [The five stages of labour].
AB  - Current obstetric and midwifery textbooks subdivide childbirth in three distinct
      phases commonly referred to as the first, second and third stage of labour. This
      differs from older textbooks in the 19 th century, which recognized five phases.
      The first one referred to the period between the onset of labour-like activity
      and the start of progressive cervical dilatation, the second to the phase of
      progressive cervical dilatation, and the third to the descent of the fetal head
      to the pelvic floor. The fourth period then reflected the active expulsion of the
      baby, while the fifth referred to what is now commonly known as the third stage
      of labour, i. e. the period between birth and delivery of the placenta. This
      difference in subdividing childbirth is to some extent reflected in the
      subdivision between latent and active first stage labour that emerged in the mid
      20 th century. It is also reflected in subdividing the second stage of labour
      into the periods before and after the start of maternal expulsive efforts. The
      review thus indicates that the history of subdividing childbirth in different
      stages or phases cannot be seen in isolation from the prevailing research and
      clinical interests at the time. It also suggests that the old subdivision in five
      periods is more helpful in the understanding and appropriate documentation of the
      dynamic process of birth than the current delineation of first, second, and third
      stage labour.

PMID- 12476397
TI  - [The effect of biological and psychosocial factors on maternal distress and
      coping in the first months after preterm delivery of an infant weighing less than
      1500 g].
AB  - PROBLEM: Several studies have shown that maternal coping after a premature birth
      has an influence on the psychosocial development of preterm infants. As maternal
      coping is so important for development of premature infants, in this prospective
      study the medical state of the child, previous negative experiences, personal and
      partnership resources and social support outside the family were examined
      regarding their effects on maternal distress and coping after preterm birth.
      SAMPLE, MATERIAL, METHODS: 63 of 68 consecutive mothers with a preterm infant
      weighing less than 1500 g were examined with a semistructured interview and
      questionnaires (F-Sozu, ADS-L, FPI-R) at the time of discharge. RESULTS: 30.2 %
      (n = 19) of the mothers had multiples. The mean gestational age of the infants
      was 28 + 4 weeks (23 + 3 to 34 + 1 weeks), the mean birthweight was 1035 g (380 
      1480 g). Although many mothers had fears concerning a handicap of their child,
      not medical complications per se influenced the mothers perception, but the
      duration of the medical treatment. Previous distressing experiences through
      complications of previous pregnancies and deliveries, as well as handicaps,
      chronic disorders and behavior problems of siblings influenced the perception of
      the child's health negatively, if they have had an effect on the current
      pregnancy. The mother's mood was not associated with the perception of the
      child's health, but with the atmosphere of the intensive care unit, partnership
      resources and social support outside the family. CONCLUSIONS: As both biological
      and psychosocial factors had an effect on the mother's experiences, it is
      necessary to evaluate previous maternal experiences and coping resources and
      offer practical counselling for the mothers to optimize the clinical care in the
      future.

PMID- 12476399
TI  - [Bilateral hypoxic-ischaemic thalamic lesions in newborns].
AB  - Bilateral hypoxic-ischaemic thalamic lesions are a rare type of neonatal
      encephalopathy with characteristic but often misinterpreted clinical features.
      This article describes history, clinical and diagnostic findings in a preterm and
      a term infant with hypoxic-ischaemic thalamic lesions after severe and abrupt
      intrauterine hypoxia. Both neonates presented with absent suckling and swallowing
      whereas other cranial nerves were unaffected. Characteristic findings in both
      newborns were profound muscular hypotonia and weak facial expressions together
      with feeding difficulties and frequent episodes of aspiration pneumonias. The
      term infant died at the age of 14 weeks following presumed aspiration pneumonia,
      the preterm infant, however, has developed severe extrapyramidal cerebral palsy.
      Absent suckling and swallowing with otherwise normal cranial nerve function
      appears to be characteristic of a bilateral hypoxic-ischaemic lesion of the
      thalamus. Animal experiments suggest that these lesions originate from a short
      but total ischaemia as it can be observed in cord prolapse or total placental
      abruption. Specific findings may initially be absent on ultrasound examination.
      Hence, magnetic resonance imaging of the brain should be performed on all
      patients with characteristic clinical symptoms even if the ultrasound scan is
      unremarkable. Evidence of bilateral ischaemic lesions of the thalamus usually
      indicates a poor prognosis.

PMID- 12476401
TI  - The management of emergencies.

PMID- 12476402
TI  - A systematic approach to the management of postoperative nausea and vomiting.
AB  - Postoperative nausea and vomiting (PONV), a common complication after anesthesia
      and surgery, often results in delayed discharge with the patient's unpleasant
      symptoms continuing at home. To effectively prevent and treat PONV, it is
      important to understand the factors implicated in PONV, the mechanisms of PONV,
      the pharmacology of the antiemetic agents, and the nonpharmacologic measures that
      have been shown to be effective. The cause of PONV is likely to be
      multifactorial, with important predictors being female gender, history of PONV,
      and history of motion sickness. The vomiting center can be triggered by
      activation of dopamine, serotonin (type 3), histamine (type 1), and muscarinic
      cholingergic receptors in the chemoreceptor trigger zone and the nucleus tractus
      solitarus, as well as acetylcholine receptors in the vestibular apparatus, vagal
      afferents from the periphery, and the endocrine environment. Antiemetic agents
      such as the serotonin antagonists (eg, ondansetron, dolasetron), droperidol,
      antihistamines (eg, diphenhydramine, dimenhydrinate), and promethazine can
      prevent and treat PONV effectively. Transdermal scopolamine and dexamethasone
      have a role in the prevention of PONV, particularly for certain high-risk
      patients. Nonpharmacologic measures and alternative treatments such as hydration,
      maintaining blood pressure, acupressure techniques, trancutaneous acupoint
      stimulation, and isopropyl alcohol must not be overlooked. Finally, an evidence
      based algorithm for the prevention and treatment of PONV in adults is presented.

PMID- 12476403
TI  - Acute renal failure in the PACU.
AB  - Acute renal failure (ARF) in the PACU can lead to serious morbidity or even
      death. The incidence of acute renal failure appears to be increasing. This review
      article is intended to provide the staff in the PACU with relatively easy means
      to recognize the development of ARF, and provide recommendations for prompt and
      intensive management. Existence of renal dysfunction, complex surgical procedures
      that require cardiopulmonary bypass, and vascular surgery involving the aorta are
      associated with a high incidence of ARF. In spite of the improved overall care of
      the patient in the PACU, the occurrence of ARF is associated with a very high
      likelihood of morbidity and mortality. Prompt recognition of the ARF and
      aggressive management in the PACU may improve the patient's chances of survival.
      Large-scale, prospective, randomized clinical trials in the PACU setting are
      needed to determine the most effective management plan. This is a U.S. government
      work. There are no restrictions on its use.

PMID- 12476400
TI  - Significant linkage on chromosome 10p in families with bulimia nervosa.
AB  - Bulimia nervosa (BN) is strongly familial, and additive genetic effects appear to
      contribute substantially to the observed familiality. In turn, behavioral
      components of BN, such as self-induced vomiting, are reliably measured and
      heritable. To identify regions of the genome harboring genetic variants
      conferring susceptibility to BN, we conducted a linkage analysis of multiplex
      families with eating disorders that were identified through a proband with BN.
      Linkage analysis of the entire sample of 308 families yielded a double peak, with
      the highest nonparametric multipoint maximum LOD score (MLS), of 2.92, on
      chromosome 10. Given the high heritability of self-induced vomiting and the
      reliability with which it can be measured, we performed linkage analysis in a
      subset (n=133) of families in which at least two affected relatives reported a
      symptom pattern that included self-induced vomiting. The highest MLS (3.39)
      observed was on chromosome 10, between markers D10S1430 and D10S1423. These
      results provide evidence of the presence of a susceptibility locus for BN on
      chromosome 10p. Using simulations, we demonstrate that both of these scores, 2.92
      and 3.39, meet the widely accepted criterion for genomewide significance. Another
      region on 14q meets the criterion for genomewide suggestive linkage, with MLSs of
      1.97 (full sample) and 1.75 (subset) at 62 centimorgans from p-ter.

PMID- 12476404
TI  - Acute postoperative delirium: definitions, incidence, recognition, and
      interventions.
AB  - Emergence excitement or delirium is a common postanesthesia complication. Often,
      the emergence excitement resolves quickly, and the patient's continued recovery
      is uneventful. Although the initial period of excitement may be short lived and
      resolve without long-term sequela, some patients may experience acute
      postoperative delirium, a phenomenon that is more difficult to assess and of
      potentially longer duration. Although patients are spending less time in the
      hospital after surgical procedures, concern over the potential development of
      acute postoperative delirium remains. Patients at risk present in ambulatory
      surgery centers and inpatient perianesthesia settings daily. Identification of at
      risk patients is crucial to avoiding the development of delirium in the acute
      postanesthesia care setting. The purpose of this selective review is to define
      acute postoperative delirium and its incidence, discuss assessment and
      recognition, describe interventions, and identify future considerations related
      to this phenomenon.

PMID- 12476405
TI  - Allergic reactions to drugs: implications for perioperative care.
AB  - Clinically, one must be able to differentiate between an allergic reaction and an
      adverse reaction. Clinical manifestations of allergic reactions range from
      urticaria and rash to bronchoconstriction, laryngeal edema, hematologic
      disorders, and other serious reactions. Many drugs administered in the
      perioperative setting can cause allergic reactions. Antibiotics such as
      penicillins, beta-lactam antibiotics, and sulfonamides are the most common class
      of drugs that produce allergic reactions. A detailed allergy history is important
      when deciding if a patient can receive a drug that may cross-react (eg, a
      cephalosporin in a patient with a penicillin allergy). Vancomycin can cause a
      reaction that ranges from erythema and pruritus to clinically significant
      hypotension. Proper dilution and rate of administration are essential in
      minimizing the histamine from vancomycin that is thought to produce this
      reaction. "Sulfa allergy" describes an allergy to sulfonamide antibiotics; a
      patient with a "sulfa allergy" is not allergic to drugs containing sulfur,
      sulfites, or sulfates. Although true allergic reactions to opioids are rare,
      naturally occurring compounds like morphine and codeine can cause allergic
      reactions. After stopping the offending drug, mild allergic reactions can be
      managed with diphenhydramine, with or without a steroid. Significant allergic
      reactions require more aggressive management with oxygen, intravenous fluids,
      epinephrine, and histamine blockers.

PMID- 12476406
TI  - Hemolytic transfusion reaction: safeguards for practice.
AB  - Most hemolytic transfusion reactions result from administration of ABO
      incompatible blood. Even a small amount of incompatible blood may initiate a
      reaction and cause devastating consequences leading to death. Careful monitoring
      of the anesthetized patient is important in recognizing symptoms of a transfusion
      reaction so that the reaction may be promptly detected and treatment quickly
      initiated. Many factors contribute to blood transfusion errors resulting from the
      misidentification of either the patient or the blood product. Nursing has
      opportunities to establish policies and procedures, design nursing practices, and
      educate staff to help avoid blood transfusion errors.

PMID- 12476407
TI  - Tension pneumothorax: a pulmonary complication secondary to regional anesthesia
      from brachial plexus interscalene nerve block.
AB  - Interscalene brachial plexus anesthesia is often used for surgeries involving the
      shoulder and upper arm. This method of regional anesthesia decreases pain,
      nausea, and vomiting associated with general anesthesia. One infrequent
      complication of interscalene brachial plexus block is tension pneumothorax.
      Recognition of early signs and symptoms of tension pneumothorax and expeditious
      treatment for rapid decompression before physiologic decompensation is mandatory.
      This article discusses the interscalene brachial plexus block procedure leading
      to the pathogenesis, clinical presentation, diagnosis, and treatment of tension
      pneumothorax.

PMID- 12476409
TI  - Sentinel event: wrong-site surgery.

PMID- 12476408
TI  - Abdominal compartment syndrome: a case review.
AB  - Compartment syndrome is classically considered a complication of a
      musculoskeletal injury. Recent research has confirmed the abdomen as a potential
      compartment with the capability to cause life-threatening local and systemic
      manifestations. Abdominal compartment syndrome (ACS) is precipitated by an acute
      increase in abdominal contents volume with resulting intraabdominal hypertension.
      Presenting signs of ACS include a firm tense abdomen, increased peak inspiratory
      pressures, and oliguria, all of which improve after abdominal decompression.
      Patients at risk for ACS include trauma (blunt or open), retroperitoneal
      hemorrhage, massive fluid resuscitation, pancreatitis, pneumoperitoneum, and
      neoplasm. Surgical decompression is the treatment of choice. The perianesthesia
      nurse plays a critical role in the team managing a patient at risk for abdominal
      compartment syndrome through intraabdominal pressure monitoring, wound care, and
      end organ perfusion support.

PMID- 12476410
TI  - Critical incident stress debriefing: application for perianesthesia nurses.

PMID- 12476411
TI  - Transderm scopolamine: a painless, noninvasive option for control of
      postoperative nausea and vomiting.

PMID- 12476412
TI  - Lessons learned.

PMID- 12476413
TI  - [Establishment and comparative genomic hybridization analysis of human esophageal
      carcinomas cell line EC9706].
AB  - OBJECTIVE: To establish a long-standing cell line of esophageal squamous cell
      carcinoma (ESCC) in pursuit of a model for in vitro study of carcinogenesis.
      METHODS: Small tissue blocks taken from resected specimens of esophageal cancer
      were cultured, and cell line EC9706 was established. The biologic properties of
      EC9706 were characterized. Comparative genomic hybridization(CGH) was performed
      on the cell line. RESULTS: The growth curve of EC9706 was detected. The cell
      generation time was 26 hours. The plate colony forming efficiency is 91.9%, with
      the capacity of forming clones in soft agar. EC9706 cells show high
      tumorigenecity as indicated by the rapid regeneration of moderate-poor
      differentiated squamous cell carcinomas after injection into nude mice. CGH
      analysis indicated copy number gains of 1p1, 1q2-4, 2p1, 2q1, 5p, 7p14, 7q21,
      11q1, 15q2, 20q and losses of 2p2, 2q2, 3p, 4, 9p, 14, 18, Xq. High-level gain of
      5p was observed. CONCLUSION: Established cell line EC9706 can serve as a useful
      tool for studying the carcinogenesis of ESCC.

PMID- 12476414
TI  - [A novel member of SH(2) signaling protein family: cloning and characterization
      of SH(2)A gene].
AB  - OBJECTIVE: Cloning and characterization of a novel gene by exon trapping and exon
      linking at chromosome 8p22. METHODS: A novel gene was cloned using exon trapping
      and exon linking, and its expression was determined by reverse transcription
      polymerase chain reaction (RT-PCR) and Northern blot. RESULTS: A sequence
      containing 3 exons was found. The sequence is homologous with the putative gene
      AK024799 which consists of 2880 bp cDNA with 1362 bp open reading frame and codes
      454 amino acids with an SH(2) domain. The gene was named SH(2)A at chromosome
      8p22. SH(2)A gene is ubiquitously expressed in various tissues with three
      transcripts. The aberrant expression of SH(2)A gene in some cancers was detected.
      CONCLUSION: SH(2)A is a novel docking protein of SH(2) signaling protein family,
      which may play an important role in cellular signal transduction. It relates to
      the pathogenesis of tumor.

PMID- 12476415
TI  - [Screening for point mutations in rhodopsin gene among one hundred Chinese
      patients with retinitis pigmentosa].
AB  - OBJECTIVE: To test the frequency and pattern of rhodopsin (RHO) mutations in
      Chinese retinitis pigmentosa (RP) patients and to evaluate their effects in the
      pathogenesis of RP. METHODS: Genomic DNA was extracted from peripheral blood
      samples of 100 Hong Kong Chinese RP patients. Sequence variants of the entire
      coding exons of the RHO gene were tested using PCR, conformation sensitive gel
      electrophoresis and DNA sequencing. RESULTS: Totally six nucleotide changes were
      identified, among which three were silent mutations, two missense mutations and
      one deletion mutation. P347L was found in one RP proband and her three children
      who also had RP. P327(1 bp del) was novel and detected in a late-onset RP patient
      of 53 years. Her 26-year-old daughter, also carrying the identified mutation, had
      no RP phenotypes except for the mottled retinal pigment epithelium (RPE) revealed
      by fundal examination. Neither of the two mutations was detected in normal
      controls. CONCLUSION: Two patients had disease-causing mutations in the RHO gene,
      thus RHO mutations cause about 2.0% (95% confidence interval: 0.2%-7.0%) of all
      RP among Chinese in Hong Kong. A highly conserved C-terminal sequence QVS(A)PA
      was altered due to P347L and thereby resulting in an aberrant subcellular
      localization of rhodopsin. Loss of all six phosphorylatable residues at the C
      terminus and the highly conserved C-terminal sequence QVS(A)PA may occur because
      of P327(1 bp del). To elucidate the predominant biochemical defects in such
      mutant, transgenic mice and transfected culture cells carrying P327(1 bp del)
      would be of greatest value.

PMID- 12476416
TI  - [Genomic structure of low density lipoprotein receptor related protein 5 gene].
AB  - OBJECTIVE: To determine the genomic structure of low density lipoprotein receptor
      related protein 5 (LRP5) gene. METHODS: cDNA sequence encoding LRP5 was used to
      screen genomic clones containing LRP5 gene by computer hybridization approach. By
      comparing the cDNA sequence of LRP5 with the genomic sequences, the genomic
      structure of LRP5 was determined, and then it was conformed by amplifying and
      sequencing the sequences of exons and splicing junction. RESULTS: The genomic
      sequence of LRP5 gene was 131.6 kb in length, containing 23 exons and 22 introns.
      Three single nucleotide polymorphisms were detected within the coding sequences
      of LRP5 gene, namely A459G in exon 2, C2220T in exon 10 and G4416C in exon 21.
      Four polymorphic markers, D11S1917, D11S4087, D11S1337 and D11S4178, located in
      the 5' flank sequence, introns 1, 4, and 13 of the LRP5 gene, respectively.
      CONCLUSION: The characterization of genomic structure of LRP5 gene allows the
      investigators to detect disease-causing mutation within the gene and further
      study the function of LRP5 gene.

PMID- 12476417
TI  - [The G894T mutation of the endothelial nitric oxide synthase gene is associated
      with coronary atherosclerotic heart disease in Chinese].
AB  - OBJECTIVE: To investigate the association of the endothelial nitric oxide
      synthase (eNOS) gene polymorphism with coronary atherosclerotic heart disease
      (CHD) in Chinese Han nationality. METHODS: For 106 patients with CHD and 108
      unrelated health individuals, the G894T mutation at exon 7 of the endothelial
      nitric oxide synthase gene was studied by using polymerase chain reaction
      restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: (1) Among
      the normal subjects of Chinese Han nationality, the frequencies of the eNOS/GG,
      GT and TT genotypes were 0.9095, 0.0883 and 0.0021, respectively. The G and T
      allele frequencies were 0.9537 and 0.0463. (2) The authors assumed the effects of
      the T allele to be dominant (GT and TT combined vs GG). The GT+TT genotype
      frequencies in CHD and myocardial infarction (MI) subgroup were 0.2219 and
      0.2387, respectively. The frequencies of eNOS/GT+TT genotypes in CHD patients, as
      well as MI subgroup were significantly higher than that of the normal subjects
      (P<0.05), respectively. The frequencies of T allele in CHD, MI subgroup were
      significantly higher than that in the normal subjects (P<0.01), respectively. (3)
      This mutation was not related to the number of affected vessels in the 58
      patients who had angiographically documented artery narrowing (P>0.05).
      CONCLUSION: The G894T mutation of the endothelial nitric oxide synthase gene may
      be a marker for genetical predisposition of CHD in Chinese Han population.

PMID- 12476418
TI  - [Cloning of human brain-derived neurotrophin-6 gene and its expression in
      procaryotic cell].
AB  - OBJECTIVE: To clone human brain-derived neurotrophin-6(NT-6) gene and to observe
      its expression in the procaryotic cell. METHODS: Total RNA was extracted from
      aborted antenatal cerebral cortex, and cDNA fragment of NT-6 was amplified
      through reverse transcript-polymerase chain reaction. After being incised and
      recovered, the NT-6 gene was cloned into pBK-CMV plasmid to construct a NT-6 gene
      expression vector. Expression of NT-6 gene in Escherichia coli was studied after
      being induced by isopropyl beta-D-thiogalactoside(IPTG). RESULTS: The NT-6 gene
      expression vector was constructed and Escherichia coli with recombinant vector
      expressed specific protein after induction by IPTG. CONCLUSION: The cloning of
      human brain-derived NT-6 gene provides a basis for further studying the
      structure, function and clinical application of NT-6.

PMID- 12476419
TI  - [Identification of AP1 cis-element and transcriptional effect on cytokeratin 13
      gene expression].
AB  - OBJECTIVE: To identify the type of CTGAATCA from -nt.199 to -nt.192 of the
      cytokeratin 13(CK13) gene 5' flanking region and determine its transcriptional
      effect on CK13 gene expression. METHODS: The CAT systems were used to assess the
      effects of different motifs of CK13 gene 5' flanking region on transcription. The
      clones of pCAT-enhancer with the total length, -nt.207 to +nt.63 and the same
      length of -nt.207 to +nt.63, but the T, G of -nt.198, -nt.197 being changed to A,
      T of the CK13 gene 5' flanking region, were constructed and transferred to HeLa
      cells with the help of lipofectin. Then work was done to detect the instant CAT
      expression of different clones and evaluate the effects of CTGAATCA of the 5'
      flanking region on CK13 gene expression. The type of the cis-element of CTGAATCA
      was identified with electrophoretic mobility shift assay (EMSA) and competition
      EMSA. RESULTS: CTGAATCA in the CK13 gene 5' flanking region is an AP1 cis-element
      by EMSA and competition-EMSA, it promotes CK13 gene expression. CONCLUSION:
      CTGAATCA from -nt.199 to nt.192 of the CK13 gene 5' flanking region is an AP1
      reaction element, not a cAMP reaction element. It promotes transcriptional
      activity of CK13 gene 5' flanking region.

PMID- 12476420
TI  - [Association of polymorphism in neurogenic differentiation factor 1 gene with
      type 2 diabetes].
AB  - OBJECTIVE: To evaluate the role of polymorphism in the neurogenic differentiation
      factor 1(Neuro D) gene in Chinese patients with type 2 diabetes mellitus.
      METHODS: The genotypes of codon 45 variant (GCC-->ACC) in the Neuro D gene were
      determined by mismatch PCR-restriction fragment length polymorphism assay in 448
      Chinese, including 124 subjects with normal glucose tolerance and 324 patients
      with type 2 diabetes mellitus. The diabetic patients were divided into two groups
      cutting off with the age of 40 at onset. RESULTS: No homozygote of the Ala45Thr
      variant was found in these subjects. The frequencies of AT heterozygous type were
      significantly higher in early-onset type 2 diabetic group than those in the
      control group and in the late-onset type 2 diabetic group   (chi(2)=7.85,
      P=0.005; chi(2)=8.81, P=0.003). The frequencies of Thr45 allele in the early
      onset type 2 diabetic group were significantly different from those of the
      control group (13.4% vs 5.2%, chi(2)=7.15, P=0.008) and the late-onset type 2
      diabetic group (13.4% vs 5.8%, chi(2)=8.13, P=0.004). The presence of Thr45
      allele was shown to have an association with early-onset type 2 diabetes
      (OR=2.52, 95% CI: 1.42-4.49). Furthermore, the subjects carrying the variant
      appeared to have lower serum concentration of C-peptide in diabetic group.
      However, the frequencies of polymorphism genotypes of Neuro D gene showed no
      difference between the late-onset type 2 diabetic group and the control group.
      CONCLUSION: The genetic polymorphism in the Neuro D is associated with the
      development of early-onset type 2 diabetes. The presence of Thr45 allele may
      represent a risk factor for early-onset type 2 diabetes among Chinese.

PMID- 12476421
TI  - [The relationship between haplotypes of angiotensinogen gene and essential
      hypertension].
AB  - OBJECTIVE: To investigate the relationship between the polymorphism of
      angiotensinogen gene (AGT) and the risk for hypertension in a Chinese population.
      METHODS: Three polymorphisms of AGT gene were analyzed in 335 patients with
      documented essential hypertension and 196 control subjects by using PCR
      restriction fragment length polymorphism. Expectation maximization(EM) algorithm
      was then used for pairwise linkage disequilibrium test and haplotype analysis of
      AGT polymorphisms. RESULTS: Linkage disequilibrium between M235T and A-20C,
      between M235T and A-6G, between A-20C and A-6G was observed (P<10(-4)). The case
      control analysis revealed that the frequency of T235 is significantly higher in
      essential hypertension patients than in control subjects. But all haplotype
      frequencies showed no significant difference between the patient and control
      groups. CONCLUSION: No association was noted between the haplotypes of AGT gene
      and hypertension in tested people, but T235 allele might play an important role
      in increased risk for essential hypertension.

PMID- 12476422
TI  - [Linkage analysis of susceptibility genes for familial schizophrenia on
      chromosome 1 in Chinese population].
AB  - OBJECTIVE: To explore the molecular genetic relationship between chromosome 1 and
      susceptibility genes for familial schizophrenia in Chinese population. METHODS: A
      genome scanning was conducted in 32 multiplex pedigrees from Chinese population
      by using 29 microsatellite markers on chromosome 1. RESULTS: Multipoint
      parametric analysis detected a maximum heterogenicity Lod of 1.70 at 262.52 cM
      under a recessive model; multipoint non-parametric analysis detected a maximum
      non-parameter linkage (NPL) of 1.71 (P=0.046) at 262.52 cM, then 1.37 (P=0.086)
      at 149.70 cM, corresponding to marker D1S206 and D1S425 respectively. CONCLUSION:
      These results give further supports to the presence of susceptibility genes on
      chromosome 1q for familial schizophrenia.

PMID- 12476423
TI  - [Up-expression of IL-6 and down-expression of TNFalpha may be involved in the
      regulation of apoptosis induced by antisense bcl-2 oligodeoxynucleotides].
AB  - OBJECTIVE: To investigate the regulation mechanism of apoptosis induced by the
      antisense bcl-2 treatment. METHODS: DNA content analysis and terminal
      deoxynucleotidyl transferase mediated nick end labeling (TUNEL) were adopted to
      detect apoptosis. Semi-quantitative reverse transcription-PCR was performed to
      detect the mRNA expression of bcl-2 c-myc survivin bax s100A(2) TNFalpha
      TGFbeta(1) and IL-6 in the small-cell lung cancer cell line NCI-H446 treated with
      antisense bcl-2 oligodeoxynucliotide. RESULTS: bcl-2 AS-PS-ODN treatment could
      induce apoptosis, accompanied with 72.71% up-regulation of IL-6 and 65.90% down
      regulation of TNFalpha, whereas little or no effect was seen on c-myc survivin
      bax s100A(2) and TGFbeta(1). CONCLUSION: IL-6 and TNFalpha may be involved in the
      regulation of apoptosis induced by antisense bcl-2 treatment.

PMID- 12476424
TI  - [Association study of heroin-dependence and -287 A/G polymorphism of catechol-O
      methyltransferase gene].
AB  - OBJECTIVE: To detect the relationship between heroin-dependence and -287 A/G
      polymorphism of catechol-O-methyltransferase(COMT) gene. METHODS: Genotype and
      allele frequencies of -287 A/G polymorphism of COMT gene were examined in 268
      heroin-dependent subjects and 177 normal controls. RESULTS: Weak but significant
      difference in genotype of -287 A/G polymorphism of COMT gene was observed between
      heroin-dependent subjects and controls (chi(2)=7.41, P=0.025), and genotype AA
      was higher in the former. The frequency of allele A of -287 A/G polymorphism of
      COMT gene was also significantly higher in heroin-dependent subjects than in the
      controls (chi(2)=5.69, P=0.017). CONCLUSION: The results suggested that liability
      to heroin-dependence was associated with -287 A/G polymorphism of COMT gene.

PMID- 12476425
TI  - [Genetic polymorphism of fifteen short tandem repeat loci in Chinese Drungs].
AB  - OBJECTIVE: To study the short tandem repeat (STR) polymorphism in Chinese Drungs
      (Tulungs). METHODS: The genetic distributions of fifteen STR loci were
      investigated with the use of coamplification, genescan and genotype from 67
      Drungs. RESULTS: There were 144 STR alleles in Drung nationality, with their
      frequencies ranging from 0.0077 to 0.7846, heterozygosity(H) 0.3723-0.8639,
      discrimination power(DP) 0.5567-0.9548, probability of paternity exclusion(EPP)
      0.2738-0.8358, polymorphism information content (PIC) 0.3461-0.8456  the
      accumulative DP 0.99999998 and EPP 0.99999894. CONCLUSION: The results of this
      study on the STR polymorphism in Chinese Drungs could be used as a basis for the
      genetic structure of Chinese ethnic groups and also be of significant application
      in anthropology and forensic science.

PMID- 12476426
TI  - [Progress in molecular genetics of epilepsy].
AB  - Epilepsy is a group of disorders characterized by recurrent seizures. The
      etiologies of idiopathic epilepsy commonly have a genetic basis. Gene mutations
      causing several of the inherited epilepsies have been mapped. In this review, the
      authors summarize the available information on the genetic basis of human
      epilepsies and epilepsy syndromes, emphasizing how genetic defects may correlate
      with the pathophysiological mechanisms of brain hyperexcitability and gene
      defects can lead to epilepsy by altering multiple and diverse aspects of neuronal
      function.

PMID- 12476427
TI  - [Recent advance in genetics of systemic lupus erythematosus].
AB  - Systemic lupus erythematosus (SLE) is the prototype systemic autoimmune disease
      and genetic component seems to play an important role in disease susceptibility.
      Studies from murine models have shown that about 30 loci are related to the
      disease. Meanwhile, 50 loci have been found in linkage to SLE in human genomic
      studies, especially 1q23-24, 1q41-42, 2q37, 4p16-15.2, 6p21-11 and 16q13. A lot
      of candidate genes contribute to the disease susceptibility and different
      combinations of genes at multiple loci in individual patient may result in the
      development of diverse clinical features.

PMID- 12476428
TI  - Which cancer patient completes a psychosocial intervention program?
AB  - The present study explored the similarities and differences in patterns of
      psychological distress, coping strategies and social support of 41 cancer
      patients who dropped out of a psychosocial therapy program and 20 patients who
      completed the program as agreed. The findings indicated that only depression, out
      of nine brief symptom inventory subscales, predicted which patients would
      complete the program, i.e. patients with a high level of depression tended to
      complete the psychosocial intervention program.

PMID- 12476429
TI  - Smoking behavior of 226 patients with diagnosis of stage IIIA/IIIB non-small cell
      lung cancer.
AB  - There is limited research of smoking cessation following diagnosis of lung
      cancer. This prospective study assessed cigarette smoking behavior among 226
      patients (142 males, 84 females) prior to, at the time of, and after the
      diagnosis of unresectable stage IIIA/IIIB non-small cell lung cancer and entry
      into a phase III trial examining combined thoracic radiation therapy and
      chemotherapy. Their mean +/-S.D. age was 62.7+/-9.4 years and 95.6% were
      Caucasian. Of 215 patients with a history of cigarette smoking, 69% (148/215)
      stopped smoking prior to entry in the trial, 9% (20/215) stopped smoking at some
      point during the course of the trial, 11% (24/215) continued smoking throughout
      the trial, 7% (16/215) were smoking at baseline but did not report subsequent
      smoking status, and smoking status at study entry was missing for the remaining
      patients. The majority of lung cancer patients were able to stop smoking. A
      notable subset of patients continued smoking despite diagnosis of lung cancer,
      enrollment in a clinical trial, treatment-related toxicity, and encouragement
      from clinicians to stop smoking. Smoking cessation interventions are needed for
      lung cancer patients who continue to smoke.

PMID- 12476430
TI  - Cancer survivorship and psychological distress in later life.
AB  - Recent research in psychosocial oncology has pointed to the traumatic nature of
      the stress experienced by cancer survivors. Most of this research has focused on
      children, young adults survivors and their families. This investigation proposes
      a conceptual model for understanding general psychological distress (anxiety,
      hostility and depression) and symptoms of posttraumatic stress (hyper-arousal,
      avoidance and intrusiveness) that may be associated with cancer survivorship
      among older adults. Findings from a survey of 180 older adult, long-term cancer
      survivors are used to illustrate the key features of this model. Results of
      multivariate analysis show that most older adult long-term cancer survivors do
      not demonstrate clinical levels of posttraumatic stress disorder (PTSD), although
      over 25% evidence clinical levels of depression. However, many survivors display
      important symptoms of psychological distress that are related to the continuing
      effects of cancer and its treatment. Current cancer-related symptoms are the
      strongest predictors of depression (beta=0.27, p=0.046) and the PTSD sub
      dimension of hyper-arousal (beta=0.377, p=0.004). These effects persist even when
      the effects of other stressors and non-cancer illness symptoms are statistically
      controlled. Additionally, it appears in this sample that symptoms of PTSD are
      significantly correlated with traditional measures of psychological distress.

PMID- 12476431
TI  - Coping and distress among women under treatment for early stage breast cancer:
      comparing African Americans, Hispanics and non-Hispanic Whites.
AB  - This study examined coping and distress in African American (n=8), Hispanic
      (n=53), and non-Hispanic White (n=70) women with early stage breast cancer. The
      participants were studied prospectively across a year beginning at the time of
      surgery. African American women reported the lowest levels of distress
      (particularly before surgery) and depression symptoms. Hispanic women reported
      the highest levels of self-distraction as a coping response, non-Hispanic Whites
      reported the highest use of humor. Hispanics reported the highest levels of
      venting, African Americans reported the lowest levels. African American and
      Hispanic women reported more religious coping than non-Hispanic Whites. The data
      also provided evidence of a maladaptive spiral of distress and avoidant coping
      over time. Although some ethnic differences were identified, findings also point
      to a great many similarities across groups.

PMID- 12476432
TI  - Treatment regimen, sexual attractiveness concerns and psychological adjustment
      among African American breast cancer patients.
AB  - BACKGROUND: Among a sample of African American women recently diagnosed with
      breast cancer, we assessed the consequences of different treatment regimens on
      sexual attractiveness concerns, and the impact of sexual attractiveness concerns
      on current and subsequent psychological adjustment. PATIENTS AND METHODS: The
      sample included 91 African American women with breast cancer; 90% had Stage I or
      II disease, 48% had chemotherapy, 47% had a lumpectomy, and 53% received a
      mastectomy. Feelings of sexual attractiveness and psychological adjustment were
      assessed an average of 3 months following surgery and again 4 months post
      baseline. RESULTS: Regression analyses revealed that chemotherapy was associated
      with greater concerns about sexual attractiveness among lumpectomy patients
      (p<0.05), but not among mastectomy patients (p>0.20). The interaction also
      suggested that chemotherapy equalized the impact of types of surgery, as there
      was no difference on sexual attractiveness between surgery groups among women who
      had received chemotherapy (p>0.20). However, among women who had not received
      chemotherapy, mastectomy patients reported greater sexual attractiveness concerns
      (p<0.01). Finally, regression analyses revealed that feelings of sexual
      attractiveness were an important component of psychological well-being, both
      cross-sectionally (p<0.001) and longitudinally (p<0.001). CONCLUSION: Assessment
      of the combined impact of different treatment regimens on feelings of sexual
      attractiveness is particularly important given the current consensus that all
      breast cancer patients should receive chemotherapy, regardless of nodal status.
      Further, concerns about sexual attractiveness should be considered for inclusion
      as one component of psychosocial support programs for African American women with
      breast cancer, as our results suggested that they played a significant role in
      psychological adjustment.

PMID- 12476434
TI  - Breast cancer survivors give voice: a qualitative analysis of spiritual factors
      in long-term adjustment.
AB  - As part of a cross-sectional, quantitative study on adjustment factors in long
      term breast cancer survival, 52 women were asked to write in their own words how
      religious and spiritual factors played a part in their understanding of and
      coping with this illness. A subsample of 39 women responded to this question. The
      qualitative method of content analysis was used to define meaning units,
      descriptive categories and themes from the data. Interpretation of themes in the
      data focused on the role or function of spiritual/religious factors in long-term
      adjustment to breast cancer. The majority of women discussed the positive role of
      various spiritual resources in their response to the experience of cancer,
      including relationship with God, religious coping activities (e.g. prayer),
      meaning and social support. A cognitive model of adjustment was proposed which
      shows how spiritual resources can help breast cancer survivors make meaning of
      and experience a sense of life affirmation and personal growth in relation to the
      cancer.

PMID- 12476433
TI  - Depression in men receiving androgen deprivation therapy for prostate cancer: a
      pilot study.
AB  - PURPOSE: Prostate cancer is the most common malignancy in men and one of the
      leading causes of cancer death in men internationally. Treatment for prostate
      cancer frequently includes androgen deprivation therapy (ADT). Reports of
      depressive symptoms arising during ADT are emerging. This study examines the
      prevalence rates and risk factors associated with major depression in this
      population. METHOD: 45 men with prostate cancer receiving ADT at the MGH Cancer
      Center were surveyed for depression with the SCID for Axis I disorders for DSM-IV
      and the Beck Depression Inventory. RESULTS: Major depressive disorder was
      prevalent in 12.8% of the men with prostate cancer receiving ADT, eight times the
      national rate of depression in men, 32 times the rate in men over 65 years old.
      Major depression was not associated with worsening disease, medical response to
      ADT, receiving chemotherapy, or the type of ADT. Past history of depression was
      associated with current depression in this population (p<0.000). No first onset
      cases of depression occurred on ADT in this sample. CONCLUSION: This data
      suggests a significant rate of major depression in men with prostate cancer
      receiving ADT and that men with past histories of depression may be at particular
      risk for recurrence of their depression while undergoing this treatment.

PMID- 12476435
TI  - Congress report of the seventh international meeting on psychosocial aspects of
      genetic testing for hereditary breast and/or ovarian cancer (HBOC) and hereditary
      non-polyposis colorectal cancer (HNPCC).

PMID- 12476436
TI  - What's in a title? Do Sprangers et al. really explain quality of life with crisis
      theory?

PMID- 12476440
TI  - Naturally and externally pulsed electrospray.
AB  - The current studies on pulsation phenomena in electrospray ionization, and pulsed
      electrospray ionization (ESI) under external electrical control are reviewed. A
      number of investigations have shown that two types of pulsation processes exist:
      low-frequency fluctuation and high-frequency droplet-formation. The low-frequency
      pulsation is induced by an imbalance between the flow rate of the input sample to
      the Taylor cone and the feed rate of the output solution to the liquid filament.
      The high-frequency pulsation mainly results from the initial droplet formation
      process, and is modulated by the low-frequency pulsation. The fundamental and
      experimental sections of these two pulsations are discussed. Experimental results
      also show that low and high pulsations can both be controlled electrically to
      create a pulsed ESI so that high sensitivity and an enhanced S/N ratio can be
      achieved. However, the co-ordination of the synchronization between a natural
      pulsation and a pulsed ESI, as well as its application to mass spectrometer (MS)
      analysis, demands further research.

PMID- 12476441
TI  - Analysis of protein-nucleic acid interactions by photochemical cross-linking and
      mass spectrometry.
AB  - Photochemical cross-linking is a commonly used method for studying the molecular
      details of protein-nucleic acid interactions. Photochemical cross-linking aids in
      defining nucleic acid binding sites of proteins via subsequent identification of
      cross-linked protein domains and amino acid residues. Mass spectrometry (MS) has
      emerged as a sensitive and efficient analytical technique for determination of
      such cross-linking sites in proteins. The present review of the field describes a
      number of MS-based approaches for the characterization of cross-linked protein
      nucleic acid complexes and for sequencing of peptide-nucleic acid
      heteroconjugates. The combination of photochemical cross-linking and MS provides
      a fast screening method to gain insights into the overall structure and formation
      of protein-oligonucleotide complexes. Because the analytical methods are
      continuously refined and protein structural data are rapidly accumulating in
      databases, we envision that many protein-nucleic acid assemblies will be
      initially characterized by combinations of cross-linking methods, MS, and
      computational molecular modeling.

PMID- 12476442
TI  - Protein disulfide bond determination by mass spectrometry.
AB  - The determination of disulfide bonds is an important aspect of gaining a
      comprehensive understanding of the chemical structure of a protein. The basic
      strategy for obtaining this information involves the identification of disulfide
      linked peptides in digests of proteins and the characterization of their half
      cystinyl peptide constituents. Tools for disulfide bond analysis have improved
      dramatically in the past two decades, especially in terms of speed and
      sensitivity. This improvement is largely due to the development of matrix
      assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI),
      and complementary analyzers with high resolution and accuracy. The process of
      pairing half-cystinyl peptides is now generally achieved by comparing masses of
      non-reduced and reduced aliquots of a digest of a protein that was proteolyzed
      with intact disulfide bonds. Pepsin has favorable properties for generating
      disulfide-linked peptides, including its acidic pH optimum, at which disulfide
      bond rearrangement is precluded and protein conformations are likely to be
      unfolded and accessible to cleavage, and broad substrate specificity. These
      properties potentiate cleavage between all half-cystine residues of the substrate
      protein. However, pepsin produces complex digests that contain overlapping
      peptides due to ragged cleavage. This complexity can produce very complex spectra
      and/or hamper the ionization of some constituent peptides. It may also be more
      difficult to compute which half-cystinyl sequences of the protein of interest are
      disulfide-linked in non-reduced peptic digests. This ambiguity is offset to some
      extent by sequence tags that may arise from ragged cleavages and aid sequence
      assignments. Problems associated with pepsin cleavage can be minimized by
      digestion in solvents that contain 50% H(2) (18)O. Resultant disulfide-linked
      peptides have distinct isotope profiles (combinations of isotope ratios and
      average mass increases) compared to the same peptides with only (16)O in their
      terminal carboxylates. Thus, it is possible to identify disulfide-linked peptides
      in digests and chromatographic fractions, using these mass-specific markers, and
      to rationalize mass changes upon reduction in terms of half-cystinyl sequences of
      the protein of interest. Some peptides may require additional cleavages due to
      their multiple disulfide bond contents and/or tandem mass spectrometry (MS/MS) to
      determine linkages. Interpretation of the MS/MS spectra of peptides with multiple
      disulfides in supplementary digests is also facilitated by the presence of (18)O
      in their terminal carboxylates.

PMID- 12476444
TI  - TGF beta/Smad signaling system and its pathologic correlates.

PMID- 12476445
TI  - Communication with close and distant relatives in the context of genetic testing
      for hereditary breast and ovarian cancer in cancer patients.
AB  - The psychological aspects of genetic testing for hereditary breast and ovarian
      cancer (HBOC) in cancer patients (diagnostic genetic testing) have so far
      received less attention than predictive genetic testing in unaffected persons.
      Our study is aimed at gaining insight into the psychological aspects of
      diagnostic genetic testing and at formulating practical recommendations for
      counseling. Cancer patients often play a key role in the communication of
      information to relatives because they were the first individuals to be tested in
      the family. The present article focuses on the communication to close and distant
      relatives about the hereditary cancer, the genetic test and its result.
      Participants previously diagnosed with breast and/or ovarian cancer, with a
      family history of these cancers and who requested DNA-testing, were eligible for
      the study. Of the 83 eligible patients who could be contacted, 63 participated
      (response rate = 76%). Twenty-six participants were members of a family where a
      BRCA1 or BRCA2 mutation was detected. The DNA-analysis in the family of 37
      participants had not revealed any mutation. Data were collected by semi
      structured interviews and psychological tests and questionnaires. The
      dissemination of information was largely focused on first-degree relatives.
      Communication to distant relatives about the genetic test and its result was
      problematic. Other than the genetic test result and age as "objective" predictors
      of informing distant relatives, little and/or superficial contact seemed to be
      the major subjective barrier to informing distant relatives. Furthermore, the
      knowledge about HBOC of these messengers reveals several shortcomings.
      Communication within the family should receive special attention during
      counseling.

PMID- 12476446
TI  - Congenital myopathy, recurrent secretory diarrhea, bullous eruption of skin,
      microcephaly, and deafness: a new genetic syndrome?
AB  - We describe three siblings with congenital myopathy, bullous eruption of the
      skin, secretory diarrhea, apparent zinc deficiency, failure to thrive, deafness,
      and microcephaly. The parents are not consanguineous and there are no other
      affected relatives. This new syndrome, which follows an apparent autosomal
      recessive pattern, appears to be distinct from known syndromes of secretory
      diarrhea, myopathy, deafness, microcephaly, and zinc deficiency.

PMID- 12476447
TI  - First patient with trisomy 21 accompanied by an additional der(4)(:p11 --> q11:)
      plus partial uniparental disomy 4p15-16.
AB  - We report on a rare additional numerical chromosomal aberration in a child with
      Down syndrome due to free trisomy 21. The karyotype showed 48,XY,+21,+mar after
      GTG banding, with the marker present in 80% of cells. The supernumerary marker
      chromosome (SMC) was as small as approximately one-third of 18p, and with the
      recently developed centromere-specific multi-color fluorescence in situ
      hybridization (cenM-FISH) technique, it was shown that the SMC was a derivative
      chromosome 4. The SMC was not specifically stained by arm-specific probes for
      chromosome 4; thus, it has been described as der(4)(:p11 --> q11:).
      Microsatellite analysis resulted in a partial maternal uniparental isodisomy
      (UPD) for chromosome 4p15-16 and a maternal origin for two chromosomes 21. Until
      now only two similar cases have been described in the literature, but without
      clarifying the origin of the SMC and without looking for an additional UPD. This
      is the only reported case of a UPD 4p in a liveborn child.

PMID- 12476448
TI  - Is immunosuppression therapy in renal allograft recipients teratogenic? A single
      center experience.
AB  - The aim of the study was to determine whether immunosuppressive agents used in
      renal allograft recipients are teratogenic or otherwise associated with pregnancy
      outcome. The study population consisted of 38 renal allograft recipients treated
      with combinations of prednisone, azathioprine, cyclosporin A, and tacrolimus
      attending our Hypertension in Pregnancy Clinic. The 48 live offspring of 73
      pregnancies in this group were evaluated for major congenital malformations and
      mild errors of morphogenesis. Findings were compared with those in 48 offspring
      of 41 women with primary renal disease not treated with immunosuppressive drugs.
      Pregnancy outcome parameters were also compared between the study and control
      groups in the perinatal period and on a long-term basis (2-7 years after birth).
      Two major anomalies (4.2%), subcoronal hypospadias and rudimentary thumb, and 10
      mild errors of morphogenesis (20.8%) were detected in the study group. These
      rates did not differ significantly from those in the control group (4.2% and
      16.6%, respectively). Pregnancy outcome was worse in the renal transplant
      patients than in the women with primary renal disease in terms of prematurity
      (60% vs. 21%, P = 0.001), growth restriction (52% vs. 17%, P = 0.001), and
      hospitalization in a neonatal intensive care unit (35% vs. 6%, P = 0.01). In
      conclusion, the similar prevalence of major anomalies and mild errors of
      morphogenesis in offspring of the renal transplant patients and the women with
      primary renal disease suggests that immunosuppressive therapy is not a
      teratogenic factor. It may, however, be associated with worse pregnancy outcome.

PMID- 12476449
TI  - 46,XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large
      kindred.
AB  - 46,XY gonadal dysgenesis is characterized by abnormal testicular determination.
      We describe a large kindred in which various disorders of sexual development were
      observed, ranging from completely female phenotype without ambiguities of the
      external genitalia (five cases) to men with isolated penile or perineal
      hypospadias (four cases), including two cases with moderate virilization and one
      case with ambiguity of the external genitalia. Histologic examination of gonadal
      tissue was performed on seven subjects. These findings were suggestive of
      complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three
      patients, and mixed gonadal dysgenesis in three patients. Four patients developed
      gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma,
      i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All
      affected subjects had no other congenital anomalies or dysmorphic features.
      Analysis of families with several affected individuals with 46,XY gonadal
      dysgenesis implied an X-linked mode of inheritance because of the apparent
      absence of male-to-male transmission. However, a sex-limited autosomal dominant
      mode of inheritance affecting only XY individuals could not be ruled out.
      Analysis of the pedigree we report indicated an autosomal dominant mode of
      inheritance because of male-to-male transmission. This kindred supports the
      involvement of at least one autosomal gene in non-syndromic 46,XY gonadal
      dysgenesis.

PMID- 12476450
TI  - A distinct neurocognitive phenotype in female fragile-X premutation carriers
      assessed with visual attention tasks.
AB  - Premature ovarian failure (POF) and underlying hormonal changes are recognized as
      a distinct phenotype in female fragile-X premutation carriers. Neurocognitive
      deficits, in particular mental retardation, are associated with the full mutation
      in males and females. In female full mutation carriers this neurocognitive
      phenotype is expressed more mildly than in males. Research on whether the fragile
      X premutation is associated with a particular neurocognitive phenotype or not has
      been equivocal. By means of the Sonneville Visual Attentions Tasks (SVAT)
      computer-based battery of neurocognitive tasks, we assessed reaction time on
      different tasks in three groups of subjects: female premutation carriers, female
      full mutation carriers, and female control subjects. The results show that a
      fraction of the female premutation carriers perform poorly on several selective
      attention tasks, but not on other tasks. Their neurocognitive profile is
      different from that of control subjects and of the majority of female premutation
      carriers. It may also be different from the phenotype of female full mutation
      carriers, though in that respect this study remains inconclusive. These findings
      support earlier findings that the fragile-X premutation may affect neurocognitive
      functioning, in particular aspects of attention.

PMID- 12476451
TI  - Gaucher disease: in vivo evidence for allele dose leading to neuronopathic and
      nonneuronopathic phenotypes.
AB  - Gaucher disease, a common lysosomal storage disorder, is associated with
      mutations at the acid beta-glucosidase (GCase) locus. Two affected individuals
      are described to share a common mutant allele, but manifest different clinical
      categorical phenotypes. A 57-year-old female, with Gaucher disease type 1 and
      Cherokee ancestry, was homozygous for a rare mutant allele encoding Lys79Asn
      (K79N). A 2-year-old Caucasian male, with Gaucher disease type 3 and Cherokee
      ancestry, was a heteroallelic homozygote for this same allele (K79N) and a novel
      complex mutation (null allele). The shared alleles were identical as determined
      by complete gene sequencing, suggesting a founder effect. The discrepant
      phenotypes (types 1 and 3) in these two patients provide support for a threshold
      of residual activity necessary to "protect" the central nervous system (CNS) from
      the pathogenic effects of Gaucher disease, indicating an allele dose-effect.
      Designation of genotype associations with specific phenotypes must be assessed
      with this perspective.

PMID- 12476452
TI  - Further delineation of Wittwer syndrome and refinement of the mapping region.
AB  - In 1996, Wittwer et al. described a XLMR-syndrome mapping in Xp22.3. This family
      was reexamined. The spectrum of clinical symptoms now includes progressive
      skeletal lesions with osteoplastic and osteoclastic changes. Haplotype analysis
      using 23 microsatellite markers on Xp22 localized the disease locus between
      DXS8095 and DXS7108 comprising 3.9-6.1 Mb. This interval overlaps with known
      contiguous gene-deletion syndromes. However, deletion analysis of identified
      genes and ESTs in the critical interval for Wittwer syndrome showed no loss of
      the corresponding marker sequences in the patients.

PMID- 12476453
TI  - Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill
      dyschondrosteosis and achondroplasia or hypochondroplasia.
AB  - We studied two children with combined genetic skeletal disorders. Both had Leri
      Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had
      hypochondroplasia. Both had severe short stature and evidence of rhizomelia and
      mesomelia as well as other phenotypic features of their individual genetic
      disorders. Achondroplasia was due to the G380R FGF3R mutation and
      hypochondroplasia to a N540K mutation in the same gene. The patient with
      hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was
      identified in the child with achondroplasia. The phenotypes of combined LWD and
      achondroplasia or hypochondroplasia appeared to be less than additive, suggesting
      that SHOX and FGFR3 act on overlapping pathways of bone growth and development.

PMID- 12476454
TI  - Molecular cytogenetic analysis of a constitutional de novo interstitial deletion
      of chromosome 12p in a boy with developmental delay and congenital anomalies.
AB  - We describe the case of a 6-month-old boy with psychomotor retardation,
      craniofacial dysmorphism, cleft lip and palate, as well as hearing and visual
      impairment. Analysis of G-banded chromosomes of the propositus showed a de novo
      interstitial deletion of the short arm of chromosome 12, del(12)(p12.1p12.3).
      Molecular cytogenetic analysis with bacterial artificial chromosomes (BAC) clones
      was used to refine the extent of the deletion. The deleted segment encompasses
      about 12.5 Mb between markers D12S1832 and G62375. The phenotypic consequences of
      the deletion are discussed and compared with other cases of interstitial
      deletions of proximal chromosome 12p.

PMID- 12476455
TI  - De novo dup(X)(q22.3q26) in a girl with evidence that functional disomy of X
      material is the cause of her abnormal phenotype.
AB  - The relationship between phenotype and Xq duplications in females remains
      unclear. Some females are normal; some have short stature; and others have
      features such as microcephaly, developmental delay/mental retardation, body
      asymmetries, and gonadal dysgenesis. There are several hypotheses proposed in the
      literature to explain this variability. We describe a 7-year-old girl with
      dup(X)(q22.3q26). The pregnancy was complicated by intrauterine growth
      retardation, and she was distressed during labor. During her first year she fed
      poorly and failed to thrive. She has microcephaly, her height is at the 10th
      centile, and her hands and feet are strikingly small. She is hypotonic and
      delayed. Asymmetries of muscle power, and of leg and foot length have been noted.
      She has mild unilateral ptosis. She has some features of Turner syndrome, and
      multiple other minor anomalies such as flat labia. These are features common to
      other described females. This report describes our patient in detail and compares
      her phenotype to those of the other females with Xq duplications, displays our
      laboratory investigations, and discusses ideas regarding the pathogenesis of
      phenotype. The duplicated X is of paternal origin. It is inactivated in all
      cells; however, the distal duplicated portion appears to be active. We suggest
      that functional disomy of the duplicated X material, due to local escape from
      inactivation, may be responsible for the phenotype in the affected females.

PMID- 12476456
TI  - Velocardiofacial syndrome in an unexplained XX male.
AB  - We report the unusual finding of velocardiofacial syndrome (VCF) in an
      unexplained 46,XX male. A microdeletion of 22q11.2 was confirmed by fluorescence
      in situ hybridization (FISH) analysis. Routine G-banded chromosome analysis
      revealed an XX sex chromosome constitution. FISH was performed using the SRY
      probe and failed to detect hybridization. The sex chromosome status of the
      patient was further investigated by PCR testing to screen for the presence of 24
      distinct loci spanning the Y chromosome. PCR screening failed to detect any
      apparent Y chromosome material.

PMID- 12476457
TI  - Two sibs with brachyolmia type Hobaek: five year follow-up through puberty.
AB  - A brother and a sister affected with brachyolmia (short trunk) are reported.
      Their radiological findings are compatible with brachyolmia, Hobaek type, which
      is characterized by platyspondyly, horizontal acetabular roof, short femoral
      neck, and vertical "mixed lucent and dense" striation pattern in the metaphyses
      of large long bones. Despite normal birth weight and length, the platyspondyly is
      present at infancy, but clinically the condition may not be noticeable until late
      childhood or early puberty, when stunted growth becomes apparent. Beyond puberty,
      the patients are short in stature, mainly due to a short trunk with decrease
      upper and lower body segment ratio. Brachyolmia type Hobaek is a relatively
      benign condition. It may cause a mild and nonspecific backache that usually is
      not debilitating. The inheritance mode is apparently autosomal recessive.

PMID- 12476458
TI  - Humeroradial synostosis, ulnar aplasia and oligodactyly, with contralateral
      amelia, in a child with prenatal cocaine exposure.
AB  - Humeral "bifurcation" due to humeroradial synostosis, and amelia are both very
      rare limb anomalies. We report on a Canadian. Aboriginal boy with both these limb
      deficiencies. The family history was unremarkable, but he was exposed prenatally
      to cocaine at the time of limb development. Humeroradial synostosis with ulnar
      aplasia has been reported by several authors. The majority of cases are
      unilateral. When both upper limbs arms are involved, cases with oligodactyly
      often have asymmetrical limb deficiencies and have all been sporadic to date.
      Some appear to represent cases of the femur-fibula-ulna or FFU complex. Affected
      individuals with normal hands usually have symmetrical defects and show an
      autosomal recessive pattern of inheritance. Limb deficiencies have been reported
      in several infants exposed prenatally to cocaine and have been inducible in
      animal models. Most are terminal transverse defects or deficiencies of middle
      digits. When more than one limb is involved, the defects are usually asymmetric.
      Our case appears to be one of the most severely affected children reported to
      date.

PMID- 12476459
TI  - Mild phenotype in a 15-year-old boy with Pallister-Killian syndrome.
AB  - Pallister-Killian syndrome is a rare disorder characterized by multiple
      congenital anomalies, coarse face, pigmentary skin changes, seizures, severe
      mental retardation, and the presence of an extra metacentric chromosome i(12p)
      confined to skin fibroblasts only. Here, we report on an unusual case of i(12p)
      in a 15-year-old boy presenting with mild mental retardation, minor facial
      features (long face, prognathism, short neck), normal weight, length, and OFC
      parameters as well as hyperpigmented streaks. The boy attended normal school
      until the age of 14 years. Because of hyperpigmented stripes, chromosome analysis
      was performed on skin fibroblasts. This study showed that 37% of the cells had an
      additional isochromosome for the short arm of chromosome 12. This observation
      illustrates the phenotypic variability of i(12p) and emphasizes the importance of
      skin fibroblasts chromosome analysis in patients with pigmentary skin changes.

PMID- 12476461
TI  - Down syndrome before Down: a postscript.

PMID- 12476460
TI  - Recurrence of complex camptopolydactyly in a sibling suggestive of autosomal
      recessive mode of inheritance.

PMID- 12476462
TI  - 45,X/46,XY mosaicism and fragile X syndrome.

PMID- 12476463
TI  - Incidence of Smith-Lemli-Opitz syndrome in Ontario, Canada.

PMID- 12476465
TI  - Hemifacial myohyperplasia: an additional case.

PMID- 12476466
TI  - Pozega--from small town to episcopal center.

PMID- 12476467
TI  - Coronary artery bypass grafting in the elderly: pros and cons after three-year
      follow-up.
AB  - AIM: The elderly represent an ever-growing proportion of the candidates for
      coronary artery bypass grafting (CABG) surgery. We analyzed the effect of
      anticipated risks on the early and mid-term outcome of coronary surgery in
      septuagenarians compared with younger patients. METHOD: We analyzed 1,475
      consecutive isolated CABG procedures performed at the Charles University Hospital
      during the 1995-1997 period and assessed their early and mid-term (3-year follow
      up) results with respect to patient age. The patients were divided into two
      groups: younger (n = 1,324, age < 70 years) and older (n = 151, age > or = 70
      years). We studied potential preoperative risk factors, perioperative parameters,
      and postoperative course. Data on functional status, incidence of major cardiac
      events, and patient satisfaction with the outcome of surgery 3 years after the
      operation were collected from the patients by a questionnaire survey. RESULTS:
      The elderly had lower body mass index and body surface area, more advanced stage
      of disease according to the New York Heart Association and Canadian
      Cardiovascular Society classifications, higher prevalence of diabetes, renal
      dysfunction, and extracardiac arteriopathy. CABG was performed in both groups,
      with no procedural differences. The older group had higher mortality (7.3% vs
      2.3%), incidence of NearMiss+ (outcome measure index; 36.4% vs 18.4%), and post
      operative morbidity (56.3% vs 34.6%). Older patients also required longer stay at
      the intensive care unit and longer hospitalization. Three-year follow-up revealed
      identical relief of symptoms and improvement of functional status in both groups,
      with higher mortality in the elderly (15.3% vs 4.5%). The stroke was also more
      frequent in the elderly (8.6% vs 3.0%), whereas the occurrence of other non-fatal
      cardiac events was similar in both groups. CONCLUSION: Coronary revascularization
      in the elderly carries higher but still acceptable risk. The elderly survivors
      showed similar functional improvement as the younger patients, but the actuarial
      survival was worse, mainly due to perpetuating cardiovascular illness. Surgical
      procedure should not be denied to elderly population based on age alone and each
      patient should be carefully evaluated.

PMID- 12476468
TI  - In-hospital outcome of 212 consecutive patients with off-pump coronary artery
      bypass at Zagreb University Hospital Center.
AB  - AIM: To determine the in-hospital outcome of patients undergoing off-pump
      coronary artery bypass grafting. METHODS: The study included 212 consecutive
      patients (147 men and 65 women) undergoing off-pump coronary artery bypass
      grafting between March 2000 and March 2002. Mean +/- SD age of the patients was
      60 +/- 8 years. We analyzed in-hospital mortality and perioperative and
      postoperative course of treatment of our patients. RESULTS: The mean +/- SD
      number of grafts was 2.9 +/- 0.9 per patient. More than 75% of patients were
      extubated within the first 6 h after surgery, and 6% received no blood
      transfusions. The mortality rate was 2.8% and there were no intraoperative
      deaths. CONCLUSION: Off-pump coronary artery bypass procedure seems a safe
      alternative to standard on-pump revascularization procedures and can also be
      safely suggested to elderly population.

PMID- 12476469
TI  - Surgical treatment of left ventricular free wall rupture after myocardial
      infarction: case series.
AB  - AIM: To analyze the results of surgical treatment of left ventricular free wall
      rupture after acute myocardial infarct in a case series. METHOD: From 1984 to
      2001, 25 patients (10 women and 15 men) were surgically treated in our Center for
      left ventricular free wall rupture after acute myocardial infarction. Their mean
      age was 62 years (range, 42-80). Cardiac symptoms (chest pain and/or dyspnea)
      prior to admission were recorded in 4 patients. One patient had acute myocardial
      infarction of the anterolateral wall, 6 patients of the lateral wall, 13 patients
      of the anterior wall, 4 patients of the inferior wall, and one patient had a
      right ventricle infarction. Thrombolytic therapy was administered in 10 patients,
      according to the criteria of the American Heart Association and Spanish Society
      of Cardiology criteria. In all patients, the final diagnosis was established
      echocardiographically before the surgery. RESULTS: All patients underwent
      surgical intervention on an emergency basis. Extracorporeal circulation was used
      in the first 9 cases, whereas the next 16 patients had off-pump surgery. Two
      patients had heart arrest during off-pump surgery, which required extracorporeal
      circulation support. One patient was found false positive for rupture only at
      surgery. In the first 4 cases, we performed a direct suture after excising
      necrotic tissue, in the next 15 cases we sutured a patch over the infarction
      zone, and in the last 5 patients we used Teflon patch fixed with fibrin glue and
      polypropylene and stitched to the epicardium with a continuous suture. Out of 24
      patients, 8 died: one in the surgical room from uncontrollable bleeding and
      another 7 between 30 and 90 days after the surgery in the intensive care unit.
      All of them underwent surgery with extracorporeal circulation. There were no
      deaths among the patients undergoing off-pump surgery. Three out of 4 patients in
      whom direct suture and necrotic tissue excision was performed died in the
      hospital. Five out of 19 patients in whom patch correction with direct suture was
      done died in the hospital. CONCLUSION: The left ventricle free wall rupture, as a
      complication of acute myocardial infarction, can be diagnosed early and treated
      on time. Rapid diagnosis and emergency surgery are crucial for successful
      treatment of patients with impending heart rupture. Off-pump surgery and patch
      with glue technique seem to yield best results.

PMID- 12476470
TI  - Implantation of aortic stentless bioprosthesis: case series.
AB  - AIM: To present our preliminary results with stentless aortic valve
      bioprostheses. METHODS: From November 2001 to February 2002, 15 patients (8 men
      and 7 women) underwent aortic valve replacement with aortic stentless
      bioprosthesis. The patients age ranged from 50 to 79 years (mean+/-SD, 63.3+/-5.7
      years). Three patients had aortic stenosis, 3 aortic regurgitation, and 9
      combined aortic pathology. Mean+/-SD left ventricle ejection fraction was 53.0+/
      13.9%. Median EuroSCORE was 4 (range, 3-10). Mean+/-SD sinotubular junction
      diameter measured by transesophageal echo (TEE) was 22.9+/-1.97 mm
      preoperatively, and the diameter of implanted prostheses was 25.9+/-2.4 mm. All
      valves were implanted using subcoronary technique. In 5 patients, concomitant
      myocardial revascularization was performed. RESULTS: Mean+/-SD total bypass time
      was 126.7+/-45.9 min (range, 96-180) and cross-clamp time was 88.7+/-15.6 min
      (range, 69-118). There were no in-hospital deaths or neurological complications.
      All patients were discharged with only antiagregation agents in therapy. TEE
      control was performed 1 week after the surgery. The mean systolic gradient across
      the prosthesis was 25.6+/-5.6 mm Hg and maximum 25.9+/-7.3 mm Hg. No aortic
      insufficiency was observed in 6 and only minor in 9 patients in postoperative
      TEE. CONCLUSION: Although the implantation of aortic stentless bioprosthesis is
      technically challenging and time-consuming, early postoperative hemodynamic
      results are satisfactory.

PMID- 12476471
TI  - Stenting of coronary bifurcation lesions: case series.
AB  - AIM: To assess the procedural success and major cardiac event rate after stenting
      of coronary bifurcation lesions. METHODS: The prospective study included 36
      patients with coronary artery bifurcation lesion treated with stenting between
      January 1999 and December 2001 at the Institute for Heart Disease, Skopje
      University Center. There were 23 men and 13 women, with a mean age of 62.5+/-12.3
      years. Seventeen patients had acute myocardial infarction and 19 patients had
      unstable angina. The follow-up lasted 6 months. The strategy of systematic
      coronary stenting in the bifurcation lesions involving a side branch of >2.2 mm
      in diameter was prospectively evaluated according to the quantitative coronary
      angiography (QCA) measurements. Procedural success was defined as a residual
      stenosis of less than 20%. Major cardiac events included deaths, emergency
      coronary artery bypass grafting (CABG), Q-wave myocardial infarction, acute and
      subacute closure, repeated percutaneous transluminal coronary angioplasty (PTCA),
      and non-Q myocardial infarction. RESULTS: Out of a total of 36 bifurcation
      lesions, the left anterior descending/diagonal bifurcation lesion was found in 22
      patients, circumflex/marginal in 8 patients, posterior descending
      artery/posterolateral artery in 4 patients, and left main coronary artery in 2
      patients. The main branch of the coronary artery (mean+/-SD reference diameter,
      or the diameter of the normal coronary artery, 2.90+/-0.36 mm) was stented in 35
      patients and the side branch of the main coronary artery (2.35+/-0.42 mm
      reference diameter) in 24 patients. The major cardiac events occured in 3
      patients: one had Q-wave myocardial infarction, one developed acute and subacute
      closure, and one underwent PTCA. There were no deaths or emergency CABG.
      CONCLUSION: The development of new surgical strategies and stent design has
      improved the safety and immediate outcome of bifurcation stenting, but procedural
      success still needs to be matched by an equal clinical improvement and long-term
      patency.

PMID- 12476472
TI  - Continuous systemic perfusion via collaterals at moderate hypothermia in aortic
      arch repairs in neonates.
AB  - AIM: To present our experience with modified cannulation with continuous,
      moderately hypothermic systemic perfusion in extensive aortic arch repair. The
      technique has fewer complications and preserves cerebral blood flow
      autoregulation. METHOD: Nine neonates, 6 with the hypoplastic left heart syndrome
      and 3 with the interrupted aortic arch with ventricular septal defect, were
      surgically treated with this technique between June and December 2001. Before
      extracorporeal circulation, 3.5-mm polytetrafluoroethylene tube was sutured onto
      the innominate artery and the arterial perfusion cannula inserted into the tube.
      Aortic arch repair was then performed with extracorporeal circulation. Right
      radial artery and femoral artery pressures were continuously monitored. Perfusion
      flows were built up gradually, with strict attention to the upper body (right
      radial artery) pressures not to exceed normal values. Procedures were carried out
      at moderate hypothermia (>28 degrees C), preferably with the beating heart.
      RESULTS: No morbidity or mortality attributable to continuous perfusion occurred.
      Mean+/-SD extracorporeal circulation duration was 114+/-26 min. Maximum perfusion
      rate (actual/required flow for body surface area) was 1.65 at normal perfusion
      pressures. Right radial artery pressure at full flow (2.2 L/m2/min) was 56.1+/
      6.7 mm Hg, whereas femoral artery pressure was 34.2+/-8.2 mm Hg. Decrease in
      right radial-to-femoral artery pressure was 21.9+/-5.6 mm Hg. The lowest
      nasopharyngeal temperature was 28.5 degrees C. There were no neurologic
      complications. CONCLUSION: Continuous, moderately hypothermic systemic perfusion
      via collaterals seems to be a method of choice in aortic arch repair in neonates.
      As there is no need for deep hypothermic total circulatory arrest, its numerous
      sequelae, such as increased postoperative bleeding and permanent neurologic
      deficit, can be avoided.

PMID- 12476473
TI  - Right ventricle failure and outcome of simple and complex arterial switch
      operations in neonates.
AB  - AIM: To analyze the causes and role of right ventricle failure in the morbidity
      and mortality after arterial switch operation for transposition of the great
      arteries in neonates. METHOD: Between January 1999 and December 2001, 62 neonates
      underwent arterial switch operation. The simple transposition group was comprised
      of 39 patients with transposition of the great arteries and intact ventricular
      septum. The complex transposition group included 23 patients with large
      ventricular septal defects, accompanied with left ventricle outflow tract
      obstruction in 6 cases and dextrocardia in 1 case. Arterial switch operation was
      performed on elective basis in all but 3 patients who underwent emergency
      operation. RESULTS: Patients with complex heart defects had significantly lower
      body weight (p = 0.008) than patients with simple trasposition of great arteries.
      The usual coronary artery pattern (ie, the left anterior descending artery and
      circumflex artery arising from the right aortic sinus; the right coronary artery
      arising from the left aortic sinus) was found in 74% of the neonates in the
      simple transposition group and 65% of the neonates in the complex transposition
      group. Age, weight, coronary artery anatomy, cardiopulmonary bypass, duration of
      aortic cross-clamp, bleeding, and the need for delayed chest closure did not
      influence the outcome of surgery. Low cardiac output after surgery was more
      common in the complex transposition group (p = 0.0001), although it was not a
      predictor of fatal outcome. Preoperative hypoxia coupled with acidosis (odds
      ratio (OR), 5.70; 95% confidence intervals (CI), 4.45-7.44), and emergency
      operations (OR, 3.62; 95% CI, 2.22-5.59) were strong predictors of unfavourable
      outcome. We lost 4 patients out of 62 (6.5%) because of right ventricle failure
      caused by persistent pulmonary hypertension. Right ventricle failure on the
      second postoperative day, e.g., sustained increased central venous pressure > 15
      mm Hg (p < 0.001) and high velocity tricuspid regurgitation > 4 m/s (p = 0.002),
      indicated bad prognosis. CONCLUSION: Difficult coronary anatomy was not a risk
      factor for morbidity and mortality after arterial switch operation. Poor
      preoperative health condition, hypoxia (despite effective balloon
      atrioseptostomy), and acidosis contributed to persistent pulmonary hypertension.
      Operation on the emergency basis and tricuspid valve insufficiency with right
      ventricle failure were strong predictors of unfavorable outcome.

PMID- 12476474
TI  - Corrective surgery of congenital heart defects in neonates: the Prague
      experience.
AB  - AIM: To assess the outcome and mortality trend in newborns undergoing corrective
      surgery for congenital heart defect. METHOD: We reviewed the hospital records of
      1,033 neonates under 30 days of life, who had congenital heart defects operated
      on at the Kardiocentrum, Motol University Hospital in Prague, Czech Republic,
      during 1977-2001. Early and late mortality and reoperation rates were analyzed.
      RESULTS: A total of 1,156 operations were performed in 1,033 neonates.
      Obstructive lesions were surgically treated in 56%, left-to-right shunts in 21%,
      and complex conotruncal lesions in 23% of the cases. Total correction has been
      achieved in 62% of the neonates. Most operations (75%) were performed in the
      first two weeks of neonate s life. Early 30-day hospital mortality was 13%. Late
      mortality, after the discharge from the hospital, was 10%. In the last three
      years, the hospital mortality rate decreased to about 2%. Out of 590
      reinterventions in 379 neonates, with the mortality of 6%, 229 were secondary
      staged corrections and 190 further palliative procedures aimed mostly toward
      Fontan or Rastelli type of circulation. Residual or recurrent defects were solved
      in 62 neonates. There were 30 valve replacements, with 18 mechanical valves and
      12 pulmonary valve autotransplantations (the Ross procedure). The homograft
      valved conduit was used in 38 children. CONCLUSION: Most newborns with critical
      congenital heart defects can undergo corrective operation under acceptable risk.
      Due to complex improvements in perioperative, anaesthetic, surgical, and
      postoperative care, contemporary hospital mortality can be reduced to 1-3%.
      Palliative procedures still play an important role in the staged treatment of
      severe complex heart defects in neonates.

PMID- 12476475
TI  - Effects of four antihypertensive monotherapies on cardiac mass and function in
      hypertensive patients with left ventricular hypertrophy: randomized prospective
      study.
AB  - AIM: To compare the effects of four antihypertensive drugs, which have reportedly
      different effectiveness in reducing myocardial mass. METHODS: A randomized,
      double-blind, prospective study included 80 hypertensive patients with left
      ventricular (LV) hypertrophy confirmed both electrocardiographically and
      echocardiographically. We investigated the effects of indapamide, nicardipine,
      propranolol, and chlorthalidone on arterial blood pressure and LV mass and
      function. RESULTS: Sixty-four patients (34 men and 30 women) completed the 6
      month study. No significant differences in antihypertensive effects of the four
      medications were found. The average decrease in systolic and diastolic blood
      pressure was 12.8% and 10.4%, respectively. All four antihypertensive medications
      caused pronounced reduction in LV mass, between 7.9% in the propranolol group and
      10.1% in the nicardipine group, with no significant difference between the
      groups. In patients receiving diuretics, predominant decrease was observed in LV
      mass and LV mass index. In patients treated with propranolol, the thickness of
      both the LV wall and interventricular septum was reduced, whereas the reduction
      in LV mass, LV wall and interventricular septum thickness was found in patients
      treated with nicardipine. There was no significant correlation between the
      changes in LV mass and other variables (blood pressure, and systolic and
      diastolic function). Systolic function did not improve with the reversion of LV
      hypertrophy in any group of patients, but improvement was observed in some
      indices of diastolic function. The early and late LV filling velocity and their
      ratio did not improve significantly, either. Clinically relevant side effects
      were not observed. CONCLUSION: All four antihypertensive monotherapies achieved a
      comparable control of hypertension and reduction in LV hypertrophy.

PMID- 12476476
TI  - Measuring cardiac output during dobutamine infusion after off-pump coronary
      artery bypass: comparison of transesophageal echo-Doppler and thermodilution.
AB  - AIM: To compare transesophageal echo-Doppler with thermodilution method for
      measuring cardiac output during dobutamine infusion after off-pump coronary
      artery bypass. METHOD: Using transesophageal echo-Doppler and thermodilution
      methods, we measured cardiac output in 30 patients after off-pump coronary artery
      bypass, immediately before and 5, 15, and 30 min after the introduction of
      continuous dobutamine infusion (3 microg/kg/min). Paired t-test and Bland-Altman
      analysis were used to compare the results obtained by two methods in this
      prospective study. RESULTS: Significant increase in cardiac output during
      dobutamine infusion was detected by both thermodilution (from 3.9 +/- 1.0 to 4.6
      +/- 1.1 L/min; p < 0.001) and transesophageal echo-Doppler (from 3.8 +/- 1.2 to
      4.8 +/- 1.4 L/min; p < 0.001). Initial measurement results of thermodilution and
      transesophageal echo-Doppler techniques showed clinically acceptable agreement,
      with a mean difference of only + 0.09 L/min (95% confidence interval (CI), 0.42
      to + 0.61). Subsequently repeated measurements after 5, 15, and 30 min showed
      almost the same agreement between the methods. The highest mean difference
      between the initial and repeated measurements was found at 5 min after the
      introduction of dobutamine infusion (-0.29 L/min, 95% CI, -1.06 to + 0.48).
      CONCLUSION: Transesophageal echo-Doppler and thermodilution can be
      interchangeable as methods for measuring cardiac output after off-pump coronary
      artery bypass.

PMID- 12476477
TI  - Elevated serum lipids in veterans with combat-related chronic posttraumatic
      stress disorder.
AB  - AIM: To assess possible differences in serum cholesterol, low density lipoprotein
      cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides,
      arteriosclerosis index, established risk factor (ERF) of arteriosclerosis, and 10
      year risk for coronary disease according to the Adult Treatment Panel III (ATP
      III) between veterans with combat-related posttraumatic stress disorder (PTSD)
      and a control group consisting of patients with major depressive disorder.
      METHOD: We determined serum cholesterol, LDL-C, HDL-C, and triglycerides in the
      patients with PTSD (n = 103) and patients with major depressive disorder (n =
      92), using the enzyme-assay method. AI, ERF, and ATP-III were calculated from
      cholesterol, LDL-C, and HDL-C levels. The groups were matched in age and body
      mass index (BMI). Patients with major depressive disorder were chosen as a
      control group because they do not have changes in serum lipids. RESULTS: Patients
      with combat-related PTSD had higher mean concentration of cholesterol (6.2+/-1.1
      mmol/L vs 5.3+/-0.9 mmol/L; p<0.001), LDL-C (3.9+/-0.7 mmol/L vs 3.5+/-1.0
      mmol/L; p = 0.005), and triglycerides (2.9+/-2.3 mmol/L vs 1.5+/-0.5 mmol/L;
      p<0.001), and lower HDL-C (1.0+/-0.3 mmol/L vs 1.3+/-0.2 mmol/L; p<0.001) than
      the control group. Arteriosclerosis index (4.2+/-1.2 vs 3.7+/-1.7; p = 0.050),
      ERF (6.4+/-1.9 vs 5.5+/-2.4; p = 0.010), and ATP-III (12.1+/-3.3 vs 10.2+/-3.8;
      p<0.001) were higher in PTSD than in the control group. CONCLUSION: Elevated
      concentrations of serum lipids are associated with combat-related PTSD. This may
      imply that patients with combat-related PTSD are under a higher risk for
      arteriosclerosis.

PMID- 12476478
TI  - Constructing a coronary scale for ischemic heart disease: case-control study.
AB  - AIM: To develop a scale measuring proneness to ischemic heart disease. METHODS:
      Ischemic heart disease was angiographically documented in 187 men. In 187 matched
      controls the diagnosis of ischemic heart disease was ruled out by examination of
      medical records and history data, and when necessary, clinical examination and
      specialized diagnostic procedures. Item analysis of the Eysenck Personality
      Questionnaire (EPQ) was performed on 100 men with ischemic heart disease and
      their male controls, and then a replication study was performed on the remaining
      87 pairs. RESULTS: A Coronary Scale was constructed from 8 EPQ items
      significantly and consistently different between the groups. Most of these items
      were drawn from the neuroticism scale. The Coronary Scale yielded significant
      correlations with emotionally saturated psychological variables. CONCLUSION:
      Coronary Scale may be useful in everyday practice to select patients with
      ischemic heart disease and those who are at higher risk to develop disease. It
      could be used for detecting a high-risk group of emotionally labile subjects to
      concentrate efforts for prevention of coronary disease.

PMID- 12476479
TI  - Biochemical risk factors in angiographically established stenosis of cerebral
      arteries.
AB  - AIM: To determine the significance of the association between biochemical risk
      factors for cerebrovascular atherosclerosis (lipid parameters, lipoprotein(a),
      total homocysteine, total antioxidant status, trace elements, and electrolytes)
      and the degree of stenosis of cerebral arteries scored by digital subtraction
      angiography. METHODS: The study included 35 patients with angiographically
      established < 50% stenosis of cerebral arteries and 55 patients with > or =50%
      stenosis of cerebral arteries, including obliteration. The control group
      consisted of 51 patients with normal cerebral arteries on ultrasound examination.
      Biochemical parameters were measured in all participants according to the
      standard laboratory protocols. RESULTS: Logistic regression analysis showed two
      independent and significant biochemical risk factors associated with the severity
      of cerebrovascular stenosis: lipoprotein(a) for patients with different degrees
      of stenosis, and total antioxidant status for patients with severe stenosis of
      more than 50%. Univariate statistical evaluation showed significantly higher
      homocysteine levels in the group of patients with > or =50% stenosis than in the
      control group (median 14.84 micromol/L vs median 12.40 micromol/L, p < 0.05).
      CONCLUSION: Increased lipoprotein(a) and low total antioxidant status values seem
      to be the most significant independent biochemical risk factors for the
      development of cerebrovascular stenosis. Mild hyperhomocysteinemia seems to be an
      additional discriminating indicator of the severe cerebrovascular stenosis. These
      factors may be useful for early identification and recognition of patients with
      cerebrovascular atherosclerosis.

PMID- 12476480
TI  - Influence of depression on patients satisfaction with the outcome of
      microsurgical "key-hole" vs classical discectomy: prospective matched-cohort
      study.
AB  - AIM: To assess the influence of depression on patients' satisfaction with lumbar
      discectomy performed by two different surgical techniques. METHODS: A prospective
      matched-cohort analysis of classical lumbar discectomy following static imaging
      (n = 45) and microlumbar "key-hole" discectomy after dynamic CT/myelography (n =
      55) was performed. The outcome was independently assessed using Prolo
      economic/activity (E) and functional/pain (F) scale, and depressiveness according
      to Hamilton rating scale. Patients without improvement on the Prolo scale were
      classified as failed back surgery syndrome, and with a Hamilton score 17 as
      depressive. RESULTS: The groups were well matched by age, sex, clinical
      presentation and incidence of depression. In the "key-hole" group, both activity
      and pain outcome were better than in the classical technique group (median E
      score (range) = 4 (2-5) vs 3 (2-4), p = 0.002, median F score (range) = 4 (2-5)
      vs 4 (1-5), p = 0.008). Eighteen patients were classified as failed back
      syndrome, 6 in the "key-hole" group, and 12 in the classical group (z = 3.16, p =
      0.075). The incidence of failed back syndrome among non-depressive patients was
      significantly lower in "key-hole" group (2/55 patients vs 8/45, z = 2.345, p =
      0.009). Occurrence of unsatisfactory results among depressive patients was very
      similar in both groups (4/55 patients vs 4/45, z = 0.296, p = 0.384). CONCLUSION:
      Introduction of functional imaging and "key-hole" technique decreased incidence
      of failed back syndrome among non-depressive patients. Unsatisfactory outcome
      among depressive patients was unrelated to the imaging and surgical technique.
      Connection between depression and failed back syndrome, although detected,
      remains unclear and must be further investigated.

PMID- 12476481
TI  - Management of guttate and generalized psoriasis vulgaris: prospective randomized
      study.
AB  - AIM: To assess the efficacy of betamethasone dipropionate 0.05% cream plus
      ultraviolet B (UVB) radiation with and without additional penicillin therapy in
      the treatment of guttate psoriasis, and to compare the efficacies of oral
      psoralen plus ultraviolet A (PUVA) therapy and systemic retinoids therapy for
      treatment of generalized psoriasis. METHODS: Sixty patients with guttate (n = 20)
      and generalized psoriasis vulgaris (n = 40) of various intensity and duration
      treated at the Department of Dermatology, Medical School in Skopje, from February
      2000 to January 2002, were included in this prospective, open-label, randomized,
      parallel group study. The clinical features of the patients were quantified
      according to the mean psoriasis area and severity index (PASI) values. Student s
      t-test for paired samples and two independent samples were used in statistical
      analysis. RESULTS: The final PASI values were not significantly different for the
      patients receiving different treatments of guttate psoriasis or generalized
      psoriasis. The initial PASI values for guttate psoriasis patients treated with
      betamethasone dipropionate plus UVB with and without penicillin treatment (5.7 +/
      2.1 and 5.9 +/- 2.5, respectively) declined to 0.5 +/- 0.8 and 1.0 +/- 0.9,
      respectively, after the therapy. The initial PASI values in generalized psoriasis
      patients receiving PUVA dropped from 24.1 +/- 3.6 to 1.7 +/- 1.5 by the end of
      the therapy. Finally, pre-treatment PASI values in patients with generalized
      psoriasis receiving retinoids decreased from 24.6 +/- 3.5 to 0.9 +/- 1.1 after
      treatment. However, patients receiving systemic retinoids for generalized
      psoriasis had statistically higher incidence of side effects than patients
      receiving PUVA therapy (t = 6.458, df = 38, p < 0.001). CONCLUSION: Penicillin
      should be applied in addition to local corticosteroids with UVB in the treatment
      of guttate psoriasis, since the disease may be triggered by a streptococcal
      infection. In cases of generalized psoriasis vulgaris, PUVA therapy caused fewer
      side effects than did systemic retinoids.

PMID- 12476482
TI  - Intensive care units in Croatia: 2001 survey.
AB  - AIM: To establish a framework for the Intensive Care Units (ICU) Register in
      Croatia, and examine the relation between their present organization and medical
      practices and their outcome performances. METHODS: The survey of a total of 123
      ICUs in Croatia was conducted between February 1 and October 31, 2001. Census
      questionnaires were filled out by ICU chiefs of staff. Demographic data, data on
      hospital and ICU structure and organization, disposable equipment, admission and
      discharge decision-making, outcome, and patient demographic data were collected
      for February 1, 2001. Descriptive statistics was used for data analysis. RESULTS:
      On February 1, 2001, there were 123 ICUs in Croatia. The questionnaire was filled
      out by 117 ICU chiefs of staff (95% response rate). The total number of ICUs beds
      was 900, comprising 3.3% of all hospital beds. Croatian ICUs were divided into 13
      subtypes; 89% of them were adjoined to hospital departments of various
      subspecialties and only 13 (11%) were freestanding. The number of ICUs per
      hospital, number of ICU beds, quantity of disposable equipment, and number of
      permanently employed medical and nursing staff within hospitals and individual
      units increased as hospitals enlarged. Also, the number of mixed surgical/medical
      and coronary care/medical units decreased, and specialized units became
      prevalent. The mortality data in Croatian ICUs were similar to those reported
      elsewhere in the world: the lowest mortality was found in psychiatric ICUs (3%)
      and the highest in an ICU for infective diseases (30%), followed by neurological
      (19%), medical (17%), and respiratory (16%) ICUs. CONCLUSION: Establishing a
      database on intensive care medicine and assessing the performance of ICUs in
      Croatia could serve as a model for improvement of ICU service in other transition
      countries.

PMID- 12476483
TI  - The trench.

PMID- 12476484
TI  - Quality of care in myocardial revascularization procedures.

PMID- 12476485
TI  - Immune response to parasitic infections--an introduction.

PMID- 12476486
TI  - Vaccination against Leishmania infections.
AB  - Leishmaniasis, that affects millions of people worldwide, is an infectious
      disease caused by the protozoan parasite Leishmania. Incidence of the condition
      appears to be increasing in several parts of the world. Of the three main
      presentations of the disease, i.e. cutaneous, mucocutaneous and visceral, only
      the first one tends to heal spontaneously, while the other two are considered
      fatal if left to run their natural course. Recovery from leishmaniasis, whether
      spontaneous or drug-induced, is usually accompanied by solid immunity against
      reinfection, which provides a rationale for attempting to design vaccines against
      the disease. This review presents an outline of the main immunological features
      of Leishmania infections and of the mechanisms thought to operate in recovery
      from the disease. It describes various experimental approaches to vaccination in
      man and animal models, including the use of virulent and avirulent organisms, of
      dead parasites and extracts thereof, and of purified parasite proteins. Assays
      using novel technologies, such as the direct injection of DNAs encoding parasite
      proteins, or the inoculation of viral or bacterial vectors expressing such
      molecules, as well as recent experiments aimed at inducing an immune response
      against saliva of the insect vector, are also reviewed. Observations made during
      the course of these studies have reinforced the notion that vaccination against
      leishmaniasis is indeed feasible. However, in spite of intensive efforts by many
      groups and many reports of success in man and in animal models, a consensus is
      yet to emerge as to what constitutes the best approach to vaccination against
      leishmaniasis.

PMID- 12476487
TI  - Prospects for a human Toxoplasma vaccine.
AB  - Human toxoplasmosis is usually benign, but may occasionally lead to severe or
      lethal damages when combined with immunosuppressive states or when transmitted to
      the fetus during pregnancy. Only a vaccine could prevent these harmful effects.
      The oral route is the natural portal of entry of T. gondii. A protective immune
      response at the mucosal level is required to kill the parasite as soon as it
      penetrates the intestinal barrier thus preventing toxoplasma from invading the
      host and settling into tissues. The probable major roles played by both CD8 T
      cells and antibodies, specially IgA, suggest that the best strategy would be to
      stimulate both the cellular and humoral arms of the mucosal immune system.
      Mucosal dendritic cells have been shown to induce good protection against oral
      toxoplasma challenge. Our hypothesis is that an acceptable and effective human
      vaccine would have to carry the optimized synthetic vaccine (subunit, DNA or
      replicon) plus an appropriate adjuvant and to target the mucosal dendritic cells
      by means of an inert delivery system such as polymer microparticles, which can be
      endocytosed by M cells of the gut or nasal-associated lymphoid tissues.

PMID- 12476488
TI  - Molecular and cellular tools in human cystic echinococcosis.
AB  - The latest developments in the molecular and cellular mechanisms that underlie
      Echinococcus infection have renewed interest in the immunodiagnosis of this
      disease and have helped in understanding the host-parasite relationship. This
      review discusses current concepts on the immune response to Echinococcus
      granulosus in humans, and relates these findings to diagnosis and clinical
      management. The two most promising molecular tools developed for the
      immunodiagnosis of cystic echinococcosis involve isolating native or recombinant
      parasite antigens to detect specific serum antibodies in patients with suspected
      echinococcosis and producing monoclonal antibodies to detect parasite antigens in
      clinical samples. Novel drugs should be designed to strengthen host immune
      responses thus combating parasitic survival. Currently, attention has been
      focused on understanding T-helper lymphocyte activity; in particular the role of
      Th1 and Th2 subsets in orchestrating immune responses. The Th1/Th2 model
      explaining how selective immune responses--including cell-mediated or humoral
      immunity--develop, seems promising as the rationale for molecular tools that
      could lead to new therapeutic strategies.

PMID- 12476489
TI  - Immunotherapy of Trypanosoma cruzi infections.
AB  - The protozoan parasite Trypanosoma cruzi, causative agent of Chagas' disease, is
      transmitted to man and other mammals by triatominae insects, or 'kissing bugs'.
      Since its discovery in 1909, by Carlos Chagas, this parasite has been the object
      of several publications in the domains of immunology, cellular biology and of
      control gene organization, regulation and expression. Although much progress has
      been made concerning prophylaxis of Chagas' disease, particularly vector
      eradication, additional cases of infection and disease development still occur
      every day throughout the world. Whilst infection was largely limited in the past
      to vector transmission in endemic areas of Latin America, its impact has
      increased in terms of congenital and blood transmission, transplants and
      recrudescence following immunosuppressive states. Reports on new insect vectors
      adapted to the parasite and domestic animals infected in more developed
      countries, emphasize the continuing worldwide public health issue. Therapy
      against this parasite is limited and cure is subjected to several criteria, such
      as susceptibility of the parasite strain, age of the host and stage of the
      disease. The ability of Trypanosoma cruzi to induce important and various host
      immune system dysfunctions makes the development of effective vaccines a
      laborious and complex task. These considerations strengthen the latent
      significance of Chagas' disease and encourage the search for new preventive
      procedures and the research on rational vaccines.

PMID- 12476490
TI  - Malaria vaccines: from the laboratory to the field.
AB  - The demonstration of the i) acquired protective immunity in adults living in
      endemic areas, ii) cure of malaria patients with passive transfer of specific
      immunoglobulins, and iii) protection conferred by vaccination with sporozoites
      attenuated by radiation, justifies the search for a malaria vaccine. Given the
      improbability that a vaccine directed against a single antigen will be completely
      protective, the preferred option is to combine several antigens of different
      stages of the parasite in a multi-component multi-stage vaccine which is likely
      to protect both the travellers and the populations living in endemic areas.
      Potential manufacturing technologies include recombinant proteins, synthetic
      peptides and DNA vaccines, the relevant genes encoding malaria antigens being
      inserted into a plasmid or a live vector such as vaccinia or poxvirus. A number
      of human trials using different antigens and technologies have been carried out
      in the last ten years. Three vaccines have undergone safety and efficacy testing
      in the field. SPf66, comprising a linear polymerised synthetic peptide with
      several distinct epitopes, has been extensively evaluated in different
      epidemiological settings. The efficacy overall was 23%, but was only 2% in
      African infants, the most susceptible group. The circumsporozoite recombinant
      protein fused with the antigen S of the hepatitis B virus and formulated in a
      potent adjuvant (RTS,S) led to a high, but short-term, level of protection
      against infection and disease in Gambian adults. The first pure asexual blood
      stage vaccine comprising three antigens of the merozoite stage (MSP1&2 and RESA,
      Combination B) had an efficacy of 62% in reducing parasite density in Papua New
      Guinean children. A malaria vaccine that can reduce the burden of disease in the
      most affected populations is thus an achievable goal, and each trial provides
      additional knowledge about mechanisms of protection as well as about new vaccine
      technology.

PMID- 12476491
TI  - The immune response to the parasitic nematode Trichinella and the ways to escape
      it. From experimental studies to implications for human infection.
AB  - The review describes different aspects of the host immune response to
      Trichinella, not only at the intestinal level on which most of the studies have
      focused until now, but also in the muscles which represent the final target of
      host invasion. The role of antibodies, T cells, mast cells, eosinophils and
      neutrophils, respectively, in immune reaction to this nematode is considered, in
      the light of the recent data derived from experimental models, both "in vivo" and
      more recently "in vitro" and when available, from clinical observations. A
      section is also devoted to the principal escape mechanisms from host immune
      responses, described in Trichinella, which are in part common to other parasites,
      in part peculiar. Two groups of mechanisms are described: antigen-dependent, such
      as anatomic seclusion, antigen stage-specificity, shedding and renewal and
      molecular mimicry, and those directly affecting the host immune response. Of the
      latter, some act at central level like immune suppression, polyclonal activation
      and eosinophilia induction, others interfere with effector functions as in the
      case of host leukocyte modification, immune complex accumulation, blocking
      antibody production or complement assembly blocking. The antigenic composition of
      the different stages is the subject of another section which has the aim to give
      an overview of the principal antigens described up to now, without giving too
      many biochemical details, but just illustrating the candidates for possible
      vaccines. Finally, the perspectives for vaccination are described. Most of the
      results described are derived from the experimental studies, but their
      implications in human infection are relevant.

PMID- 12476492
TI  - Prospects for a schistosome vaccine.
AB  - After some 20 years experience it is generally agreed that chemotherapy against
      schistosomiasis, a parasitic disease which should be considered a consequence of
      a chronic infection, does have significant limitations. In particular,
      chemotherapy does not affect transmission of the infection or the high re
      infection rates and so limits the success by demanding frequently re-scheduled
      mass treatments. For this reason, a complementary approach that can be integrated
      and could sustain chemotherapy-based control programs, i.e. vaccination, is very
      much needed. The rationale is that drug treatment would provide short-term
      reduction of worm burdens and vaccination, long-term protective immune response.
      Vaccination can either be targeted towards the prevention of infection or to the
      reduction of parasite fecundity. A reduction in worm numbers is the "gold
      standard" for anti-schistosome vaccine development but, as schistosome eggs are
      responsible for both pathology and transmission, a vaccine targeted on parasite
      fecundity and egg viability also appears to be entirely relevant. This review
      considers various aspects of anti-schistosome protective immunity that are
      important in the context of vaccine development. The current status in the
      development of vaccines against the African (Schistosoma mansoni and S.
      haematobium) and Asian (S. japonicum) schistosomes is then discussed as the new
      approaches that may improve on the efficacy of the available vaccines and aid in
      the identification of new targets for immune attack.

PMID- 12476493
TI  - Humoral and cellular immunity against Cryptosporidium infection.
AB  - Protozoans of the genus Cryptosporidium are the etiological agents of
      opportunistic infections mainly of the gastrointestinal tract of animals and
      humans. Young and elderly persons, those with concomitant infections, with AIDS,
      under an immunosuppressive therapy, with congenital T-cell, B-cell or other
      effector cell deficiencies develop persistent progressive infections of different
      degree of severity related to the level of immunodepression. Both humoral and
      cellular immunity play a role in the control of this infection, but the latter
      plays the major role, mainly in the intestinal mucosa. However, a natural
      resistance to these coccidian parasites is also involved. IgG, IgM and IgA have
      been detected in serum and mucosa of humans and animals with the resolution of
      the infection; but also high levels of these immunoglobulins have been detected
      in persons with AIDS with chronic cryptosporidiosis. In HIV-positive persons,
      CD4+ T-cells are required to prevent the establishment of the infection and IFN
      gamma and CD4+ T-cells can also limit the duration and the clinical
      manifestations of the infection. In persons exposed to cryptosporidial
      infections, it has been possible to show the important role of IFN-gamma in both
      the innate and acquired cell mediated immunity. The severity of cryptosporidiosis
      has been also associated with the inability to produce IFN-gamma. An antibody
      therapy using bovine colostrum from cows hyperimmunised with Cryptosporidium
      oocysts or monoclonal antibodies against sporozoite antigens has been developed
      at the experimental level mainly for persons with AIDS or with other
      immunodeficiencies; however, these preparations of antibodies have shown only a
      limited degree of efficacy both in animals and humans.

PMID- 12476494
TI  - Functional appliance treatment assessed using the PAR index.
AB  - The aims of this study were, first, to determine in children with Class II,
      division 1 malocclusions treated with functional appliances if, according to the
      Peer Assessment Rating (PAR) Index, lower incisor proclination affects the
      assessment of treatment outcome; and, second, to evaluate the effectiveness of
      such treatment before and after adjustment for any lower incisor proclination.
      Fifty-one children (32M, 19F; age and gender matched; 10 to 13 years) were
      randomly assigned to either an untreated group, one treated with Frankel function
      regulators or one treated with Harvold activators. Study casts were assessed at
      the start, and after 6, 12, and 18 months of treatment/observation. The
      inclination of the upper and lower incisors was measured on lateral cephalometric
      radiographs taken at the start and 18 months later. There was wide variation in
      treatment response. The PAR scores decreased by more than 30% in 33% of the
      Frankel group and by 75% in the Harvold group. When the score was adjusted to
      remove the effects of lower incisor proclination on the overjet, the treatment
      outcomes were "worse/no different" in 66% and "improved" in 33%, in both groups.
      It was concluded that functional appliances be used only on selected cases.

PMID- 12476495
TI  - Vertical facial pattern and orthodontic stability. Part I: Pretreatment vertical
      pattern and stability.
AB  - The occlusions of sixty patients treated by one experienced orthodontist were
      assessed using the PAR Index. For each patient, pretreatment, post-treatment and
      long-term follow-up study casts were examined. Follow-up casts were taken at
      least 6.5 years following the removal of all retention appliances. Following
      pretreatment cephalometric analysis, the patient sample was divided into three
      vertical facial subgroups according to the Jarabak Facial Height Quotient. Mean
      weighted PAR scores were then calculated at each stage for the total sample and
      for the three subgroups. Mean absolute and percentage occlusal changes were also
      calculated for the post-treatment period. The relationship between post-treatment
      occlusal change and pretreatment vertical facial pattern was then studied. The
      mean weighted pretreatment, post-treatment and follow-up PAR scores were 27.3,
      3.3 and 8.0, respectively. The mean-absolute and percentage post-treatment
      increases in weighted PAR score were 4.7 and 25.4, respectively. No statistically
      significant relationship could be found between the pretreatment vertical facial
      pattern and changes occurring in the weighted PAR score during the follow-up
      period. It was concluded, therefore, that pretreatment vertical facial pattern,
      at least on its own, is not likely to be predictive of the amount of post
      treatment occlusal change.

PMID- 12476497
TI  - Elsdon Storey 1924-88.

PMID- 12476496
TI  - Vertical facial pattern and orthodontic stability. Part II: Facial axis changes
      and stability.
AB  - Lateral cephalograms and study casts of 55 patients were evaluated to determine
      if any relationships exist between Facial Axis changes occurring during and after
      active treatment and either the pretreatment Jarabak Facial Height Quotient or
      the amount of post-treatment occlusal change, as measured with a weighted PAR
      score. No significant relationships could be found. There was instead a wide
      range of individual variation in the post-treatment behaviour of both the Facial
      Axis and the weighted PAR score, in both the total sample and three Jarabak
      Facial Height subgroups. Long-term Facial Axis changes occurring in individual
      patients, however, were not necessarily associated with occlusal deterioration.
      Since the Facial Axis is likely to change to some extent in the long-term, it was
      suggested that widely recommended methods for Facial Axis control during
      treatment should be considered primarily for functional and aesthetic reasons,
      rather than on the basis of directly ensuring long-term occlusal stability.

PMID- 12476498
TI  - Age changes in orthodontic treatment need: a longitudinal study of 10- and 13
      year-old children, using the Dental Aesthetic Index.
AB  - The Dental Aesthetic Index (DAI) was used to assess the prevalence of unmet
      orthodontic treatment need in 150 13-year-old schoolchildren in Dunedin, New
      Zealand, and to compare the findings with those obtained in the same children at
      10 years of age. Fewer 13-year-olds (27%) had a "mandatory" need of orthodontic
      treatment than when they were 10 years old (33%), 20% had "no/little" need for
      orthodontic treatment, 33% had an "elective" need for treatment and 20% had a
      "desirable" need for treatment. The fall in DAI scores is attributed to over
      sensitivity of the Index to mixed dentition traits. When the individual scores
      were analysed, only 7% of the 10-year-olds were given the same scores as when
      they were 13 years old, 52% were given higher scores and 41% were given lower
      scores. This disagreement between scores was masked to a limited extent by the
      DAI categories: 49% of the 10-year-olds were assigned to the same DAI category at
      13 years of age, 20% to a greater treatment-need category and approximately 30%
      to a lower treatment-need category. The DAI, in common with other malocclusion
      indices, is unreliable over time because it is affected by developmental changes
      in the occlusal traits measured.

PMID- 12476499
TI  - The effect of long-term mandibular advancement on the hyoid bone and pharynx as
      it relates to the treatment of obstructive sleep apnoea.
AB  - A cephalometric analysis was carried out to determine the effects of long-term
      mandibular advancement on the hard and soft tissues of the upper airway and, in
      particular, the relationship of the hyoid bone to both the cranium and the
      cervical spine, following mandibular advancement. One hundred consecutively
      treated patients (87 males and 13 females; mean age: 49.26 years; SD: 8.56;
      range: 33-74 years) diagnosed with obstructive sleep apnoea and/or habitual
      snoring were reviewed at 6-month intervals over 6 to 30 months of treatment with
      a mandibular advancement splint. Significant changes to both the oropharynx and
      velopharynx were observed. At 12 months, the posterior airway space had increased
      from 10.71 mm to 11.99 mm (mean difference: 1.28 mm). At 6 months, significant
      changes had occurred in the soft palate length and thickness: a mean reduction in
      length of 1.46 mm (p < 0.0001) and in thickness of 0.57 mm. No changes were
      observed in the hypopharynx: the position of the hyoid bone remained unchanged in
      relation to both the cranium and cervical spine in all linear and angular
      measurements. The author concludes that mandibular advancement with oral
      appliances should be considered as a treatment for life.

PMID- 12476500
TI  - Non-extraction tip-edge appliance management of a moderate Angle Class II
      division 1 malocclusion commenced in the late mixed dentition.
AB  - This case presentation concerns the correction of a moderate Angle Class II
      division 1 malocclusion of a patient whose treatment began during the late mixed
      dentition. Owing to the need to preserve and improve the existing facial
      aesthetics, treatment was started with a non-extraction approach and, in order to
      exploit favourable dentofacial growth changes and to avoid the possibility of
      extraction of teeth, was timed to coincide with the patient's expected adolescent
      growth spurt. Fixed appliances only were used. Special consideration had to be
      made for the patient's fractured upper central incisor teeth. An aesthetically
      pleasing treatment outcome was achieved within the expected time frame for
      correction. The case shows the successful combination of typical Begg
      mechanotherapy used during the early stages of treatment and Tip-Edge rectangular
      archwire mechanotherapy as used for the later and finishing stages.

PMID- 12476501
TI  - The impact of bioengineering on tissue viability research.

PMID- 12476502
TI  - The measurement of interface pressure and its role in soft tissue breakdown.
AB  - This paper describes the effect of applied pressure on soft tissue and its
      possible role in the development of pressure ulcers. It concentrates on the
      quantification of the applied pressure at the patient-support interface and the
      limitations and variability of current techniques, measurement systems and data
      presentation. It then describes the effects of interface pressures at the tissue
      and cellular level, and attempts that have been made to describe and model the
      tissue mechanics. Finally it sets a challenge to medical engineers to improve the
      present measurement systems and tissue models, thus increasing understanding,
      both clinically and at the cellular level, so that the incidence of pressure
      ulcers can be reduced.

PMID- 12476503
TI  - Reliability and validity of a multi-pad pressure evaluator for pressure ulcer
      management.
AB  - It is often helpful to assess the pressures exerted upon the bony prominences
      when monitoring the likely outcome of pressure ulcer prevention or treatment.
      However, in the clinical setting, hard pressure sensors may damage the skin and
      operational difficulties may influence their reliability and validity. The
      authors have developed a multi-pad pressure sensor and tested its clinical
      reliability and validity. The inter-rater and intra-rater reliability were
      calculated using the coefficient of variation data from 10 patients. After a
      comparison analysis, the multi-pad was more reliable than a single-pad type
      pressure sensor. A validation test was conducted in 79 elderly patients. The mean
      interface pressures recorded among patients who had erythema or stage I pressure
      ulcers at the sacrum were significantly higher than were the contact pressures
      measured in patients with no pressure damage. The pressure sensor exhibited
      satisfactory clinical reliability and validity. Furthermore, it may be that for
      Japanese elderly patients the maximum pressure that can be tolerated by the
      tissues around the sacrum may be 40-50 mmHg.

PMID- 12476504
TI  - Venous leg ulcer pain and its characteristics.
AB  - This study investigated the prevalence, severity and characteristics of pain
      associated with venous leg ulceration. Sixty-five patients suffering with venous
      leg ulceration were randomised to one of three treatment groups over a 12-week
      treatment period. All patients received short-stretch compression bandaging. Data
      were collected by use of a visual analogue scale and the McGill Pain
      Questionnaire. Seventy per cent of patients reported pain on entry to the study
      and within 2 weeks of effective treatment initial pain was dramatically reduced.
      Patients typically described their pain as throbbing, sharp, itchy, sore and
      tender. The affective nature of pain was often described as tiring and patients
      evaluated their pain as being annoying and nagging. This study highlights the
      importance of pain associated with venous leg ulceration.

PMID- 12476505
TI  - A call to our arms.

PMID- 12476506
TI  - How we die in America--our crisis in American health caring.

PMID- 12476507
TI  - How can we improve care at the end of life in Connecticut? Recommendations from
      focus groups.
AB  - A qualitative study to elicit views among residents of Connecticut about death,
      dying, preferences for care, and gaps in available care was conducted for the
      Connecticut Coalition to Improve End-of-Life Care. Twenty-eight focus groups were
      convened across the state between May 1999 and March 2001. The focus groups
      included adolescents and adults from diverse religious, ethnic, and professional
      backgrounds. A total of 196 individuals participated in the 90-minute sessions.
      Trained moderators conducted the discussion groups following a guide.
      Transcriptions of the groups were coded to identify themes. Thirty-two
      recommendations to improve care based on the focus group discussions are
      presented. These are grouped under the following actions: 1) enhance public
      education; 2) offer better professional provider education and support; and 3)
      augment services. The recommendations are illustrated with quotations from the
      focus groups.

PMID- 12476508
TI  - Dying in Connecticut--the facts.

PMID- 12476509
TI  - Best practices in hospital end-of-life care.
AB  - The Connecticut Best Practices in End-of-Life Care project was initiated in
      response to the concern that Connecticut hospitals were not meeting the needs of
      dying patients. The records of 420 patients with a diagnosis of cancer or with an
      admission to an intensive-care unit were reviewed for the period 04/01/2000 to
      03/31/2001. Utilizing a chart extraction tool, measures of "best practice" were
      developed as a means of assessing the quality of end-of-life care provided to the
      patient cohort. Some of the findings on the "best practice" indicators were as
      follows: 65 (15.3%) of the patient cohort died during their hospital stay. Three
      hundred forty (81.3%) had a pain assessment on admission. Three hundred eighty
      six (92.6%) had a pain assessment on at least one occasion during their hospital
      stay. Two hundred forty-two of 397 (61%) patients who received an analgesic
      medication had their pain reassessed within fours hours of receiving the
      medication. One hundred ninty-five (46.4%) patients had their prognosis discussed
      with them. Eighteen patients (< 5%) were referred to hospice. Connecticut
      hospitals are doing well in assessing patient pain. However, they are doing
      poorly in discussing prognosis with sick patients and referring them to hospice.

PMID- 12476510
TI  - Should we focus more on the individual? A discussion of current advance-care
      planning law in Connecticut.

PMID- 12476511
TI  - Management of cancer-related and noncancer-related chronic pain in Connecticut:
      successes and failures.
AB  - Findings are reported from a survey of Connecticut HMO patients who had one of
      three conditions associated with pain: cancer, arthritis, and neuropathic
      diagnoses. From each group, 145 patients were randomly selected to receive a
      mailed survey. The overall eligible response rate was 73%. About two thirds had
      experienced pain for over a year, and the same percentage was experiencing pain
      at the time of the survey. Seventy-three percent of respondents with cancer pain
      (RCs) rated their pain in the moderate range, compared to 37.5% of respondents
      with arthritis pain (RAs) and neuropathic pain (RNPs). More RAs and RNPs (41.5%)
      rated their pain in the severe range. Twenty-three percent of both RCs and RAs
      and 31% of RNPs had received no effective treatment for their pain. The
      percentage of respondents using prescription narcotics at the time of the survey
      was low (16%), and had dropped by almost half from the proportion using them in
      the past (29%). Side effects of pain medications and attitudes toward opioids
      were implicated as reasons for discontinuing pain medications. Respondents
      described substantial negative impact of pain on their abilities to perform
      various activities, but this had improved from the time when they first
      experienced their pain. Overall, the findings indicate that improvements have
      been made in the treatment of pain, particularly for patients with cancer pain.
      There is still room for improvement, particularly for individuals with chronic
      neuropathic pain. Specific recommendations are discussed.

PMID- 12476512
TI  - Perspectives on preparedness for a death among bereaved persons.
AB  - OBJECTIVE: To present opinions of recently bereaved persons regarding how they
      could have been made to feel more prepared for the death of a loved one. METHODS:
      Cross-sectional descriptive study that uses information from a longitudinal
      study. A face-to-face interview was administered to 122 recently bereaved persons
      and participants were asked to provide opinions and to describe whether health
      professionals, family/friends, or themselves could have helped them to feel more
      prepared for the death. RESULTS: Of the total sample of 122, 31 (25%) reported
      that doctors or health professionals could have done something more to help make
      them feel better prepared for the death of their loved-one. Six subjects (4.9%)
      indicated family/friends, and 16 (13.1%) stated that they themselves could have
      done something more to help prepare for the death of their loved-one. Common
      themes were: the physicians' lack of communication regarding the prognosis and
      imminence of death, family survivors' concerns about the medical care provided,
      regrets engendered by their own denial of the patient's imminent death, not
      managing the illness in a manner consistent with the patient's impending death,
      and lost opportunities for closure in family matters, both financial and
      interpersonal. DISCUSSION: Findings from this study can be used to enhance
      understanding of bereaved persons' views about health professionals' current
      practices for bereaved individuals, as well as the role of the family and the
      bereaved persons themselves in potentially effecting preparedness for the death
      of a loved one.

PMID- 12476514
TI  - The pendulum's swing.

PMID- 12476513
TI  - Physician-assisted suicide and palliative care: beliefs and empiricism in the
      policy debate.
AB  - This article provides a brief overview of recent research on the practice of
      physician-assisted suicide (PAS) in Connecticut. In addition, the article
      examines recent empirical evidence about the role of depression in patients' end
      of-life decisions, and synthesizes relevant literature on the relationship
      between PAS and palliative care in the context of recent experience in Oregon.

PMID- 12476515
TI  - Physiology of female micturition.
AB  - Micturition is a dynamic physiologic process consisting of alternating storage
      and expulsion phases and is accomplished by complex interactions among
      innervation, smooth muscle, connective tissue, urothelium and supportive
      structures. Although our current understanding of the anatomy and physiology of
      the lower urinary tract is far from complete, intensive research over the last
      decade has dramatically improved our appreciation of the neural, biomechanical,
      biochemical, and morphologic properties of the bladder and urethra, as well as
      the hormonal influences and unique pelvic and perineal anatomy of women.
      Continued research related to the physiology of female micturition promises to
      offer new insights into the complex bladder-urethral interactions and to provide
      a basis for developing better management strategies for a variety of voiding
      dysfunctions in women.

PMID- 12476516
TI  - Evaluating incontinence in women.
AB  - Urinary incontinence in women has a multitude of presentations and can be a pure
      and simple entity or a complicated combination of overlying disorders. The
      diagnosis and work-up of the incontinent woman should proceed from the classic
      tools of medical treatment, as well as the history and physical exam, and should
      incorporate modern techniques of dynamic imaging. It is vital to remember that it
      is often not until a simple treatment has failed that we appreciate a patient's
      complex problem, and, for this reason, we advocate appropriate use of the
      available technologies in order to separate more carefully the straightforward
      disorder from the intricate and convoluted problems. A thorough investigation of
      the multiple dimensions of urinary incontinence in the female patient, using
      subjective and objective testing, is the key to diagnostic and clinical success.

PMID- 12476517
TI  - Genuine stress incontinence theories of etiology and surgical correction.
AB  - Urinary loss (flow) results from a relative lack of CM resistance with respect to
      the intravesical pressure. Surgical stabilization of the continence mechanism, at
      the level of the bladder neck or mid-urethra, compensates for the existing loss
      of urethral support and function by creating new zones for compression,
      absorption of transmitted pressure, and the preservation of sphincteric
      configuration. Our understanding of the pathophysiology of stress incontinence
      and the basis for surgical compensation continues to evolve. Mid-urethral complex
      support procedures have stimulated further investigation into the mechanics of
      continence.

PMID- 12476518
TI  - Pharmacologic management of urinary incontinence in women.
AB  - This article summarizes current thought regarding the efficacy of various types
      of drug therapy for incontinence in women, borrowing liberally from similar
      previous presentations. Space limitations for this chapter necessitate some
      simplification and condensation of these subjects. References have generally been
      chosen because of their informational or review content and not because of
      originality or initial publication on a particular subject.

PMID- 12476519
TI  - Biofeedback and behavioral therapy for the management of female urinary
      incontinence.
AB  - Biofeedback is useful for teaching PFM exercises, for motivation, and for
      compliance. The advantages of behavioral treatments are that they are safe,
      effective, and low risk with no documented side effects. They can be used for
      patients with stress, urge, or mixed urinary incontinence. Behavioral therapy has
      been criticized because complete cure is uncommon. However, many patients are
      satisfied with an improvement. Behavioral therapy is also useful as an adjunct to
      other therapies, such as surgery or pharmacologic treatment.

PMID- 12476520
TI  - Beyond collagen: injectable therapies for the treatment of female stress urinary
      incontinence in the new millennium.
AB  - Previous experience with GAX-collagen has shown that the endoscopic correction of
      female SUI is both possible and effective. It is clear, however, that durability
      remains a primary concern when implementing this approach to treatment. The
      availability of recently developed and newly emerging materials, carefully
      designed using the tenets and techniques of biotechnology and materials science,
      may provide solutions to some of the difficulties beleaguering this treatment
      option. Results with currently available injectables are summarized in Table 1.
      Careful review and critical analysis of new bulking agents will soon reveal which
      materials approach the therapeutic ideal. It is likely that the ultimate choice
      of a particular substance, synthetic or biologic, may best be determined by the
      clinical circumstances involving the individual patient.

PMID- 12476521
TI  - Needle suspension procedures for female incontinence.
AB  - In the past, needle suspensions were considered a viable option to treat female
      stress urinary incontinence. There have been many modifications since the first
      needle suspension over 40 years ago. Despite these modifications, the long-term
      outcome data does not support the efficacy of needle suspension procedures, with
      only a 67% cure/dry rate at > 48 months. The long-term results are much more
      efficacious with the sling procedure (83%), as well as with retropubic
      suspensions (84%). Needle suspensions have historical significance, but because
      of the poor long-term results, they currently have a limited role in the
      management of stress urinary incontinence.

PMID- 12476522
TI  - Retropubic surgery for stress urinary incontinence.
AB  - More than 150 surgical techniques have been proposed in the literature for
      treating stress urinary incontinence. Many of the original published approaches
      were vaginal, but through the years the literature has expanded to include needle
      suspension, pubovaginal slings, and retropubic procedures. In this chapter, we
      focus on retropubic approaches for the treatment of SUI and discuss the
      physiology, indications, technical details and the complications of these
      procedures.

PMID- 12476523
TI  - Autologous and synthetic urethral slings for female incontinence.
AB  - Over the past decade, urethral slings have emerged as the procedure of choice for
      the surgical correction of most types of female urinary stress incontinence. A
      variety of materials, autologous, alloplastic, and synthetic, have been used
      successfully as urethral slings. In the next decade, it is hoped that a better
      understanding of the factors that influence surgical success will translate into
      continued refinement of surgical technique.

PMID- 12476524
TI  - Female prostatitis.
AB  - Female prostatitis is described as a frequent cause of the urethral syndrome.
      Appropriate localization of tenderness to the paraurethral glands allows the
      diagnosis and treatment of female prostatitis as in its male counterpart. All
      urologists are urged to adopt the finger pressure (Fig. 3) maneuver in the pelvic
      examinations of their female patients.

PMID- 12476525
TI  - Contemporary evaluation and management of the female urethral diverticulum.
AB  - We are in agreement with Davis and Telinde, who state, "The most important single
      diagnostic instrument for the discovery of suburethral diverticula is the high
      index of suspicion" [25]. The key to successful treatment of a female
      diverticulum is not only in the surgical management but also in the
      identification and evaluation of patients who present with a myriad of symptoms.
      It is our responsibility to include urethral diverticula in the differential
      diagnoses before the labels of interstitial cystitis, urethral syndrome, or
      urgency frequency syndrome are misplaced. The diagnosis may be elusive and the
      pathology difficult to identify on physical examination. However, if the index of
      suspicion is high and the proper radiologic imaging studies are gathered, then
      the correct diagnosis will often be made. The evaluation of the female urethral
      diverticulum has evolved greatly over the past several years. However, once
      appropriate diagnosis is made, the management scheme is fairly straightforward.
      Strict adherence to principles of surgical reconstruction allows one to eradicate
      the diverticulum while simultaneously preventing complications and recurrences.

PMID- 12476526
TI  - Endometriosis of the urinary tract.
AB  - Genitourinary endometriosis is a rare manifestation of a common disease. Ectopic
      endometrial tissue may extrinsically involve or intrinsically invade the bladder
      or ureter, and, less commonly, the urethra or kidney. Bladder involvement usually
      presents with irritative symptoms, whereas ureteral disease may present with
      asymptomatic renal failure. Therefore, a high index of suspicion is necessary,
      and genitourinary endometriosis should be considered in all symptomatic women
      with a history of cesarean delivery of other gynecologic surgery. In women beyond
      reproductive age, definitive surgical treatment is preferred, with removal of the
      ectopic tissue, relief of obstruction, and castration with or without
      hysterectomy. In those who desire future fertility, conservative surgery and/or
      hormonal therapy is often recommended.

PMID- 12476527
TI  - Diagnosis and management of chronic pelvic pain.
AB  - Chronic pelvic pain is difficult to diagnose and to treat [81] because of the
      multiple and often overlapping causes [82]. A systematic approach aids in the
      thorough evaluation and appropriate therapy. At the initial visit(s), a thorough
      history should be taken and complete physical examination performed. Screening
      for co-existing conditions, such as depression, narcotic dependency, and
      physical, sexual, or emotional abuse is crucial so these issues may be addressed
      immediately while additional causes for pelvic pain are evaluated. The relative
      likelihood of gastrointestinal, urologic, musculoskeletal, or gynecologic
      etiology must be considered to guide a more thorough initial evaluation. With
      gynecologic chronic pelvic pain, differentiation between hormonally responsive
      and nonresponsive conditions is helpful for diagnosis and treatment. Therapy can
      then be instituted or an appropriate referral made.

PMID- 12476528
TI  - Current management of interstitial cystitis.
AB  - The management of patients with IC remains a challenge because no single agent
      has proven universally effective. DMSO and PPS have been evaluated through early
      placebo-controlled trials, and these two agents are FDA approved treatments for
      IC. BCG is currently undergoing a large placebo-controlled trial, and hyaluronic
      acid is receiving similar clinical evaluation. Sacral nerve root stimulation
      shows promise with early favorable results. As with any treatment algorithm, it
      is reasonable to begin with conservative treatment using time-dependent
      milestones, allowing adequate trials of successive therapy while ensuring an
      appropriate pace for timely symptom resolution.

PMID- 12476529
TI  - Urinary incontinence in girls.
AB  - Girls with incontinence may have minor irritative conditions or undiagnosed
      anatomic abnormalities that may require surgery. These abnormalities can be
      identified during a comprehensive history and physical examination that focuses
      on voiding signs and symptoms. Urinary tract infection and constipation if
      present should be identified. Most girls with daytime wetting will respond to
      conservative therapy using timed voiding, dietary changes, and anticholinergic
      medication. Uroflowmetry with a postvoid residual urine measurement can identify
      girls who may benefit from biofeedback to treat pelvic floor dysfunction. Formal
      urodynamics and spinal magnetic resonance imaging should be done in girls
      refractory to treatment. Instruments and tools to quantify dysfunctional voiding
      symptoms are being developed. Because most dysfunctional voiding will be treated
      clinically, these validated tools will be useful in documenting severity of
      symptoms and clinical outcomes.

PMID- 12476530
TI  - Impact of pelvic floor disorders and prolapse on female sexual function and
      response.
AB  - Pelvic floor disorders and FSD are prevalent and challenging problems. These
      disorders include prolapse of the uterus, cervix, vagina, bladder, and rectum and
      incontinence. These diseases likely affect women's sexual well-being through
      physical and emotional effects. Women with pelvic floor disorders often have co
      existing urologic and sexual complaints. Patients who present with these urologic
      problems should be questioned about their sexual function. Surgical treatment in
      these patients may be curative of their sexual disorders (e.g., by repairing
      incontinence) but may also have undesired effects on sensation, blood flow, and
      the anatomy. These effects can affect sexual arousal and orgasm or cause
      dyspareunia. It is hoped that a better understanding of the anatomy of this area
      will guide us in a more targeted approach to management of these conditions.

PMID- 12476531
TI  - Biology of female sexual function.
AB  - Although the psychosocial and relationship aspects of female sexuality have been
      extensively investigated, studies concerning the anatomy, physiology and
      pathophysiology of female sexual function and dysfunction are limited. The
      paucity of biologic data may be attributed to a lack of reliable experimental
      models and tools for investigating female sexual function and to limited funding,
      which is critical for developing experimental approaches. Research efforts by
      several investigators in different laboratories have been establishing
      experimental models needed for investigating the physiologic mechanisms involved
      in the genital arousal response of sexual function. These experimental models
      have permitted assessment of genital hemodynamics, vaginal lubrication,
      regulation of genital smooth muscle contractility and signaling pathways,
      providing preliminary information about the role of neurotransmitters and sex
      steroid hormones in sexual function. Further research is needed to define the
      neurotransmitters responsible for vaginal smooth muscle relaxation and the role
      of sex steroid hormones and their receptors in modulating genital hemodynamics,
      smooth muscle contractility, and neurotransmitter receptor expression. Finally, a
      global and integral understanding of the biologic aspects of female sexual
      function requires investigation of the vascular, neurologic (central and
      peripheral), and structural components of this extremely complex physiologic
      process.

PMID- 12476532
TI  - Urinary tract infections cranberry juice, underwear, and probiotics in the 21st
      century.
AB  - There is a substantial gap between the viewpoint of urologists and the rest of
      society regarding UTIs. Urologists spend little time and effort thinking about
      UTIs. In contrast, UTIs are a major issue for many women. There is substantial
      concern about "natural compounds" and probiotics that allow women to take charge
      of their health care. It is easy to understand this concern because UTIs are
      common, costly, and cause considerable morbidity.

PMID- 12476533
TI  - The current management of urolithiasis during pregnancy.
AB  - The management of urolithiasis in pregnancy can present complex challenges to the
      urologist. However, if the principles discussed above are followed, these
      difficult clinical problems can be approached in a rational manner.

PMID- 12476534
TI  - The urologist in the delivery room.
AB  - Urologic injuries can and will occur during obstetric procedures. In my
      experience, a urologist should follow nine rules to ensure a successful outcome
      for the patient and a successful relationship with the obstetrician. These rules
      are outlined in Table 2.

PMID- 12476535
TI  - Surgical repair of vesicovaginal fistulas.
AB  - Despite the many controversies surrounding the proper surgical repair of
      vesicovaginal fistulas, the current methods available allow surgeons to select
      the procedure best suited for each specific problem. Because each fistula is
      unique, surgeons will often be required to individually vary their approach and
      technique. Regardless of whether a transabdominal or transvaginal approach is
      selected, the concepts of using healthy tissue in tension-free closures and
      reinforcing the closures in high-risk situations will ensure success nearly all
      of the time. A urinary diversion should be considered in the rare situation where
      the fistula has failed even the most technically sound repair.

PMID- 12476536
TI  - Indications and technique of the orthotopic neobladder in women.
AB  - Radical cystectomy remains the primary form of therapy for high-grade, invasive
      bladder cancer. Orthotopic substitution has become the ideal form of urinary
      diversion in appropriately selected women. Good functional results have been seen
      with intermediate follow-up in these women. Proper patient selection and surgical
      technique are critical to optimize the outcome in this group of patients.

PMID- 12476537
TI  - Early intervention for asthma prevention in children.
AB  - The last few decades have seen a global rise in asthma prevalence. In the United
      States, based on the National Health Interview Survey sample in 1998, the
      National Center for Health Statistics determined that asthma was the most
      commonly diagnosed chronic disease of childhood, with 12.1% or 8.65 million U.S.
      children reported as being diagnosed with asthma in their lifetime. As a result,
      asthma pathogenesis has received much attention, with the hope of reversing this
      concerning global trend by developing new approaches to asthma prevention.
      Current evidence suggests that most childhood asthma begins in the early years.
      In addition, early pathogenic development of the immune systems and lungs of
      children with asthma suggests that the early years may be the best time for
      preventive intervention. To consider intervention for asthma in early childhood
      (i.e., in the first 6 years of life), we will discuss (1) childhood risk factors
      for chronic persistent asthma, (2) early pathogenic changes in asthma, (3)
      potential pharmacologic and nonpharmacologic interventions for the young
      asthmaprone child, and (4) potential future immune modulatory therapies and
      prevention.

PMID- 12476538
TI  - Risk factors for asthma admissions in children.
AB  - Bronchial asthma is related to a high morbidity rate, leading to an increasing
      frequency of emergency room visits and hospital admissions. The aim of this study
      was to identify severity risk factors for childhood asthma related to
      hospitalization. The authors studied 124 children admitted to the hospital for
      asthma, during a 2-year period, correlating the obtained data with a sample of
      outpatients with asthma matched by age, gender, and socioeconomic status. A
      standardized questionnaire and skin-prick tests (SPTs) were performed on all
      children. The significant and independent risk factors identified for hospital
      admission were prior asthma hospitalization (OR = 7.63; 95% CI = 1.5-39.6; p =
      0.01) and last-year admission (OR = 3.18; 95% CI = 1.1-8.9; p = 0.02),
      environmental tobacco-smoke exposure (OR = 6.63; 95% CI = 2.5-17.8; p = 0.002),
      allergen sensitization (OR = 3.86; 95% CI = 1.4-10.7; p = 0.009), family history
      of maternal asthma (OR = 3.58; 95% CI = 1.3-9.6; p = 0.01), and onset of symptoms
      before 12 months of age (OR = 2.76; 95% CI = 1.0-7.9; p = 0.06). Attendance at
      day care or kindergarten (OR = 0.38; 95% CI = 0.2-0.9; p = 0.04) and large family
      size (OR = 0.25; 95% CI = 0.1-0.8; p = 0.01) could be protective factors. Our
      results stress the importance of early diagnosis and specialized medical care of
      childhood asthma, mainly in high-risk children, with emphasis on medication
      planning and the establishment of preventive measures such as environmental
      tobacco smoke avoidance and limitation of aeroallergen exposure.

PMID- 12476539
TI  - On the association between date of birth and pollen sensitization: is age an
      effect modifier?
AB  - An association between date of birth and development of allergy has been proposed
      by prior research. Yet, the presence of a dose-response relationship or any
      potential effect modification for this association has not been widely studied.
      The aims of our study were to investigate whether an association between birth
      during pollen season and symptomatic sensitization to pollens exists, whether
      this association is stronger for patients with high rather than low allergic
      reactivity to pollens, and whether this association is modified by the age of the
      patients. Among 3318 asthmatic and/or rhinitic outpatients, we selected 805
      patients sensitized exclusively to pollens (78 with low reactivity [LR] and 727
      with high reactivity [HR]) and 629 patients with negative skin-prick tests (SPT)
      (control group). The association between being born during pollen season
      (February-July) and each of the pollen reactivity levels was assessed by
      estimating the odds ratios (OR). HR pollinosis patients were more likely than SPT
      negative patients of being born in February-July (OR 1.38, 95% Confidence
      Intervals (CI) 1.11-1.71). The likelihood of having been born in pollen season
      significantly increased across the levels of reactivity to pollens (HR > LR > SPT
      negative). These findings were valid only among patients with an early onset of
      symptoms. Although the OR for being born in pollen season was 1.91 (95% CI 1.32
      2.77) for HR pollinosis patients with onset of symptoms < or = 15 years, it was
      1.13 (95% CI 0.87-1.48) for those with later onset of symptoms (test of
      homogeneity: p = 0.026). Our results suggest that the exposure to allergenic
      pollens in the first months of life increases the risk of developing clinically
      relevant sensitization to them, particularly in the first 15 years of life.

PMID- 12476540
TI  - Multiple-dose proportionality study of flunisolide hydrofluoroalkane.
AB  - The hydrofluoroalkane (HFA) formulation of the inhaled corticosteroid flunisolide
      is a modification of the original chlorofluorocarbon formulation. HFA flunisolide
      substitutes an HFA for a chlorofluorocarbon propellant and uses a built-in spacer
      in its pressurized metered-dose inhaler. An open-label, randomized, three-way
      crossover, multiple-dose study evaluated the dose proportionality of three doses
      of flunisolide HFA. Twenty-one healthy volunteers received the following doses
      twice daily for 4.5 days: 85, 170, and 340 micrograms. Plasma levels of
      flunisolide and of the flunisolide metabolite 6 beta-OH flunisolide were measured
      after single- and multiple-dose administration. After a single dose, dose
      proportionality was observed across the three dose levels for peak plasma
      concentration (Cmax) and the area under the plasma concentration-time curve (AUC)
      up to both the time corresponding to the last measurable concentration (AUC0-tau)
      and the time to infinity (AUC0-infinity). After multiple doses, dose
      proportionality was observed for both Cmax and AUC at the medium and high doses.
      Predose plasma levels of flunisolide measured on day 4 were below the limit of
      detection. The elimination half-life of flunisolide ranged from 0.95 to 1.34
      hours. After both single and multiple doses, dose proportionality was observed in
      dose-adjusted Cmax and AUC0-infinity for the inactive 6 beta-OH metabolite. HFA
      flunisolide was well tolerated. The lack of accumulation after repeated
      administration of HFA flunisolide suggests that the systemic exposure of
      flunisolide is low, which is a safety goal for inhaled corticosteroids.

PMID- 12476541
TI  - Complement-related diseases.
AB  - This review article will consider some basic aspects of complement biology,
      address the clinical effects of hereditary complement deficiencies and the role
      of complement related to host cell entry, pathogenesis of infectious diseases,
      and apoptosis. The immunomodulation of autoimmune and inflammatory disorders
      related to complement components, the role of intravenous gamma-globulin and
      mechanisms of autoimmune urticaria and tolerance will be discussed briefly.

PMID- 12476542
TI  - Efficacy of once-daily desloratadine/pseudoephedrine for relief of nasal
      congestion.
AB  - The majority of patients with seasonal allergic rhinitis (SAR) suffer from nasal
      congestion. Desloratadine, a nonsedating H1-receptor antagonist, has given
      decongestant relief to patients with mild-to-moderate nasal congestion associated
      with SAR. The following study was undertaken to show that a once-daily
      formulation of desloratadine/pseudoephedrine would provide greater decongestant
      relief to patients experiencing moderate-to-severe nasal congestion compared with
      component monotherapy. A total of 1018 patients were assigned randomly to receive
      desloratadine/pseudoephedrine (5 mg/240 mg), desloratdine (5 mg), or
      pseudoephedrine (240 mg) daily for 15 days. Over the 15-day study period,
      patients receiving desloratadine/pseudoephedrine combination tablets had a
      significant reduction in mean A.M./P.M. reflective nasal congestion scores
      compared with patients receiving desloratadine or pseudoephedrine (p < 0.01);
      this reduction reached significance by day 2. Desloratadine/pseudoephedrine
      combination tablets also produced a greater reduction in A.M. instantaneous nasal
      congestion scores compared with component monotherapy (p < 0.01), indicating not
      only superior efficacy but also a full 24-hour effect. Desloratadine monotherapy
      reduced all mean nasal congestion scores to a similar degree as compared with
      pseudoephedrine monotherapy (p = NS). No unusual or unexpected adverse events
      were reported in any group. It was concluded that desloratadine/pseudoephedrine
      offers additional benefit to patients with moderate-to-severe SAR-associated
      nasal congestion compared with pseudoephedrine therapy alone.

PMID- 12476543
TI  - Interleukin-6 and mast cells.
AB  - Interleukin (IL) 6 is a pleiotropic cytokine (26 kDa) that originally was named
      interferon beta 2 or B cell-stimulating factor or differentiating B cell factor
      inducing immunoglobulin production. IL-6 is produced in many diseases. After
      secretion, IL-6 binds to its receptor IL-6R alpha (gp 80), the IL-6R alpha
      complex then recruits the signal-transducing beta-subunit (gp 130), which is the
      functional complex for signal transduction. In addition, activation of Th2 cells
      or mast cells also produce IL-6, which mediates immune responses, inflammation,
      acute phase responses, hematopoiesis, cancer, inflammatory bowel disease, etc. IL
      6 also is a crucial cytokine for mast cell maturation. Human cord blood CD34+
      cells differentiate and grow into mast cells in the presence of stem cell factor
      (SCF) and IL-6, causing increases in cell size, frequency of chymase positive
      cells, and intracellular histamine levels when compared with cells treated with
      SCF alone. Activated mast cells increase IL-6 mRNA associated with protein kinase
      C (PKC) activity. IL-6 also up-regulates histamine production rather than
      increases its storage and is an important inducing factor for the expression of
      immunoglobulin E (IgE) Fc epsilon RI.

PMID- 12476544
TI  - Differential diagnosis of angioedema.
AB  - Angioedema without an associated urticarial syndrome evokes a completely
      different differential diagnosis from urticaria. This review of the literature
      discusses hereditary angioedema as prototype of angioedema without urticaria. The
      review then establishes a differential diagnosis for angioedema, which includes
      allergic contact dermatitis, connective tissue disease, endocrine associations,
      parasitic disease, tumor masses, and miscellaneous causes for angioedema.
      Angioedema without urticaria is a distinct syndrome differing from chronic
      urticaria. The astute clinician should be familiar with the spectrum of disorders
      ranging from a functional or quantitative deficiency in C1-esterase inhibitor to
      a panoply of cutaneous and internal medical disorders. Angioedema without
      urticaria is a symptom in which there are many different disease mechanisms
      producing subcutaneous swelling recognizable as angioedema.

PMID- 12476545
TI  - Urticaria and angioedema.
AB  - Urticaria and angioedema evoke a completely different differential diagnosis from
      angioedema without an associated urticarial syndrome. This review of the
      literature is to give the reader a global insight into the spectrum of urticaria
      and angioedema, focusing on differential diagnosis and pathogenic mechanisms. It
      will define the role of the mast cell, explore a possible autoimmune basis for
      urticaria, and examine the purported role of food allergy in chronic urticaria.
      Last, the work-up and treatment will be discussed. Urticaria and angioedema are
      frustrating problems for both physicians and their patients; however, the problem
      can best be approached by considering urticaria as a symptom rather than a
      specific disease. The physical examination and medical history remain the two
      most important pieces of information.

PMID- 12476546
TI  - Reactions to radiocontrast media.
AB  - Adverse reactions to radiocontrast media (RCM) occur unexpectedly and may be life
      threatening. This article describes an anaphylactoid reaction (AR) in one
      patient. The term AR refers to a syndrome clinically similar to anaphylaxis, but
      these reactions are independent of immunoglobulin E antibody-mediated mast cell
      or basophil degranulation. This article briefly reviews the literature regarding
      RCMs and types of reactions to RCM. The risk factors for AR to RCM infusions will
      be discussed along with current concepts of the pathogenesis of RCM-induced ARs.
      This article also describes the therapeutic management of patients who have had a
      previous adverse reaction to RCM and provides an approach to patients who have
      breakthrough reactions despite adequate premedication, but require additional
      radiographic studies.

PMID- 12476547
TI  - [Structural biology of signal transduction mediated by Grb2].

PMID- 12476548
TI  - [Structural biology of the Rho GTPase signaling].

PMID- 12476549
TI  - [From the structure to the function of the PX domain].

PMID- 12476550
TI  - [Three-dimensional structural view of the mechanism of Holliday junction
      migration].

PMID- 12476551
TI  - [Molecular basis of methylated DNA recognition by methyl-CpG-binding protein].

PMID- 12476552
TI  - [Molecular mechanism of cadherin-mediated cell-cell adhesion].

PMID- 12476553
TI  - [The present situation of the protein crystal structure analysis].

PMID- 12476554
TI  - [Recent developments in NMR methods for structural biology].

PMID- 12476555
TI  - [Antegrade selective cerebral perfusion for extended total arch replacement using
      separated graft technique; reassessment from the type of aneurysms and
      dissections].
AB  - One hundred eighty two patients with thoracic aortic aneurysms or dissections who
      required total arch replacement (TAR) were operated on with separated graft
      technique and selective cerebral perfusion (SCP) between 1991 and 2000. These
      patients were divided into 4 groups according to the pathology as follows: group
      1; acute type A dissection, group 2; chronic type A dissection, group 3; distal
      arch aneurysm and group 4; proximal arch aneurysm. For SCP, both the innominate
      artery and the left common carotid artery were cannulated when the patient was
      cooled to a rectal temperature of 22 degrees C. Hospital mortalities were 27% in
      group 1, 14% in group 2, 19% in group 3, and 8% in group 4. Independent
      predictors of hospital mortality were shock, visceral, and leg ischemia in group
      1, and circulatory arrest time of the lower half body to be more than 1 hour and
      cardiopulmonary bypass time to be more than 5 hours in group 3. Permanent
      neurological complication occurred in 3% in group 1 and 8% in group 3. Hospital
      mortality was affected by the type of aneurysms and dissections. It is necessary
      to give careful consideration to the indication of TAR with SCP, especially in
      acute type A dissection and distal arch aneurysm.

PMID- 12476556
TI  - [Induction chemoradiotherapy in small adenocarcinoma of the lung with bulky
      mediatinal lymph node metastasis].
AB  - A 56-year-old man, who visited our hospital due to chest pain, was pointed out a
      large tumor, 60 mm in diameter, on the left superior mediastinum on the chest
      computed tomography (CT) scan. He was diagnosed as having mediastinal lymph nodes
      metastasis of adenocarcinoma through video-assisted thoracoscopic surgery (VATS)
      biopsy. He received induction chemoradiotherapy: cisplatin and paclitaxel were
      administered once per week for 2 weeks, and radiotherapy was simultaneously
      performed. No serious adverse reactions were noted. The ipsilateral mediastinal
      lymph nodes dissection was performed. Intraoperative frozen section analysis
      showed a small nodule in the left upper lobe, 5 mm in diameter, was
      adenocarcinoma. He was finally diagnosed as having mediastinal lymph nodes
      metastasis from the small adenocarcinoma of the lung, and left upper lobectomy
      was performed. Histopathological examination of the mediastinal lymph nodes
      showed no evidence of viable maligmant cell. Induction chemoradiotherapy with
      cisplatin and paclitaxel might be effective treatment for locally advanced non
      small cell lung cancer.

PMID- 12476557
TI  - [A successful surgical treatment for original Taussig-Bing malformation 13 years
      after banding of the pulmonary artery].
AB  - A 13-year-old girl with original Taussig-Bing malformation underwent successful
      intraventricular rerouting. In this congenital heart disease, the large pulmonary
      flow elevates pulmonary arterial pressure and progress the pulmonary vascular
      diseases in early infancy. Banding of the pulmonary artery helps to prevent the
      irreversible vascular changes, while that may result in further hypertrophy of
      the right ventricle. Ideally, radical repair should be performed as soon as
      possible after definitive diagnosis. Although, she had banding operation of the
      pulmonary artery at 8 months of age, there was no difference between the right
      ventricle and the aortic pressure. The subpulmonary space was large enough to
      make the tunnel with an internal conduit. Additionally, right ventricle outflow
      tract reconstruction was performed by a Dacron patch. The postoperative
      cathetherization demonstrated no stenotic region in both left and right
      ventricular outflow tract. The Kawashima intraventricular rerouting can be
      applied to the patients without the subaortic stenosis if banding of the
      pulmonary artery have been performed long before.

PMID- 12476558
TI  - [Thymic carcinoma; analysis of nine clinical studies].
AB  - Nine cases of thymic carcinoma (mean age 53.9 years old, 8 males and 1 female)
      were treated in our hospital from 1973 to 1998. The histological subtypes of
      thymic carcinoma were squamous cell in six, adenosquamous cell in one,
      Lymphoepithelioma-like carcinoma in one, mixed type of small cell and squamous
      cell in one. We applied Yamakawa clinical staging, 9 cases consisted of 2 stage
      II cases, 2 stage III cases, and 5 stage IV b cases. Adjuvant radiotheraphy was
      administered in one case, registering remarkable reduction of tumor size. All of
      the four cases which had been performed complete resection are alive without
      recurrence for 17 to 136 months after operation. The mean survival time was 47
      months in stage III, and 18 months in stage IV b. By the review of the Japanese
      literature, most of the patient who revealed long-term survival fulfill the
      conditions as follow, squamous cell carcinoma in histologically, earlier stage
      than III at his operation, performed complete resection, performed postoperative
      radiotherapy. Our cases covering all these condition are alive without carcinoma
      for 136 months after operation.

PMID- 12476559
TI  - [Pacemaker therapy in Kearns-Sayre syndrome].
AB  - Kearns-Sayre syndrome is regarded as a type of mitochondrial encephalomyopathy
      accompanied with mitochondrial DNA abnormality of the muscle. Diagnosis of this
      disease is based upon the progressive external ophthalmoplegia, atypical retinal
      pigmentation and cardiac conduction block. We report two clinical cases of this
      disorder treated with permanent pacemaker implantation at a 20 year old man
      (patient 1) and a 27 years old woman (patient 2). Patient 1 with bifascicular
      block at 19 years old progressed into complete heart block at 20 years old.
      Patient 2 with complete heart block was occurred "torsade de pointes." Several
      problems of this disease in permanent pacing should be considered the patients'
      small size, pacing mode selection and coexistence of congenital heart disease.
      Routine electrocardiography is recommended for these patients and bifascicular
      block in this disease constitutes a definite indication for prophylactic
      pacemaker implantation.

PMID- 12476560
TI  - [Intrapleural streptokinase-streptodornase in the treatment of empyema and
      hemothorax].
AB  - Fourteen of 15 patients (93%) with retained pleural collections underwent
      successful enzymatic debridement and tube drainage with streptokinase
      streptodornase (SK-SD) injections. No significant adverse reactions occurred. One
      patient required decortication when SK-SD therapy failed. Intrapleural SK-SD is a
      safe, effective means of removing retained proteinaceous collections in the
      pleural space. It may obviate the need for more invasive procedures.

PMID- 12476561
TI  - [Graft holding system; a new device for coronary artery bypass grafting].
AB  - A new graft holding system for coronary artery bypass grafting was described.
      This system was an application of a memo-clip, which was composed of a flexible
      arm and 2 paper clips at both ends. A graft was wrapped by a piece of sponge and
      pinched indirectly by one of the clips. The other clip was fixed at an edge of
      the sternal retractor. Regardless of the size of the graft or the amount of the
      surrounding tissue, the graft can be fixed securely at one's pleased position due
      to a flexible arm of the device. Intimal injury can be avoided referring to the
      gentle holding of a piece of sponge. It enables us to place precise stitches and
      to minimize handling, anastomosis time, and leakage.

PMID- 12476562
TI  - [Application of transluminally place endoluminal prosthetic grafts for the
      treatment of multiple aortic aneurysms].
AB  - We have 5 cases with multiple aortic aneurysms who have undergone conventional
      abdominal aortic replacement with transluminally placed endoluminal prosthetic
      grafts (TPEGs) into the descending thoracic aorta. Simultaneous operation was
      done in one patient. A 2-stage operation was done in 4 patients, and the
      abdominal aortic aneurysm was performed on the first. One patient required urgent
      surgical intervention to treat migration of a stent-graft. However, there was no
      hospital death. The mean follow-up interval was 34 months and there were no
      complications correlated with the procedures. Application of TPEGs for the
      treatment of multiple aortic aneurysms may be a valuable treatment option.

PMID- 12476563
TI  - [Off-pump coronary artery bypass grafting/beating coronary artery bypass grafting
      for a patient with low left ventricular ejection fraction].
AB  - Beating coronary artery bypass grafting could be performed for a 47-year-old man
      with left ventricular ejection fraction (LVEF) of 9.3%. Post-operative LVEF was
      improved to 51.6%. Conventional coronary artery bypass grafting (CABG) used to be
      contraindicative for patients with LVEF below 20%. Recently, such patients are
      involved to indication of off-pump CABG (OPCAB) or beating CABG, because we
      consider OPCAB are lower complications than conventional CABG. We were able to
      bypass the circumflex for the patient while we had been used percutaneous cardio
      pulmonary support (PCPS). We could perform beating coronary artery bypass
      grafting for a patient of the low LVEF.

PMID- 12476564
TI  - [Bilateral multiple pulmonary arteriovenous fistulas treated by surgery and
      embolization].
AB  - A 46-year-old man, with an abnormal shadow in left lower area in chest X-ray was
      admitted to our hospital. Three dimensional computed tomography (3 D-CT) and
      pulmonary arteriogram revealed bilateral multiple pulmonary arteriovenous
      fistulas (PAVF). PAVF was simple in the right S8, and were multiple in the right
      lower lobe. PAVF in left side was treated with percutaneous transcatheter coil
      embolization. PVAFs in right side were treated by lower lobectomy. This
      combination therapy seemed to be useful for bilateral multiple PAVFs.

PMID- 12476565
TI  - [Angina pectoris with a left atrial myxoma; report of a case].
AB  - A 78-year-old woman who had been diagnosed as left atrial myxoma and angina
      pectoris underwent simultaneous coronary artery bypass grafting (CABG) and
      resection of the left atrial myxoma. CABG was preceded by resection of myxoma to
      avoid systemic embolism of fragment of myxoma. Myocardial protection was secured
      by combination of antegrade and retrograde infusion of cardioplegia. The patient
      recovered well and discharged uneventfully.

PMID- 12476566
TI  - [Reoperative off-pump coronary artery bypass surgery for restenosis after
      percutaneous coronary intervention as a part of hybrid revascularization chronic
      renal failure on hemodialysis; report of a case].
AB  - 60-year-old man on chronic hemodialysis had hybrid revascularization.
      Percutaneous coronary intervention (PCI) for right coronary artery (RCA) combined
      with left internal mammary artery-left anterior descending artery anastomosis
      through left anterior small thoracotomy were performed. But, frequent re-stenosis
      after PCI necessitated 4 repeated PCI. Finally, the patient agreed to re-do, and
      underwent reoperative off-pump coronary artery bypass through midsternotomy.
      Right internal mammary artery-saphenous vein lengthened composite graft was
      successfully anastomosed to heavily calcified RCA without heart-lung machine.
      Strategy of revascularization for hemodialysis patient was discussed.

PMID- 12476567
TI  - [Pericardiectomy for post-coronary artery bypass grafting constrictive
      pericarditis; strategy for safe and complete pericardiectomy].
AB  - Surgery for constrictive pericarditis after coronary artery bypass grafting
      (CABG) needs complete pericardiectomy without injury to bypass grafts. We
      performed pericardiectomy for post-CABG constrictive pericarditis 15 months after
      the first surgery. Preoperative multislice helical 3-dimensional computed
      tomography (CT) clearly demonstrated the patent bypass grafts and anatomical
      relationship between grafts and surrounding organs. Among surgical approaches, we
      chose bilateral thoracotomy to avoid injury to the bypass grafts and to obtain a
      good surgical exposure, especially for pericardiectomy of the left side of the
      heart. Additionally, with the use of intraoperative doppler ultrasound blood
      flowmetry, we could safely achieve complete pericardiectomy. We conclude that the
      combined application of 3-dimensional CT, bilateral thoracotomy and doppler
      ultrasound blood flowmetry was a supreme strategy for the operation of
      constrictive pericarditis after CABG.

PMID- 12476568
TI  - [Severe tricuspid regurgitation late after aortic and mitral double valve
      replacement; report of a case].
AB  - A 59-year-old man had undergone aortic and mitral valve replacement (DVR) for
      rheumatic aortic and mitral valve stenosis 15 years ago. At that time,
      echocardiography did not detect tricuspid regurgitation (TR), and catheterization
      data showed right atrial pressure v wave of 8 mmHg and pulmonary artery pressure
      of 27/12 (17) mmHg. One year after DVR, hepatomegaly and jugular venous
      dilatation appeared, and after 5 years edema of both legs became apparent. After
      7 years, chest X-ray showed an increase of cardio-thoracic ratio, and for the
      first time, echocardiography detected mild TR. Fifteen years after DVR, severe
      general fatigue, shortness of breath and hepatomegaly could not be controlled
      with medication. Catheterization data showed right atrial pressure v wave of 23
      mmHg and pulmonary artery pressure of 28/13 (17) mmHg. Right ventriculography
      showed progression of severe TR. Tricuspid valve replacement (TVR) was performed
      using a St. Jude Medical 31 M mechanical valve under natural cooling and heart
      beating. The tricuspid valve was only slightly thickened and no subvalvular
      abnormalities were seen other than a severely dilated tricuspid annulus.
      Postoperative course was uneventful and he was discharged 44 days after the TVR.
      He is currently doing well 6 years after the TVR. All terms, he did not have
      pulmonary hypertension or left-side heart problems. We suspect that the cause of
      TR was not secondary, and was included in the category of isolated TR. If the
      left heart is completely treated, as in this case, it is important to follow-up
      for signs of right heart failure, before TR is detected.

PMID- 12476569
TI  - [Acute pulmonary thromboembolism complicating lung lobectomy; report of a case].
AB  - Acute pulmonary thromboembolism is fatal if the diagnosis and treatments are
      delayed. Here we present a case of acute thromboembolism to the right and left
      pulmonary arteries after right lung lobar resection. A 52-year-old woman who
      admitted to our hospital with lung cancer was performed right upper lobectomy
      with mediastinal lymph node dissection (pT1N0M0, well differentiated
      adenocarcinoma). Two days after surgery, she complained sudden chest discomfort
      and dyspnea. The blood pressure and oxygen saturation were rapidly decreased.
      Because there was no lung edema or atelectasis in the chest portable
      roentgenogram and no ischemic change in the electrocardiogram, pulmonary
      thromboembolism was suspected and emergency chest computed tomography (CT) was
      performed. The CT showed left and right pulmonary arterial thromboembolism and
      immediate anti-coagulator therapy was started. Her condition was improved and
      chest CT, which was performed three days after the onset of the thromboembolism,
      showed decreased but still remained thrombus. The anti-coagulator therapy was
      continued and one month after the onset of the thromboembolism, thrombus was
      disappeared on chest CT. She is doing well 17 months after surgery. Early
      diagnosis and treatments are critical for the pulmonary thromboembolism.

PMID- 12476570
TI  - [Metastatic sternal tumor from thyroid papillary carcinoma; report of a case].
AB  - A 68-year-old male was referred to our department for treatment of a metastatic
      sternal tumor in the manubrium sterni. Primary lesion was papillary carcinoma of
      the left lobe of the thyroid gland. Total thyroidectomy, cervical lymph node
      dissection, resection of manubrium sterni with concomitant resection of bilateral
      clavicles, 1st ribs and 2nd ribs, and chest wall reconstruction using Marlex Mesh
      were performed on January 29, 2001. Considering relatively good prognosis and
      good response to multimodality therapy, surgical resection of sternal metastatic
      lesion from differentiated thyroid cancer seems to be a choice of therapy as a
      part of multimodality approach, including surgery, radioiodine and external
      radiation therapy, to thyroid cancer with systemic spread.

PMID- 12476572
TI  - [MRI: imaging techniques and clinical indications].

PMID- 12476571
TI  - [Multiple lung cancer with cavity; report of a case].
AB  - A case of multiple lung cancer with cavity was reported. Chest X-ray and chest
      computed tomography (CT) showed two abnormal shadows with consolidation in the
      right S1 and S2b. The shadow in S2b had a cavity. Right upper lobectomy and right
      middle lobe partial resection was performed and the histopathological examination
      revealed adenocarcinoma. This case deserves attention of difficulty in
      differentially diagnosis on the chest X-ray and chest CT from pulmonary
      tuberculosis.

PMID- 12476573
TI  - [MR angiography].

PMID- 12476574
TI  - [MR image (diffusion MRI and perfusion MRI)].

PMID- 12476575
TI  - [T2*-weighted MRI in cerebrovascular disease].

PMID- 12476576
TI  - [Functional MRI].

PMID- 12476577
TI  - [Variance in effects of subthalamic nucleus stimulation].
AB  - Chronic stimulation of subthalamus nucleus (STN) is effective in treating severe
      motor fluctuation and levodopa induced dyskinesia as well as parkinsonian motor
      symptoms. The improvement of peak-dose/diphasic dyskinesias of STN stimulation is
      considered to be due to the decrease in the daily dosage of antiparkinsonian
      drugs. However one report pointed out that STN stimulation improved directly
      levodopa induced dyskinesia. Moreover the timing of the improvement for levodopa
      induced dyskinesia is not yet obvious. In the present study, we have assessed
      variance in the latency of improvement of levodopa induced dyskinesia due to STN
      stimulation. In addition, we would clarify an issue which cite of STN stimulation
      improved parkinsonian symptoms and motor complication (motor dyskinesias and
      motor fluctuation). We have studied seven patients diagnosed with advanced
      idiopathic Parkinson's disease with motor fluctuations and levodopa induced
      dyskinesias. Before and after the implantation of stimulating electrode, patients
      were assessed by the Unified Parkinson's Disease Rating Scale and % 'OFF' motor
      state. The dosage of the antiparkinsonian medication was not modified for one
      month prior to implantation. Following implantation, dosage of the medication and
      strength of stimulation was adjusted, if necessary. Symptoms of motor fluctuation
      and dyskinesia improved in all patients six month after surgery. The mean off
      time duration and dyskinesia disability improved compared with presurgical
      conditions. However, the time course of the improvement of dyskinesias was not
      the same among patients. Contralateral limb dyskinesias in three patients
      improved immediately after the stimulation without modification of medication. In
      contrast, the stimulation worsened contralateral limb dyskinesias in other three
      patients immediately following the surgery. In two of the three patients,
      dyskinesias gradually improved within one month after surgery without reducing
      the dosage of medication. Dyskinesias of the other patient improved following a
      reduction in the dosage of medication one month after the surgery. Improvement of
      parkinsonian symptoms of the patients with longer latency of stimulation effect
      for dyskinesias was better than that of the patients with shorter latency.
      Stimulation cite of the former group appeared to locate more central than that of
      the latter group. Latency and strength of the effects of STN stimulation are
      variable.

PMID- 12476578
TI  - [Clinicopathologic characteristics of primary central nervous system malignant
      lymphoma].
AB  - We examined 13 cases of the primary central nervous system malignant lymphoma
      (PCNSML) with established histological diagnosis and valid clinical information
      to clarify the clinicopathologic characteristics of PCNSML. All tumors were
      classified according to the World Health Organization as diffuse large B-cell
      lymphoma (DLBCL), and four were positive for CD 10 or BCL-6. All of the tumors
      had a high proliferative activity containing 15.7% to 84.8% (mean = 59.8%) MIB-1
      positive cells, although there was no correlation between MIB-1 staining indices
      and the survival period of patients. Molecular analysis using PCR demonstrated
      clonal rearrangement of the IgH gene in the majority of cases analyzed (9/10 =
      90%). Tumor cell apoptosis was consistently demonstrated by the routinely
      processed histology and the immunohistochemistry for single-stranded DNA, and
      apoptotic cells were engulfed by phagocytic macrophages. These findings indicate
      that the majority of this series of PCNSML were DLBCL with high proliferative
      activity and clonal B-cell process and that a subset of the cases are of putative
      germinal center B-cell origin. Since there was no statistical correlation between
      the histopathological finding and the survival rate, additional studies,
      including quantitative investigation for the extent of apoptotic cells, in large
      numbers of patients are required.

PMID- 12476579
TI  - [The frontal assessment battery at bed side(FAB) in patients with Parkinson's
      disease].
AB  - It is by no means easy to assess the frontal lobe function precisely in patients
      with neurological disorders. Recently, Dubois et al. (2000) reported a new
      bedside cognitive and behavioral battery for evaluating frontal lobe function. To
      evaluate the clinical efficacy of this frontal assessment battery at bedside
      (FAB), we performed both FAB and Hasegawa's dementia scale (HDS), a Japanese
      version of convenient clinical scaling of dementia resembling the Mini-Mental
      State Examination, in patients with Parkinson's disease (PD) and age-matched
      controls. The FAB global score was significantly lower in the PD patients
      compared to the controls. On the other hand, there was no significant difference
      in the scores of HDS between the PD patients and controls. In the PD patients,
      there was no correlation between the FAB scores and their age or duration of the
      illness. The FAB is likely to be useful and convenient battery for assessing
      frontal lobe function at bedside in the PD patients.

PMID- 12476580
TI  - [Amyotrophic lateral sclerosis presented with alexia of kanji and word meaning
      aphasia].
AB  - We report a 63-year-old right-handed Japanese man with progressive bulbar
      dysfunction and alexia of kanji (Japanese morphograms). He was well until his 62
      years of age, when he noted difficulty of reading kanji, which was followed by
      disturbances in his speech. Reading of kana (Japanese phonograms) was preserved.
      He also showed naming difficulties with semantic memory loss for words, which
      were characterized for word meaning aphasia or semantic dementia. He showed
      dysarthria and mild dysphagia with atrophy and fasciculations of the tongue. The
      electromyographic studies disclosed diffuse neurogenic pattern. He was diagnosed
      as having bulbar type amyotrophic lateral sclerosis. Cranial magnetic resonance
      imaging and single-photon emission computed tomography revealed bilateral
      involvements of the temporal lobes. Our patient appeared to meet the clinical
      criteria for frontotemporal degeneration of motor neuron disease type, and is the
      first case of amyotrophic lateral sclerosis showing alexia of kanji and word
      meaning aphasia.

PMID- 12476581
TI  - [Dysphagia due to giant cervical osteophytes].
AB  - We reported a patient with isolated dysphagia due to an esophageal canal stenosis
      compressed by focal cervical spondylotic osteophytes. The patient was a 63-year
      old male who developed swallowing disturbance of predominantly solid materials.
      The neurological examination showed subjectively isolated dysphagia unassociated
      with any significant cranial nerve signs. Cervical magnetic resonance imaging and
      X-ray demonstrated giant cervical spurs focally at the ventral portion of the C
      5/6 vertebral bodies, protruding ventrally and compressing mildly to the
      esophageal canal. The intervertebral disc formation was relatively preserved
      between the osteophytes. At the neck flexion portion, the esophagus was severely
      compressed between the osteophytes and the epiglottis. Videofluoroscopic
      examination of swallowing function showed a congestion of the contrast medium at
      the portion of the epiglottic vallecula, unassociated with aspiration into the
      trachea. The endoscopic examination showed erosion of the posterior wall of the
      esophagus at the portion compressed by the osteophytes. The anti-inflammatory
      medication improved the symptom of dysphagia, and the patient has been carefully
      followed-up without a surgical procedure. The presence of giant osteophyte should
      be considered in the differential diagnosis of subjectively isolated dysphagia
      unassociated with any significant cranial nerve signs.

PMID- 12476582
TI  - [MR imaging of a case of spontaneous carotid-cavernous fistula].

PMID- 12476583
TI  - [MR image of an unruptured cerebral aneurysm: the usefulness of 3 D-MRA].

PMID- 12476584
TI  - [A 52-year-old woman with dyskinesia, epilepsy and gait disturbance].
AB  - We report a 52-year-old Japanese woman who developed dyskinesia, epilepsy, and
      gait disturbance. She was well until 35 years of age, when she noted the onset of
      gait disturbance. She also noted abnormal involuntary movements in her limbs. She
      also noted dysarthria at age 38. A neurologist examined her at age 41. The
      neurologist found cerebellar ataxia and dyskinesia. The atrophy of the brain stem
      and the cerebellum was on CT. She started to have generalized convulsion with
      loss of consciousness. Dementia became apparent at age 40. In October, 1993, she
      became psychotic in which she behaved violently taking off her clothes shouting
      as "Fire". She was treated with major tranquilizers and became quiet. However,
      choreic movements became prominent. Her subsequent course was complicated with
      dysphagia, dementia, convulsion, and frequent bouts of pneumonia. She expired on
      January 24, 2000 after developing pneumonia. Her father and one sibling had
      similar motor disturbances. She was discussed in a neurological CPC. The chief
      discussant arrived at conclusion that the patient had dentatorubral
      pallidoluysian atrophy. Most of the participants agreed with this diagnosis.
      Postmortem examination revealed that entire brain looked smaller than normal
      including the brain stem and the cerebellum. The cerebellar dentate nucleus
      showed loss of neurons and gliosis; glumose degenerations were also seen. The
      external segment of the pallidum showed neuronal loss and gliosis. The
      subthalamic nucleus showed gliosis without neuronal loss. A demyelinated focus
      was found in the pons; the lesion looked similar to central pontine myelinolysis.
      The cerebral white matters were unremarkable. Other areas were unremarkable. The
      pathological diagnosis was dentatorubral-pallidoluysian atrophy. The pathologic
      lesion which might explain her dementia was not apparent.

PMID- 12476585
TI  - [Committee of IgA Nephropathy--the Special Study Group of Progressive Glomerular
      Disease, the Ministry of Health, Labor and Welfare of Japan].

PMID- 12476586
TI  - [Historical remark on renal physiology in Japan (discussion)].

PMID- 12476587
TI  - [Update in primary glomerular diseases--mainly in IgA nephropathy].

PMID- 12476588
TI  - [Possible role of soluble erythropoietin receptors in renal anemia].
AB  - Recombinant human erythropoietin(rHuEpo) is effective for the treatment of renal
      anemia associated with chronic renal failure(CRF). However, we have encountered
      some patients with CRF who have sometimes developed a resistance to rHuEpo. This
      resistance can be due to iron or folate deficiency, aluminum toxicity,
      hyperparathyroidism, or auto-antibodies for rHuEpo. In this study, we focused on
      the soluble erythropoietin receptor(sEpoR), which can bind to rHuEpo. To
      demonstrate the possibility that the sweeping of rHuEpo by sEpoR results in
      resistance to rHuEpo, we performed a bioassay using the rHuEpo-dependent cell
      line, UT7/EPO. The results showed that recombinant mouse sEpoR(rmsEpoR) can
      reduce the proliferation of UT7/EPO induced by rHuEpo in a dose-dependent manner.
      We consider that this cell line could be a useful tool in a bioassay to detect
      the inhibitory factor(s) against Epo. We selected sera from three groups of
      patients with renal anemia associated with CRF who were receiving hemodialysis
      three times a week: the first was a patient group that needed a high dose of
      rHuEpo(7,500-9,000 unit/dialysis), the second was a patient group that needed an
      intermediate dose of rHuEpo (4,500 unit/dialysis), the third was a patient group
      that needed a low dose of rHuEpo(below 1,500 unit/dialysis). Interestingly, the
      proliferation of UT7/EPO determined with [3H]-thymidine incorporation was reduced
      by the addition of sera from the first group, but not by the addition of sera
      from the third group. These results suggested that serum sEpoR may play an
      important role in signal transduction via EpoR on erythroid progenitor in CRF
      patients.

PMID- 12476589
TI  - [Effect of angiotensin II receptor antagonist (losartan) on renal function, serum
      potassium and blood pressure in patients with advanced renal failure: differences
      between patients with a serum creatinine (SCr) level higher than 3 mg/dl and
      those with a lower SCr level].
AB  - The administration of angiotensin II receptor antagonist(AIIA) to patients with
      advanced chronic renal failure(CRF) is not actively recommended. This study was
      performed to verify the appropriateness of this situation and to determine if
      there are any substantial differences between patients with a serum
      creatinine(SCr) level higher than 3 mg/dl and those with a lower SCr level in
      terms of the clinical effects such as renal function, serum potassium level and
      systemic blood pressure(BP) after the administration of AIIA. Sixteen patients
      with advanced CRF who were admitted to the out-patient clinic in Jikei University
      Hospital(1998/1-1999/12) were enrolled(average age: 65 years, underlying renal
      disease: diabetic nephropathy 6, CGN 5, and other 1). They had never been
      administered AIIA before. The patients were classified into two groups in
      accordance with their level of SCr: group A(SCr lower than 3.0 mg/dl; n = 11),
      and Group B(SCr higher than 3.0 mg/dl; n = 5). Losartan(50 mg/day) administration
      was started in order to examine parameters such as the SCr, potassium, BP at the
      out-patient clinic, and urinary protein excretion at the 0, 1, 3, 6, 9, and 12
      month time points. Although the 1/SCr values provided negative slopes with time
      in both groups, no significant difference was found between the two slopes. There
      were no changes in the serum potassium levels or urinary protein excretion during
      the study period in either group, and no statistical difference was found between
      the two groups. Although the serum potassium level exceeded 5.5 mEq/l in two
      patients each in both groups, the level was controlled by diet therapy with
      restricted potassium. BP was reduced significantly in both groups during the
      study period, and no statistical difference in BP reduction was observed between
      the two groups. In conclusion, the results indicate there were no differences in
      the effect on renal function, serum potassium levels or systemic BP between the
      patients with a SCr level higher than 3.0 mg/dl and those with a lower level. The
      results also support the notion that patients with advanced renal dysfunction are
      not precluded from AIIA administration.

PMID- 12476590
TI  - [Fluctuation of the rate of renal function decline associated with fluctuation of
      compliance with a low protein diet in patients with diabetic renal failure].
AB  - We investigated fluctuation of compliance with a low protein diet and the
      influence on the rate of decline in renal function. Twenty-seven patients with
      diabetic renal failure who were prescribed a low protein diet of 0.6 g/kg/day
      were followed during a period of 12 months. Dietary compliance was evaluated
      based on a 4-day dietary diary, interview with patients and calculation of the
      protein catabolic rate from 24-hour urea excretion at every hospital visit. They
      were judged on a 4-rank system, A(adhered over 75% of the days), B(74-50%), C(49
      25%), D(less than 24%). During the twelve months, 55.5% of the patients showed
      fluctuation of their compliance with the diet. In 17 patients whose compliance
      fluctuated between rank A and B, their rate of GFR decline(ml/min/month) was
      significantly faster(-2.40 +/- 2.59 vs 0.99 +/- 1.41, p < 0.01), their rate of
      serum creatinine elevation(mg/dl/month) was significantly higher(0.90 +/- 0.79 vs
      -0.42 +/- 0.45, p < 0.01) and their rate of serum urea nitrogen
      increase(mg/dl/month) was significantly larger(15.3 +/- 12.4 vs -10.0 +/- 12.9, p
      < 0.01) during the period of rank B than rank A. There were no significant
      differences in the rates of changes in serum levels of albumin, transffering,
      HbA1c and body weight between the two periods. In conclusion, fluctuation of
      compliance with a low protein diet affects the rate of renal function decline
      synchronizedly in patients with diabetic renal failure.

PMID- 12476591
TI  - [A case of acute renal failure with marked hyperuricemia developing during
      mizoribine administration].
AB  - A 50-year-old man diagnosed as having AGA(Churg-Strauss syndrome) was
      administered steroid. After treatment with mizoribine, hyperuricemia and acute
      renal failure occurred as side effects of this drug. Accordingly we started
      dialysis treatment, terminated mizoribine treatment, and administered allopurinol
      dosage. Hemodialysis was necessary every day for 11 days and his renal function
      recovered after one month. In 67Ga scintigraphy, accumulation of 67Ga was seen in
      the kidney.

PMID- 12476592
TI  - [A case of mesangial proliferative glomerulonephritis with endothelial damage].
AB  - We describe a 71-year-old man, who had been treated for hypertension, myocardial
      infarction and abdominal aortic aneurysm, and was admitted to our hospital
      because of proteinuria(3.9 g/day at the outpatient clinic and 1.5 g/day at the
      time of admission) and edema in the extremities. Light microscopic study of the
      kidney biopsy specimen revealed mesangial proliferative glomerulonephritis and
      glomerular paralysis. Electron microscopic findings showed endothelial damage,
      including widening of the subendothelial space and detachment of endothelial
      cells from the glomerular basement membrane. Deposition of immunoglobulins and
      complement was not detected by immunofluorescence studies. These pathological
      findings resemble the findings of thrombotic microangiopathy, but there were no
      clinical pictures of HUS/TTP. These findings suggest that hypertension,
      atherosclerosis and circulating turbulence caused by an aortic aneurysm induced
      severe glomerular endothelial damage leading to mesangial proliferative
      glomerulonephritis without an immune response.

PMID- 12476593
TI  - [A case of diabetic glomerulosclerosis without concurrent diabetes mellitus].
AB  - Diabetic nephropathy is a complication of diabetes mellitus that is characterized
      by the appearance of diffuse and nodular glomerulosclerosis A 46-year-old man
      presented with generalized edema. He had severe nephrotic syndrome, renal
      insufficiency and hypertension without a family history or clinical evidence of
      diabetes mellitus. Oral glucose tolerance test showed impaired glucose tolerance,
      but several fasting plasma glucose determinations and serum hemoglobin A1c levels
      were normal. Renal biopsy revealed nodular and diffuse glomerulosclerosis
      characteristic of diabetic nephropathy. The present case demonstrates that
      nodular glomerulosclerosis may be present without clinically overt diabetes
      mellitus.

PMID- 12476594
TI  - [A case of fulminant acute poststreptococcal glomerulonephritis showing
      mesangiolysis and crescent formation preceded by erysipelas].
AB  - A 66-year-old man with erysipelas was admitted with complaints of oliguria and
      massive proteinuria/hematuria. He was diagnosed as having acute poststreptococcal
      glomerulonephritis(APSGN) due to erysipelas infected by group A streptococcus
      pyogenes. On admission, his white cell count increased to 31,000, and CRP was
      27.3 mg/dl. Serum urea nitrogen and creatinine were increased to 90.1 mg/dl and
      4.5 mg/dl, respectively. He had diabetes mellitus(HbA1c 7.9%) and liver
      dysfunction(total bilirubin 3.5 mg/dl, AST 76 IU, ALT 41 IU) caused by alcoholic
      liver cirrhosis. Hypocomplementemia was found in addition to ASO 216 U/ml and ASK
      10,240 x. After antibiotics treatment was initiated, inflammation of the
      erysipelas began to improve. Disseminated intravascular coagulation syndrome,
      probably due to sepsis, occurred on the 5th hospital day. He died of
      gastrointestinal bleeding on the 18th hospital day. Renal autopsy revealed 37%
      formation of fibrocellular crescents, and marked mesangiolysis was noted by light
      microscopy. Granular deposition of C3 and IgG was seen along the capillary walls
      on immunofluorescence study. Intramembranous deposits were scattered on electron
      microscopy. This case illustrates a fulminant type of APSGN, which was in part
      attributed to the presence of diabetes and alcoholic liver cirrhosis.
      Histological findings of crescent formation and marked mesangiolysis may account
      for the fulminant clinical course.

PMID- 12476595
TI  - In the true American spirit.

PMID- 12476596
TI  - Allergic disease and associated concurrent medical illnesses.
AB  - This retrospective study examined the pattern of medical illnesses, surgical
      procedures, and medication usage among 249 patients with allergic rhinitis
      contrasted with a comparison group of 253 patients with cerumen impaction.
      Results revealed that allergic patients experienced more frequent nasal and
      abdominal surgery, a higher prevalence of pulmonary and gastrointestinal disease,
      and used nasal sprays, antihistamines, and psychoactive medications more often
      than the comparison group. Implications for otolaryngology nursing practice are
      discussed.

PMID- 12476597
TI  - Head and neck cancer: managing xerostomia and other treatment induced side
      effects.
AB  - Patients diagnosed with head and neck cancer face a myriad of treatment options.
      Each treatment is accompanied by acute and chronic side effects. Xerostomia is a
      side effect of radiation therapy and, if not managed properly, can disrupt the
      patient's quality of life and lead to other health related issues. This article
      provides a broad overview of head and neck cancer and examines the current
      modalities utilized in the treatment and prevention of xerostomia.

PMID- 12476598
TI  - The subtle "face" of elder abuse.

PMID- 12476599
TI  - Urinary incontinence in the older acute care population: effects of knowledge,
      attitudes and beliefs of nurses on continence management.

PMID- 12476600
TI  - Certification in gerontological nursing: the evolution of an exam preparation
      workshop.

PMID- 12476601
TI  - The Murray Alzheimer Research and Education Program (MAREP)--University of
      Waterloo.

PMID- 12476602
TI  - [Abnormal menstrual bleeding].
AB  - Abnormal uterine bleeding (DUB) is one of the most frequent gynecologic problems.
      Not every DUB is pathological, yet most women feel disordered. Recurrent DUB
      needs a diagnostic work-up and has to be treated frequently. 80% of cases are due
      to hormonal disorders, called dysfunctional uterine bleeding, the others are of
      organic cause (polyps, myomas). The diagnostic work-up is essentially based on
      the vaginal ultrasound. Standard invasive diagnostic includes the combination of
      hysteroscopy and curettage or guided biopsy. Laboratory tests are rarely
      indicated. Medical treatment is based on gestagens, estrogens or combinations
      thereof. If contraception is needed, ovulation inhibitors are chosen. In case of
      contraindications, non-steroid antirheumatics or antifibrinolytics are
      efficacious alternatives. Organic causes of abnormal bleeding are treated by
      hysteroscopy. Relapse may necessitate destruction of the endometrium or
      hysterectomy.

PMID- 12476603
TI  - [Low back pain: diagnostic and therapeutic concepts].
AB  - During the last couple of years the lumbar back pain has gained importance like
      no other complaints in rheumatology and orthopaedics. This is mainly due to the
      chronic futile course and a general increase in relation to socio-economic
      factors. This is also where new therapeutic concepts have been created, which not
      only emphasise the pure somatic proceeding but also include the bio-psycho-social
      concept of treatment that on the one hand takes a lot of time and trouble, yet on
      the other hand is the treatment most likely to be a therapeutic success. However,
      in diagnosis one always has to start out from the somatic possibility and
      construct a working hypothesis within the framework of clear diagnostic steps,
      which then can be used as a basis for further therapeutic proceeding. Backache of
      young people differs greatly from backache of adults. New examinations even
      question the general belief that there is only a pure somatic reason that leads
      to backache of young people. The ergonomic way of thinking absolutely has to
      start being used for therapeutic reflections. Moreover, not only the analysis of
      the place of work and the adaption, yet also the strain in the spare time has to
      be structured usefully and sensibly.

PMID- 12476604
TI  - [From symptom to therapy: clinical reasoning].
AB  - The path from a symptom to the diagnosis and appropriate treatment begins with
      hypotheses and is characterized by uncertainties and probabilities. Hypotheses
      are developed by comparing clinical findings with internalized prototypic images
      of diseases. Heuristic, i.e. associative rather then logic thinking, is used to
      cut down the complexity of a clinical case to a size more easy to handle.
      Hypotheses are evaluated with clinical findings, laboratory tests and
      radiological images and are either refuted or eventually accepted, which leads to
      the diagnosis. Tests have a sensitivity and specificity, which are used to
      calculate the likelihood ratio of a specific test. This likelihood ratio allows
      to go from a given pretest probability to a posttest probability with the help of
      Bayes' theorem. Although daily clinical practice is hardly feasible with these
      principles, it is worthwhile to become conscious of these mechanisms, to
      understand our thinking and to prevent recurring mistakes and misinterpretations.

PMID- 12476605
TI  - [Placebo: an unappreciated factor in medicine].
AB  - Placebo is a provoking factor in medicine that is discussed controversially and
      not fully understood so far. From the scientific point of view and according to
      evidence-based medicine a proved indication to prescribe a placebo does not
      exist. Therapy of pain may be an exclusion. In our daily work we consciously use
      the placebo-effect, but on the other hand we are committed to the placebo
      phenomenon. This article gives an overview of various aspects of placebo. The
      currently supported theory about the placebo response, conditioning and
      expectancy, are discussed. Further, the side effects (nocebo-phenomenon) and the
      utility of placebo in randomised clinical trials is highlighted.

PMID- 12476606
TI  - The role of nurse consultants is dropping down the healthcare agenda.

PMID- 12476607
TI  - Haunted!

PMID- 12476608
TI  - Caring for prisoners. Their professional, educational and occupational needs.

PMID- 12476609
TI  - Combating uncertainty. Facets of successful management in the NHS.

PMID- 12476610
TI  - Sickness among nurses.

PMID- 12476611
TI  - Morphological lesions detected by light and electron microscopies in chronic type
      B hepatitis.
AB  - Apart from serological diagnosis of chronic type B hepatitis, of high importance
      is specific morphological diagnosis, based on evaluation of liver biopsies. In
      the evaluation, the techniques are employed, which directly visualize the virus
      in the cells (electron microscopy) as well as the techniques of cell biology
      which demonstrate the presence of viral genetic material and viral proteins in
      situ. This paper reviews the available data on the diagnosis of liver
      pathomorphology using the above mentioned techniques in chronic HBV infections in
      adults. The data have been compared with the results of our own studies,
      performed in children. In chronic type B hepatitis and more frequently in
      children than in adults, slight or moderate inflammation (grade 1 to 2) and
      insignificantly advanced fibrosis (stage 1 to 2) are noted in the liver. Both in
      children and in adults, lesions in hepatocyte nuclei represent the common
      morphological denominator in the patterns of light and electron microscopy. The
      cell nuclei are of variable size, irregular shape, they stain irregularly,
      manifest an altered outline of nuclear envelope, frequently exhibit numerous and
      enlarged cell nucleoli and chromatin dissociation (the so called empty cell
      nuclei). In ultrastructural studies, hepatocyte cytoplasm contains Dane's bodies
      and tubular forms of HBsAg while virus-resembling particles are noted in cell
      nuclei. Molecular biology techniques (immunocytochemistry, in situ hybridisation)
      reveals nuclear and/or cytoplasmic location of HBcAg, cytoplasmic location of
      HBsAg and a similar location of HBV DNA. The data permit us to determine
      precisely the stage of infection and to make appropriate therapeutic decisions.

PMID- 12476612
TI  - Morphological and immunological features of liver inflammatory infiltrate in
      children with chronic hepatitis C.
AB  - The aim of the study was to assess the correlation between morphological and
      immunological features of lesions in the liver in children with chronic hepatitis
      C. In the study 11 children with chronic hepatitis C were enrolled.
      Histopathological and immunomorphological investigations included antigen marking
      CD45, CD45RA, CD45RO, CD20, CD3, CD8 in liver biopsy specimens. The
      immunomorphological assessment of the inflammatory infiltrate cells showed the
      presence of CD45 antigen on the vast majority of leukocytes in the portal tracts
      and in the lobular parenchyma in all the studied children. One fourth of the
      inflammatory cells were characterised by CD20 phenotype, 1/2--by CD3 phenotype,
      1/3--by CD8 phenotype, 1/3--by CD45RA phenotype and 2/3--by CD45RO phenotype.
      CONCLUSIONS: T and B lymphocytes were predominant in hepatic inflammatory
      infiltrates (T lymphocytes are twice as numerous as B lymphocytes). Among T
      lymphocytes, cytotoxic and suppressor cells were prevailing. Most T lymphocytes
      were characterized by CD45RO phenotype, which shows their activation. A positive
      correlation between most lymphoid cell markers, staging and grading suggests the
      role of these cells in liver injury.

PMID- 12476613
TI  - Control and STZ-diabetic rat liver Golgi complexes under the influence of
      bis(2,2'-bipyridine)oxovanadium(IV) sulphate. The morphological investigation.
AB  - Identification of a vanadium compound with the highest efficacy and least
      toxicity is the main scientific problem in diabetes treatment. All vanadium
      complexes, both inorganic and organic, apart from improving physiological and
      biochemical diabetic parameters, show more or less toxic effects in living
      organisms. For this reason we decided to test a new vanadium compound: bis(2,2'
      bipyridine)oxovanadium(IV), [VO(bpy)2], not used or described so far. This paper
      stressed morphological alterations of rat liver Golgi apparatus originated from
      control or streptozotocin (STZ)-diabetic rats treated with 1.8 mmol VO(bpy)2
      solution in 0.5% NaCl as drinking liquid for 7 days and compared them with a
      parallel biochemical study. There was a correlation between the activity of Golgi
      marker enzyme i.e. galactosyl transferase and morphology of this organelle. In
      control rats treatment with VO(bpy)2 caused drastic changes, in many cases
      leading to a complete destruction of liver Golgi apparatus. In STZ-diabetic liver
      of rats treated with VO(bpy)2 the Golgi apparatus showed characteristic of
      untreated diabetes arching or even twisting of stack cisternae but improvement of
      the secretory activity (dilatation of cisternae edges, some secretory vacuoles
      and vesicles). In our opinion, the parallel action of two drugs: STZ combined
      with VO(bpy)2, relieves or even eliminate harmful effects of each compound alone.

PMID- 12476614
TI  - Expression of vascular endothelial growth factor (VEGF) in human thyroid tumors.
AB  - Vascular endothelial growth factor (VEGF) is one of the factors related to
      angiogenesis of tumors and physiological and pathological proliferative
      processes. Location of VEGF in human thyroid tissue with various thyroid
      disorders was studied in order to explore its possible involvement in
      proliferative processes. Immunohistochemical examination was performed on 69
      formalin-fixed, paraffin-embedded thyroid tissue specimens using the labelled
      streptavidin biotin peroxidase complex detection system. VEGF was not identified
      in normal thyroid follicular cells. Some but not all tumor thyreocytes expressed
      VEGF in cytoplasm. VEGF positive expression was found in 6/15 patients with
      papillary carcinoma, 4/9 with follicular carcinoma, 14/28 with follicular adenoma
      and 2/17 with adenomatous goiter. In benign follicular adenoma and adenomatous
      goiter the weak expression of VEGF was found in small areas of the tumor tissues,
      whereas in malignant tumors it was found strongly in many cells. VEGF probably
      functions as a hypoxia-inducible angiogenic factor, and the expression of VEGF is
      stronger in malignant tumors, which need more oxygen supply to proliferate. An
      intensive VEGF production by differentiated thyroid carcinomas could be a
      promising marker of tumor aggressiveness and may also be useful as a predictor of
      metastatic potential and extension of tumor mass.

PMID- 12476615
TI  - The effect of cisplatin, etoposide and quercetin on Hsp72 expression.
AB  - Heat shock protein 72 (Hsp72) belongs to a group of proteins referred to as
      molecular chaperones that protect normal and tumour cells against many stressors
      such as hyperthermia, some commonly used chemotherapeutics and other apoptotic
      stimuli. Our study was designed to determine whether heat shock and drugs like
      cisplatin, etoposide and quercetin influence the expression of heat shock protein
      72 in tumour cells: HeLa (cervical cancer), Hep-2 (larynx cancer), A549 (lung
      cancer) and normal human skin fibroblasts (HSF). Our results indicated that Hsp72
      expression was drug and cell-type specific. Cisplatin and etoposide did not
      induce Hsp72 expression in any tumour cells but cisplatin alone induced Hsp72
      expression in normal human fibroblasts. Quercetin inhibited heat shock protein
      expression in Hep-2 cells but induced in HSF. In thermally shocked tumour cells,
      the expression of Hsp72 was not altered by cisplatin and etoposide, but in normal
      HSF cells enhanced expression was observed. Quercetin inhibited Hsp72 expression
      in normal and tumour cells.

PMID- 12476616
TI  - Primary mediastinal large B-cell lymphoma is an important differential among
      mediastinal tumours.
AB  - The study involved 51 patients with histopathologically verified diagnoses of
      primary mediastinal large B-cell lymphoma (PMBL). Clinically they presented as
      the anterior mediastinal tumours, frequently with the superior vena cava syndrome
      (21 patients) and usually (in 42 out of 51) without involvement of other
      locations. Morphologically the tumours were very pleomorphic. Histopathologically
      they were composed of germinal center cells, clear cells or polymorphic cells of
      various size and shape. However, there were also PMBLs composed of cells
      resembling Reed-Sternberg and Hodgkin cells and small cells. Various types of
      stromal sclerosis were evident in most biopsies. Due to lymphoma patterns
      mimicking other tumours with primary or secondary mediastinal location it was
      necessary to use a panel of immunocytochemical stains. CD20 staining proved to be
      indispensable for distinguishing PMBL. The patients were treated with CHOP or
      MEVA (V-VIII courses) followed by radiotherapy of the mediastinum (3600
      4200cGy/t). Complete remission was obtained in 21 patients with overall survival
      ranging from 36 to 99 months. A total of 24 patients are alive, 3 of them live
      with persisting disease. One patients was lost to follow up, 26 died despite the
      treatment due to persistence of mediastinal tumour or dissemination to distant
      organs.

PMID- 12476617
TI  - Molecular aspects of bone healing and remodeling.
AB  - The process of fracture healing involves a complex series of coordinated cellular
      and molecular processes leading to removal of material contaminating the wound,
      angiogenesis validating restoration of disrupted microcirculation, and
      restoration of bone continuity by activation, proliferation and chemotaxis of
      bone progenitors from surrounding periosteum and endosteum. The regulation of
      various cell populations that orchestrate in this process depends on the
      biological effect evoked by cytokines and growth factors. The paper presents the
      state-of-the-art knowledge of the influence of growth factors and cytokines,
      namely TGF-beta, BMP, IGF, PDGF, FGF, NO, IL-1, IL-6, IL-11 on the process of
      fracture healing.

PMID- 12476618
TI  - A correlation between immunoexpression of CD44, alpha-SMA and CD68+ cells in IgA
      nephropathy and in mesangial proliferative IgA-negative glomerulonephritis.
AB  - Immunoperoxidase staining was carried out using monoclonal antibodies against
      CD44, alpha-smooth muscle actin and CD68 on renal biopsy specimens from patients
      with IgA nephropathy (IgAN, n = 16) and mesangial proliferative IgA-negative
      glomerulonephritis (MesProGN, n = 15). As a control 10 biopsy specimens of the
      kidneys removed because of trauma were used. The results showed increase in
      glomerular CD44+ cells and CD68+ cells in IgAN biopsies as compared with controls
      and MesProGN. The intensity of glomerular alpha-SMA was increased in IgAN and
      MesProGN as compared with controls, but no statistical differences were shown in
      glomerular expression of alpha-SMA between IgAN and MesProGN. In both study
      groups there were significant positive correlations between glomerular CD44+
      cells and CD68+ cells, as well as the intensity of alpha-SMA immunostaining. The
      interstitial expression of CD44 and alpha-SMA in IgAN patients was significantly
      higher as compared with controls and MesProGN group, whereas the mean values of
      interstitial CD68+ cell did not differ significantly in these glomerulopathies.
      In both IgAN and MesProGN there were significant positive correlations between
      interstitial expression of CD44 and alpha-SMA, between intensity of CD44
      immunostaining and CD68+ cells as well as interstitial volume. In conclusion, our
      study suggests possible role of CD44 interaction in macrophage recruitment and
      the development of interstitial fibrosis and glomerular sclerosis in both
      glomerulopathies.

PMID- 12476619
TI  - Rudolf Virchow and presentation of his scientific achievement in Polish medical
      magazines in the 19th century and the beginning of 20th century.
AB  - The development of pathological anatomy in the second half of the 19th century
      was mainly associated with the scientific activity of Rudolf Virchow. Last year
      we celebrated the 180th birth anniversary and this year the 100th death
      anniversary of this outstanding man. The paper presents the scientific
      achievements of Rudolf Virchow as it was presented in Polish medical magazines in
      the 19th century and the beginning of 20th century. In 1858, his theory of
      cellular pathology became a basis for the understanding and fight against
      pathologic processes in living organisms. The theory also contributed to an
      increased interest in pathologic anatomy, especially histopathology and Virchow
      himself. In 1859 an extensive summary of the article, issued a year before,
      entitled "Cellular pathology based on physiological and pathological theory of
      tissues" appeared in the subsequent issues of "Tygodnik Lekarski" ("Medical
      Weekly"). Also a translation of the XI chapter of "Cellular pathology..." devoted
      to nerve tissue appeared in the same magazine. This is the only treatise in
      Polish on the most important work in the history of pathological anatomy of the
      19th century. Three years later, in 1862, Wlodzimierz Brodowski delivered to the
      students of Medical and Surgery Academy in Warsaw a lecture "Introduction to the
      lecture on pathological anatomy" which was later printed in "Pamietnik
      Towarzystwa Lekarskiego Warszawskiego" ("Diary of Warsaw Medical Association").
      He presented the development of pathological anatomy along with the achievements
      of Virchow. Brodowski was the first Polish anatomopathologist who lectured to
      students on Virchow's theory. Moreover, a paper "Scientific activity of Rudolf
      Virchow and its importance for medicine" by Edward Przewoski was published in the
      series "Clinical Lectures" issued by the editors of "Gazeta Lekarska" ("Medical
      Magazine") in 1892. The article included a detailed description of the scientific
      activity of that outstanding scholar. Apart from the above mentioned examples,
      Virchow's opinion not only on pathological anatomy and medicine but also on, for
      example, anthropology was often presented. Rudolf Virchow's death was announced
      in all the then Polish medical magazines.

PMID- 12476620
TI  - Silicoproteinosis of the lung in a 49-year-old man.
AB  - We report a rare case of silicosis, histologically corresponding to
      silicoproteinosis and tuberculosis, in a man working consecutively as a miner,
      blacksmith and founder. A microscopic study revealed deposits in alveoli, in
      which immunohistochemistry did not reveal surfactant (SP-A), that was present in
      the alveolar fluid in alveolar lipoproteinosis.

PMID- 12476621
TI  - Ectopic thyroid tissue as a tumour of the heart--case report and review of the
      literature.
AB  - Here we report a case of a 48-year-old woman with ectopic thyroid tissue in the
      right ventricle. The tumour involved 1/3 of the ventricle and adhered to the
      myocardium. The lesion was removed completely and a bioprosthesis was placed due
      to tricuspid insufficiency, and then a pacemaker was implanted. The diagnosis was
      made upon examination of the postoperative tissue. The paper discusses
      embryological implications of the development of thyroid tissue in the heart.
      This case is first in the Polish literature.

PMID- 12476622
TI  - Primary undifferentiated small cell carcinoma (Merkel cell carcinoma) in a
      patient after heart transplantation--case report.
AB  - Here we report a case of a 48-year-old man after heart transplantation in whom
      two years after the procedure an appendage germ tumour was diagnosed and a year
      after its removal in the same area a primary undifferentiated small cell
      carcinoma (Merkel cell carcinoma) with metastases to the axillary lymph nodes was
      detected. The diagnosis of Merkel cell carcinoma was confirmed by
      immunohistochemical staining showing a typical perinuclear expression of
      cytokeratin 20 with the absence of reactivity with wide spectrum cytokeratin and
      the presence of neuroendocrine markers of neurone-specific enolase and
      chromogranin. Primary undifferentiated small cell carcinoma occurs more
      frequently in patients receiving immunosuppressive treatment as compared with a
      general population and occurs much more frequently in those below 50 years of
      age.

PMID- 12476623
TI  - [Non-palpable testicle--the role of laparoscopy].
AB  - We report our experience with 133 children treated laparoscopically for non
      palpable testis during the last eight years. Diagnostic laparoscopy eventually
      combined with orchiectomy, for atrophic testicle, was performed in 59 patients.
      An apparently normal-sized intra-abdominal testicle was found in 74 patients, ten
      of whom were bilaterally affected. In 21 children, whose testicle were located in
      the vicinity of the internal ring, immediate laparoscopic-assisted orchidopexy
      was carried out. All other 53 children underwent two-stage Fowler-Stephens
      laparoscopic orchidopexy, only four of whom developed testicular atrophy. New
      insight concerning germ cell maturation dictates a revised protocol of hormonal
      therapy followed by early surgical intervention. Hopefully, this will further
      improve the superior outcome reported herein, similar to that in most of the
      recent series, which have established the laparoscopic management of non-palpable
      testicles as "state of the art".

PMID- 12476625
TI  - [Traumatic benign paroxysmal positional vertigo: diagnosis and treatment].
AB  - Although head trauma is the cause of Benign Paroxysmal Positional Vertigo (BPPV)
      in about 15% of cases, the clinical features and response to treatment in this
      particular group of patients was not previously evaluated. We present 20 cases of
      traumatic BPPV: 12 cases identified from 150 consecutive BPPV patients diagnosed
      in our Dizziness Clinic; and 8 cases diagnosed from 75 consecutive head trauma
      patients seen in the Emergency Room. In all patients the clinical diagnosis was
      confirmed by the Dix-Hallpike maneuver and all were treated by the Epley
      procedure. Treatment results were compared to those of 40 consecutive patients
      with idiopathic BPPV. There was a wide spectrum and severity of head trauma
      including road accident (7), different falls (5), blow to the head (5) and
      miscellaneous (3). Two patients experienced brief loss of consciousness. Only two
      patients were diagnosed as BPPV before referral to our clinic. When presented to
      our Dizziness Clinic the patients were diagnosed as follows: unspecified
      dizziness (7), cervical vertigo (4) and transient ischemic attack (1). Five
      patients (25%) had bilateral BPPV. Eight patients (40%) had complete resolution
      of symptoms and signs following a single treatment while 12 patients (60%)
      required additional physical treatments until complete resolution of BPPV was
      achieved. During follow-up, 11 patients (55%) had recurrent attacks of BPPV.
      Thirty-four patients with idiopathic BPPV (85%) had a single successful treatment
      session while the others required repeated physical treatments until complete
      resolution of BPPV. We conclude that traumatic BPPV is probably under-recognized
      or misdiagnosed in clinical practice. Response to a single physical treatment
      seems to be less favorable than in idiopathic BPPV. The Dix-Hallpike maneuver is
      mandatory in all patients with dizziness and vertigo following head trauma.

PMID- 12476624
TI  - [The prevention programs for beta thalassemia in the Jezreel and Eiron valleys:
      results of fifteen years experience].
AB  - beta thalassemia is an hereditary disease caused by mutations in the beta globin
      gene. The clinical course is characterized by chronic hemolytic anemia that
      required regular blood transfusions. Secondary to the blood transfusions,
      patients developed severe hemosiderosis that can cause death in the early
      twenties unless appropriate iron chelator therapy is given. Due to the severity
      of the disease and the expensive treatment, a prevention program should be
      instituted. We report our experience in a prevention program among pregnant women
      in the Jezreel and Eiron Valleys during a period of fifteen years. RESULTS: A
      total of women were screened for beta thalassemia. Within this group, 928 were
      found to be carriers and 180 couples were found to be at risk to deliver an
      affected baby. Two hundred and fifty nine prenatal diagnoses were performed and
      in 45 cases the parents decided to abort the affected child. In ten cases the
      parents choose to deliver an affected baby. Fifteen different beta globin
      mutations were detected in the area covered by the program. CONCLUSIONS: A
      prevention program among pregnant women is feasible and prevents most of the new
      cases of hemoglobinopathies in the covered area. RECOMMENDATIONS: Based on our
      experience, and the relative low cost of this program, we recommend instituting a
      national prevention program for beta thalassemia throughout the country.

PMID- 12476626
TI  - [Ivermectin and the treatment of outbreaks of scabies in medical facilities].
AB  - In cramped facilities, including hospital wards and nursing homes, secondary
      spread of scabies to staff and patients can be widespread. This is frequently
      facilitated by a delay in diagnosis, which is not infrequent in elderly and
      immune compromised patients. A particular problem is presented in cases of
      crusted scabies--a form of hyperinfection. The common topical treatments for
      scabies share several drawbacks including compliance, slow regression of symptoms
      and failure with non-meticulous application. In crusted scabies treatment failure
      is not infrequent. Ivermectin is a drug effective against various ecto and endo
      parasites. We describe 2 typical cases of crusted scabies, one leading to an
      outbreak of scabies in a medical ward and another that was treated with
      Ivermectin. An evidence-based review of the literature shows Ivermectin to be at
      least as effective as topical treatment, with the advantages of the ease in
      treating large populations, good compliance and safety. Approval of this drug for
      this indication should be considered.

PMID- 12476627
TI  - [Porto-systemic shunts in children: Schneider Children's Medical Center
      experience].
AB  - Portal hypertension in the absence of liver disease in children remains a
      therapeutic challenge. Despite successful control of variceal bleeding in most
      children, the risk of massive GI bleeding and mechanical disturbance of a huge
      spleen associated with hypersplenism exists throughout life. Surgical shunt
      between the portal and systemic venous systems is considered a definitive
      solution for that problem. AIMS: We present our experience with the porto
      systemic shunt for extrahepatic portal hypertension. PATIENTS AND METHODS: Nine
      children (mean age 11.4 years) with portal hypertension were referred for a shunt
      procedure during a 5-year period (1996-2001). We reviewed patients charts for
      clinical parameters before and after surgery as well as surgical data (type of
      shunt, portal pressure gradient). A mesocaval shunt was constructed in 5
      children, a splenorenal shunt in 3 other children and one child with splenic vein
      thrombosis underwent splenectomy alone for presumed diagnosis of left sided
      portal hypertension. RESULTS: During a mean follow-up period of 21.2 months
      (range 6-63 months), the surgical shunt remained patent in 7 of the 8 children.
      An immediate drop in portal pressure and increased platelets count over time was
      noted in those 7 children. In two children high portal pressure persisted after
      surgery, including a child who underwent mesocaval shunt following a previous
      failed splenorenal shunt and another child who underwent splenectomy alone. None
      of the children bled following the shunt procedure and decreased splenic size was
      observed in the 3 children with massive splenomegaly. CONCLUSIONS: We suggest
      that the porto-systemic shunt is indicated for children with non-hepatic portal
      hypertension suffering with uncontrolled bleeding and those with massive
      splenomegaly associated with hypersplenism.

PMID- 12476628
TI  - [The severity and prolonged morbidity of community acquired pneumonia caused by
      group A Streptococcus].
AB  - We describe a case report of a sixteen year old patient who was admitted with
      severe group A streptococcal (GAS) pleuro-pneumonia, underwent pleurocentesis and
      recovered after two weeks of hospitalization, although complete recovery lasted
      for another three weeks. The present publication aims to highlight the severe,
      prolonged and complicated course of GAS pneumonia in children which has not yet
      been reported in Israel. Accurate diagnosis is crucial for appropriate therapy,
      which is a prolonged i.v. course of penicillin.

PMID- 12476629
TI  - [Crescentic glomerulonephritis and cerebral vasculitis in the course of Henoch
      Schonlein purpura].
AB  - Henoch-Schonlein purpura (HSP) is a systemic vasculitic disorder involving both
      arterioles and capillaries. Although mainly a disease of early childhood, it can
      occur at any age. HSP is typically recognized as a syndrome with four major
      components: rash, joint manifestations, abdominal symptoms and renal disease. It
      is usually a mild condition with a tendency to relapses and generally has a good
      prognosis. Occasionally, however, it takes on an aggressive course.
      Gastrointestinal involvement is potentially the most serious complication of HSP.
      It may mimic an abdominal emergency and in its severest form result in small
      bowel infarction and/or perforation. Renal manifestations range from asymptomatic
      haematuria and/or proteinuria through a nephrotic syndrome to progressive
      glomerulonephritis leading to end stage renal failure. Apart from the major
      components outlined above, HSP may affect almost every other bodily organ.
      Vasculitis involving the myocard, lungs (pulmonary haemorrhage), ureter
      (stenosing ureteritis) and nervous system have been reported. We describe a case
      of HSP in a 50 year old woman which was complicated by the development of
      necrotizing crescentic glomerulonephritis and a left hemiparesis due to cerebral
      vasculitis. Interestingly, this patient had first appeared at the age of 9 years
      with a nephrotic syndrome and had been diagnosed by renal biopsy at the age of 31
      as IgA nephropathy (IgAN). On her current admission, steroid and
      immunosuppressive therapy resulted in an improvement of renal function and an
      almost complete disappearance of her neurologic deficit.

PMID- 12476630
TI  - [Prevention of homozygous beta thalassemia].

PMID- 12476631
TI  - [Anti-TNF-alpha treatment and spondyloarthropathies].
AB  - Spondyloarthropathies are characterized by both axial and peripheral joint
      involvement, by the association with "other diseases" mainly Psoriasis, Crohn's
      and Anterior Uveitis and by the high prevalence of HLA B-27. While disease
      modifying drugs, such as Methotrexate or Sulfasalazine, are only partially
      effective in controlling peripheral arthritis, the treatment of the axial part
      remained only symptomatic. The recently introduced anti-TNF-alpha drugs
      Infliximab (Remicade) and Etanercept (Enbrel) for the treatment of Crohn's
      disease and Rheumatoid Arthritis has been expended to Spondyloarthropathies with
      highly promising results. The rationale and the early beneficial results of this
      new approach in spondyloarthropathies are reviewed.

PMID- 12476632
TI  - [Heat shock proteins and malignancies of the female genital tract].
AB  - Heat shock proteins (Hsp) are cytoplasmic proteins that act as molecular
      chaperones for protein molecules in various intra-cellular processes. They play
      an important role in protein-protein interactions, including folding and
      conformation, and prevention of inappropriate protein aggregation. They are
      called "heat shock proteins" since they were first discovered in cells exposed to
      high temperatures. However, their synthesis is also accentuated under other
      stress conditions, such as exposure of the cell to inflammation, infection,
      ischemia, toxins, cytotoxic drugs and malignant transformation. Hsp have been
      classified into families according to their molecular weight. In ovarian
      carcinoma, over-expression of Hsp27 was associated with increased resistance to
      chemotherapy and a worse prognosis. In endometrial carcinoma, over-expression of
      Hsp70 was associated with poorly differentiated tumors and a worse prognosis,
      whereas over-expression of Hsp27 and Hsp90 were associated with well
      differentiated tumors and better prognosis. The association between increasing
      expression of Hsp90 and better differentiation and prognosis seems to reflect
      high levels of sex steroid receptors in well-differentiated endometrial
      carcinomas. In cervical carcinoma, the presence of Hsp70 was associated with a
      worse outcome. Since Hsp are highly antigenic, their property to bind with tumor
      proteins and proteins produced by viruses may be used for the development of
      vaccines against cancers and viral diseases. It is speculated that examination of
      the lower genital tract secretions for IgA antibodies against Hsp will contribute
      to early detection of malignancies. Since Hsp may affect the growth of the tumor
      and its response to chemotherapy, it is speculated that using drugs that inhibit
      Hsp in combination with conventional chemotherapy may contribute to the
      improvement of the treatment results.

PMID- 12476633
TI  - [Fibrotic diseases].
AB  - Fibrosis is a pathologic process, which includes scar formation and over
      production of extracellular matrix, by the connective tissue, as a response to
      tissue damage. The molecular process is not different from normal formation of
      connective tissue and extracellular matrix in the normal organs. The context, the
      environment and the over production make the difference. Fibrosis formation
      includes interaction between many cell types and cytokines, and when the balance
      becomes profibrotic, there is fibrosis formation. Major profibrotic agents are
      type 2 CD4 positive lymphocytes, CD40 receptor and ligand interaction, and the
      following cytokines: IL-4, transforming growth factor b, platelet derived growth
      factor. The major antifibrotic agent is interferon gamma. Pathologies include: in
      the skin pathologic scarring as colloid and hypertrophic scar, cirrhosis of liver
      and gallbladder, in the heart and the kidneys, pulmonary and bone-marrow
      fibrosis, and scleroderma. Scleroderma is chronic connective tissue disease,
      expressed clinically by systemic sclerosis and diffuses fibrosis of the skin and
      viscera. This is a progressive degenerative disorder of the blood vessels, skin,
      lungs, kidneys, heart and GI tract and for this reason this disease plays a major
      role in fibrosis research. Fibrosis is considered an irreversible process, at
      least clinically, and is usually treated by anti-inflammatory and
      immunosuppressive agents. This kind of therapy was not proven successful and
      sometimes it harms more than cures. Many patients suffer from fibrotic diseases
      and the aim is to develop anti-fibrotic agents, targeted to the pathologic
      molecular process. Progressing step by step in this issue has direct clinic
      affect.

PMID- 12476634
TI  - [The yearly distribution of suicide and parasuicide].
AB  - The current psychiatric literature emphasizes the important risk factors of
      suicide and parasuicide, which include the following: age, family status,
      psychopathology, substance abuse, biological markers and so forth. Recently, more
      emphasis has been placed on the yearly distribution of suicide and parasuicide.
      This distribution includes parameters such as national and religious holidays,
      birthdays, anniversary days, the lunar cycle and weather. It has been suggested
      by many researchers that this distribution is an important precipitant to a
      cumulative and complicated psycho-pathological process, terminating in suicidal
      behavior. Analysis of theories and research findings regarding these topics are
      provided, together with suggestions for research and prevention.

PMID- 12476635
TI  - [Pneumocystis carinii pneumonia in patients without acquired immunodeficiency
      syndrome (AIDS)].
AB  - The incidence of Pneumocystis Carinii pneumonia (PCP) may rise due to a more
      extensive use of immunosuppressive therapy. Information and guidelines in the
      last decade regarding prevention, diagnosis and treatment of the disease were
      based upon data collected in patients with Acquired Immuno Deficiency Syndrome
      (AIDS). However, scientific data regarding risk factors, clinical manifestations
      and treatment of PCP in patients without AIDS is accumulating. The major risk
      factors for acquiring PCP are hematological malignancies and treatment with
      immunosuppressive drugs, especially corticosteroids. The clinical course
      deteriorates more rapidly than in patients with AIDS and many patients have other
      opportunistic coinfections, especially with Cytomegalovirus and Candida. The
      duration of treatment may be shorter and drug tolerance is usually better than in
      patients with AIDS. However, mortality remains high even with appropriate
      treatment and necessitates a high index of suspicion and the use of empiric
      treatment even before a definitive diagnosis is made.

PMID- 12476636
TI  - [On healthcare quality].
AB  - The quality of health care can be defined and measured. The "health basket" and
      private practice are parameters on the quality of care, whilst each has its
      problems and is under attack. Additional factors influencing the quality of care
      are: under-use, over-use and ill-use. Errors, both organizational and individual,
      adversely affect the quality of care. Errors can be prevented by correct planning
      of care systems, including diagnostic and treatment protocols and
      multidisciplinary methodologies incorporating joint control and evaluation. The
      reporting of both errors and normal results, within institutions as well as
      publicly, are vastly important in fostering a culture of quality. In contrast
      with industry, in which the six sigma/3.4 failures per million opportunities has
      been widely and successfully implemented--there is no systematic approach to
      error reduction in health care. An effort to improve quality begins with
      education and continues through the use in health care of methodologies utilizing
      protocols supported by evidence-based medical practice. The illustrious clinician
      of old differs from today's sought after practitioner. The correct blend of these
      ingredients can induce a breakthrough into a higher quality of care.

PMID- 12476637
TI  - [Hormone replacement therapy in breast cancer survivors: the Israeli Society for
      Clinical Oncology and Radiotherapy policy letter].
AB  - The Israeli Society for Clinical Oncology and Radiotherapy requested that experts
      in breast cancer therapy assess the Society's policy regarding the use of hormone
      replacement therapy (HRT) in breast cancer survivors. The following
      recommendations are based on updated literature, which is limited since it
      summarizes only retrospective data. There is currently no evidence of an
      increased risk of breast cancer recurrence, death attributable to cancer, or
      overall mortality among breast cancer survivors who use HRT. We therefore
      recommend that there is no need to avoid HRT in women with menopausal symptoms
      who are interested in receiving such treatment, as long as ovarian ablation does
      not play a major role in their adjuvant therapy. Women should be informed about
      the limitations of available data. There are some concerns regarding the use of
      HRT in patients whose tumors developed while undergoing HRT and in such cases
      treatment should be reserved only for those with severe menopausal symptoms. For
      women with milder symptoms or those who are not interested in HRT, other
      treatment options should be outlined. The policy should be updated according to
      future publication of results from ongoing randomized prospective studies.

PMID- 12476638
TI  - [Israel Medical Association conference on the role of physician in the prevention
      of elderly abuse].

PMID- 12476639
TI  - Applying business management models in health care.
AB  - Most health care management training programmes and textbooks focus on only one
      or two models or conceptual frameworks, but the increasing complexity of health
      care organizations and their environments worldwide means that a broader
      perspective is needed. This paper reviews five management models developed for
      business organizations and analyses issues related to their application in health
      care. Three older, more 'traditional' models are first presented. These include
      the functional areas model, the tasks model and the roles model. Each is shown to
      provide a valuable perspective, but to have limitations if used in isolation. Two
      newer, more 'innovative' models are next discussed. These include total quality
      management (TQM) and reengineering. They have shown potential for enabling
      dramatic improvements in quality and cost, but have also been found to be more
      difficult to implement. A series of 'lessons learned' are presented to illustrate
      key success factors for applying them in health care organizations. In sum, each
      of the five models is shown to provide a useful perspective for health care
      management. Health care managers should gain experience and training with a
      broader set of business management models.

PMID- 12476640
TI  - Regional planning implementation and its impact on integration of a mental health
      care network.
AB  - This article questions the effectiveness of a managerial tool in changing a
      health-care system. The process of implementing regional planning and its impact
      on creating integrated service networks is examined, using a case study and a
      multi-dimensional analytic model. This model highlights the influence of
      contextual, structural, cultural and dynamic factors on forming networks. The
      regional planning developed in the province of Quebec (Canada), aimed at a major
      transformation of the mental health-care system. In each district, organizations
      working with people who have serious mental disorders were mobilized to plan and
      implement a more coordinated, continuous and diversified supply of services,
      under the direction of a regional health body. This study outlines the
      limitations of regional planning as a tactic for transforming the system. It
      recommends instead developing more diversified integration strategies to further
      the process of forming integrated service networks within a complex system. In
      conclusion, a brief discussion deals with the difficulties related to the study
      of systemic change implementation.

PMID- 12476641
TI  - A shared mission? Changing relationships between government and church health
      services in Africa.
AB  - This article reviews the relationships between government and church health
      providers within sub-Saharan Africa with a particular focus on East and Southern
      Africa. This is of particular interest at this time, given the changing
      configuration of the health sector in many countries as a result of health sector
      reform policies. The article provides a historical overview of the development
      and emerging role of the church health services within this changing environment.
      The factors affecting the relationship between the government and church sector
      are identified. These include differences in objectives, types of service
      provided, and the organizational culture and management styles. The paper then
      explores key issues seen to affect the future pattern of relationships including
      the changing scene, and identifies different models for relationships and
      implications for key actors including the Ministry of Health, church health
      agencies and coordinating bodies. The article concludes that church health
      services will continue to play a key role in health care in sub-Saharan Africa;
      however, there are challenges facing them and both parties need to develop a
      response to these.

PMID- 12476642
TI  - The relative prevalence of disease symptoms for ill persons: evidence from Benin.
AB  - In developing countries, the usual modelling of the correlates of health problems
      is not a good fit for the health phenomena encountered and the available data.
      Indeed, three common situations occur: (a) it is often the observed symptoms that
      are used to determine medical interventions instead of specific disease
      diagnostics or general health indicators; (b) the ill persons described by the
      data are often affected by multiple health problems; and (c) the correlates of
      the full spectrum of all symptoms need to be considered together. In this paper,
      these issues are dealt with by proposing a statistical approach based on
      competing scores of symptoms that explain their relative prevalence among the
      observed ill persons. Using multinomial logit models, the relative prevalence of
      four symptoms was estimated for four age classes of ill persons in Benin. Socio
      demographic characteristics, household equipment and consumption behaviour are
      shown to influence the relative prevalence of symptoms and therefore could be
      used to decide what treatment to use. Moreover, living standards and economic
      activities are important and the pattern of symptoms among poor or agricultural
      ill persons differs from that of the rich or the non-peasants. The proposed
      method can be used to assist the definition of target groups and to guide the
      allocation of scarce resources in poor countries.

PMID- 12476643
TI  - Access to health care in a system transition: the case of Bulgaria.
AB  - OBJECTIVE: Throughout the 1990s, the Soviet-style model in central and eastern
      Europe that provided free health services has been subject to radical reforms.
      Socio-economic inequalities have also increased but there is little information
      on inequalities in health care utilization. This paper examines the pattern of
      illness behaviour in Bulgaria, seeking evidence of inequalities in access to
      services and eliciting users' pathways to care. DESIGN: Analysis drew on a
      representative population survey in Bulgaria (1997). The financial determinants
      of service use were tested in a multivariate model adjusted first for age, and
      then for age, marital status and self-reported health. In-depth interviews with
      users and providers addressed pathways to care, use of connections and other
      informal strategies to obtain care. RESULTS: As expected, rates of illness vary
      with income, with highest rates among the poor. After adjustment for illness,
      consultation rates are relatively equal across income levels, with the exception
      of worse-off women who tend to consult more. For first contact, there are few
      differences according to income, with the better off preferring secondary level.
      Pathways slightly differ, with women more often treated in primary care. Private
      sector utilization is low. Qualitative research reveals well-established
      strategies to obtain more advanced care, including use of connections, informal
      payments and use of emergency services. CONCLUSIONS: An apparent lack of
      inequalities in access to care conceals a more complex picture in which income
      and gender influence the pathways taken through the system.

PMID- 12476644
TI  - Outbreak of influenza, Madagascar, July-August 2002.

PMID- 12476645
TI  - Cardiovascular Interventions 2002: XIIIth International Course on Interventional
      Cardiology, Frankfurt/Main, Germany.

PMID- 12476646
TI  - Vulnerable plaque: the pathology of unstable coronary lesions.
AB  - Vulnerable plaques have been defined as precursors to lesions that rupture.
      However, coronary thrombosis may occur from other lesions like plaque erosion and
      calcified nodules, although to a lesser frequency than rupture. Therefore, the
      definition of vulnerable plaque should be all-inclusive. Using descriptive
      terminology, the authors define the precursor lesion of plaque rupture as "thin
      cap fibroatheroma" (TCFA). Morphologically, TCFAs have a necrotic core with an
      overlying thin fibrous cap (< 65 mm) consisting of collagen type I, which is
      infiltrated by macrophages. These lesions are most frequent in the coronary tree
      of patients dying with acute myocardial infarction and least common in those with
      plaque erosion. TCFAs are more common in patients with high serum total
      cholesterol (TC) and a high TC to high density cholesterol ratio, in women > 50
      years, and in those patients with elevated levels of high sensitivity C-reactive
      protein. TCFAs are mostly found in the proximal left anterior descending coronary
      arteries and less commonly in the proximal right or the proximal left circumflex
      coronary arteries. In TCFAs, necrotic core length is approximately 2-17 mm (mean
      8 mm) and the underlying cross-sectional luminal narrowing in over 75% of cases
      is < 75% (< 50% diameter stenosis). The area of the necrotic core in at least 75%
      of cases is < or = 3 mm2. Clinical studies of TCFAs are limited as angiography
      and intravascular ultrasound (IVUS) catheters cannot precisely identify these
      lesions. Newer catheters and other techniques are at various stages of
      development and will play a significant role in the understanding of plaque
      progression and the development of symptomatic coronary artery disease.

PMID- 12476647
TI  - Intracoronary ultrasound in acute coronary syndromes: from characterization of
      vulnerable plaques to guidance of percutaneous treatment of complex stenoses.
AB  - Our current knowledge on the substrate and genesis of acute coronary syndromes
      (ACS) results from the integration of pathological, angiographic, and
      intracoronary imaging techniques. To summarize briefly the current paradigm,
      eight differentiated stages of development of atherosclerotic lesions are
      currently accepted, defined not only by the cellular elements involved, but also
      by the appearance of sudden alterations of plaque structure and coronary
      thrombosis. The latter constitutes not only the dominant substrate for the most
      devastating manifestations of coronary artery disease, but also accelerates
      plaque size at a faster pace than in earlier stages. The composition of
      atherosclerotic plaque varies significantly along the different evolutive stages,
      and thus includes cellular (macrophage, smooth muscle cells) and noncellular
      elements (glicosaminglycan or collagen-rich cellular matrix, extracellular lipid
      deposits, calcification, fresh, or organized thrombus) in a varying proportion.
      Furthermore, a dynamic process of vessel remodeling occurs along the
      atherosclerotic process, resulting, in most cases, in a protective mechanism
      against myocardial ischemia by preserving luminal dimensions during plaque
      enlargement. Intravascular ultrasound (IVUS) is one of the intracoronary imaging
      techniques that has contributed to the understanding of these changes in man. In
      addition, IVUS has the potential of being a useful clinical tool for predicting
      the chances of future acute coronary events by identifying vulnerable plaques, of
      characterizing which is the culprit lesion in ACS, and in guiding
      revascularization procedures in the treacherous field of thrombotic coronary
      syndromes. In this article, we review the current evidence on the potential of
      IVUS imaging for fulfilling these purposes.

PMID- 12476648
TI  - Thermography of the cardiovascular system.
AB  - The identification of vulnerable plaque is one of the primary goals in cardiology
      during the last years. Several techniques have been developed for the anatomic
      and functional assessment of atherosclerotic plaques. Thermography is a new
      method for the evaluation of the inflammatory process locally within the
      atherosclerotic plaque. Several animal and clinical studies demonstrated the
      value of thermography not only for the detection of inflamed atherosclerotic
      plaques, but its use in new fields like in the evaluation of inflammation in the
      coronary vascular bed and the cardiovascular system. This article reviews the
      developments and the clinical implications of thermography.

PMID- 12476649
TI  - Sirolimus-eluting coronary stents.

PMID- 12476650
TI  - Initial experience with paclitaxel-coated stents.
AB  - Local delivery of immunosuppressive or antiproliferative agents using a drug
      eluting stent is a new technology that is supposed to inhibit in-stent
      restenosis, thus providing a biological and mechanical solution. This technique
      is a very promising. To date, several agents have been used, including
      paclitaxel, QP-2, rapamycin, actinomycin D, dexamethason, tacrolimus, and
      everolimus. Several studies, published recently or still ongoing, have evaluated
      these drugs as to their release kinetics, effective dosage, safety in clinical
      practice, and benefit. These studies include: SCORE (paclitaxel derivative),
      TAXUS I-VI, ELUTES, ASPECT, DELIVER (paclitaxel), RAVEL, SIRIUS (sirolimus),
      ACTION (actinomycin), EVIDENT, PRESENT (tacrolimus), EMPEROR (dexamethason), and
      FUTURE (everolimus). Paclitaxel was one of the first stent-based
      antiproliferative agents under clinical investigation that provided profound
      inhibition of neointimal thickening depending on delivery duration and drug
      dosage. The randomized, multicenter SCORE trail (Quanam stent, paclitaxel-coated)
      enrolled 266 patients at 17 sites. At 6-month's follow-up, a drop of 83% in stent
      restenosis using the drug-eluting stent could be achieved (6.4% drug-eluting
      stent vs 36.9% control group), which was attributable to a remarkable decrease in
      intimal proliferation. Unfortunately, due to frequent stent thrombosis and side
      branch occlusions, the reported 30-day MACE rate was 10.2%. The randomized TAXUS
      I safety trial (BSC, NIRx, paclitaxel-coated) also demonstrated beneficial
      reduction of restenotic lesions at 6-month's follow-up (0% vs 10%) but was
      associated with the absence of thrombotic events presumably due to less drug
      dosage. The ongoing TAXUS II-VI trials are addressing additional insight
      regarding the efficacy of the TAXUS paclitaxel-eluting stent. ASPECT and ELUTES
      evaluated paclitaxel-coated stents (i.e., Cook and Supra G), including subgroups
      with different drug dosages. With respect to stent restenosis and neointimal
      proliferation, both studies demonstrated a clear dose response. The RAVEL and the
      SIRIUS trials evaluated sirolimus-coated stents (i.e., Cordis, Johnson & Johnson,
      and Bx VELOCITY stents). Results confirmed the beneficial findings regarding
      reduction of renarrowing using a drug-eluting stent without any major adverse
      effects. Although parameters such as drug toxicity, optimal drug dosage, or
      delayed endothelial healing still need to be evaluated, today's clinical
      experience indicates that drug-coated stents are extremely beneficial in the
      interventional treatment of coronary lesions.

PMID- 12476651
TI  - Prevention of stent thrombosis following brachytherapy and implantation of drug
      eluting stents.
AB  - The implementation of coronary brachytherapy and especially the application of
      drug-eluting stents for the prevention of in-stent restenosis are of vital
      importance in the field of interventional cardiology. Despite undeniable benefits
      of these new methods a potential increased risk for the occurrence of stent
      thrombosis as a result of the mode of action of these new methods has to be taken
      into consideration. The prevention of stent thrombosis following coronary
      brachytherapy and implantation of drug-eluting stents is therefore of particular
      importance to assure the success of these forward-looking technologies. This
      article provides an overview of current data regarding the incidence of stent
      thrombosis following brachytherapy and implantation of drug-eluting stents and
      it's implication for clinical practice.

PMID- 12476652
TI  - Embolic protection devices.
AB  - The limiting factor in coronary artery bypass surgery is the relatively rapid
      progression of atheromatous disease in the saphenous vein grafts. Greater than
      one-half of these vein grafts will fail by 10 years, and the risks associated
      with repeat coronary artery bypass surgery are significantly greater than that of
      the initial surgery. Yet, catheter-based interventional treatment of saphenous
      vein grafts is hindered by distal embolization of friable lipidrich plaque. This
      is one mechanism responsible for reduced antegrade flow (i.e., "no-reflow"
      phenomenon), including spasm of the distal microcirculation and platelet
      clumping. This complication increases the risk of a major adverse clinical event
      (i.e., myocardial infarction or late mortality). Distal protection devices are
      designed to provide protection of the distal microcirculation during percutaneous
      intervention. One device type is a balloon occlusive system that temporarily
      occludes the distal vessel during the intervention followed by the aspiration of
      liberated atheromatous and thrombotic material before it reaches the arteriolar
      and capillary bed. The other device type is a nonocclusive, filter-based system
      that preserves coronary blood flow through tiny pores, as low as 100 microns.
      Atheromatous and thrombotic material is trapped in the filter-based systems and
      then removed with the retrieval of the device through a retrieval catheter. This
      article discusses the current distal protective devices.

PMID- 12476653
TI  - Guiding catheter aspiration to prevent embolic events during saphenous vein graft
      intervention.
AB  - Percutaneous coronary interventions (PCI) in saphenous vein graft (SVG) stenosis
      carries 10%-20% risk of major adverse clinical events (MACE) or reduced antigrade
      flow (No-reflow Phenomena). The PercuSurge device is not available at all United
      States hospitals and sometimes anatomically cannot be placed (distal stenosis).
      We developed a simple technique for use in patients who could not have the
      PercuSurge device placed during PCI of SVG. METHODS: The basic concept of this
      technique is the use of guiding catheter aspiration during PCI. Over a two-year
      period, seven patients underwent PCI in SVG, using this technique for symptomatic
      stenosis. They were all males, average SVG age was 14 +/- 6 years, 43% were
      degenerated SVG's, four (57%) had new stents placed, and three (43%) had
      percutaneous transluminal coronary angioplasty (PTCA) or cutting balloon therapy.
      All patients were pretreated with aspirin and clopidogrel and had baseline
      preprocedure serum creatine kinase (CK) and ECG. Following the procedure,
      patients had repeat serum CK and ECG eights hours post-procedure. No patients
      received glycoprotein platelets inhibitors. RESULTS: Twenty to 60 mL of blood
      with gross macroscopic material was recovered during aspiration. None of the
      patients experienced no-reflow phenomena or had major elevated CKs during the
      procedure as defined as 5 x normal baseline. Thirty-day MACE in all patients was
      zero. CONCLUSION: The pilot study suggests that guiding catheter aspiration may
      be effective in reducing MACE is some patients undergoing PCA in SVG.

PMID- 12476654
TI  - Role of distal protection during carotid stenting.
AB  - The most common complication of carotid angioplasty is distal embolization of
      debris and/or thrombus. The only way to avoid this complication is with the use
      of embolic protection devices. Several filters, distal balloon occlusion devices,
      and proximal balloon occlusion devices are available. These devices make it
      possible to capture arteriosclerotic debris during angioplasty and stenting.
      During the majority of procedures at least some particles can be retrieved.
      Therefore there is no doubt that these devices are important for carotid
      angioplasty. However, due to the low complication rate of carotid angioplasty
      even without embolic protection devices, large randomized trials are necessary to
      statistically prove the clinical efficacy of these devices.

PMID- 12476655
TI  - Incidence, prevention, and treatment of vascular perforations complicating
      coronary interventions.

PMID- 12476656
TI  - Vascular growth factors for coronary angiogenesis.
AB  - Coronary artery disease not amendable to conventional revascularization poses a
      significant medical problem. Advances in the understanding of blood vessel growth
      have given rise to efforts to develop novel therapeutic approaches for these "no
      option" patients. Therapeutic angiogenesis makes use of the administration of
      angiogenic growth factor protein or gene to promote the development of endogenous
      collateral vessels in ischemic myocardium. Among the growth factors that play a
      role in blood vessel growth and development, vascular endothelial growth factors
      (VEGFs) and fibroblast growth factors have been the most extensively studied.
      Various methods of delivery have been used to enhance localization and
      persistence. Preliminary animal experiments have been promising with evidence of
      capillary formation at the target myocardium after growth factor administration.
      Initial phase I and II clinical trials have been undertaken. Preliminary
      information on efficacy is beginning to become available, raising hopes and
      questions about the future direction and potential success of therapeutic
      angiogenesis as a clinical approach to the treatment of myocardial ischemia.
      Although the initial clinical results are encouraging, real efficacy has still to
      be proven and the potential side-effects of these potent angiogenic growth
      factors remain a concern. Large-scale, randomized, and placebo-controlled studies
      will be required to demonstrate the true clinical benefit of this novel
      therapeutic treatment for ischemic heart disease.

PMID- 12476657
TI  - T-stenting with drug-eluting stents for the treatment of bifurcation in-stent
      restenosis.

PMID- 12476658
TI  - Polypharmacy: overdosing on good intentions.
AB  - Polypharmacy, the concurrent use of multiple medications, is a growing problem
      that is more common than most healthcare professionals realize. Most patients are
      seeing multiple doctors and have multiple prescriptions, therefore making it
      difficult for physicians to properly monitor their patients. However, there are
      steps that the healthcare profession can take to reduce the occurrence of
      polypharmacy. The use of a well-designed polypharmacy intervention program can
      help reduce the costs associated with polypharmacy, as well as improve patients'
      health by helping to detect and avoid unnecessary drug use.

PMID- 12476659
TI  - Which prescription for the illegible and unreadable DTC (direct-to-consumer)
      brief summary--major surgery or euthanasia?
AB  - Healthcare costs are rising, mostly because of increased prescription drug use,
      chiefly as the result of direct-to-consumer drug ads on television, newspapers,
      and magazines. However, the FDA's requirement for a brief summary in direct-to
      consumer drug ads has produced summaries that are ineffective because they are
      illegible and unreadable, create information overload, and require literacy
      skills not possessed by most consumers. If the FDA wants brief summaries to be in
      a patient-friendly format, it should provide document design templates and plain
      language examples. Unless brief summaries are written so that they can be
      understood by the average patient, they should be overhauled or done away with.

PMID- 12476660
TI  - Pharmaceutical company sponsored disease management programs: an alternative for
      tax-exempt MCOs and hospitals.
AB  - On April 25, 2002, the Internal Revenue Service finalized the proposed Corporate
      Sponsorship regulations. The changes made in the final regulations pertain to the
      proposed $79 ceiling on disregarded benefits, the 2 percent threshold for
      disregarded benefits, the scope of disregarded benefits, Web site hyperlinks, the
      inclusion of certain electronic publications in the definition of periodicals,
      the valuation date for substantial return benefits, and the scope of use or
      acknowledgement. The proposed regulations were discussed in the Winter 2002 issue
      of Managed Care Quarterly in an article titled the same as this one. This article
      is based on the final IRS regulations and therefore supersedes the original
      article published in the Winter 2002 issue.

PMID- 12476661
TI  - Strategies for managing injectable drugs in a managed care setting.
AB  - Injectable medications represent one of the fastest growing and most expensive
      categories of prescription drugs with costs rising to $26 billion by 2006.
      Historically, managed care organizations have not aggressively overseen this area
      of the prescription benefit, resulting in a disjointed system. However, a growing
      number of MCOs are developing programs to better manage injectable medications.
      Key components of these programs include sophisticated infrastructure, clinical
      management, consolidated databases, and improved pharmaceutical contracting. This
      article presents a new model for managing injectables, illustrated by the
      implementation of a comprehensive injectables' management program for a large
      managed care population that resulted in a 12:1 return on investment.

PMID- 12476662
TI  - Impact of formulary restrictions on the cost-effectiveness of antidepressant
      treatment.
AB  - Newer antidepressants are associated with higher costs of treatment of anxiety
      and depression. Managed care organizations are challenged to control treatment
      costs by implementing restricted formularies based on price and perceived medical
      value. Despite unfavorable side effects of efficacious tricyclic antidepressants,
      the low acquisition cost rationalizes the inclusion of this older class of agents
      on a formulary. On the other hand, cost-containment approaches have been taken
      toward more expensive drug classes (e.g., selective serotonin reuptake
      inhibitors) despite a superior safety profile of these drug classes over
      tricyclics. There is compelling evidence that dual reuptake inhibitors (e.g.,
      venlafaxine extended-release), which have acquisition costs similar to serotonin
      reuptake inhibitors, have a broad spectrum of efficacy and thus added value,
      contributing to the cost-effectiveness of including this agent in the managed
      care formulary. Assessment of overall cost-effectiveness should not be limited by
      acquisition costs but should take total healthcare costs into consideration.

PMID- 12476663
TI  - Managed competition using both market-driven and regulatory strategies.
AB  - The market-driven managed competition concept has been successful in reducing
      increases in healthcare costs by controlling utilization and price, but has
      failed to date to produce an effective and efficient delivery of health services.
      The proposed health reform plan calls for universal access (excluding illegal
      aliens), a relatively broad range of clinically effective basic benefits, an
      option to purchase supplementary benefits, a ceiling placed on the nation's total
      health expenditures, local decisionmakers allocating available resources,
      existing insurers administering the plan and providing consumers with additional
      quality of care comparisons.

PMID- 12476664
TI  - Barriers to healthcare for people with mobility impairments.

PMID- 12476665
TI  - The age wave: knowledgeable and demanding and very, very large.
AB  - Welcome to "Consumer-Centered Care." In this space we examine healthcare quality
      issues from the consumer's point of view. Our focus on quality highlights not
      only how consumers can find quality providers and quality information but also
      how patients can help their doctors provide the best treatments and avoid medical
      mistakes. We bring you news and views, ideas and opinions on what is right and
      what is wrong in consumer health. Any practice, procedure, or approach that does
      not meet the consumer's best interest is open to review.

PMID- 12476666
TI  - How well can your members read your online privacy policy?

PMID- 12476667
TI  - Accountability and effectiveness in disease management.

PMID- 12476668
TI  - Why are HMOs leaving the Federal Employees Health Benefits Program?

PMID- 12476670
TI  - Emergency nurse practitioners: what lies ahead?

PMID- 12476669
TI  - Demanding times.

PMID- 12476671
TI  - Telemedicine: the challenges ahead.

PMID- 12476672
TI  - Care plans for familiar faces.

PMID- 12476673
TI  - Overdose of insulin and other diabetic medication.

PMID- 12476674
TI  - Injury management in the community.

PMID- 12476675
TI  - Biphasic defibrillation.

PMID- 12476676
TI  - [Influenza: a new treatment, oseltamivir].

PMID- 12476677
TI  - [Introduction to pharmaceutical sciences from the faculty of pharmaceutical
      science of Leuven: an experience of cohabitation].
AB  - Teaching Pharmacy Practice as an approach to pharmaceutical care started in 1991
      at the Katholieke Universiteit Leuven (KUL). Although completely new, none of the
      courses related to pharmacy practice was compulsory for all students, due to the
      option system adopted at the Faculty of Pharmaceutical Sciences of the KUL. After
      10 years the number of students choosing for the option community and hospital
      pharmacy (most related to pharmacy practice) is stabilized at about 60% of the
      total number of students. From the very beginning. It was quite difficult to
      harmonize the research field of pharmacy practice with the more fundamentally
      oriented research activities in the different pharmaceutical laboratories. This
      resulted in a "Living Apart Together" (LAT) relationship with some negative
      consequences on activity funding. Nevertheless interesting research projects
      emerged from the Division of Drug and Patient Information. One PhD thesis was
      achieved. In the near future external partners may play an important role in
      structural support of research activities. These research is necessary to ensure
      the presence of pharmaceutical care as a validated discipline in the training of
      future pharmacists.

PMID- 12476678
TI  - [New molecules in 2002].

PMID- 12476679
TI  - Single photon emission computerized tomography in children with developmental
      language disorder--a preliminary report.
AB  - Developmental language disorder (DLD) is a diagnosis given to a nonautistic child
      who has inadequate language acquisition despite adequate hearing, sensorimotor,
      and cognitive skills. We used high-resolution single photon emission computerized
      tomography (SPECT) with labeled technetium-99m-D, L-hexamethyl-propylene amine
      oxime (99mTc-HMPAO) to measure regional cerebral blood flow (rCBF) in 11 children
      with DLD. Their mean age was 5 years 10 months (range, 4 yr 2 mo to 10 yr 9 mo)
      and mean nonverbal IQ was 107 (range, 82-137). When inter-hemispheric flow
      discrepancy was defined as a bilateral rCBF difference of more than 10%, 10
      children (90.9%) had discrepant blood flow. Temporal lobes were involved in all
      10 children: lateral-temporal in five, medial-temporal in four, and mesial
      temporal in four. Though the study was small and the results are preliminary,
      results suggest that DLD may be a consequence of an underlying neurobiologic
      problem in areas of the brain known to be involved with language.

PMID- 12476680
TI  - Finasteride in the treatment of Taiwanese men with androgenetic alopecia: a 12
      month open-label study.
AB  - Finasteride 1 mg/day is effective in the treatment of androgenetic alopecia
      (AGA). Our open-label study assessed the efficacy and safety of finasteride for
      the treatment of Taiwanese men with AGA. We enrolled 34 Taiwanese men (aged 18-40
      yr) with AGA of modified Norwood/Hamilton scale (MNHS) grade II-V. In
      investigator assessments at 12 months, five of 21 subjects (23.8%) had two-grade
      improvement in MNHS grade and 12 of 21 subjects (57.1%) had one-grade
      improvement; the others remained at the same grade. In global photographic
      evaluation, five of 31 subjects (15.1%) had observable hair growth at 6 months
      and 11 of 21 subjects (52.4%) had observable hair growth at 12 months. Patient
      self-assessment of hair growth was favorable across all questions in the
      treatment course, more significantly at 12 months than at 6 months; nine of 21
      subjects (42.9%) were satisfied with their overall appearance at 12 months. Serum
      prostate specific antigen levels had decreased by 23.4% at 12 months. Adverse
      effects, including abnormal liver function (5/34), were minimal, and the causal
      relationship with finasteride could not be established. Thus, in Taiwanese men
      with AGA, finasteride 1 mg/day for 1 year slowed the progression of hair loss and
      increased hair growth.

PMID- 12476681
TI  - Space infection of the head and neck.
AB  - Deep neck infection may be lethal, especially when life-threatening complications
      occur. We conducted a retrospective analysis of 184 patients with deep neck
      infection who were treated at Kaohsiung Medical University Hospital during the
      past 6 years. Factors such as age, sex, hospitalization days, clinical
      presentations, involved spaces, imaging studies, microbiology, and treatment
      method were analyzed. There were 122 men and 62 women with a mean age of 41.7
      years. The average hospitalization was 8.4 days. The involved spaces, determined
      by physical examination and radiologic findings, were the peritonsillar space (59
      patients), parapharyngeal space (77 patients), submandibular space (55 patients),
      and retropharyngeal space (20 patients). Of the 49 patients for whom the origin
      of infection was identified, 29 were infected via the upper respiratory tract and
      13 had infection of odontogenic origin. The most common isolated organism was
      Klebsiella pneumoniae. One hundred and thirty-seven patients (74.5%) underwent
      surgery, including repeated needle aspiration (87 patients) and surgical drainage
      (50 patients). The remaining 47 patients recovered uneventfully with antibiotic
      therapy alone. Eighteen patients developed life-threatening complications, such
      as descending mediastinitis, sepsis, airway obstruction, and jugular vein
      thrombosis. Two patients died of septic shock. The combination of accurate
      diagnosis, effective antibiotic therapy, airway maintenance, and intensive
      surgical debridement for those who fail to respond to conservative treatment will
      lead to a good prognosis.

PMID- 12476682
TI  - Human herpesvirus-8 infection in hemodialysis patients from eastern Taiwan-
      Hualien.
AB  - Human herpesvirus-8 (HHV-8) is the causative agent in Kaposi's sarcoma (KS).
      Uremic or hemodialysis patients are known to be highly susceptible to viral
      infection, and may be at increased risk of developing KS from the increased risk
      of exposure to HHV-8 infection. We collected 77 serum samples from hemodialysis
      patients and 207 serum samples from blood donors. Serum samples were tested for
      HHV-8-specific immunoglobulin G by immunofluorescence assay. Fifteen of 77
      hemodialysis patients (19.5%) had HHV-8 antibodies. The ages of these 15 patients
      ranged from 43 to 89 years (mean, 62 yr). Six of 207 (3.0%) blood donors had HHV
      8 antibodies. Thus, the prevalence of HHV-8 antibodies in hemodialysis patients
      in Hualien is higher than that in normal blood donors. The transmission route
      should be surveyed in detail.

PMID- 12476683
TI  - Evaluation of retinal nerve fiber layer thickness in diabetic retinopathy after
      panretinal photocoagulation.
AB  - Retinal nerve fiber layer (RNFL) thickness analysis has been used in glaucoma and
      some other ocular diseases. In this study, we measured RNFL thickness using
      scanning laser polarimetry in 27 eyes with diabetic retinopathy after panretinal
      photocoagulation (PRP). Symmetry, ellipse modulation, ellipse average, average
      thickness, number (a measure of RNFL change), and superior, inferior, nasal, and
      temporal average RNFL thicknesses were measured. Mean symmetry was 0.90, mean
      ellipse modulation 1.80, mean ellipse average 63.6 microns, mean average
      thickness 63.0 microns, and mean number 45.8. Average superior RNFL was 65.8
      microns, average inferior RNFL 75.1 microns, average nasal RNFL 44.47 microns,
      and average temporal RNFL 38.78 microns. The superior/temporal and
      inferior/temporal ratios were 1.77 and 2.00, respectively; superior/nasal and
      inferior/nasal ratios were 1.51 and 1.72, respectively. Retinal edema did not
      increase laser retardation. The superior/temporal and inferior/temporal ratios
      were more reliable in evaluating nerve fiber analyzer data in patients with
      diabetic retinopathy after PRP.

PMID- 12476684
TI  - Interradicular root proximity/fusion: a possible determining factor in
      regenerating molar furcations.
AB  - Both conventional and regenerative approaches have their limitations in
      correcting furcation defects. Cases of furcation that involve particular
      anatomical configurations, i.e., interradicular root proximity/fusion, have long
      been considered relative contraindications for treatments such as root amputation
      or hemisection. However, there has been little discussion of the role of
      interradicular root proximity in regenerative procedures. The purpose of this
      article was to report the clinical significance of the interradicular root
      relationship in regenerating intrabony defects associated with furcations.

PMID- 12476685
TI  - Choroidal osteoma masquerading as central serous chorioretinopathy.
AB  - We report a rare case of choroidal osteoma masquerading as central serous
      chorioretinopathy. A 39-year-old man complained of intermittent episodes of
      blurred vision in the left eye for 2 months. Fundus examination of the left eye
      showed a dome-shaped elevation at the macular center. Fluorescein angiography
      showed a patch of pinpoint leakage resulting in a well-defined pool of dye at the
      macular center. Initial diagnosis was recurrent central serous chorioretinopathy
      with sequelae in the left eye. Five months later, serous detachment recurred.
      Computerized tomography and ultrasonography showed a bony plaque at the choroid
      level, and choroidal osteoma was diagnosed.

PMID- 12476686
TI  - Spontaneous retroperitoneal biloma: a case report.
AB  - We report a rare case of spontaneous rupture of the biliary tree with biloma in
      the retroperitoneum. A 74-year-old man was admitted with back pain and general
      weakness. Computerized tomography (CT) and sonography showed a huge lesion in the
      right retroperitoneum, and a diagnosis of biloma was made after percutaneous
      aspiration. A percutaneous drainage catheter was initially inserted into the
      right retroperitoneal lesion under sonographic guidance to treat the biloma
      because of high surgical risk. When his general condition had improved, the
      patient underwent cholecystectomy and removal of the common bile duct stone;
      there was no evidence of leakage in the extrahepatic bile duct. Non-surgical
      intervention before definitive biliary surgery is considered the first choice for
      treating bilomas in high-risk patients.

PMID- 12476687
TI  - [The pediadrician of maternity: a threatened species].

PMID- 12476688
TI  - [Metaplasia and high grade CIN. Diagnostic difficulties].
AB  - Squamous metaplasia of cervix represents the physiologic process of
      transformation of eversed glandular tissue at external orifice by a malpighian
      tissue. Primarily undifferentiated and immature, the epithelium progressively
      becomes differentiated and takes glycogen. In a high grade CIN the normal
      squamous epithelium is replaced by an undifferentiated tissue comporting basal
      cells with nuclear atypias. When cellular abnormalities are not marked,
      differential diagnosis exists with immature metaplasia. Cytology with suspicion
      of squamous intraepithelial lesion is sometimes followed by a diagnosis of high
      grade CIN on biopsy, but conisation reveals a metaplasia.

PMID- 12476690
TI  - [Prediction of the latency period by cervical ultrasonography in premature
      rupture of the membranes before term].
AB  - OBJECTIVE: To assess the value of ultrasonographic measurement of cervical length
      for predicting the duration of the latency period from admission to delivery in
      women with preterm premature rupture of the membranes (PROM). METHOD: Prospective
      study in 88 women with preterm PROM before 34 weeks of amenorrhea. The median
      gestational age at admission was of 30.1 weeks. The clinical management included:
      no digital examination of the uterine cervix, antenatal corticosteroids,
      antibiotics (amoxicillin & clavulanic acid) for 7 days, and hoding back until 34
      weeks. Cervical length at admission was determined with transvaginal
      ultrasonography. The duration of the latency period was studied in relation with
      cervical length, serum C-reactive protein (CRP) level and white blood cell (WBC)
      count at admission. RESULTS: The median latency period was longer in women with a
      cervical length > or = 25 mm (10 vs 5 days; p = 0.04), but this was not
      associated with a significant increase in birth weight. The median latency period
      was also longer in women with CRP < 20 mg/l (10 vs 3 days; p < 0.001) and this
      was associated with a significant increase in birth weight (1716 +/- 549 vs 1201
      +/- 485 g; p < 0.01). Moreover, increased CRP levels were more frequent in women
      with a cervical length < 25 mm, and cervical length was no more predictive of the
      duration of the latency period in the subgroup of women with CRP < 20 mg/l and
      WBC < 20,000 cells/mm3. CONCLUSION: In women with preterm PROM, the latency
      period from admission to delivery is shorter when cervical length is < 25 mm.
      However, the clinical value of transvaginal ultrasonography is limited in
      comparison with serum CRP.

PMID- 12476689
TI  - [Uterine morcellation during vaginal hysterectomy: apropos of a series of 216
      prospective cases].
AB  - OBJECTIVE: The purpose of this study was to compare the surgical outcomes of
      women undergoing vaginal hysterectomy with and without morcelation. PATIENTS AND
      METHOD: Between December 1999 and December 2000, 216 women underwent vaginal
      hysterectomy without laparoscopic assistance at the Department of Gynecology of
      Hotel-Dieu hospital in Paris. The patients were divided into two groups: 114 of
      them underwent vaginal hysterectomies with morcelation whereas 102 underwent
      vaginal hysterectomies without morcelation. The two groups were compared as to
      demographic data, total complications, operative time, hospital stay length and
      peri-operative hemoglobin concentration change. RESULTS: Although women
      undergoing morcelation were significantly younger (mean 49 versus 52, p = 0.01)
      and less parous (mean 1.9 versus 2.3, p = 0.03), there were no significant
      differences in other surgical or anesthetic risks factors, including weight, BMI,
      nulliparity and preexisting surgical diseases. Mean uterine weight was
      significantly greater in those undergoing morcelation (331 versus 110 g, p <
      0.001); operative time was increased in the group which had undergone morcelation
      (331 versus 110 g, p < 0.001). There were no significant differences between the
      two groups with respect to peri-operative hemoglobin concentration change or
      hospital stay length. Finally, the rate of surgical complication was similar in
      the two groups (17.5 versus 21.5%). CONCLUSION: Although vaginal hysterectomy
      requires an increase in operative time, morcelation at the time of vaginal
      hysterectomy is safe and facilitates the vaginal removal of enlarged uteri
      without increasing peri-operative morbidity.

PMID- 12476691
TI  - [Choriocarcinoma in Senegal: epidemiology, prognosis and prevention].
AB  - OBJECTIVE: The objective of this study was to define the epidemiological profile
      of choriocarcinoma in Senegal, to evaluate its prognosis and to submit a better
      way of prevention of this pathology in an area with poor medical care. MATERIAL
      AND METHOD: It was a retrospective case-control study of all choriocarcinomas
      diagnosed from January 1st to December 31st 2000 at Dakar university teaching
      hospital. The witnesses were chosen among patients who had had molar abortion at
      the same time as the cases at study and had not developed the pathology after at
      least 12 months of aftercare. The stability of association was checked by
      calculating the confidence interval in 95% by Miettinen method and using Chi 2
      test of Pearson with a risk factor alpha under 5% or Fischer test; the prognosis
      survival factors were compared by using logrank test. RESULTS: Among the 1098
      patients in follow-up treatment after molar abortion, 61 choriocarcinomas were
      diagnosed with an incidence of 5.5%. The epidemiological profile was a great
      multiparous (40 years old or more) with low socio-economical level, 51% of the
      diagnosed cases are made in the metastasis stage. The prognosis was marked by a
      complete remission in 37.7% and by global lethality in 49.2%; the average
      survival was about 48 months. DISCUSSION AND CONCLUSION: The risk factors of
      choriocarcinoma among patients who had a molar abortion were represented by an
      age superior or equal to 40 years old, high multiparity and preservation of the
      uterus after molar abortion. To improve the prognosis in a country with low
      medical care, we recommend to widen preventive hysterectomy indications after
      molar abortion among patients with risk factors of choriocarcinoma.

PMID- 12476693
TI  - [Body remodeling, or the quest of the desire].
AB  - A few thoughts about the passing of time, woman's times, and times of youth: the
      very youth our society, afraid of its new longevity, refuses to lose at least its
      visible features. How to be lovable and desirable, or rather how to stay so:
      there is the prescription our patients expect from our tender loving care. This
      was inspired by a round table on "Time lost and regained" at the January 2002 JTA
      meeting, [in Punta Cana].

PMID- 12476692
TI  - [Beta-thalassemia and pregnancy. Apropos of 2 cases].
AB  - Homozygous beta-thalassemia is a severe, transfusion dependent anaemia that also
      causes infertility. Preimplantation genetic diagnosis is possible. Very few
      pregnancies are reported among such patients. They have a very high obstetrical
      risk and a pluridisciplinary follow is necessary.

PMID- 12476694
TI  - [Prevention of port-site metastasis after laparoscopy].
AB  - Port-site metastasis is a major complication of surgical laparoscopy for
      gynaecologic oncology. Aetiology of port-site metastases is multifactorial.
      Surgical conditions and laparoscopic environment were determinant. Several means
      of prevention were evaluated to prevent occurrence of port-site metastases. Aim
      of this review is to report optimal surgical conditions, laparoscopic environment
      and means of prevention to decrease risk of port-site metastases.

PMID- 12476695
TI  - [Hysterosonography].
AB  - Hysterosonography, which consists in the injection of some cc of saline in the
      uterine cavity during sonography, allows an exploration of the uterine cavity and
      of the endometrium. Accuracy of hysterosonography is similar to that of office
      hysteroscopy. Hysterosonography distinguishes normal cavities from pathologic
      ones, endometrial atrophy from mucosal anomalies, polyps from myomas. Conversely,
      endometrial biopsy is still necessary for diagnosis of hyperplasia or cancer.
      Hysterosonography can also be proposed for first trimester bleedings, trophoblast
      retention or ectopic pregnancy. In the near future it could be applied to
      therapeutic goals such as sonographic section of polyps.

PMID- 12476696
TI  - [Ovarian stimulation: is exogenous LH necessary in all patients?].
AB  - FSH and LH play an essential but different role in the growth of ovarian
      follicles during the cycle. In stimulation protocols, good follicular development
      is obtained in most patients treated with FSH alone whereas the role of LH is
      more complex and controversial. Clinical and pre-clinical studies have shown that
      optimal follicular development is obtain if (i) exposure to endogenous and/or
      exogenous LH is sufficient ("threshold" concept) and (ii) exposure to LH is not
      excessive ("ceiling" concept). The recombinant luteinizing hormone (r-hLH,
      Luveris) is the only available stand-alone preparation of LH. Its characteristics
      are a high specific activity, the absence of undesirable proteins and an
      excellent batch to batch consistency. Luveris is indicated in association with
      FSH for stimulating follicular development in LH and FSH deficient women (defined
      by an endogenous LH level < 1.2 UI/l). In this subgroup of patients, the
      therapeutic benefit of exogenous LH at a daily dose of 75 IU is only observed
      when endogenous serum LH is below than 1.2 IU/l: LH threshold concept. In ART,
      the combination of exogenous LH at a daily dose from 75 to 150 IU and recombinant
      FSH improved the ovarian stimulation results only in a minority of patients (5 to
      17%). On the opposite, studies conducted in OMS I and II patients showed that
      high doses of exogenous LH lead to atresia of secondary follicles. So, a daily
      dose of exogenous LH greater than 225 IU had a deleterious effect on follicular
      growth: LH ceiling concept.

PMID- 12476697
TI  - [Value of cervical screening by HPV DNA testing. It is legitimate to type HPV for
      the primary screening of cervix neoplasms].

PMID- 12476698
TI  - [Value of cervical screening by HPV DNA testing. There is no justification for
      HPV typing for the primary diagnosis of cervix neoplasms].

PMID- 12476699
TI  - [Standards, Options and Recommendations 2000 for the management of patients with
      endometrial cancer (non-metastatic)(abridged report)].

PMID- 12476700
TI  - [Apropos of the jurisprudential decisions concerning nosocomial infections. J.
      Hureau. Gynecol Obstet Fertil 2002;30:(a paraitre)].

PMID- 12476701
TI  - [Virus and sterility, that which has changed. At last! How much time has been
      lost! J.L. Benifla. Gynecol Obstet Fertil 2001;29:879-80].

PMID- 12476702
TI  - [Placement of a sub-urethral band in the treatment of female urinary
      incontinence. D. Dargent et al. Gynecol Obstet Fertil 2002;30;576-82].

PMID- 12476703
TI  - [Late amniocentesis for fetal karyotyping. P. Rozenberg and M.V. Senat. Gynecol
      Obstet Fertil 2002;30:427-432].

PMID- 12476704
TI  - [Laparoscopy and gynecologic cancer. Is it necessary to debate again or just
      convince the incredulous. M. Canis et al. Gynecol Obstet Fertil 2001;29:913-8].

PMID- 12476705
TI  - [Exogenous LH and ovarian stimulation. J.N Hugues and J.M. Antoine. Gynecol
      Obstet Fertil 2002;30:79-85].

PMID- 12476706
TI  - [Endovaginal ultrasonography of the cervix uteri before artificial induction of
      labor. R. Gabriel et al. Gynecol Obstet Fertil 2001;29:919-23].

PMID- 12476707
TI  - Perspectives. Employers trim offerings, think about coinsurance.

PMID- 12476708
TI  - Perspectives. ER backups: more room needed but where? And who pays?

PMID- 12476709
TI  - Perspectives. ER patients: what do they want? Can we make them go away?

PMID- 12476710
TI  - Perspectives. ER backups not one problem, but many.

PMID- 12476711
TI  - Perspectives. Can a focus on quality even out Medicare pay, control costs?

PMID- 12476712
TI  - Traditional medicine and reproductive health in Africa.

PMID- 12476713
TI  - WHO indicators for evaluation of maternal health care services, applicability in
      least developed countries: a case study from Eritrea.
AB  - The World Health Organization has recommended a number of process indicators to
      monitor the effect of health care programmes on maternal mortality. This study
      was therefore conducted to know if the recommended process indicators are useful
      also in the least developed countries. In 1994, all 17 health facilities offering
      maternal health care in a rural province in Eritrea were visited. An assessment
      was made of the obstetric services provided, obstetric complications, and
      accessibility of health facilities. The study revealed that necessary data were
      available for most indicators. The indicators were helpful to follow the coverage
      of obstetric care and to identify problems within the health care system.
      However, in countries where the coverage of assisted deliveries is low with few
      obstetric complications seen within the health care system, the indicators cannot
      be used as a tool to monitor the effect of maternal health care programmes on
      maternal mortality.

PMID- 12476714
TI  - Correlation between intrapartum fundal height and birth weight.
AB  - In a prospective cross-sectional study, the correlation between symphysiofundal
      height (SFH) and birth weight was evaluated in 2646 consecutive parturients at
      the University of Nigeria Teaching Hospital, Enugu, over a 19-month period. The
      standard deviations of the observed birth weight were least when the SFH measured
      33-39 cm, which corresponded to the birth weight range 2500-3999 g. The overall
      standard deviation was 275 g. A second order polynomial fitted the data best,
      giving the equation y +/- 258.1-62.9x -3.8x2, where y represents the observed
      birth weight in grams and x the SFH in centimetres. The R2 statistic for the
      model was 0.82. This and other assessment showed a good model fit. The birth
      weight centiles for the various SFH measurements were derived and their
      usefulness discussed. It was concluded that the SFH-derived birth weight centiles
      are useful alternatives to ultrasonography especially in the birth weight range
      2500-3999 g.

PMID- 12476715
TI  - Assessment of awareness of HIV/AIDS among selected target groups in and around
      Addis Ababa, Ethiopia.
AB  - A total of 2278 individuals were interviewed using a pre-tested questionnaire
      with key indicators such as mode of transmission, attitude towards HIV/AIDS
      patients, information sources, sex, educational and marital status. Findings
      indicate that most of the respondents (93.2%) were aware of the reality of
      HIV/AIDS and considered it as a killer disease (89.2%). A significant number of
      them had negative attitude towards HIV/AIDS patients. Some 30.4% believed
      HIV/AIDS patients can be identified through symptoms rather than clinical
      diagnosis. There is significant association between knowledge of HIV/AIDS and
      target group (p < 0.001), age (p < 0.05), sex (p < 0.05), marital status (p <
      0.05) and educational level (p < 0.001). There is also a remarkable knowledge
      difference among respondents on means of prolonging life of individuals with
      HIV/AIDS. Some have never heard about how to prolong the life of such patients
      (10.2%). Farmers (42.5%) indicated that there is no means of prolonging the life
      of such patients. Respondents' knowledge on combating HIV/AIDS related diseases
      as a means of prolonging the life of succumbed individuals was rather low (5.5%).
      Low level awareness, therefore, may deter HIV/AIDS patients from seeking
      necessary medical attention.

PMID- 12476716
TI  - Extension personnel's sexual behaviour and attitudes toward HIV/AIDS in south
      western Nigeria.
AB  - This study examined the sexual behavioural pattern, knowledge and attitudes to
      HIV/AIDS of 216 extension personnel in south-west Nigeria. Information was
      obtained using a combination of structured interview schedule and focus group
      discussions. Results show that the extension personnel were young men and women,
      married, mostly Christians and educated. All the women had premarital sex,
      compared with 98.3% of the men, more men (46.7%) engaged in extramarital sex than
      women (18.4%), and 81.2% of the men were using condoms regularly, compared to
      57.5% women users. All the respondents were fully aware of HIV/AIDS, while 79.5%
      of men and 85.0% of women expressed negative attitudes to HIV/AIDS. This has
      serious implications for the delivery efforts of focal extension agencies.

PMID- 12476717
TI  - Sexuality, contraceptive choice and AIDS awareness among Nigerian undergraduates.
AB  - A survey of 2388 Nigerian undergraduates revealed that 87% were sexually active
      and 66% had more than one sexual partner, while 17.5% have had clandestine
      abortions. All respondents were quite knowledgeable about HIV/AIDS but few
      sexually active ones took precautions to prevent HIV transmission. Majority
      (87.5%) were knowledgeable about contraception and approved of its use, but only
      34.2% were current users of contraceptives. About 58% of these cited pharmacy
      shops as their source of contraceptives. The attitudes of the students were below
      expectation. Specially designated centres for the provision of appropriate
      contraceptive services to students by trained personnel are needed in the
      institutions in order to tackle their reproductive health problems.

PMID- 12476718
TI  - Where is the condom? Contraceptive practice in a rural district of South Africa.
AB  - Interviews were conducted with 848 African women aged 15-49 years in a rural area
      of South Africa to determine the extent to which condoms are used, reasons for
      contraceptive method choice and unmet contraceptive need. Injectable
      contraceptives were being used by 22.1% of respondents, who considered them to be
      convenient, safe, effective, and/or a method that could be used secretly. The
      decision to use this method was often made on the recommendation of a health
      worker. Eleven women said they were using the male condom, seven of whom were
      using it because it provides protection against pregnancy and sexually
      transmitted infections. Many (70.3%) women were not using any form of
      contraception. Counselling about contraceptive options should take into account
      the need for dual protection, and strategies for increasing condom use should be
      promoted.

PMID- 12476719
TI  - Indigenous healing practices and self-medication amongst pregnant women in Cape
      Town, South Africa.
AB  - This study was conducted in and around Cape Town, South Africa, at two primary
      obstetric facilities and in the antenatal clinics of two secondary hospitals.
      Findings show that majority of the Xhosa speaking women follow indigenous healing
      practices for both themselves and their babies because of the need to
      "strengthen" the womb against sorcery, to prevent childhood illnesses, and to
      treat symptoms they perceive that biomedical services would not be able to treat.
      Self-medication with non-prescribed drugs, herbs and Dutch remedies was common
      practice amongst the Afrikaans speaking women for both themselves and their
      babies. Herbs and Dutch remedies were mainly used to treat indigenous illness
      (baarwind) while non-prescribed over-the-counter drugs were used to treat minor
      ailments associated with pregnancy. There is, therefore, an urgent need to bridge
      the gap between orthodox and indigenous medical systems through reciprocal
      learning and by acknowledging each other's roles.

PMID- 12476720
TI  - Tetanus immunity among pregnant women attending antenatal care in Dar es Salaam,
      Tanzania.
AB  - This study was conducted to investigate immunity to tetanus among pregnant women
      with verbal histories or documentation of having been vaccinated under the
      current five-dose tetanus toxoid (TT) schedule. It examined sera from 176
      pregnant women attending antenatal care at Muhimbili Medical Centre in Dar es
      Salaam, Tanzania. Tetanus antitoxin level of 0.1 IU/ml was considered protective.
      Our findings show that 94.9% of women had tetanus antitoxin > or = 0.1 IU/ml.
      Multivariate analysis revealed that time after last vaccination, TT doses
      received and TT vaccination status explained 7.5%, 5.7% and 2.3% of variations in
      tetanus antitoxin levels respectively. Pregnant women with non-protective levels
      of tetanus antitoxin (5.1%) pose great risks of neonatal tetanus to their
      newborns and are also susceptible to maternal tetanus. Proper keeping of TT
      vaccination records is vitally important to avoid hyper-immunisation.

PMID- 12476721
TI  - Assessing the role of traditional birth attendants (TBAs) in health care delivery
      in Edo State, Nigeria.
AB  - This study was conducted to assess the role of traditional birth attendants
      (TBAs) in modern health care delivery in Edo State, Nigeria. A total of 391
      respondents comprising 48 TBAs, 309 childbearing mothers and 34 medical and para
      medical professionals constituted the study sample. In-depth interviews and focus
      group discussions as well as validated questionnaires were the tools used for
      data collection. The results reveal that respondents believe that TBAs can play
      meaningful roles in family planning, screening of high-risk pregnant mothers,
      fertility/infertility treatment and maternal and child care services. Rural
      dwellers prefer to use the services of TBAs, as compared to their urban
      counterparts. Reasons for the preference included TBAs, availability,
      accessibility, cheap services and rural dwellers' faith in the efficacy of their
      services. There is, therefore, the need to restructure the training of TBAs as
      well as to fully integrate their services into the Nigerian orthodox healthcare
      delivery system especially as they affect rural settings.

PMID- 12476722
TI  - Prevalence, patterns and correlates of domestic violence in selected Igbo
      communities of Imo State, Nigeria.
AB  - Three hundred and eight Igbo women were randomly selected to respond to a number
      of questions on experiences, patterns and attitudes to domestic violence. Data
      was collected using structured questionnaires that were complemented with focus
      group discussions. The results show that 78.8% of the women have ever been
      battered by their male counterparts, out of which 58.9% reported battery during
      pregnancy, while 21.3% reported having been forced to have sexual intercourse.
      The study further revealed that the practice of female circumcision is still
      common among this Igbo population, and 52.6% were of the view that it should be
      continued. Multivariate logistic regression identified the correlates of these
      forms of violence such as age, place of residence, age at first marriage, type of
      marital union, level of income of women, and level of education of husband
      against women in Imo State. While wife battery is more pronounced in the urban
      area, forced sexual relationship and female genital mutilation are more
      pronounced in the rural areas. We recommend education of women and integration of
      services in reproductive health care service delivery as appropriate measures to
      eradicate these practice.

PMID- 12476723
TI  - After five years ... welcome to the wholly African AJRH.

PMID- 12476724
TI  - African journal of reproductive health--forging a new path of development.

PMID- 12476725
TI  - Curriculum reform for reproductive health.
AB  - A new model of reproductive health care delivery is unfolding, driven by emerging
      health issues, expanding technology and increasing public expectations.
      Additional imperatives in service provision for women's health compel reforms to
      undergraduate medical education using reproductive health as the basis for
      restructuring curriculum contents. These developments provide an opportunity for
      implementing the recommendations from various international conferences through
      continuing professional development and an evidence-based approach to clinical
      decision-making. A three-pronged approach based on reproductive health, problem
      based learning and evidence-based medicine, has much potential for improving
      subsequent clinical practice and the overall reproductive health of the
      community. Appropriate changes to existing curricula will facilitate integration
      of the principles of reproductive health and the new philosophy of doctor-patient
      relationship into clinical supervision and training of students.

PMID- 12476726
TI  - (Re)defining reproductive health with and for the community: an example of
      participatory research from Mali.
AB  - Qualitative research was carried out in central Mali to inform the development of
      curricula for an intervention to improve young people's reproductive health. Both
      the young people and 'societal gatekeepers' (including religious leaders and
      traditional healers) perceived reproductive health to comprise the social
      dynamics in which reproductive health decision-making is embedded and not just
      the biological aspects of sexual relations and fertility. Their definitions of
      reproductive health reflected social taboos about pre-marital sex, infidelity and
      illegitimate children, and comprised holistic notions of bodily and spiritual
      cleanliness. It is argued that the 'Cairo' definition sees many of the social
      factors identified by respondents as comprising the context or background of
      reproductive health. The findings presented here indicate that local populations
      may see them as integral to the concept itself. It is discussed how the 'Cairo'
      definition of reproductive health needs to be made culturally specific in order
      to facilitate programme design and implementation.

PMID- 12476727
TI  - Prognostic value of absolute versus relative rise of blood pressure in pregnancy.
AB  - This study evaluated the prognostic value of absolute versus relative rise in
      blood pressure during pregnancy at the Department of Obstetrics and Gynaecology,
      University of Nigeria Teaching Hospital, Enugu, Nigeria from 17th December 1997
      to 31st March 1999. The study sample consisted of 515 consecutive healthy
      antenatal subjects of the hospital who satisfied the inclusion criteria. The
      study involved a longitudinal measurement of variables such as blood pressure and
      anthropometric data of the subjects as well as the maternal mortality rate,
      caesarean section rate, incidence of eclampsia and proteinuria, perinatal
      mortality rate, incidence of severe asphyxia and low birth weight, mean birth
      weight, birth length, ponderal index and gestational age at delivery. Differences
      in these indices between different groups of the subjects were compared using the
      chi-square test for categorical variables and one way ANOVA for continuous
      variables. Grouping was based on the absolute systolic/diastolic blood pressure
      (SBP/DBP) and relative rise in SBP/DBP from mind-pregnancy until delivery at
      term. The absolute blood pressure of 140/90 mmHg was a better predictor of feto
      maternal outcome than a relative rise in the systolic/diastolic blood pressure
      from mid pregnancy, which did not reach this absolute level. We conclude that in
      the Nigerian obstetric population, the practice of diagnosing pregnancy
      hypertension on the basis of a relative blood pressure rise of 30/15 mmHg alone
      without reference to the absolute blood pressure level needs to be reviewed.

PMID- 12476728
TI  - The nature of puerperal psychosis at Muhimbili National Hospital: its physical co
      morbidity, associated main obstetric and social factors.
AB  - Eighty six in-patients suffering from puerperal psychosis within six weeks after
      childbirth were prospectively investigated in Muhimbili National Hospital during
      two years. Formal psychiatric history, mental status evaluation, research and
      diagnostic criteria including ICD 10 and clinical progression were employed for
      diagnosis. Using a structured questionnaire, the socio-demographic
      characteristics, concomitant physical disorders, major obstetric events, period
      of onset of puerperal psychosis following delivery and social support given were
      established. Mean age was found to be 23.6 years; the majority was primiparous
      women with parity of between one and three children. Main physical co-morbidities
      included anaemia in 51.4% of cases, infections in 44.2% and EPH-gestosis in
      17.4%. Most mothers received social support from their extended families. Organic
      psychosis was found in four fifths of the mothers and schizophrenia in 8.1%. A
      high rate of early onset puerperal psychosis (3.2/1000 (births), predominantly in
      young primiparous women, was found.

PMID- 12476729
TI  - Analysis of women's reproductive health situation in Bida Emirate of Niger State,
      Nigeria.
AB  - This study examined the reproductive health situation in Bida Emirate of Nigeria,
      with a view to advancing frontiers in communication support for reproductive
      health education. Multi-stage sampling technique was used to randomly select
      1,200 women respondents that participated in the study. Data was obtained on
      reproductive health and rights, reproductive health history, and personal and
      social characteristics of respondents. Data analyses showed that majority (68.1%)
      of respondents were aware of existing methods of birth control, while 31.9% were
      not. On the use of methods, abstinence, breastfeeding and use of condoms recorded
      42.8%, 22% and 40.3% respectively. Respondents rarely used traditional methods of
      birth control. Forty five per cent blamed their husbands for not using family
      planning methods. Surprisingly, 84.8% of respondents had no idea of what HIV/AIDS
      is all about; only 13% and 3.1% could describe gonorrhoea and AIDS respectively.
      Results further revealed that there is no significant relationship between
      personal and social characteristics of respondents (religion, marital status and
      position, etc) and their attitude towards family planning. However, rural and
      urban women significantly differed in their health status (t = 0.2729; p <
      0.001). Similar trend was observed for attitude towards family decision-making (t
      = 40; p < 0.001), sexuality and STD prevention (t = 90; p < 0.001), and
      maternity/childcare (t = 0.001; p < 0.001). In conclusion, the study reveals that
      there is a wide gap between social expectations of women's reproductive health
      and cultural realities in Nupeland of Nigeria. The study thus recommends, among
      others, the need for sustainable safe motherhood campaign in culture bound
      societies.

PMID- 12476730
TI  - Can mothers afford maternal health care costs? User costs of maternity services
      in rural Tanzania.
AB  - Following the difficult economic situation various countries introduced health
      sector reforms, including user charges to finance the system. The assessment of
      user costs for maternity services in Tanzania was part of a larger study, which
      covered inputs, outputs and efficiency of services. The study was carried out
      from October 1997 to January 1998 in Mtwara urban and rural district in South
      Tanzania. One hundred and seven women attending a quarter of government health
      facilities were randomly selected and interviewed. Twenty one key informants were
      also interviewed and service procedures observed. Users of maternity services pay
      mainly for admission, drugs, other supplies and travel costs. Travel costs
      represent about half of these financial costs. The average total costs vary
      between US$11.60 for antenatal consultation and US$135.40 for caesarean section
      at the hospital. Unofficial payments are not included in the calculation. The
      amounts vary and payment is irregular. We therefore conclude that time costs are
      constantly higher than financial costs. High direct payments and the fear of
      unofficial costs are acute barriers to the use of maternity services. User costs
      can substantially be reduced by the re-organisation of service delivery
      especially at antenatal consultation.

PMID- 12476731
TI  - Experiences of mothers with antenatal, delivery and postpartum care in rural
      Gambia.
AB  - Over the last two decades, the maternal mortality ratio appears to have fallen by
      up to 50% in the Farafenni, a rural area of The Gambia. This reduction almost
      certainly reflects improvements in access to essential obstetric services. The
      ratio, however, is still 50 times higher than in Western and Northern Europe or
      North America. This paper provides information from a community-based study of
      623 women who had recently given birth in the Farafenni area. Information on how,
      when, and why care was accessed, and what type of care and information were
      provided were obtained from traditional and western methods of health care were
      during visits. Women were asked about their experiences during prenatal, delivery
      and postpartum periods. Results from this study highlight a number of
      opportunities for improving the quality of maternal health services that could be
      implemented relatively easily with existing resources.

PMID- 12476732
TI  - "Spoiling the womb": definitions, aetiologies and responses to infertility in
      north west province, Cameroon.
AB  - Only one generation ago, the Cameroonian national population policy was pro
      natalist, with great attention paid to the problem of sterility. Now, family
      planning is promoted nationwide to reduce population growth, and infertility is
      not addressed by public health policy or services. In contrast to the biomedical
      definition used by planners, at the local level infertility is defined as the
      inability to have a child when desired, and it has many causes including
      contraception, abortion and witchcraft. The young, less educated women especially
      are unlikely to use contraception as long as they feel susceptible to
      infertility, since their economic, social and psychological status hinge on their
      ability to have children. Drawing from epidemiological literature and qualitative
      data gathered in a market town in North West Province, I argue that a more
      balanced approach to reproductive health, one that recognises the importance of
      infertility, is critical for women's health and well-being.

PMID- 12476733
TI  - Parental characteristics and adolescent sexual behaviour in Bida Local Government
      Area of Niger State, Nigeria.
AB  - This study was conducted in Bida Local Government Area of Niger State, Nigeria,
      to examine how parental attributes influence adolescent sexual activity. Data
      were gathered through structured interview with 400 adolescents aged 12-24 years
      using a three-stage random sampling procedure. Findings show that more than one
      third of the adolescents interviewed had sexual intercourse in the month
      proceeding the survey. Less than one fifth of the sexually active adolescents
      were using a method of contraception to either prevent infections or avoid
      unwanted pregnancy. Further analysis confirmed the fact that adolescents with
      whom parents had discussed family life issues were less likely to be sexually
      active than those with whom parents had never discussed family life issues. The
      study also found a negative effect of family instability on adolescent sexuality.
      These findings call for the need for family-sensitive programs that will enhance
      family stability especially economically. The need for parental empowerment to be
      able to cope with the challenges of adolescent life in Nigeria is also stressed
      since adolescents who have family life education from parents are less likely to
      be sexually active.

PMID- 12476734
TI  - Effects of different temperatures for drying cervical mucus smear on their
      crystallisation pattern: a short report.
AB  - The effects of different room temperatures for drying cervical mucus on
      crystallisation of fern-tree patterns was determined using cervical mucus smears
      from 60 women undergoing investigation for infertility at the University of Benin
      Teaching Hospital. Cervical mucus smears were dried in the oven at 15, 20, 25, 30
      and 35 degrees C and examined rapidly for fern-tree crystallisation patterns
      decreased significantly in proportion (p < 0.05); they became atypical or were
      not formed at all. The finding in this study demonstrates that in tropical
      environments where ambient room temperature may reach 35 degrees C, fern-tree
      pattern would differ from those in temperate regions.

PMID- 12476735
TI  - [Variation in HLA-B27 gene subtypes and susceptibility of ankylosing spondylitis
      in the Croatian population].
AB  - The differences in amino acid residues of HLA-B27 subtypes are minor, but may
      play role in pathogenesis of ankylosing spondylitis (AS). Aim of this study was
      to investigate of frequency of B27 subtypes in Croatian AS patients and B27
      positive healthy controls. Group of 50 AS patients and 38 B27 positive controls
      were typed for B27 subtypes by PCR-SSP method. In the group of AS patients we
      found four subtypes: B*2705 (83.0%), B*2702 (13.2%), while remaining two alleles
      B*2701 and B*2704 had one individual each. In the group of B27+ controls we also
      observed B*2705 (76.3%) as most frequent allele while frequency of B*2702 was
      21.1%. No significant evidence for association between AS and a particular HLA
      B27 subtype in the Croatian population were found.

PMID- 12476736
TI  - [Effect of rheumatoid arthritis on physical performance of patients].
AB  - To determine the changes occurRing in physical performance of patients with RA,
      188 patients have been observed over a ten-year period. The observation included
      two groups: the test group comprising 93 patients with RA who have never been
      treated by any disease-modifying antirheumatic drugs (DMARDs) and the control
      group comprising 95 patients with RA who have regularly taken DMARDs under the
      rheumatologist's supervision. The average age of the test group was considerably
      higher, there were more retired persons with a prolonged course of illness, their
      physical performance being more intensely affected than that of the control
      group. Further analysis during the observation period showed significant decrease
      of physical performance in both groups regardless of their being treated or not
      by the DMARDs which, in our opinion, only modify the illness. To conclude,
      irrespective of the application of the DMARDs, RA is undoubtedly an illness with
      considerable socio-economic significance since it leads to great physical
      disability (invalidity) of all RA patients.

PMID- 12476737
TI  - [How much do we know about the prevention of diseases of the joints and spine?].
AB  - The questioner "How much do we know about prevention of joint and spine diseases"
      are presented. Questioner contained 10 questions and two possible answers. This
      investigation involved 120 medical stuff members, 187 patients on physical
      therapy and 204 patients with same medical problems without physical therapy.
      Results are showing no statistically important difference between that two group
      of patients. More interesting is that there is no difference between medical
      doctors, physiotherapists and medical technicians comparing to patients. To
      improve those bad results of medical stuff we suggest that it should be organized
      in physiatrist ordinations consultations and continuous education with practical
      examples and advices separately for medical stuff members and patients.

PMID- 12476738
TI  - [Multisegmental posterior wedge osteotomies of the lumbar vertebrae for
      correction of kyphosis in ankylosing spondylitis. A report on 5 cases].
AB  - Operative treatment of Ankylosing spondilitis is usually performed in treatment
      of extraspinal pathology, i.e. in treatment of hip contractures. Operative
      treatment of fixed spinal kyphosis in AS is rarely indicated, and patients make
      their decision for the operation when deformation becomes extreme. Instead of
      several hundred of operated patients in foreign literature, authors describe only
      5 operations from 1989 to 2000. Results suggest that multiple spinal osteotomy in
      AS is a time consuming operation with a significant intraoperative and
      postoperative blood loss. Mild, transient radicular irritations are noticed.
      However, reconstruction of lumbar lordosis significantly improve quality of life
      in operated patients. It is concluded that indication for the operation in AS
      should be indicated earlier. Better results with less risk would be achieved.

PMID- 12476739
TI  - [Juvenile dermatomyositis].
AB  - Basic aim of this paper is presentation of probable epidemiological
      characteristics of juvenile dermatomyositis (JDM) in children of Croatia, due to
      the fact that severity of condition in majority of patients require treatment in
      our Department of Pediatrics, KBC Zagreb. Our intention is to present guidelines
      of current diagnostic approach from recent literature, with special accent on
      therapy. JDM was previously considered as infaust disease, while current therapy
      has favourable prognosis for complete resolution, as the only one mesenchymopathy
      with such prognosis. In period between 1988 and 1999 we treated 18 patients with
      JDM in our Department of Pediatrics. Thirteen cases were male and 5 female
      (2.6:1). Thirteen patients had clinical course of isolated JDM (72%), while five
      had JDM inside overlap syndrome (with other mesenchymopathies) (28%). Average age
      at time of diagnosis for whole group was 10 years (6-14), for girls 10.6 years (6
      14) and boys 8.4 years (7-10). At the present time 5 patients (28%) are
      considered as cured, 7 patients are in remission with low dosis of steroids (39%)
      and one girl had relaps of JDM after therapy stopage. Three children die (16%),
      one girl due to respiratory failure and two girls with pulmonary embolia. Two
      girls have some signs of JDM with dominant clinical signs of sistemic
      sclerodermia and one girl has signs of generalized morphea. One boy has dominant
      muscular calcinosis with contractures of large joints, despite treatment and
      normal laboratory findings. JDM was not discussed in rheumatic literature in
      Croatia for more then 15 years.

PMID- 12476740
TI  - [Dermatomyositis and malignant disease--case report].
AB  - The case of patients with dermatomyositis and malignant disease has been
      described. The diagnosis of malignant disease was made after death of the
      patient, when the malignant undifferentiated cells were found in the ascites. We
      think that dermatomyosistis was caused by malignant disease. The similar cases of
      disease were described and published in the literature.

PMID- 12476741
TI  - [Clinical importance of laboratory tests in rheumatology].
AB  - Knowledge of mechanisms of rheumatic diseases has a continuing influence on the
      introduction of many laboratory tests to be used for establishing diagnosis or
      monitoring the activity of rheumatic disease. In the article presented are
      autoantibodies characteristic for distinct inflammatory rheumatic diseases, the
      role of serum complement activity, immune complexes, HLA-typing as well as other
      laboratory parameters needed for the diagnosis of rheumatic disease. The methods
      of synovial fluid analysis are described. Presented are laboratory investigations
      used by rheumatologists for the evaluation of activity of inflammatory rheumatic
      diseases and successful treatment together with investigations necessary for the
      evaluation of side-effects of treatment.

PMID- 12476742
TI  - [Vasculitis].
AB  - The term "vasculitis" encompasses a heterogeneous group of clinicopathologic
      entities characterized by inflammation and damage of blood vessels. Many attempts
      have been made to classify vasculitis into categories that will facilitate
      patients diagnosis and management since the first attempt by Zeek in 1952. The
      classification scheme that will be used in this review was proposed by the 1993
      Chapel Hill Consensus Conference and has been widely accepted.

PMID- 12476743
TI  - [Physical therapy and rehabilitation in rheumatic diseases].
AB  - General principles of physical medicine and rehabilitation of rheumatic diseases
      are described. In knee and hip osteoarthritis it is important to protect full
      extension and in evolutive phase treat with drugs, unloading and physical
      therapy. Rest and ice are efficacious in active rheumatoid arthritis and in
      chronic phase all procedures and exercises are recommended with respect to pain
      threshold. Physical therapy for spondy larthropathies is directed to maintenance
      range of motion exercise for spine and breathing exercises. Swimming is the most
      appropriate recreational activity for spondylarthropathies.

PMID- 12476744
TI  - [Is there still a role for standard nonsteroidal antirheumatic agents?].
AB  - Although beneficial and widely used, nonsteroidal anti-inflammatory drugs (NSAID)
      are asociated with serious gastrointestinal (GI) side effects including
      ulceration, hemorrhage, and perforation with annual incidence of 2-4%. Prevention
      of NSAID-induced gastroduodenal ulcerations with proton pump inhibitors (IPP) is
      recommended in patients wit greater risk for serious GI complications. It is
      reasonable to expect that specific inhibitors of COX-2 drugs will be used in 20
      30% of patients when NSAID are needed. That still leaves great importance on
      conventional NSAID. If an NSAID is indicated, it should be given at the lowest
      effective dose with regard to specific indication.

PMID- 12476745
TI  - [Celecoxib].

PMID- 12476746
TI  - [Treatment of pain with opioid analgesics and the role of TTS-fentanyl
      (Durogesic)].
AB  - Current opinions in chronic pain treatment with opioid analgesics are presented
      in this review. Justified use of opioid analgesics in treatment of chronic non
      malignant pain in inflammatory and degenerative processes is emphasised.
      Advantages of opioid analgesics compared with non-opiod analgesics are stressed.
      New form of opioid--a patch, Durogesic TTS, recently registered in Croatia, is
      described. After brief review of pharmacodynamics and pharmacokinetics of
      Durogesic, authors experiences in both chronic malignant pain and chronic non
      malignant pain treatment with this analgesic are described. Trial was performed
      in Pain clinic of Karlovac General Hospital as a part of international
      multicentric clinical trial. Regarding efficacy, compared to the previous
      therapy, TTS fentanyl was evaluated positively by patients, both in pain control
      and ease of use, and by the author, for around the clock, non-invasive
      administration. Slow dose adjustment in rapid illness progression was recognised
      as disadvantage.

PMID- 12476747
TI  - [Quality assurance in rheumatology].
AB  - The German legislation on medicine demands that each person examining or treating
      patients must prove the quality of their work. That is done by way of "external
      evidence", by application of qualified studies or, if in default of those, by
      documentation on results and evaluation of each individual patient ("internal
      evidence"). Such evidences pertain to diagnostics (methods and their evaluation),
      treatment (medication and physical therapy) and the organization of work (staff,
      timeframes, available space etc.). The demand of assuring quality means that
      those methods which have no proven efficiency are automatically dropped, which in
      turn brings cost reduction.

PMID- 12476748
TI  - [Effect of physical and athletic activity on spinal deformities due to
      osteoporosis].
AB  - Physical activity is associated with increased bone mass and reduced risk of hip
      fracture. However, scarce are data from population samples concerning the effect
      of level of physical and sport activity on the risk of osteoporotic vertebral
      deformity. The aim of the study was to determine the amount of physical and sport
      activity and to relate it to occurrence of vertebral deformity in older
      population. In total 425 subjects (269 women and 156 men) age 50 and above, were
      recruited from a population frame sample, as a random sample of city of Zagreb.
      An interviewer-administered questionnaire was used to get information about level
      of physical and sport activity in three different age periods (15-24 years, 25-49
      years and 50 years and above), and the amount of time spent walking or cycling
      each day. Lateral thoracolumbar radiographs were taken using standardised
      procedure. Radiographs were evaluated morphometrically and the presence of
      vertebral deformity was defined according to method of McCloskey and al., with an
      alternative approach for defining normal values using iterative algorithm
      described by Melton and al. Vertebral deformities were found in 50 (11.8%)
      subjects. Men were more involved in sports activities in all three life periods,
      and had heavier overall physical activity from 15-24 years. Although results
      suggest possible decreased risk for vertebral deformity with stronger physical
      activity in the first life period, no significant association was found between
      physical or sport activity and vertebral deformities, even when possible
      confounding factors were taken in account. Current walking or cycling, adjusted
      for possible confounders, did not change the risk for vertebral deformities, too.
      Various confounding factor, different from those taken in account for this study
      or inadequately large sample for sport activity could have influence the results.
      We conclude that men are more physically active in younger age, and overall do
      more sports. Warning is the fact that appreciable proportion of men and women do
      not do any sport activity. We could not confirm that level of physical or sport
      activity, as well as regular walking or cycling was significantly important for
      occurrence of vertebral deformities. Prospective studies are needed in order to
      understand better the epidemiology and the role of possible risk factors of
      osteoporotic vertebral deformities in our population, which can help us in
      planning programs of prevention.

PMID- 12476749
TI  - [Personal experience with methotrexate in the treatment of idiopathic juvenile
      arthritis].
AB  - Methotrexate was introduced in the treatment of juvenile idiopathic arthritis
      (JIA) about fifteen years ago. Today, methotrexate is the drug of choice in the
      basic treatment of JIA, especially for oligoarticular subtype The aim of this
      study is to show our experiences with this agent. In the period from 1996 to 2001
      in the Pediatric Clinic--University of Zagreb 256 children with JIA were
      hospitalised--85 with polyarticular (33.2%) and 171 with oligoarticular subtype
      (66.8%). 34 of these patients (13.28%)--21 female and 13 male--16 with
      polyarticular and 18 with oligoarticular subtype were treated with methotrexate.
      The age at the beginning of the therapy was from 3 to 18 years (mean age 11.31
      ys). The countinuos treatment with methotrexate lasted from 1 to 3 years. The
      dosage of methotrexate was 10-20 mg/m2, i.e. 0.3-0.5 mg/kg of body weight weekly.
      During patients' hospitalization the drug was administered parenterally, while at
      home it was continued to be given perorally. All of the patients took with
      methotrexate also nonsteroidal antiinflammatory drugs, and some corticosteroid
      therapy. All of the patients were submitted to regular physical therapy. The
      results of the treatment response were judged according to the global patients
      assessment (number of inflammated joints, degree of inflammation and functional
      disability), laboratory data (inflammation reactants, hemoglobin, RF).
      Statistically significant improvement of clinical and laboratory parameters (p <
      0.01) was proved in 33 patients, while the improvement in one patient was
      minimal. Adverse reactions were rare and transitory.

PMID- 12476750
TI  - [Evaluation of a 3-week hospital rehabilitation of patients with rheumatoid
      arthritis].
AB  - Essential for evaluation of disease activity and functional disability in
      rheumatoid arthritis is to monitor the disease course by the outcome measures,
      which show quality of care i.e. efficacy of drugs, physical therapy and
      rehabilitation. To assess disease activity in 21 days hospital rehabilitation we
      chose Disease Activity Score (DAS). Functional disability was measured by Health
      Assessment Questionnary (HAQ). The measures were noted at arrival and admission
      and we found statistically significant decrease in values of DAS (t = 5,836; p <
      0.01) and HAQ (h = 16.26; p < 0.05), but without clinically valid criteria for
      improvement. The conclusions are: these measures are not appropriate for
      assessment of efficacy for a short therm hospital rehabilitation, because DAS is
      measure which primary shows activity of inflammatory process, and HAQ as a long
      term measure is not sensitive enough for the assessment of short term
      rehabilitation.

PMID- 12476751
TI  - [Still's disease in adulthood--case report of a female patient and review of the
      literature].
AB  - A 29-year old women with adult onset Still's disease (AOSD) was presented. On
      addmision to hospital the patient was febrile, with sore throat,
      arthralgia/arthritis and myalgia. The patient had lymphadenopathy on the neck,
      and laboratory findings showed leukocytosis with neutrophilia, accelarated
      erythrocyte sedimation rate (ESR), increased reactants of acute inflammation and
      normocytic anemia. During the diagnostic process, infectious, hematologic and
      neoplastic diseases were ruled out and the diagnosis of AOSD was made. The
      therapy with metilprednisolone 1 mg/kg of body weight was started. One month
      latter, the clinical status of the patient improved as well as laboratory
      findings. The dose of steroids was tappered to 16 mg per day. After 6 months of
      therapy, steroids were stopped and patient was followed further one year and she
      was free of symptoms of disease.

PMID- 12476752
TI  - [Radiologic diagnosis of rheumatic diseases].
AB  - Rheumatic disease have many common radiological characteristics. They all affect
      one or more joints. Radiological exams represent a part of the diagnostic
      procedure when there is a suspicion of rheumatic disease. This paper describes
      both the basics and characteristics radiological changes visible on a classic
      radiograph which, in addition to other results, allow the discrimination of
      different rheumatic diseases. Standard or classical radiographs are the
      cornerstones of radiological evaluation, and can be improved by other
      radiological methods such as US, CT or MR.

PMID- 12476753
TI  - Overlap syndromes.
AB  - Many connective tissue diseases share common signs and symptoms, which frequently
      makes the diagnosis of a specific rheumatic disease difficult. Rheumatoid
      arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis,
      dermatomyositis (DM), mixed connective tissue disease, and Sjogren's syndrome can
      present with similar clinical features, particularly during the first 12 months
      of symptoms. Overall, a rheumatic disease can appears in conjunction with
      features of one or more other connective tissue diseases, for example, patients
      can have a combination of rheumatoid arthritis and systemic lupus erythematosus
      ("rhupus"), or systemic sclerosis and polymyositis, defining an "overlap
      syndrome", where the diseases comply with the diagnosis criterias. Finally, when
      a person has symptoms of various connective tissue diseases without meeting the
      full criteria for any one of them, it is often called Undifferentiated Connective
      Tissue Disease.

PMID- 12476754
TI  - [Low back pain--what do we really know?].
AB  - Low back pain is one of the most frequent health problems of contemporary people.
      Therapy is usually conservative and symptomatic because in the most part of cases
      the etiology remains unknown. Evidence based medicine is putting itself in front
      also in the field of low back pain diagnosis and treatment. The therapy for low
      back pain is thoroughly and scientifically rigorously analized by the
      professionals from the Cochrane Collaboration. There are still not published
      enough randomized controlled studies to conclude about the effectiveness of most
      frequently used physical therapy modalities. There is a necessity for additional
      researching in that field.

PMID- 12476755
TI  - [Osteoporosis as a problem in physiatry and rheumatology].
AB  - Most often, physiatrists and rheumatologists are the first group of physicians to
      see patients presenting with a clinical picture of postmenopausal or
      corticosteroid induced osteoporosis. In this article, measures of treatment and
      prevention that are appropriate for use by this group of specialists will be
      assessed.

PMID- 12476756
TI  - [Gastrointestinal complications in treatment with classical nonsteroidal
      antirheumatic agents].
AB  - The most frequent gastro-intestinal complications in classical NSAID treatment
      are presented. Nausea and dispepsy are present in 60 percent, and gastric
      erosions in 50 percent of patients on regular NSAID treatment. COX-2 inhibitors
      with lower rate of gastro-intestinal complications are mentioned.

PMID- 12476757
TI  - [Safety of celecoxib administration].
AB  - Celecoxib is selective cylooxygenase-2 (COX-2) inhibitor with equal efficacy like
      conventional non-steroidal antiinflammatory drugs (NSAIDs). The main advantage is
      safer gastrointestinal (GI) profile. All other adverse effects of celecoxib are
      comparable with NSAIDs adverse reactions. Clinical studies in thousands of
      patients show convincing evidence of GI safety in total number of GI events. The
      serious GI complications could not be excluded regarding safety. There is no
      antithrombotic effect and caution is required in elderly, hypertension, oedema,
      vascular and ulcer diseases. Cardioprotective aspirin therapy may be indicated in
      persons with cardiovascular risk. Celecoxib is contraindicated in people with
      known allergy on sulfonamides. The caution is needed in any NSAIDs allergy.

PMID- 12476758
TI  - [Opioids in rheumatology].
AB  - Pain and disability are the main common characteristics of rheumatic diseases.
      Chronic pain must be evaluated like disease per se and there is need to be
      systematically diagnosed and treated. Intensity of pain could be measured with
      verbal, numeric and visual analog scale. There are three therapeutic approaches
      according to WHO analgesic ladder. Opioid treatment is indicated after nonopioid
      analgesics fail. Development of addiction and tolerance are infrequent and dose
      escalation related to worsening of disease. Special caution is needed in elderly
      and previous narcotic consumers.

PMID- 12476759
TI  - [Treatment of chronic pain--use of transdermal fentanyl (Durogesic TTS)].
AB  - Incorrect treatment of chronic pain is common cause of patient's discontentment
      and suffering. The problem is mostly occurring because of inappropriate pain
      treatment. The WHO guidelines recommends declining of prejudices and using of
      strong opioids in therapy after the unsatisfactory treatment with weaker
      analgesics. Strong opioid analgesic fentanyl in transdermal system (Durogesic
      TTS) is introduced. In rheumatology, it is recommended for all conditions
      characterised by chronic pain with intensity 4 and more on the VAS scale (0-10).
      It is mostly used in rheumatoid arthritis, osteoarthritis, low back pain and
      neuropathic pain. Durogesic TTS provides continuous pain relief for 72 hours,
      with constant serum concentrations. It has to be gradually titrated and starting
      dose is 25 micrograms/h. Possible adverse events (nausea, vomiting, constipation,
      sedation, itching) are short termed, transitory and easily managed. Results of
      some clinical trials and personal experiences that are proving its efficacy and
      safety are presented.

PMID- 12476760
TI  - [Isolation frequency of Burkholderia cepacia from cystic fibrosis patients].
AB  - Microorganisms such as Pseudomonas aeruginosa, Staphylococcus aureus and
      Haemophilus influenzae frequently cause colonization and infection in airways of
      patients with cystic fibrosis. Burkholderia cepacia has also been isolated in
      patients with cystic fibrosis since 1980. In this study, we aimed to determine
      the colonization rate of B. cepacia in 286 sputum samples obtained from 129
      cystic fibrosis patients. Selective media for B. cepacia were used besides the
      routine microbiological media in order to increase the isolation rate. The
      colonies were identified by biochemical tests and the antibiotic susceptibilities
      of the strains were determined by disc diffusion method. Pathogenic bacteria (S.
      aureus, P. aeruginosa, Enterobacteriaceae, Streptococcus pneumoniae, H.
      influenzae) were isolated in 52 of 129 patients (40%) and 66 of 286 sputum
      samples (23%). In addition 2 B. cepacia strains were isolated from two different
      patients (1.55%). B. cepacia is now being considered as a pathogen isolated from
      sputum samples of patients with cystic fibrosis with an increasing frequency and
      causing severe clinical features. According to these results it can be concluded
      that, the use of selective media for B. cepacia isolation, should be taken into
      consideration especially by the clinical microbiology laboratories collaborating
      with the cystic fibrosis centers.

PMID- 12476761
TI  - [Erythromycin resistance of group A beta-hemolytic streptococci isolated from
      patients with upper respiratory tract infections].
AB  - The purpose of this study was to determine the erythromycin resistance of group A
      beta-hemolytic streptococci (GABHS) isolated from throat cultures. GABHS were
      isolated from 74 (10.4%) throat cultures of 710 patients with upper respiratory
      tract infections. Penicillin resistance was observed in none of the strains. Of
      these strains, 4 (5.4%) were found to be resistant to erythromycin. It was
      concluded that erythromycin resistance in GABHS, although high in some countries,
      was not a problem in our country at the moment. So, penicillin G and its
      alternative erythromycin and other macrolides are still reliable antibiotics for
      the treatment of GABHS infections.

PMID- 12476762
TI  - [Antibody levels to diphtheria in various community segments].
AB  - The aim of this study was to detect the immune status of our population against
      diphtheria. For this purpose, the levels of diphtheria IgG antibodies in various
      age groups were investigated in 150 subjects aged over 20 years old, by using
      ELISA method. The positive immunity rate against diphtheria was found 62%, while
      there was no statistically significant difference between the rates of males
      (66.7%) and females (57.7%) (p > 0.05). Eighty percent of subjects aged between
      20-29 years, 71.4% of 30-39 years, 50% of 40-49 years, 55.6% of 50-59 years,
      47.6% of 60-69 years and 60% of 70-79 years old groups were found to have
      protective levels (over 0.01 IU/ml) of antibodies to diphtheria. There was no
      significant difference in immunity against diphtheria between these age groups (p
      > 0.05). However, 76% of subjects aged below 40 years old were immune to
      diphtheria, while 54% of subjects aged above 40 years old were so, with a
      statistically significant difference (p < 0.05). There was no significant
      difference in the rate of immunity between subjects in terms of occupation,
      levels of education, geographic location and vaccination status (p > 0.05).

PMID- 12476763
TI  - [Retrospective microbiologic evaluation of vaginal cultures].
AB  - Vaginal culture is one of the most difficult cultures to be evaluated in clinical
      microbiology practice. The necessity of some expensive and complicated processes
      for diagnosis of some specific agents, age related variability of normal vaginal
      flora and failure caused by temporary presence of some pathogens in normal flora
      can be listed among the probable causes of that problem. In this study 8050
      vaginal cultures performed in our hospital laboratories between 1 March 1999-15
      September 2001 were evaluated retrospectively. It was shown that the most
      frequently isolated pathogens were yeasts belonging to the Candida genus (26.8%).
      The second most frequent pathogen (13.8%) was Gardnerella vaginalis which was an
      indicator of bacterial vaginosis. The rate of isolation of Trichomonas vaginalis
      was 2.2%. Group B streptococcus (GBS) was isolated in 2.0% of the total cultures.
      Some nonspecific bacteria, mainly Gram negative bacilli, were noted as colonizing
      agents (6.5%).

PMID- 12476764
TI  - [Use of transcription-based amplification and enzyme immunoassay methods to
      investigate possible Chlamydia trachomatis infections in women with genital
      complaints].
AB  - This study was performed to determine the prevalence of Chlamydia trachomatis
      infections in the female patients with genital complaints, and to compare the
      transcription mediated amplification assay and enzyme immunoassay methods for the
      diagnosis of genital C. trachomatis infections. C. trachomatis (Ct) antigens and
      ribosomal RNAs were researched by enzyme immunoassay (EIA) and transcription
      mediated amplification (TMA) assay, respectively in the endocervical swab samples
      of 90 patients. C. trachomatis IgG and IgM antibodies were also screened in the
      sera of these subjects, by EIA method. Of 90 patients, 18 (20%) were found to be
      positive for Ct-rRNA, 12 (13%) for Ct-antigen, 20 (22%) for IgG, 12 (13%) for IgM
      and 14 (16%) for both IgG and IgM. Among the patients 11 (12%) were found
      positive for Ct-antigen, Ct-rRNA and Ct-IgM antibodies. According to the TMA
      results, the sensitivity and specificity of EIA-Ct antigen method were estimated
      as 67% and 100%, respectively. There was statistically significant difference
      between TMA positivity and those of two EIA methods. In conclusion, the positive
      results obtained with EIA are reliable for the diagnosis of genital C.
      trachomatis infections, however the negative results should be confirmed by TMA.

PMID- 12476765
TI  - [Comparison of vaginal lactobacilli and Lactobacillus species discrimination
      using classic methods and polymerase chain reaction].
AB  - The aim of this study was to identify the vaginal lactobacilli in the species
      level and to investigate the concordance between classical methods and polymerase
      chain reaction (PCR) for the typing of these isolates. Vaginal swab samples which
      have been collected from women who were admitted to the outpatient clinics of
      Gynecology Department of our hospital, were examined by standard microbiological
      methods and additionally were inoculated into selective lactobacilli media. Of
      200 subjects, 59.5% have had normal vaginal flora, 31% were diagnosed as
      bacterial vaginosis and 9.5% as vaginal candidiasis. The lactobacilli isolation
      rates of these groups were found 76.5%, 45.2% and 78.9%, respectively. A total of
      160 facultative anaerobic Lactobacillus strains were isolated from 134 (67%) of
      the swab samples. Of these, 90.6% were identified into species level by classical
      methods, and the most frequently isolated species in our study was found as L.
      gasseri (40%), followed by L. delbrueckii (18%). The comparative study was
      performed only for 66 isolates, and 58 of them (87.8%) were grouped into 7
      species while 8 have not been identified by classical methods, however, all of 66
      isolates were successfully grouped into 4 species by PCR. Fourty-five of 66
      strains have been found to be identical by means of classical methods and PCR,
      and the concordance between the methods were found 68.2 percent.

PMID- 12476766
TI  - [Catalase-negative Rothia dentocariosa: evaluation of additional descriptive
      tests].
AB  - Rothia dentocariosa is one of the human oral flora members, and classified in the
      group of coryneform bacteria which are taxonomically heterogeneous. Although R.
      dentocariosa is considered as a contaminant in throat cultures generally, it may
      be the causative infectious agent in the presence of predisposing factors. The
      catalase activity which is used as a simple and initial identification test,
      becomes contradictory because of the detection of the catalase negative strains
      recently. The aim of this study was to compare several biochemical and enzymatic
      reactions for the identification of catalase positive and negative R.
      dentocariosa strains. A total of 42 R. dentocariosa strains which were isolated
      from throat cultures have been studied, and the positivity rate of mannose
      fermentation in catalase negative R. dentocariosa isolates was found to be
      significantly higher than those catalase positive (p < 0.05). In conclusion,
      mannose fermentation test seems to be a useful tool as an additional
      identification method of catalase negative R. dentocariosa isolates.

PMID- 12476767
TI  - [Candida dubliniensis studies and isolation of Candida types in oropharyngeal
      specimens from oncologic patients].
AB  - Fungal opportunistic infections, and in particular those caused by the various
      Candida species, have gained considerable significance as a cause of morbidity
      and, often, mortality. Although Candida albicans remains to be the most
      frequently isolated fungal species as an opportunistic oral pathogen, other yeast
      species are often identified in immunocompromised patients. C. dubliniensis, the
      recently described species, has been recovered primarily from oropharyngeal
      candidasis in Human Immunodeficiency Virus (HIV)-infected patients. C.
      dubliniensis shares many phenotypic characteristics with, and is phylogenetically
      closely related to, C. albicans. The aim of the present study was to investigate
      the colonization rates of fungal species, and especially C. dubliniensis, in the
      oropharyngeal samples from cancer patients. The oropharyngeal swabs of 543
      patients were collected during their visits to oncology clinic in 9 months
      period, and a total of 209 Candida species have been isolated. Of them, 147
      isolates were found to be positive for germ tube and chlamydospore formation, and
      they were tested for the growth inability at 42 degrees C and 45 degrees C,
      colony morphology in Staib agar and the intracellular beta-glucosidase activity,
      in order to identify C. dubliniensis. The results of these tests and carbohydrate
      assimilation tests by API 20C AUX yeast identification system, yielded that all
      these 147 (70.3%) isolates were C. albicans. The other isolates were identified
      as follows; 16 C. parapsilosis (7.6%), 13 C. tropicalis (6.2%), 10 C. glabrata
      (4.7%), 5 C. guilliermondii (2.3%), 4 C. krusei (1.9%), 3 C. keyfr (1.4%), 3 C.
      famata (1.4%), 2 S. cerevisiae (0.9%), 2 C. pelliculosa (0.9%), 1 C. utiles
      (0.4%), 1 C. neoformans (0.4%) and 1 Hansenula polymorpha (0.4%), while no C.
      dubliniensis was isolated.

PMID- 12476768
TI  - [Candida colonization on the surface of orthodontic brackets and the adhesion of
      these strains to buccal epithelial cells].
AB  - Many types and numbers of microorganisms may be colonized in the oral cavity.
      Candida albicans is the most frequently isolated fungal species which colonizes
      oral mucosal cells Denture prostheses play an important role by increasing the
      risk of colonization. In this study, Candida colonization and adhesion rates have
      been investigated among 60 orthodontic bracket users (mean age: 17.8 years), and
      15 (25%) of them were found to be colonized by Candida species (13 C. albicans, 1
      C. kefyr, 1 C. lusitaniae). Fourteen of 15 subjects (93.3%) were between 16-18
      years old. All the isolates were exposed with buccal epithelial cells in-vitro,
      and the adhesion rate was found to be 12%. The adhesion activity was detected
      only in C. albicans strains.

PMID- 12476769
TI  - [Evaluation of an ELISA kit made in our laboratory for intratypic discrimination
      of poliovirus type 1 strains isolated from acute flask paralysis].
AB  - In this study, we aimed to develop and evaluate an enzyme based immunological
      method (ELISA) for the intratypic differentiation (whether if Sabin like-SL, or
      non Sabin like/wild type-NSL) of poliovirus type 1 isolates, in the frame of
      Polio Eradication Programme (PEP) in Turkey. Five poliovirus type 1 strains which
      were formerly isolated and identified in our laboratory from fecal samples of
      acute flask paralysis (AFP) patients, and standard reference strains of vaccine
      type 1 and prototype wild (Mahoney) polioviruses have been tested into plate
      wells that bounded with 5 different monoclonal antibodies (mAbs B18, S2-36, M18,
      B82, M49). The wells which gave high absorbance than cutoff value estimated by
      comparing negative control wells, were accepted as positive. As a result, the
      standard poliovirus strains were differentiated correctly, whereas 2 patient
      isolates were identified as SL and 3 were NSL. In conclusion, our home-made ELISA
      method found to be successful for intratypic differentiation of poliovirus type 1
      isolates, however more detailed studies are necessary in order to increase the
      susceptibility and specificity of this test.

PMID- 12476770
TI  - [Hepatitis A and hepatitis E seroprevalence in adults in the Ankara area].
AB  - In this study, between the period of September 2000 to July 2001, hepatitis A
      virus (HAV) IgG antibodies and hepatitis E virus (HEV) total (IgG + IgM)
      antibodies have been searched by using commercially provided enzyme immunoassay
      kits (Axsym, Abbott USA), in 1046 adults aged between 15-75 years old (mean age:
      32.3 years), who were admitted to the outpatient clinics of Internal Medicine and
      Infectious Diseases Department of Ankara University Medical School, with no acute
      hepatitis signs and symptoms. As a result, anti-HAV and anti-HEV seropositivities
      were detected in 914 (87.4%) and 40 (3.8%) subjects, respectively. The
      seropositivity rate for anti-HAV was 72.7% at the ages of 15-30 years, while anti
      HEV was negative in this age group. Anti-HAV and anti-HEV seropositivity rates
      were found to be the highest between the ages of 30-60 years.

PMID- 12476771
TI  - [Retrospective evaluation of HBsAg, anti-HCV, anti-HIV and syphilis reagin
      antibody seropositivity in blood donors at the Trabzon Farabi Hospital].
AB  - Transfusion of blood and blood products is a widely used method for therapy in
      medicine, however it may result with the transmission of infectious agents from
      donor to recipient. In order to achieve safe blood transfusions and to minimize
      post-transfusion infections, several screening tests for infectious agents are
      routinely done all around the world as well as in our country. In this study,
      HBsAg, anti-HCV, anti-HIV and syphilis reagin antibody tests results have been
      retrospectively evaluated for 33.766 blood donors during January 1, 1997 to
      December 31, 2000 in Blood Center of Farabi Hospital, Black Sea Technical
      University. Testing for HBsAg, anti-HIV and anti-HCV has been done by using
      commercially available micro and/or macro enzyme immunoassays, and syphilis
      reagin antibody test by latex agglutination (RPR) method. The indeterminate
      results were confirmed by retesting of sera with microparticle enzyme immunoassay
      and Western blot methods. As a result, in 1331 (3.94%) subjects HBsAg, in 250
      (0.74%) subjects anti-HCV, and in 161 (0.47%) subjects RPR were found positive.
      Twenty samples which have had the results in gray-zone for anti-HIV, have been
      found negative with the confirmation tests.

PMID- 12476772
TI  - [Case report: evaluation of two cases of tuberculoma incident to tuberculosis
      meningitis].
AB  - Intracranial tuberculoma is one of the most serious complications of tuberculous
      meningitis. In this report, two patients who develop intracranial tuberculoma as
      a complication of tuberculous meningitis have been presented. The first patient
      was a 35 years old male patient who were still been in therapy for cavitary
      tuberculosis. The other one was 42 years old male patient and have had treated
      for subdural empyema two years ago. There was no positivity in both of the
      cerebrospinal fluid (CSF) specimens of the patients by Gram and Erlich Ziehl
      Neelsen stained preparations, while the CSF sample of the first case yielded
      Mycobacterium tuberculosis in culture. The tuberculoma diagnosis of these
      patients managed by the help of computerized tomography (CT) and nuclear magnetic
      resonance imaging (NMR) methods. As a result, it was thought that CT and NMR
      techniques have a great role in the diagnosis and management of complications in
      tuberculous meningitis patients.

PMID- 12476773
TI  - [Case report: brucellosis complicated by epididymo-orchitis and paravertebral
      abscess].
AB  - Brucellosis which is a zoonotic infection involving many systems, is widespread
      in Turkey. Although muscular and skeletal system involvements are common,
      genitourinary system complications (epididymo-orchitis) are observed rarely.
      Brucellosis accompanied by abscess formation in the vertebra is generally seen in
      the elderly and patients with chronic diseases, while epididymo-orchitis in young
      patients. However, it is very unusual to detect these two complications together.
      In this report, a case of 42 years old male patient with epididymo-orchitis and
      paravertebral abscess due to brucellosis, has been presented.

PMID- 12476774
TI  - [Enterotoxigenic Bacteroides fragilis as a factor in diarrhea].
AB  - The etiology of almost half of the diarrheal diseases has not been cleared yet,
      in spite of modern diagnostic methods. Bacteroides fragilis strains which secrete
      an enterotoxin are termed as enterotoxigenic B.fragilis (ETBF). These strains are
      associated with diarrheal diseases in children above 1 year of age and in adults.
      B. fragilis toxin (BFT) stimulates intestinal secretion and in-vitro cytotoxic
      response in HT29/C1 cells. Recent studies suggest that BFT is related to
      inflammatory bowel disease and colon cancer by triggering nuclear activation with
      potential oncogene expression. In this review, the molecular pathogenesis,
      epidemiology and laboratory diagnosis of ETBF have been reviewed to focus on ETBF
      as a diarrheal agent.

PMID- 12476775
TI  - [Ecological factors for host tissue colonization].
AB  - The first stage of microbial infection is colonization; the establishment of the
      pathogen at the appropriate portal of the entry. Organisms that have the ability
      to colonize host tissues, have usually developed tissue adherence mechanisms and
      some ability to overcome or withstand the constant pressure of host defense
      mechanisms. There are namely 3 adaptations that are important for bacteria to
      colonize human hosts: Coaggregation, osmo-adaptation, acid tolerance and
      resistance. In this review article, these adaptation mechanisms have been
      discussed under the light of literature.

PMID- 12476776
TI  - [Comparison of fixation Dio-Sensitest and disk diffusion techniques for the
      antibiotic sensitivity of some enteric bacteria].

PMID- 12476777
TI  - [Comparison of standard proportion dilution test and Etest for Mycobacterium
      tuberculosis sensitivity to ofloxacin and ciprofloxacin].
AB  - The antibacterial activities of ofloxacin and ciprofloxacin on 100 clinical
      isolates of Mycobacterium tuberculosis were determined by using standard
      proportion dilution method and Etest. When 98 of 100 M. tuberculosis isolates
      were susceptible to ofloxacin and ciprofloxacin, two were resistant to both of
      the drugs. The correlation between E test and standard proportion dilution method
      was 100%.

PMID- 12476778
TI  - Estrogens and colorectal cancer.
AB  - In recent years, several lines of epidemiologic, clinical and experimental
      evidences have been reported showing that estrogen hormones may be involved in
      malignant colorectal tumors. The sex differences in site-specific incidence, the
      increased incidence of colonic cancer in women with breast cancer, the protective
      effect of increasing parity and the reduced risk among women taking
      postmenopausal hormones, are all elements suggesting that sex hormones may play a
      role. Male rats experimentally exposed to the carcinogen dimethylhydrazine, have
      twice the risk of developing colon cancer and significantly shorter survival
      times than their female counterparts. Along with the clinical, experimental and
      epidemiologic findings there are also biologic reasons why estrogen may be
      protective. Most estrogen action appears to be exerted via the estrogen receptors
      (ERs) on target cells. ERs have been reported in several solid tumors including
      gastrointestinal neoplasms such as esophageal, gallbladder, gastric and
      colorectal cancer. At the end of 1995, a second ER (ER-beta) was cloned from the
      rat prostate cDNA library and subsequently, the human and mouse homologs. Its
      demonstration in normal and neoplastic human colorectal tissues and "in vitro" in
      colonic epithelial cells, has renewed interest in investigating the existence of
      two ER subtypes. The presence of two ERs could explain the selective actions of
      estrogens on different target tissues and, particularly, on the gastrointestinal
      tract. Finally, our studies suggest that estrogens and their receptors play an
      important role in the growth and progression of colorectal tumors, by interacting
      with other molecules required for cell proliferation like growth factors and
      polyamines.

PMID- 12476779
TI  - Pathogenetic aspects of sepsis and possible targets for adjunctive therapy.
AB  - The outcome of patients with sepsis arises from multiple factors affecting both
      the host and the invading microorganisms. Age, presence of underlying disease,
      source of infection and some specific etiological agents have been related to
      prognosis. Appropriateness of antimicrobial therapy, considering the in vitro
      susceptibility tests for the infecting bacteria, has been strongly associated
      with the outcome. Therefore even after the cascade of sepsis has been triggered,
      the control of bacteria growth is still fundamental for the outcome of the
      infection. This is a major distinction point from experimental studies in which
      whole killed bacteria and their products are used as model of sepsis. However,
      even within the setting of adequate antimicrobial use, patients still die of
      sepsis. Thus, strategies focusing on further therapy targets are an important
      area of interest for basic and clinical research. Although such adjunctive sepsis
      therapy has failed to achieve consistent better survival rates so far,
      nevertheless, it improved our understanding of the pathophysiological events seen
      in sepsis that the possibility that a new and effective treatment may arise has
      been warmly considered. In this paper we aim to review some aspects of the
      pathogenesis of sepsis, focusing on recent advances and on possible targets for
      adjunctive therapy. Published clinical trials and experimental data supporting
      such trials are commented on.

PMID- 12476780
TI  - Embryonal cardiotoxicity of the Helicobacter pylori lipopolysaccharide.
AB  - Helicobacter (H.) pylori is the causative agent of the peptic ulcer disease and a
      co-factor in the development of gastric malignancies. Recently, it has been
      maintained that chronic H. pylori infections in adults are linked to a higher
      risk of coronary heart diseases. In this respect, the acute toxic effects of the
      H. pylori lipopolysaccharide (LPS) on embryonal cardiomyocytes at different
      developmental stages was evaluated. White Leghorn chick embryos and smooth (S)-
      form NCTC 11637 strain H. pylori organisms were used. Both whole heath-killed H.
      pylori suspensions (3.10(6) bacteria/egg) and isolated S-LPS (500 ng/egg) or S
      Lipid A (500 ng/egg) were non-lethal to 4-day embryos, becoming moderately lethal
      (5% to 30%) to 6- and 8-day embryos and highly lethal (> 90%) to 10- to 17-day
      embryos. The contractile activity of isolated atrial fragments from 10-day
      embryos was completely inhibited, within 5 min, following treatments with heath
      killed H. pylori (3 x 10(6)/ml), or S-LPS (500 ng/ml), or S-Lipid A (500 ng/ml);
      the block determined by S-LPS and S-Lipid A was irreversible, while the block by
      bacterial suspensions was completely reversible upon withdrawal. Following a 24
      hour treatment with S-LPS or S-Lipid A of single-cell cultures of cardiomyocytes
      (isolated from 10-day embryos) a dose-dependent cell loss was observed, as
      assessed by total protein dosage and direct counting of adherent cells. Propidium
      Iodide/Annexin V FACS-analysis confirmed the occurrence of cellular necrosis, but
      did not show any evidence of apoptotic processes. The release of superoxide anion
      radicals by cultured cardiomyocytes was as follows: S-Lipid A (25 micrograms/ml)
      > S-LPS (25 micrograms/ml) > heath killed H. pylori suspensions (3 x 10(6)/ml);
      control cultures did not release detectable amounts of superoxide anion radicals.
      Furthermore, cultured cardiomyocytes produced increased amounts of NO (N
      monomethylarginine-inhibitable) following stimulation with S-LPS (25
      micrograms/ml) or S-Lipid A (25 micrograms/ml) (but not heath killed H. pylori 3
      x 10(6)/ml suspensions). Under all the above experimental conditions S
      polysaccharide proved to be non-toxic. Concluding, H. pylori LPS is relatively
      non-toxic to the less differentiated cardiomyocytes; cardiomyocytes which are
      more advanced in their biochemical differentiation become highly sensitive to LPS
      and produce ROS and NO. ROS are probably responsible for the early toxic actions,
      while both ROS and NO are likely to be involved in the later
      degenerative/necrotic effects.

PMID- 12476781
TI  - Treatment of rheumatoid arthritis: new therapeutic approaches with biological
      agents.
AB  - Rheumatoid arthritis is a chronic polyarthritis leading to joint destruction and
      remarkable disability. Current therapies have various degrees of efficacy, but
      toxicity frequently limits their long-term use. Furthermore, treatment of
      refractory rheumatoid arthritis includes increasing disease-modifying
      antirheumatic drugs dosage, using combination therapy, and adding or increasing
      the posology of corticosteroids. Although the etiology of the disease remains
      unknown, our increasing knowledge of the mechanisms underlying pathogenic events
      in rheumatoid synovitis, has provided opportunities to specifically target cell
      surface markers or cytokines involved in the inflammatory response. The objective
      of this review is to describe the different therapeutic approaches with
      biological agents that are either being utilized or are under development. Some
      of these products reflect the evolving capacity for the biotechnology industry to
      synthesize and humanize therapeutic agents: anti-tumor necrosis factor (TNF)
      alpha monoclonal antibodies (MoAb) and recombinant TNF-receptor construct appear
      to be validated tools. These treatments alone, or in combination with
      methotrexate are very effective in rheumatoid patients. Data from clinical trials
      and issues related to mechanisms of action, potential toxicity, and future
      perspectives for these novel therapeutic options are considered in this review.
      Anti-cytokine treatment include other interesting approaches to interfere with on
      going inflammatory processes, such as the use of recombinant human interleukin
      (IL)1 receptor antagonist, or recombinant human IL10. T cell constimulatory
      blockade, induction of apoptosis in the synovial tissue, and gene therapy could
      represent future strategies in rheumatoid disease.

PMID- 12476782
TI  - Immunoregulatory effects of L-arginine and therapeutical implications.
AB  - Arginine, initially classified as a non-essential amino acid, participates to
      multiple biological processes including release of several hormones, collagen
      synthesis during wound healing, antitumor and antibacterial activities and non
      specific immunity. Nitric oxide synthase and arginase competes for L-arginine as
      a substrate and this event appears to play a key role in the regulation of the
      inflammatory process. In this framework recent studies have identified complex
      patterns of interactions among these enzymes. This review will emphasizes some
      effects of L-arginine on immune cell functions, including triggering of L
      arginine-nitric oxide and arginase pathways, its biological properties and
      therapeutical applications.

PMID- 12476783
TI  - Plasmid DNA vaccines.
AB  - Genes that code for the production of protein antigens have been cloned and
      recombined with plasmids. Gene-plasmid constructs have been amplified in a
      bacterial host, purified and administered to a mammalian host. The gene is
      expressed in the host and the antigen that is produced induces an immune
      response. These so-called DNA vaccines have been prepared for a number of
      infectious agents, some tumors and some allergens, and were shown to be
      efficacious in animal studies. Clinical trials for some of these vaccines are
      underway. Advantages of using a DNA vaccine include the abilities to favor a T
      helper-1 or a T helper-2 lymphocyte response and to induce a cytotoxic T
      lymphocyte response. Moreover, some reports have indicated that they produce long
      lasting immunity. DNA vaccines might be used in situations where no effective
      vaccine is available for a disease. However, their use might not be risk-free.
      Further research in this field is needed to determine their efficacy and to
      identify the risks involved in using them.

PMID- 12476784
TI  - Advances in the treatment of osteoporosis.
AB  - Drugs used to treat osteoporosis act either by inhibiting bone resorption or
      stimulating bone formation. Osteoclast formation and bone resorption require cell
      to-cell contact between osteoblasts and osteoclast precursors and osteoclasts in
      the marrow. Interaction between the receptor for activation of nuclear factor
      kappa B (RANK) on the surface of preosteoclasts and osteoclasts and RANK ligand
      on the surface of osteoblasts is required to stimulate osteoclast formation and
      activation. Binding of the RANK ligand to its receptor and osteoclastogenesis are
      prevented by osteoprotegerin (OPG), a decoy receptor produced by osteoblasts and
      marrow stromal cells. Thus, interference in binding of the RANK ligand to RANK by
      OPG determines the rate of bone resorption. Antiresorptive drugs such as
      estrogen, raloxifene, bisphosphonates, salmon calcitonin, and osteoprotegerin
      increase bone mass by inhibiting osteoclast function and bone resorption.
      Osteoprotegerin is more potent since it also inhibits osteoclast formation.
      Raloxifene, a selective estrogen receptor modulator (SERM), is a member of a
      class of compounds that act through estrogen receptors and are agonists for bone,
      antagonists for breast and uterine tissue and may be cardioprotective. The drug
      was shown to prevent vertebral fractures. Alendronate and bisphosphonates are the
      only antiresorptive drugs that have been shown to decrease fracture rates for the
      hip in addition to spine and other sites. Bone morphogenetic proteins stimulate
      bone formation at local sites and are being developed to stimulate fracture
      healing. Parathyroid hormone (1-34) stimulates osteoblastic bone formation,
      markedly increases bone mass, prevents vertebral fractures and is under
      development to treat osteoporosis.

PMID- 12476785
TI  - Recombinant adenovirus-mediated cytotoxic gene therapy and lymphoproliferative
      disorders: analysis based on pharmacodynamics.
AB  - The literature has seen an incredible booming of publications related to the use
      of adenovirus-mediated gene therapy in cancer over the past decade. The use of
      recombinant adenoviruses as a therapeutic tool for lymphoproliferative disorders
      has also been evaluated in this context. Several approaches of adenovirus
      mediated gene expression have been used to transfect cell lines that are derived
      from lymphoid tumors and would have otherwise been refractory to other
      transfection methods. The identification of high affinity receptor for human
      adenoviruses serotype 2 and 5, the coxsackie-adenovirus receptor (CAR), has
      raised the question about its relevance for the efficacy of recombinant
      adenovirus-mediated gene therapy. We have reviewed the published studies that
      have examined the use of recombinant adenovirus vectors expressing cytotoxic
      genes for gene therapy in lymphomas, chronic lymphocytic leukemia and multiple
      myeloma. Based on the concept that a recombinant adenovirus particle behaves like
      a drug, we address the issue of adenovirus-mediated gene therapy in terms of
      classic pharmacodynamics. We have analyzed the use of recombinant adenovirus
      mediated cytotoxicity by assessing the importance of the biochemical and
      physiological signaling pathways interacting with these particular drugs and
      their mechanisms of action. The case of anaplastic large cell lymphoma is
      discussed as an example that better illustrates the concept of pharmacodynamics
      of recombinant adenoviral-mediated expression of cytotoxic genes. Ultimately, the
      issues derived from the use of such a modality of therapy that require further
      evaluation, are discussed in this review.

PMID- 12476786
TI  - Targeting the AMP-activated protein kinase for the treatment of type 2 diabetes.
AB  - The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is
      activated in response to conditions of cellular stress such as muscle contraction
      and hypoxia. In skeletal muscle, activation of AMPK leads to increased glucose
      uptake, enhanced insulin sensitivity and oxidation of fatty acids. In the liver,
      AMPK activation causes an increase in fatty acid oxidation and inhibition of
      glucose production. These effects on glucose and fat metabolism make AMPK an
      important pharmacological target for the treatment of type 2 diabetes. Studies
      done in animal models of type 2 diabetes have shown that pharmacological
      activation of AMPK with the compound 5-aminoimidazole-4-carboxamide
      ribonucleoside (AICAR) decreases blood glucose and insulin concentrations. While
      strong efforts are underway in order to identify novel AMPK-activating compounds,
      the safety of chronic pharmacological activation of AMPK remains to be
      determined.

PMID- 12476787
TI  - Inhibitors of post-translational modifications of G-proteins as probes to study
      the pancreatic beta cell function: potential therapeutic implications.
AB  - It is well established that glucose-induced insulin secretion involves generation
      of intracellular second messengers. Using specific inhibitors of guanosine
      triphosphate [GTP] biosynthesis [e.g., mycophenolic acid; MPA], we have
      identified a permissive role for GTP in glucose-stimulated insulin secretion.
      While the exact site of action for GTP within the islet beta cell remains to be
      identified and defined, recent evidence from several laboratories, including our
      own, indicate that it could involve activation of GTP-binding proteins [G
      proteins]. These studies have identified both trimeric and monomeric forms of G
      proteins within the pancreatic beta cell. Recent data also indicate that these G
      proteins, specifically the monomeric G-proteins and the gamma subunits of
      trimeric G-proteins undergo a series of posttranslational modifications at their
      C-terminal cysteine. Such modifications include, isoprenylation, carboxyl
      methylation and palmitoylation. These modification steps appear to be essential
      for translocation of these proteins to the membrane sites for interaction with
      their respective effector proteins. This review primarily focuses on recent
      findings that clearly support the viewpoint that these posttranslational
      modification steps not only play obligatory roles in fuel-induced insulin
      secretion, but also in cytokine-mediated apoptotic demise of the beta cell. In
      this review, we also attempted to describe those findings involving the use of
      specific inhibitors for each of these pathways, and it is our hope that these
      aspects of beta cell metabolism and function generate interest in development of
      therapeutic intervention modalities to states of perturbed insulin release.

PMID- 12476788
TI  - Novel targets for therapy in paediatric oncology.
AB  - Although the majority of children with cancer are now cured of their disease, a
      significant number either have disease resistant to current therapy, or are
      unable to tolerate the short and long term complications of their treatment.
      Therefore new therapeutic strategies which optimise existing agents by use of
      their clinical and molecular pharmacology are needed, along with the development
      of new agents. Accordingly, the agents chosen for the study need to be
      prioritized, and are thus selected on the basis of categories such as encouraging
      pre-clinical data from xenografts of paediatric tumours, novel mechanisms of
      action, drugs that modify or overcome cellular resistance and drugs that are
      active in adult studies. In this review, novel targets for chemotherapy such as
      topoisomerase I, angiogenesis and signal transduction will be discussed. In
      addition, the circumvention of methotrexate resistance by novel antifolate
      thymidylate synthase inhibition, and the modulation of alkylating agents by
      inhibition of 0(6)-alkylDNA-alkyltransferase will be discussed as strategies to
      overcome potentially important resistance mechanisms in paediatric oncology.
      Finally, recent advances in biological therapies, tumour vaccination and gene
      therapy will be highlighted. In the future, investigation of cancer biology,
      selection of new drugs, and securing of funds to support the conduct of
      integrated early clinical studies that maximise the pharmacological, cellular
      biological and molecular pathological information gained, will be the major
      challenges to be faced by paediatric oncologists.

PMID- 12476789
TI  - Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the
      prevention of hyperglycaemia.
AB  - The mitochondrial pyruvate dehydrogenase complex (PDC) catalyses the oxidative
      decarboxylation of pyruvate, and links glycolysis to the tricarboxylic acid cycle
      and ATP production. Adequate flux through PDC is important in tissues with a high
      ATP requirement, in lipogenic tissues (since it provides cytosolic acetyl-CoA for
      fatty acid (FA) synthesis), and in generating cytosolic malonyl-CoA, a potent
      inhibitor of carnitine palmitoyltransferase (CPT I). Conversely, suppression of
      PDC activity is crucial for glucose conservation when glucose is scarce. This
      review describes recent advances relating to the control of mammalian PDC
      activity by phosphorylation (inactivation) and dephosphorylation (activation,
      reactivation), in particular regulation of PDC by pyruvate dehydrogenase kinase
      (PDK) which phosphorylates and inactivates PDC. PDK activity is that of a family
      of four proteins (PDK1-4). PDK2 and PDK4 appear to be expressed in most major
      tissues and organs of the body, PDK1 appears to be limited to the heart and
      pancreatic islets, and PDK3 is limited to the kidney, brain and testis. PDK4 is
      selectively upregulated in the longer term in most tissues and organs in response
      to starvation and hormonal imbalances such as insulin resistance, diabetes
      mellitus and hyperthyroidism. Parallel increases in PDK2 and PDK4 expression
      appear to be restricted to gluconceogenesic tissues, liver and kidney, which take
      up as well as generate pyruvate. Factors that regulate PDK4 expression include FA
      oxidation and adequate insulin action. PDK4 is also either a direct or indirect
      target of peroxisome proliferator-activated receptor (PPAR) alpha. PPAR alpha
      deficiency in liver and kidney restricts starvation-induced upregulation of PDK4;
      however, the role of PPAR alpha in heart and skeletal muscle appears to be more
      complex. These observations may have important implications for the
      pharmacological modulation of PDK activity (e.g. use of PPAR alpha activators)
      for the control of whole-body glucose, lipid and lactate homeostasis in disease
      states and suggest that therapeutic interventions must be tissue targeted so that
      whole-body fuel homeostasis is not adversely perturbed.

PMID- 12476790
TI  - Molecular basis of hyperparathyroidism and potential targets for drug
      development.
AB  - Our appreciation of the molecular pathogenesis of primary hyperparathyroidism
      (HPT) has seen great advances over the past decade. This improved understanding
      may well lead to the development of new treatment options that are specifically
      targeted to defective pathways. This review summarizes recent advances in the
      molecular basis of HPT and associated endocrinopathies, and discusses the
      potential for these and future findings to provide targets for alternative
      approaches to therapy. The only proven contributors to common sporadic HPT, by
      virtue of clonal genetic abnormalities, are the cyclin D1 and MEN1 genes. Cyclin
      D1 is an oncogene that encodes a key regulator of the cell cycle, while MEN1 is a
      tumor suppressor gene that has also been implicated in familial multiple
      endocrine neoplasia type 1 (MEN1), in which primary HPT is common. In addition,
      other key parathyroid regulatory pathways may play a role in HPT pathogenesis.
      1,25 (OH)2-vitamin D. Ca2+ and phosphate are regarded as principal regulators of
      parathyroid cell proliferation and PTH secretion. Therefore, prime candidate
      targets include the Ca2+ sensing receptor (CASR) gene, the vitamin D receptor
      (VDR) gene, a putative phosphate receptor gene, their cognate gene products, and
      other genes or proteins involved in their respective biochemical pathways.
      Attempts to identify new therapies based specifically on the defective pathways
      in HPT could complement or eventually supplant traditional approaches.

PMID- 12476791
TI  - Apoptotic cell death in renal injury: the rationale for intervention.
AB  - Cell number abnormalities are frequent in renal diseases, and range from the
      hypercellularity of postinfectious glomerulonephritis to the cell depletion of
      chronic renal atrophy. Recent research has shown that apoptosis and its
      regulatory mechanisms contribute to cell number regulation in the kidney. The
      potential role of apoptosis ranges from induction and progression to repair of
      renal injury. Death ligands and receptors, such as tumor necrosis factor and Fas
      ligand, proapoptotic and antiapoptotic Bcl2 family members and caspases have all
      been shown to participate in apoptosis regulation in the course of renal cell
      injury. However, the precise role of these proteins is unclear, and the
      participation of most known apoptosis regulatory proteins has not been studied.
      We now review the role of apoptosis in renal injury, the potential molecular
      targets of therapeutic intervention, the therapeutic weapons to modulate the
      activity of these targets and the few examples of therapeutic intervention on
      apoptosis, with emphasis on the acute tubular necrosis.

PMID- 12476792
TI  - Metastatic thyroid cancer unresponsive to conventional therapies: novel
      management approaches through translational clinical research.
AB  - In this contribution, we review the limitations of the currently applied
      "standard" treatments for well-differentiated, non-medullary thyroid cancer
      (ThyrCa), and describe the molecular and cellular biologic basis of potential
      novel therapeutic modalities currently under study and/or development.
      Conventional therapy for ThyrCa consists of total/near-total thyroidectomy,
      radioiodine (RAI or 131I), and long-term thyroid hormone "suppressive" therapy
      (THST). RAI therapy remains the cornerstone of the "standard" management
      strategies for metastatic ThyrCa, and when administered under optimal conditions
      can achieve either eradication or long-term clinical "control" of the disease.
      Despite increasing sophistication in the protocols using 131I over the last 30
      years, no significant down-trend has been observed in the annual mortality rate
      for this disease, a fact reflecting the existence of a "core" population of
      patients with RAI-"resistant" disease. The molecular basis for this phenomenon is
      believed to be the progressive tumoral de-differentiation over time, with loss of
      (or marked decrease in) the expression of cellular components responsible for
      iodine uptake, organification and retention. Adjuvant methods to RAI, such as
      radiosensitizers and lithium carbonate, provide only marginal additional
      therapeutic effect. Further, the role of non-RAI-based modalities, such as
      secondary extensive metastatectomies with curative intent, external beam
      radiotherapy, and cytotoxic chemotherapy (mainly with doxorubicin-based regimens)
      has been unfortunately limited to highly selected cases. Palliative methods for
      acute clinical management of widely metastatic ThyrCa are also presented, along
      with anecdotal evidence for the potential therapeutic role for octreotide and its
      radiolabeled therapeutic peptide analogs, selective estrogen receptor modulators
      (SERM's), as well as bisphosphonates. Translational "bench-to-bedside" research
      has recently led to the identification of the transcriptional machinery as a
      valid target for future therapeutic efforts in ThyrCa. Indeed, pre-clinical
      studies with a variety or agents that affect the rate of thyroid-specific gene
      transcription, i.e. retinoids, DNA methyltransferase inhibitors, and histone
      deacetylase inhibitors, have shown their potential for induction of re
      differentiation, growth inhibition, promotion of apoptosis and cell cycle
      regulation. These concerted genomic effects of the above compounds will probably
      yield novel types of therapies in the clinical arena, especially for RAI-non-avid
      tumors. Retinoid analogs have already been used in pilot studies in ThyrCa
      patients with limited success. These re-differentiating agents have raised our
      expectations for a type of therapy for this malignancy based on a solid molecular
      rationale, while future progress in the domains of tissue-targeted gene therapy
      and anti-angiogenesis is eagerly awaited.

PMID- 12476793
TI  - Mechanisms of interferon mediated anti-viral resistance.
AB  - Interferons (IFNs) are an important part of immune responses and are believed to
      protect the host from viral and bacterial pathogens as well as having a role in
      rejection of malignancies. The well-known anti-viral and cytostatic properties of
      IFNs have led to the clinical use of these proteins to treat some cancers and
      viral infections. Extensive research has begun to unravel much of the molecular
      basis for the biological effects of IFNs, and this information could now be used
      as a foundation for the development of novel therapeutic strategies that avoid
      some of the acknowledged shortcomings of cytokine therapies. This review explains
      the current model of IFN action, during viral infections and the potential for
      well-established and emerging groups of IFN inducible genes as therapeutic
      targets is highlighted.

PMID- 12476794
TI  - Metabolic control through L calcium channel, PKC and opioid receptors modulation
      by an association of naloxone and calcium salts.
AB  - beta-endorphins (beta-ends) are released from the anterior pituitary and from
      lymphocytes directly into inflamed tissue in response to stress and pain. At the
      site of inflammation and trauma, the link of beta- ends to opioid receptors
      hyperpolarizes nerve terminal, by blocking L-calcium gated channels, induces
      modifications of receptor stereoisomerism and alters the bond-energy. Opioids
      increase potassium and decrease calcium and sodium currents through interactions
      with G-protein. In some pathologies, it has been found a loss of desensitization
      and down regulation of opioid receptors by means of Ca++ blocking that, in turn,
      inhibits PKC-activation. The physiopathological mechanism dependent on the high
      concentration of linked opioids affects cellular level of Ca++, ATP and NADH.
      This biochemical reaction exerts deep influence on energetic cell status and
      metabolism. In gram negative bacteria, expression of mu-receptors on cell surface
      has been observed, with a possibility to interfere with host cell metabolism.
      There are many human and veterinary pathologies in which the reported mechanisms
      are well known: polycystic ovary syndrome, gross cystic breast disease, milk
      fever, ruminal tympanites, pyometra, equine colic syndrome, ovarian follicular
      cyst in dairy cows, calcium deficit in post-partum cows, uterine involution in
      cows. Also incoming pathologies such as Electro-Magnetic-Field exposure may
      induce alteration of calcium channel activity through the same mechanism. On
      clinical bases, it has been pointed out that the therapeutic administration of an
      association of calcium salts and naloxone controls calcium turnover, pain and
      functional activity of endocrine glands, via down regulation/desensitization of
      opioid receptors, PKC stimulation and energy restoration.

PMID- 12476795
TI  - G protein-coupled receptor kinase 2--a feedback regulator of Gq pathway
      signalling.
AB  - G protein coupled receptors or serpentine receptors work as signalling switches
      that turn extracellular signals into activation of multiple molecules at the
      intracellular face of the plasma membrane. Serpentine receptors are the targets
      of around 70% of all current drugs in clinical medicine. We suggest that these
      receptors can be pharmacologically targeted by modification of their unique
      internal inhibitors the G protein coupled receptor kinases (GRKs). The GRKs
      constitute a family of serine/threonine kinases that specifically bind to and
      phosphorylate agonist-activated serpentine receptors. The phosphorylated
      receptors are recognized by arrestins that bind to the receptor and uncouple them
      from attached G proteins thereby terminating G protein signalling. This review
      focuses on a ubiquitously expressed GRK family member dubbed GRK2 (previously
      called beta-adrenergic receptor kinase 1) that regulates cellular signalling at
      multiple levels. In Gq-coupled signalling modules GRK2 may function as a feedback
      inhibitor molecule that monitors, inhibits and re-directs the information flow.
      GRK2 acts as a negative feedback protein by interacting with at least six key
      signalling molecules in the Gq pathway including; receptors, free G beta gamma
      subunits, activated G alpha q subunits, phosphatidylinositol-4, 5-bisphosphate
      (PIP2), protein kinase C (PKC) and calmodulin (CaM). GRK signalling is important
      for immune, endocrine and cardiovascular function manifesting itself in disorders
      such as heart failure and lymphocyte activation especially in chronic
      inflammation. This review summarizes the advances made in understanding the many
      actions of GRKs and addresses their potential as novel therapeutic targets.

PMID- 12476796
TI  - Molecular basis for designing selective modulators of retinoic acid receptor
      transcriptional activities.
AB  - Retinoic acid receptors are ligand-regulated transcription factors belonging to
      the nuclear receptor superfamily, which comprises 49 members in the human genome.
      all-trans retinoic acid and 9-cis retinoic acid receptors (RARs and RXRs) are
      each encoded by three distinct genes and several isoforms arise from alternative
      splicing and the use of different promoters. While RXRs are promiscuous
      dimerization partners of several other nuclear receptors, RARs are active, in
      vivo, when associated to RXRs. Retinoids are therefore regulators of multiple
      physiological processes, from embryogenesis to metabolism. Different combinations
      of RXR:RAR heterodimers occur as a function of their tissue-specific expression
      and their activity is mostly conditioned by the activation status of RAR. These
      heterodimers are defined as non permissive heterodimers, in opposition to
      permissive dimers whose transcriptional activity may be modulated through RXR and
      its dimerization partner. The transcriptional activity of these dimers also
      relies on their ability to recruit nuclear coactivators and corepressors, which
      function as multi proteic complexes harboring several enzymatic activities
      (acetylases, kinases). The structure of the ligand bound to the RAR moiety of the
      dimer, as well as the nature of the DNA sequence to which dimers are bound,
      dictate the relative affinity of dimers for coactivators and thus its overall
      transcriptional activity. RARs are also able to repress the activity of unrelated
      transcription factors such as AP1 and NF-kappa-B, and therefore have potent anti
      proliferative and anti inflammatory properties. This review summarizes our
      current view of molecular mechanisms governing these various activities and
      emphasizes the need for a detailed understanding of how retinoids may dictate
      transactivating and transrepressive properties of RARs and RXRs, which may be
      considered as highly valuable therapeutic targets in many diseases such as
      cancer, skin hyperproliferation and metabolical disorders (diabetes,
      atherosclerosis etc).

PMID- 12476797
TI  - Photomedical approaches for the diagnosis and treatment of gynecologic cancers.
AB  - Malignant tumors of the female reproductive organs have a high incidence and
      mortality. Despite modern technology, diagnostics and therapeutics have
      substantial limitations. Detection of autofluorescence, photosensitizer mediated
      fluorescence, and near-infrared-spectra are new approaches to diagnose
      gynecologic malignancies and premalignant lesions. Photodynamic therapy (PDT) is
      currently being evaluated for the treatment of gynecologic cancers and
      precancers. New porphyrin based photosensitizers promise a selective tumor
      targeting and consequently a selective treatment of surgically not removable
      cancers. The present article summarizes the role of photomedicine in diagnostics
      and treatments of malignant disease of the female genital tract. Interactions
      between PDT and the immune system are discussed.

PMID- 12476798
TI  - Cytomegalovirus infection in immunocompetent and immunocompromised individuals--a
      review.
AB  - This review summarizes the state-of-the-art knowledge on diagnosis, pathogenesis,
      immune response to, clinical picture, treatment and prevention of cytomegalovirus
      (CMV) infection in humans. CMVs are ubiquitous betaherpesviruses that infect
      animals as well as humans. Primary infection with human cytomegalovirus (HCMV) is
      followed by persistence of the virus in a latent form. During life, the virus can
      reactivate, resulting in renewed shedding of the virus or development of disease.
      Redundant molecular mechanisms have been identified by which CMVs interfere with
      the host immune control, but finally, the infection is held in check by the
      host's immune response. As a consequence, CMV disease is restricted to the
      immunocompromised or immunologically immature host. HCMV is the leading cause of
      congenital infections, with an incidence of 1-2.4% of live births, with possible
      severe classic "cytomegalovirus inclusion disease" in 10% of them. Congenital CMV
      infection is the leading infectious cause of brain damage and hearing loss in
      children and also a relevant health issue to transplant recipients and human
      immunodeficiency virus (HIV)-infected patients. Significant progress has been
      made in the last few years in detecting CMV, but in the immunocompromised
      patients, establishing the diagnosis of CMV infection can still be problematic.
      The most sensitive molecular amplification methods such as polymerase chain
      reaction (PCR) should be used. The decision how to treat the infection depends
      mainly on the immune status of the host. In immunocompetent patients only
      symptomatic treatment is recommended, while in immunocompromised patients
      antiviral therapy and immunotherapy should be used. The most commonly used
      antivirotics are: ganciclovir, foscarnet, cidofovir, valganciclovir,
      valaciclovir.

PMID- 12476799
TI  - Pay heed.

PMID- 12476800
TI  - Stem the tide.

PMID- 12476801
TI  - Flight control. Interview by Daniel Allen.

PMID- 12476802
TI  - Strength in numbers. Interview by Zoe Morris.

PMID- 12476803
TI  - Why be a nurse?

PMID- 12476804
TI  - Independent thought. How will Agenda for Change affect nurses in the private
      sector?

PMID- 12476805
TI  - Come in from the cold.

PMID- 12476806
TI  - Quality time.

PMID- 12476807
TI  - Improving care for patients with sexually transmitted infections in South Africa.
AB  - AIM: To assess the quality of integrated sexually transmitted infection (STI)
      services in primary health care. METHOD: A two-page questionnaire, in
      collaboration with district health service supervisors, was developed to assess
      the quality of care and health services for STIs in individual clinics. RESULTS:
      The data suggest that the quality-assessment instrument used has the potential to
      promote the improvement of STI care delivery at district and clinic levels.
      CONCLUSION: The quality-assessment instrument proved easy to use, can be adapted
      to local requirements and is appropriate for use in developing countries. The
      authors maintain that using this instrument in various district clinics could
      help supervisors identify the main impediments to the delivery of high quality
      services, and give them a platform from which to set priorities in training,
      infrastructure, equipment and supplies.

PMID- 12476808
TI  - Developing palliative care practice in the community.
AB  - The inadequacy of some areas of palliative care provision was acknowledged in the
      NHS Cancer Plan (DoH 2000). Many patients would prefer to die at home, but only
      one quarter are able to do so because of the lack of community or specialist
      palliative care teams in some parts of the country. The Lancashire and South
      Cumbria Cancer Services Network developed an initiative to meet the educational
      and training needs of practitioners delivering palliative care in the community.

PMID- 12476809
TI  - Practical aspects of stoma management.
AB  - The author provides an overview of common stoma complications and their practical
      management. The nurse's role in caring for these patients is also described.

PMID- 12476810
TI  - Breathing space.

PMID- 12476811
TI  - Demystifying ovulation timing.

PMID- 12476812
TI  - Semen collection and evaluation.
AB  - Conformation showing and a variety of dog sports are increasingly popular.
      Propagation of an excellent dog requires normal fertility. Semen collection and
      evaluation are essential skills for small animal practitioners who work with
      breeders and dog-sport enthusiasts. Semen collection can be performed on most
      dogs in the clinic setting with minimal standard equipment. Preparation of the
      collection room and presence of a teaser bitch increase the success of sample
      collection. Semen evaluation consists of several components. First, gross
      characteristics and sample volume are recorded. Percentage and quality of
      motility are evaluated immediately. The concentration of spermatozoa in the
      sample is determined and multiplied by the total sample volume to determine the
      total number of sperm in the ejaculate. Morphology of > or = 100 spermatozoa is
      evaluated and recorded to determine the percent normal spermatozoa Total normal
      sperm per ejaculate is then calculated. Additional tests are often performed.
      These include cytology of the second and third fractions, culture of the semen,
      and measurement of semen alkaline phosphatase. Knowledge of normal parameters for
      canine semen enables the practitioner to evaluate the results of these tests with
      confidence.

PMID- 12476813
TI  - Evaluation of infertility in the bitch.
AB  - The majority of bitches that are brought to a veterinarian for reproductive
      evaluation are actually healthy. Infertility in the bitch is most commonly due to
      inappropriate breeding management rather than an inability to conceive. Before
      embarking on an exhaustive medical evaluation, it is important to obtain a
      thorough history and physical examination to identify any problems. Completion of
      a routine database assists in detecting significant systemic illness that may
      impact infertility. After consideration of history, physical examination, and
      minimum database, fertility problems are most commonly considered in one of four
      categories: abnormal estrous cycles, normal estrous cycles, failure to breed, or
      failure to carry a litter to term. This classification system aids in
      construction of a differential list and systematic evaluation of all
      differentials. The majority of diagnostic tests required are available to the
      general practitioner. Before any treatment for infertility, adequate health
      management must be ensured. Specific treatment for the most common causes of
      infertility is centered on appropriate breeding management.

PMID- 12476814
TI  - Pregnancy termination in the bitch and queen.
AB  - Mismate or pregnancy termination is one of the most common "reproductive"
      requests from dog and cat owners. Ovariohysterectomy is the best alternative for
      those clients who do not really have a valid reason for keeping a reproductively
      intact animal. If the animal is a potential breeder, drugs are available that can
      prevent or terminate pregnancy. The use of these drugs must be based on the
      safety, efficacy, convenience, compliance in treatment, and cost of the drug.
      Drugs that can be given during estrus to prevent pregnancy include estrogens and
      tamoxifen. However, because most dogs presented for mismate are not truly
      pregnant, a pregnancy examination should be performed before any drug is given to
      terminate pregnancy. If a dog is known to be pregnant, multiple doses of natural
      or synthetic prostaglandins can be used throughout pregnancy, whereas multiple
      doses of prolactin inhibitors (cabergoline, bromocriptine, metergoline) or
      dexamethasone can be used in the second half of pregnancy. Combined protocols of
      prostaglandin and prolactin inhibitors are also effective at terminating
      pregnancy. Progesterone blockers such as mifepristone and aglepristone are
      effective, but very expensive. Other drugs, such as the isoquinolones and
      progesterone synthesis inhibitor epostane are available outside of the United
      States and appear to be very effective at terminating pregnancy. No drug,
      however, meets all the following criteria of a perfect mismate drug: possible to
      give at any stage of estrus or pregnancy, 100% effective, causes no vaginal
      discharge, has no side effects, does not impair future fertility, is readily
      available, and is inexpensive.

PMID- 12476815
TI  - Early spay-neuter: clinical considerations.
AB  - Early spay-neuter is ovariohysterectomy or castration of puppies or kittens 6 to
      14 weeks of age. Pediatric animals may have an enhanced response to relatively
      low doses of anesthetic agents. Animals should be fasted no more than 3 to 4
      hours before surgery to prevent hypoglycemia, and hypothermia should be avoided.
      Heart and respiratory rates must be monitored carefully throughout anesthesia.
      Pediatric gonadectomy surgeries are quick with minimal bleeding. Anesthetic
      recovery is rapid. No significant short-term or long-term effects have been
      reported. Prepuberal gonadectomy is most useful for humane organizations and
      conscientious breeders wishing to preclude reproduction of pet dogs and cats
      while placing animals at a young enough age to optimize socialization and
      training.

PMID- 12476816
TI  - Thyroid issues in reproduction.
AB  - Observations in people and animals demonstrate relationships between thyroid and
      reproductive functions. Thyroid issues of importance to small animal reproduction
      are twofold. First, some thyroid disorders, such as lymphocytic thyroiditis and
      some forms of congenital hypothyroidism, appear to be heritable. Those traits
      might be considered undesirable. If so, to eliminate the trait affected animals
      would not be selected as breeding stock. Second, thyroid disorders may adversely
      affect fertility, pregnancy, or neonatal health. If a causal relationship existed
      between thyroid and reproductive disorders, correction of one would be expected
      to result in resolution of the other. This is often not the case. Although
      animals and people with thyroid disorders may also have reproductive disorders,
      usually disorders other than thyroid disease are the cause of reproductive
      abnormalities. It appears that euthyroidism supports optimal reproductive
      performance, but clinically significant reproductive dysfunction is manifested
      only under certain uncommon conditions of thyroid disease in dogs and cats.

PMID- 12476817
TI  - Reproductive oncology.
AB  - The actual incidence of reproductive tract tumors is difficult to ascertain,
      presumably because a significant percentage of dogs and cats are neutered,
      particularly in the United States. Data from European countries, where elective
      neutering is less common, provides insights. Several studies document the
      relative frequency of reproductive tumors. Larger studies of the more common
      tumors, e.g., testicular tumors, provide a substantial amount of information on
      the clinical presentation and response to treatment of dogs, but overall there is
      less information available on cats. Numerous case reports document the less
      commonly reported tumors and will be included in the following discussion.

PMID- 12476818
TI  - [The habitat and environment-induced imbalance of trace elements in the
      populations in the population of urban and rural areas].
AB  - A comprehensive hygienic assessment was made of natural and anthropogenic risk
      factors and conditions for trace element deficiencies in the populations of urban
      and rural areas. All chemicals identified were evaluated in the environmental
      objects. The mean daily absorption dose for the population was estimated. The
      paper presents a comparative analysis of the concentrations of Cu, Fe, Zn, Pb,
      Mn, Ni, Cr, Co, Cd, Sr in the biological media (hair, blood, bone tissue,
      placenta) in the populations of an industrial town and rural areas and their
      levels in some abnormalities and also compares the spectral composition of trace
      elements in the hair and blood with that obtained by other authors.

PMID- 12476819
TI  - [Comprehensive evaluation of carcinogenic load of development areas in Orenburg].
AB  - The paper identifies a risk for cancer for the population of Orenburg. Different
      environmental objects were found to contain 27 carcinogens. The highest
      proportion of priority carcinogens was recorded in drinking water, the least one
      was in the snow cover. There was a significant direct correlation between the
      pollution of soil and that of the ambient air, as well as water and deposited
      media.

PMID- 12476820
TI  - [Estimating the hazard of toxic exposure of the population living in the area of
      the Orenburg gas-chemical complex to specific pollutants].
AB  - Health anomalies in children are induced by environmental contamination with
      pollutants specific for this region due to the long-term running of the Orenburg
      gas-chemical complex. On assessing the health hazard of exposure to non
      carcinogenic chemicals, the authors used such variable as the hazard coefficient.
      Estimations indicated that the hazard coefficient of non-carcinogenic effects was
      greater than the allowable level with reference to hydrogen sulfide in all areas
      under study, as shown by the data of stationary posts. According to the data of
      route studies, the hazard coefficient exceeded 1 with reference to hydrogen
      sulfide and nitrogen dioxide. Thus, upon exposure to specific air pollutants,
      such hydrogen sulfide and nitrogen dioxide, even at the concentrations below the
      maximum allowable concentration there is an increased hazard of their toxic
      effect on the population.

PMID- 12476821
TI  - [Hygienic assessment of ambient air pollution in rural localities in the area
      exposed to effluents of the Orenburg gas-field complex].
AB  - A complex analysis suggests that there has been an increase in airogenic load on
      the population living in an area exposed to gas waste from the Orenburg gas-field
      complex at the expense of nitrogen dioxide, which may be associated with its
      higher levels in the waste from 1058.3 tons/year in 1996 to 2084.89 tons/year in
      2000 and with the maximum effluent of 2550.79 tons/year in 1999. The study has
      revealed that the rural locality with the greatest aerogenic load is the village
      of Dedurovka.

PMID- 12476822
TI  - [Characterization of the ecological and geochemical state of soils in the
      Orenburg Region].
AB  - The data reflecting the state-of-the-art of studies into soil pollution with
      heavy metals and radionuclides in the context of hygienic evaluation of the
      environment are presented. Soil pollution with heavy metals was shown to be
      characterized by natural heterogeneity, a wide range of elements, such as
      technogenic pollutants, and by the local (mosaic) distribution. The degree of
      pollution was generally not 2-3 times higher than the maximum allowable
      concentrations. Soil pollution with radionuclide elements is associated with
      human activities and confined to the western areas of the region, and also noted
      for patchiness.

PMID- 12476823
TI  - [Hygienic estimation of the levels of chemical substances in the soil of the
      Orengurg region].
AB  - Soil pollution has been comprehensively assessed in the agroindustrial region and
      its sources were defined. The results of ecological and hygienic assessment of
      natural and anthropogenic soil pollution suggest that there are increased
      concentrations of boron, chromium, nickel, and lead and deficient levels of
      iodine throughout the territory. There are higher levels of metal accumulation in
      the soil of the Eastern area. Soil pollution with lead, zinc, copper, tin,
      manganese, chromium, and nickel was higher in the urban area than in rural one,
      that with vanadium was higher in the rural area. The following 4 types of
      correlating associations of metals in the soil were identified: cobalt--nickel-
      chromium; copper--zinc; baron--zirconium; vanadium--manganese--boron.

PMID- 12476825
TI  - [New microbiological approach to analyzing the sanitary and ecological status of
      natural water reservoirs].
AB  - The paper shows that in addition to the qualitative characteristics that are of
      rather informative value for evaluation of the sanitary and ecological conditions
      of environmental objects, there are suitable qualitative characteristics that may
      reveal the changes preceding irreversible changes in the natural environment. As
      such, the factors of persistence which are rather widely prevalent in aquatic
      microorganisms. By taking into account that the persistent properties of
      microorganisms label an ecological affiliation of bacteria, ecological type
      specific differences of hydrobionts in persistent characteristics, they may be
      used as informative criteria for an indicator value in sanitary and ecological
      work. The value of these materials is great in the applied point of view as just
      now they open up vistas for microbiological monitoring and ecological studies of
      natural water reservoirs.

PMID- 12476824
TI  - [Hazard identification and comprehensive evaluation of allergy load on the
      population of an industrial town].
AB  - The paper presents the results of qualitative and quantitative analyses of air
      allergenic chemical pollution of the environment of development lands of
      Orenburg. The pollutants forming an allergic load are identified. Additive
      exposure to chromium and vanadium was found to be a priority parameter. The main
      stationary sources of air pollution with chemical allergens in the city were
      motor-vehicle transport and, to a lesser extent, the open joint-stock company
      Invertor, the production association Strela, the sleeper-impregnating plant, the
      gas-processing plant, the joint-stock company Radiator, the furniture factory,
      and the locomotive-repairing plant. The Industrial District of the city was
      ascertained to be a highest-risk area. The greatest allergenic load has been
      recorded in winter months.

PMID- 12476827
TI  - [Sanitary-toxicological assessment of petroleum slimers undergone biological
      purification].
AB  - Pilot production and production studies using a biological method for treating
      and neutralizing toxic waste polluted with petroleum products at high
      concentrations (up to 30%) were conducted. The results have indicated that the
      use of oil degrading microorganisms is highly promising. Within the first
      vegetative period as high as 80% of petroleum products withdrew from waste and
      over 95% of those migrated into the aqueous medium. Purification decreased the
      content of mobile phases of metals to the values below the maximum allowable
      concentrations. The waste that is highly toxic for protozoa and the test crop
      wheat shall be considered to be nontoxic.

PMID- 12476826
TI  - [Lysozyme of hydrobionts and its role in self-purification of water reservoirs].
AB  - Model experiments were carried out to study the effects of hydrobiont lysozyme on
      self-purifying processes of water reservoirs through its participation in the
      formation of a community of destructive microorganisms. Lysozyme-resistant forms
      have been found to lie at basis of bacterial cenosis of the Urals, among which
      there are lysozyme-active and anti-lysozyme-active ones, their population shows
      an inverse relationship. The exogenous lysozyme that enters the water reservoir
      in the period when there is a change in the dominant forms of hydrobionts affects
      the composition of bacterial cenosis by preserving anti-lysozyme-activity with a
      high activity (6-8 (g/ml), which causes a change in the microbial community of
      water reservoir, thus affecting the processes of its self-purification. The
      bacteria having ALA, which do maintain the capacity of a water reservoir for self
      clearance from organic substance, persist under the action of endogenous lysozyme
      of phyto- and zooplankton among saprophytic microorganisms that are destructive
      agents in the biocenosis.

PMID- 12476828
TI  - [Influence of anthropogenic environmental factors on the occurrence of acute
      ischemic attacks in the population of an industrial town].
AB  - An analysis of the incidence of acute ischemic attacks (AIA) has shown its steady
      rise in the population of Orenburg in 1997-2000, men are 1.8 times more
      frequently ill than women with a relatively stable growth in both examined
      groups. Analyzing morbidity rates in age groups (under and above 50 years) has
      demonstrated a substantial increase in the incidence of AIA in the under 50-year
      group living in the Industrial District. The blood levels of essential trace
      elements in patients with AIA are lower than the normal values in the residents
      of the Industrial and Central Districts.

PMID- 12476829
TI  - [Formation of electromagnetic load under urban conditions].
AB  - Hygienic studies have revealed an increase in electromagnetic load under the
      conditions of development areas of an industrial town. Zoning the areas of the
      town by the number of electromagnetic radiation sources and by the specific power
      per unit of square made it possible to identify the priority dwelling districts.
      The individual and collective doses were calculated by using mobile communication
      facilities. The mean dose of electromagnetic radiation per urban population with
      regard to all significant sources was also estimated.

PMID- 12476830
TI  - [Environmental factors and prevalence of uterine myoma].
AB  - The hygienic assessment of the environment of development lands of an industrial
      town was made by the most priority factors. The working conditions at the
      enterprise that was one of the main sources of air pollution of the town were
      also examined. A significant relationship was found between the level of
      anthropogenic load in different districts and the mortality rates of benign
      uterine tumors. This relationship was confirmed by the establishment of that
      between the air concentrations of a number of metals and the female body's
      biosubstrates.

PMID- 12476831
TI  - [Topical problems of infectious diseases in a high natural and man-made loaded
      area].

PMID- 12476832
TI  - [The mechanism responsible for predisposition to acute respiratory diseases in
      high man-made loaded areas].

PMID- 12476833
TI  - [Residing Staphylococcal virulence as a criterion for the ecological population
      load].
AB  - In 1996-1999, a total of 8400 children living in 6 towns and 22 districts of the
      Orenburg Region were surveyed for resident Staphylococcus carriage. There was a
      relationship between the ambient air pollution, total morbidity due to
      respiratory diseases, and criterion Staphylococcus carriage. It has been found
      that resident Staphylococcus carriage determined by the persistent
      characteristics of strains may be used as universal test of microbiological
      monitoring in the ecological status of the atmosphere.

PMID- 12476834
TI  - [Ecological aspects of myasthenia gravis in the Orenburg region].
AB  - The paper reflects the problem of adverse environmental factors on human health,
      including those on the prevalence of myasthenia and on the blood levels of trace
      elements in the patient. It outlines the environmental status in the Orenburg
      Region, which is most unfavorable in the Eastern and Central areas. Myasthenia
      morbidity trends for its increase are covered in 1967 to 2006. The paper also
      shows the prevalence of myasthenia, with predominance per 100,000 individuals in
      the Eastern and Central areas, which coincides with the highest anthropogenic
      load in these areas. The data of a preliminary analysis of trace elements, such
      as copper, zinc, manganese, nickel, lead, strontium, chromium, cadmium, cobalt,
      iron, in the blood of patients with myasthenia as compared with those in controls
      and by regions reflect a general trend for the blood levels of these trace
      elements to be decreased, as well as their imbalance by the areas of the Orenburg
      Region.

PMID- 12476835
TI  - [The hygienic characterization of atmospheric pollution and indices of the health
      status of females and children under metal processing of naturally alloyed ores].
AB  - The agglocoking blast-furnace processing of naturally alloyed ores gives rise
      higher volumes of dust and gas wastes which on air dispersal yield to higher
      concentrations of air pollution with dust, sulfur-containing substances, as well
      as compounds of carbon monoxide, phenol, and ammonia than that of magnetic iron
      ore, which yields a higher prevalence of comparable forms or reproductive
      disorders in women and higher general morbidity in children.

PMID- 12476836
TI  - [The body's responses to extreme exercise: biochemical aspects].
AB  - Experiments on animals and clinical studies in athletes have shown a negative
      impact of extreme exercises on the physicochemical characteristics of
      biomembranes. The resultant decrease in the activity of different isoforms of the
      multienzymatic system of hepatic cytochrome P450 may underlie, firstly, the
      formation of a vicious circle of increases in the microviscosity of biomembranes
      and membrane-dependent processes and, secondly, the lowered resistance of
      athletes to chemical environmental factors, which should be borne in mind during
      the professional activity of high-class athletes.

PMID- 12476837
TI  - [Impact of working conditions at a gas-processing enterprise on reproductive
      health: results of clinical observation and experimental study].
AB  - Five-year clinical and statistical studies were made to examine the effects of
      hydrogen sulfide-containing natural gas and its condensate on reproductive health
      in 275 female workers at the Orenburg gas-processing enterprise and on
      reproductive function in 80 female albino rats in the experimental setting. A
      combined exposure to the components and processing products of hydrogen sulfide
      containing natural gas and its condensate of the gas-processing enterprise in the
      concentrations not greater than the maximum allowable ones for each substance
      individually was found to adversely affect female reproductive health, as
      manifested by pathological changes in infertility-complicated ovarian and
      menstrual functions, by a high incidence of complications during pregnancy and at
      labor; by anomalies in neonatal physical development and health. Experiments
      confirmed that a combined exposure to the components of hydrogen sulfide
      containing natural gas and its condensate caused morphological disadaptive
      changes in the ovaries, impairments in the fetoplacental barrier, anomalies in
      the postnatal development of the offspring of experimental animals.

PMID- 12476838
TI  - [Hygienic characterization of lactic acid bacteria products prepared by using
      hydrolysates of raw milk and soya bean materials].
AB  - The paper reflects the results of a comparative study of preparations of lactic
      acid bacteria (LAB), which are based on the hydrolysates of raw milk and soya
      bean materials, by using methods to determine the organoleptic and
      physicochemical properties, microbiological characteristics including the titer
      of microbial cells per ml of the preparation and the presence/absence of
      representatives of sanitary significant groups of microorganisms, the persistent
      properties of microorganisms. By summarizing the findings, it can be stated that
      it is possible to use a raw soya-bean hydrolysate-based nutrient medium to
      cultivate technical LAB strains with the compliance of the toxicological and
      microbiological parameters of the prepared preparations with the current sanitary
      standards. The LAB preparations grown on the hydrolysate-soya-bean medium have
      been protected with the patents of Russia. Their biological properties are highly
      competitive with those and, in some cases, superior to hydrolysate-milk medium
      based preparations. This presents in their adhesive potential and in the
      formation of more pronounced antagonistic properties against opportunistic
      microorganisms.

PMID- 12476839
TI  - [Trace element imbalance in children with environmentally induced pathology].
AB  - The study examined the balance of trace elements in children with nontoxic goiter
      and alopecia and attempted to consider these entities in terms of multiple trace
      element deficiencies. All the children examined children with nontoxic goiter and
      alopecia were found to have lower concentrations of essential elements (Cu, Zn,
      Fe) and higher levels of toxic trace elements (Sr, Ni Cr), but more pronounced in
      children with alopecia. In this connection, it is necessary to further establish
      a correlation between chronic exposure to environmental trace elements and the
      levels of trace elements in the biosubstrates (blood, hair) of children living in
      an industrial town.

PMID- 12476840
TI  - [Evaluation of immunity in children from rural localities and the levels of trace
      elements in environmental objects].
AB  - Immunity was evaluated in 890 schoolchildren living in rural localities of the
      Central and Western lands of the Orenburg Region. There was a correlation between
      the immunological parameters of the examinees and the levels of trace elements in
      environmental objects. The children's immunity showed unilateral changes in the
      studied parameters as compared with the regional standards. The closest
      correlation was found between the absolute count of T lymphocytes, stab
      neutrophils, the levels of IgA, IgM in children and the content of I, Sr, Mn, Cr
      in cereals and vegetables, as well as between the levels of IL-2 and alpha-TNF
      and the blood concentrations of Cu, Fe, Cr, Ni, Co in the examined children. The
      immunological changes may result from the imbalance of trace elements in the
      studied environmental objects and biological substrates.

PMID- 12476841
TI  - [Epidemiological aspects of bronchopulmonary morbidity in children in an
      industrial town].

PMID- 12476842
TI  - [Comparative evaluation of functioning of the main systems of the body in urban
      and rural school children of the Orenburg region].
AB  - The paper presents the results of a survey of the physical development and
      functional status of 513 urban and rural schoolchildren. Rural children showed a
      higher tension index that urban ones did. The urban pupils had higher indices of
      mental and physiological functions in the course of learning. The proportion of
      children with harmonic physical development was found to be higher among rural
      schoolchildren.

PMID- 12476843
TI  - [Influence of a combination of environmental factors on elementary school
      children].
AB  - Three-year ecological, hygienic, and physiological studies of the influence of a
      combination of environmental factors on the functional status in 510 junior
      schoolchildren have established that the leading determinants of the formation of
      the habitat of junior schoolchildren from the educational establishments under
      study are the irrational organization of a learning process, poor educational
      conditions, sociohygienic living conditions and lifestyle in the family, the
      level of environmental pollution. Dispersion and factorial analyses have
      established that there is a relationship between the quantitative and qualitative
      characteristics of these factors, as well as between the performance of the
      central nervous and cardiovascular systems and the increase in the incidence of
      diseases in the pupils. The findings may be used to draw up research-and
      practical recommendations on the optimization of training of junior pupils on
      organizing gymnasium-type education and on their health promotion whose
      introduction will increase the reserve capacities of the children and preserve
      their health.

PMID- 12476844
TI  - [Development of renal tumors in rats on intermittently injected
      methylcholanthrene and nitrosodimethylamine].
AB  - Experiments on 892 non-inbred male rats studied the development of renal tumors
      in the animals intermittently administered two substances different in the
      mechanism of carcinogenic action. Renal pre-injection of methylcholantherene (MC)
      in a small dose insufficient to induce renal tumors in the study period, followed
      by dermal applications of this agent was shown to enhance a blastomogenic effect,
      as manifested by both early occurrence of precarcinogenic changes and early
      development of renal tumors at the site of primary injection of MC into the
      kidney. The effect of nitrosodimethylamine (NDMA) intermittently injected in a
      nephrotropic dose was studied in the second series of the experiments. The
      intermittent injection of NDMA in courses during 8 weeks gave rise to renal
      tumors in the early period, caused increases in the number of tumors and in the
      area of renal tumor proliferates. The mechanism of enhanced renal blastomogenesis
      is discussed in terms of the mechanisms responsible for initiation and
      progression.

PMID- 12476845
TI  - [The hepatic xenobiotic biotransformation system in chronic ethanol
      intoxication].
AB  - Animal experiments have indicated that chronic ethanol intoxication suppresses
      the activity of microsomal oxidation of enzymes and limits their induction with
      phenobarbital.

PMID- 12476846
TI  - [Hygienic assessment of trace element levels in drinking water and food products
      within the system of socio-hygienic monitoring system].
AB  - The paper provides a comprehensive hygienic assessment of the levels of the
      essential and toxic trace elements chosen in terms of regional features in
      drinking water and foodstuffs of locally manufactured products. Priority
      pollutants of drinking water and foodstuffs are defined in the eastern, western,
      and central lands of the Orenburg Region. A significant imbalance of essential
      trace elements was revealed. Daily oral intake of priority and toxic trace
      elements were calculated in foodstuffs and drinking water.

PMID- 12476847
TI  - [Space-time water monitoring system at the Iriklinsk hydroelectric power
      station].
AB  - The Microbiosensor B 17677 F test system was applied to make a space-time
      monitoring of the biotoxicity of water used for production and everyday purposes
      at the Iriklinsk hydroelectric power station (IHEPS) and to identify the leading
      causes determining the biotoxicity of tested samples. There were seasonal
      variations in the biotoxicity with the maximum in spring and with minimum in
      winter and spring and a relationship of the spring rise in the biotoxicity to
      water pH changes. There was also an association of the certain values of the
      biotoxicity of industrial water with the concentration of petroleum products that
      are major pollutants at the IHEPS. The datum points that characterize the maximum
      level of technogenic exposure were identified.

PMID- 12476848
TI  - [Methodological aspects of risk simulation of trace element deficiencies].
AB  - Methodological aspects of risk simulation of trace element deficiencies are
      considered. A functional algorithm of epidemiological diagnosis of mass
      noncommunicable diseases is presented. The principles and a general algorithm of
      risk simulation of cause-result relationships in trace element deficiencies are
      given. The methodological aspects developed are a guideline for working out a
      conceptual subsystem model for the topical problem of health, determine the basic
      trends of integration of different services for implementation of the total
      strategy of prevention in the region.

PMID- 12476849
TI  - [Experience of the state sanitary and epidemiological service in developing and
      implementing special programs].

PMID- 12476850
TI  - [Standardization practice for salt iodine additive and estimation of a risk for
      iodine deficiency at the population level].

PMID- 12476851
TI  - [Economic evaluation of aerogenic carcinogenic risk in the population of an
      industrial town].

PMID- 12476852
TI  - Risk management in anaesthesia.

PMID- 12476853
TI  - A hospital based preliminary report on sleep disordered breathing in Pakistani
      population.
AB  - BACKGROUND: Sleep Disordered Breathing is an important medical condition leading
      to significant morbidity and mortality. Western studies have shown its prevalence
      in middle age to be 9% in women and 24% in men. The aim of this study was to have
      a preliminary assessment on the frequency of Sleep Disordered Breathing in
      Pakistani subjects. METHOD: Patients attending a medical clinic were surveyed. A
      sleep questionnaire elicited information about snoring, witnessed apnea,
      nocturnal choking and excessive daytime sleepiness. Data were recorded for age,
      height, collar size and weight. Epworth Sleepiness Scale was used to assess
      excessive daytime sleepiness. Statistical analysis was by chi square test, t-test
      and Fisher's exact test. A p-value less than 0.05 was considered significant.
      RESULTS: A total of 123 subjects (M:F = 2:1) were included in the study. The
      frequency of snoring was found to be 46%. Snoring with apnoea was reported in 7%
      and snoring with apnoea and excessive daytime sleepiness in 3%. Snorers were more
      obese (p < 0.001), older (p < 0.003), with higher body mass index (p < 0.001) and
      larger collar size (p < 0.006) than non-snorers. Hypertension was more common in
      patients with sleep disordered breathing (35%) as compared to those without
      (16%). CONCLUSIONS: This is the first preliminary data on sleep disordered
      breathing from Pakistan that reflects that the prevalence is similar to that seen
      in the West. The risk factors and association with hypertension are also
      comparable.

PMID- 12476854
TI  - Effectiveness of 48 weeks Interferon alfa-2b in combination with ribavirin as
      initial treatment of chronic hepatitis.
AB  - BACKGROUND: Chronic hepatitis C is a common problem worldwide and is becoming an
      increasingly common problem in Pakistan. This study was done to evaluate
      effectiveness and safety of 48 weeks combination treatment with Interferon and
      Ribavirin as initial therapy of chronic hepatitis C patients. METHODS: One
      hundred consecutive patients were prospectively evaluated and treated with
      combination of Interferon Alfa 2-b three million units subcutaneously three
      injection weekly and Ribavirin 800-1200 mg orally daily for 48 weeks and followed
      for another 6 months. End of the treatment, sustained viral response and side
      effects were noted. RESULTS: Of one hundred patients, 98 completed the treatment.
      There were 55 males and 43 females. Ages range from 21-60 years, mostly being 31
      55 years. Over 83% responded at the end of treatment and four relapsed. Out of
      treated, 72.7% males and 88.3% females had sustained viral response with a total
      combined sustained viral response rate of 79.5%. Patients with cirrhosis had 85.7
      sustained viral response. Four percent patients took longer than three months to
      show HCV RNA negativity. Side effects were usual and tolerable and only 2%
      discontinued the treatment. Non-responders were mostly males above age 50.
      CONCLUSION: Forty-eight weeks combination treatment with Interferon alfa 2-b and
      Ribavirin has given 79.5% sustained viral response in our patients and treatment
      was well tolerated.

PMID- 12476855
TI  - Age, pattern and symptoms of menopause among rural women of Lahore.
AB  - BACKGROUND: The occurrence and timing of reproduction-related events such as
      menarche, first birth and menopause play major roles in a woman's life. The age
      at final natural menstrual period is an important risk indicator for subsequent
      morbidity and mortality. However, the age of natural menopause and frequency of
      various menopausal symptoms differ in different societies. The concept of "local
      biologies" has been put forward to account for such inter-societal and
      intrasocietal differences. The present study was undertaken to explore the age at
      menopause and symptom complex associated with menopause. METHODS: The data for
      this cross-sectional study were collected from a geographically defined rural
      population of 28,419 individuals living in 20 villages situated about 30 KM
      outside Lahore. A systematic random sample of 130 women was drawn from those 1337
      women, who had reached natural menopause. In-depth interviews were conducted in
      local dialect. RESULTS: The mean age at menopause was 49 +/- 3.6 years; the
      median being 50 years. The majority of women (22.3%) reached menopause at 50
      years followed by 13.9%, who became menopausal at 49 years. In 66.2% cases, the
      onset of menopause was sudden. Among those, who had a gradual transition, the
      duration of climacteric ranged from 2 to 30 months. The symptoms associated with
      menopause were lethargy (65.4%), forgetfulness (57.7%), urinary symptoms (56.2%),
      agitation (50.8%), depression (38.5%), insomnia (38.5%) hot flushes (36.2%) and
      dysparunea (16.9%). CONCLUSIONS: The median age of menopause in our study is
      lower than that reported for Caucasian, Thai and Malaysian women; similar to
      figures from Africa and South America; but higher than that reported from Iran,
      Egypt, Turkey and UAE. The frequency of various symptoms was comparatively lower
      than observed among Caucasian populations. The data highlights the need for
      studying 'local biologies' and understanding the social and cultural basis of
      these differences.

PMID- 12476856
TI  - Computer skills among medical learners: a survey at King Abdul Aziz University,
      Jeddah.
AB  - BACKGROUND: We conducted a survey at King Abdul Aziz University to assess
      computer and Internet related activities, needs, and attitudes of our medical
      students towards computer assisted medical learning. METHODS: A questionnaire
      containing 16 questions was distributed among medical students. The question form
      was prepared to assess the computer skills among students and their involvement
      in computer and Internet assisted medical and clinical learning activities. Each
      question was followed by a four or five points containing Likert-type multiple
      choice answer. RESULTS: A total of 303 medical member of the university filled
      the forms. Among them majorities were medical students constituting 247 (81.5%),
      10 (3.3%) were interns, 9 (3%) residents and 36 (11.9%) were senior residents.
      55% of the responders were male and 45% were females. The most important points
      with their brief responses are: Computer skills: 6.3% Not aware; 93.7% Aware.
      Purpose of using computer: Personal 62.5%; Professional 15%; Academic 21.9%.
      Software(s) used: MS office 9.4%; MS Office and Internet 31.3%; MS Office,
      Internet and any medical software 37%; No software 21%. Connecting to Internet or
      Email: Not at all 18%; Rarely 18%; Once a week 15%; Every alternate day 25%;
      Daily 12.5%; Multiple times a day 9.4%. Use of Internet for medical learning: Not
      at all 22%; Very rarely 22%; Some times 41%; Regularly 15%. Computers and
      Internet can improve studies and professional skills: No not at all 6%; Yes, to
      some extent 41%; Yes, too much 53%. CONCLUSION: The use of modern computer and
      Internet technology will result in more effective medical education. Expansion of
      computer-assisted learning requires careful strategic planning, resource sharing,
      staff incentives, and active promotion of multidisciplinary working and effective
      quality control.

PMID- 12476857
TI  - Effects of intensity and duration of exercise on total leukocyte count in normal
      subjects.
AB  - BACKGROUND: Leucocytes the mobile units of the protective system of the body, may
      circulate freely in the blood, adhere to the vascular endothelium in sites where
      blood flow is relatively slow and then once again re-enter the circulation in a
      process of continuous exchange. This process of continuous exchange of leucocytes
      is influenced by proper stimulation such as exercise. This study was done to
      observe the effects of intensity and duration of exercise on total leucocyte
      count. METHODS: Two groups of normal healthy male adult subjects were exercised
      on treadmill. Group-I performed exercise by running for a duration of 2-3
      minutes, at 7% grade (4 degree inclination) and at constant speed ranging from
      7.5 to 9 Km/hour while group-II walked on treadmill for a duration of 7-10
      minutes at zero grade and at constant speed ranging from 5 to 6 Km/hour. Blood
      sample was drawn before exercise, immediately after exercise and after 30 minutes
      of rest after the exercise. Total leukocyte count was then done by improved
      Neubauer haemocytometer. RESULTS: The mean of pre-exercise total leucocyte count
      of Group-I subjects (n = 15) was 9750 +/- 384.47/microliter, while immediately
      after exercise the mean total leucocyte count increased to 17,856.66 +/-
      1213.24/microliter and after 30 minutes rest, it came down to 10,396.67 +/-
      648.35/microliter. Whereas, the mean of total leucocyte count of group-II
      subjects (n = 15) was 10,266.66 +/- 307.60/microliter pre-exercise, 16,336.66 +/-
      866.30/microliter immediately post-exercise and 1162.33 +/- 718.85/microliter at
      30 minutes post-exercise. The total leucocyte count increased significantly
      immediately after exercise and it significantly decreased after 30 minutes of
      rest but was still higher than the pre-exercise count in both the groups
      CONCLUSION: It is clearly reflected by this study that the magnitude of exercise
      induced leucocytosis is higher in exercise of more intensity and less duration.

PMID- 12476858
TI  - Acute appendicitis complicating pregnancy; experience with the management of 50
      patients.
AB  - BACKGROUND: The purpose of this study was to highlight the problems related to
      acute appendicitis complicating pregnancy and to lay down the principle of their
      management. MATERIALS AND METHODS: This study was conducted at Department of
      Surgery, East Surgical unit Mayo Hospital Lahore from January 1999 to June 2001.
      It included 50 pregnant patients who presented to emergency department with the
      diagnosis of acute appendicitis. RESULTS: Of these 50 patients, 16 were
      primigravida and 34 were multigravida, with the mean age of 26.5 years. Most of
      these patients were in their second trimester (n = 26), followed by first
      trimester (n = 19) and third trimester (n = 5). Pain right iliac fossa (72%) was
      the commonest symptom, followed by vague generalized abdominal pain (18%) and
      backache (10%). All the patients under went laparotomy; with 86% positive and 14%
      negative results. There was no maternal mortality in our study, however 14%
      foetal mortality was noted. CONCLUSION: Unnecessary delay in diagnosis and
      management should be avoided as it is directly related to maternal and foetal
      morbidity and mortality. The general use of this principle may explain the marked
      improvement in maternal and foetal mortality and morbidity.

PMID- 12476859
TI  - Comparison of photometric cyanmethemoglobin and automated methods for hemoglobin
      estimation.
AB  - BACKGROUND: Hemoglobin estimation is the most frequent laboratory investigation
      requested. Different methods include acid haematin, photometric cyanmethemoglobin
      estimation and automated estimation with the help of counters. Aims and
      objectives of the current study were to compare photometric cyanmethemoglobin
      method with hemoglobin estimation by Medonic automated counter. METHODS: One
      hundred and ten adult cases were included through convenience sampling. Samples
      with hemolysis were excluded from the study. Blood was drawn in CP bottles.
      Sample was thoroughly mixed and hemoglobin estimation was done by Medonic counter
      as well by photometer 4010. Commercial controls were run with each batch.
      RESULTS: By manual methods, results revealed mean 0.85% increase compared to
      automated counter. Commercial control results showed 2.3% and 2.7% coefficient of
      variation by Medonic counter and photometer 4010 respectively. CONCLUSIONS: It
      was concluded that both methods are accurate and precise, with reference range
      2.61% more in manual method. It is recommended that with small samples and with
      parameters like hemoglobin or hemoglobin with erythrocyte sedimentation rate,
      manual method is cost effective and feasible. However with multiple parameters
      like absolute values and with very large batches, like in tertiary laboratory,
      automated method is time effective and feasible, provided the laboratory can bear
      the cost.

PMID- 12476860
TI  - Frequency of glucose 6 phosphate dehydrogenase deficiency and related hemolytic
      anemia in Riyadh, Saudi Arabia.
AB  - BACKGROUND: Glucose 6 Phosphate dehydrogenase deficiency is present in over 400
      million people world wide. It is more common iin tropical and subtropical
      countries and is one of the important causes of hemolytic anemia and neonatal
      jaundice. We studied the frequency of glucose-6-phosphate dehydrogenase
      deficiency and associated complications in Central Region (Riyadh) of Saudi
      Arabia. METHODS: A total of 1740 subjects referred by Ministry of Interior and
      different hospitals in Riyadh were investigated for glucose-6-phosphate
      dehydrogenase deficiency. Glucose 6 phosphate dehydrogenase activity was
      determined by a screening test described by Beutler. RESULTS: Out of these, 106
      (6.09%) subjects were deficient. The subjects were divided into marriage and
      hospital groups. In marriage group deficiency was 4.1% while in hospital group it
      was 13.3%. In 54 glucose-6-phosphate dehydrogenase deficient patients red blood
      cell count and haemoglobin levels were determined to see the degree of anaemia.
      Sixty one percent (61%) had anaemia. In hospital patients 8% patients had severe
      anaemia while in marriage group no patients had severe anaemia. However mild
      anaemia was seen in 25% subjects in marriage group. CONCLUSIONS: In conclusion
      the study indicates that glucose-6-phosphate dehydrogenase deficiency is common
      in the central region of Saudi Arabia and a lot of patients present with
      haemolytic episodes. The haemolytic crisis however is not related to the intake
      of fava beans. The type of variant causing anaemia and suggestions for prevention
      in marriage group are outlined.

PMID- 12476861
TI  - Late presentation of Bochdalek hernia with intestinal symptoms.
AB  - Bochdalek hernia is a rare condition that usually presents in the neonatal age.
      Rarely it presents late and is usually misdiagnosed. We came across a Bochdalek
      hernia, which presented at the age of 15 years and was initially misdiagnosed as
      pulmonary tuberculosis. The case history, diagnosis and management of this
      condition along with literature review are presented here.

PMID- 12476862
TI  - Hypocellular myelodysplastic syndrome presenting as megaloblastic anemia.

PMID- 12476863
TI  - Novelity in GB virus C/hepatitis G virus and its controversy.
AB  - Several novel human RNA viruses were identified in 1995-96 and were partially
      characterized that apparently can cause acute and chronic hepatitis both in
      monkeys and humans. These new viruses are related to the flavivirus hepatitis C.
      It is known to be distinct from other human hepatitis viruses (A, B, C, D, E).
      Three viruses, identified by investigators at Abbott Labs, have been termed GB-A,
      GB-B and GB-C. GB-A and GB-B are likely tamarin viruses whereas GB-C infects
      humans only. All these three viruses are the isolates of the same virus termed
      HGV, which is positive stranded RNA virus. The genomic sequences of these viruses
      have been determined by different researchers, which were found to be 1600
      nucleotide long. Another group at Genelabs Technologies has identified and
      determined the complete genomic sequence of a virus they termed hepatitis G virus
      (HGV). Based on genomic sequence comparisons HGV is probably the same as GB-C. It
      is highly controversial virus regarding pathogenecity, mode of transmission and
      site of replication.

PMID- 12476864
TI  - Formulation and in vivo evaluation of niosome-encapsulated daunorubicin
      hydrochloride.
AB  - The central aim of this present study was to modify the reverse evaporation
      process, such that an enhanced entrapment, with increased storage stability and
      prolonged release, could be achieved, and to translate these advantages to
      increased therapeutic efficacy of daunorubicin hydrochloride on Dalton's ascitic
      lymphoma. Niosomes prepared exhibited entrapment efficiency 20% higher than
      theoretically possible by the reverse evaporation process. The niosomes were
      found to be very stable at a storage temperature of 4 degrees C for a duration of
      three months. Even the drug leakage was restricted to just 10%. The in vivo
      studies suggested a prolonged release of 20 hr. Niosomal daunorubicin
      hydrochloride exhibited an enhanced anti-tumor efficacy when compared to free
      drug. The niosomal formulation was able to destroy the Dalton's ascitic lymphoma
      cells in the peritoneum within the third day of treatment, while free drug took
      around six days and the process was incomplete. The hematological studies also
      prove that the niosomal formulation was superior to free drug treatment. An
      enhanced mean survival time was achieved by the niosomal formulation that finally
      substantiates the overall efficacy of the niosomal formulation. This study
      suggests that the multilamellar vesicles obtained by the presently utilized
      reverse evaporation process resulted in vesicles that resisted the immediate
      lysis in the Kupffer cells, whereby a prolonged drug concentration was achieved
      which enhanced the cell lysis. But the major factor responsible for the quicker
      onset of action could be the increased permeability of the niosomes into the cell
      membrane and the cytoplasm of the Dalton's ascitic lymphoma cells.

PMID- 12476865
TI  - Bioavailability assessment of oral coenzyme Q10 formulations in dogs.
AB  - The purpose of this investigation was to compare the bioavailability of three
      coenzyme Q10 (CoQ10) formulations in dogs using an open, randomized, multiple
      dose crossover design. The formulations included a powder-filled capsule (A,
      control) and two soft gelatin formulations (Q-Gel as the water-miscible form of
      CoQ10, B and Q-Nol as the water-miscible form of ubiquinol, the reduced form of
      CoQ10, C). Formulations were evaluated in pairs, allowing a washout period of 14
      days prior to crossing over. Blood samples were collected from each animal prior
      to dosing to determine the endogenous plasma CoQ10 concentrations. Serial blood
      samples were collected for 72 hr and plasma CoQ10 concentrations were determined
      by high-performance liquid chromatography. Plasma concentration-time profiles
      were corrected for endogenous CoQ10 concentrations. Results showed that the
      relative bioavailabilities of formulations B and C were approximately 3.6 and 6.2
      fold higher than that of control formulation A. The AUC(microgram.hr/mL) +/- SD,
      Cmax(microgram/mL) +/- SD, and Tmax(hr) +/- SD for formulations A, B, and C were
      1.695 +/- 0.06, 6.097 +/- 0.08, and 10.510 +/- 0.10; 0.096 +/- 0.035, 0.169 +/-
      0.038, and 0.402 +/- 0.102; and 4.2 +/- 1.48, 4.1 +/- 1.57, and 4.5 +/- 0.58,
      respectively. While no significant differences were observed between Tmax values
      of the three formulations, the AUC and Cmax values for formulations B and C were
      significantly higher than those of the control (p < 0.05). The present
      investigation demonstrates that soft gelatin capsules containing water-miscible
      CoQ10 formulations B (Q-Gel) and C (Q-Nol) are superior to powder-filled
      formulations with regard to their biopharmaceutical characteristics.

PMID- 12476866
TI  - Development of fast-disintegrating pellets in a rotary processor.
AB  - The aim of the present work was to formulate fast-disintegrating pellets by
      direct pelletization in a rotary processor. Formulations containing kaolin or
      bentonite and lactose were agglomerated with or without the addition of
      crospovidone in an instrumented rotary processor. The effects of the excipients
      on the amount of wall adhesion, the size and size distribution, the
      disintegration time, and the shape of the agglomerates, as well as the content of
      agglomerates > 2800 microns, were investigated. Further, pellets containing a
      model drug having a low aqueous solubility were prepared, and the drug
      dissolution profile was compared to that of pellets containing microcrystalline
      cellulose (MCC). Formulations containing kaolin resulted in fast-disintegrating
      pellets. Pellets containing bentonite eroded, but did not disintegrate, and the
      formulations gave rise to large amounts of wall adhesion. The addition of
      crospovidone increased the water content at the end of liquid addition for all
      formulations, and resulted in slightly more spherical agglomerates. When
      comparing formulations containing kaolin and MCC, kaolin gave rise to wider size
      distributions and a higher amount of agglomerates > 2800 microns, but the drug
      dissolution rate was much faster. Complete (100%) drug release was seen after 8
      min with the kaolin formulation, whereas only 40% was released after 2 hr from
      the MCC formulation.

PMID- 12476867
TI  - Spherical crystallization of celecoxib.
AB  - Celecoxib exhibits poor flow properties and compressibility. Spherical
      crystallization of celecoxib was carried out using the solvent change method. An
      acetone:dichloromethane (DCM):water system was used where DCM acted as a bridging
      liquid and acetone and water as good and bad solvent, respectively.
      Hydroxypropylmethylcellulose (HPMC) was used to impart strength and sphericity to
      the agglomerates. The effect of amount of bridging liquid and speed of agitation
      was studied using 3(2) factorial design. Primary properties of the agglomerates
      were evaluated by infrared spectroscopy, powder X-ray diffraction, and
      differential scanning calorimetry. The effect of variables on micromeritic,
      mechanical, compressional, and dissolution behavior was evaluated by response
      surface methodology. Particle size, bulk density, mean yield pressure (MYP), and
      drug release were found to be significantly affected by either of the two
      variables. Interaction of variables significantly affected the MYP.

PMID- 12476868
TI  - In vitro evaluation of the release of albuterol sulfate from polymer gels: effect
      of fatty acids on drug transport across biological membranes.
AB  - In this investigation, the diffusion of the beta 2 agonist albuterol sulfate
      (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver
      skin) from polymer gels was studied, and the effects of several fatty acids on
      drug permeation through skin were evaluated. The results were then used to
      predict whether transdermal delivery would be appropriate for ABS. All in vitro
      release studies were carried out at 37 degrees C using modified Franz diffusion
      cells. In preliminary studies, ABS release through cellulose membranes was
      studied from two polymeric gels, Klucel (hydroxypropylcellulose) and Methocel
      (hydroxypropylmethylcellulose). Three polymer concentrations were used for each
      gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as
      the optimal formulation to study ABS diffusion across hairless mouse skin.
      Experiments were conducted to evaluate the effects of capric acid, lauric acid,
      and myristic acid as penetration enhancers. The results suggested that lauric
      acid preferentially enhanced ABS diffusion compared to the other fatty acids
      studied, and follow-up studies were done to evaluate the release through human
      cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel. These
      experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS
      release rates. The release rate across human cadaver skin declined slowly over 24
      hr, and an average flux over 24 hr of approximately 0.09 mg/hr cm2 was measured.
      Using this value as a steady-state flux, extrapolations predicted that
      transdermal delivery can be used to maintain therapeutic ABS plasma levels (6-14
      ng/mL) for extended periods. The results of this research suggest that ABS is a
      good candidate for transdermal drug delivery.

PMID- 12476869
TI  - Formulation and stability evaluation of ketoprofen sustained-release tablets
      prepared by fluid bed granulation with Carbopol 971P solution.
AB  - The objectives of the present study were: (1) to investigate the possibility of
      using a Carbopol polymeric solution as granulating agent by the fluid bed
      granulating process; (2) to select a suitable method of tabletting for sustaining
      the release of ketoprofen for 12 hr; (3) to perform stability studies according
      to International Committee on Harmonization (ICH) guidelines and photostability
      on ketoprofen SR tablets; (4) to study the influence of the storage conditions on
      release kinetics and melting endotherm of ketoprofen; and (5) to predict the
      shelf-life of the ketoprofen SR tablets. Tabletting ingredients were ketoprofen,
      anhydrous dicalcium phosphate, Carbopol 971P, talc, and magnesium stearate.
      Carbopol 971P solution (0.8% w/v) was used as a granulating solution in the fluid
      bed granulator. For comparative evaluation, tablets were also prepared by direct
      compression and wet granulation, and subjected to dissolution. Tablets prepared
      by fluid bed granulation technique were stored in incubators maintained at 37,
      40, 50, and 60 degrees C, 40 degrees C/75% RH, 30 degrees C/60% RH, and 25
      degrees C/60% RH, and in a light chamber with light intensity of 600 ft candle at
      25 degrees C. Melting endotherms were obtained for the drug as well as the
      tablets during stability studies by differential scanning calorimetry. Tablets
      prepared by fluid bed granulation technique prolonged the release of ketoprofen
      better than tablets obtained by direct compression and wet granulation. Further,
      it complied with the requirements of ICH guidelines for stability testing. Higher
      temperature and humidity (40 +/- 2 degrees C/75% RH, 40 degrees C, 50 degrees C,
      and 60 degrees C) adversely affected the rate and extent of the dissolution.
      Ketoprofen SR tablets stored in amber-colored bottles demonstrated a good
      photostability for 6 months at 600 ft candle. The shelf-life of the formulation
      was predicted as 32 months.

PMID- 12476870
TI  - Lonidamine solid dispersions: in vitro and in vivo evaluation.
AB  - Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the
      spray-drying method. Then, the binary systems were studied and characterized
      using differential scanning calorimetry, hot stage microscopy, and x-ray
      diffractometry. In vitro dissolution studies of the solid dispersed powders were
      performed to verify if any lonidamine dissolution rate or water solubility
      improvement occurred. In vivo tests were carried out on the solid dispersions and
      on the cyclodextrin inclusion complexes to verify if this lonidamine water
      solubility increase was really able to improve the in vivo drug plasma levels.
      Drug water solubility was increased by the solid dispersion formation, and the
      extent of increase depended on the polymer content of the powder. The greater
      increase of solubility corresponded to the highest content of polymer. Both the
      solid dispersions and the cyclodextrin complexes were able to improve the in vivo
      bioavailability of the lonidamine when administered per os. Particularly, the AUC
      of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the
      type of carrier.

PMID- 12476871
TI  - Adhesive backing foil interactions affecting the elasticity, adhesion strength of
      laminates, and how to interpret these properties of branded transdermal patches.
AB  - Standard tensile strength and peel adhesion tests were carried out to investigate
      interactions of pressure-sensitive adhesives (PSAs) with several backing foils
      used for transdermal patches. Seven branded transdermal patches (Alora, Cutanum,
      Estraderm MX 50, Estraderm TTS 50, Fem7 -50 micrograms, Menorest, Oesclim) were
      included in the investigation. Their skin adhesion measured in several clinical
      trials was compared with the results of the laboratory measurements according to
      PSTC-1 (Peel Adhesion for Single Coated Tapes 180 degrees Angle, Pressure
      Sensitive Tape Council, Illinois, 1996), such as Young's modulus at 3% elongation
      and peel adhesion to stainless steel. Data obtained for the PSA-coated backings
      (laminates) show increasing elasticity with increasing PSA thickness.
      Interactions of PSAs with backing foil became evident in significant changes in
      Young's modulus by low PSA thickness, as seen for the silicone adhesive. The
      Young's moduli of the laminates were found to be influenced not only by the
      elasticity of the backing foil but also by the chemical structure of the PSA.
      There was no correlation between the elasticity and peel adhesion of both the
      laminates and the branded patches. Likewise, for the branded patches the peel
      adhesion to stainless steel does not correlate with skin adhesion values obtained
      from clinical trials. The Young's modulus of the branded patches was between 4
      N/mm2 (Oesclim) and 501 N/mm2 (Fem7). For the branded transdermal patches no
      correlation was found between Young's modulus and both the peel force on
      stainless steel and the skin adhesion reported in studies.

PMID- 12476872
TI  - Preparation of the traditional Chinese medicine compound recipe heart-protecting
      musk pH-dependent gradient-release pellets.
AB  - In this study a sustained-release formulation of traditional Chinese medicine
      compound recipe (TCMCR) was developed by selecting heart-protecting musk pills
      (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the
      refined medicinal materials contained in the recipe of HPMP. Two kinds of coated
      pellets were prepared by using pH-dependent methacrylic acid as film-forming
      material, which could dissolve under different pH values in accordance with the
      physiological range of human gastrointestinal tract (GIT). The pellets coated
      with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to
      disintegrate and release drug in the duodenum. The pellets coated with Eudragit
      L100-Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value
      6.8 or above, were designed to disintegrate and release drug in the jejunum to
      ileum. The pellets coated with HPMC, which dissolves in water at any pH value,
      were designed to disintegrate and release drug in the stomach. Finally, the heart
      protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient
      release pattern were prepared by encapsulating the above three kinds of coated
      pellets at a certain ratio in hard gelatin capsule. The results of dissolution of
      borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the
      coating load and the pH value of the dissolution medium had little effect on the
      release rate of borneol from pellets coated with hydroxypropyl methyl cellulose
      (HPMC), but had a significant effect on the release rate of borneol from pellets
      coated with Eudragit L30D-55 or Eudragit L100-Eudragit S100 combinations in the
      ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load
      or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release
      drug at pH value over 5.5. The pellets coated with Eudragit L100-Eudragit S100
      combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little
      drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6
      for 2 hr, and started to release drug at pH value 6.8 or above. The release
      profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC,
      consisting of three kinds of pellets respectively coated at a certain ratio with
      HPMC, Eudragit L30D-55, and Eudragit L100-Eudragit S100 in the ratio of 1:5,
      showed a characteristic of pH-dependent gradient release under the simulated
      gastrointestinal pH conditions and no significant difference between them. The
      results indicated that various components with extremely different
      physicochemical properties in the pH-dependent gradient-release delivery system
      of TCMCR could release synchronously while sustained-releasing. This complies
      with the organic whole concept of compound compatibility of TCMCR.

PMID- 12476873
TI  - Influence of ferrous sulfate on the solubility, partition coefficient, and
      stability of mycophenolic acid and the ester mycophenolate mofetil.
AB  - Studies were performed to (1) evaluate whether the presence of iron affected the
      physicochemical properties of mycophenolate mofetil (MMF) and mycophenolic acid
      (MPA), and (2) determine whether alteration of these properties was indicative of
      formation of an MMF-iron complex. The solubility, stability (chemical
      reactivity), and partitioning properties of MMF and MPA were evaluated over a pH
      range of 2-7 in the presence and absence of ferrous sulfate. In addition, the
      solubility and partitioning properties of MMF were assessed after the MMF drug
      product, CellCept capsules, was combined with an iron tablet (Fero-Gradumet,
      ferrous sulfate, tablets). The results of studies showed that: The solubility of
      MMF in the presence of ferrous sulfate was generally unaffected over a pH range
      of 2-7; a small increase in solubility was observed in pH 5.2 buffer solution.
      The solubility of MPA decreased in pH 5.2 and 7.0 buffer solutions. Both MMF and
      MPA were more stable in the presence of ferrous sulfate at pH 2.0; ferrous
      sulfate had no effect on the stability of MMF and MPA at pH 7.0. Overall, the
      partitioning of MMF and MPA was unaffected by the addition of ferrous sulfate.
      The solubility and partitioning of MMF from CellCept capsules combined with Fero
      Gradumet (ferrous sulfate) tablets showed a twofold increase in aqueous
      solubility of MMF as well as increased concentration of MMF in both the n-octanol
      and aqueous phases, leading to a decrease in the octanol/water partition
      coefficient due to a reduction in pH of the aqueous phase. Based on these
      results, it was concluded that the physicochemical properties of MMF and MPA were
      generally not affected by the presence of ferrous sulfate. Further, the presence
      of ferrous sulfate did not suggest the formation of an MMF-iron complex.

PMID- 12476874
TI  - Effect of fatty acid diesters on permeation of anti-inflammatory drugs through
      rat skin.
AB  - Four fatty acid diesters (diethyl succinate, diethyl adipate, diethyl sebacate,
      and diisopropyl adipate) were used to study their enhancement effect on the
      permeation of four non-steroidal anti-inflammatory drugs (NSAIDs: ketoprofen,
      indomethacin, diclofenac sodium, and ibuprofen) through rat abdominal skin. With
      the diester pretreatment, drug permeation increased and the lag times decreased.
      No relationship was observed between the solubilities of the drugs in the
      diesters and the diester enhancement effects. The enhancement effect decreased
      with an increase of the drug lipophilicity, but increased with an increase of the
      lipophilic index of the diester up to about 3.5, after which the enhancement
      effect decreased or remained constant. Attenuated total reflectance-Fourier
      transform infrared spectroscopy (ATR-FTIR) was employed to investigate the
      biophysical changes in the stratum corneum lipids caused by the diesters. The
      FTIR results showed that treatment of the skin with diesters did not produce a
      blue shift in the asymmetric and symmetric C-H stretching peak positions.
      However, all of the above diesters showed a decrease in peak heights and areas
      for both asymmetric and symmetric C-H stretching absorbances in comparison with
      water treatment. These results suggested that the diesters were more effective
      for enhancing the penetration of hydrophilic drugs than lipophilic drugs, and the
      enhancing effect of lipophilic diesters was more effective than that of
      hydrophilic diesters. The enhancement effects of diesters may be due to their
      causing lipid extraction in the skin.

PMID- 12476875
TI  - Manufacture of slow-release matrix granules by wet granulation with an aqueous
      dispersion of quaternary poly(meth)acrylates in the fluidized bed.
AB  - Slow-release matrix granules were manufactured in the fluidized bed using an
      aqueous dispersion of quaternary poly(meth)acrylates (Eudragit RS 30 D) as binder
      for granulation. A factorial design was carried out to investigate the influence
      of the following parameters, spraying rate, applied polymer amount, and inlet air
      temperature, on various granule properties. Prerequisites for a slow release of
      the model drug theophylline are high spraying rate, high amount of polymer, and
      low inlet air temperature. No considerable decrease of the drug release rate can
      be achieved without a subsequent curing of the dry granules. A clear correlation
      exists between the moisture content of the fluidized bed, indicated by the
      terminal moisture content (TMC), and the mean dissolution time for 80% of the
      drug (MDT80).

PMID- 12476876
TI  - Interaction of iodine with 2-hydroxypropyl-alpha-cyclodextrin and its
      bactericidal activity.
AB  - To obtain an effective iodine solution, the use of 2-hydroxypropyl-alpha
      cyclodextrin (2-HP-alpha-CD) as solubilizer was examined in comparison with alpha
      cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), potassium iodide (KI), and
      polyvinylpyrrolidone (PVP). The stability constants for inclusion of iodine with
      cyclodextrin and KI were ascertained by the solubility method. The apparent
      stability constants increased in the following order: KI < beta-CD < alpha-CD < 2
      HP-alpha-CD. This order was nearly in accordance with that of the stabilization
      ability. The largest volatile depression effect was exhibited by 2HP-alpha-CD.
      The measurement of the minimum inhibitory concentration (MC) using Escherichia
      coli NIH-J-2 and Staphylococcus aureus FDA209P suggested that the bactericidal
      activity of the iodine/2-HP-alpha-CD system was the same as that of the
      iodine/alpha-CD, iodine/beta-CD, and iodine/PVP systems. The present results
      suggest that the combination of 2-HP-alpha-CD and iodine is useful for a stable
      and effective iodine solution.

PMID- 12476878
TI  - Prehospital ACLS--does it work?
AB  - Cardiac disease is the most common cause of death in the United States, and
      sudden cardiac arrest frequently claims the lives of men and women during their
      most productive years. It is believed that much better survival rates can be
      achieved for victims of cardiac arrest through optimizing the "chain of survival"
      as described by the American Heart Association. The relative and incremental
      benefit of full prehospital ACLS over basic life support and defibrillation is
      unproven, however. This is an important issue in this era of cost containment.
      Some of the ongoing studies including the OPALS study may clarify the cost
      effectiveness and relative efficacy of rapid defibrillation and full ACLS
      programs for victims of prehospital cardiac arrest [6].

PMID- 12476877
TI  - EMS ... agenda for the future.
AB  - In 1996, the National Highway Traffic Safety Administration and the Health
      Resources and Services Administration, Maternal and Child Health Bureau published
      the EMS Agenda for the Future. To date, thousands of copies have been distributed
      to EMS-knowledgeable people, and those who aspire to be, throughout the United
      States. This article reviews the findings discussed within the EMS Agenda for the
      Future. This discussion also assesses the effects of these findings on EMS
      development.

PMID- 12476879
TI  - Mechanical devices for cardiopulmonary resuscitation: an update.
AB  - Despite the promise and universal use of the Kouwenhoven technique for closed
      chest cardiac massage, this method has been shown repeatedly to suffer from lack
      of clinical efficacy. Although the Kouwenhoven technique can clearly save lives,
      the inherent inefficiency of this approach and the challenges related to teaching
      and retaining the skills needed to perform the technique correctly have limited
      its overall effectiveness. This has prompted the development of newer lifesaving
      CPR techniques and devices. Some of the advances, such as the vest approach,
      active compression-decompression, and the impedance threshold valve, offer a
      benefit when compared with the Kouwenhoven technique. It is clear, however, that
      challenges related to implementation of these newer approaches will determine
      their ultimate utility. It is not sufficient to have a better technique or device
      available. Challenges to implementation of the newer approaches include
      overcoming the inertia of a universal mindset on the already-familiar Kouwenhoven
      technique and creating a cost-effective justification for change. Each year,
      approximately 10 million people in the United States are trained in the
      Kouwenhoven technique. Americans spend nearly $500,000,000 annually on this form
      of CPR training and retraining. Given the less than 5% survival rate for the
      300,000 patients who experience out-of-hospital cardiac arrest each year in the
      United States, the prudence of this societal investment when compared with other
      ways health care dollars are spent should be questioned. It is hoped that this
      mismatch between costs and benefits will be recognized and will lead to the
      adoption of more effective means to resuscitate patients.

PMID- 12476880
TI  - New concepts in transthoracic defibrillation.
AB  - The transition of biphasic waveforms from ICDs to external defibrillators
      constitutes a significant technological advances for transthoracic
      defibrillation. Impedance compensation has enabled the delivery of defibrillating
      current adapted to each patient and each shock in the same patient. Optimally
      designed biphasic waveforms have been shown clinically to have greater efficacy
      in the termination of VF when compared with monophasic waveforms, and because
      peak current delivery is less, these waveforms are likely to be less injurious to
      myocardial function. Advances in the understanding of the mechanisms of
      fibrillation and defibrillation have identified the electrophysiologic events
      that initiate and sustain VF and the effects of defibrillation shocks on those
      events. Definition of the role of VEP and postshock excitation has clarified the
      mechanisms by which shocks can either fail or succeed. The ability of the second
      phase of optimal biphasic waveform shocks to exploit recruited sodium channels in
      negatively polarized areas and thus induce rapid propagation of postshock
      excitation assures uniform depolarization and prevention of re-entry. This
      appears to be the major mechanism of greater efficacy of biphasic waveforms. It
      seems certain that continuing investigation of virtual electrodes will enhance
      our understanding of defibrillation and optimal waveforms. At the same time, much
      more needs to be known regarding translation of these experimental observations
      to mechanisms of defibrillation in human hearts with long-standing underlying
      structural heart disease, which often arises of multiple factors. This represents
      a major challenge in defibrillation research.

PMID- 12476881
TI  - Public access defibrillation.
AB  - Very early defibrillation, within the first few minutes of VF cardiac arrest,
      results in significantly improved survival rates [1,10-12,34]. Most EMS systems
      cannot consistently provide defibrillation within the first few minutes following
      cardiac arrest. Defibrillation within the first few minutes following collapse is
      potentially achievable through the use of AEDs and PAD [9-14,62]. The delivery of
      defibrillation with AEDs has been made more efficient through the use of
      impedance-compensated defibrillation, larger pad sizes, and biphasic waveforms
      [34]. The technology is simple and easy to use. Preliminary cost-effectiveness
      analysis indicates that PAD and first-responder defibrillation are economically
      as attractive as other interventions in cardiac arrest [44]. Effective PAD
      requires significant investment in time, energy, informed planning, and rigorous
      quality improvement; however, the benefits are enormous. Reported VF survival
      rates can approach 50% or higher [11,12,62]. PAD provides the potential
      opportunity to transform cardiac arrest into a survivable event for most victims
      by making the community the ultimate coronary care unit.

PMID- 12476882
TI  - Prehospital 12-lead ECG diagnostic programs.
AB  - Early reperfusion significantly reduces mortality and morbidity in patients with
      acute myocardial infarction [2-6]. Prehospital 12-lead ECG programs significantly
      decrease time to definitive reperfusion therapy [8-13]. The feasibility and
      safety of prehospital 12-lead ECG programs are well [figure: see text]
      established [8,11,13,14]. Additional potential benefits include increased
      diagnostic accuracy in the prehospital setting [14], providing a comparison ECG
      to the one obtained in-hospital [15], differentiating arrhythmias [16-18], and
      sensitive and specific computerized ECG interpretation [31,32]. Prehospital 12
      lead ECG diagnostic programs also provide the necessary clinical information to
      implement system changes or interventions such as prehospital thrombolytic
      therapy, direct CCU admission, or triage to tertiary cardiac care centers
      [22,30,34,35]. The information acquired should be used optimally to effect
      significant improvements in patient care through a well planned and coordinated
      program.

PMID- 12476883
TI  - Advances in airway management.
AB  - Emergency ventilation is an essential component of basic life support.
      Respiratory emergencies occur far more frequently than cardiac arrest and, if not
      treated promptly and effectively, may lead to cardiac arrest. Many respiratory
      emergencies require assisted ventilation to prevent the occurrence of hypoxemia,
      hypercarbia, and cardiac decompensation. Emergency assisted ventilation is often
      difficult to perform and is associated with several adverse complications, such
      as gastric inflation, regurgitation, and pulmonary aspiration. The American Heart
      Association sponsored conferences in 1999 and 2000 to review and revise
      guidelines for cardiopulmonary resuscitation. This article reviews the science
      behind guideline changes related to pulmonary resuscitation and discusses recent
      advances in emergency airway management, focusing on noninvasive techniques for
      ventilation (mouth-to-mouth ventilation, bag-mask ventilation) and alternative
      airway devices (laryngeal mask airway, the Combitube).

PMID- 12476884
TI  - Emergency medical dispatch.
AB  - EMD will always remain somewhat of an imprecise science by nature. 911 is, after
      all, the access point for lifesaving assistance, and citizens must have absolute
      freedom to this service. The consequence of having the freedom to request help
      from any location at any time is that some individuals will use it for the wrong
      reasons. Present-day dispatchers must serve ever-broadening communities with
      multiple languages, cultural diversity, and unique health needs. Along with other
      essential personnel that make up the fabric of the public safety net, emergency
      medical dispatchers have now become essential to the provision of time-critical
      skills and compassion for perceived medical emergency.

PMID- 12476885
TI  - Damage control: past, present, and future of prehospital stroke management.
AB  - Early identification of stroke patients by emergency medical services is a
      valuable part of optimal care. Accurate identification of the stroke victim by
      EMS has been shown to expedite treatment. Care is enhanced when the EMS
      professional ascertains when the patient was last at baseline state, performs an
      expeditious assessment and transport, checks the patient's blood glucose level,
      and avoids lowering the blood pressure. The death and disability toll of acute
      stroke can be lowered. There is a long way to go, however. EMS professionals can
      help make progress on that journey.

PMID- 12476886
TI  - Essential ethics for EMS: cardinal virtues and core principles.
AB  - Dutiful attention to virtue, teamwork, beneficence, justice, and respect for
      patient autonomy provides a coherent approach to addressing many ethical dilemmas
      in the out-of-hospital setting. Most of the great risks of EMS--abandonment,
      competence, and safe-driving skills--lie at the ethike or character of those who
      ply the prehospital art. Proactively fostering the personal and professional
      virtue of team members may be a kind of moral vaccination against the ethical
      pitfalls inherent in emergency medical service provision. Future training,
      education, disaster preparedness drills, and related exercises must include
      opportunities for character and team building before optimal performance and
      accountability can be assured. In the steady, almost glacial, maturation of the
      specialty of EMS medicine, truly the character of those who serve in the "line of
      fire" of evaluation, management, and transport in the out-of-hospital arena must
      be girded with more than the armor and shields of technology. Since September 11,
      2001, it has become increasingly clear that EMS workers must strengthen their
      ability to bear the "slings and arrows of outrageous fortune," armed with swords
      of discipline, virtue, and character to provide the breadth of care that only a
      well orchestrated team can deliver. Ultimately, humans perform best when they
      share themselves unselfconsciously, surrendering to an enterprise and cause far
      greater than themselves. Our citizens, patients, and heroic colleagues deserve no
      less.

PMID- 12476887
TI  - Operational issues in EMS.
AB  - Improving outcomes for patients presenting to the EMS system relies on strong
      links at every level of the EMS system. Targeted deployment strategies that serve
      to limit the number of paramedics in each system foster a cadre of experienced
      paramedics that make a difference for seriously ill patients who present in the
      out-of-hospital setting. Dedicated physician directors who act as mentors at
      every level of the EMS system are essential elements of the successful EMS
      system.

PMID- 12476888
TI  - Tactical emergency medical support.
AB  - As increases in criminal activity collide with more aggressive law enforcement
      postures, there is more contact between police officers and violent felons.
      Civilian law enforcement special operations teams routinely engage suspects in
      these violent, dynamic, and complex interdiction activities. Along with these
      activities comes the substantial and foreseeable risk of death or grievous harm
      to law officers, bystanders, hostages, or perpetrators. Further, law enforcement
      agencies who attempt to apprehend dangerous, heavily armed criminals with a
      special operations team that lacks the expertise to treat the medical
      consequences that may arise from such a confrontation may be negligent of
      deliberate indifference. Meanwhile, evidence exists within the military, civilian
      law enforcement, and medical literature that on-scene TEMS serves to improve
      mission success and team safety and health, while decreasing morbidity and
      mortality in the event of an injury or illness suffered during operations.
      National professional organizations within law enforcement and emergency medicine
      have identified and support the fundamental need for mission safety and the
      development of a standard model to train and incorporate TEMS into law
      enforcement special operations. The overall objective of TEMS is to minimize the
      potential for injury and illness and to promote optimal medical care from the
      scene of operations to a definitive care facility. The design, staffing, and
      implementation of a TEMS program that maximally uses the community resources
      integrates previously disparate law enforcement, EMS, and emergency
      medical/trauma center functions to form a new continuum of care [55].

PMID- 12476889
TI  - Prehospital care of the patient with major trauma.
AB  - Recent research efforts have demonstrated that many longstanding practices for
      the prehospital resuscitation of trauma patients may be inappropriate under
      certain circumstances. For example, traditional practices, such as application of
      anti-shock garments and i.v. fluid administration to raise blood pressure, may
      even be detrimental in certain patients with uncontrolled bleeding, particularly
      those with penetrating injuries. ETI, although potentially capable of transiently
      prolonging a patient's ability to tolerate circulatory arrest, may also be
      harmful if overzealous PPV further compromises cardiac output, particularly in
      those patients with severe hemodynamic instability. In addition, if these
      procedures delay patient transport, any benefit that they may offer could be
      outweighed by the delay in definitive care. Although traditionally taught to
      "hyperventilate" the patient with severe head injury, current recommendations are
      to avoid this tactic unless there is evidence of herniation. Even time-honored
      traditions, such as universal spinal precautions and CPR during circulatory
      arrest, are being scrutinized [2,134]. Further prospective randomized clinical
      trials are needed to better define the role of many overlapping therapies in
      prehospital trauma care. Such research must specifically address and stratify the
      different mechanisms of injury, anatomic areas involved, and the physiologic
      staging of the injury. Furthermore, the efficacy of a single intervention may be
      masked by a confounding variable [5]. For example, a trial of an effective new
      HBOC in moribund patients that indicates no advantage in the study results may
      have been confounded by overzealous PPV, which may have led to suboptimal
      outcomes. It is hoped that, in the future, EMS physicians will be able to not
      only better discriminate in their management of patients with major trauma but
      also improve outcomes as a result.

PMID- 12476890
TI  - Biologic and chemical weapons of mass destruction.
AB  - Weapons of mass destruction (WMDs) are capable of producing massive casualties
      and are typically grouped into nuclear, biologic, and chemical weapons. In the
      wake of the September 11th disasters, attention to terrorist groups and the
      potential for use of WMDs has increased. Biologic and chemical weapons are
      relatively accessible and inexpensive to develop, and are thought to be the most
      available to foreign states and subnational terrorist groups. This article
      reviews various biologic and chemical weapons, including emergency diagnosis and
      management of selected agents.

PMID- 12476891
TI  - [Association of the renin-angiotensin system gene polymorphism with nephropathy
      in type II diabetes].
AB  - Diabetic nephropathy is the most frequent cause of end-stage renal failure. One
      of the crucial factors in a development of renal and cardiovascular complications
      of diabetes is genetic predisposition. The genes of the renin-angiotensin system
      are important group of candidate genes involved in pathogenesis of chronic renal
      diseases. The purpose of our study was the evaluation of a possible role of
      genetic polymorphisms of some of the RAS system genes in the nephropathy in type
      2 diabetes. The study was performed in 117 patients with diabetic nephropathy,
      compared with 200 healthy subjects as a control group. The following
      polymorphisms: insertion/deletion (I/D) of the angiotensin-converting enzyme gene
      (ACE), M235T of the angiotensinogen gene (AGT) and A1166C of the angiotensin II
      type 1 receptor gene (AT1R) were evaluated by polymerase chain reaction (PCR). No
      statistically significant differences between groups were found in the allele
      frequency and genotype distribution for ACE and AGT polymorphisms. The results
      for the AT1R gene polymorphism revealed significant differences in allele and
      genotype frequencies. The homozygous CC genotype was more frequent in patients
      with diabetic nephropathy than in control group. Both genotypes with the C allele
      (AC + CC) were found in 56% of patients compared to 38% in control group. These
      results suggest increased susceptibility to diabetic nephropathy in individuals
      carrying the CC genotype. Therefore, the A1166C polymorphism of the AT1R gene
      could be a potential genetic marker for increased susceptibility to renal
      complications in type 2 diabetes.

PMID- 12476892
TI  - [Fused TU complexes as a new electrocardiographic marker of poor prognosis after
      myocardial infraction].
AB  - To date, the clinical significance of fused T and U waves, termed as TU
      complexes, has not been evaluated. The aim of the study was to present the
      clinical characteristics of the patients with TU complexes and to assess the
      value of this ECG abnormality in risk stratification after myocardial infarction.
      In the group of 330 postinfarction patients (mean age 61 +/- 10 years, 279 men
      and 51 women), 50 (15%) had TU complexes in one or more leads of a standard ECG.
      In patients with TU complexes, the decreased left ventricular ejection fraction,
      frequent (> or = 10/hour) ventricular premature beats and non-sustained
      ventricular tachycardia detected on 24-hours ECG monitoring, increased QT
      dispersion, ST-segment depression and ST-segment elevation on a routine ECG were
      more common than in patients without TU complexes. During a follow-up period of
      43 +/- 17 months, 88 patients died from all causes. At univariate Cox analysis
      the presence of TU complexes (hazard ratio 3.30; 95% confidence interval 2.09
      5.21) and left ventricular ejection fraction < 40% (hazard ratio 3.82; 95%
      confidence interval 2.51-5.82) were the best predictors of mortality among the 9
      evaluated clinical and electrocardiographic variables. The multivariate, stepwise
      Cox analysis selected ejection fraction < 40% (hazard ratio 3.09; 95% confidence
      interval 2.00-4.80), TU complexes (hazard ratio 2.28; 95% confidence interval
      1.42-3.69), RR interval < 800 ms (hazard ratio 1.62; 95% confidence interval 1.06
      2.47), and age of patients > 65 years (hazard ratio 1.58; 95% confidence interval
      1.03-2.42) as an independent predictors of all cause mortality. CONCLUSION: The
      presence of TU complexes on a routine ECG is associated with impaired left
      ventricular function, increased predisposition to ventricular arrhythmias and
      higher risk of mortality. TU complexes may be considered as a new
      electrocardiographic marker of poor prognosis in patients after myocardial
      infarction.

PMID- 12476893
TI  - [The influence of corticosteroids on IL-6/IL-6R system in patients with Graves'
      ophthalmopathy].
AB  - IL-6 and its soluble receptor (IL-6R) appeared as reliable markers of
      inflammation activity in autoimmune diseases. The aim of the study was an
      estimation of serum IL-6 and sIL-R in patients with Graves' disease with
      ophthalmopathy during treatment with corticosteroids to assess their potential as
      a guideline of immunosuppressive therapy. We detected serum HIL-6 and IL-6R in
      three groups of subjects: 18 patients with clinical symptoms of ophthalmopathy
      (Clinical Activity Score > or = 3, anamnesis of GO > or = 1 yr), 16 patients with
      Graves' disease without ophthalmopathy (Gd) and 14 healthy volunteers.
      Corticosteroid therapy consisted of intravenous infusions of methylprednisolone
      (MP) and subsequent treatment with oral prednisone (P). The serum samples were
      collected 24 hours before MP, 24 hours after MP, 14 days of treatment with
      prednisone and after the end of the corticosteroid therapy. The levels of soluble
      IL-6 and IL-6R in the serum were determined by the ELISA method (Quantikine kit,
      R&D Systems, Minneapolis). The statistical significance was estimated by the Mann
      Whitney U-test. IL-6 concentration was significantly increased in patients with
      GO in comparison to the controls (12.4 +/- 3.7 vs 11.8 +/- 3.2; p < 0.05). After
      MP treatment in corticosteroid-responsive patients (improvement in CAS < or = 1)
      serum concentration of sIL-6R decreased significantly in comparison to
      pretreatment values (32.8 +/- 4.2 vs 28.6 +/- 4.9; p < 0.05). We found a positive
      correlation between IL-6 concentration and degree of proptosis. CONCLUSIONS: 1.
      IL-6/IL-6R system plays an important role in the pathogenesis of GO. 2. IL-6R is
      a potent prognostic factor for efficacy of the immunotherapy but further
      investigations are needed.

PMID- 12476894
TI  - [Urine TGF-beta1 concentration in patients with type II diabetes mellitus-
      prognostic values].
AB  - Type 2 diabetes mellitus is a social and civilization-related disease that leads
      to various micro- and macroangiopathic complications, including diabetic
      nephropathy. At present, the most sensitive and non-invasive indicator of the
      progression of diabetic nephropathy is microalbuminuria. Morphological features
      such as accumulation of extracellular matrix proteins, thickening of glomerules'
      basement membranes are prior to microalbuminuria. The aim of our clinical study
      was to establish whether urine and serum TGF beta 1 levels may be significant in
      prognosing and evaluating a risk for developing diabetic nephropathy. The trial
      was carried out in 68 patients with type 2 diabetes mellitus and a group of 10
      healthy subjects served as control. Urine and serum TGF beta 1 concentrations
      were evaluated, as well as basic laboratory parameters. After one-year
      observation serum creatinine level and microalbuminuria value were investigated
      in 60 patients with type 2 diabetes mellitus. In patients with type 2 diabetes
      mellitus both urine and serum TGF beta 1 concentration were elevated. After one
      year-observation of patients with type 2 diabetes mellitus it was established
      that the increase of serum creatinine concentration and that of microalbuminuria
      value were higher in those patients, whose initial TGF beta 1 levels exceeded
      normal values. A positive correlation between urine TGF beta 1 level and the
      progression of renal failure measured by the increase of serum creatinine level
      was observed. In conclusion, our findings indicate that urine TGF beta 1 level
      may be a good prognostic factor of the development of diabetic nephropathy in the
      course of diabetes mellitus.

PMID- 12476896
TI  - [The relation between plasma leptin concentration and body fat mass in patients
      with rheumatoid arthritis].
AB  - The prospective, cross-sectional study was undertaken to evaluate the relation
      between the fat mass and serum leptin level in patients with rheumatoid arthritis
      (RA). Low body mass and anorexia are commonly found in patients with RA.
      Inflammatory cytokines may significantly influence the secretion of anorectic
      hormone--leptin--that was confirmed in both experimental and clinical studies.
      Fifty-two non-diabetic and non-obese patients (38 females, 14 males) were
      studied. Mean age was 56 +/- 11 years and mean body mass index (BMI) 24.6 +/- 4.1
      kg/m2. The disease activity score (DAS) was 3.9 +/- 1.4; range 1.4-7.4, and
      disease duration 8.1 +/- 6.7 years. Serum leptin was measured by ELISA and body
      composition by double X-ray densitometry. Mean serum leptin concentration was 2.8
      +/- 1.4 ng/ml in patients with RA was lower than in the control group (4.2 +/-
      2.0). In a simple regression analysis leptin did not correlate with BMI (R
      Spearman = 0.01), C-reactive protein (R = 0.08), total fat mass (R = 0.08), trunk
      fat (R = 0.05), limbs fat (R = 0.09) and DAS (R = -0.17). This relation was also
      not influenced by gender or type of immunosuppressive therapy. In a multiple
      regression model none of the independent variables explained the significant
      portion of variance of serum leptin. It is concluded that the physiologic
      relation of serum leptin to body fat stores is not present in patients with RA.

PMID- 12476895
TI  - [The effect of therapy with small doses of mega-3 polyunsaturated fatty acid on
      renal reserve and metabolic disturbances in patients with primary IGA
      glomerulopathy].
AB  - Renal reserve is believed to be diagnostic dynamic method for accessing both
      early renal failure and renal vascular reactivity. The aim of our study was to
      follow renal reserve during 12 month therapy with omega-3 polyunsaturated fatty
      acids. Omega-3 was given orally of a: 540 mg of eicosapentaenic acid and 810 mg
      of docosaheksenic acid daily. Before and after 12 month of therapy renal reserve
      (expressed as % change of basal creatinine clearance) was estimated during i.v.
      dopamine infusion in dose 2 ug/min/b.w. Twelve month therapy was associated with
      increase of renal reserve (respectively 14.86 +/- 16.35 vs 30.25 +/- 14.27%), HDL
      cholesterol (respectively 47.55 +/- 11.49 vs 58.05 +/- 7.89 mg/dl) and decrease
      24 hrs proteinuria (respectively 3.31 +/- 2.01 vs 1.31 +/- 1.37 g/24 h), total
      cholesterol TCH (respectively 251.15 +/- 50.91 vs 214.15 +/- 24.09 mg/dl), LDL
      cholesterol (respectively 170.0 +/- 47.22 vs 124.15 +/- 17.93 mg/dl), serum uric
      acid (respectively 7.53 +/- 1.01 vs 5.59 +/- 0.88 mg/dl), fasting insulinemia
      (respectively 11.27 +/- 5.28 vs 9.20 +/- 4.80 U/ml) for p < 0.05. The
      statistically significant correlation coefficient were found only between
      following parameters: % renal reserve vs insulin (r = -0.55, p < 0.05), delta 24
      h proteinuria vs delta TCH (r = 0.69, p < 0.05), delta 24 h proteinuria vs delta
      LDL (r = 0.51, p < 0.05). Our study suggest that omega-3 therapy improves renal
      reserve and its effect is to some extend related to improvement of some metabolic
      disturbances. Also this therapy ameliorate proteinuria which is linked with lipid
      lowering effect of omega-3.

PMID- 12476897
TI  - [Lung cancer in COPD--a clinical analysis].
AB  - Recently, increased lung cancer morbidity among patients with chronic obstructive
      pulmonary disease (COPD) has been observed. There have been efforts to determine
      the risk factors for lung cancer in these patients. In our study we analyzed
      smoking history, pulmonary function tests, arterial blood gases and selected
      laboratory investigations in a group of 46 patients with COPD and primary lung
      cancer (group I) and compared them to results obtained from 46 randomly selected
      patients with COPD without lung cancer (group II). The mean number of pack years
      was higher in group I (55.5 vs 40.0, p < 0.05) and so was the number of patients
      with severe COPD (55.8% vs 42.1%). We found no differences in ESR, blood count
      and arterial blood gases, the level of fibrinogen was significantly higher in
      group I. In 63.4% of the patients lung cancer at stage III and IV was diagnosed.
      In 15.2% of the patients pathological diagnosis was not established due to severe
      general condition and low FEV1. We conclude that coexistence of COPD may be a
      serious obstacle in the diagnosis and treatment of primary lung cancer. Patients
      with COPD require evaluation for coexistence of lung cancer.

PMID- 12476898
TI  - [Acute myocardial infarction during pregnancy complicated with pulmonary oedema].
AB  - Acute myocardial infarction, a rare peripartum event, is accompanied by
      significant maternal and fetal mortality. We report a 41-year-old woman who
      developed an acute myocardial infarction during the third trimester of pregnancy.
      The case of infarction was complicated with pulmonary oedema on the 3 day after
      delivery. Coronary angiography was performed 7 weeks post partum and no coronary
      lesions were detected. Therapeutic options in such condition are discussed and
      review of relevant literature is presented.

PMID- 12476899
TI  - [The influence of histamine and second generation of antihistamine drugs on
      cardiovascular system].

PMID- 12476900
TI  - [The role of cytokines in pathogenesis of ischaemic heart disease].

PMID- 12476901
TI  - [TNF-alpha in neoplasms treatment--clinical application].

PMID- 12476902
TI  - [Changes and progression in the nephrotic syndrome (minimal change disease)].

PMID- 12476903
TI  - [Assessment of perioperative cardiac risk in patients undergoing vascular
      surgery].

PMID- 12476904
TI  - Trends in school violence.
AB  - School violence has been a new research area since the 1980s, when Scandinavian
      and British researchers first focused on the subject. This violence has sometimes
      even resulted in murder. Since the late 1980s the World Health Organization (WHO)
      has conducted cross-national studies every fourth year on Health Behavior in
      School Aged Children (HBSC). Today 37 countries participate under the guidance of
      the WHO-European Office. The HBSC school-based survey is conducted with a
      nationally representative sample of 11, 13 and 15 year old school children in
      each country using a standard self-administrated questionnaire. The subject of
      bullying at school has been part of the questionnaire. Results from these surveys
      and studies in the United States and Israel are presented and it is hoped that
      the recent public debate and initiatives by the various government agencies will
      result in reduced school violence in the future.

PMID- 12476906
TI  - Bibliography. Current world literature. Breast.

PMID- 12476908
TI  - Kim, J.H. and DePaoli-Roach, A.A. Epinephrine control of glycogen metabolism in
      glycogen-associated protein phosphatase PP1G/R(GL) knockout mice. J. Biochem.
      Mol. Biol., (2002), 35, 283-90.

PMID- 12476907
TI  - Bibliography. Current world literature. Therapeutic modalities.

PMID- 12476909
TI  - Progressive display of very high resolution images using wavelets.
AB  - Digital or digitized biomedical images often have very high resolutions', which
      make them difficult or impossible to display on computer screens. Therefore, it
      is desirable to develop a multiresolution display method with which users can
      freely browse the contents of those high resolution images. In this paper, we
      present an improved wavelet-based progressive image display algorithm by
      stressing on the encoding and decoding process. The encoder, which dynamically
      determines levels of transform and partition of coefficients, is based on a
      modified Haar wavelet transform. The decoder retrieves the necessary data and
      reconstructs the requested region at a scale specified by the user. A prototype
      system, which enables virtually any size of images to be displayed progressively,
      has been implemented based on this algorithm. The system has low computational
      complexity for both encoding and decoding process.

PMID- 12476910
TI  - Images in neuroscience. Mitochondrial Encephalopathy with Lactic Acidosis and
      Stroke like episodes (MELAS).

PMID- 12476911
TI  - Conjoined twins and Catholic moral analysis: extraordinary means and casuistical
      consistency.
AB  - eThis article draws upon the Roman Catholic distinction between "ordinary" and
      "extraordinary" means of medical treatment to analyze the case of "Jodie" and
      "Mary," the Maltese conjoined twins whose surgical separation was ordered by the
      English courts over the objection of their Roman Catholic parents and Cormac
      Murphy-O'Connor, the Roman Catholic Cardinal Archbishop of Westminister. It
      attempts to shed light on the use of that distinction by surrogate decision
      makers with respect to incompetent patients. In addition, it critically analyzes
      various components of the distinction by comparing the reasoning used by Catholic
      moralists in this case with the reasoning used in other cases that raise similar
      issues, including women facing crisis pregnancies who prefer abortion to adoption
      and the Indiana "Baby Doe" case.

PMID- 12476912
TI  - From the Centers for Disease Control and Prevention. HIV testing among pregnant
      women--United States and Canada, 1998-2001.

PMID- 12476913
TI  - From the Centers for Disease Control and Prevention. Protecting building
      environments from airborne chemical, biologic, or radiologic attacks.

PMID- 12476914
TI  - From the Centers for Disease Control and Prevention. Use of anthrax vaccine in
      response to terrorism: supplemental recommendations of the Advisory Committee on
      Immunization Practices.

PMID- 12476915
TI  - From Lydia Pinkham to Bob Dole: what the changing face of direct-to-consumer drug
      advertising reveals about the professionalism of medicine.
AB  - From its founding in 1847, the AMA divided drugs into "ethical" and "unethical"
      preparations. Those that were ethical had a known composition and were advertised
      only to the profession. Other, patent medicines (technically proprietary drugs,
      whose trademarks were protected by copyright), were sold directly to the public.
      In spite of the AMA's efforts to ban the advertising and sale of those nostrums,
      proprietary drugs flourished during the nineteenth century. Starting in 1900,
      however, three major societal trends combined to bolster the AMA's campaign, and
      by 1920 almost all advertising was directed to physicians, who would then
      prescribe medications to their patients. This ban on advertising pharmaceuticals
      directly to the public remained virtually unchanged until approximately 1980.
      Since then, it has slowly eroded and, as recently as 1997, the FDA created
      guidelines for pharmaceutical companies to advertise on television. What does
      this change say about the profession of medicine, the role of the physician in
      society, and the doctor-patient relationship? Using a comparative historical
      approach, this paper examines these issues.

PMID- 12476916
TI  - In the high court of South Africa, case no. 4138/98: the global politics of
      access to low-cost AIDS drugs in poor countries.
AB  - In 1998, 39 pharmaceutical manufacturers sued the government of South Africa to
      prevent the implementation of a law designed to facilitate access to AIDS drugs
      at low cost. The companies accused South Africa, the country with the largest
      population of individuals living with HIV/AIDS in the world, of circumventing
      patent protections guaranteed by the intellectual property rules that were
      included in the latest round of world trade agreements. The pharmaceutical
      companies dropped their lawsuit in the spring of 2001 after an avalanche of
      negative publicity. Yet, despite the government's victory, AIDS drugs remain very
      expensive in South Africa, and the government still refuses to provide
      antiretroviral therapy to adults. These events have shone a spotlight, not only
      on the possibilities for coordinated political activism in the era of instant
      global communications, but also on the tangled social, economic, and political
      dimensions of AIDS treatment in poor countries.

PMID- 12476917
TI  - The ethics of human stem cell research.
AB  - The medical and clinical promise of stem cell research is widely heralded, but
      moral judgments about it collide. This article takes general stock of such
      judgments and offers one specific resolution. It canvasses a spectrum of value
      judgments on sources, complicity, adult stem cells, and public and private
      contexts. It then examines how debates about abortion and stem cell research
      converge and diverge. Finally, it proposes to extend the principle of "nothing is
      lost" to current debates. This extension links historical discussions of the
      ethics of direct killing with unprecedented possibilities that in vitro
      fertilization procedures yield. A definite normative region to inhabit is
      located, within a larger range of rival value judgments. The creation of embryos
      for research purposes only should be resisted, yet research on "excess' embryos
      is permissible by virtue of an appeal to the "nothing is lost" principle.

PMID- 12476918
TI  - Expanding human research oversight.

PMID- 12476919
TI  - [Is fixed sleep position with "babysleep" safe and useful for infants?].

PMID- 12476920
TI  - Sonographic appearance of scrotal wall metastases from lung adenocarcinoma.

PMID- 12476921
TI  - Happy campers. Interview by Lynne Wallis.

PMID- 12476922
TI  - Systemic vascular resistance during brief withdrawal of angiotensin converting
      enzyme inhibition in heart failure.
AB  - We tested the hypothesis that moderate increases in endogenous angiotensin II
      (Ang II) concentrations, induced by withdrawal of angiotensin converting enzyme
      inhibition (ACE-I) in patients with compensated heart failure (HF) on chronic
      medical therapy, do not increase or impair control of systemic vascular
      resistance (SVR). SVR was determined in supine and seated positions in 12 HF
      patients [NYHA class II-III; ejection fraction=0.29 +/- 0.03 (mean +/- SE)] and 9
      control subjects. HF patients were investigated during high (n=11; withdrawal of
      ACE-I treatment for 24 h) and low (n=9; sustained ACE-I therapy) endogenous
      plasma Ang II concentrations. Withdrawal of ACE-I therapy in HF caused moderately
      increased Ang II concentrations of 30 +/- 5 pg/ml compared with 12 +/- 2 pg/ml in
      controls (p<0.05 vs. HF patients). Despite this, SVR was similar in HF (supine:
      1503 +/- 159; seated: 1957 +/- 262 dyn s/cm5, p<0.05 vs. supine) and controls
      (supine: 1438 +/- 104; seated: 1847 +/- 127 dyn s/cm5, p<0.05 vs. supine). During
      sustained ACE-I therapy in HF, plasma Ang II concentrations were lower (6 +/-
      2pg/ml, p<0.05 vs. withdrawal of ACE-I in HF) with no effect on supine SVR.
      However, the posture-induced increase in SVR in response to the seated position
      was attenuated. In conclusion, brief moderate increases in circulating plasma Ang
      II concentrations in compensated HF do not increase SVR compared to control
      subjects or impair control of SVR in response to a posture change.

PMID- 12476923
TI  - Importance of preanalytical handling of samples for measurement of cardiac
      troponin T in coronary effluent from isolated rat hearts.
AB  - The isolated, buffer-perfused heart is probably the most widely used model in
      experimental heart research, and the coronary effluent is often analysed for
      markers of myocardial injury. Adsorption to surrounding materials may be a
      serious problem of protein measurements in solutions with low protein
      concentrations. The aims of the present study were to investigate the importance
      of the preanalytical phase when measuring cardiac troponin T (cTnT) in a buffer
      perfusate and to investigate whether addition of albumin to the effluent might
      increase recovery of cTnT and improve the assay. Coronary effluent was collected
      in tubes of different materials and in tubes with 40 g/L bovine albumin, and then
      frozen. cTnT was analysed at different time points after withdrawal from the
      freezer. cTnT was 2.3-119 times higher in effluent with albumin. In effluent
      without albumin, cTnT concentration declined to 2% of the initial concentration
      after two episodes of freezing and thawing. The cTnT loss could not be prevented
      by using polystyrene or siliconized glass, but was partially inhibited in
      effluent with albumin. Furthermore, creatine kinase and lactate dehydrogenase
      levels were higher in effluent with albumin. The within-series coefficient of
      variation for cTnT was markedly improved when using effluent with albumin.

PMID- 12476924
TI  - Evaluation of cerebral gas retention and oedema formation in decompressed rats by
      using a simple gravimetric method.
AB  - OBJECTIVE: The objective of the study is twofold: first, to develop a specific
      gravity method for distinguishing between bubbles and oedema following
      decompression, and, second, to evaluate the extent to which the change in
      specific gravity is due to retained gas in cerebral tissue. METHODS: A
      brombenzene/kerosene gradient column was used to measure changes in brain
      specific gravity at 100 and 300 kPa, respectively. This study was performed on 23
      rats. Non-exposed rats constituted the control group A (n=6). The exposed animals
      were divided into two groups according to the number of bubbles they developed
      upon decompression; group B (bubble grade 0-2, n=9) and group C (bubble grade 3
      5, n=8). RESULTS: Cerebral gas retention was determined by increasing the
      pressure on the gradient column from 100 to 300kPa. Median specific gravity of
      the brain at 300kPa bar was significantly higher compared to 100 kPa for the
      decompressed groups B (p= 0.018) and C (p=0.012), thus implying gas retention.
      The cerebral gas volume was significantly higher for rats with a high bubble
      score compared to rats with a low bubble score (p=0.043). However, the major
      contribution to the change in specific gravity was due to oedema formation.
      CONCLUSION: The brombenzene/kerosene gradient column was found to be a sensitive
      method for distinguishing between gas retention and oedema formation in
      decompressed animals. There was a higher gas retention in rats with a high bubble
      score compared to rats with a low bubble score. The major contribution to the
      change in specific gravity in decompressed animals is due to oedema formation.

PMID- 12476925
TI  - Effects of long-term fasting on insulin responses to fatty acids in man.
AB  - OBJECTIVE: To investigate whether the prolonged physiological elevation of
      nonesterified fatty acids (NEFA) seen in man during fasting associates with an
      altered acute insulin response to NEFA. SUBJECTS AND METHODS: Fourteen non
      diabetic subjects, age 18-25 years, BMI 23.2 +/- 0.8 kg/m2 underwent
      hyperglycemic clamps (blood glucose 11 mM) for 120 min, during which either
      saline or Intralipid was administered in the last 60 min. Subjects were tested
      after an overnight as well as after a 58 h fast. RESULTS: After the overnight
      fast, insulin levels increased during Intralipid infusion, at min 120 reaching an
      increment of 33.0 +/- 8.5 microU/ml vs. 9.5 +/- 4.4 microU/ml during saline;
      p<0.05 for difference. Conversely, after the 58 h fast. Intralipid failed to
      promote a successive increase of insulin levels (increment during Intralipid at
      min 120: 0.5 +/- 5.8 microU/ml vs. -4.3 +/- 2.5 microU/ml during saline, NS).
      Insulin sensitivity as assessed by the amount of infused glucose and its ratio to
      insulin was enhanced by Intralipid after an overnight fast, but was decreased
      after a 58 h fast. CONCLUSION: Long-term elevated NEFA during fasting associates
      with diminished beta cell responsiveness to an acute elevation of fatty acids in
      conjunction with negative effects on insulin sensitivity.

PMID- 12476926
TI  - Does short-term smoking cessation reduce plasma total homocysteine
      concentrations?
AB  - Both elevated plasma total homocysteine and cigarette smoking are associated with
      an increased risk of occlusive cardiovascular disease. We examined whether
      smoking cessation for a mean time of 10-11 weeks lowered plasma total
      homocysteine concentrations in men and women with (n=59) and without (n=55)
      established cardiovascular disease. Blood tests were available for 58 quitters
      and 29 subjects who did not stop smoking. Compared with subjects who continued to
      smoke, quitters had statistically significant higher HDL cholesterol
      concentrations, but plasma total homocysteine concentrations did not differ
      between the two groups. Likewise, no differences were found between quitters and
      non-quitters whose baseline homocysteine concentrations were above the 75th
      percentile.

PMID- 12476927
TI  - Correlation between blood glucose concentration and glucose concentration in
      subcutaneous adipose tissue evaluated with microdialysis during intensive care.
AB  - BACKGROUND: Hyper- as well as hypoglycemia may be detrimental for brain energy
      metabolism and even a moderate increase in blood glucose concentration can affect
      outcome adversely. During physiological conditions, glucose concentration
      obtained from microdialysis of subcutaneous adipose tissue adequately reflects
      plasma glucose concentration. This study examines whether this correlation is
      also obtained during intensive care in patients with severe injuries. METHODS:
      The study included 62 patients with severe traumatic brain injuries. All patients
      received one 30 mm microdialysis catheter (CMA 60, CMA Microdialysis) inserted
      into periumbilical subcutaneous adipose tissue. The probe was perfused (0.3
      microl/min) with a Ringer solution from a microinfusion pump and analyzed for
      glucose, lactate, and glycerol. The study included 2.434 simultaneous analyses of
      glucose concentration in arterial blood and subcutaneous adipose tissue. RESULTS:
      The correlation coefficient for glucose concentration in blood and interstitial
      fluid was 0.743 for the whole material. The correlation was relatively poor for 1
      6 h after insertion of the probes. During this period, a continuous increase in
      the subcutaneous level of glucose and decreases in lactate and glycerol were
      noted. CONCLUSIONS: The correlation between blood glucose concentration and
      glucose concentration in subcutaneous adipose tissue was not as good during
      intensive care as in normal humans. The poor correlation during the first 6 h
      probably reflects a stress reaction (and possibly local vasoconstriction).
      Microdialysis of subcutaneous adipose tissue permits frequent bedside analyses of
      the biochemical composition of the extracellular fluid and may be of value during
      routine intensive care provided the methodological limitations are recognized.

PMID- 12476929
TI  - Decreased large artery distensibility in borderline hypertension is related to
      increased in vivo low-density lipoprotein oxidation.
AB  - The present study tested the hypothesis that reduced arterial elasticity seen in
      hypertension is related to increased oxidation of LDL. Fifteen men with
      borderline hypertension (BHT), with blood pressure values classified as high
      normal (systolic blood pressure 130-140 mmHg or diastolic blood pressure 85-89
      mmHg) were included. The control group comprised 22 men with normal blood
      pressure values (<135/80 mmHg) matched for age, body size and LDL-cholesterol
      level. Distensibility of aorta was measured using magnetic resonance imaging, and
      distensibility of the common carotid artery using ultrasound. Baseline LDL diene
      conjugation was used as a marker for ox-LDL. Aortic and carotid distensibilities
      were lower in the BHT men than in controls (1.4 +/- 0.6 vs. 1.9 +/- 0.6%/10 mmHg,
      p<0.05 for aortic distensibility; 2.9 +/- 0.9 vs. 3.6 +/- 0.6%/10 mmHg, p<0.05
      for carotid distensibility). Ox-LDL was significantly higher in the BHT men than
      in controls (44 +/-15 vs. 28 +/- 8 micromol/L, p<0.01). In univariate analysis,
      ox-LDL associated with aortic distensibility (r=-0.43, p<0.05). In multivariate
      analysis, the differences in distensibilities between the groups disappeared when
      the values were adjusted for ox-LDL. These data show decreased arterial
      elasticity and increased LDL oxidation in young men with borderline hypertension,
      and suggest that oxidative modification of LDL particles may play a
      pathophysiological role in the development of reduced arterial distensibility in
      hypertension.

PMID- 12476928
TI  - Characterization of an enzyme-linked immunosorbent assay for soluble CD163.
AB  - We have recently identified a soluble plasma form of CD163 sCD163, the macrophage
      receptor for clearance of haptoglobin-haemoglobin complexes, and we have observed
      highly elevated levels of sCD163 in subgroups of haematological patients. In the
      present study, we describe the optimization and characterization of a sandwich
      ELISA for the determination of the concentration of sCD163 in plasma and serum.
      The optimal concentrations of antibodies were determined systematically and the
      assay was calibrated by CD163 purified from human spleen membranes. The minimum
      detection limit was below 6.25 microg/L. Recovery of CD163 added to plasma
      samples was 106%. The concentration of sCD163 in paired serum and plasma samples
      correlated well (r2=0.99); however, serum levels were 1.1 times higher than the
      plasma levels. The addition of haptoglobin-haemoglobin complexes did not
      influence the assay. A very high stability of sCD163 was measured in whole blood
      and in plasma subjected to different temperatures and after repeated freezing and
      thawing.

PMID- 12476930
TI  - Long chain polyunsaturated fatty acids may account for higher low-density
      lipoprotein oxidation susceptibility in Lithuanian compared to Swedish men.
AB  - OBJECTIVES: Mortality in coronary heart disease among middle-aged men is four
      times higher in Lithuania than in Sweden. Traditional risk factors cannot account
      for this difference. We earlier reported that low-density lipoprotein (LDL) in
      Lithuanian men showed a lower resistance to oxidation, measured as LDL lag time
      during copper oxidation, than that in Swedish men. Serum concentrations of
      several fat-soluble antioxidant vitamins were lower among Lithuanian men. The aim
      of this study was to investigate whether differences in LDL fatty acid
      composition could account for the difference in LDL oxidation susceptibility
      between men in the two countries. METHODS: This cross-sectional study included
      randomly selected healthy 50-year-old men from Vilnius, Lithuania (n=50) and
      Linkoping, Sweden (n=50). Main outcome measures were fatty acids in LDL,
      phospholipid (PL) and cholesterol ester (CE) fractions of LDL and LDL oxidation
      susceptibility. RESULTS: The mean proportions of PL 20:5n3 (eicosapentaenoic
      acid, EPA) were higher in Vilnius men (2.09 +/- 1.05 vs. 1.53 +/- 0.58%, p=
      0.004). LDL lag time was shorter in Vilnius men, mean +/- SD (75.4 +/- 13.6 vs.
      89.5 +/- 13.1 mins, p<0.0001) than in Linkoping men. Mean serum gamma-tocopherol
      was lower in Vilnius men (0.07 +/- 0.05 vs. 0.12 +/- 0.04 microg/mmol, p<0.0001)
      but alpha-tocopherol did not differ. In a multiple regression analysis controlled
      for city, high PL-EPA, low alpha-tocopherol, and high plasma triglycerides
      significantly contributed to a short LDL lag time, r2=0.53. CONCLUSIONS: Fat
      quality, i.e. poly unsaturated fatty acids, especially LDL-EPA, plasma
      triglycerides and antioxidative vitamins may partly account for the increased LDL
      oxidation susceptibility found in Vilnius men compared with Linkoping men.

PMID- 12476931
TI  - Disease activity in rheumatoid arthritis: fibrinogen is superior to the
      erythrocyte sedimentation rate.
AB  - Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are the most
      widely used assays to measure the laboratory aspect of the acute-phase response,
      being of great value in monitoring disease activity in rheumatoid arthritis (RA).
      The ESR is influenced by several factors, and mainly by fibrinogen. Therefore the
      relationships between ESR, fibrinogen and CRP and their correlations with a
      patient questionnaire score on activities of daily living, the Modified Stanford
      Health Assessment Questionnaire (MHAQ) were studied. Fifty-four consecutive
      patients with RA admitted to the hospital were recruited to this cross-sectional
      study. Strong mutual correlations were found between the studied acute-phase
      markers (p<0.000000001). Fibrinogen and CRP rates showed highly significant
      correlations with MHAQ, whereas ESR did not. We suggest that ESR could be
      replaced by fibrinogen in the assessment of RA in order more accurately to assess
      the slower component of the acute-phase response and to have a variable that
      shows better correlation with disability.

PMID- 12476932
TI  - Short-term treatment with prednisolone has no lasting effect on serum leptin.
AB  - It has been suggested that the leptin-stimulating effect of short-term treatment
      with systemic glucocorticoids may last several weeks to months. The aim of the
      present study was to assess serum leptin during and four days after withdrawal of
      short-term treatment with prednisolone. The study comprised 20 healthy subjects
      (12 men and 8 premenopausal women aged 19-45 years: mean 31 years). The design
      was a randomized, double-blind, placebo-controlled, parallel group study with 2
      days' run in, 3 days' treatment and 4 days' run out. No medication was given
      during run in and run out. During the treatment period the subjects took
      prednisolone, 20 mg twice daily, or placebo. Blood was collected on the last day
      of each period. In the prednisolone group comparisons of run in (mean serum
      leptin (+/- SEM) (4.94 (1.31)) with treatment (7.08 (1.39)) and run out (5.20
      (1.84)) microg/L) showed a significant stimulating effect of treatment (p=0.03,
      t=-2.6, 95%, confidence interval -4.0 to -0.25 microg/L), whereas no
      statistically significant variation between run in and run out was detected
      (p=0.47, t=0.8, confidence interval -2.63 to 1.35 microg/L). Inter-group
      comparisons of run in with treatment and run out showed elevated leptin
      concentrations during prednisolone treatment (p=0.03) but no statistically
      significant variations between run in and run out data (p=0.88). In healthy
      adults the stimulating effects on serum leptin of short-term prednisolone seem to
      last only a few days after withdrawal of treatment.

PMID- 12476933
TI  - Circulating DNA in plasma and serum: biology, preanalytical issues and diagnostic
      applications.
AB  - The recent studies in circulating nucleic acids have brought about a new
      dimension to medical diagnostics. In oncology, various tumor-associated molecular
      alterations have been detected in the plasma/serum of cancer patients. These
      findings have important implications for the diagnosis, prognostication and
      monitoring of many types of malignancies. In pregnancy, the discovery of fetal
      DNA in maternal circulation has opened up a new source of fetal genetic material
      for noninvasive analysis for numerous fetal conditions and detection of certain
      pregnancy-associated disorders. The measurement of circulating DNA has also found
      potential application in the post-treatment monitoring of transplant patients and
      the assessment and prognostication of trauma patients. Although much attention
      has focused on circulating DNA, the knowledge of its biology is still at an early
      stage. For example, the origin and mechanisms of release of circulating DNA
      remain to be elucidated. The eventual clinical application of circulating DNA
      technology would also require the thorough elucidation of preanalytical factors
      that may affect its measurement in clinical laboratories.

PMID- 12476934
TI  - Role of steroid hormones and growth factors in breast cancer.
AB  - Breast cancer is the most common cancer in women worldwide and its incidence is
      increasing. Oestrogens and mitogenic growth factors may play an important role in
      the development of breast cancer, whereas inhibitory growth factors may prevent
      the development of breast cancer. Only about 5 to 10% of cases of breast cancer
      are due to inheritance of mutations in the BRCA1 or BRCA2 tumour suppressor
      genes. Mutations in the p53 tumour suppressor gene are commonly found in sporadic
      breast cancers. Retinoic acid and carotenoids may play a protective role in
      breast cancer since they inhibit the growth of the oestrogen receptor-positive
      MCF-7 breast cancer cell line. The presence of oestrogen and progesterone
      receptors predicts the likelihood of benefit from hormonal therapy. Amplification
      of the c-erbB2 oncogene in breast cancers is associated with a poor prognosis. It
      is now apparent that there is a complex, productive cross-talk between oestrogen
      directed and growth factor-directed pathways which are believed to markedly
      reinforce their individual cellular effects on growth and gene responses.

PMID- 12476935
TI  - Gene polymorphism and coronary risk factors in Indian population.
AB  - Asian Indians who have settled overseas and those in urban India have increased
      risk of coronary events. Reasons for this increased risk are thought to be
      genetic but are yet unclear. Advances in molecular cardiology have revealed a
      number of single nucleotide polymorphisms associated with atherosclerosis. In
      this review, gene polymorphisms that have been associated with coronary diseases
      among Indians are discussed. Topics include the genes involved in hyperlipidemia,
      hypertension, and homocysteine. Mutations in the low-density lipoprotein receptor
      (LDLR) gene resulting in familial hypercholesterolemia have strong association
      with premature atherosclerosis. Common polymorphism of the apolipoproteins (apo)
      B-100 and E genes have been associated with variation in lipid and lipoprotein
      levels. Recently identified polymorphisms in the apoC3 (T-455C, C-482T), and
      cholesteryl ester transfer protein (CETP) (B1/B2 allele) genes are associated
      with increased triglycerides and reduced high-density lipoprotein (HDL)-levels, a
      feature now also common among Asian Indians. Angiotensin-converting enzyme
      deletion (DD) polymorphism has been shown to influence beta-blocker therapy in
      heart failure. Mutations in methylenetetrahydrofolate reductase (C667T),
      cystathionine beta-synthase (T833C), and methionine synthase (A2756G) genes cause
      hyperhomocysteinemia, an independent risk factor for atherothrombosis. As the
      genetics of atherosclerosis continues to evolve, these factors along with the
      newer emerging factors may become a part of the routine assessment, aiding
      prediction of future coronary events.

PMID- 12476936
TI  - Clinical utility of free drug monitoring.
AB  - Most drugs are bound to serum proteins to a various degree. Only unbound or free
      drug is pharmacologically active. Usually total drug is measured for therapeutic
      monitoring because there is equilibrium between bound and free drugs, and
      concentration of free drug can be predicted from total drug concentration.
      However, under certain conditions this equilibrium is disturbed and the measured
      free drug concentration can be significantly higher than expected from total drug
      concentrations, especially for strongly protein-bound drugs. In such case a
      patient may experience drug toxicity even if the total drug concentration is
      within the therapeutic range. Conditions like uremia, liver disease and
      hypoalbuminemia can lead to significant increases in free drug concentration.
      Therefore, monitoring free phenytoin and free valproic acid is recommended in
      these patients. Drug-drug interactions can also lead to a disproportionate
      increase in free drug concentration. One strongly protein-bound drug can
      significantly displace another strongly protein-bound drug if both drugs share
      the same binding site. Several over-the-counter pain medications such as
      salicylate, naproxen, and ibuprofen can cause significant displacement of both
      phenytoin and valproic acid from albumin binding site. Interestingly, such
      interactions are absent in uremic patients. Elderly patients may have increased
      free phenytoin or valproic acid due to hypoalbuminemia. Elevated free phenytoin
      concentrations have also been reported in patients with AIDS. Although digoxin is
      25% bound to protein, monitoring free digoxin is useful in patients with elevated
      endogenous digoxin-like immunoreactive substances or in patients overdosed with
      digoxin and being treated with digibind. Monitoring free digoxin can also
      eliminate interference of Chinese medicines Chan Su and Danshen in serum digoxin
      measurement by certain immunoassays. However, free drug monitoring is not a
      routine procedure in clinical laboratories due to technical difficulties and lack
      of established reference ranges for free drugs.

PMID- 12476937
TI  - Telomerase--a potential molecular marker of lung and cervical cancer.
AB  - Telomerase, a ribonucleoprotein enzyme that adds hexameric TTAGGG nucleotide
      repeats onto telomeres is reactivated in most malignancies. Lung cancer is a
      common malignant disease worldwide as well as in India. Most patients present in
      advanced stages. As noninvasive diagnostic techniques are preferred, we assayed
      the telomerase activity in pre-bronchoscopy sputum and compared it with that of
      bronchial washings and bronchoscopic biopsies by telomeric repeat amplification
      protocol (TRAP) in 53 cases of lung cancer. These were corroborated with
      cytopathological/histopathological examinations. Telomerase activity was detected
      in 58.5% of sputum samples, 70% of bronchial washings and 74% of bronchoscopic
      biopsies thereby making it a good noninvasive diagnostic marker of lung cancer.
      Cervical cancer is the 7th most common cancer worldwide, with 100,000 new cases
      being reported annually in India. It is routinely screened by Papanicolaou's
      (Pap) smear. Human papilloma virus (HPV) is one of its etiological agents. We
      have assayed telomerase activity in relation to HPV-16/18 in cervical samples
      from 93 subjects ranging from normal to precancerous to frank cancers in tissue
      biopsies and cervical scrapings. HPV infection was detected by polymerase chain
      reaction (PCR) in 81% of tumor samples, in 6% of control hysterectomy samples and
      in 2% of cervical scrapings of normal healthy controls with HPV-16 being the
      predominant type. Telomerase activity was detected in 96.5% of cervical tumor
      samples, in 68.7% of premalignant cervical scrapings but was not detected in
      control hysterectomy samples, or in cervical scrapings of normal healthy
      controls. There was 71% correlation between telomerase activity and HPV-16/18
      infection.

PMID- 12476938
TI  - Association of polymorphisms in the collagen region of human SP-A1 and SP-A2
      genes with pulmonary tuberculosis in Indian population.
AB  - Surfactant protein A (SP-A) binds to and modulates phagocytosis of Mycobacterium
      tuberculosis by macrophages. We investigated the relationship between
      polymorphisms in the collagen regions of SP-A1 and SP-A2 genes and pulmonary
      tuberculosis. In the present study, seven single nucleotide polymorphisms (SNPs)
      (4 exonic and 3 intronic) have been identified in the collagen regions of SP-A1
      and SP-A2 genes in Indian population. Two intronic polymorphisms, SP-A1C1416T ((p
      = 0.0000, odds ratio (OR) = 20.767,95% CI: 8.315-OR<51.870) and SP-A2C1382G (p =
      0.0054; OR = 3.675, 95% CI: 1.400< OR<9.644), showed significant association with
      pulmonary tuberculosis (number of patients = 10, number of controls = 7). A
      redundant SNPA1660G of SP-A2gene showed significant association with pulmonary
      tuberculosis (number of patients = 17, number of controls = 19, p = 0.0000, OR =
      8.94,95% CI: 3.311<OR<24.126). This polymorphism, when existing along with a non
      redundant polymorphism, SP-A2G1649C (Ala91Pro) resulted in a stronger association
      with pulmonary tuberculosis (number of patients = 17, number of controls = 19, p
      = 0.000, OR = 16.3, 95% CI: 7.8644<OR<33.9244). The results indicated that these
      SNPs in the collagen region of SP-A2 may be one of the contributing factors to
      the genetic predisposition to pulmonary tuberculosis.

PMID- 12476940
TI  - Total iron binding capacity and transferrin concentration in the assessment of
      iron status.
AB  - Transferrin concentration and total iron binding capacity (TIBC) are currently
      used to assess iron status. Although correlation between TIBC and transferrin is
      generally considered as good, conversion factors between the two analytes found
      in literature show large differences. Although the price per test is lower for
      TIBC, there are a number of analytical advantages of serum transferrin. Due to
      binding of iron to other plasma proteins (mainly albumin), TIBC methods generally
      overestimate the iron binding capacity of transferrin. Moreover, no generic
      reference values are available for TIBC. In contrast to TIBC, internationally
      accepted interim reference ranges are available for serum transferrin. The
      introduction of the international CRM 470 protein standard material has lead to a
      significant reduction in interlaboratory variation for transferring measurements.
      In view of these observations, determination of transferrin concentration, rather
      than TIBC, is recommended. However, in non-European populations characterized by
      a marked genetic variation in transferrin (TF BC and TF CD variants), in certain
      cases, immunochemical determination of transferrin may lead to errors. In these
      populations, TIBC measurements may be preferred.

PMID- 12476939
TI  - Effect of hemodialysis on the oxidative stress and antioxidants.
AB  - Oxidative stress plays a role in many disease states. These diseases have an
      increased incidence in uremia, and particularly in hemodialysis (HD) patients.
      This suggests an increased exposure to oxidative stress. An imbalance between
      oxidants and antioxidants has been suggested in uremic patients on HD. However,
      the respective influence of uremia and dialysis procedure has not been evaluated.
      It is postulated that antioxidant capacity in uremic patients is reduced, yet the
      mechanism remains unclear. We have determined the levels of lipid peroxidation
      expressed as thiobarbituric acid-reactive substances. We assessed oxidative
      protein damage by carbonyl content and activities of antioxidant enzymes
      including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase
      (GPx) in predialysis uremic patients and in end-stage renal disease (ESRD)
      patients before and after hemodialysis. Vitamin E and vitamin C levels, reduced
      glutathione and sulfhydryl content were also studied. We found enhanced oxidative
      stress in ESRD patients undergoing HD and in predialysis uremic patients. This
      was mostly due to defective antioxidant enzyme levels. Preventive modalities,
      including use of biocompatible membranes, ultrapure dialysate, exogenous
      supplementation of antioxidant vitamins, extracorporeal removal of reactive
      oxygen species (ROS) and oxidatively modified substances, would appear highly
      desirable to reduce complications in the long-term dialysis patients.

PMID- 12476941
TI  - Increased levels of osteoprotegerin in hemodialysis patients.
AB  - Recently identified soluble circulating osteoprotegerin (OPG), a member of tumor
      necrosis factor receptor family, is the osteoclastogenesis inhibitory factor
      (OCIF). It acts as a "decoy" receptor for receptor activator of NF-kappaB ligand
      (RANKL) and antagonises RANKL/RANK activity. This way OPG exerts the protective
      effect on bone, which is also important in hyperparathyroidism. The studies
      measuring OPG levels in secondary hyperparathyroidism have shown contradictory
      results and inconsistent conclusions. The aim of our work was to evaluate OPG
      levels in hemodialysis patients and their correlation with the intensity of bone
      turnover, bone formation and bone resorption. Serum OPG levels, bone alkaline
      phosphatase activity (bALP) and beta-CrossLaps (CTx) were measured in a control
      group (n = 20, age 30+/-6.7 years) and in two groups of dialysis patients: the
      first group with serum intact parathyroid hormone (iPTH) concentration below 200
      pg/ml (n = 28, age 62.6+/-14.8 years) and the second group with iPTH
      concentration above 200 pg/ml (n = 16, age 63.7+/-14.8 years). Compared to
      controls, serum OPG levels were 6.4-fold higher in dialysis patients. OPG levels
      in patients with high PTH were approximately 1.2-fold higher than in the low-PTH
      group. OPG correlated weakly with bALP (r = 0.277, p = 0.153), as well as with
      CTx (r = 0.018, p = 0.929) in the low-PTH group, and there was an insignificant
      negative correlation in the high-PTH group (r = -0.145, p = 0.593 and r = -0.219,
      p = 0.416, respectively). In conclusion, 6.4-fold increase in OPG might protect
      bone against intensive bone loss in hemodialysis patients, but this increase is
      probably not mediated by the increased bone formation; rather, it seems to be the
      consequence of the imbalance of bone kinetics in renal disease. The precise role
      of OPG in the pathogenesis of renal osteodystrophy remains unknown and
      establishing it requires further studies.

PMID- 12476942
TI  - Levels of testosterone, allopregnanolone and homocysteine in severe
      hypothyroidism.
AB  - Hypothyroidism is very often associated with cardiovascular diseases and
      neurological complications. Recently, homocysteine has been studied as an
      independent risk factor for atherosclerosis which negatively affects vascular
      endothelial cells. Because homocysteine metabolism is related to thyroid and
      steroid hormones, we studied these relationships in severe hypothyroidism and in
      euthyroid state. Homocysteine, testosterone and allopregnanolone concentrations
      were measured in the fasting plasma from 16 women who underwent total
      thyroidectomy, and who were either hypothyroid or euthyroid. Although all women
      used oral contraceptives, they were not protected against hyperhomocysteinemia
      during hypothyroid state. With the normalization of thyroid hormone
      concentrations homocysteine levels decreased to normal levels. There was a
      positive correlation between testosterone and homocysteine in the euthyroid state
      which suggests that not only estrogens but also androgen state should be
      considered in future studies on homocysteine.

PMID- 12476943
TI  - The levels of serum vitamin C, malonyldialdehyde and erythrocyte reduced
      glutathione in chronic obstructive pulmonary disease and in healthy smokers.
AB  - There is an increasing interest in the concept that oxidant/antioxidant imbalance
      plays a role in the pathogenesis of chronic obstructive pulmonary disease (COPD).
      However, most of the studies are concentrated on the local antioxidant/oxidant
      balance. In this study, we investigated the oxidant/antioxidant balance in
      systemic circulation of patients with COPD. Serum malonyldialdehyde (MDA),
      vitamin C and erythrocyte reduced glutathione (GSH) were determined in patients
      during acute exacerbation and during the stable phase of the disease, and
      compared with age- and sex-matched healthy controls. The levels of serum MDA,
      vitamin C and erythrocyte GSH were determined according to Yagi, Beutler and
      Bauer et al., respectively. Serum MDA levels were significantly higher in
      patients compared to controls, and during acute exacerbation compared to the
      stable phase. MDA levels in patients with acute exacerbation and in those in
      stable phase were also higher than in controls. We found significantly decreased
      levels of erythrocyte GSH and serum vitamin C in patients with acute exacerbation
      and stable COPD compared to controls. Although smoking caused an increase in
      oxidative stress in controls, the measured parameters were not affected by
      smoking in the patient group. In conclusion, there is a systemic
      oxidant/antioxidant imbalance in COPD, and this imbalance is probably independent
      of smoking.

PMID- 12476944
TI  - Highly specific, simple and rapid method for the determination of malondialdehyde
      in blood using high-performance liquid chromatography.
AB  - A novel, highly specific, simple and rapid method for the determination of
      malondialdehyde (MDA), the routinely used marker for free radical generation in
      body fluids has been developed and evaluated. Serum samples from 30 healthy
      volunteers in heparin and 1,4-dithiothreitol-containing tubes stored at -80
      degrees C were analyzed. The MDA-thiobarbituric acid complex was separated from
      interfering substances using HPLC. For the separation, reverse phase column MAC
      (4 x 250 mm, Biospher SI 120 PSI C18, particle size 7 microm) was used. The
      mixture of methanol and 8.3 mmol/l phosphate buffer, pH= 7.2, (35:65, v/v) was
      used as mobile phase. The volume of serum samples injected on the column was 50
      microl. The analyte was detected at 532 nm. Retention time of MDA-thiobarbituric
      acid complex was 4.9+/-0.1 min at the flow rate 0.7 ml/min. Excellent linearity
      was achieved. The intra- and interassay coefficient of variation was 7.3% and
      8.8%, respectively. The recovery was 95.6% and the detection limit was 0.1
      micromol/l. The validity of this method was proved by comparison with the
      spectrophotometric determination of MDA-thiobarbituric acid complex by the method
      of Yagi at three different wavelengths (485, 532 and 560 nm) with Allen's
      correction.

PMID- 12476945
TI  - Precision and accuracy of a HPLC method for measurement of fecal porphyrin
      concentrations.
AB  - We studied precision and accuracy of a HPLC method for determination of
      porphyrins in feces. A commercial standard solution appeared to contain less
      coproporphyrin (15%) than stated by the manufacturer. The between-batch
      coefficients of variation were often below 15% and were higher than the within
      batch coefficients. The precision of porphyrin measurements was not influenced by
      the type of porphyria. Recoveries of added coproporphyrin and protoporphyrin were
      90% and 108%; coefficients of variation were 6% and 19%, respectively.

PMID- 12476946
TI  - Continuous age-dependent reference ranges for thyroid hormones in neonates,
      infants, children and adolescents established using the ADVIA Centaur Analyzer.
AB  - In neonates, infants, children and adolescents serum concentrations of the
      thyroid hormones show a clear age dependency. Currently, age-dependent thyroid
      hormone reference ranges for the new ADVIA Centaur immunoanalyzer are not
      available. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), total
      thyroxine (T4), free triiodothyronine (FT3) and total triiodothyronine (T3) were
      determined in the sera of 460 healthy children aged 0 daysto 18 years from an
      inland (n=308) and a seaside city (n=152) using the Bayer ADVIA Centaur analyzer.
      Square root functions defining the upper and lower limit of the continuous age
      dependent reference range and the median line for each thyroid hormone were
      estimated applying a parametric regression technique. Continuous age-dependent
      reference ranges show a better fit to the obtained data than discontinuous
      reference ranges. The median TSH and FT4 concentrations decrease within the first
      year of life and are nearly constant until 18 years of age. The median T4
      decreases within the entire age interval, whereas the median FF3 is constant. The
      median T3 increases within the first year of life and decreases afterwards. The
      calculated continuous reference ranges for T4, T3 and partly FT4 are consistent
      with published reference ranges. However, the reference ranges obtained for FT3
      and partly TSH differed considerably, compared to published reference ranges. No
      significant residence- or sex-specific effects on age-adjusted hormone
      concentrations were found except for a slight residence-specific effect on age
      adjusted FT4, which was probably due to assay imprecision. Due to the lack of
      international standardization, the assay-specific evaluation of reference ranges
      is very important. Continuous age-dependent reference ranges comply better with
      the biological reality and are more reliable than discontinuous reference ranges.

PMID- 12476947
TI  - Diagnostic value of various urine tests in the Jordanian population with urinary
      tract infection.
AB  - We compared the performance of leukocyte esterase and nitrite reductase dipstick
      tests with microscopic examination and uroculture in cases with clinically
      suspected urinary tract infection (UTI). We studied urine specimens from 504
      Jordanian patients which were obtained by the mid-stream clean catch method and
      analyzed for bacteria. All samples were subjected to culture. Results of urine
      dipstick tests and pyuria (white blood cells (WBC)/high power field) were
      compared with urine culture for each sample. Significant bacteriuria was found in
      117 cases (23.2%) with positivity of 59% and 68.5% for the presence of nitrite
      reductase and leukocyte esterase, respectively. Echerichia coli was the most
      common organism isolated. The dipstick leukocyte esterase and nitrite testing had
      a sensitivity of 68.5% and 59% for detecting bacteriuria in UTI cases and
      specificity of 73.5% and 78%, respectively. The positive predictive value of the
      tests was 44% and 60%, and the negative predictive value 88.5% and 86.2%,
      respectively. Microscopic WBC showed 86.5% specificity but low sensitivity. Urine
      dipstick results and pyuria significantly correlated with the results of urine
      culture but demonstrated more false-positive results, which ranged from 13.4
      26.6%. The probability of growing a urinary pathogen correlated with urinary WBC
      counts and allowed prediction of the presence or absence of bacteriuria by
      counting urinary leukocytes. A combination of pyuria and urine dipstick testing
      appears to be a very useful marker for the diagnosis of UTI. Urine culture can be
      omitted if both tests are negative.

PMID- 12476948
TI  - Performance evaluation of the Precision PCx point-of-care blood glucose analyzer
      using discriminant ratio methodology.
AB  - Point-of-care glucose testing needs to be integrated into a laboratory
      information system to provide continuous care. Selecting a particular glucose
      monitoring system is based on both analytical performance and on user's
      preference. We evaluated accuracy, performance and regulatory compliance of the
      Precision PCx glucose analyzer (Abbott), with automatic download into a central
      station, for remote quality control (QC) management and automatic upgrading. We
      used the discriminant ratio (DR) methodology, which determines the DR of a test
      (e.g. the ratio between the underlying SD and the within-subject SD), and
      compares it to that of another test allegedly measuring the same parameter.
      Accuracy was evaluated by Clarke's error grid method. Seven hundred and ninety
      four blood samples were taken from 22 diabetic patients, combined with two
      capillary blood samples: one for analysis by reference method and the second for
      PCx analysis. Linear regression analysis revealed, over a 2.1 to 26.9 mmol/l
      glucose concentration range, a correlation coefficient of 0.963, an intercept of
      0.7 mmol/l and a slope of 0.851. Mean difference between meter-generated results
      and the reference method was -7.1+/-10.8%. Between-run imprecision for PCx using
      Abbott's controls at low and mid-low concentrations was 5.4 and 3.8%,
      respectively. Clarke's error grid did not show any clinical impact related to
      difference between methods. DRs were of similar magnitude using both methods.
      Nursing staff found PCx easy for everyday use. Our data show that PCx results
      agree with those obtained with the reference method, as shown by lack of
      significant difference in DRs, and by excellent correlation.

PMID- 12476949
TI  - Clinical evaluation of a new automated anti-dsDNA fluorescent immunoassay.
AB  - The measurement of anti-double-stranded DNA (anti-dsDNA) antibodies is a useful
      tool for the diagnosis and the follow-up of systemic lupus erythematosus (SLE).
      Anti-dsDNA antibodies are involved in the pathogenesis of lupus nephritis and
      they are, specially the high-avidity antibodies, the most specific antibodies
      associated with SLE nephritis and active SLE. The aim of the present study was to
      assess the clinical utility of an enzyme-linked immunosorbent assay (EUSA) that
      utilizes a circular double-stranded plasmid DNA as a nucleic acid source, adapted
      to an automated fluorescence immunoassay (EliA dsDNA, Pharmacia, Freiburg,
      Germany). Also, we compared this method with other immunoassays used in clinical
      laboratories. We have measured anti-dsDNA antibodies in the serum of 179 patients
      with a positive result for antinuclear antibodies (ANA). Seventy six sera were
      from SLE patients (14 men and 62 women), and the other 103 sera (from 20 men and
      83 women) constituted the control group. This latter group includes nine
      Sjogren's syndrome patients, six patients with rheumatoid arthritis and 88 with
      various other diseases, including connective tissue diseases (n=34),
      hepatopathies (n= 17; 11 primary biliary cirrhosis and 6 autoimmune hepatitis),
      and 37 patients with nonautoimmune diseases (viral hepatitis, renal disease,
      diabetes, exanthema and hypertension). Methods used were "EliA dsDNA" (Pharmacia,
      Germany), "Varelisa dsDNA" (Pharmacia, Germany), Farr (Amersham, UK) and
      Chritidia luciliae immunofluorescence test (Vitro-Immun, Germany). We assessed
      sensitivity, specificity, positive predictive value and negative predictive value
      in the clinical study, and kappa index and scatter plots in the comparative
      study. The results show a low concordance between methods (kappa < 0.6). The
      evaluated EliA method shows a very good specificity for SLE (93.2%) and a good
      sensitivity for active SLE (70.8%).

PMID- 12476950
TI  - Upper reference limits for urinary catecholamines, metanephrines and 3-methoxy-4
      hydroxymandelic acid in hypertensive patients.

PMID- 12476951
TI  - Growth hormone immunoassays: proposal to reduce interlaboratory variability.

PMID- 12476952
TI  - Poetry, images and visions: William Blake.
AB  - This article focuses on the work of William Blake (1757-1827), British artist,
      poet and engraver. Blake is discussed as a thinker opposed to the 'tyranny of
      reason' interpreted as rational philosophies promoted with a religious zeal. The
      visionary, mystical character of some of Blake's works is contrasted with his
      eclectic reading and sharp social criticism. Blake's work is related to the early
      discourse on science. The article is supported by the images of his two works,
      the 'Ancient of Days' and the 'Newton'.

PMID- 12476953
TI  - Role of cidofovir in the treatment of DNA virus infections, other than CMV
      infections, in immunocompromised patients.
AB  - Cidofovir is a nucleotide analog marketed for the treatment of human
      cytomegalovirus infections in immunocompromised patients. An increasing number of
      reports have appeared on the use of cidofovir for the treatment of other severe
      DNA virus infections in immunocompromised patients. The activity of cidofovir
      against herpes simplex viruses resistant to classic (acyclovir and/or foscavir)
      therapy has been widely documented. Cidofovir has also been used for the
      treatment of other herpesvirus infections, such as drug-resistant varicella
      zoster virus, and Epstein-Barr virus-induced proliferative diseases. For
      papillomavirus infections, cidofovir represents a valuable alternative to the
      conventional therapies, which are mostly based on surgery, as in the treatment of
      laryngeal papillomatosis. The role of cidofovir in the treatment of polyomavirus
      infections is more controversial, but here too, cidofovir represents, to date,
      the only available efficacious therapeutic modality. Cidofovir has demonstrated
      activity against all poxviruses and represents a unique therapeutic modality for
      use against these viruses, particularly in the immunosuppressed host, should this
      prove necessary (eg, in a bioterrorism scenario).

PMID- 12476954
TI  - Strategies for the identification of inhibitors of West Nile virus and other
      flaviviruses.
AB  - The recent outbreaks of West Nile virus (WNV) and other emerging and re-emerging
      flaviviruses, have made prevention and treatment of flavivirus infections a
      global public health priority. No inhibitor is currently available for use as an
      antiflavivirus therapy. In this communication, I review (i) stages of flavivirus
      replication representing potential targets for antiviral drug discovery; (ii)
      strategies for identification of flavivirus inhibitors; and (iii) existing
      antiviral inhibitors reported to have anti-WNV or other antiflavivirus
      activities. Flaviviruses share conserved nucleotide elements and amino acid
      sequences, and have similar genome organization and replication strategies. As
      such, it is hoped that broad spectrum flavivirus inhibitors could be identified
      through screening of compound libraries.

PMID- 12476955
TI  - The role of viruses in human cancer development and antiviral approaches for
      intervention.
AB  - Viruses are estimated to be linked to at least 15% of human cancers. Hepatitis B
      and C viruses, human papilloma viruses, Epstein-Barr virus, human herpes virus-8
      and human T-cell leukemia virus have been definitively linked to human cancer. A
      brief overview of the molecular mechanisms of carcinogenesis elucidated for these
      viruses and antiviral approaches which may provide clues to reducing the
      occurrence or progression of the resulting virally derived cancers are described.

PMID- 12476956
TI  - ACH-126443 Achillion/Yale University.
AB  - Achillion, under license from Vion, is developing the nucleoside analog ACH
      126443 (beta-L-Fd4C), a reverse transcriptase (RT) inhibitor, for the potential
      treatment of HIV and hepatitis B virus (HBV) infection. The compound is one of a
      series of antiviral compounds developed by Yale University [213319]. By February
      2002, it had entered phase II trials for chronic HBV infection [435422]; these
      were ongoing in June 2002, by which time, additional phase II clinical studies
      for chronic HBV infection had been planned [452185], [454316].

PMID- 12476957
TI  - Viramidine (Ribapharm).
AB  - Viramidine, an analog of ribavirin is a broad-spectrum antiviral under
      development by Ribapharm (previously the R&D division of ICN Pharmaceuticals) for
      the potential treatment of viral infections [378507]. In September 2000, phase I
      trials began in Europe. In December 2001, the company filed a US IND for the
      clinical development of viramidine as part of a combination therapy with
      interferon-afor the treatment of chronic hepatitis C virus (HCV) infection
      [435007], [441613]; a phase I trial was initiated in the US in late March 2002
      [435598]. In November 2002, Ribapharm reported that it would start phase II
      trials of viramidine in the treatment of chronic HCV by the end of 2002 [469062].

PMID- 12476958
TI  - Targeting tumor necrosis factor-alpha as a potential therapy in inflammatory skin
      diseases.
AB  - Tumor necrosis factor-a (TNFalpha) plays an important role in the initiation and
      persistence of inflammation in a variety of skin disorders. The availability of
      selective TNFalpha blockers has provided new therapeutic opportunities. TNFa
      inhibitors have been employed with success in treating psoriasis in controlled
      trials, although further studies are warranted to better define which subgroup of
      patients can benefit most from this treatment and modalities of combination
      therapy. In addition, an increasing number of case reports indicates that anti
      TNFalpha agents are of value in the treatment of other skin diseases, such as
      pyoderma gangrenosum and Behcet's syndrome, and in the treatment of graft-versus
      host disease.

PMID- 12476959
TI  - Novel therapies for atopic eczema.
AB  - Atopic dermatitis (AD) has been treated with topical glucocorticosteroids for
      decades. With the introduction of the topical immune modulators tacrolimus and
      pimecrolimus, a new treatment era has begun. The knowledge on pathophysiological
      interactions and immunological disturbances during the chronic inflammatory
      process in the skin has been continuously increasing and offers new therapeutical
      approaches. These are discussed in this review based on the current literature,
      my own research findings and recent patents. Development of members of the
      glucocortioid family such as retinoids, vitamin D and peroxisome proliferator
      activated receptor agonists, are discussed. Molecules from members of this family
      have profound differentiating, antiproliferative, but also immunomodulatory
      effects, which make them attractive as anti-eczematous compounds. Furthermore,
      several anti-infective and antipruritic agents, and preparations which enhance
      thedisturbed skin barrier function in AD are presented. Phytopharmacological and
      miscellaneous approaches, including Chinese tea or gamma-linolenic acid, will be
      critically discussed. Finally, recently patented, experimental compounds are
      presented, which interfere with several pathways involved in the immune response
      of AD.

PMID- 12476960
TI  - PVAC (Corixa/Genesis/Medicis).
AB  - Corixa, Genesis and Medicis are developing PVAC, an immunomodulator derived from
      killed Mycobacterium vaccae and licensed from SR Pharma [309860], [312958], for
      the potential treatment of psoriasis [365490]. In February 2001, phase II trials
      were ongoing in the US, the Philippines and Brazil for the treatment of moderate
      to-severe psoriasis [399066], [405985]. In January 2001, an NDA filing was
      expected to take place in 2003 [396733]. In January 2002, Medicis and Corixa
      planned to initiate another phase IIb trial [436398], and by June 2002, two
      studies in patients with mild-to-moderate plaque psoriasis had began in the US
      and New Zealand, with the former designed to investigate the use of PVAC in
      combination with ultraviolet B (UVB) light [453772], [456657], [456836].

PMID- 12476961
TI  - Protein tyrosine phosphatase 1B as a target for the treatment of impaired glucose
      tolerance and type II diabetes.
AB  - Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin
      signal transduction cascade, initiated when insulin binds to the insulin
      receptor. PTP1B-deficient mice are more sensitive to insulin, and have improved
      glycemic control and resistance to diet-induced obesity than wild-type control
      mice. Diabetic mice treated with PTP1B antisense oligonucleotides
      intraperitoneally have lower PTP1B protein levels in liver and fat, reduced
      plasma insulin, blood glucose and hemoglobin A1c (HbA1c) levels. These studies
      validate PTP1B as a promising drug discovery target for the treatment of insulin
      resistance, diabetes and obesity. Herein we review the recent advances in the
      structure-based design of potent and selective small molecule inhibitors of
      PTP1B, and discuss th e challenge of developing compounds with improved cell
      permeability and bioavailability.

PMID- 12476962
TI  - Glucagon receptor antagonists for the treatment of type II diabetes: current
      prospects.
AB  - As the incidence of Type II diabetes (T2DM) will increase to 200 million cases
      worldwide by 2010, the search for new, effective agentsfor its treatment has been
      pushed into overdrive. According to Unger's bihormonal hypothesis, elevated
      levels of circulating glucagon in T2DM patients results in increased rates of
      hepatic glucose synthesis and glycogen metabolism, translating to excessive
      plasma glucose levels. In this context, considerable efforts have been made to
      identify glucagon antagonists for the treatment of T2DM. This review reflects
      research in this area from 1999 to 2002.

PMID- 12476963
TI  - TAK-677 (Dainippon/Takeda).
AB  - TAK-677 is a beta3-adrenergic agonist under development by Dainippon and Takeda
      for the potential treatment of non-insulin dependent diabetes and obesity. In
      March 2001, Takeda initiated a phase II trial in the US for Type II diabetes
      [411811], [416686], [423455]. By December 2001, the compound was also in phase II
      trials for obesity in the US, and Dainippon was conducting phase II studies in
      Japan for diabetes [458750].

PMID- 12476964
TI  - Transdermal testosterone gel (Cellegy).
AB  - Cellegy is developing a drug delivery system designed to facilitate the
      transdermal and topical delivery of testosterone for the potential treatment of
      male hypogonadism (as Tostrex) and decreased sexual energy in post-menopausal
      women (asTostrelle) [218118], [314726], [351823]. Following phase III dinical
      trials of Tostrex for male hypogonadism, initiated in March 2000 [361133], an NDA
      submission for male hypogonadism was filed in June 2002, after a pre-NDA meeting
      with the FDA late in 2001 [453374]. By March 2002, phase II/III clinical studies
      in postmenopausal women were underway in the US [444857].

PMID- 12476965
TI  - Muscarinic agonists as preventative therapy for Alzheimer's disease.
AB  - Overproduction of the peptide amyloid beta (Abeta) is a critical pathogenic event
      in Alzheimer's disease (AD), leading to the formation of amyloid plaques,
      neurofibrillary tangles, synaptic loss and dementia. Decreasing Abeta production
      may therefore slow or halt the progression of AD. Recent animal experiments
      suggest that Abeta overproduction in aging and sporadic AD may be due to age
      related loss of cortical cholinergic innervation. Muscarinic agonists,
      particularly M1-selective agents, have been shown to decrease the production of
      Abeta in vitro and in vivo; these compounds may be uniquely suited to a
      preventative role in AD therapy.

PMID- 12476966
TI  - Role of CRH in the pathogenesis of dementia of Alzheimer's type and other
      dementias.
AB  - This review focuses on the role of corticotrophin-releasing hormone (CRH) in the
      pathogenesis of Alzheimer's disease (AD) and briefly discusses its role in other
      dementias, including Parkinson's disease (PD), progressive supranuclear palsy
      (PSP) and Huntington's disease (HD). During aging the hypothalamic-pituitary
      adrenal (HPA) axis changes, which has repercussions on hormonal levels in the
      brain. The significance of these changes has been examined by many researchers,
      but the relationship between CRH and other neurotransmitters needs to be further
      explored.

PMID- 12476967
TI  - Drug treatment for HIV-1-associated dementia.
AB  - The manifestation of HIV-1-associated minor motor deficits or HIV-1-associated
      dementia indicates viral activity within the CNS. Highly active antiretroviral
      therapy (HAART) has a prophylactic effect, which does not protect all patients,
      because different pathomechanisms are involved. A CNS-specific therapeutic
      efficacy can be demonstrated for nucleoside and non-nucleoside reverse
      transcriptase inhibitors (NRTIs; NNRTIs). To be effective in the CNS, HAART
      should contain either zidovudine or stavudine and NNRTI should be added if there
      is dinical or preclinical evidence of CNS involvement. Protease inhibitors may be
      sufficient to lower high systemic viral burden and thus protect the CNS from HIV
      1 invasion.

PMID- 12476968
TI  - Altropane (Boston Life Science).
AB  - Boston Life Sciences (BLS) is developing Altropane as a potential radio-imaging
      agent to be used with single photon emission tomography (SPECT), for the early
      diagnosis of Parkinson's disease (PD) and attention deficit hyperactivity
      disorder (ADHD) [329661]. Altropane is currently in phase III clinical trials for
      PD and phase II clinical trials for ADHD.

PMID- 12476969
TI  - ABC transporters and inhibitors: new targets, new agents.
AB  - P-glycoprotein (P-gp), a plasma membrane pump associated with multidrug
      resistance (MDR), is a member of the superfamily of ATP-binding cassette (ABC)
      transporters. The discovery that inhibitors of drug efflux can increase drug
      accumulation and reverse drug resistance in the laboratory has led to the
      clinical development of a number of P-gp inhibitors. Initial studies were
      performed with agents already in use in the clinic for other indications, the
      'first generation' studies. Second generation inhibitors were taken into clinical
      trials in leukemia, breast cancer, ovarian cancer and sarcoma, malignancies for
      which there is evidence that P-gp is expressed, and in some cases, associated
      with a poorer therapeutic outcome. One major limitation of these trials, however,
      was the reduction in anticancer drug doses that was required with concurrent
      administration of inhibitor. The reduction in drug dose needed in these
      combination studies, may have confounded the results and contributed to
      disappointing outcomes. Functional assays to verify the role of P-gp inhibition
      in MDR, such as sestamibi imaging are proving helpful in assessing the
      development of improved inhibitors that are providing hope for the future. This
      review focuses on attempts aimed at overcoming resistancemediated by ABC
      transporters and evaluates the prospects for addition of new inhibitors to the
      anticancer armamentarium.

PMID- 12476970
TI  - Enhancement of radiation therapy by vascular targeting agents.
AB  - The tumor vessel support network offers a tantalizing target for cancer therapy,
      given the complete dependence of a solid neoplasia on the vasculature for both
      the delivery of oxygen and other nutrients, as well as the effective removal of
      wasteproducts. Attacking a tumor's supportive blood vessel network offers ameans
      of improving cancer cure rates on the basis of two principles. The first reflects
      evidence indicating that physiological conditions in tumors, arising primarily as
      a consequence of inadequate and non-uniform vascular networks, are significant
      contributors to resistance to non-surgical anticancer treatments. The second
      involves the recognition that the inherent differences between blood vessels in
      tumors and those associated with normal tissues provide a variety of unique
      targets for the design of novel therapeutics, highly selective for neoplastic
      growth. Therapeutic approaches that aim to destroy the tumor endothelium are
      being actively pursued. The application of such vascular targeting strategies as
      adjuvants to conventional therapeutics such as radiotherapy, offers unique
      opportunities to develop even more effective cancer therapies.

PMID- 12476971
TI  - ONT-093 (Ontogen).
AB  - Ontogen is developing ONT-093 (formerly OC-144-093), a P-glycoprotein pump
      inhibitor, for the potential reversal of multidrug resistance in patients
      undergoing cancer chemotherapy. The compound is also being evaluated for its
      potential enhancement of the oral bioavailability of drugs that are P
      glycoprotein substrates requiring either high dosage forms or intravenous
      administration, and for the potential improvement of central nervous system
      penetration of P-glycoprotein substrate drugs.

PMID- 12476972
TI  - Metvix (PhotoCure).
AB  - Metvix is a photosensitive cream containing the methyl ester of 5-aminolevulinic
      acid, which has been developed and launched by PhotoCure in Sweden for the
      treatment of high-risk basal cell carcinoma and actinic keratosis.

PMID- 12476973
TI  - Methodology to predict long-term cancer survival from short-term data using
      Tobacco Cancer Risk and Absolute Cancer Cure models.
AB  - Three parametric statistical models have been fully validated for cancer of the
      larynx for the prediction of long-term 15, 20 and 25 year cancer-specific
      survival fractions when short-term follow-up data was available for just 1-2
      years after the end of treatment of the last patient. In all groups of cases the
      treatment period was only 5 years. Three disease stage groups were studied, T1N0,
      T2N0 and T3N0. The models are the Standard Lognormal (SLN) first proposed by Boag
      (1949 J. R. Stat. Soc. Series B 11 15-53) but only ever fully validated for
      cancer of the cervix, Mould and Boag (1975 Br. J. Cancer 32 529-50), and two new
      models which have been termed Tobacco Cancer Risk (TCR) and Absolute Cancer Cure
      (ACC). In each, the frequency distribution of survival times of defined groups of
      cancer deaths is lognormally distributed: larynx only (SLN), larynx and lung
      (TCR) and all cancers (ACC). All models each have three unknown parameters but it
      was possible to estimate a value for the lognormal parameter S a priori. By
      reduction to two unknown parameters the model stability has been improved. The
      material used to validate the methodology consisted of case histories of 965
      patients, all treated during the period 1944-1968 by Dr Manuel Lederman of the
      Royal Marsden Hospital, London, with follow-up to 1988. This provided a follow-up
      range of 20-44 years and enabled predicted long-term survival fractions to be
      compared with the actual survival fractions, calculated by the Kaplan and Meier
      (1958 J. Am. Stat. Assoc. 53 457-82) method. The TCR and ACC models are better
      than the SLN model and for a maximum short-term follow-up of 6 years, the 20 and
      25 year survival fractions could be predicted. Therefore the numbers of follow-up
      years saved are respectively 14 years and 19 years. Clinical trial results using
      the TCR and ACC models can thus be analysed much earlier than currently possible.
      Absolute cure from cancer was also studied, using not only the prediction models
      which incorporate a parameter for a statistically cured fraction of patients
      C(SLN), C(TCR) and C(ACC), but because of the long follow-up range of 20-44
      years, also by complete life analysis. The survival experience of those who did
      not die of their original cancer of the larynx was compared to the expected
      survival experience of a population with the same age, birth cohort and sex
      structure. To date it has been generally assumed for early stage disease that
      although for some 5-10 years after treatment the survival experience of this
      patient subgroup might be no different from that expected in the matched group,
      thereafter the death rate of this subgroup becomes lower than that of the matched
      group. This implies that surviving cancer patients cured of their disease tend to
      die of other conditions at a higher than normal rate as they become older, and
      therefore cancer is never totally cured. Our conclusion is that at least for
      cancer of the glottic larynx, the answer to the question: 'Can cancer totally be
      cured?' is 'Yes to at least 15-years post-treatment and also probably to 25
      years.'

PMID- 12476974
TI  - A unified model for the speed of sound in cranial bone based on genetic algorithm
      optimization.
AB  - The density and structure of bone is highly heterogeneous, causing wide
      variations in the reported speed of sound for ultrasound propagation. Current
      research on the propagation of high intensity focused ultrasound through an
      intact human skull for non-invasive therapeutic action on brain tissue requires a
      detailed model for the acoustic velocity in cranial bone. Such models have been
      difficult to derive empirically due to the aforementioned heterogeneity of bone
      itself. We propose a single unified model for the speed of sound in cranial bone
      based upon the apparent density of bone by CT scan. This model is based upon the
      coupling of empirical measurement, theoretical acoustic simulation and genetic
      algorithm optimization. The phase distortion caused by the presence of skull in
      an acoustic path is empirically measured. The ability of a theoretical acoustic
      simulation coupled with a particular speed-of-sound model to predict this phase
      distortion is compared against the empirical data, thus providing the fitness
      function needed to perform genetic algorithm optimization. By performing genetic
      algorithm optimization over an initial population of candidate speed-of-sound
      models, an ultimate single unified model for the speed of sound in both the
      cortical and trabecular regions of cranial bone is produced. The final model
      produced by genetic algorithm optimization has a nonlinear dependency of speed of
      sound upon local bone density. This model is shown by statistical significance to
      be a suitable model of the speed of sound in bone. Furthermore, using a skull
      that was not part of the optimization process, this model is also tested against
      a published homogeneous speed-of-sound model and shown to return an improved
      prediction of transcranial ultrasound propagation.

PMID- 12476975
TI  - Tandem shock wave cavitation enhancement for extracorporeal lithotripsy.
AB  - Extracorporeal shock wave lithotripsy (ESWL) has been successful for more than
      twenty years in treating patients with kidney stones. Hundreds of underwater
      shock waves are generated outside the patient's body and focused on the kidney
      stone. Stones fracture mainly due to spalling, cavitation and layer separation.
      Cavitation bubbles are produced in the vicinity of the stone by the tensile phase
      of each shock wave. Bubbles expand, stabilize and finally collapse violently,
      creating stone-damaging secondary shock waves and microjets. Bubble collapse can
      be intensified by sending a second shock wave a few hundred microseconds after
      the first. A novel method of generating two piezoelectrically generated shock
      waves with an adjustable time delay between 50 and 950 micros is described and
      tested. The objective is to enhance cavitation-induced damage to kidney stones
      during ESWL in order to reduce treatment time. In vitro kidney stone model
      fragmentation efficiency and pressure measurements were compared with those for a
      standard ESWL system. Results indicate that fragmentation efficiency was
      significantly enhanced at a shock wave delay of about 400 and 250 micros using
      rectangular and spherical stone phantoms, respectively. The system presented here
      could be installed in clinical devices at relatively low cost, without the need
      for a second shock wave generator.

PMID- 12476976
TI  - CdZnTe detector in mammographic x-ray spectroscopy.
AB  - A CdZnTe (CZT) detector was utilized in mammographic x-ray spectroscopy under
      clinical conditions. First, the detector response was investigated using y-rays
      from 241Am. The escape of secondary (Compton scattered and K fluorescent) x-rays
      and tailing due to carrier trapping were minor in the mammographic energy range.
      In addition, the transmission of primary x-rays was minimal from the results
      calculated using the mass attenuation coefficients of CZT. Therefore, spectral
      distortion in this energy range was expected to be negligible. Secondly, x-ray
      spectroscopy was carried out with the CZT detector. The measured spectra were in
      good agreement with the spectra obtained with the Compton-scatter method with a
      high-purity germanium detector. Moreover, the half-value layers (HVLs) calculated
      from the CZT spectra were consistent with the HVLs measured with an ionization
      chamber. The results indicate that a CZT detector can be utilized in mammographic
      x-ray spectroscopy without any corrections.

PMID- 12476977
TI  - Simulation of the effect of anode surface roughness on diagnostic x-ray spectra.
AB  - To simulate the effect of the condition of the anode surface on x-ray output the
      surface roughness of anode fragments of replaced clinical x-ray tubes was
      determined. A mean roughness of 1.32-5.22 microm giving effective tungsten
      absorption layers of up to 18 microm thickness in the direction of the x-ray beam
      was determined. X-ray spectra were then simulated using the measured surface
      profiles. The most prominent effect was the reduction of the kerma output of the
      tube with increasing roughness (-33% at 50 kV tube voltage and 5 microm
      roughness). The effects of beam hardening are less pronounced. The corresponding
      changes in the spectral parameters are generally small but largest for tube
      voltages up to 70 kV. For higher voltages the increased photon attenuation above
      the K-edge of tungsten reduces the effects of roughness on spectral parameters.
      The maximum shifts in mean photon energy of about 1 keV and in HVL of about 0.2
      mm Al were obtained for an anode roughness of 5 microm.

PMID- 12476978
TI  - A simplistic formalism for calculating entrance dose in high-energy x-ray beams.
AB  - A calculation engine for independent checking of the delivered dose to the
      prescription point has been developed and tested in an earlier work by our group.
      One drawback with the present system is the inability to accurately predict the
      absorbed dose at the depth of dose maximum, d(max), where calculations may
      deviate by as much as 6-7%. Accurate dose values at dmax are necessary in order
      to make comparisons with in vivo dose measurements. The aim of this work is to
      extend the present model to predict dose values at dmax to within +/-2%. Depth
      dose measurements at different SSD (80, 90 and 100 cm) and field sizes (5 x 5 to
      40 x 40 cm2) are made at photon energies in the range from 4 to 18 MV. The effect
      of an acrylic block tray present in the beam is also studied. Wedged beams are
      handled as separate beam qualities. An entrance dose factor is defined to correct
      the effect of electronic disequilibrium at dmax The entrance dose factor is found
      to be independent of SSD and tray, but it varies with beam quality and field
      size. After applying the entrance dose factor, the dose at dmax can be predicted
      to within 1.7% (2 SD).

PMID- 12476979
TI  - Enhancement of IMRT delivery through MLC rotation.
AB  - Multileaf collimator (MLC) based intensity modulated radiation therapy (IMRT)
      techniques are well established but suffer several physical limitations.
      Dosimetric spatial resolution is limited by the MLC leaf width; interleaf leakage
      and tongue-and-groove effects degrade dosimetric accuracy and the range of leaf
      motion limits the maximum deliverable field size. Collimator rotation is used in
      standard radiation therapy to improve the conformity of the MLC shape to the
      target volume. Except for opposed orthogonal fields, collimator rotation has not
      been exploited in IMRT due to the complexity of deriving the MLC leaf
      configurations for rotated sub-fields. Here we report on a new way that MLC-based
      IMRT is delivered which incorporates collimator rotation, providing an extra
      degree of freedom in deriving leaf sequences for a desired fluence map.
      Specifically, we have developed a series of unique algorithms that are capable of
      determining rotated MLC segments. These IMRT fields may be delivered statically
      (with the collimator rotating to a new position in between sub-fields) or
      dynamically (with the collimator rotating and leaves moving simultaneously during
      irradiation). This introductory study provides an analysis of the rotating leaf
      motion calculation algorithms with focus on radiation efficiency, the range of
      collimator rotation and number of segments. We then evaluate the technique by
      characterizing the ability of the algorithms to generate rotating leaf sequences
      for desired fluence maps. Comparisons are also made between our method and
      conventional sliding window and step-and-shoot techniques. Results show
      improvements in spatial resolution, reduced interleaf effects and maximum
      deliverable field size over conventional techniques. Clinical application of
      these enhancements can be realized immediately with static rotational delivery
      although improved dosimetric modelling of the MLC will be required for dynamic
      delivery.

PMID- 12476980
TI  - Influence of initial electron beam characteristics on monte carlo calculated
      absorbed dose distributions for linear accelerator electron beams.
AB  - The least known parameters in a Monte Carlo simulation of a linear accelerator
      treatment head are often the properties of the initial electron beam directed
      onto the exit vacuum window. Several initial beams with different spatial fluence
      distributions, angular divergences and energy spectra have been transported
      through the geometry of a scattering foil accelerator. The electron beam
      characteristics (energy spectrum and angular distribution) at the phantom surface
      and the subsequent relative absorbed dose distribution in a water phantom were
      calculated. The dose distribution was found to be insensitive to the geometrical
      properties of the initial beam. Furthermore, the lateral dose profiles are
      unaffected by the energy spectrum of the initial beam. The effect on the depth
      dose curve is negligible if the initial energy spectrum is symmetric (e.g.,
      Gaussian shaped) and its full width at half maximum (FWHM) is less than
      approximately 10% of the most probable energy. A larger FWHM will decrease the
      normalized dose gradient, but will not affect the dose in the build-up region. An
      asymmetric wedge shaped spectrum with a low-energy extension simultaneously
      increases the dose in the build-up region and decreases the dose gradient. The
      relationship between the energy spectral width and the normalized dose gradient
      is, however, smaller than published analytical expressions indicate. Some well
      established energy-range relationships were shown to be accurate for most of the
      initial beams studied. The energy spectrum at the phantom surface was also
      derived from a measured depth-dose curve through different methods. The extracted
      spectrum depends on the beam model and the spectral reconstruction algorithm.
      Even though the depth-dose curve is fairly independent of initial beam
      characteristics, a correct description of the low-energy tail of the energy
      spectrum is important to obtain good agreement between measured and Monte Carlo
      calculated doses in the build-up region.

PMID- 12476981
TI  - Finite element model of intramuscular pressure during isometric contraction of
      skeletal muscle.
AB  - The measurement of in vivo intramuscular pressure (IMP) has recently become
      practical and IMP appears well correlated with muscle tension. A numerical model
      of skeletal muscle was developed to examine the mechanisms producing IMP.
      Unipennate muscle is modelled as a two-dimensional material continuum that is
      incompressible and nonlinearly anisotropic. The finite element technique is used
      to calculate IMP and muscle stress during passive stretch and during isometric
      contraction. A novel element models the contractile portion of muscle,
      incorporating sarcomere length-force and velocity-force relations. A range of
      unipennate muscle geometries can be modelled. The model was configured to
      simulate the rabbit tibialis anterior muscle over a range of lengths. Simulated
      IMP and stress results were validated against animal experimentation data. The
      simulation agreed well with the experimental data over the range of 0.8-1.1 of
      the optimal length. Severe pressure gradients were produced near the musculo
      tendinous junctions while IMP was more uniform in the central muscle belly. IMP
      and muscle stress in relaxed (unstimulated) muscle increased nonlinearly with
      muscle length. IMP and stress in isometrically contracting muscle showed a local
      maximum at optimal length and were reduced at shorter lengths. At muscle lengths
      longer than optimal, stress and IMP increased predominately due to tension in the
      passive elastic structures.

PMID- 12476982
TI  - Noninvasive three-dimensional activation time imaging of ventricular excitation
      by means of a heart-excitation model.
AB  - We propose a new method for imaging activation time within three-dimensional (3D)
      myocardium by means of a heart-excitation model. The activation time is estimated
      from body surface electrocardiograms by minimizing multiple objective functions
      of the measured body surface potential maps (BSPMs) and the heart-model-generated
      BSPMs. Computer simulation studies have been conducted to evaluate the proposed
      3D myocardial activation time imaging approach. Single-site pacing at 24 sites
      throughout the ventricles, as well as dual-site pacing at 12 pairs of sites in
      the vicinity of atrioventricular ring, was performed. The present simulation
      results show that the average correlation coefficient (CC) and relative error
      (RE) for single-site pacing were 0.9992+/-0.0008/0.9989+/-0.0008 and 0.05+/
      0.02/0.07+/-0.03, respectively, when 5 microV/10 microV Gaussian white noise
      (GWN) was added to the body surface potentials. The average CC and RE for dual
      site pacing were 0.9975+/-0.0037 and 0.08+/-0.04, respectively, when 10 microV
      GWN was added to the body surface potentials. The present simulation results
      suggest the feasibility of noninvasive estimation of activation time throughout
      the ventricles from body surface potential measurement, and suggest that the
      proposed method may become an important alternative in imaging cardiac electrical
      activity noninvasively.

PMID- 12476983
TI  - Three-dimensional localization of fluorescent masses deeply embedded in tissue.
AB  - In this paper we present preliminary results obtained for tissue-like phantoms
      and ex vivo tissue slabs using a prototype system for CW infrared fluorescence
      imaging of fluorescent markers. Besides the design of the experimental system
      itself, we have developed a theoretical model of photon migration under
      experimental conditions and associated 3D reconstruction algorithms to estimate
      the distribution of fluorescent markers. Application of the developed algorithms
      in the analysis of 2D intensity distributions of the fluorescent light
      demonstrated their ability to reconstruct positions of the markers (including
      their depths) with good accuracy (error < or = 10%) both for the Intralipid
      phantoms and ex vivo tissue slabs.

PMID- 12476984
TI  - Signal-to-noise ratio evaluation in dual-energy radiography with synchrotron
      radiation.
AB  - Dual-energy radiography is an effective technique that allows removal of contrast
      between pairs of materials in order to display details of interest on a uniform
      background. In mammographic images the detection of small nodules is often
      impeded by obscuring background 'clutter' resulting from the contrast between
      normal tissues (glandular and adipose) in their neighbourhood. We consider
      whether it could be possible to apply dual-energy radiography to the breast,
      which is hypothetically principally composed of three tissues, glandular, adipose
      and cancerous, in order to remove the contrast due to the distribution of normal
      tissues and, as a consequence, to enhance the intrinsic contrast of the
      pathology. The purpose of this work is to test the limitations of dual-energy
      radiography on a three-component phantom under optimum conditions of the source
      and detector. We use a synchrotron monochromatic beam, produced at the ELETTRA
      synchrotron facility (Trieste, Italy), and an imaging plate detector, in order to
      acquire two images at low and high energies of a phantom composed of
      polyethylene, plexiglas and water. For evaluation of the potential of this
      procedure we studied the signal-to-noise ratio (SNR) of polyethylene and water on
      a set of images obtained by applying the dual-energy procedure. We found that the
      SNR of polyethylene and water is around the detectability threshold (according to
      Rose's criteria) at the contrast cancellation angles. Finally we evaluated the
      air entrance dose required for this double exposure, resulting in 0.81 mGy for
      the low-energy image and 0.01 mGy for the high-energy image. To obtain the same
      image quality for a standard breast of 5.5 cm, mean glandular doses of 3.50 mGy
      and 0.03 mGy at 17 keV and at 34 keV, respectively, are required.

PMID- 12476985
TI  - Calculation of the x-ray film response to heavy charged particle irradiation.
AB  - A model was developed to calculate the response of films to heavy ion irradiation
      as a function of particle type and energy. It is based on the local effect model
      and was extended to be applied to the non-homogeneous target of photographic
      emulsions. The calculation was performed for protons and carbon ions in the
      energy range from 2 to 430 MeV u(-1). The calculated film responses are in very
      good agreement with experimental data. Based on this model calculation a data
      base of film responses was set up. This enables a three-dimensional dose
      verification with films in the heavy ion tumour therapy project at GSI,
      Darmstadt.

PMID- 12476986
TI  - Comparative evaluation of Kodak EDR2 and XV2 films for verification of intensity
      modulated radiation therapy.
AB  - Film dosimetry provides a convenient tool to determine dose distributions,
      especially for verification of IMRT plans. However, the film response to
      radiation shows a significant dependence on depth, energy and field size that
      compromise the accuracy of measurements. Kodak's XV2 film has a low saturation
      dose (approximately 100 cGy) and, consequently, a relatively short region of
      linear dose-response. The recently introduced Kodak extended range EDR2 film was
      reported to have a linear dose-response region extending to 500 cGy. This
      increased dose range may be particularly useful in the verification of IMRT
      plans. In this work, the dependence of Kodak EDR2 film's response on the depth,
      field size and energy was evaluated and compared with Kodak XV2 film. Co-60, 6
      MV, 10 MV and 18 MV beams were used. Field sizes were 2 x 2, 6 x 6, 10 x 10, 14 x
      14, 18 x 18 and 24 x 24 cm2. Doses for XV2 and EDR2 films were 80 cGy and 300
      cGy, respectively. Optical density was converted to dose using depth-corrected
      sensitometric (Hurter and Driffield, or H&D) curves. For each field size, XV2 and
      EDR2 depth-dose curves were compared with ion chamber depth-dose curves. Both
      films demonstrated similar (within 1%) field size dependence. The deviation from
      the ion chamber for both films was small forthe fields ranging from 2 x 2 to 10 x
      10 cm2: < or =2% for 6, 10 and 18 MV beams. No deviation was observed for the Co
      60 beam. As the field size increased to 24 x 24 cm2, the deviation became
      significant for both films: approximately 7.5% for Co-60, approximately 5% for 6
      MV and 10 MV, and approximately 6% for 18 MV. During the verification of IMRT
      plans, EDR2 film showed a better agreement with the calculated dose distributions
      than the XV2 film.

PMID- 12476987
TI  - Corresponding dose response of radiographic film with layered gafchromic film.
AB  - This note investigates the dose response of layered HS Gafchromic film compared
      to Kodak EDR-2 radiographic film. Using five layers of HS type Gafchromic film a
      dose response greater than EDR-2 film is achieved at the peak wavelength (0.55
      OD/Gy versus 0.3 OD/Gy for EDR-2 film). Even over a broader waveband of 30 nm,
      which is similar to that found in ultra bright LED scanners, the response was
      found to be 0.38 OD/Gy as opposed to 0.29 OD/Gy. Measurements averaged over the
      entire visible spectrum produce a relative dose response of 0.165 OD/Gy for five
      layer HS and 0.29 OD/Gy for EDR-2 film. Due to this high dose response that is
      achievable, the five layer HS could be used in applications where small doses are
      delivered to certain areas and a low dependence of energy response is required
      for measurement.

PMID- 12476988
TI  - High sensitivity radiochromic film dose comparisons.
AB  - This short note investigates the dose characteristics of a relatively new high
      sensitivity radiochromic film (Gafchromic HS) and compares dose and energy
      response to various Gafchromic film types and radiographic (EDR-2) film. The
      original MD-55-1 and two improved sensitivity films, MD-55-2 and HS film, were
      investigated for energy and dose response. Results show that the energy response
      of the new HS film is relatively the same as the original MD-55-1 and MD-55-2
      films with a decrease in sensitivity at lower x-ray energies, with response
      decreasing down to approximately 0.64 (normalized to 1 for a 6 MV beam) for a 28
      keV effective energy beam. This is compared to an over response of 9.2 at the
      same energy for EDR-2 film. The dose response at the maximum absorption peak was
      found to be approximately 3.8 and 1.9 times more sensitive than MD-55-1 and MD-55
      2 films, respectively. At the absorption peak yielding the maximum optical
      density change, HS was found to be approximately 0.2 to 0.25 times the
      sensitivity of EDR-2.

PMID- 12476989
TI  - A comparison of crop and non-crop plants as sensitive indicator species for
      regulatory testing.
AB  - The effectiveness of regulatory non-target plant testing using crop species to
      predict the phytotoxicicity of herbicides to non-crop species was evaluated for
      eleven herbicides. These herbicides were representative of eight chemical classes
      and six modes of action. Data for non-crop plants from pre-emergence and post
      emergence efficacy screening studies were compared with those for the most
      sensitive crop species defined by regulatory tests conducted to meet US EPA
      requirements. Testing under pre-emergence conditions for ten compounds indicated
      that for five of the compounds (K-815910, trifluralin, pyridyloxy A, pyridyloxy B
      and cyanazine), the most sensitive crop species was more sensitive than all the
      non-crop species evaluated. For metsulfuron-methyl, chlorimuron-ethyl, hexazinone
      and bromacil, only one of the non-crop species evaluated was more sensitive than
      the most sensitive crop species from regulatory tests. Data for the tenth
      compound, chloroacetamide, showed that four of 32 non-crop species tested in
      efficacy screens had at least one rate at which greater visual effects were
      observed than were observed for the most sensitive crop response in a regulatory
      test. The results of post-emergence exposure comparisons for five of the
      compounds (pyridyloxy A, cloransulam-methyl, chlorimuron-ethyl, cyanazine and
      hexazinone) indicated that the most sensitive crop species were more sensitive
      than all the non-crop species evaluated. Data for pyridyloxy B, metsulfuron
      methyl and bromacil indicated that only one of the non-crop species evaluated was
      more sensitive than the most sensitive crop species. For trifluralin, three of
      the eight non-crop species were more sensitive than the most sensitive crop
      species. Data for K-815910 indicated that four of the fourteen non-crop species
      tested were marginally more sensitive than the most sensitive crop, but were
      within the same range of sensitivity. These results indicate that the current
      regulatory test batteries and methods using crop species effectively provide
      suitable sensitive indicator plants for the eleven diverse herbicides evaluated.
      This comparison indicates that crop species sensitivity to test substances is
      likely to be representative of non-crop herbaceous species response, regardless
      of chemical class, mode of action and magnitude or route of exposure.

PMID- 12476990
TI  - Synthesis and herbicidal activity of phenyl-substituted benzoylpyrazoles.
AB  - A novel series of substituted 3-phenyl benzoylpyrazoles were prepared and tested
      as potential grass herbicides. The targeted materials were prepared by three
      newly developed synthetic routes, which allowed a comprehensive study of the SAR
      (structure-activity relationships) of this series. The best combination of grass
      weed activity (Avena fatua L, Setaria viridis (L) Beauv and Alopecurus
      myosuroides Huds) and wheat selectivity was obtained with an alkoxy group in the
      4-position of the phenyl ring. Activity was further enhanced by the presence of
      tert-butyl on the pyrazole and a methyl group at the C-2 position of the benzoyl
      moiety. The alkoxy-substituted 3-phenylbenzoylpyrazoles are a novel class of
      herbicides with potential utility for control of important grass weeds in
      cereals.

PMID- 12476991
TI  - Transformation of carrots with mutant acetolactate synthase for Orobanche
      (broomrape) control.
AB  - Parasitic Orobanche spp are major constraints to vegetable crop production in the
      Mediterranean basin (to eastern Europe) and in localized places in India, China
      and the USA. Transgenic target-site herbicide resistance (eg, to acetolactate
      synthase inhibitors) allows for movement of unmetabolized herbicide through the
      crop to the photosynthate sink in the parasite, as well as through the soil. We
      report the successful engineering of a mutant acetolactate synthase (ALS) gene
      into carrot, allowing control of broomrape already in heterozygotes of the first
      back-crossed generation, by imazapyr, an imidazolinone ALS inhibitor. It is
      expected that homozygotes will have higher levels of resistance.

PMID- 12476992
TI  - Pirimiphos-methyl and benalaxyl losses in surface runoff from plots cultivated
      with potatoes.
AB  - Abstract: Losses of pirimiphos-methyl and benalaxyl in runoff water from clay
      soil plots cultivated with potatoes and of differing soil surface slopes were
      determined over approximately 120 days (1 October 1999-28 January 2000). The plot
      slopes were 0, 1, 2.5 and 5%, and soil erosion increased with the slope from 610
      to 1760kgha(-1). The runoff of surface water was between 3.1 and 16.6% of the
      rainfall. Surface runoff was highest for the fifth and seventh runoff events due
      to rainfall, 51 days and 72 days after the first pesticide application. The
      maximum concentrations of the two pesticides in runoff occurred in the plots with
      the greatest slope (5%) during the fifth runoff event, November 21, 1999 reaching
      8.4 and 12.3 microg litre(-1) for pirimiphos-methyl and 17.8 and 20.2 microg
      litre(-1) for benalaxyl in tilled and untilled plots respectively. The cumulative
      losses of pirimiphos-methyl in surface runoff from tilled and untilled plots with
      a slope 5% were estimated at only 0.37 and 0.59% of the initial applied active
      ingredient, respectively, while for plots with a slope 0% the percentages were
      0.013 and 0.018%. For benalaxyl the corresponding values from tilled and untilled
      plots were 1.69 and 1.76% (slope 5%), and 0.062 and 0.085 (slope 0%). Degradation
      of the pesticides in the topsoil was monitored from October 1999 and May 2000.
      Cultivation of potatoes decreased the half-life of the two pesticides compared to
      the untilled fields, for pirimiphos-methyl from 16.7 to 9.2 days and for
      benalaxyl from 26.7 to 12.6 days. The slope of soil surface and the different
      sorption capacities for the compounds are the main parameters which influenced
      the transportation of studied pesticides, pirimiphos-methyl and benalaxyl
      residues via surface water in soil-water systems.

PMID- 12476993
TI  - Synthesis of anthelmintically active N-methylated amidoxime analogues of the
      cyclic octadepsipeptide PF1022A.
AB  - The N-methylated amidoxime analogues of the cyclic octadepsipeptide PF1022A
      represent novel derivatives with activity against Trichinella spiralis Owen and
      Nippostrongylus brasiliensis Lane in vitro and against parasitic nematodes in
      mice and sheep. Some of them show better activity against Hymenolepis nana
      Siebold, Heterakis spumosa Schneider and Heligmosomoides polygyrus Dujardin in
      mice than the natural product PF1022A. In particular an improved efficacy against
      Haemonchus contortus Rudolphi and Trichostrongylus colubriformis Giles in sheep
      compared to the potent cyclic octadepsipeptide PF1022A and its mono-thionated
      derivative has been observed. Here we report on a specific modification at the N
      methyl amide linkage by using the mono-thionated PF1022A, resulting in novel
      anthelmintically active backbone analogues of PF 1022A.

PMID- 12476994
TI  - A refined method for the detection of baculovirus occlusion bodies in forest
      terrestrial and aquatic habitats.
AB  - A sensitive and efficient method was developed for the detection of genetically
      modified and wild-type baculovirus occlusion bodies (OB) in forest terrestrial
      and aquatic habitats. The protocol facilitates the analysis of a large number of
      samples collected and frozen to maintain viral integrity. Lyophilization was used
      to standardize the size of both field-collected soil samples and test substrates
      inoculated with OBs for the determination of minimum detection threshold. To
      simulate natural conditions, terrestrial test substrates were inoculated at a
      standardized moisture content determined using a soil pressure plate apparatus.
      OBs, extracted from lyophilized test substrates by washing, sieving and
      centrifugation, were subjected to alkaline lysis and viral DNA isolated using a
      purchased DNA purification kit. PCR amplified DNA was visualized using agarose
      gel electrophoresis. Minimum detection thresholds in terrestrial substrates were
      10(3), 10(2), 10(2) and 10(1) OBs from 0.5 g of lyophilized L, F-H and mineral
      soil horizons, and 1.0 ml of leachate, respectively. Detection thresholds in
      aquatic substrates were 10(0) and 10(3) OBs from 1.0 ml of pond water and 1.0 g
      of bottom sediment, respectively.

PMID- 12476995
TI  - Long-term effectiveness of grain protectants and structural treatments against
      Liposcelis decolor (Pearman) (Psocoptera: Liposcelididae), a pest of stored
      products.
AB  - Numerous strains of the psocid pest, Liposcelis decolor (Pearman) were collected
      from farms and central storages and interbred to form three representative
      strains from three major grain-growing states of Australia: Queensland, South
      Australia and New South Wales. These were tested against the grain protectants
      and structural treatments currently registered for use in Australia. Recently, L
      decolor has become an important pest of stored grain in Australia, particularly
      in the eastern and southern parts. There is no published information available on
      management of this pest and the current pest-management strategy, based
      predominantly on phosphine fumigation, has failed to control infestations of this
      pest in numerous grain storages in Australia. Alternative methods of control such
      as use of contact insecticides were explored in the present work to supplement
      phosphine fumigation to manage this new pest. From eight grain protectants tested
      as admixtures, only chlorpyrifos-methyl, bioresmethrin plus piperonyl butoxide,
      and fenitrothion were found to provide long term (3-9 months) protection against
      all three strains of L decolor. Chlorpyrifos-methyl gave the best protection,
      providing a minimum of 7.5 to a maximum of 9 months protection, depending on the
      strains tested. Three structural treatments, azamethiphos, azamethiphos plus
      carbaryl and permethrin provided long-term control (8-9 months) of all three
      strains of L decolor on galvanised steel surfaces, with permethrin delivering 9
      months protection against all strains. However, all of these treatments failed to
      provide long-term control of any strains on concrete surfaces. We conclude that
      chlorpyrifos-methyl as a grain admixture can be incorporated into fumigation
      strategies to optimise the control of L decolor infestations. Structural
      treatments, such as permethrin can be used to support a fumigation strategy in
      storages made of galvanised steel.

PMID- 12476996
TI  - Isolation and characterization of efficient isoxaben-transforming Microbacterium
      sp strains from four European soils.
AB  - Nutrient-agar plates containing isoxaben (500 mg litre(-1)) were used to isolate
      isoxaben-metabolising bacteria from four European soils incubated with the
      herbicide under laboratory conditions. In flask experiments, inoculation of a
      basal salts medium containing nitrogen and [phenyl-U-14C]isoxaben with an isolate
      (B2b) resulted in 33% recovery of the initial radioactivity as [14C]carbon
      dioxide after 2 weeks. A major metabolite identified by GC-MS and NMR analysis as
      3-(1-ethyl-1-methylpropyl)isoxazol-5-ylamine accumulated both in basal salts and
      nutrient broth media. 2,6-Dimethoxybenzoic acid, a suspected metabolite of
      isoxaben, was not detected in either liquid media. However, the capability of the
      B2b isolate to use 2,6-dimethoxybenzoic acid as a source of carbon was
      demonstrated. Soil inoculation with the B2b strain resulted in an increase in the
      recovery of [14C] carbon dioxide from both [phenyl-U-14C] and [isoxazole-5
      14C]isoxaben. The metabolite identified as 3-(1-ethyl-1-methylpropyl)isoxazole-5
      ylamine only accumulated if the soil was autoclaved before inoculation. This
      metabolite was rapidly mineralized by the microflora of a natural soil without
      history of isoxaben treatment. Homology patterns of sequenced 16S rDNA between
      isoxaben-transforming isolates and reference strains showed that the four
      isolates identified belonged to the genus Microbacterium.

PMID- 12476997
TI  - Fate in the soil of an oil additive of plant origin.
AB  - The methyl ester of oleic acid, a plant oil derivative, can be used as an
      additive oil for pesticides. We compared the biodegradability in soil of this oil
      with that of a mineral oil by means of laboratory experiments using lysimeters of
      70 cm height x 20 cm diameter. The migration in soil of the oils and of the
      metabolites of the plant ester over 120 days was examined by gas chromatography
      and liquid chromatography. The plant oil and its metabolites were completely
      degraded within 60 days, whereas degradation of the mineral oil required 90 days.
      The molecules did not migrate far into the soil and therefore presented no risk
      of contaminating groundwater.

PMID- 12476998
TI  - Ethoxylated rapeseed oil derivatives as novel adjuvants for herbicides.
AB  - Ethoxylates of rapeseed oil and of methylated rapeseed oil were synthesized and
      tested as adjuvants for 2,4-D and phenmedipham. Provided they had less than 6
      units of ethylene oxide (EO), 1.0 to 10 g litre(-1) ethoxylates in water induced
      droplet spreading on barley leaves. In an acetone-based medium all derivatives
      strongly promoted the foliar uptake of 2,4-D, with no clear influence of the
      ethoxylation degree. In the same medium there was a negative influence of
      ethoxylate chain length on the foliar uptake of phenmedipham. In a water-based
      medium, phenmedipham applied with rapeseed oil emulsified with ethoxylated (20
      EO) rapeseed oil displayed uptake rates close to a commercial preparation. The
      same was true for phenmedipham applied with ethoxylated (2 EO) methylated
      rapeseed oil. In bioassays, phenmedipham prepared with methylated rapeseed oil
      emulsified with ethoxylated (20 EO) rapeseed oil was as efficacious on barley as
      a commercial formulation. The same was true for phenmedipham prepared with
      ethoxylated (2 EO) methylated rapeseed oil. However, neither rapeseed oil nor
      methylated rapeseed oil emulsified with ethoxylated (2 EO) methylated rapeseed
      oil conferred good efficacy to phenmedipham. Hence, ethoxylated rapeseed oil
      derivatives are promising adjuvants or formulants for herbicides.

PMID- 12476999
TI  - Synthesis and insecticidal evaluation of novel N-(S-amino)sulfenylated
      derivatives of diacylhydrazines.
AB  - A series of new N-(S-amino)sulfenylated derivatives of diacylhydrazines were
      synthesized by the reaction of S-aminosulfenyl chlorides with N-tert-butyl-N'
      benzoyl-N-substituted benzoylhydrazines in the presence of sodium hydride, and
      evaluated for moulting hormone mimicking activity. In the course of syntheses, N
      N bond cleavage in diacylhydrazines was found and the reaction was studied in
      some detail. The results of bioassay showed that the title compounds exhibit
      excellent larvicidal activity. Toxicity assays indicated that these compounds can
      induce a premature, abnormal and lethal larval mount.

PMID- 12477001
TI  - Persistence and leaching of beta-cyfluthrin in alluvial soil of India.
AB  - Persistence as affected by rate of application and moisture regimes and leaching
      of beta-cyfluthrin was studied in alluvial soil under laboratory conditions. The
      effects of rate of application and moisture regimes on persistence were studied
      by incubating fortified soil at 0.1, 1.0 and 10.0 mg kg(-1) under air-dry, field
      capacity and submerged moisture regimes. The initial deposits of 0.09, 1.11 and
      10.1 mg kg(-1) dissipated with time and 78.4-100% loss was recorded at 90 days.
      The half-life values varied from 7.8 to 41.8 days. The rate of dissipation
      decreased as the rate of application increased under field capacity and submerged
      conditions. However, under air-dry conditions, the effect was less pronounced,
      and half-life values showed a reverse trend. Persistence of beta-cyfluthrin under
      different moisture regimes followed the trend: air-dry > field capacity >
      submerged. The trend could be attributed to the effect of moisture on number and
      type of microbes. Leaching was studied in a packed soil column under saturated
      flow conditions. beta-Cyfluthrin was found to be highly immobile in alluvial
      soil. No residues were detected in any leachate fraction under the experimental
      conditions. In column soil, residues were detected at 0-10 cm depth and the major
      amount (>99%) was recovered from 0-5 cm depth. Although beta-cyfluthrin showed
      moderate persistence in alluvial soil, the possibility of its leaching to ground
      water is negligible as a result of its immobility.

PMID- 12477000
TI  - Weed control in rose-scented geranium (Pelargonium spp).
AB  - Abstract: Field investigations were carried out during 1999 and 2000 to identify
      effective chemical/ cultural methods of weed control in rose-scented geranium
      (Pelargonium spp). The treatments comprised pre-emergence applications of
      oxyfluorfen (0.15, 0.20 and 0.25 kg AI ha(-1)) and pendimethalin (0.50, 0.75 and
      1.00kg AI ha(-1)), successive hand weeding, hoeing and mulching using spent of
      lemon grass (at 5 tonnes ha(-1)) 45 days after planting (DAP), three hand
      weedings 30, 60 and 90 DAP, weed-free (frequent manual weeding) and weedy
      control. Broad-leaf weeds were more predominant than grass and sedge weeds,
      accounting for 85.8% weed density and 93.0% weed dry weight in 1999 and 77.2%
      weed density and 93.9% weed dry weight in 2000. Unrestricted weed growth
      significantly reduced geranium oil yield, by 61.6% and 70.6% in 1999 and 2000,
      respectively. Pre-emergence application of pendimethalin (0.75-1.00 kgAI ha(-1))
      or oxyfluorfen (0.25 kg AI ha(-1)), successive hand-weeding, hoeing and mulching
      and three hand-weedings were highly effective in reducing weed density and dry
      weight and gave oil yield comparable to the weed-free check. Application of
      oxyfluorfen (0.15 or 0.20 kg AI ha(-1)) and pendimethalin (0.50 kg AI ha(-1))
      were less effective in controlling the weed species in geranium. None of the
      herbicides impaired the quality of rose-scented geranium oil measured in terms of
      citronellol and geraniol content.

PMID- 12477002
TI  - Insecticidal activity of N-arylalkylbenzhydrolpiperidines.
AB  - Benzhydrolpiperidine (BZP) insecticides represent a novel class of chemistry.
      Their specificity and efficacy as well as their low mammalian toxicity give them
      excellent potential for commercialization. Several N
      arylalkylbenzhydrolpiperidines were tested for activity against a variety of
      insects in the laboratory and greenhouse. These tests were used to select
      compounds for field trials and determine rates of application for field tests.
      The BZP compounds have good activity against Lepidoptera, with modest Coleoptera
      activity. They are toxic by oral administration and have about 100-fold lower
      activity by topical exposure. A methyl carbamate BZP, F4265, was the most active
      compound, with LC50 values of 6 mg litre(-1) or less for most Lepidopteran
      species tested. F4265 was active in a variety of field trials at 112-224gAI ha(
      1). Whole-plant testing methods conducted in the greenhouse were effective in
      determining field test rates.

PMID- 12477003
TI  - Ethics committee approval.

PMID- 12477004
TI  - Maximal-intensity isometric and dynamic exercise performance after eccentric
      muscle actions.
AB  - A well-documented observation after eccentric exercise is a reduction in maximal
      voluntary force. However, little is known about the ability to maintain maximal
      isometric force or generate and maintain dynamic peak power. These aspects of
      muscle function were studied in seven participants (5 males, 2 females). Knee
      extensor isometric strength and rate of fatigue were assessed by a sustained 60 s
      maximal voluntary contraction at 80 degrees and 40 degrees knee flexion,
      corresponding to an optimal and a shortened muscle length, respectively. Dynamic
      peak power and rate of fatigue were assessed during a 30 s Wingate cycle test.
      Plasma creatine kinase was measured from a fingertip blood sample. These
      variables were measured before, 1 h after and 1, 2, 3 and 7 days after 100
      repetitions of the eccentric phase of the barbell squat exercise (10 sets x 10
      reps at 80% concentric one-repetition maximum). Eccentric exercise resulted in
      elevations in creatine kinase activity above baseline (274+/-109 U x l(-1); mean
      +/- s(x)) after 1 h (506+/-116 U x l(-1), P < 0.05) and 1 day (808+/-117 U x l(
      1), P < 0.05). Isometric strength was reduced (P < 0.05) for 7 days (35% at 1 h,
      5% at day 7) and the rate of fatigue was lower (P < 0.05) for 3 days at 80
      degrees and for 1 day at 40 degrees. Wingate peak power was reduced to a lesser
      extent (P < 0.05) than isometric strength at 1 h (13%) and, although the time
      course of recovery was equal, the two variables differed in their pattern of
      recovery. Eccentrically exercised muscle was characterized by an inability to
      generate high force and power, but an improved ability to maintain force and
      power. Such functional outcomes are consistent with the proposition that type II
      fibres are selectively recruited or damaged during eccentric exercise.

PMID- 12477005
TI  - Moderate exercise and post-prandial metabolism: issues of dose-response.
AB  - In this study, we examined the effects of 1 and 2 h of brisk walking on post
      prandial metabolism. Eleven pre-menopausal women participated in three oral fat
      tolerance tests with different pre-conditions: control (no exercise), 1 h walk (1
      h of walking at 50% maximal oxygen uptake, VO2max, on the day before) and 2 h
      walk (2 h walking at 50% VO2max on the day before). Venous blood samples were
      taken in the fasted state and for 6 h after ingestion of a high-fat mixed meal.
      Compared with the control trial, the 1 h walk reduced post-prandial lipaemia by a
      mean of 9.3%, whereas the 2 h walk reduced it by 22.8% (P < 0.01 for trend).
      Similarly, the 2 h walk reduced the post-prandial insulin response to a greater
      extent than the 1 h walk (17.3 vs 7.6%; P < 0.05 for trend). The results
      demonstrate that the beneficial effects of exercise on post-prandial metabolism
      are related to the duration and, therefore, the energy expenditure of the
      exercise session.

PMID- 12477006
TI  - Evidence of a reduced home advantage when a team moves to a new stadium.
AB  - Home advantage is well documented for professional baseball, basketball and ice
      hockey in North America. One of the possible causes of this advantage is
      familiarity with the local playing facility. This was investigated and quantified
      in an analysis of 37 teams moving to new stadiums, but in the same city, from
      1987 to 2001. Home advantage during the first season in a new stadium after the
      move was significantly less than home advantage in the final season in the old
      stadium (P= 0.011). The reduction was evident in all three sports. Possible
      confounding factors, such as crowd size and crowd density, were considered but
      did not appear to have an effect. It is estimated that about 24% of the advantage
      of playing at home maybe lost when a team relocates to a new facility.

PMID- 12477007
TI  - Bilateral arm power imbalance in swim bench exercise to exhaustion.
AB  - We examined the supposition that swimmers may exhibit an imbalance in bilateral
      arm power output during simulated swimming exercise. Ten competitive front crawl
      swimmers (5 males, 5 females; age 20.5+/-2.3 years; height 1.74+/-0.09 m; body
      mass 72.0+/-16.7 kg; 400 m freestyle swim time 278+/-20.5 s; mean +/- s)
      performed four incremental (10 W x min(-1)) swim ramp tests on a computer
      interfaced biokinetic swim bench ergometer. External power output from each arm
      was measured continuously to exhaustion. The results showed that, throughout the
      course of the simulated swim, external power output clearly favoured the left arm
      (F1,9 = 12.5, P= 0.006). This was especially evident in the final 30 s to
      exhaustion, when 54.0+/-3.87% of external power output was derived from the left
      arm versus 46.0+/-3.87% from the right arm. The disparity in external power
      output was further highlighted when the participants were grouped into unilateral
      and bilateral breathers. Unilateral breathers (n = 5) produced 57.1+/-2.62% of
      external power output from the left armversus 42.9+/-2.62% from the right arm (P=
      0.001). Bilateral breathers (n = 5) exhibited a more balanced external power
      output of 51.0+/-1.82% from the left arm and 49.0+/-1.82% from the right arm (P =
      0.177). Evidence of power imbalance in the simulated swimming stroke may have
      important implications for optimizing swim performance. The observed power
      imbalance may be reduced when a bilateral breathing technique is adopted.

PMID- 12477008
TI  - Effect of the movement speed of resistance training exercises on sprint and
      strength performance in concurrently training elite junior sprinters.
AB  - The aim of this study was to determine the effects of 7 weeks of high- and low
      velocity resistance training on strength and sprint running performance in nine
      male elite junior sprint runners (age 19.0+/-1.4 years, best 100 m times 10.89+/
      0.21 s; mean +/- s). The athletes continued their sprint training throughout the
      study, but their resistance training programme was replaced by one in which the
      movement velocities of hip extension and flexion, knee extension and flexion and
      squat exercises varied according to the loads lifted (i.e. 30-50% and 70-90% of 1
      RM in the high- and low-velocity training groups, respectively). There were no
      between-group differences in hip flexion or extension torque produced at 1.05,
      4.74 or 8.42 rad x s(-1), 20 m acceleration or 20 m 'flying' running times, or 1
      RM squat lift strength either before or after training. This was despite
      significant improvements in 20 m acceleration time (P < 0.01), squat strength (P
      < 0.05), isokinetic hip flexion torque at 4.74 rad x s(-1) and hip extension
      torque at 1.05 and 4.74 rad x s(-1) for the athletes as a whole over the training
      period. Although velocity-specific strength adaptations have been shown to occur
      rapidly in untrained and nonconcurrently training individuals, the present
      results suggest a lack of velocity-specific performance changes in elite
      concurrently training sprint runners performing a combination of traditional and
      semi-specific resistance training exercises.

PMID- 12477009
TI  - The impact of a team's aggressive reputation on the decisions of association
      football referees.
AB  - It has been suggested that individuals may use heuristic methods of reasoning and
      rely on schemata when a quick decision is necessary. Accordingly, it is possible
      that decisions made by sport officials may be influenced by prior knowledge they
      have about teams they are officiating. The aim of the present study was to
      determine whether sport officials are more likely to penalize individuals who
      participate in a team with an aggressive reputation. In a balanced design, 38
      football referees were randomly assigned to either an experimental or control
      group and were presented with the same 50 video clips of incidents from football
      games, all involving a team in a blue strip ('blue team'). The incidents were
      categorized before the study by five experienced referees into fouls committed
      both by, and against, the blue team, where all participants agreed that a foul
      had been committed (certain incidents), disagreed it was a foul (uncertain
      incidents) or agreed that there was no foul (innocuous incidents). Both groups
      received written instructions before the task; in addition, the experimental
      group was informed that the blue team present in all of the clips had a
      reputation for foul and aggressive play. For each incident, the participants were
      required to indicate what action they would engage in if refereeing the game.
      Although there was no difference in the number of decisions made, the
      experimental group awarded significantly more red and yellow cards against the
      blue team both overall and for the 'certain' incidents. It is suggested that
      prior knowledge may impact referees' behaviour in a laboratory setting, although
      future research should explore whether a similar effect is observed in the
      behaviour of referees during football matches.

PMID- 12477010
TI  - Physiological characteristics of successful mountain bikers and professional road
      cyclists.
AB  - The aims of this study were to compare the physiological and anthropometric
      characteristics of successful mountain bikers and professional road cyclists and
      to re-examine the power-to-weight characteristics of internationally competitive
      mountain bikers. Internationally competitive cyclists (seven mountain bikers and
      seven road cyclists) completed the following tests: anthropometric measurements,
      an incremental cycle ergometer test and a 30 min laboratory time-trial. The
      mountain bikers were lighter (65.3+/-6.5 vs 74.7+/-3.8 kg, P= 0.01; mean +/- s)
      and leaner than the road cyclists (sum of seven skinfolds: 33.9+/-5.7 vs 44.5+/
      10.8 mm, P = 0.04). The mountain bikers produced higher power outputs relative to
      body mass at maximal exercise (6.3+/-0.5 vs 5.8+/-0.3 W x kg(-1), P= 0.03), at
      the lactate threshold (5.2+/-0.6 vs 4.7+/-0.3 W x kg(-1), P= 0.048) and during
      the 30 min time-trial (5.5+/-0.5 vs 4.9+/-0.3 W x kg(-1), P = 0.02). Similarly,
      peak oxygen uptake relative tobody mass was higher in the mountain bikers (78.3+/
      4.4 vs 73.0+/-3.4 ml x kg(-1) x min(-1), P = 0.03). The results indicate that
      high power-to-weight characteristics are important for success in mountain
      biking. The mountain bikers possessed similar anthropometric and physiological
      characteristics to previously studied road cycling uphill specialists.

PMID- 12477011
TI  - Potential vision testing--the relationship between visual acuity and Vernier
      acuity in the presence of simulated cataract.
AB  - To evaluate the utility of a computer controlled two-bar Vernier acuity
      measurement as a predictor of visual function in the presence of cataract we
      measured logMAR visual acuity and Vernier acuity in a group of 40 young normal
      observers under various levels of dioptric blur (0-3 D in dioptre steps). The
      Vernier thresholds were resistant to dioptric blur up to 2 D, but performance
      degraded with blur of 3 D for non-optimised Vernier stimulus parameters. The
      stimulus parameters, bar length and bar separation, were further investigated in
      two subjects under conditions of blur. By extending the Vernier bar length and
      increasing the bar separation the effect of blur could be further reduced even
      under the most blurred condition. The relationship between visual acuity and
      Vernier acuity was determined. Vernier acuity was measured in the presence of
      Vistech cataract simulating lenses and a prediction of visual acuity was made for
      three observers, two with no ocular abnormality and one with age-related
      maculopathy. The cataract simulating lenses affected the measured visual acuity
      in all three subjects, but had less effect on Vernier acuity. Predicted visual
      acuities were all within six letters (0.12 log units) of the visual acuity
      without the simulated cataract. As expected, the subject sufferng from age
      related maculopathy, whilst showing similar levels of Vernier acuity to the two
      ocularly healthy subjects at 1.5 degrees of retinal eccentricity, showed much
      poorer Vernier acuity for stimuli presented at fixation.

PMID- 12477012
TI  - The effect of light scattering on multifocal electroretinography.
AB  - PURPOSE: Unclear ocular media is a very common condition of older eyes
      characterized by significant light scattering and image degradation. The
      multifocal electroretinography (MERG) is a useful objective technique to measure
      retinal activity but its validity in the presence of cloudy ocular media remains
      unclear. We tested the MERG under controlled light scattering conditions using a
      liquid crystal diffuser (LCD) that simulated different degrees of image
      degradation. METHODS: The MERG were taken from 13 normal young subjects seated
      behind a LCD set under two conditions: scatter (visual acuity approximately 6/18)
      and non-scatter (visual acuity approximately6/6). The pupils had been dilated and
      the eyes were optically corrected for the working distance. The first-order
      kernel MERG response was analysed. Three subjects underwent MERG measurement with
      two additional intermediate light scattering levels (i.e. visual acuity
      approximately 6/9 and 6/12). RESULTS: The macular MERG response density was
      reduced (p < 0.001), but the peripheral MERG response densities were increased (p
      < 0.001) under the scattering condition. A similar trend was also observed with
      intermediate degrees of light scattering. Comparing the MERG waveforms without
      light scattering, a new retinal response was identified with a characteristic
      latency of about 60 ms (P60), but it was diminished in size under the scattering
      conditions. CONCLUSIONS: The veiling luminance might have caused the reduction in
      the macular MERG response and an elevation in the peripheral retina with light
      scatter. The functional suppression of P60 observed under the influence of light
      scatter may be related to retinal adaptation. Unclear optical media will affect
      the interpretation of MERG results.

PMID- 12477013
TI  - Central corneal thickness in European (white) individuals, especially children
      and the elderly, and assessment of its possible importance in clinical measures
      of intra-ocular pressure.
AB  - PURPOSE: To ascertain the impact of central corneal thickness (CCT, as assessed
      by pachometry) and central corneal curvature (as assessed by keratometry) on
      clinical measures of intra-ocular pressure (IOP, as assessed by tonometry),
      especially in the young and elderly. METHODS: Pachometry, keratometry and
      tonometry were carried out on three groups, namely children aged 5-15 years,
      adults aged 32-60 years, and elderly individuals aged between 61 and 82 years.
      For children, ultrasound pachometry was combined with non-contact tonometry
      (NCT), specular microscopy was used with Perkins tonometry in the adults, and
      ultrasound pachometry was used with Perkins tonometry for the elderly. Central
      corneal curvature was assessed by keratometry. RESULTS: The average CCT in
      children was 0.529+/-0.034 mm (n = 104, +/-S.D.), averaged 0.533+/-0.033 in
      adults (n=75) and 0.527+/-0.034 mm (n=91) in the elderly. Tonometry values
      averaged 16.7+/-2.9 mm in children, 13.0+/-3.5 mmHg in adults and 13.6+/-2.5 mm
      in the elderly group. Central corneal thickness values were not predictably
      different in relation to central corneal curvature values. Regression analyses
      indicated that the tonometry values were higher in both children and the elderly
      who had thicker corneas (and vice versa) (p < 0.003), with the measures
      increasing by 1.3+/-0.4 and 2.6+/-0.4 mmHg for a 10% difference in CCT in
      children and the elderly, respectively. For adults, no statistically significant
      difference in tonometry values could be demonstrated with respect to CCT (<1 mmHg
      for a 10% difference in CCT), and for no group were the CCT or tonometry values
      predictably different in relation to central comeal curvature values.
      CONCLUSIONS: The results of these studies, albeit relatively small scale,
      indicate that in young or elderly individuals with essentially normal IOP and CCT
      measures, the tonometry values show only small differences with respect to CCT.
      The slope in the observed relationship was not that different from an average of
      1.5 mmHg for a 10% different in CCT, as obtained from a literature analysis over
      a 30-year period. The magnitude of the effect does not provide evidence that
      pachometry needs to be routinely performed in glaucoma screening protocols based
      on tonometry. Notwithstanding, the finding of higher than expected tonometry
      values should be further investigated, by pachometry, especially in very young
      children and in the elderly.

PMID- 12477014
TI  - Repeatability of corneal thickness measurements made by a scanning slit
      topography system.
AB  - Two sets of corneal thickness (CT) measurements at five corneal locations were
      made with Orbscan on 33 normal young adults. No significant intravisit and
      intervisit differences at any of the corneal locations were found (Repeated
      measures ANOVA, F < 0.49, p > 0.49). The 95% limits of agreement (95% LA) for
      between-measurement differences for the central cornea was about +/-19 microm (or
      3%), indicating good repeatability; for the inferior, temporal and nasal corneal
      locations, the 95% LA were close to +/-30 microm (approximately 4-5%); and for
      the superior corneal location, they were about +/-35 microm (or 5.5%). The
      estimated number of repeated measurements that should be taken for accurate CT
      measurements (at any of the five corneal locations and excluding outliers of >3
      S.D.) of 2% (standard error) is < or =2, and of 3% is 1. This study shows that
      only central CT measurements with the Orbscan are repeatable. The role of the
      Orbscan pachometry is therefore limited and is recommended for central CT
      measurements only.

PMID- 12477015
TI  - Central corneal thickness is lower in osteogenesis imperfecta and negatively
      correlates with the presence of blue sclera.
AB  - BACKGROUND: Osteogenesis imperfecta (OI) is a rare, autosomal-inherited,
      connective tissue disorder characterised by bone fractures, deafness and blue
      sclera. Additional ocular findings are decreased ocular rigidity, myopia,
      glaucoma, keratoconus, corneal opacity, small corneal diameter and congenital
      Bowman's layer agenesis. PURPOSE: This cross-sectional, masked, case-control
      study aimed to assess whether central corneal thickness (CCT) is affected in
      patients with OI and to focus on the clinical significance of scleral blueness.
      MATERIALS AND METHODS: Twenty-three children with OI (13 boys, 10 girls) and 15
      age-, sex- and refraction-matched healthy control subjects (eight boys, seven
      girls) were assessed for CCT by ultrasound pachymetry. The CCT was compared
      between two different patient subgroups (type-I OI with blue sclera, n = 12; type
      IV OI without blue sclera, n = 11). Mann-Whitney U-test or analysis of variance
      was used as indicated and only right eyes of each subject were included in
      statistical analysis. Results were expressed as mean +/- S.D. and statistical
      significance was taken as p < 0.05. RESULTS: Mean age and sex distribution was
      similar between the groups (10.1+/-2.5 vs 9.8+/-1.8 years, p > 0.05). Patients
      with OI had significantly lower CCT (459.5+/-24.6 microm) than in control
      subjects (543.6+/-21.4 microm; p < 0.001). The CCT was below 500 microm in 22 of
      23 children (95.6%) with OI, 15 of which (65.2%) were below 450 microm. In
      contrast, CCT was over 500 microm in all eyes in the control group. Type-I OI
      eyes with blue sclera had significantly (p = 0.005) lower CCT readings (446.5+/
      16.3 microm) than type-IV OI eyes without blue sclera (473.6+/-25.0 microm). Mean
      keratometric values were similar between the groups (44.2+/-1.7 vs 43.8+/-1.6
      dioptre, p > 0.05). Mean cycloplegic refraction was similar between the groups (
      0.32+/-0.5 vs -0.18+/-0.4 dioptre; p > 0.05), although five of 23 OI patients had
      myopia, and mean intraocular pressure was lower in OI patients than controls
      (12.7+/-1.8 mmHg vs 15.6+/-1.9 mmHg; p < 0.001). CONCLUSIONS: The CCT is thinner
      and negatively correlated with the blueness of the sclera in patients with OI.
      The CCT readings may therefore be of utmost importance in the diagnosis of OI. An
      ophthalmologist should be aware of an artificially low intraocular pressure
      measurement in such patients. In addition, when considering a keratorefractive
      treatment, CCT must be evaluated carefully to avoid unexpected results or
      complications. Sturdy protective spectacles should be prescribed to those who are
      not bed bound. Possible correlation of low CCT with biochemical changes in
      scleral collagen or systemic parameters awaits further investigation.

PMID- 12477016
TI  - A multi-centre study of lapsed contact lens wearers.
AB  - PURPOSE: Discontinuation from contact lens wear has been identified as a
      contributing factor in the lack of growth of contact lens use in Europe. The
      purpose of this study was to determine the proportion of lapsed contact lens
      wearers that can be refitted successfully with contact lenses and to evaluate the
      reasons for discontinuation from contact lens wear. METHODS: This was a multi
      site clinical study involving 15 UK investigators and 236 lapsed contact lens
      wearers who had previously tried contact lenses and discontinued. The reasons for
      discontinuation were assessed by subjects, who were then refitted with contact
      lenses. Investigators subsequently evaluated factors associated with their
      initial discontinuation. Short-term success was defined as the successful
      completion of 1 month of contact lens wear with absence of complications that
      would prevent further wear. Subjects were interviewed by telephone 6 months after
      being refitted to determine whether they were still wearing contact lenses. Those
      who were not wearing lenses were questioned about the reasons for discontinuation
      and their likelihood of resuming lens wear. RESULTS: A majority of subjects (51%)
      cited discomfort as the principal reason for having previously given up contact
      lens wear. Problems with vision were the second most common reason (13%), either
      with reading (6%) or general vision (7%). The most common type of discomfort was
      dryness (40%). In almost all cases (97%), the investigator's assessment of the
      reasons for discontinuation agreed with the subject's own assessment but
      investigators also cited product-related and practitioner-related factors as
      contributing to previous failure. The short-term success rate for refitting
      lapsed wearers was found to be 77% (Cl: 70-82%). The highest short-term success
      rates were for 2-weekly/monthly soft spherical lenses (91%) and daily disposable
      lenses (89%). Lower success rates were found for soft toric (69%) and soft
      bifocal (53%) lenses. At the 6-month stage, 73% of those who continued in lenses
      after the 1-month visit were still wearing contact lenses and a further 18%
      indicated that they were either 'very likely' or 'likely' to resume lens wear.
      CONCLUSIONS: A high proportion of lapsed contact lens wearers can be successfully
      refitted with contact lenses. The prime reason for previous discontinuation from
      contact lenses is discomfort and, in particular, dryness-related discomfort. In
      many cases, previous contact lens failure is product or practitioner-related
      rather than because of patient-specific problems. Once refitted with contact
      lenses, lapsed wearers cite vision problems rather than discomfort as the most
      common reason for discontinuing. This finding suggests that recent advances in
      contact lens material, design, replacement frequencies and care systems have
      improved the prospects for avoiding lens-related discomfort and for continuing
      contact lens wear.

PMID- 12477017
TI  - The effect of refractive blur on postural stability.
AB  - The effect of refractive blur upon postural stability was investigated under
      three conditions: normal standing, standing with input from the somatosensory
      system disrupted and standing with input from the somatosensory and vestibular
      systems disrupted. Standing stability was assessed using the centre of pressure
      (COP) signal from force plate data in four young subjects (mean 23.9+/-3.1 years)
      and five repeated sets of measurements were taken. The subjects looked straight
      ahead at a horizontal and vertical square wave pattern of 2.5 cycles (degree)(
      1). Under each of the three test conditions, standing stability was measured with
      the optimal refractive correction and under binocular blur levels of 0, + 1, + 2,
      + 4, and + 8 D and with eyes closed. In the normal standing condition, dioptric
      blur had only a mild effect on postural stability. However refractive blur
      produced large increases in postural instability when input from one or both of
      the other two sensory systems were disrupted. We hypothesized that dioptric blur
      would have an even great effect on postural stability if the visual target used
      was of higher spatial frequency. This was confirmed by repeated measurements on
      one subject using a target of 8 cycles (degree)(-1). The study highlights the
      possible importance of an optimal correction to postural stability, particular in
      situations (or people) where input from the somatosensory and/or vestibular
      systems are disrupted, and where the visual surrounds are of high spatial
      frequency.

PMID- 12477018
TI  - The effect of coloured filters on the rate of reading in an adult student
      population.
AB  - Meares-Irlen Syndrome is characterised by visual stress (visual discomfort) and
      visual perceptual distortions that can be alleviated by individually prescribed
      coloured filters. The benefit from coloured filters can be demonstrated with the
      Wilkins Rate of Reading Test (WRRT). Previous research using individually
      prescribed coloured overlays (sheets of plastic placed on a page) found that
      between one-fifth and one-third of unselected school-children show a significant
      (> 5%) improvement in their rate of reading with their chosen overlay. This 5%
      cut-off has good sensitivity and specificity for predicting those children who
      will continue to voluntarily use their overlay for a sustained period. Previous
      research has concentrated on children, and we sought to investigate the immediate
      effect of overlays on rate of reading in an adult population. Subjects were 113
      unselected university students who answered a symptom questionnaire and were
      tested with the Wilkins Intuitive Overlays and WRRT. Some symptoms were common:
      73% reported sore or tired eyes when reading and 40% reported four to 12
      headaches a year. One hundred of the subjects chose an overlay as improving their
      immediate perception of text. These subjects were significantly more likely to
      report perceptual distortions and visual discomfort on viewing text than subjects
      who did not choose an overlay. The 100 subjects read 3.8% faster with the overlay
      than without any overlay (p < 0.00001), whereas the 13 subjects who did not
      choose an overlay read 1.7% slower with a placebo overlay than without (p =
      0.37). Of the subjects who chose an overlay, 38% read more than 5% faster with
      the overlay and 2% read more than 25% faster. These results are comparable with
      those obtained for children. We conclude that Meares-Irlen Syndrome is likely to
      be as common in adults as it is in children.

PMID- 12477019
TI  - Testing young infants with the Welch Allyn suresight non-cycloplegic
      autorefractor.
AB  - Both eyes of 74 healthy 2-12-month-old human infants were refracted twice with
      the new Welch Allyn SureSight non-cycloplegic autorefractor. At least one
      reliable estimate of sphere and cylinder was obtained from both eyes of all
      babies attempted, and 88% of infants contributed two estimates from each eye.
      These measurements were collected in less than 2 min. Although spherical
      estimates changed little over the first year (mean = +1.78 D), cylindrical error
      appeared to decrease from a mean of about 1.4 D (at 6 months) to 0.9 D (at 12
      months). Refractive estimates and variability agreed well with published infant
      data obtained with traditional cycloplegic retinoscopy. Repeatability was
      excellent for measurement of cylinder but for sphere, 17% of infants' estimates
      differed by at least 1.0 D between tests. However, given its simplicity and time
      efficiency, the SureSight should be a good candidate for the relatively easy
      screening of significant refractive error in non-verbal paediatric patients.

PMID- 12477020
TI  - Intra-observer and inter-observer repeatability of anterior eye segment analysis
      system (EAS-1000) in anterior chamber configuration.
AB  - BACKGROUND: Anterior chamber configuration can be assessed via optical or
      ultrasonic techniques. Scheimpflug photography is a non-invasive method measuring
      the anterior segment. The Anterior Eye Segment analysis system, EAS-1000,
      utilises the Scheimpflug principle and was found to have good repeatability.
      Previous repeatability studies, however, have had limitations in their design.
      The current study investigated the intra-observer and interobserver repeatability
      of the EAS-1000. METHODS: Twenty-five healthy young subjects were recruited. The
      anterior chamber angles in different quadrants were measured by two examiners for
      interobserver analysis. The first examiner repeated the measurement at another
      session for intra-observer analysis. The 95% limits of agreement and intra-class
      correlation coefficient (ICC) were calculated. The anterior chamber depth was
      also measured and compared with ultrasound biometry. RESULTS: The anterior
      chamber angle assessment demonstrated good intra-observer (ICC ranging from 0.77
      to 0.90 for different quadrants) and interobserver (ICC ranging from 0.68 to 0.81
      for different quadrants) repeatability. The 95% intra-observer limits of
      agreement were within +/-5 degrees. The 95% interobserver limits of agreement
      were within +/-6 degrees. There was no significant difference between male and
      female subjects or among angles at different quadrants. The anterior chamber
      depth was found to be repeatable (ICC > 0.90) with 95% limits of agreement +/-0.1
      mm. The anterior chamber depth was shallower than that obtained from ultrasound
      biometry. CONCLUSIONS: The EAS-100 is a non-invasive instrument which is
      repeatable for measuring the anterior chamber angle and depth. It provides quick
      results and is good for screening purposes. There is an under-estimation of
      anterior chamber depth, as previously reported.

PMID- 12477021
TI  - Clinical performance of the Reichert AT550: a new non-contact tonometer.
AB  - The aim of the present study was to assess the level of accuracy for measurements
      of intra-ocular pressure (IOP) obtained with a new non-contact tonometer (NCT)
      the Reichert AT550. Measurements were compared against those obtained with the
      Reichert Xpert Plus, Goldmann applanation tonometer and Perkins tonometer. Thirty
      five university students were assessed with the four tonometers in a randomised
      order, with non-contact tonometry performed first. Each of the four measurement
      devices had its own trained clinical observer. Plots of differences of IOP as a
      function of the mean for each pair of instruments were obtained. No statistically
      significant differences were found when comparing the AT550 NCT with contact
      applanation tonometry (AT) (p> 0.05), displaying the closest level of agreement
      (as represented by the lowest mean difference and the narrowest confidence
      interval) with the Goldmann tonometer (limits of agreement, 0.12+/-2.17). In
      conclusion, readings of IOP with the AT550 NCT are clinically comparable with
      those obtained with Goldmann tonometry in a population with IOP within the normal
      range.

PMID- 12477022
TI  - Efficacy of treatment for convergence insufficiency using vision therapy.
AB  - PURPOSE: The purpose of this study was to determine if vision therapy (VT), as
      practised within the constraints of UK optometric practice, employing graded
      routine eye exercises, is as an effective method for treatment of convergence
      insufficiency (CI) as previously published data suggest. The study also evaluates
      the associated symptoms before and after therapy. METHODS: As many optometrists
      diagnose CI solely on the basis of near point of convergence (NPC) and treat only
      when symptoms are present (Letourneau et al., 1979; Rouse et al., 1997), in this
      study CI was defined as NPC of 10 cm or greater (either with or without the
      presence of asthenopic symptoms for near work) accompanied by exophoria greater
      at near than at distance. The effect of treatment by optometric vision therapy
      (OVT) on the NPC and number of symptoms was investigated for 92 patients by
      retrospectively reviewing the clinical records. Success was defined as the
      restoration of NPC to normal values and significant reduction in the presenting
      symptoms. RESULTS: The effect of treatment on the NPC was shown to be highly
      significant (t = 14.61, p < 0.001). Although treatment times were slightly
      longer, the success rates were higher than reported by other authors. Post
      treatment values for NPC were: <10 cm (98.9%), <8.5 cm (95.7%) and <6.5 cm
      (80.4%). Longer treatment times were noted for patients who complained that the
      text appeared to move (chi2, p = 0.007). CONCLUSION: Vision therapy is an
      effective method for treatment of CI.

PMID- 12477023
TI  - Luminescence studies on europium-strontium phthalate system.
AB  - New lanthanide luminescence materials were prepared. The main component
      lanthanide chelates generally need a relatively high content of rare earth.
      Inorganic luminescence materials only need low rare earth concentration using
      doped method. Similarly, lanthanide chelates can be added to complex matrix by
      doped method. In this way, low rare earth concentration emission was successful
      in the lanthanide chelates system as well. The influence of europium ion
      concentration on luminescence intensities was discussed. When the europium ion
      weight in the complex is only about 0.6%, the sample exhibits good luminescence
      properties. The fluorescence, Fourier transform infrared spectra, micro-Raman and
      electron spin resonance spectra of the samples were measured. And a possible
      luminescence mechanism was suggested by the inorganic doped mechanism and the
      luminescence of lanthanide complexes together.

PMID- 12477024
TI  - Preparation and study on the solid inclusion complex of ciprofloxacin with beta
      cyclodextrin.
AB  - The interaction of ciprofloxacin with beta-cyclodextrin (betaCD) has been studied
      by several analytical techniques, including 1H-NMR (nuclear magnetic
      resonance),13C-NMR, fluorescence spectroscopy, infrared (IR) spectroscopy,
      thermal analysis, and scanning electron microscope. In this paper, solid
      inclusion complex of ciprofloxacin with beta-CD was synthesized by the
      coprecipitation method. In addition, the characterization of the inclusion
      complex has been proved by fluorimetry, IR, differential scanning calorimetry and
      1D, 2D NMR. The experimental results confirmed the existence of 1:1 inclusion
      complex of ciprofloxacin with beta-CD. The formation constant of complex was
      determined by fluorescence method and 1H-NMR. Spatial configuration of complex
      has been proposed on two dimensional NMR technique.

PMID- 12477025
TI  - Studies on the hydrogen bonding of aniline's derivatives by FT-IR.
AB  - The hydrogen bonding of 23 aniline's derivatives in various solvents and in solid
      states are studied by Fourier transform infrared spectroscopy. The Infrared
      absorption of their amino group is greatly influenced by solvents. Compared with
      those data determined in hexane, the symmetric stretching frequency (nu(s)) and
      asymmetric stretching frequency (nu(as)) of amino group have an obvious
      bathochromic shift in benzene, but a relatively smaller shift in CCl4. It is also
      found that the concentration of these compounds has very little effect on the
      frequencies, the band shapes and relative absorption intensities of amino group.
      This indicates that the intermolecular hydrogen bonds are very weak between the
      aniline's derivatives in the solution. The substituent of methyl (-CH3) has
      different electronic effects in organic solvents with various polarities. Methyl
      group behaves as an electron-donating functional group in hexane, however, it
      shows an electron-withdrawing effect in benzene. When methoxyl (CH3O-) is ortho
      substituted, v(as) of amino group increases and nu(s) almost does not change.
      While methoxyl (CH3O-) is meta-substituted, v(as) of amino group increases, but
      nu(s) decreases. The groups of chloro- (Cl-) and nitro- (-NO2) cause a
      hyposochromic shift of the nu(as) and nu(s) of amino group, while substituent of 
      NH2 makes a bathochromic shift. The solvents influence the relative intensities
      of nu(as) and nu(s) of amino group more greatly than the substituents do. In
      solid states, the amino group of aniline's derivatives has more than two
      absorption bands because of forming the inter- or intra-molecular hydrogen bonds.

PMID- 12477026
TI  - Surface-enhanced Raman spectroscopy study on the structure changes of 4
      mercaptopyridine adsorbed on silver substrates and silver colloids.
AB  - Surface-enhanced Raman scattering (SERS) of 4-mercaptopyridine (4-mpy) adsorbed
      on HNO3 etched silver foil, chemically deposited silver films (silver mirror) and
      silver colloids were measured. The SERS study has revealed that 4-mpy was
      adsorbed onto the three kinds of silver surfaces by a sulfur-silver bond with the
      plane of pyridine ring being normal to the silver substrates. The structure of 4
      mpy adsorbed on the silver surfaces depends largely on the pH values of
      environment. When the pH values of the environment are changed, the structure of
      4-mpy adsorbed on silver surfaces can easily be altered through a protonation or
      deprotonation reaction occurring on the N atom of the pyridine ring, and the
      modified structure shows unique characters on the SERS spectrum. Owing to the
      remarkable enhancement ability of SERS technique and characteristic spectrum of
      different species, a monolayer of 4-mpy assembled on a silver mirror holds
      potential as a H+ sensor for highly sensitive detection of the proton
      concentration in an aqueous solution.

PMID- 12477028
TI  - Vertical ionisation potentials of a number of crown ethers from charge transfer
      bands of their EDA complexes.
AB  - Vertical ionisation potentials (I(v)D) of a number of crown ethers, viz. dibenzo
      30-crown-10 (Crown 1), benzo-15-crown-5 (Crown 2), dibenzo-24-crown-8 (Crown 3),
      dicyclohexano-24-crown-8 (Crown 4) and 4'-nitrobenzo-15-crown-5 (Crown 5) are
      being reported for the first time from a study of EDA interaction of these crown
      ethers with a number of electron acceptors like C60, C70, o-chloranil, p
      chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and pyromellitic diimide
      (PMD). The study has been carried out in CCl4 medium by electronic absorption
      spectroscopy. Charge transfer (CT) absorption bands in the 360-900 nm range have
      been found in each case (excepting the 60 fullerene-Crown 4 system). The vertical
      ionisation potentials (I(v)D) of all the crown ethers thus determined show a good
      correlation with those calculated by the semiempirical AM1 method. Of the six
      acceptors under study the vertical electron affinity of PMD was not found in the
      literature. This has also been determined from an analysis of the present
      h(nu)(CT) data.

PMID- 12477027
TI  - Flow-injection spectrophotometric determination of periodate and iodate by their
      reaction with pyrogallol red in acidic media.
AB  - A simple and efficient flow-injection method was used with good results to
      determine periodate and iodate in water. The method is based on the reaction of
      periodate or iodate with pyrogallol red in sulfuric acid media. The reaction was
      monitored spectrophotometrically by measuring the decrease in absorbance of
      pyrogallol red at 470 nm. The chemical and FIA variables were established using
      the univariate and simplex optimization methods. The calibration curve was linear
      over the concentration ranges of 0.8-73.0 and 2.0-100.0 microM for IO4- and IO3-,
      respectively. The detection limits were 0.7 and 1.0 microM for IO4- and IO3-,
      respectively. The sample throughput was 20 +/- 5 h(-1). The influence of
      potential interfering ions in the determination of the anions was tested. The
      relative standard deviations for 4.20 and 5.73 microM periodate and iodate were
      1.8 and 2.2%, respectively.

PMID- 12477029
TI  - Modification of kaolinite surfaces through mechanochemical treatment--a mid-IR
      and near-IR spectroscopic study.
AB  - The modification of kaolinite surfaces through mechanochemical treatment has been
      studied using a combination of mid-IR and near-IR spectroscopy. Kaolinite
      hydroxyls were lost after 10 h of grinding as evidenced by the decrease in
      intensity of the OH stretching vibrations at 3695 and 3619 cm(-1) and the
      deformation modes at 937 and 915 cm(-1). Concomitantly an increase in the
      hydroxyl-stretching vibrations of water is observed. The mechanochemical
      activation (dry grinding) causes destruction in the crystal structure of
      kaolinite by the rupture of the O-H, Al-OH, Al-O-Si and Si-O bonds. Evidence of
      this destruction may be followed using near-IR spectroscopy. Two intense bands
      are observed in the spectral region of the first overtone of the hydroxyl
      stretching vibration at 7065 and 7163 cm(-1). These two bands decrease in
      intensity with mechanochemical treatment and two new bands are observed at 6842
      and 6978 cm(-1) assigned to the first overtone of the hydroxyl-stretching band of
      water. Concomitantly the water combination bands observed at 5238 and 5161 cm(-1)
      increase in intensity with mechanochemical treatment. The destruction of the
      kaolinite surface may be also followed by the loss of intensity of the two
      hydroxyl combination bands at 4526 and 4623 cm(-1). Infrared spectroscopy shows
      that the kaolinite surface has been modified by the removal of the kaolinite
      hydroxyls and their replacement with water adsorbed on the kaolinite surface. NIR
      spectroscopy enables the determination of the optimum time for grinding of the
      kaolinite. Further NIR allows the possibility of continual on-line analysis of
      the mechanochemical treatment of kaolinite.

PMID- 12477030
TI  - Vibrational spectroscopy of the basic copper phosphate minerals: pseudomalachite,
      ludjibaite and reichenbachite.
AB  - The vibrational spectra of pseudomalachite, reichenbachite and ludjibaite have
      been obtained at 298 K using a combination of FTIR and Raman microscopy. The
      vibrational spectra of the minerals are different, in line with differences in
      crystal structure and composition. Some similarity in the Raman spectra of the
      three polymorphs pseudomalachite, reichenbachite and ludjibaite exists,
      particularly in the OH stretching region, but characteristic differences in the
      OH deformation regions are observed. Differences are also observed in the
      phosphate stretching and deformation regions.

PMID- 12477031
TI  - The bridging bidentate perchlorato group in ReO3(ClO4), ReO3(ClO4Cl2O6 and
      Sb2Cl6(O)(OH)(ClO4), a vibrational analysis.
AB  - Raman and infrared analysis of the new compounds: ReO3(ClO4), an ivory-white
      solid, and (ClO2)xReO3(ClO4)1+x (x < or = 1), an orange-red chloryl salt, showed
      that bridging bidentate [ClO4] and terminal ReO3 groups are present in both
      complexes. Vibrational data on [ClO4] in ReO3(ClO4) were compared to those
      obtained experimentally and by DFT calculation on a bridging bidentate [ClO4] in
      Sb2Cl6(O)(OH)(ClO4).

PMID- 12477032
TI  - Structural and vibrational study of the Ci(1) conformation of 18-crown-6.
AB  - Optimized geometry, vibrational frequencies and IR absorption intensities were
      calculated for the Ci(1) conformation of 18c6. Optimized geometry was compared
      with the experimental geometry and that of the Ci(2) conformation of 18c6. The
      Ci(1) conformation is more planer than the Ci(2) conformation of 18c6, which
      provides an explanation that free 18c6 in the crystal phase has a Ci(1)
      conformation. Vibrational frequencies were scaled using an unvaried one-scale
      factor scaling of 0.928. Calculated vibrational frequencies were compared with
      the experimental vibrational frequencies. The root-mean-square deviation of the
      difference between the calculated and experimental frequencies was only 15 cm(
      1). This excellent agreement between the calculated and experimental frequencies
      is an indication of the proper assignment of the fundamental vibrational
      frequencies of the Ci(1) conformation of 18c6.

PMID- 12477033
TI  - Photophysical processes of a copolymer containing 1,1'-binaphthyl-2,2'-diamino
      and carbazolyl units.
AB  - The photophysical processes of copolymer formed by copolymerization of 2,2'
      dimethacrylamido-1,1'-binaphthyl (DMBN) with vinylcarbazole (VCZ) have been
      carefully studied. The results show that when the solution of copolymer (DMBN
      VCZ) in THF located in low concentration range (< 10(-3) mg/ml), the fluorescence
      emission is in good agreement with that of DMBN monomer and the excimer is formed
      with gradual increase in concentration of copolymer (DMBN-VCZ). The fluorescence
      of copolymer (DMBN-VCZ) can be quenched both by electron donors and acceptors
      where the quenching effects follow the Stern-Volmer equation. The dimolecular
      exciplex between copolymer (DMBN-VCZ) and N,N-dimethylaniline (DMA) are formed
      and the triple exciplexes are also observed in the same system.

PMID- 12477035
TI  - Neutron spectroscopic study of hydrogen bonding dynamics in L-serine.
AB  - Inelastic incoherent neutron scattering (IINS) spectra were obtained at 10 K for
      normal and deuterated L-serine. The geometry of L-serine molecule was optimized
      for the zwitterion form using ab initio HF, MP2 and DFT (B3LYP) levels with 6
      31G* and 6-311 + +G4** basis sets. The theoretical frequencies of normal and d4-L
      serine were compared with IINS spectra. Normal coordinate analysis and band
      assignments based on ab initio calculations and experimental data were presented.
      IINS frequencies due to the out-of-plane gamma(N-H...O) hydrogen bond motions
      were observed and identified.

PMID- 12477034
TI  - Spectroscopic behavior on the formation complex of three double-armed
      calix[4]arene derivatives with lanthanoid nitrates in acetonitrile.
AB  - The complexation spectroscopic behavior of three p-tert-butylcalix[4]arene Schiff
      bases i.e. 5,11,17,23-tetra-tert-butyl-25,27-bis[2-[N-(3
      nitrobenzylidene)amino]ethoxy]-26,28-dihydroxycalix[4]arene (1), 5,11,17,23-tetra
      tert-butyl-25,27-bis[2-[N-(2-hydroxybenzylidene)amino]ethoxy]-26,28
      dihydroxycalix[4]arene (2), and 5,11,17,23-tetra-tert-butyl-25,27-bis[2-[N-(2
      hydroxy-3-methoxybenzylidene)amino]ethoxy]-26,28-dihydroxycalix[4]arene (3) with
      lanthanoid nitrates (Tb3+ and Eu3+) has been investigated in anhydrous
      acetonitrile at 25 degrees C by using UV-vis and FT-IR as well as fluorescence
      spectra. The results obtained indicated that the spectroscopic behavior of
      compounds 1-2 upon complexation with lanthanoid ions did not show any significant
      larger difference in comparison with free compounds 1 and 2, which may be
      contributed to the poor binding ability. Contrary to compounds 1 and 2, the lower
      rim functional groups in compound 3 can form two large pi electron conjugate
      system with lanthanide ion and encapsulate lanthanide ions tightly, displaying
      the novel spectroscopic behavior upon complexation with lanthanide ions. As
      compared with compound 3, the formation complexes of compound 3 with Tb3+ and
      Eu3+ showed new broad intense absorption at 398 nm, respectively, and IR spectra
      showed that O-H stretching vibration at 3413.40 cm(-1) displayed a large drop. It
      is interestingly noted that the narrow emission line spectra were observed only
      for 3 complex with Tb3+, but did not for 3-Eu3+ complex. In the 3-Eu3+ complex,
      the broad-band emission at lambda(max) = 534 nm was obtained at the excitation of
      398 nm. The spectroscopic behavior of three calix[4]arene derivatives upon
      complexation with lanthanoids was discussed from the relationship between the
      host structure and the properties of guest lanthanide ions.

PMID- 12477036
TI  - Calculation of IR spectra of the elementoorganic dendrimers.
AB  - Various approximations to the analysis of the dendrimer vibrational spectra are
      introduced. The merits and demerits of the fragment method, calculation of the
      first generation and linear chains containing different number of the repeated
      units are discussed. The experimental spectra of two series of the phosphorus
      containing starburst dendrimer generations are interpreted on the basis of the
      calculation of the frequencies of the normal vibrations and the band intensities
      in their IR spectra. The analysis of spectra enables one to assign the
      characteristic bands for the groups in the core, in the repeating unit and the
      terminal groups of the dendrimers. This assignment is supported by the
      calculation of the absorption curves with the force constants and electro-optical
      parameters (EOP). The vibrational spectra of studied starburst dendrimers (SD)
      (up to 11 generations) are in general identical to begin with four generation.
      The most marked changes of band position and their intensities are seen in
      spectra of the first generations, when all fragments of molecule contribute
      appreciably to the spectral pattern. The comparative study of vibrational spectra
      of SD and linear polymers reveal their main characteristic features, which are
      determined by their structural peculiarities.

PMID- 12477037
TI  - Evaluation of the parameters of 1:1 charge transfer complexes from
      spectrophotometric data by non-linear numerical method.
AB  - The non-linear numerical method for evaluation of equilibrium constants and molar
      extinction coefficients of molecular complexes from a spectrophotometric
      experiment is described, which in contrast to linear models has no limitations
      with respect to concentrations of the components. The proposed procedure is
      applied to donor-acceptor interaction in solution between N-ethyl carbazole
      (EtCz) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) or n-hexyl 2,5,7-trinitro-9
      dicyanomethylenefluorene-4-carboxylate (HexDTFC) to evaluate the method and to
      obtain the parameters of charge transfer complexes (CTCs) formation. Association
      constants (K) and molar extinction coefficients (epsilon) of CTCs derived from
      non-linear approach (EtCz-TCNQ: K = 2.49+0.19 M(-1); epsilon = 2950 +/- 160 M(-1)
      cm(-1). EtCz-HexDTFC: K = 12.1 +/- 0.3 M(-1); epsilon = 1335 +/- 24 M(-1) cm(-1))
      are close to that from linear models but show lower standard errors in parameter
      estimations.

PMID- 12477038
TI  - Photochemical reaction monitoring by ultra-violet spectrophotometry.
AB  - Within the framework of the monitoring of the trichloroacetylchloride (TCAC)
      photosynthesis, ultra-violet (UV) spectrophotometry is proposed as a simple and
      rapid tool allowing, in real time, the control of the process efficiency. A good
      correlation has been obtained between the results acquired by this alternative
      method and the standard gas chromatography.

PMID- 12477039
TI  - Unusual luminescence characteristics of aminobiphenyls.
AB  - Analysis of fluorescence solvatochromic shifts of ortho, meta and para
      aminobiphenyls reveals that the change in dipolemoment of m-aminobiphenyl on
      excitation is more when compared to other isomers. This change is due to the
      resonance interaction of unsubstituted phenyl ring with -NH2 group at meta
      position in the excited singlet state. The fluorimetric titration curves of three
      aminobiphenyls are found to be different from each other. The stretched sigmoidal
      curves obtained for m-aminobiphenyl indicates that the rates of proton transfer
      in S1 state are comparable to the rates of fluorescence.

PMID- 12477040
TI  - Spectral investigations on 1,4-dimethylamino anthraquinone under laser
      excitation.
AB  - Surface enhanced Raman spectrum of 1,4-dimethylamino anthraquinone (1,4-DMAAQ)
      adsorbed on silver particles has been analyzed to understand the interaction
      between the molecule and silver surface. By studying the band intensities, the
      orientation of the molecule is determined. The high intensity and frequency
      downshifted peak due to carbonyl stretching vibration plays a major role, which
      shows that the molecules are chemisorbed through coordinating sites. The new
      peaks observed due to C-N and N-H stretching vibrations also provide the evidence
      for adsorption through co-ordinating sites. Optical absorption and laser induced
      fluorescence spectra of this molecule have also been studied in different
      solvents to understand the effect of environment. Polarization and anisotropy
      measurements provide the change in orientation induced by solvent molecules
      between absorption and emission transition dipoles.

PMID- 12477041
TI  - Paramagnetic resonance in imidazolate-bridged homobinuclear (copper-copper) and
      heterobinuclear (copper-zinc) complexes.
AB  - Bridged homobinuclear (copper-copper) and heterobinuclear (copper-zinc) complexes
      of diethylenetriamine have been prepared with 2-methyl-imidazole as bridging
      ligand. EPR spectra of the polycrystalline complexes have been studied at room
      temperature and also at liquid nitrogen temperature. Low temperature EPR and
      electronic spectroscopic studies of 50% aqueous DMSO of [(dien)Cu-(Melm)
      Zn(dien)]3+ solutions show the imidazolate bridged complex to exist mainly over
      the pH range approximately 7.0 < pH < 10.0. At low pH the 2-MelmH+ ion and
      mononuclear copper and zinc complexes are formed. Above pH > 10.0 hydroxide ion
      splits the imidazolate bridge.

PMID- 12477042
TI  - Solvent and concentration effects on the visible spectra of tri-para-dialkylamino
      substituted triarylmethane dyes in liquid solutions.
AB  - We have characterized the spectroscopy properties of crystal violet (CV+) and
      ethyl violet (EV+) in liquid solutions as a function of the solvent type and dye
      concentration. The analysis of how solvent properties and dye concentration
      affects the electronic spectra of these tri-para-dialkylamino substituted
      tryarylmethane (TAM+) dyes was performed on the basis of two spectroscopic
      parameters, namely the difference in wavenumber (deltanu) between the maximum and
      the shoulder that appears in the short-wavelength side of the respective maximum
      visible band (deltanu = 1/lambda(shoulder)-1/lambda(max) cm(-1)), and the
      wavelength of the maximum absorption (lambda(max)). The solvent and the
      concentration effects on lambda(max) and deltanu have indicated that both
      solute/solute (ion-pairing and dye aggregation) and solute/solvent (H-bonding
      type) interactions modulate the shape of the visible electronic spectra of these
      dyes in solution. In solvent with small dieletric constant (epsilon <
      approximately 10), the formation of ion-pairs represents a major contribution to
      the shaping of these spectra. Upon increasing dye concentration the formation of
      ion-pairs was characterized by an increase in deltanu observed concomitantly with
      a red shift in lambda(max) In chloroform and chlorobenzene the ion-pair
      association constant of CV+ and EV+ with Cl- ions were found to be in the order
      of 10(6) and 10(5) M(-1), respectively. In trichloroethylene the association
      constant for the CV+Cl- pair was 10(8) M(-1). In water, dye aggregation instead
      of ion-pairing represents a major contribution to the shaping of the visible
      spectra of CV+ and EV+. Dye aggregation was indicated by an increase in deltanu
      observed concomitantly with a blue shift in lambda(max) upon increasing dye
      concentration. The distinct behavior of deltanu for dye aggregation and ion
      pairing as a function of dye concentration can therefore assist in the
      characterization of these two distinct phenomena. The solute/solvent interactions
      were studied in a series of polar solvents in which solute/solute interactions do
      not occur in any detectable extent. The dependence found for deltanu as a
      function of the Kamlet-Tafts solvatochromic parameters (alpha, beta and pi*) is
      in keeping with previous inferences indicating that the splitting in the
      overlapped absorption band of CV+ and EV+ in hydroxilated solvents arises from a
      perturbation in the molecular symmetry induced by hydrogen bonding (donor
      acceptor) type interactions with solvent molecules. A distinction between the
      effects of solute/solute and solute/solvent interactions on the visible spectra
      of these dyes is provided.

PMID- 12477043
TI  - Interactions of cyclodextrins with aromatic compounds studied by vibrational
      circular dichroism spectroscopy.
AB  - The host/guest complexation between cyclodextrins (CDs) and aromatic compounds
      was studied by vibrational circular dichroism (VCD) spectroscopy in mid-IR
      region. Benzoic acid, 4-aminobenzoic acid, and 2,6-naphthalene-dicarboxylic acid
      acting as the guests with aromatic skeleton, cause the significant changes in VCD
      patterns of CD, which indicate that the secondary hydroxyl groups of the CDs are
      involved in the host/guest complexation. In addition, the intensities and
      dissymmetry factors (deltaA/A) of the VCD bands, which belong to skeletal CD
      vibrations, depend on the sizes of the guest molecules. Our results indicate that
      the formation of the CD inclusion complexes can be followed by VCD spectroscopy.

PMID- 12477044
TI  - Infrared spectra of permanganate anions in potassium perchlorate matrices:
      vibrational anharmonicity, effective symmetry and vibrational mode mixing
      effects.
AB  - Fourier transform infrared spectra of MnO4- anions isomorphously isolated in
      potassium perchlorate matrices were recorded at room and low temperature (LT,
      approximately 100 K). On the basis of the detected second-order vibrational
      transitions involving the dopant species nu3 mode components, anharmonicity
      constants and harmonic eigenvalues for these modes were calculated. Despite the
      fact that, rigorously speaking, the appearance of the spectra of dopant
      permanganate anions may be explained in terms of a Cs site symmetry, the nu3
      stretching region resembles an approximate A1+E splitting (characteristic for a
      local C3nu or even higher symmetry), which is not expected, even within the
      latent symmetry approach. We explain such spectral patterns on the basis of
      vibrational mode mixing (a 'Fermi-like' resonance) of the MnO4- nu1 mode with the
      nu3, site-group component. With the results of degenerate case stationary
      perturbation theory, we show that in the present case the Fermi-like resonance is
      predominantly responsible for the observed spectral features. The appearance of
      the region of second-order vibrational transitions in the spectra of dopant
      permanganate anions may be better explained in terms of the (rigorous)
      crystallographic Cs site group (corresponding to the crystallographic Pnma space
      group), instead of the 'latent' (effective) symmetry site group C2nu
      (corresponding to the latent symmetry space group Imma).

PMID- 12477045
TI  - Stereochemistry of new nitrogen containing heterocyclic aldehyde. VIII. Spectral
      and coordination modes of mixed-ligand of novel ruthenium(III) complexes.
AB  - Reaction of 8-hydroxy-7-quinolinecarboxaldehyde (LH) with RuC3 x XH2O afforded
      the compounds [RuL3] and/or [RuL2CIOH2]. Reactions of LH with RuCl3 x XH2O in the
      presence of N-heterocyclic bases led to the formation of complexes of type [RuL2
      x ClPy] and [RuLCl2(o-Phen)] (Py = pyridine or o-Phen = 1,10-phenanthroline). The
      amine exchange reactions of coordinated Schiff bases in these complexes have been
      also carried out which give symmetrical tetradentate Schiff base complexes. These
      complexes were characterized by a combination of elemental analysis, IR, magnetic
      susceptibility measurements, 1H, 13C NMR and electronic spectral analysis
      methods. The spectral data were utilized to compute the important ligand field
      parameters B, beta and Dq. Electronic spectra show all complexes are octahedral.
      The B-values suggest a strong covalency in the metal-ligand sigma-bond and the Dq
      values indicate a medium-strong ligand field. The stereochemistry and the nature
      of the complexes are markedly dependent upon the molar ratios of the reactants,
      the pH of the system and the nature of the anions involved. The ligands behave as
      bi-(0,0) and tetradentate (N2,O2) donors.

PMID- 12477046
TI  - Fluorescence decay of singlet excited-state of safranine T and its interaction
      with ground-state of pyridinthiones in micelles and homogeneous media.
AB  - The fluorescence decays of safranine T were studied in different homogeneous
      solvents and heterogeneous micellar solutions. It has been found that
      micellization leads to an increase in the lifetime. The lifetime distributions
      were studied in micelles and homogeneous media. It was found that the different
      half-width distributions of the dye in different micelles are related to the
      different orientation of the dye in different micelles. Also, the fluorescence
      quenching of safranine T by 4,6-disubstituted-3-cyanopyridin-2(1H)-thiones was
      studied in chloroform, methanol and acetonitrile as well as in different
      micelles. In heterogeneous media the kq values for quenching of safranine T by
      thiones in various micelles increase on the following order: kq(CTAB) < kq(TX
      100) < kq(SDS). This is due to the electrostatic interactions between the anionic
      SDS and the cationic moiety of safranine T and therefore the quenching process
      will be less significant.

PMID- 12477047
TI  - Harmonic dynamics of beta-D-fructopyranose.
AB  - The vibrational spectra of beta-D-fructopyranose crystals have been recorded in
      the 4000-400 cm(-1) region using the infrared and in the 4000-20 cm(-1) region
      using the Raman. These spectra are used as an experimental basis in order to
      establish a force field for the beta-D-fructopyranose molecule in the crystalline
      state through a normal co-ordinates analysis. For this purpose, a modified Urey
      Bradley-Shimanoushi force field was combined with an intermolecular potential
      energy function that includes the van-der-Walls interactions, the electrostatic
      terms, and an explicit hydrogen bond function. The force field parameters are
      derived from those of beta-D-glucose and are fitted so as to obtain a good
      agreement between the calculated and the observed frequencies. The results
      obtained demonstrate the reliability and the transferability of the set of
      parameters constituting the initial force field. The fitted force field
      reproduces the experimental spectra to a marked degree of accuracy.

PMID- 12477048
TI  - Cyclotides: a novel type of cytotoxic agents.
AB  - Cytotoxic activities of three naturally occurring macrocyclic peptides
      (cyclotides) isolated from the two violets, Viola arvensis Murr. and Viola
      odorata L., were investigated. A nonclonogenic fluorometric microculture assay
      was used to examine cytotoxicity in a panel of 10 human tumor cell lines
      representing defined types of cytotoxic drug resistance. Additionally, primary
      cultures of tumor cells from patients, and for comparison normal lymphocytes,
      were used to quantify cytotoxic activity. All three cyclotides, varv A, varv F,
      and cycloviolacin 02, exhibited strong cytotoxic activities, which varied in a
      dose-dependent manner. Cycloviolacin 02 was the most potent in all cell lines
      (IC50 0.1-0.3 microM), followed by varv A (IC50 2.7-6.35 microM) and varv F (IC50
      2.6-7.4 microM), respectively. Activity profiles of the cyclotides differed
      significantly from those of antitumor drugs in clinical use, which may indicate a
      new mode of action. This, together with the exceptional chemical and biological
      stability of cyclotides, makes them interesting in particular for their potential
      as pharmacological tools and possibly as leads to antitumor agents.

PMID- 12477049
TI  - Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity.
AB  - Deoxycytidine kinase (dCK) is essential for the phosphorylation of gemcitabine
      (2',2'-difluorodeoxycytidine), a deoxycytidine analogue active against various
      solid tumors. Cytidine deaminase (CDA) catalyzes the degradation of gemcitabine.
      We determined whether dCK and/or CDA levels would predict response to
      gemcitabine. Activities of dCK and CDA were measured in a panel of eight
      gemcitabine-sensitive and -resistant tumors of a different origin (pancreas,
      lung, colon, ovary, and head and neck) grown as s.c. tumors in mice. Sensitivity
      to gemcitabine was expressed as treated versus control (tumor volume treated
      mice/control mice). Gemcitabine was given on days 0, 3, 6, and 9 (q3dx4) at its
      maximum tolerated dose. In addition, we measured the mRNA expression and protein
      levels of dCK in seven human tumor xenografts. dCK activity (mean +/- SE) ranged
      from 3.3+/-0.3 to 18.4+/-1.2 nmol/h/mg protein. Sensitivity to gemcitabine,
      expressed as treated versus control, ranged from 0.98 to 0.02, and the activity
      of CDA varied from 2+/-2 to 411+/-4 nmol/h/mg protein. In contrast to CDA, dCK
      activity was clearly related to gemcitabine sensitivity (p = -0.93; P < 0.001).
      This indicates that dCK might be an important prognostic marker for gemcitabine
      sensitivity. Protein levels were significantly related to both dCK activity (r =
      0.96; P < 0.001) and gemcitabine sensitivity (rho = -0.96; P < 0.001). dCK
      expression as determined by competitive template reverse transcriptase PCR was
      significantly related with the dCK activity (r = 0.88; P = 0.025) and protein
      levels (p = 0.80; P = 0.052) but not with gemcitabine sensitivity, suggesting a
      post-translational regulation of dCK. In conclusion, the clear correlation
      between dCK levels and gemcitabine sensitivity in various murine tumors and human
      tumor xenografts may be a prognostic parameter when considering gemcitabine
      therapy.

PMID- 12477050
TI  - Inhibition of cell growth by NB1011 requires high thymidylate synthase levels and
      correlates with p53, p21, bax, and GADD45 induction.
AB  - NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is
      a novel small molecule anticancer agent. NB1011 is selectively active against
      tumor cells expressing high levels of thymidylate synthase (TS), a critical
      enzyme in DNA biosynthesis. NB1011 is different from the current TS-targeted
      drugs, which require inhibition of TS to be effective, because NB1011
      cytotoxicity depends upon activation by TS. Here we report a dose-dependent,
      antitumor activity of NB1011 against established Tomudex-resistant breast cancer
      (MCF7TDX) xenografts in athymic mice. Against 5-fluorouracil-resistant colon
      carcinoma (H630R10) xenografts, NB1011 was as efficacious as irinotecan, a drug
      recently approved for the treatment of 5-fluorouracil-resistant colon cancer. To
      gain insight into the mechanisms NB1011 uses to suppress cellular growth, we
      analyzed the downstream molecular events in the high TS-expressing MCF7TDX and
      RKOTDX cell lines upon NB1011 treatment. NB1011 treatment increased the mRNA
      levels of p21, Bax, and GADD45. Furthermore, NB1011 induced p53, p21, and Bax
      proteins specifically in high TS-expressing tumor cells, whereas no induction was
      observed in low TS-expressing tumor cells (MCF7) or normal cells (WI38). Cell
      cycle analysis demonstrated that NB1011 treatment of MCF7TDX and RKOTDX cells
      resulted in an accumulation of cells in the G2-M phase of the cell cycle.
      Altogether, our data indicate that the induction of the p53 target genes p21,
      bax, and GADD45, with a concomitant deregulation of the cell cycle, may represent
      one of the mechanisms by which NB1011 exerts its growth-suppressive effects.

PMID- 12477051
TI  - Transcriptional repression of ErbB2 by histone deacetylase inhibitors detected by
      a genomically integrated ErbB2 promoter-reporting cell screen.
AB  - The antitumor activity of histone deacetylase (HDAC) inhibitors has been linked
      to gene expression induced by acetylation of histone and nonhistone proteins; but
      the molecular basis for their antitumor selectivity remains largely unknown. With
      development of a genomically integrated, ErbB2 promoter-reporting breast cancer
      cell screen, ErbB2 promoter inhibiting activity was observed by the HDAC
      inhibitors trichostatin A (TSA) and sodium butyrate. Paradoxically, these agents
      stimulated the episomal form of this ErbB2 promoter-reporter introduced by
      transient transfection. Transcriptional run-off assays in ErbB2 amplified and
      overexpressing breast cancer cells confirmed that within 5 h, TSA exposure
      profoundly inhibits ErbB2 transcript synthesis from the amplified oncogene yet
      preserves transcription from single copy genes such as the epithelial-specific
      Ets family member, ESX. Northern analyses of ErbB2-overexpressing breast cancer
      lines (SKBR3, BT-474, and MDA-453) showed that within 24 h of submicromolar
      treatment by TSA, ESX transcript levels increase while ErbB2 transcript levels
      rapidly decline, with no TSA effect apparent on the open chromatin configuration
      of either gene as monitored by DNase I hypersensitivity. Actinomycin D studies
      confirmed that in addition to inhibiting ErbB2 transcript synthesis, TSA
      selectively destabilizes mature ErbB2 transcripts enhancing their decay. Whereas
      TSA markedly reduced ErbB2 protein levels in these overexpressing cell lines, TSA
      treatment of MCF/HER2-18 cells engineered to overexpress the ErbB2 receptor under
      control of a heterologous promoter increased their expression of ErbB2 protein.
      These findings suggest that further studies are warranted to determine whether
      ErbB2-positive human cancers represent unusually sensitive clinical targets for
      HDAC inhibitor therapy.

PMID- 12477052
TI  - CP248, a derivative of exisulind, causes growth inhibition, mitotic arrest, and
      abnormalities in microtubule polymerization in glioma cells.
AB  - Exisulind (sulindac sulfone) and two potent derivatives, CP248 and CP461, have
      been shown previously to cause growth inhibition and apoptosis in several types
      of human carcinoma cell lines. These and related compounds have not been
      previously studied with respect to glioma cell lines. In the present study, we
      found that these three compounds caused marked growth inhibition in four rat
      glioma and eight human glioma cell lines, with IC50 values of 150, 1, and 0.075
      microm, respectively. When studied at these concentrations exisulind and CP461
      had no significant effect on the cell cycle profile of glioma cells, but CP248
      caused marked arrest in mitosis. Detailed studies of CP248 in the 9L rat
      gliosarcoma cell line indicated that treatment with 0.075 microM CP248 caused
      abnormalities in the spindle apparatus and activation of the spindle assembly
      check point. In interphase glioma cells, CP248 stabilized microtubules (MTs) at
      low concentrations (0.075 microM) and depolymerized MTs at higher concentrations
      (0.2-0.4 microM). In NIH 3T3 fibroblasts, 0.1 microM CP248 caused extensive MT
      depolymerization. CP248 also caused MT depolymerization when added to assembled
      MTs in vitro, which indicated that it can directly affect MTs, perhaps because it
      shares certain structural similarities with Colcemid. In glioma cells, the
      effects of CP248 on MTs were independent of the previously reported effects of
      this compound on activation of protein kinase G. Therefore, CP248 is a novel MT
      active agent that may be useful in the treatment of glioblastoma, and possibly
      other types of cancer, because of its dual effects on protein kinase G and MTs.

PMID- 12477053
TI  - Coordinate late expression of trefoil peptide genes (pS2/TFF1 and ITF/TFF3) in
      human breast, colon, and gastric tumor cells exposed to X-rays.
AB  - The trefoil factors (TFFs) are pleiotropic factors involved in organization and
      homeostasis of the gastrointestinal tract, estrogen responsiveness, inflammatory
      disorders, and carcinogenesis. In an earlier study using cDNA array technologies
      to identify new genes expressed in irradiated cell survivors, we isolated a cDNA
      clone corresponding to the reported human TFF1 gene (E. K. Balcer-Kubiczek et
      al., Int. J. Radiat. Biol., 75: 529-541, 1999). To determine whether expression
      of other TFFs is altered by ionizing radiation, we quantified changes in
      expression of TFF3 as well as TFF1 in RNA samples obtained from irradiated and
      control human tumor breast, colon, and gastric tumor cells and examined
      expression kinetics up to 2 weeks after irradiation. X-ray-induced TFF1 and TFF3
      expression profiles were compared with those induced by hydrogen peroxide (H2O2)
      or 17beta-estradiol (ES). The results revealed that TFF1 and TFF3 mRNA are
      coinduced by X-irradiation in a subset of the lines, but substantial
      heterogeneity in their responses was observed in cells derived from a single cell
      type. TFF1 and TFF3 transcriptional response to X-irradiation differed from that
      to H2O2 or ES in the timing of their induction as well as tissue-type dependence,
      i.e., their induction pattern after X-irradiation was late and sustained, whereas
      their induction by H2O2 or ES was early and transient. TFF1 mRNA, protein
      production in the cytoplasm, and secretion in the culture supernatant were
      coordinately regulated after X-irradiation. There was no requirement for TP53 in
      this induction. These results demonstrate the existence of a novel class of
      radiation-responsive genes that might be involved in bystander effects.

PMID- 12477055
TI  - Multidrug resistance and pharmacological protection mediated by the breast cancer
      resistance protein (BCRP/ABCG2).

PMID- 12477054
TI  - Potent and specific inhibition of the breast cancer resistance protein multidrug
      transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin
      C.
AB  - Inhibitors of the breast cancer resistance protein (BCRP/ABCG2) multidrug
      transporter are of interest as chemosensitizers for clinical drug resistance, for
      improving the pharmacokinetics of substrate chemotherapeutic drugs, and in
      functional assays of BCRP activity for tailoring chemotherapy. The fungal toxin
      fumitremorgin C (FTC) is a potent and specific inhibitor of BCRP, but its
      neurotoxic effects preclude use in vivo. We have therefore evaluated a new
      tetracyclic analogue of FTC, Ko143, as a practical inhibitor of BCRP, comparing
      it with two other analogues in the same class and with GF120918. All three FTC
      analogues are effective inhibitors of both mouse Bcrp1 and human BCRP, proving
      highly active for increasing the intracellular drug accumulation and reversing
      Bcrp1/BCRP-mediated multidrug resistance. Indeed, Ko143 appears to be the most
      potent BCRP inhibitor known thus far. In contrast, the compounds have only low
      activity against P-glycoprotein, the multidrug resistance-associated protein
      (MRP1), or other known drug transporters. They are nontoxic in vitro at useful
      concentrations and evinced no signs of toxicity in mice at high oral or i.p.
      doses. Administered p.o. to inhibit intestinal Bcrp1, Ko143 markedly increased
      the oral availability of topotecan in mice. It is thus the first highly potent
      and specific BCRP inhibitor applicable in vivo. As such, Ko143 and other FTC
      analogues of this type represent valuable reagents for analysis of drug
      resistance mechanisms and may be candidates for development as clinical BCRP
      inhibitors.

PMID- 12477056
TI  - Conditionally replicative adenoviruses for ovarian cancer therapy.
AB  - The purpose of this review article is to present a logical rationale for the
      investigation of conditionally replicative adenoviral vectors for the treatment
      of ovarian carcinoma. A medline database search was performed to identify
      relevant articles in the English language for the years 1966 to present. The key
      words used included replicative adenovirus, conditionally replicative adenovirus,
      transcriptional targeting, replication selective adenovirus, and "ONYX." A total
      of 89 references were identified and reviewed. Each reference was reviewed for
      relevance to clinical translation of conditionally replicative adenoviral vector
      therapy for ovarian cancer. Data from current clinical trials would suggest that
      potential obstacles for effective replicative viral therapy of ovarian carcinoma
      include efficient tumor cell infection, restrictions of the cell surface
      coxsackie and adenovirus receptor, rapid clearance of vector in the ascites
      environment, tumor cells specificity, and limitations of current findings of
      clinical trials. The articles were, therefore, evaluated and included if they
      addressed these shortcomings. Current data would suggest that advanced generation
      conditionally replicative adenoviral vectors will soon be available for clinical
      trials in ovarian cancer. Ovarian cancer, because of expression of targetable
      receptors, transducible cells, and containment within the i.p. cavity, represents
      a solid tumor suited uniquely for investigation with advanced generation
      conditionally replicative adenoviral vectors.

PMID- 12477057
TI  - Salivary gland delivery of pDNA-cationic lipoplexes elicits systemic immune
      responses.
AB  - OBJECTIVE: To test the ability of two cationic lipoplexes, Vaxfectin and GAP
      DLRIE/DOPE, to facilitate transfection and elicit immune responses from plasmid
      DNAs (pDNAs) after retrograde instillation into salivary glands. METHODS: Two
      pDNA expression vectors encoding either the influenza NP protein or human growth
      hormone (hGH) were complexed with the cationic lipid transfection reagents, GAP
      DLRIE/DOPE or Vaxfectin, and delivered to the submandibular glands of rats.
      Samples from rats receiving the influenza NP protein pDNA and cationic lipoplexes
      were analyzed for anti-influenza NP-specific IgG1, IgG2a, and IgG2b in serum, and
      IgA in saliva, by an enzyme- linked immunosorbent assay (ELISA). Cytotoxic T-cell
      lymphocyte (CTL) assays were also performed. Transgene protein expression (hGH)
      was determined from extracts of submandibular glands of rats receiving hGH
      lipoplexes. RESULTS: Serum antibodies (IgG) against the NP protein developed and
      were highest in all rats vaccinated with GAP-DLRIE/DOPE or Vaxfectin. The major
      serum IgG subclass stimulated by this route of immunization was IgG2b, followed
      by IgG2a. CTL assay results showed statistically significantly higher percentage
      killing in the Vaxfectin group than controls (P < 0.05). No rats developed IgA
      antibodies to NP protein in saliva. Animals receiving plasmid encoding hGH and
      either lipoplex expressed significantly higher amounts of hGH compared with those
      receiving the hGH plasmid and water. Although hGH expression was higher in the
      animals receiving pDNA/Vaxfectin (approximately 30-fold > pDNA/water), the
      difference with those receiving pDNA/GAP-DLRIE/DOPE (approximately 10-fold >
      pDNA/water) was not significant. CONCLUSIONS: Retrograde instillation of pDNA
      complexed with Vaxfectin into the salivary glands can stimulate cytotoxic and
      humoral responses to the influenza NP protein antigen. Optimization of the
      conditions required to stimulate humoral and secretory antibody formation may
      facilitate use of this tissue for specific clinical applications of pDNA
      immunization.

PMID- 12477058
TI  - Salivary IgA and IgG subclasses in oral mucosal diseases.
AB  - OBJECTIVE: It was hypothesized that serum levels of immunoglobulins may play a
      role in the pathogenesis of oral mucosal diseases, or reflect clinical changes in
      these conditions, but little is known about the role of salivary immunoglobulins
      in the pathogenesis of these diseases. The aim of this study was to investigate
      possible alterations in salivary immunoglobulin A (IgA) and IgG subclasses in
      patients with oral mucosal inflammatory diseases. SUBJECTS AND METHODS: Levels of
      IgG1, IgG2, IgG3 and IgG4 were determined by enzyme-linked immunosorbent assay
      (ELISA), and IgA1 and IgA2 by radial immunodiffusion in the resting whole saliva
      of 31 patients with acute recurrent aphthous ulceration (RAU) (and followed in
      remission), 11 patients with chronic hyperplastic candidal infection (CHC), 12
      patients with Sjogren's syndrome (SS), six patients with oral lichen planus
      (OLP), and 18 healthy volunteers using the normal saliva as a comparison point
      for all. RESULTS: IgG and IgA subclasses were increased in OLP. In CHC all IgG
      subclasses were increased while IgA1 was decreased, IgG1, IgG3 and IgG4 levels
      were increased in SS, while all IgG subclasses as well as IgA2 were increased in
      acute RAU in comparison with healthy controls. No differences in any
      immunoglobulin subclasses between major and minor acute RAU were found. In
      remission, IgG1 and IgG4 returned to normal values while IgG2, IgG3, and IgA2
      remained increased in patients with RAU. CONCLUSION: Salivary immunoglobulin
      subclasses vary in different oral mucosal conditions and may play a role in oral
      mucosal inflammatory diseases and/or reflect clinical changes in these
      conditions.

PMID- 12477059
TI  - Sialochemistry in juvenile idiopathic arthritis.
AB  - OBJECTIVES: To investigate whether there are any differences in salivary flow
      rates and saliva composition that may contribute to the reported increase in
      caries prevalence in patients with juvenile idiopathic arthritis (JIA). DESIGN:
      Randomized controlled trial. SETTING: The sialochemistry of children with JIA has
      rarely been investigated. METHODS: Unstimulated and stimulated whole saliva was
      collected from 17 randomly selected JIA patients and 17 age and sex matched
      controls. Both samples were analysed for salivary flow rate, pH, calcium and
      phosphate. RESULTS: Unstimulated and stimulated JIA saliva flow rates, and the
      flow rate change from unstimulated to stimulated in JIA saliva were all
      significantly lower than the controls. There were no significant differences in
      the pH of unstimulated and stimulated JIA saliva compared with the controls,
      however, the change in pH (from unstimulated to stimulated) in the study group
      was significantly greater. The JIA patients had non-significantly lower levels of
      both calcium and phosphate ions in the unstimulated and stimulated samples.
      CONCLUSIONS: This data would suggest that there is both a reduced resting
      salivary flow and a reduced response to stimulation in JIA patients, which may
      contribute to a previously reported higher caries prevalence.

PMID- 12477060
TI  - Oral lichen planus: a preliminary clinical study on treatment with tazarotene.
AB  - OBJECTIVE: The rationale for using tazarotene in oral lichen planus (OLP) is its
      regulatory action on the growth and differentiation of keratinocytes and on
      inflammation. This randomized, placebo-controlled study addresses evaluation of
      the effects of topic tazarotene in the treatment of OLP. DESIGN: The degree of
      lesions before and after treatment scored by a 6-score scale in six cases treated
      with tazarotene was statistically compared with those of six controls treated
      with placebo. SUBJECTS: Twelve patients with hyperkeratosic OLP were randomly
      allocated to treatment with tazarotene gel 0.1% b.i.d. or with placebo for eight
      consecutive weeks. METHODS: The statistical comparison was executed by means of
      Wilcoxon analysis for paired data. RESULTS: Patients treated with tazarotene
      presented a significant reduction of their lesions as compared with the control
      group. Among transitory side-effects, burning sensation and taste abnormalities
      were observed. CONCLUSION: Topical tazarotene may be a valuable therapeutic tool
      in the treatment of hyperkeratotic OLP.

PMID- 12477061
TI  - Oral status, cognitive and functional capacity versus oral treatment need in
      nursing home residents: a comparison between assessments by dental and ward
      staff.
AB  - OBJECTIVES: The aim of this study was to study the relationships between
      cognitive and functional capacity versus oral health and treatment need and to
      compare oral status assessments and oral treatment need, assessed by nurses and
      dental professionals, respectively. DESIGN: Cross-sectional survey. SETTING:
      Nursing home. SUBJECTS: One hundred and ninety-two nursing home residents were
      examined in 1997. MAIN OUTCOME MEASURES: Cognitive and functional capacity in
      different groups of residents regarding oral health and treatment need, measured
      by a comprehensive assessment with the Resident Assessment Instrument (RAI) and
      dental status in a separate examination protocol, recorded by a dentist. RESULTS:
      There was a significant correlation between being dentate and having need of oral
      treatment. Those who were able to chew also had significantly better cognitive
      and functional capacity. Oral treatment need was identified most often by the
      dentist, intermediately by the RAI assessment and least frequently by the
      residents themselves. CONCLUSIONS: Being dentate and having a loss of cognitive
      and functional capacity is predictive of oral treatment need among nursing home
      residents. Enhanced interaction between nurses and dental professionals needs to
      be promoted for better awareness of preventive measures and better regular oral
      care for frail and dependent elderly persons.

PMID- 12477062
TI  - Recurrent aphthous stomatitis and gene polymorphisms for the inflammatory markers
      TNF-alpha, TNF-beta and the vitamin D receptor: no association detected.
AB  - OBJECTIVE: To investigate the possibility that minor recurrent aphthous
      stomatitis (MiRAS) is associated with the inheritance of specific gene
      polymorphisms for markers associated with macrophage driven inflammation, i.e.
      tumor necrosis factor-alpha (TNF-alpha), TNF-beta or the vitamin D receptor
      (VDR). SETTING: MiRAS is a common, painful, ulcerative condition of the mouth.
      Its etiology is unknown although mononuclear inflammatory cells are thought to
      play an important role. There is no clear genetic mode of inheritance, however,
      many patients report a positive family history and disease concordance is
      significantly higher in monozygotic than dizygotic twins, suggesting a polygenic
      mode of inheritance. METHODS: Ninety-five MiRAS patients and an ethnically
      matched control population were genotyped for TNFA-308, TNFB Ncol and VDR (intron
      8 and exon 9) polymorphisms. Chi-square analysis was used to compare the allele
      frequencies and genotypes of cases and controls. RESULTS: No significant
      association was identified between inheritance of specific alleles or genotypes
      of the TNFA-308, TNFB Ncol and VDR (intron 8 and exon 9) polymorphisms and
      susceptibility to MiRAS. CONCLUSIONS: Inheritance of specific gene polymorphisms
      for TNF-alpha, TNF-beta or VDR does not appear to be a significant factor in
      determining susceptibility to MiRAS.

PMID- 12477063
TI  - Congenital sinus of the upper lip with idiopathic precocious puberty.
AB  - An extremely rare case of congenital sinus of the upper lip is presented in a 22
      year-old woman with idiopathic precocious puberty. The sinus has a pin-like
      orifice located in the midline of the upper lip philtum just below the base of
      the columella. Sexual precocity was found out when she was 7 years old. A series
      of exact examinations had been performed at that time. Neither neurogenic lesions
      of the central nervous system nor other systemic abnormalities were observed.
      Oral Diseases

PMID- 12477064
TI  - Lichen sclerosus et atrophicus manifesting with localized loss of periodontal
      attachment.
AB  - Lichen sclerosus et atrophicus (LSA) is a chronic mucocutaneous inflammatory
      disorder of uncertain aetiology that is clinically characterized by the
      appearance of well delimited white plaques or papules, preferentially affecting
      the skin and genitals, and more rarely the oral cavity. We present the case of a
      woman with LSA limited to the oral cavity in the form of a well delimited, flat
      whitish lesion affecting the vestibular gingiva of the right upper incisors and
      left central incisor, and extending towards the vestibular fundus and frenulum of
      the upper lip. Widening of the periodontal space was observed, with gingival
      recession and attachment loss limited to these teeth. Local corticosteroid
      injections caused the mucosal lesion but not the periodontal alterations to
      resolve. Emphasis is placed on the importance of knowledge of this condition in
      relation to establishing a diagnosis, and on its periodontal repercussions.

PMID- 12477065
TI  - Oral solitary fibrous tumour.

PMID- 12477066
TI  - Evaluating qualitative assays using sensitivity and specificity.
AB  - Sensitivity and specificity are two important indices of performance of
      qualitative assays. Evaluating these indices usually requires one to identify the
      true disease state of each subject involved in a study. This implies that a
      perfect test, a "gold standard," is needed to test each subject. However, a gold
      standard test cannot always be performed on all subjects, whether because of cost
      or adverse effect on a subject's welfare. In these situations, a common practice
      is to apply both a currently used assay and an investigational assay to the same
      specimen. If the testing results are discordant, a gold standard test is applied.
      This approach has been criticized by many and, in fact, the statistics based on
      this approach usually overestimate sensitivity and specificity. This paper
      proposes two alternative methods to estimate sensitivity and specificity.
      Simulation results show that these methods perform better than the commonly used
      existing ones. This paper proposes new acceptance criteria and designs to
      specific topics for the evaluation of blood related assays as well. To evaluate a
      qualitative assay related to blood specimens, one must also perform studies of
      storage conditions, interfering substances, and other related factors, in order
      to establish the equivalency of the assay under standard and various other
      conditions. To conduct these studies, true negative blood donor specimens are
      used as a sample from a nondiseased population; and blood donor specimens with
      spiked analyte are used to represent a sample from a diseased population.
      Currently, the target-spiking ranges and sample sizes are determined
      subjectively. This paper presents new acceptance criteria on acceptable
      conditions and objective standards for selecting the target-spiking range and
      sample size.

PMID- 12477067
TI  - On the joint analysis of longitudinal responses and early discontinuation in
      randomized trials.
AB  - Our focus is on the joint analysis of longitudinal nonnormal responses and early
      discontinuation in (pre)-clinical trials. Separate models are fitted to the two
      series (response and discontinuation) to account for covariate and time effects.
      The serial dependence and the dependence between response and drop-out are also
      modeled. This is done using particular dependence functions, called copulas.
      Copulas are used to create a joint distribution with given marginal
      distributions. Applications are given for the analysis of heart rate/morbidity in
      toxicology and pain severity/intake of rescue medications in a trial on migraine.
      Using copulas, the level of dependence between two variables remains invariant to
      changes in the marginal distribution of either variable. This proves interesting
      in modeling the association in a longitudinal setting when responses change over
      time.

PMID- 12477068
TI  - A note on sample size calculation for mean comparisons based on noncentral t
      statistics.
AB  - One-sample and two-sample t-tests are commonly used in analyzing data from
      clinical trials in comparing mean responses from two drug products. During the
      planning stage of a clinical study, a crucial step is the sample size
      calculation, i.e., the determination of the number of subjects (patients) needed
      to achieve a desired power (e.g., 80%) for detecting a clinically meaningful
      difference in the mean drug responses. Based on noncentral t-distributions, we
      derive some sample size calculation formulas for testing equality, testing
      therapeutic noninferiority/superiority, and testing therapeutic equivalence,
      under the popular one-sample design, two-sample parallel design, and two-sample
      crossover design. Useful tables are constructed and some examples are given for
      illustration.

PMID- 12477069
TI  - Power and sample size determination for noninferiority trials using an exact
      method.
AB  - Noninferiority studies are frequently conducted to justify the development of new
      drugs and vaccines that have been shown to offer better safety profiles, easier
      administration, or lower cost while maintaining similar efficacy as compared to
      the standard treatment. Recently, exact methods have been developed to address
      the concern that existing asymptotic methods for analyzing and planning
      noninferiority may fail because of small sample size or because of skewed or
      sparse data structure. In this paper, we explore the use of exact methods in
      determining sample size and power for noninferiority studies that focus on the
      difference of two proportions. The methodology for sample size and power
      calculations is developed based on an exact unconditional test of noninferiority.
      We illustrate this exact method using a clinical trial example in childhood
      nephroblastoma and briefly discuss the optimal sample-size allocation strategy.
      This exact unconditional method performs very well in various scenarios and
      compares favorably to its asymptotic counterpart in terms of sensitivity.
      Therefore, it is a very desirable tool for planning noninferiority trials,
      especially in situations where asymptotic methods are likely to fail.

PMID- 12477070
TI  - On sample size calculation based on odds ratio in clinical trials.
AB  - Sample size calculation formulas for testing equality, noninferiority,
      superiority, and equivalence based on odds ratio were derived under both parallel
      and one-arm crossover designs. An example concerning the study of odds ratio
      between a test compound (treatment) and a standard therapy (control) for
      prevention of relapse in subjects with schizophrenia and schizoaffective disorder
      is presented to illustrate the derived formulas for sample size calculation for
      various hypotheses under both a parallel design and a crossover design.
      Simulations were performed to assess the adequacy of the sample size calculation
      formulas. Simulation results were given at the end of the paper.

PMID- 12477071
TI  - Stopping boundaries adjusted for sample size reestimation and negative stop.
AB  - We propose an approach to specify group sequential stopping boundaries adjusted
      for sample size reestimation and negative stop in interim analyses of a clinical
      trial. Sample size can be adjusted based on the observed delta at each interim to
      maintain the targeted power. The calculation of stopping boundaries incorporates
      possible changes in the type-I error due to sample size reestimation and/or
      negative stops; hence the overall type-I error is well controlled. This approach
      combines the advantages of the group sequential and sample size reestimation
      methods and is more efficient than either one alone. It provides flexibility in
      clinical trials and still maintains the integrity of these trials. When no early
      stop is planned, the stopping boundaries will be adjusted only for sample size
      reestimation. All calculations are given in closed mathematical forms and
      adjustments in stopping boundaries are based on the exact type-I error change.
      Therefore, the penalty for the type-I error inflation due to such interim
      conductions is kept to a minimum.

PMID- 12477072
TI  - Tests for inter-subject and total variabilities under crossover designs.
AB  - In this paper, we consider statistical tests for inter-subject and total
      variabilities between treatments under crossover designs. Since estimators of
      variance components for inter-subject variability and total variability in
      crossover design are not independent, the usual F-test cannot be applied.
      Alternatively, we propose a test based on the concept of the extension of the
      modified large sample method to compare inter-subject variability and total
      variability between treatments under a 2 x 2 m replicated crossover design. An
      asymptotic power of the proposed test is derived. A sensitivity analysis is
      performed based on the asymptotic power to determine how the power changes with
      respect to various parameters such as inter-subject correlation and intra-class
      correlation. Also the two methods for sample size calculation for testing total
      variability under 2 x 4 crossover design are discussed. The method based on the
      Fisher-Cornish inversion shows better performance than the method based on the
      normal approximation. Several simulation studies were conducted to investigate
      the finite sample performance of the proposed test. Our simulation results show
      that the proposed test can control type I error satisfactorily.

PMID- 12477073
TI  - A decision theoretic approach to sample size determination in clinical trials.
AB  - In this paper, we discuss a Behavioral Bayes approach to the determination of
      sample size in phase III clinical trials for which the data are assumed to come
      from a normal distribution for which the mean and variance are both unknown.
      Software is described which minimizes the expected net cost as a function of the
      sample size, thereby establishing the optimal sample size. This methodology
      extends previous work by the assumption of unknown variance. Numerical examples
      show that the more general model can have a large effect on the optimal sample
      size, compared with a procedure which uses the known variance model with an
      estimate of the variance.

PMID- 12477074
TI  - Sample size and optimal designs in stratified comparative trials to establish the
      equivalence of treatment effects among two ethnic groups.
AB  - When a new investigational medicine is intended to be applied to populations with
      different ethnic backgrounds, a stratified comparative phase III trial using
      ethnic groups as strata may be conducted to assess the influence of ethnic
      factors on clinical outcomes of this new medicine. In this paper, based on a
      binomial model with odds ratio as the measure of the treatment effect, we derive
      the score test and the associated sample size formula for establishing the
      equivalence/noninferiority of the treatment effects of a medicine among two
      ethnic groups. A simplified test together with its sample size formula are also
      given. Taking into account the sample size, cost, and power of testing,
      respectively, we derive the optimal design parameters, i.e., the allocation among
      treatment groups and ethnic groups, based on the simplified test.

PMID- 12477075
TI  - Novel targets in inflammation research. Report from the joint BIRAs/GREMI meeting
      at Nottingham University UK on 11th-12th April 2002. British Inflammation
      Research Association. Groupe de Recherche et d'Etude des Mediateurs de
      l'Inflammation.

PMID- 12477076
TI  - Vitamin E ointment at high dose levels suppresses contact dermatitis in rats by
      stabilizing keratinocytes.
AB  - OBJECTIVE: The pharmacological effect of vitamin E ointment at high dose levels
      was investigated in rats and mice during the development of contact dermatitis.
      MATERIALS AND METHODS: Allergic or irritant contact dermatitis was induced in
      sensitized or unsensitized animals by topical application of chemical agent(s).
      Cultured keratinocytes were prepared from dorsal skin of rats. RESULTS: The
      vitamin E ointment at 20-40% suppressed allergic and irritant contact dermatitis,
      exerting a comparable effect to that of 0.5% prednisolone ointment. Microscopic
      findings revealed that 20% vitamin E ointment reduced the keratinocyte damage,
      whereas 0.5% prednisolone was ineffective. The protective action of vitamin E on
      keratinocyte damage was also confirmed in a cell culture experiment. Furthermore,
      20% vitamin E ointment blocked down-regulation of skin barrier function induced
      by contact dermatitis, although 0.5% prednisolone ointment was inactive.
      CONCLUSIONS: These results indicate that 20% vitamin E ointment suppresses
      contact dermatitis by stabilizing keratinocytes, concomitantly with novel,
      interesting properties.

PMID- 12477077
TI  - Effects of polycationic peptides on mucin release from airway goblet cells:
      relationship between polymer size and activity.
AB  - OBJECTIVES AND DESIGN: Various sizes of poly-L-lysine (PLL) and poly-L-arginine
      (PLA) were tested for their possible effects on airway goblet cell mucin release
      using primary hamster tracheal surface epithelial (HTSE) cells in an attempt to
      identify the smallest size of the polycationic peptide to suppress mucin release
      without cytotoxicity. MATERIALS AND METHODS: HTSE cells were metabolically
      labeled using 3H-glucosamine and chased in the presence of varying concentrations
      of various sizes of the polycationic peptides. The amount of 3H-mucin in the
      spent media was measured by Sepharose CL-4B gel-filtration column chromatography.
      Possible cytotoxicity of the peptides was assessed by measuring the release of
      lactic dehydrogenase (LDH) during the treatment period. RESULTS: (1) PLL (MW
      78,000) inhibited whereas PLA (MW 92,000) stimulated mucin release. However,
      these peptides were cytotoxic at the effective concentrations; (2) Both PLL (MW
      9,600) and PLA (MW 8,900) could inhibit mucin release in a dose dependent manner
      without cytotoxicity; (3) Both PLL and PLA were effective in suppressing mucin
      release in 20-mer but not in either 10-mer or 5-mer; (4) 14-mers of both PLL and
      PLA also inhibited mucin release without cytotoxicity; (5) PLL and poly-D-lysine
      (PDL) of 14-mer were equipotent in its ability to suppress mucin release.
      CONCLUSION: Both PLL and PLA are cytotoxic at 'high' molecular weights, but have
      an ability to suppress mucin release without cytotoxicity at 'low' molecular
      weights. 14-mer seems to be the small, effective size, if not the smallest, for
      both PLL and PLA to suppress mucin release without cytotoxicity. The inhibitory
      effect of these polycationic peptides seems to be determined by the presence and
      the absolute number of positive charges and also to be independent of optical
      isomerism.

PMID- 12477078
TI  - Histamine release in mesenteric traction syndrome during abdominal aortic
      aneurysm surgery: prophylaxis with H1 and H2 antihistamines.
AB  - OBJECTIVE AND DESIGN: Mesenteric traction syndrome is described as sudden
      tachycardia, hypotension and flush. Among other etiological factors eventeration
      or mesenteric traction of the small intestine may cause histamine release from
      mesenteric mast cells. We hypothesized that mesenteric traction syndrome may be
      positively influenced by prophylactic antihistamine administration. METHODS: Male
      patients (n = 17, ASA groups III-IV, 48-78 years old) were investigated in a
      randomised double blind study during elective abdominal aortic aneurysm (AAA)
      repair. Eight patients had pre-anaesthetic prophylaxis with dimetindene (H1
      receptor antagonist) plus cimetidine (H2-receptor antagonist), 9 patients
      received placebo. Anaesthesia and invasive haemodynamic monitoring were
      standardised in all patients. Haemodynamic parameters, plasma histamine
      concentrations and clinical symptoms were determined 1 min after skin incision,
      as well as 5 and 20 min after mesenteric traction. Statistical analyses were
      performed using the Student's t-test, Chi2-test for incidences and Mann-Whitney-U
      test for continuous data. RESULTS: The incidence of histamine release was 55.5%
      (5/9) in the placebo group vs. 37.5% (3/8) in the antihistamine group (p > 0.05,
      Chi2-test). Plasma histamine levels (mean +/- SD) were higher in the placebo
      group than in the antihistamine group at 5 and 20 min after mesenteric traction
      but the difference did not reach statistical significance. Arrhythmias were
      significantly more frequent in the placebo group (6 times) than in the
      antihistamine group (none) (p = 0.005 Chi2-test). Systolic blood pressure was not
      statistically different between groups (e.g. 5 min after mesenteric traction,
      mean +/- SD; placebo 111 +/- 20 mm Hg vs. antihistamines 119 +/- 35 mm Hg).
      However, in the placebo group the haemodynamics only stabilised 5 min after
      mesenteric traction when anaesthetic gas concentration was repeatedly reduced and
      vasopressor/volume administration was increased (placebo-group = 20
      times/antihistamine-group = 8 times, p = 0.001, t-test). CONCLUSION: Prophylactic
      administration of antihistamines reduced the incidence of histamine release as
      well as the incidence of arrhythmias and the amount of stabilising measures
      during mesenteric traction. Prophylaxis with H1 and H2 antihistamines may be of
      perioperative benefit and should therefore be considered in AAA-surgery.

PMID- 12477079
TI  - Endotoxin tolerance in rats: influence on LPS-induced changes in excretory liver
      function.
AB  - OBJECTIVE AND DESIGN: We investigated in a rat model of endotoxic shock whether
      endotoxin tolerance (ETT) prevents lipopolysaccharide (LPS) associated lethality
      and studied the initial function of liver response to LPS. ANIMALS: Male Sprague
      Dawley rats. TREATMENT: ETT was induced by i.p. injection of LPS (Salmonella
      friedenau) intraperitoneally over 5 days. Rats (n = 6 each group) received 1 mg
      LPS/kg b. w. intravenously (Salmonella friedenau). The common bile duct was then
      canalized and bile was collected every 60 min for 6 h. 1 h after LPS-application
      liver biopsies were taken for determination of TNF-alpha by RT-PCR. Sham operated
      animals (n = 6 each group) were treated identically but without application of
      LPS. RESULTS: All ETT animals survived the duration of the experiment whereas non
      tolerant animals (NETT) died before the end of the experiment (5/6). NETT animals
      showed a continuous decrease in bile flow after 240 min. The amount of bile acids
      was significantly lower (ANOVA) in NETT animals than in sham operated controls or
      ETT-animals. Analysis of TNF-alpha mRNA expression in the liver revealed an
      upregulation 1 h after LPS application, which was significantly lower in LPS
      tolerant animals. CONCLUSIONS: Our results show that excretory liver failure and
      death subsequent to intravenous LPS application can be successfully counteracted
      by induction of ETT.

PMID- 12477080
TI  - Pseudomonas aeruginosa elastase stimulates ERK signaling pathway and enhances IL
      8 production by alveolar epithelial cells in culture.
AB  - OBJECTIVE AND DESIGN: Bacterial products as well as the host airway inflammatory
      responses contribute to the pathogenesis of Pseudomonas infections. We sought to
      determine if Pseudomonas elastase (PE) induces mitogen-activated protein (MAP)
      kinase activity in association with interleukin-8 (IL-8) production by alveolar
      epithelial cells. METHODS: We utilized Western blot analysis to detect
      phosphorylation of signaling intermediates and ELISA was used to measure IL-8
      production. RESULTS: We found that PE induces phosphorylation of the
      extracellular signal-regulated (ERK1/2) proteins of the MAPK pathway in A549
      epithelial cells. Similar results were obtained using primary cultures of rabbit
      alveolar type II epithelial cells. PE also enhanced IL-8 production, which was
      abolished in the presence of the ERK activation inhibitor U0126. CONCLUSIONS: We
      conclude that PE activates the ERK1/2 arm of the MAPK pathway and that activation
      of this pathway results in enhanced IL-8 production. The results demonstrate that
      PE may augment pulmonary inflammation via cellular signaling that regulates
      expression of IL-8.

PMID- 12477081
TI  - Kupffer cell phagocytosis blockade decreases morbidity in endotoxemic rats with
      obstructive jaundice.
AB  - OBJECTIVE AND DESIGN: The consequences of Kupffer cell phagocytosis blockade were
      studied in endotoxemic rats with obstructive jaundice. MATERIAL OR SUBJECTS: 159
      male Wistar rats. TREATMENT: Obstructive jaundice was induced by bile duct
      ligation (BDL). Gadolinium chloride (1 mg/100 g iv) was given 6 days after BDL to
      inhibit Kupffer cell activity and the animals were challenged with 1 microg/g
      endotoxin 24 h later. METHODS: Endotoxin sensitivity, tumor necrosis factor-alpha
      and interleukin-6 production were studied, liver and lung injury were assessed by
      neutrophil infiltration assay, tissue adenosine triphosphate, aspartate
      aminotransferase, alanine aminotransferase level determinations and histology,
      respectively. For statistics non-parametric methods were used. RESULTS: BDL
      sensitized the animals to endotoxin, increased endotoxin-induced tumor necrosis
      factor-alpha and interleukin-6 production and reduced ATP contents of the liver
      and the lung. Kupffer cell blockade significantly increased the resistance
      against endotoxin, diminished the inflammatory cytokine release and reduced
      endotoxin-induced tissue injury in BDL animals. CONCLUSION: Attenuation of
      Kupffer cell function decreases endotoxin-induced lethality and morbidity in
      obstructive jaundice.

PMID- 12477082
TI  - Effect of postoperative irradiation on free skin flaps: an experimental study in
      rats.
AB  - The modern treatment of musculoskeletal malignant tumours often requires
      different combinations of surgery, chemotherapy, and radiotherapy. Although
      combination treatments have allowed reconstruction of more complex defects, the
      risk of complications also rises. In clinical series the complication rate is
      influenced by the characteristics of the defect and the quality of the radiation
      used. The flap survival is high, but the overall complication rate is more than
      25%. In this study we looked at the healing of microvascular free skin flaps
      exposed to postoperative irradiation in a rat model. Epigastric microvascular
      free skin flap were exposed to a single dose of 20 Gy radiation one week
      postoperatively (n = 8). A comparison was made with free epigastric skin flaps
      without postoperative radiation (n = 8). The healing was assessed histologically
      at four weeks and by measuring the tensile strength of the wound. Biochemical
      total nitrogen and hydroxyproline contents were also measured. Results showed
      that histologically the interfaces healed similarly with only minimal
      histomorphological changes. Neither the mechanical strength of the healing
      interface nor the biochemical markers altered significantly. Postoperative
      irradiation with a single dose of 20 Gy does not affect the survival of free skin
      flaps in rats. In the future the model described could be used to study the
      effects of combination therapy of surgery, radiotherapy, and chemotherapy more
      closely to find the optimal control of malignancies with limited damage to
      treated tissue.

PMID- 12477083
TI  - Dorsal bipedicled island skin flap: a new flap model in mice.
AB  - Mice are popular animals for biomedical studies, but few skin flap models have
      been reported in them. To investigate the ischaemia/reperfusion phenomenon in
      skin flaps, we first investigated the vascular anatomy of murine dorsal skin and
      then designed a suitable murine dorsal skin flap model. In 120 mice, six distinct
      vascular patterns were identified, one being seen in 111 mice (93%). Based on
      this finding, in Part 2 of the study, 15 mice had flaps (4 x 4 cm) raised based
      on the two caudal vascular pedicles of the left and right deep circumflex iliac
      vessels as a bipedicled flap in which the mean (SD) survival was 96 (5)%. In a
      further 10 mice, flaps were raised based on a single pedicle, the left deep
      circumflex iliac vessel, as a monopedicled flap, in which the mean (SD) survival
      was 71 (12)%. The bipedicled flap model was then used to study
      ischaemia/reperfusion injury. Twenty flaps were subjected to eight hours of
      ischaemia and subsequent reperfusion, and their mean (SD) survival was 43 (26)%.
      Histological assessments were also carried out using neutrophil and leucocyte
      counts, and significant differences between groups were observed.

PMID- 12477084
TI  - Rhinoplasty and nasal function in patients with cleft lips.
AB  - The purpose of this study was to find out whether harvesting septal grafts and
      simultaneously doing a septoplasty improves nasal function in patients with
      clefts who are having a rhinoplasty to correct the external deformity. We studied
      14 patients with a unilateral cleft (UCL(P)) and four with bilateral clefts
      (BCLP). Nasal airflow resistance was measured with active rhinomanometry
      preoperatively and postoperatively. In nine of the 14 with UCL(P) and in all
      those with BCLP nasal resistance was normal or near normal both preoperatively
      and postoperatively. In five with UCL(P) postoperative nasal resistance was
      highly increased on the cleft side and in three of these patients nasal
      resistance decreased significantly but still remained abnormal. Only one patient
      subjectively complained of poor nasal airflow but all sought improvement of their
      nasal appearance. Harvesting of the graft and simultaneous straightening of the
      nasal septum during a rhinoplasty in patients with clefts neither improved, nor
      had a deleterious effect on, nasal function.

PMID- 12477085
TI  - Intraoperative expansion of skin around large congenital naevi with foley
      catheter balloons: 11 new cases.
AB  - Tissue expansion allows reconstruction of large cutaneous defects with adjacent
      skin, similar in appearance and type, without using skin grafts or multiple,
      regional, distant, or microsurgical flaps. Conventional expansion produces a
      greater increase in surface and length than intraoperative expansion, but it has
      several disadvantages and should be reserved for closing problematic defects.
      There is considerable controversy about the relative effects of intraoperative
      expansion and undermining on the tensions of closing wounds, although immediate
      expansion is commonly used particularly in head and neck reconstruction. New
      multiple external devices have recently been described to expand skin externally,
      but there are few options as internal expanders. We have chosen multiple Foley
      catheter balloons, because of their availability and low cost, to repair 11 limb
      defects after excision of large naevi. The wounds are easy to close, primarily,
      and postoperative results are good. Dark pigmentation scars are the most common
      possible complications.

PMID- 12477086
TI  - Sitting pressure and perfusion of buttock skin in paraplegic and tetraplegic
      patients, and in healthy subjects: a comparative study.
AB  - The distribution of sitting pressure and ability to respond with reactive
      hyperaemia were studied in a group of paraplegic and tetraplegic patients (n = 8)
      with spinal cord lesions and healthy controls (n = 10) using a pressure sensitive
      plate and laser Doppler perfusion imager. The results show that the mean sitting
      pressure of the patients was 9.9 N/cm2 (left) and 11.7 N/cm2 (right) compared
      with 3.5 N/cm2 (left) and 3.6 N/cm2 (right) in controls. The differences were
      significant on both the left (p < 0.01) and right (p < 0.05) sides. The maximum
      pressure in patients was 42.9 N/cm2 (left) and 48.7 N/cm2 (right), and in
      controls 12.0 N/cm2 (left) and 12.9 (right) (p < 0.01). Both groups showed a
      reduction in skin perfusion in the seat area during sitting compared with
      unloaded resting, and in the controls it was significantly increased (p < 0.001
      on both sides) during the reactive hyperaemic phase immediately after sitting.
      Compared with the preload values, the patients showed a similar but slightly
      weaker picture significant on the right side (p < 0.05), but not on the left. The
      hyperaemia was not uniformly distributed, but occurred where the pressure was
      greater than 2 N/cm2. There was no correlation between the amount of reactive
      hyperaemia and absolute values of sitting pressures. We conclude that tetraplegic
      and paraplegic patients have significantly higher sitting pressures than normal
      controls, and that the hyperaemic response in the buttock region in the upright
      position after pressure load is slightly weaker in the patients, which could be
      of importance for the development of decubitus ulcers.

PMID- 12477087
TI  - Polydactyly: a study of four generations of a Turkish family including an
      affected member with bilateral cleft lip and palate.
AB  - Polydactyly is one of the most common congenital deformities of the hands. It can
      occur as an isolated disorder, in association with other malformations of the
      hands or feet, or as part of a syndrome. It can occur sporadically but it can
      also be inherited with a mainly autosomal dominant inheritance. We present a
      Turkish family with affected members in four generations. Bilateral duplication
      of the second digit in both hands and feet with 24 digits in total was the most
      common pattern, but one affected member had 26 digits: seven on each hand and six
      on each foot. In addition, another affected member had complete bilateral cleft
      lip and complete cleft palate combined with bilateral hand and foot polydactyly
      without any syndromic association. The pedigree of the affected members of this
      family suggests an autosomal dominant mode of inheritance, but genetic expression
      is variable.

PMID- 12477088
TI  - Proximal row carpectomy: a worthwhile salvage procedure.
AB  - After proximal row carpectomy 11 patients were evaluated in the six ensuing years
      for pain relief, satisfaction, ranges of movement, grip and precision grip
      strength, and radiographic picture. The median follow-up period was 3.1 years
      (range 4 months to 6 years). They were operated on for scaphoid non-union with
      radiocarpal arthritis, late stage Kienbock's disease, chronic scapholunate
      dissociation and scapholunate advanced collapse wrist deformity. The mean
      disabilities of the arm, shoulder and hand (DASH) scoring list, which indicates
      the patient's degree of disability 28% (range 2%-64%) of maximum disability for
      the function and symptom score. Flexion, extension, and radial and ulnar
      deviation of the wrist improved to 47% (range 21%-76%), 67% (range 41%-81%), 39%
      (range 25%-55%), and 81% (range 44%-90%) of the opposite wrist. Mean grip
      strength, 70% (range 22%-117%) of the opposite site, while the three precision
      grips improved between 72% and 79%. A review of previous studies of proximal row
      carpectomy showed results comparable with those of our study. Compared with other
      treatments, it is a dependable, relatively-simple procedure that gives reliable
      relief of pain, preserves functional ranges of movement and grip strength, and
      allows most patients to return to work.

PMID- 12477089
TI  - Radiographic changes after resection of the distal ulna in patients with
      rheumatoid arthritis.
AB  - Radiographic changes in the wrist after resection of the distal ulna in 61
      rheumatoid patients (63 wrists) were evaluated more than five years after
      operation. The wrists were classified on preoperative radiographs into stable or
      unstable forms as defined by Simmen and Huber. Of 63 wrists, 52 were classified
      as stable and the remaining 11 were classified as unstable. At follow up, 50 of
      52 wrists (96%) that were stable before operation had remained stable. Five of
      the 11 wrists that were unstable before operation had bony ankylosis or partial
      radiocarpal ankylosis, and in the remaining six cases there was carpal collapse.
      Resection of the distal ulna yields good results in stable wrists but operation
      is not indicated for unstable ones.

PMID- 12477090
TI  - Pathophysiology and treatment of streptococcal toxic shock syndrome.
AB  - We have recently encountered three cases of streptococcal toxic shock syndrome,
      each of which had a different cause. All the patients had inflammation of soft
      tissue in the lower extremities, and developed shock and multiple organ failure
      immediately after the clinical visit. The inflammation of soft tissue was
      necrotising fasciitis in one case, myositis in one case, and phlegmon in one. In
      the first case the debridement was incomplete, which resulted in an extensive
      ulceration. Wary of repeating this experience, we made an early diagnosis and did
      a thorough debridement in the second case. The patient was ultimately discharged
      without complications. It is rare that a patient with extensive myositis survives
      without amputation of the extremity. The third patient responded well to early
      treatment with antibiotics.

PMID- 12477091
TI  - Laurence-Moon-Biedl syndrome with vaginal atresia.
AB  - A 15-year-old girl presented with the rare Laurence-Moon-Biedl syndrome,
      accompanied by vaginal atresia, and cervical dysgenesis. She was treated by
      hysterectomy and construction of a neovagina with bilateral pudendal thigh flaps.
      Two brothers and a sister (one of twins) were unaffected but the remaining
      brother also had the disease.

PMID- 12477092
TI  - Iatrogenic 14 cm defect in the ulnar nerve after percutaneous cross-pinning of
      supracondylar humeral fracture in a child.
AB  - We present a case of a 14 cm defect of the ulnar nerve after percutaneous pinning
      of a supracondylar humeral fracture in a child. This was treated by taking four
      sural nerve grafts (16 cm long each) from both legs. Five years later the arm was
      painless but the hand was a little clumsy and sensation in the little finger was
      reduced.

PMID- 12477093
TI  - Multiple neurilemmomas of the median and ulnar nerves with a communicating branch
      in the same upper extremity.
AB  - A 30-year-old woman presented with multiple neurilemmomas in the same upper
      extremity. One originated from the main trunk of the ulnar nerve and two others
      from the sensory branch of the median nerve. A communicating branch in the palm
      from the ulnar nerve to the median nerve was confirmed. All the tumours were
      successfully enucleated and she made a satisfactory recovery.

PMID- 12477094
TI  - Irreducible dorsal dislocation of the proximal interphalangeal joint caused by an
      osteochondral fragment.
AB  - We report two cases of irreducible dorsal dislocation of the proximal
      interphalangeal joint caused by interposition of a small osteochondral fragment
      that avulsed from the base of the middle phalanx with the volar plate and
      outstretched collateral ligament.

PMID- 12477095
TI  - Prevalence of wife rape and other intimate partner sexual coercion in a
      nationally representative sample of women.
AB  - This article provides a national estimate of wife rape and various other types of
      sexual coercion by a spouse or intimate partner. Findings from a 1997 national
      probability sample revealed that 34% of women were victims of some type of sexual
      coercion with a husband or partner in their lifetime. Of these women, 10%
      experienced rape by a current partner. This rate increased to 13% when only
      victims of rape by a current husband were included, which is consistent with
      previous studies on wife rape. Other findings reveal that women had unwanted sex
      with a current spouse or partner in return for a partner's spending money on them
      (24%), because they thought it was their "duty" (43%), after a romantic situation
      (29%), after the partner begged and pleaded with them (26%), and after their
      partner said things to bully them (9%). The importance of examining a continuum
      of sexual coercion is discussed and findings are compared and contrasted with
      other prevalence rates for sexual coercion in marriage.

PMID- 12477096
TI  - Psychological aggression in dating relationships: predictive models for males and
      females.
AB  - Variables related to the use of physical aggression in dating relationships and
      conflict management strategies were used to predict the use of psychological
      aggression in courtship. Individual factors (i.e., variables associated with
      threat susceptibility) and situational variables (i.e., relationship length and
      emotional commitment to the partner, conflict management strategies, and weekly
      alcohol intake) were proposed to be important in the prediction of male's and
      female's use of psychological aggression with their partners. Our findings
      suggest that these variables successfully predict the use of psychologically
      aggressive acts in courtship. Further, interactions with sex of participant
      suggest that different variables are important in the prediction of males' and
      females' use of such negative behaviors. These differences in the relationships
      between the predictors and criteria for males and females suggest not only
      divergent predictive models but also potential motivational differences in the
      employment of such tactics.

PMID- 12477097
TI  - Stalker profiles with and without protective orders: reoffending or criminal
      justice processing?
AB  - Research indicates that stalking is an extension of intimate partner violence.
      The overall purpose of this study was to better understand stalkers by examining
      the association between a protective order history and the court's processing of
      subsequent stalking, and to examine patterns of reoffending. This study examined
      a sample of 346 males who were charged with stalking in 1999 in one state.
      Subjects were partitioned into three groups: (1) males without protective orders;
      (2) males with one prior protective order; and (3) males with two or more prior
      protective orders. Almost two-thirds of the stalkers had a protective order
      against them at some point in the study, suggesting that stalking is associated
      with intimate partner violence. Results also found a linear trend with many of
      the criminal justice involvement variables and protective order history prior to
      1999. Those charged with first-degree stalking were more likely to be found
      guilty initially, and about one-third of all three study groups had the initial
      felony stalking charge amended. Of those charged with second-degree stalking,
      only 7% of the group with two or more protective orders was initially found
      guilty, which was substantially less than the other two groups. And, when all the
      amendment dispositions were considered, there were no significant differences by
      group in guilty and dismissed dispositions for the index stalking charge.
      Further, consistent with previous criminal justice involvement, the group with
      two or more protective orders was more likely to have subsequent felony charges
      than the other two groups. Implications are discussed.

PMID- 12477098
TI  - Incidence and correlates of posttrauma symptoms in children from backgrounds of
      domestic violence.
AB  - In recent years, evidence has emerged of the presence of posttrauma symptoms in
      children from backgrounds of domestic violence. The present study examined the
      incidence and correlates of posttrauma symptoms in 56 children of mothers who had
      been residents in women's shelters in Adelaide, South Australia. The most
      frequently endorsed symptoms among this sample of children were being troubled by
      distressing thoughts, conscious avoidance, hypervigilance, and sleep
      difficulties. Twenty percent of children met the criteria for a diagnosis of
      posttraumatic stress disorder (PTSD). Children meeting full PTSD criteria scored
      significantly higher on measures of anxiety, depression, and dissociation.
      Results support the use of a posttrauma framework for understanding the effects
      on children of living with domestic violence.

PMID- 12477099
TI  - The encounter with family violence and risky sexual activity among young
      adolescent females.
AB  - In this article, we analyze the relationship between family violence and risky
      sexual activity for female adolescents (age 14 to 17). We examine two forms of
      family violence: experience (receiving physical abuse from a parent or parent
      figure) and exposure (witnessing interparental physical violence). We hypothesize
      that either form of violence will predict greater odds of engaging in risky
      sexual behavior. We define risky sexual activity as any of the following: having
      multiple partners within the last 12 months or having sex with partners who are
      themselves engaging in risky behavior (e.g., having multiple partners of either
      sex, injecting unprescribed drugs, sharing unprescribed needles for injecting
      drugs). We analyzed data from 710 respondents taken from the National Survey of
      Family Growth, Cycle V, living with at least one biological parent. Results
      showed that experiencing violence from a parent greatly increased the likelihood
      of risky sex, even when controlling for the experience of forced sex, age,
      mother's age at first birth, race, socioeconomic status, and religiosity. Female
      adolescents who had experienced forced sex, those who were older (especially 17
      year-olds), non-Hispanic Blacks (but not Hispanics), those living in a family
      with low educational attainment (less than a high school diploma), and those for
      whom religion was not or only somewhat personally important were more likely to
      report risky sex compared to others. These effects were not modified by whether
      the respondents lived in single- or two-parent families. An interaction between
      the two forms of physical violence suggests that either form is sufficient to
      increase significantly the odds of risky sex; an analysis in which respondents
      were differentiated by their experience of either form of violence showed a
      strong effect of experience on risky sex, net of the control variables.

PMID- 12477100
TI  - Characteristics of female perpetrators and victims of dating violence.
AB  - Although many researchers have explored the topic of dating violence, limited
      attention has been paid to female perpetrators. Very little research has examined
      variables that facilitate aggression for females in dating relationships. In an
      effort to investigate distinct types of violent behavior, the present study
      separated females who experience dating violence into three categories (bi
      directional aggression, perpetrator-only, and victim-only) and compared them with
      a control group not previously exposed to interpersonal violence. The purpose of
      this study was to examine variables that discriminate violent females from non
      violent females. Variables that were hypothesized to be associated with
      aggressive behavior and investigated in the current study were interparental
      aggression, self-esteem, love attitudes, and alcohol use. Three hundred female
      college students responded to multiple self-report questionnaires examining
      psychological correlates of dating violence. Females in the bi-directional
      aggression group were more likely to have witnessed their father abuse their
      mother and scored significantly lower on a measure of self-esteem than non
      violent controls. Females in the control group demonstrated higher scores on a
      measure of mature and selfless love style than did the victim or perpetrator-only
      participants. There were no significant group differences regarding general
      alcohol consumption. Implications for prevention and intervention are presented
      and discussed.

PMID- 12477101
TI  - Intimate partner violence among married male U.S. Army soldiers: ethnicity as a
      factor in self-reported perpetration and victimization.
AB  - Correlates of self-reported intimate partner violence (IPV) were examined among
      488 married male U.S. Army soldiers. Study results were examined within the
      framework of Johnson's (1995) typology, which proposes that there are two main
      types of IPV, common couple violence and intimate terrorism. We predicted that
      poor marital adjustment would be associated with minor violence, hypothesized to
      be indicative of common couple violence. We also predicted that psychological and
      behavioral characteristics associated with perpetrators of IPV would be more
      strongly correlated with severe inflicted aggression--a pattern hypothesized to
      be indicative of intimate terrorism. The results, based on a multivariate
      analysis of covariance, generally supported our hypotheses. Furthermore, the
      higher levels of IPV reported by Black respondents in this study were associated
      with the pattern hypothesized to be characteristic of common couple violence.

PMID- 12477102
TI  - Utilization of counseling and supportive services by female victims of domestic
      abuse.
AB  - Increasing attention to the high prevalence of domestic violence (DV) and its
      impact on women's physical and mental health has resulted in expanded services
      for abused women. Abused women appear to underutilize the formal counseling
      services available in many communities, however, and further research is needed
      to identify factors related to service utilization. In the present study, 1,746
      women assaulted by a male intimate partner were identified from a larger pool of
      women interviewed by Pretrial Services following the arrest of their
      spouse/partner on domestic abuse charges. The women were selected for the current
      study if they reported prior physical assaults perpetrated by the same
      spouse/partner listed in the instant offense. In addition to describing previous
      physical assaults and psychological abuse by their current spouse/partner, women
      were also asked whether they had ever sought "formal counseling/supportive
      services" to address the abuse. Consistent with the prior literature, only a
      minority of the victims reported prior use of these services (14.9%). Additional
      analyses indicated that the likelihood of having accessed services varied as a
      function of victim demographic factors (race, relationship to the offender,
      income), characteristics of the prior DV (prior injury by partner, forced sexual
      activity, prior psychological abuse), and whether the victim's children witnessed
      the fighting. Limitations of the study and implications for service providers and
      the courts are discussed.

PMID- 12477103
TI  - Parametric dependencies of high-diffraction-order achromatized aplanatic
      configurations that employ circular or crossed-linear diffractive optical
      elements.
AB  - The parametric relationships of achromatized transmissive and reflective
      diffractive optical elements (DOEs) are explored for a number of configuration
      classes as a function of diffraction order, focal ratio, wavelength, and field
      angle. The necessity for blazing high-diffraction-order DOEs is elucidated. The
      ray image sizes are presented in dimensionless imaging space and thus are
      applicable to any size of optical system. Several aplanatic configurations are
      evaluated.

PMID- 12477104
TI  - Metrology of pulsed radiation for 157-nm lithography.
AB  - In the framework of current development in 157-nm lithography we have
      investigated the performance of photodetectors with emphasis to their stability
      and linearity. The measurements were performed in the radiometry laboratories of
      the Physikalisch-Technische Bundesanstalt at the Berlin electron-storage rings
      BESSY I and BESSY II with spectrally dispersed synchrotron radiation as well as
      with highly pulsed F2 laser radiation at 157 nm in combination with a cryogenic
      radiometer as the primary detector standard. Relative standard uncertainties of
      as little as 1% were achieved for the calibration of photodetectors in the
      spectral range of ultraviolet and vacuum-ultraviolet radiation.

PMID- 12477105
TI  - Characterization of an ultraviolet and a vacuum-ultraviolet irradiance meter with
      synchrotron radiation.
AB  - We have constructed and characterized a simple probe that is suitable for
      accurate measurements of irradiance in the UV to the vacuum UV spectral range.
      The irradiance meter consists of a PtSi detector located behind a 5-mm-diameter
      aperture. The probe was characterized at various wavelengths ranging from 130 to
      320 mm by use of continuously tunable synchrotron radiation from the Synchrotron
      Ultra-violet Radiation Facility III. We determined the irradiance responsivity by
      scanning a small monochromatic beam over the active area of the irradiance meter
      and measuring its response on a grid with regular spacing. The angular response
      was also determined and shown to be suitable for applications such as
      photolithography. In addition, we studied the radiation damage using a 157-nm
      excimer laser and found that the irradiance meter can endure more than 100 J/cm2
      of 157-nm radiation before a noticeable change occurs in its responsivity. Many
      industrial applications such as UV curing, photolithography, or semiconductor
      chip fabrication that require accurate measurement of the irradiance would
      benefit from having such a stable, accurate LTV irradiance meter.

PMID- 12477106
TI  - Sensitivity analysis of grating parameter estimation.
AB  - An optimization method for the sensitivity of diffraction efficiency measurements
      is presented. I define the sensitivity as the estimation precision of the grating
      parameters. The optimization method called sensitivity analysis for fitting scans
      all the possible measurement configurations and selects the configuration that
      yields the best sensitivity. The scan is made over the domain of the experimental
      parameters of the arrangement, such as the azimuth angle of the grating and the
      orientation angles of the analyzer and the polarizer. These parameters can be
      freely varied, and among the multitude of possible combinations there is one
      configuration that provides optimum sensitivity. Comparison with experimental
      results reveals a qualitative agreement between theory and practice.

PMID- 12477107
TI  - Phase-modulation scatterometry.
AB  - Phase-modulation scatterometry is a metrology technique for determining, by means
      of a phase modulator as a key device, the parameters of gratings. The main source
      of error to be dealt with are the fluctuations of the phase-modulation amplitude.
      The grating zeroth-order reflectance modulated by the phase modulator is
      converted into a signal by the photodetector. The measurables are the direct term
      and the first two harmonics of the signal. For experimental data fitting, we used
      the ratio of the harmonics over the direct term because it significantly improves
      the accuracy. A sensitivity analysis was performed for two samples, one real and
      one theoretical, to find the measurement configuration that insures optimum
      determination precision for the grating parameters. For the real sample,
      comparison of the theoretical predictions for sensitivity with the actual values
      showed a good agreement. For both samples the sensitivity analysis indicated
      subnanometric precision for the critical dimension (grating linewidth).

PMID- 12477108
TI  - Interleaved, sampled fiber Bragg gratings for use in hybrid wavelength
      references.
AB  - We discuss the design and fabrication of interleaved, sampled fiber Bragg
      gratings (ISFBGs) for use in hybrid wavelength calibration references covering
      the 1300-1600-nm region. We demonstrate use of sampled phase masks (SPMs) to make
      sampled gratings and ISFBGs. The success of the SPM technique suggests a single
      exposure method with an interleaved, sampled phase mask to make ISFBGs.

PMID- 12477109
TI  - Design of a fiber-optic quasi-distributed strain sensors ring network based on a
      white-light interferometric multiplexing technique.
AB  - A fiber-optic quasi-distributed strain sensors ring network has been designed
      based on a Mach-Zehnder optical paths interrogator. The optical paths matching
      for each sensor are discussed, and the optical power budgetary analysis is
      performed. The relation between the number of sensors and the intensity of the
      signals of the ring network is given for evaluation of the multiplexing capacity.
      Experimentally, a seven-sensor array ring network was realized under the
      condition of light source power 35 microW at 1310 nm, and the distribution strain
      test was also demonstrated.

PMID- 12477110
TI  - Dependence of the Brillouin gain spectrum on linear strain distribution for
      optical time-domain reflectometer-type strain sensors.
AB  - We theoretically derive the shape of the Brillouin gain spectrum, that is, the
      Briilouin backscattered-light power spectrum produced in an optical fiber under
      conditions of a strain distribution that changes linearly with a constant slope.
      The modeled measurement system is an optical time-domain reflectometer-type
      strain sensor system. The linear strain distribution is one of the fundamental
      distributions and is produced in, for example, a beam to which a concentrated
      load is applied. By analyzing a function that expresses the shape of the derived
      Brillouin gain spectrum, we show that the strain calculated from the frequency at
      which the spectrum has a peek value coincide. with that at the center of the
      effective pulsed light. In addition, the peak value and the full width at half
      maximum of the Brillouin gain spectrum are both influenced by the strain
      difference between the two ends of the effective pulse. We investigate this
      influence in detail and obtain the relationship between strain difference and
      strain measurement error.

PMID- 12477111
TI  - Conoscopic evaluation of the birefringence of gradient-index lenses: infidelity
      sources.
AB  - Gradient-index lenses are samples whose special characteristics must be taken
      into account to design the optical polariscopes that can be applied in the
      evaluation of their birefringence. We discuss the main infidelity sources that
      modify the conoscopic patterns when a traditional polariscopic setup is used.

PMID- 12477112
TI  - Strain contouring with Gabor filters: filter bank design.
AB  - A novel fringe processing method is proposed to segment whole-field strain
      distributions from interferometric deformation patterns by use of Gabor filters.
      This novel strategy is specifically proposed for strain measurement with a Gabor
      filter used as a set of wavelets. To increase computational speed as well as for
      selection of contour intervals, judicious design of the filter bank, based on the
      fringe pattern and the requirements of the user, is crucial in this methodology.
      A filter design strategy is developed and, based on the proposed filter design
      scheme, properly designed filter banks are generated and applied for strain
      contouring in low-strain and strain concentration regions. This scheme allows one
      to measure engineering strains within regions of interest and hence provides the
      design engineer great flexibility of monitoring, testing, or analysis.

PMID- 12477113
TI  - Bending wave propagation in rotating objects measured by pulsed TV holography.
AB  - Transient bending waves in a rotating hard disk is measured by means of pulsed TV
      holography. The speckle motion in the detector plane caused by the rotation is
      compensated for in the interference phase evaluation. The technique is all
      electronic and needs no image derotator.

PMID- 12477114
TI  - Characterization of a mixed sphere and film waveguide at the 1-microm scale by
      0.67-microm laser light propagation.
AB  - A mixed sphere array and film (MSF) waveguide [a mixed system with a polystyrene
      microsphere array and a poly(methyl methacrytate) thin film waveguide] was
      fabricated and characterized at a wavelength of 0.67 microm. The attenuation
      coefficients of the isolated linear thin-film waveguide and the isolated linear
      microsphere array were measured to be 0.54 dB/microm and 0.98 dB/sphere,
      respectively. In the MSF waveguide the attenuation coefficients of the thin-film
      waveguide and the polystyrene microsphere array were 0.61 dB/microm and 1.17
      dB/sphere, respectively. A curvilinear MSF waveguide was also fabricated and
      characterized. Evanescent wave interaction between the thin-film waveguide and
      the microsphere array was expected.

PMID- 12477115
TI  - Heterostructure photonic crystals: theory and applications.
AB  - A hybrid structure combining square and hexagonal photonic crystal lattices is
      presented. This structure, which we refer to as heterostructure, offers the
      ability to tailor, optimize, and match the band structure of different lattices.
      The availability of heterostructures in photonic crystals opens abroad range of
      possibilities for optical device development. In particular, heterostructure
      photonic crystals are well suited for the application of optical beam splitting
      (Y coupler) and combining. Numerical experiments performed by use of the finite
      difference time-domain method are shown to illustrate the device implemented in
      both unistructure and heterostructure lattices.

PMID- 12477116
TI  - Phase measurement in temporal speckle pattern interferometry: comparison between
      the phase-shifting and the Fourier transform methods.
AB  - The measurement of dynamic displacements by use of speckle pattern interferometry
      and temporal phase unwrapping allows for the evaluation of large-object
      displacement fields without the propagation of spatial unwrapping errors. If a
      temporal carrier is introduced in one of the beams of the interferometer, phase
      data for whole-object displacement can be retrieved by use of a temporal phase
      shifting method or a temporal Fourier transformation approach. We present a
      comparison between both methods of temporal phase measurement in terms of
      precision and execution speed. We performed the analysis by using computer
      simulated speckle interferograms, an approach that allowed us to know precisely
      the original phase distribution and also to determine the spatial rms phase error
      as a function of the phase change introduced between two consecutive speckle
      interferograms. The performance of both methods to process experimental data is
      also illustrated by use of the results from a high-speed speckle interferometry
      study of a carbon fiber panel.

PMID- 12477117
TI  - Relations between the critical angles and the optical tensor of a biaxial
      material.
AB  - The behavior of the critical angles between a high-index isotropic medium and a
      biaxial crystal with arbitrary orientation of the optical tensor has been
      theoretically analyzed and numerically modeled. The results indicate that, as the
      biaxial crystal is rotated around an axis perpendicular to the interface, two
      critical angles appear, corresponding to the excitation of two eigen modes, which
      periodically vary with a period of pi. An optical procedure for fully
      characterizing the optical tensor of a biaxial crystal is suggested on the basis
      of the twist-angle dependence of these critical angle. This procedure simply
      requires the measurement of the p- to s-conversion reflectivity against the
      sample rotation angle, with just one polished surface of a biaxial crystal.

PMID- 12477118
TI  - Nanosizing of fluorescent objects by spatially modulated illumination microscopy.
AB  - A new approach to measuring the sizes of small fluorescent objects by use of
      spatially modulated illumination (SMI) far-field light microscopy is presented.
      This method is based on SME measurements combined with a new SMI virtual
      microscopy (VIM) data analysis calibration algorithm. Here, experimental SMI
      measurements of fluorescent objects with known diameter (size) were made. From
      the SMI data obtained, the size was determined in an independent way by use of
      the SMI VIM algorithm. The results showed that with SMI microscopy in combination
      with SMI VIM calibration, subwavelength object size measurements as small as 40
      nm are experimentally feasible with high accuracy.

PMID- 12477119
TI  - Comparison of exact pupil astigmatism conditions with Seidel approximations.
AB  - The aberrations of axisymmetric imaging systems can be calculated to third order
      by use of the Seidel formula. The Coddington equations give aberrations that have
      quadratic dependence on the pupil, for all field points. The pupil astigmatism
      conditions were recently developed to predict and control aberrations that have
      quadratic field dependence and arbitrary pupil dependence. We investigate the
      relationship between the exact pupil astigmatism conditions and the classical
      Seidel treatment of pupil aberration.

PMID- 12477120
TI  - Application of the pupil astigmatism criteria in optical design.
AB  - We developed the pupil astigmatism criteria for correcting the quadratic field
      dependent aberrations. These criteria provide an elegant way to determine and
      correct aberrations that have quadratic field dependence and arbitrary pupil
      dependence in the same way that the Abbe sine condition is used for aberrations
      with linear field dependence. Like the sine condition, the pupil astigmatism
      criteria involve only the properties of the rays originating from the on-axis
      object point, so it is convenient to implement them in optical design. We
      introduce an algorithm to apply the criteria in designing new well-corrected
      optical systems. Some example designs are presented.

PMID- 12477121
TI  - Static and dynamic properties of highly turbid media determined by spatially
      resolved diffusive-wave spectroscopy.
AB  - We show that spatially resolved backscattering can be used for simultaneous
      measurements of static and dynamic properties of highly turbid media. The spatial
      variation of the backscattered intensity gives access to the transport men free
      path. The decay of the temporal intensity-intensity correlation function depends
      on the point of observation. This property can be used to probe complex dynamics
      with several time scales. The implementation of the method and the data analysis
      are tested on concentrated suspensions of polystyrene spheres.

PMID- 12477122
TI  - Influence of substrate absorption on the optical and geometrical characterization
      of thin dielectric films.
AB  - The role played by a glass substrate on the accurate determination of the optical
      constants and the thickness of a thin dielectric film deposited on it, when well
      known envelope methods are used, is discussed. Analytical expressions for the two
      envelopes of the optical transmission spectra corresponding to film. with both
      uniform and nonuniform thicknesses are derived, assuming the substrate to be a
      weakly absorbing layer. It is shown that accurate determination of the refractive
      index and the film thickness is notably improved when the absorption of the
      substrate is considered. The analytical expressions for the upper and lower
      envelope, are used to characterize optically and geometrically both uniform and
      nonuniform amorphous chalcogenide films. The results obtained are compared with
      those derived by use of expressions for the envelopes that neglect the substrate
      absorption. The comparison shows that overestimated refractive indexes and
      underestimated thicknesses are obtained when the conventional approach, in which
      the substrate absorption is neglected, is used.

PMID- 12477123
TI  - Measurements of the refractive index of yttrium in the 50-1300-eV energy region.
AB  - The first experimental results to our knowledge on the refractive index n = 1 -
      delta + ibeta of yttrium in the extreme-ultraviolet and soft x-ray energy ranges
      are discussed. To determine the absorptive part beta, transmittance measurements
      were performed on pure yttrium films in the 50-1300-eV energy region at beamline
      6.3.2 of the Advanced Light Source. The dispersive part delta was then calculated
      from the absorption results by means of the Kramers-Kronig transformation.
      Compared with prior tabulated values, the new wet of data for the refractive
      index of yttrium is in better agreement with the sum rules and contains
      previously unresolved fine structure information in the regions of the M2,3 and
      M4,5 absorption edges, where yttrium-based multilayer mirrors operate.

PMID- 12477124
TI  - Method to measure the optical properties of small volumes of diffusive media.
AB  - The method consists of measuring the perturbation provoked by a small volume of
      the diffusive medium on light propagating through a medium of known optical
      properties. The absorption and the reduced scattering coefficients of the medium
      are retrieved from multidistance continuous-wave measurements of transmittance.
      The inversion procedure is based on the solution of the diffusion equation
      obtained with a perturbative approach. The method has been validated with Monte
      Carlo results. Examples of experimental results are reported.

PMID- 12477125
TI  - Adaptive calibration for object localization in turbid media with interfering
      diffuse photon density waves.
AB  - The amplitude cancellation method that uses dual out-of-phase sources (a phased
      array system) can sensitively detect and locate small objects in turbid media.
      The balance of these two sources is crucial to the system's detection sensitivity
      and accuracy. We describe a convenient method with which to adaptively calibrate
      the amplitudes of the two sources at each scanning position by use of low
      frequency modulation of the intensity of the in-phase and the antiphase sources.
      We achieve accurate localization ability of the phased array system by accounting
      for the influence of asymmetrical boundaries and the heterogeneous background
      absorption. Experimental data on human breast phantoms demonstrate that
      localization accuracy within several millimeters has been accomplished through
      this method.

PMID- 12477126
TI  - Determination of bacterial activity by use of an evanescent-wave fiber-optic
      sensor.
AB  - A novel technique based on fiber-optic evanescent-wave spectroscopy is proposed
      for the detection of bacterial activity in human saliva. The sensor determines th
      e specific concentration of Streptococcus mutans in saliva, which is a major
      causative factor in dental caries. In this design, one prepares the fiber-optic
      bacterial sensor by replacing a portion of the cladding region of a multimode
      fiber with a dye-encapsulated xerogel, using the solgel technique. The
      exponential decay of the evanescent wave at the core-cladding interface of a
      multimode fiber is utilized for the determination of bacterial activity in
      saliva. The acidogenic profile of Streptococcus mutans is estimated by use of
      evanescent-waveabsorption spectra at various levels of bacterial activity.

PMID- 12477127
TI  - Application of Fourier transform infrared ellipsometry to assess the
      concentration of biological molecules.
AB  - Spectroscopic ellipsometry is a noninvasive optical characterization technique
      mainly used in the semiconductor field to characterize bare substrates and thin
      films. In particular, it allows the gathering of information concerning the
      physical structure of the sample, such as roughness and film thickness, as well
      as its optical response. In the mid-infrared (IR) range each molecule exhibits a
      characteristic absorption fingerprint, which makes this technique chemically
      selective. Phase-modulated IR ellipsometry does not require a baseline correction
      procedure or suppression of atmospheric CO2 and water-vapor absorption bands,
      thus greatly reducing the subjectivity in data analysis. We have found that
      ellipsometric measurements of thin films, such as the solid residuals left on a
      plane surface after evaporation of a liquid drop containing a given compound in
      solution, are particularly favorable for dosing purposes because the intensity of
      IR absorptions shows a linear behavior along a wide range of solution
      concentrations of the given compound. Our aim is to illustrate with a concrete
      example and to justify theoretically the linearity experimentally found between
      radiation absorption and molecule concentration. For the example, we prepared
      aqueous solutions of glycogen, a molecule of huge biological importance currently
      tested in biochemical analyses, at concentrations ranging from 1 mg/l to 1 g/l
      which correspond to those found in physiological conditions. The results of this
      example are promising for the application of ellipsometry for dosing purposes in
      biochemistry and biomedicine.

PMID- 12477128
TI  - Semi-three-dimensional algorithm for time-resolved diffuse optical tomography by
      use of the generalized pulse spectrum technique.
AB  - Although a foil three-dimensional (3-D) reconstruction with both 3-D forward and
      inverse models provide, the optimal solution for diffuse optical tomography
      (DOT), because of the 3-D nature of photon diffusion in tissue, it is
      computationally costly for both memory requirement and execution time in a
      conventional computing environment. Thus in practice there is motivation to
      develop an image reconstruction algorithm with dimensional reduction based on
      some modeling approximations. Here we have implemented a semi-3-D modified
      generalized pulse spectrum technique for time-resolved DOT, where a two
      dimensional (2-D) distribution of optical properties is approximately assumed,
      while we retain 3-D distribution of photon migration in tissue. We have validated
      the proposed algorithm by reconstructing 3-D structural test objects from both
      numerically simulated and experimental date. We demonstrate our algorithm by
      comparing it with the calibrated 2-D reconstruction that is in widespread use as
      a shortcut to 3-D imaging and proving that the semi-3-D algorithm outperforms the
      calibrated 2-D algorithm.

PMID- 12477129
TI  - Hispanic health: persistent disparities and promising developments.

PMID- 12477130
TI  - Hispanic health: how healthy is the fastest growing population of the United
      States?

PMID- 12477131
TI  - Is alcohol intake associated with breast cancer in Hispanic women? The New Mexico
      Women's Health Study.
AB  - OBJECTIVE: Previous studies have shown an increased breast cancer risk associated
      with modest or high alcohol intake, however, few of these studies have included
      Hispanic women. The alcohol/breast cancer association was investigated in a New
      Mexico (NM) statewide bi-ethnic study. DESIGN: A population-based, case-control
      study. METHODS: Incident breast cancer cases (N = 712), aged 30-74 years, were
      ascertained by the New Mexico Tumor Registry (NMTR). Controls (N = 844) were
      identified by random digit dialing and were frequency-matched for ethnicity, age
      group, and health planning district. Data were collected via in-person interview,
      which included questions regarding recent and past alcohol intake and breast
      cancer risk factors. RESULTS: The highest level of recent alcohol intake,
      compared to no intake, was associated with breast cancer risk for postmenopausal
      Hispanic women (odds ratio [OR] = 2.0 95%, confidence interval [CI] 0.8-5.1, 42+
      grams/ week) and postmenopausal non-Hispanic White women (OR = 2.2, 95% Cl 1.0
      5.0, 148+ grams/week), although estimates were unstable and statistically non
      significant. Lower recent alcohol intake (< 148 grams/week) was associated with
      reduced risk for non-Hispanic Whites (OR = 0.49, 95% Cl 0.35-0.69). This pattern
      was independent of hormone-receptor status and was present for both premenopausal
      (OR = 0.29, 95% Cl 0.15-0.56) and postmenopausal women (OR = 0.56, 95% Cl 0.35
      0.90). Results for past alcohol intake and breast cancer association did not
      demonstrate any trends and were non-significant. CONCLUSIONS: Alcohol intake does
      not appear to have a consistent or significant association with breast cancer in
      Hispanic women.

PMID- 12477132
TI  - Testing the weathering hypothesis among Mexican-origin women.
AB  - OBJECTIVE: To examine the "weathering hypothesis," as proposed by Geronimus
      (1986; 1987; 1992; 1996), among US-born and foreign-born Mexican-origin women.
      This hypothesis specifically argues that the relationship between age and a
      variety of reproductively related heath outcomes varies by socioeconomic and
      environmental context. METHODS: 1989-1991 National Center for Health Statistics
      (NCHS) linked birth-death files. These files include all women who experienced a
      live birth in the United States and whose infants were issued a birth certificate
      during the years 1989 to 1991 (NCHS 1995). Age and nativity specific
      distributions on infant mortality, low birth weight, anemia, pregnancy related
      hypertension, and smoking were estimated for Mexican-origin women. RESULTS: For
      the foreign-born, levels of neonatal mortality are highest for younger women and
      tend to increase again in women at the oldest ages. For the US born, the lowest
      levels are for women aged 17 and 18 years, and 27-29 years. Levels for women aged
      19-24 years and 30-34 years are higher than those for 17-and 18-year-olds. For
      both groups of women, giving birth to infants with low birth weight is most
      common at the earlier ages, declining more or less until the mid twenties when
      the rate begins to rise again slowly. Patterns for the maternal health indicators
      vary, with pregnancy related hypertension most strongly following the pattern
      suggested by weathering. CONCLUSION: Overall, this analysis suggests that there
      is evidence of weathering within the Mexican-origin population, particularly for
      the US-born population, and this is most clearly seen in levels of neonatal
      mortality and pregnancy related hypertension.

PMID- 12477133
TI  - Perinatal outcomes among Mexican Americans: a review of an epidemiological
      paradox.
AB  - This article presents a review of 3 possible explanations for the seemingly
      apparent paradox of favorable birthweight outcomes among Mexican Americans.
      Evidence is grouped into 3 explanations: cultural, under-reporting, and bio
      medical. With an emphasis on the link between acculturation among Mexican
      Americans and their perinatal outcomes, the key correlates associated with lower
      rates of low birth weight (LBW) are examined and critiqued. This review of the
      literature also explores policy and health implications for this important public
      health issue.

PMID- 12477134
TI  - Severity of illness, treatment environments, and outcomes of treating acute
      myocardial infarction for Hispanic Americans.
AB  - OBJECTIVE: To examine associations of ethnicity with severity of illness,
      treatment environments, outcomes, as well as their interactions among acute
      myocardial infarction (AMI) patients. DESIGN, SETTING, AND PARTICIPANTS: 182,374
      Hispanic and non-Hispanic White AMI discharges in the 1998-1999 National
      Inpatient Sample. MAIN OUTCOME MEASURES: In addition to measuring severity of
      illness and the treatment environments defined as care-seeking characteristics
      and process of care, the principal outcome measure was hospital mortality.
      RESULTS: Compared to non-Hispanic White patients, Hispanic patients were
      associated with a greater comorbidity index, less likely to be treated in small
      (odds ratios [OR], 0.67), rural (OR, 0.39), or low-volume hospitals (OR, 0.90),
      but more likely to be treated in teaching hospitals (OR, 1.74). Further, Hispanic
      patients were less likely to receive arteriography, PTCA, and CABG, but
      positively associated with more resource use; also, Hispanic patients were less
      likely to be discharged to non-acute health facilities (OR, 0.80) or to die in
      hospital (OR, 0.78). Finally, comorbidities and the receiving of PTCA interacted
      with ethnicity, respectively, to affect mortality. CONCLUSIONS: Substantial
      differences in the hospital care for AMI existed between Hispanic and non
      Hispanic White patients. While the treatment environments were less favorable for
      Hispanics, their survival advantage over non-Hispanic Whites remains to be
      unexplained. Biological or other social or clinical factors need to be identified
      to better explain the lower mortality rates of Hispanics. Enhancing access to
      specialized services should improve health outcomes for non-Hispanic Whites.

PMID- 12477135
TI  - Hypertension among Hispanic elders of a Caribbean origin in Massachusetts.
AB  - OBJECTIVES: We determined the prevalence and associated risk factors of
      hypertension in Hispanic elders, ages 60-92 years, living in Massachusetts.
      DESIGN: Cross-sectional study. SETTING: State of Massachusetts. SUBJECTS: A
      representative sample of 597 Hispanics of Caribbean origin (77% Puerto Ricans and
      23% Dominicans) and 243 non-Hispanic Whites from the same neighborhoods.
      MEASURES: Blood pressure, income, health behaviors, chronic conditions, body mass
      index (BMI), and waist circumference. RESULTS: Hypertension was prevalent in all
      groups: 66% for Puerto Rican and 73% Dominican men, 69% for non-Hispanic White
      men; and 75%, 76%, and 74% for women in these groups, respectively. Twenty-one
      percent of Puerto Rican and 15% of Dominican women had systolic hypertension,
      compared to 9% for non-Hispanic White women (P < .01 anti P < .05, respectively).
      The prevalence of systolic hypertension was 14% and 21% for Puerto Rican and
      Dominican men, compared to 13% for non-Hispanic White men (not significant).
      Puerto Rican women with hypertension were less likely to have their blood
      pressure under control than were non-Hispanic While women. Puerto Rican and
      Dominican elders remained more than 2.6 times more likely to have systolic
      hypertension than non-Hispanic White elders after adjusting potential
      confounders. CONCLUSION: Hypertension is prevalent in this population and
      systolic hypertension is more prevalent among Hispanic vs non-Hispanic White
      elders. Investigation of genetic or other factors associated with this apparent
      excess risk of systolic hypertension among elderly Hispanics, particularly among
      women, is warranted.

PMID- 12477136
TI  - Parental prompting and smoking among Latino youth.
AB  - OBJECTIVES: Our previous research indicated that Latino parents, more so than non
      Latino parents, may prompt their children to engage in behaviors that encourage
      them to "practice" smoking-related behaviors. The present study examined Latino
      and non-Latino adolescents' reports of parental prompting, defined as parental
      requests to: 1) empty/clean ashtrays; 2) bring cigarettes to parent; 3) accept
      tobacco industry promotional gear as a gift; 4) buy cigarettes for parent; 5)
      light parent's cigarette with a match or lighter; 6) start the cigarette in
      his/her own mouth and then pass it to parent; and 7) smoke with the parent.
      DESIGN AND METHODS: In 10 schools in the Southbay area of San Diego, 3,599 7th
      and 8th grade middle school students, the majority of whom were Latino, completed
      cross-sectional surveys assessing 7 parental prompts, past-month smoking,
      parental smoking, acculturation, and familism. RESULTS: Findings indicated that
      parental prompts were less prevalent than in our previous work. We also found
      that there were not consistent or great differences in the prevalence of
      prompting between Latinos and non-Latinos and that parental prompting,
      particularly requests that the child light the parent's cigarettes with a match
      or lighter, was associated with children's smoking. Further, we found that Latino
      adolescents may be influenced by more parental prompts than non-Latinos, and
      finally that higher familism scores were significantly associated with lower risk
      of smoking, regardless of ethnicity. CONCLUSIONS: Parental prompting and familism
      appear to be important correlates of adolescent smoking.

PMID- 12477137
TI  - Characteristics of Mexican-American elders with dementia presenting to a
      community-based memory evaluation program.
AB  - OBJECTIVE: To determine sociodemographic characteristics associated with the
      initial presentation of Mexican-American elders to a community-based memory
      evaluation clinic. METHODS: Retrospective review of the charts of 89 Mexican
      Americans presenting consecutively to an outpatient memory evaluation clinic in
      San Antonio, Texas. PRINCIPAL FINDINGS: Mexican Americans presented for
      evaluation with more moderate-to-severe cognitive impairment than previously
      reported. They also tended to have high levels of IADL (83.1%) and gait/balance
      (52.3%) impairment, as well as high levels of depressive symptoms (63.1%).
      CONCLUSIONS: Mexican Americans present for initial evaluation for memory decline
      with moderate-to-severe cognitive decline and significant dementia-associated co
      morbidities. In Mexican Americans, caregiver burden, fall risks, depressive
      symptoms, and need for IADL support should be addressed on the initial visit for
      memory decline.

PMID- 12477138
TI  - Utility of a surrogate measure of insulin resistance in American Indians: the
      Strong Heart Study.
AB  - OBJECTIVE: 1) Determine in a sample of American Indians (AI) how well insulin
      sensitivity (SI) measured by the frequently sampled intravenous glucose test
      (FSIGT) correlates with a simpler measure of insulin resistance (IR) measured by
      the homeostasis assessment (HOMA) model; (2) compare insulin sensitivity in a
      sample of diabetic and non-diabetic Al in the Strong Heart Study (SHS) with that
      of White, Black, and Hispanic Americans in the Insulin Resistance Atherosclerosis
      Study (IRAS). DESIGN: Cross sectional SETTING: Community PARTICIPANTS: Sixty-one
      Al participants in SHS MAIN OUTCOME MEASURES: Mean SI measured by FSIGT, a
      complex protocol to evaluate insulin sensitivity, and mean IR measured by the
      HOMA model, a method based on measures of fasting glucose and fasting insulin.
      RESULTS: Although 70% of sample participants were non-diabetic, only 18% were
      insulin sensitive by SI. Diabetes status strongly confounded Si among Al in SHS.
      At non-diabetic levels of fasting glucose (< 126 mg/dL), SI correlated well with
      HOMA IR (rho = -0.49, P = .0009), but SI did not reflect HOMA IR at levels of
      fasting glucose that are diagnostic of diabetes (> or = 126 mg/dL; rho = -0.13, P
      = n.s.). With the exception of some Hispanic participants in IRAS, mean SI of non
      diabetic Al in SHS was lower than that of their non-diabetic IRAS counterparts.
      Diabetic Al participants in SHS had markedly lower mean SI than all diabetic
      participants in IRAS. CONCLUSIONS: The HOMA model may be a useful tool to
      identify non-diabetic American Indians who might benefit from early CVD risk
      factor modification.

PMID- 12477139
TI  - Differential impact of cardiovascular disease (CVD) risk factor clustering on CVD
      and renal disease among African-American and white patients with type 2 diabetes
      mellitus.
AB  - OBJECTIVES: To determine if clustering of cardiovascular disease (CVD) risk
      factors has a differential impact on CVD and renal disease among African
      Americans compared to Whites with type 2 diabetes DESIGN: Cross-sectional.
      METHODS: Prevalent CVD, macroalbuminuria, and CVD risk factors were measured in
      323 African-American and White adult patients with type 2 diabetes. CVD risk
      factors were dichotomized according to standard guidelines. Data were analyzed by
      race according to the presence of any 3 or more CVD risk factors. RESULTS:
      Despite a similar prevalence of hypertension, the prevalence of macroalbuminuria
      in the presence of 3 or more CVD risk factors tended to be higher among African
      Americans compared to Whites (28.9% vs 13.6%, P = 0.05). The presence of 3+ CVD
      risk factors was associated with an odds ratio (OR) of 2.5 (P = 0.001, 95% CI,
      1.44-4.27) for macroalbuminuria in African Americans compared to an OR of 1.4 (P
      = 0.25, 95% CI, 0.78-2.53) in Whites. The race/3+ CVD risk factors interaction
      was statistically significant (P = 0.007). Conversely, the presence of 3+ risk
      factors was associated with an OR of 1.6 (P = 0.019, 95% CI, 1.08-2.28) for CVD
      in Whites compared to an OR of 0.8 (P = .287, 95% CI, 0.54-1.20) in African
      Americans. The prevalence of any CVD in the presence of 3+ risk factors was 61%
      and 49% in Whites and African Americans respectively (P = .217). The race/3+ CVD
      risk factors interaction was statistically significant (P = 0.029). CONCLUSIONS:
      These findings suggest that among persons with diabetes, a clustering of 3+ CVD
      risk factors is more predictive for renal disease among African Americans, and
      more predictive for CVD in Whites. Further research should clarify the impact of
      CVD risk factor clustering on the incidence of vascular disease among African
      Americans and Whites with type 2 diabetes.

PMID- 12477140
TI  - Black-white differences in tumor grade (aggressiveness) at diagnosis of prostate
      cancer, 1992-1998.
AB  - OBJECTIVES: To compare recent temporal trends in the proportion of high-grade
      (less differentiated, or more "aggressive") prostate cancers for Blacks (African
      Americans) and Whites. Reports of Black-White differences have generated
      speculation that genetic factors could be involved. METHODS: The study included
      all 126,889 non-Hispanic White and 20,247 Black patients with prostate cancer
      diagnosed in 1992-1998 and reported to the US National Cancer Institute's
      Surveillance, Epidemiology and End Results (SEER) Program of population-based
      cancer registries. RESULTS: Overall and stage-specific Black-White differences in
      proportion of high-grade cancers were not large and declined over time
      (especially among elderly patients). By 1998, the adjusted odds ratio for high
      (vs other known) grade was not statistically significant for Black vs White
      elderly patients when age and stage at diagnosis were included in a multiple
      logistic regression model. CONCLUSIONS: These data provide little justification
      for speculation about a genetic basis for a higher proportion of aggressive
      prostate cancer among Black patients. Trends in Black-White differences in the
      frequency of high-grade cancer suggest Black-White differences in trends in
      prostate cancer screening rates (especially in the elderly), which require
      further investigation.

PMID- 12477141
TI  - Health literacy, cervical cancer risk factors, and distress in low-income African
      American women seeking colposcopy.
AB  - OBJECTIVES: To describe the relationship between health literacy, distress, and
      cervical cancer risk factors in women at high risk for developing cervical
      cancer. DESIGN: Cross-sectional, prospective cohort design. SETTING: Two
      university-based gynecological oncology colposcopy clinics and 3 Planned
      Parenthood community dinics. PATIENTS/PARTICIPANTS: One hundred-thirty English
      speaking African-American women > or = 18 years referred for colposcopy following
      abnormal Pap testing. MAIN OUTCOME MEASURES: Avoidance and Intrusion subscales of
      the Impact of Events Scale (IES), Rapid Estimate of Adult Literacy in Medicine
      (REALM), and demographics. RESULTS: Forty-five percent of women had a low level
      of health literacy (< 9th grade). Low health literacy was related to fewer risk
      factors (P < .01) and higher levels of distress on the Impact of Events avoidance
      subscale (P < .05) after controlling for covariates. Forty-three percent of women
      with low literacy had excessive levels of distress as compared to 25% in women
      with high literacy (P < .05). CONCLUSIONS: A low level of health literacy is
      associated with increased levels of distress among women at high risk for
      developing cervical cancer. To the extent that distress serves as a barrier to
      treatment, culturally informed, effective interventions are needed.

PMID- 12477142
TI  - Patterns and correlates of alcohol consumption among African-American women.
AB  - PURPOSE: The purpose of the present study was to assess patterns and correlates
      of alcohol consumption among African-American women. METHODS: We used postal
      questionnaires to collect data in 1995 on alcohol consumption and on demographic,
      medical, and behavioral factors from 64,500 African-American women aged 21-69
      years from across the United States enrolled in the Black Women's Health Study.
      We used logistic regression analysis to assess the association of consumption
      with potential correlates. RESULTS: The prevalence of current drinking was
      highest (37.1%) among women 40-49 years of age, and lowest (23.1%) among women
      aged 21-29. In every region, heavy drinking (at least 14 drinks a week), reported
      by about 8% of current drinkers, was associated with current smoking, lower
      educational attainment, commencement of drinking at younger ages and,
      particularly, consumption of greater amounts of alcohol in the early years of
      drinking. CONCLUSION: Alcoholic beverage consumption in later life is strongly
      related to early patterns. Heavy consumption is associated with smoking and lower
      levels of education.

PMID- 12477143
TI  - Mid-life African-American women with type 2 diabetes: influence on work and the
      multicaregiver role.
AB  - PURPOSE: Few studies have examined the multicaregiver role, including the work
      role, of African-American women and the influence of that role on diabetes self
      management and the ability to cope with type 2 diabetes. Therefore, the purpose
      of this study was to explore the perceptions of work and the multicaregiver role
      of a group of such women to more clearly identify the influence of these factors
      on diabetic self-management and personal coping. METHODS: Focus group methodology
      was used to collect data from 12 mid-life African-American women. After data
      inspection, the research team extracted themes related to work and the
      multicaregiver role. Identification of relationships among and between themes
      helped delineate explanations of data and refine questions for future research.
      FINDINGS: Focus group analysis of participant responses elicited 4 themes. Family
      as core represented the participant's role as leader of her household. Work as
      survival defined the stresses of work and the physical and psychosocial responses
      to not working due to the social and economic costs of diabetes. Participants
      also identified pressures of balancing work and family responsibilities due to
      diabetes, a theme of impaired role function. The final theme, inner
      strengthening, defined participants' methods of self-preservation through
      introspection and spiritual behaviors. CONCLUSIONS: Despite their identification
      of physical and psychosocial struggles with diabetes, participants did not think
      of diabetes as a life-long illness because it affected their ability to remain at
      "the head of the table," to continue engaging in paid work outside the home, and
      to provide for their families. Historical, social, political, and economic
      factors supported the themes of the study and provide a foundation for further
      research and healthcare delivery system changes focused on improving the lives of
      these women and their families, who are facing the challenges of chronic illness.

PMID- 12477144
TI  - Healthy Growth: project description and baseline findings.
AB  - OBJECTIVES: The purpose of the study was to describe the physical activity, blood
      pressure, and body fat patterns of sixth-grade, African-American girls (N = 82),
      who participated in the Healthy Growth Study. The purpose of the primary study
      questions was to determine which sets of variables best predict blood pressure,
      physical activity, and body fat. DESIGN AND METHODS: This paper is a cross
      sectional analysis of the first assessment of a 5-year longitudinal project.
      Standard procedures were used to assess height, weight, skinfolds, blood
      pressure, physical activity, predictors of physical activity, maturation, dietary
      intake, fitness level, and health behaviors. RESULTS: The average age of the
      subjects was 12.3 years; almost two-thirds of the girls had reached menarche.
      Fifty-two percent of the 13-year-olds had body mass index (BMI) values greater
      than the 85th percentile for their age and sex compared to 32% of the 12-year
      olds. None of the variables were significantly related to diastolic or systolic
      blood pressure. Physical activity was significantly and negatively related to
      total percent of calories from fat and to breast stages and positively related to
      waist/thigh ratio. Body mass index (BMI) was significantly and positively related
      to breast stages. CONCLUSIONS: Important developmental differences between 12-
      and 1 3-year-olds were evident. Body mass index (BMI) was mainly dependent on
      physical maturity. No relationship was found between BMI and blood pressure. The
      relationship between physical activity and waist/thigh ratio merits further
      study. The importance of BMI and physical inactivity as potential indicators of
      cardiovascular risk in adolescent girls is discussed. Developmentally appropriate
      and culturally competent interventions are recommended to increase physical
      activity and healthy eating behaviors among adolescents.

PMID- 12477145
TI  - Influence of stereotyping in smoking cessation counseling by primary care
      residents.
AB  - This study examined racial differences in primary care residents' rates of
      addressing smoking cessation. We expected residents to have higher rates of
      addressing cessation with White female patients as compared with African-American
      or Hispanic female patients, due, in part, to residents having higher outcome
      expectancies, self-efficacy, lower barriers, and less reliance on stereotypes.
      Residents (N = 90) were an average of 31 years old; two-thirds were White
      internal medicine residents. Residents viewed a video of a lower-middle class
      White, African-American, or Hispanic female interacting with her physician about
      stomach pain. Results indicate that residents were very likely to address smoking
      cessation, regardless of patients' race. Compared to residents assigned to an
      ethnic minority patient, residents assigned to the White patient were less likely
      to believe the patient would follow their advice (P < .03) and also perceived
      more barriers to address smoking cessation (P < .04). Reliance on the stereotype
      of Whites mediated the racial difference in outcome expectancies. Implications
      are that residents may be relying on stereotypes when they assess lower-middle
      class White female patients' receptivity to smoking cessation advice. Future
      research on the role of stereotyping in medical settings is warranted.

PMID- 12477146
TI  - Addressing cardiovascular disease in patients with renal disease.
AB  - It is well-established that patients with renal disease are at increased risk of
      cardiovascular disease (CVD) death. Despite better understanding of CVD in
      endstage renal disease (ESRD) patients and more rigid guidelines addressing the
      major risk factors for CVD in this population, CVD continues to be the number one
      cause of death in patients with ESRD. Moreover, higher rates of CVD are seen in
      patients with moderate, and even mild, renal dysfunction and in patients with
      albuminuria (micro and macroscopic). Few studies with CVD endpoints have included
      patients with renal disease. There is sufficient evidence to support appropriate
      blood pressure reduction as having a beneficial effect on CVD morbidity and
      mortality in patients with renal disease (especially for patients with diabetes).
      Data supporting the benefit of modification of other CVD risk factors is not as
      strong, but current recommendations do stress aggressive control of lipids,
      smoking cessation, and maintenance of adequate nutritional status. Inclusion of
      patients with renal disease in studies with CVD endpoints is necessary. Until
      then, it is generally recommended that CVD risk stratification and modification
      strategies be applied to this high-risk population.

PMID- 12477147
TI  - Vascular endothelin converting enzyme-1 expression and activity is upregulated in
      clinical diabetes.
AB  - Circulating and vascular endothelin-1 (ET-1) levels are elevated in diabetes, but
      the molecular components of the enzymatic activation of ET-1 in the vasculature
      remains unknown. Furthermore, the distribution of ET receptors favors a
      contractile phenotype in African Americans with diabetes. Whether there is any
      difference in local ET-1 activation in this population is unknown. This study
      examined the expression and activity of ET converting enzyme-1 subisoforms (ECE
      1) in the internal mammary artery specimens obtained from patients undergoing
      coronary artery bypass grafting. The study groups included African-American (AA)
      and Caucasian (CA), nondiabetic (ND) and diabetic (D) patients: AAND N = 10, CAND
      N = 9, AAD N = 9, and CAD N = 11. The expression of ECE-1 a, ECE-1 b and ECE-1c
      subisoforms was studied by RT-PCR. ECE-1 a was upregulated 2- and 4-fold in the
      CAD and MD groups, respectively (P < .05). In African-American patient groups,
      ECE-1 activity (fmol/ mg protein.h) was augmented from 2,804 +/- 185 in
      nondiabetic tissue samples to 6,857 +/- 393 in the diabetic tissue (P < .05).
      There was a similar increase in the CAD group, which did not significantly differ
      from AA diabetics. ECE-1 inhibitors, phosphoramidon and FR-901533, inhibited
      vascular ECE-1 activity by more than 80%. While neutral endopeptidase (NEP) and
      matrix metalloproteinase-2 (MMP-2) are able to process big ET-1, inhibitors of
      NEP (thiorphan) and MMP (batimistat) did not affect ECE-1 activity. In
      conclusion, the enzymatic pathway essential for generating vascular ET-1 is
      activated in the vasculature of both AA and CA diabetic patients and this
      activation is highly specific for ECE-1.

PMID- 12477148
TI  - Insulin resistance, beta cell function and cardiovascular risk factors in
      Ghanaians with varying degrees of glucose tolerance.
AB  - OBJECTIVE: Type 2 diabetes is characterized by beta cell dysfunction and insulin
      resistance (IR). The disease is associated with high rates of cardiovascular
      mortality and morbidity. Recently, the American Diabetes Association Expert
      Committee recommended the measurement of fasting glucose as a tool for screening
      and diagnosing diabetes, in order to identify patients with a mild form of the
      disease as well as to enhance the detection of undiagnosed type 2 diabetes. The
      significance of these criteria with respect to cardiovascular risk factors in
      native Ghanaians is unknown. The objectives of the present study were to examine
      the cardiovascular risk factors in a sample of native Ghanaians with varying
      degrees of glucose intolerance as defined by fasting glucose levels as specified
      by the ADA criteria. RESEARCH AND METHODS: The population consisted of 200
      indigenous Ghanaian subjects, age range 25-74 years, residing in the Accra
      metropolitan areas. Subjects were categorized using the fasting plasma glucose
      (FPG) alone as normal fasting glucose (NFG, FPG < 110 mg/ dL), impaired fasting
      glucose (IFG, 11 < FPG 126 mg/dL), and diabetic (DM, FPG > 126 mg/ dL).
      Anthropometric parameters (blood pressure, waist circumference and waist-hip
      circumference ratios) were measured in each subject. Levels of serum glucose, c
      peptides and insulin were measured at baseline and after 2 hours of oral glucose
      challenge. Insulin resistance (HOMA-IR) and beta cell function (HOMA-%B) were
      assessed by homeostasis model assessment (HOMA). Levels of fasting serum
      cholesterol, high-density lipoprotein cholesterol (HDL-C), cholesterol, and
      triglycerides were measured in each subject. RESULTS: There were 181 subjects in
      the NFG category, 11 in the IFG category, and 8 newly diagnosed type 2 diabetic
      subjects. The mean age, BMI, waist circumference (WC), and WHR did not differ
      between the 3 groups. The mean fasting glucose and the corresponding 2-hour
      glucose levels rose with the worsening of glucose tolerance. Similarly, the means
      for serum fasting, post-challenge serum insulin, and c-peptide levels were
      significantly greater in the IFG and DM groups. Fasting serum cholesterol and
      high density lipoproteins did not differ statistically between the 3 groups,
      However, the means for serum triglycerides were greater in the IFG and DM groups
      when compared to the NFG group. The insulin resistance (IR) as assessed by HOMA
      was 2x and 4x greater in the IFG (3.76) and DM (6.12) groups when compared with
      the NFG (1.82, P < .05). CONCLUSIONS: We have characterized the metabolic and
      anthropometric risk factors for CVD in native Ghanaians with varying degrees of
      glucose tolerance, as defined by the ADA criteria. We found that both IFG and DM
      were associated with beta cell dysfunction, insulin resistance, and elevated
      serum triglycerides. However, the well established cardiovascular risk factors,
      such as body mass index, body fat distribution, and blood pressure did not track
      with the increasing glucose intolerance in the native Ghanaians. We conclude that
      the Ghanaian patients with IFG and type 2 diabetes were non-obese and exhibited
      severe beta cell dysfunction, insulin resistance, and elevated triglycerides, but
      none of the other conventional risk factors, at the time of diagnosis. Future
      research should focus on the sequential changes in risk factors during
      development of cardiovascular diseases in native Ghanaians with varying degrees
      of glucose tolerance.

PMID- 12477149
TI  - Decreased vascular matrix metalloproteinase abundance in diabetic patients with
      symptomatic macroangiopathy.
AB  - The incidence of diabetic amputations is 2- to 3-fold higher in African-American
      patients compared to Caucasians. Vascular remodeling characterized by
      extracellular matrix (ECM) deposition occurs in diabetes and contributes to
      vascular complications. The matrix metalloproteinases (MMP) play important roles
      in the regulation of collagen turnover and vascular remodeling. However, the
      temporal expression profile of MMPs in diabetic vascular tissue during the
      disease process remained unknown. The objective of this study was to compare the
      vascular MMP system in African-American diabetic patients without symptoms to
      patients undergoing lower limb amputation due to severe vascular complications.
      Internal mammary artery (IMA, N = 8) and anterior/posterior tibial artery (AT/PT,
      N = 8) specimens were obtained from patients undergoing coronary artery bypass
      grafting and lower limb amputation, respectively. ECM inducer protein (EMMPRIN)
      and MMP activator membrane-type MMP (MT1-MMP), as well as MMP-1, -2, and -9, were
      quantified by immunoblotting and densitometry (pixels). MMP-1 and -9 levels were
      decreased from 398 +/- 61 and 175 +/- 54 pixels, respectively, in IMA tissue to
      287 +/- 31 and 51 +/- 36 pixels in the AT/PT tissue (P < .05). Both EMMPRIN and
      MT1-MMP expression was increased by 3-fold in AT/PT preparations (P < .05). These
      results provided evidence that the molecular components required for the
      induction and activation of the MMP system exist in arterial vasculature and, MMP
      expression is downregulated in diabetic patients with severe complications
      despite elevated MMP inducer and activator proteins. Decreased MMP activity may
      contribute to pathological remodeling leading to increased incidence of
      amputations in African-American patients.

PMID- 12477150
TI  - The relationship between menstrual factors and breast cancer according to
      estrogen receptor status of tumor: a case-control study in African-American
      women.
AB  - BACKGROUND: Exposure to estrogen is a risk factor for breast cancer. Since
      estrogen executes its effect through estrogen receptors (ERs), the relationship
      between menstrual factors, which are estrogen-related, and breast cancer may be
      different depending upon ER status of tumors. This case-control study aimed to
      examine such a relationship according to ER status of breast cancer in African
      American women. METHODS: Cases were 304 African-American patients pathologically
      diagnosed with breast cancer during 1995-1998, who were 20-64 years old and lived
      in 3 Tennessee counties. Controls were 305 African-American women without breast
      cancer, selected through random-digit dialing and frequency matched to cases by
      age and county. Information on menstrual factors (age at menarche, age at
      menopause, time from menarche to menstrual regularity, cycle length, and length
      of flow) and other risk factors were collected through telephone interviews.
      Estrogen receptor status of tumor samples was defined based on
      immunohistochemical measurement. Logistic regression analysis was used to
      calculate odds ratios and 95% confidence interval (CI). RESULTS: Compared to
      women with an average cycle length less than 28 days, the risks of breast cancer
      for those with longer length were 0.62 (95% CI, 0.36-1.06) and 0.56 (95% CI, 0.32
      1.00) for ER-positive and ER-negative tumors, respectively. The corresponding
      odds ratio (OR) estimates were 0.42 (95% CI, 0.20-0.86) and 0.38 (95% CI, 0.16
      0.90) for postmenopausal women. Other menstrual factors were not significantly
      associated with breast cancer for either ER status. CONCLUSIONS: Our results did
      not show a different menstrual factor/breast cancer relationship in terms of ER
      status in African-American women, although there might be an association between
      menstrual cycle length and the disease.

PMID- 12477151
TI  - Prostate cancer risk is three-fold higher among men, aged 50-64, of African
      descent compared with men of Asian-Indian descent in Trinidad and Tobago.
AB  - OBJECTIVE: To test the hypothesis that the screening-detected prevalence of
      prostate cancer is higher among men of African descent than among men of Asian
      Indian descent living in Trinidad & Tobago. DESIGN: Population-based prostate
      cancer screening study among men aged 50-64. SETTING: Caribbean islands of
      Trinidad and Tobago. PARTICIPANTS: Tobago, population-based sample of 1196 male
      residents of African descent; Trinidad, 173 agricultural workers of Asian-Indian
      descent. INTERVENTIONS: Serum prostate specific antigen (PSA, Abbot AxSYM) and
      digital rectal exam (DRE) were used to screen men for prostate cancer. Men with
      elevated PSA (> or = 4 ng/mL) and/or abnormal DRE were offered an ultrasound
      guided sextant biopsy of the prostate gland. MAIN OUTCOME MEASURES: Prevalence of
      abnormal screen; prevalence of prostate cancer. RESULTS: Elevated PSA and/or
      abnormal DRE were observed in 29% (348/1196) of Afro-Tobagonian men. Three
      hundred sixteen men underwent biopsies. Screening-detected prostate cancer
      prevalence was: 4.9% (23/468) for those aged 50-55; 7.7% (28/366) for those aged
      55-59; and 13.3% (48/362) for those aged 60-64 years. Screening was abnormal in
      18% (31/173) of Asian-Indian men; 25 underwent biopsies. Prostate cancer
      prevalence in Asian Indian men was: 1.6% (1/63) for those aged 50-54; 1.4% (1/71)
      for those aged 55-59; and 5.1% (2/39) for those aged 60-64 years. Mantel-Haenszel
      age-adjusted rate ratio was 3.4, 95% CI 1.3-9.0. CONCLUSIONS: This study
      establishes a high prevalence of screening-detected prostate cancer among Afro
      Tobagonians compared with Indo-Trinidadians. Comparison of candidate genes,
      environmental, and lifestyle factors between these populations may identify
      factors that increase risk for, or provide protection against, prostate cancer.

PMID- 12477152
TI  - Dietary approaches for weight management in African Americans.

PMID- 12477153
TI  - Obesity clinical trials in youth: concepts and challenges.

PMID- 12477154
TI  - Scope of cardiovascular complications in patients with kidney disease.
AB  - Approximately 6 million Americans have combined chronic cardiovascular and kidney
      disease with growing epidemics of heart and kidney failure. This clinical
      intersection presents unique risks to the patient and unique challenges to the
      clinician. Observational studies have provided quantitative methods for
      estimating the risk of acute renal failure in patients undergoing percutaneous
      intervention and bypass surgery procedures. Fortunately, for the general
      cardiovascular population, these risks are small. On the other hand, patients
      with chronic kidney disease have increased risks of accelerated atherosclerosis,
      nonfatal myocardial infarction, congestive heart failure, atrial and ventricular
      arrhythmias, and cardiac death. Chronic kidney disease presents difficult
      scenarios in using conventional cardioprotective therapy. However, there are
      increasing bodies of evidence to suggest the kidney and the heart can be targeted
      with lines of therapy, specifically with renin-angiotensin system antagonism,
      which benefit both systems with respect to reduction in the progression of
      disease, and the prevention of hard kidney and cardiac endpoints. This paper will
      address the scope of cardiovascular complications in patients with chronic kidney
      disease and discuss the rationale for expanded basic and clinical investigation
      of the cardiorenal patient population.

PMID- 12477155
TI  - Therapeutic controversies in hypertension management: angiotensin converting
      enzyme (ACE) inhibitors or angiotensin receptor blockers for diabetic
      nephropathy? A case for ACE inhibitors.
AB  - Diabetic nephropathy is the number one cause of endstage renal disease in the
      United States. Blockade of the renin angiotensin system (RAS) is important in the
      treatment of diabetic nephropathy. With the reports of recently completed trials
      examining the role of angiotensin receptor blockers (ARBs) in type 2 diabetic
      nephropathy, the question has arisen as to which agents are best to block the RAS
      in type 2 diabetes. ACE inhibitors have been to preserve renal function in type 1
      diabetics with nephropathy in large, randomized, placebo controlled trials, but
      such data is lacking in type 2 diabetes. Neverthelesss, ACE inhibitors have been
      recommended for use in type 2 diabetic nephropathy for some time. In type 2
      diabetics, ACE inhibitors may have a role in preventing development of
      nephropathy, and, importantly, ACE inhibitors have been shown to reduce
      cardiovascular disease in diabetics with and without nephropathy. In addition,
      ACE inhibitors have beneficial effects on other diabetic complications such as
      retinopathy and neuropathy. Until better comparative data between ACE inhibitors
      and ARBs on nephropathy and cardiovascular outcomes is available, ACE inhibitors
      should remain an important consideration for treatment of diabetic nephropathy.

PMID- 12477156
TI  - Determinants of uncontrolled hypertension in an African-American population.
AB  - OBJECTIVES: The purpose of this study was to assess blood pressure control and
      the determinants of uncontrolled blood pressure among African-American
      hypertensive patients. DESIGN: Baseline clinical data were collected as part of a
      nationwide hypertension quality improvement initiative. An analysis of
      determinants of uncontrolled blood pressure was conducted using logistic
      regression for the following variables: angina, congestive heart failure,
      coronary artery disease, diabetes, family history of cardiovascular disease or
      stroke, hyperlipidemia, left ventricular hypertrophy, and tobacco use. SETTING:
      10 managed care/advanced physician organizations. PATIENTS: Pharmacy and medical
      claims covering 1,965,000 lives were reviewed and 292,996 members with a
      hypertension-related claim were identified between June 1, 1998 and July 1, 2001.
      A random sample (N = 5,935) was selected for chart review. The present analysis
      was conducted on the subset of African-American patients (N = 440) included in
      this sample. RESULTS: Approximately 66% of the African-American patients were
      female, the mean age was 60.4 years, 47.8% had dyslipidemia, and 31.4% had
      diabetes. Approximately 64% had uncontrolled hypertension. Patients with diabetes
      were 3 times more likely to have uncontrolled blood pressure as were patients
      without diabetes (OR = 2.92; P < .0001). CONCLUSIONS: Blood pressure control in
      the African-American population is lower than the Healthy People 2010 goal of
      50%. African Americans with hypertension and diabetes are at an increased risk
      for uncontrolled blood pressure. Treating this high-risk population more
      aggressively may reduce long-term complications and decrease mortality.

PMID- 12477157
TI  - Communication skills to improve patient satisfaction and quality of care.
AB  - While clinicians face increasing time pressure in caring for patients,
      communication with the patient can suffer. Communication is especially important
      in caring for the increasingly culturally diverse patient population in the
      United States. Different values, beliefs, and attitudes about health, illness,
      and health care can affect illness outcomes. These are best understood through
      dialogue. Patient-centered communication skills are associated with improved
      health outcomes, improved patient and clinician satisfaction, and less risk of
      malpractice suits. This paper reviews techniques to efficiently incorporate
      patient-centered communication into the medical encounter, with emphasis on
      interacting with patients of different cultures.

PMID- 12477158
TI  - Tailoring counseling on physical activity and inactivity for African-American
      women.
AB  - Physician counseling is one potential avenue to decrease levels of inactivity
      among African-American (AA) women and, possibly, to decrease the prevalence of
      adverse health outcomes, which can be reduced through regular participation in
      physical activity. Physical inactivity has been associated with increased
      morbidity and mortality, as well as risk for various health outcomes, including
      cardiovascular disease, stroke, diabetes, and some forms of cancer. The problem
      of inactivity applies to all US adults, but national data consistently show that
      levels are highest among AA women. The first section of this brief review
      provides background information related to the prevalence of physical activity,
      current physical activity recommendations for various outcomes, and the
      healthcare provider's role in increasing physical activity. The second section
      suggests practical approaches for physicians who wish to counsel AA women about
      increasing physical activity. Many of the approaches are also applicable to AA
      men and to the general population.

PMID- 12477159
TI  - Considering the whole patient with hypertension: the ethos of pharmaceutical
      care.
AB  - From a pharmaceutical care perspective, this article will assess co-existing
      factors affecting the patient with hypertension. It will begin by defining
      pharmaceutical care, the components necessary for the provision of such, and how
      the provision of pharmaceutical care has already affected patient care. Then, it
      will explore those factors that influence the development of the therapeutic
      relationship, such as culture and ethnicity, socioeconomic status, age, gender,
      and functional status. Finally, this article will conclude with the rationale for
      and impact of providing pharmaceutical care to the patient with hypertension.

PMID- 12477160
TI  - Social class and heart disease mortality among African Americans.
AB  - The purpose of the present study was to examine variation in heart disease death
      rates by the social class of decedents. The term, "social class" refers to a
      complex set of phenomena such as control over economic resources, social status,
      and power relative to others in society. The target population for this study was
      African-American adults aged 35-74 years old who resided in the United States
      during the years 1996-1997. As a proxy for social class, we examined 5 levels of
      educational attainment: 0-8 years of school completed (Social Class I), 9-11
      years of school completed (Social Class II), high school graduate/12 years of
      school completed (Social Class III), some college completed (Social Class IV),
      and college degree completed (Social Class V). Older age, male gender, and lower
      social class were all independently associated with higher heart disease death
      rates. For all ages, more disadvantaged social classes had a higher risk of heart
      disease mortality. The highest relative risks were found for Social Classes I and
      II among the younger age groups. Many of the "prerequisites" for the "heart
      healthy lifestyle" are predicated on the benefits of a privileged social class
      position. For African Americans, there are the additional stressors of
      segregation, exclusion, and discrimination to overcome, as well as the cumulative
      physiological toll of lifetime resistance to various forms of racism. For many
      African Americans in disadvantaged social class positions, the obstacles to
      reducing the risk for heart disease are very difficult to overcome.

PMID- 12477162
TI  - The challenge of community cardiovascular disease: the Dan River Region
      Cardiovascular Health Initiative Program--DRchip.

PMID- 12477161
TI  - Geographic disparities in heart disease and stroke mortality among black and
      white populations in the Appalachian region.
AB  - In this paper, we examine geographic and racial/ethnic differences in heart
      disease and stroke mortality in the Appalachian region. Initial comparisons are
      made between national rates for heart disease and stroke mortality and those for
      the Appalachian region. County-level analyses were performed to examine the
      relative mortality experience of populations in Appalachian counties compared to
      other counties in the United States and to assess the degree of geographic
      disparity in mortality from heart disease and stroke among these race/ethnic and
      gender groups within Appalachia. The Appalachian region exhibits higher rates of
      both heart disease and stroke mortality for all race/ethnic, gender, and age
      groups examined. We found that many counties in the Appalachian region endure a
      considerable burden of the national excess in both heart disease and stroke
      mortality, and these counties tend to be aggregated in particular areas as
      opposed to being dispersed regionwide. Finally, we compare 2 groups of counties
      in Appalachia based on the designation as an "economically distressed county,"
      defined by the Appalachian Regional Commission. As a group, distressed counties
      in Appalachia exhibit higher rates of both heart disease and stroke mortality
      than the rest of Appalachia.

PMID- 12477163
TI  - Stress management strategies in hypertension control.

PMID- 12477165
TI  - Differences in rates of obstructive lung disease between Africans and African
      Americans.
AB  - OBJECTIVE: The prevalence of obstructive lung disease is rising in the United
      States, particularly among those of African descent. Rates of ventilatory
      impairment and reported respiratory symptoms were examined in a cross-sectional
      study of urban Nigerian civil servants who are in transition to a westernized
      lifestyle. DESIGN: 410 civil servants (235 men, 175 women) aged 30-69 years in
      Benin City, Nigeria (West Africa) were recruited for a cross-sectional study on
      respiratory health and compared to 3,397 African Americans enrolled in NHANES III
      between 1988 and 1994. METHODS: Forced vital capacity (FVC), expiratory flow rate
      in 1 sec (FEV1), FEV1/FVC ratio, and peak expiratory flow rate (PEFR) were
      measured by spirometry. Demographic characteristics and respiratory symptoms were
      ascertained by questionnaire. RESULTS: Nigerians had lower age and height
      adjusted FVC and FEV1 than African Americans in both genders, independent of
      smoking and respiratory disease. However, relative lung function was better among
      Nigerians. Fewer Nigerians had an age-adjusted FEV1/FVC ratio below 0.70 than
      African Americans (10.54 vs 14.10/100 men, 6.29 vs 8.67/100 women). Overall,
      Nigerians had a lower age-adjusted prevalence of any self-reported respiratory
      symptoms than African Americans (3.65 vs 22.90/100 men, 4.57 vs 35.38/100 women).
      Similarly, Nigerians had a lower age-adjusted prevalence of current smoking than
      African Americans (10.82 vs 46.50/100 in men and 0 vs 30.93/100 in women).
      CONCLUSIONS: Urban Nigerians who have limited exposure to cigarette smoke and who
      work in a non-industrial setting have a low prevalence of obstructive lung
      disease.

PMID- 12477164
TI  - Reproducibility of ambulatory blood pressure measures in African-American
      adolescents.
AB  - OBJECTIVE: The primary purpose of this study was to evaluate the reproducibility
      of ambulatory blood pressure (BP) measures in African-American (AA) adolescents.
      METHODS: Forty-one AA adolescents (age 16.6 +/- 1.3 yrs, 16F) with high-normal BP
      were measured on 3 occasions at 2-month intervals. Systolic BP (SBP), diastolic
      BP (DBP), and heart rate (HR) measures were recorded using the Spacelabs
      ambulatory BP monitor 90207 (Redmond, Wash) in the natural environment over 24
      hour periods. Mixed model repeated measures ANOVAs were used to analyze the
      underlying error variance-covariance (V-C structures as well as mean differences
      for the 3 visits. RESULTS: Daytime measures: there were no significant mean
      differences across visits for daytime SBP, DSP, and HR (all Ps > .57). The error
      V-C matrix was heterogeneous Toeplitz for daytime SBP. Correlations between
      visits 1 and 2, 1 and 3, and 2 and 3 for daytime SBP were rs = 0.71, 0.47, and
      0.71, respectively. Compound symmetry (CS) was the preferred model for daytime
      DBP (r = 0.68) and HR (r = 0.75). Nighttime measures: there were no significant
      mean differences across visits for nighttime SBP, DBP, and HR (all Ps > .29). The
      error V-C matrix was unstructured for nighttime SBP. Correlations between visits
      1 and 2, 1 and 3, and 2 and 3 for SBP were rs = 0.74, 0.33, and 0.33,
      respectively. CS was preferred for night-time DBP (r = 0.58) and HR (r = 0.74).
      CONCLUSION: Collectively, these findings demonstrate that 3 measurements of
      ambulatory-derived DBP and HR measures are stable across 4 months, but SBP was
      only stable across 2 months in African-American adolescents.

PMID- 12477166
TI  - Peripheral neuropathy associated with mitochondrial disorders: 8 cases and review
      of the literature.
AB  - Forty-three cases of peripheral neuropathy (PN) have been reported in the
      literature with a proven mitochondria (mt) DNA mutation, and 21 had a peripheral
      nerve biopsy (PNB). We studied 8 patients, 1 of whom had severe sensory PN, 3
      mild PN, and 4 subclinical PN. Nerve biopsy was performed in every case; all
      patients showed axonal degeneration and 4 showed features of primary myelin
      damage. In addition, there were 2 crystalline-like inclusions in the Schwann cell
      cytoplasm of a patient with MERRF, and 1 in a patient with multiple deletions on
      the mtDNA. There are 11 cases of PNB in the literature with axonal lesions, 5
      with demyelination, and 4 with mixed lesions. One PNB was not modified. A few
      crystalline-like inclusions were seen in 1 case of MERRF. Such inclusions were
      first reported in the Schwann cell cytoplasm of unmyelinated fibers in a patient
      with Refsum disease and were considered to be modified mitochondria. However,
      their mitochondrial origin remains debatable.

PMID- 12477167
TI  - Identification of novel sequence variants in the neurofilament-light gene in a
      Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal
      individuals.
AB  - Mutations of the neurofilament-light (NEFL/NF-L) gene were examined in 124
      unrelated Japanese patients with Charcot-Marie-Tooth disease (CMT) without known
      gene mutations, and 248 normal Japanese individuals. A new method, which can
      detect basepair mismatches with RNase cleavage on agarose gel electrophoresis,
      coupled with DNA sequencing, identified 8 novel sequence variations in the NF-L
      gene. In these sequence variants, 5 variants were polymorphisms, including 3
      single nucleotide polymorphisms (SNPs), and 3 other missense mutations (Pro22Thr,
      Asn97Ser and Ala148Val) were found in the patients with CMT phenotype. The
      variant alleles in the NF-L gene could influence the developing process of CMT
      phenotype and also might cause CMT phenotype.

PMID- 12477168
TI  - Quantitative sensory testing: high sensitivity in small fiber neuropathy with
      normal NCS/EMG.
AB  - We evaluated the diagnostic sensitivity of quantitative sensory testing (QST),
      using the CASE IV system, in 14 patients with clinically diagnosed small-fiber
      neuropathy and normal traditional electrodiagnostic studies. All patients had at
      least 1 abnormal threshold, 13 patients had abnormal heat-pain thresholds, 8 had
      abnormal cold thresholds, and 7 had abnormal vibration thresholds. QST is
      therefore highly effective in documenting dysfunction in small fiber neuropathy
      patients.

PMID- 12477169
TI  - Radial tunnel syndrome in an elite power athlete: a case of direct compressive
      neuropathy.
AB  - Radial tunnel syndrome (RTS) is thought to result from intermittent and dynamic
      compression of the posterior interosseous nerve (PIN) in the proximal part of the
      forearm associated with repeated supination and pronation. The diagnostic
      criteria encompassing RTS are purely clinical and the term "radial tunnel
      syndrome" has become controversial because of the lack of focal motor weakness in
      the majority of patients diagnosed with RTS. Retrospective cadaveric and surgical
      studies have revealed several areas within the forearm in which the PIN may
      become entrapped. Recent studies have suggested that the PIN is "fixed" in the
      supinator muscle and that wrist pronation is the actual movement that places the
      most stress on the PIN. The patients most often afflicted with RTS appear to be
      those who perform repetitive manual tasks involving rotation of the forearm and
      athletes involved in racket sports. Surgical exploration with decompression of
      the PIN is often required in patients with RTS. We present the first case of RTS
      occurring in an elite power athlete and believe this case represents a direct
      compressive sensory neuropathy. The optimum nonsurgical treatment plan for the
      elite athlete in training for competition and the cause of this compressive
      neuropathy in power athletes will be discussed.

PMID- 12477170
TI  - Repair of ventral root avulsions of the brachial plexus: a review.
AB  - Traumatic root avulsions of the brachial plexus constitute a devastating lesion
      resulting in loss of function of the upper limb and carry a large emotional and
      socioeconomic impact. In this literature survey, the different factors involved
      in root avulsion are discussed in combination with various surgical techniques
      for repair of experimental ventral root avulsion. Until now repair of root
      avulsions did not generate unequivocal proof of recovery of limb function,
      particularly of the hand. More experimental studies are needed to assess the
      efficacy of several repair techniques, the optimal timing for surgery, and the
      complications associated with spinal cord manipulation.

PMID- 12477171
TI  - The effects of high stimulus rate on the electrocochleogram in normal-hearing
      subjects.
AB  - The use of high stimulus rates has the potential to improve the
      electrocochleogram's (ECochG) sensitivity and specificity in endolymphatic
      hydrops and Meniere's disease, but is currently hindered by the absence of an
      acceptable normative database. In response, this study recorded click-evoked
      ECochG tracings from 51 normal-hearing subjects (102 ears), between 18 and 60
      years of age, at 7.1, 51.1, 101.1 and 151.1 clicks/s using a tympanic membrane
      electrode. As stimulus rate increased, various statistically significant (p <
      0.05) changes were observed. In general, summating potential (SP) latency and
      amplitude and action potential (AP) latency increased, SP/AP amplitude ratio and
      waveform width increased but then plateaued, and AP amplitude fluctuated. While
      providing the largest contribution to a high-stimulus-rate ECochG normative
      database published to date, potential clinical limitations were identified and a
      possible solution proposed.

PMID- 12477172
TI  - Opting for two hearing aids: a predictor of long-term use among adult patients
      fitted after screening.
AB  - This study is a follow-up of patients fitted with one or two hearing aids,
      approximately 10 years previously. Our patients were identified through
      population screening for hearing difficulties when they were aged 50-65 years. At
      the time, they had a trial of unilateral and bilateral fittings, and then they
      made their own choice to keep one or two aids. We found that 10 of the 12 who had
      opted for two aids and were available for follow-up 10 years later continued
      using at least one aid (83%, 95% CI 55-95). Six of the 17 who opted for
      unilateral fitting and were available for follow-up used a hearing aid in the
      long term (35%, 95% CI: 17-59%). Therefore, this study suggests that people who
      are identified through population screening, are bilaterally impaired, are
      willing to try bilateral fitting, and choose to continue with two aids, are
      likely to become long-term users of (one or two) hearing aids. Those who choose
      to continue with one aid after a trial of bilateral fitting are at high risk of
      rejecting the aid in the long term. Our sample is small, and we took a number of
      steps in the analysis in order to clarify whether these findings are reliable. We
      could not identify any confounding factors. The patients' preference for
      continuing with bilateral or unilateral aids after fitting was the only predictor
      of long-term use in our sample. Remarkably, bilateral preference was a better
      predictor of long-term use than the degree of hearing impairment. We discuss how
      this study provides useful information for planning population screening for
      hearing difficulties in middle age.

PMID- 12477173
TI  - Tinnitus in cochlear implant patients--a comparison with other hearing-impaired
      patients.
AB  - As part of a quality of life study, 84 patients who received multichannel intra
      cochlear cochlear implants (CIs) were evaluated regarding tinnitus problems by a
      questionnaire. As controls, 60 hearing aid (HA) users and 35 non-operated CI
      candidates were used. The prevalence of tinnitus in the CI group was 70%, and
      that of troublesome tinnitus was 35%. In the two other groups, the prevalences of
      tinnitus were 40% (HA) and 74% (non-CI). Twenty-three per cent of HA users and
      51% of non-operated CI candidates had troublesome tinnitus. CIs were found to be
      superior to HAs in reducing tinnitus, 54% of the CI patients with tinnitus
      experiencing a reduction in tinnitus when using a CI. In the other two groups, 4%
      of HA users and 23% of non-operated CI candidates experienced a reduction in
      tinnitus when using an HA. Eight per cent of the CI patients with tinnitus
      experienced an increase in tinnitus when using their implant. Not having paid
      employment was independently associated with troublesome tinnitus in all three
      groups.

PMID- 12477174
TI  - Measuring disability-specific patient benefit in cochlear implant programs:
      developing a short form of the Glasgow Health Status Inventory, the Hearing
      Participation Scale.
AB  - As healthcare resources are limited, evidence of program effectiveness is
      necessary. To demonstrate this, measurement should be conducted at the specific
      illness level, the generic health status level, and the utility level.
      Instruments need to be parsimonious to avoid cognitive overload, response burden,
      or participation refusal. Critical analysis of the Glasgow Hearing Status
      Inventory (GHSI) suggested that several items were redundant and the instrument
      could be shortened. We administered the GHSI and Assessment of Quality of Life
      (AQoL) instruments to 148 deafened adults with cochlear implants (CIs) and to 54
      without CIs, as part of a cross-sectional study. We used standard psychometric
      procedures to examine the GHSI's structure, resulting in the removal of half of
      the items. The short version of the GHSI we labeled the Hearing Participation
      Scale (HPS), to avoid confusion with the GHSI. The HPS is an 11-item instrument
      measuring self-esteem, social handicap, and hearing handicap. Factor analysis
      suggested that each subscale was unidimensional. All items loaded on the
      principal component. Correlation with the GHSI was 0.95, suggesting that the two
      instruments could be used interchangeably. Both the HPS and the GHSI pro-vided
      evidence of monotonicity when used to predict AQoL scores. They were equally
      sensitive at differentiating between implantees and non-implantees. Although
      these findings need to be confirmed, the HPS is ready to be used in studies of
      interventions for deafness. At a time when evaluators are being asked for
      evidence of program effect, the parsimonious HPS achieves similar results to the
      GHS but requires half the items.

PMID- 12477175
TI  - Hypersensitivity to sound (hyperacusis): a prevalence study conducted via the
      Internet and post.
AB  - The present study explored the prevalence and descriptive characteristics of
      hyperacusis, defined as unusual intolerance of ordinary environmental sounds. Two
      ways of collecting data were used in the study: the first was a postal survey of
      a random sample, to which 589 responded (59.7% response rate); the second was the
      internet, and 595 self-recruited individuals responded to a call for participants
      via a banner on a web page (51.9% response rate). The point prevalence rates of
      hyperacusis were 9% in the internet group and 8% in the postal group. Exclusion
      of participants who reported hearing impairment resulted in point prevalence
      rates of 7.7% (n = 39) and 5.9% (n = 28) respectively. The data collection format
      did not result in any substantial differences. Hyperacusis was associated with
      concentration difficulties, use of ear protection, avoidance, tension, and
      sensitivity to light/colours. The present data suggest that hyperacusis is a
      common problem.

PMID- 12477177
TI  - e-CAM draws enthusiasm.

PMID- 12477176
TI  - Intra- and intersubject comparison of cochlear implant systems using the Esprit
      and the Tempo+ behind-the-ear speech processor.
AB  - A patient with bilateral profound deafness was implanted with a Nucleus CI24M
      cochlear implant (CI) and used an Esprit behind-the-ear (BTE) speech processor.
      Thirteen months later, the implant had to be removed because of a cholesteatoma.
      As the same electrode could not be reinserted, a Medel combi40s CI was implanted
      in the same ear, and the patient used a Tempo+ BTE processor. After 1 year of use
      of the Combi40s/Tempo+ system, speech recognition was better and was rated better
      subjectively than with the CI24M/Esprit system. Speech recognition and subjective
      ratings were also assessed for two matched groups of nine CI users each, using
      either an Esprit or a Tempo+ processor. On average, speech recognition scores
      were higher for the group of Tempo+ users, but the difference was not
      statistically significant. Users of the Esprit processors rated their device
      higher in terms of cosmetic appearance and comfort of wearing.

PMID- 12477178
TI  - Securing the food supply.

PMID- 12477179
TI  - Star Trek is history.

PMID- 12477180
TI  - Wiley Award: Barry McCleary and dietary fiber.

PMID- 12477181
TI  - Determination of low-level residual ethylene oxide by using solid-phase
      microextraction and gas chromatography.
AB  - Current methods of analysis for ethylene oxide (EO) in medical devices include
      headspace and simulated-use extractions followed by gas chromatography with
      either a packed or a capillary column. The quantitation limits are about 0.5-1.0
      microg/g for a packed column and about 0.1-0.2 microg/g for a capillary column.
      The current allowable levels of EO on medical devices sterilized with EO gas as
      outlined in International Organization for Standardization (ISO) 10993-7 may be
      significantly reduced from current levels by applying the ISO Draft International
      Standard 10993-17 method for establishing allowable limits. This may require EO
      test methods with detection and quantitation limits that are much lower than
      those of the currently available methods. This paper describes a new method that
      was developed for the determination of low-level EO by solid-phase
      microextraction using the direct-immersion method. Factors such as temperature
      and stirring were found to affect absorption efficiency and absorption time. A
      low extraction temperature (about 6 degrees C) was found to be more efficient
      than room-temperature extraction. Stirring was found to reduce absorption time by
      about 50%. Under these conditions, detection and quantitation limits of 0.002 and
      0.009 microg/g, respectively, were obtained by using a capillary column. As a
      result, this method makes compliance with lower EO limits feasible.

PMID- 12477182
TI  - Determination of available phenolic compounds in soils by liquid chromatography
      with solid-phase extraction.
AB  - A fast, selective, and sensitive liquid chromatographic (LC) method was developed
      for determination of derivatives of benzoic and cinnamic acids (gallic,
      protocatechuic, 2,3,4-trihydroxybenzoic, 4-hydroxybenzoic, vanillic, caffeic,
      syringic, 4-coumaric, ferulic, sinapic, benzoic, 2-coumaric, cinnamic acids, and
      4-hydroxybenzaldehyde and vanillin) in soil samples. The method for sample
      pretreatment is based on temperature-controlled extraction with water (pH 5.6)
      for 60 min. Extracts were preconcentrated and purified by solid-phase extraction
      on OASIS HLB sorbent, with subsequent separation and quantification of individual
      substances by LC with UV diode-array detection. Limits of detection (3 signal-to
      noise LODs) better than 65 ng/g (dry weight) and recoveries from 88 to 99% were
      found for each compound at absorbance 280 nm. The method was used for
      determination of bioavailable phenolic compounds in different soil samples.

PMID- 12477183
TI  - Gravimetric determination of amylase-treated neutral detergent fiber in feeds
      with refluxing in beakers or crucibles: collaborative study.
AB  - As an important constituent of animal feeds, fiber represents the portion of
      feeds that is bulky and difficult to digest. The neutral detergent fiber (NDF)
      method, developed over 30 years ago, is the method of choice for measuring total
      fiber in forages and other feeds. Several modifications that were made to improve
      its general applicability to all feeds and others developed in individual
      laboratories often resulted in variability among laboratories in measuring NDF.
      The amylase-treated NDF (aNDF) method, therefore, was developed as an accurate
      and precise method of measuring total insoluble fiber in feeds. A collaborative
      study was conducted to evaluate the repeatability and reproducibility of the aNDF
      method over the full range of animal feed materials. Twelve laboratories
      representing research, feed company, regulatory, and commercial feed testing
      laboratories analyzed 11 materials as blind duplicates. The materials represented
      feed matrixes, including animal products; high-protein, high-fat, and high-pectin
      feeds; oil seeds; grains; heated by-product feeds; and legume and grass hays and
      silages. Materials selected varied in chemical composition and contained 0-90%
      aNDF, 1-16% ash, 1-20% crude fat, 1-40% crude protein, and 0-50% starch.
      Correcting results for changes in blanks and reporting results as ash-free aNDF
      organic matter (aNDFom) improved the repeatability and reproducibility of results
      when aNDF was <25%. The within-laboratory repeatability standard deviation (Sr)
      for percentage aNDFom in feeds varied from 0.21 to 1.82 and among-laboratory
      reproducibility standard deviation (S(R)) varied from 0.37 to 2.24. The HORRAT
      was <2 for all materials except feed materials containing >10% fat. However,
      standard deviations of repeatability and reproducibility for feeds with >10% fat
      were similar to those of other materials. It is recommended that the aNDF method
      be accepted for Official First Action status.

PMID- 12477184
TI  - Determination of phosphorus in fertilizers by inductively coupled plasma atomic
      emission spectrometry.
AB  - An inductively coupled plasma atomic emission spectrometry (ICP-AES) method was
      developed for the determination of phosphorus in fertilizers. Total phosphorus,
      direct extraction available phosphorus (EDTA), and water-soluble phosphorus,
      reported as phosphorus pentoxide (P205), in 15 Magruder check fertilizers were
      measured by ICP-AES, and the results were compared with those obtained by the
      AOAC official method. Five analytical wavelengths of phosphorus, 177.499,
      178.287, 213.618, 214.914, and 253.565 nm, were tested for the determination of
      phosphorus in fertilizers, and their detection limits were obtained. Acid effects
      of perchloric acid and possible matrix effects of aluminum, calcium, magnesium,
      potassium, and sodium were negligible for phosphorus determination. Wavelength
      213.618 nm was the best analytical wavelength for phosphorus determination by all
      3 sample preparation methods for the selected Magruder fertilizers. The results
      demonstrated that the accuracy and precision of the ICP-AES method were
      comparable with those of the official methods.

PMID- 12477185
TI  - Differential pulse voltammetric assay of lercanidipine in tablets.
AB  - Lercanidipine in ethanol-0.04M Britton-Robinson buffer (20 + 80) gives an
      irreversible anodic response on a glassy carbon electrode in a broad pH range (2
      12) that depends on pH. This signal can be attributed to oxidation of the 1,4
      dihydropyridine ring to give the corresponding pyridine derivative. For
      analytical purposes, differential pulse voltammetry at pH 4 was selected. Under
      these conditions, good values of both within- and interday reproducibility were
      obtained, with coefficient of variation (CV) values of 1.56 and 1.70%,
      respectively, for 10 successive runs. For quantitation, the calibration curve
      method was used for lercanidipine concentrations ranging from 1 x 10(-5) to 1 x
      10(-4) M. The detection and quantitation limits were 1.39 x 10(-5) and 1.49 x 10(
      5), respectively. A liquid chromatographic method with electrochemical detection
      was used for comparison. The voltammetric method showed good selectivity with
      respect to both excipients and degradation products. The recovery study exhibited
      a CV of 0.94% and an average recovery of 98.3%, and it was not necessary to treat
      the sample before the analysis. The method was successfully applied to the
      individual tablet assay of lercanidipine in commercial tablets.

PMID- 12477186
TI  - Sequential determination of salicylic and acetylsalicylic acids by amperometric
      multisite detection flow injection analysis.
AB  - An amperometric multisite detection flow injection analysis (FIA) system was
      developed for sequential determination of 2 analytes with a single sample
      injection and single detector. Tubular composite carbon electrodes with an inner
      diameter similar to that of the FIA manifold tubing were constructed so that
      measurements could be made without impairing the sample plug hydrodynamic
      characteristics. The electrochemical behavior of the tubular voltammetric cell in
      a low-dispersion FIA manifold and the behavior of the FIA system incorporating
      this type of voltammetric cell intended for multisite detection were evaluated by
      performing measurements with potassium hexacyanoferrate(II). Feasibility of the
      approach was demonstrated in the sequential determination of salicylic and
      acetylsalicylic acids in pharmaceutical products at a fixed potential of 0.98 V.
      The system allows sequential determination of salicylic acid concentrations
      ranging from 1.0 x 10(-5) to 5.0 x 10(-5) M and acetylsalicylic acid
      concentrations between 1.0 x 10(-3) and 5.0 x 10(-3) M with good precision on
      both detection sites and with relative standard deviations (RSDs) > or = 1.5% (n
      = 10) and 2.1% (n = 10), respectively. A comparison of these results with those
      of the U.S. Pharmacopeia procedure showed RSDs <5.0 and 1.0% for salicylic acid
      and acetylsalicylic acid, respectively. The proposed method enables 15
      determinations per hour, which corresponds to the analysis of approximately 8
      samples per hour. The detection limits of the methodology were approximately 3.5
      x 10(-6) and 1.1 x 10(-5) M, respectively, for the first and second monitoring
      sites.

PMID- 12477187
TI  - Interlaboratory comparison of methods for the determination of incurred
      tilmicosin residues in bovine liver.
AB  - The objective of this study was to compare 2 methods for the determination of
      tilmicosin residues in bovine liver samples. Three laboratories participated in
      the comparison of the 2 methods. The first method was described in a New Animal
      Drug Application (NADA 140-929), and the second was a modification of that method
      in which hexane was substituted for carbon tetrachloride in one cleanup step.
      Each of the 3 laboratories analyzed subsamples of 10 bovine livers containing
      incurred tilmicosin. Residues ranged from 2.3 to 81 ppm tilmicosin in the 10
      liver samples with an 11.8% relative standard deviation obtained by using both
      methods. In addition, fortified-control liver tissue samples were analyzed
      concurrently with tissues containing incurred residues by using the modified
      method in one of the laboratories. The fortification levels ranged from 0.3 to
      112 ppm, with recoveries ranging from 76 to 92%. The results from the 3
      laboratories were comparable, indicating that the modified method was not only as
      effective as the original NADA method, but also more desirable because of the
      change to a less hazardous solvent.

PMID- 12477188
TI  - Determination of ciprofloxacin with a room-temperature phosphorescence flow
      through sensor based on lanthanide-sensitized luminescence.
AB  - Direct measurement of the sensitized luminescence of the europium-ciprofloxacin
      chelate immobilized on a cationic exchanger was used to develop a flow-through
      room-temperature phosphorescence optosensor for determination of ciprofloxacin.
      The phosphorescent chelate is formed on-line at room temperature in a flow
      injection system and is immobilized on a weakly acidic cation-exchange resin
      packed in a flow cell. Optimum experimental conditions and analytical performance
      are discussed in detail. The sensor response for ciprofloxacin was linear, from
      1.5 x 10(-6) to 2.0 x 10(-5)M with a relative standard deviation of 2.5% (n = 10)
      and a detection limit of 1.1 x 10(-7)M. The effect of possible interferences on
      sensor response was studied. The sensor was successfully tested for the
      determination of ciprofloxacin in pharmaceutical formulations.

PMID- 12477189
TI  - Improved thin-layer chromatographic method for the separation of cholesterol, egg
      phosphatidylcholine, and their degradation products.
AB  - Degradation products of egg phosphatidylcholine (EPC) and cholesterol were
      analyzed with different normal- and reversed-phase thin-layer chromatography
      (TLC) systems. The best separation, in terms of the highest number of degradation
      products from both analytes, was obtained with a reversed-phase system, using
      butanol-methanol-water-96-98% (v/v) acetic acid (40 + 40 + 20 + 4, v/v/v/v) as
      the mobile phase after overnight saturation at 25 degrees C. A special
      development technique was used. After a first development, the plate was dried
      and a second development was performed in the same direction. This method enabled
      us to separate lysophosphatidylcholine, several free fatty acids and
      hydroperoxides, and several undefined degradation products of EPC and
      cholesterol. All products were visualized after the plate was dipped in a 1%
      (v/v) solution of 4-methoxybenzaldehyde in 98% sulfuric acid-96-98% (v/v) acetic
      acid-ethanol-water (2 + 10 + 60 + 30), presenting a blue color or a white spot
      against a colored background. After activation at 110 degrees C, a stable color
      for both analytes was reached after 12 min. Precision of <5% was obtained at 2
      levels of analysis. Good linearity was obtained in the range of 5-30 microg for
      EPC (r = 0.991) and 5-40 microg for cholesterol (r = 0.991). These results show
      that TLC can be an inexpensive and easy alternative for the analysis of EPC and
      cholesterol.

PMID- 12477190
TI  - Spectrophotometric investigations of the assay of physiologically active
      catecholamines in pharmaceutical formulations.
AB  - Two simple, sensitive, and accurate spectrophotometric methods are proposed for
      the determination of levodopa (LD), methyldopa (MD), dopamine hydrochloride (DP),
      and pyrocatechol (PC) in pure and pharmaceutical preparations. The methods are
      based on measurement of the absorbances of tris(o-phenanthroline)iron(II) (method
      A) and tris(bipyridyl)iron(II) (method B) obtained by the oxidation of the
      catecholamines by iron(III) in the presence of 1,10-phenanthroline and 2,2'
      bipyridyl at 510 and 522 nm, respectively. The absorbances were found to increase
      linearly with increases in the concentrations of the catecholamines, results
      which were corroborated by the calculated correlation coefficients (0.9990
      0.9996). Beer's law was valid over the concentration ranges of 0.04-0.6, 0.06
      0.75, 0.06-0.65, and 0.05-0.70 microg/mL in method A and 0.02-1.0, 0.04-1.3, 0.05
      1.0, and 0.06-1.1 microg/mL in method B for PC, MD, LD, and DP, respectively. The
      common excipients and additives did not interfere in their determinations. The
      proposed methods were successfully applied to the assay of LD, MD, and DP in
      various dosage forms. The results were validated by statistical analysis.

PMID- 12477191
TI  - Concurrent determination of four fluoroquinolones in catfish, shrimp, and salmon
      by liquid chromatography with fluorescence detection.
AB  - A liquid chromatographic (LC) method with fluorescence detection was developed
      for concurrent determination of 4 fluoroquinolones: ciprofloxacin (CIPRO),
      enrofloxacin (ENRO), sarafloxacin (SARA), and difloxacin (DIFLX) in catfish,
      shrimp, and salmon. The procedure consists of extraction from fish tissue with
      acidified ethanol, isolation and retention on a cation exchange solid-phase
      extraction column, elution with basic methanol, and LC analysis with fluorescence
      detection. LC is performed by isocratic elution with acetonitrile-2% acetic acid
      (16 + 84) mobile phase, and a PLRP-S polymer column with fluorescence detection,
      excitation 278 nm and emission 450 nm. A target level of 20 ppb for each of the 4
      fluoroquinolones has been established for this method. Fortified and incurred
      fish sample results are based on a 5-point standard curve calculation (10-160
      ppb). Overall percent recoveries (% relative standard deviation) from fortified
      catfish were 78 (10), 80 (11), 70 (9.4), and 78 (10); from fortified shrimp, 69
      (5.9), 85 (4.9), 79 (5.9), and 90 (4.5); and from fortified salmon, 56 (15), 93
      (5.6), 61 (11), and 87 (5.0) for CIPRO, ENRO, SARA, and DIFLX, respectively. Data
      from the analysis of fluoroquinolone-incurred catfish, shrimp, and salmon are
      presented.

PMID- 12477192
TI  - Immunoaffinity column as sample cleanup method for determination of the beta
      adrenergic agonist ractopamine and its metabolites.
AB  - A monoclonal antibody-based immunoaffinity column (RAC-IAC) was developed as a
      cleanup method for the determination of ractopamine and ractopamine glucuronides.
      [14C]Ractopamine (5 microg) and [14C]ractopamine glucuronides (5 microg) were
      fortified into 10 mL cattle urine, and loaded onto an RAC-IAC (5 mg IgG/mL)
      column. The column was washed and the bound analytes were eluted. In the initial
      loading and washing, 22% of the radioactivity was washed off and the subsequent
      elution step recovered 78%. A blank column prepared from nonspecific IgG retained
      <10% of the radioactivity. The RAC-IACs were damaged by high methanol
      concentrations, preventing reuse. Elution of the analytes with 50mM glycine
      buffer, pH 2.8, prevented damage, and the columns could be reused at least 20
      times with no change in performance. They were stored >3 months in phosphate
      buffered saline with 0.02% sodium azide at 4 degrees C. The method was used with
      fortified cattle muscle, liver, and kidney samples with recoveries of 82.1+/-7.6,
      87.8+/-1.9, and 92.5+/-0.4%, respectively (n = 3). Similar studies with sheep
      muscle, liver, and kidney samples gave recoveries of 91.8+/-0.2, 91.7+/-0.3, and
      92.3+/-0.3, respectively (n = 3). Liver and kidney samples were diluted to
      prevent column plugging, but all of the eluants were suitable for liquid
      chromatography analysis. This IAC is a selective, efficient, and economical
      cleanup method in a variety of matrixes for ractopamine determination.

PMID- 12477193
TI  - Use of hydrophilic hydroxypropyl methacrylate/ethylene glycol methacrylate
      packing material in size-exclusion chromatography.
AB  - Spherical particles of hydroxypropyl methacrylate/ethylene glycol methacrylate
      copolymer were synthesized in-house for use in size-exclusion chromatography. The
      porous hydrophilic material was packed in glass and stainless steel columns to
      evaluate their chromatographic performance. The support particles were small
      (approximately 20 A), and the average pore size was in the low range of mesopores
      (approximately 100 A). The packed columns were calibrated by using polysaccharide
      dextrans, showing a good range of separation for molecular weights between 10000
      and 600000 daltons. The packing material appears to separate the large molecules
      through the size-exclusion mechanism. Polysaccharides and polypeptides dissolved
      in adequate mobile phases were injected into the packed column. The separation of
      the macromolecules was consistent with the size-exclusion mechanism. Application
      of the packing material to the separation of small molecules (alkyl alcohols) was
      also investigated.

PMID- 12477194
TI  - Kinetic spectrophotometric method for the determination of ranitidine and
      nizatidine in pharmaceuticals.
AB  - An accurate and simple kinetic method is described for the determination of
      ranitidine and nizatidine in pure form and in pharmaceuticals. The method is
      based on the reaction of the compounds with 7-chloro-4-nitrobenz-2-oxa-1,3
      diazole in pH 7.4 borate buffer at 60 degrees C for a fixed time of 25 min for
      both compounds. The absorbance of the reaction product is measured at 495 nm for
      ranitidine and nizatidine. Calibration graphs were linear over the concentration
      range of 2-20 microg/mL, with limits of detection of 0.13 (3.7 x 10(-7) M) and
      0.25 microg/mL (7.5 x 10(-7) M) for ranitidine and nizatidine, respectively. The
      proposed method was applied successfully to the determination of ranitidine in
      tablets and ampoules with average recoveries of 100.26+/-0.69 and 100.29+/-0.59%,
      respectively, and to the determination of nizatidine in capsules with an average
      recovery of 104.26+/-0.44%. The results obtained are in good agreement with those
      obtained by the other methods used for comparison. A proposal of the reaction
      pathway is also presented.

PMID- 12477196
TI  - Novel chromatographic separation and carbon solid-phase extraction of acetanilide
      herbicide degradation products.
AB  - One acetamide and 5 acetanilide herbicides are currently registered for use in
      the United States. Over the past several years, ethanesulfonic acid (ESA) and
      oxanilic acid (OA) degradation products of these acetanilide/acetamide herbicides
      have been found in U.S. ground waters and surface waters. Alachlor ESA and other
      acetanilide degradation products are listed on the U.S. Environmental Protection
      Agency's (EPA) 1998 Drinking Water Contaminant Candidate List. Consequently, EPA
      is interested in obtaining national occurrence data for these contaminants in
      drinking water. EPA currently does not have a method for determining these
      acetanilide degradation products in drinking water; therefore, a research method
      is being developed using liquid chromatography/negative ion electrospray/mass
      spectrometry with solid-phase extraction (SPE). A novel chromatographic
      separation of the acetochlor/alachlor ESA and OA structural isomers was developed
      which uses an ammonium acetate-methanol gradient combined with heating the
      analytical column to 70 degrees C. Twelve acetanilide degradates were extracted
      by SPE from 100 mL water samples using carbon cartridges with mean recoveries
      >90% and relative standard deviations < or =16%.

PMID- 12477195
TI  - Interlaboratory comparison of pesticide recovery from water using solid-phase
      extraction disks and gas chromatography.
AB  - An interlaboratory study was conducted to assess the suitability of C18 solid
      phase extraction disks to retain and ship different pesticides from water
      samples. Surface and deionized water samples were fortified with various
      pesticides and extracted using C18 disks. Pesticides were eluted from disks and
      analyzed in-house, or disks were sent to another laboratory where they were
      eluted and analyzed. Along with the disks, a standard pesticide solution in
      methanol was also shipped to be used for fortification, extraction, and analysis.
      The highest recovery from deionized or surface water using shipped disks was
      obtained for cyanazine (>97%), followed by metalaxyl (>96%), and atrazine (>92%).
      Although <40% of the bifenthrin, chlorpyrifos, and chlorothalonil fortified in
      surface water was recovered from shipped disks, recoveries from deionized water
      were >70%. From in-house eluted disks, bifenthrin and chlorpyrifos were recovered
      at 118 and 105%, whereas chlorothalonil showed 71% recovery, indicating that poor
      recovery from surface water was due to loss during shipping rather than low
      retention by the C18 disks. There was no consistent relationship between recovery
      from C18 disk and physicochemical properties for the pesticides included in this
      study. For most of the 13 pesticides tested, there were no differences in
      recovery between in-house extracted disks and shipped disks, indicating the
      suitability of disks to concentrate and transport pesticides extracted from water
      samples.

PMID- 12477197
TI  - In-house validation study for salmonella unique testing of juice (modification of
      AOAC official method 2000.07).
AB  - Following an industry request, a study was undertaken to validate a minor change
      to the Unique method for testing fruit juice. Twenty foods were tested in the
      original precollaborative study for TECRA Unique Salmonella test (2000.07). To
      validate the modification for juice, both the modified method (42 degrees C
      module incubation with a 5 h replication step) and the current AOAC Method
      2000.07 (37 degrees C incubation with a 4 h replication step) were compared with
      the U.S. Food and Drug Administration's Bacteriological Analytical Manual (BAM;
      8th Ed., 1998) reference method, which uses lactose broth as pre-enrichment
      medium. Twenty uninoculated replicates, 20 replicates with low-level inoculum
      (target 1-5 cells/25 g), and 20 replicates with high-level inoculum (target 10-50
      cells/25 g) were tested for a single batch of fresh orange juice in accordance
      with AOAC requirements. There was exact agreement between the 2 Unique methods
      for all samples and exact agreement between the 2 Unique methods and the BAM
      method for the uninoculated and high-level inoculum samples. For low-level
      inoculum, 17 samples were confirmed positive with the new Unique method, 17 with
      AOAC Method 2000.07, and 14 with the BAM method.

PMID- 12477198
TI  - Determination of docosahexaenoic acid and n-3 fatty acids in refined fish oils by
      1H-NMR spectroscopy: IUPAC interlaboratory study.
AB  - A high-resolution proton nuclear magnetic resonance (NMR) method for determining
      the concentration (mg/g) of docosahexaenoic acid (DHA), the molar proportion
      (mol%) of DHA, and the molar proportion of total n-3 fatty acids in fish oils was
      validated by an IUPAC interlaboratory study (the Commission VI-6 on Oils, Fats,
      and Derivatives WG 3/98). Thirteen laboratories from 5 countries tested 6 pairs
      of blind duplicate fish oils: a refined tuna oil, 2 extracted tuna oils, an
      extracted bonito oil, an extracted salmon oil, and an extracted sardine oil
      ranging from 9 to 30 mol% DHA and from 20 to 35 mol% n-3 fatty acids. Before 1 D
      proton NMR measurements with 300-500 MHz instruments, oil samples were weighed
      and diluted with deuterochloroform solution containing ethylene glycol dimethyl
      ether as internal standard. To achieve precise performance, a detailed procedure
      for signal area measurement was described in the protocol, and all participants
      were instructed about the critical importance of following the protocol.
      Statistical performances with invalid and outlier data removed were as follows:
      repeatability relative standard deviations (RSDr) ranged from 0.91 to 2.62% and
      reproducibility relative standard deviation (RSDR) ranged from 1.73 to 4.27% for
      DHA concentration (mg/g); RSDr ranged from 0.39 to 2.06%, and RSDR ranged from
      0.59 to 3.46% for mol% DHA; RSDr ranged from 0.23 to 0.90% and RSDR ranged from
      0.85 to 2.01 % for mol% total n-3 fatty acids. The method is expected to be
      recommended by IUPAC.

PMID- 12477199
TI  - Determination of deoxynivalenol in whole wheat flour and wheat bran.
AB  - A liquid chromatographic (LC) method was developed for determining deoxynivalenol
      (DON) in whole wheat flour and wheat bran. A 15 g test sample was extracted with
      acetonitrile-water (84 + 16, v/v) and applied to a Romer MycoSep cleanup column.
      The eluate was dried and then reconstituted in a 0.1 M phosphate buffer, pH 7.0,
      and applied to a Vicam DONtest-LC cleanup column. The methanol eluate was
      chromatographed with a methanol-water (17 + 83, v/v) mobile phase on a C18 column
      with UV detection at 220 nm. Five replicates at each of 5 fortification levels
      (0.25, 0.50, 1.0, 2.0, and 4.0 ppm), plus 5 controls, were determined for both
      whole wheat flour and wheat bran. For flour, the average recoveries were 72.2
      91.5% with relative standard deviations (RSDs) of 4.9-18.4%. The intra-assay
      flour recovery was 82.4% with 9.8% RSD. A 5 replicate sample of naturally
      incurred wheat had an average of 1.1 ppm DON with 6.7% RSD. For bran, average
      recoveries of fortified samples were 69.5-99.7% with RSDs of 1.7-18.8%. The intra
      assay bran recovery was 81.5% with 8.9% RSD. The limit of detection (about 3x
      noise) for the method is 0.05 ppm; the correlation coefficient (linearity) was
      >0.9995. The DON peak was clearly identified and easily integrated in the
      chromatograms.

PMID- 12477200
TI  - Determination of St. John's wort components in dietary supplements and functional
      foods by liquid chromatography.
AB  - St. John's wort (Hypericum perforatum L.) preparations, a top-selling botanical
      dietary supplement used primarily as an antidepressant, has recently been used as
      an ingredient in some food products sold as functional foods. A rapid extraction
      technique followed by a liquid chromatographic (LC) method was developed to
      determine 4 characteristic bioactive compounds (pseudohypericin, hypericin,
      hyperforin, and adhyperforin) from St. John's wort in dietary supplements and
      functional foods to which it was added. Solid samples, including dried
      leaf/flower mixture, dietary supplement capsules, tea bags, puff and snack bar,
      were extracted with methanol by sonication. Noncarbonated, fruit-flavored drinks
      were centrifuged and mixed with methanol. Compounds were then determined by
      isocratic, reversed-phase LC with UV detection at 2 wavelengths and further
      identified or confirmed by photodiode array spectra and LC/mass spectrometry.
      Within-laboratory method variations (% RSD) were satisfactory. Very low amounts,
      if any, of the 4 components were found in drink and puff samples, and none was
      found in the snack bar. The methods developed provide a useful means for the
      determination of St. John's wort components in dietary supplements and functional
      foods.

PMID- 12477201
TI  - Assessment of performance of laboratories in determining acrylamide in
      crispbread.
AB  - A proficiency testing round was undertaken to assess the performance of
      laboratories to measure acrylamide in a sample of crispbread. Retail samples of
      crispbread were ground to a fine powder and after thorough mixing were packed in
      40 g units for distribution. Ten samples were selected at random and analyzed in
      duplicate for acrylamide by liquid chromatography/mass spectrometry (LC/MS).
      Standard statistical tests showed that the material was homogeneous for the
      purposes of proficiency testing. Test samples were distributed to 55 laboratories
      in 16 countries in Europe, North America, Australia, and the Middle East. The
      results were analyzed by standard proficiency testing statistical procedures, and
      laboratories were awarded z-scores on the basis of their reported results. Based
      on a target standard deviation (sigmap value) taken from the Horwitz equation,
      for a robust mean value of 1.2 mg/kg acrylamide, satisfactory results (z-score
      within +/- 2 for those between 0.8 and 1.6 mg/kg) were obtained by 86% of the 37
      laboratories that returned results. Only 1 laboratory was unsatisfactory and 4
      had questionable results. About equal numbers of laboratories used gas
      chromatography (GC)/MS and LC/MS procedures with about 25% using MS/MS and one
      using GC with electron capture detection. There was no evident trend in
      performance or bias in results. GC/MS and LC/MS data were evenly distributed
      across the population of laboratories reporting results.

PMID- 12477202
TI  - Determination of nitrogen solubility in dilute pepsin hydrochloric acid solution
      of fishmeal: interlaboratory study.
AB  - A revised method to determine solubility of nitrogen in dilute pepsin, using
      0.0002% pepsin in place of 0.2% in AOAC Official Method 971.09, was tested in 16
      laboratories with 12 samples of fishmeal. Results were calculated according to 2
      procedures: AOAC Official Method 971.09 and a method described in 1964 by
      researchers at the Torry Research Station (Aberdeen, Scotland), and generally
      referred to as the modified Torry method. Variations in the method of shaking and
      source of pepsin were also investigated. Pepsin solubility values were lower and
      more variable when calculated by the Torry procedure. The method of shaking
      apparently affected the result when calculated according to the Torry but not the
      AOAC method. The source of pepsin had no significant effect on between-laboratory
      variability, but a comparison of the 2 main sources within one laboratory
      resulted in highly significant differences. Based on this study, the
      International Fishmeal and Fish Oil Organization has adopted this new method,
      using 0.0002% pepsin but keeping the AOAC method of calculation. The type of
      shaker and source of pepsin are recommended but are not mandatory. The
      repeatability and reproducibility limits of this new method are 1.6 and 3.3%
      units of solubility, respectively.

PMID- 12477203
TI  - Interference-free biosensor based on screen-printing technology and sol-gel
      immobilization for determination of acetaldehyde in wine.
AB  - A monoenzymatic amperometric biosensor was developed for the detection of
      acetaldehyde. The sensor is based on the association of screen-printed carbon
      electrodes and aldehyde dehydrogenase immobilized by a sol-gel entrapment method.
      Modification of screen-printed carbon electrodes with Reinecke salt of Meldola's
      Blue (MBRS) resulted in highly sensitive and interference-free nicotinamide
      adenine dinucleotide (NADH) detectors. Based on MBRS-mediated oxidation of NADH
      at -150 mV versus pseudo Ag/AgCl, acetaldehyde was determined in the range 10-260
      microM, compatible with wine quality monitoring. The method of immobilization
      based on sol-gel entrapment was optimized to obtain the best compromise between
      sensitivity and operational stability. The sensor response was stable for 40
      consecutive assays with methyltrimethoxysilane used as alkoxide precursor, thus
      allowing a possible calibration of the sensor before each measurement. The
      biosensors were used to analyze French wines. The method was validated with a
      commercially available enzymatic kit based on a standard spectrophotometric
      method.

PMID- 12477205
TI  - Interlaboratory study of a multiresidue gas chromatographic method for
      determination of organochlorine and pyrethroid pesticides and polychlorobiphenyls
      in milk, fish, eggs, and beef fat.
AB  - An interlaboratory study was conducted to validate a gas chromatographic (GC)
      method for determination of 21 organochlorine pesticides, 6 pyrethroid
      pesticides, and 7 polychlorobiphenyl (PCB) congeners in milk, beef fat, fish, and
      eggs. The method was performed at low contamination levels, which represent
      relevant contents in food, and is an extension of the European standard (method
      NF-EN-1528, Parts 1-4). It enlarges the applicable scope of the reference EN
      method to pyrethroid pesticides and proposes the use of solid-phase extraction
      (SPE) as a cleanup procedure. Cryogenic extraction was made, and SPE cleanup was
      performed with 2 successive SPE cartridges: C18 and Florisil. After injection of
      the purified extract onto a GC column, residues were measured by electron capture
      detection. Food samples (liquid milk, beef fat, mixed fish, and mixed eggs) were
      prepared, tested for homogeneity, and sent to 17 laboratories in France. Test
      portions were spiked with 27 pesticides and 7 PCBs at levels from 26 to 45, 4 to
      27, 31 to 67, and 19 to 127 ng/g into milk, eggs, fish, and fat, respectively.
      Based on results for spiked samples, the relative standard deviation for
      repeatability ranged from 1.5 to 6.8% in milk, 3 to 39% in eggs, 4.5 to 12.2% in
      fish, and 7 to 13% in fat. The relative standard deviation for reproducibility
      ranged from 33 to 50% in milk, 29 to 59% in eggs, 31 to 57% in fish, and 30 to
      62% in fat. This method showed acceptable intra- and interlaboratory precision
      data, as corroborated by HORRAT values at low levels of pesticide and PCB
      contamination. The statistical evaluation of the results was performed according
      to the International Organization for Standardization (ISO; ISO 3534 standard)
      and 5725-2 Guideline.

PMID- 12477206
TI  - On-line preconcentration and determination of cadmium in honey using knotted
      reactor coupled to flow injection-flame atomic absorption spectrometry.
AB  - An on-line cadmium preconcentration and determination system implemented with
      flame atomic absorption spectrometry (FAAS) associated with flow injection was
      studied. Cadmium was retained as Cd-2-(5-bromo-2-pyridylazo)-5-diethylaminophenol
      Cd-(5-Br-PADAP) complex, pH 9.3. The Cd complex was removed from the knotted
      reactor (KR) with ethanol. A total enhancement factor of 140 was obtained with
      respect to FAAS (40 for KR and 3.5 due to the use of ethanol) with
      preconcentration time of 120 s. The detection limit value for preconcentration of
      1 g sample was 0.5 ng/g. The repeatability for 10 replicate determinations at 5.0
      ng/g Cd level was 3.5% relative standard deviation, calculated from peak heights
      obtained. The calibration graph using the preconcentration system for Cd was
      linear with a correlation coefficient of 0.9990 at levels near the detection
      limits to at least 2000 ng/g. The method was successfully applied to
      determination of total Cd in honey samples.

PMID- 12477204
TI  - Determination of vegetal proteins in milk powder by enzyme-linked immunosorbent
      assay: interlaboratory study.
AB  - Eight laboratories participated in a collaborative study to evaluate an enzyme
      linked immunosorbent assay (ELISA) to determine soy, pea, and wheat proteins in
      pasteurized or ultra-high temperature (UHT) milk powders. To perform this assay,
      polyclonal antibodies for soy, pea, and wheat proteins were obtained from rabbit
      sera. Collaborators received calibration standards composed of milk powder
      containing 0-8% (w/w) vegetal protein in total protein and blind test samples
      containing approximately 1, 2, and 5% (w/w) vegetal protein. An indirect
      competitive ELISA was performed with a kit prepared by a participating
      laboratory; the kit contained plates coated with soy, pea, or wheat proteins, the
      corresponding specific antisera, enzyme-labeled second antibody, and substrate
      solution. Test samples and calibrants were extracted with phosphate-buffered
      saline, pH 7.4, containing 0.05% Tween and assayed with the ELISA kits. The
      degree of adulteration was affected by the type of heat treatment applied to the
      samples. The estimated percentage of vegetal protein addition was close to the
      theoretical value for pasteurized samples but much lower for UHT samples. For
      pasteurized samples, intralaboratory relative standard deviations ranged from 5
      to 22% and interlaboratory relative standard deviations ranged from 14 to 34%.

PMID- 12477207
TI  - Stability of sulfonamides, nitrofurans, and chloramphenicol residues in preserved
      raw milk samples measured by liquid chromatography.
AB  - A stability study was made of 10 antimicrobials: 6 sulfonamides, 3 nitrofurans,
      and chloramphenicol residues in raw milk samples preserved with 0.1 % potassium
      dichromate (K2Cr2O7) and 0.05% mercuric bichloride (HgCl2) during cold storage
      for 7 days. Preserved milk samples fortified with 50 ppb of each antimicrobial
      were analyzed by liquid chromatography (modified AOAC Method 993.32). Drugs were
      extracted with chloroform-acetone after solvent evaporation residues were
      dissolved with aqueous sodium acetate buffer solution (0.02M, pH 4.8), and fat
      was removed with hexane. Sulfonamides and chloramphenicol were detected at 275 nm
      (UV) by using a gradient system of sodium acetate buffer solution-acetonitrile
      starting at 95 + 5 (v/v) and finishing at 80 + 20 (v/v). Nitrofurans were
      detected at 375 nm (UV) isocratically with sodium acetate buffer solution
      acetonitrile (80 + 20, v/v). Residues stability was measured through recovery
      data. Sulfamethoxazole, sulfachloropyridazine, nitrofurazone, furazolidone, and
      furaltadone residues remained stable in the presence of either preservative for 7
      days. Sulfamethazine and chloramphenicol were not affected by K2Cr2O7, but had
      significant losses (p <0.05) when HgCl2 was used: 26.2 and 13.4%, respectively.
      Average recoveries of sulfamonomethoxine, sulfamerazine, and sulfathiazole
      significantly decreased by Day 7, with losses of 17.1, 17.2, and 23.2% for
      K2Cr2O7, and 23.3, 20.7, and 48.0% for HgCl2, respectively. During 5 days of cold
      storage all antimicrobials tested, except sulfathiazole, remained stable in milk
      samples preserved with 0.1 % K2Cr2O7 or 0.05% HgCl2.

PMID- 12477208
TI  - Determination of active ingredient in synthetic pyrethroid formulations by high
      performance thin-layer chromatography/densitometry.
AB  - A new, simple, precise, and rapid high-performance thin-layer chromatography
      (HPTLC) method was developed for the analysis of commercial emulsifiable
      concentrate (EC) formulations of cypermethrin, alpha-cypermethrin, and lambda
      cyhalothrin. A known amount of reference grade synthetic pyrethroid and its EC
      formulation was subjected to TLC, and the amount of pesticide present in the
      active ingredient spot was estimated by densitometry in a single beam, single
      wavelength reflectance mode. Calibration curves of the synthetic pyrethroid was
      linear in the range of 8-24 microg, and the correlation coefficient for the
      calibration equation ranged between 0.97 and 0.99. Recoveries from laboratory
      prepared test samples of the EC formulation were in the range of 95-99%.
      Pesticide formulations were further analyzed by gas liquid chromatography using
      flame ionization detector, and results were comparable. The proposed HPTLC method
      has application for quality control and determination of the shelf life of EC
      formulations.

PMID- 12477209
TI  - Assessing the burden of respiratory disease in the UK.
AB  - This review explores the health and social burden of some of the main respiratory
      diseases (asthma, chronic obstructive pulmonary disease, cryptogenic fibrosing
      alveolitis, cystic fibrosis, lung cancer, mesothelioma, obstructive sleep apnoea
      and tuberculosis) in order to increase awareness of these diseases and highlight
      areas where improvements in care are required. The overall impact of respiratory
      diseases in the U.K. in terms of prevalence, mortality, morbidity and economic
      costs, with particular reference to secondary care has been considered and
      comparisons made with the rest of Europe where data are available. Respiratory
      diseases are responsible for a significant proportion of serious morbidity and
      premature death among the population of the U.K. and they will continue to
      present a growing challenge; special support is needed to tackle this burden.

PMID- 12477210
TI  - Lung function abnormalities in children with type I diabetes.
AB  - Recent developments in intrabronchial administration of insulin raise lung
      function in patients with type I diabetes as important issue. Several studies in
      adults report abnormalities of lung function of these patients. The aim of this
      study was to investigate lung function in children with type I diabetes. Twenty
      seven children with type I diabetes performed measurement of airway obstruction
      (forced flow-volume curves), lung volumes and airway resistance
      (bodyplethysmography) and of pulmonary carbon monoxide diffusion capacity Mean
      age (+/- SD) of the children was 12.8 +/- 5 years. Mean time between the
      detection of type I diabetes and the lung function tests was 5.5 years with a
      variation from I to 17 years. The total airway resistance (Raw) was significantly
      higher compared to the reference values (P < 0.001). The other lung function
      parameters were not significantly different from reference values (P > 0.05). In
      this relatively small study no relationship between lung function abnormalities
      and age, the duration of disease or level of HbA1c was observed. Our data show
      that increase of airway resistance do occur in children withtype I diabetes.
      Progressive abnormalities in lung function might interfere with the promising
      results of treatment with intrabronchial administration of insulin.

PMID- 12477211
TI  - Impact of age and radiographic presentation on the presumptive diagnosis of
      pulmonary tuberculosis.
AB  - We compared delay in presumptive diagnosing pulmonary tuberculosis (PTB) in
      elderly and younger patents, yield of diagnosis and whether the yield is
      influenced by the radiographic presentation, even when PTB was suspected. Time
      from first complaints to first consideration of PTB was determined as suspicion
      interval (SI) and from first consideration to diagnosis as recognition interval
      (RI). Presumptive diagnosis was defined as positive staining for acid-fast
      bacilli or presence of granulomatous lesions in pulmonary specimens. Inthe
      elderly and in the younger patients, the mean SI was 111.1 and 878 days
      respectively (P = NS), and the mean RI was 5.9 and 8.3 days, respectively (P =
      NS). The mean RI was longer in uncharacteristic than in characteristic
      radiographic findings in both elderly (8.2 and 4.6 days; P = 0.007) and younger
      patients (10.6 and 3.9 days; P=0.0001). A diagnosis was obtained in 89/113
      elderly (79%) and in 109/138 younger (79%) patients (P=NS) and also in 59/80
      (73%) patients with uncharacteristic findings and in 139/170 (82%) patients with
      characteristic findings (P = NS). In the latter, sputum contributed for 66%
      ofdiagnosis, whereas it was only 31% in patients with uncharacteristic findings
      (P < 0.005). In elderly patients with uncharacteristic radiographic findings,
      diagnosis was obtained from sputum in 41% and from other specimens in 35% (P =
      NS); in the younger group diagnosis was obtained from sputum in 23% and from
      other specimens in 48% (P < 0.05). In conclusion, there was no difference in SI
      and RI in elderly patients in comparison with younger patients. Uncharacteristic
      radiographic findings increased RI in both age groups. Age or radiographic
      presentation did not influence diagnosing PTB. In patients with characteristic
      radiographic findings, diagnosis was especially made from examination of sputum,
      whereas in those with uncharacteristic findings, diagnosis was more often
      obtained from the complementary investigation of other specimens.

PMID- 12477212
TI  - The use of inferior vena cava filter as a treatment modality for massive
      pulmonary embolism. A case series and review of pathophysiology.
AB  - The use of inferior vena cava (IVC) filter for massive pulmonary emboli (PE) with
      cardiopulmonary instability has not been clinically studied. We present a case
      series of six such patients who received an IVC filter with anticoagulation
      rather than thrombolysis because of high risk of bleeding. Acute pulmonary
      embolectomy was considered, but was not possible for a variety of individual
      clinical situations. These six hospitalized patients prospectively followed
      during their admission. They were triaged to three medical intensive care units
      (ICUs) and one surgical ICU in three university teaching hospitals. One patient
      was transferred from another institution. All six patients had severe hypoxia and
      tenuous cardiopulmonary status. All required high inspiratory oxygen and
      hemodynamic support; two required mechanical ventilation and vasopressors. An IVC
      filter was placed emergently and anticoagulation was started immediately All six
      patients had resolution of pulmonary thromboemboli (PTE) on anticoagulation while
      the IVC filter prevented further PE. All six patients were discharged home in
      their pre-critical illness state. None ofthe patients suffered complications from
      this therapy and had excellent resolution ofcardiopulmonary collapse. The IVC
      filter placement prevented further major embolic events while the PTE resolved
      with anticoagulation. An IVC filter should be considered as an adjunct to
      anticoagulation therapy for those patients with massive PE and cardiopulmonary
      instability who are not candidates for thrombolysis, and acute pulmonary
      embolectomy is not readily available or is of very high risk.

PMID- 12477213
TI  - Subject discomfort associated with the histamine challenge in a population study.
AB  - BACKGROUND: Many review articles report the safety and lack of serious side
      effects associated with the histamine challenge. Even though methacholine and
      hypertonic saline are more commonly used to measure airway responsiveness,
      histamine challenges are used in many countries around the world. Levels of
      subjects discomfort after a challenge have not been quantified. This study
      quantified the incidence, severity and duration of subject discomfort after
      histamine challenge. METHODS: Ninety-nine subjects were recruited in an
      Australian multi-centre population-based study of the genetic epidemiology of
      asthma. Subjects completed a histamine challenge with final cumulative dose 3.2
      micromol. Immediately, and 10 min, after challenge subjects rated their
      discomfort for cough, headache, throat irritation, hoarse voice and flushed.
      Research personnel also reported their perception of subjectdiscomfort. RESULTS:
      Subjects and research personnel reported a small degree of subject discomfort for
      all symptoms immediately after the histamine challenge. Overall, median symptom
      scores were less than 1.5 out of 10. Discomfort scores improved 10 min after
      challenge and cough, throat irritation and flushed improved significantly
      CONCLUSIONS: This study confirms the tolerability of the histamine challenge.

PMID- 12477214
TI  - Short-term effectiveness of an asthma educational program: results of a
      randomized controlled trial.
AB  - Asthma educational programs have been shown to reduce the use of emergency room,
      frequency of severe asthma attacks and hospitalization. However, its
      effectiveness in other morbidity parameters and on quality of life has yet to be
      fully understood. This prospective randomized control trial evaluated the
      effectiveness of a patient education program in 77 asthmatics according to "Teach
      Your Patients About Asthma: A Clinicians Guide" (1992). Forty asthmatic
      patientswere randomly allocated to Group A (usual treatment) and 37 to Group B
      (usual treatment plus a patient education program). The effectiveness of the
      educational program was evaluated by comparing morbidity outcomes at baseline and
      3 months after initial evaluation. At enrolment, the two groups were not
      different with regard to age, sex, smoking, asthma severity atopy, FEV1, symptom
      free days, use of rescue salbutamol and quality of life. Three months later,
      subjects in Group B showed a significant improvement in the overall quality of
      life (p < 0.01) and in the "Symptoms"domain (p < 0.01). None of the other
      parameters (use of rescue salbutamol, symptom-free days, days absent from work or
      school, FEV1) showed any significant change. After stratification for asthma
      severity, only subjects with moderate-to-severe asthma showed a significant
      improvement inthe overall qualityof life (p < 0.05) and in the "Symptoms" (p <
      0.01) and 'Activities" (< 0.05) domains. Moreover, in subjects with moderate-to
      severe asthma FEV1 value at the 3rd month of follow-up was higher in Group B than
      in Group A (p < 0.05). In conclusion, the educational program improved the
      quality of life in asthratic subjects, mainly in patients with moderate-to-severe
      asthma.

PMID- 12477215
TI  - Possibilities of formoterol to enhance the peripheral lung deposition of the
      inhaled liposome corticosteroids.
AB  - The pulmonary distribution and clearance of 99m-Tc-labelled beclomethasone
      dipropionate (Bec)--dilauroylphosphatidylcholine (DLPC) were compared in nine
      asthmatic patients on inhaled steroids after a 1-week medical treatment period of
      long-acting beta2-agonist formoterol. The patients were given formoterol 12
      microg (OxisTurbuhaler) twice daily in addition to their own regular inhaled
      corticosteroid therapy. Gamma lung scintigraphy and lung function tests were
      performed before and after formoterol treatment. The bronchodilating effect ofthe
      combined therapy was significant: 1-week usage of inhaled formoterol enhanced
      peripheral lung deposition of beclomethasone liposome and thus diminished
      central/peripheral deposition ratio (C/P ratio). All measured lung function
      values except FEV1/FVC% improved after the medication period, although
      statistically significant levels were not reached. A systemic positive connection
      was seen between enhanced lung functions and greater lung deposition measured as
      AUC(0-24h)/24 Beclomethasone liposome formulation maintained its long-lasting
      effect in connection with formoterol treatment. At the 4-h measurement, 76% of
      the liposome-entrapped radioactivity still remained in the lungs before and 75%
      after the medication period.

PMID- 12477216
TI  - Incidence rates and risk factors for asthma among school children: a 2-year
      follow-up report from the obstructive lung disease in Northern Sweden (OLIN)
      studies.
AB  - Studies of incidence of asthma are still limited. A longitudinal study of asthma
      in school children was started in 1996 in Northern Sweden. The incidence of
      asthma and the associated risk factors have been studied over a 2 years period.
      The study started with a parental questionnaire, the ISAAC questionnaire with
      additional questions, and a skin-prick test. The cohort, 3,525 children, 7 and 8
      years old at start, was followed after 1 and 2 years by using the same questions,
      Each year responded 97%. The cumulative incidence of physician-diagnosed asthma
      was 1.7%, 0.9/1,000/year the first year, and 0.8/1,000/year the second year. The
      cumulative incidence of wheezing was 6.3%, and of frequent or daily users of
      asthma medicines 2.1%. Significant risk factors for incident asthma were a
      positive skin test, OR 5.64 (3.10-10.25); rhinitis,OR 3.53 (1.80-6.90); eczema,
      OR 2.19 (1.26-3.82); a family history of asthma, OR 2.83 (1.75-4.56); low birth
      weight, OR 3.38 (1.61-754); respiratory infections, OR 2.12 (1.24-3.63); male
      gender, OR 1.71 (1.06-2.81); and a smoking mother OR 2.00 (1.07-3.73). In summary
      the incidence of asthma during 2 years after age 7 was high, almost 1/100/year.
      Allergy was the most important risk factor, but other factors were influential.

PMID- 12477217
TI  - Reduction of variability of exhaled nitric oxide in healthy volunteers.
AB  - Exhaled nitric oxide (eNO) is elevated in patients with asthma in contrast to
      healthy subjects, although the variability is high. In this study, we tried to
      reduce the variability of eNO in healthy subjects. We measured eNO using ERS
      guidelines with a fixed exhalation flow of 250 ml/s in 117 (72 women, 45 men) non
      smoking healthy subjects and correlated this to antropometric data and standard
      lung function measurements. Using a model previously defined by Hyde et al., we
      selected parameters that were likely to have a high correlation with eNO. ENO was
      log-normally distributed. The normal values for eNO are significantly (P < 0.001)
      different for men and women: in women mean ln eNO levels (SD) were 1.49 (0.34),
      in men 1.74 (0.41) (back-transformed value 4.43 resp. 5.73 ppb). Using multiple
      regression analysis, only In D(m,CO), InTLC and In sG(aw) showed a significant
      positive correlation with In eNO in men, although only 20% of the variability of
      eNO could be explained. In women no correlation was observed and only 5% ofthe
      variability was explained. The high variability of eNO could only partly be
      explained in men, which makes the use of reference equations not very helpful.

PMID- 12477218
TI  - The effects of regular inhaled formoterol and budesonide on preformed Th-2
      cytokines in mild asthmatics.
AB  - In a recent placebo-controlled study in mild atopic asthmatics, we observed a
      significant decrease in eosinophils in the bronchial submucosa, after 2 months
      oftreatment with inhaled formoterol and budesonide. Biopsy material from each
      treatment group; formoterol (24 microg bid), budesonide (400 microg b. i. d.) and
      placebo has been further assessed to investigatethe role of Th-2 cytokines by
      immunohistochemistry using Mabs to eosinophils as an index of inflammation, IL-4
      and IL-5. Treatment with formoterol significantly reduced the number of
      eosinophils (EG2+) in the submucosa and epithelium, but this was not paralleled
      by changes in cytokine immunoreactivity In contrast, treatment with budesonide
      significantly reduced both the number of eosinophils (EG2+) and immunoreactivity
      for IL-4 and IL-5 in the submucosa. Thus, while budesonide has effects on
      cytokines involved in eosinophil recruitmentthis explanation does not apply tothe
      eosinopaenia observed with the long-acting beta2 adrenoreceptor agonist
      formoterol.

PMID- 12477219
TI  - Lung deposition of salbutamol in healthy human subjects from the MAGhaler dry
      powder inhaler.
AB  - The MAGhaler (Mundipharma GmbH) is a multidose dry powder inhaler (DPI)
      containing a novel formulation of drug and lactose compacted by an isostatic
      pressing technique (GGU GmbH). On actuation, a precise dose is metered from a
      compacted ring-shaped drug tablet. In this study, the lung deposition of
      salbutamol from this device has been assessed. Ten healthy non-smoking subjects
      completed a two-way cross-over study assessing the pulmonary deposition of
      salbutamol (200 microg) from the MAGhaler at high (60 l/min) and low (30 l/min)
      peak inhaled flow rates (PIFRs), representing maximal and sub-maximal inspiratory
      efforts. The formulation was radiolabelled with 99mTc, and lung and oropharyngeal
      depositions were quantified by gamma scintigraphyThe mean (SD)% ofthe delivered
      dose deposited in the lungs was 26.4 (4.3)% at 60 l/min and 21.1 (5.1)% at 30
      l/min (P < 0.05), corresponding to mean lung depositions of 52.8 and 42.2 microg
      salbutamol, respectively. The distribution of drug within different lung regions
      did not vary significantly with inhaled flow rate. The data provided proof of
      concept for the novel inhaler device and the innovative drug formulation. In
      comparison with previous deposition data obtained with other DPIs, the lung
      deposition was relatively high, relatively reproducible (coefficient of variation
      16% at 60 l/min) and relatively insensitive to the change in peak inhaled flow
      rate.

PMID- 12477220
TI  - Tuberculin reactivity: prevalence and predictors in BCG-vaccinated young
      Norwegian adults.
AB  - We studied tuberculin reactivity in young Norwegian adults and its possible
      dependency on age, gender, previous BCG vaccination, smoking habits, occupational
      exposure, diet as well as years of education as a measure of socio-economic
      status. Responders of a random sample of men and women aged 20-44 years living in
      Bergen, Norway were interviewed and tested withthe adrenaline-Pirquettest with
      Norwegian-produced synthetic mediumtuberculin at the out-patient chest clinic in
      the city of Bergen in 1992-1993. Nine hundred and three subjects out of 1200 met
      for the clinical examination (75%). Five hundred and eighty-eight subjects were
      tuberculin-tested and read, whereof 95% were BCG vaccinated by age 14. Mean
      tuberculin reactivity was 4.8 mm (SD: 3.0 mm). A positive reaction (> or = 4 mm)
      was found in 64%, whereof 7% had a strongly positive reaction (>10 mm). A
      negative reaction (<4 mm) occurred in 36%, whereof 10% had no reaction (0 mm).
      Only 30% ofthe females and 36% of the males aged 21--25 years were tuberculin
      positive 7-12 years after BCG vaccination. Linear regression analysis
      demonstrated tuberculin reactivity to increase with increasing age, male gender
      with an increasing sex effect by age, and current smoking. Occupational dust or
      gas exposure, a diet rich in vitamin C or years of education did not influence
      tuberculin reactivity significantly.

PMID- 12477221
TI  - Asthma and asthma-like disorder, a 5-year follow-up study.
AB  - Consecutive adult patients (n = 70) referred for investigation of suspected
      asthma were reinvestigated after 5 years with the same diagnostic procedures
      (airway symptom score, spirometry, methacholine test) as used at the initial
      investigation. The same diagnostic criteria for asthma, asthma-like disorder
      (current asthma-like symptoms but negative asthmatests)and chronicobstructive
      pulmonary disease (COPD) were used at both visits. At the first visit 39/70
      patients (56%) fulfilled the asthma criteria, 21/70 (27%) fulfilled the asthma
      like criteria and 5/70 (7%) the COPD criteria. Due to lack of current symptoms
      5/70 (7%) could not be classified. 5/70 patients (7%) were smokers, however, in
      the majority (72%) smoke was not tolerated as it induced asthma-like symptoms. At
      the investigation, 5 years later, 30/39 patients (76%) still fulfilled the asthma
      criteria and 12/21 patients (57%) still fulfilled the asthma-like criteria. At
      the 5-year investigation, 10% of patients in the asthma group now fulfilled the
      asthma-like criteria and 10% of patients in the asthma-like group fulfilled the
      asthma criteria. It is concluded that asthma as well an asthma-like syndrome may
      persist for 5 years or more. It is also concluded thatthe two disorders are
      closely related as patients in the asthma group over time could move into the
      diagnostic criteria ofthe asthma-like disorder and vice versa.

PMID- 12477222
TI  - Study on respiratory rate.

PMID- 12477223
TI  - Medicoeconomic evaluations in rheumatology--the example of rheumatoid arthritis.

PMID- 12477224
TI  - Is it fibromyalgia? Is it lupus? Too much or not enough: comments related to
      women referred to a tertiary care academic rheumatology research and treatment
      center.

PMID- 12477225
TI  - Does structural worsening of osteoarthritis predict clinical worsening?

PMID- 12477226
TI  - Diagnostic value of radiographs of the hands and feet in early rheumatoid
      arthritis.
AB  - The extent to which radiographs of the hands and feet can contribute to the
      diagnosis of early rheumatoid arthritis (RA) has received little research
      attention. Yet, the workup for recent-onset inflammatory joint disease usually
      includes radiographs of the hands and feet. We reviewed the literature for data
      on the value of these radiographs for diagnosing early RA. We sought to determine
      whether radiographic changes in the hands and feet constitute a valid diagnostic
      criterion, i.e., show good discrimination, good reproducibility, and an ability
      to detect early disease. Furthermore, we evaluated whether the sensitivity,
      specificity, and positive and negative predictive values of these changes could
      be calculated from published data. Few cohort studies of early inflammatory joint
      disease have been published, and the data come mainly from studies in early RA.
      Among radiographic alterations described to date, erosions seem associated with
      the best reliability and discriminating power. Radiographic alterations are of
      limited sensitivity for early rheumatoid arthritis because they occur only after
      some time. Radiographs of the hands and feet are far easier to obtain than
      magnetic resonance imaging and ultrasonography, which seem promising but are
      still undergoing validation.

PMID- 12477227
TI  - Rheumatological management of patients with hemophilia. Part 1: joint
      manifestations.
AB  - The advent of factor VIII and IX replacement therapy has radically changed the
      physiognomy of hemophilia. In patients with no inhibitors, early replacement
      therapy shortens the immobilization and decreases the structural and functional
      alterations related to recurrent hemarthrosis. Routine prophylactic replacement
      therapy before or after the first episode of hemarthrosis is still rarely used in
      France. Recurrent hemarthrosis in the same joint can cause synovitis and chronic
      arthropathy. Injection synovectomy is now the preferred treatment, as opposed to
      secondary prophylactic replacement therapy and to arthroscopic or open
      synovectomy. The palliative treatment of chronic arthropathy is difficult and
      rests on analgesics and rehabilitation therapy, with orthotic devices and/or
      surgery where appropriate. The treatment of hemophilia is far more difficult in
      patients with inhibitors and, consequently, considerable hope is being placed in
      gene therapy, whose first results are encouraging.

PMID- 12477228
TI  - The natural history of lumbar degenerative spinal stenosis.
AB  - The purpose of this review is to present current information on the natural
      course of lumbar spinal stenosis. As the population becomes older this condition
      is encountered more frequently. The diagnosis accuracy has improved and the
      number of cases detected is increasing intemationally. Because of the relative
      unpredictability of surgical treatment, good knowledge of natural evolution and
      of the predictive factors influencing the course of the disease is crucial.
      Unfortunately, and in contrast with numerous surgical series few studies have
      dealt with natural evolution. In addition to anecdotal reports, a few non
      randomized studies will be reviewed. Only one randomized study has compared
      shortand long term results of medical versus surgical treatment. Most of these
      studies are retrospective, with methodological flaws and are difficult to
      compare. At the present time no scientifically based recommandations can be made
      to LSS. patients at diagnosis. Similarly predictors of success of medical and
      surgical treatment still need to be identified. However results of the studies
      analyzed in this review suggest that a substantial proportion of patients do not
      automatically deteriorate and will remain unchanged or even improved by medical
      means. They also suggest that patients with severe baseline symptoms, block
      stenosis and degenerative spondylolisthesis tend to require surgical
      decompression. Randomized studies with the necessary ethical precautions are
      needed to obtain clear-cut conclusions.

PMID- 12477229
TI  - Distribution of HLA-DRB1 genes in patients with sporadic ankylosing spondylitis
      in the south of Spain.
AB  - OBJECTIVE: To evaluate the relationship between the presence of different HLA
      DRB1 genes and predisposition to develop a sporadic form of ankylosing
      spondylitis (AS) in a demographically well-defined population. METHODS: One
      hundred fifteen selected patients with sporadic (non-familial) forms of AS from
      six different cities and 748 bone marrow donors as control group. All individuals
      were typed for HLA-B27 by flow cytometry with monoclonal antibodies and PCR -SSP,
      as well as for HLA-DRB using the Dynal ELI SSO HLA-DRB Test (Dynal AS, Oslo,
      Norway). The Inno-Lipa DRB Decoder (Innogenetics NV Zwijndrecht, Belgium), was
      used for high-resolution HLA-DRB typing. RESULTS: The presence of the DRB1*01
      antigen in the studied population is significantiy higher in B27 positive healthy
      individuals (bone marrow donors) than in B27 positive AS patients; also, DRB1*01
      is higher in B27 negative AS patients than 827 negative controls. The frequency
      of DRB1*03 is higher in B27 negative controls than B27 negative AS patients.
      CONCLUSION: The results of this study suggest that DRB1*01 antigens might be
      involved in the development of sporadic forms of ankylosing spondylitis in HLA
      B27 negative individuals in the studied area.

PMID- 12477230
TI  - Serum levels of IL-1 beta, TNF-alpha, IL-8, and acute phase proteins in
      seronegative spondyloarthropathies.
AB  - OBJECTIVES: Some immunological abnormalities have been described in seronegative
      spondyloarthropathies (SpA). The aim of this study is to determine the serum
      levels of IL-1beta, TNF-alpha and IL-8, which are proinflammatory cytokines in
      active and inactive patients with SpA, to compare the results with those of
      controls and to investigate a relationship with clinical activity and acute phase
      proteins. METHODS: Forty-two patients (34 males and eight females) and 22 healthy
      controls (17 M and 5 F) were included in the study. All patients fulfilled Amor
      criteria for the classification of SpA. Among patients 23 had active and 19 had
      inactive disease. IL-1beta, TNF-alpha and IL-8 were determined by enzyme-linked
      immunosorbent assay ( ELISA), acute phase proteins were measured by nephelometric
      assay. RESULTS: There was no statistically significant difference between mean IL
      1beta levels of patient groups and controls. Serum mean TNF-a levels in active
      and inactive patients were significantly increased as compared to that in the
      controls (P < 0.05, P < 0.05, respectively). Serum mean IL-8 levels in active
      patients was significantly increased as compared to that in the controls and in
      inactive patients (P < 0.01, P < 0.01, respectively). High serum IL-8 levels
      correlated well with C-reactive protein and haptoglobulin, but there was no
      correlation between IL-1beta or TNF-alpha levels and acute phase proteins such as
      C-reactive protein, alpha-1 acid glycoprotein, alpha-1 antitrypsin and
      haptoglobulin. CONCLUSIONS: These results suggest that serum IL-8 may reflect
      clinical activity of the disease and may be helpful for monitoring patients with
      SpA.

PMID- 12477231
TI  - Validation of the French version of the Childhood Health Assessment Questionnaire
      (CHAQ) in juvenile idiopathic arthritis.
AB  - OBJECTIVES: To translate, cross-culturally adapt, and validate the functional
      disability tool Childhood Health Assessment Questionnaire (CHAQ), a variant of
      the Health Assessment Questionnaire (HAQ), in children with juvenile idiopathic
      arthritis (JIA). CHILDREN AND METHODS: The disability index is the mean of the
      scores on the eight domains of the CHAQ and can range from 0 (no disability) to 3
      (maximum disability). The CHAQ was first translated into French and adapted, then
      validated in a multicenter cross-sectional study in 306 children with JIA
      (systemic onset, 23%; polyarticular onset, 22%; extended oligoarticular subtype,
      25%; and persistent oligoarticular subtype, 30%). RESULTS: Overall CHAQ scores
      discriminated between the four JIA subtypes (systemic: 1.1 +/- 0.9;
      polyarticular: 0.8 +/- 0.7, extended oligoarticular 0.8 +/- 0.7, and persistent
      oligoarticular: 0.4 +/- 0.5 [P < 0.0001]). Reproducibility evaluated by test
      retest at a 7-day interval was excellent (intraclass coefficient, 0.91), as was
      agreement between the Parent's and Children's versions of the questionnaire
      (intraclass coefficient, 0.89). Significant correlations were found between the
      overall CHAO score and variables reflecting disease severity (joint counts,
      physician's and parent's global assessments, and erythrocyte sedimentation rate),
      indicating excellent convergent validity of the tool. CONCLUSION: The French
      version of the CHAQ displays good psychometric characteristics, although its
      sensitivity to change remains to be established. The French version of the CHAO
      should prove useful in international studies and can be expected to be helpful
      for monitoring individual patients with JIA.

PMID- 12477232
TI  - Osteopenia in patients infected by the human immunodeficiency virus. A case
      control study.
AB  - Summary - In the last few years, the use of highly active antiretroviral therapy
      has radically modified the prognosis of human immunodeficiency virus (HIV)
      infection. Osteonecrosis and osteoporosis are among the bone complications
      recently described in HIV-infected patients. We report a preliminary study
      comparing 47 HIV-infected patients (31 men and 16 women) to 47 age- and sex
      matched controls. Bone mineral density was lower in patients than in controls: in
      men, 0.919 +/- 0.120 g/cm2 vs. 1.010 +/- 0.139 g/cm2 (P = 0.01) at the total hip
      and 0.948 +/- 0.100 g/cm2 vs. 1.043 +/- 0.117 g/cm2 (P = 0.0008) at the lumbar
      spine; in women, 0.912 +/- 0.149 g/cm2 vs. 0.968 +/- 0.090 g/cm2 at the total hip
      (P = 0.17) and 0.989 +/- 0.152 g/cm2 vs. 1.080 +/- 0.097 g/cm2 (P = 0.01) at the
      lumbar spine. HIV-infected males were more likely to have osteopenia and
      osteoporosis, as compared to the male controls (19 vs. 14 and 4 vs. 1,
      respectively, P = 0.02). None of the women had osteoporosis; nine HIV-infected
      women and one female control had osteopenia (P = 0.003). No fractures were
      recorded. In this preliminary study, no evidence supporting a relationship
      between bone loss and protease inhibitor treatment was found.

PMID- 12477233
TI  - Effect of cyclical intravenous pamidronate therapy in children with osteogenesis
      imperfecta. Open-label study in seven patients.
AB  - OBJECTIVES: To evaluate the efficacy of pamidronate in protecting against
      fractures, increasing bone mineral density (BMD), and decreasing bone remodeling
      marker levels in children with osteogenesis imperFecta. PATIENTS AND METHODS:
      Seven children (two girls and five boys; mean age, 8.5 years) were given cyclical
      intravenous pamidronate (Aredia) for 1 to 7 years, with a mean cycle duration of
      6 months and a mean dose of 1.86 mg/kg/cycle. Four patients had type III and
      three type IV disease according to the Sillence classification scheme. RESULTS: A
      trend toward a decrease in the fracture rate as compared to the pretreatment
      period was found, but the difference was not significant in this small sample (P
      = 0.09). Lumbar spine BMD showed a significant annual increase (+26.7%, P = 0.03)
      far greater than the expected mean annual increase related to growth. No
      significant decreases in bone remodeling markers were noted. CONCLUSION:
      Pamidronate seems useful in the treatment of osteogenesis imperfecta in children,
      since it increases BMD and reduces the fracture rate, in keeping with the
      findings from the larger series studied by Glorieux. Pamidronate is a
      symptomatic, noncurative treatment that does not correct the genetic
      abnormalities responsible for the histological bone alterations.

PMID- 12477234
TI  - Opioid rotation in the treatment of joint pain. A review of 67 cases.
AB  - OBJECTIVE: To determine that opioid rotation can be useful for establishing a
      more advantageous analgesia/toxicity relationship in rheumatologic pain. METHODS:
      Among patients treated with opioids for rheumatologic non-malignant pain, 67
      patients with opioid rotation were enrolled retrospectively. In all cases, the
      other analgesics had failed. The opioids used were: oral morphine, oral
      hydromorphone, oral buprenorphine and transdermal fentanyl. The reasons for
      rotation were noted and the improvement of pain was assessed by comparing
      baseline and post-treatment visual analog scales (VAS in mm). RESULTS: The 67
      patients suffered from low back pain with sciatica in 27 cases, inflammatory
      arthritis in 14 cases, brachial neuralgia in six cases, osteoarthritis in eight
      cases and miscellaneous in 12 cases. The opioid rotations were the substitution
      of morphine by transdermal fentanyl, by oral hydromorphone in most of the cases.
      The principal reason for opioid rotation was failure of the first treatment. The
      mean of VAS improvement was 30 mm (P < 0.001). CONCLUSION: In rheumatologic non
      malignant pain, the opioid rotation might allow the physician to bypass side
      effects or failure to alleviate pain in most cases.

PMID- 12477235
TI  - Monoarthritis secondary to joint metastasis. Two case reports and literature
      review.
AB  - Synovial metastases from neoplasms are uncommon. We report two cases of knee
      monoarthritis due to joint metastasis. Joint fluid cytology established the
      diagnosis. In one patient, an epidermoid carcinoma of the ureter metastasized to
      the left knee. The other patient had chronic monoarthritis of the left knee
      unresponsive to conventional treatment and was found to have distal femoral
      metastases from a lung adenocarcinoma. Only 28 cases of synovial metastases from
      solid tumors have been reported in the literature. The knee is the most common
      target, the lung the most common site of the primary (12 cases), and
      adenocarcinoma the most common histological type (12 cases). Joint metastasis
      carries a poor prognosis with a mean survival of less than 5 months.

PMID- 12477236
TI  - Septic arthritis due to Actinomyces naeslundii: report of a case.
AB  - In a man with osteoarthritis of the knee, Actinomyces naeslundii septic arthritis
      developed after intra-articular injection of hyaluronate. Actinomyces is an
      anaerobic Gram-positive rod. The outcome was favorable after treatment with two
      antibiotics and arthroscopy. The nature of the organism and its location to a
      joint are unusual features of this case, which illustrates the need to search for
      a septic complication before accepting a diagnosis of inflammation related to
      hyaluronate injection.

PMID- 12477237
TI  - Idiopathic retroperitoneal fibrosis and ankylosing spondylitis. A new case
      report.
AB  - The case of a 52-year-old man with retroperitoneal fibrosis and ankylosing
      spondylitis is described. Inflammatory low back pain and acute renal
      insufficiency prompted a computed tomography scan of the abdomen with contrast
      agent injection. A fibrous sheath surrounding the aorta and attracting the
      ureters toward the midline was seen, strongly suggesting retroperitoneal
      fibrosis. The diagnosis of ankylosing spondylitis was based on the presence of
      inflammatory low back pain responsive to nonsteroidal anti-inflammatory drugs,
      syndesmophytes at the lumbar and cervical spine, bilateral sacroiliitis, and
      presence of the HLA-B27 antigen. Prednisone therapy in a daily dosage of 1 mg/kg
      induced a marked improvement. Only nine cases of concomitant retroperitoneal
      fibrosis and ankylosing spondylitis have been reported. These two conditions
      share similarities in some of the etiologic factors and anatomic localizations,
      suggesting that both may stem from a predisposition to fibrotic diseases.

PMID- 12477238
TI  - Radiographic follow-up of a phalangeal brown tumor.
AB  - We report the 6-year radiographic follow-up of a phalangeal brown tumor in a
      patient with severe hyperparathyroidism secondary to chronic renal failure
      treated with hemodialysis. The phalangeal lesion increased in size during the
      first 3 years, until the patient finally accepted to undergo parathyroidectomy.
      The initial radiographic change was a small intracortical lytic area. Two years
      later, an expansile cystic lesion was visible in the phalanx, and computed
      tomography showed a cortical defect. Ossification of the lesion occurred over the
      2.5 years following parathyroidectomy. The epidemiology, radiographic changes and
      post-treatment evolution of brown tumor in dialysed patients is reviewed.
      Surgical parathyroidectomy is the standard treatment for brown tumor complicating
      secondary hyperparathyroidism. The usefulness and limitations of treatment with
      vitamin D analogs, recently reported in a few case reports, are discussed.

PMID- 12477239
TI  - Non-dysraphic intramedullary spinal cord lipoma. A case report.
AB  - Non-dysraphic spinal cord lipomas are rare benign lesions, accounting for
      approximately 1% of all spinal cord tumors. Patients usually present with long
      histories of disability followed by rapid progression of their symptoms.
      Presenting symptoms include spinal pain, dysesthesic sensory changes, gait
      difficulties, weakness, and incontinence. Magnetic resonance imaging is the
      examination of choice. The T1- and T2-weighted images show increased and
      decreased signal intensity, respectively. The goal of intervention is
      decompression and generous debulking following by duraplasty. Early diagnosis of
      spinal cord lipomas and early surgery is advanced prior to irreversible disease
      progression. One new case of true non-dysraphic cervicodorsal spinal cord lipoma
      is reported.

PMID- 12477240
TI  - Bronchiectasis in a patient with CREST syndrome.
AB  - Bronchiectasis is an uncommon pulmonary manifestation of systemic sclerosis
      (SSc). We report the case of a 70-year-old woman with CREST syndrome and
      vasculitis who developed multifocal symptomatic bronchiectasis. The
      bronchiectasis and immunosuppressive therapy precipitated severe lower
      respiratory tract infection, which was fatal within a few months. The concomitant
      occurrence of bronchiectasis and SSc raises the possibility of a
      pathophysiological relationship. Several hypotheses can be put forward to explain
      the occurrence of bronchial wall damage leading to bronchiectasis. Whatever the
      mechanism, cases of bronchiectasis in patients with SSc should be reported to
      make physicians aware of the substantial risk associated with this combination.

PMID- 12477241
TI  - Delayed pressure urticaria in a patient with ulcerative colitis.

PMID- 12477242
TI  - Bisphosphonates for RSDS and prostate cancer--more benefit then revealed!

PMID- 12477243
TI  - Role of the C-domain in the biological activities of Clostridium perfringens
      alpha-toxin.
AB  - Clostridium perfringens alpha-toxin (370 residues) possesses hemolytic and lethal
      activities as well as the enzymatic activity of phospholipase C (PLC). In this
      study we examined the role of the C-domain (251-370 residues; CP251- 370) in
      biological activities of the toxin. The N-domain (1-250 residues; CP1- 250) of
      the alpha-toxin as well as the Bacillus cereus phospholipase C (BcPLC) possessed
      PLC activity, but did not bind to rabbit erythrocytes and lyse them. A hybrid
      protein (BC-CP251-370) consisting of BcPLC and CP251- 370 bound to the red cells
      and lysed them. Incubation of CP1-250 with CP251-370 completely complemented
      hemolytic and PLC activities. CP251-370 also conferred hemolytic activity on
      BcPLC. CP251-340 (251-340 residues) significantly stimulated PLC activity of CP1
      250), but did not confer hemolytic activity on CP1-250. Kinetic analysis
      suggested that CP251-370 increased affinity toward the substrate of CP1-250. The
      results suggested that CP251-370 plays an important role in binding to
      erythrocytes and the hemolytic and enzymatic activities of CP1-250. Acrylodan
      labeled CP251-370 variants (S263C and S365C) bound to liposomes and exhibited a
      marked blue shift, and in addition, an N,N'-dimethyl-N-(iodoacetyl)-N'-(7
      nitrobenz-2-oxa-1,3-diazolyl)ethylene diamine (NBD)-labeled CP251-370 (S365C)
      variant also bound to liposomes and the fluorescence intensity significantly
      increased, suggesting movement of CP251-370 to a hydrophobic environment. These
      observations suggest that interaction of CP251-370 of alpha-toxin with fatty acyl
      residues of phosphatidylcholine plays an important role in the biological
      activities of CP1-250.

PMID- 12477244
TI  - Detection of specific Helicobacter pylori DNA and antigens in stool samples in
      dyspeptic patients and healthy subjects.
AB  - In this study stool samples from dyspeptic patients and healthy subjects were
      used for detection of specific Helicobacter pylori antigens and DNA by
      immunoenzymatic test (PPHpSA) and semi-nested PCR (ureA-PCR), respectively. The
      H. pylori status was estimated by invasive endoscopy-based rapid urease test and
      histology or noninvasive urea breath test (UBT), and by serology (ELISA, Western
      blot). The coincidence of H. pylori-negative invasive tests or UBT and negative
      antigen or DNA stool tests was very high (mean 95%). The PPHpSA results were
      found positive for 56% and ureA-PCR for 26% of individuals with H. pylori
      infection confirmed by invasive tests or UBT. The detection of specific H. pylori
      antigens and especially DNA in feces is not sufficient as a one-step diagnosis of
      H. pylori infection.

PMID- 12477245
TI  - Extracellular ATP regulates cell death of lymphocytes and monocytes induced by
      membrane-bound lipoproteins of Mycoplasma fermentans and Mycoplasma salivarium.
AB  - The cytotoxicities of lipoproteins of Mycoplasma fermentans and Mycoplasma
      salivarium to a lymphocytic cell line, MOLT-4, and a monocytic cell line, HL-60,
      was upregulated by ATP added extracellularly in a dose-dependent manner. These
      lipoproteins induced ATP release and plasma membrane permeability increase in
      these cell lines. In addition, periodate-oxidized ATP, an antagonist for P2X
      purinergic receptors, suppressed the cytotoxicity of the lipoproteins, suggesting
      the possibility that P2X receptors for ATP play crucial roles in the
      cytotoxicity. Activation of caspase-3 induced by the lipoproteins, which was
      assessed by the cleavage of the synthetic substrate DEVD-pNA and the endogenous
      substrate poly(ADP-ribose) polymerase, was also upregulated and downregulated by
      extracellular ATP and periodate-oxidized ATP, respectively. On the basis of these
      results, this study suggests that mycoplasmal lipoproteins induce the
      permeability increase in lymphocytes and monocytes, by which ATP is released, and
      the ATP regulates the cytotoxicities of the lipoproteins to the cells, possibly
      by interaction with ATP receptors such as P2X purinergic receptors.

PMID- 12477246
TI  - Characterization of Borrelia afzelii isolated from Ixodes nipponensis and
      Apodemus agrarius in Chungju, Korea, by PCR-rFLP analyses of ospC gene and rrf
      (5S)-rrl (23S) intergenic spacer.
AB  - Nine Borrelia afzelii strains, which had been isolated from two vectors, Ixodes
      nipponensis and Apodemus agrarius in Chungju, Korea, were characterized by PCR
      RFLP analyses of ospC genes and rrf (5S)-rrl (23S) intergenic spacer. DraI
      restriction patterns of Chungju strains were identical to those of B. afzelii
      VS461. But MseI restriction patterns of rrf (5S)-rrl (23S) intergenic spacer
      genes of KK2, KM4, KK5 differed from those of previously reported B. burgdorferi
      sensu lato strains. Nine Chungju strains were classified with four distinct ospC
      RFLP patterns, which differed from the eight ospC RFLP patterns (A-1 to A-8) of
      previously reported B. afzelii. Moreover, five additional restriction patterns
      were deduced from published ospC sequences of reference strains. These results
      suggest that Chungju strains are very heterogeneous.

PMID- 12477247
TI  - A very late activating antigen-alpha4 (CD49d) monoclonal antibody, BU49 induces
      phosphorylation of a cAMP response element-binding protein (CREB), resulting in
      induction of homotypic cell aggregation and enhancement of interleukin-8 (IL-8)
      production.
AB  - A very late activating antigen-alpha4 (CD49d) monoclonal antibody (mAb), BU49 was
      found to induce phosphorylation of a cAMP response element-binding protein (CREB)
      in the human monocyte-like cell line, U937. This phosphorylation of CREB was
      completely inhibited by a protein kinase A (PKA) inhibitor H-89 with the optimum
      concentration (completely inhibits PKA). Furthermore, BU49 strongly and rapidly
      (within 5 hr) induced homotypic cell aggregation in the U937 cells accompanied by
      CREB phosphorylation. This cell aggregation was also completely inhibited by the
      addition of H-89. Interestingly, both of two mAbs (mAb13 and 4B4) recognizing
      different epitopes on the CD29 (beta1 integrin) completely inhibited this
      aggregation at the late phase (18 to 24 hr) but not at the early phase (5 hr)
      after cultured with BU49. On the other hand, BU49 significantly enhanced
      interleukin-8 (IL-8) production from the U937 cells into the culture supernatant.
      In addition, this IL-8 production was significantly blocked in the presence of H
      89 with the optimum concentration. However, a CD29 mAb which inhibits homotypic
      cell aggregation could not block this IL-8 production. Taken together, these
      findings indicate that BU49 induces CREB phosphorylation mainly mediated by PKA,
      which finally results in the induction of homotypic cell aggregation and the
      enhancement of IL-8 production. Furthermore, these findings also indicate that
      the enhancement of IL-8 production from the U937 cells induced by BU49 partially
      depends on CREB phosphorylation mainly mediated by PKA.

PMID- 12477248
TI  - A novel caspase dependent pathway is involved in apoptosis of human endothelial
      cells by Shiga toxins.
AB  - Shiga toxins have been shown to induce apoptosis on primary cultures, but not
      passaged ones, of human umbilical vein endothelial cells, independent of cytokine
      pre-treatment. Here, a peculiar pattern of caspase activation was observed;
      caspase-3 and -2, but not conventional upstream caspases, were activated at the
      initial phase of 6 hr, whereas a broad range inhibitor of caspases, VAD-fmk, but
      not mono-specific ones, suppressed DNA fragmentation and cell death. These
      results suggest additional analogous molecules, which have yet to be delineated,
      are involved. The requirement of retrograde uptake of toxins was also proved by
      the intervening effect of brefeldin A.

PMID- 12477249
TI  - Monitoring of active HHV-6 infection in bone marrow transplant recipients by real
      time PCR; comparison to detection of viral DNA in plasma by qualitative PCR.
AB  - Twelve (46%) of the 26 patients had human herpesvirus 6 (HHV-6) viremia after
      bone marrow transplant (BMT). All isolates were recovered from the samples
      obtained at 2 weeks after BMT. The sensitivity and the specificity of detection
      of viral DNA in plasma by qualitative polymerase chain reaction (PCR) for
      monitoring active virus replication were 92% and 97% respectively. Moreover, the
      positive (85%) and negative (99%) predictive values were also high. The patients
      with HHV-6 viremia showed a clear peak in HHV-6 DNA in peripheral blood
      mononuclear cells (PBMCs) at 2 weeks after BMT, which was measured by real time
      PCR. The virus DNA level in PBMCs between the two groups (patients with viremia
      and patients without viremia) was statistically different at 2 weeks after BMT (P
      = 0.033). In patients with HHV-6 viremia, mean HHV-6 DNA copy number was higher
      in the samples collected at 2 weeks after BMT than the samples collected at any
      other time period.

PMID- 12477250
TI  - Phosphorylation of cytokeratin 17 by herpes simplex virus type 2 US3 protein
      kinase.
AB  - We previously reported the establishment of an HEp2 cell line which expresses the
      US3 protein kinase (PK) of herpes simplex virus type 2 (HSV-2) upon induction
      with IPTG. Here we report that expression, phosphorylation and ubiquitination of
      cytokeratin 17 (CK17) are enhanced in US3-expressing HEp2 cells. In vitro kinase
      and co-immunoprecipitation assays provided evidence that US3 PK directly
      phosphorylates CK17. Expression of US3 PK caused a significant decrease in
      filamentous staining of CK17, suggesting that phosphorylation of CK17 by US3 PK
      causes a disruption of intermediate filaments. Our observations suggest a role
      for US3 in the regulation of CKs and intermediate filaments in cells. Moreover,
      we found that infection of a keratinocyte-derived cell line, A431, with a US3
      deficient virus, results in cytopathic effects that are morphologically distinct
      from those induced by wild-type and revertant viruses, suggesting that US3 PK may
      be important for interaction between HSV-2 and peripheral epithelial cells.

PMID- 12477251
TI  - A transporter gene (sodium iodide symporter) for dual purposes in gene therapy:
      imaging and therapy.
AB  - Radioiodide uptake (RAIU) in thyroid follicular epithelial cells, mediated by a
      plasma membrane transporter, sodium iodide symporter (NIS), provides a first step
      mechanism for thyroid cancer detection by radioiodide injection and effective
      radioiodide treatment for patients with invasive, recurrent, and/or metastatic
      thyroid cancers after total thyroidectomy. NIS gene transfer to tumor cells may
      significantly and specifically enhance internal radioactive accumulation of
      tumors following radioiodide administration, and result in better tumor control.
      NIS gene transfers have been successfully performed in a variety of tumor animal
      models by either plasmid-mediated transfection or virus (adenovirus or
      retrovirus)-mediated gene delivery. These animal models include nude mice
      xenografted with human melanoma, glioma, breast cancer or prostate cancer, rats
      with subcutaneous thyroid tumor implantation, as well as the rat intracranial
      glioma model. In these animal models, non-invasive imaging of in vivo tumors by
      gamma camera scintigraphy after radioiodide or technetium injection has been
      performed successfully, suggesting that the NIS can serve as an imaging reporter
      gene for gene therapy trials. In addition, the tumor killing effects of 131I
      after NIS gene transfer have been demonstrated in in vitro clonogenic assays and
      in vivo radioiodide therapy studies, suggesting that NIS gene can also serve as a
      therapeutic agent when combined with radioiodide injection. Better NIS-mediated
      tumor treatment by radioiodide requires a more efficient and specific system of
      gene delivery with better retention of radioiodide in tumor. Results thus far
      are, however, promising, and suggest that NIS gene transfer followed by
      radioiodide treatment will allow non-invasive in vivo imaging to assess the
      outcome of gene therapy and provide a therapeutic strategy for a variety of human
      cancers.

PMID- 12477253
TI  - Herpes simplex virus vectors for gene delivery to a variety of different cell
      types.
AB  - Herpes Simplex Virus (HSV) has a number of advantages as a gene delivery vector,
      particularly for the nervous system. Thus, it naturally establishes asymptomatic
      latent infections of neuronal cells. Moreover, it is readily grown in culture to
      high titre and has a large genome so allowing it to be used to deliver multiple
      or very large genes. Considerable progress has been made in effectively disabling
      the virus so that it does not damage the cells it infects but can still deliver
      an inserted gene effectively. In addition, it is now possible to obtain long-term
      expression of the transgene in the nervous system, using regulatory elements
      derived from the latency-associated transcript of the virus. As well as its use
      in the nervous system, the virus has also been used to successfully deliver genes
      to a variety of other cell types, including peripheral blood mononuclear cells
      and cardiac myocytes within the intact heart. In particular, its ability to
      deliver genes effectively to replicating cancer cells and to dendritic cells
      offers considerable potential for the use of this virus in cancer therapy.

PMID- 12477252
TI  - Challenges for gene therapy of type 1 diabetes.
AB  - Type 1 or insulin-dependent diabetes mellitus is caused by autoimmune attack and
      selective destruction of the pancreatic beta cells. Despite the development of
      various insulin replacement therapies, insulin injection still remains the
      mainstay treatment for type 1 diabetes. However, exogenous insulin administration
      cannot achieve the same degree of glycemic control as provided by endogenous
      insulin produced from the pancreatic beta cells. Insulin gene transfer is being
      developed to improve the quality of glycemic control by restoring endogenous
      insulin production in type 1 diabetes. Nevertheless, attempts to achieve
      adequately regulated insulin production are stymied by the lack of appropriate
      surrogate cells that are able to detect blood glucose variations and release
      insulin in a glucose-dependent manner. Although limited success has been made to
      control insulin gene expression in ectopic cells using hormone/glucose-regulated
      expression systems, these transcriptionally regulated systems are relatively slow
      in the "on-" and "off"-kinetics of insulin production, raising a serious safety
      concern for clinical application. In this article, we will review recent advances
      made to address this concern and highlight the importance of insulin gene
      transfer to cell types that possess an intrinsic ability to kinetically mimic the
      pancreatic beta cells in terms of glucose-responsive insulin secretion.

PMID- 12477254
TI  - Gene therapy in cardiovascular diseases.
AB  - Established modalities of treatment for obstructive coronary artery disease
      include medical therapy, bypass surgery and percutaneous coronary intervention.
      Similarly, conventional treatment of congestive heart failure is also limited to
      medical therapy, temporary assist devices and transplantation. A significant
      subset of patients with severe symptomatic coronary artery disease and end stage
      heart failure is not eligible for these traditional methods of treatment. In
      spite of maximal medical and revascularization therapy, these patients may not
      get adequate symptomatic benefit. After a decade of investigations, gene therapy
      has emerged as a promising therapeutic option for this group of patients. This
      review discusses newer modalities of therapy for this subset, including
      therapeutic angiogenesis with growth factors and cell transplantation.

PMID- 12477255
TI  - Gene therapy and biologic therapy with interleukin-4.
AB  - For more than two decades, there has been a concerted effort to define the
      biology of, and develop the clinical applications for, cytokines that influence
      the immune system. However, intrinsic potency and toxicity have complicated
      application of cytokines as therapeutic agents when applied systemically. Indeed,
      one of the major characteristics of most cytokines is that they regulate immunity
      at a local or regional level, and systemic levels provided by most conventional
      schema fail to mimic the induction of an effective immune response. IL-4 has
      pleiotropic effects on immune cells of multiple lineages, endothelial cells and
      tumor cells. Accumulating data in pre-clinical studies demonstrate that sustained
      expression of IL-4 at the targeted organs or tissues may provide an effective
      means for therapy of variety of diseases including cancers and immunologic
      disorders. This review discusses biological properties and therapeutic
      applications of IL-4, particularly when it is delivered as a transgene in the
      settings of gene therapy.

PMID- 12477256
TI  - Neuroprotective gene therapy for Parkinson's disease.
AB  - Parkinson's disease (PD) is a neurodegenerative disease characterised by a
      progressive loss of the dopaminergic neurones in the substantia nigra pars
      compacta. Accumulating evidence indicates that apoptosis contributes to neuronal
      cell death in PD patients' brain. Excitotoxicity, oxidative stress, and
      mitochondrial respiratory failure are thought to be the key inducers of the
      apoptotic cascade. Even though the initial cause and the mechanism of
      degeneration are poorly understood, neuroprotection can be achieved by
      interfering with neuronal cell death either directly or by preventing neuronal
      dysfunction. Potential agents for neuroprotection are neurotrophic factors,
      inhibitors of apoptosis or anti-oxidative agents. However, the existence of the
      blood-brain barrier precludes systemic delivery of these factors. In situ gene
      delivery provides strategies for local and sustained administration of protective
      factors at physiologically relevant doses. Viral vectors mediating stable gene
      expression in the central nervous system exist and are still under development.
      Efficacy of these vectors has repeatedly been demonstrated in the animal models
      both ex vivo and in vivo. Ex vivo gene delivery could furthermore be combined
      with cell replacement therapies by transplanting genetically modified cells
      compensating for the lost neuronal cell population in order to provide
      neuroprotection to both the grafted cells and degenerating host neurones.
      However, several aspects of gene transfer, such as uncontrolled diffusion, axonal
      transport, unpredictable site of integration and immunological responses, still
      raise safety concerns and justify further development of viral and non-viral
      vectors as well as genetic elements with tightly controlled gene expression.
      Various relevant animal models for Parkinson's disease are available for the
      evaluation of gene therapy strategies. These include induction of cell death in
      specific neurone population through administration of toxins either directly in
      the brain or systemically, as well as transgenic mice expressing human disease
      associated mutations.

PMID- 12477257
TI  - Immunogenic issues concerning recombinant adeno-associated virus vectors for gene
      therapy.
AB  - Recombinant adeno-associated virus (rAAV) vectors have emerged as highly
      promising for use in gene transfer for a variety of reasons, including lack of
      pathogenicity and wide host range. In addition, all virus-encoded genes have been
      removed from standard rAAV vectors, resulting in their comparatively low
      intrinsic immunogenicity. For gene replacement strategies, transgenes encoded by
      rAAV vectors may induce less robust host immune responses than other vectors in
      vivo. However, under appropriate conditions, host immune responses can be
      generated against rAAV encoded transgenes, raising the potential for their use in
      vaccine development. In this review, we have summarized current understanding of
      the generation of both undesirable and beneficial host immune responses directed
      against rAAV and encoded transgenes, and how they might be exploited for optimal
      use of this promising vector system.

PMID- 12477258
TI  - Embryonic hematopoiesis in mice and humans.
AB  - AIM: The aim of this report is to review briefly the ontogeny of hematopoiesis in
      mice and humans and to discuss recent evidence for an intraembryonic source of
      hematopoietic stem cells. METHODS: The hematopoiesis overview summarizes
      information present in the PubMed online database and from experiments conducted
      in our laboratories. RESULTS: The major sites of hematopoiesis change throughout
      development in mice and humans. Recent evidence suggests that hematopoietic cells
      may emerge from mesoderm precursors within the embryo as well as in the yolk sac.
      CONCLUSION: The ontogeny of hematopoiesis is similar in mice and humans. The
      murine system is a useful model to study the earliest events involved in forming
      hematopoietic stem cells.

PMID- 12477259
TI  - Developmental biology of the dendritic cell system.
AB  - AIM: To determine whether an imbalance of dendritic cell subsets might contribute
      to diminished adaptive host responses observed in newborn infants. It was
      hypothesized that the proportion of lymphoid dendritic cells would be greater
      than that of myeloid dendritic cells in cord blood. METHODS: To investigate this,
      dendritic cell subsets were evaluated in whole cord blood by flow cytometry.
      Circulating dendritic cells were also isolated from cord blood based on CD1c and
      BDCA-2 expression. Myeloid dendritic cells were also obtained by culturing cord
      and adult blood monocytes. Surface phenotypes of these cells were determined by
      flow cytometry using monoclonal antibodies directed against lineage, major
      histocompatibility, adhesion, co-stimulation and cytokine receptor molecules.
      Antigen-presenting functions of dendritic cell subsets were determined by mixed
      leukocyte reactions. RESULTS: Circulating myeloid dendritic cells were higher in
      cord blood than previously reported in adult blood, whereas lymphoid dendritic
      cell numbers were similar between cord and adult blood. Expression of CD11c,
      CD45RA and CD45RO did not accurately differentiate between dendritic cell subsets
      circulating in cord blood. Fresh and culture-derived cord blood myeloid dendritic
      cells stimulated adult allogeneic leukocyte proliferation, while lymphoid
      dendritic cells were less effective inducers of an adult allogeneic leukocyte
      response. Culture-derived dendritic cells induced modest autologous cord blood
      leukocyte proliferation, but freshly isolated myeloid and lymphoid dendritic
      cells did not stimulated autologous leukocytes. CONCLUSION: Contrary to the
      hypothesis, an imbalance in the ratio of circulating myeloid to lymphoid
      dendritic cell subsets does not exist and, therefore, does not contribute to
      diminished adaptive immune responses in newborn infants.

PMID- 12477260
TI  - Physiology of erythropoietin during mammalian development.
AB  - Growth is a fundamental process of mammalian development. Several observations
      regarding regulation of erythropoiesis during growth are not easily explained by
      the hypoxia-erythropoietin (Epo) concept. This review focuses primarily on this
      aspect of the physiology of Epo. The question is raised of whether this
      regulation during growth is based on the hypoxia-Epo mechanism alone, or whether
      Epo acts in concert with general growth-promoting factors, particularly growth
      hormone (GH) and the insulin-like growth factors (IGF-I and -II). Supporting the
      latter hypothesis is the observation that the Epo and GH/IGF systems are
      activated by hypoxia and share similar receptors and pathways. Recent studies
      indicate that human fetal and infant growth is stimulated by GH, IGF-I and IGF
      II. Epo, GH and IGFs are expressed early in fetal life. Although the rate of
      erythropoiesis in the fetus is high, serum Epo levels are low. The Epo response
      to hypoxia in the fetus and neonate is reduced compared with adults. Following
      delivery the Epo levels vary between species, probably related to the oxygen
      transport capacity of the hemoglobin (Hb) mass. IGF-I levels are low in the fetus
      and increase slowly following birth, except in preterm infants in whom the levels
      decline. In all mammals Hb declines following birth, giving rise to "early
      anemia". Except in the human, Epo levels increase proportionally with the fall in
      Hb, but there is a discrepancy between the curves for serum immunoreactive Epo
      (siEpo) and for erythropoiesis stimulating factors (ESF): the latter include
      other stimulatory factors in addition to Epo. Hypertransfusion of mice in the
      period of "early anemia" suppresses siEpo, but not ESF and erythropoiesis, as it
      does in adult mice. GH and IGF-I have direct effects on erythropoiesis in vitro
      and act particularly at the later stages of red cell differentiation. IGF-I acts
      synergistically with Epo, and its effects are most marked when Epo levels are
      low. Human recombinant (rhu) IGF-I stimulates erythropoiesis in neonatal rats,
      but not in newborn mice and lambs. In adult mice, in hypophysectomized rats and
      in mice with end-stage renal failure, however, a stimulatory effect of this
      growth factor was found on red cell production. RhuGH stimulates erythropoiesis
      in GH-deficient short children. CONCLUSION: Fetal and early postnatal
      erythropoiesis are dependent on factors in addition to Epo. The likely candidates
      are GH and IGF-I. The in vitro stimulating effects of these factors on
      erythropoiesis are convincing, but more data are needed on the in vivo effects.

PMID- 12477261
TI  - Erythropoietin and hypoxia inducible factor-1 expression in the mid-trimester
      human fetus.
AB  - AIM: Infants born prematurely lack a normal response to anemia and fail to
      increase erythropoietin (Epo) production despite an apparent need for improved
      tissue oxygenation. This anemia may involve a deficiency in the fetal and
      premature kidney to produce Epo. To evaluate fetal Epo production, Epo and
      hypoxia inducible factor-1 (HIF) mRNA expression was measured in the mid
      trimester human fetus. METHODS: Fetal liver and kidney samples were obtained at
      11-22 wk of gestation. RNA was isolated and reverse transcribed from snap-frozen
      specimens. Epo and HIF cDNA concentrations were determined using real-time
      polymerase chain reaction (PRISM). Epo cDNA concentrations were standardized to
      HIF concentrations present in each sample. RESULTS: HIF concentrations remained
      constant during gestation in kidney and liver samples. Epo cDNA concentrations in
      kidney did not change from 12 to 22 wk (8.4 +/- 3.4 fg Epo pg(-1) HIF cDNA, 4.8
      +/- 1.4, 2.6 +/- 0.4, and 4.2 +/- 1.8 at 11-14, 15-16, 17-19, and 20-22 wk of
      gestation, respectively), while Epo cDNA concentrations in liver increased with
      gestation (74.5 +/- 31.9 fg pg(-1) HIF, 23.8 +/- 6.5, 96.4 +/- 19.2 and 276.1 +/-
      28.5 at 12-14, 15-16, 17-19 and 20-22 wk of gestation, respectively, p < 0.05, 20
      22 wk of gestation liver samples vs all other gestations). Concentrations were 5
      20-fold higher in liver than in kidney in each gestational group (p < 0.01, liver
      vs kidney). CONCLUSION: HIF concentrations did not change with gestation in liver
      or kidney. The human fetal kidney produced approximately 5% of the total Epo mRNA
      measured during the second trimester. It remains to be determined how Epo
      production by these tissues is affected by premature birth.

PMID- 12477262
TI  - Roles of erythropoietin in human milk.
AB  - Erythropoietin (Epo) is one of many biologically active growth factors present in
      human and animal milk. Accumulating evidence shows important developmental roles
      for these milk-borne growth factors. Although Epo is present in biologically
      relevant amounts in mammalian milk, the roles of Epo in milk are incompletely
      defined. A significant proportion of milk-borne Epo resists proteolytic
      degradation. Epo receptors (EpoR) have been found on gastric mucosa and
      intestinal mucosa, and in mesenteric vessel endothelium. Evidence to date shows
      that intact Epo reaches these local organs, as well as distal organs. After
      feeding Epo, local gastrointestinal physiological effects are seen in suckling
      rats. In humans and rats, short-term feeding of high-dose Epo increases
      reticulocytes, but it is unclear whether sustained treatment increases red cell
      mass. CONCLUSION: Further work towards understanding the physiological and
      potential pharmacological roles of enterally administered Epo is necessary.

PMID- 12477263
TI  - Erythropoietin in the central nervous system, and its use to prevent hypoxic
      ischemic brain damage.
AB  - A new field of clinical and scientific interest has recently developed based on
      the discovery that the hematopoietic cytokine erythropoietin (Epo) has important
      non-hematopoietic functions in the brain and other organs, particularly during
      development. The biological effects of Epo in the central nervous system (CNS)
      involve activation of its specific receptor and corresponding signal transduction
      pathways. Epo receptor expression is abundant in the developing mammalian brain,
      and decreases as term approaches. Epo has been identified as a neurotrophic and
      neuroprotective agent in a wide variety of experimental paradigms, from neuronal
      cell culture to in vivo models of brain injury. Several mechanisms by which Epo
      produces neuroprotection are recognized. Epo (i) decreases glutamate toxicity,
      (ii) induces the generation of neuronal anti-apoptotic factors, (iii) reduces
      inflammation, (iv) decreases nitric oxide-mediated injury, and (v) has direct
      antioxidant effects. CONCLUSION: Collectively, the evidence suggests that Epo may
      provide a new approach to the treatment of a variety of CNS disorders in adults
      and children, especially as a possible therapy for perinatal asphyxia. This
      review summarizes the current knowledge on the neurotrophic and neuroprotective
      functions of Epo in the developing and injured brain.

PMID- 12477264
TI  - Enteral administration of hematopoietic growth factors in the neonatal intensive
      care unit.
AB  - By 20 wk of gestation, the human fetal gastrointestinal (GI) tract
      morphologically resembles that of the term infant, but functional development is
      limited before 26 wk. By 30 wk of gestation, the fetus has the capacity for
      limited digestion and enteral absorption. GI growth and development continue
      postnatally. Trophic factors, including nutrients, peptides, hormones and growth
      factors, are recognized as having important influences on the morphology and
      histology of the developing GI tract. Other trophic factors are important in
      adaptation and repair following injury. Many such factors are provided in utero
      via amniotic fluid swallowing and later by human colostrum and milk. CONCLUSION:
      This review discusses cytokines with known GI trophic effects, either in vitro or
      in vivo, and focuses on those cytokines that have been used in the neonatal
      intensive care unit.

PMID- 12477265
TI  - Developmental biology of thrombopoietin in the human fetus and neonate.
AB  - This review focuses on the biology of thrombopoietin (Tpo) during human
      development. It summarizes the current understanding on molecular biological
      aspects of Tpo, cellular effects of Tpo on fetal and neonatal megakaryopoiesis,
      regulation of Tpo production, and circulating Tpo concentrations in human fetuses
      and neonates. Some important aspects on the developmental biology of Tpo are
      highlighted. They include the finding of high Tpo gene expression in the bone
      marrow during the onset of medullary hematopoiesis, higher circulating Tpo
      concentrations in fetuses and neonates than in children or adults, and a higher
      sensitivity of neonatal megakaryocyte progenitor cells to Tpo. However, other
      aspects of the developmental biology of Tpo are incompletely understood.
      CONCLUSION: More carefully designed studies are needed to provide the necessary
      background for an optimal treatment of fetal and neonatal thrombocytopenia.

PMID- 12477266
TI  - Mechanisms underlying thrombocytopenia in the neonatal intensive care unit.
AB  - Thrombocytopenia is one of the most common hematological problems among neonates
      in the neonatal intensive care unit (NICU), but in the majority of cases the
      kinetic mechanism responsible is unclear. This review focuses on both traditional
      and innovative methods used to evaluate the mechanisms responsible for
      thrombocytopenia in neonates, and analyzes the data generated from those methods.
      CONCLUSION: Results of studies using new methods for evaluating thrombocytopenia,
      coupled with recent descriptions of marrow megakaryocyte mass, suggest that
      decreased platelet production complicates most cases of thrombocytopenia among
      neonates in the NICU.

PMID- 12477267
TI  - Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit.
AB  - Phlebotomy-induced anaemia excepted, thrombocytopenia is the most common
      haematological abnormality in neonatal intensive care unit (NICU) patients.
      Roughly one-quarter of all NICU patients and half of all sick preterm neonates
      develop thrombocytopenia. Whereas a large number of varied precipitating
      conditions has been identified, early-onset thrombocytopenia (<72 h) is most
      commonly associated with fetomaternal conditions complicated by placental
      insufficiency and/or fetal hypoxia, e.g. maternal pre-eclampsia and fetal
      intrauterine growth restriction. The resulting neonatal thrombocytopenia is
      usually mild to moderate, resolves spontaneously and requires no specific
      therapy. Deviation from this pattern of thrombocytopenia suggests the presence of
      more significant precipitating conditions. The most important of these are the
      immune thrombocytopenias, and every NICU should develop investigation and
      treatment protocols to manage these cases promptly and avoid unnecessary risk of
      haemorrhage. In contrast, late-onset thrombocytopenia (>72 h) is almost always
      associated with sepsis or necrotizing enterocolitis and the associated
      thrombocytopenia is severe, prolonged and often requires treatment by platelet
      transfusion. Unfortunately, evidence-based guidelines for platelet transfusion
      therapy in NICU patients are currently unavailable, making it difficult to define
      widely accepted thresholds for transfusion and leading to a significant variation
      in transfusion practice between centres. CONCLUSION: While improving this
      situation remains a pressing need, the growing evidence that impaired
      megakaryocytopoiesis and platelet production are major contributors to many
      neonatal thrombocytopenias suggests that recombinant haemopoietic growth factors,
      including thrombopoietin and interleukin-11, may be useful future therapies to
      ameliorate neonatal thrombocytopenia.

PMID- 12477268
TI  - Use of the bleeding time in the neonatal intensive care unit.
AB  - Impairments of primary hemostasis are frequently responsible for serious bleeding
      in sick infants in the neonatal intensive care unit (NICU). Therefore, a rational
      approach to these infants with hemorrhagic manifestations, in addition to an
      accurate medical history, a careful physical examination and routine screening
      coagulation tests, may include a bleeding time. The bleeding time is the
      traditional in vivo test for assessing primary hemostasis. It is a useful
      clinical tool to detect quantitative or qualitative platelet disorders or
      microvascular defectiveness. Its diagnostic value in neonates is controversial,
      mainly owing to limited experience in executing the test, which is performed
      uncommonly in the NICU. Using a template device expressly adapted for neonates
      (Surgicutt Newborn), a small incision 2.5 mm long and 0.5 mm deep provides a
      standardized, reproducible and sensitive bleeding time, with minimal scarring and
      pain. Various hereditary or acquired maternal and neonatal diseases, as well as
      some antepartum medications given to the mother or drugs commonly used to treat
      NICU patients, such as indomethacin, ibuprofen, penicillin compounds and
      theophylline, can impair primary hemostasis and consequently prolong the bleeding
      time in neonates. Furthermore, other factors distinctive to neonates, including
      gestational age, the increased von Willebrand factor concentration and function,
      high hematocrit, the large size of erythrocytes and platelet hyporeactivity in
      the first 10 d of life, affect platelet-vessel wall interaction and influence the
      interpretation of bleeding time results in newborn infants. Because the clinical
      evaluation of primary hemostasis consists of complex laboratory testing, largely
      reserved for specialized laboratories and currently not routinely performed in
      newborn infants, automated bleeding time devices specifically generated to make
      standardized and acceptably small incisions in newborn infants have become a
      surrogate. CONCLUSION: With awareness of its value and limitations, the bleeding
      time can be included in the baseline evaluation of neonates in the NICU, for
      guiding diagnosis and treatment of primary hemostatic disorders.

PMID- 12477269
TI  - Prothrombotic factors in neonates with cerebral thrombosis and intraventricular
      hemorrhage.
AB  - AIM: To investigate whether the factor V Leiden mutation (FVL), the prothrombin
      gene G20210A variant or the methylenetetrahydrofolate reductase (MTHFR) C677T
      genotype are risk factors for central nervous system (CNS) thrombosis or
      intraventricular hemorrhage (IVH) in neonates. METHODS: Thirteen full-term
      infants with cerebral infarct documented with magnetic resonance imaging were
      assessed with the whole spectrum of assays for thrombophilia including the three
      DNA-based prothrombotic factors. The frequency of congenital defects was compared
      with that observed in 38 healthy full-term infants. The genetic defects were also
      assessed in 55 premature neonates, gestational age <32 wk, 17 of whom developed
      IVH, grade II-IV. The remaining 38 premature neonates without IVH were used as
      controls. RESULTS: In the CNS thrombosis group: a prothrombotic factor was
      detected in 53% of patients and an underlying disease or a triggering event in
      61.5%. The frequency of FVL in thrombosed neonates was higher (23%) than in the
      group of healthy full-term infants (10.5%), although it did not reach statistical
      significance. IVH developed in 30.9% of premature neonates. Apart from several
      maternal or neonatal risk factors for IVH, FII G20210A was found in a
      considerably higher prevalence in the cohort of neonates with IVH (12%) than in
      those without (2%), although the difference was not statistically significant.
      CONCLUSION: The pathogenesis of cerebral thrombosis or IVH in neonates is
      multifactorial. Along with underlying diseases or triggering events, congenital
      prothrombotic factors (FVL or FII G20210A) showed a trend towards a higher
      frequency in full-term infants with CNS thrombosis or premature neonates with IVH
      than in controls. However, their contribution to neonatal cerebral thrombosis or
      IVH remains to be determined.

PMID- 12477271
TI  - Immune-mediated neutropenia in the neonate.
AB  - Alloimmune neonatal neutropenia, neonatal autoimmune neutropenia and autoimmune
      neutropenia of infancy have remained nebulous entities with difficulties in both
      clinical and laboratory identification. These disorders are reviewed in this
      article.

PMID- 12477270
TI  - Inflammatory mediators in perinatal asphyxia and infection.
AB  - AIM: To determine serum levels of interleukin-6 (IL-6), IL-1beta, tumor necrosis
      factor-alpha (TNF-alpha), soluble intercellular adhesion molecule-1 (sICAM-1) and
      C-reactive protein (CRP) in asphyxiated neonates and compare these inflammatory
      factors with those found in neonates with perinatal infection. METHODS: 88
      neonates were studied, of whom 36 were asphyxiated, 18 were infected and the
      remaining 34 were controls. Peripheral blood samples were obtained on the 1st,
      3rd and 5th postnatal days. RESULTS: Cytokines IL-6 and IL-1beta as well as sICAM
      1 serum levels did not differ between asphyxiated and infected neonates; however,
      at most time periods, their values were significantly higher than controls. TNF
      alpha was similar in the three groups of neonates. CRP serum values were
      significantly higher in the infected neonates than in the asphyxiated or control
      subjects. Among the 54 asphyxiated and infected neonates, 15 were considered as
      severe cases and 39 as mild. The severe cases, at most time periods, had
      significantly higher IL-6, IL-1beta and sICAM-1 levels compared with the mild
      ones. Through receiver operating characteristic curves the cut-off points,
      sensitivities, and specificities for distinguishing neonates at risk or at high
      risk for brain damage were established. CONCLUSION: Similar increases in serum
      levels of IL-6, IL-1beta and sICAM-1 were found in perinatally asphyxiated and
      infected neonates. As these increases correlated with the severity of the
      perinatal insults, neonates at high risk for brain damage might be detected.

PMID- 12477272
TI  - Late-onset neutropenia in very low birthweight infants.
AB  - AIM: To evaluate the incidence and duration of late-onset neutropenia (defined as
      an absolute neutrophil count (ANC) <1500 mm(-3) at a postnatal age of >3 wk) in a
      population of infants with birthweight <2000 g, and to determine whether copper
      deficiency, a possible cause of both anemia and neutropenia, may be associated
      with this complication. METHODS: Complete blood cell count and differential were
      assessed in 247 low (LBW) and very low birthweight (VLBW) infants who were
      discharged after 3 wk of life. In neutropenic infants plasma copper and
      ceruloplasmin levels were also measured. RESULTS: Late-onset neutropenia was
      detected in 11 out of 147 VLBW infants (7.5%) and in 7 out of 127 LBW infants
      (5.5%). A neutrophil count of <1000 mm(-3) was observed in 14 infants (5.1%). A
      significantly lower gestational age was found in neutropenic infants compared
      with non-neutropenic infants. In neutropenic infants ANCs were significantly
      correlated with hemoglobin and hematocrit. In addition, a significant negative
      correlation was found between neutrophil and reticulocyte counts. Plasma copper
      concentration was significantly correlated with birthweight. Oral copper sulfate
      was administered to infants with plasma copper concentration <50 microg dl(-1),
      and did not seem to affect ANC, hemoglobin, hematocrit or reticulocyte counts.
      CONCLUSION: Late-onset neutropenia appears to be a benign condition that is not
      associated with any particular complication and does not require specific
      treatment. Reference ranges after the early neonatal period and during the first
      few months of life in LBW and VLBW infants should probably be set at lower
      values.

PMID- 12477273
TI  - What is the rationale for the use of granulocyte and granulocyte-macrophage
      colony-stimulating factors in the neonatal intensive care unit?
AB  - Neonatal sepsis remains an unsolved major contributor to morbidity and mortality.
      In the 1980s the promise of augmenting immune function using pooled intravenous
      gammaglobulin to supplement the exceedingly low levels of immunoglobulin G in
      premature infants failed to demonstrate a clear advantage. Similarly, cytokine
      augmentation of cellular function in the 1990s largely appeared to be suffering
      the same fate. However, both results may arise from a problem in experimental
      design where the combination of both treatments may be necessary along with
      specific antibody. For example, in vitro, independently of an array of other
      humoral and cellular immature immune system issues, opsonization of bacteria is
      improved in the presence of antibody. The question is whether the same result can
      be achieved in vivo. No experiments have been reported that directly test this
      hypothesis. CONCLUSION: More investigation is needed in this challenging area of
      neonatal research.

PMID- 12477274
TI  - Deficient interferon-gamma receptor-mediated signaling in neonatal macrophages.
AB  - AIM: To describe functional and molecular characteristics of interferon-gamma
      (IFN-gamma) activation in neonatal mononuclear phagocytes (monocytes and
      macrophages). METHODS AND RESULTS: Exposure of cord and adult macrophages to IFN
      gamma gave quantitatively different results in Candida killing, as well as in
      release of superoxide anion (O2-). At concentrations of 100 U ml(-1) IFN-gamma,
      maximal increase in these functions with adult macrophages was achieved, whereas
      no enhancement of killing and O2- release by cord macrophages could be detected.
      Expression of IFN-gamma receptors was comparable on cord and adult cells and
      specific binding of [125I]IFN-gamma to cord monocytes and macrophages was even
      higher compared with adult cells. By flow cytometry, elements of IFN-gamma
      receptor-mediated signaling in cord and adult monocytes and macrophages were
      studied. Monoclonal antibodies against the native form of the signal transducer
      and activator of transcription-1 (STAT-1) revealed comparable expression of this
      protein in cord and adult macrophages. However, STAT-1 phosphorylation in
      response to IFN-gamma was significantly decreased in neonatal monocytes (p <
      0.05) and macrophages (p < 0.01) compared with adult cells. CONCLUSION: These
      data suggest deficient cytokine receptor signaling in neonatal mononuclear
      phagocytes exposed to IFN-gamma.

PMID- 12477275
TI  - Using fluorescence-activated cell sorting followed by fluorescence in situ
      hybridization to study lineage relationships: the 8;21 translocation is present
      in neutrophils but not monocytes in a patient with severe congenital neutropenia
      and a granulocyte colony-stimulating factor-responsive clonal abnormality.
AB  - Severe congenital neutropenia (Kostmann syndrome) is a disorder that presents in
      the neonatal period, but predisposes to leukemia later in life. This report
      describes a 4-y-old female with a history of severe congenital neutropenia, who
      developed a clonal abnormality associated with the translocation (7;21;8)
      (q32;q22;q22) (AML-1/ETO). She had circulating peripheral blasts and bone marrow
      blast counts as high as 64% when she received recombinant granulocyte colony
      stimulating factor (rG-CSF). Her marrow blasts decreased to 4-20% when rG-CSF was
      discontinued. Fluorescence in situ hybridization analysis was performed on bone
      marrow cell populations sorted by flow cytometry to determine which cell
      populations had the AML-1/ETO translocation. The translocation was found in
      mature neutrophils and blasts, but not in monocytes, lymphocytes or stem cells.
      CONCLUSION: These findings suggest that the translocation occurred in a
      neutrophil progenitor, past the point in ontogeny where monocytes and neutrophils
      separate. The techniques described may be useful in understanding lineage
      relationships and leukemogenesis in other clonal abnormalities associated with
      myelodysplasia and leukemia.

PMID- 12477276
TI  - Perinatal aspects of iron metabolism.
AB  - Iron sufficiency is critical for rapidly developing fetal and neonatal organ
      systems. The majority of iron in the third trimester fetus and the neonate is
      found in the red cell mass (as hemoglobin), with lesser amounts in the tissues as
      storage iron (e.g. ferritin) or functional iron (e.g. myoglobin, cytochromes).
      Iron is prioritized to hemoglobin synthesis in red cells when iron supply does
      not meet iron demand. Thus, non-heme tissues such as the skeletal muscle, heart
      and brain will become iron deficient before signs of iron-deficiency anemia.
      Gestational conditions that result in lower newborn iron stores include severe
      maternal iron deficiency, maternal hypertension with intrauterine growth
      retardation and maternal diabetes mellitus. Stable, very low birthweight
      premature infants are also at risk for early postnatal iron deficiency because
      they accrete less iron during gestation, grow more rapidly postnatally, are
      typically undertreated with enteral iron and receive fewer red cell transfusions.
      Conversely, iron overload remains a significant concern in multiply transfused
      sick preterm infants because they have low levels of iron-binding proteins and
      immature antioxidant systems. CONCLUSION: The highly variable iron status of
      preterm infants combined with their risk for iron deficiency and toxicity
      warrants careful monitoring and support in the newborn and postdischarge periods.

PMID- 12477277
TI  - Oxidant injury in neonatal erythrocytes during the perinatal period.
AB  - It has been known for many decades that oxidative stress leads to oxidation of
      hemoglobin and damage to the erythrocyte membrane. More recently, the factors
      involved in denaturating of membrane proteins and lipid peroxidation have been
      investigated in detail, as well as the mechanism of reactive oxygen species
      formation in red cells. Oxidative stress depletes adenosine triphosphate (ATP)
      and adenine nucleotides, whereas adenosine monophosphate (AMP) deaminase seems to
      depress energy metabolism by blocking the salvage pathway of purine nucleotides.
      Depletion of ATP and activation of AMP deaminase are related to calcium ion
      concentrations. Denaturating of membrane proteins generally precedes lipid
      peroxidation and consequent phagocytosis due to caspase activation. Extensive
      investigations demonstrated the key role of oxidative stress and iron release in
      a reactive form causing membrane protein damage via the Fenton reaction and
      hydroxyl radical production. In the absence of efficient protection by
      antioxidant factors and other molecules such as flavonoids, oxidative stress is
      responsible for the release of iron in reactive form, predisposing red cells to
      hemolysis through the formation of senescence antigen. Other well-known sources
      of oxidative stress in red cells are free radical production outside the red cell
      by activated phagocytes, endothelial metabolism, hyperoxia, ischemia-reperfusion
      and the arachidonic acid cascade. CONCLUSION: The recent insight into the
      mechanism of oxidative injury of red cells and evidence of relationships between
      erythrocyte oxidative stress and hypoxia suggest that increased hemolysis is
      induced by severe hypoxia and acidosis in the fetus as well as the newborn.

PMID- 12477278
TI  - New biomarkers of fetal-neonatal hypoxic stress.
AB  - The complex pathophysiological mechanisms underlying perinatal hypoxia make it
      difficult to define early markers of severe hypoxia-ischemia encephalopathy.
      However, as progress in the development of neuroprotective therapeutic measures
      continues, the early identification of neonates at risk of severe hypoxic
      ischemic encephalopathy is an important goal for appropriate decision making.
      Although the timing of perinatal hypoxic brain damage may vary and is sometimes
      unknown, high levels of non-protein-bound iron and high nucleated red blood cell
      counts in cord blood indicate an antepartum origin of neurological impairment,
      because they can occur only as a consequence of a pre-existing asphyxic event.
      CONCLUSION: The combined assessment of nucleated red blood cells and non-protein
      bound iron at birth seems extremely useful for the early identification of
      newborns at high risk of brain damage. Activin A also seems to be a reliable
      marker of perinatal hypoxia. Prospective long-term follow-up studies are needed
      to verify their predictive role.

PMID- 12477279
TI  - Cellular uptake, distribution, and stability of 10-23 deoxyribozymes.
AB  - The cellular uptake, intracellular distribution, and stability of 33-mer
      deoxyribozyme oligonucleotides (DNAzymes) were examined in several cell lines.
      PAGE analysis revealed that there was a weak association between the DNAzyme and
      DOTAP or Superfect transfection reagents at charge ratios that were minimally
      toxic to cultured cells. Cellular uptake was analyzed by cell fractionation of
      radiolabeled DNAzyme, by FACS, and by fluorescent microscopic analysis of FITC
      labeled and TAMRA-labeled DNAzyme. Altering DNAzyme size and chemistry did not
      significantly affect uptake into cells. Inspection of paraformaldehyde-fixed
      cells by fluorescence microscopy revealed that DNAzyme was distributed primarily
      in punctate structures surrounding the nucleus and that substantial delivery to
      the nucleus was not observed up to 24 hours after initiation of transfection.
      Incubation in human serum or plasma demonstrated that a 3'-inversion modification
      greatly increased DNAzyme stability (t(1/2) approximately 22 hours) in comparison
      to the unmodified form (t(1/2) approximately 70 minute). The 3'-inversion
      modified DNAzymes remained stable during cellular uptake, and catalytically
      active oligonucleotide could be extracted from the cells 24 hours
      posttransfection. In smooth muscle cell proliferation assay, the modified DNAzyme
      targeting the c-myc gene showed a much stronger inhibitory effect than did the
      unmodified version. The present study demonstrates that DNAzymes with a 3'
      inversion are readily delivered into cultured cells and are functionally stable
      for several hours in serum and within cells.

PMID- 12477280
TI  - Effects on RNA interference in gene expression (RNAi) in cultured mammalian cells
      of mismatches and the introduction of chemical modifications at the 3'-ends of
      siRNAs.
AB  - The highly specific posttranscriptional silencing of gene expression induced by
      double-stranded RNA (dsRNA) is known as RNA interference (RNAi) and has been
      demonstrated in plants, nematodes, Drosophila, and protozoa, as well as in
      mammalian cells. The suppression of expression of specific genes by chemically
      synthesized 21-nucleotide (21-nt) RNA duplexes has been achieved in various lines
      of mammalian cells, and this technique might prove to be a valuable tool in
      efforts to analyze biologic functions of genes in mammalian cells. In order to
      investigate the utility of potential modifications that can be introduced into
      small interfering RNAs (siRNAs) and also to study their functional anatomy, we
      synthesized different types of siRNA targeted to mRNA of Jun dimerization protein
      2 (JDP2). Our detailed analysis demonstrated that siRNAs with only one mismatch,
      relative to the target, on the antisense strand had reduced RNAi effect, whereas
      the corresponding mutation on the sense strand did not interfere with the RNAi.
      Moreover, one 2-hydroxyethylphosphate (hp) substitution at the 3'-end of the
      antisense strand but not of the sense strand also prevented RNAi, whereas a
      related modification at the 3'-end of either strand, using 2'-O,4'-C-ethylene
      thymidine (eT), which is a component of ethylene-bridge nucleic acids (ENA),
      completely abolished RNAi. These results support the hypothesis that the two
      strands have different functions in RNAi in cultured mammalian cells and indicate
      that their chemical modification of siRNAs at the 3'-end of the sense strand
      exclusively is possible, without loss of RNAi activity, depending on the type of
      modification. Because modification at the 3'-end of the antisense strand by hp or
      eT abolished the RNAi effect, it appears possible that the 3'-end is recognized
      by the RNA-induced silencing complex (RISC).

PMID- 12477281
TI  - Development and effects of immunoliposomes carrying an antisense oligonucleotide
      against DHFR RNA and directed toward human breast cancer cells overexpressing
      HER2.
AB  - The development and the effect of immunoliposomes directed against human breast
      cancer cells overexpressing p185/HER2 are described. These immunoliposomes carry
      an antisense oligonucleotide directed toward the translational start site of
      dihydrofalate reductase (DHFR) RNA, which causes high cytotoxicity. To prepare
      the immunoliposomes, we followed two methodologies based on the high affinity
      between streptavidin and biotin and the use of biotinylated antibodies. In the
      first approach, the streptavidin molecule is covalently attached to the
      phospholipid DOPE, which is mixed with the cationic liposome DOTAP complexed with
      the antisense oligonucleotide. The second approach, which is much easier to
      perform, involves the binding of streptavidin to antibody and oligonucleotide,
      both biotinylated, and the latter complexed with DOTAP. The formation of the
      intermediary complexes of this immunoliposome was studied sequentially by gel
      electrophoresis. The uptake of the oligonucleotide carried by the immunoliposome
      was monitored by flow cytometry and confocal microscopy. As a model, we used
      SKBR3 cells that overexpress p185. The full immunoliposomes were more toxic than
      the antisense oligonucleotide in the absence of the antibody, thus increasing the
      sensitivity of the treatment.

PMID- 12477282
TI  - Accumulation of glutathione disulfide mediates NF-kappaB activation during immune
      stimulation with CpG DNA.
AB  - Innate immune cells recognize pathogens by detecting molecular patterns that are
      distinct from those of the host. One such pattern is unmethylated CpG
      dinucleotides, which are common in bacterial DNA but not in vertebrate genomes.
      Macrophages respond to such CpG motifs in bacterial DNA or synthetic
      oligodeoxynucleotides (ODN) by inducing NF-kappaB and secreting proinflammatory
      cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF
      alpha), but the mechanisms regulating this have been unclear. CpG ODN-stimulated
      cells produce reactive oxygen species (ROS) and have a decreased ratio of
      intracellular glutathione/glutathione disulfide (GSH/GSSG), indicating a shift to
      a more oxidized intracellular redox state. To determine whether this may play a
      role in mediating the CpG-induced macrophage activation, the GSH/GSSG redox state
      was manipulated in the murine macrophagelike cell line RAW264.7. Treatment of
      cells with BCNU to inhibit glutathione reductase (GR) enhanced the CpG-induced
      intracellular oxidation and decreased the GSH/GSSG, with increased activation of
      NF-kappaB and a doubling in the CpG-induced production of IL-6 and TNF-alpha.
      Experimental manipulation of the intracellular GSSG concentration during
      inhibition of cellular prooxidant production demonstrated that increased
      intracellular GSSG is a primary signal that is directly or indirectly required
      for CpG-induced NF-kappaB activation but is not in itself sufficient to trigger
      this in the absence of CpG ODN. These data suggest the existence of a second CpG
      induced intracellular signal, independent of GSSG, mediating the activation of
      innate immunity by bacterial DNA.

PMID- 12477283
TI  - Novel method for selection of tRNA-driven ribozymes with enhanced stability in
      mammalian cells.
AB  - Intracellular stability is a critical determinant of the activity of a ribozyme
      in vivo. In previous studies, we succeeded in constructing an effective system
      for the expression of ribozymes using the promoter of a human gene for tRNA(Val).
      The resultant tRNA(Val)-driven ribozymes (tRNA-ribozymes) had a half-life of
      approximately 100 minutes. In the present study, we established a novel system
      for the selection of tRNA-ribozymes that were more stable than a previously
      generated optimally designed tRNA-ribozyme, and we confirmed that the newly
      selected tRNA-ribozymes worked well. Selective pressure was applied by treating
      cells that expressed tRNA-ribozymes with actinomycin D, and the system yielded
      tRNA-ribozymes with enhanced stability. The sequences isolated after selection
      exhibited some similarities. Furthermore, some selected tRNA-ribozymes had almost
      the same activity as or higher activity than that of the optimally designed tRNA
      ribozyme despite the fact that the selective pressure was not aimed at enhancing
      the cleavage activity. Our approach might be very useful for selection not only
      of ribozymes with enhanced stability but also of other functional nucleic acids
      in vivo.

PMID- 12477284
TI  - Trafficking of intracerebroventricularly injected antisense oligonucleotides in
      the mouse brain.
AB  - Intracerebroventricular (icv) delivery of therapeutic molecules directly into the
      brain parenchyma has attracted considerable attention because of the advantage of
      bypassing the blood-brain barrier. Exogenous icv administration of antisense
      oligodeoxynucleotides (AS-ODNs) has been implicated in modifying gene expression
      within the targeted brain area. The biodistribution, tissue penetration, and
      stability of exogenously administered AS-ODNs are the major determinants with
      regard to their potential utility as agents for modifying gene expression. This
      report examined the distribution and clearance of labeled AS-ODNs with the aim of
      exploring the feasibility of icv administration of AS-ODNs as a targeted
      treatment approach to Alzheimer's disease. A single icv injection of fluorescein
      labeled 2'-O-(methoxy) ethyl (2'MOE) ribosyl-modified AS-ODNs directed at the
      beta-secretase cleavage site of beta-amyloid precursor protein (APP) mRNA into
      the mouse brain showed rapid uptake by 15 minutes, overall gradual spread and
      retention by 30 minutes to 3 hours, and complete clearance by 8 hours
      postinjection. Labeled AS-ODNs were observed to penetrate across the cell
      membrane and accumulate in both nuclear and cytoplasmic compartments of neuronal
      and nonneuronal cell populations. Current study provides a basic pattern of
      uptake, distribution, and stability of AS-ODNs in the mouse brain.

PMID- 12477285
TI  - Immune responses to fungal infections and therapeutic implications.
AB  - Host responses to fungi result from a coordinate interplay between innate and
      adaptative immune system. Neutrophils and monocytes are involved in the non
      specific clearance of yeasts (e.g. Candida albicans and Cryptococcus neoformans),
      while T helper 1 type responses are protective via release of interferon gamma.
      By contrast, T helper 2 responses (IL-4 and IL 10 release) correlate with disease
      exacerbation and pathology. IL-12 production which enhances T helper 1 type
      responses seem to exert a beneficial role in the course of Candida infection. In
      particular, its production from neutrophilis may support memory T helper 1 cell
      responses of the fungus. With respect to anti-Candida vaccines several approaches
      are in progress, such as use of heat-killed Candida albicans in combination with
      adjuvants, purified peptides and proteins and immunogenic peptide-lipid
      conjugates. Furthermore, exogenous IL-12 may play an important role in inducing a
      T helper 1 anticandidal response, also replacing neutrophils in neutropenic
      patients. At the same time, granulocyte-colony stimulating factor has exhibited
      therapeutic efficacy in experimental and human models of fungal infection.

PMID- 12477286
TI  - Helicobacter pylori infection, immune response and vaccination.
AB  - It is well known that abnormal immune responses may play a pathogenic role in the
      H. pylori-related gastropathy. Indeed, as far as humoral immune response is
      concerned, it is still debated whether specific anti-H. pylori antibodies have a
      protective or noxious effect in infected hosts. Besides proinflammatory cytokines
      released from macrophages, such as tumor-necrosis factor-a and interleukin-1beta,
      and IFN-gamma derived from T-helper 1 lymphocytes, also interleukin-10, a product
      of T-helper 2 lymphocytes with antiinflammatory properties, seems to be
      surprisingly involved in the pathogenesis of H. pylori-induced gastritis. In
      addition, lipopolysaccharide derived from the outher membrane of H. pylori acts
      as a chemoattractant for monocytes and induces release of free radicals,
      interleukin-1beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha.
      On the other hand, H. pylori lipopolysaccharide could be responsible for the
      increased polyamine concentrations in the gastric mucosa and polyamines, such as
      putrescine, spermidine and spermine, could be involved in the increased cell
      proliferation and consequent possible neoplastic transformation of the gastric
      mucosa. Incubation of peripheral blood mononuclear cells with H. pylori increases
      significantly the surface expression of CD95 receptor (Fas), thus suggesting that
      these bacteria are able to induce apoptosis. In animal models, different types of
      vaccination have been investigated, including stimulation of nasal and rectal
      lymphoid tissue, as well as adoptive transfer of T cell from donors immunized
      with H. pylori. However, results obtained are frequently disappointing. In
      humans, urease of H. pylori was safely used as oral vaccine in the absence or
      presence of adjuvants with encouraging results. Finally, DNA vaccines could offer
      in the future advantages for prophylactic H. pylori eradication, especially where
      population is infected by this microorganism since childhood.

PMID- 12477287
TI  - A new molecular target of insulin action: regulating the pivotal PDK1.
AB  - Over the last several years, a great level of interest has rallied behind
      understanding how the pivotal kinase, 3'-phosphoinositide dependent kinase 1
      (PDK1) is regulated. PDK1 phosphorylates and activates members of the AGC kinase
      family shown to be activated downstream of phosphoinositide 3-kinase (P13K);
      however, the functional dependency of PDK1 on P13K for activation of its targets
      is less clear. The P13K signaling pathway mediates numerous cellular responses
      upon growth factor and hormone stimulation. Specifically, P13K signaling
      influences many of the metabolic and mitogenic functions of the anabolic hormone,
      insulin. Thus, the regulation of P13K and its downstream targets by insulin has
      become an important topic for investigation. Given its central role as the kinase
      upstream of those signaling pathways linked to P13K, the regulation of PDK1 by
      insulin and other factors is at the height of many of these investigations.
      Current theories on PDK1 regulation propose substrate conformation and
      subcellular localization as the primary mediators of PDK1 function. The array of
      PDK1 substrates suggests, however, that in cells PDK1 may be more tightly
      regulated. Recent data support phosphorylation as a potential regulatory
      mechanism that may play an additional role in directing the specificity of PDK1
      towards its physiological substrates. The combination of these regulatory
      mechanisms along with the potential for multiple PDK1 isoforms with select tissue
      distribution may contribute to the diversified actions of insulin signaling. The
      targeting of these various aspects of PDK1 regulation may provide for novel
      therapeutic treatments for diseases such as diabetes and cancer.

PMID- 12477288
TI  - Potential role for high and low molecular weight tissue transglutaminases in
      transforming mammalian cell properties.
AB  - Tissue transglutaminase (tTGase, tTG) is known as being implicated in the
      intracellular cross-linking of proteins occurring in a growing series of
      physiological conditions including--just to mention the most relevant ones-
      programmed cell death (apoptosis), cell adhesion, growth, spreading and
      differentiation, tumor growth, metastasis, cell adhesion, proliferation,
      differentiation, extra cellular matrix (ECM) stabilization. In the current work
      we investigated tTG activity and expression of "normal" and potential transformed
      cytosolic tTG antigens in mammalian cells. Most cell lines studied showed low tTG
      activity, which in all cases could be enhanced considerably by treating cell
      cytosol homogenates with trypsin. The results suggested the existence -in
      transformed cells- of inactive types of tTGase. We purified cytosolic tTG
      antigens from these cells utilizing a GTP-agarose resin, and we can therefore
      conclude that "normal" molecular weight (mw) tTG antigens, but also high
      molecular weight (hmw) and low molecular weight (lmw) tTG antigens from
      transformed cells, retain GTP-binding ability. The initial results from our study
      also allowed us to hypothesize that transformed hmw- and lmw- tTG antigens should
      not be considered as the result of post-translational modifications of normal mw,
      cytosolic tTG. The potentially low or absent transamidating functionality of
      cytosolic tTG species in transformed mammalian cells could be responsible for
      decreased or even abolished programmed cell death, whereas the unaffected GTP
      binding functionality of such proteins in these cells might lead to increased
      signal transduction and possibly proliferation.

PMID- 12477289
TI  - Update on sensitivity to nonsteroidal antiinflammatory drugs.
AB  - Non steroidal antiinflammatory drugs (NSAIDs) are among the most frequently
      prescribed medications worldwide. These drugs are effective for the treatment of
      a wide spectrum of diseases: musculoskeletal disorders, headhache, fever, pain,
      and others. Their widespread use explains the very high incidence of intolerance;
      reactions range from asthma, rhinitis, to urticaria/angioedema, various skin
      eruptions and anaphylactic shock. The pathogenesis of intolerance is still
      unclear: immune-mediated reactions have been reported following the use of
      pyrazolone derivatives and, less commonly aspirin, anthranilic-acid derivatives
      and diclofenac. It has been suggested that NSAIDs may induce pseudoallergic
      reactions, while in case of bronchial asthma the inhibition of cyclooxigenase by
      NSAIDs has been proposed as a pathogenetic mechanism. The diagnosis of NSAIDs
      sensitivity can usually be established by history; in fact skin prick tests with
      NSAIDs have not been successful and no reliable in vitro tests are available. The
      only definitive diagnostic test is oral test dosing. To identify an alternative
      NSAIDs in a sensitive patient a tolerance test is performed. Here we review the
      current state of knowledge concerning NSAIDs sensitivity, including personal data
      to increase awareness on this issue.

PMID- 12477290
TI  - Angiogenesis and angiogenesis inhibitors: a new potential anticancer therapeutic
      strategy.
AB  - Tumor cells cannot grow as a mass above 2 to 3 mm3 because diffusion is
      insufficient for oxygen and glucose requirements, unless the tumor induces a
      blood supply. This mechanism of induction of a new blood supply from pre-existing
      vascular bed is called angiogenesis. Furthermore, tumor invasiveness and
      metastasis require neovascularization. In fact, recent published studies suggest
      that acquisition of the angiogenic phenotype is a common pathway for tumor
      progression and neovascularization is linked with other molecular steps leading
      to tumor progression. Angiogenic process is a complex multi-step cascade under
      the control of positive and negative soluble factors. A paracrine interaction
      occurs between tumor and endothelial cells. Angiogenesis involves: endothelial
      cell proliferation, migration and tubule formation with associated changes in the
      extra-cellular matrix, allowing subsequent new vessel growth toward the tumor.
      Each of the above steps may represent a target for antiangiogenic therapy.
      Antiangiogenesis is to be distinguished from direct targeting and destruction of
      tumor vasculature (vascular targeting). Inhibition of angiogenesis represents one
      of the more promising, new approaches, to anticancer treatment and its already in
      early clinical trials. This review takes into consideration: (i) the biological
      mechanism underlining angiogenesis process; (ii) the method to assess tumor
      angiogenesis activity; (iii) inhibition of angiogenesis as an anticancer therapy;
      (iv) the methodology for the clinical development of angiogenesis inhibitors,
      that should be considered biological response modifiers; (v) some angiogenesis
      antagonists that are in development and leader compounds that are under clinical
      trial.

PMID- 12477291
TI  - The use of radioactive iodine in the management of hyperthyroidism in children.
AB  - Graves' disease is the most common form of hyperthyroidism in childhood. Current
      treatment options include antithyroid medications, surgery, and radioactive
      iodine. Medical therapy is generally associated with long term remission rates of
      less than 25% and a small risk of serious adverse reactions that include hepatic
      failure and bone marrow suppression. Total thyroidectomy is associated with very
      high cure rates and a small risk of hypoparathyroidism and recurrent laryngeal
      nerve damage. When radioactive iodine is used at appropriate doses, there is a
      very high cure rate without increased risks of thyroid cancer or genetic damage.
      Because of the theoretical risk of thyroid cancer after thyroid irradiation in
      individuals less than 20 years of age, relatively high doses of radioactive
      iodine should be administered to minimize the persistence of residual thyroid
      tissue.

PMID- 12477292
TI  - Protein-tyrosine phosphatase 1B (PTP1B): a novel therapeutic target for type 2
      diabetes mellitus, obesity and related states of insulin resistance.
AB  - Resistance to the cellular action of insulin, a fundamental pathophysiological
      defect accompanying the worldwide epidemic of obesity, is closely associated with
      the development of type 2 diabetes mellitus and the set of cardiovascular risk
      factors that constitute the "metabolic" syndrome. The development of novel
      pharmaceutical agents that help ameliorate insulin resistance will be potentially
      important not only for the prevention and treatment of diabetes, but also in
      reducing its associated cardiovascular risk profile. Studies on the cellular role
      of the protein-tyrosine phosphatase PTP1B have now clearly shown that it serves
      as a key negative regulator of the tyrosine phosphorylation cascade integral to
      the insulin signaling pathway. Genetically-modified mice that lack PTP1B protein
      expression and animals treated with a specific PTP1B antisense oligonucleotide
      have provided crucial "proof-of-concept" data to show that eradicating or
      reducing PTP1B enhances insulin signaling and glucose tolerance. PTP1B inhibition
      also reduces adipose tissue storage of triglyceride under conditions of over
      nutrition and was not associated with any obvious toxicity. The effects of the
      loss of PTP1B in vivo were also remarkably specific for components of the insulin
      action cascade, in spite of cellular studies suggesting that PTPIB may exert a
      regulatory influence on a variety of other signaling pathways. Overall, these
      studies have paved the way for the commercial development of PTP1B inhibitors
      that may serve as a novel type of "insulin sensitizer" in the management of type
      2 diabetes and the cardiovascular / metabolic syndrome.

PMID- 12477293
TI  - The evolving therapy of rheumatic diseases, the future is now.
AB  - There are two main ways in which physicians will be urged to improve the outcome
      for their patients suffering from rheumatic diseases in the coming era, these
      are, early diagnosis and timely effective therapy. Current reserch suggests that
      in rheumatoid arthritis joint damage occurs early, often within the first 2 years
      and even in the absence of associating severe symptoms, is a call for action for
      primary care physicians as well as rheumatologists. Similarly in SLE patients,
      sometimes the treatments are ineffective or too toxic with sepsis or
      opportunistic infections often limiting their use or resulting in the death of
      the patient. As primary care physicians are the clinicians most frequently
      visited by patients with initial symptoms of the disease, they first need to
      learn when to suspect it as well as its complications, and when to refer the
      patient appropriately. Rheumatologists need to determine when and how to
      prescribe the most appropriate treatment, as well as how to incorporate the new
      drugs which are emerging on the scene. At the same time, earlier initiation of
      combination therapy with the disease modifying anti-rheumatic therapy holds an
      area of continued exploration. This new information has modified our approach to
      patients' management. The age of "wait and see" is over.

PMID- 12477294
TI  - Hormone mediation of immune responses in the progression of diabetes, rheumatoid
      arthritis and periodontal diseases.
AB  - The crucial role of the immune response is common to diabetes mellitus (DM),
      rheumatoid arthritis (RA) and periodontal disease. This review identifies
      advances in this field and exciting paradigms in their management. Uncontrolled
      hyperglycaemia in diabetic patients results in the formation of advanced
      glycation end products (AGEs), which are detrimental to cell structure and
      function. Altered host resistance such as defective migration of PMN, impaired
      phagocytosis and an exaggerated inflammatory response to microbial products also
      compromises healing in uncontrolled diabetic patients, further compromised in
      smokers. Nicotine has well documented effects on the immune response, cell
      adhesion proteins and apoptosis which affect the severity of disease presentation
      and response to treatment. Rheumatoid arthritis is a multifactorial disease that
      results in severe destruction of synovial cartilage and bone. Local secretion of
      large amounts of TNF-alpha and IL-1 due to activation of immunocompetent cells
      characterises the pathophysiology of RA. This has lead to the emergence of TNF
      alpha inhibitors such as etanercept and infliximab in its management. Periodontal
      disease has a microbial aetiology. But it is similar to RA, in its cyclical
      pattern of destruction associated with high levels of pro-inflammatory cytokines,
      which can persist after removal of the antigenic stimulus. Non steroidal anti
      inflammatory agents (NSAIDs) have been used as an adjunct to mechanical removal
      of bacterial antigen, in the management of periodontal disease. The non
      reproductive functions of steroid hormones include effects on immunocompetent
      cells, fibroblasts and osteoblasts, which affect the initiation and progression
      of inflammatory diseases. Hormone replacement therapy could be another facet in a
      multifaceted treatment approach in these patients, where indicated.

PMID- 12477295
TI  - Clinical pharmacology of human growth hormone and its secretagogues.
AB  - The regulation of the synthesis and secretion of human growth hormone (hGH), its
      biologic activity, and its therapeutic use are reviewed. Both the production and
      secretion of GH are stimulated by hypothalamic GH-releasing hormone (GHRH) and by
      the endogenous GH secretagogue (GHS) ghrelin, a product of the oxyntic cells
      located within the fundus of the stomach. Ghrelin and GHRH act synergistically to
      stimulate GH secretion when administered in vivo, but they act additively when
      incubated with somatotrophs in vitro. Ghrelin is also found within the
      hypothalamic arcuate nucleus where it may enhance the release of GHRH and impair
      that of somatostatin (SRIH) thus contributing to its synergism with GHRH; ghrelin
      is an orexigenic peptide as well as a GHS and appears to play an important role
      in energy metabolism. SRIH inhibits the secretion but not the synthesis of GH and
      more effectively that stimulated by GHRH than that by ghrelin. The action of GH
      is mediated by the GH receptor, a straight chain protein of 620 amino acids with
      extracellular, transmembrane and cytoplasmic domains. GH has two specific
      receptor binding sites, (I, II) that bind sequentially to similar acceptor
      sequences of two GHRs. Activation of the GHR signal transduction pathway begins
      with attachment of two Janus kinase 2 (JAK2) molecules to the intracellular
      domains of the GHRs leading to phosphorylation of the tyrosine residues of JAK2
      and the GHRs; thereafter the signal transduction and activators of transcription
      (STAT) and Ras mitogen-activated-protein kinase pathways are enhanced. GHRH,
      SRIH, and ghrelin act through G-protein coupled receptors (GPCR); GHRH activates
      adenylyl cyclase, cyclic AMP, and protein kinase A pathways, while ghrelin
      stimulates phospholipase C activity leading to production of inositol 1,4,5
      trisphophate and diacylglycerol, increase in cytosolic calcium levels, and GH
      release; SRIH acts though an inhibitory GPCR to prevent depolarization of the
      somatotroph thus blocking GH secretion. GH has long been used to stimulate linear
      growth in children with GH deficiency (GHD); it has also been demonstrated to be
      effective in adults with GHD. The availability of large quantities of recombinant
      hGH has broadly increased the number of children with short stature being treated
      with this agent--not always with marked effectiveness. Synthesis of the GHR
      antagonist pegvisomant has provided another agent with which to treat patients
      with acromegaly. GHRH also enhances linear growth rate effectively in children
      with GHD but is less effective than hGH. The discovery of peptidyl and non
      peptidyl GH secretagogues (that preceded and led to the identification of ghrelin
      itself) presents yet other agents for stimulation of endogenous GH secretion that
      have been useful in diagnostic studies for GHD and for its treatment in small
      groups of subjects. It is likely that hGH and its secretagoguess will become of
      increasing clinical usefulness in future decades.

PMID- 12477296
TI  - Cell cycle dysregulation during HIV infection: perspectives of a target based
      therapy.
AB  - Human immunodeficiency virus (HIV) infection is characterized by a severe
      depletion of both CD4+ and CD8+ T cells, representing the result of virus
      mediated killing of infected lymphocytes and the programmed cell death
      (apoptosis) of the uninfected bystander cells. Since only a small fraction of T
      lymphocytes are depleted by viral killing, apoptosis represents one of the most
      important mechanism of T cell death during HIV infection. Several apoptotic
      pathways can be triggered by the different stimuli: persistent T lymphocyte
      activation; altered death receptor (Fas, TNF-R, TRAIL R1-R2) membrane expression;
      viral proteins as well as gp120, Tat, and Nef; host factors such as the unbalance
      of cytokine synthesis by lymphocyte. Nevertheless, new evidences have
      demonstrated that the persistent HIV induced T cell activation and proliferation
      cause a cell cycle dysregulation resulting in a 5-fold increase in apoptotic
      cells. This perturbation represents a link between HIV infection, T cell
      activation, accelerated cell turnover and increased apoptosis and may thus
      represent a new therapeutic target. In fact, Interleukin-2 administration reverts
      such a cell cycle dysregulation and reduces activation induced T cell apoptosis.
      Herein we analyze the main HIV-related mechanisms of host cell death, that are
      dysregulation of the cell cycle and apoptosis induction of T lymphocytes.
      Finally, the role of cytokines at the site of infection and their association
      with apoptosis will be discussed to get insights into the immunological
      perturbations accounting for an accelerated disease progression. Current
      therapeutic approaches and strategies, like HAART and recombinant cytokines, that
      may, successfully, improve the immune-system dysregulation, are also discussed.

PMID- 12477297
TI  - Novel peptides under development for the treatment of type 1 and type 2 diabetes
      mellitus.
AB  - Recent availability of expanded treatment options for both type 1 and type 2
      diabetes has not translated into easier and significantly better glycemic and
      metabolic management. Patients with type 1 diabetes continue to experience
      increased risk of hypoglycemic episodes and progressive weight gain resulting
      from intensive insulin treatment, despite the recent availability of a variety of
      insulin analog. Given the progressive nature of the disease, most patients with
      type 2 diabetes inevitably proceed from oral agent monotherapy to combination
      therapy and, ultimately, require exogenous insulin replacement. Insulin therapy
      in type 2 diabetes is also accompanied by untoward weight gain. Both type 1 and
      type 2 diabetes continue to be characterized by marked postprandial
      hyperglycemia. Two hormones still in development are candidates for pharmacologic
      intervention, have novel modes of action (some centrally mediated), and show
      great promise in addressing some of the unmet needs of current diabetes
      management. Pramlintide acetate, an analog of the beta cell hormone amylin and
      the first non-insulin related therapeutic modality for type 1 and type 2 diabetic
      patients with severe beta cell failure, may be useful as adjunctive therapy to
      insulin. The principal anti-diabetic effects of pramlintide arise from
      interactions via its cognate receptors located in the central nervous system
      resulting in postprandial glucagon suppression, modulation of nutrient absorption
      rate, and reduction of food intake. Another polypeptide hormone, exendin-4,
      exerts at least some of its pharmacologic actions as an agonist at the glucagon
      like peptide-1 (GLP-1) receptor. GLP-1 and related compounds exhibit multiple
      modes of action, the most notable being a glucose-dependent insulinotropic
      effects and the potential to preserve or improve the beta-cell function. The
      latter effect could potentially halt or delay the progressive deterioration of
      the diabetic state associated with type 2 diabetes. Physiologically, both amylin
      and glucagon-like peptide (GLP)-1, along with insulin, are involved in a
      coordinated and concerted interplay between hormones acting both centrally and
      peripherally to provide meticulous control over the rate of appearance of
      exogenous and endogenous glucose and to match that rate to the rate of glucose
      disappearance. Both hormones are deficient in diabetes. Therapies directed at
      restoring this complex physiology have the potential to facilitate glucose
      control and thus minimize the attendant complications of diabetes.

PMID- 12477298
TI  - Mucosal immunity--basic principles, ontogeny, cystic fibrosis and mucosal
      vaccination.
AB  - The mucosal immune system is an integral part of the whole-body immune system,
      however its regulation, maturation and function are to a great degree
      independent. Mucosal lymphoid tissue is the largest immune organ of the body,
      that stands in the first line of defence against foreign invaders. The goal of
      the immune system is immunity, however immunologic unresponsiveness (tolerance)
      is a key feature of the mucosal immune system, because the organism must tolerate
      thousands of ingested and inhaled harmless food and bacterial antigens. The
      phenomenon of oral tolerance is the unique feature of the mucosal immune system.
      If abrogated, severe autoimmune diseases like Crohn's disease, ulcerative colitis
      or coeliac sprue can develop. The quality of mucosal immune responses during
      newborn and infant age strongly influences the immune reactivity later in life.
      The most important factors influencing the development of mucosal immune
      reactivity are the feeding practices and microbial colonization. Manipulation of
      the mucosal immune system offers interesting possibilities to prevent infection
      as well as autoimmune diseases directly in the affected tissue, without
      participation of the whole-body immune system. In this review we present the most
      recent basic information about the mechanisms of mucosal immunity, ontogeny of
      mucosal immunity, mucosal tolerance and immunisation and the role of mucosal
      immunity in an inherited disease in which the main battlefield is the lung mucosa
      cystic fibrosis.

PMID- 12477299
TI  - Common treatment of polycystic ovarian syndrome and major depressive disorder:
      case report and review.
AB  - We present the case of a young woman with treatment-resistant major depression,
      who presented to the Mood Disorders Clinic with a Hamilton Psychiatric Rating
      Scale for Depression (HAM-D-21) score of 28, after a year-long treatment with
      Effexor-XR. The patient also had untreated Polycystic Ovarian Syndrome (PCOS).
      The resolution of her depressive symptoms resulted from the treatment for PCOS
      with metformin and spironolactone. The patient remained euthymic 5 months after
      discontinuation of the antidepressant while continuing therapy for PCOS. We
      briefly overview of the pertinent literature of the pathophysiology of PCOS and
      affective disorders, highlighting an overlap in phenotypical presentations
      between these two disorders. Dysregulation of the hypothalamo-pituitary axis and
      various end organ systems are implicated in both PCOS and affective disorders. As
      such, several clinical and biochemical markers are common to both disorders,
      namely insulin resistance, obesity, and hyperandrogenism. In addition, these
      metabolic abnormalities are interrelated, causing women with PCOS or affective
      disorders to get caught in a "vicious cycle" of hormonal dysregulation. The case
      report presented here illustrates how treatment of symptoms such as insulin
      resistance and hyperandrogenism can lead to remission of major depressive
      disorder and PCOS. We suggest that through treatment of underlying metabolic
      defects, both the mood of the patient and the metabolic condition of PCOS can be
      assisted.

PMID- 12477300
TI  - Orphan vaccines--bridging the gap.

PMID- 12477301
TI  - Strategic challenges in designing and producing modern biotechnology vaccines and
      transferring technology.

PMID- 12477302
TI  - The costs and economics of modern vaccine development.

PMID- 12477303
TI  - How the research-based industry approaches vaccine development and establishes
      priorities.
AB  - Over the past two decades, progress in immunology, molecular biology and genomics
      as well as some technological breakthroughs in computer science has opened the
      way to the development of prophylactic vaccines against most acute infectious
      diseases. Therapeutic vaccines against chronic infections, allergic conditions,
      auto-immune diseases and cancer have also come into the realm of possibility. It
      is estimated that wordwide there are about 400 vaccine projects in R&D
      laboratories of academic institutions, research institutes and vaccine
      manufacturers. Most of these projects will not yield a licensed vaccine for
      routine or even targeted immunisation. This is mostly not because of scientific
      barriers but due to financial and politicoeconomic obstades that make their
      development feasible only by the handful of major research-based vaccine
      manufacturers that nowadays all form part of large global pharmaceutical
      corporations. Such enterprises have to be profitable to survive and priority
      setting, when it comes to R&D projects, has to take into account potential return
      on all investments, particularly as it currently costs between 200 and 500
      million US dollars to bring a new vaccine from the concept stage to market.
      Factors that influence the decision to embark upon an R&D project on a new
      vaccine include the medical need for the vaccine, gauged by the global burden of
      the targeted disease, potential and probable market size - judged on volume
      (number of doses required) and value (total sales) -, probability of success and
      expertise of the company in the field (both R&D and marketing) as well as the
      likelihood of competitors taking a large part of the market. Moral imperatives
      such as the urgent need for vaccines against HIV/AIDS, malaria and an improved
      vaccine against tuberculosis to save the several millions of lives claimed each
      year by these diseases also play a role. However, for such investments to be
      sustainable other sources of financing than the commercial market will be
      required.

PMID- 12477304
TI  - Glovax's perspective: opportunities and approaches to vaccine business in Asia.
AB  - Glovax Co., Ltd. has focused on regional population needs, and assessed
      potentially interesting vaccine candidates for their safety, efficacy and cost
      effectiveness. Economic analysis was made to identify the area of high commercial
      potential based on quantity demands and pricing flexibility. Epidemiological data
      on the target diseases were reviewed so that we could identify the vaccines of
      more limited interests worldwide but still of high significance in regional
      public health. Several viral vaccine products were selected as our priority
      including Japanese encephalitis and Hepatitis A vaccines. Extensive safety and
      clinical studies have been projected. To ensure that a safe and effective vaccine
      be supplied at the same quality level, new manufacturing facilities are being
      constructed in our region. Several approaches have been made to overcome
      technical, financial, and managerial obstacles. Close partnerships with industry,
      biomedical community and regulatory agencies may enhance the viability of our
      approach to be a successful vaccine player in this region.

PMID- 12477305
TI  - Malaria--a global crisis.
AB  - The aim of this short review is to define the magnitude of the problem of malaria
      and the evidence that a malaria vaccine may be able to play a pivotal role in
      control of global malaria. Some of the challenges that would need to be faced in
      introducing a malaria vaccine as part of a global strategy are also discussed.

PMID- 12477306
TI  - Malaria vaccines: orphans in transition.

PMID- 12477307
TI  - HIV vaccine development.
AB  - Optimism prevails that a safe and at least partially effective HIV vaccine will
      be identified within this decade. Public, philanthropic and private sector
      efforts to expand the development pipeline and to indude candidates based on
      diverse HIV subtypes have proved successful. Yet both scientific and logistical
      obstacles remain. No vaccine candidate yet induces broadly neutralizing
      antibodies. The type, level, location and durability of immune responses
      necessary for protection remain unknown. For those vaccines that may not prevent
      HIV infection but control replication and prevent disease, the issue of
      transmissibility must be addressed. Other challenges indude improving
      infrastructure and research capabilities and establishing or strengthening
      regulatory agencies in developing countries. Another key issue is ensuring access
      to successful vaccines, which will require large-scale manufacturing and
      development of policies and processes to distribute vaccine to those most in
      need.

PMID- 12477308
TI  - Will a vaccine to nasopharyngeal carcinoma retain orphan status?
AB  - Epstein-Barr virus (EBV) infection is associated with infectious mononucleosis
      (IM) and with a number of human malignancies including nasopharyngeal carcinoma
      (NPC), Hodgkin's disease (HD) and immunoblastic lymphoma (IL). Their potential
      for immunotherapeutic treatment by cytotoxic T cells (CTL) is dependent on the
      degree of EBV antigen expression, with the best prospect revolving around IM
      where a vaccine is under development and IL of transplant patients where adoptive
      transfer of in vitro reactivated CTL has already been demonstrated to be
      effective. The opportunities for effective immunotherapy in the treatment of NPC
      is reduced since the available targets are limited to relatively non-immunogenic
      proteins. Perhaps more importantly, the development of immunotherapeutics is not
      considered a realistic commercial proposition. The best chance of developing an
      effective vaccine is to exploit the similarities in phenotype between HD and NPC
      since a vaccine to the former is likely to have more commercial appeal.

PMID- 12477309
TI  - Human cytomegalovirus vaccine is an orphan.

PMID- 12477310
TI  - Vaccination against hydatid disease.
AB  - Hydatid disease is a parasitic infection that causes widespread human morbidity
      and mortality. Livestock animals, particularly sheep, are involved in the
      parasite's lifecycle. A defined antigen vaccine has been developed which can
      prevent hydatid infection in sheep. The vaccine has been shown to be highly
      effective in animal trials, with almost complete immunity persisting for more
      than a year after vaccination. Use of the vaccine in livestock may decrease
      transmission of the parasite and, indirectly, reduce the incidence of infections
      in humans. In some regions animal vaccination or other hydatid control measures
      are unlikely to be applicable. In these areas, direct vaccination of humans
      against hydatid infection may be the only practical option for disease
      prevention. The extraordinary effectiveness of the hydatid vaccine in the
      parasite's natural animal hosts singles this vaccine out as having perhaps the
      greatest potential for development of the first effective human vaccine against a
      parasitic disease.

PMID- 12477311
TI  - Vaccine development: the biological weapon imperative.
AB  - The biological warfare capabilities of state and non-state actors continue to
      grow worldwide, both in sophistication and breadth. More than a dozen nations,
      including Iraq, Iran, Libya, Syria and North Korea, are either actively pursuing
      or possess biological weapons for use against their enemies. There is also a
      heightened awareness of the use of such agents by terrorist groups, a possibly
      deleterious side-effect of an increased awareness by the general public. This
      paper looks at the growing threat of the use of biological agents by both
      national programmes and non-state actors, the possible agents which might be
      considered for use, and the potential role that vaccine development may have in
      protecting both military and civilian populations against biological weapons
      attacks in the future.

PMID- 12477312
TI  - Development of vaccines for bio-warfare agents.
AB  - There is a recognized need for the development of new vaccines (as well as other
      biologicals and drugs) to counteract the effects of a potential bio-terrorist or
      bio-warfare event in the U.S. domestic population and military forces. Regulation
      of products to protect against potential bio-warfare agents poses unique
      challenges since the usual measures of efficacy that require exposure to natural
      disease may not currently be possible, for epidemiological and ethical reasons.
      To help to address this issue, the FDA has published and requested comments on a
      proposed animal rule intended to address certain efficacy issues for new agents
      for use against lethal or permanently disabling toxic substances. Recent product
      development activity has focused on Bacillus anthracis (anthrax) and variola
      major (smallpox), agents that are regarded as highest priority in posing a risk
      to national security. FDA resources exist to assist vaccine developers with
      regard to the novel challenges posed in the dinical development of these
      products.

PMID- 12477313
TI  - Difficulties associated with the development and licensing of vaccines for
      protection against bio-warfare and bio-terrorism.
AB  - Today there is an increasing need to license vaccines for the protection of
      individuals against bio-warfare and bio-terrorism. While the need is apparent,
      the actual road to developing, producing and licensing such vaccines successfully
      is as yet undefined. Bio-defence vaccine candidates may come from several
      sources. They may come from vaccines that were previously licensed but are no
      longer in production, vaccines that are currently in an IND status, vaccines
      currently licensed in foreign countries, and newer vaccines currently under
      development. The issues that apply to the development and licensing of these
      vaccines can be defined by currently accepted standards for manufacture, and the
      requirement to demonstrate safety and efficacy to a level that gives the
      scientific and medical community, regulatory agencies, users and the public at
      large confidence. Requirements for manufacturing and demonstration of safety will
      be consistent with vaccines being developed for traditional purposes. However,
      demonstration of efficacy will be more difficult. Because field trials for these
      vaccines are generally not feasible and the conduct of human challenge studies is
      generally considered unethical, the demonstration of efficacy will need to be
      based on existing efficacy data, a thorough understanding of both the disease's
      pathogenesis and mechanism of protection, the ability to identify surrogate
      markers for efficacy, and the use of the proposed FDA "animal rule".

PMID- 12477314
TI  - Pandemic influenza: history, extent of the problem and approaches to control.

PMID- 12477315
TI  - Influenza vaccine technologies and the use of the cell-culture process (cell
      culture influenza vaccine).
AB  - Influenza vaccines have been produced for decades in eggs by a classical
      technology. A range of new vaccine technologies and approaches has been applied
      to improving these vaccines. Foremost among these are the use of mammalian cells
      to produce influenza viruses, the use of new adjuvants, and a live attenuated
      vaccine. Mammalian cell-derived vaccines, produced in nontumorigenic cell lines,
      have been developed and shown to be effective production systems as alternatives
      to eggs. This manuscript discusses the advantages and challenges of mammalian
      cell production, as well as alternative technologies for influenza vaccines.

PMID- 12477316
TI  - Seed viruses containing novel avian HA and NA antigens for prevention against
      potential influenza pandemic.
AB  - An influenza pandemic could arise unexpectedly with rapid spread across the
      world. The efficiency of production of a vaccine and the ability to administer it
      widely will be among the most important factors in the ability to protect public
      health. The current process for producing inactivated or live attenuated
      influenza vaccines requires six to nine months. That reduces considerably the
      likelihood that the vaccine will be available during the first wave of the
      pandemic. Therefore, a key element of preparedness is to optimize the production
      process and to reduce the vaccine development time. During the 1997 H5N1 outbreak
      in Hong Kong, seed viruses were prepared for production of inactivated and live
      attenuated vaccines. We used the cold-adapted A/Ann Arbor/6/60 as the donor virus
      to generate live attenuated vaccines containing genetically modified HA and NA
      genes from H5N1 influenza viruses. These reassortants were shown to be safe and
      protective in animal models. This study indicates that production of live
      attenuated avian influenza vaccines is feasible and that development of a library
      of reassortants containing different subtype HA and NA genes may reduce the
      vaccine preparation time for future influenza pandemics.

PMID- 12477317
TI  - Regulatory barrier to new vaccine development... thinking outside the box.

PMID- 12477318
TI  - Managing vaccine development in a virtual organisation.

PMID- 12477319
TI  - Sustainable funding: options being canvassed.

PMID- 12477320
TI  - Conclusions to the conference on orphan vaccines.

PMID- 12477321
TI  - Linezolid versus ceftriaxone/cefpodoxime in patients hospitalized for the
      treatment of Streptococcus pneumoniae pneumonia.
AB  - Intravenous (i.v.) to oral linezolid (600 mg twice daily for both, with optional
      aztreonam) and a cephalosporin regimen (i.v. ceftriaxone 1 g twice daily followed
      by oral cefpodoxime 200 mg twice daily) were compared for the treatment of
      community-acquired pneumonia (CAP), with emphasis on patients with Streptococcus
      pneumoniae. This multicenter, randomized, open-label trial was conducted in 27
      countries in 6 continents. Efficacy was assessed 12-28 d following treatment.
      Clinical and laboratory safety assessments were evaluated; isolates for
      microbiologic assessments were identified primarily by sputum or blood culture.
      In all treated patients (linezolid, n = 381; ceftriaxone/cefpodoxime, n = 366),
      linezolid had a higher clinical cure rate than ceftriaxone/cefpodoxime (83.0% vs.
      76.4%, respectively; p = 0.040). S. pneumoniae was isolated in 73.2% (186/254) of
      patients at baseline, with similar eradication rates in the linezolid and
      ceftriaxone/cefpodoxime groups (88.7% vs. 89.9%, respectively; p = 0.830).
      Linezolid had a superior clinical cure rate (93.1% vs. 68.2%; p = 0.021) in
      patients with S. pneumoniae bacteremia. Logistic regression analyses revealed
      that linezolid-treated patients with bacteremia, pleural effusion, cardiac
      comorbidities, diabetes or abnormal white blood cell counts had significantly
      better outcomes than cephalosporin-treated patients. Both regimens were well
      tolerated, although the incidence of drug-related adverse events was higher in
      the linezolid group than in the ceftriaxone/cefpodoxime group (21.3% vs. 11.2%,
      respectively; p = 0.0002). In summary, empiric i.v./oral linezolid was more
      effective than ceftriaxone/cefpodoxime in patients hospitalized with CAP, with
      comparable cure rates in S. pneumoniae pneumonia and higher cure rates in
      pneumonia complicated by bacteremia.

PMID- 12477322
TI  - Clonal spread among Swedish children of a Staphylococcus aureus strain resistant
      to fusidic acid.
AB  - An increased incidence of fusidic acid-resistant Staphylococcus aureus strains
      causing superficial infections among children in Sweden has been noted since the
      mid-1990s. Based on routine susceptibility testing data from 10 laboratories
      representing 8/21 Swedish counties during 1990-2001, the increase was first
      demonstrated in southern Sweden and subsequently became apparent throughout the
      country. Epidemiological typing using pulsed-field gel electrophoresis of recent
      isolates of fusidic acid-resistant S. aureus from 11 laboratories representing
      8/21 Swedish counties revealed a high degree of similarity of band patterns,
      indicating a clonal relationship. Data from 1 of the laboratories demonstrated a
      close connection between this clone and impetigo. Sales statistics showed a
      pronounced increase in the use of fusidic acid ointments in the 0-12 y age group
      from 1998 onwards. There was, however, no statistically significant correlation
      between sales of fusidic acid ointments and resistance among S. aureus strains to
      fusidic acid.

PMID- 12477323
TI  - Listeriosis in Iceland, 1978-2000: a description of cases and molecular
      epidemiology.
AB  - The purpose of our study was to review all cases of listeriosis in Iceland during
      the period 1978-2000 and to analyse the genetic relatedness of their isolates.
      Case records of all patients in Iceland with listeriosis during the period were
      reviewed and the isolates compared using serotyping and pulsed-field gel
      electrophoresis (PFGE) using SmaI, AseI and ApaI restriction enzymes. Forty cases
      of listeriosis were diagnosed during the period, resulting in a mean annual
      incidence of 6.9 cases per million and a case fatality rate of 33%. In the first
      5 y of the study only serotype 4b was observed; subsequently serotypes 1/2a and
      1/2b appeared and serotype 4b declined in prevalence. PFGE yielded 24 different
      genotypes with 7 clusters of indistinguishable genotypes, each comprising 2-6
      cases. During 1992-95 the annual incidence of listeriosis in Iceland rose to 15
      cases per million. This was largely due to 2 clusters, 1 of 3 cases and the other
      of 6. No cases of listeriosis were diagnosed during 1998-2000. Our data show an
      increased number of cases within clusters in the latter half of the period. At
      the same time, food processing and distribution has become increasingly
      centralized in Iceland, suggesting an increased risk of listeriosis outbreaks.

PMID- 12477324
TI  - Intraocular and plasma HIV-1 RNA in HIV-infected patients with CMV retinitis and
      HIV-infected controls.
AB  - HIV-1 RNA was quantified in intraocular specimens and plasma from AIDS patients
      with CMV retinitis undergoing therapeutic vitrectomy and in 8 control subjects
      undergoing cataract surgery using the Amplicor RT-PCR-based assay. The HIV-1 RNA
      concentration in the intraocular specimens was significantly lower than in
      plasma. Patients with CMV retinitis and plasma HIV-1 RNA concentrations > 100,000
      copies/ml generally had detectable HIV-1 RNA in their intraocular specimens.
      These findings point to the risk of percutaneous injury from a sharp instrument
      used in HIV-infected patients during ophthalmic surgery and possible transmission
      of HIV during such surgery. Prevention of percutaneous contact will require the
      use of surgical instruments that reduce the likelihood of injury, as well as the
      wearing of double gloves during surgery.

PMID- 12477325
TI  - Detection of enteroviral RNA (poliovirus types 1 and 3) in endomyocardial
      biopsies from patients with ventricular tachycardia and survivors of sudden
      cardiac death.
AB  - The purpose of this study was to determine the prevalence of enteroviral
      infection in the myocardium of consecutive patients with serious ventricular
      arrhythmias by using a reverse transcription nested PCR followed by direct DNA
      sequencing. After exclusion of coronary heart disease, right ventricular
      endomyocardial biopsies were obtained from 32 consecutive patients with a history
      of ventricular tachycardia or sudden cardiac death. Control biopsies were
      obtained from 36 subjects with no history of viral myocarditis, dilated
      cardiomyopathy, ventricular tachycardia or recent infection. Enteroviral genome
      was found in endomyocardial biopsies from 4/32 patients (12.5%), 2 with a history
      of ventricular tachycardia and 2 with a history of ventricular fibrillation.
      Three of these 4 enteroviral RNA-positive patients had dilated cardiomyopathy and
      the other had normal cardiac geometry and ventricular function. In the latter and
      in 1 patient with enteroviral-positive dilated cardiomyopathy, an active
      inflammatory process in the myocardium was found by means of immunohistology.
      Enteroviral RNA in the myocardium of 3 patients had the highest homology to
      poliovirus type 1 (strain CHAT 10A-11) and in the other was similar to poliovirus
      type 3 (strain P3/119). All control samples were negative for enteroviral RNA. In
      summary, these findings raise the possibility that enteroviruses, such as
      poliovirus types 1 and 3, may be involved in the pathogenesis of ventricular
      tachycardia and sudden cardiac death.

PMID- 12477326
TI  - Prevalence of dermatomycoses in Mal de Meleda patients: a field study.
AB  - Mal de Meleda is a rare autosomal recessive form of palmoplantar keratoderma
      characterized by hyperkeratosis of the palms and soles. The presence of yeast and
      dermatophytes was investigated in 29 mal de Meleda patients from Koprucay canyon,
      Turkey, a newer geographical focus, and was found in 62.0% and 20.7% of cases,
      respectively. Antifungal resistance of isolates was not detected.

PMID- 12477327
TI  - Differentiation of old and new world leishmania species at complex and species
      levels by PCR.
AB  - The variable and conserved sequence boxes of kinetoplast DNA (kDNA) of 11
      standard strains of 6 complexes of New and Old World Leishmania were amplified
      using PCR. Four strains from 2 complexes of Old World Leishmania - L. major
      (MRHO/IR/64/Nadim-1), with 2 bands at 850 and 620 bp, L. major (MHOM/SU/73/5
      ASKH), with a band at 620 bp, L. donovani, with a band at 800 bp and L. infantum,
      with a band at 650 bp - could be differentiated from each other and from the New
      World strains, with the exception of L. infantum. Seven Leishmania strains from 4
      complexes of New World Leishmania - L. mexicana and L. pifanoi, with a band at
      730 bp, L. guyanensis, with 2 bands at 730 and 650 bp, L. peruviana, with a band
      at 710 bp and L. amazonensis, L. garnhami and L. braziliensis, each with a band
      at 650 bp - were identified. Of these strains, L. guyanensis and L. peruviana
      could be differentiated from each other and from the Old World strains. These
      results show that using PCR amplification of kDNA we could differentiate between
      New and Old World Leishmania at both complex and strain levels. The amplified
      kDNA PCR products, together with other techniques, could be useful as a
      diagnostic tool for the identification of Leishmania species.

PMID- 12477328
TI  - IL-8 and tumor necrosis factor alpha in heart valves from patients with infective
      endocarditis.
AB  - The embedding of bacteria in the vegetation of infective endocarditis impedes the
      penetration of phagocytic cells. IL-8 has a stimulating effect on the immune
      system, particularly with respect to chemotaxis and activation of granulocytes.
      Tumor necrosis factor alpha (TNF-alpha) is 1 of the major proinflammatory
      cytokines. IL-8 and TNF-alpha were visualized by means of immunohistochemistry in
      paraffin-embedded heart valve biopsies from 6 patients with infective
      endocarditis who required cardiac surgery during the active phase of the
      infection. In 5/6 patients there were signs of inflammation, and in these
      patients IL-8- and TNF-alpha-containing cells were visualized in the heart valve
      stromas or vegetations. The largest numbers of IL-8-containing cells, and the
      greatest amount of inflammation, were seen in patients with short preoperative
      treatment courses. No such relationships were seen with respect to TNF-alpha
      containing cells. These observations may suggest that the occurrence of IL-8
      containing cells in infected heart valves could be used as a marker of disease
      activity.

PMID- 12477329
TI  - Intrafamilial spread of highly virulent staphylococcus aureus strains carrying
      the gene for Panton-Valentine leukocidin.
AB  - Necrotizing pneumonia caused by Staphylococcus aureus carrying the gene for
      Panton-Valentine leukocidin is a newly described disease entity. We report 2
      cases with intrafamilial spread.

PMID- 12477330
TI  - Streptococcus bovis bacteremia from a venous access port in a patient with AIDS.
AB  - We report the first case of S. bovis bacteremia related to endoluminal
      colonization of a venous access port in a setting of advanced HIV infection,
      neutropenia and co-infection with HBV. The patient had no bowel abnormalities.
      The clinical picture was mild and was resolved by removal of the device.

PMID- 12477331
TI  - Multiple liver abscesses associated with bacteremia due to Leuconostoc lactis.
AB  - Leuconostoc species, which are members of the family Streptococcacae, have only
      recently been recognized as potential pathogens. We describe a patient with type
      II diabetes mellitus who had multiple liver abscesses associated with bacteremia
      due to Leuconostoc lactis. To our knowledge, this is the first case of this
      association to be reported in the literature.

PMID- 12477332
TI  - Helicobacter heilmannii as causative agent of chronic active gastritis.

PMID- 12477333
TI  - Multifocal simultaneous Salmonella typhi osteomyelitis in an immunocompetent
      adult.
AB  - We report a case of Salmonella typhi osteomyelitis that presented as a pathologic
      fracture of the left femur and had additional silent manifestations in the right
      tibia and humerus in an otherwise healthy adult. This is the first report in the
      literature of multifocal simultaneous Salmonella osteomyelitis in an adult with
      no underlying medical condition.

PMID- 12477334
TI  - Severe Legionella pneumophila pneumonia in a patient with iron overload.
AB  - Iron plays a crucial role in the energy metabolism of microorganisms. Humans have
      developed iron-withholding mechanisms as a form of non-specific immunity. We
      describe a patient with iron overload and severe Legionella pneumophila
      pneumonia. This report emphasizes the importance of early consideration of and
      appropriate therapy against Legionella for patients with iron overload who
      present with community-acquired pneumonia.

PMID- 12477335
TI  - Disseminated erythematous papules in a renal transplant recipient: a case of
      disseminated tuberculosis.
AB  - The incidence of tuberculosis in renal transplant patients has been reported to
      be fairly low and disseminated tuberculosis presenting with cutaneous
      manifestations has not been reported previously in these patients. We report the
      case of a 62-y-old kidney transplant recipient with a long-term history of
      chronic immunosuppressive therapy who presented with high fever, rapidly
      progressing respiratory failure and disseminated erythematous pustular cutaneous
      lesions.

PMID- 12477336
TI  - Transfusion-related infectious mononucleosis.
AB  - Careful donor selection has reduced but not eliminated the risk of transfusion
      transmitted infections. We report a case of transfusion-related infectious
      mononucleosis. Given the pivotal role of Epstein-Barr virus in the development of
      lymphoproliferative disorders after solid-organ transplantation, its potential
      transmission by blood products deserves to be considered in this population.

PMID- 12477337
TI  - Successful treatment of Candida glabrata myocarditis with voriconazole.
AB  - A 30-y-old man with Crohn's disease developed fungemia with Candida albicans.
      Subsequently, during therapy with fluconazole, Candida glabrata was repeatedly
      isolated from his blood. Myocardial abscesses were detected in the papillary
      muscles and interventricular septum. The infection was cured with amphotericin B
      lipid complex and 5-flucytosine, followed by voriconazole for 18 months.

PMID- 12477338
TI  - Reactivation of CMV retinitis after treatment with subtenon corticosteroids for
      immune recovery uveitis in a patient with AIDS.
AB  - We present the case of an HIV-infected patient who developed reactivation of CMV
      retinitis after a local steroid injection for the treatment of immune recovery
      uveitis. He responded promptly to reinduction with ganciclovir and recovered. To
      our knowledge this is the first case of CMV retinitis reactivation in an HIV
      infected patient receiving steroids for immune recovery uveitis.

PMID- 12477339
TI  - Influenza A virus infection and cardiac arrhythmia during the neonatal period.
AB  - Influenza virus infection during pregnancy increases the risk of spontaneous
      abortion, preterm contractions, fetal compromise and early neonatal mortality. We
      describe a case of fetal and neonatal cardiac arrhythmia coinciding with an
      influenza A virus infection. Viral RNA was detected in the neonate's
      nasopharyngeal secretions and also in its serum, indicating influenza viremia.
      The cardiac arrhythmia resolved spontaneously without antiarrhythmic treatment.

PMID- 12477340
TI  - Reversible panhypogammaglobulinemia associated with phenytoin treatment.
AB  - We report the case of a 24-y-old woman who presented with repeated episodes of
      otitis due to panhypogammaglobulinemia and low levels of mature CD19 + B cells
      (84 cells/microl) associated with phenytoin treatment. Lymphocyte subpopulations
      and immunoglobulin levels need to be monitored if symptoms indicating
      immunodeficiency occur after the initiation of this treatment.

PMID- 12477341
TI  - Elimination of erythrocytes from blood prior to DNA extraction improves the
      sensitivity of anaplasma phagocytophila PCR.

PMID- 12477342
TI  - 2002 Alfred Burger Award Address in Medicinal Chemistry. Natural products and
      design: interrelated approaches in drug discovery.

PMID- 12477343
TI  - Identification of arodyn, a novel acetylated dynorphin A-(1-11) analogue, as a
      kappa opioid receptor antagonist.
AB  - Arodyn (aromatic dynorphin) is a novel analogue of the opioid peptide dynorphin A
      with a nonbasic N-terminus that exhibits nanomolar affinity (K(i) = 10 nM) and
      remarkable selectivity for kappa opioid receptors (K(i) ratio (kappa/mu/delta) =
      1/174/583). Arodyn completely reverses the agonism of dynorphin A (1-13)NH(2) in
      a concentration-dependent manner in the adenylyl cyclase assay. Thus arodyn is a
      novel kappa opioid receptor selective antagonist that will be useful to study
      these receptors.

PMID- 12477344
TI  - Tumor-specific novel taxoid-monoclonal antibody conjugates.
AB  - Taxoids bearing methyldisulfanyl(alkanoyl) groups for taxoid-antibody
      immunoconjugates were designed, synthesized and their activities evaluated. A
      highly cytotoxic C-10 methyldisulfanylpropanoyl taxoid was conjugated to
      monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR)
      expressed in human squamous cancers. These conjugates were shown to possess
      remarkable target-specific antitumor activity in vivo against EGFR-expressing
      A431 tumor xenografts in severe combined immune deficiency mice, resulting in
      complete inhibition of tumor growth in all the treated mice.

PMID- 12477345
TI  - AutoDocking dinucleotides to the HIV-1 integrase core domain: exploring possible
      binding sites for viral and genomic DNA.
AB  - To understand the binding of both viral and human DNA to HIV-1 integrase, fully
      flexible dinucleotides were docked onto the core domain of integrase. AutoDocking
      did identify sites on integrase where favorable interactions with nucleotides can
      occur, and those sites were in agreement with recently published protein
      fingerprinting data. By analyzing the phosphates of the docked dinucleotides, we
      developed a model indicating where the viral cDNA and human DNA bind to the
      integrase core domain.

PMID- 12477346
TI  - NMR-based modification of matrix metalloproteinase inhibitors with improved
      bioavailability.
AB  - The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix
      metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et
      al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these
      inhibitors exhibited no in vivo activity due, at least in part, to the poor
      pharmacokinetic properties of the alkylhydroxamate moiety. To circumvent this
      liability, NMR-based screening was implemented to identify alternative zinc
      chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind
      tightly to the protein (K(D) = 50 microM) and was identified as a candidate for
      incorporation into the lead series. On the basis of NMR-derived structural
      information, the naphthyl hydroxamate and biaryl fragments were linked together
      to yield inhibitors of this enzyme that exhibited improved bioavailability. These
      studies demonstrate that the NMR-based screening of fragments can be effectively
      applied to improve the physicochemical or pharmacokinetic profile of lead
      compounds.

PMID- 12477347
TI  - Binding model for nonpeptide antagonists of alpha(v)beta(3) integrin.
AB  - A binding model for nonpeptide antagonists of integrin alpha(v)beta(3) has been
      developed through docking analyses utilizing the MMFFs force field and the
      recently published crystal structure, 1JV2. Results of this docking study have
      led to the identification of a novel binding model for selective antagonists of
      alpha(v)beta(3) over alpha(IIb)beta(3) integrins. Four different chemical classes
      are shown to bind in a similar fashion providing a measure of confidence in the
      proposed model. All alpha(v)beta(3) and alpha(IIb)beta(3) antagonists have a
      basic nitrogen separated some distance from a carboxylic acid to mimic RGD. For
      the alpha(v)beta(3) antagonists under present consideration, these charged ends
      are separated by twelve bonds. The basic nitrogen of the active alpha(v)beta(3)
      ligands are shown to interact with D150 of alpha(v) and the ligands' carboxylic
      acid interact with R214 of beta(3) while adopting an extended conformation with
      minimal protein induced internal strain. In addition, an energetically favorable
      interaction is found with all of the active alpha(v)beta(3) molecules with Y178
      of alpha(v) when docked to the crystallographically determined structure. This
      novel interaction may be characterized as pi-pi stacking for the most active of
      the alpha(v)beta(3) selective antagonists. The proposed model is consistent with
      observed activity as well as mutagenicity and photoaffinity cross-linking studies
      of the alpha(v)beta(3) integrin.

PMID- 12477348
TI  - Automated analysis of large sets of heteronuclear correlation spectra in NMR
      based drug discovery.
AB  - Drug discovery procedures based on NMR typically require the analysis of
      thousands of NMR spectra. For example, in "SAR by NMR", two-dimensional NMR
      spectra are recorded for a target protein mixed with ligand candidates from a
      comprehensive library of small molecules and are compared to the corresponding
      spectrum for the protein alone. We present an automated procedure for the
      comparative analysis of large sets of heteronuclear single quantum coherence
      spectra, which is based on three-way decomposition and implemented as the
      software package MUNIN. In a single step, spectra with differences in the peak
      positions (indicating ligand binding) and the affected peaks are identified. By
      omission of peak picking, ad hoc scoring of the quality of doubtful peaks is
      avoided. The procedure has been tested on the bacterial ribonuclease barnase,
      with a protein concentration of only 50 microM, using several small molecules
      including the substrate analogue 3'-GMP. Sets of 51 spectra were processed
      simultaneously, and it is concluded that spectra with binding ligands can be
      unambiguously identified from much larger sets of spectra.

PMID- 12477349
TI  - In silico and NMR identification of inhibitors of the IGF-I and IGF-binding
      protein-5 interaction.
AB  - Recently we have determined the crystal structure of the insulin-like growth
      factor-I (IGF-I) in complex with the N-terminal domain of the IGF-binding protein
      5 (IGFBP-5). Here we report results of computer screening for potential
      inhibitors of this interaction using the crystal coordinates. From the compounds
      suggested by in silico screens, successful binders were identified by NMR
      spectroscopic methods. NMR was also used to map their binding sites and calculate
      their binding affinities. Small molecular weight compounds (FMOC derivatives)
      bind to the IGF-I binding site on the IGFBP-5 with micromolar affinities and thus
      serve as potential starting compounds for the design of more potent inhibitors
      and therapeutic agents for diseases that are associated with abnormal IGF-I
      regulation.

PMID- 12477350
TI  - Metal-dependent inhibition of HIV-1 integrase.
AB  - Human immunodeficiency virus type 1 integrase (HIV-1 IN) is an essential enzyme
      for effective viral replication. Therefore, IN inhibitors are being sought for
      chemotherapy against AIDS. We had previously identified a series of
      salicylhydrazides as potent inhibitors of IN in vitro (Neamati, N.; et al. J.
      Med. Chem. 1998, 41, 3202-3209.). Herein, we report the design, synthesis, and
      antiviral activity of three novel mercaptosalicylhydrazide (MSH) derivatives.
      MSHs were effective against the IN catalytic core domain and inhibited IN binding
      to HIV LTR DNA. They also inhibited catalytic activities of IN in IN-DNA
      preassembled complexes. Site-directed mutagenesis and molecular modeling studies
      suggest that MSHs bind to cysteine 65 and chelate Mg(2+) at the active site of
      HIV-1 IN. Contrary to salicylhydrazides, the MSHs are 300-fold less cytotoxic and
      exhibit antiviral activity. They are also active in Mg(2+)-based assays, while IN
      inhibition by salicylhydrazides is strictly Mn(2+)-dependent. Additionally, in
      target and cell-based assays, the MSHs have no detectable effect on other
      retroviral targets, including reverse transcriptase, protease, and virus
      attachment, and exhibit no detectable activity against human topoisomerases I and
      II at concentrations that effectively inhibit IN. These data suggest that MSHs
      are selective inhibitors of HIV-1 IN and may serve as leads for antiviral
      therapeutics.

PMID- 12477351
TI  - Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance:
      explanation of structural variety (hypothesis).
AB  - A general pharmacophore model of P-glycoprotein (P-gp) drugs is proposed that is
      based on a highly diverse data set and relates to the verapamil binding site of
      the protein. It is derived from structurally different drugs using the program
      GASP. The pharmacophore model consists of two hydrophobic points, three hydrogen
      bond (HB) acceptor points, and one HB donor point. Pharmacophore patterns of
      various drugs are obtained, and different binding modes are presumed for some of
      them. It is concluded that the binding affinity of the drugs depends on the
      number of the pharmacophore points simultaneously involved in the interaction
      with P-gp. On the basis of the obtained results, a hypothesis is proposed to
      explain the broad structural variety of the P-gp substrates and inhibitors: (i)
      the verapamil binding site of P-gp has several points that can participate in
      hydrophobic and HB interactions; (ii) different drugs can interact with different
      receptor points in different binding modes.

PMID- 12477352
TI  - Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase
      inhibitors.
AB  - Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors
      have been prepared and evaluated as angiogenesis inhibitors. 2-[(4
      Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3
      isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively
      inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their
      physicochemical properties, these anthranilamides readily penetrate cells and are
      absorbed following once daily oral administration to mice. Both 5 and 7 potently
      inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7
      mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both
      the growth of the primary tumor as well as the formation of spontaneous
      peripheral metastases. The anthranilamides 5 and 7 represent a new structural
      class of VEGFR kinase inhibitors, which possess potent antiangiogenic and
      antitumor properties.

PMID- 12477353
TI  - Acyclic analogues of adenosine bisphosphates as P2Y receptor antagonists:
      phosphate substitution leads to multiple pathways of inhibition of platelet
      aggregation.
AB  - Activation by ADP of both P2Y(1) and P2Y(12) receptors in platelets contributes
      to platelet aggregation, and antagonists at these receptor subtypes have
      antithrombotic properties. In an earlier publication, we have characterized the
      SAR as P2Y(1) receptor antagonists of acyclic analogues of adenine nucleotides,
      containing two phosphate groups on a symmetrically branched aliphatic chain,
      attached at the 9-position of adenine. In this study, we have focused on
      antiaggregatory effects of P2Y antagonists related to a 2-chloro-N(6)
      methyladenine-9-(2-methylpropyl) scaffold, containing uncharged substitutions of
      the phosphate groups. For the known nucleotide (cyclic and acyclic) bisphosphate
      antagonists of P2Y(1) receptors, there was a significant correlation between
      inhibition of aggregation induced by 3.3 microM ADP in rat platelets and
      inhibition of P2Y(1) receptor-induced phospholipase C (PLC) activity previously
      determined in turkey erythrocytes. Substitution of the phosphate groups with
      nonhydrolyzable phosphonate groups preserved platelet antiaggregatory activity.
      Substitution of one of the phosphate groups with O-acyl greatly reduced the
      inhibitory potency, which tended to increase upon replacement of both phosphate
      moieties of the acyclic derivatives with uncharged (e.g., ester) groups. In the
      series of nonsymmetrically substituted monophosphates, the optimal antagonist
      potency occurred with the phenylcarbamate group. Among symmetrical diester
      derivatives, the optimal antagonist potency occurred with the di(phenylacetyl)
      group. A dipivaloyl derivative, a representative uncharged diester, inhibited ADP
      induced aggregation in both rat (K(I) 3.6 microM) and human platelets. It
      antagonized the ADP-induced inhibition of the cyclic AMP pathway in rat platelets
      (IC(50) 7 microM) but did not affect hP2Y(1) receptor-induced PLC activity
      measured in transfected astrocytoma cells. We propose that the uncharged
      derivatives are acting as antagonists of a parallel pro-aggregatory receptor
      present on platelets, that is, the P2Y(12) receptor. Thus, different substitution
      of the same nucleoside scaffold can target either of two P2Y receptors in
      platelets.

PMID- 12477355
TI  - Synthesis of novel N-1 (allyloxymethyl) analogues of 6-benzyl-1-(ethoxymethyl)-5
      isopropyluracil (MKC-442, emivirine) with improved activity against HIV-1 and its
      mutants.
AB  - This paper reports the synthesis and the antiviral activities of a series of 6
      arylmethyl-1-(allyloxymethyl)-5-alkyluracil derivatives, which can be viewed as
      analogues of the anti-HIV-1 drug emivirine (formerly MKC-442) from which they
      differ in the replacement of the ethoxymethyl group with variously allyloxymethyl
      moieties. The most active compounds N-1 allyloxymethyl- and N-1 3-methylbut-2
      enyl substituted 5-ethyl-6-(3,5-dimethylbenzyl)uracils (12 and 13) showed
      activity against HIV-1 wild-type in the picomolar range with selective index of
      greater than 5 x 10(6) and activity in the submicromolar range against the
      clinically important Y181C and K103N mutant strains known to be resistant to
      emivirine. Structure-activity relationship studies established a correlation
      between the anti-HIV-1 activity and the substitution pattern of the N-1
      allyloxymethyl group.

PMID- 12477354
TI  - Benzodiazepine receptor ligands. 7. Synthesis and pharmacological evaluation of
      new 3-esters of the 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide. 3-(2
      Thienylmethoxycarbonyl) derivative: an anxioselective agent in rodents.
AB  - The synthesis and binding study of new 8-chloropyrazolo[5,1
      c][1,2,4]benzotriazine 5-oxide 3-ester compounds are reported. A pharmacological
      evaluation of the high-affinity ligands 1-4 belonging to the 3-heteroarylester
      series is made. The 3-(2-thienylmethoxycarbonyl) derivative 4 stands out from the
      other heteroarylesters and is found, using nine different behavioral methods, to
      be a functionally selective ligand in vivo: it shows anxiolytic-like activity in
      the conflict models (light-dark box and plus maze test) similarly to diazepam,
      without any sedative and amnesic properties or interference from alcohol.

PMID- 12477356
TI  - Structure-affinity relationship study on N-[4-(4-arylpiperazin-1
      yl)butyl]arylcarboxamides as potent and selective dopamine D(3) receptor ligands.
AB  - The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3
      methoxybenzamide) (1), already reported as potent and selective dopamine D(4)
      receptor ligand, has been modified searching for structural features that could
      lead to D(3) receptor affinity. Changes in the aromatic ring linked to N-1
      piperazine ring led to the identification of 2-methoxyphenyl and 2,3
      dichlorophenyl derivatives (compounds 6 and 13) displaying moderate D(3) affinity
      (K(i) = 145 and 31 nM, respectively). Intermediate alkyl chain elongation in
      compounds 1, 6, and 13 improved binding affinity for the D(3) receptor and
      decreased the D(4) affinity (compounds 18-26). Among these latter compounds, the
      N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (19) was
      further modified with the replacement or of the 2,3-dichlorophenyl moiety
      (compounds 27-30) or of the 3-methoxyphenyl ring (compounds 31-41). In this way,
      we identified several high-affinity D(3) ligands (0.13 nM < K(i)'s < 4.97 nM)
      endowed with high selectivity over D(2), D(4), 5-HT(1A), and alpha(1) receptors.
      In addition, N-[4-[4-(2,3-dimethylphenyl)piperazin-1-yl]butyl]-3-methoxybenzamide
      (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2
      benzofurancarboxamide (41) appear to be valuable candidates for positron emission
      tomography (PET) because of their affinity values, lipophilicity properties, and
      liability of (11)C labeling in the O-methyl position.

PMID- 12477357
TI  - Structure-activity relationships of the melanocortin tetrapeptide Ac-His-D-Phe
      Arg-Trp-NH2 at the mouse melanocortin receptors. 4. Modifications at the Trp
      position.
AB  - The melanocortin pathway is involved in the regulation of several physiological
      functions including skin pigmentation, steroidogenesis, obesity, energy
      homeostasis, and exocrine gland function. This melanocortin pathway consists of
      five known G-protein coupled receptors, endogenous agonists derived from the
      proopiomelanocortin (POMC) gene transcript, the endogenous antagonists Agouti and
      the Agouti-related protein (AGRP) and signals through the intracellular cAMP
      signal transduction pathway. The endogenous melanocortin agonists contain the
      putative message sequence "His-Phe-Arg-Trp," postulated to be important for
      melanocortin receptor molecular recognition and stimulation. Herein, we report a
      tetrapeptide library, based upon the template Ac-His-D-Phe-Arg-Trp-NH(2),
      consisting of 20 members that have been modified at the Trp(9) position (alpha
      MSH numbering) and pharmacologically characterized for agonist activity at the
      mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. Results from this study
      yielded compounds that ranged in pharmacological properties from equipotent to a
      loss of melanocortin receptor activity at up to 100 microM concentrations.
      Interestingly, modification of the Trp(9) in the tetrapeptide template at the
      MC1R resulted in only up to a 220-fold potency change, while at the MC4R and
      MC5R, up to a 9700-fold decrease in potency was observed, suggesting the MC1R is
      more tolerant of the modifications examined herein. The most notable results of
      this study include identification that the Trp(9) indole moiety in the
      tetrapeptide template is important for melanocortin-3 receptor agonist potency,
      and that this position can be used to design melanocortin ligands possessing
      receptor selectivity for the peripherally expressed MC1 and MC5 versus the
      centrally expressed MC3 and MC4 receptors. Specifically, the Ac-His-D-Phe-Arg-Tic
      NH(2) and the Ac-His-D-Phe-Arg-Bip-NH(2) tetrapeptides possessed nanomolar MC1R
      and MC5R potency but micromolar MC3R and MC4R agonist potency. Additionally,
      these studies identified that substitution of the Trp amino acid with either
      Nal(2') or D-Nal(2') resulted in equipotent melanocortin receptor potency,
      suggesting that the chemically reactive Trp indole side chain may be replaced
      with the nonreactive Nal(2') moiety for the design of nonpeptide melanocortin
      receptor agonists.

PMID- 12477358
TI  - Solid-phase synthesis of polyamine toxin analogues: potent and selective
      antagonists of Ca2+-permeable AMPA receptors.
AB  - The wasp toxin philanthotoxin-433 (PhTX-433) is a nonselective and noncompetitive
      antagonist of ionotropic receptors, such as ionotropic glutamate receptors and
      nicotinic acetylcholine receptors. Polyamine toxins are extensively used for the
      characterization of subtypes of ionotropic glutamate receptors, in particular
      Ca(2+)-permeable AMPA and kainate receptors. We have previously shown that an
      analogue of PhTX-433 with one of the amino groups replaced by a methylene group,
      philanthotoxin-83 (PhTX-83) is a selective and potent antagonist of AMPA
      receptors. We now describe the solid-phase synthesis of analogues of PhTX-83 and
      the electrophysiological characterization of these analogues on cloned AMPA and
      kainate receptors. The polyamine portion of PhTX-83 was modified systematically
      by changing the position of the secondary amino group along the polyamine chain.
      In another series of analogues, the acyl moiety of PhTX-83 was replaced by acids
      of different size and lipophilicity. Using electrophysiological techniques, PhTX
      56 was shown to be a highly potent (K(i) = 3.3 +/- 0.78 nM) and voltage-dependent
      antagonist of homomeric GluR1 receptors and was more than 1000-fold less potent
      when tested on heteromeric GluR1+GluR2, as well as homomeric GluR5(Q) receptors,
      thus being selective for Ca(2+)-permeable AMPA receptors. Variation of the acyl
      group of PhTX-83 had only minor effect on antagonist potency at homomeric GluR1
      receptors but led to a significant decrease in the voltage-dependence. In
      conclusion, PhTX-56 is a novel, very potent, and selective antagonist of Ca(2+)
      permeable AMPA receptors and is a promising tool for structure/function studies
      of the ion channel of the AMPA receptor.

PMID- 12477359
TI  - Optimization of alkylidene hydrazide based human glucagon receptor antagonists.
      Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid
      [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide.
AB  - Highly potent human glucagon receptor (hGluR) antagonists have been prepared
      employing both medicinal chemistry and targeted libraries based on modification
      of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well
      as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid
      (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal
      aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles
      were found to be active. The SAR was found to be quite insensitive regarding the
      linkage to the distal aryl group, since long and short as well as polar and
      apolar linkers gave highly potent compounds. The presence of a distal aryl group
      was not crucial for obtaining high binding affinity to the hGluR. In many cases,
      however, the affinity could be further optimized with substituted distal aryl
      groups. Representative compounds have been tested for in vitro metabolism, and
      structure-metabolism relationships are described. These efforts lead to the
      discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6
      tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic
      turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon
      receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor
      (IC(50) = 430 pM, K(B) = 380 pM). Glucagon-stimulated glucose production from
      isolated primary rat hepatocytes was inhibited competitively by 74 (K(i) = 14
      nM). This compound was orally available in dogs (F(po) = 15%) and was active in a
      glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.

PMID- 12477360
TI  - Design, synthesis, and physicochemical and biological characterization of a new
      iron chelator of the family of hydroxychromenes.
AB  - Increasing evidence suggests that iron plays an important role in tissue damage
      both during chronic iron overload diseases (i.e., hemochromatosis) and when, in
      the absence of actual tissue iron overload, iron is delocalized from specific
      carriers or intracellular sites (inflammation, neurodegenerative diseases,
      postischaemic reperfusion, xenobiotic intoxications, etc.). In the present work,
      we appropriately modified an iron chelator of the hydroxychromene family in order
      to obtain a tridentate chelator that would inactivate the iron redox cycle after
      its complexation, with a view to using this molecule in human therapy and/or in
      disease prevention. We synthesized such a chelator for the first time and show,
      by different physicochemical analysis, its tridentate nature and, importantly,
      its capacity to chelate iron with enough strength to inhibit both iron-dependent
      H(2)O(2) generation and lipid peroxidation in in vitro biological systems.

PMID- 12477361
TI  - Water stability and cytotoxic activity relationship of a series of ferrocenium
      derivatives. ESR insights on the radical production during the degradation
      process.
AB  - The cytotoxicity of some ferrocenium salts and the lack of activity of the
      corresponding ferrocenes has been already demonstrated. The cytotoxic activity in
      different conditions of decamethylferrocenium tetrafluoroborate (DEMFc(+)) in
      comparison with four other ferrocenium derivatives on MCF-7 cell line is
      reported. The relative stability in aqueous solutions with different buffering
      agents is investigated by means of UV-vis spectroscopy and correlated to the
      cytotoxic properties of the compounds. DEMFc(+), the most stable compound, shows
      the highest efficiency in inhibiting cell growth (IC(50) 35 microM, for 48 h
      treatment). Relaxation time measurements point out the involvement of water
      molecules in the degradation process. ESR results confirm the ability of
      ferrocenium cations to produce oxygen radical species as a consequence of their
      degradation in water. Oxygen-dependent formation of both hydroxyl and superoxide
      radicals is established by the spin-trapping technique. A direct evidence of the
      DEMFc(+) radical production into the viable cells is obtained by means of
      fluorescence-activated cell sorter (FACS) analysis that reveals a dose-dependent
      growth of 8-oxoguanine, the initial product of the guanine oxidation. This DNA
      oxidative stress justifies the cytotoxic effect of DEMFc(+). Furthermore, the
      cytotoxic cooperative effect of bleomycin, an iron-dependent antitumor drug, and
      DEMFc(+) has been tested. We have demonstrated the synergic effect between the
      two drugs, that is explained by the complementary oxidative damage inflicted to
      DNA as well as by the increasing of bleomycin activation by the iron(II/III)
      species available in the cell compartment from ferrocenium degradation.

PMID- 12477362
TI  - Immobilization of aminothiols on poly(oxyalkylene phosphates). Formation of
      poly(oxyethylene phosphates)/cysteamine complexes and their radioprotective
      efficiency.
AB  - The necessity to apply near-toxic amounts of radioprotective drugs to achieve
      adequate protection during radiation treatments represents a major problem in
      human medicine. One of the promising strategies to suppress the toxicity of these
      drugs involves their incorporation into biocompatible polymers. In this study
      cysteamine (Cy) was attached to poly(oxyethylene phosphate), POEP, via an ionic
      bond. Radioprotection of E. coli B cells by this substance and its acute toxicity
      on male C57 BL mice were measured. The toxicity of Cy immobilized within the
      poly(oxyethylene phosphate) was significantly lower in comparison to pure Cy
      while its radioprotective efficiency remained high at half the maximum tolerable
      dose. The high radioprotective efficiency of the Cy/POEP complexes was further
      confirmed on mice at different polymer molecular weight characteristics, drug
      immobilization degrees, application times, and doses. It was found that POEP with
      molecular weight 4700 Da and containing 24% repeating units with attached Cy has
      the highest protection potential combined with a depot effect.

PMID- 12477363
TI  - Melanoma uptake of (99m)Tc complexes containing the N-(2
      diethylaminoethyl)benzamide structural element.
AB  - On the basis of the avid uptake of radioiodinated benzamides by melanoma cells,
      (99m)Tc complexes containing the structural elements of N
      (dialkylaminoalkyl)benzamide pharmacophores have been synthesized and evaluated
      in vitro and in vivo for melanoma uptake. One of the complexes Tc-12 containing
      the ligand 4-(S-benzoyl-2-thioacetyl-glycyl-glycylamido)-N-(2
      diethylaminoethyl)benzamide (11) displayed the highest melanoma uptake. The 1-h
      melanoma uptake values and the corresponding blood counts indicate an
      interdependence of tumor uptake and bioavailability of the (99m)Tc complexes.

PMID- 12477364
TI  - Isotopic effect study of propofol deuteration on the metabolism, activity, and
      toxicity of the anesthetic.
AB  - The use of isotopic substitution to delay the oxidative metabolism of the
      anesthetic propofol 1 was studied. The aromatic hydrogens of propofol 1 were
      replaced by deuterium to produce the mono- and trideuterated derivatives 4 and 5.
      In vitro metabolic studies on human hepatic microsomes showed no isotopic effect
      in the para hydroxylation of propofol, and 1, 4, and 5 display similar hypnotic
      activity and toxicity in mice.

PMID- 12477365
TI  - Formaldehyde-induced DNA cross-link of indolizino[1,2-b]quinolines derived from
      the A-D rings of camptothecin.
AB  - Camptothecin consists of a lactone E ring adjacent to tetracyclic A-D rings of a
      planar chromophore, which are essential for topoisomerase I inhibition and DNA
      interaction. The A-D rings can be exploited to develop DNA-sequence-reading
      molecules. Indolizino[1,2-b]quinoline derivatives substituted with a
      piperidinoethyloxy side chain and an aminomethyl function on rings A and D,
      respectively, were synthesized, and their DNA binding and formaldehyde-mediated
      bonding properties were investigated.

PMID- 12477366
TI  - Synthesis, antitumor activity, molecular modeling, and DNA binding properties of
      a new series of imidazonaphthalimides.
AB  - A series of mono and bisintercalators based on the 5,8-dihydrobenz[de]imidazo[4,5
      g]isoquinoline-4,6-dione system were synthesized and evaluated for growth
      inhibitory properties in several human cell lines. All target compounds showed
      activity in the micromolar range. Representative compounds were evaluated using
      UV--vis spectroscopy and viscosimetric determinations, showing that they behave
      as DNA intercalators. Molecular modeling techniques were used in order to
      rationalize the moderate activity observed for bisnaphthalimides.

PMID- 12477367
TI  - Synthesis of (aminoalkylamine)-N-aminoalkyl)azanonaborane(11) derivatives for
      boron neutron capture therapy.
AB  - New boron-containing polyamine have been synthesized: (aminoalkylamine)-N
      (aminoalkyl)azanonaborane(11) derivatives
      [H(2)N(CH(2))(n)H(2)NB(8)H(11)NH(CH(2))(n)NH(2)], where n = 4-6 and 12, and
      [H(2)N(CH(2))(3)H(2)NB(8)H(11)NH(CH(2))(4)NH(2)]. (4-Aminobutylamine)-N-(4
      aminobutyl)azanonaborane and (3-aminopropylamine)-N-(4-aminobutyl)azanonaborane
      were less toxic in vitro (LD(50) of approximately 700 and approximately 1100
      microM, respectively) than spermine, while (4-aminobutylamine)-N
      isopropylazanonaborane with its hydrophobic isopropyl group and those with n = 5,
      6, and 12 were already toxic under similar conditions (LD(50) << 500 microM).
      These compounds may be useful as delivery agents for boron neutron capture
      therapy.

PMID- 12477368
TI  - Can thermal lasers promote skin wound healing?
AB  - Lasers are now widely used for treating numerous cutaneous lesions, for scar
      revision (hypertrophic and keloid scars), for tissue welding, and for skin
      resurfacing and remodeling (wrinkle removal). In these procedures lasers are used
      to generate heat. The modulation of the effect (volatilization, coagulation,
      hyperthermia) of the laser is obtained by using different wavelengths and laser
      parameters. The heat source obtained by conversion of light into heat can be very
      superficial, yet intense, if the laser light is well absorbed (far-infrared:CO(2)
      or Erbium:Yttrium Aluminum Garnet [Er:YAG] lasers), or it can be much deeper and
      less intense if the laser light is less absorbed by the skin (visible or near
      infrared). Lasers transfer energy, in the form of heat, to surrounding tissues
      and, regardless of the laser used, a 45-50 degrees C temperature gradient will be
      obtained in the surrounding skin. If a wound healing process exists, it is a
      result of live cells reacting to this low temperature increase. The generated
      supraphysiologic level of heat is able to induce a heat shock response (HSR),
      which can be defined as the temporary changes in cellular metabolism. These
      changes are rapid and transient, and are characterized by the production of a
      small family of proteins termed the heat shock proteins (HSP). Recent
      experimental studies have clearly demonstrated that HSP 70, which is over
      expressed following laser irradiation, could play a role with a coordinated
      expression of other growth factors such as transforming growth factor (TGF)-beta.
      TGF-beta is known to be a key element in the inflammatory response and the
      fibrogenic process. In this process, the fibroblasts are the key cells since they
      produce collagen and extracellular matrix. In conclusion, the analysis of the
      literature, and the fundamental considerations concerning the healing process
      when using thermal lasers, are in favor of a modification of the growth factors
      synthesis after laser irradiation, induced by an HSR. An extensive review of the
      different techniques and several clinical studies confirm that thermal lasers
      could effectively promote skin wound healing, if they are used in a controlled
      manner.

PMID- 12477369
TI  - Recognition and management of the cutaneous manifestations of celiac disease: a
      guide for dermatologists.
AB  - In celiac disease, the ingestion of gluten-containing cereals, such as wheat,
      rye, and barley, results in small-bowel mucosal inflammation and villous atrophy
      with crypt hyperplasia. The prevalence of the condition may be as high as 1% in
      the adult population. The disease can also embrace various extraintestinal
      manifestations, of which dermatitis herpetiformis is the best known. Earlier,
      dermatitis herpetiformis was considered a skin disease occurring often
      concomitantly with celiac disease. At present, a body of evidence shows that
      dermatitis herpetiformis is a cutaneous manifestation of celiac disease, and
      affects approximately 25% of patients with celiac disease. Both conditions can
      appear in the same family and are closely linked to HLA class II locus in
      chromosome 6; 90% of patients have HLA DQ2 and, almost all the remainder, HLA
      DQ8. All patients with dermatitis herpetiformis have at least some-degree of
      mucosal inflammation or lesion consistent with celiac disease. The etiology of
      celiac disease in not fully understood, but tissue transglutaminase seems to be
      the predominant autoantigen both in the intestine and the skin. Serum antibodies
      against tissue transglutaminase can be used in the serologic screening and follow
      up of dietary compliance of patients with celiac disease. Gluten-free diet is
      essential in the treatment of both conditions, and oral dapsone is usually needed
      in newly detected dermatitis herpetiformis in order to alleviate symptoms. Oral
      mucosal lesions, alopecia areata, and vitiligo probably occur more frequently in
      patients with dermatitis herpetiformis than in the general population. By
      contrast, the reported association of celiac disease with psoriasis seems to be
      coincidental.

PMID- 12477370
TI  - Adverse cutaneous reactions to mood stabilizers.
AB  - Of all the psychotropic medications currently available, the mood-stabilizing
      agents have the highest incidence of severe and life-threatening adverse
      cutaneous drug reactions (ACDRs). An exanthematous eruption in a patient treated
      with a mood-stabilizing agent should be viewed as possibly being the initial
      symptom of a severe and life-threatening ACDR, such as a hypersensitivity
      reaction, Stevens-Johnson syndrome, or toxic epidermal necrolysis. The
      combination of mood-stabilizing agents may increase the risk of such reactions.
      The mood-stabilizing agents addressed in this article are carbamazepine, lithium
      carbonate, valproic acid, topiramate, lamotrigine, gabapentin, and oxcarbazepine.
      Prior to the initiation of a mood stabilizer, the potential benefits, risks, and
      adverse effects should be communicated to the patient. If possible, slow dose
      escalation should be attempted by the physician. Patients should also be advised
      to seek medical attention if they suspect a drug-induced skin reaction. If the
      physician suspects a severe ACDR, the offending agent should be removed
      immediately.

PMID- 12477371
TI  - Drug-induced nail abnormalities.
AB  - This article reviews the different nail symptoms produced by drugs. Drug-induced
      nail abnormalities may result from toxicity to the matrix, the nail bed or the
      periungual tissues. The most common symptoms include Beau's lines/onychomadesis,
      melanonychia, onycholysis, and periungual pyogenic granulomas. Nail changes
      usually affect several nails and in most cases are asymptomatic. Drugs that most
      frequently produce nail abnormalities include retinoids, indinavir, and cancer
      chemotherapeutic agents. In this article, we also include nail adverse effects as
      a result of radiotherapy since they are commonly observed in clinical practice.

PMID- 12477372
TI  - Terbinafine: a review of its use in onychomycosis in adults.
AB  - Terbinafine, an orally and topically active antimycotic agent, inhibits the
      biosynthesis of the principal sterol in fungi, ergosterol, at the level of
      squalene epoxidase. Squalene epoxidase inhibition results in ergosterol-depleted
      fungal cell membranes (fungistatic effect) and the toxic accumulation of
      intracellular squalene (fungicidal effect). Terbinafine has demonstrated
      excellent fungicidal activity against the dermatophytes and variable activity
      against yeasts and non-dermatophyte molds in vitro. Following oral
      administration, terbinafine is rapidly absorbed and widely distributed to body
      tissues including the poorly perfused nail matrix. Nail terbinafine
      concentrations are detected within 1 week after starting therapy and persist for
      at least 30 weeks after the completion of treatment. Randomized, double-blind
      trials showed oral terbinafine 250 mg/day for 12 or 16 weeks was more efficacious
      than itraconazole, fluconazole and griseofulvin in dermatophyte onychomycosis of
      the toenails. In particular, at 72 weeks' follow-up, the multicenter,
      multinational, L.I.ON. (Lamisil vs Itraconazole in ONychomycosis) study found
      that mycologic cure rates (76 vs 38% of patients after 12 weeks' treatment; 81 vs
      49% of recipients after 16 weeks' therapy) and complete cure rates were
      approximately twice as high after terbinafine treatment than after itraconazole
      (3 or 4 cycles of 400 mg/day for 1 week repeated every 4 weeks) in patients with
      toenail mycosis. Furthermore, the L.I.ON. Icelandic Extension study demonstrated
      that terbinafine was more clinically effective than intermittent itraconazole to
      a statistically significant extent at 5-year follow-up. Terbinafine produced a
      superior complete cure rate (35 vs 14%), mycologic cure rate (46 vs 13%) and
      clinical cure rate (42 vs 18%) to that of itraconazole. The mycologic and
      clinical relapse rates were 23% and 21% in the terbinafine group, respectively,
      compared with 53% and 48% in the itraconazole group. In comparative clinical
      trials, oral terbinafine had a better tolerability profile than griseofulvin and
      a comparable profile to that of itraconazole or fluconazole. Post marketing
      surveillance confirmed terbinafine's good tolerability profile. Adverse events
      were experienced by 10.5% of terbinafine recipients, with gastrointestinal
      complaints being the most common. Unlike the azoles, terbinafine has a low
      potential for drug-drug interactions. Most pharmacoeconomic evaluations have
      shown that the greater clinical effectiveness of oral terbinafine in dermatophyte
      onychomycosis translates into a cost-effectiveness ratio superior to that of
      itraconazole, fluconazole and griseofulvin. CONCLUSION: Oral terbinafine has
      demonstrated greater effectiveness than itraconazole, fluconazole and
      griseofulvin in randomized trials involving patients with onychomycosis caused by
      dermatophytes. The drug is generally well tolerated and has a low potential for
      drug interactions. Therefore, terbinafine is the treatment of choice for
      dermatophyte onychomycosis.

PMID- 12477373
TI  - Cutaneous drug reaction case reports: from the world literature.

PMID- 12477374
TI  - Cerebral changes during exercise in the heat.
AB  - This review focuses on cerebral changes during combined exercise and heat stress,
      and their relation to fatigue. Dynamic exercise can elevate the core temperature
      rapidly and high internal body temperatures seem to be an independent cause of
      fatigue during exercise in hot environments. Thus, in laboratory settings,
      trained participants become exhausted when they reach a core temperature of
      approximately 40 degrees C. The observation that exercise-induced hyperthermia
      reduces the central activation percentage during maximal isometric muscle
      contractions supports the idea that central fatigue is involved in the aetiology
      of hyperthermia-induced fatigue. Thus, hyperthermia does not impair the ability
      of the muscles to generate force, but sustained force production is lowered as a
      consequence of a reduced neural drive from the CNS. During ongoing dynamic
      exercise in hot environments, there is a gradual slowing of the
      electroencephalogram (EEG) whereas hyperthermia does not affect the
      electromyogram. The frequency shift of the EEG is highly correlated with the
      participants' perception of exertion, which furthermore may indicate that
      alterations in cerebral activity, rather than peripheral fatigue, are associated
      with the hyperthermia-induced development of fatigue. Cerebral blood flow is
      reduced by approximately 20% during exercise with hyperthermia due to
      hyperventilation, which causes a lowering of the arterial CO(2) pressure.
      However, in spite of the reduced blood flow, cerebral glucose and oxygen uptake
      does not seem to be impaired. Removal of heat from the brain is also an important
      function of the cerebral blood flow and the lowered perfusion of the brain during
      exercise and heat stress appears to reduce heat removal by the venous blood. Heat
      is consequently stored in the brain. The causal relationship between the
      circulatory changes, the EEG changes and the hyperthermia-induced central fatigue
      is at the present not well understood and future studies should focus on this
      aspect.

PMID- 12477375
TI  - The 'yips' in golf: a continuum between a focal dystonia and choking.
AB  - The definition of the 'yips' has evolved over time. It is defined as a motor
      phenomenon of involuntary movements affecting golfers. In this paper, we have
      extended the definition to encompass a continuum from the neurologic disorder of
      dystonia to the psychologic disorder of choking. In many golfers, the
      pathophysiology of the 'yips' is believed to be an acquired deterioration in the
      function of motor pathways (e.g. those involving the basal ganglia) which are
      exacerbated when a threshold of high stress and physiologic arousal is exceeded.
      In other golfers, the 'yips' seems to result from severe performance anxiety.
      Physically, the 'yips' is manifested by symptoms of jerks, tremors or freezing in
      the hands and forearms. These symptoms can result in: (i) a poor quality of golf
      performance (adds 4.9 strokes per 18 holes); (ii) prompt use of alcohol and beta
      blockers; and (iii) contribute to attrition in golf. Golfers with the 'yips'
      average 75 rounds per year, although many 'yips'-affected golfers decrease their
      playing time or quit to avoid exposure to this embarrassing problem. While more
      investigation is needed to determine the cause of the 'yips', this review article
      summarises and organises the available research. A small study included in this
      paper describes the 'yips' phenomenon from the subjective experience of 'yips'
      affected golfers. The subjective experience (n = 72) provides preliminary support
      for the hypothesis suggesting that the 'yips' is on a continuum. Based on the
      subjective definitions of 72 'yips'-affected golfers, the 'yips' was
      differentiated into type I (dystonia) and type II (choking). A theoretical model
      provides a guide for future research on golfers with either type I or type II
      'yips'.

PMID- 12477376
TI  - Effect of endurance exercise on autonomic control of heart rate.
AB  - Long-term endurance training significantly influences how the autonomic nervous
      system controls heart function. Endurance training increases parasympathetic
      activity and decreases sympathetic activity in the human heart at rest. These two
      training-induced autonomic effects, coupled with a possible reduction in
      intrinsic heart rate, decrease resting heart rate. Long-term endurance training
      also decreases submaximal exercise heart rate by reducing sympathetic activity to
      the heart. Physiological ageing is associated with a reduction in parasympathetic
      control of the heart; this decline in parasympathetic activity can be reduced by
      regular endurance exercise. Some research has indicated that females have
      increased parasympathetic and decreased sympathetic control of heart rate. These
      gender-specific autonomic differences probably contribute to a decreased
      cardiovascular risk and increased longevity observed in females.

PMID- 12477377
TI  - 'Psyching-up' and muscular force production.
AB  - Psyching-up refers to self-directed cognitive strategies used immediately prior
      to or during skill execution that are designed to enhance performance. This
      review focuses on research that has investigated the effect of psyching-up on
      force production; specifically, strength, muscular endurance and power. Although
      firm conclusions are not possible, the research tentatively suggests that
      psyching-up may enhance performance during dynamic tasks requiring strength
      and/or muscular endurance. However, more research is required. Power has received
      scant empirical attention and there are not enough data to support any
      conclusions. Preparatory arousal appears to be the most effective strategy
      although other strategies like imagery, self-talk and attentional focus also have
      empirical support. The range of tasks that have been used to measure force
      production have been limited to movements such as handgrip, leg extension, bench
      press, sit-ups, press-ups, pull-ups, and the standing broad jump. Additionally,
      most studies have used undergraduate and/or untrained samples. Only a very small
      number of studies have examined well-trained individuals. Currently, no
      explanation for why psyching-up may influence force production has any
      substantive support. Although a small number of studies have examined moderating
      and mediating variables, few consistent patterns have emerged and knowledge in
      this area is somewhat restricted. Given the importance that many athletes place
      on their mental preparation just prior to performance this is an area that
      warrants further examination. Research needs to examine a range of complex sport
      specific tasks and use well-trained samples. Additionally, research needs to
      further examine why psyching-up may enhance force production.

PMID- 12477378
TI  - Endurance training and performance in runners: research limitations and
      unanswered questions.
AB  - The purpose of this review is to discuss several limitations common to research
      concerning running and, secondly, to identify selected areas where additional
      research appears needed. Hopefully, this review will provide guidance for future
      research in terms of topics, as well as design and methodology. Limitations in
      the research include: lack of longitudinal studies, inadequate description of
      training status of individuals, lack of confirmation of state of rest,
      nourishment and hydration, infrequent use of allometric scaling to express oxygen
      uptake, relative neglect of anaerobic power and physical structure as
      determinants of performance, neglect of the central nervous system, and reliance
      on laboratory data. Further research in a number of areas is needed to enhance
      our knowledge of running performance. This includes: body mass as a performance
      determinant, evaluation of methods used to measure economy of running, assessing
      the link between strength and running performance, and further examination of
      training methods. While the amount of research on distance running is voluminous,
      the present state of knowledge is somewhat restricted by the limitations in
      research design and methodology identified here.

PMID- 12477379
TI  - Overview of injuries in the young athlete.
AB  - It is estimated that 30 million children in the US participate in organised
      sports programmes. As more and more children participate in sports and
      recreational activities, there has been an increase in acute and overuse
      injuries. Emergency department visits are highest among the school-age to young
      adult population. Over one-third of school-age children will sustain an injury
      severe enough to be treated by a doctor or nurse. The yearly costs have been
      estimated to be as high as 1.8 billion US dollars. There are physical and
      physiological differences between children and adults that may cause children to
      be more vulnerable to injury. Factors that contribute to this difference in
      vulnerability include: children have a larger surface area to mass ratio,
      children have larger heads proportionately, children may be too small for
      protective equipment, growing cartilage may be more vulnerable to stresses and
      children may not have the complex motor skills needed for certain sports until
      after puberty. The most commonly injured areas of the body include the ankle and
      knee followed by the hand, wrist, elbow, shin and calf, head, neck and clavicle.
      Contusions and strains are the most common injuries sustained by young athletes.
      In early adolescence, apophysitis or strains at the apophyses are common. The
      most common sites are at the knee (Osgood-Schlatter disease), at the heel
      (Sever's disease) and at the elbow (Little League Elbow). Non-traumatic knee pain
      is one of the most common complaints in the young athlete. Patellar Femoral Pain
      Syndrome (PFPS) has a constellation of causes that include overuse, poor tracking
      of the patellar, malalignment problems of the legs and foot problems, such as pes
      planus. In the child, hip pathology can present as knee pain so a careful hip
      exam is important in the child presenting with an insidious onset of knee pain.
      Other common injuries in young athletes discussed include anterior cruciate
      ligament injuries, ankle sprains and ankle fractures. Prevention of sports and
      recreation-related injuries is the ideal. There are six potential ways to prevent
      injuries in general: (i) the pre-season physical examination; (ii) medical
      coverage at sporting events; (iii) proper coaching; (iv) adequate hydration; (v)
      proper officiating; and (vi) proper equipment and field/surface playing
      conditions.

PMID- 12477380
TI  - Genomic identification and biochemical characterization of the mammalian
      polyamine oxidase involved in polyamine back-conversion.
AB  - In the polyamine back-conversion pathway, spermine and spermidine are first
      acetylated by spermidine/spermine N1 -acetyltransferase (SSAT) and then oxidized
      by polyamine oxidase (PAO) to produce spermidine and putrescine respectively.
      Although PAO was first purified more than two decades ago, the protein has not
      yet been linked to genomic sequences. In the present study, we apply a BLAST
      search strategy to identify novel oxidase sequences located on human chromosome
      10 and mouse chromosome 7. Homologous mammalian cDNAs derived from human brain
      and mouse mammary tumour were deduced to encode proteins of approx. 55 kDa having
      82% sequence identity. When either cDNA was transiently transfected into HEK-293
      cells, intracellular spermine pools decreased by approx. 30%, whereas spermidine
      increased 2-4-fold. Lysates of human PAO cDNA-transfected HEK-293 cells, but not
      vector-transfected cells, rapidly oxidized N1-acetylspermine to spermidine.
      Substrate specificity determinations with the lysate assay revealed a preference
      ranking of N1-acetylspermine= N1-acetylspermidine> N1,N12
      diacetylspermine>>spermine; spermidine was not acted upon. This ranking is
      identical to that reported for purified PAO and distinctly different from the
      recently identified spermine oxidase (SMO), which prefers spermine over N1
      acetylspermine. Monoethyl- and diethylspermine analogues also served as
      substrates for PAO, and were internally cleaved adjacent to a secondary amine. We
      deduce that the present oxidase sequences are those of the FAD-dependent PAO
      involved in the polyamine back-conversion pathway. In Northern blot analysis, PAO
      mRNA was much less abundant in HEK-293 cells than SMO or SSAT mRNA, and all three
      were differentially induced in a similar manner by selected polyamine analogues.
      The identification of PAO sequences, together with the recently identified SMO
      sequences, provides new opportunities for understanding the dynamics of polyamine
      homoeostasis and for interpreting metabolic and cellular responses to clinically
      relevant polyamine analogues and inhibitors.

PMID- 12477381
TI  - Development of a clockwork light source to enable cervical inspection by village
      health workers.
AB  - BACKGROUND: Cervical cancer can often be prevented by screening and may be
      curable if identified and treated in its early stages. However, 80% of new cases
      occur in less-developed countries where cervical cancer screening programmes are
      small-scale or non-existent. This is a human tragedy of great proportion, with
      many of those affected being young mothers. There is some evidence that cancerous
      or precancerous lesions may be detected by visual inspection with acetic acid
      (VIA) and field studies indicate that this technique is effective, safe and
      acceptable to women. However, the provision of a light source for inspection of
      the cervix presents a major problem in less-developed countries, where candles
      and torches often provide the only means of illumination. Our objective was to
      develop a light source based on clockwork technology, that required no batteries
      or external power source. METHODS: We adapted the design of a commercially
      available clockwork torch to provide a light source for cervical inspection. The
      light source was then tested under laboratory conditions in a comparison with
      other illumination methods typically used in this application. RESULTS: The light
      source gave illuminance levels greater than those produced by any other method
      tested, and also had considerable advantages in terms of ease of use and safety.
      CONCLUSION: This design is small, compact, effective and safe to use and promises
      a better and more affordable means of visualising the cervix. Further field
      trials of VIA are now required which incorporate this light source.

PMID- 12477382
TI  - Screening of transgenic proteins expressed in transgenic food crops for the
      presence of short amino acid sequences identical to potential, IgE - binding
      linear epitopes of allergens.
AB  - BACKGROUND: Transgenic proteins expressed by genetically modified food crops are
      evaluated for their potential allergenic properties prior to marketing, among
      others by identification of short identical amino acid sequences that occur both
      in the transgenic protein and allergenic proteins. A strategy is proposed, in
      which the positive outcomes of the sequence comparison with a minimal length of
      six amino acids are further screened for the presence of potential linear IgE
      epitopes. This double track approach involves the use of literature data on IgE
      epitopes and an antigenicity prediction algorithm. RESULTS: Thirty-three
      transgenic proteins have been screened for identities of at least six contiguous
      amino acids shared with allergenic proteins. Twenty-two transgenic proteins
      showed positive results of six- or seven-contiguous amino acids length. Only a
      limited number of identical stretches shared by transgenic proteins (papaya
      ringspot virus coat protein, acetolactate synthase GH50, and glyphosate
      oxidoreductase) and allergenic proteins could be identified as (part of)
      potential linear epitopes. CONCLUSION: Many transgenic proteins have identical
      stretches of six or seven amino acids in common with allergenic proteins. Most
      identical stretches are likely to be false positives. As shown in this study,
      identical stretches can be further screened for relevance by comparison with
      linear IgE-binding epitopes described in literature. In the absence of literature
      data on epitopes, antigenicity prediction by computer aids to select potential
      antibody binding sites that will need verification of IgE binding by sera binding
      tests. Finally, the positive outcomes of this approach warrant further clinical
      testing for potential allergenicity.

PMID- 12477383
TI  - Finasteride in the treatment of clinical benign prostatic hyperplasia: a
      systematic review of randomised trials.
AB  - BACKGROUND: Benign prostatic hyperplasia affects older men. This systematic
      review determined efficacy and adverse effects of finasteride. REVIEW METHODS:
      PubMed, the Cochrane Library, reference lists of reports, and reviews were
      searched for randomised, double-blind trials of finasteride in benign prostatic
      hyperplasia. Outcomes included symptom score, urinary flow rate, prostate volume,
      discontinuation, and adverse effects. Relative risk and NNT or NNH were
      calculated for dichotomous data. Sensitivity analyses assessed influences of
      baseline symptom severity, initial prostate volume, a dominating trial, and
      previous interventions. RESULTS: Three trials had active controls and 19 had
      placebo. In placebo-controlled trials, 8820 patients received finasteride 5 mg
      and 5909 placebo over 3-48 months. Over 48 months finasteride produced greater
      improvements in total symptom score, maximum urinary flow rate, and prostate
      volume. Significantly more sexual dysfunction, impotence, ejaculation disorder
      and decreased libido occurred with finasteride at 12 months; the NNH for any
      sexual dysfunction at 12 months was 14. Significantly fewer men treated with
      finasteride experienced acute retention or had surgery at 24 or 48 months than
      with placebo; at 12 months the NNT was 49 (31 to 112) to avoid one acute urinary
      retention and 31 (21 to 61) to avoid one surgery. Sensitivity analyses showed
      benefit with finasteride 5 mg to be constant irrespective of the initial prostate
      volume. CONCLUSIONS: Information from many patients in studies of high quality
      showed beneficial effects of finasteride in terms of symptoms, flow rate and
      prostate volume. More utility would result if patient centred outcomes were
      reported in dichotomous form.

PMID- 12477384
TI  - Epigenetic history of an Arabidopsis trans-silencer locus and a test for relay of
      trans-silencing activity.
AB  - BACKGROUND: Meiotically heritable epimutations affecting transgene expression are
      not well understood, even and in particular in the plant model species,
      Arabidopsis thaliana. The Arabidopsis trans-silencer locus, C73, which encodes a
      fusion protein between the repressor of photomorphogenesis, COP1, and green
      fluorescent protein (GFP-COP1), heritably modifies the expression pattern and
      cop1-like cosuppression phenotypes of multiple GFP-COP1 target loci by
      transcriptional gene silencing. RESULTS: Here we describe three additional
      features of trans-silencing by the C73 locus. First, the silencing phenotype of
      C73 and of similar complex loci was acquired epigenetically over the course of no
      more than two plant generations via a stage resembling posttranscriptional
      silencing. Second, imprints imposed by the C73 locus were maintained heritably
      for at least five generations in the absence of the silencer with only sporadic
      spontaneous reversion. Third, the pairing of two other GFP-COP1 transgene loci,
      L91 and E82, showed an increased tendency for epigenetic modification when L91
      carried an epigenetic imprint from C73, but not when E82 bore the imprint.
      CONCLUSIONS: The latter data suggest a transfer of trans-silencing activity from
      one transgene locus, C73, to another, namely L91. These results extend our
      operational understanding of interactions among transgenes in Arabidopsis.

PMID- 12477385
TI  - Polar transport in the Drosophila oocyte requires Dynein and Kinesin I
      cooperation.
AB  - BACKGROUND: The cytoskeleton and associated motors play an important role in the
      establishment of intracellular polarity. Microtubule-based transport is required
      in many cell types for the asymmetric localization of mRNAs and organelles. A
      striking example is the Drosophila oocyte, where microtubule-dependent processes
      govern the asymmetric positioning of the nucleus and the localization to distinct
      cortical domains of mRNAs that function as cytoplasmic determinants. A conserved
      machinery for mRNA localization and nuclear positioning involving cytoplasmic
      Dynein has been postulated; however, the precise role of plus- and minus end
      directed microtubule-based transport in axis formation is not yet understood.
      RESULTS: Here, we show that mRNA localization and nuclear positioning at mid
      oogenesis depend on two motor proteins, cytoplasmic Dynein and Kinesin I. Both of
      these microtubule motors cooperate in the polar transport of bicoid and gurken
      mRNAs to their respective cortical domains. In contrast, Kinesin I-mediated
      transport of oskar to the posterior pole appears to be independent of Dynein.
      Beside their roles in RNA transport, both motors are involved in nuclear
      positioning and in exocytosis of Gurken protein. Dynein-Dynactin complexes
      accumulate at two sites within the oocyte: around the nucleus in a microtubule
      independent manner and at the posterior pole through Kinesin-mediated transport.
      CONCLUSION: The microtubule motors cytoplasmic Dynein and Kinesin I, by driving
      transport to opposing microtubule ends, function in concert to establish
      intracellular polarity within the Drosophila oocyte. Furthermore, Kinesin
      dependent localization of Dynein suggests that both motors are components of the
      same complex and therefore might cooperate in recycling each other to the
      opposite microtubule pole.

PMID- 12477386
TI  - The cytoplasmic dynein and kinesin motors have interdependent roles in patterning
      the Drosophila oocyte.
AB  - BACKGROUND: Motor proteins of the minus end-directed cytoplasmic dynein and plus
      end-directed kinesin families provide the principal means for microtubule-based
      transport in eukaryotic cells. Despite their opposing polarity, these two classes
      of motors may cooperate in vivo. In Drosophila circumstantial evidence suggests
      that dynein acts in the localization of determinants and signaling factors during
      oogenesis. However, the pleiotropic requirement for dynein throughout development
      has made it difficult to establish its specific role. RESULTS: We analyzed dynein
      function in the oocyte by disrupting motor activity through temporally restricted
      expression of the dynactin subunit, dynamitin. Our results indicate that dynein
      is required for several processes that impact patterning; such processes include
      localization of bicoid (bcd) and gurken (grk) mRNAs and anchoring of the oocyte
      nucleus to the cell cortex. Surprisingly, dynein function is sensitive to
      reduction in kinesin levels, and germ line clones lacking kinesin show defects in
      dorsal follicle cell fate, grk mRNA localization, and nuclear attachment that are
      similar to those resulting from the loss of dynein. Significantly, dynein and
      dynactin localization is perturbed in these animals. Conversely, kinesin
      localization also depends on dynein activity. CONCLUSIONS: We demonstrate that
      dynein is required for nuclear anchoring and localization of cellular
      determinants during oogenesis. Strikingly, mutations in the kinesin motor also
      disrupt these processes and perturb dynein and dynactin localization. These
      results indicate that the activity of the two motors is interdependent and
      suggest a model in which kinesin affects patterning indirectly through its role
      in the localization and recycling of dynein.

PMID- 12477387
TI  - Genomic scale mutant hunt identifies cell size homeostasis genes in S.
      cerevisiae.
AB  - BACKGROUND: In most eukaryotic cells, there is a relationship between cell size
      and proliferative capacity. For example, in order to commit to cell division, the
      yeast Saccharomyces cerevisiae must attain a "critical cell size." This mechanism
      coordinates growth with cell division to maintain cell size homeostasis. Because
      very few cell size control genes are known, the genetic pathways responsible for
      cell size homeostasis remain obscure. Furthermore, elucidation of the mechanism
      of cell size homeostasis has been recalcitrant to genetic analysis primarily due
      to the difficulty in cloning cell size control genes. RESULTS: To identify new
      size control genes, the effect of 5958 single gene deletions (4792 homozygous and
      1166 heterozygous gene deletions) on cell size in yeast grown to saturation was
      systematically determined. From these data, 49 genes were identified that
      dramatically altered cell size. Of these, 34 are involved in transcription,
      signal transduction, or cell cycle control; 88% of these genes have putative
      human homologs. Sixteen genes regulate cell size in a dosage-dependent manner,
      and the majority of mutants identified fail to correctly exit the cell cycle.
      Many of these genes are components of Ccr4-Not transcriptional complexes or
      function in the PKC-MAP kinase pathway. These genes may modulate cell size by
      altering the expression or activity of G1-phase cyclins. CONCLUSIONS: These
      results illustrate how systematic genetic screens can be used to dissect
      intricate biological processes that are refractory to classic genetic approaches.
      This genomic-wide genetic screen yielded 46 new cell size mutants and
      systematically assessed the effect of 5958 single gene deletions on cell size as
      cells exited the cell cycle.

PMID- 12477389
TI  - Driving as night falls: the contribution of retinal flow and visual direction to
      the control of steering.
AB  - We have the ability to locomote at high speeds, and we usually negotiate bends
      safely, even when visual information is degraded, for example, when driving at
      night. There are three sources of visual information that could support
      successful steering. An observer fixating a steering target that is eccentric to
      the current heading must rotate their gaze. The gaze rotation may be detected by
      using head and eye movement signals (extra-retinal direction: ERD) or their
      retinal counterpart, visual direction (VD). The gaze rotation also transforms the
      global retinal flow (RF) field, which may enable direct steering judgments. In
      this study, we manipulate VD and RF to determine their contribution toward
      steering a curved path in the presence of ERD. The results suggest a model that
      uses a weighted combination of all three information sources, but results also
      suggest that this weighting may change in reduced visibility, such as in low
      light conditions.

PMID- 12477388
TI  - Experimental RNomics: identification of 140 candidates for small non-messenger
      RNAs in the plant Arabidopsis thaliana.
AB  - BACKGROUND: Genomes from all organisms known to date express two types of RNA
      molecules: messenger RNAs (mRNAs), which are translated into proteins, and non
      messenger RNAs, which function at the RNA level and do not serve as templates for
      translation. RESULTS: We have generated a specialized cDNA library from
      Arabidopsis thaliana to investigate the population of small non-messenger RNAs
      (snmRNAs) sized 50-500 nt in a plant. From this library, we identified 140
      candidates for novel snmRNAs and investigated their expression, abundance, and
      developmental regulation. Based on conserved sequence and structure motifs, 104
      snmRNA species can be assigned to novel members of known classes of RNAs
      (designated Class I snmRNAs), namely, small nucleolar RNAs (snoRNAs), 7SL RNA, U
      snRNAs, as well as a tRNA-like RNA. For the first time, 39 novel members of H/ACA
      box snoRNAs could be identified in a plant species. Of the remaining 36 snmRNA
      candidates (designated Class II snmRNAs), no sequence or structure motifs were
      present that would enable an assignment to a known class of RNAs. These RNAs were
      classified based on their location on the A. thaliana genome. From these, 29
      snmRNA species located to intergenic regions, 3 located to intronic sequences of
      protein coding genes, and 4 snmRNA candidates were derived from annotated open
      reading frames. Surprisingly, 15 of the Class II snmRNA candidates were shown to
      be tissue-specifically expressed, while 12 are encoded by the mitochondrial or
      chloroplast genome. CONCLUSIONS: Our study has identified 140 novel candidates
      for small non-messenger RNA species in the plant A. thaliana and thereby sets the
      stage for their functional analysis.

PMID- 12477390
TI  - Calmodulin dissociation mediates desensitization of the cADPR-induced Ca2+
      release mechanism.
AB  - Ryanodine receptor (RyR) activation by cyclic ADP-ribose (cADPR) is followed by
      homologous desensitization. Though poorly understood, this "switching off"
      process has provided a key experimental tool for determining the pathway through
      which cADPR mediates Ca(2+) release. Moreover, desensitization is likely to play
      an important role in shaping the complexities of Ca(2+) signaling involving
      cADPR, for example, localized release events and propagated waves. Using the sea
      urchin egg, we unmask a role of calmodulin, a component of the RyR complex and a
      key cofactor for cADPR activity, during RyR/cADPR desensitization. Recovery from
      desensitization in calmodulin-depleted purified endoplasmic reticulum
      (microsomes) is severely impaired compared to that in crude egg homogenates. An
      active, soluble factor, identified as calmodulin, is required to restore the
      capacity of microsomes to recover from desensitization. Calmodulin mediates
      recovery in a manner that tightly parallels its time course of association with
      the RyR. Conversely, direct measurement of calmodulin binding to microsomes
      reveals a loss of specific binding during cADPR, but not IP(3), desensitization.
      Our results support a mechanism in which cycles of calmodulin dissociation and
      reassociation to an endoplasmic reticulum protein, most likely the RyR itself,
      mediate RyR/cADPR desensitization and resensitization, respectively.

PMID- 12477391
TI  - Zebrafish as a model organism for the identification and characterization of
      drugs and genes affecting p53 signaling.
AB  - p53 and its main negative regulator, Mdm2, are key players in mammalian cancer
      development. Activation of the transcription factor p53 through DNA damage or
      other stresses can result in cell cycle arrest, apoptosis, or both. Because of
      the absence of characterized p53 signaling in zebrafish (Danio rerio), we have
      studied the roles of Mdm2 and p53 in zebrafish by generating early embryonic
      knockdowns and examined the involvement of p53 in DNA damage-induced apoptosis.
      p53-deficient embryos, induced by injection of antisense morpholinos, were
      morphologically indistinguishable from control embryos, when unperturbed, whereas
      Mdm2 knockdown embryos were severely apoptotic and arrested very early in
      development. Double knockdowns showed that p53 deficiency rescued Mdm2-deficient
      embryos completely, similar to observations in mice. p53 deficiency also markedly
      decreased DNA damage-induced apoptosis, elicited by ultraviolet irradiation or by
      the anti-cancer compound camptothecin. p21/Waf/Cip-1 appeared to be a downstream
      target of zebrafish p53, as revealed relative p21 mRNA levels determined via
      TaqMan analysis. In contrast to mammals, zebrafish may regulate p53 activity by
      using an internal polyA signal site. We conclude that zebrafish represents a
      promising model organism for future compound-based and genetic screens and
      believe that it will help to identify and characterize new anticancer drugs and
      new targets for cancer treatment.

PMID- 12477392
TI  - Spatial and temporal analysis of Rac activation during live neutrophil
      chemotaxis.
AB  - The ability of cells to recognize and respond with directed motility to
      chemoattractant agents is critical to normal physiological function. Neutrophils
      represent the prototypic chemotactic cell in that they respond to signals
      initiated through the binding of bacterial peptides and other chemokines to G
      protein-coupled receptors with speeds of up to 30 microm/min. It has been
      hypothesized that localized regulation of cytoskeletal dynamics by Rho GTPases is
      critical to orchestrating cell movement. Using a FRET-based biosensor approach,
      we investigated the dynamics of Rac GTPase activation during chemotaxis of live
      primary human neutrophils. Rac has been implicated in establishing and
      maintaining the leading edge of motile cells, and we show that Rac is dynamically
      activated at specific locations in the extending leading edge. However, we also
      demonstrate activated Rac in the retracting tail of motile neutrophils. Rac
      activation is both stimulus and adhesion dependent. Expression of a dominant
      negative Rac mutant confirms that Rac is functionally required both for tail
      retraction and for formation of the leading edge during chemotaxis. These data
      establish that Rac GTPase is spatially and temporally regulated to coordinate
      leading-edge extension and tail retraction during a complex motile response, the
      chemotaxis of human neutrophils.

PMID- 12477393
TI  - Rapid coevolution of the nematode sex-determining genes fem-3 and tra-2.
AB  - Unlike many features of metazoan development, sex determination is not widely
      conserved among phyla. However, the recent demonstration that one gene family
      controls sexual development in Drosophila, C. elegans, and vertebrates suggests
      that sex determination mechanisms may have evolved from a common pathway that has
      diverged radically since the Cambrian. Sex determination gene sequences often
      evolve quickly, but it is not known how this relates to higher-order pathways or
      what selective or neutral forces are driving it. In such a rapidly evolving
      developmental pathway, the fate of functionally linked genes is of particular
      interest. To investigate a pair of such genes, we cloned orthologs of the key C.
      elegans male-promoting gene fem-3 from two sister species, C. briggsae and C.
      remanei. We employed RNA interference to show that in all three species, the male
      promoting function of fem-3 and its epistatic relationship with its female
      promoting upstream repressor, tra-2, are conserved. Consistent with this, the FEM
      3 protein interacts with TRA-2 in each species, but in a strictly species
      specific manner. Because FEM-3 is the most divergent protein yet described in
      Caenorhabditis and the FEM-3 binding domain of TRA-2 is itself hypervariable, a
      key protein-protein interaction is rapidly evolving in concert. Extrapolation of
      this result to larger phylogenetic scales helps explain the dissimilarity of the
      sex determination systems across phyla.

PMID- 12477394
TI  - Motion adaptation distorts perceived visual position.
AB  - After an observer adapts to a moving stimulus, texture within a stationary
      stimulus is perceived to drift in the opposite direction-the traditional motion
      aftereffect (MAE). It has recently been shown that the perceived position of
      objects can be markedly influenced by motion adaptation. In the present study, we
      examine the selectivity of positional shifts resulting from motion adaptation to
      stimulus attributes such as velocity, relative contrast, and relative spatial
      frequency. In addition, we ask whether spatial position can be modified in the
      absence of perceived motion. Results show that when adapting and test stimuli
      have collinear carrier gratings, the global position of the object shows a
      substantial shift in the direction of the illusory motion. When the carrier
      gratings of the adapting and test stimuli are orthogonal (a configuration in
      which no MAE is experienced), a global positional shift of similar magnitude is
      found. The illusory positional shift was found to be immune to changes in spatial
      frequency and to contrast between adapting and test stimuli-manipulations that
      dramatically reduce the magnitude of the traditional MAE. The lack of sensitivity
      for stimulus characteristics other than direction of motion suggests that a
      specialized population of cortical neurones, which are insensitive to changes in
      a number of rudimentary visual attributes, may modulate positional representation
      in lower cortical areas.

PMID- 12477395
TI  - Proteomics analysis identifies new components of the fission and budding yeast
      anaphase-promoting complexes.
AB  - The anaphase-promoting complex (APC) is a conserved multisubunit ubiquitin ligase
      required for the degradation of key cell cycle regulators. Components of the APC
      have been identified through genetic screens in both Schizosaccharomyces pombe
      and Saccharomyces cerevisiae as well as through biochemical purification coupled
      with mass spectrometric protein identification. With these approaches, 11
      subunits of the core S. cerevisiae APC have been identified. Here, we have
      applied a tandem affinity purification approach coupled with direct analysis of
      the purified complexes by mass spectrometry (DALPC) to reveal additional subunits
      of both the S. pombe and S. cerevisiae APCs. Our data increase the total number
      of identified APC subunits to 13 in both yeasts and indicate that previous
      approaches were biased against the identification of small subunits. These
      results underscore the power of direct analysis of protein complexes by mass
      spectrometry and set the foundation for further functional and structural studies
      of the APC.

PMID- 12477396
TI  - hTPX2 is required for normal spindle morphology and centrosome integrity during
      vertebrate cell division.
AB  - Bipolar spindle formation is essential for the accurate segregation of genetic
      material during cell division. Although centrosomes influence the number of
      spindle poles during mitosis, motor and non-motor microtubule-associated proteins
      (MAPs) also play key roles in determining spindle morphology. TPX2 is a novel MAP
      also characterized in Xenopus cell-free extracts. To examine hTPX2 (human TPX2)
      function in human cells, we used siRNA to knock-down its expression and found
      that cells lacking hTPX2 arrest in mitosis with multipolar spindles. NuMA, gamma
      tubulin, and centrin localize to each pole, and nocodazole treatment of cells
      lacking hTPX2 demonstrates that the localization of gamma-tubulin to multiple
      spindle poles requires intact microtubules. Furthermore, we show that the
      formation of monopolar microtubule arrays in human cell extracts does not require
      hTPX2, demonstrating that the mechanism by which hTPX2 promotes spindle
      bipolarity is independent of activities focusing microtubule minus ends at
      spindle poles. Finally, inhibition of the kinesin Eg5 in hTPX2-depleted cells
      leads to monopolar spindles, indicating that Eg5 function is necessary for
      multipolar spindle formation in the absence of hTPX2. Our observations reveal a
      structural role for hTPX2 in spindles and provide evidence for a balance between
      microtubule-based motor forces and structural spindle components.

PMID- 12477397
TI  - MOESIN crosslinks actin and cell membrane in Drosophila oocytes and is required
      for OSKAR anchoring.
AB  - In Drosophila, development of the embryonic germ cells depends on posterior
      transport and site-specific translation of oskar (osk) mRNA and on interdependent
      anchoring of the osk mRNA and protein within the posterior subcortical region of
      the oocyte. Transport of the osk mRNA is mediated by microtubules, while
      anchoring of the osk gene products at the posterior pole of the oocyte is
      suggested to be microfilament dependent. To date, only a single actin binding
      protein (TropomyosinII) has been identified with a putative role in osk mRNA and
      protein anchoring. This communication demonstrates that mutations in the
      Drosophila moesin (Dmoe) gene that encodes another actin binding protein result
      in delocalization of osk mRNA and protein from the posterior subcortical region
      and, as a consequence, in failure of embryonic germ cell development. In Dmoe
      mutant oocytes, the subcortical actin network is detached from the cell membrane,
      while the polarized microtubule cytoskeleton is unaffected. In line with the
      earlier observations, colocalization of ectopic actin and OSK protein in Dmoe
      mutants suggests that the actin cytoskeleton anchors OSK protein to the
      subcortical cytoplasmic area of the Drosophila oocyte.

PMID- 12477398
TI  - Budget boosts mask management shortfall.

PMID- 12477399
TI  - Modelling fails to stall key fisheries collapse.

PMID- 12477400
TI  - Mob culture unravelled.

PMID- 12477401
TI  - Diaphanous-related Formin homology proteins.

PMID- 12477402
TI  - Oocyte patterning: dynein and kinesin, inc.
AB  - Recent studies show that dynein and kinesin are both required for cargo transport
      to the anterior cortex of the Drosophila oocyte. The orientation of microtubules
      in the oocyte suggests that kinesin mediates anterior transport indirectly, by
      activating and/or recycling dynein.

PMID- 12477403
TI  - Decision making: neural correlates of response time.
AB  - Recent studies have measured the time taken by neural processes to decide between
      alternative stimuli. Overt responses are produced only as soon as neural
      processes are completed. The brain throttles the mind.

PMID- 12477404
TI  - Left-right asymmetry: all hands to the pump.
AB  - How do embryos establish differences between their left and right sides? Previous
      studies have implicated various signaling molecules and directional beating of
      cilia. Now, a new player enters the scene: the proton-potassium pump.

PMID- 12477405
TI  - Plant patterning: TRY to inhibit your neighbors.
AB  - Two regulators of hair-cell patterning in Arabidopsis act in the cells where they
      are produced to inhibit primary cell fate in neighboring cells. Their
      relationship to the activators of the primary cell fate suggests a classical
      activator-inhibitor model for patterning that can now be analyzed in detail.

PMID- 12477406
TI  - Mammalian pheromones: from genes to behaviour.
AB  - Knocking-out selected genes for receptors of the vomeronasal organ has been found
      to impair specific aspects of pheromone-induced behaviour in the mouse. This is
      not unexpected; less predictable is the finding that deleting the gene for a
      vomeronasal-organ-specific ion channel causes gender blindness.

PMID- 12477407
TI  - Jaw development: chinless wonders.
AB  - It has been suggested that the regionally restricted expression of Dlx genes acts
      to pattern the proximodistal axis of the pharyngeal arches during vertebrate
      development. Recently, clear evidence of this has emerged from Dlx-5; Dlx-6
      double mutants, in which the lower jaw is transformed to an upper jaw.

PMID- 12477408
TI  - Cytokinesis: rho and formins are the ringleaders.
AB  - Although cytokinesis was first described in the 1830s, the molecular events
      underlying this key cellular process remain elusive. New results reveal a role
      for actin polymerization, the small GTPase Rho and formins in cytokinetic ring
      assembly.

PMID- 12477409
TI  - Ubiquitin system: JAMMing in the name of the lid.
AB  - The isopeptide bonds formed by ubiquitin or its relatives are cleaved by
      hydrolases with active site cysteines. Recent studies have revealed that similar
      metalloprotease motifs--JAMMs--in the Rpn11 subunit of the 26S proteasome lid and
      in the Csn5 subunit of the COP9 signalosome are involved in deubiquitination and
      deneddylation, respectively.

PMID- 12477410
TI  - The role of activity in development of the visual system.
AB  - Neuronal activity is important for both the initial formation and the subsequent
      refinement of anatomical and physiological features of the mammalian visual
      system. Here we examine recent evidence concerning the role that spontaneous
      activity plays in axonal segregation, both of retinogeniculate afferents into eye
      specific layers and of geniculocortical afferents into ocular dominance bands. We
      also assess the role of activity in the generation and plasticity of orientation
      selectivity in the primary visual cortex. Finally, we review recent challenges to
      textbook views on how inputs representing the two eyes interact during the
      critical period of visual cortical plasticity.

PMID- 12477412
TI  - New technology platforms in the development of vaccines for the future.
AB  - The desire for improved quality of life in both industrialised and under
      developed nations has led to the quest for greater understanding and subsequent
      prevention and treatment of diseases. Here we discuss some of the latest of
      modern medicine's approaches to vaccination and disease treatment. Our main
      subject of discussion being the novel antigen delivery systems termed
      immunopotentiating reconstituted influenza virosomes (IRIVs) and their use as
      vaccines. Particular attention is paid to the currently licensed Epaxal and
      Inflexal V, good examples of the improvements being made in vaccinology.
      Alternative uses of virosomes such as peptide delivery, cytosolic drug delivery
      and gene delivery are also considered, highlighting the flexibility of the IRIV
      formulation and method of action. The paper concludes with consideration of
      alternative novel approaches to vaccinology including bacterial carriers for DNA
      vaccines, recombinant MV vaccines and polysaccharide-protein conjugates.

PMID- 12477411
TI  - A role for liposomes in genetic vaccination.
AB  - Genetic immunization by the use of plasmid DNA encoding antigens from bacteria,
      viruses, protozoa and cancers has often led to protective humoral and cell
      mediated immunity, and has some practical advantages over conventional vaccines.
      However, naked DNA vaccines can be degraded by nucleases in situ, are unable to
      target antigen presenting cells (APCs), and exhibit poor performance when
      administered by routes other than the intramuscular, all of which have reduced
      the value of the approach. We have been able to avoid DNA degradation and also
      target DNA to APCs by the use of liposomes as DNA vaccine carriers. Entrapment of
      plasmid DNA within the aqueous spaces of cationic liposomes is effected by a one
      step procedure which results in most of the DNA being incorporated into a freeze
      dried, ready to use preparation. Animal experiments have shown that immunization
      by the intramuscular or the subcutaneous route with liposome-entrapped plasmid
      DNA encoding the hepatitis B surface antigen leads to much greater humoral (IgG
      subclasses) and cell mediated (splenic IFN-gamma) immune responses than with
      naked DNA. In other experiments with a plasmid DNA encoding a model antigen
      (ovalbumin), a cytotoxic T lymphocyte (CTL) response was also observed. These
      results could be explained by the ability of liposomes to protect their DNA
      content from local nucleases and direct it to APCs in the lymph nodes draining
      the injected site.

PMID- 12477413
TI  - Inflexal V a trivalent virosome subunit influenza vaccine: production.
AB  - Inflexal V, a novel virosome-based trivalent influenza vaccine, has been shown to
      be highly immunogenic and well tolerated in children, young adults, and the
      elderly. Here we discuss the techniques for the manufacture of Inflexal V,
      highlighting the purity and consistency of the manufacturing process. Key factors
      to be taken into account in the construction of Inflexal V are the retention of
      the natural presentation of antigens, its biodegradability and the presentation
      of few adverse events. The constituents of the vaccine were also carefully
      considered based on suitability for human use, adjuvanticity and an innate lack
      of toxicity.

PMID- 12477414
TI  - Virosome influenza vaccine in children.
AB  - The use of vaccines for the prophylaxis of influenza in children is limited. This
      is despite high annual rates of influenza in children and despite the
      complications caused by influenza in children with chronic respiratory illnesses.
      The disease burden of influenza on infants and young children is reviewed and the
      potential of recommended influenza vaccination in healthy children, to reduce the
      direct and indirect health and socio-economic costs, is considered. Clinical
      experience with a virosome-formulated subunit influenza vaccine in children is
      presented. These clinical trials in children have shown a virosome-formulated
      subunit influenza vaccine to be immunogenic and well tolerated, indicating that
      it might be recommended for immunising healthy infants and children against
      influenza virus.

PMID- 12477415
TI  - Safety and immunogenicity of influenza vaccination in individuals infected with
      HIV.
AB  - Influenza can cause severe complications in HIV infected individuals leading to
      increases in hospitalisation and mortality. Vaccination is recommended for such
      individuals, but some studies reported that immunisation against influenza may
      stimulate an increase of HIV viral load and decrease of CD4+ cells count. A
      review of published studies, including our study carried out in HIV former drug
      addicts, indicates that vaccination against influenza is well tolerated in both
      children and adult individuals with HIV, but response to vaccination is lower
      than that observed in immunocompetent individuals. Most studies, including our
      own, show that vaccination does not induce significant changes in viral load and
      CD4+ cell counts. In studies reporting modifications of such parameters there is
      a general agreement that the increased viral replication is usually transient and
      unable to determine a clear, measurable progression of the underlying HIV
      disease. Therefore, vaccination against influenza can be safely administered to
      HIV infected people.

PMID- 12477416
TI  - Immunogenicity and safety of an adjuvanted influenza vaccine in patients with
      decompensated cirrhosis.
AB  - The immunogenicity and tolerability of an adjuvanted trivalent influenza vaccine
      was evaluated in 20 patients with cirrhosis due to chronic HBV or HCV infections
      and eight healthy age matched controls. Seroconversion or a four-fold or greater
      increase in HI antibody titres to each antigen occurred in 75-85% of the patients
      and in 100% of the controls. One month after vaccination, the geometric mean
      antibody titres were significantly higher than baseline in both groups of
      vaccinees. A mild and transient erythema at the inoculation site was the only
      side effect for both groups. The results justify the use of an adjuvanted
      influenza vaccine, given as single-dose, in patients with advanced liver disease.

PMID- 12477417
TI  - Vaccination policies in the military: an insight on influenza.
AB  - Influenza, despite its generally benign clinical course, is accompanied by
      absenteeism from work, acute suffering and even mortality, mainly in the elderly
      and in subjects who have high-risk medical conditions. Its prevention consists of
      strain specific vaccination, which must be repeated annually due to the high
      antigenic variability of the influenza virus. Influenza may represent an
      important obstacle to military readiness, particularly when considering its
      infectivity within closed communities. Despite such epidemiological situations,
      influenza vaccination is seldom included in the compulsory vaccination programme
      of the military on a global level. This may be due to several reasons, namely, a
      lack of confidence in the vaccine's effectiveness, the need for annual
      administrations (with expansion of economic and organisational efforts), false
      assumption that influenza is a disease with a minor impact, contradictory results
      of cost-effectiveness analyses (examples of which have yet to be made
      specifically for the military environment). The availability of more effective,
      economic and easy to administer vaccines, together with detailed and tailored
      cost-effectiveness analyses, may have a beneficial effect on the role the
      military plays in the fight against influenza across the globe.

PMID- 12477418
TI  - Selection of influenza vaccine strains and developing pandemic vaccines.
AB  - The WHO Influenza Surveillance Programme has recently celebrated 50 years of
      success. The programme provides representative influenza viruses for antigenic
      and genetic analysis and from this information, the WHO is able to make
      recommendations on vaccine composition. The WHO has also a key important role to
      play in detecting new influenza pandemic viruses and advising on suitable vaccine
      strains and their use. Experience in developing vaccines for pandemics or
      pandemic alerts in the past, has informed us that there are considerable problems
      to solve, not least of which is the fact that the conventional vaccines used
      throughout the world are unlikely to be effective in the face of a pandemic.
      Different strategies need developing and testing, so that we are adequately
      prepared.

PMID- 12477419
TI  - The role of genetic analysis in influenza virus surveillance and strain
      characterisation.
AB  - The powerful tools of molecular genetics are being utilised in most areas of
      influenza research and control activities, including surveillance and strain
      characterisation of these fast-evolving viruses. In this paper, examples are
      given of the use of molecular methods in influenza surveillance in Norway, and
      the need for facilitated rapid exchange of up-to-date genetic data within or
      outside the existing surveillance networks is discussed. Typically, researchers
      at the individual national surveillance networks, apart from the data obtained
      from their own virus strains or through bilateral exchange with colleagues, have
      access mostly to somewhat outdated published sequences. Enhanced availability of
      current molecular data within regional and national surveillance systems would
      result in a much better understanding of the epidemiology while the outbreaks are
      unfolding, something that would benefit surveillance at all levels.

PMID- 12477420
TI  - Cost-benefit evaluation of influenza vaccination in the elderly in the Italian
      region of Liguria.
AB  - Influenza causes considerable morbidity and mortality and the damage to public
      health can be considerable. The most effective measures available for the
      prevention of influenza is vaccination. In most industrialised countries the
      objective of vaccination is to limit the disease among individuals at risk,
      especially the elderly. During the winter of 2000/2001, General Practitioners
      (GPs) monitored 14,818 elderly individuals. The objective was to evaluate the
      weekly incidence of the disease. Furthermore, we carried out a prospective study
      on 512 elderly individuals, arranged according to vaccination (304 vaccinated and
      208 non-vaccinated), with the main objective of assessing the costs of the
      disease and the efficacy of vaccination. Finally, in order to assess the
      percentage of vaccinated elderly individuals, we carried out a telephone survey
      on 500 subjects. Our clinical surveillance study enabled us to establish that
      morbidity was particularly low in elderly individuals.The results of the
      prospective study allowed us to estimate the cost-benefit ratio at 8.22, with a
      net saving of 110.20 Euros for each vaccinated subject. We were also able to
      establish that the vaccine coverage among elderly individuals was 63%. Our study,
      though carried out during a low epidemic year, confirms the economic advantage of
      vaccination in the elderly.

PMID- 12477422
TI  - Therapeutic cancer vaccines based on molecularly defined human tumor antigens.
AB  - The results of numerous phases I and II clinical trials testing the safety and
      immunogenicity of various cancer vaccine formulations based on cytolytic T
      lymphocytes (CTLs)-defined tumor antigens have been reported recently. Specific T
      cell responses can be detected in only a fraction of immunized patients. A
      smaller but significant fraction of these patients have objective tumor
      responses. Efficient therapeutic vaccination should aim at boosting naturally
      occurring anti-tumor responses and at sustaining a large contingent of tumor
      antigen-specific and fully functional effector T cells at tumor sites.

PMID- 12477423
TI  - A clinical grade cocktail of cytokines and PGE2 results in uniform maturation of
      human monocyte-derived dendritic cells: implications for immunotherapy.
AB  - Dendritic cells (DCs) can induce tumor- or pathogen-specific T cell responses in
      humans. We comprehensively compared the clinically available DC maturation
      stimuli for their ability to promote uniformly mature DCs that elicit higher
      levels of T cell responses. We compared the standard maturation stimulus,
      autologous monocyte-conditioned medium (MCM), with a synthetic double stranded
      RNA (poly I:C), soluble CD40 ligand trimer, and a defined cocktail of cytokines
      (TNF-alpha, IL-1 beta, IL-6) and PGE(2) to promote mature phenotype and function
      in human monocyte-derived DCs. The cocktail was the most efficient despite the
      lack of induction of IL-12p70. While these results support the use of the MCM
      mimic cocktail in clinical DC immunotherapy trials, the roles of it's individual
      constituents remain to be completely defined.

PMID- 12477424
TI  - Outer membrane protein A (OmpA): a new pathogen-associated molecular pattern that
      interacts with antigen presenting cells-impact on vaccine strategies.
AB  - Outer membrane protein A (OmpA) is a class of proteins highly conserved among the
      Enterobacteriaceae family and throughout evolution. We have observed that antigen
      presenting cells (APCs) recognize and are activated by the recombinant OmpA from
      Klebsiella pneumoniae (KpOmpA). KpOmpA triggers cytokine production by
      macrophages and dendritic cells (DC), induces DC maturation and signals via Toll
      like receptor 2. KpOmpA also interacts with endocytic receptor(s) expressed on DC
      and macrophages. Tumor antigens coupled to KpOmpA are taken up by APCs and gain
      access to the MHC class I pathway, triggering the initiation of protective anti
      tumor cytotoxic responses in the absence of CD4 T cell help and adjuvant. Thus,
      OmpA appears as a new type of pathogen-associated molecular pattern (PAMP) usable
      as a vector in anti-infectious and therapeutic anti-tumor vaccines to elicit
      CTLs.

PMID- 12477425
TI  - Tumor-derived exosomes: a new source of tumor rejection antigens.
AB  - Exosomes are small vesicles released by a broad array of hematopoietic cells.
      Previous studies showed that exosomes released by antigen loaded dendritic cells
      induce immune-mediated anti-tumor response in mice. Here, we will describe the
      biochemical properties of tumor-derived exosomes and, their pre-clinical activity
      as cancer vaccines.

PMID- 12477426
TI  - Synthetic and natural non-live vectors: rationale for their clinical development
      in cancer vaccine protocols.
AB  - Different arguments suggest that cytotoxic CD8 T lymphocytes (CTL) play a key
      role in the protection against tumors and in the establishment of anti-tumor
      immunity. Unfortunately, administration of soluble proteins alone generally does
      not induce CD8+ T cells presumably because antigen derived peptides are not
      introduced into the major histocompatibility complex (MHC) class I antigen
      presentation pathway. Attenuated recombinant live vectors such as viruses or
      bacteria which have the ability to deliver antigen into the cytosol of cells have
      been shown to induce cytotoxic T cell response. However, there are safety
      concerns associated with these approaches especially in immunodeficient patients.
      Synthetic vectors such as heat shock proteins, virus like particles (VLP) and
      liposomes could deliver exogenous protein into the cytosol of cells associated
      with the induction of CTL and tumor immunity. We and other groups have
      successfully exploited the original intracellular traffic of toxins to use them
      as vectors for tumor antigens.

PMID- 12477427
TI  - HLA class I antigen loss, tumor immune escape and immune selection.
AB  - Poor clinical response rates have been observed in the majority of the T cell
      based immunotherapy clinical trials conducted to date. One reason might be the
      presence of abnormalities in HLA class I antigen presentation in malignant
      lesions. An increased frequency of HLA class I abnormalities has been observed in
      malignant lesions from patients treated with T cell-based immunotherapy and in
      lesions which have recurred in patients who had experienced clinical responses
      following T cell-based immunotherapy. These observations are compatible with the
      possibility that the outgrowth of a patient's tumor reflects immune selection of
      tumor cells which have acquired escape mechanisms from immune recognition.

PMID- 12477428
TI  - Apoptosis of immune cells in the tumor microenvironment and peripheral
      circulation of patients with cancer: implications for immunotherapy.
AB  - Rapid turnover of lymphocytes observed in patients with cancer appears to be
      driven by increased apoptosis of T lymphocytes or insufficient thymic output of
      recent thymic emigrants (RTE). Using multicolor flow cytometry and apoptosis
      assays, we found that CD8+CD95+Annexin+ T cells are dying at a rate that is
      significantly higher in patients with cancer than in normal controls (NC). CD8+
      effector subsets of T cells were particularly vulnerable to apoptosis. Thymic
      excision circle (TREC) analysis of peripheral blood lymphocytes showed a
      decreased number of RTE in these patients. Together, the data suggest that a high
      rate of T-cell turnover might contribute to immunologic imbalance in patients
      with cancer and have unfavorable effects on immunotherapy, including therapeutic
      antitumor vaccines.

PMID- 12477429
TI  - Immune intervention strategies for HIV-1 infection of humans in the SIV macaque
      model.
AB  - Studies in the SIVmac macaque model have demonstrated that the extent of virus
      specific CD4+ and CD8+ T-cell responses induced by vaccination prior to virus
      challenge exposure correlate with viremia containment following establishment of
      infection. These findings led to the hypothesis that active immunization with
      vaccines able to induce virus-specific T-cell responses following the
      establishment of infection could also ameliorate the virological outcome. Here,
      we will review the relative effect of ART and vaccination during primary SIVmac
      infection of macaques.

PMID- 12477430
TI  - Do not underestimate the power of antibodies--lessons from adoptive transfer of
      antibodies against HIV.
AB  - Successes for neutralizing antibodies (nAbs) against the human immunodeficiency
      virus (HIV) include potent cross-clade neutralization of primary virus isolates
      by human neutralizing monoclonal antibodies (nmAbs) targeting conserved envelope
      epitopes. Furthermore, passively administered combinations of human nmAbs
      prevented infection in primates, indicating that epitopes recognized by such
      nmAbs are key determinants for protection. Lastly, in the absence of CD8+ T
      cells, nAbs may act as a second line of defense during chronic infection. Taken
      together, these results argue for generating nAb response-based prophylactic
      and/or therapeutic AIDS vaccines. We suggest that the epitopes identified by
      passive immunization represent excellent targets for the rational design of nAb
      response-based AIDS vaccines.

PMID- 12477431
TI  - Viral evolution and challenges in the development of HIV vaccines.
AB  - Potent virus-specific cytotoxic T lymphocyte (CTL) responses elicited by
      candidate AIDS vaccines have been shown to provide short-term control of viral
      replication following pathogenic viral challenges in rhesus monkeys. We have
      recently shown that vaccines that control rather than prevent immunodeficiency
      virus infections are still subject to immune escape. In particular, viral
      mutations can develop that result in viral escape from recognition by
      immunodominant CTL, loss of immune control of viral replication, and clinical
      disease progression. These data suggest that viral escape from CTL may prove to
      be a significant limitation of the current generation of CTL-based AIDS vaccines.

PMID- 12477432
TI  - Co-immunization of rhesus macaques with plasmid vectors expressing IFN-gamma, GM
      CSF, and SIV antigens enhances anti-viral humoral immunity but does not affect
      viremia after challenge with highly pathogenic virus.
AB  - To investigate the adjuvant capacity of granulocyte-macrophage colony-stimulating
      factor (GM-CSF) and interferon (IFN-gamma), we cloned these rhesus cytokines into
      a mammalian expression vector. Two groups of six rhesus macaques (Macaca mulatta)
      received intradermal immunizations of plasmid DNA coding for SIV Eng and Gag, and
      influenza virus nucleoprotein (Flu-NP), with or without the co-administration of
      plasmid DNA coding for these cytokines. Humoral immune responses to antigens of
      both of these viruses and SIV specific T cell proliferative responses were
      significantly enhanced by co-immunization with the cytokines. These twelve
      monkeys, and a group of six naive controls, were challenged by the oral mucosal
      route with the uncloned and highly pathogenic SIVmac251. All monkeys became
      infected. The early CD4 decline was reduced in the group co-immunized with
      cytokine and viral plasmids. Unexpectedly, plasma viremia set points were not
      different in this co-immunized group and the non-immunized control group. On the
      other hand, monkeys vaccinated with equivalent amounts of empty vector plasmid
      (i.e. no cytokine inserts) along with plasmids expressing viral antigens
      demonstrated a slight but significant decrease in acute viremia compared to non
      immunized controls (P<0.02). However, viral loads at set points were not
      significantly different between both the immunized and the non-immunized control
      group. Thus, although the cytokine vectors demonstrated detectable enhancement of
      the immune response to different viral antigens, such enhanced response did not
      translate into better anti-viral control in our experiment. These results
      underscore the need for further testing of cytokines as vaccine adjuvants in
      relevant animal models.

PMID- 12477433
TI  - The role of cytotoxic T cells and cytokines in the control of hepatitis B virus
      infection.
AB  - The aim of this study was to elucidate the molecular basis for viral clearance
      and liver disease in the pathogenesis of hepatitis B virus (HBV) infection. Using
      transgenic mice that replicate HBV at high levels in the liver as recipients of
      HBV-specific cytotoxic T cells (CTL), we have shown that the antiviral potential
      of the CTL is primarily mediated by noncytolytic mechanisms that involve the
      intra-hepatic production of IFN-gamma by these cells. We also showed that,
      following antigen recognition, HBV-specific CTL recruit antigen non-specific
      inflammatory cells that contribute to amplify the liver disease initiated by CTL.
      These results provided insight into immunological and virological processes that
      may lead to the development of new therapeutic strategies to terminate chronic
      HBV infection.

PMID- 12477434
TI  - Towards immunotherapy for chronic hepatitis B virus infections.
AB  - Chronic liver disease and hepatocellular carcinoma associated with chronic
      hepatitis B virus (HBV) infection are among the most serious human health
      problems in highly endemic regions. Although, effective vaccines against HBV have
      been available for many years, over 350 million people still remain persistently
      infected with HBV. Current therapies fail to provide long-term control of viral
      replication in most patients. Viral persistence has been associated with a defect
      in the development of HBV-specific cell-mediated immunity. Vaccine-based
      strategies to boost or to broaden the weak virus-specific T cell response of
      patients with chronic hepatitis B are proposed as a means of terminating this
      persistent infection.

PMID- 12477435
TI  - Ultra-rapid DNA analysis using HyBeacon probes and direct PCR amplification from
      saliva.
AB  - We describe a novel probe technology, termed HyBeacons, which provides a new
      homogeneous method for fluorescence-based sequence detection and allele
      discrimination. Employing a single nucleotide polymorphism located in the N
      acetyltransferase 2 gene as a model system, we demonstrate the utility of
      HyBeacon probes for rapid and reliable sequence analysis. We also demonstrate
      that homozygous and heterozygous samples may be accurately identified using a
      single HyBeacon oligonucleotide. Polymorphic DNA sequences were detected and
      differentiated by real-time PCR and melt peak methodologies, without performing
      extraction of genomic DNA prior to target amplification. Employing a combination
      of homogeneous HyBeacon analysis, the rapid thermal cycling conditions of the
      LightCycler and direct amplification from saliva, allowed samples to be genotyped
      within 30 min. Such rapid non-invasive diagnostic technologies may permit 'point
      of-care' genetic testing to be performed in hospitals and doctor's surgeries.

PMID- 12477436
TI  - A PCR-RFLP assay for the distinction between Fasciola hepatica and Fasciola
      gigantica.
AB  - Fascioliasis is of well-known veterinary importance and an increasing human
      health problem, with reported cases in the five continents. The causative agents,
      Fasciola hepatica and Fasciola gigantica, present geographical distributions,
      which overlap in many regions of Africa and Asia, and in which the
      differentiation of both species is usually difficult because of the many
      variations in their morphological characteristics. Moreover, in humans, liver
      fluke classification cannot be achieved by clinical, pathological, coprological
      or immunological methods. The differential diagnosis between F. hepatica and F.
      gigantica infection is very important because of their different transmission and
      epidemiological characteristics. A simple and rapid PCR-restriction fragment
      length polymorphism (RFLP) assay, using the common restriction enzymes Ava II and
      Dra II, is described to distinguish between both fasciolid species. It is based
      on a 618-bp-long sequence of the 28S rRNA gene recently obtained from liver fluke
      populations of South America, Europe and Africa. This sequence showed a few
      nucleotide differences between both fasciolids and no intraspecific variations
      within each species. This assay provides unambiguous results and may be useful
      for both individual subject diagnosis and epidemiological surveys of humans and
      animals in endemic regions of sympatry.

PMID- 12477437
TI  - Two methods for construction of internal amplification controls for the detection
      of Escherichia coli O157 by polymerase chain reaction.
AB  - For the detection of food born bacteria by polymerase chain reaction (PCR) in
      food products, an internal amplification control (IAC) is required in order to
      prevent false negative results that might be caused by PCR inhibitors. In the
      present study, two IACs were constructed using two different methods. These IACs
      were designed in a way that the same primer pair can be used to amplify the
      target DNA and coamplify the IAC. The first IAC with a size of approximately 200
      bp was constructed by deleting a part of the amplicon of the original target DNA
      (500 bp) between the two primer sites to produce an IAC smaller than the target
      DNA. The second IAC with a size of approximately 600 bp was synthesized in a one
      step PCR reaction. The primers used in this reaction possessed 5' over-hanging
      ends, which were identical to the primers used in the diagnostic reaction,
      whereas their 3' ends were complementary to the (pUC19) predetermined DNA
      sequence of defined length and sequence. The concentration of IACs appeared to be
      critical. Too much IAC DNA template would out-compete the target DNA template,
      thus giving a false negative result. However the use of an optimal IAC
      concentration increased the reliability of the PCR assays and appeared to be
      useful for food diagnostics.

PMID- 12477438
TI  - Development of a membrane-array method for the detection of human intestinal
      bacteria in fecal samples.
AB  - A membrane-array method was developed for the detection of human intestinal
      bacteria in fecal samples without using the expensive microarray-arrayer and
      laser-scanner. The 16S rDNA sequences of 20 predominant human intestinal
      bacterial species were used to design oligonucleotide probes. Three 40-mer
      oligonucleotides specific for each bacterial species (total 60 probes) were
      synthesized and applied to nitrocellulose membranes. Digoxigenin (DIG)-labeled
      16S rDNAs were amplified by polymerase chain reaction (PCR) from human fecal
      samples or pure cultured bacteria using two universal primers, and were
      hybridized to the membrane-array. Hybridization signals were read by NBT/BCIP
      color development. The 20 intestinal bacterial species tested were Bacteroides
      thetaiotaomicron, B. vulgatus, B. fragilis, B. distasonis, Clostridium
      clostridiiforme, C. leptum, Fusobacterium prausnitzii, Peptostreptococcus
      productus, Ruminococcus obeum, R. bromii, R. callidus, R. albus, Bifidobacterium
      longum, B. adolescentis, B. infantis, Eubacterium biforme, E. aerofaciens,
      Lactobacillus acidophilus,Escherichia coli, and Enterococcus faecium. The two
      universal primers were able to amplify full size 16S rDNA from all of the 20
      bacterial species tested. The hybridization results indicated that the membrane
      array method is a reliable technique for the detection of predominant human
      intestinal bacteria in the fecal samples. The result was also confirmed by using
      specific PCR methods for these bacteria.

PMID- 12477439
TI  - Sensitivity of multiplex real-time PCR reactions, using the LightCycler and the
      ABI PRISM 7700 Sequence Detection System, is dependent on the concentration of
      the DNA polymerase.
AB  - The introduction of multiplex PCR techniques to clinical laboratories has
      provided a means to streamline assays and to produce multiple results with
      minimal effort. While this methodology is very beneficial, care must be taken to
      ensure that reactions are properly optimized to allow for maximum sensitivity.
      This study was conducted to determine whether the sensitivity of multiplex-real
      time PCR assays could be improved by increasing the concentration of DNA
      polymerase within a reaction. Multiplex reactions were designed to simultaneously
      detect the human HLA-DQ gene and a sequence from the UL83 region of the CMV
      genome. Two real-time PCR systems, one utilizing AmpliTaq Gold DNA polymerase and
      the ABI 7700 Sequence Detection System, and one utilizing FastStart Taq DNA
      polymerase and the Roche LightCycler were tested. The results indicated that
      increasing the AmpliTaq Gold concentration from 0.050 to 0.10 U/microl and the
      FastStart Taq concentration from 0.1875 to 0.375 U/microl increased detection
      sensitivity from 5,000 to 50 CMV copies per PCR reaction. In separate
      experiments, commercially prepared mastermixes were utilized for both real-time
      PCR platforms as per the manufacturer's suggestions or with the addition of
      supplemental DNA polymerase. In assays designed to detect 4 CMV genome copies per
      reaction, the addition of 2.5 U of AmpliTaq Gold to TaqMan Universal Mastermix
      increased the detection rate from 21 to 67%, and the addition of 5 U of FastStart
      Taq to FastStart DNA Master Hybridization Probes mastermix increased the
      detection rate from 17 to 56%. These results indicate that increasing the DNA
      polymerase concentration in multiplex real-time PCR reactions may be a simple way
      to optimize assay sensitivity.

PMID- 12477440
TI  - Rapid PCR using nested primers of the 16S rRNA and the hippuricase (hip O) genes
      to detect Campylobacter jejuni and Campylobacter coli in environmental samples.
AB  - Identification of sources Campylobacter infection in the poultry houses is in
      general problematic due to the lack of reliable methods to detect campylobacteria
      in environmental samples. Detection of campylobacteria in environmental samples
      by conventional culture methods is difficult and of limited sensitivity due to
      the use of selective media, the low number of bacteria in the samples and
      possibly also due to the presence of non-culturable or sub-lethally injured
      stages of the bacteria. The present paper describes a rapid PCR assay using
      nested primers of the 16S rRNA or the hippuricase (hip O) genes to detect
      Campylobacter jejuni and Campylobacter coli in environmental samples. The
      sensitivity of the nested PCR was determined to be 0.01 pg/PCR, corresponding to
      2-3 colony forming units (cfu) per ml. The nested PCR assays were applied to
      detect C. jejuni and C. coli in 269 environmental samples collected from ten
      broiler farms. The sensitivity, specificity and the usefulness of the PCR assay
      for detection of C. jejuni and C. coli in environmental samples are presented and
      discussed.

PMID- 12477441
TI  - Virulence typing of Escherichia coli using microarrays.
AB  - We describe a microarray based broad-range screening technique for Escherichia
      coli virulence typing. Gene probes were amplified by PCR from a plasmid bank of
      characterised E. coli virulence genes and were spotted onto a glass slide to form
      an array of capture probes. Genomic DNA from E. coli strains which were to be
      tested for the presence of these virulence gene sequences was labelled with
      fluorescent cyanine dyes by random amplification and then hybridised against the
      array of probes. The hybridisation, washing and data analysis conditions were
      optimised for glass slides, and the applicability of the method for identifying
      the presence of the virulence genes was determined using reference strains and
      clinical isolates. It was found to be a sensitive screening method for detecting
      virulence genes, and a powerful tool for determining the pathotype of E. coli. It
      will be possible to expand and automate this microarray technique to make it
      suitable for rapid and reliable diagnostic screening of bacterial isolates.

PMID- 12477442
TI  - Reduced amplification efficiency of KIAA0027/MLC1 alleles: implications for the
      molecular diagnosis of megalencephalic leukoencephalopathy with subcortical
      cysts.
AB  - Autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts
      (MLC) is a rare childhood-onset spongiform leukodystrophy with macrocephaly and
      slowly progressive deterioration of motor functions. Mutations in KIAA0027/MLC1
      have recently been found associated with MLC, and a high degree of allelic
      heterogeneity has been observed. In addition, initial reports suggested that a
      rare variant in exon 11 (L309M) is involved in the etiology of schizophrenia, but
      recent studies have brought forward compelling arguments that genetic variants of
      MLC1 are not associated with schizophrenia. Using DHPLC-analysis, reproduction of
      previous findings on L309M revealed homoduplex resolution patterns among
      individuals, who had been described to be heterozygous for the variant, which was
      further confirmed by sequencing the respective PCR products. Cumulative effects
      of high GC content, secondary folding structures due to incomplete intronic
      tandem-repeats, and a complicated insertion polymorphism at the 3-end of exon 11
      may be the cause of preferential amplification of specific alleles of exon 11.
      Consistent amplification was obtained only when we employed exonic primers
      directly adjacent to the L309M variant. For mutational screening, we propose a
      two-step test: (1) testing for the 33 bp insertion polymorphism of exon 11, and
      (2) amplification of the exon using different primer sets depending on the
      presence or absence of the insertion.

PMID- 12477443
TI  - Real-time quantitative PCR for the detection of Streptococcus pneumoniae in the
      middle ear fluid of children with acute otitis media.
AB  - PCR based on the amplification of pneumolysin gene fragments has previously been
      applied to demonstrate Streptococcus pneumoniae in clinical specimens. Here, a
      real-time PCR method for the detection and quantification of pneumococci by
      amplifying a 206-bp fragment of the pneumolysin-encoding gene is described. The
      amplified fragments were detected simultaneously using fluorescent-labeled
      sequence-specific hybridization probes. The applicability of the assay to
      clinical samples was evaluated by studying 50 middle ear fluid (MEF) specimens
      from children with acute otitis media. Twenty-six of the MEF samples were
      positive by real-time PCR and the numbers of genome equivalents detected varied
      from 90 to 88,000/microl in 17 culture-positive samples and from 1 to
      1,200/microl in 9 culture-negative samples. The results were compared to culture
      findings and to results obtained by using agarose gel electrophoresis or Europium
      labeled hybridization probes for the detection of amplification products of
      conventional PCR. The sensitivity and specificity of the real-time PCR assay
      developed in the present study compared to culture were 100 and 73%, and to
      conventional PCR with agarose gel and/or TRF detection 93 and 96%, respectively.
      The real-time PCR assay was found to be rapid, easy to use, and sensitive in
      detecting and quantifying pneumococci.

PMID- 12477444
TI  - A new polymorphism in the flanking region of human VAMP2 and hPer1 genes.

PMID- 12477445
TI  - The benefit of lymph node debulking in metastatic cervical cancer: a research
      bias or an actual effect?

PMID- 12477446
TI  - Is there a role for pelvic lymph node debulking in advanced cervical cancer?
AB  - OBJECTIVE: The purpose of this study is to determine if a survival advantage
      exists from surgical debulking of enlarged pelvic lymph nodes in advanced
      cervical cancer. METHODS: Using information from studies published on the topic
      of debulking lymph nodes in locally advanced cervical cancer along with baseline
      control rates of standard treatment and patterns of failure, an estimate of how
      many patients with bulky pelvic lymph node disease would benefit from this
      procedure was calculated. The design and feasibility of a randomized trial to
      test this intervention is also discussed. RESULTS: Based on our calculations 1,
      2, and 4% of stage IB, IIB, and IIIB patients, respectively, would benefit from a
      debulking procedure. Based on our calculations with such small differences in
      survival along with other inclusion and exclusion criteria, a randomized trial,
      which would compare chemoradiation to chemoradiation and surgery, would require
      anywhere from 10,000-30,000 patients per arm. CONCLUSIONS: A very small fraction
      of patients would benefit from a surgical debulking procedure of pelvic nodes. A
      randomized controlled trial to test this research question is not feasible. A
      subset population is identified which may benefit from a debulking approach.

PMID- 12477447
TI  - A phase I study of weekly topotecan and Paclitaxel in previously treated
      epithelial ovarian carcinoma patients.
AB  - OBJECTIVE: We have previously reported on the feasibility of weekly topotecan as
      single-agent therapy in previously treated patients with ovarian cancer. The
      objective of this study was to assess the maximum tolerated dose (MTD) of weekly
      bolus intravenous (IV) topotecan combined with weekly paclitaxel in a comparable
      patient population. METHODS: Previously treated ovarian cancer patients with
      measurable disease and/or elevated cancer antigen 125 (CA-125) received (as
      second-line or third-line therapy) weekly 30-min bolus IV topotecan starting at 2
      mg/m(2) combined with weekly paclitaxel starting at a dose of 60 mg/m(2). In this
      intrapatient dose-escalation study, topotecan and paclitaxel were escalated in
      parallel until the MTD was reached, defined as the first dose level at which >or=
      2 of 6 patients experienced dose-limiting toxicity. RESULTS: Twenty-one of 26
      patients were evaluable for toxicity and received a total of 306 weeks of therapy
      (median, 13 weeks; range, 5 to 33 weeks). No significant dose-limiting toxicity
      was observed up to a weekly bolus IV topotecan dose of 3 mg/m(2) and a concurrent
      paclitaxel dose of 80 mg/m(2). The MTD was topotecan 3.5 mg/m(2) plus 90 mg/m(2)
      paclitaxel. The dose-limiting toxicities included anemia and fatigue, with 10 of
      21 patients receiving epoetin alfa for grade 3 or 4 anemia; only 1 patient
      required a blood transfusion. Two patients had a treatment delay of at least 1
      week and only 1 patient required a dose reduction to maintain the weekly
      schedule. CONCLUSIONS: Based on the results of this study, the recommended
      initial dose for this novel regimen is topotecan 3 mg/m(2) and paclitaxel 80
      mg/m(2). Further investigation of the efficacy of weekly topotecan plus
      paclitaxel in less heavily pretreated patients is warranted.

PMID- 12477448
TI  - Quality of life after treatment for gynecologic malignancies: a pilot study in an
      outpatient clinic.
AB  - OBJECTIVE: The objective of this study was to determine the health-related
      quality of life (QOL) of disease-free patients after therapy for gynecologic
      malignancies at follow-up in an outpatient clinic. METHODS: Eighty-five patients
      (P) completed the general Functional Assessment of Cancer Therapy (FACT-G) QOL
      questionnaire at least 6 months after treatment for a gynecologic malignancy.
      Responses were compared to 42 unmatched healthy women (H) who were seen for
      standard gynecologic screening exams. Statistical evaluation was done using t
      tests, chi(2),and Wilcoxon rank-sum tests, Spearman rank correlations, and linear
      regression. RESULTS: The demographic data for the groups were as follows: median
      age P, 59 years; H, 56 years; Caucasian P, 51%; H, 56%, African American P, 49%;
      H, 44%, cervix cancer (n = 51, 60%), uterine cancer (n = 24, 28%), ovarian cancer
      (n = 10, 12%). The median time since therapy was 39 months (range 6-149 months).
      There were no overall differences in FACT-G scores of patients and healthy women.
      Cancer survivors scored slightly higher on the emotional well-being subscale
      (mean 20.4 vs 19.2). Among cancer patients, all scores were lowest in patients
      with ovarian cancer. Longer treatment time was associated with a lower physical
      well-being. Older patients scored higher on emotional well-being, but lower on
      social/family well-being. Poor education and no help at home were associated with
      lower functional well-being and total FACT scores. Linear regression analysis
      revealed significantly lower total QOL scores in patients with the following
      characteristics: ovarian cancer diagnosis, treatment with radiation therapy or
      multi-modality therapy, less than high school education, and lack of help at
      home. CONCLUSION: Overall the recovery from treatment for gynecological cancer is
      good. Patients with ovarian cancer, prolonged therapy, poor education, and little
      social support have the most significant impairments in health-related quality of
      life and need additional support resources.

PMID- 12477449
TI  - Management of invasive carcinoma of the uterine cervix associated with pregnancy:
      outcome of intentional delay in treatment.
AB  - OBJECTIVE: To investigate patients with invasive cervical carcinoma associated
      with pregnancy, with special reference to the maternal and neonatal outcomes
      after planned treatment delay to improve fetal maturity. METHODS: The medical
      records of 28 patients with invasive cervical carcinoma diagnosed during
      pregnancy or within 1 month after pregnancy were retrospectively reviewed.
      RESULTS: Twenty-two patients (79%) had Stage I disease and 6 (21%) had Stage II
      or III disease. Tumor histology revealed squamous cell carcinoma in 27 cases and
      adenocarcinoma in 1. Twenty cases were diagnosed before 22 weeks gestation, 4
      between 22 and 36 weeks, 1 after 36 weeks gestation, and 3 were diagnosed
      postpartum. In the immediate treatment group (n = 16), the diseases were Stage IA
      in 3 cases, IB in 7, and II or III in 6. In 11 patients, hysterectomy was
      performed after therapeutic abortion or with fetus in situ. In 2 patients,
      cesarean section was followed by hysterectomy or radiotherapy. Three patients
      diagnosed postpartum were treated with either hysterectomy or radiotherapy.
      Fifteen patients were free of disease during the follow-up of 27 to 114 months.
      In the delayed treatment group (n = 12), the diseases were Stage IA1 in 8 cases,
      IA2 in 1, IB1 in 2, and IB2 in 1 case. In 8 patients with Stage IA1 tumor, the
      treatment was deferred until term with a delay of 6 to 25 weeks, and hysterectomy
      or therapeutic conization was performed after delivery. In 4 patients with Stage
      IA2, IB1 or IB2 tumor, the treatment was postponed until after 30 weeks gestation
      with a delay of 6 to 15 weeks. No disease progression was documented. Cesarean
      delivery was followed by hysterectomy in these patients. All patients were free
      from disease during the follow-up of 70 to 156 months and their babies were well
      with no sequelae. CONCLUSION: Delay in treatment to allow for fetal maturity is
      safe in patients with early Stage I cervical carcinoma associated with pregnancy.

PMID- 12477450
TI  - Role of hysterectomy in management of gestational trophoblastic disease.
AB  - OBJECTIVE: To evaluate incidence, indications, and outcome of hysterectomy in
      women presenting with gestational trophoblastic disease. METHODS: A prospective
      observational study using a standardized protocol for registration, assessment,
      and treatment of gestational trophoblastic disease. A total of 5976 consecutive
      new patients registered between January 1986 and December 2000 with a diagnosis
      of gestational trophoblastic disease. The setting was a supraregional tertiary
      referral center for gestational trophoblastic disease. RESULTS: Between January 1
      1986 and December 31 2000, 5976 new patients with a diagnosis of gestational
      trophoblastic disease were registered at Weston Park Hospital, Sheffield. Of
      these patients, 301 required chemotherapy. Forty patients underwent hysterectomy.
      The average pretreatment risk score in women who had hysterectomy was 7.4. The
      mean time interval between diagnosis of molar disease and hysterectomy was 17
      months. Indications for hysterectomy included uncontrollable vaginal or
      intraabdominal bleeding, localized chemo-resistant disease, and placental site
      trophoblastic tumor. In this group, 31 of 40 women had chemotherapy and 14
      patients needed more than one regimen. These women were also more likely to have
      atypical histology (3 invasive moles, 6 placental site trophoblastic tumours, 13
      choriocarcinomas, and 2 dimorphic tumours). There were 10 deaths in all
      registered patients with molar disease and 4 of these were in the hysterectomy
      group. CONCLUSION: Hysterectomy was performed in 1 in 150 northern UK women with
      gestational trophoblastic disease. Patients needing hysterectomy represent an
      increased-risk group as indicated by their high pretreatment risk scores,
      atypical histology, frequent use of salvage chemotherapy, and higher mortality.

PMID- 12477451
TI  - Development of an in vitro chemo-radiation response assay for cervical carcinoma.
AB  - PURPOSE: To determine if synergistic effects of radiation (RT) and chemotherapy
      (chemo) on human cervical carcinoma cell lines and fresh tumor explants could be
      determined using an in vitro assay. EXPERIMENTAL DESIGN: In vitro radiation
      response was determined for 4 cell lines and 26 fresh tumor explants in an agar
      based assay. Cells were exposed to increasing doses of RT with or without
      cisplatin (CDDP), carmustine (BCNU), buthionine sulfoximine (BSO), or paclitaxel
      (Tax). Cell suspensions were cultured for 5 days, with [(3)H]thymidine added on
      day 3 and proliferation was measured. Results were reported as the fraction of
      proliferation compared to control (FC). For each combination of irradiation and
      drug, synergy was tested using the Chou analysis, where a combination index (CI)
      <1 indicated synergistic interaction. In simple correlation analysis, an R value
      of >0.7 indicated cross-resistance. RESULTS: RT dose-dependent proliferation
      inhibition was observed for 2 of the 4 cell lines, and for all but 1 of the fresh
      specimens. Significant heterogeneity of tumor response to RT was seen. Four
      specimens that were 1 standard deviation below the median FC response after
      exposure to 300 cGy were classified as extremely radiation resistant. Twenty-one
      tumors were evaluated for synergistic response using the combination of chemo and
      RT with a median FC of 0.27 (+/-0.27) for 6.0 Gy of RT alone, 0.22 (+/-0.21) for
      CDDP alone, and 0.05 (+/-0.08) for the combination. A CI of 0.35 and an R value
      of 0.09 demonstrated synergy between chemo and RT without cross-resistance.
      Similar synergy without cross-resistance was found for RT in combination with
      BCNU, BSO, and TAX. CONCLUSIONS: Heterogeneous RT dose-response relationships in
      the in vitro assay were demonstrated. Explants were more sensitive to RT than
      cell lines. Unlike cell lines, fresh tumor cells consistently displayed synergy
      with RT and chemo. The synergy between RT and BSO suggests that glutathione
      depletion may enhance the effect of RT. The assay was feasible for examining
      fresh tumors and may be an important tool for studying RT or drug resistance.
      Clinical trials to evaluate this assay are indicated.

PMID- 12477452
TI  - A human ovarian carcinoma murine xenograft model useful for preclinical trials.
AB  - OBJECTIVE: To establish a murine xenograft model of human ovarian carcinoma.
      METHODS: A slurry of fresh human tumor from patients with intraperitoneal
      malignancies was heterotransplanted intraperitoneally into nude (nu/nu) and
      severely combined immunodeficient mice (CB-17, SCID). Xenograft growth was
      assessed by serial examination and necropsy. The xenografts were passaged to new
      animals when tumors were palpably greater than 1 cm(3). Histopathologic analysis
      of the xenografts was performed at each passage as well as immunohistochemical
      staining for p53 mutations. Persistent expression of human genes by the
      xenografts at higher passages was assessed by RT-PCR amplification of the human
      beta-globin gene. This xenograft model was used in the preclinical evaluation of
      an adenoviral vector containing a beta-galactosidase reporter gene and a wild
      type p53 gene. RESULTS: Tumor growth was not established in any of the nude mice
      heterotransplanted with tissue from six different ovarian cancer patients. Eleven
      of 13 specimens established xenograft growth when injected in SCID mice. Nine
      xenografts have been subsequently passaged between 6 and 24 animal generations to
      date. All xenografts retained histopathologic similarities to their original
      human tumors and the p53 expression patterns remained stable through higher
      passages. Within 24 h after intraperitoneal administration of an adenoviral
      vector, transduction of the reporter gene was evident in the xenografts. In
      addition, administration of an adenoviral vector containing a wild-type p53 gene
      significantly decreased the tumor burden compared to controls (P < 0.04).
      CONCLUSIONS: This murine xenograft model of human ovarian carcinoma appears to be
      reliable and reproducible and has utility for the study of novel therapeutics.

PMID- 12477453
TI  - Vulvar carcinoma presenting during pregnancy, associated with recurrent bone
      marrow hypoplasia: a case report and literature review.
AB  - BACKGROUND: Carcinoma of the vulva has predominantly been a disease of the
      elderly. Although occasionally it occurs in women under the age of 40 years,
      carcinoma of the vulva has been rarely diagnosed in pregnancy. Bone marrow
      hypoplasia can occur as a transient, pregnancy-related event; however, the
      recurrence of this pathology in future pregnancies is quite rare in the
      literature. CASE: A 29-year-old woman in her second pregnancy that was
      complicated by bone marrow hypoplasia had developed a squamous vulvar carcinoma.
      Each of these two conditions are quite rare in pregnancy, they may have occurred
      by chance, but there is a hypothetical possibility that bone marrow hypoplasia is
      an autoimmune disorder, with vulvar carcinoma occurring as a further complication
      in this immunoimpaired individual. CONCLUSION: This case also emphasizes the need
      to consider malignancy as a differential diagnosis in vulvar ulcers occurring in
      young women.

PMID- 12477454
TI  - Stage IV carcinoma of the Bartholin gland managed with primary chemoradiation.
AB  - BACKGROUND: Optimal management of carcinoma of the Bartholin gland is not yet
      defined. Patients with locally advanced disease have historically been managed by
      radical and, occasionally, exenterative surgery. Although the management of
      advanced vulvar cancer has shifted toward conservative management with primary
      chemoradiation, there is limited information on the similar approach to the
      management of advanced Bartholin's gland carcinoma. CASE: We present a woman with
      stage IVA basaloid squamous carcinoma of the Bartholin gland. She was managed
      with primary chemoradiation in an attempt to spare her the morbidity associated
      with exenterative surgery. We discuss a rationale for the use of chemoradiation
      in advanced Bartholin's gland carcinoma. CONCLUSION: Conservative management of
      advanced carcinoma of the Bartholin gland with primary chemoradiation may be
      appropriate while sparing patients the sequelae of exenterative surgery.

PMID- 12477455
TI  - Malignant Struma Ovarii: an autopsy report of a clinically unsuspected tumor.
AB  - BACKGROUND: Struma Ovarii represents less than 3% of ovarian teratomas. The
      malignant counterpart is very rare. CASE: A 67-year-old female with ascites and
      progressive weight loss died of respiratory failure secondary to severe chronic
      obstructive pulmonary disease. Autopsy revealed ascites, hepatic cirrhosis,
      emphysema, and bronchiectasis. As an incidental finding was seen a huge tumor (10
      x 9.5 x 6 cm) in the left ovary. Multiple nodules were detected in the lungs. The
      thyroid was normal. Microscopy revealed a follicular variant of papillary
      carcinoma arising in ectopic thyroid tissue in the ovary with metastasis to lungs
      and pleura. The thyroid gland tissue was normal. CONCLUSION: To our knowledge,
      this is the first autopsy report of a clinically unsuspected malignant Struma
      Ovarii.

PMID- 12477456
TI  - Endometrial adenocarcinoma following the insertion of a Mirena IUCD.
AB  - BACKGROUND: The case histories of two patients who developed endometrial
      adenocarcinoma with a Mirena intrauterine system (IUS) in place are reported.
      CASE: Two patients had a Mirena IUS inserted to treat abnormal vaginal bleeding.
      After 12 and 36 months with the device in place they presented with a recurrence
      of their heavy, irregular menstrual bleeding. Endometrial biopsies confirmed the
      presence of endometrial adenocarcinoma, and hysterectomies were performed. In one
      patient the cancer was localized and below the stem of the device, in the other
      metastatic disease had developed. CONCLUSION: These cases raises important issues
      regarding the use of the Mirena IUS to treat menorrhagia.

PMID- 12477457
TI  - Epithelioid trophoblastic tumor of the endocervix: a case report.
AB  - BACKGROUND: It is difficult to recognize epithelioid trophoblastic tumor (ETT) as
      a trophoblastic disease because of its rarity and growth pattern simulating a
      carcinoma. CASE REPORT: A 36-year-old woman with stage IB(1) squamous cell
      carcinoma of the uterine cervix and a high serum beta-human chorionic
      gonadotropin (beta-hCG) level underwent radical hysterectomy with pelvic and para
      aortic lymphadenectomy. However, light microscopic findings and
      immunohistochemical studies with pan-cytokeratin, epithelial membrane antigen,
      inhibin-alpha, beta-hCG, and human placental lactogen revealed ETT of the
      endocervix. The patient is alive with no evidence of disease 12 months after
      surgery. CONCLUSION: Before the patient is resorted to radical surgical
      interventions for assumed cervical carcinoma, ETT should be ruled out in women of
      reproductive age with endocervical tumors and elevated serum beta-hCG levels.

PMID- 12477458
TI  - Pneumocystis carinii pneumonia in a patient with stage IV ovarian cancer.
AB  - BACKGROUND: Immunocompromised persons are considered to be at risk of developing
      Pneumocystis carinii pneumonia, although the incidence of this condition is much
      lower compared to the human immunodeficiency virus-positive group. It is
      important to identify specific individuals at high clinical risk to guide the
      chemoprophylaxis of P. carinii pneumonia. CASE: A 42-year-old female with stage
      IV ovarian cancer developed P. carinii pneumonia during radiotherapy for brain
      metastasis while receiving 7 weeks of prednisolone. Four weeks before the
      diagnosis, her lymphocyte count dropped to 350/microl. She was treated with
      pentamidine followed by trimethoprim-sulfamethoxazole with the support of
      mechanical ventilation. The patient could then be weaned from mechanical
      ventilatory support. However, she was not able to receive any additional therapy
      for her ovarian cancer. CONCLUSION: Cancer patients who receive corticosteroids
      during chemotherapy or radiation therapy are at risk of developing P. carinii
      pneumonia and should receive P. carinii pneumonia prophylaxis.

PMID- 12477459
TI  - Arterial thrombosis in a gynecologic oncology patient: evaluation and management.
AB  - BACKGROUND: Arterial thrombosis is an extremely rare complication in gynecologic
      oncology with only two cases previously reported in the literature. Presentation,
      evaluation, and treatment varied considerably in all previous reports of arterial
      thrombosis associated with any malignancy. CASE: We report a case of
      discontinuous arterial thrombosis in the upper extremity of a patient with
      fallopian tube cancer. Her initial evaluation, done in the acute setting of the
      thrombosis, revealed multiple thrombophilia abnormalities, including an elevated
      Factor VIII, and a borderline positive lupus anticoagulant. Follow-up studies
      over 2 years showed resolution of all coagulation abnormalities, thus indicating
      no genetic propensity for thrombosis. CONCLUSION: This case highlights the need
      for appropriate timing of the initial laboratory studies and follow-up so that
      patients can be managed appropriately.

PMID- 12477460
TI  - Ovarian endometrioid adenocarcinoma arising from an endometriotic cyst in a
      postmenopausal woman under tamoxifen therapy for breast cancer: a case report.
AB  - BACKGROUND: Ovarian cancer arising from an endometriotic cyst in a postmenopausal
      woman under tamoxifen therapy is rare. CASE: We herein report the case of a 67
      year-old woman with a history of breast cancer, taking tamoxifen citrate 20
      mg/day for 4 years, who underwent an operation for left ovarian tumor. The
      postoperative histological diagnosis was endometrioid adenocarcinoma in an
      endometriotic cyst with a gradual transition of the degree of cellular atypia
      noted from typical endometriotic epithelium, to atypical endometriosis, and
      finally to adenocarcinoma. CONCLUSION: Tamoxifen may cause malignant
      transformation of endometriosis through atypical endometriosis even in the
      postmenopausal state. Atypical endometriosis may act as a precancerous lesion in
      the process of tamoxifen-induced malignant transformation of endometriosis.

PMID- 12477462
TI  - A survey of blood lead levels among young Johannesburg school children.
AB  - Studies conducted around the world have established beyond doubt that elevated
      childhood blood lead levels may lead to detrimental health effects. Research has
      shown that certain groups of South African children are at particular risk of
      elevated blood lead levels. Johannesburg is the largest urban complex in southern
      Africa, with a population of around 3 million and extensive industrial and
      manufacturing activity. Among the challenges posed in the city are rapid
      urbanization, extensive poverty, and inequity. Little information on the blood
      lead distribution of Johannesburg children is available. This study was
      undertaken to determine blood lead levels among children living in three areas of
      Johannesburg: inner city suburbs and the low-income townships of Alexandra and
      Westbury to the north and west of the city center, respectively. The results
      indicated that blood lead levels ranged from 6 to 26 micro g/dL, with a mean
      level of 11.9 micro g /dL. The blood lead levels of 78% of children equaled or
      exceeded 10 micro g/dL, the current international action level. Maternal
      educational status, the presence of smokers in the home, and living in an
      informal dwelling were among the factors associated with elevated blood lead
      levels.

PMID- 12477463
TI  - Declining risk of methylmercury exposure to infants during lactation.
AB  - Methylmercury (MeHg) can be transferred to infants through milk, in addition to
      passage through the placenta during intrauterine life. The higher MeHg
      accumulation and susceptibility to toxicity in the fetus than in the mother
      during the gestation period is well known. However, the contribution of Hg
      exposure through breast milk to the MeHg concentration in infants is not clear.
      Our objective in this study was to examine the changes in MeHg levels in infants
      who were reared on breast milk to evaluate the risks between fetal and breast
      feeding periods based on Hg concentrations in red blood cells (RBCs-Hg). RBCs-Hg
      and plasma-Hg concentrations (Plasma-Hg) in seven pairs of maternal and infant
      blood samples were compared at birth and 3 months after parturition. RBCs to
      Plasma-Hg ratio was approximately 8:1 for mothers at parturition and after 3
      months, suggesting that their Hg source is MeHg from consumed fish as is general
      in Japanese. In all seven cases, RBCs-Hg in the umbilical cords were higher than
      those in the mothers at parturition. The geometric mean of RBCs-Hg in umbilical
      cords (10.6ng/g) was about 1.4 times higher than that in the mothers (7.1ng/g).
      There was a strong correlation in RBCs-Hg in mothers and umbilical cords.
      However, all the infants showed declines in Hg concentrations throughout the
      breast-feeding period. The geometric mean RBCs-Hg at 3 months of age was 5.8ng/g,
      accounting for 54% of that in the umbilical cords. Consequently, maternal RBCs-Hg
      surpassed that of infants at 3 months, opposite to the situation at parturition.
      The decline in infant RBCs-Hg during the breast-feeding period can be explained
      by the low Hg transfer through breast milk and the rapid growth of infants after
      birth. The geometric mean Milk-Hg was low (0.21ng/g), around 20% of that in
      maternal Plasma-Hg. The average body weight of infants at 3 months increased to
      about 1.9 times of that at birth. Thus, offspring are subjected to MeHg exposure
      through both the gestation and the breast-feeding periods; the risk is especially
      high during gestation but may decrease during breast-feeding.

PMID- 12477464
TI  - In vitro vs in vivo Pb effects on brain protein kinase C activity.
AB  - Alteration of normal protein kinase C (PKC) function by environmental Pb exposure
      during neurodevelopment is hypothesized to be an important mechanism of toxicity
      underlying neurologic impairment. Previous studies have reported widely varying
      effects of Pb on PKC, possibly in part because of differences in in vitro and in
      vivo models used in those studies. Therefore, we tested the hypothesis that, with
      comparable tissue Pb levels, the effects of in vitro Pb exposure on brain PKC are
      the same as the effects caused by in vivo Pb exposure of intact animals. For
      chronic in vivo Pb exposure, female Long-Evans rats were exposed to Pb or vehicle
      from postnatal days 1 to 34-36 (n=10/treatment). For in vitro Pb exposure,
      homogenate of the frontal cortex region was exposed directly to Pb in an amount
      comparable to that accumulated in brain during chronic in vivo Pb exposure. Brain
      Pb levels were measured using ultraclean techniques and inductively coupled
      plasma mass spectrometry. PKC activity was subsequently determined in cytosolic
      and membrane subcellular fractions in the frontal cortex, hippocampus, and
      remaining brain regions. Results indicate that brain Pb levels following in vivo
      Pb exposure were increased approximately 20-fold above those of nonexposed
      animals (vehicle group [Pb] approximately 130ng Pb/g dry wt.). However, in vivo
      Pb exposure did not measurably alter brain PKC activity in the regions tested. In
      contrast, in vitro Pb exposure significantly increased PKC activity by
      approximately 20% in the frontal cortex homogenate membrane subcellular fraction.
      These results indicate that Pb added in vitro caused more dramatic effects than
      those produced by a comparable amount of Pb in the tissue from in vivo exposure.
      While the mechanisms underlying these outcomes are not clear, they suggest that
      in vitro models might not accurately reflect effects of chronic low-level in vivo
      Pb exposure.

PMID- 12477465
TI  - Characterizing and comparing risks of polycyclic aromatic hydrocarbons in a
      Tianjin wastewater-irrigated area.
AB  - A probability risk assessment was conducted to characterize the ecotoxicity of
      three polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene,
      fluoranthene, and phenanthrene, to various species in a wastewater-irrigated area
      of Tianjin, China. The relative risk of these chemicals was investigated using
      joint risk probability distribution curves, which were generated based on the
      distributions of exposure and acute toxicity data. Risk at various exposure
      levels was discussed. The results indicated that among the three PAHs studied,
      the overall risk of phenanthrene was the highest, with that of benzo[a]pyrene the
      lowest, due mainly to their exposure concentrations. For lower exposure levels at
      which the percentage of species affected was less than 20%, the risk associated
      with benzo[a]pyrene was clearly higher than that of the other two chemicals.

PMID- 12477466
TI  - Monitoring of arsenic exposure with speciated urinary inorganic arsenic
      metabolites for ion implanter maintenance engineers.
AB  - For wafer fabrication in the semiconductor industry, maintenance engineers are
      potentially exposed to hazards during their work of disassembling machine
      components for cleanup. One special concern is the presence of arsenic or arsenic
      compounds in the working environment. This study analyzed speciated urinary
      inorganic arsenic metabolites of the maintenance engineers using high-performance
      liquid chromatography-hydride generation atomic absorption spectrometry to study
      the potential arsenic exposure during their maintenance work. In total, from six
      wafer fabrication facilities, 30 maintenance engineers were recruited as the
      exposed group and another 12 office-based engineers served as the control group.
      First morning-voided urine samples of each study subject were collected for 7
      consecutive days. The levels of total urinary inorganic arsenic metabolites for
      the exposed group were 1.7+/-1.4, 1.4+/-1.1, 6.2+/-6.7, 20.2+/-14.1, and 29.5+/
      17.2 micro g/L for As3+, As5+, monomethylarsonic acid, dimethylarsinic acid, and
      total inorganic arsenic, respectively. Both the concentration of
      monomethylarsonic acid and its percentage in total urinary inorganic arsenic
      metabolites showed significantly ascending trends for the control group, for the
      engineers without preventative maintenance work prior to their urine sampling,
      and for the engineers with such work prior to their urine sampling (P<0.05 and
      P<0.0005, respectively). The data also suggested that, at low-level occupational
      arsenic exposure, the concentration of total urinary inorganic arsenic
      metabolites might be misleading due to the confounding effect resulting from
      intake of seafood, such as arsenosuger. Nevertheless, monitoring of urinary
      arsenic species by using the percentage change of monomethylarsonic acid in total
      urinary inorganic arsenic metabolites as an indicator for the verification of
      arsenic exposure is helpful and appropriate in such cases.

PMID- 12477467
TI  - Histopathological evidence of inorganic mercury and methyl mercury toxicity in
      the arctic charr (Salvelinus alpinus).
AB  - In our sustained effort to understand mechanisms of mercury toxicity in fish, the
      histopathological effects of a 96-h acute exposure to water-borne inorganic
      mercury (inorganic Hg) (15 micro gL(-1)), as well as those of a single dietary
      dose of inorganic and methyl mercury (methyl Hg) (0.260.05 micro g.Hgg(-1) body
      weight), over 30 days were examined. Samples of gills, olfactory epithelium,
      kidneys, and liver of arctic charr, Salvelinus alpinus, were studied using light
      and electron microscopy. The distribution of dietary inorganic and methyl Hg in
      the intestinal epithelium was determined using 203Hg microautoradiography. Gills
      of fish exposed to water-borne inorganic Hg presented a severe disorganization of
      epithelial cells after 12h and modifications of cilia of ciliated olfactory cells
      appeared after 24h. Nevertheless, a partial recovery was seen in both tissues by
      the end of the 96-h exposure period. Liver was little affected by water-borne and
      single-trophic-dose contamination of inorganic Hg, but dietary methyl Hg had
      drastic effects, despite its low dosage, with severe necrosis and alterations of
      cytoplasmic organization. Microautoradiograms showed that inorganic Hg was
      distributed evenly in the intestinal epithelium, whereas methyl Hg was found at
      very specific locations on the epithelial surface.

PMID- 12477468
TI  - Metal levels in horseshoe crabs (Limulus polyphemus) from Maine to Florida.
AB  - There is considerable concern for the health of spawning populations of horseshoe
      crabs (Limulus polyphemus) along the east coast of North America because of an
      increase in the harvest, an apparent decrease in population levels, and the
      dependence of migrating shorebirds on a superabundant supply of horseshoe crab
      eggs during their migratory stopover on Delaware Bay. In addition to overfishing,
      population declines could be caused or recovery slowed, by pollution. In this
      paper, we examine the levels of metals (arsenic, cadmium, chromium, lead,
      manganese, mercury, and selenium) in the eggs, leg muscle, and apodeme of 100
      horseshoe crabs collected at nine sites from Maine to Florida. Arsenic levels
      were the highest, followed by manganese and selenium, while levels for the other
      metals averaged below 100ppb for most tissues. Arsenic and mercury levels were
      highest in the leg muscle; cadmium, lead, manganese, and selenium levels were
      highest in eggs; and chromium levels were highest in the apodeme. There were
      significant geographical differences for all metals in all three tissues. No one
      geographical site had the highest levels of more than two metals. Arsenic, with
      the highest levels overall, was highest in Florida in all the three tissues.
      Manganese levels were highest in Massachusetts for eggs and apodeme, but not leg,
      which was highest in Port Jefferson, New York. Selenium was highest in apodeme
      from Florida, and in eggs and leg muscle from Prime Hook, Delaware. The patterns
      among locations and tissues were not as clear for the other metals because the
      levels generally averaged below 100ppb. The levels of contaminants found in
      horseshoe crabs, with the possible exceptions of arsenic in Florida, and mercury
      from Barnegat Bay and Prime Hook, were below those known to cause adverse effects
      in the crabs themselves or in organisms that consume them or their eggs. Our
      results indicate that site-specific data are essential for managers to evaluate
      the potential threat from contaminants to both the horseshoe crabs and those that
      consume them.

PMID- 12477469
TI  - ScienceDirect: our next step in electronic publishing.

PMID- 12477470
TI  - The potential to increase curative liver resection rates in metastatic colorectal
      cancer.

PMID- 12477471
TI  - Smoking as a risk factor for wound healing and infection in breast cancer
      surgery.
AB  - AIM: Clinical studies suggest that smoking is associated with wound necrosis
      after breast cancer surgery. However, the significance of smoking as a risk
      factor for wound infection, skin flap necrosis, and epidermolysis when adjusting
      for other potential risk factors remains to be studied. METHODS: From June 1994
      through August 1996, 425 patients underwent breast cancer surgery as simple
      mastectomy, modified radical mastectomy, or breast conserving surgery. The
      patients were evaluated postoperatively for wound infection, skin flap necrosis,
      and epidermolysis. Association between these complications and 17 patient,
      operative, and postoperative variables were analysed by three separate multiple
      logistic regression analyses. RESULTS: When compared to non-smoking, smoking was
      significantly associated with wound infection after all types of surgery (light
      smoking (1-14 grams per day): [odds ratio (OR)=2.95, 95% confidence interval (95%
      CI)=1.07-8.16], and heavy smoking (>/=15 grams per day): OR=3.46 (1.52-7.85). A
      similar significant association was found as regards skin flap necrosis and
      epidermolysis after simple mastectomy and modified radical mastectomy: both light
      and heavy smoking were predictive for skin flap necrosis: light smoking: OR=6.85
      (1.96-23.90), heavy smoking: OR=9.22 (2.91-29.25) and for epidermolysis: light
      smoking: OR=3.98 (1.52-10.43) and heavy smoking: OR=4.28 (1.81-10.13). No
      significant dose-response relation was disclosed. Other risk factors and
      confounders associated with complicated wound healing were adjusted for in the
      analysis: diabetes, obesity, alcohol, NSAIDs, duration of surgery, and surgical
      experience. CONCLUSION: Independent of other risk factors, smoking is predictive
      for post-mastectomy wound infection, skin flap necrosis, and epidermolysis.

PMID- 12477472
TI  - The effect of patient and tumour characteristics on visualization of sentinel
      nodes after a single intratumoural injection of Tc 99m labelled human albumin
      colloid in breast cancer.
AB  - AIMS: The aim of the study was to study the influence of patient- or tumour
      related factors on the lymphatic drainage patterns in breast cancer. METHODS: The
      study included 290 consecutive breast cancer patients with lymphatic mapping and
      sentinel node biopsy. Lymphoscintigraphy was performed a median of four hours
      after a single intratumoral injection of (99m)Tc labelled human albumin colloid
      with two different particle sizes. RESULTS: Lymphoscintigraphy showed axillary
      sentinel nodes in 253 (87%) and parasternal sentinel nodes in 49 (17%) patients.
      The median number of nodes seen in the axilla was one (range 0-5). No sentinel
      nodes were visualized in 27 (9%) patients. The number of the visualized axillary
      nodes was influenced by the particle size of the radiocolloid, and by metastatic
      involvement of the axillary nodes and the age and body mass index (BMI) of the
      patient. Patients with parasternal sentinel nodes were younger, had a lower BMI
      and had more often a non-palpable tumour. CONCLUSIONS: The age and BMI of the
      patient and the palpability of the tumour influence lymphatic drainage patterns
      in breast cancer. The metastatic involvement of axillary nodes seems to modify
      lymphatic drainage to the axilla.

PMID- 12477473
TI  - Compliance and findings in a Swedish population screened for colorectal cancer
      with sigmoidoscopy.
AB  - AIM: The aim of this study was to evaluate the patterns of compliance and the
      frequency of adenomas and neoplasms in a Swedish population. METHODS: In 1996,
      2000 men and women born in 1935 or 1936 were selected at random from the
      population registers of Uppsala and Malmo/Lund. All subjects were invited by mail
      to participate. In a randomised study design, subjects were either called up by a
      nurse to schedule the appointment for sigmoidoscopy or instructed to call
      themselves. At sigmoidoscopy subjects with a cancer, an adenoma (neoplastic
      polyp) or more than three hyperplastic polyps were scheduled for a complete
      colonoscopy. RESULTS: Thirty-nine percent (770/1988) of all the invited subjects
      had a sigmoidoscopy. The participation differed between the two centres, 47% at
      the Uppsala centre and 30% at the Malmo/Lund centre (P<0.01). There was no
      statistically significant difference between the two different invitation groups.
      In all, 98 subjects (13%) were planned for colonoscopy. Thirty-one (35%) of the
      subjects having a colonoscopy were women and 57 (65%) were men. Fifty-five true
      adenomas were found in 46 subjects. All together, six subjects had proximal
      adenomas. Five adenocarcinomas were diagnosed, all within the reach of the
      sigmoidoscope. CONCLUSIONS: The compliance was lower and the adenomas were fewer
      than expected. To increase compliance it is necessary with rigorously controlled
      invitation routines.

PMID- 12477474
TI  - Detection of melanoma seeding during surgical procedures--an RT-PCR based model.
AB  - AIM: It has long been suggested that malignant cells may be shed into the blood
      stream during any given surgical procedure for cancer. A number of studies have
      now reported the detection of occult melanoma cells in peripheral blood using a
      reverse transcriptase polymerase chain reaction (RT-PCR) based assay. The
      principal aim of these studies has been to determine a prognostic value for the
      test and not to evaluate the influence of intervention upon results. METHODS: In
      this pilot study we aimed to determine whether the assay could be used as a model
      to detect cells that are seeded during surgery. Peripheral blood samples were
      obtained pre- and post-operatively on twenty patients undergoing surgery for
      malignant melanoma - ten with primary disease and ten undergoing regional
      lymphadenectomy. A further ten patients undergoing surgery for non-melanoma
      conditions provided controls. RESULTS: Using RT-PCR, it was possible to identify
      tyrosinase transcripts in the peripheral blood of one of ten patients undergoing
      excision of local disease and four of ten undergoing surgery for regional
      metastatic disease. CONCLUSION: It was concluded that this technique does enable
      detection of a greater percentage of RT-PCR findings post-operatively. This in
      turn may provide a means for optimizing or comparing surgical techniques and
      provides a potential guide in the use of adjuvant therapies.

PMID- 12477475
TI  - Clinical behaviour of malignant transforming oral lichen planus.
AB  - AIMS: At present oral lichen planus (OLP) is classified among precancerous
      conditions but very few data are available in literature regarding prognosis of
      OLP-related cancers. The aim of this paper is to evaluate clinical long-term
      behaviour of OLP-related oral squamous cell carcinomas (OSCCs). METHODS: Clinical
      history and data from follow-up regarding 21 patients undergoing malignant
      transformation of OLP have been critically revised. RESULTS: In a mean time of
      2.6 years from diagnosis of OLP, patients developed OSCCs. Histopathologically,
      two carinomas showed a moderate degree of differentiation, while the others were
      well differentiated. Six (28.5%) were in situ OSCC, in eight (30%) was found a
      microinvasive pattern of infiltration, one was a stage II tumour and the
      remaining (6 cases) were stage I tumours. During follow up, four patients (19%)
      have developed another OSCC in a mean time of 11 months from the first
      occurrence. In two men (10% of cases), multiple OSCCs occurred and in five cases
      (24%) lymph nodal metastases were detected. CONCLUSIONS: Our study points out an
      alarming tendency in developing second primary metachronous tumours (33.3%) of
      the oral cavity and nodal metastases (23.8%), especially if we consider their
      early stages. Thus we always recommend a strict follow-up of OLP patients with
      clinical oral and neck examination every 2 months for 6-9 months since OSCC
      diagnosis is made and, after, three times a year.

PMID- 12477476
TI  - The prognostic significance of gastric juice CA 19-9 and CEA levels in gastric
      carcinoma patients.
AB  - AIM: The usefulness of gastric juice CA 19-9 and carcinoembryonic antigen (CEA)
      levels in the diagnosis of gastric carcinoma is controversial. There is only one
      study related with their prognostic value. In this study the clinical
      significance of gastric juice CA 19-9 and CEA levels in patients with gastric
      carcinoma was investigated. METHODS: Preoperative serum and gastric juice CA 19-9
      and CEA concentrations were measured in 139 patients with gastric carcinoma, 54
      patients with benign gastroduodenal disease and as the 'healthy' control group 46
      patients with inguinal hernia and with no other pathology. RESULTS: In all groups
      the mean gastric juice levels of CA 19-9 and CEA were significantly higher than
      the serum levels. The gastric juice CA 19-9 levels were not different between
      groups. Gastric juice CEA levels of the gastric carcinoma group were
      significantly higher than those of the benign gastroduodenal disease group
      (P=0.007) and had a tendency to increase when compared to those of the control
      group (P=0.064) whereas there was no significant difference between the benign
      gastroduodenal disease and the control group. The cut-off values of gastric juice
      CA 19-9 and CEA were 440U/ml and 320ng/ml and the positivity ratios of these
      markers in gastric carcinoma patients were 16.5 and 27.3%, respectively. There
      was no significant relationship between the histopathological features and the
      gastric juice CA 19-9 or CEA positivities. Neither univariate analysis nor the
      multivariate Cox proportional hazards model analysis showed prognostic value for
      gastric juice CA 19-9 and CEA positivities. CONCLUSIONS: The gastric juice CA 19
      9 and CEA levels have no diagnostic and prognostic significance in gastric
      carcinoma patients.

PMID- 12477477
TI  - Completeness of data entry in three cancer surgery databases.
AB  - AIMS: Clinical databases are regularly used for audit and research purposes. The
      accuracy of data input is critical to the value of these tools, but little is
      known about the factors which influence the completeness of data recording. The
      aim of this study was to evaluate the influences affecting completeness of data
      recording in computerized clinical databases of cancer treatment. METHODS: Data
      omission rates in three databases dealing with management of breast, colorectal
      and gastro-oesophageal cancers were calculated. The effects of (a) type of
      record; (b) nature of data and (c) training required to interpret data were
      evaluated by univariate and multivariate analyses. RESULTS: The overall data
      omission rate was 21.9% (upper GI 27.6%, breast 19.6%, colorectal 32.7%, P=0.13).
      For different categories of data, omission rates varied from 0% to 55%. Fields
      requiring a 'text field' or 'numerical' entry, or containing demographic data,
      data required for the process of care or data which required no interpretation
      were associated with low omission rates. Clinical data, and fields requiring a
      'yes/no' response were associated with high omission rates (45 and 48%
      respectively). Clinical data and data relating to patient demographic details
      were independently associated with high and low omission rates respectively (odds
      ratios for significant missing data 86.9 and 1 respectively). CONCLUSION:
      Clinical data are poorly captured by current cancer surgery databases. Reasons
      for the poor completion of fields requiring input by clinical staff, particularly
      availability of time and training, and prioritization of work, should be
      addressed. Re-design of databases to ensure that data entry is simple and
      unambiguous may improve accuracy.

PMID- 12477478
TI  - Long-term follow-up of surgically treated gallbladder cancer patients.
AB  - AIMS: Palliative attempts have traditionally led treatment of gallbladder cancer
      but resection offers the only chance for long-term survival. This study
      investigates the impact of surgery with curative intent in gallbladder cancer
      treatment and evaluates prognostic factors for survival. METHODS: Two hundred and
      sixty-seven patients were admitted for surgical therapy. Sixty received resection
      with curative intent and form the basis of this analysis. RESULTS: R0 resection
      (n=45) was a highly significant independent survival predictor (P<0.001). All 5
      year survivors (n=10) had tumour-free resection margins. Early T stage (P=0.017)
      and highly differentiated cancer (P=0.008) had a significant better outcome.
      Nodal spreading increased by local tumour extension and lymphatic involvement
      decreased patient survival (P=0.018). Patients' age (>75 years) was without
      influence on long-term survival. CONCLUSIONS: Long-term survival is possible both
      in elderly patients and in advanced cancer.

PMID- 12477479
TI  - Long term survival of thoracoscopic metastasectomy vs metastasectomy by
      thoracotomy in patients with a solitary pulmonary lesion.
AB  - AIMS: The aim of this study was to compare long term survival after resection of
      solitary pulmonary metastasis on CT scan performed by either thoracoscopy or
      through a standard thoracotomy. METHODS: Patients with a solitary, CT scan
      confirmed, peripherally located lesion suspected for metastasis, less than 3cm in
      diameter were included. End points were: postoperative complication rate, disease
      free and overall survival and location of recurrence in the lung. RESULTS: Thirty
      five patients who underwent a thoracoscopic metastasectomy with (n=19) or without
      (n=16) confirmatory thoracotomy were included in this study. Patients experienced
      more complications following a thoracotomy (n=5) compared to those who had a
      thoracoscopy (n=0) (P=0.049). Two patients appeared to have further disease at
      thoracotomy besides the CT scan identified lesion, and some at thoracoscopy. At
      definitive histology, seven lesions were benign and eight appeared to be a second
      primary. Analysis of 20 patients with histological confirmed metastasis
      demonstrated a 2-year disease free and overall survival rate of 50% and 67%
      respectively following thoracoscopic metastasectomy (n=8) compared to 42% and 70%
      respectively following confirmatory thoracotomy (n=12). Recurrence occurred in
      three of the patients after thoracoscopic metastasectomy and in five patients
      after thoracotomy. CONCLUSION: Our results suggest that thoracoscopic resection
      of solitary peripherally located metastasis is a safe and potentially curative
      procedure with a long term outcome that is comparable with that after resection
      by thoracotomy.

PMID- 12477480
TI  - Chondroblastoma: a study of 11 cases.
AB  - AIM: Chondroblastoma is an infrequent and unique neoplasm that is histologically
      characterized by chondroblastoma cells, osteoclast-like giant cells and sometimes
      reactive osteoid. Although it is generally regarded as benign, it may recur and
      sporadically metastasize to the lung. Many important questions concerning the
      prognostic factors and adequate surgical treatment of chondroblastoma have not
      been fully answered and remain controversial. The purpose of this study was to
      determine clinicopathological features useful in prediction of the tumour
      behaviours. METHODS: Eleven chondroblastoma cases were reviwed
      clinicopathologically. According to Enneking's radiographic grading system, seven
      cases were classified as stage I, three cases as stage II and one case was
      classified as stage III. RESULTS: Nine cases had initially been treated with
      simple curettage, one had aggressive curettage applied as a primary surgery and
      one underwent amputation. Among the nine simple curettage cases, one recurred and
      was reoperated with aggressive curettage. Adjuvant treatment (alcohol and/or
      cement) was applied in the two aggressive curettage cases; none demonstrated
      further tumour recurrence. All lesions were curettaged, and one case recurred.
      The rate of proliferating-cell nuclear antigen expression was significantly
      higher in the recurrent case. CONCLUSION: The recurrent case seemed to have a
      high growth activity. Simple curettage was effective for local control during the
      initial treatment in most cases, but aggressive curettage and adjuvant treatment
      with alcohol and/or cement was useful for local control in recurrent
      chondroblastoma and chondroblastoma presenting with an aggressive behaviour.

PMID- 12477481
TI  - Isolated liver perfusion for non-resectable liver tumours: a review.
AB  - Many treatments have been proposed for non-resectable primary or secondary
      hepatic cancer but the results have generally been disappointing. Isolated
      Hepatic Perfusion (IHP) was first attempted four decades ago but it gained
      acceptance only recently, after spectacular tumour responses were obtained by
      isolated limb perfusion with melphalan and tumour necrosis factor (TNF) for
      melanomas and sarcomas. Surgical isolation of the liver is a technically
      demanding operation that allows the safe administration of high doses of
      chemotherapeutics and TNF. Percutaneous techniques using balloon occlusion
      catheters are simpler but result in higher leakage rates from the perfusion
      circuit into the systemic circulation. Several phase I-II trials indicate that
      IHP can yield high tumour response rates, even when there is resistance to
      systemic chemotherapy. However, no significant advantage in overall survival has
      been demonstrated so far. IHP offers unique pharmacokinetic advantages for
      locoregional chemotherapy and biotherapy. It might also allow gene therapy with
      limited systemic exposure and toxicity. At present, IHP nevertheless remains an
      experimental treatment modality which should therefore be used in controlled
      trials only.

PMID- 12477482
TI  - Breast-sparing reconstruction with latissimus dorsi miniflaps.
AB  - Volume loss following breast-conserving surgery (BCS) is the key reason for major
      local deformity and a bad cosmetic outcome. Latissimus dorsi miniflaps can be
      used to reconstruct central and upper quadrant resection defects, replacing the
      volume excised with autogenous tissue. Partial mastectomy, axillary dissection,
      flap harvest and reconstruction of the resection defect is performed as a one
      stage procedure through a single lateral incision. This oncoplastic approach
      allows extensive local excision during BCS without cosmetic penalties in a group
      of patients normally treated by mastectomy.

PMID- 12477483
TI  - Estrogen receptor beta splice variant mRNAs are differentially altered during
      breast carcinogenesis.
AB  - We previously identified 10 exon deletion ERbeta variant mRNAs in various human
      tissues [FEBS Lett. 516 (2002) 133]. In the current study, we have investigated
      the expression of these variant mRNAs in normal breast tissues and their
      alterations in cancer tissues. A total of 43 cancer tissues in comparison with
      their matched normal tissues were analyzed by RT PCR using the newly developed
      'Splice Targeted Primer Approach'. The data presented here show that normal
      breast tissues express 9 of the 10 identified variant mRNAs. Of the nine
      variants, the mRNAs with exons 5-6 deletions were significantly decreased (
      approximately 80%) in a large majority of cancer tissues (two-sided paired t
      test, n=43 patients, P<0.00001). The expression of ERbeta exon 5Delta, that could
      potentially have transactivating property in the absence of hormone, was changed
      differently among different grade tumors (analysis of variance F-test, n=43
      patients, P=0.0452; Kruskal-Wallis test, n=43 patients, P=0.0356). When change in
      expression of ERbeta exon 5Delta mRNA levels was used as a categorical variable,
      a significant association was found between the change status (increase, no
      change, decrease) of this variant and grade of the tumor (Fischer's exact test,
      n=43 patients, P=0.0129). In particular, it was significantly increased in grade
      III tumors and decreased in grade II tumors. This variant was also changed
      differently in pre- and post-menopausal women. Its expression levels were
      increased in the tumors of post-menopausal women (mean change=3.6685), while they
      were decreased in pre-menopausal women (mean change=-24.3662). Thus a significant
      association was observed between the expression of this variant and menopausal
      status (a two-sided paired t-test, n=43 patients, P=0.03). Other variants were
      either expressed at very low frequency or not significantly altered.

PMID- 12477484
TI  - Ability of structurally diverse natural products and synthetic chemicals to
      induce gene expression mediated by estrogen receptors from various species.
AB  - The ability of 14 structurally diverse estrogenic compounds to induce reporter
      gene expression mediated by estrogen receptors (ERs) from different species was
      examined. MCF-7 cells were transiently transfected with a Gal4-regulated
      luciferase reporter gene (17m5-G-Luc) and Gal4-ER chimeric receptors containing
      the D, E and F domains of the human alpha (Gal4-hERalphadef), mouse alpha (Gal4
      mERalphadef), mouse beta (Gal4-mERbetadef), chicken (Gal4-cERalphadef), green
      anole (Gal4-aERalphadef), Xenopus (Gal4-xERdef) or rainbow trout alpha ERs (Gal4
      rtERalphadef). The efficacy of 17beta-estradiol (E2) in inducing reporter gene
      expression was similar among the different constructs overall, with EC(50) values
      ranging from 0.05 to 0.7nM. However, Gal4-rtERalphadef had an EC(50) value at 37
      degrees C of 28nM, though at 20 degrees C an EC(50) value of 1nM was observed.
      Despite a similar response to E2 treatment among the ERs, many differences were
      observed in the magnitude of the response to other structurally diverse
      chemicals. For example, coumestrol induced Gal4-mERbetadef- and Gal4-aERdef
      mediated reporter gene expression 164- and 8-fold greater, respectively, than
      mediated with the other Gal4-ERs. As well, in contrast to results with other Gal4
      ERs, alpha-zearalenol consistently induced Gal4-rtERalphadef-mediated reporter
      gene activity at lower concentrations than did E2. Overall, the results
      demonstrate that selected estrogenic compounds exhibit a differential ability to
      induce reporter gene activity mediated by ERs from different vertebrate species.
      These data also highlight the importance of incubation temperature when examining
      rtERalpha-mediated activity.

PMID- 12477485
TI  - Molecular modelling of the human glucocorticoid receptor (hGR) ligand-binding
      domain (LBD) by homology with the human estrogen receptor alpha (hERalpha) LBD:
      quantitative structure-activity relationships within a series of CYP3A4 inducers
      where induction is mediated via hGR involvement.
AB  - The results of homology modelling of the human glucorticoid receptor (hGR) ligand
      binding domain (LBD) based on the ligand-bound domain of the human estrogen
      receptor alpha (hERalpha) are reported. It is shown that known hGR ligands which
      induce the human cytochrome P450 enzyme CYP3A4 are able to fit the putative
      ligand-binding site of the nuclear hormone receptor and form hydrogen bonds with
      key amino acid residues within the binding pocket. Quantitative structure
      activity relationships (QSARs) have been derived for hGR-mediated CYP3A4
      induction which involve certain molecular structural and physicochemical
      properties of the ligand themselves, yielding good correlations (R=0.96-0.98)
      with fold induction of CYP3A4 known to be mediated via hGR involvement.

PMID- 12477486
TI  - Cloning of the novel isoform of the estrogen receptor beta cDNA (ERbeta isoform M
      cDNA) from the human testicular cDNA library.
AB  - Our recent report has revealed the existence of the progesterone receptor (PR)
      isoform S, which consists of the novel PR exon S and exons 4-8 of the PR gene in
      the human testicular cDNA library. More recently, we have cloned the human
      estrogen receptor alpha (ERalpha) isoform S cDNA from the library. The ERalpha
      isoform S cDNA also contains the novel ERalpha exon S and exons 4-8 of the
      ERalpha cDNA. Based on these findings, we assumed that the novel isoform of cDNA
      like the PR- and ERalpha isoforms might exist in the human ER beta (ERbeta). In
      order to investigate this possibility, we have screened the human testicular cDNA
      library using the exons 4-8 corresponding sequence of the human ERbeta cDNA.
      Consequently, we have cloned a novel isoform of the ERbeta cDNA that consists of
      a previously unidentified 5'-sequence and the exons 5-8 of the ERbeta gene. We
      termed this isoform cDNA the "ERbeta isoform M cDNA". The 5'-sequence of the
      ERbeta isoform M cDNA was confirmed to be derived from a novel exon (termed the
      "exon M") by analysis of the genomic DNA. Moreover, we have analyzed the
      molecular size of the ERbeta isoform M encoded by the ERbeta isoform M mRNA by
      transient expression of the ERbeta isoform M cDNA in the 293T cell. The
      approximately 28 kDa protein, which was recognized by the anti-rat ERbeta
      antibody against the carboxyl-terminal region, was synthesized in the cells.
      Thus, we concluded that the ATG in the exon M could be used as the translation
      initiation codon. This report revealed for the first time the existence of the
      ERbeta mRNA isoform that is not caused by the skipping of one or more exons, by
      the alternative usage of the multiple exon 8s, nor by the alternative utilization
      of the untranslated 5'-exons located on the upstream region of the exon 1.

PMID- 12477487
TI  - On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen
      production.
AB  - To examine the influence on aromatase and sulfatase pathways in estrogen pool by
      drugs reported to cause gynecomastia as the side effect, 29 ethical drugs were
      incubated with human placental microsomes as an enzyme source. The percent
      inhibition of drugs on aromatase pathway was obtained by sum of the velocity
      constants of two products, estrone (E1) and estradiol (E2) from testosterone (T)
      as the substrate, and that on sulfatase pathway was obtained as the velocity
      constant of production of E1 from estrone sulfate (E1S). Although several drugs
      including ketoconazole showed a significant inhibition effect on aromatase
      pathway at their non-clinical over-dose concentration (100 microM), no influence
      on the inhibition was observed in any drugs at their approximately therapeutic
      concentration (1 microM). However, several drugs including spironolactone gave
      the product ratio (E2/E1) having higher value than that of the control, the
      result means spironolactone inhibits the conversion of E2 to E1. No inhibitory
      effect of the drugs tested on estrogen production from E1S (sulfatase pathway)
      was confirmed. The results suggest the possibility that the tested drugs known to
      cause gynecomastia have no inhibitory effect essentially on aromatase and
      sulfatase pathways.

PMID- 12477488
TI  - In vitro and in vivo characterization of novel nonsteroidal progesterone receptor
      antagonists derived from the fungal metabolite PF1092C.
AB  - We studied the pharmacological effects of novel nonsteroidal progesterone
      receptor antagonists CP8661 and CP8754, which were synthesized from the fungal
      metabolite PF1092C. CP8661 possess a tetrahydrobenzindolone skeleton and CP8754
      possess a tetrahydronaphthofuranone skeleton. In binding assays for steroid
      receptors, CP8661 and CP8754 inhibited [(3)H]-progesterone binding to human
      progesterone receptors (hPR), though they are less potent than RU486. CP8661 also
      showed moderate affinity to rat androgen receptors (rAR), although CP8754 did
      not. Neither compound showed affinity to human glucocorticoid receptors (hGR) or
      human estrogen receptors (hER). In exogeneous and endogeneous PR-dependent enzyme
      expression assays using human mammary carcinoma T47D, CP8661 and CP8754 showed
      pure antagonistic activity. In a rabbit endometrial transformation test, CP8661
      and CP8754 showed anti-progestational activity by s.c. administration in a dose
      dependent manner; meanwhile, these compounds showed no progestational activity at
      the same dose. These results suggested that CP8661 and CP8754 are in vivo
      effective pure progesterone receptor antagonists and presented the possibility of
      synthesizing pure progesterone receptor antagonists from both
      tetrahydronaphthofuranone and tetrahydrobenzindolone skeletons.

PMID- 12477489
TI  - Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced
      by patients with 7-dehydrosterol-delta7-reductase deficiency (Smith-Lemli-Opitz
      syndrome).
AB  - Patients with Smith-Lemli-Opitz syndrome have impaired ability to synthesize
      cholesterol due to attenuated activity of 7-dehydrosterol-delta(7)-reductase
      which catalyses the final step in cholesterol synthesis. Accumulation of 7- and 8
      dehydrocholesterol is a result of the disorder and potentially these sterols
      could be used as precursors of a novel class of delta(7) and delta(8) unsaturated
      adrenal steroids and their metabolites. In this study, we have analyzed urine
      from SLOS patients in the anticipation of characterizing such metabolites. Gas
      chromatography/mass spectrometry (GC/MS) was used in the identification of two
      major metabolites as 7- and 8-dehydroversions of the well-known steroid
      pregnanetriol. Other steroids, such as 8-dehydro dehydroepiandrosterone (8
      dehydro DHEA) and 7- or 8-dehydroandrostenediol were also identified, and several
      more steroids are present in urine but remain uncharacterized. As yet, the study
      provides no evidence for the production of ring-B unsaturated metabolites of
      complex steroids, such as cortisol. We believe that the following transformations
      can utilize ring-B dehydroprecursors: StAR transport of cholesterol, p450 side
      chain cleavage, 17-hydroxylase/17,20-lyase, 3beta-hydroxysteroid dehydrogenase,
      3alpha-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, 20alpha
      hydroxysteroid dehydrogenase and 5beta-reductase. We have yet to prove the
      activity of adrenal 21-hydroxylase, 11beta-hydroxylase or 5alpha-reductase
      towards 7- or 8-dehydroprecursors.

PMID- 12477490
TI  - Inhibition of type 1 and type 2 5alpha-reductase activity by free fatty acids,
      active ingredients of Permixon.
AB  - In different cell systems, the lipido-sterolic extract of Serenoa repens (LSESr,
      Permixon inhibits both type 1 and type 2 5alpha-reductase activity (5alphaR1 and
      5alphaR2). LSESr is mainly constituted of fatty acids (90+/-5%) essentially as
      free fatty acids (80%). Among these free fatty acids, the main components are
      oleic and lauric acids which represent 65% and linoleic and myristic acids 15%.
      To evaluate the inhibitory effect of the different components of LSESr on
      5alphaR1 or 5alphaR2 activity, the corresponding type 1 and type 2 human genes
      have been cloned and expressed in the baculovirus-directed insect cell expression
      system Sf9. The cells were incubated at pH 5.5 (5alphaR2) and pH 7.4 (5alphaR1)
      with 1 or 3nM testosterone in presence or absence of various concentrations of
      LSESr or of its different components. Dihydrotestosterone formation was measured
      with an automatic system combining HPLC and an on-line radiodetector. The
      inhibition of 5alphaR1 and 5alphaR2 activity was only observed with free fatty
      acids: esterified fatty acids, alcohols as well as sterols assayed were inactive.
      A specificity of the fatty acids in 5alphaR1 or 5alphaR2 inhibition has been
      found. Long unsaturated chains (oleic and linolenic) were active (IC(50)=4+/-2
      and 13+/-3 microg/ml, respectively) on 5alphaR1 but to a much lesser extent
      (IC(50)>100 and 35+/-21 microg/ml, respectively) on 5alphaR2. Palmitic and
      stearic acids were inactive on the two isoforms. Lauric acid was active on
      5alphaR1 (IC(50)=17+/-3 microg/ml) and 5alphaR2 (IC(50)=19+/-9 microg/ml). The
      inhibitory activity of myristic acid was evaluated on 5alphaR2 only and found
      active on this isoform (IC(50)=4+/-2 microg/ml). The dual inhibitory activity of
      LSESr on 5alpha-reductase type 1 and type 2 can be attributed to its high content
      in free fatty acids.

PMID- 12477491
TI  - Neuroactive steroids, their precursors and polar conjugates during parturition
      and postpartum in maternal and umbilical blood: 3.3beta-hydroxy-5-ene steroids.
AB  - Five 3beta-hydroxy-5-ene steroids involved in the metabolic route from
      pregnenolone sulfate to dehydroepiandrosterone and its sulfate, of which three
      are known allosteric modulators of neurotransmitter receptors, were monitored in
      the serum of 20 women around parturition. In addition, their levels in maternal
      and umbilical serum were compared at delivery. On the basis of these data, a
      scheme of steroid biosynthesis in maternal organism during the critical stages
      around parturition is proposed. In maternal serum, all the steroids except
      dehydroepiandrosterone sulfate decreased during labor and even first day after
      delivery, although their changes were less distinct the more distant from
      pregnenolone sulfate (PregS) in the metabolic pathway. Calculation of
      product/immediate precursor ratios in maternal serum over all stages around
      parturition enabled identification of the respective changes in the activities of
      the relevant enzymes. The ratio of 17-hydroxypregnenolone/pregnenolone did not
      change significantly, while that of dehydroepiandrosterone/17-hydroxypregnenolone
      grew, indicating increased C17,20 side chain cleavage on the account of C17
      hydroxylation both catalyzed by C17-hydroxylase-C17,20-lyase. As was shown by
      factor analysis, the changes in the maternal steroids were associated with a
      single common factor, which strongly correlated with all the steroids except
      dehydroepiandrosterone sulfate. The lack of change in the pregnenolone
      sulfate/pregnenolone ratio and a marked increase of the ratio
      dehydroepiandrosterone sulfate to unconjugated dehydroepiandrosterone indicate a
      different means of formation of both steroid sulfates. On the basis of these
      data, a scheme of steroid biosynthesis in maternal organism during the critical
      stages around parturition is proposed.

PMID- 12477492
TI  - Studies on Bacillus stearothermophilus. Part II. Transformation of progesterone.
AB  - Bacillus stearothermophilus, a thermophilic bacterium isolated from Kuwaiti
      desert, when incubated with exogenous progesterone for 10 days at 65 degrees C
      produced two new dihydroxy isomers of progesterone, and two known compounds, 5
      alpha-pregnane-3,6,20-trione and 6-dehydroprogesterone, along with the earlier
      reported monohydroxylated metabolites and a B-Seco compound. The two new
      dihydroxy compounds were identified as 6 alpha,20 alpha-dihydroxyprogesterone and
      6 beta,20 alpha-dihydroxyprogesterone. These metabolites were purified by TLC and
      HPLC followed by their identification through 1H, 13C NMR and other spectroscopic
      data.

PMID- 12477493
TI  - Influence of substituents at C11 on hydroxylation of progesterone analogs by
      Bacillus sp.
AB  - Transformation of progesterone analogs viz., progesterone, 11 alpha-, 11 beta
      hydroxyprogesterones and 11-ketoprogesterone by Bacillus sp. is reported. Both
      progesterone and 11-ketoprogesterone were hydroxylated while the C(11) epimeric
      alcohols of progesterone remained unaltered under the conditions used. The major
      bioconverted products obtained from progesterone and 11-ketoprogesterone were
      characterized as 6 beta- and 14 alpha-hydroxyprogesterones and 14 alpha-hydroxy
      11-ketoprogesterone respectively by mass and NMR spectra. The conversion of 11
      ketoprogesterone to its 14 alpha-hydroxy derivative by microbe is unprecedented
      and novel. Moreover, hydroxylation at 6 beta- and 14 alpha-positions of
      progesterone by Bacillus sp. is significant. In conclusion, the present data
      showed that the substituents at 11-position of steroid play important role on
      hydroxylation by microbe.

PMID- 12477494
TI  - Estradiol stimulates expression of two human prolactin receptor isoforms with
      alternative exons-1 in T47D breast cancer cells.
AB  - Human prolactin receptor (hPRLR) expression is regulated by estradiol-17beta
      (E(2)) in vivo in animal tissues, and in vitro in normal human endometrial cells
      and in MCF7 human breast cancer cells. The objective of this study was to
      determine the effect of E(2) on the expression of two recently described hPRLR
      isoforms with distinct exons-1, hE1(3) and hE1(N1) that are transcribed from the
      generic hPIII promoter, also present in the rat and mouse, and the human-specific
      promoter hP(N1), respectively. Also, to determine the effect of estradiol on the
      hPIII promoter activity in cancer cells. T47D breast cancer cells were examined
      using quantitative competitive RT-PCR for the level of expression of two
      alternative non-coding exon-1 transcripts, hE1(3) and hE1(N1) following
      incubation with E(2) in presence or absence of the E(2) receptor antagonist ICI
      182,780. The effects of estradiol were also evaluated in cells transiently
      transfected with constructs of hPIII promoter luciferase reporter gene. E(2)
      significantly increased the expression of both hPRLR mRNA transcripts, hE1(3) and
      hE1(N1). In transfection studies E(2) activated the hPIII promoter. This effect
      of estradiol was markedly inhibited by coincubation with the E(2) receptor
      antagonist. Our results demonstrate a stimulatory effect of estradiol on the
      expression of hPRLR mRNA species with alternative exons-1, hE1(3) and hE1(N1)
      possibly through activation of their corresponding promoters. The lack of a
      formal ERE in these promoters suggested that the effect of estradiol is mediated
      through association of the activated ER with relevant DNA binding transfactor(s).
      These findings support the role of E(2) in the regulation of hPRLR expression in
      human breast cancer cell lines.

PMID- 12477495
TI  - The international ImMunoGeneTics Database IMGT.

PMID- 12477496
TI  - Secretion of a collectin-like protein in tunicates is enhanced during
      inflammatory responses.
AB  - The sub-cellular and humoral concentrations of a collectin-like protein from the
      solitary tunicate, Styela plicata, were measured after in vivo challenge with the
      inflammatory agent, zymosan. Tunicates were injected with zymosan before
      hemocytes and serum were harvested, subjected to western blotting and
      immunostained with an anti-S. plicata collectin antibody to determine the
      relative titers of collectin-like proteins. Concentrations of the predominant
      43kDa collectin polypeptide were found to decrease in hemocytes immediately after
      zymosan injection, before rising to levels that were six times higher than
      controls within 96h. Similarly, immunohistochemistry showed that the frequency of
      collectin-positive hemocytes in the circulating hemolymph increased significantly
      within 96h of injection. Levels of the 43kDa polypeptide in serum mirrored those
      of hemocytes. Humoral collectin concentrations decreased immediately after
      zymosan injection before rising, within 96h post-injection, to levels three times
      higher than controls. This response to an inflammatory stimulus resembles that of
      mammalian collectins like mannose-binding lectin. The data suggest that, like its
      mammalian counterparts, the tunicate collectin acts as an acute phase antigen
      recognition protein.

PMID- 12477497
TI  - Characterization and cDNA cloning of an immune-induced lysozyme from cultured
      Aedes albopictus mosquito cells.
AB  - Protein chemistry and cDNA sequencing were used to identify an Aedes albopictus
      mosquito lysozyme secreted after treatment of cultured cells with heat-killed
      bacteria. On acid gels, the putative lysozyme activity ran just ahead of the
      cecropin band. Elution of this activity yielded a single band on SDS gels, with a
      mass of approximately 14 kDa. Mass spectral analysis of the silver-stained band
      uncovered five tryptic peptides with masses that matched peptides from an Aedes
      aegypti lysozyme, which we had previously characterized from the Aag-2 mosquito
      cell line. Based on this tentative identification, the Ae. albopictus lysozyme
      cDNA was cloned using PCR-based approaches. The full length cDNA sequence was
      used to deduce the sequences and masses of theoretical tryptic peptides that
      would be detected after matrix-assisted laser desorption ionization time of
      flight (MALDI-TOF) and tandem mass spectrometry (MS/MS). In aggregate, this
      analysis uncovered seven peptides that encoded 75 of the 125 amino acids in the
      mature Ae. albopictus lysozyme. In a phylogenetic analysis, the Aedes lysozymes
      were most closely related to the Anopheles lysozymes. As a group the mosquito
      lysozymes were more closely related to lysozymes from various Lepidopteran
      species than to those from higher Diptera such as Drosophila and Musca, which
      have evolved a digestive function.

PMID- 12477498
TI  - Identification of a FasL-like molecule in leucocytes of the teleost fish gilthead
      seabream (Sparus aurata L.).
AB  - The possible expression of FasL in gilthead seabream leucocytes was studied by
      flow cytometry, immunoblotting and immunocytochemistry, using an anti-mouse FasL
      monoclonal antibody. The results pointed to a cytosolic FasL-like, but not a
      membrane-like form, in resting leucocytes from head-kidney, thymus, spleen, blood
      and peritoneal exudate. Immunoblotting revealed a 19kDa band in resting
      leucocytes, while activated leucocytes showed the same band and another of 39kDa.
      The FasL-like molecule is identified in lymphocytes, monocyte-macrophages and
      acidophilic granulocytes. Phylogenetical and functional implications are
      suggested.

PMID- 12477499
TI  - Molecular and functional characterization of carp TNF: a link between TNF
      polymorphism and trypanotolerance?
AB  - Two carp tumor necrosis factor alpha (TNFalpha) genes have been cloned and
      sequenced. Both TNF1 and TNF2 sequences have several polymorphisms in the 3' UTR
      and TNF2 has a polymorphism in the coding sequence. Lipopolysaccharide and the
      protozoan blood flagellate Trypanoplasma borreli induced expression of TNFalpha
      in carp head kidney phagocytes when added in vitro. Differential expression was
      observed, with TNF2 being higher expressed than TNF1. We used the TNFalpha
      specific inhibitor pentoxifylline to demonstrate the involvement of carp TNFalpha
      in the induction of nitric oxide and in the stimulation of cell proliferation. In
      addition, two carp lines differing in their resistance to T. borreli were typed
      for the TNF2 polymorphism and association between one isoform and resistance was
      found.

PMID- 12477500
TI  - Evolution of classic Hodgkin lymphoma in correlation to changes in the lymphoid
      organ structure of vertebrates.
AB  - In order to integrate evolutionary concepts into lymphoma research we mapped
      features of classic Hodgkin lymphoma (a disease which has been recently described
      to be derived from germinal center B-cells) onto a phylogenetic tree of
      vertebrates. Secondly, we matched the phylogenetic occurrence of classic Hodgkin
      lymphoma to the changes in the lymphoid organ structure during vertebrate
      evolution. According to our analysis, classic Hodgkin lymphoma evolved
      exclusively at the developmental stage of mammals. Interestingly the appearance
      of Hodgkin lymphoma is correlated to the evolution of germinal centers in
      mammals. This lends some credit to the hypothesis that genes specific to the
      germinal center reaction are involved in the pathogenesis of Hodgkin lymphoma.
      However, as evolution did not stop at the developmental stage of the mammalian
      stem-species, to a certain extent species with specific differences of classic
      Hodgkin lymphoma can be expected. One such difference is that classic Hodgkin
      lymphoma occurs with a significantly higher frequency in humans than in all other
      mammals. This could be partially due to Epstein-Barr virus (EBV) infection in
      approximately 40%-50% of Hodgkin disease cases, that is associated with an
      expression of the EBV-encoded oncogen LMP-1. In conclusion we propose that the
      mapping of lymphoma related characteristics onto a phylogenetic tree is a
      valuable new tool in lymphoma research.

PMID- 12477501
TI  - IMGT unique numbering for immunoglobulin and T cell receptor variable domains and
      Ig superfamily V-like domains.
AB  - IMGT, the international ImMunoGeneTics database (http://imgt.cines.fr) is a high
      quality integrated information system specializing in immunoglobulins (IG), T
      cell receptors (TR) and major histocompatibility complex (MHC) of human and other
      vertebrates. IMGT provides a common access to expertly annotated data on the
      genome, proteome, genetics and structure of the IG and TR, based on the IMGT
      Scientific chart and IMGT-ONTOLOGY. The IMGT unique numbering defined for the IG
      and TR variable regions and domains of all jawed vertebrates has allowed a
      redefinition of the limits of the framework (FR-IMGT) and complementarity
      determining regions (CDR-IMGT), leading, for the first time, to a standardized
      description of mutations, allelic polymorphisms, 2D representations (Colliers de
      Perles) and 3D structures, whatever the antigen receptor, the chain type, or the
      species. The IMGT numbering has been extended to the V-like domain and is,
      therefore, highly valuable for comparative analysis and evolution studies of
      proteins belonging to the IG superfamily.

PMID- 12477502
TI  - Role of acupuncture in the treatment of female infertility.
AB  - OBJECTIVE: To review existing scientific rationale and clinical data in the
      utilization of acupuncture in the treatment of female infertility. DESIGN: A
      MEDLINE computer search was performed to identify relevant articles. RESULTS:
      Although the understanding of acupuncture is based on ancient medical theory,
      studies have suggested that certain effects of acupuncture are mediated through
      endogenous opioid peptides in the central nervous system, particularly beta
      endorphin. Because these neuropeptides influence gonadotropin secretion through
      their action on GnRH, it is logical to hypothesize that acupuncture may impact on
      the menstrual cycle through these neuropeptides. Although studies of adequate
      design, sample size, and appropriate control on the use of acupuncture on
      ovulation induction are lacking, there is only one prospective randomized
      controlled study examining the efficacy of acupuncture in patients undergoing
      IVF. Besides its central effect, the sympathoinhibitory effects of acupuncture
      may impact on uterine blood flow. CONCLUSION: Although the definitive role of
      acupuncture in the treatment of female infertility is yet to be established, its
      potential impact centrally on the hypothalamic-pituitary-ovarian axis and
      peripherally on the uterus needs to be systemically examined. Prospective
      randomized controlled studies are needed to evaluate the efficacy of acupuncture
      in female fertility treatment.

PMID- 12477503
TI  - Serum vascular endothelial growth factor levels are poorly predictive of
      subsequent ovarian hyperstimulation syndrome in highly responsive women
      undergoing assisted conception.
AB  - OBJECTIVE: To determine whether serum vascular endothelial growth factor (VEGF)
      levels can distinguish highly responsive women who subsequently develop ovarian
      hyperstimulation syndrome (OHSS) from women with a similar ovarian response who
      do not. DESIGN: Prospective controlled study. SETTING: University IVF unit.
      PATIENT(S): Women undergoing IVF who met predetermined risk criteria for OHSS.
      Patients developing OHSS were compared with patients who did not develop OHSS.
      INTERVENTION(S): Long-protocol pituitary down-regulation followed by FSH
      stimulation by a standard protocol without coasting. A maximum of three embryos
      was transferred. Vaginal progesterone was used for luteal support. MAIN OUTCOME
      MEASURE: Occurrence of OHSS; serum VEGF concentrations on the day of embryo
      transfer (ET) and at 5 and 10 days after ET. RESULTS: Serum VEGF levels at any
      time point did not differ significantly between 9 OHSS cases and 9 controls.
      Vascular endothelial growth factor levels in samples collected from cases before
      the onset of OHSS were higher than levels in time-matched samples from controls
      (medians, 177.6 [range, 64.02-549.1] pg/mL vs. 100.7 [range, 37.59-246] pg/mL,
      respectively), but the difference failed to reach statistical significance
      (P=.0518), and there was considerable overlap between cases and controls.
      CONCLUSIONS: Serum VEGF levels in the luteal phase do not distinguish between
      high-risk women who subsequently develop OHSS and women with a similar risk
      profile who do not develop OHSS.

PMID- 12477504
TI  - Ovarian hyperstimulation syndrome is associated with reversible impairment of
      vascular reactivity.
AB  - OBJECTIVE: To determine if there is a loss of normal peripheral arteriolar
      vasoconstrictor reactivity in women with severe ovarian hyperstimulation syndrome
      (OHSS). SETTING: Prospective controlled study. DESIGN: National University
      Hospital, Singapore. PATIENT(S): Forty-three women undergoing treatment in an IVF
      program: 22 women with severe OHSS and 21 normal women without OHSS.
      INTERVENTION(S): Measurement and quantification of the cutaneous arteriolar
      vasoconstrictor response using laser Doppler fluximetry. MAIN OUTCOME MEASURE(S):
      Changes in blood flow as an index of vasoconstrictor response before and after
      treatment for OHSS with albumin. RESULT(S): The mean (+/-SE) percentage (%)
      change in normal control women was -68.3% +/- 4.7. This was significantly
      different from women with OHSS (-32.3% +/- 11.1). The response in women with OHSS
      changed significantly after treatment with IV albumin (-60.4% +/- 5.7) and was no
      different than the control response. The reproducibility of the technique was 
      13.6% (+/-2.8). CONCLUSION(S): Women with OHSS have impaired vascular reactivity
      when compared with normal women.

PMID- 12477506
TI  - Vascular endothelial growth factor, polycystic ovary syndrome, and ovarian
      hyperstimulation syndrome.

PMID- 12477505
TI  - Concentration of vascular endothelial growth factor released by cultured human
      luteinized granulosa cells is higher in women with polycystic ovaries than in
      women with normal ovaries.
AB  - To test the hypothesis that increased serum levels of vascular endothelial growth
      factor (VEGF) in women with polycystic ovaries or the polycystic ovary syndrome
      (PCOS) result from excess release by ovarian granulosa cells. Prospective study.
      Academic research setting. Twenty women undergoing IVF treatment, of whom 10 had
      normal ovaries and 10 had polycystic ovaries. Human granulosa lutein cells were
      isolated from follicular fluid obtained on the day of oocyte retrieval. Release
      of VEGF was assessed after co-incubation of granulosa lutein cells with
      gonadotropins and insulin. Serum and follicular fluid concentrations of VEGF were
      measured. Release of VEGF from granulosa lutein cells and serum levels of VEGF.
      Incubation with human hCG, and luteinizing hormone increased release of VEGF into
      the culture medium. Insulin alone did not increase release of VEGF, but addition
      of insulin increased hCG-stimulated release of VEGF. Serum and follicular fluid
      VEGF concentrations and the amount VEGF released from granulosa lutein cells
      obtained from women with polycystic ovaries or PCOS and those who developed the
      ovarian hyperstimulation syndrome were greater than those from granulosa lutein
      cells obtained from women with normal ovaries and those who did not develop the
      ovarian hyperstimulation syndrome. The amount of VEGF released by granulosa
      lutein cells is gonadotropin dependent and is augmented by insulin. The increased
      circulating concentrations of VEGF in women with PCOS may not only be due to an
      increased number of actively secreting granulosa lutein cells but also due to
      increased secretory capacity of each granulosa cell.

PMID- 12477507
TI  - Effects of vaginally administered high estradiol doses on hormonal
      pharmacokinetics and hemostasis in postmenopausal women.
AB  - OBJECTIVE: To study the effect of high doses of estradiol released from vaginal
      rings on the pharmacokinetics of hormones, and the long-term effect on hormones
      and hemostasis in postmenopausal women. DESIGN: A pilot, nonrandomized study.
      SETTING: Healthy volunteers in an academic research environment. PATIENTS:
      Postmenopausal women. Eight women were treated with 17 beta-estradiol from three
      vaginal rings, releasing 7.5 micro g per ring for a total of 22.5 micro g over 24
      hours. The rings were changed every morning for 14 days. MAIN OUTCOME MEASURE(S):
      Hemostatic changes were recorded. RESULT(S): Estradiol was rapidly absorbed, and
      statistically significant increases in the levels were found after 15 minutes;
      C(max) was obtained after 1 hour and a steady state after 24 hours. No
      statistically significant changes were found in the levels of coagulation factors
      V, von Willebrand factor, and activated factor VII; nor were any changes observed
      for activated protein C resistance, coagulation inhibitors protein C, protein S,
      or plasminogen activator inhibitor-1. No indication of increased thrombin
      formation was demonstrated by analyses of prothrombin fragment 1+2, fibrin D
      dimer, and soluble fibrin. CONCLUSION(S)No statistically significant changes in
      hemostasis were observed from the vaginal administration of estradiol using a
      dose equivalent to transdermal administration with a release rate of 100 micro g
      per 24 hours.

PMID- 12477508
TI  - A randomized, placebo-controlled trial of the effects of continuous combined
      hormone replacement therapy on coagulation and fibrinolytic systems in healthy
      postmenopausal women.
AB  - OBJECTIVE: To investigate the effects of combined hormone replacement therapy
      (HRT) on various parameters of coagulation and fibrinolysis that may contribute
      to increased risk for venous thromboembolic events. DESIGN: Prospective,
      randomized, double-blind, placebo-controlled study. SETTING: Academic hospital.
      PATIENT(S): Sixty-one healthy postmenopausal women with intact uterus.
      INTERVENTION(S): Patients were randomized to receive continuous combined HRT
      (estradiol, 2 mg/d, and norethisterone acetate, 1 mg/d) or placebo for 6 months.
      MAIN OUTCOME MEASURE(S): Markers of coagulation and fibrinolysis were measured
      before therapy and after 3 and 6 months of therapy. RESULT(S): The groups did not
      differ significantly in levels of prothrombin fragments 1 and 2 and thrombin
      antithrombin III complex after 3 and 6 months of therapy. After 6 months of HRT,
      significant decreases in activity of antithrombin III and protein C and levels of
      plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator
      antigen, and euglobulin clot lysis time and a significant increase in D-dimer
      level were found compared with placebo. CONCLUSION(S): Continuous combined HRT
      for several months produced no net activation of coagulation but improved
      fibrinolysis in healthy postmenopausal women with no risk factors for venous
      thromboembolic events.

PMID- 12477509
TI  - A polymorphism of the Nos3 gene and age at natural menopause.
AB  - To investigate the possible influence of a polymorphism of the Nos3 gene on
      menarche and onset of menopause in humans. Cohort study.Academic research
      institution.Ninety-one consecutive Caucasian postmenopausal women. Peripheral
      venous puncture and a patient questionnaire were administered.A tandem repeat
      polymorphism in intron 4 of Nos3 was analyzed by polymerase chain reaction
      amplification. The common B allele was identified on 143 of 182 chromosomes
      (frequency 0.79). The polymorphic A allele was present on 39 chromosomes
      (frequency 0.21). The genotype frequencies were as follows: 58.2% (B/B), 40.7%
      (A/B), and 1.1% (A/A). Age at menarche, number of deliveries, number of
      miscarriages, and onset of menopause did not differ between genotypes. Smoking
      and increased body mass index were associated with an earlier onset of natural
      menopause.In contrast to mouse models, in humans Nos3 does not seem to modulate
      onset and cessation of menses.

PMID- 12477510
TI  - Role of environmental estrogens in the deterioration of male factor fertility.
AB  - OBJECTIVE: To evaluate the role of the environmental estrogens polychlorinated
      biphenyls (PCBs) and phthalate esters (PEs) as potential environmental hazards in
      the deterioration of semen parameters in infertile men without an obvious
      etiology. DESIGN: Randomized controlled study. SETTING: Tertiary care referral
      infertility clinic and academic research center. PATIENT(S): Twenty-one infertile
      men with sperm counts <20 million/mL and/or rapid progressive motility <25%
      and/or <30% normal forms without evidence of an obvious etiology and 32 control
      men with normal semen analyses and evidence of conception. Semen and blood
      samples were obtained as part of the treatment protocol. MAIN OUTCOME MEASURE(S):
      Evaluation of semen parameters such as ejaculate volume, sperm count, motility,
      morphology, vitality, osmoregulatory capacity, sperm chromatin stability, and
      sperm nuclear DNA integrity. RESULT(S): PCBs were detected in the seminal plasma
      of infertile men but not in controls, and the concentration of PEs was
      significantly higher in infertile men compared with controls. Ejaculate volume,
      sperm count, progressive motility, normal morphology, and fertilizing capacity
      were significantly lower in infertile men compared with controls. The highest
      average PCB and PE concentrations were found in urban fish eaters, followed by
      rural fish eaters, urban vegetarians, and rural vegetarians. The total motile
      sperm counts in infertile men were inversely proportional to their xenoestrogen
      concentrations and were significantly lower than those in the respective
      controls. CONCLUSION(S): PCBs and PEs may be instrumental in the deterioration of
      semen quality in infertile men without an obvious etiology.

PMID- 12477511
TI  - Serum levels of inhibin B and follicle-stimulating hormone may predict successful
      sperm retrieval in men with azoospermia who are undergoing testicular sperm
      extraction.
AB  - To evaluate the predictive power for sperm retrieval in testicular sperm
      extraction of inhibin B and FSH levels in the peripheral blood in association
      with the testicular histology. Clinical study. Departments of andrology and
      urology at a university hospital.Fifty-two patients with azoospermia.
      Determination of serum levels of FSH and inhibin B in men with azoospermia.
      Testicular incision and histological investigation as well as testicular sperm
      extraction (TESE) followed by intracytoplasmic sperm injection were performed.
      Comparison of hormone levels with different histological features of seminiferous
      tubules (normospermatogenesis, hypospermatogenesis, and Sertoli cell-only
      syndrome) and TESE outcome.With respect to the histological proof of spermatozoa,
      the sensitivity of the FSH levels >10 mU/mL was 82%, and of inhibin B levels, <79
      pg/mL, 78%; the specificity was 80% for both hormone levels. With respect to the
      successful sperm extraction in the TESE procedure, the sensitivity of the FSH
      levels was 58% and the specificity was 50%; and the sensitivity of inhibin B
      levels was 52.5% and the specificity was 60%. Inhibin B and FSH levels are
      correlated with spermatogenetic activity. The combination of the two parameters
      is currently the best predictor for the presence of sperm, which may be found in
      TESE. However, the prediction is not absolutely reliable: TESE can be also
      successful when both hormone levels are outside the threshold levels.

PMID- 12477512
TI  - Comparison of polymerase chain reaction-dependent methods for determining the
      presence of human immunodeficiency virus and hepatitis C virus in washed sperm.
AB  - OBJECTIVE(S): To evaluate the effectiveness of sperm washes by double
      capacitation in patients with human immunodeficiency virus (HIV) and hepatitis C
      virus (HCV) and to compare between polymerase chain reaction (PCR)-dependent
      methods to determine viral presence after the procedure. DESIGN: Controlled
      prospective clinical trial. SETTING: Private and university-affiliated setting.
      PATIENT(S): Thirty-four HIV-positive men attending our center for assisted
      reproduction with their partners. INTERVENTION(S): Forty-one semen samples from
      seropositive males were obtained and washed through density gradients and swim-up
      and analyzed for the presence of HIV and HCV with either nested or one-round PCR.
      Qualitative and quantitative detection of DNA and RNA of HIV and RNA of HCV.
      RESULT(S): Of all the semen samples that were analyzed after washing, seven out
      of 41 samples tested positive for one or both viruses by nested PCR. The
      confirmation of these results with the currently used commercial methods of
      quantitative PCR (one-round PCR) resulted in all negatives. CONCLUSION(S): Sperm
      wash with nested PCR is the appropriate method to use in the assisted
      reproduction techniques that are offered to serodiscordant couples. The detection
      limits exhibited by one-round PCR do not offer a sufficient guarantee that
      transmission of all viral particles will be avoided since both viruses can be
      present in amounts lower than the detection threshold of this technique.

PMID- 12477513
TI  - Antioxidant treatment with carnitines is effective in infertile patients with
      prostatovesiculoepididymitis and elevated seminal leukocyte concentrations after
      treatment with nonsteroidal anti-inflammatory compounds.
AB  - OBJECTIVE: To evaluate whether the association of antioxidants and anti
      inflammatory compounds may be beneficial in treatment of patients with abacterial
      prostatovesiculoepididymitis (PVE) and elevated seminal leukocyte concentrations.
      DESIGN: Open, prospective, random study. SETTING: Academic research environment.
      PATIENT(S): Ninety-eight patients with PVE who had increased seminal leukocyte
      concentrations (>1 x 10(6) cells/mL). Carnitines (group A; n = 30) or
      nonsteroidal anti-inflammatory drugs (group B; n = 16) for 4 months; nonsteroidal
      anti-inflammatory drugs for 2 months, followed by treatment with carnitines for 2
      months (group C; n = 26); or nonsteroidal anti-inflammatory treatment given
      concomitantly with carnitines (group D; n = 26) for 4 months. MAIN OUTCOME
      MEASURE(S): Semen variables, production of reactive oxygen species, and pregnancy
      outcome were evaluated before and after treatment and following a 3-month washout
      period. RESULT(S): Patients in group C had the highest reduction in production of
      reactive oxygen species associated with increased sperm motility and viability.
      Groups B and D experienced intermediate effects, and group A experienced the
      least effect. CONCLUSION(S): Antioxidant treatment with carnitines is effective
      in patients with abacterial PVE and increased seminal leukocyte concentrations if
      these patients have been pretreated with nonsteroidal anti-inflammatory drugs.

PMID- 12477514
TI  - Clinical relevance of partial AZFc deletions.
AB  - To determine the number of DAZ gene clusters in the Y-bearing spermatozoa of
      patients who underwent intracytoplasmic sperm injection (ICSI) and to compare the
      outcome with the number of clusters found in the spermatozoa of normospermic men.
      Prospective study. Academic hospital.Forty-seven patients with impaired
      spermatogenesis who were attending our clinic for ICSI and 56 semen donors.
      Peripheral blood was drawn to obtain somatic DNA for polymerase chain reaction
      (PCR) analysis and leukocytes for karyotyping and FISH analysis. Three-color FISH
      was performed on the spermatozoa remaining after ICSI and on the spermatozoa of
      semen donors to determine the presence of the X and Y chromosome as well as the
      number of DAZ gene clusters. Number of DAZ gene clusters in Y-bearing
      spermatozoa. Five patients had only one DAZ gene cluster, one patient had a
      complete AZFc deletion, and one patient had three clusters on average. One of the
      semen donors also showed three DAZ gene clusters in his Y-bearing spermatozoa.
      None of the semen donors had only one DAZ gene cluster. Besides complete AZFc
      deletions, partial deletions are also associated with impaired spermatogenesis.
      As a result, these partial deletions that are not recognized by routine PCR are
      reintroduced into the population by the ICSI technique.

PMID- 12477515
TI  - Leukocytospermia is associated with increased reactive oxygen species production
      by human spermatozoa.
AB  - To investigate the role of increased seminal leukocytes in enhancing reactive
      oxygen species (ROS) production by human spermatozoa.A prospective study. Male
      infertility clinic.Forty-eight infertile men. Standard semen analysis. Assessment
      of sperm nuclear DNA damage by sperm chromatin structure assay. Incubation of
      spermatozoa from nonleukocytospermic samples with blood neutrophils. Spontaneous
      and phorbol 12-myristate 13-acetate (PMA)-induced ROS production in pure-sperm
      suspensions (after removal of leukocytes) as measured by a chemiluminescence
      assay. Levels of spontaneous and PMA-induced ROS production in pure-sperm
      suspensions from the infertile men with a diagnosis of leukocytospermia (n = 16)
      were significantly higher compared with the case of infertile men without
      leukocytospermia (n = 32) and with the case of a control group of healthy
      volunteers (n = 13). A similar pattern of increased ROS was observed when
      spermatozoa were incubated with blood neutrophils. Leukocytospermia was
      associated with a significant decrease in sperm motility and increase in DNA
      damage. Increased seminal leukocytes may play a role in stimulating ROS
      production by human spermatozoa. Such stimulation may be mediated via direct cell
      cell contact or by soluble products released by leukocytes. Poor sperm quality in
      leukocytospermic samples may be due to leukocyte-mediated oxidative stress.

PMID- 12477516
TI  - Long-term survival of human spermatogonial stem cells in mouse testes.
AB  - OBJECTIVE: To evaluate colonizing ability of human spermatogonial stem cells in
      mouse testes. DESIGN: Transplantation of human testis cells into the seminiferous
      tubules of immunodeficient mice. SETTING: University hospital and academic
      laboratory. PATIENT(S): Men with obstructive azoospermia or maturation arrest of
      spermatogenesis. Analyzed up to 6 months after transplantation. Also analyzed:
      cryopreservation of donor cells, donor cell concentrations, and leuprolide
      treatment of recipients. MAIN OUTCOME MEASURE(S): Detection of human donor cells
      in recipient testes using whole-mount immunohistochemistry with antibodies that
      react with human germ cells. RESULT(S): Mouse testes were colonized by human
      testis cells obtained from each of 6 patients; overall, human spermatogonia were
      found in 16 of 22 (73%) recipient testes. Human spermatogonial stem cells
      survived in mouse testes for at least 6 months and proliferated during the first
      month after transplantation. No human-differentiating spermatogonia were
      identified, and meiotic differentiation did not occur in mouse testes. In this
      initial study, human stem cell colonization was not influenced by
      cryopreservation of donor cells, donor cell concentration, or leuprolide
      treatment of recipient mice. CONCLUSION(S): Xenogeneic transplantation of human
      germ cells using mice as recipients is feasible and could be used as a biological
      assay system to further characterize human spermatogonial stem cells. This study
      might provide a mechanism to evaluate the status of the stem cell population in
      selected infertile male patients.

PMID- 12477517
TI  - Insulin-lowering treatment reduces aromatase activity in response to follicle
      stimulating hormone in women with polycystic ovary syndrome.
AB  - OBJECTIVE: To investigate the effects of reduction of insulin resistance and
      hyperinsulinemia associated with the polycystic ovary syndrome (PCOS) on FSH
      stimulated ovarian aromatase activity. DESIGN: Prospective study. SETTING:
      Academic health center, Siena, Italy. PATIENT(S): Twenty women 18 to 26 years of
      age in whom PCOS was diagnosed on the basis of oligomenorrhea or amenorrhea and
      hyperandrogenemia. INTERVENTION(S): Recombinant FSH was administered. The next
      day, therapy with metformin (500 mg t.i.d.) was begun. After 35 to 40 days of
      treatment, the pretreatment protocol was repeated. MAIN OUTCOME MEASURE(S):
      Plasma levels of estradiol (E(2)), androstenedione (A), and testosterone (T). The
      ratios of basal levels and areas under the curve (AUCs) of products and
      substrates were compared before and after metformin administration to detect
      differences in aromatase activity. RESULT(S): Metformin treatment was associated
      with significant reduction in basal free testosterone plasma levels, insulin
      plasma levels, and insulin response to oral glucose tolerance testing.
      Administration of FSH was followed by a significantly lesser E(2) response after
      metformin therapy than before this therapy. The ratios of AUC(E2) to AUC(A) and
      to AUC(T), indicative of aromatase activity in response to FSH, were
      significantly lower after metformin therapy than before. CONCLUSION(S): Metformin
      therapy in women with PCOS is associated with a reduction in aromatase activity
      in response to FSH. Insulin affects production of both androgen and estrogen.
      Insulin therefore plays a central role in regulating the activity of thecal and
      granulosa cells.

PMID- 12477518
TI  - A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin
      receptor gene is associated with polycystic ovary syndrome.
AB  - OBJECTIVE: To examine whether the insulin receptor (INSR) gene contributes to
      genetic susceptibility to the polycystic ovary syndrome (PCOS). DESIGN: Case
      control study. SETTING: Academic endocrinology clinic. PATIENT(S): Ninety-nine
      women with PCOS as defined by the National Institutes of Health consensus and
      polycystic ovaries on ultrasonography, and 136 healthy controls. MAIN OUTCOME
      MEASURE: Frequency of genotypes of a single nucleotide polymorphism of the INSR
      gene in patients and controls. RESULT(S): After stratification of participants by
      body mass index, the frequency of the uncommon T allele of the INSR single
      nucleotide polymorphism was significantly increased in lean patients with PCOS
      (body mass index < or =27 kg/m2) compared with lean controls (relative risk,
      2.1). CONCLUSION(S): The INSR gene is a susceptibility gene for PCOS among lean
      patients with PCOS. It remains to be determined whether the exon 17 C/T single
      nucleotide polymorphism is the susceptibility single nucleotide polymorphism for
      PCOS or whether it is in linkage disequilibrium with another INSR gene
      polymorphism.

PMID- 12477519
TI  - Comparison of blastocyst transfer to day 3 transfer with assisted hatching in the
      older patient.
AB  - OBJECTIVE: To compare cycle outcomes in similar populations of women over 40 who
      underwent blastocyst transfer compared with women who had day 3 embryo transfer
      with assisted hatching (ET/AH). DESIGN: Retrospective study. STTING: University
      hospital-based program. PATIENT(S): Eighty-six IVF cycles in women ages 40 to 43
      years who had more than three eight-cell embryos on day 3. On day 3 of embryo
      culture, patients chose either to undergo blastocyst transfer or day 3 ET/AH.
      MAIN OUTCOME MEASURE(S): Pregnancy and cryopreservation rates were recorded.
      RESULT(S): In 48 cycles, blastocyst transfer was performed, and in 38 cycles day
      3 ET/AH was performed. There was no statistically significant difference between
      the blastocyst transfer group and the day 3 ET/AH group with respect to age (41.1
      +/- 0.9 years vs. 41.6 +/- 0.8 years), percentage of intracytoplasmic sperm
      injection cycles (29.2% vs. and 27.6%), number of oocytes (14.9 +/- 5.6 vs. 12.8
      +/- 4.0), or number of eight-cell embryos (6.1 +/- 2.2 vs. 5.4 +/- 1.5).
      Significantly fewers embryos were transferred per cycle with blastocyst transfer
      (2.6 +/- 1.0) compared with day 3 ET/AH (5.9 +/- 2.0). The viable pregnancy rate
      was similar in the blastocyst transfer group (29.2%) and in the day 3 ET/AH group
      (26.3%). Embryos for cryopreservation were available in significantly more cycles
      in the blastocyst transfer group (52.1%) than in the day 3 ET/AH group (21.1%).
      Cleavage stage arrest occurred only in one cycle. CONCLUSIONS: Blastocyst
      transfer appears to be as effective as day 3 ET/AH in older patients with good
      embryos. Higher cryopreservation rate in the blastocyst transfer group may
      represent an advantage over day 3 ET/AH. Older women may also benefit from the
      information that extended culture provides them regarding their oocyte quality.

PMID- 12477520
TI  - High rate of mixoploidy among human blastocysts cultured in vitro.
AB  - OBJECTIVE: To determine the incidence and type of mixoploidy in human blastocysts
      produced in vitro. DESIGN: A laboratory study of spare blastocysts from an IVF
      program. SETTING: University hospital laboratory. PATIENT(S): Thirty-nine couples
      undergoing IVF or intracytoplasmic sperm injection. INTERVENTION(S): A total of
      103 blastocysts were classified as good- or poor-quality blastocysts based on
      morphology. A total of 6,927 interphase nuclei, 5,015 from 59 good-quality and
      1,912 from 44 poor-quality blastocysts, were assessed for ploidy by fluorescence
      in situ hybridization with chromosome-specific DNA probes. MAIN OUTCOME
      MEASURE(S): The percentage and the type of polyploid cells present in each
      blastocyst. RESULT(S): Mixoploidy (mixture of diploid and polyploid cells) was
      found in 86% of good-quality and 82% of poor-quality blastocysts analyzed. The
      type of polyploidy ranged from 3N to 14N, with tetraploidy being the most common
      between both groups. The proportion of polyploid cells per mixoploid blastocyst
      ranged from 1% to 88%. The percentage of polyploid nuclei within most good
      quality mixoploid blastocysts was small (10%) and significantly lower than in
      poor-quality blastocysts (19%). CONCLUSION(S): Most human blastocysts produced in
      vitro contain polyploid, predominantly tetraploid cells. The proportion of
      polyploid cells in the majority of good-quality blastocysts is low. The small
      numbers of blastocysts with a high percentage of polyploid cells may have
      implications for blastocyst transfer.

PMID- 12477521
TI  - Improvement in early human embryo development using new formulation sequential
      stage-specific culture media.
AB  - OBJECTIVE: To determine whether altering selected components of sequential
      culture media can improve early development variables of human embryos. DESIGN:
      Prospective, randomized, sibling oocyte split trial. SETTING: Private ART center.
      PATIENT(S): Two hundred eight undergoing treatment with in vitro fertilization or
      microinjection. INTERVENTION(S): Oocytes from each patient were randomly
      allocated to fertilization and cleavage media of a control and a trial culture
      medium formulation. MAIN OUTCOME MEASURE(S): Rates of fertilization, cleavage,
      and uncontrolled division; average embryo morphology score; blastomeres per
      embryo; embryo score parameter (number of blastomeres x embryo morphology grade);
      and embryo utilization. The trial media resulted in a higher fertilization rate,
      higher cleavage rate, lower rate of uncontrolled division, higher number of
      blastomeres per embryo, higher average embryo morphology score, a higher embryo
      score parameter, and higher embryo utilization rate compared to the control
      media. All differences were statistically significant. CONCLUSION(S): Improved
      sequential stage-specific culture media can reduce the occurrence of severe human
      embryo fragmentation and improve developmental variables in early IVF- and ICSI
      generated embryos.

PMID- 12477522
TI  - Hemodynamic changes induced by urinary human chorionic gonadotropin and
      recombinant luteinizing hormone used for inducing final follicular maturation and
      luteinization.
AB  - OBJECTIVE: To compare the safety of recombinant human luteinizing hormone (LH)
      with that of urinary hCG in terms of the hemodynamic changes when they are used
      to induce final follicular maturation in patients undergoing in vitro
      fertilization (IVF). A secondary end point was efficacy in terms of IVF outcome.
      DESIGN: Prospective, randomized clinical trial. SETTING: University teaching
      hospital. PATIENT(S): Thirty IVF patients. INTERVENTION(S): Ovarian stimulation
      was induced with FSH under pituitary suppression. Patients were randomized to
      receive either hCG or recombinant human LH as a trigger of oocyte maturation
      (5,000 IU) and for luteal phase support (5,000 IU, 2,500 IU, and 2,500 IU on the
      day of follicular aspiration, 2 days later, and 5 days later, respectively). MAIN
      OUTCOME MEASURE(S): Mean arterial pressure, cardiac output, peripheral vascular
      resistance, and serum levels of progesterone, plasma concentrations of
      aldosterone, norepinephrine, and plasma renin activity were measured in all
      patients on postovulatory day 7 of the spontaneous menstrual cycle preceding IVF
      (baseline) and 7 days after the hCG/recombinant human LH ovulatory injection
      during the IVF cycle. RESULT(S): Ovarian response and IVF outcome (pregnancy
      rate, 60%) were similar in both treatment groups. On the seventh day after
      hCG/recombinant human LH administration, the peripheral vascular resistance was
      significantly lower and serum progesterone concentrations significantly higher in
      the hCG group as compared with the recombinant human LH group. The percentage
      change from baseline values during IVF cycles in all hemodynamic and
      neurohormonal variables investigated was higher (albeit not statistically
      different) in the group treated with hCG vs. the group treated with recombinant
      human LH. CONCLUSION(S): Recombinant human LH is associated with less intense
      circulatory changes than hCG when it is given to induce final follicular
      maturation and luteal phase support in IVF procedures.

PMID- 12477523
TI  - Comparison of leuprolide acetate and triptorelin in assisted reproductive
      technology cycles: a prospective, randomized study.
AB  - OBJECTIVE: To compare the use of two depot GnRH-a, leuprolide and triptorelin, in
      long-suppression GnRH-a protocols. DESIGN: Prospective, randomized study.
      SETTING: An IVF unit of an academic medical center.Fifty-two women who underwent
      controlled ovarian hyperstimulation and IVF. INTERVENTION(S): Patients were
      prospectively randomized to receive 3.75 mg depot formulations of either
      leuprolide or triptorelin on days 21-23 of the menstrual cycle. Stimulation with
      gonadotropins was initiated after pituitary desensitization was achieved. MAIN
      OUTCOME MEASURE(S): The stimulation pattern and cycle outcomes were compared
      between the two groups. RESULT(S): Twenty-six patients were included in each
      group. No significant differences were observed in the patient age, estrogen, and
      P levels on day of hCG administration, gonadotropin dosage, number of oocytes
      retrieved, fertilization rate, percentage of high-quality embryos, and number of
      embryos transferred. However, significantly higher clinical implantation and
      pregnancy rates were found in the leuprolide group compared with the triptorelin
      group. CONCLUSION(S): A depot preparation of leuprolide is associated with higher
      implantation and pregnancy rates than a depot preparation of triptorelin when it
      is used in the midluteal phase as part of the long-suppression GnRH-a protocol in
      IVF.

PMID- 12477524
TI  - Vitamin C and vitamin E supplementation reduce oxidative stress-induced embryo
      toxicity and improve the blastocyst development rate.
AB  - To evaluate the adverse effects of exogenously induced reactive oxygen species
      (ROS) on mouse embryo development by using the 12-phorbol 13-myristate acetate
      (PMA)-activated leukocyte model as a source of ROS, and to examine the protective
      effect of antioxidant supplementation (vitamin C and vitamin E). Prospective
      study. Research laboratory. Effects of ROS on the blastocyst development rate in
      the presence and absence of antioxidant supplementation. After incubation with
      the PMA-activated leukocyte supernatant, the median (25th, 75th percentile) rate
      of blastocyst development significantly decreased from 73% (60%, 80%) after 3
      hours to 30% (20%, 40%) after 6 hours compared with control reactions (86% [80%,
      100%]). Co-incubating the embryos with vitamin C (50 microM) and the PMA
      activated supernatant significantly increased the blastocyst development rate
      from 73% (60%, 80%) to 90% (80%, 91%) at 3 hours and from 30% (20%, 40%) to 91%
      (89%, 91%) at 6 hours-a level similar to that of control reactions. The
      blastocyst development rate increased after vitamin E supplementation (400
      microM) at 6 hours, but not significantly and not by as much as after vitamin C
      supplementation. Exposure of mouse embryos to ROS for extended periods results in
      embryotoxicity. Vitamin C is more effective than vitamin E in reversing ROS
      induced mouse embryo toxicity.

PMID- 12477525
TI  - Nitric oxide induces gelatinase A (matrix metalloproteinase 2) during rat embryo
      implantation.
AB  - OBJECTIVE: To evaluate a reciprocal signaling interaction initiated by embryo
      derived nitric oxide (NO) to facilitate implantation by increased production of
      gelatinase A (matrix metalloproteinase 2, MMP2) in uterine stroma. DESIGN:
      Experimental animal studies. SETTING: Reproductive-physiology research
      laboratory. ANIMAL(S): Female syngeneic Wistar rats aged 14 weeks.
      INTERVENTION(S): Vaginal smears to confirm pregnancy. Oviductal ligature to avoid
      the descent of blastocysts to the uterine lumen. Plasma exudation assays to
      locate uterine blastocyst implantation sites. Organ cultures treated with NO
      donors and nitric oxide synthase (NOS) inhibitors. MAIN OUTCOME MEASURE(S):
      Expression of MMP2 and NO was assessed by Western blot and zymography of tissue
      extracts and by immunofluorescence of tissue sections. RESULT(S): An increase in
      MMP2 activity was found in uterine extracts in early pregnant rats and was
      concentrated at implantation sites. Immunolocalization experiments showed that
      inducible NOS was expressed on the surface of the implanting blastocyst adjacent
      to the uterine epithelium at the sites of increased MMP2 expression. In organ
      culture experiments, NO donors were found to increase, whereas NOS inhibitors
      were found to decrease MMP2 activity in uterine tissue sections. CONCLUSION(S):
      Blastocyst-derived NO contributes to the production of uterine-derived MMP2, an
      essential component of implantation and initiation of placentation.

PMID- 12477526
TI  - Increased frequency of the G972R variant of the insulin receptor substrate-1 (irs
      1) gene among girls with a history of precocious pubarche.
AB  - To test the hypothesis that lower sex hormone-binding globulin (SHBG)
      concentrations are associated with heterozygosity for the G972R variant of the
      IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and
      hyperinsulinemic ovarian hyperandrogenism.Association study. Academic research
      environment. Adolescent girls with a history of PP and healthy adolescent female
      control subjects. Determine body mass index; measure serum androgen, insulin-like
      growth factor (IGF)-binding protein 1, lipids, IGF-1, and SHBG concentrations;
      perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene.
      Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes.Twenty-five of
      54 (45%) girls with a history of PP developed hyperinsulinemic ovarian
      hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31%
      among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian
      hyperandrogenism, and 19% among healthy control subjects. Sex hormone-binding
      globulin concentrations were lower among girls heterozygous for G972R variant.
      Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism
      included chronological age, insulin, low-density lipoprotein cholesterol, and
      IGFBP-1 concentrations. The low mean SHBG concentration found among G972R
      carriers suggests that this variant may be a minor locus associated with
      development of hyperinsulinemic insulin resistance and ovarian androgen excess in
      girls with a history of PP.

PMID- 12477527
TI  - Abnormal expression of the angiopoietins and Tie receptors in menorrhagic
      endometrium.
AB  - OBJECTIVE: To identify changes in expression of stimulatory and inhibitory
      factors when normal endometrium becomes menorrhagic. DESIGN: Retrospective
      blinded immunohistologic study. SETTING: Private research center. PATIENTS:
      Premenopausal and postmenopausal women with non-menorrhagic and menorrhagic
      endometrium undergoing curettage or hysterectomy were selected. INTERVENTION(S):
      Samples of endometrium were obtained from all patients. MAIN OUTCOME MEASURE(S):
      Expression of angiopoietins 1 and 2, and vascular receptors Tie-1 and Tie-2 and
      endothelial nitric oxide synthase (eNOS). RESULT(S): Angiopoietin 1 (ANG-1)
      expression was similar in non-menorrhagic and menorrhagic endometrium. However,
      there was a significant increase in expression of ANG-2 and its receptor Tie-2 in
      menorrhagic tissues, which may be important in destabilizing the endometrial
      vasculature. Tie-1, responsible for endothelial integrity, was also increased in
      menorrhagic tissues, and is a likely compensatory mechanism for the existing
      vascular pathology. Expression of eNOS was also increased in menorrhagic women.
      CONCLUSION(S): Differences in the expression of ANG-2, Tie-2, Tie-1, and eNOS
      were found in menorrhagic endometrium, which may represent a new target for
      therapeutic intervention to correct menorrhagic conditions.

PMID- 12477528
TI  - Involvement of nitric oxide and the ovarian blood follicle barrier in murine
      follicular cyst development.
AB  - OBJECTIVE: To test the involvement of nitric oxide in murine ovarian follicular
      cysts. DESIGN: Controlled animal study. SETTING: Academic research environment.
      ANIMAL(S): Immature female B6D2F1 mice at 23 +/- 2 days old. Ovarian cysts were
      induced by implanting miniosmotic pumps that delivered and maintained constant
      levels of hCG. Nitric oxide studies included the delivery of nitric oxide
      synthase (NOS) inhibitors, N(G)-nitro-L-arginine methyl ester (L-NAME), or N(G)
      nitro-D-arginine methyl ester, by the same method. Ovulation assays measured
      cumulus oocyte complexes and blood follicle barrier (BFB) function. RESULT(S):
      Chronic treatment with hCG induced enlarged ovaries containing multiple
      follicular cysts, which were approximately double the size of follicles in sham
      operated mice. These cysts enclosed few, if any granulosa cells, secreted high
      levels of testosterone, and had impaired ovarian BFB function. Inhibition of NOS
      by L-NAME during ovarian cyst formation reduced the size of follicular cysts,
      sustained normal testosterone levels, and maintained hormonal BFB reactivity in
      cystic follicles. CONCLUSION(S): Nitric oxide was found to be involved in the
      formation of hCG-induced murine follicular cysts and complications associated
      with these cysts were ameliorated by the NOS inhibitor L-NAME.

PMID- 12477529
TI  - Hysteropyelogram.

PMID- 12477530
TI  - Exacerbation of ovarian hyperstimulation by leuprolide reveals a gonadotroph
      adenoma.
AB  - OBJECTIVE: To report a case of a gonadotroph adenoma diagnosed after a dramatic
      increase in estradiol level and ovarian hyperstimulation in response to a
      gonadotropin-releasing hormone agonist. DESIGN: Case report. SETTING: Outpatient
      practice and university hospital. PATIENT(S): A 35-year-old woman who presented
      with infertility, amenorrhea, and an elevated basal estradiol concentration.
      INTERVENTION(S): Ultrasonography, laparoscopy, endocrinologic assays, magnetic
      resonance imaging, transsphenoidal surgery, and immunocytochemical staining. MAIN
      OUTCOME MEASURE(S): Ultrasonography and laparoscopy demonstrated bilaterally
      enlarged ovaries containing multiple preovulatory follicles, similar in
      appearance in those women undergoing controlled ovarian hyperstimulation with
      exogenous FSH. The serum estradiol level was moderately elevated, the FSH level
      was within the normal range, and LH was suppressed. Administration of leuprolide
      acetate resulted in very elevated estradiol concentrations and even larger
      ovarian cysts. Magnetic resonance imaging demonstrated a sellar mass. Examination
      of the tissue excised by transsphenoidal excision of the mass showed a pituitary
      adenoma that stained strongly for FSH. RESULT(S): Regular menses resumed soon
      after excision of the gonadotroph adenoma, followed by a spontaneous pregnancy.
      CONCLUSIONS: Gonadotroph adenoma should be suspected in a reproductive age woman
      with oligomenorrhea or amenorrhea, infertility, multiple preovulatory follicles,
      and a persistently elevated serum estradiol concentration. Exacerbation of the
      ovarian hyperstimulation in response to a gonadotropin-releasing hormone agonist
      in this setting also strongly suggests a gonadotroph adenoma but can be avoided
      by recognizing the presenting features of this condition.

PMID- 12477531
TI  - First reported convergence of premature ovarian failure and cutis marmorata
      telangiectatica congenita.
AB  - OBJECTIVE: To describe the convergence of five rare phenotypic features in a
      woman with premature ovarian failure referred for reproductive endocrinology
      evaluation. DESIGN: Case report and literature review. SETTING: Major urban
      infertility referral center. PATIENT(S): A 24-year-old nulligravida with cutis
      marmorata telangiectatica congenita (CMTC), premature ovarian failure, unilateral
      ovarian agenesis, septate uterus, and de novo balanced autosomal translocation.
      INTERVENTION(S): High-resolution chromosomal evaluation, radiographic study of
      reproductive organs, and assessment of endogenous estrogen production. MAIN
      OUTCOME MEASURE: Patient counseling regarding future reproductive options (i.e.,
      donor oocyte in vitro fertilization/embryo transfer), and satisfactory management
      of hypoestrogenism using oral contraceptives. RESULT(S): We identified a balanced
      reciprocal translocation 46,XX t(8;9)(q22.1;p24.1), and confirmed unilateral
      ovarian agenesis with midline intrauterine septum. CONCLUSION(S): Although
      genetic factors considered contributory to premature ovarian failure usually
      involve the X chromosome, in our patient a previously undescribed autosomal
      translocation was identified in association with CMTC, a rare vascular disorder.
      The fundamental role of follicular oxygenation in oocyte competence and
      subsequent ovarian function is discussed. From the clinical and laboratory
      findings evident in this unusual case, a developmental hypothesis connecting the
      vascular abnormalities of CMTC and premature ovarian failure is offered.

PMID- 12477532
TI  - Clinical phenotype and infertility treatment in a male with hypogonadotropic
      hypogonadism due to mutations Ala129Asp/Arg262Gln of the gonadotropin-releasing
      hormone receptor.
AB  - OBJECTIVE: To characterize the genotype and phenotype of a man with idiopathic
      hypogonadism with infertility. DESIGN: Molecular analysis and clinical
      description. SETTING: Medical school laboratory and reproductive endocrine
      clinic.A 40-year-old male with idiopathic hypogonadotropic hypogonadism.
      INTERVENTION(S): Denaturing gradient gel electrophoresis analysis and DNA
      sequencing of the gonadotropin-releasing hormone receptor (GNRHR) gene were
      performed. The patient was treated with hCG and FSH. MAIN OUTCOME MEASURE(S):
      GNRHR mutation detection, genotype/phenotype correlation, and testicular response
      to exogenous gonadotropin therapy. RESULT(S): The proband demonstrated compound
      heterozygosity for Ala129Asp/Arg262Gln GNRHR mutations. He had a complete form of
      idiopathic hypogonadotropic hypogonadism, with descended testes and severe
      oligospermia but little response to exogenous gonadotropins. CONCLUSION(S): The
      phenotype of this patient differs from the one other family described with the
      same mutations. Exogenous gonadotropin therapy may not be as beneficial for
      increasing sperm concentration in older men with idiopathic hypogonadotropic
      hypogonadism.

PMID- 12477533
TI  - Intermittent human immunodeficiency type 1 virus (HIV-1) shedding in semen and
      efficiency of sperm processing despite high seminal HIV-1 RNA levels.
AB  - To study seminal excretion of human immunodeficiency virus type 1 (HIV-1) during
      4 years of follow-up in an HIV-1-infected patient, the relationship between high
      viral excretion and inflammatory status of semen, and the efficiency of sperm
      processing methods in obtaining spermatozoa with undetectable RNA and proviral
      DNA levels. Case report. University hospital and research group on human
      fertility. One HIV-1-infected patient.Paired blood and semen samples were
      obtained during 4 years of follow-up.CD4 cell count; blood and seminal plasma
      viral load; and HIV-1 RNA and proviral DNA in different cell fractions obtained
      during sperm processing, as measured by the density gradient method and the swim
      up method; sperm parameters; and polymorphonuclear granulocyte count. Shedding of
      HIV-1 in semen was intermittent. The highest seminal viral loads were associated
      with a markedly increased polymorphonuclear granulocyte count, which reflects
      inflammation of the genital tract. Spermatozoa with undetectable levels of HIV-1
      RNA or DNA were obtained regardless of the viral load in semen. In an HIV-1
      infected man with intermittent seminal viral excretion, sperm processing was
      effective in obtaining spermatozoa without detectable HIV-1 genomes.

PMID- 12477534
TI  - Diagnostic role of inhibin B in resistant ovary syndrome associated with
      secondary amenorrhea.
AB  - To report two rare cases of gonadotropin-resistant ovary syndrome associated with
      secondary amenorrhea and normal levels of inhibin B. Case report. Two university
      teaching hospitals. Two women presenting with secondary amenorrhea and
      infertility. The control group for the inhibin B levels consisted of 30 cycling
      women of reproductive age. Medical history, physical examination, laboratory
      data, histologic findings, and IVF results. Diagnosis and treatment of resistant
      ovary syndrome. Case 1 was a 25-year-old woman with secondary amenorrhea and
      primary infertility. She had high serum levels of FSH and LH, low E(2) levels,
      and normal inhibin B levels (62 pg/mL). Karyotype was 46,XX, and ovarian biopsy
      showed primordial follicles with oocytes. Administration of GnRH analogue with
      hMG for 15 days did not affect E(2) levels. She had a successful pregnancy with
      IVF using donor oocytes. Case 2 was a 24-year-old woman with secondary
      amenorrhea. She had elevated serum levels of FSH and LH, low E(2) levels, and
      normal inhibin B levels (57 pg/mL). Karyotype was 46,XX and ovarian biopsy showed
      primordial follicles. Administration of GnRH analogue with hMG for 12 days did
      not affect E(2) levels. Both women were given estrogen-progestin replacement
      therapy. Inhibin B has a diagnostic role in women with gonadotropin-resistant
      ovary syndrome associated with secondary amenorrhea. A review of the literature
      confirms the uniqueness of the diagnostic role of inhibin B in these cases.

PMID- 12477535
TI  - Expression of inducible heme oxygenase in human endometrium.

PMID- 12477537
TI  - Comparison of spironolactone and spironolactone plus finasteride in the treatment
      of hirsutism.

PMID- 12477536
TI  - Mutational analysis of the mullerian-inhibiting substance gene and its receptor
      gene in Japanese women with polycystic ovary syndrome and premature ovarian
      failure.

PMID- 12477538
TI  - Leptin receptor variant in women with polycystic ovary syndrome.

PMID- 12477539
TI  - Interlaboratory variability of the indirect mixed antiglobulin reaction in the
      assessment of antisperm antibodies.

PMID- 12477540
TI  - Adolescents with varicocele have an impaired sperm-zona pellucida binding
      capacity.

PMID- 12477541
TI  - Estrogen receptor alpha gene polymorphism is associated with idiopathic
      azoospermia.

PMID- 12477542
TI  - Correct coding for laboratory procedures during assisted reproductive technology
      cycles.

PMID- 12477543
TI  - Timing of intraurterine insemination.

PMID- 12477545
TI  - Unearthing and connecting facts-conceptual biology.

PMID- 12477546
TI  - Unearthing and connecting facts-conceptual biology.

PMID- 12477548
TI  - The use of "MOOSE".

PMID- 12477550
TI  - The use of "MOOSE".

PMID- 12477551
TI  - Safety data for sildenafil.

PMID- 12477553
TI  - Safety data for sildenafil.

PMID- 12477554
TI  - Embryos, preembryos, and stem cells.

PMID- 12477555
TI  - Embryos, preembryos, and stem cells.

PMID- 12477560
TI  - Study on the variations of the apparent diffusion coefficient in areas of solid
      tumor in high grade gliomas.
AB  - Present knowledge suggests that in glioblastoma multiforme the value of the
      apparent diffusion coefficient (ADC) is elevated in the solid part and
      hyperintense in T1, in spite of the elevated cellularity, and also in areas where
      peritumoral vasogenic edema is present. The purpose of our study has been to
      verify in vivo if the ADC increases in areas of solid tumor because of an
      increased presence of edema, like it happens in areas surrounding the tumor.
      Sixteen patients with histologically verified glioblastoma multiforme underwent a
      magnetic resonance (MR) examination with sequences: T1-weighted pre and post
      contrast, diffusion-weighted at b = 0 and b = 1000 s/mm(2), perfusion-weighted.
      One hundred sixty-five regions of interest (ROI) have been obtained for all set
      of patients. In each ROI we have estimated 4 parameters: ADC, intensity of T2
      signal normalised to the white matter (SI(T2W)(n)), regional cerebral blood
      volume (rCBV), T1-signal enhancement (E%). With the SI(T2W)(n) the presence of
      edema was estimated. For each pair of measured parameters a statistical test of
      linear regression on the set of all ROI was made. A directed linear correlation
      between: ADC and SI(T2W)(n) (p <or= 0.001; r = 0.26), E% and SI(T2W)(n) (p <or=
      0.001; r = 0.35), E% and ADC (p <or= 0.001; r = 0.33) is present. Also present is
      an inverse linear correlation between: ADC and rCBV (p <or= 0.05; r = 0.18). Any
      significant linear correlation between: E% and rCBV (r = 0.01), SI(T2W)(n) and
      rCBV (r = 0.13) was not found. In areas of solid tumor the increment of the ADC
      is correlated with the increment of edema: this result can be explained if we
      assume a three-dimensional diffusion. Furthermore, the increase of ADC is
      inversely correlated to the rCBV. The E% and the rCBV are statistically
      independent.

PMID- 12477561
TI  - Detectability of blood oxygenation level-dependent signal changes during short
      breath hold duration.
AB  - Blood oxygenation level-dependent (BOLD) signal increases induced by hypercapnia
      stress has been recently investigated in human brains, which may be clinically
      relevant because it reflects cerebral hemodynamic response to vasodilatation. The
      aims of this study were to investigate the detectability of BOLD signal changes
      due to short breath holding and the feasibility of this technique in routine
      clinical practice. The results showed that significant BOLD responses could be
      detected in the gray matter for a breath hold duration as short as 10 s. Breath
      hold duration correlated strongly with the full width at half maximum of the
      hemodynamic response (r(2) = 0.975, p < 0.02), but not with the maximum signal
      change or the onset time. The fraction activation volume increased as the breath
      hold duration lengthened, reaching a plateau approximately at 20 s. Considering
      breath-holding capability of patients and detectability of BOLD signal changes,
      breath holding with a 20-s duration is suggested to be applied for clinical
      applications.

PMID- 12477562
TI  - De-noising of left ventricular myocardial borders in magnetic resonance images.
AB  - In short axis left ventricular MR images, endocardial borders are the major
      parameters in evaluation of cardiovascular functions such as end diastolic
      volume, end systolic volume, and ejection fraction. Functional analysis captures
      the dynamic behavior of the cardiovascular system as revealed by the movement of
      the endocardial borders over time. Because of the huge number of MR images, an
      effective computerized tool is required for real time applications. One of the
      widely used automatic border detection algorithm-dynamic programming-generates
      zigzag borderlines, which lead to measurement errors. This paper surveys the
      performance of the wavelet adaptive filter, the snake, and the medial filter in
      smoothing over the zigzag borders generated by dynamic programming. Statistical
      analysis of two hundred and sixty four images from sixteen subjects show that all
      three algorithms can reduce the border line errors in terms of Hausdorff distance
      and border area error; however, only the wavelet adaptive filter is effective in
      providing the physiological measurements such as ejection fraction, end systolic
      volume and end diastolic volume.

PMID- 12477563
TI  - A correction algorithm for undersampled images using dynamic segmentation and
      entropy based focus criterion.
AB  - A post-processing technique is presented for correcting images undersampled in k
      space. The method works by taking advantage of the image's background zeros
      (dynamically segmented through the application of a threshold) to extrapolate the
      missing k-space samples. The algorithm can produce good quality images from a
      small set of k-space frequencies with only a few iterations of simple matrix
      operations, using the image entropy as the focus criterion. It does not require
      any special patient preparation, extra pulse sequences, complex gradient
      programming or specialized hardware. This makes it a good candidate for any
      application that requires short scan times or where only few frequencies can be
      sampled.

PMID- 12477564
TI  - A self consistent normalized calibration protocol for three dimensional magnetic
      resonance gel dosimetry.
AB  - In a clinical setting, mixed and inconsistent results have been reported using
      Magnetic Resonance Relaxation imaging of irradiated aqueous polymeric gels as a
      three-dimensional dosimeter, for dose verification of conformal radiation
      therapy. The problems are attributed to the difficulty of identifying an accurate
      dose calibration protocol for each delivered gel at the radiation site in a
      clinical setting. While careful calibration is done at the gel manufacturing site
      in a controlled laboratory setting, there is no guarantee that the dose
      sensitivity of the gels remains invariant upon delivery, irradiation, magnetic
      resonance imaging and storage at the clinical site. In this study, we have
      compared three different dose calibration protocols on aqueous polymeric gels for
      a variety of irradiation scenarios done in a clinical setting. After acquiring
      the three-dimensional proton relaxation maps of the irradiated gels, the dose
      distributions were generated using the off-site manufacturer provided calibration
      curve (Cal-1), the on-site external tube gel calibration (Cal-2) and the new on
      site internal normalized gel calibration (Cal-3) protocols. These experimental
      dose distributions were compared with the theoretical dose distributions
      generated by treatment-planning systems. We observed that the experimental dose
      distributions generated from the Cal-1 and Cal-2 protocols were off by 10% to 40%
      and up to 200% above the predicted maximum dose, respectively. On the other hand,
      the experimental dose distributions generated from the Cal-3 protocol matched
      reasonably well with the theoretical dose distributions to within 10% difference.
      Our result suggests that an independent on-site normalized internal calibration
      must be performed for each batch of gel dosimeters at the time of MR relaxation
      imaging in order to account for the variations in dose sensitivity caused by
      various uncontrollable conditions in a clinical setting such as oxygen
      contamination, temperature changes and shelf life of the delivered gel between
      manufacturing and MR acquisitions.

PMID- 12477565
TI  - Constrained modeling for spectroscopic measurement of bi-exponential spin-lattice
      relaxation of water in vivo.
AB  - The (1)H NMR water signal from spectroscopic voxels localized in gray matter
      contains contributions from tissue and cerebral spinal fluid (CSF). A typically
      weak CSF signal at short echo times makes separating the tissue and CSF spin
      lattice relaxation times (T(1)) difficult, often yielding poor precision in a bi
      exponential relaxation model. Simulations show that reducing the variables in the
      T(1) model by using known signal intensity values significantly improves the
      precision of the T(1) measurement. The method was validated on studies on eight
      healthy subjects (four males and four females, mean age 21 +/- 2 years) through a
      total of twenty-four spectroscopic relaxation studies. Each study included both
      T(1) and spin-spin relaxation (T(2)) experiments. All volumes were localized
      along the Sylvian fissure using a stimulated echo localization technique with a
      mixing time of 10 ms. The T(2) experiment consisted of 16 stimulated echo
      acquisitions ranging from a minimum echo time (TE) of 20 ms to a maximum of 1000
      ms, with a repetition time of 12 s. All T(1) experiments consisted of 16
      stimulated echo acquisition, using a homospoil saturation recovery technique with
      a minimum recovery time of 50 ms and a maximum 12 s. The results of the T(2)
      measurements provided the signal intensity values used in the bi-exponential T(1)
      model. The mean T(1) values when the signal intensities were constrained by the
      T(2) results were 1055.4 ms +/- 7.4% for tissue and 5393.5 ms +/- 59% for CSF.
      When the signal intensities remained free variables in the model, the mean T(1)
      values were 1085 ms +/- 19.4% and 5038.8 ms +/- 113.0% for tissue and CSF,
      respectively. The resulting improvement in precision allows the water tissue T(1)
      value to be included in the spectroscopic characterization of brain tissue.

PMID- 12477566
TI  - Magnetic resonance imaging of bone marrow metastasis with fluid-fluid levels from
      small cell neuroendocrine carcinoma of the urinary bladder.
AB  - Fluid-fluid levels have been reported as an extremely infrequent and non-specific
      condition in many benign and malignant bone lesions. We present the first
      reported MRI findings of bone marrow metastasis with fluid-fluid levels from
      small cell neuroendocrine carcinoma of the urinary bladder to the lumbar spine.
      Radiologists should be aware of the MRI appearance of these extraordinary lesions
      in order to provide a complete differential diagnosis and to guide clinicians in
      adequate treatment.

PMID- 12477567
TI  - Relationships among body mass, its components, and bone.
AB  - Body weight impacts on both bone turnover and bone density, and is therefore an
      important risk factor for vertebral and hip fractures, ranking in importance
      alongside that of age. The effect of body weight is probably contributed to by
      both fat mass and lean mass, although in postmenopausal women fat mass has been
      more consistently demonstrated to be important. A number of mechanisms for the
      fat-bone relationship exist and include the effect of soft tissue mass on
      skeletal loading, the association of fat mass with the secretion of bone-active
      hormones from the pancreatic beta cell (including insulin, amylin, and preptin),
      and the secretion of bone-active hormones (e.g., estrogens and leptin) from the
      adipocyte. These factors alone probably do not fully explain the observed
      clinical associations, and further study of the actions on bone of novel hormones
      related to nutrition is an important area of further research. An understanding
      of this aspect of bone biology may open the way for new treatments of
      osteoporosis. More immediately, the role of weight maintenance in the prevention
      of osteoporosis is an important public health message that needs to be more
      widely appreciated.

PMID- 12477568
TI  - A potential role for the mast cell in the pathogenesis of idiopathic osteoporosis
      in men.
AB  - Osteoporosis is increasingly being recognized in men. Secondary causes are often
      implicated, but the mechanism of bone loss remains unclear in about a third of
      patients. The mast cell is a complex cell that stores a number of factors known
      to affect bone metabolism. Patients with systemic mastocytosis often demonstrate
      osteoporosis and bone marrow mast cells may be increased in osteoporotic
      postmenopausal women. We address the possible role of the mast cell in the
      pathophysiology of male osteoporosis by studying the relationship between bone
      marrow infiltration with mast cells and the 24 h urine excretion of N
      methylhistamine, and the severity of osteoporosis in 48 consecutive men with
      idiopathic osteoporosis (bone mineral density Z score of <-1 and/or at least one
      prevalent vertebral fracture). Secondary causes for osteoporosis were excluded
      and none of the patients had systemic manifestations of enhanced mast cell
      activity. A widely variable number of morphologically normal mast cells were
      counted in toluidine blue-stained sections from 42 of 46 evaluable bone marrow
      biopsies. In 4 of the 42 biopsies (9%), clusters of abnormal mast cells were
      identified. These four patients were the only ones who also demonstrated
      increased 24 h urine excretion of N-methylhistamine. There was a significant
      positive relationship between mast cell number and the 24 h urine excretion of N
      methylhistamine reflecting mast cell activity (p = 0.0001), and this latter
      measurement correlated negatively with bone mineral density (BMD) at the lumbar
      spine (p < 0.001). We identified clinically important bone marrow cell
      infiltration with pathologic mast cells in the absence of systemic manifestations
      of mast cell hyperactivity as an additional secondary cause for osteoporosis in
      some 9% of men with idiopathic osteoporosis, and found urinary excretion of N
      methylhistamine to be above the upper limit of the normal laboratory reference
      range diagnostic for this cause of secondary osteoporosis. The more continuous
      spectrum in the relationship between mast cell activity and BMD supports a
      potential role for this cell in the pathogenesis of idiopathic male osteoporosis.

PMID- 12477569
TI  - Mechanotransduction in bone: genetic effects on mechanosensitivity in mice.
AB  - Bone formation is enhanced by mechanical loading, but human exercise intervention
      studies have shown that the response to mechanical loading is variable, with some
      individuals exhibiting robust osteogenic responses while others respond modestly.
      Thus, mechanosensitivity - the ability of bone tissue to detect mechanical loads 
      could be under genetic control. We applied controlled mechanical loading to the
      ulnae of 20-week-old (adult) female mice derived from three different inbred
      strains (C3H/He, C57BL/6, and DBA/2), and measured the bone formation response
      with fluorochrome labels. Mechanical properties, including mechanical strain,
      second moments of area, and cortical bone material properties, were measured in a
      group of calibration animals not subjected to in vivo loading. The C3H/He mice
      were significantly less responsive to mechanical loading than the other two
      biological strains. Material properties (flexural elastic modulus, ultimate
      stress) were greatest in the C3H/He cortical tissue. Geometric and areal
      properties at the midshaft ulna were also greatest in the C3H/He mice. Based on
      the presumed role of osteocytes in strain detection, we measured osteocyte lacuna
      population densities in decalcified midshaft ulna sections. Osteocyte lacuna
      density was not related to mechanosensitivity. Our data suggest that bone
      mechanosensitivity has a significant genetic component. Identification of the
      genes that exert their influence on mechanosensitivity could ultimately lead to
      therapies that enhance bone mass and reduce fracture susceptibility.

PMID- 12477570
TI  - Bone morphogenetic protein-7 selectively enhances mechanically induced bone
      formation.
AB  - The responses of bone cells to skeletal loading are clearly an important factor
      in bone biology, but much remains to be learned about the role of these responses
      in skeletal development, maintenance, and tissue repair. Bone morphogenetic
      proteins (BMPs) are key regulators of bone formation. We examined the effect of
      BMP-7 on periosteal and endosteal bone formation in response to increased
      mechanical loading using the rat tibial bending model. Female Sprague-Dawley rats
      were divided into four groups of six rats each. Three groups received four point
      bending loading at 60 N force; the fourth group received sham loading at the same
      force. The right tibia received 36 cycles of loading on Monday, Wednesday, and
      Friday for 2 weeks; the left tibia served as a nonloaded control. Just prior to
      loading, the three loaded groups were injected intraperitoneally with vehicle
      only or 10 microg/kg or 100 microg/kg of recombinant human BMP-7. Half the sham
      group received vehicle, and half were given 100 microg/kg of BMP-7. Bone forming
      surfaces were labeled twice in vivo with calcein, and histomorphometry was
      performed to quantify periosteal and endosteal bone formation in the loaded and
      control tibiae. BMP-7 had no effect on periosteal or endosteal bone formation in
      control or sham-loaded tibiae. Loading produced significantly more woven bone on
      the periosteal surface than sham loading, but BMP-7 treatment had no effect on
      this response. Endosteal bone formation was entirely lamellar, and loading (but
      not sham loading) increased the endosteal mineral apposition and bone formation
      rates. The higher BMP-7 dose more than doubled the load-induced increase in
      endosteal lamellar bone formation rate, primarily by increasing the amount of
      bone forming surface.

PMID- 12477571
TI  - Vitamin K2 (menatetrenone) inhibits bone loss induced by prednisolone partly
      through enhancement of bone formation in rats.
AB  - Vitamin K(2) (K(2), menatetrenone) has been reported to enhance bone formation
      and inhibit bone resorption in vitro. However, there is no evidence that K(2)
      enhances bone formation in vivo. The aim of this study was to characterize the
      effect of K(2) on bone formation in vivo. We carried out two experiments using a
      prednisolone (pred)-induced bone loss model in male (10-week-old) Fischer rats.
      Pred was orally administered three times a week. In experiment 1, we compared the
      degree of bone loss induced by a 4 week treatment (30 or 100 mg/kg) and an 8 week
      treatment (3, 10, or 30 mg/kg) with pred by peripheral quantitative computed
      tomography (pQCT). At 4 weeks, total bone mineral density (BMD) was decreased
      only with the 100 mg/kg pred treatment. At 8 weeks, total BMD was significantly
      reduced at >10 mg/kg pred. In experiment 2, we investigated the effect of K(2) on
      bone loss induced by 3 and 30 mg/kg pred. K(2) (15 mg/kg) was given to rats as a
      dietary supplement for 8 weeks. Intestinal calcium transport (S/M) and total,
      trabecular, and cortical BMD at the metaphysis and diaphysis were measured, and
      histomorphometry was performed in diaphysial cross sections. Pred treatment
      decreased total and trabecular BMD in the proximal metaphysis. A decrease in
      cortical BMD in the diaphysis was observed in the pred 30 mg/kg group. Pred
      treatment also reduced mineralizing surface (MS/BS), mineral apposition rate
      (MAR), and bone formation rate (BFR/BS). The decrease in total and trabecular BMD
      in the proximal metaphysis, and in cortical BMD in the diaphysis, was inhibited
      by K(2) treatment. K(2) treatment also inhibited the decrease in MS/BS and BFR/BS
      induced by 30 mg/kg pred. These results suggest that K(2) prevents bone loss
      partly through the enhancement of bone formation.

PMID- 12477572
TI  - Adenosine triphosphate stimulates human osteoclast activity via upregulation of
      osteoblast-expressed receptor activator of nuclear factor-kappa B ligand.
AB  - Nucleotides such as adenosine triphosphate (ATP) and uridine triphosphate (UTP)
      exist in the extracellular environment where they are agonists at P2 receptors.
      Both P2Y G-protein-coupled receptors and P2X ligand-gated ion channels are
      expressed by osteoblasts and osteoclasts, reflected in the diverse nucleotide
      induced effects reported to occur in bone. Previous reports have implicated ATP
      as a proresorptive agent; however, these studies were unable to determine whether
      ATP mediated its actions directly on osteoclasts, or indirectly via osteoblasts.
      The development of techniques to generate human osteoclasts in vitro has allowed
      us to further investigate the intriguing role of extracellular nucleotides with
      regard to osteoclast activity. This study reports that nearly all P2-receptor
      subtype mRNAs were expressed throughout human osteoclast development, and
      provides evidence for functional P2 receptor expression by these cells. In
      cultures of human osteoclasts alone, neither ATP nor UTP affected the quantity of
      resorption by these cells; however, in cocultures of osteoblast-like UMR-106
      cells and human osteoclasts, ATP, but not UTP, greatly enhanced resorption,
      indicating a role for osteoblasts in mediating the proresorptive effects of ATP.
      Furthermore, ATP, but not UTP, elevated receptor activator of nuclear factor
      kappaB ligand (RANKL) mRNA and protein expression by UMR-106 cells. These data
      are consistent with observations that UMR-106 cells predominantly express P2Y(1)
      with low expression of P2Y(2), thereby explaining the response to ATP and not
      UTP, and further substantiating the involvement of osteoblasts in ATP-induced
      effects on osteoclasts. These results significantly advance our understanding of
      the role of P2 receptors in bone, and indicate that local-acting ATP may play a
      pivotal role in osteoclast activation at bone-resorbing sites by inducing
      elevated expression of RANKL.

PMID- 12477573
TI  - Effects of short-term alendronate treatment on the three-dimensional
      microstructural, physical, and mechanical properties of dog trabecular bone.
AB  - The bisphosphonate, alendronate, is well known for its potent inhibition of
      osteoclast-mediated bone resorption. It has been used clinically for the
      treatment of osteoporosis and has also recently been used to reduce osteolysis
      around prostheses in a canine revision model of implant loosening (femoral
      condyle). In this study, the effects of alendronate on trabecular bone properties
      were assessed in dogs at an oral dose of 0.5 mg/kg per day over a 12 week period,
      and compared with control dogs. Cubic cancellous bone specimens were produced
      from lumbar vertebrae (L-1 and L-2) and bilateral proximal humeri. These
      specimens were scanned using a high-resolution microcomputed tomography (micro
      CT) system. From accurate data sets, three-dimensional microstructural properties
      were calculated and physical and mechanical properties were determined. Treatment
      with alendronate increased bone volume fraction by 9.5%, 7.7%, 7.4%, and 18.4%,
      respectively, in L-1, L-2, humeral greater tuberosity, and humeral head
      trabecular bone. In the lumbar vertebrae, the alendronate-treated trabeculae were
      thicker and lower in bone surface-to-volume ratio. In the greater tuberosity, the
      alendronate-treated trabeculae were thicker, lower in bone surface-to-volume
      ratio, and less anisotropic. In the humeral head, the alendronate-treated
      trabeculae were thicker, less anisotropic, lower in surface density, and showed
      decreased trabecular separation. Alendronate significantly increased apparent
      density and collagen density in the lumbar vertebrae and humeral heads, and
      significantly decreased collagen concentration in the vertebrae. In the lumbar
      vertebrae, Young's modulus in the cephalocaudal direction, ultimate stress, and
      failure energy were significantly increased in the alendronate-treated group. The
      changes in mechanical properties in the humeral head trabecular bone were similar
      to those seen in the lumbar vertebrae. Our results demonstrate that alendronate
      increases the mechanical properties of healthy canine trabecular bone after short
      term treatment. The physical and microstructural changes of trabecular bone are
      consistent with the significantly increased mechanical properties.

PMID- 12477574
TI  - Local secretion of parathyroid hormone-related protein by an osteoblastic
      osteosarcoma (UMR 106-01) cell line results in growth inhibition.
AB  - Parathyroid hormone-related protein (PTHrP) has been implicated as being
      important in the growth of tumor cells responsive to the peptide. We utilized a
      rat osteoblastic osteosarcoma cell line, UMR 106-01, which has PTHrP receptors
      and a PTHrP-responsive adenylate cyclase/cAMP messenger system, to produce a
      modified cell line that overexpresses PTHrP. The human PTHrP cDNA sequence was
      transfected by electroporation into UMR 106-01 cells and the stable cell lines
      UMR-36 and UMR-34 were established. The modified cell line, UMR-36, had increased
      levels of PTHrP mRNA compared with control cell lines and secreted PTHrP into the
      culture medium at levels of 0.01-0.1 pmol/10(7) cells in 12 h. The secreted
      peptide was biologically active as indicated by its ability to activate adenylate
      cyclase. The number of UMR-36 cells following 9 days in culture was reduced by up
      to 80% compared with control lines, which was associated with decreased (3)H
      thymidine incorporation into genomic DNA. Addition of 1000-fold excess of the
      PTHrP antagonist, PTHrP(7-34), to UMR-36 cells resulted in the escape of growth
      inhibition and increased rate of growth. In vivo, tumors derived from UMR-36
      cells were smaller in size compared with tumors derived from control cells. In
      conclusion, increased autocrine secretion of, and responsiveness to, PTHrP
      results in inhibited growth kinetics of an osteoblast-like bone tumor cell line
      in vitro and in vivo.

PMID- 12477575
TI  - Cementum matrix formation in vivo by cultured dental follicle cells.
AB  - Dental follicle is the fibrous tissue that surrounds the developing tooth germ,
      and it is believed to contain progenitors for cementoblasts, periodontal ligament
      cells, and osteoblasts. In this study, we report the presence of cementoblast
      progenitors in cultures of bovine dental follicle cells and demonstrate their
      differentiation capacity. Bovine dental follicle cells (BDFC) obtained from tooth
      germs by collagenase digestion were compared with bovine alveolar bone
      osteoblasts (BAOB) and bovine periodontal ligament cells (BPDL) in vitro and in
      vivo. In culture, BDFC exhibited low levels of alkaline phosphatase activity and
      expressed mRNA for osteopontin (OP) and type I collagen (COLI), as well as low
      levels of osteocalcin (OC) mRNA. In contrast, cultured BAOB exhibited high
      alkaline phosphatase activity levels and expressed mRNA for OC, OP, COLI, and
      bone sialoprotein (BSP). To elucidate the differentiation capacity of BDFC in
      vivo, cells were transplanted into severe combined immunodeficiency (SCID) mice
      and analyzed after 4 weeks. Transplanted BDFC formed fibrous tissue and cementum
      like matrix, which stained positive for anti-cementum attachment protein (CAP)
      monoclonal antibody (3G9), and expressed mRNA for OC, OP, COLI, and BSP. On the
      other hand, transplanted BAOB formed bone-like matrix, but were negative for anti
      CAP monoclonal antibody. The BPDL transplants formed fibrous tissue that
      contained a few cells expressing CAP. These results indicate that cementoblast
      progenitors are present in BDFC, which can provide a useful model for
      investigating the molecular mechanisms of cementogenesis.

PMID- 12477576
TI  - Nonassociation of interleukin-1 receptor antagonist genotypes with bone mineral
      density, bone turnover status, and estrogen responsiveness in Korean
      postmenopausal women.
AB  - Interleukin-1 receptor antagonist (IL-1ra), a natural inhibitor of interleukin-1
      (IL-1), completely inhibits the stimulatory effects of IL-1 on bone resorption.
      Bioactivity of IL-1 increases in the estrogen-deficient state with an increased
      IL-1:IL-1ra ratio and decreases after estrogen replacement therapy with a
      decreased IL-1:IL-1ra ratio. An association was found between an 86 basepair
      variable number tandem-repeat (VNTR) polymorphism of the IL-1ra gene and an
      increased production of IL-1ra in a cultured monocyte system. The IL-1ra VNTR
      polymorphism, therefore, is an attractive candidate gene for osteoporosis
      susceptibility as well as hormone responsiveness after estrogen replacement. We
      examined the association of this VNTR polymorphism with bone mass, bone turnover,
      and the change of bone mineral density (BMD) after 1 year of hormone replacement
      therapy (HRT). The frequencies of the five alleles were as follows: A1, 90.8%
      (410 bp, four repeats); A2, 7.2% (240 bp, two repeats); A3, 1.6% (500 bp, five
      repeats); A4, 0.4% (326 bp, three repeats); and A5, 0% (595 bp, six repeats), in
      714 healthy ethnically Korean postmenopausal women, aged 41-74 years (55.2 +/-
      6.3 years mean +/- SD). Spine (L2-4) and femoral neck BMD were not significantly
      different among IL-1ra genotypes, and no significant genotypic differences were
      found in bone markers. There were no differences in genotypic proportions when we
      categorized the subjects into a high-loss group and a normal-loss group with
      regard to levels of bone marker. No significant genotypic differences were found
      in changes in lumbar and femoral neck BMD and those in bone markers before and
      after 1 year of HRT in 312 women. Our data suggest that these IL-1ra
      polymorphisms are not associated with BMD, bone turnover, or the change of BMD
      after 1 year of HRT in Korean women.

PMID- 12477577
TI  - Paget's disease in New Zealand: evidence for declining prevalence.
AB  - The prevalence rate of Paget's disease in New Zealand is believed to be among the
      highest in the world, but recent data suggest that it may have decreased in
      recent decades. We estimated the current prevalence of Paget's disease in
      subjects of European origin (>55 years of age) in two New Zealand cities (Dunedin
      and Auckland) based on review of nearly 2000 pelvic radiographs. Prevalence rate
      increased with age (p = 0.022) and was higher in men (p = 0.014), but there was
      no significant difference between the two cities. The Dunedin data were compared
      with a 1983 survey from the same city, and prevalence was approximately half its
      previous level (p = 0.012). In Auckland, the prevalence of an isolated raised
      plasma alkaline phosphatase level (>150 U/L, normal range <120 U/L) was estimated
      in over 80,000 blood samples processed at a community laboratory. The prevalence
      of "biochemical Paget's disease," as assessed by this surrogate marker, was very
      similar to that observed in the radiographic survey in Auckland for subjects <80
      years of age, but not for older subjects. We conclude that the prevalence of
      Paget's disease in New Zealand has declined over the past two decades, indicating
      that there are important environmental determinants in its development.
      Biochemical estimates of the prevalence of Paget's disease agree well with
      radiographic estimates, except in the elderly. The method used herein offers an
      alternative way of determining the prevalence of Paget's disease.

PMID- 12477578
TI  - Effects of long-term risedronate on bone quality and bone turnover in women with
      postmenopausal osteoporosis.
AB  - The effects of 3 years of oral risedronate treatment on bone quality and
      remodeling were assessed in women with postmenopausal osteoporosis. Transiliac
      bone biopsies were obtained at baseline and after treatment with placebo or
      risedronate 5 mg/day in 55 women (placebo, n = 27; risedronate 5 mg, n = 28);
      these pairs of samples allowed comparison of treatment effects vs. both baseline
      values and between treatment groups. A further 15 women (placebo, n = 6;
      risedronate 5 mg, n = 9) had measurements from a posttreatment biopsy, but not
      from a baseline biopsy. Samples were examined for qualitative changes (e.g.,
      osteomalacia, peritrabecular fibrosis, and woven bone); no histological
      abnormalities were found to be associated with treatment. Among women with both
      baseline and posttreatment biopsies, risedronate-treated women experienced a
      moderate and expected reduction from baseline in bone turnover, which was
      reflected in mean decreases in mineralizing surface of 58% and in activation
      frequency of 47%. Histomorphometrical parameters indicated that bone formation
      rate decreased significantly from baseline with risedronate treatment, reflecting
      a decrease in bone turnover; bone mineralization was normal following treatment.
      Basic multicellular unit (BMU) balance tended to improve in the risedronate
      treated women, whereas it tended to worsen in the placebo-treated women, although
      these changes were not statistically significant. There were no significant
      changes in structural parameters with treatment. The effects of 3 years of
      risedronate treatment on bone histology and histomorphometry reflect the
      antiresorptive mechanism of action, and are consistent with the antifracture
      efficacy and favorable bone safety profile demonstrated in large clinical trials.

PMID- 12477579
TI  - Relationship between serum 25-hydroxyvitamin D and bone resorption markers in
      vitamin D insufficiency.
AB  - It is known that nursing-home patients with vitamin D insufficiency have elevated
      serum parathyroid hormone (PTH) as well as raised serum alkaline phosphatase
      (ALP). Although it is well known that vitamin D insufficiency and secondary
      hyperparathyroidism are common among the elderly in western countries, there is
      continuing controversy over the level of serum 25-hydroxyvitamin D [25(OH)D]
      necessary for bone health. We approached this issue by examining the
      relationships between serum 25(OH)D, ionized calcium, PTH, and ALP and the
      urinary bone resorption markers hydroxyproline, pyridinoline, and
      deoxypyridinoline, corrected for creatinine (OHPr/Cr, Pyd/Cr, and Dpd/Cr,
      respectively), in 486 postmenopausal women of mean age 63 (SD 9.5) years, who
      were referred to our osteoporosis and menopause clinics for investigation. When
      the patients were divided into two groups with 25(OH)D above and below 20 nmol/L,
      30 nmol/L, 40 nmol/L, 50 nmol/L, 60 nmol/L, or 70 nmol/L, the most significant
      differences between the two groups thus derived was found at a serum 25(OH)D
      level of 60 nmol/L (P < 0.001 for all markers). The most significant difference
      between groups for serum PTH was found when the patients were divided at a serum
      25(OH)D of 50 nmol/L. PTH, OHPr/Cr, Pyd/Cr, and ALP were inversely related to
      serum 25(OH)D. PTH was inversely related to serum ionized calcium. There was a
      trend for ionized calcium to be positively related to 25(OH)D, but this did not
      reach statistical significance. We conclude that rises in three bone resorption
      markers and ALP can be detected in postmenopausal women when the serum 25(OH)D
      level falls below 60 nmol/L. Levels above this may be required for optimal bone
      health.

PMID- 12477580
TI  - Vitamin D receptor gene allelic variants, bone density, and bone turnover in
      community-dwelling men.
AB  - The role of vitamin D receptor (VDR) gene polymorphisms in the determination of
      bone mass and bone turnover is controversial in women. The aim of the study was
      to determine whether VDR polymorphisms are associated with indices of bone
      mineral density (BMD) (by dual-energy X-ray absorptiometry and by ultrasound)
      and/or with bone turnover and muscle strength, factors related to both BMD and
      fracture risk. For this purpose, we investigated a cohort of community-dwelling
      men >70 years (n = 271) and a group of healthy control subjects between the ages
      of 20 and 50 years (n = 137). VDR TaqI, ApaI, and FokI genotypes were determined
      using enzymatic restriction digestion of polymerase chain reaction (PCR)
      fragments. In the elderly group, the lowest BMD value at the femoral neck and at
      the calcaneus was observed in subjects with the "At-At" haplotype genotype, with
      differences between extreme haplotype groups ("At-At" vs. noncarriers of the "At"
      allele) ranging from 5.8% to 34.3% (p < or = 0.05). Moreover, at the different
      subregions of the distal forearm and the tibia, the lowest BMD estimates were
      consistently associated in both elderly and younger men with the "At" haplotype
      allele, although this did not approach statistical significance. Elderly subjects
      with the "At-At" genotype had a significantly higher serum osteocalcin level. BMD
      was not significantly related to the FokI VDR polymorphism at any of the assessed
      skeletal sites, nor were any of the biochemical markers associated with the FokI
      VDR genotype. There were no differences between genotype groups for any of the
      indices of muscle strength. The present study indicates that the VDR genotype is
      associated with BMD in healthy community-dwelling elderly men and tends to be
      associated with biochemical markers, particularly of bone formation, in elderly
      men.

PMID- 12477581
TI  - A comparison of the effects of droperidol and the combination of droperidol and
      ondansetron on postoperative nausea and vomiting for patients undergoing
      laparoscopic cholecystectomy.
AB  - STUDY OBJECTIVES: To compare the prophylactic antiemetic efficacy of the
      combination of ondansetron and droperidol with that of droperidol alone in
      patients undergoing elective laparoscopic cholecystectomy. DESIGN: Randomized,
      double-blind controlled trial. University affiliated teaching hospital after
      induction of standardized general anesthesia. PATIENTS: 64 ASA physical status I
      or II patients aged 18 to 80 years, undergoing elective laparoscopic
      cholecystectomy. INTERVENTION: Following induction of general anesthesia,
      patients received either droperidol 1.25 mg intravenously (IV; n = 30; Group D)
      or the combination of droperidol 1.25 mg IV and ondansetron 4 mg IV (n = 34;
      Group D+O). MEASUREMENTS: Number and severity of nausea episodes, number of
      emetic episodes, total analgesic consumption, and rescue antiemetic
      administration were assessed at 1, 3, and 24 hours after admission to the
      recovery room. Data were analyzed using Fisher's Exact test and unpaired
      Student's t-test; a p-value <0.05 was considered significant. RESULTS: The
      proportions of patients who experienced nausea (70% and 53% for D and D+O groups,
      respectively) and vomiting (30% and 19% for D and D+O groups, respectively) were
      similar in the two groups. The frequency of moderate and severe nausea (requiring
      administration of antiemetic) was less in group D + O (7%) compared with group D
      (19%; p < 0.05). CONCLUSIONS: Patients who received the combination of droperidol
      and ondansetron experienced less severe nausea compared with patients who
      received droperidol alone.

PMID- 12477582
TI  - Opening of a new postanesthesia care unit: impact on critical care utilization
      and complications following major vascular and thoracic surgery.
AB  - STUDY OBJECTIVES: To assess the impact of a new postanesthesia care unit (PACU)
      on intensive care unit (ICU) utilization, hospital length of stay, and
      complications following major noncardiac surgery. DESIGN: Observational study.
      SETTING: University hospital. PATIENTS AND MEASUREMENTS: From 1992 to 1999, 915
      patients underwent either abdominal aortic reconstruction (n = 448) or lung
      resection for cancer (n = 467). Demographic, clinical, surgical, and anesthetic
      data, as well as perioperative complications, were abstracted from two
      institutional databases. INTERVENTIONS: Patients were divided in two study
      periods, before and after the opening of a new PACU (period 1992-1995 and period
      1996-1999). MAIN RESULTS: Utilization of ICU decreased from 35% to 16% for
      vascular patients and from 57% to less than 4% for thoracic patients during the
      second period. Readmission to the ICU, perioperative mortality, and respiratory
      complications were comparable between the two periods. Patients with congestive
      heart failure, chronic obstructive pulmonary disease, or renal insufficiency were
      more likely to be admitted to the ICU than the PACU. Following vascular surgery
      the frequency of cardiac complications decreased from 10.6% in 1992-1995 to 5.2%
      in 1996-1999 (p < 0.005), as well as the need for postoperative mechanical
      ventilation (25% vs. 12%; P < 0.05). CONCLUSIONS: Increased availability of PACU
      beds resulted in reduced utilization of ICU resources without compromising
      patient care after major noncardiac surgery.

PMID- 12477583
TI  - A comparison of the remifentanil and fentanyl adverse effect profile in a
      multicenter phase IV study.
AB  - STUDY OBJECTIVE: To compare the frequency of adverse effects of remifentanil and
      fentanyl in a large and diverse patient population. DESIGN: Prospective,
      randomized, open-label study. SETTING: Multicenter study including academic and
      community hospitals. PATIENTS: 2,438 adult patients (1,496 outpatients and 942
      inpatients) scheduled for elective surgical procedures under general endotracheal
      anesthesia of at least 30-minute duration. INTERVENTIONS: Patients were randomly
      assigned to receive either intravenous (IV) remifentanil (n = 1,229) 0.5
      microg/kg/min for induction and tracheal intubation followed by an infusion rate
      of 0.25 microg/kg/min or fentanyl (n = 1,209) administered according to the
      anesthesiologist's usual practice. Anesthesia was maintained with propofol and/or
      isoflurane (with or without nitrous oxide) titrated according to protocol.
      Transition analgesia with either morphine or fentanyl was administered in the
      remifentanil and, at the anesthesiologist's discretion, in the fentanyl group.
      MEASUREMENTS: The overall nonspecific and specific (i.e., opioid-related) adverse
      effects were recorded. MAIN RESULTS: Remifentanil was associated with more
      intraoperative hypotension than fentanyl (p < 0.05). All four cases (0.3%) of
      muscle rigidity occurred in the remifentanil-treated outpatients. There were no
      significant differences between the two drugs with respect to other adverse
      events (i.e., episodes of hypertension, bradycardia, respiratory depression, and
      apnea). CONCLUSIONS: In the doses used, both remifentanil and fentanyl have a
      similar frequency of adverse effects except for the higher frequency of
      hypotension associated with the use of remifentanil.

PMID- 12477584
TI  - Effect of maintenance bolus on the recovery profile of a short-acting
      nondepolarizing muscle relaxant.
AB  - STUDY OBJECTIVE: To evaluate the effect of different maintenance boluses of a
      short-acting nondepolarizing neuromuscular blocking drug on its spontaneous
      recovery profile during anesthesia. DESIGN: Prospective, randomized, double
      blind, dose-ranging study. SETTING: University-based medical center. PATIENTS: 69
      ASA physical status I and II consenting adult outpatients undergoing general
      anesthesia with an anticipated duration of at least 2 hours. INTERVENTIONS:
      Patients were randomized to one of three study groups. Following induction of
      anesthesia with propofol and fentanyl, rapacuronium 1.5 mg x kg(-1) intravenously
      (i.v.), was administered to facilitate tracheal intubation. Anesthesia was
      maintained with desflurane 4% end-tidal in combination with nitrous oxide 67% in
      oxygen. When the first twitch (T(1)) in the train-of-four (TOF) returned to 25%
      of its baseline value, a maintenance dose of rapacuronium 0.25 mg x kg(-1) i.v.
      (Group 1), 0.5 mg. kg(-1) i.v. (Group 2), or 0.75 mg. kg(-1) i.v. (Group 3) was
      administered. The time course of neuromuscular block was monitored at the wrist
      using standard electromyography. MEASUREMENTS AND MAIN RESULTS: The times for
      recovery of the T(1) to 25% of the baseline value following different maintenance
      doses of rapacuronium were only 6.3 +/- 2.2, 7.5 +/- 2.3, and 9.6 +/- 2.5
      minutes, in Groups 1, 2 and 3, respectively. However, the times for the TOF ratio
      to return to 0.7 were 44 +/- 15, 53 +/- 20, and 66 +/- 30 minutes in Groups 1, 2,
      and 3, respectively. Although recovery times were significantly longer after
      rapacuronium 0.75 mg x kg(-1) i.v. (Group 3), there were no significant
      differences in any of the recovery variables between Groups 1 and 2. CONCLUSIONS:
      Spontaneous recovery of the T(1) to 25% of the baseline value occurred 6 to 10
      minutes after a maintenance bolus dose of rapacuronium 0.25 to 0.75 mg x kg(-1)
      i.v. However, recovery to a TOF>0.7 required 44 to 66 minutes during desflurane
      anesthesia.

PMID- 12477585
TI  - Patient-controlled bupivacaine wound instillation following cesarean section: the
      lack of efficacy of adjuvant ketamine.
AB  - STUDY OBJECTIVE: To assess the analgesic efficacy of ketamine when administered
      as an adjuvant to bupivacaine for patient-controlled wound instillation following
      cesarean section. DESIGN: Prospective, randomized, double-blind study. SETTING:
      Large referral hospital. PATIENTS: 50 term parturients undergoing cesarean
      section. INTERVENTION: In all cases, a standard spinal anesthetic was
      administered. On completion of the surgery, a multihole 20 G epidural catheter
      (B. Braun, Melsungen, Germany) was placed above the fascia such that the tip was
      sited at the point which demarcated 50% of the length of the surgical wound.
      Thereafter, the catheter was connected to a patient-controlled drug delivery
      device. The device was filled with either 0.125% bupivacaine (bupivacaine group)
      or 0.125% bupivacaine and ketamine (1 mg/mL) (bupivacaine-ketamine group).
      Postoperatively, wound instillation was performed via the patient-controlled
      analgesia device. During the first 6 postoperative hours, a co-investigator
      administered "rescue" morphine (2 mg IV). Thereafter, "rescue" dipyrone (1 g) was
      administered on patient request. MEASUREMENTS AND MAIN RESULTS: At all time
      intervals, visual analog scale (VAS) for pain at rest, on coughing, and during
      leg raise were similar between the groups. All patients (100%) in both treatment
      groups received "rescue" morphine. Similarly, the number of doses of 2 mg
      "rescue" morphine administered was unaffected by patient randomization. The total
      "rescue" morphine administered during the first 6 postoperative hours was 11.2 +/
      4.6 mg versus 11.3 +/- 5.6 mg for the bupivacaine group and bupivacaine-ketamine
      group, respectively. The number of pump infusions during the 24-hour study period
      was 9 +/- 2 and 9 +/- 3 for the bupivacaine group and bupivacaine-ketamine group,
      respectively. The volume infused via the delivery device was similar between the
      groups (81 +/- 18 mL vs. 85 +/- 24 mL for the bupivacaine group and bupivacaine
      ketamine group, respectively). Psychomental and cognitive function as measured by
      the Digit Symbol Substitution and Mini Mental Tests were unaffected by adjuvant
      ketamine administration. Patient satisfaction was similar between the groups.
      CONCLUSION: Adjuvant local ketamine does not enhance bupivacaine-induced wound
      instillation following cesarean section.

PMID- 12477586
TI  - Preoperative blood volume deficit influences blood transfusion requirements in
      females and males undergoing coronary bypass graft surgery.
AB  - STUDY OBJECTIVE: To evaluate whether preoperative blood volume and postoperative
      blood loss influence blood transfusion in females and males undergoing coronary
      artery bypass graft (CABG) surgery. DESIGN: Prospective study. SETTING:
      Anesthesiology department of a teaching hospital. PATIENTS: 57 CABG patients (21
      females and 36 males). MEASUREMENTS: Blood volume was determined using the
      radioactivity dilution method. Preoperatively, each patient received intravenous
      (IV) injection of 1 mL Albumin I(131) tracer having 25 microcuries of
      radioactivity. Five-milliliter blood samples were collected at different
      intervals. From these samples, hematocrit (Hct) value, preoperative total blood
      volume, red blood cell (RBC) volume, and plasma volume were determined.
      Postoperatively, some consenting patients received another 1 mL dose of the
      tracer, and the postoperative blood volumes were determined. If a patient
      received a blood transfusion, the units of packed red blood cells (PRBCs),
      platelets, or fresh frozen plasma (FFP) transfused were recorded. For each
      patient we recorded the gender, age, weight, height, body surface area (BSA),
      preoperative Hct, duration of surgery, and discharge Hct. RESULTS:
      Preoperatively, the mean total blood volume, RBC volume, and plasma volume,
      respectively, were 2095 mL/m(2), 631 mL/m(2), and 1,465 mL/m(2) in females; and
      2,580 mL/m(2), 878 mL/m(2), and 1,702 mL/m(2) in males. The preoperative blood
      volumes were significantly lower (p < 0.01) in females than in males. There was
      no significant difference between males and females in the extent of blood loss
      during CABG. Intraoperatively, females received PRBC transfusion of 1.38 units,
      significantly more (p < 0.01) than the 0.39 units received by males. During the
      entire hospital stay, females received 4.33 units of PRBC, significantly more
      than (p < 0.02) the 1.33 units received by males. Significantly more (p < 0.01)
      females (12 of 21) received intraoperative PRBC transfusion than did males (6 of
      36). Multiple logistic regression analysis of the data showed that PRBC
      transfusion was significantly correlated with the preoperative total blood volume
      and RBC volume. CONCLUSION: The greater need for blood transfusion in females
      than in males during CABG is primarily attributable to significantly lower
      preoperative total blood volume and RBC volume in females.

PMID- 12477588
TI  - Elastic tourniquet technique for decompression of extremity compartment syndrome.
AB  - Compartment syndrome of the extremities is usually associated with direct trauma
      and often requires surgical fasciotomy to avert potential complications and
      morbidity. We present a case of upper extremity compartment syndrome resulting
      from pressurized infusion of autologous whole blood, in which fasciotomy was
      avoided by the application of a simple and effective technique using an elastic
      Esmarch bandage. Guidelines for surgical fasciotomy and the hazards associated
      with pressurized infusion of fluids in the anesthetized patient are discussed.

PMID- 12477587
TI  - Effect of laryngeal mask airway on esophageal motility during general anesthesia.
AB  - STUDY OBJECTIVES: To determine whether the Laryngeal Mask Airway (LMA) triggers
      the pharyngo-esophago-gastric reflex during general anesthesia by comparing the
      esophageal motility of patients with the LMA and endotracheal tube (ETT) in
      place. DESIGN: Randomized clinical trial. SETTING: Operating room and recovery
      room of a tertiary-care referral hospital. PATIENTS: 50 adult ASA physical status
      I and II patients scheduled for elective orthopedic surgery. INTERVENTIONS: All
      patients received a standardized general anesthetic technique, then were
      allocated randomly to the LMA (n = 30) or ETT (n = 20) groups. MEASUREMENTS AND
      MAIN RESULTS: The esophageal manometric inputs were recorded continuously using
      an ambulatory esophageal manometric recorder and divided into five perioperative
      phases (preanesthesia, induction, surgery, LMA, or ETT rejection and arousal
      phase). The LMA or ETT was removed at the end of the surgery, when the patient
      was awake. An awake state was defined as the presence of the following clinical
      signs: swallowing, bucking, struggling, straining, and restlessness. The
      esophageal peristaltic wave percent and esophageal contraction frequency were
      significantly decreased during induction, surgery, and the LMA or ETT rejection
      and arousal phases compared with the preanesthetic phases in both the LMA and ETT
      groups. However, there were no significant group differences in any corresponding
      perioperative phases. CONCLUSION: During the general anesthetic period before the
      arousal phase in this study, a LMA does not provoke significantly different
      esophageal peristalsis compared with an ETT. Thus, the LMA is unlikely to
      stimulate the pharyngo-esophago-gastric reflex during that period.

PMID- 12477589
TI  - Tension pneumothorax during one-lung ventilation: a case report.
AB  - A 76-year-old woman underwent double-lumen endotracheal tube intubation for right
      upper lobectomy. During one-lung ventilation, she developed tension pneumothorax
      on her dependent lung and suffered cardiac arrest. The presenting signs of
      tension pneumothorax--hypoxemia, hypotension, and increased airway pressure--are
      relatively common during this procedure, leading to a delay in diagnosis and
      effective treatment. When all three signs occur together during one-lung
      ventilation, cardiovascular collapse can result and serious consideration must be
      given to the diagnosis of tension pneumothorax in the dependent lung.

PMID- 12477590
TI  - Horner's syndrome and trigeminal nerve palsy after lumbar epidural analgesia for
      labor and delivery.
AB  - This report highlights transient Horner's syndrome and trigeminal nerve palsy
      following labor epidural analgesia. A 29-year-old primigravida had a lumbar
      epidural catheter placed for analgesia in labor. The analgesia was maintained by
      infusion of a dilute local anesthetic/opioid mixture and turned off after
      achieving complete cervical dilation. Approximately 1 hour after delivery she
      complained of heaviness in her left eyelid, and was noted to have left-sided
      ptosis and paresthesia within the distribution of the ophthalmic and maxillary
      divisions of the trigeminal nerve, which resolved over the next 2 hours. There
      were no other neurologic changes. Horner's syndrome and cranial nerve palsies can
      occur as a consequence of epidural analgesia for labor.

PMID- 12477592
TI  - Subarachnoid pneumocephalus: a rare complication of epidural catheter placement.
AB  - Several potential complications may occur during identification of the epidural
      space. We present a case of subarachnoid pneumocephalus as a rare complication of
      epidural catheter placement.

PMID- 12477591
TI  - Nalbuphine reverses urinary effects of epidural morphine: a case report.
AB  - We report the successful use of nalbuphine, a mu-receptor antagonist-kappa
      receptor agonist, to reverse the adverse effects on the bladder of epidural
      morphine.

PMID- 12477593
TI  - Accidental overdose of midazolam as intramuscular premedication.
AB  - We report two cases of overdoses of intramuscular midazolam used as a
      premedication. Both cases had no resedation or complications, but the accidents
      happened as a result of a resident and nurse's lack of experience with midazolam.
      The intramuscular doses, given at four times the normal quantity, fortunately
      caused no harm in our cases. However, the situations suggest that we should
      carefully check the dosage and review the correct procedures, even when using a
      drug that is considered to be familiar with most practitioners.

PMID- 12477594
TI  - Perioperative interscalene blockade: an overview of its history and current
      clinical use.
AB  - Use of single-dose and continuous interscalene brachial plexus block (ISB) are
      gaining widespread popularity. When compared with general anesthesia, ISB has
      been reported to provide superior postoperative analgesia with fewer side
      effects, and it is associated with greater patient satisfaction. Anatomical
      landmarks are readily identifiable, which contributes to the ease of performing
      this block. In the future, we anticipate increased use of continuous interscalene
      catheters or injection of biodegradable local anesthetic impregnated microspheres
      to provide prolonged perioperative outpatient analgesia.

PMID- 12477595
TI  - Mandibular setback osteotomy: a possible factor for difficulty of endotracheal
      intubation.

PMID- 12477596
TI  - Sevoflurane anesthesia and intrathecal sufentanil-morphine for thymectomy in
      myasthenia gravis.

PMID- 12477597
TI  - A patient with a large moustache complicating laryngoscopy: a simple solution.

PMID- 12477598
TI  - Quantitative frontal and temporal structural MRI studies in personality
      disordered offenders and control subjects.
AB  - High rates of temporal and frontal lobe dysfunction have been reported in
      neuropsychological and EEG studies of incarcerated personality-disordered (PD)
      offenders, but there have been few quantitative structural magnetic resonance
      imaging (MRI) studies. We investigated whether impulsive-aggressive male PD
      patients showed evidence of reduced brain volumes in frontal and temporal brain
      regions on MRI compared with healthy control subjects. All subjects were screened
      for axis I pathology and brain abnormalities. Quantitative measures of frontal
      and temporal lobe volume were computed on MR images of the brain in 19 control
      subjects and 18 patients who did not show any evidence of brain pathology on
      diagnostic MRI scans. Temporal lobe volumes were 20% smaller in PD patients than
      control subjects, but the predicted reductions in frontal lobe volume did not
      occur, despite evidence of impairments in executive function. There was no
      evidence of differences in asymmetry of brain structures. The study further
      implicates temporal lobes in the pathogenesis of severe personality disorder, but
      does not support the notion that PDs characterised by impulsive-aggressive traits
      have abnormalities in brain symmetry similar to those reported in mentally ill
      populations. Higher-resolution MRI studies are needed to localise the
      abnormalities and to determine their nature.

PMID- 12477599
TI  - An open pilot study of nefazodone in depression with anger attacks: relationship
      between clinical response and receptor binding.
AB  - Nefazodone has been widely used as an antidepressant, but it has not been tested
      for depression with anger attacks. In an open study, we administered nefazodone
      (maximum 600 mg/day) for 12 weeks to 16 outpatients who had major depression with
      anger attacks. Assessment instruments comprised the Structured Clinical Interview
      for DSM-IV (SCID), Anger Attacks Questionnaire (AAQ), 17-item Hamilton Rating
      Scale for Depression (HAM-D-17), Clinician Global Impression Scale (CGI), Symptom
      Questionnaire (SQ), Modified Overt Aggression Scale (MOAS), and MOAS-Self-Rated.
      Three subjects underwent positron emission tomography (PET) with [18F]-setoperone
      for 5-HT2 binding potential (BP) and [11C]-SCH-23,390 for D1 BP, both at baseline
      and after 6 weeks of treatment. Eight subjects underwent PET with [18F]
      setoperone and with [11C]-SCH-23,390 at baseline only. In an examination of
      whether D1 and 5HT2 (data available in six subjects) receptor BP predicted
      treatment response, we found significant decreases in the HAM-D-17, CGI-S,
      weighted MOAS, MOAS verbal scale, OAS Self-Rated verbal, SQ Depression and
      Anger/Hostility scales after nefazodone; 50% responded to nefazodone (defined as
      >or=50% decrease in HAM-D-17 score), and 44% reported disappearance of anger
      attacks. A statistically significant percentage decrease in 5HT2 BP was observed
      for the right mesial frontal and left parietal regions after 6 weeks of
      treatment. No significant change was observed in D1 BP in any region. Although
      CGI-I scores correlated significantly with D1 BP in the left thalamic region, the
      correlation was not significant after Bonferroni correction. The effectiveness of
      nefazodone for depression with anger attacks may be related to widespread changes
      in 5HT2 receptor BP.

PMID- 12477600
TI  - Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a
      preliminary study.
AB  - Imaging studies in patients with Type II alcohol dependence have revealed
      significant reductions in dopamine (DA) D2 receptor availability. Here we
      assessed the effects of alcohol detoxification in DA D2 receptors in alcoholic
      subjects. We evaluated 14 patients with Type II alcohol dependence tested within
      6 weeks of detoxification and then re-tested 1-4 months later while alcohol free.
      The comparison group comprised 11 healthy controls. PET was used with
      [11C]raclopride to measure DA D2 receptors. Eight alcoholics and all control
      subjects were tested with a CTI 931 PET scanner and six alcoholics with a Siemens
      HR+ PET scanner. Data were analyzed separately for the studies done in the
      different scanners. Comparisons between early and late alcohol detoxification
      showed no significant changes in DA D2 receptor availability (B(max)/K(d)) for
      the studies done with the CTI and the HR+ scanners. Comparison with controls
      showed lower DA D2 receptor levels in caudate and putamen in alcoholics tested
      during early detoxification and in caudate during late detoxification. These
      studies replicate previous findings of lower striatal DA D2 receptors in
      alcoholics than in controls and absence of significant recovery during alcohol
      detoxification. These findings suggest that low DA D2 receptor availability in
      alcoholics is not due to alcohol withdrawal and may reflect a predisposing
      factor.

PMID- 12477601
TI  - Time course of tetrahydrocannabinol-induced changes in regional cerebral blood
      flow measured with positron emission tomography.
AB  - While several studies are available on the immediate effects of marijuana and its
      active ingredient tetrahydrocannabinol (THC) on regional cerebral blood flow
      (rCBF), we examined the effects of intravenous infusion of THC on rCBF and
      behavior over a 120-min. period using positron emission tomography. Indices of
      rCBF, intoxication and physiology were measured at baseline and 30, 60, 90 and
      120 min. after a 20-min. intravenous infusion of 0.15 or 0.25 mg/min. of THC, or
      placebo given to 47 subjects. The rCBF remained increased up to 120 min. after
      the high-dose THC infusion. Significant increases were seen in global perfusion
      and in the frontal, insular and anterior cingulate regions. Changes were greater
      in the right hemisphere. After the high dose, cerebellar flow was increased at
      both 30 and 60 min. The anterioposterior ratio of cortical rCBF increased in both
      hemispheres, and remained significantly greater than in the placebo condition
      until 120 min. in the right hemisphere. Intoxication peaked at 30 min. and
      remained elevated at 120 min. THC had significant effects on global CBF and rCBF,
      and feeling intoxicated accounted for changes in rCBF better than plasma level of
      THC.

PMID- 12477602
TI  - Brain development in Turner syndrome: a magnetic resonance imaging study.
AB  - Turner syndrome (TS) results from the absence of an X chromosome in females. This
      genetic condition is associated with specific cognitive deficits and variations
      in brain volumes. The goal of this study was to use high-resolution magnetic
      resonance imaging (MRI) to determine morphological variations in TS and to
      investigate the effects of parental origin of the X chromosome on brain
      development in TS. MRI brain scans were acquired from 26 girls with TS and 26 age
      and gender-matched controls. Seventeen of the TS subjects had a maternally
      inherited X chromosome (Xm), and nine of the subjects had a paternally inherited
      X chromosome (Xp). Rater-blind morphometric analyses were conducted to compare
      tissue volume differences between girls with TS and controls. Three-way analyses
      were used to compare subgroups and controls. Subjects with TS demonstrated
      bilateral decreases in parietal gray and occipital white matter accompanied by
      increased cerebellar gray matter. Subjects with Xm showed decreased occipital
      white matter and increased cerebellar gray matter compared to controls. No
      differences were found in comparisons between subjects with Xp and controls or
      between subjects with Xm and Xp. Results suggest that X monosomy affects
      posterior cerebral and cerebellar anatomy in TS. While differences between
      comparisons of Xm and Xp to controls might suggest an imprinting effect, no
      significant differences were found when the two subgroups were directly compared
      to each other. Further investigation into the possible role of genomic imprinting
      is therefore warranted.

PMID- 12477603
TI  - The role of gender in healthcare communication.

PMID- 12477604
TI  - Gender differences in health care provider-patient communication: are they due to
      style, stereotypes, or accommodation?
AB  - This article examines gender differences in health care provider-patient
      communication within the framework of an ecological model of communication in the
      medical encounter. The ecological perspective posits that, although health care
      provider-patient interactions are situated within a number of contexts (e.g.
      organizational, political, cultural), the interpersonal domain is the primary
      context within which these interactions unfold. Hence, gender may influence
      provider-patient interaction to the extent that it can be linked to the
      interactants' goals, skills, perceptions, emotions, and the way the participants
      adapt to their partner's communication. The evidence reviewed in this essay
      indicates that gender differences in medical encounters may come from several
      sources including differences in men's and women's communicative styles,
      perceptions of their partners, and in the way they accommodate their partner's
      behavior during the interaction. However, because gender is but one of many
      personal and partner variables (e.g. age, ethnicity, personal experiences) that
      can influence these processes, gender differences are often quite modest (if
      apparent at all) when examined across a population of health care providers and
      patients. Implications for future research and communicative skill training are
      discussed.

PMID- 12477605
TI  - Empathic communication and gender in the physician-patient encounter.
AB  - Although empathy in the physician-patient relationship is often advocated, a
      theoretically based and empirically derived measure of a physician's empathic
      communication to a patient has been missing. This paper describes the development
      and initial validation of such a measure, the Empathic Communication Coding
      System (ECCS), which includes a method for identifying patient-created empathic
      opportunities. To determine the extent to which empathic communication varies
      with physician and patient gender, we used the ECCS to code 100 videotaped office
      visits between patients and general internists. While male and female patients
      created a comparable number of empathic opportunities, those created by females
      tended to exhibit more emotional intensity than those created by males. However,
      female patients were no more likely than male patients to name an emotion in
      their empathic opportunities. Physician communication behavior was consistent
      with the literature on gender differences: female physicians tended to
      communicate higher degrees of empathy in response to the empathic opportunities
      created by patients. The ECCS appears to be a viable and sensitive tool for
      better understanding empathy in medical encounters, and for detecting modest
      gender differences in patients' creation of empathic opportunities and in
      physicians' empathic communication.

PMID- 12477606
TI  - Do patients talk differently to male and female physicians? A meta-analytic
      review.
AB  - A meta-analytic review was undertaken of seven observational studies which
      investigated the relation between physician gender and patient communication in
      medical visits. In five of the studies the physicians were in general practice,
      internal medicine, or family practice and were seeing general medical patients,
      and in two of the studies the physicians were in obstetrics-gynecology and were
      seeing women for obstetrical or gynecological care. Significant findings revealed
      that, overall, patients spoke more to female physicians than to male physicians,
      disclosed more biomedical and psychosocial information, and made more positive
      statements to female physicians. Patients also were rated as more assertive
      toward female physicians and tended to interrupt them more. Several results were
      weaker, or even reversed, in the two obstetrics-gynecology studies. Partnership
      statements were made significantly more often to female than male physicians in
      general medical visits but not in obstetrical-gynecological visits.

PMID- 12477607
TI  - Women's decision-making about their health care: views over the life cycle.
AB  - This paper describes a compilation and further analysis of three qualitative
      studies, conducted independently, on women's health care decisions. Key areas
      regarding women's health, which span the life cycle, were examined including
      prenatal genetic screening, hormone replacement therapy and the use of
      complementary/alternative medicine in the treatment of breast cancer. Common
      themes were evident across all the focus groups in each of the three studies
      including: women's information seeking behavior; reliance on trusted information
      sources; the desire for information sharing; active involvement in the decision
      making process; and accepting the consequences of the final decision. The
      findings have important implications for health care professionals as they engage
      women in the decision-making process about health concerns.

PMID- 12477608
TI  - Communicating fatigue in general practice and the role of gender.
AB  - The aim of this study has been to obtain more insight into the health condition
      of fatigued patients, their expectations when visiting the general practitioner
      (GP), the way they communicate, and possible gender differences. Data consisted
      of 579 patient questionnaires and 440 video-observations of these patients and 31
      GPs. Results showed that fatigue is a common health problem but seldom on the
      agenda in general practice. More women indicated symptoms of fatigue than men
      did. Fatigued patients' health was worse than that of non-fatigued patients, and
      they expected more biomedical and especially psychosocial communication.
      Furthermore, male fatigued patients expected more biomedical communication than
      fatigued female patients did. While the GPs accommodated their verbal behavior to
      fatigued patients by giving more psychosocial information and more counseling,
      they were not more affective towards the fatigued than towards the non-fatigued
      patients. Female GPs were more affective than their male colleagues, and they
      used gender-specific communication strategies to explore the patient's agenda. It
      seems necessary to use a gender-sensitive approach in communication research.

PMID- 12477609
TI  - Gender, ethnicity, and physician-patient communication about depression and
      anxiety in primary care.
AB  - The purpose of this study was to describe the influence of patient gender and
      ethnicity on physician-patient communication about depression and anxiety. A data
      set comprised of audiotapes and transcripts of 383 patients' primary care visits
      was analyzed. Depression was brought up during 25% of medical visits. Depression
      was more likely to be brought up during the visits of patients who rated their
      emotional health poorly. Female patients and more educated patients were more
      likely to initiate the discussion. Anxiety was brought up during 29.5% of medical
      visits. Anxiety was more likely to be brought up during family practice visits
      and during visits with Asian physicians. Physicians were more likely to ask male
      patients and patients who had fewer previous visits closed-ended questions about
      anxiety. Physicians were more likely to ask Hispanic patients and patients who
      rated their emotional health poorly one or more open-ended questions about
      anxiety. Female physicians were more likely to counsel patients than male
      physicians.

PMID- 12477610
TI  - Do gender-dyads have different communication patterns? A comparative study in
      Western-European general practices.
AB  - From the viewpoint of quality of care, doctor-patient communication has become
      more and more important. Gender is an important factor in communication. Besides,
      cultural norms and values are likely to influence doctor-patient communication as
      well. This study examined (1). whether or not communication patterns of gender
      dyads in general practice consultations differ across and between Western
      European countries, and (2). if so, whether these differences continue to exist
      when controlling for patient, GP and consultation characteristics. Doctor-patient
      communication was assessed in six Western-European countries by coding video
      taped consultations of 190 GPs and 2812 patients. Cluster analysis revealed three
      communication patterns: a biomedical, a biopsychosocial and a psychosocial
      pattern. Across countries, communication patterns of the female/female dyad
      differed from that of the other gender-dyads. Differences in communication
      patterns between countries could especially be explained by differences in
      consultations of male doctors, irrespective of the patients' gender. It is
      important to take into consideration differences between gender-dyads and between
      countries when studying gender effects on communication across countries or when
      comparing studies performed in different countries.

PMID- 12477611
TI  - Treating nicotine dependence during pregnancy and postpartum: understanding
      clinician knowledge and performance.
AB  - This study investigated the relationship of clinicians' knowledge of treatments
      for nicotine dependence during pregnancy and postpartum and explored what
      provider characteristics are associated with knowledge levels. Survey data from
      community health center (CHC)-based prenatal, pediatric (PED), and WIC program
      (Special Supplemental Nutrition Program for Women, Infants, and Children)
      providers participating in a randomized clinical study were used. Providers
      reported low awareness of the health risks of smoking to the developing
      fetus/child of pregnant and postpartum women and of the effectiveness of nicotine
      replacement therapy (NRT) for doubling quit rates. Obstetric (OB) and WIC
      providers were more aware than PED providers that provider-delivered
      interventions are effective. Confidence in using counseling steps was
      significantly associated with general and NRT-related knowledge. NRT-related
      knowledge, but not general knowledge, was associated with higher performance of
      intervention steps. Educational programs targeting OB, WIC, and PED providers'
      knowledge about effective smoking cessation counseling strategies and their
      confidence in being effective with patients are needed.

PMID- 12477612
TI  - Women's views of consultations about familial risk of breast cancer in primary
      care.
AB  - Developments within genetic testing may increase demands on general practitioners
      to advise about family history of breast cancer (FHBC). This descriptive,
      qualitative study, investigated women's views of GP consultations about FHBC and
      their context. Participants were women from the general population who had
      experienced a primary care consultation in which FHBC was mentioned, as reported
      by the practitioner. Information about women's views of consultation context was
      obtained from 72 telephone interviews. More in-depth information about context
      and women's evaluations of FHBC consultations were obtained from a sub-sample of
      20 face to face interviews. FHBC was rarely the main focus of consultations. It
      featured as a part of an overall discussion of breast symptoms, treatment and
      cancer risk. Women's understanding of heredity and disease was often
      idiosyncratic and might differ from biomedical models. A main task for clinicians
      appeared to be appropriate reassurance. Failure to reassure was linked to a
      failure to provide explanations at the woman's level of understanding. Clinicians
      cannot assume that patients share their perceptions of the mechanisms of disease
      and heredity. Instead they need to ascertain the patient's understanding and
      provide explanations accordingly. GPs need to have, or access, enough knowledge
      to inform and reassure.

PMID- 12477613
TI  - Evaluating participants' use of a hormone replacement therapy decision-making
      intervention.
AB  - BACKGROUND: Associations between optimal use of a tailored decision-aid and
      levels of accuracy of perceived breast cancer risk, confidence in decision
      making, and satisfaction with decisions about HRT were evaluated in a randomized
      intervention trial with a community sample of women aged 45-54. METHODS: Data are
      from 289 women randomized to receive a computer-tailored three-step decision-aid.
      RESULTS: Forty-seven percent of participants reported optimal use of the
      intervention materials. African American women and those with low confidence in
      decision-making were less likely to use the intervention optimally than white
      women and those with higher confidence (P<0.05). Optimal use of the decision-aid
      was associated with increased accuracy of perceived risk and confidence to make a
      decision. DISCUSSION: When used optimally, self-directed decision-aids can
      improve women's ability to make decisions about HRT. Additional refinement of
      these aids is needed. For some subgroups of women, adjuncts such as telephone
      counseling also might be considered.

PMID- 12477619
TI  - UKPDS58--modeling glucose exposure as a risk factor for photocoagulation in type
      2 diabetes.
AB  - In type 2 diabetes, the risk of retinopathy, and of retinal photocoagulation,
      rises with time after diagnosis of diabetes. In this paper, mathematical modeling
      shows that this ageing effect is attributable to the rise in glycemia with time
      since diagnosis of diabetes. Mathematical models were fitted to data from 3,648
      patients from the UK Prospective Diabetes Study (UKPDS). A proportional hazards
      model, in which time and glycemia measured by HbA(1c) are independent risk
      factors for photocoagulation, was compared to a model in which time does not
      contribute except through a measure of cumulative glucose exposure. Since
      likelihood ratio tests cannot be applied to non-nested models, graphical methods
      were used to compare the two models. The glucose exposure model was able to fit
      variation in survival with time at least as well as the proportional hazards
      model. The proportional hazards model, however, seriously underestimates the
      differences in two groups of different mean HbA(1c). We conclude that duration of
      diabetes and HbA(1c) level better predict risk for photocoagulation when treated
      as two components of cumulative glucose exposure, than when treated as
      independent risk factors.

PMID- 12477620
TI  - Angiotensin-converting enzyme inhibition for the treatment of moderate to severe
      diabetic retinopathy in normotensive Type 2 diabetic patients. A pilot study.
AB  - A few reports have suggested that angiotensin-converting enzyme inhibitors (ACE
      I) have a beneficial effect on mild diabetic retinopathy (DR). This pilot study
      was carried out to determine if a small dose of an ACE-I would retard the
      progression of moderate to severe DR in normotensive Type 2 diabetic patients.
      Normotensive patients were selected to isolate the effect on the ocular RAS
      independent of any lowering of blood pressure. Thirty-five normotensive Type 2
      diabetic patients with <1+ dipstick proteinuria and with moderate to severe DR by
      modified Arlie House Classification criteria on seven field stereoscopic
      photographs through dilated pupils were randomized to an ACE-I (5 mg of
      enalapril) (n=18) or to a multivitamin (MVI) placebo (n=17). They were evaluated
      by an ophthalmologist every 3 months for a planned duration of 2 years. Endpoints
      of the study were progression to proliferative DR (PDR) or macular edema (ME) for
      which laser therapy was necessary or for the development of >/=1+ dipstick
      proteinuria times two (sustained proteinuria) for which an ACE-I was indicated.
      There were no differences in baseline age, gender, duration of diabetes, body
      mass indices, blood pressure, treatment of hyperglycemia or Hb A1C levels between
      the two groups. Blood pressure and Hb A1C levels did not change in either group
      during the study. The study was stopped prematurely after a mean duration of 7.2
      months after an interim analysis revealed that it was very unlikely that a
      beneficial effect of ACE-I could be shown. At that time in the ACE-I group, four
      patients had progressed to PDR, three to ME and one had developed sustained
      proteinuria. In the MVI group, three patients had progressed to PDR, one to ME
      and one had developed sustained proteinuria. Small doses of an ACE-I did not
      exert a beneficial effect on the progression of moderate to severe DR over a
      short period of follow-up. An analysis of previously published clinical
      information on the effects of ACE-I, most of which evaluated patients with milder
      DR, supports only a limited (if any) beneficial effect of this class of drugs on
      the early stages of this microvascular complication.

PMID- 12477621
TI  - Simvastatin reduces plasma concentration of high-sensitivity C-reactive protein
      in type 2 diabetic patients with hyperlipidemia.
AB  - High-sensitivity C-reactive protein (hs-CRP) is positively associated with the
      prevalence of coronary artery disease by epidemiologic data. Prospective studies
      indicate that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
      inhibitors reduced the plasma hs-CRP concentration and the risk of recurrent
      coronary events after myocardial infarction. Type 2 diabetes is associated with
      high mortality risk of coronary heart disease and this high risk may be involved
      in the inflammatory factors. We have therefore conducted a prospective study to
      assess whether simvastatin can rapidly reduce the plasma hs-CRP concentration in
      type 2 diabetic patients with hyperlipidemia. Seventeen type 2 diabetic patients
      with hyperlipidemia were enrolled in the study after 6 weeks on a lipid-lowering
      diet. Fourteen patients completed the study, taking simvastatin 20 mg daily for 8
      weeks. Fasting blood samples were collected from each patient before and after 8
      week administration of simvastatin. In response to 8-week administration of
      simvastatin, hs-CRP levels significantly decreased from 0.312+/-0.057 to 0.193+/
      0.045 mg/dl (P<.01). Plasma LDL cholesterol also decreased significantly from
      130+/-9 to 74+/-3 mg/dl (P=.001). This study shows that plasma hs-CRP
      concentration can be reduced by 8-week administration of simvastatin in type 2
      diabetic patients with hyperlipidemia.

PMID- 12477622
TI  - Plasma vascular endothelial growth factor in Japanese Type 2 diabetic patients
      with and without nephropathy.
AB  - AIM: To determine whether plasma vascular endothelial growth factor (VEGF) level
      is elevated in Type 2 diabetic patients with an early stage of diabetic
      nephropathy. METHODS: We studied 71 Japanese Type 2 diabetic patients with normal
      serum creatinine level (<100 micromol/l) (age 63.0 [60.3-65.6] years old,
      diabetes duration 15.6 [14.0-17.3] years, HbA1c 7.36% [7.06-7.66%], mean [95%
      confidence interval, CI]): normoalbuminuric patients (n=36); microalbuminuric
      patients (n=21); and proteinuric patients (n=14). Plasma VEGF concentration was
      measured by a quantitative sandwich enzyme immunoassay technique. RESULTS: Plasma
      VEGF concentration was not related to the degree of albuminuria: normoalbuminuric
      patients (25 [13-95] ng/l, median [25th-75th percentile]); microalbuminuric
      patients (33 [15-120] ng/l); and proteinuric patients (54 [17-107] ng/l). Plasma
      VEGF level in patients with retinopathy (25 [15-95] ng/l, n=30) was not elevated
      as compared to those without retinopathy (53 [14-126] ng/l, n=34). Plasma VEGF
      tended to correlated negatively with diabetes duration (R's=-.217, P=.0690) and
      HbA1c (R's=-.221, P=.0647), whereas there was no correlation between plasma VEGF
      level and age, serum creatinine or urinary albumin to creatinine ratio (ACR) of
      the patients, respectively. Plasma VEGF level in the group of patients with HbA1c
      equal to or below the median (<7.2%) was significantly higher than that in the
      group of patients with HbA1c above the median (>7.2%) (P<.05). CONCLUSIONS: The
      results suggested that Type 2 diabetic patients with microalbuminuria and those
      with retinopathy are not necessarily associated with an elevation of circulating
      plasma VEGF concentration. Plausible association between plasma VEGF level and
      glycemic control remains to be seen.

PMID- 12477623
TI  - Association of Gly82Ser polymorphism in the RAGE gene with diabetic retinopathy
      in type II diabetic Asian Indian patients.
AB  - AIM/HYPOTHESIS: The binding of advanced glycation end products (AGE) to the
      receptor induces cellular oxidative stress and vascular dysfunction and this is
      implicated in the pathogenesis of diabetic retinopathy (DR). This study aims to
      investigate the frequency of Gly82Ser polymorphism in exon 3 of the receptor for
      AGE (RAGE) gene and its association with DR in Asian Indian patients who have
      type II diabetes. METHODS: 200 Asian Indian patients with at least 15-year
      duration of type II diabetes were identified. This group included (1) 100
      patients with retinopathy (DR) and (2) 100 patients without retinopathy (DNR).
      Fifty unrelated healthy controls (CT) were also included in the study. Genotype
      frequencies of Gly82Ser polymorphism were studied by polymerase chain reaction
      (PCR) amplification and restriction fragment length polymorphism analysis using
      AluI enzyme. Later, the nucleotide change was confirmed by DNA sequencing.
      RESULTS: The frequency of the Ser82 allele was significantly higher, 18% in the
      DNR group compared to 7% in the DR group (P=.03). The same genotype was 2% in the
      CT group. CONCLUSION/INTERPRETATION: Our result suggests that Ser82 allele in the
      receptor for AGE gene is a low-risk allele for developing DR in Asian Indian
      patients who have type II diabetes.

PMID- 12477624
TI  - Effects of inhibition of glycation and oxidative stress on the development of
      diabetic nephropathy in rats.
AB  - We investigated whether aminoguanidine (AG), an inhibitor of advanced glycated
      end product formation, or probucol (PB), a free radical scavenger, could
      influence signs of glomerular and distal tubular function and morphological
      changes in kidneys of male Wistar rats after 6 months of streptozocin (STZ)
      induced diabetes. Diabetic rats had a higher kidney weight/body weight ratio
      (P<.001), but neither AG nor PB influenced the increased ratio. Diabetes caused
      an increased urinary albumin excretion (P<.05), which was normalized by AG, but
      further exaggerated by PB (P<.001). Diabetes also caused an increase in the
      urinary excretion of Tamm-Horsfall protein (P<.001). Both AG and PB attenuated
      this increase (P<.05 for both). A few glomeruli displayed focal thickening of
      varying degrees. Silver staining disclosed the glomerulopathy to be
      intercapillary glomerulosclerosis. Rats on PB-enriched diet displayed less
      pronounced changes than untreated rats (P<.01), while AG had no effect. The
      results suggest that oxidative stress could be involved in the development of
      diabetic nephropathy.

PMID- 12477625
TI  - Atherosclerosis in type 2 diabetes mellitus and insulin resistance: mechanistic
      links and therapeutic targets.
AB  - The ongoing heavy burden of cardiovascular disease associated with diabetes
      mellitus highlights the failure of current treatment strategies to address
      effectively the cardiovascular risk profile in such patients. Insulin resistance
      is not only an underlying feature in most cases of type 2 diabetes, but is also
      associated, through the Insulin Resistance Syndrome, with cardiovascular risk
      factors that promote atherothrombosis through diverse mechanisms. Growing
      evidence suggests that treatment with anti-diabetic agents that improve insulin
      sensitivity, such as the thiazolidinediones, improve multiple components of the
      Insulin Resistance Syndrome, have beneficial effects on various atherothrombotic
      mechanisms, and reduce atherosclerosis in animal models and perhaps humans as
      well. Given data implicating chronic inflammation as a central feature of
      atherosclerosis, the anti-inflammatory activity of the thiazolidinediones may
      contribute to their potential anti-atherosclerotic effects. An improved
      understanding of the mechanisms linking diabetes, atherosclerosis, and
      cardiovascular disease is needed in order to understand how these and other
      current and emerging therapies might reduce diabetes-associated cardiovascular
      disease.

PMID- 12477626
TI  - Application of multivariate chemometrics in forensic soil discrimination based on
      the UV-Vis spectrum of the acid fraction of humus.
AB  - Forty-four soil samples from five different areas were examined on the basis of
      the UV-Vis spectrum of the acid fraction of humus with a view to achieving good
      discrimination between them. Fulvic and humic acids were extracted from the
      samples into an alkaline aqueous solution and absorbance values, after
      appropriate transformations, were subjected to a K-mean cluster analysis (CA)
      over the objects (samples) for an initial feature reduction (20 variables
      retained). This was followed by principal component analysis (PCA) for the
      removal of outliers (four samples removed). The same statistical technique was
      used on the remaining samples to decide how many variables to enter into the
      linear discriminant function analysis (DA) and whether original variables or
      component scores should be used. It was found that the scree test was a good
      criterion for deciding on the number of components to extract (nine components
      extracted) and that the use of component scores instead of original variables led
      to a lower average redundancy (20.6%) of the variables in the discriminant model.
      From the components entered into the model and their loadings, it was concluded
      that the discrimination achieved was due to the relative concentration of
      aromatic groups and other fragments in the samples as well as the degree of soil
      humification. An overall 85% correct classification of the training dataset was
      observed (Wilks' lambda = 0.0420) and the method was judged satisfactory for
      supporting exclusionary forensic purposes.

PMID- 12477627
TI  - The expression of excitatory amino acid transporter 2 in traumatic brain injury.
AB  - It is well recognized that glutamate is the major excitatory neurotransmitter,
      which is removed from the synaptic cleft by excitatory amino acid transporter 2
      (EAAT2) located on the perisynaptic astrocytes and that neuronal death has been
      associated with an increased extracellular glutamate concentration. In this
      study, we have immunohistochemically demonstrated the expression of EAAT2 protein
      in the human brain after traumatic brain injury (TBI). The EAAT2 expression
      patterns can be divided into three types: continuous and highly extensive
      staining (E); continuous but sporadic staining (M); and sporadic pattern staining
      (S). In six of the nine short survival cases studied (1 h to 1 day), continuous
      and highly extensive staining for EAAT2 (E type) was observed in the ipsilateral
      cerebral cortex. On the other hand, we were able to demonstrate weak staining (S
      and M types) in 5 of the 7 long survival cases (> or =1 day) and in 12 of the 14
      very short survival cases (<1 h) studied. Similar findings were obtained in the
      contralateral cerebral cortex and also in the ipsilateral hippocampus. In
      addition, positive staining for glial fibrillary acidic protein was detected
      around the cerebral contusion, but the EAAT2-positive expression was not observed
      in the same region for all of the six short and long survival cases (> or =1 h)
      after TBI. These findings clearly showed the differences in EAAT2 expression in
      the cerebral cortex according to the survival time and severity of cerebral
      contusion after TBI. Therefore, we emphasized that EAAT2 might play an important
      role in contributing to extracellular glutamate concentrations and secondary
      brain injury after TBI.

PMID- 12477628
TI  - Time-dependent immunohistochemical detection of proinflammatory cytokines (IL
      1beta, IL-6, TNF-alpha) in human skin wounds.
AB  - The proinflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6)
      and tumour necrosis factor-alpha (TNF-alpha) hold important functions in the
      early and late courses of inflammation, trauma and wound healing. In the present
      study, human skin wounds due to sharp force (n = 105) were collected during
      surgery and autopsy. The wound age mainly varied from several minutes to 5 h,
      some specimens aged up to 6 weeks. Control specimens from uninjured skin were
      available in each case. After preparation of cryostat sections,
      immunohistochemistry was performed according to the APAAP technique, using
      monoclonal and polyclonal antibodies. The results were evaluated
      semiquantitatively. All markers were weakly expressed in normal human skin
      constitutively. However, the staining pattern changed significantly in vital
      wounds concerning epidermal layers, subepidermal cells, vessels and sweat glands.
      IL-1beta and IL-6 showed enhanced expression after 15 and 20 min at the earliest
      (increase of epidermal reactivity). After 30-60 and 60-90 min, respectively,
      marked expression was observed with these markers. Similar alterations were
      detectable with TNF-alpha after 15 and 60-90 min. The reactivity of all three
      markers persisted over several hours, then decreased to basal levels again and
      sometimes reappeared after days and in granulation tissue. Leukocytes reacting
      with IL-1beta and IL-6 appeared after approximately 2 h. CONCLUSION:
      proinflammatory cytokines can serve as a useful tool for the estimation of
      vitality and wound age, in particular in the early post-traumatic interval prior
      to leukocyte reaction. Autolysis did not play a role in the samples investigated
      (postmortem interval up to 8 days). Problems could sometimes rise from
      constitutive expression. Therefore, it is recommended to examine control samples
      from the same individual and to compare the reactivity with wound specimens.

PMID- 12477629
TI  - Forensic value of 14 novel STRs on the human Y chromosome.
AB  - We identified and characterized 14 novel short-tandem-repeats (STRs) on the Y
      chromosome and typed them in two samples, a globally diverse panel of 73 cell
      lines, and 148 individuals from a European-American population. These Y-STRs
      include eight tetranucleotide repeats (DYS449, DYS453, DYS454, DYS455, DYS456,
      DYS458, DYS459, and DYS464), five pentanucleotide repeats (DYS446, DYS447,
      DYS450, DYS452, and DYS463), and one hexanucleotide repeat (DYS448). Sequence
      data were obtained to designate a repeat number nomenclature. The gene
      diversities of an additional 22 Y-STRs, including the most commonly used in
      forensic databases, were directly compared in the cell line DNAs. Six of the 10
      most polymorphic markers include the newly identified Y-STRs. Furthermore, these
      novel Y-STRs greatly improved the resolution of paternal lineages, above the
      level obtained with commonly used Y-STRs, in the European-American population.

PMID- 12477630
TI  - Sequence analysis of STR polymorphisms at locus ACTBP2 in the Taiwanese
      population.
AB  - A highly polymorphic sequence structure is reported in the human beta-actin
      related pseudogene 2 (ACTBP2) (SE33) locus in members of the Taiwanese Han
      population. A total of 100 unrelated members of the Taiwanese Han population were
      used in the study. Alleles that shared the same size but differ in their sequence
      are described to allow for inter laboratory sharing of data. PCR products
      amplified from this locus were separated by single-strand conformation
      polymorphism electrophoresis, the single-stranded DNA bands were excised from the
      gels, a second amplification performed, and then the PCR products were sequenced.
      All the alleles differed by either 2 or 4 bp. Sequence variations were observed
      as deletions or insertions in the repeat units AG (or AA) and AAAG. Additionally,
      transitions in the flanking regions were recorded. A total of 27 alleles with 71
      associated genotypes were recorded if the alleles were defined by size, but 68
      alleles with 88 associated genotypes were noted with the alleles were scored on
      the basis of sequence variation. The power of discrimination (Pd) of this single
      locus was 0.9874 making the human ACTBP2 a good alternative marker for individual
      identification and paternity testing.

PMID- 12477631
TI  - Death in bathtub revisited with molecular genetics: a victim with suicidal traits
      and a LQTS gene mutation.
AB  - A 44-year-old woman with a medical history of mental disorders and previous
      suicidal behaviour was found in a bathtub and pronounced death few minutes later
      despite of resuscitation attempts. After police investigation and on the basis of
      autopsy findings, the death was classified as suicide drowning. Retrospective
      examination of clinical data revealed, a prolonged rate-corrected QT-interval
      (QTc: 468 ms) 3 months before death. Post-mortem (PM) DNA analysis disclosed
      KCNH2(FIN) mutation for the long-QT syndrome (LQTS). The value of PM molecular
      screening for LQTS is emphasised, especially for victims of putative drowning.

PMID- 12477632
TI  - Bounding the number of contributors to mixed DNA stains.
AB  - We derive a simple inequality for the probability of observing a given DNA
      profile when assuming a fixed number of unknown persons have contributed to the
      mixed stain. We then show how this inequality can be used to obtain an upper
      bound for the number of unknown contributors needed to be considered.

PMID- 12477633
TI  - Degradation profile of mRNA in a dead rat body: basic semi-quantification study.
AB  - To profile postmortem degradation of mRNA, total RNA was extracted, at given
      postmortem intervals, from the brain, lung, heart and liver of rats left at 20
      degrees C. In electrophoretic analysis, total RNA was most stable in the brain,
      moderately stable in the lung and heart, and most unstable in the liver. Northern
      blot analysis of total RNA extracts from the brain and liver of dead rats with a
      cDNA probe for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) showed that GAPDH
      mRNA degraded in a similar fashion to total RNA. Analysis of the postmortem
      degradation profile of GAPDH mRNA with real-time reverse transcriptase-polymerase
      chain reaction (real-time RT-PCR) gave results consistent with those above,
      indicating that real-time RT-PCR is reliable for estimation of the mRNA level in
      specimens from dead bodies. Real-time RT-PCR analysis showed that degradation
      rates of three housekeeping genes, GAPDH, beta-actin and hypoxanthine guanine
      phosphoribosyltransferase, in the brains of dead rats were similar. The
      degradation rate of interleukin-1beta (IL-1beta) mRNA induced by intravenous
      injection of LPS to rats was higher than that of GAPDH mRNA in the lung. In real
      time RT-PCR analysis using GAPDH mRNA as an internal standard, the detection
      level of IL-1beta mRNA decreased in the postmortem interval. However, enhanced
      expression of IL-1beta was detected for at least 3 days postmortem.

PMID- 12477634
TI  - Injuries inflicted on homicide victims. A longitudinal victiminologic study of
      lethal violence.
AB  - For the purpose of studying homicidal violence from a victiminologic point of
      view, we have examined the number and nature of injuries inflicted on homicide
      victims examined at the Department of Forensic Medicine in Stockholm during the
      periods 1976-1978, 1986-1988 and 1996-1998. Evaluation of the total number of
      injuries (both lethal and non-lethal) revealed a break in the earlier trend
      during the last of these periods, which demonstrated a clear increase in the
      number of injuries probably caused by intense and prolonged violence. Thus, there
      were 14 victims with 40 or more injuries (the maximum being 101 injuries) in the
      1996-1998 period, whereas there was only one such victim in each of the two
      earlier periods. Furthermore, the proportion of victims exhibiting multiple
      lethal injuries was greater during the last period than during the two preceding
      periods. These findings indicate a general enhancement in the level of aggression
      exerted by violent offenders, as well as an increase in the number homicide
      victims with injuries apparently inflicted by acts of aggression characterized by
      outrage.

PMID- 12477635
TI  - Simultaneous identification/determination system for phentolamine and sildenafil
      as adulterants in soft drinks advertising roborant nutrition.
AB  - An easily available, simultaneous identification/determination procedure for
      phentolamine (PHE) and sildenafil (SIL) in adulterated dietary supplements was
      established by using a combination of three different analytical methods; thin
      layer chromatography (TLC), liquid chromatography-mass spectrometry (LC/MS) and a
      high-performance liquid chromatography (HPLC)/photo-diode-array. The sample
      solution for TLC was applied to silica gel 60 F(254) plates with
      chloroform/ammonia solution (28)/methanol (70:5:3, lower layer) and
      chloroform/diethylamine/methanol (15:3:2) as the developing solvent. Spots were
      located under UV radiation at 254 nm. Mass spectra of PHE and SIL by LC/MS were
      investigated with electrospray ionization (ESI) interface, under both positive
      and negative ion mode. The HPLC analysis was performed on a column of Wakosil
      5C18 (4.6 mm x 150 mm, 5 microm) with water/methanol/acetonitrile/triethylamine
      (580:250:170:1) adjusted with phosphoric acid to pH 3.0 as the mobile phase, and
      the effluent was monitored with a photo-diode-array detector. Quantitative HPLC
      analysis of PHE and SIL were detected at 280 nm. When this procedure was applied
      to commercial soft drinks, PHE and SIL were identified and determined at a
      concentration of 17 mg PHE and 44 mg SIL per bottle, respectively. The procedure
      described here is available for the screening of PHE and SIL in adulterated
      supplements.

PMID- 12477636
TI  - Mismatch distribution analysis of Y-STR haplotypes as a tool for the evaluation
      of identity-by-state proportions and significance of matches--the European
      picture.
AB  - We suggest the use of the mismatch distribution methodology as an easy way to
      estimate the distance between all pairs of haplotypes present in a sample. This
      approach allows the evaluation of the proportion of pairs of Y-STR haplotypes
      that are prone to become identical by state (IBS), in one generation, by
      recurrent mutation, a statistic of major importance in the forensic field. The
      mismatch approach presents some advantages alternatively to the empirical one,
      since it is not necessary to have simultaneous information on STRs and SNPs, and
      it allows the evaluation of IBS also within-haplogroups. The estimation of IBS at
      an European scale showed that there is a high population substructuring for this
      parameter, increasing from southern-central European countries towards west and
      north, in accordance to what was found for Y-biallelic markers. This result seems
      to imply a more careful use of large databases for matching evaluation, even in
      the absence of population structure for general Y-STR diversity. Furthermore,
      mismatch distribution can be used to measure the distance between a particular
      haplotype and all the haplotypes in a sample. When applied to the most frequent
      haplotypes in Europe it revealed that the opportunity for IBS is not directly
      related to the frequency of a haplotype, but highly dependent on the proportion
      of neighbouring haplotypes--so, that reporting on the haplotype frequency for
      evaluating the significance of a match can be misleading.

PMID- 12477637
TI  - Motor vehicle accident with complete loss of consciousness due to vasovagal
      syncope.
AB  - Vasovagal syncope (VVS) is one of the most common causes of complete or partial
      loss of consciousness, thus it might cause harm to the patients themselves or
      innocent bystanders while driving a car. In our case report we introduce the case
      of a 60-year-old man who was admitted to hospital after a serious motor vehicle
      accident due to loss of consciousness. We demonstrate the process and results of
      complete cardiologic and neurological assessment. Our case report illustrates the
      importance of recognition of patients with a high risk for incapacitating
      symptoms due to VVS, and the use of head-up tilt-table tests to determine the
      diagnosis and to guide therapy with beta-blocking agents. As transient loss of
      consciousness during driving may cause potentially fatal accident, it has to be
      taken into consideration during decision making for issue of driving licenses to
      patients with VVS.

PMID- 12477638
TI  - Serum C-reactive protein levels in postmortem blood--an analysis with special
      reference to the cause of death and survival time.
AB  - We have investigated postmortem serum CRP levels in 408 forensic autopsy cases
      consisting of 216 acute and 192 non-acute death cases having postmortem interval
      of less than 48 h. CRP ranged from 0.03 to 66.13 mg/dl with the median of 0.28
      mg/dl. In 362 traumatic death, survival time and the presence of severe infection
      were the major factors contributing to CRP elevation, while postmortem interval,
      age, gender, hepatic injury and liver cirrhosis was not. In almost all the
      immediate deaths (15/16) CRP remained at a low level (<0.5 mg/dl). Acute deaths
      and subacute deaths within 6 h showed lower CRP levels compared to longer
      survivors, consistent with the clinical and experimental studies. As for natural
      diseases, the CRP level reflected the pathological findings. The results suggest
      a possibility of CRP as a forensic diagnostic marker.

PMID- 12477639
TI  - Drug recognition expert evaluations made using limited data.
AB  - The Drug Evaluation Classification (DEC) Program is used by Drug Recognition
      Expert (DRE) officers to determine whether a suspect is under the influence of a
      drug or drugs at the time of arrest, and, if so, what category of drug(s). The
      goal of this project was to investigate the relative importance of face-to-face
      interactions with the suspect, physical evidence (drugs or paraphernalia found),
      and confessions/statements made by the suspect (or others) in making these
      determinations. Seventy records of DRE evaluations were selected from a database
      containing information from all evaluations conducted in Oregon between 1996 and
      1998. Each of the 70 records represented a suspect who had either taken a drug
      from one of four categories (CNS depressant, CNS stimulant, narcotic analgesic,
      or cannabis) or who had not taken a drug. To be included, the original DRE
      evaluation and the subsequent toxicology analysis had to agree that the suspect
      was under the influence of a drug from one of the four categories or not under
      the influence of a drug. Records from the 70 cases were submitted in written form
      to 18 Oregon DREs with statements made by suspects or arresting officers,
      confessions, toxicology results, and descriptions of drugs or paraphernalia found
      on the suspect omitted. Based only on the written reports of direct observations,
      and with physiological and psychophysical test results, the DREs attempted to
      determine whether each of the 70 suspects was under the influence of a drug or
      drugs, and, if so, what category of drug(s). If the officers determined that a
      suspect was under the influence of a drug, their accuracy in specifying the drug
      category was 81% for cannabis, 94% for narcotic analgesics, 78% for CNS
      stimulants, and 69% for CNS depressants. Overall accuracy in recognizing drug
      intoxication was 95%. These percentages indicate that although face-to-face
      interactions, physical evidence, and confessions/statements can be useful
      adjuncts to DRE decision-making, the majority of drug category decisions can be
      made solely on the basis of recorded suspect observations and DRE evaluation
      results.

PMID- 12477640
TI  - Forensic odontology lessons: multishooting incident at Port Arthur, Tasmania.
AB  - On Sunday 28 April 1996 a lone gunman killed and injured many people at the
      historic penal settlement ruins at Port Arthur in South Eastern Tasmania,
      Australia. Thirty-two victims were shot dead and 19 were injured in a short time
      inside a cafe and along the roadway leading to the site entrance. The gunman then
      took one hostage to a nearby guest house which was occupied by a married couple.
      Police stood siege during the night. Early the next day the cottage began to burn
      and a man suspected to be the gunman eventually ran unarmed from the building
      with his clothes alight and was arrested. The house burned to the ground. Three
      bodies were later located in the burnt ruins. Forensic odontology played a role
      in the retrieval of evidence and identification of the incinerated victims. Lack
      of antemortem dental records for one victim necessitated the reliance on a single
      CT scan radiograph for matching with the remains. Fire scene procedures, evidence
      collection and other issues were reviewed. The overwhelming scale of this tragedy
      and its adverse effects on the Tasmanian community, especially the victims'
      families and survivors, cannot be overestimated. While acknowledging this, it is
      important that lessons are learnt from tragedies such as these. This paper is
      presented with a view to assisting forensic odontologists in the investigation of
      complex incidents.

PMID- 12477641
TI  - Absinthe: enjoying a new popularity among young people?
AB  - Absinthe, an alcoholic drink used in certain artistic circles and considered the
      inspiring muse of many famous artists because it was reputed to stimulate
      creativity and possess exciting, aphrodisiacal and healing properties, in the
      past enjoyed enormous popularity so much so that it led to a real collective
      abuse so causing its prohibition in many countries, is again enjoying a new
      period of popularity. Also in Italy there is increasing information about the use
      and abuse of this drink. We received a request to analyse and determine the
      nature of two samples of alcoholic drinks, obtained by macerating Artemisia
      absinthium leaves in ethanol. Analyses of extracts by gas chromatography/mass
      spectrometry (GC/MS) identified beta-thujone, which is responsible for the
      activity and toxic effects on the CNS of absinthe, in both alcohol samples.

PMID- 12477642
TI  - Allele frequencies of nine STR loci--D16S539, D7S820, D13S317, CSF1PO, TPOX,
      TH01, F13A01, FESFPS and vWA--in the population from Alagoas, northeastern
      Brazil.
AB  - The polymorphism of nine STR loci has been studied in a sample of 598 individuals
      from the population of Alagoas, Northeastern Brazil. Determination of the allele
      frequencies as well as of several commonly used statistics in forensic and
      paternity testing were defined. The most polymorphic loci were TH01 and D7S317.
      The exact test demonstrated that the nine loci analyzed in the population have no
      deviation from Hardy-Weinberg equilibrium (P > 0.05).

PMID- 12477643
TI  - Genetic variation at 15 autosomal microsatellite loci in the three highly
      endogamous tribal populations of Orissa, India.
AB  - Although microsatellite diversity in autosomal chromosomes has been extensively
      described for many of the Indian populations, there is still a lacuna left on
      information about the genetic diversity of tribal populations. This paper reports
      the genetic data on the three tribal populations belonging to the Austroloid
      ethnic group from Orissa (Juang, Paroja and Saora). The 15 STR (D3S1358, THO1,
      D21S11, D18S51, PentaE, D5S818, D13S317, D7S820, D16S539, CSF1PO, PentaD, vWA,
      D8S1179, TPOX, FGA) polymorphism would help to accentuate the STR database for
      better understanding of population genetics and forensic applications. The
      microsatellites included in the system are found to be highly polymorphic, with
      the combined power of exclusion being greater than 0.999, in all the three
      investigated populations.

PMID- 12477644
TI  - Estimating the incidence of influenza-virus infections in Dutch weaned piglets
      using blood samples from a cross-sectional study.
AB  - A cross-sectional study was carried out on 32 Dutch breeding herds to estimate
      the incidence of influenza-virus infections in piglets before the start of the
      finishing period, at the age of approximately 10 weeks. Longitudinal studies on
      two herds (8 and 10 litters, respectively) were done to obtain an average decay
      function for maternal antibodies.Each participating farm in the cross-sectional
      study was visited twice within 5 months; each time, blood samples were taken
      randomly from one compartment (a separate room with separate air flow) of 4-5
      week-old piglets and one compartment of 8-9-week-old piglets. These blood samples
      (a total of 2598; 16-23 per compartment, depending on its size) were tested in a
      haemagglutination inhibition test for antibodies against influenza-virus subtypes
      H1 and H3. Samples from 8-9-week-old piglets from the first sampling period
      (n=660) were also tested in an IgM ELISA. For each individual herd and each
      influenza-virus subtype separately, the decay function derived from the
      longitudinal studies was used to calculate an expected seroprevalence in 8-9-week
      old piglets, which was then compared to the observed seroprevalence. Depending on
      subtype and sampling period, between 10 and 15 of the 32 herds were suspected of
      virus circulation during the weaning period because the observed seroprevalence
      was significantly higher than the expected seroprevalence (P<0.05). In the first
      sampling period the IgM ELISA confirmed six of these outbreaks. However, due to
      the small window of detection of the IgM ELISA (compared to the length of the
      weaning period), it will always underestimate the number of infections.
      Infections in the first half of the weaning period will no longer be detectable
      because IgM antibodies have already disappeared. In individual pigs, an incidence
      of 16-17% was estimated for each subtype over a 4-week period between the age of
      4-5 and 8-9 weeks. For each influenza subtype, 80% of the piglets will enter the
      finishing facilities without antibodies or with decaying maternal antibodies.
      These piglets may be susceptible to an infection with influenza virus.

PMID- 12477645
TI  - Characterization of monoclonal antibodies against avian reovirus S1133 protein
      sigmaA synthesized in Escherichia coli.
AB  - Monoclonal antibodies (MAbs) were prepared against avian reovirus S1133 protein
      sigmaA (esigmaA) synthesized in Escherichia coli. MAbs were characterized and
      used to develop a diagnostic test. Ten MAbs were selected for competitive binding
      assay following coupling with horseradish peroxidase. The results indicated that
      these MAbs delineated two epitopes I and II of esigmaA. An immuno-dot binding
      assay was used to detect the effect of denaturation on antibody recognition of
      the epitopes. All MAbs bound to esigmaA in its native form. After denaturation by
      boiling in SDS and 2-mercaptoethanol, the binding of MAbs recognizing epitope I
      was fully abolished. However, the reactivity of MAbs recognizing epitope II was
      not affected. MAbs 31 and 32, recognizing epitopes I and II, respectively, were
      selected for the cross-reactivity to heterologous reovirus strains. The results
      suggest that the two epitopes are highly conserved among these virus strains. A
      MAb capture enzyme-linked immunosorbent assay (ELISA) procedure was developed
      using MAbs 32 and 31 to detect reovirus protein sigmaA in samples from tendon
      tissues of infected bird and chicken embryo fibroblast (CEF) cell cultures. Avian
      reovirus sigmaA antigens in tendon specimens were detected from the inoculated
      birds as early as 2 days post-inoculation (PI), approximated a peak at 7 days PI,
      and maintained this until 16 days PI, then decreased gradually. A clear
      difference in absorbance values between the tendon samples of the avian reovirus-
      and mock-infected birds is obtained. Positive results were also obtained from
      avian reovirus-infected CEF and from the tendon tissues of naturally infected
      broilers. These results indicated that the MAb capture ELISA is a useful methods
      for the detection of avian reovirus from chickens suspected to have avian
      reovirus infections.

PMID- 12477646
TI  - Earthworms (Oligochaeta, Lumbricidae) and mycobacteria.
AB  - The objective of the study was to define the role of earthworms in the survival
      of mycobacteria in animal populations. In 13 sampling sites mycobacteria were
      detected in 53 (5.5%) samples of faeces and parenchymatous tissues from animals,
      in 25 (7.3%) environmental and in nine (8.2%) earthworm samples. In cattle and
      goat farms affected by Mycobacterium avium subsp. paratuberculosis (M.
      paratuberculosis) of IS900 restriction fragment length polymorphism (RFLP) type B
      C1 was isolated from 37 (4.6%) faecal samples, three (1.4%) environmental and one
      (3.1%) earthworm sample. Investigations of aviaries affected by avian
      tuberculosis detected M. avium of genotype IS901+ and IS1245+ in six (7.9%)
      bird's faecal and in four (4.4%) environmental samples. M. avium (genotype IS901-
      and IS1245+) was detected in four (4.4%) and M. abscessus in one (1.1%)
      environmental sample. M. avium of genotype IS901- and IS1245+ and M. gastri were
      isolated from three (6.4%) earthworm samples. In pig farm with mycobacteriosis M.
      avium of genotype IS901- and IS1245+ was detected in five (20.0%) faecal samples
      from pigs and in four (12.9%) environmental samples. M. scrofulaceum was isolated
      in one (4.6%) sample of Lumbricus rubellus. In laboratory experiments identical
      RFLP types of M. paratuberculosis were isolated from bodies and faeces of
      earthworms 1-2 days after the last contact with the faeces contaminated with the
      same RFLP type of M. paratuberculosis. The results suggest that earthworms may
      become vectors of mycobacteria.

PMID- 12477647
TI  - Superficial bladder tumors.
AB  - This article is a summary of the 2001 French Urological Association (AFU) report
      on superficial bladder cancer. Major topics include histopathological
      classification, risk categories, natural history of the disease, standard
      treatments, the impact of molecular biology on clinical practice, the place of
      cystectomy, and modalities of intravesical instillations.

PMID- 12477648
TI  - Beware the BCG failures: a review of one institution's results.
AB  - OBJECTIVE: To review the outcome of all superficial transitional cell (TCC)
      bladder cancer treated with intravesical Bacille Calmette-Guerin (BCG) at one
      institution and, in particular, the prognosis for those patients who gained
      little benefit from BCG therapy. PATIENTS AND METHODS: The notes of 122 patients
      treated with BCG over a nine-year period were reviewed. The following details
      were recorded: time of diagnosis; time of decision to treat with BCG; results of
      cystoscopies before and after BCG; duration of follow up; time of progression if
      occurred, mortality and cause of death. RESULTS: Complete follow up data was
      available for 112 patients. At a median follow up of 23 months (range 3-107) 57
      patients (51%) remained free of tumour, 30 (27%) had progressed and 18 (16%) had
      died of transitional cell carcinoma. There was a significant association between
      a positive initial check cystoscopy and subsequent progression (p<0.001) and
      disease specific mortality (p<0.001). Of the 35 patients who had a positive
      cystoscopy after BCG treatment 21 (60%) progressed and 14 (40%) died of
      transitional cell carcinoma compared with 9 (12%) and 4 (5%) of the 77 with a
      negative cystoscopy. Adjusted odds ratios for progression and death from TCC for
      patients with a positive initial check cystoscopy were 21 and 13, respectively.
      CONCLUSION: In our series the patients found to have tumour at the initial check
      cystoscopy following intravesical BCG had a poor prognosis. This should be
      remembered when considering treatment options and counselling patients. Follow up
      of all BCG patients need to be rigorous and protocols would help to unify the
      treatment patients receive.

PMID- 12477649
TI  - Clinical utility of a multiprobe FISH assay in voided urine specimens for the
      detection of bladder cancer and its recurrences, compared with urinary cytology.
AB  - OBJECTIVES: To evaluate the clinical utility of a Multi-color FISH (fluorescence
      in situ hybridization) assay in voided urine specimens for the detection of
      bladder cancer and its recurrences, comparing the results with those afforded by
      urinary cytology. METHODS: Voided urine samples from 86 patients were obtained
      for urine cytology and FISH analysis. The latter was performed using a mixture of
      fluorescent labeled DNA probes for the centromeric regions of chromosomes 3, 7
      and 17, and the 9p21 region. Cystoscopy with biopsy or tumor resection was
      performed in all patients, comparing the pathological results with the
      cytological and FISH findings. RESULTS: Urinary cytology affords an overall
      sensitivity of 63.8%, the figure being 25% for grade 1, 66.6% for grade 2 and
      94.7% for grade 3 tumors. The sensitivities for FISH were 53.3% for grade 1,
      83.3% for grade 2 and 100% for grade 3 tumors, with an overall sensitivity of
      80.4%. The specificities of urinary cytology and FISH were 86.1 and 85.3%,
      respectively. CONCLUSIONS: FISH improves the sensitivity rates obtained with
      urine cytology for bladder cancer detection in all tumor grades and stages, and
      offers similar specificity. FISH doubles the accuracy of urinary cytology in
      application to low grade-stage tumors, and detects all high grade infiltrating
      tumors.

PMID- 12477650
TI  - Clinical pattern and therapeutic results achieved in 1490 patients with germ-cell
      tumours of the testis: the experience of the Spanish Germ-Cell Cancer Group (GG).
AB  - OBJECTIVE: To describe the clinical characteristics and treatment results
      obtained with the application of a homogeneous treatment protocol in 1490
      patients with germ-cell tumours (GCT) registered in the 55 hospitals belonging to
      the Spanish Germ-Cell Cancer Group (GG) during the period between January 1994
      and April 2001. METHODS: In general, surveillance was the common policy for stage
      I patients without local poor prognosis factors, whereas they received adjuvant
      chemotherapy in case those factor were present. Chemotherapy schedules used in
      advanced cases were cisplatin and etoposide (EP) for seminoma and BEP or BOMP-EPI
      in non-seminoma, according to whether the patient was in the good or poor
      prognosis IGCCCG (International Germ-Cell Cancer Collaborative Group) group.
      Excision of residual masses was mandatory in non-seminomatous germ-cell tumour
      (NSGCT). RESULTS: Initial local symptomatology was increased testis size in 90%
      of cases. Sonography was an excellent diagnostic tool to suggest tumour. Non
      seminoma (64.2%) was more frequent than seminoma (35.8%). Approximately 10% had
      the antecedent of cryptorchidism. Non-seminoma patients were 7 years younger than
      seminoma. Right testis was involved predominantly. Pre-orchidectomy tumour
      markers were elevated in 21% of seminoma (betaHGC) and 79% in non-seminoma
      (alphaFP and/or betaHGC). Scrotum violation occurred in only 1.8%. There were
      significant differences among stage I and the IGCCCG prognosis groups related to
      a longer interval between the first symptom and orchiectomy. Eighteen percent of
      non-seminomatous germ-cell tumour belonged to the poor prognosis IGCCCG group.
      With a median follow-up to 33 months, this series has achieved a 3 year overall
      survival of 98% for seminoma and 94% for non-seminoma. Only 10% of excised
      residual masses present after chemotherapy contained malignant cells. CONCLUSION:
      Spanish GCT have a similar clinical pattern to that described in the other
      occidental countries except for a slight increased proportion of non-seminoma
      upon seminoma. Co-operative groups as GG are unique structures to obtain quick
      and wide experience on the treatment of testis tumours, contributing to achieve a
      high cure rate.

PMID- 12477651
TI  - Is risk of testicular cancer related to body size?
AB  - BACKGROUND AND OBJECTIVES: The incidence of testicular germ cell tumors (GCT) has
      been increasing since decades but cohorts of men born during war-time and
      immediately thereafter had a lower incidence. Based on this epidemiological
      observation, a hypothesis was generated that postulated nutritional factors in
      early life to be involved in the pathogenesis of GCT. To support this hypothesis
      biomarkers for early life nutrition were analyzed. PATIENTS AND METHODS: In a
      case control study, 353 prospectively enrolled patients with GCT and 259 hospital
      based controls with bone fractures and with nephrolithiasis were assessed for
      adult height, weight and body mass index (BMI). All of the patients and controls
      were aged between 15 and 45 years. Evaluation was done by descriptive tabulation
      of data, by calculating univariate odds-ratios for potential risk factors, by
      calculating p-values for trend-tests and by multivariate logistic regression
      analysis. In addition, the literature was surveyed with respect to the suspected
      association of anthropometric measures with GCT-risk. RESULTS: No significant
      associations were found with respect to BMI and weight. However, height was
      significantly associated with GCT-risk (p<0.001). The multivariate analysis
      strengthened this association showing an increased risk of GCT with an odds-ratio
      of 2.11 (95% confidence interval 1.25; 3.55) for body height of at least 185 cm
      when compared to base-line height of 175-179 cm. Eleven previous studies with
      data on body size and GCT-risk were found in the literature. CONCLUSION: Tallness
      appears to be significantly associated with risk of germ cell cancer. As adult
      height is a proxy for energy intake during early life it is probable that the
      pathogenesis of GCT is promoted by childhood nutrition. It is conceivable that
      the increase in GCT incidence and the secular trend of increasing adult stature
      are interrelated. Increasing availability and increasing awareness of protein
      rich food in early childhood could be the common denominator to these
      observations.

PMID- 12477652
TI  - The role of initial immunotherapy as selection for nephrectomy in patients with
      metastatic renal cell carcinoma and the primary tumor in situ.
AB  - OBJECTIVE: A prospective pilot study in patients with metastatic renal cell
      cancer and the primary in situ to assess the feasibility of immunotherapy prior
      to nephrectomy and to evaluate the rationale for a future randomized trial to
      define the role of response to upfront immunotherapy as selection for
      cytoreductive surgery. PATIENTS AND METHODS: Sixteen patients with synchronous
      multiple metastases were treated with the primary tumor in place and were
      evaluated with regard to age, sex, sites of extrarenal disease, morbidity,
      response, nephrectomy rate, time to progression and overall survival.
      Immunotherapy consisted of 2 courses low-dose IL-2 4MIU/m(2), subcutaneous GM-CSF
      2.5 microg/kg and interferon-alpha (IFN-alpha) 5MU flat on day 1-13 and 22-34.
      Patients with either partial remission (PR) or stable disease (SD) underwent
      nephrectomy followed by a third and fourth course. RESULTS: No response was seen
      in the primary tumors. With regard to extrarenal sites SD was noted in nine
      cases, PR in two and progressive disease (PD) in five. Eleven patients underwent
      nephrectomy. No surgical complete response (CR) could be achieved. All patients
      with PD died after a median overall survival of 3 months versus 11.5 months
      (range 4-22) in those who underwent nephrectomy. Four patients are still alive at
      10, 12, 18 and 19 months. Median duration of response was 6 months (range 2-10).
      One patient with SD following nephrectomy developed CR after two additional
      cycles, which is currently maintained for >10 months. CONCLUSIONS: Absence of
      progression at metastatic sites following immunotherapy may be used as a
      selection for nephrectomy in this selected group. Non-responding patients can be
      spared from surgery. A randomized study is needed to assess the timing of
      nephrectomy in combination with immunotherapy with regard to morbidity, overall
      survival and quality of life.

PMID- 12477653
TI  - Combining free and total prostate specific antigen assays from different
      manufacturers: the pitfalls.
AB  - OBJECTIVES: We investigated the impact of interchanging free prostate specific
      antigen (f-PSA) concentrations from 10 different assays over a reference total
      PSA (t-PSA) on predicting prostate histology with free-to-total PSA ratios (f/t
      PSA). METHODS: Archival sera from 80 t-PSA- and age-matched pairs of
      histologically confirmed prostate cancer (PCA) and benign prostatic hyperplasia
      (BPH) patients with t-PSA levels between 2 and 25 microg/l were investigated.
      Serum aliquots were analyzed for t- and f-PSA using a reference method (Access,
      Beckmann-Coulter Hybritech) and 10 commercially available f-PSA assays. Passing
      Bablok and linear regression were performed to investigate the interassay
      agreement between f-PSA assays. To compare diagnostic performance, ROC curves for
      PCA detection were calculated for the 10 f/t-PSA combinations using the reference
      t-PSA as denominator. Sensitivities, specificities and f/t-PSA cut-offs were
      calculated for varying points of the ROC curve. RESULTS: Despite good correlation
      of all 10 f-PSA assays with the reference method 4 showed significantly lower
      mean f-PSA levels. For f/t-PSA as a predictor of prostate histology, areas under
      the ROC curve (AUC) varied between 0.65 and 0.71 and, if compared to the
      reference method (AUC=0.70), were significantly lower in three cases. Ensuring
      80% specificity, sensitivities ranged between 34% and 54% (reference method: 53%)
      and f/t-PSA cutpoints differed considerably depending on the f-PSA assay used
      (range: 0.15-0.24; reference: 0.15). Similar variations were noted at 95%
      specificity and 80% and 95% sensitivity. CONCLUSIONS: Arbitrary combinations of f
      and t-PSA assays should not be used to calculate f/t-PSA ratios unless adequate
      studies have validated the diagnostic performance and cut-offs of that particular
      assay choice.

PMID- 12477654
TI  - Urodynamic characterisation of women with naive urinary incontinence: a
      population-based study in subjectively incontinent and healthy 53-63 years old
      women.
AB  - OBJECTIVES: To compare the urodynamic characteristics in a group of middle-aged
      women with untreated urinary incontinence with the findings in a control group of
      healthy women. METHODS: Sixty women with mild-to-moderate urinary incontinence
      and 28 symptom-free women, 53-63 years old, were randomly chosen out of a large
      health questionnaire study. All were investigated with a detailed history,
      gynaecological examination, urinalysis, frequency-volume chart, and urodynamics
      including cystometry and pressure-flow analysis. RESULTS: The maximum urinary
      flow was significantly higher in the incontinent group of women, 22+/-1ml/s, than
      in the healthy controls, 16+/-2ml/s (p<0.01). The acceleration of flow, with a
      theoretical maximum of 0 degrees, was also significantly faster in the
      incontinent, 20 degrees, than in the healthy women, 32 degrees (p=0.01). In the
      five women with urge incontinence only, maximum urinary flow was 26+/-2.4ml/s and
      the flow acceleration 7 degrees. In incontinent women, both a lower opening
      pressure and detrusor pressure at maximum flow were seen compared with the
      healthy women, though the difference did not reach statistical significance. The
      incontinent and the healthy women did not differ regarding bladder volumes or
      pressures during filling. CONCLUSION: The findings of this study indicate the
      presence of an increased efficiency of the urethral opening mechanism in
      incontinent women compared to normal, irrespective of the type(s) of symptoms
      present.

PMID- 12477655
TI  - Is infundibuloureteropelvic angle (IUPA) a significant risk factor in formation
      of inferior calyceal calculi?
AB  - INTRODUCTION: Many studies confirm the fact that radiographic anatomy of inferior
      calyx has a significant role in the clearance of a stone lodged in it [Br. J.
      Urol. 50 (1978) 449; Invest. Urol. 18 (2) (1980) 167; BJU Int. 83 (Suppl) (1999)
      24; J. Urol. 132 (1984) 1085]. Acutely angled and narrow infundibular neck of a
      inferior calyx has a poorer stone clearance in comparison to that with a less
      acute angled and wider infundibular neck [Br. J. Urol. 50 (1978) 449; Invest.
      Urol. 18 (2) (1980) 167; Br. J. Urol. 82 (1998) 12; BJU Int. 83 (Suppl) (1999)
      24]. Incidence of bilateral stones in clinical practice is significantly less
      than unilateral stones. This study was taken up to define the significance of
      radiographic anatomy of the inferior calyx as a risk factor predisposing to stone
      formation in a patient and compared the anatomy of inferior calyx of the stone
      forming and contralateral kidney. The fact that inspite of the similar known
      etiological factors (intrinsic and extrinsic) of stone formation, why stone forms
      unilaterally? MATERIAL AND METHODS: 100 consecutive cases of non-obstructed
      unilateral inferior calyceal calculus with non-metabolically active stones were
      studied. The infundibuloureteropelvic angle (IUPA) and infundibular width of the
      stone forming and non-stone forming contralateral side were compared. RESULTS:
      IUPA of stone forming side was more acute than the non-stone forming side, in 74%
      of the cases, more obtuse in 18% of the cases, and same in 8% of the cases. The
      difference in the IUPA of the stone forming and that of non-stone forming
      contralateral side was statistically significant (p<0.0002). The infundibular
      width of the stone forming side ranged from 1 to 16 mm and that of non-stone
      forming side from 2 to 11 mm. There was no statistically significant difference
      between the infundibular width of both the sides. Exactly, how and more
      importantly under what influences the macromolecules in the urine transforms into
      a calculus in the pelvicalyceal system is still not known till date but from our
      observations we conclude that IUPA is a significant risk factor which predisposes
      to calculus formation in inferior calyx. CONCLUSION: IUPA is a significant risk
      factor, which predisposes to urolithiasis in inferior calyx.

PMID- 12477656
TI  - Evaluation of 100 laparoscopic varicocele operations with preservation of
      testicular artery and ligation of collateral vein in children and adolescents.
AB  - OBJECTIVES: To introduce a useful technique for identifying any collateral veins
      during laparoscopic varicocele operation and to evaluate our long-term results
      with this technique after 100 cases. METHODS: A new method was used to detect an
      incidental collateral vein. During surgery the patient was placed in anti
      Trendelenburg position after introducing laparoscopic instruments until the
      dilated scrotal varicose filled up with blood. The main spermatic vein was then
      grasped atraumatically and the blood was pressed out manually from the scrotum.
      During this manoeuvre any existing collateral vein/veins became dilated and could
      be easily identified. The dilated spermatic vein and also any collateral vessel
      were first prepared then clipped. RESULTS: Out of the 100 patients, collateral
      veins were detected and ligated in 19 cases. In 15 cases a single collateral, in
      4 cases two collaterals, and in the remaining 81 children no collateral veins
      were found. The testicular artery was identified in all operations as a pulsatile
      vessel. At a mean of 24 months (range 6-60 months) follow-up recurrence occurred
      in one patient and in five children hydrocele developed postoperatively.
      Testicular atrophy and severe intra- or postoperative complication did not occur
      in any patient of this series. CONCLUSION: The identification of incidental
      collateral vein by this method and preservation of the testicular artery resulted
      in a very good success rate in children and adolescents treated by laparoscopic
      varicocele operation.

PMID- 12477657
TI  - Endoscopic management of vesicoureteral reflux: does it stand the test of time?
AB  - Endoscopic subureteral injection of tissue-augmenting substances, a 15-minute
      outpatient procedure has become an alternative to long-term antibiotic
      prophylaxis and surgical intervention in the treatment of vesicoureteral reflux
      (VUR) in children. This paper reviews the long-term results of endoscopic
      treatment of reflux using various tissue-augmenting substances presently
      available. In terms of effectiveness and long-term successful results,
      polytetrafluoroethylene is still the most reliable injectable material for the
      endoscopic treatment of VUR.

PMID- 12477658
TI  - Is one-stage ureterocele repair possible in children?
AB  - AIM: To determine the long-term results of ureterocele repair, bearing in mind
      the relative rarity of the malformation, its very polymorphic appearance and the
      diversity of treatments. MATERIALS AND METHODS: Long-term results were assessed
      by postoperative follow-up of 126 children with 131 ureteroceles between 1970
      2000. RESULTS: With a mean follow-up of 72 months, only 64.2% of children were
      cured after a one-stage procedure. According to the anatomical type, favourable
      results were obtained in 81.6% of cases with a single ureter and 57.9% of cases
      with a duplicated ureter. Treatment success rates for single or duplicated
      ureters were 73% in the case of intravesical implantation and only 53.9% (34/63
      children) in ectopic forms. According to the technique, cure rates were 67.6%
      after distal incision in 34 children, 61.9% after total nephrectomy or upper pole
      nephrectomy in 42 children, 50% after ureterocele repair and ureterovesical
      reimplantation in 20 patients, 75% after total resection of the pathological
      ureter, parietal reconstruction and ipsilateral and/or contralateral
      reimplantation in another 20 patients. CONCLUSIONS: A one-stage procedure is only
      able to cure 2/3 of patients. In view of the tendency to progressive regression
      of often monstrous distensions during the neonatal period, first-line treatment
      should consist of a distal incision, followed, in the case of recurrent
      infections, by partial or total nephrectomy, while reserving the intravesical
      approach to cases with recurrent pyelonephritis. When this surgery is performed
      on older children or adolescents, the ureteroceles will be smaller with a lower
      risk of sphincter damage.

PMID- 12477659
TI  - Blunt renal trauma: biomechanics and origination of renal lesions.
AB  - OBJECTIVES: Computer-assisted simulation of trauma is supposed to improve
      protective systems in traffic and risky leisure activities. In case of blunt
      renal injury biomechanical data being concerned with kidneys as a whole are
      extremely sparse. To enable three-dimensional simulations this study should
      supply important data of the renal biomechanics and elucidate the relationship
      between force distribution and origination of renal lesions. MATERIALS & METHODS:
      The present study investigated 66 isolated uninjured porcine kidneys using a drop
      impactor. Changes in deformation, brake force of power, deceleration and
      intrapelvic pressure are depicted while varying energy application between 1.4
      and 14.2J. Lesions were detected by cross-dissecting the organs into slices.
      RESULTS: The measured values reflect a high correlation between load energy or
      brake force of power and deformation. Except the intrapelvic pressure all
      biomechanical parameters rise under increasing energy load. Comparing the
      different parameters over time a simultaneous concurrence of maximum brake force
      of power, deceleration and intrarenal pressure can be shown, the peak of
      deformation was reached belatedly. CONCLUSIONS: The paths of biomechanical curves
      prove a viscoelastic behaviour of the kidney. In contrast to the literature the
      region principally bearing the load seems to be the collision zone between renal
      pelvis and cortex where first lesions appear. This is mainly caused by the fluid
      filled pelvis, an incompressible support, that is supposed to change its shape
      after exceeding energy application of about 4J.

PMID- 12477660
TI  - Assessing the use of p16(INK4a) promoter gene methylation in serum for detection
      of bladder cancer.
AB  - OBJECTIVE: This study was undertaken to investigate whether hypermethylation in
      p16(INK4a) gene promoter could serve as plasma biomarker of bladder cancer.
      METHODS AND PATIENTS: We examined the p16(INK4a) status using methylation
      specific PCR in 86 cancer patients and 49 controls (31 healthy people and 18
      patients with benign urological diseases). RESULTS: The p16(INK4a) methylation
      was found in 22% of the serum samples and in 26% of the bladder cancer biopsies;
      one of them with carcinoma in situ. The presence of hypermethylated p16(INK4a) in
      serum seems to be a product from tumour cells because a strong statistical
      association was found between both matched DNA signals (p<0.0001). Using the
      control group, the presence of methylated p16(INK4a) in the serum of individuals
      with suspicion of bladder cancer was found to be associated with the tumour
      presence (p=0.0009). Aberrant p16(INK4a) methylation was also observed in one non
      cancer patient, which is undergoing further assessment. CONCLUSIONS: According
      with our results, methylation of p16(INK4a) promoter may be involved in the
      bladder cancer genesis and the presence of p16(INK4a) methylated in serum of
      these patients could be useful in the cancer diagnosis with values of
      sensitivity, specificity and positive predictive value of 0.226, 0.950 and 0.98,
      respectively. These figures support the use of methylated p16(INK4a) as a new
      class of tumour marker in bladder cancer.

PMID- 12477661
TI  - Augmentation ureterocystoplasty in bladder exstrophy: 5-year follow-up in two
      cases.
AB  - OBJECTIVE: To report two cases of bladder exstrophy managed successfully by
      augmentation ureterocystoplasty (UCP) together with bladder neck surgery and
      continent diversion. PATIENTS: Two boys, age 5 and 1 years respectively, had
      augmentation UCP. The left refluxing megaureter was used in the first case
      together with bladder neck reconstruction. In the second patient, bilateral
      obstructed magaureters were used in tandem together with bladder neck division.
      Both patients had appendicovesicostomy according to Mitrofanoff. RESULTS: In
      follow-up for over 5 years, both patients are continent with improved upper
      urinary tracts and normal or stable renal function. They are managed by clean
      intermittent catheterization (CIC) via the continent stoma with bladder
      capacities of 220 cc and 150 cc, respectively. Cystogram showed no vesicoureteric
      reflux (VUR). The procedures were considered to be successful although one
      patient was on oxybutinin because urodynamics showed high intravesical pressures.
      CONCLUSIONS: Augmentation UCP should be considered in patients with bladder
      exstrophy when a suitable megaureter is available. This may be combined with
      simultaneous bladder neck reconstruction together with a continent diversion.

PMID- 12477662
TI  - Major intra-abdominal complications following extracorporeal shockwave
      lithotripsy (ESWL) in a patient with Ehlers-Danlos syndrome.
AB  - A retroperitoneal bleeding is an unusual complication of extracorporeal shockwave
      lithotripsy (ESWL), which can be treated in a conservative way most of the time.
      However, an intra-abdominal bleeding after ESWL is extremely rare, which can
      cause life-threatening situations and requires an immediate intervention.
      Probably, only patients with a certain tissue fragility or connective tissue
      disorder are at risk to develop such an intra-abdominal bleeding. We present a
      case of a serious intra-abdominal bleeding due to a rupture of the vena
      mesenterica superior in an Ehlers-Danlos patient, evoked by an ESWL.

PMID- 12477664
TI  - Effects of organ culture on arterial gene expression and hypoxic relaxation: role
      of the ryanodine receptor.
AB  - Organ culture specifically inhibits vasorelaxation to acute hypoxia and
      preferentially decreases specific voltage-dependent K(+) channel expression over
      other K(+) and Ca(2+) channel subtypes. To isolate further potential oxygen
      sensing mechanisms correlated with altered gene expression, we performed
      differential display analysis on RNA isolated from control and cultured coronary
      arterial rings. We hypothesize that organ culture results in altered gene
      expression important for vascular smooth muscle contractility important to the
      mechanism of hypoxia-induced relaxation. Our results indicate a milieu of changes
      suggesting both up- and downregulation of several genes. The altered expression
      pattern of two positive clones was verified by Northern analysis. Subsequent
      screening of a porcine cDNA library indicated homology to the ryanodine receptor
      (RyR). RT-PCR using specific primers to the three subtypes of RyR shows an
      upregulation of RyR2 and RyR3 after organ culture. Additionally, the caffeine-
      and/or ryanodine-sensitive intracellular Ca(2+) store was significantly more
      responsive to caffeine activation after organ culture. Our data indicate that
      organ culture increases expression of specific RyR subtypes and inhibits hypoxic
      vasorelaxation. Importantly, ryanodine blunted hypoxic relaxation in control
      coronary arteries, suggesting that upregulated RyR might play a novel role in
      altered intracellular Ca(2+) handling during hypoxia.

PMID- 12477665
TI  - Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for
      bone destruction in rat cortical bone.
AB  - Bone is removed or replaced in defined locations by targeting osteoclasts and
      osteoblasts in response to its local history of mechanical loading. There is
      increasing evidence that osteocytes modulate this targeting by their apoptosis,
      which is associated with locally increased bone resorption. To investigate the
      role of osteocytes in the control of loading-related modeling or remodeling, we
      studied the effects on osteocyte viability of short periods of mechanical loading
      applied to the ulnae of rats. Loading, which produced peak compressive strains of
      -0.003 or -0.004, was associated with a 78% reduction in the resorption surface
      at the midshaft. The same loading regimen resulted in a 40% relative reduction in
      osteocyte apoptosis at the same site 3 days after loading compared with the
      contralateral side (P = 0.01). The proportion of osteocytes that were apoptotic
      was inversely related to the estimated local strain (P < 0.02). In contrast, a
      single short period of loading resulting in strains of -0.008 engendered both
      tissue microdamage and subsequent bone remodeling and was associated with an
      eightfold increase in the proportion of apoptotic osteocytes (P = 0.02) at 7
      days. This increase in osteocyte apoptosis was transient and preceded both
      intracortical remodeling and death of half of the osteocytes (P < 0.01). The data
      suggest that osteocytes might use their U-shaped survival response to strain as a
      mechanism to influence bone remodeling. We hypothesize that this relationship
      reflects a causal mechanism by which osteocyte apoptosis regulates bone's
      structural architecture.

PMID- 12477666
TI  - Blockade of maitotoxin-induced endothelial cell lysis by glycine and L-alanine.
AB  - The maitotoxin (MTX)-induced cell death cascade in bovine aortic endothelial
      cells (BAECs) is a model for oncotic/necrotic cell death. The cascade is
      initiated by an increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)),
      which is followed by the biphasic uptake of vital dyes. The initial phase of dye
      entry reflects activation of large pores and correlates with surface membrane
      bleb formation; the second phase reflects cell lysis. In the present study, the
      effect of the cytoprotective amino acid glycine was examined. Glycine had no
      effect on MTX-induced change in [Ca(2+)](i) or on the first phase of vital dye
      uptake but produced a concentration-dependent (EC(50) approximately 1 mM)
      inhibition of the second phase of dye uptake. No cytoprotective effect was
      observed with l-valine, l-proline, or d-alanine, whereas l-alanine was
      equieffective to glycine. Furthermore, glycine had no effect on MTX-induced bleb
      formation. To test the hypothesis that glycine specifically blocks formation of a
      lytic "pore," the loss of fluorescence from BAECs transiently expressing GFP and
      concatemers of GFP ranging in size from 27 to 162 kDa was examined using time
      lapse videomicroscopy. MTX-induced loss of GFP was rapid, correlated with the
      second phase of dye uptake, and was relatively independent of molecular size. The
      MTX-induced loss of GFP from BAECs was completely blocked by glycine. The data
      suggest that the second "lytic" phase of MTX-induced endothelial cell death
      reflects formation of a novel permeability pathway that allows macromolecules
      such as GFP or LDH to escape, yet can be prevented by the cytoprotective agents
      glycine and l-alanine.

PMID- 12477667
TI  - Colon carcinoma cell glycolipids, integrins, and other glycoproteins mediate
      adhesion to HUVECs under flow.
AB  - This study was undertaken to investigate the molecular constituents mediating
      LS174T colon adenocarcinoma cell adhesion to 4-h TNF-alpha-stimulated human
      umbilical vein endothelial cells (HUVECs) under flow. At 1 dyn/cm(2),
      approximately 57% of cells rolled and then became firmly adherent, whereas others
      continuously rolled on endothelium. Initial cell binding was primarily mediated
      by endothelial E-selectin. By using neuraminidase, glycolipid biosynthesis
      inhibitor d,l-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol. HCl,
      trypsin, and flow cytometry, LS174T cells were shown to express sialyl Lewis(x)
      (sLe(x))- and di-sLe(x)-decorated, but not sLe(a)-decorated, glycolipid and
      glycoprotein ligands for E-selectin. The cells preferentially employed sialylated
      glycoproteins over glycolipids in adhesion as measured by conversion of rolling
      to firm adhesion, resistance to detachment by increased shear stress, and rolling
      velocity. However, a nonsialylated E-selectin counterreceptor also exists.
      Furthermore, LS174T alpha(2), alpha(6), and beta(1) integrins support a minor
      pathway in adhesion to HUVECs. Finally, tumor cell attachment specifically
      increases HUVEC endocytosis of E-selectin. Altogether, the data indicate the
      complexity of carcinoma cell-endothelium adhesion via sialylated glycoconjugates,
      integrins, and their respective counterreceptors.

PMID- 12477668
TI  - The converter domain modulates kinetic properties of Drosophila myosin.
AB  - Recently the converter domain, an integral part of the "mechanical element"
      common to all molecular motors, was proposed to modulate the kinetic properties
      of Drosophila chimeric myosin isoforms. Here we investigated the molecular basis
      of actin filament velocity (V(actin)) changes previously observed with the
      chimeric EMB-IC and IFI-EC myosin proteins [the embryonic body wall muscle (EMB)
      and indirect flight muscle isoforms (IFI) with genetic substitution of the IFI
      and EMB converter domains, respectively]. In the laser trap assay the IFI and IFI
      EC myosins generate the same unitary step displacement (IFI = 7.3 +/- 1.0 nm, IFI
      EC = 5.8 +/- 0.9 nm; means +/- SE). Thus converter-mediated differences in the
      kinetics of strong actin-myosin binding, rather than the mechanical capabilities
      of the protein, must account for the observed V(actin) values. Basal and actin
      activated ATPase assays and skinned fiber mechanical experiments definitively
      support a role for the converter domain in modulating the kinetic properties of
      the myosin protein. We propose that the converter domain kinetically couples the
      P(i) and ADP release steps that occur during the cross-bridge cycle.

PMID- 12477669
TI  - Strategies to reduce postoperative nausea and vomiting: does metoclopramide have
      a role?

PMID- 12477670
TI  - Are children just little adults when it comes to propofol injection pain?

PMID- 12477671
TI  - Dolasetron, but not metoclopramide prevents nausea and vomiting in patients
      undergoing laparoscopic cholecystectomy.
AB  - PURPOSE: Postoperative nausea and vomiting (PONV) is one of the most frequent
      complications of general anesthesia. The aim of the study was to compare the
      antiemetic efficacy of dolasetron and metoclopramide after inhalational or i.v.
      anesthesia (IVA). METHODS: In a randomized, placebo-controlled, double-blinded
      trial we evaluated the efficacy of 12.5 mg dolasetron i.v. and 20 mg
      metoclopramide (MCP) i.v. in preventing PONV in 387 patients (ASA I-III)
      undergoing laparoscopic cholecystectomy. Patients were allocated randomly to one
      of three main groups: Group D (n = 129) received 12.5 mg dolasetron i.v., Group
      MCP (n = 129) 20 mg MCP i.v., and Group C (n = 129) saline as placebo i.v. Using
      a multifactorial study design, one third of each main group (n = 43) was further
      randomized to receive either general anesthesia with desflurane, isoflurane or
      IVA with propofol and remifentanil. PONV, postoperative piritramide and
      droperidol consumption were documented. RESULTS: Independent from the anesthesia
      regimen chosen, dolasetron reduced PONV (19%) significantly compared to MCP (45%)
      and placebo (46%). Furthermore we could show a significant difference in the
      incidence of PONV between IVA (28%) and isoflurane (46%), but not in comparison
      to desflurane (36%). Patients receiving IVA had a higher postoperative
      piritramide consumption compared to the two other groups. CONCLUSIONS: The
      results of our study suggest that dolasetron was more effective than MCP and
      placebo in preventing PONV. This action is independent of the anesthetic
      technique used.

PMID- 12477672
TI  - Metoclopramide decreases emesis but increases sedation in tramadol patient
      controlled analgesia.
AB  - PURPOSE: To evaluate the clinical benefits and disadvantages of adding
      metoclopramide to tramadol for patient-controlled analgesia (PCA). METHODS: Forty
      adult patients, undergoing elective arthroplasties, were recruited into this
      prospective, randomized, double-blind study. During general anesthesia all
      patients received 2.5 mg x kg(-1) of tramadol as a loading dose at the beginning
      of wound closure. In the postanesthesia care unit (PACU) patients were randomly
      allocated to receive PCA containing either 20 mg tramadol + 1 mg metoclopramide
      per millilitre (n = 20, Group T+M) or tramadol 20 mg per millilitre (n = 20,
      Group T). The PCA setup was 1 mL/bolus with a lockout interval of five minutes. A
      blinded investigator assessed the vital signs, visual analogue scale, and
      severity of postoperative nausea and/or vomiting in the PACU. The PCA demand and
      delivery, overall satisfaction rate and adverse effects were recorded in the PACU
      and on postoperative days one and two. RESULTS: Nausea/vomiting scores were more
      severe (1.7 +/- 1.0 vs 0.2 +/- 0.5, 2.3 +/- 1.2 vs 0.6 +/- 0.6, 1.9 +/- 0.9 vs
      0.2 +/- 0.5, at 12 hr, 18 hr, 24 hr, respectively, P < 0.05) and more frequent
      (7/20 vs 1/20, 5/20 vs 0/20 for nausea and vomiting respectively, P < 0.05) on
      postoperative day one in Group T compared to Group T+M. However, the incidence of
      sedation was higher in Group T+M (7/20 vs 1/20, P < 0.05). CONCLUSIONS: The
      incidence and severity of nausea/vomiting decreased if metoclopramide was added
      to tramadol for PCA. An increased incidence of sedation was noticed with this
      drug combination.

PMID- 12477673
TI  - P6 acupressure may relieve nausea and vomiting after gynecological surgery: an
      effectiveness study in 410 women.
AB  - PURPOSE: To investigate the effect of sensory stimulation of the P6 point on
      postoperative nausea and vomiting (PONV) after gynecological surgery in the
      everyday clinical setting (effectiveness study). METHODS: Four hundred and ten
      women undergoing general anesthesia for elective gynecological surgery were
      included in a prospective, consecutive, randomized, multicentre, placebo
      controlled, double-blind clinical trial with a reference group. One group was
      given bilateral P6 acupressure (n = 135), a second group similar pressure on
      bilateral non-acupressure points (n = 139), and a third group (n = 136) served as
      reference group. Nausea (scale 0-6), vomiting, pain, and satisfaction with the
      treatment were recorded. Primary outcome was complete response, i.e., no nausea,
      vomiting or rescue medication for 24 hr. Results were analyzed by applying
      logistic regression with indicators of treatments, type of operation and risk
      score for PONV as explanatory variables. RESULTS: Complete response was more
      frequent in the P6 acupressure group than in the reference group (P = 0.0194)
      Conversely, the incidence of PONV was 46% in the reference group, 38% after
      pressure on a non-acupoint and 33% after P6 acupressure. The decrease from 46% to
      33% was statistically significant. When considering vaginal cases separately, the
      decrease in PONV was from 36% to 20% (P = 0.0168). The corresponding decrease
      from 59% to 55% in the laparoscopic surgery group was not statistically
      significant. CONCLUSION: P6 acupressure is a non-invasive method that may have a
      place as prophylactic antiemetic therapy during gynecological surgery.

PMID- 12477674
TI  - Oxygen in air (FiO2 0.4) improves gas exchange in young healthy patients during
      general anesthesia.
AB  - PURPOSE: One hundred percent O(2) is used routinely for preoxygenation and
      induction of anesthesia. The higher the O(2) concentration the faster is the
      development of atelectasis, an important cause of impaired pulmonary gas exchange
      during general anesthesia (GA). We evaluated the effect of ventilation with 0.4
      FiO(2) in air, 0.4 FiO(2) in N(2)O and 100% O(2) following intubation on the
      development of impaired gas exchange. METHODS: Twenty-seven patients aged 18-40
      yr, undergoing elective laparoscopic cholecystectomy were administered 100% O(2)
      for preoxygenation (three minutes) and ventilation by mask (two minutes).
      Following intubation these patients were randomly divided into three groups of
      nine each and ventilated either with 0.4 FiO(2) in air, 0.4 FiO(2) in N(2)O or
      100% O(2). Arterial blood gases were obtained before preoxygenation and 30 min
      following intubation for PaO(2) analysis. Subsequently PaO(2)/FiO(2) ratios were
      calculated. Results were analyzed with Student's t test and one-way ANOVA. P
      value of < or = 0.05 was considered significant. RESULTS: Ventilation of the
      lungs with O(2) in air (FiO(2) 0.4) significantly improved the PaO(2)/FiO(2)
      ratio from baseline, while 0.4 FiO(2) in N(2)O or 100% O(2) worsened the ratio
      (558 +/- 47 vs 472 +/- 28, 365 +/- 34 vs 472 +/- 22 and 351 +/- 23 vs 477 +/- 28
      respectively; P < 0.05). CONCLUSION: Ventilation of lungs with O(2) in air
      (FiO(2) 0.4) improves gas exchange in young healthy patients during GA.

PMID- 12477675
TI  - Probable gas embolism during operative hysteroscopy caused by products of
      combustion.
AB  - PURPOSE: Gas embolism is a rare but well documented entity during operative
      hysteroscopy, with an incidence of 10-50%. Catastrophic outcomes occur at a rate
      of three in 17,000 procedures. The purpose of this report is to present a non
      fatal case of gas embolism probably caused by the gaseous products of combustion.
      CLINICAL FEATURES: A 50-yr-old woman with a history of menorrhagia was scheduled
      for hysteroscopy and endometrial ablation and polypectomy. Fifteen minutes into
      the procedure, with the patient in lithotomy position, 20 degree head down tilt,
      and breathing spontaneously, a sudden oxygen desaturation occurred from 97% to
      87%. The patient's end-tidal carbon dioxide dropped from 46 mmHg to 27 mmHg. The
      patient's breathing pattern remained normal, respiratory rate remained 11-12
      breaths x min(-1) but amplitude of the reservoir bag movement was increased.
      Cardiovascular variables remained stable. She responded rapidly to 100% oxygen
      and made an uneventful recovery. Having ruled out other possible causes, we
      concluded gas embolism was responsible for the fall in oxygen saturation and end
      tidal CO(2). CONCLUSION: With all the precautions in place to minimize the
      likelihood of fluid overload and ambient air embolism occurring, we surmised that
      products of combustion were the cause of the gas embolism. During endometrial
      ablation, gaseous products of combustion, mainly carbon dioxide, accumulate. The
      gases may then contribute to the rise in uterine pressure that occurs as
      irrigation fluid enters the uterus and this rise in pressure in turn encourages
      passage of gas into the open venous sinuses.

PMID- 12477676
TI  - The Panomat P-10 micro-volumetric infusion pump is suitable for continuous drug
      administration at minimal flow rates.
AB  - PURPOSE: To evaluate the performance of the Panomat P-10 micro-volumetric
      infusion pump for its use in drug administration at minimal flow rates (microL x
      hr(-1); e.g., intrathecal application). METHODS: Fluid delivery at steady state
      conditions, and after vertical displacement of the syringe pump by -50 cm was
      determined gravimetrically. The Panomat P-10 infusion pump was evaluated at 4,
      10, 20, 50 and 100 microL x hr(-1), and compared to a conventional syringe pump
      assembly at 100, 200, 500 and 1000 microL x hr(-1). Measurements were repeated
      twice with two different devices of each syringe pump system, and with two
      syringes. Data are reported as mean +/- SD. RESULTS: Steady state fluid delivery
      of the Panomat P-10 infusion pump revealed less than 5% deviation to set flow
      rate at 10, 20, 50 and 100 microL x hr(-1), and 12% deviation at 4 microL x hr(
      1). Mean zero-drug delivery time (ZDDT) after lowering the pump by 50 cm at 4
      microL x hr(-1) flow rate was 38.4 +/- 7.3 min. At 100 microL x hr(-1) and with
      original infusion line ZDDT was almost 20 times shorter when compared to the
      conventional syringe pump assembly (1.5 +/- 0.5 min vs 28.5 +/- 5.0 min).
      CONCLUSION: The tested Panomat P-10 micro-volumetric pump shows an acceptable
      flow accuracy as well as a low susceptibility to vertical displacement, and is
      therefore suitable for continuous drug administration at minimal flow rates. The
      technology used in this pump carries potential implications for a new generation
      of syringe pumps.

PMID- 12477677
TI  - Canadian survey of postsurgical pain and pain medication experiences.
AB  - PURPOSE: To assess the postoperative pain and pain medication experiences of
      Canadians. METHODS: Three hundred and five general population subjects from
      across Canada who had surgery in the previous three years were retrospectively
      questioned regarding pain experiences in the surgical facility and at home, pain
      medication efficacy and pain medication satisfaction. RESULTS: While in the
      surgical facility, pain was experienced by 68% of patients who expected overnight
      admission ("inpatients") and 49% of patients who expected same-day discharge
      ("outpatients"). Overall, 47% of inpatients and 15% of outpatients reported that
      their highest experience of pain was severe or extreme; 25% of inpatients and 9%
      of outpatients reported that their average pain was severe or extreme. In the two
      weeks post-discharge, 79% and 74% respectively of inpatients and outpatients
      experienced pain. Severe or extreme pain occurred at home in 25% of inpatients
      and 28% of outpatients; average pain was severe or extreme for 9% of inpatients
      and 12% of outpatients. Complete or a lot of pain relief was experienced by 54%
      to 72% patients who received pain medication; higher rates of pain medication
      satisfaction were reported than rates of pain relief from pain medication.
      CONCLUSION: Severe or extreme pain was experienced by many surgical patients.
      Improvements could be made to patients' postsurgical pain experience in Canada,
      both in the surgical facility and subsequent to discharge.

PMID- 12477678
TI  - Epidural anesthesia in three parturients with lumbar tattoos: a review of
      possible implications.
AB  - PURPOSE: To discuss the possible ramifications of neuraxial analgesia and
      anesthesia in women with tattoos involving their midline lumbar area. CLINICAL
      FINDINGS: Recently the authors have received requests for epidural anesthesia in
      three women with tattoos over the midline of their lumbar spine. In one patient
      the tattoo covered her entire back. In the other two, it was possible to locate a
      lumbar interspace that did not have tattoo pigment in the overlying skin. All
      three women received uneventful epidural analgesia. A Medline and EMBASE search
      for relevant publications using the keywords: epidural, spinal, tattoos,
      tattooing, complications did not find any reports of complications from inserting
      a needle through a tattoo. As none were found, the literature on tattoos and on
      coring with neuraxial anesthesia was reviewed to see if neuraxial anesthesia
      might be problematic if the needle passed through the tattoo. Coring is a
      complication of neuraxial anesthesia that may lead to epidermoid tumours in the
      subarachnoid space. Theoretically, a pigment-containing tissue core from a tattoo
      could be deposited into the epidural, subdural or subarachnoid spaces, leading to
      later neurological complications. CONCLUSIONS: There is no information in the
      literature about possible risks from inserting needles through tattoos during the
      performance of neuraxial anesthesia. This report discusses the possible
      implications.

PMID- 12477679
TI  - In children, nitrous oxide decreases pain on injection of propofol mixed with
      lidocaine.
AB  - PURPOSE: To investigate if 50% nitrous oxide reduces the pain during injection of
      propofol mixed with lidocaine in children. METHODS: Healthy children undergoing
      iv induction of general anesthesia for elective surgery were recruited into this
      prospective, randomized, double-blind study. None of the patients received any
      premedication except for eutectic mixture of local anesthetics cream. Before
      induction of anesthesia with propofol 1% mixed with lidocaine 0.05% (propofol
      dose 3 mg x kg(-1)), the treatment group received 50% N(2)O in O(2) and the
      control group received 100% oxygen. Pain due to propofol administration was rated
      with a four-point behavioural scale: none, mild, moderate or severe. RESULTS:
      There were 28 subjects in the control group and 26 subjects in the treatment
      group. Demographic data were similar in both groups. The incidence of pain at
      induction was 4% after N(2)O and 36% in the control group, P < 0.01. No patients
      had severe pain. Most patients had mild pain. Three of the ten patients with pain
      in the control group had moderate pain. The number needed to treat was 3:1.
      CONCLUSION: Nitrous oxide reduces pain during induction with propofol mixed with
      lidocaine in healthy children.

PMID- 12477680
TI  - An admixture of 3 mg x kg(-1) of propofol and 3 mg x kg(-1) of thiopentone
      reduces pain on injection in pediatric anesthesia.
AB  - PURPOSE: To evaluate the incidence of pain on injection in children during
      anesthetic induction with a 3:1.2 volume admixture of 1% propofol and 2.5%
      thiopentone (P/T) compared to a 10:1 volume admixture of 1% propofol and 2%
      lidocaine (P/L). METHODS: After Ethics Committee approval and informed written
      parental consent, 127 children, aged one to ten years were studied and randomized
      into two groups; Group P/L received an induction with 5 mg x kg(-1) of 1%
      propofol and 1 mg x kg(-1) of lidocaine, Group P/T with 3 mg x kg(-1) of 1%
      propofol and 3 mg x kg(-1) of 2.5% thiopentone in a standardized fashion. A
      single, blinded observer scored pain behaviour defined as a motor response of the
      arm, a verbal complaint of pain, cry and/or one of three standardized facial
      expressions of pain. RESULTS: The incidence of pain was 14% in the P/T group,
      compared to 35% in the P/L group (chi(2)(1) = 7.5, P = 0.006). Motor response was
      the most frequent pain response in the P/L group (68%). CONCLUSION: The P/T
      admixture is a practical and efficacious alternative to P/L for reducing pain on
      induction in children. Further work to evaluate the optimum proportions and
      possible adverse effects of this admixture should be done.

PMID- 12477681
TI  - Fentanyl is more effective than remifentanil at preventing increases in cerebral
      blood flow velocity during intubation in children.
AB  - PURPOSE: Controlling the cerebral and systemic hemodynamic responses to
      laryngoscopy and tracheal intubation may play a role in determining clinical
      outcome in pediatric neurosurgical patients. This study compared the effects of
      remifentanil and fentanyl on cerebral blood flow velocity (CBFV) and hemodynamic
      profile during laryngoscopy and tracheal intubation in children under sevoflurane
      anesthesia. METHODS: Sixty healthy children aged two to six years undergoing
      dental surgery under general anesthesia were enrolled. Each child was randomly
      assigned to receive a remifentanil or fentanyl infusion, at a rate of 0.75, 1.0,
      or 1.5 microg x kg(-1) x min(-1) after induction of anesthesia with 2%
      sevoflurane. Middle cerebral artery blood flow velocity was measured by
      transcranial Doppler (TCD) sonography. Once a baseline set of hemodynamic
      variables and TCD measurements were recorded, the opioid infusion was started.
      Measurements were taken at two-minute intervals, starting four minutes prior to
      laryngoscopy until four minutes following naso-tracheal intubation. RESULTS:
      Remifentanil caused a more significant decrease in mean arterial pressure and
      CBFV prior to tracheal intubation than did fentanyl (P < 0.001). During
      laryngoscopy and for two minutes following tracheal intubation, CBFV increased in
      all remifentanil groups (P < 0.05), whereas it remained stable in all fentanyl
      groups. CONCLUSION: This study suggests that fentanyl was more effective than
      remifentanil at preventing increases in CBFV during and immediately following
      laryngoscopy and tracheal intubation in children undergoing sevoflurane
      anesthesia. Fentanyl also seemed to provide a more stable hemodynamic profile
      prior to laryngoscopy and tracheal intubation when compared to remifentanil.

PMID- 12477682
TI  - Iloprost improves hemodynamics in patients with severe chronic cardiac failure
      and secondary pulmonary hypertension.
AB  - PURPOSE: Significant pulmonary hypertension is a predictor of postoperative right
      heart insufficiency and increased mortality in patients undergoing orthotopic
      heart transplantation. Since the use of iv vasodilators is limited by their
      systemic effects, we evaluated the pulmonary and systemic hemodynamic effects of
      inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated
      pulmonary vascular resistance (PVR). METHODS: Twenty-nine male heart transplant
      candidates because of dilated or ischemic cardiomyopathy with elevated PVR were
      included in the study. After assessing baseline hemodynamics, 50 micro g
      aerosolized IP were administered by inhalation. RESULTS: Inhalation of iloprost
      reduced PVR index (PVRI; 416 +/- 180 vs 349 +/- 173 dyn x sec(-1) x m(-2) x cm(
      5); P < 0.01) and mean pulmonary artery pressure (MPAP; 28.6 +/- 9 vs 24.2 +/-
      9.1 mmHg; P < 0.01), but did not affect blood pressure or systemic vascular
      resistance. An additional improvement of ventricular performance with an increase
      of cardiac index (CI; 2.8 +/- 0.7 vs 2.6 +/- 0.7 L x min(-1) x m(-2); P < 0.05)
      and a decrease of pulmonary capillary wedge pressure (PCWP; 15.6 +/- 6.8 vs 12.8
      +/- 7.1 mmHg; P < 0.01) was observed after inhalation of IP. CONCLUSIONS: Inhaled
      aerosolized iloprost effectively reduces MPAP and is accompanied by an increase
      in CI and stroke index. Further advantages of iloprost inhalation are the lack of
      adverse reactions and ease of administration. Iloprost may be a useful drug to
      screen for vascular reactivity in cardiac transplantation patients.

PMID- 12477683
TI  - Transesophageal echocardiography in the management of left atrio-femoral bypass
      during thoracoabdominal aortic aneurysm repair: a case report.
AB  - PURPOSE: To describe the utility of transesophageal echocardiography (TEE) in a
      patient undergoing thoracoabdominal aneurysm (TAA) surgery using left atrio
      femoral bypass (LAFB). CLINICAL FEATURES: A 57-yr-old female patient underwent
      repair of type II TAA. As per institutional routine, LAFB technique was used.
      Initial difficulty with the pump flow was encountered. TEE images showed that the
      left atrial cannula was positioned against the left atrial wall. The cannula
      position was adjusted and the pump flow was established. During different stages
      of the surgery, TEE was used to monitor the left ventricular cavity size and its
      function. This allowed the adjustment of LAFB pump flow relative to left
      ventricular filling and optimal fluid resuscitation in order to maintain both
      upper and lower body perfusion. CONCLUSION: In this patient, TEE was useful to
      confirm the correct position of the left atrial cannula and for hemodynamic
      management during LAFB.

PMID- 12477684
TI  - Large cuff volumes impede posterior pharyngeal mucosal perfusion with the
      laryngeal tube airway.
AB  - PURPOSE: The laryngeal tube airway (LTA) is a new extraglottic airway device with
      a large proximal cuff that inflates in the laryngopharynx and a distal conical
      cuff that inflates in the hypopharynx. We determine the influence of the cuff
      volume and anatomic location on pharyngeal mucosal pressures for the LTA.
      METHODS: Fifteen fresh cadavers were studied. Microchip sensors were attached to
      the (anatomic location) anterior, lateral and posterior surface of the distal
      cuff (hypopharynx) and proximal cuff (laryngopharynx) of the size 4 LTA.
      Oropharyngeal leak pressure (OLP) and mucosal pressures were measured at 0-140 mL
      cuff volume in 20-mL increments. In addition, mucosal pressures for the proximal
      cuff were measured in three awake, topicalized volunteers. RESULTS: OLP and
      mucosal pressure at all locations increased with cuff volume (all: P < 0.01).
      Mucosal pressures were highest posteriorly. Mucosal pressures only exceeded 35 cm
      H(2)O (pharyngeal mucosal perfusion pressure) in the anterior and posterior
      laryngopharynx and when the cuff volume was > 80-100 mL. Mucosal pressures were
      similar for cadavers and awake volunteers. CONCLUSION: Mucosal pressures for the
      LTA increase with cuff volume, are highest posteriorly and potentially exceed
      mucosal perfusion pressure when cuff volume exceeds 80-100 mL.

PMID- 12477685
TI  - A low-dose remifentanil infusion is well tolerated for sedation in mechanically
      ventilated, critically-ill patients.
AB  - PURPOSE: To study the analgesic and sedative effects of remifentanil in
      critically-ill patients. METHODS: Remifentanil infusion was started at 0.02
      microg x kg(-1) x min(-1) in ten mechanically ventilated critically-ill patients,
      and the infusion rate was increased to 0.05, 0.10, 0.15, 0.20, and 0.25 microg x
      kg(-1) x min(-1) every 30 min. Basally and 25 min after each increase we
      measured: the Ramsey sedation score (RSS) and the respiratory response subscore
      of comfort scale (CSRR); the bispectral index (BIS) before and after lightly
      touching tracheal mucosa; heart rate and systemic arterial pressure; respiratory
      variables; plasma epinephrine and norepinephrine levels. RESULTS: Infusion rates
      up to 0.05 microg x kg(-1) x min(-1) were effective against agitation and
      achieved a good degree of adaption to the respirator in all patients (RSS 2 or
      more and CSRR 3 or less); BIS decreased significantly; respiratory and
      circulatory variables were unaffected; mean plasma epinephrine levels decreased.
      At infusion rates higher than 0.05 microg x kg(-1) x min(-1) RSS but not BIS
      decreased further and patient arousability caused by noxious stimuli was not
      prevented; respiratory drive suppression occurred at the infusion rates higher
      than 0.05 microg x kg(-1) x min(-1) in four patients; bradycardia and arterial
      hypotension was observed in three patients; plasma epinephrine levels decreased
      significantly, while norepinephrine was unaffected; severe itching was
      experienced by one patient. CONCLUSIONS: Low doses of remifentanil (up to 0.05
      microg x kg(-1) x min(-1)) can be useful in critically-ill patients in order to
      achieve calm and sedation. Higher doses can inhibit respiratory drive and require
      controlled mechanical ventilation.

PMID- 12477686
TI  - The internet, medical practice, and medical education--some medico-legal issues.

PMID- 12477687
TI  - A bizarre end-tidal carbon dioxide waveform.

PMID- 12477688
TI  - An unusual case of hemolysis.

PMID- 12477689
TI  - An unusual cause of respiratory distress and hypotension following removal of a
      pheochromocytoma.

PMID- 12477690
TI  - Fentanyl abolishes the hyperdynamic response to isoflurane without affecting the
      change in bispectral index.

PMID- 12477692
TI  - Hunting (auto)immune T cells in neuroimmunological diseases.

PMID- 12477693
TI  - Lead neurotoxicity in children: basic mechanisms and clinical correlates.
AB  - Lead has been recognized as a poison for millennia and has been the focus of
      public health regulation in much of the developed world for the better part of
      the past century. The nature of regulation has evolved in response to increasing
      information provided by vigorous scientific investigation of lead's effects. In
      recognition of the particular sensitivity of the developing brain to lead's
      pernicious effects, much of this legislation has been addressed to the prevention
      of childhood lead poisoning. The present review discusses the current state of
      knowledge concerning the effects of lead on the cognitive development of
      children. Addressed are the reasons for the child's exquisite sensitivity, the
      behavioural effects of lead, how these effects are best measured, and the long
      term outlook for the poisoned child. Of particular importance are the
      accumulating data suggesting that there are toxicological effects with
      behavioural concomitants at exceedingly low levels of exposure. In addition,
      there is also evidence that certain genetic and environmental factors can
      increase the detrimental effects of lead on neural development, thereby rendering
      certain children more vulnerable to lead neurotoxicity. The public health
      implications of these findings are discussed.

PMID- 12477694
TI  - Molecular tracking of antigen-specific T cell clones in neurological immune
      mediated disorders.
AB  - T cells recognizing self or microbial antigens may trigger or reactivate immune
      mediated diseases. Monitoring the frequency of specific T cell clonotypes to
      assess a possible link with the course of disease has been a difficult task with
      currently available technology. Our goal was to track individual candidate
      pathogenic T cell clones, selected on the basis of previous extensive studies
      from patients with immune-mediated disorders of the CNS, including multiple
      sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP)
      and chronic Lyme neuroborreliosis. We developed and applied a highly specific and
      sensitive technique to track single CD4(+) and CD8(+) T cell clones through the
      detection and quantification of T cell receptor (TCR) alpha or beta chain
      complementarity-determining region 3 transcripts by real-time reverse
      transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T
      cell clones in the peripheral blood and CSF during the course of neurological
      disease. Using this approach, we detected variations of clonal frequencies that
      appeared to be related to clinical course, significant enrichment in the CSF, or
      both. By integrating clonotype tracking with direct visualization of antigen
      specific staining, we showed that a single T cell clone contributed substantially
      to the overall recognition of the viral peptide/MHC complex in a patient with
      HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further
      elucidation of the dynamics of expansion of autoreactive or pathogen-specific T
      cells that mediate pathological or protective immune responses in neurological
      disorders.

PMID- 12477695
TI  - Haploinsufficiency at the alpha-synuclein gene underlies phenotypic severity in
      familial Parkinson's disease.
AB  - To date, two point mutations, G209A and G88C, have been reported in the coding
      region of the alpha-synuclein gene in autosomal dominant familial Parkinson's
      disease. When translated, these lead to the missense mutations Ala53Thr and
      Ala30Pro, respectively. Reduced mRNA expression of the G209A allele was reported
      recently in a Greek-American family. Here, we show that alpha-synuclein mRNA is
      normally expressed in blood cells and report the results of an analysis of alpha
      synuclein mRNA and protein expression in lymphoblastoid cell lines established
      from kindreds with the G209A and G88C mutations. mRNA expression was
      characterized using a TaqMan real-time quantitative reverse transcriptase
      polymerase chain reaction (RT-PCR) assay. We assessed five affected and three
      unaffected members of a German family with the G88C mutation and two affected
      members in different, unrelated Greek families with the G209A mutation. The ratio
      of wild-type to mutant alpha-synuclein allele expression ranged from 2.2 to 9.2
      in the affected individuals with a severe clinical phenotype. The ratios of the
      expression levels of the wild-type to mutant alleles were only slightly decreased
      in mild cases and were less than 1.0 in two asymptomatic heterozygotes. Sequence
      analysis of the RT-PCR products showed only the presence of G in position 88 and
      G in position 209 in severely affected heterozygotes of the German and Greek
      families, respectively. High performance liquid chromatography/mass spectrometry
      demonstrated that, relative to wild-type alpha-synuclein, there is a reduction of
      Ala30Pro alpha-synuclein in lymphoblastoid cell lines originating from severely
      affected, but not mildly affected G88C/+ heterozygotes. Taken together, these
      data indicate that there is haploinsufficiency at the alpha-synuclein gene and
      that the ratio of expression of the wild-type to mutant alleles correlates with
      the severity of the clinical phenotype. Furthermore, these findings suggest that
      haploinsufficiency of alpha-synuclein mutations may contribute to disease
      progression in these forms of familial Parkinson's disease.

PMID- 12477696
TI  - Neuroanatomical correlates of episodic encoding and retrieval in young and
      elderly subjects.
AB  - Lesion studies have shown convincingly that the medial temporal lobes (MTL) and
      frontal lobes are critical to episodic memory. Ageing generally has been found to
      have a generally negative effect on episodic memory performance, which might
      relate to neurofunctional changes in the frontal and medial temporal brain
      regions. In the present study, we used functional MRI (fMRI) to investigate
      separately the contributions of encoding and retrieval to the age-related decline
      in memory. To this end, we compared brain activity patterns obtained during
      incidental encoding (pleasant/unpleasant judgements about nouns) and subsequent
      retrieval (recognition) in three groups: a group of young subjects, a group of
      elderly subjects showing reduced memory performance (ELD-RED), and a group of
      elderly subjects who still performed in the normal range (ELD-NORM). This allowed
      us to differentiate between age-related changes in brain activity that affect
      memory function and those that do not have an apparent effect on memory function,
      because they are found in both elderly groups. Contrary to previous imaging
      studies on this topic, we used (self-paced) event-related fMRI to control for
      differences in performance level across groups by including correct responses
      only. Comparing the encoding of successfully remembered items with baseline
      (press left/press right), the young subjects showed a significant increase in
      brain activation in the left anterior MTL compared with the ELD-RED but not the
      ELD-NORM subjects. Comparing correctly rejected items (retrieval attempt) with
      baseline, the ELD-RED group showed much increased overall activity throughout the
      brain compared with the other groups. However, when correctly recognized items
      (retrieval attempt + success) were compared directly with correctly rejected
      items (retrieval attempt), these differences were greatly reduced, revealing
      common activity in the left parietal, retrosplenial and left anterior prefrontal
      regions. Therefore, we conclude that the reduced performance in the ELD-RED group
      is likely to be due to MTL dysfunction during encoding. The differences observed
      during retrieval attempts may reflect strategic differences. The lack of
      differences observed in relation to retrieval success suggests that ageing does
      not affect the processes that support the actual recovery of information.

PMID- 12477697
TI  - Sensory function in spinal cord injury patients with and without central pain.
AB  - Spinal cord injury (SCI) frequently results in neuropathic pain. However, the
      pathophysiology underlying this pain is unclear. In this study, we compared
      clinical examination, quantitative sensory testing (QST) and somatosensory evoked
      potentials (SEPs) in SCI patients with and without pain below spinal lesion
      level, with a control group of 20 subjects without injury. All patients had a
      traumatic SCI with a lesion above T10; 20 patients presented with spontaneous
      central neuropathic pain below lesion level, and 20 patients had no neuropathic
      pain or dysaesthesia. Patients with and without pain had a similar reduction of
      mechanical and thermal detection and pain thresholds, and SEPs. SCI patients with
      central pain more frequently had sensory hypersensitivity (brush- or cold-evoked
      pain, dysaesthesia or pinprick hyperalgesia) in dermatomes corresponding to
      lesion level than SCI patients without pain. There was no difference in intensity
      of pain evoked by repetitive pinprick at lesion level between patient groups.
      There was a significant correlation between intensity of brush-evoked
      dysaesthesia at lesion level and spontaneous pain below lesion level of SCI.
      These data suggest that lesion of the spinothalamic pathway alone cannot account
      for central pain in SCI patients, and that neuronal hyperexcitability at injury
      or higher level may be an important mechanism for pain below injury level.

PMID- 12477698
TI  - Comparison of eyeblink conditioning in patients with superior and posterior
      inferior cerebellar lesions.
AB  - The aim of the present study was to compare eyeblink conditioning in cerebellar
      patients with lesions including the territory of the superior cerebellar artery
      (SCA) and in patients with lesions restricted to the territory of the posterior
      inferior cerebellar artery (PICA). The cerebellar areas known to be most critical
      in eyeblink conditioning based on animal data (i.e. Larsell lobule H VI and
      interposed nucleus) are commonly supplied by the SCA. Eyeblink conditioning was
      expected to be impaired in SCA, but not in PICA patients. A total of 27
      cerebellar patients and 25 age-matched controls were tested. Cerebellar lesions
      were primarily unilateral (n = 20). Most patients suffered from ischaemic
      infarctions of the SCA (n = 11) or the PICA (n = 13). The other patients
      presented with cerebellar tumours (n = 2) and cerebellar agenesis (n = 1). The
      extent of the cortical lesion (i.e. which lobuli were affected) and possible
      involvement of the cerebellar nuclei was determined by 3D-MRI. As expected, the
      ability to acquire classically conditioned eyeblink responses was significantly
      reduced in the group of all cerebellar patients compared with the controls. In
      the patients with unilateral cerebellar lesions, conditioning deficits were
      present ipsilaterally. In SCA patients with lesions including hemispheral lobules
      VI and Crus I, eyeblink conditioning was significantly reduced on the affected
      side compared with the unaffected side. No significant difference between the
      affected and unaffected sides was present in patients with lesions restricted to
      the common PICA territory (i.e. Crus II and below). Conditioning deficits were
      neither significantly different in SCA patients with pure cortical lesions
      compared with SCA patients with additional nuclear impairment nor in SCA patients
      with unilateral lesions compared with SCA patients with bilateral lesions. To
      summarize, unilateral cortical lesions of the superior cerebellum appear to be
      sufficient to reduce eyeblink conditioning in humans significantly.

PMID- 12477699
TI  - Disruption of information processing in the supplementary motor area of the MPTP
      treated monkey: a clue to the pathophysiology of akinesia?
AB  - It has been suggested that the underactivity of mesial frontal structures induced
      by dopamine depletion could constitute one of the main substrates underlying
      akinesia in Parkinson's disease. Functional imaging and movement-related
      potential recordings indicate an implication of the frontal lobes in this
      pathological process, but the question has not yet been investigated at a
      cellular level using single unit recording. We therefore compared neuronal
      activity in both the presupplementary motor area (pre-SMA) and the supplementary
      motor area proper (SMAp) of the Macaca mulatta monkey during a delayed motor
      task, before and after MPTP treatment. In the pre-SMA, which receives strong
      inputs from the prefrontal cortex, the baseline firing frequency and the
      percentage of neurons responding to visual instruction cues decreased in lesioned
      monkeys. In the SMAp, which sends direct outputs to the primary motor cortex, not
      only was the response to visual cues impaired, but the percentage of SMAp neurons
      responding to intracortical microstimulation fell and the threshold of response
      rose. Neuronal activity after the Go signal diminished sharply in both structures
      in the symptomatic animal and the discharge pattern became more irregular; in the
      SMAp neuronal activity remained modified longer. Most of these changes could
      already be observed in the presymptomatic animal presenting no clinical signs of
      parkinsonism. These data would indicate that, at the moment when dopamine
      depletion has impaired the ability of cortical neurons to operate the focused
      selection of incoming information giving instructions for movement, pre-SMA and
      SMAp neurons are also in a state of severe hypoactivity. The conjunction of these
      phenomena could play a critical role in the genesis of akinesia.

PMID- 12477700
TI  - Motoneuron adaptability to new motor tasks following two types of facial-facial
      anastomosis in cats.
AB  - The ability of the facial motor system to adapt to a new motor function was
      studied in alert cats after unilateral transection, 180 degrees rotation and
      suture of the zygomatic nerve, or transection and cross-anastomosis of the
      proximal stump of the buccal nerve to the distal stump of the zygomatic nerve.
      These procedures induced reinnervation of the orbicularis oculi (OO) muscle by
      different OO- or mouth-related facial motoneurons. Eyelid movements and the
      electromyographic activity of the OO muscle were recorded up to 1 year following
      the two types of anastomosis. Animals with a zygomatic nerve rotation recovered
      spontaneous and reflex responses, but with evident deficits in eyelid kinematics,
      i.e. the proper regional distribution of OO motor units was disorganized by
      zygomatic nerve rotation and resuture, producing a permanent defect in eyelid
      motor performance. Following buccal-zygomatic anastomosis, the electrical
      activity of the OO muscle was recovered after 6-7 weeks, but air puff-, flash-
      and tone-evoked reflex blinks never reached the control values on the operated
      side. Electromyographic OO activities and lid movements corresponding to licking
      and deglutition activities were observed on the operated side in buccal-zygomatic
      anastomosed animals up to 1 year following surgery. Mouth-related facial
      motoneurons did not readapt their discharges to the kinetic, timing and
      oscillatory properties of OO muscle fibres. A significant hyper-reflexia was
      observed following both types of nerve repair in response to air puffs, but not
      to light flashes or tones. In conclusion, adult mammal facial premotor circuits
      maintain their motor programmes when motoneurons are induced to reinnervate a
      foreign muscle, or even a new set of muscle fibres.

PMID- 12477701
TI  - Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations
      of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of
      205 Japanese patients.
AB  - Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin
      related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ)
      and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues
      in CMT associated with mutations of these genes. We electrophysiologically,
      pathologically and genetically evaluated demyelinating and axonal features of 205
      Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22
      duplication caused mainly demyelinating phenotypes with slowed motor nerve
      conduction velocity (MCV) and demyelinating histopathology, while axonal features
      were variably present. Two distinctive phenotypic subgroups were present in
      patients with MPZ mutations: one showed preserved MCV and exclusively axonal
      pathological features, while the other was exclusively demyelinating. These
      axonal and demyelinating phenotypes were well concordant among siblings in
      individual families, and MPZ mutations did not overlap among these two subgroups,
      suggesting that the nature and position of the MPZ mutations mainly determine the
      axonal and demyelinating phenotypes. Patients with Cx32 mutations showed
      intermediate slowing of MCV, predominantly axonal features and relatively mild
      demyelinating pathology. These axonal and demyelinating features were present
      concomitantly in individual patients to a variable extent. The relative severity
      of axonal and demyelinating features was not associated with particular Cx32
      mutations. Median nerve MCV and overall histopathological phenotype changed
      little with disease advancement. Axonal features of diminished amplitudes of
      compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and
      neuropathic muscle wasting all changed as disease advanced, especially in PMP22
      duplication and Cx32 mutations. Median nerve MCVs were well maintained
      independently of age, disease duration and the severity of clinical and
      pathological abnormalities, confirming that median nerve MCV is an excellent
      marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs
      was correlated significantly with distal muscle strength in PMP22 duplication,
      MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that
      clinical weakness results from reduced numbers of functional large axons, not
      from demyelination. Thus, the three major myelin-related protein mutations
      induced varied degrees of axonal and demyelinating phenotypic features according
      to the specific gene mutation as well as the stage of disease advancement, while
      clinically evident muscle wasting was attributable to loss of functioning large
      axons.

PMID- 12477702
TI  - Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1): a retrospective
      study of 104 patients.
AB  - In addition to multiple peripheral neurofibromas, Neurofibromatosis 1 (NF1)
      predisposes to CNS tumours. Most of them are pilocytic astrocytomas, arise in
      children and are located in the optic pathways or in the brainstem. The majority
      are indolent, but factors predictive of poor prognosis have yet to be identified.
      Furthermore, the incidence and natural history of gliomas of a higher grade,
      arising in adults or involving other locations are largely unknown in NF1. In
      order to address these issues, we performed a retrospective study of 104 patients
      followed in seven French centres between 1982 and 2000. Inclusion criteria were a
      diagnosis of NF1, according to the National Institutes of Health criteria, and
      the presence of a CNS tumour, regardless of type, location or age of onset. The
      series included 88 children (age range 3 months to 17 years) and 16 adults (age
      range 19-52 years). The median follow-up was 5.6 years. One hundred and twenty
      seven CNS tumours were observed in the 104 patients. Eighty-four (66%) were optic
      pathway tumours (OPT) and 43 (34%) extra-optic pathway tumours (extra-OPT)
      (brainstem: n = 21; other locations: n = 22). Twenty-one patients (20%) had
      multiple CNS tumours. OPT were symptomatic in 50 patients and extra-OPT in 19.
      Main clinical findings at presentation included visual loss (n = 29; 58%) and
      precocious puberty (n = 5; 10%) for OPT, increased intracranial pressure (n = 9;
      48%) for extra-OPT. Fourteen out of the 27 symptomatic tumours with histology
      were pilocytic astrocytomas. The overall survival rate was 90% at 5 years (95%
      confidence interval 82-95%). Extra-optic location, tumour diagnosis in adulthood
      and symptomatic tumours were independent factors associated with shorter survival
      time (P < 0.05, Cox model). Radiotherapy for OPT was associated with vascular
      complications (ischaemic strokes) and growth hormone deficiency in 32 and 46% of
      patients, respectively. In conclusion, mortality is high in extra-OPT,
      particularly in adults, whereas OPT are only exceptionally life-threatening.
      Radiotherapy of OPT is associated with an important morbidity in NF1.

PMID- 12477703
TI  - A neural basis for the perception of voices in external auditory space.
AB  - We used functional imaging of normal subjects to identify the neural substrate
      for the perception of voices in external auditory space. This fundamental process
      can be abnormal in psychosis, when voices that are not true external auditory
      objects (auditory verbal hallucinations) may appear to originate in external
      space. The perception of voices as objects in external space depends on filtering
      by the outer ear. Psychoses that distort this process involve the cerebral
      cortex. Functional magnetic resonance imaging was carried out on 12 normal
      subjects using an inside-the-scanner simulation of 'inside head' and 'outside
      head' voices in the form of typical auditory verbal hallucinations. Comparison
      between the brain activity associated with the two conditions allowed us to test
      the hypothesis that the perception of voices in external space ('outside head')
      is subserved by a temperoparietal network comprising association auditory cortex
      posterior to Heschl's gyrus [planum temporale (PT)] and inferior parietal lobule.
      Group analyses of response to 'outside head' versus 'inside head' voices showed
      significant activation solely in the left PT. This was demonstrated in three
      experiments in which the predominant lateralization of the stimulus was to the
      right, to the left or balanced. These findings suggest a critical involvement of
      the left PT in the perception of voices in external space that is not dependent
      on precise spatial location. Based on this, we suggest a model for the false
      perception of externally located auditory verbal hallucinations.

PMID- 12477704
TI  - Homocysteine and brain atrophy on MRI of non-demented elderly.
AB  - Patients with Alzheimer's disease have higher plasma homocysteine levels than
      controls, but it is uncertain whether higher plasma homocysteine levels are
      involved in the early pathogenesis of the disease. Hippocampal, amygdalar and
      global brain atrophy on brain MRI have been proposed as early markers of
      Alzheimer's disease. In the Rotterdam Scan Study, a population-based study of age
      related brain changes in 1077 non-demented people aged 60-90 years, we
      investigated the association between plasma homocysteine levels and severity of
      hippocampal, amygdalar and global brain atrophy on MRI. We used axial T(1)
      weighted MRIs to visualize global cortical brain atrophy (measured semi
      quantitatively; range 0-15) and a 3D HASTE (half-Fourier acquisition single-shot
      turbo spin echo) sequence in 511 participants to measure hippocampal and
      amygdalar volumes. We had non-fasting plasma homocysteine levels in 1031 of the
      participants and in 505 of the participants with hippocampal and amygdalar
      volumes. Individuals with higher plasma homocysteine levels had, on average, more
      cortical atrophy [0.23 units (95% CI 0.07-0.38 units) per standard deviation
      increase in plasma homocysteine levels] and more hippocampal atrophy [difference
      in left hippocampal volume -0.05 ml (95% CI -0.09 to -0.01) and in right
      hippocampal volume -0.03 ml (95% CI -0.07 to 0.01) per standard deviation
      increase in plasma homocysteine levels]. No association was observed between
      plasma homocysteine levels and amygdalar atrophy. These results support the
      hypothesis that higher plasma homocysteine levels are associated with more
      atrophy of the hippocampus and cortical regions in elderly at risk of Alzheimer's
      disease.

PMID- 12477705
TI  - The non-classical MHC molecule HLA-G protects human muscle cells from immune
      mediated lysis: implications for myoblast transplantation and gene therapy.
AB  - HLA-G is a non-classical MHC class I molecule with highly limited tissue
      distribution which has been attributed chiefly immune-regulatory functions. We
      previously have reported that HLA-G is expressed in inflamed muscle in vivo and
      by cultured myoblasts in vitro. Here, we used the in vitro models of human
      myoblasts or TE671 muscle rhabdomyosarcoma cells to characterize the functional
      role of HLA-G for muscle immune cell interactions. Gene transfer of the two major
      isoforms of HLA-G (transmembranous HLA-G1 and soluble HLA-G5) into TE671 rendered
      these cells resistant to alloreactive lysis by direct inhibition of natural
      killer (NK) cells, and CD4 and CD8 T cells. Further, HLA-G reduced
      alloproliferation, interfered with effective priming of antigen-specific
      cytotoxic T cells and reduced antigen-specific alloreactive lysis. HLA-G pre
      induced on cultured myoblasts inhibited lysis by alloreactive peripheral blood
      mononuclear cells. This protection was reversed by a neutralizing HLA-G antibody.
      Interestingly, a few HLA-G-positive cells within a population of HLA-G-negative
      muscle target cells conveyed significant inhibitory effects on alloreactive
      lysis. Our results reveal further insights into the immunobiology of muscle and
      suggest that ectopic expression of HLA-G may promote the survival of transplanted
      myoblasts in the future treatment of hereditary muscle diseases. Further, HLA-G
      could represent a novel self-derived anti-inflammatory principle applicable in
      strategies against inflammatory aggression.

PMID- 12477706
TI  - Demyelination and axonal loss in multifocal motor neuropathy: distribution and
      relation to weakness.
AB  - Multifocal motor neuropathy (MMN) is characterized by a slowly progressive,
      asymmetric weakness of the limbs without sensory loss. The arms are usually
      affected to a greater extent than the legs, and distal muscles more than proximal
      muscles. The distribution of electrophysiological abnormalities and its
      correlation with weak muscle groups in MMN have not been investigated
      systematically. The aim of the present study was to assess whether
      electrophysiological abnormalities have a preferential or random distribution,
      whether electrophysiological abnormalities in a nerve correlate with weakness in
      the innervated muscles, and whether these results are relevant for the
      development of optimal electrodiagnostic protocols. We compared the pattern of
      weakness and electrophysiological abnormalities in 39 patients with a lower
      motoneuron syndrome and a positive response to intravenous immunoglobulins. All
      patients underwent an extensive standardized electrophysiological examination.
      Electrophysiological evidence of demyelination was found more often in the nerves
      of the arms and was distributed randomly over lower arm, upper arm and shoulder
      segments. Electrophysiological evidence of axonal loss presented more frequently
      in longer nerves, occurring most often in the leg nerves. For the arm nerves, it
      is possible that the length dependence of axonal loss is due to the random
      distribution of demyelinating lesions that lead to axonal degeneration. Weakness
      was associated with features of demyelination and axonal loss in the nerves of
      the arm, and with features of axonal loss in leg nerves. However, a substantial
      number (approximately one-third) of electrophysiological abnormalities were found
      in nerves innervating non-weakened muscles. These results imply that in MMN,
      conduction block is most likely to be found in long arm nerves innervating
      weakened muscles, but if conduction block cannot be detected in these nerves, the
      electrophysiological examination should be extended to other arm nerves including
      those innervating non-weakened muscles.

PMID- 12477707
TI  - The cerebral oscillatory network of parkinsonian resting tremor.
AB  - Data from experiments in MPTP monkeys as well as from invasive and non-invasive
      recordings in patients with Parkinson's disease suggest an abnormal
      synchronization of neuronal activity in the generation of resting tremor in
      Parkinson's disease. In six patients with tremor-dominant idiopathic Parkinson's
      disease, we recorded simultaneously surface electromyograms (EMGs) of hand
      muscles, and brain activity with a whole-head magnetoencephalography (MEG)
      system. Using a recently developed analysis tool (Dynamic Imaging of Coherent
      Sources; DICS), we determined cerebro-muscular and cerebro-cerebral coherence as
      well as the partial coherence between cerebral areas and muscle, and localized
      coherent sources within the individual MRI scans. The phase lag between the EMG
      and cerebral activity was determined by means of a Hilbert transform of both
      signals. After overnight withdrawal from medication, patients showed typical
      Parkinson's disease resting tremor (4-6 Hz). This tremor was associated with
      strong coherence between the EMG of forearm muscles and activity in the
      contralateral primary motor cortex (M1) at tremor frequency but also at double
      tremor frequency. Phase lags between M1 activity and EMG were between 15 and 25
      ms (M1 activity leading) at single, but also at double tremor frequency,
      corresponding well to the corticomuscular conduction time. Furthermore,
      significant coherence was observed between M1 and medial wall areas
      (cingulate/supplementary motor area; CMA/SMA), lateral premotor cortex (PM),
      diencephalon, secondary somatosensory cortex (SII), posterior parietal cortex
      (PPC) and the contralateral cerebellum at single tremor and, even stronger at
      double tremor frequency. Spectra of coherence between thalamic activity and
      cerebellum as well as several brain areas revealed additional broad peaks around
      20 Hz. Power spectral analysis of activity in all central areas indicated the
      strongest frequency components at double tremor frequency. Partial coherence
      analysis and the calculation of phase shifts revealed a strong bidirectional
      coupling between the EMG and diencephalic activity and a direct afferent coupling
      between the EMG and SII and the PPC. In contrast, the cerebellum, SMA/CMA and PM
      show little evidence for direct coupling with the peripheral EMG but seem to be
      connected with the periphery via other cerebral areas (e.g. M1). In summary, our
      results demonstrate tremor-related oscillatory activity within a cerebral
      network, with abnormal coupling in a cerebello-diencephalic-cortical loop and
      cortical motor (M1, SMA/CMA, PM) and sensory (SII, PPC) areas contralateral to
      the tremor hand. The main frequency of cerebro-cerebral coupling corresponds to
      double the tremor frequency.

PMID- 12477708
TI  - Age effects on the neural correlates of successful memory encoding.
AB  - Event-related functional MRI (fMRI) was used to investigate the neural correlates
      of memory encoding as a function of age. While fMRI data were obtained, 14
      younger (mean age 21 years) and 14 older subjects (mean age 68 years) made
      animacy decisions about words. Recognition memory for these words was tested at
      two delays such that older subjects' performance at the short delay was
      comparable to that of the young subjects at the long delay. This allowed age
      associated changes in the neural correlates of encoding to be dissociated from
      the correlates of differential recognition performance. Activity in left inferior
      prefrontal cortex and the left hippocampal formation was greater for subsequently
      recognized words in both age groups, consistent with the findings of previous
      studies in young adults. In the prefrontal cortex, these 'subsequent memory
      effects' were, however, left-lateralized in the younger group but bilateral in
      the older subjects. In addition, for the younger group only, greater activity for
      remembered words was observed in anterior inferior temporal cortex, as were
      reversed effects ('subsequent forgetting' effects) in anterior prefrontal
      regions. The data indicate that older subjects engage much of the same neural
      circuitry as younger subjects when encoding new memories. However, the findings
      also point to age-related differences in both prefrontal and temporal activity
      during successful episodic encoding.

PMID- 12477709
TI  - Childhood absence epilepsy and febrile seizures: a family with a GABA(A) receptor
      mutation.
AB  - Although several genes for idiopathic epilepsies from families with simple
      Mendelian inheritance have been found, genes for the common idiopathic
      generalized epilepsies, where inheritance is complex, presently are elusive. We
      studied a large family with epilepsy where the two main phenotypes were childhood
      absence epilepsy (CAE) and febrile seizures (FS), which offered a special
      opportunity to identify epilepsy genes. A total of 35 family members had seizures
      over four generations. The phenotypes comprised typical CAE (eight individuals);
      FS alone (15), febrile seizures plus (FS(+)) (three); myoclonic astatic epilepsy
      (two); generalized epilepsy with tonic-clonic seizures alone (one); partial
      epilepsy (one); and unclassified epilepsy despite evaluation (two). In three
      remaining individuals, no information was available. FS were inherited in an
      autosomal dominant fashion with 75% penetrance. The inheritance of CAE in this
      family was not simple Mendelian, but suggestive of complex inheritance with the
      involvement of at least two genes. A GABA(A) receptor gamma2 subunit gene
      mutation on chromosome 5 segregated with FS, FS(+) and CAE, and also occurred in
      individuals with the other phenotypes. The clinical and molecular data suggest
      that the GABA(A) receptor subunit mutation alone can account for the FS
      phenotype. An interaction of this gene with another gene or genes is required for
      the CAE phenotype in this family. Linkage analysis for a putative second gene
      contributing to the CAE phenotype suggested possible loci on chromosomes 10, 13,
      14 and 15. Examination of these loci in other absence pedigrees is warranted.

PMID- 12477710
TI  - Migraine can be induced by sildenafil without changes in middle cerebral artery
      diameter.
AB  - Migraine is considered a neurovascular disease involving dilatation of cerebral
      arteries. Nitric oxide (NO) donors induce dilatation of cerebral and extracranial
      arteries and migraine, but NO has several mechanisms of action in addition to its
      cyclic guanosine monophosphate (cGMP)-mediated vasodilatation. We examined
      whether sildenafil (Viagra), a selective inhibitor of cGMP-hydrolysing
      phosphodiesterase 5 (PDE5), which acts exclusively by increasing cGMP, can induce
      migraine and dilatation of cerebral arteries. We included 12 patients with
      migraine without aura in this double-blind, placebo-controlled crossover study,
      in which placebo or sildenafil 100 mg was administered orally on two separate
      days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by
      transcranial Doppler ultrasonography and regional cerebral blood flow in the
      territory of the middle cerebral artery (rCBF(mca)) was measured using SPECT
      (single photon emission computed tomography) and xenon 133 inhalation. Radial and
      temporal artery diameters were studied using high-frequency ultrasonography.
      Headache response, tenderness of pericranial muscles, blood pressure and heart
      rate were measured repeatedly. We found that migraine attack was induced by
      sildenafil in 10 of 12 migraine patients and by placebo in two of 12 patients (P
      = 0.01). V(mca) (P = 0.1) and rCBF(mca) (P = 0.93) remained unchanged after
      sildenafil. Temporal (P = 0.47) and radial (P = 0.87) artery diameter and
      pericranial tenderness (P = 0.16) were unaffected by sildenafil. Systolic and
      diastolic blood pressures were unchanged but heart rate increased from a mean of
      62 +/- 2 to 74 +/- 3 beats/min (P = 0.01) after sildenafil. Our results
      demonstrate that migraine may be induced via a cGMP-dependent mechanism, and we
      show for the first time that this occurs without initial dilatation of the middle
      cerebral artery. We propose that triggering mechanisms may reside within the
      perivascular sensory nerve terminals or the brainstem. However, other sites of
      action may also be possible and future studies are needed to elucidate this. In
      the clinical use of sildenafil, patients who have migraine should be informed
      about the risk of migraine attacks.

PMID- 12477711
TI  - Ictal SPECT in children with epilepsy: comparison with intracranial EEG and
      relation to postsurgical outcome.
AB  - In order to validate the ability of ictal single photon emission computed
      tomography (SPECT) to localize the epileptogenic zone (EZ) in children, we
      compared in 20 patients aged from 10 months to 17 years (mean 6.5 years) the
      topography of the area of increased ictal perfusion (IPA), determined on the
      basis of ictal minus interictal scan values, with that of the EZ determined by
      intracranial EEG recordings and assessed its relationship with the postsurgical
      outcome. Eighteen patients had symptomatic epilepsy and 10 had extratemporal
      epilepsy. All patients except one had an ictal injection (mean time lag from
      clinical seizure onset was 18 s). Ictal and interictal SPECT images were
      successively co-registered, normalized, subtracted, smoothed and superimposed on
      MRI. All patients with ictal injection exhibited one or several IPAs. The
      topography of the 'highest' IPA, i.e. the maximal cerebral blood flow (CBF)
      change between ictal and interictal SPECT, significantly colocalized with the
      site of onset of the discharge, and that of the lower IPAs with that of the area
      of propagation (P < 0.0001). At a threshold of 30% of the maximal CBF change, the
      IPAs detected the onset of the discharge with a sensitivity of 0.80 and a
      specificity of 0.70. The highest IPA localized the EZ in 12 out of 15 patients.
      In the three others it missed the EZ and showed the area of propagation because
      of rapid seizure propagation or of infraclinical seizure onset. Among the
      patients with favourable surgery outcome, the highest IPA colocalized with the
      resected area in 70% of cases. Ictal SPECT could therefore plays an important
      role as a non-invasive presurgical method of investigation by optimizing the
      placement of intracranial electrodes, thus improving the postsurgery outcome of
      paediatric partial epilepsy.

PMID- 12477712
TI  - Hypoxia actively represses transcription by inducing negative cofactor 2
      (Dr1/DrAP1) and blocking preinitiation complex assembly.
AB  - Hypoxia is a growth inhibitory stress associated with multiple disease states. We
      find that hypoxic stress actively regulates transcription not only by activation
      of specific genes but also by selective repression. We reconstituted this bimodal
      response to hypoxia in vitro and determined a mechanism for hypoxia-mediated
      repression of transcription. Hypoxic cell extracts are competent for transcript
      elongation, but cannot assemble a functional preinitiation complex (PIC) at a
      subset of promoters. PIC assembly and RNA polymerase II C-terminal domain (CTD)
      phosphorylation were blocked by hypoxic induction and core promoter binding of
      negative cofactor 2 protein (NC2 alpha/beta, Dr1/DrAP1). Immunodepletion of NC2
      beta/Dr1 protein complexes rescued hypoxic-repressed transcription without
      alteration of normoxic transcription. Physiological regulation of NC2 activity
      may represent an active means of conserving energy in response to hypoxic stress.

PMID- 12477713
TI  - Caspase proteolysis of desmin produces a dominant-negative inhibitor of
      intermediate filaments and promotes apoptosis.
AB  - Caspase cleavage of key cytoskeletal proteins, including several intermediate
      filament proteins, triggers the dramatic disassembly of the cytoskeleton that
      characterizes apoptosis. Here we describe the muscle-specific intermediate
      filament protein desmin as a novel caspase substrate. Desmin is cleaved
      selectively at a conserved Asp residue in its L1-L2 linker domain (VEMD downward
      arrow M(264)) by caspase-6 in vitro and in myogenic cells undergoing apoptosis.
      We demonstrate that caspase cleavage of desmin at Asp(263) has important
      functional consequences, including the production of an amino-terminal cleavage
      product, N-desmin, which is unable to assemble into intermediate filaments,
      instead forming large intracellular aggregates. Moreover, N-desmin functions as a
      dominant-negative inhibitor of filament assembly, both for desmin and the
      structurally related intermediate filament protein vimentin. We also show that
      stable expression of a caspase cleavage-resistant desmin D263E mutant partially
      protects cells from tumor necrosis factor-alpha-induced apoptosis. Taken
      together, these results indicate that caspase proteolysis of desmin at Asp(263)
      produces a dominant-negative inhibitor of intermediate filaments and actively
      participates in the execution of apoptosis. In addition, these findings provide
      further evidence that the intermediate filament cytoskeleton has been targeted
      systematically for degradation during apoptosis.

PMID- 12477715
TI  - Role of prodomain in importin-mediated nuclear localization and activation of
      caspase-2.
AB  - Caspase-2 is unique among mammalian caspases because it localizes to the nucleus
      in a prodomain-dependent manner. The caspase-2 prodomain also regulates caspase-2
      activity via a caspase recruitment domain that mediates oligomerization of
      procaspase-2 molecules and their subsequent autoactivation. In this study we
      sought to map specific functional regions in the caspase-2 prodomain that
      regulate its nuclear transport and also its activation. Our data indicate that
      caspase-2 contains a classical nuclear localization signal (NLS) at the C
      terminus of the prodomain which is recognized by the importin alpha/beta
      heterodimer. The mutation of a conserved Lys residue in the NLS abolishes nuclear
      localization of caspase-2 and binding to the importin alpha/beta heterodimer.
      Although caspase-2 is imported into the nucleus, mutants lacking the NLS were
      still capable of inducing apoptosis upon overexpression in transfected cells. We
      define a region in the prodomain that regulates the ability of caspase-2 to form
      dot- and filament-like structures when ectopically expressed, which in turn
      promotes cell killing. Our data provides a mechanism for caspase-2 nuclear import
      and demonstrate that association of procaspase-2 into higher order structures,
      rather than its nuclear localization, is required for caspase-2 activation and
      its ability to induce apoptosis.

PMID- 12477714
TI  - The transcriptional co-activators CREB-binding protein (CBP) and p300 play a
      critical role in cardiac hypertrophy that is dependent on their histone
      acetyltransferase activity.
AB  - The CBP and p300 proteins are transcriptional co-activators that are involved in
      a variety of transcriptional pathways in development and in response to specific
      signaling pathways. We have previously demonstrated that the ability of both
      these factors to stimulate transcription is greatly enhanced by treatment of
      cardiac cells with the hypertrophic agent phenylephrine (PE). Here, we show that
      inhibition of either CBP or p300 with antisense or dominant negative mutant
      constructs inhibits PE-induced hypertrophy as assayed by atrial naturetic protein
      production, cardiac cell protein:DNA ratio and cell size. Furthermore, we show
      that overexpression of CBP or p300 can induce hypertrophy and that this effect
      requires their histone acetyltransferase (HAT) activity. Moreover, we show that
      PE can directly enhance CBP HAT activity and that artificial enhancement of HAT
      activity is sufficient to induce hypertrophy. Hence, CBP and p300 play an
      essential role in hypertrophy induced by PE, and this effect is mediated via PE
      induced enhancement of their HAT activity. This is the first time a role for
      these factors, and their HAT activity, in hypertrophy has been directly
      demonstrated.

PMID- 12477716
TI  - Changes in conserved region 3 of Escherichia coli sigma 70 reduce abortive
      transcription and enhance promoter escape.
AB  - Mutations within the Escherichia coli rpoD gene encoding amino acid substitutions
      in conserved region 3 of the sigma(70) subunit of E. coli RNA polymerase restore
      normal stress responsiveness to strains devoid of the stress alarmone, guanosine
      3',5'-(bis)pyrophosphate (ppGpp). The presence of a mutant protein, either
      sigma(70)(P504L) or sigma(70)(S506F), suppresses the physiological defects in
      strains devoid of ppGpp. In vitro, when reconstituted into RNA polymerase
      holoenzyme, these sigma mutants confer unique transcriptional properties, namely
      they reduce the probabilities of forming abortive RNAs. Here we investigated the
      behavior of these mutant enzymes during transcription of the highly abortive
      cellular promoter, gal P2. No differences between mutant and wild-type enzymes
      were observed prior to and including open complex formation. Remarkably, the
      mutant enzymes produced drastically reduced levels of gal P2 abortive RNAs and
      increased production of full-length gal P2 RNAs relative to the wild-type enzyme,
      leading to greatly reduced ratios of abortive to productive RNAs. These results
      are attributed mainly to a decreased formation of unproductive initial
      transcribing complexes with the mutant polymerases and increased rates of
      promoter escape. Altered transcription properties of these mutant polymerases
      arise from an alternative structure of the sigma(70) region 3.2 segment that
      permits efficient positioning of the nascent RNA into the RNA exit channel
      displacing sigma and facilitating sigma release.

PMID- 12477717
TI  - Red cell ICAM-4 is a novel ligand for platelet-activated alpha IIbbeta 3
      integrin.
AB  - ICAM-4 (LW blood group glycoprotein) is an erythroid-specific membrane component
      that belongs to the family of intercellular adhesion molecules and interacts in
      vitro with different members of the integrin family, suggesting a potential role
      in adhesion or cell interaction events, including hemostasis and thrombosis. To
      evaluate the capacity of ICAM-4 to interact with platelets, we have immobilized
      red blood cells (RBCs), platelets, and ICAM-Fc fusion proteins to a plastic
      surface and analyzed their interaction in cell adhesion assays with RBCs and
      platelets from normal individuals and patients, as well as with cell
      transfectants expressing the alpha(IIb)beta(3) integrin. The platelet fibrinogen
      receptor alpha(IIb)beta(3) (platelet GPIIb-IIIa) in a high affinity state
      following GRGDSP peptide activation was identified for the first time as the
      receptor for RBC ICAM-4. The specificity of the interaction was demonstrated by
      showing that: (i) activated platelets adhered less efficiently to immobilized
      ICAM-4-negative than to ICAM-4-positive RBCs, (ii) monoclonal antibodies specific
      for the beta(3)-chain alone and for a complex-specific epitope of the
      alpha(IIb)beta(3) integrin, and specific for ICAM-4 to a lesser extent, inhibited
      platelet adhesion, whereas monoclonal antibodies to GPIb, CD36, and CD47 did not,
      (iii) activated platelets from two unrelated type-I glanzmann's thrombasthenia
      patients did not bind to coated ICAM-4. Further support to RBC-platelet
      interaction was provided by showing that dithiothreitol-activated
      alpha(IIb)beta(3)-Chinese hamster ovary transfectants strongly adhere to coated
      ICAM-4-Fc protein but not to ICAM-1-Fc and was inhibitable by specific
      antibodies. Deletion of individual Ig domains of ICAM-4 and inhibition by
      synthetic peptides showed that the alpha(IIb)beta(3) integrin binding site
      encompassed the first and second Ig domains and that the G65-V74 sequence of
      domain D1 might play a role in this interaction. Although normal RBCs are
      considered passively entrapped in fibrin polymers during thrombus, these studies
      identify ICAM-4 as the first RBC protein ligand of platelets that may have
      relevant physiological significance.

PMID- 12477718
TI  - Anti-CD95-induced lethality requires radioresistant Fcgamma RII+ cells. A novel
      mechanism for fulminant hepatic failure.
AB  - The Jo2 anti-mouse CD95 monoclonal antibody induces lethality in mice
      characterized by hepatocyte death and liver hemorrhage. Mice bearing a defect in
      Fas expression or in the Fas-mediated apoptotic pathway are resistant to Jo2.
      Here we show that FcgammaRII knockout mice or mice with monoclonal antibody
      blocked FcgammaRII are also resistant to Jo2. The critical FcgammaRII(+) cells
      are radioresistant and could not be reconstituted with splenic cells. Death of
      sinusoidal lining cells and destruction of sinusoids were observed, consistent
      with the characteristic liver hemorrhage and the selective FcgammaRII expression
      in sinusoidal lining cells but not hepatocytes. Hemorrhage developed coincident
      with hepatocyte death and the sharp rise of serum alanine aminotransferase and
      alanine aminotransferase. Invariably, moribund mice showed severe liver
      hemorrhage and destruction of sinusoids. The data demonstrate a novel mechanism
      by which the destruction of liver sinusoids, induced by the Jo2-mediated co
      engagement of Fas and FcgammaRII, leads to severe hemorrhage and lethal fulminant
      hepatitis.

PMID- 12477719
TI  - Cooperation of Gq, Gi, and G12/13 in protein kinase D activation and
      phosphorylation induced by lysophosphatidic acid.
AB  - To examine the contribution of different G-protein pathways to lysophosphatidic
      acid (LPA)-induced protein kinase D (PKD) activation, we tested the effect of LPA
      on PKD activity in murine embryonic cell lines deficient in Galpha(q/11)
      (Galpha(q/11) KO cells) or Galpha(12/13) (Galpha(12/13) KO cells) and used cells
      lacking rhodopsin kinase (RK cells) as a control. In RK and Galpha(12/13) KO
      cells, LPA induced PKD activation through a phospholipase C/protein kinase C
      pathway in a concentration-dependent fashion with maximal stimulation (6-fold for
      RK cells and 4-fold for Galpha(12/13) KO cells in autophosphorylation activity)
      achieved at 3 microm. In contrast, LPA did not induce any significant increase in
      PKD activity in Galpha(q/11) KO cells. However, LPA induced a significantly
      increased PKD activity when Galpha(q/11) KO cells were transfected with
      Galpha(q). LPA-induced PKD activation was modestly attenuated by prior exposure
      of RK cells to pertussis toxin (PTx) but abolished by the combination treatments
      of PTx and Clostridium difficile toxin B. Surprisingly, PTx alone strikingly
      inhibited LPA-induced PKD activation in a concentration-dependent fashion in
      Galpha(12/13) KO cells. Similar results were obtained when activation loop
      phosphorylation at Ser-744 was determined using an antibody that detects the
      phosphorylated state of this residue. Our results indicate that G(q) is necessary
      but not sufficient to mediate LPA-induced PKD activation. In addition to G(q),
      LPA requires additional G-protein pathways to elicit a maximal response with G(i)
      playing a critical role in Galpha(12/13) KO cells. We conclude that LPA induces
      PKD activation through G(q), G(i), and G(12) and propose that PKD activation is a
      point of convergence in the action of multiple G-protein pathways.

PMID- 12477720
TI  - Functional studies on native and mutated forms of perilipins. A role in protein
      kinase A-mediated lipolysis of triacylglycerols.
AB  - Perilipin A coats the lipid storage droplets in adipocytes and is
      polyphosphorylated by protein kinase A (PKA); the fact that PKA activates
      lipolysis in adipocytes suggests a role for perilipins in this process. To assess
      whether perilipins participate directly in PKA-mediated lipolysis, we have
      expressed constructs coding for native and mutated forms of the two major splice
      variants of the perilipin gene, perilipins A and B, in Chinese hamster ovary
      fibroblasts. Perilipins localize to lipid droplet surfaces and displace the
      adipose differentiation-related protein that normally coats the droplets in these
      cells. Perilipin A inhibits triacylglycerol hydrolysis by 87% when PKA is
      quiescent, but activation of PKA and phosphorylation of perilipin A engenders a 7
      fold lipolytic activation. Mutation of PKA sites within the N-terminal region of
      perilipin abrogates the PKA-mediated lipolytic response. In contrast, perilipin B
      exerts only minimal protection against lipolysis and is unresponsive to PKA
      activation. Since Chinese hamster ovary cells contain no PKA-activated lipase, we
      conclude that the expression of perilipin A alone is sufficient to confer PKA
      mediated lipolysis in these cells. Moreover, the data indicate that the unique C
      terminal portion of perilipin A is responsible for its protection against
      lipolysis and that phosphorylation at the N-terminal PKA sites attenuates this
      protective effect.

PMID- 12477721
TI  - Bcl-2, via its BH4 domain, blocks apoptotic signaling mediated by mitochondrial
      Ras.
AB  - Bcl-2 protects cells against Ras-mediated apoptosis; this protection coincides
      with its binding to Ras. However, the protection mechanism has remained
      enigmatic. Here, we demonstrate that, upon apoptotic stimulation, newly
      synthesized Bcl-2 redistributes to mitochondria, interacts there with activated
      Ras, and blocks Ras-mediated apoptotic signaling. We also show, by employing bcl
      2 mutants, that the BH4 domain of Bcl-2 binds to Ras and regulates its anti
      apoptotic activity. Experiments with a C-terminal-truncated Ras or a
      farnesyltransferase inhibitor demonstrate that the CAAX motif of Ras is essential
      for apoptotic signaling and Bcl-2 association. The results indicate a potential
      mechanism by which Bcl-2 protects cells against Ras-mediated apoptotic signaling.

PMID- 12477722
TI  - Comprehensive proteomic analysis of breast cancer cell membranes reveals unique
      proteins with potential roles in clinical cancer.
AB  - Proteins associated with cancer cell plasma membranes are rich in known drug and
      antibody targets as well as other proteins known to play key roles in the
      abnormal signal transduction processes required for carcinogenesis. We describe
      here a proteomics process that comprehensively annotates the protein content of
      breast tumor cell membranes and defines the clinical relevance of such proteins.
      Tumor-derived cell lines were used to ensure an enrichment for cancer cell
      specific plasma membrane proteins because it is difficult to purify cancer cells
      and then obtain good membrane preparations from clinical material. Multiple cell
      lines with different molecular pathologies were used to represent the clinical
      heterogeneity of breast cancer. Peptide tandem mass spectra were searched against
      a comprehensive data base containing known and conceptual proteins derived from
      many public data bases including the draft human genome sequences. This plasma
      membrane-enriched proteome analysis created a data base of more than 500 breast
      cancer cell line proteins, 27% of which were of unknown function. The value of
      our approach is demonstrated by further detailed analyses of three previously
      uncharacterized proteins whose clinical relevance has been defined by their
      unique cancer expression profiles and the identification of protein-binding
      partners that elucidate potential functionality in cancer.

PMID- 12477723
TI  - Highly coordinated gene regulation in mouse skeletal muscle regeneration.
AB  - Mammalian skeletal muscles are capable of regeneration after injury. Quiescent
      satellite cells are activated to reenter the cell cycle and to differentiate for
      repair, recapitulating features of myogenesis during embryonic development. To
      understand better the molecular mechanism involved in this process in vivo, we
      employed high density cDNA microarrays for gene expression profiling in mouse
      tibialis anterior muscles after a cardiotoxin injection. Among 16,267 gene
      elements surveyed, 3,532 elements showed at least a 2.5-fold change at one or
      more time points during a 14-day time course. Hierarchical cluster analysis and
      semiquantitative reverse transcription-PCR showed induction of genes important
      for cell cycle control and DNA replication during the early phase of muscle
      regeneration. Subsequently, genes for myogenic regulatory factors, a group of
      imprinted genes and genes with functions to inhibit cell cycle progression and
      promote myogenic differentiation, were induced when myogenic stem cells started
      to differentiate. Induction of a majority of these genes, including E2f1 and
      E2f2, was abolished in muscles lacking satellite cell activity after gamma
      radiation. Regeneration was severely compromised in E2f1 null mice but not
      affected in E2f2 null mice. This study identifies novel genes potentially
      important for muscle regeneration and reveals highly coordinated myogenic cell
      proliferation and differentiation programs in adult skeletal muscle regeneration
      in vivo.

PMID- 12477724
TI  - A potent cell-active allosteric inhibitor of murine DNA cytosine C5
      methyltransferase.
AB  - The major DNA cytosine methyltransferase isoform in mouse erythroleukemia cells,
      Dnmt1, exhibits potent dead-end inhibition with a single-stranded nucleic acid by
      binding to an allosteric site on the enzyme. The previously reported substrate
      inhibition with double-stranded substrates also involves binding to an allosteric
      site. Thus, both forms of inhibition involve ternary enzyme-DNA-DNA complexes.
      The inhibition potency of the single-stranded nucleic acid is determined by the
      sequence, length, and most appreciably the presence of a single 5-methylcytosine
      residue. A single-stranded phosphorothioate derivative inhibits DNA methylation
      activity in nuclear extracts. Mouse erythroleukemia cells treated with the
      phosphorothioate inhibitor show a significant decrease in global genomic
      methylation levels. Inhibitor treatment of human colon cancer cells causes
      demethylation of the p16 tumor suppressor gene and subsequent p16 re-expression.
      Allosteric inhibitors of mammalian DNA cytosine methyltransferases, representing
      a new class of molecules with potential therapeutic applications, may be used to
      elucidate novel epigenetic mechanisms that control development.

PMID- 12477725
TI  - Diethylstilbestrol induces rat spermatogenic cell apoptosis in vivo through
      increased expression of spermatogenic cell Fas/FasL system.
AB  - The significant role that estrogens play in spermatogenesis has opened up an
      exciting area of research in male reproductive biology. The realization that
      estrogens are essential for proper maintenance of spermatogenesis, as well as
      growing evidence pointing to the deleterious effects of estrogen-like chemicals
      on male reproductive health, has made it imperative to dissect the role estrogens
      play in the male. Using a model estrogen, diethylstilbestrol (DES), to induce
      spermatogenic cell apoptosis in vivo in the male rat, we provide a new insight
      into an estrogen-dependent regulation of the Fas-FasL system specifically in
      spermatogenic cells. We show a distinct increase in Fas-FasL expression in
      spermatogenic cells upon exposure to diethylstilbestrol. This increase is
      confined to the spermatid population, which correlates with increased apoptosis
      seen in the haploid cells. Testosterone supplementation is able to prevent DES
      induced Fas-FasL up-regulation and apoptosis in the spermatogenic cells. DES
      induced germ cell apoptosis does not occur in Fas-deficient lpr mice. One other
      important finding is that spermatogenic cells are type II cells, as the increase
      in Fas-FasL expression in the spermatogenic cells is followed by the cleavage of
      caspase-8 to its active form, following which Bax translocates to the
      mitochondria and precipitates the release of cytochrome c that is accompanied by
      a drop in mitochondrial potential. Subsequent to this, activation of caspase-9
      occurs that in turn activates caspase-3 leading to the cleavage of poly(ADP
      ribose) polymerase. Taken together, the data indicate that estrogen-like
      chemicals can precipitate apoptotic death in spermatogenic cells by increasing
      the expression of spermatogenic cell Fas-FasL, thus initiating apoptosis in the
      same lineage of cells through the activation of the apoptotic pathway chosen by
      type II cells.

PMID- 12477726
TI  - Tumor necrosis factor alpha receptor- and Fas-associated FLASH inhibit
      transcriptional activity of the glucocorticoid receptor by binding to and
      interfering with its interaction with p160 type nuclear receptor coactivators.
AB  - Tumor necrosis factor alpha (TNF alpha) and its downstream transcription factor
      nuclear factor kappa B (NF-kappa B) suppress glucocorticoid action, contributing
      to tissue resistance to glucocorticoids in several pathologic inflammatory
      states. p160 nuclear receptor coactivators on the other hand, contribute to the
      transcriptional signal of the glucocorticoid receptor (GR) through interaction
      with it via LXXLL motifs in their nuclear receptor-binding (NRB) domain. To
      discover TNF alpha-induced factors that regulate GR activity at the coactivator
      level, we performed yeast two-hybrid screening using the NRB domain of the
      glucocorticoid receptor-interacting protein 1 (GRIP1) as bait. We found that
      FLICE-associated huge protein (FLASH), which transduces TNF alpha and Fas ligand
      signals, bound the NRB domain of GRIP1 at a region between the second and third
      LXXLL motifs. FLASH suppressed both GR transactivation and GRIP1 enhancement of
      the glucocorticoid signal and inhibited the physical interaction between GR and
      the GRIP1 NRB domain. Transfected green fluorescent protein-fused FLASH was
      located in both the cytoplasm and nucleus, while endogenous FLASH shifted its
      subcellular localization from the cytoplasm into the nucleus in response to TNF
      alpha. FLASH antisense and super-repressor I kappa B alpha inhibited the action
      of TNF alpha independently of each other and additively. These findings indicate
      that FLASH participates in TNF alpha-induced blockade of GR transactivation at
      the nuclear receptor coactivator level, upstream and independently of NF-kappa B.

PMID- 12477727
TI  - Hypoxic remodeling of Ca2+ stores in type I cortical astrocytes.
AB  - Prolonged periods of hypoxia are deleterious to higher brain functions and
      increase the likelihood of developing dementias. Here, we have used fluorimetric
      techniques to investigate the effects of chronic hypoxia (2.5% O(2), 24 h) on
      Ca(2+) stores in type I cortical astrocytes, because such stores are crucial to
      various astrocyte functions, including Ca(2+)-dependent modulation of neuronal
      activity. Rises of [Ca(2+)](i) evoked by exposure of astrocytes to bradykinin
      were enhanced following chronic hypoxia, as were transient increases in
      [Ca(2+)](i) recorded in Ca(2+)-free perfusate. The enhanced responses were due
      partly to impaired plasmalemmal Na(+)/Ca(2+) exchange following chronic hypoxia.
      More importantly, chronic hypoxia increased the Ca(2+) content of mitochondria
      (as determined by exposing cells to mitochondrial inhibitors), such that they
      were unable to act as Ca(2+) buffers following bradykinin-evoked Ca(2+) release
      from the endoplasmic reticulum. Hypoxic enhancement of mitochondrial Ca(2+)
      content was also observed in confocal images of cells loaded with the
      mitochondrial Ca(2+) indicator, Rhod-2. Confocal imaging of cells loaded with
      tetramethylrhodamine ethyl ester, an indicator of mitochondrial membrane
      potential, indicated that mitochondria were hyperpolarized in astrocytes
      following chronic hypoxia. Our findings indicate that hypoxia disturbs Ca(2+)
      signaling in type I astrocytes, primarily by causing mitochondrial Ca(2+)
      overload.

PMID- 12477728
TI  - Syk, a protein-tyrosine kinase, suppresses the cell motility and nuclear factor
      kappa B-mediated secretion of urokinase type plasminogen activator by inhibiting
      the phosphatidylinositol 3'-kinase activity in breast cancer cells.
AB  - Tumor growth and metastasis are multifaceted processes that mainly involve cell
      adhesion, proteolytic degradation of the extracellular matrix, and cell
      migration. Syk is a member of a tyrosine kinase family that is expressed mostly
      in hematopoietic cells. Syk is expressed in cell lines of epithelial origin, but
      its function in these cells remains unknown. Here we report that Syk is expressed
      in MCF-7 cells but not in MDA-MB-231 cells. The overexpression of wild type Syk
      kinase but not kinase-negative Syk suppressed cell motility and inhibited the
      activation of phosphatidylinositol (PI) 3'-kinase in MDA-MB-231 cells. In
      contrast, when Syk-specific antisense S-oligonucleotide but not the sense S
      oligonucleotide was transfected to MCF-7 cells the level of PI 3'-kinase activity
      as well as cell motility were increased. The MDA-MB-231 cells transfected with
      wild type Syk cDNA followed by treatment with piceatannol, a Syk inhibitor,
      enhanced cell motility and PI 3'-kinase activity. Pervanadate, a phosphotyrosine
      phosphatase inhibitor, induced PI 3'-kinase activity and stimulated the
      interaction between the inhibitor of nuclear factor kappa B alpha (I kappa B
      alpha) and the p85 alpha domain of PI 3'-kinase through tyrosine phosphorylation
      of the I kappa B alpha, which ultimately resulted in nuclear factor kappa B (NF
      kappa B) activation. Pervanadate had no effect on the activation of Syk in these
      cells. However, Syk suppressed the NF kappa B transcriptional activation and
      interaction between I kappa B alpha and PI 3'-kinase by inhibiting the tyrosine
      phosphorylation of I kappa B alpha. Syk, PI 3'-kinase inhibitors, and NF kappa B
      inhibitory peptide inhibited urokinase type plasminogen activator (uPA) secretion
      and cell motility in these cells. To our knowledge, this is the first report that
      Syk suppresses the cell motility and inhibits the PI 3'-kinase activity and uPA
      secretion by blocking NF kappa B activity through tyrosine phosphorylation of I
      kappa B alpha. These data further demonstrate a functional molecular link between
      Syk-regulated PI 3'-kinase activity and NF kappa B-mediated uPA secretion, and
      all of these ultimately control the motility of breast cancer cells.

PMID- 12477729
TI  - Bcl-2 on the endoplasmic reticulum regulates Bax activity by binding to BH3-only
      proteins.
AB  - Bcl-2 family members have been shown to be key mediators of apoptosis as either
      pro- or anti-apoptotic factors. It is thought that both classes of Bcl-2 family
      members act at the level of the mitochondria to regulate apoptosis, although the
      founding anti-apoptotic family member, Bcl-2 is localized to the endoplasmic
      reticulum (ER), mitochondrial, and nuclear membranes. In order to better
      understand the effect of Bcl-2 localization on its activity, we have utilized a
      Bcl-2 mutant that localizes only to the ER membrane, designated Bcl-2Cb5. Bcl
      2Cb5 was expressed in MDA-MB-468 cells, which protected against apoptosis induced
      by the kinase inhibitor, staurosporine. Data presented here show that Bcl-2Cb5
      inhibits this process by blocking Bax activation and cytochrome c release.
      Furthermore, we show that Bcl-2Cb5 can inhibit the activation of a constitutively
      mitochondrial mutant of Bax, indicating that an intermediate between Bcl-2 on the
      ER and Bax on the mitochondria must exist. We demonstrate that this intermediate
      is likely a BH3-only subfamily member. Data presented here show that Bcl-2Cb5 can
      sequester a constitutively active form of Bad (Bad3A) from the mitochondria and
      prevent it from activating Bax. These data suggest that Bcl-2 indirectly protects
      mitochondrial membranes from Bax, via BH3-only proteins.

PMID- 12477730
TI  - Mutation of interfacial residues disrupts subunit folding and particle assembly
      of Physalis mottle tymovirus.
AB  - Virus-like particles (VLPs) serve as excellent model systems to identify the
      pathways of virus assembly. To gain insights into the assembly mechanisms of the
      Physalis mottle tymovirus (PhMV), six interfacial residues, identified based on
      the crystal structure of the native and recombinant capsids, were targeted for
      mutagenesis. The Q37E, Y67A, R68Q, D83A, I123A, and S145A mutants of the PhMV
      recombinant coat protein (rCP) expressed in Escherichia coli were soluble.
      However, except for the S145A mutant, which assembled into VLPs similar to that
      of wild type rCP capsids, all the other mutants failed to assemble into VLPs.
      Furthermore, the purified Q37E, Y67A, R68Q, D83A, and I123A rCP mutants existed
      essentially as partially folded monomers as revealed by sucrose density gradient
      analysis, circular dichroism, fluorescence, thermal, and urea denaturation
      studies. The rCP mutants locked into such conformations probably lack the
      structural signals/features that would allow them to assemble into capsids. Thus,
      the mutation of residues involved in inter-subunit interactions in PhMV disrupts
      both subunit folding and particle assembly.

PMID- 12477731
TI  - Molecular interactions of yeast frequenin (Frq1) with the phosphatidylinositol 4
      kinase isoform, Pik1.
AB  - Frq1, a 190-residue N-myristoylated calcium-binding protein, associates tightly
      with the N terminus of Pik1, a 1066-residue phosphatidylinositol 4-kinase.
      Deletion analysis of an Frq1-binding fragment, Pik1-(10-192), showed that
      residues within 80-192 are necessary and sufficient for Frq1 association in
      vitro. A synthetic peptide (residues 151-199) competed for binding of [(35)S]Pik1
      (10-192) to bead-immobilized Frq1, whereas shorter peptides (164-199 and 174-199)
      did not. Correspondingly, a deletion mutant, Pik1(delta152-191), did not co
      immunoprecipitate efficiently with Frq1 and did not support growth at elevated
      temperature. Site-directed mutagenesis of Pik1-(10-192) suggested that
      recognition determinants lie over an extended region. Titration calorimetry
      demonstrated that binding of an 83-residue fragment, Pik1-(110-192), or the 151
      199 peptide to Frq1 shows high affinity (K(d) approximately 100 nm) and is
      largely entropic, consistent with hydrophobic interaction. Stoichiometry of Pik1
      (110-192) binding to Frq1 was 1:1, as judged by titration calorimetry, by changes
      in NMR spectrum and intrinsic tryptophan fluorescence, and by light scattering.
      In cell extracts, Pik1 and Frq1 exist mainly in a heterodimeric complex, as shown
      by size exclusion chromatography. Cys-15 in Frq1 is not S-palmitoylated, as
      assessed by mass spectrometry; a Frq1(C15A) mutant and even a non-myristoylated
      Frq1(G2A,C15A) double mutant rescued the inviability of frq1Delta cells. This
      study defines the segment of Pik1 required for high affinity binding of Frq1.

PMID- 12477732
TI  - Neural Wiskott-Aldrich syndrome protein is recruited to rafts and associates with
      endophilin A in response to epidermal growth factor.
AB  - Neural Wiskott-Aldrich syndrome protein (N-WASP) has been implicated in
      endocytosis; however, little is known about how it interacts functionally with
      the endocytic machinery. Sucrose gradient fractionation experiments and
      immunofluorescence studies with anti-N-WASP antibody revealed that N-WASP is
      recruited together with clathrin and dynamin, which play essential roles in
      clathrin-mediated endocytosis, to lipid rafts in an epidermal growth factor (EGF)
      dependent manner. Endophilin A (EA) binds to dynamin and plays an essential role
      in the fission step of clathrin-mediated endocytosis. In the present study, we
      show that the Src homology 3 (SH3) domain of EA associates with the proline-rich
      domain of N-WASP and dynamin in vitro. Co-immunoprecipitation assays with anti-N
      WASP antibody revealed that EGF induces association of N-WASP with EA. In
      addition, EA enhances N-WASP-induced actin-related protein 2/3 (Arp2/3) complex
      activation in vitro. Immunofluorescence studies revealed that actin accumulates
      at sites where N-WASP and EA are co-localized after EGF stimulation. Furthermore,
      studies of overexpression of the SH3 domain of EA indicate that EA may regulate
      EGF-induced recruitment of N-WASP to lipid rafts. These results suggest that,
      upon EGF stimulation, N-WASP interacts with EA through its proline-rich domain to
      induce the fission step of clathrin-mediated endocytosis.

PMID- 12477733
TI  - Regulation of isoprenoid/cholesterol biosynthesis in cells from mevalonate kinase
      deficient patients.
AB  - Mevalonic aciduria (MA) and hyper-IgD and periodic fever syndrome (HIDS) are two
      inherited disorders both caused by depressed mevalonate kinase (MK) activity. MK
      is the first enzyme to follow the highly regulated 3-hydroxy-3-methylglutaryl
      (HMG)-CoA reductase (HMGR), which catalyzes the rate-limiting step in the
      isoprenoid/cholesterol biosynthesis pathway. In fibroblasts of MA patients, but
      not of HIDS patients, HMGR activity is elevated under normal growth conditions.
      This activity is down-regulated when cells are supplemented with the isoprenoid
      precursors geraniol, farnesol, and geranylgeraniol, and a mixture of 25
      hydroxycholesterol and cholesterol. This indicates that the regulation of the
      pathway in these cells is not disturbed. The elevated HMGR activity is probably
      due to a shortage of non-sterol isoprenoid end products, as indicated by normal
      HMGR mRNA levels in MA fibroblasts. Furthermore, the HMGR activity in MA cells
      was more sensitive to geranylgeraniol suppression and less sensitive to sterol
      suppression than the HMGR activity in low density lipoprotein receptor-deficient
      cells. HMGR activity in MA cells was down-regulated also by addition of its
      product mevalonate to the culture medium. Thus, it appears that the elevation of
      mevalonate levels, which are high in MA patients and moderate in HIDS patients,
      allows the cells to compensate for the depressed MK activity. Indeed, the
      isoprenylation of Ras and RhoA protein appeared normal in HIDS and MA fibroblasts
      under normal conditions but showed increased sensitivity toward inhibition of
      HMGR by simvastatin. Our results indicate that MK-deficient cells maintain the
      flux through the isoprenoid/cholesterol biosynthesis pathway by elevating
      intracellular mevalonate levels.

PMID- 12477734
TI  - Distinct regulation of mitogen-activated protein kinases and p27Kip1 in smooth
      muscle cells from different vascular beds. A potential role in establishing
      regional phenotypic variance.
AB  - Excessive proliferation and migration of vascular smooth muscle cells (SMCs)
      participate in atherosclerotic plaque growth. In this study, we investigated
      whether SMCs from vessels with different atherogenicity exhibit distinct growth
      and migratory potential and investigated the underlying mechanisms. In fat-fed
      rabbits, we found increased cell proliferation and atheroma formation in the
      aortic arch versus the femoral artery. When examined in culture, SMCs isolated
      from the aortic arch (ASMCs) displayed a greater capacity for inducible
      proliferation and migration than paired cultures of femoral artery SMCs. Two
      lines of evidence suggested that distinct regulation of the growth suppressor
      p27(Kip1) (p27) contributes to establishing these phenotypic dissimilarities.
      First, p27 expression was comparably lower in ASMCs, which exhibited a higher
      fraction of p27 phosphorylated on Thr-187 and ubiquitinated. Second, forced p27
      overexpression in ASMCs impaired their proliferative and migratory potential. We
      found that platelet-derived growth factor-BB-dependent induction of the mitogen
      activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)
      pathway was comparably higher in ASMCs. Importantly, pharmacological inhibition
      of MAPKs increased p27 expression and attenuated ASMC proliferation and
      migration. In contrast, forced MAPK activation diminished p27 expression and
      markedly augmented femoral artery SMC proliferation and migration. We propose
      that intrinsic differences in the regulation of MAPKs and p27 play an important
      role in creating variance in the proliferative and migratory capacity of vascular
      SMCs, which might in turn contribute to establishing regional variability in
      atherogenicity.

PMID- 12477735
TI  - Health sector reform and equity -- learning from evidence?

PMID- 12477736
TI  - Equitable financing, out-of-pocket payments and the role of health care reform in
      Colombia.
AB  - For a health care system to be considered equitable in its financing, the
      financial burden of contributions has to be progressive or at least proportional.
      Out-of-pocket financing takes a larger proportion of poor than of non-poor
      households' income. To remedy this regressive burden, among other goals, Colombia
      launched a health care reform based on social insurance as a means to reduce
      health care financing through out-of-pocket payments, and to reduce financial
      barriers to access. This paper analyzes the evolution of regressivity in out-of
      pocket financing from 1984 to 1997, in order to detect if the 1993 health care
      reform had an impact on such regressivity. The Kakwani index of progressivity was
      estimated using three national household surveys. Kakwani indices showed a
      constant trend towards more regressivity (-0.126 in 1984, to -0.3498 in 1997)
      when using income to build the index, but a trend towards progressivity (-0.0092
      in 1984, to 0.0026 in 1997) when using expenses. Our findings suggest that there
      was a progressive impact of the reform on out-of-pocket financing when household
      expenses are used to build the Kakwani index; however, due to issues of
      comparability between surveys, the findings are not conclusive.

PMID- 12477737
TI  - Public health infrastructure and equity in the utilization of outpatient health
      care services in Peru.
AB  - This article analyzes the magnitude and nature of socioeconomic differences in
      the utilization of outpatient health care services in Peru. In particular, it
      explores the potential equity-enhancing effect of the expansion and improvements
      in the network of health centres during the 1990s. The Peruvian health reform
      made relatively little progress in terms of the reform agenda promoted
      internationally during the 1990s. Nevertheless, the expansion of the public
      network of health centres and the improvements in their equipment has been
      noteworthy during the same period. Using the 1997 survey of the Peruvian Living
      Standards Measurement Study (PLSMS), we find large differences in the utilization
      of outpatient health care services. The richest to poorest quintile ratio is 1.9,
      and even larger in rural areas. Estimating a probit model with random effects at
      the district level to control for the systematic geographic bias associated with
      the optimal public allocation of such infrastructure, we find the income effect
      to be very large, even after controlling for other socioeconomic characteristics.
      Finally, we also find that the expansion of the public network of health centres
      has indeed an equity-enhancing effect, but this is rather small. These results
      indicate that although the expansion of the public network of health facilities
      may be necessary, it is not sufficient to promote equity in the utilization of
      health care services by Peruvian adults, especially in rural areas. It is
      important to look deeper into the costs of consultations and drugs as economic
      barriers to the utilization of health services by the poor. In particular, the
      expansion of health insurance mechanisms for the poor should be carefully
      monitored and evaluated.

PMID- 12477738
TI  - Health equity in transition from planned to market economy in China.
AB  - This paper examines the impact of economic transition and health sector reform on
      health equities in the urban and rural populations of China in the 1990s. Since
      1980, China has experienced a rapid economic development and fundamental
      transformation of its society. Three secondary data sources were used as the
      basis for the analysis and discussion: mortality data from the National Death
      Notification System; infant mortality from the National Maternal and Child Health
      Surveillance System; and morbidity, health care utilization and financing data
      from the National Health Household Interview Surveys. The analysis revealed a
      very complex picture with: general mortality rates decreasing in both urban and
      rural populations, but the differences between urban and rural increasing;
      declining infant mortality rates with narrowing of the urban-rural gap; health
      care needs declining in both urban and rural populations, but more rapidly in the
      urban areas; health service payments increasing in both urban and rural areas,
      while, at the same time, health insurance coverage decreased. The analysis
      suggests that despite overall improvements in the population's health status, the
      economic and health system policy reforms are leading to increased inequities in
      health care. The lowest income quintiles in both urban and rural areas are
      receiving less health care compared with their needs in 1998 than in 1993, and
      the urban-rural divide, in particular with regard to receiving inpatient health
      care, is widening appreciably. The reform of the health insurance system,
      combined with the market setting of prices for care, have had profound
      implications for all population groups, in particular the lower income segments
      and the rural populations. During the period 1993-98 the proportion of the urban
      population that had to cover the increasing cost of medical care themselves
      doubled.

PMID- 12477739
TI  - Geographic patterns of deprivation in South Africa: informing health equity
      analyses and public resource allocation strategies.
AB  - There is a growing interest in the use of small area analyses in investigating
      the relationship between socioeconomic status and health, and in informing
      resource allocation decision-making. However, few such studies have been
      undertaken in low- and middle-income countries (LMICs). This paper reports on
      such a study undertaken in South Africa. It both looked at the feasibility of
      developing a broad-based area deprivation index in a data scarce context and
      considered the implications of such an index for geographic resource allocations.
      Despite certain data problems, it was possible to construct and compare three
      different indices: a general index of deprivation (GID), compiled from census
      data using principal component analysis; a policy-perspective index of
      deprivation (PID), based on groups identified as priorities within policy
      documents; and a single indicator of deprivation (SID), selected for relevance
      and feasibility of use. The findings demonstrate clearly that in South Africa
      deprivation is multi-faceted, is concentrated in specific areas within the
      country and is correlated with ill-health. However, the formula currently used by
      the National Treasury to allocate resources between geographic areas, biases
      these allocations towards less deprived areas within the country. The inclusion
      of the GID within this formula would dramatically alter allocations towards those
      areas suffering from human development deficits. The area in which analysis was
      undertaken was not, however, sufficiently small to identify pockets of
      deprivation within the less deprived metropolitan areas. These findings suggest
      that it is feasible to conduct small area analyses in LMICs but that specific
      attention needs to be given to the size of the geographic unit used in analysis.
      In addition, they highlight the importance of considering deprivation in resource
      allocation mechanisms if vertical equity goals are to be promoted through
      resource allocation, particularly within decentralized health systems.

PMID- 12477740
TI  - Quality and equity of private sector care for sexually transmitted diseases in
      South Africa.
AB  - The private sector plays a major role in the delivery of health care in South
      Africa. Over the past two decades, the quality and equity of such provision has
      been questioned internationally. A study was conducted in Gauteng Province to
      explore these issues, using care for sexually transmitted disease (STD) as a case
      study. Private general practitioners (GPs) were interviewed by telephone. Each
      was presented with a set of STD syndromes and requested to describe how s/he
      would manage the patient, first if the patient was insured, then secondly if the
      patient was paying cash (uninsured). Reported prescriptions were costed and
      assessed for effectiveness against main causative pathogens using local standard
      clinical guidelines. Knowledge of recent developments in STD syndromic management
      and effectiveness of prescribed drugs was poor, especially for genital ulcer and
      pelvic inflammatory disease, and less than half the prescriptions overall were
      judged as effective. Although the effectiveness of prescriptions for insured and
      uninsured patients were similar, for most syndromes uninsured patients were
      offered significantly cheaper and less convenient antibiotic regimens. Effective
      regimens were also significantly more expensive than ineffective regimens. The
      results suggest that GPs' perceptions of patients' willingness or ability to pay
      for drugs have a bearing on quality of care. The paper concludes that STD
      patients who present to GPs are often offered poor quality of care, and the
      choice of inconvenient antibiotics impacts disproportionately on the poor.
      Improvements in the quality and equity of GP care will require interventions that
      address the factors that determine their behaviour.

PMID- 12477741
TI  - Economic transition and maternal health care for internal migrants in Shanghai,
      China.
AB  - Economic migration and growth in informal employment in many of the major cities
      of developing countries, combined with health sector reforms that are
      increasingly relying on insurance and out-of-pocket payment, are raising concerns
      about equity and sustainability of economic and social development. In China, the
      number of internal migrants has dramatically grown since economic transition
      started in 1980, and maternal health care for these is a pressing issue to be
      addressed. To provide information for policy-makers and health administrators, a
      medical records review, a questionnaire survey and qualitative interviews were
      carried out in Minhang District, Shanghai. This paper describes important
      inequities in main maternal health outcomes and utilization indicators relating
      to economic and social transformation of the Chinese society. Analysis of the
      data collected clarifies that insufficient antenatal care is one of the main
      determinants for poor maternal health outcomes and that migrants are using
      antenatal care services significantly less than permanent residents. The data
      suggest that there is no single explanatory factor, but that migrants are faced
      with a package of obstacles to accessing health care services, and that health
      systems may need to rethink and redesign their delivery approaches to
      specifically target those groups that are faced with such multi-faceted packages
      of obstacles to service-access. Although the study addresses a specific Chinese
      phenomenon related to internal migration and registration of residency, parallels
      can be drawn to other settings where a combination of economic and social
      transitions of the society and a reform of health care financing are potentially
      creating the same conditions of significant inequalities.

PMID- 12477742
TI  - Hospital charge exemptions for the poor in Shandong, China.
AB  - Rapid economic changes in China have produced soaring hospital charges, a
      breakdown of the old social health insurance system, a resulting crisis in
      hospital affordability and renewed interest in mechanisms for discounts or
      exemptions from hospital charges for the poor. Little is known, however, about
      how effective such systems are in practice. We studied nine public hospitals in
      Shandong Province that offer discount or exemption mechanisms for the poor.
      Methods included document review, key informant interviews, detailed review of
      financial records and focus group discussions. These hospitals receive little
      government subsidy and must support themselves almost entirely through user fees.
      Hospital managers saw discount mechanisms primarily as marketing tools and
      designed them to limit their cost. Only a small fraction of hospital services
      were eligible for discount, and these were usually low cost or low utilization
      items. Discounts were generally 10-50% for selected items with very few services
      exempted from charge. The total value of discounts granted was 1% or less of
      total hospital operating budgets. Correct identification of indigents was a major
      difficulty for hospitals. Only a minority of indigents received discounts, the
      process was sometimes arbitrary and some who received discounts were not really
      poor. Government policies requiring discounts for the poor were vague and not
      enforced. The exemption programmes studied do not provide effective protection
      from hospital charges for the poor. To be effective, exemption mechanisms would
      likely require both financing and regulation by the government as well as an
      accurate way to identify the poor.

PMID- 12477743
TI  - Exemptions and waivers from cost sharing: ineffective safety nets in
      decentralized districts in Uganda.
AB  - The introduction of user-payment for health services is frequently followed by
      concern about the impact on equity of access for poor people. Decentralizing
      governments often try to remedy the created inequities by putting in place safety
      nets in the form of exemptions and waivers in the user-fee systems. However,
      where user payments merely operate as local government strategies for health
      financing, without national policy they are likely to be self-defeating, as local
      governments are frequently more interested in raising revenue to meet recurrent
      costs of devolved services than in promoting equity. Thus guidelines put in place
      by the central government to operationalize safety nets are seen by local
      governments as being contradictory to this goal, and are thus ignored or altered
      to suit the district revenue aims. This study was carried out to investigate the
      context and the constraints in implementing exemption schemes. Data were
      collected in two selected administrative districts of Uganda (Mbarara and
      Mukono). Qualitative approaches to data collection were adopted, namely focus
      group discussions and key informant interviews with policy-makers, health
      administrators, service providers and community members. These methods were
      combined with document review. We found little evidence of safety-net guidelines
      initiated by decentralized/local governments, since district local governments
      had little motivation to extend exemptions, waivers or credits. The conclusion is
      that safety nets such as waivers and exemptions will only be effective if they
      are backed by a national health financing policy, they reconcile the often
      competing demands of local government revenue needs, and are strictly enforced
      and supervised by both the local and central governments. The implications of the
      findings for remedying the tension between the needs for cost recovery and for
      attainment of equity goals through exemption policies for the poor and indigent
      are discussed.

PMID- 12477744
TI  - Equity, privatization and cost recovery in urban health care: the case of Lao
      PDR.
AB  - Along with the shift from a planned to market-oriented economy, as in many other
      developing countries, Lao PDR has promoted health care partnerships with the
      private sector, and cost recovery in public hospitals, to increase resources in
      the public sector, while at the same time attempting to ensure appropriate access
      to health care for those without means to pay. In a multi-case design, this study
      compares two neighbourhoods of different socioeconomic status comprising 10
      households, representing urban districts in three provinces. In-depth interviews
      were conducted over a 1-year period with three visits to each household. Members
      of the households were interviewed on their perceptions and utilization of health
      care services. Focus group discussions of public providers and individual
      interviews of private providers, leaders of the villages and hospital
      administrators provided complementary perspectives. The study found that both
      socioeconomic groups utilized private health services as their first choice,
      including private clinics and treatment abroad for those with high socioeconomic
      status, while the low socioeconomic group preferred private pharmacies. The
      unwelcoming attitudes of health staff and procedural barriers have led both
      groups to meet their health care needs in the private sector. Here the health
      care they receive is strictly limited to what they can pay for. For the poor, in
      most cases, this means drugs alone, i.e. no examination, no diagnosis and only
      limited advice. Limited financial resources often means receiving inappropriate
      and insufficient medication. Equity in health care remains theoretical rather
      than practical and the social goals of the reform have not been achieved.

PMID- 12477746
TI  - S, m, l, xl.

PMID- 12477745
TI  - Is intestinal metaplasia of the stomach reversible?
AB  - Intestinal metaplasia (IM) of the stomach is a risk factor in developing
      intestinal-type gastric cancer and hence the question of reversibility is vital.
      There is emerging epidemiological evidence that with long term follow up, IM may
      be reversible although a combination of antioxidant agents and eradication of H
      pylori may be necessary to achieve this. The pathogenesis of IM is currently
      being elucidated and it is likely that a combination of bacterial, host, and
      environmental factors will be shown to lead to IM. In assessing gastric cancer
      risk, histochemical typing of IM will most probably be replaced by molecular
      markers.

PMID- 12477747
TI  - HLA-DQ8 as an Ir gene in coeliac disease.
AB  - DQ8 restricted gliadin peptide is immunogenic in the intestinal mucosa of HLA-DQ8
      positive patients, representing the first demonstration that a given peptide may
      be of pathogenic significance only for a subset of coeliacs, and strongly
      suggests that DQ2 and DQ8 act as immune response (Ir) genes in this disease

PMID- 12477748
TI  - A rat virus visits the clinic: translating basic discoveries into clinical
      medicine in the 21st century.

PMID- 12477749
TI  - Dyspepsia management in the millennium: to test and treat or not?

PMID- 12477750
TI  - RUNX 3, apoptosis 0: a new gastric tumour suppressor.

PMID- 12477751
TI  - Ablative mucosectomy is the procedure of choice to prevent Barrett's cancer.

PMID- 12477752
TI  - Ablative mucosectomy is the procedure of choice to prevent Barrett's cancer.

PMID- 12477753
TI  - Biopsy surveillance is still necessary in patients with Barrett's oesophagus
      despite new endoscopic imaging techniques.
AB  - BACKGROUND AND AIMS: Endoscopic surveillance including stepwise four quadrant
      biopsies (4QB) is still regarded as the standard approach in patients with
      Barrett's oesophagus (BO). Several methods such as dye staining with methylene
      blue (MB) and tissue autofluorescence (AF) have been advocated to reduce the
      number of biopsies. We assessed their sensitivity and specificity compared with
      the standard approach-that is, endoscopy with 4QB-in the surveillance of a mixed
      BO population. PATIENTS AND METHODS: Thirty five consecutive BO patients (mean
      age 64.9 years; 30 men, five women) were included in the study. AF endoscopy was
      followed by high resolution video endoscopy (VE) plus tissue staining with 0.5%
      MB. Biopsies were taken from any suspicious area found on any of the above tests,
      in addition to 4QB every 2 cm. The results were classified as either positive or
      negative for the various tests used. Histopathological results were used as the
      reference standard. RESULTS: In the 35 study patients, a total of 345 biopsies
      showed low grade dysplasia (LGD) in 88 biopsies, high grade dysplasia (HGD) in 19
      biopsies, and carcinoma in 12 biopsies. The sensitivity and specificity rates for
      AF and MB for the diagnosis of cancer or dysplasia versus BO mucosa without
      dysplasia were 21%/91% and 37%/91%, respectively. 4QB revealed five cancer/HGD
      areas and 76 LGD areas not detected by AF, MB, or VE. The additional yield of MB
      and AF over VE with 4QB concerned only one HGD area (in the vicinity of a cancer)
      and seven LGD areas. CONCLUSIONS: Due to their low sensitivity, AF and MB are not
      suitable techniques for reducing the high numbers of routine biopsies needed for
      finding additional foci of HGD or cancer. Careful endoscopic observation and
      stepwise four quadrant biopsy therefore still represent the gold standard for
      surveillance of Barrett's oesophagus.

PMID- 12477754
TI  - Magnification chromoendoscopy for the detection of intestinal metaplasia and
      dysplasia in Barrett's oesophagus.
AB  - BACKGROUND: The presence of intestinal metaplasia (IM) in the columnar lined
      distal oesophagus defines Barrett's oesophagus with the risk of future malignant
      transformation. The distribution of both IM and dysplasia (low grade (LGD) and
      high grade (HGD)) within the columnar lined oesophagus is patchy and mosaic
      requiring random biopsies. Techniques that could help target areas of high yield
      within Barrett's mucosa would be helpful. AIM: To study the utility of high
      magnification chromoendoscopy (MCE) in the detection of IM, LGD, and HGD in
      patients with Barrett's oesophagus. METHODS: Consecutive patients detected with
      columnar mucosa in the distal oesophagus were studied using an Olympus
      magnification endoscope (GIF-Q16OZ, 115x). The distal oesophagus was sprayed with
      indigo carmine solution and the oesophageal columnar mucosa patterns were noted
      under high magnification and targeted for biopsy. All biopsies were read by
      pathologists blinded to the endoscopic findings. RESULTS: Eighty patients with
      suspected Barrett's oesophagus (that is, columnar lined distal oesophagus) were
      studied: mean age 62.7 years (range 35-81). Mean length of columnar mucosa was
      3.7 cm (range 0.5-17). Three types of mucosal patterns were noted within the
      columnar mucosa after spraying indigo carmine and using MCE: ridged/villous
      pattern, circular pattern, and irregular/distorted pattern. The yield of IM on
      target biopsies according to the patterns was: ridged/villous 57/62 (97%) and
      circular 2/12 (17%). Six patients had an irregular/distorted pattern and all had
      HGD on biopsy (6/6 (100%)). Eighteen patients had LGD on target biopsies; all had
      the ridged/villous pattern. All patients with long segment Barrett's were
      identified using MCE whereas 23/28 patients (82%) with short segment Barrett's
      had the ridged/villous pattern. CONCLUSIONS: MCE helps visually identify areas
      with IM and HGD having specific patterns but not patients with LGD (appear
      similar to IM). MCE may be a useful clinical tool for the increased detection of
      patients with IM as well as for surveillance of patients for the detection of
      HGD. If these preliminary results are validated, MCE would help identify high
      yield areas, potentially eliminating the need for random biopsies.

PMID- 12477755
TI  - Time gated fluorescence spectroscopy in Barrett's oesophagus.
AB  - BACKGROUND AND AIMS: Specialised intestinal metaplasia and its dysplastic
      transformation, which precedes cancer in Barrett's oesophagus cannot be
      differentiated in standard gastroscopy. The aim of this study was to investigate
      whether laser induced protoporphyrin IX fluorescence permits the detection of
      specialised intestinal metaplasia and dysplasia during endoscopy and to take
      biopsy specimens in a guided rather than random manner. METHODS: In 53 patients
      with Barrett's oesophagus 5-aminolaevulinic acid was sprayed on the mucosa.
      Approximately 60 to 120 minutes later, biopsy specimens were taken based on point
      like measurements of delayed fluorescence intensity ratios of protoporphyrin IX
      in vivo. Two independent pathologists examined the 596 biopsy specimens taken,
      168 of which were selected to be investigated by a third pathologist. Among these
      specimens only those (n=141) with a consensus diagnosis by at least two
      pathologists and p53 expression as additional marker were included in the
      analysis. RESULTS: The median of normalised fluorescence intensity (ratio of
      delayed PpIX fluorescence intensity to immediate autofluorescence intensity) in
      non-dysplastic specialised intestinal metaplasia (0.51, 68% CI 0.09 to 1.92) and
      low grade dysplasia (1.89, 68% CI 0.55 to 3.92) differed significantly (p<0.005).
      Dysplasia was detected at a rate 2.8-fold higher compared with screening
      endoscopy despite taking fewer specimens. In addition, three early cancers were
      detected for the first time. Moreover, this method permitted differentiation of
      specialised intestinal metaplasia from junctional or gastric-fundic type
      epithelium (p<0.013). CONCLUSIONS: For the first time it was possible to
      differentiate low grade dysplasia from non-dysplastic Barrett's mucosa during
      endoscopy based on delayed laser induced fluorescence endoscopy of PpIX.
      Furthermore, the method helps to detect specialised intestinal metaplasia in
      short Barrett's oesophagus.

PMID- 12477756
TI  - Endocinch therapy for gastro-oesophageal reflux disease: a one year prospective
      follow up.
AB  - BACKGROUND: Gastro-oesophageal reflux disease (GORD) is, in the main, treated
      with either proton pump inhibitor (PPI) drugs or a Nissen fundoplication
      operation. Recently, BARD developed Endocinch, a device used to place sutures
      just below the oesophagogastric junction (OGJ) to treat GORD. AIM: To evaluate
      the long term benefit of the Endocinch technique in patients seen up to 12 months
      post procedure. PATIENTS: Twenty six patients with symptoms of GORD were
      recruited and had the procedure performed. Four patients were lost to follow up.
      METHODS: Twenty two patients completed their one year follow up. Pre procedure
      and post procedure (up to 12 months) assessments included symptom scoring
      (DeMeester), upper intestinal endoscopy, oesophageal manometry and 24 hour
      oesophageal pH, and completion of quality of life (QOL) questionnaires. RESULTS:
      Mean age was 39 years (range 22-62). Heartburn symptom score was reduced from a
      mean value of 19.22 at baseline to 7.5 at 12 months (n=22) (p<0.0001).
      Regurgitation score reduced from a mean of 2.27 at baseline to 0.86 at 12 months
      (n=22) (p<0.001). Mean (SEM) pH DeMeester acid score was reduced from 44.1 (4.3)
      to 33.32 (4.73) (p=0.028) at three month post procedure. Percentage upright acid
      exposure and number of reflux episodes were also reduced significantly. Use of
      PPIs was reduced by 64% at 12 months post procedure. All QOL assessments showed
      significant improvement (p=0.01). All transient post procedure complaints
      resolved within 72 hours. CONCLUSION: The Endocinch procedure is an effective and
      safe outpatient procedure that offers GORD patients significant improvement in
      symptomatology, QOL, and reduced requirements for PPIs over at least a one year
      period.

PMID- 12477757
TI  - Treatment of Helicobacter pylori in functional dyspepsia resistant to
      conventional management: a double blind randomised trial with a six month follow
      up.
AB  - BACKGROUND: Previous studies on the treatment of Helicobacter pylori infection in
      functional dyspepsia have shown little, if any, effect on dyspeptic symptoms.
      However, whether such treatment might be of benefit in patients resistant to acid
      inhibitors has not been formally tested. AIM: The present study investigated the
      effect of H pylori treatment in patients with functional dyspepsia resistant to
      conventional treatment. PATIENTS: A total of 181 H pylori positive patients with
      chronic functional dyspepsia who had not responded to a one week antacid run-in
      and two week double blind antisecretory or placebo treatment were included.
      METHODS: Patients were randomised to two weeks of treatment with omeprazole 40 mg
      twice daily combined with amoxicillin 1 g twice daily or omeprazole 20 mg once
      daily alone. The primary outcome variable ("response") was defined as no need for
      further therapy or investigations for dyspeptic symptoms 4-6 months after
      treatment. RESULTS: H pylori infection was healed in 10% of patients after
      omeprazole and in 52% after omeprazole plus amoxicillin. The respective
      "response" rates were 66% and 62% (NS). H pylori treatment and cure of H pylori
      infection had no effect on complete resolution of all dyspeptic symptoms,
      individual symptoms, or various aspects of quality of life. CONCLUSION: In
      functional dyspepsia, H pylori treatment and cure of H pylori are no more
      effective for symptoms over six months than short term acid inhibition. These
      results do not support treatment of H pylori in functional dyspepsia.

PMID- 12477758
TI  - Avenin fails to induce a Th1 response in coeliac tissue following in vitro
      culture.
AB  - BACKGROUND: It is well established that the wheat protein gliadin triggers
      inflammation in coeliac patients. However, the potential toxicity of avenin, the
      equivalent protein in oats, is debated. AIM: To investigate the immunogenicity of
      avenin using the cytokines interferon gamma (IFN-gamma) and interleukin (IL)-2 as
      markers of immunological activity. METHODS: Duodenal biopsies from coeliac
      patients were cultured with 5 mg/ml of peptic tryptic (PT) gliadin (n=9) or 5
      mg/ml of PT avenin (n=8) for four hours. Biopsies cultured with RPMI 1640 alone
      served as controls. Non-coeliac biopsies were also cultured with PT gliadin (n=8)
      and PT avenin (n=8). Total RNA was extracted from the tissue after culture.
      Cytokine mRNA was quantified by TaqMan polymerase chain reaction. Secreted
      cytokine protein was measured in the culture supernatant by enzyme linked
      immunosorbent assay. RESULTS: After culture with PT gliadin, an increase in IFN
      gamma mRNA was observed in all nine patients with coeliac disease. Increased IFN
      gamma protein was also found in four of these patients. Smaller increases in IL-2
      mRNA were detected in six subjects with increased IL-2 protein found in two
      patients. In contrast with PT gliadin, there was no significant IFN-gamma or IL-2
      response when coeliac biopsies were cultured with PT avenin. Similarly, biopsies
      from normal controls did not respond to PT gliadin or PT avenin stimulation.
      CONCLUSIONS: The findings of this study suggest that the immunogenic sequences in
      gliadin are not present in avenin. Moreover, they are in keeping with in vivo
      studies which report that oats are safe for consumption by coeliac patients.

PMID- 12477759
TI  - Tachykinins potently stimulate human small bowel blood flow: a laser Doppler
      flowmetry study in humans.
AB  - BACKGROUND: The two tachykinins substance P and neurokinin A are abundantly
      present in the gastrointestinal tract. Substance P preferring neurokinin 1
      receptors are mainly found in submucosal blood vessels while neurokinin A
      preferring neurokinin 2 receptors seem to be confined to smooth muscle cells.
      Tachykinin effects on intestinal mucosal blood flow in humans are not known. AIM:
      To study the effects of substance P and neurokinin A on small bowel mucosal blood
      flow in humans. METHODS: A manometry tube supplied with single fibre microprobes
      recorded mucosal blood flow in the proximal small bowel using laser Doppler
      flowmetry, concomitant with luminal manometry, defining phases I, II, and III of
      the migrating motor complex. Simultaneously, flowmetry of temporal skin was
      performed. Under fasting conditions saline was infused intravenously over four
      hours followed by infusion of substance P, neurokinin A, or saline. RESULTS:
      During phase I, substance 1-6 pmol/kg/min increased mucosal blood flow dose
      dependently by a maximum of 158%. Blood flow of the temporal skin increased in
      parallel. Neurokinin A 6-50 pmol/kg/min increased mucosal blood flow maximally by
      86% at 25 pmol/kg/min while blood flow of temporal skin increased at all doses.
      Substance P at all doses and neurokinin A at the highest dose only, increased
      pulse rate. Systolic blood pressure was unchanged by either peptide while
      substance P at the highest dose decreased diastolic pressure. CONCLUSION:
      Tachykinins increase blood flow of the small bowel and temporal skin. With
      substance P being more potent than neurokinin A, these effects are probably
      mediated through neurokinin 1 receptors.

PMID- 12477760
TI  - An immunodominant DQ8 restricted gliadin peptide activates small intestinal
      immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8
      negative coeliac patients.
AB  - BACKGROUND: Studies on intestinal T cell clones from the mucosa of patients with
      coeliac disease have led to the identification of immunogenic gliadin epitopes.
      One is HLA-DQ8 restricted, its recognition by T cells being increased by
      introduction of negatively charged residues operated by tissue transglutaminase.
      AIM: To test HLA-DQ8 restricted epitope in both native (QYPSGQGSFQPSQQNPQA) and
      deamidated (QYPSGEGSFQPSQENPQA) forms in an organ culture system of treated
      coeliac mucosa from HLA-DQ8 positive and HLA-DQ8 negative patients. PATIENTS AND
      METHODS: Jejunal biopsies obtained from 10 patients with coeliac disease (six HLA
      DQ8 positive and four HLA-DQ8 negative) were cultured in vitro with a peptic
      tryptic digest (PT) of gliadin, or with the native (peptide A) or deamidated
      (peptide B) peptide. Intraepithelial CD3(+) and lamina propria total CD25(+) and
      CD3(+)CD25(+) cells were counted, lamina propria intercellular adhesion molecule
      1 (ICAM-1) expression was evaluated, as well as that of Fas molecules on
      epithelial cells. RESULTS: In HLA-DQ8 positive, but not in HLA-DQ8 negative,
      coeliacs the density of intraepithelial CD3(+) cells, lamina propria total
      CD25(+), and CD3(+)CD25(+) cells, as well as expression of ICAM-1 and Fas
      molecules were significantly increased in biopsies cultured with PT, peptide A,
      or peptide B compared with biopsies cultured in medium alone. CONCLUSION: These
      data show that the DQ8 restricted gliadin peptide is immunogenic only in the
      intestinal mucosa of HLA-DQ8 positive coeliac patients in both native and
      deamidated forms.

PMID- 12477761
TI  - Osteoporosis in inflammatory bowel disease.

PMID- 12477762
TI  - Increased expression of interleukin 17 in inflammatory bowel disease.
AB  - BACKGROUND AND AIM: Interleukin (IL) 17 is a cytokine which exerts strong
      proinflammatory activities. In this study we evaluated changes in IL-17
      expression in the inflamed mucosa and in the serum of patients with inflammatory
      bowel disease (IBD). METHODS: Tissue samples were obtained endoscopically or
      surgically from patients with ulcerative colitis (UC) (n=20), Crohn's disease
      (CD) (n=20), infectious colitis (n=5), ischaemic colitis (n=8), and normal
      colorectal tissues (n=15). IL-17 expression was evaluated by a standard
      immunohistochemical procedure. Serum IL-17 levels were determined by ELISA. IL-17
      mRNA expression was analysed by reverse transcriptase-polymerase chain reaction.
      RESULTS: IL-17 expression was not detected in samples from normal colonic mucosa,
      infectious colitis, or ischaemic colitis. In the inflamed mucosa of active UC and
      CD patients, IL-17 expression was clearly detectable in CD3(+) T cells or CD68(+)
      monocytes/macrophages. The average number of IL-17(+) cells was significantly
      increased in active UC and CD patients compared with inactive patients. IL-17
      mRNA expression was not detected in normal mucosa but was detectable in the
      mucosa from active UC and CD patients. IL-17 was not detected in the sera from
      normal individuals, infectious colitis, or ischaemic colitis patients but IL-17
      levels were significantly elevated in IBD patients. CONCLUSIONS: IL-17 expression
      in the mucosa and serum was increased in IBD patients. It is likely that IL-17
      expression in IBD may be associated with altered immune and inflammatory
      responses in the intestinal mucosa.

PMID- 12477763
TI  - CARD4/NOD1 is not involved in inflammatory bowel disease.
AB  - BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease
      (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a
      member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently
      been associated with genetic predisposition to CD but additional genetic factors
      remain to be identified. Because CARD4/NOD1 shares many structural and functional
      similarities with CARD15, we tested its putative role in IBD. PATIENTS AND
      METHODS: The 11 exons of CARD4 were screened for the presence of variants in 63
      unrelated IBD patients. The only non-private genetic variation encoding for a
      substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58
      UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain
      reaction-restriction fragment length polymorphism procedure. Genotyping data were
      analysed by the transmission disequilibrium test. RESULTS: Five of nine sequence
      variations identified in the coding sequence of the gene encoded for non
      conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present
      in only one family. The remaining variant (E266K), which exhibited an allele
      frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD
      patients carrying sequence variations in their CARD4 gene had a similar phenotype
      to those with a normal sequence. CONCLUSION: Our results suggest that CARD4 does
      not play a major role in genetic susceptibility to IBD.

PMID- 12477764
TI  - Association between K469E allele of intercellular adhesion molecule 1 gene and
      inflammatory bowel disease in a Japanese population.
AB  - BACKGROUND AND AIMS: The genetic contribution to inflammatory bowel disease (IBD)
      is under investigation. Recent evidence indicates a significant linkage between a
      locus on chromosome 19p13 and IBD. We investigated the association between an
      intercellular adhesion molecule 1 gene (ICAM-1) polymorphism located on
      chromosome 19p13 and IBD in a Japanese population. METHODS: We compared 207
      Japanese patients who had IBD (79 with Crohn's disease (CD); 128 with ulcerative
      colitis (UC)) with 103 unrelated Japanese controls. We determined R241G and K469E
      polymorphisms of the ICAM-1 gene using polymerase chain reaction (PCR)
      techniques. RESULTS: Both frequency and carriage rate of the K469 allele were
      significantly higher in IBD patients than in controls (allelic frequency,
      p(c)=0.0026; carriage rate, p(c)=0.0034; odds ratio 2.59; 95% confidence interval
      1.42-4.68). Furthermore, the frequency of the K469 allele was significantly
      increased in both CD and UC. Subgroup analysis demonstrated that both K469
      allelic frequency and K469 carriage rate were significantly higher in patients
      with the small bowel and colon type of CD and entire colitis compared with
      healthy controls. CONCLUSIONS: We identified an overall association between IBD
      and ICAM-1 K469 in a Japanese population. Further studies of this chromosome
      region are required to elucidate the gene responsible for IBD.

PMID- 12477765
TI  - Induction of experimental ulcerative colitis by Fusobacterium varium isolated
      from colonic mucosa of patients with ulcerative colitis.
AB  - BACKGROUND: Bacteria are implicated in certain forms of model chronic colitis but
      the identity and role of bacteria in human ulcerative colitis (UC) are uncertain.
      AIMS: To isolate pathogenic bacteria from inflamed mucosa of patients with UC, to
      examine whether the bacteria have a toxin to Vero cells, and to determine whether
      the toxin induces UC-like lesions in animals. METHODS: Bacteria were isolated
      from UC patients and supernatants from cultures were filtered and tested for
      cytotoxicity to Vero cells. Bacterial cells producing the cytotoxic supernatants
      were examined by polymerase chain reaction for verotoxin genes. Culture
      supernatants of cytotoxic strains were examined by high performance liquid
      chromatography for organic acid concentrations. Mice were given enemas containing
      organic acid at the mean concentration in the supernatants of cytotoxic strains
      to ascertain whether colonic lesions appear in UC. RESULTS: Only supernatants
      from cultures of Fusobacterium varium killed Vero cells. Bacterial cells lacked
      verotoxin genes. Bacterial culture supernatants contained high concentrations of
      n-butyric acid and the mean concentration (32 mmol/l) was cytotoxic to Vero
      cells. Twenty four hours after mice were given enemas containing either butyric
      acid or F varium culture supernatants, colonic ulcers with crypt abscesses,
      inflammatory cell infiltration, and apoptotic changes were observed. CONCLUSIONS:
      Butyric acid in culture supernatants from cultures of F varium caused UC-like
      lesions in mice. This study indicates that F varium may be one of the elusive
      pathogenic factors in UC.

PMID- 12477767
TI  - Interleukin 10 genotypes in irritable bowel syndrome: evidence for an
      inflammatory component?
AB  - BACKGROUND AND AIMS: Inflammation may play a role in the pathogenesis of
      irritable bowel syndrome in some individuals, such as in those who develop
      symptoms following a dysenteric illness. Persisting inflammation, resulting from
      an imbalance of cytokines regulating the inflammatory response, is one possible
      mechanism. As the elaboration of cytokines is under genetic control, this study
      was designed to establish whether there might be a genetic predisposition to an
      altered pattern of anti-inflammatory cytokine production in patients with
      irritable bowel syndrome. SUBJECTS: A total of 230 unselected patients with
      irritable bowel syndrome and 450 healthy, ethnically matched controls were
      studied. METHODS: DNA was extracted from peripheral blood leucocytes of subjects.
      Allele and genotype frequencies were determined for the anti-inflammatory
      cytokine interleukin 10 at the site (-1082) concerned with production in
      lymphocytes. Transforming growth factor beta(1) (codons 10 and 25) genotypes were
      also examined in a smaller group of subjects. RESULTS: Patients with irritable
      bowel syndrome had significantly reduced frequencies of the high producer
      genotype for interleukin 10 than controls (21% v 32%; p=0.003). There was no
      apparent relationship with any particular bowel habit subtype. Genotypes for
      transforming growth factor beta(1) were not altered. CONCLUSIONS: These
      preliminary results suggest that at least some patients with irritable bowel
      syndrome may be genetically predisposed to produce lower amounts of the anti
      inflammatory cytokine interleukin 10. This lends some support to the hypothesis
      that there may be an inflammatory or genetic component in some cases of this
      condition and that further studies in specific irritable bowel syndrome subgroups
      are justified.

PMID- 12477766
TI  - Changes in chemical coding of myenteric neurones in ulcerative colitis.
AB  - BACKGROUND: Morphological and functional changes in the enteric nervous system
      (ENS) have been reported in inflammatory bowel diseases but it is still uncertain
      whether neurochemical coding of myenteric neurones is altered in ulcerative
      colitis (UC). AIMS: In this study we investigated transmitter co-localisation in
      myenteric neurones of normal colon and the colon of patients with UC. METHODS:
      Choline acetyltransferase (ChAT), neurone specific enolase (NSE), vasoactive
      intestinal peptide (VIP), and substance P (SP) were detected by
      immunohistochemical methods in whole mounts of colonic myenteric plexus of UC
      patients (n=10) and controls (n=8). RESULTS: The proportion of ChAT positive and
      VIP positive neurones relative to the NSE population did not differ in inflamed
      (33.3% and 9.3%, respectively) and non-inflamed segments (33.6% and 9.7%) of UC
      colon compared with controls (35.0% and 6.9%). The proportion of SP positive
      neurones was significantly larger in both inflamed (15.5%) and non-inflamed
      (20.3%) segments than in controls (5.9%). Analysis of changes in subpopulations
      showed that 26.9% of neurones were only ChAT positive in controls but that the
      proportion was significantly smaller in inflamed (18.8%) and non-inflamed (15.8%)
      areas of UC. The proportions of neurones containing ChAT and SP were
      significantly higher in inflamed (11.8%) and non-inflamed (13.9%) areas than in
      controls (5.0%). CONCLUSION: Remodelling of myenteric neurones in UC involves a
      shift from mainly cholinergic to more SP positive innervation. This effect may
      constitute part of the neuronal basis for the motility disturbances observed in
      UC.

PMID- 12477768
TI  - Butyrate induced Caco-2 cell apoptosis is mediated via the mitochondrial pathway.
AB  - BACKGROUND: During the process of tumorigenesis most colon cancer cells acquire
      resistance to apoptosis. The short chain fatty acid butyrate is well established
      as an antitumour agent which selectively induces apoptosis in colon cancer cells
      but not in normal intestinal epithelial cells. AIMS: To analyse the signalling
      pathway of butyrate induced apoptosis. METHODS: Using Caco-2 cells we focused on
      the bcl family of proteins, mitochondrial pathway, and caspase signalling cascade
      involved in butyrate induced apoptosis. Techniques employed included western
      blots, immunofluorescence, as well as experiments with peptide inhibitors of
      specific caspases. RESULTS: Butyrate induced a clear shift of the mitochondrial
      bcl rheostat towards a proapoptotic constellation, as demonstrated by
      upregulation of proapoptotic bak accompanied by reduced antiapoptotic bcl-x(L)
      levels. This was associated with translocation of cytochrome-c from the
      mitochondria to the cytosol, resulting in activation of the caspase cascade via
      caspase-9. Key executioner enzymes were caspases-3 and -1. No effect of butyrate
      on regulatory proteins of the inhibitor of apoptosis family was observed.
      CONCLUSIONS: Butyrate induced Caco-2 cell apoptosis via the mitochondrial
      pathway. Upregulation of bak and translocation of cytochrome-c were upstream of
      the caspase cascade. Subsequently, this cascade was activated via the formation
      of an apoptosome.

PMID- 12477769
TI  - A prospective study of circulating mutant KRAS2 in the serum of patients with
      colorectal neoplasia: strong prognostic indicator in postoperative follow up.
AB  - BACKGROUND AND AIMS: Mutant tumour derived DNA has been detected in the sera of
      colorectal cancer patients. We investigated if mutant serum KRAS2 was detectable
      preoperatively in a large group of patients with colorectal neoplasia. A
      prospective study of 94 patients who underwent putative curative resection for
      colorectal carcinoma (CRC) was performed to ascertain if serum mutant KRAS2 could
      be used postoperatively as a disease marker. METHODS: Preoperative sera from 78
      patients were analysed (group A). Sera from 94 patients were obtained three
      monthly for up to three years during the postoperative period (group B). Codon 12
      and 13 KRAS2 mutations were analysed in matched tumour and serum samples.
      RESULTS: In the preoperative group (group A), KRAS2 mutation was found in 41/78
      (53%) tumours and in 32/78 (41%) preoperative sera. Of 41 tumour KRAS2 mutation
      positive cases, 31/41 (76%) had an identical serum mutation detectable. In group
      B, the postoperative follow up group, 60/94 cases were primary tumour KRAS2
      mutation positive. Of these 60, 16/60 (27%) became persistently serum mutant
      KRAS2 positive postoperatively. Ten of 16 (63%) of these developed a recurrence
      compared with only 1/44 (2%) patients who remained serum mutant negative (odds
      ratio 71.7 (95% confidence interval 7.7-663.9; p=0.0000). None of 34 tumour
      mutation negative cases became serum mutant KRAS2 positive postoperatively,
      despite recurrence in 9/34 patients. The relative hazard of disease recurrence in
      postoperative serum mutant KRAS2 positive patients was 6.37 (2.26-18.0; p=0.000).
      CONCLUSIONS: Serum mutant KRAS2 can be detected preoperatively in all stages of
      colorectal neoplasia. Postoperatively, serum mutant KRAS2 is a strong predictor
      of disease recurrence, stronger even than Dukes' stage of disease, and thus shows
      potential for use in clinical practice as a marker of preclinical disease
      recurrence.

PMID- 12477770
TI  - Gall bladder dysmotility: a risk factor for gall stone formation in
      hypertriglyceridaemia and reversal on triglyceride lowering therapy by
      bezafibrate and fish oil.
AB  - BACKGROUND AND AIM: The aim of this study was to unravel the mechanisms
      responsible for the increased risk of gall stone disease in hypertriglyceridaemia
      (HTG) and to compare the effects of triglyceride lowering therapy by bezafibrate
      and fish oil on determinants of cholelithiasis (biliary lipid composition and
      gall bladder motility) in HTG patients. PATIENTS AND METHODS: Gall bladder
      motility (ultrasonography) was studied postprandially and during infusion of
      cholecystokinin (CCK). Determinants of cholelithiasis and serum lipids were
      compared between nine HTG patients and 10 age, sex, and body mass index matched
      normolipidaemic controls. The effects of bezafibrate and fish oil in HTG patients
      were studied in a randomised cross over trial. RESULTS: HTG patients showed 14
      fold higher serum triglyceride (TG) levels than controls. Biliary lipid
      composition, fasting gall bladder volumes, and CCK levels did not differ between
      HTG patients and controls. Gall bladder emptying was reduced in HTG patients
      compared with controls during CCK infusion (-22%) as well as in response to a
      meal (-37%; both p<0.001). Postprandial CCK levels were significantly higher in
      HTG patients. Both bezafibrate and fish oil reduced serum TG levels (-68% and 
      51% v baseline, respectively; both p<0.01). Fasting CCK levels were not affected
      whereas CCK induced gall bladder emptying increased during bezafibrate (+29%;
      p<0.001) and tended to increase on fish oil therapy (+13%; p=0.07). Postprandial
      gall bladder motility improved on bezafibrate and fish oil (+47 and +25% v
      baseline, respectively; both p<0.02) at least partly due to increased gall
      bladder sensitivity to CCK (both p<0.05 v baseline). Bezafibrate but not fish oil
      increased the molar ratio of cholesterol to bile acids (+40%; p</=0.05) but no
      effects on cholesterol saturation index were seen with either treatment.
      CONCLUSIONS: We suggest that impaired gall bladder motility occurs in HTG
      patients due to decreased sensitivity to CCK, which may add to the enhanced risk
      of gall stone disease in HTG patients. Triglyceride lowering therapy by both fish
      oil and bezafibrate improve gall bladder dysmotility without adversely affecting
      biliary cholesterol saturation.

PMID- 12477771
TI  - Risk factors for recurrent bile duct stones after endoscopic papillotomy.
AB  - BACKGROUND: The long term outcome of endoscopic papillotomy (EPT) is not well
      known. The aims of this study were to clarify the clinical course of post-EPT
      patients and to detect predictors for bile duct stone recurrence. METHODS: A
      total of 1042 consecutive patients who underwent EPT for bile duct stones from
      December 1975 to September 1998 were prospectively followed up. Patients were
      divided into four groups according to gall bladder (GB) status: "acalculous GB"
      group, "calculous GB" group, "cholecystectomy" group, and "prior cholecystectomy"
      group. Reliable follow up information was obtained for 983 (94.3%) of the 1042
      patients. The following factors were considered in the evaluation of predisposing
      risk factors for recurrence of bile duct stones: age, sex, gall bladder status,
      periampullary diverticulum, number of bile duct stones, diameter of bile duct
      stones, diameter of bile duct, lithotripsy, precutting, pneumobilia, and early
      complications. RESULTS: Recurrence occurred in 111 patients. The "acalculous GB"
      group was less prone to recurrence than the "prior cholecystectomy" group and the
      "calculous GB" group. The relative risks (RR) for the latter two compared with
      the former group were 2.26 (95% confidence interval (CI) 1.24-4.14; p=0.0078) and
      2.16 (95% CI 1.21-3.87; p=0.0093), respectively. Other prognostic factors were
      lithotripsy (RR 2.37; 95% CI 1.47-3.81; p=0.0004) and pneumobilia (RR 1.57; 95%
      CI 1.01-2.43; p=0.044). CONCLUSIONS: Gall bladder status, lithotripsy, and
      pneumobilia were significantly related to bile duct stone recurrence after EPT.

PMID- 12477772
TI  - Different hepatitis B virus core gene mutations in children with chronic
      infection and hepatocellular carcinoma.
AB  - BACKGROUND: The significance of mutations of hepatitis B virus (HBV) precore/core
      antigen in causing persistent infection and subsequent liver diseases is
      debatable. AIM: To investigate HBV core gene sequence changes in children with
      chronic HBV infection and their implications in hepatocellular carcinoma (HCC).
      METHODS: Thirty one chronic HBV infected children with documented hepatitis B e
      antigen seroconversion selected from 415 long term carrier children and 12 HBV
      related HCC children were studied. Four serial serum samples before and after
      hepatitis B e antigen seroconversion from each of the 31 children, and one serum
      sample taken from the 12 HCC children were subjected to HBV core gene sequence
      analysis. RESULTS: Mutations accumulated as chronic infection persisted and most
      frequently occurred at core gene codon 21 (29%), codon 147 (29%), codon 65 (16%),
      and precore stop codon 28 (74%) in the 31 chronic HBV infected children. Core
      gene mutation sites in HCC children were identified at core codons 74, 87, and
      159. HCC children had more mutations in the core gene than those with chronic HBV
      infection (p=0.013). CONCLUSION: Accumulation of mutations of HBV core region in
      HCC children differ from those in chronic HBV infected children. This may be a
      clue to the pathogenesis of paediatric HCC.

PMID- 12477773
TI  - Impact of smoking on histological liver lesions in chronic hepatitis C.
AB  - AIMS AND METHODS: To examine the association between smoking and histological
      liver lesions in chronic hepatitis C, we studied 244 consecutive patients (152
      men, 92 women; mean age 45.9 (12.6) years) with histologically proven chronic
      hepatitis C. Daily tobacco consumption during the six months preceding liver
      biopsy was recorded as the number of cigarettes smoked daily. Total lifetime
      tobacco consumption was recorded as the number of cigarette packs smoked per year
      (packs-years). Liver biopsy specimens were graded for histological activity and
      fibrosis according to the METAVIR scoring system. RESULTS: The proportion of
      patients with moderate (A2) or marked (A3) activity increased gradually from
      62.0% in non-smokers to 81.7% in patients who smoked more than 15 cigarettes per
      day (p<0.009). A similar relationship was observed with total lifetime tobacco
      consumption: 59.0% of patients who had never smoked had grade A2 or A3 disease
      activity compared with 84.6% of patients who smoked more than 20 packs per year
      (p<0.002). Multivariate analysis showed that age over 50 years (odds ratio (OR)
      5.4), alcohol intake exceeding 20 g/day (OR 2.75), and tobacco consumption of
      more than 15 cigarettes/day (OR 3.6) were independently related to the
      histological activity score. No relationship was found between the severity of
      fibrosis and either daily tobacco consumption or total lifetime tobacco
      consumption. Multivariate analysis showed that only age over 50 years (OR 8.8),
      daily alcohol intake exceeding 30 g/day (OR 3.4), and histological activity score
      (OR 7.9) were independently related to the fibrosis score. CONCLUSION: This study
      suggests that smoking, independent of alcohol, could aggravate the histological
      activity of chronic hepatitis C and that patients with chronic hepatitis C virus
      infection should be advised to reduce or stop smoking.

PMID- 12477774
TI  - Acute propranolol administration effectively decreases portal pressure in
      patients with TIPS dysfunction. Transjugular intrahepatic portosystemic shunt.
AB  - BACKGROUND AND AIMS: Up to 60% of patients treated with transjugular intrahepatic
      portosystemic shunt (TIPS) require angioplasty or restenting during the first
      year of follow up because of TIPS dysfunction (stenosis of the intrahepatic shunt
      increasing the portal pressure gradient above the 12 mm Hg threshold). We
      hypothesised that in patients with TIPS stenosis, propranolol administration, by
      decreasing portal inflow, would markedly decrease portal pressure. PATIENTS AND
      METHODS: Eighteen patients with TIPS dysfunction were investigated by measuring
      portal pressure gradient before and after acute propranolol administration (0.2
      mg/kg intravenously; n=18). RESULTS: Propranolol markedly reduced the portal
      pressure gradient (from 16.6 (3.5) to 11.9 (4.8) mm Hg; p<0.0001), cardiac index
      (-26 (7)%), and heart rate (-18 (7)%) (p<0.0001). Portal pressure gradient
      decreased to less than 12 mm Hg in nine patients, more frequently in those with
      moderate dysfunction (portal pressure gradient 16 mm Hg) than in patients with
      severe dysfunction (portal pressure gradient >16 mm Hg) (8/10 v 1/8; p=0.015).
      CONCLUSIONS: Propranolol therapy may delay the increase in portal pressure and
      reduce the need for reintervention in patients with TIPS dysfunction.

PMID- 12477775
TI  - MELD scoring system is useful for predicting prognosis in patients with liver
      cirrhosis and is correlated with residual liver function: a European study.
AB  - BACKGROUND: Indices for predicting survival are essential for assessing prognosis
      and assigning priority for liver transplantation in patients with liver
      cirrhosis. The model for end stage liver disease (MELD) has been proposed as a
      tool to predict mortality risk in cirrhotic patients. However, this model has not
      been validated beyond its original setting. AIM: To evaluate the short and medium
      term survival prognosis of a European series of cirrhotic patients by means of
      MELD compared with the Child-Pugh score. We also assessed correlations between
      the MELD scoring system and the degree of impairment of liver function, as
      evaluated by the monoethylglycinexylidide (MEGX) test. PATIENTS AND METHODS: We
      retrospectively evaluated survival of a cohort of 129 cirrhotic patients with a
      follow up period of at least one year. The Child-Pugh score was calculated and
      the MELD score was computed according to the original formula for each patient.
      All patients had undergone a MEGX test. Multivariate analysis was performed on
      all variables to identify the parameters independently associated with one year
      and six month survival. MELD values were correlated with both Child-Pugh scores
      and MEGX test results. RESULTS: Thirty one patients died within the first year of
      follow up. Child-Pugh and MELD scores, and MEGX serum levels were significantly
      different among patients who survived and those who died. Serum creatinine,
      international normalised ratio, and MEGX(60) were independently associated with
      six month mortality while the same variables and the presence of ascites were
      associated with one year mortality. MELD scores showed significant correlations
      with both MEGX values and Child-Pugh scores. CONCLUSIONS: In a European series of
      cirrhotic patients the MELD score is an excellent predictor of both short and
      medium term survival, and performs at least as well as the Child-Pugh score. An
      increase in MELD score is associated with a decrease in residual liver function.

PMID- 12477776
TI  - Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease
      patients with azathioprine.
AB  - Thiopurine S-methyltransferase (TPMT) deficient patients develop life threatening
      haematotoxicity (for example, pancytopenia) when treated with a standard dose of
      azathioprine (AZA) and 6-mercaptopurine (6-MP) due to excessive accumulation of
      cytotoxic metabolites. At present, it is generally recommended that these
      patients should not receive AZA or 6-MP treatment for inflammatory bowel disease.
      We report for the first time that Crohn's disease patients with TPMT deficiency
      can be successfully treated with AZA. We illustrate this with three cases where
      treatment has been successful and toxicity has been avoided by carefully
      titrating the drug dose. Thus very low TPMT activity demands pharmacogenetically
      guided dosing.

PMID- 12477777
TI  - Elemental diet in the treatment of orofacial Crohn's disease.

PMID- 12477779
TI  - Endoscopic surveillance of premalignant gastric lesions.

PMID- 12477778
TI  - Mitogen activated protein (MAP) kinase signal transduction pathways and novel
      anti-inflammatory targets.
AB  - Over the last decade important advances have been made in our understanding of
      the molecular events underlying cellular responses to extracellular signals.
      Increased understanding of signal transduction mechanisms and gene regulation
      involved in immune responses has created opportunities for the discovery of novel
      therapeutic compounds useful in treating inflammatory disorders. One of the best
      studied signalling routes is the mitogen activated protein (MAP) kinase signal
      transduction pathway which plays a crucial role in many aspects of immune
      mediated inflammatory responses. Here, our current understanding of the MAP
      kinase pathway is reviewed, as well as recent advances in the design of novel
      agents that are able to modulate the activity of these signalling cascades.

PMID- 12477780
TI  - Living related liver transplantation: a Japanese experience and development of a
      checklist for donors' informed consent.

PMID- 12477781
TI  - Oesophageal pH monitoring in Barrett's oesophagus.

PMID- 12477782
TI  - Smoking and ulcer healing.

PMID- 12477783
TI  - Influence of clinical factors, drug use, and food intake on the glutathione
      system.

PMID- 12477784
TI  - Mycobacterium avium subspecies paratuberculosis as a cause of Crohn's disease.

PMID- 12477785
TI  - Cellulose synthase (CesA) genes in the green alga Mesotaenium caldariorum.
AB  - Cellulose, a microfibrillar polysaccharide consisting of bundles of beta-1,4
      glucan chains, is a major component of plant and most algal cell walls and is
      also synthesized by some prokaryotes. Seed plants and bacteria differ in the
      structures of their membrane terminal complexes that make cellulose and, in turn,
      control the dimensions of the microfibrils produced. They also differ in the
      domain structures of their CesA gene products (the catalytic subunit of cellulose
      synthase), which have been localized to terminal complexes and appear to help
      maintain terminal complex structure. Terminal complex structures in algae range
      from rosettes (plant-like) to linear forms (bacterium-like). Thus, algal CesA
      genes may reveal domains that control terminal complex assembly and microfibril
      structure. The CesA genes from the alga Mesotaenium caldariorum, a member of the
      order Zygnematales, which have rosette terminal complexes, are remarkably similar
      to seed plant CesAs, with deduced amino acid sequence identities of up to 59%. In
      addition to the putative transmembrane helices and the D-D-D-QXXRW motif shared
      by all known CesA gene products, M. caldariorum and seed plant CesAs share a
      region conserved among plants, an N-terminal zinc-binding domain, and a variable
      or class-specific region. This indicates that the domains that characterize seed
      plant CesAs arose prior to the evolution of land plants and may play a role in
      maintaining the structures of rosette terminal complexes. The CesA genes
      identified in M. caldariorum are the first reported for any eukaryotic alga and
      will provide a basis for analyzing the CesA genes of algae with different types
      of terminal complexes.

PMID- 12477786
TI  - Hyphal tip-associated localization of Cdc42 is F-actin dependent in Candida
      albicans.
AB  - The rho-type GTPase Cdc42 is important for the establishment and maintenance of
      eukaryotic cell polarity. To examine whether Cdc42 is regulated during the yeast
      to-hypha transition in Candida albicans, we constructed a green fluorescence
      protein (GFP)-Cdc42 fusion under the ACT1 promoter and observed its localization
      in live C. albicans cells. As in Saccharomyces cerevisiae, GFP-Cdc42 was observed
      around the entire periphery of the cell. In yeast-form cells of C. albicans, it
      clustered to the tips and sides of small buds as well as to the mother-daughter
      neck region of large-budded cells. Upon hyphal induction, GFP-Cdc42 clustered to
      the site of hyphal evagination and remained at the tips of the hyphae. This
      temporal and spatial localization of Cdc42 suggests that its activity is
      regulated during the yeast-to-hypha transition. In addition to the accumulation
      at the hyphal tip, GFP-Cdc42 was also seen as a band within the hyphal tube in
      cells that had undergone nuclear separation. With the F-actin-assembly inhibitor
      latrunculin A, we found that GFP-Cdc42 accumulation at the bud site in yeast-form
      cells is F-actin independent, whereas GFP-Cdc42 accumulation at the hyphal tip
      requires F-actin. Furthermore, disruption of the F-actin cytoskeleton impaired
      the transcriptional induction of hypha-specific genes. Therefore, hypha formation
      resembles mating in Saccharomyces cerevisiae in that both require F-actin for GFP
      Cdc42 localization and efficient signaling.

PMID- 12477787
TI  - Gpa2, a G-protein alpha subunit required for hyphal development in Candida
      albicans.
AB  - Candida albicans is able to respond to environmental changes by inducing a
      distinct morphological program, which is related to the ability to infect
      mammalian hosts. Although some of the signal transduction pathways involved in
      this response are known, it is not clear how the environmental signals are sensed
      and transmitted to these transduction cascades. In this work, we have studied the
      function of GPA2, a new gene from C. albicans, which encodes a G-protein alpha
      subunit homologue. We demonstrate that Gpa2 plays an important role in the yeast
      hypha dimorphic transition in the response of C. albicans to some environmental
      inducers. Deletion of both alleles of the GPA2 gene causes in vitro defects in
      morphological transitions in Spider medium and SLAD medium and in embedded
      conditions but not in medium containing serum. These defects cannot be reversed
      by exogenous addition of cyclic AMP. However, overexpression of HST7, which
      encodes a component of the filament-inducing mitogen-activated protein kinase
      (MAPK) cascade, bypasses the Gpa2 requirement. We have obtained different gain-of
      function and loss-of-function mutant alleles of the GPA2 gene, which we have
      introduced in several C. albicans genetic backgrounds. Our results indicate that,
      in response to environmental cues, Gpa2 is required for the regulation of a MAPK
      signaling pathway.

PMID- 12477788
TI  - Cloning and characterization of scon-3+, a new member of the Neurospora crassa
      sulfur regulatory system.
AB  - The sulfur regulatory system of Neurospora crassa consists of a group of sulfur
      regulated structural genes (e.g., arylsulfatase) that are under coordinate
      control of the CYS3 positive regulator and sulfur controller (SCON) negative
      regulators. Here we report on the cloning of scon-3(+), which encodes a
      polypeptide of 171 amino acids and is a Skp1 family homolog. Repeat-induced point
      mutation of scon-3(+) resulted in a phenotype of constitutive expression of
      arylsulfatase, a phenotype consistent with other sulfur controller mutants.
      Northern analysis indicated that, unlike other members of the sulfur regulatory
      system, expression of scon-3(+) is not under the direct control of the CYS3
      transcriptional activator. In particular, scon-3(+) mRNA was detectable under
      sulfur repressing or derepressing conditions in a Deltacys-3 mutant. In yeast,
      Skp1p and an F-box protein binding partner are core constituents of a class of E3
      ubiquitin ligases known as SCF complexes. The N. crassa negative regulator SCON2
      contains an F-box motif essential for the operation of the sulfur regulatory
      system and suggests a role for an SCF complex in the N. crassa sulfur regulatory
      system. A crucial set of experiments, by using a yeast two-hybrid approach with
      confirming coimmunoprecipitation assays, demonstrated that SCON3 interacts with
      SCON2 in a manner dependent upon the F-box motif of SCON2. The protein-protein
      interaction detected between SCON2 and SCON3 represents the initial demonstration
      in a filamentous fungus of functional interaction between putative core
      components of a SCF complex.

PMID- 12477790
TI  - Agrobacterium tumefaciens integrates transfer DNA into single chromosomal sites
      of dimorphic fungi and yields homokaryotic progeny from multinucleate yeast.
AB  - The dimorphic fungi Blastomyces dermatitidis and Histoplasma capsulatum cause
      systemic mycoses in humans and other animals. Forward genetic approaches to
      generating and screening mutants for biologically important phenotypes have been
      underutilized for these pathogens. The plant-transforming bacterium Agrobacterium
      tumefaciens was tested to determine whether it could transform these fungi and if
      the fate of transforming DNA was suited for use as an insertional mutagen. Yeast
      cells from both fungi and germinating conidia from B. dermatitidis were
      transformed via A. tumefaciens by using hygromycin resistance for selection.
      Transformation frequencies up to 1 per 100 yeast cells were obtained at high
      effector-to-target ratios of 3,000:1. B. dermatitidis and H. capsulatum ura5
      lines were complemented with transfer DNA vectors expressing URA5 at efficiencies
      5 to 10 times greater than those obtained using hygromycin selection. Southern
      blot analyses indicated that in 80% of transformants the transferred DNA was
      integrated into chromosomal DNA at single, unique sites in the genome. Progeny of
      B. dermatitidis transformants unexpectedly showed that a single round of colony
      growth under hygromycin selection or visible selection of transformants by lacZ
      expression generated homokaryotic progeny from multinucleate yeast. Theoretical
      analysis of random organelle sorting suggests that the majority of B.
      dermatitidis cells would be homokaryons after the ca. 20 generations necessary
      for colony formation. Taken together, the results demonstrate that A. tumefaciens
      efficiently transfers DNA into B. dermatitidis and H. capsulatum and has the
      properties necessary for use as an insertional mutagen in these fungi.

PMID- 12477789
TI  - The Glc7p-interacting protein Bud14p attenuates polarized growth, pheromone
      response, and filamentous growth in Saccharomyces cerevisiae.
AB  - A genetic selection in Saccharomyces cerevisiae for mutants that stimulate the
      mating pathway uncovered a mutant that had a hyperactive pheromone response
      pathway and also had hyperpolarized growth. Cloning and segregation analysis
      demonstrated that BUD14 was the affected gene. Disruption of BUD14 in wild-type
      cells caused mild stimulation of pheromone response pathway reporters, an
      increase in sensitivity to mating factor, and a hyperelongated shmoo morphology.
      The bud14 mutant also had hyperfilamentous growth. Consistent with a role in the
      control of cell polarity, a Bud14p-green fluorescent protein fusion was localized
      to sites of polarized growth in the cell. Bud14p shared morphogenetic functions
      with the Ste20p and Bni1p proteins as well as with the type 1 phosphatase Glc7p.
      The genetic interactions between BUD14 and GLC7 suggested a role for Glc7p in
      filamentous growth, and Glc7p was found to have a positive function in
      filamentous growth in yeast.

PMID- 12477791
TI  - Loss of the F-actin binding and vesicle-associated protein comitin leads to a
      phagocytosis defect.
AB  - Comitin is an F-actin binding and membrane-associated protein from Dictyostelium
      discoideum, which is present on Golgi and vesicle membranes and changes its
      localization in response to agents affecting the cytoskeleton. To investigate its
      in vivo functions we have generated knockout mutants by gene replacement. Based
      on comitin's in vitro functions we examined properties related to vesicular
      transport and microfilament function. Whereas cell growth, pinocytosis,
      secretion, chemotaxis, motility, and development were unaltered, comitin-lacking
      cells were impaired in the early steps of phagocytosis of Saccharomyces
      cerevisiae particles and of Escherichia coli, whereas uptake of latex beads was
      unaffected. Furthermore, the lack of comitin positively affected survival of
      pathogenic bacteria. Mutant cells also showed an altered response to hyperosmotic
      shock in comparison to the wild type. The redistribution of comitin during
      hyperosmotic shock in wild-type cells and its presence on early phagosomes
      suggest a direct involvement of comitin in these processes.

PMID- 12477792
TI  - A multigene family that interacts with the amino terminus of plasmodium MSP-1
      identified using the yeast two-hybrid system.
AB  - Merozoite surface protein 1 (MSP-1) is a high-molecular-weight protein expressed
      on the surface of the malaria merozoite in a noncovalent complex with other
      protein molecules. MSP-1 undergoes a series of proteolytic processing events, but
      no precise biological role for the various proteolytic fragments of MSP-1 or for
      the additional proteins present in the complex is known. Through the use of the
      yeast two-hybrid system, we have isolated genes encoding proteins that interact
      with a region of the amino-terminal proteolytic fragment of MSP-1 from the mouse
      parasite Plasmodium yoelii. This analysis has led to the isolation of two
      sequence-related molecules, one of which is the P. yoelii homologue of MSP-7
      originally described in Plasmodium falciparum. BLAST analysis of the P.
      falciparum database has revealed that there are six related protein molecules
      present in this species encoded near each other on chromosome 13. In P.
      falciparum, we designated these molecules MSRP-1 to -5. Analysis of the P. yoelii
      database indicates a similar chromosomal organization for the two genes in the
      mouse parasite species. The three P. falciparum sequences with the highest degree
      of homology to the P. yoelii sequences isolated in the two-hybrid screen have
      been characterized at the molecular level (MSRP-1 to -3). Expression analysis
      indicated that the mRNAs are expressed at various levels in the different asexual
      stages. Immunofluorescence studies colocalized the expression of the MSRP
      molecules and the amino-terminal portion of MSP-1 to the surfaces of
      trophozoites. In vitro binding experiments confirmed the interaction between MSRP
      1, MSRP-2, and the amino-terminal region of P. falciparum MSP-1.

PMID- 12477793
TI  - Small variant STEVOR antigen is uniquely located within Maurer's clefts in
      Plasmodium falciparum-infected red blood cells.
AB  - Malaria parasite antigens encoded by multigene families are important factors in
      virulence and in disease pathology. In Plasmodium falciparum, the virulence
      factor PfEMP-1 is encoded by the var multigene family and is exposed at the
      infected erythrocyte surface. PfEMP-1 is clonally variant, allowing the parasite
      to evade host immunity. The recently identified P. falciparum stevor multigene
      family and its products also have the potential to be involved in similar
      important aspects of host-parasite interactions. Here, we show tightly regulated
      stage-specific transcription of stevor occurring over just a few hours of the
      asexual parasite life cycle. Only a subset of stevor genes are transcribed in
      parasite populations maintained in cultures and in single micromanipulated
      parasites. Antibodies against STEVOR recognize proteins of the expected size
      (approximately 37 kDa) and localize STEVOR in Maurer's clefts, unique membranous
      structures located in the cytoplasm of infected erythrocytes. The fact that the
      timing of stevor expression and the location of STEVOR are clearly distinct from
      those of other parasite variant antigens suggests that this gene family may have
      a novel role in P. falciparum biology.

PMID- 12477794
TI  - Inhibition of HSP90 in Trypanosoma cruzi induces a stress response but no stage
      differentiation.
AB  - The 90-kDa heat shock proteins (HSP90) are important in the regulation of
      numerous intracellular processes in eukaryotic cells. In particular, HSP90 has
      been shown to be involved in the control of the cellular differentiation of the
      protozoan parasite Leishmania donovani. We investigated the role of HSP90 in the
      related parasite Trypanosoma cruzi by inhibiting its function using geldanamycin
      (GA). GA induced a dose-dependent increase in heat shock protein levels and a
      dose-dependent arrest of proliferation. Epimastigotes were arrested in G(1) phase
      of the cell cycle, but no stage differentiation occurred. Blood form
      trypomastigotes showed conversion towards spheromastigote-like forms when they
      were cultivated with GA, but differentiation into epimastigotes was permanently
      blocked. We conclude that, similar to leishmanial HSP90, functional HSP90 is
      essential for cell division in T. cruzi and serves as a feedback inhibitor in the
      cellular stress response. In contrast to L. donovani cells, however, T. cruzi
      cells treated with GA do not begin to differentiate into relevant life cycle
      stages.

PMID- 12477795
TI  - Chromosome localization changes in the Trypanosoma cruzi nucleus.
AB  - Chromosome localization in the interphase nuclei of eukaryotes depends on gene
      replication and transcription. Little is known about chromosome localization in
      protozoan parasites such as trypanosomes, which have unique mechanisms for the
      control of gene expression, with most genes being posttranscriptionally
      regulated. In the present study, we examined where the chromosomes are replicated
      in Trypanosoma cruzi, the agent of Chagas' disease. The replication sites,
      identified by the incorporation of 5-bromodeoxyuridine, are located at the
      nuclear periphery in proliferating epimastigote forms in the early S phase of the
      cell cycle. When the S phase ends and cells progress through the cell cycle, 5
      bromodeoxyuridine labeling is observed in the nuclear interior, suggesting that
      chromosomes move. We next monitored chromosome locations in different stages of
      the cell cycle by using a satellite DNA sequence as a probe in a fluorescence in
      situ hybridization assay. We found two distinct labeling patterns according to
      the cell cycle stage. The first one is seen in the G(1) phase, in hydroxyurea
      arrested epimastigotes or in trypomastigotes, which are differentiated
      nondividing forms. In all of these forms the satellite DNA is found in dots
      randomly dispersed in the nucleus. The other pattern is found in cells from the S
      phase to the G(2) phase. In these cells, the satellite DNA is found
      preferentially at the nuclear periphery. The labeling at the nuclear periphery
      disappears only after mitosis. Also, DNA detected with terminal deoxynucleotidyl
      transferase is found distributed throughout the nuclear space in the G(1) phase
      but concentrated at the nuclear periphery in the S phase to the G(2) phase. These
      results strongly suggest that T. cruzi chromosomes move and, after entering the S
      phase, become constrained at the nuclear periphery, where replication occurs.

PMID- 12477796
TI  - ras2 Controls morphogenesis, pheromone response, and pathogenicity in the fungal
      pathogen Ustilago maydis.
AB  - Ustilago maydis, a pathogen of maize, is a useful model for the analysis of
      mating, pathogenicity, and the morphological transition between budding and
      filamentous growth in fungi. As in other fungi, these processes are regulated by
      conserved signaling mechanisms, including the cyclic AMP (cAMP)/protein kinase A
      (PKA) pathway and at least one mitogen-activated protein kinase (MAP kinase)
      pathway. A current challenge is to identify additional factors that lie
      downstream of the cAMP pathway and that influence morphogenesis in U. maydis. In
      this study, we identified suppressor mutations that restored budding growth to a
      constitutively filamentous mutant with a defect in the gene encoding a catalytic
      subunit of PKA. Complementation of one suppressor mutation unexpectedly
      identified the ras2 gene, which is predicted to encode a member of the well
      conserved ras family of small GTP-binding proteins. Deletion of the ras2 gene in
      haploid cells altered cell morphology, eliminated pathogenicity on maize
      seedlings, and revealed a role in the production of aerial hyphae during mating.
      We also used an activated ras2 allele to demonstrate that Ras2 promotes
      pseudohyphal growth via a MAP kinase cascade involving the MAP kinase kinase Fuz7
      and the MAP kinase Ubc3. Overall, our results reveal an additional level of
      crosstalk between the cAMP signaling pathway and a MAP kinase pathway influenced
      by Ras2.

PMID- 12477797
TI  - Analysis of telomerase in Candida albicans: potential role in telomere end
      protection.
AB  - Telomerase is a ribonucleoprotein reverse transcriptase responsible for the
      maintenance of one strand of telomere terminal repeats. Analysis of the
      telomerase complex in the budding yeast Saccharomyces cerevisiae has revealed the
      presence of one catalytic protein subunit (Est2p/TERT) and at least two
      noncatalytic components (Est1p and Est3p). The genome of the pathogenic yeast
      Candida albicans contains putative orthologues of all three telomerase
      components. Disruption of each homologue resulted in significant but distinct
      telomere dysfunction in Candida: Similar to S. cerevisiae, the Candida EST3
      disruption strain exhibits progressive telomere loss over many generations, at a
      rate that is consistent with incomplete replication. In contrast, telomeres in
      both the Candida TERT and EST1 disruption strains can contract rapidly, followed
      by partial or nearly complete recovery, suggesting a defect in telomere
      "capping." We propose that these two telomerase subunits may participate in the
      protection of chromosomal ends in Candida: Analysis of telomerase-mediated primer
      extension in vitro indicates that only the TERT protein is absolutely essential
      for enzyme activity. Our results support the conservation of telomerase protein
      components beyond the catalytic subunit but reveal species-specific phenotypic
      alterations in response to loss of individual telomerase component. We also
      identify potential homologues of Est1p in phylogenetically diverse organisms. The
      Est1p sequence family possesses a conserved N-terminal domain predicted to be
      structurally related to tetratricopeptide repeat-containing proteins.

PMID- 12477798
TI  - Loss of compartmentalization causes misregulation of lysine biosynthesis in
      peroxisome-deficient yeast cells.
AB  - To characterize the metabolic role of peroxisomes in yeast cells under
      physiological conditions, we performed a comprehensive meta-analysis of published
      microarray data. Previous studies of yeast peroxisomes have mainly been focused
      on the function of peroxisomes under extreme conditions, such as growth on oleate
      or methanol as the sole carbon source, and may therefore not be representative of
      the normal physiological role of yeast peroxisomes. Surprisingly, our analysis of
      the microarray data reveals that the only pathway responding to peroxisome
      deficiency in mid-log phase is lysine biosynthesis, whereas classical peroxisomal
      pathways such as beta-oxidation are unaffected. We show that the upregulation of
      lysine biosynthesis genes in peroxisome-deficient yeasts shares many
      characteristics with the physiological response to lysine starvation. We provide
      data that suggest that this is the result of a "pathological" stimulation of the
      Lys14p transcriptional activator by the pathway intermediate aminoadipate
      semialdehyde. Mistargeting of the peroxisomal lysine pathway to the cytosol
      increases the active concentration of aminoadipate semialdehyde, which is no
      longer contained in the peroxisome and can now activate Lys14p at much lower
      levels than in wild-type yeasts. This is the first well-documented example of
      pathway misregulation in response to peroxisome deficiency and will be useful in
      understanding the phenotypic details of human peroxisome-deficient patients
      (Zellweger syndrome).

PMID- 12477800
TI  - Ex vivo and in vitro identification of a consensus promoter for VSG genes
      expressed by metacyclic-stage trypanosomes in the tsetse fly.
AB  - The trypanosome variant surface glycoprotein (VSG) is first expressed during
      differentiation to the infective, metacyclic population in tsetse fly salivary
      glands. Unlike the VSG genes expressed by bloodstream form trypanosomes,
      metacyclic VSGs (MVSGs) have their own promoters. The scarcity of metacyclic
      cells has meant that only indirect approaches have been used to study these
      promoters, and not even their identities have been agreed on. Here, we isolated
      trypanosomes by dissection from salivary glands and used an approach involving 5'
      rapid amplification of cDNA ends to identify the transcription start site of
      three MVSGs. This shows that the authentic start site is that proposed for the
      MVAT series of MVSGs (K. S. Kim and J. E. Donelson, J. Biol. Chem. 272:24637
      24645, 1997). In the more readily accessible procyclic trypanosome stage, where
      MVSGs are normally silent, we used reporter gene assays and linker scanning
      analysis to confirm that the 67 bp upstream of the start site is a promoter. This
      is confirmed further by accurate initiation in a homologous in vitro
      transcription system. We show also that MVSG promoters become derepressed when
      tested outwith their endogenous, subtelomeric loci. The MVSG promoters are only
      loosely conserved with bloodstream VSG promoters, and our detailed analysis of
      the 1.63 MVSG promoter reveals that its activity depends on the start site itself
      and sequences 26 to 49 bp and 56 to 60 bp upstream. These are longer than those
      necessary for the bloodstream promoter.

PMID- 12477799
TI  - Multiple functions of mfa-1, a putative pheromone precursor gene of Neurospora
      crassa.
AB  - A putative pheromone precursor gene of Neurospora crassa, mfa-1 (which encodes
      mating factor a-1), was identified as the most abundant clone in starved mycelial
      and perithecial cDNA libraries. Northern analysis demonstrated high mfa-1
      expression in all mating type a tissues and suggested low expression levels in
      mat A tissues. The mfa-1 gene was expressed as an approximately 1.2-kb transcript
      predicted to encode a 24-residue peptide, followed by a long 3' untranslated
      region (3' UTR). The predicted MFA1 sequence showed 100% sequence identity to
      PPG2 of Sordaria macrospora and structural similarity (a carboxy-terminal CAAX
      motif) to many hydrophobic fungal pheromone precursors. Mutants with a disrupted
      open reading frame (ORF) in which the critical cysteine residue had been changed
      to a nonprenylatable residue, tyrosine (YAAX mutants), were isolated, as were mfa
      1 mutants with intact ORFs but multiple mutations in the 3' noncoding region
      (CAAX mutants). The 3' UTR is required for the full range of mfa-1 gene activity.
      Both classes of mutants showed delayed and reduced vegetative growth (which was
      suppressed by supplementation with a minute amount [30 micro M] of ornithine,
      citrulline, or arginine), as well as aberrant sexual development. When crossed as
      female parents to wild-type males, the CAAX and YAAX mutants showed greatly
      reduced ascospore production. No ascospores were produced in homozygous mfa-1
      crosses. As males, YAAX mat a mutants were unable to attract wild-type mat A
      trichogynes (female-specific hyphae) or to initiate sexual development, while
      CAAX mat a mutants were able to mate and produce sexual progeny despite their
      inability to attract mat A trichogynes. In the mat A background, both CAAX and
      YAAX mutants showed normal male fertility but defective vegetative growth and
      aberrant female sexual development. Thus, the mfa-1 gene appears to have multiple
      roles in N. crassa development: (i) it encodes a hydrophobic pheromone with a
      putative farnesylated and carboxymethylated C-terminal cysteine residue, required
      by mat a to attract trichogynes of mat A; (ii) it is involved in female sexual
      development and ascospore production in both mating types; and (iii) it functions
      in vegetative growth of both mating types.

PMID- 12477801
TI  - Deletion of individual mRNA capping genes is unexpectedly not lethal to Candida
      albicans and results in modified mRNA cap structures.
AB  - Eukaryotic mRNAs are modified at the 5' end with a cap structure. In fungal
      cells, the formation of the mRNA cap structure is catalyzed by three enzymes:
      triphosphatase, guanylyltransferase, and methyltransferase. Fungal capping
      enzymes have been proposed to be good antifungal targets because they differ
      significantly from their human counterparts and the genes encoding these enzymes
      are essential in Saccharomyces cerevisiae. In the present study, Candida albicans
      null mutants were constructed for both the mRNA triphosphatase-encoding gene
      (CET1) and the mRNA methyltransferase encoding gene (CCM1), proving that these
      genes are not essential in C. albicans. Heterozygous deletions were generated,
      but no null mutants were isolated for the guanylyltransferase-encoding gene
      (CGT1), indicating that this gene probably is essential in C. albicans. Whereas
      these results indicate that Cet1p and Ccm1p are not ideal molecular targets for
      development of anticandidal drugs, they do raise questions about the capping of
      mRNA and translation initiation in this fungus. Southern blot analysis of genomic
      DNA indicates that there are not redundant genes for CET1 and CCM1 and analysis
      of mRNA cap structures indicate there are not alternative pathways compensating
      for the function of CET1 or CCM1 in the null mutants. Instead, it appears that C.
      albicans can survive with modified mRNA cap structures.

PMID- 12477802
TI  - Rvs161p and sphingolipids are required for actin repolarization following salt
      stress.
AB  - In Saccharomyces cerevisiae, the actin cytoskeleton is depolarized by NaCl
      stress. In this study, the response was maximal after 30 min, and then actin
      patches repolarized. Rvs161p was required for actin repolarization because the
      rvs161delta mutant did not repolarize actin patches after growth in a salt
      medium. Mutations suppressing the rvs161delta-related salt sensitivity all
      occurred in genes required for sphingolipid biosynthesis: FEN1, SUR4, SUR2, SUR1,
      and IPT1. These suppressors also suppressed act1-1-related salt sensitivity and
      the defect in actin repolarization of the rvs161delta mutant, providing a link
      between sphingolipids and actin polarization. Indeed, deletion of the suppressor
      genes suppressed the rvs161delta defect in actin repolarization in two ways:
      either actin was not depolarized at the wild-type level in a set of suppressor
      mutants, or actin was repolarized in the absence of Rvs161p in the other
      suppressor mutants. Rvs161p was localized as cortical patches that concentrated
      at polarization sites, i.e., bud emergence and septa, and was found to be
      associated with lipid rafts. An important link between sphingolipids and actin
      polarization is that Rvs161p was required for actin repolarization and was found
      to be located in lipid rafts.

PMID- 12477803
TI  - Role of Ptc2 type 2C Ser/Thr phosphatase in yeast high-osmolarity glycerol
      pathway inactivation.
AB  - Three type 2C Ser/Thr phosphatases (PTCs) are negative regulators of the yeast
      Saccharomyces cerevisiae high-osmolarity glycerol mitogen-activated protein
      kinase (MAPK) pathway. Ptc2 and Ptc3 are 75% identical to each other and differ
      from Ptc1 in having a noncatalytic domain. Previously, we showed that Ptc1
      inactivates the pathway by dephosphorylating the Hog1 MAPK; Ptc1 maintains low
      basal Hog1 activity and dephosphorylates Hog1 during adaptation. Here, we
      examined the function of Ptc2 and Ptc3. First, deletion of PTC2 and/or PTC3
      together with PTP2, encoding the protein tyrosine phosphatase that inactivates
      Hog1, produced a strong growth defect at 37 degrees C that was dependent on HOG1,
      providing further evidence that PTC2 and PTC3 are negative regulators. Second,
      overexpression of PTC2 inhibited Hog1 activation but did not affect Hog1-Tyr
      phosphorylation, suggesting that Ptc2 inactivates the pathway by
      dephosphorylating the Hog1 activation loop phosphothreonine (pThr) residue.
      Indeed, in vitro studies confirmed that Ptc2 was specific for Hog1-pThr. Third,
      deletion of both PTC2 and PTC3 led to greater Hog1 activation upon osmotic stress
      than was observed in wild-type strains, although no obvious change in Hog1
      inactivation during adaptation was seen. These results indicate that Ptc2 and
      Ptc3 differ from Ptc1 in that they limit maximal Hog1 activity. The function of
      the Ptc2 noncatalytic domain was also examined. Deletion of this domain decreased
      V(max) by 1.6-fold and increased K(m) by 2-fold. Thus Ptc2 requires an additional
      amino acid sequence beyond the catalytic domain defined for PTCs for full
      activity.

PMID- 12477804
TI  - ROX1 and ERG regulation in Saccharomyces cerevisiae: implications for antifungal
      susceptibility.
AB  - Yeasts respond to treatment with azoles and other sterol biosynthesis inhibitors
      by upregulating the expression of the ERG genes responsible for ergosterol
      production. Previous studies on Saccharomyces cerevisiae implicated the ROX1
      repressor in ERG regulation. We report that ROX1 deletion resulted in 2.5- to 16
      fold-lower susceptibilities to azoles and terbinafine. In untreated cultures,
      ERG11 was maximally expressed in mid-log phase and expression decreased in late
      log phase, while the inverse was observed for ROX1. In azole-treated cultures,
      ERG11 upregulation was preceded by a decrease in ROX1 RNA. These inverse
      correlations suggest that transcriptional regulation of ROX1 is an important
      determinant of ERG expression and hence of azole and terbinafine
      susceptibilities.

PMID- 12477805
TI  - Ubiquitin-dependent proteolysis of cyclin D1 is associated with coxsackievirus
      induced cell growth arrest.
AB  - Coxsackievirus group B3 (CVB3) replication is influenced by host cell cycle
      status. However, the effect of CVB3 infection on cell cycle regulation and the
      mechanisms involved are not precisely defined. In this study, we examined cell
      cycle progression and regulation when the infection was initiated in late G(1)
      phase of the cell cycle. Analysis of cellular DNA synthesis in infected cells by
      thymidine incorporation assays showed a significant reduction in [(3)H]thymidine
      uptake compared to that of sham-infected cells. To further clarify the effects of
      CVB3 on the host cell cycle, we examined the cell cycle regulatory proteins
      involved in G(1) progression and G(1)/S transition. Infection resulted in
      dephosphorylation of retinoblastoma protein and reduced G(1) cyclin-dependent
      kinase activities, accompanied by decreased levels of G(1) cyclin protein
      expression (cyclin D1 and cyclin E). We further investigated the mechanisms by
      which CVB3 infection down-regulates cyclin D1 expression. Northern blotting
      showed that cyclin D1 mRNA levels were modestly increased following CVB3
      infection, suggesting that cyclin D1 regulation occurs by a posttranscriptional
      mechanism. Viral infection resulted in only a 20 to 30% inhibition of cyclin D1
      protein synthesis 3 h postinfection. However, the proteasome inhibitors MG132 and
      lactacystin prevent CVB3-induced cyclin D1 reduction, indicating that CVB3
      induced down-regulation of cyclin D1 is facilitated by ubiquitin-proteasome
      proteolysis. Finally, using GSK3beta pathway inhibitors, we showed that the
      reduction of cyclin D1 is GSK3beta independent. Taken together, our results
      demonstrate that CVB3 infection disrupts host cell homeostasis by blocking the
      cell cycle at the G(1)/S boundary and induces cell cycle arrest in part through
      an increase in ubiquitin-dependent proteolysis of cyclin D1.

PMID- 12477806
TI  - Evidence for antibody-mediated enhancement of simian immunodeficiency virus (SIV)
      Gag antigen processing and cross presentation in SIV-infected rhesus macaques.
AB  - By using the dominant simian immunodeficiency virus (SIV) Gag Mamu-A01 restricted
      major histocompatibility complex (MHC) class I epitope p11CM, we demonstrate
      antibody-mediated enhanced MHC class I cross presentation of SIV Gag. In vitro
      restimulation of peripheral blood mononuclear cells from SIV-infected rhesus
      macaques with recombinant full-length SIV Gag p55 plus p55 affinity-purified
      immunoglobulin G (p55 Gag/p55-IgG) led to the generation of markedly higher
      frequencies of p11CM specific precursor cytotoxic T lymphocytes (p-CTLs) compared
      with restimulation with (i) SIV Gag p55 alone or (ii) optimal concentrations of
      the p11CM peptide alone. These results, along with the finding that CD4 depletion
      abrogated the enhancement, suggest a prominent role for CD4(+) T cells. Testing
      for p-CTLs against other Mamu-A01-restricted SIV Gag epitopes suggested that this
      mechanism favored recognition of the dominant p11CM peptide, potentially further
      skewing of the CTL response. The p-CTL enhancing effect was also decreased or
      abrogated by pepsin digestion of the p55-specific IgG or by the addition of
      monoclonal antibodies to Fc receptor (FcR) II/III, suggesting that the effect was
      dependent on FcR-mediated uptake of the immune-complexed antigen. Finally,
      incubation of antigen-presenting cells with SIV Gag p55 immune complexes in the
      presence of lactacystin or of bafilomycin indicated that the mechanism of
      antibody-mediated enhancement of cross presentation required both the proteasomal
      and the endosomal pathways. These data demonstrate for the first time the cross
      presentation of antigens via immune complexes in lentiviral infection and
      indicate a heretofore-unrecognized role for antibodies in modulating the
      magnitude and potentially also the breadth of MHC class I-restricted antigen
      processing and presentation and CTL responses.

PMID- 12477807
TI  - Characterization of a siberian virus isolated from a patient with progressive
      chronic tick-borne encephalitis.
AB  - A strain of Tick-borne encephalitis virus designated Zausaev (Za) was isolated in
      Siberia from a patient who died of a progressive (2-year) form of tick-borne
      encephalitis 10 years after being bitten by a tick. The complete genomic sequence
      of this virus was determined, and an attempt was made to correlate the sequence
      with the biological characteristics of the virus. Phylogenetic analysis
      demonstrated that this virus belongs to the Siberian subtype of Tick-borne
      encephalitis virus. Comparison of Za virus with two related viruses, a Far
      Eastern isolate, Sofjin, and a Siberian isolate, Vasilchenko, revealed
      differences among the three viruses in pathogenicity for Syrian hamsters,
      cytopathogenicity for PS cells, plaque morphology, and the electrophoretic
      profiles of virus-specific nonstructural proteins. Comparative amino acid
      alignments revealed 10 individual amino acid substitutions in the Za virus
      polyprotein sequence that were different from those of other tick-borne
      flaviviruses. Notably, the dimeric form of the Za virus NS1 protein migrated in
      polyacrylamide gels as a heterogeneous group of molecules with a significantly
      higher electrophoretic mobility than those of the Sofjin and Vasilchenko viruses.
      Two amino acid substitutions, T(277)-->V and E(279)-->G, within the NS1
      dimerization domain are probably responsible for the altered oligomerization of
      Za virus NS1. These studies suggest that the patient from whom Za virus was
      isolated died due to increased pathogenicity of the latent virus following
      spontaneous mutagenesis.

PMID- 12477808
TI  - Gris1, a new common integration site in Graffi murine leukemia virus-induced
      leukemias: overexpression of a truncated cyclin D2 due to alternative splicing.
AB  - The Graffi murine leukemia virus is a nondefective ecotropic retrovirus that was
      originally reported to induce myeloid leukemia in some strains of mice (A.
      Graffi, Ann. N.Y. Acad. Sci. 68:540-558, 1957). Using provirus-flanking sequences
      as DNA probes, we identified a new common retroviral integration site called
      Gris1 (for Graffi integration site 1). Viral integrations in Gris1 were detected
      in 13% of the tumors analyzed. The Gris1 locus was mapped to the distal region of
      mouse chromosome 6, 85 kb upstream of the cyclin D2 gene. Such viral integration
      in Gris1 causes overexpression of the normal 6.5-kb major transcript of cyclin D2
      but also induces the expression of a new, alternatively spliced 1.1-kb transcript
      from the cyclin D2 gene that encodes a truncated cyclin D2 of 17 kDa. The
      expression of this 1.1-kb transcript is specific to tumors in which Gris1 is
      rearranged but is also detected at low levels in normal tissue.

PMID- 12477809
TI  - The major apoptotic pathway activated and suppressed by poliovirus.
AB  - Cells respond to poliovirus infection by switching on the apoptotic program,
      implementation of which is usually suppressed by viral antiapoptotic functions.
      We show here that poliovirus infection of HeLa cells or derivatives of MCF-7
      cells was accompanied by the efflux of cytochrome c from mitochondria. This
      efflux occurred during both abortive infection (e.g., interrupted by guanidine
      HCl and ending with apoptosis) and productive infection (leading to cytopathic
      effect). The former type of infection, but not the latter, was accompanied by
      truncation of the proapoptotic protein Bid. The virus-triggered cytochrome c
      efflux was suppressed by overexpression of Bcl-2. Both abortive and productive
      infections also resulted in a decreased level of procaspase-9, as revealed by
      Western blotting. In the former case, this decrease was accompanied by the
      accumulation of a protein with the electrophoretic mobility of active caspase-9.
      In contrast, in the productively infected cells, the latter protein was absent
      but caspase-9-related polypeptides with altered mobility could be detected. Both
      caspase-9 and caspase-3 were shown to be essential for the development of such
      hallmarks of virus-induced apoptosis as chromatin condensation, DNA degradation,
      and nuclear fragmentation. These and some other results suggest the following
      scenario. Poliovirus infection activates the apoptotic pathway, involving
      mitochondrial damage, cytochrome c efflux, and consecutive activation of caspase
      9 and caspase-3. The apoptotic signal appears to be amplified by a loop which
      includes secondary processing of Bid. The implementation of the apoptotic program
      in productively infected cells may be suppressed, however, by the viral
      antiapoptotic functions, which act at a step(s) downstream of the cytochrome c
      efflux. The suppression appears to be caused, at least in part, by aberrant
      processing and degradation of procaspase-9.

PMID- 12477811
TI  - CD8(+) T cells mediate viral clearance and disease pathogenesis during acute
      hepatitis B virus infection.
AB  - Although the CD4(+)- and CD8(+)-T-cell responses to the hepatitis B virus (HBV)
      are thought to be crucial for the control of HBV infection, the relative
      contribution of each T-cell subset as an effector of viral clearance is not
      known. To examine this question, we monitored the course of HBV infection in
      control, CD4-depleted, and CD8-depleted chimpanzees. Our results demonstrate that
      CD8(+) cells are the main effector cells responsible for viral clearance and
      disease pathogenesis during acute HBV infection, and they suggest that viral
      clearance is mediated by both noncytolytic and cytolytic effector functions of
      the CD8(+)-T-cell response.

PMID- 12477810
TI  - The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad
      signaling effects in primary effusion lymphoma cells.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8 [HHV-8]) is a
      gamma-2-herpesvirus responsible for Kaposi's sarcoma as well as primary effusion
      lymphoma (PEL). KSHV is a lymphotropic virus that has pirated many mammalian
      genes involved in inflammation, cell cycle control, and angiogenesis. Among these
      is the early lytic viral G protein-coupled receptor (vGPCR), a homologue of the
      human interleukin-8 (IL-8) receptor. When expressed, vGPCR is constitutively
      active and can signal via mitogen- and stress-activated kinases. In certain
      models it activates the transcriptional potential of NF-kappaB and activator
      protein 1 (AP-1) and induces vascular endothelial growth factor (VEGF)
      production. Despite its importance to the pathogenesis of all KSHV-mediated
      disease, little is known about vGPCR activity in hematopoietic cells. To study
      the signaling potential and downstream effects of vGPCR in such cells, we have
      developed PEL cell lines that express vGPCR under the control of an inducible
      promoter. The sequences required for tetracycline-mediated induction were cloned
      into a plasmid containing adeno-associated virus type 2 elements to enhance
      integration efficiency. This novel plasmid permitted studies of vGPCR activity in
      naturally infected KSHV-positive lymphocytes. We show that vGPCR activates ERK-2
      and p38 in PEL cells. In addition, it increases the transcription of reporter
      genes under the control of AP-1, NF-kappaB, CREB, and NFAT, a Ca(2+)-dependent
      transcription factor important to KSHV lytic gene expression. vGPCR also
      increases the transcription of KSHV open reading frames 50 and 57, thereby
      displaying broad potential to affect viral transcription patterns. Finally, vGPCR
      signaling results in increased PEL cell elaboration of KSHV vIL-6 and VEGF, two
      growth factors involved in KSHV-mediated disease pathogenesis.

PMID- 12477812
TI  - Increased virus replication and virulence after serial passage of human
      immunodeficiency virus type 2 in baboons.
AB  - Similar to human immunodeficiency virus type 1 (HIV-1) infection of humans, the
      natural history of HIV-2 infection in baboons (Papio cynocephalus) is a slow and
      chronic disease that generally takes several years before an AIDS-like condition
      develops. To shorten the amount of time to the development of disease, we
      performed five serial passages of HIV-2(UC2) in baboons by using blood and bone
      marrow samples during the acute phase of infection when viral loads were at high
      levels. After these serial passages, virus levels in plasma, peripheral blood
      mononuclear cells (PBMC) and lymphatic tissues in the acutely infected baboons
      were increased. Within 1 year of the HIV-2 infection, all of the inoculated
      baboons showed specific signs of AIDS-related disease progression within the
      lymphatic tissues, such as vascular proliferation and lymphoid depletion. The HIV
      2(UC2) recovered after four serial passages showed increased kinetics of viral
      replication in baboon PBMC and cytopathicity. This study suggests that the HIV-2
      isolate recovered after several serial passages in baboons will be useful in
      future studies of AIDS pathogenesis and vaccine development by using this animal
      model.

PMID- 12477813
TI  - Sequences downstream of the 5' splice donor site are required for both packaging
      and dimerization of human immunodeficiency virus type 1 RNA.
AB  - Two copies of human immunodeficiency virus type 1 RNA are incorporated into each
      virus particle and are further converted to a stable dimer as the virus particle
      matures. Several RNA segments that flank the 5' splice donor site at nucleotide
      (nt) 289 have been shown to act as packaging signals. Among these, RNA stem-loop
      1 (SL1) (nt 243 to 277) can trigger RNA dimerization through a "kissing-loop"
      mechanism and thus is termed the dimerization initiation site. However, it is
      unknown whether other packaging signals are also needed for dimerization. To
      pursue this subject, we mutated stem-loop 3 (SL3) (nt 312 to 325), a GA-rich
      region (nt 325 to 336), and two G-rich repeats (nt 363 to 367 and nt 405 to 409)
      in proviral DNA and assessed the effects on RNA dimerization by performing native
      Northern blot analyses. Our results show that the structure but not the specific
      RNA sequence of SL3 is needed not only for efficient viral RNA packaging but also
      for dimerization. Mutations of the GA-rich sequence severely diminished viral RNA
      dimerization as well as packaging; the combination of mutations in both SL3 and
      the GA-rich region led to further decreases, implying independent roles for each
      of these two RNA motifs. Compensation studies further demonstrated that the RNA
      packaging and dimerization activity of the GA-rich sequence may not depend on a
      putative interaction between this region and a CU repeat sequence at nt 227 to
      233. In contrast, substitutions in the two G-rich sequences did not cause any
      diminution of viral RNA packaging or dimerization. We conclude that both the SL3
      motif and GA-rich RNA sequences, located downstream of the 5' splice donor site,
      are required for efficient RNA packaging and dimerization.

PMID- 12477814
TI  - Heterodimerization of the two major envelope proteins is essential for
      arterivirus infectivity.
AB  - The two major envelope proteins of arteriviruses, the membrane protein (M) and
      the major glycoprotein (GP(5)), associate into a disulfide-linked heterodimer
      that is incorporated into the virion and has been assumed to be a prerequisite
      for virus assembly. Using an equine arteritis virus (EAV) infectious cDNA clone,
      we have analyzed the requirement for GP(5)-M heterodimerization and have
      identified the Cys residues involved in the formation of the GP(5)-M disulfide
      bond. The single Cys residue (Cys-8) in the M ectodomain was crucial for
      heterodimerization and virus infectivity. Mutagenesis of any of the five Cys
      residues in the GP(5) ectodomain or removal of the single GP(5) N-glycosylation
      site also rendered the full-length clone noninfectious. However, an analysis of
      revertants yielded an exceptional pseudorevertant in which residues 52 to 79 of
      the GP(5) ectodomain had been deleted and the original Cys-80-->Ser mutation had
      been maintained. Consequently, this revertant lacked the GP(5) N-glycosyation
      site (Asn-56) and retained only a single cysteine residue (Cys-34). By using this
      GP(5) deletion, we confirmed that Cys-34 of GP(5) and Cys-8 of M are essential
      for GP(5)-M heterodimerization, a key event in the assembly of the EAV envelope.

PMID- 12477815
TI  - Epstein-Barr virus LMP2A interferes with global transcription factor regulation
      when expressed during B-lymphocyte development.
AB  - Epstein-Barr virus (EBV) is associated with the development of malignant
      lymphomas and lymphoproliferative disorders in immunocompromised individuals. The
      LMP2A protein of EBV is thought to play a central role in this process by
      allowing the virus to persist in latently infected B lymphocytes. We have
      demonstrated that LMP2A, when expressed in B cells of transgenic mice, allows
      normal B-cell developmental checkpoints to be bypassed. To identify cellular
      genes targeted by LMP2A that are involved in this process, we have utilized DNA
      microarrays to compare gene transcription in B cells from wild-type versus LMP2A
      transgenic mice. In B cells from LMP2A transgenic mice, we observed decreased
      expression of many genes associated with normal B-cell development as well as
      reduced levels of the transcription factors that regulate their expression. In
      particular, expression of the transcription factor E2A was down-regulated in bone
      marrow and splenic B cells. Furthermore, E2A activity was inhibited in these
      cells as determined by decreased DNA binding and reduced expression of its target
      genes, including the transcription factors early B-cell factor and Pax-5.
      Expression of two E2A inhibitors, Id2 and SCL, was up-regulated in splenic B
      cells expressing LMP2A, suggesting a possible mechanism for E2A inhibition. These
      results indicate that LMP2A deregulates transcription factor expression and
      activity in developing B cells, and this likely allows for a bypass of normal
      signaling events required for proper B-cell development. The ability of LMP2A to
      interfere with B-cell transcription factor regulation has important implications
      regarding its role in EBV latency.

PMID- 12477816
TI  - Impaired binding of standard initiation factors mediates poliovirus translation
      attenuation.
AB  - In the oral poliovirus vaccine, three attenuated virus strains generated by
      Albert Sabin are used. However, insufficient genetic stability of these strains
      causes major problems in poliovirus eradication. In infected cells, translation
      of the plus-strand poliovirus RNA genome is directed by the internal ribosome
      entry site (IRES), a cis-acting RNA element that facilitates the cap-independent
      binding of ribosomes to an internal site of the viral RNA. In each Sabin vaccine
      strain, a single point mutation in the IRES secondary-structure domain V is a
      major determinant of neurovirulence attenuation. Here we report how these
      decisive mutations in the IRES confer a reduction in poliovirus translation
      efficiency. These single-nucleotide exchanges impair the interaction of the
      standard translation initiation factor eIF4G with the IRES domain V. Moreover,
      binding of eIF4B and the polypyrimidine tract-binding protein and the association
      of ribosomes with the viral RNA are affected by these mutations. However, the
      negative effects of the IRES mutations are completely relieved by addition of
      purified eIF4F. This indicates that eIF4G is the crucial factor that initially
      binds to the poliovirus IRES and recruits the IRES to the other components of the
      translational apparatus, while impaired binding of eIF4G plays a key role in
      attenuation of poliovirus neurovirulence.

PMID- 12477817
TI  - A direct transposon insertion tool for modification and functional analysis of
      viral genomes.
AB  - Advances in DNA transposition technology have recently generated efficient tools
      for various types of functional genetic analyses. We demonstrate here the power
      of the bacteriophage Mu-derived in vitro DNA transposition system for
      modification and functional characterization of a complete bacterial virus
      genome. The linear double-stranded DNA genome of Escherichia coli bacteriophage
      PRD1 was studied by insertion mutagenesis with reporter mini-Mu transposons that
      were integrated in vitro into isolated genomic DNA. After introduction into
      bacterial cells by electroporation, recombinant transposon-containing virus
      clones were identified by autoradiography or visual blue-white screening
      employing alpha-complementation of E. coli beta-galactosidase. Additionally, a
      modified transposon with engineered NotI sites at both ends was used to introduce
      novel restriction sites into the phage genome. Analysis of the transposon
      integration sites in the genomes of viable recombinant phage generated a
      functional map, collectively indicating genes and genomic regions essential and
      nonessential for virus propagation. Moreover, promoterless transposons defined
      the direction of transcription within several insert-tolerant genomic regions.
      These strategies for the analysis of viral genomes are of a general nature and
      therefore may be applied to functional genomics studies in all prokaryotic and
      eukaryotic cell viruses.

PMID- 12477818
TI  - Disulfide-linked integrase oligomers involving C280 residues are formed in vitro
      and in vivo but are not essential for human immunodeficiency virus replication.
AB  - The human immunodeficiency virus type 1 integrase (IN) forms an oligomer that
      integrates both ends of the viral DNA. The nature of the active oligomer is
      unclear. Recombinant IN obtained under reducing conditions is always in the form
      of noncovalent oligomers. However, disulfide-linked oligomers of IN were recently
      observed within viral particles. We show that IN produced from a baculovirus
      expression system can form disulfide-linked oligomers. We investigated which
      residues are responsible for the disulfide bridges and the relationship between
      the ability to form covalent dimers and IN activity. Only the mutation of residue
      C280 was sufficient to prevent the formation of intermolecular disulfide bridges
      in oligomers of recombinant IN. IN activity was studied under and versus
      nonreducing conditions: the formation of disulfide bridges was not required for
      the in vitro activities of the enzyme. Moreover, the covalent dimer does not
      dissociate into individual protomers on disulfide bridge reduction. Instead, IN
      undergoes a spontaneous multimerization process that yields a homogenous
      noncovalent tetramer. The C280S mutation also completely abolished the formation
      of disulfide bonds in the context of the viral particle. Finally, the replication
      of the mutant virus was investigated in replicating and arrested cells. The
      infectivity of the virus was not affected by the C280S IN mutation in either
      dividing or nondividing cells. The disulfide-linked form of the IN oligomers
      observed in the viral particles is thus not required for viral replication.

PMID- 12477819
TI  - Sequence analysis of porcine endogenous retrovirus long terminal repeats and
      identification of transcriptional regulatory regions.
AB  - Porcine cells express endogenous retroviruses, some of which are infectious for
      human cells. To better understand the replication of these porcine endogenous
      retroviruses (PERVs) in cells of different types and animal species, we have
      performed studies of the long terminal repeat (LTR) region of known
      gammaretroviral isolates of PERV. Nucleotide sequence determination of the LTRs
      of PERV-NIH, PERV-C, PERV-A, and PERV-B revealed that the PERV-A and PERV-B LTRs
      are identical, whereas the PERV-NIH and PERV-C LTRs have significant sequence
      differences in the U3 region between each other and with the LTRs of PERV-A and
      PERV-B. Sequence analysis revealed a similar organization of basal promoter
      elements compared with other gammaretroviruses, including the presence of
      enhancer-like repeat elements. The sequences of the PERV-NIH and PERV-C repeat
      element are similar to that of the PERV-A and PERV-B element with some
      differences in the organization of these repeats. The sequence of the PERV
      enhancer-like repeat elements differs significantly from those of other known
      gammaretroviral enhancers. The transcriptional activities of the PERV-A, PERV-B,
      and PERV-C LTRs relative to each other were similar in different cell types of
      different animal species as determined by transient expression assays. On the
      other hand, the PERV-NIH LTR was considerably weaker in these cell types. The
      transcriptional activity of all PERV LTRs was considerably lower in porcine ST
      IOWA cells than in cell lines from other species. Deletion mutant analysis of the
      LTR of a PERV-NIH isolate identified regions that transactivate or repress
      transcription depending on the cell type.

PMID- 12477821
TI  - Vaccinia virus uracil DNA glycosylase has an essential role in DNA synthesis that
      is independent of its glycosylase activity: catalytic site mutations reduce
      virulence but not virus replication in cultured cells.
AB  - Previous findings that the vaccinia virus uracil DNA glycosylase is required for
      virus DNA replication, coupled with an inability to isolate a mutant with an
      active site substitution in the glycosylase gene, were surprising, as such
      enzymes function in DNA repair and bacterial, yeast, and mammalian null mutants
      are viable. To further study the role of the viral protein, we constructed
      recombinant vaccinia viruses with single or double mutations (D68N and H181L) in
      the uracil DNA glycosylase conserved catalytic site by using a complementing cell
      line that constitutively expresses the viral enzyme. Although these mutations
      abolished uracil DNA glycosylase activity, they did not prevent viral DNA
      replication or propagation on a variety of noncomplementing cell lines or human
      primary skin fibroblasts. In contrast, replication of a uracil DNA glycosylase
      deletion mutant occurred only in the complementing cell line. Therefore, the
      uracil DNA glycosylase has an essential role in DNA replication that is
      independent of its glycosylase activity. Nevertheless, the conservation of the
      catalytic site in all poxvirus orthologs suggested an important role in vivo.
      This idea was confirmed by the decreased virulence of catalytic-site mutants when
      administered by the intranasal route to mice.

PMID- 12477820
TI  - Extent of measles virus spread and immune suppression differentiates between wild
      type and vaccine strains in the cotton rat model (Sigmodon hispidus).
AB  - Infection of humans with wild-type measles virus leads to strong immune
      suppression and secondary infections, whereas immunization with an attenuated
      vaccine strain does not. Using the cotton rat model (Sigmodon hispidus), we
      investigated whether vaccine and wild-type viruses differ in viral spread and
      whether this is correlated with inhibition of of proliferation of spleen cells ex
      vivo after mitogen stimulation. After intranasal infection of cotton rats with
      wild-type and vaccine strains, it was found that wild-type virus replicates
      better in lung tissue, spreads to the mediastinal lymph nodes, and induces a more
      pronounced and longer-lasting inhibition of proliferation of spleen cells ex vivo
      after mitogen stimulation than does vaccine virus. To induce the same degree of
      proliferation inhibition, 1,000-fold less wild-type virus was required than
      vaccine virus. With this system, the virulence of various measles virus isolates
      and recombinant viruses was tested. Four (in humans and/or monkeys) highly
      pathogenic virus strains were immunosuppressive, whereas viruses of vaccine virus
      genotype A were not. Using virus pairs which, due to passage on fibroblasts
      versus lymphoid cells or due to a point mutation in the hemagglutinin (N481 -->
      Y), differed in their usage of the two receptor molecules CD46 and CD150 on human
      cells, it was found that viruses using exclusively CD150 in vitro spread to
      mediastinal lymph nodes and induced strong immune suppression. These data
      demonstrate that important parameters of virulence seen in humans, such as viral
      spread and immune suppression, are reflected in the cotton rat model.

PMID- 12477822
TI  - Mutations in the cytoplasmic domain of a paramyxovirus fusion glycoprotein rescue
      syncytium formation and eliminate the hemagglutinin-neuraminidase protein
      requirement for membrane fusion.
AB  - SER virus is closely related to the paramyxovirus simian virus 5 (SV5) but is
      defective in syncytium formation. The SER virus F protein has a long cytoplasmic
      tail (CT) domain that has been shown to inhibit membrane fusion, and this
      inhibitory effect could be eliminated by truncation of the C-terminal sequence
      (S. Tong, M. Li, A. Vincent, R. W. Compans, E. Fritsch, R. Beier, C. Klenk, M.
      Ohuchi, and H.-D. Klenk, Virology 301:322-333, 2002). To study the sequence
      requirements for regulation of fusion, codons for SER virus F protein residues
      spanning amino acids 535 to 542 and 548 were mutated singly to alanines, and the
      two leucine residues at positions 539 and 548 were mutated doubly to alanines. We
      found that leu-539 and leu-548 in the CT domain played a critical role in the
      inhibition of fusion, as mutation of the two leucines singly to alanines
      partially rescued fusion, and the double mutation L539, 548A completely rescued
      syncytium formation. Mutation of charged residues to alanines had little effect
      on the suppression of fusion activity, whereas the mutation of serine residues to
      alanines enhanced fusion activity significantly. The L539, 548A mutant also
      showed extensive syncytium formation when expressed without the SER virus HN
      protein. By constructing a chimeric SV5-SER virus F CT protein, we also found
      that the inhibitory effect of the long CT of the SER virus F protein could be
      partially transferred to the SV5 F protein. These results demonstrate that an
      elongated CT of a paramyxovirus F protein interferes with membrane fusion in a
      sequence-dependent manner.

PMID- 12477823
TI  - Immunization of newborn rhesus macaques with simian immunodeficiency virus (SIV)
      vaccines prolongs survival after oral challenge with virulent SIVmac251.
AB  - There is an urgent need for active immunization strategies that, if administered
      shortly after birth, could protect infants in developing countries from acquiring
      human immunodeficiency virus (HIV) infection through breast-feeding. Better
      knowledge of the immunogenic properties of vaccine candidates in infants and of
      the effect of maternal antibodies on vaccine efficacy will aid in the development
      of such a neonatal HIV vaccine. Simian immunodeficiency virus (SIV) infection of
      infant macaques is a useful animal model of pediatric HIV infection with which to
      address these questions. Groups of infant macaques were immunized at birth and 3
      weeks of age with either modified vaccinia virus Ankara (MVA) expressing SIV Gag,
      Pol, and Env (MVA-SIVgpe) or live-attenuated SIVmac1A11. One MVA-SIVgpe-immunized
      group had maternally derived anti-SIV antibodies prior to immunization. Animals
      were challenged orally at 4 weeks of age with a genetically heterogeneous stock
      of virulent SIVmac251. Although all animals became infected, the immunized
      animals mounted better antiviral antibody responses, controlled virus levels more
      effectively, and had a longer disease-free survival than the unvaccinated
      infected monkeys. Maternal antibodies did not significantly reduce the efficacy
      of the MVA-SIVgpe vaccine. In conclusion, although the tested vaccines delayed
      the onset of AIDS, further studies are warranted to determine whether a vaccine
      that elicits stronger early immune responses at the time of virus exposure may be
      able to prevent viral infection or AIDS in infants.

PMID- 12477824
TI  - Functional expression of chemokine receptor CCR5 on CD4(+) T cells during virus
      induced central nervous system disease.
AB  - Intracranial infection of C57BL/6 mice with mouse hepatitis virus (MHV) results
      in an acute encephalomyelitis followed by a demyelinating disease similar in
      pathology to the human disease multiple sclerosis (MS). CD4(+) T cells are
      important in amplifying demyelination by attracting macrophages into the central
      nervous system (CNS) following viral infection; however, the mechanisms governing
      the entry of these cells into the CNS are poorly understood. The role of
      chemokine receptor CCR5 in trafficking of virus-specific CD4(+) T cells into the
      CNS of MHV-infected mice was investigated. CD4(+) T cells from immunized
      CCR5(+/+) and CCR5(-/-) mice were expanded in the presence of the immunodominant
      epitope present in the MHV transmembrane (M) protein encompassing amino acids 133
      to 147 (M133-147). Adoptive transfer of CCR5(+/+)-derived CD4(+) T cells to MHV
      infected RAG1(-/-) mice resulted in CD4(+)-T-cell entry into the CNS and
      clearance of virus from the brain. These mice also displayed robust demyelination
      correlating with macrophage accumulation within the CNS. Conversely, CD4(+) T
      cells from CCR5(-/-) mice displayed an impaired ability to traffic into the CNS
      of MHV-infected RAG1(-/-) recipients, which correlated with increased viral
      titers, diminished macrophage accumulation, and limited demyelination. Analysis
      of chemokine receptor mRNA expression by M133-147-expanded CCR5(-/-)-derived
      CD4(+) T cells revealed reduced expression of CCR1, CCR2, and CXCR3, indicating
      that CCR5 signaling is important in increased expression of these receptors,
      which aid in trafficking of CD4(+) T cells into the CNS. Collectively these
      results demonstrate that CCR5 signaling is important to migration of CD4(+) T
      cells to the CNS following MHV infection.

PMID- 12477825
TI  - ZEB negatively regulates the lytic-switch BZLF1 gene promoter of Epstein-Barr
      virus.
AB  - Epstein-Barr virus (EBV) is a human herpesvirus capable of establishing a latent
      state in B lymphocytes. The product of the immediate-early BZLF1 gene, Zta, is a
      transcriptional transactivator essential for viral DNA amplification and virion
      production. Previously, we identified a negative cis-acting element within the
      BZLF1 promoter termed ZV. ZV contains the sequence 5'-CAGGTA-3' located at
      nucleotides -17 to -12 relative to the transcription initiation site. It sequence
      specifically binds a cellular factor, ZVR. Based on sequence binding specificity,
      we postulated that ZVR may be zinc finger E-box binding factor (ZEB) or a related
      zinc finger/homeodomain family member. We show here by immunoshift assays that
      ZVR and human ZEB specifically cross-react with an antibody to deltaEF1, the
      chicken homolog of ZEB. Competition electrophoretic mobility shift assays
      confirmed that ZEB binds to the ZV element with the same binding specificity as
      ZVR. Overexpression of ZEB in either B-lymphocytic DG75 cells or mammary
      epithelial MCF-7 cells repressed Zta-induced activation of the BZLF1 promoter
      four- to fivefold via the ZV site. Thus, we conclude that the previously
      identified cellular repressor ZVR is, in fact, ZEB. We also present evidence that
      other cellular factors likely affect the transcriptional activity of ZEB. Lastly,
      we identify a ZEB-binding site within the promoter of the lytic BRLF1 gene of
      EBV. We postulate that ZEB likely plays an important role in regulating the life
      cycle of EBV.

PMID- 12477826
TI  - Role of microglial cells in selective replication of simian immunodeficiency
      virus genotypes in the brain.
AB  - An accelerated, consistent macaque simian immunodeficiency virus (SIV) model in
      which over 90% of pigtailed macaques (Macaca nemestrina) coinoculated with
      SIV/17E-Fr and SIV/DeltaB670 developed encephalitis was used to determine whether
      central nervous system (CNS) lesions are associated with the replication of
      specific genotypes in the brain and, more specifically, in the microglia. Ten of
      11 inoculated macaques had severe (n = 3), moderate (n = 5), or mild (n = 2)
      encephalitis at 3 months postinoculation. To compare actively replicating viral
      genotypes in the CNS and in microglia with those in the periphery, the V1 region
      of the SIV envelope gene was amplified and sequenced from RNA extracted from
      basal ganglia, from microglial cells isolated from the brain, and from peripheral
      blood mononuclear cells (PBMC) isolated from blood at the time of death. To
      distinguish between actively replicating with latent viral genotypes in the CNS,
      viral genotypes in RNA and DNA from basal ganglia were compared. Two macrophage
      tropic, neurovirulent viruses, SIV/17E-Fr and SIV/DeltaB670 Cl-2, predominated in
      the brain RNA of macaques with encephalitis, comprising 95% of the genotypes
      detected. The same two viral genotypes were present at the same frequencies in
      microglial cell RNA, suggesting that microglia are pivotal in the selective
      replication of neurovirulent viruses. There was a significantly greater number of
      viral genotypes in DNA than there were in RNA in the brain (P = 0.004), including
      those of both the macrophage- and lymphocyte-tropic viral strains. Furthermore,
      significantly fewer viral genotypes were detected in brain RNA than in PBMC RNA
      at the time of death (P = 0.004) and the viral strain that predominated in the
      brain frequently was different from that which predominated in the PBMC of the
      same animal. These data suggest that many viral genotypes enter the brain, but
      only a limited subset of macrophage-tropic, neurovirulent viruses replicate
      terminally in the brains of macaques with encephalitis. They further suggest that
      the selection of macrophage-tropic, neurovirulent viruses occurs not at the level
      of the blood-brain barrier but at a stage after virus entry and that microglial
      cells may play an important role in that selection process.

PMID- 12477827
TI  - Novel member of the CD209 (DC-SIGN) gene family in primates.
AB  - Two CD209 family genes identified in humans, CD209 (DC-SIGN) and CD209L (DC
      SIGNR/L-SIGN), encode C-type lectins that serve as adhesion receptors for ICAM-2
      and ICAM-3 and participate in the transmission of human and simian
      immunodeficiency viruses (HIV and SIV, respectively) to target cells in vitro.
      Here we characterize the CD209 gene family in nonhuman primates and show that
      recent evolutionary alterations have occurred in this family across primate
      species. All of the primate species tested, specifically, Old World monkeys (OWM)
      and apes, have orthologues of human CD209. In contrast, CD209L is missing in OWM
      but present in apes. A third family member, that we have named CD209L2, was
      cloned from rhesus monkey cDNA and subsequently identified in OWM and apes but
      not in humans. Rhesus CD209L2 mRNA was prominently expressed in the liver and
      axillary lymph nodes, although preliminary data suggest that levels of expression
      may vary among individuals. Despite a high level of sequence similarity to both
      human and rhesus CD209, rhesus CD209L2 was substantially less effective at
      binding ICAM-3 and poorly transmitted HIV type 1 and SIV to target cells relative
      to CD209. Our data suggest that the CD209 gene family has undergone recent
      evolutionary processes involving duplications and deletions, the latter of which
      may be tolerated because of potentially redundant functional activities of the
      molecules encoded by these genes.

PMID- 12477828
TI  - Identification of a lytic-cycle Epstein-Barr virus gene product that can regulate
      PKR activation.
AB  - The Epstein-Barr virus (EBV) SM protein is a posttranscriptional regulator of
      viral gene expression. Like many transactivators encoded by herpesviruses, SM
      transports predominantly unspliced viral mRNA cargo from the nucleus to the
      cytosol, where it is subsequently translated. This activity likely involves a
      region of the protein that has homology to the herpes simplex virus type 1 (HSV
      1) ICP27 gene product, the first member of this class of regulators to be
      discovered. However, SM also contains a repetitive segment rich in arginine and
      proline residues that is dispensable for its effects on RNA transport and
      splicing. This portion of SM, comprised of RXP triplet repeats, shows homology to
      the carboxyl-terminal domain of Us11, a double-stranded RNA (dsRNA) binding
      protein encoded by HSV-1 that inhibits activation of the cellular PKR kinase. To
      evaluate the intrinsic ability of SM to regulate PKR, we expressed and purified
      several SM protein derivatives and examined their activity in a variety of
      biochemical assays. The full-length SM protein bound dsRNA, associated physically
      with PKR, and prevented PKR activation. Removal of the 37-residue RXP domain
      significantly compromised all of these activities. Furthermore, the SM RXP domain
      was itself sufficient to inhibit PKR activation and interact with the kinase.
      Relative to its Us11 counterpart, the SM RXP segment bound dsRNA with reduced
      affinity and responded differently to single-stranded competitor polynucleotides.
      Thus, SM represents the first EBV gene product expressed during the lytic cycle
      that can prevent PKR activation. In addition, the RXP repeat segment appears to
      be a conserved herpesvirus motif capable of associating with dsRNA and modulating
      activation of the PKR kinase, a molecule important for the control of translation
      and the cellular antiviral response.

PMID- 12477829
TI  - Second-generation rabies virus-based vaccine vectors expressing human
      immunodeficiency virus type 1 gag have greatly reduced pathogenicity but are
      highly immunogenic.
AB  - Rabies virus (RV) vaccine strain-based vectors show great promise as vaccines
      against other viral diseases such as human immunodeficiency virus type 1 (HIV-1)
      infection and hepatitis C, but a low residual pathogenicity remains a concern for
      their use. Here we describe several highly attenuated second-generation RV-based
      vaccine vehicles expressing HIV-1 Gag. For this approach, we modified the
      previously described RV vaccine vector SPBN by replacing the arginine at position
      333 (R333) within the RV glycoprotein (G) with glutamic acid (E333), deleting 43
      amino acids of the RV G cytoplasmic domain (CD), or combining the R333 exchange
      and the CD deletion. In addition, we constructed a new RV vector that expresses
      HIV-1 Gag from an RV transcription unit upstream of the RV phosphoprotein gene
      (BNSP-Gag) instead of upstream of the G gene. As expected and as demonstrated for
      SPBN-Gag, all vaccine vehicles were apathogenic after peripheral administration.
      However, the new, second-generation vaccine vectors containing modifications in
      the RV G were also apathogenic after intracranial infection with 10(5) infectious
      particles, and BNSP-Gag produced a 50%-reduced mortality in mice. Of note, the
      observed attenuation of pathogenicity did not result in either the attenuation of
      the humoral response against the RV G or the previously observed robust cellular
      response against HIV-1 Gag. These findings demonstrate that very safe and highly
      effective RV-based vaccines can be constructed and further emphasize their
      potential utility as efficacious antiviral vaccines.

PMID- 12477830
TI  - An internally located RNA hairpin enhances replication of Tomato bushy stunt
      virus RNAs.
AB  - Defective interfering (DI) RNAs of Tomato bushy stunt virus (TBSV), a plus-sense
      RNA virus, comprise four conserved noncontiguous regions (I through IV) derived
      from the viral genome. Region III, a 70-nucleotide-long sequence corresponding to
      a genomic segment located 378 nucleotides upstream of the 3' terminus of the
      genome, has been found to enhance DI RNA accumulation by approximately 10-fold in
      an orientation-independent manner (D. Ray and K. A. White, Virology 256:162-171,
      1999). In this study, a more detailed structure-function analysis of region III
      was conducted. RNA secondary-structure analyses indicated that region III
      contains stem-loop structures in both plus and minus strands. Through deletion
      analyses of a DI RNA, a primary determinant of region III activity was mapped to
      the 5'-proximal 35-nucleotide segment. Compensatory-type mutational analyses
      showed that a stem-loop structure in the minus strand of this subregion was
      required for enhanced DI RNA replication. The same stem-loop structure was also
      found to function in a position-independent manner in a DI RNA (albeit at reduced
      levels) and to be important for efficient accumulation within the context of the
      TBSV genome. Taken together, these observations suggest that the 5'-proximal
      segment of region III is a modular RNA replication element that functions
      primarily through the formation of an RNA hairpin structure in the minus strand.

PMID- 12477831
TI  - The RNA replication enhancer element of tombusviruses contains two
      interchangeable hairpins that are functional during plus-strand synthesis.
AB  - Replication of the RNA genomes of tombusviruses, which are small plus-sense RNA
      viruses of plants, may be regulated by cis-acting elements, including promoters
      and replication enhancers that are present in the RNA templates. Using a
      partially purified RNA-dependent RNA polymerase (RdRp) preparation (P. D. Nagy
      and J. Pogany, Virology 276:279-288, 2000), we demonstrate that the minus-strand
      templates of tombusviruses contain a replication enhancer, which can upregulate
      RNA synthesis initiating from the minimal plus-strand initiation promoter by 10-
      to 20-fold in an in vitro assay. Dissection of the sequence of the replication
      enhancer element revealed that the two stem-loop structures present within the
      approximately 80-nucleotide-long enhancer region have interchangeable roles in
      upregulating RNA synthesis. The single-stranded sequence located between the two
      stem-loops also plays an important role in stimulation of RNA synthesis. We also
      demonstrate that one of the two hairpins, both of which are similar to the
      hairpin of the minus-strand initiation promoter, can function as a promoter in
      vitro in the presence of short cytidylate-containing initiation sites. Overall,
      the in vitro data presented are consistent with previous in vivo results (D. Ray
      and K. A. White, Virology 256:162-171, 1999) and they firmly establish the
      presence of a replication enhancer on the minus-stranded RNA of tombusviruses.

PMID- 12477832
TI  - The genome length of human parainfluenza virus type 2 follows the rule of six,
      and recombinant viruses recovered from non-polyhexameric-length antigenomic cDNAs
      contain a biased distribution of correcting mutations.
AB  - Members of the Paramyxovirinae subfamily of the Paramyxoviridae family of viruses
      have the unusual requirement that the nucleotide length of the viral genome must
      be an even multiple of six in order for efficient RNA replication, and hence
      virus replication, to occur. Human parainfluenza virus type 2 (HPIV2) is the only
      member of the genus that has been reported to have a genome length that is not an
      even multiple of six, and it has also been recovered from a full-length
      antigenomic-sense cDNA that did not conform to the "rule of six." To reexamine
      the issue of nucleotide length in natural isolates of HPIV2, a complete consensus
      genomic sequence was determined for three HPIV2 strains: Greer, Vanderbilt/1994
      (V94), and Vanderbilt/1998. Each of these strains was found to have a genome
      length of 15,654 nucleotides (nt), thus conforming in each case to the rule of
      six. To directly examine the requirement that the genomic length of HPIV2 be an
      even multiple of six, we constructed six full-length antigenomic HPIV2/V94 cDNAs
      that deviated from a polyhexameric length by 0 to 5 nt. Recombinant HPIV2s were
      readily recovered from all of the cDNAs, including those that did not conform to
      the rule of six. One recombinant HPIV2 isolate was completely sequenced for each
      of the nonpolyhexameric antigenomic cDNAs. These were found to contain small
      nucleotide insertions or deletions that conferred polyhexameric length to the
      recovered genome. Interestingly, almost all of the length corrections occurred
      within the hemagglutinin-neuraminidase and large polymerase genes or the
      intervening intergenic region and thus were proximal to the insert that caused
      the deviation from the rule of six. These results demonstrate, in the context of
      complete infectious virus, that HPIV2 has a strong and seemingly absolute
      requirement for a polyhexameric genome.

PMID- 12477833
TI  - Early synthesis of budded virus envelope fusion protein GP64 enhances Autographa
      californica multicapsid nucleopolyhedrovirus virulence in orally infected
      Heliothis virescens.
AB  - Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), the type
      species of the Nucleopolyhedrovirus genus (Baculoviridae family), has two highly
      unusual traits shared by several baculovirus species. First, the occlusion
      derived virus (ODV) that establishes primary infection in the midgut following
      its ingestion by host larvae contains multiple nucleocapsids, all of which enter
      the same midgut cell. Second, GP64, the envelope fusion protein of the budded
      virus (BV) that spreads infection beyond the midgut, is synthesized both early
      and late during infection. We tested the hypothesis that, together, these two
      traits enable parental ODV nucleocapsids to bud from infected midgut cells,
      essentially as BV, to establish secondary infections prior to completion of viral
      replication within the midgut. This "pass-through" strategy would enable the
      virus to counter the host's principal defense, sloughing of infected midgut
      cells, by accelerating the onset of systemic infections. To test this hypothesis,
      we created an AcMNPV recombinant, AcLate21/20-64HB, that can express gp64 only
      during the late phase of infection (coincident with the other structural
      proteins). We then compared the virulence of this virus to that of a control
      recombinant virus that expresses gp64 in a wild-type manner. We found that when
      administered orally, the control virus was far more virulent and established
      secondary infection earlier than AcLate21/20-64HB, but when administered
      intrahemocoelically, infectivity and virulence of the two recombinants were
      identical. Our results demonstrate that early gp64 expression is a key component
      of a unique and highly adaptive baculovirus infection strategy.

PMID- 12477835
TI  - Effective inhibition of K(b)- and D(b)-restricted antigen presentation in primary
      macrophages by murine cytomegalovirus.
AB  - Macrophages play an important role in murine cytomegalovirus (MCMV) infection in
      vivo, both in disseminating infection and in harboring latent virus. MCMV encodes
      three immune evasion genes (m4, m6, and m152) that interfere with the ability of
      cytotoxic T cells (CTL) to detect virus-infected fibroblasts, but the efficacy of
      immune evasion in macrophages has been controversial. Here we show that MCMV
      immune evasion genes function in H-2(b) primary bone marrow macrophages (BMMphi)
      in the same way that they do in fibroblasts. Metabolic labeling experiments
      showed that class I is retained in the endoplasmic reticulum by MCMV infection
      and associates with m4/gp34 to a similar extent in fibroblasts and BMMphi. We
      tested a series of K(b)- and D(b)-restricted CTL clones specific for MCMV early
      genes against a panel of MCMV wild-type virus and mutants lacking m152, m4, or
      m6. MCMV immune evasion genes effectively inhibited antigen presentation. m152
      appeared sufficient to abolish D(b)-restricted presentation in infected
      macrophages, as has been previously observed in infected fibroblasts. However,
      for inhibition of recognition of infected macrophages by K(b)-restricted CTL, m4,
      m6, and m152 were all required. The contribution of m4 to inhibition of
      recognition appeared much more important in macrophages than in fibroblasts.
      Thus, MCMV immune evasion genes function effectively in primary macrophages to
      prevent CTL recognition of early antigens and show the same pattern of major
      histocompatibility complex class I allele discrimination as is seen in
      fibroblasts. Furthermore, for inhibition of K(b)-restricted presentation, a
      strong synergistic effect was noted among m152, m4, and m6.

PMID- 12477834
TI  - Ontogeny and specificities of mucosal and blood human immunodeficiency virus type
      1-specific CD8(+) cytotoxic T lymphocytes.
AB  - Induction of adaptive immunity to human immunodeficiency virus type 1 (HIV-1) at
      the mucosal site of transmission is poorly understood but crucial in devising
      strategies to control and prevent infection. To gain further understanding of HIV
      1-specific T-cell mucosal immunity, we established HIV-1-specific CD8(+)
      cytotoxic T-lymphocyte (CTL) cell lines and clones from the blood, cervix,
      rectum, and semen of 12 HIV-1-infected individuals and compared their
      specificities, cytolytic function, and T-cell receptor (TCR) clonotypes. Blood
      and mucosal CD8(+) CTL had common HIV-1 epitope specificities and major
      histocompatibility complex restriction patterns. Moreover, both systemic and
      mucosal CTL lysed targets with similar efficiency, primarily through the perforin
      dependent pathway in in vitro studies. Sequence analysis of the TCRbeta VDJ
      region revealed in some cases identical HIV-1-specific CTL clones in different
      compartments in the same HIV-1-infected individual. These results clearly
      establish that a subset of blood and mucosal HIV-1-specific CTL can have a common
      origin and can traffic between anatomically distinct compartments. Thus, these
      effectors can provide immune surveillance at the mucosa, where rapid responses
      are needed to contain HIV-1 infection.

PMID- 12477836
TI  - Mutations in human parainfluenza virus type 3 hemagglutinin-neuraminidase causing
      increased receptor binding activity and resistance to the transition state sialic
      acid analog 4-GU-DANA (Zanamivir).
AB  - Entry and fusion of human parainfluenza virus type 3 (HPF3) require the
      interaction of the viral hemagglutinin-neuraminidase (HN) glycoprotein with its
      sialic acid receptor. 4-GU-DANA, a potent inhibitor of influenza virus
      neuraminidase, inhibits not only HPF3 neuraminidase but also the receptor binding
      activity of HPF3 HN and thus its ability to promote attachment and fusion. We
      previously generated a 4-GU-DANA-resistant HPF3 virus variant (ZM1) with a
      markedly fusogenic plaque morphology that harbored two HN gene mutations
      resulting in amino acid alterations. The present study using cells that express
      the individual mutations of ZM1 HN shows that one of these mutations is
      responsible for the increases in receptor binding and neuraminidase activities as
      well as the diminished sensitivity of both activities to the inhibitory effect of
      4-GU-DANA. To examine the hypothesis that increased receptor binding avidity
      underlies 4-GU-DANA resistance, parallel studies were carried out on the high
      affinity HN variant virus C22 and cells expressing the C22 variant HN. This
      variant also exhibited reduced sensitivity to 4-GU-DANA in terms of receptor
      binding and infectivity but without concomitant changes in the neuraminidase
      activity of HN. Another high-affinity HN variant, C0, was not resistant in terms
      of infectivity; however, a small increase in the receptor binding activity of C0
      HN and a partial resistance of this activity to 4-GU-DANA were revealed by
      sensitive methods that we developed. In each virus variant, one mutation in HN
      accounted for both increased receptor binding avidity and 4-GU-DANA resistance;
      the higher affinity for the receptor overcomes the inhibitory effect of 4-GU
      DANA. Thus, in contrast to influenza viruses for which 4-GU-DANA escape variants
      include hemagglutinin mutants with decreased receptor binding avidity that
      promotes virion release, for HPF3, HN mutants with increased receptor binding
      avidity are those that can escape the growth inhibitory effect of 4-GU-DANA.

PMID- 12477837
TI  - Isolation and molecular characterization of a nelfinavir (NFV)-resistant human
      immunodeficiency virus type 1 that exhibits NFV-dependent enhancement of
      replication.
AB  - During the use of a phenotypic anti-human immunodeficiency virus type 1 (HIV-1)
      drug resistance assay in a large set of clinical virus isolates, we found a
      unique variant (CL-4) that exhibited a high level of nelfinavir (NFV) resistance
      and rather enhanced replication under subinhibitory concentrations of NFV (0.001
      to 0.1 micro M). Comparison of gag-pol sequences of the CL-4 variant and its
      predecessor virus isolates showed a stepwise accumulation of a total of 19 amino
      acid substitutions in protease (PR) and Gag p17 during 32-month NFV-containing
      antiretroviral therapy, while other Gag regions including the cleavage sites of
      the p55 precursor remained highly conserved. To understand the relationship
      between the genetic and phenotypic changes in CL-4, we constructed chimeric
      viruses using pNL4-3, replacing the PR, p24PR, or p17PR gene segment of CL-4 or
      its predecessor. A series of tissue culture infections with the chimeras in the
      absence or presence of increasing concentrations of NFV demonstrated that only
      the p17PR segment of CL-4 could confer the NFV-dependent replication enhancement
      phenotype on NL4-3. Our data suggest a novel adaptation mechanism of HIV-1 to
      NFV, in which coevolution of Gag and PR genes generates a variant that replicates
      more efficiently in the cellular environment in the presence of NFV than without
      the drug.

PMID- 12477838
TI  - Ac23, an envelope fusion protein homolog in the baculovirus Autographa
      californica multicapsid nucleopolyhedrovirus, is a viral pathogenicity factor.
AB  - Viral envelope fusion proteins are important structural proteins that mediate
      viral entry and may affect or determine the host range of a virus. The
      acquisition, exchange, and evolution of such envelope proteins may dramatically
      affect the success and evolutionary divergence of viruses. In the family
      Baculoviridae, two very different envelope fusion proteins have been identified.
      Budded virions of group I nucleopolyhedroviruses (NPVs) such as the Autographa
      californica multicapsid nucleopolyhedrovirus (AcMNPV), contain the essential GP64
      envelope fusion protein. In contrast group II NPVs and granuloviruses have no
      gp64 gene but instead encode a different envelope protein called F. F proteins
      from group II NPVs can functionally substitute for GP64 in gp64null AcMNPV
      viruses, indicating that GP64 and these F proteins serve a similar functional
      role. Interestingly, AcMNPV (and other gp64-containing group I NPVs) also contain
      an F gene homolog (Ac23) but the AcMNPV F homolog cannot compensate for the loss
      of gp64. In the present study, we show that Ac23 is expressed and is found in
      budded virions. To examine the function of F protein homologs from the gp64
      containing baculoviruses, we generated an Ac23null AcMNPV genome by homologous
      recombination in E. coli. We found that Ac23 was not required for viral
      replication or pathogenesis in cell culture or infected animals. However, Ac23
      accelerated the mortality of infected insect hosts by approximately 28% or 26 h.
      Thus, Ac23 represents an important viral pathogenicity factor in larvae infected
      with AcMNPV.

PMID- 12477839
TI  - Transcription strategy in a Closterovirus: a novel 5'-proximal controller element
      of Citrus Tristeza Virus produces 5'- and 3'-terminal subgenomic RNAs and differs
      from 3' open reading frame controller elements.
AB  - Citrus tristeza virus (CTV) produces more than thirty 3'- or 5'-terminal
      subgenomic RNAs (sgRNAs) that accumulate to various extents during replication in
      protoplasts and plants. Among the most unusual species are two abundant
      populations of small 5'-terminal sgRNAs of approximately 800 nucleotides (nt)
      termed low-molecular-weight tristeza (LMT1 and LMT2) RNAs. Remarkably, CTV
      replicons with all 10 3' genes deleted produce only the larger LMT1 RNAs. These
      5'-terminal positive-sense sgRNAs do not have corresponding negative strands and
      were hypothesized to be produced by premature termination during plus-strand
      genomic RNA synthesis. We characterized a cis-acting element that controls the
      production of the LMT1 RNAs. Since manipulation of this cis-acting element in its
      native position (the L-ProI region of replicase) was not possible because the
      mutations negatively affect replication, a region (5'TR) surrounding the putative
      termination sites (nt approximately 550 to 1000) was duplicated in the 3' end of
      a CTV replicon to allow characterization. The duplicated sequence continued to
      produce a 5'-terminal plus-strand sgRNA, here much larger ( approximately 11 kb),
      apparently by termination. Surprisingly, a new 3'-terminal sgRNA was observed
      from the duplicated 5'TR. A large 3'-terminal sgRNA resulting from the putative
      promoter activity of the native 5'TR was not observed, possibly because of the
      down-regulation of a promoter approximately 19 kb from the 3' terminus. However,
      we were able to observe a sgRNA produced from the native 5'TR of a small
      defective RNA, which placed the native 5'TR closer to the 3' terminus,
      demonstrating sgRNA promoter activity of the native 5'TR. Deletion mutagenesis
      mapped the promoter and the terminator activities of the 5'TR (in the 3' position
      in the CTV replicon) to a 57-nt region, which was folded by the MFOLD computer
      program into two stem-loops. Mutations in the putative stem-loop structures
      equally reduced or prevented production of both the 3'- and 5'-terminal sgRNAs.
      These mutations, when introduced in frame in the native 5'TR, similarly abolished
      the synthesis of the LMT1 RNAs and presumably the large 3'-terminal sgRNA while
      having no impact on replication, demonstrating that neither 5'- nor 3'-terminal
      sgRNA is necessary for replication of the replicon or full-length CTV in
      protoplasts. Differences between the 5'TR, which produced two plus-strand sgRNAs,
      and the cis-acting elements controlling the 3' open reading frames, which
      produced additional minus-strand sgRNAs corresponding to the 3'-terminal mRNAs,
      suggest that the different sgRNA controller elements had different origins in the
      modular evolution of closteroviruses.

PMID- 12477840
TI  - Heterogeneity of envelope molecules expressed on primary human immunodeficiency
      virus type 1 particles as probed by the binding of neutralizing and
      nonneutralizing antibodies.
AB  - Virion capture assays, in which immobilized antibodies (Abs) capture virus
      particles, have been used to suggest that nonneutralizing Abs bind effectively to
      human immunodeficiency virus type 1 (HIV-1) primary viruses. Here, we show that
      virion capture assays, under conditions commonly reported in the literature, give
      a poor indication of epitope expression on the surface of infectious primary HIV
      1. First, estimation of primary HIV-1 capture by p24 measurements shows a very
      poor correlation with an estimation based on infectivity measurements. Second,
      virion capture appears to require relatively low Ab affinity for the virion, as
      shown by the ability of a monoclonal Ab to capture a wild-type and a
      neutralization escape variant virus equally well. Nevertheless, in a more
      interpretable competition format, it is shown that nonneutralizing anti-CD4
      binding site (CD4bs) Abs compete with a neutralizing anti-CD4bs Ab (b12) for
      virus capture, suggesting that the nonneutralizing anti-CD4bs Abs are able to
      bind to the envelope species that is involved in virion capture in these
      experiments. However, the nonneutralizing anti-CD4bs Abs do not inhibit
      neutralization by b12 even at considerable excess. This suggests that the
      nonneutralizing Abs are unable to bind effectively to the envelope species
      required for virus infectivity. The results were obtained for three different
      primary virus envelopes. The explanation that we favor is that infectious HIV-1
      primary virions can express two forms of gp120, an accessible nonfunctional form
      and a functional form with limited access. Binding to the nonfunctional form,
      which needs only to be present at relatively low density on the virion, permits
      capture but does not lead to neutralization. The expression of a nonfunctional
      but accessible form of gp120 on virions may contribute to the general failure of
      HIV-1 infection to elicit cross-neutralizing Abs and may represent a significant
      problem for vaccines based on viruses or virus-like particles.

PMID- 12477841
TI  - The dimer interfaces of protease and extra-protease domains influence the
      activation of protease and the specificity of GagPol cleavage.
AB  - Activation of the human immunodeficiency virus type 1 (HIV-1) protease is an
      essential step in viral replication. As is the case for all retroviral proteases,
      enzyme activation requires the formation of protease homodimers. However, little
      is known about the mechanisms by which retroviral proteases become active within
      their precursors. Using an in vitro expression system, we have examined the
      determinants of activation efficiency and the order of cleavage site processing
      for the protease of HIV-1 within the full-length GagPol precursor. Following
      activation, initial cleavage occurs between the viral p2 and nucleocapsid
      proteins. This is followed by cleavage of a novel site located in the transframe
      domain. Mutational analysis of the dimer interface of the protease produced
      differential effects on activation and specificity. A subset of mutations
      produced enhanced cleavage at the amino terminus of the protease, suggesting
      that, in the wild-type precursor, cleavages that liberate the protease are a
      relatively late event. Replacement of the proline residue at position 1 of the
      protease dimer interface resulted in altered cleavage of distal sites and
      suggests that this residue functions as a cis-directed specificity determinant.
      In summary, our studies indicate that interactions within the protease dimer
      interface help determine the order of precursor cleavage and contribute to the
      formation of extended-protease intermediates. Assembly domains within GagPol
      outside the protease domain also influence enzyme activation.

PMID- 12477842
TI  - Importance of B-cell responses for immunological control of variant strains of
      simian immunodeficiency virus.
AB  - The properties of three variants of cloned simian immunodeficiency virus strain
      239 (SIV239) were compared. One strain (M5) lacked five sites for N-linked
      carbohydrate attachment in variable regions 1 and 2 (V1 and V2) of the gp120
      envelope protein, one strain (DeltaV1-V2) completely lacked V1 and V2 sequences,
      and another (316) had nine mutations in the envelope that impart high replicative
      capacity for tissue macrophages. All three strains were capable of significant
      levels of fusion independent of CD4, and all three were considerably more
      sensitive to antibody-mediated neutralization than the parent strain from which
      they were derived. Upon experimental infection of rhesus monkeys, these three
      variant strains replicated to viral loads at peak height around day 14 that were
      indistinguishable from or only slightly less than those observed in monkeys
      infected with the parental SIV239 strain. Viral loads at the set point 20 to 50
      weeks after infection, however, were more than 400- to 10,000-fold lower with the
      variant strains. Depletion of B cells around the time of infection with M5
      resulted in less effective immunological control and much higher viral loads at
      the set point in two of three monkeys. The differences between SIV239 infection,
      where there is not effective immunological control, and SIVM5 infection, where
      there is effective immunological control, cannot be easily explained by
      differences in the inherent replicative capacity of the viruses; rather, they are
      more readily explained by differences in the effectiveness of the antibody
      response. These results suggest that resistance of SIV239 to antibody-mediated
      neutralization is very important for evading effective immunological control, for
      allowing continuous viral replication, for maintenance of moderate-to-high viral
      loads at set point, and for disease progression.

PMID- 12477843
TI  - DNA immunization with hepatitis C virus (HCV) polycistronic genes or immunization
      by HCV DNA priming-recombinant canarypox virus boosting induces immune responses
      and protection from recombinant HCV-vaccinia virus infection in HLA-A2.1
      transgenic mice.
AB  - We studied immune responses to hepatitis C virus (HCV) genes delivered as DNA
      encoding the entire HCV protein coding genome in two polycistronic plasmids
      encoding HCV capsid-E1-E2-NS2-NS3 and HCV NS3-NS4-NS5 in HLA-A2.1-transgenic
      mice. Immune responses to HCV DNA prime and recombinant canarypox virus boost
      were also studied with the above constructs. At 8 weeks after a canarypox virus
      boost, the DNA prime/canarypox virus boosting regimen induced potent cellular
      immune responses to HCV structural and nonstructural proteins on target cells
      expressing the HLA-A2.1 allele. High frequencies of gamma interferon-secreting
      cells, as detected by enzyme-linked immunospot assay, were obtained in response
      to several endogenously expressed HCV proteins. We also observed cytotoxic-T
      lymphocyte reactivity in response to endogenously expressed HCV proteins in fresh
      spleen cells without in vitro expansion. Upon challenge with a recombinant
      vaccinia virus expressing HCV proteins at 2 months postimmunization, the HCV DNA
      prime/canarypox virus-immunized mice showed a complete reduction in vaccinia
      virus titers compared to HCV DNA prime/boost- and mock-immunized controls. Immune
      responses were still detectable 4 months after canarypox virus boost in immunized
      mice. Interestingly, at 10 months postimmunization (8 months after canarypox
      virus boost), the protection in HCV DNA prime/boost-immunized mice against
      recombinant HCV-vaccinia virus challenge was higher than that observed in HCV DNA
      prime/canarypox virus boost-immunized mice.

PMID- 12477844
TI  - Residues of VP26 of herpes simplex virus type 1 that are required for its
      interaction with capsids.
AB  - VP26 is the smallest capsid protein and decorates the outer surface of the capsid
      shell of herpes simplex virus. It is located on the hexons at equimolar amounts
      with VP5. Its small size (112 amino acids) and high copy number make it an
      attractive molecule to use as a probe to investigate the complex pattern of
      capsid protein interactions. An in vitro capsid binding assay and a green
      fluorescent protein (GFP) localization assay were used to identify VP26 residues
      important for its interaction with capsids. To test for regions of VP26 that may
      be essential for binding to capsids, three small in-frame deletion mutations were
      generated in VP26, Delta18-25, Delta54-60, and Delta93-100. Their designations
      refer to the amino acids deleted by the mutation. The mutation at the C terminus
      of the molecule, which encompasses a region of highly conserved residues,
      abolished binding to the capsid and the localization of GFP to the nucleus in
      characteristic large puncta. Additional mutations revealed that a region of VP26
      spanning from residue 50 to 112 was sufficient for the localization of the fused
      protein (VP26-GFP) to the nucleus and for it to bind to capsids. Using site
      directed mutagenesis of conserved residues in VP26, two key residues for protein
      protein interaction, F79 and G93, were identified as judged by the localization
      of GFP to nuclear puncta. When these mutations were analyzed in the capsid
      binding assay, they were also found to eliminate binding of VP26 to the capsid
      structure. Surprisingly, additional mutations that affected the ability of VP26
      to bind to capsids in vitro were uncovered. Mutations at residues A58 and L64
      resulted in a reduced ability of VP26 to bind to capsids. Mutation of the
      hydrophobic residues M78 and A80, which are adjacent to the hydrophobic residue
      F79, abolished VP26 capsid binding. In addition, the block of conserved amino
      acids in the carboxy end of the molecule had the most profound effect on the
      ability of VP26 to interact with capsids. Mutation of amino acid G93, L94, R95,
      R96, or T97 resulted in a greatly diminished ability of VP26 to bind capsids.
      Yet, all of these residues other than G93 were able to efficiently translocate or
      concentrate GFP into the nucleus, giving rise to the punctate fluorescence. Thus,
      the interaction of VP26 with the capsid appears to occur through at least two
      separate mechanisms. The initial interaction of VP26 and VP5 may occur in the
      cytoplasm or when VP5 is localized in the nucleus. Residues F79 and G93 are
      important for this bi-molecular interaction, resulting in the accumulation of
      VP26 in the nucleus in concentrated foci. Subsequent to this association,
      additional amino acids of VP26, including those in the C-terminal conserved
      domain, are important for interaction of VP26 with the three-dimensional capsid
      structure.

PMID- 12477846
TI  - Mapping of amino acid side chains on the surface of hepatitis B virus capsids
      required for envelopment and virion formation.
AB  - The crystal structure of recombinant hepatitis B virus (HBV) capsids formed by
      240 core proteins has recently been published. We wanted to map sites on the
      surface of the icosahedral 35-nm particle that are important for nucleocapsid
      envelopment by HBV surface proteins during virion morphogenesis. For this
      purpose, we individually mutated 52 amino acids (aa) within the N-terminal 140 aa
      of the 185-aa long core protein displaying their side chains to the external
      surface of the capsid to alanine residues. The phenotype of the mutations with
      respect to virion formation was tested by transcomplementation of a core gene
      negative HBV genome in transiently cotransfected cells, immunoprecipitation of
      nucleocapsids from cells and secreted virions from culture media, and detection
      of the particles by radioactive endogenous polymerase reactions. Thirteen point
      mutations impeded nucleocapsid detection by endogenous polymerase reactions.
      Twenty-seven mutations were compatible with virion formation. Among these were
      all capsid-forming mutations in the upper half of the spike protruding from the
      particle shell and two additional triple mutations at tip of the spike. Eleven
      mutations (S17, F18, L60, L95, K96, F122, I126, R127, N136, A137, and I139)
      allowed nucleocapsid formation but blocked particle envelopment and virion
      formation to undetectable levels. These mutations map to a ring-like groove
      around the base of the spike and to a small area at the capsid surface close to
      the pores in the capsid shell. These residues are candidate sites for the
      interaction with envelope proteins during virion morphogenesis.

PMID- 12477845
TI  - Norwalk virus-like particle hemagglutination by binding to h histo-blood group
      antigens.
AB  - Noroviruses are a major cause of epidemic acute nonbacterial gastroenteritis
      worldwide. Here we report our discovery that recombinant Norwalk virus virus-like
      particles (rNV VLPs) agglutinate red blood cells (RBCs). Since histo-blood group
      antigens are expressed on gut mucosa as well as RBCs, we used rNV VLP
      hemagglutination (HA) as a model system for studying NV attachment to cells in
      order to help identify a potential NV receptor(s). rNV VLP HA is dependent on low
      temperature (4 degrees C) and acidic pH. Of the 13 species of RBCs tested, rNV
      VLPs hemagglutinated only chimpanzee and human RBCs. The rNV VLPs hemagglutinated
      all human type O (11 of 11), A (9 of 9), and AB (4 of 4) RBCs; however, few human
      type B RBC samples (4 of 14) were hemagglutinated. HA with periodate- and
      neuraminidase-treated RBCs indicated that rNV VLP binding was carbohydrate
      dependent and did not require sialic acid. The rNV VLPs did not hemagglutinate
      Bombay RBCs (zero of seven) that lack H type 2 antigen, and an anti-H type 2
      antibody inhibited rNV VLP HA of human type O RBCs. These data indicated that the
      H type 2 antigen functions as the rNV VLP HA receptor on human type O RBCs. The
      rNV VLP HA was also inhibited by rNV VLP-specific monoclonal antibody 8812, an
      antibody that inhibits VLP binding to Caco-2 cells. Convalescent-phase sera from
      NV-infected individuals showed increased rNV VLP HA inhibition titers compared to
      prechallenge sera. In carbohydrate binding assays, the rNV VLPs bound to
      synthetic Lewis d (Le(d)), Le(b), H type 2, and Le(y) antigens, and these
      antigens also inhibited rNV VLP HA of human type O RBCs. Overall, our results
      indicate that carbohydrate antigens in the gut are a previously unrecognized
      factor in NV pathogenesis.

PMID- 12477847
TI  - Marker rescue of adeno-associated virus (AAV) capsid mutants: a novel approach
      for chimeric AAV production.
AB  - Marker rescue, the restoration of gene function by replacement of a defective
      gene with a normal one by recombination, has been utilized to produce novel adeno
      associated virus (AAV) vectors. AAV serotype 2 (AAV2) clones containing wild-type
      terminal repeats, an intact rep gene, and a mutated cap gene, served as the
      template for marker rescue. When transfected alone in 293 cells, these AAV2
      mutant plasmids produced noninfectious AAV virions that could not bind heparin
      sulfate after infection with adenovirus dl309 helper virus. However, the mutation
      in the cap gene was corrected after cotransfection with AAV serotype 3 (AAV3)
      capsid DNA fragments, resulting in the production of AAV2/AAV3 chimeric viruses.
      The cap genes from several independent marker rescue experiments were PCR
      amplified, cloned, and then sequenced. Sequencing results confirmed not only that
      homologous recombination occurred but, more importantly, that a mixed population
      of AAV chimeras carrying 16 to 2,200 bp throughout different regions of the type
      3 cap gene were generated in a single marker rescue experiment. A 100%
      correlation was observed between infectivity and the ability of the chimeric
      virus to bind heparin sulfate. In addition, many of the AAV2/AAV3 chimeras
      examined exhibited differences at both the nucleotide and amino acid levels,
      suggesting that these chimeras may also exhibit unique infectious properties.
      Furthermore, AAV helper plasmids containing these chimeric cap genes were able to
      function in the triple transfection method to generate recombinant AAV. Together,
      the results suggest that DNA from other AAV serotypes can rescue AAV capsid
      mutants and that marker rescue may be a powerful, yet simple, technique to map,
      as well as develop, chimeric AAV capsids that display different serotype-specific
      properties.

PMID- 12477848
TI  - Regulation of minute virus of mice NS1 replicative functions by atypical
      PKClambda in vivo.
AB  - Minute virus of mice NS1 protein is a multifunctional phosphoprotein endowed with
      a variety of enzymatic and regulatory activities necessary for progeny virus
      particle production. To regulate all of its different functions in the course of
      a viral infection, NS1 has been proposed to be modulated by posttranslational
      modifications, in particular, phosphorylation. Indeed, it was shown that the NS1
      phosphorylation pattern is altered during the infectious cycle and that the
      biochemical profile of the protein is dependent on the phosphorylation state of
      the polypeptide. Moreover, in vitro approaches have identified members of the
      protein kinase C (PKC) family, in particular, atypical PKC, as regulators of
      viral DNA replication through the phosphorylation of NS1 residues T435 and S473,
      thereby activating the protein for DNA unwinding activities. In order to
      substantiate these findings in vivo, we produced NS1 in the presence of a
      dominant-negative PKClambda mutant and characterized the purified protein in
      vitro. The NS1 protein produced under these conditions was found to be only
      partially phosphorylated and as a consequence to be deficient for viral DNA
      replication. However, it could be rescued for this viral function by treatment
      with recombinant activated PKClambda. Our data clearly demonstrate that NS1 is a
      target for PKClambda phosphorylation in vivo and that this modification is
      essential for the helicase activity of the viral polypeptide. In addition, the
      phosphorylation of NS1 at residues T435 and S473 appeared to occur mainly in the
      nucleus, providing further evidence for the involvement of PKClambda which,
      unlike PKCzeta, accumulates in the nuclear compartment of infected cells.

PMID- 12477849
TI  - Spontaneous mutations restore the viability of tick-borne encephalitis virus
      mutants with large deletions in protein C.
AB  - The capsid protein, C, of tick-borne encephalitis virus has recently been found
      to tolerate deletions up to a length of 16 amino acid residues that partially
      removed the central hydrophobic domain, a sequence element conserved among
      flaviviruses which may be crucial for virion assembly. In this study, mutants
      with deletion lengths of 19, 21, 27, or 30 residues, removing more or all of this
      hydrophobic domain, were found to yield viable virus progeny, but this was
      without exception accompanied by the emergence of additional mutations within
      protein C. These point mutations or sequence duplications were located downstream
      of the engineered deletion and generally increased the hydrophobicity, suggesting
      that they may compensate for the loss of the central hydrophobic domain. Two of
      the second-site mutations, together with the corresponding deletion, were
      introduced into a wild-type genetic backbone, and the analysis of these "double
      mutants" provided direct evidence that the viability of the deletion mutant
      indeed depended on the presence of the second-site mutation. Our results
      corroborate the notion that hydrophobic interactions of protein C are essential
      for the assembly of infectious flavivirus particles but rule out the possibility
      that individual residues of the central hydrophobic domain are absolutely
      required for infectivity. Furthermore, the double mutants were found to be highly
      attenuated and capable of inducing a protective immune response in mice at even
      lower inoculation doses than the previously characterized 16-amino-acid-residue
      deletion mutant, suggesting that the combination of large deletions and second
      site mutations may be a superior way to generate safe, attenuated flavivirus
      vaccine strains.

PMID- 12477850
TI  - Genome variability and capsid structural constraints of hepatitis a virus.
AB  - The number of synonymous mutations per synonymous site (K(s)), the number of
      nonsynonymous mutations per nonsynonymous site (K(a)), and the codon usage
      statistic (N(c)) were calculated for several hepatitis A virus (HAV) isolates.
      While K(s) was similar to those of poliovirus (PV) and foot-and-mouth disease
      virus (FMDV), K(a) was 1 order of magnitude lower. The N(c) parameter provides
      information on codon usage bias and decreases when bias increases. The N(c) value
      in HAV was about 38, while in PV and FMDV, it was about 53. The emergence of 22
      rare codons in front of 8 in PV and 7 in FMDV was detected. Most of the conserved
      rare codons of the P1 region were strategically located at the carboxy borders of
      beta barrels and alpha helices, their potential function being the assurance of
      proper folding of the capsid proteins through a decrease in the translation
      speed. This strategic location was not observed for amino acids encoded by the
      conserved rare codons of the 3D region. The percentage of bases with low pairing
      number values was higher in the latter region, suggesting a role of the conserved
      rare codons in the maintenance of RNA structure. Many of the rare codons in HAV
      are among the most frequent in humans, unlike in PV or in FMDV. This fact may be
      explained by the lack of cellular shutoff in HAV. One hypothesis is that HAV has
      evolved in order to avoid competition with its host for cellular tRNAs.

PMID- 12477851
TI  - Role of protein kinase C betaII in influenza virus entry via late endosomes.
AB  - Many viruses take advantage of receptor-mediated endocytosis in order to enter
      target cells. We have utilized influenza virus and Semliki Forest virus (SFV) to
      define a role for protein kinase C betaII (PKCbetaII) in endocytic trafficking.
      We show that specific PKC inhibitors prevent influenza virus infection,
      suggesting a role for classical isoforms of PKC. We also examined virus entry in
      cells overexpressing dominant-negative forms of PKCalpha and -beta. Cells
      expressing a phosphorylation-deficient form of PKCbetaII (T500V), but not an
      equivalent mutant form of PKCalpha, inhibited successful influenza virus entry
      with the virus accumulating in late endosomes. SFV, however, believed to enter
      cells from the early endosome, was unaffected by PKCbetaII T500V expression. We
      also examined the trafficking of two cellular ligands, transferrin and epidermal
      growth factor (EGF). PKCbetaII T500V expression specifically blocked EGF receptor
      trafficking and degradation, without affecting transferrin receptor recycling. As
      with influenza virus, in PKCbetaII kinase-dead cells, EGF receptor was trapped in
      a late endosome compartment. Our findings suggest that PKCbetaII is an important
      regulator of a late endosomal sorting event needed for influenza virus entry and
      infection.

PMID- 12477852
TI  - Specificity of plasma membrane targeting by the rous sarcoma virus gag protein.
AB  - Budding of C-type retroviruses begins when the viral Gag polyprotein is directed
      to the plasma membrane by an N-terminal membrane-binding (M) domain. While
      dispersed basic amino acids within the M domain are critical for stable membrane
      association and consequent particle assembly, additional residues or motifs may
      be required for specific plasma membrane targeting and binding. We have
      identified an assembly-defective Rous sarcoma virus (RSV) Gag mutant that retains
      significant membrane affinity despite having a deletion of the fourth alpha-helix
      of the M domain. Examination of the mutant protein's subcellular distribution
      revealed that it was not localized to the plasma membrane but instead was
      mistargeted to intracytoplasmic membranes. Specific plasma membrane targeting was
      restored by the addition of myristate plus a single basic residue, by multiple
      basic residues, or by the heterologous hydrophobic membrane-binding domain from
      the cellular Fyn protein. These results suggest that the fourth alpha-helix of
      the RSV M domain promotes specific targeting of Gag to the plasma membrane,
      either through a direct interaction with plasma membrane phospholipids or a
      membrane-associated cellular factor or by maintaining the conformation of Gag to
      expose specific plasma membrane targeting sequences.

PMID- 12477853
TI  - Ribavirin causes error catastrophe during Hantaan virus replication.
AB  - Except for ribavirin, no other antiviral drugs for treating hantaviral diseases
      have been identified. It is well established that ribavirin will inhibit the
      production of infectious Hantaan virus (HTNV); however, its mechanism of action
      is unknown. To characterize the inhibitory effect of ribavirin on HTNV, the
      levels of viral RNAs, proteins, and infectious particles were measured for 3 days
      posttreatment of HTNV-infected Vero E6 cells. HTNV-infected cells treated with
      ribavirin showed a slight reduction in the levels of cRNA, viral RNA, and mRNA
      populations on the first day postinfection. The amount of cRNA and viral RNA
      increased to that observed for untreated HTNV-infected cells on day 2, whereas
      mRNA levels were more greatly reduced on days 2 and 3. Despite the finding of S
      segment mRNA, albeit low, three of the viral proteins-nucleocapsid (N) protein
      and glycoproteins G1 and G2-could not be detected by immunohistochemistry in
      ribavirin-treated cells. To test the hypothesis that these effects were caused by
      incorporation of ribavirin into nascent RNA and a resultant "error catastrophe"
      was occurring, we cloned and sequenced the S-segment cRNA/mRNA from ribavirin
      treated or untreated cells from day 3. We found a high mutation frequency
      (9.5/1,000 nucleotides) in viral RNA synthesized in the presence of ribavirin.
      Hence, the transcripts produced in the presence of the drug were not functional.
      These results suggest that ribavirin's mechanism of action lies in challenging
      the fidelity of the hantavirus polymerase, which causes error catastrophe.

PMID- 12477854
TI  - Promoter sequences of varicella-zoster virus glycoprotein I targeted by cellular
      transactivating factors Sp1 and USF determine virulence in skin and T cells in
      SCIDhu mice in vivo.
AB  - Varicella-zoster virus (VZV) glycoprotein I is dispensable in cell culture but
      necessary for infection of human skin and T cells in SCIDhu mice in vivo. The gI
      promoter contains an activating upstream sequence that binds the cellular
      transactivators specificity factor 1 (Sp1) and upstream stimulatory factor (USF)
      and an open reading frame 29 (ORF29)-responsive element (29RE), which mediates
      enhancement by ORF29 DNA binding protein of immediate-early 62 (IE62)-induced
      transcription. Recombinants, rOKAgI-Sp1 and rOKAgI-USF, with two base pair
      substitutions in Sp1 or USF sites, replicated like rOKA in vitro, but infectivity
      of rOKAgI-Sp1 was significantly impaired in skin and T cells in vivo. A double
      mutant, rOKAgI-Sp1/USF, did not replicate in skin but yielded low titers of
      infectious virus in T cells. The repaired protein, rOKAgI:rep-Sp1/USF, was as
      infectious as rOKA. Thus, disrupting gI promoter sites for cellular
      transactivators altered VZV virulence in vivo, with variable consequences related
      to the cellular factor and the host cell type. Mutations in the 29RE of the gI
      promoter were made by substituting each of four 10-bp blocks in this region with
      a 10-bp sequence, GATAACTACA, that was predicted to interfere with enhancer
      effects of the ORF29 protein. One of these mutants, which was designated rOKAgI
      29RE-3, had diminished replication in skin and T cells, indicating that ORF29
      protein-mediated enhancement of gI expression contributes to VZV virulence.
      Mutations within promoters of viral genes that are nonessential in vitro should
      allow construction of recombinant herpesviruses that have altered virulence in
      specific host cells in vivo and may be useful for designing herpesviral gene
      therapy vectors and attenuated viral vaccines.

PMID- 12477855
TI  - Plasma membrane topology of syncytial domains of herpes simplex virus type 1
      glycoprotein K (gK): the UL20 protein enables cell surface localization of gK but
      not gK-mediated cell-to-cell fusion.
AB  - Most spontaneously occurring mutations that cause extensive herpes simplex virus
      type 1 (HSV-1)-induced cell fusion are single amino acid changes within
      glycoprotein K (gK). Despite the strong genetic association of gK with virus
      induced cell fusion, its direct involvement in cellular membrane fusion has been
      controversial, largely due to previously unsuccessful efforts to detect gK
      expression on virion and cellular surfaces. Recently, we showed that gK is
      expressed on HSV-1 virions and functioned in virus entry (T. P. Foster, G. V.
      Rybachuk, and K. G. Kousoulas, J. Virol. 75:12431-12438, 2001). To determine
      whether gK is expressed on cellular surfaces, as well as its membrane topology,
      we generated the recombinant viruses gKV5DI, gKV5DII, gKV5DIII, and
      gKV5DIVcontaining insertions of the V5 antigenic epitope within each of four
      domains of gK predicted to localize either in the cytoplasmic side or in the
      extracytoplasmic side of cellular membranes. Immunohistochemical and confocal
      microscopy analyses of infected cells showed that both wild-type and syncytial
      forms of gK were expressed on cell surfaces. Analysis of the topology of the V5
      tagged gK revealed that gK domains I and IV were located extracellularly, whereas
      domains II and III were localized intracellularly. Transiently expressed gK
      failed to localize in cellular plasma membranes. In contrast, infection of gK
      transfected cells with the gK-null virus DeltagK enabled expression of gK on cell
      surfaces, as well as gK-mediated membrane fusion. Transient-coexpression
      experiments revealed that the UL20 protein enabled cell surface expression of gK,
      but not gK-mediated cell-to-cell fusion, indicating that additional viral
      proteins are required for expression of the gK syncytial phenotype.

PMID- 12477856
TI  - The coat protein of turnip crinkle virus suppresses posttranscriptional gene
      silencing at an early initiation step.
AB  - Posttranscriptional gene silencing (PTGS), or RNA silencing, is a sequence
      specific RNA degradation process that targets foreign RNA, including viral and
      transposon RNA for destruction. Several RNA plant viruses have been shown to
      encode suppressors of PTGS in order to survive this host defense. We report here
      that the coat protein (CP) of Turnip crinkle virus (TCV) strongly suppresses
      PTGS. The Agrobacterium infiltration system was used to demonstrate that TCV CP
      suppressed the local PTGS as strongly as several previously reported virus-coded
      suppressors and that the action of TCV CP eliminated the small interfering RNAs
      associated with PTGS. We have also shown that the TCV CP must be present at the
      time of silencing initiation to be an effective suppressor. TCV CP was able to
      suppress PTGS induced by sense, antisense, and double-stranded RNAs, and it
      prevented systemic silencing. These data suggest that TCV CP functions to
      suppress RNA silencing at an early initiation step, likely by interfering the
      function of the Dicer-like RNase in plants.

PMID- 12477857
TI  - Tomato ringspot virus proteins containing the nucleoside triphosphate binding
      domain are transmembrane proteins that associate with the endoplasmic reticulum
      and cofractionate with replication complexes.
AB  - Replication of all known positive-strand RNA viruses occurs in replication
      complexes associated with intracellular membranes. The putative nucleoside
      triphosphate binding (NTB) protein of Tomato ringspot virus (ToRSV) contains a
      stretch of hydrophobic residues at its C terminus, suggesting that it may act as
      a membrane anchor for the replication complex. Anti-NTB antibodies detected two
      predominant proteins in membrane-enriched fractions (the 66-kDa NTB and 69-kDa
      NTB-VPg proteins) along with other, larger proteins. The proteins containing the
      NTB domain cofractionated with markers of the endoplasmic reticulum (ER) and with
      ToRSV-specific RNA-dependent RNA polymerase activity in sucrose gradients. ToRSV
      infection induced severe changes in the morphology of the ER in plants expressing
      an ER-targeted green fluorescent protein (ER-GFP), and proteins containing the
      NTB domain colocalized with ER-GFP in indirect immunofluorescence assays. The
      proteins containing the NTB domain have properties of integral membrane proteins.
      Proteinase K protection assays using purified membranes from infected plants
      revealed that although the central portion of the NTB domain is exposed to the
      cytoplasmic face of the membranes, an 8-kDa fragment, recognized by anti-VPg
      antibodies, is protected by the membranes. This fragment probably consists of the
      3-kDa VPg and the 5-kDa stretch of hydrophobic residues at the C terminus of the
      NTB protein, suggesting a luminal location for the VPg in at least a portion of
      the molecules. These results provide evidence that proteins containing the NTB
      domain are transmembrane proteins associated with ER-derived membranes and
      support the hypothesis that one or several of the proteins containing the NTB
      domain anchor the replication complex to the ER.

PMID- 12477858
TI  - Reduced expression of the immediate-early protein IE0 enables efficient
      replication of Autographa californica multiple nucleopolyhedrovirus in poorly
      permissive Spodoptera littoralis cells.
AB  - Infection of Spodoptera littoralis SL2 cells with the baculovirus Autographa
      californica multiple nucleopolyhedrovirus (AcMNPV) results in apoptosis and low
      yields of viral progeny, in contrast to infection with S. littoralis
      nucleopolyhedrovirus (SlNPV). By cotransfecting SL2 cells with AcMNPV genomic DNA
      and a cosmid library representing the complete SlNPV genome, we were able to
      rescue AcMNPV replication and to isolate recombinant virus vAcSL2, which
      replicated efficiently in SL2 cells. Moreover, vAcSL2 showed enhanced infectivity
      for S. littoralis larvae compared to AcMNPV. The genome of vAcSL2 carried a 519
      bp insert fragment that increased the distance between the TATA element and the
      transcriptional initiation site (CAGT) of immediate-early gene ie0. This finding
      correlated with low steady-state levels of IE0 and higher steady-state levels of
      IE1 (the product of the ie1 gene, a major AcMNPV transactivator, and a
      multifunctional protein) than of IE0. Mutagenesis of the ie0 promoter locus by
      insertion of the chloramphenical acetyltransferase (cat) gene yielded a new
      recombinant AcMNPV with replication properties identical to those of vAcSL2.
      Thus, the analysis indicated that increasing the steady-state levels of IE1
      relative to IE0 should enable AcMNPV replication in SL2 cells. This suggestion
      was confirmed by constructing a recombinant AcMNPV bearing an extra copy of the
      ie1 gene under the control of the Drosophila hsp70 promoter. These results
      suggest that IE0 plays a role in the regulation of AcMNPV infection and show, for
      the first time, that significant improvement in the ability of AcMNPV to
      replicate in a poorly permissive cell line and organism can be achieved by
      increasing the expression of the main multiple functional protein, IE1.

PMID- 12477859
TI  - Role of the asialoglycoprotein receptor in binding and entry of hepatitis C virus
      structural proteins in cultured human hepatocytes.
AB  - We used a baculovirus-based system to prepare structural proteins of hepatitis C
      virus (HCV) genotype 1a. Binding of this preparation to cultured human hepatic
      cells was both dose dependent and saturable. This binding was decreased by
      calcium depletion and was partially prevented by ligands of the
      asialoglycoprotein receptor (ASGP-R), thyroglobulin, asialothyroglobulin, and
      antibody against a peptide in the carbohydrate recognition domain of ASGP-R but
      not preimmune antibody. Uptake by hepatocytes was observed with both radiolabeled
      and dye-labeled HCV structural proteins. With hepatocytes expressing the hH1
      subunit of the ASGP-R fused to green fluorescent protein, we could show by
      confocal microscopy that dye stain cointernalized with the fusion protein in an
      area surrounding the nucleus. Internalization was more efficient with a
      preparation containing p7 than with one that did not. The two preparations bound
      to transfected 3T3-L1 cells expressing either both (hH1 and hH2) subunits of the
      ASGP-R (3T3-22Z cells) or both hH1 and a functionally defective variant of hH2
      (3T3-24X cells) but not to parental cells. Additionally, uptake of dye-labeled
      preparation containing p7 was observed with 3T3-22Z cells but not with 3T3-L1 or
      3T3-24X cells or with the preparation lacking p7, suggesting that p7 regulates
      the internalization properties of HCV structural proteins. Our observations
      suggest that HCV structural proteins bind to and cointernalize with the ASGP-R in
      cultured human hepatocytes.

PMID- 12477860
TI  - Concordant modulation of neutralization resistance and high infectivity of the
      primary human immunodeficiency virus type 1 MN strain and definition of a
      potential gp41 binding site in gp120.
AB  - Efforts to develop a vaccine against human immunodeficiency virus type 1 (HIV-1)
      are complicated by resistance of virus to neutralization. The neutralization
      resistance phenotype of HIV-1 has been linked to high infectivity. We studied the
      mechanisms determining this phenotype using clones of the T-cell-line-adapted
      (TCLA) MN strain (MN-TCLA) and the neutralization-resistant, primary MN strain
      (MN-P). Mutations in the amino- and carboxy-terminal halves of gp120 and the
      carboxy terminus of gp41 contributed to the neutralization resistance, high
      infectivity phenotype but depended upon sequences in the leucine zipper (LZ)
      domain of gp41. Among 23 clones constructed to map the contributing mutations,
      there was a very strong correlation between infectivity and neutralization
      resistance (R(2) = 0.81; P < 0.0001). Mutations that distinguished the gp120s of
      MN-P and MN-TCLA clones were clustered in or near the CD4 and coreceptor binding
      sites and in regions distant from those binding sites. To test the hypothesis
      that some of these distant mutations may interact with gp41, we determined which
      of them contributed to high infectivity and whether those mutations modulated
      gp120-gp41 association in the context of MN-P LZ sequences. In one clone, six
      mutations in the amino terminus of gp120, at least four of which clustered
      closely on the inner domain, modulated infectivity. This clone had a gp120-gp41
      association phenotype like MN-P: in comparison to MN-TCLA, spontaneous
      dissociation was low, and dissociation induced by soluble CD4 binding was high.
      These results identify a region of the gp120 inner domain that may be a binding
      site for gp41. Our studies clarify mechanisms of primary virus neutralization
      resistance.

PMID- 12477861
TI  - Structurally conserved amino Acid w501 is required for RNA helicase activity but
      is not essential for DNA helicase activity of hepatitis C virus NS3 protein.
AB  - Hepatitis C virus (HCV) is a positive-strand RNA virus that encodes a helicase
      required for viral replication. Although HCV does not replicate through a DNA
      intermediate, HCV helicase unwinds both RNA and DNA duplexes. An X-ray crystal
      structure of the HCV helicase complexed with (dU)(8) has been solved, and the
      substrate-amino acids interactions within the catalytic pocket were shown. Among
      these, residues W501 and V432 were reported to have base stacking interactions
      and to be important for the unwinding function of HCV helicase. It has been
      hypothesized that specific interactions between the enzyme and substrate in the
      catalytic pocket are responsible for the substrate specificity phenotype. We
      therefore mutagenized W501 and V432 to investigate their role in substrate
      specificity in HCV helicase. Replacement of W501, but not V432, with nonaromatic
      residues resulted in complete loss of RNA unwinding activity, whereas DNA
      unwinding activity was largely unaffected. The loss of unwinding activity was
      fully restored in the W501F mutant, indicating that the aromatic ring is crucial
      for RNA helicase function. Analysis of ATPase and nucleic acid binding activities
      in the W501 mutant enzymes revealed that these activities are not directly
      responsible for the substrate specificity phenotype. Molecular modeling of the
      enzyme-substrate interaction at W501 revealed a putative pi-facial hydrogen bond
      between the 2'-OH of ribose and the aromatic tryptophan ring. This evidence
      correlates with biochemical results suggesting that the pi-facial bond may play
      an important role in the RNA unwinding activity of the HCV NS3 protein.

PMID- 12477862
TI  - Rapid prion neuroinvasion following tongue infection.
AB  - Food-borne transmission of prions can lead to infection of the gastrointestinal
      tract and neuroinvasion via the splanchnic and vagus nerves. Here we report that
      the transmission of transmissible mink encephalopathy (TME) is 100,000-fold more
      efficient by inoculation of prions into the tongues of hamsters than by oral
      ingestion. The incubation period following TME agent (hereinafter referred to as
      TME) inoculation into the lingual muscles was the shortest among the five
      nonneuronal routes of inoculation, including another intramuscular route.
      Deposition of the abnormal isoform of the prion protein, PrP(Sc), was first
      detected in the tongue and submandibular lymph node at 1 to 2 weeks following
      inoculation of the tongue with TME. PrP(Sc) deposits in the tongue were
      associated with individual axons, and the initial appearance of TME in the brain
      stem was found in the hypoglossal nucleus at 2 weeks postinfection. At later time
      points, PrP(Sc) was localized to brain cell groups that directly project to the
      hypoglossal nucleus, indicating the transneuronal spread of TME. TME PrP(Sc)
      entry into the brain stem preceded PrP(Sc) detection in the rostral cervical
      spinal cord. These results demonstrate that TME can replicate in both the tongue
      and regional lymph nodes but indicate that the faster route of brain invasion is
      via retrograde axonal transport within the hypoglossal nerve to the hypoglossal
      nucleus. Topical application of TME to a superficial wound on the surface of the
      tongue resulted in a higher incidence of disease and a shorter incubation period
      than with oral TME ingestion. Therefore, abrasions of the tongue in livestock and
      humans may predispose a host to oral prion infection of the tongue-associated
      cranial nerves. In a related study, PrP(Sc) was detected in tongues following the
      intracerebral inoculation of six hamster-adapted prion strains, which
      demonstrates that prions can also travel from the brain to the tongue in the
      anterograde direction along the tongue-associated cranial nerves. These findings
      suggest that food products containing ruminant or cervid tongue may be a
      potential source of prion infection for humans.

PMID- 12477863
TI  - Complement regulation by Kaposi's sarcoma-associated herpesvirus ORF4 protein.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with three types of
      human tumor: Kaposi's sarcoma, multicentric Castleman's disease, and primary
      effusion lymphoma. The virus encodes a number of proteins that participate in
      disrupting the immune response, one of which was predicted by sequence analysis
      to be encoded by open reading frame 4 (ORF4). The predicted ORF4 protein shares
      homology with cellular proteins referred to as regulators of complement
      activation. In the present study, the transcription profile of the ORF4 gene was
      characterized, revealing that it encodes at least three transcripts, by
      alternative splicing mechanisms, and three protein isoforms. Functional studies
      revealed that each ORF4 protein isoform inhibits complement and retains a C
      terminal transmembrane domain. Consistent with the complement-regulating
      activity, we propose to name the proteins encoded by the ORF4 gene collectively
      as KSHV complement control protein (KCP). KSHV ORF4 is the most complex
      alternatively spliced gene encoding a viral complement regulator described to
      date. KCP inhibits the complement component of the innate immune response,
      thereby possibly contributing to the in vivo persistence and pathogenesis of this
      virus.

PMID- 12477864
TI  - Role of CCAAT/enhancer-binding protein alpha (C/EBPalpha) in activation of the
      Kaposi's sarcoma-associated herpesvirus (KSHV) lytic-cycle replication-associated
      protein (RAP) promoter in cooperation with the KSHV replication and transcription
      activator (RTA) and RAP.
AB  - The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded replication-associated
      protein (RAP, or K8) has been shown to induce both CCAAT/enhancer binding protein
      alpha (C/EBPalpha) and p21(CIP-1) expression, resulting in G(0)/G(1) cell cycle
      arrest during the lytic cycle. RAP and C/EBPalpha are also known to interact
      strongly both in vitro and in lytically infected cells. We recognized two
      potential consensus C/EBP binding sites in the RAP promoter and performed
      electrophoretic mobility shift assay (EMSA) analysis with in vitro-translated
      C/EBPalpha; this analysis showed that one of these sites has a very high affinity
      for C/EBPalpha. Luciferase (LUC) assays performed with a target RAP promoter-LUC
      reporter gene confirmed that C/EBPalpha can transcriptionally activate the RAP
      promoter up to 50-fold. Although RAP had no effect on its own promoter by itself,
      the addition of RAP and C/EBPalpha together resulted in a threefold increase in
      activity over that obtained with C/EBPalpha alone. Importantly, the introduction
      of exogenous Flag-tagged C/EBPalpha triggered RAP expression in BCBL-1 cells
      latently infected with KSHV, as detected by both reverse transcription-PCR and
      double-label immunofluorescence assay analyses, suggesting the presence of a self
      reinforcing loop with C/EBPalpha and RAP activating each other. The RAP promoter
      can also be activated 50- to 120-fold by the KSHV lytic-cycle-triggering protein
      known as replication and transcription activator (RTA). C/EBPalpha and RTA
      together cooperated to elevate RAP promoter activity four- to sixfold more than
      either alone. Furthermore, the addition of RAP, C/EBPalpha, and RTA in LUC
      reporter cotransfection assays resulted in 7- to 15-fold more activation than
      that seen with either C/EBPalpha or RTA alone. Site-specific mutational analysis
      of the RAP promoter showed that the strong C/EBP binding site is crucial for
      C/EBPalpha-mediated transactivation of the RAP promoter. However, the C/EBP
      binding site also overlaps the previously reported 16-bp RTA-responsive element
      (RRE), and the same mutation also both reduced RTA-mediated transactivation and
      abolished the cooperativity between C/EBPalpha and RTA. Furthermore, in vitro
      translated RTA, although capable of binding directly to the polyadenylated
      nuclear RNA (PAN) RRE motif, failed to bind to the RAP RRE and interfered with
      RRE-bound C/EBPalpha in EMSA experiments. Partial RTA responsiveness but no
      cooperativity could be transferred to a heterologous promoter containing added
      consensus C/EBP binding sites. A chromatin immunoprecipitation assay showed that
      all three proteins associated specifically with RAP promoter DNA in vivo and
      that, when C/EBPalpha was removed from a tetradecanoyl phorbol acetate-treated
      JSC-1 primary effusion lymphoma cell lysate, the levels of association of RTA and
      RAP with the RAP promoter were reduced 3- and 13-fold, respectively. Finally, RTA
      also proved to physically interact with both C/EBPalpha and RAP, as assayed both
      in vitro and by immunoprecipitation. Binding to C/EBPalpha occurred within the N
      terminal DNA binding domain of RTA, and deletion of a 17-amino-acid basic motif
      of RTA abolished both the C/EBPalpha and DNA binding activities as well as all
      RTA transactivation and the cooperativity with C/EBPalpha. Therefore, we suggest
      that RTA transactivation of the RAP RRE is mediated by an interaction with DNA
      bound C/EBPalpha but that full activity requires more than just the core C/EBP
      binding site.

PMID- 12477865
TI  - Disruption of CCL21-induced chemotaxis in vitro and in vivo by M3, a chemokine
      binding protein encoded by murine gammaherpesvirus 68.
AB  - Chemokine-binding proteins represent a novel class of antichemokine agents
      encoded by poxviruses and herpesviruses. One such protein is encoded by the M3
      gene present in the murine gammaherpesvirus 68 (MHV-68) genome. The M3 gene
      encodes a secreted 44-kDa protein that binds with high affinity to certain murine
      and human chemokines and has been shown to block chemokine signaling in vitro.
      However, there has been no direct evidence that M3 blocks chemokine activity in
      vivo, nor has the nature of M3-chemokine interaction been defined. To better
      understand the ability of M3 to block chemokine activity in vivo, we examined its
      interaction with a specific subset of chemokines expressed in lymphoid tissues,
      areas where gammaherpesviruses characteristically establish latency. Here we show
      that M3 blocks in vitro chemotaxis induced by CCL19 and CCL21, chemokines
      expressed constitutively in secondary lymphoid tissues. Moreover, we provide
      evidence that chemokine M3 binding exhibits positive cooperativity. In vivo, the
      expression of M3 in the pancreas of transgenic mice inhibits recruitment of
      lymphocytes induced by transgenic expression of CCL21 in this organ. The ability
      of M3 to block the biological activity of chemokines may represent an important
      strategy used by MHV-68 to evade immune detection and favor viral replication in
      the infected host.

PMID- 12477866
TI  - Disruption of mitochondrial networks by the human cytomegalovirus UL37 gene
      product viral mitochondrion-localized inhibitor of apoptosis.
AB  - By 24 h after infection with human cytomegalovirus, the reticular mitochondrial
      network characteristic of uninfected fibroblasts was disrupted as mitochondria
      became punctate and dispersed. These alterations were associated with expression
      of the immediate-early (alpha) antiapoptotic UL37x1 gene product viral
      mitochondrion-localized inhibitor of apoptosis (vMIA). Similar alterations in
      mitochondrial morphology were induced directly by vMIA in transfected cells. A 68
      amino-acid antiapoptotic derivative of vMIA containing the mitochondrial
      localization and antiapoptotic domains also induced disruption, whereas a mutant
      lacking the antiapoptotic domain failed to cause disruption. These data suggest
      that the fission and/or fusion process that normally controls mitochondrial
      networks is altered by vMIA. Mitochondrial fission has been implicated in the
      induction of apoptosis and vMIA-mediated inhibition of apoptosis may occur
      subsequent to this event.

PMID- 12477867
TI  - Fine mapping of the interaction of neutralizing and nonneutralizing monoclonal
      antibodies with the CD4 binding site of human immunodeficiency virus type 1
      gp120.
AB  - Alanine scanning mutagenesis was performed on monomeric gp120 of human
      immunodeficiency virus type 1 to systematically identify residues important for
      gp120 recognition by neutralizing and nonneutralizing monoclonal antibodies
      (MAbs) to the CD4 binding site (CD4bs). Substitutions that affected the binding
      of broadly neutralizing antibody b12 were compared to substitutions that affected
      the binding of CD4 and of two nonneutralizing anti-CD4bs antibodies (b3 and b6)
      with affinities for monomeric gp120 comparable to that of b12. Not surprisingly,
      the sensitivities to a number of amino acid changes were similar for the MAbs and
      for CD4. However, in contrast to what was seen for the MAbs, no enhancing
      mutations were observed for CD4, suggesting that the virus has evolved toward an
      optimal gp120-CD4 interaction. Although the epitope maps of the MAbs overlapped,
      a number of key differences between b12 and the other two antibodies were
      observed. These differences may explain why b12, in contrast to nonneutralizing
      antibodies, is able to interact not only with monomeric gp120 but also with
      functional oligomeric gp120 at the virion surface. Neutralization assays
      performed with pseudovirions bearing envelopes from a selection of alanine
      mutants mostly showed a reasonable correlation between the effects of the
      mutations on b12 binding to monomeric gp120 and neutralization efficacy. However,
      some mutations produced an effect on b12 neutralization counter to that predicted
      from gp120 binding data. It appears that these mutations have different effects
      on the b12 epitope on monomeric gp120 and functional oligomeric gp120. To
      determine whether monomeric gp120 can be engineered to preferentially bind MAb
      b12, recombinant gp120s were generated containing combinations of alanine
      substitutions shown to uniquely enhance b12 binding. Whereas b12 binding was
      maintained or increased, binding by five nonneutralizing anti-CD4bs MAbs (b3, b6,
      F105, 15e, and F91) was reduced or completely abolished. These reengineered
      gp120s are prospective immunogens that may prove capable of eliciting broadly
      neutralizing antibodies.

PMID- 12477868
TI  - Structure of isolated nucleocapsids from venezuelan equine encephalitis virus and
      implications for assembly and disassembly of enveloped virus.
AB  - Venezuelan equine encephalitis virus (VEEV) is an important human and equine
      pathogen in the Americas, with widespread reoccurring epidemics extending from
      South America to the southern United States. Most troubling, VEEV has been made
      into a weapon by several countries and is currently restricted by the Centers for
      Disease Control and Prevention as a potential biological warfare and terrorism
      agent. To facilitate the development of antiviral compounds, the structure of the
      nucleocapsid isolated from VEEV has been determined by electron cryomicroscopy
      and image reconstruction and represents the first three-dimensional structure of
      a nucleocapsid isolated from a single-stranded enveloped RNA virus. The isolated
      VEEV nucleocapsid undergoes significant reorganization relative to its structure
      within VEEV. However, the isolated nucleocapsid clearly exhibits T=4 icosahedral
      symmetry, and its characteristic nucleocapsid hexons and pentons are preserved.
      The diameter of the isolated nucleocapsid is approximately 11.5% larger than that
      of the nucleocapsid within VEEV, with radial expansion being greatest near the
      hexons. Significantly, this is the first direct structural evidence showing that
      a simple enveloped virus undergoes large conformational changes during
      maturation, suggesting that the lipid bilayer and the transmembrane proteins of
      simple enveloped viruses provide the energy necessary to reorganize the
      nucleocapsid during maturation.

PMID- 12477869
TI  - Regulation of human polyomavirus JC virus gene transcription by AP-1 in glial
      cells.
AB  - The activating transcription factor 1 (AP-1) family of proteins consists of a
      large number of inducible factors that are implicated in many biological
      processes, including cellular and viral gene expression, cell proliferation,
      differentiation, and tumorigenesis. Here, we investigated the role of the AP-1
      family members c-Jun and c-Fos in transcriptional regulation of the JC virus
      (JCV) promoter in glial cells. DNA binding studies demonstrated the specific
      association of c-Jun with its DNA sequences corresponding to the AP-1 site within
      the JCV promoter. Functional analysis of the promoter showed that ectopic
      expression of c-Jun and c-Fos results in an additive activation of the JCV early
      and late promoters. Further functional assays indicated that the JCV AP-1 binding
      site is sufficient to confer responsiveness to both c-Jun/c-Fos- and UV-induced
      activation when transposed to a heterologous promoter. Analysis of c-Jun
      expression during the viral infection cycle by Western blotting revealed that c
      Jun is posttranslationally modified by phosphorylation and its protein level is
      substantially increased at the late phases of infection cycle. Altogether, our
      findings indicate that AP-1 family members may play a role in the pathogenesis of
      JCV-induced disease in the human brain by modulating JCV gene transcription.

PMID- 12477871
TI  - Identification and characterization of a new class of human immunodeficiency
      virus type 1 recombinants comprised of two circulating recombinant forms,
      CRF07_BC and CRF08_BC, in China.
AB  - We identified a new class of human immunodeficiency virus type 1 (HIV-1)
      recombinants (00CN-HH069 and 00CN-HH086) in which further recombination occurred
      between two established circulating recombinant forms (CRFs). These two isolates
      were found among 57 HIV-1 samples from a cohort of injecting drug users in
      eastern Yunnan Province of China. Informative-site analysis in conjunction with
      bootscanning plots and exploratory tree analysis revealed that these two strains
      were closely related mosaics comprised of CRF07_BC and CRF08_BC, which are found
      in China. The genotype screening based on gag-reverse transcriptase sequences of
      57 samples from eastern Yunnan identified 47 CRF08_BC specimens (82.5%), 5
      CRF07_BC specimens (8.8%), and 3 additional specimens with the novel recombinant
      structure. These new "second-generation" recombinants thus constitute a
      substantial proportion (5 of 57; 8.8%) of HIV-1 strains in this population and
      may belong to a new but yet-undefined class of CRF. This might be the first
      example of CRFs recombining with each other, leading to the evolution of second
      generation inter-CRF recombinants.

PMID- 12477870
TI  - The ND10 component promyelocytic leukemia protein relocates to human
      papillomavirus type 1 E4 intranuclear inclusion bodies in cultured keratinocytes
      and in warts.
AB  - Human papillomavirus type 1 (HPV1) E4 protein is associated with cytoplasmic and
      nuclear inclusions in productively infected keratinocytes. Here we have used
      transient expression of HPV1 E4 (also known as E1E4) protein in keratinocytes to
      reproduce formation of E4 inclusions. Immunofluorescence analysis showed that
      progressive formation of inclusions correlated with diminished colocalization
      between E4 and keratin intermediate filaments (IFs). Our results support a model
      in which the HPV1 E4-keratin IF association is transient, occurring only at an
      early stage of inclusion formation. We also demonstrate that E4 induces
      relocation of the promyelocytic leukemia protein (PML) from multiple intranuclear
      speckles (ND10 bodies) to the periphery of nuclear E4 inclusions and that this
      activity is specific to full-length E4 protein. Analysis of HPV1-induced warts
      demonstrated that nuclear PML-E4 inclusions were present in productively infected
      keratinocytes, indicating that reorganization of PML occurs during the virus's
      replication cycle. It has been suggested that ND10 bodies are the sites for
      papillomavirus genome replication and virion assembly. Our finding that E4
      induces reorganization of ND10 bodies in vitro and in vivo is further strong
      evidence that these domains play an important role in the papillomavirus life
      cycle. This study indicates that HPV1 is analogous to other DNA viruses that
      disrupt or reorganize ND10 domains, possibly to increase efficiency of virus
      infection. We hypothesize that HPV1 E4-induced reorganization of PML is necessary
      for efficient replication of the virus during the virus-producing phase.

PMID- 12477872
TI  - Contribution of the zinc finger to zinc and DNA binding by a suppressor of
      posttranscriptional gene silencing.
AB  - The zinc finger C(36)-X1-C(38)-X7-C(46)-X6-H(53) of the nuclearly localized C2
      protein of Tomato yellow leaf curl virus China is involved in pathogenicity and
      suppression of posttranscriptional gene silencing (PTGS). Here, we demonstrate
      that the zinc finger is indispensable for the C2 protein to bind zinc and DNA.
      Mutation of cysteine residue C(36), C(38), or C(46) reduced the zinc and DNA
      binding capacity of C2 protein. When expressed from potato virus X, all three
      mutants, C2-C(36)R, C2-C(38)N, and C2-C(46)I, tagged with a green fluorescent
      protein (GFP) were still capable of transporting GFP into but aggregated
      abnormally in nuclei. Our data establish that zinc- and DNA-binding activity
      correlates with C2-mediated pathogenesis and PTGS suppression.

PMID- 12477873
TI  - Responses of herpes simplex virus type 1-infected cells to the presence of
      extracellular antibodies: gE-dependent glycoprotein capping and enhancement in
      cell-to-cell spread.
AB  - Binding of anti-herpes simplex virus (HSV) immunoglobulin G (IgG) to HSV type 1
      (HSV-1)-infected HEL and HEp-2 cells causes changes in surface viral glycoprotein
      distribution, resulting in a capping of all viral glycoproteins towards one pole
      of the cell. This occurs in a gE-dependent manner. In HEL cells, low
      concentrations of anti-HSV IgG also enhance cell-to-cell spread of wild-type HSV
      1 but not of gE deletion mutant HSV-1. These observations raised the possibility
      that gE-dependent mechanisms exist that allow some HSV-1-infected cells to
      respond to the presence of extracellular antibodies by enhancing the antibody
      resistant mode of virus transmission.

PMID- 12477874
TI  - Expression of CXCR4 on feline peripheral blood mononuclear cells: effect of
      feline immunodeficiency virus infection.
AB  - CXCR4 expression on feline peripheral blood mononuclear cells (PBMC) was
      analyzed. While monocytes and B lymphocytes expressed CXCR4, no CXCR4 was
      detected on T lymphocytes, in stark contrast to the expression pattern on T
      lymphocytes from humans. In spite of the important role that CXCR4 plays in
      infection with feline immunodeficiency virus, expression on PBMC in vivo was
      unaffected by infection with either a primary or a cell culture-adapted virus
      strain.

PMID- 12477875
TI  - CD4 binding site antibodies inhibit human immunodeficiency virus gp120 envelope
      glycoprotein interaction with CCR5.
AB  - The human immunodeficiency virus type 1 (HIV-1) gp120 exterior glycoprotein is
      conformationally flexible. Upon binding the host cell receptor, CD4, gp120
      assumes a conformation that is able to bind the chemokine receptors CCR5 or
      CXCR4, which act as coreceptors for the virus. CD4-binding-site (CD4BS)
      antibodies are neutralizing antibodies elicited during natural infection that are
      directed against gp120 epitopes that overlap the binding site for CD4. Recent
      studies (S. H. Xiang et al., J. Virol. 76:9888-9899, 2002) suggest that CD4BS
      antibodies recognize conformations of gp120 distinct from the CD4-bound
      conformation. This predicts that the binding of CD4BS antibodies will inhibit
      chemokine receptor binding. Here, we show that Fab fragments and complete
      immunoglobulin molecules of CD4BS antibodies inhibit CD4-independent gp120
      binding to CCR5 and cell-cell fusion mediated by CD4-independent HIV-1 envelope
      glycoproteins. These results are consistent with a model in which the binding of
      CD4BS antibodies limits the ability of gp120 to assume a conformation required
      for coreceptor binding.

PMID- 12477876
TI  - Blotched snakehead virus is a new aquatic birnavirus that is slightly more
      related to avibirnavirus than to aquabirnavirus.
AB  - By different approaches, we characterized the birnavirus blotched snakehead virus
      (BSNV). The sequence of genomic segment A revealed the presence of two open
      reading frames (ORFs): a large ORF with a 3,207-bp-long nucleotide sequence and a
      417-nucleotide-long small ORF located within the N-terminal half of the large
      ORF, but in a different reading frame. The large ORF was found to encode a
      polyprotein cotranslationally processed by the viral protease VP4 to generate
      pVP2 (the VP2 precursor), a 71-amino-acid-long peptide ([X]), VP4, and VP3. The
      two cleavage sites at the [X]-VP4 and VP4-VP3 junctions were identified by N
      terminal sequencing. We showed that the processing of pVP2 generated VP2 and
      several small peptides (amino acids [aa] 418 to 460, 461 to 467, 468 to 474, and
      475 to 486). Two of these peptides (aa 418 to 460 and 475 to 486) were positively
      identified in the viral particles with 10 additional peptides derived from
      further processing of the peptide aa 418 to 460. The results suggest that VP4
      cleaves multiple Pro-X-Ala downward arrow Ala motifs, with the notable exception
      of the VP4-VP3 junction. Replacement of the members of the predicted VP4
      catalytic dyad (Ser-692 and Lys-729) confirmed their indispensability in the
      polyprotein processing. The genomic segment B sequence revealed a single large
      ORF encoding a putative polymerase, VP1. Our results demonstrate that BSNV should
      be considered a new aquatic birnavirus species, slightly more related to IBDV
      than to IPNV.

PMID- 12477877
TI  - Human and simian immunodeficiency virus capsid proteins are major viral
      determinants of early, postentry replication blocks in simian cells.
AB  - The cells of most Old World monkey species exhibit early, postentry restrictions
      on infection by human immunodeficiency virus type 1 (HIV-1) but not by simian
      immunodeficiency virus of macaques (SIV(mac)). Conversely, SIV(mac), but not HIV
      1, infection is blocked in most New World monkey cells. By using chimeric HIV
      1/SIV(mac) viruses capable of a single round of infection, we demonstrated that a
      major viral determinant of this restriction is the capsid (CA) protein. The
      efficiency of early events following HIV-1 and SIV(mac) entry is apparently
      determined by the interaction of the incoming viral CA and species-specific host
      factors.

PMID- 12477878
TI  - Identification of a novel tripartite complex involved in replication of vesicular
      stomatitis virus genome RNA.
AB  - Our laboratory's recent observations that transcriptionally inactive
      phosphoprotein (P) mutants can efficiently function in replicating vesicular
      stomatitis virus (VSV) defective interfering particle in a three-plasmid-based
      (L, P, and N) reverse genetics system in vivo (A. K. Pattnaik, L. Hwang, T. Li,
      N. Englund, M. Mathur, T. Das, and A. K. Banerjee, J. Virol. 71:8167-8175, 1997)
      led us to propose that a tripartite complex consisting of L-(N-P) protein may
      represent the putative replicase for synthesis of the full-length genome RNA. In
      this communication we demonstrate that such a complex is indeed detectable in VSV
      infected BHK cells. Furthermore, coexpression of L, N, and P proteins in Sf21
      insect cells by recombinant baculovirus containing the respective genes also
      resulted in the formation of a tripartite complex, as shown by
      immunoprecipitation with specific antibodies. A basic amino acid mutant of P
      protein, P260A, previously shown to be inactive in transcription but active in
      replication (T. Das, A. K. Pattnaik, A. M. Takacs, T. Li, L. N. Hwang, and A. K.
      Banerjee, Virology 238:103-114, 1997) was also capable of forming the mutant [L
      (N-Pmut)] complex in both insect cells and BHK cells. Sf21 extract containing
      either the wild-type P protein or the mutant P protein along with the L and N
      proteins was capable of synthesizing 42S genome-sense RNA in an in vitro
      replication reconstitution reaction. Addition of N-Pmut or wild-type N-P complex
      further stimulated the synthesis of the genome-length RNA. These results indicate
      that the transcriptase and replicase complexes of VSV are possibly two distinct
      entities involved in carrying out capped mRNAs and uncapped genome and antigenome
      RNAs, respectively.

PMID- 12477879
TI  - G100R mutation within 4070A murine leukemia virus Env increases virus receptor
      binding, kinetics of entry, and viral transduction efficiency.
AB  - Passage of 4070A murine leukemia virus (MuLV) in D17 cells resulted in a G-to-R
      change at position 100 within the VRA of the envelope protein (Env). Compared
      with 4070A MuLV, virus with the G100R Env displayed enhanced binding on target
      cells, internalized the virus more rapidly, and increased the overall viral titer
      in multiple cell types. This provides a direct correlation between binding
      strength and efficiency of viral entry. Deletion of a His residue at the SU N
      terminus eliminated the transduction efficiency by the G100R virus, suggesting
      that the G100R virus maintains the regulatory characteristics of 4070A viral
      entry. The improved transduction efficiency of G100R Env would be an asset for
      gene delivery systems.

PMID- 12477880
TI  - Partial molecular characterization of two simian immunodeficiency viruses (SIV)
      from African colobids: SIVwrc from Western red colobus (Piliocolobus badius) and
      SIVolc from olive colobus (Procolobus verus).
AB  - In order to study primate lentivirus evolution in the Colobinae subfamily, in
      which only one simian immunodeficiency virus (SIV) has been described to date, we
      screened additional species from the three different genera of African colobus
      monkeys for SIV infection. Blood was obtained from 13 West African colobids, and
      HIV cross-reactive antibodies were observed in 5 of 10 Piliocolobus badius, 1 of
      2 Procolobus verus, and 0 of 1 Colobus polykomos specimens. Phylogenetic analyses
      of partial pol sequences revealed that the new SIVs were more closely related to
      each other than to the other SIVs and especially did not cluster with the
      previously described SIVcol from Colobus guereza. This study presents evidence
      that the three genera of African colobus monkeys are naturally infected with an
      SIV and indicates also that there was no coevolution between virus and hosts at
      the level of the Colobinae subfamily.

PMID- 12477881
TI  - Receptor usage and fetal expression of ovine endogenous betaretroviruses:
      implications for coevolution of endogenous and exogenous retroviruses.
AB  - Betaretroviruses of sheep include two exogenous viruses, Jaagsiekte sheep
      retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), and a group of
      endogenous viruses known as enJSRVs. The exogenous JSRV and ENTV are the
      etiological agents of ovine pulmonary adenocarcinoma (OPA) and enzootic nasal
      tumor (ENT), respectively. Sheep affected by OPA or ENT do not show an
      appreciable antibody response to JSRV or ENTV. Consequently, it is conceivable
      that enJSRV expression in the fetal lamb tolerizes sheep to the related exogenous
      viruses. In this study, possible mechanisms of interference between the sheep
      exogenous and endogenous betaretroviruses were investigated. In situ
      hybridization detected enJSRV RNAs in lymphoid cells associated with the lamina
      propria of the small intestine and in the thymus of sheep fetuses. Low-level
      expression of enJSRVs was also detected in the lungs. In addition, expression of
      enJSRVs was found to block entry of the exogenous JSRV, presumably via mechanisms
      of receptor interference. Indeed, enJSRVs, like JSRV and ENTV, were found to
      utilize hyaluronidase-2 as a cellular receptor.

PMID- 12477882
TI  - Functional replacement of nucleocapsid flanking regions by heterologous
      counterparts with divergent primary sequences: effects of chimeric nucleocapsid
      on the retroviral replication cycle.
AB  - Nucleocapsid (NC) proteins in most retroviruses have a well-conserved Cys-His
      box(es) as well as more divergent flanking regions that are rich in basic
      residues. Mutations in the flanking regions can affect RNA packaging, virus
      assembly, and reverse transcription of the viral RNA. To gain a further
      understanding of the roles of NC flanking regions in the retroviral replication
      cycle, we generated and characterized chimeric gag-pol expression constructs
      derived from murine leukemia virus and spleen necrosis virus by replacing an NC
      flanking region from one virus with the counterpart from the other virus. We
      found that all four chimeras were able to generate virions, package viral RNA,
      and complete the viral replication cycle. Two chimeras had mild defects in virus
      assembly that correlated with a decrease in the isoelectric points of NCs,
      suggesting that the basic nature of NC is important in virus assembly. This
      finding indicates that, although the primary sequences of these flanking regions
      have little homology, the heterologous sequences are functional both as part of
      the Gag polyprotein and as processed NC protein.

PMID- 12477883
TI  - Differential cytokine responses following Marek's disease virus infection of
      chickens differing in resistance to Marek's disease.
AB  - The production of cytokine mRNAs, in addition to viral DNA, was quantified by
      real-time quantitative reverse transcription-PCR (RT-PCR) (cytokines) or PCR
      (virus) in splenocytes during the course of Marek's disease virus (MDV) infection
      in four inbred chicken lines: two resistant (lines 6(1) and N) and two
      susceptible (lines 7(2) and P). Virus loads were only different after 10 days
      postinfection (dpi), increasing in susceptible lines and decreasing in resistant
      lines. Gamma interferon (IFN-gamma) mRNA was expressed by splenocytes from all
      infected birds between 3 and 10 dpi, associated with increasing MDV loads. For
      other cytokines, differences between lines were only seen for interleukin-6 (IL
      6) and IL-18, with splenocytes from susceptible birds expressing high levels of
      both transcripts during the cytolytic phase of infection, whereas splenocytes
      from resistant birds expressed neither transcript. These results indicate that
      these two cytokines could play a crucial role in driving immune responses, which
      in resistant lines maintain MDV latency but in susceptible lines result in
      lymphomas.

PMID- 12477884
TI  - Rice grassy stunt tenuivirus nonstructural protein p5 interacts with itself to
      form oligomeric complexes in vitro and in vivo.
AB  - We investigated the interaction of Rice grassy stunt tenuivirus (RGSV)
      nonstructural protein p5, a protein of 22 kDa encoded on vRNA 5, with all 12 RGSV
      proteins by using a GAL4 transcription activator-based yeast two-hybrid system.
      The p5 protein interacted only with itself and not with any other viral protein;
      the interacting domains were localized within the N-terminal 96 amino acids of
      p5. The p5-p5 interaction was reproduced in an Sos recruitment-mediated yeast two
      hybrid system as well in by far-Western blots. Native p5 protein extracted from
      RGSV-infected rice tissue was detected in a large complex with a molecular mass
      of approximately 260 kDa composed of 12 molecules of p5 or a p5 oligomer with an
      unidentified host factor(s).

PMID- 12477885
TI  - Evidence for packaging of rep-cap sequences into adeno-associated virus (AAV)
      type 2 capsids in the absence of inverted terminal repeats: a model for
      generation of rep-positive AAV particles.
AB  - We previously reported that a 350-bp region of the adeno-associated virus (AAV)
      type 2 rep gene contains a cis-acting element responsible for the Rep-dependent
      replication of a transiently transfected rep-cap plasmid. In this study, we
      further report that replicated rep-cap sequences can be packaged into AAV capsids
      in the absence of the inverted terminal repeats.

PMID- 12477886
TI  - Divergent simian T-cell lymphotropic virus type 3 (STLV-3) in wild-caught Papio
      hamadryas papio from Senegal: widespread distribution of STLV-3 in Africa.
AB  - Among eight samples obtained from a French primatology research center, six adult
      guinea baboons (Papio hamadryas papio), caught in the wild in Senegal, had a
      peculiar human T-cell leukemia virus type 2 (HTLV-2)-like Western blot
      seroreactivity (p24(+), GD21(+), K55(+/-)). Partial sequence analyses of the tax
      genes (433 bp) indicated that these baboons were infected by a novel divergent
      simian T-cell lymphotropic virus (STLV). Analyses of the complete proviral
      sequence (8,892 bp) for one of these strains (STLV-3/PPA-F3) indicate that this
      STLV was highly divergent from the HTLV-1 (61.6% of nucleotide similarity), HTLV
      2 (61.2%), or STLV-2 (60.6%) prototype. It was, however, much more closely
      related to the few other known STLV-3 strains, exhibiting 87 and 89% of
      nucleotide similarity with STLV-3/PHA-PH969 (formerly PTLV-L/PH969) and STLV
      3/CTO-604, respectively. The STLV-3/PPA-F3 sequence possesses the major HTLV or
      STLV open reading frames corresponding to the structural, enzymatic, and
      regulatory proteins. However, its long terminal repeat comprises only two 21-bp
      repeats. In all phylogenetic analyses, STLV-3/PPA-F3 clustered together in a
      highly supported single clade with the other known strains of STLV-3, indicating
      an independent evolution from primate T-cell lymphotropic virus type 1 (PTLV-1)
      and PTLV-2. The finding of a new strain of STLV-3 in a West African monkey
      (Guinea baboon) greatly enlarges the geographical distribution and the host range
      of species infected by this PTLV type in the African continent. The recent
      discovery of several different STLV-3 strains in many different African monkey
      species, often in contact with humans, strongly suggests potential interspecies
      transmission events, as it was described for STLV-1, between nonhuman primates
      but also to humans.

PMID- 12477887
TI  - Poliovirus-induced apoptosis is reduced in cells expressing a mutant CD155
      selected during persistent poliovirus infection in neuroblastoma cells.
AB  - Poliovirus (PV) can establish persistent infections in human neuroblastoma IMR-32
      cells. We previously showed that during persistent infection, specific mutations
      were selected in the first extracellular domain of the PV receptor (CD155) of
      these cells (N. Pavio, T. Couderc, S. Girard, J. Y. Sgro, B. Blondel, and F.
      Colbere-Garapin, Virology 274:331-342, 2000). These mutations included the Ala 67
      --> Thr substitution, corresponding to a previously described allelic form of the
      PV receptor. The mutated CD155(Thr67) and the nonmutated IMR-32 CD155
      (CD155(IMR)) were expressed independently in murine LM cells lacking the CD155
      gene. Following infection of the cells with PV, we analyzed the death of cells
      expressing these two forms of CD155. Levels of DNA fragmentation, caspase
      activity, and cytochrome c release were lower in LM-CD155(Thr67) cells than in LM
      CD155(IMR) cells. Thus, the level of apoptosis was lower in cells expressing
      mutated CD155 selected during persistent PV infection in IMR-32 than in cells
      expressing the wild-type receptor.

PMID- 12477888
TI  - Overcoming immunity to a viral vaccine by DNA priming before vector boosting.
AB  - Replication-defective adenovirus (ADV) and poxvirus vectors have shown potential
      as vaccines for pathogens such as Ebola or human immunodeficiency virus in
      nonhuman primates, but prior immunity to the viral vector in humans may limit
      their clinical efficacy. To overcome this limitation, the effect of prior viral
      exposure on immune responses to Ebola virus glycoprotein (GP), shown previously
      to protect against lethal hemorrhagic fever in animals, was studied. Prior
      exposure to ADV substantially reduced the cellular and humoral immune responses
      to GP expressed by ADV, while exposure to vaccinia inhibited vaccine-induced
      cellular but not humoral responses to GP expressed by vaccinia. This inhibition
      was largely overcome by priming with a DNA expression vector before boosting with
      the viral vector. Though heterologous viral vectors for priming and boosting can
      also overcome this effect, the paucity of such clinical viral vectors may limit
      their use. In summary, it is possible to counteract prior viral immunity by
      priming with a nonviral, DNA vaccine.

PMID- 12477890
TI  - Small interfering RNA-mediated inhibition of hepatitis C virus replication in the
      human hepatoma cell line Huh-7.

PMID- 12477889
TI  - Genetic interaction between distinct Dobrava hantavirus subtypes in Apodemus
      agrarius and A. flavicollis in nature.
AB  - Dobrava virus (DOBV) occurs in two different rodent species, Apodemus flavicollis
      (DOBV-Af) and A. agrarius (DOBV-Aa). We sequenced the S and M genomic segments
      from sympatric DOBV-Af and DOBV-Aa strains which fell into two distinct genetic
      lineages. Molecular phylogenetic analyses gave evidence for genetic reassortment
      between S and M segments of DOBV-Af and DOBV-Aa and indicated homologous
      recombination events in DOBV evolution. DOBV-Af and DOBV-Aa are distinct but also
      subject to genetic exchanges that affect their evolutionary trajectories.

PMID- 12477892
TI  - Freezing survival and cryoprotective dehydration as cold tolerance mechanisms in
      the Antarctic nematode Panagrolaimus davidi.
AB  - The relative importance of freezing tolerance and cryoprotective dehydration in
      the Antarctic nematode Panagrolaimus davidi has been investigated. If nucleation
      of the medium is initiated at a high subzero temperature (-1 degree C), the
      nematodes do not freeze but dehydrate. This effect occurs in deionised water,
      indicating that the loss of water is driven by the difference in vapour pressure
      of ice and supercooled water at the same temperature. If the nematodes are held
      above their nucleation temperature for a sufficient time, or are cooled slowly,
      enough water is lost to prevent freezing (cryoprotective dehydration). However,
      if the medium is nucleated at lower temperatures or if the sample is cooled at a
      faster cooling rate, the nematodes freeze and can survive intracellular ice
      formation. P. davidi thus has a variety of mechanisms that ensure its survival in
      its harsh terrestrial Antarctic habitat.

PMID- 12477893
TI  - Serotonin regulates repolarization of the C. elegans pharyngeal muscle.
AB  - Caenorhabditis elegans feeds by rhythmically contracting its pharynx to ingest
      bacteria. The rate of pharyngeal contraction is increased by serotonin and
      suppressed by octopamine. Using an electrophysiological assay, we show that
      serotonin and octopamine regulate two additional aspects of pharyngeal behavior.
      Serotonin decreases the duration of the pharyngeal action potential and enhances
      activity of the pharyngeal M3 motor neurons. Gramine, a competitive serotonin
      antagonist, and octopamine have effects opposite to those of serotonin: gramine
      and octopamine increase action potential duration and suppress M3 activity. The
      effects of serotonin, gramine and octopamine on action potential duration are
      dependent on the pharyngeal motor neurons MC and M3. When the MC and M3 motor
      neurons are functionally defective, serotonin and octopamine do not regulate the
      action potential. Our data suggest that serotonin alters pharyngeal physiology to
      allow for rapid contraction-relaxation cycles. Reciprocal regulation of
      pharyngeal behavior by serotonin and octopamine provides a mechanism for adapting
      to the presence and absence of food, respectively.

PMID- 12477894
TI  - The dependence of electrical transport pathways in Malpighian tubules on ATP.
AB  - The relationship between the intracellular ATP concentration [ATP](i) and the
      electrical properties of principal cells was investigated in Malpighian tubules
      of the yellow fever mosquito, Aedes aegypti. Under control conditions, [ATP](i)
      was 0.91 mmol l(-1), the input resistance of the principal cell (R(pc)) was 334.1
      k Omega, and the basolateral membrane was marked by a large K(+)-conductance and
      a membrane voltage (V(bl)) of -75.8 mV. Peritubular cyanide (CN, 0.3 mmol l(-1))
      reduced [ATP](i) to 0.08 mmol l(-1) in less than 2 min; however, V(bl) dropped to
      -8 mV and R(pc) increased to 3150.8 k Omega in 8 min, while the K(+)-conductance
      of the basolateral membrane disappeared. Upon washout of CN, V(bl) and R(pc)
      returned to control values within 2 min, and the basolateral membrane recovered
      its K(+)-conductance. The recovery of normal [ATP](i) took 15 min. Dose
      dependence and EC(50) values for the CN-inhibition of V(bl) and the increase in
      R(pc) were strikingly similar (184.0 micromol l(-1) and 164.4 micromol l(-1)).
      Similar effects of metabolic inhibition were observed with dinitrophenol (DNP),
      but the EC(50) values were 50.3 micromol l(-1) and 71.7 micromol l(-1) for the
      effects on V(bl) and R(pc), respectively. Barium, a blocker of K(+)-channels,
      significantly hyperpolarized V(bl) to -89.1 mV and increased R(pc) to 769.4 k
      Omega under control conditions, but had no effects during metabolic inhibition.
      These results illustrate a temporal relationship between [ATP](i) and
      electrogenic and conductive transport pathways in principal cells that is
      consistent with the role of ATP as an integrator of transport steps at apical and
      basolateral membranes of the cell. When [ATP](i) drops to levels that are 10% of
      control, the V-type H(+)-ATPase is inhibited, preventing the extrusion of K(+) to
      the tubule lumen. At the same time, basolateral membrane K(+)-channels close,
      preventing the entry of K(+) from the hemolymph. Intracellular K(+) homeostasis
      is thus protected during metabolic inhibition, allowing the cell to re-establish
      K(+) transport when ATP is synthesized again.

PMID- 12477895
TI  - K+ amino acid transporter KAAT1 mutant Y147F has increased transport activity and
      altered substrate selectivity.
AB  - KAAT1, a K(+)-coupled, neutral amino acid transporter from larval insect midgut,
      differs from other members of the Na(+):neurotransmitter transporter family (SNF)
      in two important ways: (1) it transports nutrient L-, alpha-amino acids, rather
      than neurotransmitters such as gamma-aminobutyric acid (GABA), and (2) it accepts
      K(+) as well as Na(+) as a co-substrate. To determine whether the restoration of
      KAAT1 residues to their GABA transporter GAT1 cation-binding equivalents might
      abolish its K(+) but not its Na(+) recognition site, we constructed a multiple
      mutant in which nine divergent KAAT1 residues were mutated back to the conserved
      form of the superfamily. To investigate the amino-acid-binding site, we
      constructed several single mutants that had been identified in GAT1. Wild-type
      (WT) or mutant cRNA was injected into Xenopus oocytes and the effects of external
      amino acids and ions upon labeled leucine uptake and substrate-induced currents
      were examined. The multiple mutant exhibited no amino-acid-induced currents,
      indicating that one or more of the mutated residues are crucial for function.
      W75L and R76E mutations in the first transmembrane helix of KAAT1 led to results
      equivalent to those observed in the corresponding mutants of GAT1; namely,
      substrate (leucine) uptake and substrate-evoked net inward current were severely
      curtailed. The KAAT1 A523S mutant, which corresponds to a serotonin transporter
      mutant that is thought to render Li(+) equivalent to Na(+) as a co-transported
      ion, functioned no differently to WT. The effects of mutation Y147F in the third
      transmembrane helix of KAAT1 were dramatically different from the equivalent
      mutation, Y140F, in GAT1. Although kinetic characteristics, expression levels and
      plasma membrane localization were all similar in Y147F and WT, the Y147F mutant
      exhibited a sevenfold increase in labeled leucine uptake by Xenopus oocytes in
      Na(+) buffer. This increase is in sharp contrast to the complete loss of uptake
      activity in the GAT1 Y140F mutant. KAAT1 Y147F also differed from WT in cation
      selectivity and substrate spectrum, as revealed by amino-acid-induced net inward
      currents that were measured with a two-electrode voltage clamp. Amino-acid
      independent currents induced by Li(+) and Na(+) chloride salts were observed in
      both WT and the Y147F mutant. The Li(+)-induced current was 30% higher in Y147F
      than in WT, whereas no substrate-independent K(+)-induced currents above control
      levels were detected either in WT or Y147F. These results suggest that transport
      of K(+), the physiological co-substrate in insect midgut, is tightly coupled to
      that of amino acids in KAAT1, in contrast to the independence of cation and amino
      acid transport in the closely related cation amino acid transporter channel,
      CAATCH1.

PMID- 12477896
TI  - Copepod feeding currents: flow patterns, filtration rates and energetics.
AB  - Particle image velocimetry was used to construct a quasi 3-dimensional image of
      the flow generated by the feeding appendages of the calanoid copepod Temora
      longicornis. By scanning layers of flow, detailed information was obtained on
      flow velocity and velocity gradients. The flow around feeding T. longicornis was
      laminar, and was symmetrical viewed dorsally, but highly asymmetrical viewed
      laterally, with high levels of vorticity on the ventral side. The flow rate
      through the feeding appendages varied between 77 and 220 ml day(-1) per
      individual. The morphology of the flow field ensured that water was entrained
      over the full length of the first antennae. These were kept out of areas with
      high velocity gradients that could interfere with distant mechano- or
      chemoreception. The volume of influence, i.e. the volume of water around the
      foraging copepod, where shear rates were significantly higher than background
      levels, was calculated. Implications for encounter probability and
      mechanoreception are discussed. The average rate of energy dissipation within the
      copepod's volume of influence is several times higher than the levels of
      turbulent energy dissipation these animals are likely to encounter in their
      environment. Even in highly turbulent environments, adult T. longicornis will not
      experience very significant effects of turbulence. Within the volume of influence
      of the copepods the energy dissipation due to viscous friction varied between 6.6
      x 10(-11) and 2.3 x 10(-10)W. Taking mechanical efficiency and muscle efficiency
      into account, this results in a total energetic cost of the feeding current of
      1.6 x 10(-9)W per copepod. This value represents only a small percentage of the
      total energy budget of small calanoid copepods.

PMID- 12477897
TI  - Escape from viscosity: the kinematics and hydrodynamics of copepod foraging and
      escape swimming.
AB  - Feeding and escape swimming in adult females of the calanoid copepod Temora
      longicornis Muller were investigated and compared. Swimming velocities were
      calculated using a 3-D filming setup. Foraging velocities ranged between 2 and 6
      mm s(-1), while maximum velocities of up to 80 mm s(-1) were reached during
      escape responses. Foraging took place at Reynolds numbers between 2 and 6,
      indicating that viscous forces are considerable during this swimming mode.
      Inertial forces are much more important during escape responses, when Reynolds
      numbers of more than 100 are reached. High-speed film recordings at 500 frames s(
      1) of the motion pattern of the feeding appendages and the escape movement of the
      swimming legs revealed that the two swimming modes are essentially very
      different. While foraging, the first three mouth appendages (antennae, mandibular
      palps and maxillules) create a backwards motion of water with a metachronal
      beating pattern. During escape movements the mouth appendages stop moving and the
      swimming legs beat in a very fast metachronal rhythm, accelerating a jet of water
      backwards. The large antennules are folded backwards, resulting in a streamlined
      body shape. Particle image velocimetry analysis of the flow around foraging and
      escaping copepods revealed that during foraging an asymmetrical vortex system is
      created on the ventral side of the animal. The feeding motion is steady over a
      long period of time. The rate of energy dissipation due to viscous friction
      relates directly to the energetic cost of the feeding current. During escape
      responses a vortex ring appears behind the animal, which dissipates over time.
      Several seconds after cessation of swimming leg movements, energy dissipation can
      still be measured. During escape responses the rate of energy dissipation due to
      viscous friction increases by up to two orders of magnitude compared to the rate
      when foraging.

PMID- 12477898
TI  - Auditory encoding during the last moment of a moth's life.
AB  - The simple auditory system of noctuoid moths has long been a model for anti
      predator studies in neuroethology, although these ears have rarely been
      experimentally stimulated by the sounds they would encounter from naturally
      attacking bats. We exposed the ears of five noctuoid moth species to the pre
      recorded echolocation calls of an attacking bat (Eptesicus fuscus) to observe the
      acoustic encoding of the receptors at this critical time in their defensive
      behaviour. The B cell is a non-tympanal receptor common to all moths that has
      been suggested to respond to sound, but we found no evidence of this and suggest
      that its acoustic responsiveness is an artifact arising from its proprioceptive
      function. The A1 cell, the most sensitive tympanal receptor in noctuid and
      arctiid moths and the only auditory receptor in notodontid moths, encodes the
      attack calls with a bursting firing pattern to a point approximately 150 ms from
      when the bat would have captured the moth. At this point, the firing of the A1
      cell reduces to a non-bursting pattern with longer inter-spike periods,
      suggesting that the moth may no longer express the erratic flight used to escape
      very close bats. This may be simply due to the absence of selection pressure on
      moths for auditory tracking of bat echolocation calls beyond this point.
      Alternatively, the reduced firing may be due to the acoustic characteristics of
      attack calls in the terminal phase and an acoustic maneuver used by the bat to
      facilitate its capture of the moth. Although the role of less sensitive A2 cell
      remains uncertain in the evasive flight responses of moths it may act as a
      trigger in eliciting sound production, a close-range anti-bat behaviour in the
      tiger moth, Cycnia tenera.

PMID- 12477899
TI  - A comparison of visual and haltere-mediated equilibrium reflexes in the fruit fly
      Drosophila melanogaster.
AB  - Flies exhibit extraordinary maneuverability, relying on feedback from multiple
      sensory organs to control flight. Both the compound eyes and the mechanosensory
      halteres encode angular motion as the fly rotates about the three body axes
      during flight. Since these two sensory modalities differ in their mechanisms of
      transduction, they are likely to differ in their temporal responses. We recorded
      changes in stroke kinematics in response to mechanical and visual rotations
      delivered within a flight simulator. Our results show that the visual system is
      tuned to relatively slow rotation whereas the haltere-mediated response to
      mechanical rotation increases with rising angular velocity. The integration of
      feedback from these two modalities may enhance aerodynamic performance by
      enabling the fly to sense a wide range of angular velocities during flight.

PMID- 12477900
TI  - Tissue-specific expression of inducible and constitutive Hsp70 isoforms in the
      western painted turtle.
AB  - Expression of Hsp73 and Hsp72 in four tissues of the naturally anoxia-tolerant
      western painted turtle (Chrysemys picta) was investigated in response to a 24 h
      forced dive and following 1 h recovery. Of the tissues examined, brain and liver
      displayed approximately threefold and sevenfold higher basal Hsp73 expression
      than heart and skeletal muscle. Basal Hsp72 expression was relatively low in all
      tissues examined. After the 24 h forced dive and 1 h recovery, Hsp73 expression
      did not differ significantly from basal expression with the exception of liver,
      where expression decreased significantly after 1 h recovery. Hsp72 expression was
      unchanged in liver following a 24 h dive; however, it increased twofold in brain
      and threefold in heart and skeletal muscle. Dive-induced Hsp72 expression was
      found to correlate inversely with basal Hsp73 expression. Following 1 h recovery,
      Hsp72 expression was significantly elevated in all tissues above levels in dived
      animals. These data indicate a tissue-specific pattern of Hsp73 and Hsp72
      expression in the western painted turtle during both unstressed and stressed
      conditions.

PMID- 12477902
TI  - The hydrodynamics of locomotion at intermediate Reynolds numbers: undulatory
      swimming in ascidian larvae (Botrylloides sp.).
AB  - Understanding how the shape and motion of an aquatic animal affects the
      performance of swimming requires knowledge of the fluid forces that generate
      thrust and drag. These forces are poorly understood for the large diversity of
      animals that swim at Reynolds numbers (Re) between 10(0) and 10(2). We
      experimentally tested quasi-steady and unsteady blade-element models of the
      hydrodynamics of undulatory swimming in the larvae of the ascidian Botrylloides
      sp. by comparing the forces predicted by these models with measured forces
      generated by tethered larvae and by comparing the swimming speeds predicted with
      measurements of the speed of freely swimming larvae. Although both models
      predicted mean forces that were statistically indistinguishable from
      measurements, the quasi-steady model predicted the timing of force production and
      mean swimming speed more accurately than the unsteady model. This suggests that
      unsteady force (i.e. the acceleration reaction) does not play a role in the
      dynamics of steady undulatory swimming at Re approximately 10(2). We explored the
      relative contribution of viscous and inertial force to the generation of thrust
      and drag at 10(0)<Re<10(2) by running a series of mathematical simulations with
      the quasi-steady model. These simulations predicted that thrust and drag are
      dominated by viscous force (i.e. skin friction) at Re approximately 10(0) and
      that inertial force (i.e. form force) generates a greater proportion of thrust
      and drag at higher Re than at lower Re. However, thrust was predicted to be
      generated primarily by inertial force, while drag was predicted to be generated
      more by viscous than inertial force at Re approximately 10(2). Unlike swimming at
      high (>10(2)) and low (<10(0)) Re, the fluid forces that generate thrust cannot
      be assumed to be the same as those that generate drag at intermediate Re.

PMID- 12477901
TI  - Mussel MAP, a major gonad-duct esterase-like protein, is released into sea water
      as a dual constituent of the seminal fluid and the spermatozoon.
AB  - Our interest in the comparative analysis of male reproductive-tract esterases in
      different animal groups has led us to undertake a detailed study of the Mytilus
      galloprovincialis male-associated polypeptide (MAP) throughout the mussel gonad
      duct tract and at spawning. The results of this work indicate that MAP is a major
      protein in M. galloprovincialis semen, with dual presence in both sperm cells and
      cell-free seminal fluid. Shortly after spawning, the released sperm mass is
      subdivided in diffused cloudy-like and thread-shaped 'clots', in which a soluble
      phase MAP may persist as long as the clots keep their compact form. Additional
      experiments involving the incubation of spawned spermatozoa at increasing Triton
      X-100 concentrations demonstrated that MAP is also strongly associated with sperm
      cells. These results were further validated by immunofluorescent staining, which
      revealed that MAP is localized in the mid-piece region of spawned spermatozoa.
      This unexpected finding raises the possibility that MAP may play a role in sperm
      fertility in bivalves. Using whole-mount histology and micromanipulation
      techniques, we studied the structural patterning of the mantle gonad-duct network
      and assessed the sampling of luminal contents from the ducts. Of particular
      interest is the observation that MAP content in the luminal fluid increases from
      the lumen of the spermatogenic tubules to that of the collecting gonad ducts,
      where MAP is detected at a very high concentration. These high levels may lead to
      a significant presence of MAP in semen and consequently to a prolonged survival
      of sperm spawned at sea. In addition, data related to the potential structural
      similarity between mussel MAP and esterase S of the Drosophila virilis
      ejaculatory bulb are presented and discussed. Finally, we show that the 64kDa
      protein of human semen reveals positive cross-reactivity with antibodies directed
      against Mytilus MAP and Drosophila esterase S. Taken together, the results reveal
      mussel MAP as the only esterase-like protein described so far whose distribution
      in the gonad and semen can be specifically associated with maturation, transport,
      emission and survival of spermatozoa outside.

PMID- 12477903
TI  - Visualization of modulatory effects of serotonin in the silkmoth antennal lobe.
AB  - A unique serotonin-immunoreactive neuron innervates every glomerulus of the
      contralateral antennal lobe (AL), the primary olfactory center, of the male
      silkmoth Bombyx mori. In order to examine the possible modulatory effects of
      serotonin in the AL, we utilized high-speed optical imaging with a voltage
      sensitive dye combined with bath application of serotonin. We found that
      serotonin at 10(-4)mol l(-1) caused significant and reversible increases in the
      optical responses in both the macroglomerular complex (MGC) and the ordinary
      glomeruli (Gs) evoked by electrical stimulation of the antennal nerve. Optical
      responses in both the MGC and Gs were also significantly longer lasting following
      serotonin application. Serotonin exerted a significantly greater enhancing effect
      in the toroid glomerulus of the MGC than in the cumulus, and the effects of
      serotonin were also non-homogeneously distributed in the Gs. Our results are
      evidence that serotonin acts in both the MGC and Gs to modulate the responses of
      neuronal populations.

PMID- 12477904
TI  - Endothermic heat production in honeybee winter clusters.
AB  - In order to survive cold northern winters, honeybees crowd tightly together in a
      winter cluster. Present models of winter cluster thermoregulation consider the
      insulation by the tightly packed mantle bees as the decisive factor for survival
      at low temperatures, mostly ignoring the possibility of endothermic heat
      production. We provide here direct evidence of endothermic heat production by
      'shivering' thermogenesis. The abundance of endothermic bees is highest in the
      core and decreases towards the surface. This shows that core bees play an active
      role in thermal control of winter clusters. We conclude that regulation of both
      the insulation by the mantle bees and endothermic heat production by the inner
      bees is necessary to achieve thermal stability in a winter cluster.

PMID- 12477905
TI  - Preferred temperature of juvenile Atlantic cod Gadus morhua with different
      haemoglobin genotypes at normoxia and moderate hypoxia.
AB  - Atlantic cod Gadus morhua has polymorphic haemoglobin, which can be separated
      into two homozygous types, HbI-1 and HbI-2, and one heterozygous type HbI-1/2.
      The geographical distribution of Atlantic cod with the different haemoglobin
      types varies, with the HbI(2) allele occurring at high frequency in northern
      regions, and the HbI(1) allele dominant in warmer areas. To determine if
      temperature is a selective parameter in the distribution of the haemoglobin
      types, the preferred temperature of the homozygous genotypes HbI-1 and HbI-2 was
      measured. We found that HbI-2 cod preferred a temperature of 8.2+/-1.5 degrees C
      while HbI-1 cod preferred 15.4+/-1.1 degrees C, and this preference was
      significant. The effect of hypoxia (35% oxygen saturation) on the preferred
      temperature was also measured. Previous studies showed that the preferred
      temperature of fish decreases during hypoxia, and this was the case for HbI-1
      cod, which preferred 9.8+/-1.8 degrees C during hypoxia, whereas HbI-2 cod did
      not show this effect. The results indicate that environmental temperature changes
      will lead to a distributional change in the different haemoglobin types of
      Atlantic cod, global warming providing an advantage for HbI-1 cod. However, since
      HbI-1 cod prefer a low temperature under hypoxic conditions, a combination of
      increased water temperature and hypoxia could be unfavourable for Atlantic cod
      stocks.

PMID- 12477906
TI  - Quantitative changes in yolk protein and other components in the ovary and testis
      of the sea urchin Pseudocentrotus depressus.
AB  - Both male and female sea urchins accumulate the major yolk protein (MYP; the most
      abundant yolk granule protein in sea urchin eggs) in the nutritive phagocytes of
      immature gonads before gametogenesis. In this study, quantitative changes in MYP
      as well as in other biochemical components in the ovary and testis were examined
      in the course of gametogenesis in Pseudocentrotus depressus. Before
      gametogenesis, both the ovary and testis contained large quantities of proteins,
      lipids and polysaccharides. MYP reached about 80% of total protein in both sexes.
      In the testis, MYP decreased rapidly as spermatogenesis proceeded, and the fully
      mature testis contained little MYP; the levels of lipids and polysaccharides also
      decreased. In contrast, the levels of nucleic acids and proteins other than MYP
      increased markedly. In the ovary, MYP decreased gradually as oogenesis proceeded,
      and the fully mature ovary contained less than half of the initial amount of MYP.
      Polysaccharides also decreased, whereas proteins other than MYP increased. These
      results, taken together with those from other studies, suggest that MYP serves as
      a protein reserve that accumulates before gametogenesis and is used as material
      for synthesizing new substances constituting gametes in both male and female sea
      urchins.

PMID- 12477907
TI  - Adaptive color vision in Pullosquilla litoralis (Stomatopoda, Lysiosquilloidea)
      associated with spectral and intensity changes in light environment.
AB  - Some stomatopod crustacean species that inhabit a range of habitat depths have
      color vision systems that adapt to changes in ambient light conditions. To date,
      this change in retinal function has been demonstrated in species within the
      superfamily Gonodactyloidea in response to varying the spectral range of light.
      Intrarhabdomal filters in certain ommatidia within the specialized midband of the
      eye change spectrally, modifying the sensitivity of underlying photoreceptors to
      match the spectrum of available light. In the present study, we utilized
      Pullosquilla litoralis, a member of the superfamily Lysiosquilloidea that also
      has a wide depth range. Individuals were placed within one of three light
      treatments: (1) full-spectrum, high-intensity 'white' light, (2) narrow-spectrum
      'blue' light and (3) full-spectrum, reduced-intensity 'gray' light. After 3
      months, the intrarhabdomal filters in Row 3 ommatidia of the midband in blue- and
      gray-light-treated animals were short-wavelength shifted by 10-20 nm compared
      with homologous filters in animals in white-light treatments. These spectral
      changes increase the relative sensitivity of associated photoreceptors in animals
      that inhabit environments where light spectral range or intensity is reduced. The
      adaptable color vision system of stomatopods may allow animals to make the best
      use of the ambient light occurring at their habitat regardless of depth. The
      major controlling element of the plasticity in lysiosquilloid stomatopod color
      vision appears to be light intensity rather than spectral distribution.

PMID- 12477908
TI  - Identification of magnetically responsive neurons in the marine mollusc Tritonia
      diomedea.
AB  - Behavioral experiments have demonstrated that the marine mollusc Tritonia
      diomedea can use the Earth's magnetic field as an orientation cue. Little is
      known, however, about the neural mechanisms that underlie magnetic orientation
      behavior in this or any other animal. In previous studies, two neurons in the
      brain of Tritonia, known as LPd5 and RPd5, were shown to respond with enhanced
      electrical activity to changes in earth-strength magnetic fields. We report
      evidence that two additional neurons, known as LPd6 and RPd6, also respond with
      increases in electrical activity when the magnetic field around the animal is
      altered. Anatomical analyses revealed that prominent neurites from the Pd6 cells
      are located within two ipsilateral nerves, pedal nerves 1 and 2. These nerves
      extend to the periphery of the animal and innervate tissues of the anterior
      ipsilateral foot and body wall. Electrophysiological recordings demonstrated that
      action potentials generated by the Pd6 cells propagate from the central ganglia
      toward the periphery. These results imply that the Pd6 cells play an efferent
      role in the magnetic orientation circuitry. Given that these cells contain cilio
      excitatory peptides and that Tritonia crawls using ciliary locomotion, the Pd6
      neurons may control or modulate cilia used in crawling, turning, or both.

PMID- 12477909
TI  - Escape manoeuvres in damsel-fly larvae: kinematics and dynamics.
AB  - The kinematics and hydrodynamics of rapid escape manoeuvres executed by final
      stage larvae of Enallagma cyathigerum were investigated using videography
      combined with a simple wake-visualisation technique. Two kinds of escape
      manoeuvres were identified: first, a 'rapid flex', comparable with the rapid C
      start of fish, and, second, a 'rapid twist' that involves a helical contraction
      of the body inducing motion in the yaw, pitch and roll planes. In both cases, the
      initial flexion phase is concerned with re-orientating the body, the extensional
      phase with acceleration of the body in the new direction. The behaviour of the
      caudal fin during twist indicates considerable independence of movement and
      aspect control within the three constituent lobes. Dye deposited beneath the
      resting larvae showed a thrust jet shed into the wake at the end of the extension
      phase. The estimated momentum of the ring vortex containing the jet was similar
      to that imparted to the body at the start of the translational phase.
      Similarities between the swimming dynamics of damsel-fly larvae and fish are
      discussed, as well as the wider implications of these findings to other aquatic
      invertebrates whose normal, steady swimming appears to be based on unsteady
      manoeuvres.

PMID- 12477910
TI  - Expression and localization of carbonic anhydrase and ATPases in the symbiotic
      tubeworm Riftia pachyptila.
AB  - The symbiotic tubeworm Riftia pachyptila needs to fuel its chemoautotrophic
      symbiotic bacteria with inorganic carbon. CO(2) is transported from the
      surrounding water to the bacteriocytes located in the trophosome, through the
      branchial plume and the body fluids. Previous studies have demonstrated the
      implication of carbonic anhydrase (CA) and proton pumps (ATPases) at various
      steps of CO(2) transport. The present study describes the expression pattern of
      cytosolic CA using an RNA probe and its histochemical and immunocytochemical
      localization in the trophosome and branchial plume of RIFTIA: Immunolocalization
      of V-H(+)ATPase and Na(+)K(+)-ATPase were also performed and related to CA
      localization. In the branchial plume, CA is expressed and localized in the most
      apical region of the branchial epithelium, close to the surrounding water. V
      H(+)ATPase is mostly colocalized with CA and both enzymes probably allow CO(2)
      entry against the concentration gradient while regulating intracellular pH.
      Na(+)K(+)-ATPase is mostly restricted to the basal part of epithelial cells and
      probably participates in CO(2) transport to the body fluids. In the trophosome
      lobules, cytosolic CA is expressed and found in bacteriocytes and peritoneal
      cells. Hypotheses on the role of CA in bicarbonate and CO(2) interconversion to
      fuel the symbiotic bacteria are discussed.

PMID- 12477911
TI  - Muscle fine structure may maintain the function of oxidative fibres in
      haemoglobinless Antarctic fishes.
AB  - Muscle fine structure and metabolism were examined in four species of Antarctic
      fishes that vary in their expression of haemoglobin (Hb). To determine how
      locomotory pectoral muscles maintain function, metabolic capacity, capillary
      supply and fibre ultrastructure were examined in two nototheniid species that
      express Hb (Notothenia coriiceps and Gobionotothen gibberifrons) and two species
      of channichthyid icefish that lack Hb (Chaenocephalus aceratus and Chionodraco
      rastrospinosus). Surprisingly, icefish have higher densities of mitochondria than
      red-blooded species (C. aceratus, 53+/-3% of cell volume; C. rastrospinosus, 39+/
      3%; N. coriiceps, 29+/-3%; G. gibberifrons, 25+/-1%). Despite higher
      mitochondrial densities the aerobic metabolic capacities per g wet mass,
      estimated from measurements of maximal activities of key metabolic enzymes, are
      lower in icefish compared to red-blooded species. This apparent incongruity can
      be explained by the significantly lower mitochondrial cristae surface area per
      unit mitochondrion volume in icefishes (C. aceratus, 20.8+/-1.6 microm(-1); C.
      rastrospinosus, 25.5+/-1.8 microm(-1)) compared to red-blooded species (N.
      coriiceps, 33.6+/-3.0 microm(-1); G. gibberifrons, 37.7+/-3.6 microm(-1)).
      Consequently, the cristae surface area per unit muscle mass is conserved at
      approximately 9 m(2)g(-1). Although high mitochondrial densities in icefish
      muscle do not enhance aerobic metabolic capacity, they may facilitate
      intracellular oxygen movement because oxygen is more soluble in lipid, including
      the hydrocarbon core of intracellular membrane systems, than in aqueous
      cytoplasm. This may be particularly vital in icefish, which have larger oxidative
      muscle fibres compared to red-blooded nototheniods (C. aceratus, 2932+/-428
      microm(2); C. rastrospinosus, 9352+/-318 microm(2); N. coriiceps, 1843+/-312
      microm(2); G. gibberifrons, 2103+/-194 microm(2)). These large fibres contribute
      to a relatively low capillary density, which is partially compensated for in
      icefish by a high index of tortuosity in the capillary bed (C. aceratus=1.4, N.
      coriiceps=1.1).

PMID- 12477912
TI  - Biomonitoring of industrial pollutants: health and policy implications of the
      chemical body burden.

PMID- 12477913
TI  - Winter harvest of danger: fishing on board a Maine trawler in the storm-tossed
      North Atlantic.

PMID- 12477914
TI  - Research funding, conflicts of interest, and the meta-methodology of public
      relations.

PMID- 12477915
TI  - Prevalence of safer needle devices and factors associated with their adoption:
      results of a national hospital survey.
AB  - OBJECTIVES: In this study, we collected and analyzed the first data available on
      the extent of the adoption of safer needle devices (engineered sharps injury
      protections [ESIPs]) by U.S. hospitals and on the degree to which selected
      factors influence the use of this technology. METHODS: We gathered data via a
      telephone survey of a random sample of 494 U.S. hospitals from November 1999
      through February 2000. RESULTS: Although 83% of the sample reported some ESIP
      adoption, adoption was inconsistent across types of devices. All of the
      appropriate units in 52% of the facilities had adopted needleless intravenous
      delivery systems, but the hospitals used other types of ESIPs less often. A
      respondent's perception that the cost of ESIPs would not be a problem for the
      hospital was the best predictor of adoption of ESIPs in the facility, explaining
      8% of the variance. Other predictors of adoption included the size of the
      hospital and the presence or absence of state legislative activity on the
      needlestick issue. CONCLUSIONS: Smaller hospitals may require special
      encouragement and assistance from outside sources to adopt expensive risk
      reduction innovations such as ESIPs. Although use of ESIPs is the mandated and
      preferred way to protect workers from needlesticks, complete adoption of this
      technology will depend on the support of the social systems in which it is used
      and the people who use it.

PMID- 12477916
TI  - Cumulative trauma disorder risk for children using computer products: results of
      a pilot investigation with a student convenience sample.
AB  - OBJECTIVES: Cumulative trauma disorder is a major health problem for adults.
      Despite a growing understanding of adult cumulative trauma disorder, however,
      little is known about the risks for younger populations. This investigation
      examined issues related to child/adolescent computer product use and upper body
      physical discomfort. METHODS: A convenience sample of 212 students, grades 1-12,
      was interviewed at their homes by a college-age sibling or relative. One of the
      child's parents was also interviewed. A 22-item questionnaire was used for data
      gathering. Questionnaire items included frequency and duration of use, type of
      computer products/games and input devices used, presence of physical discomfort,
      and parental concerns related to the child's computer use. RESULTS: Many students
      experienced physical discomfort attributed to computer use, such as wrist pain
      (30%) and back pain (15%). Specific computer activities-such as using a joystick
      or playing noneducational games-were significantly predictive of physical
      discomfort using logistic multiple regression. Many parents reported difficulty
      getting their children off the computer (46%) and that their children spent less
      time outdoors (35%). CONCLUSIONS: Computer product use within this cohort was
      associated with self-reported physical discomfort. Results suggest a need for
      more extensive study, including multiyear longitudinal surveys.

PMID- 12477917
TI  - Statewide prevalences of concern about enough food, 1996-1999.
AB  - OBJECTIVE: Food insecurity is defined as not having access at all times to enough
      food for an active and healthy life-style. A Healthy People 2010 objective is to
      increase food security and reduce the risk of hunger for all households. The
      objective of this study was to characterize the prevalence of concern about
      enough food and its association with other sociodemographic and health
      characteristics at the state level. METHODS: Adult respondents participating in
      the Behavioral Risk Factor Surveillance System survey provided information on
      concern about enough food from nine states from 1996 through 1999. RESULTS:
      Overall, the prevalence of concern about enough food ranged from 3.1% to 11.8%
      for individual states. Across states, low household income was the strongest
      predictor of concern about enough food. The odds of being concerned about enough
      food were generally higher among respondents who were female, younger, and
      without health care coverage. The odds were generally lower among those reporting
      excellent or very good general health and among non-Hispanic whites. CONCLUSION:
      Food security scales could be used at the state level to track progress for the
      Healthy People 2010 objective of reducing food insecurity and hunger across
      American households.

PMID- 12477918
TI  - Targeting tuberculosis testing: the yield of source case investigations for young
      children with reactive tuberculin skin tests.
AB  - OBJECTIVE: This study was designed to determine the yield of investigations whose
      aim is to identify a source case for tuberculosis infection among tuberculin
      reactors 3 years of age or younger. METHODS: The authors describe the results of
      associate investigations conducted for child tuberculin reactors reported from
      January 1, 1996, through June 30, 1998. Associates were defined as individuals
      who live with or spend significant time with a child reactor. An associate
      investigation was defined as evaluation of at least one associate. A source case
      was an associate older than 10 years of age who had culture-positive, pulmonary
      tuberculosis during a period when the child could have been exposed. RESULTS: Two
      hundred seven children had an associate investigation performed with a median of
      four associates investigated per child (range 1-21). Birthplace was known for 187
      (90%); 128 were U.S.-born. Of 1,222 associates identified, 980 (80%) were
      evaluated. Among 452 (46%) associates for whom birthplace was known, 250 (55%)
      were non-U.S.-born. Of 980 associates, 668 were household contacts; 198 (30%)
      were infected, three had prior tuberculosis disease, and three had active
      tuberculosis. Two active cases met source case criteria; the yield was 0.9 (2 of
      207) source cases per 100 children investigated. Of 312 non-household contacts,
      57 (18%) were infected and none had the disease. CONCLUSIONS: Although few source
      cases were identified for young tuberculin skin test reactors in New York City,
      investigations identified a proportion of cases and infection in associates
      similar to that identified among contacts to pulmonary tuberculosis cases. Such
      investigations may be identifying a high-risk group and should be considered,
      depending on program resources.

PMID- 12477920
TI  - A cluster of Escherichia coli O157: nonmotile infections associated with
      recreational exposure to lake water.
AB  - OBJECTIVES: To identify cases and determine risk factors for an outbreak of
      Escherichia coli (E. coli) O157: nonmotile (NM) infections in children attending
      a summer day care program in California. METHODS: The authors conducted a
      retrospective cohort study; the cohort comprised first and second graders who
      attended the day care program during the last week in August 1999. Shiga toxin
      testing and molecular subtyping using pulsed-field gel electrophoresis were
      performed on isolates. Lake water, lake bottom sediment samples, and waterfowl
      feces from the lake environs were cultured for E. coli O157. RESULTS: Three cases
      of Shiga toxin-producing E. coli O157: NM infections with matching pulsed-field
      gel electrophoresis patterns and four probable cases were found. Children who
      swallowed more than a mouthful of water had a higher attack rate than those who
      swallowed less than a mouthful or none at all (43% vs. 10%, relative risk = 4.43,
      95% confidence interval 1.12, 17.50). CONCLUSIONS: E. coli O157: NM infections
      were associated with swallowing water from a freshwater lake. Potential sources
      of contamination include feces from humans, cattle, or deer. This outbreak
      illustrates the value in screening patients with diarrhea for E. coli O157,
      submitting isolates to public health laboratories, and using molecular techniques
      to identify related cases. Outbreaks associated with contaminated freshwater
      could be averted by prevention and early detection of contamination.

PMID- 12477919
TI  - Type 2 diabetes mellitus among Florida children and adolescents, 1994 through
      1998.
AB  - OBJECTIVES: This study was undertaken to examine the trends in the diagnosis of
      Type 2 diabetes mellitus among children and adolescents with new-onset diabetes
      seen from 1994 through 1998 at the three university-based diabetes centers in
      Florida. METHODS: Data were abstracted from medical records and patients were
      categorized as having Type 1 or Type 2 diabetes. RESULTS: There were 569 patients
      classified with Type 1 diabetes and 92 with Type 2 diabetes. The proportion of
      patients diagnosed with Type 2 diabetes increased over the five years from 9.4%
      in 1994 to 20.0% in 1998 (chi-square test for trend = 8.2; p=0.004). There was
      not an associated net increase in the total number of new diabetes patients
      referred over time (chi-square test for trend = 0.6, p=0.4). Those with Type 2
      diabetes were more likely to have a body mass index in the 85th-94th percentile
      [odds ratio (OR) = 8.5; 95% confidence interval (CI) 2.5, 28.8], have a body mass
      index >or=95th percentile (OR = 6.8; 95% CI 2.6, 17.7), Hispanic ethnicity (OR =
      6.2; 95% CI 2.2, 17.9), black race (OR = 2.8; 95% CI 1.3, 6.2), female gender (OR
      = 2.2; 95% CI 1.2, 4.3), and older age (OR = 1.4 for each one-year increment in
      age; 95% CI 1.3, 1.6), compared with those having Type 1 diabetes. CONCLUSIONS:
      From 1994 through 1998, there was a significant overall increase in the
      percentage of children referred with new-onset diabetes who were considered to
      have Type 2 diabetes. Factors associated with the diagnosis of Type 2 diabetes
      relative to Type 1 diabetes include body mass index >/=85th percentile, Hispanic
      ethnicity, black race, female gender, and older age.

PMID- 12477921
TI  - Immunization registries: costs and savings.
AB  - OBJECTIVES: The objectives of this study were to quantify the actual costs of
      developing, maintaining, and operating the Boston Immunization Information System
      (BIIS), an electronic registry and tracking system, and to compare the registry's
      costs with those of performing the same functions manually. METHODS: Cost data
      were obtained from 23 BIIS health care sites, the city health department, and 13
      control sites. Actual costs of developing and operating BIIS in 1998 and
      projected 1999 costs for a hypothetical expanded registry were measured. Total
      costs of registry-supported immunization activities were compared with the costs
      of similar types and volumes of manual activities. RESULTS: The total annual cost
      of developing, maintaining, and operating BIIS in 1998 was $345,556. Annual total
      cost per record was $5.45 for all children aged <23 years and $10 when costs were
      distributed only among active users (children <8 years old). Operating BIIS saved
      $26,768 in 1998, compared with manual performance. The hypothetical projected
      total cost of an expanded BIIS in 1999 would have been $577,919, with a projected
      savings of $689,403 compared with manual costs. CONCLUSIONS: Electronic
      immunization registries potentially offer an efficient tool for the delivery of
      immunization services. Registries can save substantial funds if their data are
      kept up-to-date, and if caregivers are willing and able to use the registries
      routinely.

PMID- 12477922
TI  - Combining estimates from complementary surveys: a case study using prevalence
      estimates from national health surveys of households and nursing homes.
AB  - OBJECTIVES: When a single survey does not cover a domain of interest, estimates
      from two or more complementary surveys can be combined to extend coverage. The
      purposes of this article are to discuss and demonstrate the benefits of combining
      estimates from complementary surveys and to provide a catalog of the analytic
      issues involved. METHODS: The authors present a case study in which data from the
      National Health Interview Survey and the National Nursing Home Survey were
      combined to obtain prevalence estimates for several chronic health conditions for
      the years 1985, 1995, and 1997. The combined prevalences were estimated by ratio
      estimation, and the associated variances were estimated by Taylor linearization.
      The survey weights, stratification, and clustering were reflected in the
      estimation procedures. RESULTS: In the case study, for the age group of 65 and
      older, the combined prevalence estimates for households and nursing homes are
      close to those for households alone. For the age group of 85 and older, however,
      the combined estimates are sometimes substantially different from the household
      estimates. Such differences are seen both for estimates within a single year and
      for estimates of trends across years. CONCLUSIONS: Several general issues
      regarding comparability arise when there is a goal of combining complementary
      survey data. As illustrated by this case study, combining estimates can be very
      useful for improving coverage and avoiding misleading conclusions.

PMID- 12477925
TI  - The community research, education, and practice consortium: building
      institutional capacity for community-based public health.

PMID- 12477926
TI  - The classical pathway is the dominant complement pathway required for innate
      immunity to Streptococcus pneumoniae infection in mice.
AB  - The complement system is an important component of the innate immune response to
      bacterial pathogens, including Streptococcus pneumoniae. The classical complement
      pathway is activated by antibody-antigen complexes on the bacterial surface and
      has been considered predominately to be an effector of the adaptive immune
      response, whereas the alternative and mannose-binding lectin pathways are
      activated directly by bacterial cell surface components and are considered
      effectors of the innate immune response. Recently, a role has been suggested for
      the classical pathway during innate immunity that is activated by natural IgM or
      components of the acute-phase response bound to bacterial pathogens. However, the
      functional importance of the classical pathway for innate immunity to S.
      pneumoniae and other bacterial pathogens, and its relative contribution compared
      with the alternative and mannose-binding lectin pathways has not been defined. By
      using strains of mice with genetic deficiencies of complement components and
      secretory IgM we have investigated the role of each complement pathway and
      natural IgM for innate immunity to S. pneumoniae. Our results show that the
      proportion of a population of S. pneumoniae bound by C3 depends mainly on the
      classical pathway, whereas the intensity of C3 binding depends on the alternative
      pathway. Furthermore, the classical pathway, partially targeted by the binding of
      natural IgM to bacteria, is the dominant pathway for activation of the complement
      system during innate immunity to S. pneumoniae, loss of which results in rapidly
      progressing septicemia and impaired macrophage activation. These data demonstrate
      the vital role of the classical pathway for innate immunity to a bacterial
      pathogen.

PMID- 12477927
TI  - G2 arrest in Xenopus oocytes depends on phosphorylation of cdc25 by protein
      kinase A.
AB  - Xenopus oocytes, which are arrested in G(2) of meiosis I, contain complexes of
      cyclin B-cdc2 (M phase-promoting factor) that are kept repressed by inhibitory
      phosphorylations on cdc2 at Thr-14 and Tyr-15. Progesterone induces a cytoplasmic
      signaling pathway that leads to activation of cdc25, the phosphatase that removes
      these phosphorylations, catalyzing entry into M phase. It has been known for 25
      years that high levels of cAMP and protein kinase A (PKA) are required to
      maintain the G(2) arrest and that a drop in PKA activity is required for M phase
      promoting factor activation, but no physiological targets of PKA have been
      identified. We present evidence that cdc25 is a critical target of PKA. (i) In
      vitro, cdc25 Ser-287 serves as a major site of phosphorylation by PKA, resulting
      in sequestration by 14-3-3. (ii) Endogenous cdc25 is phosphorylated on Ser-287 in
      oocytes and dephosphorylated in response to progesterone just before cdc2
      dephosphorylation and M-phase entry. (iii) High PKA activity maintains
      phosphorylation of Ser-287 in vivo, whereas inhibition of PKA by its heat-stable
      inhibitor (PKI) induces dephosphorylation of Ser-287. (iv) Overexpression of
      mutant cdc25 (S287A) bypasses the ability of PKA to maintain oocytes in G(2)
      arrest. These findings argue that cdc25 is a physiologically relevant target of
      PKA in oocytes. In the early embryonic cell cycles, Ser-287 is phosphorylated
      during interphase and dephosphorylated just before cdc2 activation and mitotic
      entry. Thus, in addition to its role in checkpoint arrest, cdc25 Ser-287 serves
      as a site for regulation during normal, unperturbed cell cycles.

PMID- 12477928
TI  - Transcription defines the embryonic domains of cis-regulatory activity at the
      Drosophila bithorax complex.
AB  - The extensive infraabdominal (iab) region contains a number of cis-regulatory
      elements, including enhancers, silencers, and insulators responsible for
      directing the developmental expression of the abdominal-A and Abdominal-B
      homeotic genes at the Drosophila bithorax complex. It is unclear how these
      regulatory elements are primed for activity early in embryogenesis, but the 100
      kb intergenic region is subject to a complex transcriptional program. Here, we
      use molecular and genetic methods to examine the functional activity of the RNAs
      produced from this region and their role in cis regulation. We show that a subset
      of these transcripts demonstrates a distinct pattern of cellular localization.
      Furthermore, the transcripts from each iab region are discrete and the
      transcripts do not spread across the insulator elements that delineate the iab
      regions. In embryos carrying a Mcp deletion, the intergenic transcription pattern
      is disrupted in the iab4 region and the fourth abdominal segment is transformed
      into the fifth. We propose that intergenic transcription is required early in
      embryogenesis to initiate the activation of the Drosophila bithorax complex and
      define the domains of activity for the iab cis-regulatory elements. We also
      discuss a possible mechanism by which this may occur.

PMID- 12477929
TI  - Genetic variation in the 22q11 locus and susceptibility to schizophrenia.
AB  - An increased prevalence of microdeletions at the 22q11 locus has been reported in
      samples of patients with schizophrenia. 22q11 microdeletions represent the
      highest known genetic risk factor for the development of schizophrenia, second
      only to that of the monozygotic cotwin of an affected individual or the offspring
      of two schizophrenic parents. It is therefore clear that a schizophrenia
      susceptibility locus maps to chromosome 22q11. In light of evidence for
      suggestive linkage for schizophrenia in this region, we hypothesized that,
      whereas deletions of chromosome 22q11 may account for only a small proportion of
      schizophrenia cases in the general population (up to approximately 2%),
      nondeletion variants of individual genes within the 22q11 region may make a
      larger contribution to susceptibility to schizophrenia in the wider population.
      By studying a dense collection of markers (average one single nucleotide
      polymorphism20 kb over 1.5 Mb) in the vicinity of the 22q11 locus, in both family
      and population-based samples, we present here results consistent with this
      assumption. Moreover, our results are consistent with contribution from more than
      one gene to the strikingly increased disease risk associated with this locus.
      Finer-scale haplotype mapping has identified two subregions within the 1.5-Mb
      locus that are likely to harbor candidate schizophrenia susceptibility genes.

PMID- 12477930
TI  - The role of feedback in shaping neural representations in cat visual cortex.
AB  - In the primary visual cortex, neurons with similar response preferences are
      grouped into domains forming continuous maps of stimulus orientation and
      direction of movement. These properties are widely believed to result from the
      combination of ascending and lateral interactions in the visual system. We have
      tested this view by examining the influence of deactivating feedback signals
      descending from the visuoparietal cortex on the emergence of these response
      properties and representations in cat area 18. We thermally deactivated the
      dominant motion-processing region of the visuoparietal cortex and used optical
      and electrophysiological methods to assay neural activity evoked in area 18 by
      stimulation with moving gratings and fields of coherently moving randomly
      distributed dots. Feedback deactivation decreased signal strength in both
      orientation and direction maps and virtually abolished the global layout of
      direction maps, whereas the basic structure of the orientation maps was
      preserved. These findings could be accounted for by a selective silencing of
      highly direction-selective neurons and by the redirection of preferences of less
      selective neurons. Our data suggest that signals fed back from the visuoparietal
      cortex strongly contribute to the emergence of direction selectivity in early
      visual areas. Thus we propose that higher cortical areas have significant
      influence over fundamental neuronal properties as they emerge in lower areas.

PMID- 12477931
TI  - Soft and hard classification by reproducing kernel Hilbert space methods.
AB  - Reproducing kernel Hilbert space (RKHS) methods provide a unified context for
      solving a wide variety of statistical modelling and function estimation problems.
      We consider two such problems: We are given a training set [yi, ti, i = 1, em
      leader, n], where yi is the response for the ith subject, and ti is a vector of
      attributes for this subject. The value of y(i) is a label that indicates which
      category it came from. For the first problem, we wish to build a model from the
      training set that assigns to each t in an attribute domain of interest an
      estimate of the probability pj(t) that a (future) subject with attribute vector t
      is in category j. The second problem is in some sense less ambitious; it is to
      build a model that assigns to each t a label, which classifies a future subject
      with that t into one of the categories or possibly "none of the above." The
      approach to the first of these two problems discussed here is a special case of
      what is known as penalized likelihood estimation. The approach to the second
      problem is known as the support vector machine. We also note some alternate but
      closely related approaches to the second problem. These approaches are all
      obtained as solutions to optimization problems in RKHS. Many other problems, in
      particular the solution of ill-posed inverse problems, can be obtained as
      solutions to optimization problems in RKHS and are mentioned in passing. We
      caution the reader that although a large literature exists in all of these
      topics, in this inaugural article we are selectively highlighting work of the
      author, former students, and other collaborators.

PMID- 12477932
TI  - Generation and initial analysis of more than 15,000 full-length human and mouse
      cDNA sequences.
AB  - The National Institutes of Health Mammalian Gene Collection (MGC) Program is a
      multiinstitutional effort to identify and sequence a cDNA clone containing a
      complete ORF for each human and mouse gene. ESTs were generated from libraries
      enriched for full-length cDNAs and analyzed to identify candidate full-ORF
      clones, which then were sequenced to high accuracy. The MGC has currently
      sequenced and verified the full ORF for a nonredundant set of >9,000 human and
      >6,000 mouse genes. Candidate full-ORF clones for an additional 7,800 human and
      3,500 mouse genes also have been identified. All MGC sequences and clones are
      available without restriction through public databases and clone distribution
      networks (see http:mgc.nci.nih.gov).

PMID- 12477933
TI  - Spin-dependent mechanism for diatomic ligand binding to heme.
AB  - The nature of diatomic ligand recombination in heme proteins is elucidated by
      using a Landau-Zener model for the electronic coupling in the recombination rate
      constant. The model is developed by means of explicit potential energy surfaces
      calculated by using density functional theory (DFT). The interaction of all
      possible spin states of the three common diatomic ligands, CO, NO, and O2, and
      high-spin heme iron is compared. The electronic coupling, rebinding barrier, and
      Landau-Zener force terms can be obtained and used to demonstrate significant
      differences among the ligands. In particular the intermediate spin states of NO
      (S = 32) and O2 (S = 1) are shown to be bound states. Rapid recombination occurs
      from these bound states in agreement with experimental data. The slower phases of
      O2 recombination can be explained by the presence of two higher spin states, S =
      2 and S = 3, which have a small and relatively large barrier to ligand
      recombination, respectively. By contrast, the intermediate spin state for CO is
      not a bound state, and the only recombination pathway for CO involves direct
      recombination from the S = 2 state. This process is significantly slower
      according to the Landau-Zener model. Quantitative estimates of the parameters
      used in the rate constants provide a complete description that explains rebinding
      rates that range from femtoseconds to milliseconds at ambient temperature.

PMID- 12477934
TI  - Protein composition of human prespliceosomes isolated by a tobramycin affinity
      selection method.
AB  - Detailed knowledge of the composition and structure of the spliceosome and its
      assembly intermediates is a prerequisite for understanding the complex process of
      pre-mRNA splicing. To this end, we have developed a tobramycin affinity-selection
      method that is generally applicable for the purification of native RNP complexes.
      By using this method, we have isolated human prespliceosomes that are ideally
      suited for both biochemical and structural studies. MS identified >70
      prespliceosome-associated proteins, including nearly all known U1 and U2 snRNP
      proteins, and expected non-snRNP splicing factors. In addition, the DEAD-box
      protein p68, RNA helicase A, and a number of proteins that appear to perform
      multiple functions in the cell, such as YB-1 and TLS, were detected. Several
      previously uncharacterized proteins of unknown function were also identified,
      suggesting that they play a role in splicing and potentially act during
      prespliceosome assembly. These data provide insight into the complexity of the
      splicing machinery at an early stage of its assembly.

PMID- 12477935
TI  - Circadian clock protein KaiC forms ATP-dependent hexameric rings and binds DNA.
AB  - KaiC from Synechococcus elongatus PCC 7942 (KaiC) is an essential circadian clock
      protein in cyanobacteria. Previous sequence analyses suggested its inclusion in
      the RecADnaB superfamily. A characteristic of the proteins of this superfamily is
      that they form homohexameric complexes that bind DNA. We show here that KaiC also
      forms ring complexes with a central pore that can be visualized by electron
      microscopy. A combination of analytical ultracentrifugation and chromatographic
      analyses demonstrates that these complexes are hexameric. The association of KaiC
      molecules into hexamers depends on the presence of ATP. The KaiC sequence does
      not include the obvious DNA-binding motifs found in RecA or DnaB. Nevertheless,
      KaiC binds forked DNA substrates. These data support the inclusion of KaiC into
      the RecADnaB superfamily and have important implications for enzymatic activity
      of KaiC in the circadian clock mechanism that regulates global changes in gene
      expression patterns.

PMID- 12477936
TI  - Reversible infertility in male mice after oral administration of alkylated imino
      sugars: a nonhormonal approach to male contraception.
AB  - During mammalian spermatogenesis, male germ cells undergo a dramatic
      transformation, which includes a change of shape, nuclear condensation, and
      development of specialised structures, such as an acrosome, and a flagellum with
      a mitochondrial sheath. We have found a previously undescribed pharmacological
      approach to intervene in these events. After oral administration of the alkylated
      imino sugar N-butyldeoxynojirimycin (NB-DNJ) to mice, epididymal spermatozoa
      displayed a spectrum of abnormal head shapes, and acrosomal antigens were mostly
      absent or displayed irregular patterns. In addition, the mitochondria of these
      cells often had an aberrant morphology, and were arranged in relatively short and
      wide mitochondrial sheaths. The motility of the affected spermatozoa was severely
      impaired. After 3 weeks of administration of NB-DNJ, male mice became sterile,
      and regained their fertility during the fourth week off drug. The NB-DNJ-induced
      infertility was not associated with a reduction in the serum testosterone level.
      Biochemically, the capacity of imino sugars to impair spermatogenesis was
      associated with their potential to attenuate the biosynthesis of glucosylceramide
      based sphingolipids. Our study reveals that male fertility is affected by partial
      glycosphingolipid depletion, or, alternatively, by a distinct as yet unidentified
      property that is shared by alkylated imino sugars that inhibit glucosylceramide
      biosynthesis. These compounds therefore may be new leads in the development of a
      male contraceptive, especially because NB-DNJ has already been through extensive
      evaluation in various mammals, including man.

PMID- 12477937
TI  - An ensemble method for identifying regulatory circuits with special reference to
      the qa gene cluster of Neurospora crassa.
AB  - A chemical reaction network for the regulation of the quinic acid (qa) gene
      cluster of Neurospora crassa is proposed. An efficient Monte Carlo method for
      walking through the parameter space of possible chemical reaction networks is
      developed to identify an ensemble of deterministic kinetics models with rate
      constants consistent with RNA and protein profiling data. This method was
      successful in identifying a model ensemble fitting available RNA profiling data
      on the qa gene cluster.

PMID- 12477938
TI  - Functional reorganization and stability of somatosensory-motor cortical
      topography in a tetraplegic subject with late recovery.
AB  - The functional organization of somatosensory and motor cortex was investigated in
      an individual with a high cervical spinal cord injury, a 5-year absence of nearly
      all sensorymotor function at and below the shoulders, and rare recovery of some
      function in years 6-8 after intense and sustained rehabilitation therapies. We
      used functional magnetic resonance imaging to study brain activity to vibratory
      stimulation and voluntary movements of body parts above and below the lesion. No
      response to vibratory stimulation of the hand was observed in the primary
      somatosensory cortex (SI) hand area, which was conversely recruited during tongue
      movements that normally evoke responses only in the more lateral face area. This
      result suggests SI reorganization analogous to previously reported
      neuroplasticity changes after peripheral lesions in animals and humans. In
      striking contradistinction, vibratory stimulation of the foot evoked
      topographically appropriate responses in SI and second somatosensory cortex
      (SII). Motor cortex responses, tied to a visuomotor tracking task, displayed a
      near-typical topography, although they were more widespread in premotor regions.
      These findings suggest possible preservation of motor and some somatosensory
      cortical representations in the absence of overt movements or conscious
      sensations for several years after spinal cord injury and have implications for
      future rehabilitation and neural-repair therapies.

PMID- 12477939
TI  - To reconstruct or not to reconstruct?

PMID- 12477940
TI  - Outbreak of varicella at a day-care center despite vaccination.
AB  - BACKGROUND: In seven studies of the effectiveness of the varicella vaccine
      conducted since it was licensed, the effectiveness was 71 to 100 percent against
      disease of any severity and 95 to 100 percent against moderate and severe
      disease. We investigated an outbreak of varicella in a population of children
      with a high proportion of vaccinees who were attending a day-care center in a
      small community in New Hampshire. METHODS: Using standardized questionnaires, we
      collected information about the children's medical and vaccination history from
      parents and health care providers. The analysis of the effectiveness of the
      vaccine and of risk factors for vaccine failure was restricted to children who
      were enrolled in the day-care center continuously during the outbreak and
      attended for one week or more and who were cared for in the building that
      represented the epicenter of the outbreak, since transmission was not documented
      in a second building. RESULTS: Varicella developed in 25 of 88 children (28.4
      percent) between December 1, 2000, and January 11, 2001. The index case occurred
      in a healthy child who had been vaccinated three years previously and who
      infected more than 50 percent of his classmates who had no history of varicella.
      The effectiveness of the vaccine was 44.0 percent (95 percent confidence
      interval, 6.9 to 66.3 percent) against disease of any severity and 86.0 percent
      (95 percent confidence interval, 38.7 to 96.8 percent) against moderate or severe
      disease. Children who had been vaccinated three years or more before the outbreak
      were at greater risk for vaccine failure than those who had been vaccinated more
      recently (relative risk, 2.6 [95 percent confidence interval, 1.3 to 5.3]).
      CONCLUSIONS: In this outbreak, vaccination provided poor protection against
      varicella, although there was good protection against moderate or severe disease.
      A longer interval since vaccination was associated with an increased risk of
      vaccine failure. Breakthrough infections in vaccinated, healthy persons can be as
      infectious as varicella in unvaccinated persons.

PMID- 12477941
TI  - Prediction of the risk of myocardial infarction from polymorphisms in candidate
      genes.
AB  - BACKGROUND: Although epidemiologic studies have suggested that several genetic
      variants increase the risk of myocardial infarction, large-scale association
      studies that examine many polymorphisms simultaneously are required to allow
      reliable prediction of the genetic risk of myocardial infarction. METHODS: We
      used a fluorescence- or colorimetry-based allele-specific DNA-primer-probe assay
      system to determine the genotypes of 112 polymorphisms of 71 candidate genes in
      2819 unrelated Japanese patients with myocardial infarction (2003 men and 816
      women) and 2242 unrelated Japanese controls (1306 men and 936 women). RESULTS: In
      an initial screening of the 112 polymorphisms for an association with myocardial
      infarction in 909 subjects, 19 polymorphisms were selected in men and 18 in women
      by means of logistic-regression analysis, after adjustment for age, body-mass
      index, and the prevalence of smoking, hypertension, diabetes mellitus,
      hypercholesterolemia, and hyperuricemia. In a large-scale study involving the
      selected polymorphisms and the remaining 4152 subjects, similar logistic
      regression analysis revealed that the risk of myocardial infarction was
      significantly associated with the C1019T polymorphism in the connexin 37 gene
      (P<0.001) in men and the 4G-668/5G polymorphism in the plasminogen-activator
      inhibitor type 1 gene (P<0.001) and the 5A-1171/6A polymorphism in the
      stromelysin-1 gene (P<0.001) in women. CONCLUSIONS: Determination of the
      genotypes of the connexin 37, plasminogen-activator inhibitor type 1, and
      stromelysin-1 genes may prove reliable in predicting the genetic risk of
      myocardial infarction and might thus contribute to the primary prevention of this
      condition.

PMID- 12477942
TI  - An analysis of outcomes of reconstruction or amputation after leg-threatening
      injuries.
AB  - BACKGROUND: Limb salvage for severe trauma has replaced amputation as the primary
      treatment in many trauma centers. However, long-term outcomes after limb
      reconstruction or amputation have not been fully evaluated. METHODS: We performed
      a multicenter, prospective, observational study to determine the functional
      outcomes of 569 patients with severe leg injuries resulting in reconstruction or
      amputation. The principal outcome measure was the Sickness Impact Profile, a
      multidimensional measure of self-reported health status (scores range from 0 to
      100; scores for the general population average 2 to 3, and scores greater than 10
      represent severe disability). Secondary outcomes included limb status and the
      presence or absence of major complications resulting in rehospitalization.
      RESULTS: At two years, there was no significant difference in scores for the
      Sickness Impact Profile between the amputation and reconstruction groups (12.6
      vs. 11.8, P=0.53). After adjustment for the characteristics of the patients and
      their injuries, patients who underwent amputation had functional outcomes that
      were similar to those of patients who underwent reconstruction. Predictors of a
      poorer score for the Sickness Impact Profile included rehospitalization for a
      major complication, a low educational level, nonwhite race, poverty, lack of
      private health insurance, poor social-support network, low self-efficacy (the
      patient's confidence in being able to resume life activities), smoking, and
      involvement in disability-compensation litigation. Patients who underwent
      reconstruction were more likely to be rehospitalized than those who underwent
      amputation (47.6 percent vs. 33.9 percent, P=0.002). Similar proportions of
      patients who underwent amputation and patients who underwent reconstruction had
      returned to work by two years (53.0 percent and 49.4 percent, respectively).
      CONCLUSIONS: Patients with limbs at high risk for amputation can be advised that
      reconstruction typically results in two-year outcomes equivalent to those of
      amputation.

PMID- 12477943
TI  - Images in clinical medicine. Herpetic encephalitis and acute retinal necrosis.

PMID- 12477944
TI  - Views of practicing physicians and the public on medical errors.
AB  - BACKGROUND: In response to the report by the Institute of Medicine on medical
      errors, national groups have recommended actions to reduce the occurrence of
      preventable medical errors. What is not known is the level of support for these
      proposed changes among practicing physicians and the public. METHODS: We
      conducted parallel national surveys of 831 practicing physicians, who responded
      to mailed questionnaires, and 1207 members of the public, who were interviewed by
      telephone after selection with the use of random-digit dialing. Respondents were
      asked about the causes of and solutions to the problem of preventable medical
      errors and, on the basis of a clinical vignette, were asked what the consequences
      of an error should be. RESULTS: Many physicians (35 percent) and members of the
      public (42 percent) reported errors in their own or a family member's care, but
      neither group viewed medical errors as one of the most important problems in
      health care today. A majority of both groups believed that the number of in
      hospital deaths due to preventable errors is lower than that reported by the
      Institute of Medicine. Physicians and the public disagreed on many of the
      underlying causes of errors and on effective strategies for reducing errors.
      Neither group believed that moving patients to high-volume centers would be a
      very effective strategy. The public and many physicians supported the use of
      sanctions against individual health professionals perceived as responsible for
      serious errors. CONCLUSIONS: Though substantial proportions of the public and
      practicing physicians report that they have had personal experience with medical
      errors, neither group has the sense of urgency expressed by many national
      organizations. To advance their agenda, national groups need to convince
      physicians, in particular, that the current proposals for reducing errors will be
      very effective.

PMID- 12477945
TI  - Exercise training for claudication.

PMID- 12477946
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 38-2002. A 54-year-old man with hypercalcemia, renal dysfunction,
      and an enlarged liver.

PMID- 12477947
TI  - Varicella vaccine--are two doses better than one?

PMID- 12477948
TI  - Gene polymorphisms and the risk of myocardial infarction--an emerging relation.

PMID- 12477949
TI  - A broader concept of medical errors.

PMID- 12477950
TI  - Erythropoietin--an endogenous retinal survival factor.

PMID- 12477951
TI  - Homeostasis without reserve--the risk of health system collapse.

PMID- 12477952
TI  - B-type natriuretic peptide in heart failure.

PMID- 12477953
TI  - Toll-like receptor 4 polymorphisms and atherogenesis.

PMID- 12477954
TI  - Bronchiolitis in popcorn-factory workers.

PMID- 12477955
TI  - Inflammatory bowel disease.

PMID- 12477956
TI  - Abortion and maternal mortality in Africa.

PMID- 12477957
TI  - Illness after international travel.

PMID- 12477958
TI  - National Health Service provision for the management of infertility: the case for
      funding and reorganization of fertility services in the UK.

PMID- 12477959
TI  - Egg donation--the donor's view: an aid to future recruitment.
AB  - The major stumbling block for egg donation lies in the recruitment of sufficient
      suitable donors. This study ascertained the views of egg donors in the UK by
      analysing 113 completed questionnaires that asked questions about demographics,
      stimulus to donate, support network available, ethics, the 'process' of donation
      and payment. Ideas for future recruitment were also sought. The mean age of
      donors was 31.7 years, and most donors were donating for the first time. Ninety
      one per cent of donors were Caucasian and 93% had children of their own. Ninety
      six (85%) donors felt fully supported in their decision to become an egg donor
      and 60 (53%) discussed their donation with their GP. Information regarding egg
      donation came from many sources. The main motivation to donate was a desire to
      help childless couples. Many respondents had themselves suffered, or knew of
      couples with, infertility. Eighty-three (73.5%) respondents felt that expenses
      alone should be paid to egg donors, and many expressed concerns that large
      financial incentives may attract the 'wrong women' to donate. Forty-nine (43%)
      respondents found the procedure painful or stressful in some way, although 95%
      had no regrets concerning their donation, and 72% would donate again. A common
      reason for donors not wishing to donate again was age restriction. Respondents
      were asked their opinion with regard to recruitment and the enthusiasm they
      expressed needs to be harnessed if the current shortcomings in available donors
      are to be overcome. Specific recommendations to achieve this are made.

PMID- 12477960
TI  - New challenges for gamete donation programmes: changes in guidelines are needed.
AB  - In the UK, the Human Fertilisation and Embryology Act 1990 prevents children born
      as a result of donor-assisted conception from gaining access to identifying
      information about their genetic origins. There is growing concern that current
      screening protocols regarding gamete donation are ill-suited, especially in
      relation to genetic disease. There are no guidelines addressing the issues of
      confidentiality that might arise if a disease emerges after insemination and
      establishment of pregnancy. Donors may become aware that they are at risk of a
      familial condition after they have donated gametes or recipients of donated
      gametes may become aware of a genetic illness in the resulting child. At present,
      there is no agreed method for allowing this information to be given to the donor
      or other recipients of gametes from that person. We suggest that these issues
      should be raised with donors, and appropriate counselling and predictive tests
      offered to them. Changes in regulations regarding gamete donation should be
      considered that accommodate recent and possible future developments in genetics.
      Furthermore, consideration should be given to the storage of samples of DNA from
      donors for the future provision of genetic information.

PMID- 12477961
TI  - Information on genetic origins in donor-assisted conception: is knowing who you
      are a human rights issue?
AB  - It was not by my choice that my ancestral home is nothing more than a sample jar.
      (Whipp, 2000) There can be few more basic rights than a right to one's
      identity...a right not to be deceived about one's true origins. (Freeman, 1996)
      This article provides an overview of existing arrangements for the management of
      information on genetic origins in donor-assisted conception, that is, treatment
      involving sperm, eggs or embryo donation. The balance of this article reflects
      the fact that much of the debate on information on genetic origins in donor
      assisted conception has been dominated by sperm donation. A detailed discussion
      of the rather different issues of egg and embryo donation would have added
      significantly to its complexity and length. The article considers what donor
      conceived people wish to know about their genetic origins and how this might be
      seen as a human rights issue. The possibility of conflict between the interests
      and rights of donors and recipients of donated gametes or embryos is discussed,
      and possible policy and legislative options are outlined. The paper concludes
      that a donor-conceived person's own definition of their best interests should
      form the basis for the facilitation of access to information about their genetic
      origins.

PMID- 12477962
TI  - Analysis of donor heterogeneity as a factor affecting the clinical outcome of
      oocyte donation.
AB  - This study investigated factors that may affect the clinical outcome of oocyte
      donation on the basis of data from a clinical programme involving 243 treatment
      cycles analysed retrospectively. In each cohort, oocytes were distributed
      randomly to one, two or three recipients, which enabled the outcomes in terms of
      pregnancy and live birth rates to be compared among donors. The results were
      compared with respect to age of the donor and recipient, number of oocytes
      collected, fertilization and cleavage rates, qualitative embryo criteria
      (morphological grade) and other clinical criteria. Most variables had no
      significant effect on either outcome, although the live birth rate varied
      inversely with recipient age. Unsurprisingly, the pregnancy rate was correlated
      positively with the number of embryos transferred. Most of the variation in
      pregnancy and live birth rates (85-90%) could not be accounted for by any
      specific donation characteristic, indicating that interdonor heterogeneity was
      the result of idiopathic factors. The factor most predictive of a recipient's
      cycle outcome was a history of previous success of the donor, which accounted for
      approximately 30% of the variation in live birth rates. Pregnancy success rates
      varied widely among oocyte donors, as has been found among sperm donors. This
      observation highlights the need to identify markers that predict developmental
      competence and help to identify the genetic and environmental bases of
      differential fertility. In conclusion, the quality of oocytes varied widely among
      women presumed to be fertile by clinical criteria, and the causative factors set
      a major limitation on the prospects of improving the outcome of egg donation.

PMID- 12477963
TI  - Managing treatment failure: a patient's view.
AB  - This article explores how patients may deal with and manage treatment failure and
      gives suggestions to infertility clinics on how they might assist patients when
      their treatment fails. It describes the author's own experience of infertility
      treatment failure and how she and her partner coped. The article identifies
      possible reasons why a patient might contact CHILD, the national infertility
      support network, and also looks at the benefits for patients of being in contact
      with a support group.

PMID- 12477964
TI  - Human embryonic stem cells: an introduction.
AB  - Stem cell biology is currently one of the most promising areas of scientific
      development, possibly leading to new therapies for many diverse medical problems.
      A stem cell is a cell that has the potential to differentiate into other cell
      types and stem cell biology investigates the processes by which this
      differentiation is controlled. Some cells from adults have this potential, but it
      is only cells from very early embryos that have been shown to differentiate into
      all cell types. For this reason, interest has been focused on embryonic stem
      cells. This paper describes the process by which embryonic stem cells are derived
      and the associated practical problems. The potential benefits of embryonic stem
      cell biology are discussed. The need to develop cell nuclear replacement is
      considered since this may be necessary if stem cells are to be used to maximum
      benefit.

PMID- 12477965
TI  - Embryological strategies for overcoming recurrent assisted reproductive
      technology treatment failure.
AB  - In every assisted reproductive technology (ART) programme there are patients who
      experience repeated failure. If all laboratory and stimulation parameters are
      controlled, it is assumed that the underlying cause of failure is physiological,
      and is attributable to either of the gametes or the embryo. Within the
      laboratory, few tools are available, other than careful observation and embryo
      selection, to aid in selecting the right embryo to overcome this failure. The
      morphology of the zygote, the state of the cleaving embryos on day 2 and day 3 of
      development, and the blastocyst can influence implantation rates. However,
      without functional gametes it is unlikely that success can be achieved. An early
      indicator of this functionality is the morphology of the zygote, which can be
      influenced by either the oocyte or the spermatozoon, and can be altered by either
      improving oocyte quality during stimulation or by using donor sperm if the
      failure to conceive is attributable to the male gamete. Subsequently, selecting
      embryos for transfer on the basis of the morphology of zygotes and embryos at day
      3 or day 5 of development with the addition of fragmentation scoring and assisted
      hatching has been found to overcome many cases of repetitive failure to conceive
      after ART.

PMID- 12477966
TI  - Advanced embryo development during extended in vitro culture: observations of
      formation and hatching patterns in non-transferred human blastocysts.
AB  - Human embryos not chosen for fresh transfer or cryopreservation were maintained
      in extended in vitro culture for up to 9 days after fertilization to observe
      blastocyst formation and hatching features. These non-transferred embryos were
      derived from 64 consecutive IVF cycles, and were not cryopreserved either because
      of compromised morphology or because the patients did not consent to
      cryopreservation for personal reasons. Embryos were cultured individually to
      monitor daily growth until developmental arrest, and differential blastocyst
      formation and hatching were analysed among groups of patients and embryos. In the
      population studied, hatching occurred most commonly on day 7 after fertilization
      (range 5-9 days). A total of 301 blastocysts was observed, of which 116 (38.5%)
      eventually hatched in vitro irrespective of day of formation. A trend towards
      earlier blastocyst formation and a greater likelihood of hatching was noted in
      this population. Both blastocyst formation and hatching appeared negatively
      correlated with increasing maternal age and higher basal serum FSH concentrations
      on day 3 of development, although these trends did not reach statistical
      significance. Comparison of intracytoplasmic sperm injection (ICSI) (n = 25) and
      conventional insemination (n = 39) cycles showed a similar rate of blastocyst
      formation in both groups (54 and 52%, respectively; P > 0.05), but hatching
      patterns varied significantly between these groups (4.1 versus 61.6%,
      respectively; P < 0.0001). The discovery of marked impairment of hatching among
      non-transferred ICSI embryos supports the case for reconsideration of the
      appropriateness of assisted blastocyst hatching in selected cases.

PMID- 12477967
TI  - Part I: pathogenetic role of peroxynitrite in the development of diabetes and
      diabetic vascular complications: studies with FP15, a novel potent peroxynitrite
      decomposition catalyst.
AB  - BACKGROUND: Peroxynitrite is a cytotoxic oxidant formed from nitric oxide (NO)
      and superoxide. Tyrosine nitration, a footprint of peroxynitrite, has been
      demonstrated in the pancreatic islets as well as in the cardiovascular system of
      diabetic subjects. Delineation of the pathogenetic role of peroxynitrite in
      disease conditions requires the use of potent, in vivo active peroxynitrite
      decomposition catalysts. The aim of the current work was to produce a potent
      peroxynitrite decomposition catalyst and to test its effects in rodent models of
      diabetes and its complications. METHODS: FP15 was synthesized and analyzed using
      standard chemical methods. Diabetes was triggered by the administration of
      streptozotocin. Tyrosine nitration was measured immunohistochemically.
      Cardiovascular and vascular measurements were conducted according to standard
      physiologic methods. RESULTS: FP15, a potent porphyrinic peroxynitrite
      decomposition catalyst, potently inhibited tyrosine nitration and peroxynitrite
      induced cytotoxicity in vitro and in vivo. FP15 treatment (3-10 mg/kg/d) dose
      dependently and reduced the incidence and severity of diabetes mellitus in rats
      subjected to multiple low doses of streptozotocin, as well as in nonobese mice
      developing spontaneous autoimmune diabetes. Furthermore, treatment with FP15
      protected against the development of vascular dysfunction (loss of endothelium
      dependent relaxations) and the cardiac dysfunction (loss of myocardial
      contractility) in diabetic mice. FP15 treatment reduced tyrosine nitration in the
      diabetic pancreatic islets. CONCLUSIONS: The current results demonstrate the
      importance of endogenous peroxynitrite generation in the pathogenesis of
      autoimmune diabetes and diabetic cardiovascular complications. Peroxynitrite
      decomposition catalysts may be of therapeutic utility in diabetes and other
      pathophysiologic conditions.

PMID- 12477968
TI  - Part II: beneficial effects of the peroxynitrite decomposition catalyst FP15 in
      murine models of arthritis and colitis.
AB  - BACKGROUND: Peroxynitrite is a reactive oxidant species produced from nitric
      oxide and superoxide, which has been indirectly implicated in the pathogenesis of
      many inflammatory conditions including arthritis and colitis. Here, using a novel
      peroxynitrite decomposition catalyst, FP15, we directly investigate the role of
      peroxynitrite in the pathogenesis of arthritis and colitis in rodent models.
      METHODS: Arthritis was induced in mice by intradermal collagen injection;
      incidence and severity of arthritis was monitored using a macroscopic scoring
      system. At the end of the experiment paws were taken for determination of
      neutrophil infiltration (myeloperoxidase [MPO] activity), oxidative stress
      (malondialdehyde [MDA] level), and cytokine/chemokine levels. Colitis was induced
      in mice by 5% dextran sodium sulfate (DSS) in their drinking water. Colitis
      symptoms were assessed 10 days later, the parameters determined included body
      weight, rectal bleeding, colon length, colonic MPO and MDA levels, and colon
      histologic damage. RESULTS: Treatment with FP15 significantly reduced the
      inflammation and oxidative stress in arthritis and colitis. FP15 reduced both the
      incidence and severity of arthritis in mice and this was associated with reduced
      paw MPO and MDA levels. Similarly, in colitis, FP15 reduced colon damage, and
      this was associated with reduced colon neutrophil infiltration and oxidative
      stress. CONCLUSIONS: The protective effect of FP15 suggests that peroxynitrite
      plays a significant pathogenetic role in arthritis and colitis in the currently
      employed rodent models. Further work is needed to determine whether
      neutralization of peroxynitrite also represents a promising strategy to treat
      human inflammatory diseases such as arthritis and colitis.

PMID- 12477969
TI  - CS-886, a new angiotensin II type 1 receptor antagonist, ameliorates glomerular
      anionic site loss and prevents progression of diabetic nephropathy in Otsuka Long
      Evans Tokushima fatty rats.
AB  - BACKGROUND: Diabetic nephropathy is a leading cause of end-stage renal disease in
      industrialized countries. Previous studies have documented that angiotensin
      converting enzyme (ACE) inhibitors consistently reduce albuminuria and retard the
      progression of diabetic nephropathy. However, the involvement of angiotensin II
      in diabetic nephropathy is not fully understood. MATERIALS AND METHODS: In this
      study we compared the effects of CS-866, a new angiotensin II type 1 receptor
      antagonist, to that of an ACE inhibitor, temocapril hydrochloride, on the
      development and progression of diabetic nephropathy using Otsuka Long-Evans
      Tokushima fatty rats, a type II diabetes mellitus model animal. RESULTS: High
      doses of CS-866 or temocapril treatment were found to significantly improve
      urinary protein and beta(2)-microglobulin excretions in diabetic rats. In
      electron microscopic analysis, loss of glomerular anionic sites, one of the
      causes of glomerular hyperpermeability in diabetic nephropathy, was found to be
      significantly prevented by CS-866 treatment. Light microscopic examinations
      revealed that both treatments ameliorated glomerular sclerosis and
      tubulointerstitial injury in diabetic rats. Furthermore, high doses of CS-866 or
      temocapril treatment significantly reduced the positive stainings for
      transforming growth factor-beta (TGF-beta), vascular endothelial growth factor,
      and type IV collagen in glomeruli of diabetic rats. CONCLUSIONS: These results
      indicate that intrarenal angiotensin II type 1 receptor activation plays a
      dominant role in the development and progression of diabetic nephropathy. Our
      study suggests that CS-866 represents a valuable new drug for the treatment of
      diabetic patients with nephropathy.

PMID- 12477970
TI  - Induction of apoptosis of endothelial cells by Viscum album: a role for anti
      tumoral properties of mistletoe lectins.
AB  - BACKGROUND: Viscum album (VA) preparations consist of aqueous extracts of
      different types of lectins of VA. Mistletoe lectins have both cytotoxic and
      immunomodulatory properties that support their study for the development for
      cancer therapy. However, the mechanisms of the anti- tumoral properties in vivo
      of mistletoe lectins are not fully understood. Because endothelial cells (EC)
      play a pivotal role in tumor angiogenesis, we tested the hypothesis that VA
      extracts induce endothelial cell death and apoptosis. MATERIALS AND METHODS: We
      investigated the effect of various VA preparations on both human venous
      endothelial cell (HUVEC) and immortalized human venous endothelial cell line
      (IVEC) using morphologic assessment of EC, FACScan analysis after propidium
      iodine and annexin V labeling, and detection of cleavage of poly(A)DP-ribose
      polymerase (PARP). RESULTS: All tested VA preparations, except Iscador P, were
      cytotoxic in IVEC. Apoptosis, assessed by morphologic examination, annexin V
      labeling, and Western blot analysis for PARP cleavage, was involved in HUVEC cell
      death induced by VA preparations derived from plants that grow on oak trees (VA
      Qu FrF). CONCLUSIONS: Results from the present study suggest that VA extract
      induced endothelial apoptosis may explain the tumor regression associated with
      the therapeutic use of VA preparations and support further investigations to
      develop novel anti-angiogenic compounds based on mistletoe compounds.

PMID- 12477971
TI  - A 4-bp insertion in the eya-homologous region (eyaHR) of EYA4 causes hearing
      impairment in a Hungarian family linked to DFNA10.
AB  - BACKGROUND: Hereditary hearing impairment (HHI) is a heterogeneous class of
      disorders that shows various patterns of inheritance and involves a multitude of
      different genes. Mutations in the EYA4 gene are responsible for postlingual,
      progressive, autosomal dominant hearing loss at the DFNA10 locus. EYA4 is
      orthologous to the Drosophila gene eya ("eyes absent"), a key regulator of eye
      formation. EYA4 plays an important role in several developmental processes.
      MATERIAL AND METHODS: Here we report a Hungarian family displaying sensorineural,
      progressive hearing impairment. The family comprising four generations with 11
      affected and 8 unaffected members was subjected to genome-wide linkage analysis
      and candidate gene sequencing. RESULTS: By linkage analysis, the chromosomal
      region 6q22.3 was shown to segregate with the disease. Mutation analysis of the
      EYA4 gene, which maps to 6q22.3, revealed an insertion of 4 bp (1558insTTTG) in
      all affected family members. This insertion creates a frameshift and results in a
      stop codon at position 379. Hence, nearly the complete "eya homologous region"
      (eyaHR), which is essential for the protein function, would be deleted in the
      mutant EYA4 protein if the transcription were found to be stable. CONCLUSIONS:
      This family is the third one linked to DFNA10 and revealing a mutation in the
      EYA4 gene. In all three families, the mutations are localized in different
      regions of the eyaHR, suggesting that this protein contains several functional
      subregions with different tissue-specific importance.

PMID- 12477972
TI  - Differential sensitivity of endothelial cells of various species to apoptosis
      induced by gene transfer of Fas ligand: role of FLIP levels.
AB  - BACKGROUND: Fas ligand expression by cells of the vessel wall has been proposed
      to play a role in normal and pathologic conditions. Genetic engineering of
      vascularized organs for endothelial cell (EC) expression of FasL could protect
      the endothelium and underlying tissues from infiltrating Fas+ leukocytes.
      Nevertheless, the endogenous expression of FasL by ECs of different species and
      the potential deleterious effects of enforced FasL expression by ECs are largely
      unknown. In human ECs, levels of FLICE/caspase 8-inhibitory protein (FLIP) have
      been shown to control apoptosis mediated by Fas. MATERIALS AND METHODS: Cell
      surface expression of FasL in rat, mouse, human, and pig ECs was obtained using
      recombinant adenoviruses or transient plasmid transfection assays. FasL
      expression was evaluated by FACS analysis and cytotoxicity assays. Apoptosis was
      evaluated using annexin V, TUNEL, and cytotoxicity assays. FLIP levels were
      evaluated by Western blot analysis and overexpression was obtained by transient
      transfection. RESULTS: Analysis of ECs from different species showed that FasL
      was predominantly present in the cytoplasm, and depending on the species, little
      or no cell surface expression was detected. Enforced cell surface expression of
      FasL on rat or mouse ECs, either in culture or within the vessel wall resulted in
      massive apoptosis. In contrast, porcine or human ECs were completely resistant to
      apoptosis mediated by Fas-FasL interaction. Markedly reduced FLIP levels were
      observed in rat and mouse ECs compared to human and porcine ECs. Overexpression
      of FLIP in rat ECs conferred protection against cell surface expression of FasL.
      CONCLUSIONS: The consequences of FasL overexpression depend on the subcellular
      compartment and species in which FasL enforced expression is targeted and this is
      at least partially related to FLIP levels.

PMID- 12477973
TI  - The progression in the mouse skin carcinogenesis model correlates with ERK1/2
      signaling.
AB  - BACKGROUND: The ras family of proto-oncogenes encodes for small GTPases that play
      critical roles in cell-cycle progression and cellular transformation. ERK1/2 MAP
      kinases are major ras effectors. Tumors in chemically treated mouse skin contain
      mutations in the Ha-ras proto- oncogene. Amplification and mutation of Ha-ras has
      been shown to correlate with malignant progression of these tumors. Cell lines
      isolated from mouse skin tumors represent the stages of tumor development, such
      as the PDV:PDVC57 cell line pair and B9 squamous carcinoma and A5 spindle cells.
      PDVC57 cells were selected from PDV cells, which were transformed with dimethyl
      benzanthracene (DMBA) in vitro and then transplanted in adult syngeneic mice. The
      PDV:PDVC57 pair contains ratio of normal:mutant Ha-ras 2:1 and 1:2, respectively.
      This genetic alteration correlates with more advanced tumorigenic characteristics
      of PDVC57 compared to PDV. The squamous carcinoma B9 cell clone was isolated from
      the same primary tumor as A5 spindle cell line. The mutant Ha-ras allele, also
      present in B9, is amplified and overexpressed in A5 cells. Therefore these cell
      line pairs represent an in vivo model for studies of Ha-ras and ERK1/2 signaling
      in mouse tumorigenesis. MATERIALS AND METHODS: The ERK1/2 status in the above
      mouse cell lines was examined by using various molecular techniques. For the
      study of the tumorigenic properties and the role of the ras/MEK/ERK1/2 pathway in
      the cell lines mentioned, phenotypic characteristics, colony formation assay,
      anchorage-independent growth, and gelatin zymography were assessed, after or
      without treatment with the MEK inhibitor, PD98059. RESULTS: ERK1/2
      phosphorylation was found to be increased in PDVC57 when compared to PDV. This
      also applies to A5 spindle carcinoma cells when compared to squamous carcinoma
      and papilloma cells. The above finding was reproduced when transfecting human
      activated Ha-ras allele into PDV, thus demonstrating that Ha-ras enhances ERK1/2
      signaling. To further test whether ERK1/2 activation was required for growth we
      used the MEK-1 inhibitor, PD98059. The latter inhibited cell proliferation and
      anchorage-independent growth of squamous and spindle cells. In addition, PD98059
      treatment partially reverted the spindle morphology of A5 cells. CONCLUSIONS:
      These data suggest, for the first time, that oncogenicity and the degree of
      progression in the mouse skin carcinogenesis model correlates with ERK1/2
      signaling.

PMID- 12477974
TI  - Expression profiles of craniosynostosis-derived fibroblasts.
AB  - BACKGROUND: Craniosynostosis syndromes, a group of connective disorders
      characterized by abnormalities in vault osteogenesis and premature fusion of bone
      sutures, are associated with point mutations in FGF receptor family members. The
      cellular phenotype is characterized by abnormal extracellular matrix turnover.
      MATERIAL AND METHODS: We used primary cultures of periosteal fibroblasts derived
      from two different craniosynostosis syndromes, the Apert and Crouzon syndromes.
      The FGFR2 third immunoglobulin-like domain and its flanking linker regions were
      analyzed for mutation. DNA microarrays containing 19,200 cDNAs were used to study
      the gene expression profiles of Apert and Crouzon fibroblasts. The pathologic
      cells were compared to wild-type human periosteal fibroblasts. RESULTS: The P253R
      missense mutation and the G338R mutation were observed in Apert and Crouzon
      fibroblasts, respectively. The genetic profiles, as evaluated by DNA microarrays,
      yielded different clusters of expressed sequence tag (ESTs) expression within the
      experiment. Expression profiles from craniosynostosis-derived fibroblasts differ
      from those of wild-type fibroblasts (288 human ESTs, p< 0.01, pFDR = 0.12).
      Furthermore, two ESTs clusters discriminate the Crouzon from Apert fibroblasts.
      The differentially expressed genes cover a broad range of functional activities,
      including (1) bone differentiation, (2) cell-cycle regulation, (3) apoptotic
      stimulation, and (4) signaling transduction, cytoskeleton, and vesicular
      transport. CONCLUSIONS: The transcriptional program of craniosynostosis
      fibroblasts differs from that of wild-type fibroblasts. Expression profiles of
      Crouzon and Apert fibroblasts can also be distinguished by two EST expression
      clusters, thus hinting at a different genetic background.

PMID- 12477975
TI  - Transcriptional regulation of the BCL-6 gene: mechanistic dissection using mutant
      cell lines.
AB  - BACKGROUND: Mice lacking the BCL-6 gene product exhibit overexpression of T
      helper cell type 2 cytokines, and multi-organ inflammatory responses
      characterized by eosinophilia and infiltration by IgE+ B lymphocytes. Elevated
      IgE levels appear to result from loss of BCL-6's role in repression of the Stat6
      dependent processes of I-epsilon transcription and IgE class-switching.
      Understanding the regulation of the BCL-6 gene expression is therefore relevant
      to the allergic response, due to the IgE-dependent activation of mast cells and
      basophils. MATERIALS AND METHODS: We analyzed a pair of isogenic cell lines that
      exhibit differential expression of the BCL-6 gene and mapped the control point to
      transcription using nuclear run-on assays. Direct analyses of the BCL-6 gene and
      transfection experiments were carried out to map the molecular basis for the
      differential expression. RESULTS: In this study, we report that pair of isogenic
      cell lines exhibits differential expression of BCL-6. BCL-6 mRNA is barely
      detectable in Jijoye, a Burkitt lymphoma B cell line, but is abundant in Clone
      13, a mutant cell line derived from Jijoye. Corresponding to the mRNA level, BCL
      6 protein is detected only in Clone-13, but not in Jijoye. Nuclear run-on assays
      indicate that BCL-6 expression is regulated mainly at the transcriptional level
      in these two cell lines. Gene structural alterations are not detected in a region
      including a 3-kb promoter and the first intron, where most of the chromosomal
      translocations are observed in diffuse large cell lymphoma (DLCL). Interestingly,
      multiple, heterozygous point mutations are identified in the first intron, the
      hypermutation region of BCL-6, in both of the two cell lines. However, in
      transient transfection experiments these mutations have no effects on gene
      expression. CONCLUSIONS: Our data suggest that the distinct profile of BCL-6
      expression in Jijoye/Clone-13 is due to either a missing negative element in a
      different portion of the gene or that there is an issue of chromatin
      accessibility operating in BCL-6 gene regulation. This pair of isogenic cell
      lines (Jijoye/Clone-13) thus provides a new system to dissect the regulation of
      BCL-6 gene expression.

PMID- 12477976
TI  - A human novel gene DERPC on 16q22.1 inhibits prostate tumor cell growth and its
      expression is decreased in prostate and renal tumors.
AB  - BACKGROUND: Deletion of chromosome 16q is frequently associated with diverse
      tumors. Numerous studies strongly suggest the presence of one or more tumor
      suppressor genes on chromosome 16q22 to 16qter including the widely studied
      cadherin gene family. However, the specific tumor suppressor genes residing in
      this region need better definition and characterization. MATERIAL AND METHODS:
      Standard molecular biology approaches have been used to clone and characterize
      the DERPC cDNA and its protein product on chromosome 16q22.1. Northern blotting
      was used to define the expression pattern in a multiple human tissue blots. DERPC
      expression was examined in multi-tumor array (Clontech, CA, USA) dot blot as well
      as in laser capture microdissection (LCM) derived prostate cancer (CaP) specimens
      by quantitative RT-PCR. Western blot analysis and a fluorescent microscopy were
      used to characterize the molecular size and the cellular location of green
      fluorescent protein (GFP)-tagged DERPC fusion proteins. A colony formation assay
      was conducted to determine the effects of DERPC expression on tumor cell growth.
      RESULTS: A novel gene DERPC (Decreased Expression in Renal and Prostate Cancer)
      was identified and characterized. DERPC encoded a strong basic, proline- and
      glycine-rich nuclear protein. DERPC was ubiquitously expressed, with abundant
      expression in kidney, skeletal muscle, testis, liver, ovary, and heart and
      moderate expression in prostate. DERPC expression was reduced in renal (67%) and
      prostate tumors (33%). Expression of DERPC has inhibitory potential on CaP cell
      growth. Further, overexpression of DERPC in LNCaP cells caused alterations of
      nuclear morphology. CONCLUSION: This study suggests that decreased expression of
      DERPC may be implicated in tumorigenesis of renal and CaPs.

PMID- 12477977
TI  - The patient.com, 1 year later.

PMID- 12477978
TI  - Use of a meshed bilayered cellular matrix to treat a venous ulcer.

PMID- 12477979
TI  - A randomized controlled clinical trial to evaluate the effects of noncontact
      normothermic wound therapy on chronic full-thickness pressure ulcers.
AB  - OBJECTIVE: To determine the effect of noncontact normothermic wound therapy
      (NNWT) versus standard wound care on chronic full-thickness pressure ulcers.
      DESIGN: Prospective, randomized, controlled trial. SETTING: Veterans
      administration medical center and 7 long-term-care facilities. PATIENTS: 40
      inpatients with 43 Stage III and IV pressure ulcers. INTERVENTIONS: A sterile
      noncontact wound dressing was applied to 21 wounds for 24 hours per day, 7 days
      per week. Each day after the wound was irrigated and the noncontact dressing was
      changed, a heating element in the dressing was activated for 3 1-hour periods for
      12 weeks or until wound closure. Twenty-two control wounds were treated with
      standard, moisture-retentive dressings 24 hours per day, 7 days per week for 12
      weeks or until wound closure. MAIN OUTCOME MEASURE: Measurement of wound surface
      area. MAIN RESULTS: Healing rate for the NNWT group was significantly greater
      than for the control group (0.52 cm2 per week and 0.23 cm2 per week,
      respectively; P<.02). A clinically significant increase was seen among the NNWT
      group in the incidence of closure among wounds that completed the entire 12-week
      protocol compared with controls (11 of 14 or 79% and 8 of 16 or 50%,
      respectively; not significant). The mean slope of the individual regression
      analyses for the NNWT group was significantly different from the mean slope for
      the control group (-0.07 and -0.033, respectively; P<.05). Large wounds in the
      NNWT group demonstrated a significantly greater healing rate than large wounds in
      the control group (P <.05). CONCLUSION: Wounds treated with NNWT healed
      significantly faster than wounds in the control group. The healing rate was
      greatest for larger wounds treated with NNWT.

PMID- 12477980
TI  - Care of the laparoscopic colectomy patient.
AB  - Laparoscopic bowel surgery has demonstrated patient care benefits of decreased
      duration of hospital stay, smaller incisions, lower risk of cardiopulmonary
      complications, and reduced risk of small-bowel obstruction. Resection of
      complicated diverticular disease and inflammatory bowel disease can be
      technically challenging and may be associated with higher conversion rates. The
      applicability of these techniques to colon cancer is supported by a growing body
      of evidence that demonstrates similar survival and recurrence rates obtained by
      open resection and the exaggeration of the risk of port site recurrences.
      Laparoscopic colorectal surgery has also challenged much of the standard
      postoperative care plans used for colectomy. Optimal postoperative care of the
      laparoscopic colectomy patient requires an appreciation of the faster recovery
      enjoyed by these patients and the fact that ambulation and dietary advancement
      need to be accelerated. Coordination between the surgical team and the
      postoperative care team is essential to obtain all the benefits associated with
      this new approach to the management of colorectal disease.

PMID- 12477982
TI  - Pressure Ulcers in America: a commentary.

PMID- 12477983
TI  - Motor evoked potential monitoring--it's about time.

PMID- 12477984
TI  - Regulatory and medical-legal aspects of intraoperative monitoring.
AB  - Public policies are in place for health care to insure high quality, organized
      delivery of care to patients. Public policy issues for intraoperative monitoring
      include billing, coding, reimbursement, staffing, device approval, and liability.
      Staffing issues include privileging, credentialing, certifying, training, and
      professionalism. Those staffing processes provide ways that the profession passes
      judgment on individual's skills, knowledge, abilities, and training relevant to
      monitoring. These issues are reviewed here, along with a discussion of the
      respective roles of physicians and non-physicians in monitoring. Various billing
      codes for intraoperative monitoring are reviewed along with the circumstances in
      which they are to be used. Policy on the use of non-approved devices is also
      presented.

PMID- 12477985
TI  - Mechanisms of intraoperative brainstem auditory evoked potential changes.
AB  - Brainstem auditory evoked potential (BAEP) changes during intraoperative
      monitoring may reflect damage to or potentially reversible dysfunction of the
      ear, the eighth nerve, or the brainstem auditory pathways up to the level of the
      mesencephalon. They may also be caused by other physiologic mechanisms such as
      anesthesia, hypothermia, and acoustic masking from drilling noise, or they may
      result from technical factors that prevent proper stimulus delivery or recording
      of an evoked potential that is actually present. Cochlear ischemia or infarction
      resulting from compromise of the internal auditory artery and inner ear damage
      during temporal bone drilling will affect all BAEP components, including wave I.
      Direct mechanical or thermal trauma to the eighth nerve will delay, attenuate,
      and possibly eliminate waves III and V, but wave I, which is generated at the
      cochlear end of the eighth nerve, may be preserved. During scraping of tumor off
      the eighth nerve, force applied in an ear-toward-brainstem direction can avulse
      the fragile fibers of the distal eighth nerve at the area cribrosa. Prolonging
      the I-to-III interpeak interval during retraction of the cerebellum and brainstem
      reflects stretching of the eighth nerve, and is often reversible. Vasospasm
      within the eighth nerve can cause similar, potentially reversible BAEP changes.
      Damage to the brainstem auditory pathways at or below the level of the
      mesencephalon will delay and attenuate or eliminate wave V. Wave III is affected
      similarly if the damage is at or caudal to the region of the superior olivary
      complex. These BAEP changes may reflect direct mechanical or thermal damage to
      the brainstem, brainstem compression, or ischemia or infarction resulting from
      vascular compromise. During BAEP monitoring, examination of the pattern of BAEP
      changes, analysis of their correlation with surgical maneuvers, and investigation
      for possible contributory technical factors can help to determine the cause of
      the BAEP changes and provide the appropriate information to the rest of the
      surgical team.

PMID- 12477986
TI  - Mechanisms of signal change during intraoperative somatosensory evoked potential
      monitoring of the spinal cord.
AB  - In scoliosis surgery, intraoperative somatosensory evoked potential (SSEP)
      monitoring has reduced the incidence of postoperative neurologic deficits. Many
      factors affect the amplitude and latency of SSEP waveforms during surgery.
      Somatosensory evoked potential amplitude decreases with ischemia and anoxia
      because of temporal dispersion of the afferent volley and conduction block in
      damaged axons. In conjunction with surgical manipulations, minor drops in blood
      pressure may result in substantial SSEP changes that reverse when perfusion
      pressure is increased. Irreversible anoxic injury to central nervous system white
      matter with loss of SSEP waveforms is dependent on calcium influx into the
      intracellular space. Somatosensory evoked potential monitoring may be less
      sensitive for detecting acute insults in the presence of preexisting white matter
      lesions. Increased extracellular potassium from acute baro-trauma can block
      axonal conduction transiently even when there is no axonal disruption. Marked
      temperature-related drops in SSEP amplitude may occur after exposure of the spine
      but before instrumentation and deformity correction. Hypothermia may increase
      false-negative outcomes. Short-interval double-pulse stimulation may improve the
      sensitivity of the SSEP in detecting early ischemic changes. For neurosurgical
      procedures on the spinal cord the use of SSEP monitoring in improving
      postoperative outcome is less well established.

PMID- 12477987
TI  - Safety of intraoperative transcranial electrical stimulation motor evoked
      potential monitoring.
AB  - This article reviews intraoperative transcranial electrical stimulation (TES)
      motor evoked potential (MEP) monitoring safety based on comparison with other
      clinical and experimental brain stimulation methods and clinical experience in
      more than 15000 cases. Comparative analysis indicates that brain damage and
      kindling are highly unlikely. There have been remarkably few adverse events.
      Pulse train TES-induced or coincidental seizures (n = 5) are rare, probably
      because of very brief (<0.03 second) stimuli, anesthesia, and the general absence
      of predisposing cerebral conditions. Soft bite blocks may prevent tongue or lip
      laceration (n = 29) or mandibular fracture (n = 1). Rare cardiac arrhythmia (n =
      5) and intraoperative awareness (n = 1) may be coincidental. Minor scalp burns (n
      = 2) are rare. Although possible, no spinal epidural recording electrode
      complications or injuries resulting from TES-induced movement were found. There
      have been no recognized adverse neuropsychological effects, headaches, or
      endocrine disturbances. Comprehensive relative contraindications include
      epilepsy, cortical lesions, convexity skull defects, raised intracranial
      pressure, cardiac disease, proconvulsant medications or anesthetics, intracranial
      electrodes, vascular clips or shunts, and cardiac pacemakers or other implanted
      biomedical devices. Otherwise unexplained intraoperative seizures and possibly
      arrhythmias are indications to abort TES. With appropriate precautions in expert
      hands, the well-established benefits of TES MEP monitoring decidedly outweigh the
      associated risks.

PMID- 12477988
TI  - Anesthesia for intraoperative neurophysiologic monitoring of the spinal cord.
AB  - Intraoperative neurophysiologic monitoring (INM) using somatosensory and motor
      evoked potentials (MEPs) has become popular to reduce neural risk and to improve
      intraoperative surgical decision making. Intraoperative neurophysiologic
      monitoring is affected by the choice and management of the anesthetic agents
      chosen. Because inhalational and intravenous anesthetic agents have effects on
      neural synaptic and axonal functional activities, the anesthetic effect on any
      given response will depend on the pathway affected and the mechanism of action of
      the anesthetic agent (i.e., direct inhibition or indirect effects based on
      changes in the balance of inhibitory or excitatory inputs). In general, responses
      that are more highly dependent on synaptic function will have more marked
      reductions in amplitude and increases in latency as a result of the synaptic
      effects of inhalational anesthetic agents and similar effects at higher doses of
      intravenous agents. Hence, recording cortical somatosensory evoked potentials and
      myogenic MEPs requires critical anesthetic choices for INM. The management of the
      physiologic milieu is also important as central nervous system blood flow,
      intracranial pressure, blood rheology, temperature, and arterial carbon dioxide
      partial pressure produce alterations in the responses consistent with the support
      of neural functioning. Finally, the management of pharmacologic neuromuscular
      blockade is critical to myogenic MEP recording in which some blockade may be
      desirable for surgery but excessive blockade may eliminate responses. A close
      working relationship of the monitoring team, the anesthesiologist, and the
      surgeon is key to the successful conduct and interpretation of INM.

PMID- 12477989
TI  - Intraoperative electromyography.
AB  - Intraoperative electromyography (EMG) provides useful diagnostic and prognostic
      information during spine and peripheral nerve surgeries. The basic techniques
      include free-running EMG, stimulus-triggered EMG, and intraoperative nerve
      conduction studies. These techniques can be used to monitor nerve roots during
      spine surgeries, the facial nerve during cerebellopontine angle surgeries, and
      peripheral nerves during brachial plexus exploration and repair. However, there
      are a number of technical limitations that can cause false-positive or false
      negative results, and these must be recognized and avoided when possible. The
      author reviews these basic electrophysiologic techniques, how they are applied to
      specific surgical situations, and their limitations.

PMID- 12477990
TI  - Current practice of motor evoked potential monitoring: results of a survey.
AB  - Centers responding to a survey of MEP monitoring practices predominantly used
      transcranial electrical brain stimulation (TCES) with brief pulse trains and/or
      spinal cord stimulation (SCS) to elicit MEPs; transcranial magnetic stimulation
      and single-pulse TCES were not techniques of choice. Most centers using TCES had
      patient exclusion criteria (e.g., cochlear implants, cardiac pacemakers, prior
      craniotomy or skull fracture, history of seizures). Adverse effects included rare
      tongue injuries or seizures from TCES, and minor bleeding from needle electrodes
      in muscle. Spinal cord, peripheral nerve, and muscle recording sites were all
      employed. TCES with recording of muscle responses was the preferred MEP
      monitoring technique at the plurality of the centers. MEPs suitable for
      monitoring were obtained in about 91.6% of patients overall. Most of the failures
      were attributed to technical factors; preexisting neurologic dysfunction
      precluded MEP monitoring in approximately 1.7% of patients. Almost all centers
      monitored SEPs concurrently with MEPs. Overall, both measures remained stable
      during about 90.2% of cases. Adverse MEP changes occurred in about 8.3%; a little
      over half of these were accompanied by SEP changes. Adverse SEP changes without
      MEP changes occurred in about 1.5% of cases. SEPs and MEPs should be used
      together to optimally monitor the spinal cord.

PMID- 12477991
TI  - Ictal source localization in presurgical patients with refractory epilepsy.
AB  - Source localization of epileptic foci using ictal spatiotemporal dipole modeling
      (ISDM) yields reliable anatomic information in presurgical candidates. It
      requires substantial resources from EEG and neuroimaging laboratories. The
      profile and number of patients who may benefit from it are currently unknown. The
      purpose of this study is to demonstrate the clinical usefulness of source
      localization in a prospectively analyzed series. One hundred patients (51 male
      and 49 female patients) with mean age of 31 years (range, 2 to 63 years) and mean
      duration of refractory epilepsy of 20 years (range, 1 to 49 years) were enrolled
      consecutively in a presurgical protocol. Ictal EEG was available in 93 patients.
      ISDM was performed when suitable ictal EEG files were available. The clinical
      applicability of ISDM was examined in three patients groups: 37 patients in whom
      ictal EEG recording and MRI were congruent (group I), 30 patients in whom results
      were not completely congruent but not incongruent (group II), and 26 patients in
      whom the results were incongruent (group III). ISDM could be performed in 31 of
      100 patients: 11 in group I, 8 in group II, and 12 in group III. ISDM influenced
      decision making in none of the patients in group I, in 4 of 8 patients in group
      II, and in 10 of 12 patients in group III. Typically, the results of ISDM
      directed avoiding intracranial EEG recordings in what appeared to be unsuitable
      candidates for resection by clearly confirming the incongruency between ictal EEG
      and MRI findings. In this series of 100 presurgical candidates, ictal source
      localization could be performed in 31% of patients. In 14% of patients, it proved
      to be a key element in the surgical decision process.

PMID- 12477992
TI  - Infant polysomnography: reliability and validity of infant arousal assessment.
AB  - Infant arousal scoring based on the Atlas Task Force definition of transient EEG
      arousal was evaluated to determine (1). whether transient arousals can be
      identified and assessed reliably in infants and (2). whether arousal and no
      arousal epochs scored previously by trained raters can be validated reliably by
      independent sleep experts. Phase I for inter- and intrarater reliability scoring
      was based on two datasets of sleep epochs selected randomly from nocturnal
      polysomnograms of healthy full-term, preterm, idiopathic apparent life
      threatening event cases, and siblings of Sudden Infant Death Syndrome infants of
      35 to 64 weeks postconceptional age. After training, test set 1 reliability was
      assessed and discrepancies identified. After retraining, test set 2 was scored by
      the same raters to determine interrater reliability. Later, three raters from the
      trained group rescored test set 2 to assess inter- and intrarater reliabilities.
      Interrater and intrarater reliability kappa's, with 95% confidence intervals,
      ranged from substantial to almost perfect levels of agreement. Interrater
      reliabilities for spontaneous arousals were initially moderate and then
      substantial. During the validation phase, 315 previously scored epochs were
      presented to four sleep experts to rate as containing arousal or no-arousal
      events. Interrater expert agreements were diverse and considered as
      noninterpretable. Concordance in sleep experts' agreements, based on
      identification of the previously sampled arousal and no-arousal epochs, was used
      as a secondary evaluative technique. Results showed agreement by two or more
      experts on 86% of the Collaborative Home Infant Monitoring Evaluation Study
      arousal scored events. Conversely, only 1% of the Collaborative Home Infant
      Monitoring Evaluation Study-scored no-arousal epochs were rated as an arousal. In
      summary, this study presents an empirically tested model with procedures and
      criteria for attaining improved reliability in transient EEG arousal assessments
      in infants using the modified Atlas Task Force standards. With training based on
      specific criteria, substantial inter- and intrarater agreement in identifying
      infant arousals was demonstrated. Corroborative validation results were too
      disparate for meaningful interpretation. Alternate evaluation based on
      concordance agreements supports reliance on infant EEG criteria for assessment.
      Results mandate additional confirmatory validation studies with specific training
      on infant EEG arousal assessment criteria.

PMID- 12477993
TI  - A novel EEG artifact in the intensive care unit.
AB  - The authors describe a novel EEG artifact in two patients whose records were
      otherwise suppressed. The saw-toothed waveform, containing 5.5- and 11-Hz
      rhythms, was induced as a movement artifact by a hemoperfusion machine connected
      to the patient. The artifact is highly characteristic, but could be easily
      misinterpreted as a cerebral rhythm if one is not aware of the entity. The
      artifact should be suspected when invariant, saw-toothed rhythms appear beyond
      the temporal and occipital lobes, and also contaminate the electrocardiographic
      channel. It can be proved by its disappearance on stopping and reemergence with
      starting the rotary pump action of the device.

PMID- 12477994
TI  - Radioiodinated (I-125) monoclonal antibody 425 in the treatment of high grade
      glioma patients: ten-year synopsis of a novel treatment.
AB  - The present report is the follow-up of patients enrolled in a phase II clinical
      trial using I-MAb 425 as an adjuvant treatment for high grade gliomas. Patient
      median survivals support published data from an earlier preliminary report. From
      January 29, 1987 to January 25, 1997, 180 patients diagnosed with astrocytoma
      with anaplastic foci (AAF) and glioblastoma multiforme (GBM) were treated as
      outpatients with an average of three weekly intravenous or intraarterial
      injections of radiolabeled MAb 425. The mean dose was 140 mCi (5.2 GBq). Only one
      patient who received a single dose of more than 60 mCi (2.2 GBq) experienced
      acute toxicity. Patients received prior surgery and radiation therapy, with and
      without chemotherapy. Overall median survival for patients with GBM and AAF was
      13.4 and 50.9 months, respectively, with Karnofsky Performance Status (KPS)
      ranging from 40 to 100 and age ranging from 11 to 75 years. Prognostic factors
      (KPS and age) correlated positively with increased survival, with KPS the most
      important determinant of median survival. Data analysis was performed on patients
      followed 5 years or longer. We conclude that the administration of I-MAb 425 with
      intensive medical management demonstrates a significant increase in median
      survival and should be considered a therapeutic regimen for the management of
      patients with high grade gliomas.

PMID- 12477995
TI  - Long-term survival of patients with advanced/recurrent carcinoma of cervix and
      vagina after neoadjuvant treatment with methotrexate, vinblastine, doxorubicin,
      and cisplatin with or without the addition of molgramostim, and review of the
      literature.
AB  - A randomized phase III study was conducted to assess the addition of molgramostim
      (GM-CSF) to the combination of methotrexate, vinblastine, doxorubicin, and
      cisplatin (MVAC) in terms of response rate, progression-free survival, and
      survival in women with advanced, recurrent, or metastatic carcinoma of the cervix
      or vagina. Patients received four 4-week cycles of methotrexate 30 mg/m2 IV days
      1, 15, 22; vinblastine 3 mg/m2 IV days 2, 15, 22; doxorubicin 30 mg/m2 IV day 2;
      and cisplatin 70 mg/m2 IV day 2 with or without GM-CSF 5 microg/kg every 12 hours
      subcutaneously days 3 to 12. They were then reevaluated for operability. Those
      who were not surgical candidates were offered additional chemotherapy until
      progression or toxicity. Those who were surgical candidates were offered surgical
      resection of remaining tumor followed by involved-field external beam irradiation
      to sites of no prior irradiation and intraoperative irradiation to sites of prior
      external beam irradiation. This trial closed after 36 eligible patients were
      entered because of poor accrual. Although more than 40% of patients on each arm
      received fewer than four cycles of MVAC, the clinical response rate was 78% (95%
      CI: 52-94%) and 50% (95% CI: 26-74%) for MVAC and MVAC + GM-CSF, respectively;
      the median time to progression was 10.2 and 11.8 months, respectively; and median
      survival was 13.8 and 16.0 months, respectively. Toxicity was substantial, with
      more than 40% experiencing grade III to IV leukopenia, and nearly 40%
      experiencing grade III to IV stomatitis. MVAC with or without GM-CSF support
      achieves high response rates in patients with advanced, recurrent, or metastatic
      cervical carcinoma despite dose reductions and deletions. Its progression-free
      survival and overall survival rates appear promising. These results need to be
      confirmed within a large randomized phase III clinical trial.

PMID- 12477996
TI  - Randomized, placebo-controlled, phase III surgical adjuvant clinical trial of
      megestrol acetate (Megace) in selected patients with malignant melanoma.
AB  - A randomized, double-blind, placebo-controlled phase III clinical trial was
      performed to assess megestrol acetate (Megace) as a postsurgical adjuvant therapy
      for patients with locally advanced malignant melanoma. Patients whose tumors were
      greater than 1.7 mm thick and had no regional lymph node involvement and patients
      with regional lymph node involvement were randomized to receive either 160 mg
      twice per day oral suspension of megestrol acetate or placebo. Treatment was
      administered for a maximum of 2 years or until disease progression. The study
      accrued 262 eligible patients. All but two patients were followed until death or
      a minimum of 4.5 years. Disease progression was documented in 156 patients.
      Neither progression-free survival (PFS) nor overall survival (OS) was found to
      differ between the treatments. The median PFS was 2.4 years in the megestrol
      acetate arm and 2.3 years in the placebo arm. Multivariate analysis revealed a
      significantly decreased PFS for patients with four or more positive regional
      lymph nodes and metachronous nodal disease. Median OS was 5.3 years in the
      megestrol acetate arm and 3.9 years in the placebo arm. Multivariate analysis
      revealed that OS was significantly decreased for patients 70 years of age or
      older with four or more positive lymph nodes. Adjuvant therapy with megestrol
      acetate oral suspension administered at a dose of 160 mg twice a day for 2 years
      was not found to be effective in prolonging PFS or OS in patients with surgically
      resected, locally advanced melanoma.

PMID- 12477997
TI  - Goserelin acetate as treatment for recurrent endometrial carcinoma: a Gynecologic
      Oncology Group study.
AB  - This Gynecologic Oncology Group (GOG) study was designed to estimate the activity
      of goserelin acetate as treatment for advanced and recurrent endometrial
      carcinoma. Forty evaluable patients received monthly treatment with goserelin
      acetate at a dose of 3.6 mg, given subcutaneously. Standard GOG response and
      adverse effects criteria were used. The median age of patients was 71 years.
      Seventy-one percent of patients had received prior radiation therapy; 18% of
      patients were reported to have received prior progestational therapy for
      endometrial cancer. One patient had received prior chemotherapy. There were two
      complete responses (5%) and three partial responses (7%). One response occurred
      in a patient who previously did not respond to progestin therapy after having
      achieved a response. The overall response rate was 11% (95% CI: 4-27%). Median
      progression-free survival was 1.9 months and median overall survival was 7.3
      months. No severe or life-threatening toxicities occurred because of goserelin.
      Deep venous thrombosis developed in two patients. This study confirmed the
      limited activity of goserelin acetate in endometrial carcinoma, with only one
      response in a patient previously treated with hormonal therapy. The activity is
      insufficient to warrant further study of the single agent at this time.
      Elucidation of the mechanism of action of this drug may allow more effective use
      in conjunction with other agents in the future.

PMID- 12477998
TI  - Phase II trial of paclitaxel-epirubicin in patients with recurrent soft-tissue
      sarcoma.
AB  - Twenty-seven patients with recurrent soft-tissue sarcoma (STS) entered a
      multicenter study to determine the efficacy of the combination paclitaxel 200
      mg/m and epirubicin 75 mg/m administered every 21 days. Patient characteristics
      included the following: 14 women and 13 men, median age of 52 years, 12 patients
      had local recurrence and 20 had metastasis. Eighteen patients had previously
      received chemotherapy for recurrent disease. The main grade III to IV hematologic
      toxicities were neutropenia (70%), anemia (3.7%), and thrombocytopenia (7.4%).
      Febrile neutropenia occurred in 5 patients (18.5%). Severe nonhematologic
      toxicities were rare. Two patients had a partial response (7.4%; 95% CI: 2.6
      12.2%), with a median response duration of 3 and 5 months. Six patients had
      stable disease (22.2%), and 19 had progressive disease (70.5%). The median
      overall survival from study inclusion was 8 months. This study suggests the
      association paclitaxel-epirubicin does not increase the known activity of
      anthracycline in recurrent STS.

PMID- 12477999
TI  - Phase I study of combination chemotherapy with 5-fluorouracil (5-FU) and
      nedaplatin (NDP): adverse effects and eecommended dose of NDP administered after
      5-FU.
AB  - When nedaplatin (NDP) was used as a single agent in the phase I study, the dose
      limiting toxicity (DLT) was thrombocytopenia and the recommended dose (RD) was
      100 mg/m2. However, the DLT, maximum tolerated dose (MTD) and RD of NDP used in
      combination with 5-fluorouracil remained unknown. Therefore, we performed this
      study to assess the DLT and RD of NDP administered after 5-fluorouracil (5-FU).
      In this study, 5-FU was administered to 38 patients at a fixed dose (700 mg/m2/d
      on days 1-5) and NDP administered on day 6 at an initial dose of 80 mg/m2, which
      was subsequently increased to 100, 120, 130, 140, 150, and 160 mg/m2. The DLT of
      NDP was leukopenia and its MTD and RD were 160 and 150 mg/m2, respectively.
      Concerning impairment of renal function, only two patients had a grade I increase
      in serum creatinine. There were 19 responders (50%, 19/38) achieving partial
      response or complete response in the evaluation of antitumor effect. The result
      of this study is notable in that administration of 5-FU before NDP allows the
      dose of NDP to be substantially increased.

PMID- 12478000
TI  - Correlation of serum IL-2, IL-6 and IL-10 levels with International Prognostic
      Index in patients with aggressive non-Hodgkin's lymphoma.
AB  - Cytokines play important roles in the pathogenesis of lymphomas. The aim of this
      study was to determine the relations between serum levels of interleukin-2 (IL
      2), IL-6, and IL-10 and parameters of International Prognostic Index (IPI). Serum
      levels of IL-2, IL-6, and IL-10 were measured using a sensitive enzyme-linked
      immunosorbent assay in the pretreatment frozen sera from 43 patients with non
      Hodgkin's lymphoma. The patients we included in the study were divided into two
      groups, one with high risk and the other with low risk according to the IPI in
      regard to their ages, stages, performance status, extranodal involvements, and
      serum levels of lactate dehydrogenase. In the high-risk group, serum levels of IL
      2 (0.852 +/- 0.268 ng/ml), IL-6 (0.461 +/- 0.206 ng/ml), and IL-10 (0.816 +/-
      0.240 ng/ml) were found to be higher than serum levels of IL-2 (0.667 +/- 0.170
      ng/ml), IL-6 (0.355 +/- 0.075 ng/ml), and IL-10 (0.643+0.177 ng/ml) in the low
      risk group ( < 0.05). There was a correlation between the patients with high risk
      according to the IPI criteria and high levels of serum cytokines (IL-2, IL-6, IL
      10). Knowledge of the serum levels of these cytokines in patients with newly
      diagnosed aggressive non-Hodgkin's lymphoma may help us to have some information
      about the possible prognosis, the activation of disease, and to decide on
      appropriate therapeutic approaches for individual patients.

PMID- 12478001
TI  - Management of treatment-resistant cutaneous sarcoidosis with radiation.
AB  - Cutaneous manifestations of sarcoidosis frequently respond to medical management.
      Occasionally, however, this problem will reappear with the discontinuation of
      medication and ultimately result in the scarring and disfigurement of the
      patient's skin. Such a patient was treated with radiation therapy and had
      considerable improvement in her acute disease.

PMID- 12478002
TI  - CNS listeriosis confused with leptomeningeal carcinomatosis in a patient with a
      malignant insulinoma.
AB  - We describe a case of presumed listeria monocytogenes rhomboencephalitis, which
      was initially confused with leptomeningeal carcinomatosis in a patient with a
      malignant carcinoid tumor. Long-term corticosteroid treatment and
      immunosuppression caused by malignancy predisposed the patient to developing
      listeriosis. The clinical and radiologic features of this illustrative case are
      described. Listeriosis is an important treatable differential diagnosis in
      patients with malignancy presenting with neurologic signs.

PMID- 12478003
TI  - Salvage treatment of recurrent skin cancer of the midface.
AB  - Nine patients with recurrent cutaneous cancers of the midface were treated by
      definitive surgery (with adjuvant radiotherapy in five individuals). The clinical
      courses were marked by local and regional relapses in six cases. Although the
      prognosis may be generally poor, aggressive therapy, as feasible, seems warranted
      in these patients because death was not typically rapid after reappearance of
      disease in several patients.

PMID- 12478005
TI  - Predictive value of P53, BCL-2, and BAX in advanced head and neck carcinoma.
AB  - Because the apoptotic process appears to be involved in the response-to-treatment
      of chemotherapy and radiotherapy, we investigated the prognostic value of the
      expression of three apoptosis-associated genes (p53, Bax, and Bcl-2) in tumor
      biopsies from patients with locally advanced head and neck carcinoma. Using
      specific monoclonal antibodies, immunohistochemical staining for p53, Bax, and
      Bcl-2 was performed on tumor material from 43 patients before their scheduled
      adjuvant chemoradiotherapy. Results indicated that the response to treatment was
      83.7% (36 of 43 patients). Bax staining was positive in 8 cases (19.5%), p53 in
      19 (47.5%), and Bcl-2 in 4 patients (10.8%). There were no statistically
      significant correlations between any of the apoptosis genes assayed and the
      patients' response to treatment or to overall survival. In the univariate
      statistical analysis, response-to-treatment was the only significant variable (p
      = 0.013) predictive of survival rate. These results suggest that p53, Bax, and
      Bcl-2 expression are not significant predictive factors of response to induction
      treatment in locally advanced head and neck carcinoma and that their routine use
      as prognostic markers cannot be recommended.

PMID- 12478004
TI  - Subsets more likely to benefit from surgery or prophylactic cranial irradiation
      after chemoradiation for localized non-small-cell lung cancer.
AB  - After chemoradiation for localized non-small-cell lung cancer, surgery and
      prophylactic cranial irradiation (PCI) have been used as additional therapies.
      Less than a third of patients develop brain recurrences, or have local recurrence
      as their sole initial site of recurrence; these are groups that would benefit
      from PCI or surgery, respectively. Pretreatment identification of patients more
      likely to benefit from surgery or PCI would be useful. A retrospective analysis
      of 80 patients was performed to determine prognostic factors for such patterns of
      failure. Twenty-nine patients were subsequently selected for surgery in a
      nonrandomized manner. Seventeen patients had isolated local initial recurrence
      and 15 had brain recurrences. In multivariable analysis, female gender and
      elevated LDH were found to be risk factors for brain recurrence. In the subset
      with stage III disease (n = 76), squamous cell histology was a risk factor for
      isolated initial local recurrence in both univariable and multivariable analysis.
      It is possible to identify subsets that may show increased benefit from PCI or
      surgery.

PMID- 12478006
TI  - Lymphocyte subpopulations and interleukin levels in high-risk melanoma patients
      treated with high-dose interferon A-2B.
AB  - Immunologic effects of high-dose interferon are still unclear. We have evaluated
      changes in blood lymphocyte subpopulations, immunoglobulins, and multiple
      interleukin in patients with high-risk cutaneous melanoma on adjuvant treatment
      with high-dose interferon and compared pretreatment values with normal controls.
      Samples were obtained before treatment, 1 month after induction treatment and at
      3, 6, and 12 months of maintenance treatment from 24 patients with high-risk
      melanoma. Lymphocyte subpopulations were measured by flow cytometry and
      interleukin and immunoglobulin levels by radioimmunoassay. A statistically
      significant reduction in B-lymphocytes (p < 0.001), natural killer (NK) cells (p
      = 0.0004), and monocytes (p = 0.04), and an elevation in CD4/CD8 ratio (p <
      0.0001) was observed after 1 month of intravenous interferon. No changes were
      seen in CD3, CD4, and CD8 lymphocytes. No changes in interleukin (IL)-2, -4, or 
      5 were observed during 1 year of treatment. IL-2 pretreatment levels were
      significantly lower than healthy blood donors (p = 0.001), and IL-5 pretreatment
      levels were significantly higher (p = 0.0056). IL-10 levels significantly dropped
      after 6 months of treatment (p = 0.01). Immunoglobulins (IgG, IgA, IgM) remained
      within normal ranges. Three patients had elevated pretreatment levels of IgE.
      There is a time- and dose-dependent impact of interferon on numbers of
      circulating B lymphocytes, NK cells, monocytes, and CD4/CD8 ratio. Defects in
      cellular and humoral immunity are suggested by the low IL-2 and high IL-5 levels,
      measured in patients with melanoma as compared with healthy controls.

PMID- 12478007
TI  - Cutaneous angiosarcoma of breast after lumpectomy, axillary lymph node
      dissection, and radiotherapy for primary breast carcinoma: case report and review
      of the literature.
AB  - Malignant neoplasms known to develop after external beam radiation include
      angiosarcoma. Although angiosarcoma developing in a lymphedematous arm after
      radical mastectomy is a well-known phenomenon, cutaneous angiosarcoma after
      radiotherapy for breast carcinoma has been rarely documented. Herein we present a
      case with cutaneous angiosarcoma that developed in a 69-year-old woman's breast 5
      years after she underwent conservative treatment to the breast: lumpectomy,
      axillary lymph node dissection, and radiation therapy to the breast. The possible
      relation of the angiosarcoma to the initial radiotherapy, early diagnosis, and
      treatment is discussed.

PMID- 12478008
TI  - Acral erythrodysesthesia syndrome caused by intravenous infusion of docetaxel in
      breast cancer.
AB  - Docetaxel-induced skin reactions include hypersensitivity, edema, skin toxicity
      with erythrodysesthesia syndrome, infusion site reactions, alopecia, nail
      onycholysis, nail pigmentation, photosensitivity, scleroderma, and others, for
      example, stomatitis and paresthesias. However, of all reported effects, the acral
      erythrodysesthesia syndrome has only rarely been described in the literature. We
      report on two female patients with breast cancer who on treatment with docetaxel
      developed acral erythrodysesthesia syndrome. It presented as bizarrely shaped,
      burning skin reactions at their hands and feet. Histology of skin biopsies
      revealed microscopic damages to the eccrine sweat glands in both patients. Skin
      patch testing with docetaxel was negative. None of the reports dealing with side
      effects of docetaxel chemotherapy has described acral erythrodysesthesia syndrome
      with the histologic features of syringo-squamous metaplasia and eccrine
      neutrophilic hidradenitis. We propose here that these characteristic histologic
      features are essential in the differentiation from fixed drug eruption and
      localized graft-versus-host disease.

PMID- 12478009
TI  - Excellent long-term survival in patients with early-stage primary bone lymphoma
      treated with doxorubicin-based chemotherapy and local radiotherapy.
AB  - Primary bone lymphoma accounts for less than 5% of primary extranodal
      presentations, and the majority are of the diffuse, large cell, B-cell type. The
      study presents the authors' 21 years of experience (1979-2000) in ten patients
      with early stage (IE-IIE) primary bone lymphoma. All patients were treated with
      doxorubicin-based chemotherapy. Seven received consolidation radiotherapy to an
      area encompassing the primary tumor with generous margins, including the adjacent
      soft tissues, and in two stage IIE patients also to the regional lymph nodes.
      Mean total dose was 3989 cGy. Nine patients are alive with no evidence of
      recurrent disease. There are no severe late side effects, and only one patient
      died due to therapy-resistant small cell lung cancer (second primary), while in
      complete remission from his primary lymphoma. Albeit retrospective in nature with
      a small patient accrual, this study demonstrates that primary bone lymphoma is a
      curable disease following aggressive doxorubicin-based chemotherapy. The exact
      rule of radiation therapy is yet to be determined.

PMID- 12478010
TI  - Treatment of recurrent malignant gliomas with stereotactic intensity modulated
      radiation therapy.
AB  - Malignant gliomas are usually refractory to aggressive combined-modality therapy,
      and the incidence of recurrence and death after treatment is very high. State-of
      the-art techniques such as stereotactic intensity-modulated radiation therapy
      (IMRT) are now available to deliver a high dose of radiation to the tumor with
      relative preservation of surrounding tissues to achieve optimal tumor coverage
      with minimal toxicity. We report 10 patients (median age 48 years) with recurrent
      malignant gliomas that were treated with stereotactic directed IMRT. Initial
      tumor histologies included one low grade glioma (upgraded to anaplastic
      astrocytoma at recurrence), four anaplastic astrocytomas, and four glioblastomas
      multiforme. One patient was originally presumed to have a brain metastasis
      secondary to renal cell carcinoma but was pathologically confirmed as having
      glioblastoma multiforme at the time of recurrence. Before recurrence, all
      patients had been treated with external beam radiation therapy (median 59.7 Gy).
      All recurrences were confirmed by a subtotal resection (5/10) or by imaging
      (5/10). The median Karnofsky performance score at the time of IMRT was 80. The
      median tumor volume was 34.69 cm. Treatment was delivered on a 10-MV linear
      accelerator with a mini-multileaf collimator, MIMiC, and planned with
      Peacock/Corvus software. Radiation was delivered in daily fractions of 5 Gy, to a
      total median dose of 30 Gy at the 71% to 93% median isodose line. Median overall
      survival time was 10.1 months from the date of stereotactic treatment, with 1-
      and 2-year survival rates of 50% and 33.3%, respectively. Fractionated
      stereotactic intensity modulated radiation therapy is a novel technique used in
      the treatment of recurrent malignant gliomas, which produces results comparable
      to other currently used stereotactic techniques.

PMID- 12478011
TI  - Single institute experience of chemotherapy and adjuvant radiotherapy for
      localized aggressive non-Hodgkin's lymphoma: retrospective analysis of the
      clinical efficacy of radiation therapy.
AB  - We retrospectively analyzed the clinical outcome of localized aggressive lymphoma
      treated with chemotherapy and adjuvant radiotherapy. Between 1982 and 1998, 77
      patients who were diagnosed as having aggressive lymphoma stage I-II were treated
      with chemotherapy followed by radiation therapy. The median radiation dose was
      44.4 Gy (range, 30-64 Gy). Some patients who achieved complete response after
      chemotherapy received limited-field radiation to reduce toxicity. Several
      prognostic factors were analyzed in the overall (OAS) and relapse-free survival
      (RFS) by both uni- and multivariate analysis. The 5-year rates of OAS and RFS
      were 74.6% and 70.8%, respectively. Patient age (p = 0.016), radiation dose (p =
      0.043), and prognostic score proposed by the Japan Lymphoma Radiation Therapy
      Group (JLRTG; p = 0.0073) were significant predictive factors for OAS. As for
      RFS, predictive factors were patient age (p = 0.042), elevated level of serum
      lactic dehydrogenase (p = 0.046), and JLRTG score (p = 0.05). At the multivariate
      level, only patient age greater than 60 years was a significantly adverse
      variable for both OAS (p = 0.0079) and RFS (p = 0.0198). Our treatment strategy
      was thought to be acceptable with satisfactory outcomes. Limited-field radiation
      may have possible advantages in toxicity if it does not lead to worsening of the
      outcome, although a conclusive result could not be obtained by the current
      analysis.

PMID- 12478012
TI  - Adjuvant intraperitoneal chemotherapy with cisplatinum, mitoxantrone, 5
      fluorouracil, and calcium folinate in patients with gastric cancer: a phase II
      study.
AB  - Gastric carcinoma remains one of the leading causes of cancer-related death in
      the world. Clinical studies have revealed that approximately two thirds of the
      patients seek treatment for early recurrence within the abdominal cavity. The aim
      of this phase II study was to evaluate the toxicity, feasibility, and efficacy of
      adjuvant intraperitoneal chemotherapy (IPCT) with cisplatin, mitoxantrone, 5
      fluorouracil (5-FU), and folinic acid in patients with stage II-III gastric
      cancer. Patients with stage II and III gastric cancer aged between 15 and 70
      years, after curative resection, with adequate liver, renal, and cardiac function
      were included in the study. The chemotherapy regimen consisted of cisplatin 60
      mg/m2, mitoxantrone 12 mg/m2, 5-FU 600 mg/m2, and folinic acid 60 mg/m2,
      delivered intraperitoneally, diluted in 2 l normal saline. Intraperitoneal fluid
      was not drained. Each course of IPCT was repeated every 4 weeks for a total 6
      cycles. Thirty-nine patients were enrolled in the study. Twenty-eight of the 39
      patients (71.8%) completed six courses of the planned schedule. One patient
      (2.6%) died after a fourth cycle of IPCT from an undetermined reason. The major
      nonhematologic toxicity from IPCT was grade I-III nausea and/or vomiting
      experienced by 27 patients (69.2%). Twenty-four (61.5%) patients reported
      abdominal discomfort. Median follow-up was 23 (range: 3-105) months. Twenty-five
      patients (64.1%) were dead. Median disease-free survival and overall survival
      were 12 (CI 95%; 8.3-15.7 months) and 19 months (CI 95%; 10.5-27.5 months),
      respectively. The cumulative 5-year disease-free survival and overall survival
      were 24.7% and 30.7%, respectively. The regimen was generally associated with
      acceptable toxicity. However, adjuvant IPCT has similar survival rates in
      comparison to no adjuvant treatment; thus, it cannot be currently recommended
      outside the context of a clinical trial.

PMID- 12478013
TI  - Hypersensitivity reaction to cisplatin during chemoradiation therapy for
      gynecologic malignancy.
AB  - Hypersensitivity reactions to intravenous cisplatin are rare. The appearance of
      hypersensitivity reactions in 4 of 25 consecutive patients treated with
      concomitant pelvic radiation and weekly intravenous cisplatin for gynecologic
      malignancies is reported. The reactions appeared within hours of cisplatin
      delivery and included primarily fever, rash, and pruritus. Infection was ruled
      out by blood cultures and other laboratory studies. Affected patients were
      treated prophylactically with an antihistamine before subsequent courses of
      cisplatin, with excellent results. The high rate of hypersensitivity reactions in
      our series may be attributable to tumor necrosis and cytokine release caused by
      the pelvic irradiation. Clinicians should be aware of this potential side effect
      so that early premedication regimens can be instituted to prevent unnecessary
      toxicity.

PMID- 12478014
TI  - Oxaliplatin with high-dose leucovorin and infusional 5-fluorouracil in irinotecan
      pretreated patients with advanced colorectal cancer (ACC).
AB  - The purpose of this study was to evaluate the efficacy and tolerance of the
      bimonthly administration of oxaliplatin in combination with high-dose leucovorin
      and infusional 5-fluorouracil (5-FU) (FOLFOX2 regimen) in patients with advanced
      colorectal cancer (ACC) who did not respond or whose disease progressed within 3
      months after front-line treatment with CPT-11-containing regimens. Forty-one
      patients with ACC who did not respond or whose disease progressed after front
      line treatment with CPT-11 + 5-FU/leucovorin were enrolled. Oxaliplatin was
      administered at the dose of 100 mg/m2 on day 1 as a 2-hour infusion
      simultaneously but through different lines with leucovorin (500 mg/m2 on days 1
      and 2); 5-FU was given at the dose of 1,750 mg/m2/d as a 22-hour continuous
      intravenous infusion on days 1 and 2. The regimen was repeated every 2 weeks. In
      an intention-to-treat analysis, complete response was achieved in one (2.4%) and
      partial response in six (14.6%) patients (overall response rate: 17%; 95% CI:
      5.56-28.59%); stable disease and progressive disease were observed in 15 (36.6%)
      and in 19 (46.31%) patients, respectively. The median duration of response and
      the median time to tumor progression were 6 and 8.5 months, respectively. The
      median overall survival was 12 months and the probability for 1-year survival was
      42.9%. Grade III/IV neutropenia occurred in 17 (41%) patients and febrile
      neutropenia developed in one of them (2%). There was no treatment-related death.
      Peripheral neuropathy greater than or equal to grade II occurred in 24 (58%)
      patients. Other toxicities were relatively mild. The bimonthly administration of
      oxaliplatin in combination with high-dose leucovorin and 48-hour continuous
      infusion of 5-FU is a relatively active and well-tolerated regimen for patients
      with ACC resistant or refractory to CPT-11 + 5-FU (continuous
      infusion)/leucovorin.

PMID- 12478015
TI  - Case of thrombotic thrombocytopenic purpura associated with disseminated gastric
      cancer.

PMID- 12478016
TI  - High incidence of central nervous system involvement in patients with breast
      cancer treated with epirubicin and docetaxel.

PMID- 12478017
TI  - Magnetic resonance imaging in bowel imaging.

PMID- 12478018
TI  - Techniques for magnetic resonance imaging of the bowel.
AB  - This review focuses on the technical aspects that have allowed the development of
      practical bowel imaging using magnetic resonance imaging, including the
      acquisition methods and improvements in the underlying technology. An overview of
      the current techniques for small and large bowel magnetic resonance examinations
      is provided and the scene set for the more detailed examination of specific
      technical aspects such as contrast media and fecal tagging addressed in other
      later articles in this issue.

PMID- 12478019
TI  - Oral contrast agents for magnetic resonance imaging of the bowel.
AB  - The development of fast imaging sequences, which provide the ability to acquire
      motion-free T1- and T2-weighted images of static fluids, has greatly increased
      the interest in magnetic resonance imaging of the small bowel. Luminal distension
      is a necessary prerequisite for small bowel imaging methods because collapsed
      bowel loops can hide even large lesions and may mimic wall thickening. Poor
      distension of normal bowel loops in basal conditions has led researchers to study
      different oral contrast media to optimally distend the bowel lumen. Several MR
      oral contrast agents with various signal properties are available. According to
      these signal properties, agents are classified as positive ("bright" lumen),
      negative ("dark" lumen), or biphasic ("bright" lumen on T1 and "dark" on T2, or
      conversely "dark" lumen on T2 and "bright" on T1). Positive contrast agents cause
      a reduction in T1 relaxation time; consequently, these agents act on T1-weighted
      images by increasing the signal intensity of the bowel lumen. Negative contrast
      agents are based on superparamagnetic particles and act by inducing local field
      inhomogeneities, which results in shortening of both T1 and T2 relaxation times.
      Using superparamagnetic contrast agents, T2-weighted effects are predominant.
      Biphasic contrast agents are substances that have different signal intensities on
      different sequences, depending on the concentration at which they are
      administered. The choice of a single agent presents advantages and disadvantages;
      thus, the radiologist should choose the appropriate contrast medium according to
      the clinical setting, MR experience, availability of the agent, and patient
      tolerance.

PMID- 12478020
TI  - Technical challenges and clinical applications of magnetic resonance
      enteroclysis.
AB  - With the advent of gradient systems the image quality of ultrafast pulse
      sequences, i.e., half Fourier acquisition single shot turbo spin echo (HASTE),
      true fast imaging with steady-state processing and fast low angle shot (FLASH),
      improved substantially and clinical applications including small bowel imaging
      became feasible. Within this context, magnetic resonance enteroclysis was
      developed as a comprehensive examination of the small bowel, providing luminal,
      transmural, and exoenteric diagnostic information of small bowel abnormalities.
      Clinical applications of magnetic resonance enteroclysis include diagnostic
      evaluation and follow-up of patients with inflammatory or neoplastic diseases and
      small bowel obstruction.

PMID- 12478021
TI  - Small bowel magnetic resonance imaging for inflammatory bowel disease.
AB  - The presented concept of hydro-magnetic resonance imaging (MRI) using a 2.5%
      mannitol solution as an orally applicable intraluminal contrast agent is a
      meaningful, reproducible, and reliable imaging method for the depiction of the
      small bowel. Especially in patients with Crohn's disease, hydro-MRI is the
      imaging method of first choice because hydro-MRI offers the advantage of a
      superior depiction of the inflamed bowel wall and the extramural complications of
      this disease without radiation exposure. In addition, hydro-MRI allows for a
      reliable assessment of the inflammatory activity, especially for the
      differentiation between an active and an inactive (scarred) stenosis. In
      particular, the mural enhancement, the length as well as the wall thickness of
      inflamed bowel segments, are considered to be significant MR parameters for the
      determination of the activity of Crohn's disease. Hydro-MRI of the colon is
      suitable for the depiction of pathologic changes in ulcerative colitis, but in
      contrast to Crohn's disease, the assessment of disease activity by hydro-MRI is
      unreliable in ulcerative colitis, probably because of the low spatial resolution
      (mucositis in ulcerative colitis vs. transmural inflammation in Crohn's disease).
      Hydro-MRI does not allow a reliable classification of inflammatory bowel
      diseases, but in ambiguous cases, hydro-MRI may provide helpful information for
      the differentiation of Crohn's disease and ulcerative colitis. There are no data
      of larger patient groups published regarding MR findings in inflammatory bowel
      diseases besides Crohn's disease and ulcerative colitis, but hydro-MRI is a
      promising imaging tool for these entities, which should be assessed in additional
      studies.

PMID- 12478022
TI  - Colorectal cancer screening: a challenge for magnetic resonance colonography.
AB  - The high incidence of colorectal carcinoma and the fact that colorectal cancer
      mostly arises from benign adenomas have led to recommendations for screening
      programs. The introduction of ultrafast three-dimensional datasets acquired by
      cross-sectional imaging modalities (computed tomography or magnetic resonance
      imaging) in combination with new postprocessing modes, known as virtual
      endoscopy, has led to new discussion on the recommendation of screening tests for
      colorectal cancer. Published results have indicated a high sensitivity for
      computed tomographic colonography and magnetic resonance-based colonography. Both
      techniques currently must be combined with colon cleansing. Three-dimensional
      data acquisition for magnetic resonance-based colonography is less than 1 minute
      using three-dimensional gradient-echo sequences. The lack of ionizing radiation,
      the low risk and discomfort to patients, and new techniques of minimized patient
      preparation make this magnetic resonance technique an attractive diagnostic
      procedure for colorectal lesions, with many aspects for use as a screening
      method.

PMID- 12478023
TI  - Magnetic resonance colonography with fecal tagging: an innovative approach
      without bowel cleansing.
AB  - To date, virtual colonography mandates bowel cleansing in a manner similar to
      colonoscopy. Because more than half of patients undergoing bowel preparation
      complain about negative side effects, patient acceptance is negatively impacted.
      To assure high patient acceptance of MR colonography, bowel cleansing needs to be
      eliminated. This can be accomplished by fecal tagging, a concept based on
      altering the signal intensity of stool by adding contrast-modifying substances to
      regular meals. This article describes different fecal tagging approaches and
      points out both advantages and limitations of these strategies.

PMID- 12478024
TI  - Antibody responses in postsplenectomy trauma patients receiving the 23-valent
      pneumococcal polysaccharide vaccine at 14 versus 28 days postoperatively.
AB  - BACKGROUND: We have previously demonstrated, using functional antibody assays,
      that patients undergoing splenectomy for trauma exhibit a better response to
      pneumococcal immunization when vaccinated at 14 days postoperatively versus 1 or
      7 days. However, patients immunized at 14 days failed to reach the response of
      normal controls. This study was conducted to determine whether even later
      immunization would improve the antibody response. METHODS: Forty surviving
      patients undergoing emergent splenectomy were randomized to receive Pneumovax at
      14 or 28 days after splenectomy. Blood samples were drawn at the time of
      vaccination (prevaccination) and 4 weeks later (postvaccination). A control group
      of 24 healthy adults was used for comparison. Antibody titers to four of the most
      common serotypes were determined by enzyme-linked immunosorbent assay and
      opsonophagocytic assay (OPA). RESULTS: Samples from 38 patient were analyzed.
      Each serotype and each group tested demonstrated a statistically significant
      increase in geometric mean enzyme-linked immunosorbent assay immunoglobulin G
      antibody concentration (microg/mL) and OPA titer (1/dilution) after vaccination.
      There were no statistically significant differences (p >or= 0.07) in the
      immunoglobulin G antibody concentrations and OPA titers between the 14-day or the
      28-day study groups when compared with normal healthy adults regardless of the
      serotype tested. In addition, there were no differences in the antibody responses
      between the 14-day and the 28-day study groups. CONCLUSION: Despite our previous
      study suggesting that delay in vaccination after emergent splenectomy resulted in
      improved antibody response, antibody response was not improved any further by
      delaying vaccination to 28 days.

PMID- 12478025
TI  - Pelvic radiography in blunt trauma resuscitation: a diminishing role.
AB  - BACKGROUND: An anteroposterior pelvic radiograph (PXR) continues to be
      recommended by Advanced Trauma Life Support protocol as an early diagnostic
      adjunct in the resuscitation of blunt trauma patients. At the same time, computed
      tomographic (CT) scanning has become a practice standard for diagnosis of most
      abdominal and pelvic injury. The objective of this study was to determine the
      necessity of obtaining an early PXR in stable trauma patients who will undergo CT
      scanning during the initial resuscitation. METHODS: A retrospective review of all
      blunt trauma patients undergoing immediate abdomen and pelvic CT scanning was
      performed from July 2000 until June 2001 at an urban Level I trauma center. These
      patients were divided into two groups depending on whether they also received a
      PXR (group I) or not (group II). At the time of the study, there was no formal
      protocol to determine which patients underwent pelvic radiography. Radiology
      reports of all PXRs and CT scans were reviewed. Patient demographics and Injury
      Severity Scores (ISSs) were abstracted from our trauma registry. The data were
      analyzed using Student's test. RESULTS: A total of 686 patients with blunt trauma
      underwent CT scanning of the abdomen and pelvis. Group I consisted of 311 (45%)
      patients with an average ISS of 12.3 +/- 0.7. In group I, 56 (10%) patients were
      found to have at least one pelvic fracture on CT scan, 38 of which were also
      identified on the PXR. Defining CT scanning as the definitive test, the
      sensitivity and specificity of the PXR in group I was 68% and 98%, respectively.
      The false-negative rate for pelvic radiography was 32%. In all patients with a
      positive PXR, the majority (55%) had either additional fractures or an increase
      in the Young and Burgess grade of fracture diagnosed on CT scan. Group II
      consisted of 375 patients, with 16 fractures noted in 13 (3%) patients, none of
      which required treatment. The mean ISS of group II was 8.0 +/- 0.5. CONCLUSION:
      The PXR has limited sensitivity for detecting pelvic fractures compared with CT
      scanning. Selected hemodynamically stable patients who undergo CT scanning during
      their immediate resuscitation do not need a routine PXR. The PXR may continue to
      be beneficial in unstable patients, those with positive physical findings, or
      those who cannot undergo CT scanning because of other clinical priorities.

PMID- 12478026
TI  - Incidence and natural history of below-knee deep venous thrombosis in high-risk
      trauma patients.
AB  - BACKGROUND: Venous thromboembolic disease remains a difficult problem in the
      trauma patient population. The purpose of this study was to delineate the
      incidence and natural history of below-knee deep venous thrombosis (BKDVT) in
      high-risk trauma patients. METHODS: Patients were stratified into risk categories
      (low, high, or very high) for deep venous thrombosis on the basis of an
      institutional practice management guideline and known risk factors. All at-risk
      patients received either sequential compression devices (SCDs) or subcutaneous
      heparin (SQH) compounds, and high-risk patients also underwent weekly
      surveillance by duplex scanning. Very-high-risk patients had prophylactic
      inferior vena cava (IVC) filter placement. This prospective, observational study
      examines the duplex results on all high-risk patients. Data regarding method of
      prophylaxis, the incidence of proximal propagation on serial duplex examinations,
      and changes in management (anticoagulation or IVC filter placement) were
      collected on the high-risk patients who developed a BKDVT. RESULTS: Between March
      1997 and June 2001, 601 patients were stratified into the high-risk category and
      underwent a total of 1,109 duplex examinations. Eighty-five patients (14.1%) had
      113 BKDVTs. These patients underwent a total of 212 duplex examinations; all
      patients developed their BKDVTs within 34 days. Weekly incidence was 40 (47.1%),
      25 (29.4%), 15 (17.6%), 1 (1.2%), and 4 (4.7%) for weeks 1 through 5,
      respectively. SCDs, SQH compounds, and SCDs with SQH compounds were used on 73,
      3, and 9 patients, respectively. In 4 of 85 (4.7%) patients, the BKDVT propagated
      proximally to an above-knee location in 4 to 8 days. Two of these patients were
      anticoagulated, and two underwent placement of an IVC filter. One patient (1.2%)
      with a BKDVT that had not propagated on duplex study developed a pulmonary
      embolus. CONCLUSION: Patients identified as high-risk by our practice management
      guideline had a 14.1% incidence of a BKDVT; 94.1% were diagnosed within the first
      3 weeks of hospitalization. Proximal propagation occurred in 4.7% and led to
      changes in management. Serial duplex examination of the BKDVT alone, rather than
      systemic anticoagulation or IVC filter placement, appears to be a reasonable
      treatment alternative.

PMID- 12478027
TI  - Early injection of high-dose recombinant factor VIIa decreases blood loss and
      prolongs time from injury to death in experimental liver injury.
AB  - BACKGROUND: Recombinant factor VIIa (rFVIIa) is used for treatment of bleeding
      episodes in hemophilia patients who develop inhibitors to factors VIII and IX. We
      tested the hypothesis that administration of rFVIIa early after injury would
      decrease bleeding and prolong the time from injury to death after experimental
      hepatic trauma. METHODS: Anesthetized swine were cannulated for blood sampling
      and hemodynamic monitoring. Avulsion of the left median lobe of the liver induced
      uncontrolled hemorrhage. After a 10% reduction in mean arterial pressure, animals
      (n = 8 per group) were blindly randomized to receive intravenous rFVIIa 180
      microg/kg, rFVIIa 720 microg/kg, or placebo. Pathologic examination of brain,
      lung, kidney, heart, and small bowel was performed to assess intravascular
      thrombosis. RESULTS Mortality during the first hour was 50% (four of eight) in
      controls versus 0% with rFVIIa 720 microg/kg (p = 0.02, chi2). Blood loss was
      decreased in the rFVIIa 720 microg/kg group versus the placebo group (13.2 +/-
      5.5 mL/kg vs. 21.9 +/- 7.7 mL/kg;p = 0.0223). Time from injury to death was
      significantly prolonged in the rFVIIa 720 microg/kg group compared with placebo
      (116 minutes vs. 8.5 +/- 3.5 minutes; p= 0.02). No macro- or microthrombi in
      vital organs were identified on pathologic examination. CONCLUSION: Intravenous
      administration of high-dose rFVIIa early after induction of hemorrhage decreased
      bleeding and prolonged survival. No evidence of thrombosis in vital organs was
      observed.

PMID- 12478028
TI  - The injured child is resistant to multiple organ failure: a different
      inflammatory response?
AB  - BACKGROUND: Although postinjury multiple organ failure (MOF) is a well-described
      phenomenon in adults, the incidence of this syndrome in children is unknown. The
      purpose of this study was to describe the incidence, course, and severity of
      pediatric postinjury MOF. We hypothesized that the incidence and severity of
      postinjury MOF in children would be less when compared with adults. METHODS:
      Patients were retrospectively identified from the trauma registry of a regional
      pediatric trauma center and an adult Level I trauma center with pediatric
      commitment for a 3-year period. All trauma patients less than 16 years old who
      survived for longer than 24 hours and had an Injury Severity Score > 15 were
      eligible. An accepted MOF score was used. Categorical variables were compared by
      chi2 and continuous variables by t test. A value of p< 0.05 was considered
      statistically significant. RESULTS: Of 534 patients identified, 334 (63%) were
      admitted for evaluation of isolated head injury and excluded from further
      analysis. The rate of postinjury MOF in children was found to be only 3%, with a
      low (17%) mortality when compared with historical adult data (50%). CONCLUSION:
      The incidence of postinjury MOF in the child is less than in the adult, given
      equivalent injury severity. These observations solidify the contention that
      postinjury MOF is rare in children, and is less severe when it occurs.
      Delineating the mechanism(s) whereby children are protected from postinjury MOF
      may provide insight into the development of strategies to prevent MOF in other
      age groups as well as various disease states.

PMID- 12478029
TI  - Incorporation of a computerized human patient simulator in critical care
      training: a preliminary report.
AB  - BACKGROUND: The intent of the study was to document initial experience with human
      patient simulation, using a full-scale computerized mannequin, in evaluating
      cognitive performance among junior surgery residents. METHODS: This was an
      observational study of eight postgraduate year-2 surgery residents during initial
      critical care rotation that assessed their responses to three unknown scenarios
      using a human patient simulator. RESULTS: No resident successfully completed the
      first scenario. Of note was a reluctance to call for help until the scenario
      reached a critical stage. Subsequent performance improved in areas previously
      neglected. Resident acceptance of simulation scenarios as a teaching tool was
      excellent. CONCLUSION: The human patient simulator is a valuable tool in critical
      care education, identifying weaknesses both in individual student performance and
      in program content.

PMID- 12478030
TI  - The polymerized bovine hemoglobin-based oxygen-carrying solution (HBOC-201) is
      not toxic to neural cells in culture.
AB  - BACKGROUND: Recent data suggest that a neurotoxic effect of blood or its
      components may contribute to secondary neural cell dysfunction. This study
      investigated the effects of HBOC-201 (Hemopure) and purified human hemoglobin
      (hHgb) on rat fetal neural cell culture. METHODS: Neural cell cultures were
      exposed to HBOC-201 and hHgb (0.02, 0.2, 2.0, and 6.5 g/dL) for 24 hours, and
      then analyzed for proliferation, metabolism, and neurolysis. RESULTS: Cultures
      exposed to HBOC-201 maintained levels of proliferation and metabolism similar to
      controls while demonstrating no cellular lysis. However, cultures exposed to hHgb
      demonstrated decreased proliferation after exposure to 0.2, 2.0, and 6.5 g/dL
      hHgb (14,252.14, 3,221.89, and 343.12 vs. 19,509.53; p< 0.05) when compared with
      controls. In addition, cultures exposed to hHgb demonstrated decreased metabolic
      activity and increased cell lysis when compared with controls (p < 0.05).
      CONCLUSION: Cultures exposed to HBOC-201 displayed sustained metabolic activity
      and proliferation, and demonstrated no neurolysis, suggesting that HBOC-201 does
      not display the toxic characteristics of hHgb.

PMID- 12478031
TI  - When should a chest radiograph be obtained after chest tube removal in
      mechanically ventilated patients? A prospective study.
AB  - BACKGROUND: The purpose of this study was to determine the appropriate time
      interval between the removal of a chest tube and the chest radiograph (CXR). We
      hypothesized that a CXR obtained 1 hour after chest tube removal would exclude
      the presence of a recurrent pneumothorax. METHODS: Of 214 trauma intensive care
      unit patients with a chest tube during a 1-year period, 75 met entry criteria and
      underwent chest tube removal according to an institutional review board-approved
      prospective study protocol. Patients were undergoing positive-pressure
      ventilation, with an existing solitary chest tube, and had less than 150 mL of
      drainage on water seal over the previous day. After chest tube removal, serial
      CXRs were obtained at approximately 1, 10, and 36 hours. Demographic, chest tube,
      and ventilator data were collected. RESULTS: None of the patients experienced
      hemodynamic or respiratory deterioration after chest tube removal. There were
      nine pneumothoraces (12%). All pneumothoraces were present on the initial CXR
      after chest tube removal. Two patients (3%) required intervention for
      pneumothorax. Of the remaining seven small pneumothoraces, three resolved and
      four were unchanged on the third CXR. CONCLUSION: A CXR obtained within 1 to 3
      hours after chest tube removal effectively identifies pneumothorax in
      mechanically ventilated patients.

PMID- 12478032
TI  - The negative impact of the repeal of the Arkansas motorcycle helmet law.
AB  - BACKGROUND: On July 1, 1997, Arkansas became the first state in 14 years to
      repeal their adult helmet law. We examined the clinical and financial impact of
      this repeal. METHODS: A 6-year retrospective review was conducted of the
      University of Arkansas for Medical Sciences trauma registry including the 3 years
      before and the 3 years after the repeal of the helmet law. A head and neck
      Abbreviated Injury Scale (AIS) score >or= 3 was considered severe. All patients
      admitted to the hospital or who died in the emergency department were included in
      the study. The database of the Arkansas Highway and Transportation Department was
      also used to determine the number of crashes and fatalities occurring statewide
      (1995-1999). RESULTS: Although total and fatal crashes in Arkansas were not
      significantly different (1995-1996 vs. 1998-1999), nonhelmeted deaths at the
      scene of a crash significantly increased from 19 of 48 (39.6%) (1995-1996) to 40
      of 53 (75.5%) (1998-1999) (p < 0.0001). Before repeal, 25% of nonfatal crash
      admissions were nonhelmeted (18 of 73). This significantly increased to 54% (52
      of 96, p< 0.001) after repeal. Overall, patients who were nonhelmeted had
      significantly higher AIS scores for head and neck, significantly more severe head
      injuries (AIS score >or= 3), 47% (33 of 70) versus 20% (20 of 99), and
      significantly longer length of intensive care unit stay. Financially, patients
      without helmets had significantly higher unreimbursed charges compared with their
      helmeted counterparts, resulting in a total of 982,560 dollars of additional
      potentially lost revenue over the length of the study. CONCLUSION: Repeal of the
      mandatory helmet law was associated with an increase in the nonhelmeted crash
      scene fatality rate. After the repeal, there was a disproportionately higher
      admission rate for nonhelmeted motorcycle crash survivors. These patients had an
      increased use of hospital resources and poorer reimbursement of charges compared
      with their helmeted counterparts. This resulted in significantly higher
      unreimbursed charges. States considering repeal of their mandatory adult helmet
      laws should consider the potential negative financial impact on their health care
      system and the increased morbidity associated with nonhelmeted motorcycle riders
      involved in a crash.

PMID- 12478033
TI  - Fractures of the olecranon: an in vitro study of elbow joint stresses after
      tension-band wire fixation versus proximal fracture fragment excision.
AB  - BACKGROUND: Displaced fractures of the olecranon usually require operative
      treatment, by either open reduction with internal fixation (ORIF) or excision of
      the proximal fragment. However, the relative merits of these treatment options
      have not been fully delineated. One treatment outcome measure of joint function
      is residual intra-articular stress. The purpose of this study was to evaluate the
      effect of these two types of olecranon fracture treatment on humeroulnar joint
      stress. METHODS: Eight matched pairs of fresh frozen cadaveric upper extremities
      were thawed; stripped of skin, muscular, and neurovascular tissue; and potted in
      polymethylmethacrylate. The intra-articular humeroulnar joint peak pressures were
      measured at 90 degrees of elbow flexion using pressure-sensitive film after
      application of a 0.15 kg-m torque through the remaining triceps muscle
      attachment. First, pretreatment (normal) pressures were obtained from the major
      contact regions of the humeroulnar joint. A 50% olecranon osteotomy was then
      performed simulating a fracture, and the elbows from each of the paired specimens
      were randomly assigned to one or the other of two treatment groups: ORIF (using a
      tension-band wiring technique) and proximal fragment excision. Joint pressures
      were remeasured. A two-tailed paired t test was used for statistical analysis.
      RESULTS: After osteotomy, the peak pressures were higher, overall, in the
      excision group. Comparing each posttreatment experimental group to its
      pretreatment (normal) counterpart revealed that the peak pressures in the distal
      medial and distal lateral articular subzones were significantly higher for the
      fragment excision group (p = 0.005 and p= 0.0008, respectively), but were not
      significantly different in the ORIF group (p = 0.545 and p= 0.153, respectively).
      CONCLUSION: The findings of this study indicate that ORIF restores the normal
      biomechanics of the elbow joint and proximal fragment excision results in
      abnormally elevated joint stresses. These elevated joint stresses may, over time,
      contribute to the development of elbow pain and osteoarthrosis. Therefore, ORIF
      should continue to be regarded as the treatment of choice for displaced fractures
      of the olecranon involving large proximal fracture fragments similar in size to
      those in this study.

PMID- 12478034
TI  - Is there a reliable outcome measurement for displaced intra-articular calcaneal
      fractures?
AB  - BACKGROUND: The treatment of displaced intra-articular calcaneal fractures
      remains controversial, because of difficulties in assessing the outcome. The goal
      of this study, therefore, was to compare different outcome measurements with gait
      analysis, using dynamic pedography. METHODS: Twenty patients with operatively
      treated displaced intra-articular calcaneal fractures were followed up clinically
      and radiographically. In addition, foot pressure was measured using dynamic
      pedography. RESULTS: No significant difference was found between the two clinical
      outcome scores used (p = 0.08); both revealed good results. Dynamic pedography,
      however, showed a shift of the maximum impact and roll-off of the foot to the
      lateral side, as well as a widening of these zones in the heel and on the sole in
      14 of 20 patients. CONCLUSION: These results indicate that traditional outcome
      measurements underestimate functional deficits in our patients. Monitoring
      plantar pressure distribution might therefore be a useful tool for assessing foot
      function in these patients.

PMID- 12478035
TI  - The use of BoneSource hydroxyapatite cement for traumatic metaphyseal bone void
      filling.
AB  - OBJECTIVE: This prospective, randomized study was performed to determine whether
      a new, in situ setting hydroxyapatite cement is as safe or effective as
      autologous cancellous bone graft for the treatment of metaphyseal bone voids
      secondary to trauma. This was a multicenter study including Level I trauma
      centers and university hospitals. Thirty-eight patients who sustained an acute
      closed or open type I fracture of the humerus, radius, ulna, femur, tibia, or
      calcaneus and had a traumatic bone void requiring grafting of the metaphyseal or
      cancellous bone area were enrolled. Open reduction and internal fixation of the
      fracture was performed with use of either autologous cancellous bone or
      BoneSource hydroxyapatite cement to fill traumatic metaphyseal voids. Main
      outcome measures included maintenance of reduction, fracture healing, pain at
      defect site, pain at donor site, and clinical function of the limb. RESULTS:
      Patients treated with BoneSource had an 83% success rate in maintaining
      reduction, whereas patients treated with autograft had a 67% success rate. A
      successful clinical outcome, as measured by a healed fracture with minimal to no
      pain, moderate to maximum function, and no or minor donor site complications, was
      seen in 69% of patients treated with BoneSource and 57% of patients treated with
      autograft. In patients with at least 1 year of follow-up, the overall success
      rate was 79% in the BoneSource group and 70% in the autograft group. CONCLUSION:
      BoneSource is safe and effective when used to fill traumatic metaphyseal bone
      voids. It is at least as good as autograft for treatment of these defects.

PMID- 12478036
TI  - Does the pulse examination in patients with traumatic knee dislocation predict a
      surgical arterial injury? A meta-analysis.
AB  - BACKGROUND: This systematic review aimed at evaluating the diagnostic accuracy of
      pulse examination in detecting surgical arterial lesions associated with knee
      dislocation. METHODS: MEDLINE, CINAHL, and SportDiscus databases were searched in
      all languages to review articles concerning human knee dislocation and associated
      vascular injuries. RESULTS: We reviewed 116 articles. Seven met our inclusion
      criteria, providing detailed data on 284 injuries. Pooled data demonstrated that
      abnormal pedal pulses present a sensitivity of 0.79 (95% confidence interval
      [CI], 0.64-0.89), a specificity of 0.91 (95% CI 0.78-0.96), a positive predictive
      value of 0.75 (95% CI, 0.61-0.83), and a negative predictive value of 0.93 (95%
      CI, 0.85-.96). CONCLUSION: Our findings suggest that the isolated presence of
      abnormal pedal pulses on initial examination of patients with knee dislocations
      is not sensitive enough to detect a surgical vascular injury. On the basis of
      this meta-analysis, an algorithm for the evaluation of these patients is
      presented.

PMID- 12478037
TI  - Spleen hemostasis using high-intensity ultrasound: survival and healing.
AB  - BACKGROUND: Previous studies have shown that high-intensity focused ultrasound
      (HIFU) can effectively control bleeding of incised livers and spleens and
      punctured vessels. This current study investigated the long-term safety of HIFU
      in splenic hemostasis. METHODS: A total of 21 rabbits were randomly assigned to
      two groups: HIFU treatment (n = 14), and sham treatment (n = 7). All animals
      underwent sterile laparotomy and splenic exposure. The HIFU-treated animals
      received splenic incisions, 8 to 10 mm long and 4 to 5 mm deep, and immediate 9.6
      MHz HIFU until hemostasis was achieved. After recovery, ultrasound images, blood
      samples, and histologic samples were collected on days 0, 1, 3, 7, 14, 28, and
      60. RESULTS: All 14 splenic injuries were hemostatic after an average of 96
      seconds of HIFU application. There was evidence of rebleeding in one animal
      between days 3 and 7 posttreatment. Subsequent blood analysis showed no
      significant difference in serial hematologic or coagulation measures between HIFU
      and sham groups. Histologic examination up to 60 days posttreatment revealed
      scarring and spleen tissue regeneration at the treatment site. CONCLUSION: HIFU
      provides an effective and safe method of achieving hemostasis after acute splenic
      injury.

PMID- 12478038
TI  - Systemic inflammatory response secondary to abdominal compartment syndrome: stage
      for multiple organ failure.
AB  - BACKGROUND: The abdominal compartment syndrome (ACS) has been implicated in the
      pathogenesis of postinjury multiple organ failure. The ACS is defined as intra
      abdominal hypertension causing adverse physiologic response. This study was
      designed to determine the effects of IAH on the production of interleukin-1b (IL
      1beta), interleukin-6 (IL-6), tumor necrosis factor (TNF-alpha), and the effects
      on remote organ injury. METHODS: IAH was induced in Sprague-Dawley rats which
      were divided into 5 groups, 10 animals each. Intra-abdominal pressure (IAP) was
      increased to 20 mm Hg for 60 and 90 minutes in two different groups. In a third
      group following IAP of 20 mm Hg the abdomen was decompressed for 30 minutes
      before samples were collected. The other animals were used as controls.
      Hemodynamic response was monitored throughout the procedure. Cytokine levels were
      assessed in the plasma. Remote organ injury was assessed by histopathology and
      myeloperoxidase activity. RESULTS: IAH caused a significant decrease in MAP.
      After abdominal decompression MAP returned to baseline levels. A significant
      decrease in arterial pH was also noted. Increase in the levels of TNF-alpha and
      IL-6 was noted 30 minutes after abdominal decompression. Plasma concentration of
      IL-1b was elevated after 60 minutes of IAH. Abdominal decompression, however, did
      not cause a significant increase in the levels of this cytokine. Lung neutrophil
      accumulation was significantly elevated only after abdominal decompression.
      Histopathological findings showed intense pulmonary inflammatory infiltration
      including atelectasis and alveolar edema. CONCLUSIONS: IAH provokes the release
      of pro-inflammatory cytokines which may serve as a second insult for the
      induction of MOF.

PMID- 12478039
TI  - Release of abdominal compartment syndrome improves survival in patients with burn
      injury.
AB  - BACKGROUND: Abdominal compartment syndrome (ACS) has rarely been described as a
      complication of burn injury. This study describes cases of ACS in patients with
      burn injury and the physiologic results of abdominal release. METHODS: Charts for
      all patients admitted to two major burn center intensive care units from January
      1998 through August 2000 were reviewed for ACS. Physiologic parameters were
      compared before and after abdominal release. RESULTS: Ten of 1,014 patients
      developed ACS. Abdominal release improved peak inspiratory pressures and Acute
      Physiology and Chronic Health Evaluation II scores (p < 0.03). The amount of
      fluid required to maintain adequate urine output also decreased substantially.
      Forty percent of patients with ACS survived to discharge. CONCLUSION: Abdominal
      release for patients with ACS and severe burn injury results in physiologic
      improvement and a 40% survival rate. We recommend bladder pressure monitoring for
      all patients with severe burn injuries and abdominal decompression in any patient
      who develops pressures greater than 30 mm Hg if they have signs of physiologic
      compromise. Aggressive expectant management can effect a 40% survival rate in
      this group of severely injured patients.

PMID- 12478040
TI  - Prospective evaluation of the sensitivity of physical examination in chest
      trauma.
AB  - BACKGROUND: Chest radiographs are routine for patients presenting with blunt and
      penetrating chest trauma. The accuracy of physical examination in the diagnosis
      of hemopneumothorax in these patients is unclear. A prospective study was
      performed to define the utility of routine portable chest radiographs in 676
      trauma patients. METHODS: Over 19 months (January 2000-July 2001), 676 patients
      who presented with penetrating or blunt chest trauma were interviewed and
      examined for signs and symptoms of hemopneumothorax. The incidence of chest pain
      or tenderness and tachypnea was noted and both lung fields were auscultated. A
      portable chest radiograph was then performed on all the patients. RESULTS: All
      the patients were hemodynamically stable. Five hundred twenty-three patients
      sustained blunt trauma, with seven hemopneumothoraces (1.3%). The negative
      predictive values of auscultation, pain or tenderness, and tachypnea were 99& to
      100%. One hundred fifty-three patients sustained penetrating chest trauma. Of
      these injuries, 68 were gunshot wounds and 85 were stab wounds. Twenty-four (16%)
      of these patients had hemopneumothoraces. The sensitivities of auscultation, pain
      or tenderness, and tachypnea were 50%, 25%, and 32%, respectively. The negative
      predictive values of these tests were < 91%. CONCLUSION: Blunt chest trauma
      patients who are hemodynamically stable with a normal physical examination do not
      require a routine chest radiograph. In contrast, all victims of penetrating
      trauma require chest radiographs because many will have hemopneumothorax in the
      absence of clinical findings.

PMID- 12478041
TI  - Identifying injuries and motor vehicle collision characteristics that together
      are suggestive of diaphragmatic rupture.
AB  - BACKGROUND: Diaphragmatic rupture (DR) remains a diagnostic challenge because of
      the lack of an accurate test demonstrating the injury. Our purpose was to
      identify motor vehicle collision (MVC) characteristics and patient injuries that
      collectively could identify the presence of a DR. METHODS: The National
      Automotive Sampling System was used to identify occupants involved in MVCs from
      1995 to 1999 who sustained abdominal (Abbreviated Injury Scale score >or= 2)
      and/or thoracic injuries (Abbreviated Injury Scale score >or= 2). Odds ratios
      (ORs) and 95% confidence intervals (CIs) were calculated to quantify the
      association between patient injuries, vehicle collision characteristics, and DR.
      Sensitivity and specificity were also calculated to determine the ability of
      organ injury and MVC characteristics to correctly classify patients with and
      without DR. RESULTS: Overall, occupants sustaining a DR had a significantly
      higher delta-V (DeltaV) (49.8 kilometers per hour [kph] vs. 33.8 kph, p< 0.0001)
      and a greater degree of occupant compartment intrusion (70.6 cm vs. 48.3 cm, p<
      0.0001). Specific abdominal and thoracic organ injuries were associated with DR,
      including thoracic aortic tears (OR, 5.2; 95% CI, 2.2-12.5), splenic injury (OR,
      8.4; 95% CI, 3.9-17.8), pelvic fractures (OR, 4.7; 95% CI, 2.7-8.0), and hepatic
      injuries (OR, 4.2; 95% CI, 1.7-10.6). Combining frontal or near-side lateral
      occupant compartment intrusion >or= 30 cm or DeltaV >or= 40 kph with specific
      organ injuries generated a sensitivity for indicating the likelihood of diaphragm
      injury ranging from 68% to 89%. Patients with any of the following
      characteristics had a sensitivity for detecting DR of 91%: splenic injury, pelvic
      fracture, DeltaV >or= 40 kph, or occupant compartment intrusion from any
      direction >or= 30 cm. CONCLUSION: Specific MVC characteristics combined with
      patient injuries have been identified that are highly suggestive of DR. For this
      subpopulation, additional invasive procedures including exploratory laparotomy,
      laparoscopy, or thoracoscopy may be warranted to exclude DR.

PMID- 12478042
TI  - Family impact greatest: predictors of quality of life and psychological
      adjustment in pediatric burn survivors.
AB  - BACKGROUND: Although there is some knowledge of psychological adjustment, almost
      nothing is known about quality of life in pediatric burn survivors. METHODS:
      Parents of 105 burn survivors (age, 5-17 years; total body surface area burned,
      10-64%) were assessed by standardized questionnaires 1 to 13 years postburn.
      Predictive values of clinical variables and family environment were assessed.
      RESULTS: Most dimensions of quality of life and psychological adjustment were
      normal. Compared with healthy norms, burn survivors only showed less positive
      emotions. Good family relationships and younger age at burn injury were the only
      significant predictors of good quality of life. Psychological adjustment was
      predicted by family relationships. CONCLUSION: If given optimal care, most
      pediatric burn survivors demonstrate excellent quality of life. Families with
      compromised relationships and patients with higher age at burn injury should be
      identified early, monitored closely, and offered psychosocial support as soon as
      dysfunctional family dynamics are detected.

PMID- 12478043
TI  - Outcomes and costs of acute treatment of traumatic brain injury.
AB  - BACKGROUND: Although there are nearly a quarter of a million hospitalizations for
      traumatic brain injury (TBI) in the United States each year, data on the outcomes
      and costs of TBI treatment in the acute-care setting are limited. METHODS: Using
      a large, geographically diverse, multihospital database, we examined inpatient
      records for persons aged 16 years or older who were hospitalized for TBI between
      January 1, 1997, and June 30, 1999. Patients were stratified by TBI severity
      using an adaptation of the Abbreviated Injury Scale for administrative data
      (ICD/AIS), as follows: 2 = "moderate"; 3 = "serious"; 4 = "severe"; and 5 =
      "critical." Patient characteristics, patterns of treatment, and outcomes and
      costs were examined by injury severity and mechanism of injury. RESULTS: Of 8,717
      study subjects identified, 12.5% had moderate, 44.8% had serious, 29.6% had
      severe, and 13.2% had critical TBI. Falls were the most common reported cause of
      injury (40.8%), followed by motor vehicle crashes (39.3%), blows to the head
      (11.3%), and gunshot wounds (2.4%). Average length of stay in hospital ranged
      from 6.7 days for moderate TBI to 17.5 days for critical TBI. The overall rate of
      death in hospital was relatively low among patients with moderate (1.3%), serious
      (5.7%), and severe (8.7%) TBIs, but much higher among the most critically injured
      patients (52.0%). Costs of hospitalization averaged 8,189 dollars for moderate,
      14,603 dollars for serious, 16,788 dollars for severe, and 33,537 dollars for
      critical TBI. Costs also varied by injury type, averaging 20,084 dollars for
      gunshot wounds, 20,522 dollars for motor vehicle crashes, 15,860 dollars for
      falls, and 19,949 dollars for blows to the head. CONCLUSION: The economic burden
      of TBI in the acute-care setting is substantial; treatment outcomes and costs
      vary considerably by TBI severity and mechanism of injury.

PMID- 12478044
TI  - An assessment of the potential for reducing future combat deaths through medical
      technologies and training.
AB  - BACKGROUND: We examined clinical records of combat casualties that died
      subsequent to reaching a medical treatment facility in an effort to determine
      whether new medical technologies or enhanced training might contribute to a
      reduction in combat deaths. METHODS: Hospital records of 210 fatal combat
      casualties were independently reviewed by four surgeons. The surgeons assessed
      each fatality to determine whether it would be preventable if the trauma were
      sustained today and treated with currently available technology and training.
      RESULTS: In 8% of the cases, the four surgeons independently agreed that the
      deaths would be possibly preventable if the same traumas were incurred today. In
      an additional 17% of the cases, three of the four surgeons judged the deaths to
      be possibly preventable today. Causes of death viewed as most likely to be
      salvageable today included hemorrhage, severe burns, pulmonary edema, and sepsis.
      The medical technologies most often mentioned to have a potentially lifesaving
      effect were ventilators/respirators, computed tomographic scanners, ultrasound,
      and antibiotics. Areas of training most often mentioned to have a potential
      impact on the salvageability of the trauma cases reviewed were damage control,
      ventilator management, liver packing, respiratory distress management, and burn
      management. CONCLUSION: Surgeons reviewing records of past combat deaths
      indicated that reductions in the incidence of combat deaths through deployment of
      improved medical technologies and training is possible. Deployment of the noted
      technologies and proficiency in the cited training has the potential for reducing
      deaths by 8% to 25% when compared with the died-in-hospital incidence among
      casualties in the last sustained conflict.

PMID- 12478045
TI  - Purposeful delay in the repair of a traumatic left common carotid pseudoaneurysm
      in a bovine aortic arch presenting as a widened mediastinum.

PMID- 12478046
TI  - Cardiac air embolism after endoscopic retrograde cholangiopancreatography in a
      patient with blunt hepatic trauma.

PMID- 12478047
TI  - Dissociation of atlantoaxial junction in ankylosing spondylitis: case report.

PMID- 12478048
TI  - Elbow dislocation with multidirectional instability; avulsion of the triceps
      tendon; and injury to the ulnar, median, and radial nerves: case report.

PMID- 12478049
TI  - Pelvic diastasis from the saddle: not to be forgotten.

PMID- 12478050
TI  - Fluid resuscitation-induced cardiac tamponade.

PMID- 12478051
TI  - Rigid cervical collar and intracranial pressure of patients with severe head
      injury.

PMID- 12478052
TI  - In search of solutions.

PMID- 12478053
TI  - Tetanus and diphtheria toxoids now available.

PMID- 12478054
TI  - Hypotensive resuscitation in trauma.

PMID- 12478055
TI  - Fluid resuscitation during active hemorrhage: need for a step forward.

PMID- 12478056
TI  - SCIWORA in childhood. Spinal cord injury without radiographic abnormality.

PMID- 12478064
TI  - Osteonecrosis in HIV disease: epidemiology, etiologies, and clinical management.
AB  - Osteonecrosis has been increasingly associated with HIV disease throughout the
      1990s, and the incidence appears to be rising. The hip is most commonly involved
      and often bilaterally. Although anecodotal reports suggest an association between
      osteonecrosis and highly active antiretroviral therapy, controlled epidemiologic
      studies do not support a direct link. Many patients with osteonecrosis have
      established risk factors, some of which may be related to HIV disease or its
      therapy, including corticosteroid use and hyperlipidemia. Alcoholism,
      hypercoagulability, megesterol acetate use, immune reconstitution, and other
      factors may also contribute. Plain radiographs and magnetic resonance imaging are
      the cornerstones of diagnosis. Management is dependent on the stage of bone
      disease and ranges from observation to total joint arthroplasty. Clinicians may
      help to prevent HIV-associated osteonecrosis by encouraging patients to limit
      their exposure to the established risk factors for the disease.

PMID- 12478065
TI  - A specific subtype C of human immunodeficiency virus type 1 circulates in Brazil.
AB  - OBJECTIVE: To characterize the subtype C strains of HIV type 1 that circulate in
      Brazil, especially those originated from the southern part of the country. DESIGN
      AND METHODS: One hundred and twelve HIV-1-positive subjects had their plasma
      viral RNA extracted. Protease (PR) and reverse transcriptase (RT) genomic regions
      were polymerase chain reaction-amplified and sequenced for subtype determination.
      Subtype C strains were selected and compared to other strains of this subtype
      from the database, and specific amino acid signature patterns were searched.
      RESULTS: Brazilian subtype C viruses form a very strong monophyletic group when
      compared to subtype C viruses from other countries and presented specific
      signature amino acids. Recombinants between subtype C and B viruses have been
      documented in areas of co-circulation. The incidence of primary PR and RT
      inhibitor resistance mutations in drug-naive subjects was observed. An increasing
      number of secondary resistance mutations was also seen, some of which are
      characteristic of subtype C-related sequences. CONCLUSIONS: Introduction of
      subtype C of HIV-1 in Brazil was likely a single event of one or a mixture of
      similarly related strains. Recombination between subtype C and B viruses is an
      ongoing process in the country. Primary and secondary drug resistance mutations
      were observed, although some of the secondary mutations could be associated with
      subtype C molecular signatures. Subtype-specific polymorphisms of PR and RT
      sequences found in this subtype C Brazilian variant might influence this
      emergence and have an impact on HIV treatment and on vaccine development in the
      country.

PMID- 12478066
TI  - Agent and cell-type specificity in the induction of insulin resistance by HIV
      protease inhibitors.
AB  - OBJECTIVE: To test agent and cell-type specificity in insulin resistance induced
      by prolonged exposure to HIV protease inhibitors (HPI), and to assess its
      relation to the direct, short-term inhibition of insulin-stimulated glucose
      uptake. METHODS: Following prolonged (18 h) and short (5-10 min) exposure to HPI,
      insulin-stimulated glucose transport, protein kinase B (PKB) phosphorylation, and
      GLUT4 translocation were evaluated in 3T3-L1 adipocytes, fibroblasts, L6
      myotubes, and L6 cells overexpressing a myc tag on the first exofacial loop of
      GLUT4 or GLUT1. RESULTS: Prolonged exposure of 3T3-L1 adipocytes to nelfinavir,
      but not to indinavir or saquinavir, resulted in increased basal lipolysis but
      decreased insulin-stimulated glucose transport and PKB phosphorylation. In
      addition, impaired insulin-stimulated glucose uptake and PKB phosphorylation were
      also observed in the skeletal muscle cell line L6, and in 3T3-L1 fibroblasts.
      Interestingly, this coincided with increased basal glucose uptake as well as with
      elevated total-membrane glucose transporter GLUT1 protein content. In contrast to
      these unique effects of nelfinavir, the mere presence of any of the agents in the
      5 min transport assay inhibited insulin-stimulated glucose-uptake activity. This
      appeared to be caused by direct and specific interaction of the drugs with GLUT4
      fully assembled at the plasma membrane, since insulin-stimulated cell-surface
      exposure of an exofacial myc epitope on GLUT4 was normal. CONCLUSIONS:
      Independent mechanisms for HPI-induced insulin resistance exist: prolonged
      exposure to nelfinavir interferes with insulin signaling and alters cellular
      metabolism of adipocytes and muscle cells, whereas a direct inhibitory effect on
      insulin-stimulated glucose uptake may occurs through specific interaction of HPI
      with GLUT4.

PMID- 12478067
TI  - Platelet- and megakaryocyte-derived microparticles transfer CXCR4 receptor to
      CXCR4-null cells and make them susceptible to infection by X4-HIV.
AB  - OBJECTIVE: Under some circumstances the HIV virus may infect cells that do not
      express receptors essential to HIV-entry. We hypothesized that platelet- and
      megakaryocyte-derived microparticles (MP) could play a role in such infections.
      MP are circular membrane fragments shed from the surface of eukaryotic cells.
      After adhesion to target cells, MP may transfer membrane-associated proteins to
      these cells. We found that peripheral blood platelet- (PMP) and megakaryocyte
      derived MP (MegaMP) that highly express CXCR4 may transfer this receptor from the
      surface of platelets or megakaryocytes to the surface of CXCR4-null cells.
      DESIGN: Since this mechanism could potentially allow CD4+/CXCR4-null cells to
      become infected by T-tropic HIV, we incubated several human CD4+/CXCR4-null cells
      such as normal erythroblasts, glioblastomas U87, MAGI and hematopoietic cell
      lines UT-7, HEL and TF-1 with PMP or MegaMP. We found that these cells became
      CXCR4+. We next exposed these cells to X4-HIV (IIIB) and evaluated their
      susceptibility to infection by PCR, ELISA, and morphological analysis. RESULTS:
      We observed in all instances that after CD4+/CXCR4-null cell lines 'acquired'
      CXCR4 from PMP or MegaMP, they could became infected by X4 HIV. CONCLUSIONS: We
      postulate that both PMP and MegaMP may play a novel and important role in
      spreading HIV-1 infection by transferring the CXCR4 co-receptor to CD4+/CXCR4
      null cells.

PMID- 12478068
TI  - A cytostatic drug improves control of HIV-1 replication during structured
      treatment interruptions: a randomized study.
AB  - OBJECTIVE: To study the effect of highly active antiretroviral therapy (HAART)
      with and without hydroxyurea (HU) on changes in plasma viral load (VL) set-point,
      and on HIV-1-specific responses, after five cycles of structured treatment
      interruptions (STI). METHODS: A group of 20 patients taking HAART for chronic HIV
      infection with VL < 20 copies/ml were randomized to continue HAART or HAART plus
      HU for 24 weeks followed by five STI cycles. HU was also stopped in cycles 1-3
      but continued in cycles 4 and 5. The number of individuals maintaining a VL set
      point < 5000 copies/ml during the fifth interruption were determined. RESULTS: VL
      remained < 5000 copies/ml in eight out of nine patients in the HU group and in
      four out of ten patients in the HAART group after a median 48 weeks of follow-up
      after the fifth interruption ( P=0.039). By STI cycle 5, there was a significant
      increase in the neutralizing activity (NA), in both magnitude and breadth of the
      total cytotoxic T lymphocyte (CTL) response and in lymphoproliferative response
      (LPR) from baseline. No significant differences were observed between HAART and
      HU groups in NA, CTL and LPR at any time-point. There were no differences in the
      NA titers at any time-point between responder and non-responder patients. There
      was a trend for higher CTL and LPR levels in responder patients (P= 0.10).
      CONCLUSIONS: In this randomized, controlled study of STI with cycles of HAART or
      HAART plus HU, a lower peak VL rebound and a lower VL set-point was achieved in
      patients continuing HU while other drugs were discontinued. HU did not blunt anti
      HIV-1-specific responses; however, control of VL did not correlate with anti-HIV
      1-specific cellular immune responses.

PMID- 12478069
TI  - Multiple measures of HIV burden in blood and tissue are correlated with each
      other but not with clinical parameters in aviremic subjects.
AB  - OBJECTIVES: To determine the levels of residual HIV DNA and RNA in blood and gut
      reservoirs in aviremic patients, assess correlations among compartmental
      measurements of HIV burden, and evaluate association with clinical parameters.
      DESIGN: Cross-sectional analysis of baseline data only, on 40 patients enrolled
      in phase II study evaluating efficacy of autologous gene-modified CD4+ and CD8+ T
      cells. All patients were on stable antiretroviral regimen with undetectable
      plasma HIV RNA (< 50 copies/ml). METHODS: Measurements repeatedly performed over
      8-12 weeks pre-intervention: blood HIV DNA, analysis of rectal mucosa-associated
      lymphoid tissue for both HIV RNA and HIV DNA, and quantitative co-culture of HIV
      from CD8-depleted peripheral blood mononuclear cells (PBMC). RESULTS:
      Quantifiable levels of HIV detected in compartments despite undetectable levels
      of plasma HIV RNA: HIV co-culture of PBMC (88%), blood HIV DNA (95%), rectal
      biopsy HIV DNA (95%), rectal biopsy HIV RNA (65%). A significant correlation
      existed among various measures of HIV burden (HIV co-culture, blood HIV DNA,
      rectal biopsy HIV RNA and DNA) but not between assays and clinical parameters
      [duration of highly active antiretroviral therapy (HAART), type of HAART]. All
      assays had comparable or less variability than in plasma viral load assays; HIV
      co-culture had the highest coefficient of variability whereas the blood HIV DNA
      assay had the lowest and was considered the most reliable assay. CONCLUSIONS: The
      data support safety, feasibility and high compliance of quantifying reservoirs of
      residual HIV in treated subjects with undetectable plasma HIV RNA. Lack of
      correlation between levels of HIV in residual reservoirs and duration of HAART
      suggests treatment-mediated viral suppression alone does not lead to reproducible
      decay in HIV reservoirs.

PMID- 12478070
TI  - Compliance with antiretroviral regimens to prevent perinatal HIV-1 transmission
      in Kenya.
AB  - OBJECTIVE: To compare compliance and infant HIV-1 infection risk at 6 weeks with
      the Thai-CDC and HIVNET-012 antiretroviral regimens in a field setting. DESIGN:
      Randomized clinical trial. SETTING: Tertiary hospital antenatal clinic in
      Nairobi, Kenya. PARTICIPANTS: HIV-1 infected women referred from primary care
      clinics. INTERVENTIONS: Thai-CDC zidovudine regimen or HIVNET-012 nevirapine
      regimen. MAIN OUTCOME MEASURES: Women were considered compliant if they used >or=
      80% of the doses. Infants were tested for HIV-1 at 6 weeks. RESULTS Seventy women
      were randomized to Thai-CDC and 69 to HIVNET-012 regimens. More women were
      compliant with the antenatal (86%) than the intrapartum (44%) Thai-CDC regimen
      doses ( P= 0.001). Ninety-seven per cent took the maternal and 91% gave the
      infant dose of the HIVNET-012 regimen (P = 0.2). Overall, 41% were compliant with
      the Thai-CDC regimen and 87% with the HIVNET-012 regimen ( P< 0.001). Compliance
      with the Thai-CDC regimen was associated with partner support of antiretroviral
      use [odds ratio (OR), 3.0;, 95% confidence interval (CI), 1.0-9.1] and knowledge
      at recruitment that antiretroviral drugs could prevent infant HIV-1 (OR, 2.9; 95%
      CI, 1.0-8.1). Compliance with the HIVNET-012 regimen was associated with partner
      notification (OR, 8.0; 95% CI, 1.5-50) and partner willingness to have HIV-1
      testing (OR, 7.5; 95% CI, 1.4-40). There was a trend for a higher risk of
      transmission with the HIVNET-012 regimen than with the Thai-CDC regimen (22%
      versus 9%; P= 0.07). CONCLUSION: Compliance with the Thai-CDC and HIVNET-012
      regimens was comparable to that in efficacy trials. Partner involvement, support
      and education on perinatal HIV-1 prevention may improve compliance and increase
      the number of infants protected from HIV-1 infection.

PMID- 12478071
TI  - Improved survival with highly active antiretroviral therapy in HIV-infected
      patients with severe Pneumocystis carinii pneumonia.
AB  - BACKGROUND: Although the incidence of pneumonia (PCP) has declined, mortality of
      patients who require intensive care for this disease remains high. Highly active
      antiretroviral therapy (HAART) might alter the course of PCP either via effects
      on the immune system or through anti- actions; however, HAART has not been
      studied in patients acutely ill with PCP. OBJECTIVE: To assess the effects of
      HAART on outcome of patients admitted to the intensive care unit (ICU) with PCP.
      DESIGN AND SETTING: Retrospective cohort study carried out at a University
      affiliated county hospital. PARTICIPANTS: Fifty-eight HIV-infected adults with
      PCP admitted to an ICU from 1996 to 2001. MEASUREMENTS: A standardized chart
      review was performed to collect information on demographic variables, hospital
      course, and use of antiretroviral therapy. Outcome measured was death while in
      the ICU or hospital. RESULTS: A total of 20.7% of patients were either receiving
      HAART or were started on therapy while hospitalized. Mortality in this group was
      25%, whereas mortality in those not receiving therapy was 63% (P = 0.03).
      Multiple logistic regression analyses adjusting for potential confounders showed
      that HAART started either before or during hospitalization was associated with a
      lower mortality [odds ratio (OR), 0.14; 95% confidence interval (95% CI), 0.02
      0.84; = 0.03). The need for mechanical ventilation and/or development of a
      pneumothorax (OR, 20.9; 95% CI, 1.9-227.2; = 0.01) and delayed ICU admission (OR,
      9.7; 95% CI, 2.2-42.1; = 0.002) were associated with increased mortality.
      CONCLUSIONS: Use of HAART is an independent predictor of decreased mortality in
      severe PCP and may represent a potential therapy to improve outcome in this
      disease.

PMID- 12478072
TI  - Improved survival in HIV-related Hodgkin's lymphoma since the introduction of
      highly active antiretroviral therapy.
AB  - OBJECTIVE: To evaluate the evolving characteristics of HIV-related Hodgkin's
      lymphoma (HL) and survival of affected patients since the introduction of highly
      active antiretroviral therapy (HAART). DESIGN AND METHODS: A retrospective single
      institution study was performed over a 15-year follow-up period. For statistical
      analysis, patients were categorized into a pre-HAART period (1987-1996, n = 61)
      and a post-HAART period (1997-2001, n = 47). RESULTS: HL characteristics were
      similar in both groups. The chemotherapy regimens used did not differ
      significantly, although the MOPP/ABV regimen (mechlorethamine, vincristine,
      procarbazine substituted by cyclophosphamide since 2000, and prednisone
      /adriamycin, bleomycin, vinblastin) has progressively replaced the ABVD regimen
      (adriamycin, bleomycin, vinblastin, dacarbazine). A slight increase in the
      complete response rate was noted in the post-HAART population (74.5%) versus the
      pre-HAART population (64.5%), and the probability to relapse was not different
      between the two groups. Patients diagnosed since 1997 had a higher probability
      for prolonged survival with a median survival time not reached versus 19 months
      in the pre-HAART period. The estimate 2-year survival probability was 45% [95%
      confidence interval (CI), 32.3-57.8% in the pre-HAART period, and 62% (95% CI,
      46.7-77.1%) in the post-HAART period ( P= 0.03). This decreased mortality was
      associated with a decrease in AIDS-associated deaths. In the post-HAART period,
      12 patients were naive to any antiretroviral therapy and 31 were already on HAART
      at the time of HL diagnosis. Twenty of them had a plasma HIV-RNA below 500
      copies/ml. The response rate and the overall survival were not statistically
      different in these patients. CONCLUSIONS: HL still occurs in patients with HAART
      induced HIV suppression. However, overall survival has significantly improved
      since the introduction of HAART.

PMID- 12478073
TI  - Acceptability of male circumcision as a tool for preventing HIV infection in a
      highly infected community in South Africa.
AB  - BACKGROUND: Because a growing body of evidence suggests that male circumcision
      (MC) is associated with a reduced risk of HIV infection in Africa, it is being
      considered as a potential prevention tool to reduce the spread of infection. Its
      feasibility must therefore be assessed. METHODS: A community-based cross
      sectional study was conducted among a random sample of 482 men aged 19-29 years
      and 302 women aged 14-25 years, all living in the Westonaria district, South
      Africa. The prevalence of HIV infection was 11% among the men and 30% among the
      women. Trained personnel administered standardized questionnaires. RESULTS: Two
      thirds of the 108 circumcised men (CM) were circumcised during a traditional
      ceremony and one-third in a clinical setting; the latter reported less pain and
      adverse outcomes. More than 70% of the non-circumcised men (NCM) stated that they
      would want to be circumcised if MC were proved to protect against sexually
      transmitted diseases (STD). Twenty-nine per cent of the CM and 22% of the NCM
      believed that MC protects against HIV and other STD. Moreover, 30% and 18%,
      respectively, believed that CM could safely have sex with multiple partners.
      Multivariate analysis showed that CM were more likely to report many lifetime
      partners. CONCLUSION: Although the level of MC in the area is relatively low, it
      is perceived positively. A significant proportion of the CM felt protected by
      their circumcision, a feeling unfortunately translated into unsafe practices. Our
      results strongly suggest that interventions including MC should carefully address
      the false sense of security that it may provide.

PMID- 12478074
TI  - Herpes simplex 2 risk among women in a polygynous setting in rural West Africa.
AB  - OBJECTIVES: To determine risk factors for herpes simplex 2 (HSV2) infection in
      women in a polygynous rural Gambian population. METHODS: Data from women who
      participated in a cross-sectional survey of reproductive health were matched to
      their own and, for women who had been or were married (ever-married), their
      spouses' data collected in a cross-sectional survey of fertility interests,
      including information on marital histories. RESULTS: Data were available on 150
      never-married and 525 ever-married women. HSV2 prevalence was 16% amongst never
      married women and 36% amongst ever-married women. For ever-married women, their
      own personal characteristics (age, ethnicity and genital cutting status) and
      events from their husbands' marriage history were important determinants of HSV2
      infection. Women whose husbands married for the first time over age 35 were at
      greater risk than women whose husbands married by age 24 [odds ratio (OR) 2.72,
      95% confidence interval (CI) 1.20-6.10]. Women whose husband reported interest in
      a new marriage were more likely to be HSV2 positive (OR 1.91, 95% CI 1.18-3.09).
      Women whose husbands were currently monogamous but had had previous marriages (OR
      2.76, 95% CI 1.30-5.88) and women in currently polygynous marriages (OR 2.88, 95%
      CI 1.66-5.01) were three times as likely to be HSV2 positive as women who were
      their husband's only wife ever. CONCLUSION: Much transmission of HSV2 in this
      setting occurs within marriage where opportunity for personal protection is
      limited. High levels of transmission within marriage may undermine the impact of
      sexual behaviour change programmes aiming to reduce HSV2 and HIV incidence and
      complicate their evaluation.

PMID- 12478075
TI  - The relationship between condom use, sexually transmitted diseases, and location
      of commercial sex transaction among male Hong Kong clients.
AB  - OBJECTIVE: This study investigated the consistency of condom use and the
      prevalence of self-reported sexually transmitted diseases (STD) among male Hong
      Kong commercial sex clients with respect to the geographical location of these
      transactions. DESIGN AND METHODS: Male clients were identified via three
      independent, population-based surveys conducted in 1998, 1999, and 2001. A unique
      confidential telephone system was used to collect sensitive information. RESULTS:
      Respondents patronizing female sex workers (FSW) in 'mainland China only' or in
      'mainland China and other places' were more likely to be inconsistent condom
      users (28 and 34%) than those patronizing FSW in 'Hong Kong only' (9.1%). A
      similar pattern was found for self-reported STD in the past 6 months (10.1, 8.1
      and 1.0%, respectively). Patronizing FSW in mainland China was associated with a
      higher prevalence of self-reported STD (adjusted OR 4.16), independent of
      consistent condom use and other potential confounding factors, including calendar
      year of survey, age, educational attainment, HIV-related knowledge, perceived
      efficacy of condom use for HIV/AIDS prevention, number of female sex partners,
      and the presence of a regular female sex partner in the past 6 months. Clients
      who had commercial sex both in mainland China and Hong Kong were more likely to
      use condoms in Hong Kong than in mainland China (paired OR 4.67, < 0.05).
      CONCLUSION: The geographical location of commercial sexual activity is related to
      the consistency of condom use, irrespective of the clients engaged in such
      activity. Prevention programmes need to be aware of how risk behaviour is
      dependent on local contexts.

PMID- 12478076
TI  - The effect of rapid HIV-1 testing on uptake of perinatal HIV-1 interventions: a
      randomized clinical trial.
AB  - OBJECTIVE: We examined whether HIV-1 testing using a rapid assay increases the
      proportion of pregnant women obtaining HIV-1 results and the uptake of perinatal
      HIV-1 interventions. METHODS: Pregnant women attending public health clinics in
      Nairobi were offered voluntary counselling and testing for HIV-1. Consenting
      women were randomly assigned to receive either rapid or conventional HIV-1
      testing. Women randomly assigned to rapid testing were allowed to receive same
      day results or to return later. The results for women randomly assigned to
      conventional enzyme-linked immunosorbent assay (ELISA) testing were available
      after 7 days. HIV-1-infected women were referred for antiretroviral prophylaxis
      to prevent mother-to-child transmission of HIV-1. RESULTS: Among 1282 women
      offered voluntary HIV-1 testing and counselling, 1249 accepted testing, of whom
      627 were randomly assigned to rapid testing and 622 to conventional testing. The
      median duration between testing and obtaining results was 0 days for women who
      received rapid testing compared with 11 days for women who received conventional
      testing. The percentage receiving HIV-1 results was significantly higher among
      women who received rapid testing compared with conventional testing. Of 161 HIV-1
      seropositive women, only 24 received antiretroviral prophylaxis. The uptake of
      perinatal HIV-1 interventions did not differ between HIV-1-seropositive women
      randomly assigned to rapid testing or conventional ELISA testing. CONCLUSION:
      Rapid HIV-1 testing significantly increased the proportion of women receiving HIV
      1 results, which is important for sexual and perinatal HIV-1 prevention. The
      challenge remains to improve the uptake of perinatal HIV-1 interventions among
      HIV-1-seropositive women.

PMID- 12478078
TI  - Tumour necrosis factor-alpha gene -238G/A promoter polymorphism associated with a
      more rapid onset of lipodystrophy.

PMID- 12478077
TI  - Rapid declines in total lymphocyte count and hemoglobin in HIV infection begin at
      CD4 lymphocyte counts that justify antiretroviral therapy.

PMID- 12478079
TI  - Serum cortisol in HIV-infected patients with and without highly active
      antiretroviral therapy.

PMID- 12478080
TI  - Immunological changes during treatment interruptions: risk factors and clinical
      sequelae.

PMID- 12478081
TI  - Older HIV-positive patients in the era of highly active antiretroviral therapy:
      changing of a scenario.

PMID- 12478082
TI  - Decreased expression of activation markers on CD4 T lymphocytes of HIV-infected
      long-term non-progressors.

PMID- 12478083
TI  - Cytokines and AIDS dementia complex.

PMID- 12478084
TI  - Lopinavir/ritonavir absorption in a gastrectomized patient.

PMID- 12478085
TI  - Rituximab and chemotherapy is highly effective in patients with CD20-positive non
      Hodgkin's lymphoma and HIV infection.

PMID- 12478086
TI  - Initation of highly active antiretroviral therapy leads to an HIV-specific immune
      response in a seronegative infant.

PMID- 12478087
TI  - Discontinuation of secondary prophylaxis and the risk of Pneumocystis carinii
      pneumonia.

PMID- 12478088
TI  - Bcl-2 expression is moderately correlated with long-term variability of CD4 T
      cell increase under successful highly active antiretroviral therapy.

PMID- 12478089
TI  - A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross
      resistance to non-nucleoside reverse transcriptase inhibitors.
AB  - OBJECTIVE: We have shown that HIV-1 clade C variants contain a valine codon 106
      polymorphism (GTG) that facilitates a V106M transition (GTG<--ATG) after
      selection with efavirenz (EFV). This study evaluates the prevalence of V106 (GTG)
      and 106M (ATG) codons in clinical isolates as well as the effects of V106M on
      resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI). METHODS:
      Genotypic analysis ascertained sequence diversity at codon 106, including both
      valine polymorphisms (GTA and GTG) and the V106A (GCA) and V106M (ATG) resistance
      conferring mutations in B (n = 440) and non-B (n = 84) clinical isolates. Cell
      based phenotypic assays were performed to determine the effects of V106M and
      V106A on levels of resistance to EFV, nevirapine and delavirdine. RESULTS: Most
      subtype B isolates harbored GTA (valine) at codon 106 (97% of cases) while the
      GTG (valine) polymorphism was generally present in clade C viruses (94% of
      cases). Under conditions of EFV but not nevirapine or delavirdine pressure (n =
      8) in tissue culture, clade C isolates developed the V106M mutation (GTG<--ATG),
      conferring high-level (100-1000-fold) cross-resistance to all NNRTI. Generation
      of V106M recombinant viruses by site-directed mutagenesis confirmed the ability
      of V106M to confer NNRTI cross-resistance. This mutation also developed in three
      of six EFV-treated patients harboring clade C infections. In current genotypic
      interpretative reports (including 15 algorithmic databases), V106A is listed as
      an nevirapine-specific mutation while V106M is not recognized. CONCLUSIONS: V106M
      may be a signature mutation in clade C patients treated with EFV and may have the
      potential to confer high-level multi-NNRTI resistance.

PMID- 12478090
TI  - An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected
      individuals.
AB  - BACKGROUND: Tenofovir is a novel nucleotide analogue recommended for use in HIV-1
      infected treatment-experienced patients. Recent data suggest an effect on
      Hepatitis B virus (HBV) replication. We therefore investigated the use of
      tenofovir in HIV-1 and HBV co-infected individuals. METHODS: Twenty HIV-1/HBV co
      infected patients with a median of 108 weeks lamivudine experience (range, 0-270
      weeks) received tenofovir 245 mg daily in addition to or as part of their
      combination antiretroviral therapy. Their immunologic parameters and HIV-1 RNA
      and HBV DNA viral loads were followed over a period of 52 weeks. In addition,
      their HBV DNA polymerase was sequenced at baseline to measure the frequency of
      YMDD mutations that are associated with lamivudine resistance. FINDINGS: A
      significant decrease in HBV DNA viral load (4 x log ) and alanine
      aminotransferase levels was observed. There were no significant overall
      differences between the lamivudine-experienced (n = 15) and -naive (n = 5)
      individuals and tenofovir was well tolerated. Five patients (25%) underwent HBe
      antigen seroconversion during the study period. Out of the 15 lamivudine
      experienced individuals, 10 had YMDD mutations and one had YIDD mutations in HBV
      DNA. INTERPRETATION: These results indicate that 52 weeks of tenofovir in
      addition to antiretroviral therapy is active against HBV, and it appears to
      overcome lamivudine resistance.

PMID- 12478091
TI  - Adrenocortical carcinoma: diagnosis, evaluation and treatment.
AB  - PURPOSE: We describe the presenting features, imaging methods, prognosis of and
      treatment approach to adrenocortical carcinoma. MATERIALS AND METHODS: A
      comprehensive literature review of adrenal carcinoma was performed using PubMed
      and a review of current urology, oncology, radiology and pathology journals.
      RESULTS: The incidence of adrenocortical tumors has been reported to be
      approximately 2/1 x 10(6) population, although this value may be an underestimate
      due to an increase in the incidence of unexpected adrenal masses or
      incidentalomas in the last decade. There has been a bimodal age incidence of
      adrenal carcinoma with most patients 40 to 50 years old in the studies reviewed.
      Overall the prevalence of adrenal tumors was slightly higher in females with most
      presenting with Cushing's syndrome. Of the 602 adrenal tumors reviewed 62% were
      functional and 38% were nonfunctional. Modern day imaging, including ultrasound,
      computerized tomography (CT) and magnetic resonance imaging, have greatly
      improved the diagnosis and staging of adrenal carcinoma. Surgical removal of a
      localized tumor and absent metastatic disease were associated with improved
      survival. Medical therapy with mitotane and its successors in patients with
      metastatic disease appear to be of little benefit for improving survival.
      CONCLUSIONS: Based on a review of the literature we recommend that hormone levels
      should be determined in symptomatic and asymptomatic patients with adrenal
      masses. CT should be the first study done to define an adrenal mass. All solid
      incidentalomas greater than 5 cm. on CT or magnetic resonance imaging should be
      removed surgically. The best chance of survival was achieved by surgical
      extirpation with the value of adjuvant therapy yet to be determined.

PMID- 12478092
TI  - Prostate biopsy: indications and technique.
AB  - PURPOSE: The last decade has seen numerous modifications in the way prostate
      cancer is diagnosed. We review the current indications for and methods of
      prostate biopsy. MATERIALS AND METHODS: The English language literature was
      reviewed regarding major indications for and methods of prostate biopsy.
      Pertinent peer reviewed articles were collated and analyzed. RESULTS: The most
      widely accepted indication for prostate biopsy is a prostate specific antigen
      (PSA) value of greater than 4.0 ng./ml. However, some investigators advocate
      prostate biopsy for men with a PSA value in the 2.5 to 4.0 ng./ml. range,
      believing that use of this parameter results in detection of a greater number of
      cases of curable disease. Age specific PSA range, percent free PSA and presence
      of prostatic intraepithelial neoplasia or atypia are all considered to be
      relative indications for prostate biopsy. The current literature describes a
      trend toward increasing the number of cores obtained and the sites biopsied
      beyond those of the standard sextant technique. The additional cores in many
      series are obtained from more lateral regions of the gland. CONCLUSIONS: Although
      several criteria are used as indications for initial prostate biopsy, all are
      based on PSA level and/or abnormal digital rectal examination. Future
      improvements in currently used prostate cancer markers may result in better
      selection of cases to biopsy. There is no universally accepted technique of
      prostate gland biopsy. The current literature supports use of more extensive
      biopsy techniques to increase the likelihood of prostate cancer detection.

PMID- 12478093
TI  - The effect of finasteride on the expression of vascular endothelial growth factor
      and microvessel density: a possible mechanism for decreased prostatic bleeding in
      treated patients.
AB  - PURPOSE: Several studies have confirmed the benefit of finasteride in limiting
      hematuria from benign prostatic hyperplasia. Vascular endothelial growth factor
      (VEGF), a potent stimulator of angiogenesis, and microvessel density have been
      independently evaluated in the mechanism of decreased bleeding observed in
      patients treated with finasteride. We evaluated the expression of VEGF and
      suburethral prostatic microvessel density in patients with benign prostatic
      hyperplasia treated with finasteride. MATERIALS AND METHODS: The study included
      24 patients undergoing prostatic surgery for benign disease, of whom 12 were
      given finasteride for a minimum of 6 weeks before surgery and the remaining 12
      served as controls. Sections from the prostatic urothelium and hyperplastic
      prostate were individually stained for CD34 specific for nascent blood vessels
      and VEGF. Analysis of each specimen was performed in a blinded fashion.
      Microvessel density was calculated by counting the number of positively stained
      blood vessels on 10 consecutive, nonoverlapping, high power fields within the
      suburethral and hyperplastic prostate compartments. VEGF expression was examined
      by immunohistochemistry. Statistical analysis of the results was performed using
      Student's t test. RESULTS: Prostatic suburethral VEGF expression and microvessel
      density were significantly lower in the finasteride group compared to controls (p
      <0.05). Differences in VEGF expression and microvessel density at the level of
      the hyperplastic prostate were not found to be significantly different between
      the 2 groups. CONCLUSIONS Decreased expression of VEGF by finasteride inhibits
      angiogenesis and significantly decreases microvessel density in prostatic
      suburethral tissue. This sequential relationship provides histochemical insight
      into the mechanism by which finasteride reduces prostatic urethral bleeding.

PMID- 12478094
TI  - The value of quantitative 99M technetium dimercaptosuccinic acid renal
      scintigraphy for predicting postoperative renal insufficiency in patients
      undergoing nephrectomy.
AB  - PURPOSE: Radical nephrectomy is a routine urological practice. However, little is
      known about the use of dimercapto-succinic acid (DMSA) scan to evaluate
      compensatory changes after surgery and its ability to identify patient at risk
      for postoperative chronic renal failure or insufficiency. We predicted remaining
      kidney function using DMSA scan and serum creatinine. MATERIALS AND METHODS: A
      total of 42 patients were enrolled in the study. All underwent DMSA scan before
      surgery and in 38 DMSA scan was done after unilateral nephrectomy. Serum
      creatinine was determined before and 1 year after surgery. The Student t test was
      used to determine statistical significance. Spearman rank core analysis was used
      to evaluate the association of calculated creatinine clearance time after surgery
      and renal absolute uptake before surgery. We performed 1-way ANOVA comparison of
      the means to determine the influence of age distribution on kidney hypertrophy
      and the increase in kidney uptake. RESULTS: Average patient age was 61.5 years.
      Baseline mean creatinine clearance time was 71.5 ml. per minute, which decreased
      to 58.6 ml. per minute after nephrectomy (p <0.0001). Before surgery DMSA scan of
      the remaining kidney demonstrated an absolute uptake of 4.2% higher than that in
      the resected kidney (13.5% versus 9.35%, p = 0.0008). After nephrectomy the
      remaining kidney had an average increase of 3.9% of mean absolute uptake (17.7%
      versus 13.8%, p = 0.0001). Spearman rank core analysis demonstrated an
      association of higher preoperative absolute uptake in the remaining kidney with
      postoperatively high creatinine clearance time (r = 0.458, p = 0.003).
      Furthermore, 75% of patients with postoperative creatinine clearance time less
      than 40 ml. per minute presented with a preoperative absolute uptake of lower
      than 11% in the remaining kidney. In contrast, 75% of those with a postoperative
      creatinine clearance time of higher than 40 ml. per minute had a preoperative
      absolute uptake of higher than 11%. CONCLUSIONS: A preoperative absolute uptake
      of lower than 11% in the remaining kidney was a significant risk factor for
      postoperative chronic renal insufficiency.

PMID- 12478095
TI  - Long-term results of renal transplantation using kidneys harvested from non
      heartbeating donors: a 15-year experience.
AB  - PURPOSE: To expand the pool of suitable organ donors we developed an organ
      procurement program of non-heartbeating donors during the last 15 years. We
      compare graft survival in patients receiving renal transplants procured from non
      heartbeating with recipients of kidneys from heartbeating donors. MATERIALS AND
      METHODS: From 1986 to 1999, 60 renal transplantations were performed with kidneys
      harvested from non-heartbeating donors (Mastrich category IV). Kidneys were
      procured using a double balloon triple lumen catheter inserted into the femoral
      artery. The 60 kidneys were selected from 70 non-heartbeating donors based on age
      younger than 50 years, warm ischemia less than 30 minutes, creatinine less than
      200 micromol./l., and no hypertension or major histological lesions. Long-term
      results of graft survival and complications were compared with a series of 1,065
      renal transplantations performed during the same period with kidneys procured
      from heartbeating donors. RESULTS: Mean age of the recipients was statistically
      different as non-heartbeating donors were older. However, the 10-year graft
      survival rates were similar in both groups (50% versus 53%). Incidence of
      ureteral stenosis and fistula, arterial stenosis and thrombosis was not
      statistically different in both groups. On the other hand, delay graft function
      was more frequent in non-heartbeating donors (60% versus 40%, p = 0.01).
      CONCLUSIONS: Despite a high rate of acute tubular necrosis, kidneys harvested
      from non-heartbeating donors had the same graft survival rates as those procured
      from heartbeating donors. Surgical complications were not different.
      Transplantation of selected kidneys procured from non-heartbeating donors should
      be promoted as a response to organ shortage.

PMID- 12478096
TI  - Laparoscopic management of primary hyperaldosteronism: clinical experience with
      212 cases.
AB  - PURPOSE: Laparoscopy is now widely used to remove benign adrenal tumors. We
      assessed the value of transperitoneal partial or total adrenalectomy for primary
      hyperaldosteronism. MATERIALS AND METHODS: From September 1994 to October 2001,
      212 consecutive patients with a mean age of 48 years who presented with primary
      hyperaldosteronism and related arterial hypertension underwent transperitoneal
      laparoscopic adrenalectomy (193) or tumor enucleation (20) performed by a single
      surgeon, including 1 who underwent bilateral adrenalectomy. In all cases
      preoperatively high plasma and urine aldosterone was associated with low plasma
      renin and hypokalemia. RESULTS: Mean followup was 44 months. Conversion to open
      surgery was necessary in 30 patients (14%) due to bleeding or adhesion and a
      procedure duration of greater than 3 hours. Mean operative time was 102 minutes
      (range 30 to 260). Six patients (2.8%) required blood transfusion. No deaths
      occurred. Postoperatively complications were observed in 10% of patients and the
      most frequent one was electrical myocardial ischemia without infarction. Mean
      postoperative pain medication was 17 mg. morphine sulfate equivalents (range 0 to
      60). Mean and median hospital stay was 3.6 and 2.9 days, respectively (range 2 to
      20). Postoperatively blood pressure was normal in 58% of patients without any
      drug, while treatment was decreased in the remainder. Kalemia was normalized in
      all cases. CONCLUSIONS: Although some complications can occur, mostly at the
      beginning of the learning curve, laparoscopic transperitoneal adrenalectomy is
      effective treatment for primary hyperaldosteronism.

PMID- 12478097
TI  - Transperitoneal laparoscopy into the previously operated abdomen: effect on
      operative time, length of stay and complications.
AB  - PURPOSE: We evaluated the effect of previous abdominal surgery on perioperative
      outcomes in patients undergoing a renal/adrenal laparoscopic procedure via a
      transperitoneal approach. MATERIALS AND METHODS: Renal/adrenal laparoscopic
      procedures via a transperitoneal approach were assessed. Medical records were
      reviewed to obtain operative and perioperative data. RESULTS: Of the 190 patients
      76 (40%) had previously undergone abdominal surgery. Patients with versus without
      an earlier abdominal operation had a longer mean hospital stay (3.8 versus 2.6
      days, p = 0.002) but not longer median operative room time (median 220 versus 210
      minutes, p >0.05). Operative and major complication rates were greater in
      patients with previous operations (16% versus 4%, p = 0.009 and 16% versus 5%, p
      = 0.022, respectively). Access and total complication rates were not altered (4%
      versus 2% and 33% versus 24%, respectively, p >0.1). An upper midline
      scar/ipsilateral upper quadrant scar was associated with a greater access
      complication rate (12% versus 0%, p = 0.029) but not a higher operative
      complication rate (21% versus 13%, p = 0.502). Multiple logistic regression
      confirmed that previous abdominal surgery was the only factor associated with
      operative complications. CONCLUSIONS: Previous open abdominal operation increased
      the risk of operative and major complications, which most likely resulted in
      increased length of stay. The location of the scar impacted the access
      complication rate. Patients who have undergone previous open surgical procedures
      should be counseled on the greater risk of complications if the transperitoneal
      route is elected. Alternatively a retroperitoneal approach may be used.

PMID- 12478098
TI  - Pleural injury during laparoscopic renal surgery: early recognition and
      management.
AB  - PURPOSE: Injury to the diaphragm is an uncommon yet recognized complication of
      several laparoscopic procedures, including laparoscopic renal surgery. As these
      procedures increase in popularity and use, laparoscopic surgeons should be aware
      of techniques for avoiding this complication as well as methods of identifying
      pleural injury and managing it appropriately. We report our experience with the
      detection and intraoperative management of pleural injury sustained during
      laparoscopic renal surgery and its subsequent treatment. MATERIALS AND METHODS:
      From July 1993 to April 2001 at 4 institutions 1,765 patients underwent
      laparoscopic renal surgery for benign and malignant disease as well as for live
      renal donation. We retrospectively reviewed the charts and interviewed the
      primary surgeons to determine the etiology of pleural injury, intraoperative
      detection and management, and possible future prevention. RESULTS: Pleural injury
      occurred in 10 cases (0.6%). In 2 cases injury involved inadvertent trocar
      placement through the pleural cavity. These cases were managed by intraoperative
      chest tube placement. In 8 cases the diaphragm was injured in iatrogenic fashion
      during kidney dissection, including during splenic mobilization in 2, liver
      mobilization in 2, ascending colon mobilization in 1, dissection of the upper
      renal pole in 2 and dissection of a large renal cyst off of the diaphragm in 1.
      In all patients injury was detected intraoperatively and repaired via
      laparoscopy. In 1 patient residual pneumothorax postoperatively necessitated tube
      thoracostomy. CONCLUSIONS: Pleural injury sustained during laparoscopic surgery
      is an uncommon but potentially serious complication of laparoscopic renal
      procedures. The experienced laparoscopic surgeon can identify and repair the
      injury intraoperatively, minimizing patient morbidity postoperatively.

PMID- 12478099
TI  - Cytology of morcellated renal specimens: significance in diagnosis and
      dissemination.
AB  - PURPOSE: Controversy surrounds the process of morcellation for retrieving
      laparoscopically removed specimens. The inability to assess tumor stage,
      increased difficulty in pathological examination and the potential for tumor
      spillage are cited as significant disadvantages of the technique. We examined
      cytological findings in bag washings after laparoscopic nephrectomy for benign
      and malignant diseases. MATERIALS AND METHODS: We prospectively obtained cytology
      washings from the retrieval bag after laparoscopic nephrectomy and manual
      morcellation. In 22 consecutive cases after specimen fragmentation in a LapSac
      (Cook Urological, Spencer, Indiana) the bag was thoroughly irrigated with 30 cc
      normal saline. This wash was then processed by ThinPrep (Cytyc Corp.,
      Marlborough, Massachusetts) and stained with Papanicolaou stain. Standard
      pathological examination of the morcellated specimen was performed to determine
      renal histology. RESULTS: The histological diagnosis was clear cell renal
      carcinoma in 10 cases, multicystic renal carcinoma in 2, papillary renal cell
      carcinoma in 1, angiomyolipoma in 1, and oncocytoma in 1. Bag cytological results
      were accurate in 9 of 13 patients with carcinoma (69%), while in 3 cytological
      study provided additional information. In all 9 cases of benign histology,
      cytological findings were consistent with benign cellular features. Neoplastic
      cells were easily detected and classified into type and grade. CONCLUSIONS:
      Cytological examination of LapSac washings after specimen morcellation provided a
      pathological diagnosis in the majority of patients. This method may complement
      existing techniques and be useful for increasing the accuracy of pathological
      analysis of morcellated specimens. In addition, these data suggest that malignant
      cells are liberated during the morcellation process, which has significant
      implications for potential tumor dissemination.

PMID- 12478100
TI  - Laparoscopic application of radio frequency energy enables in situ renal tumor
      ablation and partial nephrectomy.
AB  - PURPOSE: To our knowledge we present the initial series of renal mass in situ
      laparoscopic radio frequency ablation. We also discuss the indications for and
      results of subsequent laparoscopic partial nephrectomy. MATERIALS AND METHODS:
      Laparoscopic radio frequency ablation was performed in 13 patients with a mean
      age of 59 years (range 18 to 81) and a total of 17 small enhancing renal masses.
      In 5 patients the tumor was subsequently excised completely, whereas in 7 it was
      left in situ after treatment. In 1 patient with 5 lesions only the largest lesion
      was excised, while the other 4 were left in situ. RESULTS: Mean tumor size was
      1.96 cm. (range 0.9 to 3.6). Tumors that remained in situ tended to be endophytic
      and located in the mid pole. Pathological analysis revealed renal cell carcinoma
      in 10 patients, angiomyolipoma in 2 and oncocytoma in the patient with multiple
      lesions. None of the 8 patients with renal cell carcinoma who had at least 6
      weeks of followup (mean 9.8 months, range 1.5 to 22) had any evidence of
      persistent tumor enhancement on surveillance computerized tomography or any other
      evidence of disease progression. There was 1 focal positive margin in a patient
      who underwent radio frequency ablation and excision of renal cell carcinoma but
      the patient remained disease-free 1 year after treatment. CONCLUSIONS: Early
      experience with laparoscopic radio frequency ablation in situ or combined with
      partial nephrectomy shows that it appears to be a safe method of managing small
      enhancing renal masses. Radio frequency assisted laparoscopic partial nephrectomy
      is reserved for easily accessible exophytic tumors, while strict surveillance is
      required for lesions remaining in situ after ablation. Additional followup is
      required to assess long-term effectiveness.

PMID- 12478101
TI  - A prospective randomized trial comparing 2 lithotriptors for stone disintegration
      and induced renal trauma.
AB  - PURPOSE: We compare the efficacy and resulting kidney trauma of the HM3 (Dornier
      Medical Systems, Inc., Marietta, Georgia) and Lithostar Plus (Siemens, Issaquah,
      Washington) lithotriptors in a prospective randomized trial treating calix and
      renal pelvis stones. MATERIALS AND METHODS: Patients with a solitary renal pelvic
      stone 2 cm. or less in diameter or a solitary calix stone 1 cm. or less in
      diameter were randomized for treatment with the HM3 or Lithostar Plus. Stone
      disintegration and dilatation of the pyelocaliceal system were evaluated by
      abdominal plain x-ray and renal ultrasound 1 day and 3 months after treatment.
      Kidney trauma was determined by measurement of N-acetyl-beta-glucosaminidase and
      beta-galactosidase (NAG) in pretreatment urine and 4, 12-hour urine samples
      collected within the first 2 days after extracorporeal shock wave lithotripsy
      (ESWL, Dornier Medical Systems, Inc.). RESULTS: Of 167 patients with 176 stones
      91 were randomized to the HM3 and 85 to the Lithostar Plus lithotriptor group.
      The preoperative stone burden was comparable in both groups. On postoperative day
      1 patients treated with the HM3 or Lithostar Plus were stone-free or had
      fragments 2 mm. or less (91% and 65%, p <0.001), 3 to 5 mm. (8% and 25%, p =
      0.003) and 6 mm. or greater (1% and 10%, p = 0.008), respectively. Patients
      treated with the HM3 had less posttreatment dilatation of the collecting system
      (p = 0.01). Obstructive pyelonephritis occurred in 1% of the HM3 and 8% of the
      Lithostar Plus group (p = 0.02). Re-treatment rate was 4% in the HM3 and 13% in
      the Lithostar Plus group (p = 0.05). Mean excretion of urinary NAG per treatment
      (including re-treatments) was comparable in both groups but NAG excretion in
      relation to stone volume and shock wave number 12 to 24 hours after ESWL was
      significantly higher in the HM3 group (p <0.05). At 3-months postoperatively 89%
      of the patients treated with the HM3 and 87% treated with the Lithostar plus were
      stone-free with no dilatation of the collecting system. CONCLUSIONS: This
      prospectively randomized study indicated that the HM3 is still the gold standard
      in regard to disintegration of pelvicaliceal stones. Stone disintegration with
      the HM3 is better with fewer shock waves, re-treatment rate is lower, and
      posttreatment dilatation of the collecting system and complications such as
      obstructive pyelonephritis are less than those with the Lithostar Plus. ESWL
      induced kidney trauma is minor and resolves within 2 days. The HM3 delivers more
      energy per shock wave into the kidney as assessed by urinary NAG.

PMID- 12478102
TI  - Matched pair analysis of shock wave lithotripsy effectiveness for comparison of
      lithotriptors.
AB  - PURPOSE: In an effort to streamline a comparison of the effectiveness of a new
      lithotriptor with the standard HM3 lithotriptor (Dornier Medical Systems, Inc.,
      Marietta, Georgia) we used a matched pair analysis design. A matched design often
      provides more efficient estimates (smaller variances) than an unmatched design
      given the same sample size. MATERIALS AND METHODS: Patients with solitary renal
      or ureteral calculi treated on a LithoTron shock wave lithotriptor
      (HealthTronics, Marietta, Georgia) between October 1999 and February 2000 with a
      minimum followup of 3 months were identified. Evaluable patients treated with the
      LithoTron were matched using 5 parameters to a data base of patients treated with
      an unmodified HM3 shock wave lithotriptor between October 1997 and February 2000.
      Matching criteria consisted of calculus side, calculus location (1 of 7
      categories), maximum stone diameter (+/-2 mm.), minimum stone diameter (+/-2 mm.)
      and patient body mass index (BMI +/-6). When more than 1 match was suitable,
      matching was directed by random numbers. Following matching, clinical charts and
      radiographic reports were evaluated for stone clearance and post-shock wave
      lithotripsy interventions. Stone treatment success was defined as residual
      fragments less than 2 mm. without need for further intervention. RESULTS: A total
      of 94 potentially evaluable patients treated with the LithoTron were identified
      and 38 matched pairs were created. Average maximum stone diameter, minimum stone
      diameter, and BMI were 9.6 and 9.9 mm., 6.7 and 6.8 mm. and 29.3 and 28.9 kg./m.
      for HM3 and LithoTron cases, respectively. All calculi were radiopaque and
      consisted of mixed calcium oxalate monohydrate (19 and 13), calcium oxalate
      dihydrate (1 and 1) or calcium phosphate (2 and 2) in the HM3 and LithoTron
      groups, respectively. Patients were not specifically matched on stone composition
      because of incomplete availability. Overall intervention-free, stone treatment
      success rate was 79% for the HM3 and 58% for the LithoTron. OR for failure of
      LithoTron versus HM3 treatment was 3.004 (McNemar test p = 0.08). There were 16
      discordant pairs. In 4 cases LithoTron was successful and HM3 failed, and in 12
      cases LithoTron failed and HM3 was successful. Subgroup analysis revealed a trend
      for LithoTron treatment failure for lower pole calculi, calculi 10 mm. or greater
      and BMI of 30 kg./m. or greater. CONCLUSIONS: In this initial evaluation the HM3,
      despite a relatively small study sample size, appeared to provide superior
      clinical results to the LithoTron (p = 0.08). The use of matched pair analysis
      using a large cohort of patients treated with the HM3 for retrospective matching
      may allow for accurate determination of the effectiveness of new lithotripsy
      technology with a relatively small clinical study group.

PMID- 12478103
TI  - Extracorporeal shock wave lithotripsy--what happened?

PMID- 12478104
TI  - Combined percutaneous and retrograde approach to staghorn calculi with
      application of the ureteral access sheath to facilitate percutaneous
      nephrolithotomy.
AB  - PURPOSE: We describe our technique and clinical experience with application of
      the ureteral access sheath for single access ablation of staghorn and partial
      staghorn calculi. MATERIALS AND METHODS: We retrospectively reviewed our
      experience with 9 patients who underwent percutaneous nephrolithotomy for
      staghorn (6) or partial staghorn (3) renal calculi using a combined antegrade and
      retrograde approach. Patient data, operative parameters, efficacy of stone
      ablation and convalescence parameters were reviewed. RESULTS: Mean operative time
      for the primary procedure was 3.1 hours with a mean estimated blood loss of 290
      ml. Postoperatively, the mean analgesic requirement was 33.2 mg. MSO(4)
      equivalents. Hospital stay was 3.2 days. There were no major and 4 minor (44%)
      complications. No patient required transfusion. Complete stone clearance was
      achieved in 7 of the 9 cases (78%) using a single percutaneous nephrostomy tract.
      CONCLUSIONS: Our preliminary clinical experience using the ureteral access sheath
      during percutaneous nephrolithotomy for simultaneous antegrade and retrograde
      stone treatment has been favorable. A large renal stone burden can be
      successfully managed with a single percutaneous access and limited blood loss.

PMID- 12478105
TI  - Durability of the medical management of cystinuria.
AB  - PURPOSE: Cystinuria is an autosomal recessive disorder of dibasic amino acid
      transport in the kidney that leads to an abundance of cystine in the urine. This
      molecule is poorly soluble in urine and it is prone to crystallization and stone
      formation at concentrations above 300 mg./l. Medical treatment in these patients
      has incorporated increasing urine volumes, alkalinization and thiol medications
      that decrease the availability of free cystine in urine. Despite a reasonable
      prognosis for reduced stone formation we and others have noted difficulties in
      patients complying with medical management recommendations. Therefore, we
      evaluated the durability of treatment success in our patients with cystinuria.
      MATERIALS AND METHODS: A retrospective chart review was performed in all patients
      with cystinuria referred to the comprehensive kidney stone center at our
      institution for an 8-year period. Medical therapy, stone recurrence rates,
      compliance with medications and scheduled followup, and the results of metabolic
      evaluations via 24-hour urine collections were reviewed. The average
      concentrations of urinary cystine in initial and followup 24-hour samples were
      compared in patients compliant and noncompliant with medical treatment. In
      addition, each patient was mailed a 1-page questionnaire to assess the self
      perception of medical compliance. RESULTS: We identified 26 patients with a mean
      age of 32 years at referral (range 13 to 67) who were followed an average of 38.2
      months (range 6 to 83). Females represented 58% of those with cystinuria. Overall
      compliance with medical recommendations was poor with a short duration of
      success. Of the 26 patients followed at our stone center only 4 (15%) achieved
      and maintained therapeutic success, as defined by urine cystine less than 300
      mg./l. An additional 11 patients (42%) achieved therapeutic success but
      subsequently had failure at an average of 16 months (range 6 to 27). Of these
      patients 7 (64%) regained therapeutic success at an average of 9.4 months (range
      4 to 20). Five patients (19%) never achieved therapeutic success, while an
      additional 6 (23%) failed to present to followup appointments or provide
      subsequent 24-hour urine studies despite referral to a tertiary care center.
      Patient self-assessment of medical compliance was uniformly high regardless of
      physician perceptions or treatment results. CONCLUSIONS The durability of
      medically treating patients with cystinuria is limited with only a small percent
      able to achieve and maintain the goal of decreasing cystine below the saturation
      concentration. Greater physician vigilance in these complicated stone formers is
      required to achieve successful prophylactic management. Furthermore, these
      patients require better insight into the own disease to improve compliance.

PMID- 12478106
TI  - Prospective analysis of computerized tomography and needle biopsy with permanent
      sectioning to determine the nature of solid renal masses in adults.
AB  - PURPOSE: We prospectively determined the accuracy of computerized tomography (CT)
      and needle biopsy of solid renal masses. MATERIALS AND METHODS: A total of 100
      patients with a solid renal mass who were scheduled for operation were
      prospectively evaluated. CT was performed before radical or partial nephrectomy.
      Biopsy of the surgical specimens was done twice through the tumor using an 18
      gauge biopsy gun. Specimens were sent for permanent section and review by 2
      pathologists blinded to each other and to the whole tissue specimens. Images were
      reviewed by 2 radiologists blinded to each other and to the results of
      pathological analysis. Results of CT and permanent biopsy were compared with the
      results of whole tissue specimen analysis. RESULTS: Specimens were obtained from
      59 radical and 41 partial nephrectomies. Malignant neoplasms were present in 85
      patients (85%). Overall accuracy was 77% and 72%, the nondiagnostic rate was 20%
      and 21%, sensitivity was 81% and 83%, and specificity was 60% and 33%. For the 2
      radiologists overall accuracy was 60% and 66%, the nondiagnostic rate was 31% and
      23%, sensitivity was 70% and 77%, and specificity was 20% and 20%, respectively.
      CONCLUSIONS: Overall permanent biopsy results were accurate in more than 72% of
      cases and CT was accurate in more than 60%. However, because the nondiagnostic
      rate for CT and needle biopsy was 20% and 31%, respectively, and specificity was
      low, we do not recommend routine preoperative CT and subsequent needle biopsy to
      guide treatment decision making. Rather, cases must be decided individually.

PMID- 12478107
TI  - Experience with an elective vacuum assisted cardiopulmonary bypass in the
      surgical treatment of renal neoplasms extending into the right atrium.
AB  - PURPOSE: We evaluate the results of an elective cardiopulmonary bypass conceived
      to minimize the surgical risk related to its use with temporary circulatory
      arrest and deep hypothermia in the treatment of patients with renal tumor
      extending into the right atrium. MATERIALS AND METHODS: From July 1996 to
      December 2000, 19 patients with renal neoplasm and venous involvement were
      admitted to our department. Three patients 4, 57 and 58 years old with a right
      (2) and left (1) renal tumor extending into the right atrium underwent radical
      nephrectomy and tumor thrombus removal using a normothermic cardiopulmonary
      bypass. The bypass circuit was connected with a vacuum assisted venous drainage
      giving a negative pressure of 20 to 40 mm. Hg. Neither circulatory arrest nor
      hypothermia was used. Tumor thrombus was extracted through a longitudinal
      "cavotomy" and removed along with the kidney. RESULTS: Total cardiopulmonary
      bypass time was 14, 19 and 22 minutes, respectively. No intraoperative or
      postoperative complications due to surgical technique occurred. No significant
      bleeding was observed at the time of cavotomy and all neoplastic tissue was
      removed. Pathological examination documented renal cell carcinoma in 2 cases and
      Wilms tumor in 1. All the patients are alive 30, 42 and 15 months, respectively,
      after the operation. CONCLUSIONS: Normothermic cardiopulmonary bypass with vacuum
      assisted venous drainage makes circulatory arrest and hypothermia unnecessary and
      avoids the potential complications associated with these procedures. With respect
      to veno-venous shunts this technique guarantees complete surgical control of the
      thrombus and avoids the need for extensive dissection of the retrohepatic vena
      cava and Pringle maneuver.

PMID- 12478108
TI  - Partial nephrectomy safely preserves renal function in patients with a solitary
      kidney.
AB  - PURPOSE: We examined the success of partial nephrectomy in a group of patients in
      whom its role is paramount, namely those with a solitary kidney requiring
      surgery. MATERIALS AND METHODS: We reviewed the records of 84 consecutive
      patients who underwent partial nephrectomy from January 1995 to August 2000. Of
      these 84 patients 30 (36%) met our study criteria for an absolute indication for
      partial nephrectomy, which included namely a solitary kidney or bilateral renal
      masses for which radical nephrectomy was indicated for at least 1 renal unit. The
      variables examined included preoperative and postoperative renal function,
      pathological evaluation, surgical margins, major and minor complication rates,
      and the need for dialysis. RESULTS: At a median followup of 24 months (range 1 to
      74) median creatinine had increased from 1.5 mg./dl. preoperatively to 1.8
      postoperatively. None of the 30 patients required dialysis in the perioperative
      period. Of the tumors 22 (73%) were renal cell carcinoma and 4 (13%) were
      oncocytoma. All surgical margins were negative for malignancy and no patient has
      had local recurrence to date. Eventually but not immediately 2 patients with
      renal insufficiency preoperatively had progression to end stage renal disease,
      necessitating dialysis at long-term followup. CONCLUSIONS: In patients who
      require partial nephrectomy this procedure can safely preserve renal function and
      effectively treat malignancy.

PMID- 12478109
TI  - Conservative elective treatment of upper urinary tract tumors: a multivariate
      analysis of prognostic factors for recurrence and progression.
AB  - PURPOSE: We evaluate the safety and efficacy of conservative elective treatment
      of upper urinary tract tumors, and determine predictive factors for recurrence
      and progression to optimize indications of this type of treatment. MATERIALS AND
      METHODS: Since 1984 we have performed a prospective study of conservative
      treatment of single, low grade and stage, less than 3 cm. upper tract tumors. The
      study includes 54 patients with a normal contralateral kidney who had been
      followed for more than 36 months. Open conservative surgery was performed in 31
      cases and endourological surgery in 23. Minimum followup was 36 months, maximum
      210 and mean 84.8. Univariate and multivariate analyses of recurrence and
      progression were performed in relation to age, sex, association with a bladder
      tumor, bladder tumor stage and grade, sequence of bladder tumor in relation to
      upper urinary tract tumor, number of previous bladder tumor recurrences,
      association with bladder carcinoma in situ, upper urinary tract tumor grade,
      stage, location, size and therapy, and upper urinary tract cytology. RESULTS: Of
      the 54 patients 19 (35%) had recurrence, which was bilateral recurrence in 4, and
      progression occurred in 9 (16%). At the end of analysis 44 (62.9%) patients were
      disease-free and alive at a mean time of 92.88 months, 13 (24%) died disease-free
      at a mean of 72.7 months and 7 (12.9%) died of disease at a mean of 97.85 months.
      Cause specific mortality occurred in 7 (12.9% cases). Among the 54 initially
      conservatively treated units 42 (77.7%) kidneys were ultimately preserved. On
      univariate and multivariate analysis tumor location in the renal pelvis and
      association with a previous multi-recurrent bladder tumor were variables
      significantly related to recurrence and progression, as well as bilateral
      recurrence. CONCLUSIONS: Conservative treatment is an optional approach for
      select upper urinary tract tumors. The strongest risk factors for recurrence and
      progression were association with a previous multi-recurrent bladder tumor and
      tumor location in the renal pelvis but these conditions were also the strongest
      risk factors for bilateral recurrence. Conservative treatment can also be
      recommended in these cases but only with compliant patients and close followup.

PMID- 12478110
TI  - Mucin 7 and cytokeratin 20 as new diagnostic urinary markers for bladder tumor.
AB  - PURPOSE: We determine the sensitivity and specificity of cytokeratin 20 (CK-20)
      and mucin 7 (MUC7) gene expression in voided urine samples taken from patients
      with bladder tumor and from control groups to investigate putative, noninvasive
      urinary markers for bladder tumor detection and monitoring. MATERIALS AND
      METHODS: Voided urine samples were collected from 50 patients with histologically
      proven bladder neoplasms (pTaN0M0G1-3 in 19 and pTisN0M0G3-pT4pN1M1G3 in 31), 20
      patients with urolithiasis, 20 patients with urinary tract infection, 20 patients
      with other urological neoplasms and 20 healthy volunteers. Total RNA was
      extracted from exfoliated cells collected from 200 ml. voided urine. All RNA
      samples were investigated by a specific CK-20 and MUC7 nested reverse
      transcriptase polymerase chain reaction. RESULTS: The overall sensitivity of CK
      20 gene expression in voided urine samples for the detection of bladder neoplasms
      was 78%. In contrast, voided urine samples from control patients and healthy
      volunteers showed a high rate of false-positive CK-20 detection resulting in a
      low specificity of 36%. The overall sensitivity of the MUC7 test for all bladder
      tumor cases was 66%. The sensitivity for papillary urothelial neoplasms
      (pTaN0M0G1-3) was 42% whereas analysis of the carcinoma in situ and invasive
      bladder cancer group (pTisN0M0G3-pT4pN1M1G3) yielded a sensitivity of 81%. The
      overall specificity of the MUC7 nested reverse transcriptase polymerase chain
      reaction method in the control groups was 80%. CONCLUSIONS: A high positive CK-20
      detection rate was found not only in voided urine samples from patients with
      bladder tumor, but also in urine specimens from control groups. Therefore, CK-20
      is not a reliable urinary tumor marker for bladder neoplasms. In contrast to CK
      20, analysis of MUC7 demonstrated a high sensitivity and high specificity for
      carcinoma in situ and invasive bladder cancer, thus fulfilling the criteria of a
      urinary tumor marker.

PMID- 12478111
TI  - Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder
      cancer: a formal meta-analysis of comparative studies on recurrence and toxicity.
AB  - PURPOSE: We compare the therapeutic efficacy and toxicity of intravesical
      bacillus Calmette-Guerin (BCG) with mitomycin C on recurrence of stages Ta and T1
      bladder carcinoma. MATERIALS AND METHODS: Combined published and unpublished data
      from comparative studies on BCG versus mitomycin C for superficial bladder
      carcinoma considering possible confounding factors were analyzed. Odds ratio (OR)
      and its 95% CI were used as primary effect size estimate. Toxicity data were
      evaluated descriptively. RESULTS: In 11 eligible clinical trials 1,421 patients
      were treated with BCG and 1,328 were treated with mitomycin C. Within the overall
      median followup time of 26 months 38.6% of the patients in the BCG group and
      46.4% of those in the mitomycin C group had tumor recurrence. In 7 of 11 studies
      BCG was significantly superior to mitomycin C, in 3 studies no significant
      difference was found, while in 1 study mitomycin C was significantly superior to
      BCG. An overall statistically significant superiority of BCG versus mitomycin C
      efficacy in reducing tumor recurrence was detected (OR 0.56, 95% CI 0.38 to 0.84,
      p = 0.005). In the subgroup treated with BCG maintenance all 6 individual studies
      showed a significant superiority of BCG over mitomycin C (OR 0.43, 95% CI 0.35 to
      0.53, p <0.001). In 4 of the 5 studies with reported data on toxicity BCG
      associated cystitis was significantly more frequent than in the mitomycin C group
      (53.8% versus 39.2%). The combined cystitis OR was 1.81 (95% CI 1.48 to 2.23, p
      <0.001). The OR for cystitis in the BCG maintenance group did not significantly
      differ from that in the nonmaintenance therapy group. CONCLUSIONS: The results
      suggest superiority of BCG over mitomycin C for prevention of tumor recurrences
      in the combined data and particularly in the BCG maintenance treatment subgroup,
      irrespective of the actual (intermediate or high) tumor risk status. The toxicity
      with BCG is higher but does not differ between BCG maintenance and nonmaintenance
      groups.

PMID- 12478112
TI  - A retrospective analysis of 153 patients treated with or without intravesical
      bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence,
      progression and survival.
AB  - PURPOSE: We retrospectively evaluated the long-term outcome in patients with
      newly diagnosed stage T1 grade 3 bladder cancer treated with transurethral
      resection with or without intravesical bacillus Calmette-Guerin (BCG). MATERIALS
      AND METHODS: Of 153 patients with a median age of 67 years (range 36 to 88) and a
      male-to-female ratio of 4:1 we treated 92 with transurethral bladder resection
      and additional BCG, and 61 with transurethral bladder resection alone. BCG was
      administered intravesically as 120 mg. BCG Pasteur F dissolved in 50 ml. saline,
      retained for up to 2 hours weekly for 6 weeks and repeated as necessary. RESULTS:
      Median followup was 5.3 years (range 0.4 to 18.2). Disease recurred in 70% of the
      patients treated with BCG and in 75% treated with transurethral resection alone.
      Median time to recurrence was 38 and 22 months for BCG and resection alone (p =
      0.19). Tumor progressed in 33% of patients with BCG and in 36% with resection
      alone. Deferred cystectomy was performed in 29% of the patients with BCG and in
      31% with resection alone. Overall and disease specific survival did not differ
      significantly. CONCLUSIONS: Our results suggest that intravesical BCG therapy
      after transurethral bladder resection for stage T1 grade 3 bladder cancer may
      delay the time to recurrence and cystectomy but it does not substantially alter
      the final outcome. Our findings reflect the rule of 30% for stage T1 grade 3
      cancer, namely approximately 30% of patients never have recurrence, 30%
      ultimately die of metastatic disease and 30% require deferred cystectomy.

PMID- 12478113
TI  - Complications of radical cystectomy for nonmuscle invasive disease: comparison
      with muscle invasive disease.
AB  - PURPOSE: Radical cystectomy is gold standard treatment for muscle invasive
      bladder cancer and is an option for many patients with nonmuscle invasive disease
      at high risk for disease progression. We assessed the early complications of
      radical cystectomy among patients with nonmuscle invasive compared to those with
      muscle invasive disease. MATERIALS AND METHODS: We reviewed the records of 304
      consecutive patients who underwent radical cystectomy from December 1995 to July
      2000. We evaluated complications that occurred within 30 days of the procedure.
      Cases were stratified into nonmuscle invasive (PO, Pa, P1 and PIS, N0) or muscle
      invasive (P2-4, N0-3) tumors based on final specimen pathology. The 2 groups were
      then compared with respect to age, gender, race, American Society of
      Anesthesiologists score, type of urinary diversion, estimated blood loss,
      operative time and length of stay, and major and minor complications. RESULTS: Of
      the 293 available patients 105 (36.8%) had nonmuscle invasive specimen pathology.
      Overall major and minor complications occurred in 4.9% and 30.4% of cases,
      respectively. Independent t test revealed no significant difference between
      groups in terms of age (p = 0.85), gender (p = 0.77), race (p = 1.0), American
      Society of Anesthesiologists (p = 0.32), type of urinary diversion (p = 0.33),
      estimated blood loss (p = 0.31), operative time (p = 0.41), length of stay (p =
      0.75), or presence of major (p = 0.78) or minor (p = 0.79) complications.
      CONCLUSIONS: The early morbidity associated with radical cystectomy for nonmuscle
      invasive disease is similar to but not less than that associated with muscle
      invasive tumors. These acceptable risks as well as the potential benefits should
      be discussed with patients with nonmuscle invasive bladder cancer at high risk
      for disease progression.

PMID- 12478114
TI  - The impact of co-morbid disease on cancer control and survival following radical
      cystectomy.
AB  - PURPOSE: We clarified the impact of concurrent medical disease on tumor control
      and survival following radical cystectomy. MATERIALS AND METHODS: A total of 106
      consecutive patients with clinically localized (cT2 or less) disease underwent
      radical cystectomy at the University of Michigan between 1997 and 1998. The
      Charlson Index, a validated risk adjustment index, was used to assess
      preoperative co-morbidity. The 3 primary end points were pathological stage,
      disease specific survival and overall survival. Logistic regression models were
      used to determine the relationship between Charlson Index and pathological stage,
      while Cox regression models were used for the 2 survival end points. RESULTS: Of
      our study population 24% had a Charlson Index score of 2 or greater. Myocardial
      infarction, nonurothelial solid malignancies and cerebrovascular disease were the
      most common co-morbid conditions at 14%, 12% and 10%, respectively. On bivariate
      analysis the Charlson Index was significantly associated with decreased disease
      specific (p = 0.049) and overall (p = 0.016) survival. In a multivariate model
      the index was independently associated with decreased cancer specific survival (p
      = 0.049) and increased risk of extravesical disease (p = 0.033). CONCLUSIONS: We
      demonstrated an association between co-morbid illness and adverse pathological
      and survival outcome following radical cystectomy. This finding underscores the
      value of assessing overall health before recommending and proceeding with
      surgery. Moreover, our results emphasize the need to adjust for co-morbidity when
      comparing outcomes following radical cystectomy.

PMID- 12478115
TI  - An interval longer than 12 weeks between the diagnosis of muscle invasion and
      cystectomy is associated with worse outcome in bladder carcinoma.
AB  - PURPOSE: The standard of care for muscle invasive transitional cell carcinoma of
      the bladder is radical cystectomy. Definitive therapy may often be delayed for
      various reasons. We assessed whether pathological stage and survival correlated
      with the length of time between diagnosis of muscle invasion and cystectomy.
      MATERIALS AND METHODS: The records of 290 consecutive patients who underwent
      radical cystectomy between February 1987 and July 2000 were reviewed. Of 265
      (91.4%) cystectomies performed for transitional cell carcinoma data were
      available for 247 (85.2%) and 189 (65.2%) patients were identified who underwent
      surgery for muscle invasive disease (T2 or greater). The interval between
      diagnosis of muscle invasion and cystectomy was calculated for each patient.
      Patients were divided into groups based on time to surgery as group 1-less than 4
      weeks, 2-4 to 6 weeks, 3-7 to 9 weeks, 4-10 to 12 weeks, 5-13 to 16 weeks, and 6
      greater than 16 weeks. Exploratory univariate and multivariate analyses were
      performed to test the association of time lag with clinical features and
      postoperative survival. RESULTS: Mean patient age was 66 years (range 37 to 84)
      and overall 3-year Kaplan-Meier estimated survival was 59.1% +/- 4% (median
      followup 36 months). For all patients mean interval from diagnosis to cystectomy
      was 7.9 weeks (range 1 to 40). Extravesical disease (P3a or greater) or positive
      nodes were identified in 84% (16 of 19) of patients when the delay was longer
      than 12 weeks, compared with 48.2% (82 of 170) in those with a time lag of 12
      weeks or less (p < 0.01). Similarly 3-year estimated survival was lower (34.9% +/
      13.5%) for patients with a surgery delay longer than 12 weeks compared to those
      with a shorter interval 62.1% +/- 4.5% (hazards ratio 2.51, 95% CI 1.30-4.83, p =
      0.006). When adjusted for nodal status, and clinical and pathological stages the
      interval was still statistically significant (adjusted hazards ratio 1.93, 95% CI
      0.99-3.76, p = 0.05). CONCLUSIONS: In patients undergoing radical cystectomy a
      delay in surgery of greater than 12 weeks was associated with advanced
      pathological stage and decreased survival. Although this relationship persisted
      after adjusting for nodal status, and clinical and pathological stages, the
      presence of lymph node metastasis remained the strongest predictor of patient
      outcome.

PMID- 12478116
TI  - Contemporary concepts of radical cystectomy and the treatment of bladder cancer.

PMID- 12478117
TI  - Primary skin closure of large groin defects after inguinal lymphadenectomy for
      penile cancer using an abdominal cutaneous advancement flap.
AB  - PURPOSE Large groin defects may be created after inguinal lymphadenectomy for
      bulky metastatic penile cancer. We describe a new method of primary closure of a
      large groin skin defect. MATERIALS AND METHODS In 3 patients with large volume
      inguinal lymph node metastases with skin breakdown and secondary infection
      extensive inguinal lymphadenectomy was done with wide surgical excision of skin
      and subcutaneous tissue. The procedures resulted in a large groin defect.
      Sartorius muscle was transferred to cover the femoral vessels. An abdominal
      advancement cutaneous flap was placed for soft tissue and skin coverage of the
      wound. RESULTS Primary closure of a large skin defect was possible using an
      abdominal advancement flap. In all patients the wound healed primarily with good
      cosmesis. A single patient underwent postoperative external beam radiation
      therapy to the flap site with no untoward effect on graft survival. CONCLUSIONS
      Large groin skin defects can be closed primarily using an abdominal advancement
      flap. This technique may also be used for bilateral groin defects. Compared with
      other types of flaps advocated for this purpose the main advantages of the
      procedure are simplicity, lower morbidity and superior cosmetic results.

PMID- 12478118
TI  - Ratio of prostate specific antigen minor molecular forms-to-total prostate
      specific antigen is constant regardless of the pathological condition of the
      prostate.
AB  - PURPOSE: We assessed 3 molecular forms of prostate specific antigen (PSA)
      prospectively to determine the real proportion of the nonfree, nonalpha1
      antichymotrypsin complex form of PSA-to-total PSA and evaluated the clinical
      significance of its various forms. MATERIALS AND METHODS: We prospectively
      assessed 1,878 serum samples from 994 subjects for total PSA, free PSA and PSA
      alpha1-antichymotrypsin complex (ACT). Nonfree, nonPSA-ACT PSA (minor form PSA)
      was calculated as the difference between total PSA and the sum of free PSA plus
      PSA-ACT complex. RESULTS: The proportion of the minor form PSA was approximately
      20% to 25% of total PSA at any range of total PSA, whereas that of free PSA and
      PSA-ACT decreased and increased, respectively, in correlation with the increment
      of total PSA. There was no significant difference in the percent of minor form
      PSA in patients with prostatic carcinoma and those with benign prostatic status.
      The proportion of minor form PSA was constant, while the percent of free PSA and
      PSA-ACT increased and decreased, respectively, in accordance with total PSA
      regression after hormonal therapy for prostatic carcinoma. PSA-ACT was judged to
      be superior to total PSA for distinguishing prostatic carcinoma in men with PSA 2
      to 10 ng./ml. by ROC analysis. CONCLUSIONS: Approximately a fourth of total PSA
      consists of minor forms of complexed PSA. The average proportion of minor form-to
      total PSA was constant at various levels of total PSA and at any prostatic status
      of patients. PSA-ACT was superior to total PSA for the early detection of
      prostatic carcinoma.

PMID- 12478119
TI  - Extended peripheral zone biopsy schemes increase cancer detection rates and
      minimize variance in prostate specific antigen and age related cancer rates:
      results of a community multi-practice study.
AB  - PURPOSE: We assessed the impact of age and prostate specific antigen (PSA) on
      extended systematic biopsy schemes for detecting prostate carcinoma and better
      characterized these tumors as a function of patient age and PSA. MATERIALS AND
      METHODS: We retrospectively reviewed the records of 2,299 consecutive patients
      who underwent initial systematic biopsy performed by 167 community based
      urologists. A total of 12 systematic biopsies of the peripheral zone were
      obtained in all patients. Various biopsy schemes were then created and cancer
      detection rates were calculated. Data analyses were stratified by patient age and
      PSA. RESULTS: On biopsy 1,020 patients (44.4%) had cancer. Detection rates
      increased with increasing patient age. Increasing age and PSA were associated
      with larger, higher grade tumors. Overall and unique site specific cancer
      detection rates were highest for laterally directed biopsies and the apical
      biopsy of the standard sextant scheme. The 12 site biopsy scheme outperformed all
      other schemes in patients with PSA 7 ng./ml. or less and in those 60 years or
      younger. The variation in age related and PSA related detection rates was
      greatest for the standard sextant scheme and this variability decreased for
      extended biopsy schemes. CONCLUSIONS: This multi-practice community based study
      confirms the inadequacy of sextant biopsies and emphasizes the need for extended
      peripheral zone sampling of the lateral aspect of the prostate. Generally
      increasing patient age and PSA were associated with larger, higher grade tumors.
      Extended biopsy schemes minimize PSA and age related detection rates.

PMID- 12478120
TI  - The relationship of prostate gland volume to extended needle biopsy on prostate
      cancer detection.
AB  - PURPOSE: We investigated the relationship between prostate volume and cancer
      detection by needle biopsy, and determined the effect of an increased number of
      cores on the sampling error of needle biopsy on large prostate glands. MATERIALS
      AND METHODS: The study cohort included 750 consecutive patients who underwent
      first time transrectal ultrasound guided prostate needle biopsy from January 1995
      to August 2001. Prostate volumes were divided into quartiles (13 to 34, 34.1 to
      45, 45.1 to 64 and 64.1 to 244 cc). Multivariate analysis controlling for age,
      prostate specific antigen (PSA) and biopsy indication was performed to determine
      the effect of the number of cores and prostate volume on prostate cancer
      detection. RESULTS: Patients diagnosed with prostate cancer were older (p =
      0.0035) and had higher PSA levels (p = 0.0002) than those with no cancer on
      biopsy. Decreasing cancer detection rates were seen with increasing prostate
      volume (p = 0.0074). The OR of detection for each additional core was 0.99 (95%
      CI 0.93, 1.06), suggesting that increasing the number of biopsy cores did not
      increase the rate of prostate cancer detection. Multivariate analysis revealed
      that patients with larger prostates had the same, or possibly lower, cancer
      detection rate as the number of biopsy cores was increased. Patients with larger
      prostates were older (p <0.0001), had higher PSA levels (p <0.0001) and were even
      more likely to have undergone biopsy for increased PSA rather than abnormal
      digital rectal examination alone (p <0.0001). CONCLUSIONS: Our study suggests
      that the lower cancer detection rate for men with large prostates may be due to a
      decrease in the use of increased serum PSA for prostate cancer detection in
      larger prostates in addition to other factors such as sampling error. Increased
      serum PSA levels in cases of larger prostates, although a risk factor for
      prostate cancer warranting biopsy, may also be due to nonmalignant sources such
      as benign prostatic hyperplasia.

PMID- 12478121
TI  - Extended prostate needle biopsy improves concordance of Gleason grading between
      prostate needle biopsy and radical prostatectomy.
AB  - PURPOSE: We examined the concordance of Gleason scores in prostate needle biopsy
      specimens and the corresponding radical retropubic prostatectomy specimens in a
      cohort of patients grouped according to the number of cores obtained during
      diagnostic needle biopsy. MATERIALS AND METHODS: We reviewed clinical and
      pathological data on a cohort of 466 men diagnosed with localized prostate cancer
      by needle biopsies who underwent radical retropubic prostatectomy between January
      1, 1990 and July 31, 2001. Two study groups were identified, including 126
      patients diagnosed with prostate cancer by extended needle biopsies (10 or more
      cores) and 340 diagnosed with cancer by nonextended needle biopsies (9 or fewer
      cores). Mean age was 60 years and median prostate specific antigen was 5.8
      ng./ml. The median number of cores in the extended and nonextended biopsy groups
      was 12 and 6, respectively. The concordance of Gleason score in the needle biopsy
      and prostatectomy specimens was compared and correlated with the number of cores
      on needle biopsy. RESULTS: In the whole cohort 311 patients (67%) had identical
      Gleason scores on the needle biopsy and prostatectomy specimens, while 53 (11%)
      were over graded and 102 (22%) were under graded on needle biopsy. In patients
      who underwent extended needle biopsies the accuracy rate for Gleason scoring was
      76% with 10% over and 14% under graded. The highest accuracy rates were in
      patients with 13, 14 and 16 cores (89%, 87% and 100%, respectively). No patients
      in the extended needle biopsy group had a discrepancy of more than 2 Gleason
      units in grade in the biopsy and surgical specimens. In those who underwent
      nonextended needle biopsies the accuracy rate for Gleason scoring was 63% with
      12% over and 25% under graded. There were significantly different rates of
      accuracy (p = 0.008) and under grading (p = 0.01) in the 2 needle biopsy groups.
      Patients with a needle biopsy Gleason score of less than 7 had significantly
      higher concordance with the prostatectomy Gleason score when extended biopsies
      were done compared with nonextended biopsies (p = 0.001). CONCLUSIONS: Prostate
      cancer grading by extended needle biopsy is a better predictor of the final
      Gleason score than nonextended needle biopsy, as determined by radical
      prostatectomy histological evaluation. Therefore, extended prostate needle biopsy
      provides better guidance to determine the appropriate treatment in patients with
      prostate cancer.

PMID- 12478122
TI  - Transperineal prostate biopsy after abdominoperineal resection.
AB  - PURPOSE: Prostate cancer evaluation in men who have undergone abdominoperineal
      resection poses a challenge for urologists. Diagnosis and staging methods are
      limited because as access to the prostate via digital rectal examination is not
      possible. Prostate specific antigen (PSA) has been used to screen for malignancy
      in this population. However, the conventional diagnostic technique with
      transrectal ultrasound guided biopsies cannot be used. Transperineal ultrasound
      and biopsy have been described to evaluate the prostate in this setting. We
      report our experience with transperineal ultrasound biopsy for evaluating the
      prostate in patients with elevated PSA who have previously undergone
      abdominoperineal resection. MATERIALS AND METHODS: We reviewed the records of 28
      patients treated at 2 institutions. All patients had a history of
      abdominoperineal resection and subsequent transperineal ultrasound guided
      prostate biopsy for evaluating elevated PSA. Mean serum PSA in this population
      was 22 ng./ml. (median 9.5, range 4.1 to 237). Abdominoperineal resection was
      done in 16 patients (57%) for colorectal cancer, in 11 (39%) for ulcerative
      colitis and in 1 (4%) for familial polyposis coli. Average time since resection
      was 14 years (range 1 to 33). Five patients had previously undergone radiation
      therapy as part of treatment for colorectal cancer before transperineal
      ultrasound biopsy. RESULTS: Of the 28 biopsies performed 23 revealed prostate
      cancer, 2 revealed prostatitis and 3 were benign. Average Gleason grade was 6.6
      (range 3 to 9). Of the 23 patients with prostate cancer 22 were treated with
      androgen deprivation therapy (7), prostatectomy (8), external beam (6) and high
      dose (1) radiation therapy. Of the 8 patients who underwent prostatectomy
      pathological stage was T2 in 3 and T3 in 4, while pathological findings were not
      determined in 1 patient in whom the prostate was removed in pieces. CONCLUSIONS:
      In patients with a history of abdominoperineal resection and elevated PSA
      transperineal ultrasound guided biopsy of the prostate can provide an accurate
      tissue diagnosis.

PMID- 12478123
TI  - Randomized prospective evaluation of extended versus limited lymph node
      dissection in patients with clinically localized prostate cancer.
AB  - PURPOSE: The low rate of pelvic node metastasis in most contemporary series of
      patients undergoing radical prostatectomy for carcinoma of the prostate has been
      attributed to earlier and better patient selection than historical series.
      Alternatively, it has been suggested that the limited dissection commonly
      performed misses nodal metastasis in a substantial number of patients. To assess
      the value of an extended node dissection in detecting nodal metastasis, we
      performed a randomized prospective study. MATERIALS AND METHODS: A total of 123
      patients undergoing radical prostatectomy were randomized to an extended node
      dissection on the right versus the left side of the pelvis with the other side
      being a limited dissection. The extended dissection included removal of all
      external iliac nodes to a point above the bifurcation of the common iliac artery,
      the obturator nodes and the presacral nodes. The limited dissection included only
      the nodes along the external iliac vein and obturator nerve. RESULTS: Mean
      patient age was 61 years. Clinical stage was T1c in 88 patients (72%), T2a in 26
      (21%), T2b in 7 (6%) and T3 in 2 (1%). Mean preoperative prostate specific
      antigen was 7.4 ng./ml. Pelvic lymph node metastasis was histologically confirmed
      in 8 patients (6.5%). Positive nodes were found on the side of the extended
      dissection in 4 patients, on the side of the limited dissection in 3 and on both
      sides in 1. Complications possibly attributable to the node dissection included
      lymphocele in 4 patients, lower extremity edema in 5, deep venous thrombosis in
      2, ureteral injury in 1 and pelvic abscess in 1. These complications occurred 3
      times more often on the side of the extended dissection (p = 0.08). CONCLUSIONS:
      Extended node dissection in contemporary series of patients undergoing radical
      prostatectomy identifies few with nodal metastases not found by a more limited
      dissection. A trend toward an increased risk of complications attributable to the
      lymphadenectomy occurs with an extended dissection.

PMID- 12478124
TI  - Transitional cell carcinoma involving the prostate: a clinicopathological
      retrospective study of 76 cases.
AB  - PURPOSE: We reviewed the degree to which extension from transitional cell
      carcinoma into the prostate affects survival. We also compared whether prostatic
      stromal invasion occurring via direct extension through the bladder wall differs
      from stromal invasion arising intraurethrally. MATERIALS AND METHODS: A total of
      76 men who underwent radical cystectomy for transitional cell carcinoma also had
      prostate involvement. Patients were separated into group 1-18 with primary
      bladder tumor extending transmurally through the bladder wall to invade the
      prostate and group 2-58 with prostate involvement arising from within the
      prostatic urethra. In the latter group the degree of prostate invasion was
      classified as urethral mucosal involvement, ductal/acinar involvement and stromal
      invasion. RESULTS: The 5-year overall survival and recurrence-free rate were 22%
      and 28% in group 1 versus 43% and 45% in group 2, respectively. In group 2
      survival rates were similar in those with prostatic urethral and ductal tumors
      (without stromal invasion). Five-year overall survival rates without and with
      stromal invasion were 49% and 25%, respectively (p = 0.024). Prostate involvement
      decreased survival, which varied according to primary bladder stages (Pis, P1,
      P2a/b and P3a/b, p = 0.004) or superficial (Pis, Pa and P1) and muscle invasive
      (P2a/b and P3/b, p = 0.045), disease in 2 groups. Those with positive lymph nodes
      experienced poorer outcomes in each group. The 5-year overall survival rate in
      the 19 men with positive lymph nodes was 13% and it was 44% with negative lymph
      nodes (p = 0.034). The major prognostic factors were age, degree of prostate
      invasion and lymph node involvement. CONCLUSIONS: The invasion pathways of
      prostate invasion in patients with transitional cell bladder carcinoma have a
      statistically significant prognostic role in survival. Transitional cell
      carcinoma of the bladder extending into the prostate through the bladder wall and
      bladder carcinoma that did not directly infiltrate the prostate through the
      bladder wall are 2 distinct clinicopathological entities that should not be
      included in the same staging grade.

PMID- 12478125
TI  - Biochemical and pathological predictors of the recurrence of prostatic
      adenocarcinoma with seminal vesicle invasion.
AB  - PURPOSE: We assessed biochemical and pathological factors as predictors of
      recurrence in men with seminal vesicle invasion. MATERIALS AND METHODS: A
      consecutive series of 812 men who underwent radical retropubic prostatectomy
      between 1992 and 2000 included 106 (13%) with seminal vesicle invasion. Disease
      recurrence was defined as prostate specific antigen (PSA) 0.4 ng./ml. or greater.
      Patients with less than 12 months of followup, salvage radical retropubic
      prostatectomy, lymph node metastases and adjuvant therapy were excluded from
      study. Data on the remaining 66 cases were analyzed using the chi-square test,
      bivariate logistic regression, Kaplan-Meier analyses and Cox proportional
      regression. Variables included demographics, recurrence, time from surgery to
      recurrence, positive margins, capsular invasion, extracapsular extension, Gleason
      score (2 to 6, 7 and 8 to 10), and dichotomized values of preoperative PSA (10 or
      less versus 10 ng./ml.) and tumor volume (20% or less versus greater than 20%).
      RESULTS: Mean patient age was 62 years (range 48 to 74). At an average followup
      of 47.7 months (range 13 to 109) 53% of the patients were free of biochemical
      recurrence. Mean time to recurrence was 18.6 months (range 1.7 to 51.6).
      Univariate analyses revealed a statistical significant increased risk of
      recurrence in patients with PSA greater than 10 ng./ml. (p <0.0001), capsular
      invasion (p = 0.01) and age (p = 0.036). When adjusting for potential covariates,
      Cox proportional regression analysis indicated that higher PSA (hazard ratio
      7.33, 95% CI 2.57 to 20.95), larger tumor volume (hazard ratio 5.64, 95% CI 1.97
      to 16.19) and higher age (hazard ratio 1.13, 95% CI 1.04 to 1.22) were
      significantly associated with shorter time to recurrence. CONCLUSIONS: PSA
      greater than 10 ng./ml., tumor volume greater than 20% and age are significant
      predictors of recurrence after radical retropubic prostatectomy in patients with
      prostate cancer and seminal vesicle invasion. Hopefully future randomized trials
      may show a survival benefit of adjuvant therapy in patients at high risk.

PMID- 12478126
TI  - Predicting recurrence after radical prostatectomy for patients with high risk
      prostate cancer.
AB  - PURPOSE: Previous studies have shown that patients with clinical stage T2c-T3
      prostate cancer, serum prostate specific antigen (PSA) at diagnosis greater than
      20 ng./ml. or a biopsy Gleason score of 8 to 10 are at high risk for disease
      recurrence after radical prostatectomy. We determined the most important
      pretreatment predictors of disease recurrence in this high risk population.
      MATERIALS AND METHODS: We identified 547 patients with high risk prostate cancer
      who underwent radical prostatectomy at University of California, San Francisco or
      as part of the Cancer of the Prostate Strategic Urological Research Endeavor data
      base, a longitudinal disease registry of patients with prostate cancer. High risk
      disease was defined as 1992 American Joint Committee on Cancer clinical stage T2c
      T3 disease in 411 patients, serum PSA at diagnosis greater than 20 ng./ml. in 124
      and/or biopsy Gleason score 8 to 10 in 114. Disease recurrence was defined as PSA
      0.2 ng./ml. or greater on 2 consecutive occasions after radical prostatectomy or
      second cancer treatment more than 6 months after surgery. The Cox proportional
      hazards analysis was performed to determine significant independent predictors of
      disease recurrence. The likelihood of disease recurrence for clinically relevant
      patient groups was determined using the Kaplan-Meier method and compared using
      the log rank test. RESULTS: Median followup after surgery was 3.1 years. Disease
      recurred in 177 patients (32%). Multivariate analysis demonstrated that serum PSA
      at diagnosis, biopsy Gleason score, ethnicity and the percent of positive
      prostate biopsies were significant independent predictors of disease recurrence,
      while patient age and clinical tumor stage were not. Patients with a Gleason
      score 8 to 10 tumor and a serum PSA of 10 ng./ml. or less had a significantly
      higher likelihood of remaining disease-free 5 years after surgery than those with
      PSA greater than 10 ng./ml. (47% versus 19%, p <0.05). Patients with a serum PSA
      at diagnosis of greater than 20 ng./ml. and a Gleason score of less than 8 had a
      significantly higher likelihood of remaining disease-free 5 years after surgery
      than similar patients with a Gleason score of 8 or greater (45% versus 0%, p
      <0.05). CONCLUSIONS: PSA, Gleason score, ethnicity and the percent of positive
      prostate biopsies appear to be the most important pretreatment predictors of
      disease recurrence in men with high risk prostate cancer. Patients with high
      grade disease may continue to be appropriate candidates for local therapy if PSA
      is less than 10 ng./ml. at diagnosis or there are fewer than 66% positive
      prostate biopsies.

PMID- 12478127
TI  - Metastatic carcinoma of the prostate: identifying prognostic groups using
      recursive partitioning.
AB  - PURPOSE While in patients with metastatic prostate cancer median survival is
      approximately 30 months when treated with hormonal therapy, there is substantial
      interpatient variation. To explain better the outcome in patients with advanced
      disease we developed a set of prognostic groups within a large-scale clinical
      trial. MATERIALS AND METHODS Southwest Oncology Group Study 8894 was a randomized
      prospective clinical trial that compared orchiectomy and flutamide to orchiectomy
      and placebo. Using the technique of recursive partitioning we analyzed 5-year
      survival outcomes using a substantial number of patient, treatment and disease
      related variables to develop a set of prognostic groups with significant
      differences in survival. RESULTS Of 1,286 eligible patients 1,076 had sufficient
      data for analysis. The patient data set was split to allow prognostic group
      development in the first half of patients, followed by validation in the second
      half of patients accrued to the study. After pruning the regression tree 4
      factors had a major impact on outcome, namely appendicular versus axial disease,
      performance status 0 versus 1 to 3, prostate specific antigen less than 65 versus
      65 ng./ml. or greater and Gleason score less than 8 versus 8 or greater. Using
      these criteria 3 prognostic groups were developed, including a good (hazards
      ratio 1), intermediate (hazards ratio 1.8) and poor (hazards ratio 2.8) group.
      Five-year survival estimates in the 3 groups were 42%, 21% and 9%, respectively.
      Using the validation test set similar 5-year survival estimates for the 3 groups
      of 46%, 25% and 14%, respectively.CONCLUSIONS These data from a large-scale
      randomized clinical trial provide a validated set of easily applied prognostic
      groups. We hope that our results may be validated by other investigators and we
      would encourage the future reporting of outcomes in patients with advanced
      prostate cancer using these prognostic groupings. Risk stratification is helpful
      for designing clinical trials and individual treatment, and it should be
      incorporated into future reports of outcomes of patients with metastatic disease.

PMID- 12478128
TI  - Urethral stricture repair with an off-the-shelf collagen matrix.
AB  - PURPOSE: In select patients with urethral strictures in whom genital skin is
      insufficient alternative tissues are needed for urethral reconstruction. We
      explored the feasibility of using a bladder submucosa collagen based inert matrix
      as a free graft substitute for urethral stricture repair. MATERIALS AND METHODS:
      A total of 28 patients 22 to 61 years old with a diagnosis of urethral stricture
      underwent reconstructive surgery using a collagen based inert matrix for urethral
      repair. The inert collagen matrix was trimmed to size as needed for each patient
      and the neourethra was created by anastomosing the matrix in an onlay fashion to
      the urethral plate with continuous 6-zero absorbable sutures. The size of the
      created neourethra ranged from 1.5 to 16 cm. A voiding history, physical
      examination, retrograde urethrography, uroflowmetry and cystoscopic examinations
      were performed preoperatively and postoperatively. Random urethral biopsies were
      also performed. RESULTS: After a 36 to 48-month followup (mean 37) 24 of the 28
      patients had a successful outcome. The remaining 4 patients had a slight caliber
      decrease at the anastomotic sites on urethrography. A subcoronal fistula
      developed in 1 patient which closed spontaneously 1 year after repair. Mean
      maximum urine flow rate increased from the preoperative value of 9 +/- 1.29 to
      19.7 +/- 3.07 ml. per second postoperatively. Cystoscopic studies revealed
      adequate caliber conduits and normal appearing urethral tissues. Histological
      examination of the biopsy specimens showed the typical urethral stratified
      epithelium. CONCLUSIONS: Use of an off-the-shelf collagen inert matrix appears to
      be beneficial for patients with urethral strictures and obviates the need for
      obtaining an autologous graft, thus eliminating donor site morbidity.

PMID- 12478129
TI  - Continent colonic urinary reservoir (Florida pouch): long-term surgical
      complications (greater than 11 years).
AB  - PURPOSE: We analyzed the long-term results (greater than 10 years) of a continent
      cutaneous colonic urinary reservoir (Florida pouch), focusing primarily on the
      incidence of significant complications. MATERIALS AND METHODS: Between January
      1986 and October 1991, 179 patients underwent continent cutaneous colonic urinary
      reservoir construction. Of these patients 105 died of primary disease or were
      lost to followup, leaving 38 males and 36 females with a mean followup of 133
      months with adequate data for analysis who are the subject of this report. The
      surgical technique has been previously reported. Briefly, a detubularized right
      colonic segment forms the reservoir, a tapered external limb reinforced at the
      ileocecal valve level allows continent catheterization and the ureters are
      directly anastomosed to the pouch. The diseases that prompted urinary diversion
      included bladder cancer in 28 cases, conversion from another diversion in 12,
      neurogenic bladder in 11, interstitial cystitis in 10, crippling incontinence in
      4, radiation cystitis in 6, hemorrhagic cystitis in 1, exstrophy in 1 and colon
      cancer in 1. A total of 146 direct ureterocolonic reimplantations were performed.
      RESULTS: Complications were grouped by etiology and the number of patients,
      including abdominal wall (peristomal hernia in 3 patients or 4%), external limb
      (incontinence in 5 or 6.7%, stomal stenosis in 3 or 4% and difficult
      catheterization in 1 or 1.4%), reservoir stones (4 or 5.4%), ureteral obstruction
      (primary reimplantation in 7 of 108 or 6.3%, repeat reimplantation in 4 of 24 or
      16.4% and radiated ureters in 4 of 14 or 28.4%) and metabolic (persistent
      diarrhea in 2 or 2.7%, renal failure in 2 or 2.7% and low vitamin B12 in 3 or
      4%). Severe acidosis developed in 4 individuals (5.5%). Of the 12 patients who
      underwent conversion from another type of diversion 7 (58%) experienced metabolic
      alterations. CONCLUSIONS: In the long term continent colonic reservoirs have an
      acceptable complication rate. The most common problem is ureteral obstruction,
      especially in patients who have previously undergone irradiation (28.4% versus
      6.3%, Fisher's test p = 0.02). Patients in whom longer bowel segments were
      resected, such as those with conversion from another type of diversions,
      experienced a greater number of complications, especially ureteral obstruction
      associated with repeat reimplantation (16.4% versus 6.3%, Fisher's test p = 0.23)
      and metabolic derangements (58% versus 6.4%, Fisher's test p = 0.0001).

PMID- 12478130
TI  - Orthotopic urinary diversion after cystectomy for bladder cancer: implications
      for cancer control and patterns of disease recurrence.
AB  - PURPOSE: The impact of orthotopic urinary diversion on the quality of cystectomy
      and ensuing cancer control has not been adequately studied. We analyzed our
      experience with this clinical problem. MATERIALS AND METHODS: The records of 214
      patients who underwent cystectomy and orthotopic diversion for bladder cancer
      were retrospectively evaluated and compared with those of 269 treated with an
      ileal conduit. Analyzed end points included overall and cancer specific survival.
      We specifically assessed the patterns of relapse and their association with
      pathological findings at cystectomy in the neobladder group. RESULTS: No cancer
      specific survival difference was identified in the neobladder and ileal conduit
      cohorts when adjusting for pathological stage. Patterns of relapse in 62 of the
      214 patients with a neobladder (29%) included local recurrence in 23 (11%),
      distant recurrence in 19 (9%), and combined local and distant recurrence in 18
      (8%). Urethral recurrence was rare (2%). Of 10 patients (4.6%) diagnosed with
      upper tract recurrence 6 and 4 initially had relapse in the ureteroenteric
      anastomosis and renal pelvis, respectively. Five of the 6 patients with
      anastomotic relapse had evidence of disease in the intramural or juxtavesical
      ureter that was removed en bloc with the cystectomy specimen. Only 1 patient
      required neobladder takedown after such anastomotic recurrence. CONCLUSIONS:
      These results indicate that neobladders do not compromise the quality of
      preceding cystectomy or interfere with management in the presence of local or
      distant disease relapse. Our data suggest that involvement of the intramural or
      juxtavesical ureteral segment at cystectomy irrespective of surgical margin
      status may identify patients at higher risk for anastomotic recurrence, which is
      associated with an ominous prognosis.

PMID- 12478131
TI  - Body image alteration after flank incision: relationship between the results of
      objective evaluation using computerized tomography and patient perception.
AB  - PURPOSE: We evaluated subjective and objective alterations in body image and
      configuration of patients who underwent urological surgery via a flank incision.
      MATERIALS AND METHODS: Eligible for study were 17 patients who underwent
      urological surgery via an 11th rib transcostal incision. Preoperative and
      postoperative abdominal computerized tomography were used for evaluation. The
      intra-abdominal contents surrounded by the vertebral bones and muscles forming
      the body trunk were divided into 4 subspaces. The areas of these 4 portions were
      measured and the calculated ratio of the contents of each portion determined
      preoperatively was compared with that determined postoperatively. Of the 17
      patients 15 answered a questionnaire on the perception and bother of body image
      alteration. We compared their subjective answers with objective results using
      computerized tomography. RESULTS: The ratio of the ipsilateral-dorsal portion
      significantly increased postoperatively from 18.7% to 21.9% at the L2 level (p
      <0.001), 19.7% to 23.1% at the L3 level (p = 0.002) and 18.3% to 21.2% at the L4
      level (p = 0.003). Posterolateral bulging was typically observed at the L2 level.
      Of the 15 patients who answered the questionnaire 9 (60%) perceived and 4 (27%)
      were bothered by body image alteration to at least a moderate extent. The ratio
      of increase in the ipsilateral-dorsal portion was significantly higher in the 9
      patients who perceived at least moderate body image alteration than in the
      remaining 6 (2.2% versus 4.6%, p = 0.031). CONCLUSIONS: The intra-abdominal
      contents deviated in the ipsilateral-dorsal direction with the patient supine
      after flank incision done via the 11th rib transcostal approach. This change,
      typically represented by posterolateral bulging, results in an altered patient
      body image.

PMID- 12478132
TI  - Isolated renal hydatidosis: experience with 20 cases.
AB  - PURPOSE: Cystic hydatidosis is an endemic disease caused by the larval form of
      Echinococcus granulosus. It is mostly evident in the liver and lungs, and renal
      hydatidosis is uncommon. Renal hydatidosis is usually associated with other organ
      involvement and isolated disease is extremely rare. We present our experience
      with isolated renal hydatidosis in 20 patients. MATERIALS AND METHODS: The charts
      of 20 patients with isolated renal hydatidosis who were hospitalized in our
      department during a 25-year period were reviewed retrospectively. The clinical,
      laboratory and radiologic diagnosis, and treatment of these cases are discussed.
      RESULTS: The main clinical symptom was lumbar pain. There was no specific or
      pathognomonic laboratory test for renal hydatidosis except hydaturia, which was
      present only in 1 patient (5%). Of radiologic examinations computerized
      tomography had the highest sensitivity and specificity. Treatment was mainly
      surgical. We performed nephrectomy in 13 patients, and cystectomy and
      marsupialization in 6. One patient refused all treatments. There was no
      postoperative morbidity or mortality. CONCLUSIONS: Isolated renal hydatidosis is
      extremely rare. The main problem is the correct preoperative diagnosis. Although
      radiologic studies and serological-immunological tests support the diagnosis of
      hydatid disease, a correct preoperative diagnosis is not always easy. The
      treatment is mainly surgical, and with appropriate diagnosis and treatment the
      prognosis is good.

PMID- 12478133
TI  - Electrophysiological assessment of sensations arising from the bladder: are there
      objective criteria for subjective perceptions?
AB  - PURPOSE: Initial bladder filling sensation, first and strong desire to void are
      subjective perceptions that occur periodically during the urine storage mode of
      bladder function, representing sensory input from the lower urinary tract. To our
      knowledge methods for evaluating sensory bladder function are not available. We
      studied a simple electrophysiological procedure for the objective assessment of
      bladder sensations using sympathetic skin responses and surface pelvic floor
      electromyography. MATERIALS AND METHODS: Informed consent was provided by 8
      healthy male subjects, who were administered 20 mg. furosemide and 1 l. fluid to
      drink. Palmar and plantar sympathetic skin responses, and surface pelvic floor
      electromyogram were continuously recorded during bladder filling, voluntary
      pelvic floor contraction and voiding. RESULTS: First desire to void evoked
      simultaneous sympathetic skin responses and pelvic floor contractions. This
      pattern appeared periodically with the desire to void sensation as well as with
      strong desire to void at maximum bladder capacity and it correlated well with the
      subjective sensation of the subjects. Voluntary pelvic floor contraction
      decreased the subjective intensity of the desire to void sensation as well as
      sympathetic skin response activity for the same short period. During voiding
      sympathetic skin responses almost complete absence of sympathetic skin responses
      was observed. CONCLUSIONS: Sensations arising from the bladder induce combined
      activation of sympathetic skin responses and pelvic floor activity. This
      coherence indicates synchronized activation and inactivation of the autonomic and
      somatic pathways necessary for appropriate urine storage and coordinated voiding.
      Our observations may introduce a new approach for objectively assessing
      subjective sensations arising from the urinary tract.

PMID- 12478134
TI  - Long-term urodynamics followup of bladder augmentation for neurogenic bladder.
AB  - PURPOSE: Augmentation enterocystoplasty is well tolerated by patients with
      neurogenic bladder in whom conservative therapy has failed. However, few studies
      exist on long-term urodynamic evaluation of these patients. We assessed the
      clinical and urodynamic outcomes of patients with neurogenic bladder treated with
      augmentation enterocystoplasty with at least 4 years of followup. MATERIALS AND
      METHODS: A total of 26 patients with neurogenic voiding dysfunction underwent
      augmentation enterocystoplasty alone or in conjunction with various continence or
      antireflux techniques. Clinical outcomes regarding incontinence, medications,
      catheterization schedule, subsequent interventions, bowel function and patient
      satisfaction were addressed. Urodynamic evaluation was performed to assess the
      long-term durability of bladder augmentation. RESULTS: Mean followup was 8.0
      years (range 4 to 13). All but 1 patient (96%) in our series had near or complete
      resolution of urinary incontinence. Mean total bladder capacity +/- SD increased
      from 201 +/- 106 to 615 +/- 204 ml. (p <0.001) and mean maximum detrusor pressure
      decreased from 81 +/- 43 to 20 +/- 12 cm. H O (p <0.01). Mean interval between
      catheterizations was 5 hours, with volumes ranging from 314 to 743 ml. Only 2
      patients (8%) needed a low dose of oxybutynin postoperatively to maintain
      continence consistently. Of the 26 patients 23 (88%) reported no significant
      change in bowel function and nearly all patients expressed extreme satisfaction
      with urological management. A subsequent urological procedure was required in 12
      patients (46%) at a mean of 4.4 years after initial surgery.(2) CONCLUSIONS:
      Bladder augmentation provides durable clinical and urodynamic improvement for
      patients with neurogenic bladder dysfunction refractory to conservative therapy.
      Furthermore, there is a high level of patient satisfaction with bladder
      augmentation.

PMID- 12478135
TI  - Puboprostatic sling repair for treatment of urethral incompetence in adult
      neurogenic incontinence.
AB  - PURPOSE: An incompetent urethral sphincter can be a significant factor
      contributing to urinary incontinence in patients with neurogenic bladders. We
      review our experience with 12 men who underwent a puboprostatic sling. MATERIALS
      AND METHODS: The study included 12 men (mean age 37.1 years) with neurogenic
      bladder due to spinal cord injury in 9 and spina bifida in 3. All patients were
      diagnosed with urethral incompetence based on fluorourodynamic evaluation.
      Medical therapy failed in all 12 patients and all complained of urine leakage
      with activity. All patients underwent placement of an autologous fascial sling
      distal to the prostatic urethra via an abdominal approach. Ten patients also
      underwent simultaneous bladder augmentation to correct high intravesical
      pressures. RESULTS: Followup ranged from 1 to 39 months (average 14.25). All
      patients manage the bladder with intermittent catheterization. Of the patients 8
      are completely dry between catheterizations and 2 had significant improvement
      with only minimal leakage (1 pad per day), with an overall success rate of 83%.
      One patient improved initially but subsequently underwent placement of an
      artificial urinary sphincter for residual stress incontinence. In 1 patient
      several external sphincterotomies failed despite adequate sling placement. There
      were no complications related to the placement of the sling and all patients are
      able to perform intermittent catheterization without difficulty. CONCLUSIONS: In
      select male patients the puboprostatic sling can be an effective and safe method
      to treat urethral incompetence secondary to neurogenic voiding dysfunction.

PMID- 12478136
TI  - How to manage acute urethral false passage due to intermittent catheterization in
      spinal cord injured patients who refused insertion of an indwelling catheter.
AB  - PURPOSE: Acute urethral false passage is an important complication of clean
      intermittent catheterization in spinal cord injured patients. Temporary urethral
      stenting with an indwelling catheter is generally an excellent conventional
      therapeutic option to treat patients with acute false passage. However, how can
      acute false passage be managed in a patient who refuses insertion of an
      indwelling catheter? MATERIALS AND METHODS: For 3 years 5 male patients with
      acute urethral false passage due to catheterization refused urethral stenting
      because indwelling catheter insertion would prevent sexual intercourse. We placed
      a nitinol prostatic stent successfully in the false urethral passage in all 5
      patients. The stents were left in place for 3 to 6 months. RESULTS: The stent
      migrated in 1 patient and it was replaced. During a retention period of 3 to 6
      months all patients continued clean intermittent catheterization without any
      difficulty and achieved sexual intercourse. On urethral cystoscopy we observed
      that all false passages disappeared without a gross tissue reaction. The stents
      were then removed without any complications. During a mean followup of 11.8
      months (range 4 to 25) none of these patients had another false passage. All
      continued to perform clean intermittent catheterization without any further
      difficulty. CONCLUSIONS: Temporary placement of a removable endourethral stent is
      a safe and effective method for managing acute urethral false passage in patients
      on clean intermittent catheterization who refuse insertion of an indwelling
      catheter. This approach makes further clean intermittent catheterization possible
      and improves patient quality of life.

PMID- 12478137
TI  - Variability of 24-hour voiding diary variables among asymptomatic women.
AB  - PURPOSE: We determine whether urinary diary values are stable over time among
      women without lower urinary tract symptoms. MATERIALS AND METHODS: Women without
      lower urinary tract symptoms completed a 24-hour log of fluid intake and volumes
      voided during June/July 2001 and again during February/March 2002. Initial and
      repeat diaries were compared using Wilcoxin signed rank tests, considered
      significant at the 5% level. RESULTS: A total of 137 subjects completed both
      diaries. Subjects voided a median of 8 times per 24 hours during the first and 7
      per 24 hours during the second diary with 95% of subjects recording fewer than 13
      voids per 24 hours during both diaries. Nighttime voids were recorded by 59 (43%)
      subjects during the first and 54 (39%) during the second diary. Urinary frequency
      and total urine volume were significantly greater during the first than second
      diary (Z = 2.1, p = 0.03 and Z = 3.3, p = 0.001, respectively). No significant
      differences in mean voided volume, maximum voided volume, voids per liter intake,
      total intake, or daytime or nighttime diuresis rates were found when the groups
      were compared. However, there were large individual differences in all diary
      variables. CONCLUSIONS: While there is large individual variation in diary
      values, pooled data from 24-hour urinary diaries concerning voids per liter
      intake, and mean and maximum voided volumes remain stable. Pooled data concerning
      raw urinary frequency and urine volumes may vary significantly without any
      treatment. When urinary frequency is of interest, the number of voids per liter
      intake may represent the most stable measure.

PMID- 12478138
TI  - Laser prostatectomy versus transurethral resection for treating benign prostatic
      obstruction: a systematic review.
AB  - PURPOSE: We conducted a systematic review of randomized controlled trials
      evaluating the efficacy and safety of laser prostatectomy techniques compared to
      transurethral resection of the prostate for symptomatic benign prostatic
      obstruction. MATERIALS AND METHODS: We searched MEDLINE, the Cochrane library and
      reference lists of retrieved studies to identify randomized trials of 6 months or
      greater in duration with at least 10 subjects in each treatment arm. We extracted
      data on study design, subject and treatment characteristics, adverse events,
      urinary symptoms and urinary flow. RESULTS: A total of 16 studies involving 1,488
      subjects were evaluated, including 8 comparisons of transurethral resection with
      contact lasers, 7 with noncontact lasers and 4 with hybrid techniques. Study
      duration ranged from 6 to 36 months. Mean patient age (67.4 years), baseline
      symptom score (20.2) and peak urinary flow (9.5 ml. per second) did not differ by
      treatment group. Transurethral resection of the prostate provided slightly
      greater improvement in urinary symptoms and flow. The pooled mean percentage
      improvement for urinary symptoms ranged from 59% to 68% with lasers and 63% to
      77% with transurethral resection. Improvement for peak urinary flow ranged from
      56% to 119% with lasers and 96% to 127% with transurethral resection of the
      prostate. Laser procedures resulted in fewer transfusions (less than 1% versus
      7%) and strictures (0% to 7% versus 8%), and required shorter hospitalizations.
      Reoperation occurred more often (RR = 5.7) following laser procedures.
      CONCLUSIONS: Laser techniques are a useful alternative to transurethral resection
      of the prostate for treating benign prostatic obstruction. Small sample sizes and
      differences in study design limit any definitive conclusions regarding the
      preferred type of laser technique.

PMID- 12478139
TI  - Penile duplex pharmaco-ultrasonography revisited: revalidation of the parameters
      of the cavernous arterial response.
AB  - PURPOSE: We revalidate parameters of the cavernous arterial response (peak
      systolic blood flow velocity) and acceleration time using penile duplex pharmaco
      ultrasonography. MATERIALS AND METHODS: Blood flow velocity in the cavernous
      artery following pharmaco-stimulation was determined with duplex ultrasonography
      in 106 patients with erectile dysfunction. Intima media thickness of the common
      carotid artery, a valid index for atherosclerosis and clinical diagnosis based on
      a comprehensive evaluation were used as references. The clinical diagnosis was
      used to determine cutoff values. For the statistical analysis, Pearson
      correlation and ROC curves were used. RESULTS: When correlating peak systolic
      velocity and acceleration time to intima media thickness, acceleration time (r =
      0.51, p <0.01) was the most valid parameter to detect cavernous atherosclerotic
      pathology (peak systolic velocity r = -0.18, p = 0.12). This finding was
      confirmed by a comparison of both parameters to the clinical diagnosis. AUC was
      0.59, 95% CI 0.49-0.69 for peak systolic velocity and 0.72 (95% CI 0.62-0.80 for
      acceleration time). The cutoff point for acceleration time to discriminate
      between atherosclerotic and nonatherosclerotic erectile dysfunction was
      determined at acceleration time 100 milliseconds or greater. Sensitivity was 66%
      and specificity was 71%. CONCLUSIONS: The results of this study show that
      acceleration time has more power than peak systolic velocity to diagnose
      atherosclerotic erectile dysfunction.

PMID- 12478140
TI  - Obtaining rigidity in total phalloplasty: experience with 35 patients.
AB  - PURPOSE: The combination of a neourethra and erection prosthesis in a single
      neophallus in the female-to-male transsexual remains a challenge. The outcome
      reported in the literature is disappointing. We report our experience with 35
      patients. MATERIALS AND METHODS: Between August 1996 and December 2001, 35
      patients underwent implantation surgery. A 1-piece hydraulic Dynaflex prosthesis
      (American Medical Systems, Minnetonka, Minnesota) was used in 10 patients, while
      a 3-piece hydraulic CXM and CX (American Medical Systems) prosthesis was placed
      in 9 and 16, respectively. The 1-piece model was withdrawn from the market in
      1997. Thereafter a 3-piece prosthesis was implanted. RESULTS: Of 10 patients in
      the 1-piece group prosthesis implantation was uneventful in 8. In 2 patients with
      technical failure the prosthesis was replaced, including 1 in whom the new
      prosthesis was removed due to infection and successfully replaced by a 3-piece
      prosthesis. To date at a mean followup of 3.5 years 9 patients have a 1-piece
      hydraulic prosthesis in place. In the 3-piece prosthesis group of 25 patients
      implantation was uneventful in 20. In 1 patient infection and partial necrosis of
      the neophallus developed, 2 had infection, in 1 a cylinder perforated the tip of
      the phallus and in 1 technical failure occurred. Of the latter 4 patients the
      prosthesis was replaced successfully in 2 patients, while the other 2 are on the
      waiting list. The patient with partial necrosis of the phallus is no longer a
      candidate for an erection prosthesis. To date at a mean followup of 1.8 years 23
      patients have a 3-piece hydraulic prosthesis in place. A single patient in the 1
      piece group has a 3-piece CX prosthesis. CONCLUSIONS: Good results were observed
      after implantation of the Dynaflex prosthesis in patients who underwent total
      phalloplasty. This model is no longer available today. For the more complex 3
      piece CX and CXM prostheses implantation results are comparable to those of the 1
      piece model.

PMID- 12478141
TI  - Androgen receptor gene polyglutamine length is associated with testicular
      histology in infertile patients.
AB  - PURPOSE: Androgens and a functioning androgen receptor are required for normal
      spermatogenesis. The androgen receptor gene (AR) has a repetitive DNA sequence in
      exon 1 that encodes a polyglutamine tract. Within the normal polymorphic range
      this (CAG)(n) tract length is inversely related to the transcriptional activity
      of the androgen receptor. In a prospective analysis we determined the association
      of AR (CAG)(n) tract length with testicular histology in infertile males.
      MATERIALS AND METHODS: Blood DNA from 70 severely infertile patients without
      obstruction who were undergoing testicular biopsy was amplified by polymerase
      chain reaction targeting the AR (CAG)(n) tract. A total of 37, 15 and 18 men
      presented with the Sertoli-cell-only syndrome, maturation arrest and
      hypospermatogenesis, respectively. Blood DNA from 55 fertile men served as the
      control. Polymerase chain reaction amplified DNA was direct sequenced using a
      genetic analyzer. RESULTS: Median CAG repeat length was 22 (range 17 to 33) in
      infertile patients and 21 (range 8 to 27) in controls (p = 0.009), including 22
      (range 17 to 30) in patients with the Sertoli-cell-only syndrome, 22 (range 18 to
      28) in those with maturation arrest and 23 (19 to 33) in those with
      hypospermatogenesis. Statistical significance was noted for the
      hypospermatogenesis versus control groups (p = 0.039) but not for the groups with
      the Sertoli-cell-only syndrome or maturation arrest versus the control group (p =
      0.054 and 0.591, respectively). CONCLUSIONS: Infertile males with testicular
      failure, particularly those with hypospermatogenesis, are more likely to have a
      longer androgen receptor polyglutamine tract than controls. Polymorphisms of the
      AR (CAG)(n) tract may contribute to spermatogenesis efficiency through a subtle
      modulatory effect on androgen receptor function.

PMID- 12478142
TI  - Cost-effective treatment for ureteropelvic junction obstruction: a decision tree
      analysis.
AB  - PURPOSE: We determined the optimal treatment for primary ureteropelvic junction
      obstruction based on cost using a decision tree model. MATERIALS AND METHODS: A
      comprehensive literature search for articles addressing surgical correction of
      ureteropelvic junction obstruction was performed and data were abstracted on
      operative time, hospital stay, complications and success rate. The overall cost
      and individual cost centers at our institution for antegrade endopyelotomy,
      retrograde ureteroscopic endopyelotomy, Acucise (Applied Medical Resources,
      Laguna Hills, California) endopyelotomy, laparoscopic pyeloplasty and open
      pyeloplasty were compared. A decision tree model estimated the cost of treatment
      and followup for each modality using commercially available software. Sensitivity
      analyses were performed to evaluate the effect of individual treatment variables
      on overall cost. RESULTS: Based on cost center review retrograde ureteroscopic
      endopyelotomy was the least costly procedure ($2,891). In the decision tree model
      the rank order of overall treatment costs was: retrograde ureteroscopic
      endopyelotomy ($3,842), Acucise endopyelotomy ($4,427), antegrade endopyelotomy
      ($5,297), laparoscopic pyeloplasty ($7,026) and open pyeloplasty ($7,119).
      Despite various hospital stay, operative time, equipment cost and success rate
      data 1-way sensitivity analysis revealed that antegrade endopyelotomy,
      laparoscopic pyeloplasty and open pyeloplasty were never cost effective compared
      with retrograde ureteroscopic endopyelotomy or Acucise endopyelotomy, while 2-way
      sensitivity analysis favored retrograde ureteroscopic endopyelotomy. CONCLUSIONS:
      Primary cost variables for ureteropelvic junction obstruction treatments include
      operative time, hospital stay, equipment cost and success rate. Decision tree
      analysis showed that retrograde ureteroscopic or Acucise endopyelotomy is the
      most cost-effective treatment modality at our institution. However, cost is only
      1 of a number of factors that are considered when deciding on an optimal course
      of treatment.

PMID- 12478143
TI  - Coping strategies in patients with interstitial cystitis: relationships with
      quality of life and depression.
AB  - PURPOSE: Previous research has demonstrated that interstitial cystitis patients
      experience depressive symptoms and decrements to quality of life. However, to our
      knowledge the extent to which patients may be able to influence quality of life
      and depressive symptoms through coping strategies has not been investigated in
      this population. In a number of other chronic conditions specific coping
      strategies have been associated with the degree of impairment beyond disease
      severity. Therefore, the association of coping strategies with depressive
      symptoms, quality of life and self-reports of pain was assessed in patients with
      interstitial cystitis. MATERIALS AND METHODS: A total of 64 females with
      interstitial cystitis were recruited from a urology clinic at a tertiary medical
      center. Questionnaires assessing depression, quality of life, coping and symptom
      severity were completed and returned at a clinic appointment. Depression was also
      measured through a standardized semi-structured interview (Hamilton Rating Scale
      for Depression). All analyses controlled for age. RESULTS: Patients coping by
      greater catastrophizing reported greater impairments in various domains,
      including depressive symptoms, general mental health, social functioning,
      vitality and pain. Greater venting was associated with greater depressive
      symptoms and poorer mental health. Seeking instrumental social support was
      associated with fewer depressive symptoms. CONCLUSIONS: These findings suggest
      that maladaptive coping strategies are associated with higher levels of
      depressive symptoms and quality of life decrements in patients with this
      condition. Psychosocial interventions aimed at increasing adaptive coping may
      positively impact the female experience with interstitial cystitis.

PMID- 12478144
TI  - A national survey of urinary and health related quality of life outcomes in men
      with an artificial urinary sphincter for post-radical prostatectomy incontinence.
AB  - PURPOSE: We determine health related quality of life and urinary outcomes of men
      undergoing implantation of an artificial urinary sphincter for post-radical
      prostatectomy incontinence. MATERIALS AND METHODS: Through a data base provided
      by American Medical Systems, we mailed the UCLA Prostate Cancer Index to men who
      underwent artificial urinary sphincter implantation during 6-month intervals in
      1995 in 1999, providing 5 and 2-year followup data, respectively. RESULTS: Of the
      anonymous questionnaires 36% were returned from the 1995 cohort and 45% from the
      1999 cohort. Age adjusted mean scores for the 8 health related quality of life
      domains were comparable in both groups. Urinary function and bother scores were
      worse in the 1995 cohort compared to the 1999 group (40 and 48 versus 53 and 58,
      respectively, p <0.001), with pad use of 97% and 83% respectively. Revision rates
      were 16% at 2 years and 28% at 5 years after implantation. CONCLUSIONS: Our
      national survey revealed that despite significant differences in urinary function
      and bother, men 2 and 5 years after artificial urinary sphincter implantation had
      similar general health related quality of life. The continence outcomes differed
      from most single institution studies in that men after sphincter implantation
      reported a high degree of urinary dysfunction and bother. Artificial urinary
      sphincter implantation may significantly improve scores in urinary function but
      continued pad use is to be expected.

PMID- 12478145
TI  - Familial prostate and breast cancer in men treated with prostatectomy for
      prostate cancer: a population based case-control study.
AB  - PURPOSE: We assessed familial prostate and breast cancer in Quebec. MATERIALS AND
      METHODS: Using a self-administered mail survey we assessed the prevalence of
      prostate and breast cancer in first degree relatives of 1,633 men treated with
      prostatectomy for prostate cancer in the province of Quebec and in first degree
      relatives of 1,386 spouse controls. RESULTS: The OR of familial breast cancer was
      1.1 (95% CI 0.9 to 1.4). The OR of 3.0 (95% CI 2.5 to 3.6) recorded for prostate
      cancer was modified by francophone versus anglophone linguistic preference (OR
      3.2, 95% CI 2.6, 3.9 versus 1.5, 95% CI 0.8 to 2.7, p = 0.02). Male sibship size
      was a statistically significant parameter modifying this association (p = 0.02),
      namely no brothers (OR 1.7, 95% CI 1.0 to 2.8), 1 or 2 (OR 3.1, 95% CI 2.2 to
      4.3) and 3 or more (OR 3.9, 95% CI 2.9 to 5.2). Geographic regions of the
      province including and neighboring greater Montreal showed a lower OR than more
      peripheral regions (2.5, 95% CI 2.0 to 3.2 versus 4.1, 95% CI 2.9 to 5.7, p =
      0.02). CONCLUSIONS: Francophone men with large male sibships residing in remote
      areas may be at higher risk for familial prostate cancer and represent the ideal
      target for further efforts to determine the genetic component of prostate cancer
      in Quebec.

PMID- 12478146
TI  - Race and survival of men treated for prostate cancer on radiation therapy
      oncology group phase III randomized trials.
AB  - PURPOSE: We assessed the impact of race on survival in men treated with external
      beam radiotherapy with or without hormonal therapy for localized prostate cancer
      in Radiation Therapy Oncology Group randomized trials. MATERIALS AND METHODS:
      Between 1975 and 1992, 2,048 men were treated for clinically localized prostate
      cancer in 1 of 4 consecutive prospective phase III randomized trials. After
      excluding nonblack and nonwhite men 2,012 remained for analysis. Patients were
      included in this analysis if they were deemed evaluable and eligible for the
      trial, and followup information and centrally reviewed pathological results were
      available. Short-term hormonal therapy consisted of goserelin acetate and
      flutamide administered 2 months before and during radiotherapy. Long-term
      hormonal therapy consisted of adjuvant goserelin acetate, which was generally
      given for 2 years or more. Pretreatment prostate specific antigen (PSA) findings
      were available in 430 cases (21%), including 213 treated with radiotherapy alone,
      60 treated with short-term hormonal therapy and 157 on long-term hormonal
      therapy. Mean pretreatment PSA was 68.8 and 35.2 ng./ml. in black and white
      patients, respectively. Cox proportional hazards models were used to identify the
      impact of previously defined risk groups on overall and disease specific
      survival. Multivariate analysis was done for the significance of race using a
      stratified Cox model. Median followup in patients treated in early and late
      studies exceeded 11 and 6 years, respectively. RESULTS: On univariate analysis
      black race was associated with lower overall and disease specific survival (p =
      0.04, RR = 1.24 and p = 0.016, RR = 1.41, respectively). After adjusting for risk
      group and treatment type (with or without short-term or long-term hormonal
      therapy) race was no longer associated with outcome (p >0.05). The trend for a
      persistent difference in survival was likely due to the higher tumor burden in
      black men, as reflected in higher PSA. CONCLUSIONS: As previously reported, tumor
      grade (Gleason score), palpation T stage, lymph node status, pretreatment PSA and
      treatment type are major predictors of overall and disease specific survival. We
      noted no evidence that race has independent prognostic significance in patients
      treated for prostate cancer in Radiation Therapy Oncology Group prospective
      randomized trials.

PMID- 12478147
TI  - Health related quality of life using serum testosterone as the trigger to re-dose
      long acting depot luteinizing hormone-releasing hormone agonists in patients with
      prostate cancer.
AB  - PURPOSE: Health related quality of life was assessed in patients with prostate
      cancer on androgen suppression therapy re-dosed based on serum testosterone, and
      observations were confirmed regarding the safety, efficacy and cost per patient
      treated with this method of re-dosing luteinizing hormone-releasing hormone
      agonists. MATERIALS AND METHODS: The study comprised 22 patients with prostate
      cancer prospectively enrolled in a control-crossover designed trial of dosing
      depot luteinizing hormone-releasing hormone agonist based on serum testosterone.
      Health related quality of life using the Expanded Prostate Index Composite and SF
      36 instruments was the primary outcome assessed. RESULTS: Median duration of
      castrate testosterone was 5.5 months (range 3.5 to 10). Longer durations of
      castrate testosterone significantly correlated with lower pretreatment serum
      testosterone and smaller body mass index. No significant change from nadir
      prostate specific antigen was observed during castrate duration. The yearly cost
      of care was significantly decreased using the method of re-dosing based on serum
      testosterone ($3,567.90 versus $7,135.80). Short-term overall health related
      quality of life and patient satisfaction were significantly improved over
      baseline measurements. However, by study completion overall health related
      quality of life was equivalent regardless of the dosing method. CONCLUSIONS:
      Patient assessed health related quality of life improved in the short term and
      the cost of care decreased with no loss in the quality of care or patient
      satisfaction using serum testosterone as the trigger to re-dose 10.8 mg.
      goserelin in patients with prostate cancer on androgen suppression therapy.

PMID- 12478148
TI  - Simple techniques for atraumatic peritoneal dissection from the abdominal wall
      and for preventing peritoneal injury during trocar placement under
      retroperitoneoscopy.
AB  - PURPOSE: Inadvertent peritoneal tearing causes pneumoperitoneum and makes
      retroperitoneal laparoscopic procedures technically more difficult. We describe
      some simple techniques of atraumatic peritoneal dissection and the prevention of
      peritoneal injury during trocar placement under retroperitoneoscopic guidance.
      MATERIALS AND METHODS: After balloon dilation and the establishment of
      pneumoretroperitoneum a laparoscopic swab stick was used for peritoneal
      dissection from the abdominal wall under retroperitoneoscopic guidance.
      Exploratory puncture using a Cathelin (Terumo, Tokyo, Japan) needle was performed
      before trocar placement in close proximity to the lateral peritoneal reflection.
      RESULTS: We applied this technique in our last 10 consecutive retroperitoneal
      laparoscopic procedures. No peritoneal rents occurred during dissection of the
      lateral peritoneal reflection or trocar insertion. CONCLUSIONS: The laparoscopic
      swab stick technique described facilitates atraumatic peritoneal dissection as
      well as creation of an adequate working space. Exploratory puncture using a
      Cathelin needle is useful for preventing inadvertent peritoneal injury during
      trocar placement.

PMID- 12478149
TI  - Anterior extraperitoneal approach to laparoscopic retroperitoneal lymph node
      dissection: a novel technique.
AB  - PURPOSE: We describe a novel technique of laparoscopic retroperitoneal lymph node
      dissection via an anterior extraperitoneal approach. MATERIALS AND METHODS: With
      the patient in a modified flank position an 8 mm. incision is made along the
      lateral border of the ipsilateral rectus muscle at the umbilical level.
      Extraperitoneal space creation with finger dissection is initially made at this
      site and adequately enlarged with a balloon dilator, followed by gas insufflation
      and placement of 4 laparoscopic trocars. Laparoscopic retroperitoneal lymph node
      dissection based on a left modified template is then performed in a completely
      extraperitoneal manner. RESULTS: Surgical time was 330 minutes, blood loss was
      150 ml. and 58 lymph nodes were removed. Resumption of physical activity and oral
      intake was achieved on postoperative day 1. Hospital stay was 36 hours.
      Postoperative narcotic requirement was 28 mg. morphine sulfate equivalent. There
      were no intraoperative or postoperative complications. Normal antegrade
      ejaculation returned postoperatively. CONCLUSIONS: This novel surgical technique
      is technically feasible and associated with satisfactory clinical outcomes in our
      preliminary study. Further studies are necessary to evaluate its potential as an
      alternative to the previously reported transperitoneal and retroperitoneoscopic
      approaches to laparoscopic retroperitoneal lymph node dissection.

PMID- 12478150
TI  - New surgical technique for sphincter urinary control system using upper
      transverse scrotal incision.
AB  - PURPOSE: Traditional implantation of the AMS Sphincter 800 Urinary Control System
      (American Medical Systems, Minnetonka, Minnesota) requires 2 incisions. The cuff
      is placed via a perineal incision, and the pressure regulating balloon and pump
      are placed through a separate suprapubic incision. We describe a novel
      implantation of all the artificial urinary sphincter components using a single
      upper scrotal incision. The scrotal incision allows excellent access to the
      proximal bulbar urethra and retropubic and subdartos spaces, and leaves the
      bulbocavernosus muscle intact. MATERIALS AND METHODS: A total of 37 patients have
      undergone artificial urinary sphincter implantation using the new operative
      technique for revisions or reimplantations of a sphincter previously removed for
      infection/erosion (12) or as an initial procedure (25). In 9 of the 25 patients
      and 2 of the 12 dual implantation of a 3-piece penile prosthesis through the same
      incision was performed. RESULTS: All patients are using the devices. Of the
      patients 66% are completely dry with no pad use and the remainder use 1 pad for
      accident prevention. Operative time was reduced due to easier exposure of the
      urethra and a second incision for placement of the pressure regulating balloon
      was not necessary. Followup at 1 year shows no difference in complication rate
      with the single incision technique compared to the traditional method.
      CONCLUSIONS: Artificial urinary sphincter implantation through a single scrotal
      incision is easier and faster than the traditional 2-incision technique. Success
      in achieving continence is similar to traditional methods. Long-term followup is
      necessary to ensure that complications remain low.

PMID- 12478151
TI  - Castleman's disease in the retroperitoneal space.

PMID- 12478152
TI  - Air embolism from pneumopyelography.

PMID- 12478153
TI  - A retained ureteral stump with calculi.

PMID- 12478154
TI  - Remote recurrence of malignant pheochromocytoma 14 years after primary operation.

PMID- 12478155
TI  - Renal chromophobe cell carcinoma and paraneoplastic linear IgA bullous
      dermatosis.

PMID- 12478156
TI  - Malignant osteoclast-like giant cell tumor of the kidney with osteosarcomatous
      transformation.

PMID- 12478158
TI  - Post-prostatectomy bleeding managed by endovascular embolization.

PMID- 12478157
TI  - Diagnostic localization of malignant bladder pheochromocytoma using 6-18F
      fluorodopamine positron emission tomography.

PMID- 12478159
TI  - Prostate carcinoma and the Lambert-Eaton myasthenic syndrome.

PMID- 12478160
TI  - Rectal squamous cell carcinoma 11 years after brachytherapy for carcinoma of the
      prostate.

PMID- 12478161
TI  - Bisphosphonate therapy for hormone refractory prostate cancer with bone
      metastasis.

PMID- 12478162
TI  - Complication of the sacral neuromodulator: lead avulsion and wire disruption.

PMID- 12478163
TI  - Meckel's diverticulum as the site of implanting ureter to the Bricker segment
      after radical cystectomy.

PMID- 12478164
TI  - Vaginal erosion after pubovaginal sling procedures using dermal allografts.

PMID- 12478165
TI  - Reduction of strangulated urethral prolapse using local anesthesia with
      hyaluronidase.

PMID- 12478166
TI  - Ectopic vas deferens opening into the bladder found during routine evaluation of
      male factor infertility.

PMID- 12478167
TI  - The case for diethylstilbestrol.

PMID- 12478168
TI  - Re: Ligation of the native ureter in renal transplantation.

PMID- 12478169
TI  - Re: Risk factors for the formation of a steinstrasse after extracorporeal shock
      wave lithotripsy: a statistical model.

PMID- 12478170
TI  - Re: Bare naked baskets: ureteroscope deflection and flow characteristics with
      intact and disassembled ureteroscopic nitinol stone baskets.

PMID- 12478171
TI  - Re: Prediction of pathological stage in patients with clinical stage T1c prostate
      cancer: the new challenge.

PMID- 12478172
TI  - Re: Giant lipoma of the adrenal gland.

PMID- 12478173
TI  - Re: Comparison of intussusception pull-through end-to-side and conventional end
      to-side microsurgical vasoepididymostomy: prospective randomized controlled study
      in male wistar rats.

PMID- 12478174
TI  - Re: Does PC-SPES interact with warfarin?

PMID- 12478175
TI  - Fetal renal growth as assessed through renal parenchymal area derived from
      prenatal and perinatal ultrasonography.
AB  - PURPOSE: Few quantitative parameters allow for comparison of serial studies in
      children with prenatally detected genitourinary abnormalities. We establish the
      first ultrasonographically based fetal renal parenchymal growth curve that could
      serve as a standard for fetal renal growth assessment. MATERIALS AND METHODS:
      Longitudinal ultrasounds of 246 normal fetal kidneys from 16 to 38 weeks of
      gestation were scanned with renal parenchymal area calculated and growth curves
      plotted. Our previously determined nomogram from birth to adolescence was then
      combined with this fetal nomogram to produce a composite renal growth curve. Data
      were plotted as mean parenchymal area +/- 2 SD using lines determined by
      polynomial regression. RESULTS: Renal growth curves were constructed
      independently for the right and left fetal kidneys as well as the total fetal
      renal parenchymal area. The polynomial regression equation for the right renal
      parenchymal area was y = -0.0076x(2) + 0.7141x - 8.5344 (r(2) = 0.91). The
      polynomial regression equation for the left renal parenchymal area was y = 
      0.0036x(2) + 0.5161x - 6.2337 (r(2) = 0.96). The polynomial regression equation
      for the total fetal renal parenchymal area was y = -0.0113x(2) + 1.234x - 14.814
      (r(2) = 0.95). CONCLUSIONS: We propose a new quantitative standard to evaluate
      appropriate fetal kidney size the prenatal renal parenchymal area growth curve.
      Renal parenchymal growth curves for the normal fetal kidney may serve as a
      valuable tool to assess fetal renal pathology.

PMID- 12478176
TI  - Spontaneous testicular hemorrhage in an adolescent.

PMID- 12478177
TI  - Preservation of renal function in children with myelomeningocele managed with
      basic newborn evaluation and close followup.
AB  - PURPOSE: Children with myelomeningocele who leak with high intravesical pressures
      are at risk for upper urinary tract deterioration. Urodynamic study shortly after
      birth and routinely thereafter has been advocated to predict which newborns are
      at risk for upper tract deterioration. We hypothesize an approach that excludes
      routine application of urodynamic evaluation in neonates, reserving this study
      for use only when clinically indicated, is a safe and effective management
      option. MATERIALS AND METHODS: Of 188 patients seen in the myelomeningocele
      clinic 84 underwent initial evaluation at age 6 months or less and comprise the
      study group. Initial evaluation consisted of a history, physical examination,
      urine culture and renal ultrasound. Infants with hydronephrosis or evidence of
      retention were placed into a high risk group and all others were placed into a
      low risk group. High risk patients underwent prompt urodynamic evaluation. High
      and low risk patients were followed closely at 2 to 4-month intervals with serial
      physical examination, upper tract imaging and urine culture. Conversion from low
      to high risk occurred with new onset hydronephrosis, febrile urinary tract
      infection, urinary retention or incidental finding of vesicoureteral reflux at
      the time of evaluation for continence. These findings warranted urodynamic
      evaluation and appropriate intervention. Upper tract deterioration, defined as
      new onset hydronephrosis, was distinguished from renal deterioration, defined as
      cortical thinning or scarring, failure of renal growth or decreased renal
      function on renal scan. RESULTS: A total of 18 infants were placed into the high
      risk group at initial evaluation, including 12 for retention and 6 for
      hydronephrosis. The majority of patients were treated with clean intermittent
      catheterization or vesicostomy. Of the 65 infants placed into the low risk group
      29 were converted to high risk at a mean age of 3.1 years, most commonly for
      febrile urinary tract infection (45%), and appropriate intervention was
      instituted. Mean followup is 10.4 years (range 0.25 to 26.5). Despite the
      occurrence of upper tract deterioration, renal deterioration occurred in only 2
      of the 162 total renal units (1.2%). CONCLUSIONS: Basic evaluation of the newborn
      with myelomeningocele along with careful followup and intervention when indicated
      results in an excellent rate of renal preservation and represents a safe method
      of management.

PMID- 12478178
TI  - Clinical characteristics of primary vesicoureteral reflux in infants: multicenter
      retrospective study in Japan.
AB  - PURPOSE: We evaluate clinical characteristics of primary vesicoureteral reflux in
      infants in a multicenter study in Japan with special reference to the relation of
      renal parenchymal damage to urinary tract infection and gender. MATERIALS AND
      METHODS: Infants younger than 1 year old with primary vesicoureteral reflux were
      recruited from 14 hospitals during the 3-year registration period beginning in
      January 1996 and ending in December 1998. Various clinical parameters as well as
      renal parenchymal lesion on dimercaptosuccinic acid scintigraphy were evaluated.
      RESULTS: Of 356 infants enrolled 296 (83%) were male and 60 (17%) were female. In
      85% of infants presenting symptom was febrile urinary tract infection. There were
      204 bilateral (57%) and 152 unilateral (43%) cases. Reflux was bilateral in 56%
      of males versus 65% of females, and high grade (grades IV and V) in 58% of males
      versus 55% of females. Diffuse parenchymal lesion was similarly noted in infants
      with or without prior urinary tract infection (38% and 46%, respectively) and was
      more often noted in male than in female infants (42% versus 25%). CONCLUSIONS:
      Despite the current use of screening prenatal ultrasound, many infants are still
      diagnosed as having vesicoureteral reflux only after the occurrence of urinary
      tract infection. The greater severity of renal parenchymal lesion in male infants
      combined with similar incidence of diffuse parenchymal lesion in those with or
      without prior infection suggests preexisting congenital abnormalities in the male
      refluxing kidney.

PMID- 12478179
TI  - Subureteral polydimethylsiloxane injection versus extravesical reimplantation for
      primary low grade vesicoureteral reflux in children: a comparative study.
AB  - PURPOSE: We compare the outcome of extravesical ureteral reimplantation to
      endoscopic polydimethylsiloxane (Macroplastique, Uroplasty, Inc., Minneapolis,
      Minnesota) subureteral injection for primary low grade vesicoureteral reflux in
      children. MATERIALS AND METHODS: Between 1997 and 2000, 180 patients underwent
      polydimethylsiloxane injection (74, 108 ureters) or extravesical ureteral
      reimplantation (106, 166 ureters) for low grade vesicoureteral reflux. Low grade
      reflux was defined as grades I to III. Outcome analysis included success rates,
      de novo hydronephrosis, voiding efficiency, urinary tract infections and
      complications. RESULTS: Mean patient age at surgery for the injection and surgery
      groups was 60 and 77 months, and mean followup was 12 and 15 months,
      respectively. Of the patients who underwent single injection 80.6% were cured of
      reflux at 3 months and 91.6% were cured at last followup. Success rate after
      reimplantation was 95.8% at 3 months which improved to 98.8% 1 year later. The
      success rate was significantly different between the injection and reimplantation
      groups at 3 and 12 months (p <0.01). Postoperative complications in the
      reimplantation group included transient urinary retention after bilateral surgery
      in 2 patients (3.3%), suprapubic fluid collections in 2 and wound seroma in 1. No
      complications occurred in the polydimethylsiloxane group. CONCLUSIONS:
      Extravesical ureteral reimplantation has near perfect success with a low but
      definite complication rate. Polydimethylsiloxane offers high success rates for
      reflux in an ambulatory setting with no short-term complications. Currently,
      endoscopic polydimethylsiloxane injection is our preferred mode of therapy for
      low grade vesicoureteral reflux in children when surgical correction is
      indicated.

PMID- 12478180
TI  - Therapeutic efficacy of extended release oxybutynin chloride, and immediate
      release and long acting tolterodine tartrate in children with diurnal urinary
      incontinence.
AB  - PURPOSE: We compare the tolerability and efficacy of extended release oxybutynin
      chloride, and immediate release and long acting tolterodine tartrate in children
      with nonneurogenic diurnal urinary incontinence and symptoms of overactive
      bladder. MATERIALS AND METHODS: Children with a history of diurnal urinary
      incontinence were arbitrarily assigned to extended release oxybutynin, immediate
      release tolterodine or long acting tolterodine. The dose was titrated until
      effective (onset of complete diurnal urinary continence), maximal recommended
      dosage was achieved or bothersome anticholinergic side effects developed. An
      independent observer recorded the dose used, anticholinergic side effects and
      efficacy of therapy (incidence of urinary frequency, urgency, posturing and
      urinary incontinence). RESULTS: The study included 86 girls and 46 boys. There
      were no statistically significant differences among the 3 treatment groups
      regarding the presence of peripheral or central nervous system anticholinergic
      side effects. Extended release oxybutynin and long acting tolterodine were
      significantly more effective at reducing daytime urinary incontinence than
      immediate release tolterodine (p <0.01 and 0 <0.05, respectively). Extended
      release oxybutynin was significantly more effective then long acting tolterodine
      for complete resolution of diurnal incontinence (p <0.05). CONCLUSIONS: Extended
      release oxybutynin and long acting tolterodine are more effective than immediate
      release tolterodine in decreasing diurnal urinary incontinence. Extended release
      oxybutynin chloride is more effective than either immediate or long acting
      tolterodine for control of daytime urinary incontinence and urinary frequency.

PMID- 12478181
TI  - The Malone antegrade continence enema procedure: quality of life and family
      perspective.
AB  - PURPOSE: Since introducing the Malone antegrade continence enema (MACE) procedure
      into our practice, it has been our bias that social confidence and independence
      are significantly improved and satisfaction is overwhelmingly high. We
      objectively determine outcomes after the MACE to refine patient selection, and
      maximize the quality of perioperative counseling and teaching. MATERIALS AND
      METHODS: An anonymous questionnaire was mailed to all patients who had undergone
      the MACE procedure within the last 4 years. Patient/parent satisfaction, impact
      on quality of life and clinical outcome were assessed with Likert scales.
      Demographic information, MACE specifics, preoperative expectations, and
      unanticipated benefits and problems were also recorded. RESULTS: A total of 65
      questionnaires were returned from our first 92 patients (71%). Myelodysplasia was
      the primary diagnosis in 88% of patients. Complete or near complete fecal
      continence was achieved in 77% of patients and all others had improved
      incontinence. The highest level of satisfaction was reported by 89% of patients.
      Social confidence and hygiene were significantly improved. Daily time commitment,
      pain/cramping, intermittent constipation and time for fine-tuning the regimen
      were cited as unanticipated issues. CONCLUSIONS: The MACE procedure has received
      high praise from patients and families after years of battling constipation and
      fecal incontinence. Significant improvement rather than perfection is the
      realistic expectation. Objective feedback from patients and families will
      continue to improve patient selection and education.

PMID- 12478182
TI  - Use of a colon based tubularized flap for an antegrade continence enema.

PMID- 12478183
TI  - Long-term efficacy of periurethral collagen injection for the treatment of
      urinary incontinence secondary to myelomeningocele.
AB  - PURPOSE: The reports of efficacy of periurethral collagen injection (Contigen,
      Bard, Covington, Georgia) for treatment of urinary incontinence in the
      myelomeningocele population are limited and variable. We reviewed the efficacy of
      periurethral collagen in patients with myelomeningocele to provide long-term
      followup data. MATERIALS AND METHODS: From 1994 to 1999, 19 children and 6 adults
      with myelomeningocele underwent periurethral injections of collagen with an
      average of 2 treatments per patient. Mean followup +/- SD from last injection in
      the pediatric and adult groups was 2.9 +/- 1.5 years and 4.7 +/- 2.6 years,
      respectively. Postoperative continence was defined as dry, improved or unchanged.
      RESULTS: No pediatric patients became dry, 7 (37%) improved and 12 (63%) were
      unchanged. A single adult was dry (17%), 4 (67%) improved and 1 remained
      unchanged. Transient improvement was noted in 8 of the 13 patients who reverted
      to an unchanged status. Response rate was 66% in nonambulatory patients versus
      42% in ambulatory patients (p = 0.38). Of 12 patients who responded and 13 who
      did not 8 in each group required 2 or more treatments. The responding group
      percentage of predicted bladder capacity was 97.6% versus 89.5% in those who
      remained unchanged (p = 0.66). CONCLUSIONS: The initial transient improvement
      following collagen injection and the long-term improvement following repeat
      injections suggest that degradation of collagen decreased its efficacy. The long
      term results of this minimally invasive technique are poor.

PMID- 12478184
TI  - Dryness and the urological armamentarium.

PMID- 12478185
TI  - Tubularized incised plate repair: functional outcome after intermediate followup.
AB  - PURPOSE: We describe the functional outcome following tubularized incised plate
      repair of hypospadias in toilet trained children after an intermediate followup.
      MATERIALS AND METHODS: Children were included in this study only if they were
      toilet trained and had flow rate data not less than 6 months after primary
      tubularized incised plate hypospadias repair or 2 months after any secondary
      procedure to correct complications. Uroflow data (peak flow, voided volume and
      post-void residuals) were analyzed and plotted on previously determined age
      volume dependent nomograms. RESULTS: Of the 48 boys 39 required no secondary
      procedures, while 9 secondary fistula closures were performed in 2, meatotomy in
      2 and dilation in 5. After either primary (26) or secondary (7) procedures 33 of
      the 48 patients (68.7%) had normal peak flow rate and 15 (31.3%) had low peak
      flow rate. Of the 48 patients 46 had post-void residual urine less than 10% of
      voided volume. CONCLUSIONS: Most children will void efficiently with no straining
      and no post-void residual (1/2) to 4 years after tubularized incised plate
      hypospadias repair. Of our patients 68.7% have normal peak flow rate.
      Intermediate followup of larger series and followup at puberty are recommended to
      resolve the debate concerning the long-term functional outcome of tubularized
      incised plate hypospadias repair.

PMID- 12478186
TI  - Heat shock proteins: their role in urological tumors.
AB  - PURPOSE: Heat shock proteins are ubiquitous molecules that are expressed in
      response to stress in all living organisms. The 3 important roles in regard to
      cancer development that have also been described are the regulation of apoptosis,
      modulation of the immune response and drug resistance. MATERIALS AND METHODS:
      Recent studies have dramatically increased our current knowledge and
      understanding of the role of heat shock protein in cancer. We used a MEDLINE
      approach to examine the past and current literature. RESULTS: The roles of heat
      shock protein in relation to urological tumors, namely those of the prostate,
      bladder, kidney and testis, are diverse. There are possible sites for heat shock
      protein modifications that may lead to new therapeutic approaches to urological
      cancer. CONCLUSIONS: The possibility of treating patients with vaccines earlier
      in the disease course may stimulate research.

PMID- 12478187
TI  - Laparoscopic partial kidney ablation with high intensity focused ultrasound.
AB  - PURPOSE: High intensity focused ultrasound has been performed for transrectal and
      extracorporeal thermal ablation of tissues. We developed and tested a
      laparoscopic probe that allows real-time ultrasound imaging during partial renal
      ablation using high intensity focused ultrasound. METHODS: A Sonablate 200 (Focus
      Surgery, Indianapolis, Indiana) high intensity focused ultrasound system with a
      modified 18 mm. laparoscopic probe was used in all experiments. In 13 Yucatan
      mini-pigs a 5Fr ureteral catheter was inserted into the renal pelvis and 10 cc
      air were instilled into the collecting system. The kidney was laparoscopically
      dissected, the high intensity focused ultrasound probe was inserted through a 33
      mm. laparoscopic port and the targeted renal pole was treated. RESULTS: Renal
      lesions were created in 12 of 13 treated kidneys under real-time ultrasound
      visualization. Median operative time was 180 minutes, average high intensity
      focused ultrasound activation time was 18.3 minutes and lesion size was 23 x 17 x
      11 mm. At 4 and 14 days 4 (acute group) and 6 (subacute group) animals were
      available for renal functional and anatomical evaluation, respectively. No
      difference in renal function was seen in treated and untreated kidneys.
      Pathological examination at 14 days revealed homogenous and complete tissue
      necrosis throughout the whole volume of the lesion with sharp demarcation from
      adjacent normal tissue. CONCLUSIONS: We were able to refine a probe for
      laparoscopic high intensity focused ultrasound delivery capable of simultaneous
      ultrasound imaging. Partial renal ablation using this probe is feasible and safe,
      and resulted in homogenous, complete and reproducible lesions.

PMID- 12478188
TI  - Whole bladder photodynamic therapy for orthotopic superficial bladder cancer in
      rats: a study of intravenous and intravesical administration of photosensitizers.
AB  - PURPOSE: Photodynamic therapy after intravenous injection of Photofrin (QLT
      Phototherapeutics, Vancouver, British Columbia, Canada) results in a contracted
      bladder and skin photosensitivity, which limits its clinical application. In an
      attempt to overcome these limitations photodynamic therapy after intravesical
      instillation of Photofrin or 5-aminolevulinic acid (ALA) in an orthotopic rat
      bladder tumor model was explored and compared with intravenous Photofrin for
      photodynamic therapy efficacy and phototoxicity. MATERIALS AND METHODS: At 2
      weeks after bladder implantation of 1.5 x 10(6) AY-27 tumor cells animals were
      randomly grouped. Photofrin was administered (5 mg./kg. intravenously and 2
      mg./ml. intravesically). The ALA concentration for intravesical instillation was
      300 mM. Whole bladder photodynamic therapy with graded doses of light (lambda =
      630 nm.) was performed 4 hours after drug administration. Tumor control and
      complications were evaluated. RESULTS: Photodynamic therapy with intravenous
      Photofrin plus 100 J./cm.(2) light resulted in severe bladder damage. Of 10 rats
      6 died and 2 of the 10 that received 50 J./cm.(2) died. There were no
      photodynamic therapy related deaths in groups receiving intravesical instillation
      of Photofrin or ALA that also received 50 to 100 J./cm.(2) Median survival in
      rats treated with ALA intravesically plus 75 J./cm.(2) (77 days), Photofrin
      intravesically plus 50 (67) or 100 J./cm.(2) (76) and Photofrin intravenously
      plus 50 J./cm.(2) (60) were significantly different from that in controls (44).
      CONCLUSIONS: Intravesical instillation of Photofrin or ALA can achieve the same
      photodynamic therapy efficacy as intravenous Photofrin in this orthotopic rat
      bladder tumor model with less phototoxicity to normal tissues.

PMID- 12478189
TI  - A phase I study of intravesical suramin for the treatment of superficial
      transitional cell carcinoma of the bladder.
AB  - PURPOSE: Suramin is a polysulfonated naphthylurea that inhibits proliferation and
      DNA synthesis of transitional cell carcinoma cell lines. Its large molecular size
      and negative charge inhibit bladder absorption, making suramin an excellent
      candidate for intravesical chemotherapy. Intravesical suramin was evaluated in a
      phase I study to define dose limiting toxicity and systemic absorption, determine
      a starting dose and regimen for phase II studies and provide a preliminary
      assessment of in vivo antitumor activity. MATERIALS AND METHODS: Intravesical
      suramin treatment was administered in 9 patients with histologically identified
      transitional cell carcinoma (Tcis, Ta or T1) in whom at least 1 course of
      standard intravesical chemotherapy (bacillus Calmette-Guerin, thiotepa or
      mitomycin C) had failed. Suramin was administered once weekly for 6 weeks.
      Patients were treated in groups of 3 using a 60 cc volume and intrapatient dose
      escalation schedule. Suramin doses of 0.3 to 614.4 mg./ml. were administered
      intravesically. The last group was treated with the same weekly dose for 6 weeks.
      RESULTS: The 9 patients underwent 54 treatments with suramin. Plasma suramin
      concentration after treatment was 1.9 to 38.0 microg./ml. and was not related to
      treatment dose. The dose escalation phase was limited by the solubility of
      suramin in solution. Complications included self-limited bladder spasms (less
      than 24 hours) in 4 of 54 treatments (7%) and new or worsening vesicoureteral
      reflux in 3 ureters (17%). Another patient who was treated after the Foley
      balloon was inflated in the urethra experienced bladder spasms, skin flushing and
      fever (39C). Mean bladder capacity before and after treatment was 600 and 540
      ml., respectively. At followup 7 patients had stage Ta tumors and 2 had carcinoma
      in situ. CONCLUSIONS: An intravesical suramin dose of 153 mg./ml was defined as a
      safe treatment parameter with acceptable plasma concentrations and minimal side
      effects. Phase II studies are needed to assess the antitumor activity of suramin
      in patients with transitional cell carcinoma of the bladder.

PMID- 12478190
TI  - Quantitative analysis of kallikrein 15 gene expression in prostate tissue.
AB  - PURPOSE: The newly discovered human kallikrein 15 gene KLK15 has been shown in
      preliminary analysis to be associated with more aggressive types of prostate
      cancer. We quantitatively measured and compared gene expression of KLK15 in
      malignant and benign prostate tissues. MATERIALS AND METHODS: Matched prostate
      tissue samples from the cancerous and noncancerous parts of the same prostates
      were obtained from 90 patients who underwent radical prostatectomy. Quantitative
      reverse transcriptase-polymerase chain reaction using SYBR Green I and the
      LightCycler system (Roche Applied Science, Mannheim, Germany) was performed.
      Associations of KLK15 expression with clinicopathological parameters were
      analyzed. RESULTS: KLK15 over expression in cancerous versus noncancerous tissue
      was found in 76 of the 90 patient samples (84.4%, p <0.001). The ratio of
      cancerous-to-noncancerous KLK15 expression tended to be higher in patients with
      stage pT3/4 versus pT2 tumors (p = 0.1). KLK15 expression tended to be higher in
      grade 3 than in grade 2 tumors and in Gleason score 7 or greater than in Gleason
      score less than 7 tumors (p = 0.18 and 0.23, respectively). A 1.7 cutoff at the
      40th percentile provided a significant difference in stages pT2 and pT3/4 tumors
      (p = 0.029). CONCLUSIONS: On quantitative real-time polymerase chain reaction
      KLK15 expression was significantly higher in cancerous than in noncancerous
      tissue. Up-regulation of the KLK15 gene in advanced and more aggressive tumors
      may indicate a possible role for KLK15 protein as future serum marker for
      prostate cancer and for distinguishing tumor aggressiveness.

PMID- 12478191
TI  - Flow cytometry analysis of proliferative lesions at the gastrocystoplasty
      anastomosis.
AB  - PURPOSE: Proliferative epithelial metaplasia that develops in the anastomotic
      line after gastrocystoplasty has unknown malignant potential. Flow cytometry
      analysis of cell cycle profiles is used to predict the neoplastic progression of
      metaplastic lesions in other proliferative epithelium. We used this technique to
      evaluate transitional cell metaplasia in rat gastrocystoplasty specimens.
      MATERIALS AND METHODS: A total of 50 prepubescent female Long-Evans rats were
      randomly assigned to an experimental group (gastrocystoplasty) or a control group
      (sham operation). At 21 to 27 months (mean 24.9) after operation 12 rats per
      group survived to sacrifice. Metaplastic lesions were microdissected to yield a
      minimum of 10(4) cells for DNA flow cytometry and cell cycle analysis.
      Transitional cell epithelium from sham specimens and gastric epithelium from
      experimental animals served as controls. RESULTS: Transitional cell hyperplasia
      and metaplasia with cyst formation were found in the anastomotic line in all 12
      augmented bladders (100%). No proliferative lesions developed in control animals.
      No nuclear pleomorphism or mitotic changes were identified on routine
      histological examination. The epithelial cell turnover rate was 10 times higher
      in the gastrocystoplasty junctional zone than in control bladders (mean 2.2%
      versus 0.1% S phase) but lower than in native stomach epithelium (mean 3.3% S
      phase). Of 12 experimental specimens 1 showed near diploid DNA aneuploidy. No DNA
      abnormalities were detected in control bladder or stomach specimens. CONCLUSIONS:
      In this animal model histologically benign appearing proliferative lesions that
      develop in the anastomotic zone after long-term gastrocystoplasty harbor cell
      cycle and DNA ploidy abnormalities.

PMID- 12478192
TI  - Prospective analysis of single nucleotide polymorphisms of the transforming
      growth factor beta-1 gene in Peyronie's disease.
AB  - PURPOSE: The detection of increased expression of transforming growth factor beta
      1 (TGF-beta1) in Peyronie's disease plaques and the possibility of initiating a
      Peyronie's disease-like condition by intratunical injection of a synthetic
      heptopeptide with TGF-beta-like activity in an animal model has provided evidence
      for the central role of this cytokine in the pathogenesis of this entity.
      Recently 2 defined single nucleotide polymorphisms in the coding region of the
      TGF-beta1 gene have been described that are associated with different levels of
      TGF-beta1 production. Based on these data we prospectively investigated the
      genetic association of distinct TGF-beta1 genotypes with Peyronie's disease.
      MATERIALS AND METHODS: DNA samples from 111 consecutive patients with idiopathic
      Peyronie's disease and 100 controls were genotyped for the 2 defined dimorphic
      single nucleotide polymorphisms T869C and G915C in the coding region of the TGF
      beta1 gene using allele specific polymerase chain reaction. RESULTS: We found an
      increased frequency of the homozygous genotype of the single nucleotide
      polymorphism G915C in patients with Peyronie's disease compared with healthy
      controls (89.2% versus 79%, p = 0.04). However, there were no significant
      differences in allele frequencies of the single nucleotide polymorphism T869C.
      CONCLUSIONS: Experimental data from other investigators have shown that TGF-beta1
      has an important role in the etiopathology of Peyronie's disease. Our results
      indicate that the homozygous wild type of the G915C single nucleotide
      polymorphism in the coding region of the TGF-beta1 gene, which was recently
      associated with elevated TGF-beta1 production and pulmonary fibrosis, may
      influence the predisposition to Peyronie's disease. However, it does not
      represent a major genetic risk factor.

PMID- 12478193
TI  - Renal hemodynamic and ureteral pressure changes in response to ureteral
      obstruction: the role of nitric oxide.
AB  - PURPOSE: Triphasic changes in renal blood flow and ureteral pressure after
      unilateral ureteral obstruction have long been known. The contribution of nitric
      oxide to the decline in renal blood flow and ureteral pressure in unilateral
      ureteral obstruction was studied in this model using arginine infusion and by
      studying the effect of 2 inhibitors of nitric oxide synthase (NOS). MATERIALS AND
      METHODS: Left ureteral obstruction was created in dogs. Renal blood flow and
      ureteral pressure were monitored. Groups 1 to 4 underwent unilateral ureteral
      obstruction and group 5 dogs underwent sham operation. Groups 2 to 5 received an
      infusion of arginine at hour 18 of obstruction that was sustained for 1 hour. In
      addition, NOS inhibitors were administered to dogs in groups 3 (N-monomethyl-L
      arginine) and 4 (triamcinolone diacetate). RESULTS: Arginine administration at 18
      hours of obstruction caused a significant increase in renal blood flow and
      ureteral pressure compared to sham operated animals. Triamcinolone diacetate
      eliminated the increase in renal blood flow and ureteral pressure, whereas N
      monomethyl-L-arginine did not, reflecting the competitive nature of its
      inhibition of NOS. CONCLUSIONS: Arginine infusion 18 hours after unilateral
      ureteral obstruction led to increases in renal blood flow and ureteral pressure
      that were not seen in control animals. These results suggest that the nitric
      oxide system of the kidney is activated in unilateral ureteral obstruction. Since
      the addition of arginine is accompanied by an increase in renal blood flow and
      ureteral pressure, it further suggests that a lack of availability of substrate
      for NOS may explain the decrease in renal blood flow and ureteral pressure in
      obstruction. Providing substrate may be a way of maintaining renal blood flow in
      unilateral ureteral obstruction.

PMID- 12478194
TI  - Electromyographic detection of purinergic activity in Guinea pig detrusor smooth
      muscle.
AB  - PURPOSE: We recorded nerve mediated extracellular electrical activity from guinea
      pig detrusor smooth muscle strips using suction electrodes and determined the
      electrophysiological origins of this signal and its relationship to contractile
      activity. MATERIALS AND METHODS: Mucosa-free detrusor strips were prepared from
      male guinea pigs sacrificed under Home Office license, physiologically
      superfused, attached to a pressure transducer and electrically stimulated (0.1
      millisecond pulses). Electrical signals recorded using a bipolar reversible
      suction electrode were processed and recorded simultaneously with changes in
      strip tension. The effect of superfusion with alpha, beta-methylene adenosine
      triphosphate (ATP), atropine, extracellular [CaCl(2)] depletion and
      pharmacological Ca2+ channel blockade on the electrical and mechanical signals
      was determined. RESULTS: A biphasic electrical signal was consistently recorded
      from 37 detrusor strips. The signal was sensitive to graded reduction in
      [CaCl(2)] of the superfusate and abolished by tetrodotoxin in 7 preparations. The
      signal was also abolished in 12 preparations by alpha, beta-methylene ATP in
      association with an attenuated contraction but not significantly reduced in
      amplitude (p = 0.77) despite a significant reduction in tension with atropine
      (mean plus or minus SD 74% +/- 14% of control, p <0.001). The signal was
      attenuated to a mean maximum of 9% +/- 3% of control by pharmacological Ca2+
      channel blockade and the remaining signal was abolished by alpha, beta-methylene
      ATP. CONCLUSIONS: The extracellular electrical signal recorded from guinea pig
      detrusor strips using suction electrodes originates from a purinergic mechanism.
      Although an atropine sensitive component may be present, the signal does not
      depend on cholinergic neuromuscular transmission and would not be expected to be
      generated by normal human detrusor. Provided that the electrophysiological basis
      of purinergic neurotransmission in guinea pig and human bladders is similar
      suction electrodes may be a valuable tool with which to evaluate in vitro and
      clinically by electromyography the pathological purinergic neuromuscular
      transmission that can be expressed in addition to normal cholinergic mechanisms
      in detrusor from dysfunctional human bladders.

PMID- 12478195
TI  - Expression of estrogen receptors alpha and beta by sympathetic ganglion neurons
      projecting to the proximal urethra of female rats.
AB  - PURPOSE: Urinary incontinence is prevalent in postmenopausal women and estrogen
      is commonly administered therapeutically. In animal models estrogen increases
      urethral smooth muscle agonist induced contraction but a consistent clinical
      benefit in humans has not been confirmed. A reason may be that estrogen affects
      tissues other than the urethra that are involved in continence. We determined if
      sympathetic nerves projecting to the urethra may also be a target for estrogen.
      MATERIALS AND METHODS: Sympathetic neurons innervating proximal urethra smooth
      muscle were identified by injection of the retrograde tracer Fast Blue (Dr.
      Illing GmbH and Co. KG, Gross-Umstadt, Germany) in 10 ovariectomized adult female
      rats. Rats received a single injection of 10 microg./kg. estradiol benzoate or
      vehicle 24 hours before tissue harvest. Retrograde labeled sympathetic neurons
      expressing estrogen receptors alpha and beta in prevertebral and paravertebral
      ganglia were identified by immunostaining. RESULTS: Approximately 80% of Fast
      Blue labeled neurons were located in the T11 to L5 paravertebral ganglia. The
      remainder was located predominantly in the prevertebral suprarenal ganglia with
      fewer in celiac and superior mesenteric ganglia. Estrogen receptor beta was
      detected in more than 90% of urethra projecting neurons, while approximately 30%
      expressed estrogen receptor alpha. No significant change occurred after estrogen
      administration. CONCLUSIONS: Almost all examined sympathetic neurons projecting
      to the proximal urethra express estrogen receptor beta and a substantial subset
      expresses estrogen receptor alpha irrespective of estrogen titer. Therefore,
      estrogen may influence continence by acting not only on the urethral target, but
      also on its excitatory sympathetic innervation.

PMID- 12478196
TI  - Direct evidence of facilitative actions of dopamine in the medial preoptic area
      on reflexive and noncontact erections in male rats.
AB  - PURPOSE: We examined the effects of alterations of the extracellular dopamine
      level in the medial preoptic area on 2 erectile contexts, namely reflexive and
      noncontact erections, in male rats. MATERIALS AND METHODS: The extracellular
      dopamine level was measured in the medial preoptic area after administering the
      dopamine reuptake inhibitor bupropion hydrochloride (Sigma Chemical Co., St.
      Louis, Missouri) into the same area through a micro-dialysis tube. We measured
      the frequency and latency of reflexive erections, and the frequency of noncontact
      erection during infusion of bupropion. RESULTS: Administration of 10 mM.
      bupropion was associated with significant elevation in the extracellular dopamine
      level in the medial preoptic area. Bupropion (1 mM.) and Ringer's solution did
      not induce significant alterations in dopamine in the medial preoptic area. The
      number of reflexive erections significantly increased and erection latency
      decreased during infusion of 10 mM. bupropion into the medial preoptic area. The
      number of noncontact erections was also increased by administering 10 mM. of
      drug. CONCLUSIONS: The altered dopamine level in the medial preoptic area
      affected 2 distinct penile erectile contexts, suggesting that the dopamine levels
      in the medial preoptic area may be involved in the regulation of erection. These
      results may have important implications for the central regulation of penile
      erection.

PMID- 12478197
TI  - Mechanisms of excitatory transmission in circular smooth muscles of the guinea
      pig seminal vesicle.
AB  - PURPOSE: Cellular mechanisms of excitatory neuromuscular transmission in circular
      smooth muscles of the seminal vesicle were investigated. MATERIALS AND METHODS:
      Circular smooth muscles of the seminal vesicle of the guinea pig were isolated.
      Changes in membrane potential produced by transmural nerve stimulation were
      recorded using intracellular microelectrode techniques. Changes in the
      intracellular Ca ion concentration induced by transmural nerve stimulation were
      measured in preparations loaded with Ca indicator fura-PE3. Responses produced by
      bath applied norepinephrine and alpha,beta-methylene adenosine triphosphate (ATP)
      were also examined. RESULTS: Transmural nerve stimulation evoked excitatory
      junction potentials that triggered action potentials and also caused transient
      increases in [Ca2+] (Ca transients). Nifedipine abolished action potentials,
      leaving underlying excitatory junction potentials unchanged, and reduced the
      amplitude of Ca transients. Excitatory junction potentials were blocked by
      alpha,beta-methylene ATP or guanethidine but not by phentolamine. A train of
      transmural nerve stimulation evoked oscillatory changes in membrane potential and
      [Ca2+], which were abolished by phentolamine or inhibited by nifedipine.
      Nifedipine insensitive components were abolished by cyclopiazonic acid.
      Norepinephrine depolarized the membrane and elicited oscillatory potentials with
      an associated elevation in [Ca2+]. These responses were inhibited by nifedipine
      and abolished by additional application of cyclopiazonic acid. Transient
      depolarization with an associated increase in [Ca2+] was elicited by alpha,beta
      methylene ATP and [Ca2+] responses but no potential changes were inhibited by
      nifedipine. CONCLUSIONS: Circular smooth muscles of the guinea pig seminal
      vesicle receive a projection of sympathetic nerves that release norepinephrine to
      initiate slow depolarization through the activation of alpha-adrenoceptors. These
      nerves also release ATP to elicit excitatory junction potentials. Neurally
      released norepinephrine and ATP are increased [Ca2+] by the influx of Ca2+
      through L-type Ca2+ channels and also by the release of Ca2+ from internal
      stores.

PMID- 12478198
TI  - Presenting symptoms and diagnosis of coronary heart disease in women.
AB  - Coronary artery disease generally presents later in women than men and more
      frequently with atypical symptoms. From the Framingham data, angina is the
      commonest initial clinical presenting symptom of coronary artery disease in
      women, compared with myocardial infarction for men. Obtaining a careful history
      is essential in evaluating a woman for possible coronary artery disease. Research
      is beginning to elucidate some barriers to the diagnosis of coronary artery
      disease in women.

PMID- 12478199
TI  - Postmenopausal hormone replacement therapy and the prevention of cardiovascular
      disease: a review.
AB  - The role of hormone replacement therapy (HRT) for the prevention of cardiac
      disease is contentious. In this review the epidemiological evidence for the role
      of HRT in primary and secondary prevention of cardiac disease is assessed.
      Although current studies suggest very little role for HRT in women with
      established cardiac disease, its use in the 'healthy woman' without vascular
      disease until recently was not clear. HRT for the sole purpose of prevention of
      cardiac disease is now not indicated.

PMID- 12478200
TI  - Women and coronary heart disease risk factors.
AB  - The prevalence of cardiovascular risk factors among women is high and
      cardiovascular risk factors often occur in clusters. Strong relationships between
      exposure to cigarette smoke, physical inactivity, hypertension, and abnormal
      levels of lipoproteins and homocysteine and subsequent coronary heart disease
      (CHD) in women are evident from many studies, while the impact of menopause,
      psychosocial factors, and inflammatory markers is less clear and requires further
      study. Observational studies document that smoking cessation reduces CHD risk
      among persons with and without existing CHD, and that moderate levels of physical
      activity are associated with lower CHD risk. Clinical trials over the last decade
      have convincingly shown that treatment of hypertension and dyslipidemia reduces
      CHD risk in both genders, but many women (and men) with hypertension and
      dyslipidemia remain either untreated or under-treated.

PMID- 12478201
TI  - Obesity, diabetes, and coronary risk in women.
AB  - The latter half of the twentieth century has witnessed rapid advances in
      cardiovascular epidemiology and medicine. Concurrently, secular trends in
      lifestyle practices and general improvements in standards of living have resulted
      in several alarming trends for cardiovascular disease prevention and health
      promotion. The adoption of unhealthy dietary patterns, growing socio-economic and
      racial disparities in chronic disease prevalence, low levels of physical
      activity, and other as yet unidentified genetic and environmental determinants
      have led to burgeoning rates of both pediatric and adult obesity and diabetes
      mellitus. Women appear to be at particular risk as the gender advantage for
      coronary heart disease (CHD) is counterbalanced by an increased incidence of
      obesity and diabetes. In order to further examine these complex associations, we
      review the available epidemiological data regarding the impact of obesity and
      diabetes on cardiovascular health in women.

PMID- 12478202
TI  - Diurnal heart rate reactivity: a predictor of severity of experimental coronary
      and carotid atherosclerosis.
AB  - BACKGROUND: Elevated awake resting heart rate (HR) has been shown to be a major
      risk factor for cardiovascular disease. Since coronary ischaemic events appear to
      peak during transition from sleep to awake HR, we sought to determine whether the
      degree of diurnal HR fluctuation (dHRV) is an independent predictor of coronary
      and peripheral atherogenesis. In this study, we varied both baseline HR and dHRV
      using sino-atrial node ablation (SNA) in a primate model of diet-induced
      atherogenesis and determined the degree of plaque formation relative to both HR
      parameters. METHODS: HR was recorded continuously for 6 months by an implantable
      intraaortic sensor/transmitter in 17 active unrestricted male cynomolgus monkeys.
      In nine monkeys, SNA was employed to create a wide spectrum of dHRV, and the
      power amplitude of dHRV was determined for the daily HRV cycle with power
      spectral analysis. After a 6-month diet induction period, percent coronary and
      carotid stenosis, intimal thickness and area were quantitated in each animal.
      RESULTS: Total serum cholesterol and mean HR were no different between high ( n=
      10) and low ( n= 7) dHRV groups (866 mg% vs. 740 mg%, P> 0.2 and 130 +/- 22 and
      115 +/- 13, P> 0.1, respectively). Percent carotid stenosis was markedly greater
      in both high HR and dHRV animals ([HR], 54 +/- 19 vs. 35 +/- 10, P< 0.04) and
      ([dHRV], 54 +/- 17 vs. 32 +/- 10, P< 0.01). Significant increases in all measures
      of coronary atherogenesis were found in high dHRV animals when compared with
      those with low dHRV (percent stenosis: 48% +/- 22 vs. 23% +/- 16, P< 0.02),
      (lesion area: 1.2 +/- 0.8 vs. 0.3 +/- 0.3, P< 0.02), and (intimal thickness: 0.3
      +/- 0.1 vs. 0.1 +/- 0.1, P< 0.01), respectively. While there was a trend towards
      greater coronary atherogenesis in animals with high HR, this did not reach
      statistical significance. CONCLUSION: Elevated HR and dHRV are both associated
      with enhanced experimental atherosclerotic plaque formation. However, a greater
      degree of carotid and coronary atherogenesis is observed in animals with high
      dHRV. These findings suggest that elevated dHRV is a stronger predictor for
      susceptibility to atherogenesis than elevated HR alone. Such a relationship may
      be attributed to the potential role of dHRV in modulating the frequency of
      adverse near wall haemodynamic forces, which have been shown to induce
      atherosclerotic plaques. Lowering of dHRV in humans by exercise or
      pharmacological agents may have a beneficial role in retarding atherosclerotic
      plaque induction, progression and complication.

PMID- 12478203
TI  - Targeting cardiovascular risk associated with both low density and high density
      lipoproteins using statin-niacin combination therapy.
AB  - BACKGROUND: Cardiovascular risk might be reduced by targeted changes in both low
      density and high density lipoprotein cholesterol (LDL-C and HDL-C). This dual
      strategy will require a well tolerated, effective regimen, as well as a better
      understanding of how HDL-C may be targeted. DESIGN: An open-label, uncontrolled,
      retrospective cohort study of combined statin-niacin therapy. METHODS: We
      reviewed all patients ( n= 132) started on this combination in a referral lipid
      clinic over a 6.5-year period for tolerability, safety and effectiveness.
      RESULTS: Combined therapy was tolerated by 77% of patients. No serious adverse
      events attributable to medication were encountered. In drug-naive patients (n =
      37), moderate doses of statin and niacin (mean 1180 mg/day) reduced LDL-C 31% and
      increased HDL-C 29% ( P< 0.002, both comparisons). At niacin doses >or= 1000
      mg/day (mean 1480) added to a constant statin regimen (n=29), HDL-C increased 20%
      ( P< 0.001). Even at niacin doses < 1000 mg/day (mean 580, n= 23), HDL-C
      increased 13% ( P< 0.05). Although mean HDL-C increased, the initial and final
      HDL-C distributions were broad and largely overlapping. Any chosen cutpoint for
      HDL-C goal would apply to only a minority of patients. The total/HDL cholesterol
      ratio had narrower distributions, as the percentage of patients with ratio < 5.0
      increased from 17% to 67%. CONCLUSION: Combined statin-niacin therapy lowers LDL
      C and raises HDL-C with acceptable tolerance and safety. If treating LDL-C is the
      primary goal, consistent with current guidelines, then a strategy of targeting
      the total/HDL cholesterol ratio as a secondary goal is applicable to more
      patients than targeting HDL-C itself.

PMID- 12478204
TI  - Coronary calcification and predicted risk of coronary heart disease in
      asymptomatic men with hypercholesterolaemia.
AB  - OBJECTIVE: To document the relationship between coronary calcification and
      coronary risk assessed clinically in asymptomatic patients with
      hypercholesterolaemia. DESIGN: Prospective observational study. SETTING: Health
      screening clinic. PATIENTS: A total of 286 asymptomatic men aged 45-64 with
      plasma cholesterol >or= 6.5 mmol/l. INTERVENTIONS: Electron beam computed
      tomography to measure coronary calcium score. MAIN OUTCOME MEASURES: The
      Framingham equation was used to separate subjects into groups with either low 10
      year risk of coronary artery disease (<or= 10%) or high 10-year risk (>or= 20%).
      Coronary calcium score was assessed in each group. RESULTS: The mean log calcium
      score was significantly higher in the 97 high-risk men than in the 189 low-risk
      men (1.58 +/- 0.84 versus 1.00 +/- 0.85, < 0.001). Arithmetic means (158 versus
      55), and the proportion with a score > 400 (11% versus 2%, p < 0.01) were also
      greater. However, 27% of the high-risk group had a low calcium score (<or= 10),
      which is known to be associated with minimal coronary artery disease assessed by
      angiography. CONCLUSIONS: Approximately one quarter of asymptomatic
      hypercholesterolaemic men aged 45 to 64 who have an estimated risk of coronary
      heart disease of >or= 20% in 10 years have minimal coronary calcification. They
      may therefore represent a subset at lower risk of disease. However, uncertainties
      about the predictive power of coronary calcification for coronary events must be
      resolved before electron beam computed tomography can be used to select high-risk
      patients for primary prevention.

PMID- 12478205
TI  - Evaluation of a cardiac prevention and rehabilitation programme for all patients
      at first presentation with coronary artery disease.
AB  - BACKGROUND: A cardiac prevention and rehabilitation (CP&R) programme was
      established for patients following their first clinical episode of coronary heart
      disease and 1-year outcomes were evaluated against British targets for coronary
      prevention. METHODS: Patients were evaluated 1 year after participation and
      outcomes compared with patients in the same health district registered with a
      random half of general practitioners not eligible for the programme (internal
      reference group) and patients identified in other English centres which
      participated in the EUROASPIRE II survey (external reference group). RESULTS:
      Three hundred and eighteen patients (76% of 417 incident cases) attended for 1
      year screening. Of those who participated in the programme 96/113 (85%) attended
      (Group 1); 152/194 (78%) attended from all those eligible for the programme
      (Group 2); 166/223 (74%) attended from those receiving usual care in the same
      health district (Group 3 - internal reference group). In the EUROASPIRE II survey
      (Group 4 - external reference group) 362/744 (58%) patients were screened.
      Current smoking at follow-up was Group 1, 8%, Group 2, 11%, Group 3, 13% and
      Group 4, 18%. Proportions with a BMI < 25 kg/m were 29%, 25%, 32%, 18%; BP <
      140/90 mmHg 58%, 56%, 49%, 48%; total cholesterol < 5.0 mmol/l 60%, 54%, 43%,
      46%; antiplatelet therapy 88%, 87%, 86%, 81%; beta-blocker therapy 48%, 46%, 46%,
      44%; and lipid lowering therapy 56%, 51%, 36%, 69% respectively. CONCLUSIONS: A
      CP&R programme was associated with a majority of coronary patients, whether
      attending the programme or not, achieving the Joint British Society's recommended
      prevention targets within the same health district. Specifically, a higher
      proportion of programme patients reached the cholesterol target of <5.0 mmol/l
      compared with both usual care and other centres elsewhere. This was achieved by
      using more lipid lowering therapy compared with usual care in the same health
      district, but less than other centres outside the health district. The overall
      results for the whole health district show a higher standard of preventive care
      compared with contemporary EUROASPIRE II results from other health districts in
      England.

PMID- 12478206
TI  - Random capillary blood sugar and coronary risk factors in a south Kerala
      population.
AB  - BACKGROUND: High prevalence of type 2 diabetes in one subdivision of a district
      in south India prompted us to look at the prevalence of other major coronary risk
      factors, and relate these to random blood sugar values. DESIGN: Cross-sectional
      survey of all adult residents of four wards (clusters of households) of a
      subdivision. Detailed investigation for diabetes and blood lipids in a selected
      subsample with random blood sugar (RBS) >109 mg/dl by glucometer. METHODS: From
      the selected wards, we conducted a standard oral glucose tolerance test and serum
      lipids in all those who had RBS above 109 mg/dl by glucometer. Risk factors such
      as smoking, obesity (body mass index > 29.9), high blood pressure (systolic
      pressure > 139; diastolic pressure > 89 mmHg) and sedentary habits were assessed
      in all irrespective of RBS. RESULTS: Prevalence of all risk factors increases
      with age. Mean RBS ranges from 92.9 +/- 15.7 to 108.8 +/- 35.7 mg/dl in males and
      88.6 +/- 16.0 to 117.3 +/- 61.6 mg/dl in females, between the age groups 20-29 to
      > 69. Risk factor prevalence varied with area of residence, with urban population
      reporting highest prevalence for type 2 diabetes and obesity, and coastal
      population for hypertension. For increasing levels of fasting plasma glucose (FPG
      < 100, 100-124 and > 125 mg/dl), serum total cholesterol values were 5.21 +/-
      1.08 mM/l, 5.38 +/- 0.86 mM/l and 5.63 +/- 1.37 mM/l for males. For females,
      corresponding values were 5.23 +/- 1.11 mM/l, 5.54 +/- 1.15 mM/l, and 5.49 +/-
      1.10 mM/l respectively. CONCLUSIONS: Risk factor prevalence varies with area of
      residence within the study population. Mean plasma lipid levels are high among
      both sexes, tending to rise with increasing mean fasting plasma glucose levels.

PMID- 12478207
TI  - Coronary artery calcification at electron beam computed tomography is increased
      in asymptomatic type 2 diabetics independent of traditional risk factors.
AB  - BACKGROUND: The risk of cardiovascular disease (CVD) is two- to fourfold greater
      in type 2 diabetics than in non-diabetics and cannot be accounted for by
      traditional risk factors alone. Coronary artery calcification (CAC) at electron
      beam computed tomography (EBCT) is a non-invasive index of coronary
      atherosclerosis. We hypothesized that the presence and extent of CAC would be
      greater in asymptomatic type 2 diabetics than in non-diabetics independent of
      traditional risk factors. METHODS: We reviewed CAC data of all asymptomatic
      subjects referred for EBCT between 1996-1999 and compared CAC scores in type 2
      diabetics ( n= 71) to all non-diabetics ( n= 1481) and to a randomly selected
      group of non-diabetics matched for all traditional CVD risk factors ( n= 71).
      RESULTS: CAC scores were greater in type 2 diabetics (272 +/- 472, median 41)
      than in all non-diabetics (104 +/- 288, median 4; < 0.01) and matched non
      diabetics (188 +/- 354; < 0.05, median 12; < 0.05). The odds ratio (OR) for the
      presence of CAC (scores > 0) in type 2 diabetics was 2.9 [95% confidence
      intervals (CI) 1.1-7.8] after adjustment for traditional CVD risk factors. Type 2
      diabetes was also associated (adjusted OR 2.15, 95%CI 1.3-3.6) with the extent of
      CAC when categorized as an ordinal outcome (CAC scores 0, 1-79, 80-399 and >
      400). In type 2 diabetics, age, sex and body mass index were associated with
      extent of CAC. CONCLUSIONS: CAC scores at EBCT are greater in type 2 diabetics
      than non-diabetic subjects, cannot be accounted for by traditional risk factors
      alone and may be useful for identifying novel factors for coronary
      atherosclerosis in type 2 diabetes.

PMID- 12478208
TI  - Exercise training alters skeletal muscle mitochondrial morphometry in heart
      failure patients.
AB  - BACKGROUND: Previous research has demonstrated that exercise intolerance in heart
      failure patients is associated with significant alterations in skeletal muscle
      ultrastructure and oxidative metabolism that may be more consequential than
      cardiac output. DESIGN: To examine the effect of exercise training on skeletal
      muscle mitochondrial size in chronic heart failure patients. METHODS: Six heart
      failure patients participated in 16-weeks of supervised upper and lower extremity
      exercise training. At the conclusion of training, percutaneous needle biopsies of
      the vastus lateralis were taken and electron microscopy was used to assess
      mitochondrial sizes. RESULTS: The exercise programme resulted in a significant
      increase in peak maximal oxygen consumption ( P< 0.05) and anaerobic threshold (P
      < 0.04). Knee extension muscle force increased following training ( P< 0.02).
      After exercise training, the average size of the mitochondria increased by 23.4%
      (0.036 to 0.046 mu(2), P< 0.015) and the average shape was unaltered. CONCLUSION:
      Exercise training with heart failure patients alters skeletal muscle morphology
      by increasing mitochondrial size, with no change in shape. This may enhance
      oxidative metabolism resulting in an increased exercise tolerance.

PMID- 12478209
TI  - Coronary artery disease risk factors & their association with physical activity
      in older athletes.
AB  - OBJECTIVE: To evaluate the effects of present-day physical activity on selected
      coronary artery disease (CAD) risk factors of older former athletes and to
      compare these selected risk factors with age-matched older non-athletes. METHODS:
      The selected CAD risk factors were compared among the active older athletes ( n=
      52; 45.9 +/- 4.75 years), sedentary older athletes ( n= 54; 47.2 +/- 4.67 years),
      and sedentary older non-athletes (n = 56; 46.0 +/- 5.26 years) of Calcutta and
      surroundings. CAD risk factors including anthropometric obesity parameters, blood
      lipids and blood pressure were measured. The present-day total physical activity
      of each individual was assessed by a questionnaire and estimated through the sum
      of energy expended during habitual, professional, recreational and conditioning
      physical activities, and sleeping time. The total physical activity was expressed
      as energy expended in mega joules per kilogram of body weight per week (MJ.kg.
      week ). Maximal oxygen consumption (VO2 max) was assessed by maximal treadmill
      test. Body score distributions in each group were also calculated. RESULTS: The
      selected CAD risk factors differed significantly among the groups. The sedentary
      older athletes had significantly higher mean values in weight, BMI, body fat
      percentage, total cholesterol, low-density lipoprotein (LDL) cholesterol,
      triglycerides and ratio of total cholesterol to high-density lipoprotein
      cholesterol (total C/HDLC) than that of active older athletes and sedentary older
      non-athletes. A reverse trend was observed in the case of HDL cholesterol. On the
      other hand, the presently active older athletes had significantly favourable
      levels of most of the selected CAD risk factors than the sedentary older athletes
      and non-athletes. The present-day total physical activity had significant
      negative association with total cholesterol, ratio of total cholesterol to HDL
      cholesterol, LDL cholesterol, triglycerides, resting systolic blood pressure when
      controlling for the effects of age, body mass index and body fat percentages. So,
      it is confirmed from this analysis that the subjects in the present study who had
      a greater present-day total physical activity had favourable CAD risk factors.
      CONCLUSIONS: The results of this study indicate that the risk for CAD or levels
      of selected CAD risk factors of former athletes after retirement from active
      sports were more related to the present-day physical activity i.e., higher total
      physical activity lowers the risk of coronary artery disease.

PMID- 12478210
TI  - Antagonism by WAY-100635 of the effects of 8-OH-DPAT on performance on a free
      operant timing schedule in intact and 5-HT-depleted rats.
AB  - In this experiment we examined the effect of a serotonin receptor (5-HT1A)
      agonist and antagonist WAY-100635 (N-[2-(4-[2-methoxy-phenyl]-1
      piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide) on temporal
      differentiation, in intact rats and rats whose serotonergic (5-HTergic) pathways
      had been destroyed by 5,7-dihydroxytryptamine (5,7-DHT). Thirteen rats received
      5,7-DHT-induced lesions of the median and dorsal raphe nuclei; 14 rats received
      sham lesions. They were trained to press two levers (A and B) in 50-s trials, in
      which reinforcement was contingent upon responding on A in the first half, and B
      in the second half, of the trial. Logistic psychophysical curves were fitted to
      the relative response rate data (percent responding on B, %B), for derivation of
      timing indices [T50 (time corresponding to %B=50%), slope, Weber fraction]
      following WAY-100635, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin],
      combinations of WAY-100635+8-OH-DPAT, and vehicle alone. WAY-100635 (30, 100 and
      300 microg/kg, s.c.) did not affect the timing indices. 8-OH-DPAT (100, 200
      microg/kg, s.c.) reduced T50 without affecting the Weber fraction. WAY-100635
      (300 microg/kg) abolished the effect of 8-OH-DPAT on T50 in both the lesioned and
      sham-lesioned groups. 5-HT levels in the neocortex, hippocampus, amygdala,
      nucleus accumbens and hypothalamus of the lesioned group were <20% of those in
      the sham-lesioned group; catecholamine levels were unaffected. The results
      confirm that 8-OH-DPAT disrupts temporal differentiation in a free-operant
      psychophysical schedule, reducing T50, and indicate that this effect of 8-OH-DPAT
      is mediated by postsynaptic 5-HT1A receptors.

PMID- 12478211
TI  - Anxiety conditioned to nicotine in the elevated plus-maze is time dependent.
AB  - Conditioning to the anxiogenic effects of nicotine has previously been
      demonstrated in the social interaction test and there was no generalization of
      conditioning between the social interaction and elevated plus-maze tests. Because
      the two tests generate distinct states of anxiety, the conditioning could have
      occurred to the cues associated with the test environment and/or to those
      associated with the type of anxiety generated by the test. The elevated plus-maze
      permits separation of these two factors, because quite distinct states of anxiety
      are generated on trials 1 and 2, whereas the apparatus cues remain the same. Rats
      that had been tested on day 1 in the plus-maze, 5 min after nicotine (0.45
      mg/kg), showed a conditioned anxiogenic response when tested undrugged on day 2.
      This was shown by significantly lower percentages of open-arm entries and
      percentage of time spent on the open arms, compared with control groups. Thus,
      conditioning to apparatus cues is sufficient to mediate a conditioned anxiogenic
      effect. The importance of the timing of the nicotine-associated cues was
      demonstrated by the failure to obtain conditioned anxiogenic effects when rats
      were exposed to the plus-maze on day 1, 30 min after nicotine (0.45 or 0.1
      mg/kg).

PMID- 12478212
TI  - Effects of dopamine receptor antagonists on nicotine-induced attentional
      enhancement.
AB  - An understanding of the neuropharmacological mechanisms mediating attentional
      enhancement by nicotine would indicate whether these effects could be dissociated
      pharmacologically from other behavioural effects of nicotine. The aim of the
      present study was to examine the involvement of dopamine neurotransmission in the
      effects of nicotine on different response indices of an attentional paradigm. The
      effects of the D2-type dopamine receptor antagonist raclopride (0.025-0.1 mg/kg)
      and the D1-type receptor antagonist SCH23390 (0.006-0.024 mg/kg) were tested, in
      both the presence and absence of nicotine (0.1 mg/kg), in rats trained in a
      modified version of the five-choice serial reaction time task (5-CSRTT). Nicotine
      robustly enhanced the accuracy of signal detection, reduced omission errors and
      shortened response latencies. Neither raclopride nor SCH23390 altered the effects
      of nicotine on accuracy and omissions, but raclopride augmented accuracy and
      SCH23390 increased omissions when given alone. By contrast, raclopride, but not
      SCH23390, reversed the nicotine-induced reductions in response latencies, at
      doses that had no effect on their own. In the presence of nicotine, both
      antagonists had rate-disruptive effects at the highest dose. Both antagonists
      also reduced responding in the intertrial interval, and this effect was additive
      to the nicotine-induced decrease in this measure. The data indicate that D2-type
      dopamine receptors may be involved in the effects of nicotine on response speed.
      Neither the D1- nor the D2-type dopamine receptor antagonist affected nicotine
      induced improvements in signal detection, at doses that reversed dependence
      related behavioural effects of nicotine in previous studies. Thus these effects
      may be pharmacologically dissociable.

PMID- 12478213
TI  - Nafadotride administration increases D1 and D1/D2 dopamine receptor mediated
      behaviors.
AB  - The administration of nafadotride, given at doses known to block the D3 dopamine
      receptors (0.75, 1.5, 3 mg/kg i.p.) increased locomotor activity both in naive
      and habituated rats and counteracted the hypothermia but not the hypomotility
      induced by a low dose of the putative D3 dopamine agonist (+/-)-7-hydroxy-2-(di-N
      propylamino)-tetralin (7-OH-DPAT; 0.04 mg/kg). Nafadotride did not antagonize
      either the motor effects induced by different doses of the D2 agonist quinpirole
      (0.05 and 0.3 mg/kg) or the hypermotility induced by 7-OH-DPAT given at a dose
      (0.32 mg/kg) stimulating D2 dopamine receptors. The same nafadotride doses
      potentiated the grooming behavior induced by the D1 dopamine agonist SKF 38393
      (10 mg/kg i.p.) as well as the stereotyped response to the D1/D2 agonist
      apomorphine (0.5 mg/kg s.c.). Stereotyped behavior was also observed in rats
      concomitantly treated with nafadotride and the D2 agonist quinpirole. As the
      activation of D1 dopamine receptors plays an important role in the occurrence of
      stereotypies, the results suggest that the blockade of D3 receptors by
      nafadotride could have favored D1/D2 dopamine receptor-mediated behaviors by
      potentiating D1 receptor function.

PMID- 12478214
TI  - The adenosine A2A receptor agonist CGS 21680 exhibits antipsychotic-like activity
      in Cebus apella monkeys.
AB  - The adenosine A2A receptor agonist CGS 21680 has shown effects similar to
      dopamine antagonists in behavioural assays in rats predictive for antipsychotic
      activity, without induction of extrapyramidal side-effects (EPS). In the present
      study, we examined whether this functional dopamine antagonism and lack of EPS in
      rodents could also be observed in non-human primates. We investigated the effects
      of CGS 21680 on behaviours induced by D-amphetamine and (-)-apomorphine in EPS
      sensitized Cebus apella monkeys. CGS 21680 was administered s.c. in doses of
      0.01, 0.025 and 0.05 mg/kg, alone and in combination with D-amphetamine and (-)
      apomorphine. The monkeys were videotaped after drug administration and the tapes
      were rated for EPS and psychosis-like symptoms. CGS 21680 decreased apomorphine
      induced behavioural unrest, arousal (0.01-0.05 mg/kg) and stereotypies (0.05
      mg/kg) while amphetamine-induced behaviours (unrest, stereotypies, arousal) were
      unaffected. EPS were not observed at any dose. At 0.05 mg/kg CGS 21680 produced
      vomiting. The two lower doses did not produce observable side-effects. Though the
      differential effect on amphetamine- and apomorphine-induced behaviours is
      intriguing, CGS 21680 showed a functional anti-dopaminergic effect in Cebus
      apella monkeys without production of EPS. This further substantiates that
      adenosine A2A receptor agonists may have potential as antipsychotics with
      atypical profiles.

PMID- 12478215
TI  - Pharmacological activity of hyperforin acetate in rats.
AB  - Hyperforin, the main antidepressant component of Hypericum extract, is not stable
      with regard to heat and light. Therefore, we investigated a newly synthetized
      derivative, hyperforin acetate. Herein we demonstrate its efficacy in animal
      models sensitive to antidepressant and anxiolytic drugs. In the forced swimming
      test, triple administration of hyperforin (5-20 mg/kg) significantly reduced the
      immobility time of rats, while in the learned helplessness test a daily treatment
      of 10 mg/kg for seven consecutive days was necessary to elicit an antidepressant
      effect. In the elevated plus-maze and in the light-dark test, the acute
      administration of hyperforin acetate (3-5 mg/kg) exerted an anxiolytic activity,
      which, however, was smaller than that of diazepam. The effect was inhibited by
      the pretreatment of rats with metergoline, a serotoninergic antagonist, but not
      with CGS-8216, a benzodiazepine receptor antagonist. Hyperforin acetate (3-10
      mg/kg) was also able to reduce locomotion in rats without eliciting myorelaxant
      activity. As Hypericum extract was claimed to exert a potential influence on the
      liver drug metabolizing system, we showed that neither acute nor repeated oral
      doses of hyperforin acetate altered pentobarbital sleeping time in rats. Taken
      together, the present results show that hyperforin acetate is a pharmacologically
      active derivative of hyperforin and may be a starting point from which to develop
      new compounds for therapeutic purposes.

PMID- 12478216
TI  - Alcohol and triazolam: differential effects on memory, psychomotor performance
      and subjective ratings of effects.
AB  - The effects of alcohol (0.80 g/kg) and the benzodiazepine hypnotic triazolam
      (0.25 mg/70 kg) were compared directly in a double-dummy, double-blind, placebo
      controlled, repeated-measures design in 18 healthy volunteers. While alcohol
      (0.80 g/kg) and triazolam (0.25 mg/70 kg) produced comparable levels of
      psychomotor performance impairment, a dissociation was observed, such that the
      magnitude of memory impairment (measured by d', participants' sensitivity in
      discriminating between old and new words in the recognition memory paradigm) was
      greater with triazolam than with alcohol, whereas subjective ratings of the
      overall strength of drug effect were higher with alcohol than with triazolam.
      Participants also adopted a more conservative response bias in the recognition
      memory paradigm in the alcohol (0.80 g/kg) condition relative to both placebo and
      triazolam (0.25 mg/70 kg). In addition to characterizing the adverse effects of
      two widely used psychoactive substances, the present results may also contribute
      to the understanding of underlying neurochemical mechanisms.

PMID- 12478217
TI  - Effects of amisulpride on consummatory negative contrast.
AB  - Two groups of rats, 'shifted' (32-4% sucrose) and 'unshifted' (4-4% sucrose),
      were given access to sucrose solutions for 5 min/day for 10 days. On day 11,
      shifted animals had access to a devalued incentive (4% sucrose) and subgroups of
      each group received doses of amisulpride (10 or 60 mg/kg, i.p.) or its vehicle
      before a 10-min access period to sucrose solutions. Lick frequency was measured
      both pre- and post-shift. A high dose of amisulpride reduced successive negative
      contrast (SNC) after a brief period of exposure to the devalued stimulus, whereas
      a low dose had no effect. The acute effects of high doses of amisulpride seem to
      act on contrast effects in a similar way to anxiolytic compounds such as the
      benzodiazepine, chlordiazepoxide.

PMID- 12478218
TI  - Latent inhibition is attenuated by noise and partially restored by a 5-HT2A
      receptor antagonist.
AB  - Latent inhibition (LI) is a model of attention, which is a cognitive process that
      can be modulated by stressors such as chronic intermittent broadband noise, e.g.
      caused by building work, which is particularly stressful to rats. The aim of this
      study was to analyse the effect of chronic noise stress, caused by a building
      project, on LI, and its interaction with SR 46,349B, a 5-HT2A receptor
      antagonist. Control groups from LI experiments conducted during periods of
      chronic intermittent noise were compared with control groups from LI experiments
      conducted in normal quiet conditions. The interaction of SR 46,349B with the
      effects of chronic noise stress was then tested. Chronic intermittent noise
      attenuated LI, an effect which was partially reversed by SR 46,349B, 2.4 mg/kg
      i.p. Attenuation of LI by chronic intermittent noise and reversal of this effect
      by SR 46,349B support suggestions that stress can modulate attention and that 5
      HT2A receptors are involved in mediating the effects of chronic stress.

PMID- 12478219
TI  - Dopamine receptor blockade in the rat medial prefrontal cortex reduces
      spontaneous and amphetamine-induced activity and does not affect prepulse
      inhibition.
AB  - The functions and interactions of cortical and subcortical dopamine systems are
      of interest because alterations in these systems have been implicated in
      neuropsychiatric diseases, such as schizophrenia. It has been proposed that
      prefrontal dopamine transmission may oppose dopamine transmission in subcortical
      sites, such as the nucleus accumbens. Accordingly, reduced prefrontal dopamine
      transmission would be expected to enhance or induce behavioral effects that have
      been associated with stimulation of accumbal dopamine receptors. In rats,
      spontaneous and amphetamine-induced activity is supported by dopamine receptor
      stimulation in the nucleus accumbens, while prepulse inhibition (PPI) of the
      acoustic startle response, which is used to measure sensorimotor gating and is
      disrupted in schizophrenia, is reduced by increased accumbal dopamine receptor
      stimulation. In the present experiments, we found that bilateral infusion of the
      dopamine D1/D2 receptor antagonist cis-flupenthixol dihydrochloride into the
      medial prefrontal cortex of Wistar rats (25 microg each side) reduced spontaneous
      activity and completely blocked induction of hyperactivity by systemic
      administration of D-amphetamine sulfate (1 mg/kg), while not affecting PPI. These
      findings do not support an antagonism between prefrontal and accumbal dopamine in
      the control of behavior. Rather, our data demonstrate that prefrontal dopamine
      transmission may modulate some behavioral processes in a similar way to accumbal
      dopamine.

PMID- 12478222
TI  - The diversity of case management models.
AB  - Case management is experiencing rapid growth and evolutionary transition. This
      article explores the diversity and richness of case management models found in
      practice. Interdisciplinary communication in case management programs can be
      facilitated by an awareness of discipline-specific definitions and models. A
      categorization of models is described as a device to stimulate multidisciplinary
      case management collaboration.

PMID- 12478223
TI  - The role of the case manager in a disease management program.
AB  - Disease management programs provide new opportunities and roles for case managers
      to provide population-based healthcare to the chronically ill. This article
      identifies common components of disease management programs and examines roles
      assumed by case managers in disease management programs such as baseline
      assessment, performing economic analyses of diseases and their respective
      associated resource utilization, developing and/or implementing care guidelines
      or algorithms, educational interventions, disease management program
      implementation, and outcomes assessment. Areas of expertise needed to be an
      effective case manager in a disease management program are also identified.

PMID- 12478224
TI  - The art of negotiation.

PMID- 12478225
TI  - A ten-step process to develop case management plans.
AB  - The use of case management plans has contained cost and improved quality of care
      successfully. However, the process of developing these plans remains a great
      challenge for healthcare executives, in this article, the author presents the
      answer to this challenge by discussing a 10-step formal process that
      administrators of patient care services and case managers can adapt to their
      institutions. It also can be used by interdisciplinary team members as a
      practical guide to develop a specific case management plan. This process is
      applicable to any care setting (acute, ambulatory, long term, and home care),
      diagnosis, or procedure. It is particularly important for those organizations
      that currently do not have a deliberate and systematic process to develop case
      management plans and are struggling with how to improve the efficiency and
      productivity of interdisciplinary teams charged with developing case management
      plans.

PMID- 12478226
TI  - Emergency department case management: the dyad team of nurse case manager and
      social worker improve discharge planning and patient and staff satisfaction while
      decreasing inappropriate admissions and costs: a literature review.
AB  - A model of emergency department (ED) case management consisting of a social
      worker and a nurse case manager can prevent inappropriate admissions, improve
      discharge planning, decrease cost, and enhance patient satisfaction. The
      individual and combined roles of the dyad team of social worker and nurse case
      manager are discussed. A literature review includes how a case management dyad
      team of social worker and nurse case manager in the ED can decrease utilization
      of the ED for nonemergent visits, promote the use of community resources, and
      improve discharge planning to avoid excessive costs. The importance of the dyad
      team working with the interdisciplinary team in the ED, the primary care
      physician (PCP), and other community health care providers in order to provide a
      holistic approach to care is addressed. A discussion about the improvement of
      both patient and staff satisfaction demonstrates the results of case management
      strategies that support and advocate for patients to receive quality, cost
      effective care across the health care continuum, while decreasing the use of the
      ED for nonemergent care.

PMID- 12478227
TI  - Case management information systems: how to put the pieces together now and
      beyond year 2000.
AB  - The case management process is a critical management and operational component in
      the delivery of customer services across the patient care continuum. Case
      management has transcended time and will continue to be a viable infrastructure
      process for successful organizations in the future. A key component of the case
      management infrastructure is information systems and technology support. Case
      management challenges include effective deployment and use of systems and
      technology. As more sophisticated, integrated systems are made available, case
      managers can use these tools to continue to expand effectively beyond the
      patient's episodic event to provide greater levels of cradle-to-grave management
      of healthcare. This article explores methods for defining case management system
      needs and identifying automation options available to the case manager.

PMID- 12478228
TI  - Designing measurements to assess case management outcomes.
AB  - Evaluating outcomes begins with determining the goals of case management. As the
      emphasis on the delivery of cost-effective patient care increases, comparing
      outcomes across settings is desirable and essential. A key component to comparing
      how an organization rates with similar institutions is to identify commonly used
      measures. Conducting a literature search, benchmarking, participating in
      initiatives of accrediting bodies, and establishing ways to collect and manage
      reliable and valid data are vital in laying the groundwork for an organization's
      ability to join evaluation projects across settings.

PMID- 12478229
TI  - Pathophysiology of coronary artery restenosis.
AB  - All forms of percutaneous coronary intervention confer injury on the vessel. The
      arterial response to that injury is the basis for long-term outcome. The stent
      prevents remodeling but enhances neointimal formation, and it is this neointima
      that is principally responsible for in-stent restenosis. Neointima forms in
      response to thrombus, inflammation, intimal and medial dissections, and elastic
      recoil of the arterial wall when a stent is not placed. Current efforts to solve
      restenosis center on limiting neointimal hyperplasia through drug-eluting stents
      and vascular brachytherapy. This article reviews arterial injury during
      revascularization in both patients and animal models and discusses the nature and
      formation of neointimal hyperplasia.

PMID- 12478230
TI  - Drug-eluting stents: role of stent design, delivery vehicle, and drug selection.
AB  - Increasing focus has recently been directed toward the different parameters of
      drug-eluting stents-stent design, delivery-vehicle materials, and drug properties
      and the manner in which each of these elements may affect the function of the
      stents. Several specific characteristics of design may affect restenosis,
      although design optimization often presents a choice between acute procedural
      success and long-term biological stability. The influence of design parameters
      such as strut thickness and cell configuration is described. Polymer material has
      frequently been used to coat drug-eluting stents, although some agents, such as
      paclitaxel, can be attached directly to the stent's surface, obviating the need
      for a polymer layer. The properties of agents used in drug-eluting stents and how
      those properties affect delivery and long-term outcome are discussed, as is the
      influence of the disease state of the target vessel on stent safety and efficacy.

PMID- 12478231
TI  - Stent design: implications for restenosis.
AB  - There is increasing evidence that stent design influences angiographic restenosis
      and clinical outcomes. After nearly 15 years of clinical experience, there is now
      a plethora of stent designs available, and yet no single design incorporates all
      the characteristics of the ideal stent. The specific metallic composition of a
      stent limits the type of stent geometry possible, and the biocompatibility of the
      metal or surface coating may affect long-term stent healing. Studies have shown
      that stent geometry designed to optimize expansion and lower recoil is a
      prerequisite for favorable clinical outcomes. Strut thickness appears to be an
      important risk factor for restenosis, but changing one parameter, such as strut
      thickness, requires altering other design characteristics, thus altering the
      overall stent design. Future stent designs should combine the best features of
      conventional stent design with special modifications to facilitate multi-agent
      drug elution for a variety of applications.

PMID- 12478232
TI  - Vascular brachytherapy: applications in the era of drug-eluting stents.
AB  - Vascular brachytherapy using beta and gamma emitters has revolutionized treatment
      of in-stent restenosis. We are witnessing a near-abolition of the restenosis
      problem for simple lesions, but the future of vascular brachytherapy depends on
      our success in improving efficacy and reducing complications such as late
      thrombosis and edge effects. Optimizing dosimetry, applying adequate radiation
      margins, and prolonging antiplatelet therapy should equalize brachytherapy
      results with those of drug-eluting stents. In this overview we examine issues
      related to progress and optimization of outcomes derived from the use of vascular
      brachytherapy. We also examine its potential to expand to other applications
      beyond in-stent restenosis, such as the treatment of de novo lesions and
      peripheral vascular disease

PMID- 12478233
TI  - Clinical experience with drug-eluting stents.
AB  - Despite dramatic improvements in catheter and stent technology, in-stent
      restenosis continues to hamper initial procedural success in 10% to 50% of
      patients undergoing coronary intervention. Recent breakthroughs in polymer
      science and local drug delivery have shown tremendous promise in the long-sought
      after goal of delivering antirestenotic therapy directly from a stent. Clinical
      trials examining several novel antirestenotic agents, particularly sirolimus and
      paclitaxel, have shown astonishing reduction in restenosis following stenting.
      Through examination of the clinical experience to date, we may gain insight into
      the current and future utility of drug-eluting stents in our clinical practice.

PMID- 12478234
TI  - Effective and efficient strategies for coronary revascularization in the drug
      eluting stent era.
AB  - We now have at our disposal a variety of new technologies for percutaneous
      coronary revascularization, including drug-eluting stents (DES), intracoronary
      radiation therapy, and glycoprotein IIb/IIIa inhibitors. Coronary stents have
      improved both early and late outcomes following percutaneous coronary
      intervention. Stent characteristics including design, stent strut thickness, and
      stent metal alloy are associated with different rates of restenosis. This article
      reviews recent findings pertaining to the use of DES and other technologies for
      the treatment of coronary artery disease in diabetics and small vessel disease.
      The causes and treatment of in-stent restenosis are discussed. The optimal
      approach to coronary revascularization remains to be determined as brachytherapy,
      improvements in stent design, and new drug-eluting stents become available.

PMID- 12478235
TI  - Arterial stiffness: clinical relevance, measurement, and treatment.
AB  - Hardening of the pulse, first described thousands of years ago by Chinese
      healers, was known even then to be an adverse prognostic sign. In Western
      medicine, the association of aging, increased large-arterial stiffness, and
      systolic hypertension has been recognized for more than a century. Yet the
      adverse consequences of age-related arterial stiffness still receive little
      attention in everyday clinical practice, perhaps because clinicians assume that
      nothing can be done about the process. Recent developments, however, suggest that
      improved clinical recognition of age-related vascular stiffening will lead to
      better therapy and improved outcomes for patients with hypertension.

PMID- 12478236
TI  - Risk assessment of patients with known or suspected CAD using stress myocardial
      perfusion SPECT. Part II: Determining cost-effective test strategies.
AB  - In this era of cost containment, each step of a testing protocol must be
      evaluated carefully for appropriateness and prognostic value. Exercise stress
      single-photon emission CT (SPECT) is finding a niche in the examination of
      patients with known or suspected coronary artery disease. When preceded by
      careful patient screening, stress SPECT, alone or combined with other testing,
      may prove to be a tool that is both cost-effective and clinically effective.

PMID- 12478237
TI  - Acute myocardial infarction following recovery from a normal treadmill exercise
      test.
AB  - Cardiologists today rely on stress testing to provide valuable diagnostic
      information about their patients. How and why can it cross the line to become a
      trigger for acute coronary events? Is patient selection important to avoid
      complications? Follow this patient through his stress test.

PMID- 12478238
TI  - Mechanisms of epithelial injury and inflammation in gastrointestinal diseases.
AB  - Using Barrett's esophagus and Crohn's disease as models of gastrointestinal
      disorders, a number of key mechanisms of cell injury and death and chronic
      inflammation are reviewed. Among them are the roles of impaired osmoregulation,
      elevated cytosolic calcium, activation of the mitochondrial permeability
      transition and levels of cytosolic adenosine triphosphate as determinates of cell
      death as well as the role of inflammatory cells, cytokines, NOD2 gene products,
      and reactive oxygen species in chronic inflammation. Further, the basis for the
      link between inflammation and cancer risk in Barrett's esophagus and Crohn's
      disease is described.

PMID- 12478239
TI  - Initial therapy for mild to moderate Crohn's disease: mesalamine or budesonide?
AB  - The initial choice of therapy for mild to moderately active Crohn's disease is
      controversial. Both the National Cooperative Crohn's Disease Study (NCCDS) and
      the European Cooperative Crohn's Disease Study (ECCDS) demonstrated that
      sulfasalazine is effective for the induction of remission. Subsequent studies of
      new mesalamine formulations showed inconsistent results; two trials, however,
      demonstrated a statistically significant improvement with Pentasa and Asacol
      treatment, and meta-analyses suggest a modest benefit of mesalamine maintenance
      therapy. The NCCDS and ECCDS trials found that corticosteroid therapy is much
      more effective than sulfasalazine for induction of remission, but corticosteroids
      did not show maintenance benefits. Corticosteroid use is frequently associated
      with adverse effects, and the majority of patients treated with prednisone become
      either steroid-refractory or steroid-dependent; many of these patients ultimately
      need treatment with immunosuppressives and/or surgery. Budesonide, a topical
      corticosteroid with high first-pass hepatic metabolism, is slightly less
      effective in inducing remission than conventional corticosteroids but is
      significantly less likely to cause side effects. Budesonide 9 mg/day was shown to
      be more effective than mesalamine (Pentasa 4 g/day) for induction therapy, but
      budesonide has been ineffective as a maintenance therapy. Mesalamine may be
      useful for patients with more extensive disease, those intolerant of
      sulfasalazine, or those with contraindications or intolerance to budesonide.
      Alternatively, sulfasalazine is effective in the presence of colonic disease.
      Clinicians must decide on the basis of the existing evidence whether budesonide
      or mesalamine is the preferred initial therapy for active Crohn's disease.

PMID- 12478240
TI  - Reduction of colorectal cancer risk in patients with Crohn's disease.
AB  - Patients with inflammatory bowel disease (IBD)-either Crohn's disease (CD) or
      ulcerative colitis (UC)-are at increased risk for developing cancers of the
      gastrointestinal tract, particularly colorectal cancer (CRC). Because of the
      relative rarity of IBD in the general population, it has been difficult to
      quantify this risk; nonetheless, within particular subsets of IBD patients, the
      cumulative risk of developing dysplasia and CRC may be substantial. Efforts to
      reduce this risk have included both prophylactic surgery and endoscopic screening
      programs. Despite the impact this disease has on quality of life and life
      expectancy, an optimal strategy for reducing the risk has yet to be defined. This
      article reviews the current literature relating to the risk of cancer for
      patients with IBD and methods available to help reduce this risk.

PMID- 12478241
TI  - Screening for Barrett's esophagus.
AB  - Screening and surveillance for Barrett's esophagus have been proposed as
      strategies for preventing deaths from esophageal adenocarcinoma. A meaningful
      discussion on the cost efficacy of screening and surveillance for Barrett's
      esophagus requires a reasonable estimate of the risk of esophageal cancer in this
      condition. The primary goal of endoscopic screening for individuals with
      gastroesophageal reflux disease is to identify patients with Barrett's esophagus
      who will benefit from an intervention to prevent cancer. There is also indirect
      evidence to suggest that surveillance for Barrett's esophagus may be beneficial.
      However, there is much debate over the efficacy of these diagnostic procedures.
      In the absence of definitive data, investigators have used computer models to
      study the cost effectiveness of screening and surveillance for Barrett's
      esophagus. It is important for physicians to recognize that such models do not
      provide a single, definitive answer.

PMID- 12478242
TI  - Does chemoprevention of Barrett's esophagus using acid suppression and/or COX-2
      inhibition prevent neoplastic progression?
AB  - Barrett's esophagus--intestinal metaplasia within the tubular esophagus - is a
      premalignant histologic lesion and a marker of cancer risk. Strategies to prevent
      Barrett's-related esophageal cancer have focused on reversal of Barrett's using
      pharmacological or surgical antireflux therapies and endoscopically-induced
      injury. Currently, however, there is little compelling evidence to support the
      reversal of Barrett's through pharmacological or surgical therapy, and endoscopic
      reversal of Barrett's has not yet been validated. Chemoprevention using intensive
      acid suppression and/or inhibition of cyclooxygenase-2 (COX-2) with nonsteroidal
      anti-inflammatory drugs remains a biologically plausible strategy that is
      supported by a rapidly growing body of scientific evidence. Data suggest that a
      combination of acid suppression with COX-2 inhibition might be the most effective
      chemopreventive strategy. Whether this approach is effective awaits the results
      of well-designed outcomes studies.

PMID- 12478243
TI  - Another British invasion?

PMID- 12478244
TI  - Fresh horizons South Korea.

PMID- 12478245
TI  - Prioritizing Australia.

PMID- 12478246
TI  - Through the protein labyrinth.

PMID- 12478247
TI  - NASA roadmap charts route to a quarter-century of exploration.

PMID- 12478248
TI  - Canada stops Harvard's oncomouse in its tracks.

PMID- 12478250
TI  - Radar array tests the atmosphere at pole position.

PMID- 12478249
TI  - Paper trail reveals references go unread by citing authors.

PMID- 12478251
TI  - Bush climate-change plan gets cool response.

PMID- 12478252
TI  - Safety panel backs principle of gene-therapy trials.

PMID- 12478253
TI  - Labs cook up strategy to test transgenic food.

PMID- 12478255
TI  - Australia sets priorities for future research.

PMID- 12478254
TI  - Syngenta ready to drop plans for Indian rice venture.

PMID- 12478256
TI  - Ousted creationist sues over website.

PMID- 12478259
TI  - Alliance for Cellular Signaling: into unknown territory.

PMID- 12478260
TI  - Research materials: share and share alike?

PMID- 12478262
TI  - What has posterity done for us? It's not the point.

PMID- 12478263
TI  - Schools can be inspired by a summer of science.

PMID- 12478264
TI  - Isolationism is not the answer to bioterrorism.

PMID- 12478269
TI  - Progressive evolution: aspirational thinking.

PMID- 12478270
TI  - Structural biology: On the wings of inhibition.

PMID- 12478271
TI  - Nuclear physics: A triple point in nuclei.

PMID- 12478274
TI  - Planetary science: Seeing double in the Kuiper belt.

PMID- 12478272
TI  - Aerodynamics: red admiral agility.

PMID- 12478275
TI  - Physiology: is brain sympathetic to bone?

PMID- 12478276
TI  - Biomechanics: frogs in and out of phase.

PMID- 12478277
TI  - Oceanography: Gas hydrates on the brink.

PMID- 12478278
TI  - HIV: conformational camouflage.

PMID- 12478279
TI  - Pollination: Rotting smell of dead-horse arum florets.

PMID- 12478280
TI  - Ontogenetic growth: Modelling universality and scaling.

PMID- 12478282
TI  - Climate change: Regional warming and malaria resurgence.

PMID- 12478284
TI  - Rho GTPases in cell biology.
AB  - Rho GTPases are molecular switches that control a wide variety of signal
      transduction pathways in all eukaryotic cells. They are known principally for
      their pivotal role in regulating the actin cytoskeleton, but their ability to
      influence cell polarity, microtubule dynamics, membrane transport pathways and
      transcription factor activity is probably just as significant. Underlying this
      biological complexity is a simple biochemical idea, namely that by switching on a
      single GTPase, several distinct signalling pathways can be coordinately
      activated. With spatial and temporal activation of multiple switches factored in,
      it is not surprising to find Rho GTPases having such a prominent role in
      eukaryotic cell biology.

PMID- 12478285
TI  - Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.
AB  - The interplay between bone morphogenetic proteins (BMPs) and their antagonists
      governs developmental and cellular processes as diverse as establishment of the
      embryonic dorsal-ventral axis, induction of neural tissue, formation of joints in
      the skeletal system and neurogenesis in the adult brain. So far, the three
      dimensional structures of BMP antagonists and the structural basis for
      inactivation have remained unknown. Here we report the crystal structure of the
      antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling
      by blocking the molecular interfaces of the binding epitopes for both type I and
      type II receptors. The BMP-7-binding affinity of site-specific variants of Noggin
      is correlated with alterations in bone formation and apoptosis in chick limb
      development, showing that Noggin functions by sequestering its ligand in an
      inactive complex. The scaffold of Noggin contains a cystine (the oxidized form of
      cysteine) knot topology similar to that of BMPs; thus, ligand and antagonist seem
      to have evolved from a common ancestral gene.

PMID- 12478286
TI  - Formation of Kuiper-belt binaries by dynamical friction and three-body
      encounters.
AB  - The Kuiper belt is a disk of icy bodies that orbit the Sun beyond Neptune; the
      largest known members are Pluto and its companion Charon. A few per cent of
      Kuiper-belt bodies have recently been found to be binaries with wide separations
      and mass ratios of the order of unity. Collisions were too infrequent to account
      for the observed number of binaries, implying that these binaries formed through
      collisionless interactions mediated by gravity. These interactions are likely to
      have been most effective during the period of runaway accretion, early in the
      Solar System's history. Here we show that a transient binary forms when two large
      bodies penetrate one another's Hill sphere (the region where their mutual forces
      are larger than the tidal force of the Sun). The loss of energy needed to
      stabilize the binary orbit can then occur either through dynamical friction from
      surrounding small bodies, or through the gravitational scattering of a third
      large body. Our estimates slightly favour the former mechanism. We predict that
      five per cent of Kuiper-belt objects are binaries with apparent separations
      greater than 0.2 arcsec, and that most are in tighter binaries or systems of
      higher multiplicity.

PMID- 12478287
TI  - Zero-resistance states induced by electromagnetic-wave excitation in GaAs/AlGaAs
      heterostructures.
AB  - The observation of vanishing electrical resistance in condensed matter has led to
      the discovery of new phenomena such as, for example, superconductivity, where a
      zero-resistance state can be detected in a metal below a transition temperature
      T(c) (ref. 1). More recently, quantum Hall effects were discovered from
      investigations of zero-resistance states at low temperatures and high magnetic
      fields in two-dimensional electron systems (2DESs). In quantum Hall systems and
      superconductors, zero-resistance states often coincide with the appearance of a
      gap in the energy spectrum. Here we report the observation of zero-resistance
      states and energy gaps in a surprising setting: ultrahigh-mobility GaAs/AlGaAs
      heterostructures that contain a 2DES exhibit vanishing diagonal resistance
      without Hall resistance quantization at low temperatures and low magnetic fields
      when the specimen is subjected to electromagnetic wave excitation. Zero
      resistance-states occur about magnetic fields B = 4/5 Bf and B = 4/9 Bf, where Bf
      = 2pifm*/e,m* is the electron mass, e is the electron charge, and f is the
      electromagnetic-wave frequency. Activated transport measurements on the
      resistance minima also indicate an energy gap at the Fermi level. The results
      suggest an unexpected radiation-induced, electronic-state-transition in the
      GaAs/AlGaAs 2DES.

PMID- 12478288
TI  - Wavelength-scalable hollow optical fibres with large photonic bandgaps for CO2
      laser transmission.
AB  - Conventional solid-core optical fibres require highly transparent materials. Such
      materials have been difficult to identify owing to the fundamental limitations
      associated with the propagation of light through solids, such as absorption,
      scattering and nonlinear effects. Hollow optical fibres offer the potential to
      minimize the dependence of light transmission on fibre material transparency.
      Here we report on the design and drawing of a hollow optical fibre lined with an
      interior omnidirectional dielectric mirror. Confinement of light in the hollow
      core is provided by the large photonic bandgaps established by the multiple
      alternating submicrometre-thick layers of a high-refractive-index glass and a low
      refractive-index polymer. The fundamental and high-order transmission windows are
      determined by the layer dimensions and can be scaled from 0.75 to 10.6 micro m in
      wavelength. Tens of metres of hollow photonic bandgap fibres for transmission of
      carbon dioxide laser light at 10.6 micro m wavelength were drawn. The
      transmission losses are found to be less than 1.0 dB m(-1), orders of magnitude
      lower than those of the intrinsic fibre material, thus demonstrating that low
      attenuation can be achieved through structural design rather than high
      transparency material selection.

PMID- 12478289
TI  - Bond-controlled configurational entropy reduction in chemical vitrification.
AB  - Glass formation is usually viewed in terms of physical vitrification: a liquid in
      a metastable state is cooled or compressed so as to avoid crystallization.
      However, glasses may also be formed by chemical vitrification, a process
      involving progressive polymerization of the constituent molecules via the
      formation of irreversible chemical bonds. The formation of most of the materials
      used in engineering plastics and the hardening of natural and synthetic resins
      are based on chemical vitrification. Despite the differences in the molecular
      processes involved in chemical and physical vitrification, surprising
      similarities are observed in the slowing down of the dynamics and in the
      thermodynamical properties of the resulting glasses. Explaining such similarities
      would improve general understanding of the glass transition and may disclose its
      universal nature. Here we report dielectric and photon-correlation measurements
      that reveal the origin of the similarity in the dynamical behaviour of physical
      and chemical glass formers. We find that the evolution of their configurational
      restrictions proceeds in a similar manner. In particular, we make a connection
      between the reduction in configurational entropy and the number of chemical
      bonds, a quantity that can be controlled in experiments.

PMID- 12478290
TI  - Decreased stability of methane hydrates in marine sediments owing to phase
      boundary roughness.
AB  - Below water depths of about 300 metres, pressure and temperature conditions cause
      methane to form ice-like crystals of methane hydrate. Marine deposits of methane
      hydrate are estimated to be large, amassing about 10,000 gigatonnes of carbon,
      and are thought to be important to global change and seafloor stability, as well
      as representing a potentially exploitable energy resource. The extent of these
      deposits can usually be inferred from seismic imaging, in which the base of the
      methane hydrate stability zone is frequently identifiable as a smooth reflector
      that runs parallel to the sea floor. Here, using high-resolution seismic sections
      of seafloor sediments in the Cascadia margin off the coast of Vancouver Island,
      Canada, we observe lateral variations in the base of the hydrate stability zone,
      including gas-rich vertical intrusions into the hydrate stability zone. We
      suggest that these vertical intrusions are associated with upward flow of warmer
      fluids. Therefore, where seafloor fluid expulsion and methane hydrate deposits
      coincide, the base of the hydrate stability zone might exhibit significant
      roughness and increased surface area. Increased area implies that significantly
      more methane hydrate lies close to being unstable and hence closer to
      dissociation in the event of a lowering of pressure due to sea-level fall.

PMID- 12478291
TI  - Unconventional lift-generating mechanisms in free-flying butterflies.
AB  - Flying insects generate forces that are too large to be accounted for by
      conventional steady-state aerodynamics. To investigate these mechanisms of force
      generation, we trained red admiral butterflies, Vanessa atalanta, to fly freely
      to and from artificial flowers in a wind tunnel, and used high-resolution, smoke
      wire flow visualizations to obtain qualitative, high-speed digital images of the
      air flow around their wings. The images show that free-flying butterflies use a
      variety of unconventional aerodynamic mechanisms to generate force: wake capture,
      two different types of leading-edge vortex, active and inactive upstrokes, in
      addition to the use of rotational mechanisms and the Weis-Fogh 'clap-and-fling'
      mechanism. Free-flying butterflies often used different aerodynamic mechanisms in
      successive strokes. There seems to be no one 'key' to insect flight, instead
      insects rely on a wide array of aerodynamic mechanisms to take off, manoeuvre,
      maintain steady flight, and for landing.

PMID- 12478292
TI  - Sex releases the speed limit on evolution.
AB  - Explaining the evolutionary maintenance of sex remains a key problem in
      evolutionary biology. One potential benefit of sex is that it may allow a more
      rapid adaptive response when environmental conditions change, by increasing the
      efficiency with which selection can fix beneficial mutations. Here I show that
      sex can increase the rate of adaptation in the facultatively sexual single-celled
      chlorophyte Chlamydomonas reinhardtii, but that the benefits of sex depend
      crucially on the size of the population that is adapting: sex has a marked effect
      in large populations but little effect in small populations. Several mechanisms
      have been proposed to explain the benefits of sex in a novel environment,
      including stochastic effects in small populations, clonal interference and
      epistasis between beneficial alleles. These results indicate that clonal
      interference is important in this system.

PMID- 12478293
TI  - Large clusters of co-expressed genes in the Drosophila genome.
AB  - Clustering of co-expressed, non-homologous genes on chromosomes implies their co
      regulation. In lower eukaryotes, co-expressed genes are often found in pairs.
      Clustering of genes that share aspects of transcriptional regulation has also
      been reported in higher eukaryotes. To advance our understanding of the mode of
      coordinated gene regulation in multicellular organisms, we performed a genome
      wide analysis of the chromosomal distribution of co-expressed genes in
      Drosophila. We identified a total of 1,661 testes-specific genes, one-third of
      which are clustered on chromosomes. The number of clusters of three or more genes
      is much higher than expected by chance. We observed a similar trend for genes
      upregulated in the embryo and in the adult head, although the expression pattern
      of individual genes cannot be predicted on the basis of chromosomal position
      alone. Our data suggest that the prevalent mechanism of transcriptional co
      regulation in higher eukaryotes operates with extensive chromatin domains that
      comprise multiple genes.

PMID- 12478294
TI  - The mechanosensory protein MEC-6 is a subunit of the C. elegans touch-cell
      degenerin channel.
AB  - Mechanosensory transduction in touch receptor neurons is believed to be mediated
      by DEG/ENaC (degenerin/epithelial Na+ channel) proteins in nematodes and mammals.
      In the nematode Caenorhabditis elegans, gain-of-function mutations in the
      degenerin genes mec-4 and mec-10 (denoted mec-4(d) and mec-10(d), respectively)
      cause degeneration of the touch cells. This phenotype is completely suppressed by
      mutation in a third gene, mec-6 (refs 3, 4), that is needed for touch
      sensitivity. This last gene is also required for the function of other
      degenerins. Here we show that mec-6 encodes a single-pass membrane-spanning
      protein with limited similarity to paraoxonases, which are implicated in human
      coronary heart disease. This gene is expressed in muscle cells and in many
      neurons, including the six touch receptor neurons. MEC-6 increases amiloride
      sensitive Na+ currents produced by MEC-4(d)/MEC-10(d) by approximately 30-fold,
      and functions synergistically with MEC-2 (a stomatin-like protein that regulates
      MEC-4(d)/MEC-10(d) channel activity) to increase the currents by 200-fold. MEC-6
      physically interacts with all three channel proteins. In vivo, MEC-6 co-localizes
      with MEC-4, and is required for punctate MEC-4 expression along touch-neuron
      processes. We propose that MEC-6 is a part of the degenerin channel complex that
      may mediate mechanotransduction in touch cells.

PMID- 12478295
TI  - HIV-1 evades antibody-mediated neutralization through conformational masking of
      receptor-binding sites.
AB  - The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is
      dependent on its avoidance of antibody-mediated neutralization. The virus elicits
      abundant, envelope-directed antibodies that have little neutralization capacity.
      This lack of neutralization is paradoxical, given the functional conservation and
      exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are
      larger than the typical antibody footprint and should therefore be accessible for
      antibody binding. Because gp120-receptor interactions involve conformational
      reorganization, we measured the entropies of binding for 20 gp120-reactive
      antibodies. Here we show that recognition by receptor-binding-site antibodies
      induces conformational change. Correlation with neutralization potency and
      analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding
      site 'conformational masking' mechanism of neutralization escape. To understand
      how such an escape mechanism would be compatible with virus-receptor
      interactions, we tested a soluble dodecameric receptor molecule and found that it
      neutralized primary HIV-1 isolates with great potency, showing that simultaneous
      binding of viral envelope glycoproteins by multiple receptors creates sufficient
      avidity to compensate for such masking. Because this solution is available for
      cell-surface receptors but not for most antibodies, conformational masking
      enables HIV-1 to maintain receptor binding and simultaneously to resist
      neutralization.

PMID- 12478296
TI  - Asymmetric inheritance of centrosomally localized mRNAs during embryonic
      cleavages.
AB  - During development, different cell fates are generated by cell-cell interactions
      or by the asymmetric distribution of patterning molecules. Asymmetric inheritance
      is known to occur either through directed transport along actin microfilaments
      into one daughter cell or through capture of determinants by a region of the
      cortex inherited by one daughter. Here we report a third mechanism of asymmetric
      inheritance in a mollusc embryo. Different messenger RNAs associate with
      centrosomes in different cells and are subsequently distributed asymmetrically
      during division. The segregated mRNAs are diffusely distributed in the cytoplasm
      and then localize, in a microtubule-dependent manner, to the pericentriolar
      matrix. During division, they dissociate from the core mitotic centrosome and
      move by means of actin filaments to the presumptive animal daughter cell cortex.
      In experimental cells with two interphase centrosomes, mRNAs accumulate on the
      correct centrosome, indicating that differences between centrosomes control mRNA
      targeting. Blocking the accumulation of mRNAs on the centrosome shows that this
      event is required for subsequent cortical localization. These events produce a
      complex pattern of mRNA localization, in which different messages distinguish
      groups of cells with the same birth order rank and similar developmental
      potentials.

PMID- 12478297
TI  - Endocytosis-mediated downregulation of LIN-12/Notch upon Ras activation in
      Caenorhabditis elegans.
AB  - The coordination of signals from different pathways is important for cell fate
      specification during animal development. Here, we define a novel mode of
      crosstalk between the epidermal growth factor receptor/Ras/mitogen-activated
      protein kinase cascade and the LIN-12/Notch pathway during Caenorhabditis elegans
      vulval development. Six vulval precursor cells (VPCs) are initially equivalent
      but adopt different fates as a result of an inductive signal mediated by the Ras
      pathway and a lateral signal mediated by the LIN-12/Notch pathway. One
      consequence of activating Ras is a reduction of LIN-12 protein in P6.p (ref. 2),
      the VPC believed to be the source of the lateral signal. Here we identify a
      'downregulation targeting signal' (DTS) in the LIN-12 intracellular domain, which
      encompasses a di-leucine-containing endocytic sorting motif. The DTS seems to be
      required for internalization of LIN-12, and on Ras activation it might mediate
      altered endocytic routing of LIN-12, leading to downregulation. We also show that
      if LIN-12 is stabilized in P6.p, lateral signalling is compromised, indicating
      that LIN-12 downregulation is important in the appropriate specification of cell
      fates in vivo.

PMID- 12478298
TI  - Signal-dependent regulation of splicing via phosphorylation of Sam68.
AB  - Evolution of human organismal complexity from a relatively small number of genes-
      only approximately twice that of worm or fly--is explained mainly by mechanisms
      generating multiple proteins from a single gene, the most prevalent of which is
      alternative pre-messenger-RNA splicing. Appropriate spatial and temporal
      generation of splice variants demands that alternative splicing be subject to
      extensive regulation, similar to transcriptional control. Activation by
      extracellular cues of several cellular signalling pathways can indeed regulate
      alternative splicing. Here we address the link between signal transduction and
      splice regulation. We show that the nuclear RNA-binding protein Sam68 is a new
      extracellular signal-regulated kinase (ERK) target. It binds exonic splice
      regulatory elements of an alternatively spliced exon that is physiologically
      regulated by the Ras signalling pathway, namely exon v5 of CD44. Forced
      expression of Sam68 enhanced ERK-mediated inclusion of the v5-exon sequence in
      mRNA. This enhancement was impaired by mutation of ERK-phosphorylation sites in
      Sam68, whereas ERK phosphorylation of Sam68 stimulated splicing of the v5 exon in
      vitro. Finally, Ras-pathway-induced alternative splicing of the endogenous CD44
      v5 exon was abolished by suppression of Sam68 expression. Our data define Sam68
      as a prototype regulator of alternative splicing whose function depends on
      protein modification in response to extracellular cues.

PMID- 12478301
TI  - Overview of the Alliance for Cellular Signaling.
AB  - The Alliance for Cellular Signaling is a large-scale collaboration designed to
      answer global questions about signalling networks. Pathways will be studied
      intensively in two cells--B lymphocytes (the cells of the immune system) and
      cardiac myocytes--to facilitate quantitative modelling. One goal is to catalyse
      complementary research in individual laboratories; to facilitate this, all
      alliance data are freely available for use by the entire research community.

PMID- 12478302
TI  - Unravelling the signal-transduction network in B lymphocytes.
AB  - The Alliance for Cellular Signaling has chosen the mouse B lymphocyte as a model
      system to understand basic principles that govern cellular signalling. Progress
      to that end has focused initially on establishing a reproducible experimental
      cell system and characterizing essential signalling responses. Although
      unravelling this complex network will take years, findings revealed in the
      interim will prove immensely useful to the scientific community at large.

PMID- 12478303
TI  - Navigating the signalling network in mouse cardiac myocytes.
AB  - Cardiac myocytes have a complex network of signals that regulates their essential
      role in the rhythmic pumping of the heart. This network is an appealing model
      system in which to study the basic principles underlying cellular signalling
      mechanisms. Progress in this effort has come through the establishment of
      standardized myocyte isolation and culture procedures and characterization of
      important signalling responses.

PMID- 12478304
TI  - The Molecule Pages database.
AB  - The Alliance for Cellular Signaling (AfCS)-Nature Molecule Pages will be a
      comprehensive database of key facts about more than 3,000 proteins involved in
      cell signalling. Each entry will be created by invited experts and be peer
      reviewed. Alongside the large-scale experiments being conducted by the AfCS
      scientists, the wealth of information contained in this database offers the
      potential of accelerating the pace of discovery in signal transduction research.

PMID- 12478305
TI  - [First conference. Neurobiology of schizophrenia].

PMID- 12478306
TI  - [Second conference. From phenotype to genotype].

PMID- 12478307
TI  - [Third conference. Model of neural development in schizophrenia].

PMID- 12478308
TI  - [Fourth conference. Why atypical antipsychotics are really atypical?].

PMID- 12478309
TI  - [Psychotic disorder secondary to suprarenal insufficiency caused by exogenous
      corticoids. Review of literature and a case report].
AB  - OBJECTIVE: Since their introduction as therapeutic agents, corticosteroids have
      been associated with psychiatric symptoms ranging from mood disturbances to
      (florid) psychosis. By the time there have been reported psychotic reactions in
      patients receiving steroids or after sudden withdrawal of long time
      corticosteroid therapy. We communicate a clinical case in which the exogenous
      short-treatment with corticosteroids produced an hypothalamic-pituitary-adrenal
      axis inhibition leads to a psychotic disorder two weeks later. METHOD: Case
      presentation, clinical and research literature review, and theoretical
      discussion. RESULTS: There is consensus in the literature that corticosteroids
      may induce psychotic disorders, but the published evidence documenting so is
      scant, consisting only of case reports. We did not find any reported case
      provoked by depot steroids like the one we present. CONCLUSIONS: The literature
      concerned with the prevention and management of corticosteroid-induced
      psychiatric adverse effects is rudimentary, and contains large amounts of
      clinical anecdotes. Due to the lack of formal and validated studies, these
      reports currently provide the only available direction to clinicians in managing
      these problems.

PMID- 12478310
TI  - [Phenomenology and psychosomatics].
AB  - By dividing the field of the human, the psyche-soma dualism ended in sectorizing
      diseases into organic illnesses, and psychic illnesses. Eventually, however, the
      so-called 'psychosomatic disorders' that, apparently, had broken up such a
      pattern have been converted to a new corpus pineale just as Descartes would have
      done. The body is reduced to a mere instrument of psyche, and the subject is
      reduced to a mere onlooker of illness he or she tries to remove one way or the
      other. Conversely, phenomenology understands that, first of all, the body is 'the
      body I am' (Leib): the body is the place for communicating with other people, and
      the place for performing exchanges with things. It is through the body that the
      world affects us, and it is by means of the body that we display all our meaning
      onto the world. In everyday life people are just unaware of their bodies.
      Whenever anxiety busts out, however, the body makes a massive comeback, giving
      expression to the complex dialectics of the speaking subject through his or her
      body. Anxiety pertains to a pre-category order of the body, to the unfathomable
      depth reason is unable to pierce. At the bottom line of a great majority of
      psychosomatic disorders there lies an intersubjective anxiety conveying a
      conflict between the loss of an object and the obstacles thus hindering the
      personal growth. Reason, as a reflexive conscience is unable to solve the
      conflict -reason is not even aware of conflict, reason does not even perceive any
      likely relationship among disorders and such or such situations. The body, as an
      'operating intentionality' (Merleau-Ponty), as a pre-reflexive access to the
      world, as a pathos life experience (Lang), will erupt and see to it that conflict
      is solved, and conflict-linked anxiety are transformed. Body and its great reason
      -- as Nietzsche would have said, 1883 -- solves everything its way.

PMID- 12478311
TI  - [Social crisis, spontaneous groups and group order].
AB  - Argentina has gone through very difficult times during the last years and, in
      particularly, new kinds of social practices have emerged in order to cope with
      the crisis. This situation demands and urges a new type of reflection upon the
      double role of groups, as tools to transform reality and as a way to elaborate
      those processes regarding subjectivity. In this paper we analyse some topics
      regarding the groupal field (considering spontaneous groups as well as groupal
      devices that allow to elaborate the crisis). We consider social bond to be the
      condition of possibility for the existence of the psyche and of time continuity,
      and that it also makes possible personal and social elaboration of trauma, crisis
      and social catastrophe. We develop some aspects of an specific device (the
      reflection group), which we have already depicted in another moment, showing it's
      usefulness to cope with social crisis and to promote the subjective elaboration
      of crisis.

PMID- 12478312
TI  - [Cognitive group therapy].
AB  - This paper presents a brief history of group psychotherapy and it also makes a
      difference between two main kinds of cognitive group therapy: one linked to
      behavioral approaches and another one more related to postmodern, constructivist
      and narrative theories. Several domains where these approaches are used are
      exposed and the differences between one kind of cognitive group therapy and the
      other are put forward. While the behavioral like intends to fix errors or
      eliminate what does not work properly, the constructivist like tries to
      reconstruct a history which can be functional to subjective experience. At last,
      AIGLE depicts its integrative approach.

PMID- 12478313
TI  - [Efficacy of group psychotherapy for homosexual aging males].
AB  - The aim of this research is try to expose and to debate the groupal psychotherapy
      experience of homosexual males older than 65 years, in Buenos Aires. The starting
      point for this work is based on that homogeneous groups are effective in some
      contexts, what is demonstrated by the results at the beginning and at the end of
      the samples of the BSI and SAS, although this data are not, like it was supposed,
      commonly linked with the selected biographical antecedents (abuse of power,
      bereavements during the last military dictatorships, bereavements as result of
      the AIDS epidemic and the difficulties in the economic survival).

PMID- 12478314
TI  - [What is mutual aid? The experience of the Fundacion de Bipolares de Argentina
      (Fubipa)].
AB  - Fubipa is a self-help organization run by bipolar patients, their relatives and
      friends. It provides emotional support to those affected by the disorder, and
      disseminates information about the illness and its treatment. This paper outlines
      its functioning and the history of its inception and development, as well as
      sharing testimonies of recovered patients who collaborate with our Foundation.

PMID- 12478315
TI  - [Discussion group upon unemployment. The report of an experience].
AB  - The present paper is the outcome of a Discussion Group focused on unemployment.
      The experience was carried out in an institution of Ituzaingo, Provincia de
      Buenos Aires. The Group activities were designed to prevent social damage. The
      Group was designed as a space to contain the participants, generate their
      reflection and make possible new alternatives to their situation. This paper
      describes the main psychosocial indicators emerging along the Group process,
      outlining stigmatization and guilt as dominant representations. The paper
      highlights the importance of the above mentioned groups regarding social damage
      recomposition, as well as the elaboration of alternatives to face social problems
      such as unemployment.

PMID- 12478316
TI  - [Psychic change in schizophrenic patients produced group therapy].
AB  - The objective of this paper is to analyze the effectiveness of group therapy to
      produce psychic change in patients with schizophrenia and other related
      psychosis. The experience took place in a Public Psychiatric Hospital. It
      involved 96 patients with this condition who entered different groups from 1998
      up to the present. During the year 2000, 66 of them were asked to answer a
      questionnaire especially designed to investigate the changes that they thought
      they had gone through during this treatment. On one hand, the results show the
      high valorization of the group appliance, while on the other hand the most valued
      operational categories were the facilitation of interpersonal links, the
      valorization of listening and being listened, the recognition of improvement and
      the recognition of one's own characteristics in the other person. On account of
      these discoveries, the mechanisms of these group appliances to produce such
      changes are postulated. In conclusion, group treatment for schizophrenic patients
      and related psychosis turns out to be useful for producing psychic changes
      different from those achieved with psychopharmacological agents.

PMID- 12478317
TI  - [Interview of Armando Bauleo by Alejandro Vainer].

PMID- 12478318
TI  - [History and development of psychology and group psychotherapy in Argentine].

PMID- 12478319
TI  - [Conceptual issues in the development of quality indicators for mental health
      systems].
AB  - Once the parameters to design and assess a Mental Health System have been put
      forward it's necessary to operationalize them into quality indicators and outcome
      measures. These indicators allow us to compare processes and results with other
      systems and services, they let us do the economic assessment and the allotment of
      resources, they give way to treatment guidelines and external evaluation,
      generating a new type of organizations evidence-based. This paper reviews the
      conceptual aspects of performance indicators and its use in some developed
      countries. It also discusses their usefulness, at the input, the process and the
      outcome level, to treat patients and to organize Mental Health Services and
      Systems. Despite therapists not benefiting directly from the use of this type of
      indicators, its importance should not be disregarded in order to organize a
      Mental Health System for large populations.

PMID- 12478320
TI  - Hepatitis agents with enteric transmission--an epidemiological analysis.
AB  - BACKGROUND: Viral hepatitis is characterized by special clinical, biochemical and
      serological findings. This study was planned to determine the seroprevalence,
      epidemiological characteristics and clinical and biochemical findings of
      hepatitis A virus (HAV) and hepatitis E virus (HEV) infections during an outbreak
      of jaundice. MATERIALS AND METHODS: 340 children aged 5-16 years were included.
      Clinical findings and alanine aminotransferase (ALT) levels were documented. Anti
      HAV IgG and IgM in addition to anti-HEV IgG and IgM were determined by
      microELISA. RESULTS: Clinical findings, high levels of ALT, anti-HAV IgM and IgG,
      anti-HEV IgM and IgG were present in 6%, 23%, 17%, 100%, 7% and 9% of cases,
      respectively. The relationship between ALT levels and anti-HAV or anti-HEV IgM
      seropositivity was significant (p </= 0.0001). CONCLUSION: HAV and HEV infection
      were both caused by a contaminated water supply.

PMID- 12478321
TI  - Infection with Nocardia species: clinical spectrum of disease and species
      distribution in Madrid, Spain, 1978-2001.
AB  - BACKGROUND: Clinical experience with nocardiosis is very limited in European
      countries. We describe 34 cases of nocardial infection seen at one Spanish
      teaching hospital. PATIENTS AND METHODS: A retrospective review of the clinical
      features and outcome of nocardial infections was conducted during a 24-year
      period (1978-2001). All cases were confirmed by culture. RESULTS: Predisposing
      factors included immunosuppression and/or pulmonary disease in 85% of patients;
      eight cases were related to HIV infection. Most isolates were initially
      identified as Nocardia asteroides complex (97%). The most common clinical form
      was pulmonary disease (41%), followed by disseminated (15%), cutaneous (12%),
      cerebral (9%) and articular disease (3%). A high proportion of patients (20%) had
      pulmonary colonization. Therapy with sulfonamides, imipenem or amikacin was given
      to 26 patients and a clinical response was observed in 65%. Overall mortality
      among patients with nocardial disease was 48% (13/27) but only seven patients
      (26%) died from nocardiosis. CONCLUSION: Nocardiosis remains a rare opportunistic
      infection that appears in immunosuppressed patients. HIV infection has become a
      common predisposing condition. The species distribution and disease spectrum are
      similar to those described in other European countries. Although most patients
      develop active disease, pulmonary colonization might not be as rare as has
      generally been assumed. Treatment with sulfonamides is usually effective and many
      patients may remain free of nocardial disease for a prolonged period.

PMID- 12478322
TI  - Invasive Aspergillosis in Italian AIDS patients.
AB  - BACKGROUND: We studied the prevalence, epidemiological features, symptoms,
      diagnosis, treatment and outcome of invasive aspergillosis in AIDS patients in
      Italy. PATIENTS AND METHODS: All patients affected by both aspergillosis and AIDS
      hospitalized between January 1986 and April 1997 (before highly-active
      antiretroviral therapy, HAART) in four Italian Department of Infectious Disease.
      Patients were included in the study only if culture, cytology or histology showed
      firm evidence of Aspergillus infection. Invasive aspergillosis was defined as the
      presence of characteristic, closely septate hyphae with repeated acute angle
      branching in either biopsy materials or percutaneous aspirates from tissues other
      than the lung. Hyphae were identified using hematoxylin-eosin and methenamine
      silver stain. RESULTS: During the study, 54 out of 2,614 patients admitted with
      AIDS showed aspergillosis (2.1%). The disease usually occurred in patients with <
      50 CD4 cells/mm(3). Aspergillosis was associated with neutropenia and steroid
      treatment. Nonspecific symptoms were frequently encountered. Fever and cough were
      both present in > 70% of the cases of pulmonary aspergillosis. Biopsy specimens
      were analyzed for definitive diagnosis. Invasive aspergillosis is usually treated
      with amphotericin B, but in 90% of the cases this did not prevent death.
      CONCLUSION: In AIDS patients with neutropenia and long-term steroid therapy, it
      is important to consider invasive aspergillosis in the differential diagnosis of
      opportunistic infections.

PMID- 12478323
TI  - Community-acquired spontaneous bacterial meningitis in adult diabetic patients:
      an analysis of clinical characteristics and prognostic factors.
AB  - BACKGROUND: We analyzed the clinical characteristics and prognostic factors of
      community-acquired spontaneous bacterial meningitis (CASBM) in adult diabetic
      patients. PATIENTS AND METHODS: Over a period of 15 years, 47 adult diabetic
      patients with CASBM were identified. The clinical characteristics, laboratory
      data and therapeutic outcome of these 47 patients were statistically analyzed.
      RESULTS: The 47 patients were 31 men and 16 women, aged 22 to 79 years, and they
      accounted for 38.5% (47/122) of our adult patients with culture-proven CASBM. The
      most common causative pathogen was Klebsiella pneumoniae (n = 32), followed by
      pathogens of the streptococcal species (n = 6). Besides classic manifestations of
      bacterial meningitis, bacteremia and focal suppuration, especially liver abscess,
      were common features in this group of patients. Liver cirrhosis and/or alcoholism
      were the other frequent underlying conditions. 27 patients survived in the course
      of therapy. The prognostic factors with statistical significance were glucose
      ratio and cerebrospinal fluid (CSF) white blood cell (WBC) count. CONCLUSION:
      This study showed the high incidence of diabetes mellitus (DM) among the adult
      patients with CASBM in Taiwan. K. pneumoniae was the most frequent causative
      pathogen. Bacteremia and focal suppuration, especially liver abscess, were common
      findings. The values of glucose ratio and CSF WBC count had a statistically
      significant influence on the prognosis of our patients.

PMID- 12478324
TI  - Surveillance of measles-mumps-rubella vaccine-associated aseptic meningitis in
      Germany.
AB  - BACKGROUND: The study objective was to detect any incidence of aseptic meningitis
      associated with measles-mumps-rubella (MMR) vaccines that would be considered of
      public health importance subsequent to the introduction of a new MMR vaccine
      (Priorix). PATIENTS AND METHODS: Adverse drug reaction (ADR) rates were
      calculated by relating the number of cases to the number of doses of the
      different MMR vaccines distributed during a 2-year period in Germany. RESULTS:
      During the 2-year study period 1,575,936 doses of Priorix and 1,907,875 doses of
      other MMR vaccines were distributed in Germany. There were no confirmed cases of
      aseptic meningitis associated with MMR vaccination during this period. Thus, the
      ADR rates (rejectable with 5% alpha error) were lower than 1/525,312 for Priorix
      and lower than 1/635,958 for other MMR vaccines. CONCLUSION: The safety profile
      of the Priorix is similar to that of other MMR vaccines used in Germany.

PMID- 12478325
TI  - High prevalence of genotypic resistance to nucleoside reverse transcriptase
      inhibitors among therapy-naive individuals from the Warsaw cohort.
AB  - BACKGROUND: The purpose of this study was to recognize nucleoside reverse
      transcriptase inhibitor (NRTI)-resistant HIV-1 strains among a group of therapy
      naive patients, and subsequently to guide the choice of antiretroviral therapy.
      PATIENTS AND METHODS: HIV strains present in sera of 128 antiretroviral therapy
      naive patients were tested for NRTI resistance-associated mutations. The RT-PCR
      amplified HIV rt regions were analyzed with an INNI-LiPA-HIV-1 RT assay. The
      number and pattern of resistance-associated mutated codons were determined and
      interpreted as resistance to particular drugs. RESULTS: Mutated codons were
      detected in 66 (51.5%) out of 128 tested samples. In 54 (81.8%) out of 66
      samples, a K70R mutation was identified, which was followed by an M184V mutation
      in 22 cases (33.3%). For a majority of these samples, mixed wild/mutant
      populations were recognized in 44 (66.6%) cases. The interpretation of
      hybridization data revealed drug-resistant strains in 37 (28.9%) out of all
      samples tested. The determined resistance to particular drugs was as follows: 20
      strains were resistant to zidovudine (ZDV), ten to lamivudine (3TC) and six to
      didanosine (ddI)/zalcitabine (ddC)/abacavir (ABC). In one case, a ZDV/3TC
      resistant HIV strain was found. CONCLUSION: The prevalence of mutations
      associated with NRTI resistance was high in the tested cohort. The key reasons
      for that were most probably needle and drug sharing within the group of
      intravenous drug users (IVDUs) and the use of ZDV in monotherapeutic regimes in
      the early 1990s.

PMID- 12478326
TI  - Analysis of T-cell receptor V-beta 2 in peripheral blood lymphocytes as a
      diagnostic marker for Kawasaki disease.
AB  - BACKGROUND: Kawasaki disease (KD) is the most frequent cause of acquired heart
      disease in children, yet there are no specific diagnostic markers for it. There
      is controversy whether and by what mechanism selective expansion of T-cell
      subsets occurs and whether this phenomenon might be helpful for early diagnosis.
      PATIENTS AND METHODS: To obtain age-related normal values of V-beta 2(+) T
      lymphocytes in healthy children and to investigate expansion in KD, we measured
      expression in 228 children. Peripheral CD3(+) cells were stained with monoclonal
      antibodies to V-beta 2.1 and the percentage of V-beta 2(+) T-cells was analyzed
      using flow cytometry. RESULTS: In a control group of 184 healthy subjects (0 to
      17 years; median age 6.0 years) we found age-related changes. Levels were highest
      from 0-2 years (9.02+/-2.80%) and declined towards adolescence (7.56+/-2.42% in
      11-15 year olds) (p < 0.001). Results were compared with 24 patients with acute
      febrile diseases of origin other than KD and with 20 patients with presumed
      diagnosis KD at admission. Interestingly, while all seven patients whose clinical
      picture retrospectively confirmed KD showed elevated levels, none of the other
      children, including none of the patients with initially suspected but not
      clinically confirmed KD, had levels higher than normal, with the exception of two
      teenage girls with toxic shock syndrome, a classical superantigen-mediated
      disease. CONCLUSION: When compared with appropriate age-matched controls,
      estimation of V-beta 2(+) T-cells might be a valuable tool when making diagnostic
      decisions suspecting KD.

PMID- 12478327
TI  - Capillary and venous leukocyte adhesiveness/aggregation to differentiate between
      viral and bacterial infection.
AB  - BACKGROUND: A simple capillary leukocyte adhesiveness/aggregation test (CAPLAAT)
      might be helpful in determining the intensity of inflammation in acute viral and
      bacterial infections. PATIENTS AND METHODS: We included 30 patients with acute
      bacterial infections, 14 with viral infections as well as 48 healthy controls.
      The leukocyte adhesiveness/aggregation test (LAAT) test was performed using a
      simple slide test and image analysis. RESULTS: The CAPLAAT had a similar
      discrimination power between bacterial and viral infections as both the white
      blood cell count (WBC) and the erythrocyte sedimentation rate (ESR). It was more
      sensitive than the WBC and the ESR (77%, 68% and 66%, respectively) for the
      detection of bacterial infections and had a comparable negative predictive value.
      By analyzing the size distribution of the aggregated leukocytes, we found that a
      venous leukocyte adhesiveness/aggregation test (VLAAT) of four cells and more had
      the best positive predictive value (94%) and specificity (95%) for diagnosis of
      an acute bacterial infection (from all the acute phase response variables
      examined). CONCLUSION: The CAPLAAT might be attractive for the detection of
      inflammation and for the assessment of its severity at points of care where the
      services of a clinical laboratory are not available around the clock.

PMID- 12478328
TI  - Ciclopiroxolamine cream for treating seborrheic dermatitis: a double-blind
      parallel group comparison.
AB  - BACKGROUND: The aim of this study was to compare the efficacy and tolerability of
      topically applied ciclopiroxolamine cream with that of the corresponding vehicle
      in patients with seborrheic dermatitis of the face. PATIENTS AND METHODS: The
      study was conducted as a multicenter prospective, randomized, double-blind
      parallel group comparison at 14 centers in Australia and New Zealand. 189
      patients with clinically diagnosed seborrheic dermatitis participated in the
      study. Each patient applied ciclopiroxolamine 1% cream or the corresponding
      vehicle twice daily as a thin film to the affected skin areas and to clinically
      unaffected skin areas surrounding the lesions for 29 days. RESULTS: The rate of
      treatment success was significantly higher with ciclopiroxolamine than with
      vehicle (73.9 vs 53.6%; p = 0.003). Treatment with ciclopiroxolamine reduced the
      sum score of the clinical signs of seborrheic dermatitis to a greater extent than
      the vehicle (p </= 0.001). CONCLUSION: This study confirms that topical treatment
      with ciclopiroxolamine is effective and well tolerated in patients with
      seborrheic dermatitis.

PMID- 12478329
TI  - Efficacy and tolerability of once-daily telithromycin compared with high-dose
      amoxicillin for treatment of community-acquired pneumonia.
AB  - BACKGROUND: This randomized, double-blind study compared the efficacy and
      tolerability of the new ketolide antimicrobial telithromycin with that of high
      dose amoxicillin in the treatment of community-acquired pneumonia (CAP). PATIENTS
      AND METHODS: Adult patients (n = 404), with signs and symptoms of CAP and
      radiologic confirmation were randomized to receive telithromycin 800 mg once
      daily (n = 199) or amoxicillin 1,000 mg three times a day (n = 205) for 10 days.
      Clinical and bacteriologic outcomes were assessed at post-therapy test-of-cure
      (days 17-24) and late post therapy (days 31-36). RESULTS: The clinical cure rate
      for telithromycin-treated patients (per protocol) pst therapy (days 17-24) was
      141/149 (94.6%) and compared well with that for amoxicillin (137/152 (90.1%)).
      Subset analysis of patients (per protocol) showed high clinical cure rates for
      patients aged >/= 65 years (telithromycin 21/24, 87.5%; amoxicillin 22/29,
      75.9%); those with documented pneumococcal bacteremia (telithromycin 10/10, 100%;
      amoxicillin 7/9, 77.8%); and patients with a Fine score >/= III (telithromycin
      31/34, 91.2%; amoxicillin 38/47, 80.9%). Bacterial eradication rates were
      comparable between treatments (telithromycin 42/48, 87.5%; amoxicillin 39/45,
      86.7%), with 22/23 vs 18/21 Streptococcus pneumoniae strains 9/12 vs 11/13
      Haemophilus influenzae strains and all Moraxella catarrhalis isolates (five and
      three patients, respectively) eradicated at the test-of-cure visit. Both
      treatments were generally well tolerated. CONCLUSION: Telithromycin 800 mg once
      daily is a convenient, optimal-spectrum, first-line treatment for CAP in adults,
      at least as effective and well tolerated as high-dose amoxicillin.

PMID- 12478330
TI  - Home and hospital antibiotic treatment prove similarly effective in cystic
      fibrosis.
AB  - BACKGROUND: Home intravenous antibiotic treatment has added to therapeutic
      options against Pseudomonas aeruginosa in cystic fibrosis (CF) patients leading
      to increased flexibility. A prospective clinical study was carried out to compare
      home and hospital iv antibiotic treatment in CF patients with chronic P.
      aeruginosa infection. PATIENTS AND METHODS: Treatment courses were planned
      selectively, exacerbations were excluded. 28 consecutive hospital courses (group
      1) were compared with 30 home care courses (group 2). Chest physiotherapy and
      nutrition therapy were carried on in both groups. Antibiotic treatment in both
      groups consisted of tobramycin and ceftazidime, with equal dosage and
      application. Groups were compared using clinical, inflammatory and
      microbiological parameters. RESULTS: There was a significant difference (p </=
      0.05) in peripheral leukocyte counts before and after therapy in both groups. The
      same was true for forced expiratory volume in 1 sec (FEV(1); p </= 0.05), weight
      for height (p </= 0.005) and for Pseudomonas counts (p </= 0.005) in sputa. There
      was no statistical difference between the two groups for any of the parameters
      tested. CONCLUSION: It is concluded that, when exacerbations are excluded, home
      iv therapy is an effective therapeutic option in CF. Long-term comparison is
      still needed to effectively evaluate the pros and cons of home and hospital
      antibiotic treatment in CF.

PMID- 12478331
TI  - Disseminated cutaneous Mycobacterium marinum infection in a patient with non
      Hodgkin's lymphoma.
AB  - A 60-year-old woman with non-Hodgkin's lymphoma was admitted to the hospital
      because of extensive subcutaneous abscesses developing on all limbs. The patient
      had an aquarium and kept tropical fish as pets. After repeated investigations,
      the diagnosis of Mycobacterium marinum was established from skin biopsy by PCR
      and culture. Long-term therapy with several drugs regimens had only a limited
      efficacy and was accompanied by severe adverse reactions. This report highlights
      the therapeutic problems posed by disseminated cutaneous M. marinum infection in
      the immunosuppressed host.

PMID- 12478332
TI  - Complex regional pain syndrome and lyme borreliosis: two different diseases?
AB  - Complex regional pain syndrome (CRPS) is a frequent complication appearing as
      pain of unexplained pathogenesis. Its association with Lyme borreliosis (LB) is
      fairly rare. In the presented clinical case, clinical features as well as the
      findings of radiological, radionuclide, neurophysiological and serological
      investigations pointed to an association between the two conditions. The patient
      fulfilled the criteria for both diagnoses, i.e. CRPS and LB. The subsequent
      antibiotic therapy resulted in a complete remission of both clinical entities.

PMID- 12478333
TI  - Acute Q fever and brachial neuritis: case report and literature review.
AB  - Peripheral nervous system complications of Q fever are uncommon. A case of
      electrophysiologically documented brachial neuritis occurring during acute
      Coxiella burnetii infection is reported. The relevant literature is reviewed.

PMID- 12478334
TI  - Recurrent bacterial vaginosis in a virgin adolescent: a new method of treatment.
AB  - Bacterial vaginosis (BV) is a polymicrobial infection of the vagina and should
      not be considered an exclusively sexually transmitted disease. We describe the
      case of a 17-year-old female virgin adolescent with recurrent malodorous vaginal
      discharge for 6 months. Before referral to us she had been treated unsuccessfully
      with conservative treatment options. Our investigation revealed Gardnerella
      vaginalis as the responsible factor for the vaginal infection. Because
      metronidazole treatment had failed as monotherapy, a new method was applied.
      Repeated vaginal washings with 3% H(2)O(2), 15% NaCl and 10% providone iodine
      were initiated. At the end of each washing, vaginal walls were thoroughly cleaned
      up with a small gauze. After 10 days of treatment the odor and the vaginal
      discharge had ceased and 12 months later no relapse had occurred. It seems to be
      reasonable to use this kind of treatment in recurrent BV.

PMID- 12478335
TI  - Fractionated stereotactic radiotherapy for acoustic neuromas.
AB  - BACKGROUND: When compared to radiosurgery, fractionated stereotactic radiotherapy
      (FSR) for acoustic neuroma (AN) offers escalation of tumor dose (Gy) and
      potential sparing of auditory and facial nerve functions. METHOD: Over the past
      6.5 years 287 consecutive patients have received FSR for AN. One hundred fifty
      patients have follow up greater than 1 year and comprise this report. Non
      invasive, repeat-fixation mask allowed simulation via spiral CT. Differential
      collimation and beam weighting achieved conformality. Three distinct schedules
      for total dose and fractionation were used. For AN<3.0 cm diameter (mean volume
      1.5+/-0.2 cc), > or =3.0 and < or =3.9 cm (mean volume 8.7+/-1.0 cc) and > or
      =4.0 cm (mean volume 28.3 cc (one case) doses of 5 Gy given in 5 consecutive
      daily fractions (25 Gy total) (131 patient), 10 fractions of 3 Gy (30 Gy total)
      (18 pts), or 20 fractions of 2 Gy (1 patient) were given. All treatments were
      prescribed to the 80% isodose and given via the dedicated 10 MeV accelerator.
      FINDINGS: The percentage decreases in tumor size were 14+/-1 (range: 0-100), 15+/
      3 (range 0-38) and 8 for the 25, 30 and 40 Gy regimens, respectively. No patient
      had growth of AN or developed facial weakness. Two patients developed transient
      decrease in facial sensation. Rates of hearing preservation were similar for both
      the larger and smaller tumors. INTERPRETATION: Fractionated stereotactic
      radiotherapy may preserve normal function and control both small and large
      acoustic neuromas.

PMID- 12478336
TI  - Paragangliomas of the temporal bone: results of different treatment modalities in
      53 patients.
AB  - BACKGROUND: The authors retrospectively compared the results of three different
      treatment modalities (surgery, conventional radiotherapy and gamma knife
      radiosurgery) in patients with paragangliomas of the temporal bone, in order to
      determine the optimal current treatment concept. METHOD: Between 1978 and August
      2001, 53 patients (12 men and 41 women; mean age, 58.3 years; range, 17 to 84
      years) with paragangliomas of the temporal bone were treated at the neurosurgery
      and ENT departments of the University of Vienna. According to the Fisch
      classification, 6 patients had class B tumours, 20 had class C, and 27 patients
      had class D tumours. Thirty-two patients (mean age, 57.0 years; 6 B, 14 C, 12 D)
      underwent surgery. In 17 cases the tumour was embolised prior to surgery. Nine
      patients (mean age, 73.9 years; 6 C, 3 D) received primary radiotherapy (median
      total dose, 46.8 Gy). Six patients (mean age, 73.5 years; 6 D) underwent primary
      radiosurgery (median centre dose 24, Gy) and 6 patients (6 D) admitted from other
      departments with recurrent tumours adjuvant radiosurgery (median centre dose,
      25.5 Gy). FINDINGS: In 20 of the surgical cases (62.5%) complete tumour resection
      was achieved and the patients required no further treatment over a mean follow-up
      period of 9.1 years. Of the 12 patients with incomplete tumour resection, 9 (5 C,
      4 D) received postoperative adjuvant radiotherapy and three patients (3 D)
      adjuvant radiosurgery. In 15 (83.4%) of the 18 patients who underwent
      radiotherapy the tumours showed no signs of progression and the patients remained
      clinically unchanged over a mean period of 9.4 years. Three patients (16,6%)
      experienced progression of their tumour within an average period of 2.8 years. In
      the 15 patients who underwent primary radiosurgery, an objective 100% tumour
      control rate with no evidence of progression of disease was observed.
      INTERPRETATION: The results indicate that the most effective current treatment
      option for patients with paragangliomas of the temporal bone is a single-stage
      radical tumour resection, performed in advanced tumours as an interdisciplinary
      neuro-otosurgical procedure. For subtotally resected or non-resectable tumours,
      gamma knife radiosurgery has proved to be a safe and effective treatment
      modality.

PMID- 12478337
TI  - Combination chemotherapy using carboplatin (JM-8) and etoposide (JET therapy) for
      recurrent malignant gliomas: a phase II study.
AB  - BACKGROUND: To study efficacy and safety of chemotherapy using carboplatin (JM-8)
      and etoposide ("JET" therapy) for the treatment of recurrent malignant glioma, a
      phase II study was conducted. Tumour control, survival time, and toxicity/side
      effects were assessed in patients with recurrent malignant glioma which failed to
      respond to a postoperative combined auxiliary therapy comprising of IFN-beta,
      ACNU and radiation. METHODS: Twenty-eight patients, fourteen with anaplastic
      astrocytoma (AA) and fourteen with glioblastoma (GB) were included in this study.
      The JET regimen consists of the intravenous administration of carboplatin (300
      mg/m(2)) on day 1 and etoposide (60 mg/m(2)) on day 1 to 5, repeated every 6
      weeks. FINDINGS: Following the therapy, we observed partial response (PR) in five
      (36%) of 14 patients with AA and two (14%) of 14 with GB, and stabilization of
      the disease (SD) in six (43%) in each group. The mean survival/survival after
      recurrence was 51 months/25 months in the AA group, and 17/9 in the GB group.
      INTERPRETATIONS: These results compare favorably with the natural course of
      recurrent malignant glioma. JET shows signs of efficacy in patients with
      recurrent malignant glioma, and a randomized trial comparing it to standard
      therapy is warranted.

PMID- 12478338
TI  - Epidemiological, forensic, clinical, and imaging characteristics of head injuries
      acquired in the suicide attempt with captive bolt gun.
AB  - The captive bolt gun (slaughterer's gun) is a tool used in the meat industry for
      "humane killing" of animals. Used with the intent of suicide, the captive bolt
      gun causes very serious injuries. We analysed 19 self-inflicted head injuries
      with captive bolt gun during the past 20 years. Autopsy of 20 pigs killed by this
      method was also performed. All 19 cases were middle-aged men from rural areas,
      with low level of education, and without a previous psychiatric history. Five of
      them used the captive bolt gun daily in their professional activities, while the
      remaining 14 handled it only sometimes. In seven cases suicide was primarily
      successful, while in five patients, despite intensive medical care, serious
      craniocerebral injuries eventually resulted in death. Total mortality was 63.2%.
      The clinical appearance of the entrance wound and the imaging characteristics of
      the cranial trauma are very specific, and can be easily differentiated from
      firearm or other penetrating injuries. These wounds were always primarily
      infected with mixed bacterial flora from the skin. Therefore, besides radical
      primary wound care, especially of the wound canal with removal of foreign bodies,
      it is important to administer high doses of wide spectrum antibiotics.

PMID- 12478339
TI  - Impact of brain shift on intraoperative neurophysiological monitoring with
      cortical strip electrodes.
AB  - BACKGROUND: Intraoperative neurophysiological monitoring has become the standard
      procedure for locating eloquent regions of the brain. Such continuous electrical
      stimulation of motor pathways is usually applied by means of flat silicon
      embedded electrodes placed directly on the motor cortex. However, shifting of the
      silicon strip on the cortical surface as well as electrode displacement due to
      brain shift underneath the electrode can lead to inaccurate recordings not
      directly caused by intraoperative impairment of the motor cortex or the motor
      pathways. METHOD: This prospective study was conducted to quantify cortical brain
      shift during open cranial surgery and to assess its impact on electrode
      positioning in 31 procedures near the precentral gyrus. Three groups of different
      lesion volumes were distinguished. Movement of the cortex between opening of the
      dura and completion of tumor removal as well as cortical electrode shifting were
      digitally measured and analyzed. FINDINGS: Cortical surface structures evidenced
      a significantly larger shift (up to 23.4 mm) in comparison to the electrode
      strips (up to 4.2 mm) in lesions with a volume of over 20 ml. Cortex shifting
      highly correlated with lesion volume, whereas strip electrode movement was almost
      unidirectional and did not differ significantly among the three groups. However,
      the way they were placed (completely on the cortex vs. partly underlying or
      overlapping the craniotomy borders) affected the magnitude of their
      intraoperative displacement. As a consequence, 3 of the 31 cases (9.3%) showed a
      significant change in the recorded motor responses due to intraoperative
      dislocation of the stimulating electrode. INTERPRETATION: Changes in the location
      of cerebral structures due to intraoperative brain shift may exert a marked
      influence on intraoperative neurophysiological monitoring if cortical strip
      electrodes are used. Therefore, long-term monitoring of the central region
      requires continuous checking of the position of stimulating electrodes and, if
      necessary, correction of their location.

PMID- 12478340
TI  - Surgery of proximal anterior cerebral artery aneurysms.
AB  - BACKGROUND: Aneurysms of the proximal segment of anterior cerebral artery (A1)
      are uncommon, but present a unique challenge to surgeons because of the risk of
      injury to the nearby perforating arteries. Surgical issues and treatment options,
      however, have not been detailed in the previous literature. METHOD: We report a
      consecutive series of 11 patients with A1 aneurysms focusing on the surgical
      considerations. The A1 aneurysms represented 3.4% of the 322 cerebral aneurysms
      treated in our hospital in the last 6 years. All patients presented with
      subarachnoid hemorrhage, and 8 patients (73%) had multiple aneurysms. FINDINGS:
      All aneurysms were secured by neck clipping via pterional craniotomy without any
      surgery-related morbidity. All of the aneurysms projected superiorly or
      posteriorly from the origin of the perforating artery of the A1 segment. The
      aneurysm dome was tightly adherent to the perforating arteries in 7 cases (64%)
      and the base extended broadly along the axis of the parent artery in 4 cases
      (36%). INTERPRETATION: Separating the perforating arteries from the neck or dome
      of the A1 aneurysm and preserving the vessel presents a substantial challenge to
      the surgeon, because the aneurysm is almost always behind the parent artery in
      the surgical field, making it difficult to achieve good access for this
      particular type of dissection. Consideration should be given to additional
      orbitotomy, wide opening of the Sylvian fissure, mobilization of the MCA and ICA,
      selection of aperture clip and intra-operative shortening of the clip blades.

PMID- 12478341
TI  - Highly reproducible rat model of reversible forebrain ischemia--modified four
      vessel occlusion model and its metabolic feature.
AB  - BACKGROUND: The four-vessel occlusion method introduced by Pulsinelli et al. is
      widely used as an experimental model for reversible forebrain ischemia in rats.
      METHOD: In this study, we further developed highly reproducible model of
      reversible forebrain ischemia. Under the microscope the visible vertebral
      arteries at the second vertebra could be easily electrocauterized and completely
      cut to yield complete cessation of circulation of both vertebral arteries. After
      24 hours, male Wistar rats were subjected to 15, 30 and 45 minutes of forebrain
      ischemia by occluding both common carotid arteries with Sugita's temporary clips.
      (31)P-magnetic resonance spectra ((31)P-MRS) and (1)H-magnetic resonance images
      ((1)H-MRI) were obtained with a 6.3-T spectrometer to investigate sequential
      change of the in vivo brain metabolism. Electroencephalogram and the cortical
      blood flow by laser Doppler flowmetry were measured during ischemia and
      recirculation. Determination of endogenous superoxide scavenging activity in the
      brain cortex was performed by electron spin resonance spectrometry. FINDINGS:
      Brain water contents evaluated by the dry-wet weight method were increased at 1
      hour and 48 hours after recirculation, which were demonstrated by (1)H-MRI. The
      superoxide scavenging activity showed a significant decrease at 45 minutes of
      recirculation and a significant increase at 12 hours of recirculation. The
      present modified model demonstrated that the mortality rates by 72 hours were
      8.3% (15 minutes ischemia), 15.0% (30 minutes ischemia), and 42.9% (45 minutes
      ischemia), all of which were higher than that of the original method described by
      Pulsinelli et al. INTERPRETATION: In conclusion, this modified four-vessel
      occlusion method gives a high level of success in producing reversible forebrain
      ischemia.

PMID- 12478342
TI  - Contractile responses to reactive oxygen species in the canine basilar artery in
      vitro: selective inhibitory effect of MCI-186, a new hydroxyl radical scavenger.
AB  - BACKGROUND: Cerebral vasospasm is one of the important pathological phenomena
      which influence morbidity and mortality following subarachnoid haemorrhage.
      Reactive oxygen species (ROSs) generated by the autoxidation of oxyhemoglobin to
      methemoglobin may be one of the essential factors in the pathogenesis of cerebral
      vasospasm. The direct vasocontractile effects of hydrogen peroxide (H(2)O(2)),
      superoxide anion (O(2)(-)), and hydroxyl radical (*OH) on the canine basilar
      artery and the inhibitory effects of MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5
      one), a new *OH scavenger, were investigated. METHOD: Isometric tension was
      recorded in basilar artery rings from dogs in vitro. H(2)O(2), pyrogallol (O(2)(
      ) donor), and vitamin C (VitC)/Fe(2+) (*OH-generating system) were used to
      generate the ROSs. FINDINGS: H(2)O(2) (10 micromol/L), pyrogallol (10
      micromol/L), and VitC/Fe(2+) (100 micromol/L each) induced fast onset and
      transient, slow onset and transient, and sustained contraction, respectively, in
      the canine basilar artery. Contractions induced by H(2)O(2) were almost
      completely inhibited by pre-incubation with catalase (800 U/mL) and those by
      pyrogallol with superoxide dismutase (150 U/mL), but neither with MCI-186 (10
      micromol/L). The contraction induced by VitC/Fe(2+) was clearly inhibited by pre
      incubation with MCI-186, but not with catalase or superoxide dismutase.
      INTERPRETATION: ROSs have direct vasocontractile effects on the canine basilar
      artery in vitro, but different ROSs have different contractile characteristics.
      Such contractions might be related to the pathophysiology of cerebral vasospasm.
      MCI-186 had a clear and selective inhibitory effect against *OH-induced
      contraction in vitro. Comparison of different radical scavengers may be important
      in pharmacological assessment, especially targeted on cerebral vasospasm.

PMID- 12478343
TI  - Temporary cardiac asystolia induced by intraoperative irritation of the eighth
      right sided anterior cervical nerve root.
AB  - BACKGROUND: The 60 year old women with no prior history of arrhythmia or other
      cardiac symptoms was operated on for a cervical disc herniation at the level
      C7/D1. The C8 nerve root was visualized via a posterior approach. FINDINGS:
      Removal of the sequestrum and irritation of the anterior root with surgical
      instruments triggered cardiac arrest. INTERPRETATION: We offer the opinion that
      irritation of the anterior root led to diminished activity of the supraspinal
      sympathetic control system and consecutive hyper-activation of the
      parasympathetic system.

PMID- 12478344
TI  - Chondroblastoma of the temporal bone associated with a persistent hypoglossal
      artery.
AB  - A case of a chondroblastoma of the skull-base associated with a persistent
      hypoglossal artery (PHA) is presented. Neuroradiological findings of the PHA and
      the tumour are reported. The existence of a carotico-basilar communication such
      as a PHA should be recognized prior to skull base surgery because of the
      potential risk of cerebral ischemia.

PMID- 12478345
TI  - Enlargement of a vestibular schwannoma after stereotactic radiotherapy.
AB  - BACKGROUND: Radiosurgery has been increasingly advocated as a primary treatment
      for vestibular schwannoma (VS), and recently fractionation of the dose has been
      proposed as a method to decrease the risk of radiation injury when treating
      larger tumors. METHOD: The authors describe a 48-year-old woman who presented
      with right-sided hearing loss and new-onset tinnitus, with a progressive decrease
      in facial sensation. The diagnosis of a large right cerebellopontine angle VS was
      made on magnetic resonance imaging (MRI). The patient was treated with a course
      of fractionated stereotactic radiotherapy (SRT) (5 treatments of 4 Gy to the 90%
      isodose line over a 3-week period). FINDINGS: Six months after the initiation of
      therapy, her symptoms increased, and a repeat MRI scan demonstrated that her
      tumor had increased in size, producing significant brainstem compression. She
      then underwent complete surgical resection of the tumor, with resolution of her
      symptoms. INTERPRETATION: Stereotactic radiosurgery has been effective in
      controlling small VSs with low complication rates. Larger tumors pose a risk for
      increasing in size and producing symptoms from mass effect with SRT. There are at
      present limited data demonstrating safety and efficacy of fractionated SRT for
      the treatment of larger tumors.

PMID- 12478346
TI  - The microsurgical anatomy of the cisternal segment of the trochlear nerve, as
      seen through different neurosurgical operative windows.
AB  - OBJECTIVE: To describe the anatomy of the cisternal segment of the trochlear
      nerve as seen through different neurosurgical approaches. METHODS: The cisternal
      course of ten trochlear nerves was observed in five cadaveric embalmed heads,
      through the view afforded by the median infratentorial-supracerebellar, the
      extreme-lateral infratentorial-supracerebellar, and the combined presigmoid
      subtemporal transtentorial approaches. The relationships of the trochlear nerve
      with the surrounding neuro-vascular structures were analyzed. RESULTS: We
      identified 3 segments of the cisternal trochlear nerve: quadrigeminal, ambient
      and tentorial. The median infratentorial-supracerebellar approach allowed
      exposure of the quadrigeminal segment, including the origin of the nerve. The
      extreme-lateral supracerebellar and the combined presigmoid-subtemporal
      transtentorial approaches provided visualization of the ambient and tentorial
      segments of the nerve. The tentorial segment runs in a dural canal contained in
      the free edge of the tentorium, surrounded by its own arachnoidal sleeve.
      CONCLUSION: The trochlear nerve is a very delicate structure that can be easily
      injured during approaches to the tentorial incisura. Accurate knowledge of its
      anatomy as seen through different operative windows is helpful in maintaining its
      integrity during surgery.

PMID- 12478347
TI  - Megalin and cubilin, role in proximal tubule function and during development.
AB  - Epithelia lining the proximal convoluted epithelium and the visceral yolk sac in
      rodents are characterized by their ability to internalize and degrade many
      proteins facing their apical pole. It has become apparent over the last decade
      that this property is mediated through a very high endocytic activity and the
      expression of at least two distinct multiligand receptors, cubilin and megalin,
      characterized by the accumulation of ligand-binding units, LDL receptor class A
      repeats and CUB domains, respectively. We review here evidence that both
      receptors are involved in proximal tubule function and embryonic development.

PMID- 12478349
TI  - Insulin-like growth factor I administration in young rats with acute renal
      failure.
AB  - The outcome of ischemic acute renal failure (IARF) is better in young than adult
      rats. Insulin-like growth factor I (IGF-I) treatment may increase mortality of
      adult rats with IARF, probably because of an exaggerated inflammatory response.
      We report the response to IGF-I therapy in young rats with IARF. Male rats, aged
      28+/-1 days, with IARF were given subcutaneous IGF-I, 50 microg/100 g at 0, 8,
      and 16 h after reperfusion (IGF) or were untreated (ARF). Sham-operated rats were
      used as controls. At 2 and 7 days after ischemia, serum urea nitrogen and
      histological damage score, cell proliferation, apoptosis, neutrophil
      infiltration, and IGF-I receptor mRNA in kidneys were analyzed. The degree of
      renal failure, mortality rate, histological damage, cell proliferation, and
      neutrophil infiltration were not different between IGF-I and ARF rats. Hence,
      short-term IGF-I treatment did not modify the course of IARF in young rats.

PMID- 12478348
TI  - Nephron number and blood pressure in rat offspring with maternal high-protein
      diet.
AB  - This study investigated the effects of a high-protein diet during pregnancy on
      nephron endowment and subsequent levels of blood pressure in the offspring.
      Female WKY rats were fed either a normal (20%, NPD) or a high (54%, HPD) protein
      diet during pregnancy. Male offspring were paired at birth. At 4 weeks of age, 1
      of the pair was randomly chosen for perfusion fixation, and total glomerular
      number, and thereby nephron number, was estimated using an unbiased stereological
      technique. The other rat of the pair was allowed to grow to 30 weeks of age,
      during which time tail cuff systolic blood pressure was monitored twice weekly.
      There was no effect of the HPD on birth weight (NPD 4.23+/-0.53 g, HPD 4.26+/
      0.45 g, mean+/-SD), kidney weight (NPD 0.372+/-0.049 g, HPD 0.337+/-0.090 g), or
      total nephron number (NPD 27,191+/-3,512, HPD 26,738+/-4,735). Systolic blood
      pressure at 30 weeks was 170+/-14 mmHg in NPD and 169+/-14 in HPD offspring.
      These findings show that a HPD during pregnancy did not lead to an increase in
      birth weight, kidney weight, or nephron endowment, nor did the HPD affect adult
      blood pressure.

PMID- 12478350
TI  - Phenotypic and genotypic features of Alport syndrome in Chinese children.
AB  - Chinese Alport syndrome (AS) was analyzed in 44 unrelated patients who were
      screened for mutations in the COL4A5 gene by polymerase chain reaction (PCR)
      single-strand conformation polymorphism analysis or PCR direct sequencing in 30
      of the 44 patients. The clinical data showed that all patients had hematuria; 25
      of 29 male patients (86%) and 9 of 15 female patients (60%) had proteinuria; 11
      of 29 male patients (38%) and 1 of 15 female patients (7%) had nephrotic-level
      proteinuria; 10 of 21 male patients examined (48%) and 1 of 12 female patients
      examined (8%) had hearing abnormalities. Renal function remained normal despite
      hearing abnormalities, and ocular lesions occurred in 10%. Among 30 of 44
      patients who had a family history of end-stage renal disease (ESRD), 80% (24/30)
      belonged to X-linked juvenile kindreds, and 20% (6/30) patients to adult
      kindreds. Of the 44 patients, 14 did not have a family history of ESRD, while 11
      of 14 patients diagnosed with X-linked AS did. DNA analysis revealed four
      missense mutations, two silent mutations, one substitution, and one in-frame
      deletion. PCR along with Southern hybridization analysis revealed a large
      deletion of the paired COL4A5 and COL4A6 genes. Chinese AS patients were
      characterized clinically with hematuria, heavy proteinuria, and more juvenile
      forms. Mutations in these patients were usually small mutations, while a large
      deletion involving the 5' part of both COL4A5 and COL4A6 genes was identified.

PMID- 12478351
TI  - De novo HNF-1 beta gene mutation in familial hypoplastic glomerulocystic kidney
      disease.
AB  - Mutations in the gene encoding the transcription factor hepatocyte nuclear factor
      (HNF)-1 beta are associated with maturity-onset diabetes of the young (type V),
      non-diabetic renal disease, and occasionally genital malformations in females.
      Recently, familial hypoplastic glomerulocystic kidney disease (GCKD) has been
      added to the clinical spectrum of HNF-1 beta gene mutations. Familial hypoplastic
      GCKD is a rare, dominantly inherited disorder characterized by small kidneys
      containing glomerular cysts, abnormal pelvicalyceal anatomy, and chronic renal
      failure. A family with hypoplastic GCKD occurring in the father and the daughter
      was screened for mutations in the HNF-1 beta gene. The sequence of exon 4 of the
      HNF-1 beta gene revealed a C insertion at codon 334 resulting in a frameshift
      mutation (P334fsinsC) in two family members. The P334fsinsC allele co-segregated
      with hypoplastic GCKD in the family. Oral glucose tolerance testing was normal in
      the 11-year-old girl. In her 38-year-old father, impaired glucose tolerance was
      detected. These studies provide further evidence that familial hypoplastic GCKD
      is associated with HNF-1 beta gene mutations. HNF-1 beta gene mutation screening
      may prove useful in patients with small cystic kidneys and chronic renal failure,
      in whom a definite renal diagnosis could otherwise only be established by renal
      biopsy.

PMID- 12478352
TI  - ACE gene polymorphism and renal scarring in primary vesicoureteric reflux.
AB  - The objective of this study was to investigate whether mutations of the renin
      angiotensin system genes are involved in primary vesicoureteric reflux (VUR) and
      VUR-associated renal scarring. The M235T polymorphism of the angiotensinogen (
      ATG) gene, the I/D polymorphism of the angiotensin converting enzyme ( ACE) gene,
      and the A1166C polymorphism of the angiotensin II type 1 receptor ( AT1) gene
      were identified in 77 patients with primary VUR (aged 6.9+/-3.2 years, mean+/-SD)
      and 80 healthy controls (aged 33+/-7 years). Thirty-eight of the 77 VUR patients
      had low-grade VUR (grade I-III) and 39 had high-grade VUR (grade IV and V). Renal
      scarring was found in 43 VUR patients, while 34 patients had normal kidneys on
      dimercaptosuccinic acid scan. The ACE gene polymorphism was determined by
      polymerase chain reaction and the ATG and AT1 gene polymorphisms were determined
      by single-step LightCycler technology. We found significant over-representation
      of the DD genotype in patients with renal scarring (44 %) compared with normal
      controls (23%, P<0.05) and patients with no scar formation (21%, P<0.05).
      Significantly higher D and significantly lower I allele frequencies were present
      in VUR patients with scarred kidneys (D allele 0.64 and I allele 0.36) compared
      with controls (D allele 0.53 and I allele 0.47, P<0.05) and patients with
      unscarred kidneys (D allele 0.4 and I allele 0.6, P<0.05). No differences in the
      ATG and AT1 genotype distributions and allele frequencies were observed in VUR
      patients compared with the normal population. The DD genotype and D allele of ACE
      may be a genetic susceptibility factor contributing to scar formation in VUR. We
      detected no linkage of genetic polymorphisms of ATG and AT1 to VUR and VUR
      associated renal scarring.

PMID- 12478353
TI  - Prospective study of renal insufficiency after bone marrow transplantation.
AB  - Since more and more children survive allogeneic bone marrow transplantation
      (BMT), knowledge of acute and late complications becomes increasingly important.
      Besides the major complications [(opportunistic) infections, veno-occlusive
      disease, graft versus host disease, and recurrence of primary disease], acute and
      chronic renal insufficiency are significant post-transplant complications that
      may contribute to transplant-related mortality. To elucidate risk factors for
      acute and chronic renal insufficiency post BMT, we performed a prospective study
      of all 66 children who received a BMT in a 2-year period at our institution; 21%
      had acute renal insufficiency post BMT. Risk factors for acute renal
      insufficiency were veno-occlusive disease, high cyclosporin serum levels, and
      foscarnet therapy. Of surviving patients, 11% developed chronic renal
      insufficiency 1 year post BMT. Acute renal insufficiency was the sole predictor
      of chronic renal insufficiency. In contrast to studies in adults, we did not find
      total body irradiation to be a risk factor for chronic renal insufficiency.
      Future long-term studies are needed to assess incidence and morbidity of chronic
      renal insufficiency in children following allogeneic BMT.

PMID- 12478354
TI  - Microhematuria after renal transplantation in children.
AB  - The renal transplant (Tx) recipient is at risk for developing various
      complications including urolithiasis, the only manifestation of which may be
      hematuria. However, there are no data on the prevalence of microscopic hematuria
      in renal Tx recipients. The objective of our study was to determine the
      prevalence of microhematuria in our pediatric Tx patients and to investigate the
      causes of microhematuria. Records of all pediatric renal Tx recipients followed
      at our center from September 1999 to September 2000 were retrospectively
      reviewed; of the 21 patients, seven (33%) had persistent microscopic hematuria
      that was first noted 2.9 years post-Tx. Patients with and without hematuria had
      similar baseline characteristics. Only one patient had pre-existing hematuria
      that continued post-Tx. The etiology of hematuria in the other six patients was:
      recurrent IgA nephropathy (one patient), CMV nephritis (one patient), and
      unexplained (four patients). None had renal calculi or hypercalciuria. Three of
      the four patients with unexplained hematuria have chronic allograft nephropathy,
      and the fourth (original disease dysplasia) has hypocomplementemia. At their last
      follow-up, 5.3 years after onset of hematuria, all patients are alive with stable
      allograft function. In conclusion, microscopic hematuria is not uncommon in
      pediatric renal Tx recipients. While causes of post-Tx hematuria are diverse,
      stones are not commonly seen. Whether chronic allograft nephropathy per se can be
      implicated as a cause of hematuria remains to be determined. Renal biopsies
      should be considered at the onset of hematuria if proteinuria and/or
      deterioration in renal function are seen concomitantly, to look for recurrent or
      de novo glomerulonephritis.

PMID- 12478355
TI  - Anticardiolipin antibodies in D+ hemolytic uremic syndrome.
AB  - The diarrhea-associated form of the hemolytic uremic syndrome (D+ HUS) is
      characterized by a triad of symptoms, namely thrombocytopenia, hemolytic anemia,
      and acute renal failure. Histopathological studies of patients with D+ HUS show
      microthrombi in arterioles and glomeruli of the kidney. Recently, it was
      suggested that antiphospholipid antibodies might play a pathogenic role in D+
      HUS. However, an epiphenomenon could not be excluded. In this study we
      investigated the relationship between antiphospholipid antibodies and clinical
      symptoms in 22 patients with the classical form of HUS (D+ HUS). The first sample
      was obtained on the day of admission. The next samples were taken on day 7 and
      14. We measured anticardiolipin (aCL) antibodies (IgM, IgA, and IgG) in the
      samples using an ELISA. A significant increase in IgM (60%) and IgG (41%) aCL
      antibodies was seen in patients versus controls. No relationship between aCL
      antibody levels and severity of renal failure could be demonstrated. These data
      suggest that antiphospholipid antibodies are increased, but have not been shown
      to have a role in the pathogenesis of the microangiopathy seen in D+HUS.

PMID- 12478356
TI  - Platelet-activating factor and Escherichia coliO157:H7 infections.
AB  - The role of platelet-activating factor (PAF), a phospholipid inflammatory
      mediator, in Escherichia coli O157:H7-associated hemolytic uremic syndrome (HUS)
      is unknown. PAF is synthesized by diverse cells and is degraded by PAF
      acetylhydrolase (PAF-AH). Deficient PAF-AH activity results from a G-->T
      transversion at position 994 of exon 9. We examined children infected with E.
      coliO157:H7 to determine if PAF levels or the PAF-AH ( G994T) mutation reflects
      the risk of developing HUS. Plasma PAF concentrations were determined using
      chloroform/methanol extraction, thin layer chromatography purification, and
      scintillation proximity assay in 10 patients with uncomplicated infection (UI),
      10 infected patients who subsequently developed HUS (pre-HUS), 5 HUS patients,
      and 8 healthy controls. The PAF-AH ( G994T) allele frequency was determined in 52
      UI children, 15 with HUS, and 11 controls. Wilcoxon rank sum tests were performed
      to test differences in location (median) of pairs of groups. PAF levels were
      higher in the UI ( P=0.04) and pre-HUS ( P=0.01) groups than in healthy controls.
      No subject had the PAF-AH ( G994T) allele. Thus, elevated plasma PAF levels occur
      in E. coliO157:H7-infected children, even without HUS, but diminish when HUS
      develops. The PAF-AH ( G994T) allele does not contribute to the risk of
      developing HUS.

PMID- 12478357
TI  - Prophylactic heparinization is ineffective in a primate model of hemolytic uremic
      syndrome.
AB  - The presence of abundant fibrin within the glomerular capillaries of patients
      with Shiga toxin (Stx)-mediated (post-diarrheal) hemolytic uremic syndrome (HUS)
      has suggested that heparin anticoagulation might be useful in the treatment of
      this disease. Although controlled studies have failed to show benefit, this lack
      of therapeutic efficacy could be due to administration of heparin after the
      thrombotic microangiopathy (TMA) had developed. If benefit could be demonstrated
      by giving heparin prior to the onset of the HUS, one could consider prophylactic
      heparinization of those at high risk of progressing from Stx colitis to HUS. We
      have developed a baboon model of Stx-mediated HUS, and have used this model to
      study the effect of prophylactic heparinization on the clinical expression and
      glomerular TMA of Stx-mediated HUS. A single intravenous infusion of Stx-1 at a
      dose that uniformly produces clinical and nephropathologic features of HUS was
      given with and without the prior administration of regular and low molecular
      weight heparin. Therapeutic levels of anticoagulation were achieved, but this did
      not reduce the clinical severity or lessen the TMA. Heparin anticoagulation may
      be ineffective because the rate of coagulation that occurs on the surfaces of
      dysfunctional endothelial surfaces exceeds the capacity of heparin/antithrombin
      III inhibitor complexes to bind and block the factor Xa and thrombin that are
      generated on these surfaces. Our observations fail to support the use of heparin
      in preventing Stx-mediated HUS.

PMID- 12478358
TI  - Sensitivity of ultrasonography in detecting renal parenchymal defects in
      children.
AB  - Renal parenchymal defects (RPD) -- scars, hypoplasia/dysplasia -- in children are
      a major risk factor for chronic renal failure. Most authors would agree that RPD
      should be detected and followed by a 99mTc-dimercaptosuccinic acid renal scan
      (DMSA), as ultrasonography (US) does not seem to be sensitive enough for this
      purpose. However, it might well be that DMSA is too sensitive and detects RPD
      that are too small to be clinically significant. The purpose of this study was to
      evaluate the sensitivity of US in identifying patients with clinically
      significant RPD and in detecting RPD of various grades as seen by DMSA. In 89
      children with abnormal DMSA, a second DMSA, US, and other tests for evaluating
      renal function were performed at least 1 year after the first DMSA. The extent of
      RPD detected by DMSA and US was correlated with renal function parameters. In all
      5 patients with diminished renal function, RPD were detected by both DMSA scan
      and US. In addition, US detected clinically insignificant RPD in 48 of 67 cases
      (71.6%). The present study has shown that, compared with DMSA, US is sensitive
      enough to detect clinically significant RPD in children. The substitution of DMSA
      with US would be beneficial, as this would eliminate radiation exposure, reduce
      costs, and increase availability.

PMID- 12478359
TI  - Familial central diabetes insipidus detected by nocturnal enuresis.
AB  - A 10-year-old male referred to our clinic with the chief complaint of nocturnal
      enuresis also complained of daytime polyuria, frequency, and polydipsia. The
      clinical diagnosis was central diabetes insipidus. Since the patient's father had
      complained of similar symptoms, the arginine vasopressin-neurophysin II gene was
      examined. This revealed a single base substitution in one of two alleles in the
      patient, his father, and his grandfather (a C to T transition at nucleotide
      position 280 at codon 19 in the first exon). In conclusion, a history of polyuria
      or polydipsia should be carefully noted and the urinary volume and urine gravity
      or osmolarity examined in cases of nocturnal enuresis.

PMID- 12478360
TI  - Long-term survival of renal graft complicated with Burkitt lymphoma.
AB  - A 10-year-old boy with steroid-resistant nephrotic syndrome developed
      disseminated Burkitt lymphoma 2 years after renal transplantation. Treatment
      consisting of reduction of immunosuppression and polychemotherapy was initiated,
      and induced complete tumor remission. A severe cerebellar syndrome attributed to
      high-dose cytarabine occurred during treatment. The patient recovered partially
      from this complication. Immunosuppression had to be resumed 2 years later because
      of a chronic rejection. Finally, at last follow-up, the patient was alive with a
      stable creatinine of 180 micromol/l.

PMID- 12478361
TI  - Reversible secondary pseudohypoaldosteronism due to pyelonephritis.
AB  - We report a 5-week-old boy who developed severe hyponatremia and hyperkalemia
      secondary to acute pyelonephritis. The patient presented with non-specific signs,
      including poor appetite, failure to thrive, and dehydration. An endocrinological
      evaluation led to a diagnosis of pseudohypoaldosteronism. The patient had
      phimosis, but no congenital urinary tract malformations. Outflow obstruction
      secondary to the phimosis appears to have caused pyelonephritis, and renal
      inflammation decreased responsiveness to aldosterone transiently.

PMID- 12478362
TI  - Proliferation and differentiation of rat anterior pituitary cells.
AB  - Studies on the proliferation and differentiation of the cells in the rat anterior
      pituitary were reviewed. The mitotic rate of anterior pituitary is low in the
      control adult animal, but it increased by stimulation, such as by ablation of the
      target organ. A high mitotic rate was also reported during ontogenesis of the
      pituitary. Concomitant with this augmented mitosis, the number of those cells
      that are double-labeled with the marker of proliferation and the antibody to
      pituitary hormones increased as well. The percentage of these double-labeled
      cells in all the proliferating cells is less than 10%, suggesting that about 1/10
      of the proliferating cells are involved in producing pituitary cells. This
      percentage for GH cells is 30-40% at most, suggesting very active production of
      them. The percentage of the double-labeled cell in all the hormone-producing
      cells is within 10% in all cell-types of the pituitary, including GH cells. When
      the proliferation is detected by a more sensitive method, this percentage
      increased to 20-40%, suggesting that the self-mitosis of the pituitary cells
      contributes considerably to their proliferation at a certain period during their
      ontogenesis.

PMID- 12478363
TI  - Behavior of epithelial root sheath during tooth root formation in porcine molars:
      TUNEL, TEM, and immunohistochemical studies.
AB  - The behavior of epithelial cells during tooth root formation in porcine molars
      was investigated using TUNEL, immunohistochemical and transmission electron
      microscopic methods. Cells of Hertwig's epithelial root sheath (HERS) expressed
      bcl-2, but were TUNEL-negative. Epithelial cells of HERS were tightly connected
      and surrounded by a continuous basement membrane. When dental papilla cells were
      attached to the inner HERS, they became positive for osteopontin (OPN). The inner
      basement membrane was intermittent immediately after those cells started to
      synthesize dentin matrix, and the intercellular spaces of the HERS became wider.
      Dental sac cells then migrated between the fragmented HERS and were directly
      connected to epithelial cells by desmosome-like structures. After the cementum
      was synthesized by these mesenchymal cells, epithelial cells aggregated to form
      cell clusters, which were again surrounded by a continuous basement membrane.
      These results suggest that fragmentation of the HERS is due to the invasion of
      dental sac cells, but is not related to cell death. Furthermore, the
      differentiation of dental papilla cells into odontoblasts occurred following
      their connection to the HERS through the basement membrane. Moreover, it is
      suggested that the differentiation of dental sac cells into cementoblasts
      occurred upon their direct connection to epithelial cells of the HERS.

PMID- 12478364
TI  - Static and dynamic osteogenesis: two different types of bone formation.
AB  - The onset and development of intramembranous ossification centers in the cranial
      vault and around the shaft of long bones in five newborn rabbits and six chick
      embryos were studied by light (LM) and transmission electron microscopy (TEM).
      Two subsequent different types of bone formation were observed. We respectively
      named them static and dynamic osteogenesis, because the former is characterized
      by pluristratified cords of unexpectedly stationary osteoblasts, which
      differentiate at a fairly constant distance (28+/-0.4 microm) from the blood
      capillaries, and the latter by the well-known typical monostratified laminae of
      movable osteoblasts. No significant structural and ultrastructural differences
      were found between stationary and movable osteoblasts, all being polarized
      secretory cells joined by gap junctions. However, unlike in typical movable
      osteoblastic laminae, stationary osteoblasts inside the cords are irregularly
      arranged, variously polarized and transform into osteocytes, clustered within
      confluent lacunae, in the same place where they differentiate. Static
      osteogenesis is devoted to the building of the first trabecular bony framework
      having, with respect to the subsequent bone apposition by typical movable
      osteoblasts, the same supporting function as calcified trabeculae in endochondral
      ossification. In conclusion, it appears that while static osteogenesis increases
      the bone external size, dynamic osteogenesis is mainly involved in bone
      compaction, i.e., in filling primary haversian spaces with primary osteons.

PMID- 12478365
TI  - Glomerular differentiation in p27 and p57 double-mutant metanephroi.
AB  - The cell cycle inhibitors p27 and p57 are initially concurrently expressed at a
      critical point of glomerulogenesis and podocyte differentiation. The present
      study generated mice lacking both p27 and p57, in order to investigate the
      synergistic roles of these molecules in glomerular differentiation. It appeared
      that p27 and p57 double-mutant mice died between E16.5 and E18.5, before
      glomerular differentiation can take place. We harvested E13.5 metanephroi to
      advance the glomerulogenesis in a metanephric organ culture. Metanephroi of
      double-mutant and wild-type mice showed no great difference in size and shape at
      harvest or after 6 days in culture. Histology and morphometry revealed that
      average glomerular size in metanephroi from double-mutant mice was significantly
      larger than those in any other mutants. Larger glomeruli in double-mutant
      metanephroi are composed of an increased number of podocytes. The glomeruli in
      the double-mutant metanephroi expressed synaptopodin and WT-1 with the same
      pattern and intensity as those found in wild type. In addition, electron
      micrography showed the presence of foot processes and slit membrane in podocytes
      in double mutant. Western blot analysis of metanephroi after 6 days in culture
      showed an up-regulation of p21 protein in p27 mutant and double-mutant, but not
      in p57 mutant metanephroi. These findings suggest that p27 and p57 are
      synergistically involved, in part, to determine the number, but not the
      differentiation, in podocytes.

PMID- 12478366
TI  - Neuropeptide Y- and catecholamine-synthesizing enzymes: immunoreactivities in the
      rat carotid body during postnatal development.
AB  - Immunocytochemical studies of the rat carotid body during postnatal development
      revealed neuropeptide Y (NPY), tyrosine hydroxylase (TH), and dopamine beta
      hydroxylase (DBH) immunoreactivities. In adult rats (at postnatal week 10), NPY
      and DBH immunoreactivities were shown in a few small chief cells (cell
      number/section shown as mean +/- SD: NPY 3.4+/-2.6, DBH 3.2+/-2.3), in large
      ganglion cells, and in numerous varicose nerve fibers of the carotid body. TH
      immunoreactivity was found in almost all chief cells, in a few ganglion cells,
      and in numerous varicose nerve fibers in the carotid body. By using the double
      immunostaining technique, most NPY-immunoreactive chief cells, ganglion cells,
      and nerve fibers exhibited DBH immunoreactivity. The NPY- and DBH-immunoreactive
      chief cells in the rat carotid body were numerous from birth (NPY 93.8+/-14.9,
      DBH 89.7+/-12.3) to postnatal week 1 (NPY 65+/-14.5, DBH 61.6+/-11.3), but
      decreased quickly from postnatal week 2 (NPY 6.1+/-3.5, DBH 3.6+/-2.8) onwards. A
      few NPY- and DBH-immunoreactive ganglion cells were found in the periphery or in
      the center of the rat carotid body during postnatal development. TH
      immunoreactivity was observed in almost all chief cells and in a few ganglion
      cells in all developmental stages. NPY- and DBH-immunoreactive nerve fibers were
      very scarce in the carotid body from birth to postnatal week 1, began to increase
      gradually after postnatal week 2, and reached the adult level by postnatal week
      5. The present study suggests that the expression of NPY and noradrenaline in
      chief cells and in the nerve fibers of the rat carotid body may be regulated
      during postnatal development.

PMID- 12478367
TI  - Proteins in the extraembryonic matrix of preimplantation rabbit embryos.
AB  - Preimplantation embryos of several species are surrounded by an extraembryonic
      matrix (often simply named zona pellucida) until briefly before implantation. All
      signals of the early embryo-maternal dialogue have to pass this matrix and
      therefore are detectable inside. We investigated the protein pattern of the
      extraembryonic matrices of 3-6-day-old rabbit embryos by two-dimensional gel
      electrophoresis. Using (35)S-methionine incorporation, embryonic proteins were
      labelled and could be distinguished from maternal proteins. Furthermore, the
      presence of three different proteins (insulin-like growth factor-binding protein
      3, uteroglobin, haptoglobin) within the matrices of day-6 embryos was
      investigated by Western blot analysis. The pattern and numbers of protein spots
      detected was clearly dependent on the time of embryonic development. Of all
      proteins detected, 19.3% and 33% are of embryonic origin (day 5 and day 6,
      respectively). At day 4 the zona proteins are no longer detectable, reflecting
      the degradation of the zona pellucida. From day 4 to day 5 proteins detectable
      within the extraembryonic matrices increase enormously. This demonstrates that
      embryo-maternal signalling accelerates at least 2 days before implantation.
      Insulin-like growth factor-binding protein-3, uteroglobin and haptoglobin are
      part of the early signalling as shown by Western blot analysis. Insulin-like
      growth factor-binding protein-3 could be detected as one spot at 38 kDa pI 6.1,
      uteroglobin at 8 kDa pI 6.0 and haptoglobin as two spots/isoforms at 36/38 kDa pI
      5.8 and pI 6.0. These results demonstrate that extraembryonic matrices serving as
      a mailbox are a valuable tool for investigating early embryo-maternal signalling.

PMID- 12478368
TI  - Distribution of interstitial cells of Cajal and gap junction protein, Cx 43 in
      the stomach of wild-type and W/Wv mutant mice.
AB  - The distribution of different subtypes of interstitial cells of Cajal (ICC) in
      the tunica muscularis of the stomach of wild-type and W/W (v) mice was studied by
      immunohistochemical staining for Kit. Special attention was also given to the
      distribution of the gap junction protein connexin 43 (Cx 43) immunoreactivity.
      Kit-immunoreactive cells of the circular and longitudinal muscle layers (ICC-CM
      and ICC-LM) were densely distributed throughout the cardia, fundus, the squamous
      epithelial portion of the corpus and the pylorus, but they were decreased in
      number within the glandular epithelial portion of the corpus. Kit-immunoreactive
      cells of the myenteric region (ICC-AP) emerged slightly proximal to the squamous
      glandular epithelial transition and increased in number towards the pylorus. Kit
      positive cells were also observed at the submucosal border of the circular muscle
      layer (ICC-SM). ICC-CM and ICC-LM were not observed in the stomachs of W/W (v)
      mice, but a few ICC-AP were observed in the pylorus. Cx 43 immunoreactive
      deposits were only sparsely distributed in the circular muscle layers of the
      cardia, fundus and the squamous epithelial portion of corpus. However, the Cx 43
      immunoreactive deposits were densely distributed in the glandular epithelial
      portion of the corpus that contained fewer ICC-CM. Cx 43 immunoreactive deposits
      were rare in the circular muscle layer of the pylorus. No Cx 43 immunoreactivity
      was detected in the longitudinal muscle layer throughout the whole stomach. The
      distribution of Cx 43 immunoreactivity in the W/W (v) mouse stomach was almost
      the same as in wild-type mice. The functional significance of each type of ICC at
      each region is discussed in reference to regional differences in the distribution
      of both ICC and Cx 43, and differences between wild-type and W/W (v) mice.

PMID- 12478369
TI  - Mitoses of thyrotrophs contribute to the proliferation of the rat pituitary gland
      during the early postnatal period.
AB  - Development of thyrotrophs in the rat pituitary at 3, 7 and 10 days after birth
      was quantitatively studied by labelling the proliferating cells with
      bromodeoxyuridine (BrdU) and with the proliferating cell nuclear antigen (PCNA),
      and the immunostaining of thyrotrophs was applied to the same tissue section.
      Double administration of BrdU at 9:00 h and 19:00 h, increased the numerical
      volume density (Nv) of labelled cells by about 1.5-fold of that obtained with a
      single injection at 9:00 h. When PCNA was used to determine hyperplasia, the Nv
      of labelled cells further increased greatly. In accordance with these results,
      the Nv of the thyrotrophs that were also labelled with BrdU or PCNA increased
      likewise. These cells comprised 3-7% of all BrdU- or PCNA-labelled cells,
      indicating that about 1/20 of the proliferating cells are involved in producing
      new thyrotrophs. On the other hand, their percentage in all thyrotrophs was 8.8%,
      18.4% or 38.7% in 3-day neonates with single or double BrdU injections, or when
      PCNA was detected. These high percentages indicate a considerable contribution by
      the mitosis of already existing thyrotrophs to their proliferation in the early
      postnatal period.

PMID- 12478370
TI  - Tgfbeta2 -/- Tgfbeta3 -/- double knockout mice display severe midline fusion
      defects and early embryonic lethality.
AB  - Given all known biological activities, it is anticipated that transforming growth
      factors beta (TGF-betas) play important roles in many different developmental
      processes. As all three TGF-beta isoforms display overlapping expression
      patterns, deletion of one TGF-beta isoform might be compensated for by another.
      In the present study, targeted disruption of both Tgfbeta2 and Tgfbeta3 genes was
      undertaken to circumvent this problem and determine the essential roles of TGF
      beta2 and TGF-beta3 in vivo. Tgfbeta2(-/-) Tgfbeta3(-/-) double knockout mice and
      their three-allelic Tgfbeta2(-/-) Tgfbeta3(+/-) littermates display a lack of
      distal parts of the rib, a lack of sternal primordia, and failure in ventral body
      wall closure, leading to an extrathoracic position of the heart and extrusion of
      the liver. In addition, abnormalities in connective tissue composition and an
      early embryonic lethality [around embryonic day (E) 15.5] are seen. In contrast,
      Tgfbeta2 (+/-) Tgfbeta3 (-/-) littermates show normal rib and sternum
      development, normal anterior body wall fusion, and are still alive on E18.5. TGF
      beta2 is already known to play a role in skeletal and craniofacial development.
      The results presented here show that beyond this: (a). TGF-betas obviously play a
      fundamental role in midline fusion and (b). the Tgfbeta2 gene seems to play a
      more important role in mediating developmental processes than the Tgfbeta3 gene,
      since Tgfbeta2 (+/-) Tgfbeta3 (-/-) mutants - in contrast to their Tgfbeta2(-/-)
      Tgfbeta3 (+)(/-) littermates - do not display severe malformations.

PMID- 12478371
TI  - Developmental changes of synaptic proteins expression within the hippocampal
      formation of the rat.
AB  - A properly structured neuronal network, which is a prerequisite of a correctly
      functioning central nervous system, depends on the proper construction of
      synaptic terminals. There are some studies concerning development of hippocampal
      cells, however, the data about maturation of the synaptic terminals network
      within the hippocampal formation are only fragmentary. The study was performed on
      Wistar rats of various ages. The following synaptic proteins: synaptophysin, SNAP
      25 and GAP-43 (a growth axon cone protein) were used to study the maturation of
      synaptic terminals. We have found that, at the time of birth, the hippocampal
      formation is very immature. Synaptogenesis begins on P4 and lasts till P10 or
      P14. The strongest immunoreactivity of all proteins is observed at the beginning
      of this period. Thereafter, immunoreactivity decreases and, after P14, it is
      similar to that of adult animals. On P60 and P90, the level of immunoreactivity
      increases again. In the pyramidal and granular cell layers, the formation of
      synaptic terminals and their maturation occur earlier in embryonal life, and are
      almost completely mature at birth.

PMID- 12478372
TI  - GAP-43 Immunoreactivity in the brain of the developing and adult wallaby (
      Macropus eugenii).
AB  - We have examined the distribution of immunoreactivity for GAP-43 in the
      developing and adult brain of a diprotodontid metatherian, the tammar wallaby (
      Macropus eugenii). The distribution of GAP-43 immunoreactivity in the neonatal
      wallaby brain was strikingly heterogeneous, in contrast to that reported for the
      newborn polyprotodontid opossum. Immunoreactivity for GAP-43 in the developing
      wallaby brain showed a caudal-to-rostral spatiotemporal gradient, with the
      brainstem well in advance of the telencephalon throughout the first 100 days of
      postnatal life. In many regions examined, GAP-43 immunoreactivity passed through
      the following phases: 1. intense immunoreactivity in developing fiber tracts and
      occasional somata; 2. diffuse homogeneous immunoreactivity; 3. selective loss of
      immunoreactivity in particular nuclei or cortical regions. In the isocortex,
      selective loss of GAP-43 immunoreactivity in the somatosensory and visual cortex
      (at postnatal day 115) coincided with the maturation of the laminar distribution
      of terminal thalamocortical axonal fields. Within adult cortical regions, GAP-43
      immunoreactivity was highest in layer I of all regions, lower layers (V and VI)
      of primary somatosensory and visual cortices, layers II/III of motor and
      cingulate cortex, and layer IV of entorhinal cortex. Our findings suggest that,
      while patterning of GAP-43 immunoreactivity in the mature brain is similar across
      meta- and eutheria, there may be early developmental differences in the
      distribution of GAP-43 immunoreactivity between poly- and diprotodontid
      metatheria.

PMID- 12478373
TI  - Anatomical evidence for somatotopic maps in the zona incerta of rats.
AB  - We explore the patterns of connectivity between the zona incerta (ZI) and major
      centres of the somatosensory system in rats. Injections of cholera toxin subunit
      B (CTb) or biotinylated dextran (BD) were made into different somatosensory
      centres (Par1, FL and HL cortex; principal and spinal trigeminal nuclei;
      cervical, thoracic and lumbar spinal cord) of rats. Double injections of
      different coloured fluorescent dextrans (fluororuby and dextran-fluorescein) or
      BD and CTb (revealed with different chromogens) were also made into adjacent
      cortical regions (Par1 and FL). After injections into each of these somatosensory
      centres, a distinctive labelling pattern becomes apparent. Labelled terminals
      from centres representing the head (Par1, trigeminal nuclei) are found in the
      medial ZI, while labelled terminals from forelimb (FL, cervical spinal cord),
      trunk (thoracic cord) and hindlimb (HL, lumbar cord) centres are found in
      progressively more lateral areas of the nucleus. In general, rich terminal
      labelling is seen in the ZI after injections into the head and forelimb centres,
      while very poor labelling is seen after injections into the trunk and hindlimb
      centres. Our double injections show that adjacent but distinct cortical areas
      (Par1 and FL) occupy mainly separate territories in the ZI, but with some
      overlap. After each injection, from the cortex to the spinal cord, only a few
      labelled cells are seen. Our results indicate anatomical evidence for a
      somatotopic map within the ZI, with a preferential representation of the head and
      upper limbs. We suggest that the ZI may function to influence arousal states and
      orientating movements in relation to particularly active somatosensory inputs.

PMID- 12478374
TI  - In utero time-course assessment of mouse embryo development using high resolution
      magnetic resonance imaging.
AB  - Magnetic resonance microscopy, a non-invasive imaging technique was used for a
      longitudinal follow-up of mouse embryonic development in utero and for the
      assessment of embryonic kidney function using 50 nm magnetite dextran particles.
      Even though the morphologic proton images obtained were still far from classical
      histological slices quality, an in-plan resolution of 195 microm was achieved for
      a slice thickness of 800 microm. Mouse embryos sub-structures such as the fourth
      ventricle, the mesencephalic vesicle, the aorta or the liver can be revealed as
      early as E11/12. Heart, diaphragm, spinal cord, third, fourth and lateral
      ventricles were unambiguously seen at E13/14; whereas skeleton, tail, kidney and
      digit can only be seen from E15/16. Kidney and bladder were certainly identified
      from E16 on. MR microscopy offers a possibility for in utero phenotyping of mice
      and can therefore be a powerful tool for post-genomic applications.

PMID- 12478375
TI  - Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively
      regulates bone size and mass, but not density, in the absence and presence of
      growth hormone/IGF-I excess in transgenic mice.
AB  - Insulin-like growth factor-binding protein-2 (IGFBP-2) has been suggested to be a
      negative regulator of bone growth and maintenance. The objective of this study
      was to characterize the effect of elevated IGFBP-2 on the skeletal phenotype of
      adult transgenic mice, in the absence and presence of growth hormone (GH) excess.
      43 male mice were examined at an age of 4 months (7 IGFBP-2 transgenic mice, 12
      GH transgenic mice, 10 mice carrying both transgenes, and 14 controls). The bone
      mineral content of the total skeleton and of isolated bones was quantified by
      dual energy X-ray absorptiometry (DXA), after validation versus ash analysis.
      Cortical and trabecular bone was quantified by peripheral quantitative computed
      tomography (pQCT), after validation versus microCT. A strong linear relationship
      was found between DXA and ash weight, and between pQCT and micro CT ( r>0.95).
      Bone size and bone mineral content were significantly reduced in IGFBP-2
      transgenic mice, the magnitude of the effect varying between skeletal sites and
      between bone compartments. Elevated IGFBP-2 negatively modulated the GH
      stimulated increase in bone size and mineral content, and completely blocked GH
      effects at cortical sites. Notably, bone density was not decreased in IGFBP-2
      transgenic animals compared with controls. In conclusion, IGFBP-2 is identified
      as a potent negative regulator of normal and GH-stimulated bone growth in vivo.
      Interestingly, elevated IGFBP-2 levels did not lead to a decrease in bone
      density, suggesting that IGFBP-2 negatively affects bone size and mineral
      content, but not bone maintenance in adult mice.

PMID- 12478376
TI  - [Drainage systems in glaucoma surgery].
AB  - Glaucoma drainage devices, also known as aqueous shunts (AS) are widely used in
      the USA. They consist of a silicone tube that is inserted into the anterior
      chamber and connected to a plate made of silicone or polypropylene, the explant.
      The latter is positioned between the recti muscles and over several weeks the
      surrounding tissue forms a fibrous bleb around the plate. This serves as a
      permanent filtration reservoir.Recurrent failure of filtrating surgery is the
      main indication for the use of AS. Other indications include situations in which
      the formation of a filtering bleb seems to be unpromising because of extensive
      conjunctival scarring. Qualified success has been achieved for many years in 50
      100% of the eyes treated depending on patient selection. The most serious
      complication is postoperative hypotonia that can lead to serious chorioidal
      detachment, suprachorioidal hemorrhage, flat anterior chamber and corneal
      decompensation. To avoid this complication some devices, i.e.the Ahmed Glaucoma
      and the Krupin valve have integrated mechanisms to sustain a residual intraocular
      pressure. With other devices i.e. the Molteno and the Baerveldt devices, the tube
      has to be temporarily ligated until bleb formation has started. On the other hand
      fibrous infiltration of the bleb 1-4 months after the surgery often leads to a
      reversible rise in introcular pressure, which can be treated by massaging the
      bulbus, needling the bleb or injection of antimetabolites. There are no obvious
      differences between the various forms of AS with regard to the success of
      pressure regulation. In summary,by close scrutiny of indications and management
      of complications,drainage systems are a useful option in the management of
      complicated glaucoma that carry a high risk of failure from conventional
      filtering surgery.

PMID- 12478377
TI  - [Filtering bleb revision. Techniques and outcome].
AB  - BACKGROUND: The surgical management and outcome of bleb-related complications
      such as leaking blebs,overfiltration and blebitis are reported. METHODS: A
      retrospective analysis was carried out of 35 patients who underwent surgical
      repair of the filtering bleb in our hospital between 1991 and 2000. RESULTS:
      Surgical techniques used were autologous blood injection, fibrin glue injection,
      conjunctival suturing, resuturing of the trabeculectomy flap, bleb excision,
      conjunctival advancement, lyodura and tenon patching. In the eyes with leaking
      blebs the mean preoperative intraocular pressure (IOP) was 11.6+/-10.3 mmHg.
      After an average followup of 12 months the IOP was 11.9+/-3.3 mmHg. In the eyes
      with overfiltration the mean IOP was 2.4+/-1.5 mmHg and after an average follow
      up of 18 months the mean IOP increased to 13.5+/-3.7 mmHg. In 77.1% the IOP was
      regulated between 8 and 21 mmHg without glaucoma medication. Mean visual acuity
      improved by 3.6+/-5.9 lines postoperatively. CONCLUSION: Surgical bleb revision
      has a high success rate with regard to maintaining a functioning filtering bleb
      and to preserving vision.

PMID- 12478378
TI  - [Endophthalmitis following cataract surgery].
AB  - BACKGROUND: Infectious endophthalmitis is a serious complication following
      cataract surgery, since it often induces a substantial reduction of visual
      acuity. PATIENTS AND METHODS: We retrospectively evaluated the clinical data of
      53 patients with endophthalmitis following cataract surgery who were treated at
      the department of ophthalmology of the University Hospital in Ulm between 1995
      and May 2001. Of these patients, 50 had been referred. Clinical presentation,
      infecting organism, treatment and visual outcome were analysed with a followup
      ranging from 2 weeks up to 42 months (median: 6 months). RESULTS: In 52 patients
      endophthalmitis was preceeded by cataract extraction and IOL implantation, in one
      case by secondary IOL implantation. Confirmed microbiologic growth was
      demonstrated from intraocular specimens in 26 out of 41 operated eyes (63%), the
      most frequent causative organisms were coagulase-negative Staphylococci (50%).
      All isolated bacteria were sensitive to a combination of the antibiotics
      vancomycin and amikacin or vancomycin and ceftazidime. 13 patients were treated
      with intravenous antibiotic therapy alone. In 46% of patients, who were initially
      treated with intraocular antibiotic injections alone, required further
      therapeutic intervention for recurrent infection. Only 7.7% of the patients who
      initially underwent intraocular antibiotic injections combined with IOL removal
      or pars plana vitrectomy with or without IOL removal, required further surgical
      intervention. Initial visual acuity was hand movements (median) only but improved
      during follow-up to 0.2 (median). CONCLUSIONS: In this series all tested bacteria
      were susceptible to the combination of vancomycin with either amikacin or
      ceftazidime. Aggressive initial treatment including IOL removal may be associated
      with a lower frequency of recurrent disease.

PMID- 12478379
TI  - [Intracanalicular trabeculostomy with the Er:YAG laser].
AB  - PURPOSE: To develop a new ab externo technique for glaucoma trabecular surgery
      using the infrared Er:YAG laser radiation (2.9 micrometer) guided into Schlemm's
      canal by an optical fiber. MATERIAL AND METHODS: In order to create a drainage
      canal to the anterior chamber, a quartz fiber (core diameter: 100 micrometer)
      coupled to an Er:YAG laser was shielded by a metal canula (diameter: 280
      micrometer) bent in conformance to the curvature of Schlemm's canal. A 45 degrees
      -mirror enabled the laser radiation to exit the canula perpendicular to the fiber
      axis. The complete surgery device was tested on agar medium and enucleated human
      eyes. RESULTS: Using the unshielded quartz fiber, eight pulses of 8 mJ
      (frequency: 7 Hz, pulse duration: 150 microseconds) were sufficient to perforate
      the trabecular meshwork of the human eye. Histology showed a rippled canal with
      50 micrometer average diameter and a surrounding necrosis zone of 15-35
      micrometer. The complete device could be easily inserted into Schlemm's canal
      similar to the classic trabeculostomy probe and a conical-shaped canal with a
      length of 2-3 mm could be created in agar medium within a few seconds.
      CONCLUSIONS: Initial experience in an experimental set-up show the ab externo
      creation of a draining canal between Schlemm's canal and the anterior chamber
      with only minimal irritation of the surrounding tissue. Further refinements of
      the laser parameters and the biomechanical set-up resulted in a new hand-held
      device with improved function. The Er:YAG laser intracanalicular trabeculostomy
      could become a new ab externo technique for minimal invasive therapy of open
      angle glaucoma.

PMID- 12478380
TI  - [KTP laser in lacrimal duct surgery].
AB  - PURPOSE: The use of endoscopic methods of examination and treatment has brought
      new possibilities for non-invasive techniques in lacrimal surgery. The
      possibilities of the use of a PTP (potassium-titanium-phosphate) laser system are
      shown. METHOD: The use of a PTP laser for external dacryocystorhinostomy (DCR) as
      well as for transcanicular methods when connected to an endoscope are shown.
      RESULTS: With a PTP laser it is possible to make a very precise hole in the bone
      which simplifies the preparation of the nasal mucosal flap. Endocanalicular
      procedures for performing laser dacryoplasty with rechanneling of the lacrimal
      system is possible and examples are demonstrated. DISCUSSION: The high output of
      a PTP laser of up to 10 W makes a precise preparation of the bone hole for DCR
      possible. The endoscopic connection opens the possibility of an endocanicular use
      but the high energy output means that increased scar tissue formation is to be
      expected.

PMID- 12478381
TI  - [Bioptic. A refractive surgery procedure for correction of high and extreme
      myopia].
AB  - BACKGROUND: The complete correction of highly or extremely myopic eyes to
      emmetropia can only be achieved by very few procedures: The combination of
      implanting phacic intraocular lenses and the use of LASIK (laser in-situ
      keratomileusis) - Bioptic - makes it possible to achieve this goal to a great
      extent. PATIENTS AND METHODS: The Bioptic procedure was carried out on 17 eyes of
      10 patients. Two weeks after corneal dissection with the Hansatom,an implantable
      phacic lens (STAAR) was introduced into the posterior chamber and 4 weeks later
      the residual myopia was treated with LASIK combined with the correction of
      astigmatic errors. The follow-up time was 10.2 (6.7) months. RESULTS:
      Preoperative average values of the manifest refraction were -16.22 sph (3.86)
      with 1.40 cyl (1.30) which changed to -3.85 sph (2.73) with -1.50 cyl (0.87)
      after implantation of an ICL trade mark into the posterior chamber. Visual acuity
      increased from uncorrected hand motion to 0.13 (0.10) and corrected from 0.53
      (0.19) to 0.63 (0.19). The refraction of implanted ICLs trade mark was 14.6 dpt
      (1.1). Following the LASIK procedure the uncorrected visual acuity improved to
      0.68 (0.16) and fully corrected to 0.79 (0.20). The final refraction measured
      +0.16 sph (0.67) with -0.48 cyl (0.25). The keratectomy depth was 80.63 -m (26.9)
      and the optical zone showed a horizontal distance of 6.28 mm (0.39). CONCLUSION:
      Bioptic is able to correct highly and extremely myopic eyes with the combination
      of phacic lenses and subsequent LASIK. A concomitant astigmatism can be corrected
      up to 2.5 dpt simultaneously. With the combination of both procedures,the optical
      zone can be enlarged. Keeping in mind that phacic lenses reveal a constant
      refraction after a few days and also that LASIK is refractively safe in low
      myopia of -4 dpt to -5 dpt, it can be expected that the refractive deviation
      following the Bioptic procedure is low.

PMID- 12478382
TI  - [Adjustment of eye muscle surgery dosage under drop anaesthesia in patients with
      Grave's orbitopathy].
AB  - BACKGROUND: Motility restrictions of the eye muscles represent a common and
      serious impairment for patients with Grave's orbitopathy. Various surgical
      approaches have been developed for the rehabilitation of these patients. In this
      study 64 patients in which only one of the rectus inferior muscles was recessed
      are presented. METHOD: The recession was performed using drop anaesthesia. The
      active cooperation of the patients was necessary for adjustment of the dosage so
      that undercorrections or more important overcorrections could be prevented.
      Indications for this recession were a constant diplopia, an abnormal head
      posture, a pseudoretraction of the upper eyelid or corneal scarring
      complications. RESULTS: In all patients the squint angle was significantly
      reduced. A statistical mathematical correlation between the intraoperatively
      chosen recession length and the reduction of squint angle was found. On the other
      hand, the variance of the effect of the operation was so large that no dosage
      recommendations could be made. This operation technique seems to be able to avoid
      overcorrections (9.3%) for the majority of patients and only a small group of
      them presented diplopia postoperatively (10.9%). CONCLUSIONS: These results show
      a good functional rehabilitation of our patients. Performing the operation under
      drop anaesthesia, while taking into account the motility situation, seems to be a
      good method in order to manage the dosage problems presenting in this clinical
      entity.

PMID- 12478383
TI  - [Excimer laser treatment in deep lamellar keratoplasty 100 micrometer over
      Descemet's membrane].
AB  - BACKGROUND: Possible improvements of best corrected visual acuity (BCVA) and the
      stability of the endothelium in deep lamellar keratoplasty (DLKP) assisted by
      Excimer laser polishing were evaluated. PATIENTS AND METHODS: A 59-year-old male
      patient was treated 1 year after DLKP with the intention of improving is BCVA.
      Excimer laser treatment was performed on the deep layers of the graft and on the
      posterior lamellae of the recipient's cornea 100 micrometer over the endothelium.
      RESULTS: BCVA improved from 20/100 to 20/22 within 9 months. Refraction remained
      identical pre- and post-laser treatment at +1.25 sph=-2.0 cyl/17 degrees The
      endothelium remained unchanged with regard to its cell count of 2,100 cells/mm(2)
      and the normal morphology. CONCLUSION: Smoothing of the interface by Excimer
      scanning laser treatment may be recommended in such cases of DLKP in which
      postoperatively the resulting visual acuity does not correspond to the retinal
      resolution. Use of scanning or flying-spot lasers are the prerequisite for the
      maintenance of the endothelium.

PMID- 12478384
TI  - [Autologous serum-eye-drops for ocular surface disorders. A literature review and
      recommendations for their application].
AB  - The natural tear film has mechanical, optical, antimicrobial and nutritional
      properties. Tear film components, such as EGF, fibronectin and vitamin A, play a
      vital role in the proliferation, migration and differentiation of the corneal and
      conjunctival epithelium. In ocular surface disease, such as severe dry eye, the
      epithelia may be depleted of these nutritional factors. Replacing the aqueous
      component of tears alone,by using pharmaceutical tear substitutes,often has
      little effect on the ocular surface.Eye-drops prepared from autologous serum are
      a new treatment option for severe ocular surface disease. They can be produced
      according to the regulations on drug use as an unpreserved blood preparation.
      Autologous serum eye-drops are non-allergenic and their biomechanical and
      biochemical properties are similar to normal tears. In cell culture experiments,
      serum was found to be superior to preserved or unpreserved pharmaceutical
      products in the maintenance of human keratinocyte morphology and function. It
      supports the migration of corneal epithelial cells and the differentiation of
      conjunctival epithelial cells. The first clinical cohort studies report its
      successful use for severe dry eyes and persistent epithelial defects. In these
      studies, however, varying methods for the preparation and different
      concentrations of autologous serum eye-drops were used. These methodological
      variations determine the biochemical properties and thus the epitheliotrophic
      effect of serum eye-drops. In this review we summarise the currently available
      clinical evidence, discuss relevant legislatory restrictions and describe a
      standard operating protocol for the use of serum eye drops. This has to be
      evaluated and optimised in more detail before any meaningful, randomised,
      controlled trial can attempt to establish the role of serum eye-drops in the
      management of severe ocular surface disease.

PMID- 12478385
TI  - [Patient compliance in glaucoma therapy].

PMID- 12478386
TI  - Prospects for functional genomics in Schizosaccharomyces pombe.
AB  - Schizosaccharomyces pombe is well established as an experimental organism for
      basic research, with well developed technologies for molecular biology, genetics
      and cell biology. Its full genome sequence has recently been published. Here, the
      prerequisites for functional genomics studies in Sch. pombe are examined and
      compared with those of some established prominent functional genomics model
      organisms, especially Saccharomyces cerevisiae. It is argued that functional
      genomics studies in certain areas of cellular and molecular biology could
      potentially be more efficiently performed in Sch. pombe than in most other
      experimental organisms.

PMID- 12478387
TI  - Mutation of TRS130, which encodes a component of the TRAPP II complex, activates
      transcription of OCH1 in Saccharomyces cerevisiae.
AB  - The Saccharomyces cerevisiae Och1p is required for the initiation of the mannose
      outer chain elongation of cell wall mannoproteins. A trs130(ts1) mutant that
      showed an elevated expression of the OCH1-reporters was isolated in our
      laboratory. In this study, we attempted to gain an understanding of the
      relationship between the defect in the Trs130p function and the elevated
      expression of OCH1. The trs130(ts1) mutant showed calcofluor white-resistant and
      hygromycin B-sensitive phenotypes, indicating that the mutant is defective in
      cell wall integrity. YPT31 and YPT32, the multi-copy suppressors of the
      trs130(ts1) mutant, differed in the extent of suppression of the mutant
      phenotypes and in their genetic interaction with TRS130. Our results suggest that
      the blocking of vesicle transport by a loss of the Trs130p function causes some
      defect in the cell wall mannoproteins, which leads to the elevated expression of
      OCH1 through the Skn7p function, to compensate for the defect.

PMID- 12478388
TI  - The mitochondrial genome can be altered or lost without lethal effect in the
      petite-negative yeast Debaryomyces (Schwanniomyces) occidentalis.
AB  - The nature of mutations affecting several cytochrome-deficient mutants of
      Debaryomyces (Schwanniomyces) occidentalis has been characterized. The DR12
      mutant, which is deficient in cytochrome b, and the B10Mn mutant, which is
      deficient in cytochromes b and a, a3, are deleted in the mitochondrial CYB and
      COX1 genes respectively. The B10 strain, which is partially deficient in
      cytochrome b, has no detectable change in its mitochondrial DNA and possibly
      carries nuclear lesion(s). These three mutants, unlike the rho(-) and rho degrees
      "petite" mutants of Saccharomyces cerevisiae, can still grow on non-fermentable
      substrates, due to the development of a salicylhydroxamic acid (SHAM)-sensitive
      alternative pathway linked to phosphorylation at site 1. A gly(-) mutant lacking
      mtDNA and respiratory capacity has been isolated. For the first time, it is
      demonstrated that mtDNA can be altered or even lost without lethal consequence in
      D. occidentalis, although this yeast was classified as a petite-negative species.

PMID- 12478389
TI  - A Blumeria graminisf.sp. hordei BAC library--contig building and microsynteny
      studies.
AB  - A bacterial artificial chromosome (BAC) library of Blumeria graminis f.sp.
      hordei, containing 12,000 clones with an average insert size of 41 kb, was
      constructed. The library represents about three genome equivalents and BAC-end
      sequencing showed a high content of repetitive sequences, making contig-building
      difficult. To identify overlapping clones, several strategies were used: colony
      hybridisation, PCR screening, fingerprinting techniques and the use of single
      copy expressed sequence tags. The latter proved to be the most efficient method
      for identification of overlapping clones. Two contigs, at or close to avirulence
      loci, were constructed. Single nucleotide polymorphism (SNP) markers were
      developed from BAC-end sequences to link the contigs to the genetic maps. Two
      other BAC contigs were used to study microsynteny between B. graminis and two
      other ascomycetes, Neurospora crassa and Aspergillus fumigatus. The library
      provides an invaluable tool for the isolation of avirulence genes from B.
      graminis and for the study of gene synteny between this fungus and other fungi.

PMID- 12478390
TI  - Expression regulation of the endochitinase chit36 from Trichoderma asperellum (T.
      harzianum T-203).
AB  - The presence of the endochitinase CHIT36 from Trichoderma harzianum TM was
      assessed in several antagonistic Trichoderma strains belonging to different
      molecular taxonomic groups. CHIT37 from T. harzianum CECT 2413 was sequenced and
      found to display 89% homology with CHIT36 at the amino acid level. Northern
      analysis showed that chit36Y from T. asperellum is regulated both by glucose and
      nitrogen levels. Stress conditions, colloidal chitin and N-acetyl-glucosamine are
      effective inducers of this gene. The promoter of chit36Y was cloned and was used
      to direct expression of a gfp reporter gene in Trichoderma transformants.
      Confrontation experiments with the plant pathogen Rhizoctonia solani revealed
      that direct contact between the fungi is not necessary for gfp expression. The R.
      solani-inducing factor appears to be a soluble molecule capable of diffusing
      through a dialysis membrane (<12 kDa). CHIT36 recombinant protein from the yeast
      Pichia pastoris was active against different phytopathogens, confirming the
      importance of this endochitinase in the mycoparasitic activity of Trichoderma
      antagonistic strains.

PMID- 12478391
TI  - Efficient gene identification and targeted gene disruption in the wheat blotch
      fungus Mycosphaerella graminicola using TAGKO.
AB  - TAGKO ( transposon- arrayed gene knock out) is a highly efficient method for gene
      discovery and gene function assignment in the rice blast fungus Magnaporthe
      grisea. Here, we report the application of genome-wide TAGKO to the wheat blotch
      fungus Mycosphaerella graminicola, including the successful development of
      electroporation-based transformation for this fungus. A M. graminicola genomic
      cosmid library was constructed and a pool of 250 cosmid clones was mutagenized by
      in vitro transposition. Sequence analysis identified 5,110 unique insertion
      events in the M. graminicola genome. Eleven transposon-tagged cosmid clones
      (TAGKO clones) were chosen and transformed into the wild-type strain by
      electroporation. Ten TAGKO clones out of 11 produced gene-specific mutants at a
      targeting frequency of 15-28%, significantly higher than that of conventional
      gene-disruption constructs. The remaining clone failed to produce viable mutants,
      thereby providing indirect evidence for the identification of an essential gene.

PMID- 12478392
TI  - Transcranial magnetic stimulation: new insights into representational cortical
      plasticity.
AB  - In the last decade, transcranial magnetic stimulation (TMS) has been used
      increasingly as a tool to explore the mechanisms and consequences of cortical
      plasticity in the intact human cortex. Because the spatial accuracy of the
      technique is limited, we refer to this as plasticity at a regional level.
      Currently, TMS is used to explore regional reorganization in three different
      ways. First, it can map changes in the pattern of connectivity within and between
      different cortical areas or their spinal projections. Important examples of this
      approach can be found in the work on motor cortex representations following a
      variety of interventions such as immobilization, skill acquisition, or stroke.
      Second, TMS can be used to investigate the behavioural relevance of these
      changes. By applying TMS in its "virtual lesion" mode, it is possible to
      interfere with cortical function and ask whether plastic reorganization within a
      distinct cortical area improves function. Third, TMS can be used to promote
      changes in cortical function. This is achieved by using repetitive TMS (rTMS) to
      induce short-term functional reorganization in the human cortex. The magnitude
      and the direction of rTMS-induced plasticity depend on extrinsic factors (i.e.
      the variables of stimulation such as intensity, frequency, and total number of
      stimuli) and intrinsic factors (i.e. the functional state of the cortex targeted
      by rTMS). Since conditioning effects of rTMS are not limited to the stimulated
      cortex but give rise to functional changes in interconnected cortical areas, rTMS
      is a suitable tool to investigate plasticity within a distributed functional
      network. Indeed, the lasting effects of rTMS offer new possibilities to study
      dynamic aspects of the pathophysiology of a variety of diseases and may have
      therapeutic potential in some neuropsychiatric disorders.

PMID- 12478393
TI  - Movement-related changes in cortical oscillatory activity in ballistic, sustained
      and negative movements.
AB  - We studied movement-related EEG oscillatory changes in the alpha, beta and low
      gamma frequency bands in three different paradigms of movement, namely ballistic,
      sustained, and negative (muscle relaxation). A time-frequency analysis of non
      phase-locked activity in the 7-47 Hz range was performed on movement-centred EEG
      sweeps using wavelet filters and Gabor transforms. All three movements were
      accompanied by a decrease in beta activity that began contralaterally about 1.5 s
      prior to the onset of movement but that extended to both sides near the beginning
      of the movement. This decrease was followed by a rebound after the end of the
      movement in the ballistic and negative movements. A decrease was also seen in the
      alpha band during the three paradigms, which began later (1 s before movement)
      and lasted longer. An increase in gamma activity was only seen during ballistic
      and sustained movements, while a decrease in gamma energy was observed during
      negative movements. It was concluded that changes in the beta band of the EEG
      before movement are related to the preparation for the movement, but an important
      afferent component may be present in the later changes. Gamma band activity may
      be just involved in the execution of the movement, related to muscle contraction.

PMID- 12478394
TI  - Crossmodal and intermodal attention modulate event-related brain potentials to
      tactile and auditory stimuli.
AB  - An increasing number of animal and human studies suggests that different sensory
      systems share spatial representations in the brain. The aim of the present study
      was to test whether attending to auditory stimuli presented at a particular
      spatial location influences the processing of tactile stimuli at that position
      and vice versa (crossmodal attention). Moreover, it was investigated which
      processing stages are influenced by orienting attention to a certain stimulus
      modality (intermodal attention). Event-related brain potentials (ERPs) were
      recorded from 15 participants while tactile and auditory stimuli were presented
      at the left or right side of the body midline. The task of the participants was
      to attend to either the auditory or to the tactile modality, and to respond to
      infrequent double-stimuli of either the left or right side. Results showed that
      spatial attention modulated both early and late somatosensory and auditory ERPs
      when touch and tones were relevant, respectively. Moreover, early somatosensory
      (N70-100, N125-175) and auditory (N100-170) potentials, but not later
      deflections, were affected by spatial attention to the other modality, suggesting
      bi-directional crossmodal links between hearing and touch. Additionally, ERPs
      were modulated by intermodal selection mechanisms: stimuli elicited enhanced
      negative early and late ERPs when they belonged to the attended modality compared
      to those that belonged to the unattended modality. The present results provide
      evidence for the parallel influence of spatial and intermodal selection
      mechanisms at early processing stages while later processing steps are restricted
      to the relevant modality.

PMID- 12478395
TI  - Intermanual transfer of procedural learning after extended practice of
      probabilistic sequences.
AB  - Previous studies using simple, repeating patterns have suggested that the
      knowledge gained in early sequence learning is not effector-specific in that it
      transfers to muscle groups other than those used during training. The current
      experiments extended these findings to transfer after extensive practice with
      probabilistic sequences using a task on which people fail to gain declarative
      knowledge of the regularity. Specifically, an alternating serial reaction time
      (ASRT) task was used in which predictable and unpredictable trials alternated.
      Participants responded for the first five sessions using their right hand, then
      switched to the left hand for the sixth session. Stimuli were spatial in the
      first experiment and nonspatial in the second. Significant near-perfect transfer
      of pattern knowledge was seen in both experiments, suggesting that muscle
      specific information for either the fingers or the eyes cannot explain the
      observed learning.

PMID- 12478396
TI  - The control of foot force during pushing efforts against a moving pedal.
AB  - The muscle component of the force applied to a bicycle pedal (foot force) by
      seated humans provided insight into the organization of the motor system. Healthy
      adults ( n=11) pedaled a stationary cycle ergometer while attempting to match
      peak foot force magnitude to visually presented force targets (200, 250,., 650
      N). Pedaling cadence was maintained at 60 rpm by a motor. Measurements of the
      foot force, pedal angle, and crank angle were recorded. The experimental design
      and data analysis allowed the isolation of the muscle component of the foot force
      from the contributions due to gravity and inertia. A graphical representation of
      the muscle component of the foot force (force path) was created for each of
      several crank angles throughout the extension phase of the pedaling cycle. The
      force paths showed several highly conserved characteristics across participants
      and crank angles. Each force path occupied a narrow range in force space despite
      the ability of the participants to produce force in a wide region of force space.
      Three control strategies were observed in the geometry of the force paths. Eighty
      five percent of the force paths were linear for six of the participants, and 79%
      of the force paths had second-order curvature for the other five participants.
      The curvature was concave to the posterior for four of the participants and
      concave to the anterior for one participant. The linear force paths were
      consistent with the previously reported linear nature of the force paths for
      pushes against a quasi-static pedal. The observation of simple force path
      geometry for two tasks with dissimilar dynamic characteristics suggests that this
      aspect of foot force control may be common to a range of lower limb tasks and may
      reflect a mechanism by which the nervous system organizes the control of foot
      force.

PMID- 12478397
TI  - Directional invariance during loading-related modulations of muscle activity:
      evidence for motor equivalence.
AB  - In the present study, we investigated the influence of external force
      manipulations on movements in different directions, while keeping the amplitude
      invariant. Subjects ( n=10) performed a series of cyclical anteroposterior,
      mediolateral, and oblique line-drawing movements (star drawing task) with their
      dominant limb in the horizontal plane. To dissociate kinematics from the
      underlying patterns of muscle activation, spring loading was applied to the
      forearm of the moving limb. Whereas spring loading of the arm resulted in
      considerable changes in the overall amount of muscle activation in the elbow and
      shoulder muscles, invariance was largely maintained at the kinematic level.
      Subjects produced the required movement directions and amplitudes of the star
      drawing largely successfully, irrespective of the force bias induced by the
      spring. These observations demonstrate motor equivalence and strengthen the
      notion that the spatial representation of drawing movements is encoded in the
      higher brain regions in a rather abstract form that is dissociated from the
      concrete muscle activation patterns underlying a particular movement direction.
      To achieve this goal, the central nervous system shifted between two or more
      muscle grouping strategies to overcome modulations in the interaction among
      posture-dependent (joint stiffness), dynamic (inertial), and elastic (spring)
      torque components in the joints. Spring loading induced general changes in the
      overall amount of EMG activity, which was largely muscle but not direction
      specific, presumably to represent the posture-dependent biasing force of the
      spring. Loading was mainly shown to increase muscle coactivation in the elbow
      joint. This indicates that the subjects tended to increase stiffness in the elbow
      to compensate for changes in the spring bias forces in order to minimize
      trajectory errors. Changes in muscle grouping of the shoulder antagonists were
      mainly a consequence of movement direction but were also affected partly by
      loading, presumably reflecting the influence of dynamic force components. Taken
      together, the results confirmed the hypothesis that changes of movement direction
      and direction of force in the end-effector generated specific sets of muscle
      grouping to overcome the dynamic requirements in the joints while keeping the
      kinematics largely unchanged. This suggests that directional tuning in muscle
      activity and changes in muscle grouping reflects the formation of appropriate
      internal models in the CNS that give rise to motor equivalence.

PMID- 12478399
TI  - Nerve growth factor improves spatial learning and restores hippocampal
      cholinergic fibers in rats withdrawn from chronic treatment with ethanol.
AB  - The cholinergic septohippocampal pathway has long been known to be important for
      learning and memory. Prolonged intake of ethanol causes enduring memory deficits,
      which are paralleled by partial depletion of hippocampal cholinergic afferents.
      We hypothesized that exogenous supply of nerve growth factor (NGF), known to
      serve as a trophic substance for septal cholinergic neurons, can revert the
      ethanol-induced changes in the septohippocampal cholinergic system. Adult rats
      were given a 20% ethanol solution as their only source of fluid for 6 months.
      During the first 4 weeks after the animals were withdrawn from ethanol, they were
      intraventricularly infused with either NGF or vehicle alone via implanted osmotic
      minipumps. The vehicle-infused withdrawn animals showed impaired performance on a
      spatial reference memory version of the Morris water maze task, both during the
      task acquisition and on the retention test. In contrast, NGF-treated withdrawn
      rats were able to learn the task as well as controls, and significantly
      outperformed the vehicle-infused withdrawn rats. The histological analysis
      revealed that, in the latter group, the length density of fibers immunoreactive
      to choline acetyltransferase was reduced relative to control values by
      approximately 25%, as measured in the dentate gyrus and regio superior of the
      hippocampal formation. However, in NGF-treated withdrawn rats, the length density
      of these fibers was identical to that of control rats. These data provide support
      to the notion that NGF is capable of ameliorating memory deficits and restoring
      septohippocampal cholinergic projections following chronic treatment with
      ethanol.

PMID- 12478398
TI  - Prehension synergies: effects of object geometry and prescribed torques.
AB  - We studied the coordination of forces and moments exerted by individual digits in
      static tasks that required balancing an external load and torque. Subjects (
      n=10) stabilized a handle with an attachment that allowed for change of external
      torque. Thumb position and handle width systematically varied among the trials.
      Each subject performed 63 tasks (7 torque values x 3 thumb locations x 3 widths).
      Forces and moments exerted by the digit tips on the object were recorded.
      Although direction and magnitude of finger forces varied among subjects, each
      subject used a similar multidigit synergy: a single eigenvalue accounted for 95.2
      98.5% of the total variance. When task parameters were varied, regular conjoint
      digital force changes (prehension synergies) were observed. Synergies represent
      preferential solutions used by the subjects to satisfy mechanical requirements of
      the tasks. In particular, chain effects in force adjustments to changes in the
      handle geometry were documented. An increased handle width induced the following
      effects: (a). tangential forces remained unchanged, (b). the same tangential
      forces produced a larger moment T (t), (c). the increased T (t) was compensated
      by a smaller moment of the normal forces T(n), and (d). normal finger forces were
      rearranged to generate a smaller moment. Torque control is a core component of
      prehension synergies. Observed prehension synergies are only mechanically
      necessitated in part. The data support a theory of hierarchical organization of
      prehension synergies.

PMID- 12478400
TI  - Adaptation of arm trajectory during continuous drawing movements in different
      dynamic environments.
AB  - Human subjects can readily adapt their movement trajectories to different dynamic
      or visuomotor environments. The focus of the current study was to determine
      whether subjects could simultaneously adapt to multiple dynamic environments.
      Subjects ( n=5) drew ellipses continuously for 70 s using a torquable
      manipulandum under six distinct dynamic conditions, representing the combination
      of load type (spring, viscous, and inertia) and load direction (assisting and
      opposing). Each subject performed two control, ten load, and five washout trials.
      A significant effect of force condition on the trajectory of the movement was
      found in 26 of 30 cases (6 conditions x 5 subjects); the magnitude of the
      distortion differed across the conditions. The extent of adaptation also differed
      across the loads. Opposing inertia and viscosity led to fast adaptation. However,
      assisting inertia and viscosity were associated with relatively slow adaptation.
      The results of adaptation to the stiffness conditions were not consistent.
      Following sudden removal of the load we saw an additional disturbance of the
      trajectory (after-effect), which was often the mirror image of the original
      distortion. The shape and size of the after-effect were different across load
      conditions. These results show that human subjects can adapt to a variety of
      different dynamic transformations and that the time-course of adaptation is
      dependent on both the state space and the direction of the load.

PMID- 12478401
TI  - Task-related power and coherence changes in neuromagnetic activity during
      visuomotor coordination.
AB  - We analyzed a set of full-head (66 channels, CTF Inc.) magnetoencephalography
      (MEG) data recorded when 5 subjects performed rhythmic right index-finger flexion
      and extension movements on the beat (synchronization) or off the beat
      (syncopation) with a visual metronome at 1 Hz. Neuromagnetic activities in the
      alpha (8-14 Hz), beta (15-30 Hz) and gamma (30-50 Hz) ranges were shown to
      correlate with different aspects of the task. Specifically, we found that,
      compared with the control condition in which subjects only looked at the visual
      metronome without making any movement, all the movement conditions were
      accompanied by a decrease of power in the alpha range (8-14 Hz) in sensorimotor
      channels of both hemispheres, and an increase of coherence among a subset of
      these channels. The same comparison showed that power changes in the beta range
      differentiate task conditions by exhibiting power increases for synchronization
      and power decreases for syncopation. Changes in the gamma range power were found
      to be related to the kinematics of movement trajectories (flexion versus
      extension). These results suggest that three important cortical oscillations play
      different functional roles in a visuomotor timing task.

PMID- 12478402
TI  - fMRI signal increases and decreases in cortical areas during small-field
      optokinetic stimulation and central fixation.
AB  - Small-field optokinetic nystagmus (OKN) was performed in seven healthy volunteers
      in order to analyze the activation and deactivation patterns of visual motion,
      ocular motor, and multisensory vestibular cortex areas by means of fMRI during
      coherent visual motion stimulation. BOLD signal decreases (deactivations) were
      found in the first and second long insular gyri and retroinsular areas (the human
      homologue of the parietoinsular vestibular cortex and the visual posterior
      sylvian area in the monkey) of both hemispheres, extending into the transverse
      temporal gyrus and inferior-anterior parts of the superior temporal gyrus (BA
      22), and the precentral gyri at two separate sites (BA 4 and 6). Further
      deactivations were found in cranioposterior parts of the superior temporal gyrus
      (BA 22) and the adjacent inferior parietal lobule (BA 40), anterior cingulate
      gyrus, hippocampus, and corpus callosum. Most of these BOLD signal decreases
      involved parts of the "multisensory vestibular cortical circuit". These findings
      support the concept of a reciprocally inhibitory visual-vestibular interaction
      that has now been demonstrated not only for large-field visual motion stimulation
      that induces vection (without eye movements) but also for optokinetically induced
      eye movements (without vection). The functional significance of this concept may
      be related to the perception of self-motion, since both large-field visual motion
      stimulation and optokinetic nystagmus are linked to the visual control of self
      motion. With respect to activation of the cortical ocular motor system two
      separate and distinct areas of activations were delineated in the precentral
      sulcus of both hemispheres, one ventrolaterally (in BA 9) and the other
      dorsomedially at the junction of the superior frontal sulcus with the precentral
      sulcus (in BA 6). Both probably correspond to different subregions of the frontal
      eye field and the premotor cortex for the ocular motor performance of OKN.

PMID- 12478403
TI  - Transfer of sensorimotor adaptation between different movement categories.
AB  - It is well known that sensorimotor adaptation will transfer from the practiced to
      the unpracticed arm, which has been taken as evidence that adaptation is located
      in the brain before the divergence point for left and right arm control. We now
      explore whether adaptation will transfer between different movement categories as
      well. Subjects were exposed to a 60-deg visual rotation first in a tracking and
      then in a pointing task, or vice versa. We found a substantial transfer of
      adaptation between tasks, but its magnitude was larger from pointing to tracking
      than from tracking to pointing. This benefit of pointing persisted when the use
      of cognitive strategies was minimized by a concurrent, attention-demanding task,
      but it was lost when pointing amplitudes were very small. We conclude that
      adaptation is located in the brain before the divergence point for different
      movement categories, and that movements with a large ballistic component
      facilitate adaptation transfer.

PMID- 12478404
TI  - How far ahead do we look when required to step on specific locations in the
      travel path during locomotion?
AB  - Spatial-temporal gaze behaviour patterns were analysed as normal participants
      wearing a mobile eye tracker were required to step on 17 footprints, regularly or
      irregularly spaced over a 10-m distance, placed in their travel path. We examined
      the characteristics of two types of gaze fixation with respect to the
      participants' stepping patterns: footprint fixation; and travel fixation when the
      gaze is stable and travelling at the speed of whole body. The results showed that
      travel gaze fixation is a dominant gaze behaviour occupying over 50% of the
      travel time. It is hypothesised that this gaze behaviour would facilitate
      acquisition of environmental and self-motion information from the optic flow that
      is generated during locomotion: this in turn would guide movements of the lower
      limbs to the appropriate landing targets. When participants did fixate on the
      landing target they did so on average two steps ahead, about 800-1000 ms before
      the limb is placed on the target area. This would allow them sufficient time to
      successfully modify their gait patterns. None of the gaze behaviours was
      influenced by the placement (regularly versus irregularly spaced) of the
      footprints or repeated exposures to the travel path. Rather visual information
      acquired during each trial was used "de novo" to modulate gait patterns. This
      study provides a clear temporal link between gaze and stepping pattern and adds
      to our understanding of how vision is used to regulate locomotion.

PMID- 12478405
TI  - No functional benefit for hDAF-transgenic rat livers despite protection from
      tissue damage following perfusion with human serum.
AB  - Currently, xenogeneic extracorporeal liver perfusion is used in the treatment of
      acute liver failure. In order to determine whether transgeneity for human
      regulatory proteins could improve the functional outcome of the ex-vivo liver in
      relation to the histopathological changes, we studied the effect of the humoral
      mechanism in xenogeneic isolated rat liver perfusion in normal and transgenic rat
      livers. Isolated rat liver perfusion was performed for 2 h in normal rat livers
      with Krebs Henseleit (KH) and human serum (HS), and in livers transgenic for
      human decay accelerating factor (hDAF; Tg HS). Function of the liver was
      established by measurement of liver enzymes and bile production, and clearance of
      bromosulphophthalein (BSP). Tissue specimens taken after perfusion were analysed
      by routine histology and immunofluorescence staining for C3c deposition. No
      change in release of liver enzymes could be established throughout the perfusion
      period. In the 2nd hour, a higher level of bile production was seen for the
      transgenic group than for the HS group. The transgenic rat livers outperformed
      the normal livers perfused with HS, when BSP concentration in the bile was
      measured; however, clearance of BSP from the perfusate was not significantly
      different. Haematoxylin-eosin (HE) staining of the liver tissue showed evidence
      of hyperacute rejection in the HS group. There was only mild tissue injury in the
      transgenic liver. High-intensity fluorescent staining for C3c deposition was seen
      in the normal livers perfused with HS, and significantly less in the transgenic
      livers. Although histologically less tissue damage and less C3c deposition was
      shown, no significantly improved function of the livers transgenic for hDAF was
      established. These results suggest that for short-term extracorporeal liver
      perfusion transgenesis offers no functional benefit.

PMID- 12478406
TI  - De-novo expression of vascular ecto-5'-nucleotidase and down-regulation of
      glomerular ecto-ATPase in experimental chronic renal transplant failure.
AB  - Ischemic injury plays an important role in chronic renal transplant failure
      (CRTF). Down-regulation of ecto-adenosine triphosphatase (ATPase) in combination
      with up-regulation of ecto-5'-nucleotidase is a hallmark of ischemic injury. We
      studied the expression of renal ecto-5'-nucleotidase and ecto-ATPase in
      experimental renal transplantation. Fisher 344-to-Lewis allografted rats were
      either treated with an angiotensin-converting enzyme inhibitor (ACEi) or left
      untreated. Lewis-to-Lewis syngrafted rats served as controls. Untreated
      allografted rats developed proteinuria, glomerulosclerosis, and mild intimal
      hyperplasia. ACEi completely prevented focal and segmental glomerulosclerosis
      (FGS) and proteinuria, but significantly enhanced intimal hyperplasia. Untreated
      allografted rats revealed marked vascular ecto-5'-nucleotidase activity, which
      increased with ACEi. Vascular ecto-5'-nucleotidase activity was absent in
      syngrafted animals. Ecto-5'-nucleotidase activity correlated well with intimal
      hyperplasia. Glomerular ecto-ATPase expression was significantly reduced in
      untreated allografted rats compared to syngrafted rats and correlated well with
      the extent of FGS. ACEi prevented reduction in glomerular ecto-ATPase. We found
      de-novo expression of ecto-5'-nucleotidase at sites of renal intimal hyperplasia.
      Glomerular ecto-ATPase expression was markedly reduced in allografted rats and
      was prevented by ACEi. These enzyme expression patterns suggest local ischemic
      damage in experimental CRTF.

PMID- 12478407
TI  - Induction of cyclo-oxygenase-2 by acute liver allograft rejection and
      cytomegalovirus infection in the rat.
AB  - Cytomegalovirus (CMV) infection has been shown to increase inflammation in rat
      liver allografts. In-vitro CMV has been shown to transactivate cyclo-oxygenase-2
      (COX-2), while COX-2 plays a role in the CMV replication cycle. Our aim was to
      investigate the expression of COX-2 in liver allograft rejection and concomitant
      CMV infection. Expression of COX-2 was studied immunohistologically in rat liver
      allografts with or without rat CMV infection, in isografts, and in normal rat
      liver. There were small amounts of COX-2-positive mononuclear inflammatory cells
      in the normal liver and isografts. Acute rejection increased the amount of COX-2
      expressing cells in the portal areas only, whereas concomitant CMV infection did
      this also in the sinusoid area. COX-2 may play a role in CMV infection in vivo as
      well. The possible role of COX-2 in the association between CMV infection and
      allograft rejection warrants further study.

PMID- 12478408
TI  - A randomized prospective controlled trial of oral ganciclovir versus oral
      valacyclovir for prophylaxis of cytomegalovirus disease after renal
      transplantation.
AB  - Oral ganciclovir and valacyclovir reduce the incidence of cytomegalovirus (CMV)
      disease after renal transplantation (RTx). Our study was designed to compare the
      efficacy, costs, and safety of oral ganciclovir and valacyclovir in the
      prophylaxis of CMV disease over the first 6 months after RTx. A total of 38
      patients was randomized to 3-month treatment with either oral ganciclovir (1 g
      t.i.d., n=14, GAN group) or oral valacyclovir (2 g q.i.d., n=12, VAL group). A
      third group (C, n=12) received no prophylaxis. The patients were monitored by CMV
      nested PCR in whole blood. No differences were found between the groups in their
      demographic characteristics, immunosuppressive protocols, or donor and recipient
      CMV serology. Thirty-six out of 38 (94.7%) recipients were CMV-seropositive. Over
      the 6-month post-RTx period, there were 13 episodes of CMV disease in eight
      (66.7%) patients of the C group compared with none in the GAN and VAL groups (
      P=0.0005, GAN vs C; P=0.001, VAL vs C). The incidence of CMV viremia was 30.8%,
      50.0%, and 91.7% in the GAN, VAL, and C groups, respectively ( P=0.004, GAN vs C;
      P=0.07, VAL vs C; P=NS, GAN vs VAL). Treatment failure (death, graft loss, CMV
      disease, or withdrawal from study) occurred in 14.3%, 0% and 66.7% in the GAN,
      VAL, and C groups, respectively ( P=0.014, GAN vs C; P=0.001, VAL vs C; P=NS, GAN
      vs VAL). The average CMV-associated costs per patient (in 2001 euros) were
      2,449+/-1,178, 2,485+/-581, and 4,259+/-4,616 in the GAN, VAL, and C groups,
      respectively. Ganciclovir and valacyclovir were well tolerated, with ganciclovir
      having had to be withdrawn shortly in one patient only because of
      thrombocytopenia. In conclusion, oral ganciclovir and valacyclovir are equally
      safe and effective in the prophylaxis of CMV disease after RTx. Both are cost
      effective and help reduce CMV-associated costs by some 40% compared with patients
      without prophylaxis.

PMID- 12478409
TI  - ROCK inhibitor Y-27632 prevents primary graft non-function caused by warm
      ischemia/reperfusion in rat liver transplantation.
AB  - Hepatic stellate cells (HSCs) can easily be activated by ischemia/reperfusion,
      and this activation results in hepatic microcirculatory disturbance by cell
      contraction. ROCK is one of the key regulators of the motility of HSCs, and Y
      27632 suppresses the activation of HSCs. We examined whether Y-27632 treatment
      prevents primary graft non-function caused by 45-min warm ischemia in orthotopic
      liver transplantation (OLT). Donor and recipient rats were administered Y-27632
      (3-30 mg/kg). Y-27632 treatment at 30 mg/kg in both donor and recipient prevented
      congestion of the grafted livers, as demonstrated by analysis of hemoglobin (Hb)
      content in the grafted livers, using in-vivo near-infrared spectroscopy. Serum
      levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and
      hyaluronic acid at 4 h after OLT in the 30-mg/kg Y-27632-treated group were
      significantly lower than those in the control group. Specimens from the untreated
      control recipients showed sinusoidal congestion and massive fresh hepatocyte
      necrosis, whereas specimens from the Y-27632-treated recipients demonstrated
      minimal histological changes. Moreover, Y-27632 pre-treatment dramatically
      improved the survival of recipients. These results suggest that Y-27632 would be
      clinically useful for preventing liver failure associated with
      ischemia/reperfusion in liver transplantation.

PMID- 12478410
TI  - Sequential protocol biopsies from renal transplant recipients show an increasing
      expression of active TGF beta.
AB  - Chronic allograft nephropathy (CAN) is a major cause of graft loss after renal
      transplantation. Implicated in the pathogenesis of this complication is
      overproduction of the cytokine transforming growth factor beta (TGF beta). In
      this study we measured changes in CAN's expression in stable patients early after
      transplantation, and studied links with established risk factors for CAN, such as
      delayed graft function, acute rejection, and cyclosporine exposure. We took
      biopsies from 40 renal allografts at time of transplantation (pre-perfusion), and
      then, using ultrasound guidance, at 1 week and 6 months after transplantation. An
      immunofluorescence technique was used to stain sections for active TGF beta.
      These were then assessed by semi-quantitative scanning laser confocal microscopy.
      There was very little variation in active TGF-beta expression among patients in
      their pre-perfusion biopsies. Expression had increased by 1 week and then very
      significantly by 6 months ( P<0.0001). Patients who suffered delayed graft
      function had increased TGF-beta expression at both time points. There was no
      difference regarding donor type, acute rejection, and immunosuppressive drug
      (cyclosporine or tacrolimus). There was no correlation between the amount of TGF
      beta expression at any time-point and isotope glomerular filtration rate (GFR) at
      12 months. This study demonstrated that in a group of stable renal allograft
      recipients, TGF-beta expression in the kidney increased after transplantation. As
      the study used protocol biopsies, this increase is unlikely to be due to acute
      events, and probably represents a genuine increase.

PMID- 12478411
TI  - Endothelial nitric oxide synthase expression in ischemia-reperfusion injury after
      living related-donor renal transplantation.
AB  - Ischemia-reperfusion injury during renal transplantation has been linked to early
      graft dysfunction and late graft failure. Nitric oxide (NO), produced by NO
      synthase (NOS), participates in the recovery from ischemia. We correlated the
      intensity of graft immunoreactivity for the endothelial NOS isoform (eNOS) during
      early reperfusion with graft function in 25 children receiving grafts from
      related donors. Renal allograft biopsy specimens were obtained before
      transplantation, 1 h after renal artery reperfusion, and 1 year after
      transplantation. Immunohistochemical staining for eNOS occurred mainly within the
      endothelium of glomerular capillaries and peritubular capillaries as well as in
      tubule cells. The mean intensity score for eNOS staining (0-9) was 3.0+/-1.4
      before transplantation, 4.5+/-1.9 at 1 h, and 3.3+/-1.9 at 1 year (baseline vs 1
      h, P<0.05). Creatinine clearance (ml/min) in patients with a 1-h eNOS score of
      below 5 and of at least 5, respectively, was 77.1+/-28.4 vs 104.3+/-25.3 at 1
      month, 78.7+/-33.4 vs 105.2+/-24.4 at 3 months, 64.7+/-30.1 vs 100.1+/-25.3 at 1
      year, 58.2+/-31.3 vs 84.7+/-18.8 at 3 years, and 71.2+/-19.7 vs 78.3+/-23.1 at 5
      years ( P<0.05 for 1 month, 1 year, and 3 years). We concluded that elevated eNOS
      expression after reperfusion in living related-donor renal transplantation
      enhances the recovery from renal ischemia and, consequently, reduces late graft
      deterioration.

PMID- 12478412
TI  - A Swedish survey of young people's views on organ donation and transplantation.
AB  - The aim of this study is to explore young people's attitudes, beliefs, and
      knowledge on organ donation and transplantation. A survey was conducted among
      1,447 students aged 15-18 years in four urban areas in Sweden. Although students
      looked upon organ transplantation favorably, only 50% were willing to donate
      their own organs, and only 20% the organs of their parents. Concerning organ
      donation, 75% of the students expressed some discomfort. There were significant
      gender differences. About 70% of the students indicated that transplantation
      issues should be included in the school curriculum. It is concluded that
      teenagers feel irresolution and discomfort regarding organ donation after death,
      but concurrently see organ transplantation as a highly valued service. One way
      that this mental conflict can be resolved is through education. Educational
      programs in school must address this ambivalence and both mediate facts and help
      students to work through the fear and discomfort associated with organ donation.

PMID- 12478413
TI  - Pharmacokinetics of oral cyclosporine (Neoral) in heart transplant recipients
      during the immediate period after surgery.
AB  - Neoral cyclosporine has better absorption characteristics than the original
      Sandimmun formulation. This has allowed Neoral to be administered orally in
      circumstances where Sandimmun had been ineffective, including the postoperative
      phase of liver transplantation. Sampling strategies, such as the measurement of
      drug concentration 2 h after oral administration, have been used in a variety of
      settings to estimate systemic exposure to Neoral (measured as the area under the
      blood concentration curve (AUC) of the drug) in blood. We conducted a pilot study
      to determine whether Neoral could be administered orally immediately after heart
      transplantation and to determine which pharmacokinetic parameters reflect
      systemic drug exposure in this setting. Eight male patients (mean age 50 years)
      undergoing a first heart transplant were studied. Neoral was administered orally
      before surgery and at 12-h intervals via a nasogastric tube after surgery. Twelve
      hour pharmacokinetic profiles were obtained on postoperative days 1, 3 and 5.
      Cyclosporine concentrations were measured with the Dade Behring Emit assay, which
      is specific for the parent drug. Drug concentrations were dose-normalised and
      drug exposure was measured by the AUC. Drug exposure following administration
      (AUC(0-12)) was low on day 1 but increased by 99% between postoperative day 1 and
      day 5 ( P<0.05), indicating more complete absorption of cyclosporine; exposure in
      the first 4 h post-dose (AUC(0-4)) increased by 126% ( P<0.01), reflecting more
      rapid cyclosporine absorption, and the maximum blood concentration observed
      increased by 137% ( P<0.05) during the same period. The correlation between the
      cyclosporine trough concentration and AUC(0-12) was low on all days. Due to the
      changing pattern of cyclosporine absorption, concentration measurements at a
      single time point could not accurately predict 12-h exposure to the drug on all
      study days. However, the drug concentration at 2 h post-dose had a high
      correlation with drug exposure during the first 4 h (correlation of C(2) to AUC(0
      4): r(2)>0.93 on all days). Absorption of Neoral was low immediately after heart
      transplantation but improved substantially during the first 5 days after surgery.
      No single timed measurement of drug concentration reflected cyclosporine
      exposure; however, the 2-h concentration did provide an accurate measure of the
      early phase of drug absorption (AUC(0-4)). Oral administration of Neoral may
      result in inadequate immunosuppression immediately after heart transplantation
      unless it is supplemented either by intravenous cyclosporine or by the use of an
      induction agent.

PMID- 12478414
TI  - Mycophenolic acid reduces renin-angiotensin-system activity in cultured mouse
      medullary thick ascending limb cells.
AB  - Mycophenolate mofetil (MMF) is a promising immunosuppressive agent. The intra
      renal renin-angiotensin system (RAS) plays an important role in the regulation of
      intra-renal hemodynamics. Mycophenolic acid (MPA) is the bioactive metabolite of
      MMF. The interaction between MPA and intra-renal RAS is still unclear. We
      hypothesized that MPA might affect intra-renal RAS activity. We chose models of
      cultured mouse medullary thick ascending limb (mTAL) cells for the experiments,
      as the mTAL is one of the major sites of intra-renal RAS. We investigated the
      angiotensin-converting enzyme (ACE) activity by means of enzymatic assay, and the
      angiotensin-receptor activity by means of a binding study with radiolabeled
      angiotensin II, and measured the intracellular calcium concentration in cultured
      cells treated with and without MPA. ACE activity changed neither in cells
      incubated with MPA nor in those treated without MPA. The binding study also
      indicated decreased angiotensin-II binding in MPA-treated (MPA 10(-7) M) cells,
      up to 43.7%. The decreased intracellular calcium concentration in MPA-treated
      cells further confirmed the MPA-inhibitory effect on the angiotensin receptor. We
      conclude that MPA reduces intra-renal RAS activity mainly through the decrease of
      AT1 receptor activity without affecting ACE activity. The results suggest that
      the inhibitory effect of MPA in the intra-renal RAS might play a role in the
      extra-immunosuppressive effect of MMF.

PMID- 12478415
TI  - Outcome of renal allografts from non-heart-beating donors with delayed graft
      function.
AB  - Delayed graft function (DGF) in renal transplantation using non-heart-beating
      donors (NHBDs) usually exceeds 80%. There is debate whether DGF in this subgroup
      is associated with poor long-term outcome. Between 1 January 1988 and 31 January
      2000, 130 of 158 (82.3%) NHBD graft recipients with functioning grafts
      transplanted within our regional NHBD programme developed DGF. Overall graft
      survival and graft survival censored for recipient death was 113/130 (86.9%)
      versus 113/121 (93.4%) at year 1, 55/84 (65.5%) versus 55/64 (85.9%) at year 5
      and 18/40 (45.0%) versus 18/28 (64.3%) at year 10 after transplantation.
      Seventeen grafts (13.1%) were lost due to rejection or graft nephropathy. Nine of
      these kidneys failed during the 1st year. Twenty-seven patients (20.8%) died with
      functioning grafts, eight within the 1st year after transplantation. In those
      patients who survived, DGF was associated with excellent long-term outcome in
      this study. The number of grafts lost due to recipient death exceeded those lost
      due to rejection or graft nephropathy.

PMID- 12478416
TI  - Endo-urological techniques in the management of stent complications in the renal
      transplant patient.
AB  - Complications following renal allograft transplantation have been well documented
      and, despite improvements in technique, continue to cause significant morbidity
      and mortality. The placement of indwelling ureteric stents is becoming more
      common both during primary neo-ureterocystostomy and in the management of
      subsequent ureteric complications. We present two cases of stent encrustation and
      urolithiasis treated by a combined percutaneous and flexible ureterorenoscopic
      approach. These cases illustrate the problems of stents in renal transplant
      patients and offer endo-urological solutions. It is imperative that stents are
      correctly placed in these patients and that appropriate plans are made for their
      removal or exchange.

PMID- 12478417
TI  - Limitations of a cosolvent for ecotoxicity testing of hydrophobic compounds.

PMID- 12478418
TI  - Foliar phenolic variation in wild tomato accessions.

PMID- 12478419
TI  - Does radiotherapy have consequences on plasma concentration of toxic pollutants?

PMID- 12478420
TI  - Detection of mutagenic activities of various pesticides in Neurospora crassa.

PMID- 12478421
TI  - Anticoagulant rodenticides and raptors: recent findings from New York, 1998-2001.

PMID- 12478422
TI  - Polychlorinated biphenyl (PCB) levels in human milk samples from Turkish mothers.

PMID- 12478423
TI  - Changes in form of rare earth elements after acid rain leaching through soil
      column.

PMID- 12478424
TI  - Identification of a water pollutant, 2-amino-6,7-dichlorobenzothiazole, at a
      river near a textile industrial complex in Korea.

PMID- 12478425
TI  - Levels of polychlorinated biphenyls in Mexican soils and their biodegradation
      using bioaugmentation.

PMID- 12478426
TI  - Mercury and selenium levels in eggs of common terns (Sterna hirundo) from two
      breeding colonies in the Ebro Delta, Spain.

PMID- 12478427
TI  - Uptake and elimination of cadmium in Rana dalmatina (Anura, Amphibia) tadpoles.

PMID- 12478428
TI  - Bacteriological indicators in fish exposed to pesticides.

PMID- 12478429
TI  - Chlorophyll a fluorescence as a potential biomarker of zinc stress in the grey
      mangrove, Avicennia marina (Forsk.) Vierh.

PMID- 12478430
TI  - Lymphoproliferative responses of splenocytes from wild cotton rats (Sigmodon
      hispidus) following acute exposure to Aroclor 1254.

PMID- 12478431
TI  - Alterations in the biochemical constituents of muscles of Cirrhinus mrigala
      following exposure to and withdrawal from metals.

PMID- 12478432
TI  - Effects of copper on respiration, reproduction, and some biochemical parameters
      of water flea Daphnia magna Straus.

PMID- 12478433
TI  - Chromium induced alterations in some biochemical profiles of the Indian major
      carp, Labeo rohita (Hamilton).

PMID- 12478434
TI  - Effect of some monocyclic aromatic hydrocarbons on freshwater invertebrates.

PMID- 12478435
TI  - Mortality and survival of Procambarus clarkii Girard, 1852 upon exposure to
      different insecticide products.

PMID- 12478436
TI  - Comparative effects of exposure to an organophosphate pesticide on locomotor
      activity of laboratory mice and five species of wild rodents.

PMID- 12478437
TI  - Toxic effects of dimethoate and carbaryl pesticides on protein metabolism of the
      freshwater snail Lymnaea acuminata.

PMID- 12478438
TI  - Toxicity assays of a compound with insecticide properties: chitosan diethyl
      phosphate.

PMID- 12478439
TI  - Brevetoxin concentrations in marine aerosol: human exposure levels during a
      Karenia brevis harmful algal bloom.

PMID- 12478440
TI  - Air quality of the trans-Gomti area of Lucknow City, India.

PMID- 12478441
TI  - Persistent organic pollutants in smoke particles emitted during open burning of
      municipal solid wastes.

PMID- 12478442
TI  - Trace metals in candle smoke.

PMID- 12478443
TI  - The constantly changing neonatal health care paradigm in California.

PMID- 12478444
TI  - The new system of perinatal care.

PMID- 12478445
TI  - Expansion of community-based perinatal care in California.
AB  - OBJECTIVE: In California, hospitals with Community Neonatal Intensive Care Units
      (NICUs) increased from 17 in 1990 to 52 in 1997. The purpose of this study was to
      investigate the effects of their growth on level-specific distribution of births,
      acuity, and neonatal mortality. STUDY DESIGN: A total of 4,563,900 infants born
      from 1990 to 1997 were analyzed by levels of care. We examined shifts in birth
      location and acuity. Neonatal mortality for singleton very-low-birth-weight
      (VLBW) infants without congenital abnormalities was used to assess differences in
      level-specific survival. RESULTS: Live births at hospitals with Community NICUs
      increased from 8.6% to 28.6%, and VLBW births increased from 11.7% to 37.4%.
      Births and VLBW births at Regional NICUs decreased, whereas acuity was unchanged.
      There were no differences in neonatal mortality of VLBW infants born at Community
      or Regional NICU hospitals. Mortality for VLBW births at other levels of care was
      significantly higher. CONCLUSION: The rapid growth of monitored Community NICUs
      supported by a regionalized system of neonatal transport represents an evolving
      face of regionalization. Survival of VLBW births was similar at Community and
      Regional hospitals and higher than in other birth settings. Reducing VLBW births
      at Primary Care and Intermediate NICU hospitals continues to be an important goal
      of regionalization. doi:10.1038/sj.jp.7210824

PMID- 12478446
TI  - Clinical process improvement: reduction of pneumothorax and mortality in high
      risk preterm infants.
AB  - OBJECTIVE: To develop multidisciplinary clinical process improvement methods
      using evidence-based medicine to decrease the incidence of pneumothorax in a
      NICU. STUDY DESIGN: All inborn infants <28 weeks' gestation (n=79) served as the
      historical baseline group. A prospective protocol, using evidence-based medicine
      and a rapid-cycle, multidisciplinary clinical process improvement method, was
      designed to measure changes in the incidence of pneumothorax in subsequent
      infants of similar gestational ages. RESULTS: Sixty consecutive inborn infants
      <28 weeks' gestational age comprised the study group. In comparison to the
      historical control group, there was a significant reduction in the incidence of
      pneumothorax (from 26.6% to 10%, p=0.018) and in mortality (36.7% to 15%,
      p=0.007) without adversely affecting any other measured outcome variable.
      CONCLUSIONS: Introduction of multidisciplinary clinical process improvement
      methods can significantly decrease the incidence of adverse outcomes in neonatal
      intensive care units.

PMID- 12478447
TI  - Mothers' milk feedings in the neonatal intensive care unit: accuracy of the
      creamatocrit technique.
AB  - OBJECTIVE: To establish the accuracy of the creamatocrit (CRCT) for estimating
      lipid and calories in a heterogeneous sample of own mothers' milk (OMM) in the
      neonatal intensive care unit (NICU), using a hematocrit reader, rather than fine
      vernier calipers. STUDY DESIGN: In this blinded study, CRCT techniques were
      performed on 32 fresh OMM samples (7 foremilk, 12 hindmilk, 13 composite milk)
      that were also analyzed for total lipid and caloric concentration. RESULTS: Mean
      lipid and caloric concentrations for the OMM samples were 50.87 g/l (28.3-86.5)
      and 703.96 kcal/l (477.2-1183.6), respectively. Results revealed a stronger
      linear relationship between CRCT and total lipid (r=0.94; p<0.001) than between
      CRCT and caloric density (r=0.76; p<0.001). CONCLUSION: The CRCT, using a
      hematocrit reader, is an accurate, inexpensive, and useful technique for
      estimating the lipid and caloric concentration of individual OMM samples in the
      NICU. The variability in lipid and calories in these 32 OMM samples underscores
      the utility of this technique.

PMID- 12478448
TI  - Spontaneous activity in premature infants affects bone strength.
AB  - OBJECTIVE: Determination of bone strength of lower extremities in very low birth
      weight (VLBW) premature infants with central nervous system pathology resulting
      in reduced unilateral spontaneous leg movements. STUDY DESIGN: Quantitative
      ultrasound (QUS) measurements of speed of sound (SOS) of the tibiae of both legs
      in three VLBW premature infants with brain insult and unilateral reduced
      spontaneous activity. Results were compared to QUS measurements of both legs in
      healthy premature infants. Measurements were performed by the same investigator
      who was blinded to the clinical course of the participants. RESULTS: Reduced
      spontaneous activity of one leg due to brain pathology resulted in decreased
      tibial SOS in the affected side. There was no difference in bone SOS between the
      legs of the healthy controls. CONCLUSION: Spontaneous movements (mainly
      antigravity flexion and extension) are important for bone structure and
      mineralization in VLBW premature infants. QUS may become an important diagnostic
      modality for the evaluation, treatment, and follow-up of bone strength and
      osteopenia in this unique population.

PMID- 12478449
TI  - The role of intrapartum fever in identifying asymptomatic term neonates with
      early-onset neonatal sepsis.
AB  - OBJECTIVE: To assess the role of intrapartum fever in identifying asymptomatic
      term neonates with early-onset neonatal sepsis. STUDY DESIGN: Retrospective
      review of all term neonates with sepsis over a 7-year period to evaluate the
      significance of symptoms at delivery and intrapartum sepsis risks factors in
      identifying neonates with sepsis. RESULTS: Fifty-three of 90 term neonates with
      sepsis (59%) were asymptomatic at delivery. Thirty-five of 53 asymptomatic term
      neonates (66%) met criteria for sepsis evaluations and 18 (34%) were evaluated
      when symptoms developed after delivery. Among the 35 asymptomatic term neonates
      meeting criteria for sepsis evaluations, 14 (40%) had evaluations because of
      intrapartum fever. Thus, 14 of 53 (26%) asymptomatic term neonates with sepsis
      (30% of GBS sepsis and 11% of non-GBS sepsis) would not have been evaluated if
      intrapartum fever were ignored. CONCLUSION: Over half of term neonates with
      sepsis were asymptomatic at delivery. Intrapartum fever was helpful in
      identifying over a quarter of asymptomatic term neonates with sepsis.

PMID- 12478450
TI  - Characterization of neonatal personnel time inputs and prediction from clinical
      variables--a time and motion study.
AB  - OBJECTIVE: To characterize and predict personnel time inputs to neonatal
      intensive care using infant characteristics from chart review. STUDY DESIGN: For
      12 hours each day, observers timed all direct care, charting, discussions, and
      procedures for 154 infants. Time inputs were correlated with 40 infant
      characteristics and resource markers, as well as the Score for Neonatal Acute
      Physiology (SNAP) for that day of care. RESULTS: Nurses accounted for 76%,
      respiratory therapists 8%, fellows 5%, nurse practitioners 7% and attendings 5%
      of total time invested in patient care. Nurses and respiratory therapists spent
      proportionately more time in direct patient care. In regression models, a limited
      number of variables explained 36% of the variance in time input per patient for
      respiratory therapists (p<0.0001), 42% for nurses (p<0.0001), and 23% for
      physicians and nurse practitioners (p<0.0001). CONCLUSIONS: Total labor inputs
      can be accurately predicted through the use of a limited number of clinical
      characteristics. This technique should be routinely employed to improve the
      accuracy of economic evaluations. Nursing accounts for the majority of time
      invested in neonatal care. Improved efficiency in neonatology is thus most likely
      to be generated by interventions that reduce direct nursing time.

PMID- 12478451
TI  - Intraparenchymal brain hemorrhage and remote soft tissue arteriovenous
      malformation in a newborn infant.
AB  - Congenital arteriovenous malformations (AVMs) often present with congestive heart
      failure. Such pathologic vascular structures typically occur in cranial, hepatic,
      or pulmonary locations and are usually associated with overlying external
      visible, tactile, or audible abnormalities. These vascular anomalies may also be
      associated with such complications as thromboembolic events, coagulopathy, and
      localized hemorrhage. We present a newborn infant with an occult but
      hemodynamically significant parascapular AVM who presented with an
      intraparenchymal brain hemorrhage, which we suspect to be a remote complication
      of the AVM.

PMID- 12478452
TI  - Successful perinatal management of hydrops fetalis due to hemolytic disease
      associated with D-- maternal phenotype.
AB  - We report the successful management of a case of hemolytic disease and hydrops
      fetalis secondary to anti Rh 17 antibodies in a woman with the rare D--
      phenotype. We discuss the efficacy of intravenous immunoglobulins in treating
      hemolytic disease of the newborn infant.

PMID- 12478453
TI  - The assessment of IgG avidity in the evaluation of perinatal herpes simplex virus
      infection.
AB  - Classical serologic assays are not useful for the diagnosis of perinatal herpes
      simplex virus (HSV) infection during the acute phase of the disease. We report
      two cases of neonatal HSV infection that highlight the diagnostic value of HSV
      specific IgG avidity and its contribution for further characterization of
      neonatal HSV infection.

PMID- 12478454
TI  - Treatment of severe pulmonary hemorrhage with activated recombinant factor VII
      (rFVIIa) in very low birth weight infants.
AB  - Clinically apparent pulmonary hemorrhage (PH) occurs in 5% to 7% of very low
      birth weight (VLBW) infants with respiratory distress syndrome (RDS). It is
      associated with a mortality rate as high as 50% and significant pulmonary and
      central nervous system morbidities. There is no consensus on treatment modality.
      We present two VLBW infants with severe PH that did not respond to conventional
      treatment but were successfully treated with activated recombinant factor VII
      (rFVIIa). No untoward side effects were noted.

PMID- 12478455
TI  - The role of placental pathology in the evaluation of interpersonal violence: a
      case of abdominal gunshot wound in a 27-week gravid uterus.
AB  - We present a 17-year-old G1P0 Asian American woman with a previously undiagnosed
      pregnancy who sustained an intra-abdominal gunshot wound at 27 weeks' gestation.
      Within 2 hours of the traumatic event, the victim was taken emergently to the
      operating room for exploratory laparotomy. Findings included a gravid uterus with
      two entrance wounds and two small exit wounds with active bleeding from the right
      broad ligament. The fetus was bradycardic but viable, having suffered a gunshot
      wound to the left shoulder. Evaluation of the placenta revealed no sequelae from
      the acute event. Unexpectedly, two older, green, 7.0 cm retromembranous hematomas
      were present, both ringed by hemosiderin-laden macrophages. These hemorrhages
      clearly preceded the acute event. Although these findings seemed suspicious for a
      history of prior abuse or trauma, corroborative clinical data were unavailable at
      the time of initial placental evaluation. However, days later, the victim
      admitted to a history of interpersonal violence, with previous abuse from her
      boyfriend, a fatal victim of the same attack. The old retroplacental hemorrhages
      proved to be the only physical documentation of her previous abuse.

PMID- 12478456
TI  - Unexpected resistance to external cardiac compression may signal pericardial
      tamponade.
AB  - Pericardial tamponade associated with central catheters is often lethal, unless
      promptly identified. We report our experience with two infants who suffered this
      complication but were successfully resuscitated. In each case, associated
      radiographs showed the tip of the central catheter beyond the superior vena cava
      right atrium (SVC-RA) junction. Identifying the clinical triad of (1) sudden
      cardiovascular collapse unresponsive to usual resuscitative measures, (2)
      thoracic transillumination not suggestive of air leak, and (3) unexpected
      resistance to external cardiac compression led to the working diagnosis of
      pericardial tamponade and therapeutic pericardiocentesis. Prompt recovery
      followed. Central catheters within the RA seem prone to cause pericardial
      tamponade.

PMID- 12478457
TI  - Pre-ECMO predictors of nonsurvival in congenital diaphragmatic hernia.

PMID- 12478459
TI  - Re: Late-onset group B streptococcal infection in identical twins: insight to
      disease pathogenesis.

PMID- 12478463
TI  - Development and death of neurons: sealed by a common fate?

PMID- 12478464
TI  - The olfactory bulb as an independent developmental domain.
AB  - The olfactory system is a good model to study the mechanisms underlying guidance
      of growing axons to their appropriate targets. The formation of the olfactory
      bulb involves differentiation of several populations of cells and the initiation
      of the central projections, all under the temporal and spatial patterns of gene
      expression. Moreover, the nature of interactions between the olfactory
      epithelium, olfactory bulb and olfactory cortex at early developmental stages is
      currently of great interest. To explore these questions more fully, the present
      review aims to correlate recent data from different developmental studies, to
      gain insight into the mechanisms involved in the specification and development of
      the olfactory system. From our studies in the pax6 mutant mice
      (Sey(Neu)/Sey(Neu)), it was concluded that the initial establishment of the
      olfactory bulb central projections is able to proceed independently of the
      olfactory sensory axons from the olfactory epithelium. The challenge that now
      remains is to consider the validity of the olfactory bulb as an independent
      development domain. In the course of evaluating these ideas, we will review the
      orchestra of molecular cues involved in the formation of the projection from the
      OB to the olfactory cortex.

PMID- 12478465
TI  - Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic
      catastrophe.
AB  - The cyclin-dependent kinase 1 (Cdk1), formerly called Cdc2 (or p34(Cdc2)),
      interacts with cyclin B1 to form an active heterodimer. The activity of Cdk1 is
      subjected to a complex spatiotemporary regulation, required to guarantee its
      scheduled contribution to the mitotic prophase and metaphase. Moreover, the
      activation of Cdk1 may be required for apoptosis induction in some particular
      pathways of cell killing. This applies to several clinically important settings,
      for instance to paclitaxel-induced killing of breast cancer cells, in which the
      ErbB2 receptor kinase can mediate apoptosis inhibition through inactivation of
      Cdk1. The activation of Cdk1 participates also in HIV-1-induced apoptosis,
      upstream of the p53-dependent mitochondrial permeabilization step. An unscheduled
      Cdk1 activation may contribute to neuronal apoptosis occurring in
      neurodegenerative diseases. Finally, the premature activation of Cdk1 can lead to
      mitotic catastrophe, for instance after irradiation-induced DNA damage. Thus, a
      cell type-specific modulation of Cdk1 might be taken advantage of for the
      therapeutic correction of pathogenic imbalances in apoptosis control.

PMID- 12478466
TI  - Cycling at the interface between neurodevelopment and neurodegeneration.
AB  - The discovery of cell cycle regulators has directed cell research into uncharted
      territory. In dividing cells, cell cycle-associated protein kinases, which are
      referred to as cyclin-dependent-kinases (Cdks), regulate proliferation,
      differentiation, senescence and apoptosis. In contrast, all Cdks in post-mitotic
      neurons, with the notable exception of Cdk5, are silenced. Surprisingly,
      misregulation of Cdks occurs in neurons in a wide diversity of neurological
      disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic
      lateral sclerosis. Ectopic expression of these proteins in neurons potently
      induces cell death with hallmarks of apoptosis. Deregulation of the unique, cell
      cycle-unrelated Cdk5 by its truncated co-activator, p25 and p29, contributes to
      neurodegeneration by altering the phosphorylation state of non-membrane
      associated proteins and possibly through the induction of cell cycle proteins. On
      the other hand, cycling Cdks such as Cdk2, Cdk4 and Cdk6, initiate death pathways
      by derepressing E2F-1/Rb-dependent transcription at the neuronal G1/S checkpoint.
      Thus, Cdk5 and cycling Cdks may have little in common in the healthy CNS, but
      they likely conspire in leading neurons to their demise.

PMID- 12478467
TI  - Apoptotic volume decrease and the incredible shrinking cell.

PMID- 12478468
TI  - The p35 relative, p49, inhibits mammalian and Drosophila caspases including DRONC
      and protects against apoptosis.
AB  - This study characterized the ability of a new member of the p35 family, p49, to
      inhibit a number of mammalian and insect caspases. p49 blocked apoptosis
      triggered by treatment with Fas ligand (FasL), Tumor necrosis factor-related
      apoptosis-inducing ligand (TRAIL) or ultraviolet (UV) radiation but provided
      negligible protection against apoptosis induced by the chemotherapeutic drug
      cisplatin. The caspase cleavage site in p49 was determined, and mutation of the
      P1 residue of this site abolished the ability of p49 to inhibit caspases,
      implying that p49 inhibits caspases through an analogous suicide-substrate
      mechanism to p35. Unlike p35, p49 inhibited the upstream insect caspase DRONC.

PMID- 12478469
TI  - Death of HT29 adenocarcinoma cells induced by TNF family receptor activation is
      caspase-independent and displays features of both apoptosis and necrosis.
AB  - The HT29 adenocarcinoma is a common model of epithelial cell differentiation and
      colorectal cancer and its death is an oft-analyzed response to TNF family
      receptor signaling. The death event itself remains poorly characterized and here
      we have examined the involvement of caspases using pan-caspase inhibitors. zVAD
      fmk did not block death of HT29 cells in response to activation of the Fas,
      TRAIL, TNF, TWEAK and LTbeta receptors. The secondary induction of TNF or the
      other known bona fide death inducing ligands did not account for death following
      LTbeta receptor activation indicating that TNF family receptors can trigger a
      caspase-independent death pathway regardless of the presence of canonical death
      domains in the receptor. To provide a frame of reference, the phenotype of HT29
      death was compared to four other TNF family receptor triggered death events; Fas
      induced Jurkat cell apoptosis, TNF/zVAD induced L929 fibroblast necrosis, TNF
      induced death of WEHI 164 fibroblastoid cells and TNF/zVAD induced U937 death.
      The death of HT29 and U937 cells under these conditions is an intermediate form
      with both necrotic and apoptotic features. The efficient coupling of TNF
      receptors to a caspase-independent death event in an epithelial cell suggests an
      alternative approach to cancer therapy.

PMID- 12478470
TI  - Differential subcellular localization of functionally divergent survivin splice
      variants.
AB  - Survivin is an inhibitor of apoptosis protein (IAP) that is markedly
      overexpressed in most cancers. We identified two novel functionally divergent
      splice variants, i.e. non-antiapoptotic survivin-2B and antiapoptotic survivin
      deltaEx3. Because survivin-2B might be a naturally occurring antagonist of
      antiapoptotic survivin variants, we analyzed the subcellular distribution of
      these proteins. PSORT II analysis predicted a preferential cytoplasmic
      localization of survivin and survivin-2B, but a preferential nuclear localization
      of survivin-deltaEx3. GFP-tagged survivin variants confirmed the predicted
      subcellular localization and additionally revealed a cell cycle-dependent nuclear
      accumulation of survivin-deltaEx3. Moreover, a bipartite nuclear localization
      signal found exclusively in survivin-deltaEx3 may support cytoplasmic clearance
      of survivin-deltaEx3. In contrast to the known association between survivin and
      microtubules or centromeres during mitosis, no corresponding co-localization
      became evident for survivin-deltaEx3 or survivin-2B. In conclusion, our study
      provided data on a differential subcellular localization of functionally
      divergent survivin variants, suggesting that survivin isoforms may perform
      different functions in distinct subcellular compartments and distinct phases of
      the cell cycle.

PMID- 12478471
TI  - Serine protease inhibitor Spi2 mediated apoptosis of olfactory neurons.
AB  - The olfactory epithelium of adult mouse, where primary sensory neurons are
      massively committed to apoptosis by removal of their synaptic target, was used as
      a model to determine in vivo mechanisms for neuronal cell death induction. A
      macro-array assay revealed that the death of olfactory neurons is accompanied
      with over-expression of the serine protease inhibitor Spi2. This over-expression
      is associated with decreased serine protease activity in the olfactory mucosa.
      Moreover, in vitro or in vivo inhibition of serine proteases induced apoptotic
      death of olfactory neuronal cells. Interestingly, Spi2 over-expression is not
      occurring in olfactory neurons but in cells of the lamina propria, suggesting
      that Spi2 may act extracellularly as a cell death inducer. In that sense, we
      present evidence that in vitro Spi2 overexpression generates a secreted signal
      for olfactory neuron death. Hence, taken together these results document a
      possible novel mechanism for apoptosis induction that might occur in response to
      neurodegenerative insults.

PMID- 12478472
TI  - Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect
      a specific DNA damage recognition associated with a different p53-mediated
      response.
AB  - Mononuclear and multinuclear platinum complexes are known to induce distinct
      types of DNA lesions and exhibit different profiles of antitumor activity, in
      relation to p53 mutational status. In this study, we investigated the cellular
      effects of exposure to two platinum compounds (cisplatin and the multinuclear
      platinum complex BBR 3464), in the osteosarcoma cell line, U2-OS, carrying the
      wild-type p53 gene and capable of undergoing apoptosis or cell cycle arrest in
      response to diverse genotoxic stresses. In spite of the ability of both compounds
      to up-regulate p53 at cytotoxic concentrations, exposure to BBR 3464 resulted in
      cell cycle arrest but only cisplatin was capable of inducing significant levels
      of apoptosis and phosphorylation at the Ser15 residue of p53. The cisplatin
      induced protein phosphorylation, not detectable in cells treated with BBR 3464,
      was associated with RPA phosphorylation, a specific up-regulation of Bax and down
      regulation of p21(WAF1). Cells treated with BBR 3464 displayed a different
      cellular response with evidence of cytostasis associated with a high induction of
      p21(WAF1). The regulation of p21(WAF1) after cisplatin or BBR 3464 exposure
      required a p53 signal, as documented using stable transfectants expressing a
      dominant-negative form of p53 (175(his)). Taken together, these results indicate
      that cellular response to different genotoxic lesions (i.e. apoptosis or growth
      arrest) is associated with a specific recognition of DNA damage and a different
      p53-mediated signaling pathway. Multinuclear platinum complexes could be regarded
      as useful tools for investigating the p53-mediated process of cell cycle arrest
      in response to DNA damage.

PMID- 12478473
TI  - Activation of metalloproteinases and their association with integrins: an
      auxiliary apoptotic pathway in human endothelial cells.
AB  - Anchorage of cells to the extracellular matrix and integrin-mediated signals play
      crucial roles in cell survival. We have previously shown that during growth
      factor deprivation-induced apoptosis in human umbilical vein endothelial cells
      (HUVECs), key molecules in focal adhesions and adherens junctions are cleaved by
      caspases. In this study we provide evidence for a selective upregulation of cell
      associated matrix metalloproteinases (MMPs). We observe a physical association of
      MMP2 with beta1 and alphav integrins, which increased three- to fourfold during
      apoptosis and is dependent upon integrin beta1 levels and activation state. Both
      enforced activation of beta1 integrin by a specific antibody and inhibition of
      MMPs protect HUVECs from apoptosis. We hypothesize that, prior to the commitment
      to apoptosis, 'inside-out' signals initiated by the apoptotic stimulus alter cell
      shape together with the activation states and/or the availability of integrins,
      which promote matrix-degrading activity around dying cells. This 'auxiliary'
      apoptotic pathway may interrupt ECM-mediated survival signaling, and thus
      accelerate the efficient execution of the cell death program.

PMID- 12478474
TI  - Peroxynitrite stimulates the activity of cytosolic phospholipase A2 in U937
      cells: the extent of arachidonic acid formation regulates the balance between
      cell survival or death.
AB  - Peroxynitrite stimulates in U937 cells release of arachidonic acid (AA) sensitive
      to various phospholipase A(2) (PLA(2)) inhibitors, including arachidonyl
      trifluoromethyl ketone (AACOCF(3)), which specifically inhibits cytosolic PLA(2)
      (cPLA(2)). This response linearly increases using non toxic concentrations of the
      oxidant, and reaches a plateau at levels at which toxicity becomes apparent.
      Three separate lines of evidence are consistent with the notion that AA generated
      by cPLA(2) promotes survival in cells exposed to peroxynitrite. Firstly, toxicity
      was suppressed by nanomolar levels of exogenous AA, or by AA generated by the
      direct PLA(2) activator melittin. Secondly AACOCF(3), or other PLA(2) inhibitors,
      promoted cell death after exposure to otherwise non toxic concentrations of
      peroxynitrite; exogenous AA abolished the enhancing effects mediated by the
      PLA(2) inhibitors. Finally, U937 cells transfected with cPLA(2) antisense
      oligonucleotides were killed by concentrations of peroxynitrite that were non
      toxic for cells transfected with nonsense oligonucleotides. This lethal response
      was insensitive to AACOCF(3) and prevented by exogenous AA.

PMID- 12478475
TI  - Cell death in adult neural stem cells.

PMID- 12478476
TI  - Natural infection of D. melanogaster by virulent parasitic wasps induces
      apoptotic depletion of hematopoietic precursors.

PMID- 12478477
TI  - GITR interacts with the pro-apoptotic protein Siva and induces apoptosis.

PMID- 12478478
TI  - Interacting genetic loci on chromosomes 20 and 10 influence extreme human
      obesity.
AB  - Obesity is a multigenic trait that has a substantial genetic component. Animal
      models confirm a role for gene-gene interactions, and human studies suggest that
      as much as one-third of the heritable variance may be due to nonadditive gene
      effects. To evaluate potential epistatic interactions among five regions, on
      chromosomes 7, 10, and 20, that have previously been linked to obesity
      phenotypes, we conducted pairwise correlation analyses based on alleles shared
      identical by descent (IBD) for independent obese affected sibling pairs (ASPs),
      and we determined family-specific nonparametric linkage (NPL) scores in 244
      families. The correlation analyses were also conducted separately, by race,
      through use of race-specific allele frequencies. Conditional analyses for a
      qualitative trait (body mass index [BMI] >/=27) and hierarchical models for
      quantitative traits were used to further refine evidence of gene interaction.
      Both the ASP-specific IBD-sharing probability and the family-specific NPL score
      revealed that there were strong positive correlations between 10q (88-97 cM) and
      20q (65-83 cM), through single-point and multipoint analyses with three obesity
      thresholds (BMI >/=27, >/=30, and >/=35) across African American and European
      American samples. Conditional analyses for BMI >/=27 found that the LOD score at
      20q rises from 1.53 in the baseline analysis to 2.80 (empirical P=.012) when
      families were weighted by evidence for linkage at 10q (D10S1646) through use of
      zero-one weights (weight(0-1)) and to 3.32 (empirical P<.001) when proportional
      weights (weight(prop)) were used. For percentage fat mass, variance-component
      analysis based on a two-locus epistatic model yielded significant evidence for
      interaction between 20q (75 cM) and the chromosome 10 centromere (LOD = 1.74;
      P=.024), compared with a two-locus additive model (LOD = 0.90). The results from
      multiple methods and correlated phenotypes are consistent in suggesting that
      epistatic interactions between loci in these regions play a role in extreme human
      obesity.

PMID- 12478479
TI  - Association of neuregulin 1 with schizophrenia confirmed in a Scottish
      population.
AB  - Recently, we identified neuregulin 1 (NRG1) as a susceptibility gene for
      schizophrenia in the Icelandic population, by a combined linkage and association
      approach. Here, we report the first study evaluating the relevance of NRG1 to
      schizophrenia in a population outside Iceland. Markers representing a core at
      risk haplotype found in Icelanders at the 5' end of the NRG1 gene were genotyped
      in 609 unrelated Scottish patients and 618 unrelated Scottish control
      individuals. This haplotype consisted of five SNP markers and two
      microsatellites, which all appear to be in strong linkage disequilibrium. For the
      Scottish patients and control subjects, haplotype frequencies were estimated by
      maximum likelihood, using the expectation-maximization algorithm. The frequency
      of the seven-marker haplotype among the Scottish patients was significantly
      greater than that among the control subjects (10.2% vs. 5.9%, P=.00031). The
      estimated risk ratio was 1.8, which is in keeping with our report of unrelated
      Icelandic patients (2.1). Three of the seven markers in the haplotype gave single
      point P values ranging from .000064 to .0021 for the allele contributing to the
      at-risk haplotype. This direct replication of haplotype association in a second
      population further implicates NRG1 as a factor that contributes to the etiology
      of schizophrenia.

PMID- 12478481
TI  - The genetic origins of the Andaman Islanders.
AB  - Mitochondrial sequences were retrieved from museum specimens of the enigmatic
      Andaman Islanders to analyze their evolutionary history. D-loop and protein
      coding data reveal that phenotypic similarities with African pygmoid groups are
      convergent. Genetic and epigenetic data are interpreted as favoring the long-term
      isolation of the Andamanese, extensive population substructure, and/or two
      temporally distinct settlements. An early colonization featured populations
      bearing mtDNA lineage M2, and this lineage is hypothesized to represent the
      phylogenetic signal of an early southern movement of humans through Asia. The
      results demonstrate that Victorian anthropological collections can be used to
      study extinct, or seriously admixed populations, to provide new data about early
      human origins.

PMID- 12478480
TI  - Comparison of genome screens for two independent cohorts provides replication of
      suggestive linkage of bone mineral density to 3p21 and 1p36.
AB  - Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture.
      Studies of BMD in families and twins have shown that this trait is under strong
      genetic control. To identify regions of the genome that contain quantitative
      trait loci (QTL) for BMD, we performed independent genomewide screens, using two
      complementary study designs. We analyzed unselected nonidentical twin pairs
      (1,094 pedigrees) and highly selected, extremely discordant or concordant (EDAC)
      sib pairs (254 pedigrees). Nonparametric multipoint linkage (NPL) analyses were
      undertaken for lumbar spine and total-hip BMD in both cohorts and for whole-body
      BMD in the unselected twin pairs. The maximum evidence of linkage in the
      unselected twins (spine BMD, LOD 2.7) and the EDAC pedigrees (spine BMD, LOD 2.1)
      was observed at chromosome 3p21 (76 cM and 69 cM, respectively). These combined
      data indicate the presence, in this region, of a gene that regulates BMD.
      Furthermore, evidence of linkage in the twin cohort (whole-body BMD; LOD 2.4) at
      chromosome 1p36 (17 cM) supports previous findings of suggestive linkage to BMD
      in the region. Weaker evidence of linkage (LOD 1.0-2.3) in either cohort, but not
      both, indicates the locality of additional QTLs. These studies validate the use,
      in linkage analysis, of large cohorts of unselected twins phenotyped for multiple
      traits, and they highlight the importance of conducting genome scans in replicate
      populations as a prelude to positional cloning and gene discovery.

PMID- 12478482
TI  - Hemangioma of the salivary gland: a study of ten cases of a rarely
      biopsied/excised lesion.
AB  - Hemangioma is a common soft tissue tumor that frequently occurs in the oral and
      maxillofacial region including salivary glands, but is rarely biopsied and is
      therefore often unfamiliar to the surgical pathologist. Our study examined the
      subclassification and histologic features of salivary gland hemangioma (SGH).
      Consultative cases coded as hemangioma and located in salivary gland from 1970 to
      2000 were retrieved from the Registry of Oral and Maxillofacial Pathology of the
      Armed Forces Institute of Pathology (Washington, DC). Only cases with histologic
      evidence of salivary gland involvement were included. Slide material and patient
      history for all cases were reviewed, subclassification assigned, and histologic
      features were noted. Ten cases coded as hemangioma with slides and history met
      our inclusion criteria. Seven cases were the "juvenile hemangioma" subtype in the
      parotid of infants, ranging in age from 3 to 10 months (mean age, 5.3 months)
      with a male predominance. These SGH had a distinctive histologic appearance of a
      cellular proliferation of capillary sized vessels around retained salivary gland
      ducts. Mitoses were easily identified. Three additional cases in females included
      an arteriovenous hemangioma of a lip minor salivary gland since birth in a 15
      month-old infant and two parotid gland lesions: a lobular capillary hemangioma of
      a 10-year-old and a cavernous hemangioma in a 51-year-old. The latter three cases
      grew as replacing masses and lacked retained salivary gland ducts within the
      lesion, despite glandular tissue at the periphery of the tumor. No SGH cases in
      our series were identified in the submandibular or sublingual glands. Despite its
      common occurrence, SGH is relatively rare in our surgical pathology files. The
      parotid gland is the most common location (90%). Salivary gland hemangioma
      includes usual hemangioma subtypes, mainly in females, and a distinctive
      infantile subtype of capillary hemangioma (juvenile hemangioma), displaying
      distinctive histology and found predominately in males. The cellularity, mitotic
      activity, and retained salivary gland ducts in the latter lesion should not make
      one consider malignancy.

PMID- 12478483
TI  - Small cell carcinoma of the cervix: a clinicopathologic and immunohistochemical
      study of 23 cases.
AB  - Twenty-three patients with primary small cell carcinoma of the uterine cervix are
      presented. Their ages ranged between 23 and 63 years (average, 43 years). Blood
      spotting or vaginal bleeding was the most common clinical presentation.
      Histologically, the tumors were densely cellular and showed trabecular nesting or
      a sheet-like pattern. The neoplastic cells had scant cytoplasm, round nuclei,
      absence of nucleoli, and finely dispersed chromatin. Nuclear molding, single cell
      necrosis, and high mitotic activity were found in all tumors. There was a minor
      component of large cell neuroendocrine carcinoma in three cases, while foci of
      adenocarcinoma were identified in two cases. Immunohistochemical studies were
      performed in all 23 tumors which showed immunoreactivity for cytokeratin. Ten
      small cell carcinomas were immunoreactive for chromogranin, 13 for synaptophysin,
      and 10 expressed p53 protein. Treatment modalities included hysterectomy alone or
      combined with chemotherapy and/or radiation therapy. A few patients received
      chemotherapy and/or radiation alone. Follow-up information was obtained in 22
      cases; 15 patients died of tumor between 6 and 43 months, while seven patients
      have remained alive 12 to 273 months. One patient was lost to follow-up. Small
      cell carcinoma of the cervix is a highly aggressive neoplasm. However, early
      diagnosis and combined therapeutic modalities may lead to longer survival in some
      patients. Although the use of immunohistochemistry may be helpful in the
      diagnosis, small cell carcinoma still remains a morphologic diagnosis.

PMID- 12478484
TI  - E-cadherin expression in pleomorphic lobular carcinoma: an aid to differentiation
      from ductal carcinoma.
AB  - Pleomorphic lobular carcinoma is a recently described entity separated from
      classical lobular carcinoma by cytologic pleomorphism. It can have an aggressive
      clinical course with a higher frequency of recurrence. Histologic differentiation
      with ductal carcinoma may be difficult, but it is important for this
      differentiation to be made. E-cadherin is a transmembrane glycoprotein, and
      complete loss of E-cadherin expression has been observed in invasive lobular
      carcinoma and lobular carcinoma in situ. Ductal carcinoma retains at least some
      expression of E-cadherin. We examined the pattern of E-cadherin expression in a
      series of 14 cases of pleomorphic lobular carcinoma by immunohistochemistry.
      Twelve of the 14 cases showed no staining (86%); the remaining two cases
      exhibited 10% to 25% positive cells. In cases with histologic equivocal features,
      immunohistochemical detection of E-cadherin expression can be a useful diagnostic
      aid for the differentiation of pleomorphic lobular and ductal carcinoma.

PMID- 12478485
TI  - Neutrophil count in the normal appendix and early appendicitis: diagnostic index
      of real acute inflammation.
AB  - It is generally accepted that the uninflammed appendix does not contain
      neutrophils. In view of that, we searched for the presence of neutrophils in 60
      uninflammed appendectomies and compared the findings with the neutrophil count in
      20 cases of early appendicitis. In the uninflammed appendix, the upper third of
      the mucosa showed a mean of 0.75 neutrophils (N) per 5 high power fields (HPF),
      4.71 N/5 HPF in the middle third, and 2.70 N/5 HPF in the deep third. At the
      suberosa, a mean of 3.41 and 3.32 N per 10 post-capillary venules in respectively
      longitudinal and transverse sections of the organ were present. The number of
      neutrophils in the mucosa showed a positive correlation with the number in the
      subserosa. In the early appendicitis we observed a mean of 12.53 N/5 HPF in the
      upper third, 11.33 N/5 HPF in the middle third, and 13.0 N/5 HPF in the deep
      third; at the subserosa, a mean of 4.95 N/10 post-capillary venules in transverse
      sections and 4.45 N/10 post-capillary venules in longitudinal sections was
      observed. No positive correlation between N in the mucosa and subserosa was
      observed. The count of N in the mucosa of normal appendix and early appendicitis
      showed a significant difference (P <.005). We conclude that, although present,
      not more than 10 neutrophils/5 HPF are found in the mucosa of uninflammed
      appendixes. Neutrophil count in the lamina propria should support the diagnosis
      of "normal" appendix and could be an indicator for suspecting early appendicitis,
      preventing underdiagnosis.

PMID- 12478486
TI  - Adenocarcinomas of the gastrointestinal tract with prominent rhabdoid features.
AB  - Rhabdoid tumor, first described in kidneys of infants and children, is an
      aggressive tumor that has been reported in several extrarenal locations.
      Gastrointestinal tumors with rhabdoid features are extremely rare. The effect of
      the rhabdoid phenotype on the aggressiveness of gastrointestinal tumors remains
      unclear. We present four cases of rhabdoid tumors of the gastrointestinal tract
      involving the esophagus, stomach, and small intestine and discuss the
      clinicopathologic, immunohistochemical, and ultrastructural features. In the four
      cases reported herein, the patients' ages ranged from 52 to 73 years, and tumor
      size ranged from 3.8 to 13 cm in greatest dimension. The noncohesive rhabdoid
      cells exhibited an eccentric nucleus with a paranuclear inclusion, which was
      shown by electron microscopic examination to be composed of intermediate
      filaments. On immunohistochemical staining, the tumor cells were positive for
      vimentin and cytokeratin. Three patients developed distant metastasis shortly
      after diagnosis and died of disease within 2 to 10 months after initial
      presentation. A retrospective review of outcomes of the current cases and
      previously published literature showed that 12 (75%) of the 16 patients died
      within 6 months of presentation. Recognition of the rhabdoid phenotype in
      gastrointestinal tract neoplasms is important because this feature is associated
      with poor prognosis and unresponsiveness to conventional therapy.

PMID- 12478487
TI  - Basaloid tumors of the salivary glands.
AB  - Basaloid tumors of the salivary glands are a heterogeneous group of benign and
      malignant lesions characterized by small tumor cells with round or ovoid nuclei
      surrounded by a thin rim of cytoplasm. Primary salivary gland tumors with this
      predominant morphology include basal cell adenoma, basal cell adenocarcinoma,
      cellular pleomorphic adenoma, adenoid cystic carcinoma, and small cell
      undifferentiated carcinoma. Certain metastatic lesions and nonepithelial
      neoplasms can also demonstrate a basaloid appearance. Histologic diagnosis based
      on resected tumors is usually straightforward when the architecture can be
      adequately assessed. However, in limited biopsies and particularly in cytologic
      samples, the evaluation can be quite challenging. A systematic approach aided by
      immunohistochemistry is essential to arrive at an accurate diagnosis.

PMID- 12478488
TI  - Low-grade osteosarcoma of the jaw.
AB  - We describe a case of low-grade osteosarcoma of the jaw. The patient is a 25-year
      old woman who presented with large, nontender, slowly progressive, expansile left
      mandibular mass. X-ray showed a predominantly hypodense mass with erosive growth
      pattern affecting the angle, posterior body, and ramus of the left mandible. The
      patient underwent left hemimandibulectomy. The tumor was a white-tan, well
      circumscribed, multinodular, firm mass that measure 7.0 cm. Microscopically, the
      tumor was composed of bland spindle cells, with minimal cellular atypia, absent
      mitotic figures, very focal osteoid formation with extensive bone destruction,
      and soft tissue infiltration. Immunhistochemical stains for a large panel of
      antibodies were noncontributory. At present the patient is alive and well 7
      months after surgery.

PMID- 12478489
TI  - Angiomyolipoma of the bladder.
AB  - Angiomyolipoma of the bladder is an extremely rare neoplasm. We report a case of
      a 55-year-old woman with an angiomyolipoma of the bladder visualized on pelvic
      sonogram as a 5 mm polyp in the floor of the bladder. The lesional tissue
      consisted of spindle cells, epithelioid cells, and adipocytes, with occasional
      thick-walled blood vessels. Immunohistochemical studies showed the spindle and
      epithelioid cells to be focally positive for HMB-45 and diffusely positive for
      actin and muscle cell antigen (HHF-35), which confirmed the diagnosis of
      angiomyolipoma. A review of the recent literature on the pathogenesis of
      angiomyolipoma follows.

PMID- 12478490
TI  - Squamous cell carcinoma of the penis with rhabdoid features.
AB  - A 76-year-old man presented with a tumoral lesion in his penis that had all the
      light microscopic and immunohistochemical features of a squamous cell carcinoma
      with rhabdoid phenotype. We believe that this is the fourth reported case of
      squamous cell carcinoma with rhabdoid features and the first one located in the
      penis. Rhabdoid cells were primarily located in areas with an alveolar pattern,
      most of them being isolated and intermixed with necrotic cells and necrotic
      debris. We suggest that the rhabdoid phenotype could represent a type of
      degeneration, or a preliminary stage before apoptosis or cell necrosis, instead
      of a specific differentiation. In extrarenal tumors with rhabdoid features, stage
      and histologic types of tumors where rhabdoid changes occur are the most
      important prognostic factors.

PMID- 12478491
TI  - Clear cell papulosis of the skin.
AB  - Clear cell papulosis is a newly described entity first described in 1987. The
      disease, characterized clinically by multiple small whitish maculopapular
      lesions, shows scattered clear cells within the basal keratinocytes that are
      immunoreactive for antibodies against cytokeratin, carcinoembryonic antigen,
      epithelial membrane antigen, and gross cystic fluid protein-15 on histologic
      examination. To date, only 10 cases have been reported; all were young children
      below the age of 4 years. We report a case of clear cell papulosis in a 46-year
      old Indian woman.

PMID- 12478492
TI  - Glandular patterns in a thyroid carcinoma with insular and anaplastic features: a
      case with possible implications for the classification of thyroid carcinomas.
AB  - We describe the case of a 33-year-old woman with a thyroid carcinoma showing
      poorly differentiated (insular), anaplastic, and glandular features, the latter
      with extensive clear cell changes. Grossly, the well-circumscribed tumor nodule
      measured 3.6 cm in maximum dimension and was confined to the thyroid.
      Microscopically, the majority of the tumor was composed of well-defined "insular"
      nests showing microfollicular formation, high mitotic activity, and areas of
      necrosis. Other regions, as well as the intervening stroma of the insular nests,
      were characterized by highly atypical and pleomorphic stromal cells, extensive
      necrosis, and malignant cartilaginous nodules. Approximately 30% of the tumor was
      composed of diffuse glandular formations, each of which were lined by elongated,
      simple columnar cells with basally situated, mildly pleomorphic nuclei, clear
      supranuclear, periodic acid-Schiff + (and diastase sensitive) cytoplasm, empty
      lumens, and no myoepithelia or basement membranes. Immunohistochemically, the
      glandular elements displayed diffuse and strong positivity for thyroid
      transcription factor-1, bcl-2, and CAM 5.2, sparse positivity for thyroglobulin
      and Ki67, and diffuse but weak positivity for p53. Calcitonin was negative
      throughout the tumor. Karyotypic analysis of a primary culture showed a complex
      hypertriploid karyotype including structural abnormalities of chromosomes X, 1,
      4, 6, 9, 13, and 14 in the majority of cells examined. This composite of
      histologic findings, especially the glandular patterns, is unusual and their
      prognostic significance is unclear. The patient is alive with no evidence of
      tumor recurrence or metastasis at 5 months follow-up. Overall, the morphologic
      and immunohistochemical properties of the glandular component suggests that they
      are less differentiated than well-differentiated carcinomas and are probably more
      differentiated than the insular component. This case supports the theory that the
      various primary carcinomas of the thyroid may represent points along a spectrum
      rather than distinct entities.

PMID- 12478493
TI  - Let's make grading of squamous cell carcinomas more meaningful to clinicians (via
      "Ed's Insight").
AB  - Histologic grading of squamous cell carcinomas seems to lack clinical import or
      usefulness in most instances. Perhaps this is because we are doing it
      incorrectly. This article suggests a simple grading philosophy that potentially
      may prove more meaningful. Comments about the nature of verrucous carcinoma are
      included.

PMID- 12478495
TI  - Pharmaceutical initiatives to combat atherosclerosis--what to do with the good,
      the bad, and the ugly lipoproteins.
AB  - The patient with peripheral arterial disease (PAD) poses a special problem. Not
      only are vascular surgeons interested in preventing the limb complications of
      PAD, but also the associated cardiac and neurological events that contribute
      greatly to the overall morbidity and mortality of their patients. Therefore, the
      control of atherosclerotic risk factors must be considered as important a
      therapeutic goal as surgical and endovascular control of limb ischemia. To
      accomplish this, the "complete" vascular surgeon must understand the common lipid
      abnormalities, their diagnosis, and treatment. The scientific literature on this
      subject is truly overwhelming in volume and scope, yet an overly simple "cook
      book" approach is not adequate or appropriate. This report summarizes current
      knowledge on this topic, providing sufficient essential detail for the reader to
      understand why, when, and how to administer which lipid-controlling agents to
      patients with PAD.

PMID- 12478496
TI  - Syndrome X and diabetes: what is the mystery?
AB  - Syndrome X describes a combination of clinical phenomena that have been
      statistically linked to hyperinsulinema in the absence of frank diabetes. Since
      its original description, Syndrome X has come to represent several phenotypes
      that have hemodynamic and metabolic effects on the individual, as well as major
      effects on the development of vascular disease. Further, this syndrome is
      reaching epidemic proportions, As such, a thorough understanding of this
      condition is becoming increasingly important for the modern vascular surgeon. The
      mainstay of therapy revolves around early diagnosis and management with diet
      changes, exercise, and reduction of cardiovascular risk factors.

PMID- 12478497
TI  - Treatment of hypertension from volume to vasoconstriction: The ACE up your
      sleeve.
AB  - Control of hypertension in the vascular patient is clearly a priority. However,
      these patients often will have significant co-morbidities that may influence the
      choice of medication, a decision that also may be affected by cost or Health Plan
      directives. Wherever possible, monotherapy should be attempted first, although in
      select circumstances combination therapy may be more appropriate. The 5 main
      categories of drugs used in the initial treatment of hypertensive vascular
      diseases are (1). diuretics, (2). beta-adrenergic blockers, (3). calcium channel
      blockers, (4). angiotensin-converting enzyme (ACE) inhibitors, and (5).
      angiotensin receptor blockers (ARBs). There are also other less commonly used
      drugs. Each of the antihypertensive agents is roughly equally effective,
      producing a good antihypertensive response in 40% to 60% of cases. Some
      antihypertensives, especially ACE and ARBs, also may have beneficial effects on
      the vascular and metabolic systems separate from their blood pressure lowering
      effects, which suggests they may be beneficial even if blood pressure is well
      maintained with other agents. This report covers the basic information required
      for the vascular surgeon to become familiar with the various medications and
      their indications, dosage, and side effects. It also provides some guidelines in
      selecting relevant antihypertensive treatment regimens for the elderly patient
      with arterial vascular disease.

PMID- 12478498
TI  - Can claudication be improved with medication?
AB  - Intermittent claudication is a common disabling condition that affects
      approximately 5% to 15% of patients with atherosclerotic disease. Recommended
      treatment involves lifestyle modification and physical conditioning through the
      adoption of a regular exercise program. These methods of treatment often have
      been unsuccessful in the past because of noncompliance, in large part related to
      the relatively minor degree of improvement experienced by the patient. However,
      some recent trials have resulted in greater relative improvements in both pain
      free and maximal walking distances in some patients treated with medication.
      Surgical and endovascular options offer greater degrees of improvement but also
      greater morbidity and should be reserved as treatment for severe claudication.
      The efficacies, as well as common adverse reactions associated with current
      medications used to treat patients with intermittent claudication are reviewed.

PMID- 12478499
TI  - Platelets: is aspirin sufficient or must we know how to pronounce abciximab?
AB  - Although vascular disease may present with symptoms that are representative of a
      focal exacerbation of atherosclerosis, it is inherently a systemic disease.
      Consequently, vascular surgeons must be capable of recommending to their patients
      pharmacologic approaches that will decrease future risk of cardiovascular-related
      morbidity and death. Antiplatelet treatments, in particular, have been shown to
      reduce future cerebrovascular and coronary events. Moreover, these medications
      have utility in maintaining peripheral vessel and graft patency after surgical
      bypass, endarterectomy, or percutaneous translumenal angioplasty. The future of
      optimal antiplatelet therapy will consist of strategies that block multiple
      platelet activation pathways simultaneously. Moreover, the use of directed
      antiplatelet medications promises more effective control of platelet physiology
      with a concomitant increase in safety. The authors review herein current
      recommendations for the use of aspirin, thienopyridines, and GP IIb/IIIa
      inhibitors in patients with peripheral vascular disease.

PMID- 12478500
TI  - Anticoagulants: to bleed or not to bleed, that is the question.
AB  - Thromboembolic vascular diseases remain the main cause of death in Western
      industrialized societies. Anticoagulants retard the formation, growth, and
      embolization of thrombi and are effective agents in the prevention and treatment
      of thromboembolic disease. Anticoagulants in venous thromboembolism have been
      investigated extensively with rigorous randomized, controlled trials, while the
      roles for anticoagulants in arterial thromboembolism generally have evolved
      through natural history studies and empirical practice. Thus, many current
      guidelines for anticoagulant use in arterial disease are based on successful
      established routines and rational therapy. To effectively balance the efficacy
      and risks of anticoagulation, the vascular surgeon needs a thorough understanding
      of anticoagulant drugs, their mechanisms of action, and their proven and unproven
      indications. Since the first use of heparin in arterial surgery, a variety of new
      and different anticoagulants have become available, including low-molecular
      weight heparins, heparin-like drugs, hirudins, and thrombin inhibitors. Despite
      their diverse actions, they all inhibit some portion of the plasma coagulation
      cascade, thus distinguishing them from platelet inhibitors or fibrinolytics.
      Every interference with the coagulation cascade carries a risk of minor, major,
      or fatal hemorrhage. To date, no drug or therapeutic strategy has succeeded fully
      in dissociating its antithrombotic effects from its risks of bleeding.

PMID- 12478501
TI  - Antibiotics-why so many and when should we use them?
AB  - Antibiotic prophylaxis in vascular surgery has been proven beneficial to reduce
      surgical site infections after reconstruction of the aorta, procedures on the leg
      that involve a groin incision, any procedure that implants a vascular prosthesis
      or endoluminal stent, and lower extremity amputation for ischemia. Bactericidal
      antibiotics administered before induction-cefazolin or cefuroxime for 1 to 2 days
      alone or in combination with vancomycin if a hospital wound surveillance program
      indicates a high incidence of methicillin-resistant Staphylococcus aureus
      infection-is recommended. If a patient is felt to be at increased risk for
      infection and require prosthetic grafting, the use of a rifampin-soaked (1 mg/mL)
      gelatin- or collagen-impregnated graft may decrease the incidence of wound and
      graft infection. Antibiotic treatment of established vascular graft infections
      should begin with broad-spectrum coverage for expected pathogens (S aureus,
      Staphylococcus epidermidis, Gram-negative bacteria) followed by culture-specific
      therapy based on antibiotic susceptibility testing. Specific antibiotic usage
      involves a decision regarding efficacy to expected or isolated pathogens versus
      its potential side effects and the drug costs. New applications for antibiotics
      in vascular surgery include the use of specific tetracyclines (doxycycline,
      azithromycin) as an inhibitor of matrix metalloproteinases to retard aortic
      aneurysm growth or for their antiinflammatory properties to retard atherogenesis
      related to Chylamydia pneumoniae.

PMID- 12478502
TI  - Miscellaneous medications for the management of atherosclerosis: mayhem or
      miracle?
AB  - A plethora of agents have been proposed to combat atherosclerosis, and many of
      these come from outside mainstream medicine. The majority have anti-oxidant
      properties, which is the scientific basis for their supposed action. Some of
      these agents have been evaluated carefully in randomized, double-blinded studies,
      whereas others have gained popularity despite a paucity of valid data. Although
      many are prescribed or physician recommended, most are used without the knowledge
      of the patient's physician. In some cases these "medications" may have harmful
      side effects or impact negatively on other aspects of the patients medical or
      surgical care. Others, however, may be extremely beneficial although not utilized
      because the doctor is unaware of their potential. Accordingly, it is important
      that the vascular surgeon become acquainted with these compounds. This report
      attempts to summarize the most commonly used herbs, vitamins, foods and other
      sundry "treatments" and makes recommendations for their use based on our current
      understanding of their scientific and clinical merit.

PMID- 12478503
TI  - Extensively porous-coated femoral revision for severe femoral bone loss: minimum
      10-year follow-up.
AB  - Of 275 femoral revisions done at our institution from 1982 to 1986, we identified
      34 patients (35 hips) who represented the senior author's (C.A.E., Sr.) most
      difficult revision cases as a result of extensive femoral bone loss at least 10
      cm below the lesser trochanter. The patients were revised with fully porous
      coated femoral components >or=190 mm. We evaluated 25 of the patients (26 hips)
      who had a minimum 10-year follow-up (mean, 13.3 years). Survivorship was 89% at
      10 years with femoral revision as the endpoint (Kaplan-Meier). The femoral
      aseptic loosening rate was 15% (4 of 26). Three stems were loose but did not
      warrant reoperation. One stem was revised for aseptic loosening, 1 was revised
      for septic loosening, and 1 was revised for a fractured femoral component.
      Bypassing weak or absent femoral bone with an extensively porous-coated stem is
      an effective reconstructive technique for patients with extensive femoral bone
      loss.

PMID- 12478504
TI  - Posterior cruciate-retaining modular total knee arthroplasty: a 9- to 12-year
      follow-up investigation.
AB  - Between November 1988 and January 1991, 101 press-fit condylar (PFC; Johnson &
      Johnson, Raynham, MA) posterior cruciate-retaining total knee arthroplasties were
      performed in 75 patients. All tibial components were modular metal-backed, and
      all patellar components were all-polyethylene. All living patients were evaluated
      at an average 10.5 years (range, 9.5-11.8 years). Only 1 knee required revision
      (at 11.1 years after the procedure), and only 1 other knee had evidence of
      radiographic failure. The average range of motion was 1 degrees (range, 0 degrees
      -10 degrees ) to 110 degrees (range, 86 degrees -130 degrees ). At 10 years of
      follow-up, the probability of prosthesis survival was 100%, and at 12 years, the
      probability of prosthesis survival was 93.3% (endpoint defined as revision for
      any reason).

PMID- 12478505
TI  - Functional outcome after total knee arthroplasty revision: a meta-analysis.
AB  - The objective of this study was to perform a systematic literature review to
      describe patient outcome after total knee arthroplasty revision procedures using
      various global knee score ratings. English language articles published from 1966
      through 2000 were identified through a computerized literature search and
      bibliography review. A multistage assessment was used to determine the articles
      containing data that could meet our objective. Meta-analyses of global knee
      scores were undertaken using a fixed effects model with the assumption that the
      variances of each individual measurement were identical across studies. The
      initial inclusion criteria were met by 58 articles with a total of 1965 patients.
      There were 42 articles comprising 45 unique patient cohorts and a total of 1515
      patients that had sufficient global knee score data for analysis and were used in
      the meta-analyses. Revision total knee arthroplasty is an effective procedure for
      failed knee arthroplasties based on global knee rating scales.

PMID- 12478506
TI  - Bipolar hemiarthroplasty in juvenile rheumatoid arthritis: long-term survivorship
      and outcomes.
AB  - Because controversy surrounds the management of end-stage hip disease in juvenile
      rheumatoid arthritis (JRA), this study evaluated the long-term outcome of bipolar
      hemiarthroplasty as an alternative to conventional joint arthroplasty. A total of
      24 JRA patients underwent 39 hemiarthroplasties; follow-up averaged 12 years
      (range, 3 to 15 years). There were 14 hips (36%) revised, and 25 hips (64%)
      maintained the original components. Mean Harris hip scores in surviving hips
      improved from 29 to 69 points (P<.001). Radiographs showed progressive bipolar
      superomedial migration (P<.01) despite attempted augmentation. Failure defined as
      revision to total hip arthroplasty or definite radiographic loosening occurred in
      15 hips (38%). Ten-year Kaplan-Meier survivorship for all prostheses was 78%.
      Independent multivariate risk factors for failure included acetabular grafting (P
      =.006), prosthesis type (P<.001), and unilateral replacement (P<.001).

PMID- 12478507
TI  - A study of polyethylene and modularity issues in >1000 posterior cruciate
      retaining knees at 5 to 11 years.
AB  - Polyethylene quality and production technique and monoblock versus modular design
      of tibial components affect the polyethylene wear of total knee arthroplasties
      (TKAs). We reviewed >1000 TKAs performed with the AGC prosthesis (Biomet, Warsaw,
      IN) using a uniform surgical technique with a 5- to 11-year follow-up. Of tibial
      components, 698 were of compression-molded monoblock design and 353 were of ram
      extruded modular assembly design. The effect of the differences in tibial
      component design on the 5- to 11-year clinical and radiologic outcomes was
      studied. Higher rates of osteolysis, radiolucent lines, and revision were found
      with the ram-extruded modular design. This modular design is similar to most
      tibial component designs currently used in TKA, yet osteolysis in completely
      cemented components is described rarely. The TKAs done with a compression-molded
      monoblock design gave better clinical and radiologic results. The improved
      results may be due to polyethylene quality, assembly design, or a combination of
      these factors.

PMID- 12478508
TI  - A radiographic study of the detection limits of bone-cement remnants in total
      joint arthroplasty.
AB  - Management of an infected hip prosthesis typically requires that all associated
      cement be removed. In the absence of gross mantle loosening, the surgeon
      frequently resorts to intraoperative radiographs to assess the completeness of
      removal. For this reason, we undertook a study to determine limits of detection
      of retained cement by routine radiography. Polymethyl methacrylate bone-cement
      beads (Simplex-P; Stryker-Howmedica-Osteonics, Allendale, NJ) were fashioned into
      graduated sizes and placed within cadaver medullary canals using 2 different
      methods. Standard radiographic images were obtained. Individually and
      independently, we viewed these images and proposed the limit of resolution to be
      2.4 to 3.2 mm. It is difficult to remove all cement based on radiographs alone.
      These results suggest a need to use techniques that permit visualization of the
      canal to ensure adequate cement removal.

PMID- 12478509
TI  - The effect of anteversion on femoral component stability assessed by
      radiostereometric analysis.
AB  - Internal rotation of a femoral stem within the femur, with posterior migration of
      the femoral head (PHM) relative to the femur, is an important mode of failure.
      The relationship between anteversion and rotational stability for the Exeter
      (Howmedica International Ltd, London, UK) and Charnley Elite (DePuy International
      Ltd, Leeds, UK) stems was investigated using radiostereometric analysis (RSA).
      For the Elite, there was a significant (P=.01) correlation between anteversion
      and PHM, whereas for the Exeter, there was no significant correlation (P=.6).
      Increasing anteversion of the Elite was associated with decreasing PHM and
      increased stability. Of stems, 20% of the Elite and none of the Exeter were
      classified as having reduced rotational stability because their PHM was >2 SDs
      from the mean. All reduced rotational stability implants had anteversion
      substantially <20 degrees. Polished collarless tapered stems such as the Exeter
      seem to have enhanced rotational stability. For conventional stems, increasing
      anteversion increases stability. It is recommended that these stems are
      anteverted 20 degrees.

PMID- 12478510
TI  - Early dislocation after total hip arthroplasty: are postoperative restrictions
      necessary?
AB  - We studied prospectively 499 cases of primary total hip arthroplasty done through
      an anterolateral approach to establish the early dislocation rate when
      restrictions on postoperative mobilization were not imposed. There were 3 early
      dislocations (within 6 weeks of surgery). All were reduced closed, and every
      patient subsequently achieved a stable hip without further intervention. Our
      results suggest that a low early dislocation rate can be achieved using an
      anterolateral approach without the need to restrict patients' postoperative
      mobilization. It may not be appropriate, however, to remove these restrictions
      when using other surgical approaches to the hip.

PMID- 12478511
TI  - Cemented ceramic YMCK total knee arthroplasty in patients with severe rheumatoid
      arthritis.
AB  - Total knee arthroplasty (cemented) using a ceramic Yokohama Medical Ceramic Knee
      (YMCK) (Kyocera Corp; Kyoto, Japan) prosthesis was evaluated in 90 knees of 64
      patients with severe rheumatoid arthritis, with a mean age of 59 +/- 11 years.
      The mean follow-up period was 56 +/- 20 months (range, 27 to 97 months). Larsen's
      grading of rheumatoid arthritis revealed grade 2 in 3, grade 3 in 36, grade 4 in
      36, and grade 5 in 15 of 90 knees. Of 64 patients, 9 were judged to have class 1,
      30 were judged to have class 2, and 25 were judged to have class 3 functional
      disability. The American Knee Society knee score and function score improved from
      41 +/- 16 and 29 +/- 22 preoperatively to 83 +/- 14 and 50 +/- 29 at the final
      follow-up (P <.0001) even in patients with multiple joint involvement.
      Radiographs at the final follow-up showed satisfactory insertion of all
      prostheses, with no osteolysis. A radiolucent line measuring <1 mm was observed
      around the tip of the pegs of the patellar dome in 3 knees. Complications
      consisted of infection (1 case) and femoral fractures (3 cases). There were no
      cases of ceramic fractures.

PMID- 12478512
TI  - Accuracy of implantation of a unicompartmental total knee arthroplasty with 2
      different instrumentations: a case-controlled comparative study.
AB  - The accuracy of implantation is an accepted prognostic factor for the long-term
      survival of unicompartmental total knee arthroplasties (UKAs). We adapted the
      conventional instruments for tricompartmental total knee arthroplasty
      implantation, with intramedullary femoral and extramedullary tibial guiding rods,
      to a UKA implantation. A total of 52 patients in whom a UKA was implanted with
      this instrumentation were matched (using age, sex, body mass index, preoperative
      coronal mechanical femorotibial angle, and severity of preoperative degenerative
      changes according to Ahlback) with 52 patients operated with the alternative
      instruments. Accuracy of implant placement measured by radiography was improved
      significantly by the new instrumentation, but there was no difference in the
      survival rate or the clinical outcome after 5 years in both groups. No
      complication related to the new instrumentation occurred. Longer follow-up is
      required to determine the advantages and disadvantages of both techniques.

PMID- 12478513
TI  - Stem fracture of the cementless spongy metal Lubeck hip prosthesis.
AB  - We performed 204 cementless total hip arthroplasties using a fully porous stem
      made of a cast cobalt-chrome-molybdenum alloy. Five stems fractured at the middle
      part. Champagne-fluted canals (P<.0001) and low canal fillings 1 cm below the
      lesser trochanter (P =.02) significantly correlated with stem fractures.
      Subsequent surgery revealed that all of the proximal parts were surrounded by
      fibrous tissue, and the distal parts showed bone ingrowth. Numerous voids were
      present close to the surface of the implant body. The core diameters of the
      fractured stems were 4 to 5 mm. The fractures may be attributed to the
      combination of the lack of proximal support, a champagne-fluted canal, the fully
      porous stem made of a cast cobalt-chrome-molybdenum alloy, and the narrow
      dimension of the stem core.

PMID- 12478514
TI  - Anthropometry of the proximal tibia to design a total knee prosthesis for the
      Japanese population.
AB  - Anthropometric data on proximal tibiae of 100 knees in 80 Japanese patients
      undergoing total knee arthroplasty were obtained. Anterior-posterior (AP) and
      medial-lateral (ML) lengths of the tibia were measured on computed tomography
      scans and intraoperatively on tibial resection surfaces. A special small
      component is unnecessary, and size variation should focus on ML length of 65 to
      75 mm because this includes 90% of women's knees. AP-to-ML ratio had a negative
      correlation with ML length, indicating that small knees were longer in the AP
      direction. Most prostheses had AP mismatch up to 5 mm for small women's knees.
      These data could provide the basis for designing the optimal tibial component for
      most of the Asian-Pacific population.

PMID- 12478515
TI  - The effects of varus tibial alignment on proximal tibial surface strain in total
      knee arthroplasty: The posteromedial hot spot.
AB  - The aim of this study was to determine the effect of varus tibial alignment on
      proximal tibial strain in total knee arthroplasty. Fourteen paired fresh-frozen
      cadaver tibiae had photoelastic coating applied. The right tibiae were cut in
      neutral alignment, and the left tibiae were cut in 5 degrees of varus. Components
      were cemented and loaded with 3 x body weight, varying medial to lateral load.
      Surface microstrain was measured. There was a statistically increased hot spot of
      highly concentrated strain in the posteromedial quadrant of the proximal tibia in
      varus-cut bones (P<.05). In neutral alignment, the strain was nearly equal medial
      and lateral. The increased strain observed helps elucidate the mechanism of
      increased failure rates of a total knee arthroplasty inserted in varus alignment.
      Neutral alignment may have a protective effect.

PMID- 12478516
TI  - In vivo determination of posterior femoral rollback for subjects having a NexGen
      posterior cruciate-retaining total knee arthroplasty.
AB  - This study determines the in vivo kinematics during a deep-knee bend activity for
      subjects implanted with a posterior cruciate-retaining total knee arthroplasty
      having asymmetric geometries. Of 20 subjects, 19 experienced posterior femoral
      rollback (PFR) of the lateral condyle (average -3.9 mm), and 13 subjects
      experienced PFR of the medial condyle (average -3.1 mm). As a result of the
      lateral condyle rolling further posterior than the medial condyle, on average,
      subjects experienced 1.4 degrees of normal axial rotation. Of 20 subjects, 10
      experienced normal axial rotation, whereas 10 experienced an opposite rotation
      pattern. Condylar lift-off occurred predominantly with the lateral condyle.
      Contrary to previous in vivo studies, the subjects in this study experienced
      consistent PFR of the posterior cruciate-retaining total knee arthroplasty. It
      can be hypothesized that having asymmetric femoral condyles may lead to PFR with
      increasing knee flexion.

PMID- 12478517
TI  - In vivo determination of knee kinematics for subjects implanted with a
      unicompartmental arthroplasty.
AB  - Femorotibial contact positions for 20 subjects implanted with a unicompartmental
      knee arthroplasty (UKA) were analyzed using videofluoroscopy. Femorotibial
      contact paths were determined using a computer-automated model-fitting technique.
      Subjects having a medial UKA experienced on average -0.8 mm of posterior femoral
      rollback, whereas subjects having a lateral UKA experienced -2.5 mm of posterior
      femoral rollback. Twelve of 17 subjects having a medial UKA and 2 of 3 subjects
      having a lateral UKA experienced normal axial rotation (average, 3.3 degrees and
      11.2 degrees ). The results for some subjects suggest that the anterior cruciate
      ligament was unable to thrust the femur anteriorly at full extension. These
      results support the findings that the anterior cruciate ligament plays a
      significant role in knee kinematics, which may contribute to UKA longevity.

PMID- 12478518
TI  - Revision of polyethylene acetabular liners with a cemented polyethylene cup: a
      laboratory study.
AB  - Various technique parameters for the revision of failed polyethylene acetabular
      liners using a cemented polyethylene cup were evaluated in this laboratory study.
      The effects of cement mantle thickness and roughening the inner surface of the
      shell or outer surface of the cup were determined by measuring cup dissociation
      strength from the metal shell after cyclic loading of the cup. The use of a
      cement mantle thickness of 2 to 4 mm provided dissociation strengths 3 to 4 times
      greater than that of the original, press-fit polyethylene liner. If a failed
      acetabular liner is revised by a cemented cup within the existing, well-fixed,
      metal shell, the size of the cup selected should create a cement mantle of <4 mm.
      Roughening the inside of a smooth shell or one with few screw-holes increases
      fixation strength approximately 20% but also creates particulate debris.

PMID- 12478519
TI  - Periprosthetic fracture of the tibia associated with osteolysis caused by failure
      of rotating patella in low-contact-stress total knee arthroplasty.
AB  - Periprosthetic fracture of the tibial plateau associated with osteolysis
      resulting from mechanical failure of the rotating patellar component after total
      knee arthroplasty with the New Jersey Low-Contact-Stress (LCS) knee (DePuy,
      Warsaw, IN) has not been reported previously. A 67-year-old woman with rheumatoid
      arthritis of the left knee had a LCS prosthesis implanted without cement, using a
      rotating patellar component. Seven years later, a fracture of the lateral tibial
      plateau occurred owing to an osteolytic defect with no traumatic accident. The
      rotating patellar bearing over-rotated and locked; consequently, wear occurred
      between the patellar metal tray and the femoral component. Immunohistochemistry
      revealed CD68-positive macrophages in the osteolytic region and phagocytosis of
      metal particles. The osteolytic region was filled with autogenous bone, and all
      components were exchanged and cemented. The patient's condition became
      satisfactory with relief of pain.

PMID- 12478520
TI  - Fat embolism in revision total hip arthroplasty.
AB  - Two patients developed fat embolism syndrome after revision of loose total hip
      arthroplasties (THAs). During both procedures, the prosthesis became rigidly
      fixed 1 to 1.5 cm before the expected level of fixation. After uncomplicated
      operative courses, Patient A remained obtunded and febrile for 2.5 days, and
      Patient B died 1 day postoperatively. In Patient A, a presumptive diagnosis of
      fat embolism syndrome was based on the postoperative course and a radiograph of
      the lungs. In Patient B, the diagnosis was confirmed by evidence of cerebral
      edema on a computed tomography scan of the head. Fat embolism syndrome is
      unexpected after revision THA because the fatty tissue is removed from the
      femoral canal during primary THA. In these 2 cases, the rigid fixation and
      multiple attempts to impact and subsequently to remove the prosthesis may have
      caused fat embolism syndrome.

PMID- 12478521
TI  - Treatment of an intraoperative patellar fracture during revision total knee
      arthroplasty.
AB  - An intraoperative vertical patellar fracture occurred through a central
      osteolytic defect during removal of a metal-backed patellar component. The
      fracture was treated successfully with cerclage wire fixation and implantation of
      a cemented patellar component.

PMID- 12478522
TI  - Fatal warfarin-induced skin necrosis after total hip arthroplasty.
AB  - Skin necrosis associated with warfarin anticoagulation is a rare but serious
      complication. Few cases of warfarin-induced skin necrosis are found in the
      orthopaedic literature. We report a fatal case of warfarin-induced skin necrosis
      after total hip arthroplasty.

PMID- 12478523
TI  - Septic arthritis of the hip after percutaneous femoral artery catheterization.
AB  - Infection of the hip joint can cause severe articular damage. Standard treatment
      of septic arthritis includes surgical debridement and intravenous antibiotics.
      Options for definitive management in the presence of joint destruction include
      excision arthroplasty, arthrodesis, and total hip arthroplasty. Two cases of
      septic arthritis of the hip as a complication of femoral artery cannulation are
      presented. These cases highlight a potential complication that may not be readily
      appreciated by clinicians who routinely perform femoral vascular cannulation.
      After all evidence of ongoing infection had disappeared, both cases ultimately
      were treated with total hip arthroplasty. Both patients have improved function
      and pain at 2.5 and 5 years of follow-up. Given the frequency with which femoral
      intravascular catheters are used in numerous procedures, methods of avoiding
      infection of the hip joint must be implemented. These 2 cases emphasize the
      potential risks of these procedures and show management with total hip
      arthroplasty.

PMID- 12478524
TI  - A comparison of the wear and physical properties of silane cross-linked
      polyethylene and ultra-high molecular weight polyethylene.

PMID- 12478526
TI  - Perioperative blood salvage as an alternative to predonating blood for primary
      total knee and hip arthroplasty.

PMID- 12478529
TI  - Prevalence and methodology of patch testing by allergists in the United States:
      results of a cross-sectional survey.
AB  - BACKGROUND: Patch testing is considered the gold standard for the diagnosis of
      allergic contact dermatitis. Whereas previous surveys have evaluated the patch
      testing practices of dermatologists, little information is available on the use
      of patch testing by allergists. OBJECTIVE: The objective of this study was to
      examine the prevalence of patch testing and associated methodologies used by
      allergists in the United States. METHODS: A cross-sectional survey of all US
      Fellows of the American Academy of Allergy, Asthma and Immunology was conducted.
      RESULTS: Of 1,239 questionnaires mailed, 519 (42%) were returned. Fifty-three
      percent of allergists reported performing patch testing. The majority (89%) patch
      tested 5 or fewer patients per month. Allergists who evaluated for latex allergy
      were twice as likely to patch test than those who did not. The most common patch
      test reading schedule was at both 48 and 72 hours (48%). Thirty-three percent of
      respondents performed only a single patch test reading. The majority (72%) used
      TRUE Test. Only 4% patch tested for Type IV allergy to dust mites. CONCLUSION:
      Many more allergists patch test than initially hypothesized. The patch testing
      methodologies used by allergists are similar to those of dermatologists.

PMID- 12478530
TI  - American College of Allergy, Asthma & Immunology Patch Testing and Allergic
      Dermatologic Disease Survey: use of patch testing and effect of education on
      confidence, attitude, and usage.
AB  - BACKGROUND: The patch test is an important tool for the diagnosis of contact
      dermatitis. In the past few years, allergists have shown increased interest in
      the diagnosis of contact dermatitis and the use of patch testing. OBJECTIVE: The
      aim of this study was to determine (1) the frequency of usage of the patch test
      among allergists, (2) the factors that affect the decision to patch test, and (3)
      the need for training the allergist to perform patch testing. METHOD: A single
      mailing survey was sent to all the members of the American College of Allergy,
      Asthma and Immunology (ACAAI). RESULTS: Fifty-seven percent of responding
      allergists performed patch testing but did so infrequently. Those who were
      fellowship trained in patch testing or attended a sponsored workshop performed
      the test more frequently than those with no training. Those who perceived the
      patch test as useful also were more likely to perform the test. Fellowship
      trained members felt more confident than workshop-trained members in performing
      the test, and both, in turn, were more confident than members with no training.
      Trained physicians also were more likely to find the test useful compared with
      those with no training in patch testing. CONCLUSIONS: Education through
      fellowship training and workshop was associated with greater self-confidence of
      the allergist in his/her ability to perform patch testing. Education also was
      associated with increased perception of patch test utility and increased usage of
      the test.

PMID- 12478531
TI  - Relationship of occupation to contact dermatitis: evaluation in patients tested
      from 1998 to 2000.
AB  - BACKGROUND: Both irritant and allergic contact dermatitis can be influenced by
      occupational and nonoccupational environmental exposures. OBJECTIVE: The aim of
      this study is to compare the occupations and allergens of occupational contact
      dermatitis cases with nonoccupational contact dermatitis cases. METHODS:
      Diagnostic patch testing was conducted with the 50 screening allergens of the
      North American Contact Dermatitis Group and occupational coding by the
      Surveillance Branch of the National Institute of Occupational Safety and Health.
      RESULTS: Of the 5,839 patients patch tested for contact dermatitis, 1,097 (19%)
      were deemed to be occupationally related. Of the occupational cases, 60% were of
      allergic and 32% were of irritant origin. The hands were the primary body part
      affected in 64% of allergic occupational cases and 80% of irritant occupational
      cases. Epoxy resin was the only allergen tested that was associated more with an
      occupational exposure than nonoccupational exposure. The allergens encountered
      most frequently in the occupational cases were carba mix, thiuram mix, epoxy
      resin, formaldehyde, and nickel. The medical field is overrepresented in the data
      compared with other occupations. CONCLUSIONS: Occupational contact dermatitis
      frequently was found to be multifactorial and associated with several specific
      allergens and occupations.

PMID- 12478532
TI  - Regional variation in prevalence and etiology of allergic contact dermatitis.
AB  - BACKGROUND: The 1994-1996 North American Contact Dermatitis Group (NACDG) patch
      test results were the first, since the inception of the NACDG in 1970, to include
      results from a medium-sized metropolitan city in the Midwest. OBJECTIVE: The aim
      of this study was to determine whether the causative allergens of allergic
      contact dermatitis (ACD) in the Midwest differ from those in other regions of the
      United States and, if so, whether occupational or other factors account for the
      observed differences. METHODS: Retrospective analyses of patch test data
      collected at the University of Kansas Medical Center (Kansas City, KS) were
      compared with the data collected by the other NACDG centers. RESULTS: Patients in
      Kansas City were statistically more likely to react to potassium dichromate,
      formaldehyde and its releasers, methylchloroisothiazolinone/methylisothiazolinone
      (MCI/MI), and glutaraldehyde. Occupational exposures to chromium and formaldehyde
      were increased significantly among patients from Kansas City, although the
      percentages of the local population engaged in these occupations did not differ
      from those in other NACDG cities. Equal percentages of workers in Kansas City and
      nationally had occupationally related allergy to glutaraldehyde, although the
      overall rate of glutaraldehyde was higher among patients from Kansas City. Most
      cases of relevant allergy to MCI/MI were cosmetically induced both in Kansas City
      and nationally. CONCLUSIONS: The current findings show significant regional
      differences in causal allergens. The increased percentages of patients seen with
      ACD to formaldehyde, formaldehyde-releasing agents, and potassium dichromate in
      Kansas City were likely caused by the referral of greater numbers of work-related
      cases. However, occupationally acquired ACD to MCI/MI and glutaraldehyde were not
      more frequent in Kansas City than nationally, suggesting that other factors might
      be operative. Although awareness of national trends is important, dermatologists
      must be cognizant of regional variations in allergen sources within their
      communities and referral networks.

PMID- 12478533
TI  - Prevalence and methodology of evaluation for latex allergy among allergists in
      the United States: results of a cross-sectional survey.
AB  - BACKGROUND: Natural rubber latex allergy is a potentially life-threatening, Type
      I, immediate allergic reaction. Despite great strides in identification of high
      risk groups, methods for diagnosis remain limited in the United States.
      OBJECTIVE: The objective of this study was to estimate the prevalence of
      evaluation for latex allergy and methodologies used by allergists in the United
      States. METHODS: A cross-sectional survey of all US Fellows of the American
      Academy of Allergy, Asthma and Immunology was conducted. RESULTS: Of 1,239
      questionnaires mailed, 519 (42%) were returned. Ninety-five percent of responding
      allergists reported evaluating patients for latex allergy. RAST and skin prick
      testing were the most commonly used tests. Sixty-two percent of respondents
      reported performing prick testing for latex allergy, with those in academic
      practices significantly more likely to do so. Whereas respondents practicing in
      the Northern United States were significantly more likely to evaluate for latex
      allergy than those in the Southern United States, no associations were found
      between practice location and prick testing for latex allergy. There was no
      association between practice type and evaluation for latex allergy. Only 6% of
      allergists reported ever witnessing a patient with anaphylaxis during latex
      allergy testing. CONCLUSIONS: Almost all responding allergists evaluated patients
      for latex allergy, with approximately two thirds utilizing prick testing.

PMID- 12478534
TI  - Low-molecular-weight contact allergens in p-tert-butylphenol-formaldehyde resin.
AB  - BACKGROUND: p-tert-Butylphenol-formaldehyde resin (PTBPFR) is a contact allergen
      that is included in most standard patch test series. This resin consists of a
      large number of substances most of which are unknown. OBJECTIVE: The aim of this
      study was to investigate if allergens in PTBPFR are molecules mainly of low (MW <
      250), medium, or high molecular weight (MW > 1,000); to isolate and identify some
      of the low molecular weight components of the resin; and for new substances to
      determine if these were allergens. METHODS: Gel permeation chromatography, patch
      testing, high-pressure liquid chromatography, mass spectrometry, and nuclear
      magnetic resonance spectrometry were used. RESULTS: Patch test reactions
      indicated allergens in low-, medium-, and high-molecular-weights fractions. The
      strongest patch test reactivity was seen to a medium molecular weight fraction
      constituting only 6% wt/wt of the resin for 4 of the patients. Two patients
      reacted positively to low molecular weight fractions, and one of these patients
      reacted only to these fractions. The following substances were isolated: 4-tert
      butyl-[1,2]benzoquinone, 4-tert-butyl-2,6-bis-hydroxymethyl-phenol, 4-tert
      butylbenzene-1,2-diol, 4-tert-butyl-2-hydroxymethyl-phenol, 5-tert-butyl-2
      hydroxy-3-hydroxymethyl-benzaldehyde, 4-tert-butyl-2-hydroxymethyl-6
      methoxymethyl-phenol, and p-tert-butylphenol. Patients reacted positively to 5
      tert-butyl-2-hydroxy-3-hydroxymethyl-benzaldehyde and 4-tert-butyl-2
      hydroxymethyl-6-methoxymethyl-phenol but not to 4-tert-butyl-[1,2]benzoquinone.
      CONCLUSION: Two new allergens in PTBPFR were found: 5-tert-butyl-2-hydroxy-3
      hydroxymethyl-benzaldehyde and 4-tert-butyl-2-hydroxymethyl-6-methoxymethyl
      phenol.

PMID- 12478535
TI  - Contact allergy to o-cresol--a sensitizer in phenol-formaldehyde resin.
AB  - BACKGROUND: In patients hypersensitive to phenol formaldehyde resin (PFR) it is,
      for therapeutic and preventive reasons, important to know the identity of the
      primary sensitizing substances, their sensitizing capacity, as well as their
      cross-reaction patterns. When elucidating the issue of cross reactivity in
      patients with contact allergy to simple methylol phenols (MP), o-cresol was shown
      to be a contact sensitizer. Besides cross reactivity, contamination of one or
      more MP(s) in o-cresol as well as o-cresol being a sensitizer of its own in PFR
      were possible explanations of the simultaneous positive patch test reactions to
      MP and o-cresol. OBJECTIVE: The aim of this study was to investigate if the
      simultaneous allergic reactions to PFR and o-cresol could be explained by the
      presence of this substance in PFR. METHODS: Patch testing, high-pressure liquid
      chromatography (HPLC), nuclear magnetic resonance spectrometry (NMR), gas
      chromatography (GC), and mass spectrometry (MS) were used. RESULTS: o-Cresol was
      isolated from the specific PFR used in our standard patch test series and
      identified. The concentration in the resin was 0.066% wt/wt. CONCLUSION: The
      current study establishes o-cresol as a contact sensitizer in a PFR. The observed
      reactions to o-cresol could be on the basis of cross reactivity or primary
      sensitization.

PMID- 12478536
TI  - Occupational allergic contact dermatitis to nitromethane.
AB  - Nitromethane has wide industrial and commercial application as a polar solvent
      for adhesives and acrylics as well as explosive fuel. Allergic contact dermatitis
      to this chemical has not been described previously. The authors documented
      allergic contact hand dermatitis in 4 coworkers who similarly handled an adhesive
      solvent containing nitromethane. All 4 cases were confirmed by patch testing and
      resolved after allergen avoidance.

PMID- 12478537
TI  - Sentinel node biopsy in oral cavity cancer: correlation with PET scan and
      immunohistochemistry.
AB  - BACKGROUND: Lymphoscintigraphy and sentinel node biopsy (LS/SNB) is a minimally
      invasive technique that samples first-echelon lymph nodes to predict the need for
      more extensive neck dissection. METHODS: We evaluated this technique in 18 oral
      cavity cancers, stages T1-T3, N0. Patients underwent CT and positron emission
      tomography (PET) of the neck, followed by LS/SNB, frozen section, immediate
      selective neck dissection, definitive histology, and immunoperoxidase staining
      for cytokeratin. Histopathology of the sentinel node was correlated with that of
      the neck specimen. RESULTS: There were 10 true positives: 6 identified on frozen
      section; 2 on permanent histology; and 2 only on immunoperoxidase staining. In
      six, the sentinel node was the only positive node. There were seven true
      negatives and one false negative. CONCLUSIONS: Gross tumor replacement of lymph
      node architecture may obstruct and redirect lymphatic flow. Overall LS/SNB holds
      promise for oral cancer.

PMID- 12478538
TI  - Transcervical superior mediastinal lymphadenectomy in the management of papillary
      thyroid carcinoma.
AB  - AIM: Surgery is the treatment of choice for lymph node metastases in papillary
      thyroid carcinoma. When adequately treated by surgical extirpation, the presence
      of lymph node involvement does not seem to have a negative impact on cure rates
      or survival. Surgical lymphadenectomy for metastatic papillary thyroid carcinoma
      has been well described for both the central and the lateral compartments of the
      neck. Superior mediastinal lymphadenectomy, however, has only sporadically been
      mentioned. We describe our experience with transcervical superior mediastinal
      lymphadenectomy (TSML) that avoids the morbidity of the traditional sternal
      split. MATERIALS AND METHODS: This retrospective analysis included 30 patients
      (24 women and 6 men; age range, 17-72 years) who underwent TSML by the senior
      author (JLF) for papillary carcinoma metastatic to the superior mediastinum
      between 1985 and 1999. Histopathologic examination confirmed positive nodes in
      all the mediastinal dissections. All patients received postoperative I(131).
      RESULTS: All the patients are alive after a median follow-up of 5 years (range, 1
      14 years). Twenty-nine of 30 patients remain free of disease, whereas one patient
      is alive with lung and bone metastases. No patient has had local or regional
      relapse. The only significant complication was a high incidence of temporary
      (70%) and later permanent (50%) hypoparathyroidism. CONCLUSIONS: TSML is a safe
      and effective treatment for superior mediastinal metastases in papillary thyroid
      carcinoma.

PMID- 12478539
TI  - Primary oromandibular reconstruction using free flaps and thorp plates in cancer
      patients: a 5-year experience.
AB  - BACKGROUND: Low-profile second-generation THORP titanium plates combined with
      soft tissues free flaps (forearm or TRAM) can be used for oromandibular
      reconstruction in patients with SCC in advanced stage (stage III-IV). METHODS: To
      evaluate long-term stability and possible complications of this reconstructive
      technique, we recorded, retrospectively, data of 25 patients with posterolateral
      oromandibular defects after tumor resection collected during a 5-year period.
      RESULTS: All free flaps were successfully transferred, although eight patients
      were initially seen with delayed hardware-related reconstructive complications:
      plate exposure in four patients and plate fracture in four patients. CONCLUSIONS:
      Nowadays, the state-of-the-art treatment for mandibular defects is primary bone
      reconstruction with bone free flaps, but in selected cases (elderly patients,
      poor performance status, posterolateral oromandibular defects, soft tissue
      defects much more important than bone defects) the association with THORP plate
      soft tissue free flaps represents a good reconstructive choice.

PMID- 12478540
TI  - The treatment of squamous cell carcinoma of the tonsil with neck node metastases.
AB  - BACKGROUND: Patients with tonsillar carcinoma and neck nodes seen at the clinic
      are not an uncommon occurrence in head and neck practice. Over the years,
      treatment has ranged from radical jaw neck dissection to radical neck dissection
      for the nodes and primary radiotherapy to the primary site. Much controversy
      exists as to which treatment modality yields the best survival. Certainly,
      surgery to the oropharynx leads to gross morbidity, with problems of swallowing,
      speech, and cosmesis, although it has been claimed that radiotherapy with neck
      dissection yields a lower cure rate. METHODS: We investigated a retrospective
      series of 96 patients all of whom had squamous cell carcinoma of the tonsil and
      associated lymph node metastases. Of these, 44 primary tumors were treated with
      surgery and 52 with irradiation. All 44 patients in the surgery group had a
      radical neck dissection, as did all but 12 in the radiotherapy group. RESULTS: Of
      the tabulations, patients in good general condition were more likely to receive
      primary surgery. Overall cause-specific survival for all patients was 69%.
      Multiple logistic regression revealed no associations; thus, the radiotherapy and
      surgery groups were well matched. Five-year actuarial survival for those having
      irradiation was 74%. The five-year survival for the group receiving surgery was
      63% (p =.4372). This lack of difference between survival for surgery and
      radiotherapy was confirmed using Cox's proportional hazards model. CONCLUSION: We
      conclude that tonsillar carcinoma with lymph nodes can be safely treated by
      applying appropriate radiotherapy to the tonsillar region and treating the neck
      with radical surgery, if the disease is more than N1.

PMID- 12478541
TI  - Use of fine-needle aspiration cytology and frozen section in the management of
      nodular goiters.
AB  - BACKGROUND: This study evaluates the role of frozen section (FS) in surgical
      decisions for nodular thyroid disease when a preoperative fine-needle aspiration
      cytology (FNAC) is available. MATERIAL AND METHOD: The charts of 113 patients who
      underwent thyroidectomy for nodular goiter were reviewed. Each patient underwent
      FNAC, FS, or both. Results were compared with the final pathologic examination to
      evaluate their effectiveness in predicting malignancy. RESULTS: The sensitivity
      and specificity of FNAC alone (49 patients) were 73% and 93.5%, respectively, and
      of FS (111 patients) 68% and 99%, respectively. The result of fine-needle
      aspiration cytology was: benign (n = 8), malignant (n = 13), indeterminate (n =
      25), and nondiagnostic (n = 3). All cases diagnosed as benign on FNAC were benign
      on final pathology, but of the six FS performed in these cases, four were benign
      and two were suspect. Of the 13 FNAC that were interpreted as malignant, 11 and
      10 proved to be malignant on final pathology and FS, respectively. The 25
      indeterminate cases on FNAC were on final pathology benign (n = 21) and malignant
      (n = 4) and on frozen section were benign (n = 12), malignant (n = 2), and
      suspect (n = 11). CONCLUSION: When results of FNAC are interpreted as benign or
      malignant, FS is of little value, because it does not change the extension of
      thyroidectomy. FS proved useful in determining the extent of thyroidectomy only
      when results of the FNAC were suspect or atypical.

PMID- 12478542
TI  - Polymorphisms of the glutathione S-transferase P1 gene and head and neck cancer
      susceptibility.
AB  - BACKGROUND: Factors determining the individual susceptibility to head and neck
      squamous cell carcinoma (HNSCC) are still largely unknown. An imbalance between
      enzymes involved in the toxification and detoxification of (pre)-carcinogens
      closely related to HNSCC, which may appear during smoking and alcohol
      consumption, may play a role. Genetic polymorphisms in glutathione S-transferases
      (GSTs) often result in altered detoxification, which may contribute to individual
      susceptibility to HNSCC. METHODS: We studied the frequencies of polymorphic
      variants in the GSTP1 gene in 235 patients with HNSCC and 285 healthy controls.
      In addition, data on exposure to alcohol and tobacco consumption were recorded.
      DNA was extracted from whole blood, and polymerase chain reaction-based methods
      were used to detect genetic polymorphisms. RESULTS: In patients with HNSCC and
      control groups, the homozygous GSTP1 BB genotype was observed in 12.3% and 13.6%,
      respectively. No statistical differences were found for the GSTP1 AA and GSTP1
      AB/GSTP1BB genotypes. CONCLUSIONS: Our study showed that genetic polymorphisms of
      GSTP1 are not associated with altered susceptibility to HNSCC.

PMID- 12478543
TI  - Inhibitory effect of p27KIP1 gene transfer on head and neck squamous cell
      carcinoma cell lines.
AB  - BACKGROUND: Although p27 gene mutations are rarely found in cancer, the level of
      p27 protein expression decreases during tumor development. In several tumors,
      including laryngeal cancer, decreased expression of p27 is associated with a poor
      prognosis. METHODS: The proliferation-inhibitory effect of p27 gene transfer on
      human head and neck squamous cell carcinoma (HNSCC) cell lines (SNU-1041, SNU
      1066, and SNU-1076) by adenoviral vector was investigated. RESULTS: On
      transduction of the human HNSCC cell line with adenovirus-p27 (Ad-p27), a high
      level of p27 expression and increase of cyclin D1 and E were observed. Cell cycle
      analysis showed a marked decrease in the proportion of cells in S phase and an
      increase in G1 phase. Soft agar clonogenic assay showed a marked decrease in
      clonogenicity. CONCLUSION: These results suggested that overexpression of p27
      could show proliferation-inhibitory effects on HNSCC cell lines. Thus, gene
      therapy using adenovirus-p27 seemed to have a potential to develop into a new
      cancer gene therapy modality.

PMID- 12478544
TI  - Prognostic impact of reoxygenation in advanced cancer of the head and neck during
      the initial course of chemoradiation or radiotherapy alone.
AB  - BACKGROUND: Previous studies have shown that radiation of hypoxic tumors can
      result in reoxygenation phenomenon. The relevance of this phenomenon for
      prognosis is unclear. This study analyzes whether the presence of hypoxia, or the
      extent to which reoxygenation occurs during the initial phase of primary
      chemoradiation or radiotherapy, can predict the clinical outcome in advanced
      tumors of the head and neck. METHODS: The distribution of oxygen partial
      pressures was determined using pO(2) histography (Kimoc 6650, Sigma pO(2)
      Histograph, Eppendorf, Hamburg, Germany). In cervical lymph node metastases of 37
      patients with advanced carcinoma of the head and neck (stage IV, UICC), these
      values were determined before the start of primary chemoradiation or radiotherapy
      alone (pO(2)x). Thirty-two of 37 patients were reexamined after 1 week of
      therapy, and measurements were taken again in the same nodes (pO(2)y). The
      results obtained from these measurements were correlated with both, the initial
      response to therapy and follow-up results (43 months). RESULTS.: In all patients,
      pronounced hypoxia (median pO(2), 3.2 mmHg) was found before therapy. In 19 of 32
      patients, chemoradiation/radiotherapy induced reoxygenation (deltaO(2) = pO(2)y -
      pO(2)x), with median deltapO(2) increasing to 6.5 mmHg after 1 week (p =.049).
      The group of patients with a complete or partial response showed only a slight
      increase of median deltapO(2) (1 mmHg) compared with a strong reoxygenation
      effect in the group of patients with no change (mean value of median deltapO(2) =
      10.3 mmHg; p =.0062). The group of patients with deltapO(2) values lower than
      median showed significantly better survival rates compared with the other group
      (p =.036). CONCLUSION: These data suggest that reoxygenation under therapy may
      have prognostic relevance in patients with advanced carcinoma of the head and
      neck treated by primary chemoradiation or radiation therapy. Remarkably, however,
      a poor outcome was associated with a higher degree of reoxygenation.

PMID- 12478545
TI  - Afferent and efferent lymph-collecting vessels of the submandibular nodes with
      special reference to the lymphatic route passing through the mylohyoid muscle.
AB  - BACKGROUND: Although metastasis of cancer in the oral region to the submandibular
      node is well described, there has been no anatomic representation of lymph
      vessels penetrating the oral floor and draining into the node. MATERIALS AND
      METHODS: Ninety specimens were obtained from formalin-fixed, donated cadavers.
      Histologic observations using serial sections followed the macroscopic
      observations. RESULTS: In 19 of 90 specimens, we found afferent collecting lymph
      vessels exiting from the mylohyoid surface and draining into the preglandular
      submandibular node. In 3 of the 19 specimens, collecting vessels passing through
      the narrow muscle gap with or without arteries, veins, and nerves were identified
      histologically. The postglandular submandibular node was not evident in the
      drainage route. CONCLUSIONS: Although it carries a low incidence, because of the
      direct lymphatic route or pathway between the oral region and preglandular
      submandibular node, the pathologically positive supraomohyoid node sometimes
      seems to be found even in elective neck dissection. However, we speculate that
      sentinel node investigation would reveal the much more critical role of the
      jugulodigastric node not only as the actual sentinel node but also as the common
      terminal node along the various drainage routes from the oral region.

PMID- 12478546
TI  - Targeting epidermal growth factor receptor in head and neck cancer.
AB  - It is well known that growth factors play an important role in normal cell
      proliferation by means of stimulation of growth factor receptors located on the
      surface of cells. Tumor cells express high levels of growth factor receptors that
      can theoretically serve as therapeutic targets in cancer treatment. Tyrosine
      kinase (type 1) growth factor receptors include the family of erbB receptors. The
      most extensively studied receptor in the erbB family is the human epidermal
      growth factor receptor (EGFR), also known as erbB1. Studies have shown that
      overexpression of EGFR is involved in the development and progression of head and
      neck squamous cell carcinoma (HNSCC). Blocking this receptor in HNSCC cell lines
      and animal models inhibits tumor growth. Strategies have been developed to target
      EGFR, including monoclonal antibodies, tyrosine kinase-specific inhibitors,
      ligand-linked immunotoxins, and antisense approaches. Laboratory studies and
      clinical trials are under way to explore the safety and efficacy of these various
      approaches in a variety of cancers, including HNSCC. Preliminary results from
      early phase clinical trials are encouraging and may lead to the incorporation of
      these EGFR targeting strategies into the management of HNSCC.

PMID- 12478548
TI  - Adverse reaction to surgical sutures in thyroid surgery.
AB  - BACKGROUND: A mild reaction to surgical sutures after thyroid surgery is common
      and is characterized by local edema and inflammation around the surgical scar.
      Severe reaction with microabscesses and granulomatous masses is quite rare.
      METHODS AND RESULTS: Two cases of severe reaction to silk sutures after thyroid
      surgery are presented. Meticulous surgical removal of all surgical sutures along
      with granulomatous masses, granulation tissue, and microabscesses cured both
      patients. Pathologic examination revealed giant cells and lymphocytes.
      Intradermal skin tests were positive to silk sutures. The etiology and the
      treatment options are discussed. CONCLUSIONS: In rare cases, severe reaction to
      silk sutures may develop after thyroid surgery. Surgical removal of the stitches
      is the treatment of choice. Intradermal skin test is a good predictor of allergy
      to sutures.

PMID- 12478547
TI  - Sparganosis presenting as a lateral neck mass.
AB  - BACKGROUND: Cervical sparganosis is rare, and its rarity makes it difficult to be
      distinguished from tumors. A case of cervical sparganosis is reported. METHODS
      AND RESULTS: An 80-year-old man was initially seen with a painless lateral neck
      mass for 3 months, which was initially diagnosed as cervical lymphadenopathy.
      Laboratory studies revealed eosinophilia, and the patient recalled that he had
      frequently taken mountain water. Serologic study of human sparganosis by a
      monoclonal antibody-based competition enzyme-linked immunosorbent assay (ELISA)
      was positive. Surgical excision was performed, and the sparganosis was confirmed
      by histologic examination. CONCLUSIONS: Sparganosis should be considered in the
      differential diagnosis of soft tissue tumors, especially among patients who have
      frequently ingested mountain water and consumed raw snakes or frogs.

PMID- 12478549
TI  - Positive and negative gas-phase ion chemistry of chlorofluorocarbons in air at
      atmospheric pressure.
AB  - This paper presents a report on the ionization/dissociation of some
      representative chlorofluorocarbons (CFCs) induced by corona discharges in air at
      atmospheric pressure. Both positive and negative ions formed from Freons 1,1,1
      trichlorotrifluoroethane (CFC 113a), 1,1,2-trichlorotrifluoroethane (CFC 113),
      and 1,1,1,2-tetrachlorodifluoroethane (CFC 112a) were analyzed using an
      atmospheric pressure chemical ionization mass spectrometry (APCI-MS) instrument.
      Energy-resolved mass spectra were obtained by modulating the kinetic energy of
      the ions via adjustment of the sampling cone potential (V(cone)). Positive ion
      spectra of the CFCs (M) at low V(cone) show no signals due to either M(+)* or
      MH(+) but only those due to species [M - Cl](+) and CX(3)(+) (X = Cl, F), likely
      formed via C-Cl and C-C bond cleavages following ionization via charge exchange.
      Charge localization in the products of C-C bond cleavage in M(+)* is driven by
      the stability of the neutral fragment. At low V(cone) the hydrates [M -
      Cl](+)(H(2)O) are also observed. In the case of 1,1,2,-trichlorotrifluoroethane,
      [M - F](+) species also form as a result of ion-molecule reactions. As V(cone) is
      increased collision-induced dissociation of [M - Cl](+) and [M - F](+), i.e., the
      perhalogenated cations C(2)X(5)(+) (X = Cl, F), takes place via carbene
      elimination. In some cases such elimination is preceded or accompanied by
      rearrangements involving transfer of halogen from one carbon to the other.
      Evidence is also presented for the occurrence of a condensation reaction of
      C(2)Cl(3)F(2)(+) with water to form a C(2)Cl(2)F(2)HO(+) species via elimination
      of HCl. Negative ion spectra are dominated by Cl(-) and its ion-neutral complexes
      with M and with water. Additional components of the plasma include ion-neutral
      complexes O(3)(-)(M), the molecular anion M(-) (observed only with 1,1,2
      trichlorotrifluoroethane), and an interesting species corresponding to [M - Cl +
      O](-). The origin and structure of these [M - Cl + O](-) species are discussed in
      terms of available thermochemical and reactivity data and current mechanistic
      views concerning reaction of O(2)(-) with halogenated compounds. The observation
      of both positive and negative ions containing oxygen is of special relevance to
      development of new processes for the treatment of volatile organic compounds
      (VOCs) based on oxidative decomposition induced by corona discharges in air at
      room temperature and pressure.

PMID- 12478550
TI  - Characterization of proanthocyanidins in grape seeds using electrospray mass
      spectrometry.
AB  - Two proanthocyanidin (PA) fractions, one (Sdp3) with the mean degree of
      polymerization (mDP) of 3 and the other (Sdp9) with mDP of 9, were obtained from
      a Vitis vinifera cv. Shiraz grape seed extract. The PA fractions were directly
      analyzed by electrospray ionization mass spectrometry (ES-MS) and negative ion
      mass spectra were recorded. The mass spectrum of Sdp3 exhibited only singly
      charged ions corresponding to the molecular mass of PA with a degree of
      polymerization (DP) up to 9 (nonamers). In contrast, Sdp9 yielded rather complex
      mass spectra featuring ions with single [M - H](-), double [M - 2H](2-) and
      triple [M - 3H](3-) charge representing the molecular masses of PAs up to a DP of
      28. In addition, the degree of galloylation per procyanidin (DG) was observed to
      be up to 5 (pentagallates) in Sdp3 and 8 (octagallates) in the Sdp9. This is the
      first evidence obtained by mass spectrometry for the distribution of grape seed
      PAs with such a high degree of polymerization and a broad diversity of
      galloylation. ES-MS data together with the complementary information provided by
      acid hydrolysis provides a detailed picture of the composition of grape seed PAs.

PMID- 12478551
TI  - Reactions of lead cluster ions with acetone.
AB  - Reactions of lead cluster cations and anions with acetone have been studied using
      a homemade reflectron time-of-flight mass spectrometer. Association with acetone
      to form Pb(k)(CH(3)COCH(3))(n)(+), high-energy pathway reactions forming
      Pb(k)CH(3)(+), and intraheterocluster reaction of Pb(k)(CH(3)COCH(3))(n+1)(+) to
      give Pb(k)CH(3)(CH(3)COCH(3))(n)(+) were the main reaction pathways for lead
      cluster cations with acetone. Decomposition of acetone by Pb(k)(-) to give
      Pb(k)C(m)(-) ions and their further association with acetone,
      Pb(k)C(m)(CH(3)COCH(3))(-), were the dominant reactions of lead cluster anions
      with acetone. Pb(7)(-), Pb(10)(-), and Pb(k)C(5)(-) were 'magic numbers' with
      special structural stabilityin Pb(k)(-) and Pb(k)C(m)(-), respectively. In
      addition, Pb(k)H(-), CH(2)COCH(3)(CH(3)COCH(3))(n)(-) and
      Pb(k)CH(2)COCH(3)(CH(3)COCH(3))(n)(-) were also observed in the reaction of lead
      cluster anions. Some reaction mechanisms are proposed for these reactions. To
      investigate the isotope effect for the reaction of lead cluster cations and
      anions with acetone and to verify the structural assignments of the observed
      ions, reactions of lead cluster cations and anions with deuterated acetone-d(6)
      were also performed.

PMID- 12478552
TI  - Enhanced resolution triple-quadrupole mass spectrometry for fast quantitative
      bioanalysis using liquid chromatography/tandem mass spectrometry: investigations
      of parameters that affect ruggedness.
AB  - In order to increase sample analysis throughput, the use of fast liquid
      chromatography in quantitative bioanalysis based on liquid chromatography coupled
      with tandem mass spectrometry (LC/MS/MS) has become prevalent. Therefore, it is
      important to increase the specificity of such bioanalytical methods. This can be
      done by enhancing both the chromatographic and mass resolving power. Increasing
      the mass spectrometric resolving power to minimize interference from endogenous
      compounds in the biological matrix is the subject of this paper. We present the
      results of our experience with developing and validating SRM-based, enhanced
      resolution bioanalytical methods using a new triple-quadrupole mass spectrometer
      with enhanced resolution capability. We have shown that SRM bioanalytical methods
      using better than unit-mass resolution (Q1 FWHM = 0.2 Th, Q3 FWHM = 0.7 Th) can
      be developed which are as rugged as unit resolution methods (Q1 FWHM = 0.7 Th, Q3
      FWHM = 0.7 Th). The enhanced resolution methods require more attention to detail
      than unit resolution methods. For instance, the mass setting for precursor ion
      selection is more critical because the mass peak is narrower. Because of this,
      enhanced resolution methods may be more easily influenced by temperature changes
      in the laboratory. We have shown that there is good correlation between the shift
      in the precursor ion mass and the ambient temperature. Other studies carried out
      to investigate the effects on mass peak shape and response (both in the SIM and
      SRM mode) as the result of varying the FWHM revealed some interesting results.
      For instance, the decrease in response with the decrease in the FWHM was larger
      using SRM compared to that using SIM. However, the decrease in both SRM and SIM
      response with decreasing FWHM was significantly smaller compared with the
      decrease obtained using an older generation instrument. We demonstrate that, at
      concentrations near the limit of detection, the signal specificity can be
      improved by using an enhanced resolution method. To compare the performance of an
      enhanced resolution method against a unit resolution method under optimized mass
      spectrometric conditions, we analyzed calibration standards and quality control
      samples using a lower limit of quantitation that could be easily achieved by
      either method. Under these conditions, the two methods were essentially the same,
      demonstrating that the enhanced resolution method is as accurate, precise and
      rugged as the unit resolution method. We propose system suitability procedures,
      based on precursor ion scan, product ion scan, SRM with fractional mass changes,
      or SIM with a narrow scan width, for the updating of the SRM set masses before
      the start of analysis. We also recommend that Q1 SRM masses be determined during
      and at the end of analysis in order to ascertain whether or not the precursor
      masses have shifted during the course of the analysis.

PMID- 12478553
TI  - Solid-phase microextraction liquid chromatography/tandem mass spectrometry for
      the analysis of chlorophenols in environmental samples.
AB  - Liquid chromatography with atmospheric pressure chemical ionisation mass
      spectrometry (LC/APCI-MS), using negative ion detection in a triple quadrupole
      instrument, was used for the determination of chlorophenols (CPs) in
      environmental samples. In-source collision-induced dissociation (CID) was
      compared with MS/MS fragmentation. In general, less fragmentation was observed in
      MS/MS as compared with in-source CID, with the latter providing more intense
      fragment ions due to chemical ionisation. Under MS/MS conditions [M - H - HCl](-)
      was the main fragment ion observed for all compounds except for
      pentachlorophenol, which showed no fragmentation. For multiple reaction
      monitoring (MRM) acquisition mode, the transition from [M - H](-) to [M - H -
      HCl](-) was selected, leading to detection limits down to 0.3 ng injected. Direct
      and headspace-solid-phase microextraction (HS-SPME) were used as preconcentration
      procedures for the analysis of CPs in wood and in industrially contaminated
      soils. CPs were quantified by standard addition, which led to good
      reproducibility (RSD between 4 and 11%) in both SIM and MRM modes, and detection
      limits down to ng/g. The combination of MS/MS and in-source CID allowed
      confirmation of the presence of CPs in environmental samples.

PMID- 12478554
TI  - Structural characterization of chromone C-glucosides in a toxic herbal remedy.
AB  - Two novel compounds, 8-C-D-glucopyranosyl-7-hydroxy-5-methylchromone-2-carboxylic
      acid and a 2-O'-p-coumaroyl derivative thereof, were identified in a herbal tea
      that caused severe vomiting in a South African patient who had taken the
      traditional remedy to clean his stomach. For structural characterization,
      electrospray (ES) ionization in combination with collision-induced dissociation
      (CID) and tandem mass spectrometry (MS/MS) were used, as well as UV and nuclear
      magnetic resonance (NMR) spectroscopy. Specific ions or neutral losses generated
      under conditions of ES-MS/CID/MS permitted the establishment of structural
      features such as the free carboxyl group, the C-hexosidic part and the p
      coumaroyl group. NMR spectroscopy was necessary to support the structure of the
      chromone-type aglycone and the glucosidic parts. Since the compounds are
      structurally related to aloesin and aloeresin A, which are chemotaxonomic markers
      of Aloe species, and have not been previously reported, we propose that they were
      formed by oxidative degradation during preparation of the herbal tea from an Aloe
      species or during its storage.

PMID- 12478555
TI  - Derivatization procedures for the detection of estrogenic chemicals by gas
      chromatography/mass spectrometry.
AB  - This work evaluated derivatization procedures for detecting both natural and
      synthetic estrogenic chemicals by gas chromatography/mass spectrometry (GC/MS).
      Different silylating agents, mainly trimethylsilylating (TMS) agents, were
      compared, and the roles of various content of trimethylchlorosilane (TMCS, as a
      stimulator) were investigated. The difference in the abundances of the
      derivatives was caused by the steric hindrance of multiple hydroxyl groups and
      ethynyl groups in the structures of estrogenic chemicals. The use of TMCS
      produces an increase in the derivatization yield, especially for the compounds
      with multiple hydroxyl groups (i.e., 17beta-estradiol (E(2)) and estriol (E(3))).
      Mass spectra of O-TMS derivatives and tentative fragmentation profiles are
      proposed. Molecular ions were the base peaks for all the derivatives, and were
      used as the quantitation ions to obtain maximum detection sensitivity and
      specificity. Sample enrichment was achieved by Oasis HLB solid-phase extraction
      cartridges. The quantitation limits of these compounds ranged from 5 to 10 ng/L
      in 1000-mL water samples. Recovery of the estrogenic chemicals in spiked various
      water samples ranged from 78 to 102% while relative standard deviation (RSD)
      ranged from 1 to 15%.

PMID- 12478556
TI  - Analysis of ceramides in cosmetics by reversed-phase liquid
      chromatography/electrospray ionization mass spectrometry with collision-induced
      dissociation.
AB  - A rapid, sensitive and selective method involving reversed-phase liquid
      chromatography (LC) with electrospray ionization (ESI) mass spectrometry (MS) was
      employed for determination of commercial ceramides in cosmetics for quality
      control of the product formulation. Using this LC/ESI-MS technique, simultaneous
      separation and characterization of ceramides and an impurity substance were
      possible. Informative fragmentation patterns were obtained by employing LC/ESI-MS
      in both positive and negative ionization modes to identify the structures of both
      sphingoid base and N-acyl chains of ceramides, and also of an impurity. The
      combination of positive and negative mass spectra can be used for unambiguous
      confirmation of ceramides and for characterization of unknown species. In-source
      collision-induced fragmentation resulted in characteristic product anions for the
      ceramides containing a phytosphingosine moiety at m/z 267, 255 and 225, and for
      those with a sphingosine moiety at m/z 263 and 237, regardless of the length of
      the fatty acyl chains. The detection limit was about 0.5 pmol in selected-ion
      monitoring mode. Quantification using internal standards showed good linearity
      and a relative standard deviation of 4%. These ceramides were more sensitively
      detected in positive than in negative ion mode.

PMID- 12478557
TI  - Characterisation of putative pentose-containing conjugates as minor metabolites
      of 4-bromoaniline present in the urine of rats following intraperitoneal
      administration.
AB  - The metabolic fate of 4-bromoaniline (4-BrA) was investigated following
      intraperitoneal administration to the rat at 50 mg kg(-1), using high-performance
      liquid chromatography/time-of-flight tandem mass spectrometry (HPLC/TOF-MS/MS).
      Up to five metabolites were detected in urine that correspond to isomeric pentose
      conjugates (possibly ribosides) of a hydroxysulphate of 4-BrA. This
      identification is supported by further studies where the water used in the
      reversed-phase solvent system was replaced with deuterated water in order to
      confirm that the number of exchangeable protons present in the metabolites was
      consistent with the proposed structures.

PMID- 12478558
TI  - The unanticipated loss of SO2 from sulfonamides in collision-induced
      dissociation.
AB  - A potent and selective sulfonamide beta3 agonist with an excellent
      pharmacokinetic profile has recently been synthesized. During the analysis by
      liquid chromatography/tandem mass spectrometry (LC/MS/MS) of metabolites of the
      sulfonamide N-[4-[2-(2-hydroxy-2-pyridin-3-ylethylamino)ethyl]phenyl]-4-[4-(4
      trifluoromethylphenyl)thiazol-2-yl]benzulfonamide (compound A), we observed loss
      of 64 Da for a few of the metabolites in the negative ion mode. Accurate mass
      measurements performed with Fourier transform ion cyclotron resonance (FTICR)
      mass spectrometry and quadrupole time-of-flight (Q-TOF) mass spectrometry
      suggested that the loss of 64 Da corresponded to the loss of SO(2). The same
      phenomenon was observed for a group of structurally related and commercially
      available compounds that also contain a sulfonamide moiety. MS/MS analysis of the
      fragment ions that had lost SO(2) in the ion source suggested that these ions
      were covalently bound rather than ion-molecule complexes. The neutral loss
      involving the cleavage of two bonds was unanticipated and suggested a complex
      rearrangement process. A mechanism for the loss of SO(2) has been proposed.

PMID- 12478559
TI  - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of
      lipids: ionization and prompt fragmentation patterns.
AB  - Ionization and prompt fragmentation patterns of triacylglycerols, phospholipids
      (PLs) and galactolipids were investigated using matrix-assisted laser
      desorption/ionization (MALDI). Positive ions of non-nitrogen-containing lipids
      appeared only in the sodiated form, while nitrogen-containing lipids were
      detected as both sodiated and protonated adducts. Lipids containing acidic
      hydroxyls were detected as multiple sodium adducts or deprotonated ions in the
      positive and negative modes, respectively, with the exception of
      phosphatidylcholines. The positive MALDI spectra of triacylglycerols contained
      prompt fragments equivalent to the loss of RCOO(-) from the neutral molecules.
      Prompt fragment ions [PL-polar head](+) were observed in the positive MALDI
      spectra of all phospholipids except phosphatidylcholines. The
      phosphatidylcholines produced only a minor positive fragment corresponding to the
      head group itself (m/z 184). Galactolipids did not undergo prompt fragmentation.
      Post-source decay (PSD) was used to examine the source of prompt fragments. PSD
      fragment patterns indicated that the lipid prompt fragment ions did not originate
      from the observed molecular ions (sodiated or protonated), and suggested that the
      prompt fragmentation followed the formation of highly unstable, probably
      protonated, precursor ions. Pathways leading to the formation of prompt fragment
      ions are proposed.

PMID- 12478560
TI  - Investigation of matrix effects in bioanalytical high-performance liquid
      chromatography/tandem mass spectrometric assays: application to drug discovery.
AB  - A series of studies was performed to investigate some of the causes for matrix
      effects ('ion suppression' or 'ion enhancement') in bioanalytical high
      performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assays.
      Previous studies have reported that matrix effects are mainly due to endogenous
      components in biological fluids and are a greater concern for electrospray
      ionization (ESI) than for atmospheric pressure chemical ionization (APCI). In
      this report we demonstrate that: (1) matrix effects can also be caused by
      exogenous materials, such as polymers contained in different brands of plastic
      tubes, or Li-heparin, a commonly used anticoagulant; (2) matrix effects are not
      only ionization mode (APCI or ESI) dependent, but also source design (Sciex,
      Finnigan, Micromass) dependent; and (3) for at least one vendor's design, we
      found the APCI mode to be more sensitive to matrix effects than the ESI mode.
      Based on these findings, we have proposed the following simple strategies to
      avoid matrix effects: (1) select the same brand of plastic tubes for processing
      and storing plasma samples and spiked plasma standards; (2) avoid using Li
      heparin as the anticoagulant; and (3) try switching the ionization mode or
      switching to different mass spectrometers when matrix effects are encountered.
      These three strategies have allowed us to use protein precipitation and generic
      fast LC techniques to generate reliable LC/MS/MS data for the support of
      pharmacokinetic studies at the early drug discovery stage.

PMID- 12478561
TI  - Behaviour of 1,3-diphenyl-2-arylhydrazono-1,3-propanediones under electron
      ionisation.

PMID- 12478562
TI  - Identification of the aromatase inhibitor aminoglutethimide in urine by gas
      chromatography/mass spectrometry.
AB  - Aminoglutethimide is used therapeutically as an aromatase inhibitor in the
      treatment of metastatic breast cancer in post-menopausal women. For doping
      purposes, aminoglutethimide may be used for treatment of adverse effects of an
      extensive abuse of anabolic androgenic steroids (gynaecomastia) and to increase
      the testosterone concentration and stimulation of testosterone biosynthesis. The
      use of aromatase inhibitors has been prohibited for male athletes since September
      1, 2001. The purpose of this study was to develop methods for the identification
      of the parent compound or its main metabolite and the inclusion of this
      information into established screening procedures in doping analysis. An
      excretion study was conducted using oral application of one single therapeutic
      dose (500 mg) of Orimeten. The analysis was performed by gas chromatography/mass
      spectrometry (GC/MS). Aminoglutethimide is excreted almost totally as
      unconjugated parent compound and is detectable by different screening procedures
      for up to 165 h. Most suitable for the detection of aminoglutethimide is the
      screening procedure for heavy volatile nitrogen-containing drugs ('Screening 2').
      However, since only competition samples are analysed in that screening procedure,
      the additional inclusion of aminoglutethimide in the screening procedure for
      anabolic androgenic agents ('Screening 4') is recommended. Full mass spectra and
      diagnostic ions for the analysis of aminoglutethimide are presented.

PMID- 12478563
TI  - Different electrospray tandem mass spectrometric approaches for rapid
      characterization of phospholipid classes of Curosurf, a natural pulmonary
      surfactant.
AB  - Curosurf is a pulmonary surfactant used in the treatment or prophylaxis of
      neonatal respiratory distress syndrome. It contains low molecular weight
      hydrophobic apoproteins and a series of lipids including phosphatidylcholines,
      lisophosphatidylcholines, phosphatidylethanolamines, sphingomyelins,
      phosphatidylinositols, phosphatidylglycerols and phosphatidylserines. In the
      present work, a rapid method to qualitatively map the Curosurf phospholipid
      classes without prior derivatization or chromatographic separations is described.
      In particular, a series of specific electrospray tandem mass spectrometric (ES
      MS/MS) experiments, i.e. product ion, precursor ion and neutral loss scans, were
      chosen on the basis of the chemical nature of each phospholipid class and then
      used to identify single components of the commercial suspension, directly infused
      into the ion source of the mass spectrometer.

PMID- 12478564
TI  - Determination of non-steroidal estrogens in breast milk, plasma, urine and hair
      by gas chromatography/mass spectrometry.
AB  - It is suspected that all the natural estrogens occurring in the human body, as
      well as dietary and synthetic estrogens, diversely affect the endocrine system
      depending on their exposure patterns. More rapid, reliable and accurate
      measurements of these compounds in various biological matrices are thus becoming
      an important task. After solid-phase extraction using an Oasis HLB extraction
      cartridge, the estrogen concentrates were derivatized with a mixture of N-methyl
      N-trifluorotrimethylsilylacetamide/ammonium iodide/dithioerythritol (1000:4:5,
      v/w/w) for analysis by gas chromatography/mass spectrometry in the selected ion
      monitoring (SIM) mode. The qualitative identification of estrogens detected in
      SIM mode was further confirmed by tandem mass spectrometry using low-energy
      collision-induced dissociation (CID) mode. The method for the assay of the 20
      estrogens was linear over the ranges of 1-1000 micro g/L for biological fluids
      and 1-200 micro g/kg for hair with high correlation coefficient (>0.99). The
      limits of quantitation (LOQ) ranged from 1.0-10 micro g/L (or micro g/kg) and the
      limit of detection ranged from 0.2-3 micro g/L (or micro g/kg). The average
      precision (% CV) and accuracy (% bias) of the method determined at the LOQ, low,
      and medium concentrations were in the ranges 2.6-9.2 and -4.1-7.7, respectively.
      The average extraction recovery of the estrogens from plasma and hair at the
      three concentration levels varied in the ranges 77-103% (1.9-14.3% CV) and 73
      104% (3.1-14%), respectively. The distribution patterns of the estrogens were
      characteristic of each biosample. Five estrogens in the range 1.5-44.9 micro g/L
      were measured in breast milk, 8 estrogens in the range 3.5-322 micro g/L in
      plasma, 12 estrogens at 1.2-442 micro g/L in urine, and biochanin-A at 13.2-39.1
      micro g/kg in hair. Because of its high sensitivity, good precision and
      specificity, the present method was found suitable for the trace analysis of
      dietary and synthetic estrogens in complex biosamples such as breast milk,
      plasma, urine and hair.

PMID- 12478565
TI  - Gas chromatography/mass spectrometric study of non-commercial C-4-substituted 1,4
      dihydropyridines and their oxidized derivatives.
AB  - A gas chromatography/mass spectrometry (GC/MS) method for the qualitative and
      quantitative determination of the calcium-channel antagonists C-4-substituted 1,4
      dihydropyridines, and their corresponding N-ethyl derivatives, is presented.
      Also, the electrochemical oxidation and the reactivity of the compounds with
      alkyl radicals derived from 2,2'-azobis-(2-amidinopropane) were monitored by
      GC/MS. Mass spectral fragmentation patterns for the C-4-substituted 1,4-dihydropy
      ridine parent drugs were significantly different from those of their oxidation
      products, generated either by electrochemical oxidation or by reaction with alkyl
      radicals. However, for N-ethyl-1,4-dihydropyridine compounds it was not possible
      to detect the final products (pyridinium salts) using these experimental
      conditions.

PMID- 12478566
TI  - Liquid chromatography/electrospray tandem mass spectrometry characterization of
      styrene metabolism in man and in rat.
AB  - Liquid chromatography with electrospray tandem mass spectrometry was used to
      characterize the metabolism of styrene in man and in rat. To improve
      identification and characterization of minor styrene metabolites, rats were co
      exposed to styrene and styrene-d(8). In addition to the main styrene metabolites,
      mandelic acid and phenylglyoxylic acid, and specific mercapturic acids,
      phenylhydroxyethylmercapturic acids (PHEMAs), other minor metabolites, including
      phenylglycine, N-acetyl-S-(phenacyl)cysteine, 4-vinylphenol and styreneglycol
      conjugates (glucuronides and sulfates) were identified and determined both in
      human and rat urine. Phenylglycine and N-acetyl-S-(phenacyl)cysteine have been
      hypothesized to occur, but never detected in human or rat urine after styrene
      exposure. 4-Vinylphenol and styrene glycol had already been recognized as styrene
      metabolites, but never determined as intact glucuronide and sulfate conjugates.
      Failure to identify 1- and 2-phenylethanol conjugates suggests that phenylethanol
      might be an intermediate metabolite, but it is not a conjugated catabolite. A
      method for the simultaneous determination of mandelic acid, phenylglyoxylic acid,
      phenyglycine and the four PHEMA diastereoisomers has been developed and
      validated. For those glucuronide and sulfate conjugates whose standards are not
      commercially available, a method for semiquantitative analysis, based on the use
      of structurally similar compounds as standards, has been developed. This approach
      was found to be valid for the determination of 4-vinylphenol glucuronide and 4
      vinylphenol sulfate.

PMID- 12478567
TI  - Quantitative analysis using gas chromatography/combustion/isotope ratio mass
      spectrometry and standard addition of intrinsically labelled standards (SAIL)-
      application to isoflavones in foods.
AB  - We have investigated a novel application of gas chromatography/combustion/isotope
      ratio mass spectrometry (GC/C/IRMS) for the quantitative analysis of the
      isoflavones in food matrices. Previous methods have been hampered by the lack of
      analytical standards to introduce early enough in the extraction procedure to
      allow compensations for losses at all stages of the procedure. In this work we
      have produced standard materials that can be added at the initial extraction, by
      intrinsically labelling soya plants by growing them in an atmosphere enriched in
      the stable isotope of carbon in CO(2). On analysis these plants were shown to
      contain phytoestrogens at a high (up to 20%) level of enrichment. The dried plant
      material has been used to estimate the isoflavone concentrations of a set of
      spiked flours. For daidzein the methodology was shown to produce results
      comparable to those achieved by GC/MS techniques. The method was less successful
      for genistein, possibly due to the greater fragility of this compound under the
      conditions required for the analysis.

PMID- 12478568
TI  - Investigation of the electrospray response of lysine-, arginine-, and
      homoarginine-terminal peptide mixtures by liquid chromatography/mass
      spectrometry.
AB  - Guanidination has been used to investigate how modification of the lysine eta
      amino group into the corresponding guanidino group affects response in
      electrospray (ES) mass spectrometry (MS). Selected ion monitoring (SIM) analysis
      of equimolar mixtures containing arginine-, lysine- and the corresponding
      homoarginine-terminal peptides following liquid chromatography (LC) showed
      differences in ES response. The ionisation behaviour of the standard peptides is
      in accordance with the postulated higher stability of the guanidino group present
      on arginine- and homoarginine-terminal peptides. Modification of the separation
      conditions employed during LC demonstrates that relative abundances of
      electrosprayed peptides ions rely mostly on peptide structure.

PMID- 12478569
TI  - Electron capture dissociation of weakly bound polypeptide polycationic complexes.
AB  - We have previously reported that, in electron capture dissociation (ECD), rupture
      of strong intramolecular bonds in weakly bound supramolecular aggregates can
      proceed without dissociation of weak intermolecular bonds. This is now
      illustrated on a series of non-specific peptide-peptide dimers as well as
      specific complexes of modified glycopeptide antibiotics with their target
      peptide. The weak nature of bonding is substantiated by blackbody infrared
      dissociation, low-energy collisional excitation and force-field simulations. The
      results are consistent with a non-ergodic ECD cleavage mechanism.

PMID- 12478570
TI  - Polyaniline-coated nanoelectrospray emitters: performance characteristics in the
      negative ion mode.
AB  - The increasing tendency to miniaturize analytical techniques has resulted in the
      widespread use of nanoelectrospray ionization mass spectrometry. A new
      polyaniline-coated nanoelectrospray emitter has shown increasing promise as a
      more durable and stable alternative to traditional metal-coated emitters. In this
      report, the utility of polyaniline-coated nanoelectrospray emitters in the
      negative ion mode is investigated. Here, oligonucleotides and peptides have been
      ionized in the negative mode using polyaniline-coated nanoelectrospray emitters.
      The emitters were found to be durable for at least an hour in the negative ion
      mode, during which time the signal was stable. The high amount of electrical
      discharge usually associated with negative ion mode nanoelectrospray was not
      problematic with the polyaniline-coated emitters. These characteristics make
      possible the reliable coupling of low-flow separations to negative ion
      nanoelectrospray without the worry of emitter failure during the course of the
      experiment.

PMID- 12478571
TI  - Electrospray ionization mass spectra of monoimidazole/polyamine conjugates.
AB  - Imidazole/polyamine amides are biologically important molecules due to their
      specific DNA binding activity, and much attention has been attracted to the
      synthesis of their derivatives or analogues. In the present studies, the
      fragmentation of a series of synthetic monoimidazole/polyamine amides was
      investigated using electrospray ionization mass spectrometry (ESI-MS) combined
      with tandem mass spectrometry (ESI-MS/MS). All of the monoimidazole/polyamine
      amides produced the fragment ion m/z 183 except for the
      monoimidazole/ethyldiamine amide. The diamine amides produced this ion after the
      elimination of an alkene, the triamine amides produced it via their corresponding
      diamine amide fragments, and the tetraamine amide via its triamine and then
      diamine amide fragments. The characterization of the mass spectra for the
      different polyamine amides allowed identification of a specific product from the
      N-acylation of spermidine, and should assist further study of the polyamine
      amides in DNA binding action.

PMID- 12478572
TI  - Electrospray ionization quadrupole time-of-flight mass spectrometry and
      quadrupole mass spectrometry for genotyping single nucleotide substitutions in
      intact polymerase chain reaction products in K-ras and p53.
AB  - Single nucleotide polymorphisms (SNPs) and mutations were genotyped for both
      homozygous and heterozygous PCR products of p53, a tumor suppressor gene, and K
      ras, an oncogene, using electrospray ionization (ESI) quadrupole time-of-flight
      (Q-TOF) mass spectrometry (MS) and ESI-quadrupole MS analysis. Mass accuracy was
      adequate for both instruments to detect genetic changes in homozygous PCR
      products, including the most difficult to distinguish (adenine [A] --> thymine
      [T] transversion). However, for the detection of A --> T shifts (9.0 Da
      difference) in heterozygous PCR products, the increased resolution of ESI-Q-TOFMS
      proved essential. Although, greater mass differences in heterozygotes (e.g.
      cytosine [C] <--> T or guanine [G] <--> A) can be discriminated using ESI
      quadrupole MS analysis.

PMID- 12478573
TI  - Differentiation of the geographical origin of durum wheat semolina samples on the
      basis of isotopic composition.
AB  - The identification of the geographical origin of foods is attracting great
      interest from consumers and producers since it may be used as a criterion for
      guaranteeing quality and authenticity. Stable isotope techniques can provide
      useful information on the origin of food products. The natural abundance isotopic
      ratios of carbon, oxygen and nitrogen were determined and a comparison made
      between the isotopic content of samples originating from Italy and those of
      samples originating from other countries (Canada, Turkey, Australia). A
      correlation was found between the isotopic composition and geographical origin of
      the samples. The relationship between isotopic content and the latitude has been
      confirmed.

PMID- 12478574
TI  - Differentiation of vegetable oils by mass spectrometry combined with statistical
      analysis.
AB  - The main triacylglycerol (TAG) composition of different plant oils (almond,
      avocado, corn germ, grape seed, linseed, mustard seed, olive, peanut, pumpkin
      seed, sesame seed, soybean, sunflower, walnut and wheat germ) were analyzed using
      two different mass spectrometric techniques: HPLC/APCI-MS (high-performance
      liquid chromatography/atmospheric pressure chemical ionization mass spectrometry)
      and MALDI-TOFMS (matrix-assisted laser desorption/ionization time-of-flight mass
      spectrometry).Linear discriminant analysis (LDA) as a multivariate mathematical
      statistical method was successfully used to distinguish different plant oils
      based on their relative TAG composition. With LDA analysis of either APCI-MS or
      MALDI-MS data, the classification among the almond, avocado, grape seed, linseed,
      mustard seed, olive, sesame seed and soybean oil samples was 100% correct. In
      both cases only 6 different oil samples from a total of 73 were not classified
      correctly.

PMID- 12478575
TI  - Studies on azaspiracid biotoxins. I. Ultrafast high-resolution liquid
      chromatography/mass spectrometry separations using monolithic columns.
AB  - In this study, the performance of monolithic columns was evaluated for ultrafast
      liquid chromatography/mass spectrometry (LC/MS) analyses and for high-resolution
      separations of several azaspiracid biotoxin analogs. Because of their high
      permeability, monolithic columns offer a number of advantages over conventional
      packed columns; viz., very low backpressures and relatively flat van Deemter
      curves at high flow rates. That is, very high flow rates can be used for
      ultrafast analyses or, by using longer than normal columns, high-resolution
      separations are possible. In a series of experiments, we varied the mobile phase
      flow rates between 1 and 8 mL/min, and studied their impact on chromatographic
      parameters such as retention time, resolution, number of plates and pressure. The
      chromatographic run times could be reduced to ca. 30 s without a significant
      change in the separation efficiency. A signal intensity comparison revealed
      interesting differences between atmospheric-pressure chemical ionization (APCI)
      and electrospray ionization (ESI) in their flow-rate dependency. An explanation
      with respect to the behavior as of a mass-flow or a concentration-dependent
      device is given in the paper. Additionally, the column length was varied between
      10 and 70 cm. As a result, the number of theoretical plates increased
      substantially. In the example shown in the report, an increase from 13 000 plates
      for a 10-cm column to 80 000 for a 70-cm column is demonstrated. In addition, the
      potential of the monolithic columns for high-resolution LC/MS separations is
      shown for a complex biotoxin mixture, which was separated on a 40-cm-long column.

PMID- 12478576
TI  - Studies on azaspiracid biotoxins. II. Mass spectral behavior and structural
      elucidation of azaspiracid analogs.
AB  - In this report, the mass spectral analysis of azaspiracid biotoxins is described.
      Specifically, the collision-induced dissociation (CID) behavior and differences
      between CID spectra obtained on a triple-quadrupole, a quadrupole time-of-flight,
      and an ion-trap mass spectrometer are addressed here. The CID spectra obtained on
      the triple-quadrupole mass spectrometer allowed the classification of the major
      product ions of the five investigated compounds (AZA 1-5) into five distinct
      fragment ion groups, according to the backbone cleavage positions. Although the
      identification of unknown azaspiracids was difficult based on CID alone, the
      spectra provided sufficient structural information to allow confirmation of known
      azaspiracids in marine samples. Furthermore, we were able to detect two new
      azaspiracid analogs (AZA 1b and 6) in our samples and provide a preliminary
      structural analysis. The proposed dissociation pathways under tandem mass
      spectrometry (MS/MS) conditions were confirmed by a comparison with accurate mass
      data from electrospray quadrupole time-of-flight MS/MS experiments. Regular
      sequential MS(n) analysis on an ion-trap mass spectrometer was more restricted in
      comparison to the triple-quadrupole mass spectrometer, because the azaspiracids
      underwent multiple [M + H - nH(2)O](+) (n = 1-6) losses from the precursor ion
      under CID. Thus, the structural information obtained from MS(n) experiments was
      somewhat limited. To overcome this limitation, we developed a wide-range
      excitation technique using a 180-u window that provided results comparable to the
      triple-quadrupole instrument. To demonstrate the potential of the method, we
      applied it to the analysis of degraded azaspiracids from mussel tissue extracts.

PMID- 12478577
TI  - Mammalian reovirus core protein micro 2 initiates at the first start codon and is
      acetylated.
AB  - Mammalian reovirus is an enteric virus that contains a double-stranded RNA
      genome. The genome consists of ten RNA segments that encode eight structural and
      three non-structural proteins. The structural proteins form a double-layered
      structure. The innermost layer, called the core, consists of five proteins
      (lambda1, lambda2, lambda3, micro 2, and sigma2). Protein lambda3 is the RNA
      dependent RNA polymerase (RdRp) and micro 2 is thought to be an RdRp cofactor.
      Translation of most reovirus proteins is known to commence at the first start
      codon. However, the translation initiation site of the viral core protein micro
      2, encoded by the M1 RNA segment, has been in dispute. Although the theoretical
      molecular weight of micro 2 is 83 267 Da the actual molecular weight is unknown
      because micro 2 runs aberrantly in SDS-PAGE and has resisted characterization by
      Edman degradation, indicating that the amino terminus is post-translationally
      modified. In this study, we used proteolysis coupled with MALDI-Qq-TOFMS to
      determine that translation of micro 2 initiates at the first AUG codon, that its
      actual molecular weight approximates the theoretical value of 83 kDa, that the
      amino terminal methionine residue is removed, and that the next amino acid
      (alanine) is post-translationally acetylated.

PMID- 12478579
TI  - A new sheathless electrospray interface for coupling of capillary electrophoresis
      to ion-trap mass spectrometry.
AB  - A simple laboratory-made sheathless electrospray interface for coupling of
      capillary electrophoresis to ion-trap mass spectrometry (CE/MS) was developed.
      The interface was machined in-house and it was designed to be freely
      interchangeable with the commercially available ionization sources for the mass
      spectrometer. Sharpened fused-silica capillaries were coated with nickel by a
      simple electrodeless plating procedure and were used as all-in-one
      columns/emitters. The electrodeless plating produced a 2-5- micro m thick smooth
      nickel layer that lasted for more than 8 h of continuous electrospraying. The
      performance of the CE/MS interface was examined by using four cationic imipramine
      derivatives as test substances. Relative detection limits were calculated on the
      basis of the extracted ion electrophorograms and were in the range 6-130 nmol/L,
      corresponding to absolute detection limits in the range of 20-400 amol. The
      system was applied for analysis of impurities in an impure imipramine N-oxide
      preparation, and two of the impurities could be identified on the basis of online
      MS(MS) spectra recorded in scan-dependent mode.

PMID- 12478578
TI  - N-Terminal peptide labeling strategy for incorporation of isotopic tags: a method
      for the determination of site-specific absolute phosphorylation stoichiometry.
AB  - Determining the phosphorylation stoichiometry at specific sites in a
      phosphoprotein is a very challenging task. We describe here a novel mass
      spectrometry based method that is capable of measuring the absolute
      phosphorylation stoichiometry at specific sites without the need for specific
      internal standards, phospho-site antibodies or radioactivity. The method is based
      on a gentle chemical labeling strategy which specifically and differentially
      labels the N-terminus of all peptides in a sample with either a D(5)- or D(0)
      propionyl group and measures the ratio of the abundance of the D(5)/D(0) peptide
      pairs simultaneously using mass spectrometry. Using matrix-assisted laser
      desorption/ionization (MALDI), the method can measure absolute stoichiometry to
      within at least 10% and can be applied to both in vitro and in vivo
      phosphorylated peptides and proteins. Furthermore, this method can potentially be
      applied to the quantitative study of other types of protein post-translational
      modifications, and the profiling of protein expression on the proteome level.

PMID- 12478580
TI  - Optimization of a liquid chromatography method based on simultaneous electrospray
      ionization mass spectrometric and ultraviolet photodiode array detection for
      analysis of flavonoid glycosides.
AB  - Different reversed-phase liquid chromatography (LC) columns of conventional
      dimensions were coupled to an ultraviolet photodiode array detector (UV-DAD) and
      a magnetic sector-type spectrometer, equipped with an electrospray ionization
      (ESI) source, by a laboratory-made flow splitter. A mixture of three flavonoid-O
      glycosides was employed to examine the effects of the solvent composition, the
      flow rate, the stationary phase, the pH and the organic acid added, on the
      chromatographic separation, the UV-DAD detection, the ESI process and the entire
      LC system with ESI-MS and UV-DAD detection. In the positive ion mode, methanol
      containing 1% acetic acid was by far the most sensitive in ESI-MS analysis,
      whereas an acetonitrile/water mobile phase containing 0.5% formic acid was proved
      to give the best sensitivity in LC/ESI-MS/UV-DAD analysis. In the negative ion
      mode, the highest sensitivity was obtained with a mobile phase containing 0.1%
      formic acid, while addition of bases decreased the sensititvity. The optimal flow
      rate was higher in negative ESI (20-50 micro L/min) than in positive ESI (5 micro
      L/min), and the percentage of organic phase had an influence on the sensitivity
      of ESI-MS detection. With regard to the selection of a suitable C(18) reversed
      phase LC column, a column which is well end-capped is to be preferred, because
      residual silanol groups appear to impair the separation of flavonoid glycosides.
      The optimized LC/ESI-MS/UV-DAD method was applied to a commercial Crataegus
      extract, which is used in phytomedicine to treat cardiovascular problems and is
      known to be rich in flavonoids. It is demonstrated how UV spectra and first-order
      ESI mass spectra allow a fast characterization of flavonoids, even if reference
      compounds are not available or at hand.

PMID- 12478581
TI  - Gas chromatography/mass spectrometric characterisation of pyrolysis/silylation
      products of glucose and cellulose.
AB  - The mass spectra of trimethylsilyl (TMS) derivatives of possible hydroxylated
      pyrolysis products of glucose and cellulose were recorded by gas
      chromatography/mass spectrometry (GC/MS) analyses of TMS derivatives of 2
      hydroxymethylfuran, 2-hydroxy-1-methyl-1-cyclopenten-3-one, 5-(hydroxymethyl)-2
      furaldehyde, 5-methyl-2-furoic acid, 4-hydroxy-6-methyl-(2H)-pyran-2-one, 2
      methyl-3-hydroxy-(4H)-pyran-4-one (maltol) and 1,6-anhydro-beta-D-glucopyranose
      (levoglucosan, LG). Also, 2-O-TMS-1,6-anhydro-beta-D-glucopyranose, 4-O-TMS-1,6
      anhydro-beta-D-glucopyranose and 2,4-bis-O-TMS-1,6-anhydro-beta-D-glucopyranose
      were identified from the interpretation of electron impact and chemical
      ionisation mass spectra of products obtained from partially silylated
      levoglucosan solutions, together with information from the known relative
      reactivities of OH groups of anhydrosugars. A peak at m/z 116 was found to be
      characteristic of the mass spectra of partially silylated anhydrosugars, and is
      absent from the mass spectra of the persilylated species. Pyrolysis/GC/MS of
      cellulose in the presence of hexamethyldisilazane afforded principally the 2- and
      4-TMS ethers and the 2,4-bis-TMS ether of LG, whereas the 5-TMS-oxymethyl-2
      furaldehyde was a prominent pyrolysis/silylation product of glucose. The mass
      spectra of other relevant pyrolysis/silylation products are presented.

PMID- 12478582
TI  - Utility of three types of mass spectrometers for determining elemental
      compositions of ions formed from chromatographically separated compounds.
AB  - Concentration factors of 1000 and more reveal dozens of compounds in extracts of
      water supplies. Library mass spectra for most of these compounds are not
      available, and alternative means of identification are needed. Determination of
      the elemental compositions of the ions in mass spectra makes feasible searches of
      commercial and chemical literature that often lead to compound identification.
      Instrumental capabilities that constrain the utility of a mass spectrometer for
      determining ion compositions for compounds that elute from a chromatographic
      column are scan speed, mass accuracy, linear dynamic range, and resolving power.
      Mass peak profiling from selected ion recording data (MPPSIRD) performed with a
      double-focusing mass spectrometer provides the best combination of these
      capabilities. This technique provides unique ion compositions for ions of higher
      mass from compounds eluting from a gas chromatograph than can be obtained by
      orthogonal acceleration time-of-flight (oa-TOF) or Fourier transform ion
      cyclotron resonance mass spectrometry. Multiple compositions are usually possible
      for an ion with a mass exceeding 150 Da within the error limits of the mass
      measurement. The correct composition is selected based on measured exact masses
      of the mass peak profiles resulting from isotopic ions higher in mass by 1 and 2
      Da and accurate measurement of the summed abundances of these isotopic ions
      relative to the monoisotopic ion. A profile generation model (PGM) automatically
      determines which compositions are consistent with measured exact masses and
      relative abundances. The utility of oa-TOF and double-focusing mass spectrometry
      using ion composition elucidation (MPPSIRD plus the PGM) are considered for
      determining ion compositions of two compounds found in drinking water extracts
      and a third compound from a monitoring well at a landfill. Published in 2002 by
      John Wiley & Sons, Ltd.

PMID- 12478583
TI  - Direct analysis of volatile organic compounds in human breath using a
      miniaturized cylindrical ion trap mass spectrometer with a membrane inlet.
AB  - Membrane introduction mass spectrometry (MIMS) coupled to a miniature mass
      spectrometer equipped with a cylindrical ion trap (CIT) analyzer was used to
      monitor the flavor components, 3-phenyl-2-propenal and methyl salicylate, found
      in cinnamon and wintergreen candies, respectively, directly from human breath.
      The poly(dimethylsiloxane) (PDMS) membrane was operated in a trap-and-release
      mode, where the temperature of the membrane was cycled during the experiments,
      which permitted temporal resolution of the two compounds of interest,
      facilitating their observation in the complex sample. Under these thermally
      driven conditions, the 10-90% rise times for both compounds are similar (15 s for
      methyl salicylate, 17 s for 3-phenyl-2-propenal), but the difference in
      diffusivity means that the signal for 3-phenyl-2-propenal is delayed and the 10%
      point occurs 6 s later than that for wintergreen. Additional specificity needed
      for complex samples was gained by using tandem mass spectrometry.

PMID- 12478584
TI  - Evaluation of protocols for reproducible electrospray in-source collisionally
      induced dissociation on various liquid chromatography/mass spectrometry
      instruments and the development of spectral libraries.
AB  - Mass spectral libraries provide a tool for identifying unknown compounds using
      both molecular weight and fragmentation information. Mass spectrometers with
      electrospray ionisation (ESI) and atmospheric chemical ionisation (ApCI) sources
      have the capability to produce data of this type using in-source collisionally
      induced dissociation (CID), and in-source CID libraries can be created. Due to
      the variation in electrospray source design from different instrument
      manufacturers, the production of reproducible in-source CID spectra that can be
      used in libraries for all instrument types is not a trivial task. To date, the
      evaluation of the production of in-source CID libraries has tended to focus on
      similar instruments from one manufacturer. The studies have also tended to focus
      on specific compound classes, with a limited molecular weight range.This report
      describes the findings from the investigation of protocols for the creation of
      mass spectral libraries using ESI in-source CID on six instruments from four
      different manufacturers. The overall goal was to create a spectral library for
      the identification of unknowns. The library could then be applied across all
      manufacturers' electrospray instruments. Two different experimental protocols
      were attempted. The first used a tuning compound to establish standard ESI source
      conditions, with fixed fragmentation potentials. The second involved the
      attenuation of the [M + H](+) ion to a known degree. A diverse range of compounds
      (pharmaceutical, photographic, pesticides) was tested to establish the
      reproducibility of the spectra on the six instruments. Both protocols produced
      spectra on the various instruments that in many cases were very similar. In other
      examples, the spectra differed not only in their relative ion abundances, but
      also in terms of the spectral content. Important observations regarding the
      effect of ion source design are also reported. The degree of spectral
      reproducibility was calculated off-line by comparing the five most abundant ions
      (20% for each ion that matches) from each spectrum on each instrument. This
      approach was adopted, as we do not possess a software package that met our
      requirements for spectral comparison. Match factors (% fit) were calculated by
      comparing each spectrum against the spectra recorded for the same compound and
      then for all other compounds, on each instrument. The % fit values derived by the
      off-line approach gave a clear view of the spectral reproducibility from
      instrument to instrument and also discriminated the spectra of the various
      compounds from each other. The applicability of this approach was tested using a
      blind trial in which several compounds were presented as unknowns, their in
      source CID spectra recorded and the five-ion approach used for identification.

PMID- 12478585
TI  - Structural confirmation of ostreocin-D by application of negative-ion fast-atom
      bombardment collision-induced dissociation tandem mass spectrometric methods.
AB  - Negative-ion fast-atom bombardment collision-induced dissociation tandem mass
      spectrometric (FAB-CID-MS/MS) methodology was successfully applied to verify the
      highly complex structure of ostreocin-D (MW 2633), a new palytoxin analog
      isolated from the marine dinoflagellate Ostreopsis siamensis and proposed to be
      42-hydroxy-3,26-didemethyl-19,44-dideoxypalytoxin based on NMR data. The charge
      remote fragmentations were facilitated by a negative charge introduced to a
      terminal amino group or to a hydroxyl group at the other terminus by a reaction
      with 2-sulfobenzoic acid cyclic anhydride. Product ions generated from the [M -
      H](-) ions provided information on the structural details of ostreocin-D.
      Comparisons between the spectral data for ostreocin-D and palytoxin also provided
      a rational basis for the assignments of product ions.

PMID- 12478586
TI  - Helicase activity is only partially required for Schizosaccharomyces pombe Rqh1p
      function.
AB  - The RecQ-related family of DNA helicases is required for the maintenance of
      genomic stability in organisms ranging from bacteria to humans. In humans,
      mutation of three RecQ-related helicases, BLM, WRN and RecQL4, cause the cancer
      prone and premature ageing diseases of Bloom syndrome, Werner's syndrome and
      Rothmund-Thompson syndrome, respectively. In the fission yeast
      Schizosaccharomyces pombe, disruption of the rqh1(+) gene, which encodes the
      single Sz. pombe RecQ-related helicase, causes cells to display reduced viability
      and elevated levels of chromosome loss. After S-phase arrest or DNA damage, cells
      lacking rqh1(+) function display elevated levels of homologous recombination and
      defective chromosome segregation. Here we show that, like other RecQ family
      members, the Rqh1p protein displays 3' to 5' DNA helicase activity.
      Interestingly, however, unlike other RecQ family members, the helicase activity
      of Rqh1p is only partially required for its function in recovery from S-phase
      arrest or DNA damage. We also report that high cellular levels of Rqh1p result in
      lethal chromosome segregation defects, while more moderate levels of Rqh1p cause
      significantly elevated rates of chromosome loss. This suggests that careful
      regulation of RecQ-like protein levels in eukaryotic cells is vital for
      maintaining genome stability.

PMID- 12478587
TI  - Characterization of a gene encoding tRNA nucleotidyltransferase from Candida
      glabrata.
AB  - A gene encoding ATP (CTP):tRNA nucleotidyltransferase (EC2.7.7.25) was isolated
      from Candida (Torulopsis) glabrata by complementation in Saccharomyces
      cerevisiae. The predicted amino acid sequence of the protein revealed a large
      region with high sequence similarity to members of the Class II group of the
      nucleotidyltransferase superfamily and an N-terminal region characteristic of a
      mitochondrial targeting sequence. The essential role of the carboxylates within
      the conserved DXD and RRD motifs was confirmed by mutagenesis. C. glabrata
      strains bearing truncated CCA1 genes that lacked sequences encoding the putative
      mitochondrial targeting peptide were unable to grow on non-fermentable carbon
      sources but were able to grow on a fermentable carbon source. These results
      suggest that, as in S. cerevisiae, the C. glabrata CCA-adding enzyme is a sorting
      isozyme that functions in multiple cellular compartments. Mapping of the 5'-ends
      of primary transcripts of CCA1 revealed multiple transcription start sites
      located both upstream of and between two in-frame start codons. When the cells
      were cultured on a non-fermentable carbon source the longer transcripts appeared
      more abundant, suggesting that the choice of transcription start sites was
      influenced by carbon source. The shorter transcripts, which lacked sequences
      encoding the mitochondrial targeting information, were more predominant in cells
      grown on glucose. These observations suggest that expression of CCA-adding
      isozymes in C. glabrata may be regulated. The DNA sequence has been assigned
      GenBank Accession No. AF098803.

PMID- 12478588
TI  - Progression of the stacked Golgi compartments in the yeast Saccharomyces
      cerevisiae by overproduction of GDP-mannose transporter.
AB  - The Golgi compartments of the yeast Saccharomyces cerevisiaeare dispersed within
      the cytoplasm, in contrast to the stacked cisternae in the mammalian cell, and
      consequently are observed as a punctate pattern by immunofluorescent staining of
      Golgi-marker proteins. The VIG4/VRG4 gene encodes the essential yeast GDP-mannose
      transporter, which is a polytopic membrane protein in the early and medial Golgi
      compartments. Upon overexpression of this gene by the aid of a strong promoter
      and multicopy vector, we found that stacked multivesicular structures, which
      resembled the cisternae of mammalian Golgi apparatus, had developed in S.
      cerevisiae. Immuno-electron microscopy showed that the GDP-mannose transporter
      was located on the stacked cisternae. Immuno-isolation and immunoblotting
      analyses of the vesicles showed that the overproduced GDP-mannose transporter
      also co-localized with the Golgi glycosyltransferases, but not with the ER- or
      late Golgi-marker proteins as in the control cell. We propose that the
      localization mechanism of the GDP-mannose transporter in the Golgi compartment
      would be efficient and hardly saturable, and therefore the overproduced protein
      induced a progression of Golgi-like compartments rather than being mislocalized
      in other compartments, such as the ER or a vacuole.

PMID- 12478589
TI  - The identification of the Saccharomyces cerevisiae gene AYT1(ORF-YLL063c)
      encoding an acetyltransferase.
AB  - The recent isolation and characterization of Tri101 in Fusarium sporotrichioides
      has led to the functional identification of the yeast open reading frame (ORF)
      YLL063c, located on chromosome XII of Saccharomyces cerevisiae. The sequence of
      YLL063c predicts a protein of 474 residues that has 45% identity and 70%
      similarity to FsTri101. FsTri101 encodes a trichothecene 3-O-acetyltransferase
      that functions in trichothecene biosynthesis. Feeding studies indicated low
      levels of C3-OH acetylation in cultures of the laboratory yeast strain, RW2802.
      No similar activity was found in RW2802 transformed with an integrative plasmid
      carrying a disrupted YLL063c gene. Based on these results, which show structural
      and functional similarities between YLL063c and FsTri101, we propose that YLL063c
      encodes an acetyltransferase capable of trichothecene 3-O-acetylation and have
      named this gene AYT1. Published in 2002 by John Wiley & Sons, Ltd.

PMID- 12478590
TI  - Isolation and characterization of the gene URA3 encoding the orotidine-5'
      phosphate decarboxylase from Torulaspora delbrueckii.
AB  - A DNA fragment containing the URA3 gene from Torulaspora delbrueckii was isolated
      by complementation cloning in Saccharomyces cerevisiae. DNA sequence analysis
      revealed the presence of an ORF of 795 bp, encoding a 264 amino acid protein,
      which shares a high similarity to the Saccharomycetaceae Ura3 proteins.
      Furthermore, the cloned ORF fully complemented the ura3 mutation of S.
      cerevisiae, confirming that it encodes for the TdUra3 protein. The GeneBank
      Accession No. for TdURA3 is AF518402.

PMID- 12478591
TI  - Polymorphism of the MPR1 gene required for toxic proline analogue resistance in
      the Saccharomyces cerevisiae complex species.
AB  - We recently discovered, on the chromosome of Saccharomyces cerevisiae sigma
      1278b, novel MPR1 and MPR2 genes required for resistance to a toxic analogue of L
      proline, L-azetidine-2-carboxylic acid. The MPR genes, which were absent in the
      S. cerevisiae genome project strain S288C, encoded a novel acetyltransferase of
      229 amino acids that detoxifies the analogue by acetylating it. The MPR1 gene
      homologue found in Schizosaccharomyces pombe was also shown to encode a similar
      acetyltransferase. To further analyse the origin and the physiological role of
      the yeast novel gene, we report here the comparative analysis of the MPR1 gene in
      the S. cerevisiae complex spp. which belong to the Saccharomyces sensu stricto
      group. Only the type strain of S. paradoxus exhibited resistance and
      acetyltransferase activity to L-azetidine-2-carboxylic acid. PCR was then used to
      isolate the new MPR1 homologue (Spa MPR1) from S. paradoxus with the primers
      based on the sequence of the MPR1 gene. Gene expression and enzymatic analysis
      showed that the cloned Spa MPR1 gene encodes an L-azetidine-2-carboxylic acid
      acetyltransferase of 231 amino acids, which has 87% identity to the MPR1 protein.
      We also found in the protein databases that S. bayanus contains a DNA fragment
      that is partly homologous to the MPR1 gene. However, the gene product was
      considered to lose the enzymatic activity, possibly due to the gene truncation or
      the base substitution(s) at the important region for catalysis. Further, genomic
      PCR analysis showed that most of the S. cerevisiae complex spp. have the sequence
      highly homologous to the MPR1 gene.

PMID- 12478593
TI  - The Emperor's new clothes.

PMID- 12478592
TI  - Cloning, sequencing and characterization of a gene encoding dihydroxyacetone
      kinase from Zygosaccharomyces rouxii NRRL2547.
AB  - The dihydroxyacetone pathway, an alternative pathway for the dissimilation of
      glycerol via reduction by glycerol dehydrogenase and subsequent phosphorylation
      by dihydroxyacetone (DHA) kinase, is activated in the yeasts Saccharomyces
      cerevisiae and Zygosaccharomyces rouxii during osmotic stress. In experiments
      aimed at investigating the physiological function of the DHA pathway in Z.
      rouxii, a typical osmotolerant yeast, we cloned and characterized a DAK gene
      encoding dihydroxyacetone kinase from Z. rouxii NRRL 2547. Sequence analysis
      revealed a 1761 bp open reading frame, encoding a peptide composed of 587 deduced
      amino acids with the predicted molecular weight of 61 664 Da. As the amino acid
      sequence was most closely homologous (68% identity) to the S. cerevisiae Dak1p,
      we named the gene and protein ZrDAK1 and ZrDak1p, respectively. A putative ATP
      binding site was also found but no consensus element associated with
      osmoregulation was found in the upstream region of the ZrDAK1 gene. The ZrDAK1
      gene complemented a S. cerevisiae W303-1A dak1delta dak2 delta strain by
      improving the growth of the mutant on 50 mmol/l dihydroxyacetone and by
      increasing the tolerance to dihydroxyacetone in a medium containing 5% sodium
      chloride, suggesting that it is a functional homologue of the S. cerevisiae DAK1.
      However, expression of the ZrDAK1 gene in the S. cerevisiae dak1delta dak2 delta
      strain had no significant effect on glycerol levels during osmotic stress. The
      ZrDAK1 sequence has been deposited in the public data bases under Accession No.
      AJ294719; regions upstream and downstream of ZrDAK1are deposited as Accession Nos
      AJ294739 and AJ294720, respectively.

PMID- 12478594
TI  - Baseline abdominal pressure and valsalva leak point pressures-correlation with
      clinical and urodynamic data.
AB  - AIMS: To characterize the factors contributing to changes in baseline abdominal
      pressure (P(abd)) and the correlation between DeltaVLPP, VLPP(tot), and other
      clinical and urodynamic variables. METHODS: Two hundred sixty-four female
      patients who had undergone an anti-incontinence procedure between February 1994
      and October 1999 were retrospectively reviewed. The urodynamics performed for
      each patient included abdominal and vesical pressures measured in a standardized
      manner with the patient sitting upright and the pressure sensors maintained at
      the level of the symphysis pubis. VLPP was determined at bladder volumes of 200
      mL during a gradually increasing Valsalva maneuver. RESULTS: Baseline P(abd)
      varied between 10 and 55 cm H(2)O (mean, 32.7 +/- 8.8) and were significantly
      correlated with patient weight (P<0.001) and with patient body mass index
      (P<0.001). Baseline P(abd) was not found to be correlated with patient age, Baden
      and Walker Classification of the grading of pelvic floor prolapse, degree of
      incontinence (determined by the number of pads used per day), or prior surgical
      procedures for stress incontinence. Higher baseline P(abd) were significantly
      correlated with the peak abdominal pressure reached during the Valsalva maneuver
      (P<0.0001) and with VLPP(tot) (P<0.0001) but not with DeltaVLPP. Higher VLPP(tot)
      significantly correlated with decreased age (P=0.004), less severe incontinence
      (P=0.004), higher peak Valsalva pressure (P<0.0001), and the ability to increase
      abdominal pressure for a longer period of time (time to peak P(abd) during
      Valsalva). VLPP(tot) and DeltaVLPP had similar statistical correlation with all
      the clinical variables examined and neither could predict the outcome of any anti
      incontinence surgery. By using a VLPP of 60 cm H(2)O as a cutoff to differentiate
      severe ISD from GSUI, 211 (67.4%) of the patients would be categorized as having
      ISD according to their DeltaVLPP compared with only 106 (40.1%) by using the
      VLPP(tot). CONCLUSIONS: Baseline P(abd) varies considerably among patients, is
      correlated with patient weight and habitus. In addition, it varies with both the
      ability to be increased for longer periods of time and with VLPP(tot). Looking at
      VLPP(tot) and DeltaVLPP will result in a different categorization of the type of
      incontinence in at least 25% of patients and, thus, affect the physician's
      selection of an anti-incontinence procedure for an individual patient.

PMID- 12478595
TI  - Measuring the sensations of urge and bladder filling during cystometry in urge
      incontinence and the effects of neuromodulation.
AB  - AIMS: As urge and urgency contribute greatly to a patient's symptoms, it follows
      that sensory evaluation combined with noninvasive neuromodulation during
      urodynamics may provide new criteria for improving patient selection for an
      implantable stimulator. The purpose of this research was to develop and validate
      an objective measure of bladder sensations during filling cystometry and then to
      apply this technique to evaluate the effects of neuromodulation on the sensations
      of urge measured in this way. METHODS: In study 1 a new patient-activated keypad
      device was tested during urodynamics to measure bladder sensations according to a
      0-4 scale and validated by using a technique adapted from a standard
      psychophysical sensory threshold testing method. In study 2 the effects of
      pudendal afferent nerve stimulation on measured sensations of urge were assessed
      during cystometry with patients as their own controls. Forty-three patients
      diagnosed with idiopathic detrusor instability were studied; 10 participated in
      study 1 and 35 in study 2. RESULTS: The new device gave reliable and repeatable
      measures of sensations with statistically significant differences in bladder
      volume at each of the urge levels tested (Wilcoxon matched pairs test).
      Neuromodulation suppressed urinary urge in 89% of the 35 patients. This effect
      was associated with a statistically significant increase in bladder volume at all
      urge levels. CONCLUSIONS: A new patient operated key-pad device provided a
      reliably objective measure of sensations of urge during urodynamics without the
      need for prompting. Neuromodulation using noninvasive pudendal afferent
      stimulation suppressed these sensations whilst increasing bladder volume.

PMID- 12478596
TI  - Posterior tibial nerve stimulation in the treatment of urge incontinence.
AB  - AIMS: The objective of this study was to evaluate the effect of posterior tibial
      nerve stimulation (PTNS) for treatment of urge incontinence. METHODS: In a
      prospective multicentre study, 35 patients with complaints of urge incontinence
      underwent 12 weekly sessions of PTNS at one of five sites in the Netherlands and
      one site in Italy. Frequency/volume charts and I-QoL and SF-36 questionnaires
      were completed at 0 and 12 weeks. Success was analysed by using subjective and
      objective criteria. Overall subjective success was defined as the willingness to
      continue treatment, whereas objective success was defined as a significant
      decrease (to<50%) in total number of leakage episodes. RESULTS: Twenty-two
      patients (63%) reported a subjective success. Twenty-four patients (70%) showed a
      50% or greater reduction in total number of leakage episodes. Sixteen (46%) of
      these-patients were completely cured (i.e., no leakage episodes) after 12
      sessions. Quality of life parameters improved significantly. CONCLUSIONS: We
      conclude that posterior tibial nerve stimulation is an effective, minimally
      invasive option for treatment of patients with complaints of urge incontinence,
      as improvement was seen in subjective as well as objective parameters.

PMID- 12478597
TI  - Urodynamic changes induced by the intravaginal electrode during pelvic floor
      electrical stimulation.
AB  - AIMS: The goal of this study was to evaluate whether the intravaginal electrode
      used to perform vaginal electrical stimulation could induce acute changes on the
      cystometrograms and urethral pressure profiles (UPP) recordings. METHODS: Three
      consecutive urodynamic examinations were performed on 30 women with stress
      urinary incontinence (SUI) symptoms. The first exam was performed without the
      electrode, the second with the electrode inserted into the vagina, but with the
      stimulator switched off and the third with the stimulator turned on. We used the
      INNOVA (Empi) stimulator with electrical parameters set at 50 Hz and 60 mA and on
      an intermittent cycle during the cystometries and a continuous stimulation during
      the UPP. The data of functional profile length (FPL), maximum urethral closure
      pressure (MUCP), and area of the resting UPP, as well as the filling sensations
      and its respective bladder volumes during the cystometries, were compared. With
      regard to the cystometries. RESULTS: No effect of the electrode was observed on
      cystometry. However, the simple presence of the electrode improved the FPL, MUCP,
      and areas of the UPP similar to those when the stimulation was applied.
      CONCLUSIONS: We conclude that, the presence of the intravaginal electrode induces
      changes in the UPP not related to the stimulation itself. The physiotherapeutic
      effect of the electrode itself is still to be evaluated.

PMID- 12478598
TI  - Urodynamically age-specific prevalence of urinary incontinence in women with
      urinary symptoms.
AB  - AIMS: To determine the age-specific prevalence rates of different types of
      urinary incontinence in women with urinary symptoms using urodynamic studies
      (UDS). METHODS: One thousand five hundred women with urinary symptoms who
      underwent UDS in our department from January 1997 through December 1999 were
      enrolled. A detailed history, physical examination, and data of multi-channel UDS
      including uroflowmetry, filling and voiding cystometry, stress urethral pressure
      profile, and 20-minute pad test were obtained for each patient. The urodynamic
      findings of each patient were analyzed and correlated with age in decades.
      RESULTS: Of 1,500 women, 329 were excluded from analysis because they had
      undergone anti-incontinence surgery (n=27), had undergone treatment for cervical
      cancer (n=147), or were being followed-up after medication (n=155). Of the
      remaining 1,171 patients, 656 (56%) had genuine stress incontinence (GSI), 68
      (5.8%) had detrusor instability (DI), 187 (16%) had mixed GSI/DI, 245 (20.9%) had
      either voiding or storing dysfunction without concomitant incontinence, and 15
      (1.3%) had normal urodynamic findings. The 41-50- and 51-60-year age groups had
      the highest prevalence rates of urinary incontinence, accounting for 31% and 28%
      of GSI cases, 35% and 25% of DI cases, and 40% and 27% of mixed GSI/DI cases,
      respectively. The prevalence of GSI and mixed GSI/DI increased consistently with
      age, but the prevalence of DI decreased after age 66. Thus, the prevalence rates
      of GSI, DI, and mixed GSI/DI were 56%, 5.8%, and 16%, respectively, in women with
      urinary symptoms. CONCLUSIONS: Female urinary incontinence had a biogenic peak
      prevalence in the 41-50-year and 51-60-year age groups.

PMID- 12478599
TI  - Video urodynamics using transrectal ultrasonography for lower urinary tract
      symptoms in women.
AB  - AIMS: To understand the properties of lower urinary tract disorders in women, we
      evaluated 60 female patients with lower urinary tract disorders or symptoms of
      recurrent cystitis by free uroflowmetry and video urodynamics using transrectal
      ultrasonography (VU-TRUS). METHODS: Results of urodynamic studies or symptoms of
      stress incontinence were used to divide 60 women into 7 normal controls and 53
      with voiding dysfunctions. RESULTS: In normal controls, VU-TRUS showed that the
      mean posterior urethrovesical angle and anteroposterior diameter of the proximal
      urethra at maximum flow was 151.4 degrees and 4.9 mm, respectively. In patients
      with voiding dysfunction, VU-TRUS during voiding revealed various urethral
      abnormalities, including 16 detrusor sphincter dyssynergia, 4 detrusor bladder
      neck dyssynergia, and 13 insufficient opening of the entire urethra. VU-TRUS also
      showed pelvic floor abnormalities, including 24 urethral hypermobilities (group
      1) and 11 cystoceles (group 2). Eighteen patients had neither urethral
      hypermobility nor cystocele (group 3). Major pressure-flow abnormalities in the
      53 patients with voiding dysfunctions were weak detrusor (72%) and/or bladder
      outlet obstruction (25%). There were no significant differences in the
      distribution of the pressure-flow abnormalities among the three groups. However,
      the mean values of abdominal pressure at maximum flow of group 1 (20.9 cm H(2)O)
      and group 2 (17.9 cm H(2)O) were significantly higher than that of group 3 (6.3
      cm H(2)O; each P < 0.05). The mean values of residual urine volume of group 2
      (60.8 mL) and group 3 (77.6 mL) were significantly higher than that of group 1
      (23.5 mL; each P < 0.05). CONCLUSIONS: The symptoms of women with lower urinary
      tract disorders were frequently accompanied by urethral and/or pelvic floor
      abnormalities during voiding that were clearly detected by VU-TRUS. VU-TRUS is
      useful for objective evaluation of female lower urinary tract symptoms.

PMID- 12478600
TI  - Assessment of prostatic obstruction: A cuff may be enough.
AB  - AIMS: To investigate the use of an inflatable perile cuff to obstruct flow
      progressively during voiding in order to provide a noninvasive measure of bladder
      pressure. METHODS: In this study, we explain the observed relationship of flow
      rate with applied cuff pressure by analogy with a simple physical model. The
      model comprised a fixed-pressure reservoir (simulating the bladder), a
      collapsible tube around which a fixed pressure could be applied (simulating the
      prostatic urethra), connected by rigid conduit to a further collapsible tube
      around which pressure could be applied (simulating the penile urethra and cuff).
      Flow was progressively obstructed by incremental increase of pressure applied to
      the "penile urethra," with the experiment being repeated for a range of fixed
      pressures applied to the "prostatic urethra." RESULTS: The model reproduced the
      typical pressure/flow curves recorded during voiding by using penile cuff
      inflation in normal and obstructed men. CONCLUSIONS: Our data led us to
      hypothesise that the relationship between cuff pressure and flow rate can be used
      to deduce bladder pressure during voiding, prostatic opening pressure, and
      urethral diameter at the flow-controlling zone, three indicators of lower urinary
      tract function. These measurements may add to the accuracy of diagnosis and
      quality of care for a large number of men with lower urinary tract symptoms.

PMID- 12478601
TI  - Modelized analysis of pressure-flow studies of patients with lower urinary tract
      symptoms due to benign prostatic enlargement.
AB  - AIMS: To gain insight from an adaptable computer model of micturition into the
      pathophysiological phenomena occurring during voiding in men with lower urinary
      tract symptoms due to benign prostatic enlargement (BPE). METHODS: By using the
      Valentini-Besson-Nelson (VBN) micturition model, we proceeded with an in-depth
      and systematic analysis of the pressure-flow studies of 71 patients (119
      tracings) provided by three different institutions. RESULTS: The modelized
      analysis identified and quantified several pathophysiological phenomena during
      voiding: compressive obstruction, variations in detrusor contraction force
      (enhanced or reduced), progressive relaxation of the prostatic fossa, occasional
      detrusor-bladder neck coupling, and sphincteric control dysfunctions. Once these
      phenomena were taken into account by using a set of new parameters, the computed
      flow rate and detrusor pressure curves became very similar to the recorded ones.
      CONCLUSIONS: The accuracy of this sophisticated analysis allows us to separate
      and to study during each voiding the phenomena belonging to the urethra, the
      detrusor, the bladder neck, the prostate, and their neurologic coordination in
      BPE patients.

PMID- 12478602
TI  - Effect of the Bowman-Birk inhibitor (a soy protein) on in vitro bladder
      neck/urethral and penile corporal smooth muscle activity.
AB  - AIMS: The Bowman-Birk inhibitor (BBI), is a serine protease inhibitor derived
      from soy beans, which is presently being evaluated in clinical trials for its
      ability to serve as a cancer preventive or anti-inflammatory agent. The form of
      BBI currently in clinical trials is known as Bowman-Birk inhibitor concentrate
      (BBIC). There have been anecdotal reports from patients of improved voiding and
      sexual functions in the ongoing BBIC trials. The objective of this study was to
      quantify the effect of BBI and BBIC on urethral and corporal smooth muscle
      activity. METHODS: In vitro muscle strip studies of New Zealand White rabbit
      urethra/bladder neck and penile corpora in the presence or absence of BBI or BBIC
      incubation (5 mg/mL) were performed. RESULTS: In dose-response curves to alpha
      stimulation, BBI mediated a shift to the right (decreased receptor sensitivity in
      bladder/urethra as well as corpora with no change in the maximal response).
      Bladder base/ urethra contraction by field stimulation was significantly
      inhibited by BBI at higher frequencies (1-32 Hz) (12.2 + 0.8 g vs. 6.3 + 0.75 g,
      P < 0.05). BBI inhibited field stimulated relaxation of corporal muscle at lower
      frequencies. Muscarinic contraction of the bladder neck/urethra in alpha
      prestimulated tissue was significantly inhibited by BBI (5.3 + 0.2 g vs. 2.7 +
      0.1 g, P < 0.05). BBI has an inhibitory effect on alpha adrenergic dose-response
      curves in bladder neck/urethral and corpora smooth muscle. BBI also significantly
      inhibited neurohumoral cholinergic release and in vitro muscarinic contraction of
      the urethra. The effects on corpora relaxation were less pronounced. CONCLUSIONS:
      The data suggest that the phytochemical BBI may promote physiologic effects of
      urethral relaxation and improved voiding by unique mechanisms and deserves
      further study as a pharmacologic agent for lower urinary tract symptoms.

PMID- 12478603
TI  - Effect of thoughtful preparation on the catheterization of children undergoing
      investigative studies.
AB  - AIMS: To evaluate an anesthetic sedation free method of transurethral
      catheterization in children. METHODS: The child and his or her parents are
      thoroughly prepared for the procedure by means of written and oral child-adapted
      information and practical instructions. To evaluate this routine, a simple
      questionnaire was given to 115 consecutive children undergoing transurethral
      catheterization. RESULTS: The questionnaire was returned by 99 children (86%).
      Most children and parents (95) found the preparation"good"or"very good"and
      tolerated the catheterization procedure well. Only six children reported the
      catheterization to be"very painful"(without requiring that the procedure was
      terminated). Complications, such as urgency, smarting pain during voidings, or
      both, after withdrawal of the catheter, occurred in 12 children and urinary tract
      infections in 3. Unexpectedly, girls were affected more often than boys.
      CONCLUSIONS: Careful preparation of children and their parents allows the great
      majority of diagnostic studies that require urethral catheterization to be
      accomplished without anesthesia.

PMID- 12478604
TI  - Differing effects of N(G)-monomethyl L-arginine and 7-nitroindazole on detrusor
      activity.
AB  - AIMS: Previous studies reported that nitric oxide (NO) synthase (NOS) inhibition
      decreases micturition volume threshold (MVT), the volume required to produce a
      centrally mediated micturition contraction, and that NO can be released from
      urothelium by means of certain stimuli. With elucidation of multiple isoforms of
      NOS, studies were performed to determine whether inhibition of specific isoforms
      of NOS altered MVT in different ways. METHODS: In naive, anesthetized cats, the
      urinary bladder was exposed by means of a midline abdominal incision and
      cannulated through a slit in the internal urethra approximately 4-5 cm distal to
      the neck of the bladder. The left renal artery and left radial vein were
      cannulated for the intra-arterial and intravenous administration of drugs,
      respectively. All nerves were left intact. A control MVT was determined by slowly
      infusing saline into the bladder at a rate of 0.018 mL/kg per minute. Varying
      doses of L-NMMA (N(G)-monomethyl-L-arginine) or 7-NI (7-nitro indazole) were
      administered and the MVT was again determined. RESULTS: Inhibition of endothelial
      NOS (eNOS), by L-NMMA, or neuronal NOS (nNOS), by 7-NI, produces varying effects
      on certain detrusor activities and that inhibition of different isoforms of NOS
      produces qualitatively different effects. L-NMMA significantly decreases MVT (up
      to 60% decrease), whereas 7-NI significantly increases MVT (over 300% increase).
      L-NMMA increases frequency and onset of small bladder contractions, whereas 7-NI
      produces opposite effects. CONCLUSIONS: The results suggest that detrusor
      relaxation and contractility may be modulated by NO levels and that NO released
      from the urothelium may be a mediator of detrusor relaxation during the storage
      phase of micturition.

PMID- 12478605
TI  - Morphometric analysis of the collagen changes induced by subcutaneous injection
      of interferon-gamma after bladder outlet obstruction in the rat.
AB  - AIMS: The objective of this study was to examine the effects of interferon-gamma
      injection on changes in collagen content, after the creation of partial bladder
      outlet obstruction in the rats. METHODS: A total of 50 Sprague-Dawley female rats
      were subjected to partial bladder outlet obstruction by using metal rods. The
      rats were divided into five groups (n = 10 in each group): normal control (N),
      sham operation (S), bladder outlet obstruction for 4 weeks (BOO), interferon
      gamma injection after sham operation (S + IFN), and interferon-gamma injection
      after bladder outlet obstruction (BOO + IFN). Interferon-gamma was subcutaneously
      injected (100,000 units per injection, LG chemical Co., Seoul, Korea) daily for 4
      weeks in the injection groups, after which all rats were sacrificed. RESULTS: The
      collagen area percentage (collagen/collagen + muscle) in each bladder, calculated
      through image analysis, was 40.7 +/- 1.6% in the N, 38.2 +/- 2.0% in the S, 26.6
      +/- 3.8% in the S + IFN, 19.9 +/- 2.5% in the BOO, and 12.4 +/- 2.0% in the BOO +
      IFN group (mean +/- standard error). The difference in the collagen area
      percentage between the N and S groups (P > 0.05) was not significant, but there
      were significant differences between the N and S + IFN groups (P < 0.05), between
      the S and S + IFN groups (P < 0.05), and between the BOO and BOO + IFN groups (P
      < 0.05). CONCLUSIONS: It appears that interferon-gamma decreases the collagen
      content in the obstructed rat bladder.

PMID- 12478606
TI  - Role of the T-type Ca2+ current on the contractile performance of guinea pig
      detrusor smooth muscle.
AB  - AIMS: The importance of the T-type Ca(2+) current in determining detrusor
      contractile function was investigated by using guinea pig muscle in vitro.
      METHODS: NiCl(2) (200 microM) was used to block selectively the T-type Ca(2+)
      current, and 20 microM verapamil was used to block the L-type Ca(2+) current in
      this tissue. The selectivity of these agents at such concentrations has been
      previously demonstrated. RESULTS: In normal extracellular solution (4 mM KCl) 200
      microM NiCl(2) and 20 microM verapamil reduced electrically stimulated
      contractions by 17 +/- 6% and 65 +/- 10%, respectively. At high concentrations of
      the two agents, the contraction was completely abolished by NiCl(2) but by only
      74 +/- 18% in the case of verapamil; this finding suggests that NiCl(2) has
      additional negative inotropic actions at higher concentrations. Carbachol and KCl
      contractures were attenuated to a similar extent to that of electrically
      stimulated contractions by NiCl(2) and verapamil, which suggests that they act on
      the muscle rather than the motor nerve. The dependence of the membrane potential
      on the relative ability of NiCl(2) and verapamil to attenuate the contraction was
      tested by varying the extracellular [KCl], [KCl](o). Varying [KCl](o) between 2
      and 10 mM depolarised detrusor myocytes from (-65.1 +/- 4.7 mV to -42.7 +/- 4.0
      mV (a slope of 32 mV per 10-fold change of [KCl](o)). In low [KCl](o),blockade by
      NiCl(2) was more effective and that of verapamil less effective; at high
      [KCl](o), the reverse potency was recorded. CONCLUSIONS: The data are consistent
      with the hypothesis that Ca(2+) influx through both T-type and L-type Ca(2+)
      channels determines the contractile status of detrusor smooth muscle and that T
      type channel activity is more important at membrane potentials near the resting
      level. A significant role for T-type channel activity in the resting state was
      evident in that spontaneous contractions were attenuated to a greater extent than
      evoked contractions.

PMID- 12478607
TI  - Developmental expression of glial cell-line derived neurotrophic factor,
      neurturin, and their receptor mRNA in the rat urinary bladder.
AB  - AIMS: Glial cell-line derived neurotrophic factor (GDNF) and related factors
      neurturin (NRTN), artemin, and persephin are members of the GDNF family of
      neurotrophic factors. GDNF and NRTN bind to the tyrosine kinase receptor Ret and
      the receptors GFRalpha1 and GFRalpha2. The objective was to examine the
      developmental expression of GDNF, NRTN, and their receptors within the rat
      urinary bladder. METHODS: Rat bladders dissected from embryonic day (E) 15,
      postnatal day (P) 0, P14, P28, and adult rats (P60) were investigated by
      semiquantitative reverse transcriptase polymerase chain reaction. Embryos (E15,
      E16, and E17) were immunohistochemically stained for neurofilament. RESULTS: GDNF
      and Ret mRNA levels at E15 were the highest of all the stages we examined and
      then immediately decreased. In contrast, NRTN mRNA levels did not change between
      E15 and postnatal day 14; thereafter, they gradually but insignificantly
      increased. GFRalpha1 and GFRalpha2 mRNA levels were high at E15, after which
      their signal intensities decreased. In whole-mounted specimens, neurofilament
      positive axons were first detected in the bladder at E16. CONCLUSIONS: Our
      results suggest that GDNF and NRTN may act as trophic factors for neural in
      growth to the bladder and/or for the maintenance of mature neurons innervating
      the bladder. These factors might also be involved in bladder morphogenesis.

PMID- 12478608
TI  - OAB--the apocalypse.

PMID- 12478609
TI  - Neural cell adhesion molecule-mediated neurite outgrowth is repressed by
      overexpression of HES-1.
AB  - The neural cell adhesion molecule (NCAM) stimulates neurite outgrowth by
      activating intracellular signaling cascades. We investigated the role of the
      transcriptional repressor HES-1 in NCAM-dependent neurite outgrowth by estimating
      neurite extension from PC12-E2 cells grown in coculture with NCAM-negative or
      NCAM-positive fibroblasts. PC12-E2 cells were transiently transfected with an
      expression plasmid encoding HES-1. We found that expression of HES-1 inhibited
      NCAM-dependent neurite outgrowth. Treatment with arachidonic acid (an important
      messenger in NCAM-dependent signaling) restored NCAM-induced neurite outgrowth
      inhibited by HES-1. These results suggest that HES-1 is a regulator of
      intracellular signal transduction stimulated by cell adhesion molecules involved
      in neurite outgrowth.

PMID- 12478610
TI  - mRNA expression of ephrins and Eph receptor tyrosine kinases in the neonatal and
      adult mouse central nervous system.
AB  - Ephrins and Eph receptors are a family of molecules that have been implicated in
      axonal pathfinding. A unique feature of B-class ephrins and Eph receptors is
      their ability to transmit bidirectional signals in both ephrin- and Eph receptor
      expressing cells upon cell-cell contact. These signals can lead to cytoskeletal
      alterations that have been attributed to regulating neuronal growth responses.
      Examination of gene-target knockout mice has supported this hypothesis, revealing
      numerous developmental defects in the nervous systems of mice mutant for both B
      class ephrins and Eph receptors. To examine the potential scope of action for
      these genes in the nervous system, we have used in situ hybridization to study
      the mRNA expression of ephrins (B1, B2, and B3) and Eph receptors (B1, B2, B3,
      A4) in neonatal and adult mice. We found ephrins and Eph receptors to be
      expressed throughout the CNS. Expression was observed in the epithelium and
      migratory regions of the neonate and adult tissues as well as in discrete regions
      of high plasticity, including the adult olfactory bulb, hippocampus, and
      cerebellum. These studies suggest additional potential roles for these molecules
      in the postnatal and adult CNS and will serve as a guide in the detailed
      evaluation of mutant mice.

PMID- 12478611
TI  - Limited growth of severed CNS axons after treatment of adult rat brain with
      hyaluronidase.
AB  - Many chondroitin sulfate proteoglycans (CSPGs) have been shown to influence CNS
      axon growth in vitro and in vivo. These interactions can be mediated through the
      core protein or through the chondroitin sulfate (CS) glycosaminoglycan (GAG) side
      chains. We have shown previously that degrading CS GAG side chains using
      chondroitinase ABC enhances dopaminergic nigrostriatal axon regeneration in vivo.
      We test the hypothesis that interfering with complete CSPGs also limit axon
      growth in vivo. Neurocan, versican, aggrecan, and brevican CSPGs may be anchored
      within extracellular matrix through binding to hyaluronan glycosaminoglycan. We
      examine whether degradation of hyaluronan using hyaluronidase might release these
      inhibitory CSPGs from the extracellular matrix and thereby enhance regeneration
      of cut nigrostriatal axons. Anesthetized adult rats were given knife cut lesions
      of the right hemisphere nigrostriatal tract and cannulae were secured
      transcranially thereby allowing repeated perilesional infusion of saline or
      saline containing hyaluronidase once daily for 10 days post-axotomy. Eleven days
      post-transection brains from animals under terminal anesthesia were recovered for
      histological evaluation. Effective delivery of substance was inferred from the
      observed reduction in perilesional immunoreactivity for neurocan and versican
      after treatment with hyaluronidase (relative to saline). Immunolabeling using
      antibodies against tyrosine hydroxylase was used to examine the response of cut
      dopaminergic nigral neurons. After transection and treatment with saline,
      dopaminergic nigral neurons sprouted in a region lacking astrocytes, neurocan and
      versican. Axons did not regenerate into the lesion surround that contained
      astrocytes and abundant neurocan and versican. After transection and treatment
      with hyaluronidase, there was a significant increase in the number of cut
      dopaminergic nigral axons growing up to 800 microm anterior to the site of
      transection. However, cut dopaminergic nigral axons still did not regenerate into
      the lesion surround that contained reduced (albeit residual) neurocan and
      versican immunoreactivity. Thus, partial degradation of hyaluronan and
      chondroitin sulfate and depletion of hyaluronan-binding CSPGs enhances local
      sprouting of cut CNS axons, but long-distance regeneration fails in regions
      containing residual hyaluronan-binding CSPGs. Hyaluronan, chondroitin sulfate and
      hyaluronan-binding CSPGs therefore likely contribute toward the failure of
      spontaneous axon regeneration in the injured adult mammalian brain and spinal
      cord.

PMID- 12478612
TI  - Early programmed cell death in human NT2 cell cultures during differentiation
      induced by all-trans-retinoic acid.
AB  - Previous studies have demonstrated that programmed cell death takes place at
      different stages during the development of the CNS in vivo. Our purpose in this
      study was to detect early programmed cell death associated with the induction of
      differentiation by retinoic acid (RA) in the NT2 cell line. By using the annexin
      V labeling as a marker of apoptosis, a significant apoptotic cell death was
      quantified during the third and the fourth days of the RA treatment. Double
      labeling studies using the staining of the genomic DNA strand breaks with the
      terminal deoxyribosyl-transferase-mediated dUTP nick end-labeling (TUNEL) assay
      and either nestin or microtubule-associated protein 2 (MAP2) showed that 1) the
      early apoptotic cell death affected mostly nestin-positive cells and 2) after 8
      days of differentiation, although cells with neuronal phenotypes are present, no
      colabeled TUNEL/MAP2 cells were detected. With regard to the neuronal protein
      MAP2, we observed discrete immunolabeling of a few NT2 cells as early as day 3 of
      the differentiation and a significant emergence of MAP2-immunopositive cells at
      days 6-8. Thus, our results show that, when as a whole the differentiating NT2
      cell population is considered, 1) the apoptotic cell death observed during the
      third day of differentiation occurs mostly in undifferentiated cells, 2) this
      process coincides with the first detection of the neuronal phenotype in NT2 cell
      cultures, and 3) the end of the cell death period in NT2 cell cultures is marked
      by both the accumulation of MAP2-positive cells and the beginning of expression
      of the Bcl-2 protein in the cultures.

PMID- 12478613
TI  - Mouse brains deficient in H-ferritin have normal iron concentration but a protein
      profile of iron deficiency and increased evidence of oxidative stress.
AB  - Several neurodegenerative disorders such as Parkinson's Disease (PD) and
      Alzheimer's Disease (AD) are associated with elevated brain iron accumulation
      relative to the amount of ferritin, the intracellular iron storage protein. The
      accumulation of more iron than can be adequately stored in ferritin creates an
      environment of oxidative stress. We developed a heavy chain (H) ferritin null
      mutant in an attempt to mimic the iron milieu of the brain in AD and PD. Animals
      homozygous for the mutation die in utero but the heterozygotes (+/-) are viable.
      We examined heterozygous and wild-type (wt) mice between 6 and 8 months of age.
      Macroscopically, the brains of +/- mice were well formed and did not differ from
      control brains. There was no evidence of histopathology in the brains of the
      heterozygous mice. Iron levels in the brain of the +/- and wild-type (+/+) mice
      were similar, but +/- mice had less than half the levels of H-ferritin. The other
      iron management proteins transferrin, transferrin receptor, light chain ferritin,
      Divalent Metal Transporter 1, ceruloplasmin, were increased in the +/- mice
      compared to +/+ mice. The relative amounts of these proteins in relation to the
      iron concentration are similar to that found in AD and PD. Thus, we hypothesized
      that the brains of the heterozygote mice should have an increase in indices of
      oxidative stress. In support of this hypothesis, there was a decrease in total
      superoxide dismutase (SOD) activity in the heterozygotes coupled with an increase
      in oxidatively modified proteins. In addition, apoptotic markers Bax and caspase
      3 were detected in neurons of the +/- mice but not in the wt. Thus, we have
      developed a mouse model that mimics the protein profile for iron management seen
      in AD and PD that also shows evidence of oxidative stress. These results suggest
      that this mouse may be a model to determine the role of iron mismanagement in
      neurodegenerative disorders and for testing antioxidant therapeutic strategies.

PMID- 12478614
TI  - Protein kinase C activity, translocation, and selective isoform subcellular
      redistribution in the rat cerebral cortex after in vitro ischemia.
AB  - Protein kinase C (PKC) involvement in ischemia-induced neuronal damage has been
      investigated in superfused rat cerebral cortex slices submitted to 15 min of
      oxygen-glucose deprivation (OGD) and in primary cultures of rat cortical neurons
      exposed to 100 microM glutamate (GLU) for 10 min. OGD significantly increased the
      total PKC activity in the slices, mostly translocated in the particulate
      fraction. After 1 hr of reperfusion, the total PKC activity was reduced and the
      translocated fraction dropped by 84% with respect to the control. Western blot
      analysis of OGD samples showed an increase in total beta(2) and epsilon PKC
      isoform levels. After reperfusion, the total levels of alpha, beta(1), beta(2)
      and gamma isoforms were significantly reduced, whereas the epsilon isoform
      remained at an increased level. Endogenous GLU release from OGD slices increased
      to about 15 times the basal values after 15 min of oxygen-glucose deprivation,
      and to 25 and 35 times the basal level in the presence of the PKC inhibitors
      staurosporine (0.1 microM) and bisindolylmaleimide (1 microM), respectively.
      Western blot analysis of GLU-treated cortical neurons showed a significant
      decrease only in the total level of beta(2) isoforms. Cell survival was reduced
      to 31% in GLU-treated neuronal cultures; PKC inhibitors were not able to modify
      this effect. These findings demonstrate that the cell response to OGD and GLU
      involves PKC in a complex way. The net role played by PKC during OGD may be to
      reduce GLU release and, consequently, neurotoxicity. The isoforms beta(2) and
      epsilon are affected the most and may play a significant role in the mechanisms
      underlying neurotoxicity/neuroprotection.

PMID- 12478615
TI  - Upregulation of c-Kit receptor and stem cell factor in cerebellar inhibitory
      synapses in response to kainic acid.
AB  - Neuronal stimulation was induced in rats by systemic administration of kainic
      acid (KA) to determine if such stimulation is responsible for changes in the
      expression patterns of c-Kit and stem cell factor (SCF) in cerebellar synapses
      between inhibitory interneurons and Purkinje cells. Using immunocytochemistry and
      immunoblotting analyses, we demonstrate that c-Kit receptor tyrosine kinase and
      its ligand SCF are present on the pre- and postsynaptic sides of inhibitory
      synapses on Purkinje cells. These proteins are upregulated during the first 48 hr
      after KA treatment, whereas their levels fall below that of the control by 1 week
      and remain as such thereafter. Expression of both c-Kit and SCF are significantly
      elevated in the Purkinje cell layer 24 hr after KA administration, and the
      Purkinje cell layer exhibits a loss of calbindin D-28K immunoreactivity.
      Expression of c-Kit in basket cell axon terminals is activated until 48 hr after
      KA treatment, suggesting the transient participation of c-Kit receptor tyrosine
      kinase in the maintenance of these axonal terminals. Also during the first 48 hr
      after KA treatment, SCF levels increase in axonal processes of Purkinje cells,
      and these SCF-positive axons correlate with c-Kit-positive pinceau structures.
      The increased expression of c-Kit and SCF in response to KA-induced neuronal
      stimulation may indicate that c-Kit receptor tyrosine kinase and its ligand SCF
      function in the inhibitory synapse between cerebellar interneurons and Purkinje
      cells, and that this role is most pronounced during the first 48 hr after KA
      treatment.

PMID- 12478616
TI  - Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase-2
      inhibitor APHS can be reversed by a prostanoid.
AB  - The neuroprotective properties of two cyclooxygenase-2 (COX-2) specific
      inhibitors, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398) and o
      (acetoxy-phenyl)hept-2-ynyl2 sulfide (APHS) were examined in vitro using a mixed
      cortical neuronal culture system. Each of these inhibitors conferred a
      concentration-dependent neuroprotective effect against an excitotoxic assault
      induced by NMDA. Neuroprotection was observed when the COX-2 inhibitor was added
      before or even 1-3 hours after NMDA, which was coincident with an NMDA-induced
      increase of COX-2 transcripts in neurons. To test whether these COX-2 inhibitors
      confer neuroprotection by inhibiting biosynthesis of prostanoids that may
      contribute toward excitotoxicity, two NMDA-induced prostanoids, PGE(2) and
      PGF(2alpha), were tested for their ability to reverse the neuroprotective
      properties of APHS. APHS-mediated neuroprotection was overcome by the
      concentration-dependent (as low as 100 nM) administration of a synthetic analog
      of PGE2, 17-phenyl-trinor-PGE(2) (17-pt-E(2)), which is a relatively specific
      agonist for the EP1 and EP3 prostaglandin receptors; however, PGF(2alpha) had no
      significant effect on neuroprotection conferred by APHS. In the absence of APHS,
      neuroprotection was observed with either prostanoid. PGE(2) may in some instances
      contribute toward excitotoxicity, and the inhibition of synthesis of this
      prostanoid may in part explain the neuroprotective properties of these COX-2
      inhibitors.

PMID- 12478617
TI  - Endogenous CD4+BV8S2- T cells from TG BV8S2+ donors confer complete protection
      against spontaneous experimental encephalomyelitis (Sp-EAE) in TCR transgenic,
      RAG-/- mice.
AB  - To investigate regulatory mechanisms which naturally prevent autoimmune diseases,
      we adopted the genetically restricted immunodeficient (RAG-1(-/-)) myelin basic
      protein (MBP)-specific T cell receptor (TCR) double transgenic (T/R-) mouse model
      of spontaneous experimental autoimmune encephalomyelitis (Sp-EAE). Sp-EAE can be
      prevented after transfer of CD4+splenocytes from naive immunocompetent mice. RAG
      1+ double transgenic (T/R+) mice do not develop Sp-EAE due to the presence of a
      very small population (about 2%) of non-Tg TCR specificities. In this study,
      CD4+BV8S2+ T cells that predominate in T/R+ mice, and three additional
      populations, CD4+BV8S2-, CD4-CD8-BV8S2+, and CD4-CD8+BV8S2+ T cells that expanded
      in T/R+ mice after immunization with MBP-Ac1-11 peptide, were studied for their
      ability to prevent Sp-EAE in T/R- mice. Only the CD4+BV8S2- T cell population
      conferred complete protection against Sp-EAE, similar to unfractionated
      splenocytes from non-Tg donors, whereas CD4-CD8-BV8S2+ and CD4+BV8S2+ T cells
      conferred partial protection. In contrast, CD4-CD8+BV8S2+ T cells had no
      significant protective effects. The highly protective CD4+BV8S2- subpopulation
      was CD25+, contained non-clonotypic T cells, and uniquely expressed the CCR4
      chemokine receptor. Protected recipient T/R- mice had marked increases in
      CD4+CD25+ Treg-like cells, retention of the pathogenic T cell phenotype in the
      spleen, and markedly reduced inflammation in CNS tissue. Partially protective
      CD4+BV8S2+ and CD4- CD8-BV8S2+ subpopulations appeared to be mainly clonotypic T
      cells with altered functional properties. These three Sp-EAE protective T cell
      subpopulations possessed distinctive properties and induced a variety of effects
      in T/R- recipients, thus implicating differing mechanisms of protection.

PMID- 12478618
TI  - Dysmyelination induced in vitro by IgM antisulfatide and antigalactocerebroside
      monoclonal antibodies.
AB  - Antiglycolipid antibodies cause a distinctive form of dysmyelination in vivo
      characterized by marked widening of the myelin period. Such "expanded" or "wide
      spaced" myelin occurs in peripheral nerves in certain paraproteinemias and in the
      CNS in multiple sclerosis. We have used an in vitro system to reproduce this
      pathology under controlled conditions to assess the role of antibody specificity
      and class and the need for cofactors in generating this kind of lesion in
      peripheral myelin. Schwann cell myelin formed in vitro around dorsal root
      ganglion cell axons was exposed for 3-14 days to hybridoma cells that produce
      specific monoclonal antibodies. Typical wide-spaced myelin developed after
      exposure to either O4, which produces an IgM antisulfatide antibody, or O1, which
      produces an IgM antigalactocerebroside antibody. In both cases, the effect was
      apparent by three days in paranodal as well as internodal myelin, especially in
      the outer lamellae. This change did not depend on the presence of complement or
      macrophages in the cultures. Exposure to anti-GalC hybridoma cells, which produce
      an IgG3 antiglycolipid antibody, did not produce wide-spaced myelin, nor did
      exposure to hybridoma cells that secrete IgM antibodies directed against a non
      myelin antigen. The location and rapidity of the pathologic changes seen after O4
      or O1 are consistent with penetration of the antibodies through the external
      mesaxon of already formed myelin and then between compact lamellae, progressively
      spreading them apart in the centripetal direction. This in vitro model shows that
      either of two specific monoclonal IgM antiglycolipid antibodies can alone
      reproduce a well known form of myelin pathology under defined conditions.

PMID- 12478619
TI  - Effects of tumor necrosis factor-alpha central administration on hippocampal
      damage in rat induced by amyloid beta-peptide (25-35).
AB  - Male Wistar rats received unilateral intrahippocampal injections of 3 nmol (3.18
      microg) aggregated Abeta(25-35), intracerebroventricular bilateral injections of
      0.5 microg human recombinant TNFalpha or both (Abeta(25-35) + TNFalpha-treated
      animals). Seven days after the surgery brain sections were stained with cresyl
      violet (Nissl), for fragmented DNA (TUNEL), glial fibrillar acidic protein (GFAP)
      and isolectin B4-reactive microglia. In addition, caspase-3 activity in brain
      regions was measured fluorometrically. The morphology of the hippocampus after
      the injection of Abeta(25-35) or both Abeta(25-35) and TNFalpha (but not TNFalpha
      alone) showed cell loss in the CA1 pyramidal cell layer. The extension of
      neuronal degeneration measured in the CA1 field was significantly larger in
      Abeta(25-35)-treated groups compared to the contralateral hemisphere of both
      vehicle-treated controls and animals injected with TNFalpha alone. TNFalpha
      augmented the Abeta(25-35)-induced damage, significantly increasing the extension
      of degenerating area. Administration of Abeta(25-35) caused reactive gliosis in
      the ipsilateral hemisphere as demonstrated by upregulation of GFAP expression and
      the presence of hypertrophic astrocytes in the hippocampus. This effect was much
      more prominent in the hippocampi of rats treated with Abeta(25-35) + TNFalpha but
      absent after administration of TNFalpha alone. In both Abeta(25-35)-treated
      groups, the damaged area of the hippocampal CA1 field and lateral band of dentate
      gyrus displayed many darkly stained round isolectin B4-positive phagocyte-like
      microglial cells. Sparse TUNEL-positive nuclei were found in the hippocampi of
      rats treated with Abeta(25-35) alone or together with TNFalpha, but not in the
      control brain sections or in brain sections of TNFalpha-injected animals. The
      activity of caspase-3 increased significantly in the ipsilateral hippocampus
      after the injection of Abeta(25-35). Surprisingly, administration of TNFalpha
      into the cerebral ventricles prevented this Abeta(25-35)-induced increase in
      hippocampal caspase-3 activity. The results are discussed from the perspective of
      dual (neuroprotective and neurodestructive) roles of TNF in the brain.

PMID- 12478620
TI  - Fullerene C60 and ascorbic acid protect cultured chromaffin cells against
      levodopa toxicity.
AB  - Adrenal chromaffin cell (ACC) transplants, alone or combined with levodopa
      treatment, were used in attempted therapy for Parkinson's disease (PD). In a
      previous study, we demonstrated that levodopa caused chromaffin cell death either
      by necrosis or by apoptosis in cell culture. Here we report the beneficial effect
      of a water-soluble derivative of fullerene C(60) (a novel molecule with potent
      antioxidant properties) and of ascorbic acid when applied to chromaffin cell
      cultures exposed to levodopa. Both antioxidants remarkably increase the ACC
      survival and prevent cell death, including apoptosis. Although ACC transplants
      are not currently considered as an option for PD treatment, these observations
      should help in exploring the possibilities of preventing the neurotoxicity
      generated by levodopa and in envisaging new strategies for PD treatment by
      combining the clinical use of levodopa and potent antioxidants. Chemical
      properties of fullerene related to biological uses are discussed.

PMID- 12478621
TI  - Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after
      treatment with antipsychotic drugs.
AB  - Typical and atypical antipsychotic drugs, though both effective, act on different
      neurotransmitter receptors and are dissimilar in some clinical effects and side
      effects. The typical antipsychotic drug haloperidol has been shown to cause a
      decrease in the expression of brain-derived neurotrophic factor (BDNF), which
      plays an important role in neuronal cell survival, differentiation, and neuronal
      connectivity. However, it is still unknown whether atypical antipsychotic drugs
      similarly regulate BDNF expression. We examined the effects of chronic (28 days)
      administration of typical and atypical antipsychotic drugs on BDNF mRNA
      expression in the rat hippocampus using in situ hybridization. Quantitative
      analysis revealed that the typical antipsychotic drug haloperidol (1 mg/kg) down
      regulated BDNF mRNA expression in both CA1 (P < 0.05) and dentate gyrus (P <
      0.01) regions compared with vehicle control. In contrast, the atypical
      antipsychotic agents clozapine (10 mg/kg) and olanzapine (2.7 mg/kg) up-regulated
      BDNF mRNA expression in CA1, CA3, and dentate gyrus regions of the rat
      hippocampus compared with their respective controls (P < 0.01). These findings
      demonstrate that the typical and atypical antipsychotic drugs differentially
      regulate BDNF mRNA expression in rat hippocampus.

PMID- 12478622
TI  - Cells exposed to a huntingtin fragment containing an expanded polyglutamine tract
      show no sign of ion channel formation: results arguing against the ion channel
      hypothesis.
AB  - Ion channels formed by expanded polyglutamine tracts have been proposed to play
      an important role in the pathological processes leading to neurodegeneration in
      Huntington's disease and other CAG repeat diseases. We tested the capacity of a
      huntingtin fragment containing an expanded polyglutamine tract to form ion
      channels in two cell types. Whole cell current from Xenopus oocytes was recorded
      using two-electrode voltage-clamp technique, and whole cell current from CHO-K1
      cells was recorded by patch-clamp technique. The fragment with an expanded
      polyglutamine sequence induced no change in the currents recorded in any of the
      two expression systems, indicating no changes in ion channel activity. The
      results therefore argue against the proposed hypothesis of expanded
      polyglutamines forming ion channels.

PMID- 12478623
TI  - Effects of chronic dermal exposure to nonlethal doses of methyl parathion on
      brain regional acetylcholinesterase and muscarinic cholinergic receptors in
      female rats.
AB  - The in vivo and in vitro effects of methyl parathion, a phosphorothionate
      insecticide, on cholinergic neurotransmitter systems in the brain of rats were
      investigated. Three groups of adult female rats received 0, 0.1, or 1.0 mg/kg
      methyl parathion via dermal exposure for 95 days. Exposure to 0.1 mg/kg methyl
      parathion produced inhibition of AChE in the caudate-putamen and thalamic nuclei,
      whereas 1.0 mg/kg resulted in inhibition of AChE in most brain regions. The same
      doses of methyl parathion had no effect on [(3)H]QNB binding to muscarinic
      receptors in the brain regions examined. The in vitro study demonstrated that
      methyl parathion causes preferential inhibition of AChE and [(3)H]QNB binding in
      specific brain regions. As an inhibitor of AChE, methyl paraoxon was 1,000-fold
      more potent than was methyl parathion. Similarly, methyl paraoxon showed brain
      region-specific inhibition of the enzyme. Generally, the brain stem was highly
      sensitive to organophosphate-induced inhibition of AChE activity and [(3)H]QNB
      binding. Because central respiratory neurons gather in the brain stem,
      preferential effects there and in other brain regions may underlie lethal
      toxicity of methyl parathion and other organophosphates.

PMID- 12478624
TI  - Molecular identity, synaptic localization, and physiology of calcium channels in
      retinal bipolar cells.
AB  - Bipolar cells convey information through the retina via graded changes in their
      membrane potential and modulate transmitter release through the influx of calcium
      via L-type calcium channels. However, the molecular identity of the alpha(1)
      subunit has not been confirmed. We report the presence of the newly cloned
      alpha(1F) subunit in mouse bipolar cell synaptic terminals. The alpha(1F)
      subunits are localized to hot spots, possibly corresponding to active zones. We
      also report the physiological properties of two calcium currents present in mouse
      bipolar cells, a low-voltage-activated L-type current and a low-voltage-activated
      T-type calcium current. The physiological properties of the T-type current
      suggest that it is completely inactivated under physiological conditions. The L
      type current may be mediated by the alpha(1F) subunit, and influx of calcium
      through the alpha(1F) channel may control neurotransmitter release from the
      bipolar cell terminal.

PMID- 12478625
TI  - Comparison of slow- and rapid-cooling protocols for early-cleavage-stage Macaca
      fascicularis embryos.
AB  - Cryostorage of nonhuman primate embryos by time-consuming slow-cooling methods is
      often limited to early cleavage stages. Effective rapid-cooling methods have been
      developed for many species and represent valuable tools for laboratory- and field
      based studies of nonhuman primate reproductive biology. However, few rapid
      cooling protocols have been applied to nonhuman primate embryos in terms of
      comparing various developmental stages. Here we compare slow cooling vs. two- and
      three-step rapid cooling of two-, four-, and eight-cell Macaca fascicularis (Mf)
      embryos. Rapid cooling was conducted in open pulled straws (OPS) using cooling
      solutions containing reduced quantities of ethylene glycol (EG) and supplemented
      with either of two high-molecular-weight polymers, ficoll and dextran. The
      survival of the slow-cooled embryos, but not the rapid-cooled embryos, was
      independent of embryonic stage at cryostorage. Slow cooling was associated with
      greater cell survival (82%) post thaw compared to warming following rapid cooling
      (18-29%). Slow cooling resulted in a high proportion of embryo survival (18/20;
      90%) and cleavage (15/18; 83%) post thaw. Rapid cooling resulted in significantly
      reduced percentages of embryo survival (26-32%) and embryo cleavage in culture
      (29-38%) after warming. Conventional slow cooling was more effective than the
      rapid-cooling protocols employed in this study for cryopreservation of early
      cleavage-stage Mf embryos.

PMID- 12478626
TI  - Incident of intense aggression by chimpanzees against an infant from another
      group in Mahale Mountains National Park, Tanzania.
AB  - We document here an unusual case of intense aggression against an infant male
      from another group by chimpanzees (Pan troglodytes schweinfurthii) of the Mahale
      Mountains National Park, in Tanzania. Adult males of the study group collectively
      attacked an unknown male infant. Although an unknown female, probably the mother,
      tried to retrieve him, the infant was seriously injured and most likely died.
      During this incident, the unknown female attacked and injured two researchers.
      After the aggressive encounter, it was found that six of the nine adult males in
      the study group were wounded. Attacking the extragroup male infant may have the
      effect of weakening the future power of the neighboring group, leading to better
      access to resources and enhanced safety in the future for the study group.

PMID- 12478627
TI  - Prenatal diagnosis of 21-hydroxylase deficiency caused by gene conversion and
      rearrangements: pitfalls and molecular diagnostic solutions.
AB  - OBJECTIVES: The present paper reports the prenatal diagnosis of congenital
      adrenal hyperplasia (CAH) in two cases of 21-hydroxylase deficiency. DNA
      diagnostic errors can be caused by the presence of the highly homologous 21
      hydroxylase pseudogene, CYP21P, adjacent to the functional gene, CYP21. The
      present paper details how complex gene conversions and rearrangements between the
      CYP21 and CYP21P pose unique complications for prenatal diagnosis. METHODS:
      Analysis of eight common mutations in the 21-hydroxylase gene as well as deletion
      of the entire gene is accomplished using polymerase chin reaction (PCR) followed
      by amplified created restriction site (ACRS) or allele-specific
      oligohybridization (ASO) and Southern blot followed by hybridization to a CYP21
      specific probe. Linkage analysis was performed using microsatellite markers
      flanking the CYP21 gene. RESULTS: The direct mutation detection assay indicated a
      complicated gene conversion and rearrangement in the probands of both families.
      Interpretation of these rearrangements made it difficult to determine whether or
      not the fetuses would be affected with CAH. Linkage studies revealed that each
      fetus had inherited both parental disease chromosomes and was therefore predicted
      to be affected with CAH. CONCLUSION: As observed in the two reported cases,
      direct DNA analysis may provide limited information due to gene conversion or
      rearrangement between the CYP21 and CYP21P genes. These cases suggest that direct
      mutation detection should be supported by linkage analysis, whenever possible, to
      provide more comprehensive information for the family.

PMID- 12478628
TI  - Prenatal sonographic diagnosis of the 49,XXXXY syndrome.
AB  - The 49,XXXXY syndrome is a rare sex chromosome anomaly with an approximate
      incidence of 1 in 85,000 male live births. The diagnosis is usually ascertained
      postnatally by the association of mental retardation, variable growth deficiency,
      Down syndrome-like facial dysmorphy, hypogenitalism and other malformations,
      especially involving the heart and skeleton. Prenatal diagnosis of the pentasomy
      49,XXXXY is generally fortuitous and sonographic features have rarely been
      described in the literature. We report here on two cases of 49,XXXXY syndrome
      diagnosed prenatally because of sonographic abnormalities. In the first,
      amniocentesis was performed at 26 weeks' gestation for polyhydramnios, unilateral
      clubfoot and micropenis. In the second, a karyotype was carried out on chorionic
      villi at 13 weeks' gestation for cystic hygroma. These observations and the six
      previously reported cases demonstrate that cystic hygroma in first or second
      trimester of pregnancy may be associated with sex chromosome aneuploidy other
      than Turner syndrome. Moreover, they emphasize the importance of detailed
      sonographic examination in the second trimester, as small penis and abnormal
      posturing of the lower extremities are very suggestive of the 49,XXXXY syndrome.

PMID- 12478629
TI  - Compromise ultrasound dating policy in maternal serum screening for Down
      syndrome.
AB  - Routine ultrasound biometry is the method of choice for gestational dating when
      screening for Down syndrome. However, it is costly and an alternative policy is
      to restrict ultrasound to women most likely to have menstrual dating errors. This
      was evaluated by statistical modelling with parameters from 14,274 women screened
      between January 1997 and July 2001 using free beta-human chorionic gonadotrophin
      (free beta-hCG), alpha-fetoprotein (AFP) and unconjugated estriol (uE(3)). A
      total of 12,711 (89%) women had both ultrasound and menstrual gestations, but in
      4101 (29%) women either the last menstrual period (LMP) was uncertain or a pill
      withdrawal period, or there were irregular or abnormal length cycles. The LMP was
      not entered in the test request form for a further 1404 (9.8%) women. Routine
      ultrasound dating yielded a predicted detection rate higher than for menstrual
      dating by 3.9-7.1%, depending on the marker combination and cut-off. The false
      positive rate was reduced by 0.2-1.1%. Selectively scanning the 39% with
      unreliable dates increased detection by 2.6-4.6%, and reduced the false-positive
      rate by 0.04-0.6%. Some centres only use the ultrasound estimate of gestation
      when it differs from the menstrual estimate by more than 7 days. Such a rule
      reduces the gain in detection rate to 2.5-4.6% for routine ultrasound and 1.7
      3.1% with the compromise policy; the false-positive rate reductions are 0.06-0.6%
      and 0.0-0.3%, respectively. We conclude that if routine ultrasound is not
      financially and practically feasible, the compromise policy yields a clinically
      important improvement in screening performance compared to menstrual dating.

PMID- 12478630
TI  - Prenatal ultrasound diagnosis of Toriello-Carey syndrome.
AB  - Toriello-Carey syndrome is a rare malformative complex, described for the first
      time in 1988, characterized by agenesis of the corpus callosum, facial anomalies,
      cardiac defects and hypotonia. Relatively few neonatal cases have been reported.
      We describe here the first prenatal ultrasound diagnosis of the syndrome based on
      the detection of agenesis of the corpus callosum and spongious cardiomyopathy in
      a 22-week-old fetus of a couple with positive family history. The first sib of
      the couple was diagnosed with Toriello-Carey syndrome at 1 year of age, and had,
      in addition to the typical facial anomalies not detectable by ultrasound,
      agenesis of the corpus callosum and the same heart lesion (spongious
      cardiomyopathy). This report demonstrates that prenatal diagnosis of Toriello
      Carey syndrome is feasible in the second trimester of pregnancy.

PMID- 12478631
TI  - Interpreting information: what is said, what is heard--a questionnaire study of
      health professionals and members of the public.
AB  - OBJECTIVE: To investigate how people perceive some of the words and phrases
      commonly used in prenatal diagnosis counselling. METHODS: A questionnaire
      containing 25 questions with forced choice answers was administered in the form
      of a lecture. Respondents were asked to report how worrying they would find
      different ways of being told about hypothetical anomalies or risks of anomalies
      in their baby. 581 questionnaires were completed by 372 health professionals and
      209 members of the public. The sample was obtained opportunistically. The exact
      number of non-responders is not known but is estimated to be less than 5%.
      RESULTS: Respondents reported being particularly worried by the use of genetic
      jargon and use of the following words: rare, abnormal, syndrome, disorder,
      anomaly and high risk. They found risk expressed as 1 in X more worrying than
      when it was expressed as a percentage, and they consistently reacted as if they
      estimated the chance of an undesired outcome occurring to be greater than that of
      a desired outcome occurring when both events were equally likely. CONCLUSIONS:
      The choice of words used to describe a condition or to inform someone about the
      level of risk of an adverse event occurring may significantly affect how the
      person perceives that condition or risk.

PMID- 12478632
TI  - Preference assessment of prenatal diagnosis for Down syndrome: is 35 years a
      rational cutoff?
AB  - OBJECTIVE: To compare the perceptions of miscarriage and birth of a child with
      Down syndrome among pregnant women and to evaluate the implications of these
      preferences for the traditional 35-year old maternal age risk boundary. METHODS:
      An interviewer-administered survey was given to 186 pregnant women receiving
      antepartum care at a university hospital. Preferences, as reflected by utilities,
      for birth of a child with Down syndrome and pregnancy miscarriage, stratified by
      patient characteristics, were assessed. RESULTS: The utility for the birth of a
      child with Down syndrome decreased (p < 0.001) as clinical severity increased
      from mild (0.78) to severe (0.65). Miscarriage of a pregnancy had a mean utility
      of 0.76 +/- 0.31. Women who desired prenatal diagnosis had a utility value for
      miscarriage (0.79 +/- 0.28) that was significantly higher than for the birth of a
      child with Down syndrome of unknown severity (0.73 +/- 0.27). In multivariable
      logistic regression, desire for prenatal diagnosis was the only factor associated
      with a preference of miscarriage over birth of an affected child (odds ratio
      2.26, 95% confidence interval 1.03, 4.96). CONCLUSION: Women who desire prenatal
      diagnosis do not perceive the birth of a child with Down syndrome and a pregnancy
      miscarriage to be equivalent health states. This finding calls into question the
      rationale of the 35-year-old maternal age criterion and suggests that actual
      patient preferences should be better incorporated into the decision to offer
      definitive prenatal diagnosis.

PMID- 12478633
TI  - The association between fetal pyelectasis on second trimester ultrasound scan and
      aneuploidy among 25,586 low risk unselected women.
AB  - OBJECTIVE: To determine the association of fetal pyelectasis FP found at the time
      of second trimester detailed ultrasound scan with aneuploidy in an unselected low
      risk population. DESIGN: Retrospective study of ultrasonographic reports, films
      and hospital notes over an eight-year period from 1991 to 1998. SETTING: District
      general hospital obstetric department with 3500 deliveries annually serving a low
      risk cosmopolitan population. MAIN OUTCOME MEASURE: The prevalence of aneuploidy
      in cases of fetal pyelectasis. METHODS: The obstetric ultrasound reports and
      films of 29,591 cases were reviewed to identify those with FP at their detailed
      anomaly scan between 18 and 24-weeks gestation. The study sample included women
      whose scan showed the fetal renal pelvis of either kidney to be five millimetres
      or more in the anteroposterior diameter. Demographic data and other
      ultrasonographic abnormalities were noted. The genotype and phenotype of the
      babies were traced from a combination of cytogenetic reports and paediatric
      notes. RESULTS: There were 320 cases of FP among the 25,586 low-risk study
      population available in the studied gestational period (18-24 weeks) giving a
      prevalence of 1.25 percent. Of these, 301 cases of FP were found in isolation and
      19 were found in association with another ultrasonographic marker. None of the
      315 cases delivering at the Northwick Park & St. Mark's Hospital had aneuploidy.
      Pyelectasis was more likely to be bilateral (57%), and more in male fetuses
      (72%). The mean diameter for the pyelectasis at diagnosis was 6.5 mm (1.4 SD)
      ranging between 5 and 15 mm. One hundred and thirty seven cases (43%) resulted in
      spontaneous resolution. CONCLUSION: The prevalence of FP at the anomaly scan in
      an unselected low-risk population is not high (1.25%). Our data suggest that the
      risk of aneuploidy associated with isolated FP in a low-risk, unselected
      population is so small that it should not be an indication for invasive prenatal
      karyotyping.

PMID- 12478634
TI  - Gender impact on first trimester markers in Down syndrome screening.
AB  - The influence of fetal gender on the level in the first trimester of the
      serological markers alpha-fetoprotein (AFP), pregnancy-associated plasma protein
      A (PAPP-A) and free beta human chorionic gonadotropin (betahCG) and on nuchal
      translucency is described for 2637 singleton pregnancies with normal outcome.
      Mean log MoM values for pregnancies with female and male fetuses were calculated
      using regression of log marker values on gestational age expressed as crown rump
      length and on maternal weight. A pronounced gender impact was found for free
      betahCG, being 16% higher for female than for male fetuses.

PMID- 12478635
TI  - Prenatal diagnosis and treatment of fetal long QT syndrome: a case report.
AB  - We report a case of a fetus presenting with bradycardia, intermittent
      atrioventricular (AV) block, ventricular tachycardia (VT) and the signs of fetal
      congestive heart failure (ascites and scrotal hydrocele) during mid-gestation.
      Prenatal treatment with beta-adrenergic blocker (propranolol) and digitalis
      glycosides was prescribed because of suspicion of long QT syndrome occurring with
      fetal congestive heart failure. The male baby was born at 39 weeks of gestation
      and showed a prolonged QT interval (QTc = 492 ms) and frequent variable AV block
      or alternating left and right bundle branch block, depending on the atrial rate.
      Prenatal administration of lidocaine failed to correct the fetal VT. Conversely,
      propranolol decreased the attack frequency of fetal VT. Postnatal administration
      of the K(+) channel opener (nicorandil) successfully shortened the QT interval
      and improved the outcome.

PMID- 12478636
TI  - Limited expression of Fas and Fas ligand in fetal nucleated erythrocytes isolated
      from first trimester maternal blood.
AB  - OBJECTIVE: Intact fetal cells isolated from maternal blood can be used for non
      invasive gender determination and genetic diagnosis. Recent studies demonstrating
      a large amount of cell-free fetal DNA in maternal plasma suggest that the
      circulating fetal DNA may result from fetal cells undergoing apoptosis. In the
      present study we evaluated the potential role of Fas and Fas ligand (FasL) cell
      surface expression with respect to apoptosis induction in fetal cells isolated
      from maternal blood. METHODS: We flow sorted candidate fetal cells that were
      gamma chain-positive and Fas- or FasL-positive or -negative, and subsequently
      analysed them by fluorescence in situ hybridization (FISH) analysis using X and Y
      chromosome-specific probes. RESULTS: Among all gamma hemoglobin-positive cells,
      there was a significant difference in the percent of cells expressing Fas versus
      FasL (4.4 and 12.3, respectively). We found no significant correlation between
      the total number of fetal nucleated red blood cells (NRBCs) and gestational age
      or the presence of Fas- and FasL-positive cells. From approximately 7 ml of
      maternal peripheral blood, most of the confirmed fetal (XY) cells were found in
      the Fas- and FasL-negative sorted population; the average numbers were 12.8 and
      15.7, respectively. CONCLUSION: We conclude that fetal NRBCs express FasL more
      than Fas, although most fetal NRBCs in first trimester maternal blood samples do
      not express Fas or FasL. This suggests the absence of a functional Fas/FasL
      apoptotic system in fetal NRBCs, and that programmed cell death in these cells,
      which may lead to circulating fetal DNA in maternal plasma, probably occurs by
      another pathway.

PMID- 12478637
TI  - Hypoechogenicity of fetal long bones: a new ultrasound marker for arthrogryposis.
AB  - OBJECTIVE: To demonstrate osteopenia associated with arthrogryposis. METHODS &
      RESULTS: We describe 3 cases of fetal arthrogryposis seen prenatally with the
      sonographic feature of severe hypoechogenicity of the long bones. This
      manifestation of presumed osteopenia is thought to represent osteoporosis
      secondary with absent fetal movement. CONCLUSION: We describe hypoechogenicity of
      the fetal bones as a new sonographic feature of arthrogryposis.

PMID- 12478638
TI  - Some observations of the structure of the choroid plexus and its cysts.
AB  - The structure of the choroid plexus was studied in five normal human embryos,
      three normal fetuses and three fetuses with choroid plexus cysts. These were
      detected by ultrasound and the fetuses were karyotypically normal. The choroid
      plexus appears in the lateral cerebral ventricles at the seventh developmental
      week. The early structure is lobulated with vessels running in the mesenchymal
      stroma and forming capillary nets under the single-layered ependymal epithelium.
      This embryonal structure is converted into the fetal type during the ninth
      developmental week as the embryonal capillary net is replaced by elongated loops
      of wavy capillaries that lie under regular longitudinal epithelial folds. The
      choroid plexus cysts exhibited accumulation of fluid within distended mesenchymal
      stroma and did not show the wavy folds on this surface, which was smooth. Within
      this connective tissue of the cyst wall were distended angiomatous
      interconnecting thin-walled capillaries. Therefore, filled cavities were not
      lined by any epithelium. We suggest that fetal choroid plexuses cysts (at least
      in many cases) are in fact pseudocysts exhibiting angiomatous patterns of
      capillaries in their walls.

PMID- 12478639
TI  - Uptake of prenatal screening for chromosomal anomalies: impact of test results in
      a previous pregnancy.
AB  - AIM: To assess whether the uptake of prenatal screening for trisomy 21 in a
      subsequent pregnancy is influenced by being classified in the 'increased risk' or
      'not at increased risk' group in the first pregnancy. SETTING: District General
      Hospital Maternity Unit. METHODS: Amongst a group of women attending for
      maternity care at this hospital, the maternity records were examined to find
      women having at least two pregnancies. Any prenatal screening record for each
      pregnancy was retrieved from the prenatal screening database. Prenatal screening
      for trisomy 21 was by a combination of maternal serum alpha-fetoprotein (AFP) and
      free beta-human chorionic gonadotrophin (beta-hCG) in the second trimester and by
      maternal serum free beta-hCG and pregnancy-associated plasma protein-A (PAPP-A)
      and fetal nuchal translucency (NT) thickness in the first trimester. Women were
      stratified according to their trisomy 21 risk into an 'increased risk' group (1:
      <250 in the second trimester and 1: <300 in the first trimester) or 'not at
      increased risk' group based on their first pregnancy. In a second pregnancy, the
      records were examined to see if the mother accepted prenatal screening in the
      second pregnancy. The rate of acceptance of screening in a subsequent pregnancy,
      depending on whether 'at increased risk' or 'not at increased risk' in the first
      pregnancy, was examined using chi square tests. RESULTS: In the second trimester
      study, 4601 women were identified with two pregnancies during the study period.
      Of these, 4559 women had prenatal screening in a subsequent pregnancy. Initially,
      273 women were identified in the high-risk group, and of these 252 (92.3%)
      elected to have prenatal screening in a subsequent pregnancy. This compared with
      4307 of 4328 (99.5%) women in the low-risk group. In the first trimester study,
      1077 women were identified with two pregnancies during the study period. Of
      these, 1072 had prenatal screening in a subsequent pregnancy. Initially, 60 women
      were identified in the high-risk group, and of these 56 (93.3%) elected to have
      prenatal screening in a subsequent pregnancy. This compared with 1016 of 1017
      (99.9%) in the low-risk group. Statistically, there was no difference between the
      rate of declining prenatal screening in a second pregnancy amongst those in the
      high-risk group in a first pregnancy or those in the low-risk group (p = 0.429
      for second trimester screening and p = 0.794 for first trimester screening).
      Similarly, no difference could be demonstrated between rates when screening in
      the first or second trimester (p = 0.961) for those in the high-risk group.
      CONCLUSION: Despite the understandable anxiety associated with being identified
      in the high-risk group (as a false positive finding) in a previous pregnancy,
      this did not seem to deter women from accepting prenatal screening in a
      subsequent pregnancy.

PMID- 12478640
TI  - Nuchal index: a gestational age independent ultrasound marker for the detection
      of Down syndrome.
AB  - OBJECTIVES: To determine if the ultrasound marker Nuchal Index (NIx) is
      gestational age independent, and to determine its specificity and sensitivity for
      Down syndrome (DS) identification. METHODS: Prospective cohort. A prospective
      database of fetal biometry and soft markers of aneuploidy was searched for
      fetuses with the following criteria: confirmed gestational age, at least two
      measurements of nuchal thickness and biparietal diameter, no major detectable
      fetal anomalies, and either normal karyotype or normal postnatal exam. Nuchal
      Index (NIx) was defined as 100x (mean nuchal thickness [mm])/(mean Biparietal
      Diameter [mm]). This cohort was divided into two groups according to the last
      digit of their hospital unit number. Initial analysis was carried out in the
      first group (analysis group), with the second group (normal) used to test the
      results. A prospective cohort of pre- and postnatally diagnosed DS fetuses with
      at least two measurements of nuchal thickness and biparietal diameter constituted
      the abnormal study group (abnormal) and was used to determine the sensitivity of
      the index. P value <0.05 was considered significant. RESULTS: Eight hundred and
      seventy-five fetuses constituted the control group with 455 in the analysis group
      and 420 in the normal group. In the analysis group, Pearson coefficient and ANOVA
      confirm that NIx was independent of gestational age between 14 + 0 and 22 + 6
      weeks of gestation. For the analysis group, mean NIx was 7.72, (SD = 2.05) and a
      threshold value of 11.0 yielded a specificity of 94%. Fifty-two DS fetuses made
      up the abnormal group. Mean NIx in this group was 17.9 (SD = 13.9), which was
      highly significant (P < 0.00001) compared to the analysis group. Using an NIx
      threshold of 11.0, sensitivity for any DS was 61.5% (32/52) and specificity
      (normal group) was 96% (402/420) (False positive rate = 4%). If DS fetuses with
      effusions, hydrops, cystic hygromas or central nervous system (CNS) defects are
      excluded, the sensitivity for an NIx of 11.0 was 50.0% (20/40). CONCLUSIONS:
      Nuchal Index (NIx) can be assumed to be constant between 14 + 0 and 22 + 6. Using
      a threshold of 11.0, the sensitivity for any Down syndrome (DS) fetus was 62%
      (32/52) with a specificity of 96% (False positive rate = 4%). Even when obvious
      fetal conditions that can cause an increase in NIx are excluded, the sensitivity
      remains acceptable at 50%. NIx appears to be a useful, gestational age
      independent ultrasound marker for Down syndrome.

PMID- 12478641
TI  - Translocation 1q15q in a fetus with holoprosencephaly.

PMID- 12478642
TI  - Trisomy 7 mosaicism: prognosis after prenatal diagnosis.

PMID- 12478643
TI  - Prenatal diagnosis of iniencephaly and alobar holoprosencephaly with trisomy 13
      mosaicism: a case report.

PMID- 12478646
TI  - Effect of transvaginal sonography on the use of invasive procedures for
      evaluating patients with a clinical diagnosis of ectopic pregnancy.
AB  - PURPOSE: Our purpose was to determine the effect of transvaginal sonography (TVS)
      on the diagnostic evaluation of patients with suspected ectopic pregnancy (EP).
      Specifically, we wished to determine what effect TVS had on the use of invasive
      procedures. METHODS: This was a retrospective review of the medical records of
      290 patients with a surgically documented diagnosis of EP. It included 147
      consecutive patients from the era of use of suprapubic sonography (SPS) (1982
      1987) and 143 consecutive patients from the era of use of TVS (1987-1995). We
      compared the percentages of patients who had undergone sonographic examinations,
      the rates of use of the invasive procedures dilatation and curettage (D&C) and
      diagnostic laparoscopy (DL), time from presentation to diagnosis, necessity for
      transfusion, status of EP at surgery, and various other characteristics of the
      patients (eg, demographics, serum level of beta human chorionic gonadotropin, and
      presenting symptoms). RESULTS: In the SPS era, 46.9% of the patients had
      undergone sonography, compared with 78.3% in the TVS era (p = 0.001). Sonographic
      sensitivity was 60.9% in the SPS era and 93.8% in the TVS era (p = 0.001). D&C
      was performed in 53.1% and DL in 76.2% of patients in the SPS era, compared with
      14.0% and 30.8%, respectively, in the TVS era (p = 0.001). In the last full year
      of the study, only 9% of the patients had undergone D&C and 9%, DL. The overall
      time from presentation to diagnosis significantly decreased from 45.6 hours in
      the SPS era to 16.8 hours in the TVS era (p = 0.002). We found no significant
      difference between the 2 eras in the need for transfusion and the percentage of
      ruptured EPs at surgery (p > 0.05). CONCLUSIONS: The introduction of TVS has had
      an important effect on the evaluation of patients with EP by nearly eliminating
      the need for D&C and DL and permitting clinicians to take a more conservative
      approach to managing EP.

PMID- 12478647
TI  - Three-dimensional sonographic evaluation of the infant spine: preliminary
      findings.
AB  - PURPOSE: The aims of this study were to evaluate normal spinal anatomy in
      neonates and infants as seen by 3-dimensional sonography (3D US), to determine
      the value of 3D US in the evaluation of occult spinal dysraphia in infants, and
      to correlate the findings of 3D US with those of 2-dimensional sonography (2D US)
      and MRI, when available. METHODS: We used 2D US and 3D US to examine the
      lumbosacral spine in infants with cutaneous stigmata, syndromes associated with
      spinal dysraphia, and abnormal radiographs. We also evaluated, as controls,
      healthy infants who had no markers of spinal abnormality. 2D sonograms, 3D
      sonograms, radiographs, and MRI scans, when available, were compared to assess
      differences in the display of the infant spine. RESULTS: In total, we examined 29
      infants: 18 subjects and 11 control infants. The correlation between 2D US and 3D
      US was 100% in the detection of congenital defects of the spinal cord, although
      3D US allowed superior visualization of the vertebral bodies and posterior spinal
      elements. When a gross abnormality of the posterior spinal elements occurred with
      pathologic overlying soft tissue, interpretation was simpler with MRI than with
      sonography. CONCLUSIONS: 3D US is a useful adjunct to 2D US when screening the
      infant spine for congenital defects, particularly in showing alignment of
      posterior spinal elements and integrity of vertebral bodies. This ability is
      important because posterior spinal defects may be associated with underlying
      spinal cord abnormalities.

PMID- 12478648
TI  - Cystic appearance of cervical lymph nodes is characteristic of metastatic
      papillary thyroid carcinoma.
AB  - PURPOSE: The usefulness of high-resolution sonography in diagnosing cervical
      lymph node metastases from papillary thyroid carcinoma was investigated. The
      accuracy of a particular sign, cystic change within a node, in establishing the
      diagnosis was assessed. METHODS: The sonographic findings in 63 patients with
      enlarged cervical lymph nodes were retrospectively reviewed. The patients had
      undergone high-resolution gray-scale and color Doppler sonography followed by
      ultrasound-guided fine-needle aspiration (FNA) in all patients and surgical
      excision in 27 patients. RESULTS: Abnormal sonographic features were present in
      the lymph nodes of all 63 patients. In 14 (70%) of 20 patients with papillary
      thyroid carcinoma, sonography depicted cystic changes. This pattern was not found
      in any of the other 43 patients, in whom FNA revealed either metastasis from
      another malignancy (22 patients) or benign reactive lymphadenopathy (21
      patients). Among the 63 patients, there were 43 true-negative, 14 true-positive,
      6 false-negative, and no false-positive results in the diagnosis of metastatic
      papillary thyroid carcinoma using the presence or absence of an intranodal cystic
      area on sonography. These results yielded a 70% sensitivity, 100% specificity,
      100% positive predictive value, 88% negative predictive value, and 90% overall
      accuracy for this criterion. CONCLUSIONS: Cystic changes within a cervical lymph
      node are highly suggestive of metastatic papillary thyroid carcinoma.

PMID- 12478649
TI  - Sonographic assessment of changes in thickness of different abdominal fat layers
      in response to diet in obese women.
AB  - PURPOSE: We evaluated the potential application of sonography to monitor
      alterations in abdominal fat thickness in obese women before and after dieting.
      METHODS: This study included 40 obese women (mean age, 42.2 +/- 9.4 years; mean
      body mass index [BMI], 36.0 +/- 5.9 kg/m2) who underwent a 3-month low-calorie
      diet. Height, weight, waist circumference (WC), and hip circumference (HC) were
      measured. BMI and waist-to-hip ratio (WHR) were calculated. Abdominal
      subcutaneous (S) and intra-abdominal preperitoneal (P) fat were measured at their
      maximum (max) and minimum (min) thickness sites using a 7.5-MHz linear-array
      probe. Intra-abdominal visceral (V) fat was measured using a 3.5-MHz convex-array
      probe. Measurements were taken before and after caloric restriction. RESULTS: The
      mean weight was reduced from 88.6 +/- 17.1 kg to 83.0 +/- 15.9 kg (p < 0.0001).
      The mean changes in S(min) (r = 0.376, p = 0.017), S(max) (r = 0.508, (p =
      0.001), P(min) (r = 0.439, p = 0.005), and V (r = 0.365, p = 0.022) fat
      thicknesses were positively correlated with change in weight; the change in
      P(max) fat thickness showed the best and most significant correlation (r = 0.591,
      p < 0.0001). BMI (r = 0.969, p < 0.0001), WC (r = 0.510, p = 0.001), and HC (r =
      0.422, p = 0.007) changes were also positively correlated with weight change, but
      the WHR change (r = 0.019, p > 0.05) was not. CONCLUSIONS: All the abdominal fat
      layers, particularly the intra-abdominal P fat, will decrease in response to loss
      of body fat by dieting. Sonography seems to be useful in monitoring small
      variations in the thicknesses of abdominal S and intra-abdominal P and V fat.

PMID- 12478650
TI  - Sonographic grading of fetal intracardiac echogenic foci in a population at low
      risk of aneuploidy.
AB  - PURPOSE: We screened pregnant women at low risk of a fetal chromosomal
      abnormality for the presence of fetal intracardiac echogenic foci (ICEF) and
      graded those foci by using sonographic gain reduction. Our objectives were to
      determine the interobserver reliability of the technique and the association of
      ICEF, by grade, with fetal aneuploidy. METHODS: Pregnant women who were 18-35
      years old, at low risk for fetal chromosomal abnormalities, and referred for
      targeted sonography at 16-24 weeks' menstrual age were eligible to participate.
      All patients whose fetuses had ICEF were offered fetal chromosomal analysis. The
      presence of ICEF was ascertained by an apical 4-chamber view of the fetal heart
      and graded independently by 2 examiners blinded to each other's assessment.
      Grading was based on the difference in echogenicity of the ICEF and the thoracic
      spine as the ultrasound gain was reduced; in grade 1, the ICEF image was lost
      before that of the thoracic spine; in grade 2, the ICEF and thoracic spine images
      disappeared at the same gain setting; and in grade 3, the thoracic spine image
      was lost before that of the ICEF. RESULTS: During the 6-month study period, 383
      eligible women were examined, and ICEF were seen in 35 fetuses (9.1%): 25 (71.4%)
      in the left ventricle, 1 (2.9%) in the right ventricle, and 9 (25.7%) in both
      ventricles. ICEF grading was successfully performed in all 33 of the women with
      fetal ICEF who elected to participate. Twenty-one (63.6%) had grade 1, 9 (27.3%)
      had grade 2, and 3 (9.1%) had grade 3 ICEF. Interobserver agreement was noted in
      27 (90.0%) of 30 available paired second-trimester observations (kappa = 0.8),
      indicating excellent agreement. Two fetuses (6.1%) with grade 1 ICEF but no other
      risk factors for aneuploidy had chromosomal abnormalities, as compared with 1
      fetus (0.3%) in the control group, which had no ICEF (p = 0.02). CONCLUSIONS:
      Sonographic grading of ICEF is feasible and reliable. The presence of fetal ICEF
      in a population otherwise at low risk for aneuploidy seems to warrant the
      performance of fetal chromosomal analysis.

PMID- 12478651
TI  - Five-year follow-up of placental involution after abdominal pregnancy.
AB  - A 29-year-old woman with an abdominal pregnancy was admitted to the hospital at
      29 weeks' menstrual age. At 30 weeks, laparotomy was performed, and a live fetus,
      wrapped in membrane remnants, was taken from the abdominal cavity. The placenta,
      inserted in the right hemipelvis, was left in situ. The patient's postoperative
      recovery was uneventful, and she was monitored periodically as follow-up. At her
      5-year follow-up visit, we assessed placental involution by measuring serum beta
      human chorionic gonadotropin and by using color and pulsed Doppler sonography.
      The dynamics of the regression of placental volume yielded a bimodal curve: a
      phase of decrease over the first 2 months, coincident with a reduction in
      vascularization, followed by stability that lasted 6-8 months, and a second phase
      of gradual volume reduction. At 5 years, the placenta appeared as a small
      residual echogenic mass with no vascularity. The use of MRI in this case provided
      no additional information to what we found using sonography.

PMID- 12478652
TI  - Posterior mediastinal arteriovenous malformation with atypical color Doppler
      sonographic findings.
AB  - An arteriovenous malformation (AVM) is an anomaly of capillary development that
      results in a direct connection between branches of an artery and veins, with no
      intervening capillary network. A definite diagnosis of AVM is usually made with
      angiography. We report the case of a posterior mediastinal AVM found on routine
      sonography in a 64-year-old woman with neglected hypertension and severe back
      pain. Color Doppler imaging showed 2 adjoined vascular structures without a
      typical mosaic-like flow pattern, and spectral Doppler analysis showed low
      resistance flow and arteriovenous shunting in 2 adjoined vascular structures. The
      diagnosis was subsequently confirmed by angiography. Because disastrous bleeding
      could result if needle biopsy were performed inadvertently in the case of a
      suspected mediastinal AVM, we suggest that color Doppler sonography be attempted
      if there is an adequate acoustic window.

PMID- 12478653
TI  - Echocardiographic diagnosis and follow-up of left ventricular pseudoaneurysm
      complicating bacterial pericarditis.
AB  - Two-dimensional echocardiography demonstrated a pseudoaneurysm of the lateral
      wall of the left ventricle in a 13-year-old girl with bacterial pericarditis. The
      echocardiographic findings included a 5-mm discontinuity in the lateral wall of
      the left ventricle, an associated anechoic collection (5.6 x 5.1 cm), and a
      narrow communication between the left ventricle and the anechoic collection.
      Color Doppler imaging demonstrated flow through the communication between the
      left ventricle and the aneurysmal cavity. The patient and her family refused
      surgery. A follow-up echocardiographic examination more than 6 years later
      demonstrated disappearance of the discontinuity of the left ventricular lateral
      wall, no flow between the left ventricle and the pseudoaneurysm, and thrombus
      formation within the pseudoaneurysm.

PMID- 12478654
TI  - Tuberculous ileitis in a renal transplant recipient with familial Mediterranean
      fever: Gray-scale and power Doppler sonographic findings.
AB  - The ileocecal area is the most common site of involvement of intestinal
      tuberculosis. We report the case of a 26-year-old renal transplant recipient with
      familial Mediterranean fever who developed tuberculous ileitis. Gray-scale
      sonography and CT showed circumferential thickening of the bowel wall and
      enlargement of the mesenteric lymph nodes. Power Doppler sonography revealed
      markedly increased vascularity in the wall of the affected ileal segment and in
      the mesenteric nodes. Some nodes had no flow at the center owing to caseation
      necrosis, a finding consistent with the diagnosis of tuberculous ileitis.
      Colonoscopy was performed, and histopathologic examination of biopsy specimens
      revealed acute inflammatory changes. Cultures of the specimens confirmed the
      presence of Mycobacterium tuberculosis. We conclude that findings on power
      Doppler sonography may support a diagnosis of tuberculous ileitis and avoid
      clinical mismanagement.

PMID- 12478656
TI  - Assessment of conventional versus real-time spatial compound imaging in breast
      sonography: preliminary results.

PMID- 12478655
TI  - Sonographic diagnosis and successful nonoperative management of sealed perforated
      duodenal ulcer.
AB  - We encountered a case of sealed perforated duodenal ulcer in a 75-year-old woman
      with rheumatoid arthritis and chronic renal failure. Abdominal sonography showed
      a bright linear echo within the thickened anterior wall of the duodenal bulb and
      the presence of free air at the anterior surface of the liver. We found no signs
      of direct communication between the duodenal lumen and the peritoneal cavity or
      any free fluid. On follow-up sonography performed every 2 days during the first
      week of the patient's hospitalization, no free fluid was found in the abdomen.
      The use of sonography to diagnose this patient's sealed perforated duodenal ulcer
      and to monitor the ulcer for the appearance of free fluid allowed us to provide
      successful nonsurgical management to this patient. We believe that the use of
      abdominal sonography in all patients suspected of having a perforated duodenal
      ulcer may help increase the diagnostic accuracy of this modality and may reduce
      the need for surgery in such patients.

PMID- 12478657
TI  - TCDD-dependent downregulation of gamma-catenin in rat liver epithelial cells (WB
      F344).
AB  - TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is the most potent tumor promoter ever
      tested in rodents. Although it is known that most of the effects of TCDD are
      mediated by binding to the aryl hydrocarbon receptor (AHR), the mechanisms
      leading to tumor promotion still remain to be elucidated. Loss of contact
      inhibition is a characteristic hallmark in tumorigenesis. In WB-F344 cells, TCDD
      induces a release from contact-inhibition manifested by a 2- to 3-fold increase
      in DNA-synthesis and the emergence of foci when TCDD (1 nM) is given to confluent
      cells. We focussed our interest on potential cell membrane proteins mediating
      contact-inhibition in WB-F344 cells, namely E-cadherin, alpha,- beta,- and gamma
      catenin (plakoglobin). Using indirect immunofluorescence, E-cadherin, alpha-,
      beta- and gamma-catenin were detected at cell adhesion sites in untreated,
      confluent cells. After TCDD-exposure, gamma-catenin was exclusively localized in
      the cytoplasm whereas localization of E-cadherin, alpha- and beta-catenin
      remained unaffected. Cytoplasmic gamma-catenin could be extracted by Triton X-100
      treatment, demonstrating that gamma-catenin was no longer bound to the actin
      cytoskeleton. Western blot analysis showed downregulation of gamma-catenin
      protein levels. This effect was not blocked by pre-incubation with the selective
      proteasome inhibitor MG-132, indicating that proteolytical degradation of gamma
      catenin by the proteasome system was not increased by TCDD. Because mRNA-levels
      of gamma-catenin were markedly diminished after TCDD-exposure, we conclude that
      transcriptional downregulation or destabilization of the mRNA contributes to the
      decrease in gamma-catenin protein levels in response to TCDD. Because gamma
      catenin is considered to be a tumor suppressor, our findings might give more
      insight into the tumor promoting actions of TCDD.

PMID- 12478658
TI  - Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by
      promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and
      p53 mutation in hepatocellular carcinoma.
AB  - O(6)-methylguanine-DNA methyltransferase (MGMT) is a repair protein that
      specifically removes promutagenic alkyl groups from the O(6) position of guanine
      in DNA. MGMT is transcriptionally silenced by promoter hypermethylation in
      several human cancers. Methylation-specific PCR (MSP) was used to analyze the
      MGMT promoter methylation status of 83 hepatocellular carcinomas (HCC) and 2 HCC
      cell lines (HepG2 and Hep3B). Hypermethylation was detected in 32 of 83 (39%) HCC
      tissues, but it was not found in either HCC cell line. We also analyzed MGMT
      expression by immunohistochemical analysis of HCC tissue samples. The presence of
      aberrant hypermethylation was associated with loss of MGMT protein. The
      relationship between methylation status and risk factors and tumor markers
      including environmental exposure to aflatoxin B(1) (AFB(1)), measured as DNA
      adducts, and status of tumor suppressor gene p53 was also investigated. A
      statistically significant association was found between MGMT promoter
      hypermethylation and high level of AFB(1)-DNA adducts in tumor tissues (OR =
      5.05, 95% CI = 1.29-19.73). A significant association was also found between
      methylation and p53 mutation status (OR = 2.97, 95% CI = 1.09-8.11). These
      results suggest that epigenetic inactivation of MGMT plays an important role in
      the development of HCC and exposure to environmental carcinogens may be related
      to altered methylation of genes involved in cancer development. The role of
      chemical carcinogens in hypermethylation needs further investigation.

PMID- 12478659
TI  - Multigene analysis of Rb pathway and apoptosis control in esophageal squamous
      cell carcinoma identifies patients with good prognosis.
AB  - Deregulation of cell-cycle G(1)-restriction point control by disruption of Rb
      pathway components is a frequent event in cancer. In concert with the
      inactivation of cell death pathways, such events not only contribute to tumor
      development but also determine the intrinsic and acquired resistance to cancer
      therapy and, ultimately, disease prognosis. We previously observed that the
      cyclin-dependent kinase inhibitor p16(INK4a) and the proapoptotic Bcl-2 homolog
      Bax are positive prognostic factors and identify patients with good prognosis in
      esophageal squamous cell carcinoma (SCC). In the present study, we therefore
      extend our analysis to additional genes controlling the G(1) restriction point
      and apoptosis, respectively. This retrospective analysis was performed in a
      cohort of 53 patients undergoing surgery for esophageal SCC with curative intent,
      i.e., R0 resection. Protein expression profiles of cyclin D1, p16(INK4a), Rb,
      p21(CIP/WAF-1), p53, Bax and Bcl-2 were analyzed by immunohistochemistry and
      compared to p53 mutational status, as determined by SSCP-PCR of exons 5-8. Loss
      of p16(INK4a), Rb, p21(CIP/WAF-1) or Bax and overexpression of cyclin D1 were
      associated individually with shorter overall survival, while Bcl-2 expression and
      p53 mutation were not of prognostic relevance. The longest survival was observed
      in a subgroup of patients whose tumors bore a combination of favorite genotypes,
      i.e., low cyclin D1 and high Rb, p21(CIP/WAF-1), p16(INK4a) and Bax protein
      expression. These results show that multigene analyses based on limited sets of
      functionally linked genes reliably identify patients with good vs. poor
      prognosis.

PMID- 12478660
TI  - Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7
      signaling.
AB  - The Glypican (GPC) family is a prototypical member of the cell-surface heparan
      sulfate proteoglycans (HSPGs). The HSPGs have been demonstrated to interact with
      growth factors, act as coreceptors and modulate growth factor activity. Here we
      show that based on oligonucleotide array analysis, GPC3 was upregulated in
      hepatocellular carcinoma (HCC). By northern blot analysis, GPC3 mRNA was found to
      be upregulated in 29 of 52 cases of HCC (55.7%). By Western blot analysis carried
      out with a monoclonal anti-GPC3 antibody we generated, the GPC3 protein was found
      to be overexpressed in 6 hepatoma cell lines, HepG2, Hep3B, HT17, HuH6, HuH7 and
      PLC/PRF/5, as well as 22 tumors (42.3%). To investigate the role of overexpressed
      GPC3 in liver cancer, we analyzed its effects on cell growth of hepatoblastoma
      derived cells. Overexpression of GPC3 modulated cell proliferation by inhibiting
      fibroblast growth factor 2 (FGF2) and bone morphogenetic protein 7 (BMP-7)
      activity. An interaction of GPC3 and FGF2 was revealed by co-immunoprecipitation,
      while GPC3 was found to inhibit BMP-7 signaling through the Smad pathway by
      reporter gene assay. The modulation of growth factors by GPC3 may help explain
      its role in liver carcinogenesis. In addition, the ability of HCC cells to
      express GPC3 at high levels may serve as a new tumor marker for HCC.

PMID- 12478661
TI  - Angiopoietin-2 expression in breast cancer correlates with lymph node invasion
      and short survival.
AB  - Angiogenic factors produced by tumor cells are essential for tumor growth and
      metastasis. In our study, the expression of Angiopoietin-1 (ANG1) and
      Angiopoietin-2 (ANG2) mRNA in archival human breast cancer tumor samples and in 6
      breast cancer cell lines was investigated. Total RNA from biopsies of 38 breast
      cancer patients was extracted and ANG1 and ANG2 mRNA expression was measured by
      means of quantitative real-time RT-PCR (Taqman). Matching data with available
      clinicopathologic and biochemical data revealed a significant association between
      ANG2 expression and axillary lymph node invasion. Univariate and multivariate
      survival analysis, by means of Kaplan-Meier method and Cox's proportional hazards
      model, showed significant and independent association between ANG2 mRNA level and
      both disease-free (p < 0.0001) and overall survival (p < 0.0003). An important
      fact is that, notwithstanding the small number of cases examined, this
      association was confirmed also in the group of lymph node-negative patients (DFS,
      p < 0.003; OS, p < 0.020). Immunohistochemical analysis demonstrated that Ang2 is
      expressed by both tumor cells and endothelial elements. Expression in tumor cells
      was confirmed by studying a panel of human breast carcinoma cell lines in culture
      by RT-PCR. In ZR75.1 and T47D cells, expression of ANG2 mRNA was increased up to
      10-fold by treatment with estrogen within 24 hr. Although preliminary, these data
      suggest a possible role of ANG2 as a prognostic factor for primary breast cancer.

PMID- 12478662
TI  - Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras
      transformed human breast epithelial cells.
AB  - Efforts have been made to develop a chemoprevention strategy that selectively
      triggers apoptosis in malignant cancer cells. Previous studies showed that
      capsaicin, the major pungent ingredient of red pepper, had differential effect
      between normal and transformed cells. As an approach to unveil the molecular
      mechanism by which capsaicin selectively induces apoptosis in transformed cells,
      we investigated the effect of capsaicin in nontransformed and ras-transformed
      cells of a common origin: parental (MCF10A) and H-ras-transformed (H-ras MCF10A)
      human breast epithelial cells. Here, we show that capsaicin selectively induces
      apoptosis in H-ras-transformed cells but not in their normal cell counterparts.
      The capsaicin-induced apoptosis, which is dependent on ras transformation,
      involves the activity of DEVDase (caspase-3 like). In H-ras MCF10A cells,
      capsaicin treatment markedly activated c-Jun N-terminal protein kinase (JNK)-1
      and p38 matigen-activated protein kinase (MAPK) while it deactivated
      extracellular signal-regulated protein kinases (ERKs). The use of kinase
      inhibitors and overexpression of dominant-negative forms of MAPKs demonstrated a
      role of JNK-1 and p38, but not that of ERKs, in apoptosis induced by capsaicin in
      H-ras-transformed MCF10A cells. Based on the present study, we propose that
      capsaicin selectively induces apoptosis through modulation of ras-downstream
      signaling molecules in ras-activated MCF10A cells. Taken in conjunction with the
      fact that uncontrolled ras activation is probably the most common genetic defect
      in human cancer cells, our finding may be critical to the chemopreventive
      potential of capsaicin and for developing a strategy to induce tumor cell
      specific apoptosis.

PMID- 12478663
TI  - Multiple meningiomas: Investigating the molecular basis of sporadic and familial
      forms.
AB  - Meningiomas are common tumors of the coverings of the central nervous system
      (CNS), comprising 20% of intracranial neoplasms. The only genes known to be
      associated with sporadic meningiomas are NF2 on chromosome 22 and the related
      cytoskeleton element DAL-1 on chromosome 18. Between 1 and 8% of patients with
      meningiomas develop multiple meningiomas, a trait transmitted occasionally in an
      autosomal dominant fashion. We investigated the DAL-1 and NF2 loci in 7 unrelated
      multiple meningioma patients without clinical evidence of NF2 by mutational and
      pathological analysis. Five novel intragenic microsatellite polymorphisms were
      developed for specific detection of loss of heterozygosity (LOH) at the DAL-1
      locus. Three of 7 patients had affected relatives and all affected individuals
      were female. No tumors from familial patients were of a fibroblastic subtype.
      Truncating NF2 mutations were detected in 3 tumor specimens, but were not present
      in the corresponding blood samples. Two tumors showed LOH at the NF2 locus. All
      tumors showing mutations at the NF2 locus originated from patients without
      affected relatives and were of the fibroblastic subtype. Five non-truncating
      alterations in the DAL-1 gene were found, however, LOH of chromosome 18 markers
      was not seen in any tumor. In contrast to the NF2 results, all DAL-1 alterations
      were found in paired blood specimens. Our findings provide further evidence that
      the molecular basis of sporadic and familial multiple meningiomas is
      fundamentally different and extend this dichotomy to pathologic subtypes. DAL-1
      does not function as a true tumor suppressor in these patients.

PMID- 12478664
TI  - Hodgkin's lymphoma cell lines are characterized by frequent aberrations on
      chromosomes 2p and 9p including REL and JAK2.
AB  - Four Hodgkin's lymphoma cell lines (KM-H2, HDLM-2, L428, L1236) were analyzed for
      cytogenetic aberrations, applying multiplex fluorescence in situ hybridization,
      chromosome banding and comparative genomic hybridization. Each line was
      characterized by a highly heterogeneous pattern of karyotypic changes with a
      large spectrum of different translocated chromosomes (range 22-57). A recurrent
      finding in all cell lines was the presence of chromosomal rearrangements of the
      short arm of chromosome 2 involving the REL oncogene locus. Furthermore, multiple
      translocated copies of telomeric chromosomal segments were frequently detected.
      This resulted in a copy number increase of putative oncogenes, e.g., JAK2 (9p24)
      in 3 cell lines, FGFR3 (4p16) and CCND2 (12p13) in 2 cell lines as well as MYC
      (8q24) in 1 cell line. Our data confirm previous cytogenetic results from primary
      Hodgkin's tumors suggesting an important pathogenic role of REL and JAK2 in this
      disease. In addition, they provide evidence for a novel cytogenetic
      pathomechanism leading to increased copy numbers of putative oncogenes from
      terminal chromosomal regions, most probably in the course of chromosomal
      stabilization by telomeric capture.

PMID- 12478665
TI  - Viral load of HPV in esophageal squamous cell carcinoma.
AB  - We previously reported the presence of HPV DNA in esophageal squamous cell
      carcinoma (ESCC) cases from Hong Kong and Sichuan. The role of HPV in the
      carcinogenesis of ESCC remains unclear, partly due to the large variations in
      infection rates reported by different studies. While some of these variations may
      truly reflect different HPV infection rates in ESCC among different geographic
      regions, differences in sensitivity and specificity of the detection methods used
      also contribute. In the present study, we used quantitative real-time PCR to
      determine the copy numbers of HPV-16 and HPV-18 in ESCC from 5 different regions
      of China with different incidence rates of ESCC. Conforming to our previous
      reports, HPV infection was detected in 2-22.2% of samples. Infection with HPV-16
      was again shown to be more common than that with HPV-18 among Chinese ESCC
      patients. The copy number of HPV-16 in these ESCC cases ranged from < or =1 to
      157 copies/genome equivalent, with 65% of samples harboring fewer than 10
      copies/genome equivalent. The median copy number of HPV-18 was 4.9/genome
      equivalent. Assays were validated using cervical carcinoma cell lines with known
      copy numbers of HPV-16 or HPV-18. The relatively low HPV copy number and
      infection rate in ESCC suggest that HPV is unlikely to play as essential a role
      in the carcinogenesis of ESCC as in cervical cancer. However, with the consistent
      detection of oncogenic HPVs in ESCC from some regions of China, the possibility
      of HPV infection being one of the multiple risk factors of ESCC in some
      geographic areas cannot be excluded.

PMID- 12478666
TI  - Potent activity of soluble B7RP-1-Fc in therapy of murine tumors in syngeneic
      hosts.
AB  - We have characterized a receptor:ligand pair, ICOS:B7RP-1, that is structurally
      and functionally related to CD28:B7.1/2. We reported previously that B7RP-1
      costimulates T cell proliferation and immune responses (Yoshinaga et al., Nature
      1999;402:827-32; Guo et al., J Immunol 2001;166:5578-84; Yoshinaga et al., Int
      Immunol 2000;12:1439-47). We report that B7RP-1-Fc causes rejection or growth
      inhibition of Meth A, SA-1 and EMT6 tumors in syngeneic mice. Established Meth A
      tumors were rejected effectively with a single dose of B7RP-1-Fc, however, the
      treatment was less effective on larger tumors. Mice that rejected Meth A tumors
      previously by Day 30, also rejected a subsequent Meth A challenge on Day 60,
      without additional B7RP-1-Fc treatment, indicating a long-lived memory response.
      Tumor cells believed to be less immunogenic, such as P815 and EL-4 cells, were
      less responsive to this treatment. The EL-4 responsiveness to the B7RP-1-Fc
      treatment was enhanced, however, by pre-treatment of the mice with
      cyclophosphamide. As expected, T cells appeared to be targeted by B7RP-1-Fc
      treatment. Thus, the administration of soluble B7RP-1-Fc may have therapeutic
      value in generating or enhancing anti-tumor activity in a clinical setting.

PMID- 12478667
TI  - Natural killer, but not natural killer T, cells play a necessary role in the
      promotion of an innate antitumor response induced by IL-18.
AB  - IL-18 administration promotes innate immunity resulting in significant antitumor
      effects in multiple murine tumor models. Here, we examined the effector
      population mediating the innate immunity. Most NK cells and some NKT cells
      express IL-18Rs without prior stimulation (65% positive in NK cells, 18% positive
      in NKT cells), though few naive T cells do. In vivo depletion of NK cells, but
      not NKT cells, using AsGM1 antibody significantly reduces IL-18-induced
      cytotoxicity. However, NK-like activity of hepatic MNCs for the NK target YAC-1
      was present in Valpha 14 NKT cell-deficient animals. Furthermore, administration
      of rIL-18 greatly reduced B16 pulmonary metastases in vivo in NKT cell-deficient
      animals. When sorted NK and NKT cells were exposed to IL-18 in vitro, NK cells
      showed more IFN-gamma production and cytolysis against YAC-1 than NKT cells in
      response to IL-18. These results are consistent with the notion that NK cells,
      but not NKT cells, are the major effectors in IL-18-induced innate immunity.

PMID- 12478668
TI  - Health-related quality of life of children with acute lymphoblastic leukaemia:
      comparisons and correlations between parent and clinician reports.
AB  - The improving prognosis for children with cancer refocuses attention to long-term
      outcomes with an emphasis on quality of life. Few studies have examined
      relationships and differences in reported results between the parent, child and
      clinician. We examined parent-proxy and clinician-reported functional status and
      health-related quality of life for children and adolescents with acute
      lymphoblastic leukemia (ALL). Children and adolescents, 5-18 years, in the
      maintenance phase of treatment for ALL attending the Haematology/Oncology
      outpatient clinic at the Royal Children's Hospital, Melbourne, were eligible.
      Measures included: 1) parent-reported functional health and well-being (Child
      Health Questionnaire [CHQ]); 2) parent-reported condition specific quality of
      life (Pediatric Cancer Quality of Life inventory [PCQL]); 3) clinician ratings of
      physical and psychosocial health; and 4) clinical indicators. Insufficient
      numbers of older patients prohibited collection of adolescent self-reports. We
      had a 94% response and 31 participants. Mean time since diagnosis: 1.5 (SD 0.4)
      years. Parents reported significantly lower functioning and well-being than
      population norms for all CHQ scales, whereas cancer-specific quality of life was
      comparable to PCQL norms. Clinician reports of the child's global physical and
      psychosocial health were moderately associated with each other (r(s) = 0.56, p <
      0.001), and with the parent-reported physical (r(s) = 0.47, p < 0.01) and
      psychosocial (r(s) = 0.56, p < 0.001) CHQ summary scores. Clinician reports of
      the child's psychosocial health were not associated with any clinical indicators
      reported regularly. The results demonstrate that the social, physical and
      emotional health and well-being of children with ALL is significantly poorer than
      the health of their community-based peers. Routinely collected indicators of
      clinical progress conceal the psychosocial burden of ALL. Data on health, well
      being and quality of life can easily be incorporated into clinical care.

PMID- 12478669
TI  - Viral load as a predictor of the risk of cervical intraepithelial neoplasia.
AB  - HPV infections are believed to be a necessary cause of cervical cancer. Viral
      burden, as a surrogate indicator for persistence, may help predict risk of
      subsequent SIL. We used results of HPV test and cytology data repeated every 4-6
      months in 2,081 women participating in a longitudinal study of the natural
      history of HPV infection and cervical neoplasia in Sao Paulo, Brazil. Using the
      MY09/11 PCR protocol, 473 women were positive for HPV DNA during the first 2
      visits. We retested all positive specimens by a quantitative, low-stringency PCR
      method to measure viral burden in cervical cells. Mean viral loads and 95% CIs
      were calculated using log-transformed data. RRs and 95% CIs of incident SIL were
      calculated by proportional hazards models, adjusting for age and HPV
      oncogenicity. The risk of incident lesions increased with viral load at
      enrollment. The mean number of viral copies/cell at enrollment was 2.6 for women
      with no incident lesions and increased (trend p = 0.003) to 15.1 for women
      developing 3 or more SIL events over 6 years of follow-up. Compared to those with
      <1 copy per cell in specimens tested during the first 2 visits, RRs for incident
      SIL increased from 1.9 (95% CI 0.8-4.2) for those with 1-10 copies/cell to 4.5
      (95% CI 1.9-10.7) for those with >1,000 copies/cell. The equivalent RR of HSIL
      for >1,000 copies/cell was 2.6 (95% CI 0.5-13.2). Viral burden appears to have an
      independent effect on SIL incidence. Measurement of viral load, as a surrogate
      for HPV persistence, may identify women at risk of developing cervical cancer
      precursors.

PMID- 12478670
TI  - Familial and second primary pancreatic cancers: a nationwide epidemiologic study
      from Sweden.
AB  - Familial risk of pancreatic cancer has been mainly assessed through case-control
      studies based on reported but not medically verified cancers in family members.
      We used the nationwide Swedish Family-Cancer Database on 10.2 million individuals
      and 21,000 pancreatic cancers to calculate standardized incidence ratios (SIRs)
      and 95% confidence intervals (CIs) for pancreatic cancer in 0- to 66-year-old
      offspring of parents with pancreatic or other specified tumors. Additionally,
      SIRs for second primary pancreatic cancers were analyzed after any first
      neoplasm. SIRs for pancreatic cancer (1.68, 95% CI 1.16-2.35) and pancreatic
      adenocarcinoma (1.73, 95% CI 1.13-2.54) were increased when a parent presented
      with pancreatic cancer. The risk was not dependent on diagnostic age of offspring
      or parents. Pancreatic cancer was associated with parental lung, rectal or
      endometrial cancer and with melanoma. SIRs for pancreatic cancer were 10.01 and
      7.96 among offspring who were diagnosed before age 50 years when parents were
      diagnosed with squamous cell and adenocarcinoma of the lung, respectively, before
      age 60 years. The population-attributable proportion of familial pancreatic
      cancer was 1.1%. Risks for second pancreatic cancers were increased in men and
      women after small intestinal, colon and bladder cancer. The degree of familial
      clustering for pancreatic cancer and its population-attributable proportion were
      lower than the data cited in the literature. Clustering of pancreatic cancer with
      sites presenting in hereditary nonpolyposis colorectal cancer was noted. The
      strong association of pancreatic and lung cancers is puzzling, and it remains
      unclear to what extent this represents familial sharing of smoking habits.

PMID- 12478671
TI  - Hepatocellular carcinoma among atomic bomb survivors: significant interaction of
      radiation with hepatitis C virus infections.
AB  - We conducted a nested case-control study within the cohort of Japanese survivors
      of the 1945 atomic bombings to study the joint effects of HBV and HCV with
      radiation on the risk of HCC. Among subjects who received autopsies during 1954
      1988, we analyzed archival tissue samples for 238 pathologically confirmed HCC
      cases and 894 controls who died from diseases other than liver cancer. Using
      logistic regression and adjusting for potential confounders and other factors, we
      found a statistically significant, supermultiplicative interaction between A bomb
      radiation and HCV in the etiology of HCC. Compared to subjects who were negative
      for HCV and radiation, ORs of HCC for HCV-positive subjects showed a
      statistically significant, greater than multiplicative increase for liver
      irradiation exposures in the second (>0.018-0.186 Sv, p = 0.04) and third (>0.186
      Sv, p = 0.05) tertiles of non-zero radiation exposure but not for first tertile
      exposure (>0-0.018 Sv, p = 0.86). Limiting analysis to subjects without
      cirrhosis, HCV-infected subjects were at 58.0-fold (95% CI 1.99- infinity )
      increased risk of HCC per Sv of radiation exposure (p = 0.017), a
      supermultiplicative interaction between radiation and HCV that was not found
      among subjects with cirrhosis (p = 0.67). We found no evidence of interaction
      between HBV infection and radiation exposure in the etiology of HCC, regardless
      of cirrhosis status (p = 0.58). We conclude that among survivors of the nuclear
      bombings of Hiroshima and Nagasaki, subjects who were both HCV-positive and
      radiation-exposed were at a significantly, supermultiplicatively increased risk
      of HCC without concurrent cirrhosis.

PMID- 12478672
TI  - Neuroblastoma trends in Osaka, Japan, and Great Britain 1970-1994, in relation to
      screening.
AB  - Japan pioneered and has maintained a nationwide mass screening programme for
      neuroblastoma since 1985 without prior evaluation among a target population.
      Convincing population-based evaluation of the ongoing programme has also been
      very limited because a population-based registry for childhood cancer has not
      been in operation. This report describes trends in incidence of and mortality
      from neuroblastoma in Osaka Prefecture, Japan, using Great Britain as an external
      control, between 1970 and 1994. Incidence and mortality rates were comparable
      between the 2 areas before the beginning of screening in Osaka. However,
      incidence rates were markedly increased in Osaka, especially among children
      younger than 1 year, from 25.9 per million children during 1970-1979 to 240.2
      during 1991-1994, while age-standardized incidence rates for metastatic tumours
      among children aged 1 year or above did not decrease after introduction of the
      programme. Age-standardized mortality rates per million were unchanged at 3.9
      (1970-1979) and 4.1 (1991-1994) in Osaka and 5.7 (1971-1979) and 5.0 (1991-1994)
      in Great Britain. Cumulative incidence rates among those up to 15 years old
      progressively increased from 103.4 per million (1970-1979) to 350.0 (1991-1994)
      in Osaka, though cumulative mortality rates did not decrease: 52.0 and 57.5,
      respectively. Corresponding figures in Great Britain were 101.0, 115.1, 78.6 and
      70.1, respectively. The present findings show little beneficial effect of the
      screening programme.

PMID- 12478673
TI  - Retinoic acid receptor-alpha as a prognostic indicator in oral squamous cell
      carcinoma.
AB  - Retinoids reverse potentially malignant lesions and inhibit the development of
      second primary tumors in oral cancer patients by binding to nuclear retinoid
      receptors. Alterations in the expression of retinoid receptor-alpha are
      implicated in tumor progression. Herein, we hypothesized that increased
      expression of RARalpha protein in oral squamous cell carcinoma (SCC) is
      associated with a poor clinical outcome and thus may serve as a prognostic
      factor. Retrospective immunohistochemical analysis of RARalpha protein expression
      was carried out in paraffin-embedded tissue sections from 115 patients with
      completely resected oral SCCs for whom clinical follow-up data were available.
      Increased expression of RARalpha protein was observed in 67/115 (58%) oral SCCs
      (weakly positive in 38 patients and strongly positive in 29 patients). Kaplan
      Meier analysis showed that patients with RARalpha positivity had significantly
      shorter disease-free survival time (median time 40 months vs. 86 months, p =
      0.0229). Furthermore, disease-free survival time of the 29 patients with strongly
      positive RARalpha was significantly worse than for the 86 patients with weak or
      undetectable levels of RARalpha (p = 0.0328). Strong RARalpha expression in oral
      SCCs was associated with a significantly worse disease-free survival, suggesting
      that RARalpha may serve as a prognostic indicator of poor clinical outcome.
      Further studies are warranted to determine its utility in identifying the subset
      of patients who would benefit from use of retinoids as adjuvant in chemotherapy
      or chemopreventive approaches.

PMID- 12478674
TI  - Detection of bone marrow-disseminated breast cancer cells using an RT-PCR assay
      of MUC5B mRNA.
AB  - The evaluation of disseminated epithelial tumor cells in breast cancer patients
      has generated considerable interest due to its potential association with disease
      recurrence. Our work was performed to analyze the usefulness of 5 mucin genes
      expression (MUC2, MUC3, MUC5B, MUC6 and MUC7), using RT-PCR assays, to detect
      disseminated cancer cells in patients with operable breast cancer. The highest
      frequencies of positive RT-PCR tests in breast tumor extracts were observed for
      MUC5B (7/15) and MUC7 (5/12). The best specificity, negative results on all
      peripheral blood mononuclear (PBMN) cell samples from healthy donors, were shown
      for MUC2, MUC5B and MUC6 RT-PCR assays. Thus, we selected MUC5B as a target gene
      for further evaluation. Using a nested RT-PCR, MUC5B mRNA transcripts were
      detected in 16/31 primary breast tumors (but not in 36 samples of normal PBMN
      cells) and in the human MCF-7 breast cancer cell line but not in BT20, MDA, T47D
      and ZR-75 breast cancer cell lines, indicating that MUC5B mRNA is expressed in a
      population of breast cancer cells. Using this method, 9/46 patients (19.5%) who
      underwent curative surgery showed positive MUC5B mRNA in bone marrow aspirates
      obtained prior to surgery, including 5/24 patients (20.8%) with stage I or II
      breast cancer, without histopathologic lymph node involvement. These results
      indicate that MUC5B mRNA could be a specific marker applicable to the molecular
      diagnosis of breast cancer cell dissemination. A comparative evaluation between
      MUC5B mRNA, cytokeratin 19 (CK19) mRNA and carcinoembryonic antigen (CEA) mRNA in
      all bone marrow aspirates suggests a putative complementation for molecular
      detection of disseminated carcinoma cells. Considering that breast cancer is
      characterized by a great phenotypic heterogeneity, the use of multimarker
      approach could contribute to tumor cell detection in bone marrow and blood.

PMID- 12478675
TI  - Risk of melanoma among radiologic technologists in the United States.
AB  - Our study examines the risk of melanoma among medical radiation workers in the
      U.S. Radiologic Technologists (USRT) study. We evaluated 68,588 white radiologic
      technologists (78.8% female), certified during 1926-1982, who responded to a
      baseline questionnaire (1983-1989) and were free of cancer other than nonmelanoma
      skin at that time. Participants were followed through completion of a second
      questionnaire (1994-1998). We identified 207 cases, 193 subjects who reported
      first primary melanoma and 14 decedents with melanoma listed as an underlying or
      contributory cause of death. We examined risks of occupational radiation
      exposures using work history information on practices, procedures, and protective
      measures reported on the baseline questionnaire. Based on Cox proportional
      hazards regression, melanoma was significantly associated with established risk
      factors, including constitutional characteristics (skin tone, eye and hair
      color), personal history of nonmelanoma skin cancer, family history of melanoma
      and indicators of residential sunlight exposure. Melanoma risk was increased
      among those who first worked before 1950 (RR = 1.8, 95% CI = 0.6-5.5),
      particularly among those who worked 5 or more years before 1950 (RR = 2.4; 0.7
      8.7; p (trend) for years worked before 1950 = 0.03), when radiation exposures
      were likely highest. Risk was also modestly elevated among technologists who did
      not customarily use a lead apron or shield when they first began working (RR =
      1.4; 0.8-2.5). Clarifying the possible role of exposure to chronic ionizing
      radiation in melanoma is likely to require nested case-control studies within
      occupational cohorts, such as this one, which will assess individual radiation
      doses, and detailed information about sun exposure, sunburn history and skin
      susceptibility characteristics.

PMID- 12478677
TI  - Adenocarcinoma in situ of the cervix: sensitivity of detection by cervical smear:
      will cytologic screening for adenocarcinoma in situ reduce incidence rates for
      adenocarcinoma.

PMID- 12478678
TI  - Misclassification of cytologic diagnoses in patients with follicular lesions or
      follicular neoplasms of the thyroid gland: implications for patient care and
      clinical research.

PMID- 12478679
TI  - One hundred percent thorough quality control rescreening of liquid-based
      monolayers in cervicovaginal cytopathology.
AB  - BACKGROUND: Quality control (QC) of Papanicolaou (Pap) smear testing focuses on
      the identification of screening errors by 10% random, rapid, or thorough manual
      rescreening of some portion of negative smears. One hundred percent thorough
      manual rescreening has been reported to be the most effective method of
      identifying screening errors in conventional Pap smears (CP), but to the authors'
      knowledge no experience with this QC method has been reported for the ThinPrep
      Pap test (TP). The current study reports the estimated screening error rate of TP
      as determined by a QC program using 100% thorough rescreening. METHODS: All TP
      samples received at the study institution between January 1, 1999 and December
      31, 2000 and initially screened as negative underwent thorough manual QC
      rescreening. RESULTS: A total of 53,419 TP samples were received during the study
      period. Of these, 5,368 cases (10%) initially were interpreted as abnormal. A
      total of 47,247 cases (88.4%) were rescreened. Abnormalities were identified in
      804 additional cases, for a screening error rate of 13.0%. Of the 804 cases, 678
      (84.3%) were atypical squamous cells of undetermined significance, 116 (14.4%)
      were low-grade squamous intraepithelial lesions, and 10 (1.2%) were high-grade
      squamous intraepithelial lesions. No tumors were identified on rescreening.
      CONCLUSIONS: In the current study, 100% thorough rescreening of TP samples was
      found to result in the detection of a significant number of abnormalities that
      would have been missed by routine random 10% QC rescreening. The screening error
      rate determined by 100% thorough QC rescreening of TP is comparable to that
      reported for CP QC rescreening.

PMID- 12478680
TI  - Adenocarcinoma in situ of the cervix.
AB  - BACKGROUND: The current study examines 1) the sensitivity of detection and 2)
      sampling and screening/diagnostic error in the cytologic diagnosis of
      adenocarcinoma in situ (AIS) of the cervix. The data were taken from public and
      private sector screening laboratories reporting 25,000 and 80,000 smears,
      respectively, each year. METHODS: The study group was comprised of women with a
      biopsy diagnosis of AIS or AIS combined with a high-grade squamous
      intraepithelial lesion (HSIL) who were accessioned by the Western Australian
      Cervical Cytology Registry (WACCR) between 1993-1998. Cervical smears reported by
      the Western Australia Centre for Pathology and Medical Research (PathCentre) or
      Western Diagnostic Pathology (WDP) in the 36 months before the index biopsy was
      obtained were retrieved. A true measure of the sensitivity of detection could not
      be determined because to the authors' knowledge the exact prevalence of disease
      is unknown at present. For the current study, sensitivity was defined as the
      percentage of smears reported as demonstrating a possible or definite high-grade
      epithelial abnormality (HGEA), either glandular or squamous. Sampling error was
      defined as the percentage of smears found to have no HGEA on review.
      Screening/diagnostic error was defined as the percentage of smears in which HGEA
      was not diagnosed initially but review demonstrated possible or definite HGEA.
      Sensitivity also was calculated for a randomly selected control group of biopsy
      proven cases of Grade 3 cervical intraepithelial neoplasia (CIN 3) accessioned at
      the WACCR in 1999. RESULTS: For biopsy findings of AIS alone, the diagnostic
      "sensitivity" of a single smear was 47.6% for the PathCentre and 54.3% for WDP.
      Nearly all the abnormalities were reported as glandular. The sampling and
      screening/diagnostic errors were 47.6% and 4.8%, respectively, for the PathCentre
      and 33.3% and 12.3%, respectively, for WDP. The results from the PathCentre were
      better for AIS plus HSIL than for AIS alone, but the results from WDP were
      similar for both groups. For the CIN 3 control cases, the "sensitivity" of a
      single smear was 42.5%. CONCLUSIONS: To the authors' knowledge epidemiologic
      studies published to date have not demonstrated a benefit from screening for
      precursors of cervical adenocarcinoma. However, in the study laboratories as in
      many others, reasonable expertise in diagnosing AIS has been acquired only within
      the last 10-15 years, which may be too short a period in which to demonstrate a
      significant effect. The results of the current study provide some encouraging
      baseline data regarding the sensitivity of the Papanicolaou smear in detecting
      AIS. Further improvements in sampling and cytodiagnosis may be possible.

PMID- 12478681
TI  - ThinPrep detection of cervical and endometrial adenocarcinoma: a retrospective
      cohort study.
AB  - BACKGROUND: The current study was performed to compare the accuracy of the
      ThinPrep trade mark Papanicoloau (Pap) test with that of the conventionally
      prepared Pap smear in detecting cervical and endometrial adenocarcinomas.
      METHODS: The subject group consisted of all ThinPrep cases of atypical glandular
      cells of undetermined significance (AGCUS) or adenocarcinoma diagnosed between
      March 1998 and March 2000. Conventional smears collected between January 1996 and
      January 1998, before laboratory conversion to the ThinPrep system, comprised the
      control group. Histologic follow-up was obtained. RESULTS: One hundred eighty-six
      (0.17%) of 112,058 ThinPrep Pap tests were interpreted as AGCUS/adenocarcinomas,
      compared with 77 (0.09%) of 83,464 conventional smears (P < 0.001). The overall
      sensitivity of a ThinPrep AGCUS/adenocarcinoma smear in detecting either cervical
      or endometrial adenocarcinoma was increased (72.0% vs. 41.5%; P < 0.001). The
      ThinPrep Pap test was more sensitive in detecting endometrial adenocarcinomas
      (65.2% vs. 38.6%; P = 0.010) and there was a trend for a higher sensitivity in
      detecting cervical adenocarcinomas (87.1% vs. 55.5%; P = 0.108). CONCLUSION: The
      ThinPrep Pap test is a more sensitive method of detecting cervical and
      endometrial adenocarcinomas than the conventional Pap smear.

PMID- 12478682
TI  - Fine needle aspiration cytology of CD56-positive natural killer/T-cell lymphoma
      of soft tissue.
AB  - BACKGROUND: Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare
      form of lymphoma with a predilection for Southeast Asians, including Koreans, and
      Central and South Americans. It has a high association with Epstein-Barr virus
      (EBV) and expression of CD56 antigen. In the current study, the authors reviewed
      the fine needle aspiration (FNA) cytology of NK/T-cell lymphoma involving soft
      tissue to identify characteristic cytologic features. METHODS: Ten FNAs of soft
      tissue involvement by histologically documented NK/T-cell lymphoma from eight
      patients (three nasal primary and five extranasal primary tumors) were included
      in the retrospective study of a six-year period (1996-2002). Diff-Quik- and
      Papanicolaou-stained smears were reviewed, as was the biopsy material, including
      immunohistochemical stains and in situ hybridization studies for EBV. Clinical
      information was obtained from the patients' medical records. RESULTS: Specimen
      sources were skin and subcutaneous tissue of the neck (3), arm (3), breast (2),
      and abdominal wall (1) and soft tissue of the buccal area (1). The smears were
      moderately to highly cellular in the extensively necrotic background, with an
      abundance of apoptotic debris. Single, scattered tumor cells had pleomorphic
      nuclei, coarse chromatin, indistinct or several small nucleoli, and eccentric
      bluish cytoplasm. Neutrophils were typically rare in most cases except in one
      case complicated by abscess. CONCLUSIONS: Fine needle aspiration can be a useful
      adjunct in the diagnosis of the nasal and extranasal NK/T-cell lymphoma. The
      presence of malignant lymphoid cells in a necrotic background with an abundance
      of apoptotic bodies is a highly characteristic and consistent finding in FNA of
      NK/T-cell lymphoma involving soft tissue.

PMID- 12478683
TI  - Cytologic features of primary, recurrent, and metastatic dermatofibrosarcoma
      protuberans.
AB  - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a low-grade spindle cell
      neoplasm involving both dermis and subcutis. Its diagnosis may be difficult to
      render from cytologic smears, as it shares some features with other spindle cell
      lesions occurring in the skin and soft tissue. METHODS: Fourteen aspiration
      smears from 12 patients with primary, recurrent, or metastatic DFSP, examined by
      fine-needle aspiration biopsy (FNAB), were reviewed and compared with
      corresponding surgical specimens (13 aspirates) and clinical data (one aspirate).
      The cytologic features of DFSP were evaluated. Other spindle cell lesions in the
      differential diagnoses were discussed. RESULTS: Unequivocal spindle cell sarcoma
      diagnoses were rendered in nine aspirates, six of which were labeled correctly as
      DFSP in the original reports. In three aspirates, the preoperative diagnoses were
      inconclusive with regard to whether the tumors were benign or malignant. Two
      aspirates were diagnosed erroneously as benign spindle cell lesions. Cytologic
      features included tight clusters of bland spindle cells embedded in a
      collagenous/fibrillar and, often, metachromatic matrix along with dissociated,
      uniform, or slightly atypical spindle cells or bare nuclei. Tissue fragments
      showing a storiform pattern and entrapped fat tissue, reported in previous
      series, were less characteristic, presenting in nine and seven aspirates,
      respectively. CONCLUSIONS: Correct subtyping of DFSP in fine-needle aspiration
      smears can be difficult, due to its morphologic overlapping with other spindle
      cell lesions. A combination of cytology with ancillary studies and appropriate
      clinical information is crucial to establishing a correct diagnosis.

PMID- 12478684
TI  - Endoscopic ultrasound guided fine-needle aspiration cytology of pancreatic
      carcinoma: a 3-year experience and review of the literature.
AB  - BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB)
      of small pancreatic lesions that are undetectable by computed tomography has
      gained wide acceptance for the procurement of cells for diagnostic purposes.
      However, this technique is not without difficulty. The authors examined the
      sensitivity, specificity, and positive and negative predictive values (PPV and
      NPV, respectively) of this technique in the evaluation of patients with
      pancreatic biliary duct strictures/masses. The authors were interested in
      reviewing their cases of pancreatic adenocarcinoma of ductal type and finding the
      sources of their false-negative cases. METHODS: A computer search was performed
      between January 1998 and July 2001. For the last 3 years, a total of 80 cases of
      suspected ductal adenocarcinoma of the pancreas was identified. Thirty-four
      patients (42%) underwent a subsequent Whipple procedure or biopsy. Cytologic and
      histologic correlation was performed in these cases. The rest of the 23 patients
      (29%) considered to be positive and the 23 patients (29%) considered to be
      negative underwent no subsequent biopsy and were followed clinically. Cases
      termed "suspicious" on cytology were considered positive and those termed
      "atypical cytology" were considered negative in the authors' final calculation.
      The causes of the false-negative diagnoses were evaluated carefully. RESULTS: Of
      the 34 cases followed with subsequent tissue biopsy or surgery; 12 were confirmed
      to be positive, 12 were confirmed to be negative, and 10 were considered to be
      false-negative. Previously identified cytomorphologic features of malignancy were
      used to review all cases. These features were: loss of the honeycomb pattern
      (100%), anisonucleosis (100%), nuclear contour irregularity (100%), a high
      nuclear/cytoplasmic ratio (100%), paranuclear chromatin clearing (77%), and the
      presence of prominent nucleoli in the absence of inflammatory cells (77%). The
      causes of the 10 false-negative cases were technical difficulty of procuring
      material in 6 cases, the nature of the lesion in 2 cases, and the scarcity of
      lesional tissue in 2 cases. CONCLUSIONS: Using strict cytoarchitectural and
      cytomorphologic criteria of malignancy for ductal pancreatic lesions previously
      described in the literature, the sensitivity of this technique at the study
      institution was 78% with a specificity of 100%. The PPV and NPV of this technique
      were 100% and 78%, respectively. The most common causes of the false-negative
      results in descending order were the technical aspect of the procedure, the size
      and nature of the lesion, and the scarcity of lesional tissue.

PMID- 12478685
TI  - The clinical utility of the Das-1 monoclonal antibody in identifying
      adenocarcinoma of the colon metastatic to the liver in fine-needle aspiration
      tissue.
AB  - BACKGROUND: The cytologic diagnosis of adenocarcinoma in a liver mass usually is
      straightforward. Identifying where the adenocarcinoma arose from is much more
      problematic. The Das-1 immunostain is directed against a colon specific antigen
      and has shown excellent sensitivity and specificity for adenocarcinoma of the
      colon in surgical pathology studies. In the current study, the authors examined
      the clinical utility of the Das-1 immunostain in the setting of fine-needle
      aspiration cell block material from the liver. METHODS: The cell block material
      from 77 fine-needle aspiration biopsy specimens from the liver were studied.
      These included 17 hepatocellular carcinomas, 20 colon adenocarcinomas that were
      metastatic to the liver, and 40 other malignancies, predominantly
      adenocarcinomas, that were metastatic to the liver from a variety of primary
      tumor sites. Each case was stained with the Das-1 immunostain using the avidin
      biotin complex method and evaluated in a blinded fashion for membranous and/or
      cytoplasmic staining. The diagnoses were unblinded and correlated with staining
      and clinical history. RESULTS: Thirteen of 20 metastatic colon carcinoma samples
      exhibited immunostaining whereas only 2 of the remaining 57 samples of malignancy
      exhibited immunostaining. CONCLUSIONS: The results of the current study suggest
      that the Das-1 immunostain may prove to be helpful in identifying adenocarcinomas
      in the liver as arising from the colon.

PMID- 12478687
TI  - Yet more regulatory change--this time from Europe.

PMID- 12478686
TI  - DNA image cytometry and fluorescence in situ hybridization for noninvasive
      detection of urothelial tumors in voided urine.
AB  - BACKGROUND: Cystoscopy and histologic examination remain the standard methods for
      initial tumor diagnosis and monitoring for early detection of recurrences, since
      the sensitivity of conventional urinary cytology for the detection of urothelial
      tumors in urinary specimens is low. DNA image cytometry (ICM) and fluorescence in
      situ hybridization (FISH) have been suggested as ancillary tools. The goal of the
      current study was to compare the diagnostic value of DNA image cytometry and FISH
      for the noninvasive detection of urothelial tumors in voided urine. METHODS:
      Cytospin preparations were prepared from voided urine collected prior to the
      resection of 26 noninvasive (pTa) and 11 invasive (pT1-2) tumors. Specimens from
      14 patients with benign prostatic hyperplasia were used as negative controls. DNA
      ICM was performed using the AUTOCYTE trade mark cell analytical system on Feulgen
      stained cytospin specimens. The commercially available UroVysion trade mark FISH
      multiprobe was used to analyze chromosomes 3, 7, and 17, and 9p21. RESULTS: The
      overall sensitivity of cytology improved from 24% to 54% and to 78% if
      supplemented by ICM or FISH, respectively. Image cytometry detected all invasive
      tumors (pT1-2), while FISH missed one; FISH identified 19 of 26 (73%) pTa tumors,
      while only 9 (35%) of these tumors were aneuploid by ICM. The results of ICM and
      FISH were concordant in 37 of 51 (72%) cases. CONCLUSIONS: The current study
      shows that both FISH and ICM can successfully be used as supplementary methods to
      detect the clinically most relevant group of invasive bladder carcinomas.
      However, UroVysion FISH is more sensitive in the detection of pTa tumors than
      ICM, as it recognizes individual chromosomal alterations that frequently prevail
      in urothelial tumors.

PMID- 12478688
TI  - Midwives object to verbal HIV explanation.

PMID- 12478689
TI  - Clinical risk management study day review.
AB  - 'A Practical Guide to Clinical Risk Management in Obstetrics, Gynaecology and
      Maternity Care', was held at the Royal College of Obstetricians and
      Gynaecologists (RCOG) to highlight the necessity for clinical risk management.
      The day examined effective risk management strategies in place, the most common
      causes of risk and how these risk factors could be counteracted.

PMID- 12478690
TI  - Birth centres--a return to the natural way.

PMID- 12478691
TI  - The Midwives Act 1902: an historical landmark.
AB  - The 1902 Midwives Act had far-reaching implications for every midwife in England
      and Wales. This paper explores the legal aspects of the Act and what it meant for
      practising midwives then and now.

PMID- 12478692
TI  - The role of pilot studies in midwifery research.
AB  - This second paper in a series on research emphasises the importance of conducting
      'pilot' or 'feasibility' studies prior to embarking on more in-depth research. It
      focuses on piloting the two main data collection methods used by midwives in
      social or health research--quantitative questionnaires and qualitative
      interviews.

PMID- 12478693
TI  - Skincare for the newborn: exploring the potential harm of manufactured products.
AB  - Many midwives routinely bath newborns using baby bath products believing these
      products are mild and suitable for delicate skins. This paper asks midwives to
      reconsider their role in the promotion of manufactured skincare products.

PMID- 12478694
TI  - Midwife-led care: local, national and international perspectives.

PMID- 12478696
TI  - Home truths.

PMID- 12478697
TI  - Stillbirths and depression.

PMID- 12478695
TI  - Midwifery research: the past, present and future.
AB  - This paper examines midwifery research in light of the Research Assessment
      Exercise and explores the research undertaken in the UK during the last ten
      years. It compares midwifery and general practice research, as well as a
      transatlantic comparison as to the research output in the UK and US. It also
      presents an assessment of the impact of midwifery research.

PMID- 12478698
TI  - Planning for success.

PMID- 12478699
TI  - The expectation and reality of bank and agency nursing.
AB  - We should all accept that temporary workers are here to stay and we should:
      Ensure that banks and agencies have thorough selection and pre-employment
      checking strategies, including professional registration and induction provision.
      Check what it costs to employ a particular nurse. A staffing agency will be
      highly profitable on a 10 per cent commission but may be charging much more. It
      may be cheaper to employ in-house staff on overtime. Accept that supply may not
      match demand and that this is not the fault of the nurses. Ensure nurses who take
      work outside their usual areas of expertise remember to tell other staff that
      they may need extra support when they arrive on duty. Ensure temporary staff are
      orientated to the clinical areas and are offered support by their colleagues. If
      and when things go wrong discuss them with clinical areas, as well as banks and
      agencies. It is vital that temporary staff are managed and patterns of
      unacceptable performance are monitored and acted upon. The growth in temporary
      working makes matching an increasingly difficult task and puts new challenges on
      monitoring performance. The effective bank or agency will offer education and
      appraisal and will have specific policies to ensure clinical governance. Not long
      ago that there were too few shifts to offer bank nurses. How things change--and
      how important it is for a service manager to ensure that temporary staff
      represent value for money and have professional integrity, and that staff realise
      that they are well supported. After all, they will be a value component of the
      workforce.

PMID- 12478700
TI  - Second sight.

PMID- 12478701
TI  - Milestones in stroke management.

PMID- 12478702
TI  - Evolution of leadership in nursing.

PMID- 12478703
TI  - Safeguarding children from fabricated or induced illness.

PMID- 12478704
TI  - Managing quality in services.
AB  - Much attention has been given to quality in recent years. But why is quality
      important, particularly in health and social care? This two-part series draws on
      material developed by Professor Euan Henderson for one of the courses offered by
      the Open University's School of Health and Social Welfare. This first article
      examines why quality is important to patients, their carers and staff.

PMID- 12478706
TI  - In the loop.

PMID- 12478707
TI  - Modern matrons. Take me to your leader.

PMID- 12478708
TI  - Data briefing. Welfare food scheme.

PMID- 12478710
TI  - Pharmaceutical industry guide. Soft sell.

PMID- 12478709
TI  - Pharmaceutical industry guide. Bitter pills.

PMID- 12478711
TI  - Pharmaceutical industry guide. The chosen few.

PMID- 12478712
TI  - Pharmaceutical industry guide. Strange bedfellows?

PMID- 12478713
TI  - Pharmaceutical industry guide. It all ads up.

PMID- 12478714
TI  - Web alert. The chemistry of process development.

PMID- 12478715
TI  - Scalable enantioselective processes for chiral pharmaceutical intermediates.
AB  - The importance and practicality of asymmetric synthesis to obtain
      enantiomerically pure drug substances has been fully recognized by process
      chemists of the pharmaceutical industry. Catalytic enantioselective processes
      would be particularly advantageous, compared to processes requiring
      stoichiometric amounts of chiral initiators, and would also be of interest from
      an environmental perspective. Since the commercialization of the Monsanto process
      for the manufacturing of L-DOPA in the early 1970s, catalytic asymmetric
      reactions have often been utilized in the commercial production of active
      pharmaceutical ingredients. This review will focus on recent advances in the
      development of scalable enantioselective processes for chiral pharmaceutical
      intermediates.

PMID- 12478716
TI  - Development of an atropselective methodology for axially chiral biaryls in the
      asymmetric synthesis of A-240610.0.
AB  - A-240610.0 is a novel non-steroidal glucocorticoid receptor-selective ligand. It
      has demonstrated an anti-inflammatory activity equivalent to that of the
      synthetic glucocorticoids, and has shown an improved side-effects profile in
      vivo. This review will present the process research and development proceeding
      from the initial racemic route to an efficient asymmetric process. This process
      relied on the development of a novel atropselective synthesis of an axially
      chiral biaryl to form the critical atropisomer intermediate in good yields (85%)
      and with high diastereoselectivity (99:1).

PMID- 12478717
TI  - Catalytic enantioselective oxidations using molecular oxygen.
AB  - The use of molecular oxygen as an atom-efficient, environmentally benign and
      inexpensive oxidant has increasingly gained consideration in catalysis. This
      review will specifically highlight catalytic enantioselective oxidations that
      utilize molecular oxygen as a terminal oxidant. The topics covered herein include
      aerobic enantioselective variants of alcohol oxidation, Baeyer-Villiger
      oxidation, dihydroxylation, epoxidation, oxidative biaryl coupling and
      sulfoxidation.

PMID- 12478718
TI  - Synthetic applications of chiral 2,3-dihydro-4-pyridones.
AB  - During the last decade, 2,3-dihydro-4-pyridones have become important
      intermediates for the synthesis of various alkaloids and biologically active
      compounds. The versatility of these heterocyclic building blocks has been
      demonstrated by the synthesis of several complex natural products. This review
      will cover recent work on the synthesis of substituted dihydropyridones, and
      their application in the synthesis of complex molecules.

PMID- 12478719
TI  - New methodology for the asymmetric reduction of ketones.
AB  - This review highlights recent reports, between 2000 and early 2002, of new
      methodologies for the asymmetric reduction of ketones, leading to the formation
      of alcohols. Since ketone reduction is a pivotal reaction in organic chemistry,
      and since its enantioselective variant constitutes an increasing fraction of this
      widely reported reaction, we have been highly selective in the choice of
      material. Emphasis will be placed on the application of asymmetric reduction of
      ketones to drug synthesis, on unusually novel applications and on new classes of
      reagents for these applications, the majority of which involve catalytic
      processes. The rapid rise of asymmetric transfer hydrogenation to prominence in
      recent years will be reflected by a high level of coverage in this review, while
      other more established methods (oxazaborolidines, hydrogenation) will also be
      featured.

PMID- 12478720
TI  - Asymmetric hydrogenation and other methods for the synthesis of unnatural amino
      acids and derivatives.
AB  - New methods to unnatural amino acids continue to be developed. This review covers
      methods, published in 2001, that employ an asymmetric hydrogenation, a transition
      metal-catalyzed reaction, an enzymatic resolution or a chiral auxiliary.

PMID- 12478721
TI  - Selective functionalization of small organic molecules using electrophilic
      nitrogen sources.
AB  - Selective functionalization of small organic molecules using electrophilic
      nitrogen-containing reagents has been a long-standing challenge in organic
      synthesis. The delivery of nitrogen in the corresponding reactions can occur via
      a nitrenoid, radical or electrophilic pathway. Nitrogen transfer processes result
      in the rapid synthesis of diverse and useful products, such as aziridines,
      aminohalides, aminoalcohols, sulfimines and amines. This review outlines advances
      in the field during the past two years.

PMID- 12478722
TI  - Aziridines and aziridinium ions in the practical synthesis of pharmaceutical
      intermediates--a perspective.
AB  - Recent methods for the synthesis of aziridines and aziridinium ions, the
      mechanisms of their nucleophilic ring-opening reactions and applications to the
      practical synthesis of pharmaceutical intermediates are reviewed.

PMID- 12478724
TI  - Heavy-metal complexation by de novo peptide design.
AB  - From poisoning caused by lead-based paint on domestic buildings to groundwater
      contamination by naturally occurring arsenic deposits in India, heavy-metal
      toxicity is a global health problem. Contaminated ground water and acute cases of
      heavy-metal poisoning are treated with chelators to remove the heavy metals from
      the contaminated site or person. This review discusses the effort to generate
      heavy-metal chelators through peptide de novo design. De novo design entails the
      design of a primary sequence that will precisely fold into a predetermined
      secondary and tertiary protein structure. The first-generation peptide chelator
      used to initiate this investigation is the three-stranded coild coil containing
      Cys. Cys provides a potential trigonal binding site with soft thiolate ligands,
      which has been proposed to provide specific interactions with heavy metals. This
      hypothesis derives from the observation that similar sites on natural proteins
      show selectivity for heavy metals over other essential metals, such as Zn or Mg.
      A description of two systems, the TRI series and the IZ-AC peptide, is given,
      highlighting the interaction of these peptides with Hg, Cd, As and Pb. Arguments
      are also presented for the potential use of three-helix bundles as a second
      generation design.

PMID- 12478723
TI  - Stereoselective transition metal-catalyzed and radical polycyclizations.
AB  - This short review presents a selection of metal-mediated and radical
      polycyclizations reported during the past two years. Palladium-catalyzed domino
      processes, cobalt-mediated cycloadditions and Pauson-Khand reactions catalyzed by
      rhodium are described. Ruthenium and platinum are shown as powerful metal
      catalysts in cyclizations, ring-closing metathesis and cycloisomerizations.
      Finally, recent examples of radical cascades, and their synthetic applications,
      are selected for their ability to build polycyclic compounds.

PMID- 12478725
TI  - Synthetic approaches to the microtubule stabilizing agent (-)-laulimalide.
AB  - In the past few years, the microtubule stabilizing agent (-)-laulimalide has
      attracted considerable attention, as it could constitute a potential treatment
      for cancer. Several total syntheses of (-)-laulimalide have now been reported.
      This review summarizes available biological data and synthetic approaches to (-)
      laulimalide, reported prior to July 2002.

PMID- 12478726
TI  - Scale-up of polymerization processes.
AB  - Scale-up and/or scale-down procedures are crucial during the development of
      chemical processes. These procedures should be integrated to form a
      multidisciplinary approach encompassing several branches of science and
      engineering. The challenge is to find a balance between chemistry, design,
      environment, hygiene and safety (EHS) compliance and economic factors. The
      iterative process of scale-up procedures also requires concept discrimination at
      early stages of process development. Scale-up studies should predict the reactor
      behavior and the quality and properties of a product from laboratory and pilot
      plant to full scale; however, not every pilot scale presents a valid industrial
      scaled-down size. A rational mathematical model describing the process reasonably
      well for large scale is important for designing industrial processing units, but
      this is only feasible if a phenomenological understanding is achieved, and if the
      necessary constants and parameters are estimated accurately. An accomplished
      process development procedure must lead to products presenting the same
      properties at both small and large scale.

PMID- 12478727
TI  - Heterogeneously functionalized dendrimers.
AB  - Significant timely advances have been made in the synthesis of heterogeneously
      functionalized dendrimers. Convergent, divergent and other functionalization
      techniques have been used to create a variety of complex dendrimer motifs with
      more than one type of surface group. Synthetic advances, as well as pertinent
      applications of heterogeneously functionalized dendrimers, are reviewed.

PMID- 12478729
TI  - Recent developments in the construction of trans-fused polycyclic ethers.
AB  - The development of new synthetic methodology for the construction of trans-fused
      polycyclic ethers has stimulated significant attention since the late 1980s. This
      review provides an update on work reported between 2000 and 2002, emphasizing the
      development of iterative, convergent and cascade/two-directional cyclization
      strategies that provide direct and efficient approaches for the assembly of these
      complex structures. Recent developments in synthetic methodology have provided
      the tools necessary to accomplish the first total syntheses of ciguatoxin CTX3C
      and gambierol. Nonetheless, significant improvements in selectivity and
      versatility are clearly necessary for progress to be made in the construction of
      this class of molecules.

PMID- 12478728
TI  - Selective RXR modulators for the treatment of type II diabetes.
AB  - Retinoid X receptor (RXR) modulators are being evaluated as a means for the
      treatment of non-insulin dependent (type II) diabetes mellitus, and substantial
      progress has been made in the preclinical evaluation of these compounds. To aid
      in this process, several structural classes of RXR modulators are now under
      investigation. The diverse structures and syntheses of these compounds will be
      discussed in this review.

PMID- 12478730
TI  - Innovative oxidation methods in fine chemicals synthesis.
AB  - Oxidation reactions are key steps of the synthetic pathway of chemicals, from the
      source, crude oil, to the ever more complicated products of the fine chemicals
      industry. Catalytic processes appear to be best suited to accommodate the new
      conditions of fine chemicals synthesis, i.e., short development time, increasing
      concerns about waste streams and economic pressure to use raw materials. Among
      various developments in oxidation chemistry, fine-tuning the reactivity of common
      oxidants, expanding the application of 'new' oxidants, new transformations by
      combination of known reagents, innovative application of oxidation reactions in
      multi-step synthesis, the use of new reaction media and new developments in bio
      oxidations constitute the main research areas. This review could be defined as a
      'spotlight' approach, pointing to significant findings in these different areas
      rather than giving an overview, and focusing on findings that show where progress
      could be made.

PMID- 12478731
TI  - Developing tools and standards in molecular informatics. Interview by Susan
      Aldridge.

PMID- 12478732
TI  - Routes to fluorinated organic derivatives by nickel mediated C-F activation of
      heteroaromatics.
AB  - New fluorinated azaheterocycles can be synthesised regio- and chemo-selectively
      via C-F activation of fluorinated precursors at nickel, with subsequent
      functionalisation and release from the coordination sphere of the metal; the
      requirements for productive C-F activation are significantly different from those
      for C-H bond activation.

PMID- 12478733
TI  - Application of hitherto unexplored macrocyclization strategies in the epothilone
      series: novel epothilone analogs by total synthesis.
AB  - A total synthesis of Epothilone 490 and a synthesis of 11-hydroxy dEpoB utilizing
      a vinyl-boronate cross-metathesis followed by a Suzuki macrocyclization. A mild
      route to reach aldehydes from terminal olefins, anticipating Nozaki-Kishi
      macrocyclization is described.

PMID- 12478734
TI  - Combinatorial parallel synthesis and automated screening of a novel class of
      liquid crystalline materials.
AB  - Combinatorial parallel synthesis has led to the rapid generation of a single
      compound library of novel fluorinated quaterphenyls. Subsequent automated
      screening revealed liquid crystalline (LC) behaviour and gave qualitative
      relationships of molecular structures and solid state properties.

PMID- 12478735
TI  - Uranium complexes supported by an aryloxide functionalised triazacyclononane
      macrocycle: synthesis and characterisation of a six-coordinate U(III) species and
      insights into its reactivity.
AB  - A reactive low-valent uranium(III) complex supported by an aryloxide
      functionalised triazacyclononane has been synthesised and provides a platform for
      enhanced uranium reactivity.

PMID- 12478736
TI  - Encapsulation of molecular Na2SiF6 by two metallacrown complexes.
AB  - A complex of molecular Na2SiF6, stabilised by two 12-metallacrown-3 host
      complexes, has been synthesised and characterised by single crystal X-ray
      diffraction.

PMID- 12478737
TI  - The first liquid crystalline dimers consisting of two banana-shaped mesogenic
      units: a new way for switching between ferroelectricity and antiferroelectricity
      with bent-core molecules.
AB  - Depending on the number of dimethylsiloxane units in the spacer connecting two
      banana-shaped molecules either ferroelectric or antiferroelectric switchable
      polar smectic C phases have been obtained.

PMID- 12478738
TI  - Insights into the Schrock 'chop-chop' reaction gained from density functional
      theory and preparation and structure of W2(mu-PhCCPh)(SC6H4-2-Me)6.
AB  - Computations employing density functional theory on the reactions between ethyne
      and the model compounds (HE)3M identical to M(EH)3, where M = Mo and W and E = O
      and S, predict that the alkyne adducts M2(mu-C2H2)(EH)6 are thermodynamically
      favored with respect to the metathesis products HC identical to M(EH)3 except
      when M = W and E = O; the reaction between (tBuO)3 W identical to CPh and 2
      MeC6H4SH (> 3 equiv.) yields W2(mu-PhCCPh)(SC6H4-2-Me)6 consistent with
      expectations based on the calculations.

PMID- 12478739
TI  - A new bis(imidazolyl)(alkylthiolate) tripodal ligand and the spontaneous
      formation of a disulfide-linked, hydroxo-bridged dinuclear zinc complex.
AB  - The new sterically encumbered, tripodal N2S(alkylthiolate) ligand, LIm2SH, has
      been synthesized and used to prepare [(LIm2S)ZnCH3], which upon protonolysis
      under acidic conditions leads to the synthesis of a novel dinucleating ligand and
      a zinc dimer with an unusual structure.

PMID- 12478740
TI  - Reversible zinc phthalocyanine fullerene ensembles.
AB  - Novel zinc phthalocyanine (ZnPc)/fullerene ligand (L) ensembles are assembled
      following simple biomimetic principles, which upon photoexcitation give rise to
      intra complex electron transfer quenching of the 1*ZnPc fluorescence.

PMID- 12478741
TI  - Synthesis of low polydispersity, controlled-structure sugar methacrylate polymers
      under mild conditions without protecting group chemistry.
AB  - We report the synthesis of low polydispersity, controlled-structure sugar
      methacrylate polymers by the ring-opening reaction of 2-aminoethyl methacrylate
      with D-gluconolactone, followed by the atom transfer radical polymerisation of
      the resulting sugar methacrylate in methanol at 20 degrees C.

PMID- 12478742
TI  - Bis(rylenedicarboximide)-a,d-1,5-diaminoanthraquinones as unique infrared
      absorbing dyes.
AB  - A hitherto unknown class of dyestuff compounds exhibiting three key
      characteristics, namely absorption in the near infrared (NIR) region, high
      photostability and good processability, is described.

PMID- 12478743
TI  - Phthalocyanine-based nanoporous network polymers.
AB  - Network polymers exhibiting large surfaces areas (450-950 m2 g-1) are prepared by
      the phthalocyanine-forming reaction of a bis(phthalonitrile) monomer containing a
      rigid spirocyclic linking group.

PMID- 12478744
TI  - Porphyrin-based nanoporous network polymers.
AB  - Network polymers exhibiting large surfaces areas (900-1000 m2g-1) are prepared by
      the highly efficient dibenzodioxane forming reaction between meso
      tetrakis(pentafluorophenyl)porphyrin and a rigid bis(catechol) monomer.

PMID- 12478745
TI  - The effect of mechanistic pathway on activity in the Pd and Pt catalysed
      methoxycarbonylation of ethene.
AB  - All the intermediates involved in the platinum catalysed methoxycarbonylation of
      ethene have been characterised by in situ NMR; the low activity of platinum
      catalysts in this reaction is shown to be due to trapping of the active
      intermediates by carbon monoxide at every step in the catalytic cycle and to the
      ready reversibility of the product forming reactions.

PMID- 12478746
TI  - p-Hydroquinone-metal compounds: synthesis and crystal structure of two novel VV-p
      hydroquinonate and VIV-p-semiquinonate species.
AB  - Reaction of the p-hydroquinone derivative H2Na4bicah.4H2O with either
      VIVOSO(4).3H2O and NaVVO3 in equivalent quantities or with NaVVo3 yields the
      tetranuclear VIVO2+ macrocycle-semiquinonate compound Na6[(VIVO)4-(mu2-O)2[mu2
      bicas.(-5)-N,O,O,O]2].Na2SO(4).20H2O (1.Na2SO(4).20H2O) and the dinuclear cis
      VVO2(+)-hydroquinone species Na4[(VVO2)2[mu2-bicah(-6)-N,O,O,O]].11H2O (2.11H2O)
      respectively. Compounds 1.Na2SO(4).20H2O and 2.11H2O were characterized by X-ray
      structure analysis and ab initio calculations.

PMID- 12478747
TI  - Shape fabrication of millimeter-sized metal-containing carboxymethyl cellulose
      hollow capsules.
AB  - Dropwise addition of an aqueous carboxymethyl cellulose solution to a solution of
      a copper or iron salt in n-butanol, leads to self-assembled, permeable millimeter
      sized metal-ion derivatized carboxymethyl cellulose hollow capsules of uniform
      dimensions and different morphologies.

PMID- 12478748
TI  - The origin of electrochemical activity in Li2MnO3.
AB  - The electrochemical activity of Li2MnO3 in non-aqueous media has been
      investigated and found to involve neither Mn(4+)-Mn5+ oxidation nor simultaneous
      O2- removal but exchange of Li+ by H+, the latter being generated in the
      electrolyte.

PMID- 12478749
TI  - Supramolecular fixation of NO2 with calix[4]arenes.
AB  - Reaction of NO2 with simple calix[4]arenes in chloroform in the presence of a
      Lewis acid rapidly results in intense coloration caused by the encapsulation of
      nitrosonium cation.

PMID- 12478750
TI  - Variable coordination chemistry of the phospha(III)guanidinate anion; application
      as a metal-functionalised phosphine ligand.
AB  - Structural investigation of Li-complexes of the phospha(III)guanidinate anion
      [Ph2PC[NiPr]2]- revealed variable coordination to lithium; synthesis of the
      dimethyl aluminium compound, (Ph2PC[NiPr]2)AlMe2, which behaves as a metal
      functionalised phosphine ligand towards platinum, is reported.

PMID- 12478751
TI  - Titanium and zirconium complexes supported by dipyrrolide ligands.
AB  - The reactions between meso-disubstituted dipyrromethanes and titanium and
      zirconium amides and alkyls have generated the first examples of dipyrrolide
      complexes of Group 4 metals.

PMID- 12478752
TI  - Electrocatalytic carboxylation of benzyl chlorides at silver cathodes in
      acetonitrile.
AB  - Silver exhibits powerful electrocatalytic activities towards the reductive
      carboxylation of benzyl chlorides (RCl): in CO2-saturated CH3CN, reduction of RCl
      occurs at potentials that are about 0.6 V more positive than those of the same
      process at Hg or carbon electrodes and gives carboxylic acids in good to
      excellent yields.

PMID- 12478753
TI  - A novel strategy for synthesis of multiblock copolymers.
AB  - Multi-block copolymers with well-controlled numbers of blocks and block chain
      length are synthesized for the first time using a 'polyinitiator'.

PMID- 12478754
TI  - Vinyl-lambda 3-iodanes act as efficient sulfur atom acceptors: vinylic SN2-based
      strategy for conversion of tertiary thioamides to amides.
AB  - Exposure of tertiary thioamides to (E)-1-hexenyl(phenyl)-lambda 3-iodane results
      in vinylic SN2 reaction to give the inverted (Z)-S-vinylthioimidonium salts,
      which under alkaline hydrolysis (Na2CO3 or K2CO3) selectively afford amides,
      while (Z)-S-vinyl thioesters are obtained in high yields via the hydrolysis under
      acidic conditions (HCl).

PMID- 12478755
TI  - Single-crystalline photochromism of diarylethenes: reactivity-structure
      relationship.
AB  - Photochromic reactivity of diarylethenes in the single-crystalline phase was
      found to be controlled by the distance between the reactive carbon atoms in the
      antiparallel conformation.

PMID- 12478756
TI  - Synthesis of crystalline boron nanowires by laser ablation.
AB  - Crystalline boron nanowires with tetragonal structure have been synthesized based
      on laser ablation of a B/NiCo target; the nanowires are sometimes single crystals
      and have a droplet at one end of the nanowire; the droplet contains B, Ni and Co
      elements, which indicates that the vapor-liquid-solid (VLS) mechanism may play a
      key role in the growth of the boron nanowires.

PMID- 12478757
TI  - 17O MQMAS NMR studies of Na-A and Ca-A.
AB  - We report, for the first time, 17O MQMAS and 17O/23Na double resonance NMR
      studies on calcium-exchanged zeolite sodium-A; the results show that the
      isotropic shifts of the framework sites are strongly affected by factors
      including the hydration level and nature of the charge-balancing cations.

PMID- 12478758
TI  - First synthesis and characterization of isolable thioselenenic acid, triptycene-9
      thioselenenic acid.
AB  - Triptycene-9-thioselenenic acid was synthesized by hydrolysis of acetyl
      triptycene-9-thioselenenate, the structure of which was determined by
      spectroscopic data and X-ray diffraction analysis.

PMID- 12478759
TI  - A fully extended tetrapeptide consisting of natural amino acids.
AB  - FGFG is the first example of a non-protected peptide consisting of natural amino
      acids that adopt a fully extended conformation in the crystalline state.

PMID- 12478760
TI  - Synthesis of silver nanoparticles via electrochemical reduction on compact
      zeolite film modified electrodes.
AB  - Monodisperse silver nanoparticles with different sizes were synthesized by
      electrochemical reduction inside or outside zeolite crystals according to the
      silver exchange degree of compact zeolite film modified electrodes.

PMID- 12478761
TI  - Comprehensive study combining surface science and real catalyst for NO direct
      decomposition.
AB  - The catalytic activity of Pd/Al2O3 prepared from various palladium precursors for
      direct NO decomposition is closely related to the fraction of surface step sites
      capable of dissociating NO, on the basis of a surface science study using single
      crystal model catalyst.

PMID- 12478762
TI  - A proton induced conformational change in metal complexes with potential hydrogen
      bonding triplet motifs.
AB  - Biguanide-like bidentate ligands in a variety of transition metal complexes of
      different geometries exhibit conformational changes upon
      protonation/deprotonation that alter their capacity to recognise complementary
      hydrogen bonding motifs.

PMID- 12478763
TI  - Heterometallic CeIII-FeIII-salicylate networks: models for corrosion mitigation
      of steel surfaces by the 'green' inhibitor, Ce(salicylate)3.
AB  - The syntheses and structures of the novel Ce-Fe bimetallic complexes
      [[Fe(sal)2(bpy)]2Ce(NO3)(H2O)3].EtOH and
      [[Fe(sal)2(bpy)]4Ce2(H2O)11][salH]2.EtOH.3H2O (salH2 = salicylic acid) suggest
      Fe(3+)-sal2- units and Ce-OC(R)O-Fe bridging contribute to the formation of
      corrosion inhibitive layers on steel surfaces exposed to [Ce(salH)3(H2O)].

PMID- 12478764
TI  - Preparation and functionalisation of emulsion-derived microcellular polymeric
      foams (polyHIPEs) by ring-opening metathesis polymerisation (ROMP).
AB  - Emulsion-derived microcellular polymeric foams (poly-HIPEs) have been prepared by
      ring opening metathesis polymerisation of a norbornene derivative using a Grubb's
      catalyst. The resulting material has been further functionalised using the active
      catalytic sites remaining on its structure.

PMID- 12478765
TI  - Bidirectional iterative synthesis of alternating benzene-furan oligomers towards
      molecular wires.
AB  - Reaction of propargylic dithioacetal 2a with BuLi gives the sulfur-substituted
      allenyllithium 3a which is allowed to react with a dialdehyde to yield the
      corresponding alternating benzene-furan oligoaryls 6. Functional group
      transformation converts the ester groups in 6 to dialdehyde 8 which can be used
      for the synthesis of higher homologues towards molecular wires. A combination of
      this furan annulation, Heck reaction and Sonogashira coupling leads to a variety
      of benzene-furan-alkene/alkyne conjugated oligomers of precise length.

PMID- 12478766
TI  - Large-scale synthesis and structure of boron nitride sub-micron spherical
      particles.
AB  - A novel method, combining chemical vapor deposition and pyrolysis of
      trimethoxyborane under ammonia atmosphere, has been developed to synthesize
      spherical boron nitride particles with a uniform diameter distribution from 50 to
      400 nm; chemical composition and high-resolution transmission electron microscopy
      analyses indicate that the sub-micron boron nitride particles exhibit a slightly
      distorted arrangement of the shell layers.

PMID- 12478767
TI  - From hydrocarbons to polyols. Cyclooctatetraene to novel cyclooctitols.
AB  - Cyclooctatetraene (COT) derived bicyclo[4.2.1]nona-2,4,7-trien-9-one has been
      recognized as a cyclooctane carbasugar equivalent and elaborated to a range of
      cyclooctane polyols (cyclooctitols) through a flexible strategy with moderate
      regio- and stereo-control.

PMID- 12478768
TI  - Thin layer cyclic voltammetry: an efficient tool to determine the redox
      characteristics of large dendrimers.
AB  - Dendrimers with an electroactive bis(phenanthroline) copper(I) core have been
      prepared and thin layer cyclic voltammetry (TLCV) found to be an efficient tool
      to determine their redox characteristics in spite of the slow electron transfer
      kinetics observed for the largest compounds.

PMID- 12478769
TI  - Highly efficient VOx/SBA-15 mesoporous catalysts for oxidative dehydrogenation of
      propane.
AB  - Highly dispersed vanadia species on SBA-15 mesoporous silica have been found to
      exhibit a highly efficient catalytic performance for the oxidative
      dehydrogenation (ODH) of propane to light olefins (propene + ethylene).

PMID- 12478770
TI  - Towards a molecular model for bismuth(III) subsalicylate. Synthesis and solid
      state structure of [Bi(Hsal)3(bipy)(C7H8]2 and [Bi(Hsal)(sal)(1,10
      phenanthroline)(C7H8]2.
AB  - The synthesis and characterization of the first bismuth salicylate complexes,
      stabilized by chelating amine ligands, offers the possibility for detailed
      investigation of molecular precursors of the biologically significant compound
      bismuth subsalicylate (BSS).

PMID- 12478771
TI  - NMR characterisation of unstable solvent and dihydride complexes generated at low
      temperature by in-situ UV irradiation.
AB  - Low temperature in-situ UV irradiation of toluene solutions containing
      bis(alkene)rhodium complexes and parahydrogen in conjunction with NMR monitoring
      enables the characterisation of unstable eta 2-solvent complexes and dihydrogen
      activation products.

PMID- 12478772
TI  - A dynamic (reversible) covalent polymer: radical crossover behaviour of TEMPO
      containing poly(alkoxyamine ester)s.
AB  - A dynamic covalent polymer incorporating thermally alkoxyamine units in the main
      chain was synthesized. Due to a radical crossover reaction between the
      alkoxyamine units, an interchange of the main chains in poly(alkoxyamine ester)
      was observed on heating.

PMID- 12478773
TI  - Photoactive chemosensors 3: a unique case of fluorescence enhancement with
      Cu(II).
AB  - Chemosensor (4a) shows fluorescence enhancement with Cu(II) and can estimate 1
      300 microM Cu(II) by using fluorescence (1-20 MicroM) and UV-Vis (10-300 microM)
      spectroscopic techniques. Ni(II), Cd(II), Zn(II), Ag(I) and Hg(II) do not
      interfere in fluorescence studies and only Ag(I) and Hg(II) interfere in UV-Vis
      studies.

PMID- 12478774
TI  - Synthesis of ordered mesoporous carbon monoliths with bicontinuous cubic pore
      structure of Ia3d symmetry.
AB  - Large-diameter-sized mesoporous carbon monoliths with bicontinuous cubic
      structure of Ia3d symmetry have been synthesized by using mesoporous silica
      monoliths as hard templates; such carbon monoliths show potential application of
      advanced electrodes and electrochemical double layer capacitors.

PMID- 12478775
TI  - Preparation of CdSe nanocrystals in a micro-flow-reactor.
AB  - A micro-reactor was utilized for continuous and controlled CdSe nanocrystal
      preparation. Effects of reaction conditions on optical properties of the
      nanocrystals were investigated; in this current system, rapid and exact
      temperature control of the micro-reactor was beneficial for controlling particle
      diameter and reproducible preparation of particles; additional effort was made
      towards narrower particle-size distributions.

PMID- 12478776
TI  - Novel resorcinarene-based pH-triggered gelator.
AB  - Iminodiacetate resorc[4]arene is shown to produce gels that are pH-reversible.
      The gels formed are clear and stable to inversion. (The gels are not stable above
      a certain temperature, which varies with concentration.) When the pH of an
      iminodiacetate resorc[4]arene solution (concentration > 7.6 mM) is lowered to
      below 2.5, which is near one of the Ka values of the molecule, the dissolved
      molecules aggregate and cause gelation of water. 1H NMR showed that at the pH of
      gelation a change occurs in the chemical environment of the iminodiacetate group.
      Scanning electron microscopy showed that the gel is composed of long strands that
      interweave and create a molecular mesh.

PMID- 12478777
TI  - Generation of a co-crystal phase with novel coloristic properties via solid state
      grinding procedures.
AB  - Co-grinding of crystals of racemic-bis-beta-naphthol (rac-BN) and benzoquinone
      (BQ) produces a novel crystal adduct through crystal sheering and molecular
      diffusion processes in the solid state, which is structurally distinct from
      adducts obtained from solution or melt.

PMID- 12478778
TI  - Unprecedented solvent-induced acceleration of free-radical propagation of methyl
      methacrylate in ionic liquids.
AB  - The rate of propagation in the free-radical polymerization of methyl methacrylate
      in an ionic liquid has been determined and shows unprecedented solvent-induced
      acceleration, partially explaining the surprising increase in overall rates of
      polymerization and molecular weights in these solvents.

PMID- 12478779
TI  - The first cobalt catalyzed [2 + 2 + 2] alkyne cyclotrimerization in aqueous
      medium at room temperature.
AB  - Chelate complex 1 (5 mol%) was found to catalyze the [2 + 2 + 2] cyclization of
      terminal alkynes in good yields in a 80/20 mixture of water and ethanol at room
      temperature without further activation.

PMID- 12478780
TI  - Drying induced phase transformation of mesoporous silica.
AB  - Solvent evaporation upon drying the precipitate was found to be the key factor
      for the phase transformation of cubic mesoporous silica SBA-1 to hexagonal SBA-3
      studied by in-situ X-ray diffraction and 29Si solid state NMR on the precipitates
      formed various crystallisation conditions.

PMID- 12478781
TI  - Photocurrent amplification by an energy/electron transfer cascade in polymer
      Langmuir-Blodgett films.
AB  - Effective photocurrent generation by visible light irradiation on hetero
      deposited polymer Langmuir-Blodgett (LB) films containing tris(bipyridine)
      ruthenium(II) (Ru(bpy)3(2+)) and anthracene derivatives was observed. The
      photocurrent amplification was found to be assisted by the photoinduced
      energy/electron transfer cascade, which consists of the interlayer triplet
      triplet energy transfer process from photoexcited Ru(bpy)3(2+) to anthracene, and
      then electron transfer processes from the triplet anthracene to a viologen
      acceptor, from Ru(bpy)3(2+) to the oxidized anthracene and from the electrode to
      Ru(bpy)3(3+).

PMID- 12478782
TI  - Porous nanocomposites of zirconium dioxide and silicate.
AB  - Highly porous nanocomposites of zirconium dioxide and silicate are synthesised in
      an aqueous system from an inorganic salt of zirconium; the nanacomposites, with
      tailorable pore structures, exhibit superior performance as catalyst supports.

PMID- 12478783
TI  - Biosynthesis of aminoglycoside antibiotics: cloning, expression and
      characterisation of an aminotransferase involved in the pathway to 2
      deoxystreptamine.
AB  - The gene btrR from Bacillus circulans has been cloned and expressed and shown to
      produce a protein which catalyses the transamination of 2-deoxy-scyllo-inosose to
      give 2-deoxy-scyllo-inosamine, an intermediate in the biosynthesis of 2
      deoxystreptamine.

PMID- 12478784
TI  - Polyethene with pendant 3-thienyl functionalities.
AB  - Polyethene with 3-thienyl functionalities pendant on short-chain branches was
      prepared by catalytic random copolymerisation of ethene and 3-(penten-1
      yl)thiophene; the functionalities can be used to graft poly(3-hexylthiophene)
      onto the polyethene surface.

PMID- 12478785
TI  - Cationic beta-cyclodextrin bilayer vesicles.
AB  - Cationic amphiphilic beta-cyclodextrins, substituted with hydrophobic n-alkylthio
      chains at the primary hydroxyl side and hydrophilic omega-amino-oligo(ethylene
      glycol) units at the secondary side, form bilayer vesicles with a diameter of 30
      35 nm (when alkyl = hexadecyl) or nanoparticles with a diameter of ca. 120 nm
      (when alkyl = hexyl) in water.

PMID- 12478786
TI  - Enhanced optical sensing of anions with amide-functionalized gold nanoparticles.
AB  - A gold nanoparticle surface-modified with amide ligands shows enhanced optical
      sensing of anions: the detection limit is increased by about three orders of
      magnitude higher than that originally expected from the anion binding ability of
      neutral amide ligands.

PMID- 12478787
TI  - Ruthenium-catalyzed carbonylation of allene: direct synthesis of methacrylates
      and methacrylamides.
AB  - Carbonylation reactions of allene in alcohols and amines in the presence of a
      ruthenium carbonyl catalyst under mild conditions gave methacrylates and
      methacrylamides, respectively, in good yields with an atom economy of 100%.

PMID- 12478788
TI  - Efficient methane/nitrogen separation with low-sodium clinoptilolite.
AB  - The presence of sodium is shown to have a highly detrimental effect on the gas
      separation ability of clinoptilolite towards methane and nitrogen.

PMID- 12478789
TI  - [Cu(I)(bpp)]BF4: the first extended coordination network prepared solvothermally
      in an ionic liquid solvent.
AB  - Use of an ionic liquid [bmim][BF4] (bmim = 1-butyl-3-methylimidazolium) as
      solvent has resulted in the first extended coordination structure, the two
      dimensional network [Cu(bpp)]BF4 [bpp = 1,3-bis(4-pyridyl)propane], produced via
      a solvothermal route.

PMID- 12478790
TI  - Syntheses and spectroscopic studies of spirobifluorene-bridged bipolar systems;
      photoinduced electron transfer reactions.
AB  - Some 9,9'-spirobifluorene-bridged bipolar systems 1-3 containing 1,3,4-oxadiazole
      conjugated oligoaryl and triarylamine moieties have been synthesized, in which 1
      exhibits remarkable solvent-polarity dependent fluorescence properties due to a
      highly efficient photoinduced electron transfer reaction.

PMID- 12478791
TI  - Formation of a remarkably robust 2:1 complex between beta-cyclodextrin and a
      phenyl-substituted icosahedral carborane.
AB  - The structure of the 2:1 complex between beta-cyclodextrin and 1-phenyl-1,2
      dicarba-closo-dodecaborane(12) is demonstrated by NOE and NOESY spectroscopy;
      this complex is remarkably refractory.

PMID- 12478792
TI  - Ia3d cubic mesoporous silicas using EO17MA23 diblock copolymers made from ATRP.
AB  - Poly(ethylene oxide)-b-poly(methyl acrylate) diblock copolymer (EOmMAn) prepared
      via an atom transfer radical polymerization (ATRP) approach was used as a
      template to synthesize Ia3d mesostructured silica with thick walls under acidic
      conditions.

PMID- 12478793
TI  - Thermic conversion of benzene into 6-phenylfulvene with high yield mediated by
      GaP nanocrystals.
AB  - With GaP nanocrystals being used in a close reaction system, 6-phenylfulvene is
      successfully obtained via a high yield thermic conversion from benzene, which
      provides the possibility of applying nanocrystals to mediate organic reactions.

PMID- 12478794
TI  - Deprotection and cleavage of peptides bound to Merrifield resin by stable
      dimethyl ether-poly(hydrogen fluoride) (DMEPHF) complex. a new and convenient
      reagent for peptide chemistry.
AB  - The newly developed stable DMEPHF (1/15) complex was found to be a highly
      effective reagent for the cleavage of peptides from Merrifield resins; ease of
      handling and its simple, complete removal from the reaction mixture make the
      reagent system a very useful HF equivalent for applications in solid-phase
      peptide synthesis.

PMID- 12478795
TI  - Towards biodegradable polyolefins: strategy of anchoring minute quantities of
      monosaccharides and disaccharides onto functionalized polystyrene, and their
      effect on facilitating polymer biodegradation.
AB  - A hypothesis was developed, and successfully tested, to greatly increase the
      rates of biodegradation of polyolefins, by anchoring minute quantities of
      glucose, sucrose or lactose, onto functionalized polystyrene (polystyrene-co
      maleic anhydride copolymer) and measuring their rates of biodegradation, which
      were found to be significantly improved.

PMID- 12478796
TI  - Alkyl isomerisation in three-coordinate iron(II) complexes.
AB  - The tertiary to iso-butyl isomerisation of three-coordinate iron(II) diketiminate
      complexes is reported and a hydride intermediate is proposed on the basis of
      exchange experiments.

PMID- 12478797
TI  - Preferential hetero-dimer formation and equilibrium dynamics of self
      complementary bifunctional oligo(p-phenylenevinylene) and C60 ureido-pyrimidinone
      derivatives in solution.
AB  - The formation of hetero-dimers of bifunctional oligo(p-phenylenevinylene) and C60
      ureido-pyrimidinone derivatives has been observed by 1H-NMR and fluorescence
      techniques.

PMID- 12478798
TI  - Synthesis of nucleoside 3',5'-cyclic boranophosphorothioate, a new type of cyclic
      nucleotide.
AB  - The first examples of a borane-containing doubly P-modified chiral cyclic
      nucleoside monophosphate (cNMP), e.g., thymidine and 5-fluoro-2'-deoxyuridine
      3',5'-cyclic boranophosphorothioates, have been synthesized; these cNMP analogues
      with increased lipophilicity could be potential anticancer prodrugs and useful
      probes for mechanistic studies.

PMID- 12478799
TI  - The important effect of ligand architecture on the selectivity of metal ion
      recognition in An(III)/Ln(III) separation with N-donor extractants.
AB  - The existence of a strong correlation between ligand architecture and metal ion
      binding selectivity is demonstrated through large differences in the separation
      efficiencies found in the selective extraction of Am3+ from an acidic mixture of
      Am3+ and Eu3+ for three new tetrapodal hexadentate ligands containing four 2
      pyrazinylmethyl groups attached to three different diamino spacers.

PMID- 12478800
TI  - Silver nanowires: inclusion in and extrusion from a mesoporous template.
AB  - Silver nanowires both included in and extruded from a purely siliceous mesoporous
      support have been produced from silver ion containing precursors prepared through
      dry salt occlusion.

PMID- 12478801
TI  - Self-assembly of a lacunary alpha-Keggin undecatungstophosphate into a three
      dimensional network linked by s-block cations.
AB  - The crystal structure of [(CH3)4N]4Na2H[alpha-PW11O39].8H2O has been determined
      by using the Weissenberg camera at the BL04B2 beamline of SPring-8, revealing
      that it contains a disorder-free lacunary [alpha-PW11O39]7- anion with one sodium
      cation embedded into its lacuna that links the oxometalate building blocks into a
      one-dimensional chain, which is then woven into a three dimensional latticework
      by another Na+.

PMID- 12478802
TI  - Self-assembly assisted polymerization (SAAP): approaching long multi-block
      copolymers with an ordered chain sequence and controllable block length.
AB  - A combination of polymer physics and synthetic chemistry has enabled us to
      develop self-assembly assisted polymerization (SAAP), leading to the preparation
      of long multi-block copolymers with an ordered chain sequence and controllable
      block lengths.

PMID- 12478803
TI  - Trivalent boron as acceptor in D-pi-A chromophores: synthesis, structure and
      fluorescence following single- and two-photon excitation.
AB  - A series of new donor-pi-acceptor type compounds with trivalent boron as acceptor
      which show strong two-photon excited up-conversion fluorescence have been
      synthesized and one crystal structure described.

PMID- 12478804
TI  - Hydrophobicity induced vapor-phase oxidation of propene over gold supported on
      titanium incorporated hybrid mesoporous silsesquioxane.
AB  - Gold nanoparticles supported on highly hydrophobic ethane bridged Ti incorporated
      mesoporous organosilica are reported for enhanced vapor phase epoxidation of
      propene using H2 and O2.

PMID- 12478805
TI  - Functionalization of Si(111) surfaces with alkyl chains terminated by
      electrochemically polymerizable thienyl units.
AB  - A Si(111) surface has been derivatized with a thiophene-terminated alkyl
      monolayer which was subsequently photoanodically oxidized in the presence of
      thiophene to yield a strongly adherent and smooth conducting film.

PMID- 12478806
TI  - Chiral ruthenium porphyrin encapsulated in ordered mesoporous molecular sieves
      (MCM-41 and MCM-48) as catalysts for asymmetric alkene epoxidation and
      cyclopropanation.
AB  - Encapsulation of chiral ruthenium porphyrin [RuII(D4-Por*)CO] in modified
      mesoporous silica supports such as MCM-41 and MCM-48 achieves active catalysts
      for asymmetric epoxidation of alkenes by 2,6-dichloropyridine N-oxide and
      intramolecular cyclopropanation, which is the first example of chiral
      metalloporphyrin supported on ordered molecular sieves.

PMID- 12478807
TI  - The structure of the blue luminescent delta-phase of tris(8
      hydroxyquinoline)aluminium(III) (Alq3).
AB  - The existence of the facial isomer in the delta-phase of Alq3 is proven by X-ray
      structural analysis, revealing that both the different molecular structure and
      the weaker overlap of the pi-orbitals of hydroxyquinoline ligands belonging to
      neighboring Alq3 molecules as compared to other phases (alpha, beta) are likely
      to be the origin of the significantly different optical properties of delta-Alq3.

PMID- 12478808
TI  - Asymmetric synthesis of (1R,2S,3R)-gamma-methyl-cis-pentacin by a kinetic
      resolution protocol.
AB  - The asymmetric synthesis of (1R,2S,3R)-3-methyl-2-amino-cyclopentane carboxylic
      acid has been achieved via kinetic resolution of racemic tert-butyl 3-methyl
      cyclopentene-1-carboxylate with homochiral lithium (S)-N-benzyl-N-alpha
      methylbenzylamide.

PMID- 12478809
TI  - Self-assembly of a twelve-component hexanuclear metallomacrocycle constructed
      with a novel tri-amino ligand.
AB  - Reaction of the novel ligand cis,trans-1,3,5-triaminocyclohexane, which contains
      two types of metal binding sites trans to each other, with palladium(II) chloride
      results in the self assembly of a hexanuclear ring cluster that has been
      characterised both in the solid state and in solution.

PMID- 12478810
TI  - Cyclopentadienyl benzamidinato chromium complexes as models for alkyl halide
      activation by chromium reagents.
AB  - Cyclopentadienyl complexes of Cr(II) and Cr(III) are stabilized by
      bis(trimethylsilyl)benzamidinato ligands, allowing the resulting well-defined
      compounds to serve as models for alkyl halide activation by mid-valent Cr-based
      reagents.

PMID- 12478811
TI  - Synthesis and structural characterization of Be(eta 5-C5Me5)(eta 1-C5Me4H).
      Evidence for ring-inversion leading to Be(eta 5-C5Me4H)(eta 1-C5Me5).
AB  - The mixed-ring beryllocene Be(C5Me5)(C5Me4H), that contains eta 5-C5Me5 and eta 1
      C5Me4H rings, the latter bonded to the metal through the CH carbon atom (X-ray
      crystal structure) reacts at room temperature with CNXyl (Xyl = C6H3-2,6-Me2) to
      give an iminoacyl product, Be(eta 5-C5Me4H)[C(NXyl)C5Me5] derived from the
      inverted beryllocene structure Be (eta 5-C5Me4H)(eta 1-C5Me5).

PMID- 12478812
TI  - The "0%" restenosis study.

PMID- 12478813
TI  - Quantitation of left ventricular mass and function: balancing evidence with
      dreams.
AB  - The quantitative evaluation of the echocardiographic geometry and function for
      non-ischemic, symmetrically contracting left ventricles is increasingly
      requested, even when the request is not clinically fully justified and does not
      take into account the feasibility and reliability of measurements. The general
      opinion is that, despite a number of technical limitations, the overall
      information gained from left ventricular (LV) quantitation has a crucial
      importance for risk stratification, mainly due to the prognostic impact of
      echocardiographically evaluated LV hypertrophy. This trend tends to automatically
      transfer epidemiological evidence into clinical application, without
      consideration of the consequences of the transition of standard errors into
      single cases. Two recent studies, through differently designed, have demonstrated
      that the test-retest intraobserver variability of LV mass performs well enough to
      allow, in most circumstances, the identification of patients with LV hypertrophy.
      In contrast, the variability of nominal, individual values is high. Tables are
      available to weight the probability of true biological change when comparing
      values in the same patient. To a lesser extent, the same conclusions as for LV
      mass can be applied to measures of systolic function. The technical reliability
      for measures of diastolic filling is generally good or very good, but the
      intrapatient variability is probably higher than with measures of LV geometry and
      systolic function. Moreover, the utility in clinical practice of measures of
      diastolic filling should be proven. In general, the accurate quantitation of LV
      geometry and function implies reliable methods and appropriate learning
      procedures in every echo lab, according to the procedures and the achievements
      recommended in the current literature. The development of new echocardiographic
      techniques and the adoption of the procedure of off-line revision of
      echocardiographic studies might further reduce the variability in the
      quantitation of measures of LV geometry and function.

PMID- 12478814
TI  - Hybrid therapy of atrial fibrillation.
AB  - Antiarrhythmic drugs have shown a poor long-term efficacy in the management of
      atrial fibrillation. It has been suggested that the association of antiarrhythmic
      drugs and non-pharmacological treatments may be superior to the prescription of a
      single treatment only. Electrical cardioversion of atrial fibrillation can be
      ineffective in several cases (long-lasting atrial fibrillation, large atria,
      advanced age, underlying diseases, high transthoracic impedance): the
      prescription of antiarrhythmic drugs prior to electrical shock has been
      demonstrated to be able to increase the success rate and to reduce the energy
      requirement. Ibutilide, amiodarone and sotalol are the most effective, while the
      efficacy of class IC drugs is controversial. The use of conventional atrial
      stimulation in case of the brady-tachy syndrome is related to the need of
      sustaining the atrial rhythm during bradycardia which can be exacerbated by the
      use of antiarrhythmic drugs. New overdrive algorithms, such as consistent atrial
      pacing and atrial rate stabilization, can increase the efficacy of physiological
      pacing. Painless electrical therapies, such as ramp and burst, have been
      implemented in specific devices, in order to combine the prevention and treatment
      of atrial arrhythmias. Multisite atrial stimulation has been introduced to
      improve the activation sequence and to reduce atrial asynchrony in case of slow
      conduction in the right atrium and of retrograde activation of the left atrium.
      Two methods are available for multisite atrial pacing: 1) simultaneous biatrial
      stimulation with the leads placed in the right appendage and in the left atrium
      through the coronary sinus; 2) dual site right atrial pacing with the leads
      positioned in the roof of the right atrium and proximal to the ostium of the
      coronary sinus. Single site non-conventional atrial pacing with the lead placed
      at the level of the interatrial septum, in the triangle of Koch, has been
      proposed in order to modulate the anisotropic conduction of this zone,
      responsible for the onset of atrial fibrillation. Non-conventional stimulation in
      association with drug therapy has been demonstrated to be more effective than
      conventional pacing in reducing the incidence of paroxysmal atrial fibrillation.
      The use of a dual-chamber defibrillator equipped with painless antitachy pacing
      therapies and atrial cardioversion can be considered the next step in the
      evolution of implantable devices. Atrioventricular nodal ablation and pacemaker
      implantation (ablate and pace) has been the first radiofrequency ablation
      procedure used to control the atrial fibrillation rate. Recently, it has been
      demonstrated that the survival rate in these patients was similar to that
      observed in subjects who received antiarrhythmic therapy. In patients in whom the
      administration of antiarrhythmic drugs (mainly class IC or amiodarone) modified
      atrial fibrillation in atrial flutter, linear lesions on the isthmus have been
      demonstrated to be effective in inhibiting the recurrence of arrhythmia. The
      first approach attempted in order to directly treat atrial fibrillation was the
      creation of linear lesions in the right atrium by means of radiofrequency current
      in patients refractory to drug therapy. This procedure was found to be feasible
      and safe, while lesions on the left atrium were associated with a high rate of
      side effects. The aim of the lesions was to create block lines in intra-atrial
      conduction, in order to electrically compartmentalize the atria and to avoid the
      propagation of reentry waves. More recently the ablation of the automatic
      activity originating from the posterior wall of the left atrium or within the
      pulmonary veins, which can trigger the onset of atrial fibrillation, has been
      performed.

PMID- 12478815
TI  - Dyslipidemias and fibrinolysis.
AB  - BACKGROUND: The relation between fibrinolysis and cardiovascular disease is an
      open debate. Fibrinolysis is related to endothelial function and presents many
      molecular links with platelet and coagulation activity. Furthermore, reduced
      fibrinolysis has been reported in several dysmetabolic conditions. METHODS: To
      detect mechanisms linking dyslipidemias and fibrinolysis we evaluated 75 subjects
      (42 males, 33 females, 20 hypercholesterolemic, 20 hypertriglyceridemic or 20
      with mixed hyperlipoproteinemia, 15 with isolated low HDL-cholesterol).
      Plasminogen activator inhibitor (PAI)-1, tissue-type plasminogen activator
      activity and plasmin-antiplasmin complexes (PAP) were determined at baseline and
      after the venous occlusion test. We also measured D-dimer, lipid pattern, soluble
      E-selectin, platelet surface P-selectin, prothrombin fragments 1 + 2 (F1 + 2),
      lipoprotein(a), factor VII, von Willebrand factor, plasma insulin, fibrinogen,
      homocysteine, thrombin activable fibrinolysis inhibitor (TAFI) activity,
      thrombomodulin, factor XIII, urokinase-type plasminogen activator. RESULTS:
      Hypertriglyceridemic patients were found to have lower PAP and D-dimer and higher
      PAI-1 serum levels (baseline and venous occlusion test, p < 0.001 and p < 0.01)
      compared to hypercholesterolemic and control subjects (p < 0.01, p < 0.001). P
      selectin, F1 + 2 and TAFI were significantly increased only in
      hypercholesterolemic subjects (p < 0.001) and associated with reduced PAP and D
      dimer, showing a linear relation with LDL-cholesterol levels (p < 0.01, r = -0.62
      and p < 0.01, r = -0.59). PAI-1 activity was not different with respect to
      controls (baseline p = 0.59, venous occlusion test p = 0.42). Serum levels of von
      Willebrand factor were significantly increased in hypertriglyceridemic/low HDL
      subjects compared to hypercholesterolemics (p < 0.01). CONCLUSIONS: Impaired
      fibrinolysis in subjects with hypertriglyceridemia/low HDL-cholesterol is
      associated with increased serum levels of PAI-1 whereas enhanced thrombin
      generation and TAFI hyperactivity are the main findings in hypercholesterolemia.
      Such data may suggest the opportunity of evaluating several fibrinolytic factors
      when studied as prognostic factors in diverse dyslipidemias.

PMID- 12478816
TI  - Variations in lipoprotein levels after myocardial infarction and unstable angina:
      the LATIN trial.
AB  - BACKGROUND: The aim of this study was to prospectively evaluate the magnitude of
      the variations in lipid levels in a large population of patients admitted for
      acute myocardial infarction (MI) and unstable angina (UA). Clinical data and
      blood samples were prospectively collected from consecutive patients with MI and
      UA. METHODS: The study population consisted of patients with symptoms lasting <
      or = 12 hours (for MI) or with the last episode of rest pain within 12 hours and
      associated with ECG changes (for UA). The exclusion criteria were recent
      hospitalization for any reason or current treatment with lipid-lowering drugs.
      Blood samples were obtained at admission, the following morning, at discharge and
      after 3 months. Samples were centrifuged immediately and 4 aliquots of serum were
      stored at -20 degrees C. The measurements were performed centrally. RESULTS: We
      enrolled 1864 patients (1275 with MI and 589 with UA). Serum levels of total and
      LDL-cholesterol decreased significantly after admission, both in MI and UA
      patients. After 3 months, serum levels of total cholesterol returned to baseline,
      while those of LDL-cholesterol were still significantly lower. Between admission
      and the following morning, total and LDL-cholesterol decreased significantly by 7
      and 10% respectively for MI and by 5 and 6% for UA. Lipid measurements not
      performed at admission accounted for a significant decrease in the number of
      patients identifiable as hyperlipidemic and suitable for lipid-lowering treatment
      (18% of MI patients and 11% of UA patients). CONCLUSIONS: Serum cholesterol
      concentrations drop significantly during hospitalization for an acute coronary
      syndrome after a few hours from admission to the coronary care unit. Lipid
      profile assessment should be scheduled at admission in order to correctly
      identify hyperlipidemic patients.

PMID- 12478817
TI  - Different patterns of interleukin-6 and von Willebrand factor antigen changes
      after coronary stenting in unstable versus stable angina.
AB  - BACKGROUND: Inflammation plays an important role in the pathogenesis of acute
      coronary syndromes. The purpose of our study was to evaluate the time course and
      the clinical relevance of inflammatory markers in patients with unstable angina
      undergoing successful coronary stent implantation. METHODS: Fifty-six patients
      (33 with unstable and 23 with stable angina) scheduled for single vessel coronary
      angioplasty followed by successful stent implantation were studied. Blood samples
      for measurements of interleukin-6 (IL-6) and von Willebrand factor antigen (vWf)
      were taken immediately before coronary angioplasty and 24 hours and 1 month after
      the procedure. Patients were clinically examined 1 month after the procedure.
      RESULTS: The mean levels of IL-6 before stenting were significaNtly higher in
      unstable than in stable angina patients (p = 0.002), whereas baseline values of
      vWf showed no difference between the two groups. In unstable angina, serum levels
      of IL-6 and of vWf did not change 24 hours after stent implantation, but
      significantly decreased 1 month after the procedure (p = 0.005 and p = 0.0015
      respectively). In stable patients, serum levels of IL-6, but not of vWf,
      increased 24 hours after the procedure and returned to baseline levels 1 month
      after stent implantation (p = 0.046). CONCLUSIONS: In unstable angina, successful
      treatment of the culprit lesion by coronary stenting results in a significant
      decrease in the serum levels of IL-6 and of vWf 1 month after the procedure,
      suggesting that, in this clinical condition, elevated levels of these parameters
      correlate with the instability of the atheromatous plaque and that their decrease
      after successful stent implantation is the result of plaque stabilization.

PMID- 12478818
TI  - Biventricular pacing for patients with severe congestive heart failure: a single
      center experience.
AB  - BACKGROUND: Biventricular pacing is becoming more and more popular as a
      therapeutic strategy for patients with severe congestive heart failure refractory
      to medical treatment. The aim of our study was to evaluate the outcome of
      resynchronization therapy on the clinical and echocardiographic statuses, to
      determine whether any factors were predictive of a positive or negative results
      after biventricular pacing and to analyze the survival curves. METHODS: From
      October 1998 to April 2002, 96 patients were selected for biventricular pacing at
      our center. The implant was successful in 95 (99%) patients. We followed-up the
      patients at 1, 3 and 6 months and then every 6 months. Follow-up evaluation
      included a clinical visit, an echocardiogram for the determination of left
      ventricular diameters, ejection fraction, E and A wave velocities, E/A ratio, E
      wave deceleration time, entity of mitral regurgitation (calculated as the
      percentage of the left atrium occupied by the mitral regurgitant jet) and aorto
      pulmonary delay (mechanical delay). RESULTS: Sixty-eight of our 96 patients were
      followed for at least 6 months. We observed a significant reduction in the
      electrical (QRS from 177 +/- 30 to 143 +/- 23 ms) and mechanical delay (aorto
      pulmonary delay from 55 +/- 33 to 25 +/- 19 ms). We also observed a significant
      clinical improvement, as demonstrated by the reduction in the NYHA functional
      class (from 3.2 +/- 0.5 to 2.1 +/- 0.8). This clinical improvement was reflected
      by the increase in ejection fraction (from 23 +/- 8 to 36 +/- 12%), by the
      decrease in mitral regurgitation (from 21 +/- 18 to 12 +/- 12%) and by the
      increase in E wave deceleration time (from 165 +/- 94 to 210 +/- 93 ms). Eight
      patients died during the first year of follow-up, with a mortality rate of 13%.
      The 2- and 3-year mortality rates were both 25.4%. CONCLUSIONS: Even though not
      randomized, our study enrolled a very homogeneous population of unselected
      patients; nevertheless, it seems to confirm that biventricular pacing is
      effective in improving the clinical and instrumental statuses of patients with
      severe congestive heart failure. Furthermore, it seems to indicate that this
      treatment could be effective in reducing the mortality rate among such patients.

PMID- 12478819
TI  - Arterial switch operation after multiple-stage left ventricular retraining.
AB  - Right ventricular dysfunction and tricuspid valve incompetence after atrial
      repair for transposition of the great arteries is an increasingly frequent
      problem. Left ventricular retraining to convert an atrial switch to an arterial
      switch is a well-known surgical option but can require a multiple-stage surgical
      approach. We report our successful multiple-stage experience with a 5-year-old
      girl.

PMID- 12478820
TI  - Complex electrocardiographic findings in a neonate with long QT syndrome.
AB  - A case of long QT syndrome diagnosed in the early neonatal period is described. A
      full-term male baby was delivered by cesarean section at 38 weeks of gestation.
      The indication to cesarean section was sudden marked fetal bradycardia. At birth,
      he presented the following rhythm disorders: a) an ectopic atrial rhythm with T
      wave alternans, and b) atrioventricular conduction disorders. Sinus rhythm, with
      a prolonged QT interval and T wave alternans, was recovered soon after birth,
      before starting beta-blocker therapy. The family history was negative for the
      long QT syndrome: sudden unexpected death and/or syncopal episodes and cases of
      congenital deafness have not been reported. Molecular screening of the five long
      QT syndrome-related genes did not reveal the presence of any mutation. At 3 years
      of follow-up, the child is well and he did not present with symptoms or
      arrhythmias during this period.

PMID- 12478821
TI  - Subannular left ventricular aneurysm in a patient with bicuspid aortic valve
      stenosis.
AB  - The term "subannular" left ventricular aneurysm (LVA) implies that the aneurysm's
      origin is very close to the aorta. In the absence of an infective etiology,
      subannular LVAs are very rare among Caucasians. Only a few cases have been
      reported in the literature. We present the case of a patient with a subannular
      LVA who underwent surgery at our Institution.

PMID- 12478822
TI  - Evidence of reverse mismatch with positron emission tomography imaging in a
      patient with reversible myocardial dysfunction.
AB  - We describe the case of a patient who came to our attention because of a
      reversible depression of myocardial contractility, probably due to myocarditis. A
      positron emission tomography study showed, in correspondence to the
      malfunctioning segments, a decreased F18-2-fluoro-2-deoxyglucose (F18-FDG) uptake
      in the presence of a normal perfusion as assessed by means of N13-labeled ammonia
      uptake. This phenomenon, called "reverse mismatch", shows that viability is not
      always dependent on FDG uptake and that it could be associated with the recovery
      of myocardial contractility. Some interpretations of the association between a
      reversible dysfunction and a reduced myocardial glucose metabolism are presented.
      The central role of nitric oxide and of cyclic guanosine monophosphate is
      hypothesized to explain both the mechanical and metabolic abnormalities.

PMID- 12478823
TI  - Noninvasive assessment of intramyocardial coronary flow in hypertrophic
      cardiomyopathy by high-resolution Doppler echocardiography.
AB  - Dyspnea and angina have been described in patients with hypertrophic
      cardiomyopathy (HCM). Given the complexity of the coronary microcirculation, the
      pathophysiological mechanisms of angina are discussed. The last generation of
      echo devices allows the investigation of epicardial coronary flow by means of the
      standard transthoracic approach (TTE). In the present study we describe 5
      patients affected by HCM (with outflow tract dynamic obstruction in 2 cases,
      intraventricular dynamic obstruction in the other 2, no obstruction in the last
      one) in whom both the epicardial and intramyocardial coronary flows were assessed
      at high-resolution TTE. Regular flow velocities were shown in epicardial coronary
      arteries, while in intramyocardial branches the diastolic peak velocity was > 75
      cm/s in all patients. Besides, the systolic flow was found to be inverted.
      Similar to what suggested by the few data presently available in the literature,
      the main findings of this study confirm the appropriateness of investigating the
      intramyocardial coronary circulation in patients with HCM by means of high
      resolution Doppler echocardiography. In order to explain this clinical finding,
      an interesting hypothesis of a diastolic "milking-like" phenomenon associated
      with systolic "blood squeezing" in the intramural coronary arteries was taken
      into consideration. The noninvasive study of the intramyocardial coronary flow
      may be clinically relevant even in the evaluation of the effectiveness of the
      adopted therapeutic strategy in reducing myocardial wall stress in severe
      ventricular hypertrophy.

PMID- 12478824
TI  - Transcatheter closure of a stabilized post-infarction apical muscular septum
      defect as an alternative to surgical repair.

PMID- 12478825
TI  - [Fetal risks related to the administration of anti-arrhythmia drugs during
      pregnancy].
AB  - The major concern about the administration of antiarrhythmic drugs during
      pregnancy is related to their effect on fetal well-being. Even if teratogenic
      risks are higher during organogenesis in the first 8 weeks of pregnancy, after
      this period undesirable effects may include depression of uterine blood flow,
      interference with fetal growth and development, and interference with labor and
      delivery. Most drugs are secreted in the mother's milk, a fact that raises
      concern about the nursing infants. In this report we review the fetal risks
      related to the management of maternal arrhythmias during pregnancy showing that
      most patients can be treated with an excellent result for their babies.

PMID- 12478826
TI  - [Clinical and organizational problems related to cardiological rehabilitation
      units].
AB  - The characteristics of patients admitted to cardiac rehabilitation units have
      progressively changed and are now represented by older age and clinical
      instability, with a higher percentage of females than in the past. Moreover, the
      demand of admission to cardiac rehabilitation departments has increased as a
      consequence of the extension of cardiac surgical procedures to older patients
      with frequent comorbidity. At the same time, the need of a shorter
      hospitalization in the acute hospital units has contributed to more frequent
      requests for cardiac rehabilitation admission. Cost factors and problems of
      organization have also contributed to the typology of the patients now admitted
      for cardiac rehabilitation. The data of patients admitted to the Cardiac
      Rehabilitation Unit of the Don Gnocchi Hospital in Milan are reported too: these
      data confirm the actual change in the typology of patients with respect to the
      past; the possible explanations and reasons, as well as the increased average age
      of the population and the increased number of surgical interventions in the
      elderly and females are also evaluated. Moreover, the programs and the
      rehabilitative aims have been consequently changed. Finally, even the use of non
      invasive alternatives to ergometric tests is here discussed.

PMID- 12478827
TI  - [Psychological stress and sudden death].
AB  - Recent studies provide relevant evidence that psychological stress significantly
      influences the pathogenesis of sudden cardiac death. Psychological stress
      expresses a situation of imbalance, derived from a real or perceived disparity
      between environmental demands and the individual's ability to cope with these
      demands. A situation of psychological stress may include different components:
      personality factors and character traits, anxiety and depression, social
      isolation and acute or chronic adverse life events. In particular, it has been
      documented that a sudden extremely hard event, such as an earthquake or a war
      strike, can significantly increase the incidence of sudden death. Nevertheless,
      each one of these factors, if not present, can balance a partially unfavorable
      situation; this overview suggests a multifactorial situation where almost all
      elements are present and in which the relative influence of each one varies
      according to the individual examined. Sudden death occurs when a transient
      disruption (such as acute myocardial ischemia, platelet activation or
      neuroendocrine variations), occurring in a patient with a diseased myocardium
      (such as one with a post-necrotic scar or hypertrophy), triggers a malignant
      arrhythmia. Psychological stress acts at both levels: by means of a "chronic"
      action it contributes to create the myocardial background, while by means of an
      acute action it can create the transient trigger precipitating sudden death. In
      the chronic action two possible mechanisms can be detected: the first is a direct
      interaction, which contributes to cause a hypertension status or to exacerbate
      coronary atherosclerosis consequent to endothelial dysfunction; the second one
      acts through adverse health behaviors, such as a poor diet, alcohol consumption
      or smoking. In case of acute psychological stress, the mechanisms involved are
      mainly the ability to trigger myocardial ischemia, to promote arrhythmogenesis,
      to stimulate platelet function, and to increase blood viscosity. Finally, some
      individuals have a sympathetic nervous system hyper-responsitivity, manifesting
      as exaggerated heart rate and blood pressure responses which result in
      accelerated atherosclerosis.

PMID- 12478828
TI  - [Alveolar-capillary dysfunction in heart failure].
AB  - Heart failure increases the resistance to gas transfer across the alveolar
      capillary interface. In different experimental conditions of vascular capillary
      injury, peculiar anatomical and functional abnormalities of the alveolar unit
      have been reported and consist of a disruption of its anatomical configuration
      and of a loss of fluid-flux regulation and gas exchange efficiency (i.e. "stress
      failure" of the alveolar-capillary membrane). In heart failure, the
      pathophysiological relevance of these changes has been only recently appreciated.
      Alveolar-capillary membrane conductance and capillary blood volume are
      subcomponents of lung diffusion capacity. A reduction of the former with an
      increase of the latter and consequent impairment of gas exchange are typical of
      heart failure syndrome. Alveolar-capillary membrane conductance abnormalities
      have been shown to be a sensitive index of the underlying lung tissue damage,
      bring an independent prognostic information and play a significant role in the
      pathogenesis of exercise limitation and ventilatory abnormalities. This review
      examines the current knowledge on this topic.

PMID- 12478829
TI  - [Safety and effectiveness of dual chamber pacing in patients over 80 years of age
      with previous episodes of paroxysmal atrial fibrillation].
AB  - BACKGROUND: Dual chamber pacing (DDD) in the elderly is still a controversial
      issue because of its short life expectancy and the risk of atrial fibrillation.
      The aim of the study was 1) to evaluate the cumulative survival and the events
      capable of modifying it, 2) to evaluate the stability of sinus rhythm, and 3) to
      try to identify patients who are at a higher risk of developing permanent atrial
      fibrillation after DDD implantation. We evaluated clinical, electrophysiological
      and pacing parameters at the time of implantation. METHODS: We examined
      retrospectively a group of 135 consecutive patients who were > 80 years old and
      who were treated with DDD in the last decade. RESULTS: At the time of evaluation
      (mean 33.51 +/- 27.10 months, range 4-148 months) after DDD implantation, 72% of
      patients were still alive. Sinus rhythm was documented in 96 (71%) patients
      (group A). Thirty-nine (29%) patients (group B) developed atrial fibrillation
      after a mean period of 28.56 +/- 30.9 months (range 1-125 months). The right
      atrial endocavitary signal amplitude was lower in group B compared to that
      observed in group A (2.6 +/- 1.16 vs 3.27 +/- 1.91 mV). The pacing and sensing
      atrioventricular delay were not statistically different in both groups. The
      minimum heart rate was higher in patients who developed atrial fibrillation
      (64.53 +/- 7.7 vs 67.7 +/- 5.72 b/min respectively in group A and in group B, p =
      0.02). Group B patients had a higher rate of atrial fibrillation pre-implantation
      episodes. The incidences of sick sinus disease and of atrioventricular nodal
      disease were similar in both groups. CONCLUSIONS: In elderly patients the
      benefits of DDD are maintained for a long period of time before the development
      of atrial fibrillation. Episodes of atrial fibrillation prior to DDD, apart from
      sinus dysfunction alone, are predictive of the development of a permanent atrial
      fibrillation. Permanent atrial fibrillation does not seem to reduce life
      expectancy. A higher minimum heart rate does not seem to prevent atrial
      fibrillation. The capability of recording a right atrial signal amplitude > 3 mV
      seems to identify those patients with a lower risk of developing atrial
      fibrillation.

PMID- 12478830
TI  - [Chest pain in women: a multicenter study of the National Association of Hospital
      Cardiologists (ANMCO) of the Lazio Region].
AB  - BACKGROUND: Chest pain is an extremely common symptom in women, but several
      previous studies have suggested that in women this complaint is more frequently
      underdiagnosed than in men. The aim of this multicenter study proposed by the
      National Association of Hospital Cardiologists (ANMCO) was to analyze the
      clinical regimen adopted for women admitted to a public hospital of the Lazio
      Region for chest pain during a short period of time (only 30 days). METHODS:
      Between March 1 and March 31, 2001, 747 women were admitted in the Emergency
      Department of 20 public hospitals in the Lazio Region for chest pain. The
      patients' age ranged between 40 to 80 years (mean age 61.4 +/- 12.6 years). An
      ECG was recorded in 727 (97.5%), 326 (44%) underwent cardiologic examination,
      blood analysis was performed for 584 (78%) and 66 (8.8%) were submitted to two
      dimensional echocardiography. RESULTS: Of the 727 ECGs, 403 (56%) were defined as
      "normal" by a cardiologist and 324 (44%) "abnormal". Of the 747 women with chest
      pain, 446 (60%) were discharged from the Emergency Department; 2 died (0.2%), and
      298 (40%) were hospitalized. Among the latter, 169 (56%) were submitted to
      echocardiography, 45 (16%) to the ECG effort test, 22 (6%) to stress
      echocardiography, 40 (11%) to coronary angiography (3 also to primary coronary
      angioplasty), 10 (3.3%) to esophagogas-troduodenoscopy, and 68 (23%) to several
      non-cardiologic exams. The final diagnosis was atypical chest pain in 336 (45%),
      acute myocardial infarction in 60 (6.7%), paroxysmal atrial fibrillation in 42
      (5.6%), typical angina in 60 (10.6%), aortic dissection in 3 (0.4%), pericarditis
      in 7 (0.9%), hypertensive crisis in 80 (11%), gastritis in 27 (3.6%), anxiety in
      15 (2%), and a surgical or orthopedic diagnosis in 107 (14%). Two patients (0.2%)
      died. During follow-up (6 months) cardiac events occurred in 7.6% of 446 women
      discharged from the Emergency Department. CONCLUSIONS: This study demonstrated
      that the diagnostic tests are underutilized in women with chest pain, even
      compared to previous studies including male and female subjects. For women
      presenting with chest pain, the use of non-invasive tests with the best
      prognostic impact should be increased.

PMID- 12478831
TI  - [Salvage angioplasty in a patient with antiphospholipid antibody syndrome and
      cardiogenic shock].
AB  - Antiphospholipid syndrome is a thrombotic disorder in which the clinical features
      are venous and/or arterial thrombosis, thrombocytopenia, and recurrent fetal
      loss. We describe the case of a 39-year-old woman affected by antiphospholipid
      syndrome and acute anterior myocardial infarction complicated by cardiogenic
      shock. The patient, after the failure of thrombolysis, was successfully treated
      by rescue angioplasty. The persistent thrombocytopenia of these patients may lead
      to safety problems in thrombolytic treatment; therefore, primary angioplasty may
      be considered the treatment of choice.

PMID- 12478832
TI  - [Primary cardiac lymphoma presenting with complete atrioventricular block. Case
      report and review of the literature].
AB  - Primary cardiac lymphoma is very rare and clinical symptoms of cardiac
      involvement are unusual. The development of conduction defects as the first
      symptom of cardiac involvement is very uncommon. We report the case of a 57-year
      old woman with syncope and complete atrioventricular block due to large B-cell
      primary cardiac lymphoma. The patient showed a refractory pericardial effusion.
      Transthoracic echocardiography revealed the presence of a mass in the pericardial
      space. The diagnosis of diffuse large B-cell lymphoma was made following open
      chest biopsy of the heart. The clinical presentation of and the diagnostic
      approach to primary cardiac lymphoma are discussed. Atrioventricular block and
      refractory unexplained pericardial effusion and/or the existence of a cardiac
      mass should arouse the clinical suspicion of this rare malignancy.

PMID- 12478833
TI  - [Task Force on Sudden Cardiac Death, European Society of Cardiology. Summary of
      recommendations].

PMID- 12478834
TI  - [Prevention of prostatitis].
AB  - Prostatitis is a common disease in men without satisfactory therapeutics methods,
      and prevention of prostatitis becomes much more important. The main methods
      include treatment of general infection and secondardy infection of the prostate
      actively, diet and life-style modification, avoiding unnecessary medical
      examination, establishing good coping styles, giving publicity to the knowledge
      of prostate and prostate-related disease, and strengthening prevention in the
      post-prostatitis patients.

PMID- 12478835
TI  - Development of selective androgen receptor modulators and their therapeutic
      applications.
AB  - Androgens control a broad range of physiological functions. The androgen receptor
      (AR), a steroid receptor that mediates the diverse biological actions of
      androgens, is a ligand inducible transcription factor. Abnormalities in the
      androgen signaling system result in many disturbances ranging from changes in
      gender determination and sexual development to psychiatric and emotional
      disorders. Androgen replacement therapy can improve many clinical conditions
      including hypogonadism and osteoporosis, but is limited by the lack of
      efficacious and safe therapeutic agents with easy delivery options. Recent
      progress in the area of gene regulation by steroid receptors and by selective
      receptor modulators provides an opportunity to examine if selective androgen
      receptor modulators (SARMs) could address some of the problems associated with
      current androgen therapy. Since the composition of the transcriptional initiation
      complex recruited by liganded AR determines the specificity of gene regulation,
      synthetic ligands aimed at initiating transcription of tissue and promoter
      specific genes offers hope for developing better androgen therapy. Establishment
      of assays that predict synthetic ligand activity is critical for SARM
      development. Advancement in high throughput compound screening and gene
      fingerprinting technologies, such as microarrays and proteomics, will facilitate
      and accelerate identification of effective SARMs.

PMID- 12478836
TI  - [Androgen receptor isoforms in LNCaP cell and human prostate].
AB  - OBJECTIVES: To investigate the androgen receptor (AR) isoforms expression in
      human benign and malignant prostatic tissues and LNCaP cells. METHODS: Using high
      resolution isoelectric focusing (IEF), the different expression of AR isoforms
      were demosntrated in human benign and malignant prostatic tissues and LNCaP
      cells. RESULTS: Data were obtained from 41 AR-positive BPH, three prostatic
      cancer specimens, and LNCaP cells. From these materials, three types of AR
      isoforms were detected with pI values at 6.5, 6.0 and 5.3. In the case of BPH
      tissues, 15 (36.5%) specimens expressed all the three types of isoforms at pI
      6.5, 6.0 and 5.3, and 10 (24.4%) samples contained isoforms at pI 6.5 and 5.3,
      five (12.2%) samples indicated isoforms at pI 6.5 and 6.0, four (9.8%) showed the
      isoforms at pI 6.0 and 5.3. Of all the 41 specimens, two (4.9%) and two (4.9%) as
      well as three (7.3%) denoted the isoforme at pI 6.5, 6.0 and 5.3 respectively. As
      for three prostatic cancer specimens, one sample showed all the three types of AR
      isoforms at pI 6.5, 6.0, 5.3, but another specimen expressed at pI 6.5 and 6.0,
      and only one failed to indicate any types of isoforms. LNCaP cells expressed all
      three types of AR isoforms at pI 6.5, 6.0 and 5.3. Binding of 3H
      dihydrotestosterone to these three types of isoforms was inhibited by the
      addition of 100-fold excess of DHT and testosterone. No effect of progesterone,
      oestradiol and diethylstilboestrol on tritiated hormone binding was observed.
      CONCLUSIONS: The expression of AR isoforms is different among various patients
      and different between BPH and LNCaP cells, though no clear explanation could be
      induced for this. These results suggest the possibility of explaining effective
      hormonal therapy to prostatic disease in the future.

PMID- 12478837
TI  - [Construction and identification for cell strain of anti-human seminal plasma
      phospholipase A2 monoclonal antibody].
AB  - OBJECTIVES: To establish and evaluate the anti-human seminal plasma phospholipase
      A2 (PLA2) monoclonal antibody (McAb). METHODS: After having been separated and
      purified from human seminal plasma by PEG precipitation, Sephacryl S-300 column
      chromatography, DEAE-Sephadex A-25 column chromatography and HA column
      chromatography, PLA2 was regarded as an antigen to immune BALB/C mouse to produce
      anti-human seminal plasma PLA2 McAb. The PLA2 McAb sensitivity and specificity
      were performed by ELISA technique and Western-blot analysis, respectively.
      RESULTS: The molecular weight of PLA2 depurated with 245 fold purification from
      human seminal plasma was about 34,900, while the sensitivity and typing of its
      McAb were 1:5(6)-1:5(8) and IgM (kappa) with a satisfied Western-Blot results.
      CONCLUSIONS: The PLA2, which had not been reported in international and domestic
      papers, may be a new type of PLA2. The establish of its McAb will provide
      significant tools for the research of the relationship between PLA2 in human
      seminal plasma and male fertility.

PMID- 12478838
TI  - [Biological characteristics of rabbit corporal smooth muscle cells cultured in
      vitro].
AB  - OBJECTIVES: To study the biological characteristics of rabbit corporal smooth
      muscle cells (SMC) cultured in vitro. METHODS: In vitro tissue culture technique,
      morphological observation, cell counting, mitosis index and adhesion rate
      evaluation were applied to study the biological features of the SMC. RESULTS: 1.
      SMC were spindle-shaped and parallel along their longitudinal axis, showing
      obvious orientation. 2. The attachment and the proliferation of SMC in vitro were
      rapid. SMC cultured in vitro can grow and maintain their steady characteristics
      provided appropriate passage rate and culture condition. CONCLUSIONS: The SMC
      cultured in vitro are proved to be used to evaluate and investigate the effect of
      some medicine on penile erection.

PMID- 12478839
TI  - [Physicians' knowledge and attitude to erectile dysfunction].
AB  - OBJECTIVES: The physicians knowledge and attitude to erectile dysfunction (ED) is
      very important to the diagnosis and management of this disease. We investigated
      the physicians and practitioners knowledge of ED, attitude to ED, and if they
      actively find the underlying ED patients. METHODS: Three hundreds and one
      physicians and practitioners in Beijing completed a questionnaire. The subjects
      included urologists, cardiologists, endocrinologists, surgeons, orthopaedicians
      and community practitioners. RESULTS: The definition of ED was well known by most
      subjects (83.4%). Many agreed that ED was a common condition in the aging men
      (85.0%), and it was an important health problem (78.7%) and it was the local
      signs of certain systemic diseases (89.7%). The most common risk factors of ED
      enumerated by the physicians were diabetes (45.5%), hypertension (12.6%) and
      coronary artery diseases (12.0%). 45.5% physicians met the patients who initiated
      questions about ED. 32.6% physicians would discuss ED with the patients if the
      patients initiate questions about ED. 95.0% non-urological physicians would refer
      the ED patients to urologists or andrologists. 43.5% of all the physicians never
      asked their patients about erectile function, this proportions in the subgroups
      of urologists, non-urological physicians and community practitioners were 7.2%,
      55.3% and 60.5% respectively (P < 0.01). The most common reasons for the
      physicians not to initiate the inquiries about ED was "the patients would not
      have ED if they didnt complain about it" (42.2%), "there was no ED patients in my
      specialty" (20.9%), "diagnosis and treatment of ED was not my business" (17.3%),
      "have no time" (15.6%), "feel embarrassed" (13.6%). CONCLUSIONS: Most physicians
      regarded ED as an important health problem and a common condition in aging men,
      but they didnt take an active attitude to ED in their clinical practice.

PMID- 12478840
TI  - [Correlation between tissue ultrastructure changes of small testis and sex
      hormone].
AB  - OBJECTIVES: To investigate the tissue ultrastructure changes of small testis and
      sex hormone and their correlation. METHODS: The patients were divided into small
      tests (n = 8) and control group(n = 12). FSH, LH, T were determined by
      radioimmunassay. Diameter and wall thickness of convoluted seminiferous tubule
      were investigated with light microscope and electro microscopy on small testis
      tissue morphology and ultrastructure. RESULTS: FSH, LH, T of small testis and
      control group were (21.05 +/- 9.15) IU/L vs (6.74 +/- 3.52) IU/L, (22.88 +/-
      6.25) IU/L vs (6.60 +/- 1.48) IU/L and (0.30 +/- 0.04) nmol/L vs (17.55 +/- 9.25)
      nmol/L, respectively. Seminiferous tubule diameter and wall thickness were(37.33
      +/- 6.80) microns vs (198.46 +/- 29.84) microns and (10.30 +/- 1.82) microns vs
      (2.95 +/- 0.20) microns. Small testis tissue ultrastructure changed
      significantly. CONCLUSIONS: Pathologic changes of small testis tissue in many
      parts such as seminiferous tubule, germinal epithelium, Sertoli cell, Leydig
      cell, limiting membrance and blood vessel may relate with genetics and
      immunoreaction.

PMID- 12478841
TI  - [Histomorphological studies on hyperplastic prostate of castrated rat caused by
      androgen].
AB  - OBJECTIVES: To investigate prostatic histomorphological changes of rat benign
      prostatic hyperplasia (BPH) models. METHODS: After castrated, SD rats were
      injected subcutaneously testosterone propionate to induce the BPH. Water
      substitution method was used to measure prostatic volumes. Prostatic tissue were
      stained by hemoloxylin and eosin, the morphometric changes of glandular and
      interstitial tissues were semi-quantified by image analysis system. Multiple
      linear regression was adopted to analyze the results. RESULTS: In comparison with
      normal group, prostatic volumes were significantly enlarged (P < 0.01) with
      glands expanded and interstitial tissues increased in BPH model. Glandular
      average diameters, volumes and surface areas in unit volume, as well as glandular
      circumferences and glandular relative total volumes were all significantly
      increased (P < 0.01). Glandular counts, density, ratio of glandular surface area
      to volume. And glandular average curvature were all declined (P < 0.05-0.01), so
      was interstitial circumference (P < 0.01). But volume density had no changes, and
      relative total interstitial volumes were obviously increased. Prostatic volume
      was significantly correlated with glandular relative total volume (r = 0.989, P <
      0.001) and interstitial relative total volume(r = 0.789, P < 0.001). Prostatic
      volume was also correlated significantly with glandular average volume(r = 0.789,
      P < 0.001). CONCLUSIONS: Action of androgen on rat prostate may mainly lie in
      glandular epithelial hyperplasia, which manifests enlargement of glandular lumen
      accompanied by hyperplasia of interstitial tissues.

PMID- 12478842
TI  - [Continuous measurement of urine beta-FSH excretion in men with hypogonadism].
AB  - OBJECTIVES: To measure continuously the urine beta-FSH excretion in the patients
      with male hypogonadism, and to evaluate the significance of urine beta-FSH when
      used in the clinical practice and pathophysiological study on male hypogonadism.
      METHODS: Four health male volunteers (aged 19, 22, 27 and 33 years), four
      patients with the hypogonadotropic hypogonadism (aged 17, 17, 19 and 24 years)
      and five patients with idiopathy hypogonadism (hypergonadotropic, aged 16, 16,
      17, 20 and 22 years) were asked to collect their morning-first urine samples for
      30 to 32 days. One normal men collected his urine samples for 63 days. The urine
      beta-FSH was assayed with the method of EIA, then corrected by creatinine (Cr)
      concentration. RESULTS: The urine beta-FSH level of normal men was (1.16 +/-
      0.20) micrograms/mg Cr, with the peak variation in their curves, peak level at
      2.76 micrograms/mg Cr. The levels of urine beta-FSH of 4 patients with the
      hypogonadotropic hypogonadism were lower significantly than those of normal men
      [(0.58 +/- 0.31) (0.93 +/- 0.47) (0.47 +/- 0.33) and (0.60 +/- 0.40)
      micrograms/mg Cr], without fluctuation in their curves. beta-FSH levels of 5
      patients with idiopathy hypogonadism were higher significantly [(3.02 +/- 0.93),
      (4.36 +/- 1.12), (4.79 +/- 0.78), (4.64 +/- 1.42) and (3.88 +/- 1.42)
      micrograms/mg Cr], with irregular fluctuation, the highest peak level at 6.83
      micrograms/mg Cr. The second sexual characteristics of hypogonadal patients were
      poor and serum testosterone levels low. CONCLUSIONS: The urine beta-FSH level
      raised with irregular fluctuation in patients with idiopathy hypogonadism, while
      lowed without any fluctuation in patients with the hypogonadism. These findings
      suggested that the urine beta-FSH excretion was useful for the clinically
      classified diagnoses and pathophysiological study on male hypogonadism, and for
      observing the treatment reaction of androgen replacement.

PMID- 12478843
TI  - [Prostaglandin E1 versus sildenafil in the management of erectile dysfunction].
AB  - OBJECTIVES: To evaluate the outcome of treatment in patients with erectile
      dysfunction (ED) using sildenafil or intracavernosal injection of prostaglandin
      E1(PGE1). METHODS: 54 patients with ED were randomly classified into two groups
      and received either oral sildenafil (group A) or intracavernosal injection of
      PGE1(group B) for 4-9 months with an average of 6 months. RESULTS: The
      percentages of efficacy in the two groups were 80.0% and 83.3%, respectively.
      There was no statistical difference between group A and B (P > 0.05). Two of six
      patients who did not respond to sildenafal in group A achieved erections
      sufficient for sexual intercourse when the six patients received intracavernous
      injection of PGE1. None of the four patients who did not respond to
      intracavernous injection of PEG1 in group B achieved erection sufficient for
      sexual intercourse when they received oral sildenafil. CONCLUSIONS: Both oral
      sildenafil and intracavernous injection of PGE1 are effective for patients with
      ED of various etiologies. The patients who do not respond to sildenafil can
      receive intracavernous injection therapy. The satisfactory results can probably
      achieved.

PMID- 12478844
TI  - [Effects of cyclosporin A on expression of FasL and Fas in the contralateral
      testis after the unilateral testis injured in KM mouse].
AB  - OBJECTIVES: To investigate the effects of Cyclosporin A (CsA) on spermatogenesis
      and expression of FasL and Fas in the contralateral testis after the unilateral
      testis was injured. METHODS: 60 mice were randomly divided equally into groups A
      (control), B (the unilateral testis was injured by glacial acetic acid), C
      (excision of ipsilateral testis at 6 hours after the unilateral testis was
      injured by glacial acetic acid) and D (CsA within 6 hours after the unilateral
      testis was injured by glacial acetic acid). Sperm density and sperm motility were
      evaluated after 4 weeks. Expression of FasL and Fas was performed by
      immunohistochemistry (SP method). The positive cells with SP staining in
      seminiferous tubules were calculated. RESULTS: Sperm density and sperm motility
      in group D were significantly increased compared with group B(P < 0.05).
      Expression of FasL and Fas in group D decreased significantly compared with group
      B (24.3 +/- 7.0 vs 37.8 +/- 5.8 and 17.8 +/- 4.3 vs 32.4 +/- 3.6, P < 0.05).
      CONCLUSIONS: CsA decreased expression of Fas and FasL and maintained
      spermatogenesis in the contralateral testis after the unilateral testis was
      injured by glacial acetic acid.

PMID- 12478845
TI  - [Detection of human sperm morphology and acrosome reaction with Coomassie
      brilliant blue staining].
AB  - OBJECTIVES: To evaluate the application of Coomassie brilliant blue (CBB) G250
      staining for the detection of human sperm deformity rate, rate of intact acrosome
      and acrosome reaction. METHODS: The smear of spermatozoa before and after
      capacitation and induced acrosome reaction with progesterone (P) were stained
      with 0.05% CBB G250 and Wright-Giemisa solution respectively, and visualized with
      light microscopy. The deformity rate of spermatozoa, rate of intact acrosome and
      acrosome reaction were calculated. RESULTS: There was no any difference in
      detection of deformity rate of spermatozoa and rate of intact acrosome with CBB
      G250 and Wright-Giemisa staining(P < 0.05). The sperm population of acrosome
      reaction with induced P was divided by CBB staining into two types: positive
      staining with dark violet blue on acrosome cap and pale or negative staining on
      the same area. The rate of the latter was increasing with increasing inductive
      time, maybe representative of the rate of acrosome reaction. The mean rate
      was(75.1 +/- 3.8)% after induced for 1 h. CONCLUSIONS: CBB G250 staining is a
      reliable method for assessment of the human sperm morphology and acrosome
      reaction.

PMID- 12478846
TI  - [Sexual hormone and sperm cytological test in patients with aspermia].
AB  - OBJECTIVES: To test the serum sexual hormone and sperm cytology in aspermia
      patients. METHODS: Radioimmunoassay (RIA) and Wright-Giemsa stain were used to
      detect serum sexual hormone and sperm cytology in 45 aspermia patients. RESULTS:
      Among the 45 patients, spermatogenetic cells were detected in 16 patients(35.6%).
      The level of serum testerone were decreased in 16 patients, and FSH, LH were
      increased in 13 cases as well as that of PRL in 4 cases. CONCLUSIONS: These
      results suggested that the testis function was demaged, the ratio of T/LH could
      further reflect the function of Leydig cells, the detection of PRL were
      significant only in diagnosis of aspermia induced by hypermia. It is an important
      index in identifying obstructive and non-obstructive aspermia and has important
      significance in estimating the extention of testis demage and commanding the
      clinical treatment of serum hormone detection and sperm cell analysis.

PMID- 12478847
TI  - [Complications with transrectal biopsy of the prostate].
AB  - OBJECTIVES: To probe into the complications of prostate biopsy. METHODS: The
      clinical data of 220 patients underwent prostate biopsy from 1997 to 2001 were
      reviewed. RESULTS: A total of 93 patients suffered slight complications, and 15
      patients suffered severe complications. CONCLUSIONS: Transrectal prostate biopsy
      is easily and safely by using 18 gague biopsy needles. These data demonstrate the
      low morbidity and less complication associated with contemporary transrectal
      prostate biopsy.

PMID- 12478848
TI  - [Estrogen and estrogen receptors in benign prostatic hyperplasia].
AB  - Estrogen is a strong growth regulator of the prostate stromal cells, it produces
      a marked effect by means of binding to specific receptors. Many researches have
      indicated that estrogen and estrogen receptors take part in the whole process and
      development of benign prostatic hyperplasia. This article gives a general
      description of the function of estrogen and estrogen receptors in benign
      prostatic hyperplasia.

PMID- 12478849
TI  - [Advances in etiology of diabetes mellitus and erectile dysfunction].
AB  - Diabetes mellitus is a well documented risk factor for erectile dysfunction.
      Significant pathological changes observed in the cavernous tissues of ED patient
      with diabetes include generation of endothelial and smooth muscle cell, increase
      in thickness of collangen bundles, changes in vascular and neurotransmitters.

PMID- 12478850
TI  - [Effects of cryopreservation on human sperm genetic substance].
AB  - Sperm cryopreservation is essential link of assisted reproductive techniques.
      Because of widespread application for AID and establish of human sperm storeroom,
      the effects of cryopreservation on human sperm genetic substance have been paid
      more and more attention. This report summarizes the effects of cryopreservation
      on human sperm genetic substance and preventive measures.

PMID- 12478851
TI  - [New targets of anticancer drugs and their pathways].
AB  - This article reviews recent advances in apoptosis on the pathway inducing cancer
      cell to death, including Bcl-2 family pathway, NF-kappa B pathway, P13K/Akt
      pathway, Rb gene and p53 gene, especially the targets of anticancer drug in these
      pathways. It could be useful for the anticancer drug design and estimate.
      Furthermore, those cancer/testis antigen gene products are potential targets for
      antigen-specific immunotherapy of carcinoma.

PMID- 12478852
TI  - [Current surgical treatment of breast cancer in Japan and its rationale:
      foreword].
AB  - This is a foreword to a collection of articles specially dedicated to describing
      the present status of local treatment of breast cancer patients in Japan, which
      continues to be a source of controversy in the midst of collaborative efforts
      between surgeons, pathologists, and medical and radiation oncologists. Surgical
      treatment of breast cancer consisting of procedures on the breast parenchyma and
      on lymph nodes do not appear to have reached the expected technical perfection. A
      variety of surgical procedures are performed under the name of breast-conserving
      surgery with widely varied rates of application ranging from 20-85% depending
      upon the institution. With regard to sentinel node biopsy/dissection, diversified
      techniques such as different types of tracers and injection sites are currently
      being utilized, and furthermore long-term analysis may be necessary to determine
      the superiority as compared with other approaches such as lower axillary
      sampling/dissection and 4-node biopsy. Since all efforts should be made to
      prevent locoregional tumor recurrence, surgeons must be alert and attuned to all
      the details of surgery. Continued efforts of surgeons with a broadened
      perspective will lead to the improvement of local treatment of breast cancer with
      the ultimate goal of obtaining better local control and consequently better long
      term survival outcomes.

PMID- 12478853
TI  - [Image-guided breast conserving surgery based on 3D-MRI].
AB  - Surgery for breast cancer has changed markedly during the past 20 years. Radical
      mastectomy, referred to as Halstead's operation, is not commonly performed at
      present, while breast-conserving surgery (BCS) has become the standard therapy
      for early breast cancer. In the era of BCS, preoperative evaluation of tumor
      extension is extremely important. Three-dimensional magnetic resonnance
      imaging(3D-MRI) is a promising diagnostic method to confirm tumor extension
      compared with other conventional methods (mammography and ultrasound). Therefore,
      3-D MRI can be used to assist image-guided surgery for nonpalpable tumors, which
      are detected as clustered microcalcifications, or in clinical complete response
      cases after neoadjuvant chemotherapy.

PMID- 12478854
TI  - [Predictive factors affect the choice of strategy for breast cancer surgery].
AB  - Predictive factors are those factors that predict the effects of chemotherapeutic
      or other agents on the tumor or the host. Many factors have been investigated for
      their predictive value of the effect of chemotherapeutic or hormonal agents.
      Estrogen or progesterone receptors are the most established predictive factors
      for hormonal therapy. Her-2/neu is a predictive of the effect of the monoclonal
      antibody trastuzumab and of certain chemotherapeutic agents. Other predictive
      factors remain under clinical investigation. Most cases of breast cancer are
      initially considered to be systemic disease. Cure can only achieved with surgery
      that leaves no residual cancer cells, followed by an appropriate form of systemic
      therapy. In the clinical situation, local therapy and systemic therapy for breast
      cancer have been considered independently. However, preoperative chemotherapy has
      become common recently. The interaction between chemotherapy and surgery should
      be considered because the results of preoperative chemotherapy affect the choice
      of operative technique. Predictive factors for the effect of radiation therapy
      should also be taken into account after breast-conserving surgery. It remains to
      be determined which predictive factors should be considered at which time.

PMID- 12478855
TI  - [Option of the surgical mode for breast cancer based on the effect of neoadjuvant
      chemotherapy].
AB  - Neoadjuvant chemotherapy has become standard treatment for breast cancer patients
      to avoid mastectomy in larger tumors. Neoadjuvant chemotherapy permits more
      breast-conserving surgery to be performed. The treatment outcome is favorable in
      women whose tumors show a complete pathological response. Histological grade, HER
      2, p53, and hormone receptor status are significant predictive factors of a good
      pathological response to neoadjuvant chemotherapy. In addition, computed
      tomography and/or magnetic resonance imaging are useful tools in determining the
      optimal resection area for breast cancer.

PMID- 12478856
TI  - [Wide excision as a method of breast-conserving surgery for breast cancer].
AB  - Breast-conserving treatment has become the standard treatment for early breast
      cancer, not only in Western countries but also in Japan. Wide excision is
      perferred to quadrantectomy because the former results in better cosmesis than
      the latter. However, the margin status may be positive more frequently in the
      former than in the latter. The results of our study indicated that positive
      margins and the absence of radiotherapy or endocrine therapy proved to be
      independent risk factors for local recurrence. Because margin status influences
      local control, tumor margins after wide excision should be accurately determined,
      and higher doses of radiotherapy and adjuvant therapy are indicated for patients
      with positive margins.

PMID- 12478857
TI  - [Breast-conserving surgery: quadrantectomy].
AB  - The surgical techniques and clinical results of quadrantectomy as a form of
      breast-conserving surgery are described. A quadrantectomy is a breast-conserving
      technique including wide resection and tumorectomy. A quadrantectomy is designed
      to remove an anatomic segment of breast tissue (duct-lobular system). It has the
      advantage of greater surgical curability than other conserving techniques in
      cases with ductal spread, because breast cancer arising in the terminal duct
      often spreads in the duct-lobular system. However, quadrantectomy poses some
      cosmetic problems due to the large volume of breast tissue excised. Additionally,
      quadrantectomy has failed to show better results in local recurrence rates
      compared with wide resection. Therefore quadrantectomy should be limited to
      breast cancer with segmental and wide ductal spread. It is important to determine
      the surgical technique that compromises between local curability and cosmetic
      results for each patient with breast cancer.

PMID- 12478859
TI  - [Current indications for mastectomy in patients with breast cancer].
AB  - Recent aggressive changes in the strategy for breast cancer treatment have
      reduced the frequency of mastectomy as the primary surgery. In addition to the
      current expanded indications for breast-conserving therapy (BCT), the
      introduction of preoperative chemotherapy for patients with operable tumors
      allows BCT to be performed in a larger population of patients. The results of a
      questionnaire on breast cancer surgery conducted in Japan in 2000 revealed that
      the frequency of radical modified mastectomy had decreased by 52.2%. However,
      mastectomy cannot be completely eliminated, since some patients still present
      with locally advanced tumors and preoperative chemotherapy cannot remove the
      requirement for mastectomy in all patients. The current standard procedure for
      mastectomy appears to be the Auchincloss operation. The Halsted radical
      mastectomy is performed only for patients with cancer involving the pectoralis
      major muscle or the chest wall, and/or with marked axillary lymph node metastasis
      and Rotter's node metastasis. Simple mastectomy is selected for wide-spread
      noninvasive cancer and recently in our department for patients confirmed to be
      node negative by preoperative sentinely lymph node biopsy. In dealing with the
      changes in the treatment algorithm, we need to select the appropriate surgical
      options flexibly.

PMID- 12478858
TI  - [Breast-conserving surgery without radiotherapy in the Cancer Institute Hospital,
      Tokyo].
AB  - We began performing breast-conserving surgery (BCS) in 1986 to achieve complete
      resection of breast cancer and omit postoperative radiotherapy (RT) if serial and
      detailed pathologic examination of the resected specimen within a 5-mm width
      showed that the of margin was cancer free. At of the end of 1998, 1,233 sides of
      the breast had been conserved, of which 827 sides were shown to have cancer-free
      margins. As of the end of 2001, with a mean observation period of 79 months,
      ipsilateral breast tumor recurrence was recognized on 46 sides (19 recurrences,
      27 multiple cancers), for a recurrence rate 5.6% and an annual recurrence rate of
      0.85%. This rate is slightly better than those reported by eminent institutions
      in the USA and Europe which all perform RT, confirming the accuracy and safety of
      our BCS.

PMID- 12478860
TI  - [Sentinel lymph node biopsy and low axillary node sampling for breast cancer].
AB  - Since sentinel lymph node(SLN) biopsy has a higher negative predictive value than
      that of four-node sampling, SLN biopsy might become the new acknowledged standard
      of clinical care for patients with early breast cancer. SLN biopsy is widely used
      in Western countries despite the lack of data from randomized trials. Clinical
      practice guidelines document that SLN biopsy should be performed with prudent
      informed consent and thorough surgical technique. Before surgeons replace
      axillary dissection with SLN biopsy as the staging procedure at their
      institution, they should perform backup axillary dissection until a detection
      rate of more than 90% and a false-negative rate of less than 5% are achieved.
      Recently, SLN biopsy has more often been indicated for multicentric breast
      cancer, larger tumors, prior excisions, and noninvasive carcinoma. While SLN
      biopsy is widely used in Western countries, there is little experience in Japan.
      If randomized studies, clinical practice guidelines, and the coverage of
      lymphoscintigraphy under health insurance were introduced, SLN biopsy would be
      used more widely in Japan.

PMID- 12478861
TI  - [Axillary lymph node dissection in clinically node-positive breast cancer].
AB  - Many Japanese surgeons think that clinically node-positive breast cancer is
      already a systemic disease. However, about 60% of surgeons believe that the
      survival rate increases with axillary lymph node dissection. Furthermore, 64% of
      surgeons change the area of axillary lymph node dissection based on the
      intraoperative diagnosis of lymph node metastases. We analyzed axillary lymph
      node dissection in clinically node-positive breast cancer using evidence-based
      medicine. We recommend that the level I and II axillary dissection be the
      preferred procedure and that the removal of level III axillary nodes is not
      necessary for staging. However, if grossly positive nodes are identified
      intraoperatively, a level III dissection should be carried out to maximize local
      control.

PMID- 12478862
TI  - [Application of endoscopic surgery for breast cancer treatment].
AB  - Endoscopic breast surgery has the advantage that it can be performed from a
      small, inconspicuous incision remote from the lesion. The cosmetic outcome is an
      important factor in the selection of the surgical technique as in addition to the
      oncologic effect on breast cancer. From this point of view, endoscopic partial
      mastectomy should be performed in patients with small tumors, especially those
      located in the upper quadrants. The approach should be selected for each case
      considering the size and location of the tumor. For patients with multiple tumors
      or with tumors accompanied by extended intraductal components, endoscopic total
      glandectomy or subcutaneous mastectomy with breast reconstruction is a good
      choice. Patients with a tumor located near the skin or invading the skin are not
      candidates for endoscopic surgery. Endoscopic axillary dissection is still
      controversial in its advantages compared with conventional surgery. To avoid
      surgical complications and an increase in the local failure rate of breast
      cancer, selection of patients and the surgical technique must be considered
      carefully.

PMID- 12478863
TI  - [Diagnosis related groups (2). Trend in Japan].

PMID- 12478864
TI  - Cell transplantation in non-ischemic dilated cardiomyopathy. A novel biological
      approach for ventricular restoration.
AB  - OBJECTIVE: With a rising incidence, dilated cardiomyopathy (DCM) is regarded as a
      major health care concern. Although both medical therapy and novel surgical
      treatments have been applied to treat DCM, the effects of preventing left
      ventricular (LV) dilatation are limited, and the mortality rate associated with
      the disease remains high. Thus novel management strategies for improved treatment
      of DCM are awaited. METHODS: Researchers have found that, in models of regional
      ventricular dysfunction, transplanted cells induced a profound biological
      phenomenon that restored contractile function and prevented ventricular
      dilatation. We have investigated muscle cell transplantation in hamsters with
      DCM, and have found that heart cells and smooth muscle cells survived in the host
      myocardium after transplantation, which suppressed LV dilatation and wall
      thinning, and preserved heart function. Our current studies are focusing on the
      clinical applicability of these encouraging early findings by evaluating the
      optimal cell types, the timing of transplantation, and cryopreservation as cell
      storage. Concurrently, we are investigating the influence of cell transplantation
      on myocardial remodeling in order to outline the mechanism of benefit afforded by
      donor cell engraftment. We believe that the timing of cell transplantation with
      respect to the progression of the underlying disease is critical in preventing
      ventricular thinning, dilation and preserving cardiac function. CONCLUSIONS: This
      novel approach can be a clinically applicable biological therapy for patients
      with progressive DCM. More studies to uncover the specific molecular and cellular
      effects of cell transplantation on the host myocardium are necessary for future
      clinical application.

PMID- 12478865
TI  - EVAHEART: an implantable centrifugal blood pump for long-term circulatory
      support.
AB  - OBJECTIVE: We developed "EVAHEART": a compact centrifugal blood pump system as an
      implantable left ventricular assist device for long-term circulatory support. The
      55 x 64 mm pump is made from pure titanium, and weighs 370 g. The entire blood
      contacting surface is covered with an anti-thrombogenic coating of diamond like
      carbon (DLC) or 2-methacryloyloxyethyl phosphorylcholine (MPC) to improve blood
      compatibility. Flows exceeding 12 L/min against 100 mmHg pressure at 2600 rpm was
      measured. A low-temperature mechanical seal with recirculating cooling system is
      used to seal the shaft. EVAHEART demonstrated an acceptably low hemolysis rate
      with normalized index of hemolysis of 0.005 +/- 0.002 g/100L. METHODS: We
      evaluated the pump in long-term in-vivo experiments with seven calves. Via left
      thoracotomy, we conducted left ventricular apex-descending aorta bypass, placing
      the pump in the left thoracic cavity. RESULTS: Pump flow rates was maintained at
      5-9 L/min, pump power consumption remained stable at 9-10 W in all cases, plasma
      free Hb levels were less than 15 mg/dl, and the seal system showed good seal
      capability throughout the experiments. The calves were sacrificed on schedule on
      postoperative day 200, 222, 142, 90, 151, 155, and 133. No thrombi formed on the
      blood contacting surface with either the DLC or MPC coating, and no major organ
      thromboembolisms occurred except for a few small renal infarcts. CONCLUSION:
      EVAHEART centrifugal blood pump demonstrated excellent performance in long-term
      in-vivo experiments.

PMID- 12478866
TI  - A new technique for muscle flap closure of the empyema space in complicated
      chronic bronchopleural fistula. Wedging the causative bronchus with a plug.
AB  - OBJECTIVES: It is difficult to close the empyema space once it is opened,
      especially in cases complicated with a chronic bronchopleural fistula. A muscle
      flap closure is generally employed to prevent this situation. However, this
      operation occasionally fails because the space newly recurs around the fistula
      due to atrophic change occurring in these translocated muscles. The aim of the
      present new technique was to prevent inspiratory pressure from the inside of the
      bronchus by bronchial emboli, and help the adhesion between the fistula stump and
      the muscle flap, even if they have become atrophic and no longer have sufficient
      volume to fill the entire empyema space. METHODS: We carried out fiberscopic
      embolism of causative bronchioles followed by muscle flap closure in 4 patients
      in whom open drainage had already been performed against parapneumonic empyema
      within the bronchial fistula. The bronchial fistula was plugged from the inside
      of the bronchus by silicon material, and stainless steel wire was used to connect
      this plug tightly to the muscle flaps, so that the fistula was sandwiched between
      them. In all cases, we succeeded in complete closure of the bronchial fistula and
      empyema space without using the omentum, and there has been no recurrence.
      CONCLUSION: The presented new technique was beneficial for achieving muscle flap
      closure of the empyema space with a chronic bronchopleural fistula.

PMID- 12478867
TI  - The effect of insufficiency of tetrahydrobiopterin on endothelial function and
      vasoactivity.
AB  - OBJECTIVE: It has recently been defined that levels of tetrahydrobiopterin, a
      cofactor of nitric oxide synthase, decreases under some disease conditions
      including atherosclerosis, hypercholesterolemia, diabetes, and ischemia
      reperfusion. The present study was designed to investigate whether or not a
      deficiency in tetrahydrobiopterin affected vasoactivation in vivo and in vitro.
      SUBJECTS AND METHODS: Male Sprague-Dawley rats were divided into two groups, and
      given either 2, 4-diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of
      tetrahydrobiopterin production, or a vehicle (10% polyethylene glycol 400 in 5%
      glucose, 20 ml/kg), intraperitoneally at 24 hr prior to examination. Responses to
      several vasodilating agents were examined in both pretreatment groups in vivo and
      in vitro. Furthermore, the isolated heart was perfused with a 37 degrees C Krebs
      Henseleit solution for 30 min. The effects of insufficient tetrahydrobiopterin on
      the left ventricular function were examined. Moreover, nitrite plus nitrate (NOx)
      in the coronary effluent was examined in both groups. RESULTS: Depressor and
      vasodilatation responses to an endothelium-dependent vasodilator were
      significantly attenuated in the DAHP Group in comparison with those in the
      vehicle Control Group, while the endothelium-independent vasodilator caused
      equivalent depressor and vasodilatation responses between the two groups. The NOx
      levels in the coronary effluent were lower in the DAHP Group than in the Control
      Group (p < 0.05). The cardiovascular parameters were also lower in the DAHP Group
      than in the Control Group. CONCLUSIONS: We concluded from these findings that a
      deficiency in tetrahydrobiopterin aggravated endothelial dysfunction and the left
      ventricular dysfunction. These findings were consistent with the hypothesis that
      decreased levels of tetrahydrobiopterin may cause cardiac and vascular
      dysfunction.

PMID- 12478868
TI  - Splenic abscess associated with active infective endocarditis.
AB  - Splenic abscess is a rare complication in infective endocarditis. Here, we
      present two cases of splenic abscess associated with active infective
      endocarditis. Body computed tomography before emergency valvular surgery revealed
      abscess in the spleen. In case 1, the abscess was localized within the spleen;
      splenectomy and valve replacement were performed through the same median skin
      incision. In case 2, the splenic abscess was diagnosed as ruptured; valve
      replacement was performed, followed by splenectomy through a separate skin
      incision. No recurrence of infection occurred after surgery in either case. In
      surgical treatment for active infective endocarditis, body computed tomography is
      essential to diagnose splenic abscess preoperatively. If there is an abscess,
      then splenectomy and valvular surgery should be performed simultaneously to
      prevent reinfection after valvular surgery. The approach to the spleen should be
      individualized according to the extension of the abscess.

PMID- 12478869
TI  - Left pulmonary artery occlusion due to compression by aortic aneurysm.
AB  - A 72-year-old man with shock was transferred to our emergency room. The computed
      tomograms revealed a ruptured giant thoracic aortic aneurysm obstructing the left
      pulmonary artery. Emergency total aortic arch replacement was performed, and the
      postoperative course was uneventful. The postoperative angiography confirmed the
      total occlusion in the left pulmonary artery which was due to compression by the
      aortic aneurysm.

PMID- 12478870
TI  - Modified Ross procedure with stentless bioprosthesis and pericardial xenograft
      for the right ventricular outflow tract. Usefulness of autologous pericardial
      patch for hemostasis.
AB  - A 31-year-old man with severe aortic regurgitation due to a defective bicuspid
      valve underwent surgery using modified Ross procedure. The right ventricular
      outflow tract (RVOT) was reconstructed with a 25 mm stentless xenograft valve
      sutured with a rolled equine pericardium. Oozy bleeding from the RVOT was
      controlled with an autologous pericardial patch and fibrin glue. Postoperative
      echocardiography showed no aortic regurgitation. No blood transfusion was
      required.

PMID- 12478871
TI  - Anastomosis between the left atrial appendage and left superior vena cava in a
      patient with mitral atresia.
AB  - A 5-day-old boy with mitral atresia and restrictive interatrial communication
      underwent an anastomosis between the left atrial appendage and left superior vena
      cava draining to the right atrium after unsuccessful balloon atrial septostomy.
      Consequent reduction of left atrial pressure improved the child's clinical
      condition, enabling palliative surgery. This procedure may be done safely without
      cardiopulmonary bypass in a seriously ill patient with combined elevated left
      atrial pressure and persistent left superior vena cava.

PMID- 12478872
TI  - Surgery for coronary artery disease with penetrating atherosclerotic ulcer of the
      ascending aorta.
AB  - Penetrating atherosclerotic ulcer (PAU) is most often found in the descending
      aorta but rarely in the ascending aorta. In such a rare case, a 63-year-old man
      with ischemic change at precordial leads in electrocardiography was found in
      coronary angiography to have the left main trunk stenosis and in aortography
      (aortic phase of left ventriculography) to have PAU in the ascending aorta. We
      conducted 3-vessel coronary artery bypass grafting and replaced the ascending
      aorta. Preoperative evaluation of the ascending aorta is thus important in
      cardiac surgery as in this case.

PMID- 12478873
TI  - Benign fibrous histiocytoma of the trachea.
AB  - Benign fibrous histiocytoma of the trachea is a rare neoplasm. We reported 2
      cases, one aged 3 years and one 5 years, with endotracheal fibrous histiocytoma
      showing no clinical evidence of malignancy. Two segments of the trachea were
      resected and an end-to-end anastomosis was done in 1 case and circular resection
      of the left bronchi and carinoplasty for the other. Pathologically, both tumors
      consisted of spindle cells arranged in storiform and fascicular patterns.
      Immunohistochemically, tumor cells stained for vimentin and CD68 but were
      negative for P53. These cellular features and immunohistochemical findings
      indicate benign fibrous histiocytoma of the trachea. No recurrence was seen.

PMID- 12478874
TI  - Congenital heart surgery nomenclature and database project. Update and proposed
      data harvest.
AB  - In 1998, the first report of the Society of Thoracic Surgery (STS) National
      Congenital Heart Surgery Database defined clinical features for 18 congenital
      heart disease categories, providing a significant amount of important information
      and pinpointing database strengths and weaknesses. Following this report, the STS
      Congenital Heart Surgery Committee, working with the European Association of
      Cardio-Thoracic Surgery and the European Congenital Heart Surgeons Foundation,
      initiated the International Congenital Heart Surgery and Nomenclature Database
      Project. To standardize nomenclature and reporting strategies and establish a
      foundation for an international congenital heart surgery database. The project's
      first report was published in the Annals of Thoracic Surgery in April 2000. The
      current report outlines modifications to the minimal dataset and diagnosis and
      procedure short lists.

PMID- 12478875
TI  - Old and new antidepressants: where are we?

PMID- 12478876
TI  - World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for
      biological treatment of bipolar disorders. Part I: Treatment of bipolar
      depression.
AB  - These practice guidelines for the biological, mainly pharmacological treatment of
      bipolar depression were developed by an international task force of the World
      Federation of Societies of Biological Psychiatry (WFSBP). Their purpose is to
      supply a systematic overview of all scientific evidence pertaining to the
      treatment of bipolar depression. The data used for these guidelines have been
      extracted from a MEDLINE and EMBASE search, and from recent proceedings of key
      conferences and various national and international treatment guidelines. Their
      scientific rigor was categorised into four levels of evidence (A-D). As these
      guidelines are intended for clinical use, the scientific evidence was not only
      graded, but also commented on by the experts of the task force to ensure
      practicability.

PMID- 12478877
TI  - Changes in the molecular structure of the brain in bipolar disorder: findings
      using human postmortem brain tissue.
AB  - Human postmortem brain studies are beginning to suggest mechanisms that underlie
      the pathology of bipolar disorder. Evidence that implicates abnormalities in G
      protein, neurotransmitter turnover, neurotransmitter receptors and
      neurotransmitter receptor signal amplification will be reviewed. In addition,
      individual studies that suggest roles for pre-synaptic proteins, neuronal
      guidance proteins, neuropeptides, intra-neuronal ion homeostasis and
      environmental factor reactive proteins in the pathology of the disorder are also
      presented. Together these studies confirm that the pathology of bipolar disorder
      is complex but is yielding to intense study of the molecular architecture of
      postmortem brain tissue from subjects with the illness.

PMID- 12478879
TI  - Myo-inositol has no beneficial effect on premenstrual dysphoric disorder.
AB  - Inositol, a simple isomer of glucose, which serves as a precursor in the
      phosphatidyl-inositol (PI) second messenger cycle, was shown to be effective in
      double-blind, placebo-controlled studies of depression, panic and obsessive
      compulsive disorders as well as in bulimia. The following study was designed to
      investigate whether inositol has beneficial effects in another disorder shown to
      be responsive to SSRIs: premenstrual dysphoric disorder (PMDD). Eleven female
      patients with PMDD diagnosed according to DSM-IV participated in a cross-over,
      double-blind, placebo-controlled trial. The active drug was myo-inositol, 12 g
      daily, whereas placebo was d-glucose administered at the same dose. Each drug was
      given during the luteal phase only (14 days prior to menses). For each patient
      treatment alternated between these two drugs for six menstrual cycles. No
      beneficial effect was demonstrated for inositol over placebo.

PMID- 12478878
TI  - Receptor and transporter imaging studies in schizophrenia, depression, bulimia
      and Tourette's disorder--implications for psychopharmacology.
AB  - Considerable progress has been achieved over the past 15 years in uncovering the
      biological basis of major psychiatric disorders. To determine patterns of brain
      dysfunction and to uncover the mechanism of action of centrally active compounds
      we used single photon emission computerized tomography (SPECT) as well as
      positron emission tomography (PET) in patients diagnosed with schizophrenia,
      depression, bulimia and Tourette's disorder. Striatal D2 and 5-HT1A receptors
      were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and
      bulimia. Patients were either drug-naive or drug free, or we studied the
      influence of specifically acting compounds on receptor/transporter occupancy. We
      could demonstrate that atypical antipsychotics have a dose-dependent (with the
      exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate
      compared with typical neuroleptics, paralleling the more favourable
      extrapyramidal side effects of atypical antipsychotics. However, no association
      between striatal D2 receptor occupancy rates and antipsychotic efficacy has been
      found. The measurement of 5-HT1A receptors in drug-naive schizophrenic patients
      using the in vivo PET methodology revealed an increase of cortical 5-HT1A
      receptor binding potential in schizophrenia. beta-CIT as a ligand for measurement
      of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared
      to age- and sex-matching healthy controls, a measurement that has also been
      obtained for bulimia. We also documented seasonal variations in brain
      serotonergic function by our finding of reduced brain 5-HTT availability in
      winter (compared to summer) in healthy controls. Furthermore, displaceable [123I]
      beta-CIT binding in the area corresponding to the left striatum (representing
      predominantly the density of dopamine transporters) was significantly reduced in
      SAD patients compared to healthy controls. In depression as well as in bulimia,
      selective serotonin reuptake inhibitors significantly decreased the beta-CIT
      binding potential, however, no significant dose relationship has been obtained in
      depression. Genotyping depressed patients for the serotonin transporter promoter
      gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation
      of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon
      pons of healthy subjects. In patients suffering from Tourette's disorder (TD) we
      were unable to detect differences of dopamine transporter densities between
      psychotropic drug-naive TD patients and controls. Furthermore, no difference
      could be found between currently treated (with antipsychotics) and psychotropic
      drug-naive TD patients. Our data provide insight into the pathophysiology of
      neuropsychiatric disorders and may guide future psychopharmacological drug
      developments.

PMID- 12478880
TI  - A pilot controlled trial of transdermal nicotine in the treatment of attention
      deficit hyperactivity disorder.
AB  - OBJECTIVE: To test the hypothesis that transdermal nicotine would be efficacious
      for the treatment of children and adolescents with attention deficit
      hyperactivity disorder (ADHD). METHOD: This was a double-blind, placebo
      controlled, randomized, pilot trial that compared the effects of daily
      transdermal nicotine (5 mg/16 hrs) to placebo in children and adolescents with
      ADHD. There was a three-day washout period of all psychotropic medication
      followed by a one-week treatment period. RESULTS: All 10 subjects enrolled (six
      males, four females; mean age = 10 years, SEM = 0.8) completed the study. As
      assessed by the 48-item Conners Parent Rating Scale at endpoint and during the
      trial, there was a significantly greater reduction in ADHD symptoms on "Learning
      Problems" and "Hyperactivity" subfactors. Nausea, stomach ache, itching under
      patch and dizziness were the most frequently reported adverse effects associated
      with transdermal nicotine. CONCLUSIONS: While the results of this study support
      previous research indicating that nicotinic receptor modulation may be a
      potentially useful strategy for the treatment of ADHD, therapeutic uses of
      nicotine are limited due to side effects. Thus, future research should
      investigate ways of improving the therapeutic index of nicotinic ligands in the
      treatment of ADHD, such as testing selective nicotinic antagonists alone or in
      combination with cholinergic agonists.

PMID- 12478881
TI  - Double-blind antiglucocorticoid treatment in schizophrenia and schizoaffective
      disorder: a pilot study.
AB  - BACKGROUND: Antiglucocorticoids, such as ketoconazole, have been investigated as
      antidepressant agents in major depression and other conditions. Despite evidence
      that a significant number of patients with schizophrenia and schizoaffective
      disorder are both hypercortisolemic and depressed, the antidepressant effects of
      antiglucocorticoids have never been assessed in these populations. METHODS:
      Fifteen symptomatic patients with diagnoses of schizophrenia or schizoaffective
      disorder, who were at least partially treatment-resistant, were treated with
      ketoconazole, up to 800 mg/day, (n = 8) or placebo (n = 7) for four weeks in a
      double-blind manner. The study medication was added to a pre-stabilized
      antipsychotic and/or antidepressant medication regimen. RESULTS: Ketoconazole
      treatment, compared to placebo, was associated with significant improvements in
      observer-rated depression, but not in subjectively rated depression, positive or
      negative psychotic symptom ratings, or cognitive performance scores. CONCLUSIONS:
      These pilot data partially support the hypothesis that antiglucocorticoids reduce
      depressive symptoms in patients with schizophrenia and schizoaffective disorder,
      although objective and subjective ratings may not be similarly affected during a
      four-week course of treatment. Further studies with larger sample sizes, more
      extensive endocrine assessments and longer duration of drug administration seem
      warranted.

PMID- 12478882
TI  - Treatment of late onset autism as a consequence of probable autommune processes
      related to chronic bacterial infection.
AB  - Two cases are described of children who at first developed normally, but before
      the age of three developed autistic symptoms following the reactivation of a
      chronic oto-rhinolaryngologic infection. The clinical and laboratory data of the
      cases support the aetiological hypothesis of an autoimmune process.
      Adrenocorticotrophic hormone (ACTH), prescribed in the first months of the
      disease, cured one case. The other patient, who was two years old when autistic
      symptoms appeared and was treated only six years later, showed a partial but
      definitive improvement with the immunosuppressive treatment. This report proposes
      that reactivation of a chronic bacterial infection be included among the
      aetiologies of Late Onset Autism, and demonstrates that, when the aetiological
      hypothesis of an autoimmune process based on clinical and laboratory data is
      considered, an immunosuppressive treatment, particularly with ACTH, can be very
      effective and also safe.

PMID- 12478883
TI  - Serotonin syndrome produced by a combination of venlafaxine and mirtazapine.

PMID- 12478884
TI  - [Correlation between the kinetics of plasma EBV DNA levels and clinical response
      during treatment in patients with nasopharyngeal carcinoma].
AB  - BACKGROUND & OBJECTIVE: Nasopharyngeal carcinoma(NPC) is an EB virus (EBV)
      related cancer. Recently, it was reported that EBV DNA can be detected in NPC
      patients' plasma or serum. This study was designed to investigate the correlation
      between the kinetics of plasma EBV DNA levels and clinical response during
      concomitant chemo-radiotherapy in the locally advanced nasopharyngeal carcinoma
      patients. METHODS: Blood samples from 20 patients were collected weekly during
      chemo-radiotherapy(7 times, in total). The first blood sample was collected
      before treatment. The content of EBV DNA in the samples were detected by using
      fluorescent quantitative PCR method in the PE Appliance Biosystems 7700 Sequence
      Detector. RESULTS: Before treatment, plasma EBV DNA was detectable in the plasma
      of 90% (18/20) NPC patients. The median concentration was 150,000(copies/ml). Two
      patients' plasma EBV DNA could not be detected during the whole course of
      treatment. Among 18 EBV DNA-positive patients, 3 patients had a continuously high
      EBV DNA and clinical examination after treatment indicated that they had residual
      tumors. Seven patients'plasma EBV DNA levels had a rapid decline to be
      undetectable. Eight patients' plasma EBV DNA levels got a slow decline, but the
      EBV DNA could not be detected at the end of therapy as well. Clinical examination
      revealed that all of these 15 patients had complete tumor regression. CONCLUSION:
      Kinetic analysis of plasma EBV DNA during treatment may be a useful tool to
      monitor the treatment response in NPC patients. Further investigation is
      warranted.

PMID- 12478885
TI  - [Apoptosis of K562 cell induced by N-phosphoryl dipeptide methyl ester].
AB  - BACKGROUND & OBJECTIVE: Phosphorus plays a crucial role in metabolism. Some N
      phosphoryl amino acids and N-phosphopeptides have important biological activities
      and medicinal value. The current study was designed to investigate the apoptosis
      of K562 cells induced by N-phosphoryl dipeptide methyl ester. METHOD: Cell growth
      inhibition of K562 cells induced by 15 kinds of N-phosphoryl dipeptide methyl
      esters was analyzed by using MTT assay. The nuclei were stained by Hoechst 33,258
      and the morphologic changes were observed. DNA agarose gel electrophoresis,
      double-staining, and flow cytomery were used to detect early apoptosis of K562
      cells. RESULT: (DIPP-L-Leu)2-L-Lys-OCH3 was the compound screened with MTT method
      that had better growth inhibiting activity with the IC50 of 22.66 mumol/L.
      Chromatin condensation and nuclear fragmentation were seen under fluorescence
      microscope in the cells treated with Hoechst 33,258. DNA agarose gel
      electrophoresis showed nuclear fragmentation (DNA ladder). Early apoptotic cells
      were also detected by flow cytometry. CONCLUSION: These results suggest that(DIPP
      L-Leu)2-L-Lys-OCH3 could induce the apoptosis of K562 cells.

PMID- 12478886
TI  - [Chemotactic peptide fMLP enhances antitumor activity of boanmycin].
AB  - BACKGROUND & OBJECTIVE: Boanmycin (BAM), a single A6 component of the bleomycin
      complex, is effective against a panel of cancers in clinical trials. Chemotactic
      peptide can activate and attract leukocytes and macrophages that may interfere
      with the process of tumor growth, invasion, and metastasis. This study was
      designed to investigate the antitumor activity of BAM in combination with
      chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine(fMLP). METHODS:
      Cytotoxicity of BAM and fMLP to tumor cells was determined by MTT assay,
      particularly in presence of macrophages. Therapeutic effect was evaluated by
      using the model of subcutaneously transplanted hepatoma 22 in mice. RESULTS: In
      vitro experiment showed that BAM and fMLP had no synergism in cytotoxicity to
      tumor cells. However, in the presence of macrophages, BAM at concentrations of
      10, 30, and 100 micrograms/ml in combination with fMLP 20 micrograms/ml displayed
      synergistic effect in cytotoxicity. In all in vivo experiments, fMLP administered
      peritumorally 3 times at the dose of 1 mg/mouse showed no significant growth
      inhibition. Three settings of BAM and fMLP combination included: (1) BAM,
      administered peritumorally x 3, was started 24 h after tumor inoculation. BAM
      (0.5 mg/kg) alone and BAM-fMLP combination inhibited the growth of hepatoma 22 by
      26.6% and 64.7%, respectively (P < 0.05, CDI = 0.36) on day 13. (2) BAM,
      administered i.p. x 3, was started 24 h after tumor inoculation. The tumor growth
      in BAM (1 mg/kg) group was faster than that in BAM-fMLP combination group. On day
      14, BAM (1 mg/kg) alone and BAM-fMLP combination suppressed the tumor growth by
      11% and 70.6%, respectively (P < 0.05, CDI = 0.42). (3) BAM, administered i.p. x
      3, was started 96 h after tumor inoculation. The tumor growth in BAM (1 mg/kg)
      group was faster than that in BAM-fMLP combination group. On day 13, BAM (1
      mg/kg) alone and BAM-fMLP combination suppressed the tumor growth by 38.2% and
      77.1%, respectively (P < 0.05, CDI = 0.51). As shown in all in vivo experimental
      settings, antitumor effect of BAM in combination with fMLP was much more potent
      than that of BAM alone. CONCLUSION: This experiment shows that chemotactic
      peptide fMLP may enhance the antitumor effect of BAM and the enhancement may need
      the participation of macrophages. Chemotactic modulation may play a role in
      cancer chemotherapy.

PMID- 12478887
TI  - [Circadian rhythms of DNA synthesis and apoptosis correlated gene expression in
      bone marrow cells of nude mice bearing human nasopharyngeal carcinoma].
AB  - BACKGROUND & OBJECTIVE: No report was found on research of circadian rhythms of
      nasopharyngeal carcinoma(NPC). This study was designed to investigate the
      circadian rhythms of DNA synthesis and apoptosis correlated gene expression in
      bone marrow cells of nude mice bearing NPC and to collect necessary data for
      making clinical chronochemotherapy schedule of NPC. METHODS: Sixty-nine BALB/C
      nude mice were synchronized with an alternative lighting regimen with 12 hours in
      light and 12 hours in dark (LD 12:12) for at least 3 weeks. Human nasopharyngeal
      poorly differentiated squamous cell carcinoma (CNE-2) cells were implanted into
      each mouse. Ten days after transplantation, the mice were sacrificed, bone marrow
      cells were collected in the 3, 7, 11, 15, 19, and 23 hours after light onset
      (HALO). Single cell suspension was obtained and stained with propidium iodide.
      The cellular DNA content was measured by flow cytometry. Data were analyzed with
      analysis of variance(ANOVA) and Cosinor analysis. Proteins were extracted from
      bone marrow cells and determined; Bcl-2, p53, and p21 expression were tested
      using Western blot analysis. RESULTS: The proportion of bone marrow cells in
      phase G1, S, and G2/M varied according to circadian sampling time with
      statistical significance (ANOVA). Moreover, such variation in G1 and G2/M was
      statistically valid by Cosinor analysis with an acrophase located at 10.8 HALO
      and 1.8 HALO, respectively. The distribution curves of phase G1 and G2/M fit to
      Cosinor changes but not for S phase cells. The expression of p53 and Bcl-2
      protein level in bone marrow cells varied in 24 h time scale. No p21 protein
      expression was found in this experiment. CONCLUSION: DNA synthesis of bone marrow
      cells in nude mice bearing human nasopharyngeal poorly differentiated squamous
      cell carcinoma (CNE-2) cells varies according to circadian rhythm. The expression
      of p53 and Bcl-2 protein level in bone marrow cells varies in 24 h time scale.

PMID- 12478888
TI  - [In situ gene therapy for murine gastric carcinoma with UPRT/5-FU enzyme/prodrug
      system mediated by retrovirus].
AB  - BACKGROUND & OBJECTIVE: 5-Fluorouracil(5-FU), a widely used chemotherapeutic
      drug, has a limited overall effect in the treatment of human solid tumors due to
      resistance. This study was designed to investigate if antitumor activation of 5
      FU could be enhanced by transfection of uracil phosphoribosyltransferase(UPRT)
      gene. METHODS: The UPRT gene encoding uracil phosphoribosyltransferase was
      amplified from Escherichia Coli K12 genome and subcloned into retrovirus
      expression vector pLXSN, Recombinant retrovirus was packaged and used further to
      infect murine gastric cancer cell line MFC. The sensitivity of MFC transfected
      with UPRT gene to 5-FU was determined by MTT method. In situ gene therapy was
      performed by regional repeated injections of concentrated and purified
      recombinant retrovirus carrying UPRT gene intratumorally and followed by
      administration of 5-FU intraperitoneally(i.p.). RESULTS: The 5-FU sensitivity in
      MFC transfected with the UPRT gene increased 17.26-fold compared to the control
      cells. In situ transfection of the UPRT gene mediated by retrovirus vector
      followed by the administration of 5-FU (10 mg/kg) significantly inhibited the
      tumor growth (P < 0.005) with an inhibition rate of 87.18% and prolonged the
      survival. CONCLUSION: Transfection of UPRT gene can render the murine gastric
      cancer cell line MFC be more sensitive to low concentration of 5-FU and
      significantly improve the antitumor effect of 5-FU both in vitro and in vivo.

PMID- 12478889
TI  - [Adriamycin thermotherapy through hepatic artery for model of VX2 carcinoma in
      rabbit liver].
AB  - BACKGROUND & OBJECTIVE: It was reported that heating can enhance sensitivity of
      rabbit VX2 cell to adriamycin and increase intracellular concentration of
      adriamycin. This study was designed to evaluate the anti-tumor effects of
      interventional hyperthermia and interventional chemotheramotherapy on VX2
      carcinoma in rabbit liver. METHODS: VX2 carcinoma cells were surgically implanted
      into the right liver lobe of 60 male New Zealand white rabbits, which were
      randomly divided into 4 groups(15 rabbits per group). To inject physiological
      saline(37 degrees C), adriamycin (37 degrees C), physiological saline(60 degrees
      C), and adriamycin (60 degrees C) in different groups via hepatic artery of the
      rabbits with liver cancer. One week later, to observe the volume of tumor, the
      serum level of aspartate transaminase(AST), and observe the survival period of
      VX2 rabbits. RESULTS: In group of ADM(60 degrees C), the tumor growth rate (0.53
      +/- 0.21)% was significantly lower than group 2(1.09 +/- 0.26)%, group 3(3.32 +/-
      1.28)%, and group 4(3.48 +/- 1.17)% (P < 0.05, P < 0.05, P < 0.01, respectively).
      The survival period of adriamycin (60 degrees C) group (50.0 +/- 2.0)d was
      significantly higher than the untreated control group (40.5 +/- 3.0)d, (P <
      0.05). The serum level of AST of TNP-470 with lipiodol group was not higher than
      the other treated groups(P > 0.05), but being significantly higher than the
      untreated control group after treated(P < 0.05). CONCLUSION: Adriamycin (60
      degrees C) greatly decreases the tumour growth rate, and prolongs the survival
      period.

PMID- 12478890
TI  - [Relationship between multidrug resistance in human colon carcinoma LoVo/Adr cell
      line and intracellular calcium ion concentration].
AB  - BACKGROUND & OBJECTIVE: Based on the findings that calcium content increased in
      multidrug resistant (MDR) cells and that the resistance could be reversed by the
      calcium channel blocker verapamil, it has been speculated that Ca2+ may have role
      in drug resistance. This study was designed to investigate the relationship
      between multidrug resistance in human colon carcinoma LoVo/Adr cells and the
      level of cytoplasmic Ca2+. METHODS: Fluo-3/AM was used to label Ca2+ in the
      cytoplasm and confocal microscope was used to observe the changes of Ca2+
      concentration. The reverse effect of verapamil was determined by MTT method. The
      content of intracellular adriamycin(ADR) was determined by flow cytometry.
      RESULTS: Fluo-3/AM fluorescent intensities of LoVo and LoVo/Adr cells were 850.45
      and 1,495.88, respectively. After treatment with verapamil, Fluo-3/AM fluorescent
      intensities of LoVo and LoVo/Adr cells were 813.25 and 1,284.14, respectively.
      The level of Ca2+ in the cytoplasm of LoVo/Adr cells was significantly higher
      than that in LoVo cells, and was not significantly changed by verapamil. The
      concentration of ADR was increased by verapamil in LoVo/Adr cells. The
      potentiation folds of adriamycin and vincristine by verapamil in LoVo/Adr cells
      were 8.85 and 5.31, respectively. CONCLUSION: The increasement of cytoplasmic
      calcium content might be a characteristic phenotype of MDR LoVo/Adr cells.
      However, there was no direct relationship between multidrug resistance and
      cytoplasmic Ca2+ concentration.

PMID- 12478891
TI  - [Inhibition of activator protein-1 on the growth of gastric cancer by
      octreotide].
AB  - BACKGROUND & OBJECTIVE: Somatostatin is a multi-functional neuropeptide.
      Somatostatin and its analogues are able to inhibit the growth of neuroendocrine
      tumors and some gastrointestinal tumors. However, the effect of octreotide on
      growth of gastric carcinoma is still unknown. This study was designed to explore
      the mechanism of the effect of octreotide on growth of gastric cancer. MATERIAL &
      METHODS: SGC-7901 cells were treated with octreotide at different concentrations
      for 24 hours. Proliferation of SGC-7901 cells was measured by 3H-thymidine
      incorporation assay. The nude mice bearing human stomach carcinoma were treated
      by octreotide for eight weeks. The c-Fos and extracellular signal-regulated
      protein kinase (ERK) protein expression levels were examined in SGC-7901 cells
      and carcinoma tissue by immunohistochemistry and immunoblotting. Activator
      protein-1 (AP-1) binding activity was detected by electrophoretic mobility shift
      assay (EMSA). RESULTS: 3H-thymidine incorporation into SGC-7901 cells was
      significantly decreased by octreotide and showed concentration-dependent.
      Octreotide could significantly inhibit the growth of orthotopical implanted
      gastric cancer, the inhibition rate for tumors was 62.3%. The c-Fos and ERK-1/ERK
      2 proteins were decreased in the nude mice carcinoma tissues and SGC-7901 gastric
      carcinoma cells which treated with octreotide by immunohistochemistry or
      immunoblotting analysis. Moreover, the fetal calf serum (FCS) stimulated AP-1
      binding activity on gastric cancer cell and the somatostatin analogue octreotide
      could inhibit this response efficiently. CONCLUSION: Octreotide inhibits not only
      ERK-1/ERK-2 and c-Fos expressions but also AP-1 binding activity, which result in
      inhibition to proliferation of gastric carcinoma cell.

PMID- 12478892
TI  - [Effect of boanmycin on apoptosis and cell cycle of human esophageal cancer(Eca
      109) cells].
AB  - BACKGROUND & OBJECTIVE: The anticancer mechanism of boanmycin was thought to
      inhibit the synthesis of protein in human esophageal cancer cell line. But it is
      not clear that there are other mechanisms of boanmycin to produce its anticancer
      effect on human esophageal cancer. This study was designed to examine the effect
      of boanmycin on apoptosis and cell cycle of human esophageal cancer cells (Eca
      109). METHODS: Microscopic observation, flow cytometry, and agarose gel
      electrophoresis were used to determine the induction of apoptosis and the changes
      of cell cycle. RESULTS: The human esophageal cancer xenografts in nude mice
      treated by boanmycin showed morphological changes of different apoptotic phases.
      In vitro, boanmycin (50-125 micrograms/ml, 30-36 hours) elicited typical
      apoptotic changes in Eca-109 cells and typical DNA ladder of apoptotic cells
      appeared. The Eca-109 cells treated by boanmycin for 42 hours were blocked at
      G2/M phase. CONCLUSION: Boanmycin could induce apoptosis of Eca-109 cells and
      block the cell cycle at G2/M phase.

PMID- 12478893
TI  - [Inhibition of alpha-interferon and cinnamic acid on proliferation of human lung
      cancer cell].
AB  - BACKGROUND & OBJECTIVE: Recently, the research showed that cinnamic acid (CINN)
      could inhibit some cancer cells. This study was designed to investigate the
      effects of alpha-interferon and CINN on proliferation of human lung cancer cells.
      METHODS: Human lung adenocarcinoma cell A549 were treated with alpha-interferon
      and CINN. The growth curve, soft-agar colony-forming rate, and methyl
      greenpyronine staining were used to analyze the inhibition to cell proliferation.
      The cell cycle was detected by flow cytometry(FCM). RESULTS: alpha-interferon and
      CINN could markedly inhibit proliferation of A549 (P < 0.05), promote the
      differentiation (P < 0.05), and reduce the colony-forming rate in the soft-agar
      drastically(P < 0.05), FCM showed that the cell cycle was arrested in the G1/G0
      phase. CONCLUSION: alpha-interferon and CINN can inhibit the proliferation of
      lung adenocarcinoma cell. Combination of the alpha-interferon and CINN show the
      stronger effect that the alpha-interferon or CINN alone.

PMID- 12478894
TI  - [Impact of arsenic trioxide on proliferation and metastasis of drug-resistant
      human ovarian carcinoma cell line].
AB  - BACKGROUND & OBJECTIVE: The drug-resistance and metastasis in early stages of
      human malignant ovarian neoplasm have significant effect on chemotherapy of human
      ovarian carcinoma. The objective of this study was to explore the impact of
      arsenic trioxide(As2O3) on proliferation and metastasis of drug-resistant human
      epithelial ovarian carcinoma cell line 3AO/cDDP, in order to treat human ovarian
      carcinoma thoroughly. METHODS: The growing inhibiting rates of drug-resistant
      human ovarian carcinoma cell line 3AO/cDDP by various concentrations of As2O3 in
      different time course were studied by methyl thiazolyl tetrazolium (MTT) method;
      Apoptosis percentage, cell cycle phase distribution and expressions of Fas, N
      myc, nm23H1 and MTA1 gene were estimated by flow cytometry (FCM); 3AO/cDDP cells
      apoptosis phenotype was observed by transmissional electron microscopy. RESULTS:
      3AO/cDDP cell growing inhibiting rates by As2O3 were significantly different in
      dose-dependent and time-dependent manners(P < 0.05); Within a certain
      concentration range, 3AO/cDDP apoptosis inducing rates by As2O3 were dose- and
      time-dependent, and the most appropriate concentration was 3.0 mumol/L. Lower
      concentrations of As2O3 perturbed cell progressing through S/G2 phase, while
      higher concentrations selectively induced S phase cells apoptosis; As2O3 up
      regulated Fas and nm23H1 gene expressions, but down-regulated N-myc and MTA1 gene
      expressions. Morphological observation indicated that As2O3 inducing 3AO/cDDP
      death characterized by apoptotic phenotype. CONCLUSION: As2O3 could influence the
      capacity of growth and proliferation of drug-resistant human ovarian carcinoma
      cell line and its mechanism could be positively and negatively related with Fas,
      nm23H1 gene and N-Myc, MTA1 gene expressions.

PMID- 12478895
TI  - [Rapid inhibition of extracellular signal-regulated kinase 1/2 in a human ovarian
      cancer cell line by dexamethasone].
AB  - BACKGROUND & OBJECTIVE: Activation of extracellular signal-regulated kinase 1/2
      (ERK1/2) plays an important role in cell proliferation of a variety of cell
      types. The authors had previously found that dexamethasone (Dex), a synthetical
      glucocorticoid, can markedly inhibit the proliferation of a human ovarian cancer
      cell line HO-8910. This study was designed to observe the effect of Dex on the
      activation of ERK1/2 in HO-8910 cells in order to explore the signal transduction
      pathway that mediates the anti-proliferation effect of Dex on these cells.
      METHODS: The activation of ERK1/2 was determined by Western blot analysis, and
      changes of cell proliferation were examined by cell count. RESULTS: Inhibition of
      activation of ERK1 and ERK2 by 1 x 10(-7) mol/L Dex occurred synchronously at 5
      min, with maximum up to 41% and 54%, respectively at 30 min compared with the
      control (P < 0.001), and sustained until 4 h. The effect increased with the
      increasement of concentration of Dex (1 x 10(-10)-1 x 10(-6) mol/L). RU486, an
      antagonist of glucocorticoid receptor (GR), did not block the effect. PD98059, an
      inhibitor of MEK1/2, also inhibited HO-8910 cell proliferation and could enhance
      the growth-inhibition effect of Dex. CONCLUSION: Dex can rapidly inhibit ERK1/2
      activation in a GR-independent manner in HO-8910 cells, which might play a role
      in Dex-mediated growth inhibition.

PMID- 12478896
TI  - [Establishment of a cisplatin-induced human hepatocellular carcinoma drug
      resistant cell line and its biological characteristics].
AB  - BACKGROUND & OBJECTIVE: Drug resistance is a popular topic in tumor study. The
      drug-resistant cell line established in vitro is generally used as the research
      model. To explore the mechanism of resistance of hepatocellular carcinoma(HCC) to
      cisplatin, we designed this study to establish a cisplatin-induced human
      hepatocellular carcinoma drug-resistant cell line and study its characteristics.
      METHODS: A resistant HCC cell line (QGY/cDDP) was established gradually by
      increasing dose of cisplatin and intermittent administration; drug sensitivity
      was detected by MTT assay; the changes of its biological characteristics were
      determined using light microscopy, electron microscopy, cell counting, flow
      cytometry(FCM), and chromatosome analysis. RESULTS: QGY/cDDP cell line was
      developed after 3 months with stable resistance to cisplatin and the resistance
      index was 10.81; QGY/cDDP cells exhibited cross-resistance to many other
      chemotherapeutic agents (5-Fuorouracil, epiadriamycin, etc). The morphology and
      chromatosome number of QGY/cDDP changed; doubling time prolonged; and the cell
      number of S-phase and G2/M-phase decreased while in G0/G1 phase increased
      compared with parent cells. CONCLUSION: QGY/cDDP cell line shows the typical and
      stable resistant phenotype.

PMID- 12478897
TI  - [Expression and significance of beta-catenin in esophageal carcinoma].
AB  - BACKGROUND & OBJECTIVE: Many reports have characterized the aberrant expression
      of beta-catenin in diverse types of human cancer. To determine whether beta
      catenin has possible roles in esophageal carcinogensis, we designed this study to
      detect the expression pattern of beta-catenin in normal esophageal epithelium and
      esophageal cancer tissue, then to study the relevance of its expression and
      localization to tumor differetiation degree and lymph node metastasis. METHODS:
      By using immunohistochemical staining(SP method), the expression of beta-catenin
      was detected in 22 normal esophageal tissue slides and 52 esophageal carcinomas.
      RESULTS: In the 22 normal esophageal tissue, beta-catenin showed high intense
      expression at the membrane and low intense expression at the cytoplasm. In
      contrast to the normal tissue, beta-catenin was expressed in the cytoplasma in
      carcinoma with varied degrees, accompanied by less, or even lost expression at
      the membrane in cancer samples. In some cases, beta-catenin could be detected in
      the nucleus. Moreover, the positive rate of beta-catenin expression in cytoplasm
      was significantly higher in those patients with lymph node metastasis than
      patients without(P < 0.05). CONCLUSIONS: The aberrant expression of beta-catenin
      occurred frequently in the esophageal carcinoma, mainly including the
      translocation of beta-catenin protein from membrane to the cytoplasm and nucleus,
      and the accumulation of beta-catenin in cytoplasma was overt. And the aberrant
      expression of beta-catenin protein was statistically correlated to the lymph node
      metastasis in esophageal cancer.

PMID- 12478898
TI  - [Factors related to acute upper gastrointestinal bleeding after transcatheter
      arterial chemoembolization in patients with hepatocellular carcinoma].
AB  - BACKGROUND & OBJECTIVE: Acute upper gastrointestinal bleeding (UGIB) often occurs
      after transcatheter arterial chemoembolization (TACE) in the patients with
      hepatocellular carcinoma (HCC). The authors studied the factors associated with
      UGIB for better prevention and management of the complication. METHODS:
      Epirubicin, cisplatin, mitomycin, 5-fluorouracil, lipidol and/or gelfoam were
      infused via catheters inserted in ciliac artery, common hepatic artery, arteria
      hepatica propria, or left or right hepatic artery by Seidinger method in 208
      cases of advanced HCC confirmed by image techniques, alpha-fetoprotein (AFP)
      and/or pathology. Factors related to UGIB (vomiting of blood and/or melena, or
      positive fecal occult blood) were analyzed with reference to endoscopy,
      biochemical parameters of liver function, selection of blood vessels, and the
      amount of drugs. RESULTS: Of 208 patients, 31 cases were complicated with UGIB.
      Acute gastric mucosal lesion was confirmed in 18 cases; acute ulcer in 3 cases;
      Mallory-Weiss syndrome in 3 cases; and esophageal varices bleeding in 2 cases.
      Positive correlation was found between B grade of Child-Pugh hepatic functional
      reserve and bleeding (r = 0.59, P < 0.005). The incidence of UGIB in patients in
      whom drugs were infused via ciliac artery (7/18, 38.9%); or common hepatic artery
      (18/38, 47.4%) was significantly higher than in those via arteria hepatica
      propria, left, or right hepatic artery (5/146, 3.4%; P < 0.005). Patients with
      larger amount of chemotherapy drug and embolization agent had higher bleeding
      rate. CONCLUSION: Many factors may be associated with UGIB after TACE in patients
      with HCC, such as higher scores of hepatic functional reserve in Child-Pugh
      grading, selection of blood vessels, and amount of drugs. In order to reduce the
      incidence of UGIB, these factors should be necessarily considered in improvement
      of TACE procedure, in inspection and management after TACE.

PMID- 12478899
TI  - [Clinical study on patients with advanced gastric cancer treated with oxaliplatin
      combining with hydroxycamptothecine].
AB  - BACKGROUND AND OBJECTIVE: Internal and external physiological research showed
      oxaliplatin could obviously suppress several kinds of tumors in combination with
      most anti-cancer drugs and help these drugs to kill the tumor cells. This study
      was designed to investigate the initial curative effects and tolerance of
      patients with advanced gastric cancer of treatment with combination of
      oxaliplatin (L-OHP) and hydroxycamptothecine (HCPT). We compared this treatment
      with traditional chemotherapy. METHODS: In a non-randomized manner, 43 patients
      with advanced gastric cancer were divided into treatment group (L-OHP plus HCPT)
      and control group (VP-16 + CF + 5-FU) (ELF). Among these patients, 28 were male
      and 15 were female. The median age was 59. Karnofsky performance status(KPS)
      scale was more than 60. We compared the initial curative effects and tolerance
      between these two groups. RESULTS: The beneficial effects for the treatment group
      (24 cases) and control group (19 cases) were 58.3% (14/24) and 42.1% (8/19),
      respectively. Obviously, the beneficial effects to the treatment group were
      higher than that of the control group (P < 0.05). The side effects of both groups
      included bone marrow suppression, nausea, vomiting, stomatitis, neuritis,
      phlebitis, hair loss, and so on. But they were slight (within I and II degree).
      CONCLUSIONS: The use of L-OHP plus HCPT appears to be a very good treatment for
      patients with advanced gastric cancer. The patients can tolerate the side
      effects.

PMID- 12478900
TI  - [Inflammatory breast cancer: 38 cases clinical report].
AB  - BACKGROUND & OBJECTIVE: Inflammatory breast cancer (IBC) is a special form of
      rapidly progressive breast cancer with poor prognosis. The purpose of this study
      was to investigate the clinical characters, treatment, and prognosis of
      inflammatory breast cancer. METHODS: Thirty-eight patients with inflammatory
      breast cancer who were diagnosed and treated from March 20, 1970 to December 21,
      2001 in our hospital were analyzed retrospectively. RESULTS: All IBC patients
      presented clinically with an erythematous or swollen and tender breast, no fever.
      The mean age of 38 patients was 45 years old. Twenty-four patients were in stage
      III b and 14 in stage IV. Eighteen patients received local treatment
      (radiotherapy or surgery) firstly and 20 patients underwent chemotherapy firstly.
      Median survival was 17 months. The 1 year and the 5 year survival rates were
      57.7% and 14.0%, respectively. The administration of chemotherapy first improved
      the outcome of IBC. Earlier stage showed more favorable prognosis. CONCLUSIONS:
      Combination therapy with chemotherapy first was an effective treatment for IBC.

PMID- 12478901
TI  - [Clinical study of rhIL-11 for prevention and treatment of chemotherapy-induced
      thrombocytopenia].
AB  - BACKGROUND AND OBJECTIVE: Cancer chemotherapy can induce thrombocytopenia. It is
      necessory to develop drugs that can prevent and treat thrombocytopenia. The
      current study was designed to evaluate the efficacy and toxicity of rhIL-11 in
      prevention and treatment of chemotherapy-induced thrombocytopenia. METHOD: A
      total of 109 cancer patients were involved randomly into AB or BA group and every
      patient received 2 cycles of chemotherapy. IL-11 was administered
      subcutaneously(50 micrograms/kg/d), beginning 24 hours after completion of
      chemotherapy for 14 consecutive days or continuing until platelet count was > 400
      x 10(9)/L during cycle A. Patients did not received IL-11 during cycle B. Another
      41 cases of cancer patients whose platelet were less than 50 x 10(9)/L after
      chemotherapy entered into open study group. IL-11 administration was the same as
      above. RESULTS: Efficacy can be evaluated in 107 cases in controlled study group.
      Mean platelet count of cycle A was (246.49 +/- 88.64) x 10(9)/L and cycle B was
      (180.24 +/- 83.34) x 10(9)/L(P = 0.000). Grade III/IV thrombocytopenia in cycle A
      and cycle B were 7/107(6.5%) and 15/107(14%), respectively (P = 0.04). The
      minimum platelet counts were (136.46 +/- 74.64) x 10(9)/L and (107.77 +/- 61.33)
      x 10(9)/L, respectively (P = 0.000). The maximum platelet counts were (381.28 +/-
      150.39) x 10(9)/L and (207.44 +/- 113.32) x 10(9)/L, respectively (P = 0.000).
      For open study group, 32 patients could be evaluated. The platelet count
      increased from(30.1875 +/- 12.13) x 10(9)/L to (226.25 +/- 163.91) x 10(9)/L
      after IL-11 administration. Major adverse effects were edema, dizziness,
      palpitation, etc. CONCLUSION: rhIL-11 can reduce thrombocytopenia induced by
      chemotherapy and is a safe and effective drug for treatment of thrombocytopenia.

PMID- 12478902
TI  - [Clinical study on single-dose rhG-CSF combined with chemotherapy in autologous
      peripheral blood stem cell transplantation].
AB  - BACKGROUND & OBJECTIVE: This study was designed to evaluate the effectiveness of
      high-dose chemotherapy plus single daily dose of 250 micrograms/d rhG
      CSF(lenograstim) in autologous peripheral blood stem cells mobilization and
      hematopoietic reconstitution after transplantation. METHODS: The study included a
      group of 55 consecutive patients with hematological malignancies (28 cases of
      acute myelogenous leukemia, 9 cases of acute lymphoblastic leukemia, 14 cases of
      non-Hodgkin's lymphoma, 4 cases of other disease) from October 1999 to December
      2001 undergoing either EA or other intensive chemotherapies as CTX, G-CSF
      mobilization began from the day when the WBC count reached nadir until the day of
      apheresis, then after stem cell reinfusion G-CSF support was given on day +3
      until neutrophil recovery. The dose of G-CSF both in mobilization and recovery
      support was 250 micrograms/d s.c. despite the body weight of patients. RESULTS:
      The average time of G-CSF administrating as a mobilizing reagent was 7.12
      days(range 3-14 days), and the mean time of interval from the beginning of
      chemotherapy to apheresis was 18.08 +/- 3.63 days. All patients need an average
      of 1.3 times for apheresis. The median mononuclear cell and CD34+ cell yield were
      4.09 x 10(8)/kg and 8.5 x 10(6)/kg, respectively. G-CSF was used after
      transplantation for a median time of 8 days(range 4-19). All patients achieved an
      ANC > 0.5 x 10(9)/L after a median of 10.5 days (range 8-26). No severe toxic
      reaction was observed. CONCLUSION: We concluded that chemotherapy plus rhG
      CSF(lenograstim) given in the single dose fashion can be used in both mobilizing
      and post transplantation setting with satisfying outcome.

PMID- 12478903
TI  - [Preliminary study on DHAP regimen for patients with relapsed and refractory non
      Hodgkin's lymphoma].
AB  - BACKGROUND AND OBJECTIVE: The treatment of the patients with relapsed and
      refractory non-Hodgkin's lymphoma(NHL) remains difficult. It was reported that
      DHAP regimen(cisplatin + Ara-C + dexamthsone) was an effective salvage therapy,
      but there was no report about it in China. The current study was designed to
      observe the efficacy and toxicity of DHAP regimen for the patients with relapsed
      and refractory NHL. METHOD: Seventeen patients with relapsed and 10 with
      refractory intermediate or high grade NHL was involved in this study. These
      patients were treated with cytarabine 1 g/m2 intravenous(i.v.) every 12 hours on
      day 1 to 2, cisplatin 20 mg/m2 i.v. on day 1 to 4, dexamethone 40 mg i.v. on day
      1 to 4. Four patients with CR after DHAP were followed by autologous peripheral
      blood stem cell transplantation(APBPCT). RESULTS: Overt responses to DHAP were
      seen in 12 patients (44.4%) including 8 complete responses(CR) (29.6%) and 4
      partial responses (PR) (14.8%). The effective release time lasted a median of 4.8
      months. Median survival time was 8.3 months. 1-year and 2-year survival rate were
      30.8% and 19.3%, respectively. Myelosuppression was the major toxicity; 15
      patients(57.7%) had grade III-IV neutropenia and 21 patients (80.8%) had grade
      III-IV thromcytopenia, but there was no treatment-related death. CONCLUSION: The
      authors conclude that DHAP regimen is an effective salvage therapy for the
      patients with relapsed and refractory NHL, but the remission duration time is
      short and long-term prognosis remains poor. High dose chemotherapy supported by
      APBPCT is necessary for improvement in long-term survival.

PMID- 12478904
TI  - [Continuous-infusion high dose ifosfamide as salvage treatment for pre-treated
      soft tissue sarcoma].
AB  - BACKGROUND & OBJECTIVE: Adriamycin, dacarbazine and ifosfamide are three
      effective chemotherapy drugs in treating progressive soft tissue sarcoma.
      However, few regimen is effective for the patients who failed in treatment with
      prior Adriamycin and ifosfamide at standard dose. This study was designed to
      observe and evaluate the efficacy and toxicity of high dose ifosfamide(HDI)
      regimen on pre-treated soft tissue sarcoma. METHODS: Ten patients with advanced
      soft tissue sarcoma and 5 patients after surgical resection were treated with HDI
      administered by continuous infusion at a dose of 14 g/m2 per cycle over 6 days.
      All patients were pretreated with anthracycline +/- standard dose ifosfamide.
      RESULTS: An overall response rate of 40% was observed with 2 complete and 2
      partial remission. In the follow up at 4-48 month, the overall median survival
      time was 21 +/- 3.29 months and the median response duration was 6 +/- 1.45
      months. The major toxicity was myelosuppression. 45.9% patients experienced grade
      3-4 neutropenia. CONCLUSION: HDI is an active salvage regimen in anthracycline +/
      standard dose ifosfamide pretreated soft tissue sarcoma.

PMID- 12478905
TI  - [Preliminary result of advanced soft tissue sarcoma treated by MAID regimen].
AB  - BACKGROUND & OBJECTIVES: Chemotherapy combined with other therapeutic modalities
      is the main option for advanced and metastatic soft tissue sarcoma(STS). So far
      there is no standard regimen for STS yet. Adrimycin, ifosfamide, and dacarbazine
      are the most effective agents at present. The purpose of this clinical trial was
      to evaluate the efficacy and toxicity of MAID regimen (mesna/ifosfamide +
      Adriamycin + dacarbazine) in the treatment of advanced soft tissue sarcoma.
      METHODS: Twenty-two patients with advanced STS were treated by MAID(Adriamycin 60
      mg/m2, ifosfamide 6,000 mg/m2, and dacarbazine 1,000 mg/m2). These drugs were
      administered as continuous intravenous infusion for 72 hours while mesna was
      infused continuously for 96 hours. RESULTS: Partial response rate was 36.4%
      without complete remission. The duration of response ranged from 2-10 months with
      median of 4.6 months. Main toxicities were myelosuppression, gastrointestinal
      toxicity and alopecia. Percentage of leucopenia, nausea/vomiting, and alopecia in
      WHO grade III and IV were 63.6%, 27.3%, and 50%, respectively. CONCLUSIONS: The
      response rate of MAID for advanced STS was not satisfactory with evident
      myelosuppression. Further study on new anti-cancer agents and regimen are needed.

PMID- 12478906
TI  - [Expression and clinical significance of mdr-1 gene in lymphoma].
AB  - BACKGROUND & OBJECTIVE: It is still unclear whether overexpression of mdr-1 gene
      play a role in the chemotherapy resistance of lymphoma. This study was designed
      to investigate P-glycoprotein(P-gp) and mdr-1 mRNA levels of lymphoma and to
      observed the impact of P-gp level upon chemotherapy response. METHODS: Ten
      samples of relapsed lymphoma and 21 samples of untreated lymphoma were assessed
      by flow cytometry(FCM). The mdr-1 mRNA levels were determined by real-time
      reverse-transcription PCR assay simultaneously in eighteen samples. The impact of
      P-gp levels upon chemotherapy response was observed in seventeen patients.
      RESULTS: Nineteen Percent (4/21) patients overexpressed P-gp at diagnosis as
      compared to 60%(6/10) in relapse(P = 0.012). The copy numbers of mdr-1 mRNA were
      4 x 10(2)-1.32 x 10(4) copies/microgram RNA in untreated group and 4 x 10(2)-4 x
      10(4) copies/microgram RNA in recurrent group. There existed significant
      difference in the distribution of mdr-1 mRNA expression between these two groups,
      P < 0.05. The complete response rates were 46% (6/13) in P-gp non-overexpression
      group and 25% (1/4) in P-gp overexpression group(P = 0.60). CONCLUSION: Relapsed
      lymphomas highly express P-gp and mdr-1 mRNA. The overexpression of mdr-1 gene
      may play a role in the multidrug resistance of relapsed lymphoma.

PMID- 12478907
TI  - [What is the value of professional nursing?].

PMID- 12478908
TI  - [Documentation and nursing diagnosis].

PMID- 12478909
TI  - [Cultural difference are not a hindrance].

PMID- 12478910
TI  - [New opportunities in nursing].

PMID- 12478911
TI  - [Healthy quality nursing].

PMID- 12478912
TI  - [Quality needs deliberation. The cooperation of nurses in the quality control
      boards like the Federal Quality Control Department and the German Quality Control
      Department (AQS and BQS) ].

PMID- 12478913
TI  - [Quality is not divisible. Nurses and physicians work together in the German
      Quality Control Department gGmbH (BQS)].

PMID- 12478914
TI  - Facing the ombudsman. Interview by Charlotte Alderman.

PMID- 12478915
TI  - Gene genies.

PMID- 12478917
TI  - The go-between. Interview by Charlotte Alderman.

PMID- 12478916
TI  - Making history.

PMID- 12478918
TI  - The hard cell.

PMID- 12478919
TI  - Prescribing: the great debate.

PMID- 12478920
TI  - And so to bed.

PMID- 12478921
TI  - Mental health and spiritual care.
AB  - BACKGROUND: Achieving holistic care is an important goal for nurses. While much
      is made of the bio-psychosocial model of holistic care, reflecting the allopathic
      bias inherent in the Western medical model, the issue of spirituality is mostly
      neglected. Where acknowledged, spirituality is often limited to recording the
      client's religion. This article asserts that religion and spirituality are not
      synonymous, although spirituality might sometimes be reflected through religious
      practices. CONCLUSION: With the move towards provision of modern mental health
      services in the community, the community mental health nurse will increasingly
      care for individuals for whom the spiritual is part of their daily lives and not
      a symptom of their illness. This is set against the backdrop of a multicultural
      society and as such will call for holistic nursing skills.

PMID- 12478922
TI  - Using heat therapy for pain management.
AB  - Many patients with chronic pain use some form of heat application in the home
      environment and frequently wish to continue using these heat therapies if
      admitted to hospital. This article provides an overview of the use of heat
      therapy with patients in the hospital setting and identifies some of the safety
      issues involved.

PMID- 12478923
TI  - Effective communication with older people.
AB  - There are many potential barriers to effective communication between nurses and
      clients. This article describes how communication with older people can be
      enhanced.

PMID- 12478924
TI  - A matter of fact.

PMID- 12478925
TI  - Is legislation protecting nurses who blow the whistle?

PMID- 12478926
TI  - Should nursing be an all-graduate profession?

PMID- 12478927
TI  - Trouble at large.

PMID- 12478929
TI  - What you need to know about... rheumatoid arthritis.

PMID- 12478928
TI  - Nurse administration of Entonox to manage pain in ward settings.
AB  - This article provides information and advice on Entonox for ward-based nurses
      carrying out routine procedures that may be painful to patients. An overview of
      Entonox is provided and the reasons that it may be underused in a ward
      environment are considered. Examples of common ward procedures in which it could
      provide effective analgesia to patients, such as the removal of wound drains, are
      given. Contraindications are also explored. It is hoped that ward-based nurses
      may be more likely to consider using Entonox to minimise the pain experienced by
      their patients during common, yet painful interventions.

PMID- 12478930
TI  - Blood glucose monitoring.

PMID- 12478931
TI  - Common forms of dementia.
AB  - Dementia occurs in various forms and may be associated with other conditions
      (secondary dementias). Each type has a different impact on the brain, leading to
      a variety of cognitive losses and behaviour problems. Appropriate identification
      is vital so that the most suitable treatment can be instigated.

PMID- 12478932
TI  - Nursing observations on ward patients at risk of critical illness.
AB  - Research findings and anecdotal evidence from outreach nurses across the country
      have suggested that key indicators of critical illness (respiratory rate and
      fluid balance) are being missed on the wards and that critically ill patients are
      not being fed adequately. A group of outreach nurses in Kent carried out a survey
      to confirm or refute these claims and to ascertain the variation in outreach
      provision in Kent. The survey found widespread deficiencies in nursing care and
      observations, which represent a serious threat to patients' safety.

PMID- 12478933
TI  - We are the champions.

PMID- 12478935
TI  - Hand decontamination.
AB  - Hand decontamination is the most effective, and certainly the most cost
      effective, method of preventing health-related infection (HRI). However, research
      has shown that health professionals, including nurses, do not decontaminate hands
      as often as they should. It has become apparent that hand decontamination does
      not always follow those activities which will probably result in the most heavy
      soiling, and the technique used to decontaminate hands is often poor.

PMID- 12478934
TI  - Winning treatment. Interview by Jennifer Taylor.

PMID- 12478936
TI  - Preventing cross-infection.
AB  - Using hand decontaminants correctly is a skilled activity that all health
      professionals need to learn and practise. All health professionals need to
      acquire an appropriate technique at the beginning of their careers, with
      continuing professional development to update them and inform them of new
      advances in research and technology.

PMID- 12478937
TI  - Using protective clothing.
AB  - The use of protective clothing is an essential element of infection prevention
      and control. Many items of protective clothing are incorporated within the
      concept of universal precautions--the precautions necessary to reduce exposure to
      blood or body fluids (Centre for Disease Prevention and Control, 1987).
      Protective clothing is also used to prevent the transmission of micro-organisms
      other than blood-borne viruses--for example, methicillin-resistant Staphylococcus
      aureus, Staphylococcus aureus and Mycobacterium tuberculosis.

PMID- 12478938
TI  - The life of a head louse.
AB  - When children return to school after the summer holiday, cases of head lice
      appear to increase. Ian Burgess describes the life cycle of the head louse and
      dispels some of the myths about transmission of this insect. A second article
      discusses the detection and treatment of head lice.

PMID- 12478939
TI  - Detection combing.

PMID- 12478940
TI  - Making public health a priority.

PMID- 12478941
TI  - Reporting abuse and violence.

PMID- 12478942
TI  - The cephalosporins: targeting respiratory infections.

PMID- 12478943
TI  - ADHD testing.

PMID- 12478944
TI  - The assessment and management of chronic pain in the elderly. A guide for
      practice.

PMID- 12478945
TI  - Patient information. Understanding migraines.

PMID- 12478946
TI  - Breathing easier with pediatric asthma. Pharmacologic management.

PMID- 12478947
TI  - Chronotherapy. Treating patients in a timely fashion.

PMID- 12478948
TI  - Bioidentical hormone replacement therapy. Customizing care for perimenopausal and
      menopausal women.

PMID- 12478949
TI  - The Women's Health Initiative. Implications for practice.

PMID- 12478951
TI  - A policy for what ails us. The current and future role of disease-specific
      insurance.

PMID- 12478950
TI  - Streamlining documentation in the primary care setting. Practical guidelines from
      NPs who made it work.

PMID- 12478952
TI  - Posttraumatic stress disorder. Recognition and recovery.

PMID- 12478953
TI  - Take heart: awareness is growing.

PMID- 12478954
TI  - On self-perceived oral health in Swedish adolescents.
AB  - Aiming to investigate adolescents' perceptions of oral health, with a focus on
      gender differences, quantitative and qualitative studies were conducted in
      Skaraborg County, Sweden. Adolescents (13-18 years; n = 17,280) answered a school
      questionnaire, epidemiological indices on oral health were collected, and 17 semi
      structured interviews were conducted. Most adolescents perceived their oral
      health as good, girls more often than boys. The oral behavior of girls was also
      more often healthy (floss usage: girls 31%, boys 21%), and they were consistently
      less satisfied with the appearance of their teeth than boys. Girls considered
      their own consumption of candy to be too high more often than boys. Acknowledging
      the importance of sound teeth was strongly associated with self-perceived oral
      health: boys, odds ratio (OR) 8.58 [confidence interval (CI) 7.12-10.34]; girls,
      OR 5.56 [CI 4.23-7.30]. Adolescents living with a single mother (13-15-yr-olds OR
      1.37 [CI 1.20-1.57], 16-18-yr-olds OR 1.51 [CI 1.28-1.77]), or with neither
      parent, more often reported bleeding gums than those who lived with both parents,
      while adolescents who lived with a single father did not. Weak correlations
      between epidemiological indices and self-perceived oral health were found at the
      school level. In the interviews, adolescents perceived the possibilities to
      influence their own oral health as limited. Perceptions of influences on oral
      health were related to personal and professional care, social support, social
      impact, and external factors such as time and economy. Support from the mother-
      more than from the father--was emphasized. This thesis showed that positive oral
      health attitudes and parental support are of great importance if oral health is
      to be perceived as good. There were gender differences in all issues related to
      self-perceived oral health.

PMID- 12478955
TI  - Must HIV-positive women give birth in hospital?

PMID- 12478956
TI  - Deprivation blamed for low birth weight babies.

PMID- 12478957
TI  - Nutritional interactions between mother and fetus.

PMID- 12478958
TI  - The Reading breastfeeding drop-in centre.

PMID- 12478959
TI  - Midwifery basics. Antenatal care--the booking history.
AB  - Joannna is in the first trimester of her first pregnancy. She has seen her
      General Practitioner who gave her some general advice about what she should and
      should not be eating. Aware of her previous medical history, the GP told Joanna
      to go to the reception desk and to make an appointment for the community midwife
      to visit her at home to undertake the 'booking'. A week later she received a
      package of information and a letter from the midwife confirming the appointment
      time and asking Joanna to produce an early morning specimen of urine (EMSU) on
      the day of the visit.

PMID- 12478960
TI  - Respecting the individual. Implications of the Code of Professional Conduct.

PMID- 12478961
TI  - Pinard wisdom. Tips and tricks from midwives ( Part 2).

PMID- 12478962
TI  - [Acute bacterial meningitis in infants observed in the A pediatric service of
      Befelatanana, Antananarivo University Hospital Center (Madagascar)].

PMID- 12478963
TI  - [First cases of cholera observed in children at the Befelatanana General Hospital
      -Antananarivo University Hospital Center (Madagascar)].
AB  - Ravages caused by cholera among children are well known. The disease invaded
      Madagascar in 1999 May. This retrospective study reported the first childhood
      cholera cases. The survey was carried out at the Befelatanana Hospital during the
      period of cholera outbreak from April 23th to July 31st. The purpose of the study
      was to specify clinical, epidemiological and bacteriological characteristics of
      the disease. 5 out of 178 suspected cholera cases were less than 15 years old. 2
      young girls out these 5 children, inhabitants of Antananarivo-City were
      hospitalized for acute diarrhoea with serious dehydratation. Their disease was
      confirmed by bacteriology. Vibrio cholera O1 strain, serovar Ogawa was
      identified. Epidemiological investigation allowed to identify the contamination
      modal in the file no 1. The authors conclude that cholera is an important problem
      of public health in developing country like Madagascar. Disease control needs
      environmental sanitation and good individual hygiene practices.

PMID- 12478964
TI  - [Mediastinal form of cat-scratch disease].
AB  - The authors reported a case of Cat--Scratch Disease (CSD) in a 14-year-old boy;
      it was an unusual CSD by its mediastinal mass location. Histopathological lesions
      which appeared as pseudo-tubercular folliculi mislead us. Disease was finally
      diagnosed by biological exams: a strongly positive Hanger-Rose reaction and
      serological assays used for the diagnosis of psittacosis, ornithosis,
      lymphagranuloma venereum and trachoma. CSD is a common cause of chronic
      lymphadenopathy in children. In the majority of patients, CSD is a mild illness.
      Some unusual forms as Parinaud's oculoglandular syndrome, neurological lesions,
      osteomyelitis and exceptionaly mediastinal lymphadenopathy have been reported. 2
      cases of the latest ones were already described.

PMID- 12478965
TI  - [Aspects of primary tuberculosis infection in children: 27 cases observed at
      Children's Hospital, Antananarivo].
AB  - A retrospective study on tubercular primary infection in children was carried-out
      for 18 months (January 1994--June 1995) at the Child Hospital of Tsaralalana in
      Antananarivo-City. 27 cases were reported. The sex-ratio was of 1,01/1. The most
      clinical forms were pulmonary tuberculosis. An associated factor was
      malnutrition. Contact has been traced back to close family. Short course
      treatment regimen was the standard applied.

PMID- 12478966
TI  - [Evaluation of the management of tuberculosis in children in Madagascar. Results
      of a multicentric study].
AB  - In Madagascar, tuberculosis remains an important cause of morbidity and letality
      with a Risk of Annual Tubercular Infection about 1% in 1996 in spite of a
      vaccination rate of 82.6% and tubercular drugs free of charge. In 1995, the
      National Tubercular Control Program detected 7,000 cases of pulmonary
      tuberculosis and expected more than 12,000 cases per year. This study was carried
      out in order to review the management and the treatment of the child tuberculosis
      in Madagascar. This retrospective study was conducted in four pediatric units of
      the General hospital of Befelatanana (A and B), Ambohimiandra Hospital and
      Regional Hospital Centre of Toliara for a twenty four months period from January
      1997 to December 1998. All the less than 15-year-old children medical files were
      consulted. 214 cases were suspected of tuberculosis. 133 of them were treated
      upon clinical presumption basis and/or radiological exams (33 bacteriological
      and/or histopathological exams were only realized). 56% of the cases were
      vaccinated by BCG vaccine. Respiratory diseases with fever motive 46% of
      hospitalization. The majority of these children are living in poor conditions and
      38% of them had malnutrition. Were found as clinical manifestations: 47% of
      pulmonary tuberculosis (among them 20% were smear-positive pulmonary
      tuberculosis), 12% had ganglionar tuberculosis, 10% peritoneal tuberculosis, 8% a
      tubercular meningitis, 5% a Pott-disease and 2% a miliary-disease. Mortality
      increases with suffocation. 18% of cases died, especially infants and in
      tubercular meningitis. The authors conclude that management and treatment of
      tuberculosis need an early diagnosis. But the diagnosis is difficult in front of
      non specific clinical manifestations in children and due to lack of means and
      national agreement which settle up diagnosis and therapy. A scoring system based
      upon clinical signs in agreement with complementary medical tests is desirable.

PMID- 12478967
TI  - [Neonatal bacterial infections: a public health problem at the maternity hospital
      of Befelatanana (1997-1998)].
AB  - Neonatal infections represented the second cause of morbidity at the neonatalogy
      service of the Maternity Hospital of Befelatanana, and they were the first cause
      of the perinatal mortality (81%). This prospective study was carried out from May
      1997 and December 1998 and had concerned neonatal infections suspicions among
      newborns. Its purpose was to identify problems with regard to the management of
      those newborns and to assess the impact of the prevention. Over 14,009 births,
      1,877 neonates had infections recorded during the first week of life. Were
      noticed as main pathogen germs isolated: Escherichia coli, groups B, A, G, D
      Streptococci and Staphylococcus aureus. The authors conclude that screening and
      early treatment of materno-fetal infections constitute with asepsis, prevention
      basis of neonatal infections.

PMID- 12478968
TI  - [Cases of abortions at the maternity hospital of Befelatanana in 1997].
AB  - The purpose of this study is to assess the frequency of spontaneous and induced
      abortions at the Hospital Maternity of Befelatanana, in Antananarivo--City by
      1997. The study was also carried out to identify causes and risk factors of
      abortions in order to draw up a control program. 958 abortion cases were counted.
      The patient average age was 28 old years. 289 cases (30.3%) of these abortions
      had complications, 1 out of 25 patients died. Some of causes of abortion have
      been specified: prior patient health, cultural, social and economic factors.
      Existence of abortions is a failure report of the Reproductive Heath Program.
      Abortion control must be based on sanitary education in which family planning is
      very important, on correct management of abortion cases and their complications.
      But all that is not possible if there are not improvements of the standard of
      living.

PMID- 12478969
TI  - [Premature deliveries at the maternity hospital of Befelatanana, Antananarivo in
      1997].
AB  - Preterm deliveries (PT) produce new-borns whose prognosis is generally very dark.
      Prematurity is the first cause of neonatal death. A retrospective study was
      carried out at the Maternity Hospital of Befelatanana, Antananarivo in order to
      specify causes and difficulties of PT and to draw up strategy for their better
      management so that premature infants have chance to survive. The survey concerned
      1394 patients: all pregnancies whose gestational age are between 22 and 36 weeks
      and those who delivery viable infants discharged home whose weights are between
      500 and 2,500 grams. PT occur frequently among teenagers and more than 35-year
      old women. Risk factors and determinative causes of PT are mothers' toxic habits,
      gyneco-obstetrical history as PT, abortion, cicatricial uterus, urogenital
      infections. 12 maternal deaths were noted. Infant perinatal mortality rate was of
      47.3 per cent. The authors conclude that difficulties were in labor and both
      antepartum and intrapartum periods. Preventive measures must surpass curative
      therapy. They will be based on the improvement of standard of living, the
      reinforcement of planning family and a strict pregnancy surveillance.

PMID- 12478970
TI  - [Internal version maneuvers at the maternity hospital of Befelatanana-
      Antananarivo University Hospital Center (Madagascar): 177 cases].
AB  - Version by internal manipulations (VIM) cause high fetal and maternal morbidity
      and mortality rates. A retrospective study was carried out in 1998 at at the
      Maternity Hospital of Befelatanana, Antananarivo in order to assess VIM
      frequency, to specify their indications and technical difficulties by performing
      them. 177 VIM were registered for the period study: 85 on singleton pregnancies,
      91 on the second twin and 1 on the third infant of a triplet pregnancy. VIM
      annual incidence was of 2.1 per cent. The average age of parturient women was 27
      years old. Risk factors and determinative causes are gyneco-obstetrical history
      as abortion, preterm delivery, urogenital infections; high blood pressure; poor
      prenatal visits; poor cares during labor; untimely and inappropriate drug
      prescriptions; low standard of living. Maternal complications were hemorrhages of
      the afterbirth (73.0 per cent), uterine rupture (8.0 per cent), cervix tearing
      (5.0 per cent). 19 maternal deaths were noted. Infant perinatal mortality was of
      68.0 per cent. The authors conclude that VIM is the only alternative to
      cesarotomy provided it is properly performed by a competent and experienced
      practitioner. VIM must be kept for the second twin in unengaged transverse lie.

PMID- 12478971
TI  - [Premature rupture of membranes seen at the Befelatanana maternity, Antananarivo
      University Hospital Center].
AB  - Generally preterm ruptures of membranes (PRM) are harmless, but they become
      serious if the labor doesn't occur in the following 24 hours. Then, they might
      generate neonatal infections which provoke heavy fetal and maternal mortality. A
      retrospective study was carried out in 1998 at the Maternity Hospital of
      Befelatanana, Antananarivo in order to sum up knowledges on epidemiology and
      fetal prognosis of this disease, and to draw up measures to aim to reduce causes
      of PRM. 4232 cases of PRM were registered for the study period. The average age
      of parturient women was of 27 years old. PRM occur frequently among primiparas
      and high level multiparas. Risk factors and determinative causes are gyneco
      obstetrical history as abortion, preterm delivery, cicatricial uterus, urogenital
      infections; uterine malformation; placenta praevia; hydramnios; dystocic labor
      presentation; uterine distension due to either multiple pregnancy or
      disproportion of fetus and birth canal; irregular and poor prenatal visits
      quality; low standard of living. Numerous premature infants of PRM outcomes had
      infections: 1,619 out of 4315 new-borns. Infant perinatal mortality rate was of
      11.7 per cent. Maternal complications were infections, uterine rupture,
      hemorrhages. 5 deaths were noted. The reduction of PRM rate might be obtained by
      improvement of standard of living and hygiene, correct cares during pregnancy and
      intergenesic periods.

PMID- 12478972
TI  - [Management of multiple pregnancies at the Befelatanana Antananarivo University
      Hospital Center (Madagascar): report of 143 cases].
AB  - Multiple pregnancies (MP) outcomes are often complicated. They deliver premature
      infants and provoke high blood pressure. A retrospective study was carried out in
      1998 at the Maternity Hospital of Befelatanana, Antananarivo in order to assess
      MP frequency and to specify the most important favourising factors and
      difficulties during labor and the quality of the labor management. All
      pregnancies with a MP were included in this survey. 143 MP were registered: 142
      twin pregnancies and 1 triplet pregnancy. 2.0 per cent of cases were recurrent
      MP. The average age of pregnancies was 26 years old. Among these 143 MP, 48.0 per
      cent were primiparas. Poor quality of prenatal visits is frequently encountered.
      As antecedents there are abortion, hormonal contraceptive taking, preterm
      delivery, gravidic toxemia, cicatricial uterus, ectopic pregnancy. 6.3 per cent
      of the first twin had breech presentation, 2.0 per cent transversal labor
      presentation. As events during labor 40.0 per cent dynamic dystocia, 26.0 per
      cent acute fetal suffering, 27.0 per cent hyperthermia, 23.0 per cent high blood
      pressure, some of them as eclampsia or pre-eclampsia were noted. 60.0 per cent of
      the first twin delivery were easy. Whatever his labor presentation, version by
      internal manipulations following by breech extraction was performed on the second
      twin (67.0 per cent of cases). 18.2 per cent of parturient women had cesaretomy.
      11 maternal deaths were noted. Infant perinatal mortality rate was of 35.7 per
      cent. Infant morbidity and mortality are essentially due to infections. The
      authors conclude that complications prevention will be obtained by improvement of
      standard of living of all female able to procreate. It needs also correct cares
      at prenatal visits and during labor. Health education must be focalized on strict
      and correct surveillance of pregnancies and intergenesic periods by the
      reinforcement of planning family.

PMID- 12478973
TI  - [Influenza in the pediatric hospital unit at Antananarivo].
AB  - 62 rhinopharingeal samples from malagasy children, aged of 6 days to 14 years
      old, hospitalized because of acute respiratory infections, with doubtful viral
      etiology case, during June to August 1992, at the "Hopital des Enfants" in
      Antananarivo, were examined by two methods: inoculation by embryonned eggs and
      inoculation by MDCK cells. 24.1% of the samples were positive. The repartition of
      the cases by age and by sex were studied. The children aged of 1 to 12 months
      were the most affected with 65.7% of all cases (male: 60%, female: 40%). One
      subtype was detected: A(H3N2).

PMID- 12478974
TI  - [Study of idiopathic thrombopenic purpura in two pediatric services of
      Antananarivo city].
AB  - Idiopathic thrombocytopenic purpura (ITP), haematologic disease affecting the
      only blood platelets, is an acquired disease. It appears as cutaneous and mucosal
      bleedings preceded by a feverish syndrome. Cerebral haemorrhage is possible but
      very rare. If the disease occurs frequently in Europe and in the United States of
      America, there is a lack of data in Africa and in Madagascar. In order to fill
      this gap, the authors carried out retrospective and prospective studies in two
      paediatric units of Antananarivo for 32 months. They reported 4 cases of PTI of
      which clinical signs were moderate. As therapy, corticosteroids were used and
      were efficiency. It is desirable to settle a program allowing to survey sick
      children.

PMID- 12478975
TI  - [Value of C-Reactive Protein (CRP) in childhood fever conditions].
AB  - C-Reactive Protein (CRP) measurement is used to orientate the diagnosis of an
      inflammation especially in childhood febrish diseases. A retrospective study was
      carried out at the pediatric service of the General hospital of Befelatanana in
      Antananarivo for 48 months (1997-1998). The population of this study was
      continued of 361 patients taken from 714 febrish children. 384 CRP were
      performed. The initial CRP measurement allowed to differentiate 152 presumed
      bacterial infections: 49 respiratory tract infections, 62 in neurological
      pathology, 10 in digestive pathology, 19 in otorhinolaryngology pathology, 12 in
      urinary pathology, and 153 presumed viral infections: 86 respiratory tract
      infections, 29 in neurological pathology, 12 in digestive pathology, 26 in
      otorhinolaryngology pathology. There was a right correlation of CRP values and
      leukocyte levels in presumed bacterial infections. Specificity and sensibility of
      the test applied in different child febrish diseases were satisfactory. CRP
      measurement is easy and rapid to perform. It is useful and seems to be the
      appropriate method to diagnose childhood febrish diseases in countries where
      facilities are insufficient and financial possibilities limited.

PMID- 12478976
TI  - [Congenital afibrinogenemia complicated by spontaneous cerebral hemorrhages: a
      case report].
AB  - Congenital afibrinogenemia is a rare autosomal recessive disease caused by
      markedly reduced or absent synthesis of fibrinogen. Consanguinity is common in
      affected family. Clinical manifestations range to minimal or moderate bleeding to
      catastrophic haemorrhage. Bleedings are often post-traumatic, sometimes
      spontaneous. Diagnosis is established by laboratory tests presenting trace or
      absence of fibrinogen. Substitutive treatment with fibrinogen concentrates or
      fresh frozen plasma is used. The authors reported the case of a 41-year-old male
      with congenital afibrinogenemia with fatal spontaneous cerebral haemorrhage.
      Diagnosis was made upon history, bleeding history, clinical examination, blood
      coagulation tests and radiography. Cerebral haemorrhage must be suspected in any
      patient presenting blood coagulation disorders with bleeding history. Drug
      therapy must be installed immediately and continued before obtention of specific
      radiology images which are often late in relation to clinical signs.

PMID- 12478977
TI  - [Value and limits of cytology in the diagnosis of cervico-vaginal lesions at the
      Mahajanga University Hospital Center: 465 cases].
AB  - Cervix neoplasms are the most frequent of female neoplasms in Madagascar. The
      authors reported a prospective study carried out at the Hospital Center of the
      University of Mahajanga for ten months (January-October 1993). 500 patients were
      investigated. 465 results of cervix and vaginal smears were considered. The
      Bethesda group classification was used to interpret lesions. 333 specific
      pathological lesions were listed. Bacterial infections and trichomoniasis were
      their principal causes. 4 cases were presumed as human papillomavirus
      condylomata. 39 SIL low-grade and 24 SIL high-grade were detected. 5 cervix
      neoplasms were diagnosed. Only few patients had consultation to perform cervix
      and vaginal smears because these exams are expensive. It may be an explication to
      the chronicity of lesions, a favourising factor of cancer. The role of viruses,
      especially human papillomavirus, in the development of cervix neoplasms is
      mentioned. The authors conclude that the low number of cervix neoplasms they
      founded is misleading. Cervix neoplasms are the first female cancers in
      Madagascar. A systematic surveillance of all female genitalia diseases must be
      programed. While its settling, cervix neoplasms control must be centred on
      Information--Education--Communication.

PMID- 12478978
TI  - [Evaluation of the use of antibiotics in the hospital pediatric milieu].
AB  - Excessive and inappropriate use of antibiotics is a world-wide serious problem
      because it contributes to the development and the spreading of antibiotic
      resistance. The authors carried out a study for one year by 1998, in order to
      evaluate antibiotic prescriptions in three childhood diseases: respiratory,
      digestive and neurological diseases. Patients hospitalized at the unit paediatric
      of the General hospital of Befelatanana are 0 month to 15 years old. Three
      antibiotic families were frequently used: cotrimoxazole, penicillins derivatives
      and aminoglycosides. Results of this study noted that antibiotic precriptions
      were irrational. Some factors may give explanations to these facts: the
      insufficiency of biological labs, but also expensive costs of exams. It is
      desirable that all paediatricians can gather in order to draw up clinical
      protocols and to assess them by a multicentric survey. Further results may be
      used as reference for empirical or probabilist antibiotic prescriptions of which
      efficacy will be checked by an experienced lab.

PMID- 12478979
TI  - [Costs directly related to acute lower respiratory tract infections in the
      pediatric hospital milieu].
AB  - The purpose of this retrospective study carried out by 1997 in two paediatric
      units of Antananarivo: paediatric unit of the General hospital of Befelatanana
      (Marfan) and paediatric unit of the Hospital Center of Soavinandriana (CI), was
      to evaluate direct service costs for an hospitalization of a child affected by
      lower acute airway diseases. In the first unit, there is partial charge, in the
      second, there is full charge. Direct services were continued by complementary
      tests, therapy and meals. The length of the hospitalization changes according to
      the cause and the severity of diseases. Average direct service costs were of 19
      and 38 US$ respectively. Maximum direct service costs were of 77 and 154 US$
      respectively. Amounts of direct service costs were crippled especially by
      inappropriate use of antibiotics.

PMID- 12478980
TI  - [What is the role of the French National College of Gynecologists and
      Obstetricians?].

PMID- 12478981
TI  - [Revisiting the role of LH in follicular development].
AB  - During the last decade, two pivotal events widened the gap between the hormonal
      dynamics of ovarian stimulation and that of the menstrual cycle. First, the
      profound and routine suppression of endogenous gonadotropins by GnRH analogues
      used in ovarian stimulation pressed us to recreate the hormonal environment
      necessary for adequate follicular maturation and steroidogenesis. Second, drugs
      with reduced or null LH activity became available, based on the hypothesis that
      FSH action was sufficient to follicular development and maturation irrespective
      of residual endogenous gonadotropin levels. Today, there is a renewed interest in
      the possible role of LH on follicular development, in an effort to mimic the
      hormonal events of the menstrual cycle to optimize ovarian stimulation outcome.

PMID- 12478982
TI  - [Trial vacuum extractor for cephalic engagement. 50 cases in French Guiana].
AB  - OBJECTIVE: Considering a population with an African culture traditionally opposed
      to a caesarean section, vertex engagement with a vacuum extractor could be a good
      alternative. PATIENTS AND METHODS: In a retrospective study of 50 cases of trial
      engagement with a vacuum extractor in French Guyana, there were 94% of vaginal
      deliveries. RESULTS: A high level of shoulder dystocia (14%) was noted, and the
      failure of this technique was the consequence of disproportions between foetus
      and pelvis that had not been correctly diagnosed. CONCLUSION: In this article,
      feasibility and obstetrical conditions to carry out a trial engagement with a
      vacuum extractor are discussed.

PMID- 12478983
TI  - [Retrospective study of 34 urogenital fistulas of obstetricalal origin].
AB  - OBJECTIVES: The aim of the study was to determine the etiologic and
      epidemiological aspects of the obstetrical uro-genital fistulas in Congo in order
      to propose a strategy of prevention. PATIENTS AND METHODS: It is a retrospective
      study concerning 34 files of obstetrical uro-genital fistulas selected within 7
      years in the department of Urology of the University Hospital Center of
      Brazzaville. The etiopathogenic, anatomoclinical and therapeutic aspects have
      been analysed for each file. RESULTS: The uro-genital fistula represents 23% of
      the female admissions in urology and 85% of them are related to obstetrical
      causes. Fifty-five percent of the patients were less than 30 years old, most of
      them being primiparas. Sixty-one percent of the patients came from rural areas.
      The prolonged time of the delivering labour and the foetal extraction manoeuvres
      were the main mechanisms causing the fistulas. With the surgical therapy, 77% of
      the abnormalities have been treated. CONCLUSION: In spite of progress made in the
      realm of surgical techniques, the best treatment for uro-genital fistulas remains
      their prevention as targeted on the education for health and the management of
      pregnant women. Besides, the development of the infrastructure of health and
      roads, the training and reeducation of the health personnel contribute to improve
      this management.

PMID- 12478984
TI  - [Botryoide sarcoma of the uterine cervix. Apropos of 1 case].
AB  - Sarcoma botryoide (SB), a variant of rhabdomyosarcoma, is a rare tumor who are
      rarely localized in the uterine cervix. Only 99 cases have been described to
      date. The authors reported this case with review of the literature in order to
      insist on diagnosis progress and a new combined modality approach using:
      radiotherapy, surgery and chemotherapy which have improved prognosis in the
      localized disease especially.

PMID- 12478985
TI  - [Risk-taking. Adolescent girls versus adolescent boys].
AB  - Epidemiologists as well as professionals working in the area of adolescent health
      generally agree that adolescence is a period characterized by a difference in
      frequency of risk-taking behaviour between girls and boys. An explanation of
      these data through ethno-psychological and psychodynamical approaches is hereby
      presented. Such approaches should be taken into account for general preventive
      strategies to take effect.

PMID- 12478986
TI  - [Above what limits is ART of no avail?].
AB  - Legal limits to assisted reproduction technologies are rather blurred. The law of
      July 1994 only says that people must be "in age of procreation"; medical
      opposable reference only says that infertility exploration must begin before 45
      years. The guide of good practice in ART writes that over 37 only women with
      normal ovarian reserve must be included in ART programs. So physicians have to
      fix their own limits, according to success rate and this limit is often 42-43
      years for women.

PMID- 12478987
TI  - [Spontaneous abortions of first trimester pregnancy: is uterine aspiration still
      in line?].
AB  - Spontaneous abortions of first trimester pregnancy is a frequent pathology in
      gynecology (more than 10% of clinical pregnancy). Since the mid of twentieth
      century, the gold standard of evacuation of spontaneous abortion is manual vacuum
      aspiration most of the time under general anesthesia. This method is used in
      France for all miscarriages after 7 weeks' gestation at the sonography (about
      40,000 women in 1999) but complications are not rare. The vaginal sonography and
      new medical management changes the view. We can now use expectative management or
      medical management with misoprostol and/or mifepristone. We summarise the current
      literature and propose a randomised multicentric control trial.

PMID- 12478988
TI  - [Age and reproduction].

PMID- 12478989
TI  - [Neuroendocrine mechanisms of puberty onset].
AB  - An increase in pulsatile release of GnRH is essential for the onset of puberty.
      However, the mechanism controlling the pubertal increase in GnRH release is still
      unclear. The GnRH neurosecretory system is already active during the neonatal
      period but subsequently enters a dormant state by central inhibition in the
      juvenile period. When this central inhibition is removed or diminished, an
      increase in GnRH release occurs with increase in synthesis and release of
      gonadotropins and gonadal steroids, followed by the appearance of secondary
      sexual characteristics. Recent studies suggest that disinhibition of GnRH neurons
      from GABA (gamma-aminobutyric acid) appears to be a critical factor in female
      rhesus monkey. After central inhibition is removed, increases in stimulatory
      input from glutamatergic neurons as well as new stimulatory input from
      norepinephrine and NPY neurons and inhibitory input from beta endorphin neurons
      appear to control pulsatile GnRH release as well as gonadal steroids.
      Nonetheless, the most important question still remains: what determines the
      timing to remove central inhibition? Because many genes are turned on or turned
      off to establish a complex series of events occurring during puberty, the timing
      of puberty must be regulated by a master gene or genes, as a part of
      developmental events.

PMID- 12478990
TI  - [Specificities of prepubertal follicles and oocytes].
AB  - Ovarian physiology of prepubertal and adult animals is different. Some
      characteristics as follicular dynamics (follicular waves and growth) are similar
      but total follicular population and number of growing follicles are higher in
      prepubertal ovary. Prepubertal oocytes represent a negative model for in vitro
      studies since they lead to lower cleavage and blastocyst rates when they are used
      to produce embryos. This reduced ability to support embryonic development is due
      to follicular and oocyte differences. Follicular fluid and granulosa cells
      proteins, and steroidogenic potential differ between prepubertal and adult
      animals. Moreover, experiments using nuclear transfer demonstrate that
      cytoplasmic maturation of prepubertal oocytes is incomplete. These deficient
      oocytes are smaller, contain lower levels of MPF and MAP Kinase and differences
      in metabolism and cytoplasmic organelles are observed.

PMID- 12478992
TI  - [Oocyte apoptosis and evolution of ovarian reserve].
AB  - In mammals, the ovarian reserve of primordial follicles is constituted early in
      fetus, then it becomes progressively exhausted by both follicular development and
      oocyte apoptosis. At least two third of the oocytes present in the reserve die by
      apoptosis before birth. Hypotheses of mechanism underlying this process are 1) a
      "quality control" leading to eliminate meiotic anomalies 2) a deficit in survival
      factors produced by somatic neighbouring cells 3) a "self sacrifice" or
      "altruistic death", as previously described in Drosophila. After birth, growth
      factors and cytokines are main actors of the dialogue which exists between
      granulosa cells and the oocyte and determines oocyte survival. Mitochondrial
      factors belonging to bcl-2 family, metabolites of sphingolipids and the aromatic
      hydrocarbon receptor participate to oocyte apoptosis and can modulate numerical
      changes in the ovarian reserve. The reserve is quantitatively and qualitatively
      under both genetic and environmental control. Therapy to preserve ovarian reserve
      will benefit from better knowledge of molecular and cellular mechanisms
      regulating oocyte apoptosis. Moreover, recent identification of genes implicated
      in ovarian premature insufficiency will allow to propose new perspectives to
      prolong ovarian lifespan.

PMID- 12478991
TI  - [Human infertility: meiotic genes as potential candidates].
AB  - Up to now, the identification of gene mutations causing infertility in humans
      remains poorly investigated. Temporal progression through meiosis and meiosis
      specific genes had been extensively characterized in yeast. Recently some
      mammalian homologous were found. The molecular mechanisms regulating entry into
      and progression through meiosis in mammals are still unknown. However, disruption
      of some meiotic genes in mouse showed an essential role of them in meiotic
      chromosome synapsis and gametogenesis. Moreover, the phenotype of gonads in null
      mutant mice for some meiotic genes (failure to initiate or blockage in meiosis,
      lack of gametes or small size of gonads...) could be strikingly similar to
      clinical observations found in human infertility. The aim of this study was to
      identify putative mutations in 5 meiotic genes of several clinically well
      characterized patients who present unexplained infertility (normal karyotype,
      women with premature ovarian failure, men with azospermia and without Y micro
      deletion). For this purpose, the exons of these 5 genes (DMC1, SPO11, MSH4, MSH5,
      CCNA1) were all amplified by PCR with specific primers and each amplified-exon
      was sequenced. Sequences were aligned in comparison to the human corresponding
      gene available in Genbank. Many heterozygous mutations were found in different
      genes. Two homozygous mutations were found in MSH4 and DMC1 genes in a young man
      presenting a testis vanishing syndrome and a woman presenting a premature ovarian
      failure, respectively. Consequences of such mutations will be examined and
      verified in model organisms (yeast, mouse) to check the relevance of the
      mutations in clinical setting.

PMID- 12478993
TI  - [Ovarian genes].
AB  - The number of ovarian follicles decreases during genital life by apoptosis, which
      accelerates from 40 until the menopause. Several findings plead in favour of a
      genetic control of these events. Ovarian insufficiency can occur by three
      mechanisms: reduction in the primary follicles reserve (ataxia-telangiectasy),
      follicular maturation blocking (modification of the genes GDF-9 and GDF-9B, null
      mutation of FSH receptor gene, auto-immune polyglandular disease, PBE syndrome),
      or apoptosis acceleration (chemotherapy, smoking, galactosemia, Turner's
      syndrome). However, the aetiology of premature ovarian insufficiencies in woman
      remains unknown in more than 90% of the cases. Genetic studies on the family
      cases should make it possible to identify new genes involved in ovarian control.

PMID- 12478994
TI  - [Parental age and genetic risks for the offspring].
AB  - Despite numerous studies, the age-related risk of genetic defects in the
      offspring remains poorly understood. It is clear that the frequency at birth of
      some mendelian disorders is related to advanced paternal age, but this
      relationship is heterogeneous and varies from one disorder to another. Similarly,
      it has been proposed that among commonly observed birth defects, a subgroup of
      cases may be due to new unrecognized dominant mutations of paternal origin.
      Finally, despite many years of enquiry, increasing maternal age remains the only
      incontrovertible factor associated with human aneuploidy.

PMID- 12478995
TI  - [What medical intervention in the late desire for a child?].
AB  - Therapeutical decisions in case of unsuccessful late child wish in a woman aged
      more than 35, must take into account several issues. In a context where time
      cannot be considered as "therapeutical" in the sense that the probability of
      onset of a pregnancy per cycle can not increase with time, the moment of check-up
      for infertility can be fixed at 6 months of sexual intercourse, assumed to be
      possibly fecundant. The assessment of ovarian age allows to formulate a double
      prognosis, that of therapeutical efficacy for obtaining onset of pregnancy and
      that of the quality of possible conceptus. The choice of treatment from the
      etiological check-up will not go from the simplest to the more sophisticated as
      is done for younger women. This is an important issue since the remaining time of
      possible fertility is short.

PMID- 12478996
TI  - Progress towards poliomyelitis eradication--horn of Africa (Ethiopia, Somalia,
      Sudan), January 2001-October 2002.

PMID- 12478997
TI  - Third meeting of the Steering Committee on Immunization Safety.

PMID- 12478998
TI  - The Global Poliomyelitis Eradication Initiative: number of endemic countries at
      lowest ever.

PMID- 12478999
TI  - [Organization of medical rehabilitation centers for servicemen during military
      operations in Afghanistan].

PMID- 12479000
TI  - [Current stage in formation of a standard unified system of military medical
      examination].

PMID- 12479001
TI  - [Medical classification of foci of multiple and unknown chemical affections].
AB  - The purpose of this work was to define the diagnostic methods in unspecific
      syndromes of exogenous intoxication and their use for conduction of medical
      classification in the foci of polychemical and unknown chemical affections.
      Detection of unspecific syndromes of extreme pathologic process in persons
      affected by dangerous chemical substances will contribute to organization of two
      stage medical support, will facilitate the conduction of medical classification,
      determination of type and volume of medical assistance.

PMID- 12479002
TI  - [Treatment of servicemen with pelvic injuries at the stage of medical evacuation
      during local military conflicts (Report II)].
AB  - Basing on the analysis of medical record data obtained from servicemen with
      pelvic unstable injuries the authors evaluate the results and effectiveness of
      the used treatment methods and give the recommendations how to improve medical
      care rendered such category of casualties at the stages of medical evacuation.
      The analysis of treatment results obtained in the casualties with pelvic unstable
      injuries shoes high frequency (up to 24.4%) of unsatisfactory results among which
      not eliminate deformations of pelvic ring (14.3%), disordered walk (20.4%) and
      painful syndrome (18.8%) prevailed. In the structure of treatment measures during
      the local armed conflicts in Afghan and Chechnyathe conservative methods of
      hipbone immobilization (and even in the cases of pelvic unstable injuries)
      prevailed. Osteosynthesis with external apparatus was used only in 2.1% of the
      cases. Such treatment tactics resulted in the large number of unsatisfactory
      anatomical and functional outcomes of medical rehabilitation (46.8%), changes in
      servicemen fitness category (30.3%) their discharge and disability. To make the
      treatment of such category of casualties more effective it is necessary to
      conduct the appropriate surgical stabilization of pelvic fractures at the stage
      of specialized medical care with the use of modern methods of external and
      internal osteosynthesis.

PMID- 12479003
TI  - [Clinical and roentgenological comparison of toxic brain injury].

PMID- 12479004
TI  - [Hepatobiliary system in patients with hepatic hemangioma].

PMID- 12479005
TI  - [Staged treatment of patients with severe hepatic alcoholic affection].

PMID- 12479006
TI  - [Antisecretory effect of losec and pariet in peptic ulcer therapy].

PMID- 12479007
TI  - [Variability of cardiac rhythm and central hemodynamics in men with early forms
      of cerebrovascular disease].

PMID- 12479008
TI  - [Immunotype of tumor cells as a basis of surgical treatment of prostate
      carcinoma].

PMID- 12479009
TI  - [Viruses and glomerulonephritis].

PMID- 12479010
TI  - [Psychophysiologic indices in evaluation of working capacity, fatigue and
      overstrain in seamen].
AB  - The authors have discussed the new conceptual neurophysiological model of genesis
      and pathogenesis of fatigue and overstrain in seamen. The complex phase character
      of the developing changes was revealed. Use of the complex of psychophysiological
      methods with consideration of neurophysiological nature of the changes detected
      allowed us to obtain the objective assessment concerning fatigue and overstrain
      in seamen. It is shown that the existing conceptions about the dynamics of
      nervous processes developed in seamen during fatigue and overstrain including
      those described in the corresponding documents of the Navy and their evaluation
      are too simplified and theoretically incorrect. These incorrect concepts
      practically prevent the conduction of appropriate medical and prophylactic
      measures, complicate the standardization of some characteristics of habitability
      of the Navy ships and submarines, not ensure trouble-free conditions at sea in
      terms of human factor.

PMID- 12479011
TI  - [Identification operations in the Republic of Croatia].

PMID- 12479012
TI  - [Keeper of the historical traditions of Russian military medicine (dedicated to
      the 60th anniversary of the Military Medical Museum of the Ministry of Defense of
      the Russian Federation)].

PMID- 12479013
TI  - [The Pacific Naval Hospital--130-years-old].

PMID- 12479014
TI  - [Jubilee of the Naval Hospital of the White Sea Naval Base].

PMID- 12479015
TI  - [Male sexual dysfunction with spinal cord injury and other neurologic diseases].
AB  - Male sexual function requires an intricate interplay between the man and his
      environment. Cognitive integration and physiological response to sexual
      stimulation is dependent on complex neurologic functions that may be impaired by
      central or peripheral neurologic disorders. This article reviews the normal
      neuroanatomy of sexual functioning in men, and the epidemiology, pathophysiology
      and management of sexual dysfunction in spinal cord injury, cerebrovascular
      accident, multiple sclerosis and Parkinson's disease.

PMID- 12479016
TI  - [The effects of antisenes oligodeoxynucleotide on the cyclic nucleotide
      monophosphates in smooth muscle cells of human corpus cavernosum].
AB  - OBJECTIVES: To investigate the effects of antisense oligodeoxynucleotide(ASON) on
      the cyclic nucleotide monophosphates (cNMP) in smooth muscle cells of human
      corpus cavernosum, and provide experimental groundwork for the gene therapy of
      erectile dysfunction. METHODS: PDE5 gene ASON(containing exon 1) was transfected
      into the corpus cavernosum smooth muscle cells with the presence of liposome
      DOTAP. Another sense oligodeoxynucleotide(SON) and 1% of bovine serum were also
      transducted into the cells as controls. Two of cNMP, cAMP and cGMP, were probed
      and measured by ELISA at 1, 2, 4, 6, 10, 24 and 48 h after transfection. RESULTS:
      After transfection, the level of cGMP(1-6 h) in human corpus cavernosum smooth
      muscle cells was significantly higher than that in controls(P < 0.01).
      CONCLUSIONS: The PDE5 gene ASON had been showed to manifest stimulative effect on
      the cGMP in smooth muscle cells of human corpus cavernosum in vitro, and it
      provides experimental groundwork for the gene therapy of erectile dysfunction.

PMID- 12479017
TI  - [Effect of acrosin inhibitor KF-950 on acrosin activity and acrosome of human
      sperm].
AB  - OBJECTIVES: To study the inhibitory effect of KF-950 on human acrosin and sperm
      acrosome. METHODS: Human acrosin was extracted and purified with 2% acetic acid,
      and its residual activity was evaluated by BAEE/ADH assay after treated with
      different concentrations of KF-950. ABC assay was used to observe the effect of
      KF-950 on human acrosome with Biotin-PSA as a probe. RESULTS: 1. The activity of
      normal sperm acrosin was (37.65 +/- 4.47) U/L. 2. The residual activity was
      inversely related to the concentration of KF-950 (r = -0.998), and had a dose
      response curve. The result could be described by Y = 7.57-1.895X. 3. With
      increase of KF-950 concentration and prolongation of action time, the staining
      rate of acrosome obviously dropped (P < 0.01). CONCLUSIONS: KF-950 directly
      inhibits acrosin activity and assumely injures sperm acrosome. It might be a new
      kind of highly effective inhibitor.

PMID- 12479018
TI  - [The inhibitory action of the antisense oligodeoxynucleotide to the expression of
      vascular endothelial growth factor by radiotherapy in a prostate cancer cell
      line].
AB  - OBJECTIVES: To investigate mechanism for the increasing level of serum vascular
      endothelial growth factor(VEGF) in tumour patients during radiotherapy and the
      inhibitory action of the antisense oligodeoxynucleotide (AS-ODN) to the
      expression of VEGF protein by radiotherapy in the prostate cancer cell line
      (PC3M). METHODS: To observe the changes of serum VEGF in the prostate cancer
      patients during radiotherapy dynamically and the inhibitory action of the
      antisense oligodeoxynucleotide to the expression of VEGF by radiotherapy in PC3M.
      RESULTS: The changes of serum VEGF in three patients receiving radiotherapy had
      been observed continuously. The levels of serum VEGF began to increase when the
      patients received radiotherapy and rised up to peak value after fifteen days,
      then declined to the range of pre-radiotherapy. Irradiating the PC3M cells with X
      rays significantly increased the VEGF expression and secretion. The expression of
      VEGF protein in the group treated by VEGF AS-ODNs and X-ray irradiation decreased
      significantly than the group treated only by X-ray irradiation. CONCLUSIONS: The
      induction of VEGF protein expression by X-ray irradiation in tumor cells may
      result in the increasing of the VEGF in the prostate cancer patients during
      radiotherapy and the induction can be blocked by VEGF AS-ODNs.

PMID- 12479019
TI  - [An experimental study of the inhibition of tamoxifen on rat model of benign
      prostatic hyperplasia].
AB  - OBJECTIVES: To study the inhibitory mechanism of tamoxifen on benign prostatic
      hyperplasia. METHODS: The Wistar male adult rats were injected into muscle with
      testosterone propionate 4-6 mg/kg, simultaneously were irrigated into stomach
      with tamoxifen citrate 0.21 mg/kg. The partly rats of each group were decapitated
      at 7, 15 and 30 days, then their index numbers of prostate were calculated, and
      the structural changes of the prostatic histocyte were observed in the light
      microscopy and scan electronic microscopy. RESULTS: At the 7th, 15th, and 30th
      day, the index numbers of prostate of those rats which had been injected only
      with testosterone propionate were higher than that of the control group and the
      irrigating group(P < 0.05). The hyperplasia of the prostatic epithelial cells and
      the ground substance of those rats, which had been irrigated with tamoxifen
      citrate, had not happened in light microscopy and the scan electronic microscopy.
      CONCLUSIONS: Tamoxifen could block the effect of the estrogen, which could
      suppress the prostatic hyperplasia. This study could provide the experimental
      evidences for using Tamoxifen to treat the human benign prostatic hyperplasia.

PMID- 12479020
TI  - [Study on the relationship between the functional integrity of sperm membrane and
      seminal parameters related to CASA].
AB  - OBJECTIVES: To evaluate the relationship between the functional integrity of
      sperm membrane and seminal parameters related to CASA. METHODS: Thirty-eight
      fertile and one hundrend and twenty four infertile males were tested the
      functional integrity of sperm membrane by the kit and parameters by CASA.
      RESULTS: There was a significant difference in the functional integrity of sperm
      membrane between fertile and infertile group (P < 0.01). The items related to
      CASA between normal and abnormal group in the functional integrity of sperm
      membrane had a remarkable difference, except motion degree, seminal volume and
      pH. CONCLUSIONS: To determine the functional integrity of sperm membrane can be
      used as a necessary supplementary method for CASA, and it has clinical
      significance in diagnosing, treating and researching male infertility.

PMID- 12479021
TI  - [Ultrastructural observation of normal spermatozoa incubated with ROS in vitro].
AB  - OBJECTIVES: To observe ultrastructural changes of spermatozoa after incubate with
      reactive oxygen species (ROS). METHODS: Spermatozoa of normal physiological
      functions selected from semen samples by Percoll gradient centrifugation
      technique were regarded as normal sperm models in present study. Ultrastructural
      changes of spermatozoa observed by transmission electron microscope after model
      spermatozoa were incubated with ROS generated by hypoxanthine and xanthine
      oxidase under aerobic environment. RESULTS: After model spermatozoa were
      incubated with ROS, impairment of various extent in membrane and acrosome of
      spermatozoa and abnormality in mitochondria of spermatozoa were found.
      CONCLUSIONS: Excessive ROS may cause ultrastructural change in membrane, acrosome
      and mitochondria of spermatozoa and impair function of spermatozoa.

PMID- 12479022
TI  - [Effect of MPA and MPA + TU on the rat spermatogenesis and sexual hormones].
AB  - OBJECTIVES: To investigate the effect of administration of MPA with/without TU on
      serum sexual hormones and spermatogenesis of male rats. METHODS: Twenty rats had
      been classified into four groups. Each group received injection of saline(group
      A) or MPA(37.5 or 75 mg/kg) (group B or group C, respectively) or MPA (75 mg/kg)
      + TU (25 mg/kg) (group D) every month during three months. Data from serum sexual
      hormones (FSH, LH, T), sperm counting and motility had been collected and
      analysed. RESULTS: Spermatogenesis of rats undergoing administration of MPA with
      or without TU had been suppressed. Serum FSH and LH of group B, C, D declined,
      and so did serum T of group D. Testis of rats of group D atrophied and sperm
      counting of group D decreased remarkably compared with group B and C. But there
      was no statistics difference of the sexual hormone level among group B, C and D.
      CONCLUSIONS: Administration of MPA alone could suppress the levels of FSH and LH
      and block the spermatogenesis of male rats. MPA combined with TU could offer
      stronger suppression on spermatogenesis. Mechanism of the suppression on
      spermatogenesis of MPA + TU is not only limited in the feed-back of gonadotropin,
      but there maybe exist a direct suppression on testis.

PMID- 12479023
TI  - [Diagnosis and treatment of urethral condyloma acuminatum in male patients].
AB  - OBJECTIVES: To present experience on the diagnosis and treatment of urethral
      condyloma acuminatum (CA) in male patients. METHODS: Twenty-one cases of urethral
      CA were studied. The lesion of urethral meatus and intraurethal were resected by
      electrofulguration or operation and Urethroscopy, respectively. All patients were
      received intraurethral instillation and local therapy of 5% 5-fluorouracil
      solution. RESULTS: The patients had been followed up for three to twelve months.
      Cure rate was 76.2%, recurrence rate was 23.89%. CONCLUSIONS: Transurethral
      endoscopy is a reliable diagnosis and treatment method. Intraurethral
      instillation and local therapy of 5% 5-fluorouracil solution may prevent the
      recurrence of CA.

PMID- 12479024
TI  - [Diagnostic value of high frequency color Doppler ultrasonography for
      epididymitis].
AB  - OBJECTIVES: To evaluate the diagnostic value of color Doppler ultrasonography for
      epididymitis. METHODS: High frequency color Doppler ultrasonography was performed
      in 42 patients with epididymitis and 21 health volunteers. RESULTS: Compared with
      control group, epididymis enlarged significantly all in head, body and tail in
      92% of patients with epididymitis. Bilateral epididymitis occurred in 73% of
      patients. Color Doppler flow imaging (CDFI), in patient group, showed the
      markedly increased flow signals bright in bundle in epididymis. Mild hydroccele
      of testis and orchitis were companied in most patients(93%). Orchitis was often
      complicated in the patients with long history. CONCLUSIONS: High frequency color
      Doppler ultrasonography can be a preferred exam method and has diagnostic value
      for epididymitis.

PMID- 12479026
TI  - [The rat model of erectile dysfunction caused by cavernous nerve injury].
AB  - OBJECTIVES: To identify rat cavernous nerve and establish a rat model of erectile
      dysfunction (ED) caused by injury of cavernous nerve. METHODS: Twenty rats were
      undergone dissections. Cavernous nerves were identified with the aid of operating
      microscope and confirmed by electrical stimulation. Then, 42 experimental rats
      were randomized into 3 groups, including sham operated controls, unilateral and
      bilateral cavernous nerve ablation groups. Three weeks after surgery, rat models
      were evaluated with Apomorphine Test. RESULTS: The major pelvic ganglion lies on
      either side of the dorsolateral lobes of the prostate. It includes 2 inflows, one
      called hypogastric nerve and another is pelvic nerve. The largest outflow is
      termed as cavernous nerve. Stimulus parameters which could induce obvious penile
      erection were 5 volts, frequency of 20 Hertz and duration of 5 milliseconds.
      Three weeks after surgery, apomorphine could induce penile erection of each rat
      in controls with mean (2.57 +/- 1.40) erections in 30 minutes, while there were
      no erections (0.00 +/- 0.00) either in unilateral or bilateral group.
      CONCLUSIONS: The rat of larger ganglion and its cavernous nerve can be easily
      identified, obvious response to electrical stimulation, low cost of animal
      purchase, easy housing and availability made rat as an ideal animal for
      establishing ED model caused by cavernous nerve injury. In addition, our study
      showed in the early period of cavernous nerve injury, either unilateral or
      bilateral, all rats lost their erectile function.

PMID- 12479025
TI  - [Effects of Seroxat on premature ejaculation: a clinical trial].
AB  - OBJECTIVES: To evaluate the effects of antidepressant Seroxat on premature
      ejaculation. METHODS: After having taken Seroxat 20 mg every noon for four weeks,
      the patients were asked to fill the investigating questionaire about the effects
      and side effects before and after the treatment. RESULTS: After the treatment, 43
      cases in our study had increased their ejaculation latency time, enhanced the
      quality of their sexy lives and their wives', and had significant difference
      compared with pre-treatment(P < 0.001). They had good effects on improving
      premature ejaculation after taking Seroxat (11.26 +/- 5.79) days; and after
      having stopped taking seroxat for (20.94 +/- 8.04) days, the situation of
      premature ejaculation in 32 cases were as same as that of before. There were
      seven cases whose sexuality and oomph increased, and two cases whose sexuality
      were decreased. A few patients had constipation, dry in mouth, insomnia and itch
      in skin, after taking the drugs. CONCLUSIONS: Antidepressant Seroxat has rather
      good effects on premature ejaculation and should be used and studied further.

PMID- 12479027
TI  - [The nNOS-containing nerve fibers changes in corpus cavernosum of diabetic rat].
AB  - OBJECTIVES: To investigate the effect of diabetes mellitus on nNOS-containing
      nerve fibers in rats corpus cavernosum. METHODS: Healthy male Sprague-Deuley rats
      (n = 34) were divided into two groups randomly, the sixth (n = 17) and eighth
      groups (n = 17). Eleven of severteen rats wree intraperitoneal injection with
      streptozotocin (STZ) to induce experimented model of diabetes medilus in each
      group. The other were injected with citrate buffer as control. Injected with
      apmorphine at sixth and eight week, penile erection in diabetic and control
      groups were observed and noted. The expression of nNOS-positive containing nerver
      fibers in corpous cavernosum were examined with streptavidin-peroxidase
      immunohistochemistry (SP method). RESULTS: The erection rate of penile diabetic
      mellitus decreased compared to that in controls (P < 0.01). The erection rate of
      two diabetic groups were 37.5% and 14.3%, respectively, with significant
      difference (P < 0.05). The controls were all 100%. The significant changes of
      nNOS-containing never fibers were observed in the two diabetic groups. The
      numbers of nNOS-containing nerver fibers in the corpus cavernosum in the two
      diabetic groups were (37.00 +/- 6.76) and (28.00 +/- 5.29), respectively, with
      significant difference compared to each other (P < 0.05). In the two controls,
      the fibers were (83.00 +/- 3.22) and (81.00 +/- 3.61), respectively. The fibers
      in diabetic groups were less than those in controls (P < 0.01). CONCLUSIONS: The
      erectile function of rats and the number of nNOS-positive containing nerve fibers
      is affected seriously by diabetes mellitus and it is positively correlated to the
      duration of diabetes mellitus. The decreasing of nNOS-positive containing nerve
      fibers may be one of the mechanisms of diabetic erectile dysfunction.

PMID- 12479028
TI  - [The changes of IL-1 and NO levels in the testes of rats with experimental
      varicocele].
AB  - OBJECTIVES: To evaluate the effects of varicocele (VC) on IL-1 and NO levels in
      testes of rats with VC. METHODS: Male adult Wistar rats were divided into two
      groups randomly, VC group (n = 30) and pseudo-operation group (n = 20), and the
      levels of IL-1 and NO in the testes were determined and compared. RESULTS: The
      levels of IL-1 and No of left tests in VC group were higher than those in pseudo
      operation group, respectively(P < 0.01). While the levels of IL-1 and NO of right
      testes between two groups were not significantly different (P > 0.05). More over,
      the level of IL-1 correlated significantly with that of NO(r = 0.572, P < 0.01).
      CONCLUSIONS: The results revealed that the changes of IL-1 and NO levels in the
      testes of rats with VC might be the reason which caused testes damage,
      disturbance of spermatogenesis and even infertility.

PMID- 12479029
TI  - [The observation of chronic prostatis patients using the National Institutes of
      Health Chronic Prostatitis Symptom Index].
AB  - OBJECTIVES: The National Institutes of Health Chronic Prostatitis Symptom Index
      (NIH-CPSI) was used to determine the chronic prostatitis syndrome in young men
      (from 20 to 48 years old) of clinical validity. METHODS: 227 patients with
      chronic prostatitis syndrome (CPS)/chronic pelvic pain syndrome and 32 patients
      with BPH were randomized to study using NIH-CPSI. RESULTS: 1. The main
      manifestations of CPS patients were pain or uncomfort. Those were more common in
      CPS than BPH. 2. 79.30% CPS patients had a sensation of not emptying bladder
      completely after finished urinating, 44.93% patients had to urinate again less
      than two hours after finished urinating. 3. 51.51% patients with CPS have more
      effect on work, 90.31% patients on free life, and 68.72% patients on quality of
      life than BPH. CONCLUSIONS: According NIH-CPSI, the main manifestations of CPS
      are pain or uncomfort. CPS patients have more effect on work and quality of life.

PMID- 12479030
TI  - [The effects of testosterone undecanoate on relaxation of rat corpus cavernosum
      smooth muscle in vitro].
AB  - OBJECTIVES: To investigate the role of Undecanoate (Andriol), as a kind of
      testosterone, in regulating the relaxation of isolated rat corpus cavernosum in
      vitro. METHODS: The castrated rats were given high and low dosage Andriol
      respectively, compared with intact and castrated rats. After treatment of 4
      weeks, the corpora cavernosa were cut, trimmed as to strips. Norepinephrine(NE)
      was added to contract each of the tissue strips. Next, sodium nitroprusside(SNP),
      electric functional stimulation(EFS) were used to relax the strips. Percent
      relaxations were examined. RESULTS: High-dose Andriol(20 mg/kg) was significantly
      effective to castrated rats on percent relaxation induced by 10(-3) mol/L SNP and
      EFS. Low-dose Andriol(10 mg/kg) was also effective to relax strips induced by 10(
      3) mol/L SNP. According to statistics, the differences were significant (P <
      0.01). CONCLUSIONS: The percent relaxations of castrated rats were increased
      after taking Andriol, and it could increase the relaxation of corpara cavernosa.

PMID- 12479032
TI  - [Intercellular gap junctions in corporal smooth muscle].
AB  - The contractility of corporal smooth muscle plays a critical role in human penile
      erectile process. Understanding the initiation, maintenance and modulation of
      corporal smooth muscle tone is a prequisite to improve understanding, diagnosis
      and treatment of erectile dysfunction. Despite this fact, indentification of both
      the precise mechanistic basis by which various agents exert their effects on
      individual corporal smooth muscle cells, moreover, the process by which these
      signals are spread among the diverse array of parenchymal cells in the paired
      corporal, remain somewhat of a physiological enigma. Therefore, this article aims
      at: 1. to review current knowledge of the regulation of corporal smooth muscle
      tone at the cellular and molecular level; 2. to review various methods used in
      the study of gap junction channel.

PMID- 12479031
TI  - [The effect of acute urinary retention on serum prostate specific antigen
      concentration].
AB  - OBJECTIVES: To study the effect of acute urinary retention on the serum prostate
      specific antigen (PSA) concentration. METHODS: Blood samples from 34 benign
      prostatic hyperplasia (BPH) patients with acute urinary retention were drawn
      immediately before suprapubic cystomy and 48 hours after relief of urinary
      retention. Serum PSA concentrations were measured with radioimmunoassay. RESULTS:
      The mean serum PSA levels of BPH patients with acute urinary retention was (24.6
      +/- 16.1) micrograms/L (range from 2.6 micrograms/L to 45.8 micrograms/L). Forty
      eight hours after relief of urinary retention, the mean serum PSA levels declined
      to (9.4 +/- 6.3) micrograms/L (range from 1.7 micrograms/L to 16.6 micrograms/L).
      The difference was significant (P < 0.01). CONCLUSIONS: Acute urinary retention
      could dramatically increase the serum PSA value of patients with BPH. After
      relief of the urinary retention, the patients had a great than 50% decreased of
      PSA values.

PMID- 12479033
TI  - [Study on the male contraceptive based on epididymis].
AB  - More and more study on the epididymal function and sperm maturation has shown
      that epididymis will be one of the best target organs of male contraception,
      although at present there is not a male contraceptive medicine based on
      epididymis for clinical practice. The promoting research aspects in epididymal
      contraception in animal included affecting directly epididymis (such as
      Sulpasalazine), interfering energy metabolism and sperm mobility (such as
      Chlorinated Glycerol), altering the internal environment of epididymis (such as
      copper particles and TW19). The epididymal specific proteins could bring out some
      new target antigens for immunological contraception, to produce contraceptive
      vaccine. Some special genes, which expressed distinctively in epididymis such as
      SC342, bin1, have been cloned and studied on their function. These works would be
      helpful not only for clinical diagnosis and treatment of epididymitis and male
      infertility, but also for male contraceptive research and progress.

PMID- 12479034
TI  - [Aetiology of female sexual dysfunction].
AB  - Female sexual dysfunction (FSD) is a significant age-related, progressive, and
      highly prevalent problem that affects a substantial number of women on their
      quality of life. However, it hasn't received enough attention. In this review,
      the local regulation mechanism and the aetiological factors are associated with
      FSD are discussed. With the increased research, an improved awareness and
      understanding of the pathophysiological machanism of FSD may, in the future,
      enable us to address it more appropriately and develop suitable treatment.

PMID- 12479035
TI  - [Testosterone and male osteoporosis].
AB  - There are various causes for male osteoporosis. The low testosterone level is one
      of the important reasons. Androgen does not only play an important role in
      gaining the peak bone mass and maintaining the bone mass, but also has an
      intimate correlation with the bone loss with ageing. Androgen affects osteoblasts
      through androgen receptors. Various local cell factors play regulating roles. The
      partial testosterone replacement therapy in aging men could elevate the bone mass
      density, but the advantages and the disadvantages should be observed further. The
      function of the estrogen in male osteoporosis is being noted as well.

PMID- 12479036
TI  - [Twenty-eight cases report of transurethral resection of the prostate combined
      with repair of inguinal hernia].
AB  - OBJECTIVES: To discuss the surgical method of benign prostatic hyperplasia (BPH)
      with inguinal hernia. METHODS: Twenty eight cases of BPH with inguinal hernia
      were treated with transurethral resection of the prostate (TURP) combined with
      repair of inguinal hernia by PPM at the same time. RESULTS: All patients had been
      followed up for six months to four years, in which recurrence of hernia or other
      complications were not found. Qmax was more than 15 ml/s after operations, and
      IPSS were about 0-7 scores for all patients. The mean time of hospitalization was
      4.2 days. CONCLUSIONS: TURP combined with repair of inguinal hernia at the same
      time is a simple and effective method, which can avoid second operation, and it
      is more significance to the aged especially.

PMID- 12479037
TI  - [Antibacterial effect of niaoluqing oral liquid on clinical drug-resistant
      strains and different serotype strains of Ureaplasma urealyticum in vitro].
AB  - OBJECTIVES: To study the antibacterial effect of Niaoluqing Oral Liquid (NOL) on
      clinical drug-resistant strains and 14 serotype strains Ureaplasma Urealyticum
      (UU). METHODS: Sixty-three clinical strains of UU were detected to determine
      their serology and antibiotic susceptibilities by the metabolic inhibition test
      (MIT). Mininum inhibitory concentration (MIC) was used to evaluate the
      sensitivity of NOL to different serotypes of UU. The sensitivity of NOL,
      erythromycin and tetracycline to 63 clinical strains of UU was also studied.
      RESULTS: In 63 clinical strains of UU, the range of MIC to NOL was from 0.48
      mg/ml to 15.63 mg/ml, MIC50 < or = 1.95 mg/ml, MIC90 < or = 3.91 mg/ml. Among
      them, 31 strains were resistant to tetracycline and 31 were resistant to
      erythromycin. No obvious correlation between the sensitivity of NOL to UU
      clinical strains and that of erythromycin and tetracycline to UU clinical strains
      (P > 0.05). Clinical strains of UU in this experiment contains all of its
      serotypes, also having a higher sensitivity to NOL (MIC < or = 3.91 mg/ml) except
      serology 1, 2, 3 and 11 (MIC > or = 7.81 mg/ml). CONCLUSIONS: NOL exerts a strong
      in vitro antibacterial effect on erythromycin-resistant and tetracycline
      resistant clinical strains of UU. All kinds of serotype strains had a higher
      sensitivity to NOL, too. Chinese medicinal herbs are of momentous significance in
      the treatment of UU infection.

PMID- 12479038
TI  - [Utility of oxidative stress test in the male infertility clinic].
AB  - The controlled generation of very low amounts of reactive oxygen species (ROS)
      appears to regulate normal sperm functions, while high levels of ROS endanger
      sperm viability and function. Oxidative stress (OS) develops as a consequence of
      excessive production of ROS and/or impaired antioxidant defense system. It is
      proposed that such OS precipitates a range of pathologies currently thought to
      afflict male reproductive function. ROS-mediated peroxidative damage to the sperm
      plasma membrane may account for defective sperm function observed in a high
      proportion of infertility patients. Excessive generation of ROS may also attack
      integrity of DNA in the sperm nucleus. DNA bases are susceptible to oxidative
      stress, and peroxidation of these structures can cause base modification, DNA
      strand breaks and chromatin cross-linking. DNA damage induced by excessive ROS
      may accelerate the process of germ cell apoptosis, leading to decline in sperm
      counts associated with male infertility, and may explain the apparent
      deterioration of semen quality observed during the past four to five decades. For
      almost a decade, our research team in the Cleveland Clinic Foundation has
      identified the critical role of OS in male infertility. The main objective of our
      research was to transfer this important knowledge from the research bench to
      clinical practice. We designed studies with the aims of: 1. understanding the
      exact mechanisms by which OS develops in semen, which we thought will help setup
      strategies to overcome the problem, 2. establishing assays for accurate
      assessment of OS status and running the quality control studies for this purpose,
      3. testing the correlation between OS and sperm nuclear DNA damage, and 4.
      identifying the clinical significance of seminal OS assessment in male
      infertility practice.

PMID- 12479039
TI  - Diagnosis and management of ejaculatory duct obstruction.
AB  - Ejaculatory duct obstruction is a rare but important cause of male infertility.
      The differential diagnosis, evaluation and treatment of patients with suspected
      ejaculatory duct obstruction is described herein. New minimally invasive
      techniques that can be utilized in both the diagnosis and treatment of
      ejaculatory duct obstruction are described.

PMID- 12479040
TI  - [Effects of fenvalerate on reproductive and endocrine systems of male rats].
AB  - OBJECTIVES: To evaluate the impairment of fenvalerate on reproductive and
      endocrine systems and clarify the mechanism of action. METHODS: Different doses
      of fenvalerate (0, 2, 4, 12, 60 mg/kg) were orally treated to the adult male SD
      rats for 15 days and 30 days, respectively. The levels of serum follicle
      stimulating hormone(FSH), luteinizing hormone (LH), testosterone(T) and testis
      homogenate T were determined by radioimmunoassay(RIA). Besides, the activity of
      testicular marked enzymes such as acid phosphatases(ACP) and gamma-glutamyl
      transpeptidase(gamma-GT) were examined, and sperm head counts were measured to
      explain the changes of daily sperm production(Spr). RESULTS: In fifteen days,
      serum FSH levels markedly increased in rats exposed to fenvalerate of < or = 12
      mg/kg groups(P < 0.01) and serum levels of LH increased in 12 mg/kg group(P <
      0.01). In addition, T levels in testis homogenates decreased after treated with
      the doses of > or = 12 mg/kg groups compared with the control group(P < 0.01). In
      thirty days, serum contents of FSH were significantly elevated in the doses of >
      or = 12 mg/kg groups(P < 0.01) and homogenate levels of T were diminished in the
      low dose group(2.4 mg/kg) (P < 0.05). Activity of ACP increased in 12 mg/kg group
      after fifteen days(P < 0.05) and was restrained in the high dose group(60 mg/kg)
      in thirty days(P < 0.05), but the contents of gamma-GT were arrested with
      different doses dependently in the testis(P < 0.05). Fenvalerate caused dose
      dependent reduction in sperm head counts and daily sperm production, which
      markedly reduced at the doses of > or = 12 mg/kg groups(P < 0.01). CONCLUSIONS:
      Fenvalerate has obvious reproductive toxicity on male rats and can change their
      serum and testis homogenate levels of sex hormone or activity of testicular
      marked enzymes, which may be correlated with the impairment of Sertoli cell and
      spermatogenic epithelium.

PMID- 12479041
TI  - [Preliminary study on hens immunized with recombinant human testis prostaglandin
      D synthase DNA].
AB  - OBJECTIVES: In order to identify whether the hens immunized with recombinant
      human testis prostaglandin D synthase (rhtL-PGDS) DNA can produce anti-L-PGDS
      antibody. METHODS: The serum were got from the hens immunized with recombinant
      plasmid pGEX-2T/htL-PGDS DNA (100 micrograms) every 2 weeks for 2 times. The
      exist of anti-L-PGDS antibody and its titer were tested with agarose dual
      immunodiffusion and ELISA with rhtL-PGDS as antigen. RESULTS: The serum anti-L
      PGDS antibody in hen immunized with pGEX-2T/htL-PGDS DNA were confirmed and its
      titer tested by ELISA was 1:2,048. CONCLUSIONS: It is feasible to produce anti-L
      PGDS antibody by immunizing hens with recombinant pGEX-2T/htL-PGES DNA.

PMID- 12479042
TI  - [Preliminary investigation of relationship between sperm apoptosis and male
      infertility].
AB  - OBJECTIVES: To evaluate the relationship between sperm apoptosis and male
      infertility. METHODS: Percentage of apoptotic sperm (PAS) in spermatozoa of
      fertile and infertile men were tested by flow cytometry (FCM). RESULTS: Sperm
      apoptosis had happened in all different people. PAS in fertile and infertile
      group was (4.28 +/- 1.66)% and (18.67 +/- 8.55)% respectively, and difference was
      significant between two groups (P < 0.01). There was negative correlation between
      PAS and semen volume, sperm density, percentage of forward motility, percentage
      of normal morphology (P < 0.01). CONCLUSIONS: There was very close relationship
      between sperm apoptosis and male infertility. FCM used to test sperm apoptosis is
      rapid, accurate, objective and reliable to analyse sperm functions and male
      fertility.

PMID- 12479043
TI  - [Isolation and identification of spermatids from mouse testis].
AB  - OBJECTIVES: To develop a simple and effective method by which spermatids can be
      isolated from mouse testis. METHODS: Combination of enzymatic digestion was used
      to prepare suspension of spermatogenic cells from adult mouse testis, and then a
      modified discontinuous Percoll gradient (15%, 22%, 30%, 40%, 50%, 60%)
      centrifugation method was introduced to isolate spermatids from the cellular
      suspension. The content of spermatids in each isolated fraction by Percoll method
      was determined by morphology (Wright-Giemsa staining) and flow cytometry
      analysis, and the viability of spermatogenic cells was assessed using Eosin Y
      exclusion test. RESULTS: More than 97% of the testicular cells remained their
      viability after enzymatic digestion. After Percoll centrifuged, six fractions
      were formed. In each isolated fraction, the 22% fraction contained mostly
      spermatids(mean 86.7%) and cell viability was more than 85.5%. While in the 30%
      fraction, immature spermatogenic cells were present, and more than 92% of the
      cells remained their viability. CONCLUSIONS: A large of relatively purified
      spermatids can be isolated from mouse testis by enzymatic digestion combined
      discontinuous Percoll gradient centrifugation method.

PMID- 12479044
TI  - [The distribution of androgen receptor and its coexistence with gonadotropin
      releasing hormone receptor in rat submaxillary].
AB  - OBJECTIVES: To study the coexistence of androgen receptor(AR) and GnRH
      receptor(GnRHR), and further identify that submaxillary is a target organ of
      androgen and GnRH in SD Rat. METHODS: Sequential deparaffinized sections of SD
      rat submaxillary were immunostained with SABC method. The first antibodies were
      rabbit anti-rat GnRH idiotypic antibodies and mouse anti-rat androgen receptor
      antibodies. RESULTS: AR immunoreactive cells were found in glandular epithelial
      cells of serous acinus and epithelial cells in all gland ducts. While the
      distribution of GnRHR coincides with that of AR. The immunoreactive substances
      were distributed in cytoplasm of all positive cells with negative nuclei.
      CONCLUSIONS: The results showed that AR existed in submaxillary and was widely
      distributed in glandular epithelial cells with distributive pattern similar to
      those of GnRHR. It suggests that submaxillary is a target organ of androgen,
      responsible for modulating biological function of submaxillary.

PMID- 12479045
TI  - [Study of correlation and effect of smoking on semen quality of men].
AB  - OBJECTIVES: To study the correlation and effect of smoking on the semen quality
      of men. METHODS: 61 men, non-smoker, who had one or more children as normal
      fertility control group and adult males attending the infertility clinic,
      including 110 non-smokers and 191 smokers, were recruited for the study. The
      smokers were divided into subgroups according to the amount and duration of
      smoking. Semen parameters(volume, sperm density, viability, motility and
      morphology) were examined and seminal plasma contents of Zn, Cu and superoxide
      dismutase (SOD) were determined. RESULTS: The semen volume, pH, sperm density,
      viability and forward progression, as well as the seminal plasma contents of Zn,
      Cu and SOD were much lower in the medium, heavy and long-term smokers than in the
      non-smokers(P < 0.01). The sperm density, viability and forward progression, and
      the seminal plasma Zn, Cu and SOD levels were negatively correlation with the
      amount and duration of cigarette smoking(P < 0.001). CONCLUSIONS: The effect of
      smoking on semen parameters of infertile men were dose-effect and time-effect
      relationship. Medium, heavy and long-term smoking adversely affected the semen
      quality in a population of men visiting the infertility clinic.

PMID- 12479046
TI  - [Chronic prostatitis symptom index of Chinese].
AB  - OBJECTIVES: To establish the chronic prostatitis symptom index which more
      suitable for Chinese to refine and standardize evaluation of current symptoms in
      men with "chronic prostatitis". METHODS: The literature of previous work was
      reviewed to develop a symptom index instrument. There were 18 questions
      representing three broad categories: pain symptoms, urinary symptoms and other
      symptoms. To evalute the clinical utility and applicability for Chinese people of
      this tool, we used it in 100 patients with chronic prostatitis and 100 control
      patients (40 with benign prostatic hyperplasia, BPH; 30 with infertility; 30 with
      erectile dysfunction). RESULTS: Of the three aspects symptoms, the primary
      component was pain. But pain in lower back and lower abdomen had less
      specificity. Pain in the rectal area was not very common but it could well
      distinguish patients with prostatitis from those BPH, infertility and ED. Urinary
      symptoms were also common. We used 5 symptom questions in urinary aspect in the
      last version of this index. In other symptoms, we dropped the question of
      uncomfortable of waist and back at last. It could not distinguish patients with
      prostatitis from those infertility and erectile dysfunction. Finally we analyzed
      the result and modified the new version of chronic prostatitis symptom index. It
      included 5 pain symptom questions, 5 urinary symptom questions and 2 other
      symptom questions. There are 12 questions in total. CONCLUSIONS: The chronic
      prostatitis symptom index we developed was validated and useful in clinical
      practice as well as research protocols. Moreover, it was more suitable for
      Chinese people.

PMID- 12479047
TI  - [The clinical efficacy of epristeride in the treatment of benign prostatic
      hyperplasia].
AB  - OBJECTIVES: To estimate the clinical safety, efficacy of Epristeride in the
      treatment of benign prostatic hyperplasia (BPH). METHODS: One hundred and fourty
      one BPH patients, aged from 50 to 83 years old [(66.18 +/- 6.41) yr], were given
      Epristeride tablets 5 mg p.o., twice daily for 120 days. To synthetically
      estimate the efficacy by the changing rate of international prostate symptom
      score (IPSS), maximum flow rate (Qmax), the volume of prostate (V) and the
      residual urine (Ru). RESULTS: The total efficacy was 81.29%. The adverse
      reactions include 1 case (0.72%) of exanthem, 1 case (0.72%) of nausea and
      vomiting, 1 case (0.72%) of insomnia, 1 case (0.72%) of tinnitus and 3 cases
      (2.16%) of erectile dysfunction. Two patients discontinued the treatment due to
      the side effects (1.44%). There was no clinical significantly abnormal laboratory
      index during the treatment. CONCLUSIONS: Epristeride tablets was safe and
      effective in the treatment of BPH.

PMID- 12479048
TI  - [The effect of cryopreservation on human sperm chromosome].
AB  - OBJECTIVES: To evaluate the effects of cryopreservation on human sperm
      chromosome. METHOD: Sperm chromosome were acquired using in vitro fertilization
      of zona-free hamster oocytes and human sperm. The frequency of sperm chromosome
      anomalies and sex chromosomes ratio before and after freezing and with different
      freezing methods were compared. RESULTS: There were no significant differences of
      frequency of sperm chromosome anomalies among fresh, fast frozen and slow frozen
      sperm (9.40%, 7.48% and 8.74%) (P > 0.75) or ratios of sex chromosomes (P >
      0.90). CONCLUSIONS: These studies indicate that cryopreservation does not exert
      effects on human sperm chromosome.

PMID- 12479049
TI  - [Treatment of external RF hyperthermia combining with alpha 1-adrenergic receptor
      blocker for patients with prostatodynia and chronic non-bacterial prostatitis].
AB  - OBJECTIVES: To evaluate a new effective treatment for prostatodynia (PD) and
      chronic non-bacterial prostatitis (CNP). METHODS: One hundred and thirty-six
      patients suffered from PD or CNP were divided randomly into experiment group (n =
      76), which were treated with external RF hyperthermia (ERFH) combining with alpha
      1-adrenergic receptor blocker Terazosin for 12 weeks, and control group (n = 60),
      which were only treated with ERFH. Symptoms scores, urodynamic indexes and
      expressed prostate secretion were recorded pre- and post-treatments. RESULTS: MFR
      and AFR were significantly improved and symptoms scores significantly decreased
      in both groups (P < 0.05). The efficacy was better in experiment group than that
      in control group. The combination treatment also led to a significantly decrease
      in MUP and MUCP (P < 0.05). Additionally, the leucocytes in expressed prostate
      secretion were also reduced in experiment group (P < 0.05). CONCLUSIONS:
      Treatment of ERFH combining with alpha 1-adrenergic receptor blocker for patients
      with PD or CNP was effective and had little side-effect, while the future
      curative effect should be observed furtherly.

PMID- 12479050
TI  - [Tamsulosin for the treatment of chronic abacterial prostatitis].
AB  - OBJECTIVES: To evaluate the efficacy of selective alpha 1A-adrenergic receptor
      antagonists for the treatment chronic abacterial prostatitis/chronic pelvic pain
      syndrome (CPPS). METHODS: From October 2000 to September 2001, a selective alpha
      1A-adrenergic receptor antagonists, tamsulosin, had been used in 43 patients with
      CPPS for four weeks. 0.2 mg dosage was given daily, and uroflowmetry was
      followed. Symptom scores were evaluated by the NIH-chronic prostatitis symptom
      index (NIH-CPSI) before and after the treatment. RESULTS: These patients had a
      clinically significant response to the treatment of tamsulosin. Of these, thirty
      two patients (74.5%) responded to one month therapy and had a decrease in NIH
      CPSI scores, while maximal urinary flow rate (MFR) and average urinary flow rate
      (AFR) in patients with poor MFR improved 30.4% and 65.4%, respectively. No severe
      side effects were observed. CONCLUSIONS: It is suggested that Tamsulosin, a
      selective alpha 1A-adrenergic receptor antagonist, is effective in the treatment
      of CPPS.

PMID- 12479051
TI  - [Chromosomal analysis of human sperm using multiple fluorescence in situ
      hybridization].
AB  - Now severe oligoasthenoteratozoospermic (OAT) patients could have offsprings
      because of the development of technique of intracytoplasmic sperm injection. But
      some researchers found these patients have increasing frequency of the aneuploid
      on the chromosome in their sperm. If the spermatozoa with chromosomal aneuploid
      were fertilized, it would be resulted in a higher rate of recurrent abortion,
      fetal abnormal and dead birth, so the analysis of the number of sperm chromosome
      will play an important role in detection on infertile men. There are many new
      development in the chromosomal analysis of human sperm using multi-FISH, now we
      have a review on them.

PMID- 12479052
TI  - [A serum marker of spermatogenesis--inhibin B].
AB  - Inhibin B is a glycoprotein secreted by testis, consisting of two disulfide
      linked subunits, an alpha-subunit and a beta B-subunit. Serum inhibin B levels
      are significantly negatively correlated with the serum FSH levels in males,
      exerting a negative feedback on FSH secretion. In males the circulating levels of
      inhibin B increase shortly after birth and peak at 4-12 months of age, then
      decrease to low levels from 3-9 year. From the onset of puberty, the levels of
      inhibin B gradually increase. By pubertal stage II, the adult levels of inhibin B
      have been reached. At stage III of puberty, a negative correlation between
      inhibin B and FSH levels is present and persists from stage III of puberty
      onward. At 20-30 year of age, the levels of inhibin B reach another peak, then
      gradually decline with increasing age. The men with hypospermatogenesis and
      spermatogenesis arrest have significantly lower levels of inhibin B than those
      with normal spermatogenesis. The men with Sertoli-cell-only syndrome (SCO) have
      extremely low levels of inhibin B. There is a closely correlation between the
      presence of SCO and the level of serum inhibin B. A significantly positive
      correlation is also observed between testis volume and inhibin B level, as well
      as between sperm count and inhibin B level. The inhibin B is a direct product of
      the seminiferous tubules, reflecting the total testicular tissue. The measurable
      inhibin B production in adult requires the presence of germ cells. Inhibin B is
      regarded as a serum marker of spermatogenesis. The determination of serum inhibin
      B in males can be used to assess the spermatogenesis of infertile men, to
      diagnose the cryptorchidism and precocious puberty, to predict the outcome of
      testicular sperm extraction in men with non-obstructive azoospermia, and to
      evaluate the damage to spermatogenesis in men after radiotherapy or
      chemiotherapy.

PMID- 12479053
TI  - [Advances in the study of trichomoniasis in men].
AB  - Trichomoniasis is an important sexually transmitted disease that is associated
      with increased perinatal morbidity and increased HIV transmission. Infection with
      Trichomonas vaginalis also results in local urogenital tract symptoms. Standard
      teaching is that trichomoniasis is an important cause of vaginitis in women, but
      that male sexual partners experience little or no morbidity. It is worth-while to
      summarize critical findings in a series of articles. The prevalence of
      Trichomonas vaginalis in men represents an important consideration in the
      differential diagnosis of urethritis.

PMID- 12479054
TI  - [Adolescent varicocele].
AB  - The incidence of varicocele in older adolescence varies from 12.4% to 17.8% with
      an average of 14.7%, similar to the incidence in adult males. Varicocele is
      associated with testicular growth arrest in adolescents. Varicocelectomy can
      reverse the testicular growth arrest. But without the testicular growth arrest,
      prophylactic surgery for every adolescent with varicocele is not advised. Surgery
      treatment should be offered to: 1. adolescents with testicular growth arrest more
      than 2 ml of difference between left and right testicle, 2. adolescents with
      abnormal semen analysis with high-grade varicocele, 3. adolescents with symptoms:
      pain, heaviness, swelling, 4. adolescents with bilateral varicoceles. Recurrence
      of the varicocele after surgery treatment can occur in 9% to 16% of adolescents.
      But rate of recurrence can be kept below 2% in adolescents treated by high
      retroperitoneal ligation with testicular artery ligation.

PMID- 12479055
TI  - [The treatment of method of regulating qi by alleviation of mental depress in
      chronic abacteria prostatitis].
AB  - OBJECTIVES: To evaluate the efficacy of method of regulating qi by alleviation of
      mental depress for chronic abacteria prostatitis (CAP). METHODS: From Aug. 2000
      to Dec. 2000, 60 patients underwent TCM treatment with either method of
      regulating qi by alleviation of mental depress (31 cases) or promoting blood
      circulation (29 cases). RESULTS: The marked rate and effective rate were 83.86%,
      93.55% in treatment group, and 65.52%, 93.10% in the control group, respectively.
      The marked rate in treatment group was higher than that of control group. Scores
      of NIH-CPSI were more decreased in treatment group than that in control group(P <
      0.05). The quality of life improved significantly in treatment group than that in
      control group (P < 0.05). CONCLUSIONS: Method of regulating qi by alleviation of
      mental depress had its advantage over methods of promoting blood circulation for
      CAP and was an effective treatment modality for CAP.

PMID- 12479056
TI  - IL-6 inhibits apoptosis of human myeloma cell line XG-7 through activation of
      JAK/STAT pathway and up-regulation of Mcl-1.
AB  - BACKGROUND & OBJECTIVE: IL-6 can protect myeloma cells from apoptosis induced by
      various stimuli. A series of intracellular molecules might participate in this
      process. Our aim in this study is to investigate which anti-apoptotic Bcl-2
      family proteins (Bcl-2, Bcl-XL, Mcl-1) and which signal transduction
      pathway(JAK/STAT, Ras/MAPK, PI-3K/Akt) can mediate the anti-apoptotic effect of
      IL-6 on a human myeloma cell line XG-7. METHODS: Apoptosis of XG-7 cells was
      analyzed by flow cytometry with propidium iodide(PI) staining of nuclei. The
      expression of three Bcl-2 family proteins in XG-7 cells were monitored by
      immunoblot assay. AG490, PD98059, and LY294002, three specific antagonists for
      JAK/STAT, Ras/MAPK, and PI-3K/Akt signal transduction pathways respectively, were
      used to determine which signal transduction pathway was responsible for the
      effect of IL-6 on XG-7 cells. RESULTS: IL-6 inhibited the apoptosis of XG-7 cells
      and up-regulated the expression of only one of the three anti-apoptotic Bcl-2
      family proteins-Mcl-1. In addition, up-regulation of Mcl-1 expression induced by
      IL-6 was significantly inhibited in the presence of AG490, while not of PD98059
      and LY294002. CONCLUSIONS: IL-6 inhibited apoptosis of XG-7 cells through up
      regulation of Mcl-1 and the activation of JAK/STAT rather than Ras/MAPK nor PI
      3K/Akt signal transduction pathway.

PMID- 12479057
TI  - [Regulation of Smad7 gene by TGF-beta 1 in process of malignant transformation].
AB  - BACKGROUND & OBJECTIVE: Escape from transforming growth factor-beta(TGF-beta)
      induced inhibition of growth and proliferation may contribute to tumorigenesis.
      Smad7 is inhibitory Smads of TGF-beta s signal transduction pathway and prevents
      TGF-beta signaling. The disorder of Smad7 may lead to the perturbation of TGF
      beta signal pathway. In this study, The authors analyzed the expression of Smad7
      mRNA and the regulation of Smad7 gene by TGF-beta 1 in the process of malignant
      transformation of BEP2D cells to investigate the mechanism of cells malignant
      transformation. METHODS: Cells were cultured and stimulated with TGF-beta 1
      followed by RNA extraction. Purified total RNA from TGF-beta 1 treated cells and
      untreated controls and performed an expression analysis with a human Smad7
      specific probe applying Northern blot. As a loading control for the Northern
      experiment, the membrane was hybridized with a human glyceraldehyde-3-phosphate
      dehydrogenase(GAPDH) probe. Proteins were extracted from BEP2D and BERP35T-2
      cells, then perform Western blot to examine the expression level of TGF-beta 1.
      RESULTS: Before stimulation with TGF-beta 1, the expression level of Smad7 in the
      BERP35T-2 cells were higher than that in the BEP2D cells. When stimulated with
      TGF-beta 1, Smad7 expression levels was upregulated evidently in BEP2D cells, but
      not significant in BERP35T-2 cells. The expression level of endogenetic TGF-beta
      1, BERP35T-2 cells was a little higher than BEP2D cells. CONCLUSION: Over
      expression of Smad7 mRNA and down-regulation of the cells' responsiveness to TGF
      beta 1 in human lung cancer cell line which induced by alpha-particles should be
      one of the mechanism of radiation induced lung cancer.

PMID- 12479058
TI  - [Cloning and expression of the mouse Doc-1R gene].
AB  - BACKGROUND & OBJECTIVE: Doc-1R gene is a new gene which was cloned in 1999.
      Recent studies suggest that Doc-1R gene is a potential tumor suppressor gene. In
      order to study the function of the Doc-1R gene, The aim of this study was to
      obtain its genomic sequences and to analyze its expression in the tissues.
      METHOD: According to the cDNA sequences of Doc-1R gene, the gene-specific primers
      were designed and synthesized. The sequence of Doc-1R gene was cloned through
      nested PCR using the Genome Walker kit. The sequence and splice donor/acceptor
      site were analyzed. Using the reverse transcription polymerase chain reaction(RT
      PCR), the expression of Doc-1R gene in thirteen tissues, including mouse liver,
      spleen, pancreas, kidney, lung, intestine, heart, brain, bone, muscle, bladder,
      ovary, spermary were determined. RESULTS: The mouse Doc-1R gene has been obtained
      by two times genomic walking. This gene spans 2,787 bp and contains four exons
      and three introns. All of the splice donor/acceptor site sequences were in
      accordance with the consensus "GT-AG" rule. RT-PCR experiments demonstrated Doc
      1R gene was expressed in the 13 tissue samples. CONCLUSION: The authors have
      successfully cloned the mouse Doc-1R gene, which will be the foundation for
      further investigating the function of that gene. The expression pattern suggests
      that the Doc-1R gene is a housekeeping gene which is important to keep the
      function of tissues and organs.

PMID- 12479059
TI  - [Apoptosis antagonizing transcription factor is a gene highly expressed in highly
      metastatic human osteosarcoma cell lines].
AB  - BACKGROUND & OBJECTIVE: Osteosarcoma is the most common malignant bone tumor in
      adolescents and yound adults. It is characterized by a high propensity for
      pulmonary metastasis. In spite of successful control of the primary tumor, death
      from pulmonary metastases occurs in > 30% of patients within 5 years. A better
      understanding of the molecular mechanisms that regulate the process of metastasis
      can provide a biological foundation for the design of more effective therapy. We
      established a metastatic model in nude mice with the method of orthotopically
      transplanting human osteosarcoma cell line SOSP-9607 and selected and isolated
      SOSP-M with highly metastatic potential. This study is to clone genes associated
      with osteosarcoma metastasis and to investigate the molecular mechanism of
      osteosarcoma metastasis by comparing the levels of gene expression between the
      two cells lines. METHODS: Using suppression subtractive hybridization, the
      substracted cDNA library of highly metastatic human osteosarcoma cell line SOSP-M
      was constructed. Positive clones were screened by differential screen technique.
      Partial positive clones were sequenced. The interested upexpressed clones in SOSP
      M cells were analyzed through Northern blot and RT-PCR for the low metastatic
      cell lines SOSP-9607 and OS-9901, highly metastatic cell line SOSP-M and three
      pulmonic metastatic nodules. RESULTS: Two positive cDNA clones from highly
      metastatic cell line SOSP-M subtracted cDNA library were identical(99% homology)
      to apoptosis antagonizing transcription factor. Northern blot and RT-PCR analysis
      demonstrated that apoptosis antagonizing transcription factor expressed highly in
      high metastatic cell line SOSP-M and three pulmonic metastatic nodules, but not
      in low metastatic cell line SOSP-9607 and OS-9901. CONCLUSION: Apoptosis
      antagonizing transcription factor may play an important role in promoting
      metastasis of osteosarcoma.

PMID- 12479060
TI  - [Expression of DPC4/Smad4, p21wafI, and p16 in human pancreatic cancer].
AB  - BACKGROUND & OBJECTIVE: DPC4/Smad4 inactivation was detected in almost half of
      the pancreatic carcinomas result in the loss of inhibition of the tumor cell
      proliferation. p21wafI is the downstream target gene of Smad4 while DPC4 and p16
      may synergistically play a role in the development of pancreatic carcinoma. By
      studying the expressions of DPC4/Smad4, p21wafI, and p16. This study was designed
      to explore the mutual relationship among them and the possible mechanism in human
      pancreatic carcinoma. METHODS: Immunohistochemistry was used to detect the
      expression of Smad4, p21wafI, and p16 in fifty-six samples of paraffin embedded
      human pancreatic cancer tissue, and in situ hybridization, immunohistochemistry,
      Western blotting technique were used to detect the expression of DPC4/Smad4 in
      five human pancreatic adenocarcinoma cell lines. RESULTS: The positive rate of
      Smad4, p21wafI, and p16 in paraffin embedded human pancreatic cancer tissue was
      58.93%, 48.21%, and 42.86%, respectively, whereas the positive rate of these
      proteins in matched normal tissue was 89.29%, 87.5%, and 76.79% respectively.
      Three out of five pancreatic adenocarcinoma cell lines (P3, P4, and P7) were
      positive for DPC4/Smad4 with in situ hybridization, immunohistochemistry and
      Western blotting, while the other two lines were all negative. There is
      statistically significant difference between cancer and normal tissue (P < 0.05).
      In pancreatic adenocarcinomas, the expression of Smad4 was related to that of
      p21wafI (P < 0.05), and so was the expression of Smad4 to that of p16 (P < 0.05).
      But no correlation was found between p21wafI and p16 (P > 0.05). CONCLUSION: The
      expression of Smad4, p21wafI, and p16 significantly decreased in pancreatic
      cancer compared with normal tissue. The decreased expression of the proteins may
      play an important role in the development of pancreatic cancer.

PMID- 12479061
TI  - [Electroporation-mediated gene transduction and expression of class 1 aldehyde
      dehydrogenase (ALDH1) and multidrug resistance gene (MDR1)].
AB  - BACKGROUND & OBJECTIVE: This study was designed to seek an efficient and safe
      method for transfer of genes of large size. METHODS: The retroviral vector
      containing different kinds drug resistance genes-class 1 aldehyde dehydrogenase
      (ALDH1) and multidrug resistance gene (MDR1) was linearized by the restriction
      enzyme NdeI digestion, and introduced into the packaging PA317 cells by
      electroporation. Selection was performed by vincristine (VCR) and 4
      hydroperoxycyclophosphamide(4-HC) to obtain ALDH1 and MDR1 stably expressing
      cells. The integration of provirus, transcription and translation of foreign
      genes were confirmed by Southern blot, reverse transcription(RT)-PCR and flow
      cytometry, respectively. The safety of this delivery system was verified by
      testing helper virus(envelop gene) using nested PCR. RESULTS: Both ALDH1 and MDR1
      were successfully transduced into PA317 cells by electroporation. Stable
      integration of foreign genes in host cells genome was determined by Southern
      hybridization blot. The transcription of ALDH1 and MDR1 was demonstrated by RT
      PCR. The overexpression of P-glycoprotein encoded by the downstream gene MDR1
      with approximately a 4-fold increase in 98% cells was analyzed by flow cytometry.
      No helper virus can be detected by nested PCR assay. CONCLUSION: These results
      implicate that the introduction and overexpression of both ALDH1 and MDR1 genes
      in vitro is attainable by a simple and convenient electroporation method, with
      the character of safety and high efficiency.

PMID- 12479062
TI  - [Efficient expression of exogenous human gp96 gene in tumor cells].
AB  - BACKGROUND & OBJECTIVE: Immunization of mice with preparations of heat shock
      protein(HSP) gp96 isolated from cancer cells has been shown to elicit specific
      protective cytotoxic T lymphocyte response against cells from which gp96
      originate. This phenomenon exploits a new practicable pathway for cancer
      immunotherapy. But gp96 is generally expressed at low level in cells. Gp96
      preparations from limited cells or tissue are difficult to meet the needs of
      study. So the current study aims to acquire minoclonal cell lines expressing gp96
      at high level in order to prepare enough gp96 with high quality. METHODS: The
      recombinant plasmid pcDNA-hgp96 of human gp96 cDNA was constructed by ligating
      the fragment of gp96 cDNA into the pcDNA3 plasmid, a eucaryotic expressing
      vector. Then the recombinant plasmid was transfected into Hela cells and the
      stable transfectants were selected with G418. The expression level of gp96 of the
      positive monoclonal cells was detected by Western blot analysis. RESULTS: The
      recombinant expression plasmid of human gp96 cDNA was successfully constructed.
      The monoclonal cell lines with stable transfection were obtained. A monoclonal
      cell line expressing gp96 on high level was selected out. CONCLUSIONS: The
      monoclonal cell line expressing gp96 at high level has been successfully
      established, which lays the groundwork for the study of its antitumor immunity.

PMID- 12479063
TI  - [Expression of growth hormone receptor mRNA in hepatocellular carcinoma and
      matched para-cancer cirrhotic liver tissue].
AB  - BACKGROUND & OBJECTIVE: The growth hormone receptor mRNA is abundant in normal
      liver tissue, but its expression was not studied in detail in the tissue of liver
      cancer or para-cancer cirrhotic liver. This study was designed to investigate the
      expression of growth hormone receptor mRNA in hepatocellular carcinoma and para
      cancer cirrhotic liver tissue. METHODS: The expression of growth hormone receptor
      mRNA was detected in 37 specimens of hepatocellular carcinoma and their para
      cancer liver tissue by RT-PCR. RESULTS: The expression rate of growth hormone
      receptor mRNA in hepatocellular cancerous tissue (30/37, 81%) was significantly
      lower than that in cirrhotic liver tissue (32/32, 100%) (P < 0.05). The
      expression rate in undifferentiated hepatocellular carcinoma (1/4, 20%) decreased
      further (P < 0.05). The expression of growth hormone receptor mRNA in cirrhotic
      liver tissue [ratio of integrated Optical Density (riOD) 30.77% +/- 8.24%, n =
      32] was significantly lower than that in normal control liver tissue (riOD 44.93%
      +/- 6.25%, n = 5) (P < 0.05). The expression in severe cirrhotic liver tissue
      (riOD 21.90% +/- 4.72%, n = 8) decreased further (P < 0.05). CONCLUSIONS: The
      down-regulated expression of growth hormone receptor mRNA was related to the
      pathological stage of hepatocellular cancer and the stage of liver cirrhosis.

PMID- 12479064
TI  - [Radiation sensitizing effect of anti HPV16E6-ribozyme on cervical carcinoma cell
      line].
AB  - BACKGROUND & OBJECTIVE: Human papillomavirus (HPV) are the most important
      etiologic factor for cervical carcinoma. E6 virus gene is one of the most
      important oncogene and expression levels of E6 transforming oncoproteins of high
      risk HPV genotypes, such as HPV16, appear to be necessary for maintaining the
      malignant phenotype. Radiation treatment represents a standardized and effective
      modality for contemporary cervical carcinoma therapy. The goal of this study was
      to investigate the radiation sensitizing effect of anti-HPV16 E6-ribozyme on
      cervical carcinoma cell line. METHODS: With the method of lipofectin
      transfection, the anti-HPV16 E6 ribozyme and empty eucaryotic expressing plasmids
      were transfected into CaSKi cell line, which named as CaSKi-R and CaSKi-P,
      respectively. The expression of ribozyme in transfected cells was observed by RNA
      dot blot. The amounts of E6 mRNA in the three kinds of cells were detected by
      Northern blot. The growth rates of the CaSKi and transfected cells were examined
      by cell count and their sensitivity to radiotherapy were examined by colony
      formation test. The apoptosis rates of each cell was determined by PI/Annexin V
      stained methods. Expressions of p53, bcl-2, and bax were determined by Flow
      cytometry analysis. RESULTS: Anti-HPV16 E6-ribozyme can be expressed stably in
      transfected CaSKi-R cells. Northern blot showed that E6 mRNA was less in CaSKi-R
      than in CaSKi and CaSKi-P. The growth rate of CaSKi-R was much slower than that
      of CaSKi and CaSKi-P. The sensitivity of CaSKi-R cells to radiotherapy increased
      more than that of CaSKi and CaSKi-P cells. The ability of colony formation
      decreased (P < 0.05), while the apoptosis rates of CaSKi-R cells increased more
      than that of CaSKi and CaSKi-P cells(P < 0.01). Anti-HPV16 E6-ribozyme did
      significantly upregulate expression of p53, bax protein, and downregulate the
      expression of bcl-2 protein before and after radiotherapy (P < 0.01). CONCLUSION:
      CaSKi-R cells transfected with Anti-HPVE 6-rivozyme showed growth inhibition and
      increased sensitivity to radiotherapy.

PMID- 12479065
TI  - [Inhibitory effect of AG1109 on recombinant human protein kinase CK2 holoenzyme].
AB  - BACKGROUND & OBJECTIVE: Protein kinase CK2 is an evolutionarily conserved
      serine/threonine kinase that is upregulated and can serve as an oncogene in many
      cancer cells. Targeted inhibition of CK2 could be useful in the treatment of many
      cancers. To search specific CK2 inhibitors we investigated the direct effect of
      tyrphostin AG1109 on recombinant human protein kinase CK2 holoenzyme and its
      kinetics. METHODS: Recombinant human protein kinase CK2 alpha and beta subunits
      were cloned and expressed by gene engineering, and purified to homogeneous. The
      two subunits were mixed at the same molar ratio and reconstituted CK2 holoenzyme,
      which exerted the maximum biological activity. The CK2 activity was assayed by
      detecting incorporation of 32P of [gamma-32P]ATP or [gamma-32P]GTP into the
      substrate in various conditions. RESULTS: The recombinant human CK2 was the
      second messengers (Ca2+, cAMP, and cGMP) independent protein kinase, the
      characterization and function of the reconstituted holoenzyme were consistent
      with those of native CK2. AG1109 strongly inhibited the holoenzyme activity of
      recombinant human protein kinase CK2 with an IC50 of 9.7 mumol/L, which was
      slightly more effective than 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole
      (DRB) and N-(2-aminoethyl)-5-chloronaphthalene-1-sulfonamide (A3), which were
      both known CK2 special inhibitors. Kinetic studies of AG1109 on recombinant human
      CK2 showed that the inhibition was mixed (competitive is dominant) with GTP and
      noncompetitive with casein. CONCLUSIONS: AG1109 is an effective inhibitor of
      recombinant human protein kinase CK2 holoenzyme. The recombinant human protein
      kinase CK2 might be used as a molecular target for simpler screening and
      development of more effective inhibitors of CK2.

PMID- 12479066
TI  - [Molecular mechanisms of tumorgenesis and metastasis in nasopharyngeal carcinoma
      cell sublines].
AB  - BACKGROUND & OBJECTIVE: The authors have selected three different biological
      character sublines, including 5-8F (the highest tumorigenic and metastatic
      ability), 6-10B(the lowest tumorigenicity and lack of metastatic ability), and 13
      9B(lack of tumorigenic ability), from colony lines of nasopharyngeal carcinoma
      cell line(SUNE-1). The aim of this study was to determine the molecular
      mechanisms of different biological character of SUNE-1 and its three sublines
      from two aspects of genetic and virology. METHOD: 1. Amplifying Epstein-Barr
      virus(EBV) BamHI W fragment by PCR. 2. Determining the expression of latent
      membrane protein1(LMP1) of EBV in the sublines using in situ hybrization. 3.
      Molecular cytogenetic analysis of the cell line and sublines by comparative
      genomic hybridization (CGH). RESULTS: 1. There was EBV BamHI W fragment in SUNE-1
      and its three sublines. 2. Expression of LMP1 was observed in the SUNE-1 and its
      three sublines, and their expression intensity was identical. 3. There were DNA
      copy number gains on chromosomes 1, 2p, 3, 4, 5p, 6, 7, 9, 10q, 11, 12q, 13q, and
      18q as well as loss on 22q in the SUNE-1 cell line; DNA copy number gains on
      chromosomes 3p, 7q, 8q, 9q, and 10q were observed in 5-8F subline; DNA copy
      number loss on few chromosomes, but no DNA copy number gain was observed in the 6
      10B and 13-9B sublines. CONCLUSION: There were expression of EBV and different
      genetic changes in the SUNE-1 and its three sublines. It is suggesting that the
      different biological character tumorgenesis and metastasis of nasopharyngeal
      carcinoma cell sublines may be due to genetic changes; and EBV infection may play
      an important role in keeping the malignant phenotypic of nasopharyngeal
      carcinoma.

PMID- 12479067
TI  - [Expression of vascular endothelial growth factor C in human breast cancer cell
      lines MCF-7 and MCF-7/Adr].
AB  - BACKGROUND & OBJECTIVE: Vascular endothelial growth factor C (VEGF-C) discovered
      recently is a new member of vascular endothelial growth factor (VEGF) family.
      Studies have shown that VEGF-C is one specific regulating factor for lymphatic
      endothelial cells, and it expresses in a variety of human tumors. In order to
      explore the role of VEGF-C in the process of human tumor formation and
      development, the authors designed this study to examine the expressions of VEGF-C
      mRNA and protein in human breast cancer cell line MCF-7 and drug resistant cell
      line MCF-7/Adr. METHODS: According to the VEGF-C gene sequence, A specific
      oligonucleotide probe labeled with digoxin was designed and constructed; Then in
      situ hybridization was applied to detect the expression of VEGF-C mRNA in the
      cultured human breast cancer cell lines MCF-7 and MCF-7/Adr respectively; Finally
      immunohistochemistry was performed to examine the expression of VEGF-C protein in
      both cell lines. RESULTS: Blue positive staining granules for VEGF-C mRNA were
      observed in the cytoplasm of these cells by in situ hybridization where brown
      positive staining granules for VEGF-C protein were also observed by
      immunohistochemistry. While there were no positive staining granules in neither
      control cells. CONCLUSION: Human breast cancer cell lines MCF-7 and MCF-7/Adr can
      transcribe VEGF-C mRNA and translate corresponding protein in their cytoplasm.

PMID- 12479068
TI  - [Expression and significance of P-glycoprotein, glutathione S-transferase-pi and
      Topoisomerase II in gastric carcinomas].
AB  - BACKGROUND & OBJECTIVE: Multi-drug resistance(MDR) is the most important failing
      reason of tumor chemotherapy, the substance that P-glycoprotein(P-gp),
      glutathione S-transferase-pi(GST-pi), Topoisomerase II (Topo II) etc was the
      fundamental substances producing MDR. Gastric carcinoma is the relatively
      familiar malignancy, the report was relatively fewness that the expression of P
      gp, GST-pi and Topo II by means of immunohistochemistry were associated with in
      the gastric carcinomas of previously untreated patients. This study was designed
      to investigate the expression and significance of P-gp, glutathione S-transferase
      pi(GST-pi) and Topoisomerase II(Topo II) in gastric carcinomas. METHODS: Seventy
      five human gastric carcinomas of previously untreated patients were studied for
      the expression of P-gp, GST-pi and Topo II by means of immunohistochemistry.
      RESULTS: The expression of P-gp, GST-pi and Topo II were 76.0%, 85.3% and 68.0%
      in gastric carcinoma tissues. There was no significant relationship between the
      expression levels and age, sex, location of tumor and depth of tumor invasion.
      Positive rate was higher in glandular-form carcinoma than that in mucoid
      carcinoma, signet-ring cell carcinoma and poorly differentiated carcinoma (P <
      0.05). There was a significant relationship between the lymph node involvement
      and the higher expression of P-gp, GST-pi, lower expression of Topo II.
      CONCLUSION: There is a correlation between the expression of P-gp, GST-pi, Topo
      II and histologic subtypes, the expression may also related to the
      differentiation and metastasis of the gastric carcinomas.

PMID- 12479069
TI  - [Effect of external gastrin on apoptosis and expression of bcl-2 gene in gastric
      cancer cells].
AB  - BACKGROUND & OBJECTIVE: It has been reported that external gastrin could
      facilitate the growth of the cells of gastrointestinal carcinomas. However, the
      modifying effect of gastrin on apoptosis of the gastric carcinoma has not been
      well appreciated. This study was designed to investigate the modifying effect of
      gastrin on apoptosis of the stomach cancer cell. METHODS: Flow cytometric
      analysis (FCM) and immunohistochemical dyeing are used to measure the rates of
      apoptosis and expression of bcl-2 gene in MKN45 cell line treated with gastrin
      and its receptor antagonist. RESULTS: Forty-eight hours later, the percentage of
      apoptosis cell in gastrin group was 1.39 +/- 0.54%, lower than that in control
      group (8.58 +/- 0.67%) (P < 0.01), but the expression rate of bcl-2 in gastrin
      treatment group was 22.3 +/- 5.3% higher than that in control group (P < 0.01).
      These effects were vanished after combined treatment with proglumide.
      CONCLUSIONS: External gastrin may restrain the apoptosis of MKN45 cell by
      inducing the expression of bcl-2 gene, and proglumide can block these effects of
      gastrin.

PMID- 12479070
TI  - [Clinical value of serum soluble Apo-1/Fas for predicting biological behaviors
      and prognosis of gastric carcinoma].
AB  - BACKGROUND & OBJECTIVE: Literatures reported that the soluble Apo-1/Fas(sApo
      1/Fas) levels in serum of patients with malignant carcinoma were higher than that
      in normal control subject, but there were fewer studies was seldom to detect the
      level of sApo-1/Fas in patients with malignancy carcinoma and effect of
      chemotherapy; the subject is to detect the level of sApo-1/Fas in patients with
      gastric carcinoma and effect of chemotherapy on it, and to investigate its
      clinical value. METHODS: Enzyme linked immunosorbent assays(ELISA) was available
      to detect the level of sApo-1/Fas in 42 case of patients with gastric carcinoma
      before and after chemotherapy, as compared with 30 case of normal control
      subject. RESULTS: Levels of sApo-1/Fas were elevated in all subgroups of patients
      with gastric carcinoma as compared to the controls (P < 0.01), sApo-1/Fas was
      correlated with clinical stage and histological grade, and not with sex, age; the
      sApo-1/Fas level in stage IV was higher in comparison with stage III and II (P <
      0.05-0.01), and in stage III it was higher than in stage II (P < 0.05); being
      lower in the well differentiated and moderately differentiated than the poorly
      differentiated(P < 0.05-0.01), that the sApo-1/Fas levels were remarkably reduced
      in complete remission or partial remission patients(P < 0.01) after chemotherapy.
      CONCLUSION: sApo-1/Fas may play closely reflect growth and regulation in gastric
      carcinoma, it may be a predictor for biological behaviors and prognosis of
      gastric carcinoma; sApo-1/Fas may be a new target in treating gastric carcinoma.

PMID- 12479071
TI  - [Detection of telomerase activity of exfoliated cells in bile and its clinical
      impact].
AB  - BACKGROUND & OBJECTIVE: Some studies revealed that telomerase activity could be
      detected in exfoliated cancer cells in body fluid such as urine, pancreatic
      juice, pleural effusion that is a good diagnostic marker for malignancies.
      However, few reports about telomerase in exfoliated cancer cells in bile are
      available. The current study was designed to determine the telomerase activity of
      exfoliated cells in bile and its clinical impact in the patients with malignant
      obstructive jaundice. METHODS: Telomerase activity was determined by using a
      modified PCR-based telomeric repeat amplification protocol(TRAP)-sliver stain
      assay. RESULT: Telomerase activity was detected in 33 of 44(75%) bile specimens
      from patients with malignant tumor. In contrast, only 1 of 19(5.3%) bile samples
      from cholelithiasis was telomerase positive. There was no relation ship between
      the positive rate of telomerase activity and the clinicopathological finds
      including metastatic status and differentiation, but telomerase positive rate was
      higher in bile from patients with pancreatic carcinoma and cholangiocarcinoma.
      Comparison of telomerase assay with cytologic examination showed that, among the
      44 patients with malignant obstructive jaundice, 31 cases underwent cytological
      examination, cancer cells were found only in 3(9.7%) bile specimens, and all
      cytological examination positive specimens were telomerase positive. CONCLUSION:
      The TRAP assay can effectively detect telomerase activity of the exfoliated
      cancer cells in bile. Telomerase could be a molecular marker for diagnosis of
      malignant bile duct disease. The detection of telomerase activity in bile could
      become a useful adjunct in the cytologic examination.

PMID- 12479072
TI  - [Clinical significance of vascular endothelial growth factor in sera of patients
      with gynaecological malignant tumors].
AB  - BACKGROUND & OBJECTIVE: Experimental and clinical evidence links tumor growth,
      invasion, and metastatic potential with neoangiogenesis. This process is
      modulated by several angiogenic growth factors, such as vascular endothelial
      growth factor(VEGF). Few data are currently available on serum level in patients
      with gynaecological malignant tumors. This study was designed to determine the
      serum VEGF level in the patients with gynaecological malignant tumors and its
      significance as a tumor marker. MATERIAL & METHODS: Preoperative serum VEGF level
      were measured in 50 cervical cancer, 39 endometrial cancer, 89 ovarian cancer
      patients, and 80 normal healthy women; The serum VEGF levels were also measured
      in 3, 6, 9 months after operation and when recurrence in three curative resection
      patients with ovarian cancer; using commercially available enzymelinked
      immonosarbent assay (R & D systems Inc. Minneapolis, MN, USA). Statistical
      analysis was performed by using the SPSS9.0 software package. Using 5th and 95th
      percentage describe the variant degree. RESULTS: The median level of VEGF in sera
      of 80 healthy women was 218.50 ng/L(42.06-671.70 ng/L), while in 50 cervical
      cancer, 39 endometrial cancer, and 89 ovarian cancer patients were 272.00
      ng/L(91.94-745.53 ng/L), 383.50 ng/L(105.67-776.50 ng/L), and 479.85 ng/L (99.47
      1326.88 ng/L), respectively. The VEGF levels in endometrial cancer and ovarian
      cancer patients were significantly higher than that in healthy women (P <
      0.0001). But in cervical cancer patients the VEGF level, was not significant
      diffent compare with health wanen. After operation, 3, 6, 9 months the VEGF
      levels in 3 ovarian cancer patients were significantly lower than that of
      preoperative but it ascended again when the disease was recurrent 14, 17 months
      later in two cases. The VEGF level was significantly higher in advanced ovarian
      cancer patients (stage III-IV) than that in the early stage (stage I-II) (P <
      0.05). CONCLUSION: The serum level of the VEGF may be used as a new tumor marker
      of endometrial cancer and ovarian cancer, for diagnoses and monitoring the
      progress of the disease.

PMID- 12479073
TI  - [Affection of neoadjuvant chemotherapy on cell apoptosis and proliferation in
      breast cancer].
AB  - BACKGROUND & OBJECTIVE: Although the researches had verified various kinds of
      chemotherapic agents can cause the apoptosis of breast cancer cells, but the
      reports with in vivo data are still scarce. This paper is to investigate whether
      neoadjuvant chemotherapy could induce tumor cell apoptosis in breast cancer
      patients, and its effect on cell proliferation. METHODS: Apoptosis index (AI) of
      tumor cells is assayed by TdT-mediated dUTP nick end labeling(TUNEL) and
      proliferating cell nuclear antigen (PCNA) is examined by immunohistochemical
      labelled streptavidin biotin (ISAB) in 100 beast cancer samples. RESULTS: Tumor
      cell AI in neoadjuvant group (mean = 7.47%) was significantly higher than that in
      control group (mean = 4.83%) (P < 0.01). PCNA positive expression rate in
      neoadjuvant group (mean = 33.71%) was significantly lower than that in control
      group (mean = 51.52%) (P < 0.01). There was significant negative association
      between AI and PCNA in both neoadjuvant chemotherapy group and control group (P <
      0.05). CONCLUSION: Neoadjuvant chemotherapy could induce tumor cell apoptosis and
      inhibit tumor cell proliferation in human breast cancer.

PMID- 12479074
TI  - [Comparison of three surgical approachs for cardiac carcinoma].
AB  - BACKGROUND & OBJECTIVE: The surgical approach for cardiac carcinoma are various.
      However, there was still controversial which one could resulting in is the best
      one to the middle-long term survival rate after the surgical operation. The
      current study was designed to explore the best surgical approach for cardiac
      carcinoma. METHODS: The authors analyzed 353 patients with cardiac carcinoma in
      Yangzhong People's Hospital. The survival rate and stump masculine rate among
      three surgery approach (improved epigastrium, left-chest, and epigastrium-chest
      groups) were compared. RESULTS: The five-year survival rate and stump masculine
      rate: epigastrium group were 46.2% and 1.46%; left-chest group were 37.6%, 1.64%;
      epigastrium-chest group were 57.6% and 2.08%; There was no significant difference
      among three groups(P < 0.05). CONCLUSIONS: Different surgical approach have no
      obvious influences to middle-long survival rate and stump masculine rate, thus,
      the authors suggest the surgery approach should based on location and bound of
      focus and health condition of the patient.

PMID- 12479075
TI  - [Clinical impact of gamma-glutamyl transpeptidase messenger RNA subtypes on early
      diagnosis of hepatocellular carcinoma].
AB  - BACKGROUND & OBJECTIVE: It has been reported that hepatocellular carcinoma (HCC)
      expresses gamma-glutamyl transpeptidase (GGT) with unique carbohydrate moieties
      compared with normal liver GGT enzymes, this unique GGT was used as a marker for
      the diagnosis of HCC. However, the genomic changes in GGT relating to the
      development of HCC are not known. This study was designed to explore the
      relationship between alteration in GGTmRNA subtypes and the development of HCC,
      and to seek a new method for early diagnosis of HCC. METHODS: Three GGTmRNA
      subtypes (F, H, P) were determined bu using RT-PCR in normal liver tissues,
      diseased liver tissues without HCC, cancerous and noncancerous tissues from the
      livers with HCC, noncancerous tissues from secondary carcinoma of liver and
      peripheral blood of all cases. RESULTS: The main subtype of GGTmRNA was type F in
      normal liver tissues, liver tissues from noncancerous liver diseases and
      paracancerous tissues from secondary carcinoma of liver. The prevalence of
      subtype H was significantly higher in cancerous tissues, adjacent paracancerous
      and distal cancerous tissues from the livers with HCC than that in tissues from
      normal livers and noncancerous liver diseases (P < 0.05). The prevalence of
      subtype F in cancerous tissues was significantly lower than that in tissues from
      normal livers and noncancerous liver diseases (P < 0.05). Among 26 patients with
      HCC, GGTmRNA-H in peripheral blood was found in 12 cases. In 10 HCC patients with
      negative AFP, GGTmRNA-H in peripheral blood was found in 5 cases. CONCLUSIONS:
      The changes of GGTmRNA subtypes are closely related to the development of HCC,
      and the analysis of GGT genes might be a sensitive assay to monitor the hepatic
      cell canceration.

PMID- 12479076
TI  - [Significance of combined determination of CK19mRNA, carcinoembryanic antigen,
      neuron-specific enolase, and tissue polypeptide antigen in peripheral blood of
      patients with lung cancer].
AB  - BACKGROUND & OBJECTIVE: Cellular keratin, an indicator for cancer cell in
      circulation gains increasing attention. Although CK19mRNA as a gene marker used
      to identify micro-metastasis is of relatively high practical value, it lacks
      specificity and sensitivity in diagnosis of cancer. The aim of this study is to
      evaluate whether the combined detection of CK19mRNA with other tumor markers,
      such as carcinoembryanic antigen(CEA), neuron-specific Enolase(NSE), tissue
      polypeptide antigen(TPA), would improve the diagnosis of lung cancer. METHODS:
      The expression level of CK19mRNA in peripheral blood mononucleated cells (PBMCS)
      was determined by RT-PCR, The levels of CEA, NSE, and TPA in serum were
      determined by enzyme-linked immunosorbent assay (ELISA) and time-resolved
      fluorometry(TRF) in 91 patients with lung cancer, 33 with benign lung diseases
      (BLD) and 50 healthy controls. The data was analyzed by t test and chi 2 test.
      RESULTS: The positive rates of CK19mRNA, CEA, NSE, and TPA in lung cancer group
      (49.5%, 65.9%, 67.0%, and 83.5%, respectively) were remarkably higher than in BLD
      group(24.2%, 9.0%, 15.2%, and 9.0%, respectively) and in healthy control group
      (10.0%, 4.0%, 8.0%, and 6.0%, respectively) (P < 0.01). The positive rate of
      CK19mRNA was not statistically different in various histological subtypes (P >
      0.05). Although the positive rate of CK19mRNA appeared to be associated with the
      clinical stage (stage I + II: 44.4%, stage III: 48.4%, stag IV: 54.2%), there was
      no statistical significance among the three groups (P > 0.05). The serum level
      (microgram/L)/positive rate of CEA(3.5/27.8%, 5.1/35.5%, and 8.5/58.3%,
      respectively), NSE (12.5/33.3%, 15.3/41.9%, and 24.7/58.3%, respectively), and
      TPA (1.1/44.4%, 1.8/58.1%, and 3.6/66.7%, respectively) in stage I + II, III, and
      IV appeared to be associated with the clinical stages of lung cancer, but no
      statistical significance among the three groups (P > 0.05). Combined detection of
      three or four tumor markers yielded significant higher effective accuracy in
      diagnosis of lung cancer than that of any of two tumor markers or single tumor
      marker (P < 0.05). In addition, the results showed that TPA, CEA, and NSE were
      relatively specific for squamous cell carcinoma (76.7%), adenocarcinomas (83.3%),
      and small-cell lung cancer (79.2%), respectively. CONCLUSION: The combined
      measurement of CK19mRNA with CEA, NSE, and TPA can increase diagnosis rate of
      lung cancer, can also provide potent diagnosis basis for treatment.

PMID- 12479077
TI  - [Surgical margin to direct the treatment and predict the prognosis of laryngeal
      carcinoma after partial laryngectomy].
AB  - BACKGROUND & OBJECTIVE: The surgical margin is very important for laryngeal
      carcinoma treatment. To preserve more laryngeal tissue can give patients good
      function, however, which increase the rate of positive surgical margin and
      recurrence. The correct surgical margin is benefit for laryngeal carcinoma
      patients' prognosis. This study was designed to investigate the value of surgical
      margin to direct the treatment of laryngeal carcinoma after partial laryngectomy
      and to evaluate the prognosis of laryngeal carcinoma. METHODS: The authors
      studied 115 cases of laryngeal carcinoma in which surgical margin samples were
      harvested during partial laryngectomy. The recurrence rate and survival curve of
      the positive and negative margin group were compared; The survival curve between
      the groups with and without postoperative radiotherapy both in negative margin
      group and positive margin group were also compared. RESULTS: The results of the
      negative group were better than that of the positive group: recurrence rate was
      higher (28.0% Vs 7.8% P = 0.006), the survival curve was better(P = 0.0241); The
      survival curve of those with positive surgical margin, at the same time, treated
      by postoperative radiotherapy was better than that of those without postoperative
      radiotherapy (P = 0.0046); but in negative group, the survival curve of those who
      treated with or without postoperative radiotherapy or not was different
      insignificantly (P = 0.0829). CONCLUSIONS: The prognosis of the positive margin
      group of laryngeal carcinoma was waster than that of the negative group, but it
      can be improved partially by postoperative radiotherapy. The best way to improve
      the prognosis was dissect entirely; There is not necessary to treat negative
      group by postoperative radiotherapy.

PMID- 12479078
TI  - [Application of cryosurgery in the treatment of liver carcinoma].
AB  - Friotherapy, using liquid N2 as cryogen, may be applied for all stages of liver
      cancer, which mechanism is tissue destruction due to low temperature, directly
      and improvement of immunity. At present, using multiprobe cryosurgical device
      result in many treatment options, such as procedure under open abdomen and
      staring blankly forward or percutaneously under Trus guidance. The advantages of
      cold therapy include its convenience, few complications, approval results, ect.
      With the invention of new probes and cryogen, cryosurgery as a treatment for
      liver cancer will have a good prospect.

PMID- 12479079
TI  - Clinical psychopharmacology guidelines: different strokes for different folks.

PMID- 12479080
TI  - World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for
      Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance
      treatment of major depressive disorder and treatment of chronic depressive
      disorders and subthreshold depressions.
AB  - These practice guidelines for the biological treatment of unipolar depressive
      disorders were developed by an international Task Force of the World Federation
      of Societies of Biological Psychiatry (WFSBP). The goal for developing these
      guidelines was to systematically review all available evidence pertaining to the
      treatment of the complete spectrum of unipolar depressive disorders, and to
      produce a series of practice recommendations that are clinically and
      scientifically meaningful based on the available evidence. These guidelines are
      intended for use by all physicians seeing and treating patients with these
      conditions. The data used for developing these guidelines have been extracted
      primarily from various national treatment guidelines and panels for depressive
      disorders, as well as from meta-analyses and reviews on the efficacy of
      antidepressant medications and other biological treatment interventions
      identified by a search of the MEDLINE database and Cochrane Library. The
      identified literature was evaluated with respect to the strength of evidence for
      its efficacy and was then categorized into four levels of evidence (A-D). The
      first part of these WFSBP guidelines on unipolar depressive disorders covered the
      acute and continuation treatment of major depressive disorder (Bauer et al 2002).
      This second part of the guidelines covers the management of the maintenance-phase
      treatment of major depressive disorder, as well as the treatment of chronic and
      subthreshold depressive disorders (dysthymic disorder, double depression, minor
      depressive disorder and recurrent brief depression). These guidelines are
      primarily concerned with the biological treatment (including antidepressants,
      lithium, other psychopharmacological and hormonal medications, and
      electroconvulsive therapy) of young adults and also, albeit to a lesser extent,
      children, adolescents and older adults.

PMID- 12479081
TI  - GABAergic neurosteroid modulation of ethanol actions.
AB  - Systemic administration of ethanol elevates plasma and cerebral cortical
      GABAergic neuroactive steroids. The increase in neurosteroids is responsible for
      specific behavioural and electrophysiological actions of ethanol in rodents. This
      article recapitulates the current knowledge of the novel interaction between
      ethanol and neurosteroids and addresses the potential mechanism for ethanol
      induced increase in brain neurosteroid levels. Ethanol-induced increase in the
      cortical neurosteroid content is modified by neurosteroid biosynthesis inhibitors
      and completely prevented by adrenalectomy in male rats. In line with this,
      adrenalectomy prevented the anticonvulsant and hypnotic effects of acute ethanol
      administration. It is speculated that acute ethanol administration might resemble
      acute stress and increase neuroactive steroids due to activation of hypothalamic
      pituitary adrenal axis. Ethanol-induced increases in neuroactive steroids might
      be responsible for the antidepressant, anxiolytic, spatial learning deficits and
      drug discriminatory actions in rodents. Thus ethanol-induced increases in
      neuroactive steroids represent a novel mechanism of ethanol's action, responsible
      for several pharmacological and behavioural actions of ethanol. The development
      of new therapeutic strategies for alcoholism may arise based on the novel
      interaction between ethanol and neurosteroids in the brain.

PMID- 12479082
TI  - Serotonin platelet-transporter measures in childhood attention
      deficit/hyperactivity disorder (ADHD): clinical versus experimental measures of
      impulsivity.
AB  - Impulsivity in terms of aggression, suicide or poor cognitive control has been
      associated with low synaptic availability of serotonin (5-HT) in adults and
      children. However, characteristics of the 5-HT transporter have not been studied
      in children with attention-deficit/hyperactivity disorder (ADHD: combined type),
      where impulsivity is a core symptom. Here, we explored in 20 children with ADHD
      the relationship of the density (Bmax) and affinity (Kd) of the platelet 5-HT
      transporter measured with [3H]paroxetine to both clinical ratings of impulsivity
      (Conners' Parent Questionnaire), and an experimental measure of impulsivity (the
      ability to withhold a prepotent response in the "stop-signal" paradigm).
      Decreases of affinity (increased Kd) correlated with a low probability of
      response inhibition, but not with the clinical ratings of impulsivity. However,
      ratings of distractibility and impulsivity correlated with the experimental
      measure of response-inhibition. In contrast, increased transporter affinity (low
      Kd) correlated modestly with higher ratings of aggressive and externalising
      behaviour. Bmax was not associated with any behavioural score. We conclude that
      the synaptic availability of 5-HT is under the control of the 5-HT transporter
      binding site affinity and that low affinity may be related to cognitive
      impulsivity (distractibility). Increased affinity of the transporter may also be
      related to conduct disturbance.

PMID- 12479083
TI  - Rate of oxygen consumption in seasonal and non-seasonal depression.
AB  - Most depressives suffer from weight loss, anorexia and insomnia, while for winter
      depressives the typical symptoms are weight gain, carbohydrate craving,
      overeating, oversleeping and extreme lack of energy. It is important to know
      whether winter depressives differ from most other depressives on measures of
      energy regulation. In wintertime, we evaluated the rate of oxygen consumption in
      relationship to neuro-vegetative depressive symptoms in 92 Siberian women. The
      seated subjects underwent oxyspirography in the mid-morning (1.5 hours after a
      standard breakfast). It was found that the oxygen consumption rate was similar in
      non-depressed women (n = 25) and depressed women with non-seasonal depression (n
      = 27). The comparatively lower values were obtained in women with winter
      depression (n = 40). This finding supports the suggestion that the behaviour
      disturbances typical for winter depression may represent a physiological feedback
      loop to energy conservation.

PMID- 12479084
TI  - Catatonia and ECT: Meduna's biological antagonism hypothesis reconsidered.
AB  - Catatonia is a motor syndrome with abnormalities in neuroendocrine regulation.
      Both the motor syndrome and the neuroendocrine abnormalities respond rapidly to
      electroconvulsive therapy (ECT). This rapid efficacy supports a neuroendocrine
      hypothesis of the mode of action of ECT and encourages neuroendocrine studies of
      catatonia.

PMID- 12479085
TI  - Side effects after phototherapy implementation in addition to fluoxetine or
      sertraline treatment: a report of two cases.
AB  - Serotonergic-type side effects (like diarrhoea, hyperthermia, nausea, confusion)
      were seen after phototherapy in patients receiving fluoxetine or sertraline.
      Phototherapy was discontinued and symptoms completely resolved. In the authors'
      opinion, the symptoms were likely to be associated with specific interaction
      (serotonin effect potentialisation). To the authors' knowledge this is the first
      report concerning such an effect.

PMID- 12479086
TI  - World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for
      Biological Treatment of Unipolar Depressive Disorders, Part 1: Acute and
      continuation treatment of major depressive disorder.
AB  - These practice guidelines for the biological treatment of unipolar depressive
      disorders were developed by an international Task Force of the World Federation
      of Societies of Biological Psychiatry (WFSBP). The goal for developing these
      guidelines was to systematically review all available evidence pertaining to the
      treatment of unipolar depressive disorders, and to produce a series of practice
      recommendations that are clinically and scientifically meaningful based on the
      available evidence. These guidelines are intended for use by all physicians
      seeing and treating patients with these conditions. The data used for developing
      these guidelines have been extracted primarily from various national treatment
      guidelines and panels for depressive disorders, as well as from meta-analyses and
      reviews on the efficacy of antidepressant medications and other biological
      treatment interventions identified by a search of the MEDLINE database and
      Cochrane Library. The identified literature was evaluated with respect to the
      strength of evidence for its efficacy and was then categorized into four levels
      of evidence (A-D). This first part of the guidelines covers disease definition,
      classification, epidemiology and course of unipolar depressive disorders, as well
      as the management of the acute and continuation-phase treatment. These guidelines
      are primarily concerned with the biological treatment (including antidepressants,
      other psychopharmacological and hormonal medications, electroconvulsive therapy,
      light therapy, adjunctive and novel therapeutic strategies) of young adults and
      also, albeit to a lesser extent, children, adolescents and older adults.

PMID- 12479087
TI  - The activity of beta-hexosaminidase (uHex) and gamma-glutamyltransferase (uGGT)
      in urine as non-invasive markers of chronic alcohol abuse: II. Opiate-dependent
      subjects receiving methadone substitution.
AB  - The usefulness of beta-hexosaminidase (uHex) and gamma-glutamyltransferase (uGGT)
      activity in urine as markers of chronic alcohol abuse was examined in male
      methadone programme participants. The group consisted of 24 non-abusing and 21
      alcohol-abusing men. It has been demonstrated that the uHex test is one of the
      best alcohol abuse markers for opiate-dependent individuals (Receiver Operating
      Characteristic (ROC) area under the curve (AUC) 0.82, sensitivity 0.70,
      specificity 0.82). The uGGT test can be used as a marker of alcohol abuse in
      opiate-dependent men, however, its parameters are worse than those of uHex (ROC
      AUC 0.73, sensitivity 0.71, specificity 0.77). Among serum markers, only the
      relative amount of carbohydrate-deficient transferrin (s%CDT) has parameters
      sufficient for diagnostic use (ROC AUC 0.74, sensitivity 0.60, specificity 0.86).
      Factors other than alcohol can render the commonly used sGGT and sHex tests
      useless (differences between means for abusing and abstinent patients were
      insignificant, AUC ROC were lower than 0.7-0.65 and 0.69, respectively). Their
      good parameters, low costs, ease of use and non-invasive character are all
      features which make uHex and uGGT highly useful tools in the detection of chronic
      alcohol abuse in opiate-dependent patients participating in a methadone
      substitution programme.

PMID- 12479088
TI  - The psychopathology of K. Jaspers and K. Schneider as a fundamental method for
      psychiatry.
AB  - The paper is intended to answer the question whether and to what extent the
      psychopathology in the direction of Karl Jaspers and Kurt Schneider is still
      meaningful for contemporary psychiatry. K. Schneider developed gradually his
      "Clinical Psychopathology", proceeding from Jaspers' 4th edition of the "General
      Psychopathology" (1946). The Jaspersian-Schneiderian approach, aiming more at the
      elucidation of the patient's own inner experiences than at the observation of
      behaviour, has overcome the overly objectifying psychiatry of Kraepelin. The
      history and bearing of Jaspersian-Schneiderian psychopathology on psychiatry, its
      tenets, positions and concepts, as well as findings and results obtained with the
      approach are outlined. Recent developments in psychiatry, underestimating or even
      neglecting the psychopathological approach, are in danger of resulting in a loss
      of psychopathological competence in research and practice. The essay shows that
      this psychopathology is far from over, but remains relevant for clinical and
      biological psychiatry and should lead now, as ever, all other special and basic
      sciences in psychiatry. The critical methodological reflection and the
      fundamental psychopathological framework, created by Jaspers and modified and
      adapted to the requirements of clinical psychiatry by K. Schneider, are also
      today practically useful and heuristically fruitful. That we need psychopathology
      for diagnostics, therapy and primary and secondary prevention of schizophrenic
      psychoses, and also for biological psychiatric research, has been demonstrated by
      means of a long string of contributions of the last decades. The Jaspersian
      Schneiderian approach does not mean definite conclusion and codification, but
      leaves enough room for new developments, completing, correcting and changing many
      aspects of classical and present psychiatric views. In ensues that the view of
      European psychiatrists that we need psychopathology, according to the axiom:
      "First things first" (Gross and Huber 1993a, 2000a), and the call of Andreasen
      (Andreasen 1998) for a serious investment in training a new generation of
      psychiatrists in psychopathology, seem to be well founded and entirely justified.

PMID- 12479089
TI  - A case of mania induced by hypericum.
AB  - We report a case of mania induced by high doses of Hypericum perforatum in a 28
      year-old depressed woman with no past history of mania or hypomania and no
      concomitant use of antidepressants.

PMID- 12479090
TI  - Dementia and the mind and brain problem.

PMID- 12479091
TI  - [Quantitative analysis of cell cyclin E expression threshold].
AB  - BACKGROUND & OBJECTIVES: It is important to analyze the threshold of cyclins when
      we research the mechanism of cell cycle progressing. However, there was no
      effective way to caculate quantitatively. This study was designed to analyze
      cyclin E expression threshold quantitatively. METHODS: MOLT-4 cells were detected
      at different photomultiplier tube (PMT) voltage by cyclin E/DNA multiparameter
      flow cytometry. Using this method, MOLT-4 cells were detected at the same voltage
      after being treated with caffeine and cycloheximide (CHX), and then MOLT-4 cells
      and JURKAT cells were detected at the same voltage. Threshold of cyclin E was
      counted by using formula B2/A x C (A, B, C indicates the minimum, threshold, and
      maximum of cyclin E fluorescence intensity respectively). RESULTS: Cyclin E
      threshold of MOLT-4 cells calculated by formula B2/A x C was invariable at
      different voltage. It decreased when cells treaded with caffeine and unchanged
      when treated with cycloheximide. At the same time, cyclin E threshold of JURKAT
      cells calculated by formula was much lower than that of Molt-4 cells.
      CONCLUSIONS: Formula B2/A x C can be used to analyze cyclin E expression
      threshold quantitatively.

PMID- 12479092
TI  - [Specific suppression of GFP gene expression by short double stranded RNA in
      mammalian cells].
AB  - BACKGROUND AND OBJECTIVE: Double-stranded RNA (dsRNA) has been shown to interfere
      the function of specific genes in various species. The current study was designed
      to investigate whether short interfering RNAs(siRNAs) of green fluorescence
      protein(GFP) can inhibit the expression of GFP in mammalian cells. METHODS: HeLa
      cells were grown in standard conditions and transfected with pEGFPC2 and long
      dsRNA or siRNAs. Fluoroscopy and fluoroscent spectrophotometer were used to
      evaluate impact of GFPds RNA, Cx26 siRNAs, and longer double-strand RNAs on GFP
      expression, and flow cytometry was used to evaluate the cell apoptosis. RESULTS:
      Synthetic siRNAs can inhibite specific expression of GFP gene in human HeLa cell
      lines and siRNAs have no such specific effect. Longer double-stranded but no
      siRNAs can induce cell apoptosis. CONCLUSION: These observations may open a path
      toward the use of siRNAs as a new tool for researching gene function in mammalian
      cells and a gene-specific therapeutic tool.

PMID- 12479093
TI  - [Mitochondrial DNA mutations in lung cancer].
AB  - BACKGROUND AND OBJECTIVE: Mitochondiral DNA (mtDNA) mutations has been identified
      in various cancers, but their significance was unknown. This study aimed to
      detect mtDNA mutations in lung cancer, and to investigate their roles in the
      carcinogenesis of human lung. METHODS: Total DNA (including nuclear DNA and
      mtDNA) was extracted from the tumor tissues, corresponding distal non-cancerous
      lung tissues, and peripheral lymphocytes derived from 58 patients with lung
      cancer. Fifty-eight overlapping fragments and covering complete sequence of mtDNA
      were amplified by nested PCR, and the PCR products were sequenced directly with
      the cycle sequencing methods. The mtDNA mutations in the tumor tissue were
      determined by comparing with corresponding and peripheral lymphocytes. RESULTS:
      Sixty-six mutations were identified in 36 cases (62.1%) of lung cancer, including
      58 point mutations, 4 insertions, and 4 deletions. These mutations were
      dispersedly distributed in the full length of mtDNA. The frequency of mutation in
      D-loop is the highest, in which 18 mutations were detected. No mutation hot spot
      was found in peptide-coding regions. Among 43 point mutations identified in
      protein-coding region, 20 were silent mutations. In 8 patients, identical
      mutations were detected both in the tumor tissues and corresponding distal non
      cancerous tissues. CONCLUSION: Most of mtDNA mutations in the lung cancers
      investigated were occurred randomly and might have no impact on carcinogenesis;
      whereas the homoplasmic mutations may provide a potential diagnostic marker for
      lung cancer.

PMID- 12479094
TI  - [Effect of co-inhibition of MCT1 gene and NHE1 gene on proliferation and growth
      of human lung adenocarcinoma cells].
AB  - BACKGROUND & OBJECTIVE: The authors previously discovered that the intracellular
      pH values (pHi) of tumor cells could be decreased, which led tumor cells to
      acidify and die, when the expressions of the first subtype of monocarboxylate
      transporter (MCT1) gene and the first subtype of Na+/H+ exchanger (NHE1) gene in
      tumor cell membranes had been inhibited by each corresponding antisense gene
      respectively. However it was not clear whether there were co-effects on the pHi,
      proliferation, and growth of tumor cells, after two genes were inhibited at the
      same time. METHODS: pLXSN-MCT1 and pLXSN-NHE1, the corresponding antisense gene
      expression vectors of MCT1 and NHE1 genes, were introduced into human lung
      adenocarcinoma A549 cells at the same time with electroporation. The positive
      colonies were selected by G418. Using PCR and RT-PCR technique, it was confirmed
      that antisense genes of MCT1 and NHE1 genes integrated with A549 genomic DNA. The
      pHi and lactate content were detected with spectrophotometry. Cell growth cycle
      was measured with flow cytometer. The cells co-transfected antisense genes, cells
      transfected MCT1 antisense gene and A549 cells were respectively inoculated in
      nude mouse subcutaneous to observe the growth of transplantation tumors. RESULTS:
      Compared with A549 cells, the pHi of cells co-transfected antisense genes was
      remarkably decreased (P < 0.05), while lactate content was remarkably increased
      (P < 0.001). The cell cycle was blocked at G0-G1 period. And the transplantation
      tumors of nude mice inoculated co-transfected antisense gene-cells and inoculated
      MCT1-antisense-gene-transfected cells were significantly lighter and smaller than
      ones inoculated A549 cells (P < 0.001). CONCLUSION: MCT1 and NHE1 genes play
      important regulation roles in proliferation and growth of tumor cells, probably
      by affecting pHi.

PMID- 12479095
TI  - [Role of suppressor encoprotein PTEN in IGF-1 induced activation of ERK in
      endometrial carcinoma cells].
AB  - BACKGROUND & OBJECTIVES: The machanism of signal transduction of insulin-like
      growth factor (IGF-1) in endometrial carcinoma is still unknow. The objective of
      this paper was to study extracellular signal-regulated kinase(ERK) activation in
      endometrial carcinoma cell line Ishikawa under the stimulation of IGF-1, and to
      elucidate the role of suppressor encoprotein phosphatase and tensin
      homologue(PTEN) in activation of ERK. METHODS: Retrovirus vector of PTEN and PTEN
      (G129E) was constructed. Ishikawa was transfected in vitro. Expressionstable cell
      line was screened by G418. Western blot was applied to examine PTEN expression in
      Ishikawa cells after transfection. Optimal concentration and time of IGF-1 and 17
      beta-estrodial which activated ERK in Ishikawa-PTEN and Ishikawa-PTEN(G129E)
      cells were detected. Western blot was applied to examine ERK activation under the
      stimulation of 17-beta-estrodial in NIH3T3 fibroblasts after transient
      transfection of pCXN2hER alpha and pCXN2hER beta. RESULTS: IGF-1 activated ERK
      cascades(mainly ERK2) in Ishikawa cells. There was no obvious difference in ERK
      activation among different doses of IGF-1 (20, 40, and 80 micrograms/L), But the
      maximal activations of ERK2 took place at 5 min after stimulation with IGF-1. The
      activation of ERK2 was inhibited obviously by PTEN at 30 min, 2 h, and 24 h.
      There was no obvious difference in ERK activation between Ishikawa-PTEN(G129E)
      and Ishikawa-EGFP. 17-beta-estrodial activated ERK cascades (mainly ERK2) in
      Ishikawa cells. The activation of ERK was increased with increasing of
      concentration. The maximal activations of ERK2 took place at 5 min after
      stimulation with 17-beta-estrodial. The activation of ERK2 was inhibited
      obviously by PTEN, not by PTEN(G129E). 17-beta-estrodial activated ERKs cascades
      in NIH3T3 fibroblasts after transient transduction of pCXN2h-ER alpha.
      CONCLUSIONS: 17-beta-estrodial and IGF-1 activated ERK cascades in Ishikawa
      cells. Lipid phosphatase of PTEN had an inhibitory role in the activation of ERK
      under the stimulation of 17-beta-estrodial and IGF-1.

PMID- 12479096
TI  - [Establishment and biological characteristics of an immortalized human ovarian
      sarcomatoid carcinoma cell line BUPH:OVSC-2].
AB  - BACKGROUND & OBJECTIVE: Cell immortalization technique has been an important
      method to establish cell lines with expected phenotype. However, there was few
      report about the establishment of immortalized human ovarian carcinoma cell
      lines. The purpose of this study was to establish an immortalized human ovarian
      sarcomatoid carcinoma cell line, and to investigate its biological
      characteristics. METHODS: A specimen derived from metastatic tumor of a human
      ovarian sarcomatoid carcinoma in abdominal wall was obtained and cultured in
      vitro. The 10th passage was transfected with SV40 T gene, colonies were isolated
      by G418 selection and expanded to immortalized cell lines. The morphology of the
      cells was observed by microscope and electromicroscope, Growth curve, karyotype
      analysis, culturing in soft agar, nude mice transplantation,
      immunohistochemistry, etc. were used to investigate its biologic characteristics.
      The biologic characteristics of BUPH: OVSC-2 were compared with its original
      cells. RESULTS: After transfection and selection, an immortalized ovarian
      carcinoma cell line BUPH: OVSC-2 was established. The cell line has been
      maintained for over 90 passages. The H&E stain finding of transplanted tumor
      showed that the cells were morphologically sarcomatoid. However, the transmission
      electron microscopic observation exposed its epithelial origin. The cells grew
      exuberantly and had high malignant characteristics. Comparative studies revealed
      that the biological properties of BUPH: OVSC-2 and its original cells were
      identical. CONCLUSIONS: BUPH: OVSC-2 was demonstrated as an immortalized human
      ovarian sarcomatoid carcinoma cell line with high malignancy. It retains similar
      properties of their parental cells and could be a useful model for the study of
      human ovarian sarcomatoid carcinoma.

PMID- 12479097
TI  - [Expression of matrix metalloproteinase-2, 9 and their inhibitor-TIMP 1,2 in
      human squamous cell carcinoma of uterine cervix].
AB  - BACKGROUND & OBJECTIVE: Studies of tumor invasion and metastasis have focused on
      the degradation of extracellular matrix (ECM). Matrix metalloproteinases (MMPs),
      which could degrade ECM, were implicated in cancer invasion and metastasis.
      Activated MMPs were controlled by specific tissue inhibitors of
      metalloproteinases (TIMPs). This study was designed to investigate the expression
      of MMP-2, MMP-9 and TIMP-1, TIMP-2 in human squamous cell carcinomas of uterine
      cervix, and the association with invasion and metastasis of human squamous cell
      carcinoma of uterine cervix. METHODS: Tissue samples from 40 cases of squamous
      cell carcinoma of the uterine cervix, 29 cases of cervical intraepithelial
      neoplasia (CIN), and 16 cases of normal cervices were stained
      immunohistochemically. RESULTS: Immunohistochemical staining of tumor cells for
      MMP-2, MMP-9, TIMP-1, and TIMP-2 were noted 82.5%, 70.0%, 62.5%, and 97.5% in
      carcinomas, 44.8%, 62.1%, 86.21%, and 96.55% in CIN lesions respectively, for MMP
      2, MMP-9, TIMP-1 in 25.0% normal cervices, but for TIMP-2 in 56.25% normal
      cervices. There was significant difference for MMP-2 among carcinomas, normal
      cervices, and CIN respectively (P < 0.01). There was significant difference for
      MMP-9 among normal cervices, carcinomas, and CIN, respectively (P < 0.05). The
      positive rates of TIMP-1 and TIMP-2 in the cervical carcinoma group and CIN group
      were obviously higher than that in normal cervical group(P < 0.01). The positive
      rates of MMP-2 and MMP-9 in lymph node metastasis were obviously higher than that
      in without lymph node metastasis(P < 0.01), but for TIMP-2 was contrary and there
      was no significant difference for TIMP-1. No significant correlation could be
      established among the expression of these markers and the tumor diameter, the
      clinical stage, and pathologic grade. CONCLUSIONS: The over-expression of MMP-2,
      MMP-9, TIMP-1, and TIMP-2 may play a key role in invasion and lymph-node
      metastasis of in squamous carcinoma of the cervix.

PMID- 12479098
TI  - [Cloning and expression of single chain Fv gene against human colorectal
      carcinoma].
AB  - BACKGROUND & OBJECTIVE: Single chain Fv(scFv) has been employed as a favorable
      targeting carrier in the therapy and diagnosis of tumors due to its advantages in
      relatively low immunogenity and stronger penetrance to tumor tissues over intact
      mAb. This study was designed to recombine the genes from the variable regions of
      light chain and heavy chain of ND-1, a monoclonal antibody against human
      colorectal carcinoma, by a short peptide (Gly4Ser)3 to construct the ND-1scFv
      gene. The ND-1scFv protein was expressed in Escherichia coli. METHODS: VH and VL
      gene were amplified from hybridoma cell IC-2, secreting monoclonal antibody ND-1,
      by RT-PCR, and then were connected to each other by a linker peptide using
      extension overlap splicing PCR to obtain the ND-1scFv gene. The latter was cloned
      into the expression vector PET-28a(+) and induced by IPTG to express a fusion
      protein scFv and His-tag in E. coli BL-21. The expressed product was purified by
      affinity chromatography using Ni-NTA resin and its immunoactivity was analyzed
      using ELISA. RESULTS: Sequence analysis showed that scFv gene consisted of 732
      bp, among them, 354 bp for heavy chain gene, located upstream of scFv gene, and
      330 bp for the light chain gene, located donstream. SDS-PAGE analysis showed that
      the relative molecular weight of fusion protein is 30 kDa which was consistent
      with the theoretically predicted value. scFv expression was in the form of an
      inclusion body, and SDS-PAGE analysis of the purified scFv showed 94% purity.
      ELISA analysis revealed that scFv had equal immunoreactivity to the parent ND-1
      antibody. CONCLUSIONS: ND-1scFv gene against human colorectal carcinoma was
      successfully constructed, and functionally expressed in E. coli.

PMID- 12479099
TI  - [Expressions of CD44s, MMP-9, and Ki-67: possible association with invasion,
      metastasis, and recurrence of osteosarcoma].
AB  - BACKGROUND & OBJECTIVE: Recent research had showed that tumor cell adhesion
      molecular CD44 and matrix metalloproteinases (MMP) were expressed strongly in
      many tumors, and was associated closely with invasion and metastasis of the
      tumors. Ki-67 was one of the proliferative markers, which indicated the growth
      rate of tumor cells. However, the relationship among these markers and the
      invasion, metastasis, and recurrence of osteosarcoma was unclear yet. In this
      research the authors studied the expression of standard-type CD44(CD44s), MMP-9,
      and Ki-67 in osteosarcoma, and their relation to the invasion, metastasis, and
      recurrence of the tumor. METHODS: Immunohistochemistry staining(SP method) was
      used to detect CD44s, MMP-9, and Ki-67 in cases of osteosarcoma. Bone benign
      disease or normal connective tissue were used as the control. The results were
      treated with semi-quantitative method and analyzed by using non-parameter rank
      sum test. RESULTS: The positive rates of CD44s, MMP-9, and Ki-67 in osteosarcoma
      were 71.0%, 75.8%, and 35.5%, respectively, which were significantly higher than
      that in control tissue. The positive rate of Ki-67 in recurrent osteosarcoma was
      81.8%, which was significantly higher than that in primary tumor. CD44s and Ki-67
      positive rates were 88.9% and 66.7% respectively in osteosarcoma with lung
      metastasis, which were both significantly higher than that in osteosarcoma
      without lung metastasis. In poorly differentiated osteosarcoma positive rates of
      CD44s and MMP-9 were 76.3% and 79.7%, respectively, which were significantly
      higher than that in well differentiated tumor. Spearman correlation analysis
      proved that the expression of CD44s, MMP-9, and Ki-67 had significant relation to
      another. CONCLUSIONS: Increase of CD44s, MMP-9, and Ki-67 were involved in the
      growth and local invasion of osteosarcoma. The recurrence of osteosarcoma was
      associated with the proliferative rate of tumor cells. Whether there were early
      lung metastasis or not was affected by the amount of CD44s and the proliferative
      rate of the tumor cell. The poorer differentiation of osteosarcoma cells, the
      higher level of CD44s and MMP-9.

PMID- 12479100
TI  - [Cloning, sequencing, expression, and primary identification of recombinant mouse
      protein kinase CK2 alpha subunit].
AB  - BACKGROUND & OBJECTIVE: Protein kinase CK2 is a highly conserved and ubiquitous
      eukaryotic serine/threonine kinase that is elevated and can serve as an oncogene
      in many tumor cells. To further research the structure and function of CK2, this
      study was designed to construct, express, and preliminarily identify a
      recombinant expression plasmid which contains the cDNA encoding mouse protein
      kinase CK2 alpha subunit. METHODS: The aimed cDNA was obtained from NIH 3T3 mouse
      fibroblasts by RT-PCR. Nde I/BamH I-digested PCR product was directly cloned into
      pT7-7 expression vector which had been digested by Nde I/BamH I and
      dephosphorylated by calf intestinal alkaline phosphatase in advance. After E.
      coli DH5 alpha was transformed with the recombinant DNA by CaCl2 method,
      transformants were obtained. The positive clones were screened out primarily by
      gel electrophoresis, and then analyzed by digesting with restriction enzyme. Four
      positive clones were selected at random and sequenced respectively. The correct
      recombinant plasmid was transformed into E. coli BL21(DE3) and then expressed by
      inducing with IPTG. The products were identified with Western blotting. RESULTS:
      The positive rate of transformants was 100%. The results of restriction analysis
      indicated that DNA band size of the insert fragment and recombinant plasmid were
      consistent with theoretically predicated values. The sequencing results showed
      one of the four clones possessed the cDNA sequence which has no mutation in the
      processing of PCR, which was termed as pTMCKA. One protein with molecular mass of
      42 kDa was overexpressed by inducing with IPTG. The Western blot results
      confirmed that the recombinant product could specially react with antibody
      against human CK2 alpha subunit. CONCLUSIONS: The authors have successfully
      cloned and expressed recombinant mouse protein kinase CK2 alpha subunit in this
      experiment.

PMID- 12479101
TI  - [Association of p53, PCNA expression and trace element content in esophageal
      mucosa].
AB  - BACKGROUND & OBJECTIVE: There were abnormal changes of trace element in
      esophageal cancer patient's hair and serum in the high risk area. But it was
      still unknown that the relationship between p53 and proliferating cell nuclear
      antigen(PCNA) expression and the trace element content in varied esophageal
      mucosa. This study was designed to probe the relationship of trace element
      content and p53 mutation, PCNA expression in esophgeal mucosa. METHODS:
      Esophageal biopsy specimen of 151 cases were divided into four groups (normal,
      esophagitis, dysplasia, and early carcinoma). The quantitative determination of
      trace element was performed was performed by using X-ray energy spectrometry and
      the detection of PCNA expression and p53 mutation was performed by using S-P
      immunohistochemistry method. RESULTS: The contents of Zn, Se, Mo, were 1.74 +/-
      0.32, 1.53 +/- 0.64, 0.58 +/- 0.21, 0.20 +/- 0.08; 0.15 +/- 0.06, 0.10 +/- 0.03,
      0.04 +/- 0.02, 0; 4.73 +/- 1.31, 3.45 +/- 1.19, 3.51 +/- 1.32, 2.51 +/- 1.04;
      respectively in four groups. There was a significant difference in varied
      histological typies(P < 0.05). The contents of Cu/Zn, Ni were 0.57 +/- 0.17, 0.89
      +/- 0.18, 2.45 +/- 0.48, 2.92 +/- 1.08; 0.45 +/- 0.05, 1.27 +/- 0.11, 2.46 +/-
      0.24, 2.58 +/- 0.33; respectively, which increased gradually in pace with upgrade
      of esophageal lesions, with significant difference (P < 0.05). The postive rates
      of p53 and PCNA were 0, 46.15%, 100%; 31.19%, 84.62%, 100% respectively in normal
      esophageal epithelium, dysplasia, and early carcinoma, with significant
      difference (P < 0.01), and had significant correlation to trace element.
      CONCLUSION: The content variation of Zn, Se, Mo, Cu, Ni could be possessed of
      certain effect on p53 mutation and PCNA overexpression of esophageal epithelium
      in the high risk area.

PMID- 12479102
TI  - [Assessment of unresectability of pancreatic carcinoma by enhanced-CT and
      selective angiography].
AB  - BACKGROUND & OBJECTIVE: One of the major limitations of curative resection in the
      patients with pancreatic cancer is local tumor extension to the major vessels
      surrounding pancreas. Therefore the assessment of the involvement of major
      arteries surrounding pancreas by tumor before operation is very important for the
      judgement of respectability of pancreatic carcinoma. This study was designed to
      assess the clinical value of contrast-enhanced CT(CECT) and selective angiography
      (SAG) in predicting the unresectability of patients with pancreatic cancer.
      METHODS: From Aug 7, 1996 to Aug 12, 2000, 67 patients with pancreatic ductal
      adenocarcinoma proved pathologically were retrospectively analyzed. Of these
      patients, 31 and 54 patients were treated with CECT and SAG, respectively. The
      involvement of major vessels surrounding pancreas in CECT and SAG were assessed
      by operator according to specific criterias, which were compared with finding in
      operation. Finally, the accuracy of the method was assessed. RESULT: Among 31
      cases who were treated with CECT, 13 were judged unresectable by CECT; and 12
      were found unresectable during operation, with predict value of 91%. Among 54
      cases who were treated with SAG, 28 were judged unresectable by SAG; and 23 were
      found unresectable during operation, with predict value of 82%. The sensitivity,
      specificity, and predict value of CECT and SAG were 60%, 91%, 92%, and 77%, 79%,
      82%, respectively. The sensitivity, specificity, and predict value of CECT
      combined with SAG were 91%, 100%, 100%, respectively. CONCLUSION: Enhanced CT and
      SAG are useful in assessing the unresectability of pancreatic carcinoma, the
      combination of two ways can improve the sensitivity, specificity and predict
      value.

PMID- 12479103
TI  - [Diagnosis and treatment of metachronous multiple primary lung cancer].
AB  - BACKGROUND & OBJECTIVE: There is much controversy on the diagnosis and treatment
      of metachronous multiple primary lung cancer (MMPLC). Until now, there is no
      absolutely accurate diagnostic criteria. This study was designed to discuss its
      diagnosis, and to compare the survival rates after different therapeutic
      modalities. METHODS: The clinical features of 44 patients with MMPLC admitted to
      our hospital since 1961 were analyzed retrospectively. RESULTS: There were 44
      patients in this series, which accounted for 0.39% of all patients with lung
      cancer treated in our hospital. As to the initial cancer and the repeated cancer,
      they shared the same pathological type in 23 patients, and located on the same
      side of the lung in 12 patients. Twenty-four patients received operations,
      including 12 curative patients. The postoperative morbidity and mortality were
      33.3% and 8.3%, respectively. The other 20 patients received radiotherapy or/and
      chemotherapy. The 5-year survival rates of operative group, curative operative
      group, and non-operative group were 20.8%, 33.4%, and 10.0%, respectively.
      CONCLUSIONS: Comprehensive consideration of clinical features may lead to a
      rational diagnosis and treatment strategy, 5-year survival rate of the operative
      group, especially the curative group, is significantly higher than that of the
      non-operative group. The repeated operation, especially the second operation on
      the same side of the lung, should be performed at the qualified institutes and by
      the experienced doctors.

PMID- 12479104
TI  - [Detection of telomerase activity in bronchoscopic brush-off samples in patients
      with lung cancer].
AB  - BACKGROUND AND OBJECTIVE: Recent studies have shown that activation of telomerase
      plays an important role in carcinogenesis. However, there was few report on the
      level of telomerase activity in small samples from the patients with lung cancer.
      This study was designed to investigate the diagnostic significance of the
      detection of telomerase activity in bronchoscopic brush-off cells from the
      patients with lung cancer. METHODS: Telomeric repeat amplification protocol(TRAP)
      based telomerase polymerase chain reaction(PCR)-enzyme-linked immunosorbent assay
      (ELISA) TRAP-PCR-silver staining were employed to detect telomerase activity in
      56 samples of brushing cells from the patients with lung cancer and 10 samples
      with inflammation. RESULTS: The positive rate of telomerase activity in 56 biopsy
      samples of lung cancer group was significantly higher than that in inflammation
      group (P < 0.001). The sensitivity, specificity, and accuracy of detection of
      telomerase activity was 87.5%, 83.3%, and 86.3%, respectively. There was no
      significant difference in the positive rate of telomerase activity between
      central lung cancer and peripheral lung cancer. Positive rate of detection of
      telomerase activity in bronchoscopic brush-off cells was 46.4%. The positive rate
      of telomerase activity detected in TRAP-PCR-ELISA was higher than that detected
      in TRAP-silver staining, but the significant difference was not found. It was
      found that samples with low absorbing value detected in the quantified way would
      show weak positive with less ladder bands or vague ladder bands if detected in
      the latter way. CONCLUSION: The telomerase activity may be a good marker for
      diagnosis of lung cancer. Combined with cytologic measure, it is possible to
      raise the early diagnostic rate of lung cancer.

PMID- 12479105
TI  - [Expression and clinical significance of surfactant protein D mRNA in peripheral
      blood of lung cancer patients].
AB  - BACKGROUND AND OBJECTIVES: The sensitive detection of circulating tumor cells in
      lung cancer patients is very important for prognosis and selection of appropriate
      treatment modalities. Based on recent promising data, the authors established
      reverse transcriptase (RT)-PCR with primers specific for surfactant protein D (SP
      D) gene to detect circulating tumor cells in the peripheral blood of lung cancer
      patients, and to initiatively discuss its clinical significance. METHODS: The
      expression of SP-D mRNA was analyzed by an improved nested RT-PCR in the
      peripheral blood of 26 lung cancer patients with metastases, 37 lung cancer
      patients without metastases, 15 benign pneumonia patients, and 15 healthy
      volunteers. RESULTS: 1) The sensitivity of the method was 1 x 10(-6), with high
      level of specificity. 2) Using this method, the positive detection rate of the
      expression of SP-D mRNA was 92.3% (24/26) and 24.3% (9/37) in the peripheral
      blood of lung cancer patients with and without metastases, respectively. While no
      sample was positive for SP-D mRNA expression in the benign pneumonia patients and
      in the healthy volunteers. CONCLUSIONS: SP-D mRNA might be a valuable marker to
      detect circulating tumor cells in the peripheral blood of lung cancer patients.
      This method may be a valuable tool for early identification of metastases in
      asymptomatic lung cancer patients. Furthermore, it can also provide important
      clinical information for the evaluation of prognosis and in the selection of
      appropriate treatment strategies.

PMID- 12479106
TI  - [Colorectal exfoliated cell in stool and its nuclear DNA quantitative analysis
      for diagnosis of colorectal cancer].
AB  - BACKGROUND AND OBJECTIVES: Detection of colorectal exfoliated epithelial cells
      and their nuclear DNA content may provide another non-invasive way of screening
      and early diagnosis of colorectal cancer. This study was designed to analyze the
      roles of exfoliated cells in stool and its nuclear DNA content in diagnosis of
      colorectal cancer. METHODS: 1. One hundred and seventy nine individuals were
      selected, forty-six of them had pathological confirmation of colorectal
      carcinoma. The other 133 persons had no colonoscopic evidence of colorectal
      malignancy and therefore served as control. Exfoliated cells in the stool were
      isolated by elutriation, and the elutriation means was modified Iyengar's method.
      All individuals in the study had stool specimens for occult blood test(FOBT). 2.
      Nuclear DNA content and morphometric quantitative analysis in the exfoliated
      cells was performed on the 33 patients with colorectal cancer and 30 individuals
      served as control. The parameters selected in this study were DNA content,
      nuclear area, nuclear irregular index, and percent of > or = 5C cells. RESULTS: 1
      Exfoliative cytology and FOBT: In 35 of 46 cases of colorectal
      malignancy(76.09%), cytology was positive: 5 cases demonstrated dysplastic cells,
      4 cases indicated suspected carcinoma cells, 26 cases showed carcinoma cells. The
      positive rate of exfoliated cells had no significant relation to locations,
      sizes, histomorphologies, histological differentiations, Dukes stages, and lymph
      node metastases of the lesion(P > 0.05). Exfoliative cytology had a 98.50%
      (131/133) specificity for colorectal cancer in the study. The sensitivity for
      colorectal cancer was no significant difference between the two methods of
      exfoliative cytology and FOBT (76.09% vs 84.78%, P > 0.05), but the specificity
      for colorectal cancer, exfoliative cytology was significant higher than
      FOBT(98.50% vs 73.68%, P < 0.05). 2. DNA analysis of exfoliated cells nuclear,
      DNA content, nuclear area, nuclear irregular index and percent of > or = 5C cells
      in the stool were significant higher in colorectal cancer than in control group(P
      < 0.05). The percentage of > or = 5C cells were significantly associated with
      histological grade (P < 0.05). CONCLUSIONS: 1. Detection of exfoliated cells in
      stool plays an important role in diagnosis of colorectal cancer. Testing of FOBT
      and exfoliated cells sequentially hopes to be a new useful non-invasive test for
      screening of colorectal cancer. 2. DNA analysis of exfoliated cell in stool may
      provide an objective method of determining malignant grades and diagnosis of
      colorectal cancer.

PMID- 12479107
TI  - [Diagnosis and prognosis of ovarian epithelial tumor with morphometry].
AB  - BACKGROUND & OBJECTIVE: Morphometry for diagnosis and prognosis of tumor becomes
      important. This study was designed to evaluate the efficiency of morphometry for
      diagnosis and prognosis of the patients with ovarian epithelial tumor. METHODS: A
      total of 110 patients with ovarian epithelial tumor were studied by three
      morphometrical methods (image analysis, determination of DNA content, and
      quantitative analysis of AgNOR). Nuclear area (NA), nuclear perimeter (NP),
      nuclear form factor (NFF), DNA content (DC), DNA index (DI), percentage of DNA
      multiploid (P > 4c), and percentage of G0/G1 phases (P2c) were determined by
      morphometrical instrument. AgNOR was counted under light microscope. RESULTS: (1)
      The results in these three groups of benign, borderline, and malignant ovarian
      epithelial tumors: the differences of all parameters (NA, NP, NFF, DC, DI, AgNOR
      counts) among these groups have a extremely significant statistical difference (P
      < 0.01 and P < 0.001). (2) A study on prognosis: NA, NP, and NFF between two
      groups of patients (survival > or = 5 years and < 5 years) with ovarian
      epithelial carcinoma have a significant difference(P < 0.05 and P < 0.01), this
      means different results of image analysis indicate different survival. AgNOR
      counts have a close correlation with month of the survivors (r = -0.73, P <
      0.001). The P > 4c had a relation to month of survivors (r = -0.75, P < 0.001).
      CONCLUSIONS: Morphometry can provide reliable parameters for diagnosis and
      prognosis of the patients with different kinds of ovarian epithelial tumors.

PMID- 12479108
TI  - [Relationship between recurrence and metastasis of gastric cancer and expression
      of EGFR, IL-6R, PCNA, and DI].
AB  - BACKGROUND AND OBJECTIVE: The primary reasons for the failure were recurrence and
      metastasis in the treatment of gastric cancer. This study was designed to
      investigate the distributive regularity of EGFR, IL-6R, PCNA, DI and the diploid
      in the gastric cancer patients with recurrence and metastasis, to provide
      reliable basis to judge whether it has metastasis before operation and recurrence
      post operation. METHOD: Immunohistochemistry SP method and image analyzer
      (Fegulgen staining) were used to test the EGFR, IL-6R, PCNA, DI and the diploid
      in 199 patients with gastric cancer, 20 cases with normal gastric mucous
      membrane, and 20 cases of atypical hyperplasia. RESULTS: The level of expression
      of EGFR was higher in the patients with metastasis and residual gastric
      cancer(61.11%, 66%, 66.67%) than in the patients with other cancers, normal
      gastric mucous membrane, atypical hyperplasia(47.83%, 0%, 35%) (P < 0.01); In the
      distribution form of DNA diploid, the rate of non-diploid cells was remarkably
      higher in the patients with metastasis and residual gastric cancer(56.9 +/- 13.3%
      vs 12.8 +/- 6.3%, 0%, 12.2), and so is the DNA index (2.91 +/- 0.33 vs 2.17 +/-
      0.29), but the rate of 2C cells is lower(43.8 +/- 12.9 vs 10.2 +/- 7.5, P <
      0.01). CONCLUSION: EGFR, DI, and the diploid are valuable targets for judging
      metastasis and recurrence of gastric cancer before and after operation.

PMID- 12479109
TI  - [Changes of glycogen or sacchariferous materials in esophageal epithelium
      tissue].
AB  - BACKGROUND & OBJECTIVE: It was known that mucosal iodine staining could be used
      to improve the endoscopic visualization of esophageal premalignant lesion and
      cancer. However, the method was not used widely because of lacking clear
      mechanism. This study was designed to investigate the mechanism of esophageal
      epithelium staining with iodine and changes of glycogen or sacchariferous
      materials. METHODS: Esophageal epithelium was stained with iodine in endoscopic
      examination. According to color of tissue, the esophageal carcinoma and
      premalignant lesion were diagnosed. Glycogen from the esophageal mucous
      epithelium was extracted with beta-glycerophosphate buffer. The content of
      glycogen in the tissue speciman was detected by periodic acid-shiff staining
      (PAS). Protein in the esophageal mucous epithelium was extracted by tissue
      homogenate method. RESULTS: After iodine staining, the normal epithelium became
      brown and easier to distinguish normal epithelium from precancerous of
      premalignant epithelium according to the change of color. Furthermore, normal
      epithelium slice stained by PAS technique had red reaction but it had no reaction
      after pretreatment by amylase. However, precancerous and premalignant epithelium
      tissue slices could not be stained whenever they were pretreated by amylase. The
      content of glycogen extracted from the esophageal epithelium was lower
      significantly than those of normal tissue (P < 0.01). But it was no deviation
      that protein contents of normal esophageal epithelium were compared with
      carcinoma tissue (P > 0.05). CONCLUSION: These results demonstrated that glycogen
      and sacchariferous materials in esophageal carcinoma and premalignant lesion
      tissue decreased significantly and result in light yellow area by iodine
      staining. It may be helpful for diagnosis of esophageal carcinoma.

PMID- 12479110
TI  - [Comparison of postoperative analgesia with tramadol, morphine versus their
      combination in patients undergoing abdominal cancer surgery].
AB  - BACKGROUND & OBJECTIVE: Morphine is a widely used analgesic in management of
      postoperative pain with well documented analgesic properties and side effects.
      Tramadol, a new synthetic mu-opioid receptor agonist, little is known about its
      efficacy and side effects when administered in epidural for pain relief. The aim
      of this study is to compare the efficacy and side effects of tramadol, morphine
      versus their combination for postoperative analgesia. METHODS: One hundred and
      twenty patients undergoing abdominal cancer surgery were assigned to one of three
      groups randomly, tramadol group (Group T, n = 40), morphine group(Group M, n =
      40) and combination of tramadol and morphine group(group T + M, n = 40), for
      postoperative analgesia. In group T, 12 mg/kg tramadol and 0.125% bupivacaine 100
      ml were used for 48 h postoperative analgesia. In group M, 0.12 mg/kg morphine
      and 0.125% bupivacaine 100 ml; and in group T + M, 6 mg/kg tramadol, 0.12 mg/kg
      morphine and 0.125%. Bupivacaine 100 ml were used for postoperative analgesia.
      Efficacy was assessed by comparing visual analogue scale(VAS), Bruggman comfort
      score (BCS), global satisfaction score (GSS) at several time points over 48
      hours. Possile adverse events were recorded. RESULTS: There is no significant
      difference among three groups in VAS, but in group T, there are more patients
      whose VAS > 5 score than those in group M and group T + M. BCS; GSS in group T +
      M are lower than that in group T and group M. The occurrence rate of nausea and
      vomiting in group T + M are lower than that in group M. CONCLUSIONS: The efficacy
      of tramadol in epidural postoperative analgesia is similar to that of morphine,
      but varied from patient to patient, so the dose of tramadol should be
      individualized. Combination of tramadol and morphine can provide effective
      analgesia for postoperative pain and cause little adverse effect, especially
      reduce the occurrence rate of nausea and vomiting.

PMID- 12479111
TI  - [Clinical observation on adoptive immunotherapy with autologous cytokine-induced
      killer cells for advanced malignant tumor].
AB  - BACKGROUND & OBJECTIVE: Cytokine-induced killer (CIK) cells have the
      characteristics of rapid proliferation, high efficiency, and broad spectrum in
      killing of tumor cells. However, there was few report about its clinical
      application on treatment for cancer patients. The current study was designed to
      evaluate the effect of adoptive transfer of autologous CIK cells on the patients
      with advanced malignant tumor. METHODS: Peripheral blood mononuclear cells of the
      patients with advanced malignant tumor were separated by fractionation on Ficoll
      Hypaque gradient, then cultured in the medium containing IFN-gamma, IL-2, and
      CD3McAb for 7 days in vitro, and than the cultured auto-CIK cells were transfused
      back to the patients. The numbers of transferred CIK cells per patient were 5-15
      x 10(9) in one course of treatment. Among these patients, 47 cases received
      chemotherapy, 3 cases received radiotherapy before CIK cells transfusion. The
      interval between chemoradiotherapy and immunotherapy was over 2 to 4 weeks.
      RESULTS: Among 63 patients receiving CIK cells immunotherapy, the total effective
      rate (PR + MR) was 44.46% (28). In the patients with increasing of CEA level in
      serum, 14 cases showed reduction of serum CEA and 1 cases remained increasing
      after the treatment with CIK cell. In the patients with increasing of AFP level
      in serum, similarly, 9 cases showed reduction of serum AFD and 1 case remained
      increasing. The absolute members of CD3, CD4, and CD8T cells increased to over
      45% after being treated with CIK cells. Among treated patients, the appetite of
      51 cases and performance and sleep of 32 cases got improved. Among 18 cases, 13
      cases showed the pain relief. CONCLUSION: Adoptive immunotherapy of auto-CIK
      cells can significantly enhance cellular immune functions and improve subjective
      symptoms, but without side effects, so this is a safe and effective treatment for
      the patients with malignant tumor.

PMID- 12479112
TI  - [Advances in research for relationship between mitochondrial DNA and solid
      tumor].
AB  - Mitochondrial DNA (mtDNA) encodes the polypeptides required for oxidative
      phosphorylation and genesis of ATP. It has been though to be involved in
      carcinogenesis because of its high mutation rate and lacking effective repair
      mechanism in contrast to nuclear DNA. Since mtDNA lacks introns, it has been
      suggested that most mutations will occur in this coding sequence and subsequent
      accumulation of mutation may lead to tumor formation. Alteration in expression of
      mitochondrial DNA may be a general characteristic of cancer cells. The research
      on mtDNA such as the mitochondrial genome instability (mtGI) and the integration
      between the mtDNA and nuclear genome have, mainly in solid tumor, been reported
      recently, meanwhile it will be a critical topic in solid tumors. In this paper,
      we reviewed the advances in research for relationship among mitochondrial DNA
      mutation, abnormal expression, integration, and mtGI in solid tumors lately.

PMID- 12479113
TI  - [Development of research for combined gene therapy and radiotherapy for cancer
      patients].
AB  - Cancer treatment is one of the most important fields in medical research. All
      strategies such as radiotherapy, chemotherapy, surgery, and gene-based therapy
      have their own advantage and disadvantages. Nowadays, a novel method which
      combined traditional therapy with gene therapy plays an important role in the
      field of cancer research. This review described the current state of combined
      therapies of gene-based and radiate radiotherapy. Meanwhile, we evaluated the
      prospect of this combined treatment.

PMID- 12479115
TI  - [Effect of antisense oligonucleotide against telomerase in rat spermatogonia and
      its reactivity to cytokine].
AB  - OBJECTIVES: To study the change of telomerase activity in rat spermatogonia when
      the telomerase RNA was enclosed, and reactivity of the change to cytokine(SCF,
      TGF-beta 1). METHODS: The antisense oligonucleotides(PS-ASON) of telomerase was
      transfected into proliferating spermatogonia in vitro with the liposomes as the
      vector. Then the cytokine, stem cell factor (SCF) or transforming growth factor
      beta 1(TGF-beta 1), was added. The proliferative activity of the spermatogonia
      was determined before and after the inhibition by MTT [3-(4,5-dimethylthiazol-2
      yl)-2,5-diphenyltetrazolium bromide]assay. The change of telomerase activity was
      detected by telomeric repeat amplification protocol (TRAP). RESULTS: 1 mumol/L PS
      ASON obviously downregulated the telomerase activity and inhibited spermatogonia
      proliferation. When the inhibition was over, the activity recovered to some
      extent(P < 0.01). Growth factors can regulate the spermatogonia after inhibition,
      SCF may improve the activity of telomerase and the proliferation of
      spermatogonia. Adversely, TGF-beta 1 may inhibit the recovery of telomerase
      activity. CONCLUSIONS: To inhibit spermatogonia telomerase activity antisensely
      can limit the proliferation of spermatogonia efficiently, which was regulated by
      cytokine. This method might be a new and efficient way in male birth control.

PMID- 12479114
TI  - [Cres (cystatin-related epididymal spermatogenic) gene regulation and function].
AB  - The CRES (cystatin-related epididymal spermatogenic) protein defines a new
      subgroup in the family 2 cystatins of the cystatin superfamily of cysteine
      protease inhibitors. However, unlike the ubiquitous expression of cystatin C, the
      Cres gene is preferentialy expressed in postmeiotic germ cells, the proximal
      caput epididymidis, and anterior pituitary gonadotrophs. Furthermore, CRES
      protein lacks two of the three consensus sites necessary for the cystatin
      inhibition of C1 cysteine proteases. Therefore, CRES may perform unique and
      tissue-specific functions in the reproductive and neuroendocrine systems. In the
      present review, we describe our studies on: 1. the Cres gene promoter and the
      transcriptional regulatory protein and their associated DNA binding sites that
      may be important for tissue-specific expression; and 2. the biochemical function
      of CRES protein. In brief, Northern blot, gel shift analyses, and transient
      transfection assays demonstrated that the C/EBP beta (CCAAT/enhancer binding
      protein) transcription factor is the predominant C/EBP family member expressed in
      the epididymis and gonadotroph cells and is necessary for high levels of Cres
      expression in these two tissues. In other studies, analyses of transgenic mice
      expressing a CAT reporter gene driven by 1.6 kb of Cres promoter revealed CAT
      mRNA and protein only in the germ cells. These studies suggest that the 1.6 kb of
      Cres 5' flanking sequence contains the required DNA elements for expression in
      the testis, but lacks the elements to correctly target expression of the reporter
      gene in the epididymis. Alternatively, repressor elements may be present.
      Finally, in vitro protease assays were performed to determine if CRES functions
      as a protease inhibitor. In contrast to cystain C, CRES did not inhibit the C1
      cysteine protease papain but rather inhibited at nanomolar concentrations the
      serine protease PC2, a prohormone processing enzyme. Therefore, CRES is a new
      cross-class inhibitor that may regulate PC2 of PC2-like proteases and suggests a
      role for CRES in the regulation of prohormone and proprotein processing.

PMID- 12479116
TI  - [Effects of infrasound on ultrastructure of testis cell in mice].
AB  - OBJECTIVES: To investigate the effects of infrasound on ultrastructure of testis
      in mouse. METHODS: Twelve male BALB/C mice were randomly divided into three
      groups according to exposed duration on 1, 7 and 14 day. The mice were separately
      exposed to infrasound environment under 8 Hz/90 dB, 8 Hz/130 dB, 16 Hz/90 dB, 16
      Hz/130 dB 2 hours per day. There was another control group which had three mice
      were separated into module with no infrasound. All the mice were killed on
      schedule. Then all the sections of testis were observed under electronic
      microscope. The alterations of structure and the chromatin were observed.
      RESULTS: Some acute alteration in one day group was found in testis cell, such as
      cellular denaturation and necrosis, intercellular edema, mitochondria swelling,
      liposome hyperplasia. When the infrasound was up to 8 Hz/130 dB, the damage
      showed seriously. In 7 and 14 day group, the acute alteration was gradually
      decreased. A plenty of abnormal sperm were found. And other alteration was
      chromatin condense. The effect of variational frequency was important in
      ultrastructure. CONCLUSIONS: The infrasound markedly effected to testicular cell
      morphology and secreting function. Infrasound will lead to the alteration of
      procreation in mouse.

PMID- 12479117
TI  - [Effect of gamma-aminobutyric acid on the sperm acrosin activity].
AB  - OBJECTIVES: To investigate the effect of gamma-aminobutyric acid (GABA) on the
      sperm acrosin activity in normal men and positive antisperm antibody (AsAb) men.
      METHODS: Sperm acrosin activity was detected by BAEE/ADH method. RESULTS: GABA
      could increase the sperm acrosin activity in normal and AsAb positive patients (P
      < 0.01). The results also indicated that GABA significantly increased Na(+)-K(+)
      ATPase activity (P < 0.01), Ca(2+)-ATPase activity (P < 0.05) and SOD activity (P
      < 0.01) of sperm. CONCLUSIONS: The results demonstrated that GABA could influence
      the sperm acrosin activity.

PMID- 12479118
TI  - [Practicability study on a group of vigilant chemical compounds including
      chlorheridine diacetate].
AB  - OBJECTIVES: To test in vitro the spermatozocidine drug which can also prevent sex
      transmitting diseases (STD) pathogens. METHODS: Chlorheridine diacetate and other
      three chemical compounds were applied in vitro spermatozocidine and sperm
      inhibitting tests. RESULTS: The lowest concentrations of chlorheridine diacetate
      and p-nitrophenol which can inhibit human sperm in 20 seconds were 1.25 mg/ml.
      The minimal inhibitory concentration and minimal bactericidal concentration of
      chlorheridine diacetate and p-nitrophenol on Streptococcus albus Stemberg were
      0.125 to 0.50 mg/ml and 0.25 to 1.00 mg/ml. CONCLUSIONS: Chlorheridine diacetate
      and p-uitrophenol have strong spermatozocidine and antibacteria effects.

PMID- 12479119
TI  - [Therapeutic choices of penile erectile dysfunction].
AB  - OBJECTIVES: To discuss the therapeutic choices of erectile dysfunction (ED) and
      to improve the therapeutic efficacy for different ED cases. METHODS: Two hundred
      and twenty-seven patients with ED were treated repectively with psychological
      treatment(31 cases), oral testosterone(30 cases), Viagra(121 cases),
      psychological treatment + Viagra (16 cases), intraurethral PGE1 (8 cases) and
      intracavemous injection(21 cases). RESULTS: Among those ED patients, 142 (62.6%)
      cases reported improved erections after they had undergone above-mentioned
      therapies. The improved patients include 12 cases(38.7%) with psychological
      treatment, 9 cases (30.0%) with oral testosterone, 91 cases (75.2%) with Viagra,
      13 cases (81.3%) with psychological and Viagar, 2 cases (25.0%) with
      intraurethral PGE1 and 21 cases (71.4%) with intracavemous injection.
      CONCLUSIONS: ED is a highly individualized disease, therapeutic choices of ED
      based on patient's situation can benefit those patients.

PMID- 12479120
TI  - [Analysis of DNA content of spermatogenic cells in the adult human testis and
      epididymis by flow cytometry].
AB  - OBJECTIVES: To detect the changes of DNA ploidy of spermatogenic cells in testis
      and epididymis. METHODS: Right epididymides and testes from 15 fertile youth
      donors who died of accident were collected. Samples of spermatogenic cells in
      different regions of epididymis (caput, corpus and cauda) and tests were
      collected. DNA of spermatogenic cells were detected by flow cyctometry (FCM).
      RESULTS: The haploid(1n), diploid(2n) and tetraploid(4n) spermatogenic cells were
      existed in different regions of epididymis and testis. The 1n cells increased
      from (24.87 +/- 7.28)% in testis to (96.33 +/- 1.58)% in epididymis cauda, there
      were significant differences among regions of testis and epididymis caput,
      corpus(P < 0.01), and the difference among regions of epididymis corpus and
      epididymis cauda were also significant(P < 0.05). While the percentages of 2n and
      4n cells decreased from (63.07 +/- 8.96)% and (9.43 +/- 3.83)% in tesits to (2.47
      +/- 0.93)% and (1.17 +/- 0.95)% in epididymis respectively. There was significant
      difference of 2n cells between testis and epididymis caput, corpus(P < 0.01), and
      was also remarkable difference between epididymis corpus and cauda (P < 0.05).
      There was no difference of 4n cells between testis and epididymis caput(P >
      0.05). There were significant difference among regions of epididymis caput,
      corpus and cauda(P < 0.05). CONCLUSIONS: The percentage of immature spermatogenic
      cells decreased along with passing through the epididymis.

PMID- 12479121
TI  - [Investigation of chronic prostatitis and altered bowel habits].
AB  - OBJECTIVES: To explore the incidence, causes, and significance of altered bowel
      habits in chronic prostatitis. METHODS: Investigating the incidence of altered
      bowel habits in chronic prostatitis, analyzing some possible causes to induce the
      symptom, such as course of disease, vegetative nerve functional disturbance,
      inflammation in expressed prostatic secretions, and digital rectal examination.
      Following up the improvement of altered bowel habits after effective treatment of
      chronic prostatitis. RESULTS: The incidence of altered bowel habits was 31.40% in
      379 chronic prostatitis patients. The detected congestion and swelling of
      prostate was closed related to altered bowel habits in chronic prostatitis. The
      incidence of improvement of altered bowel habits after effective treatment of
      chronic prostatitis reached to 78.79%. CONCLUSIONS: Congestion and swelling of
      prostate might be the main causes for altered bowel habits in chronic
      prostatitis. Altered bowel habits should be considered as a common symptom and
      cure standard for chronic prostatitis.

PMID- 12479122
TI  - [Effect of transrectal prostatic biopsy on serum prostate specific antigen
      levels].
AB  - OBJECTIVES: To assess the effect of transrectal prostatic biopsy (TPB) on the
      concentrations of serum prostate specific antigen (PSA). METHODS: Twenty patients
      with abnormal PSA levels and/or digital rectal examination (DRE) underwent TPB.
      Serum PSA levels were measured before TPB and at 0.5 h, 1 week, 1 month after
      TPB, respectively. RESULTS: The serum PSA levels before TPB and 0.5 h, 1 week, 1
      month after TPB were (12.23 +/- 8.62), (34.90 +/- 41.53), (23.59 +/- 20.78) and
      (11.31 +/- 6.95) micrograms/L, respectively. The serum PSA concentration was
      significantly higher at 0.5 h after TPB than before (P < 0.05), and then
      gradually decreased. PSA levels remained higher for at least 1 week in 85%
      (17/20) patients(P < 0.05), then returned to the baseline at one month after TPB
      (P > 0.05). CONCLUSIONS: TPB can lead to a dramatic increase of PSA in serum and
      keep the PSA value high in one week. Then the PSA in serum decreased gradully.
      Serum PSA level cannot return to baseline until one month after TPB.

PMID- 12479123
TI  - [Investigation of reproductive organs of male children and juvenile of the Meng
      and the Han nationality in Chifeng area].
AB  - OBJECTIVES: To investigate the development and the health of reproductive organs
      of male children and juvenile between the Meng and the Han nationality in the
      Meng nationality area. METHODS: Male juvenile(4-18 years old) of the Meng
      nationality (n = 2,315) and the Han nationality (n = 2,832) were divided into
      four age groups. Height, weight, length and perimeter of penis, volume of left
      and right testis and reproductive organs illness were examined. RESULTS: In 13-18
      years group, the developmental speed of reproductive organs was faster in
      Mongolia male juvenile than that in the Han nationality (P < 0.02). After 13
      years old, the developmental speed of reproductive organs of male living in town
      is faster than that in the country (P < 0.05). Illness of male reproductive
      organs was common such as hernia, varicocle etc. CONCLUSIONS: There was
      difference of developmental status and the prevalence rate of reproductive organs
      of male children and juvenile between the Meng and the Han nationality.

PMID- 12479124
TI  - [Investigation of reproductive health status and service needs among unmarried
      young men in Changshu].
AB  - OBJECTIVES: To investigate the status of pre-marital reproductive health
      education, sexual psychology behavior, contraception and pre-marital abortion in
      unmarried young men to get the correct way for pre-marital guidence and
      education. METHODS: The survey adopted the society-psychology-behavior
      methodology. Five hundred and ten objects who had pre-marital sexual living
      history were investigated randomly. RESULTS: The reasons of making sexual pre
      marital relations were thinking marriage and curiosity. 81.2% of them thought the
      best way of contraception is to use the condom. 34.8% of them used the
      prevenception when they had the first sexual experience. 39.7% of the objects
      adopted contraceptions every time, and 27.1% of the objects made the women
      pregnancy which resulted 22.4% women using the IUD for contraception. 63.6% of
      them thought the main reason of not using contraception was the fear to get
      trouble. The main source of contraceptives was pharmacy (59.8%). CONCLUSIONS:
      This survey suggested that the prevalence of pre-marital sexual behavior is
      relatively high in Changshu. It should be taken several methods to give unmarried
      young men the reproductibe education.

PMID- 12479125
TI  - [Survey of infection of Toxoplasma gondii in infertile couples in Suzhou
      countryside].
AB  - OBJECTIVES: To determine the level of anti-Toxoplasma antibody in serum of
      infertile couples to explore the relationship between toxoplasma infection and
      infertility. METHODS: Enzyme-linked immunosorbent assay (ELISA) was applied to
      detect the anti-Toxoplasma antibody, antisperm antibody (AsAb) and
      anticardiolipin antibody (ACA) in serum of 178 couples with infertility and 190
      couples who had normal pregnant history. RESULTS: The positive result of
      Toxoplasma infection in the infertile couples was significantly higher than that
      in fertile couples which was 34.83% vs 12.11% (chi 2 = 26.72, P < 0.01) with the
      odds ratio 3.88. The positive result of serum AsAb in the Toxoplasma infected
      group was significantly higher than that in the no Toxoplasma infected group
      (32.50% vs 15.94%, chi 2 = 10.76, P < 0.01) with the odds ratio 2.54.
      CONCLUSIONS: Toxoplasma infection was related to infertility. The Toxoplasma
      infection and was posibly related to the antisperm antibodies which can be
      involved in the pathogenisis of infertility.

PMID- 12479126
TI  - [Study on the sexual development of adolescent male].
AB  - OBJECTIVES: The investigation of the testicular volume, the penis length and the
      T, FSH, LH, PRL levels in serum were taken in 289 adolescent males to provide the
      valuable data for andrology. METHODS: The adolescent males were grouped according
      to their age. The testicular volume was measured with testicular model and the T,
      FSH, LH, PRL levels in serum were determined by immunoenzymetric assay. RESULTS:
      The male sexual development was rapid from age 11 to 16 and close to that of
      adult at age 18. Serum PRL of adolescent males was higher than that of adult
      males. CONCLUSIONS: The age 11 to 16 is a period of rapid growth in sexual
      maturation. PRL may play an important role in sexual maturation.

PMID- 12479127
TI  - [Epididymal sperm protein P34H and male reproduction].
AB  - During epididymal transit, mammalian spermatozoa acquire new surface proteins
      that are necessary for gamete interaction. P34H, a member of the short-chain
      dehydrogenase/reductase(SDR) superfamily, is acquired on the acrosomal cap of
      human spermatozoon during its maturation arising within epididymis. P34H has been
      shown to be involved in sperm-zona pellucida interaction. Research revealed that
      the occurrence of low concentration of sperm protein P34H were significant
      amongst the idiopathic infertile male population and P34H protein could also be
      considered as a marker of epididymal sperm maturation in human. Therefore the
      level of sperm protein P34H is proposed to be a auxiliary diagnostic tool for
      male infertility. This paper reviews the molecular properties and regulation of
      the expression of P34H and its association with male reproduction.

PMID- 12479128
TI  - [Chronic pelvic pain syndrome].
AB  - Chronic pelvic pain syndrome(CPPS) which is also named by chronic nonbacterial
      prostatitis is a common urologic disease. This disease could not be treated
      effectively and affects the living quality of the patients. This article reviews
      the progress on the CPPS about its definition, classification, etiology (e.g.
      immunology), diagnosis and treatment in recent years.

PMID- 12479129
TI  - [Advances in the research about penile erection related genes].
AB  - Molecular biologic research on erectile dysfunction (ED), especially the
      elucidation of NO-cGMP signaling pathway which plays an important role on
      modulating corpus cavernosum smooth muscle dilation, has been made the great
      advance in past ten years. The further research on the penile erection related
      genes including nitric oxide synthase (NOS), phosphodiesterases (PDEs), K+
      channal, insulin-like growth factor (IGF), heme oxygenase (HO), vascular
      endothelial growth factor (VEGF), cyclic GMP-dependent kinase (cGK I),
      angiotensin converting enzyme (ACE) and growth factor (GF) etc, has given the
      theoretical evidence for the clinical treatment of ED in future.

PMID- 12479130
TI  - [Influence of protein kinase C on motility and acrosome reaction of sperm].
AB  - Protein kinase C (PKC) is localized in the equatorial segment and the principal
      piece of the tail of spermatozoa. Activator of PKC results in increasing
      flagellar motility of sperm that is blocked by PKC inhibitors such as
      staurosporine. A good correlation (r = 0.9, P < 0.001) is found between the
      content of PKC in sperm and sperm motility. Zona pellucida (ZP) stimulates the
      spermatozoa binding the acrosome reaction resulting in the release of hydrolytic
      enzymes and in the exposure of new membrane domains. ZP binding to receptors in
      the plasma membrane can regulate adenyl cyclase (AC) leading to elevation of cAMP
      and protein kinase A (PKA) activation. The PKA activates a voltage-dependent Ca2+
      channel in the outer acrosomal membrane which releases Ca2+ from the interior of
      the acrosome to the cytosol. Activation of the PLC resulted from the rise in Ca2+
      hydrolyze phosphatidyl inositol bisphosphate. The product activate PCK to open a
      voltage-dependent Ca2+ channel (L) in the plasma membrane, leading to the second
      (II) Ca2+ higher increase which result in membrane fusion and acrosome reaction.
      It is proposed that PKC would be involved in the regulation of motility and
      acrosome reaction of sperm.

PMID- 12479131
TI  - [Partial androgen deficiency in aging males].
AB  - Partial androgen deficiency in aging males can be defined as a clincal condition
      characterized by a partial deficiency of androgen in blood and/or a decrease
      genomic sensitivity to testosterone or its active metabolites in target tissues.
      This state of hypogondism leads to a decline of physical energy, an altered state
      of well-being, a sexual dysfunction and various metabolic alterations.
      Testosterone supplement therapy can improve all these symptoms.

PMID- 12479132
TI  - [Clinical and experimental study of treatment of nanmiqing capsule for chronic
      prostatitis].
AB  - OBJECTIVES: To investigate the clinical effect and therapeutic mechanism of
      Nanmiqing capsule made of rheum palmatum, leech, astragalus memberanaceus on
      patients with chronic prostatitis(CP). METHODS: Seventy-six CP cases were treated
      with Nanmiqing, while 32 CP cases were treated with Qianliekang as a control. The
      changes of EPS were observed pre- and post-treatment. The rat model of CP got by
      Xiaozhiling inducing were treated with Nanmiqing and Qianliekang respectively.
      The concentration of endothelin, TXB2, 6-keto-PGF1 alpha and SOD, IgG, IgA in
      plasma were measured pre- and post-treatment, meanwhile, pathological changes of
      prostate tissues were observed. RESULTS: The total effective rate was 89.47% in
      treatment group, which was significantly higher than 71.88% in the control group
      (P < 0.01). Experimental study for CP rats showed that the Nanmiqing was more
      effective medicine than Qianliekang (P < 0.01). CONCLUSIONS: Nanmiqing was an
      effective medicine for CP. The mechanism of clearing heat and resolving toxin,
      activating blood and removing stasis and reinforcing Qi in chinese medicine could
      be the explanation of the useful treatment including three therapentic ways.

PMID- 12479133
TI  - Under the microscope.

PMID- 12479134
TI  - Lest we forget.

PMID- 12479135
TI  - Managing urinary continence in men.

PMID- 12479136
TI  - A diversionary tactic? Social work in an emergency assessment unit.

PMID- 12479137
TI  - Older people with confusion: capacity to consent and the administration of
      medicines.
AB  - The author examines capacity, consent and other key issues in relation to the
      administration of medicines to older people with confusion. It suggests there is
      much that can be done to improve the way in which nursing practice assesses and
      promotes therapeutic alliances between older people and medicines.

PMID- 12479138
TI  - Assessing oral health in older people.

PMID- 12479139
TI  - A bitter pill to swallow.

PMID- 12479140
TI  - Developing links. Mental health and older people.

PMID- 12479141
TI  - Blood counts.

PMID- 12479142
TI  - A briefing on lung cancer.
AB  - This article is about the latest developments in lung cancer treatment, whether
      it is intended to cure, extend survival or enhance quality of life. The
      assessment of symptoms is considered, and focuses on breathlessness, which is one
      of the most common and distressing disorders associated with the disease.
      Pharmacological and non-pharmacological approaches are outlines to assist nurses
      in meeting patients' needs and helping them to take control of their illness.

PMID- 12479143
TI  - What you need to know about abdominal hernia.

PMID- 12479144
TI  - Blood transfusion observations.

PMID- 12479145
TI  - Dementia: Alzheimer's disease.
AB  - Dementia is a common condition that will increase as the average age of the
      population increases. It is a syndrome with major health and social implications.
      There are many different types of dementia and the effects of the illness relate
      to which parts of the brain are affected. This article looks at the types of
      brain damage that occur, and focuses on Alzheimer's disease.

PMID- 12479146
TI  - The impact of health professionals' attitudes about being registered donors on
      the availability of organs.
AB  - The mismatch between supply and demand in organ donation is well documented.
      Although there are many reasons for this mismatch, failure of health
      professionals to identify potential donors or to gain consent from bereaved
      relatives is considered to be significant. Such failures may be due to the
      attitudes of health professionals themselves towards becoming organ donors. This
      study focuses on the level of commitment shown by health care professionals and
      their student equivalents to organ donation, and assesses the ways in which they
      identify themselves as potential organ donors. These findings are evaluated and
      suggestions for future practice are offered.

PMID- 12479147
TI  - Women of substance. Interview by Leona Armstrong.

PMID- 12479148
TI  - Biting changes. Interview by Carol Davis.

PMID- 12479150
TI  - The world is our oyster: celebrating our past and anticipating our future.

PMID- 12479149
TI  - Parameters for the treatment of urticaria and angioedema.
AB  - This month's CPG column reviews "The Diagnosis and Management of Urticaria: a
      Practice Parameter Part I: Acute Urticaria/Angioedema and Part II: Chronic
      Urticaria/Angioedema." As many as 15%-24% of the U.S. population may experience
      at least one episode of urticaria and/or angioedema in their lifetime. Evaluation
      and treatment is dependent on whether the urticaria/angioedema is acute or
      chronic because they are fundamentally different disorders. Acute urticaria is
      frequently self-limited and usually caused by an allergic reaction to an
      identifiable agent. Chronic urticaria is usually due to an endogenous cause, one
      that is difficult to identify and to treat. Due to the magnitude, potential
      seriousness and chronicity of urticaria and angioedema, this CPG should be quite
      useful to nurse practitioners in a variety of settings.

PMID- 12479151
TI  - Counseling middle-aged women about physical activity using the stages of change.
AB  - PURPOSE: To discuss application of the Stages of Change theoretical framework and
      provide clinical tips on exercise adherence among midlife women. Included is a
      checklist to assist the nurse practitioner (NP) in effectively delivering the
      message. DATA SOURCES: Review of the current scientific literature on exercise
      adherence and the Stages of Change model. CONCLUSIONS: Middle-aged women comprise
      a unique population. Determining the woman's readiness for change using the
      Stages of Change model, NPs can routinely include appropriate exercise
      recommendations in their practices. IMPLICATIONS FOR PRACTICE: Nurse
      practitioners are in a unique position to promote healthy behaviors by counseling
      women in midlife about adopting an active lifestyle. Exercise counseling is an
      essential component of healthcare, especially among middle-aged women who are
      experiencing physical, emotional, and social changes.

PMID- 12479152
TI  - Challenge and opportunity: nurse practitioner programs partnering with managed
      care.
AB  - PURPOSE: To examine the experiences of nurse practitioner (NP) students who
      participated in a collaborative educational program between the University of
      Massachusetts, Amherst, and Health New England (HNE) Health Plan, Springfield,
      MA. Nurse practitioner faculty and managed care executives shared resources to
      educate NP students and to address their perceptions about managed care. DATA
      SOURCES: Verbatim transcriptions and journal writings of students specifically
      designated as "Partnerships for Quality Education (PQE) trainees" and reports of
      their fellow classmates, all of whom received varying extent of access to managed
      care theory, administrative, and clinical experiences within the HNE plan.
      CONCLUSIONS: The experiences of the PQE trainees revealed a greatly expanded
      understanding of managed care that challenged students' previous beliefs. They
      reported greater satisfaction with program participation than their classmates,
      had an unprecedented opportunity to articulate the NP role to a managed care
      organization (MCO), and learned that a collaborative, rather than an adversarial,
      relationship with an MCO produces better outcomes for patients and providers.
      Many students in the class, including some of the PQE trainees, were concerned,
      however, about what they perceived as managed care "taking time away from
      clinical issues," which they considered more important. IMPLICATIONS FOR TEACHING
      AND PRACTICE: There is a need for balance between both managed care and clinical
      content in NP programs, yet students must have an intimate grasp of both if they
      are to survive in today's health care environment.

PMID- 12479153
TI  - Evaluating intimate partner violence.
AB  - PURPOSE: To describe the incidence, assessment, and management of intimate
      partner violence (IPV) from a cultural perspective emphasizing the values,
      strengths, and health care needs of African-American women. DATA SOURCES: Review
      of the published scientific literature, U.S. Bureau of Justice Statistics and the
      National Crime Victimization Survey (NCVS) supplemented with hypothetical cases.
      CONCLUSIONS: Violence is a social and public health emergency affecting over 10%
      of the population during their lives and 22% of women who are physically
      assaulted by an intimate. Roughly 3 million to 4.4 million women report being
      battered annually, although this is a low estimate. Neither gender nor age nor
      sexual orientation protects one from IPV. Violent crime causes 2.2 million known
      injuries with a huge cost in hospital days and other expenses. IMPLICATIONS FOR
      PRACTICE: Women often hesitate to report violence; health care professionals
      detect as few as 5% of battered women. Women suffer for months and years before
      accurate diagnosis. Clinicians need to be vigilant in case finding, education,
      prevention, and treatment. Cultural differences in values and beliefs, and
      behavioral norms influence evaluation, treatment, and referral.

PMID- 12479154
TI  - End-of-life treatment preferences among older adults: a nurse practitioner
      initiated intervention.
AB  - PURPOSE: To explore end-of-life treatment preferences (ELTP) among older adults
      and to test the impact of a nurse practitioner (NP) initiated intervention to
      facilitate the completion of ELTPs. DATA SOURCES: A descriptive study including
      135 older adults living in a continuing care retirement community. CONCLUSIONS:
      The findings in this study suggest that the majority of older adults do not want
      life sustaining interventions at the end of life, but are willing to accept
      interventions that will keep them comfortable. ELTP can, however, change over
      time. An NP-initiated teaching intervention about advance directives and ELTP
      significantly increased the number of individuals who completed advance directive
      forms. IMPLICATIONS FOR PRACTICE: With the advancement of medical technology,
      various life-sustaining treatments are available at the end of life. Older adults
      should be encouraged to establish their ELTPs while they are physically and
      mentally able to do so. Health care providers should initiate discussions about
      ELTP at regular intervals (yearly) to assist older adults in participating in
      decisions about their end-of-life care.

PMID- 12479155
TI  - Seton's Nursing Dashboard project--driving nursing quality through data sharing.

PMID- 12479156
TI  - Dutch perspectives on palliative care in the Netherlands.
AB  - This study reports data gathered via extensive interviews with some of the
      leading authorities on the euthanasia policy that were conducted in the
      Netherlands. They were asked: It has been argued that the policy and practice of
      euthanasia in the Netherlands is the result of undeveloped palliative care. What
      do you think? I also mentioned the fact that there are only a few hospices in the
      Netherlands. The responses were different and contradictory. Many interviewees
      agreed with the statement. Almost all of those agreeing with it said that only
      during the late 1990s were people beginning to admit that there was a need to
      improve palliative care. Some interviewees insisted that doctors first need to
      explore other options for helping the patient prior to choosing the course of
      euthanasia. Other interviewees thought that palliative care is well developed in
      the Netherlands and that euthanasia has actually paved the way for calling more
      attention to palliative care.

PMID- 12479157
TI  - A critique on the concept of "brain death".
AB  - Since the concept of "brain death" was introduced in medical terminology, enough
      evidence has come to light to show that the concept is based on an unclear and
      incoherent theory. The "brain death" concept suffers by internal inconsistencies
      in both the tests-criterion and the criterion-definition relationships. It is
      also evident that there are residual vegetative functions in "brain dead"
      patients. Since the content of consciousness is inaccessible in these patients
      who are in a profound coma, the diagnosis of "brain death" is based on an
      unproved hypothesis. A critical evaluation of the role and the limitations of the
      confirmatory tests in the diagnosis of "brain death" is attempted. Finally it is
      pointed out that a holistic approach to the problem of "brain death" in humans
      should necessarily include the inspection of the content of consciousness.

PMID- 12479158
TI  - Brief Amici Curiae of C. Everett Koop, M.D., Sc.D. et al., in support of Attorney
      General Ashcroft.

PMID- 12479159
TI  - Brief Amici Curiae of the United States Catholic Conference et al. in support of
      Attorney General Ashcroft.

PMID- 12479160
TI  - The President's Council on Bioethics: human cloning and human dignity: an ethical
      inquiry--executive summary.

PMID- 12479161
TI  - Testimony before House Government Reform Committee on Human Cloning.  May 15,
      2002.

PMID- 12479162
TI  - Statement in the Ad Hoc Committee on the International Convention Against the
      Reproductive Cloning of Human Beings, February 26, 2002.

PMID- 12479163
TI  - AAPLOG statement on induced abortion and the subsequent risk of breast cancer.

PMID- 12479164
TI  - [Editorial].

PMID- 12479165
TI  - [Preemptive analgesia--preoperative diclofenac sodium for postoperative analgesia
      in general surgery].

PMID- 12479166
TI  - Neuromuscular disorders: gene location.

PMID- 12479168
TI  - Congenital myasthenic syndromes: gene mutations.

PMID- 12479167
TI  - Mitochondrial encephalomyopathies: gene mutation.

PMID- 12479169
TI  - Bacteriology and Mycology. Proceedings of a meeting. 22-25 May 2002, Hannover,
      Germany.

PMID- 12479170
TI  - The flow of life.

PMID- 12479173
TI  - National Heart, Lung, and Blood Institute of the National Institutes of Health
      forum on immune reconstitution and cellular therapy following hematopoietic stem
      cell transplantation.

PMID- 12479171
TI  - A case if infant botulism due to neurotoxigenic Clostridium butyricum type E
      associated with Clostridium difficile colitis.
AB  - Reported here is the sixth case of intestinal toxemia botulism caused by
      Clostridium butyricum type E in Italy since 1984. In this case, the patient was
      concomitantly affected with colitis due to Clostridium difficile toxin. A review
      of previously reported cases revealed that some of these patients may also have
      had intestinal toxemia botulism associated with Clostridium difficile colitis,
      based on the reported symptoms. Given that this association has been shown to
      exist not only in Italy but also in the USA, it is recommended that individuals
      with intestinal botulism and symptoms of colitis undergo testing for Clostridium
      difficile and its toxins in fecal samples.

PMID- 12479175
TI  - Proceedings of The Bellagio Conference on the Nutrition Transition and it's
      Implications for Health in the Developing World. August 20-24, 2001. Bellagio,
      Italy.

PMID- 12479174
TI  - [Immunotherapy in envenomation. Proceedings of a meeting. Dakar, Senegal, 2001].

PMID- 12479176
TI  - Selected papers from the 3rd Conference on Quantitative Modelling in the
      Management of Health Care. University of Salford, England, United Kingdom, 5-7
      September 2000.

PMID- 12479177
TI  - A case of left ventricular endomyocardial fibrosis.
AB  - The patient was a 29-year-old woman. When she consulted a local physician with
      chief complaints of fever and fatigue of the extremities, cerebral infarction was
      detected on MRI, in addition to abnormalities found on ECG. Ultrasonic
      cardiography revealed the presence of a tumor in the left ventricle. Therefore,
      tumorectomy and endocardectomy were performed under extracorporeal circulation
      based on a diagnosis of cardiac tumor. Inflammatory cell infiltration into the
      ventricular wall was pathologically confirmed, and eosinophilia was observed
      preoperatively. Therefore, the patient was diagnosed as having endomyocardial
      fibrosis, which is rarely observed in Japan. The postoperative course of this
      patient was satisfactory, and the eosinophil count was normalized
      postoperatively. At present, this patient is being followed at the outpatient
      clinic.

PMID- 12479178
TI  - Antiphospholipid syndrome in pregnancy.

PMID- 12479179
TI  - Surgical treatment of atherosclerotic and dysplastic aneurysms of the
      extracranial internal carotid artery.
AB  - Atherosclerotic and dysplastic aneurysms of the extracranial internal carotid
      artery are rare in Japan. We have experienced only four cases since 1982. The
      patients were two men and two women with a mean age of 67 years (range 51 to 82
      years). All four patients had a saccular type aneurysm; sizes ranged from 30 to
      75 mm. Aneurysmectomy and end-to-end anastomosis of the internal carotid artery
      could be performed in two patients. One patient underwent aneurysmorrhaphy
      followed by primary closure of the internal carotid artery, and the remaining
      patient underwent aneurysmectomy followed by a prosthetic graft replacement (6 mm
      PTFE graft). During aneurysm repair, simple arterial cross-clamping (time 18 to
      57 min; mean +/- SD: 31.3 +/- 18.0 min) was used in all patients. During arterial
      clamping of the carotid artery in two patients, somatosensory evoked potentials
      and regional cerebral oxygen saturation detected by near-infrared spectroscopy
      remained within normal ranges. All patients survived without neurologic deficits.
      These findings indicate that intraluminal shunting may be unnecessary during
      aneurysm repair if the patient does not have obstructive disease in the
      contralateral carotid artery and if no somatosensory evoked potentials or
      regional cerebral oxygen saturation abnormalities occur during proximal arterial
      clamping. After aneurysmectomy, end-to-end anastomosis of the internal carotid
      artery is the preferred method of repair if the length of the distal internal
      carotid artery permits.

PMID- 12479180
TI  - Integrated chromosome aberration yields determined for V79 cells after high LET
      radiation.

PMID- 12479181
TI  - Cardiovascular Imaging 2001 and 2002. Proceedings and abstracts.

PMID- 12479182
TI  - 13th Meeting of the World Society for Stereotactic and Functional Neurosurgery.
      Adelaide, September 11-14, 2001. Proceedings and abstracts.

PMID- 12479183
TI  - Safeguards lacking for emergency equipment.

PMID- 12479184
TI  - Longevity of physicians. 1896.

PMID- 12479185
TI  - How safe is your hospital?
AB  - 21,000 Consumer Reports readers rate the care they or a relative received. What
      we learned can make a critical difference for you.

PMID- 12479186
TI  - Decoding your hospital bills.

PMID- 12479187
TI  - Of birds and bacteria.
AB  - "Superbugs" that resist the usual antibiotic treatments are nasty, and they could
      be in your chicken dinner. Here's how to protect yourself.

PMID- 12479188
TI  - Facial fractures and submental tracheal intubation.
AB  - Submental tracheal intubation is a simple, quick and effective alternative to
      oral and nasal tracheal intubation or tracheostomy in the surgical management of
      selected patients with craniomaxillofacial injuries. It has a low morbidity and
      it does not impede the surgical field, allowing for temporary maxillo-mandibular
      fixation (jaw wiring) intra-operatively, and nasal assessment, manipulation and
      bone grafting, either simultaneously or as an independent procedure. We report 12
      cases utilizing this technique in this retrospective study, this includes 11
      patients with mid-facial fractures and associated base of skull fractures, and
      one patient who underwent an elective Le Fort III advancement. The techniques and
      indications for submental tracheal intubation are described.

PMID- 12479189
TI  - Unwanted effects of morphine-6-glucoronide and morphine.
AB  - The active metabolite of morphine, morphine-6-glucuronide (M6G), may have fewer
      unwanted effects than morphine. We randomly allocated 144 women to receive either
      M6G or morphine as part of general anaesthesia for day case gynaecological
      laparoscopy. The incidence of nausea, vomiting, pain, sedation and skin rash, and
      severity of nausea, pain and sedation after surgery were recorded by direct
      observation in hospital, and by questionnaire until the next morning. Compared
      with the M6G group, patients who received morphine were more likely to report
      nausea in the first 2 h after surgery (odds ratio 2.9, CI 1.31-6.21) and to
      suffer it with greater severity. During the same time period, they were more
      likely to vomit and feel sleepy, but the intensity of pain and use of rescue
      analgesics were similar in both groups. The incidences of nausea, vomiting and
      the feeling of sleepiness continued to be greater in the morphine group during
      and after the journey home. The next morning, patients in the morphine group
      remained sleepier, but the incidence of nausea was similar for the two groups.
      M6G appears to have a better toxicity profile than morphine. More efficacy
      studies are needed to define accurately the analgesic potency of systemically
      administered M6G.

PMID- 12479190
TI  - Tracheal intubating conditions using propofol and remifentanil target-controlled
      infusions.
AB  - Using target-controlled infusions (TCI) we aimed to determine the most
      appropriate dose of remifentanil required for intubation, using a steady effect
      site concentration of propofol and without the use of neuromuscular blocking
      drugs. Sixty ASA III patients presenting for elective surgery were randomly
      allocated to one of three groups. Anaesthesia was induced in all patients using a
      target-controlled infusion of propofol 6.5 microg x ml(-1). This was reduced to 3
      microg x ml(-1) after 1 min. Each group received a different TCI of remifentanil,
      19, 15 or 11 ng x ml(-1), which was reduced to 10, 8 or 6 ng x ml(-1),
      respectively, after 1 min. Laryngoscopy and intubation were attempted at 4 min.
      Laryngoscopy and ease of intubation were assessed using a standard scoring
      system. Intubation was considered satisfactory in 75% of patients in groups 1 and
      2 and 35% of patients in group 3. Intubation was successful in 20/20, 19/20 and
      15/20 patients in groups 1, 2 and 3, respectively. Pulse oximetry, heart rate and
      noninvasive arterial pressure were measured pre-induction, and at intervals until
      after laryngoscopy and intubation. Mean arterial pressure (MAP) and heart rate
      decreased following induction of anaesthesia in all groups, which was
      statistically significant. Following laryngoscopy, MAP and heart rate increased,
      but were significantly less than the corresponding baseline values.

PMID- 12479191
TI  - Combined use of esmolol and nicardipine to blunt the haemodynamic changes
      following laryngoscopy and tracheal intubation.
AB  - We examined the effect of different combinations of esmolol and nicardipine upon
      the circulatory response to tracheal intubation. One hundred patients were
      randomly allocated into five groups of twenty to receive pretreatments of saline
      or different combinations of esmolol (0.5 or 1.0 mg x kg(-1)) and nicardipine (15
      or 30 microg x kg(-1)). Significant tachycardia persisted over a 5-min period
      after intubation in all five groups compared with baseline levels (p < 0.05).
      Patients receiving esmolol 1.0 mg x kg(-1) and nicardipine 30 g x kg(-1) showed
      no significant change in systolic blood pressure after tracheal intubation
      compared with baseline and significant lower peak systolic blood pressure than
      those receiving saline (p = 0.023).

PMID- 12479192
TI  - B-type natriuretic peptide in heart failure.

PMID- 12479193
TI  - B-type natriuretic peptide in heart failure.

PMID- 12479194
TI  - Toll-like receptor 4 polymorphisms and atherogenesis.

PMID- 12479195
TI  - Bronchiolitis in popcorn-factory workers.

PMID- 12479196
TI  - Bronchiolitis in popcorn-factory workers.

PMID- 12479197
TI  - Inflammatory bowel disease.

PMID- 12479198
TI  - Inflammatory bowel disease.

PMID- 12479199
TI  - Inflammatory bowel disease.

PMID- 12479200
TI  - Illness after international travel.

PMID- 12479201
TI  - Bibliography. Current world literature. Renal system.

PMID- 12479202
TI  - Bibliography. Current world literature. Trauma.

PMID- 12479204
TI  - Induction chemoimmunotherapy.

PMID- 12479203
TI  - Bibliography. Current world literature. Ethical, legal & organizational issues in
      the ICU.

PMID- 12479205
TI  - Conservation biology: the new consensus.

PMID- 12479206
TI  - Ethanol and the osmolal gap.

PMID- 12479207
TI  - Ethanol and the osmolal gap.

PMID- 12479208
TI  - Managing interdependence: emergency medicine's competitive advantage; fellowships
      in cardiovascular emergencies.

PMID- 12479209
TI  - Managing interdependence: emergency medicine's competitive advantage; fellowships
      in cardiovascular emergencies.

PMID- 12479210
TI  - Spot the diagnosis.

PMID- 12479211
TI  - Wellcome, Dr. Callaham.

PMID- 12479213
TI  - Intraoperative MRI in neurosurgery: becoming mature?

PMID- 12479212
TI  - Contemporary issues in women's health.

PMID- 12479214
TI  - Matters of life and death: the hospital of San Pedro in Puebla, 1790-1802.
AB  - The last decade of the eighteenth century may be described as a "golden age" in
      the history of the Hospital of San Pedro of Puebla. Under the stewardship of its
      director, Father Ignacio Domenech, San Pedro underwent an extensive renovation of
      its physical plant and a thorough administrative reorganization that turned it
      into one of the best medical care and research institutions in New Spain. The
      article draws a profile of the patients who filled the hospital's wards and adds
      a human dimension to the many names and ailments listed in the registries. It
      also describes the valiant efforts of the medical staff who daily shared the
      patients' struggle against illness. Fighting immense odds, the practitioners
      sought to provide good-quality care and to further their limited understanding of
      disease. A detailed analysis of San Pedro's everyday life reveals a portrait of
      human suffering, professional dedication, and humanity's pursuit of knowledge.

PMID- 12479215
TI  - ACOG technology assessment. Genetics and molecular diagnostic testing. Number 1,
      July 2002. American College of Obstetrics and Gynecology.
AB  - Human genetics and molecular testing is playing an increasingly important role in
      obstetric and gynecologic practice. It is essential that obstetricians and
      gynecologists are aware of the advances in our understanding of genetic disease
      and the fundamental principles of molecular testing and genetic screening as
      genetics is integrated into routine medical practice. In the future, elucidation
      of the genetic basis for reproductive disorders, common diseases, and cancer with
      improved high throughput technology for genetic testing will expand testing
      opportunities and influence treatment options and prevention strategies.

PMID- 12479216
TI  - The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse
      transcriptase expression and inhibits tumor growth in vivo.
AB  - Cationic porphyrins are being studied as possible anticancer agents because of
      their ability to bind to and stabilize DNA guanine quadruplexes (G-quadruplexes).
      We have shown previously that the cationic porphyrin TMPyP4 is able to bind to
      and stabilize G-quadruplexes in human telomere sequences, resulting in inhibition
      of telomerase activity. To better understand the mechanism of action behind
      telomerase inhibition by TMPyP4, we performed a cDNA microarray analysis on cells
      treated with TMPyP4 and TMPyP2, a positional isomer of TMPyP4 that has low
      affinity for G-quadruplexes. Analysis of time course data from the microarray
      experiments revealed that TMPyP4 and TMPyP2 treatment altered the expression of
      several gene clusters. We found that c-MYC, an oncogene nearly ubiquitous in
      human tumors that bears the potential in its promoter to form a G-quadruplex, was
      among the genes specifically down-regulated by TMPyP4, but not by TMPyP2. The
      hTERT gene, which encodes the catalytic subunit of telomerase, is
      transcriptionally regulated by c-MYC, and we have found that TMPyP4 also causes a
      decrease in human telomerase reverse transcriptase transcripts, suggesting two
      possible mechanisms for the effect of TMPyP4 on telomerase activity. We also show
      that TMPyP4, but not TMPyP2, is able to prolong survival and decrease tumor
      growth rates in two xenograft tumor models. We believe that, because of the
      actions of TMPyP4 in decreasing both c-MYC protein levels and telomerase
      activity, as well as its anticancer effects in vivo, it is a worthwhile agent to
      pursue and develop further.

PMID- 12479217
TI  - Reversion of RhoC GTPase-induced inflammatory breast cancer phenotype by
      treatment with a farnesyl transferase inhibitor.
AB  - Inflammatory breast carcinoma (IBC) is a highly aggressive form of locally
      advanced breast cancer that has the ability to invade and block the dermal
      lymphatics of the skin overlying the breast. In a previous series of studies, our
      laboratory identified overexpression of RhoC GTPase in >90% of IBCs (K. L. van
      Golen et al., Clin. Cancer Res., 5: 2511-2519, 1999) and defined RhoC as a
      mammary oncogene involved in conferring the metastatic phenotype (K. L. van Golen
      et al., Cancer Res., 60: 5832-5838, 2000). RhoC GTPase is involved in
      cytoskeletal reorganization during cellular motility. Farnesyl transferase
      inhibitors (FTIs) were previously shown to be effective in modulating tumor
      growth in Ras-transformed tumor cells. Recently, studies have focused on RhoB as
      a putative non-Ras target of FTI action. In the present study, we assessed the
      effect of the FTI L-744,832 on RhoC-overexpressing IBC and RhoC-transfected human
      mammary epithelial (HME-RhoC) cells. Treatment of the SUM149 IBC cell line and
      HME-RhoC transfectants with the FTI L-744,832 led to reversion of the RhoC
      induced phenotype, manifested by a significant decrease in anchorage-independent
      growth, motility, and invasion. Although RhoC expression and activation were not
      affected, RhoB levels were increased by FTI treatment. Transient transfection of
      geranylgeranylated RhoB (RhoB-GG) into the same cells reproduced the effects of
      the FTI, thus suggesting that FTI-induced reversion of the RhoC phenotype may be
      mediated by an increase in RhoB-GG levels. These data provide direct evidence
      that FTIs may find use in the clinic when directed against RhoC-overexpressing
      tumors and suggest appropriate biological markers to evaluate during FTI
      treatment.

PMID- 12479218
TI  - Antitumor activity and metabolic activation of N-methanocarbathymidine, a novel
      thymidine analogue with a pseudosugar rigidly fixed in the northern conformation,
      in murine colon cancer cells expressing herpes simplex thymidine kinase.
AB  - N-Methanocarbathymidine [(N)-MCT], a thymidine analogue incorporating a
      pseudosugar with a fixed Northern conformation, exhibits antiherpetic activity
      against both herpes simplex virus (HSV) HSV-1 and HSV-2, with a potency greater
      than that of the reference standard, ganciclovir (GCV). In the present study, we
      have assessed the cytotoxic activity in vitro of (N)-MCT in wild-type murine
      colon cancer cells (MC38) and in cells expressing the herpes simplex thymidine
      kinase gene (MC38/HSV-tk), and the antitumor activity of (N)-MCT in vivo against
      HSV-tk transduced and nontransduced MC38 murine tumors. In vitro, when assessed
      over a 48-h period, the growth-inhibitory activity (IC50) of (N)-MCT toward
      MC38/HSV-tk cells was 2.9 microM. In parallel studies, the cytostatic activity of
      the reference compound GCV in these tumor lines was 3.0 microM. In studies in
      vivo, both (N)-MCT and GCV (100 mg/kg) given twice daily for 7 days completely
      inhibited the growth of HSV-tk-transduced MC38 tumors while exhibiting no effect
      on nontransduced MC38 tumors in mice. In nontransduced cells both in vitro and in
      vivo, only low levels of (N)-MCT and its monophosphate could be detected after
      administration of the parent drug, whereas in HSV-tk-transduced cells (N)-MCT was
      phosphorylated to its respective mono-, di-, and triphosphates. Furthermore, data
      showed that (N)-MCT incorporated in high levels into cellular DNA whereas trace
      levels were measured into RNA. These observations indicate that (N)-MCT may be a
      useful candidate prodrug for HSV-tk suicide gene therapy of cancer.

PMID- 12479219
TI  - Targeted therapy against human lung cancer in nude mice by high-affinity
      recombinant antimesothelin single-chain Fv immunotoxin.
AB  - Several tumors, including mesothelioma and ovarian cancer, can overexpress
      mesothelin, a glycosylphosphatidylinositol-linked differentiation glycoprotein.
      The membrane-bound type of mesothelin is found in the blood of cancer patients at
      a very low level, which makes mesothelin a good candidate for targeted therapy of
      certain cancers. An antimesothelin disulfide-linked Fv (SS1 Fv) was fused to a
      truncated mutant of Pseudomonas exotoxin A to produce the recombinant immunotoxin
      SS1(dsFv)-PE38, which has a high binding affinity to mesothelin (Kd = 0.7 nM).
      Our studies in vitro showed that SS1(dsFv)-PE38 is significantly more cytotoxic
      to the high-mesothelin-producing NCI-H226 human non-small cell lung cancer cells
      than to human lung adenocarcinoma PC14PE6 cells, which do not express mesothelin.
      When administered at a nontoxic dose of 500 microg/kg on days 7, 9, and 11 to
      nude mice injected i.v. with the two human lung cancer cell lines, SS1(dsFv)-PE38
      selectively inhibited experimental lung metastases produced by the mesothelin
      producing NCI-H226 cells. Our data indicate that mesothelin-producing squamous
      cell carcinoma of the lung may be a good target for this immunotoxin.

PMID- 12479220
TI  - Oncostatin M induces growth arrest of mammary epithelium via a CCAAT/enhancer
      binding protein delta-dependent pathway.
AB  - Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up
      regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein in
      nonneoplastic HC11 mouse mammary epithelial cells. This up-regulation is
      dependent on signaling by phospho-Stat3 (signal transducers and activators of
      transcription). The same signaling pathway is activated in two human breast
      cancer cell lines, a neoplastic mouse mammary epithelial cell line and a second
      nonneoplastic mouse mammary epithelial cell line. [3H]Thymidine incorporation and
      flow cytometry demonstrate that OSM inhibits the growth of HC11 cells by reducing
      the number of S-phase cells. These phenotypic changes are accompanied by reduced
      expression of S-phase genes with a corresponding increased expression of G0 genes
      in HC11 cells. Reduction of C/EBPdelta protein in HC11 cells by expression of a
      C/EBPdelta antisense construct inhibits OSM-mediated growth arrest. These data
      demonstrate that OSM induces up-regulation of C/EBPdelta via a Stat3-dependent
      pathway in mammary epithelial cells and that the growth inhibition induced by OSM
      depends on the presence of C/EBPdelta.

PMID- 12479221
TI  - C421A polymorphism in the human breast cancer resistance protein gene is
      associated with low expression of Q141K protein and low-level drug resistance.
AB  - Breast cancer resistance protein (BCRP) confers multidrug resistance to cancer
      cells against agents such as SN-38 (an active metabolite of irinotecan),
      mitoxantrone, and topotecan. Among 59 human tumor cell lines tested, 6 cell
      lines, A549, NCI-H460, KM-12, HT-29, OVCAR-5, and RPMI8226, showed high BCRP
      expression. BCRP cDNA was isolated from 11 cancer cell lines and three variant
      cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln
      141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (delta315-6)] were
      identified. G34A and C421A variants were polymorphisms, and 944-949 deletion was
      a splicing variant. C421A BCRP-transfected PA317 cells showed markedly decreased
      protein expression and low-level drug resistance compared with wild-type BCRP
      transfected cells when transfectants expressed similar levels of BCRP mRNA. G34A
      or 944-949-deleted BCRP-transfected PA317 cells showed similar or somewhat lower
      protein expression and drug resistance compared with wild-type BCRP-transfected
      cells. Of 124 healthy Japanese volunteers, 67 were wild-type, 48 were
      heterozygous, and 9 were homozygous for the C421A allele. These results suggest
      that some people possess the C421A polymorphic BCRP gene and express low amounts
      of Q141K BCRP. In addition to that, C376T polymorphism in exon 4 substituting
      stop codon for Gln-126 was found in 3 of the 124 general Japanese population.
      This C376T polymorphism may also have high impact because active BCRP protein
      will not be expressed from the C376T allele. Therefore, people with C376T and/or
      C421A polymorphisms may express low amounts of BCRP, and this low BCRP expression
      might result in hypersensitivity of normal cells to such anticancer drugs as
      irinotecan and mitoxantrone.

PMID- 12479222
TI  - Regulation of intracellular pH in human melanoma: potential therapeutic
      implications.
AB  - Melanoma cells in vivo maintain intracellular pH (pHi) in a viable range despite
      an extracellular tumor pH (pHe) that is typically below 7.0. In general, three
      families of transporters are capable of removing metabolic protons, but the
      specific transporters responsible for the maintenance of pHi at low pHe in
      melanomas have not been identified. Although the transporters exist in most
      cells, an inhibitor would be predicted to have selectivity for cells located in
      an acidic tumor bed because cells in that environment would be expected to have
      transporters chronically activated. In this report, the levels and extent of
      expression of the Na+/H+ exchanger (NHE-1) and two of the H+-linked
      monocarboxylate transporters (MCTs) were evaluated in three melanoma cell lines.
      The effects of inhibitors of each transporter were tested at an extracellular pH
      (pHe) of 7.3, 6.7, or 6.5 in melanoma cells that were grown at pHe 7.3 or 6.7.
      The activity of MCT isoform 1 (MCT-1) was up-regulated in three melanoma cell
      lines at low pHe, but that of NHE-1 was not. Furthermore, NHE-1 activity was
      lower in the melanomas than in other normal and malignant cell lines that were
      tested. Reverse transcription-PCR using primers specific for MCT-1, MCT-4, and
      NHE-1 showed that expression of none of these transporters was reproducibly up
      regulated at the level of transcription when cells were grown at pHe 6.7 instead
      of pHe 7.3. Ex vivo experiments using DB-1 human melanoma xenografts grown in
      severe combined immunodeficient mice found that MCT-1 and not NHE-1 was a major
      determinant of DB-1 tumor cell pHi. Taken together, the data indicate that MCTs
      are major determinants of pH regulation in melanoma. In contrast, keratinocytes
      and melanocytes under low pHe conditions relied on NHE-1. Inhibitors of MCTs thus
      have great potential to improve the effectiveness of chemotherapeutic drugs that
      work best at low pHi, such as alkylating agents and platinum-containing
      compounds, and they should be selective for cells in an acidic tumor bed. In most
      tissues, it is proposed that the NHE-1 could compensate for an inhibited MCT to
      prevent acidification, but in melanoma cells this did not occur. Therefore, MCT
      inhibitors may be particularly effective against malignant melanoma.

PMID- 12479223
TI  - Characterization of a new in vivo hollow fiber model for the study of progression
      of prostate cancer to androgen independence.
AB  - Research investigating the molecular events underlying progression of prostate
      cancer to androgen independence has been impeded by the lack of an appropriate in
      vivo model that yields "pure" populations of prostate cancer cells that are not
      contaminated with host cells. Here we characterize a new in vivo model that uses
      hollow fibers and allows for the retrieval of uncontaminated prostate cancer
      cells during various stages of endocrine progression to androgen independence in
      male immunocompromised mice. Prostate-specific antigen (PSA) gene expression,
      proliferation of cells, and histology were examined in these mice before and
      after castration. LNCaP cells seeded at a density of 1 x 10(7) cells/ml, or a
      total of approximately 4.8 x 10(6) cells/animal, provided measurable serum PSA
      levels that increased in intact (noncastrated) animals, decreased by 80% to a
      nadir after castration, and subsequently increased by 4 weeks after castration,
      indicating progression to androgen independence. In vivo proliferation of LNCaP
      cells inside the fibers continued in the presence of androgens and continued to
      increase, albeit at a slower rate, in the castrated animals. Histology of cells
      cultivated in hollow fibers demonstrated that initially the cells grew along the
      wall of the fiber and tended to stack up, forming layers and scaffold structures
      resembling a solid tumor. Fibers removed from castrated animals with elevated
      levels of serum PSA contained spheroids of cells that had detached from the fiber
      wall. The development of the LNCaP hollow fiber model described here provides a
      reproducible means of obtaining "pure" populations of LNCaP cells during
      different stages of progression to androgen independence for molecular analysis
      requiring RNA and protein extracts free of host cell contamination.

PMID- 12479224
TI  - The role of the cyclin-dependent kinase inhibitor p21 in apoptosis.
AB  - Cancer develops when the balance between cell proliferation and cell death is
      disrupted, and the ensuing aberrant proliferation leads to tumor growth. The
      cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and 
      independent mechanisms following stress, and induction of p21 may cause cell
      cycle arrest. As a proliferation inhibitor, p21 is poised to play an important
      role in preventing tumor development. This notion is supported by data indicating
      that p21-null mice are more prone to spontaneous and induced tumorigenesis, and
      p21 synergizes with other tumor suppressors to protect against tumor progression
      in mice. However, a number of recent studies have pointed out that in addition to
      being an inhibitor of cell proliferation, p21 acts as an inhibitor of apoptosis
      in a number of systems, and this may counteract its tumor-suppressive functions
      as a growth inhibitor. In the current review, we discuss the role of p21 in
      regulating cell death and the potential relevance of its expression in cancer.

PMID- 12479225
TI  - Tumor immunology and the Battle of Waterloo.

PMID- 12479226
TI  - Calcium and the failing heart.

PMID- 12479227
TI  - Expression of the L-type calcium channel in human heart failure.
AB  - L-type calcium channels play an important role in excitation-contraction
      coupling. After cardiomyocyte depolarization L-type calcium channels open and
      Ca2+ ions enter the cell. These small Ca2+ inward currents trigger calcium
      release from the junctional sarcoplasmic reticulum, a process called calcium
      induced calcium release. Subsequently, the cytosolic Ca2+ concentration rises
      rapidly to levels that initiate contraction. In heart failure calcium-induced
      calcium release is disturbed, and in this review we focus on the L-type calcium
      channel and its contribution to this defective excitation-contraction coupling.

PMID- 12479228
TI  - Voltage-gated Ca2+ currents in the human pathophysiologic heart: a review.
AB  - The L-type Ca2+ current (I(Ca-L)) plays a key role in the cardiac excitation
      contraction (E-C) coupling. Thus, it is a major target for many transmitters and
      hormones modulating cardiac function and, therefore, for pharmacological drugs to
      regulate inotropy. Ca2+ (and other) ion currents are commonly studied in animal
      tissues for practical reasons. Investigations in human cardiomyocytes started
      extensively only ten years ago with the development of patch-clamp techniques,
      enzymatic cell dissociation procedures, and surgical techniques. These studies
      have already provided valuable information concerning the nature, biophysics,
      pharmacology and regulation of human cardiac ionic currents in normal and
      diseased tissues. Interesting advances have been made to understand the role of
      I(Ca-L) in the development of chronic atrial fibrillation (AF). Alterations of
      single channel activity and regulation of macroscopic I(Ca-L) have also been
      found in heart failure (HF), ugh some of the data are divergent and puzzling. The
      T-type Ca2+ current (I(Ca-T)) has never been recorded in human cardiomyocytes.
      After a rapid overview of the basic properties of human cardiac Ca2+ currents, we
      focus on selected aspects of pathophysiology that are still unsolved.

PMID- 12479229
TI  - The cardiac sodium pump: structure and function.
AB  - Cardiac sodium pumps (Na,K-ATPase) influence cell calcium and contractility by
      generating the Na+ gradient driving Ca++ extrusion via the Na+/Ca++ exchanger
      (NCX), and are the receptors for cardiac glycosides such as digitalis which
      increases cardiac contractility by decreasing the Na+ gradient driving Ca++
      extrusion. There are multiple isoforms of the sodium pump expressed in the heart
      indicating the potential for isoform specific expression patterns, function and
      regulation. Regarding isoform expression patterns, human heart expresses alpha1,
      alpha2, alpha3, beta1 and a small amount of beta2. Within the human heart,
      alpha3, beta1 and NCX levels are 30-50% lower in atria than ventricles,
      associated with increased sensitivity to inotropic stimulation. Distribution at
      the cellular level has been studied in the rat heart where both alpha1 and alpha2
      are detected in the T-tubules along with NCX. Regarding isoform function, we
      focussed on human sodium pumps as cardiac glycoside receptors. A study of human
      sodium pump expressed alone (alpha1) or in combination (alpha1 with alpha2, or
      alpha1 with alpha2 and alpha3) in their native membranes aimed to determine
      whether different isoforms had distinct affinities for the cardiac glycoside
      ouabain by evaluating whether the ouabain binding data were best fit with a
      single site or two site model. The results indicated that the affinity of these
      human a subunit isoforms for ouabain is indistinguishable, and that changes in
      sensitivity to cardiac glycosides during heart failure are likely due to a
      decrease in the total number of pumps rather than a shift in expression to a more
      sensitive isoform. Regarding isoform regulation, we hypothesized that a primary
      decrease in cardiac Na,K-ATPase expression would be associated with a secondary
      increase in cardiac Na+/Ca++ exchanger expression as a homeostatic mechanism to
      blunt an increase in cell Ca++ stores (and visa versa with an increase in Na,K
      ATPase). Supporting the hypothesis: in a rat model of renovascular hypertension,
      or after treatment with amiodarone there are 50% decreases in alpha2 levels with
      35-40% increases in NCX levels in left ventricle, while in the transition from
      hypo- to hyperthyroid, there are increases in both alpha1 (2-fold) and alpha2 (8
      fold) with decreases in NCX (0.45-fold). In comparison, in transgenic mice
      overexpressing NCX, there was no secondary change in Na,K-ATPase alpha1 or alpha2
      levels indicating that primary changes in NCX do not drive secondary changes in
      Na,K-ATPase in the heart. This information provides the basis for addressing the
      significant gaps in our understanding of the physiologic, structural and
      homeostatic coupling between sodium pump isoforms and Na+/Ca++ exchangers in the
      heart and how coupling is related to control of cardiac contractility in health
      and disease.

PMID- 12479230
TI  - Sodium pump isoform expression in heart failure: implication for treatment.
AB  - In the human heart several isoforms of the sodium pump (Na,K-ATPase, the cardiac
      glycoside receptor) are expressed (alpha1beta1, alpha2beta1, and alpha3beta1).
      Their expression is regulated in a highly specific manner, so that there are
      region specific differences in the expression pattern. The isoform expression
      pattern is also known to be organ specific in many cases (e.g., kidney, skeletal
      muscle), suggesting isoform specific functions. In human heart, we have
      demonstrated that the isoform composition of the left ventricle is altered during
      heart failure in man and postulate a role of Na,K-ATPase isoforms in the
      compensatory mechanisms of this disease. When Na,K-ATPase isoforms were expressed
      separately in yeast cells, we found that the affinities of K and ouabain were
      lower for alpha2beta1 than for alpha1beta1 or alpha3beta1. In addition,
      alpha3beta1 had a lower turnover rate than alpha1beta1. Similar results were
      found in a study, where Na,K-ATPase isoforms were expressed in Xenopus oocytes.
      Thus, there is evidence for specific biochemical properties of the Na,K-ATPase
      isoforms. In heterozygous knock-out mice, in which either alpha1 or alpha2
      isoforms were selectively reduced, only the lower expression and activity of
      alpha2 led to a hypercontractile response as seen with cardiac glycosides.
      Therefore in mice, the effect of cardiac glycosides seems to be mediated
      specifically by alpha2. In summary, there is a tissue-specific regulation of Na,K
      ATPase isoform expression in humans, as well as a highly specific regulation of
      the isoforms during disease, e.g., heart failure. There is also evidence for
      specific biochemical properties of different isoforms of the human Na,K-ATPase as
      well as for a specific functional impact on cardiac contractility in mice.
      Therefore, the isoforms of human Na,K-ATPase are not exchangeable and targeting
      specific isoforms by drugs or gene therapy may promise therapeutic benefit in
      diseases like heart failure or atrial fibrillation.

PMID- 12479231
TI  - Sodium-calcium exchanger overexpression in the heart--insights from a transgenic
      mouse model.
AB  - Overexpression of the cardiac Na+-Ca2+ exchanger may play an important role in
      pathological conditions like hypertrophy and heart failure. To investigate the
      contribution of enhanced Na+-Ca2+ exchange to intracellular Ca2+ handling both
      under physiological as well as pathological conditions, we have generated a
      transgenic mouse overexpressing the canine cardiac Na+-Ca2+ exchanger. In
      transgenic mouse myocytes, the exchanger contributed significantly to the onset
      and decay of contraction and was able to compensate for impaired SR Ca2+
      handling. Under appropriate conditions enhanced Na+-Ca2+ exchange may support
      development of an intracellular Ca2+ transient and induce contraction. Na+-Ca2+
      exchange may be an important Ca2+ transport mechanism in myocardial dysfunction
      like heart failure, for which impaired SR function has been postulated.
      Nevertheless, studies on the transgenic mouse model also provide evidence that
      under pathological conditions such as ischemia/reperfusion, increased SR Ca2+
      content, or increased hemodynamic load, overexpressed Na+-Ca2+ exchange activity
      may compromise contractile performance and lead to hypertrophy and heart failure.

PMID- 12479232
TI  - Upregulated Na/Ca exchange is involved in both contractile dysfunction and
      arrhythmogenesis in heart failure.
AB  - Systolic heart failure (HF) is characterized by reduced systolic function and
      often by arrhythmias. We studied a rabbit model of HF (induced by combined aortic
      insufficiency and stenosis) which shows both contractile dysfunction and
      arrhythmogenesis. In this model we find an approximately 100% increase in Na/Ca
      exchange (NaCaX) expression at the level of mRNA, protein and function, but only
      a modest decrease in SR Ca-ATPase (approximately 24%, only detectable in cellular
      function). This combination results in a 40% reduction in SR Ca content in HF,
      which is sufficient to explain the 40% reduction in twitch Ca transients and 30
      38% decrease in contractile function in this HF model. When stimulated by
      isoproterenol the SR Ca load readily reaches the threshold for spontaneous SR Ca
      release (this threshold Ca load is unchanged in HF). This SR Ca release activates
      a transient inward current (I(ti)) carried exclusively by NaCaX. For a given SR
      Ca release there is greater I(ti) in HF (due to higher NaCaX). We also find a 49%
      decrease in the inward rectifier potassium current (I(K1)), which allows greater
      depolarization for a given I(ti). Thus, higher NaCaX and lower I(K1) greatly
      increase the likelihood that an SR Ca release-induced delayed afterdepolarization
      (DAD) will trigger an arrhythmogenic action potential. We conclude that NaCaX
      contributes in major ways to both contractile dysfunction (by reducing SR Ca) and
      increased propensity for triggered arrhythmias (by increasing I(ti) and DADs).

PMID- 12479233
TI  - Functional interplay between dual site phospholambam phosphorylation: insights
      from genetically altered mouse models.
AB  - Dephosphorylated phospholamban (PLB) is an inhibitor of the affinity of the
      sarcoplasmic reticulum (SR) Ca2+ pump (SERCA2) for Ca2+. Phosphorylation of PLB
      relieves its inhibitory effects on SERCA2, with subsequent acceleration of Ca2+
      transport into the SR lumen, which has been suggested to underlie the positive
      inotropic and lusitropic actions of beta-adrenergic agonists in the mammalian
      heart. PLB can be phosphorylated at Ser16 by cAMP-dependent protein kinase (PKA)
      and Thr17 by Ca2+-calmodulin-dependent protein kinase (CaMKII) during beta
      agonist stimulation. However, the interrelationship and relative contribution of
      dual site phosphorylation to the cardiac stimulatory effects are not clear. The
      recent availability of the PLB knockout mouse, in combination with mutagenesis
      and transgenic technologies, have provided excellent model systems for expression
      of each of the phosphorylation site-specific PLB mutants in the heart and
      elucidation of the functional interplay between PKA- and CaMKII-dependent
      pathways of PLB phosphorylation. Transgenic mice expressing similar levels of the
      wild-type, S16A, or T17A mutant PLB in the null background were generated and
      they were characterized in parallel. Our results indicate that 1) reinsertion of
      PLB into the knockout mouse heart reverses the hyperdynamic cardiac function
      associated with PLB deficiency, 2) phosphorylation of Ser16 in PLB is sufficient
      to mediate its maximal cardiac contractile responses to beta-adrenergic
      stimulation, and 3) Ser16 phosphorylation is a prerequisite for Thr17
      phosphorylation in vivo during beta-agonist stimulation, but Thr17 can be
      phosphorylated independently of Ser16 in vitro. Thus, these studies revealed
      novel insights into the interdependence and physiological significance of PKA
      (Ser16) and CaMKII (Thr17) pathways of PLB phosphorylation during beta-adrenergic
      stimulation in the mammalian heart.

PMID- 12479234
TI  - Regulation of the ryanodine receptor in heart failure.
AB  - In the heart, calcium (Ca2+) regulates muscle contraction and electrical signals
      that determine cardiac rhythm and cell growth pathways. The ryanodine receptor
      (RyR), an intracellular Ca2+ release channel, is required for excitation
      contraction coupling. The cardiac RyR has a large cytoplasmic structure that
      serves as a scaffold for modulatory proteins that regulate the function of the
      channel. Protein kinase A (PKA) phosphorylation of RyR2 dissociates the
      regulatory protein FKBP 12.6 and regulates the open probability of the channel.
      In failing hearts, RyR2 is PKA hyperphosphorylated resulting in defective channel
      function due to increased sensitivity to Ca2+ induced activation.

PMID- 12479235
TI  - Junctional sarcoplasmic reticulum transmembrane proteins in the heart.
AB  - The uptake of calcium into the sarcoplasmic reticulum (SR) and its subsequent
      release from the SR play a key role in the regulation of the cytosolic calcium
      concentration and the excitation-contraction coupling in cardiac muscle. While
      calcium uptake, catalyzed by the calcium-dependent ATPase, is thought to occur
      throughout the SR, the release of calcium is controlled by a complex of proteins
      localized to a distinct region, the junctional SR. This complex consists of the
      calcium release channel or ryanodine receptor (RyR), the high capacity calcium
      binding protein calsequestrin located in the lumen of the junctional SR, and the
      junctional SR transmembrane proteins triadin 1 and junctin which are hypothesized
      to anchor calsequestrin to the RyR. Transgenic mice with cardiac-specific
      overexpression of triadin 1 or junctin show distinct cardiac phenotypes with
      altered cellular and subcellular morphology, changes in contractile properties
      and/or in the expression of junctional SR proteins suggesting that these
      junctional sarcoplasmic reticulum transmembrane proteins are of functional
      relevance for the regulation of calcium release in the heart.

PMID- 12479236
TI  - The small EF-hand Ca2+ binding protein S100A1 increases contractility and Ca2+
      cycling in rat cardiac myocytes.
AB  - S100A1 is an interesting Ca2+ binding protein with respect to muscle physiology
      as it is preferentially expressed in cardiac muscle and colocalizes with the
      sarcolemmal and the sarcoplasmic reticulum membranes as well as with the
      sarcomere. It is therefore conceivable that S100A1 may play a specific role in
      the regulation of cardiac Ca2+ homeostasis and contractility. We therefore
      investigated the impact of adenoviral S100A1 overexpression on fractional
      shortening (FS%) and systolic Ca2+ transients in adult rat cardiomyocytes as well
      as of S100A1 protein on SERCA activity in skinned cell preparation. In our
      setting S100A1 gene transfer increased FS% by 55%, systolic Ca2+ amplitudes by
      62%, while S100A1 protein increased SERCA activity by 28%. Importantly, the gain
      in systolic Ca2+ supply was not only seen on basal conditions but also with
      isoproterenol-stimulated Ca2+ cycling. Thus, S100A1 enhances cardiac
      contractility by increasing intracellular Ca2+ fluxes at least in part due to a
      modulation of SERCA. Since earlier observations demonstrated S100A1 protein
      levels to be increased in compensatory hypertrophy and significantly
      downregulated in end stage heart failure, these functional data suggest that
      S100A1 is a novel determinant of cardiac function whose expression levels are
      causally related to the prevailing contractile state of the heart.

PMID- 12479237
TI  - Sarcoplasmic reticulum Ca2+ load in human heart failure.
AB  - Excitation-contraction coupling and intracellular Ca2+ homeostasis are altered in
      heart failure. We tested the hypothesis that these changes are related to
      disturbed Ca2+ handling of the sarcoplasmic reticulum (SR). Isolated,
      electrically stimulated trabeculae were obtained from end-stage failing (NYHA IV)
      and nonfailing human hearts. Isometric twitch tension, intracellular Ca2+
      transients (aequorin method) and SR Ca2+ content (rapid cooling contractures)
      were assessed under basal conditions (1 Hz, 37 degrees C) as well as after
      stepwise increasing rest intervals from 2-240 s (post-rest contractions). Protein
      expression of SERCA2a and phospholamban (Western blot) was assessed in a subset
      of failing trabeculae. In addition, the effects of SERCA1 overexpression on
      contractile function of isolated myocytes was tested. On average, post-rest
      twitch tension continuously increased with increasing rest intervals in
      nonfailing, but declined with rest intervals longer than 15 s in failing
      myocardium. The rest-dependent contractile changes were accompanied by parallel
      changes in intracellular Ca2+ transients. Failing trabeculae (n = 40) were
      grouped (group A: post-rest potentiation (force of contraction > pre-rest twitch
      force) after 120 s rest interval; group B: post-rest decay (force of contraction
      < pre-rest twitch force) after 120 s rest interval), and post-rest contractile
      function was related to SERCA2a and PLB expression. While PLB protein expression
      was not different, SERCA2a protein expression as well as SERCA2a/PLB ratio was
      significantly higher in group A vs. group B. Transfection of SERCA1 increased
      shortening amplitude and enhanced relaxation kinetics in failing human myocytes.
      In conclusion, SR Ca2+ handling is severely altered in human heart failure.
      Reduced SR Ca2+ release is due to diminished SR Ca2+ content directly related to
      a depressed expression of SERCA2a protein. Enhancing SERCA function or expression
      may improve SR Ca2+ handling in failing human myocardium.

PMID- 12479238
TI  - Modulation of SERCA: implications for the failing human heart.
AB  - Human heart failure is characterized by distinct alterations in the intracellular
      homeostasis and key regulators of the sarcoplasmic reticulum Ca2+ sequestration
      mechanisms. Systolic peak Ca2+ is reduced, diastolic Ca2+ levels are increased
      and diastolic Ca2+ decay is prolonged. Recently specific changes in the
      expression, function and modulation of SR Ca2+-ATPase (SERCA) have been
      elucidated. As such, in a variety of studies SERCA expression appeared to be
      decreased in the failing human heart, although these findings have been discussed
      controversially depending on the studied tissue, especially with respect to the
      non-failing samples and regional variation in the obtained samples. However,
      consistent findings of a diminished Ca2+ dependent SERCA activation were found.
      Increasing evidence has been provided that one of the underlying mechanisms for a
      decreased activation of SERCA is its altered regulation. With respect to this,
      the modulations through phospholamban and Ca2+-dependent protein kinase II (CaMK
      II) play a detrimental role in regulating SERCA function. Phospholamban
      phosphorylation of SERCA at the serine-16 and threonine-17 site is diminished in
      human heart failure resulting in decreases in the apparent affinity for Ca2+ of
      the SR Ca2+ uptake rates. In contrast, activation of CaMK II leads to an
      increased maximal velocity of SR Ca2+ sequestration that may enhance SR Ca2+
      load. Additional regulation has been recently elucidated by changes in the
      apparent coupling ratio of Ca2+ transported per ATP hydrolysed. This review
      summarizes recent advances in the understanding how SERCA is modulated under
      physiological and pathophysiological conditions.

PMID- 12479239
TI  - Ca2+-handling in heart failure--a review focusing on Ca2+ sparks.
AB  - [Ca2+]i-transients have been shown to be altered in isolated ventricular myocytes
      from terminally failing human myocardium. It has been demonstrated that one
      reason for this alteration is a reduction in the Ca2+ content of the sarcoplasmic
      reticulum (SR). Further investigations were done to investigate, whether there
      may be an additional defect of the Ca2+-release mechanisms from the SR. These
      release mechanisms were investigated through the recording of Ca2+ sparks in
      single human myocytes. In cardiac myocytes, Ca2+ sparks are elementary units of
      Ca2+ release, which occur spontaneously, or which are triggered by Ca2+ influx
      through L-type Ca2+-channels (Ca2+-induced Ca2+ release). Ca2+ sparks have been
      investigated in various animal models of cardiac hypertrophy and cardiac failure
      and results were conflicting. Discrepancies may be explained by different species
      and also by the mechanisms underlying hypertrophy and heart failure. This review
      summarizes our current knowledge on Ca2+ sparks in heart failure.

PMID- 12479240
TI  - PDE3 cyclic nucleotide phosphodiesterases and the compartmentation of cyclic
      nucleotide-mediated signalling in cardiac myocytes.
AB  - PDE3 cyclic nucleotide phosphodiesterase inhibitors raise cAMP and cGMP content
      in cardiac and vascular myocytes. Their administration to patients with dilated
      cardiomyopathy leads to improvements in hemodynamic parameters in the short term
      but reduces survival with chronic administration. The reasons for this 'biphasic'
      response have not been elucidated, but it is likely that beneficial and harmful
      effects of PDE3 inhibition reflect the phosphorylation of different substrates of
      cAMP- and cGMP-dependent protein kinases (PK-A and PK-G). It is now apparent that
      cardiac and vascular myocytes contain several isoforms of PDE3 that differ in
      their intracellular distribution and thus regulate cAMP and cGMP levels in
      different subcellular compartments. These isoforms also differ in their
      regulation by extracellular signals that may be important in the pathophysiology
      of dilated cardiomyopathy. An intriguing possibility is that the beneficial and
      harmful effects of PDE3 inhibition may be attributable to the inhibition of
      different isoforms of these enzymes.

PMID- 12479241
TI  - Altered phosphatase activity in heart failure, influence on Ca2+ movement.
AB  - Many cardiac proteins undergo reversible phosphorylation. While the protein
      kinases which bring about phosphorylations are well studied, less effort has been
      put into the dephosphorylating phosphatases (for an earlier review compare 14).
      An important event in the heart, which is controlled by phosphorylation, is the
      uptake of Ca2+ by the sarcoplasmic reticulum (SR). This process is brought about
      by a SR Ca2+ ATPase (SERCA) and accounts for relaxation. The amount of Ca2+
      pumped by SERCA is enhanced when phospholamban (PLB), an intrinsic protein of the
      SR, is phosphorylated and is diminished when PLB is dephosphorylated. PLB is
      dephosphorylated by protein phosphatases (PPs) like PP1. As the activity of PP1
      is enhanced in heart failure, subsequent dephosphorylation by of, e.g., PLB may
      explain the impaired relaxation of the human heart. Thus, PPs may play an
      important role in the etiology and/or symptoms of heart failure.

PMID- 12479242
TI  - Hypertrophic phenotype of cardiac calcium/calmodulin-dependent protein kinase II
      is reversed by angiotensin converting enzyme inhibition.
AB  - Calcium-dependent mechanisms and the renin angiotensin system (RAS) are
      critically involved in the hypertrophic growth of the myocardium. The
      calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator
      in calcium signaling and modulates calcium handling and growth mechanisms in
      cardiomyocytes. Here we present data on expression of cardiac isoforms of
      CaMKIIdelta, the dominant form in the myocardium, in compensatory hypertrophy of
      stroke-prone spontaneously hypertensive rats (SHRSP) compared to the normotensive
      Wistar-Kyoto (WKY) control strain. Cardiac hypertrophy in SHRSP was documented by
      an increased heart weight/body weight ratio (HW/BW) of 31% (p < 0.05) and a more
      than six-fold elevated atrial natriuretic factor (ANF) transcript level (p <
      0.05). Compensatory hypertrophic growth in SHRSP produced a specific phenotype of
      CaMKIIdelta isoforms characterized by increased transcript levels of the
      embryonic/neonatal isoform delta4 (48%, p < 0.05) and the isoform delta9 (31%, p
      < 0.05) with no changes in delta2 and delta3. Inhibition of angiotensin
      converting enzyme (ACE) by cilazapril completely regressed myocardial
      hypertrophy, normalized ANF transcript levels, and restored the normal phenotype
      of CaMKIIdelta by reducing transcripts for delta4 and delta9 to levels present in
      WKY controls. Our data suggest the importance of specific changes in the CaMKII
      isoform composition for growth processes in the myocardium.

PMID- 12479243
TI  - Molecular mechanisms of cardiac myofilament activation: modulation by pH and a
      troponin T mutant R92Q.
AB  - Activation of cardiac myofilaments is a complex process involving steric,
      allosteric, and cooperative mechanisms. The complexity of the protein-protein
      interactions that result in the rise and fall of tension in the heartbeat provide
      many points that may be modified by various control mechanisms. These include
      modulation by the sarcomere length, covalent modulation by protein
      phosphorylation and non-covalent modulation by the chemical environment
      surrounding the myofilaments. We focus here on effects of pH change in the
      context of one of the mutations in cardiac troponin T (R92Q) that causes familial
      hypertrophic cardiomyopathy (FHC). We tested whether this change in charge would
      manifest itself functionally by a difference in the pCa-force relations of
      skinned fiber bundles activated at pH values of 6.5, 7.0 and 7.5. Fiber bundles
      containing the cTnT-R92Q mutant demonstrated an increase in sensitivity to Ca2+
      at all three pH values. However, the relative magnitude of the increase in Ca2+
      sensitivity induced by the mutant cTnT increased as the pH was decreased from pH
      7.5 to pH 7.0 and to pH 6.5. Maximum force generated by the myofilaments fell as
      pH was lowered over this range, but the percent fall in maximum force was the
      same for fiber bundles containing wild-type and mutant cTnT. Our results indicate
      that ischemia that may be associated with FHC may exacerbate the functional
      changes induced by the cTnT mutation.

PMID- 12479244
TI  - Increased Ca2+-sensitivity of myofibrillar tension in heart failure and its
      functional implication.
AB  - In human failing myocardium, an increased Ca2+-sensitivity of myofilament tension
      development has been described in Triton X skinned cardiac myocytes compared to
      cardiomyocytes obtained from non-failing human donor hearts. The present study
      aimed to investigate whether there are functional implications of the increased
      Ca2+-sensitivity in heart failure and whether alterations of myofilament function
      are already obvious at earlier stages of heart failure, such as in cardiac
      hypertrophy or whether alterations of the intracellular Ca2+-homeostasis are able
      to induce alterations in myofilament function. Ca2+-activated tension development
      was measured in Triton X-skinned fibers from human failing and non-failing
      myocardium. Ca2+-sensitivity of myofilament tension development was significantly
      shifted to the left in human failing myocardium. Plots of diastolic free Ca2+
      versus diastolic tension development showed that in a range of similar diastolic
      Ca2+-concentrations, diastolic tension was significantly enhanced in the failing
      hearts. The Ca2+/tension relationship was shifted to the right in Triton X
      skinned fiber preparations from transgenic renin overexpressing rats
      (TG(mREN2)27), shown to have concentric hypertrophy. In addition, the
      Ca2+/tension relationship was unchanged in phospholamban knock-out mice with an
      increased systolic Ca2+ (and enhanced diastolic Ca2+-load). It is concluded that
      the increased Ca2+-sensitivity of myofilament tension observed in single
      cardiomyocytes from failing human myocardium may be a phenomenon also present in
      multicellular preparations and may contribute to the diastolic dysfunction
      observed in human heart failure. Alterations of myofilament function occur at
      very early stages of heart failure and may be species dependent, or dependent on
      intracellular free Ca2+-levels.

PMID- 12479245
TI  - Calcium sensitivity of force in human ventricular cardiomyocytes from donor and
      failing hearts.
AB  - In failing human myocardium changes occur, in particular, in isoform composition
      and phosphorylation level of the troponin T (TnT) and troponin I (TnI) subunits
      of the actin filament and the myosin light chains (MLC-1 and -2), but it is
      unclear to what extent they influence cardiac performance. This overview
      concentrates on the relation between contractile function, contractile protein
      composition and phosphorylation levels in small biopsies from control (donor)
      hearts, from biopsies obtained during open heart surgery (NYHA Class I-IV) and
      from end-stage failing (explanted, NYHA class IV) hearts. Furthermore, attention
      is paid to the effect of the catalytic subunit of protein kinase A on isometric
      force development in single Triton-skinned human cardiomyocytes isolated from
      donor and end-stage failing left ventricular myocardium at different resting
      sarcomere lengths. A reduction in sarcomere length from 2.2 to 1.8 microm caused
      reductions in maximum isometric force by approximately 35% both in donor and in
      failing cardiomyocytes. The midpoints of the calcium sensitivity curves (pCa50)
      of donor and end-stage failing hearts differed markedly at all sarcomere lengths
      (mean delta pCa50 = 0.22). Our findings indicate that 1) TnI phosphorylation
      contributes to the differences in calcium sensitivity between donor and end-stage
      failing hearts, 2) human ventricular myocardium is heterogeneous with respect of
      the phosphorylation of TnT, MLC-2 and the isoform distribution of MLC-1 and MLC
      2, and 3) the Frank-Starling mechanism is preserved in end-stage failing
      myocardium.

PMID- 12479246
TI  - Isometric force kinetics upon rapid activation and relaxation of mouse, guinea
      pig and human heart muscle studied on the subcellular myofibrillar level.
AB  - The kinetics of force development and relaxation upon rapid application and
      removal of Ca2+ was measured in bundles of few myofibrils isolated from triton X
      100 skinned left ventricular trabeculae of mice (M), guinea pigs (G) and humans
      (H). Upon rapidly switching from relaxing solution (pCa 7.5) to activating
      solution (pCa 4.5) at 10 degrees C, force rose by a single exponential with a
      rate constant k(act) of 5.2 s(-1) (M), 1.7 s(-1) (G) and 0.3 s(-1) (H) to a
      plateau of 0.14 microN/microm2 (M), 0.16 microN/microm2 (G) and 0.15
      microN/microm2 (H). A rapid release followed by a rapid restretch to the original
      length applied during steady-state Ca2+ activation at pCa 4.5 induced an
      exponential force redevelopment with a rate constant k(redev) that was
      indistinguishable from k(act), indicating that k(act) is limited by cross-bridge
      turnover kinetics rather than by the Ca2+-induced activation of the regulatory
      system. Upon rapidly switching from pCa 4.5 to pCa 7.5, force decayed in a
      pronounced biphasic manner. Thus a slow initial, almost linear decay with a rate
      constant k(lin) of 1.8 s(-1) (M), 0.6 s(-1) (G) and 0.15 s(-1) (H) and a duration
      t(lin) of 0.06 s (M), 0.11 s (G) and 0.3 s (H) was followed by a rapid
      exponential decay with a rate constant k(rel) of 18 s(-1) (M), 11 s(-1) (G) and
      4.6 s(-1) (H). The pronounced biphasic shapes of the force decays determined here
      for the first time in cardiac myofibrils differs from the force decays that had
      been reported for multicellular skinned trabeculae in which relaxation was
      induced by rapid removal of Ca2+ by flash photolysis of caged Ca2+ chelators. In
      the skinned trabeculae, no pronounced initial slow phase was observed. The force
      decays shown here are much more similar to those reported for single skeletal
      myofibrils. The kinetics of isometric relaxation of skinned trabeculae (i.e.,
      multicellular preparations), therefore, do not reflect the kinetics of force
      relaxation at the cardiac myofibrillar level.

PMID- 12479247
TI  - Targeting Ca2+ cycling proteins and the action potential in heart failure by gene
      transfer.
AB  - Cardiomyocytes isolated from failing human hearts are characterized by
      contractile dysfunction including prolonged relaxation, reduced systolic force
      and elevated diastolic force. These contractile abnormalities are paralleled by
      abnormal Ca2+ homeostasis such as reduced sarcoplasmic reticulum (SR) Ca2+
      release, elevated diastolic Ca2+ and reduced rate of Ca2+ removal. In addition,
      failing human myocardium is characterized by a frequency-dependent decrease in
      systolic force and Ca2+ as opposed to normal myocardium where an increase in
      pacing rate results in potentiation of contractility and an increase in SR Ca2+
      release. In the failing heart, the decrease in SR Ca2+ load has been linked to a
      decrease in SR Ca2+ ATPase (SERCA2a) function. We have recently shown that
      overexpression of SERCA2a by adenoviral gene transfer restores contractile
      function in cardiac myocytes from failing human hearts. In addition, we have
      shown that overexpression of SERCA2a in a model of pressure-overload hypertrophy
      in transition to failure improves contractile function and reserve in these
      animals. We are currently exploring the effect of long-term expression of SERCA2a
      in failing animals along with the energy cost of SERCA2a expression using NMR
      methods. We are also using a different strategy to improve SR Ca2+ ATPase
      activity which involves decreasing the expression of phospholamban by antisense
      strategies to enhance SR Ca2+ ATPase activity. The Na/Ca exchanger is also being
      targeted to enhance calcium removal in failing hearts. Action potential
      prolongation is attributed to reductions in transient outward current (Ito)
      density in human heart failure. This prolongation can alter contractility but can
      also cause afterdepolarization. Using gene transfer of various K channels
      responsible for Ito, we are investigating the molecular and the ionic basis of
      action potential prolongation in cardiac hypertrophy and failure and we are
      examining how intracellular calcium handling changes in response to alterations
      in action potential duration. Gene transfer, which serves initially as an
      experimental tool, may provide a novel therapeutic approach.

PMID- 12479248
TI  - 3D engineered heart tissue for replacement therapy.
AB  - Myocardial infarction results in irreversible loss of cardiac myocytes and heart
      failure. Tissue or cell grafting offers the prospect of reintroducing contractile
      elements into impaired hearts. However, implanted cardiac myocytes remain
      physically and electrically isolated from the viable myocardium. Accordingly, the
      proof of increased contractile function attributable specifically to cell
      grafting procedures is sparse. Over the last few years, we have developed a new
      method to generate three-dimensional engineered heart tissue (EHTs) in vitro from
      embryonic chick or neonatal rat cardiac myocytes. EHTs comprise functional and
      morphological properties of intact myocardium. We hypothesized that EHTs,
      preformed in vitro into suitable geometric forms, represent appropriate graft
      material for in vivo tissue repair with advantages over isolated cells. Herein we
      describe initial results from implantation experiments of EHTs in the peritoneum
      of Fisher 344 rats. EHTs survived for at least 14 days, maintained a network of
      differentiated cardiac myocytes, and were strongly vascularized. Thus, the
      present study provides the first evidence for the general feasibility of EHTs as
      material for a novel tissue replacement approach.

PMID- 12479249
TI  - Regulation of voltage-dependent Ca2+ channels in the early developing heart: role
      of beta1 integrins.
AB  - In contrast to adult ventricular cardiomyocytes the developmentally early stage
      cardiomyocytes show a suppression of the basal voltage-dependent calcium channels
      (DCC L-type Ca2+ channels, I(Ca)) by carbachol (CCh). This effect is mediated by
      the endothelial NO-synthase (NOS III). In contrast late stage and adult
      cardiomyocytes a direct coupling of the muscarinic receptor to the adenylyl
      cyclase. Thus, NO may function as an early signal transduction molecule during
      development. This review elucidates the role of beta1-integrins in mediating
      signal transduction between muscarinic receptors and coupled downstream target
      proteins such as ion channels. The key finding is that in embryonic stem cell
      derived cardiomyocytes deficient of beta1-integrins, the modulation of L-type
      Ca2+ channels via the M2 receptor is absent. Experiments indicate that this
      selective signaling defect occurs at the G-protein level. This suggests a novel
      critical role for integrins in membrane delimited signal transduction processes.

PMID- 12479250
TI  - Clinical pharmacology of opioids for pain.
AB  - The pharmacological effects of the opioid analgesics are derived from their
      complex interactions with three opioid receptor types (mu, delta, and kappa;
      morphine is an agonist at the mu opioid receptor). These receptors are found in
      the periphery, at presynaptic and postsynaptic sites in the spinal cord dorsal
      horn, and in the brain stem, thalamus, and cortex, in what constitutes the
      ascending pain transmission system, as well as structures that comprise a
      descending inhibitory system that modulates pain at the level of the spinal cord.
      The cellular effects of opioids include a decrease in presynaptic transmitter
      release, hyperpolarization of postsynaptic elements, and disinhibition. The
      endogenous opioid peptides are part of an endogenous pain modulatory system. A
      number of opioids are available for clinical use, including morphine,
      hydromorphone, levorphanol, oxymorphone, methadone, meperidine, oxycodone, and
      fentanyl, and their advantages and disadvantages for the management of pain are
      discussed. An understanding of the pharmacokinetic properties, as well as issues
      related to opioid rotation, tolerance, dependence, and addiction are essential
      aspects of the clinical pharmacology of opioids for pain.

PMID- 12479251
TI  - Assessment and treatment of comorbid psychiatric disorders in opioid-dependent
      patients.
AB  - The purpose of this article is to provide a review of the prevalence, assessment,
      and treatment of common psychiatric disorders found among patients with opioid
      dependence. Dependence on opioids can include both persons who are physically
      dependent on opioids and persons who fulfill the criteria for a syndrome of
      opioid dependence, such as that found in the Diagnostic and Statistical Manual,
      fourth edition (DSM-IV). The latter grouping of persons typically abuse illicit
      opioids, and prevalence of comorbid conditions and approaches in diagnosis and
      treatment have been studied in these patients. High rates of other psychiatric
      disorders--both other substance-use disorders as well as non-substance-use
      psychiatric disorders--have been reported. The most common non-substance-use
      psychiatric disorders are depressive, anxiety, and personality disorders. When
      evaluating and planning treatment of opioid-dependent patients with concurrent
      psychiatric symptoms, it is important to determine if such symptoms are
      independent of the substance use or substance induced. In the former case,
      treatment should follow routine clinical practice, whereas in the latter case,
      treatment stability in substance use should be the first therapeutic step. The
      presence of a pain condition can further complicate assessment and treatment, as
      either pain itself or treatments used for pain may produce symptoms that overlap
      with psychiatric disorders.

PMID- 12479252
TI  - Assessment for addiction in pain-treatment settings.
AB  - The identification of the disease of addiction is important to safe and effective
      clinical management of pain in persons with addictive disorders. The disease of
      addiction affects approximately 10% of the general population, and its prevalence
      may be higher in subpopulations of patients with pain. The presence of active
      addiction may facilitate the experience of pain. Both active and recovering
      addiction may complicate the use of medications, such as opioids, important to
      the management of pain. There is, further, persistent misunderstanding among
      health care providers, regulators, and the general population regarding the
      nature and manifestations of addiction that may result in undertreatment of pain
      and stigmatization of patients using opioids for pain control. The author seeks
      to clarify understanding of addiction, to underscore the importance of
      identifying addiction in the context of pain treatment, and to provide a rational
      approach to assessment for addiction in patients with pain. Current scientific
      understanding of addiction as a chronic illness is briefly reviewed. Recent
      definitions related to addiction are presented. The impact of addictive disorders
      on pain and pain treatment are explored. The roles of medical interview, physical
      examination, laboratory studies, and standard addiction screening tools in
      assessing for addiction are outlined. Differential considerations in
      distinguishing therapeutic use of opioids for analgesia from addictive or other
      nontherapeutic use of opioids are discussed. In summary, the article provides
      salient background and a detailed approach to assessment for addictive disorders
      in the context of pain treatment.

PMID- 12479253
TI  - Assessment of efficacy of long-term opioid therapy in pain patients with
      substance abuse potential.
AB  - Clinical experience supports the notion that opioids can be used successfully to
      treat many chronic pain conditions. Unfortunately, few controlled trials have
      assessed which individuals benefit from long-term opioid therapy, and there is
      concern about the use of long-term opioid therapy in individuals with a substance
      abuse history. This article contains three sections relevant to the assessment of
      individuals with chronic pain and a substance-abuse history who are receiving
      long-term opioid therapy. The first reviews the literature on opioid therapy,
      with a critique of biologic and environmental susceptibility factors for
      addiction. The second briefly reviews uncontrolled and controlled trials of
      opioid therapy for pain. The third reviews areas critical in assessing treatment
      efficacy and substance abuse in patients with chronic pain, both in terms of
      documentation of past behaviors and as a measure of outcome of opioid therapy.
      Potential guidelines for use of opioids in patients with chronic noncancer pain
      are outlined. Finally, questions are posed for future investigations of the
      efficacy of opioid therapy for patients with chronic pain and a substance-abuse
      history.

PMID- 12479254
TI  - Abuse and addiction issues in medically ill patients with pain: attempts at
      clarification of terms and empirical study.
AB  - The assessment of addiction-related outcomes is crucial to the management of
      chronic pain with opioid drugs in all patients. Pain management for patients who
      have concomitant drug abuse or addiction issues is a particularly complex task
      involving a need for a common nomenclature as well as empirically derived data to
      support management strategies during treatment regimens. Complicating the issue
      is the notion of pseudoaddiction, which is an abuse of medications driven by
      unrelieved pain that appears on the surface to be very similar to the behavior
      patterns of addicts. For proper adherence to medical therapy and safety during
      treatment, it is necessary to address and manage substance abuse-related
      behaviors. Aberrant drug-taking behavior presents many threats to the integrity
      of pain treatment. Unfortunately, the current state of the art still has a long
      way to go before clear guidelines for treatment and management can emerge. What
      is ultimately needed is a broad-based spectrum of research that highlights the
      epidemiology of drug-taking behaviors for different medical illnesses ranging
      from cancer to back pain. This article focuses on some of these issues as well as
      recounting attempts by our research group to address these issues systematically
      in hopes of shedding light on the nature of abuse issues in the medically ill.
      Although advances have been made, there is a definite need for large-scale
      studies that address the issues of identification and treatment of aberrant
      behavior in medically ill patients in the effort to provide the best possible
      outcomes for patients with chronic pain.

PMID- 12479255
TI  - Abuse liability in opioid therapy for pain treatment in patients with an
      addiction history.
AB  - Patients may present to physicians with complaints of acute or chronic pain. Some
      of these patients will have a history of addiction to drugs or alcohol, and a few
      will have active addiction. Controlled-substance prescriptions, especially opioid
      pain medications, can be very beneficial for treatment of pain in patients. There
      are clear differences between physical dependence on medication, active
      addiction, addiction in remission, and pseudoaddiction. A search of the medical
      literature revealed different rates of addiction in patients with chronic pain
      because different criteria were used to define addiction and the types of chronic
      pain. It appears that rates of addiction in patient populations with chronic pain
      are no different than rates of addiction in the general population, according to
      some recent studies. "Drug-seeking behavior" may be seen with either active
      addiction or pseudoaddiction. A way to distinguish between these conditions is by
      giving the patient more pain medication and observing the patient's pattern of
      behavior. Some patients may be at higher risk to abuse prescription opioids, and
      some types of drug-seeking behavior may be more predictive of active addiction
      than pseudoaddiction. General guidelines can improve physicians' comfort level in
      prescribing opioids for patients with chronic pain, even those with a history of
      addiction. These include using a medication agreement or contract, setting
      appropriate goals with the patient, giving appropriate amounts of pain
      medication, monitoring with drug screens and pill counts, and documenting the
      case carefully. Even patients with a history of addiction can benefit from opioid
      pain medications if the patients are monitored appropriately.

PMID- 12479256
TI  - The opioid contract.
AB  - Opioid contracts are widely used but not well studied. Despite the widespread use
      of the opioid contract or agreement, there is no standard approach. Some studies
      have found both considerable variability between opioid contracts as well as
      consistent core themes. While an opioid contract may be an appealing tool for
      obtaining informed consent, providing education, or otherwise overcoming some of
      the problems associated with chronic opioid therapy for noncancer pain, its
      efficacy is not well established. This article will consider many of the
      significant factors that impact clinicians and patients using a contract or
      agreement for chronic opioid therapy.

PMID- 12479257
TI  - Role of urine toxicology testing in the management of chronic opioid therapy.
AB  - Recognition is growing that self-report of drug use, prescribed or otherwise,
      among patients with chronic pain treated with opioids is often unreliable. This
      fact is well known to the addiction management community. Patients may
      inaccurately report use of prescribed medications, fail to report use of
      nonprescribed medications or medications prescribed by other physicians, or fail
      to report use of illicit drugs. Although there are yet no accepted diagnostic
      criteria for addiction or other forms of medication misuse in the patient with
      chronic pain, most clinicians would agree that awareness of a patient's
      inappropriate use of nonprescribed medications or illicit drugs is relevant to
      proper patient management. The use of external sources of information, therefore,
      such as testing of biologic material (e.g., urine), interviews with spouses,
      review of medical records, or input from prescription monitoring programs, may
      improve patient management. Of these methods, urine toxicology testing has by far
      the largest experience. Urine toxicology testing may reveal the presence of
      illicit drugs, such as heroin or cocaine, or controlled substances not prescribed
      by the physician ordering the test (e.g., hydromorphone in a patient prescribed
      oxycodone). The authors review the use of urine toxicology testing in monitoring
      patients with chronic pain, including laboratory aspects. They also present
      evidence from recent studies that suggests that monitoring the behavior alone of
      patients on chronic opioid treatment will fail to detect potential problems
      revealed by urine toxicology testing. The authors conclude that, although further
      research is urgently needed, at this time it is appropriate to conduct routine
      urine toxicology testing in patients with chronic pain treated with opioids.

PMID- 12479258
TI  - Effects of intermediate- and long-term use of opioids on cognition in patients
      with chronic pain.
AB  - The authors review research on the intermediate- and long-term effects of taking
      opioid medication on cognitive functioning in patients with chronic cancer and
      noncancer pain. Opioids seem to be more likely to worsen cognitive performance
      during the first few days of use and during the first few hours after a given
      dose, particularly on timed performance in psychomotor tasks. Results have been
      inconsistent regarding what decrements in cognitive performance are observed when
      patients with chronic pain who have been using opioids for more than three days
      are compared with healthy volunteers. Relatively few differences have been found
      when cognitive performance in these patients is compared with their performance
      before taking opioids, or with the performance of a comparable pain population
      not taking opioids. Major unresolved questions remain regarding such important
      issues as effects of different types of opioids, dose effects, interactions with
      other medications, and subject variables.

PMID- 12479259
TI  - U.S. policies relevant to the prescribing of opioid analgesics for the treatment
      of pain in patients with addictive disease.
AB  - Undertreatment of pain is likely to occur among patients with active addiction or
      those who have a history of addiction. One of the factors that can contribute to
      the inadequate treatment of pain in this patient population is the presence of
      laws and regulations that, when implemented, could impede effective pain
      management. This article describes the current status of federal and state policy
      governing the medical use of opioid analgesics for pain management with patients
      who have an addictive disease in the U.S. Three types of policy barriers are
      discussed: (1) those that can affect pain management in any patient, (2) those
      that can lead to patients in pain being classified as "addicts," and (3) those
      that relate specifically to patients with a high risk of addiction. Also
      presented are recent policy initiatives that can improve the use of controlled
      substances to treat pain and, thus, ultimately enhance pain relief for patients
      with an addictive disease.

PMID- 12479260
TI  - Ethical perspectives: opioid treatment of chronic pain in the context of
      addiction.
AB  - The authors apply eight ethical domains of analysis to the question of treatment
      of chronic pain with opioids in patients with histories of substance use
      disorders: autonomy, nonmaleficence, beneficence, justice, medical condition,
      patient preference, quality of life, and consideration of specific individual or
      sociocultural issues. These eight domains are drawn from principle-based and case
      based ethical perspectives. The domains are developed by review of available
      literature and through application to a specific presented case. Factors that
      interfere with rational, ethical decision-making regarding opioid pain management
      are identified. Chronic pain and substance use disorders share a history of
      stigmatization, underdiagnosis, and undertreatment. Using the presented case as a
      point of departure, the authors discuss principles for prescription of opioids
      for treatment of chronic noncancer pain in the setting of history of substance
      use disorders.

PMID- 12479261
TI  - Pregnancy and HIV infection: A european consensus on management.

PMID- 12479262
TI  - Characterization of overlapping XAGE-1 transcripts encoding a cancer testis
      antigen expressed in lung, breast, and other types of cancers.
AB  - Cancer testis (CT) antigens have an expression pattern that is predominantly
      restricted to testis in normal tissues, yet they are expressed in many different
      histological types of cancers. One previously described member of the CT antigen
      family, XAGE-1, was shown to be expressed in Ewing's sarcomas and
      rhabdomyosarcomas. Here we show that XAGE-1 is also expressed in breast cancer,
      prostate cancer, and different types of lung cancers, including lung squamous
      cell carcinoma, adenocarcinoma, small cell lung carcinoma, and non-small cell
      lung carcinoma. In addition, XAGE-1 mRNA was present in ovarian cancer, melanoma,
      glioblastoma, T-cell lymphoma, chronic myelogenous leukemia, and histiocytic
      lymphoma cell lines. We also characterized the XAGE-1 transcript by primer
      extension analysis and found that transcription of the XAGE-1 gene is initiated
      from two distinct start sites, resulting in two overlapping transcripts, XAGE-1a
      and XAGE-1b. XAGE-1a contains two in-frame ATG translational start codons;
      whereas XAGE-1b initiates downstream of the first ATG start codon. Our results
      suggest that XAGE-1b is the dominant transcript, and that translation begins with
      the second ATG start codon, producing a 9 kDa protein. Because XAGE-1 is
      expressed in such a diverse range of cancers, it has potential to be used as a
      target for many cancer immunotherapies.

PMID- 12479263
TI  - A prostate-specific antigen (PSA)-activated vinblastine prodrug selectively kills
      PSA-secreting cells in vivo.
AB  - Currently, there is no therapy for men with androgen-refractory prostate cancer
      that substantially extends survival. This report characterizes by in vitro and in
      vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine
      covalently linked to a peptide that contains a peptide bond that can be
      hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as
      vinblastine-conjugate) is minimally toxic to cells in culture which do not
      express PSA. In the presence of PSA, the peptide moiety is hydrolyzed, generating
      several highly toxic metabolites that contain vinblastine. Animals bearing PSA
      positive human prostate tumors that were treated with the vinblastine-conjugate
      experienced a >99% reduction in PSA serum level. In contrast, animals bearing PSA
      positive human prostate tumors treated with the cytotoxic metabolites derived
      from the PSA hydrolysis of the vinblastine-conjugate showed a nonsignificant
      change in both PSA and tumor weight values. The cell killing activity of the
      vinblastine-conjugate is PSA dependent because animals bearing non-PSA-producing
      human tumor xenografts had a nonsignificant increase in tumor weight after
      vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP
      tumor-bearing nude mice were conducted with animals treated for 5 consecutive
      days with various doses of either the vinblastine-conjugate or a PSA-generated
      toxic metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment
      resulted in 10-70% mortality with a very slight effect on tumor growth. In
      contrast, vinblastine-conjugate treatments resulted in no mortality, good to
      excellent antitumor efficacy, very slight to slight peripheral neuropathy and
      myelopathy, and slight to severe testicular degeneration. Similar treatment of
      beagle dogs with the vinblastine-conjugate showed even less toxicity. These data
      support the use of the PSA-hydrolyzable vinblastine-conjugate as an experimental
      therapy for prostate cancer in man.

PMID- 12479264
TI  - Prolonged stability and sustained prodrug cell killing activity using receptor
      mediated delivery of malarial circumsporozoite-cytosine deaminase fusion protein
      into liver cancer cells.
AB  - An effective strategy of delivering recombinant DNA or protein by nonviral
      vectors faces two major challenges: (a) the selective delivery to the specific
      target tissue; and (b) a long-term expression of the protein once inside the
      cells. The present study describes a receptor-mediated delivery strategy using
      recombinant fusion protein consisting of malaria circumsporozoite (CS) protein as
      a ligand and bacterial cytosine deaminase (CD), which catalyzes the production of
      5-fluorouracil from its prodrug 5-fluorocytosine. We demonstrate that the CD-CS
      fusion protein can be internalized in a receptor-mediated manner, providing a
      target delivery. The internalized CD-CS is capable of synthesizing 5-fluorouracil
      from the exogenously added 5-fluorocytosine and elicits cell killing with
      bystander activities. Most importantly, the internalized recombinant protein is
      stable and remains functional for at least several days, probably because of the
      entrapment of the fusion protein in particular cytoplasmic compartments that are
      free from cytoplasmic degradation machinery. Thus, it is possible to use a simple
      recombinant fusion strategy to enhance intracellular protein stability for
      manufacturing biological active product in a cell type-specific manner. The
      application of this strategy in the treatment of liver cancers and liver
      metastasis of colorectal cancers is discussed.

PMID- 12479265
TI  - Novel extranuclear-targeted anthracyclines override the antiapoptotic functions
      of Bcl-2 and target protein kinase C pathways to induce apoptosis.
AB  - Bcl-2 inhibits apoptosis induced by numerous antitumor drugs, including
      doxorubicin and daunorubicin and is, thus, a major impediment to successful
      cancer chemotherapy. Here, we report the ability of a novel family of nonnuclear
      targeted anthracyclines to induce rapid apoptosis in cells despite Bcl-2 or Bcl
      X(L) expression. Typified by N-benzyladriamycin-14-valerate (AD 198) and N
      benzyladriamycin-14-pivalate (AD 445), this family of compounds binds to the C1
      regulatory domain of protein kinase C (PKC), competitively inhibits phorbol ester
      binding in cell-free studies, and induces PKC translocation in intact cells. PKC
      delta has an established role as a pro-apoptotic protein through the association
      of the holoenzyme or catalytic fragment with mitochondria. In proliferating 32D.3
      myeloid cells, or in 32D.3 cells engineered to overexpress Bcl-2, substantial
      levels of PKC-delta are associated with mitochondria. However, after a 1-h
      exposure to 5 microM AD 198, cytochrome c release, caspase-3 activation, poly(ADP
      ribose) polymerase (PARP) cleavage, PKC-delta cleavage, and DNA fragmentation are
      observed. Pretreatment of 32D.3 cells with the selective PKC-delta inhibitor,
      rottlerin, but not the general PKC inhibitor, GF 109203X, or PKC-alpha and -beta
      inhibitor, Go 6976, delayed the 50% cell kill to >24 h for control and Bcl-2
      overexpressing 32D.3 cells treated with 5 microM AD 198. Rottlerin delayed PKC
      delta and PARP cleavage to >20 h post-drug exposure and also delayed
      mitochondrial membrane depolarization. In contrast, the pan-caspase inhibitor Z
      Val-Ala-Asp-CH2F blocked PKC-delta and PARP cleavage, but not mitochondrial
      membrane depolarization. These results suggest that AD 198 induces mitochondrial
      dependent apoptosis in 32D.3 cells by activating PKC-delta holoenzyme on
      mitochondria, which, in turn, overrides the antiapoptotic effects of Bcl-2.

PMID- 12479266
TI  - Interaction of the novel anthracycline antitumor agent N-benzyladriamycin-14
      valerate with the C1-regulatory domain of protein kinase C: structural
      requirements, isoform specificity, and correlation with drug cytotoxicity.
AB  - Anthracycline antibiotics like doxorubicin (DOX) are known to exert their
      antitumor effects primarily via DNA intercalation and topoisomerase II
      inhibition. By contrast, the noncross-resistant cytoplasmically localizing DOX
      analogue, N-benzyladriamycin-14-valerate (AD 198), only weakly binds DNA and does
      not inhibit topoisomerase II, yet it displays superior antitumor activity,
      strongly suggesting a distinct cytotoxic mechanism. In recent modeling studies,
      we reported a structural similarity between AD 198 and commonly accepted ligands
      for the C1-domain of protein kinase C (PKC), and we hypothesized that the unique
      biological activity of AD 198 may derive, in part, through this kinase.
      Consistent with this hypothesis, the present biochemical studies demonstrate that
      AD 198 competes with [3H]phorbol-12,13-dibutyrate ([3H]PDBu) for binding to
      phorbol-responsive PKC isoforms, the isolated C1b domain of PKC-delta (delta
      C1b), and the nonkinase phorbol ester receptor, beta2-chimaerin. In NIH/3T3
      cells, AD 198 competitively blocks PKC activation by C1-ligands. Importantly,
      neither DOX nor N-benzyladriamycin, the principal AD 198 metabolite, inhibits
      basal or phorbol-stimulated PKC activity or appreciably competes for [3H]PDBu
      binding. In CEM cells, structure activity studies with 14-acyl congeners indicate
      that the rapid induction of apoptosis correlates with competition for [3H]PDBu
      binding, strongly implicating phorbol-binding proteins in drug activity.
      Collectively, these studies support the conclusion that AD 198 is a C1-ligand and
      that C1-ligand receptors are selective drug targets. These studies provide the
      impetus for continuing efforts to understand the molecular basis for the unique
      biological activity of AD 198 and provide for the design of analogues with
      improved affinity for C1-domains and potentially greater antitumor activity.

PMID- 12479267
TI  - Retinoic acid-induced growth arrest and differentiation: retinoic acid up
      regulates CD32 (Fc gammaRII) expression, the ectopic expression of which retards
      the cell cycle.
AB  - Retinoic acid is known to cause the cell cycle arrest and myeloid differentiation
      of HL-60 myeloblastic leukemia cells. Evidence suggesting the possible
      involvement of the Fc gammaRII immunoglobulin receptor in mediating retinoic acid
      induced growth arrest and differentiation of HL-60 cells is presented. HL-60
      cells stably transfected with the delta205 mutant polyoma middle T antigen, a
      largely debilitated polyoma middle T antigen, are known to undergo accelerated
      retinoic acid-induced growth arrest and differentiation compared with parental HL
      60 cells. Delta205 transfected cells were compared with parental HL-60 cells by
      differential display to identify differentially expressed genes, which are
      regulated downstream of delta205 and might facilitate cellular response to
      retinoic acid. Differential display revealed that the Fc gammaRII immunoglobulin
      receptor was differentially expressed. HL-60 cells express Fc gammaRIIA but not
      Fc gammaRIIB. In parental HL-60 cells, retinoic acid up-regulated Fc gammaRII
      expression, and Fc gammaRII membrane protein expression increased concomitantly
      with retinoic acid-induced cell cycle arrest and differentiation. Ectopic
      expression of Fc gammaRIIa1 in HL-60 cells retarded cellular progression through
      all phases of the cell cycle. For HL-60 cells stably transfected with Fc
      gammaRIIa1, onset of retinoic acid-induced growth arrest and differentiation
      occurred in fewer cell cycles than for parental HL-60 cells. Similar results
      occurred with 1,25-dihydroxy vitamin D3. Retinoic acid-induced tyrosine
      phosphorylation of various PAGE-detected protein bands in HL-60 cells was
      enhanced by cross-linking ectopically expressed Fc gammaRIIa1 receptor. The known
      retinoic acid-induced sustained activation of various mitogen-activated protein
      kinase signaling molecules, including extracellular signal-regulated kinase 2,
      src-like kinases, and adapter molecules, may in part reflect induced expression
      of Fc gammaRIIA, which is known to activate a similar ensemble of signaling
      molecules through its ITAM domain. The data suggest that retinoic acid induces
      increased Fc gammaRIIA expression, which is of functional consequence in
      eliciting growth arrest and differentiation.

PMID- 12479268
TI  - Molecular inhibition of angiogenesis and metastatic potential in human squamous
      cell carcinomas after epidermal growth factor receptor blockade.
AB  - Tumor metastasis represents a complex multistep process that requires migration,
      invasion, and angiogenesis. In this study, we examined the impact of molecular
      blockade of the epidermal growth factor receptor on the invasive and metastatic
      capacity of human squamous cell carcinoma (SCC) of the head and neck using in
      vitro and in vivo model systems. Treatment with the anti-epidermal growth factor
      receptor antibody C225 attenuated the migration of SCC-1 tumor cells through a
      chemotaxis chamber in a dose-dependent manner. Incubation of SCC cells with 10
      100 nM C225 for 4 h resulted in 40-60% inhibition of cell migration. Furthermore,
      in the presence of C225, the capacity of SCC-1 to invade across a layer of
      extracellular matrix (Matrigel) was significantly inhibited. Using an in vivo
      orthotopic floor-of-mouth xenograft model, locoregional tumor invasion of SCC-1
      into muscle, vessel, bone, and perineural tissues was inhibited in C225-treated
      mice. This inhibition was additionally characterized by down-regulation in the
      expression of matrix metalloproteinase-9. These data suggest that inhibition of
      metastatic potential by C225 may be mediated via decreased migration and invasion
      of SCC cells. Regarding angiogenesis in vitro, we first studied human umbilical
      vascular endothelial cells, which established a capillary-like network structure
      (tube formation) in the presence of reconstituted Matrigel. Treatment with C225
      reduced cell-to-cell interaction of human umbilical vascular endothelial cells,
      resulting in disruption of tube formation. The effect of C225 was additionally
      examined using an in vivo tumor xenograft neovascularization model of
      angiogenesis. Systemic treatment with C225 not only reduced tumor growth and the
      number of blood capillaries but also hindered the growth of established vessels
      toward the tumor. Taken together, these results provide evidence that C225 can
      suppress tumor-induced neovascularization and metastasis in SCC of the head and
      neck.

PMID- 12479269
TI  - The xenoestrogen bisphenol A induces inappropriate androgen receptor activation
      and mitogenesis in prostatic adenocarcinoma cells.
AB  - Treatment for prostatic adenocarcinoma is reliant on the initial androgen
      dependence of this tumor type. The goal of therapy is to eliminate androgen
      receptor activity, either through direct inhibition of the receptor or through
      inhibition of androgen synthesis. Although this course of therapy is initially
      effective, androgen-refractory tumors ultimately arise and lead to patient
      morbidity. Factors contributing to the transition from a state of androgen
      dependence to the androgen-refractory state are poorly understood, but clinical
      evidence in androgen-refractory tumors suggests that the androgen receptor is
      inappropriately activated in these cells. Thus, the mechanisms that contribute to
      inappropriate (androgen-independent) activation of the androgen receptor (AR) is
      an area of intensive research. Here we demonstrate that bisphenol A (BPA), a
      polycarbonate plastic monomer and established xenoestrogen, initiates androgen
      independent proliferation in human prostatic adenocarcinoma (LNCaP) cells. The
      mitogenic capacity of BPA occurred in the nanomolar range, indicating that little
      BPA is required to stimulate proliferation. We show that BPA stimulated nuclear
      translocation of the tumor-derived receptor (AR-T877A), albeit with delayed
      kinetics compared with dihydrotestosterone. This translocation event was followed
      by specific DNA binding at androgen response elements, as shown by
      electrophoretic mobility shift assays. Moreover, the ability of BPA to stimulate
      AR-T877A activity was demonstrated by reporter assays and by analysis of an
      endogenous AR target gene, prostate-specific antigen. Thus, BPA is able to
      activate AR-T877A in the absence of androgens. Lastly, full mitogenic function of
      BPA is dependent on activation of the tumor-derived AR-T877A. These data
      implicate BPA as an inappropriate mitogen for prostatic adenocarcinoma cells and
      provide the impetus to study the consequence of BPA exposure on prostate cancer.

PMID- 12479270
TI  - Inhibition of retinoblastoma protein (Rb) phosphorylation at serine sites and an
      increase in Rb-E2F complex formation by silibinin in androgen-dependent human
      prostate carcinoma LNCaP cells: role in prostate cancer prevention.
AB  - Several studies have identified silibinin as an anticarcinogenic agent. Recently,
      we showed that silibinin inhibits cell growth via G1 arrest, leading to
      differentiation of androgen-dependent human prostate carcinoma LNCaP cells (X. Zi
      and R. Agarwal, Proc. Natl. Acad. Sci. USA, 96: 7490-7495,1999). Here, we extend
      this study to assess the effect of silibinin on total retinoblastoma protein (Rb)
      levels and its phosphorylation status, levels of E2F family members, and Rb-E2F
      binding in LNCaP cells. Compared with controls, silibinin resulted in an increase
      in total Rb levels that was largely attributable to an increase in
      unphosphorylated Rb (up to 4.1-fold). This effect of silibinin was mainly
      attributable to a large decrease (70-97%) in the amount of Rb phosphorylated at
      specific serine sites. In other studies, silibinin showed a moderate effect on
      E2F1 but up to 98 and 90% decreases in E2F2 and E2F3 protein levels,
      respectively. Silibinin treatments also resulted in an increase in the amount of
      Rb binding to E2F1 (3.8-fold), E2F2 (2.2-fold), and E2F3 (2.2-fold). Cyclin
      dependent kinases (CDKs), together with their catalytic subunit cyclins,
      phosphorylate Rb, which makes transcription factor E2Fs free from Rb-E2F
      complexes, resulting in cell growth and proliferation. Conversely, CDK inhibitors
      inhibit this phosphorylation, maintaining E2Fs bound to Rb, which causes growth
      inhibition. On the basis of our data showing that silibinin induces both
      unphosphorylated Rb levels and Rb-E2F binding, we also assessed its effect on
      upstream cell cycle regulators. Silibinin-treated cells showed up to 2.4- and 3.6
      fold increases in Cip1/p21 and Kip1/p27 levels, respectively, and a decrease in
      CDK2 (80%), CDK4 (98%), and cyclin D1 (60%). Consistent with these results,
      silibinin showed both G1 arrest and growth inhibition. Together, these findings
      identify modulation of Rb levels and its phosphorylation status as a molecular
      mechanism of silibinin-induced neuroendocrine differentiation of human prostate
      carcinoma LNCaP cells and suggest that this could be a novel approach for
      prostate cancer prevention by silibinin.

PMID- 12479271
TI  - Identification of differentially expressed genes in human salivary gland tumors
      by DNA microarrays.
AB  - Differentially expressed genes among different benign and malignant salivary
      gland tumors were identified by use of cDNA microarrays containing 19,000 human
      expressed sequence tags. Tumors were classified by using a subset of 486 genes.
      Benign Warthin's tumor and pleomorphic adenoma showed very distinctive gene
      expression patterns. One hundred and thirty-three genes differentiated the single
      malignant clear cell carcinoma from non-tumor salivary glands (P < 0.01), whereas
      only 16 genes separated it from the highly related benign pleomorphic adenoma (P
      < 0.01). Fifty-seven cDNAs were associated with mucoepidermoid carcinoma (P <
      0.01). The identified genes might help to disclose the molecular mechanisms and
      processes underlying malignant salivary gland tumors.

PMID- 12479272
TI  - The biological sequelae of stromal cell-derived factor-1alpha in multiple
      myeloma.
AB  - Stromal cell-derived factor (SDF)-1alpha mediates migration of normal
      hematopoietic stem cells, but its role in hematological malignancies is
      undefined. In this study, we detected SDF-1alpha in bone marrow (BM) plasma from
      10 patients with MM (multiple myeloma; 2.6 +/- 1.5 ng/ml) and BM stromal cell
      culture supernatants from 5 patients with MM (0.6 +/- 0.2 ng/ml). We show that
      SDF-1alpha promotes proliferation, induces migration, and protects against
      dexamethasone-induced apoptosis in MM cells, but these effects are only modest.
      In MM cell lines and patient MM cells, SDF-1alpha induces phosphorylation of
      p42/44 mitogen-activated protein kinase, as well as Akt and its downstream target
      Bad, and also activates nuclear factor-kappaB. In the BM milieu, SDF-1alpha up
      regulates secretion of interleukin 6 and vascular endothelial growth factor in BM
      stromal cells, which promote tumor cell growth, survival, and migration. These
      data demonstrate that SDF-1alpha promotes growth, migration and drug resistance
      of MM cells in the BM microenvironment, but these effects are only modest, SDF
      1alpha therefore does not represent a target for novel therapeutics in this
      disease.

PMID- 12479273
TI  - Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from
      pemetrexed therapy.
AB  - The purpose of this study was to identify predictive factors for severe toxicity
      caused by antifolate-chemotherapy using pemetrexed (ALIMTA, LY231514), as a
      model. Data on potential predictive factors for severe toxicity from pemetrexed
      were collected from 246 patients treated between 1995 and 1999. Multivariate
      stepwise regression methods were used to identify markers predictive of severe
      toxicity. Using a multiple logistic regression model allowed us to quantify the
      relative risk of developing toxicities and to generate a validated clinical
      hypothesis on ways to improve the safety profile of pemetrexed. Pretreatment
      total plasma homocysteine (tHcy) levels significantly predict severe
      thrombocytopenia and neutropenia with or without associated grade 3/4 diarrhea,
      mucositis, or infection. Pretreatment methylmalonic acid (MMA) levels
      significantly and independently predict grade 3/4 diarrhea and mucositis;
      however, these toxicities are still predicted by tHcy alone. Patients with
      elevated baseline levels of tHcy alone, or of both tHcy and MMA, were found to
      have a high risk of severe toxicity that led us to postulate that reducing tHcy
      would result in a reduction of severe toxicity with no harm to efficacy. This
      study points out for the first time the importance of pretreatment tHcy levels in
      predicting severe toxicity associated with an antifolate and sets the stage for a
      prospective clinical intervention to protect patients from pemetrexed-induced
      severe toxicity and possibly improve the drug's efficacy. Antifolates as a class
      have been associated with sporadic severe myelosuppression with gastrointestinal
      toxicity. Although infrequent, a combination of such toxicities can carry a high
      risk of mortality. This phenomenon had been unpredictable until now. Our work
      shows that by measuring tHcy, one can identify patients that are at risk of
      toxicity before treatment. Most importantly, decreasing homocysteine levels via
      vitamin supplementation leads to a better safety profile of pemetrexed and
      possibly to an improved efficacy.

PMID- 12479274
TI  - Molecular advances in pretargeting radioimunotherapy with bispecific antibodies.
AB  - The use of antibodies against tumor-associated cell surface antigens for the
      targeted delivery of radionuclides was introduced >20 years ago. Although
      encouraging results have been achieved with radiolabeled antibodies in the
      management of hematopoietic malignancies, there remains a need for successfully
      treating solid tumors with this modality. One promising approach involving
      pretargeted delivery of radionuclides has been shown to be capable of
      significantly increasing the radioactive uptake in tumor relative to normal
      organs, thereby potentially improving the efficacy of both detection and therapy
      of cancer. Uncoupling of the radionuclide from the tumor-targeting antibody
      allows the relatively slow process of antibody localization and clearance to
      occur before a very rapid and highly specific delivery of the radioactive payload
      carried on a small molecule, such as a peptide. This minireview discusses the
      various strategies and advancements made since the concept of pretargeting was
      proposed in the mid-1980s, with emphasis on those comprising bispecific
      antibodies for cancer therapy. Critical aspects of these pretargeting systems for
      achieving higher tumor:nontumor ratios are considered. In addition, both
      preclinical and clinical results obtained from a pretargeting method known as the
      Affinity Enhancement System are presented. Future directions of pretargeting
      technology are also suggested.

PMID- 12479275
TI  - Prosthesis-related complications: first-year annual rates.
AB  - The rates of valve-related complications determine the clinical performance of
      biological and mechanical heart valve prostheses by valve position. The crude
      rates of valve-related complications within the first year after implantation
      have not been previously reported. The Food and Drug Administration (FDA) of the
      United States guidance document for the performance of new heart valve prostheses
      uses objective performance criteria (OPC) as target values for valve-related
      complications. The FDA requirement for each valve-related complication is that
      the rate cannot be greater than twice the OPC. This report provides the first
      year rates of valve-related complications from a university database of over
      7,000 implants, followed longitudinally between 1982 and 1999, of currently
      marketed biological and mechanical heart valve prostheses. The aim of this report
      was to provide an additional method for consideration by regulatory authorities
      in determination of the standards of performance for pre-market approval of new
      prosthetic valves for heart valve replacement surgery.

PMID- 12479276
TI  - Using Bayes' theorem to answer a practical heart valve question.
AB  - BACKGROUND AND AIM OF THE STUDY: The risk of thromboembolism (TE) risk in a heart
      valve patient who has lived perhaps for 15 years since implant without TE or
      thrombosis is unknown. As patients are heterogeneous with regard to embolic risk,
      these patients must have a lower than average risk; whether this risk reduction
      could be quantified was the aim of the present study. METHODS: If all patients
      had the same risk, the TE-free curve would be exponential, with a constant hazard
      (equal to the 'linearized' rate). With a mixture of risks in a population, the
      population hazard will be a decreasing function of time. By fitting a certain
      parametric function to the TE-free curve, the mixing distribution can be
      estimated. Subsequently, given an observation for a particular patient, e.g. zero
      emboli in 15 years, Bayes' theorem can be used to update the mixing distribution
      for these patients. RESULTS: Using observed TE-free curves for Starr-Edwards
      valves, the mixing distribution for TE-free periods from one to 25 years was
      estimated. Because the risk distributions were skewed, the mean value was higher
      than the median. The mean (median) risk (% per year) fell from 4.5 (1.8) at
      implant to 1.7 (0.7) at 15 years for the aortic position, and from 7.0 (3.4) to
      2.4 (1.2) for the mitral position. Thus, the average risk after 15 years was
      approximately 35-40% of the risk at implant for both the aortic and mitral
      positions, using either the mean or median risk. CONCLUSION: The mean risk for
      patients after 15 TE-free years is approximately one-third of the risk of all
      patients at implant. However, there is a wide range, with some patients still
      having higher risks. Bayes' theorem is useful for deriving such answers.
      Linearized rates have limited value for describing TE risk in a heterogeneous
      population.

PMID- 12479277
TI  - Trends in aortic valve surgery in a large multi-surgeon, multi-hospital practice,
      1979-1999.
AB  - BACKGROUND AND AIM OF THE STUDY: Trends in aortic valve operations (AVO) may help
      to predict the future of aortic valve surgery in the context of changing case
      mix, population demographics, emerging technology and shifting paradigms.
      METHODS: All adults undergoing single AVO between 1979 and 1999 were reviewed
      retrospectively according to age, gender and other typical clinical variables,
      surgical complexity, specific operation and immediate outcome. RESULTS: There
      were 3,917 single AVO. Although coronary artery bypass (CAB) volumes declined by
      15.3% between 1996 and 1999, AVO volumes have continued to increase by 11.7%
      since 1996. Over the entire period, there was no significant change in mean age
      or percent female gender, but increases in the prevalence of octogenarians and
      aortic stenosis were noted. During the 1990s, degenerative valve disease
      predominated and the prevalence of sicker patients according to heart failure
      class and surgical priority decreased. Trends in surgical complexity included an
      increase in AVO combined with CAB, but a stable 9:1 distribution of first
      operations to reoperations. Technology adoption included a decreased prevalence
      of mechanical valve use at the expense of increased use of tissue valves,
      especially stented xenografts and homografts. Transient technology adoption
      included stentless xenografts. Small numbers of pulmonary autografts, aortic
      valve repairs and valve-sparing aortic replacements were carried out. Predictors
      of hospital mortality rates for AVO included age 65 years, reoperation and
      combined AVO. Hospital mortality rates for AVO decreased for most age groups
      between the 1980s and 1990s, but not during the 1990s. CONCLUSION: AVO volumes
      are steadily increasing, apparently as a result of the increase in octogenarians
      and the start of the 'baby boom' wave. Hospital mortality risk is related to age
      and surgical complexity, but is modest and has stabilized during the past decade.
      The prevalence of mechanical valve implants has decreased in favor of tissue
      valve replacement categories. The fastest growth rates have been with stented
      xenografts, and especially homografts. This may represent a paradigm shift away
      from mechanical solutions in favor of tissue solutions for aortic valve disease.

PMID- 12479278
TI  - Long-term follow up in patients receiving a small aortic valve prosthesis.
AB  - BACKGROUND AND AIMS OF THE STUDY: Concern persists regarding the long-term
      effects of aortic valve replacement (AVR) in the small aortic root. METHODS:
      Twenty-eight patients (21 females, seven males; mean age 54.1+/-11.7 years; mean
      body surface area (BSA) 1.39+/-0.07 m2) who underwent AVR with a 19 mm mechanical
      valve more than 10 years previously at the authors' institute, were followed up.
      Long-term echocardiographic evaluations were performed in 18 of 21 survivors.
      RESULTS: Follow up in the 28 patients was complete for up to 19.2 years (mean
      11.4 years); cumulative follow up was 318.1 patient-years. Actuarial survival
      rates at 5, 10 and 15 years were 88.5+/-6.3%, 72.0+/-9.0% and 72.0+/-9.0%,
      respectively. In general, NYHA class showed satisfactory improvement. Long-term
      echocardiography showed significant reductions in left ventricular (LV) wall
      thickness and mass index compared with preoperative values, despite the existence
      of pressure gradients. A negative correlation was found between the rate of
      reduction of LV wall thickness and BSA. CONCLUSION: Implantation of the 19 mm
      aortic mechanical prosthesis was viable in patients with a small aortic annulus,
      especially if their BSA was <1.45 m2.

PMID- 12479279
TI  - Value of automated segmental motion analysis in the assessment of aortic stenosis
      severity.
AB  - BACKGROUND AND AIMS OF THE STUDY: Left ventricular (LV) contraction is slowed in
      patients with aortic stenosis (AS). Although the possible role of LV systolic
      function abnormalities in the assessment of AS severity has been evaluated,
      current echocardiographic techniques cannot offer precise quantification of LV
      motion velocity. The study aim was to evaluate an automated segmental motion
      analysis (ASMA) system to assess AS severity. METHODS: Twenty-two patients with
      AS, sinus rhythm and preserved LV ejection fraction were studied prospectively.
      Patients underwent both conventional Doppler echocardiography to measure
      transaortic gradient and aortic valve area by the continuity equation, and ASMA
      of the interventricular septum. The ASMA line graph mode displays changes in area
      through the cardiac cycle. The RR interval and time from the R-wave to peak
      maximum area shortening were measured, and an ASMA index was calculated. RESULTS:
      A significant and strong inverse correlation was found between aortic valve area
      and ASMA index (r = -0.78; 95% CI -0.90 to -0.55; p <0.001). The area under the
      ROC curve in the diagnosis of severe AS (aortic valve area < or =0.8 cm2) was
      0.97 (95% CI 0.90-1.0). Sensitivity, specificity, positive and negative
      predictive values and overall accuracy for an ASMA index >0.40 were 100, 91.7,
      92.3, 100 and 95.8%, respectively. CONCLUSION: The ASMA system may be valuable in
      evaluating AS, as it offers a strong correlation with aortic valve area
      calculated by the continuity equation, and very high sensitivity and specificity
      in the diagnosis of severe AS.

PMID- 12479280
TI  - Mitral valve relpair and revascularization for ischemic mitral regurgitation:
      predictors of operative mortality and survival.
AB  - BACKGROUND AND AIMS OF THE STUDY: Surgery for ischemic mitral regurgitation (IMR)
      is required in 4-5% of patients subjected to coronary artery surgery, and may be
      challenging. The study aim was to determine outcome following mitral valve repair
      and myocardial revascularization for moderate-to-severe IMR. METHODS: A total of
      102 patients (mean age 68+/-7 years) underwent mitral valve repair for IMR
      between 1998 and 2001 at the authors' unit. Among patients, 28 had acute and 74
      chronic mitral regurgitation (MR). Valve repair was achieved with an annuloplasty
      ring in all 102 patients, while 99 underwent concomitant myocardial
      revascularization. Preoperatively, 69 patients had MR grade III-IV, 62 had CCS
      angina class III-IV, 59 were in NYHA class II-IV, 81 had impaired left
      ventricular function, and 10 were in cardiogenic shock. Follow up was 100%
      complete (mean 14+/-7 months; range: 0-38 months). RESULTS: Overall operative
      mortality was 8.8% (n = 9) (17.8% for acute IMR, 5.4% for chronic, p = 0.048). On
      multiple logistic regression analysis, cardiogenic shock (p = 0.028) was the only
      significant risk factor for operative death. There were 11 late deaths. Kaplan
      Meier survival at one and three years was 82+/-4% and 79+/-4%, respectively. On
      Cox proportional hazards regression model, preoperative left ventricular end
      systolic diameter (LVESD) >4.5 cm (p = 0.01) and NYHA class III-IV (p = 0.02)
      were independent adverse predictors of survival. Three patients required
      reoperation. Kaplan-Meier three-year freedom from reoperation was 97+/-2%.
      CONCLUSION: Surgery for IMR carries a considerable, but acceptable, operative
      risk and provides satisfactory freedom from reoperation and mid-term survival.
      Cardiogenic shock before surgery is the major determinant of an unfavorable in
      hospital outcome. LVESD >4.5 cm and poor preoperative NYHA status limit the
      probability of late survival. The study results support early surgical
      intervention for IMR, before ventricular dilatation occurs.

PMID- 12479281
TI  - Management of persistent atrial fibrillation following balloon mitral valvotomy:
      safety and efficacy of low-dose amiodarone.
AB  - BACKGROUND AND AIM OF THE STUDY: Atrial fibrillation (AF) is the most common
      sustained cardiac arrhythmia encountered in clinical practice. In developing
      countries, rheumatic mitral stenosis (MS) is the most frequent underlying
      condition in patients with AF. Sinus rhythm (SR) is difficult to achieve and
      maintain in these patients, but would be more easily achieved with reduction of
      left atrial pressure after successful balloon mitral valvotomy (BMV). METHODS:
      Eighty-five patients with persistent AF following BMV received amiodarone (600 mg
      once daily for two weeks, 200 mg daily thereafter). Electrical cardioversion was
      performed in those with persistent AF (at six and 12 weeks of drug therapy).
      RESULTS: Among patients, 33 (39%) converted with amiodarone alone. Of 52 patients
      who underwent cardioversion at six weeks, 41 (79%) converted to SR. Overall, 87%
      of patients converted to SR. None of the 11 patients with persistent AF could be
      converted to SR, despite a second attempt with direct current (DC) cardioversion
      at 12 weeks. Those who converted to SR had significantly shorter AF duration
      (AFD) (2.7+/-1.1 versus 3.2+/-0.7 years) and smaller left atrial (LA) size
      (50.0+/-7.7 versus 57.9+/-4.7 mm). Patient age, gender, NYHA class, ejection
      fraction and post-BMV variables were comparable between the two groups.
      Successful maintenance of SR was possible in 61/74 (82%) patients at a mean
      follow up of 30.6+/-7.1 months (range: 16-43 months). Again, mean AFD was shorter
      (1.8+/-0.6 versus 3.0+/-0.7 years) and LA size smaller (48.9+/-7.5 versus 54.7+/
      6.9 mm) among those who maintained SR. However, even in patients with AFD > or =2
      years, successful conversion and maintenance of SR was possible in 74% and 62% of
      patients, respectively. Among patients with LA size > or =60 mm (n = 16), the
      corresponding value were 84% and 77%, respectively. On multivariate analysis,
      only AFD was a predictor of acute and long-term success. The probability of SR
      remaining in those with AFD <2 years at 21, 30 and 43 months was 96%, 95% and
      94.6%, respectively, while for those with AFD > or =2 years these values were
      62%, 48% and 40%. CONCLUSION: Low-dose amiodarone was safe and effective in
      restoring and maintaining SR in patients with AF and rheumatic heart disease.

PMID- 12479282
TI  - 3-D computational analysis of the stress distribution on the leaflets after edge
      to-edge repair of mitral regurgitation.
AB  - BACKGROUND AND AIM OF THE STUDY: Edge-to-edge repair is an effective, recently
      introduced method to correct mitral insufficiency by suturing the leaflets at the
      site of regurgitation, though durability of the method has not been proven. To
      overcome the limitations of the clinical approach, simulations may be used to
      predict clinical outcome. In this study, the mechanical stress acting on leaflets
      imposed by the edge-to-edge suture was evaluated as a means of assessing the
      clinical risk of late fibrosis or tissue degeneration. METHODS: A 3-D finite
      element simulated the stress pattern following edge-to-edge repair. Valve
      behavior was evaluated both in systole and in diastole. Both 4-mm and 8-mm edge
      to-edge sutures were simulated, as well as annular dilation. RESULTS: Systolic
      simulations validated the model by comparison with previous models of the mitral
      valve. Diastolic stresses were negligible in the native mitral valve; after edge
      to-edge repair (8-mm suture), circumferential and longitudinal stress values were
      308 kPa and 489 kPa, respectively, and comparable with those observed at systolic
      peak (449 kPa and 617 kPa, respectively). With a 4-mm suture, longitudinal
      stresses decreased both close to the suture (-41.5%) and in the annular region (
      68%), while circumferential stresses increased (+37%) close to the suture and
      decreased (-27%) in the annular region. A 20% dilation of the annulus was
      followed by increased stresses in the annular region and close to the suture.
      CONCLUSION: Leaflet distortion and altered stress distribution occur on the
      leaflets after edge-to-edge repair. Diastolic peak stress values were comparable
      with those calculated in systole. The clinical implication is a doubled exposure
      of valve components to systolic stresses, as if the heart rate were doubled. The
      use of a prosthetic annuloplasty ring is favorable in the presence of annular
      dilation to reduce stresses acting on the leaflets after edge-to-edge repair.

PMID- 12479283
TI  - Ischemia-induced malcoaptation of scallops within the posterior mitral leaflet.
AB  - BACKGROUND AND AIMS OF THE STUDY: The posterior mitral leaflet is divided into a
      variable number of scallops, and little is known about the role of
      scallopmalcoaptation in ischemic mitral regurgitation. The study aim was to
      assess whether acute ischemia in the posterolateral wall of the left ventricle
      would induce scallop separation that would contribute to mitral regurgitation.
      METHODS: Radio-opaque markers were surgically placed in the left ventricle,
      around the mitral annulus, and at three sites along the posterior mitral leaflet
      edge in eight sheep. Three-dimensional marker coordinates were obtained by
      biplane videofluoroscopy at 60 Hz and 0.1 mm resolution before and during
      echocardiographically verified acute ischemic mitral regurgitation produced by
      balloon occlusion of the circumflex coronary artery. RESULTS: During systole, the
      mean (+/-SD) distance between the central and anterolateral markers, both placed
      on the central scallop of the posterior mitral leaflet, was unaffected by
      ischemia (7.4+/-2.4 versus 7.4+/-2.5 mm; n = 8; p = NS). In contrast, the
      systolic distance between the central scallop marker and the posteromedial marker
      increased by 2.3+/-0.2 mm (p = 0.008) in three hearts with the posteromedial
      marker on the posteromedial scallop, compared with no separation (0.2+/-0.5 mm; p
      = NS) in five hearts with both the central and posteromedial markers on the
      central scallop itself. This result shows systolic separation of the central and
      posteromedial scallops during acute ischemic mitral regurgitation. CONCLUSION:
      During acute left ventricular ischemia, the central and posteromedial scallops of
      the posterior mitral leaflet can fail to coapt during systole, potentially
      contributing to the mitral regurgitation observed.

PMID- 12479284
TI  - Association between angiotensinogen gene M235T polymorphism and mitral valve
      prolapse syndrome in Taiwan Chinese.
AB  - BACKGROUND AND AIM OF THE STUDY: It has been reported that patients with mitral
      valve prolapse syndrome (MVPS) also have a disorder in autonomic or
      neuroendocrine function which can cause many related symptoms. Although a
      potential role of the reninangiotensin system in the pathogenesis of MVPS has
      been addressed, the role of the angiotensinogen (AGT) genetic variant in MVPS has
      not been studied. Thus, a case-controlled study was performed to investigate the
      possible relationship between AGT gene polymorphisms and MVPS. METHODS: A total
      of 100 patients with MVP diagnosed by echocardiography and 100 age- and sex
      matched normal control subjects was studied. AGT gene M235T and T174M
      polymorphisms were identified by polymerase chain reaction-based restriction
      analysis. RESULTS: There was a significant difference in the distribution of AGT
      gene M235T genotypes (p <0.001) and allelic frequencies (p <0.001) between MVPS
      cases and controls. An Odds Ratio (OR) for risk of MVPS associated with M235T TT
      genotype was 8.55 (95% CI 4.51-16.18). An OR for risk of MVPS associated with the
      T allele at the M235T locus of the AGT gene was 3.27 (95% CI 2.05-5.22). The
      T174M polymorphism of AGT gene showed no association with MVPS (p = 0.94).
      CONCLUSION: These findings suggest that the M235T polymorphism of the AGT gene is
      associated with MVPS in the Chinese population of Taiwan. The association of the
      TT genotype with MVPS is more noteworthy than an overall increase in the
      frequency of the T allele at the M235T locus.

PMID- 12479285
TI  - Mitral valve repair for severe mitral regurgitation caused by endomyocardial
      biopsy.
AB  - Mitral regurgitation (MR) following endomyocardial biopsy is a rare and severe
      complication. A 70-year-old man with severe MR due to chordal injury caused by
      left ventricular endomyocardial biopsy is described. In this patient, a few
      chordae tendineae of the posterior-median papillary muscle were injured by the
      biopsy forceps. Due to the chordal rupture, both anterior and posterior leaflets
      were prolapsed and severe MR developed. MR was successfully treated by artificial
      chordal replacement using extended polytetrafluoroethylene sutures and ring
      annuloplasty. This mitral valve repair with artificial chordal replacement was
      considered suitable to treat MR resulting from iatrogenic chordal injury as the
      leaflets were not involved in the degenerative process and papillary muscle
      function was preserved. To avoid MR, the transvenous approach should be used
      routinely for endomyocardial biopsies; biopsy from the left ventricle is not
      justified.

PMID- 12479286
TI  - Treatment of left-sided prosthetic valve thrombosis: thrombolysis or surgery?
AB  - Although, traditionally, surgery has been the treatment of choice for left-sided
      prosthetic valve thrombosis (PVT), there are significant risks associated with re
      do surgery. Thrombolysis is an alternative to surgery and has a success rate in
      excess of 80%, but is associated with an -10% risk of systemic embolism and a 7%
      mortality rate. Guidelines for the use of thrombolytic therapy for PVT were
      produced using data acquired from older valves, and largely without the use of
      transesophageal echocardiography (TEE). Data from more recent studies suggest
      that thrombolysis should be regarded as first-line therapy for PVT in all NYHA
      classes. The use of TEE is recommended to visualize thrombus in suspected cases.

PMID- 12479287
TI  - Clinical evaluation of the carbomedics prosthesis: experience at providence
      health system in Portland.
AB  - BACKGROUND AND AIMS OF THE STUDY: This study details the authors' experience with
      the CarboMedics bileaflet mechanical prosthesis, and assesses the valve's
      efficacy in terms of early mortality and long-term morbidity. METHODS: Between
      July 1994 and December 2000, a total of 696 CarboMedics valves was implanted in
      616 patients. Aortic valve replacement (AVR) was performed in 350 (57%) patients,
      mitral valve replacement (MVR) in 161 (26%), double (aortic + mitral) valve
      replacement (DVR) in 79 (13%), and other procedures in 26 (4%). RESULTS: There
      were 32 operative deaths. Operative mortality was 4.3% for AVR, 6.8% for MVR, and
      7.6% for DVR. Linearized rates for late death were 3.4%/patient-year (pt-yr),
      5.5%/pt-yr and 7.7%/pt-yr for AVR, MVR and DVR, respectively. Survival at five
      years was 80.1% for AVR, 73.0% for MVR, and 64.6% for DVR (p = 0.004). Freedom
      from reoperation at five years was 97.6% for AVR, 98.1% for MVR, and 94.1% for
      DVR (p = 0.718); freedom from thromboembolism at five years was 96.3% for AVR,
      98.6% for MVR, and 88.3% for DVR (p = 0.04). Linearized rates of late
      thromboembolism were 0.7%/pt-yr, 0.4%/pt-yr and 2.3%/pt-yr, respectively. Freedom
      from PVE at five years was 98.4% for AVR, 97.0% for MVR, and 89.7% for the DVR
      group (p = 0.172). Linearized rates of PVE were 0.5%/pt-yr, 0.9%/pt-yr and
      1.8%/pt-yr, respectively. Freedom from anticoagulant-related bleeding at five
      years was 98.0% in the AVR group, 97.8% in the MVR group, and 88.3% in the DVR
      group (p <0.001); linearized rates of this event were 0.4%/pt-yr, 0.6%/pt-yr and
      3.2%/pt-yr, respectively. One valve thrombosis was found after MVR, and another
      in the mitral position after DVR. CONCLUSION: Early and intermediate-term follow
      up of the CarboMedics prosthesis indicates that the clinical performance of this
      valve is satisfactory, and results are comparable with those obtained for other
      mechanical valves.

PMID- 12479288
TI  - Chronic, preclinical assessment of the Medtronic Advantage aortic valve
      prosthesis.
AB  - BACKGROUND AND AIMS OF THE STUDY: Medtronic, Inc. has designed and developed a
      new bileaflet, aortic prosthesis (Advantage) and, following an in-vitro analysis,
      a chronic in-vivo 20-week evaluation was performed in sheep. METHODS: Fourteen
      adult male and female sheep underwent implantation of either a 19 mm Advantage or
      St. Jude Medical (SJM) aortic prosthetic valve for chronic in-vivo evaluation,
      using a previously reported aortic model technique. RESULTS: There were two
      operative deaths, and the remaining sheep (eight with Advantage, four with SJM
      prostheses) underwent chronic hemodynamic and pathologic evaluations at
      approximately 140 days. One sheep (SJM prosthesis) died unexpectedly at 122 days;
      postmortem evaluation revealed valvular thrombosis, though the valve was well
      seated with no excessive pannus formation or paravalvular leaks. Hemodynamic and
      hematologic data in the remaining sheep were comparable. Pathologic examination
      of the remaining implanted valves revealed well-seated prostheses, with no
      evidence of thrombosis, no excessive pannus formation, and no evidence of
      paravalvular leaks. CONCLUSION: This preclinical animal study showed that the
      Advantage prosthesis has acceptable features, including equivalent hemodynamic
      and hematologic data, and a lack of pathological abnormalities when compared with
      a commercially available prosthetic bileaflet mechanical valve.

PMID- 12479289
TI  - Comparison of hemodynamic performance of Medtronic Hall 21 mm versus St. Jude
      Medical 23 mm prostheses in pigs.
AB  - BACKGROUND AND AIM OF THE STUDY: The ideal prosthesis for aortic valve
      replacement in the small annulus remains controversial, and has yet to be
      defined. In previous studies, the Medtronic Hall (MH) tilting disc valve showed
      superior hemodynamic performance in the hemodynamically optimum orientation
      compared to the St. Jude Medical (SJM) bileaflet valve, especially in smaller
      sized valves. Using an animal model, the hemodynamics of 21 mm MH and 23 mm SJM
      valves, both of which have shown identical performance in previous clinical
      studies, were compared. METHODS: A rotation device holding either a MH or a SJM
      aortic valve was implanted into eight pigs. The device allowed rotation of the
      implanted valve without reopening the aorta. In different orientations (best and
      worst orientation hemodynamically as defined previously), transvalvular pressure
      gradients and ventricular dimensions were measured using transesophageal
      echocardiography at constant hemodynamic conditions. RESULTS: In the optimum
      hemodynamic orientation, pressure gradients of the MH valve (6.3+/-1.7 mmHg)
      corresponded to those obtained with the SJM valve (6.3+/-3.7 mmHg), whereas in
      the worst orientation the MH showed a tendency towards higher gradients (14.0+/
      2.9 versus 10.3+/-4.0 mmHg) (p = not significant). A significant increase in left
      ventricular enddiastolic diameter was observed for both valve designs with
      rotation from the optimal into the worst orientation. CONCLUSION: In the optimum
      hemodynamic orientation, the 21 mm MH valve matched the hemodynamic performance
      of the 23 mm SJM valve. Thus, implantation of the MH valve might be an
      alternative to root enlargement and implantation of a larger SJM valve in
      patients with a small aortic annulus, though optimum orientation is required.

PMID- 12479290
TI  - Influence of pregnancy after bioprosthetic valve replacement in young women: a
      prospective five-year study.
AB  - BACKGROUND AND AIMS OF THE STUDY: Prosthetic heart valve placement in young women
      does not normally prevent successful pregnancy, though either thrombosis in
      mechanical prostheses or degeneration in biological prostheses may cause risks
      for both mother and fetus. Although pericardial prostheses avoid the risks of
      anticoagulation therapy, it has been suggested that pregnancy accelerates
      structural degeneration in bioprostheses. The study aim was to assess the
      influence of pregnancy on five-year outcome after pericardial bioprosthesis
      replacement. METHODS: A total of 85 women was studied prospectively over five
      years from prosthesis implantation, using annual clinical and echocardiographic
      investigations. Women were allocated to two groups based on pregnancy occurring
      during follow up: 48 patients (56%; group A) became pregnant, and 37 (44%; group
      B) did not. RESULTS: At five-year follow up, the clinical events occurred in 29
      patients (34.1%): 11 (22.9%) women in group A (mean (+/-SE) linearized rate 3.6+/
      0.24%/patient-year (pt-yr)), and 18 (45.6%) in group B (linearized rate 8.6+/
      0.30%/pt-yr). Probability of freedom from clinical events was higher (p = 0.0096)
      in group A (77.9+/-6.1 versus 51.3+/-8.2%). Structural bioprosthesis
      degeneration, thrombosis or infective endocarditis occurred in 13 patients
      (27.1%) in group A (linearized rate 2.75+/-0.20%/pt-yr) and 11 (29.7%) in group B
      (linearized rate 2.5+/-0.18%/pt-yr). Probability of structural bioprosthesis
      degeneration (e.g. stenosis, calcification or rupture) did not differ (p =
      0.6440) between groups (85.4+/-5.1 versus 89.5+/-5.1%), even after age-adjusted
      analysis (p = 0.3112). CONCLUSION: Structural changes found at five years after
      bioprosthesis placement may be attributed to the natural course of the
      bioprosthesis, and independent of any occurrence of pregnancy.

PMID- 12479292
TI  - Profile and localization of matrix metalloproteinases (MMPs) and their tissue
      inhibitors (TIMPs) in human heart valves.
AB  - BACKGROUND AND AIMS OF THE STUDY: Tissue turnover is one of many factors involved
      in the operational longevity of heart valves. An understanding of how valves
      remodel their matrix in response to the hemodynamic environment in health and
      disease is crucial to the design and biological responsiveness of tissue
      engineered valve substitutes. Matrix metalloproteinases (MMPs) are proteolytic
      enzymes involved in matrix remodeling in several tissues, and include
      interstitial collagenase (MMP-1, MMP-13), the gelatinases (MMP-2, MMP-9) and
      stromelysin (MMP-3). METHODS: Expression of MMPs and their tissue inhibitors
      (TIMPs) in human aortic, mitral, tricuspid and pulmonary valves from unused donor
      or transplant recipient hearts was determined by immunohistochemical staining
      using antibodies against human MMP-1, MMP-2, MMP-3 and MMP-9 and their inhibitors
      TIMP-1, TIMP-2, TIMP-3. Cell identification was achieved using antibodies against
      CD31(endothelial cells), smooth muscle alpha-actin (microfilaments) and CD68
      (macrophages). RESULTS: MMP-1 was expressed in all valves, whereas MMP-2 was only
      expressed in aortic and pulmonary leaflets. MMP-3 and MMP-9 were not expressed.
      TIMP-1 and TIMP-2 were expressed in all leaflets, whereas TIMP-3 was observed
      only in tricuspid leaflets. CONCLUSION: Valves have a specific pattern of
      expression of MMPs and TIMPs, which appears to vary in different heart valves.
      The functional implications and central mechanisms responsible require further
      study. These findings have important implications in understanding the dynamic
      nature of valve remodeling and in aiding the development of tissue-engineered
      valves.

PMID- 12479291
TI  - Development of broad-range polymerase chain reaction (PCR) bacterial
      identification in diagnosis of infective endocarditis.
AB  - BACKGROUND AND AIMS OF THE STUDY: The study aim was to identify the value of
      broad-range bacterial PCR in infective endocarditis (IE) of bacterial etiology,
      and to determine its specificity and sensitivity. METHODS: Thirty blood samples
      were taken for analysis from patients with IE (diagnosed according to Duke
      criteria) and acquired valvular heart disease. Two control groups of patients
      with (n = 10) or without (n = 15) urinary tract infection were defined. DNA was
      isolated, and three different primer pairs for the region of the gene coding for
      16S rRNA were tested, to determine the most specific pair. Amplification products
      were analyzed with gel electrophoresis, stained with ethidium bromide, and
      located under UV light. RESULTS: Positive blood cultures were found in 25
      patients with IE. A typical echocardiography picture with bacterial vegetations
      was found in all patients with sterile blood cultures, and in 20 patients with
      positive blood cultures. The highest specificity was found for forward/reverse
      (F/R) primers, as the relevant amplified PCR product was present in all blood
      samples with IE, and in four of 10 patients with urinary tract infection.
      CONCLUSION: Broad-range PCR in bacterial endocarditis is a rapid, sensitive and
      inexpensive technique for the detection of bacteria, but is far more prone to
      contamination than species-specific PCR. However, under controlled conditions,
      broad-range PCR may be valuable for the identification of non-specific infection,
      permitting a more rapid clinical diagnosis of endocarditis.

PMID- 12479293
TI  - Aortic valve interstitial cells: an evaluation of cell viability and cell
      phenotype over time.
AB  - BACKGROUND AND AIM OF THE STUDY: In investigating the mechanisms of aortic valve
      disease processes and to accurately construct tissue-engineered heart valve
      prostheses, a complete understanding of the native interstitial cell population
      is required. Previously, autopsy samples have been deemed unsuitable for
      immunocytochemical studies due to the ischemic time before harvesting. In this
      study, the viability and phenotypic profile of cells explanted from normal
      porcine heart valves up to 120 h post mortem was examined. METHODS: The aortic
      valve leaflets of porcine hearts were excised at 0, 6, 24, 48, 72, 96 and 120 h
      post mortem; one half of the tissue was used to explant cells, and the other half
      was fixed in 3.7% formalin for sectioning. Samples taken at each time point were
      cultured and cell viability was determined using a trypan blue exclusion assay.
      Immunocytochemical and immunohistochemical analyses, using specific markers for
      fibroblasts, myofibroblasts and smooth muscle cells, were used to compare cell
      phenotypes both in vitro and in situ. RESULTS: Absolute numbers of cells obtained
      from each leaflet decreased significantly over time; however, cell viability in
      culture was unaffected up to 96 h. At each time point, explanted cell populations
      expressed similar phenotypes when compared with histological samples prepared
      from the same valves. CONCLUSION: Porcine aortic valve interstitial cells may be
      explanted up to and including 96 h post mortem, with no statistically significant
      change in cell viability in vitro, and with a population that phenotypically
      resembles aortic valve interstitial cells in situ. These data suggest that human
      aortic valve interstitial cells may be successfully harvested at autopsy for in
      vitro studies.

PMID- 12479294
TI  - Cardiac relapse of squamous cell carcinoma of the maxillary sinus.
AB  - An unusual case of maxillary sinus carcinoma presenting with heart metastasis is
      reported. The epicardium, myocardium and endocardium were infiltrated with the
      tumor, but no evidence of recurrent maxillary sinus carcinoma and other organ
      metastasis was found. Surgical excision was not possible due to massive invasion
      of the heart by the tumor mass. The right ventricular inflow tract obstruction
      was relieved by surgical dilatation.

PMID- 12479295
TI  - Tension apparatus the mitral valve.

PMID- 12479296
TI  - PETS extended to the USA and Canada.

PMID- 12479297
TI  - Incidence and risk factors for exertional rhabdomyolysis in thoroughbred
      racehorses in the United Kingdom.
AB  - Telephone surveys of 34 racing yards with 1276 horses in training were made to
      establish the overall incidence of exertional rhabdomyolysis in the previous
      year. A case-control study was used to investigate the risk factors for the
      syndrome in 12 yards selected on the basis of the routine confirmation of
      diagnoses by the evaluation of the serum activities of creatine kinase and
      aspartate aminotransferase. The overall incidence of the syndrome was 6.7 per
      cent and 80 per cent of the trainers had at least one affected horse. In 74 per
      cent of the affected horses it frequently recurred, with an average of six lost
      training days per episode. Risk factors identified for the syndrome included
      being female, having a nervous, excitable temperament, and being two years old.

PMID- 12479298
TI  - Serological survey of Toxoplasma gondii, feline immunodeficiency virus and feline
      leukaemia virus in urban stray cats in Belgium.
AB  - Three hundred and forty-six serum samples taken between 1998 and 2000 from urban
      stray cats in the city of Ghent were tested for antibodies to Toxoplasma gondii
      and feline immunodeficiency virus (FIV), and antigens of feline leukemia virus
      (FeLV). Of these 346 samples, 243 (70.2 per cent) were seropositive for Tgondii.
      Thirty-nine cats (11.3 per cent) had antibodies against FIV and 13 (3.8 per cent)
      had circulating antigens of FeLV. Fewer of the female cats had FIV and heavier
      cats had a higher seroprevalence of FIV. Exact logistic regression showed that
      cats that were infected with FIV were more likely to be infected with T gondii (P
      = 0.04), and the cats with FIV had a higher titre of Tgondii antibodies than FIV
      negative animals. However, FeLV was not associated with either T gondii or FIV.

PMID- 12479299
TI  - Evaluation of a new immunocapture test for the diagnosis of ovine brucellosis
      caused by Brucella melitensis.
AB  - A new immunocapture technique has been applied to the diagnosis of ovine
      brucellosis under experimental conditions. The tests were made on a serum bank
      derived from both young and adult ewes vaccinated conjunctivally with the Rev 1
      strain at a dose of 10(8) to 10(9) colony-forming units. Adult ewes were infected
      experimentally two-and-a-half years after they had been vaccinated and the
      results were compared with an unvaccinated control group. The condition of each
      animal in terms of infection with Brucella melitensis was determined by clinical
      and bacteriological investigations. The development of the immune response was
      compared by the rose bengal test, the complement fixation test, the Coombs' test
      and the immunocapture technique for 180 days after the vaccination and for 410
      days after the experimental infection, that is, the two following gestations. The
      results suggest that the new technique is more specific in animals vaccinated
      conjunctivally, regardless of their age when they were vaccinated. After the
      experimental infection, significantly (P < 0.05) fewer of the vaccinated sheep
      which were free of clinical signs and were not excreting B melitensis reacted
      positively to the test.

PMID- 12479300
TI  - Ultrasonographic diagnosis of fetal sex in small ruminants bearing multiple
      fetuses.

PMID- 12479301
TI  - Isolation and identification of a reovirus from a lizard, Uromastyx hardwickii,
      in the United Kingdom.

PMID- 12479302
TI  - Myocardial necrosis and severe metabolic acidosis associated with isoniazid
      poisoning in a dog.

PMID- 12479303
TI  - In vitro maturation of bubaline oocytes in serum-free media in the in vivo bovine
      vagina.

PMID- 12479304
TI  - Prescribing cascade for non-food-producing species, and changes relating to
      Cushing's disease.

PMID- 12479305
TI  - Studies of PMWS and Salmonella infection in UK pigs.

PMID- 12479306
TI  - Mastitis and somatic cell counts.

PMID- 12479307
TI  - Reticulitis due to an identification bolus?

PMID- 12479308
TI  - What is veterinary science?

PMID- 12479310
TI  - Report calls for plan to protect U.S. agriculture from terrorism.

PMID- 12479311
TI  - Is it ethical to keep animals in zoos?

PMID- 12479312
TI  - Zoos wrestle with fate of surplus animals.

PMID- 12479313
TI  - Measuring stress in captive animals.

PMID- 12479314
TI  - Designing zoo habitats that promote animal well-being.

PMID- 12479315
TI  - Avian influenza debate continues.

PMID- 12479316
TI  - Blueprint for action receives praise.

PMID- 12479317
TI  - Final letters for now on feral cats.

PMID- 12479319
TI  - Final letters for now on feral cats.

PMID- 12479321
TI  - Progress being made in live animal classroom conditions.

PMID- 12479322
TI  - Animal welfare, social progress, and the veterinary profession.

PMID- 12479323
TI  - What is your diagnosis? Retrobulbar mass indenting the inferior aspect of the
      right globe.

PMID- 12479324
TI  - The carnivore connection to nutrition in cats.

PMID- 12479326
TI  - Results of the AVMA survey on companion animal ownership in US pet-owning
      households. American Veterinary Medical Association.

PMID- 12479325
TI  - Fluoroquinolone-induced retinal degeneration in cats.
AB  - Although the exact mechanism of fluoroquinolone-induced retinal degeneration in
      cats remains to be elucidated, it appears from the literature that a similar
      retinal degeneration can be reproduced from either direct intravitreal injection
      of high concentrations of drug or exposure to UVA light and drug in laboratory
      animals. (19,25) The fluoroquinolone molecular structure is also similar
      structurally to other drugs that are known to directly induce retinal
      degeneration, including the cinchona alkaloids and halogenated hydroquinolones.
      Experimental evidence suggests that both the parent compound and its breakdown
      products via metabolism and photodegradation are active inducers of retinal
      degeneration. (18,25) Development of toxicoses also appears to be dependent on
      the maximum concentration of active drug, metabolite, or both reaching the retina
      over time. (18) Evaluation of the literature suggests that risk factors
      predisposing cats to fluoroquinolone-induced retinal degeneration may include the
      following: 1) large doses or plasma concentrations of drug, 2) rapid IV infusion
      of the antibiotic, 3) prolonged courses of treatment, and 4) age. Theoretically,
      other risk factors may also be involved including the following: 1) prolonged
      exposure to UVA light while the antibiotic is being administered, 2) drug
      interactions, and 3) drug or metabolite accumulation from altered metabolism or
      reduced elimination. To date, there are no published reports suggesting that the
      dose of fluoroquinolones should be reduced in geriatric cats or those with renal
      or hepatic failure. However, accumulation of fluoroquinolone metabolites in dogs
      and of the parent compound in humans with decreased renal function has been
      reported. (8-10) In humans with decreased renal function has been reported. (8
      10) humans, fluoroquinolone doses are typically decreased in response to the
      degree of renal impairment. (28) In general, all fluoroquinolone antibiotics
      should be reserved for severe or recurrent infections, and whenever possible
      their use should be based on results whenever possible their use should be based
      on results of culture and susceptibility tests. When indicated, the
      fluoroquinolones, including enrofloxacin, can be used with limited risk of
      developing retinal degeneration in cats, provided the manufacturer's guidelines
      are adhered to and dose reduction is considered in geriatric cats or those with
      renal impairment. Dosing on renal impairment. Dosing on exact body weight using
      split dosing (2.5 mg/kg, PO, q 12 h) and avoidance of rapid IV infusions, and
      drug interactions may help to reduce the risk of retinal degeneration in some
      cases. Furthermore, monitoring cats for mydriasis and avoidance of UVA light
      while undergoing treatment may also be of benefit. Further evaluation of the
      pharmacokinetics of enrofloxacin and the other fluoroquinolones is required in
      geriatric cats or those with mild to moderate renal or liver impairment to
      determine whether drug accumulation, elevated peak concentrations of drug, or
      both may be occurring in this subset of cats. Therapeutic monitoring of drug
      concentrations may not always be feasible because of time and cost, but renal
      panels with dose or frequency reduction in response to the degree of renal
      impairment and the site and severity of infection may help to reduce retinal
      toxicosis.

PMID- 12479327
TI  - Prospective evaluation of laparoscopic-assisted gastropexy in dogs susceptible to
      gastric dilatation.
AB  - OBJECTIVE: To determine long-term outcome associated with laparoscopic-assisted
      gastropexy in prevention of gastric dilatation-volvulus (GDV) in susceptible dogs
      and to evaluate use of laparoscopy to correct GDV. DESIGN: Prospective study.
      ANIMALS: 25 client-owned large-breed dogs. PROCEDURE: 23 dogs susceptible to GDV
      were referred as candidates for elective gastropexy. These dogs had a history of
      treatment for gastric dilatation, clinical signs of gastric dilatation, or family
      members with gastric dilatation. Laparoscopic-assisted gastropexy was performed.
      One year after surgery, abdominal ultrasonography was performed to evaluate the
      attachment of the stomach to the abdominal wall. Two dogs with GDV were also
      treated with laparoscopic-assisted derotation of the stomach and gastropexy.
      RESULTS: None of the dogs developed GDV during the year after gastropexy, and all
      20 dogs examined ultrasonographically had an intact attachment. Another dog was
      euthanatized at 11.5 months for unrelated problems. Two dogs with GDV
      successfully underwent laparoscopic-assisted gastropexy after the stomach was
      repositioned. CONCLUSIONS AND CLINICAL RELEVANCE: Laparoscopic-assisted
      gastropexy resulted in a persisting attachment between the stomach and abdominal
      wall, an absence of GDV development, and few complications. Dogs with a high
      probability for development of GDV should be considered candidates for minimally
      invasive gastropexy. Carefully selected dogs with GDV can be treated
      laparoscopically.

PMID- 12479328
TI  - Comparison of a sidestream capnograph and a mainstream capnograph in mechanically
      ventilated dogs.
AB  - OBJECTIVE: To compare the ability of a sidestream capnograph and a mainstream
      capnograph to measure end-tidal CO2 (ETCO2) and provide accurate estimates of
      PaCO2 in mechanically ventilated dogs. DESIGN: Randomized, double Latin square.
      ANIMALS: 6 healthy adult dogs. PROCEDURE: Anesthesia was induced and
      neuromuscular blockade achieved by IV administration of pancuronium bromide.
      Mechanical ventilation was used to induce conditions of standard ventilation,
      hyperventilation, and hypoventilation. While tidal volume was held constant,
      changes in minute volume ventilation and PaCO2 were made by changing the
      respiratory rate. Arterial blood gas analysis was performed and ETCO2
      measurements were obtained by use of either a mainstream or a sidestream
      capnographic analyzer. RESULTS: A linear regression model and bias analysis were
      used to compare PaCO2 and ETCO2 measurements; ETCO2 measurements obtained by both
      capnographs correlated well with PaCO2. Compared with PaCO2, mainstream ETCO2
      values differed by 3.15 +/- 4.89 mm Hg (mean bias +/- SD), whereas the bias
      observed with the sidestream ETCO2 system was significantly higher (5.65 +/- 5.57
      mm Hg). Regardless of the device used to measure ETCO2, bias increased as PaCO2
      exceeded 60 mm Hg. CONCLUSIONS AND CLINICAL RELEVANCE: RelevancehAlthough the
      mainstream cas slightly more accurate, both methods of ETCO2 measurement
      correlated well with PaCO2 and reflected changes in the ventilatory status.
      However, ETCO2 values > 45 mm Hg may inaccurately reflect the severity of
      hypoventilation as PaCO2 may be underestimated during conditions of hypercapnia
      (PaCO2 > 60 mm Hg).

PMID- 12479329
TI  - Transvenous retrograde portography for identification and characterization of
      portosystemic shunts in dogs.
AB  - Transvenous retrograde portography for identification and characterization of
      portosystemic shunts in dogs A method for transvenous retrograde portography
      (TRP) in dogs suspected to have a portosystemic shunt (PSS) and results in 20
      dogs are described. For TRP, dogs were anesthetized and positioned in left
      lateral recumbency A dual-lumen balloon-tipped catheter was inserted into the
      right jugular vein and advanced into the azygos vein. The balloon was inflated to
      occlude the azygos vein, and contrast material was injected during fluoroscopic
      evaluation. The catheter was then positioned in the caudal vena cava just cranial
      to the diaphragm. The balloon was again inflated to occlude the vena cava, and
      contrast material was again injected. Once a shunt was identified, selective
      catheterization was attempted with a guide wire and angled catheter. A PSS was
      identified in 18 of the 20 dogs. In 10 of the 18, the shunt vessel could be
      selectively catheterized, allowing measurement of portal pressures while the
      shunt was occluded with the balloon. In 1 dog, results of TRP were normal, but
      subsequent exploratory celiotomy revealed a single extrahepatic PSS, which was
      surgically attenuated. The other dog in which results of TRP were normal did not
      have a macroscopic PSS. In dogs suspected to have a PSS, TRP may be a useful
      adjunctive diagnostic test that is less invasive than operative mesenteric vein
      portography and allows measurement of portal pressures before and after temporary
      shunt occlusion.

PMID- 12479330
TI  - Idiopathic mesenteric and omental steatitis in a dog.
AB  - A 2-year-old Miniature Dachshund was admitted to the hospital because of fever,
      frequent vomiting, and watery diarrhea. An intra-abdominal mass and a gastric
      ulcer were detected. At laparotomy, the omentum was yellow but not icteric,
      irregularly thickened, and fragile, and a large mass involving the root of the
      mesentery and the gastrosplenic ligament was found. The histopathologic diagnosis
      was steatitis, and the dog was treated with prednisolone and cyclosporine for 2.5
      years. After 1.5 years, the abdominal mass was not detectable. The dog died
      suddenly from perforation of the small intestine caused by a foreign body.
      Necropsy revealed severe adhesions between portions of the small intestine, and
      cicatrization of the mesentery. Cause of the mesenteric and omental steatitis was
      not apparent.

PMID- 12479331
TI  - Intramedullary spinal cord damage associated with intervertebral disk material in
      a dog.
AB  - Intervertebral disk extrusions into the spinal cord are rarely reported in
      veterinary medicine, and only necropsy findings are described in previous
      reports. It is hypothesized that a disk lesion results in forceful injection of
      disk material into the spinal cord. In the 3-year-old Miniature Doberman Pinscher
      of our report, acute clinical signs and results of magnetic resonance imaging
      were consistent with this disease and helped determine the extent and character
      of the lesions. Alteration in the appearance of the nucleus pulposus was
      important in determining that intervertebral disk disease may have been present
      in this dog. However, a definitive diagnosis of intramedullary disk extrusion can
      be made only via histologic examination of a biopsy specimen or at necropsy. The
      dog improved substantially after surgical decompression of the spinal cord, and
      histologic findings in a biopsy specimen of material found within the spinal cord
      were consistent with mature degenerate intervertebral disk material.

PMID- 12479332
TI  - Surgery alone or in combination with radiation therapy for treatment of
      intracranial meningiomas in dogs: 31 cases (1989-2002).
AB  - OBJECTIVE: To compare, for dogs with intracranial meningiomas, survival times for
      dogs treated with surgical resection followed by radiation therapy with survival
      times for dogs treated with surgery alone. DESIGN: Retrospective study. ANIMALS:
      31 dogs with intracranial meningiomas. PROCEDURE: Medical records of dogs with
      histologic confirmation of an intracranial meningioma were reviewed. For each
      dog, signalment, clinical signs, tumor location, treatment protocol, and survival
      time were obtained from the medical record and through follow-up telephone
      interviews. RESULTS: Dogs that underwent tumor resection alone and survived > 1
      week after surgery had a median survival time of 7 months (range, 0.5 to 22
      months). Dogs that underwent tumor resection followed by radiation therapy had a
      median survival time of 16.5 months (range, 3 to 58 months). CONCLUSIONS AND
      CLINICAL RELEVANCE: Results suggest that in dogs with intracranial meningiomas,
      use of radiation therapy as a supplement to tumor resection can significantly
      extend life expectancy.

PMID- 12479333
TI  - Arthroscopic evaluation of menisci in dogs with cranial cruciate ligament
      injuries: 100 cases (1999-2000).
AB  - OBJECTIVE: To determine prevalence of meniscal injuries by use of arthroscopic
      examination in dogs with cranial cruciate ligament (CCL) injuries. DESIGN:
      Retrospective study. ANIMALS: 94 dogs with 100 injured CCLs. PROCEDURE: Records
      for 94 large dogs (> 20 kg [44 lb]) with 100 naturally occurring CCL injuries
      that were examined arthroscopically were reviewed. Pathologic findings in the CCL
      (complete or partial tears), prevalence and type of meniscal injuries, and
      periarticular osteophytes were recorded. RESULTS: 77% of joints had tears of the
      lateral meniscus; most were a series of small radial tears of the cranial horn.
      Fifty-eight percent of joints had tears of the medial meniscus. Positive
      correlation between complete tears of the CCL and medial meniscal damage was
      found. No significant relationships were detected between periarticular
      osteophyte formation and meniscal injury, medial and lateral meniscal injury, or
      degree of CCL tear and lateral meniscal injury. CONCLUSIONS AND CLINICAL
      RELEVANCE: There is a strong association between CCL injury and lateral and
      medial meniscal injuries in dogs. Clinical importance of lateral meniscal lesions
      is not known; a much higher percentage of dogs had such injuries than has been
      reported previously, possibly because of use of arthroscopy.

PMID- 12479334
TI  - Comparison of refractometers and test endpoints in the measurement of serum
      protein concentration to assess passive transfer status in calves.
AB  - OBJECTIVE: To evaluate 3 refractometers for detection of failure of passive
      transfer (FPT) of immunity in calves, and assess the effect of refractometric
      test endpoints on sensitivity, specificity, and proportion of calves classified
      correctly with regard to passive transfer status. DESIGN: Prospective study.
      ANIMALS: 90 calves. PROCEDURE: Blood samples were obtained from calves that were
      < 10 days old. Serum IgG concentration was determined by use of a radial
      immunodiffusion assay. Accuracy of 3 refractometers in the prediction of serum
      IgG concentration was determined by use of standard epidemiologic methods and a
      linear regression model. RESULTS: At a serum protein concentration test endpoint
      of 5.2 g/dL, sensitivity of each refractometer was 0.89 or 0.93, and specificity
      ranged from 0.80 to 0.91. For all refractometers, serum protein concentration
      test endpoints of 5.0 or 5.2 g/dL resulted in sensitivity > 0.80, specificity >
      0.80, and proportion of calves classified correctly > 0.85. Serum protein
      concentrations equivalent to 1,000 mg of IgG/dL of serum were 4.9, 4.8, and 5.1
      g/dL for the 3 refractometers. CONCLUSIONS AND CLINICAL RELEVANCE: The
      refractometers, including a nontemperature-compensating instrument, performed
      similarly in detection of FPT. Serum protein concentration test endpoints of 5.0
      and 5.2 g/dL yielded accurate results in the assessment of adequacy of passive
      transfer; lower or higher test endpoints misclassified larger numbers of calves.

PMID- 12479335
TI  - The Swedish Total Hip Replacement Register.

PMID- 12479336
TI  - Percutaneous internal fixation of scaphoid fractures via an arthroscopically
      assisted dorsal approach.
AB  - Percutaneous internal fixation of scaphoid fractures allows for more predictable
      union and less morbidity than cast treatment or open internal fixation. A
      headless cannulated compression screw (standard Acutrak) is implanted by way of a
      dorsal percutaneous approach with the aid of fluoroscopy and arthroscopy to
      confirm screw position and fracture reduction. This technique is indicated in the
      correction of acute proximal pole fractures, acute waist fractures, and delayed
      unions that are not associated with avascular necrosis or collapse. The details
      of this technique are reviewed. In a consecutive series of twenty-seven fractures
      (seventeen waist fractures and ten proximal pole fractures) treated with
      arthroscopically assisted dorsal percutaneous fixation, computed tomographic
      scanning confirmed 100% union at an average of twelve weeks. Eighteen fractures
      were treated within one month after the injury, and nine were treated more than
      one month after the injury. In this series, the fractures that were treated early
      (less than one month after the injury) healed more quickly than those treated
      later.

PMID- 12479337
TI  - Mechanism of anterior impingement damage in total knee arthroplasty.

PMID- 12479338
TI  - Emergent management of pelvic ring fractures with use of circumferential
      compression.

PMID- 12479339
TI  - Using the transepicondylar axis to define the sagittal morphology of the distal
      part of the femur.

PMID- 12479340
TI  - Neurophysiologic intraoperative monitoring during revision total hip
      arthroplasty.

PMID- 12479341
TI  - Surgical treatment of adult idiopathic cavus foot with plantar fasciotomy,
      naviculocuneiform arthrodesis, and cuboid osteotomy. A review of thirty-nine
      cases.

PMID- 12479342
TI  - Magnetic resonance imaging of the cervical spine. Current techniques and spectrum
      of disease.

PMID- 12479343
TI  - Why a taper?

PMID- 12479344
TI  - Computer-assisted navigation in total knee replacement: results of an initial
      experience in thirty-five patients.

PMID- 12479345
TI  - Computer-integrated anterior cruciate ligament reconstruction system.

PMID- 12479346
TI  - An evaluation of all-ultra-high molecular weight polyethylene unicompartmental
      tibial component cement-fixation mechanisms.

PMID- 12479347
TI  - Posterior medial capsular release and external rotation of the tibia to enhance
      exposure during total knee arthroplasty.

PMID- 12479348
TI  - Combined percutaneous internal and external fixation of type-C tibial plafond
      fractures. A review of twenty-two cases.

PMID- 12479349
TI  - Monitoring pelvic osteolysis following total hip replacement surgery: an
      algorithm for surveillance.

PMID- 12479350
TI  - Hip prosthesis of antibiotic-loaded acrylic cement for the treatment of
      infections following total hip arthroplasty.

PMID- 12479351
TI  - Polyethylene wear performance of oxidized zirconium and cobalt-chromium knee
      components under abrasive conditions.

PMID- 12479352
TI  - Clinical research in obstetrics and gynecology: a Baedeker for busy clinicians.

PMID- 12479353
TI  - A novel method for preparing histology slides without a microtome.
AB  - A study was undertaken to determine if it might be possible to prepare tissue
      sections on slides without the use of paraffin embedding, microtome sectioning,
      or cryostat sectioning which involve equipment and training not always available
      to scholars or professionals wishing to examine tissue microscopically. After
      evaluating many different reagents, cutting instruments and solid supports, we
      developed a method involving application of super glue to a slide, adhering a
      section of tissue to it, cutting the tissue with a disposable microtome blade,
      staining the tissue and removing the superglue with a commercially available
      product. The sections are similar to those sectioned on a microtome, but do not
      at this time equal their quality. However, histoarchitecture is preserved and
      individual cell morphology is usually good. We conclude that this is a viable
      method for preparing histology sections without the use of a microtome or
      cryostat, something long thought impossible. We have dubbed the method 'RAMP'
      (Rapid Adhesive-Mediated Procedure).

PMID- 12479354
TI  - Anatomical study of the diaphragm of the opossum (Didelphis albiventris).
AB  - The anatomical characteristics of the South American opossum diaphragm were
      described. Five male and seven female adult opossums, weighing between 700 and
      1110 g, were used. Animals were killed by ether inhalation saturation. The
      abdominal and thoracic walls were dissected and opened, the viscerae were removed
      and the diaphragm anatomy was described and photographed in situ. After diaphragm
      removal, some dimensional data were taken and tabled. Primary branches of the
      phrenic nerves were dissected under a surgical microscope. The secondary branches
      were studied and described by transillumination after clarification in acetic
      acid. The opossum diaphragm is domed and has a mean area of 54.33 +/- 3.8 cm2.
      Well-identified costal, sternal and lumbar parts form the peripheral muscular
      region. The central tendinous region presents with a V-like form. Three folioles
      comprise the phrenic centre and present different dimensions. The caudal vena
      cava passes through its foramen between the ventral and right dorsal folioles.
      Both right and left phrenic nerves present one ventral branch and one
      dorsolateral trunk in 50.0% and 66.67% of the cases, respectively.

PMID- 12479355
TI  - A quantitative study of the neural changes underlying pyloric stenosis in dogs.
AB  - This study aimed to quantify the neural changes in congenital pyloric stenosis in
      dogs and to study the comparative anatomy between this condition in dogs and that
      in infantile hypertrophic pyloric stenosis. Eight specimens from the pylorus of
      dogs with pyloric stenosis and six control specimens were examined using
      conventional histology and immunohistochemistry for a range of neural antigens.
      The changes in the proportion of nerves immunoreactive for each antigen were
      quantified and analysed statistically. The morphology of the nerves in the
      diseased dogs was similar to that in controls. Only vasoactive intestinal peptide
      was reduced in expression in dogs (median proportion in control dogs 0.57, in
      diseased dogs 0.17; P = 0.065). This study demonstrates both morphological
      similarities and significant differences between closely related conditions in
      dogs, humans and other species.

PMID- 12479356
TI  - Study of the nervous tissue development in rainbow trout (Oncorhynchus mykiss)
      embryos treated with oxytetracycline.
AB  - The purpose of this study was to discover whether the use of different doses of
      oxytetracycline causes any alteration in the development of nervous tissue in
      rainbow trout embryos. Five thousands eggs of females rainbow trout were divided
      into five groups. One group acted as control and the other four were administered
      with one of four doses of oxytetracycline, 0.025, 0.050, 0.100, or 0.201 microM,
      at the moment of fertilization. The eggs were incubated under pisciculture
      conditions to just before being ready to spring off. From the 10th day, 10-egg
      samples were taken regularly and fixed. Five were processed for histological
      techniques and stained with haematoxylin and eosin, cresyl fast violet and
      silver, the other five were homogenized for antibiotic detection. Histological
      alterations appeared in 37-day-old embryos, with an abnormal migration of the
      neuroblasts to the marginal layer of the neural cord, and alterations in the
      development of the lens and eye layers. Some embryos showed abnormal curvature of
      the spinal cord but these changes were not statistically significant.

PMID- 12479357
TI  - Ultrastructural observations on the platelets of the Arabian tahr (Hemitragus
      jayakari).
AB  - The ultrastructure of platelets was studied in specimens of peripheral blood from
      18 healthy adult Arabian tahrs (Hemitragus jayakari). The platelets were
      characterized by their extreme polymorphism. The number of alpha granules,
      typically one to six per cell, was considerably less than that reported for most
      animal platelets. Similar to humans, the platelets of the Arabian tahr had
      nucleoids within the alpha granules. However, nucleoids were not a consistent
      finding. One or more electron-dense granules, most commonly contained within
      clear vesicles, was commonly observed. A unique feature was the lack of an open
      canalicular system, which is considered a hallmark feature of this cell type in
      most mammalian and reptilian platelets.

PMID- 12479358
TI  - Effects of bovine serum albumin and estrous cow serum on development and
      ultrastructure of in vitro-produced porcine embryos.
AB  - This study evaluated the effects of bovine serum albumin (BSA; 4 mg/ml) and
      estrous cow serum (ECS; 10%) in North Carolina State University (NCSU) 23 medium
      on the development of in vitro-matured and in vitro-fertilized porcine oocytes.
      Early cleavage rate was significantly (P < 0.05) higher in NCSU/ECS (71.3 +/-
      14.7%) vs. NCSU/BSA (60.6 +/- 4.7%). Cleavage beyond the four-cell stage was not
      different between the two culture media (43.5 +/- 9.5% and 41.4 +/- 17.7%,
      respectively). The proportion of development to blastocysts was--with borderline
      significance (P = 0.05)--higher in NCSU/BSA (28.0 +/- 4.4%) than in NCSU/ECS
      (20.4 +/- 7.3%). Blastocysts produced in NCSU/BSA had significantly (P < 0.001)
      higher cell numbers than those cultured in NCSU/ECS (29.5 +/- 20.1 vs. 16.9 +/-
      10.8). The ultrastructure of in vitro-produced blastocysts from both culture
      systems was compared vs. in vivo-derived blastocysts. The latter showed a clear
      differentiation between trophectoderm (TE) and inner cell mass (ICM) cells. The
      TE cells were anchored to other TE cells or ICM cells by long, well-developed
      junctional complexes. The apical membrane of trophoblast cells was covered with
      numerous microvilli. Mitochondria were abundant, round to elongated in shape, and
      showed clear transverse cristae. The ultrastructure of blastocysts cultured in
      NCSU/BSA mimicked that of in vivo-derived embryos closely. In contrast,
      blastocysts from the NCSU/ECS culture system displayed an irregular
      ultrastructure with reduced numbers of organelles and numerous cytoplasmic
      inclusions, such as lipid-yolk-vacuoles and vacuoles with lipid content. In some
      sections of these embryos, cellular debris was detected in cytoplasm. The shape
      of mitochondria was more ovoid and cristae were not visible. In summary, our
      results demonstrate a beneficial influence of ECS in the culture medium on
      initial cleavage of in vitro-produced porcine embryos. Clearly negative effects
      of ECS in the subsequent culture period are associated with marked
      ultrastructural changes of embryonic cells.

PMID- 12479359
TI  - Ultrastructure of the spermatozoa from three odontocetes: a killer whale (Orcinus
      orca), a Pacific white-sided dolphin (Lagenorhynchus obliquidens) and a beluga
      (Delphinapterus leucas).
AB  - Semen was collected from three captive odontocetes: a killer whale (Orcinus
      orca); a Pacific white-sided dolphin (Lagenorhynchus obliquidens) and a beluga
      (Delphinapterus leucas). Semen was collected from the killer whale and Pacific
      white-sided dolphin using behavioural commands, whereas semen from the beluga was
      collected postmortem. Ultrastructure of the spermatozoa was examined using
      scanning and transmission electron microscopy. Species differences were more
      pronounced in the head sections followed by the midpiece and finally, the tail
      sections. Spermatozoa from the killer whale and beluga were similar but differed
      from the Pacific white-sided dolphin spermatozoa.

PMID- 12479360
TI  - Pluripotent stem cells--model of embryonic development, tool for gene targeting,
      and basis of cell therapy.
AB  - Embryonic stem (ES) cells are pluripotent cell lines with the capacity of self
      renewal and a broad differentiation plasticity. They are derived from pre
      implantation embryos and can be propagated as a homogeneous, uncommitted cell
      population for an almost unlimited period of time without losing their
      pluripotency and their stable karyotype. Murine ES cells are able to reintegrate
      fully into embryogenesis when returned into an early embryo, even after extensive
      genetic manipulation. In the resulting chimeric offspring produced by blastocyst
      injection or morula aggregation, ES cell descendants are represented among all
      cell types, including functional gametes. Therefore, mouse ES cells represent an
      important tool for genetic engineering, in particular via homologous
      recombination, to introduce gene knock-outs and other precise genomic
      modifications into the mouse germ line. Because of these properties ES cell
      technology is of high interest for other model organisms and for livestock
      species like cattle and pigs. However, in spite of tremendous research
      activities, no proven ES cells colonizing the germ line have yet been established
      for vertebrate species other than the mouse (Evans and Kaufman, 1981; Martin,
      1981) and chicken (Pain et al., 1996). The in vitro differentiation capacity of
      ES cells provides unique opportunities for experimental analysis of gene
      regulation and function during cell commitment and differentiation in early
      embryogenesis. Recently, pluripotent stem cells were established from human
      embryos (Thomson et al., 1998) and early fetuses (Shamblott et al., 1998),
      opening new scenarios both for research in human developmental biology and for
      medical applications, i.e. cell replacement strategies. At about the same time,
      research activities focused on characteristics and differentiation potential of
      somatic stem cells, unravelling an unexpected plasticity of these cell types.
      Somatic stem cells are found in differentiated tissues and can renew themselves
      in addition to generating the specialized cell types of the tissue from which
      they originate. Additional to discoveries of somatic stem cells in tissues that
      were previously not thought to contain these kinds of cells, they also appear to
      be capable of developing into cell types of other tissues, but have a reduced
      differentiation potential as compared to embryo-derived stem cells. Therefore,
      somatic stem cells are referred to as multipotent rather than pluripotent. This
      review summarizes characteristics of pluripotent stem cells in the mouse and in
      selected livestock species, explains their use for genetic engineering and basic
      research on embryonic development, and evaluates their potential for cell therapy
      as compared to somatic stem cells.

PMID- 12479361
TI  - Distribution of nociceptin-like immunoreactivity in the central nervous system of
      the Mongolian gerbil: an immunohistochemical study.
AB  - This study is designed to demonstrate the distribution of nociceptin, endogenous
      ORL1 receptor ligand, in the central nervous system of the Mongolian gerbil. To
      intensify the nociceptin-like immunoreactivity (NOC-LI), colchicine was
      administered into the lateral ventricle, at 48 h prior to the transcardiac
      perfusion. In the group without colchicine treatment, NOC-LI was observed in the
      fibres of the spinal dorsal horn, specifically in the superficial layers.
      However, the NOC-LI in the superficial layers disappeared after the
      administration of colchicine. In the brain, NOC-LI was prominent in the
      hypothalamus, hippocampus, cerebral peduncle, substantia nigra, dorsal raphe,
      periaqueductal grey, locus coeruleus and trapezoid nucleus. Colchicine treatment
      markedly intensified the NOC-LI in the somata of the central nervous system,
      whereas the untreated sections were too weak to observe and analyse. The
      distribution of NOC-LI provides informative data for studies of the neuronal
      circuit that nociceptin may be involved in.

PMID- 12479362
TI  - Telomere shortening and growth inhibition of human cancer cells by novel
      synthetic telomerase inhibitors MST-312, MST-295, and MST-1991.
AB  - Epidemiological studies suggest potent anticancer effects of tea catechins.
      Previously, we have reported (I. Naasani et aL, Biochem. Biophys. Res. Commun.,
      249: 391-396, 1998) that epigallocatechin gallate (EGCG), a major tea catechin,
      strongly and directly inhibits telomerase, a ribonucleoprotein that maintains
      telomeres and has been implicated in tumorigenesis. Here, we describe newly
      synthesized compounds MST-312, MST-295, and MST-199, as more effective telomerase
      inhibitors than EGCG. Continuous treatment of human monoblastoid leukemia U937
      cells with a nontoxic dose of each drug caused progressive telomere shortening
      and eventual reduction of growth rate accompanied by induction of the senescence
      associated beta-galactosidase activity. Particularly, in the case of MST-312, the
      effective dose required for the telomere shortening was 1-2 microM, which was 15-
      to 20-fold lower than that of EGCG. These compounds may provide a novel
      chemotherapeutic strategy for the treatment of cancers.

PMID- 12479363
TI  - Apoptosis induction by 1alpha,25-dihydroxyvitamin D3 in prostate cancer.
AB  - Calcitriol [1alpha,25-dihydroxyvitamin D3] is the natural ligand of the vitamin D
      receptor (VDR). Using cultured prostate cancer (PC) cell lines, LN-CaP and ALVA
      31, we studied the effects of 1alpha,25(OH)2-Vitamin D3 (VD3) on expression of
      several apoptosis-regulating proteins including: (a) Bcl-2 family proteins (Bcl
      2, Bcl-X(L), Mcl-1, Bax, and Bak); (b) the heat shock protein 70-binding protein
      BAG1L; and (c) IAP family proteins (XIAP, cIAP1, and cIAP2). VD3 induced
      decreases in levels of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1, BAG1L,
      XIAP, cIAP1, and cIAP2 (without altering proapoptotic Bax and Bak) in association
      with increases in apoptosis. In contrast to VDR-expressing LN-CaP and ALVA-31
      cells, VDR-deficient prostate cancer line Du-145 demonstrated no changes in
      apoptosis protein expression after treatment with VD3. In sensitive PC cell
      lines, VD3 activates downstream effector protease, caspase-3, and upstream
      initiator protease caspase-9, the apical protease in the mitochondrial
      ("intrinsic") pathway for apoptosis, but not caspase-8, an initiator caspase
      linked to an alternative ("extrinsic") apoptosis pathway triggered by cytokine
      receptors. VD3 induced declines in antiapoptotic proteins and also stimulated
      cytochrome c release from mitochondria by a caspase-independent mechanism.
      Moreover, apoptosis induction by VD3 was suppressed by overexpressing Bcl-2, a
      known blocker of cytochrome c release, whereas the caspase-8 suppressor CrmA
      afforded little protection. Thus, VD3 is capable of inhibiting expression of
      multiple antiapoptotic proteins in VDR-expressing prostate cancer cells, leading
      to activation of the mitochondrial pathway for apoptosis.

PMID- 12479364
TI  - p53 mediates DNA damaging drug-induced apoptosis through a caspase-9-dependent
      pathway in SH-SY5Y neuroblastoma cells.
AB  - The signaling pathway for DNA damaging drug-triggered apoptosis was examined in a
      chemosensitive human neuroblastoma cell line, SH-SY5Y. Doxorubicin and etoposide
      induce rapid and extensive apoptosis in SH-SY5Y cells. After the drug treatment,
      p53 protein levels increase in the nucleus, leading to the induction of its
      transcription targets p21(Waf1/Cip1) and MDM2. Inactivation of p53, either by the
      human papillomavirus type 16 E6 protein or by a dominant-negative mutant p53
      (R175H), completely protects SH-SY5Y cells from drug-triggered apoptosis.
      Cytochrome c and caspase-9 function downstream of p53 in mediating the drug
      triggered apoptosis in SH-SY5Y cells. In drug-treated cells, cytochrome c is
      released, and caspase-9 becomes activated. Inactivation of p53 blocks cytochrome
      c release and caspase-9 activation. Furthermore, drug-induced cell death can be
      prevented by expression of a dominant-negative mutant of caspase-9. These
      findings define a molecular pathway for mediating DNA damaging drug-induced
      apoptosis in the human neuroblastoma SH-SY5Y cells and suggest that inactivation
      of essential components of this apoptotic pathway may confer drug resistance on
      neuroblastoma cells.

PMID- 12479365
TI  - Induction of apoptosis in mesothelioma cells by antisurvivin oligonucleotides.
AB  - Malignant pleural mesothelioma is a rare and aggressive tumor characterized by
      rapid progression, late metastases, and poor prognosis. In this study, we
      investigated the expression of survivin, a member of the inhibitors of apoptosis
      protein gene family, in mesothelioma and an antisense oligonucleotide-based gene
      therapy for mesothelioma using survivin as a target. Initially, we documented the
      expression of survivin in human mesothelioma cell lines and fresh tissues using
      reverse transcription-PCR and Western blot analysis. Our results showed that
      survivin was overexpressed in 7 of 8 (87.5%) mesothelioma cell lines assayed and
      in all (12 of 12; 100%) freshly resected mesothelioma tissues analyzed. To
      investigate the use of survivin as a therapeutic target on mesothelioma, we
      carried out transfections with antisurvivin oligonucleotides to induce apoptosis
      in mesothelioma cell lines MS-1 and H28. Results from cellular transfection and
      subsequent analysis using the flow cytometry demonstrated that antisurvivin
      oligonucleotides induced significantly greater apoptosis rates in the survivin
      positive mesothelioma cell line H28 (42.5%) as compared with the control
      oligonucleotides (16.2%; P < 0.001). The survivin-negative cell line LRK1A
      (survivin-/-) did not apoptose with antisense oligonucleotides. Furthermore, time
      course evaluation by Western blot analysis showed that survivin was inhibited by
      antisurvivin oligonucleotides within 12 h after transfection. Our results show,
      for the first time, that survivin, an inhibitors of apoptosis protein family gene
      member, is highly overexpressed in malignant pleural mesothelioma. Down
      regulation of survivin by a targeted antisense oligonucleotide appears to be an
      effective gene therapy approach to the treatment of mesothelioma.

PMID- 12479366
TI  - Flavopiridol and trastuzumab synergistically inhibit proliferation of breast
      cancer cells: association with selective cooperative inhibition of cyclin D1
      dependent kinase and Akt signaling pathways.
AB  - Cyclin D1 is essential for Neu-induced cell growth and is induced by growth
      factors through Ras-dependent and Ras-independent signaling pathways (1). Because
      flavopiridol, a novel flavanoid cyclin-cyclin-dependent kinase inhibitor, may
      function through Ras-dependent and/or -independent pathways, we hypothesized that
      treatment of breast cancer cells with inhibitors of Neu signaling and
      flavopiridol might synergize to inhibit proliferation. Human breast cancer cell
      lines, which express high levels of endogenous Neu receptor, were treated with
      the anti-Neu antibody, trastuzumab, together with flavopiridol and subject to MTT
      assay. Cell lines were assayed for alterations in cell cycle by fluorescence
      activated cell sorter and signaling proteins by Western blot. Flavopiridol and
      trastuzumab synergistically inhibited DNA synthesis, cellular proliferation, and
      contact-dependent growth. Cytotoxic synergy was observed independent of the
      sequence of addition of the two drugs to cultured cells. In SKBR3 cells, a
      combination of trastuzumab and flavopiridol inhibited the Ras-MAPK-Akt pathway,
      decreased cyclin D1 abundance, and kinase activity to a greater extent than
      either drug alone. Compared with single-agent treatment, combination treatment
      selectively inhibited Akt and pRB phosphorylation. Cytotoxic synergy was observed
      with flavopiridol plus LY294002 (selective phosphatidylinositol 3-kinase
      inhibitor) but not with PD98059 (selective mitogen-activated protein kinase
      kinase 1 inhibitor) suggesting that Akt inhibition may be important in synergy.
      Zinc-induced overexpression of cyclin D1 in T-47D deltaMTcycD1 cells were more
      resistant to drug-induced cell death when compared with vector-transfected T-47D
      deltaMT cells. Cyclin D1 overexpression reverses drug treatment induced cell
      cycle arrest in SKBR3 cells. Flavopiridol and trastuzumab yield cytotoxic synergy
      in human breast cancer cells overexpressing Neu. Cyclin D1 overexpression results
      in combination drug resistance. In addition, inhibition of Akt may prove to be a
      useful therapeutic strategy in combination with flavopiridol.

PMID- 12479367
TI  - Constitutive and inducible Akt activity promotes resistance to chemotherapy,
      trastuzumab, or tamoxifen in breast cancer cells.
AB  - To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in
      breast cancer cell survival and therapeutic resistance, we analyzed a panel of
      six breast cancer cell lines that varied in erbB2 and estrogen receptor status.
      Akt activity was constitutive in four cell lines and was associated with either
      PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival
      because a PI3K inhibitor, LY294002, or transient transfection of a dominant
      negative Akt mutant inhibited Akt activity and increased apoptosis. When combined
      with therapies commonly used in breast cancer treatment, LY294002 potentiated
      apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide.
      Potentiation of apoptosis by LY294002 correlated with induction of Akt by
      doxorubicin or trastuzumab alone that occurred before the onset of apoptosis.
      Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen
      in estrogen receptor-positive cells greatly potentiated apoptosis, which was
      correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To
      confirm that the effects of LY294002 on chemotherapy-induced apoptosis were
      attributable to inhibition of Akt, we transiently transfected breast cancer cells
      with dominant-negative Akt and observed increased doxorubicin-induced apoptosis.
      Conversely, stably transfecting cells with constitutively active Akt increased
      Akt activity and attenuated doxorubicin-induced apoptosis. These studies show
      that endogenous Akt activity promotes breast cancer cell survival and therapeutic
      resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen
      might be an early compensatory mechanism that could be exploited to increase the
      efficacy of these therapies.

PMID- 12479368
TI  - Enhanced de novo ceramide generation through activation of serine
      palmitoyltransferase by the P-glycoprotein antagonist SDZ PSC 833 in breast
      cancer cells.
AB  - SDZ PSC 833 (PSC 833), a P-glycoprotein-targeted multidrug resistance modulator,
      sensitizes cancer cells to chemotherapy. Here we show that PSC 833 also
      potentiates the formation of ceramide. Because ceramide is a second messenger in
      chemotherapy-induced apoptosis, knowledge of the lipid pathways influenced by PSC
      833 is of relevance. In intact MDA-MB 468 breast cancer cells, ceramide
      generation increased 3-fold 1 h after PSC 833 addition (5.0 microM). Cyclosporine
      A, a structural analogue, failed to impact ceramide metabolism. Sphinganine, the
      upstream precursor of ceramide, also increased in response to PSC 833, and this
      could be blocked by adding L-cycloserine, a serine palmitoyltransferase (SPT)
      inhibitor. Exposure of cultured cells to PSC 833 (30 min to 4 h; 1-10 microM),
      followed by isolation of microsomes for in vitro assay, increased SPT activity
      60%, whereas palmitoyl CoA synthetase and ceramide synthase activities were not
      altered. SPT activity was also heightened by pretreating cells with either
      paclitaxel, N-(4-hydroxyphenyl)retinamide, etoposide, or daunorubicin; however,
      activation was half that attained by PSC 833. PSC 833 stimulated ceramide
      generation in other breast cancer cell lines as well, including BT-20, MDA-MB
      231, Hs 578T, T-47D, and MCF-7. In summary, several types of anticancer agents
      and the P-glycoprotein modulator PSC 833 share the ability to increase cellular
      ceramide levels by activation of SPT, the rate-limiting enzyme in the de novo
      pathway of ceramide synthesis. These data provide novel insight in the area of
      lipid-mediated cell death.

PMID- 12479369
TI  - Mechanisms of resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea in human
      medulloblastoma and rhabdomyosarcoma.
AB  - Medulloblastoma (D-341 MED) and rhabdomyosarcoma (TE-671) cell lines, which are
      resistant to either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the
      combination of BCNU and O6-benzylguanine (O6-BG), were generated by serial
      escalation of BCNU. The activities of O6-alkylguanine-DNA alkyltransferase (AGT),
      glutathione-S-transferase (GST), and total glutathione (GSH) of the parental,
      BCNU-resistant (BR), and BCNU + O6-BG-resistant (OBR) cells were measured. No
      significant differences in GST activity or total GSH were seen between the
      parental, BR, and OBR cells of both TE-671 and D-341 MED. The AGT activities of D
      341 MED (BR) and TE-671 (BR) were twice those of D-341 MED and TE-671,
      respectively, confirming the importance of this enzyme for BCNU resistance. The D
      341 MED (OBR) cells did not exhibit any AGT activity, suggesting that another
      mechanism must play a role in the drug resistance. Fewer DNA interstrand cross
      links (ICLs) were observed in D-341 MED (OBR) than in D-341 MED after 8 h BCNU
      (100-400 microM) treatment. However, the amounts of DNA ICLs observed in D-341
      MED and D-341 MED (OBR) were stable after 24 h. Microarray analysis showed the
      increased expressions of several metallothionein genes and down-regulation of
      several proapoptotic genes. The AGT activity of TE-671 (OBR) was 223 fmol/mg when
      the cells were grown in 10 microM O6-BG and decreased to about half this value
      when the O6-BG concentration was increased 60 microM. The AGT cDNA of TE-671
      (OBR) cells was cloned and found to contain a G-to-T transversion at codon 156,
      resulting in conversion of glycine to cysteine (G156C). In vitro mutagenesis has
      shown that the G156C AGT mutant is resistant to inactivation by O6-BG. Thus, the
      selection of a mutant AGT with decreased sensitivity to O6-BG is a significant
      contributing factor to BCNU + O6-BG resistance.

PMID- 12479370
TI  - BCH-1868 [(-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl)
      tetrahydrofuran]: a cyclic nucleoside phosphonate with antitumor activity.
AB  - Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum
      of antiviral activity. However, only a few of them are reported to have antitumor
      activity. In this study, we show that a tetrahydrofuran phosphonate analogue of
      guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl)
      tetrahydrofuran (BCH-1868), previously reported as having antiviral activity,
      also displays antitumor activity. In vitro, BCH-1868 inhibited the proliferation
      of several murine and human cancer cell lines with IC50s in the microM range
      independently of the tissue type or the presence of multidrug resistance protein
      MRP/gp190. In vivo, BCH-1868 was active against a variety of human tumor
      xenograft models (Caki-1, HT-29, DU 145, COLO 205, and CCRF-CEM). In all tumors
      tested, a significant tumor growth inhibition was noted at 40-50 mg/kg (daily x
      5), but no tumor regression was observed in the settings used. To better
      understand these results, we partially characterized, at the cellular level, the
      mechanism of action of this new cyclic nucleoside phosphonate and investigated
      its pharmacokinetic characteristics in mice. We showed that BCH-1868 exerts its
      antitumor activity by an inhibitory mechanism at the level of DNA polymerase a,
      resulting in arrest of DNA synthesis and a block of cell division at the S phase
      of the cell cycle. Low-circulating plasma concentration (Cmax = 87 microM; area
      under the curve = 1138 micromol x min/liters; after a bolus i.v. injection of 10
      mg/kg) and rapid clearance of the drug (terminal half-life, t1/2 = 16 min) may
      contribute to the modest antitumor efficacy observed in vivo.

PMID- 12479372
TI  - QSAR for anti-HIV activity of HEPT derivatives.
AB  - QSARs were derived for 103 analogues of 1-[(2-hydroxyethoxy)methyl]-6
      (phenylthio)thymine (HEPT), a potent inhibitor of the HIV-1 reverse transcriptase
      (RT). The activity of these compounds was investigated by means of multiple
      linear regression (MLR) and artificial neural network (ANN) techniques.
      Considering the relevant descriptors obtained from the MLR, a correlation
      coefficient of 0.92 (n = 95) was obtained with a 4-5-1 ANN model. The
      contribution of each descriptor to the structure-activity relationships was
      evaluated. The results showed that the anti-HIV activity of HEPT derivatives was
      strongly dependent on hydrophobic character and also steric factors of
      substituents.

PMID- 12479371
TI  - Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual
      inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase
      type-I.
AB  - Farnesyl:protein transferase (FPTase) inhibitors were developed as anti-Ras
      drugs, but they fail to inhibit Ki-Ras activity because Ki-Ras can be modified by
      geranylgeranyl:protein transferase type-I (GGPTase-I). L-778,123, an inhibitor of
      FPTase and GGPTase-I, was developed in part because it can completely inhibit Ki
      Ras prenylation. To support the clinical development of L-778,123, we developed
      pharmacodynamic assays using peripheral blood mononuclear cells (PBMCs) to
      measure the inhibition of prenylation of HDJ2 and Rap1A, proteins that are FPTase
      and GGPTase-I substrates, respectively. We validated these assays in animal
      models and show that inhibition of HDJ2 prenylation in mouse PBMCs correlates
      with the concentration of FPTase inhibitors in blood. In dogs, continuous
      infusion of L-778,123 inhibited both HDJ2 and Rap1A prenylation in PBMCs, but we
      did not detect inhibition of Ki-Ras prenylation. We reported previously results
      from the first L-778,123 Phase I trial that showed a dose-dependent inhibition of
      HDJ2 farnesylation in PBMCs. In this report, we present additional analysis of
      patient samples from this trial and a second Phase I trial of L-778,123, and
      demonstrate the inhibition of both HDJ2 and Rap1A prenylation in PBMC samples.
      This study represents the first demonstration of GGPTase-I inhibition in humans.
      However, no inhibition of Ki-Ras prenylation by L-778,123 was detected in patient
      samples. These results confirm the pharmacologic profile of L-778,123 in humans
      as a dual inhibitor of FPTase and GGPTase-I, but indicate that the intended
      target of the drug, Ki-Ras, was not inhibited.

PMID- 12479373
TI  - Development and validation of an average mammalian estrogen receptor-based QSAR
      model.
AB  - Development and evaluation of quantitative structure activity relationships
      (QSARs) for predicting estrogen receptor binding from chemical structure requires
      reliable algorithms for three-dimensional (3D) QSAR analysis and establishment of
      structurally diverse training sets of chemicals whose modes of action and
      measures of potency are well defined. One approach to selecting an appropriate
      training set is to minimize the biological variability in the model development,
      by using structurally restricted data sets. A second approach is to extend the
      structural diversity of chemicals at the cost of increased variability of
      biological assays. In this study, the second approach was used by organizing a
      training set of 151 chemicals with measured human alpha Estrogen Receptor
      (ERalpha), mouse uterine, rat uterine, and MCF7 cell Relative Binding Affinities
      (RBAs). The structurally augmented training set was submitted to a 3D pattern
      recognition analysis to derive a model for average mammalian ER binding affinity
      by employing the COmmon REactivity PAttern (COREPA) approach. Elucidation of this
      pattern required examination of the conformational flexibility of the compounds
      in an attempt to reveal areas in the multidimensional descriptor space, which are
      most populated by the conformers of the biologically active molecules and least
      populated by the inactive ones. The approach is not dependent upon a
      predetermined and specified toxicophore or an alignment of conformers to a lead
      compound. Reactivity patterns associated with mammalian ER binding affinity were
      obtained in terms of global nucleophilicity (E(HOMO)), interatomic distances
      between nucleophilic sites, and local nucleophilicity (charges or
      delocalizabilities) of those sites. Based on derived patterns, descriptor
      profiles were established for identifying and ranking compounds with RBA of >
      150, 150-10, 10-1 and 1-0.1% relative to 17beta-estradiol. Specificity of
      reactivity profiles was found to increase gradually with increasing affinities
      associated with RBAs ranges under study. Using the results of this analysis, an
      exploratory expert system was developed for use in ranking relative mammalian ER
      binding affinity potential for large chemical data sets. The validity of the RBA
      predictions were confirmed by independent development and comparison with
      measured RBA values.

PMID- 12479374
TI  - Linear free energy relationships on rate constants for dechlorination by zero
      valent iron.
AB  - By correlation analysis, molecular structural factors governing surface area
      normalized rate constants (k) for dechlorination by zero-valent iron, were
      identified. Twenty-nine quantum chemical descriptors computed by MNDO, AM1 and
      PM3 Hamiltonians for gas-phase and the conductor-like screening model (COSMO) for
      incorporating solvent (H2O) effects were studied. Besides the energy of the
      lowest unoccupied molecular orbital (E(LUMO)), the character of carbon-chlorine
      bonds (C-Cl bonds) and especially the strength of C-Cl bonds was found
      significant in governing the magnitude of log k. By PLS analysis, six two
      parameter linear free energy relationships (LFER) were obtained. The best two
      parameter LFER model was the one using E(LUMO) and C (the Coulombic interaction
      energy of the two-center term for the C-Cl bonds) computed by PM3/H2O method as
      molecular structural descriptors. Chlorinated compounds with high E(LUMO) and C
      values tend to have low dechlorination rate constants.

PMID- 12479375
TI  - Global government applications of analogues, SARs and QSARs to predict aquatic
      toxicity, chemical or physical properties, environmental fate parameters and
      health effects of organic chemicals.
AB  - Faced with the need to predict physical and chemical properties, environmental
      fate, ecological effects and health effects of organic chemicals in the absence
      of experimental data, several Government organizations have been applying
      analogues, Structure Activity Relationships (SARs) and Quantitative Structure
      Activity Relationships (QSARs) to develop those predictions. To establish some
      benchmarks for monitoring future increases in applications of analogues, SARs and
      QSARs by global Government organizations, this paper describes the current
      applications of analogues, SARs and QSARs by Australian, Canadian, Danish,
      European, German, Japanese, Netherlands, and United States Government
      organizations to predict physical and chemical properties, environmental fate,
      ecological effects and health effects of organic chemicals.

PMID- 12479376
TI  - Kinetic evaluation of the reactivity of flavonoids as radical scavengers.
AB  - The reactivity of flavonoids as radical scavengers was investigated under kinetic
      considerations using radical polymerization of methyl methacrylates initiated by
      benzoyl peroxide. The number of radicals which are trapped by each molecule of
      phenol (the stoichiometric factors, n values) decreased in the order of
      epigallocatechin-3-O-gallate (ECG) (5.5) > catechin (3.5) > resveratrol (2.4) >
      quercetin (1.9) > n-propylgallate (1.5) > hesperetin (1.0). The inhibition rate
      constants (k(inh)) (1-3 x 10(3) 1/(mol s)) for the flavonoids were not different
      from each other, and, therefore, the radical scavenging activity depend on n
      values. The n values of the fully oxidized flavonoids were estimated from the
      frontier orbital theory, using PM3 semiempirical molecular orbital calculation.
      The experimental n values were consistent with the calculated values.

PMID- 12479377
TI  - Mushroom body influence on locomotor activity and circadian rhythms in Drosophila
      melanogaster.
AB  - Whether or not mechanisms underlying circadian locomotor rhythms and learning are
      related anatomically through the mushroom bodies (MBs) was investigated by
      monitoring behavioral rhythmicity in flies with MB lesions induced by chemical
      ablation and by mutations in five different genes. All flies tested were later
      examined histologically to assess (1) MB neuroanatomy, and (2) the condition of
      the putative pacemaker cells--the ventral Lateral Neurons (LN(v)s) and their
      terminals that project to the vicinity of the MB calyces. All groups of flies had
      normal rhythms except for mushroom body miniature (mbm; only in a wild-type
      Berlin genetic background) and mushroom body defect (mud). MB ablation had no
      effect on the gender-specific differences in the rhythmic activity profile that
      are typical of wild-type flies. However, ablated males had a slightly longer
      period than untreated males and were more active under constant dark conditions.
      LN(v)s and their arborization patterns appeared normal in MB-ablated and in most
      mutant flies. Activity defects of mbm flies were attributed to genetic background
      rather than to the mutation alone. Misrouted LN(v) projections and approximately
      14% arrhythmia of mud flies were uncorrelated and attributed to pleiotropy rather
      than to specific effects of MB lesions. Our results imply that MBs are not
      involved in circadian activity rhythms but that they do have an inhibitory effect
      on activity levels of male flies.

PMID- 12479378
TI  - Diminishing Purkinje cell populations in the cerebella of aging heterozygous
      Purkinje cell degeneration but not heterozygous nervous mice.
AB  - Mice homozygous for the recessive, cerebellar affected mutations nervous and
      Purkinje cell degeneration display an almost complete loss of Purkinje cells
      during their first two postnatal months. We have recently shown a progressive and
      age-related loss of Purkinje cells in mutant mice heterozygous for mutations
      apparently recessive, such as staggerer and reeler, and have thus chosen to
      investigate whether a similar Purkinje cell loss occurred with aging in +/nr and
      +/pcd heterozygous mice. Purkinje cells were counted on serial sections stained
      with thionin obtained from 17-month-old male and female heterozygous mice and
      their respective wild-type controls. In the case of the +/nr and wild-type mice,
      no difference in cell counts was observed. However, +/pcd mice had significantly
      fewer (-18%) Purkinje cells (143.700+/-5.400) than control wild-types (175.100+/
      2.300); p<0.0001) at 17 months. These results extend our previous findings and
      further support the idea that apparently recessive neurological mutations may
      exert, at the heterozygous state, a deleterious effect upon Purkinje cells during
      the aging process.

PMID- 12479379
TI  - The effects of three Drosophila melanogaster myotropins on the frequency of
      foregut contractions differ.
AB  - Myotropic peptides can be grouped into different families based on their
      structure. Three Drosophila melanogaster myotropin families are represented by
      TDVDHVFLRFamide, dromyosuppressin (DMS), pEVRYRQCYFNPISCF, an allatostatin C-type
      peptide named flatline (FLT), and SDNFMRFamide, a FMRFamide-containing peptide.
      The structures of DMS, FLT, and SDNFMRFamide differ and each peptide is encoded
      by a different gene. In addition, the spatial and temporal distributions of DMS,
      FLT, and SDNFMRFamide are dissimilar. DMS, FLT, and SDNFMRFamide each decreases
      heart rate; however, their effects are profoundly different. Likewise, the
      effects of these three myotropins on the frequency of the spontaneous
      contractions of the crop, an anterior portion of the foregut, differ. DMS stops
      crop movement without recovery for at least a 10-min period after applying the
      peptide, FLT significantly decreases the frequency of spontaneous contractions,
      but its effect partially reverses within a few minutes after applying the
      peptide, and SDNFMRFamide only slightly decreased crop motility, an effect that
      was not significantly different from the effect of saline. The differences in the
      structures, distributions, and activities of DMS, FLT, and SDNFMRFamide suggest
      their synthesis and release are under different sensory inputs and regulatory
      mechanisms, and that roles in affecting the frequency of crop contractions
      differ.

PMID- 12479380
TI  - C-reactive protein as a biomarker of emergent osteoarthritis.
AB  - OBJECTIVE: We evaluated C-reactive protein (C-RP), a quantitative marker of the
      acute phase response, as a potential biomarker of prevalent and incident
      osteoarthritis of the knee (OAK). METHODS: Serum C-reactive protein
      concentrations were characterized with ultrasensitive rate nephelometry in a
      population-based sample of 1025 women (318 African-American and 707 Caucasian)
      who are enrollees in a study of musculoskeletal conditions at the mid-life.
      Assignment of OAK was based on Kellgren-Lawrence (K-L) scores of 2 or more on
      radiographs. Prevalent OAK was based on the baseline (1996) score while the
      classification of incident OAK was based on a score of 2 or greater at the follow
      up examination 2.5 years later amongst those with a baseline K-L scores of 0 or
      1. RESULTS: At baseline, the prevalence of radiographic OAK was 12% in
      participants who were aged 27-53 years and 18% in the subgroup of women aged 40
      53 years. The mean C-RP value was 2.31 mg/L, with values ranging from below
      detection (0.3 mg/L) to 47.4 mg/L. Higher C-RP concentrations were associated
      with both prevalent and incident OAK (P < 0.0001, and P < 0.0001, respectively).
      For each K-L score increase from 0 to 3, there was a significantly higher mean C
      RP value. Compared to women without incident OAK, women who developed OAK in the
      2.5-year follow-up had significantly higher baseline C-RP concentrations. Women
      with bilateral OAK had higher C-RP concentrations than women with unilateral OAK
      (6.65 mg/L +/- 0.56 vs 3.63 mg/L +/- 0.42, P < 0.007). BMI was highly correlated
      with C-RP (r = 0.58) and obesity was an effect modifier with respect to OAK and C
      RP concentrations. When stratified according presence or absence of OAK and
      obesity (BMI > 30 kg/m2), mean C-RP values were: obesity and OAK, 6.3 +/- 0.4
      mg/L; obesity but not OAK, 4.3 mg/L +/- 0.2; no obesity but OAK, 1.7 mg/L +/-
      0.8; and neither obesity nor OAK, 1.3 mg/L +/- 0.2 mg/L. These stratum means were
      significantly different from each other, indicating a higher C-RP with OAK after
      accounting for obesity. CONCLUSION: C-RP, as a measure of an acute phase response
      and inflammation, is highly associated with OAK; however, its high correlation
      with obesity limits its utility as an exclusive marker for OAK.

PMID- 12479381
TI  - Algo-functional assessment of knee osteoarthritis: comparison of the test-retest
      reliability and construct validity of the WOMAC and Lequesne indexes.
AB  - OBJECTIVE: To assess and compare the test-retest reliability and the construct
      validity of the Lequesne and the French-Canadian version of the WOMAC indexes.
      DESIGN: Patients with symptomatic knee osteoarthritis (OA) fulfilling the revised
      criteria of the American College of Rheumatology completed both the Lequesne and
      the French-Canadian version of the WOMAC indexes twice at a 3-h interval.
      Impairment outcome measures, patients' perceived discomfort in walking and
      handicap were recorded. For both questionnaires, an analysis was performed item
      by item. Repeatability was assessed using the intraclass correlation coefficient
      (ICC) and the Bland and Altman method. Construct validity was investigated using
      the Spearman rank correlation coefficient and a factor analysis was performed.
      RESULTS: 88 patients were included. Eight questions of the WOMAC section C and
      one question of the Lequesne index had insufficient psychometric properties.
      Although repeatability of questionnaires was fair to excellent (0.82, 0.68, 0.74,
      0.95 for the WOMAC sections A, B, C and Lequesne index respectively), construct
      validity could not be demonstrated. Factor analysis of the WOMAC extracted five
      factors which differed from the a priori triple stratification. Factor analysis
      of the WOMAC section C extracted two factors explaining 71% of the variance which
      could not be clinically characterized. For the Lequesne index, expected
      convergent correlations were not always achieved. Three factors were extracted by
      factor analysis explaining 58% of the variance. CONCLUSION: Despite their good
      test-retest reliability, the two composite indexes evaluated are not valid to
      assess the concept of functional disability induced by knee OA in a French
      population.

PMID- 12479382
TI  - History of acute knee injury and osteoarthritis of the knee: a prospective
      epidemiological assessment. The Clearwater Osteoarthritis Study.
AB  - OBJECTIVE: To evaluate the association between acute joint injury to the knee and
      knee osteoarthritis (OA). DESIGN: Prospective cohort. Sample size = 1,436. Men
      and women aged 40 years and older participating in the population-based
      Clearwater Osteoarthritis Study (1988-current) with biennial physical exams
      including serial radiographs. Radiologically confirmed knee OA = 27%; self
      reported knee injury = 11%. Lawrence and Kellgren ordinal scale was used to
      determine radiological evidence of the study outcome, knee OA. Self-reported
      history of knee injury was used to determine the study exposure. RESULTS:
      Individuals with a history of knee injury were 7.4 (95% C.I. 5.9-9.4) times as
      likely to develop knee OA than were those individuals who did not have a history
      of knee injury. CONCLUSION: Acute knee joint injury appears to be a risk factor
      for the development of knee OA. Prevention strategies for OA should be targeted
      to those individuals with a history of acute knee injury.

PMID- 12479383
TI  - The association between joint stress from physical activity and self-reported
      osteoarthritis: an analysis of the Cooper Clinic data.
AB  - OBJECTIVE: The purpose was to evaluate the association between estimated joint
      stress from physical activity (PA) and hip/knee osteoarthritis (OA). DESIGN: A
      nested case-control study was performed using data from the Aerobics Center
      Longitudinal Study. Participants without self-reported OA at baseline who
      attended the clinic between 1974 and 1993 and returned a follow-up questionnaire
      in 1990 or 1995 were eligible. Cases were those who reported a physician
      diagnosis of OA of the knee and/or hip at follow-up (N = 415). A random sample of
      persons in the remaining cohort were classified as controls (N = 1995). PA was
      measured at baseline by self-report and subjects were classified as
      'moderate/high' or 'low' joint stress by PA type. Those reporting no PA were
      classified as sedentary with 'no' joint stress (the reference group). Men and
      women were analyzed separately. Stratified analysis and multiple logistic
      regression were used to assess the relationship between hip/knee OA and joint
      stress as predicted by PA. RESULTS: After adjustment for age, body mass index,
      years of follow-up, and history of hip/knee joint injury, among men, there was no
      association between hip/knee OA and low joint stress while moderate/high joint
      stress was associated with reduced risk of hip/knee OA (adjusted odds ratio (OR)
      = 0.62, 95% confidence interval (CI) = 0.43-0.89). Among women, both levels of
      joint stress were associated with reduced risk of hip/knee OA (OR = 0.58, 95% CI
      = 0.34-0.99 for low and OR=0.24, 95% CI = 0.11-0.52 for moderate/high).
      CONCLUSIONS: PA may reduce the risk of hip/knee OA, especially among women.
      Further research should assess the combined effects of frequency, intensity,
      duration and joint stress level of PA on incidence of hip/knee OA.

PMID- 12479384
TI  - A prospective study on knee pain and its risk factors.
AB  - OBJECTIVES: To evaluate the effects of work-related and individual factors as
      well as physical activity and sports on the incidence and persistence of knee
      pain among a working population. DESIGN: Employees of a large Finnish forestry
      company replied to a questionnaire (a modified version of the Nordic
      Questionnaire) on musculoskeletal pain and its possible risk factors at the
      baseline of this study. A cohort of 2122 workers free of knee pain and another
      cohort of 333 workers with severe knee pain were followed up for one year. The
      effects of the risk factors on the incidence and persistence of knee pain were
      studied using multivariable logistic regression models. RESULTS: A total of 214
      (10%) workers developed knee pain during the follow-up. Significant predictors of
      incident knee pain in the multivariable model were higher age, overweight,
      smoking, and previous knee injuries. Also, working with the trunk forward flexed
      in kneeling or standing position and physically strenuous work were non
      significant predictors of incident knee pain. Of those 333 workers with severe
      knee pain at baseline, 220 (66%) still reported severe knee pain after one year.
      Higher age and job dissatisfaction increased the risk of persistent symptoms.
      General physical exercise and different sports activities did not predict the
      incidence or persistence of knee pain. CONCLUSIONS: In this large prospective
      study, the risk factors for self-reported knee pain seemed to be highly similar
      to the risk factors for knee osteoarthritis (OA) reported in other papers. Age,
      previous knee injuries, overweight, and knee-straining work were those risk
      factors, which contributed to the incidence of knee pain. Psychosocial elements
      of work were more involved in the persistence of the symptoms in the knee.

PMID- 12479385
TI  - Interaction of chondrocytes, extracellular matrix and growth factors: relevance
      for articular cartilage tissue engineering.
AB  - The abundant extracellular matrix of articular cartilage has to be maintained by
      a limited number of chondrocytes. Vice versa, the extracellular matrix has an
      important role in the regulation of chondrocyte function. OBJECTIVE: In this
      review we discuss the role of the extracellular matrix in the regulation of
      chondrocyte function and the relevance for cartilage tissue engineering. To reach
      this goal the international literature on this subject has been searched with a
      major focus on the last 5 years. RESULTS: Structural matrix macromolecules (e.g.
      collagen, hyaluronate), but also growth factors (e.g. IGF-I, TGF beta) entrapped
      in the matrix and released under specific conditions affect chondrocyte behavior.
      These factors communicate with the chondrocyte via specific membrane receptors.
      In this way there is a close interaction between the extracellular and
      intracellular milieu. Articular cartilage has a limited capacity of intrinsic
      repair, which has resulted in the development of tissue engineering approaches to
      repair damaged cartilage. Successful application of scaffolds has to take into
      account the important role of both soluble and insoluble matrix-derived factors
      in cartilage homeostasis. CONCLUSION: Functional tissue engineering will only be
      realized when the scaffolds used will provide cartilage cells with the correct
      extracellular signals.

PMID- 12479386
TI  - The murine COMP (cartilage oligomeric matrix protein) promoter contains a potent
      transcriptional repressor region.
AB  - OBJECTIVE: A subgroup of patients with pseudoachondroplasia (PSACH) and multiple
      epiphyseal dysplasia (MED) have been found to harbor mutations within the
      cartilage oligomeric matrix protein (COMP) gene. These two diseases are autosomal
      dominant disorders that are characterized by an early onset of osteoarthritis
      (OA). The COMP gene is expressed primarily in chondrocytes in articular cartilage
      as well as in tendon and ligament. Therefore, control over tissue specific COMP
      expression may be an important aspect in cartilage biology. To begin an analysis
      of the regulation of COMP expression, we have cloned, sequenced and characterized
      the entire genomic clone for mouse COMP that includes the COMP promoter. METHODS
      AND RESULTS: The COMP coding region spans 19 exons over approximately 8.4 kb of
      DNA. The arrangement and size of the exons have a remarkable similarity to those
      of the human COMP genomic sequence, indicating a significant degree of genomic
      conservation. Analysis of a 453 basepair region of the putative COMP promoter
      reveals two strong transcriptional repressor elements located between position 
      356 and -304 and between -251 and -180, relative to the start site for
      transcription. These repressor elements down-regulate transcription from the
      promoter in a broad spectrum of cell lines. Removal of the repressor DNA sequence
      from the COMP promoter leads to significant enhancement in transcriptional
      activity, indicating that this region acts in a dominant manner to
      transcriptional activators located more proximal to the start site of
      transcription. This region also represses transcription when linked to a
      heterologous promoter. CONCLUSIONS: This repressor region probably down-regulates
      transcription from the COMP promoter in vivo. It may help to repress
      transcription of COMP in non-cartilaginous tissues and/or may aid in the
      expression of COMP to the appropriate level in tissues such as cartilage, tendon
      and ligament.

PMID- 12479387
TI  - Comparative calcification of native articular cartilage matrix vesicles and
      nitroprusside-generated vesicles.
AB  - OBJECTIVE: Articular cartilage matrix vesicles generate calcium pyrophosphate-
      and basic calcium phosphate-like mineral in vitro. We sought to determine the
      morphologic features and calcifying capacity of sodium nitroprusside (SNP)
      induced vesicles for comparison to those of controls. METHODS: Porcine articular
      cartilage was exposed to 1 mM SNP for 24 h and vesicles were isolated by
      enzymatic digestion and serial ultracentrifugation. Control vesicles were derived
      from an equal weight of untreated articular cartilage. Vesicles-containing
      fractions pelleted at 2 x 10(5) g x min (pellet I), 3 x 10(6) g x min (pellet II,
      the heavy vesicle fraction) and 8 x 10(6) g x min (pellet III, the light vesicle
      fraction) were analysed for Lowry protein content, nucleoside triphosphate
      pyrophosphohydrolase specific activity (NTPPPH) and ATP-dependent calcifying
      capacity. RESULTS: Electron micrographs (EM) revealed two populations of
      vesicular structures in both SNP and control pellets. In most experiments, there
      were no significant differences between the protein contents or ATP-dependent
      calcium accumulation of SNP vesicles compared to control vesicles. SNP vesicles
      in pellets I and II had lower NTPPPH activities than their respective controls, P
      < or = 0.01. CONCLUSIONS: Our data confirmed that 24-hour treatment with the
      apoptosis-inducing agent did not increase matrix vesicle protein or alter the
      calcifying activity of vesicles compared to those from control cartilage. SNP did
      generate vesicles with lower NTPPPH specific activity in most experiments. SNP
      vesicles, although morphologically similar to controls, are not biochemically
      identical to them.

PMID- 12479388
TI  - Microscopic localization of active gelatinases in equine osteochondritis
      dissecans (OCD) cartilage.
AB  - OBJECTIVE: To investigate the relationship between matrix metalloproteinase (MMP)
      activity and osteochondritis dissecans (OCD) in the equine joint. METHODS: Equine
      articular cartilage was obtained from normal (N = 8) and osteochondrotic (OCD) (N
      = 6) femoropatellar joints from horses at necropsy. The activity of gelatinase
      MMPs was determined in sections of cartilage by in situ gelatin zymography.
      RESULTS: Gelatinase activity was markedly increased in articular cartilage
      obtained from OCD samples and was particularly prominent in the deep cartilage
      zone. Activity was only seen in the pericellular area of chondrocytes. In
      addition, in OCD cartilage there were vertical lines of activity, starting from
      the deep zone and radiating towards the articular surface. In contrast, normal
      cartilage showed only a very small amount of gelatinolytic activity, which was
      not restricted to specific cartilage zones. Gelatin zymography of culture
      supernatants from isolated chondrocytes demonstrated increased production of MMP
      2 and MMP-9 from OCD chondrocytes. CONCLUSIONS: Sections of articular cartilage
      from OCD lesions revealed MMP activity, especially in the deep zone adjacent to
      the calcified subchondral bone. This MMP activity could account for the loss of
      cartilage integrity in the deep cartilage zone and the vertical lines of activity
      could represent areas of mechanical weakness, likely to result in fissures and
      the release of cartilage fragments into the joint space.

PMID- 12479389
TI  - Elevation of a collagenase generated type II collagen neoepitope and proteoglycan
      epitopes in synovial fluid following induction of joint instability in the dog.
AB  - CLINICAL RELEVANCE: Measurement of markers of cartilage pathology in synovial
      fluid may provide clinical rheumatologists and osteoarthritis (OA) researchers
      important information for early diagnosis of OA as well as a method for
      monitoring disease progression and response to treatment. This study demonstrates
      the value of this approach in an established model of OA (cranial cruciate
      ligament rupture) at a point distant enough from the original surgical
      manipulation so as to have little to no effect on the marker concentrations.
      OBJECTIVE: The objective of this study was to determine whether measurement of
      markers of cartilage collagen cleavage and proteoglycan turnover in synovial
      fluid from a canine model could be used to detect cartilage changes following the
      onset of joint instability during the development of OA. DESIGN: A model of joint
      instability that develops OA was created in 18 mature dogs using monopolar
      radiofrequency energy (MRFE). MRFE was arthroscopically applied to one cranial
      cruciate ligament (CCL) while the contralateral CCL was sham treated. The treated
      CCLs ruptured approximately 8 weeks (55 +/- 1.6 days) after MRFE treatment.
      Synovial fluid was collected at time zero prior to MRFE treatment, 4 weeks after
      MRFE treatment, and at 4, 8, and 16 weeks after CCL rupture. Synovial fluid
      concentrations of the neoepitope COL2-3/4C long (type II collagen cleavage by
      collagenase) and epitopes 3B3(-) (proteoglycan aggrecan sulfation) and 846
      (associated with aggrecan synthesis) were analyzed. RESULTS: Compared to sham
      treated joints, the synovial fluid concentrations of COL2-3/4C long and 3B3(-)
      were significantly increased 2.2 fold and 2.9 fold, respectively, in joints with
      MRFE treated CCLs following CCL rupture. Concentrations of the 846 epitope in
      synovial fluid showed a trend toward an increase, which was not significant,
      after CCL rupture. CONCLUSIONS: Concentrations of the collagenase-cleaved type II
      collagen neoepitope and 3B3(-) epitope in synovial fluid were significantly
      increased by 4 weeks and remained elevated for at least 16 weeks after CCL
      rupture. This suggests that in dogs the COL2-3/4C long neoepitope and 3B3(-)
      epitope are sensitive markers for changes in joint cartilage turnover in joints
      that are developing OA.

PMID- 12479390
TI  - Measles virus.

PMID- 12479391
TI  - Role for heat shock proteins in the immune response to measles virus infection.
AB  - Heat shock proteins (HSPs) are recognized for their support of protein
      metabolism. Interaction with viral proteins also enhances the development of
      innate and adaptive immune responses against the infecting agent. At the level of
      the infected cell, HSPs are uniquely expressed on the cell surface, where they
      represent targets of lymphokine activated killer cells. Necrosis of the infected
      cell releases complexes of HSP and viral protein, which, in turn, binds antigen
      presenting cells (APCs). One effect of binding is to stimulate APC maturation and
      the release of proinflammatory cytokines, an adjuvant effect that prepares the
      way for adaptive immune responses. A second effect of binding is to direct the
      antigenic cargo of the HSP into endogenous MHC presentation pathways for priming
      of naive cytotoxic T cells (CTL) or activation of antigen-specific CTLs. This
      alternate pathway of antigen presentation is essential to CTL priming following
      primary brain infection. Using heat shock to elevate brain levels of HSP in a
      mouse model of measles virus (MV) persistent infection, we provide evidence
      supporting a role for HSPs in promoting cell-mediated viral clearance from brain.
      The findings highlight the probable relevance of HSPs to anti-MV immunity,
      suggesting novel routes of both therapeutic intervention and preventative
      measures.

PMID- 12479392
TI  - Triggering of and interference with immune activation: interactions of measles
      virus with monocytes and dendritic cells.

PMID- 12479393
TI  - Measles virus-specific T-cell immunity in rodent models.
AB  - Measles virus (MV) infection still belongs to the most important infectious
      diseases world wide. To identify the components of the immune system that combat
      MV infection, infection models in rodents have been established. In rats and
      mice, the immune response to experimental MV infection is governed by the major
      histocombatibility complex (MHC). According to the MHC haplotype, the functional
      composition of the T-cell subsets determines the degree of susceptibility to
      experimental measles virus infection. CD4+ T-cells are the most important T-cell
      subset in combating experimental MV infection in rodents. However, the mechanism
      of action still remains to be elucidated.

PMID- 12479394
TI  - T cell responses in acute measles.
AB  - Immune containment of measles virus (MV) infection has long been a focus of
      interest for investigators. An emerging theme is that MV immunity is conferred by
      appropriately polarized antiviral CD4+ and CD8+ T cell populations. Recent
      technological advances permit the analysis of the composition and dynamics of
      these CD4+ and CD8+ T cell responses at the single cell level, and of the
      molecular events responsible for their induction. Novel insights into these
      issues for measles are discussed in the light of their importance for the
      development of an improved vaccine.

PMID- 12479395
TI  - Neutralizing B cell response in measles.
AB  - Co-evolving mechanisms of immune clearance and of immune suppression are among
      the hallmarks of measles. B cells are major targets cells of measles virus (MV)
      infection. Virus interactions with B cells result both in immune suppression and
      a vigorous antibody response. Although antibodies fully protect against
      (re)infection, their importance during the disease and in the presence of a
      potent cellular response is less well understood. Specific serum IgM appears with
      onset of rash and confirms clinical diagnosis. After isotype switching, IgG1
      develops and confers life-long protection. The most abundant antibodies are
      specific for the nucleoprotein, but neutralizing and protective antibodies are
      solely directed against the two surface glycoproteins, the hemagglutinin and the
      fusion protein. Major neutralizing epitopes have been mapped mainly on the
      hemagglutinin protein with monoclonal antibodies, producing an increasingly
      comprehensive map of functional domains.

PMID- 12479396
TI  - Ultraviolet-irradiated vaccinia virus recombinants, exposing HIV-envelope on
      their outer membrane, induce antibodies against this antigen in rabbits.
AB  - The construction and isolation of recombinants of vaccinia virus (IHD-J strain),
      bearing on their outer membrane a chimeric protein consisting of the cytoplasmic
      and transmembrane domains of vaccinia B5R protein and the external domain of HIV
      envelope, has been previously described by us. The present study aimed to
      investigate the potential use of such recombinants as a vaccine, following
      inactivation of their infectivity by ultraviolet (UV) irradiation. The minimal
      dose of UV irradiation, required for the complete inactivation of the infectivity
      of these recombinants, was determined. Injections of rabbits with the irradiated
      noninfectious recombinant viruses successfully induced specific antibodies
      against the HIV envelope antigen, in addition to those against the poxvirus.

PMID- 12479397
TI  - Mapping of two dominant sites of VP35 of Marburg virus.
AB  - Five types of anti-VP35 monoclonal antibodies (MAbs), four immune sera against
      Marburg virus (MBGV), and 11 overlapping recombinant VP35 fragments were used to
      map the epitopes for VP35 of MBGV. The purified full-size recombinant VP35 was
      highly immunogenic and retained the B-cell epitopes that were identical to those
      of the viral VP35. Two major sites on VP35 and a set of truncated VP35 fragments
      were found by use of an enzyme immunoassay and immunoblot. Site I was located in
      a region between amino acids 1 and 174 of the VP35 sequence, and only polyclonal
      antibodies (PAbs) against MBGV recognized epitopes at this site. Site II was
      mapped by use of anti-VP35 MAbs to the region between amino acid residues 167 and
      278 of VP35. Amino acids 252-278 of VP35 might be involved in the formation of
      the epitopes for MAbs. B-cell epitopes were not found on the C-terminus of VP35
      by use of PAbs or MAbs.

PMID- 12479398
TI  - Cell type-dependent cytokine expression after canine distemper virus infection.
AB  - Canine cells of different histogenesis were infected with the Onderstepoort
      strain of distemper virus (CDV) to study the effect of viral infection on
      cytokine production. Included were primary brain cells, dermal fibroblasts, and
      two cell lines, DH 82 cells (macrophage-like) and epithelial Madin-Darby canine
      kidney (MDCK) cells. All cultures produced infective virus. MDCK cells had the
      lowest percentage of CDV-antigen positive cells, and infection did not cause a
      significant increase of cell death. After infection, mRNA steady state levels of
      interleukin (IL)-1, IL-6, IL-8, IL-12, tumor necrosis factor-alpha (TNF), and
      transforming growth factor-beta (TGF) were analyzed using RT-PCR. IL-6 and TNF
      protein were assessed immunohistochemically. In general, CDV infection resulted
      in induction of pro-inflammatory cytokines. In primary brain and DH 82 cells, IL
      1, IL-6, and TNF were induced, and IL-1 and TNF but not IL-6 were upregulated in
      dermal fibroblasts. In contrast, in MDCK cells IL-1 and TNF expression was
      similar in infected and noninfected cells, whereas IL-6 was not produced in
      either condition. In addition, cytokine induction correlated to the degree of
      level of CDV production, and therefore cytopathic effects are presumed to be due
      to a direct virus-mediated or cytokine-mediated process. These findings suggest
      that pro-inflammatory cytokines, namely IL-1, IL-6, and TNF, which might play an
      important role in CDV pathogenesis, are induced in a cell-specific manner.

PMID- 12479399
TI  - Memory cytotoxic T cell responses to viral tegument and regulatory proteins
      encoded by open reading frames 4, 10, 29, and 62 of varicella-zoster virus.
AB  - Cytotoxic T cell recognition of tegument and regulatory proteins encoded by open
      reading frames (ORFs) 4, 10, 29, and 62 of varicella-zoster virus (VZV) was
      evaluated using limiting dilution conditions to estimate the precursor
      frequencies of memory T cells specific for these proteins in immune subjects.
      Responder cell frequencies for ORFs 4, 10, and 62 gene products, which are virion
      tegument components and function as immediate early viral transactivating
      proteins, were equivalent. CTLp recognition of VZV proteins made in latently
      infected cells, which include ORF4 and ORF62 proteins, was not maintained
      preferentially when compared to ORF10 protein, which has not been shown to be
      expressed during latency. T cell recognition of ORF29 protein, the major DNA
      binding protein, which is expressed during replication but not incorporated into
      the virion tegument, was less common than responses to ORFs 4, 10, and 62 gene
      products. Older individuals had diminished numbers of memory CTLp that lysed
      autologous targets expressing IE62 protein; these responses were increased after
      immunization with live attenuated varicella vaccine to the range observed in
      younger adults. Adaptive immunity to VZV is characterized by a broad repertoire
      of memory CTL responses to proteins that comprise the virion tegument and
      regulate viral gene expression in infected cells.

PMID- 12479400
TI  - The crystallization of biological macromolecules under microgravity: a way to
      more accurate three-dimensional structures?
AB  - The crystallization of proteins and other biological particles (including nucleic
      acids, nucleo-protein complexes and large assemblies such as nucleosomes,
      ribosomal subunits or viruses) in a microgravity environment can produce crystals
      having lesser defects than crystals prepared under normal gravity on earth. Such
      microgravity-grown crystals can diffract X-rays to a higher resolution and have a
      lower mosaic spread. The inferred electron density maps can be richer in details
      owing to which more accurate three-dimensional structure models can be built.
      Major results reported in this field of research are reviewed. Novel ones
      obtained with the Advanced Protein Crystallization Facility are presented. For
      structural biology, practical applications and implications associated with
      crystallization and crystallography onboard the International Space Station are
      discussed.

PMID- 12479401
TI  - Differences in the solution structures of the parallel beta-helical pectate
      lyases as determined by limited proteolysis.
AB  - The pectate lyase family of proteins has been shown to fold into a novel domain
      motif, the right-handed parallel beta-helix. As a means of gaining insight to the
      solution structure of the pectate lyases, the enzymes were subjected to limited
      proteolytic digestion by the endoproteases AspN, GluC and trypsin. The effects of
      proteolytic cleavage on enzymatic activity were determined, and the early
      products of proteolysis were identified by capillary electrophoresis, MALDI-TOF
      mass spectrometry and HPLC. A single peptide bond between Lys158 and Asp159 in
      pectate lyase B (PLb) was cleaved by both AspN and trypsin, with no detectable
      hydrolysis of PLb by GluC. Pectate lyase E (PLe) was hydrolyzed by trypsin
      between Lys164 and Asp165, a bond on an analogous loop structure found to be
      susceptible to proteolytic attack in PLb. AspN and GluC preferentially hydrolyzed
      peptide bonds (at Asp127 and Glu124, respectively) on another loop extending from
      the central beta-helical core of PLe. A single beta-strand of the central
      cylinder of the pectate lyase C (PLc) molecule was susceptible to all three
      proteases used. These data demonstrate that the most susceptible peptide bonds to
      proteolytic scission within the native enzymes lie on or near one of the three
      parallel beta-sheets that compose the core domain motif Despite the proximity of
      the proteolytic cleavages to the catalytic sites of the enzymes, significant
      retention of lyase activity was observed after partial proteolysis, indicating
      preservation of functional tertiary structure in the proteolytic products.

PMID- 12479402
TI  - Production, isolation and characterization of a sterol esterase from Ophiostoma
      piceae.
AB  - We studied extracellular sterol esterase production by the ascomycete Ophiostoma
      piceae in liquid culture. Esterase activity was found in low levels in glucose
      medium but it was strongly induced by olive oil. An esterase was purified from
      the 0.5% olive oil-supplemented cultures using ultrafiltration followed by a
      single chromatographic step on a hydrophobic interaction column. The enzyme was a
      glycoprotein with 8% N-linked carbohydrate content, a molecular mass by SDS/PAGE
      around 56.5 kDa and an isoelectric point of 3.3. Its N-terminal sequence was
      TTVNVKYPEGEVV. Substrate specificity studies showed that the O. piceae esterase
      hydrolyzes p-nitrophenol esters, tributyrin, triolein and different cholesterol
      esters. Both affinity (Km) and catalytic constant (k(cat)) were positively
      affected by the length of the fatty acid esterifying glycerol and cholesterol.
      The presence of double bonds in the acyl chain increased the enzyme efficiency,
      although it affected the k(cat) values rather than the Km on the cholesterol
      esters. The O. piceae enzyme showed no interfacial activation. This enzyme could
      have biotechnological applications in paper manufacturing since it efficiently
      hydrolyzes both triglycerides and sterol esters, which form pitch deposits during
      manufacturing of softwood and hardwood paper pulps, respectively.

PMID- 12479403
TI  - Induction of thermal and chemical stability of O6-methylguanine-DNA
      methyltransferase by Ca2+.
AB  - Divalent cations stabilized rat recombinant O6-methylguanine-DNA
      methyltransferase (rMGMT) protein against heat treatment. Activity of rMGMT was
      completely abolished by incubating at 45 degrees C for 30 min, however, addition
      of 1.0 mM Mg2+, Ca2+ or Mn2+ significantly protected heat-induced inactivation of
      MGMT activity (50-60% vs. 97% inactivation). Protective effect of Ca2+ on the
      MGMT activity was concentration-dependent up to 3 mM, and the thermal protection
      was effective up to 45 degrees C. In order to investigate Ca2+ binding site in
      rMGMT protein, truncated GST-rMGMT proteins containing N-terminal 39 amino acids
      (GST-rMGMT39), 70 amino acids (GST-rMGMT70) and full-length protein (GST-rMGMT)
      were prepared. Radiolabeled calcium ion [45Ca2+] was bound only to the GST
      rMGMT70 and GST-rMGMT, but not to the GST-rMGMT39, indicating that divalent
      cations could bind the residues between 40th and 70th of the rMGMT protein.
      Calcium binding was not observed in the site-directed mutant rMGMT proteins
      (rMGMT(D42A) and rMGMT(E45A)), confirmed by autoradiography using [45Ca2+] after
      nondenaturing gel electrophoresis; however, the above two mutants had the same
      catalytic activity as well as proteolytic sensitivity as the wild MGMT protein.
      Analysis by equilibrium dialysis revealed stoichiometric binding of one molecule
      of Ca2+ to one molecule of the protein. Since circular dichroism (CD) spectra
      indicated no discernible difference before and after Ca2+ binding, the above
      results suggested that neutralization of two negative charges of Asp42 and Glu45
      by Ca2+ resulted in thermal stabilization of the protein with minimum
      perturbation of its tertiary structure.

PMID- 12479404
TI  - Nested MWC model describes hydrolysis of GroEL without assuming negative
      cooperativity in binding.
AB  - Folding assistance and ATPase activity of GroEL are based on the existence of
      different conformations. In order to characterise these conformations, published
      data on steady state ATPase activity in the absence of GroES were reanalysed
      simultaneously in terms of the Nested MWC model. This model is a hierarchical
      extension of the symmetry-model of Monod et al. [J. Mol. Biol. 12 (1965) 88]. An
      unique set of GroEL specific parameters was obtained. This set was supported by
      comparison of predictions arising from this set of values with experimental data
      for hydrolysis of ATP in the presence of ADP and ATPgammaS, binding of ATPgammaS
      and ADP to GroEL in the absence of ATP, and binding of ATP as monitored by
      fluorescence labelling. Thus, for the first time, multiple data sets for the
      interaction of nucleotides with GroEL are described quantitatively by an
      allosteric model. A noteworthy feature of our model is that no negative
      cooperativity in ATP binding occurs in accordance to experimental observations.
      Furthermore, the model also includes the existence of a conformation with very
      high ATPase activity. Such a conformation might be of importance at a certain
      stage in the folding cycle.

PMID- 12479405
TI  - Structural and functional properties of apolipoprotein A-I mutants containing
      disulfide-linked cysteines at positions 124 or 232.
AB  - Recombinant Cys mutants of apolipoprotein A-I (apoA-I) (A124C and A232C) have
      been prepared in disulfide-linked forms in order to assess the effects of
      unnatural covalent constraints on the folding of apoA-I in solution, its ability
      to bind lipids, form HDL-like particles, activate LCAT, and undergo structural
      adaptations to changing lipid contents. Both mutants, in dimer form, were shown
      to fold similarly to plasma apoA-I in solution, but had a slightly decreased
      alpha-helix content and no evidence of intermonomer interactions. All forms of
      the mutants bound to and disrupted dimyristoylphosphatidylcholine (DMPC)
      liposomes with similar kinetics and efficiency to plasma apoA-I, and formed
      reconstituted HDL (rHDL) particles with palmitoyloleoylphosphatidylcholine (POPC)
      in high yields at three different ratios of lipid/protein. While the monomeric
      mutants produced identical rHDL to plasma apoA-I, the disulfide-linked dimers had
      distinct particle distributions from each other and from native apoA-I. The A124C
      dimer formed rHDL with diameters of 86 and 78 A, while the A232C-dimer
      predominantly formed 96 A rHDL. These particles, and particles containing plasma
      apoA-I (96 and 78 A), were purified prior to structural and functional analyses.
      The structural properties of particles with similar diameters were comparable, as
      were their reactivities with LCAT; however, their ability to undergo structural
      rearrangements differed. The larger rHDL particles (96 and 86 A) containing
      native apoA-I or A124C-dimer, rearranged into smaller 78 A particles, while the
      96 A particles containing A232C-dimer were resistant to rearrangement and did not
      form 78 A particles. From the results, it is concluded that synthetic, random
      disulfide-linked dimers of apoA-I have many properties analogous to those of the
      naturally occurring Cys mutants, apoA-I-Milano and apoA-I-Paris, which are
      thought to have antiatherogenic effects in vivo. Also, the results have
      implications for current models of rHDL structure.

PMID- 12479406
TI  - Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase: theoretical and
      experimental study of the effect of glutamic acid 284 on the protonation state of
      lysine 213.
AB  - The crystal structure of Escherichia coli phosphoenolpyruvate (PEP) carboxykinase
      shows Lys213 is one of the ligands of enzyme-bound Mn2+ [Nat. Struct. Biol. 4
      (1997) 990]. The direct coordination of Mn2+ by N(epsilon) of Lys213 is only
      consistent with a neutral (uncharged) Lys213, suggesting a low pKa for this
      residue. This work shows, through theoretical calculations and experimental
      analyses on homologous Saccharomyces cerevisiae PEP carboxykinase, how the
      microenvironment affects Mn2+ binding and the protonation state of Lys213. We
      show that Glu284, a residue close to Lys212, is required for correct protonation
      states of Lys212 and Lys213, and for Mn2+ binding. deltaG and deltaH values for
      the proton reorganization processes were calculated to analyze the energetic
      stability of the two different protonation states of Lys212 and Lys213 in wild
      type and Glu284Gln S. cerevisiae PEP carboxykinase. Calculations were done using
      two modeling approaches, ab-initio density functional calculations and free
      energy perturbation (FEP) calculations. Both methods suggest that Lys212 must be
      protonated and Lys213 neutral in the wild-type enzyme. On the other hand, the
      calculations on the Glu284Gln mutant suggest a more stable neutral Lys212 and
      protonated Lys213. Experimental measurements showed 3 orders of magnitude lower
      activity and a threefold increase in Km for Mn2+ for Glu284Gln S. cerevisiae PEP
      carboxykinase when compared to wild type. The data here presented suggest that
      Glu284 is required for Mn2+ binding by S. cerevisiae PEP carboxykinase. We
      propose that Glu284 modulates the pKa value of Lys213 through electrostatic
      effects mediated by

PMID- 12479407
TI  - Identification of two calcineurin B-binding proteins: tubulin and heat shock
      protein 60.
AB  - Calcineurin (CaN) is a Ca++/calmodulin-dependent protein phosphatase with two
      subunits: a catalytic subunit (CaNA) and a regulatory subunit (CaNB). With four
      Ca(++)-binding sites and a sequence homology to calmodulin, CaNB has been defined
      as the regulatory subunit for CaNA. However, we have shown that mitochondrial
      expression of CaNB far exceeds that of CaNA. To investigate the role of this
      excess CaNB, we have generated glutathione-S-transferase-CaNB (GST-CaNB) fusion
      protein and demonstrated that the fusion protein predominantly bound to alpha
      tubulin, a 57 kDa protein in bovine brain extracts, and heat shock protein 60
      (Hsp60) in bovine kidney extracts. Their Ca(++)-dependent interactions with CaNB
      were verified by immunoprecipitation. The binding of CaNB could be demonstrated
      with purified alpha/beta tubulins and Hsp60, but not GroEL, a bacterial Hsp60
      analog. The interaction of CaNB and Hsp60 was not disrupted by the incubation
      with Hsp10, ATP and Mg++, suggesting that CaNB was not associated with Hsp60 as a
      misfolded substrate, and may serve as a regulatory protein. Thus, CaNB may play
      other regulatory roles in Ca(++)-dependent events in addition to its interaction
      with CaNA, and may be important for Ca(++)-dependent processes in mitochondria.

PMID- 12479408
TI  - Exceptional stability of a [2Fe-2S] ferredoxin from hyperthermophilic bacterium
      Aquifex aeolicus.
AB  - Aquifex aeolicus is the only hyperthermophile that is known to contain a plant-
      and mammalian-type [2Fe-2S] ferredoxin (Aae Fd1). This unique protein contains
      two cysteines, in addition to the four that act as ligands of the [2Fe-2S]
      cluster, which form a disulfide bridge. We have investigated the stability of Aae
      Fd1 with (wild-type) and without (C87A variant) the disulfide bond, with respect
      to pH, thermal and chemical perturbation, and compared the results to those for
      the mesophilic [2Fe-2S] ferredoxin from spinach. Unfolding reactions of all three
      proteins are irreversible due to cluster decomposition in the unfolded state.
      Wild-type and C87A Aae Fd1 proteins are extremely stable: unfolding at 20 degrees
      C requires high concentrations of the chemical denaturant and long incubation
      times. Moreover, their thermal-unfolding midpoints are 40-50 degrees higher than
      that for spinach ferredoxin (pH 7). The stability of the Aae Fd1 protein is
      significantly lower at pH 2.5 than pH 7 and 10, suggesting that ionic
      interactions play a role in structural integrity. Interestingly, the iron-sulfur
      cluster in C87A Aae Fd1 rearranges into a transient species with absorption bands
      at 520 and 610 nm, presumably a linear three-iron cluster, in the high-pH
      unfolded state.

PMID- 12479409
TI  - Reversible unfolding of bovine odorant binding protein induced by guanidinium
      hydrochloride at neutral pH.
AB  - An analysis of the unfolding and refolding curves at equilibrium of dimeric
      bovine odorant binding protein (bOBP) has been performed. Unfolding induced by
      guanidinium chloride (GdnHCl) is completely reversible as far as structure and
      ligand binding capacity are concerned. The transition curves, as obtained by
      fluorescence and ellipticity measurements, are very similar and have the same
      protein concentration-independent midpoint (C1/2 approximately 2.6 M). This
      result implies a sequential, rather than a concerted, unfolding mechanism, with
      the involvement of an intermediate. However, since it has not been detected, this
      intermediate must be present in small amounts or have the same optical properties
      of either native or denatured protein. The thermodynamic best fit parameters,
      obtained according to a simple two-state model, are: deltaG degrees un,w = 5.0 +/
      0.6 kcal mol(-1), m = 1.9 +/- 0.2 kcal mol(-1) M(-1) and C1/2 = 2.6 +/- 0.1 M.
      The presence of the ligand dihydromyrcenol has a stabilising effect against
      unfolding by GdnHCl, with an extrapolated deltaG degrees un,w of 22.2 +/- 0.9
      kcal mol(-1), a cooperative index of 3.2 +/- 0.3 and a midpoint of 4.6 +/- 0.4 M.
      The refolding curves, recorded after 24 h from dilution of denaturant are not yet
      at equilibrium: they show an apparently lower midpoint (C1/2 = 2.2 M), but tend
      to overlap the unfolding curve after several days. In contrast to chromatographic
      unfolding data, which fail to reveal the presence of folded intermediates,
      chromatographic refolding data as a function of time clearly show a rapid
      formation of folded monomers, followed by a slower step leading to folded dimers.
      Therefore, according to this result, we believe that the preferential
      unfolding/refolding mechanism is one in which dimer dissociation occurs before
      unfolding rather than the reverse.

PMID- 12479410
TI  - Effect of PPX1 inactivation on exopolyphosphatases of different cell compartments
      of the yeast Saccharomyces cerevisiae.
AB  - Inactivation of PPX1 encoding a major exopolyphosphatase (PPX1) in Saccharomyces
      cerevisiae results in a change of exopolyphosphatase spectra in the yeast cells.
      In the PPX1-deficient strain, an elimination of approximately 45 kDa enzyme is
      observed in cytosol and cell envelopes, and the activity of an exopolyphosphatase
      with a molecular mass of approximately 830 kDa increases 5-fold in the cytosol.
      These two enzyme activities differ greatly from each other not only in molecular
      masses but also in biochemical properties. Inactivation of PPX1 does not result
      in any changes in the content and properties of vacuolar exopolyphosphatase as
      compared with the wild strain of S. cerevisiae. In response to PPX1 mutation,
      exopolyphosphatase properties in the cell as a whole undergo modifications
      including the ability to hydrolyze polyphosphates with different lengths of the
      chain.

PMID- 12479411
TI  - Purification, characterization and molecular cloning of Vibrio fluvialis
      hemolysin.
AB  - Hemolysin of Vibrio fluvialis (VFH) was purified from culture supernatants by
      ammonium sulfate precipitation and successive column chromatographies on DEAE
      cellulose and Mono-Q. N-terminal amino acid sequences of the purified VFH were
      determined. The purified protein exhibited hemolytic activity on many mammalian
      erythrocytes with rabbit erythrocytes being the most sensitive to VFH. Activity
      of the native VFH was inhibited by the addition of Zn2+, Ni2+, Cd2+ and Cu2+ ions
      at low concentrations. Pores formed on rabbit erythrocytes were approximately 2.8
      3.7 nm in diameter, as demonstrated by osmotic protection assay. Nucleotide
      sequence analysis of the vfh gene revealed an open reading frame (ORF) consisting
      of 2200 bp which encodes a protein of 740 amino acids with a molecular weight of
      82 kDa. Molecular weight of the purified VFH was estimated to be 79 kDa by SDS
      PAGE and N-terminal amino acid sequence revealed that the 82 kDa prehemolysin is
      synthesized in the cytoplasm and is then secreted into the extracellular
      environment as the 79 kDa mature hemolysin after cleavage of 25 N-terminal amino
      acids. Deletion of 70 amino acids from the C-terminus exhibited a smaller
      hemolytic activity, while deletion of 148 C-terminal amino acids prevented
      hemolytic activity.

PMID- 12479412
TI  - Enhancement of proteinase inhibitory activity of recombinant human cystatin C
      using random-centroid optimization.
AB  - We had previously written a random-centroid optimization computer program for
      genetics (RCG) to optimize protein engineering, which was successfully applied to
      modify single site of the 16 amino acid residues at the active site of B.
      stearothermophilys neutral protease for improving thermostability [J. Agric. Food
      Chem., 46 (1998) 1655]. The same program was applied in this study to double-site
      mutation of the entire sequence of human cystatin C (HCC) with 120 residues for
      improving its protease inhibitory activity. The RCG program selected two sites
      simultaneously and amino acid residues to replace the sites selected in the
      sequence in order to find the best papain-inhibitory activity and stability of
      the protease inhibitor. Twenty-three double mutants and twenty-two single mutants
      were expressed by Pichia pastoris. Of the total 45 mutants, G12W/H86V mutant
      showed a 5-fold increase in the bioactivity over the recombinant wild-type (WT)
      cystatin. Also, P13F mutant exhibited a half-life temperature (T1/2) 5.2 degrees
      C higher than 68.2 degrees C of WT in addition to a 56% greater papain inhibitory
      activity. Mutation for diminishing beta-sheet content reduced polymerization of
      cystatin C, thus improving papain-inhibitory activity. The approach using RCG was
      able to improve the functional properties of cystatin by least relying on the
      prior knowledge of its molecular structure.

PMID- 12479413
TI  - Reaction kinetic pathway of the recombinant octaprenyl pyrophosphate synthase
      from Thermotoga maritima: how is it different from that of the mesophilic enzyme.
AB  - Octaprenyl pyrophosphate synthase (OPPs) catalyzes the chain elongation of
      farnesyl pyrophosphate (FPP) via consecutive condensation reactions with five
      molecules of isopentenyl pyrophosphate (IPP) to generate all-trans C40-octaprenyl
      pyrophosphate. The polymer forms the side chain of ubiquinone that is involved in
      electron transport system to produce ATP. Our previous study has demonstrated
      that Escherichia coli OPPs catalyzes IPP condensation with a rate of 2 s(-1) but
      product release limits the steady-state rate at 0.02 s(-1) [Biochim. Biophys.
      Acta 1594 (2002) 64]. In the present studies, a putative gene encoding for OPPs
      from Thermotoga maritima, an anaerobic and thermophilic bacterium, was expressed,
      purified, and its kinetic pathway was determined. The enzyme activity at 25
      degrees C was 0.005 s(-1) under steady-state condition and was exponentially
      increased with elevated temperature. In contrast to E. coli OPPs, IPP
      condensation rather than product release was rate limiting in enzyme reaction.
      The product of chain elongation catalyzed by T. maritima OPPs was C40 and the
      rate of its conversion to C45 was negligible. Under single-turnover condition
      with 10 microM OPPs-FPP complex and 1 microM IPP, only the C20 was formed rather
      than C20-C40 observed for E. coli enzyme. Together, our data suggest that the
      thermophilic OPPs from T. maritima has lower enzyme activity at 25 degrees C,
      higher product specificity, higher thermal stability and lower structural
      flexibility than its mesophilic counterpart from E. coli.

PMID- 12479414
TI  - Quantitative characterization of the nucleophile reactivity in penicillin acylase
      catalyzed acyl transfer reactions.
AB  - Nucleophile reactivity of two most known nuclei of penicillins and
      cephalosporins, 6-aminopenicillanic (6-APA) and 7-aminodesacetoxycephalosporanic
      (7-ADCA) acids, was quantitatively characterized. In penicillin acylase (PA)
      catalyzed acyl transfer reactions the relative reactivity of the added
      nucleophile compared to the water (i.e. nucleophile reactivity) is defined by two
      complex kinetic parameters beta(0) and gamma, and depends on the nucleophile
      concentration. In turn, parameters beta(0) and gamma were shown to be dependent
      on the structure of both reactants involved: nucleophile and acyl donor. Analysis
      of the kinetic scheme revealed that nucleophile reactivity is one of a few key
      parameters controlling efficiency of PA-catalyzed acyl transfer to the added
      nucleophile in an aqueous medium. Computation of the maximum nucleophile
      conversion to the product using determined nucleophile reactivity parameters in
      the synthesis of three different antibiotics, ampicillin, amoxicillin and
      cephalexin, showed good correlation with the results of corresponding synthetic
      experiments. Suggested approach can be extended to the quantitative description
      and optimization of PA-catalyzed acyl transfer reactions in a wide range of
      experimental conditions.

PMID- 12479415
TI  - Reversible fast-dimerization of bovine serum albumin detected by fluorescence
      resonance energy transfer.
AB  - Self-association of bovine serum albumin (BSA) was explored using fluorescence
      resonance energy transfer (FRET) between two populations of the protein labeled
      separately with either fluorescein-5'-isothiocyanate (FITC) or eosin-5'
      isothiocyanate (EITC). The energy transfer reached the steady state after 5 s at
      25 degrees C, indicating a fast exchange between oligomer subunits. The
      dependence of the energy transfer efficiency on the protein concentration and its
      reversion by unlabeled BSA demonstrate that association between BSA monomers
      occurs through a reversible path that involves specific interactions between the
      protein molecules. Because energy transfer took place even after blocking Cys 34
      with iodoacetamide, this residue might not be involved in the reversible self
      association process. The number of subunits forming the oligomer and its
      dissociation constant were determined from measurements of energy transfer as a
      function of the donor-acceptor ratio and of the total protein concentration.
      Analysis of these data indicated that BSA is in a monomer-dimer equilibrium with
      a dissociation constant of 10 +/- 2 microM at 25 degrees C in 10 mM MOPS-K (pH
      5.8).

PMID- 12479416
TI  - Crystallization and preliminary X-ray crystallographic analysis of human Geminin
      coiled-coil domain.
AB  - Initially discovered in Xenopus laevis, Geminin is a DNA replication initiation
      inhibitor found in higher eukaryotes. The coiled-coil domain of Human Geminin
      (termed GemH-37) has been crystallized by the vapor-diffusion sitting-drop
      method. A complete 1.74 A data set has been collected on a single orthorhombic
      crystal with unit cell parameters a = 25.25, b = 44.35, c = 68.58 A. Successful
      molecular replacement shows that GemH-37 is a dimeric parallel coiled-coil.
      Structural analysis is now in progress.

PMID- 12479417
TI  - SSDP1 gene encodes a protein with a conserved N-terminal FORWARD domain.
AB  - I describe the characterization of mouse, human and chicken SSDP1 orthologs that
      encode a highly conserved protein with over 90% identity at the amino acid level.
      Structurally, the protein consists of a well-preserved FWD (FORWARD)-domain at
      the N-terminal end and a proline-, glycine-, methionine- and serine-rich sequence
      in the central and C-terminal regions. The FORWARD domain, comprised of three
      alpha-helices, is characterized by the presence of a FWD-box of unknown function
      conserved not only in vertebrates, but also in nematode, plants, fly and yeast.
      Human SSDP1 spans about 200 kb on the chromosome 1p31-p32 region and consists of
      17 exons. The SSDP1 mRNA transcripts are distributed ubiquitously in adult human
      and mouse tissues.

PMID- 12479418
TI  - Plastic surgery research in the UK.
AB  - There is no single source of information on plastic surgery research in the UK.
      We sought to compile such information from a survey of trainees and consultants,
      and present an overview of the research activity, the number and designation of
      those engaged in research, sources of funds, principal areas of investigation and
      the perceived future for research.

PMID- 12479419
TI  - Altered speech following adenoidectomy: a 20 year experience.
AB  - Altered speech related to velopharyngeal insufficiency is a rare but well
      recognised complication of adenoidectomy. Over a 20 year period, 42 patients were
      referred to the Edinburgh cleft team for investigation of altered speech
      persisting for more than 12 months after adenoidectomy. We studied the cases to
      ascertain the incidence, clinical features and causes of altered speech in these
      patients and to assess the efficacy of a selective treatment policy. All data
      were prospectively collected when the patients were assessed in a
      multidisciplinary clinic and investigated by videofluoroscopy. Nasopharyngoscopy
      was also possible in half of the patients. Overall, 27 patients were male and 15
      were female, and their mean age was 6.5 years. The incidence was one in 1200
      adenoidectomies. Diagnoses included five submucous cleft palates, six occult
      submucous cleft palates, 22 cases of velopharyngeal disproportion, seven
      developmental or neurological causes, one iatrogenic palatal injury and one case
      that defied diagnosis. In six patients treatment was not required, 13 responded
      to speech therapy and 23 required surgical intervention. The choice of operation
      was based on the findings at investigation. Ten patients were treated by a
      superiorly based pharyngeal flap, 10 underwent a sphincteric pharyngoplasty and
      three had an intravelar veloplasty. Speech outcome was assessed in 36 cases.
      Treatment resulted in significantly improved speech in all but one patient and
      normal speech in 16 patients. Persistently altered speech is a rare complication
      of adenoidectomy. Preoperative screening by clinical examination will prevent
      some but not all of such problems. When patients present they should undergo
      multidisciplinary assessment and multi-modality investigation. A good outcome can
      be anticipated in most patients.

PMID- 12479420
TI  - Is hemifacial microsomia linked to multiple maternities?
AB  - Hemifacial microsomia describes a congenital orofacial malformation in which
      there is insufficient or disrupted development of the mandible affecting one side
      of the face. The aetiology of this condition remains unclear, but it has been
      postulated that twins (predominantly monozygotic) are more liable to be affected
      than singletons. This study investigates the incidence of multiple births amongst
      a large number of affected individuals and their families. Data were collected on
      145 individuals with hemifacial microsomia and microtia, using postal
      questionnaires and interviews in a hospital setting. These data were compared
      with the mean age-standardised twin maternity prevalence for England and Wales
      between 1975 and 1995 of 1.06% and the triplet maternity prevalence for England
      and Wales for 1995 of 0.034% (a multiple maternity being where more than one baby
      is born, either alive or stillborn). The prevalence of twin maternities amongst
      the affected individuals was 3.96% (P>0.05) and amongst their siblings it was
      4.02% (P<0.02). There was also an excess of twins in the rest of the family
      groups, predominantly due to a stronger history of twinning on the maternal side.
      As there were more twins amongst the affected individuals than in the general
      population, it seems likely that whatever the aetiology of hemifacial microsomia
      and microtia, the presence of a co-twin (or co-triplets) may make the causal
      event, or series of causal events, more likely to occur. This study supports the
      hypothesis that hemifacial microsomia and microtia are in some way linked to
      multiple births. Analysis of this link may provide new directions for research
      into the aetiology of a variety of congenital defects.

PMID- 12479421
TI  - The history of Trilucent implants, and a chemical analysis of the triglyceride
      filler in 51 consecutively removed Trilucent breast prostheses.
AB  - This study set out to detect specific classes of potentially genotoxic aldehydes
      resulting from soybean-oil peroxidation in oil samples from 51 Trilucent implants
      in 26 patients and two factory-retained prostheses. The chemical analysis was
      performed independently of AEI inc. All of the implants showed evidence of shell
      deterioration suggestive of lipid absorption, and of lipid bleed throughout the
      implant shell. The mean implant weight loss was found to be almost 2% per year.
      Although none of the implants had actually ruptured in-situ, we identified
      specific problems with anterior and posterior patch delaminations, making the
      implant prone to rupture. Our data suggest that the soybean oil in all the
      explanted Trilucent implants and the two factory-retained prostheses had
      undergone peroxidation, yielding aldehyde by-products in millimolar
      concentrations. These concentrations are over 1000 times that thought to be
      potentially genotoxic. The clinical implications of these findings remain
      unclear. Capsular tissue was submitted to AEI Inc for histological and chemical
      analysis, but the data have not been forthcoming, which is disappointing as this
      may provide further evidence for the risks of long-term complications in these
      patients.

PMID- 12479422
TI  - Bilateral parotid-duct diversion using autologous vein grafts for the management
      of chronic drooling in cerebral palsy.
AB  - Chronic drooling is a major problem in patients with cerebral palsy and other
      neurological dysfunctions. Various treatments, ranging from speech therapy to
      radical surgery, have been used to overcome this distressing problem, with
      surgery the most consistently successful. In this study, we used a new surgical
      technique to manage severe drooling. This involved the dissection of both parotid
      duct orifices, and their relocation, via a submucosal tunnel, into the tonsillar
      pillar using autologous vein grafts. Four patients were treated using this
      technique together with bilateral submandibular duct rerouting. The results were
      analysed by subjective judgements of drooling and retrograde sialography at 90
      days postoperatively. In all cases, salivary flow was reduced and drooling was
      significantly improved. Retrograde sialography revealed no signs of obstruction
      or stricture formation in any of the cases. No postoperative complications
      occurred. These preliminary results suggest that the bilateral surgical
      transposition of Stensen's ducts into the tonsillar pillar using autologous vein
      grafts together with bilateral submandibular duct rerouting can provide effective
      control of chronic drooling.

PMID- 12479423
TI  - Two in one: patient-controlled epidural analgesia (PCEA) to prevent erection and
      control pain in adult hypospadias-surgery patients.
AB  - Following penile surgery, erections are painful and may prejudice the result,
      because the sutures may not withstand a rigid erection. Therefore, prevention of
      erection and management of pain are extremely important following hypospadias
      repair, especially in adult patients. In this prospective study, we aimed to
      achieve these goals by using an epidural block with patient-controlled analgesia.
      We allocated 20 adult patients scheduled for hypospadias repair randomly either
      to receive or not to receive epidural analgesia. Postoperative pain was scored
      according to a standardised scoring system, based on a 10 point visual analogue
      scale. In group I (n = 10), analgesia was provided by a 3 ml h(-1) continuous
      infusion of fentanyl (2 microg) and bupivacaine solution (0.125%) in 1 ml saline
      via an epidural catheter for the first 3 days. Patient-controlled epidural
      analgesia was administered with an additional 5 ml of the same solution when the
      pain score was high (> 4). After 3 days, fentanyl was excluded from the treatment
      protocol, and analgesia was maintained with bupivacaine (0.125%). In group II (n
      = 10, control group), an epidural catheter was not inserted, and analgesia was
      maintained with pethidine (1 mg kg(-1)). Pain management was found to be more
      effective in group I. No erections occurred in group I, but the erection rate in
      group II was mean +/- s.d. = 1.7 +/- 0.2. The differences were found to be
      statistically significant (P<0.05). We highly recommend the technique described
      here, which offers efficient analgesia and control of erection in adult
      hypospadias patients.

PMID- 12479424
TI  - Early surgical treatment of Cyrano-nose haemangiomas with Rethi incision.
AB  - Nasal haemangiomas may cause great social distress. Complete involution of these
      haemangiomas does not usually result in a return to normality. The subcutaneous
      tumour infiltrates the alar cartilages, resulting in a globular aspect of the
      nasal tip. In this location, haemangiomas are slow to regress, and contour
      deformities result from the fibrofatty tissue that remains after total involution
      and also from definitive deformation of the nasal cartilages. Surgery to remove
      the affected tissue and preserve the anatomy seems to be the best treatment for
      these tumours. We report six cases of nasal haemangiomas removed using the Rethi
      incision and a double rim incision. This procedure allows complete dissection of
      the tumour, and leaves only a small scar. The alar cartilages are returned to
      their anatomical position to allow normal growth. Surgery is performed at around
      2 years of age; skin excision is not necessary because spontaneous skin
      retraction occurs. Our patients were evaluated by their parents, the surgeon and
      members of the dermatology staff not involved in their treatment. Pain, scar and
      final aspect were evaluated using statistical analysis. The parents and surgeon
      rated the postoperative results as very satisfactory or satisfactory. The
      dermatology staff also reported improvement after surgery. The scar is nearly
      invisible and the procedure allows excision of large nasal haemangiomas.

PMID- 12479425
TI  - The Marshall technique: an economic one-stage technique for nipple-areola
      reconstruction.
AB  - The goals of nipple-areola reconstruction are symmetry in position, shape, size,
      colour, tone, texture, sensation and responsiveness. These goals are best
      attempted when the breast-mound reconstruction has been completed. We describe a
      technique in which the skin of the neo-areola is raised as a split-thickness skin
      graft, and then re-grafted to the same site with a free nipple graft. This
      technique is always available, requires no special equipment, causes no donor
      site morbidity and produces excellent results. The disadvantage is that it may be
      more difficult following radiotherapy or if the mastectomy scar traverses the
      desired site of nipple-areola reconstruction. As with any skin graft, the neo
      areola may lose pigmentation, imperfectly 'take' or contract with time. This
      technique has not been previously described in the literature.

PMID- 12479426
TI  - Split-thickness skin grafts and negative-pressure dressings in the treatment of
      axillary hidradenitis suppurativa.
AB  - Although a number of different reconstructive techniques have been described for
      the treatment of axillary skin defects, split-thickness skin grafting continues
      to be the most common surgical modality. Here, we present our recent experience
      of using split-thickness skin grafts together with negative-pressure dressings
      for the management of defects following wide surgical excision of severe
      hidradenitis suppurativa. This technique ensures complete skin-graft take whilst
      allowing full shoulder mobility, thereby minimising the undesirable sequelae
      associated with split-thickness skin grafting alone.

PMID- 12479427
TI  - Adverse alteration of wound flora with topical negative-pressure therapy: a case
      report.
AB  - Topical negative pressure (TNP) has achieved widespread use in the treatment of
      problematic wounds. We report the case of a patient treated with TNP for groin
      wound dehiscence following inguinal block dissection. During treatment, clinical
      signs of sepsis developed, in association with a progressively worsening
      anaerobic wound infection. This infection settled with antibiotic therapy and
      cessation of TNP treatment. We postulate that the air-free environment created by
      TNP potentiated the growth of the anaerobic bacteria, resulting in significant
      sepsis, and therefore recommend close surveillance of bacterial flora while using
      this therapy, particularly in susceptible patients.

PMID- 12479428
TI  - Halo naevus or malignant melanoma? A case report.
AB  - It is generally felt that a halo naevus is benign, and patients can be reassured.
      The lesion is frequently left alone. We present a case where the clinician felt
      reassured, but at the patient's insistence the lesion was excised. The histology
      result was not anticipated.

PMID- 12479429
TI  - Microvascular myocutaneous flaps in the lumbosacral area using the iliac artery
      and vein as recipient vessels.
AB  - Lumbosacral tissue defects are usually closed with local flaps. Sometimes in
      large high-situated defects free microvascular flaps are used. However, finding a
      suitable recipient vessel for microvascular anastomosis in this region is
      difficult. In large soft-tissue defects high in the lumbar area, closure with a
      free flap using the iliac artery and vein as recipient vessels channelled from
      the pelvic cavity to the back through a drill canal in a bone presents an
      alternative option where other vessels are damaged by radiotherapy or infection.
      This has been used successfully in two cases.

PMID- 12479430
TI  - Extensor-tendon hypoplasia and multiple pterygia: Escobar syndrome in a 7-year
      old boy.
AB  - Escobar syndrome is a rare condition with autosomal-recessive inheritance,
      characterised by multiple pterygia, kyphoscoliosis, multiple joint contractures
      and craniofacial dysmorphisms. A number of other abnormalities are also
      attributed to the syndrome. Here, we present a case of isolated extrinsic
      extensor-tendon hypoplasia of the right index finger in a 7-year-old patient with
      Escobar syndrome. To our knowledge, this has not been previously described in
      connection with this syndrome.

PMID- 12479431
TI  - One-stage treatment of chronic osteomyelitis of the proximal tibia using a
      pedicled vascularised double-barrel fibular flap together with a muscle flap.
AB  - Although segmental bone loss together with a soft-tissue defect after debridement
      of a chronic osteomyelitic lesion of the tibia represents a challenging problem
      for the reconstructive surgeon, bone management has not usually been carried out
      at the time of soft-tissue coverage. In a one-stage procedure, we treated a
      patient who had suffered from chronic osteomyelitis of the tibia for 12 years,
      using a pedicled vascularised double-barrel fibular flap together with a pedicled
      medial gastrocnemius muscle flap, immediately after radical debridement of the
      osteomyelitic lesion. Bony union was obtained at 4 months. Full unprotected
      weight-bearing for normal walking was achieved 10 months after fibular transfer.
      Follow-up at 2 years showed no recurrence of the osteomyelitis.

PMID- 12479432
TI  - Reconstruction of an amputated fingertip by a prefabricated free volar forearm
      flap.
AB  - An amputated fingertip was banked temporarily under the skin of the volar wrist.
      This prefabricated fingertip was transferred back to the finger 2 months later,
      together with a free flap from the volar wrist based on the superficial palmar
      branch of the radial artery. The fingertip pulp showed a little pale
      pigmentation, but maintained its length well. The dorsal tip of the finger looked
      normal. This two-stage procedure made it possible to salvage the amputated bone
      and nail.

PMID- 12479433
TI  - Melanotic neuroectodermal tumour of infancy involving the orbit and maxilla:
      surgical management and follow-up strategy.
AB  - Melanotic neuroectodermal tumour (MNET) of infancy is a rare benign but locally
      aggressive tumour. We describe our surgical treatment of MNET of the orbital
      region. There was osteogenic relapse involving the bone of the orbit, 20 days
      after macroscopically complete excision of the primary tumour when the patient
      was 12 weeks old. This is only the second report of osteogenic relapse in MNET.
      The relapse was treated by excision of the involved orbital floor, preserving the
      orbital periosteum. The tumour has not recurred in 23 months of follow-up.
      Residual tumour islets may regress spontaneously after incomplete excision of
      MNET, but the relapse rate is between 15% and 45%. In our opinion, excising a
      safety margin of a few mm of apparently healthy bone reduces the risk of relapse.
      In contrast, the orbital contents should be preserved if they are macroscopically
      normal. Follow-up consisted of frequent physical examinations and CT scans.

PMID- 12479434
TI  - Management of aplasia cutis congenita in a non-scalp location.
AB  - We report the conservative management of a newborn with extensive aplasia cutis
      congenita of the thighs, associated with a monochorionic co-twin foetus
      papyraceous. The skin defects on both thighs, measuring 340 cm2, healed in 38
      days. The child was treated under medical supervision on an outpatient basis,
      with regular dressing changes at home by a district nurse. During the healing
      period, no local or systemic complications were noted. At 1 year follow-up the
      scars were stable with an acceptable appearance.

PMID- 12479435
TI  - A new conservative treatment for retention cyst of the lip: OK-432 injection.

PMID- 12479436
TI  - The use of preoperative swabs in cleft lip and palate repair.

PMID- 12479437
TI  - Painless steroid injections for hypertrophic scars and keloids.

PMID- 12479438
TI  - A simple technique for areolar marking.

PMID- 12479439
TI  - Retained tongue stud: an unusual complication of tongue piercing.

PMID- 12479440
TI  - Madelung's disease: which surgical treatment?

PMID- 12479441
TI  - The splint prescription.

PMID- 12479442
TI  - Optimisation of serial excision.

PMID- 12479443
TI  - A technical modification for effective fenestration of small split-skin grafts.

PMID- 12479444
TI  - Internal mammary node metastases in breast cancer: influence on patient and flap
      survival.

PMID- 12479445
TI  - Taking a leech to blood: but can you make him drink?

PMID- 12479446
TI  - Heavy metals extraction from anaerobically digested sludge.
AB  - This paper reports on the chemical extraction efficiency in the removal of heavy
      metals from sludge from an activated-sludge system, which receives as influent
      both industrial and municipal wastewater. Utilizing a series of chemical
      extractants in a sequential order comprised the first phase of the research,
      called sequential chemical extraction (SCE). The work started with the well-known
      Tessier method followed by Veeken and by Sims and Kline SCE schemes. Afterwards,
      modified versions of Tessier and Veeken schemes were applied. The second phase,
      named chemical extraction using pH progressive changes, concerns an alternative
      to the extraction process. Four acids were tested: nitric, hydrochloric, oxalic
      and citric and the pH values as well as the time were varied. Some conclusions
      reveal that although modifying Tessier and Veeken schemes provides more
      consistent results, SCE is still an imperfect method regarding specificity and
      selectivity. Besides, it is not advisable to apply one SCE scheme developed for
      one specific situation to another one, once the accurateness of the method
      depends on several factors such as sort of material and chemicals, contact time,
      temperature, etc. The extraction efficiency increases using nitric or
      hydrochloric acids at low pH values, promoting high extraction efficiency level.

PMID- 12479447
TI  - Characterization of wastewater and solids odors using solid phase microextraction
      at a large wastewater treatment plant.
AB  - A simple and reliable technique has been developed and used to detect odorous
      gases, i.e. propionic and butyric acids, carbon disulfide, dimethyl sulfide,
      dimethyl disulfide, and trimethylamine, emitted from various materials generated
      by the wastewater treatment process. The method detection limits are in the low
      ppb range and comparable to the odor threshold for human detection. In this study
      solid phase microextraction (SPME) was employed to characterize and quantify
      odorous compounds in the headspace over samples collected from various unit
      processes at the District of Columbia Wastewater Treatment Plant, Washington DC,
      USA. The patterns of odorous chemicals released from wastewater influent,
      thickened sludge, dewatered sludge and biosolids were evaluated. Volatile reduced
      sulfurs were more prevalent in samples collected from downstream processes and
      corresponded with decreased oxidation-reduction potential (ORP) conditions.
      Volatile fatty acids were consistently identified in the primary gravity
      thickeners, while trimethylamine could only be detected from biosolids after the
      post-liming process.

PMID- 12479448
TI  - Comparison of the quantity and quality of the microbiological content of sludge
      in countries with low and high content of pathogens.
AB  - The parasites present in the residual sludge generate by the diverse treatment
      processes of residual water vary, depending on the socioeconomic and
      epidemiological conditions of different communities. And although data exist at
      the global level regarding the microbiological quality of sludge, these data are
      practically nonexistent in developing countries. Therefore, this project compares
      the content of the four principal groups of parasites in residual sludge from the
      United States and Mexico. The marked differences between the orders of magnitude
      found in the two countries (coliphages 10(3)-10(6) and 1.3 x 10(5) PFU/gTS, fecal
      coliforms 10(7)-10(10) and 10(7), Salmonella typhi 10(6)-10(8) and 10(3) MPN/gTS,
      Giardia lamblia 10(2)-10(4) and 10(2) cysts/gTS and helminth ova from 73-177 and
      <1 to 10 viable HO/gTS, respectively) will permit proposing real, effective and
      economical stabilization processes (undoubtedly different from those of
      industrialized countries), and will thus take advantage of the benefits
      represented by the reuse and disposal of sludge, in addition to developing
      regulations in agreement with the conditions of each region.

PMID- 12479449
TI  - Relationship between partition of heavy metals in sewage sludge and elution of
      heavy metals.
AB  - Heavy metals in sewage sludge were classified into three partitions associated
      with extracellular and intracellular organic matters and the residue before and
      after different elution processes of heavy metals from the sludge. Alkalization
      of the sludge to pH 11 decreased the content of Cu in the three partitions and
      that of Ni in extracellular organic and residual ones. Acidification of the
      sludge to pH 3 decreased the content of Cd, Mn, Ni and Zn in all of the
      partitions and that of Cu in the intracellular organic one. A further decrease in
      the pH to 2 caused a decrease in the content of Cu in extracellular organic and
      residual partitions and that of Ni in the inorganic one. The addition of ferric
      sulfate to the sludge effectively lowered the content of Cd and Cu in
      extracellular organic and inorganic partitions under acidic conditions. These
      results would give information on a selection of the method for removing heavy
      metals from the sludge.

PMID- 12479450
TI  - Different options for metal recovery after sludge decontamination at the Montreal
      Urban Community wastewater treatment plant.
AB  - The MUG (Montreal Urban Community) treatment plant produces approximately 270
      tons of dry sludge daily (270 tds/day) during the physico-chemical treatment of
      wastewater. Recently, this treatment plant endowed a system of drying and
      granulation of sludge for valorization as an agricultural fertilizer having a
      capacity of 70 tds/day (25% of the daily sludge production). However, the metal
      content (mainly Cu and Cd) of the sludge surpasses the norms for biosolids
      valorization. In order to solve this problem, a demonstration project, from the
      lab scale to the industrial pilot plant, was carried out to test the Metix-AC
      technology for the removal of metals. A strongly metal-loaded filtrate was
      generated during the sludge decontamination. Tests concerned the study of the
      metal recovery by total precipitation and selective precipitation, as well as the
      use of alternative products for the metal precipitation. Other works consisted to
      simulate the acid filtrate recirculation from the decontaminated sludge (25% of
      the total volume) in the untreated sludge (75% of the total volume) intended for
      the incineration. The total precipitation with hydrated
      limeappearedeffectivefortherecoveryof metals (87% Cd, 96% Cr, 97% Cu, 98% Fe, 71%
      Ni, 100% Pb, 98% Zn). However, this option entails the production of an important
      quantity of metallic residue, which should be disposed of expensively as
      dangerous material. The selective iron precipitation does not appear to bean
      interesting option because the iron in solution within the leached sludge was
      principally present in the form of ferrous iron, which cannot be precipitated at
      pH lower than five. On the other hand, the use of commercial precipitating agents
      (TMT-15, CP-33Z, CP-NB and CPX) without pH adjustment of filtrate gave good
      results for the recovery of Cu and, to a lesser degree for the recovery of Pb.
      However, the efficiency for the other metals' (Cd, Cr, Fe, Ni and Zn) recovery
      was weaker (< 25%). Finally, the acid filtrate recirculation containing
      solubilised metals in untreated sludge destined for incineration appears to be
      the most interesting option. Metals in solution in the acid filtrate, precipitate
      or adsorb effectively (97% Cd, 97% Cr, 99% Cu, 82% Ni, 100% Pb and 87% Zn) on the
      solids of the untreated sludge. Moreover, TCLP tests were done on ashes produced
      during the incineration of sludge mixed with the acid filtrate produced during
      sludge decontamination. These tests showed that there were no significant
      differences, as regards the extractability of metals, between such ashes and
      those produced during the untreated sludge incineration without addition of
      filtrate. Therefore, it was predictable that this method can respect the current
      environmental standards required by the different governmental authorities.

PMID- 12479451
TI  - Characterisation and conditioning of Fenton sludges issued from wastewater
      treatment.
AB  - Characterisation tests were conducted to determine the feasibility of land
      application of the sludges produced in wastewater treatment by means of Fenton's
      Reagent. Physicochemical and microbiological parameters of Fenton sludges were
      compared to the values obtained for raw alum sludges. The Fenton sludges
      presented preferable characteristics such as the specific resistance to
      filtration (SRF), metals and pathogen content (fecal and tot al coliforms,
      helminth ova, and Salmonella sp.). The SRF ofthe Fenton sludges (1.55 x 10(13)
      m/kg) was 24% less than the alum sludge value (1.92 x 10(13) m/kg). The
      concentrations of fecal coliforms (0 MPN/g TS), Salmonella sp. (0 MPN/g TS),
      Helminth ova (22 HH/g TS) and metals correspond to the limits for biosolids of
      Class B for land application of the Mexican legislation. The Fenton reagent
      efficiently removes most of the pathogens, considered by the norms, by means of
      the combined action of the different stages that constitute this process. These
      results exhibit the Fenton reagent as a feasible treatment for generating sludges
      with characteristics of biosolids of Class B for land application. The
      preliminary results of conditioning tests show that Fenton sludges present better
      dewatering characteristics with regard to the alum sludge, for a dose of cationic
      polymer of 1 mg/g TS.

PMID- 12479452
TI  - Complete characterisation of thermally treated sludges.
AB  - As disposal options for sludges become more difficult to find and more expensive
      to operate, those relying on some form of thermal treatment are becoming more
      commercially attractive. The incentive, especially for more heavily populated
      countries, is the production of treated solids suitable for beneficial
      application to land. It is the level of treatment required to achieve this cost
      effectively which has been the focus of much of the research in this field. There
      are now several commercially available plants designed to thermally treat sludges
      and many have been in full scale operation for a number of years. One of the
      auxiliary claims often made by proponents of such treatments, is that the
      resultant sludges are more amenable to dewatering and therefore easier and
      cheaper to handle. In this work we have used a novel filtration rig to obtain
      complete sets of filtration data for different sludges. Historically sludge
      characterisation has been achieved by measurement of an empirical Capillary
      Suction Time (CST) parameter, however with the new filtration apparatus it is now
      possible to obtain fundamental sludge characteristics across a wide range of
      volume fractions in hours not days. We have applied this technology to
      characterise different sludge samples before and after thermal treatment under
      different sets of operating conditions (pH, temperature and pressure) to simulate
      some of the commercially available thermal treatment technologies. We have also
      examined the effects of various chemical oxidants (hydrogen peroxide and Fenton's
      reagent) used as pretreatments to the thermal process and attempted to compare
      their cost efficiencies. The results show that the physical structure of the
      sludge is irreversibly altered by decreasing the pH or heating to temperatures in
      excess of 150 degrees C in a way which significantly enhances the dewaterability
      of the material. The treated sludge not only has a higher permeability but also
      has a higher final per cent solids (often in the autothermal region). In contrast
      the amounts of chemical additives used in pretreatment to achieve similar effects
      are cost prohibitive.

PMID- 12479453
TI  - Use of lysis and recycle to control excess sludge production in activated sludge
      treatment: bench scale study and effect of chlorinated organic compounds.
AB  - The most widely used treatment system in the pulp and paper industry--the
      activated sludge--produces high quantities of sludge which need proper disposal.
      In this paper a modified activated sludge process is presented. A synthetic
      wastewater, prepared to simulate the effluent of bleached and unbleached pulp and
      paper plant wastewater, was submitted to treatment in a bench scale aerobic
      reactor. The excess sludge was lysed in a mechanical mill--Kaddy mill--and
      totally recycled to the aeration tank. In the first phase the synthetic
      wastewater, without the chlorinated compounds, was fed to the reactor. In the
      second phase increasing dosages of the chlorinated compounds were used. Total
      recycle of excess sludge after disintegration did not produce adverse effects.
      During the first phase average COD removal efficiency was 65% for the control
      unit, which operated in a conventional way, and 63% for the treatment unit, which
      operated with total recycle. During the second phase the COD removal efficiency
      increased to 77% in the control unit and 75% in the treatment unit. Chlorinated
      organics removal was 85% in the treatment unit and 86% for the control unit.
      These differences are not significant.

PMID- 12479454
TI  - Minimization of sludge production in biological processes: an alternative
      solution for the problem of sludge disposal.
AB  - A combined system associating activated sludge and ozonation was evaluated for
      the treatment of urban wastewater. Experiments have shown that 70% reduction in
      sludge production can be reached (compared to a reference system running in low
      loaded conditions Y(obs) = 0.28 g VSS.g COD(-1)) by applying an ozone dosage of
      0.05 g O3/g VSS(treated) Recycling of the ozonated sludge to the aeration tank
      induces a slight increase in effluent COD, but the biological treatment
      performance is maintained. Nitrification capabilities are not altered by the
      sludge reduction process and active biomass measurements revealed that
      autotrophic biomass seems to be less affected than the heterotrophs. Significant
      improvements in sludge settling characteristics are observed.

PMID- 12479455
TI  - Ozonation of wastewater sludge for reduction and recycling.
AB  - An ozone treatment system was introduced as an alternative method for municipal
      sludge treatment and disposal. A pilot-scale facility was built to investigate
      the feasibility of the ozonation for sludge reduction and recycle. The system
      consists of three main parts; advanced wastewater treatment, sludge ozone
      treatment and belt press dewatering. Ozonation of wastewater sludge resulted in
      mass reduction by mineralization as well as volume reduction by improvement of
      dewatering characteristics. The supernatant of the ozonated sludge, consisting of
      solubilized organics and micro-particles, proved to be an effective carbon source
      for denitrification. A simple economic assessment reveals that the ozonation
      process can be more economical than incineration for sludge treatment and
      disposal at small- and medium-sized wastewater treatment plants.

PMID- 12479456
TI  - A comparative study between mechanical, thermal and oxidative disintegration
      techniques of waste activated sludge.
AB  - The release performances of an organic and mineral activated sludge matrix were
      studied for a wide range of disintegration treatments like mechanical, thermal,
      thermal-chemical and oxidative disintegration techniques. The maximal COD release
      was 35% of total COD after 24 hours contact time at 95 degrees C. A limiting
      value of 60% COD release was obtained for 500 and 700 bars after 10 passes.
      Concerning theoxidative disintegration techniques (O3 and H2O2), a limiting value
      of around 60-65% of TOC release was observed. Therefore, it was hypothesised that
      thermal and mechanical treatments allow mainly for breaking apart the micro
      organisms while the oxidative treatment destroys the sludge flocs and disrupts
      the micro-organisms. A release effect of the mineral fraction is observed only
      oxidative disintegration techniques.

PMID- 12479457
TI  - The AF-BNR-SCP process as a way to reduce global sludge production: comparison
      with classical approaches on a full scale basis.
AB  - The paper presents a comparison between the performances of two full scale
      wastewater treatment plants operating in Italy, considering the mass balances
      including P treatments, and results coming from an analysis of 16 similar plants
      in Europe and USA, in order to evaluate sludge overproduction due to chemical P
      removal adoption. Specific production of 9.5 and 12.5 kgTS/P.E.y were found for a
      BNR and denitrification plant scheme respectively. These results were compared,
      on a mass balance basis, with the performances coming from the adoption of the
      integrated waste/wastewater cycles, in which OFMSW fermentation is used as C
      source to promote BNR performances and P removal from anaerobic supernatants as
      struvite crystals. ASM2 simulations are used to verify the advantages coming from
      this approach in terms of sludge reduction. A complete mass balance of the
      process is carried out, and it is shown that this last process allows us to
      achieve the lowest sludge production among the processes considered, coupling
      this with the economic benefits coming from OFMSW disposal and struvite
      crystallisation.

PMID- 12479458
TI  - Feasibility study of mechanically disintegrated sludge and recycle in the
      activated-sludge process.
AB  - The action mechanisms and performances of a combined system associating activated
      sludge and mechanical treatment (High Pressure Homogenizer) were evaluated for
      urban wastewater. Discontinuous experiments showed that the energy applied at the
      first pass was high enough to modify the sludge particulate fraction (high COD
      release) but without cell lysis. The applied shear forces led to a progressive
      cell break up (maximal COD release 90% total COD). Continuous experiments showed
      less than 20% reduction in sludge production (compared to a control run under the
      same loading conditions Y(TSS) = 0.35 g TSS x g(-1) COD(removed)) through the
      application of mechanical treatment (stress frequency = 0.2 d(-1)). Recycling of
      mechanical treated sludge to the aeration tank induced a slight increase in
      effluent TSS, but the biological performance seemed to be maintained. Significant
      improvements in sludge settling characteristics were observed.

PMID- 12479459
TI  - Key parameters in sludge dewatering: testing for the shear sensitivity and EPS
      content.
AB  - The fraction of extractable extracellular polymeric substances (EPS) and the
      shear sensitivity (k(ss)) are key parameters with respect to sludge dewatering,
      affecting the dry matter content of dewatered sludge and the dewatering rate and
      conditioner demand, respectively. Methods are described for determination of the
      two key parameters by use of the same laboratory test reactor. The implications
      of such characterisation with respect to dewatering are discussed based on
      examples of application to sludge processing and novel process development for
      sludge minimisation.

PMID- 12479460
TI  - Polymer conditioning of alum sludge and discrepancies between estimates of the
      optimum dosage.
AB  - The paper outlines the effects of polymer conditioning on alum sludge properties,
      such as floc size, density, fractal dimension (DF) and rheological properties.
      Experimental results demonstrate that polymer conditioning of alum sludge leads
      to: larger floc size with a plateau reached in higher doses; higher densities
      associated with higher doses; increased degree of compactness; and an initial
      decrease followed by an increase of supernatant viscosity with continued increase
      in polymer dose. The secondary focus of this paper dwells on a comparison of the
      estimates of optimum dose using different criteria that emanate from established
      dewatering tests such as CST, SRF, liquid phase viscosity and modified SRF as
      well as a simple settlement test in terms of CML30. Alum sludge was derived from
      a water works treating coloured, low-turbidity raw waters.

PMID- 12479461
TI  - Characterization and dewaterability of raw and stabilized sludge using different
      treatment methods.
AB  - A comparison of the characteristics and stabilization potential of the four most
      used sludge treatment systems in Mexico was made. A pilot plant constituted by
      separate systems for anaerobic and aerobic digestion, lime stabilization,
      conditioning and dewatering, was built and operated during four months in one of
      the biological wastewater treatment plants in Acapulco, Mexico. Composting of
      sludge was also made. An aerobic static pile was built using bulking materials
      available in the region. A turbine centrifuge was used for dewatering the
      stabilized sludge and results showed good performance of the device. The main
      problem for the beneficial use of treated sludge was its pathogenicity. The
      composting process allowed us to obtain a product with approximately 20 fecal
      coliform density (MPN/g); with lime stabilization, the sludge produced had a
      fecal coliform density of 2 MPN/g. From these results, it is concluded that both
      the composting process and the alkaline stabilization with lime produce a well
      stabilized sludge, bacteriologically safe that accomplishes the requirements for
      its use on soil without restrictions. Related to parasitological removal, the
      best helminth egg removals were obtained also using these two processes. Ascaris
      sp. densities in raw sludge (309-430 eggs/g) were reduced to a final density of 3
      14 eggs/g in the aerobic composting process and to 4-18 eggs/g in the lime
      stabilized sludge. Removal is not high enough to reach the recommended level for
      unrestricted use of stabilized sludge.

PMID- 12479462
TI  - Identification of factors contributing to degradation in autothermal thermophilic
      sludge digestion.
AB  - A laboratory scale ATAD reactor (6 days SRT, 24 h feed cycle) was operated at
      quasi steady-state conditions with real waste activated sludge feed. Hydrolysis
      tests of waste activated sludge demonstrated that 10% of feed suspended matter is
      hydrolysed practically instantaneously and 20-30% of all fed suspended matter is
      dissolved after 60 minutes in tap water and in cell free reactor liqueur equally.
      Respirometric, VSS and COD concentration data served as basis for calibration of
      a simple VSS based kinetic model. The calibrated model provided good fit to two
      separate sets of measured data. This model was used to evaluate different
      operation strategies. Modification of cycle length does not affect overall VSS
      emoval rate, while shorter cycle length or continuous operation helps avoid
      oxygen limited conditions. Further advantages of shorter feed cycles (reduced
      cooling effect, greater realizable load) support choosing continuous operation of
      the ATAD system if the main goal is VSS reduction. While reactor cascades
      increase efficiency, this advantage diminishes with increasing load. At high load
      rates increased construction costs are not justified by the expected improvement
      in efficiency.

PMID- 12479463
TI  - Improved alkaline stabilization of municipal wastewater sludge.
AB  - In Mexico, physicochemical sludge contains high levels of pathogens; and alkaline
      stabilization is an alternative for their control. However, the odours caused
      mainly by ammonia generation represent a disadvantage. On the other hand, the
      ammonia is known as an effective disinfectant. The aim of this study was to
      evaluate the disinfectant properties of ammonia in sludge, and use it in a closed
      alkaline stabilization system, which, not only copes with odours but also
      increases the efficiency of the process. Raw sludge from a municipal wastewater
      treatment plant using a physicochemical process was used. Ammonia was applied in
      doses from 10 to 50% w/w; also, doses from 5 to 40% of CaO were applied in open
      and closed systems and raw and treated sludge quality was evaluated. Results
      showed that ammonia removed 6 and 5 logs of faecal coliforms and Salmonella spp.,
      respectively and up to 94% of viable helminth ova. The closed system was more
      efficient than the open system when applying doses from 5 to 20% of CaO. Finally,
      the results indicate that the ammonia represents an alternative to disinfecting
      wastewater sludge and it can be used to enhance alkaline stabilization processes.

PMID- 12479464
TI  - Removal of fecal coliforms by thermophilic anaerobic digestion processes.
AB  - Recent U.S. EPA regulations (40 CFR Section 503) specify maximum concentrations
      of pathogens and metals for Class A wastewater treatment plant sludges. The most
      common sludge process is mesophilic (35 degrees C) digestion which stabilizes the
      solids, produces a combustible gas but does not create an effluent that meets the
      503 Class A pathogen requirements. This investigation was conducted to determine
      whether anaerobic digestion processes incorporating a thermophilic stage could
      achieve 503 Class A pathogen levels. The research reported here was a bench-scale
      screening study meant to identify the most promising process alternatives for
      further investigation. Fecal Coliform (FC) concentrations were used to assess
      disinfection efficiency. Digesters were 30 L capacity fed semi-continuously in
      draw-fill mode. Digester startup was rapid to produce true thermophiles.
      Temperature staging and pH were assessed in 3 sets of experiments: Set 1 were one
      stage ("acid phase"), Set 2 were one stage ("acid + methane phases") and Set 3
      were two stage ("acid phase" then "methanogenic phase"). Feed was a 1:1 mixture
      of Thickened Waste Activated Sludge and Primary Sludge. The following anaerobic
      digestion configurations and operating parameters allowed the production of
      digested sludge with a mean FC concentration statistically less than 10(3) (the
      regulatory value for Class A sludge): thermophilic single stage acid phase at 52
      and 62 degrees C; thermophilic single stage acid + methane phase at 48 degrees C,
      52 degrees C and 62 degrees C; two-stage mesophilic acid phase followed by
      mesophilic methane phase; two stage mesophilic acid phase followed by
      thermophilic methane phase at 48 degrees C, 52 degrees C and 62 degrees C. If the
      maximum digested FC concentration must be below 10(3) MPN/g TS then the following
      digester configurations and operating conditions will be compliant: two stage
      mesophilic acid phase followed by thermophilic methane phase at 52 degrees C and
      62 degrees C.

PMID- 12479465
TI  - Vermicomposting of sewage sludge: a new technology for Mexico.
AB  - In Mexico 31% of the treatment plants have a flow less than 60 l/s. This study
      offers a simple and economical alternative through vermicomposting to resolve the
      management of sewage sludge and water hyacinth for these small treatment plants.
      This study was developed with laboratory and pilot scale systems. In the
      laboratory Eisenia foetida survival was quantified. They were fed three doses of
      sludge and water hyacinth and different percentages of humidity were applied. The
      production of worm cocoons was quantified as biomass production and the reduction
      in the TV/STS ratio as an indicator of stability. To install the pilot system the
      mixture with the highest cocoon production was chosen. In the pilot test the
      effect of the worm population density on the waste degradation was observed, the
      experiment was divided into five modules, four with densities from 2.5 to 15
      kg/m2 and one module without worms that served as a blank test. RESULTS: the best
      mixture was 70% sewage sludge and 30% water hyacinth, with 80% humidity and an
      average production of 298 cocoons/kg of vermicompost. There were no significant
      differences in the TVS/TS reduction between the different modules with worms, but
      in the blank test module there was no reduction. The Type A vermicompost
      obtained, with non-restricted use, 900 fecal coliforms NMP/g, 0.0 helminth ova/g,
      highly organic (60% M.O.), high concentration of total nitrogen (2.5%),
      phosphorus (0.96%) and cationic exchange capacity (60.2 meq/100 g), which
      indicates that soil fertility would increase if used in agriculture.

PMID- 12479466
TI  - Anaerobic treatment of sludge: focusing on reduction of LAS concentration in
      sludge.
AB  - Anaerobic degradation of linear alkylbenzene sulfonates (LAS) was tested in
      continuous stirred tank reactors (CSTR). LAS12 was used as a model compound and
      was spiked on sewage sludge. The experiments clearly showed that transformation
      of LAS12 occurred under anaerobic conditions. The degree oftransformation varied
      between 14% and 25%. HPLC analysis showed that disappearance of LAS12 was
      followed by the formation of a metabolite. The experiments indicated that there
      is a clear correlation between degradation of organic matter contained in sludge
      and transformation of LAS 12. When the reduction degree of the organic matter
      increased from 22% to 28%, the transformation degree of LAS12 also increased,
      from 14% to 20%. Decreasing the total solids concentration of the influent sludge
      or increasing the spiked concentration of LAS12 did not alter the degree of LAS12
      transformation significantly. A clear correlation between transformed and
      bioavailable LAS12 was found, indicating that it is merely the bioavailable
      fraction of LAS12 that is transformed by anaerobic digestion. The results from
      the present study are promising and indicate that a great potential for
      biological degradation of LAS is possible even at anaerobic conditions.

PMID- 12479467
TI  - Two combined techniques to enhance anaerobic digestion of sludge.
AB  - The rate-limiting step during anaerobic digestion is the hydrolysis of the
      particulate organic matter and methanogenesis. Certain elements, such as iron,
      nickel and cobalt and some growth factors such as coenzymes are needed for the
      adequate growth of the organisms. The main objective of this research was to
      enhance anaerobic digestion of primary sludge combining thermal and alkaline pre
      treatment with stimulation of the methanogenic activity by adding yeast extract.
      Primary sludge was exposed, separately, to alkaline and thermal pre-treatment
      procedures. After this pre-treatment, different amounts of yeast extract were
      added to the sludge. The best COD, TSS and VSS removal rates were observed
      without pre-treatment and with the addition of 0.1% in weight of yeast extract.
      The highest specific methane production was obtained with thermal pre-treatment
      and 0.1% yeast addition. A second experimental stage was run for a closer
      analysis of the preliminary results. Thermal pre-treatment and 0.1% yeast
      addition was tested. The best results regarding both COD, TSS and VSS removal
      rates and methane production were obtained without thermal pre-treatment and with
      addition of yeast extract. The calculated F-values for the ANOVA-test show that
      the main influencing factor was the addition of yeast extract where the
      Biochemical Methane Production was doubled compared with the blank. The highest
      values for the hydrolysis constants were obtained at hydraulic retention times of
      six days after adding 0.1% of yeast extract.

PMID- 12479468
TI  - Thermochemical pretreatment in the anaerobic digestion of waste activated sludge.
AB  - Effects of a thermochemical pretreatment on the anaerobic digestion of waste
      activated sludge (WAS) was investigated by semicontinuously-fed digesters
      operated at 37 degrees C. WAS from a return sludge line of a municipal sewage
      treatment plant was pretreated by autoclaving at 130 degrees C for 5 minutes
      after adding 0.3g NaOH/g VSS. Solids of WAS were thermochemically solubilized to
      one half and then 60% or more were in totality solubilized in anaerobic digesters
      fed with pretreated WAS at 2-8 days of hydraulic retention times (HRT), while
      only 16-36% were solubilized in digesters fed with raw WAS. The adverse effect of
      the set temperature (130 degrees C) on the biodegradability of protein was not
      found. As a result, removal rates of COD in digestion was increased from 38% to
      57% at 8 days HRT by the pretreatment. A specific methane production rate in the
      pretreated process was three times as high as the normal process. The
      thermochemical pretreatment was found to be very effective to enhance
      biodegradability as well as solubilization of WAS in anaerobic digestion.

PMID- 12479469
TI  - Effects of aerobic and anaerobic digestion systems on pathogen and pathogen
      indicator reduction in municipal sludge.
AB  - In this study, the effectiveness of anaerobic treatment systems in reducing
      pathogenic density levels was evaluated under the US EPA municipal sludge rule
      (40 CFR Part 503 Rule). Wastewater and sludge samples were analyzed for both
      pathogens and pathogenic indicator organisms from six different existing
      wastewater treatment systems. The results indicate that Class B sludge
      requirements under the US 503 Rule are reasonable and can be achievable by the
      existing treatment systems while Class A sludge requirements under the same rule
      may not be easily achieved by the existing treatment systems. The effects of
      volatile solids loading rates on anaerobic digester performance were
      investigated. Under anaerobic digestion conditions, it appears that the log
      reductions in fecal coliform and fecal streptococcus appeared to be dependent on
      VSS loading rates. On the other hand, Salmonella sp. density reductions did not
      appear to be dependent on VSS loading rates.

PMID- 12479470
TI  - Evaluation of bacteriophages during the treatment of sludge.
AB  - The aim of this work was to determine the effect of liming and composting on the
      fate of three bacteriophages (somatic coliphages, F-RNA phages, Bacteroides
      fragilis phages) considered as potential indicators of viral contamination. It
      was shown that the three bacteriophages studied exhibited variable densities in
      sludge. Somatic coliphages were most abundant (10(4) to 10(5) x 10 g(-1) DM) then
      F-RNA bacteriophages (10(2) to 10(4) x 10 g(-1) DM) and Bacteroides fragilis
      phages (10(1) to 10(2) x 10 g(-1) DM). The efficacy of liming was found to be pH
      dependent but also sludge dependent. The pH allowing 99% elimination of somatic
      coliphage is close to 9 for solid sludges and close to 13.5 for liquid sludges.
      For composting, our findings clearly demonstrated that phage inactivation is very
      clearly temperature-dependent. For temperatures reaching 70 degrees, there is a 5
      log reduction in somatic coliphages while for temperature in the 50-55 degrees C
      range, the drop off is only 2 log. Considering the efficacy of the treatment
      methods, it is clear that the well-established industrial procedures that reach
      temperatures in the 60-70 degrees C range totally inactivate all 3 phages tested
      and present in sludge before composting.

PMID- 12479471
TI  - Volatile organic compound emissions during the composting of biosolids from a
      domestic wastewater treatment plant.
AB  - VOCs emitted by two composting static piles of biosolids coming from the "El
      Salitre" wastewater treatment plant (Bogota, Colombia) were analysed during the
      composting process. Each pile in its sampling time was maintained with a
      different aeration system. The sampling was made using Solid Phase
      Microextraction (SPME); separation and identifications were made using Gas
      Chromatography (GC) coupled to Mass Spectrometry (MS). Aliphatic and aromatic
      hydrocarbons, chlorinated compounds, ketones, mercaptans, alcohols and amines
      were identified in concentrations greater than the norms stipulated by the EPA
      for inhalation in humans beings. The emission behavior varied according to the
      aeration system used.

PMID- 12479472
TI  - Biological nutrient removal wastewater treatments and sewage sludge anaerobic
      mesophilic digestion performances.
AB  - The paper deals with the performances of the mesophilic anaerobic digestion
      treatment of sewage sludge from a full scale BNR process without primary settling
      (nominally 300,000 PE). A relation between the activated sludge observed yields,
      Y(obs), and the anaerobic digester performance was preliminarily found: for
      values of Y(obs) of 0.25 kgVSS/kgCOD the anaerobic digester specific gas
      production showed the best performances (0.22 m3/kgVS(fad)). This has to be
      confirmed with wider future studies. It was also shown the level of sludge pre
      thickening to be reached for the self-sustaining warming of the digester also in
      wintertime. According to the energetic balance and to a comparison with an
      aerobic stabilisation process, it was pointed out as when a co-generation unit
      for heat and energy production was introduced about 3.4 kWh/PE y of energy were
      produced in the anaerobic digestion process. On the other hand, 4.3 kWh/PE y were
      spent if an aerobic stabilisation process was applied. The economic assessment,
      carried out on the basis of the energy balances, showed that the anaerobic
      digestion is always economically advantageous if compared to aerobic
      stabilisation processes, also for small WWTPs. According to the energetic
      evaluations an environmental balance was assessed, in terms of CO2 emissions. The
      difference between anaerobic and aerobic processes was about 5.3 kgCO2/PE y in
      favour of anaerobic processes application.

PMID- 12479473
TI  - Effect of the employment of biosolids as recovery agent for degraded areas.
AB  - The solid residue generated from the sewage treatment receives the denomination
      of sewage sludge, being also called biosolid. The present work compared the
      effect of 3 levels of fertilization (sewer sludge, mineral fertilization and
      proof) in the recovery of areas with 2 levels of soil degradation simulation
      (removal of 15 cm and 30 cm of soil), plus a proof. In the parcels destined for
      the biosolid, 40 dry t./ha of aerobic limy stabilized 30% had been used. The
      content of Ca+Mg, K, V% and CTC in the parcels that received biosolids had its
      value increased by 11.7%, 28.0%, 8.3% and 6.0% respectively, when compared with
      the values of the proof at the end of the maize culture. The contents of
      phosphorus were statistically higher for the Tukey test at 5% of probability in
      the treatment with biosolid, verifying also the trend of accumulation of
      phosphorus in the parcels, with the simulated level of degradation of 30 cm.
      There was a significant increase in carbon content due to the application of
      biosolids. The production of dry substance was still evaluated, where the biggest
      productions had been statistically verified in the treatments, being slightly
      influenced by the different levels of soil degradation, evidencing the great
      capacity of silt as recovery agent.

PMID- 12479474
TI  - Impact on crops, plants and soils of metal trace elements transfer and flux,
      after spreading of fertilizers and biosolids.
AB  - In France, the yearly production of sludge from wastewater treatment plants is
      900,000 metric tons dry matter and 60% of this is reused for land application.
      Today, the sustainability of this pathway is open to question. Among the
      different arguments cited are the levels of metal trace elements and the risks of
      accumulation in soils. With the ultimate aim of agronomic sludge recycling, the
      transfer of metal trace elements has been studied using vegetation containers
      planted with rye-grass under controlled conditions of temperature and humidity.
      Samples of a domestic sludge, an industrial sludge and a fertilizer have been
      mixed with the soil. By monitoring the growth of the rye-grass, we have been able
      to observe that the addition of sludge increases production of plant matter. It
      appears that the roots absorb higher quantities of metal trace elements and form
      a barrier to their transfer to the above ground parts of the rye-grass. For the
      group of metal trace elements studied, no significant differences have been
      observed between the rye-grass grown on soil alone and that on soils amended with
      fertilizer or urban sludge. For the majority of the vegetation containers
      studied, there has been no significant modification in the soil metal
      distribution over time, as a result of the addition of urban sludge, and no
      significant difference between fertilizers and sludges.

PMID- 12479475
TI  - A risk assessment of emerging pathogens of concern in the land application of
      biosolids.
AB  - Since the development of the United States Environmental Protection Agency's 503
      biosolids Rule, which includes treatment requirements to reduce the threat of
      pathogen transmission, many new pathogens have been recognized which could be
      transmitted by biosolids. A risk analysis was performed assess which emerging
      pathogens would be most likely to survive treatments required for Class B
      biosolids before land application. The literature was reviewed on the resistance
      of emerging pathogens to temperature and other environmental factors to assess
      their probability of surviving various biosolids treatment processes. In addition
      existing information on occurrence in biosolids and dose response models for each
      pathogen was reviewed. It was concluded that adenoviruses and hepatitis A virus
      are the most thermally resistant viruses and can survive for prolonged periods in
      the environment. The protozoan parasites microsporidia and Cyclospora were
      unlikely to survive the temperatures achieved in anaerobic digestion and do not
      survive well under low moisture conditions. A risk model was used to assess the
      risk of infection and illness from enteric viruses after application of class B
      biosolids.

PMID- 12479476
TI  - Sludge utilisation in agriculture: possibilities and prospects in Greece.
AB  - The paper presents the prospects for agricultural utilisation of the sludge
      produced from wastewater treatment plants in Greece and more specifically focuses
      on a critical review of the legislatory framework, determination of the
      quantitative and qualitative characteristics of the produced sludges, examination
      of possible sludge treatment methods and evaluation of the possibilities and
      prospects of sludge utilisation on the basis of the above considerations.
      Landfilling is practically the only route to sludge disposal in Greece. However,
      in view of the anticipated future restrictions for landfilling within the
      European Union, this method is clearly a short-term solution and alternative
      options, including agricultural reuse, must be implemented. The results of a
      recent survey are presented and discussed in relation to this need.

PMID- 12479477
TI  - Effects of substrates composed of biosolids on the production of Eucalyptus
      viminalis, Schinus terebinthifolius and Mimosa scabrella seedlings and on the
      nutritional status of Schinus terebinthifolius seedlings.
AB  - Six substrates made up with heated and composted anaerobic biosolid were tested
      for the production of Eucalyptus viminalis, Schinus terebinthifolius and Mimosa
      scabrella forest seedlings in a nursery in Southern Brazil. The produced
      seedlings were statistically evaluated in relation to height, stem diameter,
      height/stem diameter ratio, aerial and root dry biomass, survival, and also for
      nutritional status on S. terebinthifolius seedlings. As a function of their high
      pH, heated biosolids turned out to be viable only in low composition percentages.
      Composted biosolids turned out to be sufficiently suitable in percentages between
      30% and 60% of the substratum--whose Mn and Zn concentrations relate the nutrient
      contents in theseedlings -with use viability up to 100% in substratum
      composition.

PMID- 12479478
TI  - Simultaneous production of biopesticide and alkaline proteases by Bacillus
      thuringiensis using sewage sludge as a raw material.
AB  - The simultaneous production of Bacillus thuringiensis (Bt) based biopesticide and
      proteases was studied using synthetic medium and wastewater sludge as a raw
      material. The studies were conducted in shake flask and computer controlled 15-L
      capacity fermentors. Measuring viable cell and spore counts, entomotoxicity and
      protease activity monitored the progress of the biopesticide production process.
      A higher viable cell count and spore count was observed in synthetic Soya medium,
      however, higher entomotoxicity and protease activity were observed in wastewater
      sludge medium. Thus, the wastewater sludge is a better raw material than
      commercial Soya medium for the biopesticides and enzyme production. The maximum
      entomotoxicity and protease activity observed in the fermentor was 9,332
      IU/microL and 4.58 IU/mL, respectively. The proteases produced by Bt were also
      characterised. Two types of proteases were detected; neutral proteases with pH
      optimum 7.0 and alkaline proteases with pH optimum 10-11. Further, two types of
      alkaline proteases were detected; one having a pH and temperature optimum at 10
      and 50 degrees C while the other at 11 and 70 degrees C. The protease thermal
      stability was found to increase in the presence of CaCl2, indicating the
      proteases were metalloproteases.

PMID- 12479479
TI  - Reuse of sewage sludge as raw material of Portland cement in Japan.
AB  - A potential alternative of sewage sludge reuse is the substitute of raw material
      for Portland cement. This paper overviews Japanese implementation of this and
      discusses the best selection of pretreatment for this purpose. The pretreatment
      includes dewatering, incineration, and lime treatment.

PMID- 12479480
TI  - Sustainability of thermal oxidation processes: strengths for the new millennium.
AB  - Incineration of sludge is occasionally accused of pollution. This paper shows
      that if it is correctly designed and implemented, it can be environmentally
      friendly. For this purpose, sludge incineration is compared to agricultural
      spreading of limed sludge with respect to toxicity criteria, greenhouse effect
      gases (GEG) release, energy wasting and other environmental parameters.
      Landfilling is also considered but as a standby route. Since present regulations
      on agricultural use and gas emission release from incinerators are stringent,
      incineration cannot be suspected to release more noxious substances in the
      environment than agriculture. A distinction is made between biogenic CO2 and
      fossil CO2. Nevertheless case studies show that incineration produces more GEG
      and wastes more energy than agricultural spreading if no energy is recovered from
      hot flue gas. In the case of thermal power or electrical power generation, the
      environmental balance becomes dramatically more favorable for incineration.

PMID- 12479481
TI  - Effect of extracellular polymers on freeze-thaw conditioning of activated sludge.
AB  - In this study, the effects of extracellular polymers on freeze-thaw conditioning
      of activated sludge are investigated. Various physical and chemical extraction
      methods including centrifugation, blending, heat, EDTA, EGTA, and NaOH extraction
      were used to remove extracellular material from sludge matrix. The improvements
      in freeze-thaw conditioning were evaluated by commonly used measures of sludge
      dewaterability. The results of this study indicate that removal of extracellular
      polymers using relatively gentle extraction methods before freeze-thaw
      conditioning improves the sludge dewaterability after the freeze-thaw. In
      addition to extracellular polymers, cations also play an important role in
      determining the freeze-thaw effectiveness on activated sludge. Best
      dewaterability is achieved when both extracellular polymers and cations are
      removed from activated sludge before freeze-thaw conditioning.

PMID- 12479482
TI  - Low temperature conversion of sludge and shavings from leather industry.
AB  - Abstract Brazil has one of the largest herds of cattle in the world, with more
      than 170 million heads. Over 400 farms have exported more than 2,875 ton (in
      1997) of leather to Europe. The wet blue tanning process uses chemicals such as
      chromium compounds and produces liquid wastes that must be treated by
      physicochemical and biological systems. About 15,000 ton per month of dewatering
      sludge with 24% solids content is disposed of into landfills. During the process,
      pre-tanned skins (wet blue leather) are shaved to the desired thickness and the
      shavings, like sludge, are among the wastes that must have special attention. The
      organic content and chromium concentration are high. About 12% of the leather
      production from cattle hides are shavings, and its chromium concentration ranges
      from 3.5 to 5.5% of dry matter. The Environmentally friendly leather project, a
      co-operation between Brazilian and German tanneries, universities and technical
      schools, is looking for process optimisation, waste minimisation and adequate
      treatment for solid and liquid wastes from the leather industry. This work
      presents results of Low Temperature Conversion of chrome-containing sludge and
      shavings in a laboratory batch reactor, offering a solution for these hazardous
      wastes, recovering the energy content and transforming metals in insoluble
      sulphides.

PMID- 12479483
TI  - The challenge of faecal sludge management in urban areas--strategies, regulations
      and treatment options.
AB  - In urban centres of industrialising countries, the majority of houses are served
      by on-site sanitation systems such as septic tanks and unsewered toilets. The
      faecal sludges (FS) collected from these systems are usually discharged untreated
      into the urban and peri-urban environment, posing great risks to water resources
      and to public health. Contrary to wastewater management, the development of
      strategies to cope with faecal sludges, adapted to the conditions prevailing in
      developing countries, have long been neglected. The authors describe the current
      situation and discuss selected issues of FS management. A proposal is made for a
      rational setting of sludge quality or treatment standards in economically
      emerging countries. The authors stipulate that regulatory setting should take
      into account local economic, institutional and technical conditions. Defining
      suitable treatment options as critical control points in securing adequate sludge
      quality is better than setting and relying on numerical sludge quality standards.
      A separate section is devoted to the practice and to regulatory aspects of
      (faecal) sludge use in Argentina. An overview of treatment options, which may
      prove sustainable in less industrialized countries is provided. Planted sludge
      drying beds are one of these options. It has been piloted in Thailand for four
      years and details on its performance and operation are presented along with data
      on the hygienic quality of treated biosolids.

PMID- 12479484
TI  - Wastewater sludge as a resource: sludge disposal strategies and corresponding
      treatment technologies aimed at sustainable handling of wastewater sludge.
AB  - The paper discusses different strategies for the disposal of wastewater sludge,
      particularly the "use on land" strategy and the "productification" strategy. In
      the "use on land" strategy the new regulations in Europe call for stabilization
      as well as disinfection of sludge to be used on land. The paper discusses the
      design and operation experiences with stabilization/disinfection methods in
      Norway where such treatment has been compulsory since 1995. In the
      "productification" strategy it is differentiated between the production of "bio
      soils" and production of specific products (energy, nutrients, coagulants etc)
      and the "marketability" of these products is evaluated. An example of a sludge
      treatment concept aimed at recycling--the KREPRO process--is presented.

PMID- 12479485
TI  - Sludge management regulations and their applicability in mountainous regions.
AB  - The Commission of the European Communities (CEC) is just working out a new
      directive in order to regulate the agricultural reuse of sewage sludge. This new
      regulation will also effect a "special case"--sludge usage in a mountainous
      environment--which will be discussed in this paper. Three reuse sites at small
      wastewater treatment plants of mountain refuges at altitudes more than 2,000 m
      a.s.l. are investigated. Applied sludge, soil and drainage flow from lysimeters
      are analysed. Concerning heavy metal concentrations domestic sewage sludge from
      these sites differs significantly from municipal sludge. A comparison with
      background concentrations reveals that no relevant accumulative pollution of the
      soil is possible. An increase of coliform bacteria of maximum two orders of
      magnitude is preserved during the long winter period and indicates a limited
      hygienic risk.

PMID- 12479486
TI  - European policy on biodegradable waste: a management perspective.
AB  - The main characteristics of the European environmental policy are reviewed.
      Focusing on EU policy on waste, the paper presents the principles on which EU
      waste management is founded, particularly the waste hierarchy. In this hierarchy,
      priority shall be given to prevention of the generation of wastes and of its
      hazardousness. Secondly, the reuse and the recovery of materials (recycling),
      which implies the separation of waste at source involving consumers in the scheme
      of waste management. Priority should be given to material recycling over energy
      recovery. The less desirable option is the disposal of waste. The paper reviews
      specific directives on organic waste management, following the scheme of the
      waste hierarchy, together with the general trends observed in producing common
      regulations for all types of organic residuals. Afterwards, key issues and
      measures for the implementation of a feasible strategy for organic residuals
      management, e.g. quality requirements and quality assurance, are discussed.
      Finally, there is a view from a manager's perspective on the current EU policy,
      public acceptance and suitable waste management operations.

PMID- 12479487
TI  - Reducing racial and ethnic disparities in health care.

PMID- 12479488
TI  - Addressing health disparities: where should we start?

PMID- 12479489
TI  - Quality of cardiac surgeons and managed care contracting practices.
AB  - OBJECTIVE: To evaluate the association between contracting practices of managed
      care organizations (MCOs) with cardiac surgeons and the quality of the cardiac
      surgeons. DATA SOURCES/STUDY SETTING: The study included all cardiac surgeons
      offering coronary artery bypass graft (CABG) surgery and 78 percent of MCOs in
      New York State in 1998. Primary data: The MCOs' panel composition with respect to
      hospitals and cardiac surgeons. Secondary data: New York State (NYS) Cardiac
      Surgery Reports. STUDY DESIGN: Statistical analyses of the probability of a
      contract between cardiac surgeons and MCOs conditional on the surgeon's risk
      adjusted mortality rates (RAMR), outlier and low volume status, and controlling
      for other confounding variables, were performed. PRINCIPAL FINDINGS: Contract
      probability exhibited a tendency to decrease with RAMR, low volume and low
      quality outlier status and to increase with high-quality outlier status. These
      effects were statistically significant for RAMR and high-quality outliers in
      Downstate and for low volume in Downstate and Upstate. CONCLUSIONS: In some, but
      not all cases, MCOs are seeking higher-quality providers. Further research is
      required to understand regional variability and the effect of market structure on
      the quality profile of MCOs.

PMID- 12479490
TI  - The effects of primary care depression treatment on patients' clinical status and
      employment.
AB  - OBJECTIVE: To evaluate the effects of depression treatment in primary care on
      patients' clinical status and employment, over six months. DATA SOURCES/STUDY
      SETTING: Data are from a randomized controlled trial of quality improvement for
      depression that included 938 adults with depressive disorder in 46 managed
      primary care clinics in five states. STUDY DESIGN: Observational analysis of the
      effects of evidence-based depression care over six months on health outcomes and
      employment. Selection into treatment is accounted for using instrumental
      variables techniques, with randomized assignment to the quality improvement
      intervention as the identifying instrument. DATA COLLECTION/EXTRACTION METHODS:
      Patient-reported clinical status, employment, health care use, and personal
      characteristics; health care use and costs from claims data. PRINCIPAL FINDINGS:
      At six months, patients with appropriate care, compared to those without it, had
      lower rates of depressive disorder (24 percent versus 70 percent), better mental
      health-related quality of life, and higher rates of employment (72 percent versus
      53 percent), each p<.05. CONCLUSIONS: Appropriate treatment for depression
      provided in community-based primary care substantially improves clinical and
      quality of life outcomes and employment.

PMID- 12479491
TI  - Whom should we profile? Examining diabetes care practice variation among primary
      care providers, provider groups, and health care facilities.
AB  - OBJECTIVE: To evaluate the amount of variation in diabetes practice patterns at
      the primary care provider (PCP), provider group, and facility level, and to
      examine the reliability of diabetes care profiles constructed using electronic
      databases. DATA SOURCES/STUDY SETTING: Clinical and administrative data obtained
      from the electronic information systems at all facilities in a Department of
      Veterans Affairs' (VA) integrated service network for a study period of October
      1997 through September 1998. STUDY DESIGN: This is a cohort study. The key
      variables of interest are different types of diabetes quality indicators,
      including measures of technical process, intermediate outcomes, and resource use.
      DATA COLLECTION/EXTRACTION METHODS: A coordinated registry of patients with
      diabetes was constructed by integrating laboratory, pharmacy, utilization, and
      primary care provider data extracted from the local clinical information system
      used at all VA medical centers. The study sample consisted of 12,110 patients
      with diabetes, 258 PCPs, 42 provider groups, and 13 facilities. PRINCIPAL
      FINDINGS: There were large differences in the amount of practice variation across
      levels of care and for different types of diabetes care indicators. The greatest
      amount of variance tended to be attributable to the facility level. For process
      measures, such as whether a hemoglobin A1c was measured, the facility and PCP
      effects were generally comparable. However, for three resource use measures the
      facility effect was at least six times the size of the PCP effect, and for inter
      mediate outcome indicators, such as hyperlipidemia, facility effects ranged from
      two to sixty times the size of the PCP level effect. A somewhat larger PCP effect
      was found (5 percent of the variation) when we examined a "linked" process
      outcome measure linking hyperlipidemia and treatment with statins). When the PCP
      effect is small (i.e., 2 percent), a panel of two hundred diabetes patients is
      needed to construct profiles with 80 percent reliability. CONCLUSIONS: little of
      the variation in many currently measured diabetes care practices is attributable
      to PCPs and, unless panel sizes are large, PCP profiling will be inaccurate. If
      profiling is to improve quality, it may be best to focus on examining facility
      level performance variations and on developing indicators that promote specific,
      high-priority clinical actions.

PMID- 12479492
TI  - Relationship between regulatory status, quality of care, and three-year mortality
      in Canadian residential care facilities: a longitudinal study.
AB  - OBJECTIVES: To compare the mortality rate in regulated and unregulated
      facilities, controlling for confounding variables, and investigate the effect of
      care quality on residents' length of survival. DATA SOURCES/STUDY SETTING: At
      baseline, subjects were assessed in their living environment with respect to
      their functional autonomy, cognitive abilities, and quality of care. Vital
      status, disease-related information, and hospitalization data were retrieved
      three years later from the subjects' medical files. STUDY DESIGN: A three-year
      follow-up study of 299 residents from 88 long-term care facilities located in the
      province of Quebec, Canada. The effect of regulatory status and quality of care
      on length of survival was investigated by means of multivariable Cox proportional
      hazards regression models, from both traditional and competing risks
      perspectives. PRINCIPAL FINDINGS: Controlling for age, comorbidity, and baseline
      functional abilities, a resident's length of survival is not significantly
      influenced by the regulatory status of the facility in which he or she lived at
      baseline. However, residents with poor quality ratings at baseline had shorter
      survival times than those provided with good care. Median survival was 28 months
      among residents classified as receiving inadequate care compared to 41 months for
      those adequately cared for (p = 0.0217). CONCLUSIONS: The study suggests that
      quality of care has a much stronger influence on resident outcomes than
      regulation per se. This finding underscores the relevance of testing innovative
      interventions aimed at improving the quality of care provided in long-term care
      facilities, regardless of their regulatory status.

PMID- 12479493
TI  - Plan characteristics and SSI enrollees' access to and quality of care in four
      TennCare MCOs.
AB  - OBJECTIVE: To assess hypotheses about which managed care organization (MCO)
      characteristics affect access to care and quality of care--including access to
      specialists, providers' knowledge about disability, and coordination of care--for
      people with disabilities. DATA SOURCES/STUDY SETTING: Survey of blind/disabled
      Supplemental Security Income (SSI) enrollees in four MCOs serving TennCare,
      Tennessee's Medicaid managed care program, in Memphis, conducted from 1998
      through spring 1999. STUDY DESIGN: We compared enrollee reports of access and
      quality across the four MCOs using regression methods, and we use case study
      methods to assess whether patterns both within and across MCOs are consistent
      with the hypotheses. DATA COLLECTION: We conducted computer-assisted telephone
      surveys and used regression analysis to compare access and quality controlling
      for enrollee characteristics. PRINCIPAL FINDINGS: Although the four MCOs'
      characteristics varied, access to providers, coordination of care, and access to
      some services were generally similar across MCOs. Enrollees in one plan, the only
      MCO with a larger provider network and that paid physicians on a fee-for-service
      basis, reported their providers were more knowledgeable, and they had more
      secondary preventive care visits. Differences found in access to specialists and
      delays in approving care appear to be unrelated to characteristics reported by
      the MCOs, but instead may be related to how tightly utilization is reviewed.
      CONCLUSIONS: Plan networks, financial incentives, utilization management methods,
      and state requirements are important areas for further study, and, in the
      meantime, ongoing monitoring of SSI enrollees in each MCO may be important for
      detecting problems and successes.

PMID- 12479494
TI  - Expanding the Andersen model: the role of psychosocial factors in long-term care
      use.
AB  - OBJECTIVE: To examine a prevailing conceptual model of health services use
      (Andersen 1995) and to suggest modifications that may enhance its explanatory
      power when applied to empirical studies of race/ethnicity and long-term care.
      STUDY SETTING: Twelve focus groups of African-American (five groups) and white
      (seven groups) individuals, aged 65 and older, residing in Connecticut during
      2000. STUDY DESIGN: Using qualitative analysis, data were coded and analyzed in
      NUD-IST 4 software to facilitate the reporting of recurrent themes, supporting
      quotations, and links among the themes for developing the conceptual framework.
      Specific analysis was conducted to assess distinctions in common themes between
      African-American and white focus groups. DATA COLLECTION: Data were collected
      using a standardized discussion guide, augmented by prompts for clarification.
      Audio taped sessions were transcribed and independently coded by investigators
      and crosschecked to enhance coding validity. An audit trail was maintained to
      document analytic decisions during data analysis and interpretation. PRINCIPAL
      FINDINGS: Psychosocial factors (e.g., attitudes and knowledge, social norms, and
      perceived control) are identified as determinants of service use, thereby
      expanding the Andersen model (1995). African-American and white focus group
      members differed in their reported accessibility of information about long-term
      care, social norms concerning caregiving expectations and burden, and concerns of
      privacy and self-determination. CONCLUSIONS: More comprehensive identification of
      psychosocial factors may enhance our understanding of the complex role of
      race/ethnicity in long-term care use as well as the effectiveness of policies and
      programs designed to address disparities in long-term care service use among
      minority and nonminority groups.

PMID- 12479495
TI  - Quantifying components of drug expenditure inflation: the British Columbia
      seniors' drug benefit plan.
AB  - OBJECTIVE: To quantify the relative and absolute importance of different factors
      contributing to increases in per capita prescription drug costs for a population
      of Canadian seniors. DATA SOURCES/STUDY SETTING: Data consist of every
      prescription claim from 1985 to 1999 for the British Columbia Pharmacare Plan A,
      a tax-financed public drug plan covering all community-dwelling British
      Columbians aged 65 and older. STUDY DESIGN: Changes in per capita prescription
      drug expenditures are attributed to changes to four components of expenditure
      inflation: (1) the pattern of exposure to drugs across therapeutic categories;
      (2) the mix of drugs used within therapeutic categories; (3) the rate of generic
      drug product selection; and (4) the prices of unchanged products. DATA
      COLLECTION/EXTRACTION METHODS: Data were extracted from administrative claims
      files housed at the UBC Centre for Health Services and Policy Research. PRINCIPAL
      FINDINGS: Changes in drug prices, the pattern of exposure to drugs across
      therapeutic categories, and the mix of drugs used within therapeutic categories
      all caused spending per capita to increase. Incentives for generic substitution
      and therapeutic reference pricing policies temporarily slowed the cost-increasing
      influence of changes in product selection by encouraging the use of generic drug
      products and/or cost-effective brand-name products within therapeutic categories.
      CONCLUSIONS: The results suggest that drug plans (and patients) would benefit
      from more concerted efforts to evaluate the relative cost-effectiveness of
      competing products within therapeutic categories of drugs.

PMID- 12479496
TI  - Competition among hospitals for HMO business: effect of price and nonprice
      attributes.
AB  - OBJECTIVE: To investigate patterns of competition among hospitals for the
      business of health maintenance organizations (HMOs). The study focused on the
      relative importance of hospital price and nonprice attributes in the competition
      for HMO business. DATA SOURCES/STUDY SETTING: The study capitalized on hospital
      cost reports from Florida that are unique in their inclusion of financial data
      regarding HMO business activity. The time frame was 1992 to 1997. STUDY DESIGN:
      The study was designed as an observational investigation of acute care hospitals.
      PRINCIPAL FINDINGS: Results indicated that a hospital's share of HMO business was
      related to both its price and nonprice attributes. However, the importance of
      both price and nonprice attributes diminished as the number of HMOs in a market
      increased. Hospitals that were market share leaders in terms of HMO business
      (i.e., 30 percent or more market share) were superior, on average, to their
      competitors on both price and nonprice attributes. CONCLUSIONS: Study results
      indicate that competition among hospitals for HMO business involves a complex set
      of price and nonprice attributes. The HMOs do not appear to focus on price alone.
      Hospitals likely to be the most attractive to HMOs are those that can
      differentiate themselves on the basis of nonprice attributes while being
      competitive on price as well.

PMID- 12479497
TI  - The cost of doing business: cost structure of electronic immunization registries.
AB  - OBJECTIVE: To predict the true cost of developing and maintaining an electronic
      immunization registry, and to set the framework for developing future cost
      effective and cost-benefit analysis. DATA SOURCES/STUDY SETTING: Primary data
      collected at three immunization registries located in California, accounting for
      90 percent of all immunization records in registries in the state during the
      study period. STUDY DESIGN: A parametric cost analysis compared registry
      development and maintenance expenditures to registry performance requirements.
      DATA COLLECTION/EXTRACTION METHODS: Data were collected at each registry through
      interviews, reviews of expenditure records, technical accomplishments development
      schedules, and immunization coverage rates. PRINCIPAL FINDINGS: The cost of
      building immunization registries is predictable and independent of the
      hardware/software combination employed. The effort requires four man-years of
      technical effort or approximately $250,000 in 1998 dollars. Costs for maintaining
      a registry were approximately $5,100 per end user per three-year period.
      CONCLUSIONS: There is a predictable cost structure for both developing and
      maintaining immunization registries. The cost structure can be used as a
      framework for examining the cost-effectiveness and cost-benefits of registries.
      The greatest factor effecting improvement in coverage rates was ongoing, user
      based administrative investment.

PMID- 12479498
TI  - Breast cancer and women's labor supply.
AB  - OBJECTIVE: To investigate the effect of breast cancer on women's labor supply.
      DATE SOURCE/STUDY SETTING: Using the 1992 Health and Retirement Study, we
      estimate the probability of working using probit regression and then, for women
      who are employed, we estimate regressions for average weekly hours worked using
      ordinary least squares (OLS). We control for health status by using responses to
      perceived health status and comorbidities. For a sample of married women, we
      control for spouses' employer-based health insurance. We also perform additional
      analyses to detect selection bias in our sample. PRINCIPAL FINDINGS: We find that
      the probability of breast cancer survivors working is 10 percentage points less
      than that for women without breast cancer. Among women who work, breast cancer
      survivors work approximately three more hours per week than women who do not have
      cancer. Results of similar magnitude persist after health status is controlled in
      the analysis, and although we could not definitively rule out selection bias, we
      could not find evidence that our results are attributable to selection bias.
      CONCLUSIONS: For some women, breast cancer may impose an economic hardship
      because it causes them to leave theirjobs. However, for women who survive and
      remain working, this study failed to show a negative effect on hours worked
      associated with breast cancer. Perhaps the morbidity associated with certain
      types and stages of breast cancer and its treatment does not interfere with work.

PMID- 12479499
TI  - Using a standardized donor ratio to assess the performance of organ procurement
      organizations.
AB  - OBJECTIVE: To develop a Standardized Donor Ratio (SDR) as an outcome measure for
      evaluating the effectiveness of organ procurement organizations (OPOs). DATA
      SOURCES/STUDY SETTING: All deaths by cause in the United States during 1993-1994
      as reported in the Vital Mortality Statistics, Multiple Cause of Death files. The
      OPO-specific data were provided by the United Network for Organ Sharing (UNOS).
      STUDY DESIGN: Each OPO's expected number of donors was calculated by applying
      national donation rates to deaths with potential for donation in 24 age, sex, and
      race cells. The SDR was calculated by dividing the observed number of donors by
      the expected number. The chi2 tests of the hypothesis that the OPO's performance
      differed from the national norm of 1.0 were performed. The SDR was compared to
      the existing performance standard based on the unadjusted number of donors per
      million live population in the OPO's service area. An ordinary least squares
      (OLS) regression assessed predictors of the SDR. PRINCIPAL FINDINGS: The SDRs
      ranged from 0.41 to 1.99. Twenty-nine of 64 OPOs had SDRs significantly different
      than 1.0. The SDRs were positively associated with the percent of white living
      population and the number of organ types transplanted per transplant center
      served by the OPO. CONCLUSIONS: The SDRs can be used by Centers for Medicare and
      Medicaid Services (CMS), UNOS, and OPOs to target quality improvement
      initiatives, present more accurate comparisons of OPO performance, and develop
      public policy on the evaluation of the effectiveness of organ procurement
      efforts.

PMID- 12479500
TI  - Assessing population health care need using a claims-based ACG morbidity measure:
      a validation analysis in the Province of Manitoba.
AB  - OBJECTIVES: To assess the ability of an Adjusted Clinical Group (ACG)-based
      morbidity measure to assess the overall health service needs of populations. Data
      Sources/Study Setting. Three population-based secondary data sources:
      registration and health service utilization data from fiscal year 1995-1996;
      mortality data from vital statistics reports from 1996-1999; and Canadian census
      data. The study included all continuously enrolled residents in the universal
      health care plan in Manitoba. STUDY DESIGN: Using 60 small geographic areas as
      the units of analysis, we compared a population-based "ACG morbidity index,"
      derived from individual ACG assignments in fiscal year 1995-1996, with the
      standardized mortality ratio (ages < 75 years) for 1996-1999. Key variables
      included a population-based socioeconomic status measure and age- and sex
      standardized physician utilization ratios. DATA EXTRACTION METHODS: The ACGs were
      assigned based on the complement of diagnoses assigned to persons on physician
      claims and hospital separation abstracts. The ACG index was created by weighting
      the ACGs using average health care expenditures. PRINCIPAL FINDINGS: The ACG
      morbidity index had a strong positive linear relationship with the subsequent
      rate of premature death in the small areas of Manitoba. The ACG index was able to
      explain the majority of the relationships between mortality and both
      socioeconomic status and physician utilization. CONCLUSIONS: In Manitoba, ACGs
      are closely related to premature mortality, commonly accepted as the best single
      indicator for health service need in populations. Issues in applying ACGs in
      settings where needs adjustment is a primary objective are discussed.

PMID- 12479501
TI  - An approach to forecasting health expenditures, with application to the U.S.
      Medicare system.
AB  - OBJECTIVE: To quantify uncertainty in forecasts of health expenditures. STUDY
      DESIGN: Stochastic time series models are estimated for historical variations in
      fertility, mortality, and health spending per capita in the United States, and
      used to generate stochastic simulations of the growth of Medicare expenditures.
      Individual health spending is modeled to depend on the number of years until
      death. DATA SOURCES/STUDY SETTING: A simple accounting model is developed for
      forecasting health expenditures, using the U.S. Medicare system as an example.
      PRINCIPAL FINDINGS: Medicare expenditures are projected to rise from 2.2 percent
      of GDP (gross domestic product) to about 8 percent of GDP by 2075. This increase
      is due in equal measure to increasing health spending per beneficiary and to
      population aging. The traditional projection method constructs high, medium, and
      low scenarios to assess uncertainty, an approach that has many problems. Using
      stochastic forecasting, we find a 95 percent probability that Medicare spending
      in 2075 will fall between 4 percent and 18 percent of GDP, indicating a wide band
      of uncertainty. Although there is substantial uncertainty about future mortality
      decline, it contributed little to uncertainty about future Medicare spending,
      since lower mortality both raises the number of elderly, tending to raise
      spending, and is associated with improved health of the elderly, tending to
      reduce spending. Uncertainty about fertility, by contrast, leads to great
      uncertainty about the future size of the labor force, and therefore adds
      importantly to uncertainty about the health-share of GDP. In the shorter term,
      the major source of uncertainty is health spending per capita. CONCLUSIONS:
      History is a valuable guide for quantifying our uncertainty about future health
      expenditures. The probabilistic model we present has several advantages over the
      high-low scenario approach to forecasting. It indicates great uncertainty about
      future Medicare expenditures relative to GDP.

PMID- 12479502
TI  - Using administrative data to identify indications for elective primary cesarean
      delivery.
AB  - OBJECTIVE: To develop a methodology to identify indications and normative rates
      for elective primary cesarean delivery using administrative data. DATA
      SOURCES/STUDY SETTING: All delivery discharges in 1995, as reported to the
      California Office of Statewide Health Planning and Development (secondary data).
      STUDY DESIGN: Retrospective population based study. DATA COLLECTION/EXTRACTION:
      Data were entered into a recursive partitioning algorithm to develop a hierarchy
      of conditions by which patients with multiple conditions could be sorted with
      respect to the binary outcome of labor or elective primary cesarean without
      labor. This hierarchy was examined for its clinical consistency, validated on a
      second sample, and compared with results obtained from logistic regression.
      PRINCIPAL FINDINGS: Four percent (19,664) of delivery discharges in 1995
      underwent elective primary cesarean. Twelve clinical conditions contributed to
      the hierarchy, and accounted for 92.9 percent of all women experiencing elective
      primary cesarean delivery. The remaining 7.1 percent of the elective primary
      cesarean cases were classified as "unspecified." CONCLUSIONS: A standardized
      methodology (utilizing recursive partitioning algorithms) for assigning
      indications for elective primary cesarean is presented. This methodology relies
      on administrative data, classifies women with complex comorbidity patterns into
      clinically relevant subpopulations, and can be used to establish normative rates
      for benchmarking specific indications for cesarean delivery.

PMID- 12479503
TI  - A demonstration of the impact of response bias on the results of patient
      satisfaction surveys.
AB  - OBJECTIVES: The purposes of the present study were to examine patient
      satisfaction survey data for evidence of response bias, and to demonstrate, using
      simulated data, how response bias may impact interpretation of results. DATA
      SOURCES: Patient satisfaction ratings of primary care providers (family
      practitioners and general internists) practicing in the context of a group-model
      health maintenance organization and simulated data generated to be comparable to
      the actual data. STUDY DESIGN: Correlational analysis of actual patient
      satisfaction data, followed by a simulation study where response bias was
      modeled, with comparison of results from biased and unbiased samples. PRINCIPAL
      FINDINGS: A positive correlation was found between mean patient satisfaction
      rating and response rate in the actual patient satisfaction data. Simulation
      results suggest response bias could lead to overestimation of patient
      satisfaction overall, with this effect greatest for physicians with the lowest
      satisfaction scores. CONCLUSIONS: Findings suggest that response bias may
      significantly impact the results of patient satisfaction surveys, leading to
      overestimation of the level of satisfaction in the patient population overall.
      Estimates of satisfaction may be most inflated for providers with the least
      satisfied patients, thereby threatening the validity of provider-level
      comparisons.

PMID- 12479504
TI  - Trust in the medical profession: conceptual and measurement issues.
AB  - OBJECTIVE: To develop and test a multi-item measure for general trust in
      physicians, in contrast with trust in a specific physician. DATA SOURCES: Random
      national telephone survey of 502 adult subjects with a regular physician and
      source of payment. STUDY DESIGN: Based on a multidimensional conceptual model, a
      large pool of candidate items was generated, tested, and revised using focus
      groups, expert reviewers, and pilot testing. The scale was analyzed for its
      factor structure, internal consistency, construct validity, and other
      psychometric properties. PRINCIPAL FINDINGS: The resulting 11-item scale
      measuring trust in physicians generally is consistent with most aspects of the
      conceptual model except that it does not include the dimension of
      confidentiality. This scale has a single-factor structure, good internal
      consistency (alpha = .89), and good response variability (range = 11-54; mean =
      33.5; SD = 6.9). This scale is related to satisfaction with care, trust in one's
      physician, following doctors' recommendations, having no prior disputes with
      physicians, not having sought second opinions, and not having changed doctors. No
      association was found with race/ethnicity. While general trust and interpersonal
      trust are qualitatively similar, they are only moderately correlated with each
      other and general trust is substantially lower. CONCLUSIONS: Emerging research on
      patients' trust has focused on interpersonal trust in a specific, known
      physician. Trust in physicians in general is also important and differs
      significantly from interpersonal physician trust. General physician trust
      potentially has a strong influence on important behaviors and attitudes, and on
      the formation of interpersonal physician trust.

PMID- 12479505
TI  - Efficacy of topical phenol decontamination strategies on severity of acute phenol
      chemical burns and dermal absorption: in vitro and in vivo studies in pig skin.
AB  - Pure phenol is colorless and used in the manufacture of phenolic resins,
      plastics, explosives, fertilizers, paints, rubber, textiles, adhesives,
      pharmaceuticals, paper, soap, and wood preservatives. The purpose of this study
      was to compare the efficacy of several phenol decontamination strategies
      following dermal exposure using the pig as a model for human exposure, and then
      assess the effect of the two best treatments on phenol absorption in the isolated
      perfused porcine skin flap (IPPSF). Six anesthetized Yorkshire pigs were exposed
      to 89% aqueous phenol for 1 min using Hilltop chambers (10 skin sites/pig; 400
      microl/site). Exposure to phenol was followed by one of 10 different
      decontamination procedures: 1-, 5-, 15-, and 30-min water wash; Ivory soap
      solution; polyethylene glycol (PEG 400); PEG 400/industrial methylated spirits
      (IMS); PEG 400/ethanol (EtOH); polyvinyl pyrrolidone (PVP)/70% isopropanol (IPA);
      and 70% IPA. For each of the last five strategies, 1-min treatment washes were
      repeatedly alternated with 1-min water washes for a total of 15 min. Evaluation
      was based on scoring of erythema, edema, and histological parameters such as
      intracellular and intercellular epidermal edema, papillary dermal edema,
      perivascular infiltrates, pyknotic stratum basale cells, and epidermal-dermal
      separation. It was concluded that PEG 400 and 70% IPA were superior to the other
      treatments investigated and equally efficacious in the reduction of phenol
      induced skin damage. In addition, phenol absorption was assessed utilizing the
      two most effective in vivo treatments in the IPPSF. The assessment of
      percutaneous absorption of phenol found the PEG 400, 70% IPA, and 15-min water
      treatments significantly (P < 0.05) reduced phenol absorption relative to no
      treatment.

PMID- 12479506
TI  - Serum hormone levels in humans with low serum concentrations of 2,3,7,8-TCDD.
AB  - We measured current serum hormone and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
      concentrations in 37 men who sprayed 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)
      in the State of Victoria, Australia. TCDD levels were consistently significantly
      inversely related to prolactin levels in all analyses. In correlation analyses,
      TCDD levels were also inversely related to triiodothyronine (T3), thyroid
      stimulating hormone (TSH), and testosterone levels, and positively associated
      with glucagon levels. The mean serum TCDD concentration in these sprayers was
      between 2.6 and 8.1 parts per trillion (ppt). Since such TCDD levels are commonly
      found in the general population in countries such as the US, the results could
      suggest that background levels of TCDD in the general population could have an
      effect on hormone levels. The findings are preliminary and need to be replicated
      in order to evaluate their full public health significance.

PMID- 12479507
TI  - Validation of exposure estimation for benzene in the Australian petroleum
      industry.
AB  - A nested case-control study was undertaken to investigate whether an excess of
      lympho-haematopoietic cancers in the Australian petroleum industry was associated
      with benzene exposure. The benzene exposures of the cases and controls were
      estimated using a quantitative algorithm based largely on exposures measured in
      the Australian petroleum industry. The algorithm was used to estimate, for each
      subject, the benzene exposure in parts per million (ppm) for each job held in the
      industry, and the cumulative exposure in ppm years. Because of the critical
      importance of the exposure assessment in this design of epidemiological study,
      particular attention was paid to the reliability of the inputs to the algorithm.
      The inputs [base estimates (BEs) of exposure and technology-specific exposure
      modifiers (EMs)] were compared to data from other sources including the
      occupational hygiene literature. Where such comparison data were available, they
      were generally found to confirm the values used in the algorithm, although four
      input values were changed as a result of the validation exercise. The integrity
      of the task-based algorithm was validated by employing it to calculate the
      exposures of the tanker drivers in the study and comparing these with measured
      daily exposure for tanker drivers in the Australian petroleum industry and
      exposure values found in the occupational hygiene literature. After adjustment
      for the mix of products carried by the Australian tanker drivers, the estimates
      from the algorithm were found to be comparable to the measured and literature
      values. This exercise provided evidence that the exposure assessment for the
      epidemiological study was reliable and that the results of the study can be used
      as the basis for evaluating the relationship between exposure to benzene and the
      risk of lympho-haematopoietic cancer.

PMID- 12479508
TI  - Cognitive performance and cerebrohemodynamics associated with the Persian Gulf
      Syndrome.
AB  - The Persian Gulf Syndrome generally manifests as a set of nonspecific complaints
      with emphasis on central nervous system impairment. The purpose of this study was
      to determine if cognitive performance and middle cerebral artery blood flow
      velocity (MCABFV) were altered in symptomatic Gulf War veterans (sGWVs) and
      asymptomatic Gulf War veterans (aGWVs) by exposure to low levels of acetone.
      MCABFV was assessed in male aGWVs (n = 8) and sGWVs (n = 8) during cognitive
      challenges while breathing 1) clean air, 2) a clean air placebo, and 3) a mixture
      of air and 40 parts per million (ppm) acetone. Pulmonary function was also
      evaluated. Pulmonary function tests showed no statistical differences between
      aGWVs and sGWVs while breathing clean air or 40 ppm acetone in air. Cognitive
      performance was similar during the clean air, placebo, and acetone test
      conditions for sGWVs and aGWVs. Data pooled across test conditions for each group
      indicated a statistically significant (P < 0.05) poorer performance primarily in
      memory and executive function tasks by sGWVs. sGWVs had a 34.2% higher baseline
      MCABFV than aGWVs (P < 0.05). Increases in MCABFV for aGWVs (averaged over all
      cognitive tasks for each test condition) ranged between 7.8% and 8.8%, and were
      not statistically significant. Increases for sGWVs ranged between 0.3% and 4.8%,
      averaged over all cognitive tasks for each test condition. No significant
      differences were noted between the clean air and placebo test conditions but both
      were significantly different to the acetone condition. Differences in MCABFV
      increases for each of the test conditions between aGWVs and sGWVs were also
      statistically significant. sGWV did not appear to demonstrate pulmonary
      dysfunction following exposure to acetone. They did, however, appear to have
      generally lower cognitive function as compared to aGWVs. sGWVs appeared to have a
      significant degree of autoregulatory disruption in cerebral perfusion, resulting
      in reduced cognitive reserve capacity and potentially impaired ability to handle
      complex cognitive tasks.

PMID- 12479509
TI  - Asbestos content of omentum and mesentery in nonoccupationally exposed
      individuals.
AB  - Asbestos fibers in occupationally exposed individuals relocate from the lung to
      extrapulmonary sites. A mechanism for relocation is via the lymphatic
      circulation. Indeed, asbestos fibers have been found in lymph nodes as well as
      pleural plaques. Our laboratory has recently shown that asbestos fibers also
      reach the mesentery and omentum in the peritoneal area where a small percentage
      of mesotheliomas occurs in exposed individuals. The present study uses light and
      analytical transmission electron microscopy for defining the asbestos burden in
      digested lung, omentum, and mesentery tissues from individuals considered as
      representing the general population in East Texas. The findings, when compared
      with previous data from occupationally exposed individuals, indicate extreme
      contrasts as to the level and types of fiber burden between individuals
      representing the groups.

PMID- 12479510
TI  - Drug-related valvular heart disease: here we go again: will we do better this
      time?

PMID- 12479511
TI  - Diagnosing primary amyloidosis.

PMID- 12479512
TI  - Valvular heart disease in patients taking pergolide.
AB  - OBJECTIVE: To determine whether an association exists between pergolide and
      valvular heart disease. PATIENTS AND METHODS: Three patients with severe,
      unexplained tricuspid regurgitation were examined at our institution from
      September 2000 to April 2002. Echocardiography and histology of surgically
      explanted valves revealed abnormalities suggestive of carcinoid involvement,
      methysergide or ergotamine treatment, or use of fenfluramine and dexfenfluramine.
      Carcinoid valvular heart disease was excluded. None of the patients had prior
      treatment with these drugs. All 3 patients were taking pergolide. RESULTS: Of the
      3 patients, 2 had predominantly right-sided congestive heart failure. In all 3
      patients, echocardiography showed unusual valve morphology, with severe tricuspid
      valve regurgitation. Significant left-sided valve regurgitation was noted in 2
      patients. Histologic analysis revealed surface fibroproliferative lesions with
      preserved underlying valve architecture. CONCLUSION: The echocardiographic and
      histopathologic features of these cases are strikingly similar to those
      associated with carcinoid-, ergot-, and fenfluramine-induced valve disease. An
      association between pergolide and valvular heart disease may therefore exist.

PMID- 12479513
TI  - Utility of subcutaneous fat aspiration for diagnosing amyloidosis in patients
      with isolated peripheral neuropathy.
AB  - OBJECTIVE: To determine the value of subcutaneous fat aspiration in patients with
      sensorimotor peripheral neuropathy. PATIENTS AND METHODS: We retrospectively
      reviewed the medical records of all patients undergoing subcutaneous fat
      aspiration for suspected amyloidosis from January 1, 1994, through December
      31,1999. We classified patients undergoing subcutaneous fat aspiration due to
      peripheral neuropathy into 2 groups: (A) those with isolated peripheral
      neuropathy and (B) those with any family history and laboratory or clinical
      findings typically associated with systemic amyloidosis. RESULTS: The study
      population consisted of 450 patients with peripheral neuropathy in whom fat
      aspiration was performed for suspected amyloidosis. This constituted 56% of all
      fat aspirations performed during the study period. Group A had 143 patients, and
      group B had 307 patients. None of the patients in group A had a positive
      subcutaneous fat aspirate, whereas 17 patients (6%) in group B had a positive
      subcutaneous fat aspirate (P=.002, Fisher exact test). The subcutaneous fat
      aspirate was most commonly positive in patients with a monoclonal protein or
      other clinical findings associated with amyloidosis. CONCLUSIONS: The yield of a
      subcutaneous fat aspirate in patients with isolated peripheral neuropathy and no
      other associated family history, signs, or symptoms of amyloidosis is low.
      Subcutaneous fat aspiration should be reserved for evaluating patients with
      peripheral neuropathy who also have findings associated with systemic
      amyloidosis.

PMID- 12479514
TI  - Association of family history of epilepsy with earlier age at seizure onset in
      patients with focal cortical dysplasia.
AB  - OBJECTIVE: To establish the contribution of family history of epilepsy to seizure
      onset in patients with focal cortical dysplasia (FCD). PATIENTS AND METHODS: From
      January 1998 to January 2001, we prospectively evaluated 19 consecutive patients
      (10 male, 9 female) with a diagnosis of FCD based on magnetic resonance imaging.
      All patients and at least 1 family member were directly interviewed by the same
      observer after completion of a semistructured questionnaire. Initially, we
      classified patients into 2 groups: presence or absence of family history of
      epilepsy. Patients with a family history of epilepsy were subdivided into 2
      groups: patients with a family history of epilepsy in first-degree relatives or
      multiple relatives (n=5) and patients with a family history of epilepsy in
      relatives who were not first-degree (n=4). Statistical analysis was performed
      with use of the nonparametric tests Kruskal-Wallis and Kaplan-Meier (survival
      analysis). P=.05 was considered statistically significant. RESULTS: The ages of
      the patients ranged from 3 to 41 years (mean, 15.6 years). All patients had
      similar type and extent of cortical dysgenesis. Ages at seizure onset varied from
      1 month to 22 years, with a mean of 5.8 years. Nine patients had a family history
      of epilepsy. The mean age at the first seizure in patients with a family history
      of epilepsy was 2.6 years compared with 8.5 years in those with no relatives
      having epilepsy (P=.02). When patients with a family history of epilepsy were
      classified further, the mean age at first seizure was 1.9 years for patients with
      a family history of epilepsy in first-degree or multiple relatives and 3.9 years
      for patients with a family history of epilepsy in relatives who were not first
      degree compared with 8.5 years for patients with no family history of epilepsy
      (P=.04). CONCLUSION: Our results show that a family history of epilepsy is
      associated with an earlier age at seizure onset in patients with FCD. Although
      this is a preliminary finding and a larger sample is needed to confirm these
      results, we believe these observations provide evidence that genetic modifiers
      could become an important issue in the clinical presentation of patients with
      dysplastic lesions.

PMID- 12479515
TI  - Partial normalization of the heart rate response to exercise after cardiac
      transplantation: frequency and relationship to exercise capacity.
AB  - OBJECTIVE: To determine the frequency of partial normalization of the heart rate
      response to graded exercise and its relationship to exercise capacity in cardiac
      transplant recipients. SUBJECTS AND METHODS: The study subjects were 95 adults
      (77 men, 18 women) who were available to perform a cardiopulmonary exercise test
      1 year after orthotopic cardiac transplantation, which occurred between June 1988
      and September 1998. All subjects received standard immunosuppressant medications.
      At the time of the exercise tests, the mean +/- SD age of the subjects was 49+/
      14 years. The mean +/- SD resting left ventricular ejection fraction was 62%+/
      8%. All subjects participated in a 6- to 8-week supervised exercise program,
      starting no later than 1 month after surgery. Subjects were given an exercise
      prescription for independent exercise training after finishing the supervised
      program. Self-reported weekly exercise training had a median value of 90 minutes
      (interquartile range, 0-210 minutes). Symptom-limited graded exercise was
      performed on a treadmill, with breath-by-breath analysis of expired air. RESULTS:
      For the entire cohort, peak exercise oxygen uptake was 19.9+/-4.8 mL x kg(-1) x
      min(-1) (61%+/-15% of age and sex predicted). Thirty-two subjects (34%) had a
      partially normalized heart rate response to graded exercise. The frequency was
      similar for men (25/77 [33%]) and for women (7/18 [39%]) and was independent of
      recipient or donor age. Peak exercise heart rate (147+/-18 vs 134+/-21 beats/min;
      P=.008) and heart rate reserve (46+/-15 vs 33+/-15 beats/min; P<.001) were
      greater for subjects with a partial normalization of heart rate response. Peak
      exercise oxygen uptake was similar for subjects with or without partial
      normalization of the heart rate response (20.9+/-5.8 vs 19.4+/-4.2 mL x kg(-1) x
      min(-1); P=.22). Submaximal exercise oxygen uptake during the first few minutes
      of exercise was also not affected by normalization of the heart rate response.
      CONCLUSION: At 1 year after cardiac transplantation, approximately one third of
      subjects had partial normalization of the heart rate response to graded exercise.
      However, a higher peak exercise heart rate and a larger heart rate reserve did
      not result in better aerobic exercise capacity.

PMID- 12479516
TI  - Radical retropubic prostatectomy and blood transfusion.
AB  - OBJECTIVE: To determine whether there is a reduction in blood loss and blood
      transfusions associated with radical retropubic prostatectomy (RRP) by measuring
      the amount of blood loss and incidence of red blood cell (RBC) transfusions over
      time along with factors that may influence transfusions. PATIENTS AND METHODS:
      This is a retrospective study of patients who underwent RRP with and without the
      nerve-sparing dorsal venous complex (DVC) technique from 1985 to 1993 and in
      1999. Transfusion rate, mean RBC loss, and preoperative and postoperative
      hemoglobin values were assessed. Univariate and multivariate regression analyses
      were performed. RESULTS: A total of 438 RRPs (276 DVC technique, 162 non-DVC
      technique) were reviewed and included in the study. The percentage of patients
      receiving allogeneic RBC transfusion decreased from 69% during 1985 to 1986 to
      7.1% during 1999, and there was a decline in discharge hemoglobin values from
      12.0 to 10.9 g/dL during this period. There was a significant reduction in mean
      hemoglobin concentration lost over time in the DVC technique group from 4.9 to
      4.0 g/dL (P=.04) during the 1985 to 1990 study period, which persisted in 1999.
      CONCLUSION: Improvement in surgical technique and reduction in transfusion
      triggers resulted in large decreases of allogeneic RBC transfusions in patients
      undergoing RRP.

PMID- 12479517
TI  - Observations from the Mayo Clinic National Conference on Medicine and the Media.
AB  - In September 2002, the Mayo Clinic National Conference on Medicine and the Media
      convened to consider the accurate, timely, and responsible reporting of medical
      news to the public. The more than 500 participants included medical and health
      journalists, scientific journal editors, physicians and other health care
      professionals, industry representatives, government officials, institutional
      public information officers, public relations professionals, patients, and
      representatives of patient advocacy groups. The goal of the conference was to
      bring together all facets of the medical news dissemination process with the hope
      of identifying ways to serve the public more effectively. Several key
      observations emerged: Medical news reports may be confusing because the
      underlying scientific issues are unresolved and open to multiple interpretations.
      People who are ill have different information needs than the rest of the public.
      Journalists' primary concern is accurate, clear reporting, with secondary concern
      for a story's consequences. Journalists consider themselves primarily reporters
      rather than educators, but the public expects reporting to contain an educational
      element. Financial and other more subtle interests may influence the quality and
      content of scientific news releases, presentations in scientific journals, and
      stories covered by print and broadcast news media. Full disclosure of commercial
      support and affiliations, peer review of study reports, and formal guidelines for
      conduct may limit inappropriate financial influence.

PMID- 12479518
TI  - J. Michael Bishop--Nobel Laureate in medicine or physiology.

PMID- 12479519
TI  - Genetic causes of inherited cardiac hypertrophy: Robert L. Frye Lecture.
AB  - Cardiac hypertrophy is well recognized as a cardiac manifestation of systemic
      disorders such as hypertension or intrinsic myocardial disease, but it can also
      reflect an underlying genetic defect. Molecular studies of inherited forms of
      cardiac hypertrophy have defined 2 novel pathways that lead to cardiac remodeling
      in adults, discoveries that increasingly provide insights relevant for both
      diagnosis and management. This article reviews the genetic studies that led to
      the current molecular understanding of hypertrophic cardiomyopathy and discusses
      more recently discovered causes of inherited cardiac hypertrophy.

PMID- 12479520
TI  - A contemporary conceptual model of hypochondriasis.
AB  - Hypochondriasis (HC), which involves preoccupation with the fear of having a
      serious illness despite appropriate medical examination, is often encountered in
      medical settings. The most conspicuous feature of this disorder is seeking
      excessive reassurance from physicians, medical references, or self-inspection;
      however, many patients also fear they will receive upsetting information if
      evaluated and thus avoid consultations and remain preoccupied with physiologic
      events, believing they are physically ill. Thus, HC causes personal suffering for
      the patient and practical and cost management problems for professionals across
      fields of clinical practice. The past 2 decades have seen considerable
      improvement in the understanding and treatment of HC. In this article, we review
      a contemporary conceptual model of HC and an effective form of treatment called
      cognitive-behavioral therapy that is derived from this model. Recommendations for
      presenting this conceptualization to patients and encouraging proper treatment
      are also discussed.

PMID- 12479521
TI  - Management of persistent symptoms in patients with asthma.
AB  - The main goals of asthma therapy are to control symptoms, prevent acute attacks,
      and maintain lung function as close to normal as possible. Customizing the
      regimen to relieve the patient's symptoms and control airway inflammation is
      important. If asthma is not well controlled, an initial inhaled corticosteroid
      boost will treat the underlying heightened airway inflammation, and the addition
      of a long-acting beta2-adrenergic agonist or leukotriene receptor antagonist will
      rapidly control symptoms. Most patients do not require prolonged treatment with
      expensive combination or additive agents. Exercise-induced bronchoconstriction is
      a common source of symptoms. Treatments for scheduled and unscheduled exercises
      differ. Inhaled corticosteroids prevent frequent and severe asthma exacerbations.
      When patients have persistent symptoms despite a pharmacological regimen,
      environmental factors and nonpharmacological interventions must be considered
      before medication is increased. When an inhaled corticosteroid is being
      considered, issues of compliance, drug delivery device, and proper inhaler
      techniques are as important as issues of potency, clinical efficacy, and adverse
      effects. The new hydrofluoroalkane preparations offer more lung deposition and
      may be important in treating inflammation of the small airways in patients with
      asthma.

PMID- 12479522
TI  - Pulmonary hemorrhage after percutaneous coronary intervention with abciximab
      therapy.
AB  - Abciximab has a key role in the treatment of patients with acute coronary
      syndromes undergoing percutaneous coronary intervention; however, an increased
      risk of bleeding complications is well recognized. We report a case of serious
      pulmonary hemorrhage after use of abciximab therapy. A definitive indication and
      treatment guideline should be available to minimize serious bleeding
      complications. Additionally, respiratory symptoms should be monitored closely for
      early detection of serious pulmonary hemorrhage in patients receiving abciximab
      therapy during percutaneous coronary intervention.

PMID- 12479523
TI  - Combined tracheal and esophageal stenting for palliation of tracheoesophageal
      symptoms from mediastinal lymphoma.
AB  - Mediastinal lymphoma as a cause of tracheobronchial obstruction is uncommon, and
      a malignant tracheoesophageal fistula in the setting of mediastinal lymphoma is
      rare. Malignant tracheoesophageal fistulas are associated with pronounced
      morbidity and mortality. We describe a patient with mediastinal lymphomatous
      infiltration resulting in tracheal obstruction, esophageal obstruction, and
      tracheoesophageal fistula that were successfully palliated with combined airway
      and esophageal stent placement.

PMID- 12479524
TI  - Aspergillosis related to long-term nasal corticosteroid use.
AB  - Aspergillus is a ubiquitous mold that can cause several types of symptomatic
      infections: allergic aspergillosis, typically in young atopic patients;
      aspergillomas (often referred to as fungus balls); and invasive aspergillosis,
      typically seen in debilitated or immunocompromised patients. We describe an 85
      year-old woman who was not immunocompromised but had invasive aspergillosis of
      the paranasal sinus that resulted in unilateral headache and retrobulbar optic
      neuropathy. After extensive differential diagnostic examination, we concluded
      that the condition was possibly related to the long-term use of nasal
      corticosteroids (fluticasone propionate aqueous nasal spray). Surgical removal of
      solid masses of Aspergillus organisms followed by extended treatment with
      antifungal agents resulted in a favorable outcome.

PMID- 12479525
TI  - Epilepsy with severe abdominal pain.
AB  - We describe a patient who experienced recurrent episodes of abdominal pain as a
      prominent feature of his seizure disorder. Treatment with carbamazepine could not
      prevent these painful sensations, but a selective amygdalohippocampectomy
      completely controlled the episodic pain and the seizures associated with loss or
      alteration of consciousness. During the presurgical evaluation, the episodes of
      abdominal pain correlated with amygdalar seizure discharges.

PMID- 12479526
TI  - Iliac arterial thrombosis after inguinal hernia repair.
AB  - Vascular complications after inguinal hernia repair have been well documented. To
      our knowledge, all previously reported cases have been due to direct injury or
      compression of the vessels during the repair. We present the first case of
      thrombosis of the left common iliac artery after inguinal herniorrhaphy that was
      not due to direct injury or compression of the artery. Special coagulation
      testing revealed that the patient was a heterozygous carrier of the factor V
      R506Q (Leiden) mutation. This mutation is the most common cause of familial
      thrombophilia (hypercoagulable disorder) and is a known risk factor for venous
      thromboembolism. However, the association of this mutation with arterial
      thrombosis is less certain. Patients with thrombosis of the iliofemoral artery or
      vein after inguinal herniorrhaphy should be considered for special coagulation
      testing because of potentially important differences in anticoagulant treatment
      of the affected patient and for genetic counseling of potentially affected family
      members.

PMID- 12479527
TI  - Antiepileptic drug therapy for adults: when to initiate and how to choose.
AB  - Although antiepileptic drugs (AEDs) are commonly used to control and prevent
      seizures, their long-term use carries a considerable risk of morbidity. The
      decision to start AEDs is made once the risks of further seizures outweigh the
      risks of treatment. Despite a large body of literature on the subject, this
      common clinical issue perplexes many practitioners because of its neurologic,
      psychological, and, at times, legal implications. Adding to the confusion is the
      recent approval of several new AEDs. This article summarizes the current evidence
      to support individual clinical decisions regarding initiation of AEDs in adults
      and considers the use of AEDs as seizure prophylaxis. Recently approved AEDs are
      discussed to help the practitioner understand when to initiate and how to choose
      the appropriate AED for the patient with seizures.

PMID- 12479528
TI  - Antiepileptic drug withdrawal: literature review.
AB  - Of patients with epilepsy, 60% to 70% achieve control with antiepileptic
      medication. Antiepileptic drugs may be associated with unwanted adverse effects,
      inconvenience, and cost. Remission may occur in some patients, raising the issue
      of whether continued treatment is necessary. Identifying patients from whom
      treatment can be withdrawn successfully would be beneficial on many levels, but
      selecting patients may be difficult. Several published antiepileptic drug
      withdrawal studies show variable rates of success, with relapse rates ranging
      from 12% to 63%. Several prognostic factors help identify patients who may be
      amenable to antiepileptic drug withdrawal. The results and limitations described
      in the antiepileptic drug withdrawal literature, prognostic factors, and general
      guidelines for antiepileptic drug withdrawal are presented in this article.

PMID- 12479529
TI  - Refractory acquired von Willebrand disease despite successful treatment of the
      associated lymphoma.

PMID- 12479530
TI  - Effect of lipid infusion on plasma leptin and neuropeptide Y levels in women.

PMID- 12479531
TI  - Thalidomide-induced neuropathy.

PMID- 12479532
TI  - Gene function far from understood.

PMID- 12479533
TI  - A need for new ideas.

PMID- 12479534
TI  - Building upon our values: health care's promises to its patients and communities.
AB  - Originally presented as an endowed lecture, this paper outlines the values that
      have always driven health care management and how those values can be used to
      confront today's challenges. The challenges are discussed in a way that clearly
      calls for promises to build upon the values that will improve the health care
      environment and the obligations that health care managers have to fulfill those
      promises.

PMID- 12479535
TI  - Managed care: an industry snapshot.
AB  - Together with the American Association of Health Plans (AAHP), we surveyed health
      maintenance organizations (HMOs) in 1998 to characterize their basic structure
      and management strategies. The findings show that more than half of HMO enrollees
      belong to plans that contract with primary care physician (PCP) groups on a
      predominantly capitated basis. Such plans tend to be larger and to contract with
      large physician groups. Thirty percent to 40% of enrollees are in plans that
      delegate utilization and network management to physician groups paid by
      capitation, but plans almost never delegate these functions to groups paid by fee
      for-service. Plans tend to retain quality assurance functions irrespective of
      whether they use fee-for-service or capitation as a basis for physician payment.
      The autonomy of PCPs to order tests and procedures varies with the test and
      procedure.

PMID- 12479536
TI  - Has Medicaid managed care affected beneficiary access and use?
AB  - This paper uses data from the 1997 National Survey of America's Families to
      examine the effects of the various forms of mandatory Medicaid managed care on
      access and use among beneficiaries not receiving Supplemental Security Income or
      Medicare benefits. The results show that mandatory health maintenance
      organization (HMO) programs have had a positive impact on both children and
      adults, particularly when compared to Medicaid fee-for-service plans. We observed
      less dependence on emergency rooms as a usual source of care, a greater
      probability of visiting a doctor and, for children, greater use of preventive
      care. In contrast, mandatory primary care case management plans (PCCM) provided
      some benefits to children, but appeared to have very little impact on adult
      Medicaid beneficiaries. Mandatory programs that use both HMOs and PCCM produced
      mixed results. With the exception of mandatory HMO programs, discrepancies in
      access and use continue to exist between Medicaid managed care enrollees and low
      income privately insured people.

PMID- 12479537
TI  - Participation in a public insurance program: subsidies, crowd-out, and adverse
      selection.
AB  - This paper examines how varying the level of subsidies affects participation in a
      public insurance program, crowd-out of private insurance, and adverse selection.
      We study the experience in Washington's Basic Health program in 1997. Findings
      show that adverse selection is not a problem in voluntary public programs.
      Increasing subsidies have only modest effects on participation in subsidized
      programs, though the gains are not at the expense of the private market. Overall
      participation in the subsidized plan is also modest, even though participants
      benefit from it. The challenge to policymakers is to find program design
      characteristics, beyond subsidies, that attract the uninsured.

PMID- 12479538
TI  - The economic implications of case-mix Medicaid reimbursement for nursing home
      care.
AB  - In recent years, there has been large growth in the nursing home industry in the
      use of case-mix adjusted Medicaid payment systems that employ resident
      characteristics to predict the relative use of resources in setting payment
      levels. Little attention has been paid to the access and quality incentives that
      these systems provide in the presence of excess demand conditions due to
      certificate-of-need (CON) and construction moratoria. Using 1991 to 1998 panel
      data for all certified U.S. nursing homes, a fixed-effects model indicates that
      adoption of a case-mix payment system led to increased access for more dependent
      residents, but the effect was modified in excess demand markets. Quality remained
      relatively stable with the introduction of case-mix reimbursement, regardless of
      the presence of excess demand conditions. These results suggest that CON and
      construction moratoria are still important barriers within the nursing home
      market, and recent quality assurance activities related to the introduction of
      case-mix payment systems may have been effective.

PMID- 12479539
TI  - Does informal care from adult children reduce nursing home admissions for the
      elderly?
AB  - Despite the policy importance, particularly as society ages, little is known
      about the impact of informal care on nursing home admissions. This paper jointly
      models the receipt of regular help from adult children and subsequent nursing
      home care, using data from the Study of Asset and Health Dynamics Among the
      Oldest Old (AHEAD). Results indicate that frequent help from children with basic
      personal care reduces the likelihood of nursing home use over a subsequent two
      year period by about 60% for disabled Americans age 70 and older. However, we
      found no significant reduction in nursing home admissions when help was measured
      more broadly to include assistance with chores and errands.

PMID- 12479540
TI  - Hospital advertising in California, 1991-1997.
AB  - This paper examines the advertising behavior of California hospitals from 1991 to
      1997. Using highly detailed hospital-level information, we found that hospital
      advertising in California increased dramatically: annual spending on advertising
      grew (inflation adjusted) more than sixfold over the period. In addition,
      advertising expenditures varied significantly across hospitals. We found that
      hospital advertising increased with market concentration; with the number of
      nearby potential patients; with the percentage of nearby patients insured through
      Medicare, health maintenance organizations (HMOs), and indemnity insurance; and
      with chain affiliation. For-profit hospitals were not found to advertise more
      than their not-for-profit counterparts.

PMID- 12479541
TI  - Productivity vs. training in primary care: analysis of hospitals and health
      centers in New York City.
AB  - This paper examines the indirect costs of primary care residency in terms of
      ambulatory care site productivity and the influence of graduate medical education
      (GME) subsidies on the employment of primary care residents. Using a sample of
      hospitals and health centers in New York City (NYC), we find that most facilities
      employ significantly more primary care residents relative to nonresident primary
      care physicians than would be dictated by cost-minimizing behavior in the
      production of primary care. We also find evidence that New York's GME subsidy
      encourages the "overemployment" of residents, while the Medicare GME subsidy does
      not. We conclude that the trade-off between productivity and teaching is more
      serious in primary care than in inpatient settings, and that facilities heavily
      involved in ambulatory care teaching will be at a competitive disadvantage if GME
      subsidies are not targeted specifically for primary care.

PMID- 12479542
TI  - Diagnostic value of molecular markers in chloroquine-resistant falciparum malaria
      in Southern Mauritania.
AB  - Despite its diminishing efficacy because of increased resistance, chloroquine
      remains the primary antimalarial agent in many endemic areas. Evidence is
      mounting that point mutations on the Pfcrt and possibly the Pfmdr1 genes are
      conferring plasmodial resistance to chloroquine. In 1998, atypically strong
      rainfalls led to an increased activity of falciparum malaria in Mauritania that
      affected non-endemic regions bordering the Saharan desert. An in vivo study on
      chloroqine resistance was combined with studies for molecular markers of drug
      resistance. Detection of Pfmdr1-76-tyrosine showed an increased odds ratio (2.91)
      for resistance (P = 0.0195). However, by use of this codon alone, sensitivity for
      detection of resistance was 60.6%, and specificity was 65.3%. In comparison,
      detection of the K76T mutation at Pfcrt showed a very high sensitivity (100%)
      while specificity remained relatively low (65.4%). For the combination of
      mutations on both genes, the odds ratio for detection of resistance increased to
      5.31 (P = 0.0005). Here, sensitivity was again decreased to 60.6% while
      specificity increased to 76.9%. The results of this study suggest that detection
      of Pfcrt T76 can be applied for predicting chloroquine resistance in
      epidemiologic settings with sufficiently high sensitivity to make it an
      attractive alternative to time- and labor-consuming in vivo trials. Additional
      testing for Pfmdr Y76 provides increased specificity to this approach.

PMID- 12479543
TI  - Potential of the Panama strain of Plasmodium vivax for the testing of malarial
      vaccines in Aotus nancymai monkeys.
AB  - Aotus monkeys were infected with a strain of Plasmodium vivax from Panama to
      determine its potential for the testing of malarial vaccines. After sporozoite
      inoculation, 3 splenectomized Aotus nancymai that had been infected previously
      with Plasmodium falciparum and P. vivax had prepatent periods of 13, 15, and 15
      days with maximum parasite counts of 12,726/microl, 5,310/microl, and
      9,180/microl. Three other A. nancymai previously infected with P. falciparum only
      had prepatent periods of 17, 15, and 15 days with maximum parasite counts of
      44,460/microl, 31,500/microl, and 42,660/microl. One monkey with no previous
      history of infection had a prepatent period of 14 days after sporozoite
      inoculation, and a maximum parasite count of 100,000/microl; detectable
      parasitemia persisted for almost 500 days with 13 recognizable peaks in the
      parasite count. Anopheles dirus, Anopheles freeborni, Anopheles stephensi, and
      Anopheles quadrimaculatus mosquitoes were readily infected with the Panama
      strain.

PMID- 12479544
TI  - The population structure of Plasmodium falciparum and Plasmodium vivax during an
      epidemic of malaria in the Eastern Highlands of Papua New Guinea.
AB  - Although most of the Papua New Guinea highlands are too high for stable malaria
      transmission, local epidemics are a regular feature of the region. Few detailed
      descriptions of such epidemics are available, however. We describe the
      investigation of a malaria epidemic in the Obura Valley, Eastern Highlands
      Province, Papua New Guinea. Of the 244 samples examined by microscopy, 6.6% were
      positive for Plasmodium falciparum only, 9.4% were positive for Plasmodium vivax
      only, and 1.2% were mixed infections. MSP2 and MSP3alpha genotyping and AMA1
      sequencing were used to determine the genetic variation present in a sample of P.
      falciparum and P. vivax infections. The P. vivax infections were found to be
      genetically highly diverse. In contrast, all P. falciparum samples were of a
      single genotype. This striking difference in genetic diversity suggests endemic,
      low-level local transmission for P. vivax but an outside introduction of P.
      falciparum as the most likely source of the epidemic.

PMID- 12479545
TI  - Artesunate and mefloquine given simultaneously for three days via a prepacked
      blister is equally effective and tolerated as a standard sequential treatment of
      uncomplicated acute Plasmodium falciparum malaria: randomized, double-blind study
      in Thailand.
AB  - The combination of artesunate and mefloquine is currently one of the most
      effective treatments against multidrug-resistant Plasmodium falciparum malaria.
      To improve patient compliance to such a combination, the two agents have been
      combined in a prepacked single blister. Patients were instructed to
      simultaneously co-administer the drugs once a day for three days. In the present
      randomized, double-blind, parallel group, comparative, single center study in
      Thailand, this concept was investigated in 204 adults and children with acute,
      uncomplicated P. falciparum malaria. Patients were randomized into two treatment
      groups and received once a day over a three-day period the following: Group A
      received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg,
      approximately 8.5 mg/kg/day, simultaneously. Group B received artesunate, 4-5
      mg/kg/day, and mefloquine, total dose = 25 mg/kg, sequentially (i.e., no
      mefloquine dose on the first day, 15 mg/kg on the second day, and 10 mg/kg on the
      third day). Both treatment groups showed no relevant differences in baseline
      demographic and clinical characteristics. Intent-to-treat analysis revealed a
      cure rate at day 28 (primary endpoint) of 100% in group A and 99% in group B
      (difference not significant). The secondary endpoints of mean time to fever
      clearance (group A = 34 hours, group B = 31 hours) and mean time to parasite
      clearance (group A = 44 hours group B = 48 hours) were similar between groups
      (both differences not significant). Tolerability was good in both treatment
      groups, with no difference in the overall incidence of adverse events. There was
      a low incidence of nausea/vomiting (4.9% in both groups) and central nervous
      system side effects (4.9% in group A versus 8.8% in group B). These were
      comparable between groups and generally of a mild nature. The three-day
      combination of artesunate and mefloquine (Artequin, Mepha, Ltd., Aesch,
      Switzerland) with the introduction of mefloquine on day 1 offers a practical
      dosing regimen that is highly effective and well tolerated in patients of
      different ages with uncomplicated P. falciparum malaria. It is likely that the
      prepacked blister approach translates clinically into a better patient
      compliance, thereby contributing to limit the development of drug resistance.

PMID- 12479546
TI  - Diuretic effect of sodium artesunate in patients with malaria.
AB  - Previously, we described a direct inhibitory effect of sodium artesunate on
      sodium chloride transport in the thick ascending limb of Henle's loop, indicating
      that artesunate acts as a diuretic agent. Here we present 2 cases of falciparum
      malaria treated with 4 intravenous 60-mg doses of sodium artesunate. Neither
      diuretics nor vasoactive drugs were administered. A rise in diuresis (6 L/24
      hours) was accompanied by an increase in natriuresis, and both declined at the
      end of the treatment. This diuretic effect has not been reported previously in
      patients and may modify the course of renal failure and respiratory distress
      syndrome, both of which complicate severe malaria.

PMID- 12479547
TI  - Onchodermal skin disease in a hyperendemic onchocerciasis focus in western
      Uganda.
AB  - To assess the degree of skin disease in Simulium neavei s.s.-transmitted
      onchocerciasis, 72 patients infected with Onchocerca volvulus in the Kabarole
      district of Uganda were studied. They were clinically and parasitologically
      evaluated. Onchocercal skin lesions were determined using a modified Murdoch skin
      assessment, and skin scores were calculated. The chronic skin score (4.0) was
      associated with age, and the acute skin score (8.5) was significantly higher in
      males. The burden of onchocercal skin lesions was found to be high in most
      patients. The number of nodules (median number 1.9) and the microfilarial load
      (geometric mean of microfilaria 11.5) were not determinants for the burden of
      onchocercal skin disease in infected individuals. The study concludes that
      onchodermatitis is a serious medical condition in Kigoyera Parish and needs to be
      considered in all efforts to control onchocerciasis.

PMID- 12479548
TI  - A geostatistical analysis of the geographic distribution of lymphatic filariasis
      prevalence in southern India.
AB  - Gaining a better understanding of the spatial population structure of infectious
      agents is increasingly recognized as being key to their more effective mapping
      and to improving knowledge of their overall population dynamics and control.
      Here, we investigate the spatial structure of bancroftian filariasis distribution
      using geostatistical methods in an endemic region in Southern India. Analysis of
      a parasite antigenemia prevalence dataset assembled by sampling 79 villages
      selected using a World Health Organization (WHO) proposed 25 x 25 km grid
      sampling procedure in a 225 x 225 km area within this region was compared with
      that of a corresponding microfilaraemia prevalence dataset assembled by sampling
      119 randomly selected villages from a smaller subregion located within the main
      study area. A major finding from the analysis was that once large-scale spatial
      trends were removed, the antigenemia data did not show evidence for the existence
      of any small-scale dependency at the study sampling interval of 25 km. By
      contrast, analysis of the randomly sampled microfilaraemia data indicated strong
      spatial contagion in prevalence up to a distance of approximately 6.6 kms,
      suggesting the likely existence of small spatial patches or foci of transmission
      in the study area occurring below the sampling scale used for sampling the
      antigenemia data. While this could indicate differences in parasite spatial
      population dynamics based on antigenemia versus microfilaraemia data, the result
      may also suggest that the WHO recommended 25 x 25 km sampling grid for rapid
      filariasis mapping could have been too coarse a scale to capture and describe the
      likely local variation in filariasis infection in this endemic location and
      highlights the need for caution when applying uniform sampling schemes in diverse
      endemic regions for investigating the spatial pattern of this parasitic
      infection. The present results, on the other hand, imply that both small-scale
      spatial processes and large-scale factors may characterize the observed
      distribution of filariasis in the study region. Our preliminary analysis of a
      mountain range associated large-scale trend in the antigenemia data suggested
      that a nonlinear relationship of infection prevalence with elevation might be a
      factor behind such observed global spatial patterns. We conclude that
      geostatistic methods can provide a powerful framework for carrying out the
      empirical investigation and analysis of parasite spatial population structure.
      This study shows that their successful application, however, will crucially
      depend on our gaining a more thorough understanding of the appropriate geographic
      scales at which spatial studies should be carried out.

PMID- 12479549
TI  - Short report: seasonal pattern of respiratory syncytial virus in a region with a
      tropical climate in southeastern Brazil.
AB  - Among acute respiratory infections (ARIs), respiratory syncytial virus (RSV) is
      an important pathogen, especially in infants and preschool children. This study
      focused on RSV epidemiology in a region of southeastern Brazil with a tropical
      climate. A total of 406 nasopharyngeal secretion samples were taken from children
      less than five years of age with ARIs. Of these, 114 (28%) were RSV-positive.
      These samples were found in all age groups, but showed a higher prevalence in
      newborns. Infection with RSV was identified in 10 of the 12 months of the study
      period, but the majority (88.5%) of cases occurred from late summer to mid-fall.

PMID- 12479550
TI  - Detection of West Nile virus-infected mosquitoes and seropositive juvenile birds
      in the vicinity of virus-positive dead birds.
AB  - Mosquitoes and wild birds were collected from three sites near locations in the
      New York City metropolitan area where single, West Nile (WN) virus-positive dead
      birds were found early in the 2000 transmission season. The mosquitoes were
      tested for the presence of infectious virus with a Vero cell culture assay and
      for WN viral RNA by using reverse transcriptase-polymerase chain reaction (RT
      PCR) protocols. Serum samples from wild birds were tested for the presence of
      neutralizing antibodies against WN virus. Infectious WN virus and WN viral RNA
      were found in Culex species adult mosquitoes from each of the three sites, and a
      seropositive hatch-year house sparrow (Passer domesticus) was found in one of the
      three sites. Molecular techniques used to identify the species in the positive
      mosquito pools found that most of the pools contained a combination of Culex
      pipiens and Cx. restuans. The minimum infection rate in Culex species mosquitoes
      from the sites ranged from 0.2 to 6.0 per 1,000 specimens tested. The results
      demonstrated that, at least early in the transmission season, detection of a WN
      virus-positive dead bird indicates a local WN virus transmission cycle. This
      information is valuable in focusing subsequent surveillance and vector management
      programs. In addition, the RT-PCR procedure for detecting WN viral RNA in
      mosquito pools detected more positive pools than did the Vero cell plaque assay.

PMID- 12479551
TI  - Comparative evaluation of selected diagnostic assays for the detection of IgG and
      IgM antibody to Orientia tsutsugamushi in Thailand.
AB  - We compared the performance of 2 commercially available dipstick assays, 2 enzyme
      linked immunosorbent assays (ELISAs), and an indirect immunofluorescent antibody
      (IFA) assay for the diagnosis of scrub typhus, using the indirect
      immunoperoxidase (IIP) test as the reference standard. The dipstick assays were
      the Integrated Diagnostics (Baltimore, MD) Dip-S-Ticks Scrub Recombinant (r56)
      dipstick test (INDX assay) and the PanBio (Brisbane, Australia) Scrub Typhus IgM
      and IgG Rapid Immunochromatographic test (PanBio assay). One of the ELISAs used
      pooled cell lysates of Karp, Kato, and Gilliam strain Orientia tsutsugamushi as
      antigen (pooled-antigen ELISA), and the other used a recombinant r56 protein as
      the antigen (recombinant ELISA). With a panel of 123 positive and 227 negative
      sera, sensitivity and specificity of the assays were as follows: INDX assay, IgG,
      60% and 95%, IgM, 60% and 97%; PanBio assay, IgG, 94% and 96%, IgM, 83% and 93%;
      IFA (1:400 cutoff), IgG, 91% and 96%, IgM, 85% and 98%; pooled-antigen ELISA, IgG
      (1:1600 cutoff), 97% and 89%, IgM (1:400 cutoff), 94% and 91%; recombinant ELISA,
      IgG (1:1600 cutoff), 97% and 92%, IgM (1:400 cutoff), 93% and 94%. Because of its
      excellent performance and use of a standardized, commercially available antigen,
      the recombinant ELISA is suitable for use in a diagnostic laboratory, where it
      may be able to replace the IFA and IIP assays. In contrast, the PanBio dipstick
      assay was easy to perform and did not require sophisticated equipment, making it
      suitable for use in rural areas where more sophisticated diagnostic tests such as
      the ELISA and IFA may not be available.

PMID- 12479552
TI  - Molecular characterization of Lyme disease spirochetes (Borrelia burgdorferi
      sensu lato) isolated in Taiwan by restriction fragment length polymorphism
      analysis of 5S(rrf)-23S(rrl) intergenic spacer amplicons.
AB  - We analyzed the 5S (rrf)-23S (rrl) intergenic spacer amplicon gene of Lyme
      disease spirochetes (Borrelia burgdorferi sensu lato) for the first time in
      Taiwan. The genetic identities of these Taiwan isolates (TWKM1-7) were clarified
      by comparing their restriction fragment length polymorphism patterns and sequence
      similarities of the polymerase chain reaction-amplified intergenic spacer
      amplicon genes with 3 major genospecies of Lyme disease spirochetes. Amplified
      spacer DNAs were purified further and subjected to the cleavage by nuclease DraI
      or MseI. Differential fragment patterns in relation to different genospecies of
      Lyme disease spirochetes were observed among tested Borrelia isolates, and all of
      these Taiwan isolates were closely related to the genospecies of B. burgdorferi
      sensu stricto. The phylogenetic analysis also revealed that the sequence
      similarity of polymerase chain reaction-amplified spacer genes of these Taiwan
      isolates was highly homogeneous (95.7-100%) within the genospecies of B.
      burgdorferi sensu stricto and can be distinguished clearly from other genospecies
      of Lyme disease spirochetes with a 4.1% sequence divergence. Based on the
      differential fragment patterns and sequence similarity among these Taiwan
      isolates, the genetic identity of these Taiwan isolates should be classified into
      the genospecies of B. burgdorferi sensu stricto.

PMID- 12479553
TI  - Domestic dog ownership in Iran is a risk factor for human infection with
      Leishmania infantum.
AB  - One explanation proposed for the widespread failure to control zoonotic visceral
      leishmaniasis by culling infected domestic dogs is that wild canids or humans
      play significant roles in transmission. The aim of this study was to determine
      the importance of domestic dogs as the reservoir hosts of visceral leishmaniasis
      in northwest Iran. A random sample of 3,872 children and 199 dogs in 38 villages
      was surveyed by the direct agglutination test. Dog ownership details among these
      households were collected by questionnaire. Parasites isolated from 16 patients
      and 12 dogs were characterized as Leishmania infantum MON-1. Average
      seroprevalence in dogs (21.6%) was much higher than in children (7%). Child
      seropositivity increased significantly with village dog density in absolute terms
      (P < 0.001) and in relation to dog/human ratios (P = 0.028). Dog ownership within
      villages also was a significant risk factor for child seropositivity (P = 0.003).

PMID- 12479554
TI  - Ecologic niche modeling and differentiation of populations of Triatoma
      brasiliensis neiva, 1911, the most important Chagas' disease vector in
      northeastern Brazil (hemiptera, reduviidae, triatominae).
AB  - Ecologic niche modeling has allowed numerous advances in understanding the
      geographic ecology of species, including distributional predictions,
      distributional change and invasion, and assessment of ecologic differences. We
      used this tool to characterize ecologic differentiation of Triatoma brasiliensis
      populations, the most important Chagas' disease vector in northeastern Brazil.
      The species' ecologic niche was modeled based on data from the Fundacao Nacional
      de Saude of Brazil (1997-1999) with the Genetic Algorithm for Rule-Set Prediction
      (GARP). This method involves a machine-learning approach to detecting
      associations between occurrence points and ecologic characteristics of regions.
      Four independent "ecologic niche models" were developed and used to test for
      ecologic differences among T. brasiliensis populations. These models confirmed
      four ecologically distinct and differentiated populations, and allowed
      characterization of dimensions of niche differentiation. Patterns of ecologic
      similarity matched patterns of molecular differentiation, suggesting that T.
      brasiliensis is a complex of distinct populations at various points in the
      process of speciation.

PMID- 12479555
TI  - Exacerbation of HIV viral load simultaneous with asymptomatic reactivation of
      chronic Chagas' disease.
AB  - Chronic Trypanosoma cruzi infection can reactivate in patients with
      immunosuppression related to human immunodeficiency virus (HIV) infection,
      resulting in severe meningoencephalitis or myocarditis and high parasitemia. The
      effects of T. cruzi on HIV infection are unknown. We describe an HIV-infected
      patient with chronic Chagas' disease who experienced an asymptomatic T. cruzi
      reactivation characterized by the finding of the parasite in direct microscopic
      examination of blood. The patient's HIV viral load had increased simultaneously
      with the exacerbation of T. cruzi parasitemia and decreased to previous levels
      after successful antiparasitic treatment. This otherwise unexplained finding
      suggests that T. cruzi infection might up-regulate HIV replication, which may
      affect HIV disease progression. Asymptomatic reactivation of Chagas' disease has
      not been reported before. This could mean that the severe clinical manifestations
      related to the reactivation of trypanosomiasis are just the tip of the iceberg.

PMID- 12479556
TI  - Hepatic hydatid cysts with superinfection in a non-endemic area in Taiwan.
AB  - Hepatic hydatid cysts are extremely rare in Taiwan. We report a case of
      complicated, multivesicular, hydatid cysts in the liver and a secondary infection
      with Klebsiella pneumoniae. The cysts were detected in an early stage by
      ultrasonography and computed tomography and treated successfully with radical
      resection.

PMID- 12479557
TI  - Prevalence and incidence density of Mycobacterium leprae and Trypanosoma cruzi
      infections within a population of wild nine-banded armadillos.
AB  - A total of 415 wild 9-banded armadillos from the East Atchafalaya River Levee
      (Point Coupee, LA) were collected over 4 years to estimate the incidence and
      prevalence of Mycobacterium leprae and Trypanosoma cruzi and to discern any
      relationship between the 2 agents. M. leprae infections were maintained at a high
      steady prevalence rate year to year averaging 19%. T. cruzi antibody prevalence
      remained relatively low, averaging 3.9%, and varied markedly between years.
      Prevalence rates were independent, with only 3 armadillos coinfected with both
      agents. M. leprae incidence density ranged from 0.47 to 3.5 cases per 1,000
      animal-days, depending on case definition, confirming active intense transmission
      of M. leprae among armadillos. No incident T. cruzi cases were found. These
      infections seem to occur independently and may be used in comparisons to
      understand better factors that may influence transmission of these agents.

PMID- 12479558
TI  - An observational clinic-based study of diarrheal illness in deployed United
      States military personnel in Thailand: presentation and outcome of Campylobacter
      infection.
AB  - Campylobacter is a leading cause of traveler's diarrhea in Thailand. Since
      resistance to quinolones is high among Campylobacter isolates, empiric therapy
      with quinolones for traveler's diarrhea may be ineffective in this region. We
      conducted an observational study among 169 U.S. military personnel with acute
      diarrhea and compared their microbiologic findings to those of 77 asymptomatic
      personnel deployed to Thailand in May 1998. Of 146 pathogenic bacterial isolates,
      the most common were nontyphoidal Salmonella (n = 31), enterotoxigenic
      Escherichia coli (n = 24), and C. jejuni/coli (n = 23). Campylobacter was
      strongly associated with disease (odds ratio = 5.9; 95% confidence interval = 1.3
      37.3), with a more severe clinical presentation, and with a reduced functional
      ability at presentation (P = 0.02). In vitro resistance to ciprofloxacin was
      observed in 96% of the Campylobacter isolates. Sub-optimal treatment response to
      ciprofloxacin was observed in 17% of the cases of Campylobacter infection versus
      6% due to other causes. These results highlight the importance of Campylobacter
      as a cause of severe traveler's diarrhea in Thailand and illustrates the ongoing
      problem with antibiotic-resistant strains and associated treatment problems.

PMID- 12479559
TI  - The role of dogs in transmission of gastrointestinal parasites in a remote tea
      growing community in northeastern India.
AB  - The prevalence and risk factors associated with canine gastrointestinal parasitic
      zoonoses and the role of dogs in the mechanical transmission of human Ascaris
      infection was examined in three tea estates in Assam, India. Nearly all (99%)
      dogs harbored one or more zoonotic species of gastrointestinal parasites, with
      hookworm infection being most common (94%). Parasitic stages presumed to be host
      specific for humans such as Ascaris spp. (31%), Trichuris trichiura (25%), and
      Isospora belli (2%) were also recovered from dog feces. A polymerase chain
      reaction-linked restriction fragment length polymorphism technique was used to
      differentiate the species of Ascaris eggs in dog feces. The results of this study
      demonstrate the role of the dog as a significant disseminator and environmental
      contaminator of Ascaris lumbricoides in communities where promiscuous defecation
      by humans occurs.

PMID- 12479560
TI  - Detection of Enterobius vermicularis eggs in the submucosa of the transverse
      colon of a man presenting with colon carcinoma.
AB  - We report a case of a chronic infiltrate of the intestinal wall of the transverse
      colon by the eggs of Enterobius vermicularis in a man who had immigrated to
      Taiwan from mainland China 50 years ago. During surgery for suspected transverse
      colon carcinoma, histologic examination of the tumor mass revealed eggs of E.
      vermicularis embedded in granulation tissue in the submucosa of the transverse
      colon. Results of a stool examination were negative for eggs but strongly
      positive for occult blood. The mass in the transverse colon was completely
      removed during surgery. At the present time, the patient remains asymptomatic.

PMID- 12479561
TI  - Seroprevalence of rubella among women of childbearing age in Taiwan after
      nationwide vaccination.
AB  - Taiwan initiated a nationwide program in 1986 to have all 15-year-old schoolgirls
      vaccinated against rubella and another program in 1992 to encourage all women of
      childbearing age to receive rubella vaccination. To assess the immunity among
      women after the implementation of these programs, we conduct a serosurvey. We
      recruited women who were 15-44 years old and received pre-employment health
      examinations at the clinic of an industrial park from January 1 to June 30, 2000.
      Anti-rubella antibody titers were determined by enzyme-linked immunoassays. All
      1,087 women who fit the selection criteria agreed to participate, and the overall
      susceptible (seronegative) rate was 5.7%. The susceptible rate was much lower
      among women who were covered by both programs than women who were not (4% versus
      23%, P < 0.001). The nationwide vaccination programs were effective, but a
      substantial proportion of childbearing-age women were still susceptible and need
      booster vaccination.

PMID- 12479562
TI  - Cellular lipid binding proteins as facilitators and regulators of lipid
      metabolism.
AB  - Evidence is accumulating that cellular lipid binding proteins are playing central
      roles in cellular lipid uptake and metabolism. Membrane-associated fatty acid
      binding proteins putatively function in protein-mediated transmembrane transport
      of fatty acids, likely coexisting with passive diffusional uptake. The
      intracellular trafficking of fatty acids, bile acids, and other lipid ligands,
      may involve their interaction with specific membrane or protein targets, which
      are unique properties of some but not of all cytoplasmic lipid binding proteins.
      Recent studies indicate that these proteins not only facilitate but also regulate
      cellular lipid utilization. For instance, muscle fatty acid uptake is subject to
      short-term regulation by translocation of fatty acid translocase (FAT)/CD36 from
      intracellular storage sites to the plasma membrane, and liver-type cytoplasmic
      fatty acid-binding protein (L-FABPc) functions in long-term, ligand-induced
      regulation of gene expression by directly interacting with nuclear receptors.
      Therefore, the properties of the lipid-protein complex, rather than those of the
      lipid ligand itself, determine the fate of the ligand in the cell. Finally, there
      are an increasing number of reports that deficiencies or altered functioning of
      both membrane-associated and cytoplasmic lipid binding proteins are associated
      with disease states, such as obesity, diabetes and atherosclerosis. In
      conclusion, because of their central role in the regulation of lipid metabolism,
      cellular lipid binding proteins are promising targets for the treatment of
      diseases resulting from or characterised by disturbances in lipid metabolism,
      such as atherosclerosis, hyperlipidemia, and insulin resistance.

PMID- 12479563
TI  - Critical steps in cellular fatty acid uptake and utilization.
AB  - Despite decades of extensive research, the transport routes, mechanisms of uptake
      and points of flux control of long-chain fatty acids (FA) in mammalian organs are
      still incompletely understood. In non-fenestratred organs such as heart and
      skeletal muscle, membrane barriers for blood-borne FA are the luminal and
      abluminal membranes of endothelial cells, the sarcolemma and the mitochondrial
      membranes. Transport of FA through the phospholipid bilayer of the cellular
      membrane is most likely accomplished by diffusion of protonated FA. Evidence is
      accumulating that membrane-associated proteins, such as plasmalemmal fatty acid
      binding protein (FABPpm) and fatty acid translocase (FAT/CD36), either alone or
      in conjunction with albumin binding protein (ABP), are instrumental in enhancing
      the delivery of FA to the cellular membrane. Inside the cell, cytoplasmic fatty
      acid-binding proteins (FABPc) are involved in diffusion of FA from the
      plasmalemma to the intracellular sites of conversion, such as the mitochondrial
      outer membrane. After conversion of FA to FACoA, the fatty acyl chain is
      transported across the mitochondrial inner membrane in a carnitine-mediated
      fashion. Uptake and utilization of FA by muscle cells are finely tuned, most
      likely to avoid the intracellular accumulation of FA, as these are cytotoxic at
      high concentrations. On a short-term basis, net uptake is, among others,
      regulated by intracellular translocation of FAT from intracellular stores to the
      sarcolemma and by the concentration gradient of FA across the sarcolemma. The
      latter implies that, among others, the rate of FA utilization determines the rate
      of uptake. The rate of utilization is governed by a variety of factors, including
      malonylCoA, the ratio acetylCoA/CoA and the availability of competing substrates
      such as glucose, lactate, and ketone bodies. Long-term regulation of uptake and
      utilization is accomplished by alterations in the rate of expression of genes,
      encoding for FA-handling proteins. Circumstantial evidence indicates that FA
      themselves are able to modulate the expression of FA-handling genes via nuclear
      transcription factors such as peroxisome proliferator-activated receptors
      (PPARs).

PMID- 12479564
TI  - Mechanism of cellular uptake of long-chain fatty acids: Do we need cellular
      proteins?
AB  - Defining the mechanism(s) of long-chain fatty acid movement through membranes is
      vital to understanding whether or not entry of fatty acids into cells can be
      controlled at the plasma membrane of a typical cell. Is there a protein that acts
      as gatekeeper, regulating the amount, and possibly the type, of fatty acid that
      can enter the cell for metabolism? Is the lipid bilayer of the membrane highly
      permeable to fatty acids, and is the rate of simple diffusion on the time scale
      of metabolism? We will briefly review efforts to study diffusion in model lipid
      membranes that are devoid of proteins. We also present new results using dual
      fluorescence approaches showing that fatty acids diffuse very rapidly across the
      plasma membrane of the adipocyte.

PMID- 12479565
TI  - Similar mechanisms of fatty acid transfer from human anal rodent fatty acid
      binding proteins to membranes: liver, intestine, heart muscle, and adipose tissue
      FABPs.
AB  - The mammalian fatty acid-binding proteins (FABPs) are thought to be important for
      the transport and metabolism of fatty acids in numerous cell types. The transfer
      of FA from different members of the FABP family to membranes has been shown to
      occur by two distinct mechanisms, an aqueous diffusion-based mechanism and a
      collisional mechanism, wherein the FABP interacts directly with membrane
      acceptors. Much of the work that underlies this concept comes from efforts using
      rodent FABPs. Given the increasing awareness of links between FABPs and several
      chronic diseases in humans, it was important to establish the mechanisms of FA
      transfer for human FABPs. In the present studies, we examined the rate and
      mechanism of fatty acid transfer from four pairs of human and rodent (rat or
      mouse, as specified) FABPs: hLFABP and rLFABP, hIFABP and rIFABP, hHFABP and
      rHFABP, and hAFABP and mAFABP. In the case of human IFABP, both the Ala54 and
      Thr54 forms were examined. The results show clearly that for all FABPs examined,
      the mechanisms of ligand transfer observed for rodent proteins hold true for
      their human counterparts. Moreover, it appears that the Ala to Thr substitution
      at residue 54 of the human IFABP does not alter the fundamental mechanism of
      ligand transfer to membranes, but nevertheless causes a consistent decrease in
      the rate of transfer.

PMID- 12479566
TI  - Cytosolic fatty acid binding proteins catalyze two distinct steps in
      intracellular transport of their ligands.
AB  - Cytosolic long-chain fatty acid binding proteins (FABPs) are found in tissues
      that metabolize fatty acids. Like most lipid binding proteins, their specific
      functions remain unclear. Two classes have been described. Membrane-active FABPs
      interact directly with membranes during exchange of fatty acids between the
      protein binding site and the membrane, while membrane-inactive FABPs bind only to
      fatty acids that are already in aqueous solution. Despite these binding proteins,
      most fatty acids in cell cytoplasm appear to be bound to membranes. This paper
      reviews data suggesting that FABPs catalyze transfer of fatty acids between
      intracellular membranes, often across considerable intracellular distances. This
      process occurs in three distinct steps: dissociation of the fatty acid from a
      'donor' membrane, diffusion of the fatty acid across the intervening water layer,
      and binding to an 'acceptor' membrane. Membrane-active FABPs catalyze
      dissociation of the fatty acid from the donor membrane and binding to the
      acceptor membrane, while membrane-inactive FABPs catalyze diffusion of fatty
      acids across the aqueous cytosol. Thus, FABPs catalyze all three steps in
      intracellular transport. A simple quantitative model has been developed that
      predicts the rate of intracellular transport as a function of the concentration,
      affinity and diffusional mobility of the binding protein. Different FABPs may
      have evolved to match the specific transport requirements of the cell type within
      which they are found.

PMID- 12479567
TI  - Insights into binding of fatty acids by fatty acid binding proteins.
AB  - Members of the phylogenetically related intracellular lipid binding protein
      (iLBP) are characterized by a highly conserved tertiary structure, but reveal
      distinct binding preferences with regard to ligand structure and conformation,
      when binding is assessed by the Lipidex method (removal of unbound ligand by
      hydrophobic polymer) or by isothermal titration calorimetry, a true equilibrium
      method. Subfamily proteins bind retinoids, subfamily II proteins bind bulky
      ligands, examples are intestinal bile acid binding protein (I-BABP) and liver
      fatty acid binding protein (L-FABP) which binds 2 ligand molecules, preferably
      monounsaturated and n-3 fatty acids. Subfamily III intestinal fatty acid binding
      protein (I-FABP) binds fatty acid in a bent conformation. The fatty acid bound by
      subfamily IV FABPs has a U-shaped conformation; here heart (H-) FABP preferably
      binds n-6, brain (B-) FABP n-3 fatty acids. The ADIFAB-method is a fluorescent
      test for fatty acid in equilibrium with iLBP and reveals some correlation of
      binding affinity to fatty acid solubility in the aqueous phase; these data are
      often at variance with those obtained by the other methods. Thus, in this review
      published binding data are critically discussed, taking into account on the one
      hand binding increments calculated for fatty acid double bonds on the basis of
      the 'solubility' hypothesis, on the other hand the interpretation of calorimetric
      data on the basis of crystallographic and solution structures of iLBPs.

PMID- 12479568
TI  - The effect of charge reversal mutations in the alpha-helical region of liver
      fatty acid binding protein on the binding of fatty-acyl CoAs, lysophospholipids
      and bile acids.
AB  - Liver fatty acid binding protein (LFABP) is unique among the various types of
      FABPs in that it can bind a variety of ligands in addition to fatty acids. LFABP
      is able to bind long chain fatty acids with a 2:1 stoichiometry and the crystal
      structure has identified two fatty acid binding sites in the binding cavity. The
      presumed primary site (site 1) involves the fatty acid binding with the
      carboxylate group buried in the cavity whereas the fatty acid at site 2 has the
      carboxylate group solvent-exposed within the ligand portal region and in the
      vicinity of alpha-helix II. The alpha-helical region contains three cationic
      residues, K20, K31, K33 and modelling studies suggest that K31 on alpha-helix II
      could make an electrostatic contribution to anionic ligands binding to site 2.
      The preparation of three charge reversal mutants of LFABP, K20E, K31E and K33E
      has allowed an investigation of the role of site 2 in ligand binding,
      particularly those ligands with a bulky anionic head group. The binding of oleoyl
      CoA, lysophosphatidic acid, lysophosphatidylcholine, lithocholic acid and
      taurolithocholate 3-sulphate to LFABP has been studied using the alpha-helical
      mutants. The results support the concept that such ligands bind at site 2 of
      LFABP where solvent exposure allows the accommodation of their bulky anionic
      group.

PMID- 12479569
TI  - Solution structure of fatty acid-binding protein from human brain.
AB  - Human brain-type fatty acid-binding protein (B-FABP) has been recombinantly
      expressed in Escherichia coli both unlabelled and 15N-enriched for structure
      investigation in solution using high-resolution NMR spectroscopy. The sequential
      assignments of the 1H and 15N resonances were achieved by applying
      multidimensional homo- and heteronuclear NMR experiments. The ensemble of the 20
      final energy-minimized structures, representing human B-FABP in solution, have
      been calculated based on a total of 2490 meaningful distance constraints. The
      overall B-FABP structure exhibits the typical backbone conformation described for
      other members of the FABP family, consisting often antiparallel beta-strands
      (betaA to betaJ) that form two almost orthogonal beta-sheets, a helix-turn-helix
      motif that closes the beta-barrel on one side, and a short N-terminal helical
      loop. A comparison with the crystal structure of the same protein complexed with
      docosahexaenoic acid reveals only minor differences in both secondary structure
      and overall topology. Moreover, the NMR data indicate a close structural
      relationship between human B-FABP and heart-type FABP with respect to fatty acid
      binding inside the protein cavity.

PMID- 12479570
TI  - Evolution of the family of intracellular lipid binding proteins in vertebrates.
AB  - Members of the family of intracellular lipid binding proteins (iLBPs) have been
      implicated in cytoplasmic transport of lipophilic ligands, such as long-chain
      fatty acids and retinoids. iLBPs are low molecular mass proteins (14-16 kDa)
      sharing a common structural fold. The iLBP family likely arose through
      duplication and diversification of an ancestral iLBP gene. Phylogenetic analysis
      undertaken in the present study indicates that the ancestral iLBP gene arose
      after divergence of animals from fungi and plants. The first gene duplication was
      dated around 930 millions of years ago, and subsequent duplications in the
      succeeding 550 millions of years gave rise to the 16 iLBP types currently
      recognized in vertebrates. Four clusters of proteins, each binding a
      characteristic range of ligands, are evident from the phylogenetic tree.
      Evolution of different binding properties probably allowed cytoplasmic
      trafficking of distinct ligands. It is speculated that recruitment of an iLBP
      during evolution of animals enabled the mitochondrial oxidation of long-chain
      fatty acids.

PMID- 12479571
TI  - Intracellular lipid binding proteins of the small intestine.
AB  - The small intestine contains three distinct proteins belonging to the
      intracellular lipid binding protein family: the liver-type fatty acid binding
      protein (L-FABP), the intestinal fatty acid binding protein (I-FABP) and the
      ileal lipid binding protein (ilbp). The function of these proteins in the small
      intestine has remained enigmatic. Targeted gene disruption studies may shed
      insights into the physiological importance of these proteins. In the case of I
      FABP, this approach has demonstrated that the complete elimination of this
      protein in murine intestine does not compromise dietary fat absorption in vivo
      but is associated with the development of insulin resistance.

PMID- 12479572
TI  - Analysis on the phenotype of E-FABP-gene knockout mice.
AB  - The fatty acids are shown to be critical in the maintenance of the water
      permeability barrier that is ascribed to the lipids in the intracellular milieu
      of the cornified cell layer in the epidermis. In view of this importance in the
      skin, we examined the phenotype of epidermal fatty acid binding protein (E-FABP)
      deficient mice. In spite of total lack of E-FABP expression in the various
      tissues of E-FABP deficient mice, these animals appeared normal in gross and
      histological examination. In Northern blot analysis for other FABPs, the gene
      expression of heart (H-)-type FABP is specifically elevated in the liver of
      neonatal heterozygous and homozygous mice, suggesting the functional compensation
      of H-FABP for E-FABP deficiency during their development. In functional analyses
      of the skin, the basal transepidermal water loss (TEWL) of the adult homozygous
      mice showed lower levels compared with the wild-type mice, and the impairment of
      recovery in TEWL was observed in the homozygous mice when the lipid barrier of
      the skin was disrupted by acetone. These results demonstrate that E-FABP is
      responsible for the water permeability barrier of the skin, although the
      molecular mechanism remains to be further elucidated.

PMID- 12479573
TI  - Sterol carrier protein-2: not just for cholesterol any more.
AB  - Although sterol carrier protein-2 (SCP-2) mediates cholesterol esterification in
      L-cell fibroblasts and stimulates an accumulation of cholesterol in these cells,
      a potential role for SCP-2 in fatty acid uptake and trafficking has not been
      appreciated. Certainly, recent experiments have shown that SCP-2 binds fatty
      acids in vitro with an affinity similar to that observed for fatty acid binding
      proteins. Because of the ubiquitous tissue distribution of SCP-2, as opposed to
      the specific distribution of fatty acid binding proteins, as well as the need for
      fatty acid trafficking in all cells, I have recently proposed that SCP-2 is the
      universal fatty acid trafficking protein. This supposition is based on a number
      of observations made with L-cell fibroblasts expressing either the 13.2 kDa SCP-2
      or the 15 kDa proSCP-2. In L-cells expressing the 13.2 kDa SCP-2, fluorescent
      fatty acid uptake was increased by 10-30% depending upon the probe used. In 15
      kDa proSCP-2 expressing cells, fluorescent fatty acid uptake was increased 20-40%
      depending upon the probe used. However, only expression of the 15 kDa pro-SCP-2
      increased the cytoplasmic diffusion of the fluorescent fatty acid. Expression of
      either protein increased the uptake of [3H]-oleic acid 1.9-fold compared to
      control, with targeting of [3H]-oleic acid for esterification into cholesteryl
      esters. The 13.2 kDa SCP-2 did target a significant amount of [3H]-oleic acid for
      esterification into the triacylglycerol pool. Expression of either protein
      markedly reduced total cellular phospholipid levels, however both proteins
      increased cholesteryl ester levels. Interestingly, expression of the 15 kDa
      proSCP-2 decreased ethanolamine plasmalogen levels with a concomitant increase in
      choline plasmalogen. Expression of both proteins increased PUFA content of the
      phospholipids, although this effect was greater in 15 kDa proSCP-2 expressing
      cells. Hence, expression of SCP-2 increased fatty acid uptake and targeted fatty
      acid to unique lipid pools, suggesting that SCP-2 may effectively serve as
      universal fatty acid binding and trafficking protein.

PMID- 12479574
TI  - Fatty acid binding protein expression in different human adipose tissue depots in
      relation to rates of lipolysis and insulin concentration in obese individuals.
AB  - Two fatty acid binding proteins (FABPs) are expressed in adipose tissue,
      adipocyte lipid binding protein (ALBP) and keratinocyte lipid binding protein
      (KLBP). This study investigated FABP expression in visceral and subcutaneous
      human adipose tissue depots and associations with lipolytic differences between
      the depots and circulating insulin concentrations. ALBP and KLBP (protein and
      RNA) were quantified in subcutaneous and omental adipose tissue from obese
      individuals and expressed relative to actin. ALBP RNA and protein expression was
      significantly higher in subcutaneous compared to omental adipose tissue (both p <
      0.05), whereas KLBP RNA and protein expression was no different between the two
      sites. There were significant inverse correlations between serum insulin
      concentrations and the ALBP/KLBP RNA ratio in both subcutaneous and omental
      adipose tissue (both p < 0.02). Basal rates of glycerol and fatty acid release
      measured in adipocytes isolated from subcutaneous and omental adipose tissue were
      significantly higher in the former (p < or = 0.02). Therefore the relative
      ALBP/KLBP content of human adipose tissue is different in different adipose
      tissue depots and at the RNA level is related to the circulating insulin
      concentration, at least in obese subjects. The higher rates of basal lipolysis in
      adipocytes isolated from subcutaneous compared to omental adipose tissue might be
      related to the increased ALBP content of the former. Therefore adipose tissue
      FABPs are interesting candidates for investigation to further our understanding
      of the insulin resistance syndrome and regulation of lipolysis.

PMID- 12479575
TI  - Protein acylation in the cardiac muscle like cell line, H9c2.
AB  - Besides serving as oxidisable substrates, fatty acids (FA) are involved in co-
      and post-translational modification of proteins (protein acylation). Despite the
      high rate of fatty acid utilisation in the heart, information on protein
      acylation in cardiac muscle is scarce. To explore this subject in more detail, we
      used the H9c2 cell line as an experimental model. After incubation with 3H
      palmitate or 3H-myristate, cells were lysed and proteins precipitated, followed
      by extensive delipidation. The delipidated proteins were subjected to SDS-PAGE
      and transferred to nitro-cellulose prior to autoradiography. In addition, TLC was
      used to separate the various lipid classes. The first aspect we addressed was the
      extent of protein acylation as a function of time, relative to fatty acid
      incorporation into various lipid classes. Cells were incubated for 30 min, 1 h
      and 2 h with 100 microCi palmitate (PA, 2.3 nmol) or 125 microCi myristate (MA,
      2.5 nmol). Palmitoylation increased from 0.48 +/- 0.25 to 1.25 +/- 0.56
      microCi/mg protein between 30 min to 2 h, while myristoylation increased from
      0.25 +/- 0.12 to 0.77 +/- 0.36 microCi/mg protein. Furthermore, delipidated
      proteins subjected to autoradiography showed that a set of distinct proteins was
      labelled with 3H-palmitate. Incorporation into phospholipids (PL) increased from
      40-60% of the total amount of radio-labelled PA or MA supplied between 30 min and
      2 h. Only the FA pool differed between MA and PA, with a higher FA content
      present after incubations with MA. Second, we investigated palmitoylation and
      incorporation into cellular lipids as a function of the amount of PA applied.
      Palmitoylation showed saturation at high PA concentrations. The percentage
      incorporation of 3H-PA in the various lipids depended on the amount of PA added:
      a decline in the PL pool with a concomitant increase in the size of the
      diacylglycerol pool at high PA concentrations. Third, inhibition of
      palmitoylation by cerulenin and tunicamycin was investigated. While both were
      able to inhibit palmitoylation, cerulenin also inhibited the incorporation of PA
      into various lipid classes, indicating differences in inhibitory action.

PMID- 12479576
TI  - Alternative lipid mobilization: the insect shuttle system.
AB  - Lipid mobilization in long-distance flying insects has revealed a novel concept
      for lipid transport in the circulatory system during exercise. Similar to energy
      generation for sustained locomotion in mammals, the work accomplished by non-stop
      flight activity is powered by oxidation of free fatty acids (FFA) derived from
      endogenous reserves of triacylglycerol. The transport form of the lipid, however,
      is diacylglycerol (DAG), which is delivered to the flight muscles associated with
      lipoproteins. In the insect system, the multifunctional lipoprotein, high-density
      lipophorin (HDLp) is loaded with DAG while additionally, multiple copies of the
      exchangeable apolipoprotein, apoLp-III, associate with the expanding particle. As
      a result, lipid-enriched low-density lipophorin (LDLp) is formed. At the flight
      muscles, LDLp-carried DAG is hydrolyzed and FFA are imported into the muscle
      cells for energy generation. The depletion of DAG from LDLp results in the
      recovery of both HDLp and apoLp-III, HDLp, identified which are reutilized for
      another cycle of DAG transport. A receptor for as a novel member of the
      vertebrate low-density lipoprotein (LDL) receptor family, does not seem to be
      involved in the lipophorin shuttle mechanism operative during flight activity. In
      addition, endocytosis of HDLp mediated by the insect receptor does not seem to
      follow the classical mammalian LDL pathway. Many structural elements of the lipid
      mobilization system in insects are similar to those in mammals. Domain structures
      of apoLp-I and apoLp-II, the non-exchangeable apolipoprotein components of HDLp,
      are related to apoB 100. ApoLp-III is a bundle of five amphipathic alpha-helices
      that binds to a lipid surface very similar to the four-helix bundle of the N
      terminal domain of human apoE. Despite these similarities, the functioning of the
      insect lipoprotein in energy transport during flight activity is intriguingly
      different, since the TAG-rich mammalian lipoproteins play no role as a carrier of
      mobilized lipids during exercise and besides, these lipoproteins are not
      functioning as a reusable shuttle for lipid transport. On the other hand, the
      deviant behavior of similar molecules in a different biological system may
      provide a useful alternative model for studying the molecular basis of processes
      related to human disorders and disease.

PMID- 12479577
TI  - Giant membrane vesicles as a model to study cellular substrate uptake dissected
      from metabolism.
AB  - In order to use giant vesicles for substrate uptake studies in metabolically
      important tissues, we characterized giant vesicles isolated from heart, liver,
      skeletal muscle and adipose tissue. We investigated which cell types and which
      plasma membrane regions are involved in giant vesicle formation and we examined
      the presence of transporters for metabolic substrates. Analysis of giant vesicles
      with markers specific for distinct cell types and distinct domains of the plasma
      membrane reveals that the plasma membrane of parenchymal cells, but not
      endothelial cells, are the source of the vesicle membranes. In addition, plasma
      membrane regions enriched in caveolae and involved in docking of recycling
      vesicles from the endosomal compartment are retained in giant vesicles,
      indicating that KCl-induced alterations in recycling processes are involved in
      giant vesicle formation. Giant vesicles contain vesicular lumen consisting of the
      soluble constituents of the cytoplasm including, fatty-acid binding proteins.
      Furthermore, giant vesicles isolated from heart, liver, skeletal muscle and
      adipose tissue are similar in size (10-15 microm) and shape and do not contain
      subcellular organelles, providing the advantage that substrate fluxes in the
      different organs can be studied independently of the surface/volume ratio but
      most importantly in the absence of intracellular metabolism.

PMID- 12479578
TI  - Peroxisome proliferator-activated receptors: lipid binding proteins controling
      gene expression.
AB  - The peroxisome proliferator-activated receptors (PPARs) are members of the
      nuclear hormone receptor superfamily. Since their discovery in the beginning of
      the nineties the three isoforms (PPARalpha, beta/delta and gamma, encoded by
      different genes) have been implicated in the regulation of almost every single
      aspect of lipid metabolism and, consequently, in diseases that involve
      disturbances in lipid metabolism (obesity, diabetes, atherosclerosis, cardiac
      failure). Although their prominent role in these processes has hardly been
      disputed, the way in which the activity of these transcription factors is
      regulated under physiological and pathological conditions awaits further
      clarification. An unresolved issue has been the nature of the natural ligand of
      these receptors. Biochemical studies have shown that the PPAR isoforms are rather
      promiscuous with respect to ligand binding, with a large variety of naturally
      occurring lipid-like substances acting as low-affinity ligands. More recently
      this concept has been confirmed by crystallographic studies on the ligand-binding
      pocket. In addition to ligand availability, the trans-activating capacity likely
      depends on phosphorylation status of the PPARs and on the recruitment of
      auxiliary proteins (co-activators and corepressors). Accordingly, the biological
      activity of these key-regulators of metabolism is controlled at multiple levels,
      which enables each tissue to fine tune its metabolic machinery to the demands of
      the body in a specific fashion.

PMID- 12479579
TI  - New insights into the fatty acid-binding protein (FABP) family in the small
      intestine.
AB  - The fatty acid-binding protein (FABP) superfamily is constituted by 14-15 kDa
      soluble proteins which bind with a high affinity either long-chain fatty acids
      (LCFAs), bile acids (BAs) or retinoids. In the small intestine, three different
      FABP isoforms exhibiting a high affinity for LCFAs and/or BAs are expressed: the
      intestinal and the liver-type (I-FABP and L-FABP) and the ileal bile acid-binding
      protein (I-BABP). Despite of extensive investigations, their respective
      physiological function(s) are not clearly established. In contrast to the I-FABP,
      L-FABP and I-BABP share several common structural features (shape, size and
      volume of the hydrophobic pocket). Moreover, L-FABP and I-BABP genes are also
      specifically regulated by their respective preferential ligands through a very
      similar molecular mechanism. Although, they exhibit differences in their binding
      specificities and location along the small intestine supporting a specialization,
      it is likely that L-FABP and I-BABP genes exert the same type of basic
      function(s) in the enterocyte, in contrast to I-FABP.

PMID- 12479580
TI  - Regulation of the ileal bile acid-binding protein gene: an approach to determine
      its physiological function(s).
AB  - Ileal bile acid-binding protein (I-BABP) is a soluble bile acids (BA) carrier
      protein which belongs to the fatty acid-binding protein (FABP) family. In the
      gut, its expression is strictly restricted to the ileum, where it is thought to
      be involved in the active BA reabsorption. Therefore, I-BABP gene expression
      levels might be rate limiting for the BA enterohepatic circulation, and hence,
      might be crucial for cholesterol (CS) homeostasis. Indeed, BA not reclaimed by
      intestinal absorption constitute the main way to eliminate a CS excess. However,
      such a function is not yet established. Because generally rate limiting genes are
      tightly controlled, we have undertaken the study of the I-BABP gene regulation.
      It was found that both BA and CS, probably via oxysterols, are able to up
      regulate the transcription rate of I-BABP gene. The fact that intracellular
      sterol sensors (FXR, LXR and SREBP1c) are involved in the control of I-BABP gene
      expression strongly suggest a crucial role for I-BABP in the ileum.

PMID- 12479581
TI  - Role of adipocyte lipid-binding protein (ALBP) and acyl-coA binding protein
      (ACBP) in PPAR-mediated transactivation.
AB  - Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors
      that are activated by a number of fatty acids and fatty acid derivatives. By
      contrast, we have recently shown that acyl-CoA esters display PPAR antagonistic
      properties in vitro. We have also shown that the adipocyte lipid binding protein
      (ALBP), the keratinocyte lipid binding protein (KLBP) and the acyl-CoA binding
      protein (ACBP) exhibit a prominent nuclear localization in differentiating 3T3-L1
      adipocytes. Similarly, ectopic expression of these proteins in CV-1 cells
      resulted in a primarily nuclear localization. We therefore speculated that FABPs
      and ACBP might regulate the availability of PPAR agonists and antagonists by
      affecting not only their esterification in the cytoplasm but also their transport
      to and availability in the nucleus. We show here that coexpression of ALBP or
      ACBP exerts a negative effect on ligand-dependent PPAR transactivation, when
      tetradecylthioacetic (TTA) is used as ligand but not when the thiazolidinedione
      BRL49653 is used as ligand. The results presented here do not support the
      hypothesis that ALBP facilitates the transport of the fatty acid-type ligands to
      the nucleus, rather ALBP appears to sequester or increase the turn-over of the
      agonist. Similarly, our results are in keeping with a model in which ACBP
      increase the metabolism of these ligands.

PMID- 12479582
TI  - Analysis of tissue-specific and PPARalpha-dependent induction of FABP gene
      expression in the mouse liver by an in vivo DNA electroporation method.
AB  - Peroxisome proliferator (PPAR)alpha ligand Wy14,643 induces liver-fatty acid
      binding protein (FABP) spontaneously and heart-FABP gradually, but not intestine
      FABP mRNA expression in the mouse liver. These strict regulations have not been
      reproduced in cultured cell systems. We applied a DNA electroporation method to
      directly introduce reporter gene constructs into the livers of mice. This system
      reproduced the in vivo responses of the above three FABP gene promoters to the
      PPARalpha ligand but not that of a promoter containing the typical three PPAR
      binding sites in tandem. Deletion and mutation analyses of the mouse L-FABP gene
      suggested that, in addition to the binding site for PPARalpha, a far upstream
      sequence is required for PPAR-dependent transactivation in the liver. In contrast
      to the cultured cell systems, our in vivo DNA electroporation method showed that
      PPARalpha binding to the promoter is necessary but not sufficient for PPARalpha
      ligand-dependent transcriptional activation of the L-FABP gene in vivo.

PMID- 12479583
TI  - Characterization of a new fatty acid response element that controls the
      expression of the locust muscle FABP gene.
AB  - In vertebrate and invertebrate muscles, the expression of fatty acid binding
      proteins (FABP) is induced by long chain fatty acids. To identify the fatty acid
      response elements that mediate this up-regulation, the gene of the FABP expressed
      in locust flight muscle was cloned, and its upstream sequences analyzed for
      potential regulatory elements. Comparison with other muscle FABP promoters
      revealed the presence of a 19-bp imperfect inverted repeat sequence that contains
      two hexanucleotide half sites (AGTGGT and ATGGGA), interspersed by 3 nucleotides.
      The promoter activity was studied with reporter gene constructs in L6 myoblasts,
      in which H-FABP expression is stimulated by long-chain fatty acids in a similar
      manner as in adult cardiomyocytes. The 19 bp element, located 180 bp upstream of
      the transcription start site, was found to be essential for the fatty acid
      induction of gene expression, and gel shift analysis confirmed that this fatty
      acid response element is capable of binding nuclear proteins both from rat
      myoblasts and locust muscle in the presence of fatty acids. A similar, but
      reverse sequence that is present upstream of all mammalian H-FABP promoters may
      modulate the expression of the rat H-FABP gene.

PMID- 12479584
TI  - Regulation of fatty acid transport and membrane transporters in health and
      disease.
AB  - Long chain fatty acid uptake across the plasma membrane occurs, in part, via a
      protein-mediated process involving a number of fatty acid binding proteins known
      as fatty acid transporters. A critical step in furthering the understandings of
      fatty acid transport was the discovery that giant vesicles, prepared from tissues
      such as muscle and heart, provided a suitable system for measuring fatty acid
      uptake. These vesicles are large (10-15 microm diameter), are oriented fully
      right side out, and contain cytosolic FABP in the lumen, which acts as a fatty
      acid sink, while none of the fatty acid taken up is metabolized or associated
      with the plasma membrane. The key fatty acid transporters FAT/CD36 and FABPpm are
      expressed in muscle and heart and their plasma membrane content is positively
      correlated with rates of fatty acid transport. These transporters are regulated
      acutely (within minutes) and chronically (days). For instance, both muscle
      contraction and insulin can translocate FAT/CD36 from an intracellular pool to
      the plasma membrane, thereby increasing fatty acid transport. With obesity, fatty
      acid transport is increased along with a concomitant increase in plasmalemmal
      FAT/CD36 (heart, muscle) and FABPpm (heart only), but without change in the
      expression of these transporters. This latter observation suggests that some of
      the fatty acid transporters are permanently relocated to the plasma membrane. In
      other studies it also appears that fatty acid transport rates are altered in a
      reciprocal manner to glucose transport. Since disorders in lipid metabolism
      appear to be an important factor contributing to the etiology of a number of
      common human diseases such as diabetes and obesity, our evidence that protein
      mediated fatty acid transport is a key step in lipid metabolism allows the
      speculation that malfunctioning of the fatty acid transport process could be a
      common critical factor in the pathogenesis of these diseases.

PMID- 12479585
TI  - The impact of overexpression and deficiency of fatty acid translocase (FAT)/CD36.
AB  - Fatty acid translocase (FAT)/CD36 has been associated with diverse normal and
      pathologic processes. These include scavenger receptor functions (uptake of
      apoptotic cells and modified lipid), lipid metabolism and fatty acid transport,
      adhesion, angiogenesis, modulation of inflammation, transforming growth factor
      beta activation, atherosclerosis, diabetes and cardiomyopathy. Although CD36 was
      identified more than 25 years ago, it is only with the advent of recent genetic
      technology that in vivo evidence has emerged for its physiologic and pathologic
      relevance. As these in vivo studies are expanded, we will gain further insight
      into the mechanism(s) by which CD36 transmits a cellular signal, and this will
      allow the design of specific therapeutics that impact on a particular function of
      CD36.

PMID- 12479586
TI  - Intestinal lipid absorption is not affected in CD36 deficient mice.
AB  - Increasing evidence has implicated the membrane protein CD36 (or fatty acid
      translocase, FAT) to be involved in high affinity fatty acid uptake. CD36 is
      expressed in tissues active in fatty acid metabolism, like adipose tissue and
      skeletal and cardiac muscle, but also in intestine. CD36 is localized in the
      intestine mainly in the jejunal villi, where it is confined to enterocyte apical
      membrane. The aim was to determine the role of CD36 in intestinal lipid
      absorption. Lipid absorption was determined by administering 3H-labeled triolein
      and 14C-labeled palmitic acid as an olive oil bolus by intragastric gavage and
      determine appearance of 3H and 14C label in plasma, after blocking lipolysis by
      i.v. injections of Triton WR 1339. Surprisingly, no differences in plasma
      appearance of 3H-label or 14C-label were observed in CD36(-/-) mice compared to
      wild type controls. These results suggest that CD36 does not play a role in
      intestinal lipid absorption after an acute lipid load.

PMID- 12479587
TI  - Surface expression of fatty acid translocase (FAT/CD36) on platelets in
      myeloproliferative disorders and non-insulin dependent diabetes mellitus: effect
      on arachidonic acid uptake.
AB  - Increased platelet reactivity has been implicated in the vascular complications
      of myeloproliferative diseases and diabetes mellitus. The mechanisms of platelet
      hyperresponsiveness have not been fully explained. Expression of CD36 or fatty
      acid translocase (FAT) and its role in arachidonic acid (AA) uptake by platelets
      were examined in subjects with myeloproliferative disorders (MPD), those with non
      insulin-dependent diabetes mellitus (NIDDM), and in normal, healthy, age-matched
      controls. Surface expression of CD36 on platelet membranes was increased in MPD
      (10.94 +/- 0.76 pmol/mg protein) compared with normal controls (6.94 +/- 0.48
      pmol/mg protein), p < 0.001. Total platelet content of CD36 was also
      significantly higher (32.1 +/- 0.61 pmol/mg protein, p < 0.01) compared with
      those in sex and age matched normal controls (25.7 +/- 1.09 pmol/mg protein). In
      contrast, platelet surface expression of CD36 in NIDDM (6.5 +/- 0.56 pmol/mg
      protein) was not significantly different from those of normal controls despite
      higher total content of CD36 (32.8 +/- 1.2, pmol/mg protein, p < 0 .01). Intact
      MPD platelets bound significantly more arachidonic acid (AA) (1.53 +/- 0.16
      nmol/mg protein, p < 0.05), compared with controls (1.12 +/- 0.07 nmol/mg
      protein) or NIDDM subjects (1.16 +/- 0.16 nmol/mg protein). The capacity of MPD
      platelet membranes to bind 14C-AA was also increased (1.72 +/- 0.25 nmol/mg
      protein, p < 0.05) compared with that of controls (1.62 +/- 0.05 nmol/mg protein)
      and of NIDDM (1.22 +/- 0.08 nmol/mg protein). This is consistent with higher
      surface expression of CD36 in MPD platelets. Membrane fatty acid analysis
      indicated that the % of AA in platelet phospholipids was significantly lower in
      MPD (3.15 +/- 0.81%) compared with the controls (5.62 +/- 1.7%, p < 0.05. The AA
      content of diabetic platelets (4.82 +/- 1.1%) was not significantly different
      from normal controls. In summary, both total and surface expression of CD36 are
      increased in MPD, consistent with an enhanced capacity for uptake of AA by
      platelets. Increased expression of CD36 in platelets may play a role in the vaso
      occlusive manifestations of MPD.

PMID- 12479588
TI  - Sulfo-N-succinimidyl esters of long chain fatty acids specifically inhibit fatty
      acid translocase (FAT/CD36)-mediated cellular fatty acid uptake.
AB  - Sulfo-N-succinimidyl esters of LCFAs are a powerful tool to investigate the
      functional significance of plasmalemmal proteins in the LCFA uptake process. This
      notion is based on the following observations. First, sulfo-N-succinimidyl oleate
      (SSO) was found to inhibit the bulk of LCFA uptake into various cell types, i.e.
      rat adipocytes, type II pneumocytes and cardiac myocytes. Second, using cardiac
      giant membrane vesicles, in which LCFA uptake can be investigated in the absence
      of mitochondrial beta-oxidation, SSO retained the ability to largely inhibit LCFA
      uptake, indicating that inhibition of LCFA transsarcolemmal transport is its
      primary action. Third, SSO has no inhibitory effect on glucose and octanoate
      uptake into giant membrane vesicles derived from heart and skeletal muscle,
      indicating that its action is specific for LCFA uptake. Finally, SSO specifically
      binds to the 88 kDa plasmalemmal fatty acid transporter FAT, a rat homologue of
      human CD36, resulting in an arrest of the transport function of this protein. In
      addition to its inhibitory action at the plasma membrane level, evidence is
      presented for the lack of a direct inhibitory effect on subsequent LCFA
      metabolism. First, the relative contribution of oxidation and esterification to
      LCFA uptake is not altered in the presence of SSO. Second, isoproterenol-mediated
      channeling of LCFAs into oxidative pathways is not affected by sulfo-N
      succinimidyl palmitate (SSP). As an example of its application, we used SSP to
      study the role of FAT/CD36 in contraction- and insulin-stimulated LCFA uptake by
      cardiac myocytes, showing that this transporter is a primary site of regulation
      of cellular LCFA utilization.

PMID- 12479589
TI  - Ex-FABP, extracellular fatty acid binding protein, is a stress lipocalin
      expressed during chicken embryo development.
AB  - Extracellular Fatty Acid Binding Protein (Ex-FABP) is a 21 kDa lipocalin,
      expressed during chicken embryo development in hypertrophic cartilage, in muscle
      fibres and in blood granulocyte. The protein selectively binds with high affinity
      fatty acids, preferably long chain unsaturated fatty acids in chondrocyte and
      myoblast cultures Ex-FABP expression is increased by inflammatory-agents and
      repressed by anti-inflammatory-agents. In adult cartilage, Ex-FABP is expressed
      only in pathological conditions such as in dyschondroplastic and osteoarthritic
      chicken cartilage. We propose that lipocalin Ex-FABP represents a stress protein
      physiologically expressed in tissues where active remodelling is taking place
      during development and also present in tissues characterized by a stress response
      due to pathological conditions.

PMID- 12479590
TI  - Plasma concentration of intestinal- and liver-FABP in neonates suffering from
      necrotizing enterocolitis and in healthy preterm neonates.
AB  - Both early diagnostic and prognostic assessment of the acute abdomen in preterm
      infants are hampered by the lack of a sensitive and specific parameter for
      intestinal injury. In this prospective clinical study we wanted to estimate the
      value of intestinal (I-) and liver (L-) fatty acid binding protein (FABP) in
      diagnosing necrotizing enterocolitis (NEC). Using highly sensitive and specific
      sandwich ELISAs which employ recombinant human I- and L-FABP as standard proteins
      (limit of detection 0.1 ng/ml plasma), the L-FABP concentration (median 7.6
      ng/ml) was determined to be about 3 fold that of I-FABP (median 2.52 ng/ml) in
      plasma of healthy preterm infants. I- and L-FABP concentrations significantly
      increased with birth weight (1.6 and 5.0 ng/ ml per kg, respectively). At onset
      of symptoms, I-FABP concentration was significantly higher in infants who later
      developed severe NEC compared to healthy infants and those, whose illness
      remained confined to stage I or II. L-FABP was significantly elevated compared to
      the control group at onset of symptoms regardless of the further course of NEC.
      In conclusion, I-FABP appears to be a specific parameter for early detection of
      intestinal injury leading to severe NEC stage III. L-FABP, however, is a
      promising sensitive marker even for stage I of NEC.

PMID- 12479591
TI  - Colony-stimulating factors for the management of neutropenia in cancer patients.
AB  - Neutropenia and its subsequent infectious complications represent the most common
      dose-limiting toxicity of cancer chemotherapy. Febrile neutropenia (FN) occurs
      with common chemotherapy regimens in 25 to 40% of treatment-naive patients, and
      its severity depends on the dose intensity of the chemotherapy regimen, the
      patient's prior history of either radiation therapy or use of cytotoxic
      treatment, and comorbidities. The occurrence of FN often causes subsequent
      chemotherapy delays or dose reductions. It may also lengthen hospital stay,
      increase monitoring, diagnostic and treatment costs, and reduce patient quality
      of life. A decade after their introduction, colony-stimulating factors (CSFs)
      such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage
      colony-stimulating factor (GM-CSF) are now an integral part of the prevention of
      potentially life-threatening FN; however, only G-CSF has US Food and Drug
      Administration approval for use in chemotherapy-induced neutropenia. These
      adjunctive agents accelerate formation of neutrophils from committed progenitors,
      thereby reducing the duration and severity of neutropenia. Important uses of CSFs
      in oncology are prevention of FN after chemotherapy, treatment of febrile
      neutropenic episodes and support following bone marrow transplantation, and
      collection of CSF-mobilised peripheral blood progenitor cells. G-CSF is used more
      frequently than GM-CSF for all of these indications because of fewer associated
      adverse effects. Clinical trials to date have not demonstrated a significant
      effect on overall survival or disease-free survival, which is most likely to be
      due to small sample size and lack of power to prove effect. However, they have
      demonstrated clinical utility in allowing the delivery of planned chemotherapy
      dose on schedule, an important clinical goal especially in curative tumour
      settings. The high cost of these agents limits their widespread use. Current
      American Society of Clinical Oncology guidelines recommend primary prophylaxis,
      or first cycle use, with CSFs being confined to patients with > or = 40% risk of
      FN, which may include elderly patients and other high-risk patients. In addition
      to the risk of FN, primary prophylaxis should also be considered if the patient
      has risk factors that place them in the Special Circumstances category. These
      risk factors may include decreased immune function in patients who are already at
      an increased risk of infection and pre-existing neutropenia due to disease,
      extensive prior chemotherapy, or previous irradiation to the pelvis or other
      areas containing large amounts of bone marrow. Future studies are needed to
      better define the patients most likely to benefit from CSF therapy, both for
      prophylaxis and as an adjunct to antibiotics for treatment of FN. Other potential
      uses include combination therapy with stem cell factors and other cytokines to
      boost progenitor cell development, maintaining dose intensity of salvage therapy
      in metastatic cancer patients, and application in patients with pneumonia,
      Crohn's fistulas, diabetic foot infections and a variety of other infectious
      conditions.

PMID- 12479592
TI  - Treatment of breast cancer with chemotherapy in combination with filgrastim:
      approaches to improving therapeutic outcome.
AB  - Chemotherapy improves disease-free and overall survival in breast cancer, and its
      benefit is directly related to the percentage of the planned dose that is
      actually administered. In all current chemotherapeutic regimens, a substantial
      proportion of patients have reductions and/or delays in dosage due to side
      effects. In about half such cases, the delays or reductions are related to
      neutropenia. Overall, approximately 30% of patients have a reduction to less than
      85% of the planned dosage. Women aged > or = 50 years are more likely to
      experience a reduction or delay in dose. Dose-intense regimens (excluding
      myeloablative high-dose chemotherapy) which increase the dose of chemotherapy or
      reduce the interval between cycles, or both, are a promising approach now under
      investigation. The human granulocyte colony-stimulating factor filgrastim reduces
      the incidence of neutropenia and facilitates adherence to full dose intensity in
      both standard and dose-intensified regimens. A model based on the first-cycle
      absolute neutrophil count nadir has been developed and validated to determine
      which patients should receive filgrastim. A cost benefit associated with the use
      of filgrastim in patients with breast cancer has been realised. This may lead to
      a re-evaluation of the current treatment guidelines.

PMID- 12479593
TI  - Treatment of aggressive non-Hodgkin's lymphoma with chemotherapy in combination
      with filgrastim.
AB  - Non-Hodgkin's lymphoma (NHL) is one of the ten most common cancers in the
      developed world. The incidence has increased significantly over the past two
      decades and it is a particular burden in patients over the age of 60 years. The
      gold standard for primary treatment of aggressive NHL is combination chemotherapy
      with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).
      Haematological growth factors, such as granulocyte colony-stimulating factor (G
      CSF), can be used to ameliorate chemotherapy-induced neutropenia, thus
      facilitating delivery of chemotherapy at the planned dose intensity. The
      International Prognostic Index is able to identify high-risk patients who are
      unlikely to be cured with standard primary chemotherapy. In these patients, the
      use of dose-intensive therapy, including high-dose chemotherapy with stem cell
      support, is being evaluated as potential primary therapy. Stem cell
      transplantation is currently the treatment of choice for patients with relapsed
      NHL or those with chemosensitive refractory disease. Autologous peripheral blood
      stem cells mobilised into the circulation by G-CSF help achieve rapid
      haematological reconstitution and are now the preferred source of stem cells over
      bone marrow for this form of therapy. G-CSF is also used to support allogeneic
      transplantation, which exerts a therapeutic graft-versus-lymphoma effect.
      Administration of G-CSF following autologous or allogeneic peripheral blood stem
      cell transplantation accelerates neutrophil recovery.

PMID- 12479594
TI  - The role of myelopoietic growth factors in managing cancer in the elderly.
AB  - More than 50% of all malignancies are diagnosed in patients aged > 65 years and
      most cancer-related deaths occur in this population. Misconceptions about
      prognosis and treatment contribute to the undertreatment of elderly cancer
      patients and consequent poor outcomes. Although older patients have been excluded
      from cancer treatment trials in the past, response rates to chemotherapy in a
      variety of common cancers in otherwise healthy elderly patients are comparable to
      those attained in younger patients. Lower functional reserve in many organ
      systems alters the pharmacokinetics of chemotherapeutic drugs as well as the
      patient's response to treatment-induced toxicity. Except for myelosuppression and
      mucositis, otherwise fit elderly cancer patients are not at significantly
      enhanced risk of toxicity to chemotherapy. Severe neutropenia and related
      infection are encountered much more frequently during the treatment of elderly as
      compared with younger cancer patients. These lead to treatment delays, dose
      reductions and higher hospitalisation rates. Myelopoietic growth factor support
      reduces myelosuppression and the associated risk of severe infection, thereby
      allowing delivery of chemotherapy at full dose intensity. Beneficial responses to
      granulocyte colony-stimulating factor (G-CSF; filgrastim) in elderly patients
      have been found in aggressive non-Hodgkin's lymphoma with standard
      cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy and
      acute myeloid leukaemia (AML) during induction and consolidation chemotherapy.
      Granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) has been
      found to reduce myelosuppression in elderly AML patients receiving induction but
      not consolidation chemotherapy. These prophylactic treatments produce significant
      cost benefits because of the reduced hospitalisation and antibiotic use
      associated with neutropenia. To maximise positive outcomes, elderly patients
      should be included in clinical trials of new cancer agents. Since
      myelosuppression is the main risk factor for elderly patients undergoing
      chemotherapy, optimisation of growth factor support and the development of more
      effective and safer myelopoietic agents may improve success rates and reduce
      adverse events. Such information will lead to better management of cancer in
      older patients.

PMID- 12479595
TI  - Filgrastim in patients with neutropenia: potential effects on quality of life.
AB  - Treatment- and disease-related neutropenia are associated with a number of
      negative clinical effects such as febrile neutropenia, documented infection,
      hospitalisation for infection-related morbidity, infection-related mortality, and
      decreased ability to administer the planned chemotherapy dose on schedule.
      Reductions or delays in dosage have the ability to jeopardise the effectiveness
      of treatment by lowering response rates. Not only are clinical outcomes adversely
      affected, but these complications can have a negative influence on patient
      quality of life. Filgrastim is a haematopoietic growth factor that primarily acts
      to stimulate the proliferation and differentiation of neutrophil progenitor
      cells. Filgrastim is capable of reducing the incidence and severity of
      neutropenia and the complications that accompany it in patients with cancer or
      HIV infection. Although there are few data evaluating the effect of treatment
      with granulocyte colony-stimulating factor on quality of life, it is assumed that
      the benefits would be seen through both the reduction of treatment-related
      complications and the enhanced potential for long-term disease control. A new,
      longer-acting form of filgrastim is now available that has the potential to
      simplify the management of neutropenia and further improve patient quality of
      life by decreasing the number of necessary injections. Additional prospective
      controlled trials that contain quality-of-life issues as endpoints are needed.

PMID- 12479596
TI  - Use of filgrastim for stem cell mobilisation and transplantation in high-dose
      cancer chemotherapy.
AB  - Myeloablative or high-dose chemotherapy regimens utilise doses that are
      significantly greater than those used in standard treatments. The neutropenia
      caused by these high-dose therapies can be associated with an increased incidence
      of bacterial and fungal infections and remains an important clinical issue among
      patients with advanced-stage cancers. Filgrastim is approved for stem cell
      mobilisation in both chemotherapy-treated patients and normal donors. Harvested
      peripheral blood progenitor cells have been used effectively in allogeneic and
      autologous transplantation, increasing the speed and extent of neutrophil and
      platelet recovery. Accelerated haematopoietic recovery is associated with a
      significantly shorter hospital stay and, therefore, leads to a reduction in
      treatment costs. The contribution of filgrastim to the acceleration of
      haematopoietic recovery after peripheral blood progenitor cell transplant has
      been assessed in a number of prospective clinical trials after high-dose
      chemotherapy. Controversy remains over whether growth factors should be
      administered shortly after stem cell infusion or after several days. The recently
      approved, once-weekly form of filgrastim, pegfilgrastim, has been shown to have
      efficacy comparable to that of the native molecule and can be expected to enhance
      patient quality of life through the need for fewer injections. This article will
      review the role of filgrastim for stem cell mobilisation and transplantation in
      patients receiving high-dose chemotherapy.

PMID- 12479598
TI  - Piezoelectric thick film ultrasonic transducers fabricated by a sol-gel spray
      technique.
AB  - Thick film broadband ultrasonic transducers (UTs) produced by a sol-gel spray
      technique and operated below 10 MHz are presented. These UTs are formed by
      dispersing PZT and LiTaO3 particles, respectively in Al2O3 and PZT sol-gel
      solution. The 50-100 microm thick films have been deposited on curved steel, flat
      steel and aluminum substrates and steel rods. Ultrasonic pulse-echo signals with
      a signal to noise ratio of more than 25 dB are experimentally obtained for the
      operating temperatures up to 250 degrees C.

PMID- 12479597
TI  - Pegfilgrastim administered once per cycle reduces incidence of chemotherapy
      induced neutropenia.
AB  - Neutropenia is a common and potentially dangerous adverse effect of cancer
      chemotherapy. It also often necessitates a reduction or delay in dose, thus
      compromising efficacy. The human granulocyte colony-stimulating factor filgrastim
      has been proven to have a good safety profile and to be effective in accelerating
      neutrophil recovery and reducing the incidence of infections following
      myelosuppressive chemotherapy. However, its short serum half-life necessitates
      daily administration. Pegylated filgrastim (pegfilgrastim) was developed by
      attaching a polyethylene glycol moiety to the filgrastim protein. Pegfilgrastim
      binds to the same cell surface receptor on neutrophils and their precursors as
      filgrastim and stimulates the proliferation and differentiation of neutrophils
      through the same mechanism. However, because of the pegylation, it is minimally
      cleared by the kidneys and has a much longer serum half-life. Furthermore, its
      clearance is neutrophil dependent and thus 'self-regulated'. Pegfilgrastim is
      administered as a single subcutaneous injection per cycle of chemotherapy. In
      clinical trials it has been shown to be comparable in efficacy to filgrastim in
      decreasing the incidence of infection as manifested by febrile neutropenia
      following chemotherapy. Its safety profile and tolerability are similar to those
      of filgrastim.

PMID- 12479599
TI  - Diagnostic ultrasound artifacts during imaging of two-body interfaces: part 1-
      wavelength resonance.
AB  - A diagnostic ultrasound technique is to be developed for measuring surface
      contact areas at the tibio-femoral interface of a total knee replacement in an in
      vitro industrial engineering setting as a design tool. As a first step, a
      previous study mathematically characterized the ultrasound behaviour expected at
      a two-body circular-on-flat interface of known geometry. In the current
      investigation, a series of test objects was constructed and imaged to
      experimentally validate the theoretical contact models. Specifically, several
      unique metal-on-polymer test objects, whose interfaces were point, non-point, and
      circular contact areas, were ultrasonically imaged. The effects of interface
      geometry, ultrasound resonance wavelength, lambda/2, and compressive load were
      studied.

PMID- 12479600
TI  - Diagnostic ultrasound artifacts during imaging of two-body interfaces: part 2-
      beam thickness artifact.
AB  - A diagnostic ultrasound method is being developed for measuring surface contact
      areas at the tibio-femoral interface of a total knee replacement in a non
      clinical industrial setting as an engineering design tool. As an initial step
      towards this, a previous study mathematically predicted the effect of ultrasound
      beam thickness on contact area measurements at a two-body interface. In the
      current study, a novel metal-on-polymer acoustic test object was constructed to
      create circular two-body interfaces of known geometry. The object was
      ultrasonically imaged, contact areas measured, and the results compared with the
      theoretical model previously developed.

PMID- 12479601
TI  - A digital image analysis method for diagnostic ultrasound calibration.
AB  - Acoustic test objects are commonly used for quality assurance testing of
      diagnostic ultrasound machines. However, the accompanying calibration protocols
      rely heavily on the judgment of the sonographer, are dependent on machine
      settings and are semi-quantitative. In the current study, two unique test objects
      and protocols were designed to quantitatively determine diagnostic ultrasound
      parameters, namely axial resolution and geometric uniformity, and lateral
      resolution and geometric uniformity of the ultrasound field. The effect of focal
      zone, signal gain, and distance from the ultrasound probe on these parameters was
      assessed. The investigation was performed using a typical low-frequency
      diagnostic unit equipped with a 7.5 MHz linear pulse-echo probe. Results
      underline the need to ensure that sensitivity of routine testing regimes is
      adequate for the measurements to be made. This study is a preliminary part of a
      larger project developing an ultrasound technique to be used as an engineering
      design tool in a non-clinical industrial setting for quality assurance testing of
      total knee replacements immersed in water.

PMID- 12479602
TI  - Spectral power density calculations for pulsed Doppler.
AB  - Range-gated pulsed Doppler can be used to make localized velocity measurements
      within a blood vessel. A spectral flow profile can be created by stepping a
      sufficiently small sample volume across the lumen, but no set of spectra will
      correspond directly to the true velocity profile. Spectral flow profiles are
      affected by a complex interplay between different sources of spectral broadening.
      In this study we developed a systematic theoretical method which allows spectral
      power density functions to be calculated under a very wide range of conditions,
      and used it to obtain simulated flow spectra. The model was formulated
      analytically. It is based on the weighted-volume approach and incorporates,
      through the concept of a spread function, the intrinsic spectral broadening
      associated with a focused transducer. It can be applied for arbitrary values of
      the spread parameter; for non-uniform beam profiles; with maximal (continuous
      wave-type) or minimal (pulse wave-type) range-gated sample volumes; and for beams
      that intersect the flow tube axis, or are off centre. Results are presented for a
      Gaussian beam and parabolic flow. Simulated spectral flow profiles are given
      which illustrate how a profile's appearance can be altered by the different
      sources of spectral broadening.

PMID- 12479603
TI  - Characterization of suspensions of particles in water by an ultrasonic resonant
      cell.
AB  - This paper presents a resonant technique to accurately measure phase-velocity and
      attenuation of longitudinal acoustic waves in suspensions of solid particles in
      water. The technique is based on exciting thickness resonances of a layer of
      fluid and analyzing its spectrum. To this end, a resonant cell to contain the
      fluid is described and used. Two different type of water suspensions are studied:
      titanium dioxide and alumina particles; particle volume fraction is in the range
      0-0.18. Simultaneous determination of particle size distribution in the
      suspension by an optical method are also carried out. Finally, the experimental
      results are compared with theoretical predictions obtained from three different
      approaches.

PMID- 12479604
TI  - The oxidation of fullerene [C70] with various oxidants by ultrasonication.
AB  - The reaction of C70 by ultrasonication with various oxidants such as 3
      chloroperoxy benzoic acid (Fluka 99%), 4-methyl morpholine N-oxide (Aldrich 97%),
      chromium (VI) oxide (Aldrich 99.9%), and oxone monopersulfate compound, at room
      temperature causes the oxidation of fullerene [C70(O)n] (n = 1-2 or n = 1). The
      FAB-MS, UV-visible, FT-IR spectra, and HPLC analysis confirmed that products of
      fullerene oxidation are [C70(O)n] (n = 1-2 or n = 1).

PMID- 12479605
TI  - Behavior of a PZT ring under non-uniform mechanical stress.
AB  - Ring-shaped lead zirconate titanate (PZT) piezoelectric vibrators were subjected
      to non-uniform mechanical stress applied by bolt clamping. The effect of
      mechanical stress on the effective electromechanical coupling factor (k(eff)) and
      mechanical quality factor (Qm) of the thickness and wall thickness modes was
      studied by an equivalent electric circuit analysis. The initiation and
      propagation of cracks under mechanical stress were also discussed based on the
      resonance method and the indentation technique. k(eff) for both the thickness and
      wall thickness modes decreased with increase in mechanical stress due to de
      poling of the PZT. Qm of the thickness mode dropped sharply with increase in
      mechanical stress while Qm of the wall thickness mode remained almost unchange.
      Existence of microcracks in a PZT vibrator can be detected by the occurrence of
      spurious vibrations at the wall thickness mode in the electrical impedance vs.
      frequency spectra.

PMID- 12479606
TI  - Contraception--past and future.
AB  - Modern contraceptive methods have a surprisingly short history and are dominated
      by the oral contraceptive pill, which came on to the market in 1960. New
      developments since the advent of the pill have been largely limited to tinkering
      with the contents and routes of administration of hormonal contraception. The
      knowledge that would allow a more exciting approach to new contraceptives does
      exist but the will to proceed is hampered by financial, political and moral
      factors, and perhaps ironically by the AIDS epidemic.

PMID- 12479607
TI  - Channels of communication in the ovary.

PMID- 12479608
TI  - ART: boon or bane?
AB  - In 1978, the birth of the first baby through in vitro fertilization resulted in
      an explosion of new techniques that are now widely used in reproductive medicine
      and biology around the world. With these advances have also come many concerns
      for the safety of these techniques. In addition, even newer technologies are on
      the horizon, such as cloning and the production/use of stem cells. The 18th
      annual meeting of the European Society of Human Reproduction and Embryology
      (ESHRE), held in Vienna from 30 June to 3 July 2002, provided a forum for
      discussion of these and other relevant topics.

PMID- 12479609
TI  - Are we ignoring potential dangers of in vitro fertilization and related
      treatments?
AB  - By conventional assessments, in vitro fertilization (IVF) is one of the safest
      medical treatments. But producing new life brings immense responsibilities.
      Recently, there have been disquieting reports of foetal abnormality after these
      treatments and here we evaluate the potential risks associated with
      intracytoplasmic sperm injection (ICSI), embryo freezing and pre-implantation
      genetic diagnosis. In our opinion, before translating new techniques into
      practice, more research, particularly in animals,is desirable. In addition,
      better child follow-up and a fresh approach to regulation are also needed.

PMID- 12479610
TI  - Safeguarding ART.
AB  - Assisted reproductive technologies (ART) are exceptional among clinical
      therapies, as unlike most medical procedures, ART have generational consequences.
      Further, human embryo research in the US has been sponsored solely by the private
      sector and, until recent biotechnology forays into human embryonic stem cell
      (hESC) and cloning research, exclusively by infertility clinics. Additionally,
      the relatively brief clinical history of ART has made it difficult for
      practitioners and researchers to agree on criteria for its safety and success.
      Against this backdrop, market pressure on biotechnology companies to create hESC
      lines and on clinical practices to occupy the innovative forefront has resulted
      in arguably risky experiments with human embryo cloning, as well as in
      unintentional germ-line genetic modifications during ART and perhaps during gene
      therapy. Reproduction, once governed largely by passions and instinct, now seems
      to need further governance. Some argue that it could now be time for the
      biomedical community, especially in the US, to take further steps to safeguard
      ART.

PMID- 12479611
TI  - Children by choice: reproductive technologies and the boundaries of personal
      autonomy.
AB  - Unlike other countries that regulate assisted reproduction, the US has largely
      left this field to the domain of professional self-regulation and market
      preferences. The reason lies both in the confused jurisprudence of reproductive
      liberty and the paralysing effect of the abortion debate on US politics. The
      debate surrounding cloning, however, has galvanized both activists and the
      government to revisit the question of regulation, and recent cases in the US
      Supreme Court suggest that if the political will to regulate this field is found,
      governmental authority to intervene in areas such as pre-implantation diagnosis,
      gamete donation and surrogacy might well be upheld, even in the face of
      constitutional challenges.

PMID- 12479612
TI  - The economic impact of the assisted reproductive technologies.
AB  - Thousands of cycles of in vitro fertilization (IVF) are performed each year. In
      the US, multiple births occur after 39% of IVF cycles, whereas in Europe, the
      figure is 26%. Indeed, multiple births are a major factor in the costs
      attributable to IVF. Reducing the multiple birth rate may reduce the overall
      costs of IVF, and providing insurance coverage of IVF may contribute to lowering
      multiple birth rates. The use of IVF is likely to expand in response to increases
      in infertility and scientific advances.

PMID- 12479613
TI  - Environment, lifestyle and infertility--an inter-generational issue.
AB  - The effects of adult lifestyle--primarily smoking and diet in women, and
      sedentary habits generally--are important factors affecting the fertility of men
      and women, and can also impact the fertility of their children. This review
      summarizes the effects of season, modern lifestyles and environmental chemicals
      on human fertility, and discusses the implications of these effects for future
      generations.

PMID- 12479614
TI  - Genetic dissection of mammalian fertility pathways.
AB  - The world's population is increasing at an alarming rate and is projected to
      reach nine billion by 2050. Despite this, 15% of couples world-wide remain
      childless because of infertility. Few genetic causes of infertility have been
      identified in humans; nevertheless, genetic aetiologies are thought to underlie
      many cases of idiopathic infertility. Mouse models with reproductive defects as a
      major phenotype are being rapidly created and discovered and now total over 200.
      These models are helping to define mechanisms of reproductive function, as well
      as identify potential new contraceptive targets and genes involved in the
      pathophysiology of reproductive disorders. With this new information, men and
      women will continue to be confronted with difficult decisions on whether or not
      to use state-of-the-art technology and hormonal treatments to propagate their
      germline, despite the risks of transmitting mutant genes to their offspring.

PMID- 12479615
TI  - Playing for half the deck: the molecular biology of meiosis.
AB  - Meiosis reduces the number of chromosomes carried by a diploid organism by half,
      partitioning precisely one haploid genome into each gamete. The basic events of
      meiosis reflect three meiosis-specific processes: first, pairing and synapsis of
      homologous chromosomes; second, high-frequency, precisely controlled, reciprocal
      crossover; third, the regulation of sister-chromatid cohesion (SCC), such that
      during anaphase I, SCC is released along the chromosome arms, but not at the
      centromeres. The failure of any of these processes can result in aneuploidy or a
      failure of meiotic segregation.

PMID- 12479616
TI  - The state of the union: the cell biology of fertilization.
AB  - Fertilization is the process by which sperm and egg unite. An expanded
      understanding of the mechanisms that underlie these events has provided insights
      into an important aspect of early development and also has proven to be a
      valuable model in which to study cellular function. In addition, many emerging
      strategies for contraception and for the treatment of infertility are based on
      the mechanism of gamete interaction. Here, we discuss the cell and molecular
      biology of mammalian fertilization, highlight selected recent breakthroughs and
      attempt to identify key unanswered questions.

PMID- 12479617
TI  - Basic principles on toe-to-hand transplantation.
AB  - Within the last three decades, toe-to-hand transplantation has become a well
      established method for function and appearance reconstruction after trauma and in
      congenital hand anomalies. An otherwise healthy and cooperative patient is the
      ideal candidate for toe transplantation after trauma. In such patient, even
      primary toe transplantation is possible, if the stump is clean and viable. If
      secondary reconstruction after completed wound healing is considered, emphasis
      should be laid on tissue sacrifice during the acute management of non-replantable
      amputations at the hand. Specific considerations regarding selection of toe(s) to
      be transplanted, technique of toe harvest and inset, sequence of transplantations
      if more than one digit is to be reconstructed such as in the metacarpal hand, and
      postoperative regimen are important to achieve satisfying functional and
      aesthetic results on both recipient and donor sites. A trimmed great toe is ideal
      for thumb reconstruction if the amputaiton is located at or distal to the middle
      metacarpal shaft. However, in more proximal amputations a second toe may be more
      suitable as it allows transmetatarsal harvest without increasing donor site
      morbidity. Distal finger reconstruction with partial toe or second toe warp
      around flap gives most gratifing result to those patients who are critically
      concerned about their body images and also those who need distal fingers for jobs
      or recreation activities. Combined second and third toe or third and fourth toe
      transplantations are particular useful in metacarpal hand reconstruction to
      provide tripod pinch. The role of toe-to-hand transplantation in the new
      millenium assuming progress in tissue engineering, gene transfer, and the
      development of new immunosuppressive drugs is discussed.

PMID- 12479618
TI  - Tolerability assessment of maximal androgen blockade with 50 mg daily of
      bicalutamide and castration in patients with advanced prostate cancer.
AB  - BACKGROUND: Androgen is the most important growth factor for the development and
      growth of prostatic adenocarcinomas. For patients with advanced prostate cancer,
      hormonal manipulation including castration and antiandrogen therapy is a well
      established mode of treatment. The choice of hormonal therapy for prostate cancer
      depends not only on the desired progression-free and overall survival, but also
      on the patient's quality of life, treatment costs, and treatment toxicities.
      METHODS: This was an open, non-comparative trial to determine the tolerability of
      50 mg bicalutamide (Casodex) in combination with castration; we also investigated
      whether the prostate-specific antigen (PSA) rates of change at weeks 4 and 12
      were indicative of an increased risk of progression. RESULTS: Thirty-seven
      patients were enrolled in the study from December 1996 to June 1999 in Chang Gung
      Memorial Hospital, Taoyuan. The overall incidence rate of adverse events was 27%.
      The most frequent adverse event was hot flushes (5.4%). The rate of overall
      disease response was 85.3%. No evidence was found for any predictive relationship
      between serum PSA concentration and risk of progression. CONCLUSION: The overall
      results indicate that bicalutamide administered as a 50-mg daily dosage in
      combination with castration is a well-tolerated therapy for the treatment of
      patients with advanced prostate cancer.

PMID- 12479619
TI  - Effects of balance training on hemiplegic stroke patients.
AB  - BACKGROUND: The purpose of this study was to evaluate the delayed effects of
      balance training program on hemiplegic stroke patients. METHODS: A total of 41
      ambulatory hemiplegic stroke patients were recruited into this study and randomly
      assigned into two groups, the control group and trained group. Visual feedback
      balance training with the SMART Balance Master was used in the trained group.
      Bruunstrom staging of affected limb scores and Functional Independent Measure
      (FIM) scores of each patient were recorded. Quantitative balance function was
      evaluated using the SMART Balance Master. Data were collected before training and
      6 months after completing the training program. RESULTS: Significant improvements
      in dynamic balance function measurements were found for patients in the trained
      group at 6 months after completing the training program. The ability of self-care
      and sphincter control also improved for patients in the trained group. On the
      other hand, no significant differences were found in static balance functions
      between the trained group and control group at 6 months of follow up. The
      locomotion and mobility scoring of FIM also revealed no differences between the
      groups. CONCLUSION: Dynamic balance function of patients in the visual feedback
      training group had significant improvements when compared with the control group.
      Activities of daily living (ADL) function in self-care also had significant
      improvements at 6 months of follow up in the trained group. The results showed
      that balance training was beneficial for patients after hemiplegic stroke.

PMID- 12479620
TI  - Aseptic nonunion of a femoral shaft treated using exchange nailing.
AB  - BACKGROUND: There are many methods for treating femoral shaft aseptic nonunions
      of which exchange nailing is the simplest technique. However, the reported
      success rate varies. Therefore, a prospective study was conducted to further
      clarify the role of exchange nailing. METHODS: From October 1994 through December
      1999, 40 femoral shaft aseptic nonunions in 39 patients were treated using
      exchange nailing. The indications for this technique included a femoral shaft
      aseptic nonunion with a previously inserted intramedullary nail, less than 1 cm
      shortening, a radiolucent line of the nonunion, and no segmental bony defects.
      The surgical technique consisted of close removal of the previously inserted
      intramedullary nail, reaming the intramedullary canal as widely as possible (1 or
      2 mm oversized), and re-insertion of a stable unlocked or locked intramedullary
      nail. RESULTS: Thirty-six femoral shaft aseptic nonunions in 35 patients were
      followed-up for at least 1 year (median, 2.9 years; range, 1.1-6.0 years) and 33
      nonunions healed. The union rate was 91.7% (33/36) and the union period was
      median 4 months (range, 3-8 months). No major surgical complications were noted.
      The other three patients with persistent nonunions were continuously followed-up
      due to their reluctance for further operations. CONCLUSION: Although exchange
      nailing is a relatively simple surgical technique, it can still achieve a high
      union rate with a low complication rate. Despite that factors to induce a
      persistent nonunion are still unclear, clinically, exchange nailing should be
      used as the first choice in the treatment of an indicated femoral shaft aseptic
      nonunion.

PMID- 12479621
TI  - Orbital exenteration for secondary orbital tumors: a series of seven cases.
AB  - BACKGROUND: Exenteration is indicated in patients with malignant neoplasms of
      orbital contents. It entails the removal of the eyeball together with its
      extraocular muscles and other soft tissues. Exenterations can be classified into
      (1) total, (2) subtotal, and (3) supertotal exenteration. Retrospectively study,
      we reviewed 7 patients that had received exenteration/subtotal exenteration with
      spontaneous granulation/myocutaneous flap implantation or eyelid-sparing
      exenteration with myocutaneous flap. Primary lesions, histopathological
      examination results, treatments, and recurrences are discussed. METHODS: A
      retrospective study of the years 1987 through 2000 disclosed 7 patients that
      underwent exenteration/subtotal exenteration. The patients ranged in age from 41
      to 68 years. Two patients underwent total exenteration without socket
      augmentation; 4 patients underwent exenteration/ subtotal exenteration with
      immediate facial reconstruction, and 1 with delayed facial reconstruction.
      RESULTS: Classification of the 7 patients showed that 2 had basal cell carcinoma
      of the skin, 2 had squamous cell carcinoma of the conjunctiva, 1 had squamous
      cell carcinoma of the paranasal sinus, 1 had rhabdomyosarcoma of the paranasal
      sinus, and 1 had intracranial meningioma. Radiotherapy was performed in 6 of the
      patients and chemotherapy in 2. Central nerve system invasion was noted in 2
      patients, and 1 died due to it. CONCLUSION: Secondary orbital tumors involved the
      orbit from adjacent tissues: paranasal sinuses, nasopharynx, lacrimal sac,
      conjunctiva, eyelid, intraocular tissue, and intracranial tissues. Combined
      surgeries are necessary for complete tumor removal. And the imaging studies
      should include the field of the orbit, sinus, and brain to search for the primary
      lesions.

PMID- 12479622
TI  - Levamisole aids in treatment of refractory oral candidiasis in two patients with
      thymoma associated with myasthenia gravis: report of two cases.
AB  - Oral candidiasis is associated with defects in cell-mediated immunity and is
      common among patients undergoing cytotoxic chemotherapy, or corticosteroid or
      antibiotic therapy, and those patients seropositive for AIDS and HIV (human
      immunodeficiency virus). This paper demonstrates the important role of cell
      mediated immunity in oral candidiasis in 2 cases of thymoma associated with
      myasthenia gravis. Both suffered from recurrent oral candidiasis after a
      thymectomy, radiotherapy, and chemotherapy. There was an initial good response to
      conventional antifungal therapy, which later became refractory. Lymphocyte subset
      quantitation showed a T cell deficiency and a decreased CD4/CD8 ratio.
      Levamisole, an immunomodulator, or an immunopotentiating drug was added as
      adjunctive therapy in combination with oral nystatin treatment. Oral candidiasis
      responded favorably, and substantial relief was obtained with a concurrent
      increase in T cells and the CD4/CD8 ratio. These findings clearly demonstrate a
      significant role of cell-mediated immunity in oral candidiasis, and that
      eradication of infection is dependent on the host defense mechanism.

PMID- 12479623
TI  - Stroke after intraaortic balloon counterpulsation associated with mobile atheroma
      in thoracic aorta diagnosed using transesophageal echocardiography.
AB  - We describe a patient who developed embolic stroke after coronary artery bypass
      grafting (CABG) associated with intraaortic balloon pump (IABP) insertion.
      Intraoperative transesophageal echocardiography (TEE) revealed marked irregular
      mass and disruption of the intimal surface of the thoracic aorta with overlying
      shaggy echogenic material on the intimal surface of the descending thoracic
      aortic lumen. This case of stroke after IABP insertion suggested that the balloon
      inflation fragmented some mobile components on the inner surface of the aorta,
      and this floating debris entered the systemic circulation. TEE might be able to
      predict the risk of stroke in such a patient.

PMID- 12479624
TI  - Rocuronium-induced generalized spontaneous movements cause pulmonary aspiration.
AB  - Rapid-sequence induction with cricoid pressure is a standard procedure for
      inducing anesthesia in patients with a potentially full stomach. During the
      induction period, if the patient develops generalized movements of the body, the
      pressure level of the cricoid may change unexpectedly. As a result, the increase
      in intragastric pressure may cause gastric regurgitation and consequent pulmonary
      aspiration. Rocuronium has been widely used as an alternative to succinylcholine
      during the induction of anesthesia. However, most patients who received
      rocuronium complained of severe burning pain in their arm during intravenous
      injection. Even after the administration of the induction agents, rocuronium
      injection can also cause withdrawal of the hand or other generalized movements of
      the body. We describe a case of gastric regurgitation with pulmonary aspiration
      following generalized spontaneous movements associated with rocuronium injection
      in a girl who received pediatric emergent surgery.

PMID- 12479625
TI  - Rosai-Dorfman disease manifesting as relapsing uveitis and subconjunctival
      masses.
AB  - Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy, SHML) is
      a rare, non-hereditary, benign histiocytic proliferative disorder mainly
      affecting young people with common clinical characteristics such as painless
      bilateral cervical lymphadenopathy, fever, leukocytosis and polyclonal
      gammopathy. Extranodal manifestations have been reported in 28-43% of cases. Eye
      involvement is relatively uncommon (8.5%), and most of cases have presented as
      lymphoproliferation in the soft tissues of the orbit and eyelids. Uveitis is an
      even more rare presentation as a review of all the literature. We describe a 63
      year-old man with SHML with unusual ophthalmic manifestations of relapsing
      uveitis and bilateral subconjunctival masses. The results of biopsies were
      compatible with the characteristic histopathological findings of SHML: focal
      aggregations of S100-positive foamy histiocytes and the existence of
      lymphocytophagocytosis. During the clinical course, the patient relapsed but the
      relapse was relatively benign and the patient showed fair response to topical as
      well as systemic corticosteroid treatment. Here we describe this unusual
      presentation of SHML to inform physicians of the possibility for this systemic
      granulomatous disease to contribute to relapsing uveitis.

PMID- 12479626
TI  - Secondary aortoduodenal fistula.
AB  - Secondary aortoenteric fistula (SAF) is now recognized as an uncommon but
      exceedingly important complication of abdominal aortic reconstruction. The
      complication often occurs months to years after the original surgery. The main
      clinical manifestation of the disease is always upper gastrointestinal bleeding.
      Treatment of the disease is early surgical intervention. The mortality is high if
      no prompt operation. We present a case of secondary aortoduodenal fistula (SADF)
      found 20 days after aortic reconstructive surgery, with the clinical presentation
      of upper gastrointestinal bleeding. Even immediate exploratory laparotomy was
      performed, the patient died 48 hrs after the surgical management. Because of the
      increasing number of elective aortic aneurysm repairs in the aging population, it
      is likely that more patients with SAF will present to the clinical physicians in
      the future. So, a high index of suspicion is necessary for prompt diagnosis and
      treatment of this actually life-threatening event.

PMID- 12479627
TI  - Microbiological markers for prediction and assessment of treatment outcome
      following non-surgical periodontal therapy.
AB  - BACKGROUND: Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and
      Bacteroides forsythus are considered major putative periodontal pathogens.
      However, it remains unclear what combinations or what levels of these bacteria
      influence treatment outcome. The purpose of the present study was to establish
      useful pathogenic markers for prediction and assessment of treatment outcome
      following scaling and root planing (SRP). METHODS: A total of 1,149 sites in 104
      chronic periodontitis patients were clinically examined at baseline. Three months
      after SRP, 606 sites in 56 of these patients were reexamined. Subgingival plaque
      samples taken from the examined sites at baseline and 3 months were analyzed for
      the detection and quantification of A. actinomycetemcomitans, P. gingivalis, and
      B. forsythus using a colorimetric polymerase chain reaction technique. RESULTS:
      At baseline, high levels and a combination of P. gingivalis and B. forsythus were
      frequently detected in diseased sites (74%). SRP reduced the levels and the
      coexistence of P. gingivalis and B. forsythus (from 75% to 43%). However, in
      treated sites where there was less reduction of probing depth (<2 mm), or where
      bleeding on probing (BOP) or suppuration was detected, residual coexistence of P.
      gingivalis and B. forsythus and a high level of P. gingivalis after SRP were
      significantly more frequent. Furthermore, SRP did not improve BOP at sites
      exhibiting initially high levels of A. actinomycetemcomitans. CONCLUSIONS: These
      results suggest that the combination of P. gingivalis and B. forsythus, as well
      as the level of P. gingivalis, is useful in assessing treatment outcome.
      Furthermore, the high level of A. actinomycetemcomitans before SRP is a possible
      valuable predictor of treatment outcome.

PMID- 12479628
TI  - In vitro effect of laser irradiation on cementum-bound endotoxin isolated from
      periodontally diseased roots.
AB  - BACKGROUND: In a previous study, we evaluated the in vivo effects of an Nd:YAG
      laser on periodontal disease by measuring crevicular interleukin (IL)-1beta
      levels before and after laser application. It was found that laser therapy was
      less effective than traditional scaling and root planing. These results might be
      due to incomplete removal of microbial residues and cementum-bound endotoxin on
      root surfaces by the laser. In this study, we explored the in vitro effectiveness
      of an Nd:YAG laser for the elimination of cementum-bound endotoxin by measuring
      IL-1beta changes in stimulated monocytes. METHODS: Fresh human monocytes were
      harvested from adults without periodontitis and grown in RPMI 1640 medium.
      Diseased cementum particles were collected and prepared from teeth with untreated
      periodontitis and were irradiated with 5 levels of laser energy. Cementum
      particles were subjected to endotoxin testing by a limulus amebocyte lysate (LAL)
      assay and then were incubated with cultured monocytes. Production of IL-1beta in
      stimulated monocytes was measured by enzyme-linked immunosorbent assay and
      quantified by spectrophotometry. RESULTS: The endotoxin unit (EU) of diseased
      cementum was 18.4 EU/mg, which seemed to be remarkably lower than that of common
      periodontal pathogens including Porphyromonas gingivalis (381) at 15,300
      EU/mg/ml, Prevotella intermedia (ATCC 25611) at 227 EU/mg/ml, and Fusobacterium
      nucleatum (ATCC 25586) at 1,987 EU/mg/ml. Monocytes subjected to stimulation by
      diseased cementum particles without laser irradiation produced 124 to 145 pg/ml
      IL-1beta, 9- to 18-fold higher than that of unstimulated monocytes (7.07 to 15.95
      pg/ml). Diseased cementum particles after irradiation with various energy levels
      of the Nd:YAG laser could still stimulate monocytes to secrete 89 to 129 pg/ml IL
      1beta. No statistically significant difference was found in the production of IL
      1beta induced by diseased-bound cementum with or without laser irradiation.
      CONCLUSIONS: The Nd:YAG laser varying from 50 mJ, 10 pps to 150 mJ, 20 pps, for 2
      minutes, did not seem to be effective in destroying diseased cementum endotoxin.

PMID- 12479629
TI  - An in vitro model of ciprofloxacin and minocycline transport by oral epithelial
      cells.
AB  - BACKGROUND: Fluoroquinolones and tetracyclines can penetrate epithelial cells,
      but the mechanism by which they cross the plasma membrane is unclear. In this
      study, a cell line derived from oral epithelium was used as a model to
      demonstrate a role for active transport. METHODS: Transport of ciprofloxacin and
      minocycline by confluent cell monolayers was assayed by measuring the increase in
      cell-associated fluorescence. RESULTS: Uptake of both agents was saturable and
      was inhibited at low temperatures. At 37 degrees C, the cells transported
      ciprofloxacin and minocycline with Km values of 351 and 133 microg/ml,
      respectively, and maximum velocities of 5.11 and 13.4 ng/min/microg cell protein,
      respectively. When ciprofloxacin and minocycline were removed from the
      extracellular medium, the intracellular levels of both agents decreased.
      Ciprofloxacin efflux from loaded cells occurred more rapidly than with
      minocycline. Cells accumulated intracellular drug levels that were at least 8
      fold higher than extracellular levels for ciprofloxacin and at least 40-fold
      higher for minocycline. Transport of ciprofloxacin and minocycline was
      significantly influenced by pH and was most favorable at pH 7.7 and 7.2,
      respectively. While ciprofloxacin transport was Na+ independent, minocycline
      transport was strongly inhibited when sodium in the medium was replaced with
      choline. Transport of both agents was inhibited by a variety of organic cations,
      but the pattern of inhibition was different. Papaverine, phenylephrine, and
      doxycycline competitively inhibited minocycline transport, but inhibited
      ciprofloxacin transport by a non-competitive mechanism. CONCLUSIONS: Epithelial
      cells take up ciprofloxacin and minocycline via different active transport
      systems. These transporters may play an important role in enhancing the
      effectiveness of these agents against invasive pathogens.

PMID- 12479630
TI  - Evaluation of matrix metalloproteinase-1 and tissue inhibitor of
      metalloproteinase-1 levels in gingival fibroblasts of cyclosporin A-treated
      patients.
AB  - BACKGROUND: Cyclosporin A (CsA) is a potent immunosuppressant used to prevent
      organ transplant rejection and to treat various autoimmune diseases. CsA-induced
      gingival overgrowth (CsA GO) is the most widely seen side effect of this drug;
      its pathogenesis is not completely understood. The aim of this study was to
      identify and compare matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of
      metalloproteinase-1 (TIMP-1) levels in gingival fibroblast cultures of tissues
      derived from renal transplant patients receiving CsA and exhibiting gingival
      overgrowth and from periodontally healthy control subjects. METHODS: Gingival
      overgrowth samples were obtained from patients undergoing therapy with CsA, and
      control tissues were obtained from systemically healthy donors. Gingival
      fibroblasts were grown using explant cultures. Three different study groups were
      identified: 1) CsA GO fibroblast culture; 2) CsA-treated healthy gingival
      fibroblast culture (H+CsA); and 3) healthy gingival fibroblast culture (H). The
      levels of MMP-1 and TIMP-1 in these groups of gingival fibroblasts were analyzed
      by enzyme-linked immunoabsorbent assay (ELISA). RESULTS: The levels of TIMP-1
      were significantly lower in CsA GO than H (P < 0.05). There was no statistically
      significant difference in the levels of MMP-1 between H and CsA GO (P = 0.505).
      The ratio of MMP-1 to TIMP-1 was significantly higher in CsA GO than H (P <
      0.05). CONCLUSIONS: The results of this study indicate that CsA therapy does not
      have a significant effect on MMP-1 levels. However, low TIMP-1 levels can be an
      important factor in the pathogenesis of CsA GO, since the balance between MMP-1
      and TIMP-1 levels was changed by CsA.

PMID- 12479631
TI  - The pattern of alveolar crest height change in healthy postmenopausal women after
      3 years of hormone/estrogen replacement therapy.
AB  - BACKGROUND: The loss of ovarian function at menopause is associated with loss of
      postcranial and oral bone. Hormone/estrogen replacement therapy (HRT/ERT) has a
      positive effect on both postcranial and oral bone. The objective of the study was
      to determine if the positive effect of HRT/ERT on alveolar crest height (ACH) is
      generalized or site specific. METHODS: The sample consisted of 49 women who
      completed a 3-year, HRT/ERT prospective study. Cemento-enamel junction distances
      (ACH) were measured on digitized images of bitewing radiographs. Lumbar spine and
      proximal femur bone mineral densities (BMDs) were determined with dual-energy x
      ray absorptiometric scans. Measurements were made at baseline and at the end of
      year 3. For the 3-year study period, mean change in ACH was determined for each
      patient. In addition, the sites with the greatest, second and third greatest ACH
      changes were determined for each patient. Correlations between changes in ACH (as
      determined by the various methods) and postcranial BMD were determined. RESULTS:
      Mean ACH changes had an average correlation (r) of -0.24 with femoral and lumbar
      spine BMDs. Although the largest site-specific change in ACH resulted in a mean
      correlation of -0.21, the correlations for the second and third largest changes
      in ACH dropped to -0.15 and -0.12. Overall, the correlations for site-specific
      changes were substantively smaller than those for generalized change.
      CONCLUSIONS: The data of this study indicate that ACH change attributable to
      HRT/ERT is generalized rather than site specific. Studies of the effect of
      HRT/ERT on ACH should employ multiple measurements to minimize measurement errors
      associated with site-specific measurements.

PMID- 12479632
TI  - Pharmacokinetic profile of a locally administered doxycycline gel in crevicular
      fluid, blood, and saliva.
AB  - BACKGROUND: With the help of so-called controlled release delivery systems, the
      half-life period of locally administered antibiotics in gingival crevicular fluid
      (GCF) can be extended significantly. The aim of this study was to characterize
      the delivery profile of a new one-component 14% doxycycline free amine gel for
      local application. Pharmacokinetics of doxycycline (DOXY) were analyzed in GCF,
      saliva, and serum. METHODS: Twenty patients with persisting or recurring pockets
      (probing depths > or = 5 mm and bleeding on probing) after mechanical treatment
      (surgical or non-surgical) took part in the study. In each patient 1 periodontal
      defect was treated with DOXY gel. Samples of GCF, saliva, and serum were obtained
      before application of DOXY gel; 15 minutes after application; at 2 and 5 hours;
      and at 1, 2, 3, 4, 7, 9, and 11 days after application. Separation and
      quantitative measurement of DOXY was performed with high performance liquid
      chromatography and UV detection at lambda = 260 nm. RESULTS: Coefficients of
      variation were lower than 2% (intraassay) and 4% (interassay), respectively. For
      concentrations between 50 to 1000 microg/ml, we found a linear relationship
      between expected and measured DOXY values (linear coefficient of correlation: r =
      0.998). Within the first 5 hours after application, concentration of DOXY in GCF
      (maximum after 15 minutes 19.97 +/- 5.85 mg/ml) and saliva (maximum after 15
      minutes 17.83 +/- 2.84 mg/ml) was similar. Then concentration fell to a lower
      level (28.90 +/- 19.44 microg/ml) compared to GCF (577.41 +/- 127.34 microg/ml)
      after 3 days. Up to 10 days after application, the concentration of DOXY in GCF
      was 34.24 microg/ml. With the exception of 1 patient, all serum samples were DOXY
      negative. CONCLUSIONS: 1) After subgingival application of biodegradable 14%
      doxycycline gel, mean doxycycline levels in GCF that exceeded 16 microg/ml could
      be maintained for at least 12 days. Thus, the antimicrobial agent may be
      classified as a controlled release device. 2) The antibiotic effect was limited
      mainly to the subgingival sites of application of the doxycycline gel. 3) The
      doxycycline gel possesses the pharmacokinetic and clinical properties to deliver
      efficacious levels of antibiotics to the periodontal pocket and to maintain these
      levels for at least 1 week without the need of further drug retention by a
      periodontal dressing.

PMID- 12479633
TI  - Bactericidal effect of the Er:YAG laser on dental implant surfaces: an in vitro
      study.
AB  - BACKGROUND: The aim of the in vitro study was to examine the bactericidal effect
      of an Er:YAG laser on common dental implant surfaces. METHODS: Seventy-two
      titanium platelets with 3 different surfaces--sandblasted and acid-etched (SA),
      titanium plasma-sprayed (TPS), and hydroxyapatite-coated (HA)--were incubated
      with a suspension of Streptococcus sanguinis (ATCC 10556). Irradiation at pulse
      energies of 60 and 120 mJ and a frequency of 10 pps was performed on a computer
      controlled XY translation stage. After laser treatment the specimens were
      sonicated and the bacterial growth examined by counting colony forming units on
      blood agar plates. Temperature elevations during irradiation were investigated
      using K-type thermocouples. Laser treated implant surfaces were analyzed by means
      of electron microscopy. RESULTS: Compared to non-irradiated specimens, mean
      bacterial reductions of 99.51% (SA), 98.39% (HA), and 99.6% (TPS) at a pulse
      energy of 60 mJ and 99.92% (SA), 99.85% (HA), and 99.94% (TPS) at 120 mJ were
      calculated. At these laser parameters, no excessive temperature elevations or
      morphological implant surface alterations were detected. CONCLUSIONS: Even at low
      energy densities, the Er:YAG laser has a high bactericidal potential on common
      implant surfaces. Clinical studies are justified to evaluate the applicability
      and efficacy of the Er:YAG laser in the treatment of peri-implantitis.

PMID- 12479634
TI  - Subpedicle acellular dermal matrix graft and autogenous connective tissue graft
      in the treatment of gingival recessions: a comparative 1-year clinical study.
AB  - BACKGROUND: Many surgical techniques have been proposed for the correction of
      dental root exposition. Among these, bilaminar techniques (BTs) have been
      reported as offering the best results in terms of root coverage (RC). However,
      BTs require a second surgical site to harvest the graft, with discomfort for the
      patient. The use of an acellular dermal matrix (ADM) avoids the need for a donor
      site. The aim of this study was to compare the clinical results of 2 BTs by
      autogenous connective tissue (CT) or ADM. METHODS: In 30 systemically healthy,
      non-smoking patients aged 34.5 +/- 5.2 years, who showed no periodontal pockets
      >4 mm after a hygienic phase, a Miller's class I or II gingival recession was
      treated for root coverage. All patients underwent a BT: in 15 patients, an
      autogenous connective tissue graft was employed (CT group); in the other 15
      subjects, ADM was used as a subepithelial graft (ADM group). Prior to and 1 year
      after surgical treatment, the following clinical parameters were recorded:
      gingival recession (GR), probing depth (PD), clinical attachment level (CAL),
      width of keratinized tissue (KT), and gingival thickness (GT); the percentage of
      RC (%RC) was also calculated, and the data were statistically analyzed. The
      number of weeks needed to obtain complete healing with mature tissue appearance
      was also recorded. RESULTS: Both groups yielded significant improvements in terms
      of GR decrease, CAL and KT gain, and GT increase as compared to baseline values.
      The mean %RCs were 88.80 +/- 11.65% and 83.33 +/- 11.40% in the CT and ADM
      groups, respectively. Complete RC was observed in 46.6% of patients from the CT
      group, and 26.6% of the ADM group patients. No significant differences were
      observed between the two techniques for GR, CAL, and GT improvements; however,
      the CT group produced a significantly (P <0.01) greater increase in KT as
      compared to the ADM group. Complete healing of the surgical procedure was
      observed 6.20 +/- 1.01 and 8.93 +/- 1.33 weeks after suture removal in the CT and
      ADM groups, respectively (P <0.001). CONCLUSIONS: The CT and ADM subepithelial
      grafts were similarly able to successfully treat gingival recession defects;
      however, the CT group obtained a significantly greater increase in KT, and showed
      a quicker complete healing.

PMID- 12479635
TI  - Effects of CO2 laser treatment on fibroblast attachment to root surfaces. A
      scanning electron microscopy analysis.
AB  - BACKGROUND: The aim of this study was to analyze the CO2 laser effects on root
      surfaces affected by periodontal disease in comparison to scaling and root
      planing for fibroblast attachment. METHODS: Thirty single-rooted human teeth
      extracted because of advanced periodontal disease were included in this study. A
      total of 60 specimens, obtained from all selected teeth, were randomly assigned
      to 3 groups: 1) control (untreated); 2) hand scaling and root planing (SRP); or
      3) laser (CO2 defocused pulsed) and ultrasonic scaling. All the specimens were
      incubated in Petri dishes with fibroblast suspension, and then observed by
      scanning electron microscopy (SEM). RESULTS: The control group showed the lowest
      number of attached cells, with no tightly attached fibroblasts. The laser plus
      scaling group showed the highest number of attached fibroblasts, with the tightly
      attached fibroblast prevailing. The laser-treated and scaled root specimens did
      not show any damage or morphologic alteration of the root surfaces. CONCLUSION:
      CO2 laser treatment in defocused, pulsed mode with a low power of 2W combined
      with mechanical instrumentation constitutes a useful tool to condition the root
      surface and increase fibroblast attachment to root surfaces.

PMID- 12479636
TI  - Expression of matrix metalloproteinases in cyclosporin-treated gingival
      fibroblasts is regulated by transforming growth factor (TGF)-beta1 autocrine
      stimulation.
AB  - BACKGROUND: Gingival overgrowth is a common side effect following the
      administration of cyclosporin A (CsA). The pathogenesis of this condition is not
      fully understood; however, recent studies show that CsA regulates the
      transcription of several cytokines including transforming growth factor-beta1
      (TGF-beta1). The aim of this study was to investigate the potential role of TGF
      beta1 in the pathogenesis of CsA-induced gingival overgrowth, exploring a
      possible autocrine stimulation of TGF-beta1 as a cellular regulator of synthesis
      of matrix metalloproteinases (MMPs) and its tissue inhibitors (TIMPs). METHODS:
      Gingival fibroblasts from human normal gingiva were incubated with increasing
      concentrations of CsA, cultured for 24 hours, and the expression and production
      of TGF-beta1 determined by semiquantitative reverse transcriptase-polymerase
      chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA),
      respectively. MMP and TIMP mRNA expression levels were also analyzed by RT-PCR.
      To determine the effect of TGF-beta1 on the expression of MMP and TIMP by human
      gingival fibroblasts under CsA treatment, human gingival fibroblast cultures were
      treated with sense oligonucleotides (SON) or antisense oligonucleotides (AON).
      RESULTS: CsA simultaneously stimulated TGF-beta1 expression and production and
      inhibited expression of MMP-1 and MMP-2 by human gingival fibroblasts, whereas
      CsA has a slight effect on TIMP-1 and TIMP-2 expression. AON reduced TGF-beta1
      production as demonstrated by ELISA, whereas TGF-beta1 mRNA expression levels
      were not significantly modified. The inhibition of TGF-beta1 production by AON
      modulated MMP expression, demonstrating the autocrine inhibitory effect of TGF
      beta1 in CsA-treated human gingival fibroblasts. CONCLUSIONS: The data presented
      here suggest that TGF-beta1 in an autocrine fashion may contribute to a reduction
      of proteolytic activity of human gingival fibroblasts in CsA-induced gingival
      overgrowth, which favors the accumulation of extracellular matrix.

PMID- 12479637
TI  - Macrophage subpopulations in gingival overgrowth induced by nifedipine and
      immunosuppressive medication.
AB  - BACKGROUND: The immunomodulating effects of both immunosuppressive and nifedipine
      medication have been associated with drug-induced gingival overgrowth. The aim of
      the study reported here was to evaluate the presence of macrophage subpopulations
      in normal human gingiva and in gingival overgrowth induced by nifedipine and
      immunosuppressive medication. METHODS: Gingival samples were taken from 11
      nifedipine-medicated cardiac outpatients (nifedipine group), 11 triple-medicated
      organ-transplant recipients also taking nifedipine (immunosuppression plus
      nifedipine group), 12 triple-medicated organ-transplant recipients
      (immunosuppression group), and 20 generally healthy individuals (control group).
      Cryostat sections were stained with mAbs for inflammatory 27E10, reparative
      RM3/1, and resident 25F9 macrophages using an avidin-biotin enzyme complex
      method. Total numbers of mAb-labeled cells were determined in connective tissue
      beneath sulcular epithelium, connective tissue beneath oral epithelium, and
      middle connective tissue. Expression of 27E10 was determined in keratinocytes in
      the oral epithelium. Statistics analyses were undertaken using the chi-square
      test, the Mann-Whitney U test, the independent samples t test, analysis of
      variance, and analysis of covariance. RESULTS: Greater numbers of inflammatory
      27E10-positive macrophages were found in all 3 medicated groups and counting
      zones than in the control group except in connective tissue beneath sulcular
      epithelium in the immunosuppression group. The incidence of specimens expressing
      27E10 antigen throughout the oral epithelium was significantly higher in the
      immunosuppression group (8 of 12) than in the control group (4 of 20) and the
      nifedipine group (2 of 11). Numbers of reparative RM3/1-positive macrophages were
      significantly greater in the immunosuppression group in connective tissue beneath
      oral epithelium than in the control group. The effect was markedly associated
      with degree of inflammation. Numbers of resident 25F9-positive macrophages were
      lower in connective tissue beneath sulcular epithelium in the immunosuppression
      group, and higher in middle connective tissue in the nifedipine group than in the
      control group. CONCLUSION: Our results show that the nature of drug-induced
      gingival overgrowth differs somewhat between immunosuppressive and nifedipine
      medications.

PMID- 12479638
TI  - Expression and activity of hyaluronidase in human periodontal ligament
      fibroblasts.
AB  - BACKGROUND: Hyaluronan is a major component of the extracellular matrix of
      periodontal ligament (PDL) contributing to the structural and functional
      integrity. Hyaluronans contribute to the buffering effect of the PDL during
      chewing, and they are also important in inflammation and wound healing.
      Hyaluronan is known to be synthesized and turned over by the resident PDL cells,
      although the mechanisms of hyaluronan metabolism still remain unclear.
      Hyaluronidase (HAase), an endoglycosidase, degrades hyaluronan into small
      fragments. Currently, 3 human HAases, HYAL1, HYAL2, and PH-20, have been
      identified and well characterized. METHODS: This study was conducted to
      investigate the expression and activity of these HAases in cultured human PDL
      fibroblasts and to elucidate the mechanisms involved in hyaluronan metabolism
      under normal and inflammatory conditions. Human PDL fibroblasts derived from the
      periodontium of 3 premolars were cultured with or without interleukin (IL)-1beta
      (0.1 to 10 ng/ml) and tumor necrosis factor (TNF)-alpha (1 to 100 ng/ml) for 0 to
      48 hours. The expression of HAase mRNA was assessed by reverse transcription
      polymerase chain reaction (RT-PCR) and quantitative real-time PCR, and the
      enzymatic activity was examined using hyaluronan zymography. RESULTS: PDL
      fibroblasts expressed HYAL1 and HYAL2 mRNAs, but not PH-20 mRNA. The expression
      of HYAL1 mRNA was enhanced by about 3.5- and 3.7-fold at maximum after 1-hour
      stimulation with 1 ng/ml IL-1beta and after 3-hour stimulation with 10 ng/ml TNF
      alpha, respectively. The expression of HYAL2 and PH-20 mRNAs was not affected by
      stimulation with cytokines. HAase activity was detected in conditioned medium
      from PDL fibroblast cultures, and the activity was enhanced by treatment with 10
      ng/ml TNF-alpha. CONCLUSION: These results suggest that PDL fibroblasts express
      HAases and generate HAase activity essential for extracellular hyaluronan
      metabolism under physiological and inflammatory conditions.

PMID- 12479639
TI  - The relationship of oral malodor in patients with or without periodontal disease.
AB  - BACKGROUND: Halitosis has been correlated with the concentration of volatile
      sulfur compounds (VSC) produced in the oral cavity by metabolic activity of
      bacteria colonizing the periodontal area and the dorsum of the tongue. The aim of
      this study was to determine whether there is some relationship between the
      presence of N-benzoyl-DL-arginine-2-napthylamide (BANA)-positive species
      Treponema denticola, Porphyromonas gingivalis, and Bacteroides forsythus and
      clinical and oral malodor parameters. METHODS: Twenty-one subjects (21 to 59
      years old) with probing depths (PD) > 3.0 mm and 20 subjects (21 to 63 years old)
      with PD < or = 3.0 mm (controls) participated. The quality of the mouth air was
      assessed organoleptically, and a portable sulfide monitor was used to measure the
      concentration of VSC. Clinical parameters, plaque index (PI) and gingival index
      (GI), were obtained from 6 teeth. Samples for BANA test were taken from the
      dorsal surface of the tongue, saliva, and the 6 reference teeth. RESULTS: The
      scores of PI, GI, subgingival samples that tested positive for BANA hydrolyzing
      species, organoleptic ratings, and VSC values were significantly higher in the
      subjects with PD > 3.0 mm (P < 0.01, Mann-Whitney U test). There was a
      correlation between BANA hydrolysis by subgingival plaque bacteria and VSC values
      (r = 0.55, P < 0.01), and between GI and VSC values (r = 0.48, P < 0.05) in
      patients with PD > 3.0 mm. There was no significant correlation between these
      parameters in the control group. CONCLUSION: These results confirm that the BANA
      hydrolyzing bacteria in the subgingival plaque are an important source of malodor
      production in the oral cavity.

PMID- 12479640
TI  - Coping with stress: its influence on periodontal disease.
AB  - BACKGROUND: Various forms of stress behavior were documented and in patients with
      periodontitis their relationship with periodontal disease was investigated.
      METHODS: Eighty-nine patients with different forms of chronic periodontitis were
      included in this retrospective case-control study. They were all undergoing
      periodontal treatment at the Department of Dental Prosthetics, University of
      Graz, or a private dental practice. The control group consisted of 63 persons
      employed in health care at the Clinic of Graz. All participants completed a
      stress coping questionnaire of 114 items and 19 actional and intrapsychic stress
      coping modes. The questionnaire served as a psychodiagnostic survey aimed at
      collecting data on stress coping strategies. Clinical attachment loss (CAL)
      served as the clinical parameter. RESULTS: With the help of a factor analysis
      with a factorization and Varimax rotation, 5 factors were extracted from the 19
      subtests. The reliability of the questionnaire was less than 0.70 only for
      subtests "escape" and "pharmaceutical drugs." Otherwise the internal consistency
      ranged between 0.74 and 0.92, and the retest reliability between 0.72 and 0.84.
      Subsequent assessment with the t test for independent random samples at the 5%
      level showed that patients differ significantly from controls in regard of factor
      2 (active coping, P = 0.40) and 3 (distractive coping, P = 0.033), and that they
      differ very significantly from controls in regard of factor 4 (defensive coping,
      P = 0.000) and 5 (coping through aggression and pharmaceutical drugs, P = 0.007).
      In the statistical analysis of factors with regard to the severity of periodontal
      disease, the patients were divided into 2 groups (mild to moderate and severe).
      The t test for independent random samples showed significance for factor 4
      (defensive coping) in that patients with a defensive coping style had greater
      attachment loss (pF4 = 0.04). CONCLUSIONS: The data corroborate the thesis that
      periodontitis patients with inadequate stress behavior strategies (defensive
      coping) are at greater risk for severe periodontal disease. However, further
      investigations are required to confirm the significance of inappropriate coping
      styles with respect to the advancement of periodontal disease.

PMID- 12479641
TI  - Medical grade calcium sulfate hemihydrate versus expanded polytetrafluoroethylene
      in the treatment of mandibular class II furcations.
AB  - BACKGROUND: Guided tissue regeneration (GTR) techniques have been reported to
      enhance bone regeneration of molar furcation defects. The current trends in
      therapy encourage the use of a bioabsorbable barrier. The efficacy of the
      bioabsorbable barrier needs to be equal to, if not better than, the non
      absorbable barrier. METHODS: This clinical study compared the bone regeneration
      capacity of a commonly used GTR procedure (demineralized freeze-dried bone
      allograft [DFDBA] and an expanded polytetrafluoroethylene [ePTFE] membrane) to
      DFDBA and an exclusion barrier of medical grade calcium sulfate hemihydrate
      [MGCSH]). Thirteen pairs of mandibular molar Class II furcation defects were
      evaluated in 13 patients. Clinical measurements of keratinized gingival width,
      probing depth, and recession were recorded prior to treatment. Following flap
      elevation and furcation defect debridement, an occlusal reference stent and
      periodontal probes were used to measure vertical, horizontal, and intrabony
      defect dimensions to the nearest millimeter. Paired defects were randomly
      assigned to receive either DFDBA/ePTFE or DFDBA/MGCSH. At 6 months, study sites
      were surgically re-entered and the treated furcations were debrided to a firm
      bone surface. Intraoperative measurements were repeated. Clinical measurements
      were repeated at 12 months. RESULTS: The MGCSH-treated furcations demonstrated
      mean probing depth reduction between baseline and 6 months (1.00 +/- 0.82 mm,
      P<0.05) and baseline and 12 months (1.31 +/- 0.85 mm, P<0.05). There was no
      statistically significant change in probing depth in the ePTFE group at any time
      interval. The horizontal defect fill was significantly greater for ePTFE (36.7%)
      versus MGCSH (23.8%) (P<0.02). CONCLUSIONS: In selected defects, improved
      clinical measurements were achieved with DFDBA/MGCSH as well as DFDBA/ePTFE. Both
      treatments obtained significant horizontal defect fill at 6 months. DFDBA/ePTFE
      showed a significantly greater horizontal defect fill compared to DFDBA/MGCSH.
      Attachment level gains achieved with MGCSH held for 12 months, whereas ePTFE
      attachment level gains did not.

PMID- 12479642
TI  - Treatment of intrabony periodontal defects with enamel matrix derivative: a
      literature review.
AB  - The enamel matrix derivative (EMD) has been recently introduced in the
      periodontal field to overcome short-comings associated with currently available
      regenerative techniques. Information accumulated over the past years with
      application of EMD guided regeneration (EGR) in intrabony periodontal defects
      allowed a thorough evidence-based retrospective analysis. Clinical data from EMD
      controlled studies were pooled for meta-analysis and weighted according to the
      number of treated defects. Clinical attachment gain amounted to 3.2 +/- 0.9 mm
      (33% of the original attachment level) and probing reduction averaged 4.0 +/- 0.9
      mm (50% of the baseline probing depth) for a total of 317 lesions with a mean
      baseline depth of 5.4 +/- 0.8 mm. Improvements in clinical parameters achieved
      with EMD were statistically significant in reference to preoperative
      measurements. However, despite the overall efficacy of EGR therapy, a significant
      variation in clinical outcomes was observed. Similar therapeutic results were
      reported in studies where EGR was compared directly to guided tissue
      regeneration. However, the controlled clinical trials did not have adequate
      statistical power to firmly support superiority or equivalency between the 2
      regenerative therapies. The statistical superiority of EGR over treatment with
      open flap debridement has been established. Preliminary histologic investigations
      with surgically created defects and experimental periodontal lesions demonstrated
      the ability of EGR to induce formation of acellular cementum and promote
      significant anaplasis of the supporting periodontal tissues. The potential of EMD
      to encourage periodontal regeneration was also confirmed in human intrabony
      defects. However, recent human histologic studies have questioned both the
      consistency of the histologic outcomes and the ability of EGR to predictably
      stimulate formation of acellular cementum. Identifying clinical modifying
      parameters and understanding cellular interactions are apparently essential for
      the development of methodologies to enhance predictability and extent of EGR
      clinical and histologic results.

PMID- 12479643
TI  - Mediators of periodontal osseous destruction and remodeling: principles and
      implications for diagnosis and therapy.
AB  - Osteoclastic bone resorption is a prominent feature of periodontal disease. Bone
      resorption via osteoclasts and bone formation via osteoblasts are coupled, and
      their dysregulation is associated with numerous diseases of the skeletal system.
      Recent developments in the area of mediators of osteoclastic differentiation have
      expanded our knowledge of the process of resorption and set the stage for new
      diagnostic and therapeutic modalities to treat situations of localized bone loss
      as in periodontal disease. This review describes the current state of knowledge
      of osteoclast differentiation and activity, mediators, and biochemical markers of
      bone resorption and their use and potential use in clinical periodontics.
      Finally, therapeutic strategies based on knowledge gained in the treatment of
      metabolic bone diseases and in periodontal clinical trials are discussed, and the
      potential for future strategies is proposed relative to their biologic basis. The
      intent is to update the field of periodontics on the current state of
      pathophysiology of the osteoclastic lesion and outline diagnostic and therapeutic
      strategies with a rational basis in the underlying biology.

PMID- 12479644
TI  - Acute streptococcal infection of the gingiva, lower lip, and pharynx--a case
      report.
AB  - BACKGROUND: Streptococcal gingivostomatitis is a rare phenomenon in a non
      compromised host and not commonly reported in the dental literature. Early
      diagnosis and distinction from viral infections, especially HSV infection, are of
      the utmost importance. The early use of penicillin is essential in preventing a
      cascade of events, resulting in severe fasciitis, destruction of tissues, and
      subsequent rheumatic fever and rheumatic heart disease. METHODS: A unique case of
      group A beta-hemolytic streptococcal infection affecting the pharynx, lower lip,
      and gingiva of a healthy 19-year-old male is presented. RESULTS: The
      streptococcal infection was responsive to penicillin treatment. CONCLUSIONS: In
      view of the increased use of antibiotics and the development of aggressive
      strains, the dental clinician has to consider streptococcal infection in the
      differential diagnosis of gingival and soft tissue infections.

PMID- 12479645
TI  - Azathioprine or 6-mercaptopurine before colectomy for ulcerative colitis is not
      associated with increased postoperative complications.
AB  - AIM: To determine whether the use of azathioprine/6-mercaptopurine before
      colectomy is associated with an increased rate of postoperative complications.
      METHODS: All patients who underwent colectomy with ileal pouch-anal anastomosis
      for ulcerative colitis between 1997 and 1999 were identified. Medical records
      were abstracted for demographics, extent and duration of disease, dose and
      duration of corticosteroids and azathioprine/6-mercaptopurine, albumin, and
      Truelove/Witts score. Early (30-day) and late (6-month) complications were
      identified. Noncorticosteroid immunosuppressive use was coded as none,
      azathioprine/6-mercaptopurine within 1 week of surgery, or therapy with other
      immunosuppressive agents within 1 month of surgery. A logistic regression
      analysis assessed the association between these variables and complications.
      RESULTS: Early complications occurred in 49 of 151 (32%) patients not treated
      with immunosuppressive agents, 12 of 46 (26%) azathioprine/6-mercaptopurine
      treated patients, and 4 of 12 (33%) patients treated with other immunosuppressive
      agents (p = 0.71). Late complications occurred in 72 of 148 (49%), 20 of 46
      (43%), and 8 of 12 (67%) patients in these same groups, respectively. Intravenous
      or oral steroids at doses of 40 mg/d or greater (p < 0.01) and severe or
      fulminant disease (p = 0.0094) were associated with greater early complication
      rates. CONCLUSION: Early complications after restorative proctocolectomy for
      ulcerative colitis are associated with high dose steroids and severe disease but
      not use of azathioprine/6-mercaptopurine.

PMID- 12479646
TI  - Response of refractory colitis to intravenous or oral tacrolimus (FK506).
AB  - Intravenous cyclosporine has proven to be an alternative to emergency colectomy
      in steroid-refractory ulcerative colitis, whereas the experience with FK506 is
      limited. In this report we compare intravenous to oral FK506 treatment in 38
      patients with refractory ulcerative (n = 33) or indeterminate (n = 5) colitis.
      FK506 was started intravenously in the first group (n = 18) at a dose of 0.01 to
      0.02 mg/kg up to 14 days, followed by 0.1 to 0.2 mg/kg orally, or was started
      orally at this dose in a second group (n = 20). Additional azathioprine/6
      mercaptopurine was given and steroids were tapered in responding patients,
      followed by a dose reduction of FK506. Clinical disease activity and laboratory
      parameters were assessed to evaluate efficacy and safety. Primary objectives were
      the induction of remission (Truelove index of mild) and colectomy-free survival.
      Treatment lasted for a mean of 7.6 months, and the mean observation period was
      16.2 months. Eighteen of 38 patients improved within 14 days, and a complete
      remission was achieved in 13 patients after 1 month. A colectomy within 1 month
      was performed in 3 of 38 patients. The overall colectomy rate was 34%. One-half
      of the patients with a minimum follow-up of 2 years required a colectomy.
      Intravenous and per oral administration were equally safe and effective. The most
      frequent adverse events included tremor, hyperglycemia, hypertension, and
      infection, but none were severe. Renal impairment was rare and subsided upon drug
      withdrawal. In conclusion. FK506 is effective in the treatment of refractory
      colitis with per oral dosing being equivalent to intravenous administration.

PMID- 12479647
TI  - Role of serology and routine laboratory tests in childhood inflammatory bowel
      disease.
AB  - INTRODUCTION: Serology is reported to be helpful in evaluating children for
      inflammatory bowel disease (IBD), and distinguishing chronic ulcerative colitis
      (CUC) from Crohn's disease (CD). The markers include perinuclear staining
      antineutrophil cytoplasmic antibody (pANCA) for CUC and anti-Saccharomyces
      cerevisiae antibody (ASCA) for CD. In the clinical setting, hemoglobin (Hgb) and
      erythrocyte sedimentation rate (ESR) are commonly performed for screening
      symptomatic children for IBD. We examined whether there was an additional benefit
      of serology in addition to specific symptoms and routine laboratory tests in
      screening for IBD. METHOD: Medical record data was reviewed on children
      investigated for IBD from February 1999 to April 2001. Children were included if
      they had blood analyzed for pANCA and ASCA, Hgb, ESR, and colonoscopy as part of
      their assessment. RESULTS: Of 177 cases reviewed, 51 were diagnosed with CUC, 39
      with CD, and 26 other inflammatory conditions. Visible rectal bleeding was the
      most discriminating symptom (occurred in 60/90 cases of IBD and 5/61 without
      IBD). There was a significant difference between the proportion with CUC positive
      for pANCA (42/51) and those with abnormal Hgb and ESR (30/51) (p < 0.05), but not
      between children with CD who were ASCA positive (18/39) and those with abnormal
      Hgb and ESR (26/39) (p = 0.27). The sensitivity and specificity of combined pANCA
      and ASCA was 68% and 92%, respectively. For the combination of Hgb, ESR, and the
      presence of rectal bleeding the respective values were 86% and 67%. Serology
      combined with Hgb and ESR and rectal bleeding as independent factors
      significantly (p < 0.05) improved sensitivity (89%) but reduced specificity
      (60%). Screening with the combination of rectal bleeding, Hgb, and ESR identified
      86% (77/90) patients with IBD prior to an endoscopic procedure. A further 3 of 90
      (3.3%) screened positive with the addition of serology. CONCLUSION: Serology
      tests have a high degree of specificity for IBD while routine laboratory test
      have a higher sensitivity. When serology is combined with rectal bleeding, Hgb,
      and ESR, the sensitivity of screening children for IBD is significantly improved.
      However the large majority of children with IBD can be identified with a clinical
      history and routine laboratory tests as needing an endoscopic procedure with
      little benefit of adding serology.

PMID- 12479648
TI  - Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2
      cytokine response and prevent acute colitis.
AB  - Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of a
      nuclear transcription factor family, has been previously demonstrated to have
      antiinflammatory activity. The effects of PPARgamma activation in the development
      of an immune response are less well characterized. Through evaluation of
      PPARgamma heterozygote mice (PPARgamma(+/-) and specific PPARgamma agonist ligand
      binding, we evaluated the immunologic effects of PPARgamma activation in a well
      described model of colitis. Increased susceptibility to dextran sodium sulfate
      (DSS)-induced colitis as defined by body weights, histologic injury, and survival
      was observed in the PPARgamma(+/-) mice in comparison to wild-type mice. Three
      different PPARgamma ligands (troglitazone, pioglitazone, and rosiglitazone)
      demonstrated beneficial dose-related treatment effects when administered prior to
      the onset of colitis. However, no protection was observed when PPARgamma ligand
      activation occurred after the onset of colitis. The reduction in DSS-induced
      inflammation noted with PPARgamma ligand treatment was associated with decreased
      interferon-gamma and tumor necrosis factor-alpha and increased interleukin (IL)-4
      and IL- 10 levels as assessed by quantitative reverse transcriptase-polymerase
      chain reaction. Consistent with this shift towards a T helper (Th2) cytokine
      dominance, PPARgamma ligand treatment stimulated increased GATA-3 expression.
      These results indicate that the protective effects exhibited by PPARgamma ligands
      in intestinal inflammation may be due to immune deviation away from Th1 and
      towards Th2 cytokine production.

PMID- 12479649
TI  - Potato glycoalkaloids adversely affect intestinal permeability and aggravate
      inflammatory bowel disease.
AB  - BACKGROUND: Disruption of epithelial barrier integrity is important in the
      initiation and cause of inflammatory bowel disease (IBD). Glycoalkaloids,
      solanine (S), and chaconine (C) are naturally present in potatoes, can
      permeabilize cholesterol-containing membranes, and lead to disruption of
      epithelial barrier integrity. Frying potatoes concentrates glycoalkaloids.
      Interestingly, the prevalence of IBD is highest in countries where fried potatoes
      consumption is highest. OBJECTIVE: To further understand the role of potato
      glycoalkaloids on intestinal barrier integrity, we examined the effect of varying
      concentrations of solanine and chaconine on intestinal permeability and function.
      METHODS: Solanine (0-50 microM), chaconine (0-20 microM), or a 1:1 mixture (0-20
      microM) were exposed to T84 cultured epithelial monolayers for varying periods of
      time to determine concentration response effect on epithelial permeability. Next,
      a 1:1 mixture (5 microM) of solanine-to-chaconine (C:S) was exposed to sheets of
      normal murine small intestine, mounted in Ussing chambers, from control and
      interleukin-10 gene-deficient mice to determine whether glycoalkaloids affected
      intestine from mice with a genetic predisposition for IBD greater than controls.
      Finally, the effects of glycoalkaloids on colonic histologic injury were examined
      in mice orally fed amounts of glycoalkaloids that would normally be consumed in a
      human diet. RESULTS: Glycoalkaloids embedded and permeabilized the T84 monolayer
      epithelial membrane bilayer in a concentration-dependent fashion, with C:S > C >
      S. In vitro Ussing chamber experiments also illustrated a concentration-dependent
      disruption of intestinal barrier integrity in animals with a genetic
      predisposition to develop IBD, but not in control animals. Similarly, in vivo
      oral feeding experiments demonstrated that C:S ingestion, at physiologic
      concentrations, aggravated histologic colonic injury in mice genetically
      predisposed to developing IBD. CONCLUSION: Concentrations of glycoalkaloids
      normally available while eating potatoes can adversely affect the mammalian
      intestine and can aggravate IBD.

PMID- 12479650
TI  - Genetic and environmental context determines the course of colitis developing in
      IL-10-deficient mice.
AB  - This review summarizes how interleukin-10 (IL-10)-deficient mice have permitted
      new insight into the complex interaction between genes and environment underlying
      pathogenesis of inflammatory bowel disease (IBD). The C57BL/6J strain develops
      only mild typhlocolitis in response to IL-10 deficiency. In contrast, C3H/HeJBir
      represents an unrelated inbred strain with high IBD susceptibility. Ability to
      identify quantitative trait loci segregating for susceptibility when the two IL
      10-deficient stocks were intercrossed depended both on genome "context" (F2
      versus reciprocal backcrosses) and on the physical environment. These findings
      are discussed in the context of recent advances in understanding the complex
      genetic basis for IBD in humans.

PMID- 12479651
TI  - Cancer prevention in inflammatory bowel disease and the chemoprophylactic
      potential of 5-aminosalicylic acid.
AB  - The risk of colorectal cancer is increased in ulcerative colitis and Crohn's
      colitis. Regular dysplasia surveillance colonoscopy in chronic colitis generally
      has been adopted as a strategy to prevent colorectal cancer or at least to
      diagnose it in an earlier stage. This has not been proven to reduce mortality,
      but it does provide the clinician and the patient with some confidence that they
      are participating in an active strategy to deal with the problem of colorectal
      cancer in chronic colitis. Disease extent and duration have long been held to be
      risk factors for colorectal cancer in chronic colitis, and recently some special
      risk groups have been identified which may require either more intensive
      surveillance or alternative approaches to cancer prevention. These include
      patients with primary sclerosing cholangitis, patients with first-degree
      relatives with sporadic colon cancer, and possibly, patients with backwash
      ileitis. There is an emerging interest in potential chemopreventative strategies
      in both sporadic and colitis-associated colorectal cancer. There also have been
      suggestive data that chronic maintenance 5-aminosalicylate use might reduce the
      risk of developing colorectal cancer. Recent data have suggested some potential
      preventative benefit of using ursodeoxycholic acid in patients with ulcerative
      colitis and primary sclerosing cholangitis. The scientific rationale for using
      these agents is sound but clinical data are lacking to fully support these
      approaches as chemoprevention in chronic colitis at present.

PMID- 12479652
TI  - Is ileoanal the proper operation for indeterminate colitis: the case for.

PMID- 12479653
TI  - Is ileoanal the proper operation for indeterminate colitis: the case against.

PMID- 12479654
TI  - Lowering the stress of inflammatory bowel disease.

PMID- 12479655
TI  - IBD5: the second Crohn's disease gene?

PMID- 12479656
TI  - Perhaps we can, but should we?

PMID- 12479657
TI  - Irritable-inflammatory bowel disease: recognizing a new overlap syndrome and an
      enigma wrapped inside a puzzle.

PMID- 12479658
TI  - Clinical indicators for the use of antidepressants in the treatment of bipolar I
      depression.
AB  - OBJECTIVES: Current guidelines provide little practical information on the
      clinical characteristics of bipolar I patients who are likely to benefit from the
      combination of a mood stabilizer and an antidepressant. Rather, guidelines simply
      state that an adjunctive antidepressant is recommended in cases of 'severe'
      depression. Our objective was to evaluate the clinical and demographic
      differences between patients who remitted on a mood stabilizer alone and patients
      who subsequently required an adjunctive antidepressant to achieve stabilization.
      METHODS: We retrospectively compared the pharmacological treatment strategies of
      39 patients with bipolar I disorder who were in a current depressive episode.
      Patients who did not respond to mood stabilizer monotherapy were prescribed an
      adjunctive antidepressant. We evaluated the clinical differences at baseline and
      week 1, 2 and 3 of treatment between patients stabilizing on a mood stabilizer
      alone and patients that did not remit until they subsequently received an
      adjunctive antidepressant. RESULTS: Patients who required an adjunctive
      antidepressant had significantly higher total Hamilton Depression Rating (HRS-D)
      scores at week 1, 2 and 3 of treatment, but not at baseline. Patients who
      remitted on mood stabilizer monotherapy were more likely to be married, achieved
      stabilization in less time, presented with higher Young Mania Rating Scale (YMRS)
      scores, and experienced the previous episode of depression more recently than
      patients who required an antidepressant. CONCLUSIONS: Our findings suggest that
      rapid improvement after achieving a therapeutic dose of a mood stabilizer is
      clinically significant and represents a surrogate endpoint in the treatment of
      bipolar I depression. Larger, prospective, and controlled studies are needed to
      verify our results and to identify additional indicators for a mood stabilizer
      and antidepressant combination treatment strategy.

PMID- 12479659
TI  - Tiagabine in treatment refractory bipolar disorder: a clinical case series.
AB  - OBJECTIVES: Anticonvulsants have provided major treatment advances for patients
      with bipolar disorder. Many of these drugs, including several with proven
      efficacy in bipolar mania or depression, enhance the activity of the gamma-amino
      butyric acid (GABA) neurotransmitter system. A new anticonvulsant, tiagabine, has
      selective GABAergic activity and is approved for patients with partial epilepsy.
      Few reports of its potential effectiveness in bipolar disorder, however, have
      been published. We sought to evaluate the effectiveness of tiagabine added to
      ongoing medication regimens in patients with bipolar disorder inadequately
      responsive to or intolerant of usual treatments. METHODS: Seventeen treatment
      refractory patients participating in the Stanley Foundation Bipolar Network
      (SFBN) long-term follow-up study were offered open treatment with add-on
      tiagabine after discussion of the risks, benefits, other treatment options and
      giving informed consent. Patients' clinical symptoms and somatic complaints were
      closely monitored with SFBN longitudinal and cross-sectional ratings. Four
      patients discontinued low-dose tiagabine prior to the second visit and were
      excluded from data analysis. RESULTS: Thirteen patients received a mean of 38
      days of treatment at a mean dose of 8.7 mg/day of tiagabine. On the Clinical
      Global Impression Scale for Bipolar Disorder Overall category, three (23%)
      patients showed much or very much improvement and 10 (77%) patients showed no
      change or worsening. Three significant adverse events were noted, including two
      presumptive seizures. CONCLUSIONS: Open add-on tiagabine for treatment-refractory
      patients with bipolar disorder demonstrated limited efficacy with the majority of
      patients showing no change or worsening of clinical symptoms. In addition,
      patients experienced serious side-effects attributed as likely due to the
      medication, which resolved without lasting consequence when tiagabine was
      discontinued.

PMID- 12479660
TI  - Laterality of pain in migraine with comorbid unipolar depressive and bipolar II
      disorders.
AB  - OBJECTIVES: The purpose of the present study has been to examine differences in
      the laterality of pain in patients with migraine and comorbid unipolar depressive
      (UP) and bipolar II (BP II) disorders. METHODS: Semi-structured interviews of 102
      patients with major affective disorders were conducted, using DSM-IV criteria for
      affective disorders combined with Akiskal's criteria for affective temperaments
      and International Headache Society criteria for migraine. The group of patients
      reported on in the present study encompass 47 subjects with UP (n = 24) or BP 11
      (n = 23) disorders. Fifteen of the bipolar II patients fulfilled DSM-IV criteria
      while eight were diagnosed according to the broader criteria of Akiskal. RESULTS:
      Sixteen of the 38 patients with migraine headaches had bilateral pain or pain
      equally often on the left or right side while 22 had pain predominantly located
      on one side. Among the UP patients the pain was most often on the right side
      (8/10) while among the BP II patients the pain was most often on the left (9/12,
      p = 0.01). Apart from the presence of hypomanic symptoms in the BP II group there
      were no clinical or demographic characteristics that distinguished these two sub
      groups of affective disorders. CONCLUSIONS: These results indicate that there may
      be a differential affection of the cerebral hemispheres in patients with migraine
      and comorbid unipolar depressive disorder versus patients with migraine and
      comorbid bipolar II disorder.

PMID- 12479661
TI  - Gabapentin augmentation therapy in bipolar depression.
AB  - BACKGROUND: Gabapentin (GBP) may be useful in bipolar disorders, including as
      adjunctive therapy for bipolar depression, although controlled studies suggest
      inefficacy as primary treatment for mania or treatment-resistant rapid cycling.
      METHODS: We performed a 12-week trial of open GBP (mean dose 1725 mg/day) added
      to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women,
      mean age 38.4 years) depressed (28-item Hamilton Depression Rating Scale (HDRS) >
      18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness
      duration was 18.6 years, current depressive episode duration was 18.0 weeks.
      Prospective 28-item HDRS, Young Mania Rating Scale (YMRS) and Clinical Global
      Impression-Severity (CGI-S) ratings were obtained. RESULTS: Overall, HDRS ratings
      decreased 53% from 32.5 +/- 7.7 at baseline to 16.5 +/- 12.8 at week 12 (p <
      0.0001). Twelve of 22 (55%) patients had moderate to marked improvement (HDRS
      decrease = 50%) with HDRS decreasing 78% from 27.9 +/- 6.2 to 6.2 +/- 4.5 (p <
      0.0001). Eight of 22 (36%) patients remitted (HDRS > or = 8). In non-responders,
      HDRS decreased from 38.0 +/- 5.4 to 28.9 +/- 6.7 (p = 0.005). Ten of 13 (77%)
      mild to moderately depressed (baseline HDRS > 18 and <35) patients responded,
      while only two of nine patients (22%) with severe depression (HDRS > or = 35)
      responded (p < 0.03). Both groups, however, had similar, statistically
      significant HDRS decreases. GBP was well tolerated. CONCLUSION: Open adjunctive
      GBP was effective and well tolerated in patients with mild to moderate bipolar
      depression. This open pilot study must be viewed with caution, and randomized
      controlled studies are warranted.

PMID- 12479662
TI  - 3'(2')-phosphoadenosine 5'-phosphate phosphatase is reduced in postmortem frontal
      cortex of bipolar patients.
AB  - OBJECTIVE: 3'(2')-Phosphoadenosine 5'-phosphate (PAP) phosphatase is a novel
      lithium (Li) inhibitable enzyme. Thus the enzyme seemed an important candidate
      for studies of the molecular etiology of bipolar disorder. METHODS: RT-PCR,
      Western-blot analysis and Pi liberation were used to measure PAP phosphatase mRNA
      levels, protein levels and enzyme activity (respectively) in postmortem frontal
      cortex specimens of bipolar patients versus normal subjects. RESULTS: The PAP
      phosphatase protein levels were 24% significantly lower in bipolar patients than
      in normal subjects. PAP phosphatase mRNA levels and enzymatic activity did not
      differ between normal controls and bipolar patients. CONCLUSIONS: Abnormality of
      PAP phosphatase in bipolar patients offers a new direction for study of bipolar
      disorder etiology.

PMID- 12479663
TI  - Pramipexole in treatment-resistant depression: a 16-week naturalistic study.
AB  - OBJECTIVE: To assess the antidepressant efficacy and tolerability of adjunctive
      pramipexole, a D2-D3 dopamine agonist, in patients with drug-resistant
      depression. METHODS: The study sample consisted of in-patients with major
      depressive episode, according to the DSM-IV, and drug resistance. Pramipexole was
      added to antidepressant treatment with TCA or SSRI, at increasing doses from
      0.375 to 1.0 mg/day. Two independent response criteria were adopted: a > 50%
      reduction of the Montgomery-Asberg Depressive Rating Scale (MADRS) total score
      and a score of I or 2 on the Clinical Global Impression scale (CGI-1) at
      endpoint. Side-effects were assessed by the Dosage Record Treatment Emergent
      Symptom Scale (DOTES). RESULTS: Thirty-seven patients were enrolled. Of these. 16
      had unipolar depression and 21 had bipolar depression. Six patients dropped out
      in the first week. Of the 31 patients included in the analyses. 19 completed the
      16-week follow-up. Mean maximal dose of pramipexole was 0.95 mg/day. Mean scores
      on MADRS decreased from 33.3 +/- 8.4 at baseline to 13.9 +/- 11.5 at endpoint (p
      < 0.001) and the CGI-S decreased from 4.6 +/- 0.8 at baseline to 2.8 +/- 1.3 at
      endpoint (p < 0.001). At endpoint, 67.7% (21/31) of patients were responders on
      MADRS and 74.2% on CGI-I. Of the 37 patients enrolled, 10 discontinued
      pramipexole because of adverse events. CONCLUSIONS: These preliminary data
      suggest that pramipexole adjunction to antidepressant treatment may be effective
      and well tolerated in patients with resistant major depression.

PMID- 12479664
TI  - Insight into illness in patients with mania, mixed mania, bipolar depression and
      major depression with psychotic features.
AB  - BACKGROUND: Poor insight into illness is a common feature of bipolar disorder and
      one that is associated with poor clinical outcome. Empirical studies of illness
      awareness in this population are relatively scarce with the majority of studies
      being published over the previous decade. The study reported here sought to
      replicate previous report findings that bipolar patients frequently show high
      levels of poor insight into having an illness. We also wanted to examine whether
      group differences in insight exist among bipolar manic, mixed and unipolar
      depressed patients with psychotic features. METHODS: A cohort of 147 inpatients
      with DSM-III-R bipolar disorder and 30 with unipolar depression with psychotic
      features, were evaluated in the week prior to discharge using the Structured
      Clinical Interview for DSM-III-R-Patient Edition (SCID-P), the Brief Psychiatric
      Rating Scale (BPRS) and the Scale to assess Unawareness of Mental Disorder
      (SUMD). RESULTS: Insight into specific aspects of the illness was related to the
      polarity of mood episode: patients with mania showed significantly poorer insight
      compared with those with mixed mania, bipolar depression and unipolar depression.
      A linear regression analysis using SUMD score as the dependent variable and
      symptoms of mania as the independent variable found that specific manic symptoms
      did not account for level of insight. Similar results were obtained when the mean
      insight scores of patients with and without grandiosity were contrasted.
      CONCLUSIONS: We hypothesize that the lack of association between level of insight
      and total number of manic symptoms or with specific manic symptoms may be related
      to the persistence of subsyndromal symptoms in patients remitting from a manic
      episode.

PMID- 12479665
TI  - A clinical monitoring form for mood disorders.
AB  - OBJECTIVE: The Clinical Monitoring Form (CMF) for mood disorders was developed as
      a time efficient record keeping tool for routine clinical use. This report
      presents preliminary data evaluating the correlation between the CMF's
      dimensional subscales for depression and mood elevation and formal mood rating
      scales across a wide spectrum of mood states. METHODS: To harvest data for 500
      follow-up visits required collection of data from consecutive records accumulated
      during the conduct of seven double blind clinical trials involving a total of 58
      participants. These trials utilized the CMF as a source document in conjunction
      with formal study outcome scales, e.g. Hamilton Rating Scale for Depression
      (HRSD), the Montgomery-Asberg Depression Rating Scale (MADRS), the Young Mania
      Rating Scale (YMRS) and the Mania Rating Scale (MRS) from the Schedule of
      Affective Disorders-Current (SUM-C). Correlation coefficients were calculated to
      examine the relationship between the formal rating scales, Clinical Global
      Impression and the depression (SUM-D) and mood elevation (SUM-ME) subscales of
      the CMF. RESULTS: Robust correlations were observed between SUM-D and the formal
      depression scales, HRSD and MADRS, r = 0.79, r = 0.88. respectively. Similar
      robust correlations were also found between the SUM-ME and the formal mood
      elevation scales, YMRS and the MRS, r = 0.84, r = 0.86, respectively. CONCLUSION:
      The CMF appears to offer a reasonable alternative to the formal rating scales
      typically used in research studies.

PMID- 12479666
TI  - Olanzapine in diverse syndromal and subsyndromal exacerbations of bipolar
      disorders.
AB  - OBJECTIVE: To evaluate effects of olanzapine in diverse exacerbations of bipolar
      disorders. METHODS: Twenty-five evaluable bipolar disorder [14 bipolar I (BPI),
      10 bipolar II (BPII) and one bipolar disorder not otherwise specified (BP NOS)]
      outpatients received open olanzapine (15 adjunctive, 10 monotherapy). Thirteen
      had elevated (11 syndromal, two subsyndromal) and 12 depressed (four syndromal,
      eight subsyndromal) mood symptoms of at least mild severity, with Clinical Global
      Impression-Severity (CGI-S) scores of at least 3. Only one had psychotic
      symptoms. RESULTS: With open olanzapine (15 adjunctive, 10 monotherapy), overall
      symptom severity (CGI-S) as well as mood elevation (Young Mania Rating Scale),
      depression (Hamilton and Montgomery-Asberg Depression Rating Scales), and anxiety
      (Hamilton Anxiety Rating Scale), rapidly decreased (significantly by days 2-3).
      Patients with the greatest baseline severity (CGI-S) had the greatest
      improvement. Fifteen of 25 (60%) patients responded. Time to consistent response
      was bimodal, with five early (by 0.5 +/- 0.3 weeks) and 10 late (by 7.0 +/- 1.9
      weeks) responders. Early compared with late responders had 51% lower final
      olanzapine doses. Olanzapine was generally well tolerated, with sedation and
      weight gain the most common adverse effects. CONCLUSIONS: Olanzapine was
      effective in diverse exacerbations of bipolar disorders. The bimodal distribution
      of time to response and different final doses are consistent with differential
      mechanisms mediating early compared with late responses. Controlled studies are
      warranted to further explore these preliminary observations.

PMID- 12479668
TI  - A pilot study of loading versus titration of valproate in the treatment of acute
      mania.
AB  - OBJECTIVE: This double-blind pilot study compares the effectiveness and incidence
      of adverse effects of oral loading versus titration schedules of valproate in
      acute mania. METHOD: Consecutive new admissions for an acute manic episode were
      prescribed either an oral loading dose (20 mg/kg/day; n = 5; mean age = 33.4) or
      slower titration dose (10 mg/kg/day, n = 6. mean age = 30.6) of valproate for 7
      days without other psychotropic agents. with the exception of benzodiazepines.
      Daily outcome measures included: serum valproic acid levels, the Young Mania
      Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical
      Global Impression Scale (CGI) and the Adverse Effect Rating Scale. RESULTS: The
      mean serum valproic acid levels were significantly higher in the loading group
      when compared with the titration group after 1 and 2 days following the
      initiation of treatment (p < 0.05). After 3 days of treatment there was a trend
      for the group that received the loading regimen to have slightly more improvement
      in YMRS scores compared with the titration group. Side-effects were minor for
      both treatments, however, a higher incidence of side-effects was reported in the
      titration group, with 50% of patients reporting sedation most likely because of
      increased use of benzodiazepines. CONCLUSION: This suggests that a loading dose
      of valproate is likely safe and may provide an earlier onset of antimanic effects
      in patients with bipolar disorder. Future studies with larger sample sizes are
      indicated.

PMID- 12479667
TI  - Quetiapine in the treatment of rapid cycling bipolar disorder.
AB  - INTRODUCTION: This prospective open-label study assessed the impact of add-on
      quetiapine in the treatment of rapid cycling bipolar patients. METHODS: Fourteen
      rapid cycling bipolar patients were treated with quetiapine, which was added to
      their ongoing medication regimen for 112 +/- 33 days. At the beginning of the
      study, five were manic, three were in a mixed state, three were depressed, two
      hypomanic and one was euthymic. Patients were assessed prospectively with a
      modified version of the Clinical Global Impression Scale for Bipolars (CGI-BP),
      the Young Scale for mania (YMRS) and the Hamilton Scale for Depression (HDRS).
      RESULTS: A significant reduction of the following scale scores was observed: a
      1.8 point reduction for the general CGI-BP (p = 0.013), a -1.3 point for the
      mania subscale (p = 0.016), a -1.01 point for the YMRS (p = 0.025). Improvement
      in depressive symptoms was not significant, neither in the CGI-BP (-1 point, p =
      0.074) nor in the HDRS (-5.2 points, p = NS). The most common side-effect was
      sedation (n = 6, 43%). Doses of quetiapine were significantly reduced by the end
      of the study (443 +/- 235 mg/day versus 268 +/- 190 mg/day, p = 0.008) and they
      also differed according to the initial episode to be treated (720 +/- 84 mg/day
      for mania, and 183 +/- 29 mg/day for depression, p = 0.023). CONCLUSIONS:
      Quetiapine could possibly be an effective treatment for rapid cycling bipolar
      patients. Adequate doses for acute episodes could significantly differ according
      to the episode polarity and the length of treatment.

PMID- 12479669
TI  - A new bipolar spectrum concept: a brief review.
AB  - Research on the broad bipolar spectrum is dependent on the definition of
      hypomania. We recently proposed a new, softer syndromal definition with clinical
      validity. This broadens the diagnosis of bipolar II (BP-II) disorder at the
      expense of major depressive disorder (MDD). There is evidence for a third group
      of suspected BP-II manifesting major depression plus hypomanic symptoms. The two
      bipolar-II groups together are as prevalent as MDD. A new concept of minor
      bipolar disorder embracing dysthymia, minor and recurrent brief depression with
      hypomanic syndromes and symptoms is discussed. Some methodological pitfalls of
      research on drug-induced hypomania as an element of the bipolar spectrum are also
      summarized.

PMID- 12479670
TI  - Myo-inositol-1-phosphate (MIP) synthase: a possible new target for antibipolar
      drugs.
AB  - Inositol metabolism is well characterized in yeast at a molecular level, and
      yeast is the only eukaryote in which genetic, molecular and functional genomic
      approaches to identify lithium. valproate and inositol targets may be combined
      readily. It has been shown that lithium inhibits yeast inositol monophosphatase
      (encoded by INM1 and INM2), and both valproate and lithium reduce intracellular
      inositol. Unlike lithium, valproate causes a decrease in intracellular inositol-1
      phosphate as well. suggesting that myo-inositol-1-P (MIP) synthase is a site of
      valproate action in the yeast PI cycle. MIP synthase is the rate-limiting step in
      inositol biosynthesis and is highly regulated in response to inositol. Yeast
      genes that are affected by both lithium and valproate in the phosphoinositide
      pathways (INO1 increased over 10-fold, INO2 increased twofold and INM1 decreased
      about twofold) have been identified. It has also been reported previously that
      both lithium and inositol mildly up-regulate IMPA1 (encoding mammalian inositol
      monophosphatase) expression in human cells. These findings indicate that IMPA is
      regulated only mildly by lithium, and therefore may not be the major target in
      the inositol pathway. Given the substantial evidence for the role of inositol in
      the mechanism of action of lithium and valproate. the opposing and mild effects
      of lithium on the genes encoding inositol monophosphatase in yeast and human
      cells, but the powerful effect of lithium and valproate on INO1 in yeast, it is
      hypothesized that human hIANO1 is a factor in the psychopharmacology of mood
      stabilizers.

PMID- 12479671
TI  - Bipolar disorders and suicidal behaviour.
AB  - Major depressive disorder is the leading cause of suicide, particularly in the
      absence of adequate treatment. The aim of this paper is to analyse the
      relationship between different forms of major mood disorders and suicidal
      behaviour. Population-based epidemiological surveys as well as clinical studies
      on the clinically explorable suicide risk factors in bipolar and unipolar
      depressive disorders are reviewed. The present literature shows that patients
      with bipolar disorders are at higher risk of attempted and completed suicide than
      that of patients with unipolar major depression. Contrasting only bipolar I and
      bipolar II patients, current findings indicate that the rate of prior suicide
      attempt is higher in bipolar II patients, and bipolar II disorder is
      overrepresented in depressed suicide victims. Among patients with different
      clinical manifestations of major mood disorders (unipolar major depression.
      bipolar I and bipolar II disorder), bipolar patients in general, and bipolar II
      subjects in particular carry the highest risk of suicide.

PMID- 12479672
TI  - The volumetric findings in MRI brain study of bipolar twins and their healthy co
      twins.

PMID- 12479673
TI  - Evaluation of parent-of-origin effect in bipolar affective disorder relating to
      susceptibility loci on chromosome 18.

PMID- 12479674
TI  - Prevalence of bipolar disorder: a further study in The Netherlands.

PMID- 12479676
TI  - Predictors of outcome in a representative population of bipolar disorder.

PMID- 12479675
TI  - First episode bipolar disorder: systematic comparison of incidence with other
      affective and non-affective psychoses among an epidemiologically complete, rural
      population.

PMID- 12479677
TI  - Dimensions of psychopathology in bipolar disorder versus other affective and non
      affective psychoses among an epidemiologically complete population.

PMID- 12479678
TI  - Does inositol signalling have a role in disease susceptibility and drug treatment
      of bipolar disorder?

PMID- 12479679
TI  - Do we need placebo control in maintenance studies in bipolar disorders?

PMID- 12479680
TI  - Can we conduct some large simple trials in bipolar disorder?

PMID- 12479681
TI  - Outcome measures in treatment trials in bipolar disorder.

PMID- 12479682
TI  - Limits of the applicability and generalizability of drug trials in mania.
AB  - During recent years, the majority of drug trials in mania have been conducted for
      the purpose of drug approval. On this background, this paper addresses to what
      extent these trials may actually provide the practising clinician with useful
      information. One major point is that selection prior to the point of
      randomization in RCTs in mania may limit the applicability of study results to
      patients seen in ordinary clinical practice. Limitations in study credibility and
      study design are also discussed. The need for large scale pragmatic studies using
      broad inclusion criteria, comparing the various treatments, alone or in
      combination, is emphasized.

PMID- 12479683
TI  - Gene expression in bipolar disorder and schizophrenia: new approaches to old
      problems.

PMID- 12479684
TI  - Immune activation, steroid resistancy and bipolar disorder.

PMID- 12479685
TI  - Expression of G-proteins and regulators of G-protein signalling in neutrophils of
      patients with bipolar disorder: effects of mood stabilizers.

PMID- 12479686
TI  - Subtraction libraries for the molecular characterization of gene-environmental
      interactions in bipolar disorder.
AB  - OBJECTIVES: We endeavoured to identify gene-environmental interactions related to
      bipolar disorder. METHODS: We generated subtraction libraries from the frontal
      cortex of brains obtained postmortem from individuals with bipolar disorder and
      age- and sex-matched unaffected controls. RESULTS: There are a number of RNA
      transcripts which are apparently up-regulated or down-regulated in the frontal
      cortex of individuals with bipolar disorder as compared with the controls. Many
      of these transcripts are involved in processes crucial to brain function. Several
      are also related to pathways involved in infections or the inflammatory response
      in environmental stimuli. CONCLUSIONS: Bipolar disorder may involve a complex set
      of interactions between genes which affect brain function and infections which
      control the expression of these genes.

PMID- 12479687
TI  - Infection, treatment and immune response in patients with bipolar disorder versus
      patients with major depression, schizophrenia or healthy controls.
AB  - Bipolar disorder is the least studied among the three major psychiatric disorders
      of schizophrenia, major depression and bipolar disorder. Furthermore,
      investigations on infection and immunity in bipolar disorder make up only a small
      portion of the sparse research done on this disorder. However, there are reports
      that modulation of the immune system and certain infections might be associated
      with bipolar disorder and that there might be differences between bipolar and the
      other disorders. The purpose of this paper is to briefly review published data on
      these issues in bipolar versus the other disorders, and to present an ongoing
      clinical study on the putative involvement of infection with the parasite
      Toxoplasma gondii in these three major psychiatric disorders.

PMID- 12479688
TI  - Response to ECT in major depression: are there differences between unipolar and
      bipolar depression?

PMID- 12479689
TI  - Transcranial magnetic stimulation in patients with bipolar depression: a double
      blind, controlled study.

PMID- 12479690
TI  - Transcranial magnetic stimulation and neuroimaging.

PMID- 12479691
TI  - Transcranial direct current stimulation: a new treatment for depression?

PMID- 12479692
TI  - The mechanism of action of psychotherapy.

PMID- 12479693
TI  - Life charts on a palmtop computer: first results of a feasibility study with an
      electronic diary for bipolar patients.

PMID- 12479694
TI  - Thyroid hormone augmentation with levothyroxine in bipolar depression.

PMID- 12479695
TI  - Interferon-alpha, cytokines and possible implications for mood disorders.

PMID- 12479696
TI  - Targeting the neurophysin-related cell surface antigen on small cell lung cancer
      cells using a monoclonal antibody against the glycopeptide region (MAG-1) of
      provasopressin.
AB  - The vasopressin (VP) gene is largely expressed in hypothalamic neurons, where the
      resultant pro-VP protein is enzymatically cleaved into its peptide hormone
      components, which include the neuropeptide VP, VP-associated neurophysin, and VP
      associated glycopeptide (VAG). Small cell lung cancer (SCLC) tumors also express
      the VP gene, but the tumor pro-VP protein can remain intact and localize to the
      cell surface membrane. Previous studies have shown that polyclonal antibodies
      directed against different regions of the pro-VP protein bind specifically to the
      surface of cultured SCLC cells and recognize proteins of approximately 20 and
      approximately 40 kDa in cultured SCLC whole-cell lysate. Thus, these proteins
      have been designated neurophysin-related cell surface antigen (NRSA). A
      monoclonal antibody (mAb) designated MAG-1 was raised in this laboratory using a
      synthetic peptide representing the COOH-terminal sequence of VAG. The MAG-1 mAb
      recognizes NRSA in SCLC cell and tissue lysates by Western analysis, whereas
      immunofluorescent cytometric and microscopic analyses indicate that MAG-1 reacts
      specifically with NRSA on the surface of viable SCLC cells of both the classical
      and the variant subtype. Immunohistochemical analysis demonstrates that MAG-1
      reacts with human SCLC tumor, but not with normal pulmonary epithelial cells in
      lung tissue. Additionally, a MAG-1 Fab fragment was generated that was also able
      to recognize NRSA. This is the first study to demonstrate that a mAb directed to
      the VAG region of the pro-VP protein has the potential for development into an in
      vivo diagnostic and therapeutic tool that targets plasma membrane-incorporated
      NRSA.

PMID- 12479697
TI  - Indole-3-carbinol inhibits protein kinase B/Akt and induces apoptosis in the
      human breast tumor cell line MDA MB468 but not in the nontumorigenic HBL100 line.
AB  - We have identified a new target for the chemopreventive dietary agent indole-3
      carbinol (13C) in the antiapoptotic signaling pathway involving
      phosphatidylinositol 3'-kinase and protein kinase B (PKB)/Akt. 13C inhibited
      phosphorylation and activation of PKB in the tumor-derived breast cell line MDA
      MB468, but not in the immortalized breast line HBL100. We propose that this cell
      type-specific response to 13C contributes to the differential induction of
      apoptosis and sensitivity to growth inhibition of the two cell lines (approximate
      IC50 = 30 microM for the MDA MB468 line, compared with 120 microM for the HBL100
      line). 13C only induced apoptosis in the MDA MB468 cell line, but at higher
      doses, it increased necrosis in the HBL100 line. The tumor cell line was also
      markedly less able to recover when 13C was removed from the culture medium.
      Downstream of PKB, 13C decreased nuclear factor kappaB DNA binding, independently
      of an effect on IkappaB kinase, in the MDA MB468 cell line only. The tumor
      suppressor PTEN, which prevents phosphorylation and activation of PKB, was
      expressed in HBL100 cells but was not detected in MDA MB468 cells. In
      corroboration of the results obtained with the breast cell lines, 13C decreased
      phospho-PKB levels and induced apoptosis in the prostate cell line LNCaP, which
      expresses very low levels of PTEN, but did not do so in PTEN-positive DU145
      cells. 13C did not affect PTEN levels in any cell line. This is the first study
      to report a differential mechanistic response of tumor-derived and nontumorigenic
      cell lines and of PTEN high- and low-expressing cells to 13C and indicates a
      promising chemopreventive role for 13C against estrogen receptor-alpha-negative,
      aggressive-phenotype breast tumors.

PMID- 12479698
TI  - Targeting the tumor microenvironment with chemically modified tetracyclines:
      inhibition of laminin 5 gamma2 chain promigratory fragments and vasculogenic
      mimicry.
AB  - The laminin 5 (Ln-5) gamma2 chain and matrix metalloproteinases (MMPs) MMP-2 and
      membrane type 1 (MT1)-MMP act cooperatively and are required for highly
      aggressive melanoma cells to engage in vasculogenic mimicry when cultured on a
      three-dimensional matrix. Furthermore, generation of Ln-5 gamma2 chain
      promigratory fragments by MMP-2 and MT1-MMP proteolysis is necessary for an
      aggressive tumor cell-preconditioned matrix to induce vasculogenic mimicry in
      poorly aggressive tumor cells. These observations suggest that treatment regimes
      that specifically target aggressive tumor cells may fail to take into account
      changes in the extracellular microenvironment that persist after removal or
      destruction of an aggressive tumor and could result in a recurrence or
      continuance of the tumor. As a potential therapeutic approach to address this
      concern, the work presented here measured the molecular consequences of adding a
      chemically modified tetracycline (CMT-3; COL-3) that inhibits MMP activity to
      aggressive metastatic melanoma cells in three-dimensional culture. COL-3
      inhibited vasculogenic mimicry and the expression of vasculogenic mimicry
      associated genes in aggressive cells, as well as the induction of vasculogenic
      mimicry in poorly aggressive cells seeded onto an aggressive cell-preconditioned
      matrix. Furthermore, molecular analysis revealed that COL-3 not only inhibited
      the generation of Ln-5 gamma2 chain promigratory fragments in the aggressive cell
      preconditioned matrix but also inhibited the induction of Ln-5 gamma2 chain gene
      expression in poorly aggressive cells by the aggressive cell-preconditioned
      matrix. These results suggest that COL-3 (and related chemically modified
      tetracyclines) may be useful in targeting molecular cues in the microenvironment
      of aggressive tumors and could potentially be used in a combinatorial manner with
      other therapies that specifically target and kill aggressive tumor cells.

PMID- 12479699
TI  - Cell cycle blockade and differentiation of ovarian cancer cells by the histone
      deacetylase inhibitor trichostatin A are associated with changes in p21, Rb, and
      Id proteins.
AB  - Inhibitors of histone deacetylase activity are emerging as a potentially
      important new class of anticancer agents. In the current studies, exposing A2780
      ovarian cancer cells to the histone deacetylase inhibitor trichostatin A (TSA)
      produced a marked change in cellular morphology, proliferation, and
      differentiation. Within 24 h of TSA treatment, there was a morphological
      transformation of the cells, with increased cytoplasm, a more epithelial-like
      columnar appearance, and the emergence of distinct cellular boundaries.
      Commensurate with the morphological transformation, TSA also inhibited cell
      proliferation; cells treated with TSA for 72 h increased to 110% of the initial
      cell numbers versus control cell numbers of 622%, with a corresponding reduction
      in mitotic activity and a flow cytometry S-phase fraction of 3.9% in TSA-treated
      cells versus 28.8% for control. TSA also induced epithelial-like differentiation
      with increased cytokeratin expression from 2% of controls to 22-25% of TSA
      treated cells and the reappearance of intercellular plasma membrane junctions and
      primitive microvilli. Immunocytochemical analyses indicate the molecular
      mechanism underlying the actions of TSA on A2780 cell cycle progression and
      differentiation involves reexpression of the CDK inhibitor p21. Elevated levels
      of p21, in TSA-treated cells, were associated with a reduction in the
      phosphorylation of the cell cycle regulator retinoblastoma protein (Rb). TSA also
      caused a decrease in the helix-loop-helix inhibitor of differentiation/DNA
      binding protein Id1, with no change in Id2 levels. In conclusion, the observed
      TSA-induced changes in p21, Rb, and Id1 are consistent with cell cycle senescence
      and differentiation of A2780 ovarian cancer cells.

PMID- 12479700
TI  - Inhibition of endothelial cell function in vitro and angiogenesis in vivo by
      docetaxel (Taxotere): association with impaired repositioning of the microtubule
      organizing center.
AB  - A number of cancer chemotherapeutic drugs designed to have cytotoxic actions on
      tumor cells have recently been shown to also have antiangiogenic activities.
      Endothelial cell migration and proliferation are key components of tumor
      angiogenesis, and agents that target the microtubule cytoskeleton can interfere
      with these processes. In this study, the effect on endothelial cell functions of
      the microtubule-stabilizing drugs Taxotere and Taxol were evaluated in three in
      vitro assays: a chemokinetic migration assay, an angiogenesis factor-mediated
      chemotactic migration assay, and a three-dimensional Matrigel tubule formation
      assay, using rat fat pad endothelial cells (RFPECs) and/or human umbilical vein
      endothelial cells (HUVECs). Taxotere was active in all three assays at
      concentrations that were not cytotoxic and did not inhibit endothelial cell
      proliferation. In the RFPEC chemokinetic migration and in vitro tubule formation
      assays, the IC50 values were approximately 10(-9) M for both Taxotere and Taxol.
      HUVEC migration, however, was more sensitive to Taxotere, with an observed IC50
      of 10(-12) M in a chemokinetic assay. In a Boyden chamber assay, HUVEC chemotaxis
      stimulated by either of two angiogenic factors, thymidine phosphorylase or
      vascular endothelial growth factor, was inhibited by Taxotere with an IC50 of 10(
      11) M and was ablated at 10(-9) M. Taxotere was also up to 1000-fold more potent
      than Taxol in inhibiting either chemokinetic or chemotactic migration. When the
      microtubule cytoskeleton was visualized using immunofluorescence staining of
      alpha-tubulin, there were no gross morphological changes observed in HUVECs or
      RFPECs treated with Taxotere at concentrations that inhibited endothelial cell
      migration but not proliferation. The effects of Taxotere on migration were
      associated with a reduction in the reorientation of the cell's centrosome, at
      concentrations that did not affect gross microtubule morphology or proliferation.
      Reorientation of the centrosome, which acts as the microtubule organizing center,
      in the intended direction of movement is a critical early step in the
      stabilization of directed cell migration. These data indicate that endothelial
      cell migration correlates more closely with changes in microtubule plasticity
      than with microtubule gross structure. The antiangiogenic activity of Taxotere in
      vivo was assessed in a Matrigel plug assay. In this assay, the angiogenic
      response to fibroblast growth factor 2 was inhibited in vivo by Taxotere with an
      ID50 of 5.4 mg/kg when injected twice weekly over a 14-day period, and
      angiogenesis was completely blocked in mice that received 10 mg/kg Taxotere. The
      in vivo data further suggested that Taxotere had selectivity for endothelial cell
      migration and/or microvessel formation because infiltration of inflammatory cells
      into the Matrigel plug was much less sensitive to inhibition by Taxotere. In
      conclusion, Taxotere is a potent and potentially specific inhibitor of
      endothelial cell migration in vitro and angiogenesis in vitro and in vivo.

PMID- 12479701
TI  - The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by
      depolymerizing tubulin in non-small cell lung cancer cells.
AB  - Microtubules have a critical role in cell division, and consequently various
      microtubule inhibitors have been developed as anticancer drugs. In this study, we
      assess mebendazole (MZ), a microtubule-disrupting anthelmintic that exhibits a
      potent antitumor property both in vitro and in vivo. Treatment of lung cancer
      cell lines with MZ caused mitotic arrest, followed by apoptotic cell death with
      the feature of caspase activation and cytochrome c release. MZ induces abnormal
      spindle formation in mitotic cancer cells and enhances the depolymerization of
      tubulin, but the efficacy of depolymerization by MZ is lower than that by
      nocodazole. Oral administration of MZ in mice elicited a strong antitumor effect
      in a s.c. model and reduced lung colonies in experimentally induced lung
      metastasis without any toxicity when compared with paclitaxel-treated mice. We
      speculate that tumor cells may be defective in one mitotic checkpoint function
      and sensitive to the spindle inhibitor MZ. Abnormal spindle formation may be the
      key factor determining whether a cell undergoes apoptosis, whereas strong
      microtubule inhibitors elicit toxicity even in normal cells.

PMID- 12479702
TI  - The glutathione-activated thiopurine prodrugs trans-6-(2-acetylvinylthio)guanine
      and cis-6-(2-acetylvinylthio)purine cause less in vivo toxicity than 6
      thioguanine after single- and multiple-dose regimens.
AB  - trans-6-(2-Acetylvinylthio)guanine (trans-AVTG) and cis-6-(2
      acetylvinylthio)purine (cis-AVTP) are glutathione-activated prodrugs of 6
      thioguanine (6-TG) and 6-mercaptopurine, respectively. In tumor cell lines, these
      prodrugs exhibit similar IC50 values that are comparable to or lower than those
      of 6-TG and 6-mercaptopurine, respectively. In this study, the in vivo toxicity
      and metabolism of the prodrugs were assessed. Mice given multiple treatments of 6
      TG and, to a lesser extent, trans-AVTG exhibited decreased peripheral WBC and RBC
      counts and increased myeloid:erythroid ratios in bone marrow; no change was
      observed in mice given cis-AVTP. Similarly, intestinal epithelial crypt cell
      apoptosis was more extensive in mice treated with 6-TG than in those treated with
      trans-AVTG, whereas mice given cis-AVTP had little apoptosis. Epithelial crypt
      cell apoptosis was more extensive in the small intestine than in the large
      intestine in all treatment groups. Histopathological examination detected no
      kidney or liver toxicity, whereas mild increases in the activities of
      hepatocellular leakage enzymes were observed in mice treated with trans-AVTG.
      Only metabolites of trans-AVTG and cis-AVTP were recovered in urine. A higher
      fraction of the dose was recovered in urine as the parent thiopurine and the
      metabolites thiopurine riboside, thioxanthine, and thiouric acid after 6-TG
      treatment than after trans-AVTG treatment; cis-AVTP recovery was slightly less
      than that of 6-TG. Thioxanthine and thiouric acid comprised a higher fraction of
      the recovered dose after cis-AVTP treatment than after trans-AVTG or 6-TG
      treatment. Overall, the results suggest that the prodrugs exhibit less in vivo
      toxicity than 6-TG. Thus, investigations into their antitumor efficacy are
      warranted.

PMID- 12479703
TI  - Caspase activation is required for gemcitabine activity in multiple myeloma cell
      lines.
AB  - The objective of this study was to determine potential mechanisms of apoptotic
      activity of gemcitabine, a pyrimidine nucleoside analogue, in the MM1.S multiple
      myeloma (MM) cell line. A MM cell line that is sensitive to glucocorticoids
      (MM1.S) was used for this study. Immunoblotting analysis, cell cycle assays, and
      annexin V staining were performed to determine whether gemcitabine induced
      apoptosis in this model. Furthermore, we attempted to delineate the apoptotic
      pathway by measuring caspase-8 and -9 activity using fluorometric assays. Loss of
      mitochondrial membrane potential was measured by flow cytometry. Gemcitabine
      treatment caused apoptosis in MM cell lines as measured by an increase in DNA
      cleavage, an increase in annexin V binding, a decrease in the mitochondrial
      membrane potential, and activation of caspase activity. Furthermore, cleavage of
      the caspase substrate poly(ADP-ribose) polymerase and caspase-3 activation were
      documented as early as 8 h after treatment with gemcitabine. Caspase-8 and -9
      were activated by gemcitabine treatment in this cell line, suggesting several
      mechanisms of action including death receptor pathway and mitochondrial damage.
      The addition of interleukin 6 to MM1.S cells treated with gemcitabine offered no
      protection against gemcitabine-induced cell death. Gemcitabine induced apoptosis
      in the MM1.S cell line, and its activity required caspase activation. There is a
      suggestion that mitochondrial integrity is being affected with gemcitabine in
      this system. Gemcitabine acts independently of interleukin 6, suggesting
      potential important therapeutic implications in MM patients.

PMID- 12479704
TI  - Identification of combination gene sets for glioma classification.
AB  - One goal for the gene expression profiling of cancer tissues is to identify
      signature genes that robustly distinguish different types or grades of tumors.
      Such signature genes would ideally provide a molecular basis for classification
      and also yield insight into the molecular events underlying different cancer
      phenotypes. This study applies a recently developed algorithm to identify not
      only single classifier genes but also gene sets (combinations) for use as glioma
      classifiers. Classifier genes identified by this algorithm are shown to be strong
      features by conservatively and collectively considering the misclassification
      errors of the feature sets. Applying this approach to a test set of 25 patients,
      we have identified the best single genes and two- to three-gene combinations for
      distinguishing four types of glioma: (a) oligodendroglioma; (b) anaplastic
      oligodendroglioma; (c) anaplastic astrocytoma; and (d) glioblastoma multiforme.
      Some of the identified genes, such as insulin-like growth factor-binding protein
      2, have been confirmed to be associated with one of the tumor types. Using
      combinations of genes, the classification error rate can be significantly
      lowered. In many instances, neither of the individual genes of a two-gene set
      performs well as an accurate classifier, but the combination of the two genes
      forms a robust classifier with a small error rate. Two-gene and three-gene
      combinations thus provide robust classifiers possessing the potential to
      translate expression microarray results into diagnostic histopathological assays
      for clinical utilization.

PMID- 12479705
TI  - Molecular modeling of mutations in the DNA-binding domain of the oncoprotein Qin.
AB  - The retroviral oncogene qin, homologue of mammalian brain factor 1 (FOXG1 B),
      belongs to the family of winged helix transcription factors. Oncogenic
      transformation by Qin requires sequence-specific DNA binding. Missense mutations
      in the forkhead domain of Qin modulate its oncogenic transforming ability in
      chicken embryonic fibroblasts. We used homology model building (threading)
      techniques to generate atomic structures of wild-type c-Qin and c-Qin mutants,
      using the solution structure of the forkhead domain of the adipocyte
      transcription factor as a template (M. J. van Dongen et al., J. Mol. Biol., 296:
      351-359, 2000). Energy calculations indicate that the Qin forkhead structure is
      stabilized primarily by hydrophobic interactions between residues at the helical
      interface. None of the missense mutations analyzed here were responsible for
      maintaining the most critical pairwise interactions holding the forkhead domain
      together. The mutated proteins form the overall structure of the forkhead domain,
      but the mutations do interfere with DNA binding.

PMID- 12479706
TI  - Staging of acute pancreatitis.
AB  - Management of patients with acute pancreatitis is based on the early assessment
      of severity of disease. Initial staging is established on clinical and laboratory
      grounds and on the findings of contrast-enhanced CT imaging. Individual clinical
      parameters and laboratory indices, although sometimes helpful, are not
      sufficiently accurate to reliable assess the severity of an acute attack.
      Numerical grading systems (Ranson's, APACHE II) with sensitivities of about 70%
      are commonly used today as indicators of systemic failure and predictors of
      disease severity. Helical or MDCT scanning performed during the administration of
      a bolus of i.v. contrast material is performed to evaluate pancreatic morphology,
      detect pancreatic necrosis, and depict retroperitoneal complications. CT staging
      and the CT severity index have proved to be a reliable indicator of disease
      severity, having shown an excellent correlation with the risk of death and the
      development of local and systemic complications in this population.

PMID- 12479707
TI  - Complications of acute pancreatitis: clinical and CT evaluation.
AB  - Mortality of acute pancreatitis is dependent on the development of potentially
      lethal complications that can coexist and occur at any time following an acute
      attack. The nature and clinical relevance of these complications differ,
      contingent on the time of occurrence following a severe episode of pancreatitis.
      They can be divided into (1), early complications that manifest at the onset or
      within the first 2 to 3 days, (2) intermediate complications that occur
      predominantly during the second to fifth week, and (3) late complications that
      usually manifest months or years following the resolution of an acute attack.
      Early complications are systemic in nature with diverse clinical manifestations
      of the cardiovascular, pulmonary, renal, and/or metabolic systems. Intermediate
      complications are abdominal, pancreatic, and retroperitoneal, and are mostly
      septic in nature, associated with pancreatic or peripancreatic fat necrosis and
      pseudocysts. Late, life-threatening complications are mainly vascular or
      hemorrhagic in nature or involve the development of chronic pancreatic ascites.
      The early detection and objective evaluation of these complications by clinical
      and imaging methods leads to specific treatment options in the continuous attempt
      to decrease mortality rates in acute pancreatitis.

PMID- 12479708
TI  - Imaging of chronic pancreatitis.
AB  - This article reviews the recognized findings of chronic pancreatitis on CT and
      endoscopic retrograde cholangiopancreatography. It also discusses more recently
      developed techniques including gadolinium-enhanced MR imaging, MR
      cholangiopancreatography, and endoscopic ultrasound. Variants of chronic
      pancreatitis and difficulties in differentiating pancreatic neoplasms from
      inflammatory pancreatic masses are also discussed.

PMID- 12479709
TI  - Imaging of cystic diseases of the pancreas.
AB  - Although the majority of cystic lesions of the pancreas seen in clinical practice
      represent postinflammatory pseudocysts, it is important for the radiologist to be
      knowledgeable of the wide spectrum of cystic masses of the pancreas and the
      variable prognoses they possess. As a result of similarities in the imaging
      features of these lesions, a definitive diagnosis is often not possible. By
      combining imaging features with clinical history, a reasonable differential
      diagnosis can be offered to the referring physician. In some cases, biopsy or
      fluid aspiration may be required prior to surgery. In a patient without the
      appropriate history of pancreatitis and the presence of a cystic pancreatic mass,
      it is incumbent upon the radiologist to offer alternative diagnoses of cystic
      neoplasms of the pancreas.

PMID- 12479710
TI  - Adenocarcinoma of the pancreas: CT imaging.
AB  - CT currently plays a vital role in pancreatic cancer staging. Continued
      advancements in computers, scanner technology, and 3D software have improved CT
      detection of smaller masses and staging. In particular, the introduction of MDCT
      and real-time 3D volume-rendering software have greatly improved the
      visualization of the pancreas and adjacent vasculature. This progress will
      continue as manufacturers introduce the next generation of scanners, which can
      acquire up to 32 slices per second with ever faster scan times. The impact of
      these new scanners on diagnostic accuracy will need to be carefully evaluated.

PMID- 12479711
TI  - Imaging of uncommon tumors of the pancreas.
AB  - In this article, the radiological manifestations of a variety of uncommon tumors
      of the pancreas are illustrated, with emphasis placed on their appearance at
      helical CT. Islet cell tumors, because of their vascularity, typically present as
      masses that are hyperattenuating to the normal pancreas at dual-phase helical CT.
      Lymphomas appear as hypoattenuating focal lesions or can diffusely infiltrate the
      gland. Absence of biliary tree dilatation, despite the presence of a bulky tumor,
      or associated extensive retroperitoneal adenopathy should offer clues to the
      diagnosis. Pancreatic metastases are usually seen in patients with advanced
      cancers, although isolated metastases from renal cell carcinoma can occurs years
      after the original tumor; such patients may benefit from surgical resection.
      Finally, the appearance of some rare neoplasms of mesenchymal origin is
      discussed.

PMID- 12479712
TI  - MR imaging of the pancreas: a practical approach.
AB  - This article reviews the current practical MRI techniques in assessment of the
      pancreas. With the comprehensive "one-stop-shopping" approach, the great majority
      of pancreatic diseases can be detected and characterized by the use of a
      combination of T1, T2-weighted, MRCP, and fat-suppressed T1-weighted dynamic post
      gadolinium SGE sequences. This approach may provide the clinician with
      information regarding the site, nature, and staging of pancreatic tumor in a
      single setting. In many institutions worldwide, however, including our own, CT
      remains the main imaging method for the assessment of acute pancreatic diseases,
      due largely to its wide availability. MR imaging is reserved for the indications
      listed above, most importantly, the detection of small and non-organ-deforming
      pancreatic ductal adenocarcinoma, islet cell tumors, choledocholithiasis and
      pancreatic duct calculi, cholangiocarcinomas, and in cases of pancreatic head
      enlargement with no mass discernable on CT.

PMID- 12479713
TI  - Imaging benign and malignant disease of the gallbladder.
AB  - This article reviews the imaging of various benign and malignant diseases of the
      gallbladder. Clinical findings and imaging features using ultrasound, CT, and MR
      for the detection and evaluation of gallstones, acute cholecystitis,
      xanthogranulomatous cholecystitis, adenomyomatosis, and carcinoma of the
      gallbladder among other disorders are discussed.

PMID- 12479714
TI  - Imaging the spectrum of biliary tract disease.
AB  - An understanding of underlying biliary pathology and the corresponding subtle
      changes reflected at imaging can greatly improve imaging accuracy in evaluating
      the biliary tract. The optimal demonstration of biliary tract imaging findings
      requires attention to specific imaging and contrast techniques, regardless of the
      modality used.

PMID- 12479715
TI  - Pancreas and biliary system: imaging of developmental anomalies and diseases
      unique to children.
AB  - The focus of this article is on the development of the pancreas and biliary
      system, with a review of the most common congenital anomalies affecting the
      pancreas and biliary tree, including pancreas divisum, annular pancreas,
      congenital shortening of the pancreas, and choledochal cysts. Additionally,
      biliary atresia and pancreatoblastoma--both diseases of the pancreas and biliary
      system that almost exclusively affect children--are considered, with a discussion
      regarding the clinical presentation and imaging appearances of these disorders.

PMID- 12479716
TI  - MR cholangiopancreatography.
AB  - In summary, over the past decade, MRCP has evolved not only as a feasible means
      of noninvasively evaluating the pancreaticobiliary tract but also as a technique
      with documented clinical utility. With the evolution of MRCP, there has been, by
      necessity, an evolution of ERCP. In fact, at some institutions MRCP has replaced
      diagnostic ERCP such that ERCP is reserved primarily for therapeutic
      interventions. When MRCP is performed in conjunction with abdominal MR and MRA, a
      comprehensive examination results that permits evaluation of the solid organs and
      vessels of the abdomen as well as the ductal systems.

PMID- 12479717
TI  - Endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography
      imaging for pancreaticobiliary pathology: the gastroenterologist's perspective.
AB  - With advances in noninvasive radiologic technology, additional adjunctive
      techniques are developing, and the roles for ERCP and EUS are continuously
      changing. In a diagnostic setting, ERCP is currently best reserved for patients
      with a high likelihood of needing endoscopic therapy, and EUS is especially
      useful for cases in which other imaging techniques have been inconclusive or are
      of inferior diagnostic capability. In a therapeutic setting, ERCP and EUS retain
      important roles in the management of both benign and malignant pancreatic and
      biliary disease. Certainly, technological advances also directly affect these
      modalities and expanded applications for ERCP and EUS for the pancreas and
      biliary tract are anticipated.

PMID- 12479718
TI  - Staging and surgical management of pancreatic and biliary cancer and
      inflammation.
AB  - Management of benign and malignant diseases of the pancreas, liver, and biliary
      tract has made remarkable progress in the last two decades. Advances in minimally
      invasive surgery, interventional radiology, and diagnostic and therapeutic
      endoscopy have changed the treatment of common diseases such as cholelithiasis
      and more serious diseases such as pancreatic adenocarcinoma. Advances in biliary
      tract and pancreatic surgery have paralleled the advances in ultrasonographic
      imaging, CT, and MR imaging. This article outlines the surgeon's perspective on
      radiologic imaging and preoperative staging of benign and malignant biliary and
      pancreatic disease.

PMID- 12479719
TI  - Retained ventilation tubes: should they be removed at 2 years?
AB  - OBJECTIVES: To assess the complications of ventilation tubes that were retained
      in children for 2 years or longer and the necessity of removal. DESIGN: A
      retrospective chart review of all patients who underwent ventilation tube removal
      from 1997 to 2000, with the exclusion of patients with craniofacial anomalies.
      SETTING: A tertiary children's hospital. PATIENTS: One hundred twenty-six
      children with ventilation tubes that were retained for 2 years or longer.
      INTERVENTIONS: Ventilation tube removal and tympanic membrane (TM) patching. MAIN
      OUTCOME MEASURES: Otorrhea, formation of granulation tissue, TM perforation,
      development of cholesteatomas, and tube reinsertion. RESULTS: A total of 126
      patients aged 2(1/2) to 14 years (59 girls and 67 boys) underwent removal of
      their ventilation tubes after 2 years or more. The patients were divided into 2
      groups. Group 1 included 67 patients (29 girls and 38 boys) who were younger than
      7 years at the time of tube removal. The tubes were retained for 2 to 5(1/2)
      years (mean retention time, 3.3 years). Group 2 included 59 patients (30 girls
      and 29 boys) aged 7 years and older at the time of tube removal. The tubes were
      retained for 2 to 10(1/2) years (mean retention time, 4.2 years). Complications
      such as otorrhea, formation of granulation tissue, and TM perforation were seen
      in 10.3%, 13.8%, and 5.2% of the patients with tube retention of 2 to 3 years,
      compared with 40.0%, 40.0%, and 46.7% of patients with tube retention of more
      than 5 years. In group 1, transient otorrhea, formation of granulation tissue,
      and TM perforation occurred in 13.4%, 7.4%, and 6.0% of the patients,
      respectively, after 2 years of tube retention. In group 2, similar complications
      occurred in 23.7%, 25.4%, and 27.1% of the patients, respectively. Forty-six
      patients in group 1 underwent TM patching (31 with paper and 15 with absorbable
      gelatin film, with a success rate of 91.3%; however, 8 patients (11.9%) required
      tube reinsertion. In group 2, patching of the TM was done in 40 patients (13 with
      paper, 24 with absorbable gelatin film, and 3 with fat), with a success rate of
      67.5%. Tube reinsertion was necessary in 1.7% of the patients in group 2. No
      cholesteatoma was encountered. CONCLUSIONS: Higher complication rates are seen in
      children when ventilation tubes are retained longer than 2 years. Children 7
      years and older have a higher incidence of complications from the tube retention
      than children younger than 7 years. Early removal of ventilation tubes in
      children younger than 7 years of age, when the risk for otitis media is still
      present, may result in the need for tube reinsertion.

PMID- 12479720
TI  - Presentation, diagnosis, and management of deep-neck abscesses in infants.
AB  - OBJECTIVE: To clarify the presenting signs and symptoms, clinical course,
      pathogenic organisms, and management of deep-neck-space abscesses in infants.
      DESIGN: Retrospective chart review. SETTING: Tertiary care academic children's
      hospital. PATIENTS: Records of 25 patients 9 months or younger with deep-neck
      space abscesses from July 1989 through May 1999 were reviewed. MAIN OUTCOME
      MEASURE: Resolution of abscess. RESULTS: Presenting symptoms included neck mass,
      92% (n = 23); fever, 60% (n = 15); and dysphagia and/or poor intake by mouth, 36%
      (n = 9). Overall, patients were symptomatic for a mean duration of 3.8 days
      before presenting to the hospital; 21 of 22 evaluated patients had elevated white
      blood cell counts. Imaging included 68% computed tomographic scan (n = 17) and
      44% plain radiographs (n = 11). On the basis of radiology and operative findings,
      locations of the abscesses were as follows: anterior triangle, 8; parapharyngeal,
      5; posterior triangle, retropharyngeal, and undefined, 3 each; submandibular, 2;
      and parotid, 1. Of 17 scanned patients, 13 had some degree of airway compromise
      evident on computed tomography. All were treated with incision and drainage, 3 of
      25 intraorally and 22 of 25 externally. Pus was identified in all 25; 20 of these
      grew Staphylococcus aureus, 1 grew group A Streptococcus, and 4 grew no organism.
      All patients received intravenous antibiotics for a mean of 4.8 days and oral
      antibiotics for a mean of 11 days. Only 1 patient required a second procedure.
      CONCLUSIONS: Deep-neck-space abscesses in infants are rapidly progressive, often
      cause airway compromise, and usually present with fever and neck mass. The most
      common pathogen is S aureus. Patients are effectively treated with incision and
      drainage coupled with intravenous followed by oral antibiotics.

PMID- 12479721
TI  - Otolaryngologic surgery in children with von Willebrand disease.
AB  - OBJECTIVE: To assess the efficacy, safety, and complications of otolaryngologic
      surgery in children with von Willebrand disease (vWD) undergoing surgery. DESIGN:
      A prospective, controlled study of 41 children with vWD who underwent surgery
      between June 1, 1999, and January 31, 2001. SETTING: A tertiary care, university
      based children's hospital. INTERVENTIONS: All children had a preoperative
      diagnosis of vWD. The patients were treated with either a protocol that includes
      the use of desmopressin acetate and tranexamic acid (37 children) or factor VIII
      concentrate in children with a positive history of seizures (4 children). MAIN
      OUTCOME MEASURES: Immediate and delayed postoperative bleeding, hyponatremia,
      seizures, and urine output. RESULTS: Two adenotonsillectomy patients (5%) had an
      immediate postoperative hemorrhage. Delayed postoperative bleeding was not
      detected in our patients. Severe hyponatremia occurred in 2 patients (1 of them
      with clinical manifestations). CONCLUSIONS: Our management of children with vWD
      was efficacious in otolaryngologic surgery. One child had important adverse
      effects with the use of desmopressin (seizure). Thus, the use of desmopressin
      should be weighed and closely monitored.

PMID- 12479722
TI  - Nonsurgical treatment of prominent ears with the Auri method.
AB  - OBJECTIVE: To present and test a new method for conservative correction of
      prominent pinnae in children aged between 2 weeks and 5.5 years. DESIGN:
      Prospective study on 56 pinnae from 44 children aged between 0.25 and 5.5 years,
      treated with the Auri method, which consists of a clip and a strip. The clip is a
      specially designed plastic clamp used during the night for an average of 4.3
      hours per night. It squeezes the cartilage and makes a fold at the place of the
      missing anthelix. The strip is a double adhesive fixture used during daytime for
      an average of 8.9 hours per day. To test the efficiency of the treatment
      objective (thickness and stiffness of the pinna, cephaloauricular distance, and
      photo-documentation) and subjective (investigators' and parents' judgment of the
      shape and grade of the correction of the pinnae) parameters have been applied.
      RESULTS: Of the children, 38 (86%) achieved good to fair correction of their
      pinnae. Of the parents, all 44 (100%) were satisfied with the treatment and 35
      (80%) reported good to fair correction of their child's pinnae. Slight
      complications were observed in 13 children (30%): 10 (23%) had temporary
      irritation of the skin of the pinna and 3 (7%) had slight temporary squeeze marks
      of the pinnae. Of the 44 children, 31 were evaluated 10 months after completing
      treatment, and the pinnae of 38 children (86%) maintained their corrected shape.
      CONCLUSIONS: Correction of the prominent pinna can be done by the new nonsurgical
      Auri method in children aged between 0.25 and 5.5 years, which provided good to
      fair results in 89% of pinnae in this study. The method is efficient in the short
      term and easy to use by the parents, but it requires long-term motivation of the
      parents as well as the child. The child can be treated at early age, avoiding
      psychosocial and cosmetic problems during school age.

PMID- 12479723
TI  - The influence of reconstructive modality on cost of care in head and neck
      oncologic surgery.
AB  - OBJECTIVE: To determine the differential costs of 3 reconstructive modalities in
      patients undergoing head and neck oncologic surgery. DESIGN: Cost-identification
      analysis. SETTING: Academic tertiary care medical center. METHODS: Retrospective
      review of 104 major head and neck resections involving primary tumors of the
      upper aerodigestive tract requiring a tracheotomy (primary hospital discharge,
      diagnosis related group 482 from the International Classification of Diseases,
      Ninth Revision, Clinical Modification) from July 2, 1999, through June 30, 2000.
      Patients were stratified by reconstruction modality: (1) microvascular free
      tissue transfer (MFFT), (2) pedicle myocutaneous flaps (PMF), and (3) primary
      reconstruction and/or skin graft (PR). Dependent variables included length of
      hospitalization, direct and indirect hospital costs, total hospital costs, the
      percentage of total costs attributable to direct costs, and the percentage of
      total costs attributable to indirect costs. RESULTS: No significant age
      differences existed among the 3 patient groups. Significant differences (Kruskal
      Wallis) were observed for all variables. The PR group was compared with the PMF
      and MFFT groups. Total patient charges were greatest in the MFFT group (mean, $22
      821.04) and least for the PR group (mean, $13 125.70). Length of stay was
      greatest in the PMF group (mean, 7.53 days) and shortest in the PR group (mean,
      5.53 days). CONCLUSIONS: Intricate reconstructions are frequently more times
      consuming than primary closure, and the additional surgical procedures are more
      likely to use more hospital resources. Efforts at providing superior functional
      outcomes must be balanced against increasing restrictions on the use of health
      care dollars. Careful evaluation of functional outcomes and quality of life will
      be required to justify the increased expenditure incurred when providing complex
      reconstructions.

PMID- 12479724
TI  - A proposal for redefining the boundaries of level V in the neck: is dissection of
      the apex of level V necessary in mucosal squamous cell carcinoma of the head and
      neck?
AB  - In 1991, the Committee for Head and Neck Surgery and Oncology of the American
      Academy of Otolaryngology-Head and Neck Surgery proposed to define the anatomic
      boundaries between the lymph node levels in the neck, as initially described by
      the Memorial Sloan-Kettering Cancer Center (New York, NY). Recently, radiological
      parameters have been outlined to identify boundaries between various neck levels.
      The lymphatics of the posterior triangle of the neck are gathered in level V,
      recently subdivided into 2 subgroups: level Va and level Vb. The superior
      boundary of level Va is defined by the apex of the convergence of the
      sternocleidomastoid muscle and trapezius muscle. Based on anatomic evidence and
      surgical experience, we advocate the subdivision of level Va into 2 sections: the
      apex of level Va or level Vas (superior) and level Vai (inferior), demarcated by
      the lower two thirds of the spinal accessory nerve. Dissection of level Vas is
      not necessary in most head and neck cancers but should be considered only in
      selected skin cancer of the posterior cephalic area (retroauricular region,
      occipital scalp).

PMID- 12479725
TI  - Laparoscopic harvest of the jejunal free flap for reconstruction of
      hypopharyngeal and cervical esophageal defects.
AB  - BACKGROUND: Reconstruction of hypopharyngeal and cervical esophageal defects
      remains one of the greatest challenges to head and neck and reconstructive
      surgeons. Although the jejunal free flap is a well-known reconstructive choice,
      many authors prefer alternative methods because of the complication rates and
      donor site morbidity associated with traditional jejunal flap harvest.
      Laparoscopic resection of the small intestine is a well-documented surgical
      technique. However, laparoscopic harvest of a jejunal segment for use in free
      tissue transfer reconstruction of defects of the hypopharynx and cervical
      esophagus has primarily been described in animal models, with only a few clinical
      studies existent in the recent literature. OBJECTIVE: To evaluate the use of a
      laparoscopic technique for harvesting jejunal segments for use in free tissue
      transfer reconstruction of pharyngoesophageal defects. PATIENTS AND METHODS: The
      records of 12 patients who underwent laparoscopic jejunal flap harvest for
      reconstruction of large hypopharyngeal or cervical esophageal defects at the
      University of Washington, Seattle, from January 1998 through April 2001 were
      retrospectively reviewed. Time of harvest, need to convert to "open" technique,
      failure rate, complications, and length of hospital stay were evaluated. RESULTS:
      All harvests were completed laparoscopically. The average operative time for the
      abdominal portion of the procedure was 2.4 hours. Warm ischemia time required for
      flap removal from the peritoneal cavity was less than 4 minutes. Each patient
      received a completely endoscopic jejunum harvest, bowel reanastomosis, and
      placement of a feeding jejunostomy tube. Enteral feedings began on the first
      postoperative day. No major complications were seen resulting from this
      technique, and no donor site morbidity was identified. All flaps were viable,
      with no revisions required. Activity in hospital and time to discharge were
      independent of the abdominal procedure. CONCLUSION: Given the low complication
      rate and relative ease of harvest, we conclude that this new technique is
      currently the best way to harvest jejunal flaps for reconstructing these
      challenging defects and should renew enthusiasm for this versatile flap.

PMID- 12479726
TI  - Fasciocutaneous flap reconstruction of the tongue and floor of mouth: outcomes
      and techniques.
AB  - OBJECTIVES: To quantify functional and other outcomes after major resection and
      fasciocutaneous free-flap reconstruction of the tongue and floor of mouth, and to
      describe reconstructive technique. DESIGN: A hypothesis-generating, retrospective
      cohort study of 43 patients who underwent, at minimum, a hemiglossectomy and
      resection of the floor of the mouth for oral cancer followed by fasciocutaneous
      free-flap reconstruction. SETTING: A tertiary academic medical center in the
      midwestern United States. MAIN OUTCOME MEASURES: Speech intelligibility,
      swallowing, interval to decannulation, length of stay, free-flap success rates,
      patient survival, and complications. RESULTS: Thirty patients underwent oral
      tongue reconstructions, and 13, tongue base reconstructions. Median
      intelligibility scores were greater among patients in the tongue base group (98%
      intelligibility) than in the oral-tongue group (76% intelligibility) (P<.001). Of
      the 38 patients undergoing swallowing evaluation, 32 (85%) were able to feed
      entirely by mouth, most with mild to moderate dysphagia. All patients underwent
      decannulation (mean interval, 13.7 days). The mean length of hospital stay was 11
      days, and free flaps in 42 patients (98%) survived. Twenty-eight patients (65%)
      were still alive by the end of the study, yielding a mean survival time of 27.4
      months. Seven patients (16%) had severe medical and 3 (7%) had major surgical
      complications. CONCLUSION: The folding techniques used in this study for
      reconstruction of the tongue with fasciocutaneous free flaps were associated with
      recovery of adequate speech and swallowing in most patients.

PMID- 12479727
TI  - Glutathione S-transferase pi expression in nasopharyngeal cancer.
AB  - BACKGROUND: Glutathione S-transferase pi (GST-pi) is an enzyme that catalyzes the
      conjugation of electrophilic substrates and prevents oxidative damage. Although
      GST-pi expression has been analyzed in many cancers, the significance of GST-pi
      expression in nasopharyngeal cancer (NPC), a tumor with a high treatment failure
      rate, is still unclear. OBJECTIVE: To elucidate the significance of GST-pi
      expression in NPC. DESIGN: Evaluation of GST-pi expression in NPC tissue
      specimens and determination of its relationship with tissue iron (a pro-oxidant)
      and clinicopathological factors in NPC. MATERIALS AND METHODS:
      Immunohistochemical expression of GST-pi was carried out in 55 NPC and 4 normal
      nasopharyngeal tissue sections. Eleven nasopharyngeal biopsy specimens (4 normal
      and 7 NPC) were analyzed for tissue iron levels. The expression of GST-pi in NPC
      was correlated with corresponding tissue iron levels. The relationships between
      GST-pi expression with sex, race, tumor stage, cervical nodal status, and
      clinical staging were also analyzed. RESULTS: Glutathione S-transferase pi
      immunoreactivity was observed in all NPC sections, with the percentage of
      immunopositive cells ranging from 1.0% to 72.0%. Tissue iron levels were
      significantly higher in the NPC tissues compared with normal tissues (P =.001). A
      direct correlation was observed between GST-pi expression and total and nuclear
      iron levels in NPC (P =.01 and P =.047, respectively). A significant association
      was also observed between GST-pi expression and cervical nodal disease (P =.007).
      CONCLUSIONS: Nasopharyngeal tumor cells may respond to pro-oxidant conditions by
      modulating intracellular antioxidant defense. Glutathione S-transferase pi
      expression appears to be associated with lymphogenous metastasis in NPC.

PMID- 12479728
TI  - Pleomorphic adenoma of the submandibular gland: clinicopathological and
      immunohistochemical features of 60 cases in Brazil.
AB  - The submandibular gland is involved in only 5% to 10% of the salivary gland
      tumors, and pleomorphic adenoma (PA) is the most common tumor affecting it. This
      study describes the clinicopathological features and immunohistochemical
      expression of Ki-67 and p53 in 60 cases of submandibular salivary gland PAs. Most
      of the patients were in the third and fifth decades of life and 37 (62%) of them
      were women. Tumor sizes varied from 1 to 10 cm and the mean time between symptom
      onset and treatment was 52 months. Only 1 patient experienced local recurrence, 3
      years after treatment. Histologically, most tumors consisted chiefly in a
      chondromyxoid stroma. Stroma-rich PAs were larger than stroma-poor ones (P<.02).
      All PAs were found negative for Ki-67 and p53. These results show that PAs of the
      submandibular gland are histologically similar to PAs of other salivary glands,
      and that they have a low proliferative rate and a good prognosis.

PMID- 12479729
TI  - Bilateral vocal fold paresis and multiple system atrophy.
AB  - OBJECTIVE: To review a case series of patients with systemic neurodegenerative
      disease presenting to a laryngologist for workup of dysphonia and found to have
      bilateral vocal fold paresis. DESIGN: Case series. SETTING: Tertiary care voice
      center. PATIENTS: Series of patients with neurodegenerative disorders examined
      for dysphonia. MAIN OUTCOME MEASURES: History and physical examination including
      fiberoptic laryngoscopy were performed on all patients. Some patients underwent
      polysomnography. RESULTS: Seven patients during a 2-year period were noted to
      have bilateral abductor vocal fold paresis. Five of 7 (71%) had the diagnosis of
      multiple system atrophy proposed by the laryngologist. All 7 patients described
      sleep-disordered breathing with stridor. CONCLUSIONS: Patients with systemic
      neurodegenerative disorders such as Parkinson disease should be examined for
      multiple system atrophy and for evidence of bilateral vocal fold paresis. Workup
      for stridor should include polysomnography. Treatment of glottic obstruction in
      these patients includes constant positive airway pressure at night or
      tracheotomy. The finding of bilateral vocal fold paresis can be life threatening.

PMID- 12479730
TI  - Otolaryngologic manifestations of the 22q11.2 deletion syndrome.
AB  - BACKGROUND: The 22q11.2 chromosome deletion syndrome occurs at a frequency of 1
      in 4000 live births. Fluorescent in situ hybridization is a reliable means of
      testing for this genetic abnormality. OBJECTIVE: To describe the otolaryngologic
      manifestations of the 22q11.2 deletion syndrome to improve recognition and
      management of these disorders. PATIENTS AND DESIGN: A retrospective medical
      record review of 102 patients with chromosome 22q 11.2 deletions confirmed by
      fluorescent in situ hybridization. SETTING: A multidisciplinary 22q11.2 deletion
      clinic at an academic children's hospital. OUTCOME MEASURE: All otolaryngologic
      problems were recorded, including facial dysmorphic features, velopharyngeal
      insufficiency, speech and airway abnormalities, feeding difficulties,
      gastroesophageal reflux, hearing loss, otitis media, sinus problems, and vascular
      anomalies. Additionally, available objective test results were recorded,
      including those from audiograms, imaging studies, endoscopies, speech
      evaluations, and vascular studies. RESULTS: Dysmorphic facial features were found
      in most patients. Velopharyngeal incompetence was noted in 76 patients, while
      overt submucosal clefts were found in 11 patients. Most patients had speech and
      language delays. In addition, 53 patients had chronic or recurrent otitis media,
      and 28 had recurrent sinorhinitis. Furthermore, feeding problems were found in 48
      patients, while vascular anomalies of the head and neck were found in 16
      patients. CONCLUSION: Otolaryngologic abnormalities are relatively common and
      important to recognize with the 22q11.2 deletion syndrome.

PMID- 12479731
TI  - Evaluation and surgical management of isolated sphenoid sinus disease.
AB  - OBJECTIVES: To evaluate the pathologic conditions, preoperative evaluation,
      treatment, and clinical outcomes associated with sphenoid sinus disease. DESIGN:
      Retrospective study. SETTING: Tertiary university-based referral center.
      PATIENTS: All patients with isolated sphenoid sinus disease managed surgically or
      in which surgery was considered a primary treatment option. MAIN OUTCOME
      MEASURES: Demographic data, presenting signs and symptoms, endoscopic and imaging
      findings, surgical management, surgical pathology, and clinical outcomes were
      investigated in patients presenting with sphenoid sinus disease to the Medical
      College of Wisconsin, Milwaukee, between January 1, 1991, and December 31, 2001.
      RESULTS: The study population included 17 women and 12 men with a mean age of
      52.3 years (range, 15-82 years). The most common presenting symptom was headache
      (20 patients [69%]). Imaging evaluation included computed tomography and/or
      magnetic resonance imaging studies in all cases. Sphenoid sinus abnormality was
      variable and included sinusitis (11 patients [38%]), tumor (7 [24%]), mucocele (5
      [17%]), fungal process (3 [10%]), and cerebrospinal fluid fistula (3 [10%]).
      Twenty-one cases (72%) were managed endoscopically and 4 (14%) were managed with
      a transseptal approach. One patient (3%) underwent combined extracranial
      endoscopic transnasal approach, while another (3%) underwent a midface degloving
      approach. The remaining 2 patients (7%) did not undergo surgical intervention.
      CONCLUSIONS: Given the high prevalence of noninflammatory lesions within the
      sphenoid sinus, thorough preoperative evaluation is imperative. Initially, this
      should include nasal endoscopy and computed tomography to help define the
      location, extent, and character of the lesion. In some cases, magnetic resonance
      imaging may help further define the nature and extent of a lesion. Angiography
      should be considered if a vascular lesion is suspected. The clinical and imaging
      findings should all be taken into consideration when the surgical approach is
      planned.

PMID- 12479732
TI  - Antiepiligrin cicatricial pemphigoid of the larynx successfully treated with a
      combination of tetracycline and niacinamide.
AB  - A case of antiepiligrin cicatricial pemphigoid that primarily involved the larynx
      and required a tracheostomy was studied. The diagnosis was based on the direct
      immunofluorescence findings of a biopsy specimen from the glottis,
      immunofluorescence using normal and 1M sodium chloride-split normal human skin as
      substrates, and immunoprecipitation. A dramatic clinical improvement was observed
      after the combined administration of tetracycline hydrochloride and niacinamide.
      The tracheal stoma could be shut after the narrow segment was cut by means of
      carbon dioxide laser therapy. The patient showed no respiratory difficulty during
      the 2-year follow-up period. The combined therapy of tetracycline and niacinamide
      is thus considered to be an effective treatment for various types of cicatricial
      pemphigoid.

PMID- 12479734
TI  - Clinical problem solving: pathology: pathology quiz case 2. Tumoral calcinosis.

PMID- 12479733
TI  - Clinical problem solving: pathology: pathology quiz case 1. Atypical
      mycobacterial infection.

PMID- 12479735
TI  - Clinical problem solving: radiology: radiology quiz case 1. Pneumosinus dilatans
      of the maxillary, ethmoid, and sphenoid sinuses.

PMID- 12479736
TI  - Clinical problem solving: radiology: radiology quiz case 2. Cystic hygroma
      (lymphangioma).

PMID- 12479738
TI  - A piece of my mind. Lessons in friendship.

PMID- 12479739
TI  - Banking (on) genes: DNA sought as key to disease causes and cures.

PMID- 12479740
TI  - How useful are automated external defibrillators?

PMID- 12479741
TI  - Change in kidney transplantation priority will help organ recipients in the
      minority.

PMID- 12479746
TI  - Effects of mandatory parental notification on adolescents' use of sexual health
      care services.

PMID- 12479748
TI  - Effects of mandatory parental notification on adolescents' use of sexual health
      care services.

PMID- 12479749
TI  - Standards for medical expert testimony.

PMID- 12479750
TI  - Standards for medical expert testimony.

PMID- 12479751
TI  - Standards for medical expert testimony.

PMID- 12479753
TI  - Upper respiratory tract infections among airline passengers.

PMID- 12479756
TI  - Limiting residents' work hours.

PMID- 12479757
TI  - Limiting residents' work hours.

PMID- 12479758
TI  - Limiting residents' work hours.

PMID- 12479760
TI  - Relationships between pharmaceutical and tobacco companies.

PMID- 12479761
TI  - Relationships between pharmaceutical and tobacco companies.

PMID- 12479762
TI  - Graves Disease in a US Army Special Forces Group.

PMID- 12479763
TI  - Major outcomes in high-risk hypertensive patients randomized to angiotensin
      converting enzyme inhibitor or calcium channel blocker vs diuretic: The
      Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
      (ALLHAT).
AB  - CONTEXT: Antihypertensive therapy is well established to reduce hypertension
      related morbidity and mortality, but the optimal first-step therapy is unknown.
      OBJECTIVE: To determine whether treatment with a calcium channel blocker or an
      angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart
      disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a
      diuretic. DESIGN: The Antihypertensive and Lipid-Lowering Treatment to Prevent
      Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled
      clinical trial conducted from February 1994 through March 2002. SETTING AND
      PARTICIPANTS: A total of 33 357 participants aged 55 years or older with
      hypertension and at least 1 other CHD risk factor from 623 North American
      centers. INTERVENTIONS: Participants were randomly assigned to receive
      chlorthalidone, 12.5 to 25 mg/d (n = 15 255); amlodipine, 2.5 to 10 mg/d (n =
      9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned follow-up of
      approximately 4 to 8 years. MAIN OUTCOME MEASURES: The primary outcome was
      combined fatal CHD or nonfatal myocardial infarction, analyzed by intent-to
      treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (primary
      outcome, coronary revascularization, or angina with hospitalization), and
      combined CVD (combined CHD, stroke, treated angina without hospitalization, heart
      failure [HF], and peripheral arterial disease). RESULTS: Mean follow-up was 4.9
      years. The primary outcome occurred in 2956 participants, with no difference
      between treatments. Compared with chlorthalidone (6-year rate, 11.5%), the
      relative risks (RRs) were 0.98 (95% CI, 0.90-1.07) for amlodipine (6-year rate,
      11.3%) and 0.99 (95% CI, 0.91-1.08) for lisinopril (6-year rate, 11.4%).
      Likewise, all-cause mortality did not differ between groups. Five-year systolic
      blood pressures were significantly higher in the amlodipine (0.8 mm Hg, P =.03)
      and lisinopril (2 mm Hg, P<.001) groups compared with chlorthalidone, and 5-year
      diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg,
      P<.001). For amlodipine vs chlorthalidone, secondary outcomes were similar except
      for a higher 6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI,
      1.25-1.52). For lisinopril vs chlorthalidone, lisinopril had higher 6-year rates
      of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs
      5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07
      1.31). CONCLUSION: Thiazide-type diuretics are superior in preventing 1 or more
      major forms of CVD and are less expensive. They should be preferred for first
      step antihypertensive therapy.

PMID- 12479764
TI  - Major outcomes in moderately hypercholesterolemic, hypertensive patients
      randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering
      Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
AB  - CONTEXT: Studies have demonstrated that statins administered to individuals with
      risk factors for coronary heart disease (CHD) reduce CHD events. However, many of
      these studies were too small to assess all-cause mortality or outcomes in
      important subgroups. OBJECTIVE: To determine whether pravastatin compared with
      usual care reduces all-cause mortality in older, moderately hypercholesterolemic,
      hypertensive participants with at least 1 additional CHD risk factor. DESIGN AND
      SETTING: Multicenter (513 primarily community-based North American clinical
      centers), randomized, nonblinded trial conducted from 1994 through March 2002 in
      a subset of participants from the Antihypertensive and Lipid-Lowering Treatment
      to Prevent Heart Attack Trial (ALLHAT). PARTICIPANTS: Ambulatory persons (n = 10
      355), aged 55 years or older, with low-density lipoprotein cholesterol (LDL-C) of
      120 to 189 mg/dL (100 to 129 mg/dL if known CHD) and triglycerides lower than 350
      mg/dL, were randomized to pravastatin (n = 5170) or to usual care (n = 5185).
      Baseline mean total cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density
      lipoprotein cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66
      years, 49% were women, 38% black and 23% Hispanic, 14% had a history of CHD, and
      35% had type 2 diabetes. INTERVENTION: Pravastatin, 40 mg/d, vs usual care. MAIN
      OUTCOME MEASURES: The primary outcome was all-cause mortality, with follow-up for
      up to 8 years. Secondary outcomes included nonfatal myocardial infarction or
      fatal CHD (CHD events) combined, cause-specific mortality, and cancer. RESULTS:
      Mean follow-up was 4.8 years. During the trial, 32% of usual care participants
      with and 29% without CHD started taking lipid-lowering drugs. At year 4, total
      cholesterol levels were reduced by 17% with pravastatin vs 8% with usual care;
      among the random sample who had LDL-C levels assessed, levels were reduced by 28%
      with pravastatin vs 11% with usual care. All-cause mortality was similar for the
      2 groups (relative risk [RR], 0.99; 95% confidence interval [CI], 0.89-1.11; P
      =.88), with 6-year mortality rates of 14.9% for pravastatin vs 15.3% with usual
      care. CHD event rates were not significantly different between the groups (RR,
      0.91; 95% CI, 0.79-1.04; P =.16), with 6-year CHD event rates of 9.3% for
      pravastatin and 10.4% for usual care. CONCLUSIONS: Pravastatin did not reduce
      either all-cause mortality or CHD significantly when compared with usual care in
      older participants with well-controlled hypertension and moderately elevated LDL
      C. The results may be due to the modest differential in total cholesterol (9.6%)
      and LDL-C (16.7%) between pravastatin and usual care compared with prior statin
      trials supporting cardiovascular disease prevention.

PMID- 12479765
TI  - Changing incidence of out-of-hospital ventricular fibrillation, 1980-2000.
AB  - CONTEXT: Recent reports from 2 European cities and an earlier observation from
      Seattle, Wash, suggest that the number of patients treated for out-of-hospital
      ventricular fibrillation (VF) has declined. OBJECTIVE: To analyze the incidence
      of cardiac arrest and to examine relationships among incidence, sex, race, age,
      and first identified cardiac rhythm in Seattle. DESIGN, SETTING, AND PATIENTS:
      Population-based study of all cardiac arrest cases with presumed cardiac etiology
      who received advanced life support from Seattle Fire Department emergency medical
      services during specified periods between 1979 and 2000. United States Census
      data for Seattle in 1980, 1990, and 2000 were used to determine incidence rates
      for treated cardiac arrest with adjustments for age and sex. MAIN OUTCOME
      MEASURES: Changes in incidence of cardiac arrest and initial recorded cardiac
      rhythm. RESULTS: The adjusted annual incidence of cardiac arrest with VF as the
      first identified rhythm decreased by about 56% from 1980 to 2000 (from 0.85 to
      0.38 per 1000; relative risk [RR], 0.44; 95% confidence interval [CI], 0.37
      0.53). Similar reductions occurred in blacks (54%; RR, 0.45; 95% CI, 0.26-0.79)
      and whites (53%; RR, 0.47; 95% CI, 0.38-0.58) and was most evident in men (57%;
      RR, 0.43; 95% CI, 0.35-0.53), in whom the baseline incidence was relatively high.
      When all treated arrests with presumed cardiac etiology were considered, that
      incidence decreased by 43% (RR, 0.58; 95% CI, 0.49-0.67) in men but negligibly in
      women, for whom a relatively low incidence of VF also declined but was offset by
      more cases with asystole or pulseless electrical activity. CONCLUSION: We
      observed a major decline in the incidence of out-of-hospital VF and in all cases
      of treated cardiac arrest presumably due to heart disease in Seattle. These
      changes likely reflect the national decline in coronary heart disease mortality.

PMID- 12479766
TI  - Risk of hip fracture among dialysis and renal transplant recipients.
AB  - CONTEXT: Renal failure places people at particularly high risk of hip fracture.
      However, the possible differential impact of dialysis and renal transplantation
      on this risk is not well understood. OBJECTIVE: To determine if patients who
      receive kidney transplants are at greater risk of hip fracture compared with
      those who continue to undergo dialysis. DESIGN, SETTING, AND PARTICIPANTS: Cohort
      study of 101 039 patients with end-stage renal disease placed on the renal
      transplant waiting list in the United States between January 1, 1990, and
      December 31, 1999. MAIN OUTCOME MEASURES: Hip fractures, identified from Medicare
      claims data. RESULTS: Among the patients included in this analysis, 971 hip
      fractures were observed during the follow-up period of 314 767 person-years. The
      incidence rate of hip fracture in patients receiving dialysis was 2.9 per 1000
      patients per year compared with 3.3 hip fractures per 1000 patients per year in
      those who had previously received a renal transplant. Initially, the relative
      risk (RR) of hip fracture associated with transplantation was 1.34-fold greater
      when compared with dialysis (adjusted RR, 1.34; 95% confidence interval [CI],
      1.12-1.61) but then decreased by 1% per month (adjusted RR, 0.99; 95% CI, 0.98
      0.99) until the estimated risk became equal for dialysis and transplant
      recipients approximately 630 days after transplantation (adjusted RR, 1.00; 95%
      CI, 0.87-1.15). Among transplant recipients, risk of fracture was relatively
      higher in persons with a prolonged period of dialysis before transplantation.
      CONCLUSION: The high risk of hip fracture among dialysis patients is exceeded by
      that among renal transplant patients during the first 1 to 3 years after
      transplantation.

PMID- 12479767
TI  - Association between licensure examination scores and practice in primary care.
AB  - CONTEXT: Standards for licensure are designed to provide assurance to the public
      of a physician's competence to practice. However, there has been little
      assessment of the relationship between examination scores and subsequent practice
      performance. OBJECTIVE: To determine if there is a sustained relationship between
      certification examination scores and practice performance and if licensing
      examinations taken at the end of medical school are predictive of future practice
      in primary care. DESIGN, SETTING, AND PARTICIPANTS: A total of 912 family
      physicians, who passed the Quebec family medicine certification examination
      (QLEX) between 1990 and 1993 and entered practice. Linked databases were used to
      assess physicians' practice performance for 3.4 million patients in the universal
      health care system in Quebec, Canada. Patients were seen during the follow-up
      period for the first 4 years (1993 cohort of physicians) to 7 years (1990 cohort
      of physicians) of practice from July 1 of the certification examination to
      December 31, 1996. MAIN OUTCOME MEASURES: Mammography screening rate, continuity
      of care index, disease-specific and symptom-relief prescribing rate,
      contraindicated prescribing rate, and consultation rate. RESULTS: Physicians
      achieving higher scores on both examinations had higher rates (rate increase per
      SD increase in score per 1000 persons per year) of mammography screening (beta
      for QLEX, 16.8 [95% confidence interval [CI], 8.7-24.9]; beta for Medical Council
      of Canada Qualifying Examination [MCCQE], 17.4 [95% CI, 10.6-24.1]) and
      consultation (beta for QLEX, 4.9 [95% CI, 2.1-7.8]; beta for MCCQE, 2.9 [95% CI,
      0.4-5.4]). Higher subscores in diagnosis were predictive of higher rates in the
      difference between disease-specific and symptom-relief prescribing (beta for
      QLEX, 3.9 [95% CI, 0.9-7.0]; beta for MCCQE, 3.8 [95% CI, 0.3-7.3]). Higher
      scores of drug knowledge were predictive of a lower rate (relative risk per SD
      increase in score) of contraindicated prescribing for MCCQE (relative risk, 0.88;
      95% CI, 0.77-1.00). Relationships between examination scores and practice
      performance were sustained through the first 4 to 7 years in practice.
      CONCLUSION: Scores achieved on certification examinations and licensure
      examinations taken at the end of medical school show a sustained relationship,
      over 4 to 7 years, with indices of preventive care and acute and chronic disease
      management in primary care practice.

PMID- 12479768
TI  - Health-related quality-of-life assessments and patient-physician communication: a
      randomized controlled trial.
AB  - CONTEXT: There has been increasing interest in the use of health-related quality
      of-life (HRQL) assessments in daily clinical practice, yet few empirical studies
      have been conducted to evaluate the usefulness of such assessments. OBJECTIVE: To
      evaluate the efficacy of standardized HRQL assessments in facilitating patient
      physician communication and increasing physicians' awareness of their patients'
      HRQL-related problems. DESIGN: Prospective, randomized crossover trial. SETTING:
      Outpatient clinic of a cancer hospital in the Netherlands. PARTICIPANTS: Ten
      physicians and 214 patients (76% women; mean age, 57 years) undergoing palliative
      chemotherapy who were invited to participate between June 1996 and June 1998.
      INTERVENTION: At 3 successive outpatient visits, patients completed an HRQL
      questionnaire (European Organization for Research and Treatment of Cancer Quality
      of Life Questionnaire-Core 30). The responses were computer scored and
      transformed into a graphic summary. Physicians and patients received a copy of
      the summary before the consultation. MAIN OUTCOME MEASURES: Audiotapes of the
      consultations were content analyzed to evaluate patient-physician communication.
      Physicians' awareness of their patients' health problems was assessed by
      comparing physicians' and patients' ratings on the Dartmouth Primary Care
      Cooperative Information Functional Health Assessment (COOP) and the World
      Organisation Project of National Colleges and Academics (WONCA) charts. RESULTS:
      The HRQL-related issues were discussed significantly more frequently in the
      intervention than in the control group (mean [SD] communication composite scores:
      4.5 [2.3] vs 3.7 [1.9], respectively (P =.01). Physicians in the intervention
      group identified a greater percentage of patients with moderate-to-severe health
      problems in several HRQL domains than did those in the control group. All
      physicians and 87% of the patients believed that the intervention facilitated
      communication and expressed interest in its continued use. CONCLUSION:
      Incorporating standardized HRQL assessments in daily clinical oncology practice
      facilitates the discussion of HRQL issues and can heighten physicians' awareness
      of their patients' HRQL.

PMID- 12479769
TI  - Resuscitation after cardiac arrest: a 3-phase time-sensitive model.

PMID- 12479770
TI  - The verdict from ALLHAT--thiazide diuretics are the preferred initial therapy for
      hypertension.

PMID- 12479771
TI  - The ALLHAT lipid lowering trial--less is less.

PMID- 12479781
TI  - The relationship between episodic memory and context: clues from memory errors
      made while under stress.

PMID- 12479782
TI  - The enigma of conditioned taste aversion learning: stimulus properties of 2
      phenylethylamine derivatives.
AB  - The functional aversive stimulus properties of several IP doses of (+/-)
      amphetamine (1.25-10 mg.kg-1), 2-phenylethylamine (PEA, 2.5-10 mg.kg-1, following
      inhibition of monoamine oxidase with pargyline 50 mg.kg-1) and phenylethanolamine
      (6.25-50 mg.kg-1) were measured with the conditioned taste aversion (CTA)
      paradigm. A two-bottle choice procedure was used, water vs. 0.1 % saccharin with
      one conditioning trial and three retention trials. (+/-)-Amphetamine and
      phenylethanolamine induced a significant conditioned taste aversion but PEA did
      not. (+/-)-Amphetamine and PEA increased spontaneous locomotor activity but
      phenylethanolamine had no effects on this measure. Measurement of whole brain
      levels of these drugs revealed that the peak brain elevation of PEA occurred at
      approximately 10 min whereas the peak elevations of (+/-)-amphetamine and
      phenylethanolamine occurred at approximately 20 min. The present failure of PEA
      to elicit conditioned taste aversion learning is consistent with previous reports
      for this compound. The differential functional aversive stimulus effects of these
      three compounds are surprising since they exhibit similar discriminative stimulus
      properties and both (+/-)-amphetamine and PEA are self-administered by laboratory
      animals. The present data suggest that time to maximal brain concentrations
      following peripheral injection may be a determinant of the aversive stimulus
      properties of PEA derivatives.

PMID- 12479783
TI  - Taste aversion learning and aging: a comparison with the effect of dorsal
      hippocampal lesions in rats.
AB  - The relationship between hippocampal function and aging was explored in Wistar
      rats using taste aversion learning by comparing the performance of adult dorsal
      hippocampal lesioned and fifteen-month-old intact rats with that of adult intact
      rats. In experiment 1 the conditioned blocking phenomenon was absent in the
      hippocampal and the aging rats. Unlike the adult intact rats, the hippocampal and
      aging rats were not impaired in acquiring a learned aversion to a cider vinegar
      solution (3 %) presented as a serial compound with a previously conditioned
      saccharin solution (0.1 %). In experiment 2 both the hippocampal and the aging
      rats developed reduced aversions to a saline solution (0.5 %) followed by an i.p.
      injection of lithium chloride (0.15 M; 2 % b.w.) if the taste solution was
      previously preexposed without consequences. This latent inhibition effect was
      similar to that seen in intact adult rats. In both experiments, the aging rats
      exhibited enhanced conventional learned taste aversions. It is concluded that
      aging is not a unitary process but induces both hippocampal dependent and
      hippocampal independent complex changes in the functioning of the neural
      circuits, implementing taste aversion learning.

PMID- 12479784
TI  - Disturbance of motivated behavior in rats by epileptic afterdischarges.
AB  - Nearly all epileptic seizures in patients are characterized by deranged
      consciousness. We started to study changes in motivated behavior (drinking in
      thirsty rats) as a possible analogue of compromised consciousness during and
      after epileptic seizures. Epileptic afterdischarges (ADs) were elicited by
      stimulation of the dorsal hippocampus and/or thalamus. Rats with implanted
      electrodes (deprived of water for 24 hours) were trained to lick water from a
      narrow tube. After pretraining ADs were elicited eight times in each animal and
      access to water was allowed during different phases of the AD. Stimulation did
      not affect licking if no AD was induced. If stimulation was successful, licking
      was stopped in nearly 70 % of stimulations and modified (biting the tube) in 30
      %. Hippocampal ADs (characterized by serrated waves in the EEG and by an arrest
      of behavior with subsequent automatisms) completely blocked licking, signs of
      recovery appeared during the interval between the AD and recurrent AD and it
      progressed during recurrent ADs. Thalamic ADs abolished licking in 82% of cases
      and immediately after ADs normal licking reappeared in 49 % of these
      observations. Our results suggest that changes in motivated behavior might serve
      as an analogue of compromised human consciousness.

PMID- 12479785
TI  - Hippocampus-dependent retrieval and hippocampus-independent extinction of place
      avoidance navigation, and stress-induced out-of-context activation of a memory
      revealed by reversible lesion experiments in rats.
AB  - The use of reversible lesion techniques in memory research was pioneered in the
      laboratory of Jan Bures and Olga Buresova. We use the occasion of Jan's 75th
      birthday to briefly review the experimental utility of this approach. Two
      experiments from our current research are reported in which reversible lesioning
      methods are used to ask otherwise experimentally untenable questions about memory
      retrieval. The first experiment used intra-hippocampal injections of tetrodotoxin
      to temporarily inactivate the hippocampus during retrieval of a well-learned
      place avoidance navigation memory. This revealed that the hippocampus is
      necessary for place avoidance retrieval but that the extinction of place
      avoidance can occur independently of retrieving the memory and intact hippocampal
      function. The second experiment used KCl-induced cortical spreading depression in
      an interhippocampal transfer paradigm to demonstrate that a Y-maze memory that is
      learned by only one cortical hemisphere can be made to transfer to the other
      hemisphere by forcing the rat to swim, a unique stressful experience that
      occurred in a different apparatus, different behavioral context, and involved
      different behaviors than the Y-maze training. This demonstrates, we believe for
      the first time behaviorally, that memories can be activated outside of the
      behavioral context of their acquisition and expression in rats.

PMID- 12479786
TI  - Rat spatial memory tasks adapted for humans: characterization in subjects with
      intact brain and subjects with selective medial temporal lobe thermal lesions.
AB  - In the present paper we describe five tests, 3 of which were designed to be
      similar to tasks used with rodents. Results obtained from control subjects,
      patients with selective thermo-coagulation lesions to the medial temporal lobe
      and results from non-human primates and rodents are discussed. The tests involve
      memory for spatial locations acquired by moving around in a room, memory for
      objects subjects interacted with, or memory for objects and their locations. Two
      of the spatial memory tasks were designed specifically as analogs of the Morris
      water task and the 8-arm radial-maze tasks used with rats. The Morris water task
      was modeled by hiding a sensor under the carpet of a room (Invisible Sensor
      Task). Subjects had to learn its location by using an array of visual cues
      available in the room. A path integration task was developed in order to study
      the non-visual acquisition of a cognitive representation of the spatial location
      of objects. In the non-visual spatial memory task, we blindfolded subjects and
      led them to a room where they had to find 3 objects and remember their locations.
      We designed an object location task by placing 4 objects in a room that subjects
      observed for later recall of their locations. A recognition task, and a novelty
      detection task were given subsequent to the recall task. An 8-arm radial-maze was
      recreated by placing stands at equal distance from each other around the room,
      and asking subjects to visit each stand once, from a central point. A non-spatial
      working memory task was designed to be the non-spatial equivalent of the radial
      maze. Search paths recorded on the first trial of the Invisible Sensor Task, when
      subjects search for the target by trial and error are reported. An analysis of
      the search paths revealed that patients with lesions to the right or left
      hippocampus or parahippocampal cortex employed the same type of search strategies
      as normal controls did, showing similarities and differences to the search
      behavior recorded in rats. Interestingly, patients with lesions that included the
      right parahippocampal cortex were impaired relative to patients with lesions to
      the right hippocampus that spared the parahippocampal cortex, when recall of the
      sensor was tested after a 30 min delay (Bohbot et al. 1998). No differences were
      obtained between control subjects and patients with selective thermal lesions to
      the medial temporal lobe, when tested on the radial-maze, the non-spatial
      analogue to the radial-maze and the path integration tasks. Differences in
      methodological procedures, learning strategies and lesion location could account
      for some of the discrepant results between humans and non-human species. Patients
      with lesions to the right hippocampus, irrespective of whether the right
      parahippocampal cortex was spared or damaged, had difficulties remembering the
      particular configuration and identity of objects in the novelty detection of the
      object location task. This supports the role of the human right hippocampus for
      spatial memory, in this case, involving memory for the location of elements in
      the room; learning known to require the hippocampus in the rat.

PMID- 12479787
TI  - Striatal level of regulation of learned forepaw movements in rats.
AB  - The role of the striatal adenylyl cyclase (AC) and cholinergic systems in the
      learning and expression of new forepaw movements (reaching with prolonged pushing
      on a fixed piston) was studied in male Wistar rats. Motor learning processes,
      prenatal hypoxia, and cholinergic drugs changed the properties of the AC system
      in the striatum. After learning, the striatal basal AC activity was decreased
      compared to untrained control rats. In addition, the AC activity was more
      decreased in animals with a good ability to learn compared to poor learners (up
      to 31 % and 51 %, correspondingly; p<0.01). Rats subjected to prenatal hypoxia
      (13-14th days of embryogenesis) had a lower ability to learn the new movements
      requiring tactile control and the striatal AC activity in these rats was 1.8
      times higher (p<0.001) than controls. In vitro application of the cholinergic
      agonist carbachol (CARB) 10-5 M (corresponding to approximately 0.3 microg), as
      well as the antagonist scopolomine (SCOP) 10(-5) M (approximately 0.3 microg)
      decreased AC activity in the synaptosomal fraction of the striatum. In vivo
      injections of CARB (0.3-3 microg/1microl) or SCOP (0.3-3 microg/1microl) into the
      ventral striatum (nucleus accumbens) modified the newly learned sensorimotor
      skill. After CARB injections the rats performed slower movements with more
      prolonged pushing. After SCOP the rats could not retain the learned pushing
      movement. These in vivo and in vitro data suggest that the cholinergic mediator
      system of the striatum is involved in learning sensory-controlled forepaw
      movements as well as the regulation of new motor skills by modulating the AC
      signal transduction process in the striatum. The data confirmed that modification
      of the striatal AC system resulted in the modulation of reaching behavior and
      better expression of the learned reflex.

PMID- 12479788
TI  - Glutamate induces different neuronal conditioned responses than ACPD when used as
      a locally ionophoresed unconditioned stimulus in the cat motor cortex.
AB  - Single unit recordings were made from the motor cortex of conscious cats with
      glass micropipettes that allowed ionophoretic application of 0.5 M glutamate in 2
      M NaCl or 0.5 M ACPD (1S,3R-1-amino-cyclopentane-1,3-dicarboxylic acid, a mGluR
      agonist) in 2 M NaCl. Activity in response to a 70 dB click (1 ms rectangular
      pulse to loudspeaker) was studied before, during, and immediately after applying
      each agent locally as a paired US (90 nA current 570 ms after click for 300 ms in
      combination with glabella tap). A 70 dB hiss sound was presented 4.4 sec after
      the click as a discriminative stimulus (DS). CS and DS were presented 10 times
      initially (adaptation); then CS, US plus tap, and DS (approximately 10 times as
      conditioning); and then CS and DS (2-10 times to test post-conditioning).
      Glutamate potentiated the mean, early, 8-16 ms response to the click after
      conditioning (t=18.2, p<0.0001), but not the baseline activity which decreased
      from a mean of 17 spk/sec to 7 spk/sec (t=3.71, p<0.001). Baseline activity
      increased to 31 spk/sec when glutamate was applied during conditioning (t=3.30,
      p<0.005). ACPD reduced the intermediate, 64-72 ms response to the click after
      conditioning (t=8.18, p<0.0001), and potentiated the late 104-112 ms response
      (t=15.4, p<0.0001). Baseline activity was slightly increased after conditioning
      with ACPD. Saline did not potentiate the response to click. The results indicate
      that glutamate agonists that differ in their receptor affinities can induce
      different CRs when used as locally applied USs to condition neuronal responses to
      a click CS in the motor cortex of cats.

PMID- 12479789
TI  - Changes in extracellular space volume and geometry induced by cortical spreading
      depression in immature and adult rats.
AB  - Changes in extracellular space (ECS) diffusion parameters, DC potentials and
      extracellular potassium concentration were studied during single and repeated
      cortical spreading depressions (SD) in 13-15 (P13-15), 21 (P21) and 90-day-old
      (adult) Wistar rats. The real-time iontophoretic method using tetramethylammonium
      (TMA+)-selective microelectrodes was employed to measure three ECS parameters in
      the somatosensory cortex: the ECS volume fraction alpha (alpha = ECS volume/total
      tissue volume), ECS tortuosity lambda (increase in diffusion path length) and the
      nonspecific TMA+ uptake k'. SD was elicited by needle prick. SD was significantly
      longer at P13-15 than at P21 and in adults. During SD, alpha in all age groups
      decreased from 0.21-0.23 to 0.05-0.09; lambda increased from 1.55-1.65 to 1.95
      2.07. Ten minutes after SD, alpha (in adults) and lambda (all age groups)
      increased compared to controls. This increase persisted even 1 hour after SD.
      When SD was repeated at 1 hour intervals, both alpha and lambda showed a gradual
      cumulative increase with SD repetition. Our study also shows that cortical SD is,
      as early as P13, accompanied by severe ECS shrinkage and increased diffusion path
      length (tortuosity) with values similar to adults, followed by a long-lasting
      increase in ECS volume and tortuosity when compared to pre-SD values.

PMID- 12479790
TI  - Changes in the acoustically evoked activity in the inferior colliculus of the rat
      after functional ablation of the auditory cortex.
AB  - The role of the cortico-tectal pathways in the processing of auditory signals was
      investigated by recording the click-evoked responses and extracellular multiple
      unit activity in the inferior colliculus (IC) after functional ablation of the
      auditory cortex (AC) by local intracortical application of a sodium channel
      blocker, tetrodotoxin (TTX). Click-evoked IC responses (IC-ER) and multiple unit
      activity in response to tone bursts were recorded with implanted electrodes in
      the IC of rats lightly anaesthetized with xylazine. Neural activity was recorded
      before and after the application of TTX into the ipsilateral auditory cortex (AC)
      through three implanted cannulas in a total dose of 30 ng. The functional status
      of the AC was monitored by recording click-evoked middle latency responses from a
      ball electrode implanted on the AC. During inactivation of the AC, IC-ER
      amplitudes were either increased (48 % of the cases), decreased (32 % of the
      cases) or not evidently changed (20 % of the cases). Corresponding effects were
      observed in the firing rate of IC neurons. Functional ablation of the AC also
      resulted in a significant prolongation of the latencies of individual waves of
      the IC-ER. However, the discharge pattern of the multiple unit responses,
      response thresholds and tuning were not altered during AC inactivation. IC neural
      activity recovered within several hours, and maximally during 2 days. The results
      reveal principles of the interaction of cortico-tectal pathways with IC neuronal
      activity.

PMID- 12479791
TI  - Decomposing stimulus complexes and dissecting art: a theory of evaluation.
AB  - A theoretical model is presented, which attempts to account for the evaluation of
      complex stimuli in terms of their constituent elements that are relevant to the
      intent of the assessment. The subjective evaluation of a compound stimulus is
      postulated to be a function of the number, weight and integrity of critical
      components, or sub-qualities, and their interactions. The model has application
      to the evaluation of any stimulus complex including works of "art". For
      illustrative purpose, it will here be applied to the analysis of pictorial works
      of art.

PMID- 12479792
TI  - Kinetic model of the inositol trisphosphate receptor that shows both steady-state
      and quantal patterns of Ca2+ release from intracellular stores.
AB  - The release of Ca(2+) from intracellular stores via InsP(3) receptors shows
      anomalous kinetics. Successive additions of low concentrations of InsP(3) cause
      successive rapid transients of Ca(2+) release. These quantal responses have been
      ascribed to all-or-none release from stores with differing sensitivities to
      InsP(3) or, alternatively, to a steady-state mechanism where complex kinetic
      properties of the InsP(3) receptor allow partial emptying of all the stores. We
      present here an adaptive model of the InsP(3) receptor that can show either
      pattern, depending on the imposed experimental conditions. The model proposes two
      interconvertible conformational states of the receptor: one state binds InsP(3)
      rapidly, but with low affinity, whereas the other state binds slowly, but with
      high affinity. The model shows repetitive increments of Ca(2+) release in the
      absence of a Ca(2+) gradient, but more pronounced incremental behaviour when
      released Ca(2+) builds up at the mouth of the channel. The sensitivity to Ins P
      (3) is critically dependent on the density of InsP(3) receptors, so that
      different stores can respond to different concentration ranges of Ins P (3).
      Since the model generates very high Hill coefficients (h approximately 7), it
      allows all-or-none release of Ca(2+) from stores of differing receptor density,
      but questions the validity of the use of h values as a guide to the number of
      InsP(3) molecules needed to open the channel. The model presents a mechanism for
      terminating Ca(2+) release in the presence of positive feedback from released
      Ca(2+), thereby providing an explanation of why elementary Ca(2+) signals
      ('blips' and 'puffs') do not inevitably turn into regenerative waves.

PMID- 12479793
TI  - Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells
      requires receptor-interacting protein-dependent nuclear factor kappa B
      activation.
AB  - Tumour necrosis factor alpha (TNF-alpha) binds to its receptor (TNFR1) and
      activates both death- and inflammation/survival-related signalling pathways. The
      inflammation and survival-related signalling cascade results in the activation of
      the transcription factor, nuclear factor kappa B (NF-kappa B) and requires
      recruitment of receptor-interacting protein (RIP) to TNFR1. The indispensable
      role of RIP in TNF-induced NF-kappa B activation has been demonstrated in RIP(-/
      ) mice and in cell lines derived from such mice. In the present study, we show
      that the TNF-alpha-induced accumulation of hypoxia-inducible factor 1 alpha (HIF
      1 alpha) protein in normoxic cells is RIP-dependent. Exposing fibroblasts derived
      from RIP(-/-) mice to either cobalt or PMA resulted in an equivalent HIF-1 alpha
      induction to that seen in RIP(+/+) fibroblasts. In contrast, RIP(-/-) cells were
      unable to induce HIF-1 alpha in response to TNF-alpha. Further, transient
      transfection of NIH 3T3 cells with an NF-kappa B super-repressor plasmid (an
      inhibitor of NF-kappa B activation) also prevented HIF-1 alpha induction by TNF
      alpha. Surprisingly, although HIF-1 alpha mRNA levels remained unchanged after
      induction by TNF, induction of HIF-1 alpha protein by the cytokine was completely
      blocked by pretreatment with the transcription inhibitors actinomycin D and 5,6
      dichlorobenzimidazole riboside. Finally, TNF failed to induce both HIF-1 alpha,
      made resistant to von Hippel-Lindau (VHL), and wild-type HIF-1 alpha transfected
      into VHL(-/-) cells. These results indicate that HIF-1 alpha induction by TNF
      alpha in normoxic cells is mediated by protein stabilization but is nonetheless
      uniquely dependent on NF-kappa B-driven transcription. Thus the results describe
      a novel mechanism of HIF-1 alpha up-regulation and they identify HIF-1 alpha as a
      unique component of the NF-kappa B-mediated inflammatory/survival response.

PMID- 12479794
TI  - Degradation of mutant initiator protein DnaA204 by proteases ClpP, ClpQ and Lon
      is prevented when DNA is SeqA-free.
AB  - A mutant form of the Escherichia coli replication initiator protein, DnaA204, is
      unstable. At low growth rates, the dnaA204 mutant cells experience a limitation
      of initiator protein and grow with reduced initiation frequency and DNA
      concentration. The mutant DnaA protein is stabilized by the lack of SeqA protein.
      This stabilization was also observed in a dam mutant where the chromosome remains
      unmethylated. Since unmethylated DNA is not bound by SeqA, this indicates that
      DnaA204 is not stabilized by the lack of SeqA protein by itself, but rather by
      lack of SeqA complexed with DNA. Thus the destabilization of DnaA204 may be due
      either to interaction with SeqA-DNA complexes or changes in nucleoid organization
      and superhelicity caused by SeqA. The DnaA204 protein was processed through
      several chaperone/protease pathways. The protein was stabilized by the presence
      of the chaperones ClpA and ClpX and degraded by their cognate protease ClpP. The
      dnaA204 mutant was not viable in the absence of ClpY, indicating that this
      chaperone is essential for DnaA204 stability or function. Its cognate protease
      ClpQ, as well as Lon protease, degraded DnaA204 to the same degree as ClpP. The
      chaperones GroES, GroEL and DnaK contributed to stabilization of DnaA204 protein.

PMID- 12479795
TI  - Organochlorine pollutants [corrected] in California sea lions revisited.
AB  - BACKGROUND: Dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls
      (PCBs) are ubiquitous environmental contaminants that have been banned in most
      countries, but considerable amounts continue to cycle the ecosphere. Top trophic
      level predators, like sea birds and marine mammals, bioaccumulate these
      lipophilic compounds, reflecting their presence in the environment. RESULTS: We
      measured concentrations of tDDT (p,p' - DDT + p,p' - DDD + p,p' - DDE) and PCBs
      in the blubber of dead California sea lions stranded along the California coast.
      tDDT and PCB concentrations were 150 +/- 257 ug/g lipid weight (mean +/- SD) and
      44 +/- 78 ug/g lipid weight, respectively. There were no differences in tDDT or
      PCB concentrations between animal categories varying in sex or age. There was a
      trend towards a decrease in tDDT and PCB concentrations from northern to southern
      California. The lipid content of the blubber was negatively correlated with
      levels of tDDT and PCBs. tDDT concentrations were approximately 3 times higher
      than PCB concentrations. CONCLUSIONS: tDDT levels in the blubber of California
      sea lions decreased by over one order of magnitude from 1970 to 2000. PCB level
      changes over time were unclear owing to a paucity of data and analytical
      differences over the years. Current levels of these pollutants in California sea
      lions are among the highest among marine mammals and exceed those reported to
      cause immunotoxicity or endocrine disruption.

PMID- 12479797
TI  - Outliers involving the Poly(A) effect among highly-expressed genes in
      microarrays.
AB  - BACKGROUND: The Poly(A) effect is a cross-hybridization artifact in which poly(T)
      containing molecules, which are produced by the reverse transcription of a
      poly(A)+ RNA mixture, bind promiscuously to the poly(A) stretches of the DNA in
      microarray spots. It is customary to attempt to block such hybridization by
      adding poly(A) to the hybridization solution. This note describes an experiment
      intended to evaluate circumstances under which the blocking procedure may not
      have been successful. RESULTS: The experiment involves a spot-by-spot comparison
      between the hybridization signals obtained by hybridizing a microarray to: (1)
      end-labeled oligo(dT), versus, (2) cDNA prepared from muscle tissue. We found
      that the blocking appears to be successful for the vast majority of microarray
      spots, as evidenced by the weakness of the correlation between signals (1) and
      (2). However, we found that for microarray spots having oligo(dT) hybridization
      levels greater than a certain threshold, the blocking might be ineffective or
      incomplete, as evidenced by an exceptionally strong signal (2) whenever signal
      (1) is greater than the threshold. CONCLUSION: The PolyA effect may be more
      subtle than simply a hybridization signal that is proportional to the PolyA
      content of each microarray spot. It may instead be present only in spots that
      hybridize oligo(dT) greater than some threshold level. The strong signal
      generated at these "outlier" spots by cDNA probes might be due to the formation
      of hybridization heteropolymers.

PMID- 12479798
TI  - A MyoD-dependent differentiation checkpoint: ensuring genome integrity.
AB  - In a recent paper, the concept of a genotoxic stress-induced differentiation
      checkpoint has been proposed. The suggested function of this checkpoint is to
      preserve the integrity of the genome in terminally differentiated cells.

PMID- 12479799
TI  - Disulfide bond formation, a race between FAD and oxygen.
AB  - The long-running race to find the source of oxidizing potential for disulfide
      bond formation is over. The winner is one of the first contestants to enter:
      oxygen.

PMID- 12479800
TI  - The web and the rock: cell adhesion and the ARP2/3 complex.
AB  - Cell locomotion entails functional and structural cooperation between cell
      surface adhesion and the actin cytoskeleton. A new paper by DeMali et al.
      provides new insights into the link between actin assembly and integrin adhesion
      at the leading edges of migrating cells.

PMID- 12479801
TI  - One ring to bind them. Septins and actin assembly.
AB  - Septins are GTPases required for cytokinesis and other processes requiring
      spatial organization of the cell cortex, but their molecular functions in these
      processes are unknown. In this issue of Developmental Cell, Kinoshita et al. take
      an important step in elucidating the molecular functions of septins by developing
      an in vitro assay for septin assembly and exploring the relationship between
      mammalian septins and actin.

PMID- 12479802
TI  - Hijacking the host cell proteasome.
AB  - Uropathogenic Escherichia coli subvert host cell signaling mechanisms to induce
      cellular responses that facilitate bacterial invasion and colonization. A recent
      publication in the November 15 issue of Cell shows that the bacterium may
      accomplish such a feat by hijacking the proteasome machinery.

PMID- 12479803
TI  - The Jak/STAT pathway in model organisms: emerging roles in cell movement.
AB  - The JAK/STAT pathway was originally identified in mammals. Studies of this
      pathway in the mouse have revealed that JAK/STAT signaling plays a central role
      during hematopoeisis and other developmental processes. The role of JAK/STAT
      signaling in blood appears to be conserved throughout evolution, as it is also
      required during fly hematopoeisis. Studies in Dictyostelium, Drosophila, and
      zebrafish have shown that the JAK/STAT pathway is also required in an unusually
      broad set of developmental decisions, including cell proliferation, cell fate
      determination, cell migration, planar polarity, convergent extension, and
      immunity. There is increasing evidence that the versatility of this pathway
      relies on its cooperation with other signal transduction pathways. In this
      review, we discuss the components of the JAK/STAT pathway in model organisms and
      what is known about its requirement in cellular and developmental processes. In
      particular, we emphasize recent insights into the role that this pathway plays in
      the control of cell movement.

PMID- 12479804
TI  - Dma1 prevents mitotic exit and cytokinesis by inhibiting the septation initiation
      network (SIN).
AB  - In the fission yeast Schizosaccharomyces pombe, the septation initiation network
      (SIN) triggers cytokinesis after mitosis. We investigated the relationship
      between Dma1p, a spindle checkpoint protein and cytokinesis inhibitor, and the
      SIN. Deletion of dma1 inactivates the spindle checkpoint and allows precocious
      SIN activation, while overexpressing Dma1p reduces SIN signaling. Dma1p seems to
      function by inhibiting the SIN activator, Plo1p kinase, since dma1 overexpression
      and deletion phenotypes suggest that Dma1p antagonizes Plo1p localization.
      Furthermore, failure to maintain high cyclin-dependent kinase (CDK) activity
      during spindle checkpoint activation in dma1 deletion cells requires Plo1p. Dma1p
      itself localizes to spindle pole bodies through interaction with Sid4p. Our
      observations suggest that Dma1p functions to prevent mitotic exit and cytokinesis
      during spindle checkpoint arrest by inhibiting SIN signaling.

PMID- 12479805
TI  - Self- and actin-templated assembly of Mammalian septins.
AB  - Septins are polymerizing GTPases required for cytokinesis and cortical
      organization. The principles by which they are targeted to, and assemble at,
      specific cell regions are unknown. We show that septins in mammalian cells switch
      between a linear organization along actin bundles and cytoplasmic rings,
      approximately 0.6 microm in diameter. A recombinant septin complex self-assembles
      into rings resembling those in cells. Linear organization along actin bundles was
      reconstituted by adding an adaptor protein, anillin. Perturbation of septin
      organization in cells by expression of a septin-interacting fragment of anillin
      or by septin depletion via siRNA causes loss of actin bundles. We conclude that
      septins alone self-assemble into rings, that adaptor proteins recruit septins to
      actin bundles, and that septins help organize these bundles.

PMID- 12479806
TI  - Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and
      required for signal transduction.
AB  - Eukaryotic cells use the extracellular signal regulated kinase (ERK) cascade to
      connect cell-surface receptors to intracellular targets. Although various signals
      are routed through the ERK pathway, cells respond accordingly to a given
      stimulus. To regulate proper signal transduction, scaffolds and adaptors are
      employed to organize specific signaling units. The scaffold protein MP1 (MEK1
      partner) assembles a scaffold complex in the ERK cascade. We show that p14
      functions as an adaptor protein, which is required and sufficient to localize MP1
      to endosomes. Reduction of MP1 or p14 protein levels by siRNAi results in
      defective signal transduction. Therefore, our results suggest that the endosomal
      localization of the p14/MP1-MAPK scaffold complex is crucial for signal
      transduction.

PMID- 12479807
TI  - Studies of cargo delivery to the vacuole mediated by autophagosomes in
      Saccharomyces cerevisiae.
AB  - In the yeast Saccharomyces cerevisiae, aminopeptidase I (API), a vacuolar
      hydrolase, is selectively transported to the vacuole via the autophagosome. API
      forms a cytosol to vacuole targeting (Cvt) complex in the cytoplasm. The complex
      is engulfed by the autophagosome under starvation conditions. In this study, the
      Cvt complex is visualized as a dot in the cytoplasm by fluorescence microscopy
      with API-GFP. The Cvt complex associates with the preautophagosomal structure
      (PAS), which plays a central role in autophagosome formation. In a Deltacvt19
      mutant, which is specifically defective in API transport, but not in autophagy,
      the Cvt complex forms normally but never associates with the PAS. This indicates
      that Cvt19p mediates association between the Cvt complex and the PAS.

PMID- 12479808
TI  - Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway.
AB  - The proper functioning of eukaryotic organelles is largely dependent on the
      specific packaging of cargo proteins within transient delivery vesicles. The
      cytoplasm to vacuole targeting (Cvt) pathway is an autophagy-related trafficking
      pathway whose cargo proteins, aminopeptidase I and alpha-mannosidase, are
      selectively transported from the cytoplasm to the lysosome-like vacuole in yeast.
      This study elucidates a molecular mechanism for cargo specificity in this pathway
      involving four discrete steps. The Cvt19 receptor plays a central role in this
      process: distinct domains in Cvt19 recognize oligomerized cargo proteins and link
      them to the vesicle formation machinery via interaction with Cvt9 and Aut7.
      Because autophagy is the primary mechanism for organellar turnover, these results
      offer insights into physiological processes that are critical in cellular
      homeostasis, including specific packaging of damaged or superfluous organelles
      for lysosomal delivery and breakdown.

PMID- 12479809
TI  - Scabrous controls ommatidial rotation in the Drosophila compound eye.
AB  - Establishment of planar polarity in the Drosophila compound eye requires precise
      90 degrees rotation of the ommatidial clusters during development. We found that
      the morphogenetic furrow controls the stop of ommatidial rotation at 90 degrees
      by emitting signals to posterior ommatidial clusters. One such signal, Scabrous,
      is synthesized in the furrow cells and transported in vesicles to ommatidial row
      6-8. Scabrous vesicles are transported through actin-based cellular extensions
      but not transcytosis. Scabrous functions nonautonomously to control the stop of
      ommatidial rotation by suppressing nemo activity in the second 45 degrees
      rotation. We propose that the morphogenetic furrow regulates precise ommatidial
      rotation by transporting Scabrous and perhaps other factors through actin-based
      cellular extensions.

PMID- 12479810
TI  - Nonautonomous planar polarity patterning in Drosophila: dishevelled-independent
      functions of frizzled.
AB  - The frizzled (fz) gene of Drosophila is required for planar polarity
      establishment in the adult cuticle, acting both cell autonomously and
      nonautonomously. We demonstrate that these two activities of fz in planar
      polarity are temporally separable in both the eye and wing. The nonautonomous
      function is dishevelled (dsh) independent, and its loss results in polarity
      phenotypes that resemble those seen for mutations in dachsous (ds). Genetic
      interactions and epistasis analysis suggest that fz, ds, and fat (ft) act
      together in the long-range propagation of polarity signals in the eye and wing.
      We also find evidence that polarity information may be propagated by modulation
      of the binding affinities of the cadherins encoded by the ds and ft loci.

PMID- 12479811
TI  - VASA localization requires the SPRY-domain and SOCS-box containing protein,
      GUSTAVUS.
AB  - VASA (VAS), a key protein in establishing the specialized translational activity
      of the Drosophila pole plasm, accumulates at the posterior pole of the developing
      oocyte. We identified a gene, gustavus (gus), that encodes a protein that
      interacts with VAS. A gus mutation blocks posterior localization of VAS, as does
      deletion of a segment of VAS containing the GUS binding site. Like VAS, GUS is
      present in cytoplasmic ribonucleoprotein particles. Heterozygotes for gus or a
      deletion including gus produce embryos with fewer pole cells and posterior
      patterning defects. Therefore, GUS is essential for the posterior localization of
      VAS. However, gus is not required for the posterior localization of oskar (osk).
      Apparent gus orthologs are present in mammalian genomes.

PMID- 12479812
TI  - IGF-2 is a mediator of prolactin-induced morphogenesis in the breast.
AB  - The mechanisms by which prolactin controls proliferation of mammary epithelial
      cells (MECs) and morphogenesis of the breast epithelium are poorly understood. We
      show that cyclin D1(-/-) MECs fail to proliferate in response to prolactin and
      identify IGF-2 as a downstream target of prolactin signaling that lies upstream
      of cyclin D1 transcription. Ectopic IGF-2 expression restores alveologenesis in
      prolactin receptor(-/-) epithelium. Alveologenesis is retarded in IGF-2-deficient
      MECs. IGF-2 and prolactin receptor mRNAs colocalize in the mammary epithelium.
      Prolactin induces IGF-2 mRNA and IGF-2 induces cyclin D1 protein in primary MECs.
      Thus, IGF-2 is a mediator of prolactin-induced alveologenesis; prolactin, IGF-2,
      and cyclin D1, all of which are overexpressed in breast cancers, are components
      of a developmental pathway in the mammary gland.

PMID- 12479813
TI  - Induction and activation of the transcription factor NFATc1 (NFAT2) integrate
      RANKL signaling in terminal differentiation of osteoclasts.
AB  - Signaling by RANKL is essential for terminal differentiation of
      monocytes/macrophages into osteoclasts. The TRAF6 and c-Fos signaling pathways
      both play important roles downstream of RANKL. We show here that RANKL
      selectively induces NFATc1 expression via these two pathways. RANKL also evokes
      Ca(2+) oscillations that lead to calcineurin-mediated activation of NFATc1, and
      therefore triggers a sustained NFATc1-dependent transcriptional program during
      osteoclast differentiation. We also show that NFATc1-deficient embryonic stem
      cells fail to differentiate into osteoclasts in response to RANKL stimulation,
      and that ectopic expression of NFATc1 causes precursor cells to undergo efficient
      differentiation without RANKL signaling. Thus, NFATc1 may represent a master
      switch for regulating terminal differentiation of osteoclasts, functioning
      downstream of RANKL.

PMID- 12479814
TI  - The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte
      differentiation.
AB  - The retinoblastoma protein (RB) has previously been shown to facilitate adipocyte
      differentiation by inducing cell cycle arrest and enhancing the transactivation
      by the adipogenic CCAAT/enhancer binding proteins (C/EBP). We show here that the
      peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor
      pivotal for adipogenesis, promotes adipocyte differentiation more efficiently in
      the absence of RB. PPARgamma and RB were shown to coimmunoprecipitate, and this
      PPARgamma-RB complex also contains the histone deacetylase HDAC3, thereby
      attenuating PPARgamma's capacity to drive gene expression and adipocyte
      differentiation. Dissociation of the PPARgamma-RB-HDAC3 complex by RB
      phosphorylation or by inhibition of HDAC activity stimulates adipocyte
      differentiation. These observations underscore an important function of both RB
      and HDAC3 in fine-tuning PPARgamma activity and adipocyte differentiation.

PMID- 12479815
TI  - T cell development in culture.
AB  - The T cell compartment is continuously replenished by a renewable source of stem
      cells. In the adult, bone marrow-derived stem cells seed the thymus and initiate
      a developmental program that requires a series of incompletely understood signals
      that are normally provided by the thymus. Failure to recapitulate this process in
      simple in vitro cultures has hampered efforts to fully characterize these unique
      signals. In this issue of Immunity, Schmitt and Zuniga-Pflucker describe a simple
      in vitro culture system that is able to generate mature T cells from fetal liver
      stem cells by expressing the Notch ligand Delta-1 on the OP9 stromal cell line.
      This finding should greatly enhance efforts to study T cell development and may
      provide a tool for generating defined T cell populations in vitro.

PMID- 12479816
TI  - Real-time visualization of mycobacterium-macrophage interactions leading to
      initiation of granuloma formation in zebrafish embryos.
AB  - Infection of vertebrate hosts with pathogenic Mycobacteria, the agents of
      tuberculosis, produces granulomas, highly organized structures containing
      differentiated macrophages and lymphocytes, that sequester the pathogen. Adult
      zebrafish are naturally susceptible to tuberculosis caused by Mycobacterium
      marinum. Here, we exploit the optical transparency of zebrafish embryos to image
      the events of M. marinum infection in vivo. Despite the fact that the embryos do
      not yet have lymphocytes, infection leads to the formation of macrophage
      aggregates with pathological hallmarks of granulomas and activation of previously
      identified granuloma-specific Mycobacterium genes. Thus, Mycobacterium-macrophage
      interactions can initiate granuloma formation solely in the context of innate
      immunity. Strikingly, infection can redirect normal embryonic macrophage
      migration, even recruiting macrophages seemingly committed to their
      developmentally dictated tissue sites.

PMID- 12479817
TI  - IFN-gamma represses IL-4 expression via IRF-1 and IRF-2.
AB  - Polarization of CD4(+) T helper cells toward either a Th1 or Th2 response can
      significantly influence host immunity to pathogens. IL-4 and IFN-gamma are the
      signature cytokines of Th2 and Th1 cells, respectively. IFN-gamma was shown to
      assist Th1 development by promoting IL-12 and IL-12 receptor expression. So far,
      direct influence of Th2 cytokine expression by IFN-gamma has not been described.
      We show here that IFN-gamma directly suppresses IL-4 gene expression. IRF-1 and
      IRF-2 induced by IFN-gamma bind to three distinct IL-4 promoter sites and
      function as transcriptional repressors. Our data demonstrate a direct negative
      feedback of IFN-gamma on expression of the Th2 cytokine gene IL-4 and, thus,
      provide evidence for another important mechanism by which IFNgamma assists Th1
      and attenuates Th2 responses.

PMID- 12479818
TI  - Complement receptors CD21/35 link innate and protective immunity during
      Streptococcus pneumoniae infection by regulating IgG3 antibody responses.
AB  - The CD21/35 receptor provides an important link between innate and adaptive
      immunity. Its importance during protective immune responses to encapsulated
      extracellular bacteria was assessed using a new line of mice completely deficient
      in CD21/35 expression (CD21/35(-/-)). CD21/35 expression was essential for the
      rapid trapping of C3dg-antigen complexes by B cells in vivo, especially in
      splenic marginal zones. Despite normal B cell development in CD21/35(-/-) mice, T
      cell-independent and -dependent antibody responses to low-dose antigens were
      significantly decreased, with a striking impairment in IgG3 responses.
      Accordingly, CD21/35(-/-) mice were more susceptible to acute lethal
      Streptococcus pneumoniae infection. Thus, CD21/35 expression is critical for
      early protective antibody responses to lethal pathogens that rapidly multiply and
      quickly overwhelm the immune system.

PMID- 12479819
TI  - NKT cells inhibit the onset of diabetes by impairing the development of
      pathogenic T cells specific for pancreatic beta cells.
AB  - To determine the precise regulatory effect of NKT cells on CD4(+) T cells
      involved in autoimmune diabetes, we developed an in vivo model in which
      transferred naive transgenic T cells are stimulated by their antigen in the
      presence or absence of NKT cells or in the presence of another conventional
      transgenic alphabeta T cell. The presence of NKT cells did not block the initial
      activation and expansion of the CD4(+) T cells but did inhibit their IL-2 and IFN
      gamma production and later proliferation, resulting in an anergic phenotype.
      These CD4(+) T cells did not induce significant insulitis and were unable to
      destroy the beta cells. Thus, NKT cells prevent alphabeta CD4 T cell
      differentiation into effector cells.

PMID- 12479820
TI  - Increasing tumor antigen expression overcomes "ignorance" to solid tumors via
      crosspresentation by bone marrow-derived stromal cells.
AB  - To explain why solid cancers grow or are rejected, we examined how the tumor
      stroma affected the level of antigen expression necessary to induce an immune
      response. We applied a tamoxifen-regulated Cre-loxP system to induce a model
      SIYRYYGL antigen recognized by the 2C T cell receptor. Solid tumors expressing
      the antigen at lower levels grew, whereas solid tumors expressing antigen induced
      to 26-fold higher levels were rejected. In contrast, mice rejected cell
      suspensions expressing higher or lower levels of the antigen. The antigen was
      likely crosspresented because draining lymph node responses required bone marrow
      derived cells in the tumor stroma. Thus, tumor antigens expressed at levels
      sufficient for crosspresentation by bone marrow-derived stromal cells may
      overcome immunological "ignorance" to solid tumors.

PMID- 12479821
TI  - Induction of T cell development from hematopoietic progenitor cells by delta-like
      1 in vitro.
AB  - The molecular interactions provided by the thymic microenvironment that predicate
      T cell development remain obscure. Here, we show that a bone marrow stromal cell
      line ectopically expressing the Notch ligand Delta-like-1 loses its ability to
      support B cell lymphopoiesis, but acquires the capacity to induce the
      differentiation of hematopoietic progenitors into CD4 CD8 double- and single
      positive T cells. Both gammadelta-TCR(+) and alphabeta-TCR(+) T cells are
      generated, and CD8(+) TCR(hi) cells produce gamma-interferon following CD3/TCR
      stimulation. These results establish that expression of Delta-like-1 on stromal
      cells provides key signals for the induction of T cell lineage commitment, stage
      specific progenitor expansion, TCR gene rearrangement, and T cell differentiation
      in the absence of a thymus. Thus, it is likely that Delta-like-1/Notch
      interactions by the thymus underpin its unique ability to promote lineage
      commitment and differentiation of T cells.

PMID- 12479822
TI  - A structural basis for LCMV immune evasion: subversion of H-2D(b) and H-2K(b)
      presentation of gp33 revealed by comparative crystal structure.Analyses.
AB  - LCMV infection of H-2(b) mice generates a CD8(+) CTL response mainly directed
      toward three immunodominant epitopes. One of these, gp33, is presented by both H
      2D(b) and H-2K(b) MHC class I molecules. The virus can escape immune recognition
      in the context of both these MHC class I molecules through single mutations of
      the peptide. In order to understand the underlying structural mechanism, we
      determined the crystal structures of both complexes. The structures reveal that
      the peptide is presented in two diametrically opposed manners by H-2D(b) and H
      2K(b), with residues used as anchor positions in one MHC class I molecule
      interacting with the TCR in the other. Importantly, the peptide's N-terminal
      residue p1K protrudes from the binding cleft in H-2K(b). We present structural
      evidence that explains the functional consequences of single mutations found in
      escape variants.

PMID- 12479823
TI  - Importance of innate immunity and collagen binding integrin alpha1beta1 in TNBS
      induced colitis.
AB  - Inflammation occurs in the context of integrin-mediated adhesive interactions of
      cells with their extracellular matrix environment. We investigated the role of
      the collagen binding integrin alpha1beta1 in a model of colitis. alpha1beta1 was
      expressed on lamina propria T cells and monocytes during disease. Both alpha1
      deficiency and anti-alpha1 mAb treatment (prophylactic and therapeutic) protected
      against colitis. In vivo alpha1beta1 blockade improved macroscopic and histologic
      scores, decreased inflammatory cytokine production, and profoundly affected the
      ability of lamina propria mononuclear cells to proliferate and produce IFN-gamma
      in vitro. Development and alpha1-mediated inhibition of colitis can be lymphocyte
      independent, suggesting that activated monocytes also represent a key alpha1beta1
      expressing cell type involved in colitis. These results underscore the importance
      of innate immunity and, specifically, of leukocyte/matrix interactions in
      regulating local inflammatory responses.

PMID- 12479824
TI  - Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1.
AB  - The B lineage commitment factor Pax5 (BSAP) is exclusively expressed in B
      lymphocytes of the blood system. To study the effect of Pax5 on the development
      of other hematopoietic lineages, we generated a heterozygous knockin mouse
      carrying a Pax5 minigene under the control of the Ikaros locus. Conditional and
      constitutive activation of the Ik(Pax5) allele demonstrated that precocious Pax5
      expression in hematopoietic stem cells and progenitors failed to interfere with
      myeloid development and only weakly affected erythroblast formation. Instead, pan
      hematopoietic Pax5 expression strongly promoted B cell development at the expense
      of T lymphopoiesis. Pax5 thereby interfered with T lineage commitment and early
      thymocyte development by repressing the transcription of the T cell specification
      gene Notch1.

PMID- 12479825
TI  - Cell membrane modification for rapid display of proteins as a novel means of
      immunomodulation: FasL-decorated cells prevent islet graft rejection.
AB  - Long-term display of exogenous proteins on the cell surface may have important
      research and therapeutic implications. We report a novel method for the cell
      surface display of proteins that involves generation of a chimeric protein with
      core streptavidin, biotinylation of cells, and "decoration" with the protein. A
      chimeric protein with the extracellular portions of FasL (SA-FasL) was
      efficiently displayed on the cell surface within 2 hr without detectable cellular
      toxicity. Biotin and SA-FasL persisted on the cell surface for weeks in vitro and
      in vivo. Immunomodulation with SA-FasL-decorated splenocytes effectively blocked
      alloreactive responses in naive and presensitized rodents and prevented the
      rejection of allogeneic pancreatic islets. This approach may serve as an
      alternative to gene transfer-based expression with broad research and therapeutic
      applications.

PMID- 12479826
TI  - Dynamics of p56lck translocation to the T cell immunological synapse following
      agonist and antagonist stimulation.
AB  - To study the spatio/temporal recruitment of lck during immunological synapse
      formation, we utilize high-speed time-lapse microscopy to visualize green
      fluorescent protein (GFP) fusions of lck and CD3zeta following agonist or altered
      peptide ligand (APL) stimulation. The dynamics of lck and CD3zeta recruitment are
      comparable; however, lck becomes excluded to the periphery of mature synapses,
      while most CD3zeta is centrally localized, suggesting a limited time frame within
      which lck can efficiently phosphorylate CD3 molecules during synapse maturation.
      Exposure of T cells to specific APLs affects the efficiency of conjugate
      formation and lck accumulation. Most surprisingly, we find an intracellular pool
      of lck associated with recycling endosomes that translocates to mature synapses
      within 10 min of calcium flux. This bolus of lck may contribute to intermediate
      late signal transduction.

PMID- 12479827
TI  - Different cytokines induce surface lymphotoxin-alphabeta on IL-7 receptor-alpha
      cells that differentially engender lymph nodes and Peyer's patches.
AB  - The formation of lymph nodes (LN) and Peyer's patches (PP) can be distinguished
      by the requirement of RANK for LN but not IL-7R(alpha), which is essential for PP
      development. However, lymphotoxin-alphabeta (LT(alpha)beta) signaling is required
      for both organs. The cellular basis underlying this dichotomy was revealed by the
      finding that the fetal IL-7R(alpha)(+) population responded equally well to IL-7
      and RANKL to express LT(alpha)beta. IL-7R(alpha)(+) cells harvested from TRAF6(-/
      ) embryos expressed LTalphabeta in response to IL-7 but not RANKL, demonstrating
      that the RANK-TRAF6 signaling pathway regulates LT(alpha)beta expression in LN
      but not in PP. Soluble IL-7 administered to TRAF6(-/-) embryos was sufficient to
      restore LN genesis indicating the functional similarities of the IL-7R(alpha)(+)
      inducer cells for LN and PP genesis.

PMID- 12479828
TI  - Determination of serine/threonine protein phosphatase type 2B PP2B in lymphocytes
      by HPLC.
AB  - Current cyclosporin (CsA) and tacrolimus (FK506) monitoring methods are based on
      blood concentrations determination, but the optimal sampling times are not
      clearly defined. An alternative pharmacodynamic approach has recently been
      introduced, based on assaying lymphocytes activity of calcineurin (PP2B), a
      phosphatase that is partially inhibited by CsA and FK506. However, the princeps
      method uses large amounts of radioactive [32P]substrate, raising a number of
      safety issues. Here we describe an alternative method for PP2B activity
      determination, based on HPLC coupled with spectrophotometric detection. A 19
      amino-acid peptide is phosphorylated by a protein kinase, and further
      dephosphorylated by lymphocyte PP2B in the presence of okadaic acid. The two
      peptides are separated by using reverse-phase chromatography with a detection
      wavelength of 205 nm. After lymphocyte isolation by density-gradient
      centrifugation, PP2B activity is derived from the dephosphorylated peptide
      concentration measured during the first 6 min of the enzymatic reaction. This
      technique gives reproducible results and good analytical sensitivity with 10(6)
      lymphocytes. With an average isolation rate of 59.6%, only 7 ml of blood is
      required, making the method suitable for lymphopenic patients. Moreover, PP2B
      activity is stable in blood samples kept for 24h at room temperature and in
      isolated lymphocytes stored for 48 h at -20 degrees C. We validated the method by
      comparing median PP2B activity in 10 healthy volunteers (285.0+/-46.5
      pmol/min/10(6)lymphocytes) and in 10 liver transplant patients (147.8+/-71.0
      pmol/min/10(6)lymphocytes) (p<0.001). The relation between calcineurin activity
      and tacrolimus blood concentrations was also studied.

PMID- 12479829
TI  - Detection of fumonisin B1: comparison of flow-injection liposome immunoanalysis
      with high-performance liquid chromatography.
AB  - Fumonisins are secondary metabolites of the fungus Fusarium moniliforme, a common
      mycotoxin in corn, which are known to cause cancer in a number of experimental
      animals and have been linked to human esophageal cancer in China and South
      Africa. A high-performance liquid chromatographic (HPLC) method is currently the
      most widely used method for the quantitative determination of fumonisins. This
      method utilizes precolumn derivatization with o-phthaldialdehyde, isocratic
      elution, and fluorescence detection. In this study, the HPLC method was chosen as
      the reference method to evaluate the reproducibility and accuracy of FILIA (flow
      injection liposome immunoanalysis) for the detection of the fumonisin B1 (FmB1).
      Studies indicate that a recovery of 86-90% could be obtained when commercial
      yellow cornmeal spiked with FmB1 was extracted in 75% methanol, which correlated
      favorably (correlation coefficient, r(2)=0.945) with the result of 80-92%
      obtained using the flow-injection liposome immunoanalysis (FILIA) system. The
      data suggest that the FILIA method is comparable to HPLC for the detection of
      fumonisins in corn, animal feeds, and human foods. Important features of FILIA as
      compared to HPLC are, most importantly, lower detection limit (ca. 25 x lower),
      and also less complex and faster sample preparation and therefore increased
      analytical throughput. In addition, 24 human corn-based foods and 6 animal feeds
      were examined for the presence of FmB1 using HPLC and FILIA.

PMID- 12479830
TI  - Method for determining monohydroxybenzo[a]pyrene isomers using column-switching
      high-performance liquid chromatography.
AB  - A method for determining monohydroxybenzo[a]pyrene (OHBaP) isomers using column
      switching high-performance liquid chromatography with fluorescence detection was
      developed. Eleven of 12 isomers of OHBaP (all except 6-OHBaP) were separated on
      an alkylamide-type reversed-phase column and, via column-switching, on a beta
      cyclodextrin-bonded silica gel column. The detection limits for the OHBaPs were
      in the range 0.3-8 pg/injection (S/N=3). By using this method, 1-, 3-, and 9
      OHBaPs were identified as major metabolites of benzo[a]pyrene in vitro by human
      recombinant p450 1A1. The method was used to determine OHBaPs in the urine of a
      nonsmoker subject. After enzymatic hydrolysis of the conjugated metabolites by
      beta-glucuronidase/aryl sulfatase, the analytes were selectively adsorbed on blue
      rayon (a cellulose-supported copper phthalocyanine) from the urine matrix.
      Methanol as the eluting solvent from the rayon gave the best recoveries of OHBaPs
      and 1-hydroxypyrene (1-OHP) in the range of 91-103%, which was superior to that
      of the solid-phase extraction method. 1-OHP, a well-known biomarker of the
      exposure to polycyclic aromatic hydrocarbons, was simultaneously analyzed. Intra-
      and interday accuracy values for the determination of 3-OHBaP in 200 ml of urine
      were 95.5 and 100.9%, and those for 1-OHP were 96.4 and 103.6%, respectively. The
      intra- and interday precision values were 3.9 and 2.4% for 3-OHBaP and 2.4 and
      3.2% for 1-OHP, respectively. In 11 kinds of isomers, only 3-OHBaP was detected
      in the human urine. Urinary concentration of 3-OHBaP was quantified at 0.5 ng/g
      creatinine concentration and the 3-OHBaP/1-OHP ratio was approximately 1/130.

PMID- 12479831
TI  - Direct spectrophotometric assay of monooxygenase and oxidase activities of
      mushroom tyrosinase in the presence of synthetic and natural substrates.
AB  - Alternative substrates were synthesized to allow direct and continuous
      spectrophotometric assay of both monooxygenase (cresolase) and oxidase
      (catecholase) activities of mushroom tyrosinase (MT). Using diazo derivatives of
      phenol, 4-[(4-methoxybenzo)azo]-phenol, 4-[(4-methylphenyl)azo]-phenol, 4
      (phenylazo)-phenol, and 4-[(4-hydroxyphenyl)azo]-benzenesulfonamide, and diazo
      derivatives of catechol 4-[(4-methylbenzo)azo]-1,2-benzenediol, 4-(phenylazo)-1,2
      benzenediol, and 4-[(4-sulfonamido)azo]-1,2 benzenediol (SACat), as substrates
      allows measurement of the rates of the corresponding enzymatic reactions through
      recording of the depletion rates of substrates at their lambda(max)(s) with the
      least interference of the intermediates' or products' absorption. Parallel
      attempts using natural compounds, p-coumaric acid and caffeic acid, as substrates
      for assaying both activities of MT were comparable approaches. Based on the
      ensuing data, the electronic effect of the substituent on the substrate activity
      and the affinity of the enzyme for the substrate are reviewed. Kinetic parameters
      extracted from the corresponding Lineweaver-Burk plots and advantages of these
      substrates over the previously used substrates in similar assays of tyrosinases
      are also presented.

PMID- 12479832
TI  - Determination of molecular weight of heparin by size exclusion chromatography
      with universal calibration.
AB  - The molecular weight (MW) of heparin can be accurately determined by size
      exclusion chromatography using "universal calibration." A universal calibration
      curve was constructed for Superose 12 with standard pullulan samples and verified
      using characterized ficoll fractions. This calibration yielded the correct MW of
      heparin as determined by light scattering, when the ionic strength of the mobile
      phase was maintained over 1.0M. Sodium poly(styrenesulfonate) samples were not
      suitable standards because of adsorption at high salt concentration and repulsion
      from the packing material at low ionic strength. The extraordinarily high charge
      density of heparin leads to the need for high salt concentration to screen such
      repulsions.

PMID- 12479833
TI  - Profiling substrate phosphorylation at the phosphopeptide level.
AB  - The identification of substrates is a key aspect in the study of the biological
      function of protein kinases. The procedure here described is aimed at profiling
      substrate phosphorylation at the phosphopeptide level by sequentially involving
      (i). the assessment of the in vitro activity of individual protein kinases on a
      complex mix of immobilized proteins, (ii). the fractionation of the
      phosphopeptides being released upon proteolysis of substrates, and (iii). the
      final identification of the targeted sequences. In particular, the protein sample
      is spotted onto nitrocellulose membrane and then subjected to a solid-phase
      kinase assay in the presence of [32P]ATP, prior to solid-phase proteolytic
      digestion and two-dimensional phosphopeptide mapping. Radiolabeled
      phosphopeptides are subsequently isolated and sequenced to identify the
      substrates being targeted by the examined protein kinase. Using the gamma-isotype
      of p21-activated protein kinase (gamma-PAK) and its known in vitro substrates, I
      verified that both the specificity of substrate phosphorylation and its
      efficiency are similar upon solid- and liquid-phase conditions. To demonstrate
      the feasibility of the overall experimental system, I then employed a fairly
      crude cell extract as a source of candidate substrates and successfully
      identified the sequence of a putative substrate of gamma-PAK.

PMID- 12479834
TI  - Enumeration of bacterial cell numbers by amplified firefly bioluminescence
      without cultivation.
AB  - We recently developed a novel bioluminescent enzymatic cycling assay for ATP and
      AMP with the concomitant use of firefly luciferase and pyruvate orthophosphate
      dikinase (PPDK), where AMP and pyrophosphate produced from ATP by firefly
      luciferase were converted back into ATP by PPDK. Background luminescence derived
      from contaminating ATP and AMP in the reagent was reduced using adenosine
      phosphate deaminase which degrades ATP, ADP, and AMP, resulting in constant and
      highly amplified bioluminescence with low background luminescence. To detect
      bacterial cells without cultivation, we applied the above bioluminescent
      enzymatic cycling reagent to rapid microbe detection system. ATP spots (0.31-5.0
      amol/spot) at the level of a single bacterial cell were detected with 5 min
      signal integration, signifying that integrated luminescence was amplified 43
      times in comparison to traditional ATP bioluminescence. Consequently, Escherichia
      coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Lactobacillus brevis in
      beer were detected without cultivation. Significant correlation was observed
      between the number of signal spots obtained using this novel system and the
      colony-forming units observed with the conventional colony-counting method
      (R(2)=0.973).

PMID- 12479835
TI  - Analysis of exponential data using a noniterative technique: application to
      surface plasmon experiments.
AB  - The analysis of experimental data of exponential type plays a central role in
      many biophysical applications. We introduce a novel noniterative algorithm to
      analyze the association phase and dissociation phase of surface plasmon resonance
      experiments. It is shown that this algorithm can determine kinetic constants with
      a high level of accuracy in the presence of significant levels of noise. This
      algorithm should provide a valuable alternative to existing data analysis
      techniques.

PMID- 12479836
TI  - Determination of D-alanine in the rat central nervous system and periphery using
      column-switching high-performance liquid chromatography.
AB  - A column-switching chiral HPLC system for the determination of minute amounts of
      D-Ala in mammalian tissues has been established. D-Ala and its L-enantiomer are
      purified as a DL mixture on a micro-ODS column after precolumn fluorescence
      derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole and are introduced to a
      chiral column to determine each enantiomer. The calibration curve of D-Ala spiked
      into a rat cerebellum sample is linear from 5 to 5000 fmol with a correlation
      coefficient of 1.0000. The lower limit of quantitation of D-Ala is 5 fmol
      (S/N=5). Within-day and day-to-day precisions of spiked D-Ala (15 fmol) are 3.9
      and 4.8% (R.S.D), respectively. With this system, the anatomical distribution of
      free D-Ala in the rat central nervous system and periphery has been investigated.
      Among the 22 examined tissues of the rat, the highest amount of D-Ala has been
      observed in the anterior pituitary gland (86.4+/-9.9 nmol/g wet tissue), and the
      second highest amount has been observed in the pancreas (29.2+/-5.0 nmol/g wet
      tissue). Postnatal and day-night changes in D-Ala amounts in the anterior
      pituitary gland have also been studied. The amount of D-Ala is highest at 6 weeks
      of age and significantly decreases with age, and the amount of D-Ala is
      significantly higher during the daytime than during the nighttime.

PMID- 12479837
TI  - Zymogram with Remazol brilliant blue-labeled Micrococcus lysodeikticus cells for
      the detection of lysozymes: example of a new lysozyme activity in Formosan
      termite defense secretions.

PMID- 12479838
TI  - Mobile element-based assay for human gender determination.

PMID- 12479839
TI  - Facile variation of reagent concentrations in rapid quench enzymology.

PMID- 12479840
TI  - Contributions of the prefrontal cortex to the neural basis of human decision
      making.
AB  - The neural basis of decision making has been an elusive concept largely due to
      the many subprocesses associated with it. Recent efforts involving neuroimaging,
      neuropsychological studies, and animal work indicate that the prefrontal cortex
      plays a central role in several of these subprocesses. The frontal lobes are
      involved in tasks ranging from making binary choices to making multi-attribute
      decisions that require explicit deliberation and integration of diverse sources
      of information. In categorizing different aspects of decision making, a division
      of the prefrontal cortex into three primary regions is proposed. (1) The
      orbitofrontal and ventromedial areas are most relevant to deciding based on
      reward values and contribute affective information regarding decision attributes
      and options. (2) Dorsolateral prefrontal cortex is critical in making decisions
      that call for the consideration of multiple sources of information, and may
      recruit separable areas when making well defined versus poorly defined decisions.
      (3) The anterior and ventral cingulate cortex appear especially relevant in
      sorting among conflicting options, as well as signaling outcome-relevant
      information. This topic is broadly relevant to cognitive neuroscience as a
      discipline, as it generally comprises several aspects of cognition and may
      involve numerous brain regions depending on the situation. The review concludes
      with a summary of how these regions may interact in deciding and possible future
      research directions for the field.

PMID- 12479841
TI  - Intrauterine position effects.
AB  - A review of the literature suggests that individual variability in sex-related
      traits may be influenced by variations in hormonal exposure during fetal
      development. In litter-bearing mammals, fetuses develop in utero and may be
      subjected to differing hormonal environments based upon the sex of neighboring
      fetuses. Female fetuses developing between two males tend to show masculinized
      anatomical, physiological and behavioral traits as adults. Female fetuses
      developing without adjacent males, on the other hand, tend to show more feminized
      traits as adults. These traits include permanently altered hormone levels,
      reproductive organs, aggressive behaviors, secondary sex ratios and
      susceptibility to endocrine disruption. This intrauterine effect is due to the
      transfer of testosterone from male fetuses to adjacent fetuses. While these
      effects have been most clearly demonstrated in mice, other rodents and swine also
      show intrauterine position (IUP) effects. Some of these effects are similar to
      the influence of prenatal stress on adult phenotypes. A few reports on human
      twins suggest that variability in some masculine and feminine traits may be due
      to intrauterine hormonal signals. IUP effects may impact a number of scientific
      fields of research such as endocrine disruption, toxicology, population biology,
      animal production and health.

PMID- 12479842
TI  - Landmark discrimination learning in the dog: effects of age, an antioxidant
      fortified food, and cognitive strategy.
AB  - The landmark discrimination learning test can be used to assess the ability to
      utilize allocentric spatial information to locate targets. The present
      experiments examined the role of various factors on performance of a landmark
      discrimination learning task in beagle dogs. Experiments 1 and 2 looked at the
      effects of age and food composition. Experiments 3 and 4 were aimed at
      characterizing the cognitive strategies used in performance on this task and in
      long-term retention. Cognitively equivalent groups of old and young dogs were
      placed into either a test group maintained on food enriched with a broad-spectrum
      of antioxidants and mitochondrial cofactors, or a control group maintained on a
      complete and balanced food formulated for adult dogs. Following a wash-in period,
      the dogs were tested on a series of problems, in which reward was obtained when
      the animal responded selectively to the object closest to a thin wooden block,
      which served as a landmark. In Experiment 1, dogs were first trained to respond
      to a landmark placed directly on top of coaster, landmark 0 (L0). In the next
      phase of testing, the landmark was moved at successively greater distances (1, 4
      or 10 cm) away from the reward object. Learning varied as a function of age
      group, food group, and task. The young dogs learned all of the tasks more quickly
      than the old dogs. The aged dogs on the enriched food learned L0 significantly
      more rapidly than aged dogs on control food. A higher proportion of dogs on the
      enriched food learned the task, when the distance was increased to 1cm.
      Experiment 2 showed that accuracy decreased with increased distance between the
      reward object and landmark, and this effect was greater in old animals.
      Experiment 3 showed stability of performance, despite using a novel landmark, and
      new locations, indicating that dogs learned the landmark concept. Experiment 4
      found age impaired long-term retention of the landmark task. These results
      indicate that allocentric spatial learning is impaired in an age-dependent manner
      in dogs, and that age also affects performance when the distance between the
      landmark and target is increased. In addition, these results both support a role
      of oxidative damage in the development of age-associated cognitive dysfunction
      and indicate that short-term administration of a food enriched with supplemental
      antioxidants and mitochondrial cofactors can partially reverse the deleterious
      effects of aging on cognition.

PMID- 12479843
TI  - The neuropsychological profile of early and continuously treated phenylketonuria:
      orienting, vigilance, and maintenance versus manipulation-functions of working
      memory.
AB  - In this paper, we review neuropsychological test results of early and
      continuously treated Phenylketonuria (PKU) patients. To increase insight into the
      neuropsychological profile of this population, we have attempted to place the
      results within an attentional network model [Images of the mind, 1994], which
      proposes interacting but dissociable attentional networks for orienting,
      vigilance, and executive control of attention. Executive control of attention is
      discussed against the background of the process-specific theory of working memory
      (WM) [Handbook of neuropsychology, 1994], which postulates a distinction between
      the 'maintenance'-function of WM and the 'manipulation and monitoring'-function.
      Neuropsychological results are presented for 67 early and continuously treated
      PKU patients and 73 controls aged 7-14 years. Four neuropsychological tasks were
      employed to measure orienting, mnemonic processing, interference suppression, and
      top-down control in visual search. No differences were found in orienting and the
      maintenance-function of WM. In addition to previously reported impairments in
      sustained attention/vigilance and inhibition of prepotent responding, PKU
      patients exhibited deficits when top-down control was required in a visual search
      task, but showed no impairment when interference suppression was required. It is
      discussed how the specific neuropsychological impairments in PKU may be a
      consequence of mid-dorsolateral prefrontal cortex (DLPFC) dysfunctioning due to
      deficiencies in catecholamine modulation.

PMID- 12479844
TI  - Opioid peptides and the control of human ingestive behaviour.
AB  - A variety of evidence suggests that endogenous opioid peptides play a role in the
      short-term control of eating. More recently, opioid receptor antagonists like
      naltrexone have been approved as a treatment for alcohol dependence. Here we
      review the evidence for a role of opioid peptides in both normal and abnormal
      eating and drinking behaviours and in particular try to identify the nature of
      the role of opioids in these behaviours. Particular attention is paid to the idea
      that opioid reward processes may be involved both in the short-term control of
      eating and hedonic aspects of alcohol consumption, and parallels are drawn
      between the effects of opiate antagonists on food pleasantness and the experience
      of drinking alcohol. The review also explores the extent to which data from
      studies using opiate antagonists and agonists provide evidence for a direct role
      of endogenous opioids in the control of ingestive behaviour, or alternatively
      whether these data may be better explained through non-specific effects such as
      the nausea commonly reported following administration of opiate antagonists. The
      review concludes that the present data suggests a single opioid mechanism is
      unlikely to explain all aspects of ingestive behaviour, but also concludes that
      opioid-mediated reward mechanisms play an important control in hedonic aspects of
      ingestion. The review also highlights the need for further empirical work in
      order to elucidate further the role of opioid peptides in human ingestive
      behaviour.

PMID- 12479845
TI  - Commentary: topoisomerases as targets in acute leukemia: I, II, I plus II or
      none?

PMID- 12479847
TI  - Elevated thrombopoietin levels in patients with myelofibrosis may not be due to
      enhanced production of thrombopoietin by bone marrow.
AB  - Thrombopoietin (TPO) is recognized as the primary regulator of megakaryocyte and
      platelet production. Two alternative hypotheses for the mechanism of regulation
      have been proposed: (1) platelet and/or megakaryocyte mass regulate circulating
      TPO levels by binding to TPO through TPO receptors (c-MPL), with subsequent
      internalization and degradation of the protein; (2) TPO mRNA produced by bone
      marrow (BM) stromal cells or BM cells modulates blood TPO levels or platelet
      counts. In myeloproliferative disorders (MPD), including primary myelofibrosis
      (MF) and essential thrombocythemia (ET), elevated blood TPO levels occur despite
      increased platelet and megakaryocyte mass. Therefore, in these diseases, elevated
      blood TPO levels cannot be explained by the first mechanism. The present study,
      was designed to measure TPO mRNA production by BM mononuclear cells and BM
      stromal cells using a relative RT-PCR technique, to verify the second mechanism.
      We found no increase of TPO mRNA production in either BM cells or in BM stromal
      cells in patients with MF and ET. Furthermore, in those patients with MF who had
      elevated plasma TPO levels, TPO mRNA levels in bone marrow fibroblasts (BMFs) or
      BM cells were not elevated as compared with controls. Therefore, we concluded
      that in patients with MF, the elevated plasma TPO levels are not due to enhanced
      production of TPO mRNA either by BMF, or BM cells. The TPO receptor (c-MPL)
      abnormalities including reduced MPL protein levels or defective TPO induced
      signal transduction pathways are the likely mechanisms.

PMID- 12479846
TI  - Factors influencing the collection of peripheral blood stem cells in patients
      with acute myeloblastic leukemia and non-myeloid malignancies.
AB  - Factors influencing the collection of autologous peripheral blood stem cells
      (PBSCs) were studied in 182 mobilization procedures performed on 145 consecutive
      patients with acute myeloblastic leukemia (AML; n=67) and with various non
      myeloid malignancies (NMM; n=78). PBSC were collected following mobilization with
      chemotherapy, treatment with granulocyte colony-stimulating factor (G-CSF) or
      chemotherapy plus G-CSF. Fewer colony-forming unit granulocyte-macrophages (CFU
      GMs) were collected from patients with AML than from patients with NMM
      (P<0.0001), although there were no differences in the numbers of CD34+ cells
      collected between both groups. Multiple regression analysis showed that
      chemotherapy alone was predictive of a low CD34+ yield in patients with NMM
      (regression coefficient (RC)=-2.1; P=0.003). In addition, the interactions
      "diagnosis mutliple myeloma (MM)xmobilization with chemotherapy" (RC=2.9;
      P=0.004) and "diagnosis MMxmobilization with chemotherapy plus G-CSF" (RC=2.1;
      P=0.04) also remained in the model, both showing a favorable influence. In AML,
      mobilization with chemotherapy plus G-CSF was associated with higher CD34+ yields
      (P=0.003). In this subgroup of patients, multiple regression analysis identified
      the number of cycles of previous chemotherapy (< or =2 cycles; RC=1.3; P=0.03)
      and peripheral blood counts (WBC > or =1.5 x 10(9)/l and monocytes >20%; RC=0.8;
      P=0.02) as the factors most predictive of CD34+ cell yield. These findings
      emphasize the need to optimize harvesting technique to enhance safety and
      minimize morbidity and costs of this valuable procedure.

PMID- 12479848
TI  - The effect of short-course high-dose methylprednisolone on peripheral blood
      lymphocyte subsets in children with acute leukemia during remission induction
      treatment.
AB  - We have previously demonstrated a favorable effect of high-dose steroid in the
      treatment of children with acute lymphoblastic leukemia (ALL) and acute
      myeloblastic leukemia (AML). This study was performed to determine the effect of
      short-course high-dose methylprednisolone (HDMP) treatment on the peripheral
      blood (PB) T lymphocyte subsets, and blast cells, during remission induction
      treatment in 23 children with newly diagnosed acute leukemia (16 with ALL, seven
      with AML). All patients were administered HDMP as a single daily oral dose of
      30mg/kg for the first 4 days of induction therapy. The number of PB lymphocyte
      subsets (CD3, CD4, CD8, CD16+56, CD45RA, and CD45RO) were determined by flow
      cytometry before and after 4 days of HDMP treatment. While the number of PB blast
      cells significantly decreased, the absolute number of T lymphocytes expressing
      CD3, CD4, CD8, CD45RA and the absolute number of CD16+56 (natural killer) cells
      increased in all patients. We suggest that the beneficial effects of HDMP in the
      induction treatment of acute leukemia may occur partly due to an increase in the
      number of PB T lymphocyte subsets. A study randomly assigning patients to
      treatment with either conventional therapy or HDMP may provide further
      information.

PMID- 12479849
TI  - Microsatellite mutations of transforming growth factor-beta receptor type II and
      caspase-5 occur in human precursor T-cell lymphoblastic lymphomas/leukemias in
      vivo but are not associated with hMSH2 or hMLH1 promoter methylation.
AB  - In solid cancers, defective DNA mismatch repair (MMR) is most commonly caused by
      hMSH2 or hMLH1 mutations, or epigenetic silencing of hMLH1 by promoter
      hypermethylation, and results in the acquisition of characteristic frameshift
      microsatellite mutations of mononucleotide repeats located within the coding
      regions of defined target genes. We previously identified hMSH2 mutations in T
      cell lymphoblastic lymphoma (T-LBL) patient tumor samples and others have
      reported coding region microsatellite mutations in T-cell acute lymphoblastic
      leukemia (T-ALL) cell lines. Thus, while MMR gene mutations are known to occur in
      some human T-lymphoblastic tumors in vivo, it is still unknown if the coding
      region microsatellite mutations detected in human cell lines also occur in vivo
      or if hMLH1 or hMSH2 promoter hypermethylation contributes to defective MMR in
      these tumors. We analyzed the TGFbetaRII (A)10 and caspase-5 (A)10 coding region
      repeats in 16 human T-LBL/ALL patient tumor samples and identified six with
      microsatellite mutations in one or both repeats. There was no evidence of hMSH2
      or hMLH1 promoter methylation as assessed by standard methylation specific PCR or
      by a novel temporal temperature gradient electrophoresis (TTGE) method that
      analyzed 25 and 30 CpG sites in the hMLH1 and hMSH2 promoters, respectively. Our
      results indicate that coding region microsatellite mutations characteristic of
      defective MMR occur in some human T-LBL/ALL in vivo but not as a consequence of
      hMLH1 or hMSH2 promoter hypermethylation. Furthermore, the identification of
      TGFbetaRII and caspase-5 coding region mutations in vivo implicates these genes
      in the pathogenesis of human T-LBL/ALL.

PMID- 12479850
TI  - A phase I and pharmacodynamic study of sequential topotecan and etoposide in
      patients with relapsed or refractory acute myelogenous and lymphoblastic
      leukemia.
AB  - We designed a pharmacokinetic and pharmacodynamic phase I study of sequential
      topotecan (2.55-6.3mg/m2) by 72h infusion followed by five daily doses of
      etoposide for patients with refractory acute leukemia based upon synergistic anti
      tumor activity of topoisomerase I and II inhibitors in vitro. Eight of the 29
      patients achieved bone marrow aplasia and two patients achieved clinical
      remission. Common grade 3-4 toxicities included hepatic and gastrointestinal
      dysfunction, and correlated with increased steady-state plasma topotecan
      concentration. The predicted up-regulation of topoisomerase II activity by
      topoisomerase I inhibition was not observed at this dose and schedule and may
      provide insight into the modest anti-leukemia activity of the regimen.

PMID- 12479851
TI  - Dental abnormalities in children after chemotherapy treatment for acute lymphoid
      leukemia.
AB  - The frequency of dental abnormalities, such as delayed dental development,
      microdontia, hypoplasia, agenesis, V-shaped root and shortened root was evaluated
      in 76 acute lymphoblastic leukemia (ALL) pediatric patients who had been off
      chemotherapy for 6 months. These children had been subjected to one of the three
      Brazilian Protocols or the BFM86 Protocol. The patients were divided into three
      groups: Group I (GI; high risk) treated with one of the three Brazilian Protocols
      who received high-dose chemotherapy, intensive maintenance and cranial
      radiotherapy; Group II (GII; low risk) who were also treated with one of the
      three Brazilian Protocols using low-intensive chemotherapy with no radiotherapy;
      and Group III (GIII) based on the BFM86 Protocol. Of 76 children, 13 showed no
      dental abnormalities (8 were at the age of tooth formation). The remaining 63
      children (82.9%) showed at least one dental anomaly. The abnormalities were
      probably caused by the type, intensity, frequency of the treatment and age of the
      patients at ALL diagnosis and this might have important consequences for the
      children's dental development.

PMID- 12479853
TI  - Cytotoxic and inhibitory effects of 4,4'-dihydroxy chalcone (RVC-588) on
      proliferation of human leukemic HL-60 cells.
AB  - Chalcones have been identified as interesting compounds with cytotoxic and tumor
      reducing properties. In the present study, the biological activity of synthetic
      chalcones on myeloid leukemic cells was investigated. Human myeloid HL-60
      leukemia cells were exposed to 1-20 micro M chemicals for 0-96h. The viability of
      the cells was measured using trypan blue dye exclusion method. 4,4'-Dihydroxy
      chalcone (RVC-588) was selected for further experiments to determine
      characteristics of cytotoxicity among other compounds. The data show that cell
      viability decreased after treatment and IC(50) value was approximately 2 micro M
      for RVC-588. Cell differentiation was analyzed with cytofluorometry by changes in
      expression of glicoprotein surface markers CD11b/Mac-1, CD11c and CD14 together
      with morphological analysis. A maximum level of expression changes was determined
      at 72h but these changes were not statistically significant to show the
      differentiation of HL-60 cells to mature myeloid and/or monocytoid cells.
      Apoptotic DNA degradation was evaluated and quantitated using sensitive enzyme
      linked immunoabsorbant (ELISA) method. Using this technique, a maximum level of
      apoptosis 1.2-fold higher than control was observed in cultures exposed for 48h
      to 2 micro M RVC-588. The DNA ladder assay was subsequently used to determine DNA
      breaks qualitatively. After 24h, the cells exposed to 2 micro M RVC-588 was shown
      to have cytotoxic-late apoptotic ladder pattern compared to control cells. These
      data demonstrate that RVC-588 has a high cytotoxic and antitumor activity in HL
      60 cells among other chemicals we synthesized. Although the mechanism by which
      RVC-588 initiated cell death in these cells is presently not known and apoptotic
      mechanisms are likely to play less role compared to other chalcone analogues
      reported previously.

PMID- 12479852
TI  - Cyclic AMP induces activation of extracellular signal-regulated kinases in HL-60
      cells: role in cAMP-induced differentiation.
AB  - It is well known that elevated intracellular cAMP induces growth arrest and the
      differentiation of HL-60 cells to neutrophil-like cells. The present study was
      designed to assess the regulation of the extracellular signal-regulated kinase
      (ERK) pathway by cAMP and its association with differentiation in HL-60 cells. We
      found that 8-bromoadenosine-3',5'-cyclic-monophosphate (8Br-cAMP)-induced the
      activation of ERK and mitogen-activated protein kinase (MEK), but inhibited B-Raf
      kinase via a protein kinase A (PKA)-mediated mechanism. Prolonged exposure to 8Br
      cAMP increased the phorbol 12-myristate 13-acetate (TPA)-stimulated superoxide
      generation and CD14 expression that characterize the differentiation phenotype,
      which was blocked by MEK-1 inhibitor. These data suggest that cAMP-induced ERK
      activation is essential for the differentiation of HL-60 cells, independently of
      B-Raf.

PMID- 12479854
TI  - Effects of flavonoids on cisplatin-induced apoptosis of HL-60 and L1210 leukemia
      cells.
AB  - Effects of three flavonoids, quercetin (QU), galangin (GA), and chrysin (ChR) on
      cisplatin (cis-Pt)-induced apoptosis of human promyelocytic leukemia HL-60 cells
      and murine leukemia L1210 cells were investigated. The quantitative analysis of
      apoptotic DNA fragmentation was used to show that preincubation of cells with
      flavonoids can influence cis-Pt-induced apoptosis in different way. ChR had no
      effect, QU enhanced, and GA reduced apoptotic DNA fragmentation. It is also shown
      that combined treatment with QU and cis-Pt showed synergistic effect, however, GA
      combined with cis-Pt exhibited antagonism on cytotoxicity in L1210 murine
      leukemia cells. We assume that tested flavonoids affect the important biological
      activities connected with cancer chemotherapy and chemoprevention as they
      differently modulated the sensitivity of cells to cis-Pt treatment. QU is
      presented as pro-apoptotic agent and GA as agent with anti-apoptotic potential.

PMID- 12479855
TI  - Antisense p53 transduction leads to overexpression of bcl-2 and dexamethasone
      resistance in multiple myeloma.
AB  - Multiple myeloma is a malignant proliferation of plasma cells which fail to
      undergo apoptosis. To understand events associated with lack of apoptosis in
      these cells, we studied effect of antisense p53 gene transduction in a multiple
      myeloma cell line, ARH77. Adeno-associated virus was used as a vector to
      introduce p53 cDNA in an antisense orientation driven by a herpes virus thymidine
      kinase promoter. We observed, that an antisense p53 (p53as) transduced cell line
      showed marked reduction in p53 mRNA and protein expression and increased growth
      when compared to the control cell lines transduced with neomycin-resistance gene
      or untransduced cells. There was a concomitant up-regulation of bcl-2 expression
      by over five-fold in p53as-transduced cells compared with controls; while there
      was no significant change in expression of c-myc and IL-6, genes implicated in
      myeloma growth. We measured apoptosis in the transduced cells by DNA end-labeling
      reaction which revealed decrease in apoptosis from 15.6% in control cells to 1.6%
      in p53as-transduced cells. Additionally, the p53as cells over expressing bcl-2
      also showed resistance to killing by dexamethasone. In summary, our data
      demonstrates that loss of p53 function leads to myeloma cell progression and
      resistant phenotype through bcl-2-related mechanisms.

PMID- 12479857
TI  - A unique case of splenic marginal zone-cell lymphoma with synchronous clonal T
      cell large granular lymphocyte proliferation: an immunologic, immunohistochemical
      and genotypic study.
AB  - We describe a case of synchronous splenic marginal zone-cell lymphoma (SMZL) and
      T-cell large granular lymphocyte leukemia involving the spleen, liver, bone
      marrow and peripheral blood. The synchronous occurrence of these two processes
      was documented by morphological, immunophenotypical and molecular (PCR) analyses
      of all affected tissues. The pathogenetic mechanisms which may be responsible for
      the concomitant appearance of these two rather infrequent entities in the same
      anatomic sites are discussed.

PMID- 12479856
TI  - The diphtheria toxin/urokinase fusion protein (DTAT) is selectively toxic to CD87
      expressing leukemic cells.
AB  - Diphtheria fusion proteins are a novel class of agents for the treatment of
      chemotherapy resistant acute myelogenous leukemia (AML). We prepared diphtheria
      toxin/urokinase fusion protein (DTAT) composed of the amino terminal fragment of
      the urokinase-type plasminogen activator (uPA) fused to the catalytic and
      translocation domains of diphtheria toxin (DT) and assessed its activity on
      leukemic cell lines. The number of uPA receptors (uPAR or CD87) was measured
      using a phycoerythrin conjugated monoclonal antibody to CD87 and flow cytometry.
      Seven of 23 cell lines (30%) showed CD87 expression (> or =5000 receptors/cell).
      DTAT cytotoxicity (IC(50)< or =30pM) was observed in all seven of these samples
      and none of the 16 samples with low or absent CD87 expression. There was a
      significant correlation between DTAT sensitivity and CD87 density (P=0.0007).
      These results show that specific CD87 binding is one factor important in the
      sensitivity of patient's leukemic blasts to DTAT and demonstrate for the first
      time that the CD87/uPAR can be used as a target for fusion protein therapy of
      AML.

PMID- 12479858
TI  - Periodic oscillation of blood leukocytes, platelets, and hemoglobin in a patient
      with chronic eosinophilic leukemia.
AB  - Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative disease in which
      autonomous, clonal proliferation of eosinophilic precursors results in persistent
      increase of eosinophils in the blood and bone marrow. A case of CEL spontaneous
      oscillation of white blood cell (WBC) count is presented. The cycle of WBC
      variation comprised about 60 days. Similar cyclic variations were noted in his
      platelet count, hemoglobin level and bone marrow cellularity, as well as in the
      spleen size, which was directly correlated with the WBC count. The numbers of
      bone marrow erythroid colony-forming units (CFU-E), granulocyte-macrophage colony
      forming units (CFU-GM) and the serum level of colony-stimulating factors (CSFs)
      were also regularly changed during the oscillation of WBC. Bone marrow
      hyperplasia was accompanied with the increase in peripheral WBC count, suggesting
      that the variation of cell production caused the cyclic oscillation.

PMID- 12479859
TI  - A polymorphism in the angiogenesis inhibitor, endostatin, in multiple myeloma.

PMID- 12479860
TI  - The cardiac valve interstitial cell.
AB  - Cardiac valve interstitial cells (ICs) are a heterogeneous and dynamic population
      of specific cell types that have many unique characteristics. They are
      responsible for maintaining the extracellular scaffold that provides the
      mechanical characteristics vital for sustaining the unique dynamic behaviour of
      the valve. A number of cellular phenotypes can be distinguished: some are
      sparsely arranged throughout the valve leaflets, whilst others are arranged in
      thin bundles. These cells express molecular markers similar to those of skeletal,
      cardiac and smooth muscle cells (SMCs) and in particular, many ICs express smooth
      muscle (SM) alpha-actin, a marker of myofibroblasts. In this respect, these cells
      exhibit a profile unlike skin fibroblasts, which may allude to their role in
      valve function.

PMID- 12479861
TI  - Cancer diagnosis and microarrays.
AB  - Microarray technology allows the investigation of the cell status on a molecular,
      genome-wide scale and has been shown to identify a given cell species by its gene
      expression profile. This may be highly valuable in future cancer diagnosis,
      because traditional clinical and pathological assessments of the tumour status
      cannot distinguish between morphologically similar but molecularly different
      tumours. These molecular differences, however are crucial in determining the
      clinical course of the disease. Despite this, in the majority of cases it has
      remained impossible to reliably characterise molecular phenotype and predict the
      response to therapy and the ultimate outcome for the patient. Microarray
      technology holds the potential to revolutionise the diagnosis and therapy of
      cancer. Recent developments in microarray technology and data analysis are
      discussed as well as examples of their application to define molecular phenotype.

PMID- 12479862
TI  - Glypicans.
AB  - A family of lipid-linked heparan sulfate (HS) proteoglycans, later named
      glypicans, were identified some 15 years ago. The discoveries that mutations in
      genes involved in glypican assembly cause developmental defects have brought them
      into focus. Glypicans have a characteristic pattern of 14 conserved cysteine
      residues. There are also two-three attachment sites for HS side-chains near the
      membrane anchor. The HS side-chains consist of a repeating disaccharide back-bone
      that is regionally and variably modified by epimerization and different types of
      sulfations, creating a variety of binding sites for polycationic molecules,
      especially growth factors. Recycling forms of glypican-1 are potential vehicles
      for transport of cargo into and through cells. The glypican-1 core protein is S
      nitrosylated and nitric oxide released from these sites cleave the HS chains at
      glucosamine units lacking N-substitution. This processing is necessary for
      polyamine uptake.

PMID- 12479863
TI  - Eph receptors and ephrins.
AB  - Eph receptors, the largest subfamily of receptor tyrosine kinases (RTKs), and
      their ephrin ligands are important mediators of cell-cell communication
      regulating cell attachment, shape, and mobility. Eph signaling is crucial for the
      development of many tissues and organs including the nervous and cardiovascular
      systems. Both Ephs and ephrins are membrane-bound and their interactions at sites
      of cell-cell contact initiate unique bi-directional signaling cascades where
      information is transduced in both the receptor- and the ligand-expressing cells.
      Recent studies summarized in this review reveal how the signaling process is
      triggered upon ligand-receptor binding via the formation of a 2:2 circular
      heterotetramer. This fixes the orientation of the participating molecules and
      facilitates phosphorylation of their cytoplasmic domains which then interact with
      downstream signaling factors. The elucidation of the structural details of Eph
      ephrin recognition and binding should yield insight into the future development
      of novel therapeutic agents targeting cardiovascular function, nerve
      regeneration, and cancer.

PMID- 12479864
TI  - Gene therapy of neoplastic liver diseases.
AB  - Since advanced liver cancer lacks effective therapy in most cases, a considerable
      interest has been drawn towards gene therapy. Natural or chimerical genes can be
      transferred to the tumour itself, the non-tumoral liver, or even distant tissues
      using a variety of vectors administered by intratumoral or intravascular routes.
      The desired selectivity in gene expression can be achieved by increasing the
      specificity of gene delivery or by controlling gene expression with tumour
      specific promoters, such as alpha-fetoprotein or carcinoembryonic antigen. There
      are two main approaches to gene therapy of liver cancer aiming at killing
      directly malignant cells or at improving the host's defensive systems,
      respectively. The former include replacing the lost function of tumour suppressor
      genes, inhibiting the action of activated oncogenes, sensitising tumour cells to
      prodrugs, or infecting the tumoral tissue with viruses that replicate selectively
      in cancer cells. Host defences can be improved by stimulating the antitumoral
      immune response, or by interfering with tumour vessel formation. Progress in gene
      therapy of liver cancer depends very much on information collected from well
      designed clinical trials. This information includes knowledge of whether an
      efficient gene transfer has been achieved and what is the duration and magnitude
      of gene expression in the transduced tissues. Hopefully, magnetic resonance or
      positron emission tomography (PET) may turn out to be reliable procedures for
      tracing transgene expression in humans. Pre-clinical evidence and early clinical
      trials strongly suggest that there is a place for gene therapy of liver
      malignancies.

PMID- 12479865
TI  - L-Carnitine alters nitric oxide synthase activity in fibroblasts depending on the
      peroxisomal status.
AB  - Fibroblast cellular models are widely used for research on fatty acid metabolism.
      Due to the importance of L-carnitine in intermediary metabolism we studied the
      effects of L-carnitine on healthy human skin fibroblasts and fibroblasts without
      functional peroxisomes (Zellweger Syndrome) cultivated under carnitine
      deficiency, which is caused by standard media compositions. The application of
      physiological (0.1mM) or super-physiological (1mM) doses of L-carnitine causes a
      significant decrease of the specific activity of nitric oxide synthase (NOS,
      2.25+/-0.10 to 1.36 pmol/(minmg)+/-0.09 pmol/(minmg) at 0.1mM), proliferation and
      a tendentious decrease of the antioxidant defence potential against hydrogen
      peroxide only in control cells. Simultaneous application of L-carnitine and 100
      micro M N-acetylcysteine (NAC) prevents the alterations in control cells. Thus, L
      carnitine alters the cellular regulation of the NOS probably by reactive oxygen
      species (ROS), which suggests that carnitine deficient media neither reflect
      physiological conditions for cellular models for fatty acid metabolism nor for
      the regulation of NOS.

PMID- 12479866
TI  - The coenzyme thiamine pyrophosphate inhibits the self-splicing of the group I
      intron.
AB  - Effects of the coenzyme thiamine pyrophosphate and its analogs on the inhibition
      of self-splicing of primary transcripts of the phage T4 thymidylate synthase gene
      (td) were investigated. Of all compounds tested, the coenzyme thiamine
      pyrophosphate was the most potent inhibitor and the order of inhibitory
      efficiency for compounds tested was as follows: thiamine pyrophosphate>thiamine
      monophosphate>thiamine>thiochrome. Increasing guanosine concentration overcame
      the suppression of self-splicing by thiamine pyrophosphate close to the level of
      normal splicing. Kinetic analysis demonstrated that thiamine pyrophosphate acts
      as a competitive inhibitor for the td intron RNA with a Ki of 2.2mM. The splicing
      specificity inhibition by thiamine pyrophosphate is predominantly due to changes
      in Km.

PMID- 12479867
TI  - Involvement of transcription factors in plasma HDL protection against TNF-alpha
      induced vascular cell adhesion molecule-1 expression.
AB  - Plasma HDL has been reported to protect against the initial development of
      inflammatory atherosclerosis. Although cellular and molecular mechanisms of this
      HDL protection are not fully understood, they may involve prevention of the
      endothelial trafficking of circulating leukocytes via its down-regulation of
      inflammatory genes. To test this hypothesis, HDL inhibition of monocyte adherence
      to the endothelium and of the expression of vascular cell adhesion molecule-1
      (VCAM-1) and its transcriptional regulatory mechanism were elucidated in human
      umbilical vein endothelial cells (HUVECs) stimulated by pro-inflammatory TNF
      alpha. Plasma HDL (1mg/ml apo A1) markedly prevented the monocyte adhesion to TNF
      alpha-activated HUVECs with blunting the increased expression levels of VCAM-1
      protein and its mRNA at a maximal TNF-alpha stimulation. Electrophoretic mobility
      shift assay showed that in the activated HUVECs HDL substantially inhibited DNA
      binding activities of transcription factors of nuclear factor-kappaB (NF-kappaB)
      and activator protein-1 (AP-1) that have binding sites in the promoter region of
      the VCAM-1 gene. In addition, immunocytochemical staining analysis confirmed that
      HDL inhibited TNF-alpha-induced VCAM-1 expression via reduced nuclear
      translocation of NF-kappaB. These results suggest that HDL down-regulates the
      expression of VCAM-1 gene in TNF-alpha-activated HUVECs at transcriptional levels
      via blunted translocation and transactivation of NF-kappaB and AP-1 transcription
      factors. Plasma HDL may block the initial atherosclerotic process via inhibited
      monocyte adhesion to the endothelium, which is independent of modulating the
      cholesterol reverse transport of plasma HDL.

PMID- 12479868
TI  - Anomalous oxidation of MDL 73,404 by horseradish peroxidase.
AB  - 3,4-Dihydro-6-hydroxy-N,N,N-2,5,7,8-heptamethyl-2H-1-benzopyran-2-ethanaminium-4
      methylbenzene sulfonate (MDL 73,404) is a cardioselective water-soluble
      quaternary ammonium analogue of Vitamin E which is synthesized to augment the
      antioxidant defence in situations of free radical injury such as myocardial
      infarction/reperfusion. Its oxidation by any peroxidative enzyme has not been
      studied kinetically. This paper describes its enzymatic oxidation by horseradish
      peroxidase (HRP). The activity was followed spectrophotometrically at 255nm, and
      the experimental results were simulated using the program "KINETIC 3.1" for
      Windows 3.x. The MDL 73,404 was oxidized by horseradish peroxidase in the
      presence of H2O2 to its corresponding MDL 73,404 quinone. During this oxidation,
      the horseradish peroxidase showed an unexpectedly slow kinetic response with
      time, which contrast with the linear product accumulation curve measured with
      2,2'-azino-bis-(3-estilbenzotiazol-6-sulfonic acid) (ABTS). This response was
      dependent on the respective concentrations of enzyme, MDL 73,404 and H2O2.
      However, when the enzyme was incubated with H2O2, the slow kinetic response
      disappeared and a lag period was observed. Furthermore, when p-coumaric acid
      (PCA) was added, the activity increased and the slow kinetic response became a
      straight line. In order to explain this anomalous behaviour, a kinetic model has
      been proposed and its differential equations simulated. From the correlation
      between experimental and simulated results it is concluded that MDL 73,404 can
      act as a slow response substrate for peroxidase, probably due to the presence of
      a quaternary ammonium side chain that confers on it a slow capacity to convert
      compound III into ferriperoxidase.

PMID- 12479869
TI  - Plasma phospholipid transfer protein-mediated reactions are impaired by
      hypochlorite-modification of high density lipoprotein.
AB  - The two main functions of phospholipid transfer protein (PLTP) are the transfer
      of phospholipids between plasma lipoproteins and the conversion of high density
      lipoprotein (HDL), where prebeta-HDL particles are generated. HDL is considered
      an anti-atherogenic lipoprotein due to its function in the reverse cholesterol
      transport, where prebeta-HDL accepts cellular membrane cholesterol from
      peripheral tissues. However, the anti-atherogenic properties of native HDL may be
      abolished by oxidation/modification. Hypochlorous acid/hypochlorite (HOCl/OCl-)-a
      potent oxidant generated in vivo only by the myeloperoxidase-H2O2-chloride system
      of activated phagocytes-alters the physiological properties of HDL by generating
      a pro-atherogenic lipoprotein particle. Therefore, we have studied the effect of
      HOCl on the function of HDL subclass 3 (HDL3) and triglyceride-enriched HDL3 (TG
      HDL3) in PLTP-mediated processes in vitro. Modification of HDL3 and TG-HDL3 with
      increasing HOCl concentrations (oxidant:lipoprotein molar ratio between 25:1 and
      200:1) decreased the capacity of the corresponding lipoprotein particles to
      accept phospholipids. Although binding of PLTP to unmodified and HOCl-modified
      lipoprotein particles was similar, the degree of PLTP-mediated HDL conversion was
      decreased upon HOCl oxidation. PLTP released apolipoprotein A-I (apoA-I) from
      HOCl-modified HDL3, but the particles formed displayed no prebeta-mobility. Based
      on these findings, we conclude that the substrate properties of HOCl-modified
      HDL3 and TG-HDL3 in PLTP-mediated processes are impaired, which indicates that
      the anti-atherogenic properties of HDL are impaired.

PMID- 12479870
TI  - The subcellular distribution of the human ribosomal "stalk" components: P1, P2
      and P0 proteins.
AB  - The ribosomal "stalk" structure is a distinct lateral protuberance located on the
      large ribosomal subunit in prokaryotic, as well as in eukaryotic cells. In
      eukaryotes, this ribosomal structure is composed of the acidic ribosomal P
      proteins, forming two hetero-dimers (P1/P2) attached to the ribosome through the
      P0 protein. The "stalk" is essential for the ribosome activity, taking part in
      the interaction with elongation factors. In this report, we have shown that the
      subcellular distribution of the human P proteins does not fall into standard
      behavior of regular ribosomal proteins. We have used two approaches to assess the
      distribution of the P proteins, in vivo experiments with GFP fusion proteins and
      in vitro one with anti-P protein antibodies. In contrast to standard r-proteins,
      the P1 and P2 proteins are not actively transported into the nucleus compartment,
      remaining predominantly in the cytoplasm (the perinuclear compartment). The P0
      protein was found in the cytoplasm, as well as in the nucleus; however, the
      nucleoli were excluded. This protein was scattered around the nuclei, and the
      distribution might reflect association with the so-called nuclear bodies. This is
      the first example of r-proteins that are not actively transported into the
      nucleus; moreover, this might imply that the "stalk" constituents are assembled
      onto the ribosomal particle at the very last step of ribosomal maturation, which
      takes part in the cell cytoplasm.

PMID- 12479871
TI  - Substitutional mutations in the uncoupling protein-specific sequences of
      mitochondrial uncoupling protein UCP1 lead to the reduction of fatty acid-induced
      H+ uniport.
AB  - Mutants were constructed for mitochondrial uncoupling protein UCP1, with single
      or multiple substitutions within or nearby the UCP-signatures located in the
      first alpha-helix and second matrix-segment, using the QuickChange site directed
      mutagenesis protocol (Stratagene), and were assayed fluorometrically for kinetics
      of fatty acid (FA)-induced H+ uniport and for Cl- uniport. Their ability to bind
      3H-GTP was also evaluated. The wild type UCP1 was associated with the FA-induced
      H+ uniport proportional to the added protein with a Km for lauric acid of 43
      micro M and Vmax of 18 micro molmin(-1)(mg protein)(-1). Neutralization of Arg152
      (in the second matrix-segment UCP-signature) led to approximately 50% reduction
      of FA affinity (reciprocal Km) and of Vmax for FA-induced H+ uniport. Halved FA
      affinity and 70% reduction of Vmax was found for the double His substitution
      outside the signature (H145L and H147L mutant). Neutralization of Asp27 in the
      first alpha-helix UCP-signature (D27V mutant) resulted in 75% reduction of FA
      affinity and approximately 50% reduction of Vmax, whereas the triple C24A and
      D27V and T30A mutant was fully non-functional (Vmax reduced by 90%).
      Interestingly, the T30A mutant exhibited only the approximately 50% reduced FA
      affinity but not Vmax. Cl- uniport and 3H-GTP binding were preserved in all
      studied mutants. We conclude that amino acid residues of the first alpha-helix
      UCP signature may be required to hold the intact UCP1 transport conformation.
      This could be valid also for the positive charge of Arg152 (second matrix-segment
      UCP signature), which may alternatively mediate FA interaction with the native
      protein.

PMID- 12479872
TI  - Determination of the P1', P2' and P3' subsite-specificity of factor Xa.
AB  - Factor Xa is a central protease in the coagulation cascade and the target for
      many anticoagulant compounds currently under development. The preferences of the
      enzyme for substrates incorporating residues N-terminal to the cleavage site (P1,
      P2, etc.) have been elucidated, but little is known of its preferences for
      residues C-terminal to the cleavage site (P1', P2', etc.). The preferences of
      bovine factor Xa for substrate residues in the P1', P2' and P3' positions were
      mapped using fluorescence-quenched substrates. Bovine factor Xa, often used as a
      model for factor Xa, was most selective for the P2' position, less selective at
      the P1' position and almost completely non-selective at the P3' position. It
      appears that while the prime side subsites of factor Xa impose some selectivity
      towards substrates, the influence of these sites on factor Xa cleavage
      specificity is relatively low in comparison to related enzymes such as thrombin.

PMID- 12479873
TI  - Molecular cloning and characterization of a novel human protein phosphatase, LMW
      DSP3.
AB  - Reversible phosphorylation is recognized to be a major mechanism for the control
      of intracellular events in eukaryotic cells. From a human fetal brain cDNA
      library, we isolated a cDNA clone encoding a novel dual specificity protein
      phosphatase, which showed 88% identity with previously reported mouse LMW-DSP3 at
      the amino acid level. The deduced protein had a single dual-specificity
      phosphatase catalytic domain, and lacked a cdc25 homology domain. LMW-DSP3 was
      expressed in the heart, lung, liver, and pancreas, and the expression level in
      the pancreas was highest. The LMW-DSP3 gene was located in human chromosome 2q32,
      and consisted of five exons spanning 21kb of human genomic DNA. LMW-DSP3 fused to
      GST showed phosphatase activity towards p-nitrophenyl phosphate which was optimal
      at pH 7.0 and 40 degrees C, and the activity was enhanced by Ca(2+) and Mn(2+).
      The phosphatase activity of LMW-DSP3 was inhibited by orthovanate. LMW-DSP3
      showed phosphatase activity toward oligopeptides containing pSer/Thr and pTyr,
      indicating that LMW-DSP3 is a protein phosphatase with dual substrate
      specificity.

PMID- 12479874
TI  - Tissue specific, sex and age--related differences in the 6-phosphogluconate
      dehydrogenase gene expression.
AB  - Data presented in thid paper indicate that: (1) the age-related changes in 6
      phosphogluconate dehydrogenase (6PGDH) activity depend on sex and tissue. No
      differences in the liver 6PGDH activity between young (1-month-old) males and
      females were found. In adult males, the activity was the same as in young animals
      but, in adult females, it reached the value twice as high as in the young. In
      adipose tissue (both white and brown) and kidney cortex, the enzyme activity
      decreased with age both in males and females. There were no differences between
      males and females 6PGDH activity in brain, heart and skeletal muscle. (2) The sex
      and age-related changes in the liver 6PGDH activity occur predominantly at the
      level of mRNA cellular concentration. (3) In the liver of ovariectomized rats
      decrease of 6PGDH activity and mRNA level was observed. Oestradiol administration
      to ovariectomized rats restored liver 6PGDH activity and liver 6PGDH mRNA levels
      to that observed in controls. No changes in 6PGDH activity and mRNA levels were
      found in white adipose tissue (WAT) of ovariectomized adult rats and in
      ovariectomized rats treated with oestradiol. (4) Oestradiol administration to
      males caused an increase of liver 6PGDH activity and mRNA levels to values
      observed in females, but was without an effect on WAT 6PGDH activity and mRNA
      level. (5) These results suggest that 6PGDH activity in different tissues is not
      regulated in coordinate fashion and that oestradiol plays an important role in
      the liver enzyme activity regulation.

PMID- 12479875
TI  - Down-regulation and decreased activity of cyclin-dependent kinase 2 in H2O2
      induced premature senescence.
AB  - Premature senescence of human diploid fibroblasts (HDFs) induced by exposure to
      H2O2 at subcytotoxic concentration is characterized by many biomarkers of normal
      senescence such as irreversible growth arrest. Cyclin-dependent kinase inhibitor
      (CdKI) p21(Waf-1) is overexpressed in H2O2- and tert-butylhydroperoxide-induced
      premature senescence, likely explaining in part the hypophosphorylation of the
      retinoblastoma protein. p21(Waf-1) is known to inhibit the kinase activity of the
      cyclin-dependent kinase (CdK) 4 and 6 cyclin complexes. In this work, we
      investigated whether the kinase activity of the CdK4 and 6 cyclin complexes can
      be modulated by CdKI p16(Ink-4a), by changes in the protein level of CdKs and
      cyclins, or by changes in kinase activity of these CdKs not directly involving
      CdKIs. RNase protection assay, semi-quantitative RT-PCR, Western blot and kinase
      assay showed that the mRNA level, protein and kinase activity of CdK2 are
      decreased at 72h after H2O2 stress. These results suggest that the
      hypophosphorylation of the retinoblastoma protein is mediated in part by a
      decrease of the kinase activity of CdK2 not directly involving CdKIs. This CdK2
      mediated effect should be considered in addition to the inhibition of cyclin D
      CdK4 and 6 complexes by CdKI p21(Waf-1).

PMID- 12479876
TI  - Purification and characterization of a new lectin from the hard roe of skipjack
      tuna, Katsuwonus pelamis.
AB  - Fish eggs are known as a rich source of lectins. In this study we purified and
      characterized a lectin from unfertilized Katsuwonus pelamis hard roe. K. pelamis
      lectin (KPL) was purified by separation into two fractions above and below the
      molecular weight of 10kDa using ultramembrane, gel filtration on a Sephadex G
      100, and affinity chromatography on an asialofetuin-Sepharose 4B. KPL is a
      glycoprotein of 140kDa, composed mainly of aspartic acid, glycine, phenylalanine,
      glutamic acid, threonine and serine residues. Analysis of the carbohydrate
      composition by gas-liquid chromatography indicated that carbohydrates constituted
      14% of the total weight and this 14% is comprised of mannose, galactose, N-acetyl
      D-glucosamine, N-acetyl-D-galactosamine, fucose, arabinose and sialic acid. The
      lectin is comprised of four subunits. These subunits have a molecular mass
      corresponding to 35kDa. KPL specifically agglutinated human blood type A
      erythrocytes and, in a hemagglutination inhibitory test, the potent inhibitors
      were D-galactose, lactose, lactosamine, asialofetuin, N-acetyl-D-galactosamine, O
      serinyl-2-acetamido-2-deoxy-alpha-D-galactopyranoside and O-serinyl-2-acetamido-2
      deoxy-beta-D-galactopyranoside (O-serinyl-beta-D-GalNAc). The first 10 residues
      of the N-terminal region were determined as PVELCDAKCT. Furthermore it was
      determined that the hemagglutinating activity of KPL was dependent on divalent
      metal cations and that the optimum activity of KPL was exhibited at 40 degrees C
      and pH 6.0-8.5 in the presence of Ca2+.

PMID- 12479877
TI  - Elevated homocysteine serum level is associated with low enrichment of
      homocysteine in coronary arteries of patients with coronary artery disease.
AB  - In the present study, we sought to investigate whether elevated serum levels of
      homocysteine (Hcy), predisposing to endothelial dysfunction during progression of
      atherosclerosis, were paralleled by increased Hcy concentrations in human
      coronary arteries. Paraffin sections of coronary arteries were obtained from
      explanted hearts of cardiac transplant recipients suffering from coronary artery
      disease (CAD, n=32, mean age=56.6+/-6.8), and from heart donors where
      transplantation was not performed due to organization-related circumstances (Co,
      n=6, mean age 25.0+/-10.6), and characterized immunohistochemically for Hcy,
      CD68, and smooth muscle alpha-actin. Although the CAD group presented with high
      serum Hcy levels (27.7+/-12.8 micromol/l), the media and intimal layers
      containing the endothelium showed the lowest enrichment of Hcy (media: 20.8+/
      4.4%; intima: 6.1+/-2.3%). Surprisingly, the control group revealed an extensive
      Hcy enrichment, co-localizing with vascular smooth cells (media: 32.3+/-14.0%;
      intima: 7.0+/-2.0%). In conclusion, we have provided evidence for a reverse
      relation between Hcy serum concentration and enrichment of Hcy in coronary
      arteries of patients with severe CAD, suggesting that Hcy is not likely to be
      involved directly in atheromatosis development of coronary arteries.

PMID- 12479878
TI  - Evaluation of advanced D-dimer assay for the exclusion of venous thromboembolism.
AB  - The performances for thromboembolic disease exclusion of a new microlatex
      enhanced D-dimer immunoassay have been evaluated. Advanced D-dimer (Dade-Behring,
      Marburg, Germany) was tested with two automated analyzers, namely BCS and CA
      1500. Precision studies yielded coefficients of variation (within-run and run-to
      run) of 3% and 6.3% at D-dimer levels near the cut-off value, for BCS and CA-1500
      respectively. Frozen samples from 294 consecutive symptomatic outpatients
      suspected of either deep venous thrombosis (140) or pulmonary embolism (154) from
      a previous management study were tested with both analyzers, as well as with the
      VIDAS New assay (BioMerieux, Marcy-l'Etoile, France). For BCS, sensitivity and
      specificity were 96.6% (95% CI, 90.5, 99.3) and 42% (35.1, 49.0) respectively at
      a cut-off value of 1.35 microg/ml. For CA-1500, the corresponding figures were
      95.5% (88.9, 98.8) and 47.8% (40.8, 54.9) at a cutt-off value of 1.1 microg/ml.
      This assay appears promising and should be validated in clinical practise to
      assess its place in the work-up schemes of thromboembolism.

PMID- 12479879
TI  - Inhibition of platelet aggregation by rat globin.
AB  - This study was undertaken to identify and characterize the anti-aggregatory
      protein factor present in rat polymorphonuclear leukocytes (PMNs) supernatant.
      Since the purified protein exhibited sequence homology to beta globin, globin was
      also isolated from rat blood by acid-acetone precipitation and was purified on
      Superdex-75 column in FPLC. Elution of rat globin on the gel filtration column
      yielded two peaks of approximately 60 and 30 kDa as observed in the PMNs
      supernatant. Purity of globin and eluted fractions was further evaluated by SDS
      PAGE. Platelet aggregation induced by agonists viz. adenosine-5'-diphosphate
      (ADP; 2-5 microM), arachidonic acid (AA; 10 microM), A23187 (2.50 microg/ml) was
      inhibited by globin and the purified fractions. ADP-induced rise in intracellular
      calcium levels and expression of CD62 on the platelets were reduced by both
      globin and active fraction of PMNs supernatant. Results obtained suggest that
      globin or globin-related protein present in the PMNs supernatant inhibits
      platelet aggregation response.

PMID- 12479880
TI  - Effects of insulin on platelet and leukocyte activity in whole blood.
AB  - Diabetes mellitus (DM) is associated with platelet and leukocyte dysfunction.
      Previous observations with regard to insulin effects on platelet and leukocyte
      function are less than consistent. We thus investigated the effects of insulin on
      platelets and leukocytes, as well as on platelet-leukocyte interactions in whole
      blood. Hirudinized whole blood from 20 healthy subjects was preincubated at 37
      degrees C in the absence or presence of insulin (30 and 300 microU/ml), and
      further incubated without or with adenosine diphosphate (ADP) (10(-5) M) or N
      formyl-methionyl-leucyl-phenylalanine (fMLP) (10(-7) M), respectively. Platelet P
      selectin expression, platelet fibrinogen binding, single platelet and platelet
      platelet aggregate (PPA) counts, and leukocyte CD11b expression and superoxide
      anion production were monitored by flow cytometry. Insulin decreased single
      platelet counts (P<0.05) and increased PPAs (P<0.01) at 300 microU/ml in
      unstimulated samples, but did not significantly influence the P-selectin
      expression or fibrinogen binding of single platelets. Insulin also enhanced ADP
      induced platelet aggregation, seen as an augmented decrease of single platelet
      counts. Insulin (30 microU/ml) increased leukocyte CD11b mean fluorescence
      intensity (MFI) in unstimulated, as well as fMLP- and ADP-stimulated samples
      (P<0.05 for all). fMLP-induced superoxide anion (O(2)(-)) production was,
      however, attenuated by insulin. Furthermore, fMLP-activation of leukocytes was
      associated with enhanced platelet fibrinogen binding and P-selectin expression.
      In conclusion, clinically relevant concentrations of insulin enhance platelet
      aggregability and leukocyte CD11b expression, but attenuate leukocyte respiratory
      burst activity. Our results suggest that insulin may modulate thrombotic and
      inflammatory processes in vivo in a complex manner.

PMID- 12479881
TI  - Thrombin activity and platelet microparticle formation are increased in type 2
      diabetic platelets: a potential correlation with caspase activation.
AB  - Diabetics suffer from many complications including a prothrombotic condition.
      Activated platelet membrane provides an anchor, phosphatidylserine, for the
      attachment of the prothrombinase complex, which allows increased thrombin
      formation. This study aimed to further elucidate the interrelationship between
      coagulation proteins and activated platelets in type 2 diabetic blood. We found
      that there was a significant increase (30 x) in thrombin activity in the type 2
      diabetic (ZDF) blood as compared to age-matched (ZL) controls (p<0.001). There
      was also a significant increase in the number of platelet microparticles in the
      type 2 diabetic rat compared to the lean control (p<0.001). Further, there were
      significant increases in caspase-3, -6, and -8 activities in the type 2 diabetic
      rats as compared to the lean controls (p<0.05). The combination of increased
      thrombin activity, increased PMP formation and increased caspase activity may
      contribute to the hypercoagulability of the diabetic blood. These results give
      more insight into the mechanisms underlying the interrelationship between
      diabetic platelets and coagulation proteins causing a prothrombotic condition in
      this patient population at increased risk from thromboembolic events.

PMID- 12479882
TI  - Observation on tissue factor pathway and some other coagulation parameters during
      the onset of acute cerebrocardiac thrombotic diseases.
AB  - It is widely recognized that thrombosis is the major event in the evolution of
      acute myocardial infarction (AMI) and acute ischemic stroke (AIS). But the
      contribution of coagulation factors to the development of ischemic arterial
      diseases is still not clearly established. The goal of this study was to
      establish the possible relationship between coagulation factors as well as
      anticoagulant and the onset of AMI and AIS. The study population consisted of 69
      patients with AMI and 71 with AIS as well as 50 age-matched healthy volunteers.
      Compared with the control group, plasma tissue factor (TF) and tissue factor
      pathway inhibitor (TFPI) activities and both TF and TFPI antigens were
      significantly higher in the AMI group; plasma TF activity and antigen in AIS
      group were significantly increased, but the activity and antigen of plasma TFPI
      were significantly decreased in the AIS group. Plasma FVII coagulation (FVII:C)
      activity was markedly higher in patients with AIS, but not statistically
      different to the control in patients with AMI. FVIII coagulation (FVIII:C)
      activity was remarkably higher in patients with AMI but slightly lower than the
      control in patients with AIS. In the AMI and AIS groups, prothrombin activity and
      clottable fibrinogen were significantly higher and plasma antithrombin III
      activity was remarkably lower than the control. The results suggested that during
      the onset of AMI and AIS, the initiation of TF pathway would be associated with
      the thrombotic events and that the blood be in hypercoagulable state. But the
      changes of FVII:C, TFPI and FVIII:C in AMI are different from those in AIS.

PMID- 12479883
TI  - Parameters of coagulant and fibrinolytic capacity and activity in postmenopausal
      women: within-subject variability.
AB  - We have analyzed the within-subject variability of a battery of parameters of
      coagulant and fibrinolytic capacity and activity in postmenopausal women. We
      observed large differences in within-subject variability among the tests and have
      demonstrated how such data can be used to estimate the number of times a
      parameter must be measured to produce a statistically adequate sample.

PMID- 12479884
TI  - Monitoring of unfractionated heparin with the activated partial thromboplastin
      time: determination of therapeutic ranges.
AB  - The purpose of the present study was to determine therapeutic ranges for
      unfractionated heparin therapy using the activated partial thromboplastin time
      (APTT) by calibration against anti-Xa concentration. APTT assays were performed
      locally, i.e. at the institution of blood collection, on fresh plasma samples
      from patients treated with intravenous unfractionated heparin. The measurements
      were performed by 25 Dutch clinical laboratories using 11 different APTT reagents
      and 10 different types of coagulometers. After the local APTT measurement, the
      samples were frozen and transported to a central laboratory for measurement of
      anti-Xa activity. The number of samples from the participating laboratories
      ranged from 10 to 48. Local APTT results were correlated with the central anti-Xa
      measurements. Orthogonal regression analysis of log-transformed values was used
      to calculate APTT therapeutic ranges corresponding to anti-Xa concentrations of
      0.29-0.47 IU/ml. The calculated APTT ranges were different between laboratories,
      even when the same reagent was used. In many laboratories, the therapeutic APTT
      range in use was much wider than the calculated range. Imprecision of the
      calculated APTT range was influenced by the wide scatter of the measurement
      points and by the selection of samples for the orthogonal regression equation.
      The present results show that, if anti-Xa concentrations of 0.29-0.47 IU/ml
      reflect the true therapeutic range, many laboratories do not use the proper
      therapeutic APTT range.

PMID- 12479885
TI  - In vitro comparison of the effect of heparin, enoxaparin and fondaparinux on
      tests of coagulation.
AB  - Low-molecular weight heparin (LMWH) is increasingly used in place of
      unfractionated heparin (UFH) in patients with unstable angina, and phase II
      clinical trials using fondaparinux for this indication are underway. Because
      unstable angina patients often require urgent percutaneous coronary interventions
      (PCI) or aortocoronary bypass surgery, a point-of-care test is needed to monitor
      the anticoagulant effect of these agents. The activated clotting time (ACT) and
      activated partial thromboplastin time (aPTT) are the tests most often used to
      monitor heparin. The purpose of this in vitro study was to determine whether the
      ACT or the aPTT can be used to monitor the anticoagulant effect of low-molecular
      weight heparin and fondaparinux. The ACT and aPTT were measured after heparin,
      enoxaparin or fondaparinux was added to the blood of healthy volunteers, in doses
      with equivalent inhibitory activity against activated factor X (factor Xa). To
      mimic the clinical scenario where an unstable angina patient, who has already
      received enoxaparin, is urgently taken for PCI or bypass surgery, the ACT was
      determined after heparin was added to blood containing clinically relevant doses
      of enoxaparin. We determined that enoxaparin produced significantly less
      prolongation of both the ACT and the aPTT than heparin, whereas fondaparinux had
      no effect on either of these tests. Addition of enoxaparin to heparin-containing
      plasma did not prolong the ACT beyond that produced by heparin alone. The ACT and
      aPTT therefore cannot be used to monitor low-molecular weight heparin or
      fondaparinux, highlighting the need for a point-of-care anti-factor Xa assay.

PMID- 12479887
TI  - Hypertonic resuscitation and blood coagulation: in vitro comparison of several
      hypertonic solutions for their action on platelets and plasma coagulation.
AB  - Resuscitation with hypertonic saline (HS) appears to aggravate bleeding in a
      model of uncontrolled hemorrhage [J. Trauma 28 (1988) 751; J. Trauma 29 (1989)
      79; Arch. Surg. 127 (1992) 93]. This property may be related to the anticoagulant
      effects of HS on plasma clotting factors and platelets [J. Trauma 31 (1991) 8].
      The hypothesis in this study is that a hypertonic solution can be developed that
      would not disturb the blood coagulation mechanism and could be used as an
      alternative to hypertonic saline.HS and four different 2400 mosM solutions
      containing monosaccharides and/or glycine were screened for their in vitro
      effects on plasma clotting times and platelets. Significant prolongations falling
      outside the normal range were detected in prothrombin time (PT) and thrombin rime
      (TT) when only 5% of the volume of normal plasma is HS. Platelet function as
      measured by extent of shape change (ESC) induced by ADP and aggregation induced
      by thrombin were also critically impaired by HS at a 5% dilution. All alternative
      solutions-hypertonic glucose, sorbitol, glycine, glucose/glycine,
      glucose/mannitol/glycine, sorbitol/glycine-caused a significantly reduced
      impairment in platelet function and the plasma coagulation system. Hypertonic
      glycine showed a unique ability to fully preserve the function and integrity of
      the plasma coagulation system. Considering the pre-deposition of the trauma
      patient to coagulopathy, administration of HS which clearly is a potent
      anticoagulant and anti-platelet risks further aggravating the coagulopathy. In
      contrast, hypertonic glycine preserves the blood coagulation mechanism and
      exhibits the potential for numerous therapeutic applications. Therefore, prompt
      evaluation of hypertonic glycine as a resuscitative fluid is highly desirable.

PMID- 12479886
TI  - Purification of salmon thrombin and its potential as an alternative to mammalian
      thrombins in fibrin sealants.
AB  - A method to produce highly purified thrombin from salmon blood is described, and
      a series of biochemical, cell biologic, and biophysical assays demonstrate the
      functional similarities and some differences between salmon and human thrombins.
      Salmon thrombin with specific activity greater than 1000 units/mg total protein
      can be prepared by modifications of the methods used for purification of human
      thrombin. Using a synthetic substrate based on the human fibrinogen A-alpha
      polypeptide sequence as an indicator of enzymatic activity, salmon and human
      thrombin preparations contain similar specific activities per mass of purified
      protein. Salmon thrombin activates human fibrinogen and initiates the formation
      of fibrin clots whose structure and rheologic properties are indistinguishable
      from those of human fibrin clotted by human thrombin. Salmon thrombin also
      activates human platelets. Approximately 10 times higher activities are needed
      for the same rate of platelet aggregation compared to human thrombin, and some
      aspects of platelet activation, most notably phosphatidylserine exposure, are
      diminished relative to the effects of human thrombin. This latter finding
      suggests that salmon thrombin may not activate all of the receptors that are
      targets of human thrombin, although it does appear to activate signals that are
      sufficient to produce normal rates of activation and aggregation as measured by
      conventional aggregometry. Together with the recent purification of salmon
      fibrinogen and its application in mammalian wound healing, the availability of
      salmon thrombin allows the formulation of biological sealants devoid of any
      exogenous mammalian proteins and so may aid the design of materials with
      increased safety from infectious disease transmission.

PMID- 12479888
TI  - Effect of freeze-drying, freezing and frozen storage of blood plasma on fibrin
      network characteristics.
AB  - INTRODUCTION: We investigated the effect of freezing, freeze-drying and the
      duration of frozen storage of blood plasma on fibrin network characteristics of
      clots subsequently produced. MATERIALS AND METHODS: Fibrin network
      characteristics of clots made from freeze-dried and frozen plasma were compared
      to those made from fresh plasma. Freeze-dried pooled plasma was reconstituted and
      frozen each month for 4 months to describe the differences in fibrin networks
      that occur as a result of storage of the plasma over this period. RESULTS:
      Compared to freezing, freeze-drying of plasma had fewer undesirable effects on
      the fibrin network characteristics measured. Only the permeability of the clots
      from freeze-dried plasma was significantly less compared to the values of clots
      from the fresh plasma (p=0.005). Fibrinogen activity and mass-length ratio,
      compaction and fibrin content of the clots made from frozen plasma were, however,
      all significantly affected by freezing. Mass-length ratio and compaction showed a
      linear decrease and fibrin content a linear increase over a 4-month frozen
      storage period, thereby indicating that these variables were probably not stable.
      Large variation found in the data from each month indicates that there may be
      other factors, apart from storage time, that have a larger influence on these
      fibrin network characteristics, than frozen storage of plasma for 4 months.
      Storage of plasma in the freeze-dried form for 4 months resulted in a significant
      increase in fibrinogen (p=0.0004) but significant decrease in fibrin content
      (p=0.0002). CONCLUSIONS: Although the process of freeze-drying had fewer
      undesirable effects on the measured fibrin network characteristics compared to
      freezing, storage in both forms resulted in altered activity upon rehydration and
      thawing.

PMID- 12479889
TI  - Protease-activated receptor 2 (PAR2) mediates vascular smooth muscle cell
      migration induced by tissue factor/factor VIIa complex.
AB  - Protease-activated receptor 2 (PAR2) is one of G-protein-coupled receptors able
      to be activated by trypsin and coagulation factor VIIa. We previously reported
      that tissue factor/factor VIIa (TF/FVIIa) complex was a strong chemotactic factor
      for cultured vascular smooth muscle cells (SMCs). The migratory response was
      dependent on a catalytic activity of FVIIa, and did not involve factor Xa and
      thrombin generation. In this study, we examined TF/FVIIa-induced SMC migration.
      METHODS: The contribution of PAR2 to TF/FVIIa-induced vascular SMC migration was
      investigated using a modified Boyden's chamber method, and the distribution of
      PARs in the human coronary arteries and cultured SMCs was also examined. RESULTS:
      Trypsin and PAR2-activating peptide (AP; SLIGKV) stimulated SMC migration in a
      dose-dependent manner, of which abilities were comparable to those of TF/FVIIa
      complex and platelet-derived growth factor-BB, but PAR1-AP (TFLLR or SFLLR) or
      PAR4-AP (AYPGOV) did not elicit the migration. The antisera against PAR2-AP
      significantly inhibited TF/FVIIa-induced SMC migration, but that of PAR1-AP did
      not. In immunostaining, both intimal SMCs of the human coronary arteries and
      cultured SMCs showed positive reaction for PAR2-AP. CONCLUSION: These results
      suggest that PAR2 in SMCs plays a crucial role in the cell migration induced by
      TF/FVIIa complex.

PMID- 12479890
TI  - Variations of prothrombin time and international normalized ratio in patients
      treated with warfarin.
AB  - Prothrombin time is a standard screening test to monitor patients treated with
      oral anticoagulants. We hypothesize that INR measurements will not vary a lot
      within a given day in a given patient. The present study was thus conducted to
      compare the change of the international normalized ratio (INR) of prothrombin
      time (PT) within 1 day in patients treated with warfarin. Thirty such patients
      and nineteen healthy controls were enrolled into this study. PT was performed in
      four time points of a day in all subjects, two in the morning and two in the
      afternoon. The four INR values obtained were compared with each other to find
      little change in the series of time either in patients or in healthy controls.
      Neither were they affected by renal function, liver function, sex, age,
      hemoglobin, white cell count, platelet, treatment duration of warfarin, or
      alcoholic drinking. INR could be measured in any time of a day to have values
      equally valuable in clinical use.

PMID- 12479891
TI  - Aptamer and inhibition of thrombin clotting activity: a note of caution.

PMID- 12479892
TI  - The use of generalized estimating equations in the analysis of motor vehicle
      crash data.
AB  - The purpose of this study was to determine if it is necessary to use generalized
      estimating equations (GEEs) in the analysis of seat belt effectiveness in
      preventing injuries in motor vehicle crashes. The 1992 Utah crash dataset was
      used, excluding crash participants where seat belt use was not appropriate
      (n=93,633). The model used in the 1996 Report to Congress [Report to congress on
      benefits of safety belts and motorcycle helmets, based on data from the Crash
      Outcome Data Evaluation System (CODES). National Center for Statistics and
      Analysis, NHTSA, Washington, DC, February 1996] was analyzed for all occupants
      with logistic regression, one level of nesting (occupants within crashes), and
      two levels of nesting (occupants within vehicles within crashes) to compare the
      use of GEEs with logistic regression. When using one level of nesting compared to
      logistic regression, 13 of 16 variance estimates changed more than 10%, and eight
      of 16 parameter estimates changed more than 10%. In addition, three of the
      independent variables changed from significant to insignificant (alpha=0.05).
      With the use of two levels of nesting, two of 16 variance estimates and three of
      16 parameter estimates changed more than 10% from the variance and parameter
      estimates in one level of nesting. One of the independent variables changed from
      insignificant to significant (alpha=0.05) in the two levels of nesting model;
      therefore, only two of the independent variables changed from significant to
      insignificant when the logistic regression model was compared to the two levels
      of nesting model. The odds ratio of seat belt effectiveness in preventing
      injuries was 12% lower when a one-level nested model was used. Based on these
      results, we stress the need to use a nested model and GEEs when analyzing motor
      vehicle crash data.

PMID- 12479893
TI  - Stated preference in the valuation of interurban road safety.
AB  - In Chile, as in most less-developed nations, if life savings are valued at all
      the human capital approach is used in a rather non-consistent fashion. As part of
      a 5-year research project on the value of transport externalities, a stated
      preference (SP) experiment was carried out in order to assess the value of a
      statistical life for Chilean interurban motorways. Interviewees had to choose
      among different routes for a hypothetical trip, based on the following
      attributes: travel time, toll charge and level of risk. The results of our
      experiment show that people were sensitive to the risk variable, thus "stating" a
      preference for safer routes. Several models were estimated with linear and non
      linear utility specifications, and also incorporating the effects of socio
      economic variables in a novel and interesting fashion. We were able to estimate
      subjective values of time consistent with previous values obtained in the country
      and reasonably looking values (in comparison to Chilean prices and foreign
      experience) of a statistical life. The paper discusses the experimental design,
      data collection and analysis, with emphasis on the role of lexicographic
      individuals that are a feature of SP studies that has not been carefully explored
      in the literature. We also present our modelling results and compare our derived
      values (of time and of a statistical life) with values found previously and/or
      elsewhere.

PMID- 12479894
TI  - The impact of hands-free message reception/response on driving task performance.
AB  - A series of closed-course driving experiments were conducted in which 41 drivers
      ranging in age from 19 to 70 were put through a series of increasingly
      challenging driving performance tasks both in the presence and absence of audible
      messages. The messages required specific responses and these, along with driving
      performance measures based on driver/vehicle response characteristics, were
      recorded. The results clearly showed a negative impact of the message task on
      driver decision-making performance when this involved the more complex tasks of
      weaving and especially left-turning. Such decision-making decrements in the
      presence of the messages were exacerbated by adverse pavement surface conditions.

PMID- 12479895
TI  - Health-health analysis-an alternative method for economic appraisal of health
      policy and safety regulation. Some empirical Swedish estimates.
AB  - Health-health analysis (HHA) focuses on statistical lives themselves as a
      numeraire. The underlying principle is that the expected gains in health and
      safety of reduced risks in one area may result in increasing risks somewhere else
      in society. By reducing one risk other risks may increase due to changed
      individual behaviour. In addition to this direct effect, another indirect effect
      will also be present. Expenditure on a particular health policy or safety
      regulation must be financed in one way or another, which will result in an
      opportunity cost or income effect leaving less resources for other health and
      safety promoting activities in society. Thus, we will have an effect that reduces
      safety and health benefits induced by that income loss. Whether the total net
      health effect from a specific safety regulation or health policy is positive or
      negative must be empirically analysed. One way of estimating the income loss that
      induces one death, which we call the value of an induced death (VOID), is to
      estimate it as a multiple of the traditional value to avert a statistical death,
      also named the value of a statistical life (VOSL).A contingent valuation (CV)
      study eliciting the willingness-to-pay (WTP) for reducing the overall risk of
      dying was performed as a postal questionnaire in Sweden in 1998. By use of data
      from this study, it was possible to estimate the VOID and the VOSL in Sweden
      amounting to SEK116 and SEK20.8 million respectively, indicating that the net
      health result confined to mortality effects, will be negative (more lives will be
      lost than saved) if a health policy or safety regulation will cost more than
      SEK116 million per life saved.

PMID- 12479896
TI  - Decision aid for allocation of transportation funds to guardrails.
AB  - We address the need for allocation of resources to run-off-road and fixed-object
      hazards on immense secondary road systems. In Virginia, there are 95,000km of
      roadway with uncharacterized hazards in need of guardrail upgrade, installation,
      or related warning signs or other protection. A decision aid is developed to
      assist the planner in guardrail resource allocation by accounting for the
      potential crash severities, traffic exposures, costs of treatment, and other
      factors. A premise is that no single benefit-cost ratio or selection criterion
      applies across all localities. The decision aid enables the planner to interpret
      the variety of benefits and costs in their own units, emphasizing the needs and
      preferences of individual localities. The paper describes: (1) archiving and
      comparison of protected and unprotected hazards; (2) regional screening of
      hazardous corridors and (3) multicriteria benefit-cost analyses of guardrail
      sites. A case study of guardrail selection is presented.

PMID- 12479897
TI  - The use of multilevel models for the prediction of road accident outcomes.
AB  - An important problem in road traffic accident research is the resolution of the
      magnitude by which individual accident characteristics affect the risk of
      fatality for each person involved. This article introduces the potential of a
      recently developed form of regression models, known as multilevel models, for
      quantifying the various influences on casualty outcomes. The application of
      multilevel models is illustrated by the analysis of the predictors of outcome
      amongst over 16,000 fatally and seriously injured casualties involved in
      accidents between 1985 and 1996 in Norway. Risk of fatality was found to be
      associated with casualty age and sex, as well as the type of vehicles involved,
      the characteristics of the impact, the attributes of the road section on which it
      took place, the time of day, and whether alcohol was suspected. After accounting
      for these factors, the multilevel analysis showed that 16% of unexplained
      variation in casualty outcomes was between accidents, whilst approximately 1% was
      associated with the area of Norway in which each incident occurred. The benefits
      of using multilevel models to analyse accident data are discussed along with the
      limitations of traditional regression modelling approaches.

PMID- 12479898
TI  - The influence of extrinsic and intrinsic risk factors on the probability of
      sustaining an injury.
AB  - This study was designed to quantify the relative contributions of extrinsic and
      intrinsic risk factors to the probability of an injury event. A case-control
      design was used with data collected from injured patients at an emergency
      department (n=797) and a community sample matched on area of residence and time
      of injury (n=797). Principal components analysis was used to develop scales for
      the measurement of 'intrinsic' risk taking tendencies that were slightly modified
      versions of previously published measures. Two principal components were
      identified: 'health risk taking' (HRT) and 'adventurous risk taking' (ART).
      Logistic regression analysis identified variables that significantly predicted
      membership of the group of injured cases. The main hypothesis was supported by
      the results: that 'extrinsic' factors such as location, activity, drug and
      alcohol use and the type of people present at the time of the injury were related
      to a greater risk of injury than 'intrinsic' variables (health and adventurous
      risk taking tendencies). The results suggest that injury research and prevention
      efforts should continue to focus on the identification and modification of
      situational risk factors for injury rather developing programs that focus on high
      risk individuals. High-risk alcohol use, use of prescribed drugs and aspects of
      work and recreational environments were identified as warranting particular
      attention.

PMID- 12479899
TI  - Economic consequences of injury and resulting family coping strategies in Ghana.
AB  - The toll of human suffering from illness and injury is usually measured by
      mortality and disability rates. Economic consequences, such as treatment costs
      and lost productivity, are often considered as well. Lately, increasing attention
      has been paid to the economic effects of illness on a household level. In this
      study, we sought to assess the economic consequences of injuries in Ghana by
      looking at the effects on households and the coping mechanisms these households
      employed. Using cluster sampling and household interviews, we surveyed 21,105
      persons living in 431 urban and rural sites. We sought information on any injury
      that occurred to a household member during the prior year and that resulted in
      one or more days of disability time.A total of 1609 injuries were reported for
      the prior year. Treatment costs and disability days were higher in the urban area
      than in the rural. Coping strategies were different between the two areas. Rural
      households were more likely to utilize intra-family labor reallocation (90%) than
      were urban households (75%). Rural households were also more likely to borrow
      money (24%) than were urban (19%). Households in both areas were equally likely
      to sell belongings, although the nature of the belongings sold were different.
      Although injuries in the urban area had more severe primary effects (treatment
      cost and disability time), the ultimate effect on rural households appeared more
      severe. A greater percentage of rural households (28%) reported a decline in food
      consumption than did urban households (19%). These findings result in several
      policy implications, including measures that could be used to assist family
      coping strategies and measures directed toward injuries themselves.

PMID- 12479900
TI  - A Bayesian hierarchical model for accident and injury surveillance.
AB  - This article presents a recent study which applies Bayesian hierarchical
      methodology to model and analyse accident and injury surveillance data. A
      hierarchical Poisson random effects spatio-temporal model is introduced and an
      analysis of inter-regional variations and regional trends in hospitalisations due
      to motor vehicle accident injuries to boys aged 0-24 in the province of British
      Columbia, Canada, is presented. The objective of this article is to illustrate
      how the modelling technique can be implemented as part of an accident and injury
      surveillance and prevention system where transportation and/or health authorities
      may routinely examine accidents, injuries, and hospitalisations to target high
      risk regions for prevention programs, to evaluate prevention strategies, and to
      assist in health planning and resource allocation. The innovation of the
      methodology is its ability to uncover and highlight important underlying
      structure of the data. Between 1987 and 1996, British Columbia hospital
      separation registry registered 10,599 motor vehicle traffic injury related
      hospitalisations among boys aged 0-24 who resided in British Columbia, of which
      majority (89%) of the injuries occurred to boys aged 15-24. The injuries were
      aggregated by three age groups (0-4, 5-14, and 15-24), 20 health regions (based
      of place-of-residence), and 10 calendar years (1987 to 1996) and the
      corresponding mid-year population estimates were used as 'at risk' population. An
      empirical Bayes inference technique using penalised quasi-likelihood estimation
      was implemented to model both rates and counts, with spline smoothing
      accommodating non-linear temporal effects. The results show that (a) crude rates
      and ratios at health region level are unstable, (b) the models with spline
      smoothing enable us to explore possible shapes of injury trends at both the
      provincial level and the regional level, and (c) the fitted models provide a
      wealth of information about the patterns (both over space and time) of the injury
      counts, rates and ratios. During the 10-year period, high injury risk ratios
      evolved from northwest to central-interior and the southeast [corrected].

PMID- 12479901
TI  - Field relevance of a suite of rollover tests to real-world crashes and injuries.
AB  - The objective of this study was to assess the distribution of rollover accidents
      occurring in the field and to compare the vehicle kinematics in the predominant
      field crash modes with available laboratory tests. For this purpose, US accident
      data were analyzed to identify types and circumstances for vehicle rollovers.
      Rollovers were most commonly induced when the lateral motion of the vehicle was
      suddenly slowed or stopped. This type of rollover mechanism is referred to as
      "trip-over". Trip-overs accounted for 57% of passenger car and 51% of light truck
      vehicle (LTV) rollovers. More than 90% of trip-overs were initiated by ground
      contact. Fall-overs were the second most common rollover type, accounting for 13%
      of passenger car and 15% of LTV rollovers. Bounce-overs only accounted for 8% of
      both passenger car and LTV rollovers. The FMVSS 208 dolly and the ADAC corkscrew
      rollover tests are well-known laboratory tests, but do not simulate many of the
      real-world rollovers. Three additional tests have been devised to more fully
      address the field relevant conditions identified in this study. To do so,
      assumptions were made and adding the new laboratory tests (soil-trip, curb-trip
      and ditch fall-over) increases representativeness to 83% of passenger car and 75%
      of LTV rollovers reported in the field. Accident data were also used to identify
      injuries in belted drivers so the information could later be used to better
      understand occupant kinematics in various roll conditions. The injury
      distribution for belted/non-ejected drivers was assessed for trip-over, fall-over
      and bounce-over accidents. Serious injuries (AIS 3+) were most common to the head
      and thorax, in particular for bounce-overs. Head injuries occurred from contact
      with the roof, pillar and the interior, while thoracic injuries resulted from
      contact with the interior and steering wheel assembly. Field data are useful in
      the development of laboratory test conditions for rollovers as it provides
      insights on the significance of various rollover types, understanding of injury
      biomechanics, guidance for future testing and inputs for mathematical modeling.

PMID- 12479902
TI  - A before-and-after study of driver stopping propensity at red light camera
      intersections.
AB  - This paper reports a before-and-after study which evaluated the impacts of
      installing and operating red light cameras at two "T" and one "X" signalized
      intersections on driver stopping propensity upon the onset of amber. Rather than
      using video cameras, a special purpose data logger working in conjunction with
      loop sensors was used to gather traffic parameters, vehicle stopping/crossing
      movements, and signal phases. Logistic modeling was employed to model the
      revealed stopping/crossing decisions of non-platoon vehicle drivers in response
      to the onset of amber with traffic, situational and behavioral variables,
      including their interactions. The results indicate that the variable Cam_Inst
      that gathered the impacts of red light camera (RLC) installation on driver
      decision-making at signalized intersection was significant at 5% level only for
      the camera approach model of the cross-intersection. The significance of Cam_Inst
      was undermined for the camera approaches at the T-intersections by the inclusion
      of a significant two-order variable defining the interaction of Cam_Inst with
      distance from the stop-line. One may, thus, infer that RLC has a fixed-quantum
      effect at the cross-intersection, but an accentuated effect with distance at the
      two T-intersections. Lastly, the effects of a RLC at an intersection on the
      stopping decision at the non-camera approaches were minimal.

PMID- 12479903
TI  - Personal, temporal and spatial characteristics of seriously injured crash
      involved seat belt non-users in Hawaii.
AB  - The characteristics of crash-involved seat belt non-users in a high use state
      (Hawaii) are examined in order to better design enforcement and education
      programs. Using police crash report data over a 10-year period (1986-1995), we
      compare belted and unbelted drivers and front seat occupants, who were seriously
      injured in crashes, in terms of personal (age, gender, alcohol involvement, etc.)
      and crash characteristics (time, location, roadway factors, etc.). A logistic
      regression model combined with the spline method is used to analyze and
      categorize the salient differences between users and non-users. We find that
      unbelted occupants are more likely to be male, younger, unlicensed, intoxicated
      and driving pickup trucks versus other vehicles. Moreover, non-users are more
      likely than users to be involved in speed-related crashes in rural areas during
      the nighttime. Passengers are 70 times more likely to be unbelted if the driver
      is also unbelted than passengers of vehicles with belted drivers. While our
      general findings are similar to other seat belt studies, the contribution of this
      paper is in terms of a deeper understanding of the relative importance of various
      factors associated with non-use among seriously injured occupants as well as
      demonstrating a powerful methodology for analyzing safety problems entailing the
      categorization of various groups. While the former has implication for seat belt
      enforcement and education programs, the latter is relevant to a host of other
      research questions.

PMID- 12479904
TI  - Matched-pair cohort methods in traffic crash research.
AB  - Standard analysis of matched-pair cohort data requires information only from
      pairs in which at least one had the study outcome. This can be useful in traffic
      fatality studies of characteristics that can vary among vehicle occupants, such
      as seat belt use, as crash databases often lack information about vehicles in
      which all survived. However, matching crash victims who were in the same vehicle
      does not necessarily eliminate confounding by vehicle or crash related factors,
      because the matched occupants must be in different seat positions. This paper
      reviews three methods for estimating relative risks in matched-pair crash data.
      The first, Mantel-Haenszel stratified methods, may produce biased estimates if
      seat position is associated with the outcome. The second, the double-pair
      comparison method, was designed to deal with confounding by seat position. If the
      effects of seat position vary according to some vehicle or crash characteristic
      which is associated with the study exposure, adjustment for this characteristic
      may be needed to produce unbiased estimates. Third, conditional Poisson
      regression and Cox proportional hazards regression can produce unbiased
      estimates, but may require model interaction terms between seat position and
      vehicle or crash characteristics. This paper reviews some of the strengths and
      limitations of each of these methods, and illustrates their use in simulated and
      real crash data.

PMID- 12479905
TI  - Estimating seat belt effectiveness using matched-pair cohort methods.
AB  - Using US data for 1986-1998 fatal crashes, we employed matched-pair analysis
      methods to estimate that the relative risk of death among belted compared with
      unbelted occupants was 0.39 (95% confidence interval (CI) 0.37-0.41). This
      differs from relative risk estimates of about 0.55 in studies that used crash
      data collected prior to 1986. Using 1975-1998 data, we examined and rejected
      three theories that might explain the difference between our estimate and older
      estimates: (1) differences in the analysis methods; (2) changes related to car
      model year; (3) changes in crash characteristics over time. A fourth theory, that
      the introduction of seat belt laws would induce some survivors to claim belt use
      when they were not restrained, could explain part of the difference in our
      estimate and older estimates; but even in states without seat belt laws, from
      1986 through 1998, the relative risk estimate was 0.45 (95% CI 0.39-0.52). All of
      the difference between our estimate and older estimates could be explained by
      some misclassification of seat belt use. Relative risk estimates would move away
      from 1, toward their true value, if misclassification of both the belted and
      unbelted decreased over time, or if the degree of misclassification remained
      constant, as the prevalence of belt use increased. We conclude that estimates of
      seat belt effects based upon data prior to 1986 may be biased toward 1 by
      misclassification.

PMID- 12479907
TI  - Brachytherapy. Editorial note 3:1.

PMID- 12479908
TI  - Vascular brachytherapy after percutaneous transluminal angioplasty of superficial
      femoral arteries-Polish pilot group.
AB  - PURPOSE: The article presents the results of treatment with vascular
      brachytherapy (VBT) in superficial femoral arteries. This method aims to minimize
      frequency of restenosis after percutaneous transluminal angioplasty (PTA).
      METHOD: Treatment was carried out in 20 cases. The patients with severe stenoses
      or total occlusions verified in angiography were selected. In the group of 19
      patients, two were women (the average age of the patients was 58.7 years). VBT
      was performed immediately after PTA. A 15-Gy dose, with high dose rate, was
      applied. The dose was calculated based on individually chosen distance from the
      internal surface of the artery wall, which varied from 2 to 3 mm. The mean
      observation time after treatment was 8 months. The shortest time was 1 month and
      the longest 14 months. At the end of the observation time, the control DSA
      angiography was performed on every patient. RESULTS: During the first 2 months,
      in three cases, an acute thrombosis in treated artery was observed. In the third
      month, one treated artery occluded. In the sixth month of observation, one case
      of acute thrombosis was observed. The rest of the patients were free of
      restenoses. CONCLUSIONS: (1) In superficial femoral arteries, a low value of
      ankle brachial pressure index (ABPI; below 0.4) is very probably responsible for
      acute thrombosis after PTA with or without stent implantation followed by VBT.
      (2) Diabetes, rest ischaemia before treatment, poor vessel status confirmed in
      angiography may also be responsible for acute thrombosis after VBT. (3)
      Anticoagulants or antiplatelet (ticlipidine) treatment must be ordered for 6
      months after VBT in patients with implanted stents.

PMID- 12479909
TI  - Endovascular gamma-irradiation to prevent recurrent femoral in-stent restenosis.
      A case report.
AB  - We report about a patient with twice recurrence of femoral in-stent restenoses.
      Centered endoluminal gamma-irradiation with 192 iridium was performed immediately
      after the second stent recanalization. The irradiation dose was 14 Gy calculated
      at 2-mm depth of vessel wall. One-year follow-up demonstrates neither clinical
      nor angiographic evidence of restenosis.

PMID- 12479910
TI  - Clinical outcomes of patients treated with the cutting balloon and Sr-90 beta
      irradiation for instent restenosis.
AB  - BACKGROUND: The cutting balloon (CB) is an emerging therapy for the treatment of
      instent restenosis (ISR), but its impact on the clinical outcomes of patients
      treated with intracoronary radiation therapy (IRT) with Sr-90 compared with
      conventional PTCA and IRT is not clearly defined. METHODS: We compared the
      baseline demographics, angiographic characteristics and clinical outcomes of 102
      consecutive patients with ISR treated either with CB+IRT (n=45) or with
      conventional PTCA+IRT (n=57). The combined endpoint was the occurrence of major
      adverse cardiac events (MACE), which was defined as a composite of death,
      myocardial infarction (MI) or target vessel revascularization (TVR) at 6 months.
      RESULTS: The CB+IRT group had a shorter mean lesion length (14.3+/-6.5 vs. 21.1+/
      15.7, P=.009), and greater utilization of glycoprotein IIb/IIIa inhibitors during
      the procedure (48.9% vs. 26.3%, P=.02) compared to the PTCA+IRT group. There were
      no significant differences in the baseline demographics, angiographic and
      procedural results, or subsequent MACE at 6 months between the two groups.
      CONCLUSION: The strategy of CB+IRT using Sr-90 for ISR is associated with similar
      procedural and clinical outcomes compared to conventional PTCA+IRT. Further study
      is warranted to determine which patient subgroups would derive the most benefit
      from this approach.

PMID- 12479911
TI  - Topical application of beta-radiation to reduce intimal hyperplasia after carotid
      artery balloon injury in rabbit. A possible application for brachytherapy in
      vascular surgery.
AB  - PURPOSE: Endovascular brachytherapy for the prevention of intimal hyperplasia
      (IH) and restenosis after balloon/stent angioplasty has proven effective both in
      animal preparations and clinical trials. A variety of beta-emitting isotopes and
      catheter-based devices have been developed for the delivery of low-dose radiation
      in clinical coronary and peripheral trials. No platform, however, has yet been
      developed for brachytherapy in concert with vascular surgical operations. The
      purpose of this study was to evaluate the vascular histopathologic response
      following balloon injury to rabbit carotid arteries with and without topically
      applied low-dose beta-radiation. METHODS: The beta-emitting isotope strontium-90
      (Sr-90) was conjugated onto the matrix of polypropylene (PLYP) mesh. Rabbit
      carotid arteries were balloon-injured with a #2 embolectomy catheter. Six carotid
      arteries were wrapped with nonradioactive PLYP mesh (controls) and Sr-90 (
      approximately 90 microCi) PLYP mesh in order to deliver low-dose radiation to the
      vessel wall from the external (adventitial) surface. Tissue was harvested at 6
      weeks and processed for histologic examination. RESULTS: There was consistent
      blockade of fibrocellular neointima formation with virtually no neointima present
      in all treated segments, compared to moderate neointima formation in controls.
      Medial thinning and smooth muscle cell (SMC) necrosis were also associated with
      topical brachytherapy. CONCLUSION: beta-Radiation applied by an externally
      wrapped PLYP mesh labeled with Sr-90 markedly suppressed neointima formation in
      an animal vascular surgical injury model. Further studies, however, are necessary
      to determine a suitable isotope and dosage for clinical application.

PMID- 12479912
TI  - External beam irradiation in angioplasted arteries of hypercholesterolemic
      rabbits. The dose and time effect.
AB  - PURPOSE: To study the dose and time effect of external beam irradiation on the
      morphometry of both angioplasted and nonangioplasted arteries in a
      hypercholesterolemic rabbit model. METHODS AND MATERIALS: Eight groups of rabbit
      femoral arteries were studied: arteries (a) with no intervention, (b) irradiated
      with a 12-Gy 6 MV X-ray dose, (c) with a 18-Gy, (d) treated with balloon
      angioplasty, (e) dosed with 12-Gy half an hour post-angioplasty, (f) dosed with
      18-Gy half an hour post-angioplasty, (g) dosed with 12-Gy 48 h post angioplasty,
      (g) dosed with 18-Gy 48 h post angioplasty. RESULTS: External irradiation at
      either 12 or 18 Gy was not found to change vessel morphometry in noninjured
      arteries. The 12-Gy dose given soon after angioplasty further increased
      percentage stenosis (63% on the average), despite the preservation of the lumen
      cross-sectional area. Positive remodeling was not observed in arteries given 18
      Gy half an hour post angioplasty to counterbalance the increased neointimal
      formation. Therefore, this treatment resulted in a drastic reduction in lumen
      area and in enhancement of percentage stenosis (84% on the average). On the
      contrary, the delayed irradiation of the angioplasted arteries at either 12 or 18
      Gy was not found to influence any of the studied morphometric parameters 5 weeks
      after angioplasty. CONCLUSIONS: Uniform external beam irradiation up to 18 Gy was
      well tolerated by intact femoral arteries. Prompt 12- or 18-Gy irradiations
      accentuated percentage stenosis. However the lumen cross-sectional area was
      preserved only at the lower dose point. Delayed irradiation at any dose did not
      influence the restenosis process.

PMID- 12479913
TI  - Complete vascular healing and sustained suppression of neointimal thickening
      after local delivery of advanced c-myc antisense at six months follow-up in a
      rabbit balloon injury model.
AB  - BACKGROUND: Neointimal hyperplasia following percutaneous transluminal coronary
      angioplasty (PTCA) is one of the major components of the process of restenosis.
      We evaluated the long-term impact of local delivery of c-myc neutrally charged
      antisense oligonucleotides (Resten-NG) upon neointimal formation following PTCA
      in a rabbit model. METHODS: PTCA was performed in the iliac arteries of 10 New
      Zealand white rabbits at 8 atm for 30 s, three times. An infusion of 500 micro g
      Resten-NG (n=6) or saline (n=4) was delivered to the site at 2 atm via the outer
      balloon pores of the transport catheter over 2 min. The diet was supplemented
      with 0.25% cholesterol for 10 days before and 6 months following PTCA. RESULTS:
      After 6 months, animals were sacrificed and vessels were fixed in formalin,
      processed and stained with hematoxylin, eosin, and movat. Histological analysis
      revealed complete vascular healing in both groups of animals. Planimetry showed
      that intimal areas were 1.71+/-0.25 and 0.65+/-0.36 mm2 in the control and
      antisense delivery groups, respectively (P<.05). CONCLUSION: We conclude that
      local delivery of Resten-NG significantly inhibited neointimal thickening
      following PTCA in a rabbit for up to 6 months.

PMID- 12479914
TI  - A comparison of intravascular source designs based on the beta particle emitter
      114mIn/114In. Line source versus stepping source.
AB  - BACKGROUND: Catheter-based intravascular brachytherapy (IVB) sources of the next
      generation will have to meet high demands in terms of miniaturization,
      flexibility, safety, reliability, costs and versatility. The radionuclide pair
      114mIn/114In (half-life 49.51 days, maximum beta energy 2.0 MeV, average beta
      energy 0.78 MeV) is an attractive beta emitter for application in such a source.
      METHODS: Since metallic indium is unfit for the manufacture of a brachytherapy
      source, the feasibility, safety and dosimetric properties of a design concept
      comprising a linear array of ceramic In2O3 spheres within a thin-walled,
      superelastic Ni/Ti capsule are investigated. RESULTS: Neutron activation of
      enriched In2O3 spheres yields a specific activity sufficiently high for the
      manufacture of a stepping source, keeping treatment times limited to a few
      minutes. Although 114mIn/114In also emits some gamma radiation, the effective
      doses received by members of the medical staff are an order of magnitude lower
      than those received from fluoroscopy. The dose distributions about a 40-mm line
      source and a 5-mm stepping source (outer diameter 0.36 mm) are calculated using
      MCNP4C. Dose-volume histograms (DVHs) are calculated for the line source
      (centered and noncentered) and the stepping source (centered) using the geometry
      of a human coronary artery. CONCLUSION: The results show that a centered stepping
      source with optimized dwell times delivers the most homogenous dose within the
      target volume.

PMID- 12479915
TI  - Monte Carlo calculations of dose distribution for intramural delivery of
      radioisotopes using a direct injection balloon catheter.
AB  - PURPOSE: A unique method of delivering radiation dose to the coronary vessel wall
      to prevent restenosis is by direct injection of radioactive compounds into the
      vessel wall using a specially designed angioplasty balloon catheter. The
      radiation dose distribution resulting from such intramural delivery was
      investigated using Monte Carlo simulations. MATERIALS AND METHODS: The
      radioisotope source distribution was modeled for two configurations within the
      vessel wall: (1) uniform to a depth of 0.5 mm and (2) confined to discrete pools
      surrounding the delivery injection ports. Monte Carlo MCNP4B computer simulations
      were utilized to estimate the associated radiation dose distribution for the
      following radioisotopes: 188Re, 186Re, 32P, 153Sm, 111In, 123I, and 99mTc.
      RESULTS: For the uniform case where the radioisotopes are distributed uniformly
      to the depth of 0.5 mm into the vessel wall, an essentially constant radiation
      dose is delivered within the source distribution. Outside of the source volume,
      the dose falls off at a rate depending on the emission properties of the
      particular radioisotope. The nonuniform case involving discrete pools of activity
      showed the dose distribution being confined largely to the regions surrounding
      the delivery ports with significant regions between these ports receiving very
      little dose. CONCLUSIONS: Direct injection of selected radioisotopes into the
      arterial wall appears to represent a potentially effective method for delivering
      radiation dose for the prevention of restenosis. Sufficiently high doses may be
      obtained from relatively low activity and the dose falls off rapidly outside of
      the target area for certain radioisotopes.

PMID- 12479916
TI  - Required treatment margin for coronary endovascular brachytherapy with iridium
      192 seed ribbon.
AB  - PURPOSE: Preliminary clinical trials (SCRIPPS I, WRIST and Gamma 1) employing
      catheter-based endovascular brachytherapy (EVBT) with iridium-192 (Ir-192) seeds
      show promising results in reducing restenosis after coronary intervention.
      Failure analysis of these studies showed a significant number of restenosis at
      the treatment margin called "edge effect." The objective of this study is to
      investigate the factors that contribute to the adequacy of treatment margin.
      METHODS AND MATERIALS: The factors contributing to the margins are penumbra
      effect at the end of the seed train, uncertainty in target localization,
      longitudinal seed movement during cardiac cycle and barotrauma due to stent
      deployment. The magnitudes of the penumbra effect, which refers to the tapering
      off the prescribed isodose line near the ends of the source train, were
      calculated for various source lengths of Ir-192 seed ribbon using AAPM TG-43
      algorithm. Uncertainty in target localization refers to the fact that the visual
      estimation of proximal and distal extent of the injury is not accurate, and this
      can be obtained by comparing the "estimate" from the interventional cardiologist
      with careful review of the cine-angiogram. Longitudinal seed movements relative
      to the coronary vessel during the cardiac cycle were determined by frame-by-frame
      reviewing cine-angiograms of 30 patients. The proximal and distal source points
      were measured in reference to branching vessels during the contrast phase of the
      cine-angiogram. The maximum proximal and distal longitudinal movement was
      captured and source displacement was measured from the closest proximal and
      distal branching vessel. Barotrauma, additional injury to the vessel arising from
      the stent deployment balloon, was obtained by reviewing specifications from
      commercially available stent delivery systems. RESULTS: The penumbra effect
      ranges from 3.9 to 4.5 mm for 6-22 Ir-192 seed ribbons. The uncertainty in target
      localization is within 3 mm for our interventional cardiologists. The results of
      seed movements were categorized by three major coronary vessels and by proximal
      versus distal ends. The mean and standard deviation of seed movement are 1.1 and
      0.8 mm, respectively. The average length of barotrauma beyond the stent margins
      for reviewed stents was 1.7 mm, ranging from 0.5 to 2.5 mm. CONCLUSION: A minimum
      of 8-mm treatment margin is recommended for coronary vascular brachytherapy with
      Ir-192 seed ribbon. This was derived by considering the above contributing
      factors. Excessive margins should be avoided due to possible increase risk of
      late effect. By providing adequate treatment margins, one can avoid geographic
      miss; hence, one can further improve the effect of EVBT in reducing restenosis.

PMID- 12479917
TI  - Safety and efficacy of manual stepping and overlapping of beta-emitter for
      diffuse in-stent restenosis lesions.
AB  - BACKGROUND: The effects of overlapping beta-emitter sources on the treatment of
      in-stent restenosis (ISR) lesions as a result of manual stepping are unknown.
      METHODS AND RESULTS: In the BETA WRIST (Beta Washington Radiation for In-stent
      Restenosis Trial), 17 out of the 50 patients who received radiation treatment had
      diffuse ISR in native coronaries that required manual stepping of the beta
      emitter (90Y) source in order to cover the lesion and the edges. Fourteen of
      those patients received radiation with an overlap of up to 3 mm in the middle of
      the stented segment. The prescribed dose was 20.6 Gy to a distance of 1.0 mm from
      the surface of the inflated balloon, and the calculated dose to the vessel wall
      at the overlapped area did not exceed 75 Gy. There was no difference in late
      total occlusion (7.1% vs. 9.0%, P=NS) and target lesion revascularization (28.5%
      vs. 27.2%, P=NS) between patients with stepping and those without stepping. At 6
      months, there was no evidence of perforation or aneurysm at the overlapped
      segments. Quantitative coronary angiographic (QCA) analysis revealed
      significantly reduced late loss in the overlapped segment compared to the
      adjacent segment (P=.04). Serial (postradiation vs. follow-up) IVUS measurement
      showed larger mean lumen cross-sectional area (CSA) (P=.0035) and smaller mean
      intimal hyperplasia (IH) CSA (P=.0010) in the overlapped segment compared to the
      adjacent segment. CONCLUSION: Manual stepping of beta-emitter source with a short
      overlapped segment is safe for diffuse ISR. Further increase in lumen dimension
      and reduction in IH formation are observed at the overlapped segment.

PMID- 12479918
TI  - Nuclear Regulatory Commission regulatory status of approved intravascular
      brachytherapy systems.
AB  - PURPOSE: To review current and potential future regulatory status of
      intravascular brachytherapy (IVB) systems. METHODS: There are three approved IVB
      systems; two commercial IVBs are hand-operated manual devices; the third is
      remotely operated. In three Guidances, the Nuclear Regulatory Commission (NRC)
      applied certain regulatory concepts applicable to remotely operated high dose
      rate (HDR) afterloaders to manually operated IVBs. This article reviews these
      Guidances, newly released NRC regulations on the medical use of by-product
      material, and potential regulatory issues related to IVB systems. RESULTS: The
      Guidances are specific. However, newly released NRC regulations on the medical
      use of byproduct material, including HDR afterloaders, omit IVB systems as a
      category. NRC licensure of IVB systems is considered case-by-case. CONCLUSIONS:
      The current limited application of regulations applicable to HDR remote
      afterloaders to hand-held IVB systems could lead to other HDR-like regulations
      for hand-held IVB systems in future regulations.

PMID- 12479925
TI  - 2- and 8-alkynyladenosines: conformational studies and docking to human adenosine
      A3 receptor can explain their different biological behavior.
AB  - Adenosine (Ado) derivatives substituted at the C2 position with an alkynyl chain
      are endowed with high affinity for A(1), A(2A) and A(3) human adenosine
      receptors, while being less active at the low affinity A(2B) subtype. On the
      other hand, the introduction of an alkynyl chain at the C8 position of adenosine
      is detrimental for the affinity and potency at A(1), A(2A), and A(2B) receptors,
      while is more tolerated by the A(3) receptor. The evaluation of the stimulation
      of [35S]GTPgammaS binding revealed that 2-alkynyladenosines behave as adenosine
      receptors agonists while, on the contrary, 8-alkynyladenosines behave as
      antagonists. With this work we demonstrated, by means of an NMR-based and a
      computational conformational analysis, that 8-alkynyladenosines, differently from
      2-alkynyladenosines, cannot adopt the sugar-base anti conformation required for
      adenosine receptor activation.Furthermore, using the recently reported X-ray
      crystal structure of bovine rhodopsin as template, we built a 3D model of the
      seven transmembrane domains of the human adenosine A(3) receptor with the
      homology modeling. After identification of the binding site we carried out
      docking experiments, demonstrating that the two class of molecules have different
      binding modes that explain their different degree of affinity and the shift of
      their activity from agonism to antagonism.

PMID- 12479926
TI  - Investigation of structural requirements of anticancer activity at the
      paclitaxel/tubulin binding site using CoMFA and CoMSIA.
AB  - CoMFA and CoMSIA analysis were utilized in this investigation to define the
      important interacting regions in paclitaxel/tubulin binding site and to develop
      selective paclitaxel-like active compounds. The starting geometry of paclitaxel
      analogs was taken from the crystal structure of docetaxel. A total of 28
      derivatives of paclitaxel were divided into two groups-a training set comprising
      of 19 compounds and a test set comprising of nine compounds. They were
      constructed and geometrically optimized using SYBYL v6.6. CoMFA studies provided
      a good predictability (q(2)=0.699, r(2)=0.991, PC=6, S.E.E.=0.343 and F=185.910).
      They showed the steric and electrostatic properties as the major interacting
      forces whilst the lipophilic property contribution was a minor factor for
      recognition forces of the binding site. These results were in agreement with the
      experimental data of the binding activities of these compounds. Five fields in
      CoMSIA analysis (steric, electrostatic, hydrophobic, hydrogen-bond acceptor and
      donor properties) were considered contributors in the ligand-receptor
      interactions. The results obtained from the CoMSIA studies were: q(2)=0.535,
      r(2)=0.983, PC=5, S.E.E.=0.452 and F=127.884. The data obtained from both CoMFA
      and CoMSIA studies were interpreted with respect to the paclitaxel/tubulin
      binding site. This intuitively suggested where the most significant anchoring
      points for binding affinity are located. This information could be used for the
      development of new compounds having paclitaxel-like activity with new chemical
      entities to overcome the existing pharmaceutical barriers and the economical
      problem associated with the synthesis of the paclitaxel analogs. These will boost
      the wide use of this useful class of compounds, i.e. in brain tumors as the most
      of the present active compounds have poor blood-brain barrier crossing ratios and
      also, various tubulin isotypes has shown resistance to taxanes and other
      antimitotic agents.

PMID- 12479927
TI  - Hydrogen bonding descriptors in the prediction of human in vivo intestinal
      permeability.
AB  - Hydrogen bonding has been identified as an important parameter for describing
      drug permeability. Recently, we derived models for predicting intestinal
      permeability using the hydrogen bonding descriptors polar surface area (PSA) and
      number of hydrogen bond donors (HBD), and a lipophilicity descriptor [J. Med.
      Chem. 41 (1998) 4939]. We have now explored other types of hydrogen bonding
      descriptors to see if these improve the models. Both an experimental hydrogen
      bonding descriptor, deltalogP, and calculated descriptors, based either on
      semiempirical calculations or on experimentally derived hydrogen bond strength
      values of small molecules, were used. Principal component analyses (PCA) were
      performed in order to characterize the different parameters, using both a drug
      data set and a data set of small non-drug-like molecules for which deltalogP
      values had been published. For a set of diverse drug molecules, for which human
      intestinal permeability data was available, a PLS-analysis was performed to study
      the correlation of permeability to the different hydrogen bonding parameters. No
      correlation could be identified between deltalogP and human intestinal
      permeability in this data set. However, the combination of a hydrogen bond donor
      descriptor, a general hydrogen bonding descriptor and a lipophilicity descriptor
      enabled the prediction of human intestinal permeability, whereas hydrogen bond
      acceptor descriptors were found to be less important. The obtained models
      successfully predicted the intestinal permeability values of two external data
      sets.

PMID- 12479928
TI  - LigandFit: a novel method for the shape-directed rapid docking of ligands to
      protein active sites.
AB  - We present a new shape-based method, LigandFit, for accurately docking ligands
      into protein active sites. The method employs a cavity detection algorithm for
      detecting invaginations in the protein as candidate active site regions. A shape
      comparison filter is combined with a Monte Carlo conformational search for
      generating ligand poses consistent with the active site shape. Candidate poses
      are minimized in the context of the active site using a grid-based method for
      evaluating protein-ligand interaction energies. Errors arising from grid
      interpolation are dramatically reduced using a new non-linear interpolation
      scheme. Results are presented for 19 diverse protein-ligand complexes. The method
      appears quite promising, reproducing the X-ray structure ligand pose within an
      RMS of 2A in 14 out of the 19 complexes. A high-throughput screening study
      applied to the thymidine kinase receptor is also presented in which LigandFit,
      when combined with LigScore, an internally developed scoring function, yields
      very good hit rates for a ligand pool seeded with known actives.

PMID- 12479929
TI  - Correlation between normal modes in the 20-200 cm-1 frequency range and localized
      torsion motions related to certain collective motions in proteins.
AB  - In certain biologically relevant collective motions, such as protein domain
      motions and sub-domain motions, large amplitude movements are localized in one or
      a few flexible regions consisting of a small number of residues. This paper
      explores the possible use of normal mode analysis in probing localized
      vibrational torsion motions in these flexible regions that may be related to
      certain collective motions. The normal modes of 10 structures of five proteins in
      different conformation (TRP repressor, calmodulin, calbindin D(9k), HIV-1
      protease and troponin C), known to have shear or hinge domain or sub-domain
      motion, respectively, are analyzed. Our study identifies, for each structure,
      unique normal modes in the 20-200 cm-1 frequency range, whose corresponding
      motions are primarily concentrated in the region where large amplitude torsion
      movements of a known domain or sub-domain motion occur. This suggests possible
      correlation between normal modes at 20-200 cm-1 frequency range and initial
      fluctuational motions leading to localized collective motions in proteins, and
      thus the potential application of normal mode analysis in facilitating the study
      of biologically important localized motions in biomolecules.

PMID- 12479930
TI  - The expression of Fas and Fas ligand, and the effects of interferon in chronic
      liver diseases with hepatitis C virus.
AB  - In viral hepatitis, binding of Fas ligand (FasL) with Fas expressed on the
      surfaces of infected hepatocytes induces apoptosis, removing hepatitis virus
      along with infected hepatocytes. We measured serum concentrations of soluble Fas
      (sFas) and FasL (sFasL), expression of membrane-bound FasL, and expression of
      FasL-mRNA in patients with chronic hepatitis C without cirrhosis (CH-C) and
      chronic hepatitis C with liver cirrhosis (LC-C). In CH-C, sFasL concentrations
      were lower and FasL-mRNA expression was significantly less than in volunteers. In
      LC-C, sFas concentrations were significantly greater than in healthy volunteers,
      while sFasL, membrane-bound FasL expression, and FasL-mRNA expression did not
      show significant differences. We also examined these variables over 24 h
      following the first interferon (IFN) treatment in patients with CH-C. Serum
      concentrations of sFas and sFasL, and FasL-mRNA expression increased markedly
      beyond amounts present before IFN injection until 12 h after IFN injection.
      However, membrane-bound FasL expression decreased until 6 h, followed by an
      increase until 24 h. Our findings suggest that the ratio of membrane-bound FasL
      to sFasL may be regulated to remove virally infected cells in CH-C. In addition,
      apoptosis mediated by the Fas/FasL system may be influenced by IFN injection for
      treatment of CH-C.

PMID- 12479931
TI  - A randomized clinical trial with natural interferon-alpha monotherapy for 24 or
      48 weeks on patients with chronic hepatitis C having genotype 1b infection in
      high viral titers.
AB  - Patients with chronic hepatitis C who are infected with hepatitis C virus of
      genotype 1b and have a high viral load in serum (>1 Mega equivalents/ml) poorly
      respond to interferon with the standard regimen. Natural interferon-alpha (nIFN
      alpha: OPC-18) was given to 106 such patients randomized into two different
      therapeutic schedules. One group consisting of 53 patients received daily
      intramuscular injection with 10 mega units (Meq) for 2-4 weeks and then 5 Meq
      three times per week until 24 weeks and the other group of 53 patients were
      placed on the same regimen until 48 weeks. At 24 weeks after the completion of
      therapy, HCV RNA turned negative in 11 (25%) patients with the 48-week therapy,
      significantly more frequently than in two (5%) patients with the 24-week therapy
      (P=0.014). There were no differences in the incidence and severity of adverse
      effects between the patients who received 24- and 48-week nIFN-alpha. Based on
      these results, nIFN-alpha with a high-dose induction and extended to 48 weeks
      would be a reasonable therapeutic option for the patients infected with HCV/1b in
      high viral loads who do not respond to the standard regimen with a 24-week
      schedule.

PMID- 12479932
TI  - Thymosin-alpha1 increases intrahepatic NKT cells and CTLs in patients with
      chronic hepatitis B.
AB  - BACKGROUND AND AIM: Thymosin-alpha1 (T-alpha1) influences T-cell maturation,
      production of Th1-type cytokines, and activity of NK cell-mediated cytotoxicity.
      The aim of this study is to evaluate the types of lymphocytes that contribute to
      the reduction in viral load in patients with chronic hepatitis B (CHB) following
      T-alpha1 treatment. METHODS: Seven patients with CHB were treated with 1.2 mg of
      T-alpha1 for 24 weeks. Peripheral blood lymphocytes (PBL) and intrahepatic
      lymphocytes were analyzed by flow cytometry. Serum cytokines (IL-4 and IFN-gamma)
      were measured by ELISA. RESULTS: Forty-eight weeks after T-alpha1 treatment, two
      patients (28.6%) showed normalized alanine aminotransferase and decreased HBV-DNA
      to undetectable level from serum. The histology activity index score
      significantly decreased (P<0.05). Although elevated serum interferon (IFN)-gamma
      was not observed, IFN-gamma producing Th1-type CD4(+) PBL appeared to be
      increased. CD56(+) natural killer T (NKT) cells in PBL did not increase, these
      cells in the liver remained significantly augmented even at the end of treatment
      (P<0.05). CD57(+) NKT cells slightly increased and the ratio of CD4(+) T/CD8(+) T
      cells decreased in the liver. T-alpha1 did not influence either double-positive
      CD4(+)8(+) T or double-negative CD4(-)8(-) cell subsets. CONCLUSION: NKT cells
      and CD8(+) cytotoxic T lymphocytes augmented in the liver by T-alpha1 may
      eliminate hepatitis B virus infected hepatocytes.

PMID- 12479933
TI  - Interferon beta induction/interferon alpha therapy in patients with interferon
      resistant chronic hepatitis C.
AB  - The treatment of chronic hepatitis C with a standard regimen of therapy with
      interferon (IFN) alpha for 6 months results in a sustained response (SR) in a
      minority of patients with high levels of HCV-RNA. The aim of this study was to
      assess whether a high dose of IFN and IFN beta induction/IFN alpha therapy
      increase efficacy, and to identify the determinants or predictive factors of SR
      in patients with IFN resistant chronic hepatitis C. In 99 patients with high
      levels of HCV-RNA (>1 Meq/ml), we compared the efficacy of IFN beta induction/IFN
      alpha therapy (n=50) and IFN alpha monotherapy (n=49). HCV-RNA clearence was
      observed in 22 patients (44%) in IFN beta induction/IFN alpha group and 11
      (22.4%) in IFN alpha monotherapy group at 7 days after the start of treatment,
      there were significant difference between these two groups (P=0.0327); in 26
      (52%) and 13 (26.5%) at the end of treatment, there were significant difference
      between these two groups (P=0.0134); in 9 (18%) and 3 (6.1%) at 6 months after
      the end of treatment, there was no difference between these two groups
      (P=0.1212), respectively. SR was observed in 9 (18%) and non-response in 41 (82%)
      with the IFN beta induction/IFN alpha therapy, and in 3 (6.1%) and 46 (93.9%)
      with IFN alpha monotherapy, respectively. IFN beta induction/IFN alpha therapy
      was better than IFN alpha monotherapy by HCV-RNA clearance at 7 days after the
      start of treatment and at the end of treatment, but there was no significant
      difference between these two groups at 6 months after the end of treatment. IFN
      beta induction/IFN alpha therapy was superior to IFN alpha monotherapy in the
      treatment of chronic hepatitis C, and this therapy may be recommended for
      patients with high levels of HCV-RNA of chronic hepatitis C.

PMID- 12479934
TI  - Establishment of an assay method for human mast cell chymase.
AB  - Chymase secreted by mast cells found in fibroblast-containing interstitial
      connective tissue has been implicated in collagen fiber formation and
      extracellular matrix production. We established a method for determination of
      human chymase activity, and applied this technique to measurements in serum and
      liver tissue. The mean chymase concentration in liver biopsy specimens from 26
      patients with chronic hepatitis was 5.23+/-5.98 ng/mg (ranges 0.32-21.4). The
      serum chymase concentration was below the limit of detection, in both chronic
      hepatitis patients and healthy individuals. No significant relationship was seen
      between chymase activity in liver tissue and severity of liver fibrosis, but
      further investigation in larger numbers of patients is warranted.

PMID- 12479935
TI  - Degeneration of skeletal muscle fibers in the rat administrated carbon
      tetrachloride: similar histological findings of the muscle in a 64-year-old
      patient of LC with muscle cramp.
AB  - It is well known that painful muscle cramps occur frequently in patients with
      advanced liver cirrhosis (LC). Although many studies discuss the
      pathophysiological causes of these muscle cramps in various conditions, the
      results are not clear as far as the cause associated to LC is concerned. In order
      to investigate the cause of muscle cramps in LC, we examined the histological
      findings of skeletal muscle fibers in LC rat model and in a patient with LC. LC
      (n=9) was induced in rats by chronic carbon tetrachloride administration. The
      histological findings of skeletal muscle tissues from the lower leg in LC rats
      and those of the upper arm in a patient with LC were compared. The degenerated
      muscle fibers and centronucleus in LC rats were similar to the opaque fibers
      frequently observed in myotonic dystrophy with severe muscle rigidity in patients
      with LC. In conclusion, results of this study suggest that one of the causes for
      muscle cramps in patients with LC is due to skeletal muscle fiber degeneration.
      Therefore, histological observation of skeletal muscle fibers should be
      considered in the treatment of painful muscle cramps.

PMID- 12479936
TI  - Hepatitis B and C virus infection and p53 mutations in human hepatocellular
      carcinoma in Harbin, Heilongjian Province, China.
AB  - To clarify the importance of hepatitis B (HBV) and C virus (HCV) infection and
      p53 gene mutation in the genesis of hepatocellular carcinoma (HCC), we
      investigated DNA samples of formalin-fixed paraffin-embedded HCC tissue specimens
      from patients in the North China area of Harbin, Heilongjian province. Fifty
      eight DNA samples from 43 cases obtained during surgery and the remaining 15
      autopsy materials were analyzed by polymerase chain reaction (PCR) about HBV and
      HCV. The p53 gene (exon 7) mutant testing, in addition, was performed by PCR
      direct sequencing. Histopathologically, we determined the histological grade of
      HCC in all specimens. Forty-five (77.6%) of 58 cases were HBV DNA-positive; only
      two (3.4%) HCV RNA-positive cases were found. Two of 37 samples screened showed a
      point mutation (AGG to AGT) at codon 249, the exon 7 hot spot of the p53 gene.
      The fact implies that HBV plays a very important role, but aflatoxin B1 is not an
      important factor in the genesis of HCC in Harbin, Heilongjian district, People's
      Republic of China.

PMID- 12479937
TI  - Detection of serum and intrahepatic hepatocyte growth factor during DEN-induced
      carcinogenesis in the rat.
AB  - We studied changes in serum levels of hepatocytes growth factor (HGF), as well as
      the levels of HGF expression in the livers, of rats with chemically-induced
      cancer. Rats were given diethylnitrosamine (DEN) orally in their drinking water.
      The serum HGF level was measured by enzyme-linked immunosorbent assay. The degree
      of HGF expression in liver, detected by immunoperoxidase staining, was classified
      from negative to high. For two DEN-treated rats, the nucleotide sequence of HGF
      DNA was determined from the livers containing cancerous foci (CA). The serum HGF
      levels tended to be higher in the DEN-treated rats than in the control rats. In
      the DEN-treated rats, low to moderate levels of expression of HGF were found in
      hepatocytes with strong atypia at 8, 12, and 14 weeks. Low levels of HGF
      expression were found in moderately differentiated cancer cells. The sequence of
      HGF showed the loss of three nucleotides, in comparison with a sequence reported
      previously. In conclusion, the results of this study suggest that HGF may
      contribute to hepatocarcinogenesis in chemically induced cancer in rats.

PMID- 12479938
TI  - Prognostic performance of the new classification of primary liver cancer of Japan
      (4th edition) for patients with hepatocellular carcinoma: a validation analysis.
AB  - The Japanese staging system that is generally used for hepatocellular carcinoma
      (HCC) (3rd edition) was considerably revised recently, especially T category. No
      study, however, has revealed how well the new classification (4th edition) works
      to stratify HCC patients at a pre-intervention stage. The purpose of this study
      is to assess the discriminatory value and predictive power of the 4th edition,
      and to compare its utility with the clinical utilities of the 3rd edition and the
      cancer of the liver Italian program (CLIP) score, as determined from 662 Japanese
      patients. We performed a retrospective analysis of the HCC diagnoses at four
      Japanese institutions from 1990 and 1998. Overall survival was the only end-point
      used in the analysis. The discriminatory ability and homogeneity of the 4th
      edition were compared to those of the 3rd edition and the CLIP score. As of
      January 1999, 440 patients (66.4%) had died. The overall median survival was 37.7
      months. Liver function and tumor variables, which are already accounted for by
      the different scoring systems, were significantly associated with survival.
      Compared with the 3rd edition, the 4th editions' discriminatory ability (tested
      by the linear trend test) and homogeneity of survival within each category
      (tested by the likelihood ratio test) were enhanced in both the overall group of
      patients and the subgroups of patients receiving transcatheter arterial
      chemoembolizations and percutaneous ethanol injections. In patients receiving
      surgery, however, the 4th edition's abilities were the lowest among the indices.
      Multivariate analysis revealed that the CLIP score that includes liver function
      had additional explanatory power above that of the 4th edition. These findings
      indicate that the 4th edition has a higher stratification value than the 3rd
      edition. However, this benefit is due to the non-surgical patients, rather than
      to the surgical patients. If the 4th edition had an additional scoring system
      based on its original tumor staging and liver damage, it might be highly
      beneficial, although relative risk ratios of those should be analyzed.

PMID- 12479939
TI  - Relationship between response to previous interferon therapy and postoperative
      recurrence of hepatitis C virus-related hepatocellular carcinoma.
AB  - Although interferon (IFN) therapy suppresses the development of hepatitis C virus
      (HCV)-related hepatocellular carcinoma (HCC), the relationship between response
      to previous IFN therapy and postoperative outcome has not been clarified in
      patients who underwent curative resection for HCC. Of 175 patients who underwent
      curative hepatic resection for HCV-related HCC, 24 patients had HCC detected
      after IFN therapy. 11 patients who had a biochemical response (a normalized
      alanine aminotransferase (ALT) activity with or without disappearance of serum
      HCV RNA) were classified as the response group, while 13 patients were classified
      as the non-response group because they had no decrease in their ALT activity and
      had persistence of serum HCV RNA. The non-IFN group included 151 patients who had
      not received previous IFN therapy. The clinicopathologic findings and surgical
      outcomes were compared among these three groups. The serum activities of the
      aspartate aminotransferase and ALT just before surgery were significantly lower
      in the response group than in the other groups. Although no significant
      differences were noted in the other clinicopathologic findings or the operation
      method among these groups, the tumor-free survival rate of the response group was
      significantly higher than that of the two other groups. By multivariate analysis,
      the response group had an independently lower risk for postoperative recurrence
      (risk ratio, 0.07; P=0.0072). Hepatic resection offers hope for low incidence of
      postoperative recurrence in patients with HCC, especially when previous IFN
      therapy has controlled their active hepatitis associated with HCV.

PMID- 12479940
TI  - Clinical significance of intrahepatic interleukin-8 in chronic hepatitis C
      patients.
AB  - Background/AIM: Interleukin-8 (IL-8) is known as a chemotactic and angiogenetic
      cytokine and is a potential mediator of host response to injury or inflammation.
      In order to identify the role of IL-8 in the pathogenesis of chronic hepatitis C
      (CHC), we assessed semiquantitatively the messenger RNA (mRNA) expression of IL-8
      and other cytokines in liver biopsy specimens of CHC patients. METHOD: Liver
      biopsy specimens were obtained under peritoneoscopy from 35 patients with CHC.
      The mRNA expression of IL-8 and other cytokines in the liver were determined by
      real-time PCR and the correlation between the mRNA expression and histological
      classification of liver were studied. Liver histology was classified by both
      staging of fibrosis (F0-F4) and grading of activity (A1, mild; A2, moderate and
      A3, severe). RESULTS: Patients were classified into F1, 8; F2, 9; F3, 9 and F4, 9
      and A1, 6; A2, 14 and A3, 15, by staging of fibrosis and grading of activity,
      respectively. Expression of IL-8 mRNA increased with staging of fibrosis (F1,
      0.402+/-0.65; F2, 0.413+/-0.246; F3, 1.388+/-2.166; F4, 1.991+/-1.879) and
      grading of activity (A1, 0.560+/-0.808; A2, 0.780+/-1.268; A3, 1.548+/-1.957).
      The mRNA expressions of IL-2, IL-1alpha, IL-1beta, IL-15 and TNF-alpha were found
      to be closely correlated with IL-8 mRNA (R=0.638; 0.522; 0.487; 0.465 and 0.495,
      respectively, in all P<0.05). CONCLUSION: In CHC, intra-hepatic expression of
      both IL-8 and IL-2 increased with fibrosis and inflammatory activity. Positive
      correlations were found between IL-8 and other cytokines and between cytokines
      themselves. These findings suggest that these interacting cytokines play an
      active role in the pathogenesis of CHC, and maybe involved in the upregulation or
      induction of one and other.

PMID- 12479941
TI  - Effects on liver functions of gastric variceal therapy by endoscopic ligation
      using a detachable snare and sclerotherapy with O-ring ligation.
AB  - Although various effects of therapy for gastric varices, a complication of portal
      hypertension, on portal hemodynamics have been suggested, the effects of the
      therapy on liver functions have not yet been clarified. The aim of this study was
      to examine the effects of endoscopic gastric variceal therapy on liver functions
      in patients with hepatic cirrhosis. The subjects were 18 hepatic cirrhosis
      patients with the complication of gastric varices, who could be monitored for a
      long term (at least 1-year after therapy). They consisted of patients receiving
      prophylactic treatments after being confirmed to have a risk of rupture of
      gastric varices (16 prophylactic cases) and those with a history of bleeding and
      receiving palliative treatments to prevent rebleeding (two palliative cases). To
      evaluate liver functions, blood tests before the therapy, just after the therapy
      and at 1, 3, 6 and 12 months after the therapy were retrospectively examined and
      the levels of albumin, total bilirubin (T.Bil), ALT, choline esterase (ChE),
      platelets and the Child-Pugh classification were assessed. The albumin levels
      tended to increase after the therapy, and the level at 6 months after the therapy
      was significantly higher than the pre-treatment value (P=0.0311). At 1 year after
      the therapy, the level was higher than the pre-treatment value, but there was no
      significant difference. The ChE level tended to decrease just after the therapy,
      but it tended to be increased at 3 and 6 months after the therapy. Although
      significant improvement was not seen in T.Bil, ALT, platelet levels or the Child
      Pugh classification after the therapy, none of these worsened. Endoscopic gastric
      variceal ligation therapy significantly improved liver functions, or at least
      albumin synthesis.

PMID- 12479942
TI  - Nonalcoholic steatohepatitis: risk factors for liver fibrosis.
AB  - The purpose of this study was to clarify the clinicopathological features of
      nonalcoholic steatohepatitis (NASH) and identify risk factors for severe hepatic
      fibrosis. MATERIALS AND METHODS: Eighty-one patients with biopsy-proven NASH were
      studied. In all patients, the diagnosis of NASH was established on the basis of
      following criteria: (1) the presence of steatosis, lobular inflammation, and
      ballooning degeneration on liver biopsy, (2) intake of less than 20 g of ethanol
      per week, and (3) appropriate exclusion of other liver diseases. RESULTS: The
      median age was 54 years (range: 21-82 years) and 41 patients were women (51%).
      Obesity was present in 58 patients (72%), while 25 patients (31%) had diabetes
      mellitus and 33 patients (41%) had hyperlipidemia. Histologically, 58 patients
      (72%) had trivial to moderate fibrosis, 6 patients (7%) had bridging fibrosis,
      and 17 patients (21%) had established cirrhosis. Multiple logistic regression
      analysis assessed clinical, laboratory and histological factors showed that the
      risk factors for fibrosis were a low platelet count (P=0.0016), a high AST/ALT
      ratio (P=0.0229), and the presence of Mallory bodies (P=0.0209). To exclude
      factors that were a consequence of liver cirrhosis, variables included in the
      multiple logistic analysis were age, gender, diabetes, obesity, and
      hyperlipidemia. This showed that older age (P=0.0037) and the absence of
      hyperlipidemia (P=0.0150) were risk factors for fibrosis. CONCLUSIONS: We found
      that a low platelet count, a high AST/ALT ratio, and the presence of Mallory
      bodies were significant predictors of severe liver fibrosis.

PMID- 12479943
TI  - An adult patient with acute hepatitis type B which was protracted and complicated
      by polyarteritis nodosa: a case report.
AB  - Polyarteritis nodosa (PAN), an extra-hepatic complication of hepatitis type B, is
      usually treated with a combination of immunosuppressive and antiviral drugs. Less
      commonly, interferon (IFN) has been used alone. A 57-year-old man was admitted to
      our hospital with epididymitis and acute hepatitis with genotype A, hepatitis B
      virus (HBV). He became a carrier with complicating PAN. The administration of
      interferon alpha2b (IFNalpha2b) at a dose of 6 MU/day for 4 weeks alleviated
      abdominal and neuronal symptoms related to PAN, although HBV replication was not
      eliminated. This is the first case of PAN with HBV of genotype A and which was
      treated with IFN alone. This case indicates the possibility that IFN is
      efficacious for extra-hepatic complications of hepatitis type B and suggests that
      differences in genotype may be associated with variation in the likelihood of
      progression to persistent infection and the incidence of extra-hepatic
      complications in Japan.

PMID- 12479944
TI  - Diet influences cocaine withdrawal behaviors in the forced swimming test.
AB  - The effects of drugs of abuse might depend on several environmental factors,
      among them the individual's feeding habits. It was our objective to study the
      influence of the diet on cocaine acute behavioral effects and during the first 5
      days of withdrawal after prolonged treatment. Rats were fed a balanced diet, high
      protein diet, high-carbohydrate diet or high-fat diet from weaning to adulthood.
      Adult rats were injected with 15 mg/kg cocaine 24, 5 and 1 h before the forced
      swimming retest or the drug was administered daily during 15 days and the animals
      were evaluated in the forced swimming test on five daily occasions after drug
      withdrawal. Diets alone did not induce significant behavioral differences in
      locomotion, immobility, swimming, climbing or head shakes. Acute cocaine reduced
      immobility during the forced swimming test and increased locomotion demonstrating
      a nonspecific antiimmobility effect related to hyperactivity. Acute cocaine
      reduced head shakes of rats fed high-protein and high-carbohydrate diets. After
      cocaine withdrawal, head shakes were decreased for rats fed any of the diets and
      rats were more immobile if fed a high-fat diet and were less immobile if fed a
      high-protein or high-carbohydrate diet. In conclusion, differences in the amounts
      of macronutrients in the diet may cause different behavioral outcomes after acute
      cocaine and during cocaine withdrawal.

PMID- 12479945
TI  - The L-type calcium channel blocker nimodipine mitigates "learned helplessness" in
      rats.
AB  - We assessed the effect of nimodipine, an L-type calcium channel blocker, on the
      escape deficit induced by prior exposure to inescapable shock in rats in four
      experiments. In Experiment 1, we injected rats at each of three time points
      (i.e., before shock exposure, after shock exposure, and before shuttle escape
      testing) with one of four doses of nimodipine (0, 0.5, 2.5, 5.0 mg/kg). The 5.0
      mg/kg dose was most effective, acting to reduce shuttle escape latencies of
      inescapably shocked rats to a level comparable with nonshocked controls. No
      benefit occurred in Experiment 2, however, when nimodipine was administered at
      only one of the three time points used in the first experiment. Moreover, escape
      performance did not improve when rats received injections of nimodipine on the 2
      days prior the experiment, and then one additional injection at one of the three
      time points identified above in Experiment 3. Finally, administration of
      nimodipine at two of the three time points did improve escape responding, but
      only when injected immediately prior both to shock exposure and the shuttle
      escape test.

PMID- 12479946
TI  - Lobeline attenuates locomotor stimulation induced by repeated nicotine
      administration in rats.
AB  - Lobeline inhibits [3H]nicotine binding to rat brain membranes and nicotine
      induced [3H]dopamine release from superfused rat striatal slices, indicating that
      lobeline acts as a nicotinic receptor antagonist. To determine whether lobeline
      also inhibits the effects of nicotine in vivo, the present study assessed the
      effect of lobeline pretreatment on nicotine-induced hyperactivity and
      sensitization. For 12 consecutive days, rats were injected subcutaneously with
      lobeline (3 mg/kg) or saline, followed 10 min later by nicotine (0.3 mg/kg) or
      saline injection, and activity was monitored. To determine if lobeline inhibits
      induction of sensitization to nicotine, 1 or 28 days later, rats were pretreated
      with saline followed by nicotine or saline. Lobeline attenuated nicotine-induced
      hyperactivity when both drugs were administered repeatedly. Although an initial
      injection of lobeline produced hypoactivity, tolerance to this effect developed.
      Importantly, tolerance did not develop to the lobeline-induced attenuation of
      nicotine hyperactivity. Lobeline attenuated the induction of sensitization to
      nicotine 1 day, but not 28 days, after the cessation of lobeline treatment. These
      results demonstrate that systemic administration of lobeline attenuates the
      locomotor-activating effects of repeated nicotine injection and the sensitization
      to nicotine, consistent with lobeline inhibition of nicotinic receptors and/or
      neurotransmitter transporters.

PMID- 12479947
TI  - Cocaine's effects on detection, discrimination, and identification of auditory
      stimuli by baboons.
AB  - The perceptual effects of cocaine were examined under conditions that required
      baboons to detect the presence of tones as well as to identify tones of different
      pitches, and the results compared to the results of prior studies on cocaine's
      effects on the detection of tones, the discrimination of different tone pitches,
      and the discrimination of different human vowel sounds of similar pitch. A
      reaction time procedure was employed in which baboons were trained to press a
      lever in the presence of a visual "ready" signal, and release the lever only when
      one tone pitch occurred, but not release the lever when a second, different tone
      pitch occurred. Changes in the percentage of correct detections and median
      reaction times for each tone were measured following intramuscular administration
      of cocaine (0.01-1.0 mg/kg). Cocaine impaired tone identification and shortened
      reaction times to the tones in all baboons. Cocaine's effects on accuracy,
      however, were primarily due to elevations in false alarm rates, as opposed to
      detection of the stimuli themselves. The results demonstrate that cocaine impairs
      the discriminability of tone pitches in baboons, and that such impairments can
      depend upon the type of stimuli employed (tones vs. speech sounds) and the type
      of procedure employed (discrimination vs. identification).

PMID- 12479948
TI  - The 5-HT3 antagonist Y-25130 blocks cocaine-induced lowering of ICSS reward
      thresholds in the rat.
AB  - Serotonin-3 (5-HT(3)) receptor antagonists have been shown to attenuate drug
      induced increases in mesolimbic dopamine (DA), locomotor activation, and drug
      self-administration. In the present study, we tested whether the selective 5
      HT(3) antagonist Y-25130 would attenuate cocaine-induced lowering of intracranial
      self-stimulation (ICSS) reward thresholds. Rats (n=6) were surgically prepared
      with bipolar stimulation electrodes and trained to self-administer electrical
      stimulation delivered to the medial forebrain bundle-lateral hypothalamus (MFB
      LH). A discrete-trial, rate-free threshold determination procedure was used to
      detect pharmacologically induced changes from baseline reward thresholds. Four
      doses of Y-25130 (0.0, 0.03, 0.3, and 3.0 mg/kg ip) were given alone and in
      combination with cocaine (4.0 mg/kg ip). Y-25130 did not significantly alter
      reward thresholds or response latencies when given alone as compared to baseline
      measures. While there were no significant effects at lower doses, the middle and
      highest doses of Y-25130 (0.3 and 3.0 mg/kg) did attenuate the threshold-lowering
      effect of cocaine. These findings suggest that the rewarding effects of cocaine
      are mediated through 5-HT(3) receptor activity.

PMID- 12479949
TI  - The epileptogenic effect of seizures induced by hypoxia: the role of NMDA and
      AMPA/KA antagonists.
AB  - Hypoxia of the brain may alter further seizure susceptibility in a different way.
      In this study, we tried to answer the question how episode of convulsion induced
      by hypoxia (HS) changes further seizure susceptibility, and how N-methyl-D
      aspartic acid (NMDA) and AMPA/KA receptor antagonists influence this process.
      Adult Albino Swiss mice exposed to hypoxia (5% O(2)) developed clonic/tonic
      convulsions after about 340 s. Mice which underwent 10 s but not 5 s seizures
      episode subsequently exhibited significantly increased seizure susceptibility to
      low doses (equal ED(16)) of bicuculline (BCC) and NMDA during a 3-week
      observation period. No morphological signs of brain tissue damage were seen in
      light microscope on the third day after a hypoxia-induced seizure (HS). Learning
      abilities assessed in passive avoidance test as well as spontaneous alternation
      were not disturbed after an HS episode. Pretreatment with AMPA/KA receptor
      antagonist NBQX effectively prolonged latency to HS and given immediately after
      seizure episode also attenuated subsequent convulsive susceptibility rise,
      however, NMDA receptor antagonist, MK-801, appeared to be ineffective. These
      results suggest that a seizure episode induced by hypoxia, depending on its
      duration, may play an epileptogenic role. The AMPA/KA receptor antagonist
      prolongs the latency to HS, and given after this episode, prevents the long-term
      epileptogenic effect.

PMID- 12479950
TI  - Attenuation of the stimulant and convulsant effects of cocaine by 17-substituted
      3-hydroxy and 3-alkoxy derivatives of dextromethorphan.
AB  - Pharmacological evidence has suggested a role for both sigma and N-methyl-D
      aspartate (NMDA) receptors in the behavioral stimulant effects of cocaine and its
      convulsant effects observed at higher doses. A series of dextromethorphan (DM)
      analogs with a range of affinities for sigma-1 binding sites and for the NMDA
      receptor ion channel were used to explore the contribution of these two
      mechanisms in controlling the stimulant and convulsant effects of cocaine. These
      compounds were potent and efficacious blockers of both stimulant and convulsant
      effects produced by acute cocaine administration in mice (cocaine 10 or 75 mg/kg
      ip for locomotor activity or convulsions, respectively). Generally, the DM
      analogs blocked these effects of cocaine at doses that did not display ataxic and
      sedative side effects as measured in the inverted screen test. In contrast to the
      high-affinity NMDA blockers, (+)-MK-801 (dizocilpine) and dextrorphan (DX), DM
      and analogs did not stimulate locomotor activity. There was no significant
      correlation between the affinities of the DM analogs for the sigma-1 or the
      phencyclidine (PCP) binding site and their potencies to produce behavioral
      effects on their own or to attenuate the behavioral or toxic effects of cocaine.
      The present study has identified a series of agents that have cocaine-blocking
      effects that appear to be distinct from that of classical sigma-1 receptor
      ligands and that of traditional uncompetitive NMDA receptor antagonists. These
      findings point to potentially novel pharmacological strategies for blocking
      cocaine stimulant and toxic effects.

PMID- 12479951
TI  - Effects of nicotine and stress on locomotion in Sprague-Dawley and Long-Evans
      male and female rats.
AB  - Locomotor activity is widely used to study nicotine effects, including genotypic
      differences, in rodents. In rats, chronic nicotine's (administered via osmotic
      minipump) effects on locomotion may differ based on animal strain, with Long
      Evans rats more sensitive than Sprague-Dawley rats. Males and females also may
      differ in sensitivity. No studies, however, have compared males and females of
      the two strains. In addition, stress relief is a frequently cited reason for
      smoking, but the behavioral consequences of nicotine-stress interactions have
      rarely been examined. This experiment evaluated locomotor responses of male and
      female Sprague-Dawley and Long-Evans rats to 0, 6, or 12 mg/kg/day nicotine
      administered by minipump. Half of the animals in each drug condition were exposed
      to 20 min/day of immobilization stress to examine nicotine-stress interactions.
      Horizontal and vertical activities were measured on Drug Days 4 and 10. Stress
      effects were minimal and stress did not alter effects of nicotine. Nicotine (6
      mg/kg/day) increased horizontal activity among Long-Evans but not among Sprague
      Dawleys, with greater effects in Long-Evans females. Nicotine (6 mg/kg/day)
      increased vertical activity of all groups and 12 mg/kg/day decreased vertical
      activity of all groups except for Sprague-Dawley males. Results indicate that
      genotype and sex are relevant to understand nicotine's behavioral actions.

PMID- 12479952
TI  - Regional CNS densities of serotonin 1A and dopamine D2 receptors in
      periadolescent alcohol-preferring P and alcohol-nonpreferring NP rat pups.
AB  - The objective of the present study was to use quantitative autoradiography to
      determine binding densities of serotonin(1A) (5-HT(1A)) and dopamine (DA) D(2)
      receptors in alcohol-naive periadolescent P and NP rat pups. P (n=8) and NP (n=7)
      rat pups, 25 days of age, from different litters were used. Coronal brain
      sections were incubated with 2 nM [3H]8-OH-DPAT or 20 nM [3H]sulpiride for 5
      HT(1A) or D(2) binding, respectively. Approximately 15-40% higher densities of
      [3H]8-OH-DPAT binding were observed in the anterior cortical regions of the
      periadolescent P rat compared with NP rat pups. Similar differences were also
      observed in posterior cortical regions with P rats having 25-40% higher [3H]8-OH
      DPAT binding than NP rats. [3H]8-OH-DPAT binding was approximately 10-20% higher
      in posterior hippocampal regions of the P rat pups compared with the NP line.
      [3H]sulpiride binding was significantly different only in the ventral tegmental
      area (VTA), where binding was approximately 20% lower in the periadolescent P
      rats compared with the NP rat pups. Overall, these results are very similar to
      findings observed in adult alcohol-naive P and NP rats, and suggest that the
      innate differences in the neural systems implicated in high alcohol drinking
      behaviors may already be established in the periadolescent animal.

PMID- 12479953
TI  - Possible mechanism involved in the anticonvulsant action of butorphanol in mice.
AB  - The study was designed to examine the effect of butorphanol, a classical opioid
      on convulsive behaviour using maximal electroshock (MES) test. An attempt was
      also made to investigate the role of possible receptor mechanisms involved. MES
      seizures were induced in mice via transauricular electrodes (60 mA, 0.2 s).
      Seizure severity was assessed by the duration of tonic hindlimb extensor phase
      and mortality due to convulsions. Intraperitoneal administration of butorphanol
      produced a dose-dependent (0.25-2 mg/kg) protection against hindlimb extensor
      phase. The anticonvulsant effect of butorphanol was antagonized by all the three
      opioid receptor antagonists (i.e., naloxone [mu], MR2266 [kappa], and naltrindole
      [delta], respectively). Coadministration of gamma-aminobutyric acid (GABA)-ergic
      drugs (diazepam, GABA, muscimol, and baclofen) and N-methyl-D-aspartate (NMDA)
      receptor antagonist, dizocilpine (MK801), with butorphanol augmented the
      anticonvulsant action of the latter drug. In contrast, flumazenil, a central
      benzodiazepine (BZD) receptor antagonist, reversed the facilitatory effect of
      diazepam on the anti-MES effect of butorphanol. Similarly, delta-aminovaleric
      acid (DAVA), a GABA(B) receptor antagonist, antagonized the facilitatory effect
      of baclofen, a GABA(B) agonist on anti-MES action of butorphanol. These BZD
      GABAergic antagonists, flumazenil or DAVA, per se also counteracted the anti-MES
      effect of butorphanol given alone. These data exemplify the benefits of using the
      MES test, which is sensitive to opioidergic compounds and distinguished
      convulsive behavioural changes associated with GABAergic and NMDAergic effects.
      Taken together, the results implicate a role for multitude of neurotransmitter
      systems, i.e., opioid (mu, kappa, delta), NMDA channel, BZD-GABA(A) chloride
      channel complex, and GABA(B) receptors in the anti-MES action of butorphanol.

PMID- 12479954
TI  - Interaction of stress and strain on glutamatergic neurotransmission: relevance to
      schizophrenia.
AB  - Psychosis caused by phencyclidine (PCP) stimulated interest in characterizing
      rodent behaviors elicited by PCP and its analogues. We have shown that MK-801
      antagonizes electrically precipitated seizures (defined as tonic hindlimb
      extension) and elicits episodes of intense jumping behavior, referred to as
      "popping," in mice. Moreover, 24 h after stress, MK-801's ability to antagonize
      electrically precipitated seizures is reduced in outbred NIH Swiss mice. Inbred
      BALBc mice are more resistant to electrically precipitated seizures than the NIH
      Swiss strain, and are more sensitive to both MK-801's anticonvulsant effect and
      ability to elicit popping. In the current experiments, we examined the influence
      of stress and genetic mouse strain on both MK-801's ability to antagonize
      electrically precipitated seizures and elicit popping. Stress significantly
      reduced the threshold voltage for precipitation of seizures in BALBc mice and the
      anticonvulsant properties of MK-801 in both strains. These data show that factors
      relevant to schizophrenia and its exacerbation (i.e., acute stress and genetics)
      influence N-methyl-D-aspartic acid (NMDA) receptor-mediated neurotransmission in
      intact mice. The BALBc inbred strain of mouse may possess advantages in
      preclinical screening paradigms designed to assess NMDA receptor agonist
      interventions for disorders such as schizophrenia. Specifically, stressed BALBc
      mice showed the greatest behavioral sensitivity to MK-801 with regard to
      electrically precipitated seizures in the incremental electroconvulsive shock
      (IECS) paradigm, whereas unstressed BALBc showed the greatest behavioral
      sensitivity to MK-801 in the "popping" paradigm, relative to BALBc and NIH Swiss
      mice in the appropriate comparison conditions.

PMID- 12479955
TI  - Evidence that tryptophan reduces mechanical efficiency and running performance in
      rats.
AB  - It has been reported that exercise increases brain tryptophan (TRP), which is
      related to exhaustive fatigue. To study this further, the effect of increased TRP
      availability on the central nervous system (CNS) with regard to mechanical
      efficiency, oxygen consumption (VO(2)) and run-time to exhaustion was studied in
      normal untrained rats. Each rat was anesthetized with thiopental (30 mg/kg ip b.
      wt.) and fitted with a chronic guiding cannula attached to the right lateral
      cerebral ventricle 1 week prior to the experiments. Immediately before exercise,
      the rats were randomly injected through these cannulae with 2.0 microl of 0.15 M
      NaCl (n=6) or 20.3 microM L-TRP solution (n=6). Exercise consisted of running on
      a treadmill at 18 m min(-1) and 5% inclination until exhaustion. TRP-treated rats
      presented a decrease in their mechanical efficiency (21.25+/-0.84%, TRP group vs.
      24.31+/-0.98%, saline-treated group; P< or =.05), and increased VO(2) at
      exhaustion (40.3+/-1.6 ml kg(-1) min(-1), TRP group vs. 36.0+/-0.8 ml kg(-1) min(
      1), saline group; P< or =.05), indicating that the metabolic cost of exercise was
      higher in the former group. In addition, a highly significant reduction was also
      observed in run-time to exhaustion of TRP animals compared to those of the saline
      treated group (15.2+/-1.52 min, TRP group vs. 50.6+/-5.4 min, saline group; P< or
      =.0001). It can be deduced from the data that intracerebroventricular TRP
      injection in rats increases O(2) consumption and reduces mechanical efficiency
      during exercise, diminishing running performance.

PMID- 12479956
TI  - Cross-tolerance between morphine- and nicotine-induced conditioned place
      preference in mice.
AB  - The acquisition of morphine and nicotine conditioned place preference (CPP) and
      cross-tolerance between the response of two drugs was studied in mice. A biased
      CPP paradigm was used to study the effect of the agents. Morphine (5 mg/kg) and
      nicotine (1 mg/kg) induced CPP. Naloxone (0.5, 1 and 2 mg/kg), but not
      mecamylamine (0.025, 0.05 and 0.1 mg/kg), induced conditioned place aversion
      (CPA). Both antagonists reversed CPP induced by morphine and nicotine.
      Administration of one daily dose of morphine (12.5, 25 or 50 mg/kg) for 3 days or
      nicotine (0.5, 1 or 2 mg/kg) three times a day for 12 days, in order to develop
      tolerance to the drugs, reduced the conditioning induced by morphine (5 mg/kg) or
      nicotine (1 mg/kg). CPA-induced by naloxone was reduced in animals, which were
      rendered tolerant to morphine (50 mg/kg) or nicotine (2 mg/kg). Mecamylamine,
      however, which did not induce any response in the nontolerant mice, elicited CPP
      in the tolerant animals. It is concluded that there may be a cross-tolerance
      between morphine- and nicotine-induced CPP.

PMID- 12479957
TI  - Further evidence that the discriminative stimulus properties of indorenate are
      mediated by 5-HT 1A/1B/2C receptors.
AB  - Indorenate (5-methoxytryptamine beta-methylcarboxylate, INDO) is a serotonin (5
      hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT(1A/1B/2C) receptors.
      Unlike other anxiolytics such as 5-HT receptor agonists, INDO may not share
      tolerance or dependency with the benzodiazepine anxiolytics. It has been reported
      that the discriminative stimulus properties of 5-HT(1A/1B/2C) agonists, but not
      those of 5-HT(3/4) agonists, generalize to INDO. Therefore, the aim of the
      present study was to obtain further evidence on the differential involvement of 5
      HT(1A/1B/2C) receptors in the discriminative stimulus properties of INDO by
      evaluating its interactions with antagonists of the 5-HT(1A), 5-HT(1B), 5-HT(2C),
      and 5-HT(3/4) receptor subtypes. Rats were trained to discriminate INDO from
      saline in a conditioned taste aversion paradigm. For Group D(+)S(-),
      administration of INDO signalled that saccharin flavour was followed by LiCl,
      while injection of vehicle signalled safe consumption of saccharin solution.
      Group D(-)S(+) had the contingencies reversed. After this training, rats had
      generalization tests where INDO administration was preceded by different doses of
      the following antagonists: WAY100635 (5-HT(1A)), NAN190 (5-HT(1A)), methiothepin
      (5-HT(1A/1B/2C)), GR127935 (5-HT(1B/1D)), ketanserin (5-HT(2A/2C)), ritanserin (5
      HT(2C/2A)), mesulergine (5-HT(2C/2A)), metergoline (5-HT(2C/2A)), SB206553 (5
      HT(2B/2C)), and tropisetron (5-HT(3/4)). In Group D(+)S(-), the order of potency
      to block the discriminative stimulus properties of INDO was
      WAY100635>ketanserin>ritanserin>GR127935>mesulergine congruent with
      SB206553>metergoline>methiothepin>NAN190, while in Group D(-)S(+), the order was
      WAY100635>GR127935>ketanserin>ritanserin>mesulergine congruent with
      SB206553>metergoline>methiothepin>NAN190. Tropisetron did not produce any
      alteration of the discriminative control by INDO. These results suggest that the
      discriminative signal of INDO is mediated by 5-HT(1A/2C/1B) receptors and that
      blockade of any of its components produces a degradation of its discriminative
      effects.

PMID- 12479958
TI  - A pharmacological dose of estradiol can enhance appetites for alcoholic
      beverages.
AB  - Each of 30 female Sprague-Dawley rats were given 2 mg of estradiol valerate (EV),
      30 others were given placebos. EV is a preparation that delivers estradiol for
      more than 12 days, but probably less than 20. Fifteen days later, the females had
      the opportunity to take sweetened alcoholic beverage 24 h a day across 25 days.
      Subsequently, they could self-administer other alcoholic beverages, including one
      of only alcohol and water. After a period of abstinence, rats had another
      opportunity to take sweetened alcoholic beverage (94 to 96 days after the single
      injection of EV). With every measurement, rats given EV consumed significantly
      more ethanol than controls. For example, mean of measurements representing daily
      intake for the fourth week of availability of palatable alcoholic beverage for
      placebo-treated=5.29 grams of ethanol per kilogram of bodyweight (g'E/kg); for EV
      treated=8.13 g'E/kg; P=.003. The data support the conclusion that pharmacological
      doses of estradiol can induce marked, enduring changes in appetite for alcoholic
      beverages.

PMID- 12479959
TI  - Effects of calcium and glutamate receptor agonists on leaf consumption by
      lepidopteran neonates.
AB  - Calcium and glutamate receptor (GluR) agonists affect apple leaf consumption by
      neonates of the apple pest, the codling moth, Cydia pomonella (L.) Initial apple
      leaf consumption was advanced by the presence of trans-1-amino-(1S,3R)
      cyclopentanedicarboxylic acid (trans-ACPD), but not by calcium chloride or N
      methyl-D-aspartate (NMDA). However, during the 3 h following hatch, CaCl(2) and
      NMDA increased the quantity of apple leaf tissue consumed, but trans-ACPD had no
      such effects. Stimulatory effects of CaCl(2) and NMDA on leaf consumption were
      abolished if codling moth larvae were concurrently exposed to calcium chelator
      EDTA. (RS)-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) and
      kainic acid had no effects either on commencement or intensity of leaf
      consumption. We hypothesize that in codling moth larvae, apple leaf consumption
      is induced via metabotropic GluR, and sustained feeding is regulated via NMDA
      GluRs. Practical aspects of this finding are discussed.

PMID- 12479960
TI  - Lack of midazolam-induced anxiolysis in the plus-maze Trial 2 is dependent on the
      length of Trial 1.
AB  - The influence of the first exposure length upon the effect of midazolam (MDZ)
      administration prior to the second exposure in the elevated plus-maze (EPM) was
      investigated. Drug-free rats were assigned to freely explore the EPM for 1, 2 or
      5 min (Trial 1). Twenty-four hours later, each group was subdivided in two
      further groups, which were retested in the EPM for 5 min, 30 min after either
      saline or MDZ (1.5 mg kg(-1)) administration (Trial 2). The data showed that
      during Trial 2, the percentage of entries (%Open arm entries) and time spent in
      the open arms (%Open arm time) were decreased if rats were pre-exposed to the EPM
      for 2- or 5-min Trial 1, while the group submitted to 1-min Trial 1 length
      displayed decreased %Open arm time only. The anxiolytic effect of MDZ prior to
      Trial 2 was present in the group submitted to 1-min, impaired in the group
      submitted to 2-min and absent in the group submitted to 5-min Trial 1 length.
      Data are analyzed taking into account the emotional learning which underlies the
      exploratory behavior during the EPM Trial 2.

PMID- 12479961
TI  - Attenuated adrenocortical and blood pressure responses to psychological stress in
      ad libitum and abstinent smokers.
AB  - Chronic smoking may alter physiological systems involved in the stress response.
      This study was designed to examine the effects of ad libitum smoking and
      abstinence on adrenocortical and cardiovascular responses to acute psychological
      stress in dependent cigarette smokers. We evaluated differences among abstinent
      smokers, smokers who continued to smoke at their normal rate, and nonsmokers in
      salivary cortisol concentrations, systolic and diastolic blood pressure (BP),
      heart rate (HR), and mood reports. Measurements were obtained during rest and in
      response to acute psychological stress (public speaking) in one session (stress
      session) and during continuous rest in a control session. Thirty-eight smokers
      (21 women) and 32 nonsmokers (18 women) participated. Smokers were assigned to
      either abstain from smoking the night prior to and the day of each session, or to
      continue smoking at their normal rate before each session. All groups showed
      significant stress-induced changes in BP and HR. Smokers, regardless of their
      assigned condition, showed attenuated systolic BP responses to the public
      speaking stressor when compared to nonsmokers. While resting cortisol levels were
      greater among smokers than nonsmokers, no cortisol response to the acute stressor
      was demonstrated in either ad libitum or abstinent smokers. These results
      indicate that chronic smoking diminishes adrenocortical and cardiovascular
      responses to stress, and that short-term abstinence does not correct these
      alterations.

PMID- 12479962
TI  - Role of hippocampal M1 and M4 muscarinic receptor subtypes in memory
      consolidation in the rat.
AB  - Muscarinic receptors in the hippocampus are relevant to learning and memory, but
      the role of each subtype is poorly understood. Muscarinic toxins (MTs) from
      Dendroaspis snakes venom are selective for muscarinic receptor subtypes. MT2, a
      selective agonist for M(1) receptors, given into the hippocampus immediately
      after training, improved memory consolidation of an inhibitory avoidance task in
      rats, whereas the antagonist pirenzepine was amnestic, supporting a facilitatory
      role of M(1) receptors. Instead, MT3, a selective antagonist at M(4) receptors,
      caused amnesia. Neither M(1) nor M(4) receptor appeared involved in habituation
      to a new environment. Thus, our results suggest that memory consolidation of an
      inhibitory avoidance task in the rat involves the participation of both M(1) and
      M(4) hippocampal receptors, with a positive modulatory role.

PMID- 12479963
TI  - Evidence for involvement of neuropeptide Y and melanocortin systems in the
      hyperphagia of lactation in rats.
AB  - Hypothalamic neuropeptide Y (NPY) systems are upregulated during lactation in
      rats. Because NPY is central to the hypothalamic control of energy balance, the
      present studies tested the hypothesis that NPY contributes to the marked
      hyperphagia during lactation. A 4-day infusion of [D-tyr (27,36), D-thr (32)] NPY
      (27-36) (D-NPY(27-36)), a peptide analogue of NPY that antagonizes NPY-induced
      feeding, into the third ventricle at 1 microg/h transiently inhibited nocturnal
      feeding in nonlactating female rats. However, this antagonist had no effect on
      nocturnal feeding, but did transiently reduce food intake during the light hours,
      when infused into the third ventricle at the same dose in lactating females. An
      essentially similar pattern of results was obtained with chronic infusion into
      the third ventricle of the anorexigenic peptide alpha-melanocyte-stimulating
      hormone (alpha-MSH, 1 microg/h), in nonlactating and lactating rats. Both D
      NPY(27-36) and alpha-MSH transiently reduced nocturnal food intake in lactating
      rats by approximately 10% when infused at the higher dose of 5 microg/h, and a
      marked inhibition of approximately 40% of both nocturnal and diurnal feeding was
      produced by a combined infusion of both at 5 microg/h. These results provide the
      first pharmacological evidence implicating specific neuromessengers in mediating
      the hyperphagia of lactation, and suggest that, while an action of NPY may
      contribute to the increased food intake seen in lactating animals, other systems
      are also involved. In particular, a reduction in melanocortin signaling during
      lactation may allow for an increased orexigenic influence of the agouti-related
      protein (AgRP), which is co-expressed with NPY.

PMID- 12479964
TI  - Effects of catecholamine depletion on D2 receptor binding, mood, and
      attentiveness in humans: a replication study.
AB  - The effect of catecholamine depletion, achieved by per-oral administration of
      5250 mg alpha-methyl-para-tyrosine (AMPT) given in the 29 h prior to
      [11C]raclopride positron emission tomography (PET) was studied on measures of
      dopamine (DA) release, mood, and attention. Neostriatal DA levels in vivo were
      estimated by comparing the neostriatal DA D(2) receptor binding potential
      (D(2)RBP) before and after catecholamine depletion using PET and the radiotracer
      [11C]raclopride. Six healthy subjects completed the protocol. The AMPT treatment
      increased D(2)RBP significantly by 13.3+/-5.9% (average+/-standard deviation) and
      decreased plasma levels of the DA metabolite homovanillic acid (HVA) by 62+/-17%,
      and levels of the norepinephrine (NE) metabolite 3-methoxy-4
      hydroxyphenethyleneglycol (MHPG) by 66+/-5%. Catecholamine depletion resulted in
      decreased happiness, euphoria, energy, talkativeness, vigor, and attentiveness,
      and in increased sleepiness, fatigue, sedation, and eye blink rate (EBR). These
      changes were not correlated with the D(2)RBP increments. The results of this
      study are overall consistent with previous findings by our group using the same
      methodology in a different cohort of six healthy subjects.

PMID- 12479965
TI  - Sex differences in the effects of muramyl dipeptide and lipopolysaccharide on
      locomotor activity and the development of behavioral tolerance in rats.
AB  - Administration of bacterial agents, such as muramyl dipeptide (MDP) or
      lipopolysaccharide (LPS), induces a number of illness symptoms including
      decreased locomotor activity and weight loss. This study provides a detailed
      multivariate assessment of the effects of repeated exposures of various doses of
      MDP and LPS, alone and in combination, on various aspects of locomotion in male
      and female rats. Animals were given a single intraperitoneal injection of either
      MDP (0.8 or 1.6 mg/kg), LPS (100 or 200 microg/kg), a combination of MDP and LPS
      (0.8 mg/kg and 100 microg/kg, respectively), or vehicle on Days 1, 4, and 7. Two
      hours after each injection, locomotor activity was recorded for 30 min in an
      automated open-field. Both doses of LPS and the high dose of MDP produced
      significant decrements in locomotor activity in male and female rats, with
      tolerance becoming evident over repeated administrations, although LPS decreased
      activity more robustly than MDP. Sex differences were evident in the combined
      effects of MDP and LPS. Together, MDP and LPS reduced male activity levels in an
      additive manner but significantly potentiated both horizontal and vertical
      activity decrements in females. In addition, the rate of behavioral tolerance
      development to repeated bacterial injections was significantly higher in females
      than in males. These findings provide evidence for sex differences in the actions
      of MDP and LPS on various aspects of locomotor activity and in the development of
      behavioral tolerance to infection.

PMID- 12479966
TI  - Effects of chronic cocaine on monoamine levels in discrete brain structures of
      lactating rat dams.
AB  - Chronic gestational cocaine administration has been correlated with high levels
      of postpartum maternal aggression towards intruders and altered levels of
      oxytocin in the amygdala. Cocaine may alter both oxytocin and maternal aggression
      either directly or indirectly through changes in monoamine levels in relevant
      brain regions. In this study, pregnant female rats were randomly assigned to one
      of four groups; three cocaine dose groups (7.5, 15 or 30 mg/kg), or a saline
      treated group (0.9% normal saline) and given subcutaneous injections twice daily
      (total volume 2 ml/kg) throughout gestation. Behavioral responses to an inanimate
      object placed in the homecage were assessed on Postpartum Day (PPD) 6.
      Immediately following testing, animals were sacrificed and four brain regions
      implicated in maternal/aggressive behavior (medial preoptic area [MPOA], ventral
      tegmental area [VTA], hippocampus, and amygdala) were removed for monoamine level
      analyses using high-performance liquid chromatography. Dams given 30 mg/kg
      cocaine throughout gestation had significantly higher levels of dopamine (DA) and
      nonsignificantly elevated serotonin (5-HT) levels relative to saline-treated
      controls. These dams also exhibited higher frequencies of defensive behavior
      toward an inanimate object compared to saline-treated controls. Potential
      mechanisms mediating cocaine-induced increases in responding are proposed.

PMID- 12479967
TI  - A microdialysis study of glutamate concentration in the hippocampus of rats after
      TsTX toxin injection and blockade of toxin effects by glutamate receptor
      antagonists.
AB  - Scorpion toxins act on ionic channels changing the release of neurotransmitters.
      In the present study, we investigated the glutamatergic release evoked by
      intrahippocampal injection of TsTX toxin isolated from Tityus serrulatus scorpion
      venom in male Wistar rats and the blockade of the toxin effect by glutamatergic
      antagonists. Microdialysis for neurotransmitter level quantification,
      electroencephalographic recording, and histopathological analysis were performed.
      The microdialysis method revealed enhanced levels of extracellular glutamate in
      the hippocampal area. The toxin injection preceded by injection of the glutamate
      receptor antagonists dizolcipine maleate (MK-801), D(-)2-amino-5
      phosphonopentanoic acid (AP-5), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), L(+)
      2-amino-3-phosphonopropionic acid (AP-3), and (+)-alpha-methyl-4
      carboxyphenylglycine (MCPG) demonstrated that MK-801 and AP-5 fully blocked the
      electrographic alterations and the CA1 cell loss induced by the toxin. CNQX, AP
      3, and MCPG partially blocked the epileptiform discharges and no hippocampal
      damage was observed. Thus, we conclude that the toxin evokes glutamate release
      and that glutamate receptor antagonists can partially or totally block the toxin
      effect.

PMID- 12479968
TI  - Possible involvement of potassium channels in peripheral antinociception induced
      by metamizol: lack of participation of ATP-sensitive K+ channels.
AB  - The present work assessed the possible participation of K+ channels in the
      peripheral antinociceptive action of metamizol in the 1% formalin test.
      Ipsilateral, but not contralateral, local peripheral administration of metamizol
      produced a dose-dependent antinociception only during the second phase of the
      formalin test. K+ channel blockers alone did not modify formalin-induced
      nociceptive behavior. However, local peripheral pretreatment of the paw with
      charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated K+
      channel blockers, respectively), 4-aminopyridine and tetraethylammonium (voltage
      dependent K+ channel inhibitors), but not glibenclamide or tolbutamide (ATP
      sensitive K+ channel inhibitors), dose-dependently prevented metamizol-induced
      antinociception. The above results suggest that metamizol could open large- and
      small-conductance Ca(2+)-activated K+ channels, but not ATP-sensitive K+
      channels, in order to produce its peripheral antinociceptive effect in the
      formalin test. The participation of voltage-dependent K+ channels was also
      suggested, but since nonselective inhibitors were used, the data await further
      confirmation.

PMID- 12479969
TI  - Ethanol effects on three strains of zebrafish: model system for genetic
      investigations.
AB  - The effects of acute and chronic ethanol administration on the wild-type (WT),
      long-fin striped (LFS), and blue long-fin (BLF) strains of zebrafish were
      investigated. In the LFS strain, acute exposure to 0.25% (v/v) ethanol inhibited
      the startle reaction and increased both the area occupied by a group of subjects
      and the average distance between each fish and its nearest neighbor. Similar
      effects were found in the WT fish although higher concentrations of ethanol were
      required. No effects on the behavior of the BLF fish were observed with up to
      1.0% (v/v) ethanol. Brain alcohol levels were comparable among the three strains
      precluding a pharmacokinetic explanation for the behavioral results. In LFS
      zebrafish, behavioral tolerance was observed after 1 week of continual exposure
      to ethanol. Conversely, chronic ethanol exposure of the WT fish for up to 2 weeks
      did not result in the development of tolerance, but rather appeared to increase
      the disruptive action of the drug. The present results suggest the observed
      strain differences in the effects of ethanol reflect genotypic differences in
      both the response of the central nervous system (CNS) to ethanol as well as the
      ability of the CNS to adapt to ethanol exposure. Although preliminary, the
      present study indicates that the zebrafish is an excellent model system to
      investigate the genetic determinants involved in regulating the responses to
      ethanol.

PMID- 12479970
TI  - Protective effect of Nardostachys jatamansi in rat cerebral ischemia.
AB  - The protective effect of Nardostachys jatamansi (NJ) on neurobehavioral
      activities, thiobarbituric acid reactive substance (TBARS), reduced glutathione
      (GSH), thiol group, catalase and sodium-potassium ATPase activities was studied
      in middle cerebral artery (MCA) occlusion model of acute cerebral ischemia in
      rats. The right MCA of male Wistar rats was occluded for 2 h using intraluminal 4
      0 monofilament and reperfusion was allowed for 22 h. MCA occlusion caused
      significant depletion in the contents of glutathione and thiol group and a
      significant elevation in the level of TBARS. The activities of Na(+)K(+) ATPase
      and catalase were decreased significantly by MCA occlusion. The neurobehavioral
      activities (spontaneous motor activity and motor coordination) were also
      decreased significantly in MCA occlusion group. All the alternations induced by
      ischemia were significantly attenuated by 15 days pretreatment of NJ (250 mg/kg
      po) and correlated well with histopathology by decreasing the neuronal cell death
      following MCA occlusion and reperfusion. The study provides first evidence of
      effectiveness of NJ in focal ischemia most probably by virtue of its antioxidant
      property.

PMID- 12479971
TI  - Intrathecal histamine induces spinally mediated behavioral responses through
      tachykinin NK1 receptors.
AB  - Intrathecal injection of histamine elicited a behavioral response consisting of
      scratching, biting and licking in conscious mice. Here, we have examined the
      involvement of substance P (SP) by using intrathecal injection of tachykinin
      neurokinin (NK)(1) receptor antagonists and SP antiserum. Histamine-induced
      behavioral response was evoked significantly 5-10 min after intrathecal injection
      and reached a maximum at 10-15 min. Dose-dependency of the induced response
      showed a bell-shaped pattern from 200 to 3200 pmol, and maximum effect was
      observed at 800-1000 pmol. The H(1) receptor antagonist, d-chlorpheniramine and
      pyrilamine but not the H(2) receptor antagonists, ranitidine and zolantidine,
      inhibited histamine-induced behavioral response. The NK(1) receptor antagonists,
      CP-99,994, RP-67580 and sendide, inhibited histamine-induced behavioral response
      in a dose-dependent manner. A significant antagonistic effect of [D-Phe(7), D
      His(9)]SP (6-11), a selective antagonist for SP receptors, was observed against
      histamine-induced response. The NK(2) receptor antagonist, MEN-10376, had no
      effect on the response elicited by histamine. Pretreatment with SP antiserum
      resulted in a significant reduction of the response to histamine. No significant
      reduction of histamine-induced response was detected in mice pretreated with NK A
      antiserum. The present results suggest that elicitation of scratching, biting and
      licking behavior induced by intrathecal injection of histamine may be largely
      mediated by NK(1) receptors via H(1) receptors in the spinal cord.

PMID- 12479972
TI  - Meal patterns in male rats during and after intermittent nicotine administration.
AB  - Continuous administration of nicotine (NIC) reduces food intake (FI) and body
      weight (BW), whereas rebound eating and BW gain occur after NIC cessation.
      However, generalizations derived from prior studies on meal patterns in rats
      using continuous 24-h NIC administration are limited, because human smokers use
      NIC intermittently during their active period. In the present study, computerized
      meal pattern analyses (MPA) were conducted for adult male rats treated for 14
      days with either saline or 2 or 4 mg/kg/day of NIC spread over five equal amounts
      during the dark phase. MPA analyses continued for 14 days after cessation of NIC.
      Only the 4 mg/kg/day NIC dose caused consistent changes in meal patterns and only
      that dose is reported herein. Dark period FI was reduced, whereas light period FI
      was unchanged in the NIC-treated group; thus, there was no rebound eating during
      the 12-h nontreatment phase. MPA analyses revealed the FI reduction on Day 1 of
      NIC administration was caused by a persistent decrease in dark phase meal size.
      On Day 5 of NIC, the rats compensated by significantly increasing the number of
      meals they took, which tended to normalize dark phase FI. Congruently, dark phase
      intermeal interval was decreased. Importantly, these changes in meal patterns
      persisted for 2 weeks after termination of NIC. Upon NIC cessation, the NIC group
      had a transient elevated FI. The NIC-treated group's BW was significantly
      suppressed by Day 6 of NIC and after stoppage these rats slowly, but
      incompletely, regained lost BW over the next 14 days. These results document that
      administration of NIC during the dark phase resulted in a reorganization of the
      microstructure of FI in male rats and that long-lasting alterations in the
      microstructure of FI (e.g., meal size and meal number) were noted for up to 2
      weeks after cessation of NIC. These results differ from studies in which NIC was
      given continuously 24-h/day and indicate that dark phase NIC administration in
      rats may represent an appropriate model to study the impact of NIC on meal
      patterns.

PMID- 12479973
TI  - Evidence that the anorexia induced by lipopolysaccharide is mediated by the 5
      HT2C receptor.
AB  - Rats consistently reduce their food intake following injections of bacterial
      lipopolysaccharides (LPS). Because inhibition of serotonergic (5-HT) activity by
      8-OH-DPAT (5-HT(1A) activation) attenuates LPS-induced anorexia, we conducted a
      series of studies to examine whether other 5-HT-receptors are involved in the
      mediation of peripheral LPS-induced anorexia. In all experiments, rats were
      injected with LPS (100 microg/kg body weight [BW] ip) at lights out (hour 0).
      Antagonists were administered peripherally at hour 4, shortly after the onset of
      anorexia, which presumably follows the enhanced cytokine production after LPS.
      Food intake was then recorded during the subsequent 2 h or longer. 5-HT receptor
      antagonists cyanopindolol and SB 224289 (5-HT(1B)), ketanserin (5-HT(2A)), RS
      102221 (5-HT(2C)), and metoclopramide (5-HT(3)) failed to attenuate LPS-induced
      anorexia. In contrast, both ritanserin (5-HT(2A/C)-receptor antagonist) (0.5
      mg/kg BW) and SB 242084 (5-HT(2C)) (0.3 mg/kg BW) attenuated LPS-induced anorexia
      at doses that did not alter food intake in non-LPS-treated rats (all P<.01). Our
      results suggest that at least part of the anorexia following peripheral LPS
      administration is mediated through an enhanced 5-HT-ergic activity and the 5
      HT(2C) receptor.

PMID- 12479974
TI  - Biosynthesis and processing of pro CCK: recent progress and future challenges.
AB  - Pro Cholecystokinin (CCK) like other prohormones that pass through the regulated
      secretory pathway, undergoes a number of post-translational modifications during
      its biosynthesis including tyrosine sulfation, endoproteolytic cleavages,
      trimming by carboxypeptidase and c-terminal amidation. This minireview summarizes
      what is known about this process, what specific enzymes are involved in endocrine
      and neuronal tumor cells and in mutant and knockout mouse strains. It also points
      out the major challenges that remain for future research.

PMID- 12479975
TI  - Ginsenoside Rf potentiates U-50,488H-induced analgesia and inhibits tolerance to
      its analgesia in mice.
AB  - In the present study, the effect of ginsenoside Rf (Rf), a trace component of
      Panax ginseng on U-50,488H (U50), a selective kappa opioid-induced analgesia and
      its tolerance to analgesia was studied using the mice tail-flick test. In
      addition, the possible mechanism by which Rf may affect U50-induced analgesia was
      investigated. Intraperitoneal administration of U50 (40 mg/kg) produced
      analgesia. Rf (10(-14)-10(-10) mg/kg) on co treatment dose-dependently
      potentiated the U50 (40 mg/kg)-induced analgesia. Rf (10(-12)-10(-2) mg/ml) did
      not alter the binding of [3H] naloxone, a opioid ligand and [3H]PN200-110, a
      dihydropyridine ligand to mice whole brain membrane. Twice daily administration
      of U50 (40 mg/kg) for six days induced tolerance to its analgesia. Chronic
      treatment (day 4-day 6) of Rf (10(-14)-10(-10) mg/kg) to U50-tolerant mice, dose
      dependently inhibited the tolerance. The inhibition of tolerance to U50-induced
      analgesia by Rf was not altered by flumazenil (0.1 mg/kg), a benzodiazepine
      receptor antagonist and picrotoxin (1 mg/kg), a GABA(A)-gated chloride channel
      blocker on chronic treatment. In conclusion, these findings for the first time
      demonstrated that ginsenoside Rf potentiates U50-induced analgesia, inhibits
      tolerance to its analgesia, and suggests that Rf affects U50-induced analgesia
      via non-opioid, non-dihydropyridine-sensitive Ca(+2) and non-benzodiazepine
      GABA(A)ergic mechanisms in mice.

PMID- 12479976
TI  - Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant
      activity against kainate in mice.
AB  - The effects of dextromethorphan (DM), and its major metabolite dextrorphan (DX)
      on kainic acid-induced seizures in mice were examined. Intracerebroventricular DM
      or DX (5 or 10 microg/0.5 microl) pretreatment significantly attenuated seizures
      induced by kainic acid (0.07 microg/0.07 microl) in a dose-related manner. DM or
      DX pretreatment significantly attenuated kainic acid-induced increases in AP-1
      DNA-binding activity and fos-related antigen-immunoreactivity as well as neuronal
      loss in the hippocampus. DM appears to be a more potent neuroprotectant than DX.
      Since the high-affinity DM binding sites are recognized as being identical to the
      sigma-1 site, we examined the role of the sigma-1 receptor on the pharmacological
      action mediated by DM or DX. Pretreatment with the sigma-1 receptor antagonist
      BD1047 (2.5 or 5 mg/kg, i.p.) blocked the neuroprotection by DM in a dose-related
      manner. This effect of BD 1047 was more pronounced in the animals treated with DM
      than in those treated with DX. Combined, our results suggest that metabolism of
      DM to DX is not essential for DM to exert its effect. They also suggest that DM
      provides neuroprotection from kainic acid via sigma-1 receptor modulation.

PMID- 12479977
TI  - Longitudinal study of tryptophan degradation during and after pregnancy.
AB  - In mice, activation of indoleamine-2,3-dioxygenase (IDO), an enzyme converting
      tryptophan to N-formyl-kynurenine, was found to be necessary requirement to
      achieve immunotolerance against the fetus and thus uncomplicated pregnancy. In
      plasma from 20 healthy pregnant women with singleton pregnancies we consecutively
      analyzed kynurenine and tryptophan concentrations during pregnancy (1 specimen at
      each trimester of gestation) and postpartum (week 6). None of the women had any
      signs of infection at the time of plasma sampling, but the study population was
      otherwise unselected. The kynurenine to tryptophan ratio (kyn/trp) was calculated
      as an estimate of IDO activity, and data were compared to concentrations of
      neopterin and 55kD soluble tumor necrosis factor receptor (sTNF-R55), two
      indicators of immune activation, and to alanineaminotransferase (ALT) levels.
      Increasing kynurenine and decreasing tryptophan concentrations were found during
      pregnancy, data suggesting significant degradation of tryptophan. In parallel,
      increasing concentrations of immune activation markers neopterin and sTNF-R55
      were observed, correlating significantly to kyn/trp. The data point to an
      involvement of cytokine-induced IDO activation in the degradation of tryptophan
      observed during pregnancy. After pregnancy, sTNF-R55 and also neopterin
      concentrations declined, whereas tryptophan concentrations increased, indicating
      that immune activation and activation-induced tryptophan degradation returned to
      baseline. By contrast, still increased kynurenine concentrations and also
      increased kyn/trp point to continuing catabolism of tryptophan. Postpartum
      elevation of liver enzyme ALT may suggest that increased activity of hepatic
      tryptophan pyrrolase could be involved in increased conversion of tryptophan
      despite low degree of immune activation. We conclude that IDO is activated in
      pregnancy and that the decrease of tryptophan might be related to immune
      activation phenomena. Sustained increase of kynurenine postpartum seems
      independent from immune activation process.

PMID- 12479978
TI  - Angiotensin II induces prostaglandin E(2) release in human gingival fibroblasts.
AB  - We investigated the effect of angiotensin II on prostaglandin E(2) release in
      human gingival fibroblasts. Stimulation of human gingival fibroblasts with
      angiotensin II elicited prostaglandin E(2) release in a concentration- and time
      dependent manner. Angiotensin III also induced prostaglandin E(2) release, but
      the effect was weaker than that of angiotensin II. Angiotensin II- and
      angiotensin III-induced prostaglandin E(2) release was inhibited by AT(1)
      receptor antagonist FR-130,739, but not AT(2) receptor antagonist PD-123,319.
      Angiotensin II evoked an increase in intracellular Ca(2+) in fura-2-loaded human
      gingival fibroblasts. These results suggest that angiotensin II functions as a
      physiological mediator via Ca(2+)-mobilizing AT(1) receptor activation in human
      gingival fibroblasts.

PMID- 12479979
TI  - Ontogeny of thyroid hormones, cortisol, hsp70 and hsp90 during silver sea bream
      larval development.
AB  - We studied the profiles of silver sea bream (Sparus sarba) thyroxine (T(4)),
      triiodothyronine (T(3)), cortisol and the heat shock protein (hsp) families hsp70
      and hsp90 during larval development. Eggs from sexually mature female sea bream
      were fertilized and larvae were collected at incremental time intervals between 1
      46 days post hatch (dph). Both T(4) and T(3) were detected in 1 dph larvae and it
      was found that both increased as development progressed with a distinct surge in
      amounts between 21-35 dph, a time associated with direct development of larvae to
      juveniles. Cortisol increased from 1 dph reaching a maximum and constant level
      from 35 dph onwards. Using RT-PCR coupled with radioisotope hybridization of
      immobilized cDNA we assessed the transcript levels of hsp70 and it was found that
      transcript remained unaltered between 1-14 dph before progressively increasing.
      Immunoblotting was used to study the larval concentrations of hsp70 and hsp90 and
      it was found that hsp70 was not significantly changed between 1-14 dph whereas
      hsp90 increased from 1 dph onwards. These findings suggest an important role for
      hsp90 in the corticosteroid receptor complex during silver sea bream larval
      development.

PMID- 12479980
TI  - Effect of electrical stimulation of the baso-lateral amygdala nucleus on
      defensive burying shock probe test and elevated plus maze in rats.
AB  - In the present report, the putative effect of a single electrical stimulation
      (75, 150 or 300 microA) to the baso-lateral amygdala (BLA) nucleus was assessed
      in shock probe defensive burying behavior test (DB) and elevated plus maze (EPM).
      These models have been used for measuring anxiety levels and screening putative
      anxiolytic compounds. A group of 28 rats were randomly divided for the following
      experimental conditions: Control-control, sham-operated, BLA stimulated groups:
      75, 150 and 300 microA tested for DB. The cumulative defensive burying in a 15
      min-test, the latency of burying, the number of shock received and the height of
      the bedding material in the probe were recorded. Another group of 28 individuals
      was also randomly distributed for the following experimental conditions: Control
      control, sham-operated, BLA stimulated animals: 75, 150, 300 microA and tested in
      the EPM. The time the subjects spent in the open arms, the crosses and the faeces
      number excreted during the test were recorded. Decreased levels of defensive
      burying were observed in 75, 150 and 300 microA stimulated groups. The 150 and
      300 microA groups reached statistical significance. The fact that 300 microA
      stimulated group showed statistically significant increase in the latency of
      defensive burying, in the number of shock received and decreased amount in
      bedding material suggests a sedative action of electrical stimulation. Increased
      time in the open arms and augmented number of crossings in 150 microA group was
      observed. No changes in the number of faeces were observed in any group. The
      evidence supported the notion of an inhibitory amygdaline mechanism triggered by
      sub-threshold electrical stimulation.

PMID- 12479981
TI  - Expression of nuclear retinoic acid receptor in peripheral blood mononuclear
      cells (PBMC) of healthy subjects.
AB  - In vertebrates, both nuclear all-trans and 9-cis retinoic acid receptors (RAR and
      RXR) belonging to the steroid/thyroid/retinoid nuclear receptor superfamily play
      a crucial role in the vitamin A action. Qualitative analysis of all known RAR or
      RXR subtypes in both pooled and non-pooled peripheral blood mononuclear cells
      (PBMC) from healthy human subjects has been performed by reverse transcription
      and polymerase chain reaction (RT-PCR). Our data, based on qualitative RT-PCR
      analysis has shown that human PBMC are capable to express RAR alpha, RAR gamma,
      RXR alpha, and RXR beta.

PMID- 12479982
TI  - Topically administered CB(2)-receptor agonist, JWH-133, does not decrease
      intraocular pressure (IOP) in normotensive rabbits.
AB  - Recent IOP and receptor localization studies suggest that the IOP effects of
      cannabinoids are mediated via ocular CB(1) receptors. However, it is not yet
      known whether CB(2) receptor agonists decrease IOP. In this study, the IOP
      lowering effects of the CB(2) receptor agonist JWH-133 were studied in
      normotensive rabbits, and compared with CP55,940. JWH-133 and CP55,940 were
      dissolved in aqueous hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions and
      propylene glycol. The eye drops (25 microl) were administered unilaterally to the
      rabbit eye, and IOPs were measured at fixed time intervals. JWH-133, dissolved in
      either HP-beta-CD (doses = 10 microg and 25 microg) or propylene glycol (dose =
      62.5 microg), did not have any effect on IOP when compared to vehicle treatments.
      In contrast, CP55,940 formulated in HP-beta-CD (doses = 25 microg and 62.5
      microg) or propylene glycol (dose = 62.5 microg) reduced IOP significantly
      compared to vehicle treatments. The results suggest that topically administered
      CB(2) receptor agonist, JWH-133, does not decrease IOP in normotensive rabbits at
      the doses and formulations used, and thus, CB(2) receptor agonists may not be
      useful as cannabinoid-based IOP-lowering therapeutics.

PMID- 12479983
TI  - Inhibition of collagenase and metalloproteinases by aloins and aloe gel.
AB  - The effects of Aloe barbadensis gel and aloe gel constituents on the activity of
      microbial and human metalloproteinases have been investigated. Clostridium
      histolyticum collagenase (ChC) results dose-dependently inhibited by aloe gel and
      the activity-guided fractionation led to an active fraction enriched in phenolics
      and aloins. Aloins have been shown to be able to bind and to inhibit ChC
      reversibly and non-competitively. Aloe gel and aloins are also effective
      inhibitors of stimulated granulocyte matrix metalloproteinases (MMPs). The
      remarkable structural resemblances between aloins and the pharmacophore structure
      of inhibitory tetracyclines, suggest that the inhibitory effects of aloins are
      via an interaction between the carbonyl group at C(9) and an adjacent hydroxyl
      group of anthrone (C(1) or C(8)) at the secondary binding site of enzyme,
      destabilizing the structure of granulocyte MMPs.

PMID- 12479984
TI  - A single administration of adenoviral-mediated HGF cDNA permits survival of mice
      from acute hepatic failure.
AB  - Heptatocyte growth factor (HGF) having a variety of biological activity was
      suggested as a protective agent against acute toxic hepatic injury or a
      potentially therapeutic agent. For the efficient in vivo application of this
      factor, we employed adenoviral-mediated HGF gene delivery system. In this study,
      we constructed E1-deleted recombinant adenovirus carrying cDNA of human HGF
      (Ad.hHGF) and elucidated that HGF was efficiently expressed in the liver of
      C57/BL mice. A mouse model of acute hepatic failure was induced by high dose
      (1000mg/kg) of thioacetamide (TA) administration. Mice infected with Ad.hHGF
      showed a dramatic resistance to TA-induced acute hepatic injury. Serum ALT was
      increased transiently and then the level was normalized in Ad.hHGF-infected mice
      with TA administration. Furthermore, the survival rate was remarkably enhanced in
      the mice infected with Ad.hHGF. In the histological examination, massive hepatic
      necrosis induced by TA was almost completely protected by HGF produced by
      Ad.hHGF. Our results indicate that a single dose of HGF-encoding adenoviral
      vector maintained liver function and prevented the progression of liver necrosis
      in a mouse model of acute hepatic failure.

PMID- 12479985
TI  - The predictive value of the Toronto Alexithymia Scale among patients with asthma.
AB  - OBJECTIVE: The present study examines how alexithymia, self-report of symptoms,
      and pulmonary function are related to each other among a sample of patients with
      asthma. The goal was to extend previous research showing that alexithymia may
      complicate treatment of asthma. METHODS: Seventy-four participants with asthma
      completed the Toronto Alexithymia Scale (TAS), Asthma Symptom Checklist (ASC),
      Taylor Manifest Anxiety Scale (TMAS), and spirometry testing. RESULTS: The
      "Difficulty identifying feelings" subscale (IDE) of the TAS was associated with
      increased report of emotional symptoms (panic-fear) as well as physical symptoms
      (fatigue) during the past week, but not pulmonary function on the day of testing.
      This relationship appeared to be influenced by trait anxiety. The "Difficulty
      communicating feelings" subscale (COM) was correlated with decreased pulmonary
      function, but not report of emotional or physical sensations experienced during
      the prior week. The "Externally oriented thinking" subscale (EOT) was not related
      to any of the dependent measures. CONCLUSION: These data suggest that alexithymia
      may complicate optimal management of asthma and this relationship is best studied
      by examining the subscales of the TAS separately.

PMID- 12479986
TI  - Prevalence of anxiety in adults with diabetes: a systematic review.
AB  - BACKGROUND: Anxiety is associated with decreased functioning and quality of life.
      It may have added importance in diabetes for its potential adverse effects on
      regimen adherence and glycemic control. OBJECTIVE: To estimate the prevalence of
      clinically significant anxiety in adults with diabetes. RESEARCH DESIGN AND
      METHODS: MEDLINE and PsycINFO databases and published reference lists were
      searched to identify studies that determined the prevalence of anxiety in
      diabetes from threshold scores on self-report measures or from diagnostic
      interviews. Prevalence was calculated as an aggregate mean weighted by the
      combined number of subjects in the included studies. RESULTS: Eighteen studies
      having a combined population (N) of 4076 (2584 diabetic subjects, 1492 controls)
      satisfied the inclusion criteria. Most did not adjust for the effects of
      moderator variables such as gender, and only one was community-based. Generalized
      anxiety disorder (GAD) was present in 14% of patients with diabetes. The
      subsyndromal presentation of anxiety disorder not otherwise specified and of
      elevated anxiety symptoms were found in 27% and 40%, respectively, of patients
      with diabetes. The prevalence of elevated symptoms was significantly higher in
      women compared to men (55.3% vs. 32.9%, P<.0001) and similar in patients with
      Type 1 vs. Type 2 diabetes (41.3% vs. 42.2%, P=.80). CONCLUSION: GAD is present
      in 14% and elevated symptoms of anxiety in 40% of patients with diabetes who
      participate in clinical studies. Additional epidemiological studies are needed to
      determine the prevalence of anxiety in the broader population of persons with
      diabetes.

PMID- 12479987
TI  - Ways of coping with asthma in everyday life: validation of the Asthma Specific
      Coping Scale.
AB  - OBJECTIVE: This study examines the validity of the Asthma Specific Coping Scale.
      METHODS: Study samples were comprised of persons with drug-treated asthma
      (n=3464) drawn from the Drug Reimbursement Registry and asthma rehabilitation
      participants [brief (n=278) and comprehensive (n=316) intervention]. Data were
      collected by questionnaires. RESULTS: The expected structure of the six subscales
      (restricted lifestyle, hiding asthma, positive reappraisal, information seeking,
      ignoring asthma, and asthma worry) was supported. The Cronbach's alpha
      reliabilities of the subscales ranged from .63 to .84. Concurrent validity was
      supported by meaningful correlations between asthma coping scales and
      psychosocial resources, health-related quality of life, and general coping. The
      asthma coping scales discriminated between the intervention participants and the
      population-based sample. Four out of six subscales also showed sensitivity to
      change after rehabilitation. CONCLUSION: Though further longitudinal studies are
      needed, this scale seems to be a promising instrument to be used in surveys and
      outcome studies.

PMID- 12479988
TI  - Effect of asthma in childhood on psycho-social problems in the family.
AB  - OBJECTIVE: The responsibility for treating children with asthma has gradually
      shifted from the medical health service to the family and parents, which may
      cause new psycho-social problems in the family. This study aimed at describing
      the psycho-social effects on families having a child with asthma, and at
      determining whether a relation exists between the medical severity of disease and
      psycho-social problems. METHODS: The findings are based on a questionnaire with
      the following domains: economy, work, free time, health, environment, and family,
      as well as a health-related medical questionnaire. They are built on psycho
      social problems and on medical records. RESULTS: The frequency of psycho-social
      problems was high regarding single questions in the evaluated psycho-social
      domains. A relation was found between high drug consumption and severe psycho
      social problems. However, no positive correlation was detected among visits at
      the hospital's emergency department, absence from school due to asthma or
      disturbed sleep, and psycho-social problems. On the contrary, a negative
      correlation was found between absence from school due to asthma and psycho-social
      problems. CONCLUSION: We conclude that for single questions in each psycho-social
      domain, the problem rate is high, but when taking into account the mean value of
      different psycho-social problems in each domain, the reported problem rate is
      fairly low. This method permits selection of the psycho-social domains with the
      most severe problems in each family. It can, therefore, be used to direct help
      from the medical service. We also found a relation between the medical severity
      of asthma and the extent of the psycho-social problems caused by the disease.

PMID- 12479989
TI  - Distinct biopsychosocial profiles emerge among nonpatients.
AB  - OBJECTIVES: The cross-sectional study comprised 30- to 55-year-old permanent
      employees (N=1784) of the Finnish Broadcasting Company (YLE). METHODS: The
      participants (N=1339, response rate 75%) completed standardised questionnaires
      covering demographic items, physical health, work performance, stress symptoms,
      pain and musculoskeletal symptoms, and overall biopsychosocial health. RESULTS:
      Physical symptoms (present often or continually) were reported by 15%,
      psychosomatic by 19% and psychosocial by 14%. The intercorrelations between 73
      biopsychosocial variables revealed nine factors explaining 54.5% of variance for
      intrapersonal profiles and four factors explaining 59.2% of variance for
      interpersonal profiles. The Cronbach alphas for reliability ranged from.76 to.83.
      Three distinct biopsychosocial cluster profiles were found: Cluster 1 (n=290,
      27%) loaded positively with the somatic and psychosocial variables, Cluster 2
      (n=558, 51%) loaded negatively with the various biopsychosocial symptoms, and
      Cluster 3 (n=235, 22%) loaded positively with anxiety. CONCLUSION: Discriminant
      function analysis confirmed that this cluster solution correctly classified 95.2%
      of the subjects in a nonpatient multiprofessional population, which supports the
      biopsychosocial approach also in work life issues.

PMID- 12479990
TI  - The assessment of alexithymia: a critical review of the literature and a
      psychometric study of the Toronto Alexithymia Scale-20.
AB  - OBJECTIVE: The objectives were to give an overview of studies on the validity of
      the Toronto Alexithymia Scale (TAS-20) and to present data regarding the validity
      of the TAS-20. METHODS: The literature on the psychometric properties of the TAS
      20 was reviewed and a study was conducted of its psychometric properties in a
      sample of students and a sample of psychiatric outpatients using a statistical
      method allowing identification of a stable factor structure. RESULTS: The review
      revealed that the majority of studies on the TAS-20 were conducted with
      nonpatient samples. The factorial validity and reliability of the dimensions
      'identifying feelings' (DIF) and 'describing feelings' (DDF) could be replicated
      in many of these studies. However, in practically all studies the dimension
      'externally oriented thinking' (EOT) appears to be unreliable. In addition, the
      presupposed fantasy aspect of the alexithymia construct is not included in the
      TAS-20. Although many studies were conducted on the construct validity of the TAS
      20, no studies have been published on its criterion validity. Some studies show a
      different factor structure to exist in patient samples. This was confirmed in our
      own study in which the dimensions 'identifying feelings' and 'describing
      feelings' collapsed into one single subscale. As in other studies, the
      reliability of the dimension 'EOT' was low. CONCLUSION: The TAS-20 has some
      important shortcomings with respect to validity and reliability. For the
      assessment of alexithymia in empirical research, it is recommended to use the TAS
      20 in combination with other instruments. We do not recommend the TAS-20 to be
      used in clinical practice.

PMID- 12479991
TI  - Are polysomnographic measures of sleep correlated to alexithymia? A study on
      laboratory-adapted sleepers.
AB  - OBJECTIVE: Since recent findings have pointed to a correlation between
      alexithymia and measures of poor sleep quality during the first night of
      adaptation to a sleep laboratory, the aim of the current study was to assess the
      same relation in healthy laboratory-adapted sleepers. As a further measure of
      rapid eye movement (REM) sleep characteristics, REM density was also measured.
      METHODS: Twenty-seven male subjects, without sleep or psychiatric disorders,
      filled out the 20-item Toronto Alexithymia Scale (TAS-20) and slept for two
      consecutive undisturbed nights. Polysomnography and REM density were measured in
      the postadaptation night. RESULTS: Alexithymia scores did not correlate
      significantly with any polysomnographic variable or with REM density. Only the
      Externally Oriented Thinking (EOT) subscale showed a negative association with
      REM latency. Multiple regression on selected sleep measures as predictors
      confirmed these results. CONCLUSION: Results do not extend to normal sleep the
      association previously found between alexithymia and a poor quality of sleep
      during the adaptation night in the sleep laboratory. The only polysomnographic
      measure showing an association, albeit little, with one facet of alexithymia was
      REM latency.

PMID- 12479992
TI  - Psychological correlates of functional status in chronic fatigue syndrome.
AB  - BACKGROUND: The present study was designed to test a cognitive model of
      impairment in chronic fatigue syndrome (CFS) in which disability is a function of
      severity of fatigue and depressive symptoms, generalized somatic symptom
      attributions and generalized illness worry. METHODS: We compared 45 CFS and 40
      multiple sclerosis (MS) outpatients on measures of functional ability, fatigue
      severity, depressive symptoms, somatic symptom attribution and illness worry.
      RESULTS: The results confirmed previous findings of lower levels of functional
      status and greater fatigue among CFS patients compared to a group of patients
      with MS. Fatigue severity was found to be a significant predictor of physical
      functioning but not of psychosocial functioning in both groups. In CFS, when
      level of fatigue was controlled, making more somatic attributions was associated
      with worse physical functioning, and both illness worry and depressive symptoms
      were associated with worse psychosocial functioning. CONCLUSIONS: Our findings
      support the role of depression and illness cognitions in disability in CFS
      sufferers. Different cognitive factors account for physical and psychosocial
      disability in CFS and MS. The SF-36 may be sensitive to symptom attributions,
      suggesting caution in its interpretation when used with patients with ill-defined
      medical conditions.

PMID- 12479993
TI  - Cognitive-behavioral therapy of pediatric headache: are there differences in
      efficacy between a therapist-administered group training and a self-help format?
AB  - OBJECTIVE: The efficacy of cognitive-behavioral training in a therapist
      administered group format (TG) and a self-help format (SH) for children with
      recurrent headache was compared. METHODS: A total of 77 children (10-14 years)
      were randomly assigned to TG (n=29), SH (n=27) and a waiting-list control group
      (WC; n=19). TG consisted of eight 90-min sessions with groups of five children.
      SH was conducted via a written manual in which instructions were given and
      homework tasks were assigned. In both training formats, the topics covered were
      identical (e.g., self-monitoring of headache, trigger analysis, relaxation,
      etc.). Main outcome variables related to changes in headache intensity, duration
      and frequency as assessed with a diary prior to and following training, as well
      as at 6-month follow-up. RESULTS: Children reported a high degree of satisfaction
      with the training. No significant differences between the two conditions were
      found. Differences between treatment groups and WC were statistically
      corroborated for two headache variables. In both treatments, headache decreased
      markedly from posttraining to follow-up, with 68-76% of children reporting
      clinically significant improvement. No differential effects of age, gender or
      headache diagnosis were found. Changes in self-concept and ability to cope with
      stress after training point to further positive effects of the intervention.
      CONCLUSION: The efficiency of the two training formats is nearly identical. The
      group format, because of its better acceptance, is recommended for practical use.

PMID- 12479994
TI  - Perceived vulnerability to illness in individuals with irritable bowel syndrome.
AB  - OBJECTIVE: To determine whether individuals with irritable bowel syndrome (IBS)
      differ from other individuals in their perceived lifetime risk of an unrelated
      medical condition. METHOD: A questionnaire was used to assess worry about deep
      vein thrombosis (DVT) and perceived future risk of developing the condition in
      individuals with IBS and controls following a media scare concerning DVT.
      RESULTS: Individuals with IBS reported higher perceived lifetime risk of DVT than
      did healthy controls or individuals with asthma. Current physical symptoms,
      exposure to information about DVT and the illness attitudes measured could not
      entirely account for the higher perceived health risk among individuals with IBS.
      CONCLUSIONS: A perception of enhanced personal vulnerability to illness appears
      to be present in individuals with IBS, although it is possible that this
      perception is related to higher levels of negative affect amongst this group.
      Whilst a perception of enhanced vulnerability to illness is likely to contribute
      to IBS-related illness behaviour, it does not appear to be specific to reasoning
      about IBS and is also apparent when individuals consider an unrelated health
      issue.

PMID- 12479995
TI  - Early psychological adjustment in breast cancer patients: a prospective study.
AB  - OBJECTIVE: A significant proportion of breast cancer patients experiences
      psychiatric morbidity in the first year after a breast cancer diagnosis and/or
      beginning of treatment. This study attempted to identify and understand the risk
      factors for developing such problems. METHODS: A consecutive series of 87
      patients, aged 40-75 years, was assessed prior to diagnosis of breast cancer and
      followed-up approximately 8 weeks after beginning of cancer treatment and again 9
      months after first follow-up. Assessments included measures of psychiatric
      morbidity using the General Health Questionnaire (GHQ-12), coping style using the
      Mental Adjustment to Cancer (MAC) Scale, symptom attribution, beliefs about
      breast cancer, social support, socio-demographic and clinical variables. RESULTS:
      A total of 85.1% of patients completed both follow-ups. Pre-diagnostically, 32.2%
      of breast cancer patients scored as a GHQ-12 'case.' GHQ scores fell
      significantly between pre-diagnostic and both post-diagnostic assessments,
      especially in women who had thought they had cancer. Predictors of psychological
      morbidity at first follow-up included pre-diagnostic GHQ-12 score, lack of social
      support and feelings of 'personal responsibility/avoidance.' GHQ-12 'caseness' at
      second follow-up was predicted by lack of social support alone. CONCLUSIONS:
      Overall, psychiatric morbidity is higher prior to, than following, a definitive
      diagnosis of breast cancer. Early reactions of this kind are predictive of post
      treatment adjustment. However, only the presence of social support in this study
      seems to be associated with successful adjustment in the first year following a
      breast cancer diagnosis. Women at increased risk of psychological morbidity after
      a breast cancer diagnosis may be thus identifiable and targeted therapeutically.

PMID- 12479996
TI  - The effect of hypnotic-guided imagery on psychological well-being and immune
      function in patients with prior breast cancer.
AB  - OBJECTIVE: To determine the effect of hypnotic-guided imagery on immune function
      and psychological parameters in patients being treated for Stage I or II breast
      cancer. METHODS: To determine the effects of hypnotic-guided imagery on immune
      function and psychological parameters, the following study was undertaken.
      Psychological profiles, natural killer (NK) cell number and activity were
      measured at baseline, after the 8-week imagery training program and at the 3
      month follow-up. RESULTS: There were significant increases in improvement in
      depression (P<.04) and increase in absolute number of NK cells, but these were
      not maintained at the 3-month follow-up. Hypnotic-guided imagery did cause some
      transient changes in psychological well-being and immune parameters. However,
      these changes were not retained after the treatment ended. CONCLUSIONS: Many
      studies during the last 15 years have demonstrated interactions between the
      central nervous and the immune systems. While a negative effect of stress on
      immune responses has been demonstrated, there have also been published reports
      that psychological treatments can positively alter the immune system. However,
      given the complexities of immune system kinetics, the transient nature of any
      psychological effect and the insensitivity of immune assays, our study indicates
      that there is a role for hypnotic-guided imagery as an adjuvant therapy.

PMID- 12479997
TI  - Marital status and eating disorders: an analysis of its relevance.
AB  - OBJECTIVES: This study attempts to understand the clinical impact of marital
      status on the psychopathology and symptomatology of anorexia (AN) and bulimia
      nervosa (BN) patients. METHOD: Eating disorder (ED) patients (n=332, 198 BN and
      134 AN) consecutively admitted to our unit participated in the study. All
      subjects met DSM-IV criteria for those pathologies and were female. Our sample
      was divided retrospectively into three subgroups based on their marital status.
      For the assessment, commonly applied questionnaires in the field of ED were used
      [Eating Attitudes Test (EAT-40), Eating Disorder Inventory (EDI), Bulimic
      Investigatory Test Edinburgh (BITE), Body Shape Questionnaire (BSQ), Beck
      Depression Inventory (BDI) and Social Avoidance and Distress Scale (SAD)].
      RESULTS: 2 x 3 (Diagnostic x Marital status) ANOVA and ANCOVA (with age as
      covariance) designs were applied in the current study. Our results suggested that
      ED patients who lived with a partner were significantly different with respect to
      the other ED patients in the following variables: higher age (P<.0001), higher
      motivation for change (P<.004), perfectionism (P<.03) and purging behavior
      (P<.04). DISCUSSION: The main finding in this study is that ED patients who live
      with a partner are those who presented greater eating symptomatology and
      psychopathology but even higher motivation for change. Interpersonal
      functionality has to be considered in the development and maintenance of ED.

PMID- 12479998
TI  - Distress of infertile males after fertility workup: a longitudinal study.
AB  - OBJECTIVE: Former research has revealed that distress declines after fertility
      workup. It was the aim of the present study to explore whether this decline
      depends on such aspects as the diagnosis or the former usage of fertility
      services. METHODS: Patients attending an andrological clinic filled out
      questionnaires on distress and coping behaviour at clinic attendance as well as 4
      months later. RESULTS: For distress scores there was an interaction between time
      and former usage of infertility services, indicating that only first-time
      consulters show a decline in distress after fertility workup. No impact of
      diagnosis on distress scores could be detected. Generally, patients showed a
      decrease of active coping behaviour after fertility workup, along with a greater
      tendency to accept infertility as one's fate. CONCLUSION: The findings indicate
      that there are different processes working in first-time and repeat consulters
      with respect to the course of distress.

PMID- 12479999
TI  - Chronic stress in nonelderly caregivers: psychological, endocrine and immune
      implications.
AB  - OBJECTIVE: This investigation examined whether the immune dysregulation that
      characterises elderly informal caregivers (e.g., spousal caregivers of dementia
      patients) extends to a younger caregiver population, specifically spousal carers
      of patients with multiple sclerosis (MS). METHOD: MS spousal caregivers (n=41,
      mean age 43 years, 14 women, 27 men) and noncaregiving controls (n=62, mean age
      33 years, 44 women, 18 men) were recruited. Psychological morbidity (i.e., self
      reported stress, anxiety and depression), endocrine activity (i.e., salivary
      cortisol and DHEAs) and immunity (i.e., IgG and HAI responses to influenza
      vaccination and IFN-gamma and IL-4 levels) were assessed. RESULTS AND
      CONCLUSIONS: MS caregivers and noncaregivers did not differ significantly in
      their IgG or HAI responses to influenza vaccination or in levels of IFN-gamma and
      IL-4. However, it remains unclear whether the "preserved" immune response of
      these younger caregivers was due to (1) an absence of immune senescence, (2) a
      relative absence of psychological morbidity, or both.

PMID- 12480000
TI  - Common mental disorder and physical illness in the Renfrew and Paisley (MIDSPAN)
      study.
AB  - OBJECTIVE AND METHODS: The relationship between psychological distress measured
      by the General Health Questionnaire 30 (GHQ-30) and risk factors for coronary
      heart disease, angina, electrocardiogram (ECG) abnormalities and chronic sputum
      was modelled using logistic regression on baseline data from a community study of
      15,406 men and women. RESULTS: Psychological distress was associated with low
      forced expiratory volume (FEV(1)) and low body mass index (BMI) in men, and low
      systolic blood pressure only in women. There were associations between
      psychological distress and coronary heart disease and cardiorespiratory outcomes.
      The associations were particularly strong for angina without ECG abnormalities
      (Men: OR 3.26, 95% CI 2.52-4.21; Women: OR 2.89, 95% CI 2.35-3.55) and for angina
      with ECG abnormalities (Men: OR 2.68, 95% CI 2.03-4.52; Women: OR 2.88, 95% CI
      1.89-4.39), in both men and women, even after adjusting for classical CHD and
      cardiorespiratory risk factors. An association between psychological distress and
      severe chest pain, indicative of previous myocardial infarction, was found in
      both men and women (Men: OR 1.89, 95% CI 1.44-2.47; Women: OR 1.91, 95% CI 1.48
      2.47), respectively, and between psychological distress and ECG ischaemia, but in
      men only (OR 1.32, 95% CI 1.00-1.76). CONCLUSION: The association between
      psychological distress and cardiorespiratory outcomes is likely to be a
      consequence of the pain and discomfort of the symptoms of the illness. Chest pain
      may also be a symptom of psychological distress. However, psychological distress,
      as a predictor and possible risk factor increasing the risk of coronary heart
      disease, cannot be ruled out.

PMID- 12480001
TI  - The role of personality variables and social support in distress and perceived
      health in patients following myocardial infarction.
AB  - OBJECTIVES: (1) To investigate whether patients with low versus high social
      support and satisfaction with support report less distress and health complaints
      following a first myocardial infarction (MI). (2) To examine whether personality
      traits mediate social support and its effect on distress and health complaints.
      METHODS: A questionnaire was distributed to 112 consecutive patients with a first
      MI 4-6 weeks postinfarction. Objective clinical measures were obtained from the
      patients' medical records. RESULTS: Patients with low social support were at
      increased risk of depression and posttraumatic stress disorder (PTSD). Patients
      less satisfied with support were at increased risk of anxiety, depression, PTSD,
      and reported more health complaints. Generally, larger effect sizes were found
      for satisfaction with support compared with social support per se in relation to
      distress and health complaints. Neuroticism was identified as an independent
      predictor of all types of distress and health complaints when including both
      traits and social support variables in multivariable analyses, adjusted for
      demographic and clinical variables. Satisfaction with support only remained an
      independent predictor of depression. CONCLUSION: These results suggest that
      personality traits may mediate social support and its effect on distress and
      health complaints. Hence, it may be important to include personality variables
      when investigating social support in relation to distress and health. In clinical
      practice, screening for particular personality traits could identify patients at
      risk of distress and recurrent cardiac events.

PMID- 12480002
TI  - Treatment needs of patients admitted for acute chest pain.
AB  - OBJECTIVE: To examine the characteristics, subsequent resource use and outcome of
      a consecutive cohort of admissions with acute chest pain not due to myocardial
      infarction. METHODS: Subjects (N=356) identified in the course of a
      epidemiological study of myocardial infarction were interviewed and completed
      HAD, SF-36 and other self-report information in hospital and at 3 months and 1
      year. Hospital casenotes were reviewed at 1 year. RESULTS: A total of 218
      subjects were given cardiac diagnoses and 138 noncardiac diagnoses. Cardiac
      subjects were more distressed and disabled and used more resources. Those in the
      noncardiac group reported distress and disability and resource use comparable to
      infarct admissions. CONCLUSION: Awareness of psychosocial variables would aid in
      the assessment and management of those with and without ischaemic heart disease.

PMID- 12480007
TI  - Antibiotics after rattlesnake envenomation.
AB  - To record the outcome, with regard to infection rate, of patients with
      rattlesnake bites (RSBs) who do not receive prophylactic antibiotics, a
      prospective observational study was performed of patients with RSBs treated at
      our institution during a consecutive 18-month period. The inclusion criteria were
      RSBs <24 h old and completion of follow-up (telephone call, mail reply, medical
      toxicologist, or private physician examination) 7-10 days following envenomation.
      Fifty-six consecutive patients (Median age: 32.8 years [range 4-67 years]) were
      enrolled. One patient was excluded because of presentation 38 h after
      envenomation and two patients failed to complete the required follow-up. One
      patient received a dose of antibiotics before transfer. Antibiotics were
      discontinued upon arrival. Of the total 56 RSB patients, 34 (61%) RSBs involved
      the upper extremity and 22 (39%) involved the lower extremity. Six patients (11%)
      applied ice and two (4%) used a tourniquet before evaluation. The mean arrival
      time was 2.7 h (Range <1-24 h). Forty-three patients (81%) received antivenin.
      Fifty-three patients (100%) had extremity swelling and 38 patients (72%) had
      tender proximal lymph nodes. Of the 53 patients who completed the study, 3 (6%)
      received antibiotics from their primary care physicians at 7-10 day follow-up,
      with no cases (0%) of documented infection. Prophylactic antibiotics are not
      indicated in patients with rattlesnake bites.

PMID- 12480008
TI  - Respiratory compromise in patients with rattlesnake envenomation.
AB  - Respiratory compromise after rattlesnake envenomation (RSE) is an uncommon yet
      potentially lethal complication. We were interested in determining the frequency
      of respiratory compromise in patients treated for RSE. The incidence and
      indications for intubation were also determined. A retrospective chart review was
      conducted of all patients treated by medical toxicologists at a tertiary referral
      hospital between July, 1994 and November, 2000. Out of 294 total patients, 289
      charts were reviewed. Of all 289 patients, 214 (74%) received Crotalidae
      Polyvalent Antivenin (Wyeth-Ayerst) and 23 (8%) had clinical evidence of
      respiratory compromise. Thirteen of 289 patients (4.4%) were intubated following
      RSE. No one was intubated for antivenin-induced complications. There were no
      deaths among studied patients during acute hospitalization. Respiratory
      compromise following RSE is rare, occurring in only 8% of studied patients. Only
      2 patients (0.7%) required intubation as a direct consequence of RSE. No one
      required intubation for antivenin-induced hypersensitivity reactions.

PMID- 12480009
TI  - Is single observer identification of wound infection a reliable endpoint?
AB  - The majority of wound studies over the past 20 years have relied on single
      observer determination of infection presence or absence as a study endpoint.
      Nevertheless, there are few data on the reliability of those determinations. If
      single observer determinations are not reliable, the validity of studies using
      this endpoint should be questioned. Two physicians independently evaluated wounds
      for presence or absence of the primary endpoint of infection and the secondary
      endpoints of purulence, tenderness, warmth, and erythema. Kappa values were
      calculated as measures of inter-observer agreement, which was used as a measure
      of reliability. Of 125 patients enrolled, 115 wounds were available for analysis.
      Kappa =.57 [95%CI.39 to.75] for the primary endpoint of infection,.84 for
      purulence,.72 for tenderness,.48 for warmth, and.48 for erythema. Agreement on
      two features of infection and overall agreement on the presence or absence of
      wound infection was only 'moderate.' Single observer determination of wound
      infection by inexperienced observers using imprecise definitions, though commonly
      used, is an unreliable measure for scientific study.

PMID- 12480010
TI  - Toomey syringe aspiration may be inaccurate in detecting esophageal intubation
      after gastric insufflation.
AB  - We sought to determine whether gastric distention from air insufflation affects
      the accuracy of the Toomey syringe in detecting esophageal intubation. We
      conducted a randomized, single-blinded, crossover trial using human cadavers in
      which cuffed endotracheal (ET) tubes were placed into the esophagus and trachea.
      Operators used the Toomey syringe to determine the location of the ET tube before
      and after gastric insufflation via Ambu-bag ventilation. Greater amounts of air
      were aspirated (35.4 cc vs. 13.7 cc, respectively, p < 0.001) and less resistance
      was noted on a five-point scale (3.2 vs. 4.8, respectively, p < 0.001) from
      esophageally placed ET tubes after gastric insufflation. Sensitivity in detecting
      esophageally placed ET tubes decreased from 100% in noninsufflated cadavers to
      only 58% after gastric insufflation (p < 0.001). In the thawed fresh frozen
      cadaveric model, the Toomey syringe was unreliable in detecting an esophageal
      intubation after gastric distention insufflation.

PMID- 12480011
TI  - Child abuse and neglect presentations to a pediatric emergency department.
AB  - This study describes the epidemiology of reported abuse (physical, sexual, and
      neglect) in a teaching, metropolitan Pediatric Emergency Department (PED) with
      approximately 30,000 annual visits. A retrospective chart review was conducted of
      all cases from the PED that were referred to the Department of Social Work and
      reported to the Administration for Children's Services (ACS), the New York
      children's protective services, from May 1996 through December 1998. Demographic
      information about the victims as well as past medical history, number of previous
      PED visits, information about the perpetrator and the nature of the injuries were
      obtained. We identified 106 cases over this period of time that were reported for
      child abuse or neglect from the PED. Fifty-five percent of cases were reported
      for suspected physical abuse, 15% for sexual abuse, and 30% for neglect. The
      suspected perpetrator was the mother in 41% of cases and the father in 21% of
      cases. Bruises were the most frequent injury reported, seen in 25% of cases. The
      mean age of the patients was 6.4 years old. They averaged 4.6 previous PED
      visits. The majority of patients lived near the hospital. Sixty-nine percent of
      the patients presented for care between the hours of 5 PM and 9 AM. Most of the
      patients claimed their primary physician was located in a clinic near their home
      (44%). Only 12.7% were unsure of their primary physician. Significantly more
      victims (89%) had Medicaid or no insurance compared with other PED patients
      (71%). Victims did not live in zip codes with lower incomes compared with other
      PED patients. Upon complete investigation by ACS, 49 cases (46%) were deemed
      'indicated,' 21 cases (20%) 'unfounded,' and for the remaining 36 cases (34%)
      follow-up information could not be determined. The incidence of reported abuse
      and neglect was lower than previous studies have shown. The majority of reported
      cases (especially those of sexual abuse) did not have any physical findings at
      the time of presentation, stressing the need of a careful search for both abuse
      and neglect.

PMID- 12480012
TI  - The Cubital Tunnel syndrome: a case report and discussion.
AB  - Cubital Tunnel Syndrome is the second most common peripheral neuropathy of the
      upper extremity. It presents as elbow, forearm, or hand pain in the ulnar nerve
      sensory distribution and it is the result of overuse, trauma, or entrapment of
      the ulnar nerve at the elbow. Proper physical diagnosis can localize the site of
      ulnar nerve entrapment to the elbow or wrist. Both conservative and operative
      modalities exist to treat the Cubital Tunnel Syndrome; optimal management is
      still unclear.

PMID- 12480013
TI  - Diplopia in a patient with carcinomatous meningitis: a case report and review of
      the literature.
AB  - In a patient with a history of malignancy, an isolated neurologic sign or symptom
      may indicate metastasis to the central nervous system. To exclude this
      possibility, a lumbar puncture should still be performed after a nondiagnostic
      cranial computed tomography (CT) scan even in the absence of signs of infection.
      A case is presented of a 59 year-old man recently diagnosed with non-Hodgkin's
      lymphoma that presented to the Emergency Department (ED) with the sole complaint
      of diplopia. Examination was unremarkable except for a left abducens nerve palsy.
      Cranial CT scan was normal but initial cerebrospinal fluid results were
      suggestive of carcinomatous meningitis, and cytology results later confirmed this
      diagnosis. A review of diplopia and carcinomatous meningitis is presented, along
      with a suggested conservative diagnostic algorithm for cancer patients presenting
      with neurologic signs or symptoms.

PMID- 12480014
TI  - Simultaneous open and closed dislocations of adjacent metacarpophalangeal joints:
      a case report.
AB  - Metacarpophalangeal joint (MCP) dislocations are uncommon, and when open are
      often complex, requiring surgical intervention for reduction. A 38-year-old man
      presented to the Emergency Department (ED) with simultaneous open and closed
      dorsal dislocations of adjacent MCP joints of the index and long fingers that
      were successfully treated by closed reduction in the ED. Injuries to the MCP
      joint can severely affect hand function when treatment is delayed and, thus, it
      is an accepted principle that definitive treatment should be achieved as quickly
      as possible for optimal functional outcome. In the case of dorsal dislocations of
      the MCP joints, aggressive ED intervention followed by brief immobilization and
      early hand therapy referral may result in dramatic clinical improvement for the
      patient without the need for surgery.

PMID- 12480015
TI  - Broncholithiasis: a case report.
AB  - A case is reported of broncholithiasis in a 29-year-old female factory worker
      presenting with cough and lithoptysis. Broncholithiasis is a rare disorder
      characterized by calcified perihilar and mediastinal lymph nodes eroding into the
      tracheobronchial tree. Although cough, hemoptysis, lithoptysis, pneumonia and
      bronchoesophageal fistula formation have been reported, broncholithiasis may also
      result in potentially life-threatening conditions such as airway obstruction from
      endobronchial polypoid granulation masses, and massive hemorrhage from an aorto
      tracheal fistula or erosion of a pulmonary artery branch.

PMID- 12480016
TI  - First place winner. Recurrent febrile seizures: an unusual presentation of
      nutritional rickets.
AB  - Nutritional rickets is a serious disease that is infrequently encountered in the
      United States today because of the fortification of infant formulas and dairy
      products with vitamin D. We report a case of undiagnosed nutritional rickets
      presenting with recurrent febrile seizures. Febrile seizures, a common and
      usually benign presenting complaint, are not among the symptoms generally known
      to be associated with rickets. Therefore, the disease was uncovered only after a
      careful history and physical examination prompted a more thorough investigation
      into an underlying cause for recurrent seizures. The diagnosis was subsequently
      confirmed by quantitative laboratory testing. We review the historical and
      cultural factors, symptoms, and physical findings suggestive of this potentially
      serious yet easily treatable disease.

PMID- 12480017
TI  - Second place winner. Absorption of topical ophthalmic medications presenting as
      lethargy and apnea in an infant.
AB  - The case of a previously healthy 3-week-old infant with lethargy and apnea
      resulting from topical absorption of ophthalmic antiglaucoma medications is
      described. This case illustrates the importance of including topical drugs in
      medication histories and considering them as potential causes of systemic
      toxicity. It also emphasizes the high level of vigilance that is needed in
      monitoring infants and small children when prescribing concentrated topical
      medications that are usually given to adults.

PMID- 12480018
TI  - Third place winner. Three-year-old female with intermittent ovarian torsion.
AB  - We report an atypical case of ovarian torsion, an uncommon cause of abdominal
      pain in a very young girl. She presented with intermittent episodes of groin and
      thigh pain over a 10-week period. The child had minimal objective findings at the
      time of each evaluation. Despite the delay in diagnosis, the ovary was preserved.
      Despite its rarity, ovarian torsion must be considered in the differential
      diagnosis of abdominal pain in young girls.

PMID- 12480019
TI  - Lionfish envenomation.
AB  - Lionfish (Pterois volitans) are venomous fish most often found as aquarium pets
      throughout the United States. Lionfish envenomations frequently occur on the
      upper extremities, with pain as the predominant symptom. Immersing the injured
      part in warm (45 degrees C) water is considered the first and foremost important
      treatment as it is reported to relieve pain and inactivate the venom. Other
      methods of analgesia are discussed. We present a case of lionfish envenomation
      that failed to respond to warm water immersion.

PMID- 12480020
TI  - The surgical abdomen associated with cocaine abuse.
AB  - Cocaine use is common and is associated with gastrointestinal complications that
      can present as a surgical abdomen. We report a case of a previously healthy 25
      year-old man who presented to the Emergency Department with severe abdominal pain
      and vomiting after using IV cocaine. Exploratory celiotomy revealed massive free
      intraperitoneal (IP) clotted blood with no evidence of underlying pathology. This
      unusual case underscores the possibility of life-threatening hemorrhage in
      cocaine consumers.

PMID- 12480021
TI  - Computed tomography diagnosis of facet dislocations: the "hamburger bun" and
      "reverse hamburger bun" signs.
AB  - Unilateral or bilateral facet dislocations are difficult to diagnose. Computed
      tomography (CT) is being used more extensively to screen patients with suspected
      cervical vertebral injury. We describe two new signs, the "hamburger bun" sign of
      normal facet joints and the "reverse hamburger bun" sign that should be useful in
      establishing a diagnosis of facet dislocation. Normal facet joints are oriented
      on a CT examination so that they resemble the sides of a hamburger bun. Facet
      dislocations upset this relationship and reverse the orientation of the "bun"
      halves to each other.

PMID- 12480022
TI  - Serum phosphate abnormalities in the emergency department.
AB  - Abnormalities in serum phosphate levels are more prevalent in certain subsets of
      Emergency Department patients than in the general population. Patients with
      diabetic ketoacidosis, chronic obstructive pulmonary disease, alcoholism,
      malignancy, and renal failure are at increased risk. Multiple factors, including
      nutritional intake, medications, renal or intestinal excretion, and cellular
      redistribution, are potential etiologies. The clinical manifestations of mild
      hypophosphatemia or hyperphosphatemia are typically minor and nonspecific
      (myalgias, weakness, anorexia). When the imbalance is severe, critical
      complications may occur (tetany, seizures, coma, rhabdomyolysis, respiratory
      failure, ventricular tachycardia). Mild asymptomatic hypophosphatemia can be
      treated with oral phosphate supplementation (15 mg/kg daily) on an outpatient
      basis. Patients with severe or symptomatic hypophosphatemia should be treated
      with IV phosphate therapy (0.08-0.16 mg/kg over 6 h) and admitted for monitoring
      and subsequent serum electrolyte testing. Mild asymptomatic hyperphosphatemia is
      commonly managed in renal failure by limiting dietary intake and reducing
      absorption with phosphate-binding salts. Hemodialysis may be required for severe
      hyperphosphatemia with symptomatic hypocalcemia.

PMID- 12480023
TI  - Change in mental status.

PMID- 12480024
TI  - Two cases of too elevated beta-HCG.

PMID- 12480025
TI  - Pericardial effusion in a patient with advanced lung cancer.

PMID- 12480026
TI  - Fournier's gangrene: an unusual presentation of sepsis.

PMID- 12480027
TI  - Jefferson fracture.

PMID- 12480028
TI  - Incidental finding of nonaccidental trauma in a patient reportedly found
      unconscious.

PMID- 12480029
TI  - Prehospital advance directives--a better way.

PMID- 12480030
TI  - Case of the day.

PMID- 12480031
TI  - Two fatal cases of infants with congenital leukemia presenting with skin lesions.

PMID- 12480032
TI  - Out-of-hospital do-not-resuscitate orders by primary care physicians.
AB  - The objective of this study was to determine the knowledge, utilization, and
      experience of primary care physicians (PCPs) with nonhospital do-not-resuscitate
      (NH-DNR) orders. An anonymous survey was sent to all PCPs in a single
      northeastern county. Up to two surveys were mailed to each PCP. Descriptive
      statistics were used to report provider responses. The main variable of interest
      was issuance of NH-DNR orders. Surveys were mailed to 820 PCPs; 348 (42%) were
      returned. Respondents had practiced an average 17 +/- 11 years, and cared for an
      average of 720 patients per month, 7 of whom were terminally ill. Seventy percent
      issued NH-DNR orders. Twenty-five percent reported resuscitation had been
      attempted for at least one patient with a NH-DNR order; 64% reported this had
      happened more than once. Of respondents who had a NH-DNR order ignored, 14% had
      instructed family members to call police, fire, or EMS following death of the
      patient. Of the PCPs who did not issue NH-DNR orders, 71% reported not caring for
      any appropriate patients, yet 41% reported caring for at least 1 terminally ill
      patient per month. Seventy-nine percent disagreed that intubation and mechanical
      ventilation were appropriate treatment for DNR patients in severe respiratory
      distress, and 71% disagreed that cardioversion was appropriate treatment for an
      unconscious DNR patient with unstable ventricular tachycardia. In conclusion, a
      majority of respondents issued NH-DNR orders and one quarter reported these
      orders had not been followed. A majority felt intubation, mechanical ventilation,
      and cardioversion should not be performed for noncardiac arrest DNR patients with
      an indication, but not in cardiac arrest.

PMID- 12480034
TI  - Clinical depression and inflammatory risk markers for coronary heart disease.
AB  - Despite mounting evidence that psychiatric depression heightens risk for cardiac
      morbidity and mortality, little is known about the mechanisms responsible for
      this association. The present study examined the relation between depression and
      the expression of inflammatory risk markers implicated in the pathogenesis of
      coronary heart disease (CHD). One hundred adults were enrolled (68% women, 48%
      Caucasian, 48% African-American, mean age 30 +/- 2 years). Fifty subjects met the
      diagnostic criteria for clinical depression; the remaining 50 were
      demographically matched controls with no history of psychiatric illness. All
      subjects were in excellent health, defined as having no acute infectious disease,
      chronic medical illness, or regular medication regimen aside from oral
      contraceptives. The depressed subjects exhibited significantly higher levels of
      the inflammatory markers C-reactive protein (3.5 +/- 0.5 vs 2.5 +/- 5 mg/L, p =
      0.04) and interleukin-6 (3.0 +/- 0.3 vs 1.9 +/- 0.2 pg/ml, p = 0.007) compared
      with control subjects. Mediational analyses aimed at identifying the pathways
      contributing to this association revealed that neither cigarette smoking nor
      subclinical infection with cytomegalovirus or Chlamydia pneumoniae had been
      responsible. However, depressed subjects exhibited greater body mass than control
      subjects, and analyses were consistent with adiposity accounting for a portion of
      the relation between clinical depression and increased expression of inflammatory
      markers. These findings indicate that in otherwise healthy adults, depression is
      associated with heightened expression of inflammatory markers implicated in the
      pathogenesis of CHD. Increased body mass appears to be partially, although not
      completely, responsible for this relation.

PMID- 12480035
TI  - Left atrial volume as a morphophysiologic expression of left ventricular
      diastolic dysfunction and relation to cardiovascular risk burden.
AB  - Left ventricular (LV) diastolic dysfunction is prevalent in the community.
      Current assessment of diastolic function can be complex, involving Doppler
      evaluation of an array of hemodynamic data. The relation between left atrial (LA)
      volume and diastolic function, and between LA volume and cardiovascular risk and
      disease burden are not well known. In the present prospective study of 140
      adults, mean age 58 +/- 19 years, referred for a clinically-indicated
      echocardiogram and in sinus rhythm, with no history of atrial arrhythmias or
      valvular heart disease, we determined the LA volume, LV diastolic function
      status, cardiovascular risk score (based on age, gender, history of systemic
      hypertension, diabetes mellitus, hyperlipidemia, and smoking), and cardiovascular
      disease burden (based on confirmed vascular disease, congestive heart failure,
      and transient ischemic attack or stroke). LA volume was found to correlate
      positively with age, body surface area, cardiovascular risk score, LV end
      diastolic and end-systolic dimensions, LV mass, diastolic function grade, tissue
      Doppler E/E', tricuspid regurgitation velocity, and negatively with LV ejection
      fraction (all p <0.006). In a multivariate clinical model, LA volume indexed to
      body surface area (indexed LA volume) was independently associated with
      cardiovascular risk score (p <0.001), congestive heart failure (p = 0.014),
      vascular disease (p = 0.012), transient ischemic attack or stroke (p = 0.021),
      and history of smoking (p = 0.008). In a clinical and echocardiographic model,
      indexed LA volume was strongly associated with diastolic function grade (p
      <0.001), independent of LV ejection fraction, age, gender, and cardiovascular
      risk score. In patients without a history of atrial arrhythmias or valvular heart
      disease, LA volume expressed the severity of diastolic dysfunction and provided
      an index of cardiovascular risk and disease burden.

PMID- 12480036
TI  - Genome scan linkage results for heart rate variability (the Framingham Heart
      Study).
AB  - There is a substantial heritable component to the beat-to-beat variation in heart
      rate. However, the molecular mechanisms underlying the control of heart rate
      variability (HRV) remain unknown. The present study sought to identify
      chromosomal regions linked to HRV phenotypes. The first 2 hours of ambulatory
      electrocardiographic recordings obtained from Framingham Heart Study subjects
      attending a routine examination were processed for HRV. HRV variables analyzed
      included very-low-frequency power, low-frequency power, and high-frequency power.
      Gender-specific residuals were used for log-transformed HRV data after adjustment
      for age, HR, systolic and diastolic blood pressures, and coffee and alcohol
      consumption. In conjunction with a 10-cM genome-wide scan, HRV data were
      available for 725 subjects in 230 extended families, including 390 sibling pairs.
      Variance component log-of-the-odds (LOD) scores were obtained. The highest
      multipoint LOD scores were obtained for log very-low frequency on chromosome 15
      at 62 cM (LOD 1.84) and for log low frequency on chromosome 2 at 153 cM (LOD
      1.81). These data suggest there may be influential genetic regions contributing
      to HRV. Further studies are warranted to identify genes in these regions that may
      influence autonomic tone. Recognition of the genetic determinants of HRV may
      provide additional insights into the pathophysiology of the autonomic nervous
      system and offer clues to its modulation.

PMID- 12480037
TI  - Acute blood pressure effects at the onset of supraventricular and ventricular
      tachycardia.
AB  - This study was designed to assess the effects of tachycardia origin, the
      significance of atrial contribution, and the effects of left ventricular ejection
      fraction on hemodynamically tolerated ventricular tachycardia (VT) and
      supraventricular tachycardia (SVT). Forty-one subjects with inducible
      hemodynamically tolerated VT (n = 24) or SVT (n = 17) with mean ages of 60 +/- 13
      and 40 +/- 16 years and mean ejection fractions of 32 +/- 15% and 59 +/- 5%,
      respectively, were studied. VT and SVT were induced by standard techniques, and
      femoral arterial blood pressure (BP) was recorded for 30 seconds. After
      tachycardia termination, with >/=3 minutes between conditions, ventricular
      overdrive pacing was performed from the right ventricular (RV) apex and then the
      RV outflow tract, followed by atrioventricular (AV) pacing at the tachycardia
      cycle length. Mean BP was measured every 5 seconds. Linear regression methods
      were used to model BP response for the 2 groups. There was a significant increase
      in BP over the 20-second interval after the induction of VT and SVT (0.55 +/-
      0.21 and 1.0 +/- 0.20 mm Hg/s, respectively, p <0.05). In patients with
      hemodynamically tolerated VT, RV apex and RV outflow tract pacing at the
      tachycardia cycle length decreased BP by 6.7 +/- 2.0 (p <0.002) and 4.7 +/- 2.5
      mm Hg (p = 0.06), respectively. AV pacing at the tachycardia cycle length did not
      improve BP compared with RV pacing alone. In patients with SVT, RV apex and RV
      outflow pacing at the tachycardia cycle length decreased BP by 5.6 +/- 2.9 (p =
      0.05) and 4.1 +/- 2.7 mm Hg (p = 0.12), respectively. However, AV pacing at the
      tachycardia cycle length was associated with improved BP response over RV pacing
      alone. Increased age and lower ejection fraction adversely influenced BP response
      in the VT group and longer cycle length, and higher preinduction BP favorably
      influenced BP response in the SVT group. The determinants of BP response after
      tachycardia onset are complex and differ in patients with SVT and VT.

PMID- 12480038
TI  - Efficacy and safety of propafenone sustained release in the prophylaxis of
      symptomatic paroxysmal atrial fibrillation (The European Rythmol/Rytmonorm Atrial
      Fibrillation Trial [ERAFT] Study).
AB  - We report a double-blind, multicenter, multinational, placebo-controlled, and
      well-controlled trial to prove that the sustained-release (SR) formulation of
      propafenone is superior to placebo in preventing symptoms of paroxysmal atrial
      fibrillation (AF). A total of 594 patients were enrolled in the qualifying period
      of the study and 293 patients were randomized at 53 centers. There were
      significant increases in the arrhythmia-free periods from day 5 of randomization
      to the first recurrence of symptomatic atrial arrhythmia in the propafenone SR
      325 mg twice daily (p = 0.004) and propafenone SR 425 mg twice daily (p = 0.003)
      treatment groups compared with placebo. The median arrhythmia-free time was 9
      days in the placebo group, 35 days in the propafenone SR 325 mg twice daily
      group, and 44 days in the propafenone SR 425 mg twice daily group. There was a
      significant reduction in average heart rate during the first recurrence of
      symptomatic arrhythmia after day 5 in the low-dose propafenone group compared
      with placebo. The median treatment failure time from day 5 (arrhythmia
      recurrence, adverse events, and withdrawals) was prolonged from 8 days in the
      placebo group to 19 days in the propafenone SR 325 mg twice daily group (p =
      0.002) and to 24 days in the propafenone SR 425 mg twice daily group (p = 0.006).
      The percentage of patients with >/=1 serious adverse event was similar in the
      propafenone SR treatment groups (propafenone SR 325 mg twice daily, 10.0%;
      propafenone SR 425 mg twice daily, 11.2%) but lower in the placebo group (1.1%).
      In conclusion, the SR formulation of propafenone is superior to placebo, well
      tolerated, and prevents symptoms of paroxysmal AF.

PMID- 12480039
TI  - Cardiac contractility modulation by electric currents applied during the
      refractory period in patients with heart failure secondary to ischemic or
      idiopathic dilated cardiomyopathy.
AB  - We assessed the feasibility of cardiac contractility modulation (CCM) by electric
      currents applied during the refractory period in patients with heart failure
      (HF). Extracellular electric currents modulating action potential and calcium
      transients have been shown to potentiate myocardial contractility in vitro and in
      animal models of chronic HF. CCM signals were biphasic square-wave pulses with
      adjustable amplitude, duration, and time delay from sensing of local electric
      activity. Signals were applied to the left ventricle through an epicardial vein
      (in 12 patients) or to the right ventricular (RV) aspect of the septum
      endocardially (in 6 patients). Simultaneous left ventricular (LV) and aortic
      pressure measurements were performed using a Millar catheter (Millar Instruments,
      Houston, Texas). Hemodynamics during RV temporary dual-chamber pacing was
      regarded as the control condition. Both LV and RV CCM stimulation increased
      dP/dt(max) to a similar degree (9.1 +/- 4.5% and 7.1 +/- 0.8%, respectively; p
      <0.01 vs controls), with associated aortic pulse pressure changes of 10.3 +/-
      7.2% and 10.8 +/- 1.1% (p <0.01 vs controls). Regional systolic wall motion
      assessed quantitatively by color kinesis echocardiography was markedly enhanced
      near the CCM electrode, and the area of increased contractility involved 4.6 +/-
      1.2 segments per patient. In 6 patients with HF with left bundle branch block,
      CCM signals delivered during biventricular pacing (BVP) produced an additional
      16.1 +/- 3.7% increase in dP/dt(max) and a 17.0 +/- 7.5% increase in pulse
      pressure compared with BVP alone (p <0.01). CCM stimulation in patients with HF
      enhanced regional and global measures of LV systolic function, regardless of the
      varied delivery chamber or whether modulation was performed during RV pacing or
      BVP.

PMID- 12480040
TI  - Meta-analysis of results from eight randomized, placebo-controlled trials on the
      effect of cilostazol on patients with intermittent claudication.
AB  - We examined the effect of cilostazol, a type III phosphodiesterase inhibitor, on
      pain-free and maximal walking distance and quality of life measures. The present
      study examined adverse effects in 2,702 patients with stable, moderate to severe
      claudication enrolled in 8 randomized, double-blind, placebo-controlled trials.
      Treatment duration ranged from 12 to 24 weeks. Cilostazol therapy increased
      maximal and pain-free walking distances by 50% and 67%, respectively. In subgroup
      analysis, cilostazol increased pain-free and maximal walking distance similarly
      in men and women, in older (>/=65 years) and younger patients, and in patients
      with and without diabetes. Quality-of-life assessments revealed enhanced scores
      for physical well-being. Cilostazol-treated patients reported a higher incidence
      of headache, bowel complaints, and palpitations than patients given placebos.
      Cilostazol decreased triglycerides by 15.8% and increased high-density
      lipoprotein cholesterol by 12.8%, but there were no deleterious effects on any
      hematologic or serum markers. We conclude that cilostazol significantly increases
      walking distance and quality-of-life measures in patients with claudication
      without major adverse effects.

PMID- 12480041
TI  - Effect of treatment on the incidence of stroke and other emboli in 519 patients
      with severe thoracic aortic plaque.
AB  - Severe aortic plaques seen on transesophageal echocardiography (TEE) are a high
      risk cause of stroke and peripheral embolization. Evidence to guide therapy is
      lacking. Retrospective information was obtained regarding the occurrence of
      embolic events (stroke, transient ischemic attacks, or peripheral emboli) in 519
      patients with severe thoracic aortic plaque seen on TEE since 1988. Treatment
      with statins, warfarin, or antiplatelet medications was noted. Treatment was not
      randomized. In a matched-paired analysis, each patient taking each class of
      therapy was matched for age, gender, previous embolic event, hypertension,
      diabetes, congestive failure, and atrial fibrillation to someone not taking that
      medication. Multivariate analysis was also performed. An embolic event occurred
      in 111 patients (21%). Multivariate analysis showed that statin use was
      independently protective against recurrent events (p = 0.0001). Matched analysis
      also showed a protective effect of statins (p = 0.0004; absolute risk reduction
      17%, relative risk reduction 59%, number needed to treat [n = 6]). No protective
      effect was found for warfarin or antiplatelet drugs. The odds ratio for embolic
      events was 0.3 (95% confidence interval [CI] 0.2 to 0.6) for statin therapy, 0.7
      (95% CI 0.4 to 1.2) for warfarin, and 1.4 (95% CI 0.8 to 2.4) for antiplatelet
      agents. Thus, there is a protective effect of statin therapy, and no significant
      benefit of warfarin or antiplatelet drugs on the incidence of stroke and other
      embolic events in patients with severe thoracic aortic plaque on TEE.

PMID- 12480042
TI  - Usefulness of B-type natriuretic peptide levels in predicting hemodynamic
      perturbations after heart transplantation despite preserved left ventricular
      systolic function.
AB  - The aim of this prospective study was to evaluate the association of peripheral B
      type natriuretic peptide (BNP) levels with clinical symptoms and central
      hemodynamic and echocardiographic measures in cardiac transplantation. BNP
      reflects ventricular wall stress and correlates with severity of heart failure.
      No previous investigation has comprehensively assessed the rapid bedside BNP
      assay for predicting hemodynamic measures of cardiac allograft function in heart
      transplantation. We evaluated BNP levels using a rapid point-of-care assay in 87
      stable cardiac transplant recipients who had 237 consecutive measurements along
      with endomyocardial biopsy, right-sided cardiac catheterization, and
      echocardiography. Using median tendencies, 2 groups were identified: the low BNP
      group (n = 116, BNP <150 pg/ml) and the high BNP group (n = 121, BNP >/=150
      pg/ml). The high BNP group had increased right atrial pressures, higher pulmonary
      artery systolic pressures, pulmonary capillary wedge pressures, and lower cardiac
      index. Besides hemodynamic variables, the presence of right ventricular
      dysfunction (p = 0.05) and significant tricuspid regurgitation (p = 0.003) were
      associated with higher BNP levels. Independent predictors of BNP levels on
      multivariate analysis included elevated pulmonary capillary wedge pressure, lower
      cardiac index, and symptoms of dyspnea and fatigue. This initial investigation
      establishes the accuracy of a point-of-care BNP assay in predicting
      cardiopulmonary hemodynamic aberrations despite preserved left ventricular
      systolic function in heart transplant recipients. Rapid bedside BNP analysis may
      provide a noninvasive surrogate method for the comprehensive assessment of
      cardiac allograft function and hemodynamics in heart transplantation.

PMID- 12480043
TI  - Justifying lipid-lowering therapy in persons >/=65 years of age.

PMID- 12480044
TI  - Atherosclerosis of the thoracic aorta: from risk stratification to treatment.

PMID- 12480045
TI  - Dean Towle Mason, MD: a conversation with the Editor. Interview by William
      Clifford Roberts.

PMID- 12480047
TI  - Role of infarct size in explaining the higher mortality in older patients with
      acute myocardial infarction.

PMID- 12480046
TI  - Relation of levels of serum lipoproteins to depression after acute myocardial
      infarction.

PMID- 12480048
TI  - Comparison of outcomes of patients with myocardial infarction when living alone
      versus those not living alone.

PMID- 12480049
TI  - Intravascular ultrasound analysis of the impact of gamma radiation therapy on the
      treatment of saphenous vein graft in-stent restenosis.

PMID- 12480050
TI  - Sustained platelet activation following intracoronary beta irradiation.

PMID- 12480051
TI  - Safety and mechanisms of intracoronary manual stepping brachytherapy as gained
      from serial angiographic and intravascular ultrasound studies.

PMID- 12480052
TI  - Effects of gemfibrozil conversion to fenofibrate on lipids in patients on statin
      therapy.

PMID- 12480053
TI  - Long-term prognostic significance of isolated minor electrocardiographic T-wave
      abnormalities in middle-aged men free of clinical cardiovascular disease (The
      Multiple Risk Factor Intervention Trial [MRFIT]).

PMID- 12480054
TI  - Serum lipid levels in a major league baseball team.

PMID- 12480055
TI  - Effectiveness and safety of long-term anticoagulation of patients >/=90 years of
      age with atrial fibrillation.

PMID- 12480056
TI  - Comparison of usefulness of systolic, diastolic, and mean blood pressure and
      pulse pressure as predictors of cardiovascular death in patients >/=60 years of
      age (The Dubbo Study).

PMID- 12480057
TI  - Effect of congestive heart failure on the insulin-like growth factor-1 system.

PMID- 12480058
TI  - Type of liver dysfunction in heart failure and its relation to the severity of
      tricuspid regurgitation.

PMID- 12480059
TI  - Palliative stent implantation for aortic coarctation in premature infants
      weighing <1,500 g.

PMID- 12480060
TI  - Comparison of exercise performance in patients after pulmonary valvulotomy for
      pulmonary stenosis and tetralogy of Fallot.

PMID- 12480061
TI  - Relation of the discrete subaortic stenosis position to mitral valve function.

PMID- 12480062
TI  - Quantitative assessment of atherosclerosis by electron beam tomography.

PMID- 12480063
TI  - Diagnosis and treatment of cardiac myxomas by transesophageal echocardiography.

PMID- 12480064
TI  - Enhanced early inhibition of platelet aggregation with an increased bolus of
      tirofiban.

PMID- 12480065
TI  - Does N-acetylcysteine prevent contrast-induced nephropathy?

PMID- 12480067
TI  - Prevalence of mitral valve prolapse in the Framingham Heart Study.

PMID- 12480069
TI  - Differential effect of a distractor on primary saccades and perceptual
      localization.
AB  - A distractor presented nearby the target of a goal-directed short latency saccade
      leads to spatial averaging, that is, the saccade lands between the target and the
      distractor. This so-called global effect is a characteristic feature of the
      spatial processing underlying the programming of saccadic eye movements. To
      determine whether this effect of near distractors on saccade metrics is also
      reflected in perceptual localization, subjects performed a saccade task and a
      perceptual localization task using identical, briefly flashed visual stimuli. To
      make the available visual processing time for saccades and perception more
      similar, we followed the target with a mask. Without the mask, primary saccades
      with short latency landed between target and distractor. The distractor had less
      effect on primary saccades with longer latencies (>200 ms) and did not affect the
      final eye position after late secondary saccades in the dark. This indicates that
      the oculomotor system can correctly use information about the target location 200
      ms after the target flash even if no visual stimulus is present during this
      period. Likewise the presence of a distractor did not affect perceptual
      localization. Under the masking condition a similar global effect occurred for
      primary saccades with short latencies, but the latency dependence of the global
      effect was weakened. Secondary saccades and perceptual localization still did not
      show a global effect. The results suggest that the primary saccade is based on a
      specific target acquisition process that differs from that used for spatial
      perception and for the programming of memory-guided corrective saccades.

PMID- 12480070
TI  - Segmentation of objects from backgrounds in visual search tasks.
AB  - In most visual search experiments in the laboratory, objects are presented on an
      isolated, blank background. In most real world search tasks, however, the
      background is continuous and can be complex. In six experiments, we examine the
      ability of the visual system to separate search items from a background. The
      results support a view in which objects are separated from backgrounds in a
      single, preattentive step. This is followed by a limited-capacity search process
      that selects objects that might be targets for further identification. Identity
      information regarding the object's status (target or distractor) then accumulates
      through a limited capacity parallel process. The main effect of background
      complexity is to slow the accumulation of information in this later recognition
      stage. It may be that recognition is slowed because background noise causes the
      preattentive segmentation stage to deliver less effectively segmented objects to
      later stages. Only when backgrounds become nearly identical to the search objects
      does the background have the effect of slowing item-by-item selection.

PMID- 12480071
TI  - Similarities between visual processing of shear and uniform motion.
AB  - A number of papers have claimed that at moderate to high contrasts, sensitivity
      is higher for shear motion than for uniform motion. We show in a 2 x 2AFC task,
      designed to minimize any potential artefacts due to criterion level or response
      bias, that sensitivities are essentially equal for shear and uniform motion under
      general conditions. It has also been claimed that position tracking enhances
      sensitivity for shear motion. We added moving sinusoidal gratings to stationary
      sinusoidal gratings of the same spatial frequency and orientation, to create
      stimuli in which position changes and motion energy have opposite directions, to
      show that shear and uniform motion are both subserved by motion-energy mechanisms
      at speeds above 2.0 deg/s and by position tracking at slower speeds.

PMID- 12480072
TI  - Perceptual learning of temporal structure.
AB  - We investigated the extent to which the ability to perceive spatial form from
      temporal structure (TS) improves with practice. Observers trained monocularly for
      a number of consecutive days on a shape discrimination task, with one group of
      observers judging shape defined by luminance contrast between target and
      background elements and another group judging shape defined by correlated TS
      (synchronized changes in motion direction between target and background
      elements). Substantial learning was found for both shape tasks, with complete
      interocular transfer of training. Observers trained on TS showed no transfer of
      learning to the luminance condition, but observers trained using the luminance
      display with incidental synchronized changes did show transfer to the TS task.
      Possible underlying neural changes are discussed.

PMID- 12480073
TI  - Global speed processing: evidence for local averaging within, but not across two
      speed ranges.
AB  - A primary task of the visual system is to extract the direction and speed of
      animate objects from the retinal image. We examined global speed processing by
      determining how local speeds are integrated and whether integration occurs across
      all speeds or within fixed speed ranges. The first experiment addressed how local
      motion signals are combined to determine the speed of an object in motion.
      Observers judged the speed of a moving cloud of dots that took a random walk in
      direction while the dots inside the cloud moved somewhat independently of the
      cloud itself. The apparent speed of the cloud of dots is found to change in
      proportion with the dot speed and is well predicted by calculating the average
      speed resulting from nearest neighbour matches across stimulus frames. The second
      experiment addressed whether local speeds are combined across all speeds or
      within fixed speed ranges for the detection of global motion. Global dot motion
      (GDM) stimuli that moved in a radial or rotational directions moving at a low
      speed of 1.2 degrees /s or a high speed of 9.6 degrees /s were used to measure
      the thresholds for detecting structured motion as a function of the speed of
      noise dots (0 degrees /s-10.8 degrees /s) added to the stimulus. With low-speed
      targets, only additional noise dots moving at low speeds interfered with signal
      detection. High-speed targets were only interfered with by dots moving at high
      speeds. This finding established the existence of at least two independent speed
      tuned systems in the range of speeds tested. Experiment 3 investigated how speed
      signals are combined within a system to determine the global speed. Using
      sectored radial GDM stimuli the perceived speed of the fastest dots was measured
      as a function of whether the speed of the dots in alternate sectors either
      activated the high or low-speed systems. Averaging only occurred when dots were
      all within the sensitivity range of the high-speed system, however, if alternate
      sectors activated separate speed systems, averaging did not occur. Thus local
      speeds are averaged, independent of direction, to derive a global speed estimate,
      but averaging only occurs within, and not across, speed tuned mechanisms.

PMID- 12480074
TI  - Computing heading in the presence of moving objects: a model that uses motion
      opponent operators.
AB  - Psychophysical experiments have shown that human heading judgments can be biased
      by the presence of moving objects. Here we present a theoretical argument that
      motion differences can account for the direction of bias seen in humans. We
      further examine the responses of a computer simulation of a model for computing
      heading that uses motion-opponent operators similar to cells in the primate
      middle temporal visual area. When moving objects are present, this model shows
      similar biases to those seen with humans, suggesting that such a model may
      underlie human heading computations.

PMID- 12480075
TI  - Central versus peripheral visual field stimulation results in timing differences
      in dorsal stream sources as measured with MEG.
AB  - Small, achromatic circular sinusoids were presented in the central and peripheral
      visual fields to investigate dorsal visual stream activation. It was hypothesized
      that peripheral stimulation would lead to faster onset latencies, as well as
      preferentially activate dorsal stream visual areas relative to central field
      stimulation. Although both central and peripheral stimulation activated similar
      areas, the onset latencies of neuromagnetic sources in two dorsal stream areas
      were found to be significantly shorter for peripheral versus central field
      stimulation. The results suggest that information from central versus peripheral
      fields arrives in the higher-order visual areas via different routes.

PMID- 12480076
TI  - Cholinesterase inhibitors: more than one function in AD?

PMID- 12480077
TI  - Apolipoprotein E, dementia and strokes.

PMID- 12480078
TI  - Specificity of autoantibodies to epitopes of myelin proteins in multiple
      sclerosis.
AB  - An autoimmune response to one or more myelin-protein components is thought to be
      part of the pathogenesis of multiple sclerosis (MS). The immunodominant
      autoantibody epitope may be localized on a linear peptide segment, on a
      conformation-sensitive epitope, or on an epitope resulting from post
      translational modifications. Primary, secondary, and tertiary structures of
      myelin proteins may determine the specific site for binding of autoantibodies. A
      myelin protein-specific autoantibody can bind to either a linear or
      conformational epitope, whereas all of the T cell epitopes are linear. At
      present, the conformational epitopes of myelin proteins have not been identified;
      most of the methods used to identify the myelin-protein epitopes corresponding to
      the pathogenesis of multiple sclerosis are involved in the linear epitope
      mapping. Polymorphism or mutations may cause inappropriate expression of the
      myelin proteins with alterations to their linear and/or conformational epitopes,
      and make them susceptible to autoantibody binding, especially if these changes
      occur at the surface of the protein. This review focuses on the specificity of
      autoantibodies to the epitopes of myelin proteins and correlates this to the
      structures of proteins. Factors that influence the expression of myelin-protein
      epitopes such as the alpha-helical or beta-sheet structure of the protein, the
      tri-proline site, and the post-translational modifications as well as
      physicochemical properties of amino acid changed are included.

PMID- 12480079
TI  - The clinical and pathological features of peripheral neuropathy accompanied with
      HTLV-I associated myelopathy.
AB  - We describe the clinical and pathological studies in HTLV-I associated myelopathy
      (HAM)/tropical spastic paraparesis (TSP) patients with peripheral neuropathy as
      proven by sural nerve biopsy. Sural nerve pathology in HAM/TSP patients revealed
      that the most common type of pathologic change is a combination of both
      demyelination and remyelination and axonal degeneration and regeneration, and
      this change is modified by the complications. The pathologic changes were
      correlated with neither the duration of disease nor human T lymphotropic virus
      type I (HTLV-I) proviral load. This study suggests that peripheral nerves could
      be involved in HAM/TSP.

PMID- 12480080
TI  - Cholinesterase inhibitor rivastigmine enhance the mitochondrial electron
      transport chain in lymphocytes of patients with Alzheimer's disease.
AB  - Electron transport chain (ETC) dysfunction has been claimed to contribute to the
      expression of neurodegenerative disorders. We have investigated the effects of
      the treatment with rivastigmine, a commonly used cholinesterase inhibitor, on
      lymphocyte mitochondria of patients with Alzheimer's disease (AD). Increased
      enzymatic activities of diverse complexes and oxidative capacity of the ETC were
      found. Enhanced mitochondrial ETC function may contribute to the beneficial
      effects of rivastigmine on clinical manifestations of AD.

PMID- 12480081
TI  - A diffusion tensor MRI study of basal ganglia from patients with ADEM.
AB  - Using diffusion tensor (DT) MRI and histogram analysis, we measured mean
      diffusivity ((-)D) of basal ganglia grey matter (GM) from eight patients with
      acute disseminated encephalomyelitis (ADEM), 10 patients with multiple sclerosis
      (MS), and 10 healthy controls. Patients with ADEM had higher average (-)D
      (p=0.02) and lower (-)D histogram peak height (p=0.008) of the basal ganglia GM
      than patients with MS. Microscopic tissue damage occurs in the basal ganglia of
      ADEM patients, but not in MS patients with a similar burden of MRI-visible brain
      lesions.

PMID- 12480082
TI  - The apolipoprotein E epsilon4 haplotype is an important predictor for recurrence
      in ischemic cerebrovascular disease.
AB  - OBJECTIVE: To determine whether a specific apolipoprotein E (APOE) allele is a
      predictor for ischemic cerebrovascular disease (ICVD). BACKGROUND: The role of
      APOE in atherosclerosis has been a focus of intensive research. The APOE epsilon4
      allele is overrepresented in Alzheimer's disease, atherosclerosis, ischemic heart
      disease, and ICVD. Also, epsilon4 carriers have higher cholesterol levels than
      non-epsilon4 carriers. METHODS: We performed a prospective, longitudinal study on
      patients who have ICVD. The patients were recruited from St. Mary Hospital,
      Korea, and investigated for ICVD through interviews and by reviewing their
      medical records and neuroimaging studies. APOE genotypes were determined for each
      patient. RESULTS: 20 of the 91 enrolled patients had recurrent ICVD, yielding a 3
      year cumulative recurrence rate of 22%. Carriers of the epsilon4 allele had a 3
      year recurrence rate of 53%, as compared with only 16% for patients who had the
      APOE non-epsilon4 allele (the risk ratio was 4.11; the 95% CI was 1.49-11.32;
      P<0.01). CONCLUSIONS: Our results make possible the identification of patients
      with ICVD who are at high risk for recurrence by assessing their APOE genotype.
      Also, this data might be clinically useful in methods for assessing potential
      strategies for prevention.

PMID- 12480083
TI  - Is atopic dermatitis a risk factor for intervertebral disc degeneration? A
      preliminary clinical and MRI study.
AB  - Atopic dermatitis (AD) is a common allergic disease that has recently been
      reported to be complicated with acute myelitis. To clinically evaluate the
      occurrence of myelitis in AD, 65 consecutive AD patients were neurologically
      examined. Of these, 37 underwent cervical MRI scans. Unexpectedly, the neurologic
      and MRI findings did not suggest myelitis, but rather, in most cases, cervical
      spondylosis. Therefore, we assessed the relationship between AD and cervical
      spondylosis. In addition, cervical MRI findings in 26 patients with multiple
      sclerosis (MS) and in 12 normal controls were also evaluated. The neurologic
      examinations in the AD patients frequently showed hyperreflexia in the legs, and
      sensory and motor disturbances were often present in the limbs. Cervical MRI
      findings suggestive of spondylosis, such as intervertebral disc degeneration and
      bulging/protrusion, were found more frequently in AD patients than in MS
      patients, with statistical significance. Posterior spondylolisthesis was observed
      with higher frequency in AD and MS patients than in normal controls. We concluded
      that AD might be a risk factor for intervertebral disc degeneration. As far as we
      know, this is the first paper describing the potential association between disc
      degeneration and AD.

PMID- 12480084
TI  - Expression of matrix metalloproteinases, sICAM-1 and IL-8 in CSF from children
      with meningitis.
AB  - The combined expression of the inflammatory mediators, matrix metalloproteinases
      (MMPs), soluble form of intracellular adhesion molecule ICAM-1 (sICAM-1) and
      interleukin (IL)-8, was evaluated in children infected with bacterial or viral
      meningitis. MMP-2 and IL-8 were detected in all CSF samples and were enhanced in
      both bacterial and viral infected samples, compared to those from control
      children. The expression of MMP-9 as well as sICAM-1 was not detected in control
      CSF while observed in viral infected and further elevated in bacterial infected
      samples. This pilot study supports a role for MMPs, IL-8 and sICAM in infectious
      meningitis and suggests further research to determine their possible use as
      biomarkers for various forms of meningeal infection as well as the use of their
      specific antagonists as potential therapeutic agents for central nervous system
      (CNS) inflammatory processes.

PMID- 12480085
TI  - A synthetic heparin-mimicking polyanionic compound inhibits central nervous
      system inflammation.
AB  - The immunomodulating capacity of heparin led us to test the effect of the
      synthetic heparin-mimicking and low anticoagulant compound RG-13577 on the course
      of experimental autoimmune encephalomyelitis (EAE) and central nervous system
      (CNS) inflammation. EAE was induced in SJL mice by inoculation with whole mouse
      spinal cord homogenate. RG-13577, delivered intraperitoneally, inhibited the
      clinical signs of acute EAE and markedly ameliorated inflammation in the spinal
      cord, primarily by inhibiting heparanase activity in lymphocytes and astrocytes
      and thus impairing lymphocyte traffic. RG-13577 treatment was effective when
      started on day of disease induction or day 7 after induction. The low molecular
      weight heparin, enoxaparin, tested under the same conditions, exerted only a
      minor insignificant inhibitory effect. RG-13577 also inhibited the tyrosine
      phosphorylation of several proteins, particularly Erk1 and Erk2 of the MAP kinase
      signaling pathways associated with inflammation and cell proliferation. RG-13577
      blocked the activity of sPLA(2) and inhibited CNS PGE(2) production both in vivo
      and in vitro.

PMID- 12480086
TI  - Movement disorders in Friedreich's ataxia.
AB  - Since the discovery of the gene mutation causing Friedreich's ataxia (FA), the
      rich spectrum of clinical manifestations of this autosomal recessive disorder is
      being increasingly recognized. Movement disorders besides ataxia, however, have
      not been fully characterized in patients with FA. We describe here two young male
      patients who, in addition to progressive ataxia, kinetic tremor and other typical
      features of FA, also manifest axial and limb dystonia. The primary purpose of
      this report is to draw attention to the broad spectrum of hyperkinetic movement
      disorders that can present as or be associated with FA.

PMID- 12480087
TI  - A novel SOD1 gene mutation in a Korean family with amyotrophic lateral sclerosis.
AB  - BACKGROUND: Superoxide dismutase 1 (SOD1) gene mutations are responsible for
      approximately 20% of all familial amyotrophic lateral sclerosis (ALS) cases.
      However, these cases, especially those with SOD1 gene mutations, have not been
      reported in Korea. OBJECTIVES: The SOD1 gene in Korean family with ALS was
      screened for potential mutations and the clinical data was collected. MATERIALS
      AND METHODS: The clinical histories and neurological findings of the family
      members were obtained. Genomic DNA was isolated from the leukocytes of whole
      blood samples and the coding region of the SOD1 gene was analyzed by PCR and
      sequencing. RESULTS: The family with ALS showed a novel missense mutation in the
      SOD1 gene, which was heterozygous for the mutation, GGC to GTT, causing the
      substitution of valine for glycine at codon 10 (Gly10Val) in exon 1. Clinically,
      the patients exhibited early onset and rapid disease progression. CONCLUSIONS:
      Familial ALS with a novel Gly10Val mutation in the SOD1 gene showed severe
      clinical features. The mutation lies in a region involved in a dimer contact in
      the three-dimensional structure of the SOD1 protein. This study expands the
      number of ALS-associated SOD1 gene mutations.

PMID- 12480088
TI  - Filamin C accumulation is a strong but nonspecific immunohistochemical marker of
      core formation in muscle.
AB  - Filamin C is the muscle isoform of a group of large actin-crosslinking proteins.
      On the one hand, filamin C is associated with the Z-disk of the myofibrillar
      apparatus and binds to myotilin; on the other hand, it interacts with the
      sarcoglycan complex at the sarcolemma. Filamin C may be involved in reorganizing
      the cytoskeleton in response to signalling events and in muscle it may, in
      addition, fulfill structural functions at the Z-disk. An examination of biopsies
      from patients with multi-minicore myopathy, central core myopathy and neurogenic
      target fibers with core-like target formations (TF) revealed strong reactivity of
      all the cores and target formations with two different anti-filamin C antibodies.
      In all three conditions, the immunoreactivity in the cores for filamin C was
      considerably stronger than that for desmin. Only for alphaB-crystallin were
      comparable levels of immunoreactivity detected. There was no difference in
      intensity for filamin C between the three pathological conditions. Thus, filamin
      C along with alphaB-crystallin is a strong and robust, but nonspecific marker of
      core formation. The reason why filamin C accumulates in cores is unclear at
      present, but we postulate that it may be critically involved in the chain of
      events eventually leading to myofibrillar degeneration.

PMID- 12480089
TI  - Isatin, an endogenous MAO inhibitor, improves bradykinesia and dopamine levels in
      a rat model of Parkinson's disease induced by Japanese encephalitis virus.
AB  - Isatin, an endogenous monoamine oxidase (MAO) inhibitor, has an important role in
      the control of neurotransmitter concentration. We previously reported that
      exogenously administered isatin significantly increased acetylcholine (ACh) and
      dopamine (DA) levels in the rat striatum. In order to test the possibility of
      treating Parkinson's disease by isatin, we evaluated DA levels in the striatum
      and bradykinesia using a rat model of Parkinson's disease induced by the Japanese
      encephalitis virus (JEV).We have already reported that in adult Fischer rats
      infected with JEV at day 13, there was a marked decrease of tyrosine hydroxylase
      positive neurons in the bilateral substantia nigra after 12 weeks. Effects of
      isatin were investigated in JEV-induced post-encephalitic parkinsonism rats by a
      pole test and high performance liquid chromatograph (HPLC) with an
      electrochemical detector (ECD). Isatin (100 mg/kg per day for 1 week,
      intraperitoneal injection) improved the bradykinesia observed in the JEV-induced
      parkinsonism rats. Dopamine (DA) concentrations in the JEV-infected rats were
      profoundly reduced in the striatum as compared with controls. Isatin also
      increased DA in the striatum of parkinsonism rats. These results suggest that
      isatin could be a possible treatment for Parkinson's disease as well as for post
      encephalitic parkinsonism.

PMID- 12480090
TI  - Conditions of iodine contrast transfer from lumbosacral CSF to blood.
AB  - PURPOSE: To determine conditions which influence transfer of iopamidol from
      lumbosacral cerebrospinal fluid (CSF) to blood. METHODS: Iopamidol transfer was
      measured in 32 patients over 180 min after radiculography and compared with
      patient variables. RESULTS: Iopamidol transfer began early in 12 patients, more
      slowly in 13 patients, and was not detected during sample period in 7 patients.
      Transfer of sequential samples correlated highly with each other (r>0.8).
      Transfer was more pronounced in patients with prominent nerve root sleeves on
      radiculogram (p=0.006, t test), and correlated inversely with body weight (r=
      0.4258), and with albumin CSF/serum quotient (r=-0.4702). CONCLUSION: Early
      iopamidol transfer probably indicates transfer through spinal arachnoid villi and
      granulations with CSF bulk flow. Prominent nerve root sleeves may facilitate
      access to transfer sites. No transfer during sample period suggests no such
      spinal transfer, possibly due to sparse access to or presence of spinal transfer
      sites. Inverse correlation of transfer with body weight may reflect influence of
      body weight on retroperitoneal venous pressure, which regulates outflow of CSF
      and of compounds dissolved in it. Awareness of wide interindividual transfer
      variation and steady intraindividual transfer may help to specify dosage and
      effect expectation of intrathecal drug therapy.

PMID- 12480091
TI  - Low concentrations of glutamate induce apoptosis in cultured neurons:
      implications for amyotrophic lateral sclerosis.
AB  - Evidence is accumulating that excessive glutamate concentration in the
      extracellular space is neurotoxic and plays a role in amyotrophic lateral
      sclerosis (ALS). However, the published results on glutamate levels in
      cerebrospinal fluid (CSF) and on glutamate-mediated toxicity of CSF in ALS
      disease remain controversial. In this report, we studied CSF from patients with
      sporadic ALS and controls to determine glutamate concentrations, and then
      analyzed the neurotoxic effect of glutamate at the concentrations present in CSF
      from ALS patients on cultured cortical neuronal cells. Our study shows that
      glutamate, at the concentrations found in CSF from ALS patients (5.8 microM),
      diminished cell viability and increased apoptosis determined by the fluorescent
      DNA-binding dye Hoechst 33342 as well as by Terminal deoxynucleotidyl transferase
      (TdT)-mediated dUTP Nick End-Labeling (TUNEL) reaction in cultured neuronal
      cells. However, glutamate concentrations as those found in CSF from controls (2.8
      microM or below) did not induce any effect. Both significant glutamate-induced
      effects were inhibited in the presence of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl
      benzo(f)quinoxaline-2,3-dione), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole
      propionic acid (AMPA)/kainate-sensitive glutamate receptor antagonist. These
      results demonstrate that AMPA/kainate receptors are involved in the glutamate
      mediated neurotoxic effects on cultured neurons, according to reports that
      implicate these receptors in ALS disease. We conclude that the glutamate-mediated
      neuronal apoptosis through AMPA/kainate receptors could occur in ALS patients who
      have elevated CSF glutamate concentration.

PMID- 12480092
TI  - Primary progressive aphasia and Pick complex.
AB  - Ten autopsied patients from a prospectively followed, clinically defined,
      neuropsychologically and radiologically documented cohort with primary
      progressive aphasia were histologically characterized. All were variants of
      frontotemporal degeneration (Pick complex): Pick body dementia, n=3,
      corticobasals degeneration (CBD), n=4, and tau and synuclein negative
      ubiquitinated inclusions of the motor neuron disease type, n=3. All shared
      superficial cortical spongiosis, neuronal loss, and gliosis. Although most
      patients had fluent anomic aphasia at onset, all progressed to a nonfluent or
      mute state. Comprehension, episodic memory, and activities of daily living were
      initially preserved. Three cases with Pick body dementia had verbal apraxia and
      stuttering at onset. Two of the patients with CBD pathology were older than the
      average primary progressive aphasia (PPA). All patients developed secondary
      syndromes either of frontotemporal dementia (FTD) and/or extrapyramidal-apraxic
      manifestations (CBD). By the time autopsy was obtained, the pathology appeared
      outside the language areas. Progressive aphasias secondary to Alzheimer's disease
      (AD) were excluded on the basis of early loss of memory and comprehension.Rather
      than the previously emphasized histological heterogeneity, clinically probable
      PPA has a predictive value of a group of related pathologies, collectively named
      frontotemporal degeneration, or Pick complex. This series of autopsied cases
      provides evidence for the clinical and pathological overlap of PPA with FTD and
      CBD, and contributes to the diagnostic and neuropsychological definition of PPA.

PMID- 12480093
TI  - Juvenile muscular atrophy of distal upper extremity associated with airway
      allergy: two cases successfully treated by plasma exchange.
AB  - Juvenile muscular atrophy of the distal upper extremity (JMADUE) is postulated to
      be a type of flexion myelopathy. However, patients with typical clinical features
      of JMADUE but without evidence of flexion myelopathy have been reported. We
      recently reported a significant association of JMADUE with airway allergy. Here
      we report the successful treatment by plasma exchange (PE) of two patients with
      both airway allergy and JMADUE without evidence of flexion myelopathy. Patient 1
      had a 5-year history of allergic rhinitis and high titers of mite antigen
      specific IgE, and patient 2 had an 8-year history of pollinosis and high titers
      of cedar pollen-specific IgE. Both patients noted progressive distal muscle
      atrophy and weakness of the upper extremities: patient 1 for 3 months and patient
      2 for 3 years. Neurologically, both showed asymmetric intrinsic hand muscle
      atrophy, oblique atrophy of the forearm muscles, and weakness and contraction
      fasciculation (minipolymyoclonus) of these muscles without any sensory
      impairment. Neither had any evidence of flexion myelopathy on magnetic resonance
      imaging (MRI) in a flexed position. Both were subjected to PE three times. Soon
      after the PEs, both showed improvement of distal muscle weakness of the upper
      extremities and marked reduction of contraction fasciculation of the forearm
      muscles. Patient 1 showed marked reduction in ongoing denervation potentials in
      the distal muscles on needle electromyography, while patient 2 showed marked
      improvement of F wave persistence of bilateral median and ulnar nerves. Serum
      total and allergen-specific IgE decreased after PEs in both patients. PE was thus
      considered to be effective in these two patients having JMADUE without evidence
      of flexion myelopathy. These observations may suggest the involvement of an
      immune-mediated process in the neural damage of JMADUE without evidence of
      flexion myelopathy, especially in patients with atopic diathesis, and may support
      the notion that JMADUE is etiologically heterogeneous.

PMID- 12480095
TI  - Current status of pathogenetic mechanisms in staphylococcal arthritis.
AB  - Interactions between staphylococci and the joint tissues of the host lead
      typically to rapidly progressing and highly destructive processes. Staphylococci
      possess a vast arsenal of components and products that contribute to the
      pathogenesis of joint infection. Occasionally these compounds have overlapping
      activities and act either in concert or alone. Host responsiveness to
      staphylococcal infection displays an even more complex pattern. Most of the cells
      and molecules that participate in the innate immune system protect the host
      against bacteria. However, the staphylococci have developed systems that
      counteract endogenous protective mechanisms. Interestingly, certain cells and
      molecules of the acquired immune system potentiate the severity of infection by
      triggering exaggerated responses to the staphylococcal danger signals. This
      review deals with the intricate host-bacterium interactions that occur during
      experimental septic arthritis, and outlines potential preventive and treatment
      modalities.

PMID- 12480096
TI  - The microbiology of butyrate formation in the human colon.
AB  - Butyrate arising from microbial fermentation is important for the energy
      metabolism and normal development of colonic epithelial cells and has a mainly
      protective role in relation to colonic disease. While certain dietary substrates
      such as resistant starch appear to be butyrogenic in the colon, it is not known
      to what extent these stimulate butyrate production directly, e.g. by promoting
      amylolytic species, or indirectly, e.g. through cross-feeding of fermentation
      products. Cultural and molecular studies indicate that the most numerous butyrate
      producing bacteria found in human faeces are highly oxygen-sensitive anaerobes
      belonging to the Clostridial clusters IV and XIVa. These include many previously
      undescribed species related to Eubacterium, Roseburia, Faecalibacterium and
      Coprococcus whose distribution and metabolic characteristics are under
      investigation. A better understanding of the microbial ecology of colonic
      butyrate-producing bacteria will help to explain the influence of diet upon
      butyrate supply, and to suggest new approaches for optimising microbial activity
      in the large intestine.

PMID- 12480097
TI  - Specific identification and molecular typing analysis of Lactobacillus johnsonii
      by using PCR-based methods and pulsed-field gel electrophoresis.
AB  - A fast and reliable Multiplex-PCR assay was established to identify the species
      Lactobacillus johnsonii. Two opposing rRNA gene-targeted primers have been
      designed for this specific PCR detection. Specificity was verified with DNA
      samples isolated from different lactic acid bacteria. Out of 47 Lactobacillus
      strains isolated from different environments, 16 were identified as L. johnsonii
      by PCR. The same set of strains was investigated with five alternative molecular
      typing methods: enterobacterial repetitive intergenic consensus PCR (ERIC-PCR),
      repetitive extragenic palindromic PCR (REP-PCR), amplified fragment length
      polymorphism, single triplicate arbitrarily primed PCR, and pulsed-field gel
      electrophoresis in order to compare the discriminatory power of these methods.
      The reported data strongly support the highly significant heterogeneity among all
      L. johnsonii isolates, potentially linked to their origin of isolation. The use
      of species-specific primers as well as rapid and highly powerful PCR-based
      molecular typing tools (namely ERIC- and REP-PCR techniques) should be
      respectively envisaged for identifying, differentiating and monitoring L.
      johnsonii strains from various environmental samples, for product monitoring, for
      species tracing in clinical studies as well as bacterial profiling of various
      microecological or gastrointestinal environments.

PMID- 12480098
TI  - Genomic analysis of protein kinases, protein phosphatases and two-component
      regulatory systems of the cyanobacterium Anabaena sp. strain PCC 7120.
AB  - Anabaena sp. PCC 7120 is a cyanobacterium capable of performing several important
      biological functions: photosynthesis, nitrogen fixation, cell differentiation,
      cell-cell communication, etc. These activities require an extensive signaling
      capability in order to respond to the changing environment. Based on the genomic
      data, we have retrieved several gene families encoding signaling components. It
      is estimated that 211 genes encode two-component signaling elements, and 66 genes
      encode Ser/Thr kinases and phosphatases. These genes together represent 4.2% of
      the coding capacity of the whole genome, making Anabaena PCC 7120 a leading
      member among prokaryotes in terms of its signaling potential. It is known that
      two-component systems are composed of a few basic modules that can arrange into
      different structures best adapted for each signaling system. Many proteins in
      Anabaena PCC 7120 have incorporated both modules of two-component systems and
      catalytic domains of either Ser/Thr kinases or phosphatases. A family of 13 genes
      encode proteins with both a Ser/Thr kinase domain and a His kinase domain, and
      another four genes were also found whose products have both a response regulator
      domain and a Ser/Thr phosphatase domain. Of all the signaling proteins in
      Anabaena PCC 7120, about one third (35%) are conserved in the genome of the
      unicellular cyanobacterium strain Synechocystis sp. PCC 6803. Interestingly, one
      subfamily of His kinases and two subfamilies of response regulators are found in
      Anabaena PCC 7120 but are absent in Synechocystis PCC 6803. This study
      constitutes a basis for analyses of signal transduction in Anabaena PCC 7120
      using functional genomic approaches.

PMID- 12480099
TI  - Chlamydia pneumoniae infection alters the junctional complex proteins of human
      brain microvascular endothelial cells.
AB  - Chlamydia pneumoniae has been identified and associated with multiple sclerosis
      (MS) and Alzheimer's disease (AD) pathogenesis, although the relationship of this
      organism in these diseases remains controversial. We have hypothesized that one
      potential avenue of infection is through the junctional complexes between the
      blood-brain barrier (BBB) endothelia. C. pneumoniae is characteristically a
      respiratory pathogen, but has been implicated in atherosclerosis, coronary artery
      disease, and neuroinflammatory conditions. C. pneumoniae infection may lead to
      endothelial damage, junctional alterations, and BBB breakdown. Therefore, in this
      study, C. pneumoniae infection of human brain microvascular endothelial cells
      (HBMECs) resulted in increased expression of the zonula adherens proteins beta
      catenin, N-cadherin, and VE-cadherin, and decreased expression of the tight
      junctional protein occludin, as determined by immunocytochemistry and Western
      blot analyses. These events may underlie a mechanism for the regulation of
      paracellular permeability while maintaining barrier integrity during C.
      pneumoniae infection associated with neuropathologies such as MS and AD.

PMID- 12480100
TI  - Antibiotic resistance in oral commensal streptococci from healthy Mexicans and
      Cubans: resistance prevalence does not mirror antibiotic usage.
AB  - Antibiotic resistance genes might be maintained by selection pressures different
      from those which are responsible for initially selecting resistant bacteria. This
      possibility was suggested from a comparison of oral commensal streptococci
      isolated from healthy people not taking antibiotics. Resistance frequencies were
      similar for organisms from Mexico and Cuba despite significant differences in
      antibiotic usage in these two countries. Resistance to > or = 4 drugs was far
      more common in Mexico, the only detectable trend that can be related to the
      higher use of antibiotics in Mexico. If resistance is not uniquely maintained by
      antibiotics, then other environmental factors must also be at work. These need to
      be identified if a strategy to control antibiotic resistance is to be successful.

PMID- 12480101
TI  - Comparison of partial tuf gene sequences for the identification of lactobacilli.
AB  - Comparative analysis of partial tuf sequences was evaluated for the
      identification and differentiation of lactobacilli. Comparison of the amino acid
      sequences allowed differentiation between species and also between the subspecies
      of Lactobacillus delbrueckii. The nucleotide sequence comparison allowed
      differentiation between other subspecies and between some strains. Lactobacilli
      from several collections and isolates from dairy samples were clearly identified
      by comparison of short tuf sequences with those of the type strains. In
      evaluating the taxonomy of the Lactobacillus casei-related taxa, different tuf
      amino acid signatures are in favour of a classification into three distinct
      species. The type strain designation for the L. casei species is discussed.

PMID- 12480102
TI  - The influence of metal ions on malic enzyme activity and lipid synthesis in
      Aspergillus niger.
AB  - In the presence of copper significant induction of citric acid overflow was
      observed, while concomitantly lower levels of total lipids were detected in the
      cells. Its effect was more obvious in a medium with magnesium as sole divalent
      metal ions, while in a medium with magnesium and manganese the addition of copper
      had a less pronounced effect. Since the malic enzyme was recognised as a supplier
      of reducing power in the form of reduced nicotinamide adenine dinucleotide
      phosphate for lipid biosynthesis, its kinetic parameters with regard to different
      concentrations of metal ions were investigated. Some inhibition was found with
      Fe(2+) and Zn(2+), while Cu(2+) ions in a concentration of 0.1 mM completely
      abolished malic enzyme activity. The same metal ions proportionally reduced the
      levels of total lipids in Aspergillus niger cells. A strong competitive
      inhibition of the enzyme by Cu(2+) was observed. It seemed that copper competes
      with Mg(2+) and Mn(2+) for the same binding site on the protein.

PMID- 12480103
TI  - Cell-detaching Escherichia coli (CDEC) strains from children with diarrhea:
      Identification of a protein with toxigenic activity.
AB  - Twenty-four strains of cell-detaching Escherichia coli (CDEC) isolated from stool
      specimens in different cities in Brazil were examined for virulence properties.
      Aerobactin production and multiple antibiotic resistance were observed in most of
      the isolates. In hybridization studies, the alphahly, pap, and cnf sequences,
      common properties of this category of E. coli, were found in a minority of
      isolates. Half of the CDEC isolates had enteroaggregative DNA sequences (pet,
      astA, aggA), six strains carried the shet1 gene, nine strains carried the daaC
      sequence, and one strain carried the stp gene. Thirteen strains induced fluid
      accumulation in the rabbit intestinal loop assay. Supernatant filtrate of one of
      those strains, which did not hybridize with any of the toxin probes tested,
      induced destructive lesions in the rabbit ileal loop and enterotoxic activity in
      the Ussing chamber. A 12-kDa protein purified by 60% ammonium sulfate
      precipitation of the supernatant filtrate demonstrated a toxigenic effect that
      was inhibited by the anti-12-kDa protein antiserum.

PMID- 12480104
TI  - Screening for biologically active metabolites with endosymbiotic bacilli isolated
      from arthropods.
AB  - Endosymbiotic bacteria from the genus Bacillus were isolated from different
      compartments of the gut of various members of insects (Hexapoda) and millipedes
      (Diplopoda). They were grown in submerged culture and investigated by biological
      assays and HPLC-diode array analysis regarding their production of bioactive
      metabolites, which were isolated and determined in structure. Known compounds and
      yet unknown derivatives from the primary metabolism were detected, as well as
      antibacterially and antifungally acting peptide antibiotics.

PMID- 12480105
TI  - Pythium segnitium sp. nov., isolated from the Canary Islands--its taxonomy, ITS
      region of rDNA, and comparison with related species.
AB  - Pythium segnitium (CI-44) was isolated from some soil samples taken in the Canary
      Islands (Spain). This new species is a slow-growing fungus and is perfectly
      adapted to terrestrial habitat. It belongs to the group of Pythium that have
      smooth-walled oogonia, mostly hypogynous antheridia, and plerotic oospores. The
      fungus lacks sporangia, zoospores, and hyphal bodies are rarely formed. Thus the
      asexual reproduction, which is so common for fungi and especially for the aquatic
      ones, is completely lacking in this case. However the fungus reproduces sexually
      by the formation of oogonia, antheridia and oospores plentifully. The taxonomic
      description of this fungus, the nucleotide sequence of the internal transcribed
      region (spacers ITS1, ITS2, and the gene 5.8 S) of its ribosomal nuclear DNA, and
      its comparison with related species are given here.

PMID- 12480106
TI  - Models of 2,4,6-trinitrotoluene (TNT) initial conversion by yeasts.
AB  - The original models of the initial steps of 2,4,6-trinitrotoluene (TNT)
      conversion by yeasts are presented. Saccharomyces sp. ZS-A1 reduced nitro groups
      of TNT producing isomeric monohydroxylaminodinitrotoluenes (HADNT) as the key
      initial metabolites (molar ratio HADNT/TNT was up to 0.81), whereas
      aminodinitrotoluenes (ADNT) and the hydride-Meisenheimer complex of TNT (H-TNT)
      were the minor products. Conversely, Candida sp. AN-L13 transformed TNT almost
      quantitatively into H-TNT, thus realizing the alternative attack, consisting of
      the TNT aromatic ring reduction. The third type of conversion, revealed in
      Candida sp. AN-L14, is the combination of both above mechanisms and produces an
      equimolar mix of HADNT and H-TNT. In the toxicity tests with Paramecium caudatum,
      the supernatant of Saccharomyces sp. ZS-A1, which converts TNT into HADNT, was
      most toxic while the supernatant of Candida sp. AN-L13 (TNT --> H-TNT) was least
      toxic. The microorganisms converting TNT quantitatively to the reactive
      metabolites can be useful for their immobilization through the detoxifying
      interaction with the soil components such as humic compounds.

PMID- 12480107
TI  - Screening of large numbers of Streptococcus pneumoniae isolates for mutations
      associated with fluoroquinolone resistance using an oligonucleotide probe assay.
AB  - Mutations at a relatively small number of sites in parC, parE and gyrA account
      for most of the fluoroquinolone resistance in Streptococcus pneumoniae clinical
      isolates. A high throughput oligonucleotide probe assay was developed to screen
      for mutations in the quinolone-resistance determining region (QRDR) of parC
      (Ser79), gyrA (Ser81) and parE (Asp435) of Streptococcus pneumoniae. Eight
      oligonucleotide probes (17mers) were used in the presence of tetramethyl ammonium
      chloride so that the melting temperature was dependent on length and not on base
      composition. Using this assay it was possible to accurately detect QRDR mutations
      from several hundred S. pneumoniae clinical isolates that were grown on nylon
      membranes.

PMID- 12480108
TI  - Molecular cloning and characterization of a cDNA encoding cellobiose
      dehydrogenase from the wood-rotting fungus Grifola frondosa.
AB  - Cloning of a cDNA encoding cellobiose dehydrogenase (CDH) from the wood-rotting
      fungus Grifola frondosa, which produces the edible maitake mushroom, was
      performed using reverse transcription-polymerase chain reaction (RT-PCR) and
      rapid amplification of cDNA ends. The CDH cDNA consisted of 2469 bp, including an
      open reading frame encoding the 18-amino acid signal peptide at the N-terminal
      region and the 750-amino acid mature protein with a predicted molecular mass of
      79.6 kDa and a pI value of 4.32. Analysis of the amino acid sequence revealed
      that it contains a flavin-binding motif, two glucose-methanol-choline
      oxidoreductase motifs, and two possible residues for heme ligand binding (Met61
      and His58). The amino acid sequence of G. frondosa CDH (GfrCDH) has a high degree
      of identity with three known CDHs from basidiomycetes, but not with two CDHs from
      ascomycetes. In addition, transcription of the CDH gene in G. frondosa grown on
      several carbon sources was analyzed by RT-PCR. mRNA of GfrCDH was detected from
      mycelia grown on cellobiose and cellulose, but not on glucose. Consequently,
      transcription of the GfrCDH gene seems to be promoted under conditions favoring
      cellulose degradation, and to be regulated by carbon catabolite repression.

PMID- 12480109
TI  - A defined human gastrin sequence stimulates the growth of Helicobacter pylori.
AB  - This study describes the interaction between gastrin and Helicobacter pylori.
      Human gastrin amino acids 4-17 were found to be the minimal growth-stimulating
      sequence. Gastrin from other mammals did not stimulate bacterial growth. When
      human serum was used to stimulate bacterial growth in brucella broth, gastrin was
      shown to be a necessary and sufficient growth-stimulating factor. Competition for
      the gastrin effect by pentagastrin and cholecystokinin (CCK-8) resulted in
      inhibition of bacterial growth. This effect was mediated by the four C-terminal
      amino acids which are shared by gastrin, CCK-8 and pentagastrin. In conclusion,
      the interaction between gastrin and H. pylori was shown to be specific,
      essential, and dependent on a defined gastrin sequence.

PMID- 12480110
TI  - Aerotactic responses in bacteria to photoreleased oxygen.
AB  - Bacterial aerotaxis is a rapid response towards or away from oxygen. Here we
      report on the use of computer-assisted motion analysis coupled to flash
      photolysis of caged oxygen to quantify aerotactic responses in bacteria. The
      caged compound (mu-peroxo)(mu-hydroxo)bis[bis(bipyridyl) cobalt(III)] perchlorate
      liberates molecular oxygen upon irradiation with near-UV light. A mixture of
      cells and the caged oxygen compound was placed in a capillary tube and challenged
      by discrete stimuli of molecular oxygen produced by photolysis. We then recorded
      the rate of change of direction (rcd) as an estimate of tumble frequency in
      response to liberated oxygen and measured the signal processing (excitation)
      times in Bacillus subtilis, Bacillus halodurans and Escherichia coli. This
      computer-assisted caged oxygen assay gives a unique physiological profile of
      different aerotaxis transducers in bacteria.

PMID- 12480112
TI  - Establishment of uncharacterized plasmids in Escherichia coli by in vitro
      transposition.
AB  - We present a simple approach that permits any circular plasmid, such as
      uncharacterized plasmids from diverse prokaryotes, to be established in
      Escherichia coli, thereby facilitating subsequent structural and functional
      studies. An in vitro transposition reaction is used to introduce a well
      characterized replicon and selectable marker into purified plasmids, which are
      then used to transform E. coli. The approach was demonstrated using a small 3.4
      kb archaeal plasmid and a large 60-kb uncharacterized plasmid from a Gram
      negative bacterium. Replicon function in E. coli was tested for each plasmid, and
      direct sequencing of the large plasmid revealed similarity to restriction
      modification systems.

PMID- 12480111
TI  - Phage mediated horizontal transfer of the sopE1 gene increases
      enteropathogenicity of Salmonella enterica serotype Typhimurium for calves.
AB  - Epidemiological evidence shows that the sopE1 gene is associated with Salmonella
      Typhimurium phage types causing epidemics in cattle. In this study we demonstrate
      that horizontal transfer of the sopE1 gene by lysogenic conversion with the
      SopEphi increased enteropathogenicity of S. Typhimurium in the bovine ligated
      ileal loop model. These data support the hypothesis that phage mediated
      horizontal transfer of the sopE1 gene contributes to the emergence of epidemic
      cattle-associated S. Typhimurium clones.

PMID- 12480113
TI  - Oleomonas sagaranensis gen. nov., sp. nov., represents a novel genus in the alpha
      Proteobacteria.
AB  - A Gram-negative bacterium was previously isolated from an oil field in Shizuoka,
      Japan, and designated strain HD-1. Here we have performed detailed
      characterization of the strain, and have found that it represents a novel genus.
      The 16S rRNA sequence of strain HD-1 displayed highest similarity to various
      uncultured species (86.7-99.7%), along with 86.2-88.2% similarity to sequences
      from Azospirillum, Methylobacterium, Rhizobium, and Hyphomicrobium, all members
      of the alpha-Proteobacteria. Phylogenetic analysis revealed that HD-1 represented
      a deep-branched lineage among the alpha-Proteobacteria. DNA-DNA hybridization
      analysis with Azospirillum lipoferum and Hyphomicrobium vulgare revealed low
      levels of similarity among the strains. We further examined the biochemical
      properties of the strain under aerobic conditions. Among carbon sources, ethanol,
      n-propanol, n-butanol, and n-tetradecanol were the most preferred, while acetate,
      propionate, and pyruvate also supported high levels of growth. The strain could
      also grow on aromatic compounds such as toluene, benzene and phenol, and
      aliphatic hydrocarbons such as n-octane and n-tetradecane. In contrast, glycerol
      and various sugars, including glucose, fructose, maltose, and lactose, failed to
      support growth of HD-1. Under an anaerobic gas phase with butanol as the carbon
      source, little increase in cell weight was observed with the addition of several
      possible electron acceptors. As strain HD-1 represents a novel genus in the alpha
      Proteobacteria, we designated the strain as Oleomonas sagaranensis gen. nov., sp.
      nov., strain HD-1.

PMID- 12480114
TI  - Analysis of Bacillus megaterium lipolytic system and cloning of LipA, a novel
      subfamily I.4 bacterial lipase.
AB  - The lipolytic system of Bacillus megaterium 370 was investigated, showing the
      existence of at least two secreted lipases and a cell-bound esterase. A gene
      coding for an extracellular lipase was isolated and cloned in Escherichia coli.
      The cloned enzyme displayed high activity on short to medium chain length (C(4)
      C(8)) substrates, and poor activity on C(18) substrates. On the basis of amino
      acid sequence homology, the cloned lipase was classified into subfamily I.4 of
      bacterial lipases.

PMID- 12480115
TI  - In vitro anti-Neisseria gonorrhoeae activity of Terminalia macroptera leaves.
AB  - We used the agar dilution method to evaluate the antibacterial effect of
      Terminalia macroptera leaf (Tml) extract against nine reference and clinical
      Neisseria gonorrhoeae strains, including penicillin- and tetracycline-resistant
      and -susceptible strains. Tml possesses anti-N. gonorrhoeae activity against all
      of the strains and the minimum inhibitory concentrations (MIC) were between 100
      and 200 microg ml(-1). We then used a liquid-liquid partition method to divide
      the Tml extract into five fractions and determined the anti-N. gonorrhoeae
      activity of each of the fractions. All of the fractions showed antibacterial
      activity. The most active one was identified as the diethyl ether fraction and
      had MIC values of between 25 and 50 microg ml(-1) against all of the strains.

PMID- 12480116
TI  - Impact of coaching by community pharmacists on drug attitude of depressive
      primary care patients and acceptability to patients; a randomized controlled
      trial.
AB  - OBJECTIVE: To investigate whether an intervention by Dutch community pharmacists
      improves the drug attitude of depressive patients, who are prescribed a
      nontricyclic antidepressant by their general practitioner (GP). METHOD: A
      randomized controlled trial with a 3-month follow-up was conducted among
      consecutive general practice patients who go to 19 pharmacists for
      antidepressants. The trial consisted of a control group (n=79) that received
      usual care and an intervention group (n=69) that received three drug coaching
      contacts at the pharmacy and a 25-min take-home video on the background of
      depression and the effects of medication. OUTCOME MEASURE: Drug attitude (DAI).
      RESULTS: At the baseline measurement there were no significant differences
      between the intervention and control group on any demographic and health status
      variables or on clinical symptoms. At the 3-month follow-up intervention patients
      had a better drug attitude (P=0.03) than their controls and evaluated the
      coaching of their pharmacist as more positive. They also felt the video to be
      useful. It had changed their ideas about medication. CONCLUSIONS: Coaching by
      community pharmacists is an effective way to improve drug attitude of depressive
      primary care patients and it is acceptable to them.

PMID- 12480117
TI  - Chronic citalopram treatment induces time-dependent changes in the expression and
      DNA-binding activity of transcription factor AP-2 in rat brain.
AB  - Imbalances in the midbrain monoaminergic systems have been implicated to play a
      role in neuropsychiatric conditions. Several genes in these systems have binding
      sites for transcription factor activating protein-2 (AP-2) in their regulatory
      regions. Thus, AP-2 may be a factor controlling the expression of genes in the
      monoaminergic systems important for maintaining normal psychiatric functions. The
      present study indicates that subchronic treatment with the antidepressant
      citalopram induces time-dependent changes in DNA-binding activity and levels of
      transcription factor AP-2 in rat whole brain. Rats were treated with citalopram
      (10 mg/kg) for 1, 3, 7 and 21 days. Animals treated for 7 days had significantly
      decreased DNA-binding activity and levels of AP-2 alpha and AP-2 beta isoforms
      when compared to saline-treated animals. There was no observed difference between
      citalopram- and saline-treated animals after 21 days. Elucidation of the
      molecular mechanisms underlying mental disorders is important for future drug
      development, where transcription factors might be important drug targets.

PMID- 12480118
TI  - Effects of partial locus coeruleus denervation and chronic mild stress on
      behaviour and monoamine neurochemistry in the rat.
AB  - It has been proposed that lesions of the ascending noradrenergic projections
      render animals more vulnerable to stress. In this study, the effects of partial
      denervation of the locus coeruleus (LC) by DSP-4 (10 mg/kg) treatment, chronic
      mild stress (CMS) and their combination were examined. DSP-4 was administered to
      rats 1 week before the onset of CMS, which was applied for 5 weeks. In the forced
      swimming test, the immobility time was decreased by both DSP-4 and CMS. In the
      open field test, the number of defecations was increased after DSP-4 treatment
      plus CMS. Partial LC denervation decreased the levels of noradrenaline (NA) by
      34%, increased NA turnover, and decreased the density of beta-adrenoceptors in
      the cerebral cortex. CMS decreased the binding affinity of beta-adrenoceptors, an
      effect not observed in the DSP-4 treated animals. In conclusion, 6 weeks after
      partial LC denervation NA turnover is increased in the cortex, and the effect of
      CMS on emotionality is enhanced.

PMID- 12480119
TI  - Clozapine decreases rat brain dehydroepiandrosterone and dehydroepiandrosterone
      sulfate levels.
AB  - We examined the influence of the atypical antipsychotic agent clozapine compared
      to haloperidol, on levels of dehydroepiandrosterone and dehydroepiandrosterone
      sulfate ester (both gamma-aminobutyric acid(A) (GABA(A)) receptor allosteric
      antagonists) in the rat cortex. i.p. injections of clozapine (5 and 15 mg/kg),
      but not haloperidol (1 mg/kg), for 8 days decreased rat brain cortical
      dehydroepiandrosterone and dehydroepiandrosterone sulfate levels. These findings
      support the role of neurosteroids and possibly GABA(A) receptor modulation in the
      mechanism of action of clozapine.

PMID- 12480120
TI  - The influence of dyslipidemia on the plasma protein and lipoprotein distribution
      of haloperidol.
AB  - The objective of this study is to determine the effect of dyslipidemia on the
      plasma protein and lipoprotein distribution of haloperidol. In doing so, total
      plasma cholesterol and triglyceride levels were adjusted by adding differing
      volumes of concentrated low-density lipoproteins and very-low-density
      lipoproteins to normolipidemic plasma. Following the incubation of [3H]
      haloperidol plus cold haloperidol (18 microg/ml) the plasma was separated into
      its lipoprotein and lipoprotein deficient fractions by density gradient ultra
      centrifugation and [3H]-haloperidol distribution was determined. Our results
      revealed a significant positive correlation between total cholesterol
      concentration and haloperidol recovery in the low-density lipoprotein fraction
      (r=0.975, df=13, P<0.005). A positive correlation was also observed between total
      plasma triglyceride concentration and haloperidol recovery from both the very low
      density lipoprotein (r=0.965, df=16, P<0.002) and low-density lipoprotein
      fractions (r=0.935, df=16, P<0.005). This redistribution was the result of
      haloperidol leaving the lipoprotein-deficient fraction were it is primarily bound
      to albumin and alpha(1)-acid glycoprotein. This redistribution of haloperidol may
      influence its clinical efficacy.

PMID- 12480121
TI  - Safety of olanzapine versus conventional antipsychotics in the treatment of
      patients with acute schizophrenia. A naturalistic study.
AB  - BACKGROUND: Conventional antipsychotics although effective in treating acute
      psychotic and behavioural symptoms are subject to certain limitations due to the
      high incidence of side effects associated, mainly extrapyramidal symptoms (EPS),
      and insufficient response shown in some cases. EPS are a major factor in
      neuroleptic non compliance and high relapse rates among patients. This study was
      designed to assess the safety and effectiveness of olanzapine compared to typical
      antipsychotics drugs in the treatment of schizophrenic inpatients at acute
      psychiatric in-patient units. METHOD: Data from 904 patients schizophrenic
      patients (F20 of ICD10, WHO) were collected in this prospective, comparative, non
      randomized, open and observational study. Patients were followed during their
      entire hospital stay. Safety was assessed through the collection of spontaneous
      adverse events and a specific extrapyramidal symptoms questionnaire (EPS).
      Clinical status was measured through the Brief Psychiatric Rating Scale (BPRS),
      Clinical Global Impression of Severity (CGI-S), Patient Global Impression of
      Improvement (PGI) and the Nursing Observational Scale for In-patient Evaluation
      (NOSIE). RESULTS: A total of 483 patients received olanzapine (olanzapine group,
      OG), and 421 received typical antipsychotics (control group, CG). Treatment
      emergent EPS, or worsening of previous EPS were statistically significantly
      higher in the CG (P=0.001). Responder rate was statistically greater in the OG
      (P<0.001). Mean change in BPRS-total, BPRS-negative, BPRS-agitation subscales and
      PGI was significantly higher in the OG (P<0.001). Mean decrease in CGI, BPRS
      positive and BPRS depression sub-scales was also significantly lower (P< or
      =0.05). Mean change in the NOSIE scale was similar between both groups.
      CONCLUSION: Olanzapine has been shown to be better tolerated in comparison with
      conventional antipsychotics in a large unselected sample of acutely psychotic
      schizophrenic in-patients. Its effectiveness may be greater than that of
      conventional antipsychotics.

PMID- 12480122
TI  - Increased corneal temperature in drug-free male schizophrenia patients.
AB  - Schizophrenia patients may exhibit altered body temperature. We hypothesized that
      drug-free patients may have a higher corneal temperature than normal subjects.
      The corneal temperature of seven remitted drug-free schizophrenia outpatients and
      seven healthy volunteers was evaluated with a flir thermal imaging camera. A
      significantly higher corneal temperature was observed in the patient group
      (34.60+/-1.89 vs. 33.05+/-0.58 degrees C; P=0.005) and it correlated with their
      BPRS score (r=0.82; P=0.024). The relevance of these preliminary findings merit
      further investigation.

PMID- 12480123
TI  - Influence of antidepressants on intracellular levels of cyclic adenosine
      monophosphate in human peripheral blood mononuclear cells.
AB  - This study examines the effects of paroxetine and imipramine on intracellular
      concentrations of cyclic adenosine monophosphate (cAMP) in human peripheral blood
      mononuclear cells. It was found that imipramine and paroxetine had no effect on
      basal cAMP-levels. Stimulation with lipopolysaccharides and phytohaemagglutinin
      increased intracellular cAMP concentrations. However, pre-incubation with
      imipramine or paroxetine, did not influence this increase. These data do not
      support the hypothesis that cAMP may be related to the in vitro anti-inflammatory
      effects of antidepressants.

PMID- 12480124
TI  - Effects of ethanol and 5-HT1A agonists on astroglial S100B.
AB  - Previous studies from this and another laboratory demonstrated that in utero
      ethanol exposure reduces 5-HT neurons and S100B-immunopositive glia that are
      proximal to these neurons. Our laboratory also found that these effects are
      prevented by maternal treatment with a 5-HT(1A) agonist. Because of S100B's
      important role in the development of 5-HT neurons, the present study used both in
      vivo and in vitro models to investigate the potential involvement of S100B with
      the damaging effects of ethanol and with the protective effects of 5-HT(1A)
      agonists. We used in situ hybridization to address whether a 5-HT(1A) agonist
      could potentially affect S100B mRNA in vivo. Maternal treatment with buspirone
      between gestation days 13 and 20 significantly increased S100B mRNA in
      neuroepithelium of G20 offspring of control (40%) and ethanol-fed dams (20%).
      However, S100B mRNA was not altered in neuroepithelium from ethanol-exposed
      offspring. In astroglial cultures, we examined whether ethanol reduces the
      release of S100B and whether a 5-HT(1A) agonist could stimulate the release of
      this protein. We also evaluated the effects of ethanol and ipsapirone on
      astroglial content of S100B. Neither the concentration of S100B in astroglial
      media nor astroglial content of S100B were affected by ethanol. However,
      treatment with 100 nM ipsapirone, a 5-HT(1A) agonist, between the 6th and 7th day
      in vitro, increased astroglial release of S100B 2- to 3-fold. Thus, the
      protective effects of a 5-HT(1A) agonist on ethanol-treated 5-HT neurons might be
      associated with the ability of these drugs to release the neurotrophic factor
      S100B from astrocytes.

PMID- 12480125
TI  - GABA(A) receptor sites in the developing human foetus.
AB  - GABA(A) receptor sites were characterised in cerebral cortex tissue samples from
      deceased neurologically normal infants who had come to autopsy during the third
      trimester of pregnancy. Pharmacological parameters were obtained from homogenate
      binding studies which utilised the 'central-type' benzodiazepine ligands
      [3H]diazepam and [3H]flunitrazepam, and from the GABA activation of [3H]diazepam
      binding. It was found that the two radioligands behaved differently during
      development. The affinity of [3H]flunitrazepam for its binding site did not vary
      significantly between preparations, whereas the [3H]diazepam K(D) showed marked
      regional and developmental variations: infant tissues showed a distinctly lower
      affinity than adults for this ligand. The density of [3H]flunitrazepam binding
      sites increased approximately 35% during the third trimester to reach adult
      levels by term, whereas [3H]diazepam binding capacity declined slightly but
      steadily throughout development. The GABA activation of [3H]diazepam binding was
      less efficient early in the trimester, in that the affinity of the agonist was
      significantly lower, though it rose to adult levels by term. The strength of the
      enhancement response increased to adult levels over the same time-frame. The
      results strongly suggest that the subunit composition of cortical GABA(A) sites
      changes significantly during this important developmental stage.

PMID- 12480126
TI  - Transport of 14C-gamma-aminobutyric acid into brain, cerebrospinal fluid and
      choroid plexus in neonatal and adult rats.
AB  - In general blood to brain entry of amino acids is greater in the neonatal rats
      compared to the adults. gamma-Aminobutyric acid (GABA), a neurotransmitter amino
      acid, shows limited transport across the blood-brain barrier (BBB) in the adult
      rat. Characteristics of GABA entry into the immature rat brain is yet to be
      addressed. This investigation was set to study the entry of GABA into brain of
      the neonatal rat compared to the adult. Using the bilateral in situ brain
      perfusion technique, the entry of 14C-GABA into brain, cerebrospinal fluid (CSF)
      and lateral ventricles choroid plexuses was studied in the adult and neonatal
      rats. 14C-GABA uptake into neonatal rat brain after 20 min perfusion was 0.116+/
      0.014 ml g(-1), approximately twice that of the adults (P<0.01). Half saturation
      constant, K(m), did not change with age (P>0.05), whereas maximal transport into
      the brain, V(max), was reduced from 0.152 to 0.068 nmol min(-1) g(-1) showing a
      significant reduction with age (P<0.05). In the neonate the entry of GABA into
      the CSF was dominant when compared to that into the brain, this could be due to a
      greater diffusional component, K(d), which was detected to be high in the
      neonate. In conclusion, the uptake of 14C-GABA into brain of the immature rats
      exceeded that in the adults which is thought to be due to both greater maximal
      transport and greater diffusion in the neonate compared to the adult.

PMID- 12480127
TI  - Spontaneous activity-independent intracellular calcium signals in the developing
      spinal cord of the zebrafish embryo.
AB  - Calcium signals play an important role in a variety of processes necessary for
      neuronal development. Whilst the characteristics and function of calcium signals
      have been comprehensively examined in vitro, the significance of these signals
      during development in an intact embryo remains unclear. In this study, we have
      examined the spatial and temporal patterns of intracellular calcium signals in
      precursor cells (cells without processes) within the spinal cord of the intact
      zebrafish embryo aged between 17 and 27 h. In total, approximately one-third of
      cells displayed spontaneous intracellular calcium transients. The calcium
      transients had an average peak amplitude of 33.3 (+/-2.8%) above baseline, a
      duration of 52.2 (+/-6.3 s) and occurred with an average frequency of 4.6 (+/-0.4
      per hour). Calcium transients were observed in precursor cells located throughout
      the spinal cord, with the highest percentage of active cells (35.1+/-8%)
      occurring at a developmental time of 21-22 h. Furthermore these intracellular
      calcium signals were observed in the presence of tricaine, indicating that they
      are not generated via sodium-dependent action potentials. In precursor cells
      loaded with the calcium buffer BAPTA both the frequency and the amplitude of the
      calcium transients was significantly reduced. The intracellular calcium
      transients may represent a common activity-independent calcium-mediated mechanism
      that contributes to the regulation of neuronal development in the spinal cord of
      the zebrafish embryo during the segmentation and early pharyngula period.

PMID- 12480128
TI  - BDNF mRNA expression during postnatal development, maturation and aging of the
      human prefrontal cortex.
AB  - Brain derived neurotrophic factor (BDNF) is widely distributed in the central
      nervous system (CNS) and has survival-promoting actions on a variety of CNS
      neurons. We have examined changes in the level of BDNF mRNA expression in the
      dorsolateral prefrontal cortex (DLPFC) of the postnatal human brain using both
      RNAse protection assay and in situ hybridization. Expression of BDNF mRNA in the
      DLPFC was compared to that in the occipital cortex. BDNF mRNA levels vary between
      layers, with layer VI consistently higher than other layers in both the DLPFC and
      occipital regions. BDNF mRNA levels increase approximately one-third from infancy
      to adulthood, i.e. they are relatively low during infancy and adolescence, peak
      during young adulthood, and are maintained at a constant level throughout
      adulthood and aging. The significant increase in BDNF mRNA levels in the DLPFC
      during the young adult period coincides with the time when the frontal cortex
      matures both structurally and functionally. The increase in BDNF at this critical
      time in human development may have important implications for the etiology and
      treatment of the severe mental disorders that tend to present during this time.

PMID- 12480129
TI  - Ontogeny of sexually dimorphic astrocytes in the neonatal rat arcuate.
AB  - The arcuate nucleus of the hypothalamus is one of several sexually dimorphic
      hypothalamic nuclei. We have previously demonstrated that astrocytes in the
      neonatal arcuate nucleus exhibit a marked sexually dimorphic morphology as a
      result of differential exposure to gonadal steroids by postnatal day (PN) 2, with
      males having complex stellate cells compared to the simple bipolar ones found in
      females. Here, we present data demonstrating that arcuate astrocytes are sexually
      dimorphic by the day of birth and continue as such throughout postnatal
      development (PN0-PN15), and persist into adulthood. These data suggest that early
      gonadal steroid exposure permanently organizes arcuate astrocyte morphology. The
      male versus female difference in astrocyte morphology may contribute to the
      sexually dimorphic regulation of neuroendrocrine secretions from the pituitary in
      the adult.

PMID- 12480130
TI  - The effect of the timing of prenatal X-irradiation on Purkinje cell numbers in
      rat cerebellum.
AB  - Exposure of the developing brain to X-irradiation in utero is known to cause
      various deleterious consequences. We have previously reported the effects of
      prenatal X-irradiation on the development of the cerebral cortex in rats. We have
      now extended this study to examine the effects of such X-irradiation on the
      development of the cerebellum. Wistar rats were exposed to 1.5 Gy X-irradiation
      either on days 14, 15 or 16 of gestation (E14, E15, E16). Sham-irradiated animals
      were used as controls. At seven postnatal weeks of age, male rats from each group
      were deeply anesthetized and killed by intracardiac perfusion with 2.5%
      glutaraldehyde in 0.1 M phosphate buffer. The unbiased stereological procedure
      known as the fractionator method was used to estimate the total number of
      Purkinje cells in the cerebellum of each animal. Body and cerebellar weights from
      E14 and E15, but not E16 irradiated rats showed significant deficits compared to
      control animals. Rats irradiated on E16 and control rats had about 285100-304800
      Purkinje cells in the cerebellum. There was no significant difference between
      these values. However, E14 and E15 irradiated animals had about 117500 and 196300
      Purkinje cells, respectively. These estimates were significantly different from
      those observed in both control and E16 irradiated rats. Given that the phase of
      division of Purkinje cell progenitors is mainly between E14-E15 and the phase of
      differentiation and migration is between E16-E20, it is concluded that the
      vulnerable period of the Purkinje cells to X-irradiation closely overlaps the
      phase of division of progenitors.

PMID- 12480131
TI  - Effects of elevated serotonin levels on patterns of GAP-43 expression during
      barrel development in rat somatosensory cortex.
AB  - Elevating cortical serotonin (5-HT) in rats with clorgyline, a monoamine oxidase
      A (MAO(A)) inhibitor, from postnatal day (P-0) to P-6 delays the organization of
      thalamocortical afferent fibers into a vibrissae-related pattern in the
      somatosensory cortex (S-I). Despite continued elevation of cortical 5-HT through
      P-8, the thalamocortical fibers do form, albeit with some delay, a characteristic
      vibrissae pattern of barrels in layer IV of S-I by P-8. The growth-associated
      protein, GAP-43, is transiently expressed in developing S-I cortex of normal rats
      in a vibrissae related pattern until P-7. After P-7, GAP-43 expression is reduced
      in the barrel centers and increased in the septa. The present study evaluated the
      effect of elevated 5-HT levels on the distribution of GAP-43 immunoreactivity in
      S-I. We employed 5-HT immunocytochemistry and 1,1'-dioctadecyl-3,3,3",3'
      tetramethylindocarbocyanine perchlorate (DiI) labeling of thalamic radiations to
      confirm a 'barrelless' phenotype in P-6 clorgyline-treated animals and a
      recovered barrel pattern in treated animals allowed to survive until P-8 and P
      10. GAP-43 immunocytochemistry was used to evaluate the cortical distribution of
      this protein in similarly treated littermates. Continuous inhibition of MAO(A)
      from P-0 to P-6 resulted in a corresponding loss of the GAP-43 vibrissae-related
      pattern at P-6. Despite continued elevation of cortical 5-HT until P-8 and P-10,
      the characteristic vibrissae-complementary pattern of GAP-43 emerged with
      expression concentrated in the septa and rows. GAP-43 vibrissae-related
      thalamocortical axon pattern never appeared in the clorgyline-treated animals.
      Thus, while elevated 5-HT delays development of a vibrissae-related pattern of
      thalamocortical afferents, it does not appear to alter the time when a GAP-43
      vibrissae-related complementary pattern emerges.

PMID- 12480132
TI  - Development of the alpha7 nicotinic cholinergic receptor in rat hippocampal
      formation.
AB  - The alpha7 nicotinic receptor has been implicated in the regulation of a variety
      of developmental processes. The goal of the present study was to assess whether
      the alpha7 receptor might participate in the regulation of hippocampal ontogeny
      by describing the spatiotemporal development of alpha7 mRNA and alpha
      bungarotoxin binding in rat hippocampal formation. Message for the alpha7
      receptor was initially observed in the hippocampal neuroepithelium at embryonic
      day 13 and in the anlage of the hippocampal formation on embryonic day 14.
      Binding of alpha-bungarotoxin was initially seen on embryonic day 15 in the
      dorsal portion of the anlage of stratum oriens and stratum radiatum-lacunosum
      moleculare, but was never observed in the neuroepithelium. Dramatic elevations in
      both alpha7 mRNA and alpha-bungarotoxin binding were observed in most regions of
      the hippocampal formation neonatally. The levels of both alpha7 message and
      protein gradually decreased during the first three postnatal weeks to adult
      levels in most regions. The lack of alpha-bungarotoxin binding in the
      neuroepithelium suggests that the alpha7 receptor does not influence
      neurogenesis. The early appearance and complex, prolonged pattern of development
      of the alpha7 receptor suggest that it may influence processes as diverse as cell
      migration, dendritic elaboration and apoptosis during hippocampal maturation.

PMID- 12480133
TI  - Expression of voltage-dependent calcium channels in the embryonic rat midbrain.
AB  - The diversity of expression of high-voltage activated voltage-dependent calcium
      channels (VDCC) was investigated with whole-cell voltage-clamp recordings from
      dissociated embryonic rat ventral mesencephalic cells over a 7-day culture
      period. Cell phenotype was identified post-recording by fluorescent
      immunocytochemistry as tyrosine hydroxylase positive (TH+) or glutamic acid
      decarboxylase positive (GAD+). Both TH+ and GAD+ cells displayed high-threshold
      calcium (Ca(2+)) currents activated by depolarisations positive to -60 mV. In
      both cell types, pharmacological dissection using selective VDCC inhibitors,
      omega-agatoxin IVA (Aga IVA), omega-conotoxin GVIA (GVIA) and nifedipine
      demonstrated the existence of P/Q-, N- and L-type VDCC, respectively. The
      remaining residual current could be blocked by cadmium. It was found that the
      contribution to the whole-cell current by the N-type channel was greater in TH+
      cells than GAD+ cells at each time point examined, whilst the contribution to the
      whole-cell current by the L-type channel was greater in GAD+ cells than TH+
      cells. However, over the 7-day culture period, the expression of VDCC types in
      both cell phenotypes changed in a similar fashion, with the contribution to the
      whole-cell current from the N-type current decreasing, and the contribution from
      the R-type current increasing. Our data could provide new insights into a range
      of neurodevelopmental mechanisms related to Ca(2+) homeostasis in developing
      mesencephalic neurons.

PMID- 12480134
TI  - Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7
      receptor.
AB  - Glucocorticoid receptor expression in primary hippocampal cell cultures was
      significantly increased with either 10 mM 8-bromo cAMP, 50 nM 5
      carboxamidotryptamine (5-CT), a potent 5-HT7 receptor agonist, or 100 nM 5-HT.
      The effect of 5-HT or 5-CT was blocked with methiothepin or by a protein kinase A
      inhibitor, but not pindolol. These results suggest that the effects of 5-HT on
      hippocampal GR expression is mediated by a 5-HT7 receptor.

PMID- 12480135
TI  - Expression of the Ste20-like kinase SLK during embryonic development and in the
      murine adult central nervous system.
AB  - Cell growth and terminal differentiation are controlled by complex signaling
      cascades that regulate the expression of specific subsets of genes controlling
      cell fate and morphogenic processes. We have recently cloned and characterized a
      novel Ste20-like kinase termed SLK (Sabourin et al., Mol. Cel. Biol. 20 (2000)
      684). However, the specific function of SLK is poorly understood. To gain further
      insights into the role of SLK we have characterized its activity, expression and
      distribution in the CNS during embryonic development and in the adult brain.
      Although SLK is expressed ubiquitously in adult tissues, our results show that it
      is expressed preferentially in neuronal lineages during development. We find that
      SLK is preferentially expressed in the neurons and neuroepithelium of the
      developing embryo and can be detected at 10.5 and 12.5 days post-coitum (dpc) in
      the forebrain, midbrain and hindbrain of the developing CNS. At later stages
      (14.5 dpc), SLK is expressed in the hypothalamus region, all layers of the neural
      tube, dorsal root ganglion and in the proliferating ependymal layers.
      Surprisingly, following middle cerebral artery occlusion, SLK expressing neuronal
      cells are lost and SLK is localized to phagocytic macrophages/microglia. These
      results suggest a functional role for SLK in early neuronal development as well
      as in the adult CNS.

PMID- 12480136
TI  - Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB
      phosphorylation in the rat brain.
AB  - In the present study we show that chronic exposure to low levels of lead (Pb(2+))
      during development alters the type of N-methyl-D-aspartate receptor (NMDAR)
      expressed in the developing and young adult rat brain. Ifenprodil inhibition of
      [3H]MK-801 binding to the NMDAR channel in cortical and hippocampal neuronal
      membranes expressed high and low affinity components. Previous studies have shown
      that the high affinity component is associated with NR1/NR2B receptor complexes
      while the low affinity component is associated with the appearance and insertion
      of the NR2A subunit to NMDAR complexes. Pb(2+)-exposed rats express a greater
      number of [3H]MK-801 binding sites associated with the high affinity and low
      affinity components of ifenprodil inhibition. Further, [3H]ifenprodil saturation
      isotherms and Scatchard analysis in cortical and hippocampal membranes showed a
      higher number of binding sites (B(max)) with no change in binding affinity (K(d))
      in Pb(2+)-exposed animals relative to controls. Quantitative [3H]MK-801
      autoradiography in response to glutamate and glycine provided evidence that NMDAR
      complexes in Pb(2+)-exposed rat brain were maximally activated in situ. Higher
      levels of ifenprodil-sensitive binding sites and increased sensitivity to
      agonists are properties characteristic of NR1/NR2B recombinant receptors. Thus,
      our results strongly suggest that a greater proportion of the total number of
      NMDAR are NR1/NR2B receptors in the Pb(2+)-exposed rat brain. This Pb(2+)-induced
      change in NMDAR subtypes in the rat brain was associated with reduced CREB
      phosphorylation in cortical and hippocampal nuclear extracts. These findings
      demonstrate that chronic exposure to environmentally relevant levels of Pb(2+)
      altered the subunit composition of NMDAR complexes with subsequent effects on
      calcium-sensitive signaling pathways involved in CREB phosphorylation.

PMID- 12480137
TI  - Ontogeny of ionotropic glutamate receptor subunit expression in the rat
      hippocampus.
AB  - The ionotropic glutamate receptors play key roles in multiple developmental
      mechanisms, including regulation of neuronal migration and differentiation, and
      synaptic organization. In this study, we investigated the developmental
      expression of these glutamate receptors in the postnatal rat hippocampus. We
      examined the transcripts encoding the subunits composing the N-methyl-D-aspartate
      (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate
      (KA) subtypes of glutamate receptors by in situ hybridization at multiple time
      points from postnatal day (PND) 1 to PND 35. In the case of the AMPA receptor,
      gluR1 expression did not change over this time period, while gluR2, gluR3, and
      gluR4 did. These three subunits each underwent a transient period of increased
      expression at either PND 7 or PND 18. All five of the kainate receptor subunits
      changed during this time, all starting at relatively high levels of expression
      that declined by PND 35. Similar to most of the AMPA subunits, all of the kainate
      subunits had transient periods of significantly increased expression. The NMDA
      receptors all changed during over time as well, and each had a period of
      increased expression. The periods of transiently increased expression of all of
      these subunits coincide with known periods of plasticity and other critical times
      in development. These results suggest the different glutamate receptor subtypes
      may be critical at specific times during postnatal brain development.

PMID- 12480138
TI  - Effects of prenatal exposure to ethanol on the cyclin-dependent kinase system in
      the developing rat cerebellum.
AB  - Prenatal exposure to ethanol inhibits neurogenesis in the developing cerebellum.
      Cyclin-dependent kinases (CDKs) are a family of protein kinases that play
      multiple roles in the regulation of cell proliferation, differentiation and
      survival. The activity of CDKs is positively regulated by CDK activators,
      cyclins, and negatively regulated by CDK inhibitors (CDKIs). We hypothesize that
      impaired cerebellar development induced by gestational ethanol exposure is
      mediated by disruption of the CDK system. Pregnant rats were fed ad libitum with
      an ethanol-containing liquid diet (Et) or pair-fed an isocaloric control diet
      (Ct). Cerebella were collected from pups (postnatal day (P) 0 through P21) and
      examined for CDK, cyclin, or CDKI expression using a quantitative immunoblotting
      procedure. In Ct-treated rats, the expression of CDK2 and its activator, cyclin
      A, paralleled the pattern of granule cell proliferation. Prenatal ethanol
      exposure produced a significant down-regulation of CDK2/cyclin A expression.
      Although the amounts of CDK4/CDK6 and their activator, cyclin D2, did not
      oscillate during postnatal development, their expression in Et-treated pups was
      significantly (P<0.05) higher than in controls. The expression of a CDK
      inhibitor, p27(Kip), was inversely correlated to proliferation of cerebellar
      granule progenitors. Prenatal ethanol exposure caused the down-regulation of
      p27(Kip) between P0 and P21. Thus, prenatal exposure to ethanol disturbed the
      expression of cell cycle machineries in the postnatal cerebellum. This may
      account for the teratogenic effects of ethanol on the developing cerebellum.

PMID- 12480139
TI  - Changes of steroidogenic acute regulatory protein mRNA expression in postnatal
      rat development.
AB  - The present study investigated the expression pattern of steroidogenic acute
      regulatory protein (StAR) mRNA in several brain regions and peripheral endocrine
      organs using Northern blot, RT-PCR and in situ hybridization. StAR mRNA in the
      adrenal gland was detected at birth and decreased for 2 weeks postnatally. In
      gonads, it was also detected at birth though at a lower level than adrenal, and
      was maintained until week 3. Thereafter StAR mRNA expression in both endocrine
      organs was increased. Though the amount of StAR mRNA in the brain was much less
      than that of peripheral endocrine organs, it was expressed from birth and, in
      general, appeared to gradually increase during postnatal development. A gradual
      increase was found in the hypothalamus, while a sigmoidal expression was shown in
      the olfactory bulb. The increased expression of StAR mRNA in the postnatal period
      suggests that it might have a role in the regulation of neurosteroidogenesis
      needed in neuronal cell growth and differentiation in postnatal rat brain
      development.

PMID- 12480140
TI  - Neuropeptide tyrosine-like immunoreactive system in the brain, olfactory organ
      and retina of the zebrafish, Danio rerio, during development.
AB  - The anatomical distribution of neuropeptide tyrosine (NPY)-like immunoreactivity
      was investigated in the brain, olfactory organ and retina of the zebrafish, Danio
      rerio, during development and in juvenile specimens, by using the indirect
      immunofluorescence and the peroxidase-antiperoxidase methods. In 60 h post
      fertilization (hpf) embryos, NPY-like immunoreactive cell bodies appeared in the
      hypothalamus, within the posterior periventricular nucleus. Few positive nerve
      fibers were found in the hypothalamus and in the tegmentum of the mesencephalon.
      In 72 hpf embryos, a new group of NPY-like immunoreactive cells was found in the
      olfactory pit. At day 4 of development, NPY-like immunoreactive cell bodies were
      detected between the olfactory pit and the olfactory organ. In the hypothalamus
      the location of positive cell bodies was similar to that reported in the previous
      developmental stages. A few positive nerve fibers appeared in the tegmentum of
      the rhombencephalon. At days 7 and 15 of development, the distribution of NPY
      like immunoreactivity was very similar to that reported at day 4. However, at day
      15, NPY-like immunoreactivity appeared for the first time in amacrine cells of
      the retina and in nerve fibers of the tectum of the mesencephalon. In 1-month/3
      month-old animals, additional groups of NPY-like immunoreactive cell bodies
      appeared in the glomerular layer of the olfactory bulbs, the terminal nerve, the
      lateral nucleus of the ventral telencephalic area, the entopeduncular nucleus and
      in the medial region of the reticular formation of the rhombencephalon. These
      results show that NPY-like immunoreactive structures appear early during ontogeny
      of zebrafish. The distribution of the immunoreactive system increases during the
      ontogeny, the juvenile stages, and reaches the complete development in mature
      animals. The location of NPY-like immunoreactivity indicates that, during
      development, NPY could be involved in several neuromodulatory functions,
      including the processing of visual and olfactory information. In 1-month/3-month
      old animals, NPY-like immunoreactive nerve fibers are present in the pituitary,
      suggesting that, from these stages onward, NPY may influence the secretion of
      pituitary hormones.

PMID- 12480141
TI  - alpha-Ketoisocaproic acid regulates phosphorylation of intermediate filaments in
      postnatal rat cortical slices through ionotropic glutamatergic receptors.
AB  - In this study we investigated the effects of alpha-ketoisocaproic acid (KIC), the
      main keto acid accumulating in the inherited neurometabolic disorder maple syrup
      urine disease (MSUD), on the in vitro incorporation of 32P into intermediate
      filament (IF) proteins from cerebral cortex of rats during development. KIC
      decreased the in vitro incorporation of 32P into the IF proteins studied up to
      day 12, had no effect on day 15, and increased this phosphorylation in cortical
      slices of 17- and 21-day-old rats. A similar effect on IF phosphorylation was
      achieved along development by incubating cortical slices with glutamate.
      Furthermore, the altered phosphorylation caused by the presence of KIC in the
      incubation medium was mediated by the ionotropic receptors NMDA, AMPA and kainate
      up to day 12 and by NMDA and AMPA in tissue slices from 17- and 21-day-old rats.
      The results suggest that alterations of IF phosphorylation may be associated with
      the neuropathology of MSUD.

PMID- 12480142
TI  - Effects of lesions of basal forebrain cholinergic neurons in newborn rats on
      susceptibility to seizures.
AB  - The cholinergic system modulates cerebral excitability. We recently reported that
      immunolesions of the basal forebrain (BF) cholinergic neurons in adult rats
      increase the susceptibility to generalized seizures. In this study we
      investigated the effects of lesions of the BF cholinergic neurons in neonatal
      rats on seizure susceptibility and cognitive function. Neonatal rats at postnatal
      day (P) 7 received intracerebroventricular (i.c.v.) injections of 192 IgG-saporin
      (SAP) or phosphate-buffered saline. Following 3 weeks after the injection the
      first group of rats was implanted with hippocampal electrodes for
      electroencephalogram (EEG) recordings while the second group of rats was tested
      for visual spatial memory using the hidden platform version of the water maze
      test. The first group of rats was then tested for seizure susceptibility using
      flurothyl 1 week after the electrode implantation. Rats that received
      immunolesions of the BF cholinergic neurons at P7 had significantly shorter
      latencies to onset of myoclonic jerks and tonic-clonic seizures than controls.
      However, no significant differences were found in the duration of seizures, or
      EEG ictal duration. No significant deficits in spatial learning were found
      between rats that received i.c.v. injections of SAP at P7 and controls. As in
      adult rats, lesions of the BF cholinergic system in rat pups result in subsequent
      increase in seizure susceptibility.

PMID- 12480143
TI  - CRMP-4 expression in the adult cerebral cortex and other telencephalic areas of
      the lizard Podarcis hispanica.
AB  - The control of neuritogenesis is crucial for the development, maturation and
      regeneration of the nervous system. The collapsin response-mediated protein 4
      (CRMP-4) is a member of a family of proteins that are involved in neuronal
      differentiation and axonal outgrowth. In rodents, this protein is expressed in
      recently generated neurons such as some granule neurons of the dentate gyrus, as
      well as in certain differentiated neurons undergoing neurite outgrowth or
      synaptogenesis during adulthood. Since CRMP-4 protein appears to be highly
      conserved throughout the evolutionary scale, we have used immunocytochemistry to
      study its distribution in the lizard cerebral cortex. We have found pronounced
      CRMP-4 immunolabeling in certain neurons of the medial cortex, the homologous
      region to the dentate gyrus, but also in the dorsal and lateral cortices. Double
      labeling with 5'-BrdU indicated that these medial cortex neurons were recently
      generated. However, it is also possible that many of these cells were not new but
      undergoing some kind of plasticity implicating neurite outgrowth. Similar CRMP-4
      labeled neurons and processes were observed in subcortical regions as the PDVR
      and the nucleus sphericus. Our results show for the first time the expression of
      CRMP-4 in a reptile brain, where it appears to be expressed in regions where
      adult neurogenesis and/or neurite outgrowth occur.

PMID- 12480144
TI  - NMDA receptor subunit expression following early postnatal exposure to ethanol.
AB  - Changes in NMDA receptor function following early postnatal exposure to ethanol
      may be related to the expression of NMDA receptor subunits. Following early
      postnatal exposure to ethanol, the expression of NMDA receptor subunits was
      examined. In cortex from ethanol-exposed rat pups at postnatal day 21, NR2A was
      significantly increased. There was no change in NR2B, thus suggesting that
      ethanol exposure during the third-trimester equivalent produces distinct effects
      on the NMDA receptor.

PMID- 12480145
TI  - Paradoxical locomotor activating effects of kappa-opioid receptor stimulation in
      the preweanling rat: role of the ventromedial thalamus and superior colliculus.
AB  - Stimulating kappa-opioid receptors in the substantia nigra pars reticulata
      robustly increases the locomotor activity of preweanling rats. To determine
      whether nigrothalamic and nigrotectal connections are necessary for this kappa
      opioid-mediated locomotor activity, preweanling rats were given a systemic
      injection of saline or 5 mg/kg U50,488 (a kappa-opioid receptor agonist) 2 days
      after receiving sham or bilateral electrolytic lesions of the ventromedial
      thalamus (VMT) or superior colliculus (SC). Results showed that lesions of the
      VMT and SC attenuated the U50,488-induced locomotor activity of preweanling rats,
      indicating that the locomotor activating effects of kappa-opioid receptor
      stimulation require that nigrothalamic and nigrotectal connections be intact.

PMID- 12480146
TI  - Functional maturation of periodontal mechanoreceptors during development in rats.
AB  - The influence of development on periodontal mechanoreceptors (PMRs) was
      investigated in four groups of male Wistar albino rats aged 1, 3, 5 weeks and 6
      months using an in vitro jaw-nerve preparation. The mean values of conduction
      velocities of the nerve innervating PMRs in 5-week and 6-month groups were
      significantly higher than those in the other two groups. All fiber types obtained
      in the 5-week and 6-month groups were Abeta. The mechanical thresholds of 5-week
      and 6-month groups were significantly higher than those of 1- and 3-week groups.
      These data suggest that the response properties of rat's PMRs are matured by 5
      week after birth, when functional molar occlusion and transition of dietary
      contents from liquid to hard-diet can be achieved.

PMID- 12480147
TI  - The ganglionic eminence--a putative intermediate target of amygdaloid
      connections.
AB  - The superior part of the ganglionic eminence has been shown to act as an
      intermediate target for outgrowing axons of projections between the thalamus and
      the cerebral cortex. This study aims at investigating whether amygdaloid
      projections transiently contact the inferior portion of the human ganglionic
      eminence which directly borders upon the amygdala. Between 16 and 20 weeks of
      gestation a high number of small fiber bundles which were immunolabelled with
      anti-MAP1b and anti-SNAP-25 could be traced from the amygdala towards the mantle
      zone of the ganglionic eminence. These fiber bundles left a fiber system which
      coursed from the amygdala towards the entorhinal cortex. Within the mantle zone
      of the ganglionic eminence immunoreactive puncta indicative of fiber termination
      were observed. After 22 weeks of gestation the number of fibers entering the
      ganglionic eminence gradually decreased. These results provide the first evidence
      that the marginal zone of the inferior ganglionic eminence is likely to
      constitute an intermediate target for growing axons which belong the amygdaloid
      projection to the entorhinal cortex.

PMID- 12480148
TI  - Differential growth of goldfish retinal explants on regenerating and non
      regenerating optic tract membranes.
AB  - Regenerating goldfish retinal explants were cultured on poly-L-lysine (control)
      or poly-L-lysine overlaid with membranes isolated from non-regenerating optic
      tract (OTr) and 10- or 21-day regenerating OTr. Non-regenerating OTr substrate
      inhibited all neurite growth while 10- and 21-day regenerating OTr substrates
      significantly increased the average neurite number per explant and average
      neurite length compared to controls. These results indicate an upregulation of
      neurite growth permissive properties of regenerating OTr membranes.

PMID- 12480149
TI  - Cell death in the inner nuclear layer of the retina is modulated by BDNF.
AB  - Developing amacrine cells in the vertebrate retina undergo naturally-occurring
      cell death which is accentuated by the early removal of retinal ganglion cells.
      We show that providing BDNF or decreasing endogenous BDNF via competitive binding
      with soluble TrkB receptors in a whole-retina culture assay modulates the
      frequency of dying cells in the amacrine cell layer. Ganglion cells synthesize
      BDNF, and amacrine cells express TrkB receptors, suggesting a likely signaling
      mechanism.

PMID- 12480150
TI  - Absence of selectivity in the loss of neurons from the developing cortical
      subplate of the rat.
AB  - Neurons of the cortical subplate display evidence of cell death, although a
      significant population survives to the mature brain. The present study examined
      different populations of neurons to determine if the loss of cells was specific
      for a particular cell type. Immunocytochemical procedures for neurons expressing
      GluR2/3, GAD, or NPY, were used on tissue sections taken from animals at
      gestational day 18 to postnatal day 21. The rate of loss of labeled cells was
      similar for all groups of neurons. Thus, these data reveal no evidence that the
      loss of subplate neurons is specific to any major cell type.

PMID- 12480151
TI  - Microglial distribution and apoptosis in fetal rat brain.
AB  - By histochemical and immunocytochemical techniques, this study aimed to determine
      the possible involvement of apoptosis in regulating the microglial distribution
      in fetal rat brain. While microglial cells were labeled with the isolectin
      Griffonia simplicifolia (GSA I-B4), apoptotic cells were detected by using
      terminal transferase-mediated dUTP nick end-labeling (TUNEL). TUNEL-labeled cells
      occurred mainly in the dorsal midline along its rostral-caudal axis of the brain
      where lectin-labeled microglia were also observed. Occasional TUNEL-labeled cells
      were observed in the intermediate zone lateral to the striatum (IZS) where lectin
      labeled microglia were common from embryonic day 16 (E16) onwards. Some of lectin
      labeled microglia showing different morphological forms ingested TUNEL-labeled
      bodies. In contrast, lectin-labeled microglia showing signs of apoptosis appeared
      to be lacking. These results clearly demonstrated that lectin-labeled microglia
      were distributed in areas with and without the occurrence of a large
      concentration of TUNEL-labeled cells. Our studies suggest that microglia in fetal
      rat brain will undergo differentiation and activation rather than apoptotic death
      to govern their population.

PMID- 12480152
TI  - Stable synchronized high-frequency signals from the main sensory and spinal
      nuclei of the pig activated by Abeta fibers of the maxillary nerve innervating
      the snout.
AB  - The primary somatosensory cortex of various species including man, monkey, pig
      and rat is capable of producing high-frequency signals in the 600 Hz range and
      above with very little latency jitter. We have recently observed such cortical
      signals for the trigeminal system of the swine. This study determined the
      projection of the maxillary nerve innervating the snout to the sensory trigeminal
      nuclear complex in the brain stem and stability of outputs of each nucleus
      receiving the projection. The snout stimulation activated large-caliber Abeta
      fibers in the trigeminal nerve with a mean velocity of 64.4+/-2.7 m/s (mean+/-1
      S.E.M., six animals) comparable in velocity to the tooth pulp Abeta fibers
      (57.9+/-3.4 m/s) obtained from the same animals. These afferents activated the
      main sensory nucleus, and subnuclei oralis, interpolaris and caudalis of the
      spinal nucleus, as judged by evoked field potential maps superimposed on the
      histological maps of the trigeminal nuclei from the same animals. Inputs from
      these fast afferents arrived at all the four trigeminal nuclei almost
      simultaneously within a span of 0.7+/-0.2 ms (mean+/-1 S.D., seven animals).
      Evoked high-frequency signals were reproducible with a latency jitter of less
      than 0.2 ms during the first 4 ms of postsynaptic activity for each of main
      sensory and spinal nuclei. These results indicate that the snout stimulation
      activates fast-conducting peripheral afferents which project to all the sensory
      trigeminal nuclei and produces highly reproducible initial responses nearly
      simultaneously across the multiple trigeminal nuclei. These outputs from the
      trigeminal nuclei may play an important role in triggering the stable high
      frequency signals in the cortex.

PMID- 12480153
TI  - Characterization of a multipotent neural progenitor cell line cloned from an
      adult p53-/- mouse cerebellum.
AB  - Here we report developmental characteristics of clonal cell line 2Y6f1, which was
      established from an adult p53(-/-) mouse cerebellum. 2Y6f1 began as a homogeneous
      population of small polygonal epithelial cells, but during passages it gradually
      became heterogeneous, containing cells of varying size and shape that expressed
      either neuron- or astrocyte-specific proteins. Supplements to the culture medium
      altered the levels of some of the cell type markers. For example, addition of
      insulin increased expression of neurofilaments, while cholera toxin increased
      that of glial fibrillary acidic protein. In a colony assay, 2Y6f1 cells gave rise
      to both homogeneous and heterogeneous colonies, consistent with the idea that
      they contained multipotent neural progenitor cells. Establishment of subclones
      that were exclusively neuronal or astroglial in differentiation further supported
      the conclusion that 2Y6f1 cells have many features that may qualify them as bona
      fide stem cells and make them a useful new model in neural stem cell biology.

PMID- 12480154
TI  - Effect of central angiotensin II on body weight gain in young rats.
AB  - Systemic infusion of ANG II decreases body weight and food intake and increases
      energy expenditure. We recently reported that young rats receiving a 1-week
      intracerebroventricular (i.c.v.) infusion of angiotensin II (ANG II) exhibited
      decreased body weight compared to control. The aim of the present investigation
      was to determine if chronic i.c.v. infusion of ANG II also decreases food intake
      and increases energy expenditure. Young rats were infused with i.c.v. 0.9% saline
      or ANG II (16.7 or 4.2 ng/min) for at least 10 days and body weight and food
      intake were monitored daily. Pair-fed rats had the same daily food intake as the
      ANG II-infused rats. The i.c.v. ANG II decreased body weight gain and food
      intake. The decrease in weight gain was greater than in the pair-fed groups. The
      expression of mRNA for uncoupling protein-1 (UCP-1) in BAT was increased
      significantly in the ANG II-infused rats compared to the pair-fed animals.
      Subcutaneous infusion of ANG II at the same doses used for i.c.v. infusion had no
      effect on body weight or food intake. The expression of CRH mRNA in the
      paraventricular nucleus was not increased in the ANG II-infused rats. These data
      are consistent with the idea that i.c.v. ANG II decreases body weight gain in
      young rats, in part, by decreasing food intake and, in part, by increasing
      thermogenesis (although via a CRH-independent mechanism). This central effect of
      ANG II may contribute to or complement the effect of peripheral ANG II on body
      weight.

PMID- 12480155
TI  - A possible role of RhoA/Rho-kinase in experimental spinal cord injury in rat.
AB  - Secondary injury following traumatic spinal cord injury is induced by the
      activation of a number of cellular and molecular changes. RhoA, a small GTPase,
      regulates the organization of the actin cytoskeleton, gene expression, cell
      proliferation, and has been implicated in the regenerative process. This study
      was undertaken to investigate the involvement of the RhoA signaling pathway in
      the secondary injury that follows traumatic spinal cord injury in rats. RhoA mRNA
      and protein expressions were enhanced significantly in the injured spinal cord 1
      week after surgery (P<0.05, ANOVA). C3 exozyme (RhoA inhibitor), Y-27632
      (selective Rho kinase inhibitor), and Fasudil (non-selective protein kinase
      inhibitor) were administered after spinal cord injury, and the subjects were
      evaluated for 5 weeks as per BBB locomotor score. Poor rat response interrupted
      the C3 experiment. Y-27632 slightly, but significantly (P<0.05, ANOVA), delayed
      the recovery. Fasudil significantly improved the BBB score (P<0.05, ANOVA). In
      conclusion, spinal cord injury activates the RhoA/Rho-kinase alpha, beta
      associated pathway. However, their role in secondary injury or in the improvement
      of functional recovery remains unclear. Fasudil might exert a cytoprotective
      effect by mechanisms other than inhibiting Rho-kinase alpha, beta.

PMID- 12480156
TI  - GABA(B) receptor-mediated heterosynaptic depression of excitatory synaptic
      transmission in rat frontal neocortex.
AB  - Neocortical synapses display several forms of short-term plasticity including
      paired-pulse facilitation and depression. The mechanisms underlying this
      diversity are unclear. Synaptic currents in response to paired stimulation were
      recorded from layer II/III pyramidal neurons in rat frontal neocortical slices
      using the whole-cell patch-clamp method. Both paired-pulse facilitation (PPF) and
      paired-pulse depression (PPD) were observed in control saline. In the presence of
      10 microM bicuculline (BIC), prominent PPD was consistently elicited. The maximal
      depression of the second EPSC occurred around 100 ms although PPD was still
      observed at intervals up to 1500 ms. Manipulations that reduced the probability
      of transmitter release significantly affected PPD. Both conditioning (C)- and
      test (T)-EPSCs were reduced when the extracellular Ca(2+) concentration was
      lowered from 3 to 1 mM. The decrease was greater in the C-EPSC resulting in a
      decrease in PPD. The gamma-aminobutyric acid (GABA)(B) receptor agonist baclofen
      (10 microM) reduced the amplitude of both evoked EPSCs and changed PPD to PPF. In
      the presence of the GABA(B) antagonists 2(OH)-saclofen (200-400 microM) or
      SCH50911 (10 microM), PPF was commonly observed. The metabotropic glutamate
      receptor antagonist MCPG (500 microM) had no effect on neocortical PPD. Brief
      stimulus trains induced a progressive depression that was insensitive to GABA(B)
      antagonists. Paired-pulse depression of excitatory synaptic transmission is a
      prominent phenomenon in frontal neocortex. At least two components of depression
      were observed. They may play an important role in regulating the balance between
      excitation and inhibition, therefore maintaining stability in cortical circuits.

PMID- 12480157
TI  - Delayed transient ischemic attacks kill some CA1 neurons previously salvaged with
      postischemic hypothermia: neuroprotection undone.
AB  - Delayed hypothermia reduces ischemic hippocampal CA1 injury. However, there are
      residual structural and functional abnormalities. Therefore, we studied whether
      these apparently vulnerable rescued neurons are susceptible to secondary insults.
      All gerbils were subjected to normothermic forebrain ischemia (ISC, 5 min) or
      SHAM operation. Gerbils were treated with mild hypothermia (HYPO; 33 degrees C
      for 24 h+35 degrees C for 24 h) beginning 12 h after surgery, or they remained
      normothermic (NORMO). Then 5 and 6 days following ISC/SHAM operation gerbils
      received sublethal transient ischemic attacks (TIA, 1.5 min) or sham (SH)
      surgeries. Behavioral testing was done and animals survived for 30 days for
      quantification of medial, middle and lateral CA1 sector cell death. The SHAM
      groups were not significantly different. The ISC+NORMO+SH group lost 87.3% (of
      SHAM) of medial CA1 neurons, which was not significantly exacerbated in the
      ISC+NORMO+TIA group (91.1%, P=0.633). However, the ISC+HYPO+TIA group (58.8%
      loss) had significantly more cell death than the ISC+HYPO+SH group (42.8%;
      P=0.035), although CA1 protection was still better than in ISC+NORMO groups
      (P<0.001). Trends were similar in middle and lateral CA1, but the deleterious
      effects of TIAs were not statistically significant. Behavioral testing did not
      distinguish groups with or without TIA, but did reveal deficits in ISC+NORMO
      groups and protection in ISC+HYPO groups. These data, like previous
      ultrastructural findings, show that while most hypothermia-rescued CA1 neurons
      are healthy, some are susceptible. Perhaps other neuroprotectants, especially
      weaker ones, might be undone by delayed insults (e.g. TIA, fever).

PMID- 12480158
TI  - The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing
      neurons in the rat brain.
AB  - The 5-HT(1A) receptor is a well-characterized serotonin receptor playing a role
      in many central nervous functions and known to be involved in depression and
      other mental disorders. In situ hybridization, immunocytochemical, and binding
      studies have shown that the 5-HT(1A) receptor is widely distributed in the rat
      brain, with a particularly high density in the limbic system. The receptor's
      localization in the different neuronal subtypes, which may be of importance for
      understanding its role in neuronal circuitries, is, however, unknown. In this
      study we show by immunocytochemical double-labeling techniques, that the 5-HT(1A)
      receptor is present on both pyramidal and principal cells, and calbindin- and
      parvalbumin-containing neurons, which generally define two different subtypes of
      interneurons. Moreover, semiquantitative analysis showed that the receptor's
      distribution in the different neuronal types varies between brain areas. In
      cortex, hippocampus, hypothalamus, and amygdala the receptor was located on both
      principal cells and calbindin- and parvalbumin-containing neurons. In septum and
      thalamus, the receptor was mostly present on calbindin- and parvalbumin
      containing cells. Especially in the medial septum and thalamic reticular nucleus,
      the receptor highly colocalized with parvalbumin-positive neurons. These results
      suggest a diverse function of the 5-HT(1A) receptor in modulating neuronal
      circuitry in different brain areas, that may depend on the type of neuron the
      receptor is predominantly located on.

PMID- 12480159
TI  - The cytoplasmic polyadenylation element binding protein and polyadenylation of
      messenger RNA in Aplysia neurons.
AB  - Translation of some mRNAs in nerve terminals has been shown to be regulated by
      polyadenylation in an experience-dependent manner. The transcripts whose
      translation is controlled by regulated polyadenylation contain the cytoplasmic
      polyadenylation element (CPE), which binds to the highly conserved CPE-binding
      protein (CPEB). In Aplysia, neuron-specific actin mRNA, which has a CPE in its 3'
      UTR, is located both in cell bodies and at nerve endings (synaptosomes). We found
      that actin mRNA from pleural ganglion sensory neurons becomes polyadenylated
      during long-term facilitation produced by treatment with serotonin or 8-bromo
      cAMP. We cloned two isoforms of CPEB (ApCPEB77 and ApCEPB49) from Aplysia nervous
      tissue. The larger form, which is predominant in nervous tissue, is similar to
      p82, the clam binding protein, as well as to vertebrate CPEBs. Moreover,
      synaptosomal actin mRNAs are polyadenylated following the treatment with 5-HT.
      Since both CPEB and polyadenylated actin mRNA are present in synaptosomes and
      synaptosomal actin protein increases during long-term facilitation, we suggest
      that the translation of actin message in nerve endings is up-regulated by
      polyadenylation to grow new synapses.

PMID- 12480160
TI  - Chemical activation of cardiac receptors affects activity of superficial and
      deeper T3-T4 spinal neurons in rats.
AB  - The purposes of this study were to examine responses of superficial (depth <300
      microm) and deeper thoracic spinal neurons to chemical stimulation of cardiac
      afferents and effects of descending influences on these neurons. Extracellular
      potentials of single T(3)-T(4) neurons were recorded in pentobarbital
      anesthetized, paralyzed and ventilated male rats. A catheter was placed in the
      pericardial sac to administer 0.2 ml of a mixture of algogenic chemicals that
      contained adenosine (10(-3) M), bradykinin, histamine, serotonin, prostaglandin
      E(2) (10(-5) M). Fifteen of 55 (27%) superficial neurons responsive to
      intrapericardial chemicals were compared to 80/169 (47%) deeper neurons. All 15
      superficial neurons that responded to cardiac afferents were excited (E), whereas
      66 deeper neurons were excited, ten were inhibited and four showed excitation
      inhibition. Spontaneous activity of superficial neurons with short-lasting
      excitatory responses was significantly lower than that of deeper neurons
      (P<0.05). Somatic receptive fields on chest, axilla, arm and upper back areas
      were found for 77/95 (81%) neurons that responded to intrapericardial chemicals.
      The proportion of somatic field properties and their sizes in superficial neurons
      were similar to deeper neurons. After cervical spinal transection, both
      spontaneous activity and responses to chemical stimulation of cardiac afferents
      significantly increased in six out of six neurons excited by intrapericardial
      injections. Results showed that chemical stimulation of cardiac afferents excited
      superficial T(3)-T(4) spinal neurons, whereas deeper neurons exhibited multiple
      patterns of responses. Some characteristics of subgroups of superficial neurons
      were quantitatively different from deeper neurons. Thoracic spinal neurons
      processing cardiac nociceptive information were under tonic descending
      inhibition.

PMID- 12480161
TI  - Stimulatory effects of chlorzoxazone, a centrally acting muscle relaxant, on
      large conductance calcium-activated potassium channels in pituitary GH3 cells.
AB  - Chlorzoxazone, a centrally acting muscle relaxant, has been used as a marker for
      hepatic CYP2E1 activity. However, little is known about the mechanism of
      chlorzoxazone actions on ion currents in neurons or neuroendocrine cells. We thus
      investigated its effects on ion currents in GH(3) lactotrophs. Chlorzoxazone
      reversibly increased Ca(2+)-activated K(+) current (I(K(Ca))) in a concentration
      dependent manner with an EC(50) value of 30 microM. The chlorzoxazone-stimulated
      I(K(Ca)) was inhibited by iberitoxin (200 nM) or clotrimazole (10 microM), but
      not by glibenclamide (10 microM) or apamin (200 nM). Chlorzoxazone (30 microM)
      suppressed voltage-dependent L-type Ca(2+) current. In the inside-out
      configuration, chlorzoxazone applied to the intracellular side of the patch did
      not modify single-channel conductance of large conductance Ca(2+)-activated K(+)
      (BK(Ca)) channels, but did increase channel activity by increasing mean open time
      and decreasing mean closed time. Chlorzoxazone also caused a left shift in the
      activation curve of BK(Ca) channels. However, Ca(2+)-sensitivity of these
      channels was unaffected by chlorzoxazone. 1-Ethyl-2-benzimidazolinone (30
      microM), 2-amino-5-chlorobenzoxazole (30 microM) or chlormezanone (30 microM)
      enhanced BK(Ca) channel activity, while 6-hydroxychlorzoxazone (30 microM)
      slightly increased it; however, chlorphenesin carbamate (30 microM) had no effect
      on it. Under the current-clamp condition, chlorzoxazone (10 microM) reduced the
      firing rate of action potentials. In neuroblastoma IMR-32 cells, chlorzoxazone
      (30 microM) also stimulated BK(Ca) channel activity. The stimulatory effects of
      chlorzoxazone on these channels may be responsible for the underlying mechanism
      of chlorzoxazone actions on neurons and neuroendocrine cells.

PMID- 12480162
TI  - Cytisine binds with similar affinity to nicotinic alpha4beta2 receptors on the
      cell surface and in homogenates.
AB  - Cytisine and nicotine bound to specific sites in homogenates prepared from HEK
      293 cells which stably express human neuronal nicotinic alpha4 and beta2
      subunits. The number of sites was the same for both ligands and nicotine was a
      full competitive inhibitor of cytisine binding. However, when binding was done to
      intact cells the number of binding sites per cell for nicotine was approximately
      4-fold the number of sites for cytisine. Nicotine fully blocked cytisine binding,
      but cytisine only partially blocked nicotine binding to intact cells. When cells
      were permeabilized with saponin, the number of sites for nicotine was unchanged,
      while the number of sites for cytisine was increased, and cytisine was able to
      fully block nicotine binding. These data indicate that cytisine binds only to
      surface receptors on intact cells. The apparent affinity of cytisine for surface
      receptors (K(d)=0.8 nM) was not significantly different from that for receptors
      in the cell homogenate (0.3 nM).

PMID- 12480163
TI  - Facilitative interactions between vasoactive intestinal polypeptide and receptor
      type-selective opioids: implications for sensory afferent regulation of spinal
      opioid action.
AB  - Afferent tone is known to influence spinal opioid antinociception but the
      underlying neurochemical events are not well defined. This study investigates the
      consequence on cAMP formation of the coincident activation of signal transduction
      sequelae initiated by an afferent transmitter and opioid using dissociated spinal
      cord tissue. Afferent transmission was simulated via the addition of vasoactive
      intestinal polypeptide (VIP), a pelvic visceral afferent transmitter.
      Individually, mu, delta-, or kappa-selective opioids (1 microM each) did not
      alter basal spinal content of cAMP. However, VIP (1 microM) and the delta-opioid
      selective agonist, [D-Pen(2,5)] enkephalin (DPDPE; 1 microM), in combination,
      manifest a striking facilitative interaction to augment spinal levels of cAMP.
      Facilitative interactions between VIP and kappa- or mu-opioids were of a reduced
      magnitude or not observed, respectively. Blockade of delta-opioid or VIP
      receptors using naltrindole or VIP6-28, respectively antagonized the VIP-DPDPE
      facilitative interaction, as did pertussis toxin treatment. The VIP-DPDPE
      facilitative interaction was also eliminated by phospholipase Cbeta inhibition
      and inositol trisphosphate receptor blockade. This suggests that modulation of
      Ca(2+) trafficking by VIP and delta-opioid agonists is a point of convergence of
      their respective signal transduction cascades, the concomitant action at which
      achieves cytosolic Ca(2+) concentrations that are now sufficient for the
      activation of signaling molecules, e.g. Ca(2+)/calmodulin-stimulated adenylyl
      cyclase isoforms. These data underscore the plasticity of spinal delta-opioid
      neurochemical sequelae and their dependence on concomitant afferent transmitter
      initiated neurochemical events.

PMID- 12480164
TI  - Effects of beta-adrenergic blockers on glutamate-induced calcium signals in adult
      mouse retinal ganglion cells.
AB  - Betaxolol, a selective beta(1)-adrenoceptor antagonist, is an antiglaucoma drug
      commonly used to lower the intraocular pressure (IOP) in treatment of glaucoma.
      Recent evidence has also shown that it attenuates ligand- and voltage-gated
      currents in retinal ganglion cells, which may lead to reduction of intracellular
      calcium and prevention of glutamate-induced ganglion cell damage in glaucoma. In
      the present study, we examined the effectiveness of betaxolol and other beta
      adrenergic blockers on glutamate-induced calcium signals. Dissociated adult mouse
      retinal ganglion cells were immuno-labeled with antibody CD90.2 and loaded with
      Fura-2AM. Calcium signals were recorded with optical recording techniques. Low
      doses of glutamate cause an increase in intracellular calcium that may result in
      pathological changes in ganglion cells. The action of glutamate could be
      reversibly suppressed by beta-adrenergic blockers and the order of inhibitory
      potency is (s)(-)-propranolol>betaxolol>>timolol, with average IC(50) of 78.05,
      235.7 and 2167.05, microM, respectively. Betaxolol compressed the dose-response
      curve of glutamate. The EC(50) of glutamate was shifted from 6.19 to 23.53
      microM, indicating that betaxolol acts as a non-competitive inhibitor of
      glutamate response in retinal ganglion cells. Our data are consistent with
      previous reports that betaxolol and other beta-adrenergic blockers may exert its
      neuroprotective action by suppression of glutamate-induced intracellular calcium
      increase in retinal ganglion cells.

PMID- 12480165
TI  - Brevetoxin derivatives act as partial agonists at neurotoxin site 5 on the
      voltage-gated Na+ channel.
AB  - Brevetoxins (PbTx-1 to PbTx-10) are potent lipid-soluble polyether neurotoxins
      produced by the marine dinoflagellate Karina brevis, an organism associated with
      'red tide' blooms in the Gulf of Mexico. Ingestion of shellfish contaminated with
      K. brevis produces neurotoxic shellfish poisoning (NSP) in humans. NSP symptoms
      emanate from brevetoxin activation of neurotoxin site 5 on voltage-gated sodium
      channels (VGSC) [Toxicon 20 (1982) 457]. In primary cultures of rat cerebellar
      granule neurons (CGN), brevetoxins produce acute neuronal injury and death. The
      ability of a series of naturally occurring and synthetic brevetoxins to trigger
      Ca(2+) influx in CGN was explored in the present study. Intracellular Ca(2+)
      concentration was monitored in fluo-3-loaded CGN using a fluorescent laser
      imaging plate reader. The naturally occurring derivatives PbTx-1, PbTx-2 and PbTx
      3 all produced a rapid and concentration-dependent increase in cytosolic
      [Ca(2+)]. The maximum response to PbTx-1 was approximately two-fold greater than
      that of either PbTx-2 or PbTx-3. Two synthetic derivatives of PbTx-3, alpha
      naphthoyl-PbTx-3 and beta-naphthoyl-PbTx-3, were also tested. Both alpha- and
      beta-naphthoyl-PbTx-3 stimulated a rapid and concentration-dependent Ca(2+)
      influx that was, however, less efficacious than that of PbTx-3. These data
      indicate that, analogous to neurotoxin site 2 ligands, activators of neurotoxin
      site 5 display a range of efficacies, with PbTx-1 being a full agonist and other
      derivatives acting as partial agonists.

PMID- 12480166
TI  - Local, but not systemic, administration of serotonergic antidepressants decreases
      hippocampal nitric oxide synthase activity.
AB  - Nitric oxide (NO) is an unconventional transmitter molecule in the nervous
      system, synthesized by nitric oxide synthase (NOS) following activation of the N
      methyl-D-aspartate (NMDA) receptor. Several in vivo studies have demonstrated
      that NO modulates the extracellular levels of various neurotransmitters in the
      central nervous system, while serotonin (5-HT) re-uptake may be influenced by the
      NO pathway. Moreover, inhibitors of NOS exhibit antidepressant-like and
      anxiolytic-like properties in various animal models. Therefore, the aims of the
      present study were to clarify the involvement of distinct antidepressants acting
      on the serotonin re-uptake site in the regulation of the activity of hippocampal
      NOS in vitro, in vivo and ex vivo. We found that citalopram, paroxetine,
      imipramine and N(G)-nitro-L-arginine dose dependently decreased the hippocampal
      NOS activity in vitro. Moreover, local administration of citalopram, paroxetine,
      tianeptine, imipramine and N(G)-nitro-L-arginine significantly decreased the
      hippocampal NOS activity in vivo at a concentration significantly lower than in
      vitro. No effect on NOS activity following retrodialysis with 5-HT was observed.
      Acute (5 mg/kg, s.c.) and chronic (3 weeks, 20 mg/kg/24 h) systemic
      administration of citalopram did not influence NOS activity ex vivo. The effects
      on NOS represent a response to structurally dissimilar serotonergic
      antidepressants. However, since these data reflect effects on basal NOS activity,
      we believe that serotonergic antidepressants do not directly affect NOS at
      dosages used clinically, but the findings may reflect a secondary action of
      antidepressants on the glutamate NMDA receptor following their primary inhibitory
      action at the 5-HT transporter.

PMID- 12480167
TI  - Background potassium concentrations and epileptiform discharges. I.
      Electrophysiological characteristics of neuronal activity.
AB  - Intra- and extracellular recording techniques were used to study the epileptiform
      activity generated by guinea pig hippocampal slices perfused with free-magnesium
      artificial cerebrospinal fluid in the presence of physiologic (4 mM), reduced (2
      mM) or elevated (8 mM) extracellular potassium concentrations ([K(+)](o)).
      Extracellular field potentials along with intracellular recordings were recorded
      in CA1 or CA3 region. Reduction of [K(+)](o) significantly increased the latency
      of epileptiform field potential (EFP) appearance as well as burst discharge
      duration and decreased EFP repetition rate. Depending on different background
      [K(+)](o), epileptiform burst discharges appeared in different patterns including
      varied types of paroxysmal depolarisation shifts and burst activity in CA1 and
      CA3 subfields. Comparison with physiological and increased [K(+)](o,) reduction
      of [K(+)](o) significantly increased the mean duration of bursts, mean amplitude
      of depolarisation, mean after-hyperpolarisation duration, and inter-spike
      intervals in both CA1 and CA3 areas. Three distinct patterns were distinguished
      on the basis of their evoked firing pattern in response to application of
      depolarising current pulses in the interval of epileptiform burst discharges.
      Neurons superfused with 2 mM [K(+)](o) presented fast adapting pattern while
      cells washed with 4 or 8 mM [K(+)](o) exhibited intrinsically bursting or slow
      adapting patterns. Comparing the groups with different background [K(+)](o),
      there is a more severe form of discharges in low K(+) and a subtle difference
      between 4 and 8 mM K(+). The data indicate the importance of background [K(+)](o)
      on epileptiform burst discharge pattern and characteristics.

PMID- 12480168
TI  - Background potassium concentrations and epileptiform discharges. II. Involvement
      of calcium channels.
AB  - Potassium- and calcium conductances regulate neuronal excitability and
      epileptiform activity. In this study, the effects of different extracellular
      potassium concentrations ([K(+)](o)) were investigated on the modulatory effect
      of the L-type transmembranous calcium currents on epileptiform discharges. The in
      vitro brain slice technique was used to examine the effects of calcium channel
      blockers, verapamil and nifedipine, on the repetition rate, amplitude, and
      duration of epileptiform field potentials (EFP) in the presence of low,
      physiological, and high background [K(+)](o) in guinea pig hippocampal slices.
      Epileptiform activity was induced by omission of Mg(2+) from artificial
      cerebrospinal fluid contained 2, 4, and 8 mM [K(+)](o). Both verapamil and
      nifedipine suppressed EFP after a transient increase in repetition rate. The
      extent of EFP frequency rate acceleration significantly increased with reduction
      of [K(+)](o). The increase in EFP frequency rate induced by application of
      verapamil and nifedipine was accompanied by a reduction in the EFP amplitude and
      a reversible increase in the burst discharge duration. The extent of burst
      discharge prolongation was also significantly higher with decreasing [K(+)](o).
      Further application of verapamil and nifedipine suppressed the epileptiform burst
      activity in the presence of different [K(+)](o). The latency of EFP depression
      was significantly diminished both with increased and decreased background
      potassium concentrations. The data indicate the importance of the effect of the L
      type transmembranous calcium currents on the regulatory effect of background
      [K(+)](o) on epileptiform burst discharge frequency and duration.

PMID- 12480169
TI  - Colocalization of taurine and glial fibrillary acidic protein immunoreactivity in
      mouse hippocampus induced by short-term ethanol exposure.
AB  - Morphological changes of the hippocampus were investigated in mice exhibiting
      signs of intoxication following short-term exposure to 6% ethanol. These
      alterations were examined by a double immunofluorescent study using antibodies to
      taurine and anti-glial fibrillary acidic protein (GFAP) antibody. Antibody
      labeled taurine was localized mainly in the astrocytes and endothelial cells of
      control mice. Ethanol administration resulted in a significant increase in the
      accumulation of taurine and GFAP immunoreactivity (IR) in the stratum lacunosum
      moleculare (sl-m) of the hippocampus. Specifically, the cell bodies of taurine
      positive astrocytes were hypertrophied, their processes were elongated in the
      pericapillary region, and some colocalized with GFAP-IR cells. Furthermore,
      quantitative analysis revealed that the merged area in ethanol-treated mice was
      twice that (71.6% vs. 35.8%) of control mice. Since taurine is involved in
      various neuroprotective functions, the present observations suggest that the
      expression of taurine IR in reactive astrocytes after ethanol exposure might play
      an important role in neuroprotective processes.

PMID- 12480170
TI  - Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of
      anesthetized rats: an effect mediated via 5-HT1A receptors.
AB  - A selective 5-HT reuptake inhibitor, fluvoxamine (10 and 30 mg/kg, i.p.)
      suppressed long-term potentiation (LTP) in the hippocampal CA1 field of
      anesthetized rats. Fluvoxamine (30 mg/kg, i.p.)-induced suppression of LTP was
      completely reversed by the 5-HT(1A) receptor antagonist NAN-190 (0.5 mg/kg, i.p),
      but not by the 5-HT(4) receptor antagonist GR 113808 (20 microg/rat, i.c.v.) and
      the 5-HT(7) receptor antagonist DR 4004 (10 microg/rat, i.c.v.). These data
      suggest that the inhibitory effect of fluvoxamine on LTP induction is mediated
      via 5-HT(1A) receptors.

PMID- 12480171
TI  - Neuroprotective effects of YM872 coadministered with t-PA in a rat embolic stroke
      model.
AB  - YM872, an AMPA receptor antagonist, was administered together with t-PA to
      investigate the effects of coadministration on neuroprotection in a rat embolic
      stroke model, when administered 2 h after embolism. T-PA or YM872 alone decreased
      infarct volume and improved the neurological deficit score. Coadministration of
      YM872 and t-PA resulted in a further decrease in infarct volume and improvement
      of the neurological score as compared with single administration of t-PA. These
      data demonstrate that coadministration of YM872 and t-PA produces more potent
      neuroprotective effects than when t-PA is administered alone.

PMID- 12480172
TI  - Contribution of ionotropic glutamate receptors and voltage-dependent calcium
      channels to the potentiation phenomenon induced by transient pentylenetetrazol in
      the CA1 region of rat hippocampal slices.
AB  - The role of ionotropic glutamate receptors and voltage-dependent calcium channels
      (VDCCs) in potentiation phenomenon and epileptic activity induced by a transient
      pentylenetetrazol (PTZ) application in the CA1 region of rat hippocampal slices
      was investigated. Also we examined whether adenosine as an inhibitory
      neuromodulator would interact with expression of the long-lasting effect of
      transient PTZ. Population spikes (PS) were recorded in the CA1 cell body layer of
      the hippocampal slices following stratum radiatum stimulation. Changes in the PS
      amplitude potentiation and number of extra PS, which induced by transient PTZ
      were used as indices to quantify the effects of drugs. PS input-output curve was
      significantly increased 10 min after PTZ application and persisted at least for
      60 min after PTZ washout. Polyspikes also appeared, but did not persist. Both
      ketamine and APV reduced the extent of potentiation of PS amplitude but had no
      effect on number of extra PS. The selective non-NMDA receptor antagonist CNQX
      prevented the amplitude potentiation and the generation of extra PS. The blocker
      of VDCCs, verapamil, prevented the amplitude potentiation and inhibited polyspike
      activity. Co-application of adenosine and PTZ produced a rapid and reversible
      decrease in the PS amplitude, but PTZ-induced potentiation phenomenon was
      observed after washout. It is concluded that ionotropic glutamate receptors as
      well as VDCCs involve in the PTZ-induced LTP of PS amplitude. PTZ-induced LTP is
      also insensitive to adenosine. The epileptiform activity induced by a transient
      PTZ application could be attributed to VDCCs. The polyspikes mediated by VDCCs
      are dependent on prior activation of AMPA receptors.

PMID- 12480173
TI  - Folate quenches oxidative damage in brains of apolipoprotein E-deficient mice:
      augmentation by vitamin E.
AB  - We demonstrate that folate and vitamin E can compensate for the diminished
      oxidative buffering capacity of brains of apolipoprotein E-deficient mice. Normal
      and ApoE(tmlUne) homozygous 'knockout' mice were maintained for 1 month on a diet
      either lacking or supplemented with folate, vitamin E or iron as a pro-oxidant
      after which brain tissue was harvested and analyzed for for thiobarbituric acid
      reactive substances (TBARs) as an index of oxidative damage. Normal mice
      exhibited no significant difference in TBARs following iron challenge in the
      presence or absence of vitamin E, folic acid or both. Similarly, ApoE knockout
      mice exhibited no significant differences following dietary iron challenge in the
      presence or absence of vitamin E. However, ApoE knockout mice accumulated
      significantly increased TBARs following iron challenge when folic acid was
      withheld, and accumulated even more TBARs when both folic acid and vitamin E were
      withheld. These findings demonstrate that ApoE knockout mice during vitamin
      deficiency are less capable of buffering the consequences of dietary iron
      challenge than are normal mice. Since the apolipoprotein E4 allele, which
      exhibits diminished oxidative buffering capacity, is linked to Alzheimer's
      disease (AD), these data underscore the possibility that critical nutritional
      deficiencies may modulate the impact of genetic compromise on neurodegeneration
      in AD.

PMID- 12480174
TI  - c-Jun N-terminal kinase pathway mediates Lactacystin-induced cell death in a
      neuronal differentiated Neuro2a cell line.
AB  - The ubiquitin-proteasome pathway is an intracellular protein degradation pathway
      responsible for degradation of many regulatory proteins that must be rapidly
      eliminated normally. Some recent studies reported that a proteasome dysfunction
      was involved in the pathogenesis of neurodegenerative diseases. Thus, there is
      now considerable interest in the possible role of proteasome in this regard. Here
      we show that inhibition of proteasomal function by Lactacystin-induced cell death
      in a neuronal differentiated Neuro2a (nN2a) cell line but not in an
      undifferentiated Neuro2a (N2a) cell line. Cell death was accompanied by both the
      activation of c-Jun N-terminal kinase, p38 and caspase-3. A pan-caspase
      inhibitor, Z-VAD-FMK, or SB203580, a p38 inhibitor could not inhibit cell death
      induced by Lactacystin, whereas nN2a cell lines with stable expression of the
      dominant negative mutant of c-Jun N-terminal kinase showed a remarkable
      suppression of cell death. Lactacystin-induced cell death is mediated through the
      c-Jun N-terminal kinase pathway but not the caspase-dependent pathway in a nN2a
      cell line. Our results shed light on the association among the proteasomal
      dysfunction, JNK pathway and neuronal cell death, leading to the elucidation of
      its possible role in the pathogenesis of neurodegenerative diseases.

PMID- 12480175
TI  - In vivo role of caspases in excitotoxic neuronal death: generation and analysis
      of transgenic mice expressing baculoviral caspase inhibitor, p35, in postnatal
      neurons.
AB  - Caspases, a family of cysteine proteases, are thought to be critical mediators of
      apoptosis. To examine the role of neuronal caspases in excitotoxic
      neurodegeneration in vivo, we have generated transgenic mice expressing the
      baculovirus protein p35, a potent viral caspase inhibitor, using the neuron
      specific calmodulin dependent kinase-II alpha (CaMKII-alpha) promoter. The
      expression of p35 was confirmed by reverse transcriptase-polymerase chain
      reaction (RT-PCR), Western blotting and immunohistochemistry. We analyzed caspase
      activation and cell death by employing an experimental paradigm, in which the
      excitotoxin kainate (KA) was injected into CA1 of hippocampus and the
      distribution of the caspase-generated actin fragment was detected
      immunohistochemically. While kainate treatment led to selective neuronal death in
      the CA1, CA3 and CA4 of non-transgenic control mice, we observed restricted
      caspase activation only in the CA3 sector. The transgenic expression of p35
      consistently inhibited the kainate-induced caspase activation, but failed to
      influence the death of neurons to any extent. In addition, we observed
      concomitant early calpain activation in the specific areas where neurons
      underwent degeneration in both the transgenic and non-transgenic mice. These
      results indicate that p35-inhibitable caspases play rather minor roles in the
      kainate-induced excitotoxicity and that the relative contribution of calpain is
      likely to be greater than that of caspases.

PMID- 12480176
TI  - 14-3-3 protein is a component of Lewy bodies in Parkinson's disease-mutation
      analysis and association studies of 14-3-3 eta.
AB  - Mutations in alpha-synuclein have been identified in some rare families with
      autosomal dominant Parkinson's disease (PD). The synuclein gene family shares
      physical and functional homology with 14-3-3 proteins and binds to 14-3-3
      proteins and to its ligands. We therefore investigated whether 14-3-3 proteins
      are also involved in the pathogenesis of PD. Here we demonstrate that 14-3-3
      proteins are colocalized with Lewy bodies in PD. We investigated the 14-3-3 eta
      (YWHAH) gene by mutation analysis and association studies as it maps to human
      chromosome 22q12.1-q13.1, a region which has been recently implicated in PD and
      carried out immunohistochemical studies of Lewy bodies with two different 14-3-3
      eta antibodies. In 358 sporadic and familial PD patients, disease causing
      mutations were not identified. Furthermore, association studies with intragenic
      polymorphisms do not provide evidence for an involvement of 14-3-3 eta in the
      pathogenesis of PD. In accordance with these findings, there was no staining of
      substantia nigra Lewy bodies with antibodies specific for the 14-3-3 eta subunit.

PMID- 12480177
TI  - The role of the conserved GXXXRXG motif in the expression and function of the
      human norepinephrine transporter.
AB  - Highly conserved motifs in the monoamine transporters, e.g. the human
      norepinephrine transporter (hNET) GXXXRXG motif which was the focus of the
      present study, are likely to be important structural features in determining
      function. This motif was investigated by mutating the glycines to glutamate
      (causing loss of function) and alanine, and the arginine to glycine. The effects
      of hG117A, hR121G and hG123A mutations on function were examined in COS-7 cells
      and compared to hNET. Substrate K(m) values were decreased for hG117A and hG123A,
      and their K(i) values for inhibition of [3H]nisoxetine binding were decreased 3-4
      fold and 4-6-fold, respectively. Transporter turnover was reduced to 65% of hNET
      for hG117A and hR121G and to 28% for hG123A, suggesting that substrate
      translocation is impaired. K(i) values of nisoxetine and desipramine for
      inhibition of [3H]norepinephrine uptake were increased by 5-fold for hG117A, with
      no change for cocaine. The K(i) value of cocaine was increased by 3-fold for
      hG123A, with no change for nisoxetine and desipramine. However, there were no
      effects of the mutations on the K(d) of [3H]nisoxetine binding or K(i) values of
      desipramine or cocaine for inhibition of [3H]nisoxetine binding. Hence, glycine
      residues of the GXXXRXG motif are important determinants of NET expression and
      function, while the arginine residue does not have a major role. This study also
      showed that antidepressants and psychostimulants have different NET binding sites
      and provided the first evidence that different sites on the NET are involved in
      the binding of inhibitors and their competitive inhibition of substrate uptake.

PMID- 12480178
TI  - Long-term high-frequency electro-acupuncture stimulation prevents neuronal
      degeneration and up-regulates BDNF mRNA in the substantia nigra and ventral
      tegmental area following medial forebrain bundle axotomy.
AB  - Electroacupuncture (EA) has been used in China for many years to treat
      Parkinson's disease (PD) with reportedly effective results. However, the
      physiological and biological mechanism behind its effectiveness is still unknown.
      In the present study, different frequencies of chronic EA stimulation (0, 2, 100
      Hz) were tested in a partially lesioned rat model of PD which was induced by
      transection of the medial forebrain bundle (MFB). After 24 sessions of EA
      stimulation (28 days after MFB transection), dopaminergic neurons in the ventral
      midbrain were examined by immunohistochemical staining, and brain-derived
      neurotrophic factor (BDNF) mRNA levels in ventral midbrain were measured by in
      situ hybridization. The results show a marked decrease of dopaminergic neurons on
      the lesioned side of the substantia nigra (SN) comparing with the unlesioned
      side. Zero Hz and 2 Hz EA stimulation had no effect on the disappearance of
      dopaminergic neurons. However, after 100 Hz EA, about 60% of the tyrosine
      hydroxylase (TH)-positive neurons remained on the lesioned side of the SN. In
      addition, levels of BDNF mRNA in the SN and ventral tegmental area (VTA) of the
      lesioned side were significantly increased in the 100 Hz EA group, but unchanged
      in the 0 and 2 Hz groups. Our results suggest that long-term high-frequency EA is
      effective in halting the degeneration of dopaminergic neurons in the SN and up
      regulating the levels of BDNF mRNA in the subfields of the ventral midbrain.
      Activation of endogenous neurotrophins by EA may be involved in the regeneration
      of the injured dopaminergic neurons, which may underlie the effectiveness of EA
      in the treatment of PD.

PMID- 12480179
TI  - Kainate treatment alters TGF-beta3 gene expression in the rat hippocampus.
AB  - In order to evaluate the role of transforming growth factor (TGF)-beta3 in the
      neurodegenerative process, we examined the levels of mRNA and immunocytochemical
      distribution for TGF-beta3 in the rat hippocampus after systemic kainic acid (KA)
      administration. Hippocampal TGF-beta3 mRNA level was reduced 3 h after KA
      injection. However, the levels of TGF-beta3 mRNA were elevated 1 day post-KA and
      lasted for at least 30 days. A mild TGF-beta3 immunoreactivity (TGF-beta3-IR) in
      the Ammon's horn and a moderate TGF-beta3-IR in the dentate granule cells were
      observed in the normal hippocampus. The CA1 and CA3 neurons lost their TGF-beta3
      IR, while TGF-beta3-positive glia-like cells proliferated mainly throughout the
      CA1 sector and had an intense immunoreactivity at 7, 15 and 30 days after KA.
      This immunocytochemical distribution of TGF-beta3-positive non-neuronal
      populations was similar to that of glial fibrillary acidic protein (GFAP)
      positive cells. Double labeling immunocytochemical analysis demonstrated
      colocalization of TGF-beta3- and GFAP-immunoreactivity in the same cells. These
      findings suggest a compensatory mechanism of astrocytes for the synthesis of TGF
      beta3 protein in response to KA-induced neurodegeneration. In addition, exogenous
      TGF-beta3 (5 or 10 ng/i.c.v.) significantly attenuated KA-induced seizures and
      neuronal damages in a dose-related manner. Therefore, our results suggest that
      TGF-beta3 plays an important role in protective mechanisms against KA-induced
      neurodegeneration.

PMID- 12480180
TI  - Dopamine efflux via wild-type and mutant dopamine transporters: alanine
      substitution for proline-572 enhances efflux and reduces dependence on
      extracellular dopamine, sodium and chloride concentrations.
AB  - The dopamine transporter (DAT) can mediate not only inward uptake of dopamine,
      but also its outward efflux by mechanisms that have been only partially
      elucidated. DAT-dependent dopamine efflux can be studied kinetically and apparent
      substrate affinity and V(max) values determined. We now report that wild-type DAT
      displays apparent affinities for efflux more than 300-fold lower than those for
      uptake. Efflux rates are enhanced by increased extracellular concentrations of
      dopamine or amphetamine and by lowered extracellular concentrations of Na(+) or
      Cl(-). Alanine substitutions for six proline residues located in or near DAT
      transmembrane domains increase apparent affinity and decrease V(max) values for
      dopamine efflux mediated by these mutant transporters. Mutant 12P572A displays
      increased DAT efflux with reduced dependence on ion or dopamine concentrations.
      These data add to evidence for the specificity of transporter-mediated efflux
      processes and begin to elucidate DAT candidate domains that may be preferentially
      involved with efflux activities.

PMID- 12480181
TI  - DNA microarray analysis of cortical gene expression during early recirculation
      after focal brain ischemia in rat.
AB  - Focal brain ischemia is followed by changes in gene expression as reflected by
      altered mRNA levels. DNA microarray analysis can be used to survey thousands of
      genes for differential expression triggered by ischemic metabolic stress. In this
      study, Sprague-Dawley rats were subjected to 2 h of middle cerebral artery
      occlusion (MCAO) using an intravascular poly-L-lysine-coated filament, and brains
      were removed after 3 h of recirculation for mRNA isolation. A differential
      measurement of mRNAs from post-ischemic and sham control animals was performed
      using the Mouse UniGene 1 microarray. Established values for differential
      expression were used (> or =1.7 or < or =-1.7 fold), and hits (n=2-3 arrays)
      divided into known 'ischemia-hypoxia response' genes and 'newly connected'
      annotated genes. n=28 ischemia-hypoxia response genes were up-regulated and n=6
      were down-regulated. Regulated genes comprised immediate early genes, heat shock
      proteins, anti-oxidative enzymes, trophic factors, and genes involved in RNA
      metabolism, inflammation and cell signaling. Based on the ability of the
      microarray to replicate known changes in gene expression, n=35 newly connected
      genes were found up-regulated and n=41 down-regulated. DNA microarray analysis
      allows one to develop novel working hypotheses for responses to brain ischemia
      based on the regulation of annotated genes.

PMID- 12480182
TI  - Synaptotagmin I and IV are differentially regulated in the brain by the
      recreational drug 3,4-methylenedioxymethamphetamine (MDMA).
AB  - 3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) is a widely abused drug. In
      brains of mice exposed to MDMA, we recently detected altered expression of
      several cDNAs and genes by using the differential display polymerase chain
      reaction (PCR) method. Expression of one such cDNA, which exhibited 98% sequence
      homology with the synaptic vesicle protein synaptotagmin IV, decreased 2 h after
      MDMA treatment. Herein, the effect of MDMA on expression of both synaptotagmin I
      and IV was studied in detail, since the two proteins are functionally
      interrelated. PCR analyses (semi-quantitative and real-time) confirmed that upon
      treatment with MDMA, expression of synaptotagmin IV decreased both in the
      midbrain and frontal cortex of mice. Decreases in the protein levels of
      synaptotagmin IV were confirmed by Western immunoblotting with anti-synaptotagmin
      IV antibodies. In contrast, the same exposure to MDMA increased expression of
      synaptotagmin I in the midbrain, a region rich in serotonergic neurons, but not
      in the frontal cortex. This differential expression was confirmed at the protein
      level with anti-synaptotagmin I antibodies. MDMA did not induce down- or up
      regulation of synaptotagmin IV and I, respectively, in serotonin transporter
      knockout mice (-/-) that are not sensitive to MDMA. Therefore, psychoactive
      drugs, such as MDMA, appear to modulate expression of synaptic vesicle proteins,
      and possibly vesicle trafficking, in the brain.

PMID- 12480183
TI  - Anti-apoptotic wild-type Alzheimer amyloid precursor protein signaling involves
      the p38 mitogen-activated protein kinase/MEF2 pathway.
AB  - Alzheimer amyloid precursor protein (APP) effectively protects against apoptosis
      in neuronal cells under stress, but the mechanisms of this anti-apoptotic effect
      remain largely unknown. Transcription factors act as critical molecular switches
      in promoting neuronal survival. The myocyte enhancer factor-2 (MEF2) is a
      transcription factor, and is known to be necessary for neurogenesis and activity
      dependent neuronal survival. This study examined the possible role of MEF2 in the
      anti-apoptotic signaling pathways activated by APP. We report that expression of
      wild-type human APP (hAPPwt) but not familial Alzheimer's disease mutant APP (FAD
      hAPPmut) in APP-deficient rat B103 cells led to a significant increase in the
      level of phosphorylated MEF2. This differential phosphorylation was dependent on
      enhanced activation of p38 mitogen-activated protein kinase (p38 MAPK). Also,
      expression of hAPPwt mediated an increase in MEF2 DNA binding affinity that
      correlated with p38 MAPK-dependent trans-activation of a MEF2-responsive reporter
      gene. Furthermore, over-expression of dominant negative MEF2 in hAPPwt-expressing
      cells enhanced staurosporine-induced apoptosis, in contrast MEF2wt enhanced the
      capacity of hAPPwt to confer resistance to apoptosis. Thus, MEF2 plays a critical
      role in APP-mediated signaling pathways that inhibit neuronal apoptosis. A model
      of anti-apoptotic APP signaling is proposed where APP mediates p38 MAPK-dependent
      phosphorylation and activation of MEF2. Once activated MEF2 regulates neuronal
      survival by stimulation of MEF2-dependent gene transcriptions. Alteration of this
      function by mutations in APP and aberrant APP processing could contribute to
      neuronal degeneration seen in AD.

PMID- 12480184
TI  - Modulation of olfactory bulb tyrosine hydroxylase and catecholamine transporter
      mRNA by estrogen.
AB  - Since estrogen exerts wide ranging effects within the central nervous system, it
      is important to investigate the sites and actions of this gonadal steroid hormone
      at extra-hypothalamic locations. In the present report, the effects of estrogen
      upon catecholaminergic function within the olfactory bulb were examined. To
      assess the role of estrogen at this site, ovariectomized mice received either no
      further hormonal treatment or were treated with estrogen, the anti-estrogen,
      tamoxifen, or a combination of estrogen and tamoxifen as administered in a 21-day
      release pellet. At 14 days post-hormonal treatment, the olfactory bulbs were
      assayed for mRNA levels of tyrosine hydroxylase, dopamine transporter and
      norepinephrine transporter using competitive-PCR. Tyrosine hydroxylase mRNA
      levels in either estrogen or estrogen+tamoxifen treated females were
      significantly decreased compared with non-hormonally treated controls. In
      addition, tyrosine hydroxylase mRNA levels of tamoxifen-treated mice were
      significantly greater than that of estrogen-treated mice. Dopamine transporter
      mRNA levels of tamoxifen-treated females were significantly greater than that of
      non-hormonally treated controls and estrogen treated mice. The combination of
      estrogen+tamoxifen significantly increased dopamine transporter mRNA levels
      compared to that of estrogen treated mice. No overall statistically significant
      differences in norepinephrine transporter mRNA levels were obtained among the
      four treatment groups. The data demonstrate that estrogen can exert significant
      modulatory effects upon olfactory bulb catecholaminergic function. Therefore,
      events which alter estrogen levels (menstrual/estrogen cycle,
      pregnancy/lactation, menopause, tamoxifen treatment) can modulate olfactory bulb
      catecholaminergic functions which may be involved with the detection and
      processing of olfactory stimuli.

PMID- 12480185
TI  - Expression of OASIS, a CREB/ATF family transcription factor, in CNS lesion and
      its transcriptional activity.
AB  - We reported the expression patterns of a novel member of the CREB/ATF family,
      OASIS, in central nervous system (CNS) lesions and its transcriptional activity.
      OASIS gene expression was upregulated in the stab-injured spinal cord. Double
      labeling experiments revealed that the distribution of OASIS mRNA-positive cells
      overlapped with a population of GFAP-immunoreactive cells. This finding suggested
      that OASIS might regulate expression of important downstream molecules in certain
      subset of the reactive astrocytes (e.g. inhibitory substances in injured brain).
      In gel shift assays, OASIS was able to specifically bind to CRE as CREB family
      members were. We then examined transcriptional activity of full-length OASIS with
      GAL4-UAS-luciferase reporter assay in COS7 cells. OASIS protein activated
      transcription, but did not inhibit basal transcription driven by AdML promoter.
      To determine critical portion(s) of the OASIS protein in transcriptional
      activation, we examined the activity of various deletion constructs of OASIS
      gene. The assay revealed that a strong transcriptional activation domain lay in
      the N-terminal region where acidic amino acids clustered and a possible
      repression domain, which had not been reported for other CREB/ATF family members,
      lay in the more C-terminal region. We therefore proposed that OASIS protein
      positively regulated gene transcription in a subset of reactive astrocytes, and
      thereby influenced the reaction of injured CNS tissues.

PMID- 12480186
TI  - Microtubule associated protein (MAP1A) mRNA was up-regulated by hypergravity in
      the rat inner ear.
AB  - Differential display analysis of differential mRNA expression in the rat inner
      ear under hypergravity identified two down- and four up-regulated genes. The up
      regulation of microtubule associated protein 1A (MAP1A) in one of these was
      confirmed by real-time polymerase chain reaction. Since MAP1A is believed to work
      as a cell stabilizer connecting the actin with microtubule, this is possibly a
      response to strengthen this stabilizer under hypergravity. The MAP1A gene is the
      first found to be affected by gravity change in the inner ear.

PMID- 12480187
TI  - 1,25-Dihydroxyvitamin D(3) increases striatal GDNF mRNA and protein expression in
      adult rats.
AB  - Glial cell line-derived neurotrophic factor (GDNF) has been postulated as a
      possible candidate for therapeutic treatment in Parkinson's disease (PD). Recent
      in vitro data suggest that 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D(3)] treatment
      may enhance GDNF mRNA expression. In the present study, using semiquantitative RT
      PCR and Western blot, we have shown that 1,25(OH)(2)D(3) administration
      intraperitoneally, significantly increases GDNF mRNA and protein levels in the
      striatum of adult rats.

PMID- 12480188
TI  - New approaches in the treatment of non-small cell lung cancer: taxanes in the
      treatment of NSCLC: pathways to progress.

PMID- 12480189
TI  - Second line chemotherapy for NSCLC: establishing a gold standard.
AB  - When compared with best supportive care alone, the second-line treatment of non
      small cell lung cancer (NSCLC) with 75 mg/m(2) docetaxel significantly improved
      the 1-year survival rate (37 vs. 12%) and lengthened time to disease progression
      (median 12.3 vs. 7.0 weeks) in study TAX 317. Quality of life was superior with
      docetaxel and the need for tumor-related therapy was reduced. Docetaxel 75
      mg/m(2) in this setting is safe, and offers clinically meaningful benefit to
      patients. These findings are supported by data from study TAX 320 in which a
      heavily pre-treated population of advanced NSCLC patients was randomized to
      receive docetaxel 100 mg/m(2), docetaxel 75 mg/m(2) or a comparator arm of either
      vinorelbine or ifosfamide. Treatment with either dose of docetaxel significantly
      increased the proportion of patients without disease progression at 26 weeks. By
      intent to treat analysis, 1-year survival was 32% in patients randomized to
      docetaxel 75 mg/m(2). This was significantly greater than the 19% 1-year survival
      rate in the comparator arm. Prior exposure to paclitaxel did not lessen the
      response rate or survival advantage of docetaxel in this second-line setting.
      Future development is likely to lie in the combination of docetaxel with novel
      molecular-targeted agents such as EGFR tyrosine kinase inhibitors.

PMID- 12480190
TI  - First-line chemotherapy for NSCLC: an overview of relevant trials.
AB  - In advanced non-small cell lung cancer (NSCLC), monotherapy with gemcitabine
      improves quality of life when compared to best supportive care alone, while
      single-agent taxanes and vinorelbine also improve survival. Platinum-based
      combinations achieve benefits in response rate, time to progression and survival
      compared to single-agent cisplatin. With the introduction of combinations of
      newer agents, 2-year survival rates of 10-20% are being seen in co-operative
      group trials. Until recently, the various doublets that have been subjected to
      randomized comparison appear to have achieved similar rates of response and
      survival, though toxicities differ considerably depending on the choice of drugs
      used. However, study TAX 326, the largest trial yet conducted in advanced NSCLC,
      has now demonstrated that the combination of docetaxel with cisplatin is superior
      to that of vinorelbine and cisplatin. Controlled trials of platinum-containing
      vs. non-platinum combinations have yet to demonstrate any superiority of one over
      the other. Hopes for further improvement in survival are focused on the
      combination of cytotoxic agents with novel molecularly-targeted drugs such as the
      anti-angiogenics and EGFR inhibitors.

PMID- 12480191
TI  - Challenging the platinum combinations in the chemotherapy of NSCLC.
AB  - In previously untreated patients with locally advanced or metastatic non-small
      cell lung cancer (NSCLC) the combination of docetaxel and gemcitabine is active
      and well tolerated. In the phase II setting using a 3-week schedule, response
      rates (RR) ranged from 25 to 50%, and median survival from 11 to 13 months.
      Preliminary data with weekly and bi-weekly schedules indicate maintained efficacy
      while reducing the risk of neutropenia. A randomized phase III trial has shown
      that the combination of docetaxel and gemcitabine is as active as docetaxel plus
      cisplatin, achieving a 1-year survival rate of 39%, with significantly less
      neutropenia and gastro-intestinal toxicity. The combination of docetaxel with
      vinorelbine is equally active and the associated toxicities are manageable. In
      phase II studies the average response rate is 40%, and in one study using a 2
      week schedule the 1-year survival rate was 60%. With this combination neutropenia
      is the commonest adverse event while clinically significant neuropathy is
      infrequent. In a randomized phase II trial, docetaxel plus cisplatin was compared
      to docetaxel plus irinotecan. The non-platinum doublet achieved comparable levels
      of activity, though with a different toxicity profile (more diarrhea but less
      nausea and vomiting). The combination of docetaxel with irinotecan and
      carboplatin has achieved 1-year survival of 55%. All three docetaxel combinations
      (gemcitabine, vinorelbine, and irinotecan) could provide a valuable alternative
      to platinum-based chemotherapy and should be further evaluated in phase III
      setting.

PMID- 12480192
TI  - Adjuvant and neoadjuvant treatments for NSCLC.
AB  - In stage III non-small cell lung cancer (NSCLC), the use of induction
      chemotherapy prior to radiotherapy produces a significant increase in median
      survival of three to four months (from 11 to 14 months), a benefit which appears
      to be achieved through improved systemic control of the disease.
      Hyperfractionated radiotherapy, although it enhances local control, seems not to
      improve survival. Concurrent chemoradiotherapy has emerged as the most successful
      strategy. It led to increased locoregional control and to a 3-4 month improvement
      of median survival when compared with induction chemotherapy prior to
      radiotherapy. Docetaxel is a radiosensitizing agent and has been extensively
      investigated in phase I/II settings of concurrent chemoradiotherapy. Use of the
      other cytotoxics such as paclitaxel, or irinotecan in concurrent
      chemoradiotherapy strategies is also feasible. Of particular interest are the
      results of SWOG 9504, a phase II study in which cisplatin/etoposide concurrent
      chemoradiotherapy was followed by three cycles of docetaxel consolidation. Median
      survival is 26 months, 1-year survival 76% and 3-year survival 40%. These
      survival data, achieved in pathologically staged IIIB patients, are highly
      encouraging and support further evaluation of this approach. Among stage III
      patients eligible for radical treatment with surgery or radiotherapy, the
      addition of neoadjuvant docetaxel at 100 mg/m(2) for three cycles is tolerable
      and appears to be associated with a trend towards increased survival.

PMID- 12480193
TI  - Meeting the chemotherapy needs of elderly and poor performance status patients
      with NSCLC.
AB  - Increasing interest in designing chemotherapy suitable for use in the elderly and
      in poor performance status (PS) patients has led to clinical trials in advanced
      non-small cell lung cancer (NSCLC) which have demonstrated a number of important
      points. First, the randomized Elderly Lung Cancer Vinorelbine Study Group (ELVIS)
      trial makes clear that elderly patients treated with vinorelbine plus best
      supportive care (BSC) have significantly improved survival and quality of life
      when compared with patients treated with BSC alone. Secondly, the Multicenter
      Italian Lung Cancer in the Elderly Study (MILES) trial demonstrates that the
      combination of gemcitabine plus vinorelbine in this patient population does not
      further improve survival or quality of life as compared to single chemotherapy
      with vinorelbine or gemcitabine. Weekly docetaxel has considerable potential
      among patients judged likely to tolerate poorly cisplatin-based chemotherapy. In
      a trial among 39 previously untreated elderly, poor PS or medically compromised
      patients, weekly 36 mg/m(2) docetaxel produced a 19% response rate and 28% 1-year
      survival. These data compare favorably with results achieved with other single
      agents. Weekly, docetaxel is better tolerated than the q 3-week schedule, and
      myelosuppression is not severe. Weekly docetaxel is also active as second-line
      therapy. The combination of gemcitabine and docetaxel, both administered weekly,
      is well tolerated by elderly and/or poor PS patients, is active (median survival
      7 months, 1-year survival 29%) and merits further study.

PMID- 12480194
TI  - Molecular markers and targeted therapy with novel agents: prospects in the
      treatment of non-small cell lung cancer.
AB  - Detection of genomic differences predictive of drug response or resistance in
      individual patients may allow therapy to be customized to the characteristics of
      particular tumors. Preliminary findings are that non-small cell lung cancer
      patients overexpressing ERCC1 mRNA have lower response to cisplatin chemotherapy,
      while those overexpressing ribonucleotide reductase mRNA have limited benefit
      from gemcitabine. In addition, overexpression of beta-tubulin III and stathmin
      can influence the sensitivity to microtubule interacting drugs, like vinorelbine
      and paclitaxel. The introduction of biological agents which target highly
      specific intracellular pathways offers the promise of enhancing the efficacy of
      cytotoxic chemotherapy. Among many promising biological agents is the monoclonal
      antibody C225, which blocks the EGFR receptor. The addition of C225 appears to
      induce responses in a proportion of colon cancer patients refractory to 5-FU or
      irinotecan, supporting pre-clinical evidence of synergistic activity. It also
      appears from xenograft data that C225 enhances the sensitivity of tumors to
      radiation and docetaxel or the combination.

PMID- 12480196
TI  - The diameter-cube hypothesis: a new biophysical model of aneurysm rupture.
AB  - BACKGROUND: Recent discussions on the relationship between intracranial aneurysm
      diameter and rupture probability have focused on the presence of an apparent
      critical diameter of 10 mm for aneurysm rupture. Despite the fact that many
      investigators have argued against the existence of this critical diameter, no one
      has yet proposed a viable alternative concept. In this report we present a
      scientifically rigorous alternative concept, that the size-specific rupture
      probability (RP) of an aneurysm varies as the third power of the aneurysm
      diameter. METHODS: We utilized a new biophysical model of aneurysm rupture that
      predicts the relationship between the size-specific rupture probability of an
      aneurysm and the diameter (D) to be RP = kD(3). We tested this hypothesis against
      data from two autopsy studies and one large clinical aneurysm study.
      Subsequently, using this D(3) hypothesis and the different size distributions of
      aneurysms in the study populations, we predicted the variation of cumulative
      rupture probability (CRP) with diameter for each population. RESULTS: Data from
      the autopsy studies supported the diameter-cube hypothesis, with the log-log
      plots of size-specific rupture probability versus aneurysm diameter from the two
      autopsy series yielding lines with slopes 3.54 (R(2) = 0.61, p < 0.12) and 3.05
      (R(2) = 0.98, p << 0.001). Plots of cumulative rupture probability versus
      diameter were determined to be sensitive to the size distributions of the
      unruptured aneurysms in the population. Furthermore, none of the CRP plots showed
      evidence of a critical diameter for aneurysm rupture. CONCLUSIONS: RP varies as
      the third power of aneurysm diameter, a relationship that predicts a continuous
      increase in RP with increasing size rather than the existence of a threshold
      diameter that separates low- from high-risk aneurysms. Accordingly, all aneurysms
      have finite risk for rupture and deserve consideration for treatment. Much of the
      current controversy regarding the relationship between rupture rates and diameter
      is a result of different size distributions in study populations rather than
      differences in aneurysm biology.

PMID- 12480208
TI  - Attenuation of hemolysate-induced cerebrovascular endothelial cell injury and of
      production of endothelin-1 and big endothelin-1 by an endothelin-converting
      enzyme inhibitor.
AB  - BACKGROUND: Endothelin-1 (ET-1) is a potent and long-acting vasoconstrictive
      peptide that has been implicated in the pathogenesis of cerebral vasospasm after
      subarachnoid hemorrhage (SAH). ET-1 has been shown to be present in the
      cerebrospinal fluid of patients after SAH, and substances produced during
      hemolysis of subarachnoid blood clots are believed to be responsible for
      stimulating the production of ET-1. The biosynthesis of ET-1 is a multi-step
      process, involving the conversion of the relatively inactive precursor big ET-1
      to the mature peptide by endothelin converting enzyme (ECE), a metalloprotease.
      Consequently, ECE inhibitors are expected to suppress the biosynthesis of ET-1
      and reduce the pathologic impact resulting from overproduction of this peptide.
      The purpose of the present study was to investigate the effects of an ECE
      inhibitor, CGS 26303, on hemolysate-induced injury of cerebral vessel endothelial
      cells as well as the production of ET-1 from these cells. METHODS: Different
      doses of CGS 26303 and hemolysate were added to the culture medium for 48 hours.
      Cell injury was assessed by cell morphology and density, while the productions of
      ET-1 and big ET-1 were determined by radioimmunoassays. RESULTS: Hemolysate alone
      increased the levels of ET-1 and big ET-1 in culture medium and caused
      substantial cell loss. Treatment with CGS 26303 inhibited the hemolysate-induced
      increases in the levels of ET-1 and big ET-1 and reduced endothelial cell injury.
      The protective effects of CGS 26303 were modest when this inhibitor was added
      simultaneously with hemolysate, but were prominent and dose-dependent when the
      inhibitor was given 30 minutes before the addition of hemolysate. CONCLUSION:
      These results suggest that overproduction of ET-1 contributes significantly to
      hemolysate-induced damage to cerebrovascular endothelial cells.

PMID- 12480212
TI  - Long-lasting improvement of arterial hypertension after surgical treatment of a
      foramen magnum meningioma: case report.
AB  - BACKGROUND: Neurogenic arterial hypertension has been proposed to be caused by
      neurovascular compression in many cases. However, there is little reference to
      tumors causing hypertension by local compression of the vagal nerve or the
      ventrolateral medulla oblongata. The following case illustrates the effects of
      surgery for a meningioma of the foramen magnum on arterial hypertension. CASE
      DESCRIPTION: A 54-year-old woman suffered from arterial hypertension for at least
      7 months, for which she required a combined medical treatment regime. She
      suffered for 6 months from dizziness and tinnitus, more in the left ear than in
      the right. Neurologic examination revealed a horizontal fixation nystagmus and a
      mild left-sided hearing loss. Magnetic resonance imaging and computed tomographic
      angiography showed a contrast-enhancing tumor on the left side of the foramen
      magnum compressing the medulla oblongata close to the vertebral artery and
      vascularized by branches of the left PICA. Complete surgical extirpation was
      performed using a medial craniocervical approach. The tinnitus and dizziness were
      gone and hearing improved. Postoperatively, the arterial hypertension showed a
      long-lasting improvement (observation period 8 months) with only minimal medical
      treatment. CONCLUSION: Based on our case, we conclude that tumors in close
      proximity to the ventrolateral medulla oblongata may induce neurogenic
      hypertension, similar to neurovascular compression.

PMID- 12480213
TI  - Posterior approaches in the management of cervical spondylosis and ossification
      of the posterior longitudinal ligament.
AB  - BACKGROUND: If the cervical lordotic curvature has been well preserved,
      spondylostenosis or ossification of the posterior longitudinal ligament, with or
      without instability, may be approached posteriorly in selected older patients
      (over 65 years of age). Posterior surgical alternatives include the laminectomy
      with or without fusion, or laminoplasty. However, in younger patients or in
      geriatric patients with predominantly anterior disease with kyphosis, direct
      anterior surgical procedures yield better results. METHODS: Laminectomy with
      medial facetectomy and foraminotomy is classically performed in cases in which
      stability is preserved. However, posterior stabilization using either facet
      wiring or lateral mass fusion may be warranted. Although some consider the "open
      door" laminoplasty a reasonable alternative for dorsal decompression, limitations
      include restricted access to the hinged side, a potential for "closing of the
      door," and it does not offer a "real" fusion. RESULTS: Postoperative neurologic
      improvement may approximate an 85% incidence of good to excellent results.
      However, where a posterior decompression has been chosen, particularly in younger
      individuals with or without a lordotic curvature, or in older patients with
      kyphosis, they will fail to significantly improve, and will be susceptible to
      early neurologic deterioration. CONCLUSIONS: Posterior approaches to cervical
      disease may be successful in geriatric individuals in whom the cervical lordotic
      curvature has been well preserved. However, it is inappropriate for either older
      or younger patients with predominantly anterior disease, for whom direct anterior
      decompression with or without posterior stabilization is indicated. In those
      patients with significant ventral ossification of the posterior longitudinal
      ligament (OPLL), direct anterior resection will result in improved neurologic
      outcomes, whereas posterior decompression will fail to achieve a similar degree
      of neurologic recovery. Furthermore, dorsal decompression of OPLL may promote a
      more rapid progression of OPLL growth and concomitant neurologic deterioration.

PMID- 12480218
TI  - Lumbar disc herniation: level increases with age.
AB  - BACKGROUND: Prompted by the clinical impression that L4 radicular syndrome and
      disc herniations at L3-4 occurred at older ages we studied the correlation
      between age and level of herniated discs. METHODS: We retrospectively correlated
      mean age and level of disc herniation of patients suffering from lumbar disc
      herniation. Data from 1431 patients were obtained from the neurologic database of
      the Atrium Medical Center Heerlen from 1995 through 1998. Nonparametric data were
      analyzed with the Mann-Whitney U test, and correlation was analyzed using linear
      regression. RESULTS: Mean ages of the patients with disc herniation at L5-S1, L4
      5, L3-4, and L2-3 were 44.1 +/- 0.5 years, 49.5 +/- 0.6 years, 59.5 +/- 0.9
      years, and 59.6 +/- 2.7 years, respectively. Mean ages were significantly higher
      with herniation levels at L4-5, L3-4, and L2-3 compared to L5-S1 (p < 0.0001).
      Analogously, the mean age of patients with disc herniation at L3-4 was
      significantly higher compared to those with herniation at L4-5 (p < 0.0001). No
      difference in mean age was seen between L3-4 and L2-3 (p = 0.815). A strong
      correlation was observed between the level of herniation and increasing age (R =
      0.371; p < 0.0001). CONCLUSION: These results indeed prove that with increasing
      age, lumbar disc herniation is more cranially localized. It may help in
      understanding the patho-anatomic process of disc herniation, and in recognizing
      higher level radicular syndromes in advanced age.

PMID- 12480222
TI  - Seizure-induced thoracic spine compression fracture: case report.
AB  - BACKGROUND: Vertebral fracture caused solely by a convulsive seizure has rarely
      been reported in the neurosurgical literature. CASE DESCRIPTION: We describe a 34
      year-old male with severe back pain from a thoracic fracture occurring in
      association with a seizure during hospitalization for treatment of temporal lobe
      epilepsy. Bone mineral densities in the lumbar spine and the femoral neck were
      decreased, possibly by long-term anti-epileptic medication. Muscle contractions
      during a seizure can result in vertebral fractures, especially at the thoracic
      levels. CONCLUSION: A complaint of back pain after a convulsive seizure should
      prompt radiologic investigation for vertebral fracture, even in the absence of
      external trauma.

PMID- 12480224
TI  - Acute subdural hematoma in infancy.
AB  - BACKGROUND: Acute subdural hematoma in infants is distinct from that occurring in
      older children or adults because of differences in mechanism, injury thresholds,
      and the frequency with which the question of nonaccidental injury is encountered.
      The purpose of this study is to analyze the clinical characteristics of acute
      subdural hematoma in infancy, to discover the common patterns of this trauma, and
      to outline the management principles within this group. METHODS: Medical records
      and films of 21 cases of infantile acute subdural hematoma were reviewed
      retrospectively. Diagnosis was made by computed tomography or magnetic resonance
      imaging. Medical records were reviewed for comparison of age, gender, cause of
      injury, clinical presentation, surgical management, and outcome. RESULTS: Twenty
      one infants (9 girls and 12 boys) were identified with acute subdural hematoma,
      with ages ranging from 6 days to 12 months. The most common cause of injury was
      shaken baby syndrome. The most common clinical presentations were seizure,
      retinal hemorrhage, and consciousness disturbance. Eight patients with large
      subdural hematomas underwent craniotomy and evacuation of the blood clot. None of
      these patients developed chronic subdural hematoma. Thirteen patients with
      smaller subdural hematomas were treated conservatively. Among these patients, 11
      developed chronic subdural hematomas 15 to 80 days (mean = 28 days) after the
      acute subdural hematomas. All patients with chronic subdural hematomas underwent
      burr hole and external drainage of the subdural hematoma. At follow-up, 13 (62%)
      had good recovery, 4 (19%) had moderate disability, 3 (14%) had severe
      disability, and 1 (5%) died. Based on GCS on admission, one (5%) had mild (GCS 13
      15), 12 (57%) had moderate (GCS 9-12), and 8 (38%) had severe (GCS 8 or under)
      head injury. Good recovery was found in 100% (1/1), 75% (8/12), and 50% (4/8) of
      the patients with mild, moderate, and severe head injury, respectively. Sixty
      three percent (5/8) of those patients undergoing operation for acute subdural
      hematomas and 62% (8/13) of those patients treated conservatively had good
      outcomes. CONCLUSIONS: Infantile acute subdural hematoma if treated
      conservatively or neglected, is an important cause of infantile chronic subdural
      hematoma. Early recognition and suitable treatment may improve the outcome of
      this injury. If treatment is delayed or the condition is undiagnosed, acute
      subdural hematoma may cause severe morbidity or even fatality.

PMID- 12480225
TI  - Civilian infratentorial gunshot injuries: outcome analysis of 26 patients.
AB  - BACKGROUND: Craniocerebral missile injuries have steadily increased to become the
      most common form of penetrating neurotrauma in our environment resulting in
      continued morbidity and neuropsychological sequelae. Civilian infratentorial
      gunshot injuries are uncommon but generally regarded as fatal injuries, with many
      patients dying before reaching hospital. METHODS: A retrospective analysis of
      1,069 patients with civilian gunshot wounds (GSW), admitted to our unit over a 14
      year period (1986-2000), identified 26 patients with infratentorial gunshot
      injuries (2.4%). A detailed analysis of these patients was carried out, which
      included demographic factors, clinical and anatomic correlation, computed
      tomography scans, surgical management, and outcome. RESULTS: All patients were
      male. The mean age was 26.5 +/- 11.5 years and the mean admission Glasgow Coma
      Score 11.8 +/- 2.7. Twenty-four of 26 patients required cerebrospinal fluid (CSF)
      diversion to control secondary hydrocephalus. The second commonest surgical
      procedure was posterior fossa decompression. Five of 26 patients died (19.2%).
      Severe morbidity was noted in 9 of 21 surviving patients (42.8%). Significant
      predictors: good outcome was associated with primary missile entry of the
      infratentorial compartment (p = 0.005), while patients with supratentorial to
      infratentorial missile trajectory were noted to have a poorer outcome (p =
      0.041). Location of cerebellar injury (lateral or medial) and missile caliber had
      no significant influence on patient outcome. CONCLUSION: Early control of
      incipient or established hydrocephalus and aggressive surgical management where
      appropriate, with careful postoperative monitoring, is necessary for good outcome
      in patients with civilian infratentorial missile injuries.

PMID- 12480227
TI  - Primary osteogenic sarcoma of the skull.
AB  - BACKGROUND: An osteogenic sarcoma of the skull is rare, particularly as a primary
      tumor. The incidence of primary osteogenic sarcomas of the skull is about 1 to 2%
      of all skull tumors. CASE DESCRIPTION: A 21-year-old male was initially evaluated
      because of a large mass that had been growing for 7 months. The patient had been
      experiencing frequent headaches and tenderness at the site of the lump for about
      a month before being seen by the neurosurgeon. A computed tomography scan
      revealed a large mass, 12 cm x 7 cm, involving the scalp extending from the right
      temporal region to the vertex. A magnetic resonance imaging (MRI) scan showed a
      large mass arising from the posterolateral aspect that was 90% extracranial and
      10% intracranial on the right side of the skull. The MRI showed marked
      vascularity and neovascularity of the tumor. An angiogram was performed, which
      demonstrated that the mass was fed by the branches from the right external
      carotid artery. The patient subsequently underwent surgery for embolization of
      the right occipital and superficial temporal arteries and removal of the mass.
      Pathology evaluation of a specimen revealed a high-grade osteoblastic
      osteosarcoma. CONCLUSION: We review the literature of reported cases of primary
      osteogenic sarcomas of the skull to discuss the common clinical presentation,
      evaluation methods, and recommended treatment plans.

PMID- 12480230
TI  - Intracranial metastasis or meningioma? An uncommon clinical diagnostic dilemma.
AB  - BACKGROUND: Cerebral metastases are the most frequent brain tumors in adults and
      they may occasionally present as an isolated meningeal mass, suggesting a
      meningioma. Because of the prognostic relevance in discriminating both tumors, we
      review the literature and analyze four patients in whom the diagnosis of
      meningioma was initially made. CASE DESCRIPTION: Four cases of isolated meningeal
      metastases are presented and in all of them a meningioma was considered as the
      main preoperative diagnosis. Only one patient had a history of previous cancer.
      The primary tumors found after pathological testing of the lesions were thyroid
      carcinoma, prostate adenocarcinoma, breast adenocarcinoma, and hypernephroma. The
      clinical and neuroimaging features as well as the differential diagnoses are
      discussed. The literature regarding these forms of meningeal metastases was
      reviewed. CONCLUSIONS: Although they are uncommon, dural metastases can be
      mistaken for meningiomas. Our experience in these cases has led us to consider
      ordinary metastases as a differential diagnosis even when a meningioma is
      suspected. The definitive diagnosis of a meningioma should be established only
      after the histopathological report has been analyzed.

PMID- 12480233
TI  - Primary B-cell lymphoma of the clivus: case report.
AB  - BACKGROUND: Lymphomas usually present in extranodal sites late in the course of
      the disease. Moreover, it is uncommon for a primary non-Hodgkin's lymphoma to
      present with cranial nerve palsies; reports in the literature are rare. CASE
      DESCRIPTION: We report the case of a 60-year-old woman with complaints of
      headache and double vision. MRI revealed an expansive clival lesion without
      pituitary invasion. An endoscopic transsphenoidal procedure was performed for
      diagnosis and partial resection of the mass. CONCLUSION: Primary diffuse large B
      cell lymphoma of the clivus is rare. An endoscopic transsphenoidal approach to
      the skull base is described, along with characteristic clinical, radiologic, and
      pathologic findings of the lesions.

PMID- 12480235
TI  - Intracranial dural arteriovenous fistula showing diffuse MR enhancement of the
      spinal cord: case report and review of the literature.
AB  - BACKGROUND: Cervical myelopathy resulting from intracranial dural arteriovenous
      fistula (AVF) is uncommon. Knowledge of the magnetic resonance imaging (MRI)
      appearance of such lesions is important because many patients with myelopathy are
      initially examined by MRI, and an incorrect diagnosis could result in delayed or
      improper treatment. We describe a rare case of myelopathy due to an intracranial
      dural AVF showing diffuse enhancement of the cervical spinal cord. CASE
      DESCRIPTION: A 64-year-old male presented with progressive myelopathy and
      respiratory insufficiency. Cerebral angiography disclosed an AVF at the
      craniocervical junction draining intrathecally into the spinal medullary veins.
      MRI revealed dilated perimedullary vessels around the craniocervical junction, as
      well as spinal cord swelling with high signal intensity changes. Diffuse intense
      enhancement of the cervical spinal cord was also seen on postcontrast images.
      Embolization via the afferent artery was successfully performed, and the fistula
      was then microsurgically obliterated via a lateral suboccipital approach. This
      procedure arrested a rapidly progressive myelopathy. CONCLUSION: Intracranial
      dural AVF showing diffuse enhancement of the spinal cord is extremely rare, and
      this enhancement effect may indicate pathologic changes of the spinal cord. MRI
      only is not useful for diagnosis, but also for demonstrating pathologic changes
      and predicting the outcomes of patients with intracranial dural AVF.

PMID- 12480237
TI  - Pseudoaneurysms of the superficial temporal artery secondary to placement of
      external ventricular drainage catheters.
AB  - BACKGROUND: Pseudoaneurysms of the superficial temporal artery have been
      described following trauma and various surgical procedures. There are no reports
      in the literature of these lesions following the placement of external
      ventricular drainage catheters. This article describes two patients and their
      successful treatment, and reviews diagnostic and treatment strategies. CASE
      DESCRIPTION: Two patients developed tender, nonpulsatile masses in the scalp
      along the former subcutaneous tract of an EVD catheter. Both lesions were
      successfully excised in the operating room and found to be thrombosed
      pseudoaneurysms of the superficial temporal artery. CONCLUSION: Pseudoaneurysms
      of the parietal branch of the STA may occur secondary to incision of the skin for
      twist drill hole placement or the use of a sharp trocar for subcutaneous
      tunneling of catheters. Use of a blunt-tipped trocar may reduce the risk of
      developing pseudoaneurysms secondary to EVD placement. Knowledge of the
      possibility of developing these lesions from catheter placement may aid the
      neurosurgeon in proper diagnosis and treatment.

PMID- 12480238
TI  - Subarachnoid hemorrhage as a result of fungal aneurysm at the posterior
      communicating artery associated with occlusion of the internal carotid artery:
      case report.
AB  - BACKGROUND: Fungal or "true" mycotic aneurysms of the intracranial circulation
      are very rare. Rupture of a fungal aneurysm is fatal in almost 100% of cases.
      CASE DESCRIPTION: We report a 65-year-old woman with a ruptured fungal aneurysm
      on the posterior communicating artery associated with occlusion of the internal
      carotid artery. She had a past history of gastric malignant lymphoma and
      subsequent granulocytopenia. She survived after surgical treatment including
      trapping of the aneurysm and a superficial temporal artery-to-middle cerebral
      artery bypass. CONCLUSION: Improved immune response at the time of the onset of
      subarachnoid hemorrhage, as well as additional vasoreconstructive surgery, may
      have contributed to favorable outcome after surgical treatment.

PMID- 12480239
TI  - Cerebellar abscesses secondary to occipital dermoid cyst with dermal sinus: case
      report.
AB  - BACKGROUND: Hydrocephalus and cerebellar abscesses as the principal
      manifestations of posterior fossa dermoid cyst are rare. In addition, extradural
      dermoid cyst of the posterior fossa has been described in only 9 cases in the
      literature. We present an unusual case of obstructive hydrocephalus due to
      cerebellar abscesses induced by an adjacent extradural dermoid cyst with complete
      occipital dermal sinus. CASE DESCRIPTION: A 14-month-old child presented with
      acute raised intracranially pressure, seizures, and meningitis. Neuroradiological
      studies revealed cerebellar cysts with ring enhancement associated with a
      contiguous occipital cyst, with compression of the adjacent cisterns and the
      fourth ventricle causing hydrocephalus. The diagnosis of cerebellar abscesses
      with congenital occipital defect was briefly entertained. The patient was treated
      by radical excision of the occipital cyst with hair contents, the dermal sinus,
      and the abscesses through a suboccipital approach, followed by systemic
      antibiotic therapy with a good outcome. Pathologic examination revealed a dermoid
      cyst. CONCLUSION: Posterior fossa dermoid cyst should be considered in all
      children with occipital skin lesions, especially dermal sinus. CT scan and MRI
      are the methods of choice for further investigation of suspect congenital dermal
      lesions. Neurosurgical treatment of these malformations should be planned early
      to prevent the high incidence of infections such as bacterial meningitis and
      cerebellar abscess. Clinical presentation, diagnostic evaluation, and treatment
      of these rare lesions are reviewed.

PMID- 12480240
TI  - Gas-containing otogenic brain abscess.
AB  - BACKGROUND: Gas-containing brain abscesses are very rare. Two mechanisms may be
      responsible for the presence of intracavitary gas: bacterial fermentation or
      penetration through an abnormal communication between the exterior and the
      intracranium. The need to search for this potential communication is considered
      an indication for open surgery. We report the case of a surgically treated gas
      containing brain abscess originating from an undiagnosed chronic otitis media.
      CASE DESCRIPTION: A 54-year-old man developed acute neurologic deterioration,
      becoming comatose within 24 hours. A contrast-enhanced computed tomography (CT)
      scan disclosed a gas-containing cystic mass in the right temporal lobe. Urgent
      surgical decompression revealed the presence of an abscess, which was excised.
      During the same surgery, we performed a radical mastoidectomy, removing a
      previously undiagnosed attic cholesteatoma. Neither procedure revealed a
      discontinuity of the floor of the middle cranial fossa. Cultures grew a mixed
      flora. Antibiotics were administered for 6 weeks. The patient made a complete
      neurologic recovery. CONCLUSION: This report demonstrates that otogenic brain
      abscesses may contain gas due to fermentation of nonclostridial bacteria.

PMID- 12480241
TI  - Perioperative deep vein thrombosis in Chinese patients undergoing craniotomy.
AB  - BACKGROUND: We attempted to determine the incidence of perioperative deep vein
      thrombosis (DVT) in Chinese patients undergoing elective craniotomy for brain
      tumors and to assess the efficacy of clinical and serial calf circumference
      assessment in detecting DVT. METHODS: Between June 1999 and February 2001, 100
      consecutive patients who underwent elective craniotomy for brain tumors at the
      Department of Neurosurgery, University of Hong Kong Medical Centre were examined
      for perioperative DVT. The demographic data, Glasgow coma score (GCS), mobility
      status, and the operative details were recorded. Graduated compression stockings
      and intermittent pneumatic compression were applied perioperatively as
      prophylaxis against DVT. Serial duplex scans were performed before and after
      operation. Clinical examination was also performed daily to look for signs of
      DVT. The calf circumference was measured at fixed levels for both limbs before
      each duplex scan surveillance. RESULTS: The study group consisted of 44 males and
      56 females, with a mean age of 54 +/- 15 years (range, 20-81 years). There was no
      preoperative DVT. Postoperative DVT was detected on duplex scan in four patients
      (4%), two of whom had bilateral involvement. The thrombosis was confined to the
      calf veins in two limbs. The demographic data, neurologic status and operative
      details of patients with and without DVT were similar. Patients with DVT had no
      clinically recognizable signs. The change in calf circumference measurement was
      also not predictive of DVT. CONCLUSIONS: The incidence of perioperative DVT in
      Chinese patients undergoing elective craniotomy for brain tumors appears to be
      low with the present mechanical prophylactic measures. Given the low incidence of
      proximal DVT as detected by duplex scan, the use of heparin prophylaxis may not
      be justified because of the increased risk of intracranial bleeding. Clinical
      assessment with calf circumference measurement is unreliable in the diagnosis of
      DVT.

PMID- 12480247
TI  - Practice patterns in the U.S.

PMID- 12480244
TI  - Cerebrospinal fluid leak demonstrated by three-dimensional computed tomographic
      myelography in patients with spontaneous intracranial hypotension.
AB  - BACKGROUND: Precise determination of the spinal level of a cerebrospinal fluid
      leak is important in the diagnosis and treatment of spontaneous intracranial
      hypotension. The authors report two cases of SIH in which a cerebrospinal fluid
      leak was demonstrated by three-dimensional computed tomographic (3D-CT)
      myelography. CASE DESCRIPTION: By overlaying 3D-CT images of contrast-enhanced
      CSF and the spine, the point of leakage was clearly depicted in the three
      dimensional spinal structure, which assisted targeted epidural blood patch under
      the guidance of fluoroscopy. Although associated chronic subdural hematoma had to
      be treated by burr hole drainage, the patients' postural headaches subsided after
      treatment. CONCLUSION: Clear CSF images in relation to vertebral bones are
      obtainable with 3D-CT myelography, rendering this modality very useful for the
      diagnosis and treatment of spontaneous intracranial hypotension.

PMID- 12480248
TI  - Why the International Study of Unruptured Intracranial Aneurysms has lost
      credibility with neuroscientists.

PMID- 12480249
TI  - Uncover the mystery of plasmacytoid dendritic cell precursors or type 1
      interferon producing cells by serendipity.

PMID- 12480250
TI  - Developmental origin of pre-DC2.
AB  - It is generally accepted that dendritic cells can be generated from either
      myeloid or lymphoid derived progenitors. Ample information has been collected on
      the development and nature of myeloid DC type 1 (DC1). In contrast, our current
      understanding on the origin and function of the lymphoid derived DC type 2 (DC2)
      is still limited but is increasing rapidly. Here we will summarize recent
      findings on the developmental origin of the precursor of DC2 (pre-DC2). The
      presence of pre-DC2 has been revealed in bone marrow, fetal liver, and cord
      blood, where they develop from hematopoietic stem cells (HSC) most likely via an
      intermediate pro-DC2 stage. Both in human and mouse, development of pre-DC2
      depends on the cytokine FLT3-ligand (FLT3-L). In addition, transcription factors
      such as Spi-B and members of the basic helix-loop helix (bHLH) family have been
      shown to be involved in the proper differentiation of HSC into pre-DC2. The human
      thymus contains a population of cells that closely resembles the peripheral pre
      DC2, including interferon (INF)-a production after viral stimulation. Some
      phenotypic differences have been observed however. Furthermore, we have shown
      that the thymic microenvironment is able to support development of pre-DC2 from
      HSC in vivo. A thymus independent pathway of pre-DC2 development exists as well,
      although at present it is not clear where these extrathymic pre-DC2 are
      generated. In regard of the absence of a phenotypic defined pro-DC2 population in
      the thymus, we speculate that development of thymic pre-DC2 may differ from
      peripheral pre-DC2. The challenge of the near future will be to determine the
      role of pre-DC2 during thymic T cell development.

PMID- 12480251
TI  - Origin and filiation of human plasmacytoid dendritic cells.
AB  - Human plasmacytoid dendritic cells represent a rare population of leukocytes
      which produce high amounts of type I interferon in response to certain viruses.
      Although those cells were first described in 1958, there are still unsolved
      issues related to their origin and function. Recently, a leukemic counterpart of
      plasmacytoid dendritic cells was identified. Molecular approaches using either
      normal or leukemic plasmacytoid dendritic cells provide some new insights into
      the controversial lymphoid origin of those cells. The need for specific markers
      is still a critical aspect for the identification of plasmacytoid dendritic
      cells, whatever stage of differentiation, in normal as well as in pathological
      conditions. Hopefully, novel markers will allow delineation of the relationships
      between dendritic cells at different stages of differentiation/maturation along
      the myeloid and lymphoid lineages.

PMID- 12480252
TI  - The multifaceted murine plasmacytoid dendritic cell.
AB  - Plasmacytoid dendritic cells (PDCs) or natural interferon-producing cells,
      function as the body's innate defense against viral infections. As discussed
      here, they may play additional roles in response to bacterial pathogens and may
      have the capacity to induce different type of T-cell responses depending on what
      signals they receive. The discovery of murine PDCs will allow for the design of
      models to study viral immunobiology in vivo and to determine their function in
      various diseases that involve plasmacytoid dendritic cells, such as selected
      leukemias, lymphomas, allergies, different autoimmune conditions, and their
      possible role in inducing and maintaining tolerance.

PMID- 12480253
TI  - Human and mouse plasmacytoid dendritic cells.
AB  - By virtue of their enormous potential to produce type I interferons it is clear
      that plasmacytoid dendritic cells are major players in the host defense against
      viruses and various pathogens. Plasmacytoid dendritic cells were first identified
      in humans and very recently the mouse equivalents have been isolated. This review
      focuses, where possible, on a comparison between the cells in these two species.
      The mouse and human plasmacytoid DC are remarkably similar in surface phenotype
      and they display similar responses to pathogenic stimuli. The discovery of the
      mouse plasmacytoid dendritic cells has allowed for further biological properties
      of these cells to be investigated and it is now clear that they represent a long
      lived family of cells that differentiate into novel dendritic cells upon
      microbiologic stimulation.

PMID- 12480254
TI  - Plasmacytoid dendritic cells: the key to CpG.
AB  - The vertebrate immune system has established TLR9 to detect microbial DNA based
      on unmethylated CG dinucleotides within certain sequence contexts (CpG motifs).
      In humans, the expression of toll-like receptor 9 (TLR9) is restricted to B cells
      and plasmacytoid dendritic cells (PDC). The PDC is characterized by the ability
      to rapidly synthesize large amounts of type I IFN (IFN-alpha and IFN-beta) in
      response to viral infection. In contrast to other dendritic cell subsets which
      express a broad profile of TLRs, the TLR profile in PDC is restricted to TLR7 and
      TLR9. So far, CpG DNA is the only defined microbial molecule recognized by PDC.
      An intriguing feature of PDC is its ability to simultaneously produce the two
      major Th1-inducing cytokines in humans, IFN-alpha and IL-12, both at high levels.
      The ratio of IFN-alpha versus IL-12 and the quantity of these cytokines are
      regulated by T helper cell-mediated costimulation via CD40 ligation. The ratio
      also depends on the differentiation stage of the PDC at the time of stimulation
      and the type of CpG ODN used. We propose a model in which the establishment of
      Th1 responses in vivo is improved by appropriately stimulated PDC that otherwise 
      in the absence of CpG DNA--support Th2 or Th0 responses and thus have been
      called DC2.

PMID- 12480255
TI  - Roles of toll-like receptors in natural interferon-producing cells as sensors in
      immune surveillance.
AB  - Natural IFN-alpha/beta producing cells (IPCs) play a central role in innate
      immunity against microbial infections. In primary immune responses, toll-like
      receptors (TLRs), as major pattern-recognition receptors, are essential for IPCs
      as well as other antigen presenting cell (APC) subsets to recognize microbes.
      IPCs unequivocally express TLR7 and TLR9, and can respond to the respective
      ligand to produce IFN-alpha/beta and to rapidly differentiate into dendritic
      cells (DCs). Thereby, IPCs can not only activate innate immune system but also
      provoke T cell responses. Thus, IPCs link innate and adaptive immunity through
      TLR system. In addition, recent work has revealed the regulatory system of DC
      subsets in response to microbial invasion. In this context, by the different but
      complementary expression profile of TLRs, IPCs together with myeloid APC subsets
      constitute a rational system of immune surveillance that can cover a wide variety
      of pathogens and enlarge immune adjuvant effects.

PMID- 12480256
TI  - Natural type I interferon-producing cells as a link between innate and adaptive
      immunity.
AB  - Type I interferons (IFNs) are promptly produced upon invasion of pathogens, and
      activate a broad range of effector cells in the innate and adaptive immune
      system. Lin(-)CD4(+)CD11c(-) plasmacytoid dendritic cell precursors (plasmacytoid
      pre-DCs) produce enormous amounts of type I IFNs in response to viruses and CpG
      DNA, thus corresponding to the previously described but not fully defined natural
      type I IFN-producing cells (IPCs). Plasmacytoid pre-DCs strongly express toll
      like receptor (TLR) 7 and TLR9, in contrast to monocytes, which mainly express
      TLR1, 2, 4, 5, and 8, suggesting that these two DC precursors recognize different
      microbial molecules and that they may have developed through different
      evolutionary trails. Three different stimuli, CpG DNA plus CD40 ligand,
      interleukin-3 (IL-3), and herpes simplex virus, stimulate plasmacytoid pre-DCs to
      differentiate into DCs that induce distinct types of T helper cells, i.e., Th1,
      Th2, and IFN-gamma- and IL-10-producing T cells, respectively. The remarkable
      versatility of plasmacytoid pre-DCs distinguishes them from other cell types in
      the immune system that have only limited functions, and suggests that these cells
      may play a key role in integrating the innate and adaptive aspects of various
      immune responses.

PMID- 12480257
TI  - Plasmacytoid dendritic cells: from specific surface markers to specific cellular
      functions.
AB  - We have recently described a panel of monoclonal antibodies (mAb), that recognize
      two novel leukocyte surface antigens, BDCA-2 and BDCA-4. BDCA-2 is a novel type
      II C-type lectin specifically expressed by plasmacytoid dendritic cells (PDCs)
      that can internalize antigen for presentation to T cells. Furthermore, signaling
      via BDCA-2 may play a role in switching from interferon (IFN)-alpha/beta
      controlled to interleukin (IL)-12-controlled immune response pathways, as
      triggering of BDCA-2 potently inhibits secretion of IFN-alpha/beta by PDCs and
      thereby promotes IL-12 p70 production in PDCs and other cells. Viruses may
      exploit this switch to escape innate antiviral immunity, but it may be beneficial
      for patients with systemic lupus erythematosus (SLE) if induced, for instance by
      anti BDCA-2 mAb treatment. BDCA-4 is shown here to be identical to neuropilin-1
      (NP-1), a neuronal receptor for the axon guidance factors belonging to the class
      3 semaphorin subfamily, and a receptor on endothelial and tumor cells for
      vascular endothelial growth factor (VEGF-A). In blood and bone marrow, BDCA-4/NP
      1 is exclusively expressed on PDCs, but in tonsils also on a few other cells,
      primarily follicular B helper memory T cells (T(FH)).

PMID- 12480258
TI  - Human plasmacytoid-derived dendritic cells and the induction of T-regulatory
      cells.
AB  - Suppression by T-regulatory (Tr) cells is essential for the induction of T-cell
      tolerance and the prevention of autoimmune diseases, organ rejection, and graft
      versus-host disease. Increasing attention has been devoted to understand the role
      of dendritic cells (DC) in the control of Tr-cell differentiation. Here we review
      the recent evidence that cluster designation (CD)40-ligand activated plasmacytoid
      derived DCs (DC2) have the ability to induce primary Tr-cell differentiation. We
      propose that in addition to the regulatory functions of immature myeloid DC, Tr
      cell induction by DC2 represents a nonredundant mechanism for the safeguard of
      peripheral T-cell tolerance. DC2 can be used as tool to drive potent antigen
      specific Tr-cell differentiation and expansion in vitro and in vivo.

PMID- 12480259
TI  - Induction of anergic and regulatory T cells by plasmacytoid dendritic cells and
      other dendritic cell subsets.
AB  - The induction of antigen-specific tolerance is critical for maintaining immune
      homeostasis and preventing autoimmunity. Because the central tolerance that
      eliminates potentially harmful autoreactive T cells is incomplete, peripheral
      mechanisms for suppressing self-reactive T cells play an important role.
      Dendritic cells (DCs) are professional antigen-presenting cells, which have an
      extraordinary capacity to stimulate naive T cells and initiate primary immune
      responses. Recent accumulating evidence indicates that several subsets of human
      DCs also play a critical role in the induction of peripheral tolerance by
      anergizing effector CD4(+) and CD8(+) T cells or by inducing the differentiation
      of naive T cells into T-regulatory cells, which produce interleukin (IL)-10.
      Human DC subsets with the property of suppressing an antigen-specific T-cell
      response include plasmacytoid DCs, which are either in an immature state or in a
      mature state induced by CD40 ligand stimulation, and monocyte-derived DCs, which
      are either in an immature state or have had their state modulated by treatment
      with IL-10 or CD8(+)CD28(-) T cells. These "tolerogenic" DCs may be relevant to
      therapeutic applications for autoimmune and allergic diseases as well as organ
      transplant rejection.

PMID- 12480260
TI  - Differential migration behavior and chemokine production by myeloid and
      plasmacytoid dendritic cells.
AB  - The existence of dendritic cell (DC) subsets is firmly established, but their
      trafficking properties are still largely unknown. We have indicated that myeloid
      dendritic cells (M-DCs) and plasmacytoid dendritic cells (P-DCs) isolated from
      human blood differ widely in the capacity to migrate to chemotactic stimuli. The
      pattern of chemokine receptors expressed ex vivo by both subsets is similar, but
      P-DCs display, compared with M-DCs, higher levels of CC chemokine receptor
      (CCR)5, CCR7, and CXCR3. Intriguingly, most chemokine receptors of P-DCs, in
      particular those specific for inflammatory chemokines and classical chemotactic
      agonists, are not functional in circulating cells. Following maturation induced
      by cluster designation (CD)40 ligation, the receptors for inflammatory chemokines
      are downregulated and CCR7 on P-DCs becomes coupled to migration. The drastically
      impaired capacity of blood P-DCs to migrate in response to inflammatory
      chemotactic signals contrasts with the response to lymph node-homing chemokines,
      indicating a propensity to migrate to secondary lymphoid organs rather than to
      sites of inflammation. The distinct migration behavior of DC subsets is
      accompanied by a different profile of chemokine production. In contrast to the
      high production by M-DCs, the homeostatic CC chemokine ligand (CCL)17/ thymus-
      and activation-regulated chemokine (TARC) is not produced by PDCs in response to
      any stimulus tested and their production of CCL22/MDC is minimal, if any,
      compared with M-DCs. Thus, stimulated M-DCs, but not P-DCs, are able to produce
      high levels of chemokines recruiting T-helper 2 cells (Th2) and T-regulatory
      cells. Conversely, the proinflammatory chemokine CCL3/macrophage inflammatory
      protein (MIP)-1alpha is predominantly produced by P-DCs. Therefore, P-DCs appear
      to produce preferentially proinflammatory chemokines, but to respond selectively
      to homeostatic ones, whereas the reverse is true for M-DCs, highlighting not only
      the different migratory properties of these DC subsets, but also their capacity
      to recruit different cell types at inflammation sites.

PMID- 12480261
TI  - Blood dendritic cells and DC-poietins in systemic lupus erythematosus.
AB  - Dendritic cells (DCs) control immunity and tolerance. Hence, we surmised that
      systemic lupus erythematosus (SLE), a systemic autoimmune disease with
      autoreactive T and B cells, might be due to alterations in DC homeostasis. Taken
      together, our results demonstrate profound alterations of DCs and DC-poietins
      homeostasis in SLE. Elevated levels of interferon-alpha (IFN) in serum of SLE
      patients coexist with decreased numbers of cells producing IFN-alpha, i.e.,
      plasmacytoid dendritic cells (PDCs). Decreased numbers of circulating DCs
      correlate with increased levels of soluble tumor necrosis factor (TNF) receptors,
      thus suggesting the potential role of TNF pathway in the observed DC alterations.
      Finally, increased FMS-like tyrosine kinase 3-ligand (FLT3-L) and its correlation
      with soluble TNF receptors suggest a physiologic response to compensate low DC
      numbers. Although IFN-alpha remains at the center of immunologic aberrations in
      SLE, it remains to be determined whether increased shedding of soluble TNF
      receptors could also be ascribed to IFN-alpha.

PMID- 12480262
TI  - The natural interferon-alpha producing cells in systemic lupus erythematosus.
AB  - Prolonged exposure of the immune system to type I interferons (IFN
      alpha/beta/omega) in patients receiving IFN-alpha therapy frequently results in
      development of autoantibodies and autoimmune disease. This is attributed to the
      many immunostimulatory effects of these cytokines. Patients with the autoimmune
      disease systemic lupus erythematosus (SLE) have an ongoing IFN-alpha production.
      Recent studies of SLE demonstrated the presence of endogenous IFN-alpha inducers,
      acting specifically on natural IFN-alpha producing cells (NIPC), often termed
      plasmacytoid dendritic cells (PDC). These IFN-alpha inducers were potent, present
      at the blood level, and characterized as immune complexes that contained DNA and
      IgG as essential components. They were considered a likely reason for the
      activated IFN-alpha production in SLE, which, in turn, might be an important
      etiopathogenic factor. Here, we briefly review the biology of the type I IFN
      system, with emphasis on inducers, producing cells (especially NIPC/PDC), IFN
      alpha actions, and target immune cells, which might be relevant in SLE. Based on
      such information and results from studies in SLE patients, we propose a
      hypothesis that explains how NIPC/PDC become activated and play a pivotal
      etiopathogenic role in SLE and perhaps also other autoimmune diseases. This
      hypothesis furthermore indicates new therapeutic targets.

PMID- 12480263
TI  - Plasmacytoid dendritic cells: do they have a role in immune responses after
      hematopoietic cell transplantation?
AB  - Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and are
      able to modulate immune responses. Investigators are studying methods to exploit
      the immunogenic and tolerogenic properties of DC. In the context of hematopoietic
      cell transplantation, DC might be helpful to facilitate engraftment and prevent
      graft-versus-host disease (GVHD) reactions. In this paper, we review
      circumstantial evidence that immature plasmacytoid DC might affect immune
      responses after transplantation of hematopoietic cells from allogeneic donors.

PMID- 12480264
TI  - Involvement of plasmacytoid dendritic cells in human diseases.
AB  - In vitro studies have reported that plasmacytoid dendritic cells (PDCs) exert
      multiple functions, including production of interferon (IFN)-alpha as effector
      cells and regulation of T-cell responses as mature DCs. Here we review recent
      data obtained in situ showing that PDCs accumulate in lesions of type I IFN
      related disorders (virus infections and lupus erythematosus), Th2 cell-dominated
      allergic reactions, and ovarian carcinoma. These results demonstrate that PDCs do
      migrate to peripheral tissues during inflammation, which lends further support to
      the view that PDCs most likely are important players in innate and adaptive
      immunity in vivo. Future research should aim at defining the exact pathogenic or
      defense roles of PDCs in such disorders and determine whether these cells are
      potential targets for therapeutic intervention in microbial infections, allergy,
      autoimmunity, or cancer.

PMID- 12480265
TI  - Natural type 1 interferon producing cells in HIV infection.
AB  - Natural type 1 interferon producing cells (IPCs) are in the first line of defense
      against infectious pathogens. Besides the known properties of type 1 interferons
      in inhibiting human immunodeficiency virus (HIV) replication, the recent
      characterization of human IPCs and the possibility to purify them for in vitro
      studies has greatly accelerated the study of their role in HIV infection. The
      blood IPC numbers and function are decreased in HIV primary infection and in
      advanced stages of HIV infection. Loss of circulating IPCs correlates with a high
      HIV viral load and the occurrence of opportunistic infections. Moreover, HIV can
      directly infect IPCs in vitro, providing a potential explanation for their in
      vivo depletion. Thus, the balance between IPCs and HIV replication might be
      critical in determining the control or progression of HIV infection.

PMID- 12480266
TI  - Nomenclature for factors of the HLA system, 2002.

PMID- 12480268
TI  - A compaction process to enhance dissolution of poorly water-soluble drugs using
      hydroxypropyl methylcellulose.
AB  - The purpose of this study was to develop a technique to enhance the dissolution
      rate of poorly water-soluble drugs with hydroxypropyl methylcellulose (HPMC)
      without the use of solvent or heat addition. Three poorly water-soluble drugs,
      naproxen, nifedipine, and carbamazepine, were studied with low-viscosity HPMC USP
      Type 2208 (K3LV), HPMC USP Type 2910 (E3LV and E5LV), and methylcellulose.
      Polymer and drug were dry-blended, compressed into slugs on a tablet press or
      into ribbons on a roller compactor, and then milled into a granular powder.
      Dissolution testing of the milled powder was performed on USP Apparatus II, 100
      rpm, 900 ml deionized water, 37 degrees C. Drug distribution vs. particle size
      was also studied. The compaction processes enhanced drug dissolution relative to
      drug alone and also relative to corresponding loosely mixed physical mixtures.
      The roller compaction and slugging methods produced comparable dissolution
      enhancement. The mechanism for dissolution enhancement is believed to be a
      microenvironment HPMC surfactant effect facilitated by keeping the HPMC and drug
      particles in close proximity during drug dissolution. The compaction methods in
      this study may provide a lower cost, quicker, readily scalable alternative for
      formulating poorly water-soluble drugs.

PMID- 12480269
TI  - Artificial neural networks (ANNs) and modeling of powder flow.
AB  - Effects of micromeritic properties (bulk, tapped and particle density, particle
      size and shape) on the flow rate through circular orifices are investigated, for
      three pharmaceutical excipients (Lactose, Emcompress and Starch) separated in
      four sieve fractions, and are modeled with the help of artificial neural networks
      (ANNs). Eight variables were selected as inputs and correlated by applying the
      Spearman product-moment correlation matrix and the visual component planes of
      trained Self-Organizing Maps (SOMs). Back-propagation feed-forward ANN with six
      hidden units in a single hidden layer was selected for modeling experimental data
      and its predictions were compared with those of the flow equation proposed by. It
      was found that SOMs are efficient for the identification of co-linearity in the
      input variables and the ANN is superior to the flow equation since it does not
      require separate regression for each excipient and its predictive ability is
      higher. Besides the orifice diameter, most influential and important variable was
      the difference between tapped and bulk density. From the pruned ANN an
      approximate non-linear model was extracted, which describes powder flow rate in
      terms of the four network's input variables of the greatest predictive importance
      or saliency (difference between tapped and bulk density (x(2)), orifice diameter
      (x(3)), circle equivalent particle diameter (x(4)) and particle density [equation
      in text].

PMID- 12480270
TI  - Calcium phosphate nanoparticles as novel non-viral vectors for targeted gene
      delivery.
AB  - Calcium phosphate nanoparticles present a unique class of non-viral vectors,
      which can serve as efficient and alternative DNA carriers for targeted delivery
      of genes. In this study we report the design and synthesis of ultra-low size,
      highly monodispersed DNA doped calcium phosphate nanoparticles of size around 80
      nm in diameter. The DNA encapsulated inside the nanoparticle is protected from
      the external DNase environment and could be used safely to transfer the
      encapsulated DNA under in vitro and in vivo conditions. Moreover, the surface of
      these nanoparticles could be suitably modified by adsorbing a highly adhesive
      polymer like polyacrylic acid followed by conjugating the carboxylic groups of
      the polymer with a ligand such as p-amino-1-thio-beta-galactopyranoside using 1
      ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a coupling agent.
      We have demonstrated in our studies that these surface modified calcium phosphate
      nanoparticles can be used in vivo to target genes specifically to the liver.

PMID- 12480271
TI  - Rheological behavior and the SPF of sunscreens.
AB  - Due to a large variety of sunscreens, it is important to study among other
      things, the effect of the vehicle on the thickness and uniformity of sunscreen
      films. In this study, we determined the physical stability of five sunscreens SPF
      15 (FA to FG), containing or not PVP/eicosene crosspolymer (PVP/EC), and two
      different self-emulsifying bases (SEB), and also evaluated the influence of the
      vehicle in their SPF. In the study of physical stability, formulations were
      stored at 25, 37 and 45 degrees C, for 28 days. Viscosity and rheological
      behavior of the formulations were determined using a Brookfield rheometer.
      Investigations of the SPF were carried out in a group of 30 volunteers (COLIPA
      methodology). The FC samples (phosphate-based SEB), with a lower thixotropy,
      showed statistically higher SPF (13.6) when compared with FB (non-ionic SEB),
      which presented higher thixotropy and a SPF of 9.84. The FE sample (phosphate
      based SEB+PVP/EC) presented the same SPF as the FC, but had a higher thixotropy.
      The FB formulation (stable with higher thixotropy) showed the lowest SPF while FC
      (an unstable formulation with lower thixotropy) presented a higher SPF. We
      concluded that FE was the best formulation showing a higher SPF and stability and
      the study of rheology can help the development of sunscreens.

PMID- 12480272
TI  - An alternative paclitaxel microemulsion formulation: hypersensitivity evaluation
      and pharmacokinetic profile.
AB  - Based on the clinical fact that paclitaxel injection (Taxol) frequently causes
      hypersensitivity reactions, we prepared an alternative paclitaxel microemulsion
      with small particle size (17.2 nm). The hypersensitivity evaluation and
      pharmacokinetic behavior in rats were conducted to assess the new microemulsion.
      The results showed that the new microemulsion was negative and the placebo Taxol
      solution was positive with regard to allergic reactions. In the pharmacokinetic
      study, five rats were administrated Taxol or paclitaxel microemulsion. Blood
      samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 14 h and
      paclitaxel determined by HPLC. The area under the curve (AUC) was significantly
      higher in the microemulsion group (34.98 microg ml(-1) h) than that in the Taxol
      group (21.98 microg ml(-1) h). Also, the K(10) was much smaller in the
      microemulsion group (0.57 h(-1)) compared with the Taxol group (1.29 h(-1)),
      showing the elimination rate was much slower in the former than in the latter.
      Compared with Taxol, the paclitaxel microemulsion caused less toxicity and had a
      longer circulation time in rats.

PMID- 12480273
TI  - Sampling and characterization of pharmaceutical powders and granular blends.
AB  - We use a variety of experimental results to illustrate issues and challenges
      involved in the sampling and characterization of pharmaceutical mixtures.
      Accurate and reliable characterization of granular mixtures is hindered by both
      the complexity of granular systems and the lack of validated and reliable
      sampling technology and techniques. Both sampling tools and sampling protocols
      are critically important for accurate characterization. Using cohesive and free
      flowing powders and four thief probe designs, we reveal a large potential for
      extremely misleading results as well as severe disturbance of the granular bed.
      We also discuss results from several experiments designed to test the validity of
      various sampling protocols by varying parameters such as sampling location and
      frequency of sampling. These experiments illustrate the importance of effective
      sampling procedures to achieve the best and most efficient results.

PMID- 12480274
TI  - Formulation of electrically conducting microemulsion-based organogels.
AB  - Gelatin-containing, electrically conducting, rigid water-in-oil (w/o)
      microemulsion-based organogels (MBG), both with and without the presence of a
      model drug, have been prepared using pharmaceutically acceptable oils and
      surfactants. As a precursor to MBG formation, preliminary formulation work was
      carried out investigating the factors affecting the preparation of w/o
      microemulsions containing large amounts of dispersed aqueous phase. From these
      studies isopropyl myristate (IPM) was favoured as oil due to its ability to
      support w/o microemulsion formation over a wide range of compositions. The single
      most effective surfactant for stabilising the w/o microemulsions was found to be
      Aerosol-OT (AOT), although synergistic effects on the extent of w/o microemulsion
      formation were observed upon its combination with a variety of non-ionic
      surfactants. Upon addition of gelatin to the w/o microemulsion, MBG could be
      formed when using AOT as stabiliser with most of the oils investigated (with the
      exception of the medium and large triglyceride oils, Miglyol 812 and soybean oil,
      respectively) and with a number of AOT/non-ionic surfactant/IPM combinations
      (both in the presence and absence of model drugs such as sodium salicylate). MBG
      could not however be formed with non-ionic surfactants alone, or when used in
      combination with another non-ionic surfactant (regardless of the oil used). This
      latter observation was found to be not only a result of the inadequate level of
      water available for hydration of the surfactant head group and any gelatin
      present but also a consequence of the inability of these systems to form, upon
      heating, the percolated microstructures necessary to facilitate the
      supramolecular assembly of gelatin at the macroscopic level, a pre-requisite for
      MBG formation.

PMID- 12480275
TI  - Crystal modification of phenytoin using different solvents and crystallization
      conditions.
AB  - Phenytoin crystals having different types of habits, were prepared by
      recrystallization from ethanol and acetone solutions under different conditions
      (cooling rate or crystallization temperature, solvent evaporation and watering
      out techniques). Scanning electron microscopy, X-ray powder diffractometry, FT-IR
      spectrometry and differential scanning calorimetry were used to investigate the
      physical characteristics of the crystals. The dissolution behavior and compaction
      properties of various batches of crystals were also studied. It was found that
      using watering-out technique as a crystallization method, produced thin plate
      crystals, while the crystals obtained by other methods were needle shape for
      alcoholic solutions and rhombic for acetone solutions. X-ray diffraction spectra
      and differential scanning calorimetry studies, did not show any polymorphic
      change. The dissolution rate of different crystals was lower than that of
      untreated samples. The compacts of phenytoin crystals produced from alcohol or
      acetone (especially those made by watering-out method) had higher crushing
      strengths than untreated phenytoin compacts due to the lower porosity and the
      lower elastic recovery.

PMID- 12480276
TI  - Measurement of agitation force in dissolution test and mechanical destructive
      force in disintegration test.
AB  - The purpose of this study was to investigate the effect of the agitation force
      and mechanical destructive force on the drug dissolution of a tablet in the
      paddle rotation dissolution test and in the disintegration test. The agitation in
      the paddle method and the mechanical destructive force in the disintegration test
      were considered to be conclusive factors for drug dissolution. The dissolution
      rate of planar-constant-release tablets increased with increasing paddle rotation
      speed and increased with increasing distance from the center of the vessel
      bottom. Separately, the fluid resistance (agitation force) in the vessel was
      measured using a modified paddle method apparatus equipped with a fluid
      resistance sensor. The fluid resistance was 0.03 x 10(-3) N/(64 mm(2)) when the
      paddle rotation speed was 50 rpm at a position 4 mm away from the center. A
      considerable position-dependent change in agitation force intensity was seen with
      the fluid resistance sensor. The impulsive force (mechanical destructive force)
      in the disintegration test apparatus was measured using a modified basket-rack
      assembly with a strain gauge transducer. The fluid resistance was measured using
      the basket-rack assembly with a different sensor probe and amplifier. The
      impulsive force applied by the auxiliary disk was 0.31 N and the fluid resistance
      at the bottom of the basket-rack assembly was 1.66 x 10(-3) N/(64 mm(2)).

PMID- 12480277
TI  - Possibility of a patch system as a new oral delivery system.
AB  - A new oral patch system has been designed to increase the residence time of model
      drugs within the gastrointestinal tract. The system consisted of three layers (1)
      water-insoluble backing layer (2) drug-carrying adhesive layer composed of a
      model drug, fluorescein (FL) or fluorescein isothiocyanate-dextran (FD), and gel
      forming polymer and (3) pH-sensitive enteric polymer. These three layers system
      was prepared as 3.0 mm diameter patches. As references, tablet containing FL or
      FD was prepared. In vitro dissolution studies showed that the mean dissolution
      time (MDT) of model drugs from patch preparation was 0.739+/-0.021 h for FL and
      0.407+/-0.021 h for FD, which were longer than from tablet, 0.327+/-0.008 h for
      FL and 0.270+/-0.019 h for FD. The two test preparations were orally administered
      to beagle dogs in a crossover manner at a FL dose of 30 mg/dog and the measured
      plasma FL concentrations were used for pharmacokinetic analysis. With FL patch
      preparation, area under the plasma drug concentration vs. time curve (AUC) was
      2.12+/-0.24 microgh/ml and mean residence time (MRT) was 4.60+/-0.18 h, which
      were greater than those of tablet, AUC was 1.52+/-0.16 microgh/ml and MRT was
      3.18+/-0.09 h, respectively. Oral patch preparation also increased both AUC and
      MRT of FD, a model macromolecular drug, which was formulated into both patches
      and tablets and administered to dogs (30 mg/dog). The AUC and MRT of FD from the
      patch preparation were 1.11+/-0.13 microgh/ml and 5.58+/-0.55 h and from tablets
      were 0.53+/-0.08 microg h/ml and 4.09+/-0.29 h, respectively. These results
      suggest that oral patch preparation has as a potential a new oral delivery system
      to obtain a long residence time of drug in the gastrointestinal tract.

PMID- 12480278
TI  - Enhanced transdermal delivery of phenylalanyl-glycine by chemical modification
      with various fatty acids.
AB  - We synthesized three novel lipophilic derivatives of phenylalanyl-glycine (Phe
      Gly), C4-Phe-Gly, C6-Phe-Gly and C8-Phe-Gly by chemical modification with butyric
      acid (C4), caproic acid (C6) and octanoic acid (C8). The effect of the acylation
      on the stability, permeability and accumulation of Phe-Gly in the skin was
      investigated by in vitro studies. The stability of Phe-Gly in skin homogenates
      was low, but was significantly improved by the acylation. In the transport
      studies, a Franz-type diffusion cell was used for the permeability experiments
      with Phe-Gly and its acyl derivatives. The permeability of acyl-Phe-Gly
      derivatives across the intact skin was higher than that of native Phe-Gly. Of all
      the acyl-Phe-Gly derivatives, C6-Phe-Gly was the most permeable compounds across
      the intact skin. On the other hand, the permeability of acyl-Phe-Gly derivatives
      across stripped skin was less than that of native Phe-Gly in the initial time
      period of transport studies, but their permeability was higher than that of
      native Phe-Gly at the end of the transport studies. When the skin was pretreated
      with ethanol, which could inactivate the peptidases responsible for the
      degradation of Phe-Gly, the permeability of native Phe-Gly was higher than that
      of acyl derivatives. These findings indicated the involvement of peptidases on
      the permeability of Phe-Gly across the skin. The relationship between the
      lipophilic indexes of Phe-Gly derivatives and the permeability coefficients
      indicated that there is an optimal carbon number of fatty acid for improving the
      transdermal permeability of Phe-Gly by the acylation. A good correlation was
      found between the accumulation of these acyl-Phe-Gly derivatives in the intact
      skin and their lipophilicity. These results suggest that the stability and
      permeability of Phe-Gly were improved by chemical modification with fatty acids
      and this enhanced permeability of Phe-Gly by the acylation may be attributed to
      the protection of Phe-Gly from the enzymatic degradation in the skin and the
      increase in the partition of Phe-Gly to the stratum corneum.

PMID- 12480279
TI  - Equilibrium properties and mechanism of kinetic release of metoclopramide from
      carbomer hydrogels.
AB  - Equilibrium properties and kinetics of metoclopramide release of carbomer
      metoclopramide (C-M) hydrogels are reported. A set of (C-M)(X) (x=moles percent
      of M=50, 75, 100) that covers a pH range between 6.49 and 8.40 was used.
      Hydrogels exhibited a high negative electrokinetic potential (zeta).
      Concentrations of ion pair [R-COO(-)MH(+)] and free species [M] and [MH(+)] were
      determined by the selective extraction of M with 1,2-dichloroethane (DCE)
      together with pH measurements. The system (C-M) is characterized by a high
      proportion of drug present in the form of ion pairs and a negative zeta potential
      that attracts MH(+) and H(+) and repeals OH(-), providing a microenvironment of
      higher acidity than the bulk medium. Delivery rates of M were measured in a Franz
      type bi-compartmental device using water and NaCl 0.9% solution as receptor
      media. (C-M) hydrogels behave as a reservoir that releases the drug at a slow
      rate to water; the rate increases 14 times as water is replaced by NaCl solution.
      The pH effect on delivery rate suggests that, under the main conditions assayed,
      the rate of dissociation of R-COO(-)MH(+) together with the low change of pH in
      the polyelectrolyte environment are the factors that control releasing rates.

PMID- 12480280
TI  - Drug release modeled by dissolution, diffusion, and immobilization.
AB  - This article presents a novel drug release model that combines drug dissolution,
      diffusion, and immobilization caused by adsorption of the drug to the tablet
      constituents. Drug dissolution is described by the well-known Noyes-Whitney
      equation and drug adsorption by a Langmuir-Freundlich adsorption isotherm, and
      these two processes are included as source and sink terms in the diffusion
      equation. The model is applicable to tablets that disintegrate into a number of
      approximately spherical fragments. In order to simplify the analysis it is
      assumed that liquid absorption, matrix swelling, and tablet disintegration are
      much faster than drug dissolution and subsequent drug release. The resulting
      model is shown to yield release characteristics in good agreement with those
      observed experimentally.

PMID- 12480281
TI  - Assessment of oral bioavailability enhancing approaches for SB-247083 using flow
      through cell dissolution testing as one of the screens.
AB  - SB-247083 is a potent, nonpeptidic, orally active, ETA-selective, endothelin
      receptor antagonist. The diacid form and three salts (monoarginine, diarginine
      and disodium) of SB-247083 were evaluated during the pre-clinical phase of
      development. The developability attributes (i.e. hygroscopicity, thermal
      behavior, aqueous solubility, and drug-excipient compatibility) of these
      compounds were evaluated. In addition to these attributes, the flow-through cell
      (FTC) dissolution testing (using USP Apparatus 4) was used as a screening
      technique to evaluate several SB-247083 formulations of the diacid and its salts.
      FTC dissolution testing offers two distinct advantages over the more traditional
      static-condition dissolution testing: (1) maintenance of sink conditions; and (2)
      the ability to change the dissolution medium during a dissolution run. The former
      advantage is especially important for poorly aqueous soluble drugs having
      associated dissolution-rate-limitations, and the latter advantage allows one to
      more closely simulate the pH gradient associated with transit through the GI
      tract. Based on the comparative dissolution data, three formulations were chosen
      for oral dosing in dogs. The reasonable correlation found between the FTC
      dissolution results and the oral bioavailability data demonstrate that FTC
      dissolution testing can be a valuable tool for aiding in salt (solid-state form)
      and formulation selection in the early stages of development of drug candidates.

PMID- 12480282
TI  - Enhanced transport of a novel anti-HIV agent--cosalane and its congeners across
      human intestinal epithelial (Caco-2) cell monolayers.
AB  - PURPOSE: Cosalane is a potent inhibitor of HIV replication with activity against
      a broad range of viral targets. However, oral bioavailability of this highly
      lipophilic compound is extremely poor (<1%). The purpose of this study is to
      screen a variety of permeation enhancers (cyclodextrin derivatives, cremophor EL,
      bile salts and mixed micelles) for their ability to enhance the transport of
      cosalane and its analogs/prodrugs across Caco-2 cell monolayers. METHODS:
      Cosalane and its different analogs/prodrugs were synthesized and their
      physicochemical properties were determined. Caco-2 cells were cultured at a
      density of 66,000 cells/cm(2) either on collagen coated clear polyester membranes
      or Transwell inserts. Side-bi-side diffusion cells and Transwell inserts were
      employed to study for the transport of cosalane and its analogs/prodrugs with
      various permeation enhancers across Caco-2 cell monolayers. RESULTS:
      Permeabilities of EH-3-39, EH-3-55 and EH-3-57 significantly improved compared to
      that of cosalane in the presence of bile salt, sodium desoxycholate. Among the
      various cyclodextrins studied, hydroxypropyl beta cyclodextrin (HP-beta-CD) and
      dimethyl beta cyclodextrin (DM-beta-CD) exhibited 22.3-fold and 19-fold
      permeability enhancement of cosalane respectively across Caco-2 cell monolayers.
      Sodium desoxycholate (10 mM) also showed a remarkable (105-fold) enhancement on
      the permeability of cosalane (P(app) 11.72+/-3.31 x 10(-6) cm/s) without causing
      any measurable cellular damage. Cremophor EL resulted in higher transport of 14C
      mannitol. The mechanism of enhancement effect can be mainly attributed to the
      alteration of membrane fluidity by cyclodextrin and opening of tight junctions by
      cremophor EL. CONCLUSIONS: Among the enhancers tested, 10 mM sodium desoxycholate
      and HP-beta-CD appear to be viable candidates for further development of an oral
      formulation of cosalane and its congeners.

PMID- 12480283
TI  - Absorption into silicone rubber membranes from powders and aqueous solutions.
AB  - This study compared the rate and amount of absorption from aqueous solutions and
      pure powders of 3- and 4-cyanophenol (CP) into silicone rubber (SR) membranes. SR
      membranes were cast directly onto a zinc-selenide attenuated total reflectance
      (ATR) crystal, which was then mounted on a Fourier transform infrared (FTIR)
      spectrometer. CP was presented to the SR membrane from aqueous solutions or
      powders sufficient to completely cover the membrane surface. The concentration of
      CP in the membrane at the interface with the crystal was determined by IR
      absorption of the C triple bond N stretch. The amount of CP in the SR membrane at
      steady state was determined by extraction and UV absorption measurements of the
      extract. The concentration of CP in SR membranes was found to depend weakly on
      the concentration of the aqueous solution. The amount of CP in SR membranes
      equilibrated with pure powders was essentially the same as for the CP-saturated
      solutions. Diffusion coefficients for 3 and 4-CP (2.8+/-0.2 and 2.5+/-0.6 x 10(
      7) cm(2) s(-1), respectively) were not statistically different. The absorption
      rate of CP into SR membranes was almost the same from the powder and aqueous
      solution indicating that the rate of mass transfer from the powder to membrane
      was larger than 0.04 cm h(-1).

PMID- 12480284
TI  - Enhanced intestinal absorption of vancomycin with Labrasol and D-alpha-tocopheryl
      PEG 1000 succinate in rats.
AB  - Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic used for the
      treatment of infections caused by methicillin-resistant staphylococci. It is
      water soluble, having a high molecular weight, and poorly absorbed from the
      gastrointestinal tract. Mixtures of VCM with Labrasol and D-alpha-tocopheryl
      polyethylene glycol 1000 succinate (TPGS) were prepared to improve oral
      absorption of VCM. Administration of VCM solution to rat ileum at a dose of 20
      mg/kg did not result in detectable plasma VCM concentration. Formulation
      containing 50% of Labrasol resulted in a Cmax value of 5.86+/-0.97 microg/ml and
      an AUC(0-6h) value of 16.06+/-1.78 microgh/ml. Addition of TPGS to VCM solution
      at 12.5% concentration also increased the plasma VCM concentration with a Cmax
      value of 4.98+/-0.45 microg/ml. But the AUC(0-6 h) (9.87+/-1.90 microgh/ml) was
      significantly lower than that obtained with Labrasol. The addition of 5.0 and
      25.0% TPGS to solutions of VCM containing 50% of Labrasol did not result in any
      significant increase either in Cmax or AUC(0-6 h) of VCM. Whereas the addition of
      12.5% of TPGS has resulted in an increase in Cmax and AUC(0-6 h) by 2.2 and 2.4
      times, respectively, suggesting that this concentration of 50% Labrasol and 12.5%
      TPGS (1:0.25) was optimum for improving intestinal absorption of VCM. A dose
      dependent decrease in the Cmax and AUC(0-6 h) values was observed when the dose
      of absorption enhancers was decreased by 50% with formulation containing Labrasol
      and TPGS in 1:0.25 ratio. The results of the study indicate that formulations
      containing Labrasol and TPGS improve intestinal absorption of hydrophilic
      macromolecular drug, VCM.

PMID- 12480285
TI  - The use of a porcine organotypic cornea construct for permeation studies from
      formulations containing befunolol hydrochloride.
AB  - The purpose of this study was to develop an organotypic cornea equivalent
      consisting of three different cell types (epithelial, stromal and endothelial
      cells) and to investigate its usefulness as in vitro model for permeation
      studies. The different cell types of a porcine cornea were selectively isolated
      and a multilayer tissue construct was created step-by-step in Transwell cell
      culture insert. Histology, basement membrane components (laminin, fibronectin)
      and surfaces of cornea construct were investigated to evaluate the degree of
      comparability to porcine cornea from slaughtered animals. The cornea construct
      exhibited similarities to the original cornea. Ocular permeation of befunolol
      hydrochloride from different formulations across the cornea construct was tested
      using modified Franz cells and compared with data obtained from excised cornea.
      The cornea construct showed a similar permeation behavior for befunolol
      hydrochloride from different formulations compared with excised porcine cornea.
      However, permeation coefficients K(p) obtained with the construct were about
      three to fourfold higher for aqueous formulations and same for the w/o-emulsion.
      The reconstructed cornea could be an alternative to excised animal tissue for
      drug permeation studies in vitro.

PMID- 12480286
TI  - Buccal delivery of thiocolchicoside: in vitro and in vivo permeation studies.
AB  - Thiocolchicoside, a muscle-relaxant agent, is administered by the oral, intra
      muscular and topical route. After oral administration the extent of
      bioavailability compared with intra-muscular administration is low, due to a
      first pass effect. In this paper, the delivery of thiocolchicoside through oral
      mucosa is studied to improve the bioavailability. Thiocolchicoside in vitro
      permeation through porcine oral mucosa and in vivo buccal transport in humans
      were investigated. Two dosage forms, a bioadhesive disc and a fast dissolving
      disc for buccal and sublingual administration of thiocolchicoside, respectively,
      were designed. The in vitro permeation of thiocolchicoside through porcine buccal
      mucosa from these dosage forms was evaluated and compared with in vivo
      absorption. Results from in vitro studies demonstrated that thiocolchicoside is
      quite permeable across porcine buccal mucosa and that permeation enhancers, such
      as sodium taurocholate and sodium taurodeoxycholate, were not able to increase
      its flux. The in vivo thiocolchicoside absorption experiments, in which the drug
      loss from oral cavity was measured, indicated that both formulations could be
      useful for therapeutic application. The fast dissolving (sublingual) form
      resulted in a quick uptake of 0.5 mg of thiocolchicoside within 15 min whereas
      with the adhesive buccal form the same dose can be absorbed over an extended
      period of time.

PMID- 12480287
TI  - Effect of molecular structure of chitosan on protein delivery properties of
      chitosan nanoparticles.
AB  - Chitosan nanoparticles (CS NP) with various formations were produced based on
      ionic gelation process of tripolyphosphate (TPP) and chitosan. They were examined
      with diameter 20-200 nm and spherical shape using TEM. FTIR confirmed
      tripolyphosphoric groups of TPP linked with ammonium groups of chitosan in the
      nanoparticles. Factors affecting delivery properties of bovine serum albumin
      (BSA) as model protein have been tested, they included molecular weight (Mw) and
      deacetylation degree (DD) of chitosan, the concentration of chitosan and initial
      BSA, and the presence of polyethylene glycol (PEG) in encapsulation medium.
      Increasing Mws of chitosan from 10 to 210 kDa, BSA encapsulation efficiency was
      enhanced about two times, BSA total release in PBS (phosphate buffer saline) pH
      7.4 in 8 days was reduced from 73.9 to 17.6%. Increasing DD from 75.5 to 92%
      promoted slightly the encapsulation efficiency and decelerated the release rate.
      The encapsulation efficiency was highly decreased by increase of initial BSA and
      chitosan concentration; higher loading capacity of BSA speeded the BSA release
      from the nanoparticles. Adding PEG hindered the BSA encapsulation and accelerated
      the release rate.

PMID- 12480288
TI  - In vivo evaluation of matrix granules containing microcrystalline chitosan as a
      gel-forming excipient.
AB  - Interest in drug delivery to the gastrointestinal tract by means of chitosan has
      been increasing. In the study reported, the biopharmaceutical properties of
      granules containing microcrystalline chitosan (MCCh; molecular weight 150 kDa,
      degree of deacetylation 75%) were evaluated via bioavailability tests in human
      volunteers. Ibuprofen and furosemide were used as model drugs. With ibuprofen,
      granules containing 40% of MCCh behaved as a slow-release formulation (t(max) 2.9
      h). With furosemide, the most marked difference between a conventional dosage
      form and granules containing 40% MCCh was a marked lag time (0.5 h) before
      absorption from the latter. This difference was reflected in t(max) values for
      furosemide. Despite the lag time, AUC values for furosemide were high, indicating
      that the granules containing MCCh had remained in the stomach and that drug
      release had taken place in the stomach rather than in the intestine. The results
      of the bioavailability studies indicate that MCCh matrix granules allow a simple
      preparation of slow-release and perhaps stomach-specific dosage forms. Use of
      model drugs differing in relation to sites of absorption in the gastrointestinal
      tract aided identification of sites of absorption of drugs from the granules.
      Further studies, including gamma-scintigraphic evaluations, will be performed on
      how the granules behave in the stomach.

PMID- 12480289
TI  - Molecular interactions between DPPC and morphine derivatives: a DSC and EPR
      study.
AB  - The interaction between different morphine derivatives (morphine, codeine, N
      methyl-morphine, N-methyl-codeine) and alpha-L-dipalmitoyl phosphatidylcholine
      (DPPC) liposomes was studied with differential scanning calorimetry (DSC) and
      electron paramagnetic resonance (EPR) spectroscopy. Small unilamellar DPPC
      liposomes with the given morphine-derivative were prepared by sonication. The
      size distribution of liposomes was checked by dynamic light scattering (DLS). The
      amount of entrapped morphine was determined spectrophotometrically. Our results
      indicate that the morphine and its derivatives principally interact with the
      lipid head groups, and this interaction leads to a decrease in the mobility of
      the polar head groups, especially in case of codeine and N-methyl-codeine.

PMID- 12480290
TI  - Leaching of pectin from mixed films containing pectin, chitosan and HPMC intended
      for biphasic drug delivery.
AB  - Mixed films containing pectin, chitosan and HPMC, prepared by solvent casting
      from 0.1 M HCl (pH 1.5) and 0.1 M acetic acid (pH 2.9) were evaluated for their
      morphological and leaching properties. Films cast at pH 1.5 were uniform with
      smooth surfaces while films cast at pH 2.9 showed particle aggregation and had
      rough surfaces due to polyelectrolyte complex (PEC) formation between pectin and
      chitosan in the medium. The leaching of pectin was higher from films at cast pH
      1.5 due to the absence of PEC formation. Pectin leaching was controlled in
      simulated upper gastrointestinal conditions but was accelerated in the presence
      of pectinolytic enzymes. The leaching of pectin from the mixed films was a
      function of the pH of the film casting solvent, pH of the incubation medium, PEC
      formation and HPMC content.

PMID- 12480291
TI  - Chitinosan-drug complexes: effect of electrolyte on naproxen release in vitro.
AB  - The purpose of this study was to examine the potential use of electrolytes to
      control naproxen sodium (I) release from chitinosan (II) tablets. An ANOVA was
      employed to evaluate the effects of molecular weight (MW) of II, electrolyte
      valence (EV), and pH of the dissolution medium on I's release. The intrinsic
      dissolution rates and saturation solubilities of I were determined at each of the
      pHs used. Directly compressed tablets were prepared from admixtures containing:
      I, NaCl, CaCl(2), or AlCl(3), Mg stearate, and II. The tablets were characterized
      for their dimensions, crushing strengths, friability, disintegration times, and
      in vitro dissolution profiles. The slopes of the log-log cumulative percent
      released-time curves (t=0-5 h) were compared using ANOVA. Based on the ANOVA,
      each of the variables-chitinosans, EVs, and pHs-significantly affected drug
      release (P<0.05). Besides the poor aqueous solubility of I, the factors possibly
      affecting drug release included: (a) the formation of a rate-limiting II gel
      barrier; (b) the interaction of I with ionized amino groups of II; (c) the effect
      of electrolyte on the II's gel barrier formation; and/or (d) decreased aqueous
      solubility of I in the presence of electrolyte.

PMID- 12480292
TI  - Atovaquone-loaded nanocapsules: influence of the nature of the polymer on their
      in vitro characteristics.
AB  - Nanocapsules with atovaquone concentration of 1,000 micrograms/ml were prepared
      according to the interfacial deposition technique using different polymers: poly-
      epsilon -caprolactone (PECL), poly(lactic acid) (PLA) and poly(lactic-co-glycolic
      acid) (PLAGA). The following characteristics of nanoparticles were determined:
      percentage of encapsulation of atovaquone, percentage of encapsulation of benzyl
      benzoate (BB), nanoparticle size, nanoparticle wall thickness, suspension pH, and
      in vitro stability. The different formulations showed similar characteristics:
      maximal percentage of encapsulation (100%), particle size of approximately 230
      nm, neutral pH and wall thickness of approximately 20 nm. The type of polymer
      used was the main factor influencing stability, in decreasing order:
      PECL>PLA>PLAGA. No release of atovaquone or benzylbenzoate was noted with PECL
      nanoparticles over 4 months. Release of atovaquone (25.9%) was found with PLA
      nanoparticles at 4 months. Release of both atovaquone (18.9%) and benzylbenzoate
      (54.2%) was noted with PLAGA nanoparticles from the third month, indicating a
      disruption of the nanoparticle membrane.

PMID- 12480293
TI  - Comparison between polyvinylpyrrolidone and silica nanoparticles as carriers for
      indomethacin in a solid state dispersion.
AB  - States of interaction between indomethacin (IM) and polyvinylpyrrolidone (PVP) in
      an amorphous solid dispersion prepared by co-grinding were compared with those
      between IM and silica nanoparticles. Changes in the carbon chemical states of the
      solid dispersions were evaluated based on the chemical shift in the 13C-CP/MAS
      NMR. Hydrogen bonds between the amide carbonyl of PVP particles and the carboxyl
      groups of IM molecules were formed by co-grinding. Despite the wide difference in
      carrier properties, the apparent equilibrium solubility (AES) of IM in the ground
      IM-PVP mixture was predicted by solid state NMR on the basis of the relationship
      previously established for IM with SiO(2). This indicates that AES is affected
      solely by the state of IM, irrespective of the carrier species, and despite
      carrier-dependent chemical interactions.

PMID- 12480294
TI  - Effect of temperature on imipramine hydrochloride permeation: role of lipid
      bilayer arrangement and chemical composition of rat skin.
AB  - The aim of this investigation was to study the effect of temperature on the
      permeation of imipramine hydrochloride (IMH) across rat skin from two different
      vehicles. Differential scanning calorimetry (DSC) was used to characterize the
      phase transitions of rat epidermis and extracted rat SC lipids, and the
      transition temperatures were correlated with the permeability of IMH at different
      temperatures. Permeability of IMH from ethanol and propylene glycol (PG) was
      determined at five different temperatures and observed that a significant
      increase in IMH permeability occurred 45 degrees C from both the vehicles.
      Further, high energies of activation for rat skin permeation suggested that IMH
      diffuses across intercellular lipid matrix and therefore any change in the
      packing of SC lipids will have an effect on IMH permeation. Three endotherms
      T(1), T(2) and T(3) of rat epidermis were observed in DSC thermograms at 44, 53
      and 64 degrees C and were assigned as transitions corresponding to orthorhombic
      to hexagonal, hexagonal to more disordered phase and melting of lipids with high
      cholesterol content, respectively. The high permeability values of IMH above 45
      degrees C were therefore reasoned to be because of orthorhombic to hexagonal
      phase transition in rat skin from close to that temperature.

PMID- 12480295
TI  - Occupational exposure to organic solvents and long-term nervous system damage
      detectable by brain imaging, neurophysiology or histopathology.
AB  - The purpose of the present review is to assess the evidence published in
      scientific literature that industrial organic solvents as a generic group have
      the ability to induce long-term nervous system damage in workers that can be
      detected by techniques other than neuropsychological testing. The main body of
      evidence considered in this review was 40 studies involving the use of brain
      imaging, neurophysiological testing, gross autopsy or histopathology in groups of
      workers with long-term solvent exposure. Case reports involving both solvent
      abuse and occupational exposure, and experimental animal data have also been
      reviewed as supporting data. A number of the studies in groups of workers provide
      evidence of the presence of marginal atrophic abnormalities in the brain or
      deficits in nerve conduction velocity in solvent-exposed workers. However, there
      are limitations in the design of many of these studies, the strength of
      association between exposure and effect is not consistently strong, no dose
      response relationship can be detected, the reported changes lack specificity and
      there is no coherence between the human and experimental animal data. Overall, it
      is not possible to draw reliable conclusions with respect to the presence or
      absence of nervous system damage related to the common properties of organic
      solvents.

PMID- 12480296
TI  - Study on the mutagenicity and antimutagenicity of a natural food colour (annatto)
      in mouse bone marrow cells.
AB  - Most manufactured foods contain chemicals added as a deliberate part of the
      manufacturing process. The aims of the present study were to evaluate the
      mutagenicity and antimutagenicity of annatto, a natural pigment extracted from
      the Bixa orellana L. and widely used as a colorant in foods. The micronucleus
      test was performed in bone marrow cells from Swiss male mice treated with one of
      the three concentrations of annatto (1330, 5330 and 10,670 ppm), incorporated
      into the diet. The animals were fed with the diets for 7 days and sacrificed 24 h
      after the last treatment. For the evaluation of the antimutagenic potential of
      annatto, at day 7, the animals received an intraperitoneal injection of
      cyclophosphamide (50 mg/kg body weight). Under the concentrations tested annatto
      did not present mutagenic or antimutagenic activities on the mice bone marrow
      cells. However, an increased frequency of micronucleated cells was observed when
      the highest concentration (10,670 ppm) was administered simultaneously with
      cyclophosphamide. In conclusion, the data indicate that annatto colour, for the
      conditions used, is neither mutagenic nor an inhibitor of induced mutations,
      although it should be used carefully since high doses may increase the effect of
      a mutagen.

PMID- 12480297
TI  - Differences in ethoxyquin nephrotoxicity between male and female F344 rats.
AB  - Dose-response studies have shown a sharp threshold for the renal papillary toxic
      effect in male rats between 0.25% and 0.5% ethoxyquin (Eto) in the diet over 6
      months. Although similar elevated urinary protein (albumin) levels resulted from
      dietary Eto (0.5%) in both males and females, papillary necrosis was male
      specific. Following [14C]Eto administration, radiolabel was associated with
      urinary albumin but not alpha 2 globulin (alpha(2mu)-g). Autoradiographic studies
      indicated that the sex differences in nephrotoxicity do not involve differences
      in distribution or retention of Eto. Faecal and urinary metabolic profiles were
      also similar in the two sexes. The sharp threshold of toxicity in the male rat
      could indicate a fine balance between toxifying/detoxifying metabolism of Eto.

PMID- 12480298
TI  - Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for
      risk assessment.
AB  - CYP3A4 constitutes the major liver cytochrome P450 isoenzyme and is responsible
      for the oxidation of more than 50% of all known drugs. Human variability in
      kinetics for this pathway has been quantified using a database of 15 compounds
      metabolised extensively (>60%) by this CYP isoform in order to develop CYP3A4
      related uncertainty factors for the risk assessment of environmental contaminants
      handled via this route. Data were analysed from published pharmacokinetic studies
      (after oral and intravenous dosing) in healthy adults and other subgroups using
      parameters relating primarily to chronic exposure [metabolic and total
      clearances, area under the plasma concentration-time curve (AUC)] and acute
      exposure (Cmax). Interindividual variability in kinetics was greater for the oral
      route (46%, 12 compounds) than for the intravenous route (32%, 14 compounds). The
      physiological and molecular basis for the difference between these two routes of
      exposure is discussed. In relation to the uncertainty factors used for risk
      assessment, the default kinetic factor of 3.16 would be adequate for adults,
      whereas a CYP3A4-related factor of 12 would be required to cover up to 99% of
      neonates, which have lower CYP3A4 activity.

PMID- 12480299
TI  - Polymorphic CYP2C19 and N-acetylation: human variability in kinetics and pathway
      related uncertainty factors.
AB  - CYP2C19-mediated oxidation and N-acetylation constitute major phase I and phase
      II polymorphic pathways of xenobiotic metabolism in humans. Analysis of human
      variability in kinetics for these pathways has been carried out for compounds
      metabolised extensively (>60%) by these routes. Data for minor substrates for
      CYP2C19 metabolism (10-60%) have also been analysed. Published pharmacokinetic
      studies (after oral and intravenous dosing) in CYP2C19 non-phenotyped healthy
      adults (NPs), and phenotyped extensive (EMs), slow-extensive (SEMs) and poor
      metabolisers (PMs) have been analysed using data for parameters that relate
      primarily to chronic exposure (metabolic and total clearances, area under the
      plasma concentration-time curve) and primarily to acute exposure (peak
      concentration). Similar analyses were performed for the N-acetylation pathway
      using data for fast acetylators (FA) and slow acetylators (SA). Interindividual
      variability in the kinetics of CYP2C19 substrates after oral dosage was greater
      in EMs than in NPs (60 vs 43% for clearances and 54 vs 45% for Cmax). Lower
      variability was found for N-acetylation for both phenotypes (32 and 22% for FA
      and SA, respectively). The internal dose of CYP2C19 substrates in PM subjects
      would be 31-fold higher than in EMs, while for N-acetylated substrates there was
      a three-fold difference between SA and FA subjects. Pathway-related uncertainty
      factors were above the default safety factor of 3.16 for most subgroups and
      values of 52 and 5.2 would be necessary to cover to the 99th centile of the poor
      metaboliser phenotype for CYP2C19 and N-acetylation, respectively. An exponential
      relationship (R(2)=0.86) was found between the extent of CYP2C19 metabolism and
      the difference in internal dose between EMs and PMs. The kinetic default factor
      (3.16) would cover PMs for substrates for which CYP2C19 was responsible for up to
      20-30% of the metabolism in EMs.

PMID- 12480300
TI  - Comparative metabolism and kinetics of coumarin in mice and rats.
AB  - Coumarin, a well recognized rat hepatotoxicant, also causes acute, selective
      necrosis of terminal bronchiolar Clara cells in the mouse lung. Further, chronic
      oral gavage administration of coumarin at 200 mg/kg, a dose that causes Clara
      cell death, resulted in a statistically significant increased incidence of
      alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. In contrast, mouse
      lung tumors were not observed at the 100 and 50 mg/kg dose levels in the oral
      gavage study, or in CD-1 mice following chronic intake of coumarin at levels
      equivalent to 276 mg/kg in diet. The current studies were designed to determine
      the impact of oral gavage vs dietary administration on the pharmacokinetics and
      metabolism of coumarin in CD-1 and B6C3F1 mice and F344 rats. Following the
      administration of 200 mg/kg 14C-coumarin via oral gavage, lung C(max) values
      (total 14C-associated radioactivity) were five- and 37-fold greater than those
      resulting from a 50 mg/kg oral gavage dose or 1000 ppm in diet, respectively.
      Coumarin (200 mg/kg) pharmacokinetics and metabolism was also examined in F344
      rats following oral gavage dosing. Total 14C-coumarin associated radioactivity in
      plasma was 3.5-fold lower than in the mouse, and the plasma half-life in rats was
      five-times longer than in mice. Using non-radiolabeled compound (200 mg/kg),
      coumarin and products of the coumarin 3,4-epoxidation pathway were quantitated in
      plasma and urine after oral gavage administration to mice and rats. 7
      Hydroxycoumarin (7-HC) was quantitated in mouse plasma and urine. o
      Hydroxyphenylacetic acid (o-HPAA) reached a concentration of 37 microg/ml in
      plasma, and accounted for 41% of the dose in the urine, whereas the C(max) for 7
      hydroxycoumarin was 3 microg/ml, and represented 7% of the administered dose. In
      the rat, the plasma C(max) for o-HPAA was 6 microg/ml, and accounted for 12% of
      the dose. The coumarin C(max) in rat plasma was comparable to that in mouse.
      Coumarin 3,4-epoxide (CE) and its rearrangement product o
      hydroxyphenylacetaldehyde (o-HPA) and o-hydroxyphenylethanol (o-HPE), were not
      detected at any time point in plasma or urine. This analysis of coumarin and CE
      pharmacokinetics in rodents suggests that the differential tumor response in the
      mouse oral gavage and dietary bioassays is a function of the route of exposure,
      whereas species differences in lung toxicity between mice and rats result from
      heightened local bioactivation in the mouse lung.

PMID- 12480301
TI  - Evaluation of the dermal subchronic toxicity of diphenyl ether in the rat.
AB  - Diphenyl ether (DPE) was investigated to determine the dermal absorption
      parameters and subchronic toxicity of this fragrance ingredient. For the
      absorption, distribution and elimination study, Sprague-Dawley rats received a
      dermal application of [14C]DPE under a semi-occlusive dressing for 6 h. DPE was
      diluted in diethyl phthalate (DEP) to administer a total application volume of 2
      ml/kg and concentrations of 0.5, 5 and 50% (approximately equal to 10, 100 and
      1000 mg DPE/kg body weight). Approximately 17.7% of the administered dose was
      eliminated in the urine, with small amounts also found in the feces (1.18-3.79%).
      At 72 h post-dosing, approximately 0.2% of the applied dose was retained in the
      body with low levels also measured in the liver, kidney and gastrointestinal
      tract (approximately equal to 0.04, 0.02 and 0.3%, respectively). The 13-week
      subchronic toxicity study was performed with groups of 12 Sprague-Dawley
      rats/sex/dose that received semi-occluded daily dermal applications of DPE for 6
      h/day. All groups were dosed at a constant 2 ml/kg body weight volume of DPE in
      the DEP vehicle at concentrations to administer 0, 100, 300 or 1000 mg DPE/kg
      body weight/day. At the high dose level, there was a slight reduction in body
      weight gain in males (13%), increase in albumin (5-6%) and phosphate (10-15%)
      levels in both sexes, a reduction of cholesterol in females (14%), an increase in
      kidney (17%) and brain (8%) weights in males, and an increase in liver weight (18
      19%) in both sexes. No histopathological lesions were seen in any organ examined.
      At 300 mg/kg body weight/day, the only notable findings were an increase in liver
      weight (10%) in both sexes and a slight increase in albumin (5%) in females. In
      addition, skin irritation reactions at the site of application were observed in
      all DPE dose groups. The systemic no-observed-effect level (NOEL) in this study
      is 100 mg/kg body weight/day. Owing to mitigating factors, the systemic findings
      were judged to lack biological significance and the no-observed-adverse-effect
      level (NOAEL) was determined to be 1000 mg/kg body weight/day.

PMID- 12480302
TI  - Development of a urinary biomarker of human exposure to deoxynivalenol.
AB  - Deoxynivalenol (DON) is a mycotoxin frequently found as a contaminant of cereal
      crops and may be etiologically associated with adverse health effects in
      developing countries where considerable quantities of contaminated crops are
      consumed. We investigated the metabolism of DON in rats as a basis to establish
      methodology for a candidate biomarker of human exposure to this toxin and tested
      this methodology on urine samples from a potentially highly exposed population.
      Sprague-Dawley rats received a single dose of [14C]DON (5.0+/-0.1 mg/kg body
      weight, 5.5+/-0.1 microCi/kg) and the distribution of DON in body fluids was
      investigated over 72 h. DON and its metabolites were detectable in the plasma of
      rats with the highest levels at 8 h, at which time approximately 9% was bound to
      plasma protein. A total of 37% of the administered DON was excreted in the urine
      and DON-glucuronide was implicated as the major urinary metabolite based on
      reverse-phase HPLC analysis of beta-glucuronidase- and sulphatase-treated
      samples. An immunoaffinity column (IAC)-HPLC method was subsequently developed to
      measure urinary metabolites, with a view to establishing a urine-based human
      biomarker. Urine samples were collected from female inhabitants of Linxian
      County, China, a high risk region for oesophageal cancer (OC) and an area of
      potentially high DON exposure, and Gejiu, a low risk region in China. DON was
      detected in all 15 samples following beta-glucuronidase treatment and IAC
      enrichment with the identity of DON being confirmed by mass spectrometry. The
      mean levels of DON from the suspected high and low exposure regions of China were
      37 ng/ml (range 14-94 ng/ml) and 12 ng/ml (range 4-18 ng/ml), respectively. This
      is estimated to correspond to daily exposures of 1.1-7.4 microg/kg/day and 0.3
      1.4 microg/kg/day, respectively. This is the first reported measurement of a
      urinary biomarker for DON in both animals and humans and should facilitate
      epidemiological studies of disease associations with this mycotoxin.

PMID- 12480303
TI  - Implication of nitro group reduction in the mutagenic and chromosome damaging
      activities of 22 new 5-nitroisoquinolines by the Salmonella mutagenicity test and
      the cytokinesis-blocked micronucleus assay.
AB  - The mutagenic (MUT) and chromosome-damaging (CHR) activities of 22 potential
      antimalarial drugs (5-nitroisoquinoline derivatives) were evaluated by the
      Salmonella test and the cytokinesis-blocked micronucleus assay (CBMN). The
      Salmonella mutagenicity test was performed with and without metabolic activation
      (S9 mix) in S. typhimurium strains TA100 and YG1042 (an overproducing
      nitroreductase and O-acetyltransferase TA100 strain). The CBMN was carried out on
      human lymphocytes without metabolic activation. Four concentrations were tested:
      1, 10, 100 and 1000 ng/ml. MUT was expressed as minimal mutagenic concentrations
      (MMC, microM) and CHR was expressed as minimal chromosome-damaging concentrations
      (MCDC, nM) to compare both activities. All the 5-nitroisoquinoline compounds were
      mutagenic in TA100. MMC ranged from 0.1 to 52.9 microM in TA100. A statistically
      significant decrease in MMC was observed in YG1042 (8 x 10(-3) to 3.5 microM),
      implicating reduction of the nitro group. Modulation of MUT by S9 mix was not
      significant in TA100 and YG1042. CHR was detected in 13 products for at least one
      concentration. Among the chromosome-damaging compounds, the MCDC ranged from 2.9
      x 10(-3) to 3.6 nM. No relationship was found between MUT and CHR, suggesting two
      distinct pathways of DNA damage.

PMID- 12480304
TI  - Toxicity of the chlordane metabolite oxychlordane in female rats: clinical and
      histopathological changes.
AB  - Due to widespread usage of the pesticide chlordane until the 1980's, this toxic
      and persistent mixture has accumulated in the food chain. The Arctic acts as a
      global sink for these and other persistent organic pollutants, which
      bioaccumulate in the marine and freshwater food chains. As a result, humans
      consuming diets high in Arctic fish and marine mammal fat can ingest higher
      levels of chlordane contaminants than humans consuming "southern" diets. The most
      abundant constituents of the chlordane mixture are trans-chlordane, cis
      chlordane, trans-nonachlor, cis-nonachlor and heptachlor; oxychlordane is the
      major metabolite of the chlordanes and nonachlors. In humans the predominant
      chlordane-related contaminants detected in breast milk and adipose tissues are
      trans-nonachlor and oxychlordane. The present studies were undertaken to provide
      toxicological data on oxychlordane for the purpose of clarifying target organ
      toxicity and risks to human health associated with ingesting contaminated foods.
      Female rats were gavaged with oxychlordane at doses ranging from 0.01 to 10 mg/kg
      body weight/day for up to 28 days. In terms of general toxicity oxychlordane had
      a steep dose-response curve: 10 mg/kg oxychlordane was acutely toxic and 1 mg/kg
      oxychlordane caused no measurable effects. Weight loss, reduced feed consumption
      and thymic atrophy were the hallmarks of acute oxychlordane toxicity. At lower
      doses rats showed signs of hepatic changes indicative of microsomal enzyme
      induction. Oxychlordane was more bioaccumulative and was toxic at levels
      approximately 8 times lower than trans-nonachlor and cis-nonachlor. Thus,
      ingestion of trans-nonachlor and related chlordane contaminants in foods results
      in the formation of a metabolite that is more toxic and bioaccumulative than the
      parent contaminants.

PMID- 12480305
TI  - Concentrations of nine alkenylbenzenes, coumarin, piperonal and pulegone in
      Indian bidi cigarette tobacco.
AB  - Indian-made bidi cigarettes sold in the United States are available in a variety
      of exotic (e.g. clove, mango) and candy-like (e.g. chocolate, raspberry) flavors.
      Because certain tobacco flavorings contain alkenylbenzenes and other toxic or
      carcinogenic chemicals, we measured the concentration of flavor-related compounds
      in bidi tobacco using a previously developed method. Twenty-three brands of bidis
      were sampled using automated headspace solid-phase microextraction and
      subsequently analyzed for 12 compounds by gas chromatography-mass spectrometry.
      Two alkenylbenzene compounds, trans-anethole and eugenol, were found in greater
      than 90% of the brands analyzed. Methyleugenol, pulegone and estragole were each
      detected in 30% or more of the brands, whereas safrole and elemicin were not
      detected in any of the brands. The flavor-related compounds with the highest
      tobacco concentrations were eugenol (12,000 microg/g tobacco) and trans-anethole
      (2200 microg/g tobacco). The highest eugenol and trans-anethole concentrations
      found in bidi tobacco were about 70,000 and 7500 times greater, respectively,
      than the highest levels previously found in US cigarette brands. Measurement of
      these compounds is crucial to evaluation of potential risks associated with
      inhaling highly concentrated flavor-related compounds from bidis or other tobacco
      products.

PMID- 12480306
TI  - Sustained-release injectables formed in situ and their potential use for
      veterinary products.
AB  - The controlled drug delivery of hydrophilic and lipophilic drug substances via
      the parenteral route has gained increasing importance in the development of
      pharmaceutical dosage forms. In particular, the animal health industry has
      generated strong interest in long-term drug delivery for both companion and farm
      animals during the past few years. At present sustained-release injectables
      formed in situ for s.c./i.m. administration have become an attractive alternative
      to common slow release technologies such as microspheres or standard implants. In
      this context, technologies based on PLA/PLGA, sucrose acetate isobutyrate (SAIB)
      and the amphipathic molecules Poloxamer, glycerol monooleate or PEG-PLA-PEG
      copolymers, are discussed. Release periods from hours to months can be obtained
      by choosing one of these drug delivery technologies. The release times are
      strongly dependent on the biodegradation of the polymers and the physico-chemical
      properties of the drug substance used. Furthermore, the use of different solvents
      for the matrix-forming agents and the individual loading capacity are critically
      assessed. Additionally acceptance of the excipients for parenteral use by the
      regulatory authorities is closely considered. Scientific articles as well as
      patent publications are reviewed to give a wide overview of the existing
      approaches and their future potential for animal health products.

PMID- 12480307
TI  - Bacterial ghosts as vaccine candidates for veterinary applications.
AB  - The application of new strategies to develop effective vaccines is essential in
      modern veterinary medicine. The bacterial ghost system is a novel vaccine
      delivery system endowed with intrinsic adjuvant properties. Bacterial ghosts are
      nonliving Gram-negative bacterial cell envelopes devoid of cytoplasmic contents
      while maintaining their cellular morphology and native surface antigenic
      structures including bioadhesive properties. They are produced by PhiX174 protein
      E-mediated lysis of Gram-negative bacteria. The intrinsic adjuvant properties of
      bacterial ghost preparations enhance immune responses against envelope bound
      antigens, including T-cell activation and mucosal immunity. Since native and
      foreign antigens can be expressed in the envelope complex of ghosts before E
      mediated lysis, multiple antigens of various origins can be presented to the
      immune system simultaneously. The advantages of bacterial ghosts include the
      simplicity of the production method, safety, independence from the cold chain,
      and versatility as a combination vaccine.

PMID- 12480308
TI  - Applying peptide antigens onto bare skin: induction of humoral and cellular
      immune responses and potential for vaccination.
AB  - The development of non-invasive immunisation procedures is a top priority for
      public health agencies when it is realised that the current immunisation
      practices are unsafe, particularly in developing countries due to the widespread
      reuse of non-sterile syringes. There is a risk of abscess formation resulting in
      impairment of meat quality or the value of the hide, and the risk of transmission
      of infectious diseases when vaccines are administered to food animals by
      injection. Recently, the skin has emerged as an alternative route for non
      invasive delivery of vaccines. Topical application of various types of antigens
      (mainly proteins and toxoids) with an adjuvant resulted in the induction of
      systemic and mucosal immune responses. However, due to skin barrier constraints
      and the physicochemical properties of large molecular weight proteins, the immune
      responses are variable and require further optimisation. Small molecular size
      synthetic peptides when applied onto bare skin with an adjuvant are effective
      immunogens, inducing both humoral and cellular immune responses. Their use as
      vaccines offers considerable advantages over conventional preparations in terms
      of safety, purity, stability, availability and cost. Therefore, they could be the
      most suitable candidate immunogens for skin immunisation. This review describes
      our recent observations on the immunogenicity of synthetic peptides applied onto
      bare skin in relation to vaccination.

PMID- 12480309
TI  - Comparison of microencapsulation techniques for the water-soluble drugs
      nitenpyram and clomipramine HCl.
AB  - In this investigation, the water-soluble drugs nitenpyram and clomipramine HCl
      were encapsulated using coacervation, solvent evaporation and film-coating. The
      effect of different process factors on the encapsulation efficiency and the
      release profile of the microparticles was evaluated. For coacervation it was
      shown that the core to wall ratio was the most important factor. For solvent
      evaporation using an w/o emulsion the type and concentration of the surfactant
      were the most important parameters for a successful encapsulation. Additionally
      the coated material was tested for its stability under different conditions as a
      powder or compressed into tablets. It could clearly be demonstrated that the
      coated drug substance exhibited a better stability then the uncoated material.
      The particles prepared by film-coating showed the best stability.

PMID- 12480310
TI  - Oral bioavailability in sheep of albendazole from a suspension and from a
      solution containing hydroxypropyl-beta-cyclodextrin.
AB  - Albendazole (ABZ) is a benzimidazole derivative with a broad spectrum of activity
      against human and animal helminthe parasites. ABZ has a very poor aqueous
      solubility. This study shows that hydroxypropyl-beta-cyclodextrin (HP-beta-CD) is
      able to form inclusion complexes with ABZ and that is able to increase its
      aqueous solubility. A synergistic effect exists between HP-beta-CD and citric
      acid. The combination of HP-beta-CD (200 mM) and citric acid (50 mM) allows
      dissolution of more than 1.5 mg of ABZ per ml. The aim of this study is the in
      vivo evaluation in sheep of a solution of the inclusion complex of ABZ with HP
      beta-CD in comparison with a suspension of the same drug. A significant (P<0.05)
      increase in the relative bioavailability is obtained with the solution containing
      the ABZ-HP-beta-CD complex as measured by ABZSO plasma levels. The area under the
      curve (AUC(0--> proportional, variant )) of the solution is 37% higher than that
      obtained with the suspension. Likewise the peak plasma concentration (C(max)) is
      twice that of the solution while the time to reach C(max) (T(max)) is reduced.

PMID- 12480311
TI  - Pluronic F127 gel formulations of deslorelin and GnRH reduce drug degradation and
      sustain drug release and effect in cattle.
AB  - The objective of this study was to compare the effectiveness of intramuscular
      sustained release Pluronic F127 (PF127) gel formulations of deslorelin, a potent
      GnRH agonist, and GnRH to their solution formulations in inducing the release of
      luteinizing hormone and formation of luteal tissue in cattle. Injectable gel
      formulations of deslorelin and GnRH were prepared using Pluronic F127 (25%, w/w),
      a block copolymer. PF127 gels sustained the in vitro release of deslorelin as
      well as GnRH at similar rates and reduced drug degradation in muscle tissue when
      compared to the solution formulations. Deslorelin, as well as GnRH, elicited
      desirable elevations in plasma LH and progesterone concentrations in vivo. When
      compared to the solution formulations, the gel formulations of both drugs induced
      a broader peak of LH. Also, the peak LH levels were lower and the peak times were
      delayed with the gel formulations compared to the solution formulations. While
      the solution dosage form of deslorelin and GnRH elicited similar responses, the
      PF127 gel formulation of deslorelin induced peak LH levels at an earlier time (3
      h for deslorelin versus 5.25 h for GnRH). The results indicate that, deslorelin
      exerts a pharmacological effect in cattle. The LH response to deslorelin as well
      as GnRH can be altered by controlling the input or the release rate of the drug.
      PF127 gel formulations can sustain peptide release and reduce peptide
      degradation.

PMID- 12480312
TI  - Development of an injection molded poly(epsilon-caprolactone) intravaginal insert
      for the delivery of progesterone to cattle.
AB  - This paper reports experiments conducted to research, develop and clinically
      evaluate an injection molded intravaginal insert manufactured from the
      biodegradable polyester poly(epsilon-caprolactone). The study demonstrated that
      it is possible to engineer poly(epsilon-caprolactone) into a shape that is well
      retained, and can be used as a platform for the controlled delivery of
      progesterone via the vagina of cows. Field evaluation showed that the
      poly(epsilon-caprolactone) intravaginal inserts containing 10% (w/w) progesterone
      were at least as effective clinically as the commercially available CIDR
      intravaginal insert.

PMID- 12480313
TI  - Development and in-vitro evaluation of sustained release poloxamer 407 (P407) gel
      formulations of ceftiofur.
AB  - The objective of this study was to develop sustained release Poloxamer 407 (P407)
      gel formulations of ceftiofur for treating foot infections in cattle. The
      formulations contained 25-35% (w/v) P407 alone or with polyvinyl pyrrolidone
      (PVP), carboxy methylcellulose (CMC), or hydroxylpropyl methylcellulose (HPMC) as
      an additive. The in-vitro release profiles of ceftiofur from the P407
      formulations and the gel dissolution profiles were obtained simultaneously.
      Ceftiofur release followed zero order kinetics and correlated well with the
      weight percentage of P407 dissolved, indicating that the overall rate of release
      of ceftiofur is controlled by dissolution of the P407. An increase in P407
      content from 25 to 35% resulted in a decrease in the rate of ceftiofur release.
      However, it appears that other factors may have also affected the drug release
      rate. Inclusion of PVP, CMC, and HPMC in the gel decreased the rate of release of
      ceftiofur to some extent. A decrease in the temperatures of the release medium
      decreased the release rate of ceftiofur, but not the rate of gel dissolution. The
      pH of the release medium showed a very slight effect on the release of ceftiofur
      and did not affect gel dissolution due to the non-ionic nature of P407.

PMID- 12480314
TI  - Boar semen controlled delivery system: storage and in vitro spermatozoa release.
AB  - Swine spermatozoa were encapsulated in barium alginate and protamine-barium
      alginate membranes to lengthen their preservation time and to provide a means of
      controlling their release. Precocious acrosome reactions and secondary anomalies
      were measured as indices of semen quality. These characteristics were observed
      for two forms of encapsulated spermatozoa when stored at 18 and 38 degrees C for
      24 h and for semen diluted in a classical extender at both temperatures. The
      results indicate that encapsulation enhances semen preservation, providing
      protection against membrane damage upon dilution. The effect is even more evident
      at the higher temperature (38 degrees C), where cell metabolism is higher. An in
      vitro release test of spermatozoa showed a massive cell delivery from barium
      alginate capsules within 6 h, and a slow release from protamine-barium alginate
      capsules. The properties of spermatozoa 24 h after release did not differ from
      the semen stored at the same temperature in capsules, indicating that the release
      process does not impair semen quality.

PMID- 12480315
TI  - The metabolic barrier of the lower intestinal tract of salmon to the oral
      delivery of protein and peptide drugs.
AB  - Oral delivery of peptide and protein drugs has potential advantages for the
      aquaculture industry. The bioavailability of proteins and peptides from the
      intestinal tract is very low. This can be attributed in part to the proteolytic
      activities of the intestine. Bovine serum albumin (BSA), human (hLHRH) and salmon
      (sLHRH) luteinizing-hormone releasing hormones were used to evaluate the
      proteolytic activity of anterior, middle and posterior sections of the Quinnat
      salmon (Oncorhynchus tshawytscha) intestinal tract. The lumenal proteolytic
      activities of the posterior intestinal section towards BSA were approximately
      half that of the anterior and middle sections. The half-lives of the LHRH
      analogues in the posterior were twofold longer than for the anterior and middle
      sections. Proteolytic activity of the posterior mucosal homogenates towards BSA
      was fourfold higher than the middle mucosal homogenates. LHRH analogues were
      hydrolysed by the posterior mucosal homogenate, whereas in the middle mucosal
      homogenate they were stable. Soybean trypsin inhibitor was shown to be the most
      effective inhibitor of lumenal proteolytic activity towards LHRH analogues.
      Sodium deoxycholate, EDTA and bestatin significantly inhibited the posterior
      mucosal hydrolytic activity towards the LHRH analogues. The posterior intestine
      of salmon is the most favourable site for the delivery of BSA and LHRH analogues
      with respect to the lumen, however the higher proteolytic activity of the
      posterior mucosa has to be overcome.

PMID- 12480316
TI  - Reengineering of a commercially available bovine intravaginal insert (CIDR
      insert) containing progesterone.
AB  - The purpose of this study was to reengineer a commercially available intravaginal
      insert containing 1.9 g progesterone (CIDR intravaginal insert) for a 7-day
      insertion period in cattle. The reengineering process resulted in a reduced
      initial drug load (1.38 g) and a reduction in the residual drug load following
      insertion, while at the same time maintaining the biological performance of the
      insert. The in vitro and in vivo pharmaceutical properties of the commercially
      available CIDR intravaginal insert were characterized initially to gain a
      thorough understanding of the factors that affected progesterone release from the
      insert. The effect of changing a selection of formulation and physical variables
      of the insert was also investigated (including surface area, drug load, addition
      of pore forming materials, silicone shore hardness and drug particle size). The
      knowledge gained from these studies was used to define the characteristics of the
      reengineered insert which was then manufactured and shown to be bioequivalent and
      clinically equivalent to the commercially available insert.

PMID- 12480317
TI  - In vitro inhibition of bovine herpes virus 1 reproduction with native and
      microencapsulated proteinase inhibitor aprotinin.
AB  - This study evaluated the antiviral effect of various dosage forms of proteinase
      inhibitor-aprotinin as a potential remedy for prophylactics and therapy of
      infectious bovine rhinotracheitis. Formulations of the inhibitor were tested for
      their influence on bovine herpes virus reproduction in cell cultures.
      Starch/bovine serum albumin microcapsules with aprotinin were prepared using
      interfacial cross-linking with terephthaloyl chloride and characterized for their
      morphology, size and release of the inhibitor. Two types of these microcapsules
      impregnated and loaded with the inhibitor-were used in virus infectious studies.
      Native aprotinin possessed palpable dose-dependent antiviral effect inhibiting
      the virus reproduction up to 4.0 lg (10000-fold) and delaying the cytopathic
      effect up to 96 h in the concentration 800-3300 TIU/ml. The bioadhesive,
      biodegradable aprotinin-loaded microcapsules were the most effective antiviral
      drug as this formulation allowed to decrease virus infectious titer up to 4.0 lg
      and a delay in the cytopathic effect of up to 144 h in lesser doses of inhibitor
      compared with the native form. In comparison the antiviral effect of
      microcapsules impregnated with aprotinin was not so appreciable. It was
      interesting to note that the results of the experiments on diverse cultures were
      very similar. This was because the drugs influenced the fundamental processes of
      virus replication cycle.

PMID- 12480318
TI  - Controlled release of oxytetracycline in sheep.
AB  - A novel biodegradable injectable formulation of oxytetracycline (OTC) was
      administered subcutaneously to sheep at a dose of 40 mg/kg. Blood samples were
      collected from the jugular vein at predetermined time intervals. The
      concentration of OTC in plasma was analyzed by an HPLC method. The concentrations
      of OTC in plasma were maintained at or above 0.5 microg/ml (minimum inhibitory
      concentration) for approximately 6 days. The pharmacokinetic parameters of OTC in
      sheep were also determined by monitoring the plasma concentration of OTC after a
      single intravenous injection of a commercially available OTC formulation at 10
      mg/kg body weight. The in vivo release profiles of OTC from the biodegradable
      injectable formulations in sheep were determined from the plasma concentration
      time profiles by the deconvolution method using PCDCON software. The in vitro
      release of OTC from the biodegradable injectable formulation was tested in
      phosphate buffer (pH 7.4), containing 0.686% w/v of sodium sulfite as
      antioxidant. The correlation between the in vitro and in vivo release of OTC from
      the injectable formulation was also evaluated. The results of the in vivo
      evaluation of the formulation in sheep indicated that a controlled release
      biodegradable injectable dosage form of OTC for food animals is feasible.

PMID- 12480319
TI  - Poly(methyl methacrylate) synthetic grit formulations sustain the delivery of
      nicarbazin, a contraceptive agent, in pest waterfowl.
AB  - Sixty-three mallards were fed one of ten poly(methyl methacrylate) based
      synthetic grit formulations containing varying concentrations of a proposed
      wildlife contraceptive (nicarbazin), plasticizer (acetyl tributylcitrate) and/or
      cross-linking agent (1,4-butanediol diacrylate). Release characteristics of the
      contraceptive agent were monitored for the purpose of developing a contraceptive
      formulation for control of pest waterfowl in urban settings. The addition of
      plasticizer increased the erosion rate (t(1/2)=0.97-2.85 days), cross-linking the
      polymer matrix slightly decreased the erosion rate (t(1/2)=4.45-5.05 days) and
      increasing the concentration of the contraceptive agent increased the erosion
      rate (t(1/2)=3.3 and 9.9 days at 60% and 7.5% active ingredient, respectively).
      The larger and smaller grit pieces had longer half lives at 11.0 and 11.6 days,
      respectively while the mid sized grit had a half life of 4.95 days. Control grit
      had a half life of 12.7 days based on weight loss. Analysis of blood and feces
      for monitoring release from the grit and approximate indirect plasma levels of
      the active ingredient proved feasible.

PMID- 12480320
TI  - Development and assessment of mini projectiles as drug carriers.
AB  - This paper describes a novel technology for the delivery of drugs into the
      subcutaneous and intramuscular tissue of farmed animals. The technology comprises
      small, hollow mini projectiles into which drug formulations can be loaded and
      administered using compressed air from an administration device which is held a
      few millimeters (3-10 mm) from the surface of the animals' skin. The design of
      the mini projectiles and administration procedure allows administration without
      contacting the skin, thereby avoiding cross-contamination between handlings and
      ensuring safe injection practice in livestock. In vitro experiments are described
      which investigate the parameters that affect mini projectile penetration into
      excised porcine and bovine skin. These include shape and weight of the mini
      projectiles and species type and injection site of the animal. An in vitro skin
      model for assessing mini projectile administration is described which permits
      visualization of the penetration of the mini projectiles through excised bovine
      or porcine skin into an underlying tissue simulant made from gelatin. The
      quantities of energy necessary to inject mini projectiles through excised porcine
      and bovine skin into the tissue simulant of the in vitro skin model were
      determined. The paper also describes the processes that occur during the
      administration of mini projectiles. The results suggest that tissue damage caused
      during administration of mini projectiles is comparable to the tissue damage
      caused by conventional syringe-needle injections. Finally, three different
      formulations of the model vaccine BSA, without adjuvant, are loaded into mini
      projectiles and administered to pigs. A seroconversion was shown for all three
      formulations, thus demonstrating proof of concept for the miniprojectiles.

PMID- 12480321
TI  - Clinical evaluation of bioadhesive ophthalmic drug inserts (BODI) for the
      treatment of external ocular infections in dogs.
AB  - In the case of external ocular diseases such as conjunctivitis,
      keratoconjunctivitis sicca (KCS) and superficial corneal ulcers, topical
      administration of eyedrops containing an antibacterial agent is often prescribed.
      Numerous daily instillations of eyedrops over several days are required for
      successful treatment, often leading to bad compliance. In addition, the reflex
      lachrymation following instillation promotes rapid elimination of the drug from
      the corneal surface. To overcome the disadvantage of repeated instillations, a
      soluble bioadhesive ophthalmic drug insert (BODI) to be placed in the lower cul
      de sac of the eye was developed. The clinical efficacy, after deposition of one
      insert and a classical eyedrop treatment (Tiacil), Virbac Laboratories), was
      investigated in dogs presenting conjunctivitis, superficial corneal ulcer or
      keratoconjunctivitis sicca (KCS). Similar total clinical recovery results were
      obtained after 3 and 7 days for both treatments. BODI can therefore
      advantageously be prescribed for the treatment of external ophthalmic diseases,
      by reducing the treatment to a single application and therefore improving
      compliance compared to classical eyedrop treatment.

PMID- 12480322
TI  - Delivery of subunit vaccines in maize seed.
AB  - The use of recombinant gene technologies by the vaccine industry has
      revolutionized the way antigens are generated, and has provided safer, more
      effective means of protecting animals and humans against bacterial and viral
      pathogens. Viral and bacterial antigens for recombinant subunit vaccines have
      been produced in a variety of organisms. Transgenic plants are now recognized as
      legitimate sources for these proteins, especially in the developing area of oral
      vaccines, because antigens have been shown to be correctly processed in plants
      into forms that elicit immune responses when fed to animals or humans. Antigens
      expressed in maize (Zea mays) are particularly attractive since they can be
      deposited in the natural storage vessel, the corn seed, and can be conveniently
      delivered to any organism that consumes grain. We have previously demonstrated
      high level expression of the B-subunit of Escherichia coli heat-labile
      enterotoxin and the spike protein of swine transmissible gastroenteritis in corn,
      and have demonstrated that these antigens delivered in the seed elicit protective
      immune responses. Here we provide additional data to support the potency,
      efficacy, and stability of recombinant subunit vaccines delivered in maize seed.

PMID- 12480323
TI  - Effects of cellulose derivatives and poly(ethylene oxide)-poly(propylene oxide)
      tri-block copolymers (Pluronic)surfactants) on the properties of alginate based
      microspheres and their interactions with phagocytic cells.
AB  - The goal of this study was to examine the phagocytosis of alginate based
      microspheres with different surface properties. Favorable interaction with
      macrophages is critical for uptake subsequent processing of the microspheres used
      for oral vaccine delivery. We examined the effects of size of alginate
      microspheres and hydrophobicity on cellular uptake. We also examined the toxicity
      of formulation components to phagocytic cells. Alginate microspheres were made by
      the emulsion-cross-linking technique. Five different formulations of microspheres
      were evaluated for size, hydrophobicity, cellular uptake and toxicity to
      macrophages. The formulations examined were: alginate alone (A), alginate with
      methylcellulose (AA) AA with Pluronic L61 (AA61), alginate with hydroxypropyl
      methylcellulose (AK3), and AK3 with Pluronic (L61 (AK3 61). Microspheres with
      without poly-L-lysine (PLL) coating were tested. The mean volume sizes of A, AA,
      AA61, AK3, AK3 61 microspheres (MS) were 11, 10.5, 3.8, 8.7 and 3.9 mocrom,
      respectively. After coating them with PLL the mean volume sizes were 10.4, 10,
      3.7, 8.8 and 3.5 microm, respectively. Hydrophobicity of the microspheres was
      evaluated by measuring contact angle on a glass slide coated with the
      microspheres. The contact angles measured using a goniometer on A, AA, AA61, AK3,
      AK3 61 MS were 20, 34.8, 71, 29 and 80 degrees, respectively whereas those MS
      coated with PLL were 49.7, 55.8, 91, 48.25 and 84.4 degrees, respectively.
      Cellular uptake studies using flow cytometery revealed that AA61 MS coated with
      PLL were phagocytosed most often by mouse macrophages. There was no statistically
      significant difference in cellular uptake among those MS without PLL coating.
      Toxicity to macrophages was shown to depend on the ratio of microspheres to
      cells. These studies suggest that formulation can dramatically affect the
      physical characteristics of alginate MS in ways that can affect how they will
      interact with cells in the body when administered as a vaccine delivery system.

PMID- 12480324
TI  - Mucosal immune responses following oral immunization with rotavirus antigens
      encapsulated in alginate microspheres.
AB  - Availability of effective oral vaccine delivery vehicles should contribute to the
      success of oral immunization in domestic animals. To achieve this goal, we
      evaluated alginate microspheres for their capacity to induce mucosal immune
      responses following oral and enteric immunizations. Mice were immunized with
      either live porcine rotavirus (PRV) or its recombinant VP6 protein, encapsulated
      in alginate microspheres or unencapsulated. VP6-specific IgG (but no IgA)
      antibodies were detected in the sera of mice after a single intraperitoneal
      (i.p.) immunization with either VP6 in Incomplete Freund's adjuvant (VP6-IFA),
      VP6 in alginate microspheres (VP6-MS) or with live PRV in incomplete Freund's
      adjuvant (PRV-IFA). In contrast, VP6-specific IgA (but no IgG) was detected in
      culture supernatants of mesenteric lymph nodes from mice immunized i.p. with
      either VP6-IFA or with PRV-IFA. Oral immunization with VP6-MS induced the highest
      level of VP6-specific fecal IgA antibody, similar to responses induced by oral
      immunization with live PRV. Furthermore, the VP6-specific fecal IgA could be
      boosted by a secondary i.p. immunization with VP6. Further experiments were
      performed in a sheep intestinal 'loop' model to evaluate uptake of microspheres
      by Peyer's patches. Microspheres containing colloidal carbon were specifically
      bound and transported by follicle-associated epithelium of Peyer's patches.
      Additionally, mucosal immune responses were detected following enteric
      immunization with porcine serum albumin (PSA) encapsulated in alginate
      microspheres. Our results confirm that alginate microspheres are an effective
      oral delivery vehicle for protein antigens and intestinal IgA antibody responses
      are induced by antigens encapsulated in alginate microspheres without any
      additional mucosal adjuvant. These investigations confirm that alginate
      microspheres have the potential as an effective delivery vehicle for oral
      immunization of ruminants.

PMID- 12480325
TI  - Immersion delivery of plasmid DNA. I. A study of the potentials of a liposomal
      delivery system in rainbow trout (Oncorhynchus mykiss) fry.
AB  - A successful regime for intramuscular injection of naked DNA is developed in
      fish, but the exploration of other ways of administration has not yet been
      studied in any detail. Immersion is a delivery route offering many advantages
      compared to conventional ways of administration. Applying cationic liposomes as a
      delivery system for DNA by this route, however, is met with severe toxicity
      problems. In this report, the underlying mechanisms of the acute toxicity were
      investigated in vivo and in vitro. The most critical factor was found to be the
      charge of the liposomes. Cationic liposomes above a certain threshold
      concentration had a lethal effect in rainbow trout fry. In contrast, similar
      concentrations of neutral or anionic liposomes were not toxic. Furthermore, large
      liposome-mucin complexes were formed upon addition of mucin to cationic
      liposomes. This was not observed with neutral or anionic liposomes. Lipoplexes
      were less toxic and interacted less with mucin compared to cationic liposomes.
      Hence, the mechanism of the acute toxicity in rainbow trout fry is suggested to
      be an interaction between the cationic liposomes and anionic components of gill
      mucin. The consequence is hypoxia and this is most likely the cause of acute
      toxicity observed in rainbow trout fry.

PMID- 12480326
TI  - Immersion delivery of plasmid DNA. II. A study of the potentials of a chitosan
      based delivery system in rainbow trout (Oncorhynchus mykiss) fry.
AB  - The possibility of utilising DNA vaccines for aquaculture fish has been of
      growing interest in recent years and novel methods to deliver DNA to the fish are
      under investigation. One of the delivery methods of interest is immersion. Due to
      the favourable properties of chitosan in gene delivery and bioadhesion, chitosan
      DNA formulations have been investigated for use for immersion delivery to fish.
      Initial studies on this system, however, revealed an acute toxic effect of the
      formulations. In this study, factors important for the acute toxicity of chitosan
      and chitosan formulations are identified and attempts are made to explain the
      underlying mechanisms for the toxicity. In vivo methods revealed that the
      toxicity mainly was dependent on the concentration of chitosan, but also the
      molecular weight and the degree of acetylation of the chitosans were of
      importance. Noteworthy, the toxicity of the polymer decreased dramatically when
      the chitosan was 'decharged' by complexation with DNA. In vitro experiments
      supported the in vivo observations. Most likely, the observed toxicity is caused
      by an electrostatic interaction between the cationic polymer and the anionic
      parts of the gill mucus. The result is obstructed oxygen diffusion over the gills
      and the fish are killed by acute hypoxia. Careful selection of chitosan type and
      charge of the particles may result in a potential for chitosan based immersion
      delivery of plasmid DNA.

PMID- 12480327
TI  - Immunization of rabbits against a bacterial pathogen with an alginate
      microparticle vaccine.
AB  - Pasteurella multocida is an important bacterial pathogen of domestic rabbits. To
      evaluate the ability of a thiocyanate extract (PTE) of P. multocida to stimulate
      an immune response and protect against infection with P. multocida, rabbits were
      immunized subcutaneously or intranasally on Days 7, 21 and 35. Cholera toxin, a
      potent mucosal adjuvant, was included in one treatment group. Rabbits immunized
      subcutaneously (SC) or intranasally (IN) had significant increases in serum anti
      PTE IgG but not IgA. In contrast, only rabbits immunized IN with PTE developed
      significant titers of nasal lavage anti-PTE IgA and cholera toxin significantly
      enhanced this response. In a second study rabbits were immunized via the drinking
      water with PTE incorporated into alginate microparticles on Days 7, 14 and 21.
      Mild increases in serum IgG were noted in rabbits immunized with PTE in
      microparticles, with or without cholera toxin, and this increase was significant
      (P<or=0.05) on Day 21 for rabbits receiving PTE and cholera toxin. Nasal lavage
      anti-PTE IgA was significantly (P<or=0.05) increased in rabbits immunized orally
      with PTE, with or without cholera toxin, in microparticles. This effect was not
      enhanced by cholera toxin. Rabbits orally immunized with PTE in microparticles
      had significantly fewer colony forming units of homologous P. multocida recovered
      from the lungs and nasopharynx following an intranasal challenge. These results
      demonstrate that PTE incorporated into alginate microparticles and administered
      orally is immunogenic and confers protective immunity.

PMID- 12480328
TI  - Modulation of the cellular immune response after oral or subcutaneous
      immunization with microparticles containing Brucella ovis antigens.
AB  - An antigenic extract (HS) from Brucella ovis was encapsulated in either poly
      epsilon-caprolactone (PEC) or poly-lactic-co-glycolic acid 75:25 (PLGA)
      microparticles containing beta-cyclodextrin and Pluronic F-68 as stabilising
      agents. The resulting microparticles displayed sub-5 microm sizes. Antigen
      loading was 5.2 and 3.8 microg/mg for HS-PEC and HS-PLGA microparticles,
      respectively. Specific HS cytokine profiles were determined after subcutaneous
      and oral immunisation of BALB/c mice. Gut distribution studies of the
      formulations after oral administration showed that HS-PEC microparticles
      interacted more strongly with mucosa and Peyer's patches than HS-PLGA.
      Accordingly, oral immunisation with HS-PLGA induced a negligible immune response,
      whereas HS-PEC elicited a Th1 response although of low intensity. Subcutaneous
      immunisation with HS-PEC induced high IFN-gamma and IL-2 release; in contrast, HS
      PLGA particles induced a Th2 profile characterized by significant levels of IL-4.
      Splenic cells from free-HS immunised mice released IFN-gamma and IL-2 but not IL
      4. A less intense Th1 pattern was also found from HS stimulated nai;ve splenic
      cells. These results suggest that the HS itself possesses Th1 immunopotentiating
      properties, required to control brucellosis, that can be specifically increased
      by encapsulation in PEC microparticles. In contrast, PLGA microparticles modulate
      the response toward a Th2 pathway.

PMID- 12480329
TI  - Enhancement of immune responses by co-delivery of a CpG oligodeoxynucleotide and
      tetanus toxoid in biodegradable nanospheres.
AB  - Synthetic oligodeoxynucleotides (ODN) consisting of unmethylated bacterial DNA
      sequences with CpG motifs are potent immunological adjuvants. Immunostimulatory
      CpG sequences are species-specific. Optimal CpG sequences specific for humans,
      rodents, livestock, and companion animals have been reported. Nearly all of these
      reports describe the use of soluble forms of CpG ODN and antigens. We
      investigated the co-delivery of CpG ODN and antigens in biodegradable nanospheres
      as an alternative approach for immunization using tetanus toxoid (TT) as the
      model antigen and ODN #1826 as the model CpG sequence. TT and CpG ODN were co
      encapsulated in poly(D,L-lactic-co-glycolic acid) nanospheres. Separate groups of
      C57BL/6 mice were subcutaneously immunized twice with TT and CpG ODN in
      nanospheres (test group), TT alone in nanospheres, TT alone in nanospheres mixed
      with CpG ODN in solution, TT and CpG ODN both in solution (reference group), TT
      alone in solution, and alum adsorbed TT. T cells isolated from the test group
      showed strong antigen-specific T cell proliferation ex vivo (stimulation
      index=45). This was significantly (P<0.0001) higher than that observed for T
      cells isolated from the reference group. The T cell proliferation of the test
      group was associated with higher levels of interferon gamma secretion (IFN-gamma
      2694.7+/-41.1 pg/ml) than that of the reference group (814.7+/-50.2 pg/ml).
      Interleukin 4 (IL-4) secretion, if any, was below the detection limit (<13 pg/ml)
      in all the groups. Anti-sera obtained from the test group also showed very high
      total IgG titers (end point titers, 2560000) that were 16 times higher than the
      reference group. Similarly, differences of 8-fold for IgG1 and IgG3, and 5-fold
      for IgG2b titers were observed. Noticeably, the antibody response induced in the
      alum-TT group was far less (total IgG, end point titers 160000) than that
      obtained in the TT-CpG ODN nanospheres group. Overall, the results show that co
      delivery of CpG and TT resulted in induction of both T helper type 1 and type 2
      (Th1 and Th2) immune responses with a bias towards Th1 type. These results
      suggest that the co-delivery of CpG ODN adjuvants and antigens in nanospheres is
      a more efficient approach for immunization than the use of CpG ODN and TT in
      solution.

PMID- 12480330
TI  - Intranasal immunization with influenza vaccine and a detoxified mutant of heat
      labile enterotoxin from Escherichia coli (LTK63).
AB  - Groups of 10 Balb/c mice were immunized intranasally (IN) with influenza
      haemagglutinin (HA), and a genetically detoxified mutant of heat-labile
      enterotoxin from Escherichia coli (LTK63) at several different doses. IN
      immunization at the optimal dose combination for HA and LTK63 induced equivalent
      levels of serum IgG antibodies to intramuscular (IM) immunization with HA alone,
      and induced significantly enhanced IgA titers in nasal wash. However,
      haemagglutination inhibition (HI) assays showed that the IM vaccine induced
      approximately 10-fold higher HI titers than IN immunization with HA and LTK63. In
      a second study, HA and LTK63 was compared to a licensed emulsion adjuvant MF59 by
      the IN route. LTK63 was shown to be significantly more potent than MF59 when
      evaluated at the optimal dose combination with HA. Hence, the LTK63 and HA
      combination represents an attractive candidate for evaluation as an IN vaccine in
      larger animal models, or humans.

PMID- 12480333
TI  - Building bridges through collaboration--a pathway for interdisciplinary research.

PMID- 12480334
TI  - Gene expression and the myth of the average cell.
AB  - We all know that gene expression occurs within cells, yet we do not think of
      expression in terms of its fundamental unit -- a single cell. Instead, we
      understand the expression of genes in terms of a cell population as all of our
      information comes from samples containing millions of cells. From a complex
      mixture of cells, we attempt to infer the probable state of an average cell in
      the population. In truth, what we obtain is an averaged cell, a contrivance for
      representing biological knowledge beyond the limits of detection. We never know
      the variation among the members of the population that our methods average into a
      mean. Recent technological advances allow the precise measurement of single-cell
      transcriptional states to study this variability more rigorously. How genes are
      expressed in the population is strikingly different to what we have assumed from
      extrapolating to an average cell. Does the average cell actually exist? As we
      discuss, it is becoming increasingly clear that it doesn't.

PMID- 12480335
TI  - PHD domains and E3 ubiquitin ligases: viruses make the connection.
AB  - PHD domains constitute a widely distributed subfamily of zinc fingers whose
      biochemical functions have been unclear until now. Recently, several PHD
      containing viral proteins have been identified that promote immune evasion by
      downregulating proteins that govern immune recognition. Studies show that these
      viral regulators lead to ubiquitination of their targets by functioning as E3
      ubiquitin ligases -- an activity that requires the PHD motif. These are the first
      examples linking the PHD domain to E3 activity, but the recent discovery of PHD
      dependent E3 activity in the cellular kinase MEKK1 and the close structural
      relation of PHD domains to RING fingers hint that many other PHD proteins might
      share this activity.

PMID- 12480336
TI  - Rho GTPase-activating proteins in cell regulation.
AB  - Rho family small GTPases serve as molecular switches involved in the regulation
      of diverse cellular functions including various cytoskeleton-related events and
      gene transcription. The Rho GTPase-activating proteins (RhoGAPs) are one of the
      major classes of regulators of Rho GTPases found in all eukaryotes that are
      crucial in cell cytoskeletal organization, growth, differentiation, neuronal
      development and synaptic functions. Recent studies have implicated them as
      specific negative regulators of Rho protein signalling pathways and provided
      insight into how the RhoGAP-catalysed GTPase-activating reaction might proceed.
      Progress has also been made in understanding how various intracellular signals
      might converge on or diverge from RhoGAPs leading to their tight regulation or
      GAP-independent function.

PMID- 12480337
TI  - Invasion of mammalian cells by Listeria monocytogenes: functional mimicry to
      subvert cellular functions.
AB  - The bacterium Listeria monocytogenes has the unusual capacity to enter and to
      multiply in nonphagocytic cells. Bacterially induced phagocytosis is triggered
      mainly by the two surface proteins internalin (also called InlA) and InlB, which
      interact with host cell receptors and either mimic or act in place of the normal
      cellular ligands. Internalin interacts specifically with human E-cadherin,
      whereas InlB activates the tyrosine kinase receptor Met and also interacts with
      the ubiquitous receptor gC1qR and proteoglycans. Signals induced by crosstalk
      between the bacterium and the host cell allow internalization, which is a prelude
      to intracellular multiplication, actin-based movement and spread of the bacterium
      from cell to cell. Manipulating the bacterial invasion proteins offers us an
      unprecedented tool with which to understand the complex phenomenon of
      phagocytosis.

PMID- 12480338
TI  - The on-off story of protein palmitoylation.
AB  - Palmitoylation is one of the most frequent post-translational modifications found
      on proteins. It contributes to membrane association, protein sorting and many
      other processes. Through its reversibility, palmitoylation also provides
      mechanisms to regulate the functional activities of integral and peripheral
      membrane proteins. Here we discuss evidence that proteins can be palmitoylated at
      different locations in the cell, how targeting to these locations might be
      directed, and aspects of the proposed functions of palmitoylation.

PMID- 12480339
TI  - Computational modeling of the EGF-receptor system: a paradigm for systems
      biology.
AB  - Computational models have rarely been used as tools by biologists but, when
      models provide experimentally testable predictions, they can be extremely useful.
      The epidermal growth factor receptor (EGFR) is probably the best-understood
      receptor system, and computational models have played a significant part in its
      elucidation. For many years, models have been used to analyze EGFR dynamics and
      to interpret mutational studies, and are now being used to understand processes
      including signal transduction, autocrine loops and developmental patterning. The
      success of EGFR modeling can be a guide to combining models and experiments
      productively to understand complex biological processes as integrated systems.

PMID- 12480340
TI  - Extracellular matrix in vascular morphogenesis and disease: structure versus
      signal.
AB  - The vascular system matures during embryonic development to form a stable, well
      organized tubular network. In vivo data have established that the extracellular
      matrix (ECM) is crucial in providing structural support to the vascular system.
      In vitro studies are defining the involvement of ECM-smooth-muscle cell signaling
      in establishing and maintaining the mature tubular structure. However,
      correlating cell signaling with established structural functions for the ECM and
      determining the relative importance of these two roles in vivo is often
      difficult. Here, we examine human genetics, murine gene targeting and cell
      biology to better understand the relationship between structural and signaling
      roles for the ECM in vascular morphogenesis and disease.

PMID- 12480341
TI  - More review content in TIBTECH 2003.

PMID- 12480342
TI  - Knockdown stands up.
AB  - In the past year, the genetic research of mammalian cells in vitro has gained the
      advantages of RNA interference (RNAi), a process found in worms and plants by
      which double stranded RNAs mediate selective gene inactivation through mRNA
      destruction. Recently, two papers have shown that genes could be suppressed in
      vivo in mammals by RNAi, which has potential implications for both therapeutics
      and research.

PMID- 12480343
TI  - PNA and LNA throw light on DNA.
AB  - In some aspects, homogeneous (all-in-solution) nucleic acid hybridization assays
      are superior to the traditionally used heterogeneous (solution-to-surface)
      alternatives. Profluorescent probes, which reveal fluorescence enhancement or
      fluorescence polarization upon their binding to DNA and RNA targets, are a
      paradigm for the real-time sequence-specific homogeneous detection of nucleic
      acids. A variety of such DNA or RNA-derived probes of different constructs has
      already been developed with numerous applications. However, the recent additions
      to the field - locked nucleic acids (LNAs) and peptide nucleic acids (PNAs) -
      significantly increase the potential of profluorescent probes and provide a
      robust impulse for their new uses.

PMID- 12480344
TI  - Safe choice of metals in food bioprocess enzyme-mimicry?

PMID- 12480345
TI  - Promoters can contribute to the elucidation of protein function.
AB  - Protein interaction maps are valuable tools in the understanding of the actions
      of genes and proteins in a real-life context. However, many proteins and genes
      interact functionally - without physical contact - via transcriptional
      coregulation of the genes, which is partially manifested in functional promoter
      structures called promoter modules. Here, the example of interleukin 9 (IL-9)
      induction by IL-1 and tumour necrosis factor (TNF) is used to demonstrate how
      comparative promoter analysis can identify a shared promoter module and thus
      indicate the crucial partners. This strategy can be used for genes from a small
      initial set of coregulated genes, such as can be derived from expression array
      data. The combination of expression and promoter analysis with proteomics should
      be considered as an important link in functional genomics.

PMID- 12480346
TI  - Avian transgenesis: progress towards the promise.
AB  - The hen has long held promise as a low cost, high-yield bioreactor for the
      production of human biopharmaceuticals in egg whites. A typical egg white
      contains 3.5-4.0 grams of protein, more than half of which comes from a single
      gene (ovalbumin). Harnessing the power of the gene to express a recombinant
      protein could yield up to a gram or more of the protein in the naturally sterile
      egg. Accordingly, a major effort has been underway for more than a decade to
      develop robust methods for modification of the chicken genome. This effort
      intensified in the mid-1990s when several avian transgenic companies entered the
      scene. Progress has been made in that time but much remains to be done.

PMID- 12480347
TI  - Progress towards commercialization of plastid transformation technology.
AB  - Tobacco chloroplasts are ready to be tested as a platform for the expression of
      recombinant proteins on a commercial scale. They hold the promise of reproducible
      yields of 5-25% of total soluble cellular protein in leaves and reliability has
      been achieved through refinement of an expression toolkit that includes vectors,
      recently developed expression cassettes and systems for marker gene removal.
      Implementation of plastid transformation technology in other crops, however, has
      met with difficulty and has delayed agronomic applications.

PMID- 12480348
TI  - Accelerated design of bioconversion processes using automated microscale
      processing techniques.
AB  - Microscale processing techniques are rapidly emerging as a means to increase the
      speed of bioprocess design and reduce material requirements. Automation of these
      techniques can reduce labour intensity and enable a wider range of process
      variables to be examined. This article examines recent research on various
      individual microscale unit operations including microbial fermentation,
      bioconversion and product recovery techniques. It also explores the potential of
      automated whole process sequences operated in microwell formats. The power of the
      whole process approach is illustrated by reference to a particular bioconversion,
      namely the Baeyer-Villiger oxidation of bicyclo[3.2.0]hept-2-en-6-one for the
      production of optically pure lactones.

PMID- 12480349
TI  - Biomineralization of metal-containing ores and concentrates.
AB  - Biomining is the use of microorganisms to extract metals from sulfide and/or iron
      containing ores and mineral concentrates. The iron and sulfide is microbially
      oxidized to produce ferric iron and sulfuric acid, and these chemicals convert
      the insoluble sulfides of metals such as copper, nickel and zinc to soluble metal
      sulfates that can be readily recovered from solution. Although gold is inert to
      microbial action, microbes can be used to recover gold from certain types of
      minerals because as they oxidize the ore, they open its structure, thereby
      allowing gold-solubilizing chemicals such as cyanide to penetrate the mineral.
      Here, we review a strongly growing microbially-based metal extraction industry,
      which uses either rapid stirred-tank or slower irrigation technology to recover
      metals from an increasing range of minerals using a diversity of microbes that
      grow at a variety of temperatures.

PMID- 12480350
TI  - Microbial cell-surface display.
AB  - Cell-surface display allows peptides and proteins to be displayed on the surface
      of microbial cells by fusing them with the anchoring motifs. The protein to be
      displayed - the passenger protein - can be fused to an anchoring motif - the
      carrier protein - by N-terminal fusion, C-terminal fusion or sandwich fusion. The
      characteristics of carrier protein, passenger protein and host cell, and fusion
      method all affect the efficiency of surface display of proteins. Microbial cell
      surface display has many potential applications, including live vaccine
      development, peptide library screening, bioconversion using whole cell
      biocatalyst and bioadsorption.

PMID- 12480352
TI  - The future of the World Health Organization.

PMID- 12480351
TI  - An open letter to the Executive Board of WHO.

PMID- 12480353
TI  - WHO's next Director-General: the person and the programme.

PMID- 12480354
TI  - Outpatient care for severely malnourished children.

PMID- 12480355
TI  - Unravelling the mysteries of influenza.

PMID- 12480356
TI  - Low dose mifepristone and two regimens of levonorgestrel for emergency
      contraception: a WHO multicentre randomised trial.
AB  - BACKGROUND: A single 10 mg dose of mifepristone, and two 0.75 mg doses of
      levonorgestrel 12 h apart, are effective for emergency contraception. Because no
      studies had compared the efficacies of both compounds, or investigated a single
      dose of 1.5 mg levonorgestrel, we undertook this three-arm trial. METHODS: We did
      a randomised, double-blind trial in 15 family-planning clinics in 10 countries.
      We randomly assigned 4136 healthy women with regular menstrual cycles, who
      requested emergency contraception within 120 h of one unprotected coitus, to one
      of three regimens: 10 mg single-dose mifepristone; 1.5 mg single-dose
      levonorgestrel; or two doses of 0.75 mg levonorgestrel given 12 h apart. The
      primary outcome was unintended pregnancy; other outcomes were side-effects and
      timing of next menstruation. Analysis was by intention to treat, but we did
      exclude some patients from the final analyses. FINDINGS: Of 4071 women with known
      outcome, pregnancy rates were 1.5% (21/1359) in those given mifepristone, 1.5%
      (20/1356) in those assigned single-dose levonorgestrel, and 1.8% (24/1356) in
      women assigned two-dose levonorgestrel. These proportions did not differ
      significantly (p=0.83). The relative risk of pregnancy for single-dose
      levonorgestrel compared with two-dose levonorgestrel was 0.83 (95% CI 0.46-1.50),
      and that for levonorgestrel (the two regimens combined) compared with
      mifepristone, 1.05 (0.63-1.76). Side-effects were mild and did not differ greatly
      between groups, and most women menstruated within 2 days of the expected date.
      Women who took levonorgestrel had earlier menses than did those who took
      mifepristone. INTERPRETATION: The three regimens studied are very efficacious for
      emergency contraception and prevent a high proportion of pregnancies if taken
      within 5 days of unprotected coitus. Mifepristone and levonorgestrel do not
      differ in efficacy. A 1.5 mg single levonorgestrel dose can substitute two 0.75
      mg doses 12 h apart.

PMID- 12480357
TI  - Fibrinogen and LDL apheresis in treatment of sudden hearing loss: a randomised
      multicentre trial.
AB  - BACKGROUND: Sudden sensorineural hearing loss (SSHL) is thought to have many
      different origins, including disturbances of microcirculation, autoimmune
      pathology, and viral infection. We aimed to determine whether acute reduction of
      plasma fibrinogen and serum LDL is effective for treatment of SSHL of suspected
      vascular origin. METHODS: Between January, 2000, and June, 2001, we recruited 201
      patients with sudden hearing loss from four otorhinolaryngology clinics in
      Germany. Patients were randomly allocated to single fibrinogen/LDL apheresis or
      standard treatment (250 mg prednisolone reduced by 25 mg per day, 500 mL 6%
      hydroxyethyl starch, 400 mg pentoxifylline per day). The primary outcome was
      recovery of hearing as measured by pure-tone audiometry 48 h after the start of
      treatment. Secondary outcomes were recovery of hearing 6 weeks after treatment,
      improvement of speech audiometry, tinnitus, and frequency of side-effects.
      Analysis was done per protocol. FINDINGS: Overall improvement of pure-tone
      thresholds was slightly but not significantly better in patients given apheresis
      than in those given standard treatment (difference 7.7, 95% CI -8.2 to 23.6).
      However, the mean sound level at which 50% of recorded digits were recognised was
      significantly lower after 48 h in the apheresis group (21.6 dB, SD 20.8) than in
      the standard group (29.3 dB, 29.4; p=0.034). After 6 weeks, the mean 50% speech
      perception was at 13.6 dB (SD 14.3) in the apheresis group and at 20.8 dB (25.4)
      in those on standard treatment (p=0.059). At 48 h, in patients with plasma
      fibrinogen concentrations of more than 295 mg/dL, speech perception was improved
      much more in those on apheresis (15.3 dB, 17.3) than in those on standard
      treatment (6.1 dB, 10.4; p=0.005). INTERPRETATION: A single fibrinogen/LDL
      apheresis lasting for 2 h could be used as an alternative to conventional
      infusion treatment and prednisolone for 10 days. Patients with a plasma
      fibrinogen of more than 8.68 micromol/L improve much better when treated with
      apheresis, especially if serum LDL concentrations are also raised.

PMID- 12480358
TI  - Secular trends in mortality by stroke subtype in the 20th century: a
      retrospective analysis.
AB  - BACKGROUND: Since both cerebral infarction and coronary heart disease are caused
      by atherosclerosis, they would be expected to have similar secular trends in
      mortality. Because differential diagnosis of stroke subtype on routine death
      certificates is inaccurate, we aimed to estimate secular trends in cerebral
      infarct and haemorrhage throughout the 20th century, for England and Wales, with
      data from autopsy studies. METHODS: We calculated the ratio of cerebral infarct
      to cerebral haemorrhage from all available sources of autopsy data from the 20th
      century. These data were used to estimate the ratio of cerebral infarct to
      haemorrhage for every year, and hence to estimate rates of cerebral infarct and
      cerebral haemorrhage from the total stroke mortality rate, obtained from the UK
      Office for National Statistics. FINDINGS: Data about stroke subtypes from
      autopsies were available from 1932 to 1999. The ratio of cerebral infarct to
      cerebral haemorrhage increased fourfold from 0.5 in the 1930s to 2.0 by the
      1990s; most of the increase took place between the 1930s and the 1970s. Estimated
      secular trends suggested that there was a steady fall in mortality from cerebral
      haemorrhage throughout the 20th century, whereas mortality from cerebral infarct
      increased to a peak in the 1970s and then fell. Trends in estimated cerebral
      infarct mortality closely matched those for coronary heart disease mortality.
      INTERPRETATION: The closely related trends in cerebral infarct and coronary heart
      disease suggest common causes, but the very different trend in cerebral
      haemorrhage shows that its cause probably differs importantly from these
      conditions.

PMID- 12480359
TI  - Outpatient care for severely malnourished children in emergency relief
      programmes: a retrospective cohort study.
AB  - BACKGROUND: In emergency nutritional relief programmes, therapeutic feeding
      centres are the accepted intervention for the treatment of severely malnourished
      people. These centres often cannot treat all the people requiring care.
      Consequently, coverage of therapeutic feeding centre programmes can be low,
      reducing their effectiveness. We aimed to assess the effectiveness of outpatient
      treatment for severe malnutrition in an emergency relief programme. METHODS: We
      did a retrospective cohort study in an outpatient therapeutic feeding programme
      in Ethiopia from September, 2000, to January, 2001. We assessed clinical records
      for 170 children aged 6-120 months. The children had either marasmus,
      kwashiorkor, or marasmic kwashiorkor. Outcomes were mortality, default from
      programme, discharge from programme, rate of weight gain, and length of stay in
      programme. FINDINGS: 144 (85%) patients recovered, seven (4%) died, 11 (6%) were
      transferred, and eight (5%) defaulted. Median time to discharge was 42 days (IQR
      28-56), days to death 14 (7-26), and days to default 14 (7-28). Median rate of
      weight gain was 3.16 g kg(-1) x day(-1) (1.86-5.60). In patients who recovered,
      median rates of weight gain were 4.80 g kg(-1) day(-1) (2.95-8.07) for marasmic
      patients, 4.03 g x kg(-1) x day(-1) (2.68-4.29) for marasmic kwashiorkor
      patients, and 2.70 g x kg(-1) x day(-1) (0.00-4.76) for kwashiorkor patients.
      INTERPRETATION: Outpatient treatment exceeded internationally accepted minimum
      standards for recovery, default, and mortality rates. Time spent in the programme
      and rates of weight gain did not meet these standards. Outpatient care could
      provide a complementary treatment strategy to therapeutic feeding centres.
      Further research should compare the effectiveness of outpatient and centre-based
      treatment of severe malnutrition in emergency nutritional interventions.

PMID- 12480360
TI  - Mycobacterium ulcerans disease (Buruli ulcer) following human bite.

PMID- 12480361
TI  - Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1)
      viruses: a mechanism for the unusual severity of human disease?
AB  - BACKGROUND: In 1997, the first documented instance of human respiratory disease
      and death associated with a purely avian H5N1 influenza virus resulted in an
      overall case-fatality rate of 33%. The biological basis for the severity of human
      H5N1 disease has remained unclear. We tested the hypothesis that virus-induced
      cytokine dysregulation has a role. METHODS: We used cDNA arrays and quantitative
      RT-PCR to compare the profile of cytokine gene expression induced by viruses
      A/HK/486/97 and A/HK/483/97 (both H5N1/97) with that of human H3N2 and H1N1
      viruses in human primary monocyte-derived macrophages in vitro. Secretion of
      tumour necrosis factor alpha (TNF alpha) from macrophages infected with the
      viruses was compared by ELISA. By use of naturally occurring viral reassortants
      and recombinant viruses generated by reverse genetic techniques, we investigated
      the viral genes associated with the TNF-alpha response. FINDINGS: The H5N1/97
      viruses induced much higher gene transcription of proinflammatory cytokines than
      did H3N2 or H1N1 viruses, particularly TNF alpha and interferon beta. The
      concentration of TNF-alpha protein in culture supernatants of macrophages
      infected with these viruses was similar to that induced by stimulation with
      Escherichia coli lipopolysaccharide. The non-structural (NS) gene-segment of
      H5N1/97 viruses contributed to the increase in TNF alpha induced by the virus.
      INTERPRETATION: The H5N1/97 viruses are potent inducers of proinflammatory
      cytokines in macrophages, the most notable being TNF alpha. This characteristic
      may contribute to the unusual severity of human H5N1 disease.

PMID- 12480362
TI  - A swollen neck.

PMID- 12480363
TI  - Arsenic in cooked rice in Bangladesh.
AB  - In Bangladesh, rice is boiled with an excessive amount of water, and the water
      remaining after cooking will be discarded. We did an on-site experiment to assess
      the effect of this cooking method on the amount of arsenic retained in cooked
      rice. The concentration of arsenic in cooked rice was higher than that in raw
      rice and absorbed water combined, suggesting a chelating effect by rice grains,
      or concentration of arsenic because of water evaporation during cooking, or both.
      The method of cooking and water used can affect the amount of arsenic in cooked
      rice, which will have implications for the assessment of the health risks of
      arsenic.

PMID- 12480364
TI  - Effect of sunlight and season on serotonin turnover in the brain.
AB  - Alterations in monoaminergic neurotransmission in the brain are thought to
      underlie seasonal variations in mood, behaviour, and affective disorders. We took
      blood samples from internal jugular veins in 101 healthy men, to assess the
      relation between concentration of serotonin metabolite in these samples and
      weather conditions and season. We showed that turnover of serotonin by the brain
      was lowest in winter (p=0.013). Moreover, the rate of production of serotonin by
      the brain was directly related to the prevailing duration of bright sunlight
      (r=0.294, p=0.010), and rose rapidly with increased luminosity. Our findings are
      further evidence for the notion that changes in release of serotonin by the brain
      underlie mood seasonality and seasonal affective disorder.

PMID- 12480365
TI  - UN pleads for better reproductive health in poor nations.

PMID- 12480369
TI  - Breaking down the barriers to a good death.

PMID- 12480370
TI  - Uganda stands firm on health spending freeze.

PMID- 12480371
TI  - South African rocked by allegations about squandered AIDS funds.

PMID- 12480372
TI  - Tanzania loses Global Fund money because of internal wrangling.

PMID- 12480373
TI  - False accounts for false teeth in Germany.

PMID- 12480374
TI  - Which direction for universal Canadian health care?

PMID- 12480375
TI  - Who's looking at your DNA?

PMID- 12480376
TI  - Hot flushes.
AB  - Almost every woman and some men will encounter hot flushes during their lifetime.
      Despite the prevalence of the symptoms, the pathophysiology of hot flushes
      remains unknown. A decline in hormone concentrations might lead to alterations in
      brain neurotransmitters and to instability in the hypothalamic thermoregulatory
      setpoint. The most effective treatments for hot flushes include oestrogens and
      progestagens. However, many women and their physicians are reluctant to accept
      hormonal treatments. Women want non-pharmacological treatments but unfortunately
      such treatments are not very effective, and non-hormonal drugs are often
      associated with adverse effects. Results from recent studies showed that
      selective serotonin reuptake inhibitors and other similar compounds can safely
      reduce hot flushes. Moreover, the efficacy of these drugs provides new insight
      into the pathophysiology of hot flushes. In this critical review, we assess
      knowledge of the epidemiology, pathophysiology, and treatment of hot flushes.

PMID- 12480377
TI  - Access to antiretroviral drugs in Brazil.
AB  - Since 1996, the Brazilian Ministry of Health has guaranteed free and universal
      access to antiretroviral treatment for people living with HIV/AIDS.
      Implementation of this policy has had political, financial, and logistical
      challenges. I have investigated the history and context of antiretroviral policy
      in Brazil, the logistics of the drugs' distribution, and the government's
      strategies for acquisition of the drugs. Many antiretrovirals used in Brazil are
      produced domestically; the remainder, including some of the most expensive drugs,
      are purchased from abroad. Although the Brazilian policy of antiretroviral
      distribution has had notable success, it remains threatened by the high cost of
      acquisition of drugs, which has led to disputes with international pharmaceutical
      companies over prices and patents. Whether or not the Brazilian model of
      guaranteeing access to antiretroviral treatment for people living with HIV/AIDS
      can be applied in other countries or regions, much can be learnt from the
      country's experience.

PMID- 12480378
TI  - The need for resources for clinical research: the European Society of Cardiology
      calls for European, international collaboration.

PMID- 12480379
TI  - Reactions.

PMID- 12480380
TI  - The second greatest benefit to mankind?

PMID- 12480381
TI  - The right to health: from the margins to the mainstream.

PMID- 12480382
TI  - Doctors urgently need education in human rights.

PMID- 12480383
TI  - Do human rights have a role in public health work?

PMID- 12480385
TI  - Infrared ear thermometers versus rectal thermometers.

PMID- 12480386
TI  - Infrared ear thermometers versus rectal thermometers.

PMID- 12480387
TI  - Infrared ear thermometers versus rectal thermometers.

PMID- 12480388
TI  - Infrared ear thermometers versus rectal thermometers.

PMID- 12480389
TI  - Spinal cord injury.

PMID- 12480390
TI  - Development of Cushing's syndrome after use of a herbal remedy.

PMID- 12480392
TI  - The OPTIMAAL trial: losartan or captopril after acute myocardial infarction.

PMID- 12480393
TI  - The OPTIMMAL trial: losartan or captopril after acute myocardial infarction.

PMID- 12480394
TI  - The OPTIMMAL trial: losartan or captopril after acute myocardial infarction.

PMID- 12480396
TI  - The OPTIMMAL trial: losartan or captopril after acute myocardial infarction.

PMID- 12480397
TI  - The OPTIMMAL trial: losartan or captopril after acute myocardial infarction.

PMID- 12480398
TI  - Sex ratio of offspring born to men exposed to polychlorinated biphenyls.

PMID- 12480399
TI  - Role of nicorandil in ischaemic preconditioning.

PMID- 12480401
TI  - Role of nicorandil in ischaemic preconditioning.

PMID- 12480402
TI  - Role of nicorandil in ischaemic preconditioning.

PMID- 12480403
TI  - Teenage African women and HIV-1 infection.

PMID- 12480404
TI  - Questions about anastrozole for early breast cancer.

PMID- 12480405
TI  - Questions about anastrozole for early breast cancer.

PMID- 12480407
TI  - Underdiagnosis and undertreatment of osteoporosis.

PMID- 12480408
TI  - UK government's response to health inequalities.

PMID- 12480409
TI  - William Harvey trophy.

PMID- 12480410
TI  - Effect of latitude on suicide rates in Japan.

PMID- 12480417
TI  - A way forward for US health care?

PMID- 12480418
TI  - Time to act: global apathy towards HIV/AIDS is a crime against humanity.

PMID- 12480419
TI  - Mercury in vaccines--reassuring news.

PMID- 12480420
TI  - Public use of automatic defibrillators: a bolt from the blue.

PMID- 12480421
TI  - The chronic anaemia of rheumatoid arthritis: iron banking or blocking?

PMID- 12480422
TI  - Blood vessels and nerves: together or not?

PMID- 12480423
TI  - Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.
AB  - BACKGROUND: Treatment decisions in asthma are based on assessments of symptoms
      and simple measures of lung function, which do not relate closely to underlying
      eosinophilic airway inflammation. We aimed to assess whether a management
      strategy that minimises eosinophilic inflammation reduces asthma exacerbations
      compared with a standard management strategy. METHODS: We recruited 74 patients
      with moderate to severe asthma from hospital clinics and randomly allocated them
      to management either by standard British Thoracic Society asthma guidelines (BTS
      management group) or by normalisation of the induced sputum eosinophil count and
      reduction of symptoms (sputum management group). We assessed patients nine times
      over 12 months. The results were used to manage those in the sputum management
      group, but were not disclosed in the BTS group. The primary outcomes were the
      number of severe exacerbations and control of eosinophilic inflammation, measured
      by induced sputum eosinophil count. Analyses were by intention to treat.
      FINDINGS: The sputum eosinophil count was 63% (95% CI 24-100) lower over 12
      months in the sputum management group than in the BTS management group (p=0.002).
      Patients in the sputum management group had significantly fewer severe asthma
      exacerbations than did patients in the BTS management group (35 vs 109; p=0.01)
      and significantly fewer patients were admitted to hospital with asthma (one vs
      six, p=0.047). The average daily dose of inhaled or oral corticosteroids did not
      differ between the two groups. INTERPRETATION: A treatment strategy directed at
      normalisation of the induced sputum eosinophil count reduces asthma exacerbations
      and admissions without the need for additional anti-inflammatory treatment.

PMID- 12480424
TI  - Comparison of single-dose azithromycin and 12-dose, 3-day erythromycin for
      childhood cholera: a randomised, double-blind trial.
AB  - BACKGROUND: Cholera is a major public-health problem, with children most
      affected. However, effective single-dose antimicrobial regimens have been
      identified only for adults. Our aim was to compare the efficacy of azithromycin
      and erythromycin regimens in the treatment of children. METHODS: We did a double
      blind, randomised study of 128 severely dehydrated children (age 1-15 years) with
      cholera, treated at one of two treatment centres in Bangladesh in 1999. Children
      were assigned single-dose azithromycin (20 mg/kg bodyweight, maximum individual
      dose 1 g; n=65) or 12.5 mg/kg erythromycin (maximum dose 500 mg; n=63) every 6 h
      for 3 days. Patients stayed in hospital for 5 days. We measured fluid balance
      every 6 h, and obtained a rectal swab or stool sample for culture daily. Our
      primary outcome measures were clinical success of treatment-ie, cessation of
      watery diarrhoea within 48 h-and bacteriological success-ie, absence of Vibrio
      cholerae O1 or O139 from cultures of stool or rectal swab samples after study day
      2. Analysis was per protocol. FINDINGS: Two children in both groups withdrew from
      the study, and we excluded one child in the erythromycin group. Treatment was
      clinically successful in 48 (76%) patients who received azithromycin and 39 (65%)
      who received erythromycin (difference 11%, 95% CI -5 to 27, p=0.244); and
      bacteriologically successful in 45 (71%) and 49 (82%) patients, respectively
      (10%, -5 to 25, p=0.261). Patients treated with azithromycin had a shorter
      duration of diarrhoea (median 24 h vs 42 h; difference 12 h, 0-18 h, p=0.019) and
      fewer episodes of vomiting (1 vs 4; difference 1 episode, 0-3 episodes, p=0.023).
      INTERPRETATION: Single-dose azithromycin is as effective for treatment of cholera
      in children as standard erythromycin therapy, but is associated with less
      vomiting.

PMID- 12480425
TI  - Risk factors for suicide in China: a national case-control psychological autopsy
      study.
AB  - BACKGROUND: Suicide is the fifth most important cause of death in China, but the
      reasons for the high rate and unique pattern of characteristics of those who kill
      themselves are unknown. METHODS: We pretested, and then administered a
      comprehensive interview to family members and close associates of 519 people who
      committed suicide and of 536 people who died from other injuries (controls)
      randomly selected from 23 geographically representative sites in China. FINDINGS:
      After adjustment for sex, age, location of residence, and research site, eight
      significant predictors of suicide remained in the final unconditional logistic
      regression model. In order of importance they were: high depression symptom
      score, previous suicide attempt, acute stress at time of death, low quality of
      life, high chronic stress, severe interpersonal conflict in the 2 days before
      death, a blood relative with previous suicidal behaviour, and a friend or
      associate with previous suicidal behaviour. Suicide risk increased substantially
      with exposure to multiple risk factors: none of the 265 deceased people who were
      exposed to one or fewer of the eight risk factors died by suicide, but 30%
      (90/299) with two or three risk factors, 85% (320/377) with four or five risk
      factors, and 96% (109/114) with six or more risk factors died by suicide.
      INTERPRETATION: Despite substantial differences between characteristics of people
      who commit suicide in China and the west, risk factors for suicide do not differ
      greatly. Suicide prevention programmes that concentrate on a single risk factor
      are unlikely to reduce suicide rates substantially; preventive efforts should
      focus on individuals exposed to multiple risk factors.

PMID- 12480426
TI  - Mercury concentrations and metabolism in infants receiving vaccines containing
      thiomersal: a descriptive study.
AB  - BACKGROUND: Thiomersal is a preservative containing small amounts of ethylmercury
      that is used in routine vaccines for infants and children. The effect of vaccines
      containing thiomersal on concentrations of mercury in infants' blood has not been
      extensively assessed, and the metabolism of ethylmercury in infants is unknown.
      We aimed to measure concentrations of mercury in blood, urine, and stools of
      infants who received such vaccines. METHODS: 40 full-term infants aged 6 months
      and younger were given vaccines that contained thiomersal (diptheria-tetanus
      acellular pertussis vaccine, hepatitis B vaccine, and in some children
      Haemophilus influenzae type b vaccine). 21 control infants received thiomersal
      free vaccines. We obtained samples of blood, urine, and stools 3-28 days after
      vaccination. Total mercury (organic and inorganic) in the samples was measured by
      cold vapour atomic absorption. FINDINGS: Mean mercury doses in infants exposed to
      thiomersal were 45.6 microg (range 37.5-62.5) for 2-month-olds and 111.3 microg
      (range 87.5-175.0) for 6-month-olds. Blood mercury in thiomersal-exposed 2-month
      olds ranged from less than 3.75 to 20.55 nmol/L (parts per billion); in 6-month
      olds all values were lower than 7.50 nmol/L. Only one of 15 blood samples from
      controls contained quantifiable mercury. Concentrations of mercury were low in
      urine after vaccination but were high in stools of thiomersal-exposed 2-month
      olds (mean 82 ng/g dry weight) and in 6-month-olds (mean 58 ng/g dry weight).
      Estimated blood half-life of ethylmercury was 7 days (95% CI 4-10 days).
      INTERPRETATION: Administration of vaccines containing thiomersal does not seem to
      raise blood concentrations of mercury above safe values in infants. Ethylmercury
      seems to be eliminated from blood rapidly via the stools after parenteral
      administration of thiomersal in vaccines.

PMID- 12480427
TI  - Fatal meningococcal septicaemia with "blebbing" meningococcus.

PMID- 12480428
TI  - Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism.
AB  - BACKGROUND: Calprotectin (complex of S100A8 and S100A9) is the major calcium and
      zinc-binding protein of phagocytes. We report a new syndrome with recurrent
      infections, inflammation, and hyperzincaemia associated with excessively high
      plasma concentrations of calprotectin. METHODS: We measured calprotectin in
      plasma and protein fractions by ELISA assay and zinc by atomic absorption
      spectrometry. Plasma proteins were fractionated by size exclusion chromatography
      and electrophoresis. Mass spectra of purified proteins were determined by MALDI
      TOFMS. FINDINGS: We assessed five patients, two of whom are related. All patients
      had much the same biochemical findings of hyperzincaemia (77-200 micromol/L,
      reference range 11-18 micromol/L) and raised plasma calprotectin concentrations
      (1.4-6.5 g/L, reference range <1 mg/L). All patients presented with recurrent
      infections, hepatosplenomegaly, anaemia, and evidence of systemic inflammation.
      Three patients had cutaneous inflammation and three presented in infancy with
      severe growth failure. Size exclusion chromatography showed that zinc and
      calprotectin were associated in a broad fraction with molecular weight range 100
      300 kDa. Analysis by electrophoresis and mass spectrometry showed that the
      patients' protein contained normal S100A8 and S100A9 subunits. INTERPRETATION:
      Dysregulation of zinc metabolism associated with accumulation in plasma of S100A8
      and S100A9 defines a new disease, which encompasses a pathological role for
      dysregulation of two members of the large S100 protein family.

PMID- 12480429
TI  - Balancing on the edge.

PMID- 12480430
TI  - Protease inhibitors and cardiovascular outcomes in patients with HIV-1.
AB  - Protease inhibitors for treatment of HIV-1 have been linked with increased risk
      of hyperlipidaemia and hyperglycaemia. In a cohort of 5672 outpatients with HIV-1
      seen at nine US HIV clinics between January, 1993, and January, 2002, the
      frequency of myocardial infarctions increased after the introduction of protease
      inhibitors in 1996 (test for trend, p=0.0125). We noted that 19 of 3247 patients
      taking, but only two of 2425 who did not take, protease inhibitors had a
      myocardial infarction (odds ratio 7.1, 95% CI 1.6-44.3; Cox proportional hazards
      model-adjusted for smoking, sex, age, diabetes, hyperlipidaemia, and hypertension
      hazard ratio 6.5, 0.9-47.8). Our findings suggest that, although infrequent, use
      of protease inhibitors is associated with increased risk of myocardial infarction
      in patients with HIV-1.

PMID- 12480431
TI  - Measurement of volume of cerebral blood flow in healthy preterm and term neonates
      with ultrasound.
AB  - Changes in cerebral blood flow are important in the pathogenesis of ischaemic
      brain damage, but standard methods cannot measure volume of cerebral blood flow
      quantitatively in neonates. We used colour duplex sonography of the extracranial
      cerebral arteries to measure volume of global cerebral blood flow in 67 healthy
      preterm and term neonates. Volume of cerebral blood flow increased between the
      postmenstrual ages of 34 weeks (median 33 mL/min [range 23-43]) and 42 weeks (85
      mL/min [57-104]). However, intersession and interobserver variability was quite
      large. This non-invasive method will allow quantitative bedside monitoring of
      global brain perfusion in preterm and term neonates with pathological disorders,
      and could also be used to monitor effects of neuroprotective measures.

PMID- 12480432
TI  - And the nominees for Director-General of WHO are...

PMID- 12480433
TI  - WHO's Executive Board election proceedings are low-key and secretive.

PMID- 12480434
TI  - Patient-actors can improve students' consultation skills.

PMID- 12480435
TI  - Japan opens dating agency to improve birth rate.

PMID- 12480438
TI  - Hong Kong tackles health-service overload by charging emergency fee.

PMID- 12480439
TI  - Wrong test used for checking arsenic contamination of wells in Bangladesh.

PMID- 12480440
TI  - Germany's sick health-care system.

PMID- 12480441
TI  - The dementias.
AB  - Dementia affects about 5% of the elderly population over age 65 years and has an
      unexplained predominance in women and a low rate in some cultures. Different
      forms of dementia are now distinguished-Alzheimer's disease, dementia with Lewy
      bodies, frontotemporal dementia, and dementia secondary to disease, such as AIDS
      dementia. However, such nosological boundaries are being re-evaluated because
      different dementias are believed to have common underlying neuropathology.
      Neurochemical and neurobiological research has led to advances in understanding
      causes of dementia, and functional imaging has allowed identification of possible
      biomarkers; from these, a range of potential treatment approaches have arisen
      that focus on enhancement of neurotransmitter function, intervention at the level
      of amyloid production and deposition, and reduction of secondary risk factors
      such as hypertension, depression, and hypolipidaemia. Molecular diagnostic
      testing and genetic counselling for families with autosomal dominant early-onset
      dementia are new developments; however, this approach is not useful for late
      onset dementia, in which the identified candidate susceptibility genes have a
      relatively small effect on risk. While fundamental research works towards new
      biological treatment strategies, much remains to be done in the area of disease
      management and the development of appropriate models of long-term care.

PMID- 12480442
TI  - Dopamine agonist monotherapy in Parkinson's disease.
AB  - CONTEXT: Levodopa is the gold-standard therapy for Parkinson's disease. However,
      long-term treatment leads to involuntary movements and response fluctuations
      which add to the complexities of later disease-management. In addition,
      preclinical evidence suggests that levodopa is toxic to dopaminergic neurons.
      These problems have led to a move away from levodopa towards initial monotherapy
      with a dopamine agonist. STARTING POINT: Positron-emission tomography (PET) and
      single-photon emission computed tomography (SPECT) tracers have been developed
      which may be considered surrogate markers for remaining dopaminergic neurons. In
      a randomised controlled trial in patients with early Parkinson's disease, the
      Parkinson Study Group used 123I-beta-CIT SPECT (JAMA 2002; 287: 1653-61). Those
      patients given pramipexole had significantly reduced loss of striatal uptake at
      46 months compared with those given levodopa (16.0% vs 25.5%). In a similar
      trial, Alan Whone and colleagues used 18F-DOPA PET (Neurology 2002; 58 [suppl 3]:
      A82-83). Patients given ropinirole had significantly reduced loss of striatal
      uptake at 24 months compared with those given levodopa (13% vs 20%). These
      studies suggest that agonist monotherapy may be neuroprotective and/or that
      levodopa is toxic. This work has been criticised as the SPECT results may have
      resulted from a differential effect of the agonist and levodopa on the regulation
      of the dopamine transporter, thereby influencing the imaging outcome measure.
      Other criticisms include insufficient data on the use of the potential
      neuroprotectant selegiline and patients on pramipexole in the SPECT study appear
      to have been clinically slow progressors. Single clinical trials with each of the
      four modern agonists compared with levodopa show that as monotherapy the agonists
      delay the onset of involuntary movements, although at the expense of poorer
      treatment of motor impairments and disability and more dopaminergic adverse
      events. The only health-related quality of life data show no difference between
      pramipexole and levodopa after 4 years. No information on health-economics
      measures is available but agonists cost two to three times as much as levodopa.
      WHERE NEXT? Young patients should be treated with agonist monotherapy since the
      trials included predominantly younger patients who have a higher incidence of
      motor complications. Those with significant co-morbidity, dementia, or a short
      life-expectancy should be treated with the lowest dose of levodopa required to
      maintain motor function. For the vast majority though, no clear guidance can be
      given. Further large-scale pragmatic trials in large numbers of patients over
      prolonged periods are urgently required.

PMID- 12480443
TI  - Blood banking in China.
AB  - While transfusion-transmissible diseases, including AIDS and viral hepatitis,
      continue to spread especially in developing countries, the issue of safeguarding
      the world's blood supply is of paramount importance. China houses more than 20%
      of the earth's population, and thus its blood supply has the potential to affect
      the global community. In recent years, Chinese blood centres have tried to
      improve the nation's blood safety. Although substantial progress has already been
      made, many daunting difficulties remain. Traditional cultural barriers need to be
      overcome to successfully mobilise volunteer blood donors. Gaps in information and
      technology still need to be closed. Insufficiency of economic resources also
      restrict the blood bank industry. Other developing countries face many of the
      same challenges as China.

PMID- 12480444
TI  - Clinical errors.

PMID- 12480445
TI  - The Charcot foot.

PMID- 12480446
TI  - MRC/BHF Heart Protection Study.

PMID- 12480447
TI  - MRC/BHF Heart Protection Study.

PMID- 12480448
TI  - MRC/BHF Heart Protection Study.

PMID- 12480449
TI  - MRC/BHF Heart Protection Study.

PMID- 12480450
TI  - MRC/BHF Heart Protection Study.

PMID- 12480451
TI  - MRC/BHF Heart Protection Study.

PMID- 12480452
TI  - MRC/BHF Heart Protection Study.

PMID- 12480454
TI  - Tamoxifen for breast cancer in hysterectomised women.

PMID- 12480455
TI  - Dietary effect on blood pressure.

PMID- 12480457
TI  - Dietary effect on blood pressure.

PMID- 12480459
TI  - HIV/AIDS in Africa.

PMID- 12480461
TI  - HIV/AIDS in Africa.

PMID- 12480463
TI  - HIV-1 incidence and prevalence trends in Uganda.

PMID- 12480464
TI  - HIV/AIDS control in India.

PMID- 12480465
TI  - Update from Mbarara University Teaching Hospital.

PMID- 12480466
TI  - -759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain.

PMID- 12480467
TI  - 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain.

PMID- 12480468
TI  - Human pituitary growth hormone and cancer risk.

PMID- 12480469
TI  - Abstinence, monogamy, and sex.

PMID- 12480470
TI  - Benign paroxysmal positional vertigo relief on a roller coaster.

PMID- 12480473
TI  - Focal infection.

PMID- 12480476
TI  - Eye movements and spoken language comprehension: effects of visual context on
      syntactic ambiguity resolution.
AB  - When participants follow spoken instructions to pick up and move objects in a
      visual workspace, their eye movements to the objects are closely time-locked to
      referential expressions in the instructions. Two experiments used this
      methodology to investigate the processing of the temporary ambiguities that arise
      because spoken language unfolds over time. Experiment 1 examined the processing
      of sentences with a temporarily ambiguous prepositional phrase (e.g., "Put the
      apple on the towel in the box") using visual contexts that supported either the
      normally preferred initial interpretation (the apple should be put on the towel)
      or the less-preferred interpretation (the apple is already on the towel and
      should be put in the box). Eye movement patterns clearly established that the
      initial interpretation of the ambiguous phrase was the one consistent with the
      context. Experiment 2 replicated these results using prerecorded digitized speech
      to eliminate any possibility of prosodic differences across conditions or
      experimenter demand. Overall, the findings are consistent with a broad
      theoretical framework in which real-time language comprehension immediately takes
      into account a rich array of relevant nonlinguistic context.

PMID- 12480477
TI  - Are there representational shifts during category learning?
AB  - Early theories of categorization assumed that either rules, or prototypes, or
      exemplars were exclusively used to mentally represent categories of objects. More
      recently, hybrid theories of categorization have been proposed that variously
      combine these different forms of category representation. Our research addressed
      the question of whether there are representational shifts during category
      learning. We report a series of experiments that tracked how individual subjects
      generalized their acquired category knowledge to classifying new critical
      transfer items as a function of learning. Individual differences were observed in
      the generalization patterns exhibited by subjects, and those generalizations
      changed systematically with experience. Early in learning, subjects generalized
      on the basis of single diagnostic dimensions, consistent with the use of simple
      categorization rules. Later in learning, subjects generalized in a manner
      consistent with the use of similarity-based exemplar retrieval, attending to
      multiple stimulus dimensions. Theoretical modeling was used to formally
      corroborate these empirical observations by comparing fits of rule, prototype,
      and exemplar models to the observed categorization data. Although we provide
      strong evidence for shifts in the kind of information used to classify objects as
      a function of categorization experience, interpreting these results in terms of
      shifts in representational systems underlying perceptual categorization is a far
      thornier issue. We provide a discussion of the challenges of making claims about
      category representation, making reference to a wide body of literature suggesting
      different kinds of representational systems in perceptual categorization and
      related domains of human cognition.

PMID- 12480478
TI  - Language input and child syntax.
AB  - Existing work on the acquisition of syntax has been concerned mainly with the
      early stages of syntactic development. In the present study we examine later
      syntactic development in children. Also, existing work has focused on
      commonalities in the emergence of syntax. Here we explore individual differences
      among children and their relation to variations in language input. In Study 1 we
      find substantial individual differences in children's mastery of multiclause
      sentences and a significant relation between those differences and the proportion
      of multiclause sentences in parent speech. We also find individual differences in
      the number of noun phrases in children's utterances and a significant relation
      between those differences and the number of noun phrases in parent speech. In
      Study 2 we find greater syntactic growth over a year of preschool in classes
      where teachers' speech is more syntactically complex. The implications of our
      findings for the understanding of the sources of syntactic development are
      discussed.

PMID- 12480479
TI  - Is there a natural order for expressing semantic relations?
AB  - All languages rely to some extent on word order to signal relational information.
      Why? We address this question by exploring communicative and cognitive factors
      that could lead to a reliance on word order. In Study 1, adults were asked to
      describe scenes to another using their hands and not their mouths. The question
      was whether this home-made "language" would contain gesture sentences with
      consistent order. In addition, we asked whether reliance on order would be
      influenced by three communicative factors (whether the communication partner is
      permitted to give feedback; whether the information to be communicated is present
      in the context that recipient and gesturer share; whether the gesturer assumes
      the role of gesture receiver as well as gesture producer). We found that, not
      only was consistent ordering of semantic elements robust across the range of
      communication situations, but the same non-English order appeared in all
      contexts. Study 2 explored whether this non-English order is found only when a
      person attempts to share information with another. Adults were asked to
      reconstruct scenes in a non-communicative context using pictures drawn on
      transparencies. The adults picked up the pictures for their reconstructions in a
      consistent order, and that order was the same non-English order found in Study 1.
      Finding consistent ordering patterns in a non-communicative context suggests that
      word order is not driven solely by the demands of communicating information to
      another, but may reflect a more general property of human thought.

PMID- 12480480
TI  - Challenging the widespread assumption that connectionism and distributed
      representations go hand-in-hand.
AB  - One of the central claims associated with the parallel distributed processing
      approach popularized by D.E. Rumelhart, J.L. McClelland and the PDP Research
      Group is that knowledge is coded in a distributed fashion. Localist
      representations within this perspective are widely rejected. It is important to
      note, however, that connectionist networks can learn localist representations and
      many connectionist models depend on localist coding for their functioning.
      Accordingly, a commitment to distributed representations should be considered a
      specific theoretical claim regarding the structure of knowledge rather than a
      core principle, as often assumed. In this paper, it is argued that there are
      fundamental computational and empirical challenges that have not yet been
      addressed by distributed connectionist theories that are readily accommodated
      within localist approaches. This is highlighted in the context of modeling word
      and nonword naming, the domain in which some of the strongest claims have been
      made. It is shown that current PDP models provide a poor account of naming
      monosyllable items, and that distributed representations make it difficult for
      these models to scale up to more complex language phenomena. At the same time,
      models that learn localist representations are shown to hold promise in
      supporting many of the core reading and language functions on which PDP models
      fail. It is concluded that the common rejection of localist coding schemes within
      connectionist architectures is premature.

PMID- 12480481
TI  - Neuroethics: an emerging new discipline in the study of brain and cognition.
AB  - The vision for the special issue in Brain and Cognition is rooted in the need to
      bring to the foreground the state of scientific knowledge in research and
      clinical neuroimaging ethics. To this end, the issue highlights a broad range of
      relatively unexplored ethical challenges in functional neuroimaging with MR,
      alone or in combination with other neuroimaging modalities, from imaging the
      central nervous system of the fetus in utero through neural activation patterns
      associated with cognition and behavior in childhood and in adulthood.
      Theoretical, practical, and ethical considerations at the heart of imaging
      healthy research subjects and cognitively compromised patients are explored.

PMID- 12480482
TI  - Legal and ethical issues in neuroimaging research: human subjects protection,
      medical privacy, and the public communication of research results.
AB  - Humans subjects research entails significant legal and ethical obligations.
      Neuroimaging researchers must be familiar with the requirements of human subjects
      protection, including evolving standards for the protection of privacy and the
      disclosure of risk in "non-therapeutic" research. Techniques for creating
      veridical surface renderings from volumetric anatomical imaging data raise new
      privacy concerns, particularly under the federal medical privacy regulation.
      Additionally, neuroimaging researchers must consider their obligation to
      communicate research results responsibly. The emerging field of neuroethics
      should strive to raise awareness of these issues and to involve neuroimaging
      researchers in the legal, ethical, and policy debates that currently surround
      human subjects research.

PMID- 12480483
TI  - Ethical and practical considerations in managing incidental findings in
      functional magnetic resonance imaging.
AB  - Functional magnetic resonance imaging has emerged as a powerful tool for mapping
      the neurologic underpinnings of sensory, motor and cognitive function. Much of
      this evolution carries assumptions about the subject population under study and,
      in particular, the neurologic status of subjects entered into studies either as
      healthy controls or as belonging to a specific disease group. Recent reports of
      incidental MRI abnormalities in normal volunteers for fMRI studies have brought
      to attention a variety of practical challenges and ethical dilemmas for
      researchers, many of whom are not physicians and most of whom have no formal
      radiological training. We propose a minimum standard for consenting subjects in
      fMRI protocols, and consider strategies over the longer term that call for expert
      physician participation, archiving of incidental findings including false
      positives, and the adoption of guidelines for handling variation in neural
      activations or performance that appear outside expected norms.

PMID- 12480484
TI  - Transcranial magnetic stimulation: neurophysiological applications and safety.
AB  - TMS is a non-invasive tool for measuring neural conduction and processing time,
      activation thresholds, facilitation and inhibition in brain cortex, and neural
      connections in humans. It is used to study motor, visual, somatosensory, and
      cognitive functions. TMS does not appear to cause long-term adverse neurological,
      cardiovascular, hormonal, motor, sensory, or cognitive effects in healthy
      subjects. Single-pulse (<1Hz) TMS is safe in normal subjects. High frequency,
      high-intensity repetitive TMS (rTMS) can elicit seizures even in normal subjects.
      Safety guidelines for using rTMS have been published.

PMID- 12480485
TI  - Treatment, enhancement, and the ethics of neurotherapeutics.
AB  - Emerging neurotechnologies, including psychopharmaceuticals, brain stimulation,
      implantable brain chips, transcranial magnetic stimulation, and brain imaging
      raise a number of ethical questions. One of the most contentious is the proper
      role of these technologies in improving or increasing mental and neurological
      traits and skills in those with no identifiable pathology. The "enhancement"
      debate centers around a number of concerns and philosophical approaches to the
      proper role of medicine, therapeutics, and desirable human qualities. Arguements
      for and against neurological enhancement are reviewed, and historical and social
      perspectives are offered.

PMID- 12480486
TI  - Diffusion-tensor imaging of cognitive performance.
AB  - MR methods have for some years been used to assess cognitive performance.
      Recently, studies have shown that diffusion-tensor imaging (DTI), which provides
      noninvasive maps of microscopic structural information of oriented tissue in
      vivo, is finding utility in studies of cognition in the normal and abnormal aging
      population. These studies suggest that water proton nonrandom, anisotropic
      diffusion measured by DTI is highly sensitive to otherwise subtle disease
      processes not easily seen with conventional MRI tissue contrast mechanisms and
      raises new issues of the role of MR in assessing cognitive potential.

PMID- 12480487
TI  - Neuroimaging of emotion and personality: scientific evidence and ethical
      considerations.
AB  - Affective neuroscience has seen an explosion of research efforts using modern
      neuroimaging approaches to uncover the neural basis of emotion and personality.
      The first section of this paper reviews studies from the domains of affective and
      forensic neuroimaging. These studies illustrate some of the topics likely to be
      the subject of future ethical debates. The second section relates limitations of
      the neuroimaging approach to ethical considerations in predicting future
      psychopathology on the basis of brain state analysis.

PMID- 12480488
TI  - MR imaging of fetal central nervous system abnormalities.
AB  - Ultrasound is the screening modality of choice for fetal imaging. However, when
      additional information regarding fetal anatomy or pathology is needed, fast MR
      imaging is increasingly being used as a correlative imaging modality.
      Performances of high quality sonographic and MR examinations as well as
      interpretation by individuals familiar with prenatal diagnosis are important
      factors for optimal parental counseling. MR imaging frequently adds additional
      information regarding fetal central nervous system anomalies beyond that
      available with ultrasound. This information commonly changes patient counseling,
      and at times patient management.

PMID- 12480489
TI  - Ethical considerations in neuroimaging and its impact on decision-making for
      neonates.
AB  - Neuroimaging can now provide information about structure and function. Despite
      new and improved neuroimaging technologies applicable to the newborn, predictions
      about later cognition, learning, social and emotional behavior, and neuromuscular
      capabilities, based on images of a fetus inside or a newborn outside the womb,
      are fraught with difficulties that go beyond technical ones. The interpretation
      of neuroimages may be necessary but it is not sufficient for decision-making
      related to the withholding or withdrawing of medical support for neonates. As the
      explanatory reach of neuroimaging increases, there will still need to be
      consideration of ethical issues as they relate to the best interests of the
      neonate and the neonate's parents, the quality of life of the neonate and non
      beneficial treatment. Once this is appreciated, the boundary between the
      technical and the ethical will be less often disputed.

PMID- 12480490
TI  - Ethics of neuroimaging in pediatric development.
AB  - Neuroimaging in pediatrics is accompanied by all the ethical dilemmas associated
      with neuroimaging in adults, magnified significantly. The defining
      characteristics of childhood make working ethically with the population
      particularly problematic. Children have not developed the rational capabilities
      necessary to make informed decisions and the variability and change associated
      with development contribute to heightened risks and/or benefits of any procedure
      and limit interpretation of data. As a consequence, fewer pediatric than adult
      neuroimaging research studies have been done, further limiting general knowledge
      of the field. Significant strides have been made just within the past few years
      with the collection of normative data sets of healthy children. Recommendations
      on how to proceed with pediatric neuroimaging studies while ensuring ethical
      treatment of the participants are presented.

PMID- 12480491
TI  - Ethical considerations for neuropsychologists as functional magnetic imagers.
AB  - This discussion highlights ethical and practical issues potential
      neuropsychologist-imagers should consider in conducting functional magnetic
      resonance imaging (fMRI). While fMRI is not currently approved for clinical use,
      research is ongoing which has implications for clinical practice, from refining
      brain-behavior relationships, to assisting with diagnosis and treatment
      decisions. To protect the welfare of cognitively impaired populations requires
      special care with respect to MR risks and informed consent. Competent functional
      imaging requires an understanding of the strengths, limitations, and appropriate
      domain of applications of the measure.

PMID- 12480492
TI  - Ethical issues in the clinical application of fMRI: factors affecting the
      validity and interpretation of activations.
AB  - The ability of functional magnetic resonance imaging (fMRI) to localize
      activations in a single patient, along with the safety and widespread
      availability of this methodology, has lead to an increasing use of fMRI for
      clinical purposes such as pre-surgical planning. As methodology continues to
      improve and more experience with fMRI in the clinical setting is acquired,
      clinical functional neuroimaging will likely have an increasing influence over
      patient care. Therefore, ethical use of fMRI, as with other medical techniques,
      requires understanding the factors impacting the interpretation of the
      methodology. Issues affecting the validity and interpretation of clinical
      functional neuroimaging, including effects of altered hemodynamic response
      function, head motion, and structural changes in the brain, are reviewed. The
      distinction between correlated and necessary activation in a clinical context is
      discussed. Different types of statistical errors in fMRI analysis are described,
      along with their consequences to the patient. Finally, for the future of clinical
      fMRI development, the need for normative patient data, as well as standardized
      tasks, scan protocols, and data analyses, is discussed.

PMID- 12480493
TI  - Ethical, and practical issues in applying functional imaging to the clinical
      management of Alzheimer's disease.
AB  - This review outlines ethical, legal, and practical issues related to conducting
      functional imaging research with Alzheimer's disease (AD) patients. Imaging
      techniques, with an emphasis on functional MRI and positron emission tomography,
      are compared and contrasted with respect to the manner in which they can be
      applied to issues of clinical relevance to AD. Methodological difficulties are
      raised to assist with critical evaluation of current imaging results. Various
      potential clinical applications of functional imaging are briefly reviewed and
      discussed with respect to associated ethical conflicts.

PMID- 12480494
TI  - Do activated lymphocytes communicate clone-specific information to the CNS?

PMID- 12480495
TI  - Stress and the inflammatory response: a review of neurogenic inflammation.
AB  - The subject of neuroinflammation is reviewed. In response to psychological stress
      or certain physical stressors, an inflammatory process may occur by release of
      neuropeptides, especially Substance P (SP), or other inflammatory mediators, from
      sensory nerves and the activation of mast cells or other inflammatory cells.
      Central neuropeptides, particularly corticosteroid releasing factor (CRF), and
      perhaps SP as well, initiate a systemic stress response by activation of
      neuroendocrinological pathways such as the sympathetic nervous system,
      hypothalamic pituitary axis, and the renin angiotensin system, with the release
      of the stress hormones (i.e., catecholamines, corticosteroids, growth hormone,
      glucagons, and renin). These, together with cytokines induced by stress, initiate
      the acute phase response (APR) and the induction of acute phase proteins,
      essential mediators of inflammation. Central nervous system norepinephrine may
      also induce the APR perhaps by macrophage activation and cytokine release. The
      increase in lipids with stress may also be a factor in macrophage activation, as
      may lipopolysaccharide which, I postulate, induces cytokines from hepatic Kupffer
      cells, subsequent to an enhanced absorption from the gastrointestinal tract
      during psychologic stress. The brain may initiate or inhibit the inflammatory
      process. The inflammatory response is contained within the psychological stress
      response which evolved later. Moreover, the same neuropeptides (i.e., CRF and
      possibly SP as well) mediate both stress and inflammation. Cytokines evoked by
      either a stress or inflammatory response may utilize similar somatosensory
      pathways to signal the brain. Other instances whereby stress may induce
      inflammatory changes are reviewed. I postulate that repeated episodes of acute or
      chronic psychogenic stress may produce chronic inflammatory changes which may
      result in atherosclerosis in the arteries or chronic inflammatory changes in
      other organs as well.

PMID- 12480496
TI  - Chemical sympathectomy increases numbers of inflammatory cells in the peritoneum
      early in murine listeriosis.
AB  - Here, we investigated the effects of sympathectomy on systemic bacterial loads
      following infection with Listeria monocytogenes, and on innate and specific
      immune responses in the peritoneum. Sympathectomy decreased systemic bacterial
      loads, and increased the number of peritoneal leukocytes and the percentage of
      peritoneal macrophages three days postinfection. This suggests that sympathectomy
      induced decreases systemic bacterial loads are associated with increased
      recruitment of inflammatory cells into tissues during the innate immune response.

PMID- 12480497
TI  - Systemic immune parameters and sleep after ultra-low dose administration of IL-2
      in healthy men.
AB  - A somnogenic function is suspected for various cytokines. Foregoing experiments
      in humans indicated a selective increase in the production of interleukin-2 (IL
      2) during sleep as compared with nocturnal wakefulness. Here, we examined whether
      conversely, IL-2 exerts a promoting influence on sleep. Also, the effects of IL-2
      administered at ultra-low doses on systemic immune and endocrine parameters were
      assessed. Eighteen healthy men participated in three night sessions, receiving
      subcutaneously at 19:00 h either placebo or recombinant human IL-2 at doses of
      1000 and 10,000 IU/kg bw. Polysomnographical recordings were obtained between
      23:00 and 07:00 h. Blood was collected repeatedly to determine (i) white blood
      cell (WBC) counts including the enumeration of monocytes, natural killer (NK)
      cells, and lymphocyte subsets, (ii) serum concentrations of IL-2, soluble IL-2
      receptor (sIL-2r), IL-4, IL-6, and interferon-gamma (IFN-gamma), and (iii)
      concentrations of adrenocorticotropin (ACTH), cortisol, thyreotropin (TSH), and
      growth hormone (GH). Changes after 1000 IU/kg bw IL-2 generally remained non
      significant. However, distinct effects occurred after 10,000 IU/kg bw IL-2,
      inducing serum IL-2 concentrations selectively activating the high affinity IL-2
      receptor. At this dose, IL-2 reduced the number of circulating lymphocytes
      (including all major subtypes) and NK cells, while counts of monocytes and
      neutrophils were increased. IL-4 release was stimulated and IFN-gamma
      concentration reduced after IL-2. Also, IL-2 increased the TSH concentration.
      There were no hints at a sleep promoting effect of IL-2. Immune changes suggest
      that nocturnal IL-2 administration induces a shift towards Th2 mediated defense.

PMID- 12480498
TI  - The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated
      tumor necrosis factor (TNF)-alpha by blood monocytes from normal men.
AB  - Aggression, hostility, and anger significantly predict morbidity and mortality
      from atherosclerotic cardiovascular disease (ACVD). ACVD is believed to be an
      inflammatory disease characterized by increased expression of a number of
      proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha. This study
      examined the relation of aggression, hostility, and anger to monocyte-associated
      TNF-alpha expression following lipopolysaccharide (LPS) stimulation. Participants
      were 62 healthy, non-smoking men (aged 18-45 years). Hostility, anger, verbal,
      and physical aggression were assessed using the Buss-Perry aggression
      questionnaire (BPAQ). LPS-stimulated TNF-alpha expression was determined using
      dual-color flow cytometry gating for CD14(+) cells. After controlling for age,
      race, education, and alcohol use, scores on the hostility (p=.013), physical
      aggression (p=.010), and verbal aggression (p=.034) subscales, and the total
      score (p=.007) on the BPAQ were positively associated with LPS-stimulated TNF
      alpha expression. The results suggest that hostility and aggression are
      associated with an increased expression of TNF-alpha, a cytokine implicated in
      ACVD.

PMID- 12480499
TI  - TGF-beta 1 synergizes with GM-CSF to promote the generation of glial cell-derived
      dendriform cells in vitro.
AB  - Microglia are often considered a type of tissue macrophages analogous Langerhans'
      cells, while dendritic cells (DC) can be generated in vitro from cultured
      microglia in the presence of GM-CSF. In this study, we show that TGF-beta 1, in
      the presence of GM-CSF, promoted the growth and differentiation of glial cell
      derived dendritic cells (GC-DC). TGF-beta 1-driven GC-DC exhibited an immature
      state reflected by low CD11c expression, augmented endocytosis, and reduced
      antigen presentation. Expression of Fas was inhibited in GM-CSF+TGF-beta 1
      supplemented cell cultures and may relate to a long life span of GC-DC treated
      with GM-CSF+TGF-beta 1. IL-10 and IL-12 mRNA on GC-DC was not affected upon
      exposure to GM-CSF alone or to GM-CSF+IFN-gamma, GM-CSF+IL-10 or GM-CSF+TGF-beta
      1. In sharp contrast, TGF-beta 1, in the presence of GM-CSF, dramatically up
      regulated the expression of TNF-alpha and TGF-beta 1 mRNA. These results
      demonstrate that TGF-beta 1 seems to play a crucial role in the differentiation,
      functional skewing, and cytokine profile of GC-DC. TGF-beta 1-driven GC-DC awaits
      further investigation to facilitate a better understanding of the glia-T cell
      dialog as well as the pathogenesis and immunotherapy of central nervous system
      inflammatory and degenerative diseases.

PMID- 12480500
TI  - Panic disorder and immunity: few effects on circulating lymphocytes, mitogen
      response, and NK cell activity.
AB  - Altered immune measures are commonly found in major depression (MD), however,
      less is known about the immune system in anxiety disorders. We examined
      quantitative and functional in vitro immune measures in patients with panic
      disorder (PD), which is often comorbid with MD. Fourteen otherwise healthy
      medication-free adults (ages 23-49; 11 female) meeting SCID-UP DSM-IIIR criteria
      for PD with agoraphobia and without current MD, were compared with 14 subjects
      free of PD, MD, or other major psychiatric disorders, matched by gender, age, and
      racial background. PD was associated with decreased percentage (p<.03) and total
      (p<.03) circulating CD19+ B lymphocytes, but no differences in other enumerative
      lymphocyte measures. Mitogen responses (Con A, PHA, PWM) did not differ except
      for possibly decreased PHA in PD (p<.06). NK cell activity did not differ between
      PD and control subjects. The few immune measure changes in PD contrast with those
      found in MD, providing further evidence for the specificity of immune changes in
      psychiatric disorders.

PMID- 12480501
TI  - Effects of hemispheric lateralization and site specificity on immune alterations
      induced by kindled temporal lobe seizures.
AB  - The effects of kindled seizures elicited from sites in the left and right
      temporal lobes on mitogen-induced proliferation (LPS, Con A, PHA) and induction
      of representative TH1 (IFN-gamma) and TH2 (IL-10, IL-4) cytokines were determined
      in activated rat splenocytes. With reference to cell proliferation, the changes
      depended on the hemispheric side and location of kindling. Kindling of the left
      side mediated significant increase in cell proliferation by LPS. Left side
      kindling resulted in decreased cell proliferation by PHA. Although right side
      kindling showed no change when taken together, further analysis showed that the
      reduced proliferation by PHA was mediated when the pyriform cortex was kindled
      with no change from amygdaloid nuclei. Similar hemispheric polarization was
      observed in the production of IL-10 and IFN-gamma by Con A-stimulated splenocytes
      in left side kindled rats. Hence, kindled temporal lobe seizures induced changes
      in specific immune functions. These effects are not only lateralized but are also
      specific with respect to the particular region kindled. Since epileptic patients
      have altered immune functions, this report contributes to our understanding of
      this complex immune-brain cross-talk in epilepsy.

PMID- 12480502
TI  - Intracerebral HIV-1 glycoprotein 120 produces sickness behavior and pituitary
      adrenal activation in rats: role of prostaglandins.
AB  - HIV infection is associated with profound neurobehavioral and neuroendocrine
      impairments. Previous studies demonstrated that HIV causes neuropathological
      alterations indirectly, via shedding of glycoprotein 120 (gp120) within the
      brain. To extend these findings, we examined the neurobehavioral and
      neuroendocrine effects of central administration of gp120, as well as the role of
      brain prostaglandins in mediating these effects. Intracerebroventricular (i.c.v.)
      injection of gp120 in rats produced a marked sickness behavior syndrome,
      consisting of reduced exploratory behavior, suppressed consumption of food and
      saccharin solution, and reduced body weight. Gp120 also induced a significant
      febrile response and increased serum levels of ACTH and corticosterone. Following
      i.c.v. gp120 administration, the ex vivo production of PGE2 by the hypothalamus,
      frontal cortex, and hippocampus was significantly elevated, and indomethacin, a
      prostaglandin synthesis inhibitor, attenuated this elevation. Pre-treatment with
      indomethacin reduced the fever and adrenocortical activation induced by gp120
      administration, but not its behavioral effects. These findings indicate that
      gp120 may be responsible for some of the behavioral and endocrine abnormalities
      seen in HIV-infected patients. Prostaglandins are important mediators of the
      physiological, but not the behavioral effects of brain gp120.

PMID- 12480503
TI  - Neonatal sex steroids affect responses to Seoul virus infection in male but not
      female Norway rats.
AB  - Previous studies illustrate that after inoculation with Seoul virus (i.e., the
      naturally occurring hantavirus found in Norway rats), adult male rats produce
      higher antibody responses, exhibit higher Th1 responses (i.e., IgG2a, IL-2, and
      IFN gamma), and shed virus longer than females, but these difference are not
      altered by manipulation of sex steroids in adulthood. To determine whether sex
      steroid hormones organize adult responses to hantavirus infection, at 2-4 days of
      age, male rats were gonadectomized and female rats were injected with
      testosterone. As adults, animals were inoculated with 10(4)pfu of Seoul virus.
      Neonatally gonadectomized males (NGM), control females (CF), and neonatal
      testosterone-treated females (NTF) had lower anti-Seoul virus IgG and IgG2a
      responses than control males (CM) 20, 30, and 40 days post-inoculation. Neonatal
      testosterone treatment had no effect on female antibody responses to infection.
      NGM, CF, and NTF shed virus in saliva and feces for a shorter duration than CM.
      There was no effect of neonatal hormone manipulation either on the percentage of
      animals with detectable virus or on the number of virus copies within each target
      organ. Genetic males, regardless of hormone manipulation, had higher virus
      replication in lung tissue than did genetic females. Neonatal sex steroids
      influence the sexual dimorphism in host immune function but do not modify virus
      replication in target tissues.

PMID- 12480504
TI  - Increased IgG 3:4 ratios in adolescent antisocial females: evidence of Th1/Th2
      imbalance?
AB  - Female antisocial behavior in adolescence and late childhood has been associated
      with low basal cortisol levels. Because low cortisol has also been correlated
      with T helper cell Type 1 (Th1) predominance and suppression of T helper cell
      Type 2 (Th2), we investigated whether adolescent antisocial girls demonstrated
      this immunologic profile. Using plasma levels of IgG3 and IgG4 as markers for Th1
      and Th2 activity, we studied IgG 3:4 ratios in 16-year-old girls with conduct
      disorder (CD) (n=42) or no psychiatric disorder (normal controls (NC)) (n=35).
      The mean IgG 3:4 ratio was higher in the CD group; this relationship remained
      significant after controlling for the effects of other variables. These data
      indicate that immunologic abnormalities are present in adolescent antisocial
      girls. Future studies should measure cytokine levels and investigate the clinical
      implications of these findings.

PMID- 12480505
TI  - Contrasting pattern of cytokines in antigen- versus mitogen-stimulated splenocyte
      cultures from chemically denervated mice.
AB  - Sympathetic nervous system (SNS) regulation of immune function has been studied
      by ablating the SNS with a peripheral injection of the neurotoxin 6
      hydroxydopamine (6-OHDA). Our previous data indicate that sympathectomy of mice
      results in enhanced antibody production and in vitro levels of antigen-specific
      IL-2 and IFN-gamma. Other investigators have observed either increased or
      decreased immune function following sympathectomy. Here we present data showing
      that culture supernatants from spleen cells from the same denervated animals
      contain increased IL-2 and IFN-gamma levels in response to antigen-specific
      (keyhole limpet hemocyanin (KLH)) stimulation, but decreased cytokines levels in
      response to the T cell mitogen Con A compared to vehicle control mice. KLH
      induced type 2 cytokines were also increased; no decrease in Con A-stimulated
      type 2 cytokines was observed. We evaluated whether the antigen presenting cell
      (APC) or the T cell might be the main target of the observed sympathectomy
      effects. Cell separation and mixing experiments suggest that the sympathectomy
      induced alterations of antigen-specific and mitogen-induced type 1 cytokines are
      mediated primarily via the T cell. These data directly address some apparent
      discrepancies in the literature, and highlight potential regulatory sites to be
      further investigated in pathways of neural-immune communication.

PMID- 12480506
TI  - Inflammatory cytokines, socioeconomic status, and acute stress responsivity.
AB  - Socioeconomic status is a major determinant of coronary heart disease (CHD).
      Proinflammatory cytokines are implicated in the etiology of CHD, and are also
      sensitive to emotional stress. We hypothesised that concentration of interleukin
      6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 receptor
      antagonist (IL-1Ra) would be inversely related to socioeconomic status, and that
      cytokine responses to stress would be associated with SES. One hundred and twenty
      five middle-aged men and 105 women from the Whitehall II epidemiological cohort
      were tested, and socioeconomic status was indexed by grade of employment, with
      participants divided into high, intermediate, and low status groups. Plasma
      concentrations at rest of TNF-alpha, IL-1Ra, and IL-6 (women only) were
      associated with socioeconomic status, with lower levels in the high status group,
      but the effect was non-linear. There was no relationship between socioeconomic
      status and cytokine responses to stress, but sex differences were observed, with
      men showing greater TNF-alpha, and women greater IL-6 and IL-1Ra increases. The
      role of inflammatory cytokines in mediating psychosocial influences on CHD is
      discussed.

PMID- 12480507
TI  - Stress-induced augmentation of immune function--the role of stress hormones,
      leukocyte trafficking, and cytokines.
AB  - Delayed-type hypersensitivity (DTH) reactions represent cell-mediated immune
      responses that exert important immunoprotective (resistance to viruses, bacteria,
      and fungi) or immunopathological (allergic or autoimmune hypersensitivity)
      effects. We initially utilized the skin DTH response as an experimental in vivo
      model to study neuro-endocrine-immune interactions in rodents. We hypothesized
      that just as an acute stress response prepares the cardiovascular and
      musculoskeletal systems for fight or flight, it may also prepare the immune
      system for challenges which may be imposed by a stressor. The skin DTH model
      allowed us to examine the effects of stress at the time of primary and secondary
      exposure to antigen. Studies showed that acute (2h) stress experienced before
      primary or secondary antigen exposure induces a significant enhancement of skin
      DTH. Importantly, this enhancement involved innate as well as adaptive immune
      mechanisms. Adrenalectomy eliminated the stress-induced enhancement of DTH. Acute
      administration of physiological (stress) concentrations of corticosterone and/or
      epinephrine to adrenalectomized animals enhanced skin DTH. Compared with
      controls, DTH sites from acutely stressed or hormone-injected animals showed
      significantly greater erythema and induration, numbers of infiltrating
      leukocytes, and levels of cytokine gene expression. In contrast to acute stress,
      chronic stress was immunosuppressive. Chronic exposure to corticosterone, or
      acute exposure to dexamethasone significantly suppressed skin DTH. These results
      suggest that during acute stress, endogenous stress hormones enhance skin
      immunity by increasing leukocyte trafficking and cytokine gene expression at the
      site of antigen entry. While these results are discussed from a mechanistic and
      clinical relevance perspective, it is acknowledged that much work remains to be
      done to elucidate the precise mechanisms mediating these bi-directional effects
      of stress and stress hormones and their clinical ramifications.

PMID- 12480508
TI  - Regulated expression of alpha-1 adrenergic receptors in the immune system.
AB  - The catecholamines norepinephrine and epinephrine are used by the sympathetic
      nervous system to communicate with other organ systems, including the immune
      system. Adrenergic receptors on target cells bind these catecholamines and
      modulate the activity of the target cell. The beta 2-adrenergic receptor is the
      most abundantly expressed and best studied adrenergic receptor in the immune
      system. Here, I summarize data from our own laboratory and from others on the
      expression and possible function of alpha 1-adrenergic receptors in the immune
      system. alpha 1-Adrenergic receptor expression in the immune system can be
      regulated by glucocorticoids, by beta 2-adrenergic agonists, and by cytokines. In
      addition, the possible pathophysiological implications of the expression of alpha
      1-adrenergic receptors on immune cells from arthritis patients are discussed.

PMID- 12480509
TI  - Functional recovery after facial nerve crush is delayed in severe combined
      immunodeficient mice.
AB  - The goal of the current study was to determine if T and B lymphocytes play a role
      in functional recovery after peripheral nerve injury. The time course of
      behavioral recovery following facial nerve crush injury at the stylomastoid
      foramen was established in scid mice which lack functional T and B cells and
      reconstituted scid mice as compared to wild-type mice. The average time necessary
      for recovery of full eye blink reflex and vibrissae movements in wild-type mice
      was 10.3+/-0.2 and 9.9+/-0.34 days, respectively. In contrast, recovery of full
      eye blink reflex and vibrissae movements took 14.8+/-0.54 and 12.3+/-0.41 days,
      respectively, in scid mice. Reconstitution of scid mice with whole splenocytes
      resulted in functional recovery times similar to wild-type, with eye blink reflex
      recovery and vibrissae movement being 10.5+/-0.3 and 10.0+/-0.0 days,
      respectively. These results suggest that the delayed behavioral recovery time
      observed in scid mice may be due to the absence of T and B lymphocytes.

PMID- 12480510
TI  - Acupuncture has no immediate treatment effect on the neutrophil respiratory
      burst: a randomized single-blinded two-period crossover study.
AB  - Little is known about the influence of acupuncture treatment on the immune
      system. The respiratory burst (RB) of polymorphonuclear leukocytes (PMN) is a
      recognized measure of their cytotoxicity, an important component of the immune
      system. The present trial was therefore performed to examine whether a single
      acupuncture treatment has an immediate effect on the RB of neutrophil PMNs.
      Sixteen volunteers were enrolled in the study. After randomization, eight
      volunteers were treated bilaterally with standard needles at acupoint LI11 and
      eight volunteers with placebo needles at the same acupoint, each for 30 min. The
      RB was determined before and 30 min after treatment. After two weeks, each group
      received the alternative treatment. There was a drop-out of two volunteers. No
      period or carryover effects were found in the remaining fourteen volunteers. No
      effect of acupuncture on the neutrophil RB was observed.

PMID- 12480512
TI  - A conversation with Saul Roseman.

PMID- 12480511
TI  - Multiple roles of cysteine in biocatalysis.
AB  - In biology, sulfur frequently occurs in the form of cysteine, an amino acid that
      fulfills a wide range of different functions in proteins including disulfide
      formation, metal-binding, electron donation, hydrolysis, and redox-catalysis. The
      'redox-chameleon' sulfur appears in several oxidation states in vitro, each of
      them exhibiting specific reactivity, redox-activity, and metal-binding
      properties. While cysteine-peptidases rely on reduced cysteine to catalyze
      hydrolytic reactions, many redox-enzymes use distinctively different cysteine
      redox-couples for exchange, electron, atom, and radical transfer reactions.
      Although cysteine and cystine can still be considered as the most abundant forms
      of cysteine in vivo, other modifications such as cysteine acids and sulfur
      centered radicals are becoming increasingly important in biochemical research. As
      such, the biochemistry of sulfur remains a source of continuous investigation and
      excitement.

PMID- 12480513
TI  - Xenopus hoxc8 during early development.
AB  - Vertebrate hoxc8 homologous genes have been shown to be involved in the formation
      of lower thoracic/lumbar vertebrae during early embryonic development. We report
      the isolation of a Xenopus hoxc8 (Xhoxc8), which shows 94% amino acid sequence
      identity to the mouse counterpart. Xhoxc8 is initially expressed in a broad
      region of blastopore lip at gastrular stage; however, at later stages, the region
      of expression is progressively restricted to the dorsal region caudal to the
      third somite and to the central trunk region of abdomen. Retinoic acid treatment
      that caused a severe malformation in antero-posterior axis did not induce any
      significant change in the spatio-temporal expression pattern of Xhoxc8 mRNA.
      Antisense RNA injection into 2- or 4-cell stage embryos resulted in a severe
      malformation in the abdominal structure leading to embryonic death. The results
      strongly indicate that Xhoxc8 expression is critical for the formation of
      abdominal structure.

PMID- 12480514
TI  - Reversibility of established diabetic glomerulopathy by anti-TGF-beta antibodies
      in db/db mice.
AB  - Treatment with a neutralizing anti-transforming growth factor-beta (TGF-beta)
      antibody can prevent the development of diabetic nephropathy in the db/db mouse,
      a model of type 2 diabetes. However, it is unknown whether anti-TGF-beta therapy
      can reverse the histological lesions of diabetic glomerulopathy once they are
      established. Diabetic db/db mice and their non-diabetic db/m littermates were
      allowed to grow until 16 weeks of age, by which time the db/db mice had developed
      glomerular basement membrane (GBM) thickening and mesangial matrix expansion. The
      mice were then treated with an irrelevant control IgG or a panselective,
      neutralizing anti-TGF-beta antibody for eight more weeks. Compared with control
      db/m mice, the db/db mice treated with IgG had developed increased GBM width
      (16.64+/-0.80 nm vs. 21.55+/-0.78 nm, P<0.05) and increased mesangial matrix
      fraction (4.01+/-0.81% of total glomerular area vs. 9.55+/-1.04%, P<0.05).
      However, the db/db mice treated with anti-TGF-beta antibody showed amelioration
      of GBM thickening (18.40+/-0.72 nm, P<0.05 vs. db/db-IgG) and mesangial matrix
      accumulation (6.32+/-1.79%, P<0.05 vs. db/db-IgG). Our results demonstrate that
      inhibiting renal TGF-beta activity can partially reverse the GBM thickening and
      mesangial matrix expansion in this mouse model of type 2 diabetes. Anti-TGF-beta
      regimens would be useful in the treatment of diabetic nephropathy.

PMID- 12480515
TI  - Fluorescence polarization: a novel indicator of cardiomyocyte contraction.
AB  - The changes measured in intracellular fluorescein fluorescence polarization
      (IFFP) are used as a new tool for tracing cytoplasmic effects during contractile
      cycles of cardiac myocytes (1-2-day-old rat hearts), in addition to the
      established Ca(2+) monitoring and/or videometric methods of tracking cell
      shortening. This novel method was found to be non-intrusive to the contraction
      cycles. The decay of the transient IFFP signal (from 0.220+/-0.01 to 0.170+/
      0.013) seems to be closely related to the extended phase of contractile
      activation. This fact was further supported when Ca(2+) exchanger inhibitor was
      introduced and significantly decreased (90%) the rate of beats of contraction and
      IFFP, but not the Ca(2+) beat rate changes. This result suggests that the IFFP
      indicator is probably associated with the physiological activation, rather than
      with Ca(2+) alterations. The IFFP measure monitors the average of effective
      changes in the micro-viscosity of the cytoplasm protein matrix, associated with
      cellular activation.

PMID- 12480516
TI  - Fluorescence and folding properties of Tyr mutant tryptophan synthase alpha
      subunits from Escherichia coli.
AB  - The fluorescence of tyrosine has been used to monitor a folding process of
      tryptophan synthase alpha-subunit from Escherichia coli, because this protein has
      7 tyrosines, but not tryptophan. Here to assess the contribution of each Tyr to
      fluorescence properties of this protein during folding, mutant proteins in which
      Tyr was replaced with Phe were analyzed. The result shows that a change of Tyr
      fluorescence occurring during folding of this protein is contributed to
      approximately 40% each by Tyr(4) and Tyr(115), and to the remaining approximately
      20% by Tyr(173) and Tyr(175). Y173F and Y175F mutant proteins showed an increase
      in their fluorescence intensity by approximately 40% and approximately 10%,
      respectively. These increases appear to be due to multiple effects of increased
      hydrophobicity, quenching effect of nearby residue Glu(49), and/or energy
      transfer between Tyrs. Two data for Y173F alpha-subunit of urea-induced unfolding
      equilibrium monitored by UV and fluorescence were different. This result,
      together with ANS binding and far UV CD, shows that folding intermediate(s) of
      Y173F alpha-subunit, contrary to that of wild-type, may contain self-inconsistent
      properties such as more buried hydrophobicity, highly quenched fluorescence, and
      different dependencies on urea of UV absorbance, suggesting an ensemble of
      heterogeneous structures.

PMID- 12480518
TI  - Structure of human alpha1-acid glycoprotein and its high-affinity binding site.
AB  - Secondary and tertiary structures of human blood alpha(1)-acid glycoprotein, a
      member of the lipocalin family, have been studied for the first time by infrared
      and Raman spectroscopies. Vibrational spectroscopy confirmed details of the
      secondary structure and the structure content predicted by homology modeling of
      the protein moiety, i.e., 15% alpha-helices, 41% beta-sheets, 12% beta-turns, 8%
      bands, and 24% unordered structure at pH 7.4. Our model shows that the protein
      folds as a highly symmetrical all-beta protein dominated by a single eight
      stranded antiparallel beta-sheet. Thermal dynamics in the range 20-70 degrees C
      followed by Raman spectroscopy and analyzed by principle component analysis
      revealed full reversibility of the protein motion upon heating dominated by
      decreasing of beta-sheets. Raman difference spectroscopy confirmed the proximity
      of Trp(122) to progesterone binding.

PMID- 12480517
TI  - Characterization of two Cu-containing protein fragments obtained by limited
      proteolysis of Hyphomicrobiumdenitrificans A3151 nitrite reductase.
AB  - The unusual Hyphomicrobium denitrificans nitrite reductase containing two type 1
      Cu sites and one type 2 Cu site (MW, 50 kDa) has been proteolyzed to two protein
      fragments (14 and 35 kDa) with subtilisin. The visible absorption, CD, and EPR
      spectra of these proteins imply that the blue 14-kDa protein fragment has one
      type 1 Cu site, which is axially elongated trigonal bipyramidal, and the green 35
      kDa protein fragment has one type 1 Cu site having a flattened tetrahedral
      geometry with one type 2 Cu site. The 35-kDa fragment shows the nitrite reduction
      activity a little higher than to that of native HdNIR. The redox potentials of
      the 14- and 35-kDa fragments are +345 and +353mV vs. NHE at pH 7.0, respectively.
      Moreover, the intermolecular electron transfer rate constant of the 35-kDa
      fragment from an electron donor, cognate cytochrome c(550), is nearly the same as
      that of the native enzyme.

PMID- 12480519
TI  - Implication of the exon region in the regulation of the human telomerase reverse
      transcriptase gene promoter.
AB  - The expression of the catalytic subunit (hTERT) represents the limiting factor
      for telomerase activity. In transfection studies, high level of activity of hTERT
      promoter is found, whereas low copy numbers of hTERT mRNA are detected in vivo.
      To explain this discrepancy, a series of vectors containing the hTERT promoter
      and gene were transiently transfected into HeLa cells. Four important regions
      were identified. First, the core promoter has bidirectional activity. Second, the
      distal upstream region (-1821 to -811bp) involved in the splicing of the first
      intron and could be a key of splicing specificity. Third, the intermediate
      promoter region (-800 to -300bp) could play an important role in silencing the
      reverse promoter activity. Fourth, the structural gene (up to +1077) strongly
      reduced hTERT promoter activity. These results provide the first evidence that
      the first two exons play a major role in the down-regulation of the hTERT
      promoter in telomerase-positive cells.

PMID- 12480520
TI  - Differences in the betaC-S lyase activities of viridans group streptococci.
AB  - betaC-S Lyase catalyzes the alpha,beta-elimination of L-cysteine to hydrogen
      sulfide, which is one of the main causes of oral malodor and is highly toxic to
      mammalian cells. We evaluated the capacity of six species of oral streptococci to
      produce hydrogen sulfide. The crude enzyme extract from Streptococcus anginosus
      had the greatest capacity. However, comparative analysis of amino acid sequences
      did not detect any meaningful differences in the S. anginosus betaC-S lyase. The
      capacity of S. anginosus purified betaC-S lyase to degrade L-cysteine was also
      extremely high, while its capacity to degrade L-cystathionine was unremarkable.
      These findings suggest that the extremely high capacity of S. anginosus to
      produce hydrogen sulfide is due to the unique characteristic of betaC-S lyase
      from that organism.

PMID- 12480521
TI  - Exchange characteristics of calcium ions bound to anthrax protective antigen.
AB  - Protective antigen (PA), the receptor-binding moiety of anthrax toxin, contains
      two calcium atoms buried within domain 1(') (amino acid residues 168-258). We
      showed that these ions are stably bound and exchange with free 45Ca(2+) only
      slowly (t(1/2) approximately 4.0 h). Dissociation is the rate-limiting step.
      PA(63), the heptameric prepore form of PA, showed a slightly higher exchange rate
      than the monomeric intact protein. Exchange by this form was retarded by binding
      of the enzymatic moieties of the toxin, but was unaffected by reducing the pH to
      5.0, a condition known to trigger conversion of the prepore to the pore form.
      These results are consistent with the hypothesis that bound Ca(2+) within PA
      plays primarily a structural role, maintaining domain 1(') in a conformation that
      allows PA(63) to oligomerize and bind the enzymatic moieties of the toxin.

PMID- 12480523
TI  - Carnosine promotes the heat denaturation of glycated protein.
AB  - Glycation alters protein structure and decreases biological activity. Glycated
      proteins, which accumulate in affected tissue, are reliable markers of disease.
      Carnosine, which prevents glycation, may also play a role in the disposal of
      glycated protein. Carnosinylation tags glycated proteins for cell removal. Since
      thermostability determines cell turnover of proteins, the present study examined
      carnosine's effect on thermal denaturation of glycated protein using cytosolic
      aspartate aminotransferase (cAAT). Glycated cAAT (500 microM glyceraldehyde for
      72h at 37 degrees C) increased the T(0.5) (temperature at which 50% denaturation
      occurs) and the Gibbs free energy barrier (DeltaG) for denaturation. The enthalpy
      of denaturation (DeltaH) for glycated cAAT was also higher than that for
      unmodified cAAT, suggesting that glycation changes the water accessible surface.
      Carnosine enhanced the thermal unfolding of glycated cAAT as evidenced by a
      decreased T(0.5) and a lowered Gibbs free energy barrier. Additionally, carnosine
      decreased the enthalpy of denaturation, suggesting that carnosine may promote
      hydration during heat denaturation of glycated protein.

PMID- 12480522
TI  - Choline head groups stabilize the matrix loop regions of the ATP/ADP carrier
      ScAAC2.
AB  - ATP/ADP carriers (AACs) are essential to the cell as they exchange ATP produced
      in mitochondria for cytosolic ADP. Monoclonal antibodies against the isoform 2 of
      Saccharomyces cerevisiae AAC (ScAAC2) were used to probe the accessibility of the
      matrix loops 1 and 3 depending on the environment of the carrier. In
      mitochondrial membranes ScAAC2 was not recognized, whereas in dodecylmaltoside
      the antibodies bound to the carrier, suggesting that the epitopes are hidden in
      the native environment. Exposure of the epitopes by detergents was reversed by
      reconstitution of the carrier in phospholipids or by exchanging with detergents
      having a choline or a trimethylammonium head group. Circular dichroism
      spectroscopy on peptides representing the C-terminal regions of all three matrix
      loops showed that only phosphocholine detergents induced a structural
      reorganization. Since in addition phosphatidylcholine was found to be tightly
      associated with the purified carrier, the matrix loop regions are likely to be
      associated to the membrane by phosphatidylcholine.

PMID- 12480524
TI  - Inhibition of mammalian ribonucleases by endogenous adenosine dinucleotides.
AB  - The most potent low molecular weight inhibitors of pancreatic RNase superfamily
      enzymes reported to date are synthetic derivatives of adenosine 5(')
      pyrophosphate. Here we have investigated the effects of six natural nucleotides
      that also incorporate this moiety (NADP(+), NADPH, ATP, Ap(3)A, Ap(4)A, and
      Ap(5)A) on the activities of RNase A and two of its homologues, eosinophil
      derived neurotoxin and angiogenin. With eosinophil-derived neurotoxin and
      angiogenin, Ap(5)A is comparable to the tightest binding inhibitors identified
      previously (K(i) values at pH 5.9 are 370 nM and 100 microM, respectively); it
      ranks among the strongest small antagonists of RNase A as well (K(i)=230 nM). The
      K(i) for NADPH with angiogenin is similar to that of Ap(5)A. These findings
      suggest that Ap(5)A and NADPH may serve as useful new leads for inhibitor design.
      Examination of inhibition under physiological conditions indicates that NADPH,
      ATP, and Ap(5)A may suppress intracellular RNase activity significantly in vivo.

PMID- 12480525
TI  - Influence of TFIIIA-type linker at the N- or C-terminal of nine-zinc finger
      protein on DNA-binding site.
AB  - The central three-zinc finger connection of the native nine-zinc finger protein
      transcription factor IIIA (TFIIIA) is composed of unique linker sequences, 
      NIKICV-, -TQQLP-, -AG-, and -QDL-. New artificial nine-zinc finger proteins,
      Sp1ZF9TC and Sp1ZF9TN, which use the TFIIIA-type linker for their C- and N
      terminal three-zinc finger connections have been created. To investigate the
      influence of TFIIIA-type linker sequences by their different locations in the
      proteins, gel mobility shift assays (GMSA), DNase I footprinting assays,
      methylation interference analyses, and hydroxyl radical footprinting assays were
      performed. The GMSA revealed similar DNA-binding affinities of these two
      proteins. The footprinting analyses indicated that the two zinc finger proteins
      recognize the same part of GCII or GCIII DNA. Moreover, the specific base
      contacts were observed in the same sites of the substrate DNA. In the present
      proteins, Sp1ZF9TC and Sp1ZF9TN, the four zinc fingers (fingers 1-4 or 5-9)
      situated in the site opposite to the TFIIIA-type linker position participate in
      their DNA bindings. The position of the TFIIIA-type linker is important in DNA
      recognition by multi-zinc finger proteins.

PMID- 12480526
TI  - Cloning and characterization of the glycogen branching enzyme gene existing in
      tandem with the glycogen debranching enzyme from Pectobacterium chrysanthemi
      PY35.
AB  - The glycogen branching enzyme gene (glgB) from Pectobacterium chrysanthemi PY35
      was cloned, sequenced, and expressed in Escherichia coli. The glgB gene consisted
      of an open reading frame of 2196bp encoding a protein of 731 amino acids
      (calculated molecular weight of 83,859Da). The glgB gene is upstream of glgX and
      the ORF starts the ATG initiation codon and ends with the TGA stop codon at 2bp
      upstream of glgX. The enzyme was 43-69% sequence identical with other glycogen
      branching enzymes. The enzyme is the most similar to GlgB of E. coli and
      contained the four regions conserved among the alpha-amylase family. The glycogen
      branching enzyme (GlgB) was purified and the molecular weight of the enzyme was
      estimated to be 84kDa by SDS-PAGE. The glycogen branching enzyme was optimally
      active at pH 7 and 30 degrees C.

PMID- 12480527
TI  - Differential expression of CYP102 in Bacillus megaterium by 17-beta-estradiol and
      4-sec-butylphenol.
AB  - Previously we have reported the induction of CYP102 in Bacillus megaterium by
      17beta-estradiol (E2) and 4-sec-butylphenol (4-sBP). Electrophoretic mobility
      shift assay analyses demonstrated that E2 and 4-sBP both cause a dose-dependent
      disassociation of the Bm3R1 repressor protein from its binding site on the
      operator sequence of the CYP102 gene. Equimolar combinations of E2 and 4-sBP
      demonstrated additive induction of CYP102 compared to equivalent samples of E2
      and 4-sBP added alone. Two gene constructs were used in this investigation. One
      construct designated BMC143 contained the entire regulatory region of CYP102. The
      other gene construct, designated BMA45, had the "Barbie box" sequence deleted.
      While the induction of CYP102 by 4-sBP was much higher in the BMC 143 construct,
      E2 induced CYP102 in both constructs to the same extent. This difference in
      induction of CYP102 by these two inducers indicates that they act at different
      sites, either on the Bm3R1 repressor protein or on positive regulatory sites, or
      that they act, in part, through different mechanisms.

PMID- 12480528
TI  - DNA adduct formation by the ubiquitous environmental pollutant 3
      nitrobenzanthrone and its metabolites in rats.
AB  - Diesel exhaust is known to induce tumours in animals and is suspected of being
      carcinogenic in humans. Of the compounds found in diesel exhaust, 3
      nitrobenzanthrone (3-NBA) is an extremely potent mutagen and suspected human
      carcinogen forming multiple DNA adducts in vitro. 3-Aminobenzanthrone (3-ABA), 3
      acetylaminobenzanthrone (3-Ac-ABA), and N-acetyl-N-hydroxy-3-aminobenzanthrone (N
      Ac-N-OH-ABA) were identified as 3-NBA metabolites. In order to gain insight into
      the pathways of metabolic activation leading to 3-NBA-derived DNA adducts we
      treated Wistar rats intraperitoneally with 2mg/kg body weight of 3-NBA, 3-ABA, 3
      Ac-ABA, or N-Ac-N-OH-ABA and compared DNA adducts present in different organs.
      With each compound either four or five DNA adduct spots were detected by TLC in
      all tissues examined (lung, liver, kidney, heart, pancreas, and colon) using the
      nuclease P1 or butanol enrichment version of the 32P-postlabelling method,
      respectively. Using HPLC co-chromatographic analysis we showed that all major 3
      NBA-DNA adducts produced in vivo in rats are derived from reductive metabolites
      bound to purine bases and lack an N-acetyl group. Our results indicate that 3-NBA
      metabolites (3-ABA, 3-Ac-ABA and N-Ac-N-OH-ABA) undergo several
      biotransformations and that N-hydroxy-3-aminobenzanthrone (N-OH-ABA) appears to
      be the common intermediate in 3-NBA-derived DNA adduct formation. Therefore, 3
      NBA-DNA adducts are useful biomarkers for exposure to 3-NBA and its metabolites
      and may help to identify enzymes involved in their metabolic activation.

PMID- 12480529
TI  - Integration efficiency of a hybrid adenoretroviral vector.
AB  - The frequency with which the hybrid vector AdLTR-luc mediates genomic integration
      [Nat. Biotech. 18 (2000) 176-180] is unknown. To address this, we constructed
      AdLTR-red, using the AdLTR-luc backbone and the enhanced red fluorescence protein
      cDNA. Kinetic studies showed that AdLTR-red and a conventional adenoviral vector,
      AdCMV-red, entered and transduced epithelial cells comparably. AdLTR-red
      integration frequency in vitro, i.e., the percentage of red clones after 10-12
      doubling times from limiting dilutions, was 8.0% (36/450; at 67 particles/cell).
      With AdCMV-red, 0/549 clones were integration-positive. Seven days after AdLTR
      luc or AdCMV-luc (10(11) particles) femoral vein administration to adult rats
      splenocytes were prepared, stimulated with concanavalin A, and examined by FISH.
      AdLTR-luc integration occurred in 5-11% of mitotic rat splenocytes, while no
      unequivocal integration was found with AdCMV-luc. These data provide the first
      quantitative evidence of the frequency for genomic integration with this hybrid
      vector.

PMID- 12480530
TI  - Cybip, a starfish cyclin B-binding protein, is involved in meiotic M-phase exit.
AB  - We designed a screen to identify starfish oocyte proteins able to bind monomeric
      cyclin B by affinity chromatography on a cyclin B splice variant displaying low
      affinity for cdc2. We identified a 15kDa protein previously described as a cdk
      binding protein [Biochim. Biophys. Acta Mol. Cell Res. 1589 (2002) 219-231].
      Cybip is encoded by a single polymorphic gene and the native protein is matured
      by cleaving a signal peptide. We firmly establish the fact that it is a true
      cyclin B-binding protein, since the recombinant protein binds recombinant cyclin
      B in absence of any cdk. Finally, we show that the microinjection of GST-cybip,
      and of anti-cybip antibody, in maturing starfish oocytes, inhibits H1 kinase and
      MPF inactivation, and first polar body emission.

PMID- 12480531
TI  - Possible involvement of aryl hydrocarbon receptor (AhR) in adult T-cell leukemia
      (ATL) leukemogenesis: constitutive activation of AhR in ATL.
AB  - Human T-cell leukemia virus type 1 is the etiologic agent of adult T-cell
      leukemia (ATL), although the precise mechanism involved in the transformation
      process has not yet been defined. The aryl hydrocarbon receptor (AhR) is a ligand
      activated transcription factor that can influence cell proliferation and
      differentiation. We investigated the expression and activation of AhR in ATL. RT
      PCR and Western blot analyses showed high expression levels of AhR in ATL cell
      lines. The elevated expression of AhR was in part attributable to the action of
      the viral transactivator protein, Tax. Interestingly, activation of the AhR was
      found in ATL cell lines in the absence of apparent exogenous ligands.
      Importantly, the increased expression and activation of AhR were also observed in
      some primary ATL cells. To our best knowledge, this is the first report to show
      the lymphoid malignancy having constitutive activation of AhR. A possible link
      between increased AhR expression and leukemogenesis in ATL is discussed.

PMID- 12480532
TI  - Dimerization of the Polycomb-group protein Mel-18 is regulated by PKC
      phosphorylation.
AB  - The Polycomb-group (Pc-G) gene products form complexes via protein-protein
      interactions and maintain the transcriptional repression of genes involved in
      embryogenesis, cell cycle, and tumorigenesis. Previously, we have shown that
      mouse Mel-18, a Pc-G protein, has tumor suppressor gene-like activity and
      negatively regulates transcription. Here, we show in vitro by pull-down assays
      and in vivo in transiently transfected COS-7 cells that Mel-18 forms homodimers.
      Deletion analysis revealed that the N-terminal RING-finger and alpha-helix
      domains are required for homodimer formation. In addition, we demonstrated that
      Mel-18 homo-dimerization is regulated by protein kinase C (PKC) and protein
      phosphatases, such that dephosphorylated Mel-18 is able to homo-dimerize. These
      results suggest that the stoichiometry and/or equilibrium of subunits of the
      class II Polycomb complex containing Mel-18 might be regulated by changes in
      phosphorylation status via the PKC signaling pathway.

PMID- 12480533
TI  - Phosphorylation-dependent cleavage of p130cas in apoptotic rat-1 cells.
AB  - We previously demonstrated caspase-mediated cleavage of p130cas during apoptosis
      and identified two caspase-3 cleavage sites [1]. In this study, we investigated
      the phosphorylation-dependent cleavage of p130cas in apoptotic Rat-1 fibroblast
      cells. Lysophosphatidic acid and fibronectin induced p130cas phosphorylation,
      which in turn resulted in resistance to caspase-mediated cleavage. Alternatively,
      dephosphorylation by calf intestinal alkaline phosphatase, PP1, and LAR
      stimulated cleavage of p130cas by caspase-3, generating a 31-kDa fragment. During
      apoptosis, p130cas dephosphorylation seems to precede its cleavage. The
      phosphorylation of tyrosine and serine residues immediately adjacent to the two
      cleavage sites (DVPD(416) and DSPD(748)) strongly affected p130cas cleavage by
      caspase-3, both in vitro and in vivo. Furthermore, the generation of the 31-kDa
      cleavage fragment was strongly regulated by phosphorylation of a tyrosine residue
      at position 751 (DSPD(748) and GQY(751)). Our results collectively suggest that
      degradation of p130cas during apoptosis is modulated in a phosphorylation
      dependent manner.

PMID- 12480534
TI  - The activation of glycolysis performed by the non-phosphorylating glyceraldehyde
      3-phosphate dehydrogenase in the model system.
AB  - Influence of non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPN)
      on glycolysis was investigated. The addition of GAPN-which oxidizes
      glyceraldehyde-3-phosphate directly to the 3-phosphoglyceric acid-led to the
      strong increase in the rate of lactate accumulation in the rat muscle extract
      with low ADP content. The lactate accumulation was also observed in the presence
      of GAPN in rat muscle extract, which contained only ATP and no ADP. This can be
      the evidence of the "futile cycle" stimulated by GAPN. Here ADP can be
      regenerated from ATP by the phosphoglycerate kinase reaction. The high resistance
      of GAPN from Streptococcus mutans towards inactivation by natural oxidant
      H(2)O(2) was showed. This feature distinguishes GAPN from phosphorylating
      glyceraldehyde-3-phosphate dehydrogenase, which is very sensitive to modification
      by hydrogen peroxide. A possible role of the oxidants and non-phosphorylating
      glyceraldehyde-3-phosphate dehydrogenase in the regulation of glycolysis is
      discussed.

PMID- 12480535
TI  - Association of phospholamban with a cGMP kinase signaling complex.
AB  - The cGMP kinase signaling complex identified previously in tracheal smooth muscle
      membranes contains a number of cGMP kinase substrates termed G0 through G4. G0,
      G1, and G2 were identified as IP(3) receptor I (IP(3)RI), IRAG, and cGMP kinase
      I. Sequencing of purified G3 and G4 showed that these proteins were proteolytic
      cleavage products of IRAG. However, the purified cGMP kinase signaling complex
      contained following additional proteins: alpha-actin, calponin H1, and
      phospholamban (PLB) as verified by MALDI-TOF as well as MS/MS sequencing and
      immune detection. The complex of these six proteins was immune precipitated by
      antibodies to each protein. The proteins were phosphorylated by the endogenous
      cGMP kinase I with the exception of alpha-actin and calponin H1. The complex did
      not contain the Ca(2+)-ATPase SERCA II. PLB, IP(3)RI, and cGMP kinase Ibeta were
      co-immune precipitated after expression in COS-7 cells. These results suggest
      that PLB may have additional functions to regulate the activity of SERCA II.

PMID- 12480536
TI  - Comparative modeling of the N-terminal domain of the 67kDa laminin-binding
      protein: implications for putative ribosomal function.
AB  - Laminin-binding protein/p40 (LBP/p40) precursor appears to be involved in two
      seemingly unrelated activities-cell adhesion and ribosomal biogenesis. Analysis
      of primary structure revealed a two-domain organization of the LBP/p40. The N
      terminal portion of LBP is similar to the S2 family of prokaryotic ribosomal
      proteins, while the C-terminus is unique for Metazoa and is involved in
      extraribosomal functions. To gain insight into putative ribosomal functions of
      LBP we performed comparative modeling of the N-terminal domain using crystal
      structures of S2p from Thermus thermophilus. The LBP model assumes an alpha-beta
      sandwich fold similar to that of S2. Modeling revealed the loss of a significant
      portion of ribosomal RNA (rRNA) interaction domain, lack of conservation of many
      residues involved in interactions with rRNA, and a major shift in surface charge
      distribution (compared to the S2 protein). The overall stability of the fold
      argues against a proposed transmembrane domain in the central part of the
      protein. Partial overlap in S2 and laminin-binding domains suggests that
      ribosomal and surface receptor functions would be mutually exclusive. The
      possible biological role of LBP/p40 bifunctionality is discussed.

PMID- 12480537
TI  - Late onset of obesity in male androgen receptor-deficient (AR KO) mice.
AB  - An androgen receptor (AR) null mutant mice line was generated by means of a Cre
      lox P system. The male (AR(L-/Y)) (KO) mice exhibited typical features of
      testicular feminization mutant (Tfm) disease in external reproductive organs with
      growth retardation. The growth curve of the male AR KO mice was similar to that
      of the wild-type female littermates until the 10th week of age, but thereafter a
      drastic increase in the growth was observed with development of obesity. Clear
      increase in the wet weights of white adipose tissues, but not of brown adipose
      tissue, was found in the 30-week-old male AR KO mice. However, no significant
      alteration in serum lipid parameters and food intake was observed. Thus, the
      present results suggest that AR may serve as a negative regulator of adipose
      development in adult males.

PMID- 12480538
TI  - Acetylcholine promotes the proliferation and collagen gene expression of
      myofibroblastic hepatic stellate cells.
AB  - The mechanisms that initiate and perpetuate the fibrogenic response, during liver
      injury, are unclear. Animal studies, however, strongly support a role for the
      autonomic nervous system (ANS) in wound healing. Therefore, the ANS may also
      mediate the development of cirrhosis. Hepatic stellate cells (HSC), the liver's
      major matrix-producing cells, are activated by injury to become proliferative,
      fibrogenic myofibroblasts. HSC respond to sympathetic neurotransmitters by
      changing phenotype, suggesting that HSC may be the cellular effectors of ANS
      signals that modulate hepatic fibrogenesis during recovery from liver damage. We
      show here that the parasympathetic neurotransmitter acetylcholine markedly
      stimulates the proliferation of myofibroblastic HSC and induces HSC collagen gene
      expression in these cells. By extending evidence that HSC are direct targets of
      the ANS, these results support the proposed neuroglial role of HSC in the liver
      and suggest that interrupting ANS signalling may be useful in constraining the
      fibrogenic response to liver injury.

PMID- 12480539
TI  - DNazyme-mediated cleavage of Twist transcripts and increase in cellular
      apoptosis.
AB  - DNazymes is a group of catalytic nucleic acids that can be designed to cleave
      target mRNA molecules in a base-specific way. Twist is a basic helix-loop-helix
      transcription factor that is involved in the regulation of cellular
      differentiation and apoptosis. Moreover, it was shown to function in skull
      development and cause craniosynostosis. DZ-TWT DNazyme was designed to down
      regulate Twist expression. The ability of DZ-TWT to cleave mouse Twist mRNA was
      first shown in a cell-free environment against full-length Twist mRNA. Following
      transfections of the DZ-TWT in C3H10T1/2 cells, a significant reduction of Twist
      mRNA levels was observed. This was accompanied by a significant rise in p21 mRNA
      levels. Finally, DZ-TWT transfections resulted in an increase of cellular
      apoptosis, demonstrating the importance of Twist in apoptotic pathways. These
      results prove the usefulness of DNazymes to characterize Twist gene function and
      further experiments in animals should demonstrate its complete physiological
      role.

PMID- 12480540
TI  - AP endonuclease 1 has no biologically significant 3(')-->5(')-exonuclease
      activity.
AB  - The 3(')-->5(')-exonucleolytic activity of human apurinic/apyrimidinic
      endonuclease 1 (APE1) on mispaired DNA at the 3(')-termini of recessed, nicked or
      gapped DNA molecules was analyzed and compared with the primary endonucleolytic
      activity. We found that under reaction conditions optimal for AP endonuclease
      activity the 3(')-->5(')-exonuclease activity of APE1 manifests only at enzyme
      concentration elevated by 6-7 orders of magnitude. This activity does not show a
      preference to mismatched compared to matched DNA structures as well as to nicked
      or gapped DNA substrates in comparison to recessed ones. Therefore, the 3(')-
      >5(')-exonuclease activity associated with APE1 can hardly be considered as key
      mechanism that improves fidelity of DNA repair.

PMID- 12480541
TI  - Influence of fungal infection on the DOPA-semiquinone and DOPA-quinone production
      in haemolymph of Galleriamellonella larvae.
AB  - The formation of reactive oxygen metabolites in haemolymph of Galleria mellonella
      larvae was studied by ESR spectroscopy. The inhibition of the production of the
      reactive oxygen metabolites of DOPA in haemolymph under the action of fungal
      infection was shown using spin trap 1-hydroxy-3-carboxy-pyrrolidine. This
      inhibition correlated with decrease of phenoloxidase activity in haemolymph of
      infected insects. Simultaneously, the decrease of production of DOPA-semiquinone
      was detected using method of spin stabilization by diamagnetic metal ions.
      Moreover, it was shown that the formation of DOPA-quinone was slowed down in
      haemolymph of infected insects. Our results suggest that the DOPA-derived
      quinones/semiquinones may be involved in immune response of insects as part of
      its defense mechanism.

PMID- 12480542
TI  - Increased Ca2+ storage capacity in the sarcoplasmic reticulum by overexpression
      of HRC (histidine-rich Ca2+ binding protein).
AB  - The histidine-rich Ca(2+) binding protein (HRC) is a high capacity Ca(2+) binding
      protein in the sarcoplasmic reticulum (SR). Because HRC appears to interact
      directly with triadin, HRC may play a role in the regulation of Ca(2+) release
      during excitation-contraction coupling. In this study, we examined the
      physiological effects of HRC overexpression in rat neonatal cardiomyocytes. Both
      caffeine-induced and depolarization-induced Ca(2+) release from the SR were
      increased significantly in the HRC overexpressing cardiomyocytes. Consistently,
      the Ca(2+) content, normally depleted from the SR in the presence of
      cyclopiazonic acid (CPA), remained elevated in these cells. In contrast, the
      density and the ryanodine-binding kinetics of the ryanodine receptor (RyR)/Ca(2+)
      release channel were slightly reduced or not significantly altered in the HRC
      overexpressing cardiomyocytes. We suggest that HRC is involved in the regulation
      of releasable Ca(2+) content into the SR.

PMID- 12480543
TI  - Application of a real-time biosensor to detect bacteria in platelet concentrates.
AB  - A spore-based biosensor for detecting low levels of bacteria in real-time has
      been recently developed. The system (termed LEXSAS, label-free exponential signal
      amplification system) exploits spore's ability to produce fluorescence when
      sensing neighboring bacterial cells. We studied the LEXSAS as a possible approach
      for identifying bacterially contaminated platelet concentrates prior to
      transfusion because the system offers rapid analysis, high sensitivity, and low
      cost. If successful, this approach could reduce the risk of morbidity and
      mortality from transfusion-related bacteremia and sepsis. In this study, we used
      the LEXSAS for detecting bacteria in platelet concentrates spiked with Bacillus
      cereus, Enterobacter cloacae, Escherichia coli, Pseudomonas aeruginosa,
      Staphylococcus aureus, or Streptococcus pyogenes. Bacteria were separated from
      platelets using a 2-min procedure based on bacterial resistance to detergents and
      osmotic shock. The results indicate that the LEXSAS could be used to design a
      practical biosensor for identifying bacterially contaminated platelets in real
      time.

PMID- 12480544
TI  - Cell adhesion aside from integrin system can abrogate anoikis in rat liver cells
      by down-regulation of FasL expression, not by activation of PI-3K/Akt and ERK
      signaling pathway.
AB  - Epithelial cells require contact with extracellular matrix (ECM) to inhibit
      detachment-induced apoptosis (anoikis). The ERK and PI-3K/Akt signaling pathways
      have been identified to inhibit anoikis. We present here a different story. An
      adult rat liver cell line, ARLJ301-3, underwent apoptosis within 4h under
      suspension conditions even with active forms of Akt and ERK1/2. Once ARLJ301-3
      cells are plated on tissue culture plates coated with synthetic polymer, such as
      poly-(N-p-vinyl benzyl-O-beta-D-galactopyranosyl-D-gluconamide) (PVLA), poly-L
      lysine or polystyrene, instead of functional ECM such as fibronectin, they could
      survive and proliferate without activation of Akt and ERK1/2. The expression of
      Fas receptor ligand (FasL) is specifically detected in cells under suspension
      conditions or treated with cytochalasin-D. We present here the first report that
      FasL expression is up-regulated by the cytoskeletal disruption directed by
      cytochalasin-D treatment or cell detachment from ECM.

PMID- 12480545
TI  - 17alpha-estradiol-induced VEGF-A expression in rat pituitary tumor cells is
      mediated through ER independent but PI3K-Akt dependent signaling pathway.
AB  - 17alpha-E(2), a weak estrogen exhibited both agonistic and antagonistic effects,
      and caused a time- and dose-dependent induction of VEGF-A mRNA expression in GH3
      rat pituitary tumor cells. This effect was unaffected by the presence of the pure
      estrogen receptor antagonist ICI 182,780 but was specifically blocked by a
      protein synthesis inhibitor puromycin. Inhibition of phosphatidylinositol-3
      kinase (PI3K) activity by wortmannin decreased the effect of 17alpha-E(2) on VEGF
      A mRNA expression. This inhibitor also blocked the increase in phosphorylation of
      Akt induced by exposure to 17alpha-E(2). In contrast, exposure to the MAP kinase
      inhibitor, U0126, had no impact on 17alpha-E(2)-induced VEGF-A mRNA expression.
      Taken together, these studies indicate that like potent estrogens 17alpha-E(2) up
      regulates VEGF-A mRNA expression in estrogen responsive GH3 rat pituitary tumor
      cells, but this induction is not mediated through a classical estrogen receptor
      pathway. PI3K-Akt signaling pathway is required for the induction of VEGF-A mRNA
      in GH3 cells by 17alpha-E(2).

PMID- 12480546
TI  - Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta
      cells.
AB  - Pancreatic beta-cells exposed to hyperglycemia produce reactive oxygen species
      (ROS). Because beta-cells are sensitive to oxidative stress, excessive ROS may
      cause dysfunction of beta-cells. Here we demonstrate that mitochondrial ROS
      suppress glucose-induced insulin secretion (GIIS) from beta-cells. Intracellular
      ROS increased 15min after exposure to high glucose and this effect was blunted by
      inhibitors of the mitochondrial function. GIIS was also suppressed by H(2)O(2), a
      chemical substitute for ROS. Interestingly, the first-phase of GIIS could be
      suppressed by 50 microM H(2)O(2). H(2)O(2) or high glucose suppressed the
      activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a glycolytic
      enzyme, and inhibitors of the mitochondrial function abolished the latter
      effects. Our data suggested that high glucose induced mitochondrial ROS, which
      suppressed first-phase of GIIS, at least in part, through the suppression of
      GAPDH activity. We propose that mitochondrial overwork is a potential mechanism
      causing impaired first-phase of GIIS in the early stages of diabetes mellitus.

PMID- 12480547
TI  - Structure determination and conformational change induced by tyrosine
      phosphorylation of the N-terminal domain of the alpha-chain of pig gastric H+/K+
      ATPase.
AB  - It has been well established that phosphorylation is an important reaction for
      the regulation of protein functions. In the N-terminal domain of the alpha-chain
      of pig gastric H(+)/K(+)-ATPase, reversible sequential phosphorylation occurs at
      Tyr 10 and Tyr 7. In this study, we determined the structure of the peptide
      involving the residues from Gly 2 to Gly 34 of pig gastric H(+)/K(+)-ATPase and
      investigated the tyrosine phosphorylation-induced conformational change using CD
      and NMR experiments. The solution structure showed that the N-terminal fragment
      has a helical conformation, and the peptide adopted two alpha-helices in 50%
      trifluoroethanol (TFE) solvent, suggesting that the peptide has a high helical
      propensity under hydrophobic conditions. Furthermore, the CD and NMR data
      suggested that the structure of the N-terminal fragment becomes more disordered
      as a result of phosphorylation of Tyr 10. This conformational change induced by
      the phosphorylation of Tyr 10 might be an advantageous reaction for sequential
      phosphorylation and may be important for regulating the function of H(+)/K(+)
      ATPase.

PMID- 12480549
TI  - The protozoa dinoflagellate Oxyrrhis marina contains selenoproteins and the
      relevant translation apparatus.
AB  - In the phylogenetic tree, selenoproteins and the corresponding translation
      machinery are found in Archaea, Eubacteria, and animals, but not in fungi and
      higher plants. As very little is known about Protozoa, we searched for the
      presence of selenoproteins in the primitive dinoflagellate Oxyrrhis marina,
      belonging to the Protoctista kingdom. Four selenoproteins could be obtained from
      O. marina cells cultured in the presence of 75Se. Using O. marina or bovine liver
      cytosolic extracts, we could serylate and selenylate in vitro total O. marina
      tRNAs. Moreover, the existence of a tRNA(Sec) could be deduced from in vivo
      experiments. Lastly, an anti-serum against the specialized mammalian translation
      elongation factor mSelB reacted with a protein of 48-kDa molecular mass.
      Altogether, our data showed that O. marina contains selenoproteins and suggests
      that the corresponding translation machinery is related to that found in animals.

PMID- 12480548
TI  - Arsenic trioxide inhibits the growth of A498 renal cell carcinoma cells via cell
      cycle arrest or apoptosis.
AB  - Previously, we showed that arsenic trioxide potently inhibited the growth of
      myeloma cells and head and neck cancer cells. Here, we demonstrate that arsenic
      trioxide inhibited the proliferation of all the renal cell carcinoma cell lines
      (ACHN, A498, Caki-2, Cos-7, and Renca) except only one cell line (Caki-1) with
      IC(50) of about 2.5-10 microM. Arsenic trioxide induced a G(1) or a G(2)-M phase
      arrest in these cells. When we examined the effects of this drug on A498 cells,
      arsenic trioxide (2.5 microM) decreased the levels of CDK2, CDK6, cyclin D1,
      cyclin E, and cyclin A proteins. Although p21 protein was not increased by
      arsenic trioxide, this drug markedly enhanced the binding of p21 with CDK2. In
      addition, the activities of CDK2- and CDK6-associated kinase were reduced in
      association with hypophosphorylation of Rb protein. Arsenic trioxide (10 microM)
      also induced apoptosis in A498 cells. Apoptotic process of A498 cells was
      associated with the changes of Bcl-(XL), caspase-9, caspase-3, and caspase-7
      proteins as well as mitochondria transmembrane potential (Deltapsi(m)) loss.
      Taken together, these results demonstrate that arsenic trioxide inhibits the
      growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.

PMID- 12480550
TI  - Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone
      deacetylase inhibitor, via suppression of HIF-1alpha activity.
AB  - Hypoxia is generally detected in central regions of solid tumors and regulates a
      variety of transcription factors including hypoxia-inducible factor-1 (HIF-1).
      HIF-1 plays a pivotal role in cellular response to low oxygen concentration, such
      as angiogenesis in tumor. Here, we found that a histone deacetylase (HDAC)
      inhibitor, FK228, inhibits the induction and activity of HIF-1 in response to
      hypoxia. Moreover, FK228 significantly suppressed the induction of vascular
      endothelial growth factor (VEGF) under hypoxia, suggesting that FK228 contributes
      to the inhibition of tumor angiogenesis. In Lewis lung carcinoma model, FK228
      also blocked angiogenesis induced by hypoxia. These results suggest that FK228
      can downregulate hypoxia-responsive angiogenesis through suppression of HIF
      1alpha activity.

PMID- 12480553
TI  - Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications
      for patients with Gilbert's syndrome.
AB  - BACKGROUND/AIMS: UDP-glucuronosyltransferases (UGTs) are important enzymes
      involved in glucuronidation of various exogenous and endogenous compounds.
      Studies were undertaken on the variability of three UGT enzyme activities in
      human livers. Enzyme activities were associated with genetic polymorphisms in
      UGT1A1 (UGT1A1*28) and UGT1A6 (UGT1A6*2). UGT1A1*28 is associated with Gilbert's
      syndrome, a deficiency in glucuronidation of bilirubin leading to mild
      hyperbilirubinemia, whereas UGT1A6*2 may result in low glucuronidation rates of
      several drugs. METHODS: Enzyme activities and genetic polymorphisms were assessed
      in 39 human liver samples, and polymorphisms were also assessed in blood of 253
      healthy controls. RESULTS: Associations were found between UGT enzyme activities
      of bilirubin (B) and 4-nitrophenol (NP; r=0.47, P=0.0024), B and 4
      methylumbelliferone (MUB; r=0.54, P=0.0003), and NP and MUB (r=0.89, P<0.0001).
      In addition to the association between B-UGT enzyme activity and UGT1A1*28
      (r=0.45, P=0.0034) as reported earlier, an association between B-UGT and UGT1A6*2
      (r=0.43, P=0.007) was found. In 253 Dutch Caucasian controls, co-occurrence of
      UGT1A1*28 and UGT1A6*2 was found (r=0.9, P<0.0001). CONCLUSIONS: Most patients
      with Gilbert's syndrome, in addition to their reduced B-UGT enzyme activity, may
      have abnormalities in the glucuronidation of aspirin or coumarin- and dopamine
      derivatives, due to this combination of UGT1A1*28 and UGT1A6*2 genotypes.

PMID- 12480554
TI  - Bacterial lipopolysaccharide decreases thrombomodulin expression in the
      sinusoidal endothelial cells of rats -- a possible mechanism of intrasinusoidal
      microthrombus formation and liver dysfunction.
AB  - BACKGROUND/AIMS: To elucidate the mechanism of liver dysfunction occurring in
      patients with sepsis, we evaluated the effect of bacterial lipopolysaccharide
      (LPS) on the expression of thrombomodulin (TM) in rat sinusoidal endothelial
      cells (SECs) and the therapeutic efficacy of exogenous recombinant TM. METHODS:
      We induced endotoxemia in rats by bolus intraperitoneal injection of LPS. TM
      antigen levels within tissues were assessed by immunohistochemistry. We measured
      TM in cultured SECs by enzyme immunoassay, functional analysis and real-time
      polymerase chain reaction (PCR). RESULTS: TM antigen and activity levels were
      significantly decreased in SECs isolated from LPS-treated rats after 3 and 6 h
      treatment, and recovered after 12 h treatment, correlating with
      immunohistochemical observations. In contrast, TM messenger RNA was decreased
      after 6 and 12 h treatment, and slightly recovered after 24 h treatment. TM
      expression in cultured SECs isolated from normal rats was also reduced after
      treatment with LPS and tumor necrosis factor (TNF)-alpha in vitro. The increased
      levels of serum fibrin degradation products (FDP), fibrin deposition within liver
      sinusoids, injury of SECs and liver dysfunction induced by LPS in our rat model
      was improved by recombinant TM treatment. CONCLUSIONS: Decreased TM expression in
      SECs of LPS-treated rats may result in intrasinusoidal microthrombus formation
      and subsequent liver dysfunction during sepsis.

PMID- 12480555
TI  - Glucose intolerance and serum aminotransferase activities in Japanese men.
AB  - BACKGROUND/AIMS: Elevated activities of serum aminotransferase are commonly
      observed in patients with diabetes mellitus. Few studies have addressed the
      relation between glucose intolerance and serum activities of aminotransferase in
      free-living populations. METHODS: Using a 75 g oral glucose tolerance test, we
      examined the association of impaired fasting glycemia (IFG), impaired glucose
      tolerance (IGT), and type 2 diabetes mellitus with serum aspartate
      aminotransferase (AST), alanine aminotransferase (ALT), and gamma
      glutamyltransferase (GGT) among 4621 men aged 49-59 years of the Japan Self
      Defense Forces. Statistical adjustment was made for body mass index, waist-hip
      ratio, and other possible confounding factors. RESULTS: Proportions of an
      elevated ALT (>50 IU/l) in men with normal glucose tolerance, IFG, IGT, and newly
      diagnosed diabetes mellitus were 3.5%, 9.5%, 7.7%, and 18.0%, respectively.
      Adjusted odds ratios of an elevated ALT for IFG, IGT, and newly diagnosed
      diabetes mellitus were 2.2 (95% confidence interval 1.1-4.3), 1.7 (1.2-2.4), and
      4.4 (3.0-6.6), respectively. IGT and diabetes mellitus were also significantly
      positively associated with elevated AST (>40 IU/l) and GGT (>50 IU/l).
      CONCLUSIONS: Glucose intolerance is associated with elevated serum
      aminotransferase independent of obesity, but even a mildly elevated ALT is
      relatively uncommon in free-living men with glucose intolerance.

PMID- 12480556
TI  - Extracorporeal liver support with molecular adsorbents recirculating system in
      patients with severe acute alcoholic hepatitis.
AB  - BACKGROUND/AIMS: The mortality of patients with severe acute alcoholic hepatitis
      (AH) remains high, leading to interest in the use of extracorporeal liver
      support. The molecular adsorbents recirculating system (MARS) is a liver support
      device based upon a hollow fibre module in which the patient's blood is dialyzed
      across an albumin-impregnated membrane. The aim of this paper is to assess the
      safety, efficacy and feasibility of using MARS in patients with severe AH.
      METHODS: Eight patients (all encephalopathic; hepatorenal syndrome: Type 1, five
      patients; Type 2, two patients) were treated with MARS. Clinical, biochemical and
      haemodynamic assessments were done. RESULTS: Five patients were discharged from
      hospital, and four are alive at 3 months of follow-up, compared with an estimated
      survival of about 20%. There were significant improvement in serum bilirubin
      (P=0.008), creatinine (P=0.02), prothrombin time (P=0.04), and grade of
      encephalopathy (P=0.05). Sustained improvements in mean arterial pressure,
      systemic vascular resistance and cardiac output were observed. Thrombocytopaenia
      was the only MARS-related adverse event observed. CONCLUSIONS: MARS resulted in
      improved liver biochemistry, cardiovascular haemodynamics, renal function and
      encephalopathy in patients with severe AH, with an apparent reduction in
      mortality. On this basis, a multi-centre, randomized clinical trial has been
      initiated.

PMID- 12480557
TI  - Serum thioredoxin levels as a predictor of steatohepatitis in patients with
      nonalcoholic fatty liver disease.
AB  - BACKGROUND/AIMS: Thioredoxin (TRX) is a stress-inducible thiol-containing
      protein. The aim of this study was to evaluate the clinical significance of serum
      TRX in patients with nonalcoholic steatohepatitis (NASH) or simple steatosis.
      METHODS: Serum TRX levels were determined using an enzyme-linked immunosorbent
      assay kit in 25 patients with NASH, 15 patients with simple steatosis, and 17
      healthy volunteers. RESULTS: Serum TRX levels (medians and (ranges), ng/ml) were
      significantly elevated in patients with NASH (60.3 (17.6-104.7)), compared to
      those in patients with simple steatosis (24.6 (16.6-69.7), P=0.0009) and in
      healthy controls (23.5 (1.3-50.7), P<0.0001). Serum ferritin levels in patients
      with NASH were also significantly higher than the levels in patients with simple
      steatosis. The receiver operating characteristic curve confirmed that serum TRX
      and ferritin levels were predictors for distinguishing NASH from simple
      steatosis. Higher grades of histological iron staining were observed in NASH than
      in simple steatosis. Serum TRX tended to increase in accordance with hepatic iron
      accumulation and the histological severity in patients with NASH. CONCLUSIONS:
      The pathogenesis of NASH may be associated with iron-related oxidative stress.
      The serum TRX level is a parameter for discriminating NASH from simple steatosis
      as well as a predictor of the severity of NASH.

PMID- 12480558
TI  - Polycystic liver disease is genetically heterogeneous: clinical and linkage
      studies in eight Finnish families.
AB  - BACKGROUND/AIMS: Polycystic liver disease (PCLD), a dominantly inherited
      condition separate from polycystic kidney disease (PKD), has recently been found
      to be linked to a locus on chromosome 19p13.2-13.1 in two North American
      families. Our aim was to study whether there is clinical or genetic heterogeneity
      within PCLD families. METHODS: We collected clinical data of eight Finnish PCLD
      families and performed both linkage analysis and an extended admixture test. We
      used genetic markers located on chromosome 19p13.2-13.1 and, in addition, on the
      three known PKD loci on chromosomes 4q21-q23 (PKD2), 6p21 (ARPKD) and 16p13.3
      p13.12 (PKD1). RESULTS: There were a total of 33 PCLD patients among which the
      severity of the disease varied greatly even within families. Seven patients had
      disabling symptoms requiring cyst decompression while ten patients were found
      only when the symptomless family members were studied by abdominal ultrasound.
      When genetic homogeneity was assumed, the PCLD locus on chromosome 19p13.2-13.1
      was excluded but when genetic heterogeneity was allowed, five families out of
      seven showed linkage to that locus. All three PKD loci were excluded.
      CONCLUSIONS: Most Finnish PCLD families are linked to chromosome 19p13.2-13.1 but
      there exists also a second PCLD locus yet to be found.

PMID- 12480559
TI  - Nitric oxide mediates the reduced vasoconstrictor response to angiotensin II in
      patients with preascitic cirrhosis.
AB  - BACKGROUND/AIMS: Altered vascular responses to vasopressor agents contribute to
      the pathogenesis of the circulatory dysfunction in cirrhosis. This study aims to
      assess the role of endogenous nitric oxide (NO) in the reduced vascular
      responsiveness to angiotensin II (ANG-II) in eight patients with preascitic
      cirrhosis compared with eight age- and sex-matched healthy controls. METHODS:
      Forearm blood flow (FBF) responses to sub-systemic, locally-active intra-brachial
      infusions of ANG-II were measured using venous occlusion plethysmography before
      and during the application of an 'NO-clamp', a balanced co-infusion of L-N(G)
      monomethyl-arginine (a selective NO synthase inhibitor) and sodium nitroprusside
      (an exogenous NO donor) to block endogenous NO production and restore normal NO
      mediated basal blood flow, respectively. RESULTS: Before applying the 'NO-clamp',
      ANG-II caused dose-dependent reductions of FBF in both groups (P<0.001) that were
      significantly attenuated in the cirrhotic patients (P=0.012). In the presence of
      the 'NO-clamp', the ANG-II-mediated vasoconstriction was enhanced in cirrhotic
      patients (P<0.01), unchanged in controls, and now similar in both groups.
      CONCLUSIONS: This study confirms that vasoconstriction to ANG-II is reduced in
      patients with preascitic cirrhosis, and suggests that this is principally due to
      enhanced NO generation mediated by ANG-II.

PMID- 12480560
TI  - Comparison of rifaximin and lactitol in the treatment of acute hepatic
      encephalopathy: results of a randomized, double-blind, double-dummy, controlled
      clinical trial.
AB  - BACKGROUND/AIMS: The efficacy and safety of rifaximin in comparison with lactitol
      in the treatment of acute hepatic encephalopathy was assessed in a prospective
      randomized, double-blind, double-dummy, controlled trial. METHODS: A total of 103
      patients with grade I-III acute hepatic encephalopathy were randomized to receive
      rifaximin (50 patients, 1200 mg/day) or lactitol (53 patients, 60 g/day) for 5-10
      days. Changes in the portal-systemic encephalopathy (PSE) index on entry and at
      the end of the study were used to evaluate the efficacy of the two therapies.
      RESULTS: Both groups were comparable before treatment with regard to demographic
      data and characteristics of the hepatic encephalopathy episode. The global
      efficacy of both therapies was similar: 81.6% in the rifaximin group and 80.4% in
      the lactitol group showed improvement or total regression of the episode. A
      significantly better evolution of the PSE index was observed in the rifaximin
      group, due to a greater effect of rifaximin in two components of the index: EEG
      abnormalities and ammonia levels. No serious adverse events related to either
      treatment were found during the study. CONCLUSIONS: Rifaximin may be considered a
      useful and safe alternative therapy to lactitol in the treatment of acute hepatic
      encephalopathy in cirrhosis.

PMID- 12480561
TI  - Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by
      preservation of microcirculation and mitochondrial redox-state.
AB  - BACKGROUND/AIMS: Ischemic preconditioning (IP) is known to protect hepatic tissue
      from ischemia-reperfusion injury. However, the mechanisms involved are not fully
      understood yet. METHODS: Using intravital multifluorescence microscopy in the rat
      liver, we studied whether IP exerts its beneficial effect by modulating
      postischemic Kupffer cell activation, leukocyte-endothelial cell interaction,
      microvascular no-reflow, mitochondrial redox state, and, thus, tissue
      oxygenation. RESULTS: Portal triad cross-clamping (45 min) followed by
      reperfusion induced Kupffer cell activation, microvascular leukocyte adherence,
      sinusoidal perfusion failure (no-reflow) and alteration of mitochondrial redox
      state (tissue hypoxia) (P<0.05). This resulted in liver dysfunction and
      parenchymal injury, as indicated by decreased bile flow and increased serum
      glutamate dehydrogenase (GLDH) levels (P<0.05). IP (5 min ischemia and 30 min
      intermittent reperfusion) was capable to significantly reduce Kupffer cell
      activation (P<0.05), which was associated with a slight attenuation of leukocyte
      adherence. Further, IP markedly ameliorated sinusoidal perfusion failure
      (P<0.05), and, thereby, preserved adequate mitochondrial redox state (P<0.05). As
      a consequence, IP prevented the decrease of bile flow (P<0.05) and the increase
      in serum GLDH levels (P<0.05). CONCLUSIONS: IP may exert its beneficial effects
      on hepatic ischemia-reperfusion injury by preserving mitochondrial redox state,
      which is guaranteed by the prevention of reperfusion-associated Kupffer cell
      activation and sinusoidal perfusion failure.

PMID- 12480562
TI  - Liver-infiltrating lymphocytes in end-stage hepatitis C virus: subsets,
      activation status, and chemokine receptor phenotypes.
AB  - BACKGROUND: Hepatitis C virus (HCV) is a leading cause of chronic liver disease,
      yet little is known about the intrahepatic immune response in end-stage patients.
      Chemokines and their receptors are important regulators of immunity, particularly
      in the migration and localization of circulating leukocytes within peripheral
      tissues. AIMS: This report provides a comprehensive comparison of the chemokine
      receptor and activation phenotype of the major leukocyte subsets present in end
      stage HCV-infected and non-HCV infected livers. METHODS: Lymphocytes were
      purified from homogenized explant liver tissue and analyzed by flow cytometry.
      RESULTS: NK cells are the predominant cell type, followed by T cells, B cells and
      NK-T cells, independent of HCV status. T cells displayed a memory phenotype and
      low levels of activation markers. CCR5, CXCR3 and CXCR6 were expressed on a large
      fraction of activated cells, while moderate to low expression of CCR2, CCR6 and
      CX(3)CR1 was observed. Several other tissue-specific and inflammatory chemokine
      receptors were absent from infiltrating lymphocytes. CONCLUSIONS: These results
      identify the chemokine receptors present on infiltrating lymphocytes during end
      stage liver disease and suggest that such infiltration is predominantly
      controlled by non-tissue-specific inflammatory chemokines, a situation that may
      be distinct from liver homing pathways under normal conditions.

PMID- 12480563
TI  - The large GTPase dynamin is required for hepatitis B virus protein secretion from
      hepatocytes.
AB  - BACKGROUND/AIMS: The hepatocellular transport pathways and cellular proteins
      utilized during the packaging and secretion of hepatitis B virus are poorly
      understood. In this study, we tested if the large GTPase dynamin, a protein
      involved in vesicle formation and secretion at the trans-Golgi network in
      hepatocytes, is also used by hepatitis B virus (HBV) in secreting viral proteins.
      METHODS: Using HepG2.2.15 cells expressing the full-length HBV genome, we tested
      the effects of wild-type and mutant dynamin on the localization and secretion of
      two hepatitis B antigens, hepatitis B surface antigen (HBsAg) and hepatitis B e
      antigen (HBeAg). Distribution of these two antigens was analyzed morphologically
      in cells transiently transfected with wild-type or mutant dynamin constructs,
      whereas secretion of the antigens was measured by testing for antigen levels in
      the media of transfected cells. RESULTS: Mutant dynamin was found to induce a
      striking redistribution of HBsAg and HBeAg to a perinuclear compartment, as well
      as a decrease in the levels of HBsAg and HBeAg present in cell culture media
      indicating a reduction in viral protein secretion. At the electron microscopy
      level, cells expressing the mutant dynamin showed a marked accumulation of viral
      particles in dilated cisternae of an uncharacterized cellular compartment.
      CONCLUSIONS: Intact dynamin function is required for secretion of HBV proteins
      from hepatocytes through an uncharacterized cellular compartment.

PMID- 12480564
TI  - Complete genome sequence of hepatitis B virus (HBV) from a patient with fulminant
      hepatitis without precore and core promoter mutations: comparison with HBV from a
      patient with acute hepatitis infected from the same infectious source.
AB  - BACKGROUND/AIMS: There is a paucity of information regarding hepatitis B virus
      (HBV) from patients with fulminant hepatitis (FH) without precore (pre-C, nt
      1896) and core promoter (CP, nt 1762, 1764) mutations. METHODS: Pre-C and CP
      mutations were studied in eight patients with FH and 26 patients with acute
      hepatitis (AH) due to HBV. One patient with FH (FH1) was infected with HBV
      without these mutations. Interestingly, the sera of the infectious source (IS1)
      and of a patient with AH (AH1) infected from IS1 were available. Complete HBV
      genomes from these three patients were analyzed. RESULTS: These mutations were
      found in seven of eight FH and five of 26 AH (P<0.01). HBV from FH1, IS1 and AH1
      belonged to genotype D. Nucleotide difference between FH1 and AH1 was six of 3182
      bases (nt 493, 998, 1173, 2928, 3067, and 3078). Two and five substitutions of
      deduced amino acid sequences were found in the pre-S1 and polymerase regions,
      respectively. The same nucleotide substitutions at nt 493, 1173, 2928 and 3067
      were found in several patients with FH in our laboratory or GenBank. CONCLUSIONS:
      These six nucleotide substitutions of HBV DNA could be candidates of mutations
      relating to FH.

PMID- 12480565
TI  - Long-term prognosis by lamivudine monotherapy for severe acute exacerbation in
      chronic hepatitis B infection: emergence of YMDD motif mutant and risk of
      breakthrough hepatitis -- an open-cohort study.
AB  - BACKGROUND/AIMS: Comparison of long-term prognosis in patients with chronic
      hepatitis B treated with lamivudine, with or without severe acute exacerbation
      (SAE). METHODS: In chronic hepatitis B HBeAg-positive patients on lamivudine
      monotherapy, 21 patients with SAE were retrospectively compared with 63 patients
      without SAE. Both groups were matched for age and sex. We investigated the
      efficacy and problems associated with monotherapy with respect to SAE. RESULTS:
      In SAE and non-SAE, HBeAg seroconversion rates were 21.1 vs. 27.6%, 20.0 vs.
      50.0%, and 14.3 vs. 66.7% at 1, 2, and 3 years, respectively. YMDD mutant emerged
      later in SAE than in non-SAE, but the emergence rates in SAE almost exceeded
      those of non-SAE from 2 years (rates of about 35%). DNA breakthrough (hepatitis B
      virus DNA becoming detectable after a period of negativity, accompanied by
      emergence of YMDD mutant) and breakthrough hepatitis (alanine aminotransferase
      becoming abnormal after a period of normalization, accompanied by DNA
      breakthrough) also appeared later in SAE than in non-SAE, but the rates in SAE
      exceeded those of non-SAE at 3 years. CONCLUSIONS: Our results suggest that
      Japanese genotype C-dominant hepatitis B patients with SAE seem to be at greater
      risk of re-exacerbation after temporary relief of the initial SAE by long-term
      lamivudine monotherapy, compared with those without SAE.

PMID- 12480566
TI  - Precore and core promoter mutations of hepatitis B virus and hepatitis B e
      antigen-negative chronic hepatitis B in Korea.
AB  - BACKGROUND/AIMS: The aims of this study were to determine the frequency of
      precore/core promoter mutations and hepatitis B e antigen (HBeAg)-negative
      chronic hepatitis B (e-CHB) in Korea. METHODS: Patients with chronic hepatitis B
      virus (HBV) infection were tested for HBeAg, anti-HBe, liver profile and HBV-DNA
      by a branched DNA (bDNA) assay. Serum HBV-DNA was amplified by a polymerase chain
      reaction and the precore/core promoter sequence was determined. RESULTS: Among
      the 413 consecutive HBeAg-negative patients, 19.6% were bDNA-positive. Evidence
      of liver disease was found in 90.1% of bDNA-positive and 41.7% of bDNA-negative
      patients. Overall, 17.7% of HBeAg-negative patients had e-CHB. Precore mutation
      (A1896) was detected in 93.7% of HBeAg-negative bDNA-positive and 93.9% of HBeAg
      negative bDNA-negative patients. In 59 HBeAg-positive patients, 78% had wild-type
      and 22% had a mixture of wild-type and A1896 mutant. Core promoter TA mutation
      was detected in 89.9% of HBeAg-negative bDNA-positive patients, 89.8% of HBeAg
      negative bDNA-negative patients, and 74.6% of HBeAg-positive patients. No
      correlation was found between the presence of precore/core promoter mutations and
      HBV-DNA levels or disease severity. CONCLUSIONS: In Korean patients infected with
      HBV genotype C, precore mutation occurred almost invariably along with HBeAg
      seroconversion and core promoter TA mutation was frequent irrespective of viral
      replication levels or disease severity.

PMID- 12480567
TI  - Extracorporeal liver support with MARS in liver failure: has it a role in the
      treatment of severe alcoholic hepatitis?

PMID- 12480568
TI  - Inherited disorders of bilirubin metabolism.

PMID- 12480569
TI  - Ruptured amoebic liver abscess with amoebic colitis.

PMID- 12480570
TI  - Macroenzymes: too often overlooked.

PMID- 12480572
TI  - Solving hemochromatosis with knock-out mice.

PMID- 12480573
TI  - [Cause-specific treatment for nonspecific low back pain].
AB  - Nonspecific low back pain has long been a troublesome clinical entity in that the
      diagnoses are usually hard to define, and the effect of treatment unsure. We have
      been conducting long-term basic and clinical research in Zhujiang Hospital in an
      effort to find the exact mechanism for this disease and to explore its causal
      treatment. On the basis of literature review and treatment result evaluation, we
      recommend the following approaches for origin-specific diagnosis and treatments:
      (1) For spinal nerve dorsal ramus syndrome caused by mechanical stimulation on
      the stem part of the dorsal ramus, freezing the dorsal ramus with liquid-nitrogen
      may constitute the primary treatment. (2) In cases of low back pain originated
      from the lumbar disc due to degeneration of discs, treatment may be implemented
      through disc resection with or without arthrodesis. (3) Facet syndrome, a
      condition with low back pain that is seldom caused by pathological changes in the
      facet itself, but mostly by the pulling of the dorsal ramus due to the
      dislocation of the facet, should be attributed to the dorsal ramus syndrome. (4)
      Lumbar vertebra instability arising from loosened intervertebral conjunction
      calls for arthrodesis as the primary choice. (5) Interspinal ligaments injury can
      be most effectively treated by the combination of blocking and needle knife
      loosing. (6) Low back pain with underlying causes in the internal organs is often
      caused by diseases in the pelvic organs, and only these diseases are cured can
      the back pain be relieved. These origin-specific diagnosis and treatments we
      proposed here await further investigation and comments from our peers interested
      in this problem.

PMID- 12480574
TI  - [Superparamagnetic iron oxide-enhanced magnetic resonance imaging of
      hepatocellular carcinoma in rats].
AB  - OBJECTIVE: To evaluate the value of superparamagnetic iron oxide (SPIO)-enhanced
      magnetic resonance (MR) imaging in the diagnoses of focal liver lesions. METHODS:
      Twenty rat models of hepatocellular carcinoma were induced by feeding the rats
      with N-nitrosodiethylamine. Before and after SPIO injection into the rats, MR
      imaging was performed including the sequences of spin-echo (SE) T1WI (390 ms/14
      ms), TSE T2WI (4 100 ms/99 ms), SE Dual-echoes (1 800 ms/20 ms/70 ms), GRE FLASH
      T2*WI (600 ms/15 ms/15  ), and GRE FLASH T1WI (150 ms/14 ms/70  ). Another 5
      normal rats were selected as negative control, which also received SPIO and MR
      imaging in the same manner as described above. The characteristics of SPIO
      enhanced MRI of different liver lesions were analyzed. RESULTS: After SPIO
      enhancement, the signal intensity of normal liver and cirrhotic liver both
      decreased, especially on GRE T2*WI. The signal intensity of hepatocellular
      carcinoma (HCC), regenerative nodules (RN), and focal nodule hyperplasia (FNH)
      all increased on T1WI images. On T2WI and T2*-weighted images, the signal
      intensity of HCC remained high, while significant signal loss occurred in RN and
      FNH. After SPIO administration, the contrast-to-noise (CNR) of HCC on GRE T2*
      weighted images was greater than that of other sequences. CONCLUSION: SPIO has
      not only considerable T2-negative effect but also slightly T1-shortening effect,
      which is of great value in the differential diagnosis of focal liver lesions.

PMID- 12480575
TI  - [Application of Agilent 2100 Bioanalyzer in the study of differential gene
      expression].
AB  - OBJECTIVE: To study the application of Agilent 2100 Bioanalyzer in the study of
      gene differential expression. METHODS: The total RNAs were extracted and purified
      from Saccharomyces cerevisiae to synthesize double-stranded cDNAs by reverse
      transcription. Restriction display-PCR was employed to obtain the cDNA fragments,
      which were examined by Agilent 2100 Bioanalyzer and agarose gel electrophoresis.
      RESULTS: The analysis showed that Agilent 2100 Bioanalyzer was more sensitive and
      faster to isolate and display the differentially expressed genes, providing at
      the same time accurate quantitative information for each fragment in the DNA
      sample. CONCLUSION: Agilent 2100 Bioanalyzer can be instrumental for the study of
      differential gene expression.

PMID- 12480576
TI  - [Development and application of cDNA microarray of tumor metastasis-associated
      genes].
AB  - OBJECTIVE: To study the method of preparing cDNA microarray of tumor metastasis
      associated genes and its application in the investigation of gene expression
      profile. METHODS: After amplification and purification by PCR, 400 tumor
      metastasis-associated gene clones were obtained and dotted onto the slides coated
      by poly-lysine. Total RNA from specimens of human colorectal carcinoma, lung
      carcinoma, and normal tissue samples were extracted and labeled by fluorescent
      staining. The labeled probes were then hybridized with the cDNA microarray.
      RESULTS: Uniform background and clear signal of the microarray were demonstrated
      by ScanArrayTM 4000. Specific mRNA expression profiles in association with
      colorectal cancer and lung cancer were subsequently obtained, showing that 30
      genes were consistently up-regulated or down-regulated in the tissue samples
      examined, including motility factors, adhesion molecules, extracellular matrix
      degrading enzymes, oncogenes, tumor-suppressor genes, apoptosis and anti
      apoptosis genes, tumor angiogenesis factors and signal transduction factors, etc.
      CONCLUSION: The optimized method is highly sensitive and applicable in examining
      gene expression profile. The two cancers investigated in this study do not
      obviously differ in light of tumor metastasis-associated gene expression
      profiles, indicating similar molecular mechanism accounting for the infiltration
      and metastatic behavior of different types of cancers.

PMID- 12480577
TI  - [Construction of MHC I gene retroviral expression vector and its expression in
      hematopoietic cells].
AB  - OBJECTIVE: To construct the retroviral expression vector of BALB/c mouse H-2Dd
      gene and study its expression in C57BL/6 mouse hematopoietic cells (MHC).
      METHODS: A retroviral vector pMSCV encoding H-2Dd gene was transduced into the
      packaging cell line PT67 by lipofectin, and the hematopoietic cells of C57BL/6(H
      2Dd negative) were infected by the above viral supernatant. Reverse transcriptase
      polymerase chain reaction and flow cytometry were employed to examine the
      expression of H-2Dd on the infected cells. RESULTS: The cDNA encoding H-2Dd was
      correctly inserted into the vector pMSCV, as confirmed by restriction
      endonuclease digestion. The H-2Dd gene was integrated into the C57BL/6 mouse
      hematopoietic cell genome and expressed on the cell surface. CONCLUSION:
      Recombinant H-2Dd of BALB/c mouse retroviral expression vector has been
      successfully constructed and its expression obtained in C57BL/6 mouse
      hematopoietic cells, which may facilitate further study of the function of MHC in
      transplantation immunology.

PMID- 12480578
TI  - [Application of laser capture microdissection in screening phage-display peptide
      library from osteosarcoma tissues].
AB  - OBJECTIVE: To establish a novel approach by using laser capture microdissection
      (LCM) for phage-display peptide library screening and direct recovery of the
      peptides specifically bound to the cells from fresh human tissue. METHODS: Fresh
      human osteosarcoma (OS) tissue specimens obtained from biopsy were incubated in
      phage peptide library solution, followed by shaking at 4 degrees celsius and
      subsequent preparation of frozen sections. Immunohistochemistry was employed to
      examine the infiltration of the phage in the tissues. After modification to
      improve the viability of the phage during the operation, LCM was used to isolate
      the targeted tumor cells that specifically bound the phage peptides. The phage
      was then recovered by transfecting the host bacteria, and the specificity of the
      selected phage was assessed by calculating the recovered phage transfection unit
      on different tissue sections. RESULTS: Enough phages that specifically bound to
      tumor cells were recovered from the sections. After three rounds of screening,
      the eluted phage showed up to 16-fold selectivity for OS tissue. CONCLUSION:
      Application of LCM makes it possible to screen phage display peptide library
      directly from fresh human tissue. Specific cell-binding peptides can be selected
      directly from fresh human tumor cells in their native tissue environment at the
      single cell level.

PMID- 12480579
TI  - [An experimental study of treatment of comminuted distal femur fracture with
      locked double- plating].
AB  - OBJECTIVE: To explore new techniques for the treatment of comminuted distal
      femoral fractures to promote functional restoration and reduce the complications
      of the fracture. METHODS: Sixteen adult canines were selected for this study, and
      the experimental and control hindlimb for each canine were randomly determined.
      Distal comminuted fracture (AO/ASIF Type C2) was induced in both sides of the
      canine's femurs, and one side was fixed with the double plates (steel plate and
      polyethylene plate), whereas the other with a single steel plate. By the end of
      3, 6, 9 and 12 weeks respectively after surgery, 4 of the dogs were used for
      weight-bearing observation and radiological and histological examination of the
      limbs. RESULTS: In comparison with dogs in single plate group, double plate
      fixation resulted in earlier recovery of weight bearing, more abundant and better
      callus, finer callus moulding and quicker healing. There were slightly more
      inflammatory cells, however, in the tissues under the polyethylene than those
      under the steel plate. CONCLUSION: Locked double-plate internal fixation is an
      excellent alternative for treating comminuted fractures of the distal femur, and
      may have its potential use in clinical settings.

PMID- 12480580
TI  - [Proliferation and denucleation of K562 cells induced by cytochalasin B].
AB  - OBJECTIVE: To observe the effect of cytochalasin B on the denucleation of K562
      cells. METHODS: K562 cells were grown in RPMI 1640 medium supplemented with 10%
      calf serum and 4 microL cytochalasin B (CB). Denucleation was induced in the
      cultured cells by CB, and the cells were examined by phase contrast microscopy
      and Giemsa staining respectively. RESULTS: The denucleation of K562 cells induced
      by CB was clearly observed, and the cell proliferation was obviously inhibited.
      CONCLUSION: The denucleation efficiency of K562 cells is positively correlated
      with CB concentrations and the duration of CB treatment. CB at low doses may
      inhibit the cell proliferation and at high doses causes cell death.

PMID- 12480581
TI  - [Interferon-gamma up-regulates Fas expression and increases Fas-mediated
      apoptosis in tumor cell lines].
AB  - OBJECTIVE: To investigate effect of interferon-gamma (IFN-gamma) on Fas
      expression and Fas-mediated apoptosis in tumor cell lines. METHODS: Fas
      expression was detected by flow cytometry, and the tumor cell apoptosis evaluated
      by enzyme-linked immunosorbent assay and AnnexinV staining assay. RESULTS: All
      the 4 tumor cell lines used in this study, e.g. gastric cancer cell lines Kato
      III AGS, lung cancer cell line A549 and laryngeal cancer cell line Hep-2,
      expressed Fas protein to varied degrees. Fas expression was up-regulated by IFN
      gamma (P<0.05), which alone was enough to induce apoptosis in tumor cells and
      increase the susceptibility of them to anti-Fas antibodies. IFN-gamma induced Fas
      expression up-regulation and tumor cell apoptosis in a time-dependent manner.
      CONCLUSION: Fas-mediated apoptosis is one of the mechanisms for IFN-gamma to
      exercise its anti-tumor effect.

PMID- 12480582
TI  - [Role of the marginal division of human neostriatum in working memory capacity
      for numbers received through hearing: a functional magnetic resonance imaging
      study].
AB  - OBJECTIVE: With the help with functional magnetic resonance imaging (fMRI)
      technique, we aim to clarify whether the marginal division of the striatum (MrD)
      is involved in the working memory function of human brain for remembering numbers
      received through hearing. METHODS: Thirteen healthy volunteers were instructed to
      undertake both a working memory task, in which the subjects were asked to
      remember as many numbers read to them as possible, and a non-working memory
      control task, in which the subjects were not asked to remember the numbers. FMRI
      of the brain was performed in the 2 groups while the tests were being carried out
      separately, and the activity of the brain regions was compared between these 2
      tasks. RESULTS: Eleven volunteers passed the working memory task for digit
      remembering. Highly active areas were observed in the prefrontal cortex and the
      MrD with predominance by the left side during performance of the working memory
      task, while other regions of the neostriatum were not excited. The prefrontal
      cortex and the MrD were not obviously activated during the performance in the
      control test. CONCLUSION: The results suggest that the MrD, along with the
      prefrontal cortex in the human brain, is involved in working memory function in
      remembering numbers assigned through hearing. The MrD is probably a subcortical
      memory center, which is linked to other memory-related brain areas.

PMID- 12480583
TI  - [Expression of tumor necrosis factor receptor on peripheral blood mononuclear
      cells from patients with primary hepatocellular carcinoma and effects of
      treatment on the expression].
AB  - OBJECTIVE: To conduct an intensive investigation of the abnormal immune status of
      patients with primary hepatocellular carcinoma and explore the possible mechanism
      of biotherapy for these patients. METHODS: The expression of tumor necrosis
      factor receptor (TNFR)I and TNFR II on peripheral blood mononuclear cells (PBMCs)
      obtained from 30 normal subjects and 31 patients with primary hepatocellular
      carcinoma were examined by flow cytometry and S-P staining assay. The effects of
      biotherapy and chemotherapy administered in the patients were also investigated
      in terms of the changes in the expressions. RESULTS: The TNFR I and TNFR II
      expressions in the patients were (28.35+/-9.09) % and (37.45+/-9.51) %
      respectively, significantly lower than those of normal subjects [(38.54+/-8.51) %
      and (44.89+/-9.08) %]. The biotherapy for the patients caused an increase of TNFR
      I expression to (42.86+/-9.02)%. CONCLUSION: There are significant immune
      abnormalities in patients with primary hepatocellular carcinoma, and this study
      may offer some theoretical basis for the implementation of biotherapy in such
      cases.

PMID- 12480584
TI  - [Obstructive diseases of the biliary tree: an imaging analysis of 76 cases].
AB  - OBJECTIVE: To test the value of magnetic resonance cholangiopancreatography
      (MRCP) with half-Fourier acquisition single-shot (HASTE) sequence in the
      diagnosis of the biliary obstructive diseases in comparison with other imaging
      examinations. METHODS: Altogether 76 patients with pancreaticobiliary duct
      diseases underwent MRCP on Siemens 1.5T Vision Plus scanner, and a heavily T2
      weighted HASTE was obtained during a breath-hold. The findings of MRCP images
      were analyzed and compared with those of ultrasound, CT, (endoscopic retrograde
      cholangiopancreatography ERCP) or PTC. RESULTS: The sensitivity, specificity and
      accuracy of MRCP were 91.0%, 96.50%, and 94.00% respectively in detecting both
      benign and malignant obstructions. The diagnostic accuracy of MRCP was close to
      ERCP, and obviously superior to CT and ultrasound (P<0.05). Benign obstructions
      were characterized by dilatation of proximal end of the common bile duct (CBD)
      and gradual stenosis in the distal CBD with tapered margin without interruptions,
      known as "duct-penetrating sign". It was most commonly seen that malignant
      obstructive ends presented "truncated form" and "rat-tail" form. CONCLUSION: T2
      weighted HASTE is the T2 optional noninvasive technique with excellent accuracy
      in diagnosing biliary obstruction and defining their causes. The degree of
      biliary dilation, the pattern of obstructive ends and the "double duct sign"and
      "duct-penetrating sign" may serve as important indicators for differentiating
      benign and malignant obstructions.

PMID- 12480585
TI  - [Study of immunological indicators in peripheral blood for nasopharyngeal
      carcinoma].
AB  - OBJECTIVE: To find reliable diagnostic immunological indicators in peripheral
      blood for nasopharyngeal carcinoma, and to evaluate the possibility of cancer
      screening and early diagnosis of the malignancies in the future. METHODS: Plasma
      samples were obtained from 83 patients with nasopharyngeal carcinoma and from 105
      patients with benign diseases. Nine cytokines were selected as the candidates for
      the indicators and their quantity in the plasma samples determined by enzyme
      linked immunosorbent assay, the result of which was analyzed statistically.
      RESULTS: Interleukin (IL)-4 level was obviously increased, while IL-6, IL-12,
      transforming growth factor (TGF)-beta, interferon (IFN)-gamma levels
      significantly reduced (P<0.05) in the plasma from patients with nasopharyngeal
      carcinoma. CONCLUSION: These cytokins may serve as the indicators in the
      diagnosis of nasopharyngeal carcinoma.

PMID- 12480586
TI  - [Combined operations for patients with hepatic cancer complicated by portal
      hypertension].
AB  - OBJECTIVE: To study the feasibility and operative procedures of liver resection
      in combination with collateral devascularization for treating patients with
      hepatic cancer complicated by portal hypertension. METHODS: A retrospective
      analysis was conducted in 45 cases of hepatectomy for hepatic cancer in
      combination with portaazygous devascularization for portal hypertension from Jan.
      1995 to Jan. 2002. RESULTS: Operative mortality was zero. The absolute survival
      rate in 1/2, 1, 2, 3, 4, 5, 6, and 7 years was 44/45(97.8%), 30/41(73.2%), 26/36
      (72.2%), 13/27(48.1%), 10/19(52.6%), 5/13(38.5%), 1/7(14.3%), 0/2(0)
      respectively. During hospitalization, refractory ascites occurred in 1 case and
      hepatorenal syndrome in another. Upper gastrointestinal hemorrhage occurred in 2
      cases during the follow-up period. In the 14 patients who died during the follow
      up, 9 died of cancer recurrence, 4 of liver function failure, and 1 of upper
      gastrointestinal hemorrhage. CONCLUSION: Hepatectomy in combination with
      portaazygous devascularization for patients with liver cancer complicated by
      portal hypertension is safe and feasible.

PMID- 12480587
TI  - [Effects of fluvastatin on the levels of C-reactive protein and lipids in
      patients with hyperlipidemia].
AB  - OBJECTIVE: To observe the changes of C-reactive protein (CRP) level and its
      relationship with blood lipids, and the effects of fluvastatin on CRP and the
      lipids in patients with hyperlipidemia. METHODS: Serum levels of cholesterol
      (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), low
      density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol
      (VLDL-C) and lipoprotein(a)[Lp(a)] were measured by enzyme assay, and plasma CRP
      level by immunonephelometry before and after fluvastatin treatment (20 mg/d for 4
      weeks) in patients with hyperlipidemia. RESULTS: CRP levels were above normal in
      90.3% hyperlipidemia cases in spite of the various accompanying diseases.
      Fluvastatin treatment significantly reduced TC (-7.49%), TG (-14.32%), LDL (
      13.88%), VLDL (-18.48%) and TC/HDL(-13.50%) levels (P<0.01), and also brought
      down Lp(a) concentration (-13.81%). CRP levels was very effectively reduced after
      the treatment (-15.92%, P<0.001). No association between basal CRP levels and
      basal lipids and Lp(a) concentrations was observed. Positive correlation of CRP,
      however, was observed after fluvastatin treatment with TC/HDL (r=0.62, P=0.041)
      and Lp(a) (r=0.320, P=0.011), while inverse relations were noted between CRP and
      HDL (r=-0.288, P=0.023). CONCLUSION: CRP levels increases markedly in patients
      with hyperlipidemia, a fact that is independent of the accompanying diseases. In
      addition to modulating blood lipid levels, fluvastatin also reduces CRP level,
      the latter possibly serving as an independent predictive factor for
      atherosclerotic cardiovascular diseases and also as an indicator for estimating
      the effectiveness of the treatment.

PMID- 12480588
TI  - [Clinical study of the effects of radiotherapy in combination with traditional
      Chinese medicine on non-small cell lung cancer].
AB  - OBJECTIVE: To study the therapeutic effects of radiotherapy combined with
      traditional Chinese medicine (TCM) on non-small cell lung cancer (NSCLC).
      METHODS: Ninety-two patients with NSCLC were randomly divided into combined
      treatment group (n=50) and radiotherapy group (n=42). The former group was given
      TCM in combination with radiotherapy, and the latter group received radiotherapy
      only. The adverse effects and quality-of-life (QOL) of all the patients were
      observed after the treatments. RESULTS: The incidence of adverse effects was much
      lower in combined treatment group than in radiotherapy group, and significantly
      greater improvement in QOL of the patients was observed in the former group
      (P<0.01). CONCLUSION: TCM in the combined treatment for patients with NSCLC can
      reduce the adverse effects of radiotherapy, and improve the life quality of the
      patients.

PMID- 12480589
TI  - [Observations on the efficacy of Botai ointment in treating dermatosis common
      among armed forces receiving at-sea training].
AB  - OBJECTIVE: To observe the efficacy of Botai ointment in the treatment of common
      dermatosis. METHODS: Botai ointment was the only drug applied for the treatment.
      The ointment was smeared on the affected area twice daily for 4 weeks. RESULTS:
      The total efficacy rates were 96% for eczema, 100% for eczematous dermatitis, 97%
      for contact dermatitis, 92% for folliculitis, 96% for tinea manuum or tinea
      pedis, 97% for tinea corporis or tinea cruris. CONCLUSION: Botai ointment is
      effective in the treatment of common dermatosis.

PMID- 12480590
TI  - [Clinical value of carbohydrate antigen 50 and carbohydrate antigen 242 in the
      diagnosis of colorectal carcinoma].
AB  - OBJECTIVE: Carbohydrate antigen 50 (CA50) and 242 (CA242), recently recognized as
      serum tumor markers, are studied for their value in the diagnosis of the
      colorectal carcinoma. METHODS: This study included 48 patients with benign bowel
      disease and 71 patients with colorectal carcinoma, whose serum CA50 and CA242
      levels were measured by immunoradiometric assay. RESULTS: The total positivity of
      CA50 and CA242 in colorectal carcinoma cases were 69.0% and 73.2% respectively,
      and were only 6.3% and 8.3% in benign cases. In non-metastatic colorectal
      carcinoma cases, the positivity rates for CA50 and CA242 were 52.8% and 44.4%
      respectively, which were 82.8% and 88.6% in cases with metastasis. Marked
      elevation in CA242 level was noted in the patients with colon carcinoma (77.5%).
      But at early stage of the malignancy, both tumor markers had low sensitivity.
      CONCLUSION: CA50 and CA242 are valuable tumor markers in the diagnosis of
      colorectal carcinoma.

PMID- 12480591
TI  - [Clinical analysis of 62 cases of encephalopathy during puerperium].
AB  - OBJECTIVE: To study the clinical features, therapeutic methods and prognosis of
      encephalopathy during puerperium. METHODS: The clinical data of 62 patients with
      onset of mental symptoms and signs of extensive cerebral involvement during
      puerperium were retrospectively analyzed. RESULTS: The clinical representations
      and treatment method of encephalopathy during puerperium were similar to those of
      viral encephalitis, but the former disease showed no evident signs of infection
      in the initial stage, with longer course and poorer curative effect and prognosis
      than viral encephalitis. CONCLUSION: Patients with onset of mental abnormalities
      during puerperium should receive systemic neurological examination as early as
      possible for timely diagnoses and treatment. In early stage of the disease,
      cerebral edema should be brought under control and the duration of edema
      minimized so as to prevent or alleviate the degeneration and demyelination of the
      cerebral cells. Prolonged comprehensive rehabilitation treatments are recommended
      for the patients' optimal recovery in later stages of the disease.

PMID- 12480592
TI  - [Application of continuous epidural analgesia with ropivacaine and fentanyl
      during delivery].
AB  - OBJECTIVE: To evaluate the safety and efficiency of ropivacaine and fentanyl for
      continuous epidural analgesia during delivery. METHODS: Altogether 98 full-term
      primigravidas with vertex presentation were selected for this study. Epidural
      catheter was placed during delivery with the cervical dilation of 3 cm, and the
      mixture of 0.2% ropivacaine and 2 microgram/ml fentanyl at the initial dose of 5
      ml was given for continuous epidural analgesia. Drug infusion was discontinued
      when the second stage of delivery started. Another 98 primigravidas of similar
      conditions without analgesia served as the control group. RESULTS: Analgesic
      group showed obvious pain-relieving effect (P<0.001) during the delivery, in
      which the active phase was significantly shortened (P<0.05). No obvious adverse
      effect arose in the mother and fetuses from the administration of analgesia.
      CONCLUSION: Continuous epidural analgesia by pumping ropivacaine and fentanyl is
      effective and convenient for pain relief during delivery, and can be beneficial
      to the smooth progress of delivery.

PMID- 12480593
TI  - [Relationship between risk factors for coronary artery disease and thallium-201
      myocardial scintigraphy].
AB  - OBJECTIVE: To investigate the relation of 5 major risk factors (hypertension,
      diabetes, hyperlipidemia, overweight, smoking) of coronary artery disease (CAD)
      to the findings from thallium-201 single photon emission computed tomography.
      METHODS: Exercise 201TI myocardial scintigraphy was performed in 346 patients
      with clinically suspected CAD, who were divided into no risk, low risk, moderate
      risk, and high risk groups, based on CAD risk scores. RESULTS: The rate of
      thallium-201 perfusion abnormalities in no risk, low risk, moderate risk, and
      high risk groups were 48.1%, 70.6%, 89% and 100%, respectively, showing
      significant difference between them (X2=49.6, P=0.000 1). In patients with CAD
      risk factors, significant relation was found between the risk scores and
      semiquantitative scores, lung-to-heart ratios or segment abnormalities (0.133  r 
      0.450, 0.000 1  P  0.031). CONCLUSION: A close relation between CAD risk factors
      and thallium-201 myocardial scintigraphy is found. Routine thallium-201
      myocardial scintigraphy should be performed in patients clinically suspected of
      coronary artery disease with CAD risk factors, especially those with moderate to
      high risk factors.

PMID- 12480594
TI  - [Quinone oxidoreductase gene polymorphism and genetic susceptibility to
      nasopharyngeal carcinoma].
AB  - OBJECTIVE: To ascertain whether the point mutation of cDNA609 C to T of quinone
      oxidoreductase (NQO1) gene is associated with the genetic susceptibility to
      nasopharyngeal carcinoma. METHODS: Polymerase chain reaction-restriction fragment
      length polymorphism was employed to assess the polymorphism of NQO1 genes both in
      120 patients with nasopharyngeal carcinoma and 120 healthy subjects matched for
      age, gender and origin. RESULTS: The allelic frequency of mutant T allele of NQO1
      gene was significantly higher in patients with nasopharyngeal carcinoma than in
      the healthy subjects (P<0.05), and the individuals with T allelic genotype of
      NQO1 gene were at greater risk to develop nasopharyngeal carcinoma. CONCLUSION:
      The cDNA 609 T allele of NQO1 gene is very likely to be associated with the
      genetic susceptibility to nasopharyngeal carcinoma.

PMID- 12480595
TI  - [Finite element analysis of shape memory alloy intrasegmental fixator for lumbar
      spondylolysis].
AB  - OBJECTIVE: To study the tensile strength of shape memory alloy intrasegmental
      fixator and tensile stress distribution in the device during force loading with
      finite element method (FEM). METHODS: The designed parameters, scanning image,
      and mechanical properties of shape memory alloy intrasegmental fixator were input
      into computer for the construction of the FEM model of the device in inherent
      coordinate of ANSYS. The model was extended with restriction in different parts,
      and the tensile strength and the distribution of tensile stress in the model was
      calculated. RESULTS: When the device was loaded with pulling force to induce a
      relative displacement of 2 mm between the 2 hooks along the two midpoints, the
      pull was about 281 N, and the tensile stress concentrated more on the middle of
      device than on the two sides. CONCLUSION: The shape memory alloy intrasegmental
      fixator is strong enough against tensile stress, which concentrates in the middle
      portion of the device where fatigue breakage is liable to occur when excessive
      force is loaded.

PMID- 12480596
TI  - [Fast elimination of 50-Hz noise in PC-based application system].
AB  - The interference by 50-Hz noise arising from the power supply cables is common in
      PC-based application system, often considerably affecting the detection of useful
      signals. On the basis of self-adapting correlation method, we attempt to address
      the problem of fast elimination of 50-Hz noise from the useful signals in PC
      based application system such as digital ECG recording system.

PMID- 12480597
TI  - [Thirteen-year follow-up in 8 cases of penis reconstruction by ilio-inguinal and
      umbilical-thoracic compound flaps].
AB  - OBJECTIVE: To observe the long-term effect of ilio-inguinal and umbilical
      thoracic compound flaps in one-stage reconstruction of the penis. METHODS: Eight
      patients, who received one-stage reconstruction of the penis using ilio-inguinal
      and umbilical-thoracic compound flaps, were all followed up regularly at 6
      months, 1, 3, 7 and 13 years postoperatively. The color, diameter, length, and
      sense recovery of the organ, along with urodynamics and satisfaction degree of
      both patients and their wives were recorded. RESULTS: The reconstructed organ
      retained the original color all through the follow-up, but had shrunk and
      shortened to some degree within the first 3 years after the operation, a
      condition that was stabilized afterwards. The sense of the proximal end of the
      constructed organ began to recover six months after the operation and almost
      assumed normal sense. The sense of the distal end also recovered, though
      relatively slowly. Few long-term complications were observed, and the patients
      and their wives were reasonably satisfied with the reconstructed organs in terms
      of their shape and function. CONCLUSION: Good long-term effect of one-stage
      reconstruction of the penis can be achieved by using illio-inguinal and umbilical
      thoracic compound flaps, which can be adopted clinically in cases of penis
      reconstruction.

PMID- 12480598
TI  - [Laparoscopic radical hysterectomy and pelvic lymphadenectomy: analysis of 14
      cases].
AB  - OBJECTIVE: To evaluate the feasibility and safety of surgical removal of the
      tumors through laparoscopy in patients with early-stage uterine cancer. METHODS:
      A retrospective analysis of the clinical data of 10 cervical cancer and 4
      endometrial cancer cases, in which laparoscopic radical hysterectomy and pelvic
      lymphadenectomy were performed following the same surgical procedures as in
      laparotomy. RESULTS: The mean operating time was 302 min, and mean estimated
      blood loss was 760 ml, with the mean postoperative gastrointestinal recovery time
      of 30 h and average number of removed lymph nodes of 22. CONCLUSION: Laparoscopic
      surgery has equivalent curative effect to laparotomy, and laparoscopic radical
      hysterectomy and pelvic lymphadenectomy in the patients with early-stage uterine
      cancer is both feasible and efficient.

PMID- 12480599
TI  - [Clinical and pathological investigation of polymyositis and dermatomyositis:
      report of 83 cases].
AB  - OBJECTIVE: To study the clinical and pathological characteristics and treatment
      of polymyositis (PM) and dermatomyositis (DM). METHODS: Eighty-three DM/PM cases
      were reviewed and analyzed. RESULTS: The main clinical presentations of PM/DM
      included amyosthenia, muscular tenderness, elevation of serum enzymes,
      accompanied by abnormal electromyography and muscular pathology. A total efficacy
      rate of 86.7% was achieved after treatment with corticosteroid and immuno-
      depressants. CONCLUSION: The different clinical and pathological presentations of
      various types of PM/DM suggest different pathogenesis between DM and PM. Nerve
      damage is a part of the systemic damages due to the disease, the prognosis of
      which is related to its classification and then timing of the treatment. Early
      effective treatment can improve the prognosis.

PMID- 12480600
TI  - [Therapeutic effects of bifonazole gel on tinea versicolor in infants: analysis
      of 22 cases].
AB  - OBJECTIVE: To evaluate the efficacy and safety of 1% bifonazole gel in the
      treatment of tinea versicolor in infants. METHODS: Twenty-two infants with tinea
      versicolor were treated with 1% bifonazole gel for 2 weeks, and the therapeutic
      effects were evaluated. RESULTS: Total cure was achieved in 16 cases and
      significant improvement observed in 4 cases, with a total effective rate of
      90.91%. The fungi were cleared in 19 cases with the clearance rate of 86.36%.
      CONCLUSION: Use of 1% bifonazole gel can be effective and safe in treating tinea
      versicolor in infants.

PMID- 12480601
TI  - [Meningoencephalitis caused by Angiostrongylus cantonensis: report of 1 case].
AB  - One rare case of meningoencephalitis caused by Angiostrongylus cantonensis is
      reported. The development of the disease, clinical features, accessory
      examinations, and the subsequent treatment were described and analyzed briefly.

PMID- 12480602
TI  - [Misdiagnosis of corticomedullary mixed pathological changes in adrenals: report
      of 4 cases].
AB  - Pathological changes usually occur independently in the adrenal cortex and
      medulla because of their distinct embryonic origins, and changes involving both
      the cortex and medulla are rare. We report 4 cases of corticomedullary mixed
      pathological changes adrenal glands. CT scanning of the adrenal glands showed
      unilateral abnormalities in all the 4 cases, 3 of which were diagnosed as
      aldosteronism and the other pheochromocytoma before surgery. Unilateral
      adrenalectomy was performed in the 4 patients 3 being cured and discharged. The
      other 1 had recurrence 18 months postoperatively with suspected pathological
      changes on the other side. Subsequent pathological examination confirmed the
      suspicion in both the cortex and medulla of the other adrenal gland. In cases
      with clinical presentations as simultaneous onset of aldosteronism and
      catecholamine responses, pathological changes in both the cortex and medulla of
      the adrenal glands should be considered. Perioperative management of such cases
      should be the same as that in cases of catecholamine responses, and the diagnosis
      relies on histopathological examination.

PMID- 12480603
TI  - [Economy of words and conversion of sentence structures in English medical
      paper].
AB  - Translation often involves economy of certain words or phrases, and conversion of
      sentence structures is not uncommon. In this paper, the authors demonstrate with
      examples the application of these techniques and postulate the general principle
      that should be followed in the application.

PMID- 12480604
TI  - [Cyclosporin and portal venous inoculation of donor splenocytes prolongs cardiac
      allograft survival in mice].
AB  - OBJECTIVE: To investigate the effect of portal venous inoculation of donor
      splenocytes combined with cyclosporin A (CsA) administration on cardiac allograft
      survival in mice. METHODS: Heterotopic cardiac transplantation between fully
      allogenic NIH/q and BALB/C strain mice was performed. A modified procedure of
      neonatal heart-in-ear transplantation, as originally described by Fulmer et al,
      was adopted. We prepared donor splenocytes from NIH/q or third-party C57BL/6
      spleens for BALB/C recipients, which were injected preoperatively via the
      recipient portal vein or the systemic vein 1 week before the heart-in-ear
      transplantation. The recipients were subsequently treated with a short course of
      the immunosuppressive agent, CsA (4 mg/kg starting from 7 d before the operation
      till 5 d after it). RESULTS: Portal venous inoculation of donor splenocytes
      combined with CsA significantly prolonged cardiac graft survival (n=6, P<0.05)
      that reached 31.00+/-3.23 d, and 2 of the 6 allografts survived for more than 35
      d. Donor splenocytes injected via the systemic vein or third-party C57BL/6 mice
      splenocytes injected via the portal vein did not prolong graft survival (P>0.05).
      CsA alone or portal venous inoculation of donor-specific splenocytes alone also
      prolonged graft survival (P<0.05), with mean graft survival time of 18.50+/-2.59
      d and 16.11+/-1.97 d respectively. CONCLUSION: Combination of portal venous
      inoculation of donor-specific splenocytes and CsA can prolong murine cardiac
      allograft survival, which is donor antigen-specific.

PMID- 12480605
TI  - [Microsurgical repair of syndactyly of the fingers in children].
AB  - OBJECTIVE: To evaluate the effectiveness of microsurgical technique for repairing
      syndactyly of the fingers in children. METHODS: Microsurgical repair of
      syndactyly of the fingers was performed in 32 children. The skin joining the
      syndactyly was incised and relaxed under microscope, and dorsal metacarpal flap
      of comparable size was used to repair the lateral skin defect of the finger and
      also to reconstruct the finger web. RESULTS: All the flaps survived without scar
      leaving on the lateral skin of the fingers, and the reconstruction of the finger
      web was satisfying. CONCLUSION: Microsurgical technique is applicable in the
      surgical repair of syndactyly of the fingers in children.

PMID- 12480606
TI  - Critical oxygen delivery in conscious septic rats under stagnant or anemic
      hypoxia.
AB  - Although evidence shows that critical O2 delivery (QO2crit), the point at which
      oxygen consumption becomes limited by O2 delivery (QO2), is not affected by the
      method used to decrease QO2 in healthy subjects, microcirculatory injury caused
      by sepsis may modify QO2crit in a unique manner. We therefore designed this study
      to compare QO2crit in anemic and stagnant hypoxia in conscious septic rats. Rats
      were randomized to control or sepsis induced by cecal ligation and perforation;
      24 hours later, oxygen consumption was measured using expired gas analysis,
      whereas QO2 was calculated from standard formula. Rats were further randomized to
      anemic hypoxia by isovolemic hemodilution or stagnant hypoxia by stepwise
      inflation of a balloon-tip catheter in the right atrium. QO2crit and critical
      hemoglobin concentration were calculated by dual linear regression analysis. We
      found that (1) QO2crit was not different between anemic and stagnant hypoxia in
      sepsis and that (2) the critical hemoglobin concentration in anemic hypoxia was
      similar between sepsis and control, indicating that tolerance to acute anemia is
      not altered by sepsis. Further studies are needed before the clinical relevance
      of these conclusions can be fully understood.

PMID- 12480607
TI  - Postlipopolysaccharide oxidative damage of mitochondrial DNA.
AB  - Selected structural and functional alterations of mitochondria induced by
      bacterial lipopolysaccharide (LPS) were investigated on the basis of the
      hypothesis that LPS initiates hepatic mitochondrial DNA (mtDNA) damage by
      oxidative mechanisms. After a single intraperitoneal injection of Escherichia
      coli LPS, liver mtDNA copy number decreased, as determined by Southern analysis,
      within 24 hours relative to nuclear 18S rRNA (p < 0.05). LPS induced a novel
      oxidant-dependent 3.8-kb mtDNA deletion in the region encoding NADH dehydrogenase
      subunits 1 and 2 and cytochrome c oxidase subunit I, which correlated with
      mitochondrial glutathione depletion. Expression of mitochondrial mRNA and
      transcription of mitochondrial RNA were suppressed, whereas mRNA expression
      increased for selected nuclear-encoded mitochondrial proteins. Resolution of
      mtDNA damage was mediated by importation of mitochondrial transcription factor A
      protein, a central regulator of mtDNA copy number, accompanied by binding of
      mitochondrial protein extract to the mitochondrial transcription factor A DNA
      binding site. Hence, mtDNA integrity and transcriptional capacity after LPS
      administration appeared to be reinstated by mitochondrial biogenesis. These data
      provide the first link between LPS-mediated hepatic injury and a specific
      oxidative mtDNA deletion, which inhibits mitochondrial transcription and is
      restored by activation of mechanisms that lead to biogenesis.

PMID- 12480608
TI  - Effects of early onset asthma and in utero exposure to maternal smoking on
      childhood lung function.
AB  - Both in utero exposures to maternal smoking and asthma are associated with
      chronic deficits in lung function. We hypothesized that in utero exposure affects
      lung function in children without asthma and synergistically affects children
      with early onset asthma. To investigate effects of in utero exposure and age at
      asthma diagnosis on lung function, we examined longitudinal medical history,
      tobacco smoke exposure, and lung function data from 5,933 participants in the
      Children's Health Study. We found that children exposed in utero, but without
      asthma, showed decreased FEV1/FVC, FEF25-75, and FEF25-75/FVC ratio. Among
      children without in utero exposure, early asthma diagnosis was associated with
      larger decreases in FEV1, FEF25-75, and FEV1/FVC ratio compared with later
      diagnosed asthma. Children with in utero exposure alone and early onset asthma
      showed deficits in FEV1 (-13.6%; 95% confidence interval [CI], -18.9 to -8.2) and
      FEF25-75 (-29.7%; 95% CI, -37.8 to -20.5) among boys; and FEF25-75 (-26.6%; 95%
      CI, -36.4 to -15.1) and FEV1/FVC (-9.3%; 95% CI, -12.9 to -5.4) among girls. The
      absolute differences in FEF25-75 associated with in utero exposure increased with
      age in children with early onset asthma. We found little evidence for effects
      from environmental tobacco smoke exposure alone. In summary, deficits in lung
      function were largest among children with in utero exposure and early onset
      asthma.

PMID- 12480609
TI  - Disruption of L-histidine decarboxylase reduces airway eosinophilia but not
      hyperresponsiveness.
AB  - Histamine has a variety of airway actions and is considered to be an important
      mediator in asthma. This study examined the role of endogenous histamine in
      allergic airway eosinophil recruitment and hyperresponsiveness using L-histidine
      decarboxylase gene knockout mice. Histamine levels of the airways in L-histidine
      decarboxylase knockout mice were largely diminished compared with wild-type mice.
      Inhalation challenge with ovalbumin (OVA) in OVA-sensitized wild-type mice caused
      eosinophil accumulation in the lung as well as airway hyperresponsiveness to
      methacholine 3 days after the challenge. The eosinophil recruitment was
      significantly reduced in the knockout mice. In the bone marrow, the proliferation
      of eosinophils was enhanced after OVA challenge in the wild-type mice; however,
      the proliferation was significantly reduced in the knockout mice. The induction
      of P-selectin in the lung after OVA challenge was also inhibited in the knockout
      mice. In contrast, airway hyperresponsiveness was not suppressed in the knockout
      mice. These results suggest that endogenous histamine is involved in the
      accumulation of eosinophils into the airways after allergic challenge, possibly
      acting in the bone marrow and producing P-selectin in the airways. Furthermore,
      allergen-induced airway hyperresponsiveness appeared to occur independently of
      airway eosinophilia in our present model.

PMID- 12480610
TI  - Effect of the addition of montelukast to inhaled fluticasone propionate on airway
      inflammation.
AB  - The aim of the study was to investigate the effect of addition of montelukast to
      inhaled fluticasone propionate (FP) therapy, compared with FP therapy alone (100
      microg twice a day) on airway immunopathology in individuals with mild asthma.
      Twenty-eight subjects received FP (100 microg twice a day) or FP (100 microg
      twice a day) plus montelukast (10 mg at night) for 8 weeks and were then crossed
      over to the alternate treatment for a further 8 weeks. Physiological measurements
      and bronchial biopsies were obtained at +/- 2 days before treatment and +/- 2
      days at the end of each treatment period. A two-period crossover analysis was
      performed and the mean and SE were calculated. There was no significant
      difference in percent predicted FEV1 (p = 0.51) or PC20 mg/ml (p = 0.81) between
      the two treatment regimes after 8 weeks of therapy. There was no difference in
      the efficacy of either treatment in decreasing T cell (p = 0.97), CD45RO+ (p =
      0.37), mast cell (p = 0.37), or activated eosinophils (p = 0.55) numbers in
      bronchial biopsies. There was no significant difference in the percentage area
      stained for IFN-gamma (p = 0.76) or interleukin-4 (p = 0.61) between treatments.
      Reduction of inflammatory cell numbers in the bronchial mucosa achieved with FP
      plus montelukast was not significantly different from the reduction observed with
      FP alone in individuals with mild asthma.

PMID- 12480611
TI  - Left atrial pressure can be accurately transmitted to the pulmonary artery
      despite zone 1 conditions.
AB  - Pulmonary arterial occlusion pressure is not thought to reflect left atrial
      pressure (Pla) when alveolar pressure (PA) exceeds pulmonary venous pressure
      because alveolar capillaries collapse and the required continuous fluid column
      between the pulmonary artery and left atrium is interrupted. However, arterial-to
      venous flow can occur when PA exceeds both the pulmonary arterial pressure (Ppa)
      and pulmonary venous pressure (i.e., in Zone 1 conditions), indicating the
      existence of a continuous patent vascular channel. Accordingly, Ppa should
      reflect Pla under these conditions. To investigate this connection cannulas were
      placed in the pulmonary arteries and left atria of eight excised rabbit lungs.
      Ppa and Pla were set 5 cm H2O above PA, which ranged from 0 to 25 cm H2O. Pla was
      then reduced in 2 to 4 cm H2O decrements while recording Ppa when arterial-to
      venous flow ceased. At all PAs greater than 0 cm H2O, Pla was accurately
      reflected by the Ppa when both were exceeded by PA. The greater the PA, the lower
      the Ppa could track Pla below PA. Pla can be accurately measured by a pulmonary
      arterial catheter under Zone 1 conditions.

PMID- 12480613
TI  - Ventilator-induced cell wounding and repair in the intact lung.
AB  - We tested the hypothesis that cells of ventilator-injured lungs are subject to
      reversible plasma membrane stress failure. Rat lungs were perfused with the
      membrane impermeable fluorescent marker propidium iodide and randomized to one of
      four ventilation strategies. Subpleural lung regions were imaged with confocal
      microscopy, and cell injury was quantified as the number of propidium iodide
      positive cells per alveolus. The number of injured cells was significantly
      greater in lungs ventilated with large tidal volumes and zero end-expiratory
      pressure than in lungs ventilated with small tidal volumes and positive end
      expiratory pressure (p < 0.01). Cell injury correlated with lung weight gain,
      change in dynamic compliance, and histologic injury scores. In a second set of
      experiments, lungs were mechanically ventilated for 30 minutes at high tidal
      volume settings, whereas propidium iodide was perfused either during or after
      injurious ventilation. Labeling after removal of injurious stress revealed
      significantly fewer injured cells (0.25 +/- 0.09 to 0.08 +/- 0.08, p < 0.01). We
      conclude that cells of ventilator-injured lungs are subject to reversible plasma
      membrane stress failure.

PMID- 12480612
TI  - Significant microbiological effect of inhaled tobramycin in young children with
      cystic fibrosis.
AB  - We conducted a double-blind, placebo-controlled, multicenter, randomized trial to
      test the hypothesis that 300 mg of tobramycin solution for inhalation
      administered twice daily for 28 days would be safe and result in a profound
      decrease in Pseudomonas aeruginosa (Pa) density from the lower airway of young
      children with cystic fibrosis. Ninety-eight subjects were to be randomized;
      however, the trial was stopped early because of evidence of a significant
      microbiological treatment effect. Twenty-one children under age 6 years were
      randomized (8 active; 13 placebo) and underwent bronchoalveolar lavage at
      baseline and on Day 28. There was a significant difference between treatment
      groups in the reduction in Pa density; no Pa was detected on Day 28 in 8 of 8
      active group patients compared with 1 of 13 placebo group patients. We observed
      no differences between treatment groups for clinical indices, markers of
      inflammation, or incidence of adverse events. No abnormalities in serum
      creatinine or audiometry and no episodes of significant bronchospasm were
      observed in association with active treatment. We conclude that 28 days of
      tobramycin solution for inhalation of 300 mg twice daily is safe and effective
      for significant reduction of lower airway Pa density in young children with
      cystic fibrosis.

PMID- 12480614
TI  - Echocardiographic assessment of pulmonary hypertension in patients with advanced
      lung disease.
AB  - Doppler echocardiography is commonly used to estimate systolic pulmonary artery
      pressure and to diagnose pulmonary hypertension, but data relating to its utility
      in patients with advanced lung disease are limited. In a cohort study of 374 lung
      transplant candidates, the performance characteristics of echocardiography
      compared with right heart catheterization in the determination of systolic
      pulmonary artery pressure and diagnosis of pulmonary hypertension were
      investigated. The prevalence of pulmonary hypertension was 25% in the study
      population. Estimation of systolic pulmonary artery pressure by echocardiography
      was possible in 166 patients (44%). The correlation between systolic pulmonary
      artery pressure estimated by echocardiography and measured by cardiac
      catheterization was good (r = 0.69, p < 0.0001). However, 52% of pressure
      estimations were found to be inaccurate (more than 10 mm Hg difference compared
      with measured pressure), and 48% of patients were misclassified as having
      pulmonary hypertension by echocardiography. Sensitivity, specificity, and
      positive and negative predictive values of systolic pulmonary artery pressure
      estimation for diagnosis of pulmonary hypertension were 85%, 55%, 52%, and 87%,
      respectively. In conclusion, despite a statistically significant correlation with
      directly measured values, estimation of systolic pulmonary artery pressure by
      echocardiography is frequently inaccurate in patients with advanced lung disease
      and leads to considerable overdiagnosis of pulmonary hypertension.

PMID- 12480619
TI  - Feedback and reflection: teaching methods for clinical settings.
AB  - Feedback and reflection are two basic teaching methods used in clinical settings.
      In this article, the authors explore the distinctions between, and the potential
      impact of, feedback and reflection in clinical teaching. Feedback is the heart of
      medical education; different teaching encounters call for different types of
      feedback. Although most clinicians are familiar with the principles of giving
      feedback, many clinicians probably do not recognize the many opportunities
      presented to them for using feedback as a teaching tool. Reflection in medicine
      the consideration of the larger context, the meaning, and the implications of an
      experience and action-allows the assimilation and reordering of concepts, skills,
      knowledge, and values into pre-existing knowledge structures. When used well,
      reflection will promote the growth of the individual. While feedback is not used
      often enough, reflection is probably used even less.

PMID- 12480620
TI  - A course director's perspectives on problem-based learning curricula in
      biochemistry.
AB  - Knowledge of the applications of biochemistry, molecular biology, and genetics in
      the practice of medicine has been and continues to be a vital part of medical
      students' and continuing education. The technical background and the rapid
      expansion of information and new applications have made it an arduous task to
      learn and teach this material within the already crowded medical school
      curriculum. Problem-based learning (PBL) formats are rapidly being adopted at all
      levels of education as not only a major paradigm shift in education but also a
      solution for the instruction of biochemistry in medical school. Designing an
      effective biochemistry curriculum with PBL-based or lecture-based formats
      requires an appreciation for their strengths and weakness. The author's
      experiences in the Double Helix Curriculum at the University of Rochester School
      of Medicine and Dentistry (which employs PBL cases and complementing lectures)
      has shown that students are excited about learning in the PBL environment and
      explore in depth ways of integrating biochemistry, cell biology, genetics, and
      molecular biology into the practice of medicine. At the same time, complementary
      lectures greatly enhance uniformity in the quality and, importantly, the accuracy
      of the students' learning.

PMID- 12480621
TI  - Evidence-based medicine and informed consent.
AB  - The author applauds the paradigm shift in medical education and practice toward
      evidence-based medicine. However, he maintains that an important part of this
      shift should be a careful consideration of its implications for the physician's
      legal and ethical obligations to sufficiently inform patients about the nature of
      proposed medical interventions. Should the traditional informed-consent
      requirement be expanded to mandate that the physician also disclose the basis or
      reasons for the physician's expectations about likely benefits? Particularly,
      should the physician have to reveal whether a recommendation is based on
      scientifically analyzed evidence of efficacy or instead on the sorts of factors
      (custom, habit, gut instinct, personal impressions and experience) that have
      influenced much of medical practice in the past in the absence of relevant
      evidence? What should the physician tell the patient when the evidence base
      regarding a specific intervention is just beginning to be developed, is
      ambiguous, or is engulfed in controversy? The author examines the implications of
      these questions, and cautions that while the trend to evidence-based medicine is
      commendable, careful consideration of patients' proper roles regarding evidence
      based medicine-as both recipients of and decision makers about their own proven
      and unproven forms of medical care-should not be overlooked.

PMID- 12480622
TI  - Clinical trials at AHCs: the perspective of an academic clinical trials office.
AB  - Industry-sponsored clinical trials represent a substantial portion of the
      clinical investigator's portfolio of patient-oriented research. In academia's
      efforts to reclaim lost ground with respect to the performance of industry
      sponsored clinical trials, many academic health centers have established clinical
      trials offices. An underlying assumption has been that with improved service on
      the part of universities will come new opportunities for clinical research. The
      experiences and vantage points of academic research offices have sometimes been
      ignored and an analysis of what new business might ensue has not been reported.
      The authors discuss the rationale for creating a centralized clinical trials
      office and the means of financing such an effort. They then describe the initial
      experiences (1997-2000) of a central clinical trials office (the Research
      Services Organization, or RSO) at the University of Minnesota Academic Health
      Center, analyze the value of such an office to the academic health center, and,
      based on their experiences with the RSO and elsewhere, consider how industry and
      academia might further enhance their collaborations. Of 354 clinical research
      proposals evaluated by the RSO, only 62% were found to be acceptable or highly
      likely to be acceptable to investigators and the institution. Reasons for not
      participating in specific clinical trials are discussed. Academic health centers
      contemplating developing clinical trials offices must be aware of the significant
      overhead cost associated with evaluating the appropriateness and feasibility of
      clinical trial proposals that may never be performed. Valuable lessons learned
      from working with sponsors and from working with investigators are also reviewed.

PMID- 12480623
TI  - A new first-year course designed and taught by a senior medical student.
AB  - Senior medical students have been utilized at some institutions in limited
      teaching roles for first-year medical students. The authors describe a pilot
      program in which a motivated senior medical student completely designed and
      taught an original course to a group of first-year students in academic year 2000
      01. The 16-hour course was offered as a selective for first-year students. This
      course concentrated on clinically-focused topics, evidence-based medicine, and
      physical examination skills. Evaluations from the students in the course, as well
      as from a faculty advisor, were uniformly positive. This unique course filled an
      existing need in the first-year curriculum, and could be permanently integrated
      in various settings. This novel approach of a senior medical student's developing
      and teaching an entire first-year course benefited both the senior and first-year
      students and could be implemented at other institutions using similar methods or
      a number of suggested variations.

PMID- 12480625
TI  - Performing procedures on the newly deceased.
AB  - The report explores whether it is necessary to obtain informed consent before
      training procedures can be performed on the newly dead, weighing two conflicting
      considerations: the importance of protecting the integrity of the newly deceased
      with respect to family, society, and profession, and the need to educate health
      care providers. The report considers arguments against the need for consent,
      namely the benefit of having well-trained physicians, the contention that
      alternative models for teaching are inadequate, and the concerns that if consent
      were required, it rarely would be granted. These considerations are weighed
      against the value of respecting the sensitivities not only of families but also
      of medical teams, and the importance of preserving trust in the medical
      profession. The report concludes that performing procedures on the newly dead
      must proceed not randomly but rather in the context of a structured training
      sequence completed under close supervision, and recommends that physicians
      request permission from family members before performing such procedures.

PMID- 12480626
TI  - Educational theory and medical education practice: a cautionary note for medical
      school faculty.
AB  - Educational theory is routinely cited as justification for practice in medical
      education, even though the justification for the theory itself is unclear.
      Problem-based learning (PBL), for example, is said to be based on powerful
      educational principles that should result in strong effects on learning and
      performance. But research over the past 20 years has produced little convincing
      evidence for the educational effectiveness of PBL, which naturally raises doubts
      about the underlying theory. This essay reflects on educational theory, in
      particular cognitive theory, and concludes that the theory is little more than
      metaphor, not rigorous, tested, confirmed scientific theory. This metaphor/theory
      may lead to ideas for basic and applied research, which in turn may facilitate
      the development of theory. In the meantime, however, the theory cannot be trusted
      to determine practice in medical education. Despite the intuitive appeal of
      educational theory, medical educators have a responsibility to set aside their
      enthusiasm and make it clear to medical school faculty and administrators that
      educational innovations and practice claims are, at best, founded on conjecture,
      not on evidence-based science.

PMID- 12480627
TI  - The academic prince.
AB  - The author presents advice to deans and chairs of academia by imagining what
      Machiavelli might recommend were he to write a modern version of The Prince for
      academics. "Machiavelli" cautions that since modern academic "princes" have
      little power (except, perhaps, over teaching and laboratory space), the success
      of their rule depends upon respect. Regarding the choice of an academic prince,
      find someone who can be a good role model, set standards, and reward academic
      excellence, and who will, above all, be respected. Avoid choosing a prince who is
      a nice, nonthreatening candidate with "good human relations" and "good executive
      skills." Choose candidates who are already successful and fulfilled and who will
      see the new post not as a promotion or a balm for their insecurity, but as an
      intrusion into their academic lives. Fill empty positions as quickly as possible
      better a weak prince than no prince at all. Seek short terms for princes, both
      because respected academics will want to return to their normal lives as soon as
      possible, and because with short mandates, greater chances can be taken with
      young, unproved, but promising candidates. At the same time, the appointment of
      aging administrators who have lost their academic skills is to be avoided. Above
      all, respect the throne-i.e., the position of chair or dean-even if the person
      holding the position may not deserve the respect, since when the prince retires
      with honor, the position becomes more attractive to future good candidates.

PMID- 12480629
TI  - Medicine and the arts. At the Gynecologist's.

PMID- 12480630
TI  - Medicine and the arts. Riding Chaucer in the Stirrups.

PMID- 12480632
TI  - Gender discrimination and sexual harassment in medical education: perspectives
      gained by a 14-school study.
AB  - PURPOSE: The authors attempted to determine male and female medical students'
      exposures to and perceptions of gender discrimination and sexual harassment
      (GD/SH) in selected academic and nonacademic contexts. METHOD: An anonymous, self
      report questionnaire was administered in the spring of 1997 to senior medical
      students at 14 U.S. medical schools. Data were collected about students'
      exposures to GD/SH during undergraduate medical education and outside the medical
      training environment. Students' perceptions of GD/SH in various medical
      specialties and practice settings were also measured. RESULTS: Of the 1,911
      questionnaires administered, 1,314 were completed (response rate, 69%). Both men
      and women reported exposures to GD/SH. More women than men reported all types of
      exposures to GD/SH across all academic and nonacademic contexts. Differences
      between men and women in the frequencies of exposures were greatest outside the
      medical training environment (t = 15.67, df = 1171, p <or=.001). Within academic
      medical training contexts, the differences by sex were most evident in core
      clerkships (t = 11.17, df = 1176, p <or=.001). Women students perceived the
      prevalence of GD/SH to be significantly (p <or=.001) higher in a number of
      medical specialties than did men. However, both groups believed these behaviors
      to be most common in general surgery and obstetrics-gynecology. Women perceived
      significantly more GD/SH in academic medical centers and community hospitals.
      Both groups perceived these behaviors to be significantly more prevalent in
      academic medical centers than in community hospitals, and more prevalent in
      community hospitals than in outpatient office settings. CONCLUSIONS: This study
      suggests that mistreatment in the form of GD/SH is prevalent in undergraduate
      medical education, particularly within core clerkships. Interventions focused on
      particular specialties and training periods may be helpful.

PMID- 12480634
TI  - Physicians' perceptions of institutional and leadership factors influencing their
      job satisfaction at one academic medical center.
AB  - PURPOSE: Academic physicians' perceptions about their institution's function and
      leadership should provide insights toward improving faculty recruitment and
      retention. METHOD: The authors surveyed 105 non-management and non-emeritus
      physicians who had been hired by (57%) or left (43%) the University of Missouri
      Columbia School of Medicine (MUHC) in 1991-1998. The questionnaire measured both
      the importance and the availability of 14 institutional and leadership factors
      and the physicians' perceptions of satisfaction with their careers. Open-ended
      questions assessed additional concerns. RESULTS: In all, 56% of the overall
      satisfaction scores were unfavorable and, when grouped by faculty department,
      correlated inversely with departure rates (p =.04). Scores were surprisingly
      similar between those who left and those who remained at the institution.
      "Protected time for research or personal use" was the highest faculty priority
      regardless of level of overall satisfaction. "Equitable distribution of
      salary/resources" (p =.007) and "trust-communication with chair/division head" (p
      =.003) predicted good satisfaction independently. Openended responses for
      remaining at the university related to the pleasant local community (49%),
      intellectual issues (46%), and humanitarian issues (5%). Responses for
      considering opportunities elsewhere were administrative frustration (59%), income
      enhancement (18%), career advancement (9%), academic frustration (9%), and other
      (5%). Recommendations for enhancing recruitment and retention were fix
      administrative concerns (45%); improve research (20%), income (9%), physician
      support (9%), clinical programs (8%), and autonomy (5%); and other (4%).
      CONCLUSIONS: Surveying physicians who were recently hired or who have left an
      institution provides useful information to promote organizational changes that
      could improve physician retention.

PMID- 12480635
TI  - Differences in clinical experiences based on gender of third-year medical
      students in a required family medicine preceptorship.
AB  - PURPOSE: To investigate whether the gender of a student or preceptor affects the
      students' level of experience with clinical skills in a preceptorship. METHOD: A
      total of 451 third-year medical students completed a required family medicine
      preceptorship during three academic years (1997-2000) at one medical school.
      Students recorded their highest levels of experience with 57 clinical skills at
      the completion of the preceptorship using a five-point scale. Mean levels of
      experience were compared according to student and preceptor gender and by student
      preceptor gender dyads. RESULTS: For the majority of clinical skills, levels of
      experience did not differ according to gender of the student or preceptor.
      However, women students received more experience with seven of 12 female-specific
      skills and men students received more experience with two of three male-specific
      skills. Women preceptors provided more experience with seven of 12 female
      specific skills, as well as with depression and anxiety; men preceptors provided
      more experience with procedures. For the vast majority of gender-specific skills,
      the highest levels of student experience were received by pairs of students and
      preceptors of the same gender who were seeing patients of their same gender; the
      lowest levels of experience occurred in student-preceptor pairs of the same
      gender seeing patients of the opposite gender. There was no evidence for student
      preceptor interactions. CONCLUSIONS: The gender of a student and that of the
      preceptor affect the level of experience the student receives with a number of
      gender-specific skills and procedures. Ways should be found to minimize these
      differences in training.

PMID- 12480636
TI  - Performance assessment of community-based physicians: evaluating the reliability
      and validity of a tool for determining CME needs.
AB  - PURPOSE: To evaluate the reliability, validity, and feasibility of the Physician
      Assessment in Medical Practice (PAMP) as a means of determining the CME needs of
      practicing, community-based physicians. METHOD: A group of 45 randomly selected
      community-based physicians (19 certified family physicians and 26 general
      practitioners) affiliated with the Department of Family Medicine at Bruce
      Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel,
      volunteered to participate in the study, conducted in 1997. All participants took
      a ten-station, performance-based examination designed to closely represent the
      physicians' work settings. At each station, a different medical problem was
      presented by a standardized patient. Physician-candidates' performances were
      assessed by physician-examiners using global ratings. The following performance
      domains were assessed: information gathering, diagnosis and management plan, and
      communication skills. A CME needs assessment score was determined for each of the
      participants and a CME level to meet the needs of the physician was recommended.
      RESULTS: Overall reliability of the examination was high (.87), with domain
      reliabilities ranging from.76 to.87. Reliability of the examiners' judgments of
      the physicians' competence was.66. All the stations' validity scores were
      significant, and differences in performances between family physicians and
      general practitioners demonstrated construct validity of the test results.
      Overall, the cost of running the examination was U.S. $250 per physician
      candidate. CONCLUSIONS: Using the PAMP to determine CME needs of community-based
      physicians was found to reliable, valid, and feasible, and the cost per physician
      candidate was not excessive. Performance results provided indepth information for
      use by both the individual physician and providers of CME programs.

PMID- 12480637
TI  - Looking at the forest instead of counting the trees: an alternative method for
      measuring faculty's clinical education efforts.
AB  - PURPOSE: To present an alternative approach to mission-based management (MBM) for
      assessing the clinical teaching efforts of the faculty in the third and fourth
      years of medical students' education. METHOD: In fiscal years 2000 and 2001,
      interviews were conducted with department chairs and faculty members with major
      responsibilities in education at the University of Maryland School of Medicine.
      Using a standard worksheet, each rotation was categorized according to the
      amounts of time students spent in five teaching modes. After each department
      described its rotation and maximum teaching time, the department team and the MBM
      team negotiated the final credit received for its course. This final
      determination of departmental clinical teaching was used in subsequent
      calculations. Adjustments were made to the department clinical education time
      based on the teaching mode. Groups of medical students were surveyed to determine
      the relative value of each teaching mode. These relative values were then used to
      modify the clinical education times credited to the department. The last step was
      to distribute the effort of the faculty between clinical and educational
      missions. RESULTS: The data analysis showed approximately 57,000 credited faculty
      hours in one year for direct education of medical students in each curriculum
      year. These hours equal the annual workload of 28 full-time faculty members.
      CONCLUSIONS: A powerful use of MBM data is to move from thinking about resource
      allocation to thinking about the effective management of a complex organization
      with interlaced missions. Reliable data on faculty's contributions to medical
      students' education across departments enhances other MBM information and
      contributes to a picture of the dynamic interconnectedness of missions and
      departments.

PMID- 12480638
TI  - How physicians feel about assisting female victims of intimate-partner violence.
AB  - PURPOSE: To assess the feelings of physicians about assisting female victims of
      intimate-partner violence (IPV), and to examine factors related to positive and
      negative feelings about assisting victims of IPV. METHOD: In 1998, a total site
      sample of 150 physicians practicing in a large general hospital in the area of
      Virginia Beach, Virginia, was surveyed by questionnaire via the mail. Four
      specialties were represented: emergency medicine, family practice, obstetrics
      gynecology, and psychiatry. The questionnaire asked about medical training and
      training in assisting victims of IPV. The physicians' feelings about working with
      victims of IPV were measured on a nine-item, five-point semantic differential
      scale. RESULTS: A total of 76 physicians responded to the questionnaire (response
      rate = 51%). Only a minority (11%) had overall positive feeling scores about
      assisting victims of IPV. While most physicians reported that it was "significant
      work," the great majority also felt that it was difficult, low-paying, and
      stressful. Training in assisting victims of IPV, in medical school or afterwards,
      did not appear to influence feelings about assisting victims of IPV. However,
      physicians who were white and who were married (the majority of the respondents)
      were significantly more likely than the other respondents to feel negatively
      about providing services to victims of IPV. CONCLUSION: Graduate medical
      education and training programs need to address the association of negative
      feelings with helping women harmed by IPV, because these feelings may interfere
      with the appropriate screening, referral, and treatment of these victims.

PMID- 12480640
TI  - Patents, genomics, and academic medicine.

PMID- 12480641
TI  - A brief guide to understanding patentability and the meaning of patents.
AB  - This author provides a brief overview to the U.S. patent system with respect to
      DNA-based or gene patents, examines the statutory requirements for the U.S.
      Patent and Trademark Office (USPTO) and its processes of review, and explains how
      this system is implemented in the issue or decline of a patent. The author
      describes the important role played by the courts in their continuing
      reinterpretation and application of the patent law. He notes that many issues
      raised in discussions about the perceived benefits to society or general concerns
      arising from the patenting of gene sequences actually pertain to matters of
      enforcement and licensing of patents. These aspects, the author notes, lie
      outside of the USPTO's purview. Social questions about access to patented subject
      matter-such as the practice of patented gene-based diagnostic tests-must be
      addressed in other forums.

PMID- 12480642
TI  - Human gene patents.
AB  - The concept of a patent on a human gene seems foreign to most people. Even those
      who understand the fundamentals of the patent system seem bewildered and confused
      by many issues relating to human genes. This article describes the scope and
      limitations of gene patents and the types of exemptions that have been proposed
      or allowed. It addresses and clarifies these and other issues, including the
      often reported and misdirected question, Who "owns" one's genes? The paper
      reviews the historical origins of patents as a mechanism to provide incentives
      for innovation. It also discusses the legal criteria unambiguously supporting
      patenting of human genes that are isolated and purified apart from their
      naturally occurring context. Concerning enforcement and issues related to
      academic research, there is no U.S. statutory exemption for non-commercial
      research on patented subject matter, but a narrow, judicially-created exemption
      does permit use of patented subject matter for non-commercial purposes. Patents
      and licenses on gene-based diagnostic tests are properly enforceable and do not
      permit academic or other clinical practitioners to practice such tests without
      license or other authorization from the patent holder. The paper concludes that
      an effective legal system cannot draw sharp distinctions that some genes or uses
      are patentable to some parties while other genes are not. In addition, precluding
      certain genes from patentability would be shortsighted in that it would create
      prohibitions that might well be regretted in the future.

PMID- 12480643
TI  - Patents and research--an uneasy alliance.
AB  - Critics of the patent system have argued that rather than promoting the progress
      of science and the useful arts, the patent system as it exists in the United
      States and perhaps elsewhere may actually inhibit such progress. Much of the
      criticism has been focused on patenting of research tools. The author attempts to
      evaluate the extent of this effect, and to suggest some possible modifications to
      the patent system to address its shortcomings. She considers the advantages
      attributed to the patenting system-providing incentives for finance and
      development and spurring creativity-with the disadvantages perceived by the
      academic community, including impediments to the communication of research
      findings and other transaction costs. Also examined are possible options for
      mitigating these problems, including legislative restrictions of certain subject
      matter from patentability, or strengthening the criteria used in review of patent
      applications, especially non-obviousness and utility. In addition, the author
      discusses potential "post-patent solutions," such as legislative or other
      restrictions on licensing.

PMID- 12480644
TI  - Patents, genomics, research, and diagnostics.
AB  - Two kinds of currently available genomic patents may significantly interfere with
      medical research: (1) patents such as those on specific single nucleotide
      polymorphisms (SNPs), which may include claims that control the inference of
      phenotypic characteristics from specific genotypes, and (2) patents on computer
      based genomic information, databases, or manipulation procedures. These will
      create more serious encumbrances than will patents on expressed sequence tags
      (ESTs). Two approaches should be considered vis-a-vis these genomic patents: (1)
      Reconsideration and redefinition of the recent extensions of patentable subject
      matter into more and more intangible areas. This could be pursued by legislation
      or by test litigation to seek Supreme Court reversal of certain of the decisions
      of the Court of Appeals for the Federal Circuit (CAFC). (2) A narrow legislative
      exemption protecting the ability to use SNPs and phenotypic-genotypic
      relationships in medical research, including contexts in which medical research
      and clinical practice are substantially intertwined.

PMID- 12480645
TI  - The economics of human gene patents.
AB  - The author examines patents on DNA sequences, including data on gene sequence
      grants issued by the PTO during a 33-month period from 1998 to 2001. Policy
      supporting patents on DNA sequences and other elemental information that are far
      "upstream" in the product development pathway is contrasted with the economic
      bases and rationale for patents to pharmaceuticals, which require a protracted
      and expensive process of development and testing but that can be relatively
      cheaply and competitively imitated once they are approved and disclosed. How to
      allocate appropriately the economic returns among the upstream and downstream
      inventors is a challenging problem for economic theory, as well as for
      contemporary biomedical research, and is perhaps most familiarly embodied in
      licensing and cross-licensing disputes involving "reach-through" and "reach-back"
      rights. Such disputes can generate enormous transaction costs. They may become
      increasingly frequent and vexing with respect to the scope and overlap of patent
      claims on human gene sequences. On the basis of his analyses, the author argues
      that genome patent claims should be interpreted narrowly. He is particularly
      concerned with ensuring that the development of new (therapeutic) products is not
      blocked or retarded by a multiplicity of prior patent claims, but he is
      pessimistic that the diversity of participants in biotechnology will provide a
      "sufficient community of interest to organize comprehensive low-royalty cross
      licensing" regimes. Accordingly, he suggests mandatory arbitration as one
      mechanism for resolving such problems.

PMID- 12480646
TI  - Genome patents: a case study in patenting research tools.

PMID- 12480647
TI  - Gene patents and innovation.

PMID- 12480648
TI  - Why the gene patenting controversy persists.

PMID- 12480649
TI  - Medical practice and gene patents: a personal perspective.

PMID- 12480650
TI  - Public vs. proprietary science: a fruitful tension?
AB  - The authors examine the presumption that basic scientific research is most
      effectively utilized when the findings of that research are openly disseminated
      without significant restriction, while research with more practical application
      should be the prerogative of private enterprise. However, many fields, including
      molecular biology generally and genomics in particular, lie in the intersection
      between basic research and application. Moreover, institutional boundaries that
      once reasonably sharply demarcated basic research from technological development
      have grown porous, with more academic research finding application in industry.
      The authors consider the Human Genome Project and rival industry sequencing
      efforts as a case in point of the new political economy of scientific research.
      Since the inception of the Human Genome Project, there has been general agreement
      among researchers that the project would be most advantageous to science if the
      sequence data were made publicly available, quickly and without restriction. Many
      of these arrangements required federal agencies and some universities to
      "maneuver around" the Bayh-Dole Act. In several cases, most notably genomic
      sequences and the SNPs (i.e., single nucleotide polymorphisms) consortium, it was
      the pharmaceutical industry that initiated or helped enable the project to ensure
      open and unencumbered access to information, the type of access that has
      historically been the provenance of academia and the raison d'etre of academic
      research. The authors conclude by reasserting the value of public science as a
      broadly valuable and enabling social commitment, not limited simply to the
      products or technologies it spawns.

PMID- 12480651
TI  - Increases in hypertension and blood pressure during pregnancy with increased bone
      lead levels.
AB  - Prior studies have revealed associations of current lead exposure (blood lead)
      and past lead exposure (bone lead) with risks of hypertension and elevated blood
      pressure. The authors examined the effects of blood and bone lead on hypertension
      and elevated blood pressure in the third trimester and postpartum among 1,006
      women enrolled in Los Angeles prenatal care clinics between 1995 and 2001. The
      authors measured bone lead concentration by K-shell x-ray fluorescence in the
      tibia (mean = 8.0 micro g/g (standard deviation (SD) 11.4)) and calcaneus (heel)
      (mean = 10.7 micro g/g (SD 11.9)). Geometric mean prenatal and postnatal blood
      lead levels were 1.9 micro g/dl (geometric SD +3.6/-1.0) and 2.3 micro g/dl
      (geometric SD +4.3/-1.2), respectively. For each 10- micro g/g increase in
      calcaneus bone lead level, the odds ratio for third-trimester hypertension
      (systolic blood pressure > or =140 mmHg or diastolic blood pressure > or =90
      mmHg) was 1.86 (95% confidence interval (CI): 1.04, 3.32). In normotensive
      subjects, each 10- micro g/g increase in calcaneus bone lead level was associated
      with a 0.70-mmHg (95% CI: 0.04, 1.36) increase in third-trimester systolic blood
      pressure and a 0.54-mmHg (95% CI: 0.01, 1.08) increase in diastolic blood
      pressure. Tibia bone lead concentration was not related to hypertension or
      elevated blood pressure either in the third trimester or postpartum, nor was
      calcaneus bone lead related to postpartum hypertension or elevated blood
      pressure. Past lead exposure influences hypertension and elevated blood pressure
      during pregnancy. Controlling blood pressure may require reduction of lead
      exposure long before pregnancy.

PMID- 12480652
TI  - Invited commentary: lead, bones, women, and pregnancy--the poison within?

PMID- 12480653
TI  - Hostility predicts recurrent events among postmenopausal women with coronary
      heart disease.
AB  - Psychosocial characteristics may be associated with an increased risk of coronary
      heart disease (CHD). Whether hostility predicts recurrent coronary events is
      unknown. A total of 792 women in the Heart and Estrogen/progestin Replacement
      Study (HERS) were evaluated prospectively to determine the role of hostility as a
      risk factor for secondary CHD events (nonfatal myocardial infarction and CHD
      death). The mean age of study participants was 67 years, and the average length
      of follow-up was 4.1 years. The study was conducted between 1993 and 1998, and
      all study sites were in the United States. High Cook-Medley hostility scores were
      associated with greater body mass index (p = 0.01) and higher levels of serum
      triglycerides (p = 0.05), and they were inversely associated with high density
      lipoprotein cholesterol (p = 0.04), self-rated general health (p < 0.001), age (p
      = 0.05), and education (p = 0.001). Compared with women in the lowest hostility
      score quartile, women in the highest quartile were twice as likely to have had a
      myocardial infarction (relative hazard = 2.03, 95% confidence interval: 1.02,
      4.01). The relation between hostility and CHD events was not mediated or
      confounded by the biologic, behavioral, and social risk factors studied. In this
      study, hostility was found to be an independent risk factor for recurrent CHD
      events in postmenopausal women.

PMID- 12480654
TI  - Is there a sex difference in the association between birth weight and systolic
      blood pressure in later life? Findings from a meta-regression analysis.
AB  - The aim of this study was to determine whether a sex difference exists in the
      association between birth weight and systolic blood pressure. A meta-analysis of
      all observational studies (n = 57) in which the study population contained both
      males and females and the association between birth weight and blood pressure was
      presented as a linear regression coefficient was undertaken. There were no
      differences in the pooled regression coefficients between males and females
      combining all studies; the regression of blood pressure on birth weight for males
      was -1.27 (95% confidence interval: -1.77, -0.77) mmHg/kg and for females was 
      1.24 (95% confidence interval: -1.90, -0.58) mmHg/kg. When studies in which blood
      pressure had been measured in childhood were considered separately from those in
      which it was measured in adulthood, there were no sex differences in either age
      group. The pooled regression coefficient tended to be weaker in studies reporting
      sex-specific results than in those reporting combined results. These findings
      suggest that reports of sex differences in the association between birth weight
      and blood pressure are chance findings.

PMID- 12480655
TI  - Homocysteine and blood pressure in the Third National Health and Nutrition
      Examination Survey, 1988-1994.
AB  - Studies suggest that homocysteine may elevate blood pressure and increase the
      risk of hypertension. The association of homocysteine with blood pressure and
      with the risk of hypertension was investigated using cross-sectional data from
      the Third National Health and Nutrition Examination Survey (1998-1994).
      Homocysteine had an independent positive association with blood pressure after
      adjusting for cardiovascular risk factors. A 1 standard deviation ( approximately
      5 micro mol/liter) increase in homocysteine was associated with increases in
      diastolic and systolic blood pressure of 0.5 and 0.7 mmHg, respectively, in men
      and of 0.7 and 1.2 mmHg in women. Similarly, higher levels of homocysteine were
      associated with an increased risk of hypertension. In a comparison of the highest
      and lowest quintiles of homocysteine, women had a threefold increase in the risk
      of hypertension (95% confidence interval (CI): 1.7, 5.4), and men had a twofold
      increase (95% CI: 0.7, 5.1). In light of the homocysteine-blood pressure
      association, the association of homocysteine with prevalent cardiovascular
      disease was examined with and without adjusting for blood pressure. The results
      support a mediating role for blood pressure in women and suggest that the full
      effect of homocysteine on cardiovascular risk may be underestimated when blood
      pressure is adjusted.

PMID- 12480656
TI  - Adenocarcinoma of the lung is strongly associated with cigarette smoking: further
      evidence from a prospective study of women.
AB  - In a prospective cohort of 41,836 Iowa women aged 55-69 years with 13 years of
      follow-up from 1986 through 1998, the authors examined the association between
      cigarette smoking history and three common histologic subtypes of lung cancer
      (123 small cell, 115 squamous cell, and 234 adenocarcinoma). Using Cox
      proportional hazards and additive Poisson regression analysis, they estimated
      four epidemiologic measures of effect: age-adjusted incidence rate, relative
      risk, excess risk (or risk difference), and population attributable risk. Of the
      three major lung cancer subtypes, the excess risk for heavy smokers compared with
      never smokers was higher for adenocarcinoma (excess risk = 206) than for squamous
      cell (excess risk = 122) and small cell (excess risk = 104) carcinomas.
      Adenocarcinoma of the lung is more strongly associated with tobacco smoke
      exposure than previously recognized.

PMID- 12480657
TI  - Exposure to different forms of nickel and risk of lung cancer.
AB  - The International Agency for Research on Cancer has classified nickel compounds
      as carcinogenic to humans, but it is still not known with certainty which forms
      of nickel pose the risk. In a case-control study of Norwegian nickel-refinery
      workers, the authors examined dose-related associations between lung cancer and
      cumulative exposure to four forms of nickel: water-soluble, sulfidic, oxidic, and
      metallic. A job-exposure matrix was based on personal measurements of total
      nickel in air and quantification of the four forms of nickel in dusts and
      aerosols. Data on smoking habits were collected for 213 cases identified in the
      Cancer Registry of Norway between 1952 and 1995 and 525 age-matched controls (94%
      participation rate). The nickel exposures were moderately to highly correlated. A
      clear dose-related effect was seen for water-soluble nickel (odds ratio = 1.7 per
      unit in the log(e)-transformed exposure, ln[(cumulative exposure) + 1],
      originally given in (mg/m(3)) x years (95% confidence interval: 1.3, 2.2)). A
      general rise in risk from other types of nickel could not be excluded, but no
      further dose-dependent increase was seen. Smoking was a weak to moderate
      confounder. The study suggests an important role of water-soluble nickel species
      in nickel-related cancer.

PMID- 12480658
TI  - Uropathogenic Escherichia coli are more likely than commensal E. coli to be
      shared between heterosexual sex partners.
AB  - Because uropathogenic Escherichia coli are better adapted than other E. coli to
      the urethra, periurethra, and vagina, the authors reasoned that uropathogenic E.
      coli would be more likely than commensal E. coli to be shared between sex
      partners. In this 1996-1999 Michigan study, the genetic identity of E. coli
      isolated from 166 women with E. coli urinary tract infection (UTI) and 94 women
      without UTI and their sex partners was determined by pulsed-field gel
      electrophoresis. Rectal isolates were considered uropathogenic E. coli if
      genetically identical to the urinary isolate causing UTI. All eight urinary
      isolates from men with UTI partners were identical to the E. coli found in the
      urine or vagina of their sex partner. When the 550 unique rectal E. coli isolates
      from couples were considered the unit of analysis, E. coli that caused UTI were
      nine times (odds ratio (OR) = 8.87, 95% confidence interval (CI): 5.41, 14.54)
      more likely than other E. coli to be shared between sex partners. Sharing
      occurred twice as frequently (OR = 1.87, 95% CI: 1.13, 3.08) if the E. coli had P
      pili or if the couples engaged in oral sex (OR = 2.09, 95% CI: 1.09, 4.00).
      Uropathogenic E. coli are more likely than commensal E. coli to be shared with a
      current heterosexual sex partner. Both sexual behaviors and a bacterial virulence
      factor, P pili, modified sharing.

PMID- 12480659
TI  - Defective waste disposal: does it induce autoantibodies in SLE?

PMID- 12480661
TI  - Will pharmacogenetics allow better prediction of methotrexate toxicity and
      efficacy in patients with rheumatoid arthritis?
AB  - Methotrexate (MTX) remains the most commonly used disease modifying antirheumatic
      drug in rheumatoid arthritis (RA) because of its cost and experience in its use,
      despite the availability of new treatments such as leflunomide and the biological
      agents. However, a significant number of patients with RA either do not benefit
      from the drug or are unable to tolerate it. Pharmacogenetic approaches may help
      optimise treatment with MTX, and also other agents, in RA.

PMID- 12480662
TI  - Time between onset of apoptosis and release of nucleosomes from apoptotic cells:
      putative implications for systemic lupus erythematosus.
AB  - OBJECTIVE: To investigate the kinetics of nucleosome leakage from apoptotic cells
      in an in vitro system and extrapolate the results to autoimmune disease, in
      particular systemic lupus erythematosus. METHODS: A sensitive nucleosome enzyme
      linked immunosorbent assay (ELISA) was developed, using a monoclonal antibody
      (mAb) against histone 3 and an mAb against nucleosomes. Nucleosome release during
      apoptotic cell death was studied in Jurkat cells. AnnexinV binding (early
      apoptosis) and propidium iodide positivity (late apoptosis) of the cells were
      compared with nucleosome release at different times after apoptosis induction.
      RESULTS: Nucleosomes appeared in culture supernatant of Jurkat cells 24 to 48
      hours after apoptosis induction, when the cells had been late apoptotic for more
      than 12 hours. CONCLUSION: Nucleosomes are released from late apoptotic Jurkat
      cells, with a 12 hour delay from the appearance of AnnexinV binding cells. This
      result suggests that in vivo scavenger mechanisms have 12 hours to remove
      apoptotic material from the circulation.

PMID- 12480663
TI  - Contribution of patient related differences to multidrug resistance in rheumatoid
      arthritis.
AB  - BACKGROUND: There is a wide variation in responses to standard disease modifying
      antirheumatic drug (DMARD) treatment in rheumatoid arthritis (RA). Whether
      multidrug resistance, failure to respond to several DMARDs, is a specific entity
      over and above that expected by chance alone is unclear. OBJECTIVE: To identify
      patients with RA who demonstrate a multidrug resistant phenotype and to determine
      what proportion of the variance in drug responses is due to patient related
      factors. METHODS: Patients with RA (1987 American College of Rheumatology
      criteria) were identified from clinics at Manchester Royal Infirmary and through
      the Arthritis Research Campaign National RA Repository. The clinic records were
      reviewed and multidrug resistance was defined as stopping three or more DMARDs
      owing to lack of efficacy after an adequate trial of the drug. Logistic
      regression measured by a random effects model was used to determine the relative
      contribution of the drug and subject related differences to the multidrug
      resistance. RESULTS: 265 patients (210 (79.3%) female) were studied. The mean
      (SD) age and disease duration were 52.2 (12.9) and 10.7 (8.8) years,
      respectively. Patients had a median (range) of 2 (1-8) DMARD courses. Failure of
      at least one DMARD due to inefficacy occurred in 105 (40%) and 13 (5%) were
      multidrug resistant. Overall, 35% of the variance in drug responses was due to
      between-subject differences (p=0.02). Rheumatoid factor (RF) status contributed
      significantly to this (OR=2.15, 95% confidence interval (95% CI) 1.00 to 4.62)
      but explained only 3% of the total variance in drug inefficacy. CONCLUSION:
      Multidrug resistance occurs in an uncommon (5%) but important subgroup of
      patients with RA. The between-subject variance is not fully explained by
      demographics and RF status. Understanding the biological mechanisms that
      contribute to multidrug resistance may suggest new therapeutic approaches and
      targets in RA.

PMID- 12480664
TI  - Development of the ASQoL: a quality of life instrument specific to ankylosing
      spondylitis.
AB  - BACKGROUND: Although disease-specific health status measures are available for
      ankylosing spondylitis (AS), no instrument exists for assessing quality of life
      (QoL) in the condition. OBJECTIVE: To produce an AS-specific QoL measure that
      would be relevant and acceptable to respondents, valid, and reliable. METHODS:
      The ASQoL employs the needs-based model of QoL and was developed in parallel in
      the UK and the Netherlands (NL). Content was derived from interviews with
      patients in each country. Face and content validity were assessed through patient
      field test interviews (UK and NL). A postal survey in the UK produced a more
      efficient version of the ASQoL, which was tested for scaling properties,
      reliability, internal consistency, and validity in a further postal survey in
      each country. RESULTS: A 41 item questionnaire was derived from interview
      transcripts. Field testing interviews confirmed acceptability. Rasch analysis of
      data from the first survey (n=121) produced a 26 item questionnaire. Rasch
      analysis of data from the second survey (UK: n=164; NL: n=154) showed some item
      misfit, but showed that items formed a hierarchical order and were stable over
      time. Problematic items were removed giving an 18 item scale. Both language
      versions had excellent internal consistency (alpha=0.89-0.91), test-retest
      reliability (r(s)=0.92 UK and r(s)=0.91 NL), and validity. CONCLUSIONS: The ASQoL
      provides a valuable tool for assessing the impact of interventions for AS and for
      evaluating models of service delivery. It is well accepted by patients, taking
      about four minutes to complete, and has excellent scaling and psychometric
      properties.

PMID- 12480665
TI  - Procollagen II C propeptide level in the synovial fluid as a predictor of
      radiographic progression in early knee osteoarthritis.
AB  - OBJECTIVE: To investigate the prognostic value of procollagen type II carboxy
      terminal propeptide (PIICP) level in synovial fluid in relation to early
      tibiofemoral joint osteoarthritis (OA). METHODS: Data were collected on 172 women
      (age 40 to 59 years) who had knee pain and tibiofemoral joint OA in the early
      stage. Standing semiflexed knee radiographs were obtained by fluoroscopy at
      baseline and at four year follow up and a computerised, magnification corrected
      measurement system was applied to measurement of minimal joint space width in the
      tibiofemoral compartment. Synovial fluid sampling was performed at baseline and
      at the four year follow up. Levels of PIICP in the synovial fluid were measured
      by enzyme immunoassay. The outcome measures were assessed by radiographic joint
      space narrowing (JSN) in the tibiofemoral joints over four years. Multiple linear
      regression analyses were used to examine the relation between radiographic JSN
      and synovial fluid level of PIICP. RESULTS: The number of women available at both
      baseline and at four year follow up was 110. The average of radiographic JSN over
      four years was 0.53 mm (range 0.00-2.01). Body mass index showed a slightly
      positive association with baseline PIICP level. In multiple linear regression
      analyses adjusted for age and body mass index, radiographic JSN over four years
      had a direct positive correlation with baseline PIICP level (r=0.395; 95%
      confidence interval (95% CI) 0.231 to 0.529; p<0.001). CONCLUSION: In a four year
      prospective study of women, quantification of synovial fluid PIICP was able to
      predict subsequent radiographic progression in early tibiofemoral joint OA.

PMID- 12480666
TI  - Smoking and musculoskeletal disorders: findings from a British national survey.
AB  - OBJECTIVES: To explore the relation between smoking habits and regional pain in
      the general population. METHODS: A questionnaire was mailed to 21 201 adults,
      aged 16-64 years, selected at random from the registers of 34 British general
      practices, and to 993 members of the armed services, randomly selected from pay
      records. Questions were asked about pain in the low back, neck, and upper and
      lower limbs during the past 12 months; smoking habits; physical activities at
      work; headaches; and tiredness or stress. Associations were examined by logistic
      regression and expressed as prevalence ratios (PRs). RESULTS: Questionnaires were
      completed by 12 907 (58%) subjects, including 6513 who had smoked at some time,
      among whom 3184 were current smokers. Smoking habits were related to age, social
      class, report of headaches, tiredness or stress, and manual activities at work.
      After adjustment for potential confounders, current and ex-smokers had higher
      risks than lifetime non-smokers for pain at all of the sites considered. This was
      especially so for pain reported as preventing normal activities (with PRs up to
      1.6 in current v never smokers). Similar associations were found in both sexes,
      and when analysis was restricted to non-manual workers. CONCLUSIONS: There is an
      association between smoking and report of regional pain, which is apparent even
      in ex-smokers. This could arise from a pharmacological effect of tobacco smoke
      (for example, on neurological processing of sensory information or nutrition of
      peripheral tissues); another possibility is that people with a low threshold for
      reporting pain and disability are more likely to take up and continue smoking.

PMID- 12480667
TI  - Immune complexes from SLE sera induce IL10 production from normal peripheral
      blood mononuclear cells by an FcgammaRII dependent mechanism: implications for a
      possible vicious cycle maintaining B cell hyperactivity in SLE.
AB  - BACKGROUND: Raised interleukin (IL)6 and IL10 levels are thought to contribute to
      the pathogenesis of systemic lupus erythematosus (SLE) by enhancing autoantibody
      production and immune complex (IC) formation. These immune complexes can then
      stimulate cellular reactions through Fc and complement receptors. OBJECTIVE: To
      investigate whether circulating SLE ICs stimulate type 2 cytokine production.
      METHODS: Twenty serum samples from patients with active SLE were compared with
      sera from 18 healthy controls. Sera and polyethylene glycol (PEG) precipitates
      from sera were added to peripheral blood mononuclear cell (PBMC) cultures, and
      the production of IL10 and IL6 was investigated by enzyme linked immunospot assay
      (ELISPOT) and enzyme linked immunosorbent assay (ELISA). Fc gamma receptor
      (FcgammaR) antibodies were used in blocking experiments, and flow cytometry was
      used to assess the correlation between monocyte FcgammaR expression and IC
      induced cytokine production. RESULTS: Ten per cent dilutions of the SLE sera
      induced a significantly increased number of IL10-producing cells in comparison
      with control sera (median, 11.75 v 1.25 spot forming cells/50 000 PBMC;
      p<0.0001). PEG precipitates from SLE sera also induced significantly increased
      levels of IL10 (p=0.016) and IL6 (p=0.042) in comparison with control PEG
      precipitates. IL10 production induced by SLE PEG precipitates or by artificial
      ICs could be blocked by anti-FcgammaRII antibodies, and the FcgammaRII expression
      on CD14+ monocytes correlated with the IC-induced production of IL10 and IL6.
      CONCLUSIONS: SLE sera stimulate IL10 and IL6 production from PBMC, and this
      effect is at least partly explained by precipitable ICs acting through
      FcgammaRII. This effect provides a possible mechanism for the enhanced production
      of IL10 in SLE, whereby B cell activation, antibody production, IC stimulated
      monocytes/macrophages, and type 2 cytokines create a vicious cycle that may help
      to maintain B cell hyperactivity in SLE.

PMID- 12480668
TI  - Analysis of lapine cartilage matrix after radiosynovectomy with holmium-166
      ferric hydroxide macroaggregate.
AB  - OBJECTIVE: To study the short and long term effects of radiosynovectomy on
      articular cartilage in growing and mature rabbits. METHODS: The articular
      cartilage of the distal femurs of rabbits was examined four days, two months, and
      one year after radiosynovectomy with holmium-166 ferric hydroxide macroaggregate
      ([(166)Ho]FHMA). Arthritic changes were evaluated from histological sections by
      conventional and polarised light microscopy, and glycosaminoglycan measurements
      using safranin O staining, digital densitometry, and uronic acid determination.
      Proteoglycan synthesis was studied by metabolic [(35)]sulphate labelling followed
      by autoradiography, and electrophoretic analysis of extracted proteoglycans.
      Northern analyses were performed to determine the mRNA levels of type II
      collagen, aggrecan, and Sox9 in cartilage samples. RESULTS: Radiosynovectomy had
      no major effect on the histological appearance of articular cartilage in mature
      rabbits, whereas more fibrillation was seen in [(166)Ho]FHMA radiosynovectomised
      knee joints of growing rabbits two months after treatment, but not after one
      year. Radiosynovectomy did not cause changes in the glycosaminoglycan content of
      cartilage or in the synthesis or chemical structure of proteoglycans. No
      radiosynovectomy related changes were seen in the mRNA levels of type II
      collagen, whereas a transient down regulation of aggrecan and Sox9 mRNA levels
      was seen in young rabbits two months after [(166)Ho]FHMA radiosynovectomy.
      CONCLUSIONS: [(166)Ho]FHMA radiosynovectomy caused no obvious chondrocyte damage
      or osteoarthritic changes in mature rabbits, but in growing rabbits some
      transient radiation induced effects were seen--for example, mild cartilage
      fibrillation and down regulation of cartilage-specific genes.

PMID- 12480670
TI  - Suicide attempts in patients with systemic lupus erythematosus.
AB  - BACKGROUND: Suicide and suicide attempts, although well recognised in patients
      with systemic lupus erythematosus (SLE), have been commented on relatively
      little. OBJECTIVE: To obtain a better understanding of the reasons for suicidal
      behaviour in patients with SLE. METHODS: The records of 300 patients with SLE
      were reviewed to identify completed or attempted suicides. RESULTS: Five patients
      made seven attempts at suicide over a 20 year follow up period; one of them was
      fatal. All of those attempting suicide had a history of neuropsychiatric SLE
      (NPSLE) presenting with depression and they made the attempts soon after the
      onset of NPSLE (median time 12.5 months). Two patients had appreciable disease
      activity at the time of the suicide attempt. Lymphopenia was present in five
      suicide attempts. Anti-SSA/Ro antibodies were detected in three patients, none of
      whom had anti-SSB/La. All patients apart from one responded to treatment for
      depression; the remaining female patient made two subsequent suicide attempts,
      with a fatal outcome despite intensive treatment. CONCLUSION: Greater awareness
      of the risk of suicide in patients with psychiatric manifestations of SLE may
      help to reduce the incidence of this potentially fatal phenomenon.

PMID- 12480671
TI  - Joint and soft tissue injections in the community: questionnaire survey of
      general practitioners' experiences and attitudes.
AB  - OBJECTIVES: To investigate the numbers and types of joint and soft tissue
      injections performed by general practitioners (GPs) and to explore attitudes to
      training in joint and soft tissue injection and perceived barriers to performing
      injections. METHODS: A self administered questionnaire was mailed to a random
      sample of 410 (30%) of 1367 GPs in Northern Ireland. Two mailings were used to
      increase the response rate. Questions explored the GPs' demographic
      characteristics, types and numbers of injections performed, previous training
      experience, attitudes towards training, and perceived barriers. RESULTS: The
      overall response rate was 75%. Practitioners who were men, worked in a "rural" or
      "mixed" locality, and had had a previous post in rheumatology, orthopaedics, or
      sports medicine were more likely to perform joint and soft tissue injections.
      Forty six per cent of GPs did not currently perform any injections; 5% of GPs
      performed most of the injections in the community. Injections into the shoulder,
      knee, and lateral epicondylitis were found to be the most commonly performed
      injections. The GPs preferred to train on "real patients" rather than "mannequin
      models". Those GPs who had trained on "real patients" were more likely to perform
      injections. The main perceived barrier to performing joint and soft tissue
      injections in the community was the "inability to maintain injection skills".
      CONCLUSION: Postgraduate training, methods of training, and the ability to
      maintain injection skills seemed to be determinants affecting GP confidence and
      the amount of joint and soft tissue injections that they performed. Most
      injections were performed by a few GPs in the community. These findings may have
      implications for the developing role of GP specialists in primary care trusts.

PMID- 12480669
TI  - Infectious CNS disease as a differential diagnosis in systemic rheumatic
      diseases: three case reports and a review of the literature.
AB  - BACKGROUND: Immunosuppressive treatment of rheumatic diseases may be associated
      with several opportunistic infections of the brain. The differentiation between
      primary central nervous system (CNS) involvement and CNS infection may be
      difficult, leading to delayed diagnosis. OBJECTIVE: To differentiate between CNS
      involvement and CNS infection in systemic rheumatic diseases. METHODS AND
      RESULTS: Three patients with either longstanding or suspected systemic rheumatic
      diseases (systemic lupus erythematodes, Wegener's granulomatosis, and cerebral
      vasculitis) who presented with various neuropsychiatric symptoms are described.
      All three patients were pretreated with different immunosuppressive drugs
      (leflunomide, methotrexate, cyclophosphamide) in combination with
      corticosteroids. Magnetic resonance imaging of the brain was suggestive of
      infectious disease, which was confirmed by cerebrospinal fluid analysis or
      stereotactic brain biopsy (progressive multifocal leucoencephalopathy (PML) in
      two and nocardiosis in one patient). DISCUSSION: More than 20 cases of PML or
      cerebral nocardiosis in patients receiving corticosteroids and cytotoxic drugs
      for rheumatic disease have been reported. The clinical aspects of opportunistic
      CNS infections and the role of brain imaging, cerebrospinal fluid analysis and
      stereotactic brain biopsy in the differential diagnosis are reviewed.

PMID- 12480673
TI  - Evaluation of free and peptide bound collagen crosslink excretion in different
      skeletal diseases.
AB  - OBJECTIVE: To investigate urinary fractions of free and peptide forms of collagen
      crosslinks in patients with rheumatoid arthritis (n=50), osteoarthrosis (n=38),
      psoriatic arthritis (n=38) and in healthy volunteers (33 adults, 17 children).
      METHODS: Pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high
      performance liquid chromatography. RESULTS: In rheumatoid arthritis (RA) all
      fractions of PYD and DPD were significantly raised compared with osteoarthritis,
      psoriatic arthritis, and healthy controls. PYD and DPD correlated with disease
      activity in RA. In RA the collagen degradation resulted in primarily peptide
      bound forms. CONCLUSION: The correlation between total peptide bound or free
      collagen crosslinks in different chronic joint diseases varies; however, this
      variation does not allow for a reliable differentiation between inflammatory and
      degenerative joint diseases.

PMID- 12480674
TI  - A polyarticular onset predicts erosive and deforming disease in psoriatic
      arthritis.
AB  - OBJECTIVES: To analyse the factors predicting erosive-deforming arthropathy in
      patients with psoriatic arthritis (PsA). METHODS: A prospective cohort study was
      undertaken with 71 patients diagnosed as having PsA (44 men and 27 women, mean
      age 47 (SD 12) years). At the recruitment period patients had disease without
      evidence of radiological damage. Patients were studied and followed up according
      to a standard protocol from January 1991 to June 2001. Erosive and deforming
      disease was defined by the presence of erosions, joint space narrowing,
      subluxation, and/or ankylosis of peripheral joints. Univariate and multivariate
      analyses were performed to evaluate factors predicting erosive and deforming
      disease. RESULTS: At the end of the study 32 of 71 (45%) patients had developed
      erosive and deforming disease. Among them, 18 of 32 (56%) had a polyarticular
      onset, two of 32 (6%) showed a distal interphalangeal joint disease onset, six of
      32 (19%) presented with oligoarthritis, and six of 32 (19%) presented with axial
      disease as the form of disease onset (p=0.001). Mean time to detect erosions or
      joint space narrowing was 20 (SD 4) months. Men showed fewer erosions than women
      (p=0.05). Patients who carried the HLA-B27 antigen showed less erosive disease
      than patients who lacked it (p=0.05). Patients with erosive and deforming disease
      had poorer functional performance than those without it as measured with the
      Health Assessment Questionnaire (HAQ) and the American College of Rheumatology
      (ACR) criteria (p<0.05 with both measurements). In multivariate analysis, only a
      polyarticular onset remained as an indicator of erosive and deforming disease
      (odds ratio (OR) 37, 95% confidence interval (95% CI) 3.6 to 88, p=0.025).
      CONCLUSIONS: A polyarticular onset (five or more swollen joints) of PsA was the
      unique independent risk factor which predicted the appearance of erosive and
      deforming disease over time. These data may be useful for clinicians treating
      patients with PsA, as it may guide treatment towards a more aggressive and
      earlier intervention.

PMID- 12480675
TI  - Polymerase chain reaction based C4AQ0 and C4BQ0 genotyping: association with
      systemic lupus erythematosus in southwest Han Chinese.
AB  - OBJECTIVE: To investigate the association of complement C4 null genes (C4Q0,
      including C4AQ0 and C4BQ0) and C2 gene with systemic lupus erythematosus (SLE) in
      southwest Han Chinese; 136 patients with SLE and 174 matched controls were
      genotyped. METHODS: C4 null genes were determined by a polymerase chain reaction
      (PCR) procedure with sequence specific primers (PCR-SSP). The 2 bp insertion in
      exon 29, which was previously identified in non-Chinese populations and caused
      defective C4A genes, was directly typed by sequencing the whole exon 29 using
      exon specific primers. The exon 6 of complement C2 was also sequenced in both the
      patients and controls. RESULTS: The frequency of homozygous C4AQ0 allele was
      12.5% (17/136) in patients with SLE compared with 1.1% (2/174) in controls
      (p<0.001, odds ratio (OR)=12.286, 95% confidence interval (95% CI) 2.786 to
      54.170). There was no significant difference for homozygous C4BQ0 allele between
      patients with SLE and controls (p=0.699). Patients with the C4AQ0 gene had an
      increased risk of acquiring renal disorder, serositis, and anti-dsDNA antibodies
      compared with those without C4AQ0 (for renal disorder, p=0.018, OR=8.951, 95% CI
      1.132 to 70.804; for serositis, p=0.011, OR 4.891, 95% CI 1.574 to 15.198; for
      anti-dsDNA, p=0.004, OR 7.630, 95%CI 1.636 to 35.584). None of the patients or
      controls had the 2 bp insertion in exon 29 of the C4 gene. The type I C2
      deficiency was not detected in the 310 samples. CONCLUSION: It is suggested that
      deficiency of C4A (not due to a 2 bp insertion in exon 29), but not C4B or C2,
      may be a risk factor for acquiring SLE in south west Han Chinese; this results in
      increased risk of renal disorder, serositis, and anti-dsDNA antibodies in
      patients with SLE. Racial differences seem to be relevant in susceptibility to
      SLE

PMID- 12480676
TI  - Efficacy of etanercept for treatment of Crohn's related spondyloarthritis but not
      colitis.
AB  - The seronegative spondyloarthropathies (SpAs) are associated both with clinical
      and subclinical colitis. Recently biological blockade with the tumour necrosis
      factor alpha (TNFalpha) antagonists infliximab and etanercept has been shown to
      be effective in the treatment of SpA. However, only infliximab is efficacious in
      the treatment of colitis in patients with Crohn's SpA. We report on two patients
      with SpA and associated Crohn's disease treated with etanercept whose arthritis
      showed an excellent response with complete resolution of spinal pathology,
      whereas their Crohn's disease persisted or flared. These findings suggest that
      the effect of TNFalpha blockade in SpA differs between the joint and the bowel.

PMID- 12480677
TI  - Cell death by apoptosis is a feature of the rheumatoid nodule.
AB  - OBJECTIVE: To examine the site and extent of apoptosis in the rheumatoid nodule
      and to determine whether this process make a significant contribution to the
      control of inflammation in the rheumatoid nodule as in other granulomas. METHODS:
      Nine nodules and seven synovial membranes were examined by terminal
      deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) in situ and a
      subset was further examined by DNA electrophoresis. The phenotype of apoptotic
      cells was identified using monoclonal antibodies and immunohistology. RESULTS:
      Apoptosis occurred in all zones of the nodule and, except in one case, was not
      focused adjacent to the necrotic centre. Apoptosis occurred in 3.5 (4.5)% (mean
      (SD)) of cells in the nodule and 3.6 (3.1)% of cells in synovial membranes.
      Apoptosis was more common in nodule T cells (4.1 (2.9)%) than fibroblasts (1.0
      (1.4)%), p = 0.01. Among macrophages 3.2 (4.7)% were apoptotic. Banding of DNA
      consistent with apoptosis was seen in two of three nodules examined. CONCLUSION:
      Apoptosis occurs at a low level in the nodule, similar to the synovial membrane.
      The results suggest that two modes of cell death occur in the nodule: apoptosis,
      which occurs throughout the nodule; and necrosis, which is concentrated near the
      necrotic centre. Apoptosis was more common in infiltrating inflammatory cells
      than in resident fibroblasts. These results are consistent with the proposal that
      apoptosis of infiltrating inflammatory cells is important in controlling
      accumulation of cells in the rheumatoid nodule as has been established in
      experimental granulomas.

PMID- 12480678
TI  - Severe septicaemia in a patient with polychondritis and Sweet's syndrome after
      initiation of treatment with infliximab.

PMID- 12480679
TI  - Adrenomedullin in synovial fluids from patients with rheumatoid arthritis
      inhibits interleukin 6 production from synoviocytes.

PMID- 12480680
TI  - Abnormal IgA levels in patients with rheumatoid arthritis.

PMID- 12480681
TI  - Asymptomatic diffuse pulmonary embolism caused by acrylic cement: an unusual
      complication of percutaneous vertebroplasty.

PMID- 12480682
TI  - No association between human parvovirus B19 infection and Sjogren's syndrome.

PMID- 12480683
TI  - Recurrent uveitis in a patient with juvenile spondyloarthropathy associated with
      tumour necrosis factor alpha inhibitors.

PMID- 12480684
TI  - Enhancement by iron of interleukin 1 induced granulocyte macrophage colony
      stimulating factor (GM-CSF) production by human synovial fibroblasts.

PMID- 12480685
TI  - Clinical analysis of gouty patients with normouricaemia at diagnosis.

PMID- 12480686
TI  - HLA-DRB1*03 and DQB1*0302 associations in a subset of patients severely affected
      with systemic lupus erythematosus from western India.

PMID- 12480687
TI  - Classification criteria for Sjogren's syndrome.

PMID- 12480688
TI  - Etanercept treatment of rheumatoid arthritis in the "real world".

PMID- 12480689
TI  - A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human
      beta-globin gene transfer.
AB  - Patients affected by beta-thalassemia major require lifelong transfusions because
      of insufficient or absent production of the beta chain of hemoglobin (Hb). A
      minority of patients are cured by allogeneic bone marrow transplantation. In the
      most severe of the hitherto available mouse models of beta-thalassemia, a model
      for human beta-thalassemia intermedia, we previously demonstrated that globin
      gene transfer in bone marrow cells is curative, stably raising Hb levels from 8.0
      8.5 to 11.0-12.0 g/dL in long-term chimeras. To fully assess the therapeutic
      potential of gene therapy in the context of a lethal anemia, we now have created
      an adult model of beta(0)-thalassemia major. In this novel model, mice engrafted
      with beta-globin-null (Hbb(th3/th3)) fetal liver cells succumb to ineffective
      erythropoiesis within 60 days. These mice rapidly develop severe anemia (2-4
      g/dL), massive splenomegaly, extramedullary hematopoiesis (EMH), and hepatic iron
      overload. Remarkably, most mice (11 of 13) treated by lentivirus-mediated globin
      gene transfer were rescued. Long-term chimeras with an average 1.0-2.4 copies of
      the TNS9 vector in their hematopoietic and blood cells stably produced up to 12
      g/dL chimeric Hb consisting of mu alpha(2):hu beta(2) tetramers. Pathologic
      analyses indicated that erythroid maturation was restored, while EMH and iron
      overload dramatically decreased. Thus, we have established an adult animal model
      for the most severe of the hemoglobinopathies, Cooley anemia, which should prove
      useful to investigate both genetic and pharmacologic treatments. Our findings
      demonstrate the remarkable efficacy of lentivirus-mediated globin gene transfer
      in treating a fulminant blood disorder and strongly support the efficacy of gene
      therapy in the severe hemoglobinopathies.

PMID- 12480690
TI  - Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple
      myeloma cells using oligonucleotide arrays.
AB  - Our previous study demonstrated that 2-methoxyestradiol (2ME2), an estrogen
      derivative, induces apoptosis in multiple myeloma (MM) cells; however, the
      related transcriptional events are unclear. In the present study, we used
      oligonucleotide microarrays to identify genes altered during 2ME2-induced
      apoptosis in MM cells. 2ME2 triggers an early transient induction of genes known
      to trigger cell death and repression of growth/survival-related genes. Many genes
      regulating cell defense/repair machinery also were transiently induced. Since
      2ME2 also induces apoptosis in MM cells resistant to conventional therapies such
      as dexamethasone (Dex), we compared the gene profiles of 2ME2-treated and Dex
      resistant MM cells. Our results suggest that 2ME2 overcomes Dex resistance by
      modulating genes that confer chemoresistance in MM cells. Microarray results were
      confirmed by Northern and Western blot analyses. A comparative analysis of
      selected genes from freshly isolated MM patient cells and 2ME2-treated MM.1S MM
      cells further provides an in vivo relevance of our in vitro studies.
      Collectively, these findings suggest genetic events mediating anti-MM activity of
      2ME2, as well as mechanisms whereby 2ME2 overcomes Dex resistance in MM cells.
      These studies may therefore allow improved therapeutic use of 2ME2, based upon
      targeting genes that regulate MM cell growth and survival.

PMID- 12480691
TI  - Aberrant development of Plasmodium falciparum in hemoglobin CC red cells:
      implications for the malaria protective effect of the homozygous state.
AB  - Although selection of hemoglobin C (HbC) by malaria has been speculated for
      decades, only recently have epidemiologic studies provided support for HbC
      protection against malaria in West Africa. A reduced risk of malaria associated
      with the homozygous CC state has been attributed to the inability of CC cells to
      support parasite multiplication in vitro. However, there have been conflicting
      data and conclusions regarding the ability of CC red cells to support parasite
      replication. Reports that parasites cannot multiply in CC cells in vitro contrast
      with detection of substantial parasite densities in CC patients with malaria. We
      have therefore investigated Plasmodium falciparum growth in CC cells in vitro.
      Our data show that the multiplication rate of several P falciparum lines is
      measurable in CC cells, but lower than that in AA (HbA-normal) cells. A high
      proportion of ring forms and trophozoites disintegrates within a subset of CC
      cells, an observation that accounts for the overall lower replication rate. In
      addition, knobs present on the surface of infected CC cells are fewer in number
      and morphologically aberrant when compared with those on AA cells. Events in
      malaria pathogenesis that involve remodeling of the erythrocyte surface and the
      display of parasite antigens may be affected by these knob abnormalities. Our
      data suggest that only a subset of CC cells supports normal parasite replication
      and that components of malaria protection associated with the CC state may affect
      the parasite's replication capacity and involve aberrant knob formation on CC
      cells.

PMID- 12480692
TI  - Multiple myeloma tumor progression in the 5T2MM murine model is a multistage and
      dynamic process of differentiation, proliferation, invasion, and apoptosis.
AB  - At clinical presentation, multiple myeloma (MM) is already a well-established
      disease. The processes involved in earlier stages are, however, unknown. Here the
      5T2MM murine model was used to analyze differentiation, proliferation, invasion,
      and apoptosis of MM cells during disease progression. Naive mice were injected
      with 5T2MM cells and from the onset of the experiment 3 mice were killed each
      week until the end stage. Myeloma cells were isolated from the bone marrow and
      selected by sequential gating of 5T2MM idiotype(+) cells by flow cytometry.
      Microscopic analysis of these sorted 5T2MM idiotype(+) cells confirmed their
      identity as true myeloma cells. Based on serum paraprotein concentration and bone
      marrow tumor load, 3 disease stages were distinguished: a quiescent stage, an
      intermediate stage, and an end stage, of slow, moderate, and accelerated tumor
      progression, respectively. In the quiescent stage, the majority of the myeloma
      cells were CD45(+)CD138(-)IL-6R alpha(+), corresponding to an immature, invasive,
      and apoptosis-resistant phenotype. In the end stage the majority of the myeloma
      cells had differentiated into CD45(-)CD138(+)IL-6R alpha(-) cells, corresponding
      to a mature, less invasive, and apoptosis-sensitive phenotype. In the
      intermediate stage a gradual transition from the quiescent toward the end stage
      was observed. In line with these data, analysis of sorted 5T2MM cells
      demonstrated a significant decrease in invasive capacity and a significant
      increase in (dexamethasone-induced) apoptosis sensitivity and in proliferation
      during the disease progression. These data suggest that myeloma disease
      progression is a multistage and dynamic process of differentiation,
      proliferation, invasion, and apoptosis.

PMID- 12480693
TI  - Regulation of human beta 2-microglobulin transactivation in hematopoietic cells.
AB  - beta(2)-Microglobulin (beta(2)m) is a chaperone of major histocompatibility
      complex (MHC) class I (-like) molecules that play a central role in antigen
      presentation, immunoglobulin transport, and iron metabolism. It is therefore of
      importance that beta(2)m is adequately expressed in cells that perform these
      functions, such as hematopoietic cells. In this study, we investigated the
      transcriptional regulation of beta(2)m in lymphoid and myeloid cell lines through
      a promoter containing a putative E box, Ets/interferon-stimulated response
      element (ISRE), and kappa B site. Here we show that upstream stimulatory factor 1
      (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation. The
      nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box
      and p65 transactivates beta(2)m. Interferon regulatory factor 1 (IRF1), IRF2,
      IRF4, and IRF8, but not PU.1, bind to the Ets/ISRE, and IRF1 and IRF3 are strong
      transactivators of beta(2)m. Together, all 3 boxes are important for the
      constitutive and cytokine-induced levels of beta(2)m expression in lymphoid and
      myeloid cell types. As such, beta(2)m transactivation is under the control of
      important transcriptional pathways, which are activated during injury, infection,
      and inflammation.

PMID- 12480694
TI  - Combined carrier status of prothrombin 20210A and factor XIII-A Leu34 alleles as
      a strong risk factor for myocardial infarction: evidence of a gene-gene
      interaction.
AB  - Studies associating the prothrombin 20210G>A (FII 20210A), factor V Leiden (FVL),
      and factor XIII Leu34 (FXIII-A Leu34) alleles with myocardial infarction (MI)
      have yielded conflicting results. Complicated gene-gene interactions, small
      sample sizes, and heterogeneous genetic and environmental backgrounds may
      contribute to opposing findings. Simultaneous analysis of multiple gene variants
      in a large sample size from a genetically isolated population may overcome these
      weaknesses. Genotyping was performed in 500 MI patients and 500 control subjects
      from the genetically isolated Newfoundland population to determine the prevalence
      of the FII 20210A, FVL, and FXIII-A Leu34 variants and their association with MI.
      Gene-gene interactions were also analyzed. The prevalence of the FII 20210A
      allele was higher in MI patients (3.2%) than in control subjects (1.0%; P =.015).
      The FII 20210A allele was also 5.6-fold higher in MI patients younger than 51
      years than in age-matched control subjects (P =.04). FVL showed 3.9-fold higher
      prevalence in young patients than in patients older than 50 years (P =.004) and
      2.7-fold higher than in age-matched control subjects (P =.007). Furthermore, the
      prevalence of combined carriers of the FXIII-A L34 and FII 20210A alleles was 12
      fold higher in MI patients than in control subjects (P =.002) and with 92%
      penetrance. There was disequilibrium of the FXIII-A Leu34 allele to MI patients
      carrying the FII 20210A allele as a genetic background. Based on our data, we
      determined that (1) the FII 20210A allele is a risk factor for MI, possibly
      important for early onset; (2) FVL may predispose for early-onset MI; (3) the
      FXIII-A Leu34 allele predisposes for MI in males only; however, (4) interaction
      between the FII 20210A and FXIII-A Leu34 alleles forms a synergistic coeffect
      that strongly predisposes for MI, placing combined carriers at high risk for MI.

PMID- 12480695
TI  - Non-T-cell-depleted HLA haploidentical stem cell transplantation in advanced
      hematologic malignancies based on the feto-maternal michrochimerism.
AB  - Feto-maternal microchimerism suggests that immunologic tolerance exists between
      mother and fetus. Based on this hypothesis, we performed haploidentical stem cell
      transplantation (SCT) without T-cell depletion (TCD) in 5 patients with advanced
      hematologic malignancies. HLA incompatibilities for graft-versus-host disease
      (GVHD) direction included 3-loci mismatches in 4 patients, and 2-loci mismatches
      in one patient. Recipient chimeric cells were detected in all patients. The
      prophylaxis against GVHD was tacrolimus with minidose methotrexate. Engraftment
      was obtained in all patients. An acute GVHD of less than or equal to grade 2
      developed in all patients except one who developed tacrolimus encephalopathy. Two
      patients died, 1 from fungal pneumonia and 1 from disease progression. The other
      3 patients survived, with one patient in complete remission. These observations
      suggest that haploidentical SCT based on the feto-maternal microchimerism without
      TCD is possible.

PMID- 12480696
TI  - CD56bright natural killer cells are present in human lymph nodes and are
      activated by T cell-derived IL-2: a potential new link between adaptive and
      innate immunity.
AB  - Natural killer (NK) cells are innate lymphocytes that provide cytokines critical
      for early host defense against pathogens. One subset of human NK cells
      (CD56(bright)) constitutively expresses the high-affinity interleukin 2 (IL-2)
      receptor and produces immunoregulatory cytokines. Here, we demonstrate that
      CD56(bright) NK cells are present in human lymph nodes and that endogenous T cell
      derived IL-2, acting through the NK high-affinity IL-2 receptor, costimulates
      CD56(bright) NK cells to secrete IFN-gamma. Thus, adaptive immunoregulators
      influence innate cytokine production, which in turn may influence the developing
      antigen-specific immune response. These data show a dynamic interaction between
      innate and adaptive human lymphocytes and emphasize the importance of studying
      interactions between immune components to understand the immune response as a
      whole.

PMID- 12480697
TI  - SCID-repopulating cell activity of human cord blood-derived CD34- cells assured
      by intra-bone marrow injection.
AB  - Precise analysis of human CD34-negative (CD34(-)) hematopoietic stem cells (HSCs)
      has been hindered by the lack of a simple and reliable assay system of these rare
      cells. Here, we successfully identify human cord blood-derived CD34(-) severe
      combined immunodeficiency (SCID)- repopulating cells (SRCs) with extensive
      lymphoid and myeloid repopulating ability using the intra-bone marrow injection
      (IBMI) technique. Lineage-negative (Lin(-)) CD34(-) cells did not show SRC
      activity by conventional tail-vein injection, possibly due to their low levels of
      homing receptor expression and poor SDF-1/CXCR4- mediated homing abilities, while
      they clearly showed a high SRC activity by IBMI. They generated CD34(+) progenies
      not only in the injected left tibia but also in other bones following migration.
      Moreover, they showed slower differentiating and reconstituting kinetics than
      CD34(+) cells in vivo. These in vivo-generated CD34(+) cells showed a distinct
      SRC activity after secondary transplantation, clearly indicating the long-term
      human cell repopulating capacity of our identified CD34(-) SRCs in nonobese
      diabetic (NOD)/SCID mice. The unveiling of this novel class of primitive human
      CD34(-) SRCs by IBMI will provide a new concept of the hierarchy in the human HSC
      compartment and has important implications for clinical HSC transplantation as
      well as for basic research of HSC.

PMID- 12480698
TI  - Degenerate specificity of HTLV-1-specific CD8+ T cells during viral replication
      in patients with HTLV-1-associated myelopathy (HAM/TSP).
AB  - Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic
      paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-1
      infection, in which HTLV-1-infected CD4(+) T cells and HTLV-1-specific CD8(+) T
      cells may play a role in the disease pathogenesis. Patients with HAM/TSP have
      high proviral loads despite vigorous virus-specific CD8(+) T-cell responses;
      however, it is unknown whether the T cells are efficient in eliminating the virus
      in vivo. To define the dynamics of HTLV-1-specific CD8(+) T-cell responses, we
      investigated longitudinal alterations in HTLV-1 proviral load, amino acid changes
      in an immunodominant viral epitope, frequency of HTLV-1-specific T cells, and
      degeneracy of T-cell recognition in patients with HAM/TSP. We showed that the
      frequency and the degeneracy of the HTLV-1-specific CD8(+) T cells correlated
      well with proviral load in the longitudinal study. The proviral load was much
      higher in a patient with low degeneracy of HTLV-1-specific T cells compared to
      that in a patient with comparable frequency but higher degeneracy of the T cells.
      Furthermore, in a larger number of patients divided into 2 groups by the proviral
      load, those with high proviral load had lower degeneracy of T-cell recognition
      than those with low proviral load. Sequencing analysis revealed that epitope
      mutations were remarkably increased in a patient when the frequency and the
      degeneracy were at the lowest. These data suggest that HTLV-1-specific CD8(+) T
      cells with degenerate specificity are increased during viral replication and
      control the viral infection.

PMID- 12480699
TI  - Features of the overexpressed V1-69 genes in the unmutated subset of chronic
      lymphocytic leukemia are distinct from those in the healthy elderly repertoire.
AB  - Chronic lymphocytic leukemia (CLL) comprises 2 subsets, distinguished by
      expression of unmutated or mutated V(H) genes, with the former having a worse
      prognosis. Biased usage of the V1-69 gene is found in unmutated cases and is
      combined with selected D gene segments and J(H)6. It is controversial whether
      this is a CLL-associated feature or mirrors the normal B-cell pattern. Since CLL
      is a disease of the elderly, where changes in the B-cell repertoire may occur, we
      have analyzed V1-69 usage in the elderly (older than 75 years) population. Using
      monoclonal antibody (MoAb) G6, specific for 51p1-related V1-69 alleles, we found
      no increased expression with age. In 51p1-encoded immunoglobulin M (IgM),
      complementarity-determining region 3 (CDR3) length and frequency of D and J(H)
      genes were similar to those in the healthy young and distinct from those in CLL.
      These findings support the concept that CLL arises from B cells driven by
      antigen/superantigen and is not a stochastic event in the elderly B-cell
      population.

PMID- 12480702
TI  - Estimating the rate of thrombin and fibrin generation in vivo during
      cardiopulmonary bypass.
AB  - Our objective was to estimate the in vivo rates of thrombin and fibrin generation
      to better understand how coagulation is regulated. Studied were 9 males
      undergoing cardiopulmonary bypass (CPB). The rates of thrombin, total fibrin, and
      soluble fibrin generation in vivo were based on measured levels of prothrombin
      activation peptide F1.2, thrombin-antithrombin complex, fibrinopeptide A, and
      soluble fibrin, combined with a computer model of the patient's vascular system
      that accounted for marker clearance, hemodilution, blood loss, and transfusion.
      Prior to surgery, the average thrombin generation rate was 0.24 +/- 0.11 pmol/s.
      Each thrombin molecule in turn generated about 100 fibrin molecules, of which 1%
      was soluble fibrin. The thrombin generation rate did not change after sternotomy
      or administration of heparin, then rapidly increased 20-fold to 5.60 +/- 6.65
      pmol/s after 5 minutes of CPB (P =.000 05). Early in CPB each new thrombin
      generated only 4 fibrin molecules, of which 35% was soluble fibrin. The thrombin
      generation rate was 2.14 +/- 1.88 pmol/s during the remainder of CPB, increasing
      again to 5.47 +/- 4.08 pmol/s after reperfusion of the ischemic heart (P =.000
      08). After heparin neutralization with protamine, thrombin generation remained
      high (5.34 +/- 4.01 pmol/s, P =.0002) and total fibrin generation increased,
      while soluble fibrin generation decreased. By 2 hours after surgery, thrombin and
      fibrin generation rates were returning to baseline levels. We conclude that
      cardiopulmonary bypass and reperfusion of the ischemic heart results in bursts of
      nonhemostatic thrombin generation and dysregulated fibrin formation, not just a
      steady increase in thrombin generation as suggested by previous studies.

PMID- 12480701
TI  - Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by
      inhibiting leukocyte activation through promotion of prostacyclin production.
AB  - Antithrombin (AT) supplementation in patients with severe sepsis has been shown
      to improve organ failures in which activated leukocytes are critically involved.
      However, the precise mechanism(s) for the therapeutic effects of AT is not well
      understood. We examined in rats whether AT reduces ischemia/reperfusion (I/R)
      induced renal injury by inhibiting leukocyte activation. AT markedly reduced the
      I/R-induced renal dysfunction and histologic changes, whereas neither dansyl
      glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-F.Xa), a
      selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks
      affinity for heparin, had any effect. Renal tissue levels of 6-keto-PGF(1 alpha),
      a stable metabolite of prostacyclin (PGI(2)), increased after renal I/R. AT
      enhanced the I/R-induced increases in renal tissue levels of 6-keto-PGF(1 alpha),
      whereas neither DEGR-F.Xa nor Trp49-modified AT had any effect. AT significantly
      inhibited I/R-induced decrease in renal tissue blood flow and the increase in the
      vascular permeability. Ischemia/reperfusion-induced increases in renal tissue
      levels of tumor necrosis factor-alpha, cytokine-induced neutrophil
      chemoattractant, and myeloperoxidase were significantly inhibited in animals
      given AT. Pretreatment of animals with indomethacin reversed the effects induced
      by AT. Iloprost, an analog of PGI(2), produced effects similar to those induced
      by AT. These observations strongly suggest that AT reduces the I/R-induced renal
      injury by inhibiting leukocyte activation. The therapeutic effects of AT might be
      mainly mediated by PGI(2) released from endothelial cells through interaction of
      AT with cell surface glycosaminoglycans.

PMID- 12480700
TI  - Monoclonal T-cell expansions in asymptomatic individuals and in patients with
      large granular leukemia consist of cytotoxic effector T cells expressing the
      activating CD94:NKG2C/E and NKD2D killer cell receptors.
AB  - We have analyzed the phenotype, cytokine profile, and mitotic history (telomere
      length) of monoclonal T-cell expansions in 5 CD3(+) T-cell large granular
      lymphocyte (TLGL) leukemia patients by fluorescence activated cell sorting (FACS)
      and single-cell polymerase chain reaction (PCR). We confirm that the common
      phenotype of TLGL leukemia is CD3(+)CD8(+)CD45RA(+)CD27(-)CD94(+)(CD57(+)).
      Interestingly, the C-type lectin-like type killer cell receptor CD94 was
      invariably associated with the activating form of its signal-transducing molecule
      NKG2. Furthermore, when judged by criteria such as interferon gamma (IFN
      gamma)/tumor necrosis factor (TNF) production, expression of granzyme, FasL, and
      NKG2D, the TLGL cells had all the features of a cytotoxic effector T cell.
      Telomere shortening in TLGL cells was in the normal range for CD8(+) T cells,
      indicating that they had not divided significantly more than chronically
      stimulated CD8(+) T cells in healthy individuals. In 25 of 27 controls, cells
      with a TLGL phenotype occurred at low (1%-3%) frequencies. However, in the other
      2 individuals (ages 28-36 years), large stable (> 3 years) monoclonal expansions
      of CD3(+)CD8(+)CD45RA(+)CD27(-)CD57(+)CD94(+) NKG2C(+) were found which rendered
      these controls phenotypically indistinguishable from TLGL leukemia patients. We
      believe that the TLGL clonopathy, rather than being of a neoplastic nature, is
      more likely an extreme manifestation of the large and stable clonal size
      characteristic of CD8(+) effector cells. Such a TLGL clone consisting of cells
      without any particular pathologic trait might exist in a considerable number of
      individuals. Clinical symptoms may occur in individuals in whom the TLGL clone
      encounters antigen and is triggered to produce large amounts of effector
      molecules that dysregulate the immune system, which could manifest itself as
      autoimmunity or as a FasL-mediated neutropenia.

PMID- 12480703
TI  - Roles of neutrophil beta 2 integrins in kinetics of bacteremia, extravasation,
      and tick acquisition of Anaplasma phagocytophila in mice.
AB  - Tick saliva contains anti-inflammatory and immunosuppressive substances that
      facilitate blood feeding and enhance tick-vectored pathogen transmission,
      including Anaplasma phagocytophila an etiologic agent of granulocytic
      ehrlichiosis. As such, inflammation at a tick-feeding site is strikingly
      different than that typically observed at other sites of inflammation. Up
      regulation of CD11b/CD18 occurs in host granulocytes following interaction or
      infection with A phagocytophila, and the absence of CD11b/CD18 results in early
      increases in bacteremia. We hypothesized that beta 2 integrin-dependent infection
      kinetics and leukocyte extravasation are important determinants of neutrophil
      trafficking to, and pathogen acquisition at, tick-feeding sites. A phagocytophila
      infection kinetics were evaluated in CD11a/CD18, CD11b/CD18, and CD18 knock-out
      mice using quantitative polymerase chain reaction (PCR) of blood, ticks, and skin
      biopsies in conjunction with histopathology. A marked increase in the rate of A
      phagocytophila infection of neutrophils and pathogen burden in blood followed
      tick feeding. Infection kinetics were modified by beta 2 integrin expression and
      systemic neutrophil counts. Significant neutrophil-pathogen trafficking was
      observed to both suture and tick sites. Despite the prominent role for beta 2
      integrins in neutrophil arrest in flowing blood, successful pathogen acquisition
      by ticks occurred in the absence of beta 2 integrins. Establishment of feeding
      pools that rely less on leukocyte trafficking and more on small hemorrhages may
      explain the ready amplification of A phagocytophila DNA from ticks infested on
      CD11/CD18-deficient mouse strains.

PMID- 12480705
TI  - Involvement of ABC7 in the biosynthesis of heme in erythroid cells: interaction
      of ABC7 with ferrochelatase.
AB  - A mitochondrial half-type ATP-binding cassette (ABC) protein, ABC7, plays a role
      in iron homeostasis in mitochondria, and defects in human ABC7 were shown to be
      responsible for the inherited disease X-linked sideroblastic anemia/ataxia. We
      examined the role of ABC7 in the biosynthesis of heme in erythroid cells where
      hemoglobin is a major product of iron-containing compounds. RNA blots showed that
      the amount of ABC7 mRNA in dimethylsulfoxide (Me(2)SO)-treated mouse
      erythroleukemia (MEL) cells increased markedly in parallel with the induction of
      the mRNA expression of ferrochelatase, the last enzyme in the pathway to
      synthesize heme. The transfection of the antisense oligonucleotide to mouse ABC7
      mRNA into Me(2)SO-treated MEL cells led to a decrease of heme production, as
      compared with sense oligonucleotide-transfected cells. ABC7 protein was shown to
      be colocalized with ferrochelatase in mitochondria, as assessed by
      immunostaining. Furthermore, in vitro and in vivo pull-down assays revealed that
      ABC7 protein is interacted with the carboxy-terminal region containing the iron
      sulfur cluster of ferrochelatase. The transient expression of ABC7 in mouse
      embryo liver BNL-CL2 cells resulted in an increase in the activity and level of
      ferrochelatase and thioredoxin, a cytosolic protein containing iron-sulfur. These
      increases were also observed in MEL cells stably expressing ABC7. When ABC7
      transfectants were treated with Me(2)SO, an increase in cellular heme concomitant
      with a marked induction of the expression of ferrochelatase was observed. The
      extent of these increases was 3-fold greater than in control cells. The results
      indicated that ABC7 positively regulates not only the expression of
      extramitochondrial thioredoxin but also that of an intramitochondrial iron-sulfur
      containing protein, ferrochelatase. Then, the expression of ABC7 contributes to
      the production of heme during the differentiation of erythroid cells.

PMID- 12480704
TI  - Signal transducer and activator of transcription proteins in leukemias.
AB  - Signal transducer and activator of transcription (STAT) proteins are a 7-member
      family of cytoplasmic transcription factors that contribute to signal
      transduction by cytokines, hormones, and growth factors. STAT proteins control
      fundamental cellular processes, including survival, proliferation, and
      differentiation. Given the critical roles of STAT proteins, it was hypothesized
      that inappropriate or aberrant activation of STATs might contribute to cellular
      transformation and, in particular, leukemogenesis. Constitutive activation of
      mutated STAT3 has in fact been demonstrated to result in transformation. STAT
      activation has been extensively studied in leukemias, and mechanisms of STAT
      activation and the potential role of STAT signaling in leukemogenesis are the
      focus of this review. A better understanding of mechanisms of dysregulation of
      STAT signaling pathways may serve as a basis for designing novel therapeutic
      strategies that target these pathways in leukemia cells.

PMID- 12480706
TI  - Sustained complete hematologic remission after administration of the tyrosine
      kinase inhibitor imatinib mesylate in a patient with refractory, secondary AML.
AB  - Imatinib mesylate, a tyrosine kinase inhibitor targeting bcr-abl, platelet
      derived growth factor receptor (PDGF-R), and c-Kit, effectively induces
      hematologic and cytogenetic remissions in bcr-abl(+) chronic myeloid leukemia
      (CML) and acute lymphoblastic leukemia (ALL) with only mild to moderate side
      effects. Here, we describe the successful treatment of a 64-year-old man with c
      Kit(+) secondary acute myeloid leukemia (AML) refractory to standard
      chemotherapy. Upon 2 weeks of imatinib mesylate administration, the patient
      achieved a complete hematologic remission in peripheral blood. In addition,
      complete clearance of leukemic blasts in bone marrow and a significant
      cytogenetic response lasting for more than 5 months was observed. Sequence
      analysis of exons 2, 8, 10, 11, and 17 of the c-Kit receptor did not reveal
      structural alterations as previously described in a subset of AML cases. This is
      the first report of complete remission achieved upon administration of imatinib
      mesylate in a patient with highly refractory, secondary AML.

PMID- 12480707
TI  - AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid
      differentiation of t(8;21)-positive leukemic cells.
AB  - The translocation t(8;21) yields the leukemic fusion gene AML1/MTG8 and is
      associated with 10%-15% of all de novo cases of acute myeloid leukemia. We
      demonstrate the efficient and specific suppression of AML1/MTG8 by small
      interfering RNAs (siRNAs) in the human leukemic cell lines Kasumi-1 and SKNO-1.
      siRNAs targeted against the fusion site of the AML1/MTG8 mRNA reduce the levels
      of AML1/MTG8 without affecting the amount of wild-type AML1. These data argue
      against a transitive RNA interference mechanism potentially induced by siRNAs in
      such leukemic cells. Depletion of AML1/MTG8 correlates with an increased
      susceptibility of both Kasumi-1 and SKNO-1 cells to tumor growth factor beta(1)
      (TGF beta(1))/vitamin D(3)-induced differentiation, leading to increased
      expression of CD11b, macrophage colony-stimulating factor (M-CSF) receptor, and
      C/EBP alpha (CAAT/enhancer binding protein). Moreover, siRNA-mediated AML1/MTG8
      suppression results in changes in cell shape and, in combination with TGF
      beta(1)/vitamin D(3), severely reduces clonogenicity of Kasumi-1 cells. These
      results suggest an important role for AML1/MTG8 in preventing differentiation,
      thereby propagating leukemic blast cells. Therefore, siRNAs are promising tools
      for a functional analysis of AML1/MTG8 and may be used in a molecularly defined
      therapeutic approach for t(8;21)-positive leukemia.

PMID- 12480708
TI  - Intravenous immunoglobulins induce the in vitro differentiation of human B
      lymphocytes and the secretion of IgG.
AB  - The therapeutic effects of intravenous immunoglobulins (IVIGs) in several
      autoimmune diseases are characterized by a decrease in pathologic autoantibody
      levels. Although little direct evidence has been reported in humans, the large
      repertoire of natural immunoglobulin G (IgG) antibodies in IVIGs is expected to
      be involved in the regulation of autoreactive B lymphocytes. In normal adult
      mice, IVIGs have been reported to modulate immature B cells as well as peripheral
      B lymphocytes through V-region connections. Studies with human serum also
      indicated that anti-idiotypic antibodies, present in IVIG preparations, could
      recognize both natural and pathologic autoantibodies. We have used an in vitro
      culture system to characterize the direct effect of IVIGs on human B lymphocytes.
      This in vitro culture system involves CD40 activation of B lymphocytes by its
      ligand CD154 in the presence of cytokines. In this system, addition of IVIGs
      decreased by 50% to 80% the expansion of B lymphocytes. This reduced expansion
      was due to a decrease in the proliferation rate. In addition, a portion of B
      lymphocytes was differentiated into IgG-secreting cells in the presence of IVIGs
      and the secreted IgGs were reactive with antigens such as nucleoprotamine, dsDNA,
      tetanus toxin, and human IgG F(ab')(2) fragments. These observations indicate
      that IVIGs can have direct effects on B lymphocytes and suggest that such IVIG
      regulation of B lymphocytes could be involved in the therapeutic effects of IVIGs
      in autoimmune diseases.

PMID- 12480709
TI  - Mesenchymal stem cells distribute to a wide range of tissues following systemic
      infusion into nonhuman primates.
AB  - Ex vivo-expanded mesenchymal stem cells (MSCs) were transduced with a green
      fluorescent protein (GFP) retroviral construct and subsequently infused into 3
      adult baboons following lethal total body irradiation and hematopoietic support
      or without any prior conditioning. To study the long-term fate of these MSCs,
      necropsies were performed between 9 and 21 months following MSC infusion, and an
      average of 16 distinct tissues were recovered from each recipient and evaluated
      for the presence of the GFP transgene in purified genomic DNA by sensitive real
      time polymerase chain reaction (PCR). Two baboons received autologous and one
      allogeneic GFP-transduced MSCs. Both allogeneic and autologous MSCs appeared to
      distribute in a similar manner. Gastrointestinal tissues harbored high
      concentrations of transgene per microgram of DNA. Additional tissues including
      kidney, lung, liver, thymus, and skin were also found to contain relatively high
      amounts of DNA equivalents. Estimated levels of engraftment in these tissues
      ranged from 0.1% to 2.7%. The nonconditioned recipient appeared to have less
      abundant engraftment. These data suggest that MSCs initially distribute broadly
      following systemic infusion and later may participate in ongoing cellular
      turnover and replacement in a wide variety of tissues.

PMID- 12480710
TI  - Effective contribution of transplanted vascular progenitor cells derived from
      embryonic stem cells to adult neovascularization in proper differentiation stage.
AB  - We demonstrated that Flk-1(+) cells derived from mouse embryonic stem (ES) cells
      can differentiate into both endothelial cells (ECs) and mural cells (MCs) to
      suffice as vascular progenitor cells (VPCs). In the present study, we
      investigated the importance of the stage of ES cell differentiation on effective
      participation in adult neovascularization. We obtained Flk-1(+) LacZ-expressing
      undifferentiated VPCs. Additional culture of these VPCs with vascular endothelial
      growth factor (VEGF) resulted in a mixture of ECs and MCs (differentiated VPCs).
      We injected VPCs subcutaneously into tumor-bearing mice. Five days after the
      injection, whereas undifferentiated VPCs were often detected as nonvascular
      cells, differentiated VPCs were more specifically incorporated into developing
      vasculature mainly as ECs. VPC-derived MCs were also detected in vascular walls.
      Furthermore, transplantation of differentiated VPCs augmented tumor blood flow in
      nude mice. These results indicate that a specific vascular contribution in adult
      neovascularization can be achieved by selective transplantation of ES cell
      derived VPCs in appropriate differentiation stages, which should be the basis for
      vascular regeneration schemes.

PMID- 12480711
TI  - Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic
      leukemia cells from chlorambucil- and radiation-induced apoptosis.
AB  - Activation of the phosphatidylinositol 3- kinase/AKT pathway antagonizes
      apoptosis in diverse cellular systems. We previously showed that human plasma
      activated AKT and potently blocked the ability of chlorambucil or gamma radiation
      to induce apoptosis of B-chronic lymphocytic leukemia (CLL) cells. Here we report
      experiments that identify albumin as the major component of plasma that blocks
      CLL cell killing by chlorambucil or radiation. Intact plasma depleted of albumin
      by chromatography on Cibacron blue-Sepharose or plasma from a subject with
      analbuminemia failed either to activate AKT or to protect CLL cells from
      chlorambucil-induced apoptosis. Both functions were restored by re-addition of
      albumin. The protective action of albumin as well as AKT activation was
      compromised by the binding of lipids. Fluorescence-activated cell sorter
      (FACScan) analysis demonstrated the uptake of fluoresceinated albumin by CLL
      cells. Accumulation of albumin in intracellular vesicles was also shown by
      confocal microscopy. Indirect inhibition of AKT activation by the
      phosphatidylinositol 3-kinase inhibitor LY294002 reversed the blockade of
      chlorambucil-induced killing by plasma albumin. The data suggest that activation
      of AKT consequent to binding of albumin by CLL cells blocks chlorambucil- and
      radiation-induced apoptosis. Strategies designed to block albumin-induced
      antiapoptotic signaling may, therefore, be of value in enhancing cytotoxic drug
      action on CLL cells.

PMID- 12480712
TI  - UbcH5A, a member of human E2 ubiquitin-conjugating enzymes, is closely related to
      SFT, a stimulator of iron transport, and is up-regulated in hereditary
      hemochromatosis.
AB  - SFT, a stimulator of iron (Fe) transport, has been described as a transmembrane
      protein that facilitates the uptake of ferrous and ferric iron in mammalian
      cells. This study was initiated to investigate the 5' regulatory region of SFT
      and its role in the etiology of hereditary hemochromatosis. Sequence analyses of
      the putative 5' regulatory region revealed that the SFT cDNA sequence corresponds
      to intron 6/exon 7 of UbcH5A, a member of E2 ubiquitin-conjugating enzymes, which
      is involved in the iron-dependent ubiquitination of the hypoxia-inducible factor
      (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Further
      mRNA expression studies using a sequence-specific reverse transcriptase
      polymerase chain reaction (RT-PCR) assay showed that UbcH5A is significantly up
      regulated in the liver of iron-overloaded patients with hereditary
      hemochromatosis, as previously published for SFT. However, in vitro studies on
      HepG2 cells failed to demonstrate any significant UbcH5A regulation in response
      to iron loading or iron chelation. In conclusion, in vivo mRNA expression data
      previously obtained for SFT might be attributed to UbcH5A. The role of UbcH5A and
      the ubiquitination pathway in the etiology of hereditary hemochromatosis remains
      to be elucidated further.

PMID- 12480713
TI  - The incidence of heparin-induced thrombocytopenia in hospitalized medical
      patients treated with subcutaneous unfractionated heparin: a prospective cohort
      study.
AB  - Although heparin-induced thrombocytopenia (HIT) is a known complication of
      intravenous unfractionated heparin (UFH), its incidence in medical patients
      treated with subcutaneous UFH is less well defined. To determine the incidence of
      HIT in this category of patients, the platelet count was performed at baseline
      and then every 3 +/- 1 days in 598 consecutive patients admitted to 2 medical
      wards and treated with subcutaneous UFH for prophylactic (n = 360) or therapeutic
      (n = 238) indications. The diagnosis of HIT was accepted in the case of a
      platelet drop of 50% or more and either the demonstration of heparin-dependent
      antibodies or (when this search could not be performed) the combination of the
      following features: (1) the absence of any other obvious clinical explanation for
      thrombocytopenia, (2) the occurrence of thrombocytopenia at least 5 days after
      heparin start, and (3) either the normalization of the platelet count within 10
      days after heparin discontinuation or the earlier patient's death due to an
      unexpected thromboembolic complication. HIT developed in 5 patients (0.8%; 95%
      CI, 0.1%-1.6%); all of them belonged to the subgroup of patients who received
      heparin for prophylactic indications. The prevalence of thromboembolic
      complications in patients with HIT (60%) was remarkably higher than that observed
      in the remaining 593 patients (3.5%), leading to an odds ratio of 40.8 (95% CI,
      5.2-162.8). Although the frequency of HIT in hospitalized medical patients
      treated with subcutaneous heparin is lower than that observed in other clinical
      settings, this complication is associated with a similarly high rate of
      thromboembolic events.

PMID- 12480714
TI  - Platelet P-selectin facilitates atherosclerotic lesion development.
AB  - P-selectin is an adhesion molecule expressed on activated platelets and
      endothelium. It is known to play an important role in atherosclerosis. P-selectin
      also circulates in plasma in a soluble form (sP-selectin), which induces
      procoagulant microparticle formation. We investigated the role of platelet versus
      endothelial P-selectin in generating sP-selectin and in the formation of
      atherosclerotic lesions in the apolipoprotein E (apoE)-deficient mouse model. For
      this we transplanted apoE(-/-)P-selectin(-/-) and apoE(-/-)P-selectin(+/+)
      lethally irradiated mice with bone marrow of either genotype. Seven months after
      transplantation, we determined from the chimeric animals that the majority of
      circulating sP-selectin was of endothelial origin. Thus, in atherosclerosis, the
      procoagulant sP-selectin reflects endothelial rather than platelet activation. We
      found that endothelial P-selectin was crucial for the promotion of
      atherosclerotic lesion growth because in its absence only relatively small
      lesions developed. However, platelet P-selectin also contributed to the lesion
      development because lesions in wild-type recipients receiving transplants with
      wild-type platelets were 30% larger than those receiving P-selectin-deficient
      platelets (P <.008) and were more frequently calcified (80% versus 44%). In
      comparison with P-selectin wild-type animals, absence of either endothelial or
      platelet P-selectin inhibited migration of smooth muscle cells into the lesion.
      Thus, in addition to endothelium, platelets and their P-selectin also actively
      promote advanced atherosclerotic lesion development.

PMID- 12480715
TI  - The tetrapeptide AcSDKP, an inhibitor of primitive hematopoietic cell
      proliferation, induces angiogenesis in vitro and in vivo.
AB  - The tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP), purified from bone marrow and
      constitutively synthesized in vivo, belongs to the family of negative regulators
      of hematopoiesis. It protects the stem cell compartment from the toxicity of
      anticancer drugs and irradiation and consequently contributes to a reduction in
      marrow failure. This current work provides experimental evidence for another
      novel biologic function of AcSDKP. We report that AcSDKP is a mediator of
      angiogenesis, as measured by its ability to modulate endothelial cell function in
      vitro and angiogenesis in vivo. AcSDKP at nanomolar concentrations stimulates in
      vitro endothelial cell migration and differentiation into capillary-like
      structures on Matrigel as well as enhances the secretion of an active form of
      matrix metalloproteinase-1 (MMP-1). In vivo, AcSDKP promotes a significant
      angiogenic response in the chicken embryo chorioallantoic membrane (CAM) and in
      the abdominal muscle of the rat. Moreover, it induces the formation of blood
      vessels in Matrigel plugs implanted subcutaneously in the rat. This is the first
      report demonstrating the ability of AcSDKP to interact directly with endothelial
      cells and to elicit an angiogenic response in vitro and in vivo.

PMID- 12480716
TI  - Recombinant P-selectin glycoprotein ligand-1 directly inhibits leukocyte rolling
      by all 3 selectins in vivo: complete inhibition of rolling is not required for
      anti-inflammatory effect.
AB  - Selectin-dependent leukocyte rolling is one of the earliest steps of an acute
      inflammatory response and, as such, contributes to many inflammatory diseases.
      Although inhibiting leukocyte rolling with selectin antagonists is a strategy
      that promises far-reaching clinical benefit, the perceived value of this strategy
      has been limited by studies using inactive, weak, or poorly characterized
      antagonists. Recombinant P-selectin glycoprotein ligand-1-immunoglobulin (rPSGL
      Ig) is a recombinant form of the best-characterized selectin ligand (PSGL-1)
      fused to IgG, and is one of the best prospects in the search for effective
      selectin antagonists. We have used intravital microscopy to investigate the
      ability of rPSGL-Ig to influence leukocyte rolling in living blood vessels and
      find that it can reduce rolling dependent on each of the selectins in vivo.
      Interestingly, doses of rPSGL-Ig required to reverse pre-existing leukocyte
      rolling are 30-fold higher than those required to limit inflammation, suggesting
      additional properties of this molecule. In support of this, we find that rPSGL-Ig
      can bind the murine chemokine KC and inhibit neutrophil migration toward this
      chemoattractant in vitro.

PMID- 12480717
TI  - Stable amorphous calcium carbonate is the main component of the calcium storage
      structures of the crustacean Orchestia cavimana.

PMID- 12480718
TI  - Revised estimates of the effects of turbulence on fertilization in the purple sea
      urchin, Strongylocentrotus purpuratus.

PMID- 12480719
TI  - Long-term culture of decapsulated gastropod embryos: a transplantation study.
AB  - Encapsulated embryos of the pond snail Helisoma trivolvis have been useful for
      examining neural development and neural circuit function during development.
      However, their full potential in developmental studies is limited by the lack of
      an effective method for long-term culture of decapsulated embryos. In the present
      study, decapsulated early embryos were either cultivated ex ovo in various media
      under different environmental conditions or transplanted into host egg capsules.
      Although diluted capsular fluid, 30% M199, and albumen-gland-conditioned medium
      were partially effective in promoting embryonic growth for a short time, none of
      the media promoted normal embryonic development in long-term tests. In contrast,
      after previously decapsulated and experimentally manipulated embryos were
      transplanted into host capsules, their growth and development were similar to
      their intact siblings. In combination with laser ablation, this transplantation
      technique was used to demonstrate the role played by a pair of serotonergic
      neurons in regulating an embryonic rotational behavior. These results suggest
      that embryonic transplantation is an extremely effective technique for achieving
      long-term growth and development of previously decapsulated embryos and therefore
      can be instrumental in investigating cell lineage, function, and development in
      encapsulated embryos.

PMID- 12480720
TI  - Structure, formation, mechanical properties, and disposal of the embryo
      attachment system of an estuarine crab, Sesarma haematocheir.
AB  - In most decapod crustaceans, fertilized eggs extruded from the gonopore attach to
      ovigerous hairs within the incubation chamber of the female. The attachment is
      effected by an "embryo attachment system." The three continuous components of
      this system are the egg envelope, the funiculus, and the investment coat, which
      wraps around an ovigerous hair. Transmission electron microscopy (TEM) revealed
      that the embryo of Sesarma haematocheir is enfolded by three distinct envelopes
      (E1, E2, and E3), whereas the embryo attachment system is composed of only the
      outermost, single envelope (E1) with two sublayers (E1a and E1b). This envelope
      (E1) originates from the outer layer of the vitelline membrane (envelope of the
      ovum) with two sublayers (E1a' and E1b'). The sequence and timing of events in
      the formation of the embryo attachment system was determined on the basis of
      observations of female behavior, ultrastructure, and mechanical properties of the
      membranes. The egg envelope (E1a' + E1b') is not adhesive immediately after
      extrusion from the gonopore; but 5 min after egg-laying, it becomes adhesive-a
      change associated with "fusion" of the two sublayers (E1)-and attaches the eggs
      to the ovigerous hairs from 5 to 30 min after egg-laying. The layer E1a' always
      binds to an ovigerous hair at specific, electron-dense attachment sites that are
      distributed longitudinally on the surface of each hair. Plasticity of the egg
      envelope changes, and the female kneads her eggs by the movement of ovigerous
      setae; this movement forms the investment coat on the ovigerous hair (10-40 min
      after egg-laying). Thirty minutes after egg-laying, the egg envelope again
      divides into two sublayers (E1a and E1b), and the adhesiveness rapidly decreases.
      The plasticity of the envelope remains, and the funiculus is formed, accompanied
      by kneading of the eggs (40-90 min after egg-laying). The embryos hatch one month
      after incubation, and the attachment systems all slip off their ovigerous hairs
      by the actions of the ovigerous-hair slipping substance (OHSS). This substance
      appears to act specifically at the attachment sites on the hair, lysing the bond
      with layer E1a, and thereby disposing of the embryonic attachment system and
      preparing the hairs for the next clutch of embryos.

PMID- 12480721
TI  - Spectral sensitivity of vertically migrating marine copepods.
AB  - Light is a critical factor in the proximate basis of diel vertical migration
      (DVM) in zooplankton. A photobehavioral approach was used to examine the spectral
      sensitivity of four coastal species of calanoid copepod, representing a diversity
      of DVM patterns, to test whether species that migrate (nocturnal or reverse DVM)
      have response spectra that differ from non-migratory surface dwellers. The
      following species were given light stimuli at wavelengths from 350 to 740 nm, and
      their photoresponses were measured: Centropages typicus (nocturnal migrator),
      Calanopia americana (nocturnal migrator), Anomalocera ornata (reverse migrator),
      and Labidocera aestiva (non-migrator). Centropages typicus and A. ornata had peak
      responses at 500 and 520 nm, respectively, while Calanopia americana had maximum
      responses at 480 and 520 nm. Thus, the species that undergo DVM have peak
      photobehavioral responses at wavelengths corresponding to those available during
      twilight in coastal water, although the range of wavelengths to which they
      respond is variable. Non-migratory surface-dwelling L. aestiva had numerous
      response peaks over a broad spectral range, which may serve to maximize photon
      capture for vision in their broad-spectrum shallow-water habitat.

PMID- 12480722
TI  - Mycosporine-like amino acid content in four species of sea anemones in the genus
      Anthopleura reflects phylogenetic but not environmental or symbiotic
      relationships.
AB  - We examine the occurrence of UV-absorbing, mycosporine-like amino acids (MAAs) in
      four sympatric species of sea anemones in the genus Anthopleura, all collected
      from intertidal habitats on the Pacific Coast of temperate North America. We
      compare patterns of MAAs in A. elegantissima of several types: specimens having
      predominately zooxanthellae (dinoflagellates comprising at least two species) or
      zoochlorellae as symbionts; those containing algal endosymbionts of both kinds,
      and naturally occurring aposymbiotic specimens that lack the endosymbionts
      typically found in most specimens. We also compare MAAs in zooxanthellate
      specimens of A. sola and A. xanthogrammica, and specimens from the asymbiotic
      species A. artemisia. Our findings indicate that the complements of the four
      major MAAs in these species of Anthopleura (mycosporine-taurine, shinorine,
      porphyra-334, and mycosporine-2 glycine) broadly reflect phylogenetic differences
      among the anemones rather than the taxon of endosymbionts, presence or absence of
      symbionts, or environmental factors. An exception, however, occurs in A.
      elegantissima, where mycosporine-2 glycine increases in concentration with the
      density of zooxanthellae. Our evidence also shows that A. elegantissima can
      accumulate MAAs from its food, which may explain the occasional occurrence of
      minor MAAs in some individuals.

PMID- 12480723
TI  - Osmotic induction of stress-responsive gene expression in the lobster Homarus
      americanus.
AB  - The American lobster, Homarus americanus, encounters osmotic stress throughout
      its life cycle. To understand the molecular basis of osmotic stress responses in
      vivo, we used homologous cDNA probes to characterize the mRNA patterns of lobster
      HSP70 (=70-kDa heat-shock protein), HSP90 (=90-kDa heat-shock protein), and
      polyubiquitin during hypo- and hyper-osmotic stress in abdominal muscle and
      hepatopancreas (a digestive tissue) at 30, 60, and 120 min of osmotic stress.
      Hypo- and hyper-osmotic stress significantly increased the levels of the mRNAs
      encoding HSP70 and HSP90 in abdominal muscle. Hyper-osmotic stress increased
      HSP90 mRNA levels in hepatopancreas, but hypo-osmotic stress did not. Both
      abdominal muscle and hepatopancreas exhibited significant changes in
      polyubiquitin gene expression during osmotic stress. In abdominal muscle,
      polyubiquitin mRNA levels increased during both hypo- and hyper-osmotic stress.
      Hepatopancreas, however, showed a significant elevation in polyubiquitin mRNA
      only during hypo-osmotic stress.

PMID- 12480724
TI  - Biochemical differences between trail mucus and adhesive mucus from marsh
      periwinkle snails.
AB  - The composition of the adhesive form of marsh periwinkle mucus was compared to
      the trail mucus used during locomotion. The trail mucus consists primarily of
      large, carbohydrate-rich molecules with some relatively small proteins. In
      contrast, the adhesive mucus has 2.7 times as much protein with no significant
      difference in carbohydrate concentration. The resulting gel has roughly equal
      amounts of protein and carbohydrate. This substantial increase in protein content
      is due to the additional presence of two proteins with molecular weights of 41
      and 36 kD. These two proteins are absent from the trail mucus. Both proteins are
      glycosylated, have similar amino acid compositions, and have isoelectric points
      of 4.75. This change in composition corresponds to an order of magnitude increase
      in tenacity with little clear change in overall concentration. The difference
      between adhesive and non-adhesive mucus suggests that relatively small proteins
      are important for controlling the mechanics of periwinkle mucus.

PMID- 12480725
TI  - Tests of hypotheses on the adaptive value of an extended male phase in the
      hermaphroditic shrimp Lysmata wurdemanni (Caridea: Hippolytidae).
AB  - Hypotheses on delayed sex change in the protandric simultaneous hermaphrodite
      Lysmata wurdemanni were tested with observations from population samples, mating
      experiments, and experiments on sex change under optimal and suboptimal breeding
      conditions. Male-phase individuals (MPs) much larger than the minimum size of sex
      change were most frequent in a natural population from fall through early spring.
      The hypothesis was tested that some MPs delay sex change to the simultaneous
      hermaphrodite female-phase (FP) because MPs are more competitive in obtaining
      copulations with parturial FPs than are FPs mating as males (MFPs). In different
      experiments, parturial FPs were maintained with two potential male mating
      partners (large MP and MFP, small MP and MFP, large MP and small MP) through the
      parturial molt and spawning; activities were recorded with time-lapse video. MFPs
      gained the single copulation with the parturial FP as frequently as MPs, large or
      small, but large MPs copulated with more FPs than small MPs. The hypothesis of FP
      reversion to large MP was tested experimentally and rejected. Rate of change of
      MP to FP was much lower in large MPs maintained under suboptimal (fall/winter)
      than optimal (spring/summer) breeding conditions. The results presented here
      suggest that the occurrence of large MPs from the fall to early spring is better
      explained by abiotic proximate factors related to breeding than by socially
      mediated sex change in different demographic environments.

PMID- 12480728
TI  - Incidence and risk factors of dementia in a defined elderly Japanese population:
      the Hisayama study.
AB  - Vascular dementia (VaD) is more common than Alzheimer's disease (AD) in Japan,
      while AD is much more frequent in Western countries. The Hisayama study, an
      epidemiological study on dementia in a Japanese elderly population aged 65 years
      or older, has shown that the prevalence of VaD decreased for men, while AD
      remained unchanged in both sexes during a 7-year follow-up period (1985-1992).
      Decreased prevalence of VaD seems to be due to decreased incidence of stroke in
      recent years, resulting from the management of hypertension. The age-adjusted
      incidence of total dementia was approximately 20 per 1000 person-years in either
      sex; VaD was more frequent for men and AD for women. Risk factors for VaD were
      age, hypertension, previous stroke, and alcohol consumption, while age was only a
      significant risk factor for AD. Although the Hisayama study failed to demonstrate
      the relationship of vascular factors to AD, the previously reported studies
      suggest that either hypertension per se or blood pressure changes appear to
      partially participate in the pathogenesis of AD.

PMID- 12480729
TI  - Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study
      participants.
AB  - Clinicopathologic data from 285 autopsies were analyzed. The decedents were long
      standing participants in the Honolulu-Asia Aging Study, a prospective
      epidemiologic investigation of stroke, neurodegenerative diseases, and aging. We
      assessed the prevalence at death of four primary neuropathologic processes using
      specific microscopic lesions as indicators. An algorithm was developed to assign
      each decedent to one of six subsets, corresponding to pathologic dominance by
      microvascular lesions (14% of decedents), Alzheimer lesions (12%), hippocampal
      sclerosis (5%), cortical Lewy bodies (5%), codominance by two or more primary
      processes (9%), or without a dominant pathologic process recognized (55%).
      Definite or probable dementia had been identified in 118 of the decedents. The
      proportions of men in each subset identified as demented were (in the same order)
      57%, 53%, 79%, 57%, 76%, and 25%. In this autopsied panel of older Japanese
      American men, the importance of microvascular lesions as a likely explanation for
      dementia was nearly equal to that of Alzheimer lesions. The cerebrovascular
      lesion type most essentially and inclusively related to dementia was multiple
      microinfarction.

PMID- 12480730
TI  - Vascular dementia in Japan.
AB  - Patients with vascular dementia are frequently encountered in Japan reaching
      nearly 50% of those with senile dementia, which is equal to or even slightly
      higher than patients with Alzheimer's disease. This contrasts with a much lower
      ratio of patients with vascular dementia in the United States. The majority of
      vascular dementia seen in Japan is of the multiple lacunar type or Binswanger
      disease, often without any episode of stroke. Clinically, those patients tend to
      have attention deficit and reduction of spontaneous activities. The observed
      characteristics of vascular dementia likely reflect the main type of
      cerebrovascular disease prevalent in Japan since the majority of cerebral
      infarction in Japan is of lacunar type in contrast to that in the United States
      and Europe. For patients without any episode of stroke, it is important to
      differentiate from Alzheimer's disease. As in the United States and Europe, mixed
      dementia exists in Japan with Alzheimer's disease and vascular dementia together
      and poses problems in clinical diagnosis because many patients may not have any
      episode of stroke, but they have neuroimaging characteristics compatible with
      both. The number of patients with atherosclerosis in large cervical and cerebral
      arteries is said to be increasing in Japan, and vascular dementia in Japan may
      present with different clinical pictures in the future.

PMID- 12480731
TI  - Hypertension and related factors in the etiology of Alzheimer's disease.
AB  - The prevalence of hypertension is estimated to approach 50% in individuals above
      age 70. The consequences of hypertension include cerebrovascular disease,
      coronary heart disease, and general atherosclerosis. Several recent studies
      suggest that there may be an association also between hypertension and
      Alzheimer's disease (AD). This review will examine the evidence for this
      association and possible pathways between hypertension, Alzheimer encephalopathy,
      and clinical dementia.

PMID- 12480732
TI  - Risk factors for cerebral amyloid angiopathy in the elderly.
AB  - To elucidate risk factors for cerebral amyloid angiopathy (CAA) in the elderly,
      we have investigated 201 autopsy cases of elderly Japanese (ages: 62-104 years),
      including 82 patients with Alzheimer's disease (AD). Severity of CAA showed no
      relationship with the history of hypertension, hyperlipidemia, or diabetes
      mellitus, nor with severity of atherosclerosis of cerebral and systemic arteries,
      indicating that common vascular risk factors would not be related to CAA.
      Incidence and severity of CAA were significantly higher in the AD cases compared
      with the non-AD cases (p < 0.0001). Severity of CAA correlated with densities of
      senile plaques and neurofibrillary tangles in total and non-AD cases, although
      the correlations were not significant within the AD cases. Associations of
      genetic polymorphisms with CAA have been investigated for genes of apolipoprotein
      E (APOE), presenilin 1 (PS1), alpha1-antichymotrypsin (ACT),
      butyrylcholinesterase, alpha2-macroglobulin, and paraoxonase. Severity of CAA in
      APOE epsilon4 carriers is significantly higher than that in non-epsilon4 carriers
      in total cases, although no significant difference was found in the CAA severity
      between the epsilon4 carriers and non-epsilon4 carriers within the AD or non-AD
      group. An intronic polymorphism of PS1 was significantly associated with the
      severity of CAA, indicating that the PS1 2/2 genotype may be related to lower
      risk of CAA. A polymorphism in the signal peptide sequence of ACT was
      significantly associated with the CAA severity in the AD group. Our results
      suggest that CAA shares risk factors with AD and that multiple genetic factors
      would be associated with the risk of CAA in the elderly.

PMID- 12480733
TI  - Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a
      central target for the development of human AD and AD-like pathology in aged
      transgenic mice.
AB  - We have studied the ultrastructural features of vascular lesions and mitochondria
      in brain vascular wall cells from human AD brain biopsy, human short postmortem
      brain tissues, and yeast artificial chromosome (YAC) and C57B6/SJL transgenic
      positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In
      situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5
      kb deleted, and mouse mtDNA was performed, along with immunocytochemistry using
      antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8
      OHG), and cytochrome c oxidase (COX). There was a higher degree of amyloid
      deposition in the vascular walls of the human AD, YAC, and C57B6/SJL Tg (+) mice
      compared to age-matched controls. In addition, vessels with more severe lesions
      showed immunopositive staining for APP and possessed large, lipid-laden vacuoles
      in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial
      abnormalities were seen in human AD, YAC, and C57B6/SJL Tg (+) mouse microvessels
      where lesions occurred. In situ hybridization using wild and chimera (5 kb) mtDNA
      probes revealed positive signals in damaged mitochondria from the vascular
      endothelium and in perivascular cells of lesioned microvessels close to regions
      of large amyloid deposition. These features were absent in undamaged regions of
      human AD tissues, YAC and C57B6/SJL Tg (+) mouse tissues, and in age-matched
      control subjects. In addition, vessels with atherosclerotic lesions revealed
      endothelium and perivascular cells possessing clusters of wild and deleted mtDNA
      positive probes. These mtDNA deletions were accompanied by increased amounts of
      immunoreactive APP, 8-OHG, and COX in the same cellular compartment. Our
      observations demonstrate that vascular wall cells, especially their mitochondria,
      appear to be a central target for oxidative stress-induced damage.

PMID- 12480734
TI  - Proinflammatory and vasoactive effects of Abeta in the cerebrovasculature.
AB  - Abeta peptides are thought to be critical molecules in the pathophysiology of
      Alzheimer's disease (AD) and are the major protein constituents of senile
      plaques. In most AD cases, Abeta peptides also form some deposits in the
      cerebrovasculature, leading to cerebral amyloid angiopathy and hemorrhagic
      stroke. Regional cerebral hypoperfusion is one of the earlier clinical
      manifestations in both the sporadic and familial forms of AD. In addition, a
      variety of vascular risk factors of different etiologies (for instance, diabetes,
      hypertension, high cholesterol level, atherosclerosis, and smoking) constitute
      risk factors for AD as well, suggesting that functional vascular abnormalities
      may contribute to AD pathology. We studied the effect of Abeta on constrictor
      responses elicited by endothelin-1 in isolated human cerebral arteries collected
      following rapid autopsies. We report that freshly solubilized Abeta potentiates
      endothelin-1-induced vasoconstriction in isolated human middle cerebral and
      basilar arteries. The vasoconstriction elicited by Abeta in these large human
      cerebral arteries appears to be completely antagonized by NS-398, a selective
      cyclooxygenase-2 inhibitor, or by SB202190, a specific p38 mitogen-activated
      protein kinase inhibitor, suggesting that Abeta vasoactivity is mediated via the
      stimulation of a proinflammatory pathway. In addition, a similar proinflammatory
      response appears to be mediated by Abeta in isolated human brain microvessels,
      resulting in an increased production of prostaglandin E(2) and F(2alpha). Using a
      scanner laser Doppler imager, we show a progressive decline with aging in
      cortical perfusion level in transgenic APPsw mice (line 2576) compared with age
      matched control littermates. The relation between the acute proinflammatory and
      vasoactive properties of Abeta and the chronic progressive hypoperfusion seen in
      AD (and transgenic models thereof) is yet to be elucidated.

PMID- 12480735
TI  - Systemic effects of dietary n-3 PUFA supplementation accompany changes of CNS
      parameters in cerebral hypoperfusion.
AB  - Dietary supplementation with long-chain polyunsaturated fatty acids (PUFAs) has
      become an attractive possibility to alleviate or prevent cerebrovascular
      pathophysiology. To characterize the potentially beneficial cerebrovascular
      action of n-3 PUFAs that predominantly occur in fish oil, we set up an
      experimental paradigm where rats with chronic cerebral hypoperfusion were
      supplied with n-3 PUFA-enriched diets. Cerebral hypoperfusion was created by a
      permanent, bilateral occlusion of the common carotid arteries (2VO) of rats at
      the age of 4 months, with a survival of 3 months. Simultaneously, the rats were
      provided with experimental diets from the time of weaning until the termination
      of the experiments. The control diet was comparable to standard rat chow, while
      diet 1 contained additional n-3 PUFAs and diet 2 was further enriched with
      structural phospholipids and neurotransmitter precursors. In summary, the data
      show that diet 2 improved spatial learning of 2VO rats in the Morris water maze.
      Both diet 1 and diet 2 augmented blood-brain barrier parameters and increased the
      density of the M1-type muscarinic cholinergic receptors in the hippocampus
      independent of the rate of cerebral perfusion. In addition to an overview of
      these results, changes that were supportive or accompanying those described in
      the CNS are also presented. Briefly, plasma corticosterone concentration was
      elevated most explicitly by 2VO, while the relative weight of the liver and
      spleen increased due to the diets. The data draw attention to changes not only in
      the CNS, but also in the periphery as a consequence of chronic supplementation
      with n-3 PUFA-enriched diets.

PMID- 12480737
TI  - Paraoxonase 1 activity: a new vascular marker of dementia?
AB  - Paraoxonase 1 (PON1), an A-esterase with peroxidase-like activity present on the
      surface of HDL, decreases the peroxidation of LDL. Serum PON1 activity (PON1a)
      decreases with aging and in disorders associated with a high risk of adverse
      cardiovascular events (acute myocardial infarction, diabetes mellitus, and
      chronic renal failure). The implication of vascular factors in Alzheimer-type
      dementia (ATD) is strongly suspected. We measured PON1a by spectrophotometry
      using the paraoxon substrate in 180 healthy subjects (controls; mean age: 75.3 +/
      8.9 years; 98 women) and 154 patients admitted for cognitive testing. According
      to criteria, 45 patients had mild cognitive impairments (MCI; mean age: 75.6 +/-
      9.3 years; 28 women), 60 had ATD (mean age: 75.6 +/- 8.3 years; 47 women), and 49
      had vascular dementia (VaD; mean age: 77.5 +/- 7.2 years; 33 women). Mean PON1a
      was lower in VaD (0.25 +/- 0.1 U/mL) than in controls or ATD (both 0.41 +/- 0.2
      U/mL, p < 0.01). Mean PON1a values in MCI (0.34 +/- 0.2 U/mL) and ATD (0.41 +/-
      0.2 U/mL) were not significantly different. In multiple linear regression, PON1a
      was negatively correlated with male sex, age, and VaD, and positively correlated
      with ATD (each correlation p < 0.001). As shown in other high-risk cardiovascular
      disorders, PON1a seems to be a reliable marker of VaD. Its modification in
      Alzheimer's disease supports the implication of vascular risk factors in this
      type of dementia.

PMID- 12480736
TI  - Molecular and functional dissection of TGF-beta1-induced cerebrovascular
      abnormalities in transgenic mice.
AB  - Cerebrovascular abnormalities, such as reduced blood flow, microvascular
      fibrosis, and cerebrovascular amyloid angiopathy, are prominent in Alzheimer's
      disease (AD). However, their etiology is poorly understood and it is unclear
      whether cerebrovascular changes contribute to functional impairments in the
      absence of neurodegeneration. In humans with AD, transforming growth factor-beta1
      (TGF-beta1) mRNA levels in the midfrontal gyrus correlate positively with the
      relative degree of cerebrovascular amyloid deposition in that brain region,
      suggesting a possible role for TGF-beta1 in human cerebrovascular abnormalities.
      Transgenic mice overexpressing TGF-beta1 in astrocytes develop AD-like
      cerebrovascular abnormalities, including perivascular astrocytosis, microvascular
      basement membrane thickening, and accumulation of thioflavin S-positive amyloid
      in the absence of parenchymal degeneration. Mice overexpressing TGF-beta1 alone
      or in addition to human amyloid precursor protein (hAPP) show selective
      accumulation of human beta-amyloid (Abeta) in blood vessels and develop cerebral
      hemorrhages in old age. In 9-month-old TGF-beta1 transgenic mice, cerebral blood
      flow (CBF) in the limbic system was significantly less than in nontransgenic
      littermate controls. Aged TGF-beta1 mice also showed overall reduced cerebral
      glucose uptake (CGU) as a measure of brain activity. Thus, chronic overproduction
      of TGF-beta1 in the brain results in structural and functional impairments
      reminiscent of those in AD cases with amyloid angiopathy.

PMID- 12480738
TI  - Astroglial expression of the beta-amyloid in ischemia-reperfusion brain injury.
AB  - Vascular damage and reactive gliosis are found colocalized with amyloid deposits
      in Alzheimer's disease brain, suggesting that the cerebrovasculature may be a
      clinically relevant site of Alzheimer's disease pathology and may contribute to
      the neurodegeneration process in Alzheimer's disease. In ischemic conditions,
      amyloid precursor protein and amyloid peptide are reported to be upregulated in
      neurons and in extracellular space. Expression and distribution of amyloid
      precursor protein and amyloid peptide in astroglial cells were examined
      immunohistochemically after 10-min cardiac arrest. After reperfusion for 2, 7,
      and 14 days and 1, 6, 9, and 12 months, brains were immunostained. The indirect
      reactive astrocytes with fragments of the full-length amyloid precursor protein
      were observed in brains until 7 days postischemia. Direct immunoreactivity only
      of amyloid peptide and the C-terminal of amyloid precursor protein was also
      localized in the reactive astrocytes in ischemic brains at 6 months after
      ischemia. Ischemia temporarily induced amyloid peptide overexpression in reactive
      astrocytes, but this expression peaked at 7 days and 6 months. A glial appearance
      of amyloid peptide and C-terminal of amyloid precursor protein staining occurred
      when extensive neuronal loss and the onset of brain atrophy were evident. The
      localization of the C-terminal of amyloid precursor protein within ischemic
      astroglial cells underscores the likely importance of the C-terminal of amyloid
      precursor protein in the pathogenesis of ischemia as in Alzheimer's disease.

PMID- 12480739
TI  - Adaptive capacities of the synaptic contact areas in hypertensive and ischemic
      young rats.

PMID- 12480740
TI  - Spatiotemporal changes of free cholesterol and neutral lipids after transient
      middle cerebral artery occlusion in rats.

PMID- 12480741
TI  - Transient ischemia associated with hypertension significantly affects synaptic
      plasticity in young rats.

PMID- 12480742
TI  - Mixed dementia--the most common cause of 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. 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, including 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 are more data on how to prevent
      strokes (and presumably VaD) than AD. Moreover, many factors that were identified
      as contributing to cerebrovascular disease in general and VaD in particular are
      frequently suspected as predisposing to AD as well. This surprising finding
      highlights the importance of mixed vascular-degenerative dementia as a disorder
      that has to be properly defined and has important implications on prevention and
      treatment.

PMID- 12480743
TI  - Cerebral blood flow and oxygen metabolism in vascular dementia evaluated by
      positron emission tomography: importance of frontal lobe hypoperfusion and
      hypometabolism.

PMID- 12480744
TI  - Impact of subcortical ischemic lesions on behavior and cognition.
AB  - Both cerebrovascular disease and AD are common in the elderly. There are various
      types of underlying damage to tissue and vessels in vascular cognitive
      impairment, and the neural mechanisms producing cognitive impairment and the
      clinical picture are different among the subtypes. Among them, small subcortical
      infarcts disrupting cortico-subcortical circuits and white matter lesions are the
      commonest types, and the combination of these two types of lesions might be more
      realistic than each pure form. Moreover, cognitive impairment of vascular origin
      may be superimposed on AD. Both vascular and degenerative mechanisms contribute
      to the development of cognitive impairment, especially in old age, whether they
      are two independent parallel processes or interacting pathologies. Subcortical
      small lesions involving the thalamus, caudate, and globus pallidus disrupt
      cortico-subcortical circuits, resulting in cognitive dysfunction. Disruption of
      the frontal-subcortical circuits leads to cognitive impairment with striking
      frontal lobe features, and disruption of the memory-related circuits leads to
      amnesia. White matter changes, which are certainly related to chronic cerebral
      ischemia in some patients, are another issue. Patients with dementia and white
      matter changes may have either AD with cerebrovascular changes or a form of VaD,
      or a combination of these two etiologies. However, our series of studies have
      suggested that white matter changes in AD patients are superimposed phenomena of
      vascular origin and that white matter changes contribute to specific neurological
      and neuropsychiatric manifestations, but not to global cognitive impairment,
      which is more closely associated with the degenerative process.

PMID- 12480745
TI  - Enhanced Abeta40 deposition was associated with increased Abeta42-43 in cerebral
      vasculature with Dutch-type hereditary cerebral hemorrhage with amyloidosis
      (HCHWA-D).
AB  - Cerebrovascular deposition of the amyloid beta-protein (Abeta) is a common
      pathologic event in patients with Alzheimer's disease (AD) and certain related
      disorders. Such an Abeta vascular deposition occurs primarily in the medial layer
      of the cerebral vessel wall in an assembled fibrillar state. These deposits are
      associated with several pathological responses, including degeneration of the
      smooth muscle cells in the cerebral vessel wall. Severe cases of cerebrovascular
      Abeta deposition are also accompanied by loss of vessel wall integrity and
      hemorrhagic stroke. Although the reasons for this pathological consequence are
      unclear, altered proteolytic mechanisms within the cerebral vessel wall may be
      involved. We analyzed cerebral Abeta deposition in brains with AD and Dutch-type
      hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) on the basis of two
      amyloid species of Abeta(40) and Abeta(42/43) using specific monoclonal
      antibodies. Compared to Abeta deposition in senile plaques, the molecular
      composition of Abeta was distinguishable, indicating that the Abeta(40) species
      is the main component for vascular amyloid. Furthermore, we found Abeta(42/43)
      immunoreactivity was also much increased in amyloid angiopathy of all cases with
      HCHWA-D. Taken together, amyloid angiopathy in HCHWA-D may share an Abeta(42)
      driven deposition mechanism with plaque amyloid, resulting in enhanced Abeta(40)
      deposition.

PMID- 12480746
TI  - Similarities and differences between Alzheimer's disease and vascular dementia
      from the viewpoint of nutrition.
AB  - Dietary habits were compared in patients with Alzheimer's disease (AD) and those
      with vascular dementia (VaD). Twenty-seven patients with AD, 15 patients with
      VaD, and 49 age-matched controls were enrolled. Nutritional status was assessed
      using a semiquantified food-frequency questionnaire. Dietary habits were very
      similar in male patients with AD and VaD. Both groups had significantly higher
      energy intake than their energy demands: +25% for AD and +35% for VaD,
      respectively. However, major sources of energy were different: grains and animal
      fats for AD versus only grains for VaD. Calculation of nutrients revealed excess
      intake of n-6 polyunsaturated fatty acids (PUFA) and relative deficiencies of
      multiple vitamins including antioxidants, vitamin C and carotene, and the vitamin
      B group. In contrast, dietary habits in female patients with AD differed
      significantly from those of male patients. Female patients consumed significantly
      lower amounts of fish and green vegetables. Calculation of nutrients showed
      absolute deficiencies of n-3 PUFA, multiple vitamins, and minerals. Our results
      show that AD and VaD are similar from the viewpoint of nutrition, except for the
      higher consumption of animal fats for AD patients, probably reflecting
      Westernization of dietary habits in recent years. Nutrition may be relevant to
      the pathogenesis of dementia through many processes. Higher intake of energy and
      lower intake of antioxidants may exaggerate the process of dementia through
      oxidative stress. Excessive amounts of n-6 PUFA or deficiency of n-3 PUFA may
      cause chronic inflammation, platelet aggregation, or endothelial dysfunction of
      microvasculature. Nutrition may be useful for preventing dementia, although
      gender-specific differences must be taken into account.

PMID- 12480747
TI  - Cerebrovascular disease is a major factor in the failure of elimination of Abeta
      from the aging human brain: implications for therapy of Alzheimer's disease.
AB  - Alzheimer's disease (AD) is characterized by the intracellular deposition of
      ubiquitinated tau and by the extracellular accumulation of soluble, insoluble,
      and fibrillary Abeta. Previous studies suggest that Abeta is normally eliminated
      from the brain along perivascular pathways that may become blocked in the aging
      brain, resulting in cerebral amyloid angiopathy. As age is a major risk factor
      for AD and for cerebrovascular disease (CVD), we test the hypothesis that CVD
      inhibits the elimination of Abeta from the aging human brain. Sections from 100
      aged and AD brains were stained for Abeta by immunohistochemistry and by
      reticulin and Masson trichrome techniques. Early deposition of Abeta in brain
      parenchyma was related to individual arterial territories in the cortex. In areas
      of more extensive accumulation of Abeta, there was an inverse relationship
      between capillary amyloid angiopathy and plaques of Abeta. Thus, arterial
      territories with extensive capillary amyloid angiopathy were devoid of Abeta
      plaques, whereas in areas with abundant diffuse plaques there was no capillary
      amyloid angiopathy. Serial sections showed that cortical arteries feeding
      capillary beds with Abeta angiopathy were occluded by thrombus. We conclude that
      CVD inhibits the elimination of Abeta along capillary walls and changes the
      distribution of Abeta in the cerebral cortex. Loss of pulsations in thrombosed or
      arteriosclerotic arteries may thus abolish the motive force necessary for the
      drainage of Abeta and inhibit the elimination of Abeta. Therapies to increase
      elimination of Abeta in AD need to consider the effects of CVD on the elimination
      of Abeta from the aging human brain.

PMID- 12480748
TI  - Subclinical brain hemorrhages in Alzheimer's disease: evaluation by magnetic
      resonance T2*-weighted images.

PMID- 12480749
TI  - Possible assessment for antioxidant capacity in Alzheimer's disease by measuring
      lymphocyte heme oxygenase-1 expression with real-time RT-PCR.

PMID- 12480750
TI  - Neuropsychological deficits in older stroke patients.
AB  - This paper examines the frequency of CIND, the profile of early cognitive
      deficits in stroke patients, the differences in the profile of cognitive
      impairment in people with CIND and those with vascular dementia, and the MRI
      associations of CIND in older stroke patients.

PMID- 12480751
TI  - Neurocardiovascular instability in cognitive impairment and dementia.
AB  - Neurocardiovascular instability (NCVI, neurally mediated disorders causing
      hypotension with or without bradycardia) represents abnormal neural control of
      the cardiovascular system and presents as dizziness, syncope, or falls. The
      mechanisms underpinning NCVI are incompletely understood. The three most common
      disorders are carotid sinus syndrome (CSS), orthostatic hypotension (OH), and
      vasovagal syndrome (VVS): CSS, cardioinhibition > 3 s and/or vasodepressor
      response > or = 50 mmHg drop in systolic pressure during carotid sinus
      stimulation; OH: fall in systolic blood pressure > 20 mmHg during standing; VVS:
      cardioinhibition > 3 s and/or vasodepressor response > 50 mmHg during prolonged
      head-up tilting. In fallers with cognitive impairment or dementia, the prevalence
      of NCVI is 70%. Multifactorial interventions, including treatment of NCVI,
      significantly reduce falls and syncope. The predominant components of NCVI in
      fallers with cognitive impairment and dementia are CSS and OH. In Lewy body and
      Alzheimer's dementia, the prevalence of NCVI is up to 60%, again predominantly
      CSS and OH. The prevalence of cardioinhibitory carotid sinus hypersensitivity is
      particularly high in Lewy body dementia-41% compared with 12% in Alzheimer's
      disease and 3% in case controls. In addition, patients with Lewy body dementia
      have greater heart rate slowing (>2 s) and falls in systolic blood pressure (>20
      mmHg) than those with Alzheimer's disease or controls during carotid sinus
      stimulation. The extent of deep white matter hyperintensities on MRI correlates
      with systolic fall during carotid sinus stimulation (R = 0.58; p < 0.005),
      suggesting a possible causal association between bradyarrhythmia-induced
      hypotension and microvascular pathology. NCVI is common in patients with dementia
      and may be a reversible cause of falls and syncope. Repeated hypotensive episodes
      may exaggerate cognitive decline in these patients.

PMID- 12480752
TI  - Vascular basis of Alzheimer's pathogenesis.
AB  - Considerable evidence now indicates that Alzheimer's disease (AD) is primarily a
      vascular disorder. This conclusion is supported by the following evidence: (1)
      epidemiologic studies linking vascular risk factors to cerebrovascular pathology
      that can set in motion metabolic, neurodegenerative, and cognitive changes in
      Alzheimer brains; (2) evidence that AD and vascular dementia (VaD) share many
      similar risk factors; (3) evidence that pharmacotherapy that improves
      cerebrovascular insufficiency also improves AD symptoms; (4) evidence that
      preclinical detection of potential AD is possible from direct or indirect
      regional cerebral perfusion measurements; (5) evidence of overlapping clinical
      symptoms in AD and VaD; (6) evidence of parallel cerebrovascular and
      neurodegenerative pathology in AD and VaD; (7) evidence that cerebral
      hypoperfusion can trigger hypometabolic, cognitive, and degenerative changes; and
      (8) evidence that AD clinical symptoms arise from cerebromicrovascular pathology.
      The collective data presented in this review strongly indicate that the present
      classification of AD is incorrect and should be changed to that of a vascular
      disorder. Such a change in classification would accelerate the development of
      better treatment targets, patient management, diagnosis, and prevention of this
      disorder by focusing on the root of the problem. In addition, a theoretical
      capsule summary is presented detailing how AD may develop from chronic cerebral
      hypoperfusion and the role of critically attained threshold of cerebral
      hypoperfusion (CATCH) and of vascular nitric oxide derived from endothelial
      nitric oxide synthase in triggering the cataclysmic cerebromicrovascular
      pathology.

PMID- 12480753
TI  - Decreased cerebrospinal fluid levels of neurosin (KLK6), an aging-related
      protease, as a possible new risk factor for Alzheimer's disease.
AB  - Neurosin is a kallikrein-like serine protease expressed preferentially in the
      human brain. It is localized in senile plaques and neurofibrillary tangles in the
      brains of individuals with Alzheimer's disease (AD) and in Lewy bodies in
      patients with Parkinson's disease. Neurosin is present in the cerebrospinal fluid
      (CSF) as a proenzyme and does not show any enzymatic activity. We have developed
      a sandwich ELISA system using monoclonal and polyclonal antibodies against human
      neurosin and have measured neurosin levels in the CSF from AD and non-CNS disease
      patients. Both male and female patients with peripheral neuropathy showed
      statistically positive correlations between CSF neurosin concentrations and age
      (males, n = 52, r = 0.482, p < 0.005; females, n = 43, r = 0.365, p < 0.005). In
      contrast, such positive correlation was not observed in the CSF from patients
      with AD. Further, some such patients showed extremely low levels of CSF neurosin.
      Our results suggest that neurosin is an aging-related protease and that a
      decreased CSF concentration of neurosin may be a risk factor for developing AD.

PMID- 12480754
TI  - Lessons from CADASIL.
AB  - Vascular dementia (VaD) includes several different vascular mechanisms and
      changes in the brain. Among VaD, CADASIL is an inherited angiopathy caused by
      mutations in the Notch3 gene. The pathological hallmark of CADASIL is a granular
      osmiophilic material deposit (GOM) that is not only found in the brain, but also
      in the peripheral vascular tree. Consequently, a window into the brain was opened
      from a strictly neurological disease with tremendous consequences thanks to a
      skin biopsy. The latter was and continues to be used as a diagnostic tool for
      CADASIL, despite an immunohistochemical test that is now available. The skin
      biopsy first used as a diagnostic tool revealed the existence of numerous other
      VaDs presenting systemic vascular changes. Later, skin biopsy became a research
      tool, and a morphological skin vessel change classification was proposed on 300
      patients. Interestingly, similar skin vessel lesions appear to be related to the
      same biological modifications. In addition, an early destruction of the medial
      muscle cells was noticed in 74% of cases. Because vascular smooth muscle cells
      secrete a powerful endothelial permeability factor (VEGF), their destruction
      could lead to a decrease in vascular permeability. Cocultures of endothelial
      cells with vascular muscle cells showed that their presence doubled vascular
      permeability. Thus, alteration or the loss of vascular muscle cells likely
      results in hypopermeability, in addition to vessel wall hypotonia and a watershed
      hypoperfusion. The wealth of information brought forth by knowledge of CADASIL
      provided new tools for research and clues for understanding the consequences of
      vascular impairments in dementia.

PMID- 12480755
TI  - Genetic analysis of vascular factors in Alzheimer's disease.
AB  - Genetic risk factors for Alzheimer's disease (AD) have been extensively examined.
      Several risk factors for AD are shared with vascular dementia (VaD). We performed
      genetic case-control studies on polymorphisms of the apolipoprotein E (ApoE)
      gene, the methylene tetrahydrofolate reductase (MTHFR) gene, and the angiotensin
      converting enzyme (ACE) gene. The most acceptable genetic risk factor for the
      development of AD is the ApoE epsilon-4 (ApoE epsilon4) allele. ApoE promoter
      polymorphisms have also been reported to be associated with AD. As expected, the
      ApoE epsilon4 allele had strong association with AD in our samples. The ApoE
      epsilon4 allele was also estimated as a risk factor for VaD. An ApoE promoter
      polymorphism (-291T/G) did not show positive association with AD or any other
      diseases. Common MTHFR phenotypes are thought to genetically regulate blood
      homocysteine level, which has been associated with AD. We failed to show
      independent associations between AD and the common MTHFR polymorphisms (C677T and
      A1298C). A deletion polymorphism at intron 16 of the ACE gene has also been
      associated with AD. In our study, we found a significant ethnic difference of the
      genotype distribution, but failed to replicate the positive association between
      the I allele and AD.

PMID- 12480756
TI  - Paraoxonase 1 192/55 gene polymorphisms in Alzheimer's disease.
AB  - An esterase, paraoxonase 1 (PON1), protects against organophosphate neurotoxicity
      and decreases lipoprotein oxidation. Two polymorphisms of PON1 [192 (R or Q) and
      55 (M or L)] exist and are associated with coronary artery disease. We have
      previously shown that serum PON1 activity (PON1a) is lower in vascular dementia
      (VaD) than in Alzheimer's disease (AD), suggesting that PON1a may distinguish VaD
      from AD. As PON1 polymorphism modifies PON1a, we determined 192 and 55 PON1
      polymorphisms by sequence-specific primer PCR in 64 healthy subjects (HS; mean
      age: 79.5 +/- 6.3 years; 38 women) and in 72 patients (mean age: 80.2 +/- 6.8
      years; 51 women) undergoing cognitive evaluations. According to DSM
      IV/NINCDS/ADRDA/NINDS/AIREN criteria, 45 patients (mean age: 80.0 +/- 7.2 years,
      34 women) had AD and 27 patients (mean age: 79.8 +/- 6.6 years, 16 women) had
      VaD. We also measured serum PON1a by spectrophotometry. No significant
      differences in phenotype distributions among the three study groups were detected
      by chi(2) test. Among the variables, age, sex, and phenotypes 192 and 55,
      logistic regression selected only polymorphism 192, but not 55, as a
      discriminating factor between AD and VaD (p < 0.05). Substitution of serum PON1a
      for genotype yielded a similar result. PON1 polymorphism 192 appears to be a
      reliable marker to distinguish patients with AD from patients with VaD and from
      healthy subjects. Changes in 192 polymorphism distributions in AD and in VaD may
      at least partially explain the significant difference in PON1a in these two types
      of dementia.

PMID- 12480757
TI  - Vascular changes in Iowa-type hereditary cerebral amyloid angiopathy.
AB  - Vascular dysfunction due to cerebral amyloid angiopathy (CAA) may contribute to
      cognitive impairment. The Iowa D694N amyloid precursor protein mutation, a
      recently identified cause of hereditary CAA with dementia, offers an opportunity
      to explore the anatomic basis of CAA-related vascular dysfunction. Examination by
      immunolabeling and confocal microscopy demonstrated extensive loss of smooth
      muscle cells in affected segments as well as a perivascular inflammatory reaction
      of astrocytes and microglia. On 3-D reconstruction, vessels appeared tortuous
      with twiglike projections that may represent areas of vascular degeneration. The
      observed changes in the Iowa brain suggest pathophysiologic mechanisms for
      vascular dysfunction in CAA and possible approaches to treatment of CAA-related
      cognitive impairment.

PMID- 12480758
TI  - Lack of association between NOTCH3 gene polymorphism and cerebrovascular disease
      in Japanese patients.

PMID- 12480759
TI  - Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta
      protein precursor.
AB  - Cerebral amyloid beta-protein angiopathy (CAA) is a key pathological feature of
      patients with Alzheimer's disease and certain related disorders. Several
      mutations have been identified within the Abeta region of the Abeta protein
      precursor (AbetaPP) gene that appear to enhance the severity of CAA. A new
      mutation has been identified within the Abeta region (D23N) of AbetaPP that is
      associated with severe CAA in an Iowa kindred. Recently, we showed that E22Q
      Dutch, D23N Iowa, and E22Q/D23N Dutch/Iowa double-mutant Abeta40 peptides rapidly
      assemble in solution to form fibrils compared to wild-type Abeta40. Similarly,
      the E22Q Dutch and D23N Iowa Abeta40 peptides were found to induce robust
      pathologic responses in cultured human cerebrovascular smooth muscle (HCSM)
      cells, including elevated levels of cell-associated AbetaPP, proteolytic
      breakdown of actin, and cell death. Double-mutant E22Q/D23N Dutch/Iowa Abeta40
      was more potent than either single-mutant form of Abeta in causing pathologic
      responses in HCSM cells. These in vitro data suggested that the E22Q Dutch and
      D23N Iowa substitutions promote fibrillogenesis and the pathogenicity of Abeta
      towards HCSM cells. Moreover, the presence of both CAA substitutions in the same
      Abeta peptide further enhances the fibrillogenic and pathogenic properties of
      Abeta. We also have generated transgenic mouse models to examine the effects of
      single and double CAA mutations in AbetaPP in vivo. Preliminary analysis of
      transgenic mouse brains indicates that expression of double-mutant E22Q/D23N
      Dutch/Iowa AbetaPP leads to robust deposition of Abeta in a vascular-weighted
      manner.

PMID- 12480760
TI  - Clinical Features of CADASIL.
AB  - Cerebral autosomal dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy (CADASIL) is a rare hereditary disease characterized by
      recurrent transient ischemic attacks, strokes, and vascular dementia. Various
      mutations in the Notch3 gene cause the disease, whereas the mechanism of how they
      cause the disorder remains unknown. We recently identified two Japanese CADASIL
      families with an R141C mutation. The mean age of onset was 44.6, and the main
      symptoms were recurrent strokes and progressive motor disturbances in
      extremities, as well as pseudobulbar palsy. Besides those in white matter and
      basal ganglia, ischemic lesions in temporal edge and corpus callosum were present
      on magnetic resonance images, which seemed to be characteristic of CADASIL.
      Moreover, in our cases, nocturnal arterial blood pressure fall was significantly
      lower in patients compared with control subjects, suggesting that it might be
      partly associated with ischemic lesions in deep white matter in CADASIL. We also
      compared Japanese and Caucasian CADASIL cases and found that dementia and
      pseudobulbar palsy were observed more frequently in Japanese patients, although
      typical migraine was rather rare. In the present study, we describe the clinical
      features of CADASIL, hoping to help reveal the mechanism of chronic ischemic
      brain diseases, including leukoaraiosis or Binswanger's disease.

PMID- 12480761
TI  - Cerebral autosomal dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy (CADASIL) and CADASIL-like disorders in Japan.
AB  - We reviewed 12 patients from 11 Japanese families diagnosed as having CADASIL
      from 1998 to 2001. The age of onset of focal neurologic deficits ranged from 38
      to 71 years (mean: 50.4 +/- 9.8 years). Japanese CADASIL patients rarely had
      migraine and frequently presented with symptoms of dementia at diagnosis. Notch3
      mutations were concentrated in exons 3, 4, and 5. Cysteine was replaced by
      another amino acid or vice versa in the majority of Japanese CADASIL patients.
      However, in 2 families, the mutations were not related to cysteine. In the
      prospective study, 2030 patients with stroke were hospitalized in 6 hospitals
      with stroke units in the Kumamoto district from 1999 to 2001. Among them, 14
      patients fulfilled the criteria of being less than 60 years of age, showing
      lacunar strokes and/or TIA, presence of a family history, and no risk factors of
      stroke. One of these 14 patients was diagnosed as having CADASIL by DNA analysis.
      However, if hyperlipidemia was excluded from the list, 16 patients fulfilled the
      criteria and 2 patients were diagnosed as having CADASIL by DNA analysis. It was
      suspected that the incidence of CADASIL is not so rare in Japan. There were some
      families with CADASIL-like features, but without Notch3 mutations or GOM,
      suggesting the need for genetic analysis in the future.

PMID- 12480762
TI  - Pathological lesions in vascular dementia.
AB  - According to current diagnostic criteria, a definite diagnosis of vascular
      dementia (VaD) can be reached on pathological grounds by showing the presence of
      vascular lesions and the absence of degenerative changes exceeding those expected
      for age. However, while it is commonly accepted that VaD is a group of
      heterogeneous entities rather than a process with a unique pathological
      substrate, the spectrum of vessel and parenchyma changes etiologically associated
      with the clinical syndrome remains basically unidentified. The review of some
      recent clinical-pathological series shows that different studies have assessed
      the presence of dissimilar vascular lesions and that, in many cases, no
      pathological definition was given. This has hindered the clarification of
      clinical-pathological correlations in the field of VaD. In this scenario, the use
      of animal models of cerebrovascular diseases may help to elucidate the type of
      lesions possibly linked with cognitive impairment in humans and might provide
      insight into some of the pathophysiological mechanisms of vascular cognitive
      impairment. A consensus is today needed in order to harmonize the pathological
      examination of vascular lesions in cases of dementia. An ongoing survey aimed at
      collecting information about the procedures used in different pathological
      laboratories in the assessment of lesions possibly associated with dementia is
      finally presented.

PMID- 12480763
TI  - EPC-K1 reduces the expression of inducible nitric oxide synthase (iNOS) in
      delayed neuronal death (DND).

PMID- 12480764
TI  - Beta-amyloid fragment 25-35 selectively damages platelets from patients with
      Alzheimer's disease.
AB  - In order to analyze the metabolic response of AD patient platelets to beta
      amyloid, we have carried out fluorimetric measurements of intracellular calcium
      and an ultrastructural survey of platelets exposed to the beta-amyloid active
      fragment 25-35 (betaA(25-35)). Since it is not possible to analyze directly the
      damaged neurons in AD, the study of peripheral blood cells, especially platelets,
      may be of great value for the investigation of the toxic effects of beta-amyloid
      on AD neuronal cells.

PMID- 12480765
TI  - Vascular pathology in Alzheimer's disease.
AB  - This report briefly describes the morphological examination in several types of
      senile plaques made by using serial sections for both light and electron
      microscopy in order to observe the relationship between senile plaques and
      cerebral microvessels.

PMID- 12480767
TI  - Cystatin C induces neuronal cell death in vivo.

PMID- 12480766
TI  - Endothelial cell activation is associated with cerebral white matter lesions in
      patients with cerebrovascular disease.
AB  - Cerebral MRI scanning frequently shows white matter lesions in elderly people.
      They are related to cognitive impairment and may result in dementia. Although
      vascular risk factors are associated with the presence of white matter lesions,
      the exact pathogenesis remains unclear. Animal studies have indicated involvement
      of endothelial cells in the pathogenesis of white matter lesions and possibly
      dementia. We investigated the relation between endothelial cell activation and
      white matter lesions in individuals with cerebrovascular disease. In 29 patients
      with an acute stroke (n = 11) or TIAs associated with a symptomatic internal
      carotid artery stenosis (n = 18), markers of endothelial cell activation such as
      intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1
      (sVCAM-1), sE-selectin, and sP-selectin were measured by means of ELISA. All
      individuals underwent 1.5-T MRI scanning. White matter lesions were rated for the
      periventricular and the subcortical region separately. Individuals with severe
      periventricular white matter lesions had higher levels of sP-selectin (245.5
      ng/mL vs. 172.7 ng/mL, p = 0.01) and sVCAM-1 (547.8 ng/mL vs. 454.0 ng/mL, p =
      0.04) than those without. This association was only found in individuals with a
      symptomatic carotid artery stenosis. No such association was found for
      subcortical white matter lesions. We did not detect any relation between sICAM-1
      and sE-selectin and white matter lesions. Endothelial cell activation may play a
      role in the pathogenesis of white matter lesions, especially in periventricular
      white matter. Possibly, this activation represents the influence of vascular
      factors on the cerebral endothelium as a prelude to increasingly severe small
      vessel disease.

PMID- 12480768
TI  - Deafferentative synaptopathology in physiological aging and Alzheimer's disease.

PMID- 12480769
TI  - Possible involvement of ER chaperone Grp78 on reduced formation of amyloid-beta
      deposits.

PMID- 12480770
TI  - Pathologies and pathological mechanisms for white matter hyperintensities in
      depression.
AB  - Signal hyperintensities on magnetic resonance imaging (MRI) are increased in the
      white matter (WMH) and deep gray matter in dementia and depression and may have
      similar pathologies. However, no previous study has examined WMH in subjects with
      major depression. We carried out in vitro MRI on brain tissue from elderly
      subjects who had suffered major depression and elderly control subjects to
      identify and rate WMH. The tissue was subsequently prepared for histopathological
      analysis using a number of conventional and immunohistochemical stains, and the
      WMH were examined to identify their underlying pathological causes. Cerebral
      microvessels were also assessed and the findings compared with assessments of
      atheromatous disease in these subjects. PVH were found to be due to one of three
      causes: dilated perivascular spaces (with and without ischemia in the
      perivascular area), oligemic demyelination, and ischemic demyelination. DWMH also
      showed three types of causes: dilated perivascular spaces (with and without
      ischemia in the perivascular area), oligemic demyelination, and ischemic
      demyelination. Cerebral microvascular disease only contributed to a few of the
      lesions and atheromatous disease did not show associations with WMH in these
      subjects. These findings are similar to previous reports in other diseases and
      demonstrate WMH in elderly depression to be a manifestation of cerebrovascular
      disease. However, since large vessel and small vessel disease were not associated
      with WMH, our findings suggest hypotensive disease might be an important and
      unrecognized mechanism underlying WMH in late-life depression.

PMID- 12480771
TI  - Platelet microparticles as carriers of soluble Alzheimer's amyloid beta (sAbeta).

PMID- 12480772
TI  - The unfolded protein response is involved in the pathology of Alzheimer's
      disease.
AB  - The endoplasmic reticulum (ER) performs the synthesis, posttranslational
      modification, and proper folding of proteins. A variety of conditions can be ER
      stress, causing the accumulation of unfolding or misfolding proteins in the ER.
      Eukaryotic cells have three different mechanisms for dealing with an accumulation
      of unfolded proteins in the ER known as the unfolded protein response (UPR):
      transcriptional induction, translational attenuation, and degradation. This paper
      focuses on the relationship between UPR and the pathogenesis of AD. Our results
      indicate a new mechanism by which PS1 mutations may affect the sensing of ER
      stress. Experimental manipulation of IRE1, PERK, or eIF2alpha phosphorylation or
      GRP78 expression might allow the development of therapeutic strategies for FAD.

PMID- 12480773
TI  - Cholesterol and cognition: rationale for the AD cholesterol-lowering treatment
      trial and sex-related Differences in beta-amyloid accumulation in the brains of
      spontaneously hypercholesterolemic Watanabe rabbits.
AB  - This report presents the scientific rationale and hypothesis for the investigator
      initiated, double-blind, placebo-controlled Alzheimer's Disease Cholesterol
      Lowering Treatment Trial. As part of the supporting preclinical data,
      accumulation of neuronal beta-amyloid immunoreactivity was investigated in 12
      month-old male spontaneously hypercholesterolemic Watanabe rabbits, female
      Watanabe rabbits between 3 and >36 months of age, and untreated female New
      Zealand white rabbits between 6 and 12 months of age. Prior evidence suggests
      that there are significant accumulations of neuronal beta-amyloid
      immunoreactivity in the cholesterol-fed New Zealand white rabbit. At 3 months of
      age, abundant beta-amyloid immunoreactive neurons are also found in female
      hypercholesterolemic Watanabe rabbits. By 6 months of age, as female Watanabe
      rabbits are approaching sexual maturity, the number of beta-amyloid
      immunoreactive neurons was somewhat reduced, but the intensity of the
      immunoreactivity was clearly and consistently diminished. Very few neurons
      expressing beta-amyloid immunoreactivity were identifiable among the 12-month-old
      Watanabe female rabbits. Variably increased numbers of intensely stained beta
      amyloid immunoreactive neurons were observed in retired breeder female animals
      over 3 years of age. Twelve-month-old male Watanabe rabbits exhibited levels of
      neuronal beta-amyloid immunoreactivity consistent with younger and older female
      animals, but greater than the adult 12-month-old females. Cholesterol levels in
      the blood were not noticeably different among females over the age range
      investigated or compared to 12-month-old males. Estrogen levels varied with age
      in female Watanabe rabbits in an apparent inverse relationship with neuronal beta
      amyloid immunoreactivity. However, there was no evidence of increased neuronal
      beta-amyloid immunoreactivity in untreated female New Zealand white rabbits with
      "normal" circulating cholesterol levels at any age investigated. Therefore, under
      conditions of stable, but elevated, circulating cholesterol levels, pathologic
      accumulation of neuronal beta-amyloid immunoreactivity was similar in male
      Watanabe rabbits and female animals prior and subsequent to estrus. The intensity
      of observable neuronal beta-amyloid immunoreactivity accumulation decreases in
      female animals as circulating estrogen levels increased with sexual maturity.
      These data suggest that a loss of circulating estrogen could mark the collapse of
      a system previously protecting a female from conditions conducive to production
      of beta-amyloid as a putative neurotoxin in AD. This may, in part, explain the
      epidemiological evidence for "protective" effects of estrogen in AD.

PMID- 12480774
TI  - Cholesterol in Alzheimer's disease and tauopathy.
AB  - Cholesterol has been implicated in the pathogenesis of amyloid plaques in
      Alzheimer's disease (AD) and in the formation of neurofibrillary pathology in
      Niemann-Pick disease. Several epidemiology studies have implicated high
      cholesterol as a risk factor for AD and have shown that the use of cholesterol
      reducing agents (statins) can be protective against the disease. We and others
      have shown that cholesterol levels modulate the processing of the amyloid
      precursor protein (APP) both in vivo and in vitro, affecting the accumulation of
      A-beta (Abeta) peptides that may directly impact the risk of AD. Mutations in the
      Niemann-Pick C gene (NPC) result in deficient cholesterol transport/storage.
      Clinically, Niemann-Pick disease causes a severe childhood lipidosis, with
      neurodegeneration characterized by the presence of AD-type neurofibrillary
      tangles (NFTs) composed of hyperphosphorylated tau. Studies of mouse models of
      NPC show that defects in cellular cholesterol trafficking are associated with
      enhanced generation of Abeta and the hyperphosphorylation of tau, further
      implicating the cholesterol homeostasis pathway as a risk factor for amyloidosis.

PMID- 12480775
TI  - Cholesterol, a modulator of membrane-associated Abeta-fibrillogenesis.
AB  - One of the major pathological features of Alzheimer's disease (AD) is the
      presence of extracellular amyloid plaques that are predominantly composed of the
      amyloid-beta peptide (Abeta). Characterization of plaques demonstrated the
      predominance of two peptides differing at the carboxyl terminus by two
      hydrophobic amino acids, Abeta40 and Abeta42. Diffuse plaques associated with AD
      are composed predominantly of Abeta42, whereas senile plaques contain both
      Abeta40 and Abeta42. Recently, it has been suggested that diffuse plaque
      formation is initiated as a plasma membrane-bound Abeta species and that Abeta42
      is the critical component. In order to investigate this hypothesis, we have
      examined Abeta40/42-lipid interactions using in situ atomic force microscopy,
      electron microscopy, and fluorescence anisotropy. While the association of
      Abeta42 with planar bilayers resulted in peptide aggregation, but no fiber
      formation, this was not the case for Abeta40, where we observed preferential
      fiber formation. Cholesterol, a key membrane component and modulating factor in
      AD, is inversely correlated with the extent of Abeta40/42-bilayer interaction.
      These results were confirmed using fluorescence anisotropy to evaluate the effect
      of Abeta on membrane fluidity and fluorimetry to confirm membrane integrity. Our
      results suggest that the enhanced amyloidogenic properties of Abeta42 are not
      correlated with fibril formation, but with aggregation on bilayer surfaces.

PMID- 12480776
TI  - Cholesterol-dependent aggregation of amyloid beta-protein.
AB  - One of the fundamental pathological processes of Alzheimer's disease (AD) is the
      aggregation of the amyloid beta-protein (Abeta). In the case of familial AD, the
      expression of genes responsible for this disease is likely to enhance aggregation
      of Abeta through its enhanced generation. However, there is no evidence to
      indicate thus far that in the case of sporadic AD, a major form of the disease,
      the generation of Abeta is altered. Thus, one could assume that the aggregation
      of Abeta in AD is induced by unknown posttranslational modification or by an
      altered clearance mechanism, or both. We previously identified a novel Abeta
      species in the human brain that exhibited early pathological changes of AD. This
      Aalpha is characterized by its tight binding to GM1 ganglioside (GM1). Based on
      its unique molecular characteristics, including its extremely high aggregation
      potential and altered immunoreactivity, we hypothesized that Abeta undergoes
      conformational alteration and acts as a seed for Abeta fibrillogenesis. In regard
      to the molecular mechanism underlying the formation of GM1-Abeta, we recently
      found that binding of Abeta to GM1 was facilitated in cholesterol-rich
      environments and, furthermore, it was dependent on the cholesterol-induced
      clustering of GM1 in the host membranes. Recently, increasing evidence indicates
      that cholesterol is a risk factor for AD development. The results of our current
      studies may provide a new insight into the molecular mechanism underlying the
      cholesterol-dependent development of AD.

PMID- 12480777
TI  - Lipid metabolism, epidemiology, and the mechanisms of Alzheimer's disease.
AB  - Global variations in the incidence and prevalence of Alzheimer's disease (AD)
      have not been explained. Patterns of dietary intake of fats and other nutrients
      may be partly responsible. Recent work with transgenic mice overexpressing the
      beta-amyloid precursor protein suggests that anti-Abeta antibodies enhance
      clearance of the Abeta protein from the brain and reduce plaque burden. This has
      been shown even with anti-Abeta antibodies that do not enter the brain. Many
      factors other than circulating anti-Abeta antibodies may influence this important
      process of Abeta clearance, including the Abeta-binding elements, apolipoproteins
      E and J, circulating LDL, HDL, and LRP, alpha-2-macroglobulin, and transthyretin.
      Also important may be clearance of antibody-antigen complexes from the
      circulation, as well as complement, metals, and estrogen. Dietary intake of
      lipids may influence the ability of Abeta-binding proteins to enhance clearance
      of Abeta from the brain to blood. Understanding processes of Abeta clearance from
      brain may aid in determining the causes of AD in individuals, as well as the
      causes of global variations in incidence and prevalence of the disease.

PMID- 12480778
TI  - Hemodynamic aspects of Alzheimer's disease.
AB  - Neuroradiological functional imaging techniques demonstrate the patterns of
      hypoperfusion and hypometabolism that are thought to be useful in the
      differential diagnosis of Alzheimer's disease (AD) from other dementing
      disorders. Besides the distribution patterns of perfusion or energy metabolism,
      vascular transit time (VTT), vascular reactivity (VR), and oxygen extraction
      fraction (OEF), which can be measured with positron emission tomography (PET),
      provide hemodynamic aspects of brain pathophysiology. In order to evaluate the
      hemodynamic features of AD, PET studies were carried out in 20 patients with
      probable AD and 20 patients with vascular dementia (VaD). The PET findings were
      not included in their diagnostic process of AD. Using oxygen-15-labeled
      compounds, cerebral blood flow (CBF), cerebral metabolic rate of oxygen
      (CMRO(2)), OEF, cerebral blood volume, and VTT were measured quantitatively
      during resting state. To evaluate VR, CBF was also measured during CO(2)
      inhalation. There was a significant increase in OEF in and around the
      parietotemporal cortices, but both VTT and VR were well preserved in patients
      with AD. By contrast, VR was markedly depressed and VTT was mildly prolonged in
      patients with VaD. Thus, from the hemodynamic point of view, the preservation of
      vascular reserve may be a distinct difference between AD and VaD. Furthermore,
      this indicates a hemodynamic integrity of the vasculature in the level of
      arterioles in AD.

PMID- 12480779
TI  - Imaging Interactions between Alzheimer's disease and cerebrovascular disease.
AB  - There is a growing body of evidence suggesting that Alzheimer's disease (AD) and
      cerebrovascular disease (CVD), two common disorders of aging, are related in ways
      that extend beyond their coincident co-occurrence. Thus, there is a need to
      understand how the two pathological processes interact to contribute to dementia.
      In this article, we review two recent studies from our laboratory that use MRI
      and PET to begin to reveal the nature and mechanisms of the relationship between
      AD, CVD, and dementia.

PMID- 12480780
TI  - White matter lesions and dementia: MRI-pathological correlation.
AB  - An MRI-pathological correlation study was performed to determine the pathological
      background of white matter lesions depicted on MR images. The pathological
      findings were various combinations of myelin loss, axonal loss, scattered
      microinfarcts, astrogliosis, dilatation of perivascular space, and relative
      preservation of subcortical U-fibers. Concerning the dilated perivascular space,
      we proposed a new classification according to the present study: (1) etat crible
      in the basal ganglia and the thalamus, (2) etat crible in the cerebral white
      matter, (3) enlarged perivascular space of the lenticulostriate arteries, and (4)
      etat crible in other sites. In conclusion, when effects of white matter lesions
      on cognitive function are to be evaluated, it is necessary to clarify tissues in
      at least three sequences: T2-weighted, T1-weighted, and FLAIR method.

PMID- 12480781
TI  - Inositol phospholipid metabolism in Alzheimer's disease: a positron emission
      tomographic study.

PMID- 12480782
TI  - Proton magnetic resonance spectroscopy and white matter hyperintensities on
      magnetic resonance imaging in patients with Alzheimer's disease.

PMID- 12480783
TI  - Clinical significance of white matter changes in senile dementia of the Alzheimer
      type.

PMID- 12480784
TI  - Cognitive associations of subcortical white matter lesions in older people.
AB  - Hyperintense lesions (HL), as visualized on T2-weighted or FLAIR MRI, are a
      common finding in older people, but their clinical significance and influence on
      cognitive function remain to be clarified. We investigated the relationship
      between HL in deep white and gray matter structures and cognition in older
      subjects. We recruited 154 nondemented (Mini-Mental State Examination > 24)
      subjects (79 males) over the age of 70 from primary care (103 subjects with mild
      hypertension and 51 normotensive subjects). All subjects underwent FLAIR and
      proton density and T2-weighted axial 1.5-tesla MRI scans (slice thickness: 5 mm).
      The scans were rated for the presence and distribution of HL in the subcortical
      gray matter (caudate, putamen, globus pallidus, thalamus) and associated white
      matter tracts (internal/external capsule). Subjects (n = 149) underwent a
      comprehensive cognitive assessment involving tests of attention, processing
      speed, episodic memory, working memory, and executive function. Partial
      correlations (correcting for age, systolic blood pressure, and New Adult Reading
      Test [NART] score) were performed to investigate the relationship between
      cognition and white matter change. HL were found in 49% of subjects. HL in both
      the gray (thalamus and caudate) and white matter were significantly associated
      with impaired cognitive function in tasks involving processing speed and/or
      executive function, but showed no associations with episodic or working memory.
      HL in both subcortical gray matter structures and associated fiber tracts
      correlate with impairments in attention, executive function and processing, and
      memory retrieval speed in nondemented older community-dwelling subjects. Such
      lesions may be an important cause of age-related attentional and executive
      dysfunction in the elderly, as well as temporal lobe and hippocampal changes that
      have previously been reported to be associated with impairments to the ability to
      actually store and retrieve information from memory.

PMID- 12480785
TI  - Acetazolamide vasoreactivity in vascular dementia and persistent vegetative state
      evaluated by transcranial harmonic perfusion imaging and Doppler sonography.
AB  - To clarify the pathophysiological differences of the cerebrovascular reserve
      capacity in relation to cerebral cognitive impairments between vascular dementia
      (VaD) and persistent vegetative state (PVS), we evaluated acetazolamide (ACZ)
      vasoreactivity testing by transcranial harmonic perfusion imaging (HPI) and
      Doppler sonography (TCD). Sixteen patients (age: 29-85 years; mean: 62) were
      divided into three groups: 7 VaD, 4 PVS, and 5 nondementia patients. Mean
      velocity (Vm) in the middle and posterior cerebral artery (MCA, PCA) was
      measured, and time-intensity curves of the HPI were evaluated at three regions of
      interest-the bilateral temporal lobe (TL), basal ganglia (BG), and thalamus (Th).
      TCD and HPI were evaluated before (resting state) and after ACZ administration,
      and vasoreactivity was compared among the three groups in terms of resting values
      and relative changes (%Delta) of Vm, peak intensity (PI), area under curve (AUC),
      and mean transit time (MTT). Results of the resting state: Decreased Vm, PI, and
      AUC of the VaD and PVS groups were more obvious in the right side. Results of
      vasoreactivity: In the PVS group, %DeltaVm decreased in the left PCA and MCA;
      %DeltaPI and %DeltaAUC decreased in the left TL and bilateral BG. In the VaD
      group, %DeltaPI and %DeltaAUC decreased in the right TL; %DeltaMTT tended to
      increase in the left side. ACZ vasoreactivity tests by transcranial HPI and TCD
      allowed bedside, noninvasive quantitative evaluation of the pathophysiology of
      cognitive function impairment in relation to cerebrovascular reserve capacity in
      VaD and PVS.

PMID- 12480786
TI  - Treatment of Alzheimer's disease by transposition of the omentum.
AB  - There is increasing evidence that cerebral hypoperfusion plays a key role in the
      development of Alzheimer's disease (AD). As one ages, cerebral blood flow (CBF)
      decreases as a direct reflection of a normal aging process. Coupled with this
      expected drop in CBF are a host of other factors, such as hypertension, stress,
      smoking, diabetes, cholesterol buildup, etc., which further decrease blood flow
      to the brain. Maintaining a critical level of CBF is essential if adequate
      amounts of oxygen and glucose are to be presented to neurons to sustain their
      cellular energy production (ATP). If CBF drops below a critical flow level,
      insufficient ATP will be produced and, if this situation is not corrected,
      neurons will deteriorate and eventually die. When a critical mass of neurons die
      in areas of the brain involved with cognition and memory, AD will result. Omentum
      transposition to the brain is a surgical procedure by which a large volume of
      blood and other biological agents can be delivered to the brain over an
      indefinite period of time. The omentum gives metabolic support to deteriorating
      neurons and its presence on the brain has resulted in the reversal of AD
      symptoms. Additionally, omentum transposition to the brain can markedly reduce
      senile plaque accumulation, but has no apparent effect on reducing
      neurofibrillary tangles. Omental transposition may play an important role in the
      future treatment of AD, especially in early and moderate cases.

PMID- 12480787
TI  - Neuroprotective effect of apolipoprotein E against ischemia.
AB  - Apolipoprotein E (APOE) deficiency has been shown to worsen neuronal injuries
      after cerebral ischemia. However, the molecular mechanism underlying the
      protective effect of APOE remains uncertain, even though several mechanisms
      including excitotoxicity, free radicals, and apoptosis have been cited as causes
      of selective neuronal vulnerability in cerebral ischemia. In the present study,
      we compared the vulnerability of cultured neurons prepared from APOE-knockout
      mice upon exposure to glutamate, hydrogen peroxide, and staurosporine. No
      significant difference in cell viability was observed after exposure to glutamate
      or staurosporine between APOE-deficient and wild-type mice. However, exposure to
      hydrogen peroxide significantly increased the level of cell death in APOE
      deficient mice compared with that in wild-type mice. In the adult mice, after
      transient forebrain ischemia for 12 min, APOE-deficient mice showed more neuronal
      death than wild-type mice. Pretreatment of APOE-deficient mice with vitamin E for
      2 months markedly reduced neuronal death caused by ischemia. The results
      suggested that APOE exerted the neuroprotective effect against ischemia through
      its antioxidant action, but not through mitigation of glutamate toxicity or
      blocking of apoptosis.

PMID- 12480788
TI  - A novel treatment for patients with Alzheimer's disease and with vascular
      dementia.

PMID- 12480789
TI  - Donepezil treatment of vascular dementia.
AB  - Cholinergic deficits are clinicopathological hallmarks of Alzheimer's disease
      (DAT) and during the past decade have been the sole target for clinically
      effective treatments. By contrast, vascular dementia subtypes (VaD) are
      heterogeneous clinical syndromes, and therapeutic approaches have been directed
      toward control of vascular risk factors. Little attention has been paid to
      cholinergic deficits as a mechanism contributing to cognitive impairments in VaD
      as a potential target for treatment. The purpose of the study was to determine
      whether there are therapeutic benefits from long-term treatment with
      cholinesterase inhibitors among VaD patients. Ten VaD patients were diagnosed
      according to DSM-III-R and NINDS-AIREN criteria and classified into subtypes by
      neuroimaging. All were treated with titrated doses of donepezil for a mean
      interval of 15 months. At baseline and follow-up clinic visits, patients
      underwent medical and neurological examinations, as well as neuropsychological
      testing including Mini-Mental Status Examinations (MMSE) and Cognitive Capacity
      Screening Examinations (CCSE). Cognitive statuses of 10 treated patients were
      then compared before and after treatment. Net changes were expressed as annual
      MMSE score changes (DeltaMMSE/year) and annual CCSE score changes
      (DeltaCCSE/year). Of the 10 treated VaD patients, cognitive improvements were
      found when comparisons were made before and after treatment. Ten treated patients
      also showed greater cognitive improvements, while untreated patients showed
      continued cognitive decline. This study suggests that cholinergic deficits in VaD
      are due to neuronal ischemic damage with loss of acetylcholine and that treatment
      of VaD with cholinesterase inhibitors is a rational therapy.

PMID- 12480790
TI  - Broad therapeutic benefits in patients with probable vascular dementia or
      Alzheimer's disease with cerebrovascular disease treated with galantamine.

PMID- 12480791
TI  - Responses to donepezil in Alzheimer's disease and Parkinson's disease.
AB  - Alzheimer's disease is the most common cause of dementia, but Parkinson's disease
      also shows dementia in the later stages. Donepezil is a cholinesterase inhibitor
      used for the treatment of Alzheimer's disease. Variable responses to this drug
      suggest that Alzheimer's disease is clinically heterogeneous. In the clinical
      trial of tacrine, a first developed cholinesterase inhibitor, three cases
      markedly improved and, several years later, they were pathologically confirmed as
      dementia with Lewy bodies (DLB). In recent years, another cholinesterase
      inhibitor, rivastigmine, has also been reported to be effective for patients with
      DLB by a placebo-controlled, double-blind, multicenter study. Parkinson's disease
      with dementia, which is known to fulfill the pathological criteria of DLB, also
      shows a favorable response to donepezil. In some cases, not only does cognitive
      function improve, but also parkinsonism. Both DLB and Parkinson's disease with
      dementia show characteristic CBF patterns: While the parietal and temporal lobes
      are involved in Alzheimer's disease, the occipital lobe is additionally affected
      in these diseases. Alzheimer's disease and Parkinson's disease have been
      considered discrete disease entities. However, viewed from the aspects of
      response to donepezil treatment and CBF patterns, both diseases overlapped. A
      brain SPECT may be a useful tool to detect such treatable conditions.

PMID- 12480792
TI  - Possible protective mechanisms of heme oxygenase-1 in the brain.

PMID- 12480793
TI  - Treatment of vascular dementia.
AB  - We report positron emission tomography (PET) findings of our patients with
      vascular dementia, asymptomatic cerebral infarction, and chronic cerebral
      circulatory insufficiency. According to the PET studies, it was suggested that
      frontal lobe hypoperfusion and hypometabolism play important roles in dementia
      caused by cerebral infarctions. It was also suggested that patients with
      subjective complaints associated with asymptomatic strokes and patients with
      chronic cerebral circulatory insufficiency already exhibited decreased cerebral
      circulation. Since therapeutic approaches to vascular dementia after its
      development are limited, active control of risk factors and prevention of
      recurrent stroke during the developmental process of vascular dementia are
      important. We review recent situations in prevention and treatment of vascular
      dementia.

PMID- 12480794
TI  - Donepezil-treated patients with probable vascular dementia demonstrate cognitive
      benefits.

PMID- 12480795
TI  - Omega-3 fatty acids in inflammation and autoimmune diseases.
AB  - Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which
      possess the most potent immunomodulatory activities, and among the omega-3 PUFA,
      those from fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-
      are more biologically potent than alpha-linolenic acid (ALA). Some of the effects
      of omega-3 PUFA are brought about by modulation of the amount and types of
      eicosanoids made, and other effects are elicited by eicosanoid-independent
      mechanisms, including actions upon intracellular signaling pathways,
      transcription factor activity and gene expression. Animal experiments and
      clinical intervention studies indicate that omega-3 fatty acids have anti
      inflammatory properties and, therefore, might be useful in the management of
      inflammatory and autoimmune diseases. Coronary heart disease, major depression,
      aging and cancer are characterized by an increased level of interleukin 1 (IL-1),
      a proinflammatory cytokine. Similarly, arthritis, Crohn's disease, ulcerative
      colitis and lupus erythematosis are autoimmune diseases characterized by a high
      level of IL-1 and the proinflammatory leukotriene LTB(4) produced by omega-6
      fatty acids. There have been a number of clinical trials assessing the benefits
      of dietary supplementation with fish oils in several inflammatory and autoimmune
      diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative
      colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine
      headaches. Many of the placebo-controlled trials of fish oil in chronic
      inflammatory diseases reveal significant benefit, including decreased disease
      activity and a lowered use of anti-inflammatory drugs.

PMID- 12480796
TI  - Risk factors for Alzheimer's disease: role of multiple antioxidants, non
      steroidal anti-inflammatory and cholinergic agents alone or in combination in
      prevention and treatment.
AB  - The etiology of Alzheimer's disease (AD) is not well understood. Etiologic
      factors, chronic inflammatory reactions, oxidative and nitrosylative stresses and
      high cholesterol levels are thought to be important for initiating and promoting
      neurodegenerative changes commonly found in AD brains. Even in familial AD,
      oxidative stress plays an important role in the early onset of the disease.
      Mitochondrial damage and proteasome inhibition represent early events in the
      pathogenesis of AD, whereas increased processing of amyloid precursor protein
      (APP) to beta-amyloid (Abeta) fragments (Abeta(40) and Abeta(42)) and formation
      of senile plaques and neurofibrillary tangles (NFTs) represent late events. We
      propose a hypothesis that in idiopathic AD, epigenetic components of neurons such
      as mitochondria, proteasomes and post-translation protein modifications
      (processing of amyloid precursor protein to beta-amyloid and hyperphosphorylation
      of tau), rather than nuclear genes, are the primary targets for the action of
      diverse groups of neurotoxins. Based on epidemiologic, laboratory and limited
      clinical studies, we propose that a combination of non steroidal anti
      inflammatory drugs (NSAIDs) and appropriate levels and types of multiple
      micronutrients, including antioxidants, may be more effective than the individual
      agents in the prevention, and they, in combination with a cholinergic agent, may
      be more effective in the treatment of AD than the individual agents alone. In
      addition, agents, which can prevent formation of plaques or dissolve these
      plaques may further enhance the efficacy of our proposed treatment strategy.

PMID- 12480797
TI  - Nutritional characteristics of a rural Southern Italy population: the Ventimiglia
      di Sicilia Project.
AB  - OBJECTIVE: Knowledge of alimentary habits among populations permits a better
      definition of appropriate public health interventions. We designed the
      epidemiological project "Ventimiglia di Sicilia" to characterize the risk profile
      in a rural village with low total cholesterol levels and low early cardiovascular
      mortality but with a large prevalence of overweight and obesity, which previously
      have been significantly associated with total mortality. METHODS: 488 individuals
      of age 20 to 69 years were included in the dietary survey conducted by a seven
      day food record. RESULTS: Alimentary habits were characterized by high
      consumption of total and complex carbohydrates (respectively 52.5 +/- 7.6% and
      46.6 +/- 8.2% of daily energy) and by a low cholesterol intake (92.5 +/- 35.0
      mg/1000 kcal/day). Fat intake was 34.7 +/- 7.7% of daily energy due to a higher
      consumption of monounsaturated fats in respect to saturated fats (respectively
      20.5 +/- 5.1% and 10.2 +/- 2.9% of daily energy). In particular, in this
      population there was a large consumption of bread, pasta, fresh vegetables, olive
      oil and fruits. We also observed an excess of total calories (about 2900 kcal/day
      in men and 2100 kcal/day in women) not balanced by a high degree of physical
      activity levels. Furthermore we found a significant higher total and saturated
      fat consumption in the youngest individuals and in people with higher educational
      levels. CONCLUSIONS: Dietary habits of Ventimiglia di Sicilia still follow the
      nutritional characteristics typical of the Mediterranean diet. The high total
      calorie intake indicates a quantitative more than qualitative problem, which may
      account the large prevalence of overweight and obesity and may represent a public
      health issue that needs to be corrected in such a rural population.

PMID- 12480798
TI  - Development and validation of a stages of change algorithm for calcium intake for
      college female students.
AB  - OBJECTIVES: The purpose of this study was to develop and validate a staging
      algorithm for calcium intake. METHODS: Three hundred seventy-six college-aged
      females at a private university were randomly selected to participate. After 8.5%
      of the data were omitted due to incomplete surveys, the sample consisted of 344
      female participants. Calcium intake was measured as self-reported consumption
      with a 26-item food frequency questionnaire. Stages of change classifications
      were based on a four-item algorithm for calcium intake, and self-efficacy was
      measured with three items. RESULTS: Significant differences were found between
      calcium intake levels between precontemplation, contemplation/preparation and
      action/maintenance. Results also showed that 40% of the participants were in
      action/maintenance and were consuming the Dietary Reference Intake level of 1,000
      mg of daily calcium. Participants in the action and maintenance stages had
      significantly higher self-efficacy than the preaction group. CONCLUSION: The
      study suggests that the stages of change algorithm may be used as an effective
      tool in assessing daily calcium intake among a college female population.

PMID- 12480799
TI  - To drink or not to drink: how are alcohol, caffeine and past smoking related to
      bone mineral density in elderly women?
AB  - OBJECTIVES: To determine relationship between alcohol, caffeine, past smoking and
      bone mineral density of different skeletal sites in elderly women, accounting for
      other biological and life-style variables. METHODS/DESIGN: A cross-sectional
      study in 136 Caucasian women, mean +/- SD age 68.6 +/- 7.1 years, all healthy and
      free of medications affecting bones, including estrogen. Bone mineral density
      (BMD) of multiple skeletal regions and body composition were measured by dual X
      ray absorptiometry. Serum vitamin D (25-OHD) and parathyroid hormone (PTH) were
      analyzed and used as confounders. Calcium (Ca) intake was assessed by food
      frequency questionnaire. Alcohol and caffeine consumption was assessed by
      questionnaires determining frequency, amount and source of each. There were no
      current smokers, but the history of smoking was recorded, including number of
      years and packages smoked/day. Past physical activity was assessed by Allied
      Dunbar National Fitness Survey and used as confounder. Statistical significance
      was considered at p <or= 0.05. RESULTS: In the correlational analysis, alcohol
      was positively associated with spine BMD (r = 0.197, p = 0.02), 25-OHD and
      negatively with PTH. Smoking was negatively related to Ca intake, 25(OH)D and
      number of reproductive years. In subgroup (stratified by Ca intake) and multiple
      regression analyses, alcohol (average approximately 0.5-1 drinks/day or
      approximately 8 g alcohol/day) was favorably associated with BMD of spine and
      total body. Caffeine (average approximately 2.5 6-fl oz cups/day or 200-300 mg
      caffeine/day) had negative association with most of the skeletal sites, which was
      attenuated with higher Ca intake (>or=median, 750 mg/day). The past smokers who
      smoked on average 24 years of approximately 1 pack cigarettes/day had lower BMD
      in total body, spine and femur than never-smokers when evaluated in subgroup
      analyses, and the association was attenuated in participants with >or=median Ca
      intake. There was no significant association between past smoking and BMD of any
      skeletal site in multiple regression analyses. CONCLUSION: The results support
      the notion that consumption of small/moderate amount of alcohol is positively,
      while caffeine and past smoking are negatively associated with most of the
      skeletal sites, which might be attenuated with Ca intake above 750 mg/day.

PMID- 12480800
TI  - Non-anemic iron depletion, oral iron supplementation and indices of copper status
      in college-aged females.
AB  - OBJECTIVES: Indices of copper status, specifically serum copper and ceruloplasmin
      concentrations and erythrocyte superoxide dismutase activity, and iron status,
      including serum ferritin, transferrin receptors, hemoglobin and hematocrit, were
      studied in 27 college-aged females with adequate iron versus low iron stores.
      METHODS: Serum copper and ceruloplasmin concentrations, erythrocyte superoxide
      dismutase activity, serum ferritin, transferrin receptors, hemoglobin and
      hematocrit were studied in 15 females with non-anemic iron depletion before and
      after five weeks of iron supplementation and in 12 healthy iron-adequate females
      aged 19 to 28 years. RESULTS: Mean hemoglobin, hematocrit and ferritin
      concentrations of the control group (144 +/- 11 g/L, 43 +/- 3% and 38 +/- 15
      micro g/L, respectively) were significantly higher than those of the iron
      depleted group prior to supplementation (134 +/- 9 g/L, 39 +/- 2% and 11 +/- 6
      micro g/L, respectively). The serum transferrin receptor to serum ferritin ratio
      was significantly greater for the iron depleted group prior to supplementation
      (890 +/- 753) versus the control group (151 +/- 61). Mean serum copper and
      ceruloplasmin concentrations and erythrocyte superoxide dismutase activity of the
      iron-adequate control group (20.0 +/- 5.7 micro mol/L, 463 +/- 142 mg/L and 527
      +/- 124 U/mL, respectively) were significantly higher than those of the iron
      depleted group (12.4 +/- 3.8 micro mol/L, 350 +/- 108 mg/L and 353 +/- 186 U/mL,
      respectively) prior to supplementation. Following iron supplementation,
      hematocrit and ferritin concentrations of the iron depleted group significantly
      increased to 42 +/- 3% and 26 +/- 8 micro g/L, respectively. Mean serum
      transferrin receptor concentrations and the serum transferrin receptor to
      ferritin ratios significantly decreased in the iron depleted group following
      supplementation (6.1 +/- 1.6 mg/L to 4.6 +/- 1.5 mg/L and 890 +/- 753 to 198 +/-
      114, respectively). Iron supplementation also significantly increased the mean
      serum copper concentration to 14.2 +/- 5.4 micro mol/L and, in subjects with
      serum ferritin concentrations </=12 micro g/L, the mean serum ceruloplasmin
      concentration. CONCLUSIONS: Non-anemic iron depletion characterized by low iron
      stores is associated with negative impacts on copper status. Iron supplements
      improved indices of iron status and serum copper and ceruloplasmin
      concentrations. Whether the diminished serum copper and ceruloplasmin
      concentrations and superoxide dismutase activity are associated with free radical
      damage to iron depleted cells requires further investigation.

PMID- 12480801
TI  - Food intake and electrolyte status of ultramarathoners competing in extreme heat.
AB  - OBJECTIVE: To relate changes in laboratory indices to dietary intake during
      extremely prolonged running and to determine if dietary intake influences the
      ability of runners to finish an 160 km trail race. METHODS: We monitored intake
      and serum chemistries of 26 runners competing in an 160 km foot race in
      temperatures which peaked at 38 degrees C. Blood was drawn pre-, mid- and post
      race. Dietary intake and incidence of gastrointestinal distress or changes in
      mental status were determined by interview with runners approximately every 13
      km. Twenty-three runners completed at least 88 kms and, of these 23 runners, 13
      finished 160 km in a mean time of 26.2 +/- 3.6 hours. RESULTS: Finishers ingested
      nearly 30,000 J, 19.4 +/- 8.1 L of fluid and 16.4 +/- 9.5 g of sodium (Na).
      Sodium and fluid intake per hour was estimated to be 0.6 g/hour and 0.7 L/hour,
      respectively. Electrolyte intake during the first half of the race was similar
      between those that finished the race and those that did not. Finishers ingested
      fluid at a greater rate than non-finishers (p = 0.01) and tended to meet their
      caloric needs more closely than did non-finishers (p = 0.09). Body weight was
      unchanged over time (ANOVA, p = 0.52). Serum Na concentration tended to fall from
      143 to 140 mEq/L during the race (p = 0.06), and was inversely correlated with
      weight loss (p = 0.009). Serum Na concentration was lower mid-race in runners
      experiencing changes in mental status than in runners without changes (p = 0.04).
      Fluid intake was inversely correlated with serum Na concentrations (p = 0.04).
      Most of the runners experienced nausea or vomiting; these symptoms were not
      related to serum sodium concentration. Hyponatremia (<135 mEq/L) was seen in one
      runner at 88 kms, but resolved by 160 km. Urinary sodium excretion decreased (p =
      0.002) as serum aldosterone concentration increased pre- to post-race (p <
      0.001). From start to finish of the race plasma volume increased by 12%.
      CONCLUSIONS: Food and fluid was ingested at a greater rate than described
      previously. Runners consumed adequate fluid to maintain body weight although
      dietary sodium fell far short of the recommended 1 g/hour. The rate of fluid
      intake was greater in finishers than in non-finishers, and finishers tended to
      more nearly meet their energy needs. Maintenance of body mass despite large
      exercise energy expenditures in extreme heat is consistent with fluid overload
      during a running event lasting more than 24 hours in hot and humid conditions.

PMID- 12480802
TI  - Soybean isoflavones reduce postmenopausal bone resorption in female Japanese
      immigrants in Brazil: a ten-week study.
AB  - OBJECTIVE: Some human studies and animal models of experimental osteoporosis have
      shown that soy isoflavones may be effective on bone health. In this study, we
      carried out an intervention study to explore the effects of dietary isoflavone on
      bone metabolism. METHODS: Forty healthy female postmenopausal Japanese immigrants
      living in Brazil were divided into two groups: isoflavone-administered (n = 20)
      or placebo (n = 20). Subjects in the isoflavone-administered group ingested 37.3
      mg per day for 10 weeks. The collection of 24-hour urine and the measurement of
      bone stiffness were performed at 0 and 10 weeks. Urinary excretion of isoflavones
      and bone resorption markers were analyzed. RESULTS: Urinary isoflavone excretion
      in the isoflavone-administered group was significantly increased at weeks 3 and
      10. Urinary excretion of bone resorption markers was reduced in the isoflavone
      administered group, while the placebo group did not show any significant
      reduction. Differences in levels of urinary isoflavones and bone resorption
      markers between the two groups were significant. CONCLUSION: This study
      demonstrated that the bone resorption was associated with the intake of soy
      isoflavones in postmenopausal women, and continuous dietary intake of isoflavone
      may inhibit postmenopausal osteoporosis.

PMID- 12480803
TI  - Lower calcium absorption in infants fed casein hydrolysate- and soy protein-based
      infant formulas containing palm olein versus formulas without palm olein.
AB  - OBJECTIVE: Quantitative balance studies were performed to compare fat and calcium
      absorption in healthy, full term infants fed casein hydrolysate-based (CHF) and
      soy protein-based (SPF) infant formulas with or without palm olein (PO). Previous
      studies have reported that PO significantly reduced absorption of both fat and
      calcium in cow's milk-based formulas in which most of the calcium is inherent in
      the milk protein. In both SPF and CHF virtually all calcium is added as calcium
      salts. METHODS: Two randomized, blinded, crossover balance studies were conducted
      in normal term infants using a three-day home balance method. One study evaluated
      10 infants fed commercially available CHF with or without PO, and the other study
      evaluated 12 infants fed commercially available SPF with or without PO. Fat and
      calcium absorption were determined based on the weight of formula intake, weight
      of stools, and measured calcium and fat in formula and stools. RESULTS: Fat and
      calcium intake did not differ between the groups fed CHF. However, infant's
      calcium and fat absorption was less, 41 +/- 6% (Mean +/- SEM) and 92.0 +/- 0.8%,
      respectively, when fed CHF with PO compared to 66 +/- 5% and 96.6 +/- 1.1%,
      respectively, when fed CHF without PO, (p < 0.01). For infants fed SPF, fat and
      calcium intake did not differ between the feeding groups. Mean calcium absorption
      was also significantly less when infants were fed SPF with PO, 22 +/- 3%, than
      when fed SPF with no PO, 37 +/- 4% (p < 0.05). Fat absorption did not differ
      between the two SPFs. CONCLUSION: This study demonstrates that PO, as the
      predominant fat, is associated with significantly lower absorption of calcium
      from infant formulas in which calcium salts are the source of calcium. These
      findings corroborate previous reports of this negative effect of PO in cow milk
      based infant formulas in which most of the calcium is a component of the cow milk
      protein source.

PMID- 12480804
TI  - Ready-to-eat cereal used as a meal replacement promotes weight loss in humans.
AB  - OBJECTIVES: The primary aim was to determine whether ready-to-eat cereal used as
      a portion-controlled, meal replacement promotes weight loss. Additional aims were
      to determine whether weight loss differed if the cereal was provided as a single
      brand or variety of brands and whether this use of ready-to-eat cereal promotes
      continued weight loss following transition to a high-fiber, high-volume
      (Volumetric) diet. METHODS: Body composition was measured and diet records,
      appetite questionnaires and activity logs were completed during baseline and end
      of intervention weeks 2 and 6. Participants were assigned to one of four
      treatment groups. Group 1 (6 M, 22 F, mean age 43.0 +/- 1.9 years, mean initial
      BMI 28.9 +/- 0.4 kg/m(2)) consumed a serving of a single brand of ready-to-eat
      cereal with 2/3 C skim milk and a 100 Kcal portion of fruit for breakfast and as
      a replacement for either lunch or dinner for weeks 1 and 2. No restrictions were
      placed on the non-cereal meal. They then followed the Volumetric diet for weeks 3
      to 6 with a target energy restriction of 500 kcal/day. Group 2 (3 M, 25 F, mean
      age 40.9 +/- 2.3 years, mean initial BMI 29.39 +/- 0.6 kg/m(2)) followed the same
      protocol, but was permitted to select from a variety of ready-to-eat cereals
      during weeks 1 and 2. Group 3 (7 M, 19 F, mean age 41.6 +/- 2.4 years, mean
      initial BMI 29.3 +/- 0.6 kg/m(2)) received no dietary instruction during the six
      week study and Group 4 (9 M, 18 F, mean age 38.2 +/- 2.8 years, mean initial BMI
      29.3 +/- 0.6 kg/m(2)) received no intervention prior to adoption of the
      Volumetric diet for weeks 3 to 6. RESULTS: The cereal interventions resulted in
      640 +/- 109 and 617 +/- 105 kcal/day reductions of energy intake in Groups 1 and
      2, respectively, during the two-week cereal intervention. This led to comparable
      mean weight losses (1.91 +/- 0.19 kg-Group 1, 1.37 +/- 0.15 kg-Group 2) that were
      significantly greater than that observed in Group 3 (0.08 +/- 0.15 kg). The
      losses were primarily of fat mass. No significant changes of total body water
      were observed. Weight loss continued during the Volumetric diet in Groups 1 and
      2. The changes were comparable to those observed in Group 4, and all were
      significantly greater than that of Group 3. Self-reported hunger was slightly,
      but significantly higher than baseline in Groups 1 and 2 during the cereal
      intervention, but similar to baseline in Groups 1, 2 and 3 during the Volumetric
      diet. Based on predicted weight loss, compliance with the Volumetric diet was
      similar and limited in all three intervention groups. CONCLUSIONS: Ready-to-eat
      cereals may be used to promote weight loss when consumed as a portion-controlled,
      meal replacement. Provision of a variety of brands does not compromise efficacy.
      Weight losses may be maintained or increased after transition to the Volumetric
      diet. The later regimen effectively controls hunger and may lead to weight loss,
      but compliance is limited.

PMID- 12480806
TI  - Bioactive peptide signaling within the myocardial interstitium and the matrix
      metalloproteinases.

PMID- 12480807
TI  - Alive and kicking: endothelium at the geographic nexus of vascular rejection.

PMID- 12480808
TI  - Neuronal nitric oxide synthase gene transfer promotes cardiac vagal gain of
      function.
AB  - Nitric oxide (NO) generated from neuronal nitric oxide synthase (NOS-1) in
      intrinsic cardiac ganglia has been implicated in parasympathetic-induced
      bradycardia. We provide direct evidence that NOS-1 acts in a site-specific manner
      to promote cardiac vagal neurotransmission and bradycardia. NOS-1 gene transfer
      to the guinea pig right atrium increased protein expression and NOS-1
      immunolocalization in cholinergic ganglia. It also increased the release of
      acetylcholine and enhanced the heart rate (HR) response to vagal nerve
      stimulation (VNS) in vitro and in vivo. NOS inhibition normalized the HR response
      to VNS in the NOS-1-treated group compared with the control groups (enhanced
      green fluorescent protein and sham) in vitro. In contrast, an acetylcholine
      analogue reduced HR to the same extent in all groups before and during NOS
      inhibition. These results demonstrate that NOS-1-derived NO acts presynaptically
      to facilitate vagally induced bradycardia and that upregulation of NOS-1 via gene
      transfer may provide a novel method for increasing cardiac vagal function.

PMID- 12480809
TI  - Stem cells for myocardial regeneration.
AB  - Stem cells are being investigated for their potential use in regenerative
      medicine. A series of remarkable studies suggested that adult stem cells undergo
      novel patterns of development by a process referred to as transdifferentiation or
      plasticity. These observations fueled an exciting period of discovery and high
      expectations followed by controversy that emerged from data suggesting cell-cell
      fusion as an alternate interpretation for transdifferentiation. However, data
      supporting stem cell plasticity are extensive and cannot be easily dismissed.
      Myocardial regeneration is perhaps the most widely studied and debated example of
      stem cell plasticity. Early reports from animal and clinical investigations
      disagree on the extent of myocardial renewal in adults, but evidence indicates
      that cardiomyocytes are generated in what was previously considered a postmitotic
      organ. On the basis of postmortem microscopic analysis, it is proposed that
      renewal is achieved by stem cells that infiltrate normal and infarcted
      myocardium. To further understand the role of stem cells in regeneration, it is
      incumbent on us to develop instrumentation and technologies to monitor myocardial
      repair over time in large animal models. This may be achieved by tracking labeled
      stem cells as they migrate into myocardial infarctions. In addition, we must
      begin to identify the environmental cues that are needed for stem cell
      trafficking and we must define the genetic and cellular mechanisms that initiate
      transdifferentiation. Only then will we be able to regulate this process and
      begin to realize the full potential of stem cells in regenerative medicine.

PMID- 12480810
TI  - Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy.
AB  - Structural remodeling of the ventricular wall is a key determinant of clinical
      outcome in heart disease. Such remodeling involves the production and destruction
      of extracellular matrix proteins, cell proliferation and migration, and apoptotic
      and necrotic cell death. Cardiac fibroblasts are crucially involved in these
      processes, producing growth factors and cytokines that act as autocrine and
      paracrine factors, as well as extracellular matrix proteins and proteinases.
      Recent studies have shown that the interactions between cardiac fibroblasts and
      cardiomyocytes are essential for the progression of cardiac remodeling. This
      review addresses the functional role played by cardiac fibroblasts and the
      molecular mechanisms that govern their activity during cardiac hypertrophy and
      remodeling. A particular focus is the recent progress toward our understanding of
      the transcriptional regulatory mechanisms involved.

PMID- 12480811
TI  - Brugada syndrome: a decade of progress.
AB  - The Brugada syndrome has gained wide recognition throughout the world and today
      is believed to be responsible for 4% to 12% of all sudden deaths and
      approximately 20% of deaths in patients with structurally normal hearts. The
      incidence of the disease is on the order of 5 per 10 000 inhabitants and, apart
      from accidents, is the leading cause of death of men under the age of 50 in
      regions of the world where the inherited syndrome is endemic. This minireview
      briefly summarizes the progress made over the past decade in our understanding of
      the clinical, genetic, cellular, ionic, and molecular aspects of this disease.

PMID- 12480812
TI  - Tumor necrosis factor-alpha-induced AT1 receptor upregulation enhances
      angiotensin II-mediated cardiac fibroblast responses that favor fibrosis.
AB  - Extracellular matrix (ECM) remodeling after myocardial infarction (MI) is an
      important determinant of cardiac function. Tumor necrosis factor-alpha (TNF
      alpha) and angiotensin (Ang) II levels increase after MI and both factors affect
      fibroblast functions. The type 1 (AT1) receptor that mediates most Ang II effects
      is upregulated after MI in cardiac fibroblasts, and there is evidence that this
      is caused by TNF-alpha. We sought to determine if TNF-alpha-induced AT1 receptor
      upregulation alters fibroblast responsiveness to Ang II and if this effect
      differs from direct TNF-alpha effects on fibroblast functions. In cultured
      neonatal rat cardiac fibroblasts, TNF-alpha reduced cellular [3H]-proline
      incorporation, increased matrix metalloproteinase-2 (MMP-2) activity and protein,
      and increased TIMP-1 protein levels. In cardiac fibroblasts with TNF-alpha
      induced AT1 receptor upregulation, Ang II-stimulated [3H]proline incorporation
      and TIMP-1 protein production was approximately 2-fold greater than in
      nonpretreated fibroblasts. Angiotensin II reduced MMP-2 activity and protein
      level only in TNF-alpha-pretreated fibroblasts. Angiotensin II effects were
      inhibited by selective AT1 (but not AT2) receptor blockers. Thus, TNF-alpha
      induced AT1 receptor upregulation enhances Ang II-mediated functions that favor
      fibrosis. These effects are mostly directionally opposite of direct TNF-alpha
      effects on cardiac fibroblasts. Recognition of multifaceted TNF-alpha effects
      provides new insights into post-MI ECM remodeling.

PMID- 12480813
TI  - Brain natriuretic Peptide is produced in cardiac fibroblasts and induces matrix
      metalloproteinases.
AB  - Cardiac fibroblasts (CFs) produce extracellular matrix proteins and participate
      in the remodeling of the heart. It is unknown if brain natriuretic peptide (BNP)
      is synthesized by CFs and if BNP participates in the regulation of extracellular
      matrix turnover. In this study, we examined the production of BNP in adult canine
      CFs and the role of BNP and its signaling system on collagen synthesis and on the
      activation of matrix metalloproteinases (MMPs). BNP mRNA was detected in CFs, and
      a specific radioimmunoassay demonstrated that BNP(1-32) was secreted into the
      media at a rate of 11.2+/-1.0 pg/10(5) cells per 48 hours (mean+/-SEM). The
      amount of BNP secretion was significantly (P<0.01) augmented by 10(-7) mol/L
      tumor necrosis factor-alpha in a time-dependent manner. BNP significantly
      (P<0.01) inhibited de novo collagen synthesis as assessed by [3H]proline
      incorporation, whereas zymographic MMP-2 (gelatinase) abundance was significantly
      (P<0.05) stimulated by BNP between 10(-7) and 10(-6) mol/L. In addition, protein
      expression of MMP-1, -2, and -3 and membranous type-1 MMP was significantly
      increased by 10(-6) mol/L BNP. The cGMP analogue 8-bromo-cGMP (10(-4) mol/L)
      mimicked the BNP effect, whereas inhibition of protein kinase G by KT5823 (10(-6)
      mol/L) significantly (P<0.05) attenuated BNP-induced zymographic MMP-2 abundance.
      In summary, this study reports that BNP is present in cultured CFs and that BNP
      decreases collagen synthesis and increases MMPs via cGMP-protein kinase G
      signaling. These in vitro findings support a role for BNP as a regulator of
      myocardial structure via control of cardiac fibroblast function.

PMID- 12480814
TI  - Apoptosis and cellular activation in the pathogenesis of acute vascular
      rejection.
AB  - Acute vascular or humoral rejection, a vexing outcome of organ transplantation,
      has been attributed by some to activation and by others to apoptosis of
      endothelial cells in the graft. We asked which of these processes causes acute
      vascular rejection by tracing the processes during the development of acute
      vascular rejection in porcine cardiac xenografts performed in baboons. Apoptosis,
      assayed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling
      (TUNEL), expression of activated caspase-3, and proapoptotic genes Bax and Bcl
      x(L), was not detected until acute vascular rejection was well advanced, and even
      then, apoptosis was largely confined to myocytes. Activation of the endothelium,
      as evidenced by expansion of rough endoplasmic reticulum and increased ribosomal
      antigen and phospho-p70 S6 kinase, occurred early in the course of acute vascular
      rejection and progressed through the disease process. These findings suggest that
      acute vascular rejection is caused by an active metabolic process and not by
      apoptosis in the endothelium.

PMID- 12480815
TI  - Estrogens inhibit angiotensin II-induced leukocyte-endothelial cell interactions
      in vivo via rapid endothelial nitric oxide synthase and cyclooxygenase
      activation.
AB  - Angiotensin II (Ang II) may be a key molecule in the development of
      atherosclerosis. Because the incidence of coronary atherosclerosis in
      premenopausal women is lower than that observed in men or postmenopausal women,
      we have investigated the effect of estrogens on Ang II-induced leukocyte
      recruitment in vivo using intravital microscopy in the rat mesenteric
      microcirculation. Superfusion for 60 minutes with Ang II induced a significant
      increase in leukocyte rolling flux, adhesion, and emigration. Administration of
      17-beta-estradiol (17-beta-E) after 30 minutes of Ang II superfusion produced a
      reduction of these leukocyte responses by 55.1%, 72.7%, and 70.9%, respectively,
      an additional 30 minutes later. The effect observed with 17-beta-E was receptor
      mediated and specific. 17-beta-E superfusion did not modify either L-NAME or
      indomethacin-induced leukocyte responses. Inhibitory responses caused by 17-beta
      E were not altered by either 7-nitroindazole or actinomycin D cosuperfusion.
      Stimulation of endothelial cells with 17-beta-E caused a rapid and dose-dependent
      release of prostacyclin. Finally, tamoxifen or ICI 182,780 administration
      provoked a significant increase in leukocyte-endothelial cell interactions 90
      minutes later, which were significantly attenuated by systemic preadministration
      with an Ang II AT(1) receptor antagonist. Tamoxifen-induced leukocyte responses
      were also reduced by systemic pretreatment with an anti-P-selectin mAb and an
      anti-CD18 mAb. Hence, the antiatherogenic effects of estrogens may be mediated by
      inhibition of Ang II-induced leukocyte recruitment through endothelial NO and
      prostacyclin release. Furthermore, scarcity of estrogens resulted in decreased
      levels of vasodilators and the exposure of the endothelium to the deleterious
      action of Ang II, which may explain the higher incidence of coronary
      atherosclerosis in men and postmenopausal women.

PMID- 12480816
TI  - Cell-specific regulatory modules control expression of genes in vascular and
      visceral smooth muscle tissues.
AB  - A novel approach with chimeric SM22alpha/telokin promoters was used to identify
      gene regulatory modules that are required for regulating the expression of genes
      in distinct smooth muscle tissues. Conventional deletion or mutation analysis of
      promoters does not readily distinguish regulatory elements that are required for
      basal gene expression from those required for expression in specific smooth
      muscle tissues. In the present study, the mouse telokin gene was isolated, and a
      370-bp (-190 to 180) minimal promoter was identified that directs visceral smooth
      muscle-specific expression in vivo in transgenic mice. The visceral smooth muscle
      specific expression of the telokin promoter transgene is in marked contrast to
      the reported arterial smooth muscle-specific expression of a 536-bp minimal
      SM22alpha (-475 to 61) promoter transgene. To begin to identify regulatory
      elements that are responsible for the distinct tissue-specific expression of
      these promoters, a chimeric promoter in which a 172-bp SM22alpha gene fragment (
      288 to -116) was fused to the minimal telokin promoter was generated and
      characterized. The -288 to -116 SM22alpha gene fragment significantly increased
      telokin promoter activity in vascular smooth muscle cells in vitro and in vivo.
      Conversely, a fragment of the telokin promoter (-94 to -49) increased the
      activity of the SM22alpha promoter in visceral smooth muscle cells of the
      bladder. Together, these data demonstrate that both vascular- and visceral smooth
      muscle-specific regulatory modules direct gene expression in subsets of smooth
      muscle tissues.

PMID- 12480817
TI  - Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial
      growth factor-induced signaling and angiogenesis.
AB  - Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating
      endothelial cell proliferation and migration, primarily through the receptor
      tyrosine kinase VEGF receptor2 (Flk1/KDR). Reactive oxygen species (ROS) derived
      from NAD(P)H oxidase are critically important in many aspects of vascular cell
      regulation, and both the small GTPase Rac1 and gp91(phox) are critical components
      of the endothelial NAD(P)H oxidase complex. A role of NAD(P)H oxidase in VEGF
      induced angiogenesis, however, has not been defined. In the present study,
      electron spin resonance spectroscopy is utilized to demonstrate that VEGF
      stimulates O2*- production, which is inhibited by the NAD(P)H oxidase inhibitor,
      diphenylene iodonium, as well as by overexpression of dominant-negative Rac1
      (N17Rac1) and transfection of gp91(phox) antisense oligonucleotides in human
      umbilical vein endothelial cells (ECs). Antioxidants, including N-acetylcysteine
      (NAC), various NAD(P)H oxidase inhibitors, and N17Rac1 significantly attenuate
      not only VEGF-induced KDR tyrosine phosphorylation but also proliferation and
      migration of ECs. Importantly, these effects of VEGF are dramatically inhibited
      in cells transfected with gp91(phox) antisense oligonucleotides. By contrast, ROS
      are not involved in mediating these effects of sphingosine 1-phosphate (S1P) on
      ECs. Sponge implant assays demonstrate that VEGF-, but not S1P-, induced
      angiogenesis is significantly reduced in wild-type mice treated with NAC and in
      gp91(phox-/-) mice, suggesting that ROS derived from gp91(phox)-containing
      NAD(P)H oxidase play an important role in angiogenesis in vivo. These studies
      indicate that VEGF-induced endothelial cell signaling and angiogenesis is tightly
      controlled by the reduction/oxidation environment at the level of VEGF receptor
      and provide novel insights into the NAD(P)H oxidase as a potential therapeutic
      target for angiogenesis-dependent diseases.

PMID- 12480818
TI  - Nicotinic acid adenine dinucleotide phosphate mediates Ca2+ signals and
      contraction in arterial smooth muscle via a two-pool mechanism.
AB  - Previous studies of arterial smooth muscle have shown that inositol 1,4,5
      trisphosphate (IP3) and cyclic ADP-ribose mobilize Ca2+ from the sarcoplasmic
      reticulum. In contrast, little is known about Ca2+ mobilization by nicotinic acid
      adenine dinucleotide phosphate, a pyridine nucleotide derived from beta-NADP+. We
      show here that intracellular dialysis of nicotinic acid adenine dinucleotide
      phosphate (NAADP) induces spatially restricted "bursts" of Ca2+ release that
      initiate a global Ca2+ wave and contraction in pulmonary artery smooth muscle
      cells. Depletion of sarcoplasmic reticulum Ca2+ stores with thapsigargin and
      inhibition of ryanodine receptors with ryanodine, respectively, block the global
      Ca2+ waves by NAADP. Under these conditions, however, localized Ca2+ bursts are
      still observed. In contrast, xestospongin C, an IP3 receptor antagonist, had no
      effect on Ca2+ signals by NAADP. We propose that NAADP mobilizes Ca2+ via a 2
      pool mechanism, and that initial Ca2+ bursts are amplified by subsequent
      sarcoplasmic reticulum Ca2+ release via ryanodine receptors but not via IP3
      receptors.

PMID- 12480819
TI  - Localization of sodium channels in intercalated disks modulates cardiac
      conduction.
AB  - It is well known that the sodium current (I(Na)) and the degree of gap-junctional
      electrical coupling are the key determinants of action potential (AP) conduction
      in cardiac tissue. Immunohistochemical studies have shown that sodium channels
      (NaChs) are preferentially located in intercalated disks (IDs). Using dual
      immunocytochemical staining, we confirmed the colocalization of NaChs with
      connexin43 in cultures of neonatal rat ventricular myocytes. In mathematical
      simulations of conduction using the Luo-Rudy dynamic model of the ventricular AP,
      we assessed the hypothesis that conduction could be modulated by the preferential
      localization of NaChs in IDs. Localization of I(Na) at the ID caused a large
      negative potential in the intercellular cleft, which influenced conduction in two
      opposing ways, depending on the degree of electrical coupling: (1) for normal and
      moderately reduced coupling, the negative cleft potential led to a large
      overshoot of the transmembrane potential resulting in a decreased driving force
      for I(Na) itself (self-attenuation), which slowed conduction; (2) for greatly
      reduced coupling (<10%), the negative cleft potential induced by I(Na) in the
      prejunctional membrane led to suprathreshold depolarization of the postjunctional
      membrane, which facilitated and accelerated conduction. When cleft potential
      effects were not incorporated, conduction was not significantly affected by the
      ID localization of I(Na). By enhancing conduction through the establishment of
      cleft potentials, the localization of NaChs in IDs might protect the myocardium
      from conduction block, very slow conduction, and microreentry under conditions of
      greatly reduced coupling. Conversely, by supporting moderately slow conduction,
      this mechanism could also promote arrhythmias.

PMID- 12480820
TI  - Defect in microvascular adaptation to chronic changes in blood flow in mice
      lacking the gene encoding for dystrophin.
AB  - Dystrophin has a key role in striated muscle mechanotransduction. In mice lacking
      the gene encoding for dystrophin (mdx mice), the absence of dystrophin and
      several other proteins of the dystrophin-glycoprotein complex induces a defect in
      flow (shear stress)-mediated NO-dependent dilation (FMD). Because the endothelium
      is essential for the adaptation of arteries to chronic changes in blood flow, the
      long-term consequences of this vascular deficiency might affect flow-induced
      vascular remodeling. Thus, we submitted mouse mesenteric resistance arteries to
      chronic changes in flow by alternatively ligating arteries. Arteries were thus
      submitted to high flow (HF), low flow (LF), or normal flow. After 2 weeks,
      arteries were studied in vitro in an arteriograph. Increases in diameter (from
      174+/-10 to 210+/-15 microm, pressure 75 mm Hg) found in HF arteries were not
      significant in mdx mice. Arterial diameters in LF arteries decreased similarly in
      control and mdx mice. FMD increased in HF arteries and decreased in LF arteries.
      FMD was not increased in HF arteries in mdx mice. NO-dependent FMD and NO
      synthase expression increased in the HF arteries of control mice but not in those
      of mdx mice. Dilatory and contractile tone, depending on the smooth muscle, was
      unaffected in HF arteries but decreased in LF arteries of both strains. We
      conclude that resistance arteries of mdx mice do not adapt properly to chronic
      changes in flow, inasmuch as the increases in diameter, endothelial NO synthase
      expression, and FMD did not occur in mdx mice submitted to HF for 2 weeks. This
      study suggests that blood flow regulation might be disturbed in dystrophin
      related myopathies, possibly increasing organ damage.

PMID- 12480821
TI  - Physical training increases eNOS vascular expression and activity and reduces
      restenosis after balloon angioplasty or arterial stenting in rats.
AB  - The effects of dynamic exercise on restenosis after vascular injury are still
      unknown. The consequences of balloon dilation-induced injury on neointimal
      hyperplasia, vascular negative remodeling, and reendothelialization were assessed
      in sedentary and trained rats. Ex vivo eNOS vascular expression and activity were
      investigated in carotid arteries isolated from sedentary and exercised rats. The
      in vivo effects of eNOS inhibition by L-NMMA on vessel wall after balloon
      dilation were evaluated in sedentary and exercised rats. We also investigated the
      effects of exercise on neointimal formation in a rat stent model of vascular
      injury. Compared with sedentary group, the arteries isolated from trained rats
      showed higher levels of eNOS protein expression and activity 7 days after balloon
      dilation. A significant reduction of both neointimal hyperplasia and negative
      remodeling was observed 14 days after balloon injury in trained compared with
      sedentary rats. Moreover, we demonstrated that exercise training produced
      accelerated reendothelialization of the balloon injured arterial segments
      compared with sedentary. L-NMMA administration eliminated the benefits of
      physical training on vessel wall after balloon dilation. Finally, a decrease of
      neointimal hyperplasia as well as of platelet aggregation was observed after
      stent deployment in trained rats compared with sedentary. In conclusion, physical
      exercise could favorably affect restenosis after balloon angioplasty and
      stenting. Increase in eNOS expression and activity might contribute to the
      potential beneficial effects of exercise on the vessel wall after vascular
      injury.

PMID- 12480822
TI  - Reduced myocardial and systemic L-arginine uptake in heart failure.
AB  - Altered nitric oxide (NO) bioavailability has been ascribed an important role in
      the pathophysiology of congestive heart failure (CHF). In the peripheral
      vasculature, we recently demonstrated a depression of L-arginine transport in
      association with pharmacological evidence of reduced endothelial function. In
      contrast, increased myocardial NO generation has been proposed to account for a
      component of the reduced myocardial contractility in CHF, although this remains
      controversial. We determined the whole body clearance rate and cardiac fractional
      extraction of L-arginine during a steady-state intravenous infusion of [3H]L
      arginine (300 nCi/min) in 9 healthy control subjects and 7 patients with moderate
      to severe CHF. In patients with CHF, there was a 30% reduction in the
      transcardiac extraction of [3H]L-arginine compared with controls (P<0.05), which
      was accompanied by a trend toward reduced [3H]L-citrulline release (P=0.06). In
      conjunction, the systemic clearance rate of [3H]L-arginine was significantly
      lower in patients with CHF (778+/-148 versus 1278+/-144 mL/min, P<0.05). In
      association with these biochemical indices, we observed a 38% reduction (P<0.05)
      in the mRNA expression of the cationic amino acid transporter CAT-1 in
      ventricular myocardial samples from patients with CHF compared with healthy
      unused donor myocardium, whereas myocardial NOS enzymatic activity and NOS
      protein were unchanged. These data indicate the presence of a significant
      reduction in the myocardial uptake of L-arginine in patients with CHF.
      Furthermore, this abnormality seems to be part of a systemic downregulation of L
      arginine transport.

PMID- 12480825
TI  - Cardiomyocyte cultures with controlled macroscopic anisotropy: a model for
      functional electrophysiological studies of cardiac muscle.
AB  - Structural and functional cardiac anisotropy varies with the development,
      location, and pathophysiology in the heart. The goal of this study was to design
      a cell culture model system in which the degree, change in fiber direction, and
      discontinuity of anisotropy can be controlled over centimeter-size length scales.
      Neonatal rat ventricular myocytes were cultured on fibronectin on 20-mm diameter
      circular cover slips. Structure-function relationships were assessed using
      immunostaining and optical mapping. Cell culture on microabraded cover slips
      yielded cell elongation and coalignment in the direction of abrasion, and
      uniform, macroscopically continuous, elliptical propagation with point
      stimulation. Coarser microabrasion (wider and deeper abrasion grooves) increased
      longitudinal (23.5 to 37.2 cm/s; r=0.66) and decreased transverse conduction
      velocity (18.1 to 9.2 cm/s; r=-0.84), which resulted in increased longitudinal-to
      transverse velocity anisotropy ratios (1.3 to 3.7, n=61). A thin transition zone
      between adjacent uniformly anisotropic areas with 45 degrees or 90 degrees
      difference in fiber orientation acted as a secondary source during 2x threshold
      field stimulus. Cell culture on cover slips micropatterned with 12- or 25- micro
      m wide fibronectin lines and previously coated with decreasing concentrations of
      background fibronectin yielded transition from continuous to discontinuous
      anisotropic architecture with longitudinally oriented intercellular clefts,
      decreased transverse velocity (16.9 to 2.6 cm/s; r=-0.95), increased velocity
      anisotropy ratios (1.6 to 5.6, n=70), and decreased longitudinal velocity (36.4
      to 14.6 cm/s; r=-0.85) for anisotropy ratios >3.5. Cultures of cardiac myocytes
      with controlled degree, uniformity and continuity of structural, and functional
      anisotropy may enable systematic 2-dimensional in vitro studies of macroscopic
      structure-related mechanisms of reentrant arrhythmias. The full text of this
      article is available at http://www.circresaha.org.

PMID- 12480826
TI  - Nonendothelial source of nitric oxide in arterioles but not in venules:
      alternative source revealed in vivo by diaminofluorescein microfluorography.
AB  - This study aimed to examine topographic distribution of microvascular NO
      generation in vivo. To this end, nitrosonium ion (NO+)-sensitive
      diaminofluorescein diacetate was superfused continuously on the rat mesentery and
      the fluorescence was visualized in the microvessels through laser confocal
      microfluorography. Two major sites exhibited a time-dependent elevation of the
      fluorescence: microvascular endothelia and mast cells. As judged by the
      fluorescence sensitivity to local application of different inhibitors of NO
      synthase (NOS), NO availability in arteriolar endothelium and mast cells appeared
      to be maintained mainly by NOS1, whereas that in venular endothelium greatly
      depends on NOS3. In venules, the magnitude of inhibitory responses elicited by
      the inhibitors was positively correlated with the density of leukocyte adhesion.
      NOS inhibitors significantly reduced, but did not eliminate, the NO+-associated
      fluorescence in arterioles, capillaries, and venules, suggesting alternative
      sources of NO in circulation for these microvessels. Immunohistochemistry for NOS
      isozymes revealed that NOS1 occurred not only in nerve fibers innervated to
      arterioles but also abundantly in mast cells. Laser flow cytometry of peritoneal
      cells in vitro revealed abundant expression of NOS1 in mast cells. Interestingly,
      NOS3 occurred in endothelia of capillaries and venules but not in those of distal
      arterioles with comparable diameters. These results suggest that the arterioles
      receive NO from nonendothelial origins involving NOS1 present in nerve terminals
      and mast cells, whereas venules depend on the endothelial NOS as a major source.
      Furthermore, nonenzymatic sources of NO from circulating reservoirs constitute a
      notable fraction throughout different classes of microvessels. The full text of
      this article is available at http://www.circresaha.org.

PMID- 12480827
TI  - Interim smallpox guidelines for the United Kingdom.

PMID- 12480828
TI  - Evaluating treatment effects reliably.

PMID- 12480829
TI  - Ultrasound guided central venous access.

PMID- 12480830
TI  - Influences of the media on suicide.

PMID- 12480831
TI  - Making progress with competing interests.

PMID- 12480833
TI  - FDA limits research of former AHA president for submitting false information.

PMID- 12480838
TI  - Congress criticises drugs industry for misleading advertising.

PMID- 12480840
TI  - India announces plan to inform HIV infected blood donors.

PMID- 12480841
TI  - Air pollution responsible for 600 000 premature deaths worldwide.

PMID- 12480842
TI  - HIV infection rate among South African children found to be 5.6%.

PMID- 12480843
TI  - Oregon's governor apologises for forced sterilisations.

PMID- 12480846
TI  - Tobacco giant wins appeal over document shredding.

PMID- 12480847
TI  - Doctor may face manslaughter charges after a confidential report is made public.

PMID- 12480849
TI  - Proposals for UK body to investigate research fraud "lack teeth".

PMID- 12480850
TI  - Self help smoking cessation in pregnancy: cluster randomised controlled trial.
AB  - OBJECTIVES: To evaluate the effectiveness of a self help approach to smoking
      cessation in pregnancy. DESIGN: Pragmatic cluster randomised controlled trial
      with community midwife as the unit of randomisation. SETTING: Three NHS hospital
      trusts in England. PARTICIPANTS: 1527 women who smoked at the start of pregnancy.
      INTERVENTION: A series of five self help booklets comprising a step by step
      programme to increase motivation for quitting smoking and to teach strategies for
      cessation and relapse prevention. The first booklet was given to the women by a
      midwife at the earliest opportunity in antenatal care, together with a booklet
      for partners, family members, and friends. The remaining four booklets were
      mailed directly to the women. MAIN OUTCOME MEASURES: The primary outcome was
      smoking cessation validated by cotinine measurement at the end of the second
      trimester of pregnancy. Other outcomes were self reported smoking status and
      cigarette consumption among daily smokers. Qualitative data exploring the
      acceptability of the intervention and the way that smoking cessation advice was
      delivered in both trial arms were also collected. RESULTS: Smoking cessation
      rates were low: the cotinine validated rates were 18.8% (113/600) in the
      intervention group and 20.7% (144/695) in the normal care group (difference 1.9%,
      95% confidence intervals -3.5% to 7.3%). Self reported quit rates were higher. In
      the intervention group, 156 (25.6%) women reported not smoking for at least seven
      days, compared with 207 (29.1%) in the normal care group. In both groups, median
      self reported daily cigarette consumption among daily smokers was 10 cigarettes
      per day. Pregnant women and midwives approved of the intervention, but the way in
      which it was delivered varied considerably. For the primary smoking outcome, the
      degree of clustering at the midwife level was non-trivial (intracluster
      correlation coefficient 0.031). CONCLUSION: The self help intervention was
      acceptable but ineffective when implemented during routine antenatal care. More
      intensive and complex interventions, appropriately targeted and tailored, need to
      be developed and evaluated. Validated smoking cessation rates among pregnant
      women are substantially lower than the self reported rates on which current
      smoking policy is based.

PMID- 12480851
TI  - Evaluation of early abdominopelvic computed tomography in patients with acute
      abdominal pain of unknown cause: prospective randomised study.
AB  - OBJECTIVES: To evaluate the impact of early abdominopelvic computed tomography in
      patients with acute abdominal pain of unknown cause on length of hospital stay
      and accuracy of diagnosis. DESIGN: Randomised, prospective controlled trial.
      SETTING: Teaching hospital in England. PARTICIPANTS: 120 patients admitted with
      acute abdominal pain for which no immediate surgical intervention or computed
      tomography was indicated. INTERVENTION: 55 participants were prospectively
      randomised to early computed tomography (within 24 hours of admission) and 65 to
      standard practice (radiological investigations as indicated). MAIN OUTCOME
      MEASURES: Length of hospital stay, accuracy of diagnosis, and, owing to a
      possible effect on inpatient mortality, deaths during the study. RESULTS: Early
      computed tomography reduced the length of hospital stay by 1.1 days (geometric
      mean 5.3 days (range 1 to 31) v 6.4 days (1 to 60)), but the difference was non
      significant (95% confidence interval, 8% shorter stay to 56% longer stay,
      P=0.17). Early computed tomography missed significantly fewer serious diagnoses.
      Seven inpatients in the standard practice arm died. Only 50% (59 of 118) of
      diagnoses on admission were correct at follow up at 6 months, but this improved
      to 76% (90) of diagnoses after 24 hours. CONCLUSIONS: Early abdominopelvic
      computed tomography for acute abdominal pain may reduce mortality and length of
      hospital stay. It can also identify unforeseen conditions and potentially serious
      complications.

PMID- 12480852
TI  - Prevalence of gastroschisis at birth: retrospective study.

PMID- 12480853
TI  - Mortality from methicillin resistant Staphylococcus aureus in England and Wales:
      analysis of death certificates.

PMID- 12480854
TI  - Does declaration of competing interests affect readers' perceptions? A randomised
      trial.

PMID- 12480855
TI  - Young women's accounts of factors influencing their use and non-use of emergency
      contraception: in-depth interview study.
AB  - OBJECTIVES: To explore young women's accounts of their use and non-use of
      emergency contraception. DESIGN: Qualitative study using in-depth interviews.
      PARTICIPANTS: 30 women aged 16-25; participants from socially deprived inner city
      areas were specifically included. SETTING: Community, service, and educational
      settings in England. RESULTS: Young women's accounts of their non-use of
      emergency contraception principally concerned evaluations of the risk conferred
      by different contraceptive behaviours, their evaluations of themselves in needing
      emergency contraception, and personal difficulties in asking for emergency
      contraception. CONCLUSIONS: The attitudes and concerns of young women, especially
      those from disadvantaged backgrounds, may make them less able or willing than
      others to take advantage of recent increases in access to emergency
      contraception. Interventions that aim to increase the use of emergency
      contraception need to address the factors that influence young women's non-use of
      emergency contraception.

PMID- 12480856
TI  - Beta blockers for glaucoma and excess risk of airways obstruction: population
      based cohort study.

PMID- 12480857
TI  - Impact of NHS Direct on general practice consultations during the winter of 1999
      2000: analysis of routinely collected data.

PMID- 12480858
TI  - Recent developments in gastroenterology.

PMID- 12480859
TI  - Alcohol breath testing.

PMID- 12480860
TI  - Antithrombotic strategies in acute coronary syndromes and percutaneous coronary
      interventions.

PMID- 12480861
TI  - Managing acute renal colic across the primary-secondary care interface: a pathway
      of care based on evidence and consensus.

PMID- 12480862
TI  - How the tobacco industry responded to an influential study of the health effects
      of secondhand smoke.

PMID- 12480863
TI  - Screening for domestic violence. Cultural shift is needed.

PMID- 12480864
TI  - Treating head injuries. Outcomes in specialist units using protocols may not be
      better.

PMID- 12480865
TI  - Association between competing interests and conclusions. Denominator problem
      needs to be addressed.

PMID- 12480866
TI  - Robust evidence is needed in treating acne.

PMID- 12480867
TI  - Galantamine may be effective in treating autistic disorder.

PMID- 12480869
TI  - Watchfulness may not be as good as surgery for prostate cancer.

PMID- 12480868
TI  - Broad statements do not tell whole story of prison medicine.

PMID- 12480870
TI  - People with partial hearing need to seek hearing potential.

PMID- 12480871
TI  - On communication--editors and reporters should not be blamed.

PMID- 12480876
TI  - Cohesion of sister chromosomes in Escherichia coli.

PMID- 12480877
TI  - The minimal mobile element.

PMID- 12480878
TI  - Sequence similarity between the channel-forming domains of voltage-gated ion
      channel proteins and the C-terminal domains of secondary carriers of the major
      facilitator superfamily.

PMID- 12480879
TI  - Quorum sensing in context: out of molecular biology and into microbial ecology.

PMID- 12480880
TI  - A putative transcription factor inducing mobility in Mycoplasma pneumoniae.

PMID- 12480881
TI  - Options for the control of enterohaemorrhagic Escherichia coli in ruminants.

PMID- 12480882
TI  - An unexpected absence of queuosine modification in the tRNAs of an Escherichia
      coli B strain.
AB  - The post-transcriptional processing of tRNAs decorates them with a number of
      modified bases important for their biological functions. Queuosine, found in the
      tRNAs with GUN anticodons (Asp, Asn, His, Tyr), is an extensively modified base
      whose biosynthetic pathway is still unclear. In this study, it was observed that
      the tRNA(Tyr) from Escherichia coli B105 (a B strain) migrated faster than that
      from E. coli CA274 (a K-12 strain) on acid urea gels. The organization of
      tRNA(Tyr) genes in E. coli B105 was found to be typical of the B strains.
      Subsequent analysis of tRNA(Tyr) and tRNA(His) from several strains of E. coli on
      acid urea gels, and modified base analysis of tRNA preparations enriched for
      tRNA(Tyr), showed that E. coli B105 lacked queuosine in its tRNAs. However, the
      lack of queuosine in tRNAs was not a common feature of all E. coli B strains. The
      tgt and queA genes in B105 were shown to be functional by their ability to
      complement tgt and queA mutant strains. These observations suggested a block at
      the step of the biosynthesis of preQ(1) (or preQ(0)) in the B105 strain.
      Interestingly, a multicopy vector harbouring a functional tgt gene was toxic to
      E. coli B105 but not to CA274. Also, in mixed cultures, E. coli B105 was readily
      competed out by the CA274 strain. The importance of these observations and this
      novel strain (E. coli B105) in unravelling the mechanism of preQ(1) or preQ(0)
      biosynthesis is discussed.

PMID- 12480883
TI  - O-antigen expression in Salmonella enterica serovar Typhi is regulated by
      nitrogen availability through RpoN-mediated transcriptional control of the rfaH
      gene.
AB  - The authors previously reported increased expression of the Salmonella enterica
      serovar Typhi (S. typhi) rfaH gene when the bacterial cells reach stationary
      phase. In this study, using a lacZ fusion to the rfaH promoter region, they
      demonstrate that growth-dependent regulation of rfaH expression occurs at the
      level of transcription initiation. It was also observed that production of the
      lipopolysaccharide (LPS) O-antigen by S. typhi Ty2 correlated with the
      differential expression of rfaH during bacterial growth. This was probably due to
      the increased cellular levels of RfaH, since expression of the distal gene in the
      O-antigen gene cluster of S. typhi Ty2, wbaP, was also increased during
      stationary growth, as demonstrated by RT-PCR analysis. Examination of the
      sequences upstream of the rfaH coding region revealed homologies to potential
      binding sites for the RcsB/RcsA dimer of the RcsC/YopJ/RcsB phosphorelay
      regulatory system and for the RpoN alternative sigma factor. The expression of
      the rfaH gene in rpoN and rcsB mutants of S. typhi Ty2 was measured. The results
      indicate that inactivation of rpoN, but not of rcsB, suppresses the growth-phase
      dependent induction of rfaH expression. Furthermore, production of beta
      galactosidase mediated by the rfaH-lacZ fusion increased approximately fourfold
      when bacteria were grown in a nitrogen-limited medium. Nitrogen limitation was
      also shown to increase the expression of the O-antigen by the wild-type S. typhi
      Ty2, as demonstrated by a similar electrophoretic profile to that observed during
      the stationary phase of growth in rich media. It is therefore concluded that the
      relationship between LPS production and nitrogen limitation parallels the pattern
      of rfaH regulation under the control of RpoN and is consistent with the idea that
      RpoN modulates LPS formation via its effect on rfaH gene expression during
      bacterial growth.

PMID- 12480884
TI  - Regulation of yodA encoding a novel cadmium-induced protein in Escherichia coli.
AB  - Bacterial accommodation to moderate concentrations of cadmium is accompanied by
      transient activation of general stress proteins as well as a sustained induction
      of other proteins of hitherto unknown functions. One of the latter proteins was
      previously identified as the product of the Escherichia coli yodA ORF. The yodA
      ORF encodes 216 aa residues (the YodA protein) and the increased synthesis of
      YodA during cadmium stress was found probably to be a result of transcriptional
      activation from one single promoter upstream of the structural yodA gene.
      Analysis of a transcriptional gene fusion, P(yodA)-lacZ, demonstrated that basal
      expression of yodA is low during exponential growth and expression is increased
      greater than 50-fold by addition of cadmium to growing cells. However,
      challenging cells with additional metals such as zinc, copper, cobalt and nickel
      did not increase the level of yodA expression. In addition, hydrogen peroxide
      also increased yodA expression whereas the superoxide-generating agent paraquat
      failed to do so. Surprisingly, cadmium-induced transcription of yodA is dependent
      on soxS and fur, but independent of oxyR. Moreover, a double relA spoT mutation
      abolished induction of yodA during cadmium exposure but ppGpp is not sufficient
      to induce yodA since expression of the gene is not elevated during stationary
      phase. After 45 min of cadmium exposure the YodA protein was primarily detected
      in the cytoplasmic fraction but was later (150 min) found in both the cytoplasmic
      and periplasmic compartments.

PMID- 12480885
TI  - Resistance to hydrogen peroxide in Helicobacter pylori: role of catalase (KatA)
      and Fur, and functional analysis of a novel gene product designated 'KatA
      associated protein', KapA (HP0874).
AB  - Helicobacter pylori infection elicits an aggressive inflammatory response that
      the bacterium is able to resist by virtue of its well-adapted antioxidant defence
      mechanisms. Catalase (KatA) appears to be a key enzyme in this resistance.
      Upstream of katA, a low-affinity ferric uptake regulator (Fur)-box has been
      identified. Downstream of katA, an ORF (HP0874) with no known function has also
      been identified. Non-polar isogenic mutants of katA, fur and HP0874 were
      constructed by allelic exchange. The impact of these mutations on the catalase
      activities and bacterial viability following exposure to hydrogen peroxide was
      studied. Concurrently, the effect of variation in the iron content of the media
      used to grow the cells was determined. The data showed that catalase-deficient
      isolates of H. pylori were hypersensitive to hydrogen peroxide, whereas wild-type
      cells could resist approximately approximately 100 mM hydrogen peroxide. Fur
      deficient mutants and cells grown on low-iron-containing medium showed a distinct
      reduction in catalase activity and increased sensitivity to hydrogen peroxide.
      The data suggest a direct or indirect effect of Fur and iron on the activity of
      catalase. HP0874-deficient mutants showed no reduction in catalase activity but
      showed an increased sensitivity to hydrogen peroxide. That is, the protein
      encoded by HP0874 appears to have a role in resistance to hydrogen peroxide not
      directly related to catalase activity. This is the first report of a functional
      relationship of the product of this ORF. There is evidence of protein-protein
      interaction between KatA and the product encoded by HP0874, and the name 'KatA
      associated protein' (KapA) is proposed.

PMID- 12480886
TI  - Growth phase-dependent and differential transcriptional control of flagellar
      genes in Helicobacter pylori.
AB  - Helicobacter pylori possesses two different flagellin genes, flaA and flaB, which
      are unlinked on the chromosome and transcribed from sigma(28) and sigma(54)
      promoters, respectively. Both flagellins are hypothesized to be present in
      varying amounts in the flagellum, to adapt the physical properties of the
      flagellar filament to different environmental conditions. The influence of growth
      phase and environmental conditions on the transcriptional regulation of both
      flagellin genes has not been investigated so far. Using three different reporter
      genes as well as Northern blot analyses and RT-PCR, it was determined that both
      flagellin genes are transcribed in a growth phase-dependent fashion. Growth phase
      dependency was also found for the flagellar basal body export apparatus gene flhA
      which is involved in the transcriptional regulation of both flagellin genes. Peak
      transcription of flaB and flhA occurred earlier during the growth phase than that
      of flaA, possibly consistent with a hook-proximal localization of the minor
      flagellin FlaB. Of the reporter gene systems, luciferase fusions reflected best
      the dynamic regulation patterns of H. pylori flagellin genes. Growth phase in
      vitro had the strongest influence on transcriptional control of H. pylori flaA
      and flaB, while differences in supplements to a rich culture medium had only a
      modest modulatory effect on flagellin gene transcription.

PMID- 12480887
TI  - Malate:quinone oxidoreductase is essential for growth on ethanol or acetate in
      Pseudomonas aeruginosa.
AB  - Pseudomonas aeruginosa ATCC 17933 growing aerobically on ethanol uses a
      pyrroloquinoline quinone-dependent ethanol oxidation system. A mutant with an
      interrupted putative mqo gene, in which malate:quinone oxidoreductase (MQO), an
      enzyme involved in the citric acid cycle/glyoxylate cycle, was defective, showed
      a severe growth defect on ethanol and was unable to grow on acetate. Glucose,
      lactate, succinate or malate supported growth of the mutant. However, an NAD
      dependent malate dehydrogenase activity could not be detected. Complementation of
      the mutant by the wild-type allele of the mqo gene restored wild-type behaviour.
      The wild-type expressed the dye-dependent MQO and NAD(P)-dependent malic enzymes
      (MEs). Pyruvate carboxylase (PC) was found upon growth of the wild-type and the
      mutant on all substrates studied. PC activity in the wild-type was induced on
      glucose and lactate and was always higher on all substrates in the mqo mutant. In
      P. aeruginosa ATCC 17933, an active MQO is required for growth on ethanol or
      acetate, while with glucose, lactate, succinate or malate an apparent bypass
      route operates, with MEs using malate for generating pyruvate, which is
      carboxylated to oxaloacetate by PC. To the authors' knowledge, this is the first
      time that a specific mutant MQO phenotype has been observed, caused by the
      inactivation of a gene encoding MQO activity. mqo of P. aeruginosa ATCC 17933
      corresponds to mqoB (PA4640) of the P. aeruginosa PAO1 genome project.

PMID- 12480888
TI  - Beta-ketoacyl acyl carrier protein reductase (FabG) activity of the fatty acid
      biosynthetic pathway is a determining factor of 3-oxo-homoserine lactone acyl
      chain lengths.
AB  - The two acyl-homoserine lactones (AHLs) N-(butyryl)-L-homoserine lactone and N-[3
      oxododecanoyl]-L-homoserine lactone (3-oxo-C(12)-HSL) are required for quorum
      sensing in Pseudomonas aeruginosa. These AHLs derive their invariant lactone
      rings from S-adenosylmethionine and their variable acyl chains from the cellular
      acyl-acyl carrier protein (ACP) pool. This reaction is catalysed by specific AHL
      synthases, which exhibit acyl chain specificity. Culture supernatants of P.
      aeruginosa contain multiple 3-oxo-AHLs that differ in their acyl chain lengths
      but their physiological role, if any, remains unknown. An in vitro fatty acid-3
      oxo-AHL synthesis system was established utilizing purified P. aeruginosa Fab
      proteins, ACP and the LasI 3-oxo-AHL synthase. In the presence of excess protein,
      substrates and cofactors, this system produced almost exclusively 3-oxo-C(12)
      HSL. When the beta-ketoacyl-ACP reductase (FabG) catalysed step was made rate
      limiting by switching from the preferred NADPH cofactor to NADH, increased levels
      of short chain 3-oxo-AHLs were produced, presumably because shorter-chain
      ketoacyl-ACPs accumulated and thus became LasI substrates. Consistent with these
      in vitro observations, a fabG(Ts) mutant produced increased amounts of 3-oxo-AHLs
      in vivo. Thus, in vitro and in vivo evidence indicated that modulation of FabG
      activity of the fatty acid biosynthetic pathway may determine the acyl chain
      lengths of these 3-oxo-AHLs and that the LasI 3-oxo-AHL synthase is sufficient
      for their synthesis.

PMID- 12480889
TI  - Effect of replacing the general energy-coupling proteins of the PEP:sugar
      phosphotransferase system of Salmonella typhimurium with their fructose-inducible
      counterparts on utilization of the PTS sugar glucitol.
AB  - A strain of Salmonella typhimurium in which the genes encoding the general
      phosphoenolpyruvate:sugar phosphotransferase system (PTS) proteins HPr and Enzyme
      I have been deleted, the normally cryptic gene encoding the fructose-inducible
      Enzyme I (EI* or EI(fructose)) is expressed, and the fructose repressor protein
      is inactive (fruR or cra mutant) was studied. This strain lacks HPr and EI, but
      expresses FPr (DTP) and EI(fructose) constitutively. Since FPr and EI(fructose)
      can substitute for HPr and EI, the strain grew in minimal liquid medium
      supplemented with the PTS sugars glucose, fructose, N-acetylglucosamine, mannitol
      or mannose. However, it showed very poor to negligible growth on the PTS sugar
      glucitol. It also grew very poorly on the non-PTS sugars maltose, melibiose and
      especially glycerol. Adding cAMP to the medium allowed growth on glucitol, but
      did not affect growth on glycerol. We suggest that poor phosphorylation of the
      regulatory molecule Enzyme IIA(glucose) by FPr is responsible for these effects.

PMID- 12480890
TI  - Involvement of a putative molybdenum enzyme in the reduction of selenate by
      Escherichia coli.
AB  - Selenium oxyanions, particularly selenite, can be highly toxic to living
      organisms. Few bacteria reduce both selenate and selenite into the less toxic
      elemental selenium. Insights into the mechanisms of the transport and the
      reduction of selenium oxyanions in Escherichia coli were provided by a genetic
      analysis based on transposon mutagenesis. Ten mutants impaired in selenate
      reduction were analysed. Three of them were altered in genes encoding transport
      proteins including a porin, an inner-membrane protein and a sulfate carrier. Two
      mutants were altered in genes required for molybdopterin biosynthesis, strongly
      suggesting that the selenate reductase of E. coli is a molybdoenzyme. However,
      mutants deleted in various oxomolybdenum enzymes described so far in this species
      still reduced selenate. Finally, a mutant in the gene ygfK encoding a putative
      oxidoreductase was obtained. This gene is located upstream of ygfN and ygfM in
      the ygfKLMN putative operon. YgfN and YgfM code for a molybdopterin-containing
      enzyme and a polypeptide carrying a FAD domain, respectively. It is therefore
      proposed that the selenate reductase of E. coli is a structural complex including
      the proteins YgfK, YgfM and YgfN. In addition, all the various mutants were still
      able to reduce selenite into elemental selenium. This implies that the transport
      and reduction of this compound are clearly distinct from those of selenate.

PMID- 12480891
TI  - Involvement of the fadD33 gene in the growth of Mycobacterium tuberculosis in the
      liver of BALB/c mice.
AB  - The potential pathogenic role of Mycobacterium tuberculosis H37Rv fadD33, a gene
      encoding an acyl-CoA synthase that is underexpressed in the attenuated strain
      H37Ra, was investigated. In a first approach, fadD33 was cloned and expressed in
      strain H37Ra to restore gene expression and fadD33-complemented bacteria were
      used to investigate whether fadD33 might confer any growth advantage to M.
      tuberculosis H37Ra in an infection model of BALB/c mice. No differences were
      found in the growth rates of M. tuberculosis H37Rv, H37Ra and fadD33-complemented
      H37Ra in the lungs and spleen. In contrast, in the liver, where the attenuated
      strain H37Ra showed impaired growth compared to the virulent strain H37Rv,
      complementation of the attenuated strain H37Ra with fadD33 restored bacterial
      replication. In a further approach, the fadD33 gene of strain H37Rv was disrupted
      by allelic exchange mutagenesis and the virulence of the mutant strain was tested
      by mouse infection. It was found that disruption of fadD33 decreased M.
      tuberculosis H37Rv growth in the liver, but not in the lungs or spleen, and
      complementation of the fadD33-disrupted mutant with fadD33 restored bacterial
      replication in the liver, but did not affect replication in the lungs and spleen.
      These findings suggest that fadD33 plays a role in M. tuberculosis virulence by
      supporting bacterial growth in the liver.

PMID- 12480892
TI  - Expression of the mceA, esat-6 and hspX genes in Mycobacterium tuberculosis and
      their responses to aerobic conditions and to restricted oxygen supply.
AB  - The expression of six of the mammalian cell-entry (mce1a-mce1f) genes of the mce1
      operon of Mycobacterium tuberculosis has been described previously. In this
      study, data are presented for the expression of other mammalian cell-entry
      homologues (mce-2a, mce-3a and mce-4a) at the RNA level, as determined by RT-PCR.
      The stress responses of these genes and of other immunologically important
      antigens are also characterized with respect to the introduction of oxygen
      depletion. Analysis of the expression of the mceA genes in relation to oxygen
      depletion revealed that they were expressed differentially. The RT-PCR results
      showed that mce-1a, mce-2a, hspX (encoding the alpha-crystallin antigen Acr) and
      esat-6 (encoding the early secretory antigenic target-6) were expressed
      throughout the cultivation period, whereas the expression of mce-3a and mce-4a
      was downregulated in the later stages of cultivation. This study gives new
      insights into the expression profiles of the different mce operons and the hspX
      and esat-6 genes in an in vitro model of dormant-like bacilli. Identification of
      the genes that are differentially expressed under aerobic conditions and under
      oxygen-limited conditions contributes to our understanding of the bacilli
      involved in latent tuberculosis.

PMID- 12480893
TI  - Conditional expression of Mycobacterium smegmatis dnaA, an essential DNA
      replication gene.
AB  - To begin to understand the role of Mycobacterium smegmatis dnaA in DNA
      replication, the dnaA gene was characterized at the genetic level. Western
      analyses revealed that DnaA accounts for approximately 0.18% of the total
      cellular protein during both the active and stationary growth periods. Expression
      of antisense dnaA RNA reduced viability, indicating that dnaA is an essential
      gene in replication. To further understand the role(s) of dnaA in replication, a
      conditionally expressing strain was constructed in which expression of dnaA was
      controlled by acetamide. Growth in the presence of 0.2% acetamide elevated the
      intracellular levels of DnaA and increased cell length, but did not affect
      viability. Visualization of DNA by fluorescence microscopy revealed that DnaA
      overproducing cells were multinucleoidal, indicating a loss of synchrony between
      the replication and cell-division cycles. Withdrawal of acetamide resulted in the
      depletion of the intracellular levels of DnaA, reduced viability and gradually
      blocked DNA synthesis. Acetamide-starved cells were very filamentous, several
      times the size of the parent cells and showed either abnormal or multi-nucleoid
      morphology, indicating a blockage in cell-division events. The addition of
      acetamide to the starved cells restored their viability and shortened the lengths
      of their filaments back to the size of the parent cells. Thus, both increasing
      and decreasing the levels of DnaA have an effect on the cells, indicating that
      the level of DnaA is critical to the maintenance of coordination between DNA
      replication and cell division. It is concluded that DNA replication and cell
      division processes in M. smegmatis are linked, and it is proposed that DnaA has a
      role in both of these processes.

PMID- 12480894
TI  - Molecular cloning and sequence analysis of the clorobiocin biosynthetic gene
      cluster: new insights into the biosynthesis of aminocoumarin antibiotics.
AB  - The biosynthetic gene cluster of the aminocoumarin antibiotic clorobiocin was
      cloned by screening of a cosmid library of Streptomyces roseochromogenes DS
      12.976 with two heterologous probes from the novobiocin biosynthetic gene
      cluster. Sequence analysis revealed 27 ORFs with striking similarity to the
      biosynthetic gene clusters of novobiocin and coumermycin A(1). Inactivation of a
      putative aldolase gene, cloR, by in-frame deletion led to the abolishment of the
      production of clorobiocin. Feeding of the mutant with 3-dimethylallyl-4
      hydroxybenzoic acid (Ring A of clorobiocin) restored clorobiocin production.
      Here, it is suggested that the formation of Ring A of clorobiocin may proceed via
      a retro-aldol reaction catalysed by CloR, i.e. by a mechanism different from the
      previously elucidated benzoic acid biosynthetic pathway in Streptomyces
      maritimus. A comparison of the gene clusters for clorobiocin, novobiocin and
      coumermycin A(1) showed that the structural differences between the three
      antibiotics were reflected remarkably well by differences in the organization of
      their respective biosynthetic gene clusters.

PMID- 12480895
TI  - Characterization of Mycobacterium tuberculosis ribosome recycling factor (RRF)
      and a mutant lacking six amino acids from the C-terminal end reveals that the C
      terminal residues are important for its occupancy on the ribosome.
AB  - Ribosome recycling factor (RRF), coded for by the frr locus, is involved in the
      disassembly of post-termination complexes and recycling of the ribosomes for a
      fresh round of initiation in bacteria and in eukaryotic organelles. In a cross
      species-complementation experiment, it was shown that the Thermus thermophilus
      RRF protein lacking five amino acids from its C-terminal end (deltaC5TthRRF) but
      not the full-length protein (TthRRF) complemented Escherichia coli for its
      frr(ts) phenotype. It was also shown that the Mycobacterium tuberculosis RFF
      protein (MtuRRF) did not complement E. coli LJ14 for frr(ts). However,
      simultaneous expression of elongation factor G (EFG) and RRF from M. tuberculosis
      resulted in complementation of E. coli LJ14. Here it is shown that unlike
      deltaC5TthRRF, an equivalent mutant of MtuRRF lacking six amino acids from its C
      terminal end (deltaC6MtuRRF) did not complement E. coli LJ14. Surprisingly,
      deltaC6MtuRRF failed to complement the strain even in the presence of homologous
      EFG (MtuEFG). The biochemical and biophysical characterization of these proteins
      suggested that the mutant RRF folded properly. However, ribosome-binding assays
      showed that the mutant protein was compromised in its binding to E. coli
      ribosomes. It is suggested that the conserved amino acids at the C-terminal end
      of the RRFs contribute to their residency on ribosomes and that the specific
      interactions between RRF and EFG are crucial in the disassembly of the
      termination complex.

PMID- 12480896
TI  - Binding and invasion of HeLa and MRC-5 cells by Streptococcus agalactiae.
AB  - The interactions of group B streptococci (GBS) with HeLa cells (an epithelial
      cell line) and MRC-5 cells (a fibroblastic cell line) were explored. A host-cell
      invasion assay using GBS strains from all serotypes revealed that GBS invaded
      HeLa cells to a greater extent than MRC-5 cells. One strain, a serotype V
      (NCS13), was highly invasive against HeLa cells. All strains were poorly invasive
      against MRC-5 cells. Further characterization of the binding of NCS13 to HeLa and
      MRC-5 cell surfaces showed that the lack of recoverable c.f.u. from MRC-5 cells
      was due to a lack of binding of NCS13 to the MRC-5 cell surface in comparison to
      HeLa cells. Although fibronectin had been reported to bind to GBS, fibronectin
      assays showed 2.7-fold more fibronectin on the MRC-5 cell surface in comparison
      to HeLa cells, suggesting that other extracellular matrix proteins besides
      fibronectin may be involved in GBS binding. Scanning electron microscopy of NCS13
      and HeLa cells over a 6 h time period showed increased numbers of NCS13 on the
      HeLa cell surface over time until cell death at 6 h. Direct contact of the HeLa
      cell surface by NCS13 was found to be necessary for cell death to occur. Further
      scanning electron microscopy studies found that, once GBS are bound to the HeLa
      cell surface, HeLa cell microvilli entwine the bacteria, which then enter the
      HeLa cell in a polar fashion. Cytoskeletal actin is involved, as this process is
      disrupted by cytochalasin D, and recruitment of actin is visible at the site of
      adherent chains of GBS. Also, the host-cell signalling enzyme, PI 3-kinase, is
      involved in the GBS internalization process, since the PI 3-kinase inhibitor,
      wortmannin, inhibited NCS13 invasion of HeLa cells in a dose-dependent manner.

PMID- 12480898
TI  - The variant undecapeptide sequence of the Arcanobacterium pyogenes haemolysin,
      pyolysin, is required for full cytolytic activity.
AB  - The cholesterol-dependent cytolysins (CDCs) are characterized by an undecapeptide
      sequence (ECTGLAWEWWR) that is located near the C terminus and within domain 4 of
      these proteins. Pyolysin (PLO), the CDC of Arcanobacterium pyogenes, has a
      variant undecapeptide sequence (EATGLAWDPWW). Site-directed mutants were
      constructed in undecapeptide residues in a recombinant PLO molecule containing a
      hexahistidine tag (His-PLO). Mutations in each of the three undecapeptide
      tryptophan residues resulted in low haemolytic activity, confirming the
      importance of these residues in the protein. Deletion of a proline residue
      (P(499)), inserted in PLO, or substitution of this residue with either
      phenylalanine or glycine resulted in mutant proteins with undetectable or low
      haemolytic activities, indicating that P(499) is essential for His-PLO haemolytic
      activity. Substitution of the PLO undecapeptide sequence with a consensus
      undecapeptide resulted in a His-PLO protein with only 0.1% activity, confirming
      that the variant PLO undecapeptide is required for the full cytolytic activity of
      this toxin. The presence of the conserved undecapeptide cysteine residue either
      alone (His-PLO.C(492)) or in a consensus sequence resulted in His-PLO molecules
      which were activated in the presence of reducing compounds, confirming the
      importance of this residue in the thiol-activated nature of many CDC toxins. The
      ability of His-PLO mutant proteins to bind cholesterol mimicked haemolytic
      activity, with the exception of His-PLO.C(492), which, despite having reduced
      haemolytic activity, showed an increased ability to bind cholesterol compared to
      His-PLO. Despite reductions in haemolytic activity and cholesterol-binding, all
      mutant proteins were still able to bind to erythrocyte membranes, suggesting that
      other regions of PLO may recognize host-cell membranes, through receptors other
      than cholesterol.

PMID- 12480897
TI  - Roles of the plasminogen activator streptokinase and the plasminogen-associated M
      protein in an experimental model for streptococcal impetigo.
AB  - Primary infection by group A streptococci (GAS) takes place at either the throat
      or skin of the human host, often leading to pharyngitis or impetigo,
      respectively. Many GAS strains differ in their preference for throat and skin
      tissue sites. Previous epidemiological findings show that many of the strains
      displaying strong tropism for the skin have a high-affinity binding site for
      plasminogen, located within M protein (PAM), a prominent surface fibril.
      Plasminogen bound by PAM interacts with streptokinase, a plasminogen activator
      secreted by GAS, to yield bacterial-bound plasmin activity. In this study, PAM
      and streptokinase were tested for their roles in infection using an experimental
      model that closely mimics human impetigo. Inactivation of genes encoding either
      PAM or streptokinase led to a partial, but significant, loss of virulence in
      vivo, as measured by net growth of the bacteria and pathological alterations. The
      relative loss in virulence in vivo was greater for the streptokinase mutant than
      for the PAM mutant. However, the PAM mutant, but not the streptokinase mutant,
      displayed a partial loss in resistance to phagocytosis in vitro. The combined
      experimental and epidemiological data provide evidence that PAM and streptokinase
      play a key role in mediating skin-specific infection by GAS. In addition,
      secreted cysteine proteinase activity due to SpeB leads to degradation of
      streptokinase in stationary phase broth cultures. Since SpeB is also a
      determinant of tissue-specific GAS infection at the skin, direct interactions
      between these two proteolytic pathways may constitute an important pathogenic
      mechanism. An integrated model for superficial infection at the skin is
      presented.

PMID- 12480899
TI  - Infection of myocytes with chlamydiae.
AB  - Chlamydial infection has been associated with myocarditis in animals and humans.
      However, the mechanism resulting in myocarditis following infection is not known.
      Here, evidence is presented that both Chlamydia trachomatis and Chlamydia
      pneumoniae can infect and replicate in myocytes isolated from neonate rats. The
      infected myocytes contained chlamydial inclusions, indicative of chlamydial
      growth, and infectious particles were recovered from the infected myocytes. It
      was also found that chlamydial infection at a late stage induced significant
      damage to the infected myocytes, as evidenced by an increased lactate
      dehydrogenase release, reactive oxygen species production and a reduced ATP
      level. However, no nuclear apoptosis was detected in the infected myocytes.
      Collectively, these observations have demonstrated that Chlamydia spp. are able
      to both infect and damage myocytes, suggesting a potential role of chlamydial
      infection in myocarditis.

PMID- 12480900
TI  - lcd from Streptococcus anginosus encodes a C-S lyase with alpha,beta-elimination
      activity that degrades L-cysteine.
AB  - Hydrogen sulfide is highly toxic to mammalian cells. It has also been postulated
      that hydrogen sulfide modifies haemoglobin resulting in haemolysis. The enzyme
      that produces hydrogen sulfide from L-cysteine was purified from Streptococcus
      anginosus. Using the N-terminal amino acid sequence of the purified enzyme, the
      lcd gene encoding L-cysteine desulfhydrase was cloned; the recombinant protein
      was then purified to examine its enzymic and biological characteristics. This L
      cysteine desulfhydrase had the Michaelis-Menten kinetics K(m)=0.62 mM and
      V(max)=163 micro mol min(-1) mg(-1). DL-Cystathionine, L-cystine, S-(2
      aminoethyl)-L-cysteine, 3-chloro-DL-alanine and S-methyl-L-cysteine were
      substrates for the enzyme, whereas D-cysteine, DL-homocysteine, L-methionine, DL
      serine, DL-alanine, L-cysteine methyl ester, L-tryptophan, L-tyrosine and L
      phenylalanine were not. These findings suggest that this L-cysteine desulfhydrase
      is a C-S lyase that catalyses the alpha,beta-elimination (alphaC-N and betaC-S)
      reaction. In addition, it is demonstrated that the hydrogen sulfide produced by
      this enzyme caused the modification and release of haemoglobin in sheep
      erythrocytes.

PMID- 12480901
TI  - Proteomics characterization of novel spore proteins of Bacillus subtilis.
AB  - The spores of Bacillus subtilis have characteristic properties and consist of
      complex structures including various types of proteins. To perform comprehensive
      analysis of the protein composition of the spores, the proteins extracted from
      the spore were analysed by a combination of one-dimensional PAGE and liquid
      chromatography coupled to tandem mass spectrometry (LC-MS/MS) using Turboquest
      SEQUEST software interfaced with the DNA sequence database of B. subtilis. A
      total of 154 proteins were identified, and 69 of them were novel. The remaining
      85 proteins have been previously reported as sporulation-specific proteins or as
      proteins that are synthesized in vegetative cells. The expression pattern of each
      gene deduced to encode novel spore proteins was analysed using a series of
      strains carrying a lacZ reporter gene. The results revealed that the expression
      of 26 genes was dependent on sporulation-specific sigma factors, namely sigma(F),
      sigma(E), sigma(G) and sigma(K). In this study, it is demonstrated that the
      combination of the techniques of SDS-PAGE and LC-MS/MS, with the mutant library
      of B. subtilis, is an effective tool for the analysis of complicated cellular
      structures.

PMID- 12480902
TI  - The divergent chromosomal ars operon of Acidithiobacillus ferrooxidans is
      regulated by an atypical ArsR protein.
AB  - The chromosomal arsenic-resistance (ars) operon of Acidithiobacillus ferrooxidans
      is atypical in that it is divergent, with its arsCR and arsBH genes transcribed
      in opposite directions. Furthermore, the amino-acid sequence of the putative ArsR
      like regulator of the ars operon is not conserved in regions that have been shown
      to be responsible for binding to arsenic. Instead, the ArsR-like protein of At.
      ferrooxidans is related to a group of unstudied ArsR-like proteins that have been
      found to be associated with chromosomal ars-like operons identified during genome
      sequencing projects. Using arsB-lacZ, arsR-lacZ and arsC-lacZ fusions, it was
      shown that the ArsR-like protein of At. ferrooxidans is a repressor of the arsBH
      and arsRC genes of this organism, and that induction of gene expression took
      place when either AsIII (arsenite) or AsV (arsenate) were added. Deletion of 19
      aa from the C terminus of the 118 aa ArsR protein did not affect the regulation
      of its activity, but deletion of an additional 28 aa inactivated ArsR. Northern
      blot hybridization suggested that on induction of expression, the arsRC genes
      were transcribed in greater quantities than the arsBH genes, but that the level
      of induction was not affected by the form of arsenic added (AsIII or AsV).

PMID- 12480903
TI  - Differences in iron acquisition from human haemoglobin among strains of
      Actinobacillus actinomycetemcomitans.
AB  - To get a better insight into the physiology of the high-toxic JP2 clone of
      Actinobacillus actinomycetemcomitans serotype b, which is strongly associated
      with juvenile periodontitis in adolescents of African descent, the modes of iron
      acquisition in this clone were examined and compared to those of other strains of
      the species. None of the strains examined could utilize human transferrin as a
      source of iron. This was in accordance with the presence of a non-functional tbpA
      gene, which normally encodes the A subunit of the transferrin-binding-protein
      complex. Southern blot analysis indicated that functional duplications of tbpA
      were not present in the genome. Thus, A. actinomycetemcomitans seems to be in a
      process of evolution, in which iron acquisition from host transferrin is not
      essential as in many other members of the pasteurellaceae. All strains could
      utilize haem as a source of iron. All 11 A. actinomycetemcomitans strains
      examined harboured a single genomic sequence with homology to the hgpA gene
      encoding haemoglobin-binding protein A in Haemophilus influenzae. However, in all
      three strains belonging to the JP2 clone and in one serotype e strain hgpA was a
      pseudogene. Seven other strains possessed a functional hgpA gene which, according
      to insertion mutagenesis experiments, was responsible for the ability of these
      strains to utilize haemoglobin as a source of iron. Thus, the presence of an hgpA
      pseudogene and the inability to use human haemoglobin as an iron source
      discriminate the high-toxic JP2 clone from low-toxic serotype b strains and most
      other strains of A. actinomycetemcomitans.

PMID- 12480904
TI  - Molecular cloning of a laccase isozyme gene from Pleurotus sajor-caju and
      expression in the heterologous Pichia pastoris host.
AB  - The Psc lac4 gene from Pleurotus sajor-caju has been cloned and expressed in the
      heterologous host Pichia pastoris, under the control of the AOX1 methanol
      inducible promoter. The native Ple. sajor-caju laccase signal sequence was
      effective in directing the secretion of lac4 expressed in Pic. pastoris. The
      control of media pH and temperature was found to be important in obtaining
      sufficient quantities of the protein to allow purification and subsequent
      biochemical characterization. The recombinant Psc Lac4 was purified to
      electrophoretic homogeneity and was shown to be immunologically related to
      Pleurotus eryngii Lac1. The purified laccase was estimated to have a molecular
      mass of around 59 kDa, to have a carbohydrate content of approximately 7% and a
      calculated pI of 4.38. The enzyme oxidized the substrates 2,2-azinobis-(3
      ethylbenzthiazoline-6-sulphonate) (ABTS), 2,6-dimethoxyphenol, syringaldazine and
      guaiacol, exhibiting optimal pHs of 3.3, 6, 6.5 and 7 respectively. With ABTS as
      substrate the enzyme displayed optimal activity at 35 degrees C and pH 3.5. The
      enzyme was strongly inhibited by sodium azide and thioglycolic acid but not by
      EDTA.

PMID- 12480905
TI  - Genetics of biosynthesis and structure of the capsular exopolysaccharide from the
      Asian pear pathogen Erwinia pyrifoliae.
AB  - Erwinia pyrifoliae is a novel bacterial pathogen, which causes Asian pear blight
      and is related to Erwinia amylovora, the causative agent of fire blight. E.
      pyrifoliae produces exopolysaccharide (EPS) related to amylovoran in its sugar
      composition and sugar linkages. This was shown by degradation of the EPS with a
      viral depolymerase, and by methylation analysis and ESI/MS. The structure of the
      repeating units was confirmed by (1)H-NMR spectra. The EPS of E. pyrifoliae
      carried side chains, which were mainly terminated by acetyl and pyruvyl residues
      as found previously for amylovoran. On the other hand, a second side chain with
      glucose found for up to 65% of the repeating units of amylovoran was completely
      absent. The nucleotide sequences of five genes of the cps cluster of E.
      pyrifoliae encoding proteins for EPS synthesis were characterized and displayed a
      high homology with the corresponding ams genes. Similar functions of the gene
      products are assumed. As for ams mutants of E. amylovora, a cpsB mutant of E.
      pyrifoliae did not synthesize EPS and did not produce ooze on slices of immature
      pears or symptoms on pear seedlings. The cps mutant was complemented for EPS
      synthesis and virulence on pear slices with a gene cluster of E. amylovora that
      included amsB.

PMID- 12480906
TI  - Altering the expression of two chitin synthase genes differentially affects the
      growth and morphology of Aspergillus oryzae.
AB  - In Aspergillus oryzae, one full-length chitin synthase (chsB) and fragments of
      two other chitin synthases (csmA and chsC) were identified. The deduced amino
      acid sequence of chsB was similar (87% identity) to chsB from Aspergillus
      nidulans, which encodes a class III chitin synthase. The sequence obtained for
      csmA indicated that it had high similarity to class V chitin synthases. chsB and
      csmA disruption strains and a strain in which chsB transcription was controlled
      were constructed using the nitrite reductase (niiA) promoter. The strains were
      examined during hyphal growth by Northern analysis, analysis of the cell-wall
      composition and growth in the presence of Calcofluor white (CFW). The chsB
      disrupted strain and the uninduced p(niiA)-chsB strain exhibited hyperbranching,
      they had a lower level of conidiation than the wild-type and were sensitive to
      CFW at 50 mg l(-1). When chsB transcription was induced in the strain containing
      the p(niiA)-chsB construct, the strain displayed wild-type morphology on solid
      medium and at sub-maximum growth rates but the wild-type morphology was not fully
      restored during rapid growth in batch cultivation. The csmA disruption strain
      displayed morphological abnormalities, such as ballooning cells, intrahyphal
      hyphae and conidial scars. The growth was severely inhibited in the presence of
      10 mg CFW l(-1). In none of the constructed strains did the cell-wall composition
      differ from the wild-type. Northern analysis indicated no change in the
      transcription of the chitin synthase genes csmA and chsC when chsB expression was
      altered, and there was no change in the transcription of chsB and chsC when csmA
      was disrupted.

PMID- 12480907
TI  - The protein kinase Kic1 affects 1,6-beta-glucan levels in the cell wall of
      Saccharomyces cerevisiae.
AB  - KIC1 encodes a PAK kinase that is involved in morphogenesis and cell integrity.
      Both over- and underexpressing conditions of KIC1 affected cell wall composition.
      Kic1-deficient cells were hypersensitive to the cell wall perturbing agent
      calcofluor white and had less 1,6-beta-glucan. When Kic1-deficient cells were
      crossed with various kre mutants, which also have less 1,6-beta-glucan in their
      wall, the double mutants displayed synthetic growth defects. However, when
      crossed with the 1,3-beta-glucan-deficient strain fks1delta, no synthetic growth
      defect was observed, supporting a specific role for KIC1 in regulating 1,6-beta
      glucan levels. Kic1-deficient cells also became highly resistant to the cell wall
      degrading enzyme mixture Zymolyase, and exhibited higher transcript levels of the
      cell wall protein-encoding genes CWP2 and SED1. Conversely, overexpression of
      KIC1 resulted in increased sensitivity to Zymolyase and in a higher level of 1,6
      beta-glucan. Multicopy suppressor analysis of a Kic1-deficient strain identified
      RHO3. Consistent with this, expression levels of RHO3 correlated with 1,6-beta
      glucan levels in the cell wall. Interestingly, expression levels of KIC1 and the
      MAP kinase kinase PBS2 had opposite effects on Zymolyase sensitivity of the cells
      and on cell wall 1,6-beta-glucan levels in the wall. It is proposed that Kic1
      affects cell wall construction in multiple ways and in particular in regulating
      1,6-beta-glucan levels in the wall.

PMID- 12480908
TI  - Identification and functional expression of tahA, a filamentous fungal gene
      involved in copper trafficking to the secretory pathway in Trametes versicolor.
AB  - In this study, cDNA and genomic clones encoding a homologue of the yeast gene
      anti-oxidant 1 (ATX1) from the white-rot fungus Trametes versicolor, a
      basidiomycete known to produce several laccase isoenzymes involved in lignin
      degradation, were identified. This gene, named Trametes ATX homologue (tahA),
      encodes a protein of 7.9 kDa with 56% identity to the yeast Atx1p sequence. Two
      different alleles of tahA were obtained that differed mainly in their intervening
      sequences and in a 425 nt insertion located 183 nt upstream of the transcription
      start site. tahA is present as one copy per haploid nucleus in T. versicolor, as
      shown by Southern analysis. Expression of tahA cDNA restored high-affinity iron
      uptake in a deltaatx1 yeast strain and oxygen sensitivity in a deltasod1
      deltasod2 yeast strain, showing that tahA is also a functional homologue of ATX1.
      The inability of tahA to rescue the deltasod1 phenotype on copper-deficient
      medium indicated that tahA function is copper-dependent. Sequence analysis of the
      tahA promoter revealed several motifs that were similar to the conserved motifs
      found in the copper-regulated metallothionein and Cu, Zn superoxide dismutase
      genes, CUP1 and SOD1, of Saccharomyces cerevisiae, Neurospora crassa and Candida
      glabrata. In contrast to its yeast homologue ATX1, tahA is induced under elevated
      copper concentrations in the medium (>0.25 micro M CuSO(4)) and repressed under
      copper starvation. The transcription of tahA was analysed in response to copper
      and iron, and after adding xenobiotica. The results are discussed in relevance to
      laccase expression.

PMID- 12480909
TI  - RirA, an iron-responsive regulator in the symbiotic bacterium Rhizobium
      leguminosarum.
AB  - Mutations in a Rhizobium leguminosarum gene, rirA (rhizobial iron regulator),
      caused high-level, constitutive expression of at least eight operons whose
      transcription is normally Fe-responsive and whose products are involved in the
      synthesis or uptake of siderophores, or in the uptake of haem or of other iron
      sources. Close homologues of RirA exist in other rhizobia and in the pathogen
      Brucella; many other bacteria have deduced proteins with more limited sequence
      similarity. None of these homologues had been implicated in Fe-mediated gene
      regulation. Transcription of rirA itself is about twofold higher in cells grown
      in Fe-replete than in Fe-deficient growth media. Mutations in rirA reduced growth
      rates in Fe-replete and -depleted medium, but did not appear to affect symbiotic
      N(2) fixation.

PMID- 12480911
TI  - Fas and Fas ligand gene mutations in Hashimoto's thyroiditis.
AB  - To clarify whether Fas and Fas ligand (FasL) mutations are involved in the
      pathogenesis of Hashimoto's thyroiditis (HT), we examined the open reading frame
      of Fas and FasL in 21 cases. Mutations of Fas and FasL genes were detected in 8
      (38.1%) and 1 (4.8%) of 21 cases, respectively. All but one of the Fas mutations
      were frameshift mutations, which affect the cytoplasmic region (death domain)
      known to be involved in apoptotic signal transduction and thus could be loss-of
      function mutations. FasL mutation in one case was a 46-bp deletion from
      nucleotide 349 to 394, which corresponded to exon 2. Lack of exon 2 results in a
      frameshift, which generates a stop codon at residue 128. This mutant encodes the
      protein that contains only a part of the intracellular domain, thus the abnormal
      protein might not be expressed on the cell surface. The cells with Fas mutations
      were confined to the mantle zone and the germinal center, as determined by
      microdissection methods. These findings suggest that the cells with Fas mutations
      might accumulate in those areas and might be involved in the pathogenesis of
      Hashimoto's thyroiditis.

PMID- 12480912
TI  - Neurologic defects and selective disruption of basement membranes in mice lacking
      entactin-1/nidogen-1.
AB  - Entactin-1 (nidogen-1) is an ubiquitous component of basement membranes. From in
      vitro experiments, entactin-1 was assigned a role in maintaining the structural
      integrity of the basement membrane because of its binding affinity to other
      components, such as type IV collagen and laminin. Entactin-1 also interacts with
      integrin receptors on the cell surface to mediate cell adhesion, spreading, and
      motility. Targeted disruption of the entactin-1 gene in the mouse presented in
      this study revealed a duplication of the entacin-1 locus. Homozygous mutants for
      the functional locus lacked entactin-1 mRNA and protein and often displayed
      seizure-like symptoms and loss of muscle control in the hind legs. The behavior
      patterns suggested the presence of neurologic deficits in the central nervous
      system, thus providing genetic evidence linking entactin-1 to proper functions of
      the neuromuscular system. In homozygous mutants, structural alterations in the
      basement membranes were found only in selected locations including brain
      capillaries and the lens capsule. The morphology of the basement membranes in
      other tissues examined superficially appeared to be normal. These observations
      suggest that the lost functions of entactin-1 result in pathologic changes that
      are highly tissue specific.

PMID- 12480913
TI  - Fluorescence imaging of mobility shifts: an expression cloning method for
      identification of cell signaling targets.
AB  - There is a need for a simple global approach to identify signaling targets that
      are posttranslationally modified in response to physiologic or pathologic stimuli
      within living cells. Reported here is a simple method, fluorescence imaging of
      mobility shifts (FIMS), which relies on in-gel detection of cell-expressed green
      fluorescent protein fusion proteins undergoing electrophoretic mobility shifts.
      This detection method is applied to a small pool cDNA library screening protocol.
      The readout is essentially a differential display of posttranslational
      modifications. Unlike biochemical approaches to identifying signaling targets,
      the screen is performed in living cells using standard methods for transient
      transfection. This enables detection of intracellular targets modified in
      response to either molecularly defined stimuli, such as growth factors or drugs,
      or complex pathologic stimuli, such as oxidative stress or hypoglycemia. FIMS is
      rapid, sensitive, inexpensive, and nonradioactive and easily adapted to automated
      high throughput methods, including capillary electrophoresis. The technique is
      sufficiently sensitive to easily detect fluorescent proteins expressed in a
      single well in 384-well format. FIMS is applicable to traditional cDNA library
      screening, but the method will be especially attractive for screening preselected
      collections of autofluorescent fusion proteins. A bonus of the technique is that
      examination of transfected cells by fluorescence microscopy provides immediate
      information about intracellular localization and stimulus-induced translocation
      of putative targets. We illustrate the utility of the technique with pilot
      screens for apoptotic and mitogenic targets modified by staurosporine and serum
      stimulation, respectively.

PMID- 12480914
TI  - Molecular and cellular phenotypic profiles of gastric noninvasive neoplasia.
AB  - According to the Padova international classification, 52 gastric noninvasive
      neoplasias (NIN) were classified as follows: 20 low-grade NIN (L-NIN); 9 high
      grade NIN including suspicion for carcinoma without invasion (H-NIN); and 23 high
      grade NIN including carcinoma without invasion (Ca-NIN). The molecular and
      cellular phenotypic profiles were investigated and compared. The APC gene was
      mutated in seven (35%) L-NIN, two (22%) H-NIN, and two (9%) Ca-NIN tumors; APC
      mutations were significantly more frequent in L-NIN compared with Ca-NIN tumors
      (p < 0.05). Mutations of the p53 gene were found in five (22%) Ca-NIN tumors but
      were not observed in L-NIN or H-NIN tumors (p < 0.05). Loss of heterozygosity
      involving at least one chromosomal locus was detected in 14 (61%) Ca-NIN tumors
      but was not detected in L-NIN or H-NIN tumors. High-frequency microsatellite
      instability (MSI-H) was detected in one (5%) L-NIN tumor and in six (26%) Ca-NIN
      tumors. The frequencies of loss of heterozygosity and MSI-H were significantly
      higher in Ca-NIN than in L-NIN or H-NIN tumors (p < 0.05). Nuclear accumulation
      of p53 protein was detected in no L-NIN tumors, 1 (11%) H-NIN tumor, and 10 (44%)
      Ca-NIN tumors (p < 0.01). All tumors with loss of hMLH1 expression exhibited MSI
      H (p < 0.01). Cellular phenotypic analysis revealed that seven (35%) L-NIN tumors
      and one (4%) Ca-NIN tumor had complete-type intestinal metaplastic phenotype and
      that one (5%) L-NIN tumor and one (4%) Ca-NIN tumor had a gastric foveolar
      epithelial phenotype, whereas the remaining tumors exhibited an ordinary
      phenotype. Thus, the complete-type intestinal metaplastic phenotype was more
      characteristic of L-NIN tumors than of H-NIN or Ca-NIN tumors (p < 0.01). In
      summary, the Padova international classification correlated with both the
      molecular and cellular phenotypic profiles. In practice, p53 and hMLH1
      immunohistochemistry discriminated Ca-NIN from L-NIN and H-NIN tumors.

PMID- 12480915
TI  - Expression of calnexin reflects paneth cell differentiation and function.
AB  - It has been suggested that the behavior and function of Paneth cells in
      metaplasia are different from those found in normal intestinal mucosa. In this
      study, we investigated whether calnexin, a protein involved in secretory
      pathways, might be associated with differentiation and function of Paneth cells
      in normal small intestine, in complete intestinal metaplasia of the stomach, and
      in Paneth cell-rich adenomas. Differentiation and function of Paneth cells was
      monitored by Ki67, lysozyme, and morphologic features. Using a newly established
      monoclonal antibody, we found that calnexin is regularly synthesized by Paneth
      cells of normal small intestine. In these cells, the staining intensity of
      calnexin was inversely correlated with their content of secretory granules
      (lysozyme). In contrast, Paneth cells of intestinal metaplasia and Paneth cell
      rich adenomas showed a reduced immunostaining of both calnexin and lysozyme.
      Moreover, these Paneth cells synthesized the proliferation marker Ki67, a
      phenomenon that was never observed in Paneth cells of normal small intestine. In
      vitro experiments using CaCo2 cells showed that the expression of calnexin is not
      directly affected by the induction of mitosis. In conclusion, calnexin probably
      reflects the status of Paneth cell differentiation and function. The results do
      not necessarily indicate that calnexin has a function in Paneth cell
      proliferation.

PMID- 12480916
TI  - TNF-alpha protects human primary articular chondrocytes from nitric oxide-induced
      apoptosis via nuclear factor-kappaB.
AB  - TNF-alpha plays a key role in rheumatoid arthritis, but its effect on chondrocyte
      survival is still conflicting. In the present study, we tested how TNF-alpha
      influences chondrocyte survival in response to nitric oxide (NO)-related
      apoptotic signals, which are abundant during rheumatoid arthritis. Human primary
      articular chondrocytes or cartilage explants were pretreated with TNF-alpha for
      24 hours and then treated with the proapoptotic NO donor sodium-nitro-prusside
      (SNP) for an additional 24 hours. TNF-alpha pretreatment markedly protected
      chondrocytes from SNP-induced cell death. Preincubation of chondrocytes with TNF
      alpha inhibited both SNP-induced high-molecular weight DNA fragmentation and
      annexin V-FITC binding. Of interest, TNF-alpha induced persistent nuclear factor
      kappaB (NF-kappaB)-DNA binding activity even in the presence of SNP, mirroring
      apoptosis protection effects. Both the TNF-alpha antiapoptotic effect and NF
      kappaB-DNA binding activity were significantly inhibited by NF-kappaB inhibitors,
      Bay 11-7085, MG-132, and adenovirus-expressing mutated IkappaB-alpha.
      Phosphatidylinositol-3 kinase inhibitor LY 294002 also markedly inhibited the
      antiapoptotic effect of TNF-alpha. In primary chondrocytes, TNF-alpha induced
      expression of the antiapoptotic protein Cox-2, which persisted in the presence of
      SNP, and a specific Cox-2 inhibitor significantly blocked the TNF-alpha
      protective effect. We therefore conclude that TNF-alpha-mediated protection of
      chondrocytes from NO-induced apoptosis acts through NF-kappaB and requires Cox-2
      activity.

PMID- 12480917
TI  - Rapid trafficking of membrane type 1-matrix metalloproteinase to the cell surface
      regulates progelatinase a activation.
AB  - Pericellular matrix degradation during cancer invasion and inflammation is
      dependent on activation of progelatinase A by membrane type 1-matrix
      metalloproteinase (MT1-MMP); a stoichiometric concentration of tissue inhibitor
      of metalloproteinase-2 (TIMP-2) is required. Activation of progelatinase A has
      generally been considered to be a slow process occurring as a result of enhanced
      expression of MT1-MMP. We herein report that ConA treatment of HT1080
      fibrosarcoma cells is followed by MT1-MMP-induced activation of progelatinase A
      on the cell surface within 1 hour. Cell surface biotinylation,
      immunohistochemistry, and (125)I-labeled TIMP-2 binding to cell surface MT1-MMP
      were used to characterize the appearance and function of MT1-MMP on the plasma
      membrane. Treatment of HT1080 cells with ConA resulted in increased specific
      binding of (125)I-labeled TIMP-2 to cell surface receptors within 5 minutes. TIMP
      2 binds almost exclusively to activated MT1-MMP on the surface of HT1080 cells.
      MT1-MMP function at the cell surface was also accelerated by treatment of cells
      with cytochalasin D, an inhibitor of actin filaments, PMA, a stimulator of
      protein kinase C, and bafilomycin A(1), an inhibitor of lysosome/endosome
      function. A functional pool of intracellular MT1-MMP available for trafficking to
      the cell surface was demonstrated by repetitive ConA stimulation. ConA-induced
      expression of MT1-MMP mRNA (Northern blot analysis) in HT1080 cells was a delayed
      event (>6 hours). These data suggest that presynthesized MT1-MMP is sorted to a
      transient storage compartment (trans-Golgi network/endosomes), where it is
      available for rapid trafficking to the plasma membrane and cell surface
      proteolytic activity.

PMID- 12480918
TI  - (-)Epigallocatechin-3-gallate directly inhibits MT1-MMP activity, leading to
      accumulation of nonactivated MMP-2 at the cell surface.
AB  - Consumption of green tea has been associated with prevention of cancer
      development, metastasis, and angiogenesis. Given the crucial role of the matrix
      metallo-proteinase-2 (MMP-2) on the degradation of the extracellular matrix
      instrumental to invasion, we examined the effect of the main flavanol present, (
      )epigallocatechin-3-gallate (EGCG), on membrane-type 1 MMP (MT1-MMP), the
      receptor/activator of MMP-2. In-solution fluorimetric assay with activated MT1
      MMP and gelatin-zymography with MT1-MMP catalytic domain alone and pro-MMP-2
      activation by the same domain revealed dose-dependent inhibition of MT1-MMP at
      EGCG concentrations slightly lower than that reported to inhibit MMP-2 and MMP-9.
      Cytofluorimetry and immunolocalization revealed that EGCG does not impair MT1
      MMP/TIMP-2/MMP-2 presence on the cell membrane. In the membrane extract of HT
      1080 human fibrosarcoma cells, 10 micro M EGCG caused a strong increase in MT1
      MMP level and accumulation of pro-MMP-2 while leaving activated MMP-2 unchanged.
      EGCG thus exerts inhibition of MT1-MMP, which restrains activation of MMP-2; this
      may confer the antiangiogenic and antimetastatic activity associated with green
      tea.

PMID- 12480919
TI  - Mitochondria-mediated apoptosis of lung epithelial cells in idiopathic
      interstitial pneumonias.
AB  - We previously demonstrated that the up-regulation of p53, Fas, and DNA damage are
      present in lung epithelial cells from patients with idiopathic interstitial
      pneumonias (IIP). Fas ligation induces apoptosis of lung epithelial cells
      predominantly through the direct activation of the caspase cascade via caspase-8
      activation, whereas the up-regulation of p53 and other cellular stresses can
      induce mitochondria-mediated apoptosis. In this study, we investigated the
      incidence of mitochondria-mediated apoptosis of epithelial cells in IIP. We
      performed TUNEL staining to detect apoptotic cells and western blot analysis and
      immunohistochemistry to assess the expression and activation of caspases and the
      cytochrome c release from mitochondria in lung tissues from eight patients with
      usual interstitial pneumonia, five patients with nonspecific interstitial
      pneumonia, and eight patients with normal lung parenchyma. The expressions of pro
      and cleaved caspase-8, 9, 3, and cytochrome c release from the mitochondria were
      all significantly increased in the lung tissues of IIP compared with normal lung
      parenchyma. The positive signals for caspases in epithelial cells were increased
      in IIP compared with normal lung parenchyma by immunohistochemistry. The results
      of TUNEL and electron microscopy suggested that apoptotic cells were
      predominantly epithelial cells. TUNEL-positive cells in % of epithelial cells
      were significantly increased in IIP compared with normal lung parenchyma, and
      significantly correlated with cytochrome c release from the mitochondria and with
      the expression of cleaved caspase-3 in epithelial cells. We conclude that
      mitochondria-mediated apoptosis may be involved in the pathophysiology of IIP.

PMID- 12480920
TI  - Construction of cDNA libraries from microdissected benign and malignant thyroid
      tissue.
AB  - cDNA libraries were constructed from thyroid epithelial cells gained by laser
      capture microdissection for gene expression analysis of the progression of
      thyroid cancer. Six histologically diverse thyroid tissue specimens were used. A
      mean of 93 ng of total RNA was gained per tissue sample from a mean estimated
      number of 25,000 microdissected cells per sample. Analysis of randomly selected
      clones from six libraries showed an average insert size of 600 (range, 300-1500)
      bp. Preliminary sequencing of clones selected from the six libraries indicates a
      range of 46% to 62% known genes per library, 4% to 25% anonymous expressed
      sequence tags per library, and 15% to 43% novel expressed sequence tags per
      library. Thyroglobulin was found in normal thyroid epithelium and follicular
      thyroid adenoma, whereas calcitonin precursor transcripts were found in medullary
      thyroid carcinoma. We demonstrate production of high-quality cDNA libraries of
      microdissected tissue of the thyroid, which should prove useful for gene
      expression analysis of human thyroid tumors.

PMID- 12480921
TI  - Complementary DNA arrays identify CD63 tetraspanin and alpha3 integrin chain as
      differentially expressed in low and high metastatic human colon carcinoma cells.
AB  - SUMMARY: Malignant tumor cell invasion is determinant for metastasis to occur. E2
      and C5 colon carcinoma cells that were derived from the parental Lovo line and
      that differ experimentally in spontaneous metastatic ability have been monitored
      for gene expression by cDNA arrays. Among genes found differentially expressed,
      the CD63 tetraspanin, not previously recognized in colon cancer progression, and
      the alpha3 integrin chain were both up-regulated in low metastatic E2 cells and
      were analyzed for their functional role using adhesion, migration, and invasion
      assays. Cell surface expression of CD63 and alpha3 integrin was about 2-fold
      higher in E2 than in C5 cells and confocal microscopy showed that CD63 and alpha3
      integrin colocalized evenly on C5 cells whereas they concentrated at elongated
      tips of the low-metastatic more substrate-adhesive E2 cells. Antibody
      interference experiments identified laminin-5 (LN-5) as a ligand interacting with
      the alpha3beta1/CD63 complex. Substrate-immobilized anti-CD63 antibodies enhanced
      tumor cell migration and invasion and induced prominent cell surface protrusions
      that were repressed by the PI3-kinase LY294002 inhibitor. Our results suggest
      that changes in the expression of surface CD63 and alpha3beta1 integrin
      interacting with LN-5 could affect migratory signals and the progression of the
      metastatic disease.

PMID- 12480922
TI  - Down-regulation of HLA-A expression correlates with a better prognosis in
      colorectal cancer patients.
AB  - To evaluate the prognostic impact of human leukocyte antigen class I (HLA-I)
      expression on immune surveillance in colorectal cancer, we studied 88 curatively
      resected tumors for HLA-A and HLA-B/C expression and correlated these data to
      clinical and histopathological parameters. HLA-A was normal (all tumor cells had
      HLA expression) in 32%, reduced (HLA-negative and -positive tumor cells
      coexisted) in 56%, or absent (no tumor cells expressed HLA) in 12% of evaluable
      cases. HLA-B/C was normal in 47%, reduced in 47%, and absent in 7% of the cases.
      Considering both markers, total HLA-I expression was normal in 27%, reduced in
      63%, absent in 7%, and could not be evaluated in 3% of the cases due to absent
      HLA-A expression in tumor and normal cells. Down-regulation of HLA-A expression
      significantly correlated with a lower tumor stage (p = 0.005), mucinous tumors (p
      = 0.05), a lower incidence of recurrences (p = 0.03), and a longer disease-free
      survival (p = 0.02). Down-regulation of HLA-B/C expression correlated with a
      lower tumor stage (p < 0.001) and a longer disease-free survival (p = 0.04). In
      multivariate analysis, HLA-A down-regulation was the only prognostic factor
      correlated with a longer disease-free survival (p = 0.02). Six tumors were
      negative for HLA-A and -B/C and did not recur during follow-up. Therefore, we
      analyzed microsatellite instability (MSI) in these cases. Three of these six
      tumors indeed showed down-regulation of MLH-1, MSH-2, or MSH-6, indicating a MSI
      high phenotype. Beta-2-microglobulin protein expression was lost in five of six
      of the HLA-I-negative cases, but frame shift mutations in three repetitive
      sequences in beta2-microglobulin were absent. In contrast, loss of MLH-1, MSH-2,
      and MSH-6-protein expression was only observed in two of nine matched controls
      with reduced or normal HLA-A and -B/C expression. Our data showed that HLA-I was
      down-regulated in 72% of colorectal cancers and provided independent prognostic
      information for a longer disease-free survival. The better prognosis may be
      caused by elimination of HLA-negative cells by natural killer cells or by an
      attenuated tumor aggressiveness, as is seen in tumors with a MSI-high phenotype.

PMID- 12480923
TI  - Raft.1, a monoclonal antibody raised against the raft microdomain, recognizes G
      protein beta1 and 2, which assemble near nucleus after shiga toxin binding to
      human renal cell line.
AB  - SUMMARY: Raft microdomains are glycolipid-enriched microdomain scaffolding
      molecules involved in signal transduction. The binding of Shiga toxin to
      globotriaosyl ceramide in raft microdomains of the human renal tubular cell line
      ACHN causes temporal activation of Src-kinase Yes. To study the downstream
      signaling mechanism proceeding to the activation of Yes, we raised monoclonal
      antibodies (MAbs) against raft microdomains. The MAbs were screened on the basis
      of, first, binding to raft microdomains with dot-blot immunostaining, second,
      intracellular localization of the epitope by flowcytometry after
      permeabilization, and third, translocation of the antigen molecules after Stx
      treatment by immunohistochemical staining. Raft.1 MAb bound to the molecules that
      accumulated to the particular region near the nucleus after Stx treatment. Two
      dimensional Western blotting and matrix-assisted laser desorption/ionization time
      of flight mass spectrometry analysis revealed that the antigen molecule is GTP
      binding protein beta subunits 1 and 2 (Gbeta1 and 2). That Raft.1 recognized
      Gbeta1 and 2 was further confirmed by the reactivity to recombinant Gbeta1 and 2
      proteins. To our knowledge, this is the first report of production of a MAb
      recognizing Gbeta1 and 2. Because Gbeta1 and 2 are highly conserved all through
      organisms and are deeply involved in signal transduction, Raft.1 is expected to
      be utilized frequently in research.

PMID- 12480924
TI  - Fibroblast growth factor-2 in remodeling of the developing basement membrane zone
      in the trachea of infant rhesus monkeys sensitized and challenged with allergen.
AB  - SUMMARY: Remodeling of the epithelial basement membrane zone (BMZ) involves
      increased deposition of collagen, resulting in thickening of the BMZ. The current
      study focuses on fibroblast growth factor-2 (FGF-2) in the tracheal BMZ in house
      dust mite allergen (HDMA)-sensitized infant rhesus monkeys, challenged with HDMA
      at a time when the BMZ is undergoing active postnatal development. To detect
      structural changes in the BMZ, we measured collagens I, III, and V. To detect
      changes in the function of the BMZ, we measured immunoreactivity of the heparan
      sulfate proteoglycan, perlecan, and FGF-2. We found significant thickening of the
      tracheal BMZ (p < 0.05) with each of these parameters. We also found that all
      HDMA tracheal samples expressed thin focal areas of the BMZ associated with
      leukocyte trafficking. These areas were depleted of perlecan and FGF-2; however,
      increased FGF-2 immunoreactivity was present in the adjacent basal cells. We
      conclude that basal cells and FGF-2 are involved with significant remodeling of
      the BMZ in the developing trachea of infant rhesus monkeys exposed to HDMA.

PMID- 12480925
TI  - Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal
      tract epithelia and is aberrantly expressed in human malignancies.
AB  - CaT1 is a highly selective calcium entry channel that has been proposed to be
      responsible for apical calcium entry in the vitamin D-regulated transcellular
      pathway of Ca(2+) absorption; however, the lack of a CaT1 antibody suitable for
      immunohistochemistry has prevented the direct testing of this hypothesis by the
      localization of CaT1 protein in the gastrointestinal tract and other tissues. In
      this study, we developed two CaT1 antibodies and have used them to establish for
      the first time that CaT1 localizes to the apical membrane of intestinal
      absorptive cells, thereby providing the first direct evidence that this protein
      is in fact an apical entry channel in the gastrointestinal tract. In addition, we
      found that CaT1 protein is highly expressed in a number of exocrine organs
      including pancreas, prostate, and mammary gland, suggesting an, as yet,
      unrecognized role in secretory epithelia. Finally, we found CaT1 protein to be
      present at elevated levels in comparison with normal tissues in a series of
      prostate, breast, thyroid, colon, and ovarian carcinomas, consistent with
      previous reports of up-regulation of CaT1 mRNA in prostate cancer tissues. Our
      findings indicate that CaT1 is likely to serve as a component of transcellular
      calcium transport mechanisms in many tissues and epithelial cancers.

PMID- 12480926
TI  - Efficient germline transmission of mouse embryonic stem cells grown in synthetic
      serum in the absence of a fibroblast feeder layer.

PMID- 12480927
TI  - A deficiency in dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl alpha3
      glucosyltransferase defines a new subtype of congenital disorders of
      glycosylation.
AB  - The underlying causes of type I congenital disorders of glycosylation (CDG I)
      have been shown to be mutations in genes encoding proteins involved in the
      biosynthesis of the dolichyl-linked oligosaccharide (Glc(3)Man(9)GlcNAc(2)-PP
      dolichyl) that is required for protein glycosylation. Here we describe a CDG I
      patient displaying gastrointestinal problems but no central nervous system
      deficits. Fibroblasts from this patient accumulate mainly Man(9)GlcNAc(2)-PP
      dolichyl, but in the presence of castanospermine, an endoplasmic reticulum
      glucosidase inhibitor Glc(1)Man(9)GlcNAc(2)-PP-dolichyl predominates, suggesting
      inefficient addition of the second glucose residue onto lipid-linked
      oligosaccharide. Northern blot analysis revealed the cells from the patient to
      possess only 10-20% normal amounts of mRNA encoding the enzyme, dolichyl-P
      glucose:Glc(1)Man(9)GlcNAc(2)-PP-dolichyl alpha3-glucosyltransferase (hALG8p),
      which catalyzes this reaction. Sequencing of hALG8 genomic DNA revealed exon 4 to
      contain a base deletion in one allele and a base insertion in the other. Both
      mutations give rise to premature stop codons predicted to generate severely
      truncated proteins, but because the translation inhibitor emetine was shown to
      stabilize the hALG8 mRNA from the patient to normal levels, it is likely that
      both transcripts undergo nonsense-mediated mRNA decay. As the cells from the
      patient were successfully complemented with wild type hALG8 cDNA, we conclude
      that these mutations are the underlying cause of this new CDG I subtype that we
      propose be called CDG Ih.

PMID- 12480928
TI  - Role of cyclooxygenase 2 in protein kinase C beta II-mediated colon
      carcinogenesis.
AB  - Elevated expression of protein kinase C beta II (PKC beta II) is an early
      promotive event in colon carcinogenesis (Gokmen-Polar, Y., Murray, N. R.,
      Velasco, M. A., Gatalica, Z., and Fields, A. P. (2001) Cancer Res. 61, 1375
      1381). Expression of PKC beta II in the colon of transgenic mice leads to
      hyperproliferation and increased susceptibility to colon carcinogenesis due, at
      least in part, to repression of transforming growth factor beta type II receptor
      (TGF-beta RII) expression (Murray, N. R., Davidson, L. A., Chapkin, R. S.,
      Gustafson, W. C., Schattenberg, D. G., and Fields, A. P. (1999) J. Cell Biol.,
      145, 699-711). Here we report that PKC beta II induces the expression of
      cyclooxygenase type 2 (Cox-2) in rat intestinal epithelial (RIE) cells in vitro
      and in transgenic PKC beta II mice in vivo. Cox-2 mRNA increases more than 10
      fold with corresponding increases in Cox-2 protein and PGE2 production in RIE/PKC
      beta II cells. PKC beta II activates the Cox-2 promoter by 2- to 3-fold and
      stabilizes Cox-2 mRNA by at least 4-fold. The selective Cox-2 inhibitor Celecoxib
      restores expression of TGF-beta RII both in vitro and in vivo and restores TGF
      beta-mediated transcription in RIE/PKC beta II cells. Likewise, the omega-3 fatty
      acid eicosapentaenoic acid (EPA), which inhibits PKC beta II activity and colon
      carcinogenesis, causes inhibition of Cox-2 protein expression, re-expression of
      TGF-beta RII, and restoration of TGF-beta1-mediated transcription in RIE/PKC beta
      II cells. Our data demonstrate that PKC beta II promotes colon cancer, at least
      in part, through induction of Cox-2, suppression of TGF-beta signaling, and
      establishment of a TGF-beta-resistant, hyperproliferative state in the colonic
      epithelium. Our data define a procarcinogenic PKC beta II --> Cox-2 --> TGF-beta
      signaling axis within the colonic epithelium, and provide a molecular mechanism
      by which dietary omega-3 fatty acids and nonsteroidal antiinflammatory agents
      such as Celecoxib suppress colon carcinogenesis.

PMID- 12480929
TI  - Solution 1H NMR investigation of the active site molecular and electronic
      structures of substrate-bound, cyanide-inhibited HmuO, a bacterial heme oxygenase
      from Corynebacterium diphtheriae.
AB  - The molecular structure and dynamic properties of the active site environment of
      HmuO, a heme oxygenase (HO) from the pathogenic bacterium Corynebacterium
      diphtheriae, have been investigated by (1)H NMR spectroscopy using the human HO
      (hHO) complex as a homology model. It is demonstrated that not only the spatial
      contacts among residues and between residues and heme, but the magnetic axes that
      can be related to the direction and magnitude of the steric tilt of the FeCN unit
      are strongly conserved in the two HO complexes. The results indicate that very
      similar contributions of steric blockage of several meso positions and steric
      tilt of the attacking ligand are operative. A distal H-bond network that involves
      numerous very strong H-bonds and immobilized water molecules is identified in
      HmuO that is analogous to that previously identified in hHO (Li, Y., Syvitski, R.
      T., Auclair, K., Wilks, A., Ortiz de Montellano, P. R., and La Mar, G. N. (2002)
      J. Biol. Chem. 277, 33018-33031). The NMR results are completely consistent with
      the very recent crystal structure of the HmuO.substrate complex. The H-bond
      network/ordered water molecules are proposed to orient the distal water molecule
      near the catalytically key Asp(136) (Asp(140) in hHO) that stabilizes the
      hydroperoxy intermediate. The dynamic stability of this H-bond network in HmuO is
      significantly greater than in hHO and may account for the slower catalytic rate
      in bacterial HO compared with mammalian HO.

PMID- 12480930
TI  - Cloning and characterization of CXIP1, a novel PICOT domain-containing
      Arabidopsis protein that associates with CAX1.
AB  - Regulation of Ca(2+) transporters is a vital component of signaling. The
      Arabidopsis H(+)/Ca(2+) exchanger CAX1 contains an N-terminal autoinhibitory
      domain that prevents Ca(2+) transport when CAX1 is heterologously expressed in
      yeast. Using a yeast screen, we have identified three different proteins that
      activate CAX1. One of these, CXIP1 (CAX-interacting protein-1; 19.3 kDa) has
      amino acid similarity to the C terminus of PICOT (protein kinase C-interacting
      cousin of thioredoxin) proteins. Although PICOT proteins are found in a variety
      of organisms, a function has not been previously ascribed to a plant PICOT
      protein. We demonstrate that CXIP1 activated the CAX1 homolog CAX4, but not CAX2
      or CAX3. An Arabidopsis homolog of CXIP1 (CXIP2) weakly activated CAX4, but not
      CAX1. In a yeast two-hybrid assay, CXIP1 interacted with the N terminus of CAX1.
      In competition analysis, CXIP1 and a CAX1 N-terminal peptide appeared to bind to
      similar N-terminal domains of CAX1. Chimeric CAX3 constructs containing the N
      terminus of CAX1 were activated by CXIP1. In Arabidopsis, CXIP1 transcripts, like
      CAX1, accumulated in response to different metal conditions. This work thus
      characterizes a new class of signaling molecules in plants that may regulate CAX
      transporters in vivo.

PMID- 12480931
TI  - A novel S100 target conformation is revealed by the solution structure of the
      Ca2+-S100B-TRTK-12 complex.
AB  - The Alzheimer-linked neural protein S100B is a signaling molecule shown to
      control the assembly of intermediate filament proteins in a calcium-sensitive
      manner. Upon binding calcium, a conformational change occurs in S100B exposing a
      hydrophobic surface for target protein interactions. The synthetic peptide TRTK
      12 (TRTKIDWNKILS), derived from random bacteriophage library screening, bears
      sequence similarity to several intermediate filament proteins and has the highest
      calcium-dependent affinity of any target molecule for S100B to date (K(d) <1
      microm). In this work, the three-dimensional structure of the Ca(2+)-S100B-TRTK
      12 complex has been determined by NMR spectroscopy. The structure reveals an
      extended, contiguous hydrophobic surface is formed on Ca(2+)-S100B for target
      interaction. The TRTK-12 peptide adopts a coiled structure that fits into a
      portion of this surface, anchored at Trp(7), and interacts with multiple
      hydrophobic contacts in helices III and IV of Ca(2+)-S100B. This interaction is
      strikingly different from the alpha-helical structures found for other S100
      target peptides. By using the TRTK-12 interaction as a guide, in combination with
      other available S100 target structures, a recognition site on helix I is
      identified that may act in concert with the TRTK-12-binding site from helices III
      and IV. This would provide a larger, more complex site to interact with full
      length target proteins and would account for the promiscuity observed for S100B
      target protein interactions.

PMID- 12480932
TI  - Nitric oxide binding properties of neuroglobin. A characterization by EPR and
      flash photolysis.
AB  - Neuroglobin is a recently discovered member of the globin superfamily. Combined
      electron paramagnetic resonance and optical measurements show that, in
      Escherichia coli cell cultures with low O(2) concentration overexpressing wild
      type mouse recombinant neuroglobin, the heme protein is mainly in a
      hexacoordinated deoxy ferrous form (F8His-Fe(2+)-E7His), whereby for a small
      fraction of the protein the endogenous protein ligand is replaced by NO.
      Analogous studies for mutated neuroglobin (mutation of E7-His to Leu, Val, or
      Gln) reveal the predominant presence of the nitrosyl ferrous form. After
      sonication of the cells wild-type neuroglobin oxidizes rapidly to the
      hexacoordinated ferric form, whereas NO ligation initially protects the mutants
      from oxidation. Flash photolysis studies of wild-type neuroglobin and its E7
      mutants show high recombination rates (k(on)) and low dissociation rates (k(off))
      for NO, indicating a high intrinsic affinity for this ligand similar to that of
      other hemoglobins. Since the rate-limiting step in ligand combination with the
      deoxy-hexacoordinated wild-type form involves the dissociation of the protein
      ligand, NO binding is slower than for the related mutants. Structural and kinetic
      characteristics of neuroglobin and its mutants are analyzed. NO production in
      rapidly growing E. coli cell cultures is discussed.

PMID- 12480933
TI  - Reconstitution of the Mcm2-7p heterohexamer, subunit arrangement, and ATP site
      architecture.
AB  - The Mcm2-7p heterohexamer is the presumed replicative helicase in eukaryotic
      cells. Each of the six subunits is required for replication. We have purified the
      six Saccharomyces cerevisiae MCM proteins as recombinant proteins in Escherichia
      coli and have reconstituted the Mcm2-7p complex from individual subunits. Study
      of MCM ATPase activity demonstrates that no MCM protein hydrolyzes ATP
      efficiently. ATP hydrolysis requires a combination of two MCM proteins. The
      fifteen possible pairwise mixtures of MCM proteins yield only three pairs of MCM
      proteins that produce ATPase activity. Study of the Mcm3/7p ATPase shows that an
      essential arginine in Mcm3p is required for hydrolysis of the ATP bound to Mcm7p.
      Study of the pairwise interactions between MCM proteins connects the remaining
      MCM proteins to the Mcm3/7p pair. The data predict which subunits in the ATPase
      pairs bind the ATP that is hydrolyzed and indicate the arrangement of subunits in
      the Mcm2-7p heterohexamer.

PMID- 12480934
TI  - A human topoisomerase II alpha heterodimer with only one ATP binding site can go
      through successive catalytic cycles.
AB  - Eukaryotic DNA topoisomerase II is a dimeric nuclear enzyme essential for DNA
      metabolism and chromosome dynamics. It changes the topology of DNA by coupling
      binding and hydrolysis of two ATP molecules to the transport of one DNA duplex
      through a temporary break introduced in another. During this process the
      structurally and functionally complex enzyme passes through a cascade of
      conformational changes, which requires intra- and intersubunit communication. To
      study the importance of ATP binding and hydrolysis in relation to DNA strand
      transfer, we have purified and characterized a human topoisomerase II alpha
      heterodimer with only one ATP binding site. The heterodimer was able to relax
      supercoiled DNA, although less efficiently than the wild type enzyme. It
      furthermore possessed a functional N-terminal clamp and was sensitive to ICRF
      187. This demonstrates that human topoisomerase II alpha can pass through all the
      conformations required for DNA strand passage and enzyme resetting with binding
      and hydrolysis of only one ATP. However, the heterodimer lacked the normal
      stimulatory effect of DNA on ATP binding and hydrolysis as well as the
      stimulatory effect of ATP on DNA cleavage. The results can be explained in a
      model, where efficient catalysis requires an extensive communication between the
      second ATP and the DNA segment to be cleaved.

PMID- 12480935
TI  - Bacteriophage phi 29 early protein p17. Self-association and hetero-association
      with the viral histone-like protein p6.
AB  - Gene 17 of the Bacillus subtilis phage Phi29 is expressed early after infection,
      and it has been shown to be required at the very beginning of phage replication
      under conditions of low but not high multiplicity of infection. It has been
      proposed that, at the beginning of the infection, protein p17 could be recruiting
      limiting amounts of initiation factors at the viral origins. Once the infection
      process is established and the replication proteins reach optimal concentration,
      protein p17 becomes dispensable. In this paper we focused, on the one hand, on
      the study of protein p17 dimerization and the role of a putative coiled-coil
      region. On the other hand, we focused on its interaction with the viral origin
      binding protein p6. Based on our results we propose that protein p17 function is
      to optimize binding of protein p6 at the viral DNA ends, thus favoring the
      initiation of replication and negatively modulating its own transcription.

PMID- 12480937
TI  - Secretion and intracellular generation of truncated Abeta in beta-site amyloid
      beta precursor protein-cleaving enzyme expressing human neurons.
AB  - Insoluble pools of the amyloid-beta peptide (Abeta) in brains of Alzheimer's
      disease patients exhibit considerable N- and C-terminal heterogeneity. Mounting
      evidence suggests that both C-terminal extensions and N-terminal truncations help
      precipitate amyloid plaque formation. Although mechanisms underlying the
      increased generation of C-terminally extended peptides have been extensively
      studied, relatively little is known about the cellular mechanisms underlying
      production of N-terminally truncated Abeta. Thus, we used human NT2N neurons to
      investigate the production of Abeta11-40/42 from amyloid-beta precursor protein
      (APP) by beta-site APP-cleaving enzyme (BACE). When comparing undifferentiated
      human embryonal carcinoma NT2- cells and differentiated NT2N neurons, the
      secretion of sAPP and Abeta correlated with BACE expression. To study the effects
      of BACE expression on endogenous APP metabolism in human cells, we overexpressed
      BACE in undifferentiated NT2- cells and NT2N neurons. Whereas NT2N neurons
      produced both full-length and truncated Abeta as a result of normal processing of
      endogenous APP, BACE overexpression increased the secretion of Abeta1-40/42 and
      Abeta11-40/42 in both NT2- cells and NT2N neurons. Furthermore, BACE
      overexpression resulted in increased intracellular Abeta1-40/42 and Abeta11
      40/42. Therefore, we conclude that Abeta11-40/42 is generated prior to deposition
      in senile plaques and that N-terminally truncated Abeta peptides may contribute
      to the downstream effects of amyloid accumulation in Alzheimer's disease.

PMID- 12480938
TI  - Identification of active site residues of the adeno-associated virus type 2 Rep
      endonuclease.
AB  - Adeno-associated virus type 2 Rep endonuclease activity is necessary for both
      viral DNA replication and site-specific integration of the viral genome into
      human chromosome 19. The biochemical activities required for site-specific
      endonuclease activity (namely specific DNA binding and transesterification
      activity) have been mapped to the amino-terminal domain of the AAV2 Rep protein.
      The amino-terminal 208 amino acids are alone sufficient for site-specific
      endonuclease activity, and nicking by this domain is metal-dependent. To identify
      this metal-binding site, we have employed a cysteine mutagenesis approach that
      targets conserved acidic amino acids. By using this technique, we provide
      functional biochemical data supporting a role for glutamate 83 in the
      coordination of metal ions in the context of Rep endonuclease activity. In
      addition, our biochemical data suggest that glutamate 164, although not involved
      in the coordination of metal ions, is closely associated with the active site.
      Thus, in lieu of a crystal structure for the AAV type 2 amino-terminal domain,
      our data corroborate the recently published structural studies of the AAV type 5
      endonuclease and suggest that although the two enzymes are not highly conserved
      with respect to the AAV family, their active sites are highly conserved.

PMID- 12480936
TI  - Potent suppression of viral infectivity by the peptides that inhibit
      multimerization of human immunodeficiency virus type 1 (HIV-1) Vif proteins.
AB  - Virion infectivity factor (Vif) is essential for the replication of human
      immunodeficiency virus type 1 (HIV-1) in vivo, but its function remains
      uncertain. Recently, we have shown that Vif proteins are able to form multimers,
      including dimers, trimers, or tetramers. Because the multimerization of Vif
      proteins is required for Vif function in the viral life cycle, we propose that it
      could be a novel target for anti-HIV-1 therapeutics. Through a phage peptide
      display method, we have identified a set of 12-mer peptides containing a PXP
      motif that binds to HIV-1 Vif protein. These proline-enriched peptides potently
      inhibited the Vif-Vif interaction in vitro. We have also screened a set of
      synthesized Vif peptides (15-mer), which covers all the amino acids of the HIV-1
      Vif protein sequence, for their ability to inhibit the Vif-Vif interaction in
      vitro. We demonstrated that Vif-derived proline-enriched peptides that contain
      the (161)PPLP(164) domain are able to inhibit the Vif-Vif interaction.
      Conversely, the deletion of the (161)PPLP(164) domain of Vif protein will
      significantly impair the capability of Vif proteins to interact with each other,
      indicating that the (161)PPLP(164) domain plays a key role in Vif
      multimerization. All these results demonstrate that the proline-enriched peptides
      block the multimerization of Vif through interfering with the polyproline
      interfaces of Vif formed by (161)PPLP(164) domain. Moreover, these peptides which
      inhibit the Vif-Vif interaction in vitro potently inhibit HIV-1 replication in
      the "nonpermissive" T-cells. We propose that this study starts a novel strategy
      to develop structural diverse inhibitors of Vif such as peptidomimetics or small
      organic molecules.

PMID- 12480939
TI  - Bcl-2 controls caspase activation following a p53-dependent cyclin D1-induced
      death signal.
AB  - MCF-7 and ZR-75 breast cancer cells infected with an adenovirus constitutively
      expressing high levels of cyclin D1 demonstrated widespread mitochondrial
      translocation of Bax and cytochrome c release that was approximately doubled
      after the addition of all-trans retinoic acid (RA) or Bcl-2 antisense
      oligonucleotide. By comparison, the percentage of cells in Lac Z virus-infected
      cultures containing translocated Bax and cytoplasmic cytochrome c was markedly
      less even after RA treatment. Despite this, RA-treated Lac Z and untreated cyclin
      D1 virus-infected cultures contained similarly low proportions of cells with
      active caspase or cells that were permeable to propidium iodide. Bax activation
      was p53-dependent and accompanied by arrest in G(2) phase. Although constitutive
      Bcl-2 expression prevented Bax activation, it did not alter cyclin D1-induced
      cell cycle arrest, illustrating the independence of these events. Both RA and
      antisense Bcl-2 oligonucleotide decreased Bcl-2 protein levels and markedly
      increased caspase activity and apoptosis in cyclin D1-infected cells. Thus
      amplified cyclin D1 expression initiates an apoptotic signal inhibited by
      different levels of cellular Bcl-2 at two points. Whereas high cellular levels of
      Bcl-2 prevent mitochondrial Bax translocation, lower levels can prevent apoptosis
      by inhibition of caspase activation.

PMID- 12480940
TI  - Redox properties of human endothelial nitric-oxide synthase oxygenase and
      reductase domains purified from yeast expression system.
AB  - Characterization of the redox properties of endothelial nitric-oxide synthase
      (eNOS) is fundamental to understanding the complicated reaction mechanism of this
      important enzyme participating in cardiovascular function. Yeast overexpression
      of both the oxygenase and reductase domains of human eNOS, i.e. eNOS(ox) and
      eNOS(red), has been established to accomplish this goal. UV-visible and electron
      paramagnetic resonance (EPR) spectral characterization for the resting eNOS(ox)
      and its complexes with various ligands indicated a standard NOS heme structure as
      a thiolate hemeprotein. Two low spin imidazole heme complexes but not the
      isolated eNOS(ox) were resolved by EPR indicating slight difference in heme
      geometry of the dimeric eNOS(ox) domain. Stoichiometric titration of eNOS(ox)
      demonstrated that the heme has a capacity for a reducing equivalent of 1-1.5.
      Additional 1.5-2.5 reducing equivalents were consumed before heme reduction
      occurred indicating the presence of other unknown high potential redox centers.
      There is no indication for additional metal centers that could explain this extra
      electron capacity of eNOS(ox). Ferrous eNOS(ox), in the presence of l-arginine,
      is fully functional in forming the tetrahydrobiopterin radical upon mixing with
      oxygen as demonstrated by rapid-freeze EPR measurements. Calmodulin binds
      eNOS(red) at 1:1 stoichiometry and high affinity. Stoichiometric titration and
      computer simulation enabled the determination for three redox potential
      separations between the four half-reactions of FMN and FAD. The extinction
      coefficient could also be resolved for each flavin for its semiquinone, oxidized,
      and reduced forms at multiple wavelengths. This first redox characterization on
      both eNOS domains by stoichiometric titration and the generation of a high
      quality EPR spectrum for the BH(4) radical intermediate illustrated the
      usefulness of these tools in future detailed investigations into the reaction
      mechanism of eNOS.

PMID- 12480941
TI  - Daphnetin methylation by a novel O-methyltransferase is associated with cold
      acclimation and photosystem II excitation pressure in rye.
AB  - In plants, O-methylation of phenolic compounds plays an important role in such
      processes as lignin synthesis, flower pigmentation, chemical defense, and
      signaling. However, apart from phenylpropanoids and flavonoids, very few enzymes
      involved in coumarin biosynthesis have been identified. We report here the
      molecular and biochemical characterization of a gene encoding a novel O
      methyltransferase that catalyzes the methylation of 7,8-dihydroxycoumarin,
      daphnetin. The recombinant protein displayed an exclusive methylation of position
      8 of daphnetin. The identity of the methylated product was unambiguously
      identified as 7-hydroxy-8-methoxycoumarin by co-chromatography on cellulose TLC
      and coelution from high performance liquid chromatography, with authentic
      synthetic samples, as well as by UV, mass spectroscopy, (1)H NMR spectral
      analysis, and NOE correlation signals of the relevant protons. Northern blot
      analysis and enzyme activity assays revealed that the transcript and
      corresponding enzyme activity are up-regulated by both low temperature and
      photosystem II excitation pressure. Using various phenylpropanoid and flavonoid
      substrates, we demonstrate that cold acclimation of rye leaves increases O
      methyltransferase activity not only for daphnetin but also for the lignin
      precursors, caffeic acid, and 5-hydroxyferulic acid. The significance of this
      novel enzyme and daphnetin O-methylation is discussed in relation to its putative
      role in modulating cold acclimation and photosystem II excitation pressure.

PMID- 12480942
TI  - Molecular architecture of the phosphorylation region of the yeast plasma membrane
      H+-ATPase.
AB  - The molecular architecture of the yeast plasma membrane H(+)-ATPase
      phosphorylation region was explored by Fe(2+)-catalyzed cleavage. An ATP
      Mg(2+).Fe(2+) complex was found to act as an affinity cleavage reagent in the
      presence of dithiothreitol/H(2)O(2). Selective enzyme cleavage required bound
      adenine nucleotide, either ATP or ADP, in the presence of Mg(2+). The fragment
      profile included a predominant N-terminal 61-kDa fragment, a minor 37-kDa
      fragment, and three prominent C-terminal fragments of 39, 36, and 30 kDa. The 61
      kDa N-terminal and 39-kDa C-terminal fragments were predicted to originate from
      cleavage within the conserved MLT(558)GDAVG sequence. The 37-kDa fragment was
      consistent with cleavage within the S4/M4 sequence PVGLPA(340)V, while the 30-kDa
      and 36-kDa C-terminal fragments appeared to originate from cleavage in or around
      sequences D(646)TGIAVE and DMPGS(595)ELADF, respectively. The latter are
      spatially close to the highly conserved motif GD(634)GVND(638)APSL and conserved
      residues Thr(558) and Lys(615), which have been implicated in coordinating Mg(2+)
      and ATP. Overall, these results demonstrate that Fe(2+) associated with ATP and
      Mg(2+) acts as an affinity cleavage agent of the H(+)-ATPase with backbone
      cleavage occurring in conserved regions known to coordinate metal-nucleotide
      complexes. This study provides support for a three-dimensional organization of
      the phosphorylation region of the yeast plasma membrane H(+)-ATPase that is
      consistent with, but not identical to, typical P-type enzymes.

PMID- 12480943
TI  - Structural and functional characteristics of two sodium-coupled dicarboxylate
      transporters (ceNaDC1 and ceNaDC2) from Caenorhabditis elegans and their
      relevance to life span.
AB  - We have cloned and functionally characterized two Na(+)-coupled dicarboxylate
      transporters, namely ceNaDC1 and ceNaDC2, from Caenorhabditis elegans. These two
      transporters show significant sequence homology with the product of the Indy gene
      identified in Drosophila melanogaster and with the Na(+)-coupled dicarboxylate
      transporters NaDC1 and NaDC3 identified in mammals. In a mammalian cell
      heterologous expression system, the cloned ceNaDC1 and ceNaDC2 mediate Na(+)
      coupled transport of various dicarboxylates. With succinate as the substrate,
      ceNaDC1 exhibits much lower affinity compared with ceNaDC2. Thus, ceNaDC1 and
      ceNaDC2 correspond at the functional level to the mammalian NaDC1 and NaDC3,
      respectively. The nadc1 and nadc2 genes are not expressed at the embryonic stage,
      but the expression is detectable all through the early larva stage to the adult
      stage. Tissue-specific expression pattern studies using a reporter gene fusion
      approach in transgenic C. elegans show that both genes are coexpressed in the
      intestinal tract, an organ responsible for not only the digestion and absorption
      of nutrients but also for the storage of energy in this organism. Independent
      knockdown of the function of these two transporters in C. elegans using the
      strategy of RNA interference suggests that NaDC1 is not associated with the
      regulation of average life span in this organism, whereas the knockdown of NaDC2
      function leads to a significant increase in the average life span. Disruption of
      the function of the high affinity Na(+)-coupled dicarboxylate transporter NaDC2
      in C. elegans may lead to decreased availability of dicarboxylates for cellular
      production of metabolic energy, thus creating a biological state similar to that
      of caloric restriction, and consequently leading to life span extension.

PMID- 12480944
TI  - Sphingosine 1-phosphate and platelet-derived growth factor (PDGF) act via PDGF
      beta receptor-sphingosine 1-phosphate receptor complexes in airway smooth muscle
      cells.
AB  - Platelet-derived growth factor (PDGF) and sphingosine 1-phosphate (S1P) act via
      PDGF beta receptor-S1P(1) receptor complexes in airway smooth muscle cells to
      promote mitogenic signaling. Several lines of evidence support this conclusion.
      First, both receptors were co-immunoprecipitated from cell lysates with specific
      anti-S1P(1) antibodies, indicating that they form a complex. Second, treatment of
      airway smooth muscle cells with PDGF stimulated the phosphorylation of p42/p44
      MAPK, and this phosphorylated p42/p44 MAPK associates with the PDGF beta receptor
      S1P(1) receptor complex. Third, treatment of cells with antisense S1P(1) receptor
      plasmid construct reduced the PDGF- and S1P-dependent activation of p42/p44 MAPK.
      Fourth, S1P and/or PDGF induced the formation of endocytic vesicles containing
      both PDGF beta receptors and S1P(1) receptors, which was required for activation
      of the p42/p44 MAPK pathway. PDGF does not induce the release of S1P, suggesting
      the absence of a sequential mechanism. However, sphingosine kinase 1 is
      constitutively exported from cells and supports activation of p42/p44 MAPK by
      exogenous sphingosine. Thus, the presentation of sphingosine from other cell
      types and its conversion to S1P by the kinase exported from airway smooth muscle
      cells might enable S1P to act with PDGF on the PDGF beta receptor-S1P(1) receptor
      complex to induce biological responses in vivo. These data provide further
      evidence for a novel mechanism for G-protein-coupled receptor and receptor
      tyrosine kinase signal integration that is distinct from the transactivation of
      receptor tyrosine kinases by G-protein-coupled receptor agonists and/or
      sequential release and action of S1P in response to PDGF.

PMID- 12480945
TI  - Retinoid X receptor alpha represses GATA-4-mediated transcription via a retinoid
      dependent interaction with the cardiac-enriched repressor FOG-2.
AB  - Dietary vitamin A and its derivatives, retinoids, regulate cardiac growth and
      development. To delineate mechanisms involved in retinoid-mediated control of
      cardiac gene expression, the regulatory effects of the retinoid X receptor alpha
      (RXR alpha) on atrial naturietic factor (ANF) gene transcription was
      investigated. The transcriptional activity of an ANF promoter-reporter in rat
      neonatal ventricular myocytes was repressed by RXR alpha in the presence of 9-cis
      RA and by the constitutively active mutant RXR alpha F318A indicating that
      liganded RXR confers the regulatory effect. The RXR alpha-mediated repression
      mapped to the proximal 147 bp of the rat ANF promoter, a region lacking a
      consensus retinoid response element but containing several known cardiogenic cis
      elements including a well characterized GATA response element. Glutathione S
      transferase "pull-down" assays revealed that RXR alpha interacts directly with
      GATA-4, in a ligand-independent manner, via the DNA binding domain of RXR alpha
      and the second zinc finger of GATA-4. Liganded RXR alpha repressed the activity
      of a heterologous promoter-reporter construct containing GATA-response element
      recognition sites in cardiac myocytes but not in several other cell types,
      suggesting that additional cardiac-enriched factors participate in the repression
      complex. Co-transfection of liganded RXR alpha and the known cardiac-enriched
      GATA-4 repressor, FOG-2, resulted in additive repression of GATA-4 activity in
      ventricular myocytes. In addition, RXR alpha was found to bind FOG-2, in a 9-cis
      RA-dependent manner. These data reveal a novel mechanism by which retinoids
      regulate cardiogenic gene expression through direct interaction with GATA-4 and
      its co-repressor, FOG-2.

PMID- 12480946
TI  - c-Myc is required for the glucose-mediated induction of metabolic enzyme genes.
AB  - Glucose exerts powerful effects on hepatocyte gene transcription by mechanisms
      that are incompletely understood. c-Myc regulates hepatic glucose metabolism by
      increasing glycolytic enzyme gene transcription while concomitantly decreasing
      gluconeogenic and ketogenic enzyme gene expression. However, the molecular
      mechanisms by which c-Myc exerts these effects is not known. In this study, the
      glucose-mediated induction of L-type pyruvate kinase and glucose-6-phosphatase
      mRNA levels was diminished by maneuvers involving recombinant adenoviral vectors
      that interfere with (i) c-Myc protein levels by antisense expression or (ii) c
      Myc function through a dominant-negative Max protein. These results were obtained
      using both HL1C rat hepatoma cells and primary rat hepatocytes. Furthermore, a
      decrease in c-Myc abundance reduced glucose production in HL1C cells, presumably
      by decreasing glucose-6-phosphatase activity. The repression of hormone-activated
      phosphoenolpyruvate carboxykinase gene transcription by glucose was not affected
      by a reduction in c-Myc levels. The basal mRNA levels for L-pyruvate kinase and
      glucose-6-phosphatase were not altered to any significant degree by adenoviral
      treatment. Furthermore, adenoviral overexpression of the c-Myc protein induced
      glucose-6-phosphatase mRNA in the absence of glucose stimulation. We conclude
      that multiple mechanisms exist to communicate the glucose-derived signal and that
      c-Myc has a key role in the hepatic glucose signaling pathway.

PMID- 12480947
TI  - Interaction of dystrophin rod domain with membrane phospholipids. Evidence of a
      close proximity between tryptophan residues and lipids.
AB  - Dystrophin is assumed to act via the central rod domain as a flexible linker
      between the amino-terminal actin binding domain and carboxyl-terminal proteins
      associated with the membrane. The rod domain is made up of 24 spectrin-like
      repeats and has been shown to modify the physical properties of lipid membranes.
      The nature of this association still remains unclear. Tryptophan residues tend to
      cluster at or near to the water-lipid interface of the membrane. To assess
      dystrophin rod domain-membrane interactions, tryptophan residues properties of
      two recombinant proteins of the rod domain were examined by (1)H NMR and
      fluorescence techniques in the presence of membrane lipids. F114 (residues 439
      553) is a partly folded protein as inferred from (1)H NMR, tryptophan
      fluorescence emission intensity, and the excited state lifetime. By contrast,
      F125 (residues 439-564) is a folded compact protein. Tryptophan fluorescence
      quenching shows that both proteins are characterized by structural fluctuations
      with their tryptophan residues only slightly buried from the surface. In the
      presence of negatively charged small vesicles, the fluorescence characteristics
      of F125 change dramatically, indicating that tryptophan residues are in a more
      hydrophobic environment. Interestingly, these modifications are not observed with
      F114. Fluorescence quenching experiments confirm that tryptophan residues are
      shielded from the solvent in the complex F125 lipids by a close contact with
      lipids. The use of membrane-bound quenchers allowed us to conclude that
      dystrophin rod domain lies along the membrane surface and may be involved in a
      structural array comprising membrane and cytoskeletal proteins as well as
      membrane lipids.

PMID- 12480948
TI  - Inhibition of HIV-1 ribonuclease H by a novel diketo acid, 4-[5
      (benzoylamino)thien-2-yl]-2,4-dioxobutanoic acid.
AB  - Human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase (RT)
      coordinates DNA polymerization and ribonuclease H (RNase H) activities using two
      discrete active sites embedded within a single heterodimeric polyprotein. We have
      identified a novel thiophene diketo acid, 4-[5-(benzoylamino)thien-2-yl]-2,4
      dioxobutanoic acid, that selectively inhibits polymerase-independent RNase H
      cleavage (IC(50) = 3.2 microm) but has no effect on DNA polymerization (IC(50) >
      50 microm). The activity profile of the diketo acid is shown to be distinct from
      previously described compounds, including the polymerase inhibitor foscarnet and
      the putative RNase H inhibitor 4-chlorophenylhydrazone. Both foscarnet and the
      hydrazone inhibit RNase H cleavage and DNA polymerization activities of RT, yet
      neither inhibits the RNase H activity of RT containing a mutation in the
      polymerase active site (D185N) or an isolated HIV-1 RNase H domain chimera
      containing the alpha-C helix from Escherichia coli RNase HI, suggesting these
      compounds affect RNase H indirectly. In contrast, the diketo acid inhibits the
      RNase H activity of the isolated RNase H domain as well as full-length RT, and
      inhibition is not affected by the polymerase active site mutation. In isothermal
      titration calorimetry studies using the isolated RNase H domain, binding of the
      diketo acid is independent of nucleic acid but strictly requires Mn(2+) implying
      a direct interaction between the inhibitor and the RNase H active site. These
      studies demonstrate that inhibition of HIV-1 RNase H may occur by either direct
      or indirect mechanisms, and they provide a framework for identifying novel agents
      such as 4-[5-(benzoylamino)thien- 2-yl]-2,4-dioxobutanoic acid that specifically
      targets RNase H.

PMID- 12480950
TI  - Enzyme replacement therapy for Fabry disease: proving the clinical benefit.

PMID- 12480951
TI  - Screening for microalbuminuria in the general population: a tool to detect
      subjects at risk for progressive renal failure in an early phase?

PMID- 12480952
TI  - Progress in the treatment of rheumatic disease.

PMID- 12480953
TI  - Frequent prolonged home haemodialysis: three old concepts, one modern solution.

PMID- 12480954
TI  - PHD: the technological solution for daily haemodialysis?

PMID- 12480955
TI  - The living kidney donor: giving life, avoiding harm.

PMID- 12480956
TI  - Inflammation modifies lipid-mediated renal injury.

PMID- 12480957
TI  - Enzyme replacement therapy in Anderson-Fabry's disease: beneficial clinical
      effect on vital organ function.
AB  - Two recent randomized trials pointed out the beneficial effect of enzyme
      replacement therapy on biochemical parameters in patients with Anderson-Fabry's
      disease. Clinical end-points, such as amelioration or stabilization of renal
      function deterioration, or improvement of left ventricular hypertrophy have not
      been evaluated in depth. We report the case of a patient whose moderately
      impaired renal function was stabilized with the start of enzyme treatment. In
      addition, left ventricular hypertrophy tended to regress. To our knowledge this
      is the first observation of clinical efficacy of the enzyme replacement therapy
      in Anderson-Fabry's disease in patients with moderately impaired renal function.

PMID- 12480958
TI  - Polymeric IgA increases the synthesis of macrophage migration inhibitory factor
      by human mesangial cells in IgA nephropathy.
AB  - BACKGROUND: It has been suggested that polymeric IgA (pIgA) or IgA immune
      complexes play a significant pathogenic role in IgA nephropathy (IgAN).
      Macrophage migration inhibitory factor (MIF) shares many activities with other
      pro-inflammatory cytokines. In human glomerulonephritis, including IgAN,
      glomerular expression of MIF is found to correlate with progressive renal injury.
      We hypothesized that deposition of pIgA within the kidney may lead to enhanced
      synthesis of MIF by mesangial cells. METHODS: In this study we examined the
      effect of pIgA and monomeric IgA (mIgA) from randomly selected patients with IgAN
      in clinical quiescence on the gene expression and protein synthesis of MIF in
      cultured human mesangial cells (HMC). RESULTS: Both pIgA and mIgA from IgAN
      patients or matched healthy controls increased MIF gene expression and protein
      synthesis in a dose-dependent fashion. The magnitude of MIF protein induction by
      pIgA (100 microg/ml) was similar to that of tumour necrosis factor-alpha (TNF
      alpha) at 10 pg/ml. In all subjects, the induction of MIF was higher for pIgA
      when compared with mIgA (P < 0.01). Furthermore, the up-regulation of MIF
      synthesis by either pIgA or mIgA was significantly higher in IgAN patients than
      in healthy controls (P < 0.05). Similarly, pIgA and mIgA were able to induce TNF
      alpha gene expression and protein synthesis in mesangial cells. Incubation of
      mesangial cells with neutralizing antibody to TNF-alpha reduced the MIF synthesis
      induced by pIgA. CONCLUSION: We demonstrate that pIgA is capable of inducing MIF
      and TNF-alpha production in HMC, which may play a major pathogenic role in IgAN.
      Induction of MIF can be partially blocked by neutralizing antibody to TNF-alpha,
      suggesting the possibility that up-regulation of MIF synthesis in HMC is mediated
      via an amplifying proinflammatory loop involving TNF-alpha.

PMID- 12480959
TI  - Cellular uptake of beta2M and AGE-beta2M in synovial fibroblasts and macrophages.
AB  - BACKGROUND: Beta-2-microglobulin (beta(2)M) amyloidosis is a destructive
      articular disease affecting dialysis patients. The amyloid deposits contain both
      beta(2)M and beta(2)M altered with advanced glycation end products (AGE
      beta(2)M). We have shown that beta(2)M increases the expression of matrix
      metalloproteinase-1, vascular cell adhesion molecule-1 and cyclooxygenase-2 in
      human synovial fibroblasts, while the effect of AGE-beta(2)M in this model is
      markedly reduced. Conversely, in human monocyte/macrophages, AGE-beta(2)M
      stimulates cytokine release whereas beta(2)M is less potent. METHODS: To
      understand why the two forms of beta(2)M produce variable responses in different
      cells, AGE-beta(2)M was labelled with the fluorochrome Cy5, and beta(2)M was
      labelled with the fluorochrome Texas Red (TR) and the uptake of 50 microg/ml of
      each was examined through live cell imaging at different time points using
      confocal microscopy. RESULTS: In human synovial fibroblasts, the AGE-beta(2)M-Cy5
      could be seen in endosome-like structures inside cells by 45 min. After 3.5 h the
      distribution of endosome-like structures had become perinuclear in nature and the
      concentration of AGE-beta(2)M-Cy5 within these structures had increased. When a
      20-fold excess of AGE-BSA was added to the synovial fibroblasts with the AGE
      beta(2)M-Cy5, the endosome-like particles were not seen, suggesting competitive
      inhibition of uptake through an AGE-receptor. In contrast, beta(2)M-TR
      progressively concentrated along the surface of synovial fibroblasts with minimal
      cellular uptake indicated by faint endosome-like structures seen only after 8 h.
      Interestingly, in a different model, human and mouse monocyte/macrophages, the
      AGE-beta(2)M-Cy5 and beta(2)M-TR had similar patterns of distribution and
      kinetics of uptake. CONCLUSION: Our results suggest that beta(2)M and AGE
      beta(2)M are endocytosed via different mechanisms in human synovial fibroblasts
      and monocytes/macrophages. These results may offer a potential explanation of
      differences observed in cell culture experiments.

PMID- 12480960
TI  - Estradiol is nephroprotective in the rat remnant kidney.
AB  - BACKGROUND: Female sex hormones may influence the progression of renal diseases.
      We therefore evaluated the effects of estradiol on the development of
      glomerulosclerosis in a remnant kidney model. METHODS: Ovariectomized or intact
      female Wistar rats underwent 5/6 nephrectomy. Ovariectomized animals were treated
      with vehicle, 17beta-estradiol alone or in combination with progesterone, intact
      rats received vehicle only. Twenty-four weeks after renal ablation, histological
      as well as molecular analysis were performed. RESULTS: Vehicle-treated
      ovariectomized animals developed severe proteinuria and glomerulosclerosis as
      compared with vehicle-treated intact rats. In addition, renal mRNA levels of
      platelet-derived growth factor-A chain (PDGF-A) were increased. Estradiol
      replacement reduced proteinuria, which was paralleled by a diminished glomerular
      injury and reduced transforming growth factor-beta1 (TGF-beta1) and PDGF-A mRNA
      expression. In animals that received combined hormone treatment there were no
      significant differences in proteinuria, creatinine clearance, renal
      histopathology and growth factor mRNA levels compared with those measured in
      vehicle-treated ovariectomized rats. Serum cholesterol and triglyceride levels
      were comparable between all groups during the whole follow-up period.
      CONCLUSIONS: The data suggest that estrogens protect against the development of
      glomerulosclerosis in the rat remnant kidney model.

PMID- 12480961
TI  - Combination treatment with an ET(A)-receptor blocker and an ACE inhibitor is not
      superior to the respective monotherapies in attenuating chronic transplant
      vasculopathy in different aorta allotransplantation rat models.
AB  - BACKGROUND: The effect of the specific endothelin (A) (ET(A))-receptor antagonist
      LU 302146 (LU) was assessed in a normotensive model of chronic transplant
      vasculopathy, i.e. orthotopic allotransplantation of the infrarenal abdominal
      aorta from spontaneously hypertensive-to-Wistar-Kyoto (SHR-to-WKY) rats. A second
      experimental setting was used to confirm the results in a different model, which
      to some extent may also address the issue of blood pressure (BP) in transplant
      vasculopathy, i.e. orthotopic allotransplantation of infrarenal abdominal aorta
      from WKY-to-SHR rats. Untreated sham-operated and isografted WKY and SHR served
      as controls. Allotransplanted animals treated with the angiotensin-converting
      enzyme (ACE) inhibitor trandolapril served as positive treatment controls.
      METHODS: Rats were randomized to receive standard diet or a diet designed to
      deliver either 30 mg LU/kg bw/day, 0.3 mg/kg bw/day trandolapril or a combination
      of both. The duration of either experiment was 8 weeks. BP was measured by tail
      plethysmography. RESULTS: Treatment with LU did not affect systolic BP in either
      experimental setting. In contrast, trandolapril and combination treatment
      significantly reduced systolic BP in SHRs. The increase in aortic wall thickness
      (given in mm) was abrogated to a similar extent in the three treatment groups as
      compared with untreated allotransplanted animals in either experimental setting
      (e.g. WKY sham-operated 0.084 +/- 0.013, P < 0.05 vs treatment groups; WKY
      isotransplanted 0.100 +/- 0.010, P < 0.05 vs treatment groups; WKY
      allotransplanted 0.289 +/- 0.077, P < 0.05 vs all groups; WKY allotransplanted +
      trandolapril 0.185 +/- 0.025; WKY allotransplanted + LU 301246 0.192 +/- 0.049;
      WKY allotransplanted + LU 301246 + trandolapril 0.190 +/- 0.041). This was due to
      an attenuation of the increase of intima and media thickness. Treatment with LU
      and trandolapril were similarly effective in attenuating the increase of the
      number of proliferating cell nuclear antigen (PCNA)-positive cells in the intima.
      Again, combination treatment did not confer additional benefit. In contrast,
      trandolapril was more effective than LU in attenuating the increase in the number
      of PCNA-positive cells in the media. Trandolapril or combination treatment, but
      not LU, attenuated transforming growth factor-beta expression in aortic
      allografts. CONCLUSIONS: The ET(A)-receptor blockade abrogates allograft
      vasculopathy in two different aorta allotransplantation models to a similar
      extent as ACE inhibition even in the absence of concomitant immunosuppression. At
      least in SHRs the effect of ET(A)-receptor blockade is independent of BP. This
      finding is consistent with the notion that ET(A)-receptor mediated events play a
      partly BP-independent role in the genesis of chronic transplant vasculopathy.

PMID- 12480963
TI  - Prediction of acute renal failure after cardiac surgery: retrospective cross
      validation of a clinical algorithm.
AB  - BACKGROUND: Acute renal failure (ARF) after cardiac surgery is associated with
      high costs and a poor prognosis. Based on the results of a large US study, an
      algorithm has been developed for predicting ARF from pre-operative risk factors.
      The aim of this study was to cross-validate this algorithm in a patient
      population from Europe, and to assess its usefulness as a clinical tool. METHODS:
      All coronary bypass and valvular surgery patients from a 5-year period were
      included. Data on pre-operative risk factors for all patients who developed
      dialysis-dependent ARF and for a random sample of patients without ARF were
      retrospectively obtained from hospital databases and medical records. For each
      patient, a risk score for ARF was calculated on the basis of the algorithm. The
      sensitivity, specificity, positive and negative predictive values and area under
      receiver operating characteristic (ROC) curve of the score's ability to predict
      ARF were estimated. RESULTS: 2037 patients were included. The risk of ARF was
      1.9%, and the area under the ROC curve 0.71. For a risk score of 6 or higher, the
      sensitivity was 0.53, the specificity 0.71, the positive predictive value 0.03
      and the negative predictive value 0.99. CONCLUSIONS: The validity of the
      algorithm was confirmed in a population differing in several aspects from the US
      populations where it was developed. Although it is useful for estimating the risk
      of ARF in groups of patients, the low risk of ARF limits the algorithm's ability
      to predict the outcome for individual patients.

PMID- 12480962
TI  - Altered ultrastructural distribution of nephrin in minimal change nephrotic
      syndrome.
AB  - BACKGROUND: Nephrin is a cell-adhesion protein that is defective in congenital
      nephrotic syndrome of the Finnish type (CNF). Nephrin is synthesized by the
      podocytes and is localized to the slit membrane between individual foot processes
      of the podocytes. Although nephrin is apparently pivotal in the development of
      CNF, the role of nephrin in other causes of nephrotic syndrome is not fully
      understood. METHODS: Renal biopsy specimens from patients with minimal change
      nephrotic syndrome (MCNS) were investigated. Nephrin distribution was studied
      with immunohistochemical and semiquantitative immunoelectron microscopic
      techniques and the results were related to the degree of foot process effacement
      found under the electron microscope. RESULTS: In normal kidney,
      immunofluorescence revealed a linear staining along the capillary basement
      membranes, corresponding to the localization of nephrin in the slit membranes. In
      the biopsies from patients with MCNS, the nephrin pattern had become granular.
      The degree of granularization corresponded to the degree of foot process
      effacement. Ultrastructural semiquantification showed the amount of nephrin to be
      reduced both in areas with and without foot process effacement compared with the
      control specimens. The concentration of nephrin was lowest in the areas with foot
      process effacement and there was redistribution from the slits into the
      cytoplasm. CONCLUSIONS: These findings demonstrate that nephrin expression is
      altered in MCNS. Whether this reflects a pathogenetic role for nephrin in MCNS or
      a phenomenon secondary to other causes of foot process effacement remains to be
      elucidated.

PMID- 12480964
TI  - Socio-economic status and chronic renal failure: a population-based case-control
      study in Sweden.
AB  - BACKGROUND: Low socio-economic status is associated with the occurrence of
      several different chronic diseases, but evidence regarding renal disease is
      scant. To explore whether the risk of chronic renal failure varies by socio
      economic status, we performed a population-based case-control study in Sweden.
      METHODS: All native residents from May 1996 to May 1998, aged 18-74 years, formed
      the source population. Cases (n = 926) were incident patients with chronic renal
      failure in a pre-uraemic stage. Control subjects (n = 998) were randomly selected
      within the source population. Exposures were assessed at personal interviews and
      relative risks were estimated by odds ratios (OR) in logistic regression models,
      with adjustment for age, sex, body mass index (BMI), smoking, alcohol consumption
      and regular analgesics use. RESULTS: In families with unskilled workers only, the
      risk of chronic renal failure was increased by 110% [OR = 2.1; 95% confidence
      interval (CI), 1.1-4.0] and 60% (OR = 1.6; 95% CI, 1.0-2.6) among women and men,
      respectively, relative to subjects living in families in which at least one
      member was a professional. Subjects with 9 years or less of schooling had a 30%
      (OR = 1.3; 95% CI, 1.0-1.7) higher risk compared with those with a university
      education. The excess risk was of similar magnitude regardless of underlying
      renal disease. CONCLUSIONS: Low socio-economic status is associated with an
      increased risk of chronic renal failure. The moderate excess was not explained by
      age, sex, BMI, smoking, alcohol or analgesic intake. Thus, socio-economic status
      appears to be an independent risk indicator for chronic renal failure in Sweden.

PMID- 12480965
TI  - PRE-dialysis survey on anaemia management.
AB  - BACKGROUND: The PRE-dialysis survey on anaemia management (PRESAM) was designed
      to assess the care given to pre-dialysis patients in the 12 months before
      haemodialysis or peritoneal dialysis, with emphasis on anaemia management.
      METHODS: For this epidemiological study, a retrospective chart review was
      conducted for patients who started haemodialysis or peritoneal dialysis between 1
      August, 1999 and 6 April, 2000. All adult patients who entered one of the 779
      participating centres in 21 European countries, Israel or South Africa were
      included, except for patients who underwent dialysis only during an acute
      episode. In addition to demographic characteristics, the study examined the
      prevalence of anaemia, anaemia management including the use of iron
      supplementation and epoetin, source of referral to the dialysis centre,
      comorbidities and major clinical events. RESULTS: A total of 4333 new dialysis
      patients were included in the survey. At the first visit to the dialysis centre,
      68% of the patients had a haemoglobin (Hb) concentration < or = 11.0 g/dl; Hb
      concentration was positively correlated with creatinine clearance rate (r = 0.43,
      P < 0.01). Patients who received epoetin had a mean Hb concentration of 8.8 g/dl
      at the start of epoetin treatment, and 96% of these patients had an Hb
      concentration < or = 11.0 g/dl. Only 26.5% of the patients received epoetin
      before dialysis. The length of time under the care of a nephrologist was
      associated with meeting the European Best Practice Guidelines (EBPG) target Hb
      concentration, as well as receiving epoetin. CONCLUSIONS: Few pre-dialysis
      patients met the EBPG target for Hb concentration, despite regular nephrology
      care.

PMID- 12480966
TI  - Comparison of skinfold thicknesses and bioelectrical impedance analysis with dual
      energy X-ray absorptiometry for the assessment of body fat in patients on long
      term haemodialysis therapy.
AB  - BACKGROUND: Body composition assessment in patients with chronic renal failure is
      of paramount importance since studies have demonstrated the association of
      protein-energy malnutrition with an increased morbidity and mortality in this
      population. However, practical and sensible indicators of body compartments are
      still needed for clinical purposes. Thus, we aimed to evaluate the simple methods
      of skinfold thicknesses (SKF) and bioelectrical impedance analysis (BIA), using
      dual-energy X-ray absorptiometry (DEXA) as a reference method, for the assessment
      of body fat in patients on long-term haemodialysis therapy. METHODS: We studied
      30 clinically stable patients (15 men/15 women) undergoing haemodialysis at the
      Dialysis Unit of the Federal University of Sao Paulo. Body fat assessment was
      performed by the SKF, BIA and DEXA methods after a haemodialysis session.
      Analysis of variance, intra-class correlation coefficient and Bland and Altman
      plot analysis were used for comparative analysis among the methods. RESULTS: Body
      fat estimates by SKF (17.7 +/- 7.8 kg) and BIA (18.6 +/- 9.2 kg) were not
      significantly different from those obtained by DEXA (18.2 +/- 7.9 kg) considering
      the whole population. However, the BIA technique worked differently from DEXA
      when analysed by gender, measuring less fat content in men and higher fat content
      in women (P < 0.01). No differences were observed for SKF. Strong intra-class
      correlation coefficients (r) were found between DEXA with SKF (r = 0.94) and BIA
      (r = 0.91). DEXA showed a relatively good agreement with both SKF [0.47 +/- 2.8 (
      5.0 to 6.0) kg] and BIA [-0.39 +/- 3.3 (-6.9 to 6.1) kg] in all patients
      according to the Bland and Altman plot analysis. However, considering gender, BIA
      showed greater mean prediction error of 1.93 +/- 2.5 (-3.0 to 6.8) kg for men and
      -2.71 +/- 2.3 (-7.2 to 1.8) kg for women. CONCLUSIONS: The simple and long
      established method of SKF was preferable over BIA, which showed gender-specific
      variability in the assessment of body fat in patients undergoing haemodialysis.
      However, more comparative and longitudinal studies are needed to evaluate the
      applicability of these practical methods for monitoring body composition in the
      routine care of patients with chronic renal failure.

PMID- 12480967
TI  - Homocysteine, C-reactive protein, lipid peroxidation and mortality in
      haemodialysis patients.
AB  - BACKGROUND: Cardiovascular disease (CVD) is common in haemodialysis patients with
      chronic renal insufficiency and is the leading cause of death. The accelerated
      state of atherosclerosis found in these patients is due to a combination of
      different mechanisms. Recent studies confirm that inflammation plays an important
      role in the development of atherosclerosis. However, the role of
      hyperhomocysteinaemia and the immune response to oxidation of low-density
      lipoproteins (LDL) remains unclear and studies show contradictory results. The
      objective of this study was to determine whether there is a relationship between
      inflammation, hyperhomocysteinaemia and oxidative stress and whether these CVD
      risk factors are predictors of mortality in haemodialysis patients. METHODS: A
      prospective follow-up study was carried out in 94 stable, chronic haemodialysis
      patients for 24 months (July 1999-July 2001). All the patients were given folic
      acid and vitamin B complex supplements. Homocysteine was determined by
      fluorescence polarization immunoassay. C-reactive protein (CRP) levels were
      determined by chemiluminescent enzyme-labelled immunometric assay. Plasma copper
      oxidized anti-LDL (oxLDL) antibodies were measured by ELISA using native LDL and
      oxLDL as antigens. RESULTS: Thirty-two patients died during the study and 59.3%
      of the deaths could be attributed to CVD (eight to acute myocardial infarction
      and 11 to non-coronary vascular disease). The patients had slight
      hyperhomocysteinaemia (25.8 +/- 7.82 micromol/l), evidence of inflammation (CRP
      5.16 mg/l (0.35-88.7)) and oxidative stress (oxLDL antibodies = 162 +/- 77
      optical density at 495 nm x 1000). Age (P < 0.01), CRP (P = 0.03) and the oxLDL
      antibody titre (P < 0.01) were predictive of mortality. The patients who died
      from heart disease showed higher oxLDL antibody titres (P = 0.03). No correlation
      was found between homocysteine, CRP and the oxLDL antibody titre, or between
      serum homocysteine levels and the different causes of mortality. CONCLUSIONS:
      These results suggest that lipid peroxidation and inflammation, but not
      hyperhomocysteinaemia, are the main risk factors for mortality in haemodialysis
      patients receiving vitamin supplements. As the study was carried out in a
      relatively limited number of patients, our findings need to be confirmed in a
      larger patient population.

PMID- 12480968
TI  - Carotid atherosclerosis is associated with inflammation and endothelial cell
      adhesion molecules in chronic haemodialysis patients.
AB  - BACKGROUND: Recently emerging evidence suggests that endothelial adhesion
      molecules may participate in atherogenesis. The aim of the present report was to
      investigate the probable association of circulating ICAM-1, VCAM-1 and E-selectin
      with atherosclerotic disease in chronic haemodialysis (HD) patients. METHODS: One
      hundred and twelve HD patients and 50 age- and sex-matched healthy normotensive
      controls participated in the study. Atherosclerotic disease in both groups was
      assessed by measuring intima-media thickness (IMT) and plaque score of the common
      carotid arteries using an ultrasound scanner. In addition, in a follow-up study,
      the survival of 81 patients after a mean period of 26 months was analysed in
      relation to ICAM-1 and VCAM-1 levels. RESULTS: IMT and plaque score were
      significantly higher in HD patients compared with control subjects (P < 0.001 and
      P < 0.0001, respectively). The above ultrasonographic indices were correlated
      with age both in controls (P = 0.0001 and P = 0.002, respectively) and HD
      patients (P = 0.0001 and P = 0.0001, respectively). A significant relationship
      was observed between IMT and systolic blood pressure (BP) both in controls and in
      HD patients (P = 0.002 and P = 0.01, respectively). In HD patients, plaque score
      was also correlated with systolic BP (P = 0.02). In HD patients, IMT and plaque
      score were correlated significantly with log CRP values (P = 0.01 and P = 0.01,
      respectively). Multivariate analysis showed that log CRP values were a strong
      independent contributor to plaque score (P = 0.01). IMT was significantly
      correlated with ICAM-1 and VCAM-1 concentrations (P = 0.0001 and P = 0.003,
      respectively). Multivariate analysis showed that ICAM-1 concentrations were a
      strong independent correlate of IMT (P = 0.001). E-selectin concentrations did
      not show any relation with IMT or plaque score. During the follow-up period, 13
      of the 81 patients died. Survival analyses showed that patients with increased
      ICAM-1 had a shorter survival than patients with normal ICAM-1 values and that
      serum ICAM-1 levels were a strong predictor of death. CONCLUSIONS: In HD
      patients, carotid atherosclerosis is associated with inflammation and circulating
      levels of soluble adhesion molecules ICAM-1 and VCAM-1. The correlations between
      serum ICAM-1 and IMT and ICAM-1 and survival may indicate that this molecule
      could be a marker of a process that contributes to the high mortality of HD
      patients.

PMID- 12480969
TI  - Intoxication by star fruit (Averrhoa carambola) in 32 uraemic patients: treatment
      and outcome.
AB  - BACKGROUND: Clinical symptoms and outcomes of uraemic patients ingesting star
      fruit are quite variable and may progress to death. The purpose of the present
      report was to discuss the neurotoxic effects of star fruit intoxication in
      uraemic patients and to present the efficacy of different therapeutic approaches.
      METHODS: We studied a total of 32 uraemic patients who had ingested star fruit.
      Before the intoxication episodes, 20 patients were on regular haemodialysis,
      eight were on peritoneal dialysis and four were not yet undergoing dialysis. Two
      patients were analysed retrospectively from their charts, 17 were directly
      monitored by our clinic and 13 were referred by physicians from many areas
      throughout the country, allowing us to follow their outcome from a distance.
      Intoxicated patients were given different therapeutic approaches (haemodialysis,
      peritoneal dialysis and supportive treatment), and their outcomes were analysed.
      RESULTS: The most common symptoms were persistent and intractable hiccups in 30
      patients (93.75%), vomiting in 22 (68.7%), variable degrees of disturbed
      consciousness (mental confusion, psychomotor agitation) in 21 (65.6%), decreased
      muscle power, limb numbness, paresis, insomnia and paresthesias in 13 (40.6%) and
      seizures in seven (21.8%). Patients who were promptly treated with haemodialysis,
      including those with severe intoxication, recovered without sequelae. Patients
      with severe intoxication who were not treated or treated with peritoneal dialysis
      did not survive. CONCLUSIONS: Haemodialysis, especially on a daily basis, is the
      ideal treatment for star fruit intoxication. In severe cases, continuous methods
      of replacement therapy may provide a superior initial procedure, since rebound
      effects are a common event. Peritoneal dialysis is of no use as a treatment,
      especially when consciousness disorders ensue.

PMID- 12480970
TI  - Quality of sleep and health-related quality of life in haemodialysis patients.
AB  - BACKGROUND: Sleep complaints are common in haemodialysis patients. In the general
      population, insomnia impacts negatively on health-related quality of life
      (HRQoL). The objective of this study was to examine the association between
      quality of sleep and HRQoL in haemodialysis patients independent of known
      predictors of HRQoL. METHODS: Quality of sleep was measured using the Pittsburgh
      Sleep Quality Index (PSQI) and HRQoL was measured using the Medical Outcomes
      Study 36-item Short Form (SF-36) in 89 haemodialysis patients. RESULTS: Sixty
      three (71%) subjects were 'poor sleepers' (global PSQI >5). The SF-36 mental
      component summary (MCS) and physical component summary (PCS) correlated inversely
      with the global PSQI score (MCS, r = -0.28, P < 0.01; PCS, r = -0.45, P < 0.01).
      The PCS score also correlated with age (r = -0.24, P = 0.02), haemoglobin (r =
      0.21, P = 0.048) and comorbidity (r = -0.40, P < 0.01), and mean PCS was lower in
      depressed subjects (26.2 vs 35.9, P = 0.02). Subjects with global PSQI >5 had a
      higher prevalence of depression, lower haemoglobin and lower HRQoL in all SF-36
      domains. The global PSQI score was a significant independent predictor of the MCS
      and PCS after controlling for age, sex, haemoglobin, serum albumin, comorbidity
      and depression in multivariate analysis. CONCLUSIONS: Poor sleep is common in
      dialysis patients and is associated with lower HRQoL. We hypothesize that end
      stage renal disease directly influences quality of sleep, which in turn impacts
      on HRQoL.

PMID- 12480972
TI  - The effect of correction of anaemia in diabetics and non-diabetics with severe
      resistant congestive heart failure and chronic renal failure by subcutaneous
      erythropoietin and intravenous iron.
AB  - BACKGROUND: A mild anaemia is often found in patients with congestive heart
      failure (CHF), but its significance is uncertain. In an open uncontrolled study
      we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5-11.5
      g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron
      (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to
      severe CHF which was resistant to maximally tolerated doses of standard CHF
      medications. METHODS: Epo, s.c., was given every 1-3 weeks to achieve and
      maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary
      to maintain the Fe stores. Duration of treatment was 11.8 + 8.2 months. RESULTS:
      With the Epo-Fe treatment the Hb increased from 10.41 +/- 1.0 to 13.1 +/- 1.3 g%
      in diabetics and from 10.5 +/- 1.0 to 12.9 +/- 1.2 g% in non-diabetics. Comparing
      the diabetics and non-diabetics, the New York Heart Association functional class
      improved by 34.8 and 32.4%, respectively. breathlessness and/or fatigue, as
      measured by a self-administered Visual Analogue Scale, improved by 69.7 and
      67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%,
      respectively. The number of hospitalizations fell by 96.4 and 95.3%,
      respectively, compared with the pre-treatment period. Although the glomerular
      filtration rate (GFR) was falling at a rate of approximately 1 ml/min/month
      before the study in both groups, neither the mean serum creatinine nor the GFR
      changed significantly during the study period. The mean dose of Epo needed,
      measured in IU/week/kg body weight, was similar in the two groups. CONCLUSION:
      The correction of the mild anaemia that was found in diabetics and non-diabetics
      with resistant CHF and mild to moderate chronic renal failure improved the
      cardiac function and patient functional status, stabilized the renal function and
      markedly reduced the need for hospitalization.

PMID- 12480971
TI  - Poor response to recombinant erythropoietin is associated with loss of T
      lymphocyte CD28 expression and altered interleukin-10 production.
AB  - BACKGROUND: Recombinant erythropoietin (Epo) therapy is well established as an
      effective treatment for the anaemia of end-stage renal disease. However, 5-10% of
      such patients do not respond adequately and an important contributory factor to
      this is chronic inflammation. METHODS: The present study compares the circulating
      T-cell phenotypes of haemodialysis patients who respond poorly to Epo with those
      who respond well, along with normal controls. Isolated peripheral blood
      mononuclear cells were labelled with immunofluorescent monoclonal antibodies to
      surface antigens and analysed by flow cytometry. In vitro mononuclear cell
      cytokine secretion was also studied in the three subject groups. The cells were
      cultured for 48 h either without stimulus, with lipopolysaccharide or with
      monoclonal antibodies to CD3 and CD28. RESULTS: C-reactive protein levels were
      increased in poor responders to Epo (18.6 +/- 20.7 mg/l) compared with good
      responders (8.7 +/- 8.0 mg/l) and normal controls (3.8 +/- 1.1 mg/l). Patients
      responding poorly to Epo had increased circulating levels of CD4+/CD28- and
      CD8+/CD28- T-cells compared with patients responding well to Epo and normal
      controls. Unstimulated mononuclear cells from poor responders showed increased in
      vitro generation of interleukin-10 (IL-10) compared with both patients responding
      well to Epo and normal controls. Additionally, IL-10 generation stimulated by
      monoclonal antibodies to CD3 and CD28 was increased in poor responders compared
      with normal controls. CONCLUSIONS: These findings suggest that patients
      responding poorly to Epo may show enhanced immune activation as manifest by
      changes in both T-cell function and phenotype.

PMID- 12480973
TI  - Regional variability in anaemia management and haemoglobin in the US.
AB  - BACKGROUND: Regional differences in haemoglobin values and process care measures
      were examined using data from the Centers for Medicare & Medicaid Services' End
      Stage Renal Disease (ESRD) Clinical Performance Measures Project. It was posited
      that regional differences in haemoglobin values are consequent upon differences
      in components of clinical practice. METHODS: A national random sample of 8336
      adult, in-centre haemodialysis patients, stratified by the 18 regional ESRD
      Networks, was drawn. Information was collected for October-December 1998.
      Multivariable stepwise linear and logistic regression analyses were performed to
      identify variables associated with haemoglobin. Linear regression analysis was
      used to identify variables associated with Epo/Hb index (mean weight-adjusted
      treatment level erythropoietin (Epo) dose divided by mean haemoglobin). RESULTS:
      The percentage of patients with haemoglobin concentration < 11 g/dl ranged from
      34 to 52% across ESRD Networks. In addition to haemoglobin there was significant,
      non-random variation among ESRD Networks with regard to prescribed Epo dose and
      administration route, intravenous (IV) iron prescription and dialyser flux (high
      flux = KUf > or = 20 ml/mmHg/h) (all P-values < 0.001). Higher haemoglobin was
      associated with older age, male gender, higher serum albumin, higher transferrin
      saturation, higher Kt/V, lower serum ferritin and lower prescribed Epo dose (all
      P-values < 0.01). Diabetes mellitus as cause of ESRD, high-flux dialyser use, IV
      iron prescription or subcutaneous Epo prescription were not associated with
      haemoglobin. Male gender, diabetes as cause of ESRD, older age, higher
      transferrin saturation and higher albumin concentrations were associated with
      lower Epo/Hb index. Prescription of IV iron and IV Epo were associated with
      higher Epo/Hb index. CONCLUSIONS: Regional mean haemoglobin levels vary
      considerably across the US and the variation in haemoglobin is explained by both
      non-modifiable factors and modifiable clinical practice-derived variables.

PMID- 12480974
TI  - Increased plasma S-nitrosothiol levels in chronic haemodialysis patients.
AB  - BACKGROUND: An impairment of nitric oxide (NO) bioavailability and/or metabolism
      may contribute to the excessive incidence of atherosclerotic complications
      observed in haemodialysis (HD) patients. Recent evidence indicates that NO
      metabolism involves a family of NO-related molecules that have not yet been
      explored in such patients. The aim of our study was to determine the plasma
      levels of S-nitrosothiol and nitrotyrosine in chronic HD patients, and to
      evaluate potential factors influencing their levels. METHODS: Plasma levels of S
      nitrosothiols and nitrotyrosine were determined in 22 non-smoking HD patients and
      12 healthy control subjects, together with albumin, homocysteine, haemoglobin,
      highly sensitive C-reactive protein (hsCRP) and various components of the oxidant
      antioxidant system at the plasma and erythrocyte levels. RESULTS: While plasma
      nitrosothiol levels were significantly higher in HD patients than in controls
      (2.25 +/- 1.17 vs 0.45 +/- 0.45 micromol/l, respectively, P < 0.0001),
      nitrotyrosine levels were not different. HD patients also exhibited a marked
      deficit of ascorbate and low plasma glutathione peroxidase activity. An inverse
      relationship was found between plasma S-nitrosothiol and blood haemoglobin in HD
      patients (P < 0.005). No direct relationship was observed between plasma S
      nitrosothiol levels and any of the oxidative stress markers, or hsCRP levels.
      CONCLUSION: This study demonstrates high plasma S-nitrosothiol levels in HD
      patients, which are partially related to low blood haemoglobin concentrations.
      The pathophysiological significance of this elevation remains to be elucidated. A
      possible protective role against nitrosative stress is suggested in presence of
      normal plasma nitrotyrosine levels in such patients.

PMID- 12480975
TI  - Clinical relevance of immunohistochemical staining for ecto-AMPase and ecto
      ATPase in chronic allograft nephropathy (CAN).
AB  - INTRODUCTION: Chronic allograft nephropathy (CAN) is a major cause of
      deterioration of kidney function in transplanted patients. It is thought that
      glomerular ischaemia may contribute to glomerular dysfunction and proteinuria in
      these subjects. As reduced expression of glomerular ecto-ATPase concurrent with
      upregulation of glomerular ecto-AMPase activity is associated with local
      ischaemia, we compared the expression of these glomerular ecto-enzymes in kidney
      biopsies from subjects with CAN or with acute rejection vs normal human kidney
      tissue. METHODS: Kidney biopsies in comparison with normal kidney tissue samples
      (n = 10) were studied from subjects with CAN (n = 6), acute interstitial
      rejection (n = 13), acute vascular rejection (n = 3), or subjects whose biopsies
      were histologically difficult to classify (n = 8). Cryostat sections (4 micro m)
      were stained for ecto-ATPase using standard procedures. For the demonstration of
      ecto-AMPase activity, conventional enzyme histochemistry was used. Reaction
      product of individual sections was quantified using computerized image analysis.
      RESULTS: The results clearly show decreased expression of glomerular ecto-ATPase
      in combination with increased glomerular ecto-AMPase in all biopsies from
      subjects with CAN vs normal kidney tissue (P < 0.001). Although to a lesser
      extent, this staining pattern was also observed in patients with vascular
      rejection as well as in subjects whose biopsies were histologically difficult to
      classify (P < 0.01), while biopsies from subjects with interstitial rejection and
      normal control tissue stained negative for glomerular ecto-AMPase. CONCLUSION: In
      CAN diminished glomerular ecto-ATPase expression occurs in association with
      significantly enhanced activity of glomerular ecto-AMPase. This is a strong
      indication for ischaemic injury of the glomerular microvasculature. As positive
      staining for ecto-AMPase in acute rejection episodes may be an important sign for
      long-term prognosis, we feel that screening of biopsies from individual subjects
      for glomerular ecto-AMPase activity should be considered.

PMID- 12480976
TI  - Post-transplant hyperglycaemia: a study of risk factors.
AB  - BACKGROUND: Post-transplant diabetes mellitus (PTDM) has several identifiable pre
      and post-transplant risk factors. The link to nutritional status pre-transplant
      has not been explored previously. This study was conducted to identify risk
      factors for the development of PTDM, with emphasis on pre-transplant nutritional
      status and glucose tolerance. METHODS: Non-diabetic adult end-stage renal failure
      patients awaiting renal transplantation were studied prospectively. Their
      nutritional status was assessed as body mass index (BMI), serum albumin, and the
      evolution of these parameters over time prior to transplantation. An oral glucose
      tolerance test (OGTT) was performed pre- and serially post-transplant until 6
      months. Pre- and post-transplant risk factors such as age, nutritional status,
      glucose tolerance parameters and immunosuppression were related to the
      development of PTDM or impaired glucose tolerance (IGT) post-transplant. RESULTS:
      The mean age of 174 patients studied over a 2-year period was 32.9 +/- 9.7 years.
      The mean post-transplant follow-up was 25.6 +/- 12.8 months. The mean BMI at
      recruitment was 18.3 +/- 2.4 kg/m(2). The rate of increase in BMI pre-transplant
      showed an inverse correlation with the baseline BMI (r = -0.34, P = 0.000) and
      formed an independent marker of nutritional status. PTDM developed in 21.4%
      patients and 24.1% had IGT. On univariate and multivariate analyses, the factors
      significantly associated with the development of PTDM were greater age, more
      rapid increase in dry weight after starting haemodialysis (HD), elevated pre
      transplant OGTT responses and cyclosporin (CsA) and prednisolone doses early post
      transplant. Additionally, on multivariate analysis, higher CsA trough level > 300
      ng/ml at 3 months increased the risk for the development of PTDM. Of patients who
      developed PTDM, 57% had impairment of glucose tolerance pre-transplant (> 140
      mg/dl at 2 h). Patients with a 1-h glucose value greater than the 50th percentile
      on pre-transplant OGTT had a 3.9-fold greater risk for the development of PTDM (P
      = 0.05, 95% CI = 1.03-11.1). In those patients with higher 1-h glucose (> 50th
      percentile) who also gained in dry weight rapidly pre-transplant, the risk
      increased to 5.3 (P = 0.02). Of 76 patients with abnormal OGTT early post
      transplant, only 68% continued to have PTDM or IGT post-transplant, the remainder
      reverting to normal glucose tolerance. CONCLUSIONS: Persistent abnormal glucose
      tolerance after transplantation was seen in 45% of the patients. Pre-transplant
      factors including greater age, abnormal glucose tolerance parameters, and rapid
      gain in dry weight on HD, along with higher prednisolone and CsA doses early post
      transplant were the important factors associated with the development of PTDM.
      Identification of patients with pre-transplant risks might allow modification of
      post-transplant immunosuppression with non-diabetogenic agents.

PMID- 12480977
TI  - Dialysis prior to living donor kidney transplantation and rates of acute
      rejection.
AB  - BACKGROUND: The relationship between transplantation prior to chronic dialysis
      initiation and the pattern of acute rejection of kidneys from living donors
      (LDKT) has not been fully explored. METHODS: Using data provided by the United
      States Renal Data System, we performed a retrospective cohort study fitting
      multivariate proportional hazards models to characterize the association of
      chronic use of dialysis prior to transplantation [non-pre-emptive LDKT (non
      PLDKT)] and acute rejection, and to examine if this association varies throughout
      the first year. RESULTS: Non-PLDKT was associated with a 2.5-fold higher rate of
      biopsy-confirmed rejection during the first month [adjusted HR 2.5, 95%
      confidence interval (1.85-3.33)], compared with no dialysis prior to
      transplantation. Increasing duration of pre-transplant dialysis was associated
      with increasing rate of biopsy-confirmed acute rejection during the first month
      (P = 0.001 for trend). Over the first year, there was a diminishing relationship
      between non-PLDKT and acute rejection: 2.5-, 2.22-, 2.13- and 1.78-fold elevation
      in the episodes of biopsy-confirmed acute rejection during the first, second,
      third through to the sixth and seventh through to the twelfth month post
      transplant, respectively (P = 0.05 for trend). CONCLUSIONS: The waning of the
      association of non-PLDKT with acute rejection over time supports the hypothesis
      that dialysis exposure prior to transplantation may modulate the immune system to
      increase the rates of acute rejection.

PMID- 12480978
TI  - Heterogeneity of antigen expression explains controversy over glomerular
      macrophage accumulation in mouse glomerulonephritis.
AB  - BACKGROUND: Many antibody labelling studies have suggested that there are few or
      no glomerular macrophages in mouse models of glomerulonephritis, despite the
      presence of a prominent interstitial macrophage infiltrate. These findings
      conflict with studies of human and rat glomerulonephritis. Therefore, we examined
      whether heterogeneity of macrophage antigen expression could explain this
      apparent discrepancy. METHODS: Kidneys were collected from normal mice and mice
      killed at 2 and 10 days after induction of accelerated anti-glomerular basement
      membrane (GBM) glomerulonephritis. Following fixation, macrophages were detected
      by immunoperoxidase staining in serial kidney sections using antibodies
      recognising CD11b, F4/80 and CD68. RESULTS: Induction of anti-GBM nephritis
      caused a progressive increase in glomerular and interstitial leukocytes. At days
      2 and 10, there were more CD68+ macrophages in glomeruli than macrophages
      expressing CD11b or F4/80. At day 10, CD68+ macrophages accounted for almost all
      glomerular CD45+ total leukocytes. In contrast, CD11b+ and F4/80+ macrophages at
      day 10 accounted for only 65 and 13% of glomerular leukocytes, respectively.
      However, in the interstitium the number of macrophages expressing CD68, CD11b and
      F4/80 were not different. CONCLUSION: Antibody detection of mouse CD68 identifies
      all glomerular macrophages in mouse anti-GBM nephritis, indicating a similar
      infiltrate to that seen in human and rat anti-GBM nephritis. Our finding of
      substantial heterogeneity in glomerular macrophage antigen expression in this
      model suggests that previous studies of mouse glomerulonephritis may have
      underestimated glomerular macrophages and their role in glomerular injury.

PMID- 12480979
TI  - Clinical features and genetic analysis of a Chinese kindred with Fabry's disease.
AB  - BACKGROUND: Fabry's disease is an X-linked recessive inborn error of
      glycosphingolipid catabolism resulting from deficient activity of lysosomal
      enzyme alpha-galactosidase A causing occlusive microvascular diseases affecting
      the kidney, heart, peripheral nerves and brain. It is an uncommon disease in the
      Oriental population. METHODS AND RESULTS: We report a Chinese kindred of Fabry's
      disease and the relevant clinical features are discussed. The diagnosis of
      Fabry's disease was based on serum alpha-galactosidase A activity and typical
      histological features from renal biopsy in the index patient. Genetic analysis of
      two hemizygous male patients revealed a missense mutation predicting a leucine to
      proline substitution (L14P) in the alpha-galactosidase gene causing classical
      Fabry's disease in this family. This is a novel point mutation not described
      previously in the literature and the second report describing novel genetic
      mutations for Fabry's disease in Chinese patients. CONCLUSIONS: Fabry's disease
      is rare in Chinese patients but this diagnosis should be considered in patients
      with positive family history of kidney disease and relevant clinical features.

PMID- 12480980
TI  - Acute cytomegalovirus infection complicated by collapsing glomerulopathy.

PMID- 12480981
TI  - Infertility in adults with polycystic kidney disease.

PMID- 12480982
TI  - Diarrhea, nephrotic syndrome and hidradenitis suppurativa: an unusual case.

PMID- 12480983
TI  - Fatal necrotizing fasciitis due to Streptococcus pneumoniae after renal
      transplantation.

PMID- 12480984
TI  - Severe hyperkalaemia in association with diabetic ketoacidosis in a patient
      presenting with severe generalized muscle weakness.

PMID- 12480985
TI  - Life-threatening vascular complications of severe hyperphosphataemia.

PMID- 12480986
TI  - An uncommon genetic syndrome with acute renal failure in a 30-year-old diabetic
      patient.

PMID- 12480987
TI  - Not so acute renal failure with crystals in the urine.

PMID- 12480988
TI  - Amoxycillin, a rare but possible cause of crystalluria.

PMID- 12480989
TI  - Strontium and osteomalacia in renal failure patients.

PMID- 12480992
TI  - Is HIV infection a contraindication for kidney transplantation?

PMID- 12480993
TI  - Restless legs syndrome in maintenance haemodialysis patients.

PMID- 12480995
TI  - Acute renal and hepatic failure due to accidental percutaneous absorption of 1,2
      dichlorpropane contained in a commercial paint fixative.

PMID- 12480996
TI  - Carbamazepine poisoning: treatment with haemodialysis.

PMID- 12480997
TI  - Posterior fossa stroke during cardiopulmonary resuscitation secondary to
      haemodialysis arterio-venous fistula.

PMID- 12480998
TI  - C-reactive protein levels in dialysis patients are highly variable and strongly
      related to co-morbidity.

PMID- 12480999
TI  - Excess interdialytic sodium intake is not always dietary.

PMID- 12481000
TI  - Chylous ascites due to bile duct tumour in a patient receiving automated
      peritoneal dialysis.

PMID- 12481003
TI  - Loss of heterozygosity associated with uniparental disomy in breast carcinoma.
AB  - Loss of heterozygosity is commonly assumed to be due to deletion of the
      appropriate genomic region in one chromosome within a neoplastic cell but may be
      due to other mechanisms such as mitotic non-disjunction or somatic recombination
      leading to uniparental heterodisomy. We chose to study the genomic regions
      surrounding the p53 and RB1 tumor suppressor genes in breast carcinoma to
      evaluate the different mechanisms that could mediate loss of heterozygosity. A
      microsatellite analysis of polymorphic markers in 50 breast cancer samples showed
      loss of heterozygosity for at least 1 of the 10 markers analyzed in 50% of the
      tumors studied, and an overall 8.47% of the informative loci showed loss of
      heterozygosity. All of the cases with loss of heterozygosity were further
      analyzed for gene copy number of the tumor suppressor genes RB1 and p53 by
      fluorescence in situ hybridization of either tumor touch preparations or
      microdissected tumor nuclei with specific genomic probes. Surprisingly, all
      samples showed the presence of both copies of tumor suppressor genes, including
      4/50 cases showing loss of heterozygosity of tumor suppressor gene-spanning
      markers. One of the 4 cases showed loss of heterozygosity of markers spanning a
      distance of 6 cM over the RB1 gene, with normal copy numbers of the gene. Three
      other cases showed loss of heterozygosity of markers within the tumor suppressor
      gene (RBI or p53) and at least one other spanning marker. No cases showed a
      simultaneous reduction to homozygosity of markers both near the tumor suppressor
      gene and distal loci. We suggest that the presence of both copies of the tumor
      suppressor gene in the cases with loss of heterozygosity of spanning markers and
      internal markers for that tumor suppressor gene could be explained by somatic
      recombination resulting in uniparental disomy, but not mitotic nondisjunction or
      deletion. As the mechanism for physical deletion of a chromosome may be different
      from those mediating somatic recombination, study of this phenomenon may identify
      different pathways of genomic instability that may be of diagnostic or treatment
      significance in breast or other cancers, particularly in those treatments based
      upon DNA-altering agents.

PMID- 12481004
TI  - Invasive papillary carcinomas of the extrahepatic bile ducts: a clinicopathologic
      and immunohistochemical study of 13 cases.
AB  - Carcinomas of the extrahepatic bile ducts are uncommon neoplasms that are
      morphologically heterogeneous and associated with a poor prognosis. We have
      previously shown that the noninvasive and minimally invasive papillary carcinomas
      of the extrahepatic bile ducts behave as in situ carcinomas and are associated
      with a better prognosis. We reviewed the clinical records of 13 patients with
      invasive papillary carcinomas of the extrahepatic bile ducts and analyzed the
      microscopic features and selected immunohistochemical reactivity (p53, Mib-1, and
      Dpc4) that might correlate with patient survival. In addition, we present the
      updated SEER (Surveillance, Epidemiology, and End Results) data of the National
      Cancer Institute for the invasive extrahepatic bile duct carcinomas compiled from
      1975 to 1998. The 13 patients with papillary carcinoma had a male to female ratio
      of 1:1, and their ages ranged from 33 to 89 years. Painless jaundice and
      abdominal pain were the most common complaints. Five tumors were located in the
      distal portion, one in the mid portion, and six in the proximal portion of the
      common bile duct. One papillary carcinoma arose in the right hepatic duct. The
      Whipple procedure was performed in six patients, common bile duct resection in
      six, and right hepatic lobectomy in one. The cell phenotype of the papillary
      carcinomas was biliary in nine and intestinal in three. One tumor had both
      biliary and intestinal phenotypes. Four tumors dedifferentiated (two to
      undifferentiated small cell carcinomas, one to small [oat] cell carcinoma, and
      one to giant cell carcinoma). Two papillary carcinomas extended into the pancreas
      and three into the liver. Only one patient had lymph node metastases at
      presentation. Follow-up was available in 10 patients. Six patients died of
      disease from 2 weeks to 2 years and 1 month after surgery. Four patients are
      alive with no evidence of disease from 4 months to 8 years and 8 months after
      surgery. Of 174 invasive papillary carcinomas compiled by the SEER program, 71
      were confined to the ductal wall, and 61 had regional lymph node metastases.
      Papillary carcinomas confined to the ductal wall have better 10-year relative
      survival rates than adenocarcinomas limited to the wall (21% versus 12%).
      Likewise papillary carcinomas with lymph node metastasis have better prognosis
      than adenocarcinoma with nodal metastases (10-y survival rate of 12% versus 5%).
      Currently, the histologic type and the stage of the disease are the most
      important prognostic factors in these papillary carcinomas. Separation of
      invasive and noninvasive or minimally invasive papillary carcinoma is critical in
      estimating the patient outcome. Our findings suggest that there is no correlation
      between p53, Ki-67, and Dpc4 expression in these tumors and survival of the
      patients.

PMID- 12481005
TI  - Diagnostic sensitivity of bronchoalveolar lavage versus lung fine needle
      aspirate.
AB  - Bronchoalveolar lavage (BAL) and lung fine-needle aspirate (LFNA) are commonly
      performed as the first line of investigation for a myriad of pulmonary problems
      associated with abnormal imaging findings (mass, cavitary lesion, infiltrates,
      etc.). The relative sensitivities of these two procedures are not well
      established for cytologic diagnosis of lesions for any single disease event.
      Records were searched for single pulmonary disease events with closely timed BAL
      and LFNA, as defined by both procedures occurring within <or=8 days of each
      other. No samples with "unsatisfactory" diagnoses were considered for the
      analyses. Success of identifying malignancy and/or an infectious agent was
      recorded for both procedures. Between January 1989 and June 2000, 52 episodes of
      closely timed (65% within 3 d) BAL and LFNA procedures were identified in 45
      patients for a single disease event. The clinical scenarios as per the sample
      requisitions were as follows: consolidation/infiltrate (60%), mass/nodule (23%),
      cavitary lesion (5.7%), pneumonia (5.7%), or not specified (5.7%). For all cases
      examined (n = 52), in 18 (35%) of the episodes, LFNA uniquely identified either
      malignancy, 6/18 (12%), or infectious agents such as Aspergillus and acid-fast
      bacteria, 12/18 (23%), with a corresponding nondiagnostic BAL. In one episode
      with a clinical diagnosis of infiltrates, the BAL was positive for acid-fast
      bacteria, whereas the LFNA was negative. Chi-square analysis of the data revealed
      statistical significance with P <.0001 with 2 degrees of freedom, indicating LFNA
      to be a superior method for the diagnosis of pulmonary pathology over BAL. Based
      on our data, LFNA is the superior method for the cytologic diagnosis of pulmonary
      pathology amenable to cytologic examination.

PMID- 12481006
TI  - Mantle cell lymphoma with 8q24 chromosomal abnormalities: a report of 5 cases
      with blastoid features.
AB  - The t(11;14)(q13;q32) resulting in cyclin D1 overexpression is consistently
      present in mantle cell lymphoma. However secondary chromosomal aberrations are
      also extremely common. Of these, 8q24 abnormalities associated with the t(11;14)
      are rare. Over the course of 10 years at M.D. Anderson Cancer Center, we
      identified five cases of mantle cell lymphoma in which conventional cytogenetic
      analysis revealed complex karyotypes, including the t(11;14) and 8q24
      abnormalities: one with t(8;14)(q24;q32), one with t(2;8)(q13;q24), and three
      with add(8)(q24). We performed fluorescence in situ hybridization (FISH) studies
      on all cases. In the case with the t(8;14), IgH/myc fusion signals were
      identified, and in the case with the t(2;8), split c-myc signals were detected.
      In the three cases with add(8)(q24), one case had split c-myc signals and two
      cases had three copies of c-myc. Thus, the c-myc gene was involved in all cases.
      All five neoplasms had blastoid morphologic features, and four cases, including
      the cases with the t(8;14) and t(2;8), had leukemic involvement. We conclude that
      8q24 abnormalities involving the c-myc gene are uncommon secondary abnormalities
      that occur in a subset of mantle cell lymphomas. C-myc gene abnormalities are
      associated with blastoid cytologic features and also may be associated with
      leukemic involvement.

PMID- 12481007
TI  - Isolated bone marrow manifestation of HIV-associated Hodgkin lymphoma.
AB  - Human immunodeficiency virus-associated Hodgkin lymphoma frequently involves the
      bone marrow and is usually recognized at staging after Hodgkin lymphoma diagnosis
      on a lymph node or other tissue biopsies, but occasionally the marrow involvement
      is the only apparent manifestation of disease. In the latter setting, diagnosis
      can be problematic. From a total of 42 patients with newly diagnosed human
      immunodeficiency virus-associated Hodgkin lymphoma, 22 subjects had positive
      marrow involvement at diagnosis; 16 of them had additional substantial
      histological and/or clinical extramedullary Hodgkin lymphoma. In the remaining 6
      patients the bone marrow was the only site of disease at diagnosis. In all six
      cases, bone marrow biopsy revealed obvious lymphomatous involvement. Reed
      Sternberg cells were identified both morphologically and immunophenotypically in
      all cases. Spared marrow tissue consistently showed fibrosis. All patients were
      males with a median age of 35 years (range, 31-58 years). All presented with
      fever, blood cytopenias, and severe CD4+ lymphocyte depletion (median, 70
      cells/mm(3)). After diagnosis, all staging procedures were negative, and all
      patients were treated with chemotherapy. Median survival was 4 months (range, 2
      118 mo). Longer survival was achieved in the patients who completed chemotherapy
      regimens; three subjects, however, died shortly before the full completion of
      chemotherapy, two of them from Hodgkin lymphoma. Isolated bone marrow HIV
      associated Hodgkin lymphoma may be an underestimated condition in HIV-infected
      patients; in those individuals with unexplained fever and blood cytopenias, bone
      marrow biopsy should be performed with the aim of assessing for Hodgkin lymphoma,
      even in the absence of nodal and visceral lymphomatous involvement. A rapid
      diagnosis of isolated bone marrow HIV-associated Hodgkin lymphoma could expedite
      therapy.

PMID- 12481008
TI  - A comparison of CD10 to pCEA, MOC-31, and hepatocyte for the distinction of
      malignant tumors in the liver.
AB  - The distinction of hepatocellular carcinoma (HCC) from metastatic adenocarcinoma
      (MA) and cholangiocarcinoma (CC) in some cases requires the use of
      immunohistochemistry. CD10 has recently been suggested as a useful stain for HCC.
      We directly compared CD10 with other immunohistochemical markers, Hepatocyte,
      pCEA, and MOC31, that have previously shown to be useful for the distinction
      between tumors in the liver to help define the current panel of stains that most
      readily distinguishes HCC from CC and MA. One hundred previously well
      characterized tumors in the liver were evaluated and included 25 HCC, 15 CC, and
      60 MAs (15 each from breast, esophageal/gastric, pancreatic, and colorectal
      origin). Tumors were immunostained with the commercially available antibodies
      Hepatocyte, pCEA, MOC31, and CD10. CD10 stained 13 of 25 HCC and was rarely
      positive in MA and CC (3/75). Hepatocyte stained 24 of 25 HCC and was negative in
      all 75 MA and CC. pCEA stained 24 of 25 HCC and 71 of 75 MA and CC with the
      proper pattern of immunoreactivity, but the pattern of staining was difficult to
      interpret in several cases. MOC31 stained 1 of 25 HCC and 65 of 75 MA and CC.
      Hepatocyte was the most sensitive and specific single marker for HCC. CD10 is not
      a useful addition or substitution to the panel of Hepatocyte, MOC31, and pCEA.
      The combination of Hepatocyte, MOC31, and pCEA correctly classified 99 of 100
      tumors in this study and is our proposed panel of immunostains for the initial
      workup of malignant tumors in the liver.

PMID- 12481009
TI  - Diagnostic value of HMB-45 and anti-Melan A staining of sentinel lymph nodes with
      isolated positive cells.
AB  - Numerous immunohistochemical stains have been employed to detect metastatic
      melanoma in sentinel lymph node (SLN) biopsies. HMB-45 is considered by some as a
      specific tool to detect early metastatic melanoma (1). Occasionally, one or two
      isolated HMB-45-positive cells may cause complications in diagnostic
      interpretation. The goal of this study was to evaluate the reliability of HMB-45
      staining of SLNs with sparse isolated positive cells and to compare its staining
      with anti-Melan A antibody. HMB-45 and anti-Melan A antibody immunostaining was
      performed on (Group A) 15 histologically negative SLNs excised from patients with
      malignant melanoma (MM) and on (Group B) 15 histologically negative SLNs excised
      from patients with breast carcinoma (BC). None of the patients had clinical
      evidence of systemic metastasis at the time of SLN biopsy. Five cutaneous
      biopsies with changes of postinflammatory hyperpigmentation (PIHP) were also
      stained with both antibodies. HMB-45 staining was repeated in all Group B SLNs
      after blocking endogenous biotins. Electron-microscopic studies were performed on
      all cases of PIHP. Isolated HMB-45-stained cells were present in 6 of 15 SLNs
      removed for MM; 8 of 15 for BC; and 3 of 5 cutaneous biopsies of PIHP. HMB-45
      reactivity persisted after blocking endogenous biotins in 6 of 8 positive SLNs
      from Group B. Anti-Melan A antibody was negative in all SLNs of group A and B and
      in dermal melanophages of all five cases of PIHP. HMB-45 positivity was
      demonstrated in histologically negative SLNs and cutaneous biopsies, especially
      in the milieu of aggregated melanophages. Phagocytosis of premelanosomes by
      macrophages in the draining lymph nodes may account for isolated cell positivity
      and can hinder correct diagnostic interpretation. HMB-45 may not be a reliable
      marker for the detection of micro-metastasis of MM and requires correlation with
      other immunohistochemical markers, such as anti-Melan A antibody, to enhance
      specificity.

PMID- 12481010
TI  - Changes in galectin-7 and cytokeratin-19 expression during the progression of
      malignancy in thyroid tumors: diagnostic and biological implications.
AB  - Galectin-7 is associated with p53-dependent onset of apoptosis and proliferation
      control/differentiation in keratinocyte development. It is also up-regulated in
      chemically induced rat mammary carcinogenesis. Because the levels of expression
      of galectin-7 have never been investigated in thyroid tumors (in contrast to
      those of galectin-1 and -3 associated with malignancy), we initiated analysis of
      the expression of galectin-7 in benign and malignant thyroid lesions together
      with that of cytokeratin-19 (CK19), a marker already demonstrated to be useful in
      diagnosing this kind of lesion. The immunohistochemical expression levels were
      quantitatively determined by means of computer-assisted microscopy on a series of
      84 thyroid lesions including 10 multinodular goiters, 32 adenomas, and 42
      carcinomas. Our data clearly indicate a marked down-regulation of galectin-7
      expression in a large proportion of adenomas (including the normomacrofollicular,
      microfollicular, and trabecular variants) if compared with carcinomas. In
      accordance with results of previous studies, a marked up-regulation of CK19
      expression was observed in the thyroid carcinomas, and this contrasted in
      particular with the low CK19 expression observed in the microfollicular adenomas.
      Of importance for diagnostic implications, the combination of these two markers
      enabled our series of microfollicular adenomas (characterized by low galectin-7
      and CK19 expression) to be efficiently distinguished from the encapsulated
      follicular variant of papillary thyroid carcinomas (high galectin-7 and CK19
      expression).

PMID- 12481011
TI  - Diagnostic utility of immunohistochemical staining for p63, a sensitive marker of
      prostatic basal cells.
AB  - Diagnostically reliable identification of prostatic basal cells has depended on
      staining for high molecular weight cytokeratin. The diagnosis of malignancy is
      often based on the absence of basal cells. False-negative staining is
      occasionally observed. Thus, a second method of identifying basal cells might
      prove useful. Selective expression of p63, a homologue of p53, has been
      demonstrated in prostatic basal cells. We investigated the diagnostic utility of
      p63 staining in 70 consecutive specimens for which the differential diagnosis
      included prostatic adenocarcinoma: 68 needle biopsies and 2 transurethral
      resection blocks. High molecular weight cytokeratin staining was the gold
      standard when material was available. A total of 61 specimens were diagnosed as
      carcinoma, 4 as atrophy, 2 as high-grade prostatic intraepithelial neoplasia, 2
      as unclassified collections of benign glands, and 1 as carcinoma versus high
      grade prostatic intraepithelial neoplasia. Sections mounted on charged slides
      were used for p63 staining for 14 specimens. Sections previously hematoxylin and
      eosin stained on uncharged slides were used for 56 specimens. In every case in
      which there was successful p63 staining (55 specimens), basal cells in benign
      lesions were properly marked and other cell types were not stained. Uninformative
      staining in the remaining 15 specimens was due to failure of tissue adherence in
      14 specimens in which sections were on uncharged slides and, in 1 specimen, to
      poor positive internal control staining of benign glands. Thus, p63 staining was
      informative in 55 of 56 specimens (98%) for which there was material for
      examination. No case with satisfactory p63 and high molecular weight staining
      showed disagreement between the two stains. An additional group of 21
      transurethral resection specimens was stained (p63 and high molecular weight
      cytokeratin). There was less false-negative staining for p63 compared with the
      case of high molecular weight cytokeratin. No false-positive staining was seen.
      We conclude that p63 staining is at least as sensitive and specific for the
      identification of basal cells in diagnostic prostate specimens as is high
      molecular weight cytokeratin staining.

PMID- 12481012
TI  - Microsatellite instability in intraductal papillary neoplasms of the biliary
      tract.
AB  - Intraductal papillary neoplasms of the biliary tree are unusual lesions
      characterized by solitary or diffuse growth along the intra- and/or extrahepatic
      biliary tract. Biliary papillary neoplasms bear some clinicopathologic similarity
      to intraductal papillary mucinous neoplasms of the pancreas. Like intraductal
      papillary mucinous neoplasms of the pancreas, biliary papillary neoplasms can be
      purely intraductal lesions or can give rise to invasive adenocarcinomas. We
      recently studied the genetic alterations present in a series of biliary papillary
      neoplasms and noted the presence of allelic shifts in some biliary tumors during
      allelic loss assays on chromosomes 5q and 18q. This suggested that microsatellite
      instability might play a role in the molecular pathogenesis of biliary papillary
      neoplasms. Genomic DNA was extracted from 17 intraductal papillary neoplasms, 6
      associated invasive cholangiocarcinomas, and corresponding normal tissues, and
      microsatellite instability testing was performed using the 5 microsatellite loci
      recommended by the 1997 National Cancer Institute-sponsored consensus conference
      (D2S123, D5S346, D17S250, Bat-25, and Bat-26). High-level microsatellite
      instability was considered to be present when at least two of five microsatellite
      loci showed allelic shifts, and low-level microsatellite instability, when only
      one locus was shifted, as per the National Cancer Institute criteria. We also
      determined the methylation status of the DNA mismatch repair gene hMLH1 by
      bisulfite treatment of genomic DNA, followed by methylation-specific PCR. High
      level microsatellite instability was present in 2 of 17 (11.8%) biliary papillary
      neoplasms, including 1 case of purely intraductal tumor and 1 case with both
      intraductal and invasive cholangiocarcinoma components. In both cases there was
      extensive microsatellite instability, with allelic shifts in five of five and
      four of five microsatellite markers, respectively. Low-level microsatellite
      instability was present in 6 of 17 (35.3%) biliary papillary neoplasms, including
      2 cases of purely intraductal tumor and 4 cases with both intraductal and
      invasive cholangiocarcinoma components. Interestingly, the pattern of allelic
      shifts was frequently not identical between the intraductal and invasive
      cholangiocarcinoma components; although the same microsatellite markers were
      shifted, alleles of differing lengths were generated in the intraductal and
      invasive components of the neoplasms with high-level microsatellite instability
      and of two neoplasms with low-level microsatellite instability. None of the
      biliary papillary neoplasms (0 of 10 cases with adequate DNA for evaluation)
      showed methylation of hMLH1. These results indicate that microsatellite
      instability is a relatively frequent event in papillary neoplasms of the biliary
      tree but is not associated with hMLH1 promoter hypermethylation. The finding that
      alleles of differing lengths were frequently generated between the intraductal
      and invasive components of those tumors with microsatellite instability suggests
      that there is significant genetic heterogeneity within these neoplasms.

PMID- 12481013
TI  - The role of HER2/neu overexpression/amplification in the progression of ductal
      carcinoma in situ to invasive carcinoma of the breast.
AB  - HER2/neu overexpression/amplification is seen more frequently in ductal carcinoma
      in situ, particularly high-grade ductal carcinoma in situ (50-60%), than in
      invasive ductal carcinoma of the breast (25-30%). To date, however, the role of
      HER2/neu in the progression of in situ to invasive disease has not been
      clarified. Two hundred fifty-one breast tumors were retrieved from the pathology
      files at Mount Sinai Hospital. These included 91 cases of ductal carcinoma in
      situ, 136 cases of invasive ductal carcinomas with associated ductal carcinoma in
      situ, and 24 cases of pure invasive carcinomas. All cases were reviewed and
      stained with two monoclonal antibodies to HER2/neu (CB11 and TAB250).
      Immunohistochemical staining was recorded using a semiquantitative scoring system
      (1). Representative cases were also investigated using fluorescence in situ
      hybridization. HER2/neu protein overexpression (defined as immunohistochemical
      staining with score of >or=5) was seen in 34% of cases of pure ductal carcinoma
      in situ, 17% of invasive carcinomas with associated ductal carcinoma in situ, and
      12.5% of pure invasive carcinomas (P =.01). Sixty percent of cases of high-grade
      ductal carcinoma in situ showed HER2/neu protein overexpression, versus 29% of
      high-grade invasive carcinomas with associated ductal carcinoma in situ and 22%
      of high-grade pure invasive ductal carcinomas (P =.02). The concordance between
      the immunohistochemical staining in the in situ and invasive components of
      individual tumors was 90%. Thirty-three cases were also evaluated by fluorescence
      in situ hybridization and showed concordance between the immunohistochemical
      results and the degree of gene amplification in 91% of cases, whereas 3 of 33
      cases showed HER2/neu gene amplification (HER2/CEP17 = 2.3-3.7) by fluorescence
      in situ hybridization in the absence of positive immunohistochemical staining.
      One case showed HER2/neu gene amplification in the associated ductal carcinoma in
      situ (HER2/CEP17 ratio = 6.5), with no evidence of gene amplification in the
      invasive tumor (HER2/CEP17 ratio = 1.14). Multiple genetic events are required
      for the development of an invasive phenotype. The findings from this study
      suggest that the genetic event of HER2/neu gene amplification/protein
      overexpression may not play a key role in the progression of ductal carcinoma in
      situ to invasive carcinoma and that other molecular alterations may be more
      important in the initiation of invasion in ductal carcinoma of the breast.

PMID- 12481014
TI  - Proliferative activity and apoptosis in thymic epithelial neoplasms.
AB  - The classification of thymic epithelial tumors is controversial because
      prediction of the biological behavior of these tumors from their morphologic
      appearance is difficult. The aim of this study was to evaluate the proliferative
      activity and rate of apoptosis of thymic epithelial tumors classified according
      to World Health Organization histological classification. We also attempted to
      determine the importance of a number of proapoptotic factors in these processes.
      We investigated 46 surgically resected thymic epithelial tumors (8 Type A, 8 Type
      AB, 7 Type B1, 7 Type B2, 6 Type B3, and 10 Type C). Immunohistochemical staining
      was performed to determine the tumor expression of p53 protein, Bax, Bcl-2, and
      survivin. In addition, the Ki-67 labeling index (LI) and apoptotic index (AI) of
      these tumors were evaluated. Type C thymoma had a higher LI (16.55 +/- 12.12%)
      than did the other histological subtypes. Stage IV thymoma (12.36 +/- 9.99%) had
      a higher LI than did Stage I tumor. The AI was significantly elevated in Type B1
      thymoma (1.47 +/- 0.55%). Overexpression of p53 protein was observed in Type B3
      and C thymomas. p53 protein-positive tumors had a higher LI than did p53 protein
      negative tumors (P <.0001). Bcl-2 expression was observed in Type A, AB, and C
      thymomas. Bcl-2-positive thymoma had a lower AI than did Bcl-2-negative thymoma
      (P =.0157). These results suggest that overexpression of p53 protein is
      associated with a higher tumor proliferative activity and that Bcl-2 acts as an
      inhibitor of apoptosis in thymoma. Bcl-2 and p53 protein expression may be useful
      markers in differentiating thymoma subtypes.

PMID- 12481015
TI  - Expression of cell adhesion molecules, CD44s and E-cadherin, and microvessel
      density in carcinoid tumors.
AB  - Although all carcinoids are potentially malignant, their biologic behavior is
      quite variable. Currently there are no reliable morphological criteria to predict
      metastatic potential. Cell adhesion molecules, such as CD44 and E-cadherin, are
      considered important in regulating invasion and metastasis of tumors. Also,
      angiogenesis has been shown to be associated with tumor growth and progression.
      In this study, we examined 51 carcinoids, including 13 carcinoids with known
      lymph node and/or visceral metastasis, for expression of CD44s (the standard form
      of CD44) and E-cadherin by immunohistochemistry. We found that 55% and 37% of
      carcinoids were negative for CD44s and E-cadherin, respectively. Carcinoids with
      lymph node and/or visceral metastasis were significantly more frequently negative
      for CD44s than were those without demonstrated metastasis (P =.030). Ten of 11
      tumors with lymph node metastasis lacked CD44s (P =.022), whereas E-cadherin was
      negative in only 3 (P =.975). Additionally, we analyzed microvessel density to
      evaluate the role of tumor angiogenesis in the tumor behavior. Carcinoid tumors
      in general demonstrated high microvessel density (160 +/- 82/five 200x fields),
      irrespective of location and with and without metastasis. These results suggest
      that loss of CD44s, but not E-cadherin, may be a useful predictor of metastatic
      potential of carcinoid tumors.

PMID- 12481016
TI  - Biotinyl-tyramide-based in situ hybridization signal patterns distinguish human
      papillomavirus type and grade of cervical intraepithelial neoplasia.
AB  - In this study, the prevalence of human papillomavirus integration in cervical
      intraepithelial neoplasia Grades I, II, and III has been investigated using a
      highly sensitive biotinyl-tyramide-based in situ hybridization methodology. This
      method is able to demonstrate integrated viral DNA by punctate signals within the
      nucleus and episomal viral DNA by a diffuse signal throughout the nucleus.
      Fifteen viral types were identified by General Primer 5+/6+ polymerase chain
      reaction assay among 26 Grade I and 22 Grade II/III lesions. High-risk human
      papillomavirus (Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66) was
      found in 20 (77%) Grade I and in 22 (100%) Grade II/III lesions (P =.025). Human
      papillomavirus Type 16 was identified in 2 (7%) Grade I and in 15 (68%) Grade
      II/III samples (P <.0001) and was distinguished from other high-risk types by its
      demonstration in both Grade I and Grade II/III lesions as frequent punctate
      signals, detectable at all levels of the epithelium including the basal layer. In
      contrast, punctate signals, when detected among Grade I lesions that were
      positive for other high-risk types, did not involve the basal layer and were
      restricted to occasional cells in the superficial layers. However, Grade II/III
      lesions positive for high-risk types other than human papillomavirus Type 16
      demonstrated frequent punctate signals throughout the epithelium. Overall,
      punctate signals were detected in 22 (100%) high-risk human papillomavirus
      positive Grade II/III lesions and in 5 (25%) high-risk positive Grade I lesions
      (P <.0001). These data are consistent with human papillomavirus Type 16
      possessing a high potential for integration, which may explain its frequent
      association with cervical intraepithelial neoplasia Grade III and carcinomas.
      Acquisition of the punctate correlate, especially in the basal layer, is also
      indicated as important in the development of Grade II/III lesions. The data
      illustrate the unique potential of biotinyl-tyramide-based in situ hybridization
      to address key issues concerning the biology of cervical intraepithelial
      neoplasia.

PMID- 12481017
TI  - Morphological changes in breast tissue with menstrual cycle.
AB  - Whether the breast tissue undergoes morphologic changes in relation to the
      menstrual cycle had been a subject of debate. Elegant studies performed in the
      early 1980s provided conclusive evidence of cyclical changes in the normal breast
      lobules. These studies were almost entirely based on autopsy material and have
      not been validated in the clinical setting. In the present study, we examine
      breast tissues from surgical specimens from 73 premenopausal women and use
      morphological criteria to characterize the stage of the menstrual cycle. Patients
      taking oral contraceptives or hormonal therapy were excluded from this study. The
      following histological parameters were used to assess the menstrual stage: number
      of cell layers in the acini and presence and degree of vacuolation of the
      myoepithelial cells, stromal edema, infiltrate, mitosis, and apoptosis. The
      morphological stage was then correlated with the stage of the cycle, as
      determined by last menstrual period and the usual menstrual cycle length and in
      some patients with serum estrogen and progesterone levels. The morphologic stage
      was concordant with dates in 54 of the 73 patients (74%, P =.001). In 31 of these
      patients, serum levels of estradiol and progesterone at the time of surgery were
      available for correlation. Twenty-five (80%) of these were phase concordant by
      morphology and progesterone levels (P =.01), and 25 (80%), by dates and
      progesterone levels (P =.007). Women with a high morphologic score were seven
      times as likely to be in luteal phase as were women with a low score (odds ratio,
      7.1; 95% confidence interval). Menstrual phase can be determined by the
      morphology of the normal lobules present within the surgically excised breast
      specimens. This will permit retrospective analysis of large archival databases to
      analyze the effect of timing of surgery in relation to menstrual cycle phase. It
      will also aid the design of epidemiological studies for breast cancer risk
      assessment.

PMID- 12481018
TI  - Role of E-cadherin, alpha-, beta-, and gamma-catenins, and p120 (cell adhesion
      molecules) in prolactinoma behavior.
AB  - E-cadherin/catenin complex regulates cellular adhesion and motility and is
      believed to function as an invasion suppressor system. In a number of cancers,
      abnormal and reduced expression of E-cadherin/catenin complex is associated with
      tumor invasion and metastasis. Prolactinomas show frequent invasion on the
      surrounding structures, despite their histologically benign nature. Furthermore,
      gender-based differences in endocrine and surgical findings are found in patients
      with prolactinoma. To understand biological factors governing prolactinoma
      behavior, this study analyzed the expression of E-cadherin; alpha-, beta-, and
      gamma-catenins; p120; and cell proliferation marker MIB-1 labeling index in 13
      invasive tumors (9 in men, 4 in women), 26 noninvasive tumors (4 in men, 22 in
      women), and 8 normal anterior pituitaries by immunohistochemistry. Immunostaining
      of E-cadherin; alpha-, beta-, and gamma-catenins; and p120 showed a membranous
      pattern of reactivity and generally stronger in normal pituitaries than in
      prolactinomas. Expression of E-cadherin and beta-catenin was significantly lower
      in invasive than in noninvasive prolactinomas (P <.002 and P <.005,
      respectively), and reduced expression of E-cadherin and beta-catenin was more
      frequent in invasive than in noninvasive prolactinomas (P <.001 and P <.05,
      respectively); in contrast, gamma-catenin expression showed higher in invasive
      than in noninvasive prolactinomas (P <.05). Expression of E-cadherin was
      significantly lower in macroprolactinomas than in microprolactinomas (P <.01),
      and decreased expression of E-cadherin and beta-catenin predicted high MIB-1
      expression (P <.05). Moreover, the expression of E-cadherin and beta-catenin was
      significantly lower in macroprolactinomas in men than in those in women (P <.01
      and P <.02, respectively). No statistical correlations were observed between
      expression of alpha-catenin, p120, and clinicopathologic features. In conclusion,
      the reduction of E-cadherin and beta-catenin expression was related to
      invasiveness and proliferative status of prolactinomas and correlated with the
      more aggressive behavior of prolactinomas in men compared with in women.

PMID- 12481019
TI  - Tissue micro-array: a cost and time-effective method for correlative studies by
      regional and national cancer study groups.
AB  - Tissue micro-arrays have been used for molecular and immunohistochemical studies.
      We sought to evaluate whether such arrays could substitute for whole sections in
      correlative studies performed by the Radiation Therapy Oncology Group. Four
      multitumor 150-sample arrays were built using formalin-fixed, paraffin-embedded,
      archival prostate, brain, and head/neck tumor blocks from RTOG tissue bank. p53
      immunostaining of arrays and whole sections was done. Blind evaluation of each
      slide was made, and agreement rates between the two techniques were determined in
      various scenarios. Cost was also evaluated. Results demonstrate excellent
      agreement for p53 between slides and arrays. Agreement improved when three or
      four replicate arrays were used. Findings based on one to four arrays agree well
      with those obtained from analysis of the whole tissue samples. Minimal tissue
      damage, improved tissue salvage, cost reduction, ease of interpretation, and
      significant time savings were realized by using the arrays. Tissue micro array
      technique is a valuable tool for evaluation of patient materials associated with
      clinical trials.

PMID- 12481020
TI  - Tissue microarrays are an effective quality assurance tool for diagnostic
      immunohistochemistry.
AB  - There has been considerable variability in the reported results of
      immunohistochemical staining for some diagnostically relevant antigens. Our
      objectives in this study were to (1) use a multitumor tissue microarray with
      tissue from 351 cases received in our department, representing 16 normal tissues
      and 47 different tumor types, to compare immunohistochemical staining results in
      our laboratory with published data, using a panel of 22 antibodies; (2) assess
      interlaboratory variability of immunohistochemical staining for S-100 using this
      microarray; and (3) test the ability of hierarchical clustering analysis to group
      tumors by primary site, based on their immunostaining profile. Tissue microarrays
      consisting of duplicate 0.6-mm cores from blocks identified in the hospital
      archives were constructed and stained according to our usual protocols.
      Antibodies directed against the following antigens were used: B72.3, bcl-2,
      carcinoembryonic antigen, c-kit, pankeratin, CD 68, CD 99, CK 5/6, CK 7, CK 8/18,
      CK19, CK 20, CK 22, epithelial membrane antigen, estrogen receptor, melan-A, p53,
      placental alkaline phosphatase, S-100, synaptophysin, thyroid transcription
      factor-1, and vimentin. Staining results on the array cases were compared with
      published results, and hierarchical clustering analysis was performed based on
      the immunohistochemical staining results. Unstained slides of the multitumor
      tissue microarray were sent to five other diagnostic immunohistochemistry
      laboratories and stained for S-100 protein. The staining results from the
      different laboratories were compared. Staining results using our current methods
      and samples from our laboratory were compatible with those described in the
      literature for most antigens. Placental alkaline phosphatase staining was not
      specific with our protocol, showing staining of a broad spectrum of different
      tumors; this finding initiated a review of our recent requests for placental
      alkaline phosphatase immunostaining and revealed two instances in which placental
      alkaline phosphatase positivity was incorrectly interpreted as evidence of a germ
      cell tumor. S-100 staining was less sensitive but more specific for the diagnosis
      of melanoma or neural tumor in our laboratory, compared to some published
      reports. Assessment of interlaboratory variability of S-100 immunostaining showed
      that there was more frequent staining of carcinomas in some laboratories,
      resulting in decreased specificity of S-100 staining in distinguishing melanoma
      from carcinoma. Hierarchical clustering analysis showed a strong trend for tumors
      to cluster by tissue of origin, but there were significant exceptions. We
      conclude that multiple-tumor microarrays are an efficient method for assessing
      the sensitivity and specificity of staining with any antibody used
      diagnostically. As a tool for quality assurance, they offer the advantage of
      taking into account local differences in tissue fixation, processing, and
      staining. They also allow cost-effective assessment of interlaboratory
      variability in immunohistochemical staining. Results of hierarchical clustering
      analysis show the potential for panels of immunohistochemical stains to identify
      the primary site of metastatic carcinomas but also confirm the limitations of
      currently available antibodies in giving unequivocal tissue-specific staining
      patterns.

PMID- 12481022
TI  - Oxygen-mediated diffusion of oxygen vacancies on the TiO2(110) surface.
AB  - Defects such as oxygen vacancies play a crucial role in the surface properties of
      transition metal oxides. By means of time-resolved, high-resolution scanning
      tunneling microscopy, we unraveled an adsorbate-mediated diffusion mechanism of
      oxygen vacancies on rutile TiO2(110). Adsorbed oxygen molecules mediate vacancy
      diffusion through the loss of an oxygen atom to a vacancy and the sequential
      capture of an oxygen atom from a neighboring bridging oxygen row, leading to an
      anisotropic oxygen vacancy diffusion pathway perpendicular to the bridging oxygen
      rows.

PMID- 12481023
TI  - Endoproteolytic activity of the proteasome.
AB  - The proteasome plays a central role in the degradation of regulatory and
      misfolded proteins. Current models suggest that substrates access the internal
      catalytic sites by processively threading their termini through the gated
      substrate channel. Here, we found that latent (closed) and activated (open)
      proteasomes degraded two natively disordered substrates at internal peptide bonds
      even when they lacked accessible termini, suggesting that these substrates
      themselves promoted gating of the proteasome. This endoproteolysis provides a
      molecular mechanism for regulated release of transcription factors from inactive
      precursors as well as a means of accessing internal folding defects of misfolded
      multidomain proteins.

PMID- 12481024
TI  - Alternate surfaces of transcriptional coregulator GRIP1 function in different
      glucocorticoid receptor activation and repression contexts.
AB  - Members of the mammalian p160 family, such as GRIP1, are known as glucocorticoid
      receptor (GR) coactivators; at certain glucocorticoid response elements (GREs),
      however, GRIP1 acts as a GR corepressor. We characterized functional interactions
      of GR and GRIP1 in a repression complex where GR tethers to DNA-bound activator
      protein-1 (AP-1), as at the human collagenase-3 gene, and tested whether the
      identified interactions were similar or different at other response elements. At
      the AP-1 tethering GRE, we mapped the GRIP1 corepressor activity to a domain
      distinct from the two known GRIP1 activation domains; it exhibited intrinsic GR
      independent repression potential when recruited to DNA via Gal4 DNA-binding
      domain. Interestingly, neither the domain nor the activity was detected in the
      other two p160 family members, SRC1 and RAC3. The same GRIP1 corepression domain
      was required for GR-mediated repression at the nuclear factor-kappaB (NF-kappaB)
      tethering GRE of the human IL-8 gene. In contrast, at the osteocalcin gene GRE,
      where GR represses transcription by binding to a DNA site overlapping the TATA
      box, both GRIP1 and SRC1 corepressed, and the GRIP1-specific repression domain
      was dispensable. Thus, in a single cell type, GR and GRIP1 conferred one mode of
      activation and two modes of repression by selectively engaging distinct surfaces
      of GRIP1 in a response element-specific manner.

PMID- 12481025
TI  - Trbp111 selectively binds a noncovalently assembled tRNA-like structure.
AB  - Transfer RNAs are key components of the genetic code by virtue of aminoacylation
      reactions whereby each amino acid is linked to the tRNA that bears the anticodon
      for the attached amino acid. The L-shaped tRNA structure contains two domains
      connected at right angles through a corner formed from tertiary interactions
      involving loops of each domain. Some evidence suggests that the domains arose
      separately and eventually were fused into a single covalent structure. In this
      scenario, the present-day tRNA possibly developed through a noncovalently
      assembled heterodimeric intermediate. Trbp111 is an ancient structure-specific
      tRNA binding protein that interacts specifically with the outside corner of the L
      shaped molecule. Plausibly, this protein could act as a chaperone to cover and
      protect the fragile corner and thereby have a historical role in the development
      of tRNA. Here we show that Trbp111 interacts with a noncovalently assembled tRNA
      like structure, under conditions where it does not interact with individual tRNA
      domains. Trbp111 binding specifically requires formation of the tRNA-like corner.
      In a mixture of RNA domains, it selects those that can make the L-like structure.
      Thus, cofactors such as Trbp111 have the capacity to help assemble and stabilize
      RNA dimers that are tRNA-like.

PMID- 12481026
TI  - Ten-nanosecond molecular dynamics simulation of the motions of the horse liver
      alcohol dehydrogenase.PhCH2O- complex.
AB  - Molecular dynamics simulations have been carried out for a period of 10 ns with
      the dimeric enzyme horse liver alcohol dehydrogenase (HLADH) present as the
      reactive complex HLADH.NAD+. PhCH2O-. Cross-correlation analysis of the
      trajectory was carried out with the latter from 500 ps to 10 ns. The resulting
      cross-correlation map allowed the identification of the correlated and
      anticorrelated motions, which involve the entire protein. Anticorrelated and
      correlated motions are carried into the active site-aligned residues.

PMID- 12481027
TI  - A structural model for Alzheimer's beta -amyloid fibrils based on experimental
      constraints from solid state NMR.
AB  - We present a structural model for amyloid fibrils formed by the 40-residue beta
      amyloid peptide associated with Alzheimer's disease (Abeta(1-40)), based on a set
      of experimental constraints from solid state NMR spectroscopy. The model
      additionally incorporates the cross-beta structural motif established by x-ray
      fiber diffraction and satisfies constraints on Abeta(1-40) fibril dimensions and
      mass-per-length determined from electron microscopy. Approximately the first 10
      residues of Abeta(1-40) are structurally disordered in the fibrils. Residues 12
      24 and 30-40 adopt beta-strand conformations and form parallel beta-sheets
      through intermolecular hydrogen bonding. Residues 25-29 contain a bend of the
      peptide backbone that brings the two beta-sheets in contact through sidechain
      sidechain interactions. A single cross-beta unit is then a double-layered beta
      sheet structure with a hydrophobic core and one hydrophobic face. The only
      charged sidechains in the core are those of D23 and K28, which form salt bridges.
      Fibrils with minimum mass-per-length and diameter consist of two cross-beta units
      with their hydrophobic faces juxtaposed.

PMID- 12481028
TI  - An epigenetic mouse model for molecular and behavioral neuropathologies related
      to schizophrenia vulnerability.
AB  - Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical gamma
      aminobutyric acid-ergic interneurons are down-regulated in schizophrenia. Because
      epidemiological studies of schizophrenia fail to support candidate gene
      haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms
      (i.e., cytosine hypermethylation of CpG islands present in the promoter of these
      genes) may be responsible for this down-regulation. Protracted l-methionine (6.6
      mmolkg for 15 days, twice a day) treatment in mice elicited in brain an increase
      of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl
      methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and
      heterozygous reeler mice. This effect of l-methionine was associated with an
      increase in the number of methylated cytosines in the CpG island of the reelin
      promoter region. This effect was not observed for GAD65 or neuronal-specific
      enolase and was not replicated by glycine doses 2-fold greater than those of l
      methionine. Prepulse inhibition of startle declined at a faster rate as the
      prepulsestartle interval increased in mice receiving l-methionine. Valproic acid
      (2 mmolkg for 15 days, twice a day) reverted l-methionine-induced down-regulation
      of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an
      epigenetic action through the inhibition of histone deacetylases. The same dose
      of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold.
      This epigenetic mouse model may be useful in evaluating drug efficacy on
      schizophrenia vulnerability. Hence the inhibition of histone deacetylases could
      represent a pharmacological intervention mitigating epigenetically induced
      vulnerability to schizophrenia in individuals at risk.

PMID- 12481029
TI  - The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by
      Dnmt3a.
AB  - Dnmt3L is required for the establishment of maternal methylation imprints at
      imprinting centers (ICs). Dnmt3L, however, lacks the conserved catalytic domain
      common to DNA methyltransferases. In an attempt to define its function, we
      coexpressed DNMT3L with each of the two known de novo methyltransferases, Dnmt3a
      and DNMT3B, in human cells and monitored de novo methylation by using replicating
      minichromosomes carrying various ICs as targets. Coexpression of DNMT3L with
      DNMT3B led to little or no change in target methylation. However, coexpression of
      DNMT3L with Dnmt3a resulted in a striking stimulation of de novo methylation by
      Dnmt3a. Stimulation was observed at maternally methylated ICs such as small
      nuclear ribonucleoprotein polypeptide N (SNRPN), Snrpn, and Igf2rAir, as well as
      at various nonimprinted sequences present on the episomes. Stimulation of Dnmt3a
      by DNMT3L was also observed at endogenous sequences in the genome. Therefore,
      DNMT3L acts as a general stimulatory factor for de novo methylation by Dnmt3a.
      The implications of these findings for the function of DNMT3L and Dnmt3a in DNA
      methylation and genomic imprinting are discussed.

PMID- 12481030
TI  - Genomic diversity of enterohemorrhagic Escherichia coli O157 revealed by whole
      genome PCR scanning.
AB  - Enterohemorrhagic Escherichia coli O157 is one of the leading worldwide public
      health concerns, causing large outbreaks of hemorrhagic colitis as well as
      numerous small outbreaks and sporadic cases. The variability of restriction
      enzyme-digestion patterns of O157 genomes, which is widely used to distinguish
      strains in the molecular epidemiology of O157 infections, suggests the presence
      of some genomic diversity among the strains. Based on the complete genome
      sequence of O157 Sakai, we analyzed the whole genome structures of eight O157
      strains displaying diverse XbaI-digestion patterns by a systematic PCR analysis
      that we have named whole genome PCR scanning. This analysis identified not only
      the O157-specific sequences that are highly conserved among the strains, but also
      revealed an unexpectedly high degree of genomic diversity. In particular,
      prophages, including Shiga toxin-transducing phages, exhibited extensive
      structural and positional diversity, implying that variation of bacteriophages is
      a major factor in generating genomic diversity among the O157 lineage.

PMID- 12481031
TI  - CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF
      like complex.
AB  - Selective protein degradation targeted by members of the F-box protein family
      plays pivotal roles in cell biology. It is widely accepted that an F-box protein
      directs substrate ubiquitination within a Skp1.CUL1.F-box protein.ROC1 (SCF-ROC1)
      E3 ubiquitin ligase complex. This assembly utilizes the CUL1 molecular scaffold,
      allowing the F-box protein to position its bound substrate for ubiquitination by
      a ROC1-recruited E2-conjugating enzyme. Here, we describe an alternative
      mechanism for assembling an F-box protein-based E3 complex through a previously
      uncharacterized cullin, CUL7, identified by mass spectrometry as a ROC1
      interacting protein. CUL7 is a large polypeptide containing a cullin domain,
      which is responsible for ROC1 binding, and a DOC domain, which is also present in
      the anaphase-promoting complex. Remarkably, CUL7 assembles an SCF-ROC1-like E3
      ubiquitin ligase complex consisting of Skp1, CUL7, the Fbx29 F-box protein, and
      ROC1. In contrast to CUL1 that binds Skp1 by itself, CUL7 interacts with the
      Skp1.Fbx29 complex, but not with Skp1 alone. Strikingly, CUL7 selectively
      interacts with Skp1.Fbx29 but not with Skp1.betaTRCP2 or Skp1.Skp2. Thus, CUL7
      may define a previously uncharacterized, Fbx29-mediated, and ubiquitin-dependent
      proteolysis pathway.

PMID- 12481032
TI  - Molecular conformation of a peptide fragment of transthyretin in an amyloid
      fibril.
AB  - The molecular conformation of peptide fragment 105-115 of transthyretin, TTR(105
      115), previously shown to form amyloid fibrils in vitro, has been determined by
      magic-angle spinning solid-state NMR spectroscopy. 13C and 15N linewidth
      measurements indicate that TTR(105-115) forms a highly ordered structure with
      each amino acid in a unique environment. 2D 13C-13C and 15N-13C-13C chemical
      shift correlation experiments, performed on three fibril samples uniformly
      13C,15N-labeled in consecutive stretches of 4 aa, allowed the complete sequence
      specific backbone and side-chain 13C and 15N resonance assignments to be obtained
      for residues 105-114. Analysis of the 15N, 13CO, 13Calpha, and 13Cbeta chemical
      shifts allowed quantitative predictions to be made for the backbone torsion
      angles phi and psi. Furthermore, four backbone 13C-15N distances were determined
      in two selectively 13C,15N-labeled fibril samples by using rotational-echo double
      resonance NMR. The results show that TTR(105-115) adopts an extended beta-strand
      conformation that is similar to that found in the native protein except for
      substantial differences in the vicinity of the proline residue.

PMID- 12481033
TI  - The patterns of accumulation of cellular RNAs in cells infected with a wild-type
      and a mutant herpes simplex virus 1 lacking the virion host shutoff gene.
AB  - Cellular RNA extracted from quiescent human foreskin fibroblasts harvested at 1,
      3, 7, or 12 h after infection was profiled on Affymetrix HG-U95Av2 arrays
      designed to detect 12,626 unique human transcripts. We also profiled RNA
      extracted from cells harvested at 1 and 7 h after infection with a mutant lacking
      the gene (DeltaU(L)41) encoding a protein (vhs) brought into cells by the virus
      and responsible for nonselective degradation of RNA early in infection. We report
      the following: (i) of the 12 tested genes, up-regulated at least 3-fold relative
      to the values of mock infected cells, 9 were confirmed by real-time PCR. The
      microchip assays analyses indicate that there were 475 genes up-regulated > or =3
      fold. The up-regulated genes were clustered into 15 groups with respect to
      temporal pattern of transcript accumulation, and classified into 20 groups on the
      basis of their function. The preponderance of cellular genes up-regulated early
      in infection play a predominant role in transcription, whereas those up-regulated
      at later times respond to intracellular stress or concern themselves with the
      cell cycle and apoptosis. (ii) The number of genes up-regulated early in
      infection was higher in cells infected with the DeltaU(L)41 mutant. Conversely,
      more genes were down-regulated late in infection with wild-type virus than with
      mutant viruses. Both observations are compatible with the known function of the
      U(L)41 gene product early in infection and with degradation of cellular RNAs in
      the absence of replenishment by de novo transcription of cellular genes.

PMID- 12481034
TI  - Dynamics and selection of many-strain pathogens.
AB  - Strain structure is of fundamental importance in the underlying dynamics of a
      number of pathogens. However, previous models have been too complex to
      accommodate many strains. This paper offers a solution to this problem, in the
      form of a simple model that is capable of capturing the dynamics of a large
      number of antigenic types that interact via host cross-immunity. We derive the
      structure of the model, which can manage the complexity of many strains by using
      a status-based formulation, assuming polarized immunity and cross-immunity act to
      reduced transmission probability. We then apply the model to address basic
      questions in strain dynamics, focusing particularly on the interpandemic dynamics
      of influenza. This model shows that strains have a tendency to "cluster." For a
      long infectious period, relative to host lifetime, clusters may coexist. By
      contrast, a short infectious period leads to a single dominant cluster at any
      given time. We show how the speed of cluster replacement depends on the
      specificity of cross-immunity and on the underlying pathogen mutation rate.

PMID- 12481035
TI  - Allopolyploidization and evolution of species with reduced floral structures in
      Lepidium L. (Brassicaceae).
AB  - Understanding the pattern of speciation in a group of plants is critical for
      understanding its morphological evolution. Lepidium is the genus with the largest
      variation in floral structure in Brassicaceae, a family in which the floral
      ground plan is remarkably stable. However, flowers in more than half of Lepidium
      species have reduced stamen numbers, and most of these also have reduced petals.
      The species with reduced flowers are geographically biased, distributed mostly in
      the Americas and Australia New Zealand. Previous phylogenetic studies using
      noncoding regions of chloroplast DNA and rDNA internal transcribed spacer were
      incongruent in most New World species relationships. These data, combined with
      the presence of many polyploid Lepidium species, implied a reticulate history of
      the genus but did not provide enough information to infer the evolutionary
      pattern of flower structures. To address this question more thoroughly, sequences
      of the first intron of a single copy nuclear gene, PISTILLATA, were determined
      from 43 species. Phylogenetic analysis of the PI intron suggests that many
      species in the New World have originated from allopolyploidization, and that this
      is correlated with floral reduction. Interspecific hybrids were generated to
      understand why allopolyploidization is associated with reduced flowers. The
      phenotypes of F1 flowers indicate allelic dominance of the absence of lateral
      stamens, suggesting that propagation of dominant alleles through interspecific
      hybridization could account for the abundance of the allopolyploid species
      without lateral stamens.

PMID- 12481036
TI  - Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappa B, and
      AP1 DNA binding, and affects DNA repair in a rat glioma cell line.
AB  - Approximately 10% of the U.S. population ingests <50% of the current recommended
      daily allowance for zinc. We investigate the effect of zinc deficiency on DNA
      damage, expression of DNA-repair enzymes, and downstream signaling events in a
      cell-culture model. Low zinc inhibited cell growth of rat glioma C6 cells and
      increased oxidative stress. Low intracellular zinc increased DNA single-strand
      breaks (comet assay). Zinc-deficient C6 cells also exhibited an increase in the
      expression of the zinc-containing DNA-repair proteins p53 and apurinic
      endonuclease (APE). Repletion with zinc restored cell growth and reversed DNA
      damage. APE is a multifunctional protein that not only repairs DNA but also
      controls DNA-binding activity of many transcription factors that may be involved
      in cancer progression. The ability of the transcription factors p53, nuclear
      factor kappaB, and activator protein 1 (AP1) to bind to consensus DNA sequences
      was decreased markedly with zinc deficiency, as assayed by electrophoretic
      mobility-shift assays. Thus, low intracellular zinc status causes oxidative DNA
      damage and induces DNA-repair protein expression, but binding of p53 and
      important downstream signals leading to proper DNA repair are lost without zinc.

PMID- 12481037
TI  - Characterization of the intergenic RNA profile at abdominal-A and Abdominal-B in
      the Drosophila bithorax complex.
AB  - The correct spatial expression of two Drosophila bithorax complex (BX-C) genes,
      abdominal-A (abdA) and Abdominal-B (AbdB), is dependent on the 100-kb intergenic
      infraabdominal (iab) region. The iab region is known to contain a number of
      different domains (iab2 through iab8) that harbor cis-regulatory elements
      responsible for directing expression of abdA and AbdB in the second through
      eighth abdominal segments. Here, we use in situ hybridization to perform high
      resolution mapping of the transcriptional activity in the iab control regions. We
      show that transcription of the control regions themselves is abundant and
      precedes activation of the abdA and AbdB genes. As with the homeotic genes of the
      BX-C, the transcription patterns of the RNAs from the iab control regions
      demonstrate colinearity with the sequence of the iab regions along the chromosome
      and the domains in the embryo under the control of the specific iab regions.
      These observations suggest that the intergenic RNAs may play a role in initiating
      cis regulation at the BX-C early in development.

PMID- 12481038
TI  - Delayed reentry of recycling vesicles into the fusion-competent synaptic vesicle
      pool in synaptojanin 1 knockout mice.
AB  - Synaptojanin 1 is a polyphosphoinositide phosphatase implicated in synaptic
      vesicle recycling. We used FM1-43 imaging and electron microscopy in cultured
      cortical neurons from control and synaptojanin 1 knockout mice to study how the
      absence of this protein affects specific steps of the synaptic vesicle cycle.
      Exoendocytosis after a moderate stimulus was unchanged. However, during prolonged
      stimulation, the regeneration of fusion-competent synaptic vesicles was severely
      impaired. In stimulated nerve terminals, there was a persistent accumulation of
      clathrin-coated vesicles and a backup of newly reformed vesicles in the
      cytomatrix-rich area around the synaptic vesicle cluster. These findings
      demonstrate that synaptojanin 1 function is needed for the progression of
      recycling vesicles to the functional synaptic vesicle pool.

PMID- 12481039
TI  - Reduced sodium channel density, altered voltage dependence of inactivation, and
      increased susceptibility to seizures in mice lacking sodium channel beta 2
      subunits.
AB  - Sodium channel beta-subunits modulate channel gating, assembly, and cell surface
      expression in heterologous cell systems. We generated beta2(-/-) mice to
      investigate the role of beta2 in control of sodium channel density, localization,
      and function in neurons in vivo. Measurements of [(3)H]saxitoxin (STX) binding
      showed a significant reduction in the level of plasma membrane sodium channels in
      beta2(-/-) neurons. The loss of beta2 resulted in negative shifts in the voltage
      dependence of inactivation as well as significant decreases in sodium current
      density in acutely dissociated hippocampal neurons. The integral of the compound
      action potential in optic nerve was significantly reduced, and the threshold for
      action potential generation was increased, indicating a reduction in the level of
      functional plasma membrane sodium channels. In contrast, the conduction velocity,
      the number and size of axons in the optic nerve, and the specific localization of
      Na(v)1.6 channels in the nodes of Ranvier were unchanged. beta2(-/-) mice
      displayed increased susceptibility to seizures, as indicated by reduced latency
      and threshold for pilocarpine-induced seizures, but seemed normal in other
      neurological tests. Our observations show that beta2-subunits play an important
      role in the regulation of sodium channel density and function in neurons in vivo
      and are required for normal action potential generation and control of
      excitability.

PMID- 12481040
TI  - Current status of the sequence of the rice genome and prospects for finishing the
      first monocot genome.

PMID- 12481041
TI  - The impact of polyploidy on grass genome evolution.

PMID- 12481042
TI  - The Maize Genome Sequencing Project.

PMID- 12481043
TI  - Genetic, physical, and informatics resources for maize. On the road to an
      integrated map.

PMID- 12481044
TI  - Gramene, a tool for grass genomics.
AB  - Gramene (http://www.gramene.org) is a comparative genome mapping database for
      grasses and a community resource for rice (Oryza sativa). It combines a semi
      automatically generated database of cereal genomic and expressed sequence tag
      sequences, genetic maps, map relations, and publications, with a curated database
      of rice mutants (genes and alleles), molecular markers, and proteins. Gramene
      curators read and extract detailed information from published sources, summarize
      that information in a structured format, and establish links to related objects
      both inside and outside the database, providing seamless connections between
      independent sources of information. Genetic, physical, and sequence-based maps of
      rice serve as the fundamental organizing units and provide a common denominator
      for moving across species and genera within the grass family. Comparative maps of
      rice, maize (Zea mays), sorghum (Sorghum bicolor), barley (Hordeum vulgare),
      wheat (Triticum aestivum), and oat (Avena sativa) are anchored by a set of
      curated correspondences. In addition to sequence-based mappings found in
      comparative maps and rice genome displays, Gramene makes extensive use of
      controlled vocabularies to describe specific biological attributes in ways that
      permit users to query those domains and make comparisons across taxonomic groups.
      Proteins are annotated for functional significance using gene ontology terms that
      have been adopted by numerous model species databases. Genetic variants including
      phenotypes are annotated using plant ontology terms common to all plants and
      trait ontology terms that are specific to rice. In this paper, we present a brief
      overview of the search tools available to the plant research community in
      Gramene.

PMID- 12481045
TI  - Targeted analysis of orthologous phytochrome A regions of the sorghum, maize, and
      rice genomes using comparative gene-island sequencing.
AB  - A "gene-island" sequencing strategy has been developed that expedites the
      targeted acquisition of orthologous gene sequences from related species for
      comparative genome analysis. A 152-kb bacterial artificial chromosome (BAC) clone
      from sorghum (Sorghum bicolor) encoding phytochrome A (PHYA) was fully sequenced,
      revealing 16 open reading frames with a gene density similar to many regions of
      the rice (Oryza sativa) genome. The sequences of genes in the orthologous region
      of the maize (Zea mays) and rice genomes were obtained using the gene-island
      sequencing method. BAC clones containing the orthologous maize and rice PHYA
      genes were identified, sheared, subcloned, and probed with the sorghum PHYA
      containing BAC DNA. Sequence analysis revealed that approximately 75% of the
      cross-hybridizing subclones contained sequences orthologous to those within the
      sorghum PHYA BAC and less than 25% contained repetitive and/or BAC vector DNA
      sequences. The complete sequence of four genes, including up to 1 kb of their
      promoter regions, was identified in the maize PHYA BAC. Nine orthologous gene
      sequences were identified in the rice PHYA BAC. Sequence comparison of the
      orthologous sorghum and maize genes aided in the identification of exons and
      conserved regulatory sequences flanking each open reading frame. Within genomic
      regions where micro-colinearity of genes is absolutely conserved, gene-island
      sequencing is a particularly useful tool for comparative analysis of genomes
      between related species.

PMID- 12481046
TI  - Contiguous genomic DNA sequence comprising the 19-kD zein gene family from maize.
AB  - A new approach has been undertaken to analyze the sequences and linear
      organization of the 19-kD zein genes in maize (Zea mays). A high-coverage, large
      insert genomic library of the inbred line B73 based on bacterial artificial
      chromosomes was used to isolate a redundant set of clones containing members of
      the 19-kD zein gene family, which previously had been estimated to consist of 50
      members. The redundant set of clones was used to create bins of overlapping
      clones that represented five distinct genomic regions. Representative clones
      containing the entire set of 19-kD zein genes were chosen from each region and
      sequenced. Seven bacterial artificial chromosome clones yielded 1,160 kb of
      genomic DNA. Three of them formed a contiguous sequence of 478 kb, the longest
      contiguous sequenced region of the maize genome. Altogether, these DNA sequences
      provide the linear organization of 25 19-kD zein genes, one-half the number
      previously estimated. It is suggested that the difference is because of
      haplotypes exhibiting different degrees of gene amplification in the zein
      multigene family. About one-half the genes present in B73 appear to be expressed.
      Because some active genes have only been duplicated recently, they are so
      conserved in their sequence that previous cDNA sequence analysis resulted in
      "unigenes" that were actually derived from different gene copies. This analysis
      also shows that the 22- and 19-kD zein gene families shared a common ancestor.
      Although both ancestral genes had the same incremental gene amplification, the 19
      kD zein branch exhibited a greater degree of far-distance gene translocations
      than the 22-kD zein gene family.

PMID- 12481047
TI  - T-DNA insertional mutagenesis for activation tagging in rice.
AB  - We have developed a new T-DNA vector, pGA2715, which can be used for promoter
      trapping and activation tagging of rice (Oryza sativa) genes. The binary vector
      contains the promoterless beta-glucuronidase (GUS) reporter gene next to the
      right border. In addition, the multimerized transcriptional enhancers from the
      cauliflower mosaic virus 35S promoter are located next to the left border. A
      total of 13,450 T-DNA insertional lines have been generated using pGA2715.
      Histochemical GUS assays have revealed that the GUS-staining frequency from those
      lines is about twice as high as that from lines transformed with the binary
      vector pGA2707, which lacks the enhancer element. This result suggests that the
      enhancer sequence present in the T-DNA improves the GUS-tagging efficiency.
      Reverse transcriptase-PCR analysis of a subset of randomly selected pGA2715 lines
      shows that expression of the genes immediately adjacent to the inserted enhancer
      is increased significantly. Therefore, the large population of T-DNA-tagged lines
      transformed with pGA2715 could be used to screen for promoter activity using the
      gus reporter, as well as for creating gain-of-function mutants.

PMID- 12481048
TI  - Starch biosynthesis during pollen maturation is associated with altered patterns
      of gene expression in maize.
AB  - Starch biosynthesis during pollen maturation is not well understood in terms of
      genes/proteins and intracellular controls that regulate it in developing pollen.
      We have studied two specific developmental stages: "early," characterized by the
      lack of starch, before or during pollen mitosis I; and "late," an actively starch
      filling post-pollen mitosis I phase in S-type cytoplasmic male-sterile (S-CMS)
      and two related male-fertile genotypes. The male-fertile starch-positive, but not
      the CMS starch-deficient, genotypes showed changes in the expression patterns of
      a large number of genes during this metabolic transition. In addition to a
      battery of housekeeping genes of carbohydrate metabolism, we observed changes in
      hexose transporter, plasma membrane H(+)-ATPase, ZmMADS1, and 14-3-3 proteins.
      Reduction or deficiency in 14-3-3 protein levels in all three major cellular
      sites (amyloplasts [starch], mitochondria, and cytosol) in male-sterile relative
      to male-fertile genotypes are of potential interest because of interorganellar
      communication in this CMS system. Further, the levels of hexose sugars were
      significantly reduced in male-sterile as compared with male-fertile tissues, not
      only at "early" and "late" stages but also at an earlier point during meiosis.
      Collectively, these data suggest that combined effects of both reduced sugars and
      their reduced flux in starch biosynthesis along with a strong possibility for
      altered redox passage may lead to the observed temporal changes in gene
      expressions, and ultimately pollen sterility.

PMID- 12481049
TI  - Functional specialization of maize mitochondrial aldehyde dehydrogenases.
AB  - The maize (Zea mays) rf2a and rf2b genes both encode homotetrameric aldehyde
      dehydrogenases (ALDHs). The RF2A protein was shown previously to accumulate in
      the mitochondria. In vitro import experiments and ALDH assays on mitochondrial
      extracts from rf2a mutant plants established that the RF2B protein also
      accumulates in the mitochondria. RNA gel-blot analyses and immunohistolocation
      experiments revealed that these two proteins have only partially redundant
      expression patterns in organs and cell types. For example, RF2A, but not RF2B,
      accumulates to high levels in the tapetal cells of anthers. Kinetic analyses
      established that RF2A and RF2B have quite different substrate specificities;
      although RF2A can oxidize a broad range of aldehydes, including aliphatic
      aldehydes and aromatic aldehydes, RF2B can oxidize only short-chain aliphatic
      aldehydes. These two enzymes also have different pH optima and responses to
      changes in substrate concentration. In addition, RF2A, but not RF2B or any other
      natural ALDHs, exhibits positive cooperativity. These functional specializations
      may explain why many species have two mitochondrial ALDHs. This study provides
      data that serve as a basis for identifying the physiological pathway by which the
      rf2a gene participates in normal anther development and the restoration of Texas
      cytoplasm-based male sterility. For example, the observations that Texas
      cytoplasm anthers do not accumulate elevated levels of reactive oxygen species or
      lipid peroxidation and the kinetic features of RF2A make it unlikely that rf2a
      restores fertility by preventing premature programmed cell death.

PMID- 12481050
TI  - Down-regulation of caffeic acid o-methyltransferase in maize revisited using a
      transgenic approach.
AB  - Transgenic maize (Zea mays) plants were generated with a construct harboring a
      maize caffeic acid O-methyltransferase (COMT) cDNA in the antisense (AS)
      orientation under the control of the maize Adh1 (alcohol dehydrogenase) promoter.
      Adh1-driven beta-glucuronidase expression was localized in vascular tissues and
      lignifying sclerenchyma, indicating its suitability in transgenic experiments
      aimed at modifying lignin content and composition. One line of AS plants, COMT
      AS, displayed a significant reduction in COMT activity (15%-30% residual
      activity) and barely detectable amounts of COMT protein as determined by western
      blot analysis. In this line, transgenes were shown to be stably integrated in the
      genome and transmitted to the progeny. Biochemical analysis of COMT-AS showed:
      (a) a strong decrease in Klason lignin content at the flowering stage, (b) a
      decrease in syringyl units, (c) a lower p-coumaric acid content, and (d) the
      occurrence of unusual 5-OH guaiacyl units. These results are reminiscent of some
      characteristics already observed for the maize bm3 (brown-midrib3) mutant, as
      well as for COMT down-regulated dicots. However, as compared with bm3, COMT down
      regulation in the COMT-AS line is less severe in that it is restricted to
      sclerenchyma cells. To our knowledge, this is the first time that an AS strategy
      has been applied to modify lignin biosynthesis in a grass species.

PMID- 12481051
TI  - Characterization of three maize bacterial artificial chromosome libraries toward
      anchoring of the physical map to the genetic map using high-density bacterial
      artificial chromosome filter hybridization.
AB  - Three maize (Zea mays) bacterial artificial chromosome (BAC) libraries were
      constructed from inbred line B73. High-density filter sets from all three
      libraries, made using different restriction enzymes (HindIII, EcoRI, and MboI,
      respectively), were evaluated with a set of complex probes including the 185-bp
      knob repeat, ribosomal DNA, two telomere-associated repeat sequences, four
      centromere repeats, the mitochondrial genome, a multifragment chloroplast DNA
      probe, and bacteriophage lambda. The results indicate that the libraries are of
      high quality with low contamination by organellar and lambda-sequences. The use
      of libraries from multiple enzymes increased the chance of recovering each region
      of the genome. Ninety maize restriction fragment-length polymorphism core markers
      were hybridized to filters of the HindIII library, representing 6x coverage of
      the genome, to initiate development of a framework for anchoring BAC contigs to
      the intermated B73 x Mo17 genetic map and to mark the bin boundaries on the
      physical map. All of the clones used as hybridization probes detected at least
      three BACs. Twenty-two single-copy number core markers identified an average of
      7.4 +/- 3.3 positive clones, consistent with the expectation of six clones. This
      information is integrated into fingerprinting data generated by the Arizona
      Genomics Institute to assemble the BAC contigs using fingerprint contig and
      contributed to the process of physical map construction.

PMID- 12481052
TI  - Dasheng and RIRE2. A nonautonomous long terminal repeat element and its putative
      autonomous partner in the rice genome.
AB  - Dasheng is one of the highest copy number long terminal repeat elements and one
      of the most recent elements to amplify in the rice (Oryza sativa) genome.
      However, the absence of any significant coding capacity for retroviral proteins,
      including gag and pol, suggests that Dasheng is a nonautonomous element. Here, we
      have exploited the availability of 360 Mb of rice genomic sequence to identify a
      candidate autonomous element. RIRE2 is a previously described gypsy-like long
      terminal repeat retrotransposon with significant sequence similarity to Dasheng
      in the regions where putative cis factors for retrotransposition are thought to
      be located. Dasheng and RIRE2 elements have similar chromosomal distribution
      patterns and similar target site sequences, suggesting that they use the same
      transposition machinery. In addition, the presence of several RIRE2-Dasheng
      element chimeras in the genome is consistent with the copackaging of element
      mRNAs in the same virus-like particle. Finally, both families have recently
      amplified members, suggesting that they could have been co-expressed, a necessary
      prerequisite for RIRE2 to serve as the source of transposition machinery for
      Dasheng. Consistent with this hypothesis, transcripts from both elements were
      found in the same expressed sequence tag library.

PMID- 12481053
TI  - Expressed sequence tag-based gene expression analysis under aluminum stress in
      rye.
AB  - To understand the mechanisms responsible for aluminum (Al) toxicity and tolerance
      in plants, an expressed sequence tag (EST) approach was used to analyze changes
      in gene expression in roots of rye (Secale cereale L. cv Blanco) under Al stress.
      Two cDNA libraries were constructed (Al stressed and unstressed), and a total of
      1,194 and 774 ESTs were generated, respectively. The putative proteins encoded by
      these cDNAs were uncovered by Basic Local Alignment Search Tool searches, and
      those ESTs showing similarity to proteins of known function were classified
      according to 13 different functional categories. A total of 671 known function
      genes were used to analyze the gene expression patterns in rye cv Blanco root
      tips under Al stress. Many of the previously identified Al-responsive genes
      showed expression differences between the libraries within 6 h of Al stress.
      Certain genes were selected, and their expression profiles were studied during a
      48-h period using northern analysis. A total of 13 novel genes involved in cell
      elongation and division (tonoplast aquaporin and ubiquitin-like protein SMT3),
      oxidative stress (glutathione peroxidase, glucose-6-phosphate-dehydrogenase, and
      ascorbate peroxidase), iron metabolism (iron deficiency-specific proteins IDS3a,
      IDS3b, and IDS1; S-adenosyl methionine synthase; and methionine synthase), and
      other cellular mechanisms (pathogenesis-related protein 1.2, heme oxygenase, and
      epoxide hydrolase) were demonstrated to be regulated by Al stress. These genes
      provide new insights about the response of Al-tolerant plants to toxic levels of
      Al.

PMID- 12481054
TI  - Starch biosynthesis and intermediary metabolism in maize kernels. Quantitative
      analysis of metabolite flux by nuclear magnetic resonance.
AB  - The seeds of cereals represent an important sink for metabolites during the
      accumulation of storage products, and seeds are an essential component of human
      and animal nutrition. Understanding the metabolic interconversions (networks)
      underpinning storage product formation could provide the foundation for effective
      metabolic engineering of these primary nutritional sources. In this paper, we
      describe the use of retrobiosynthetic nuclear magnetic resonance analysis to
      establish the metabolic history of the glucose (Glc) units of starch in maize
      (Zea mays) kernels. Maize kernel cultures were grown with [U-(13)C(6)]Glc, [U
      (13)C(12)]sucrose, or [1,2-(13)C(2)]acetate as supplements. After 19 d, starch
      was hydrolyzed, and the isotopomer composition of the resulting Glc was
      determined by quantitative nuclear magnetic resonance analysis. [1,2
      (13)C(2)]Acetate was not incorporated into starch. [U-(13)C(6)]Glc or [U
      (13)C(12)]sucrose gave similar labeling patterns of polysaccharide Glc units,
      which were dominated by [1,2,3-(13)C(3)]- and [4,5,6-(13)C(3)]-isotopomers,
      whereas the [U-(13)C(6)]-, [3,4,5,6-(13)C(4)]-, [1,2-(13)C(2)]-, [5,6-(13)C(2)],
      [3-(13)C(1)], and [4-(13)C(1)]-isotopomers were present at lower levels. These
      isotopomer compositions indicate that there is extensive recycling of Glc before
      its incorporation into starch, via the enzymes of glycolytic, glucogenic, and
      pentose phosphate pathways. The relatively high abundance of the [5,6-(13)C(2)]
      isotopomer can be explained by the joint operation of glycolysis/glucogenesis and
      the pentose phosphate pathway.

PMID- 12481056
TI  - The National Plant Genomics Initiative: objectives for 2003-2008.

PMID- 12481055
TI  - Comparative sequence analysis of the sorghum Rph region and the maize Rp1
      resistance gene complex.
AB  - A 268-kb chromosomal segment containing sorghum (Sorghum bicolor) genes that are
      orthologous to the maize (Zea mays) Rp1 disease resistance (R) gene complex was
      sequenced. A region of approximately 27 kb in sorghum was found to contain five
      Rp1 homologs, but most have structures indicating that they are not functional.
      In contrast, maize inbred B73 has 15 Rp1 homologs in two nearby clusters of 250
      and 300 kb. As at maize Rp1, the cluster of R gene homologs is interrupted by the
      presence of several genes that appear to have no resistance role, but these genes
      were different from the ones found within the maize Rp1 complex. More than 200 kb
      of DNA downstream from the sorghum Rp1-orthologous R gene cluster was sequenced
      and found to contain many duplicated and/or truncated genes. None of the
      duplications currently exist as simple tandem events, suggesting that numerous
      rearrangements were required to generate the current genomic structure. Four
      truncated genes were observed, including one gene that appears to have both 5'
      and 3' deletions. The maize Rp1 region is also unusually enriched in truncated
      genes. Hence, the orthologous maize and sorghum regions share numerous structural
      features, but all involve events that occurred independently in each species. The
      data suggest that complex R gene clusters are unusually prone to frequent
      internal and adjacent chromosomal rearrangements of several types.

PMID- 12481057
TI  - Enhancer trap expression patterns provide a novel teaching resource.
AB  - A collection of Arabidopsis enhancer trap transposants has been identified for
      use as a teaching tool. This collection serves to assist students in
      understanding the patterning and organization of plant tissues and cells, and
      will be useful in plant anatomy, morphology, and developmental biology courses.
      Each transposant exhibits reporter gene expression in a specific tissue, cell
      type, or domain, and these lines collectively offer a glimpse of compartments of
      gene expression. Some compartments correspond to classical definitions of
      botanical anatomy and can assist in anatomical identification. Other patterns of
      reporter gene expression are more complex and do not necessarily correspond to
      known anatomical features. The sensitivity of the beta-glucuronidase
      histochemical stain provides the student with a colorful and direct way to
      visualize difficult aspects of plant development and anatomy, and provides the
      teacher with an invaluable tool for a practical laboratory session.

PMID- 12481058
TI  - Rapid structural phenotyping of plant cell wall mutants by enzymatic
      oligosaccharide fingerprinting.
AB  - Various biochemical, chemical, and microspectroscopic methods have been developed
      throughout the years for the screening and identification of mutants with altered
      cell wall structure. However, these procedures fail to provide the insight into
      structural aspects of the cell wall polymers. In this paper, we present various
      methods for rapidly screening Arabidopsis cell wall mutants. The enzymatic
      fingerprinting procedures using high-performance anion-exchange-pulsed
      amperometric detection liquid chromatography, fluorophore-assisted carbohydrate
      electrophoresis, and matrix-assisted laser-desorption ionization time of flight
      (MALDI-TOF) mass spectrometry (MS) were exemplified by the structural analysis of
      the hemicellulose xyloglucan. All three techniques are able to identify
      structural alterations of wall xyloglucans in mur1, mur2, and mur3, which in
      comparison with the wild type have side chain defects in their xyloglucan
      structure. The quickest analysis was provided by MALDI-TOF MS. Although MALDI-TOF
      MS per se is not quantitative, it is possible to reproducibly obtain relative
      abundance information of the various oligosaccharides present in the extract. The
      lack of absolute quantitation by MALDI-TOF MS was compensated for with a
      xyloglucan-specific endoglucanase and simple colorimetric assay. In view of the
      potential for mass screening using MALDI-TOF MS, a PERL-based program was
      developed to process the spectra obtained from MALDI-TOF MS automatically.
      Outliers can be identified very rapidly according to a set of defined parameters
      based on data collected from the wild-type plants. The methods presented here can
      easily be adopted for the analysis of other wall polysaccharides. MALDI-TOF MS
      offers a powerful tool to screen and identify cell wall mutants rapidly and
      efficiently and, more importantly, is able to give initial insights into the
      structural composition and/or modification that occurs in these mutants.

PMID- 12481059
TI  - Do plant caspases exist?

PMID- 12481060
TI  - Independent control of gibberellin biosynthesis and flowering time by the
      circadian clock in Arabidopsis.
AB  - Flowering of the facultative long-day plant Arabidopsis is controlled by several
      endogenous and environmental factors, among them gibberellins (GAs) and day
      length. The promotion of flowering by long days involves an endogenous clock that
      interacts with light cues provided by the environment. Light, and specifically
      photoperiod, is also known to regulate the biosynthesis of GAs, but the effects
      of GAs and photoperiod on flowering are at least partially separable. Here, we
      have used a short-period mutant, toc1, to investigate the role of the circadian
      clock in the control of flowering time by GAs and photoperiod. We show that toc1
      affects expression of several floral regulators and a GA biosynthetic gene, but
      that these effects are independent.

PMID- 12481061
TI  - Cell death processes during expression of hybrid lethality in interspecific F1
      hybrid between Nicotiana gossei Domin and Nicotiana tabacum.
AB  - Hybrid lethality, a type of reproductive isolation, is a genetically controlled
      event appearing at the seedling stage in interspecific hybrids. We characterized
      the lethality of F(1) hybrid seedlings from Nicotiana gossei Domin and Nicotiana
      tabacum cv Bright-Yellow 4 using a number of traits including growth rate,
      microscopic features of tissues and cells, ion leakage, DNA degradation, reactive
      oxygen intermediates including superoxide radical (O(2)(-)) and hydrogen peroxide
      (H(2)O(2)), and expression of stress response marker genes. Lethal symptoms
      appeared at 4 d after germination in the basal hypocotyl and extended toward both
      the hypocotyl and root of the plants grown at 26 degrees C. Microscopic analysis
      revealed a prompt lysis of cell components during cell death. Membrane disruption
      and DNA degradation were found in the advanced stage of the lethality. The death
      of mesophyll cells in the cotyledon was initiated by the vascular bundle,
      suggesting that a putative factor inducing cell death diffused into surrounding
      cells from the vascular tissue. In contrast, these symptoms were not observed in
      the plants grown at 37 degrees C. Seedlings grown at 26 degrees C generated
      larger amounts of reactive oxygen intermediate in the hypocotyl than those grown
      at 37 degrees C. A number of stress response marker genes were expressed at 26
      degrees C but not at 37 degrees C. We proposed that a putative death factor
      moving systemically through the vascular system induced a prompt and successive
      lysis of the cytoplasm of cells and that massive cell death eventually led to the
      loss of the hybrid plant.

PMID- 12481062
TI  - Characterization of Arabidopsis AtAMT2, a high-affinity ammonium transporter of
      the plasma membrane.
AB  - AtAMT2 is an ammonium transporter that is only distantly related to the five
      members of the AtAMT1 family of high-affinity ammonium transporters in
      Arabidopsis. The short-lived radioactive ion (13)NH(4)(+) was used to show that
      AtAMT2, expressed in yeast (Saccharomyces cerevisiae), is a high-affinity
      transporter with a K(m) for ammonium of about 20 microM. Changes in external pH
      between 5.0 and 7.5 had little effect on the K(m) for ammonium, indicating that
      NH(4)(+), not NH(3), is the substrate for AtAMT2. The AtAMT2 gene was expressed
      in all organs of Arabidopsis and was subject to nitrogen (N) regulation, at least
      in roots where expression was partially repressed by high concentrations of
      ammonium nitrate and derepressed in the absence of external N. Although
      expression of AtAMT2 in shoots responded little to changes in root N status,
      transcript levels in leaves declined under high CO(2) conditions. Transient
      expression of an AtAMT2-green fluorescent protein fusion protein in Arabidopsis
      leaf epidermal cells indicated a plasma membrane location for the AtAMT2 protein.
      Thus, AtAMT2 is likely to play a significant role in moving ammonium between the
      apoplast and symplast of cells throughout the plant. However, a dramatic
      reduction in the level of AtAMT2 transcript brought about by dsRNA interference
      with gene expression had no obvious effect on plant growth or development, under
      the conditions tested.

PMID- 12481063
TI  - Molecular characterization of a novel gene family encoding ACT domain repeat
      proteins in Arabidopsis.
AB  - In bacteria, the regulatory ACT domains serve as amino acid-binding sites in some
      feedback-regulated amino acid metabolic enzymes. We have identified a novel type
      of ACT domain-containing protein family in Arabidopsis whose members contain ACT
      domain repeats (the "ACR" protein family). There are at least eight ACR genes
      located on each of the five chromosomes in the Arabidopsis genome. Gene structure
      comparisons indicate that the ACR gene family may have arisen by gene
      duplications. Northern-blot analysis indicates that each member of the ACR gene
      family has a distinct expression pattern in various organs from 6-week-old
      Arabidopsis. Moreover, analyses of an ACR3 promoter-beta-glucuronidase (GUS)
      fusion in transgenic Arabidopsis revealed that the GUS activity formed a gradient
      in the developing leaves and sepals, whereas low or no GUS activity was detected
      in the basal regions. In 2-week-old Arabidopsis seedlings grown in tissue
      culture, the expression of the ACR gene family is differentially regulated by
      plant hormones, salt stress, cold stress, and light/dark treatment. The steady
      state levels of ACR8 mRNA are dramatically increased by treatment with abscisic
      acid or salt. Levels of ACR3 and ACR4 mRNA are increased by treatment with
      benzyladenine. The amino acid sequences of Arabidopsis ACR proteins are most
      similar in the ACT domains to the bacterial sensor protein GlnD. The ACR proteins
      may function as novel regulatory or sensor proteins in plants.

PMID- 12481064
TI  - An endoplasmic reticulum-derived structure that is induced under stress
      conditions in Arabidopsis.
AB  - The endoplasmic reticulum (ER) body is a characteristic structure derived from ER
      and is referred to as a proteinase-sorting system that assists the plant cell
      under various stress conditions. Fluorescent ER bodies were observed in
      transgenic plants of Arabidopsis expressing green fluorescent protein fused with
      an ER retention signal. ER bodies were widely distributed in the epidermal cells
      of whole seedlings. In contrast, rosette leaves had no ER bodies. We found that
      wound stress induced the formation of many ER bodies in rosette leaves. ER bodies
      were also induced by treatment with methyl jasmonate (MeJA), a plant hormone
      involved in the defense against wounding and chewing by insects. The induction of
      ER bodies was suppressed by ethylene. An electron microscopic analysis showed
      that typical ER bodies were induced in the non-transgenic rosette leaves treated
      with MeJA. An experiment using coi1 and etr1-4 mutant plants showed that the
      induction of ER bodies was strictly coupled with the signal transduction of MeJA
      and ethylene. These results suggested that the formation of ER bodies is a novel
      and unique type of endomembrane system in the response of plant cells to
      environmental stresses. It is possible that the biological function of ER bodies
      is related to defense systems in higher plants.

PMID- 12481065
TI  - Forms of zinc accumulated in the hyperaccumulator Arabidopsis halleri.
AB  - The chemical forms of zinc (Zn) in the Zn-tolerant and hyperaccumulator
      Arabidopsis halleri and in the non-tolerant and nonaccumulator Arabidopsis lyrata
      subsp. petraea were determined at the molecular level by combining chemical
      analyses, extended x-ray absorption spectroscopy (EXAFS), synchrotron-based x-ray
      microfluorescence, and muEXAFS. Plants were grown in hydroponics with various Zn
      concentrations, and A. halleri specimens growing naturally in a contaminated site
      were also collected. Zn speciation in A. halleri was independent of the origin of
      the plants (contaminated or non-contaminated) and Zn exposure. In aerial parts,
      Zn was predominantly octahedrally coordinated and complexed to malate. A
      secondary organic species was identified in the bases of the trichomes, which
      contained elevated Zn concentrations, and in which Zn was tetrahedrally
      coordinated and complexed to carboxyl and/or hydroxyl functional groups. This
      species was detected thanks to the good resolution and sensitivity of synchrotron
      based x-ray microfluorescence and muEXAFS. In the roots of A. halleri grown in
      hydroponics, Zn phosphate was the only species detected, and is believed to
      result from chemical precipitation on the root surface. In the roots of A.
      halleri grown on the contaminated soil, Zn was distributed in Zn malate, Zn
      citrate, and Zn phosphate. Zn phosphate was present in both the roots and aerial
      part of A. lyrata subsp. petraea. This study illustrates the complementarity of
      bulk and spatially resolved techniques, allowing the identification of: (a) the
      predominant chemical forms of the metal, and (b) the minor forms present in
      particular cells, both types of information being essential for a better
      understanding of the bioaccumulation processes.

PMID- 12481066
TI  - Ectopic expression of carpel-specific MADS box genes from lily and lisianthus
      causes similar homeotic conversion of sepal and petal in Arabidopsis.
AB  - Two MADS box genes, Lily MADS Box Gene 2 (LMADS2) and Eustoma grandiflorum MADS
      Box Gene 1 (EgMADS1), with an extensive similarity to the petunia (Petunia
      hybrida) FLORAL BINDING PROTEIN 7/11 and Arabidopsis AGL11, were characterized
      from the lily (Lilium longiflorum) and lisianthus (Eustoma grandiflorum). The
      expression of LMADS2 and EgMADS1 mRNA was restricted to the carpel and was absent
      in the other flower organs or vegetative leaves. LMADS2 mRNA was detected mainly
      in ovules and weakly in style tissues of the carpel, whereas EgMADS1 mRNA was
      only expressed in the ovules. Transgenic Arabidopsis plants ectopically
      expressing LMADS2 or EgMADS1 showed similar novel phenotypes resembling
      35S::AGAMOUS plants by significantly reducing plant size, flowering early, and
      losing inflorescence indeterminacy. Ectopic expression of these two genes also
      generated similar ap2-like flowers by inducing homeotic conversion of the sepals
      into carpel-like structures in which stigmatic papillae and ovules were observed.
      In addition, the petals were converted into stamen-like structures in the second
      whorl of 35S::LMADS2 and 35S::EgMADS1 transgenic Arabidopsis. Our data indicated
      that LMADS2 and EgMADS1 are putative D functional MADS box genes in lily and
      lisianthus with a function similar to C functional genes once ectopically
      expressed in Arabidopsis.

PMID- 12481067
TI  - Cloning, functional expression, and subcellular localization of multiple NADPH
      cytochrome P450 reductases from hybrid poplar.
AB  - NADPH:cytochrome P450 reductase (CPR) provides reducing equivalents to diverse
      cytochrome P450 monooxygenases. We isolated cDNAs for three CPR genes (CPR1,
      CPR2, and CPR3) from hybrid poplar (Populus trichocarpa x Populus deltoides).
      Deduced CPR2 and CPR3 amino acid sequences were 91% identical, but encoded
      isoforms divergent from CPR1 (72% identity). CPR1 and CPR2 were co-expressed
      together with the P450 enzyme cinnamate-4-hydroxylase (C4H) in yeast
      (Saccharomyces cerevisiae). Microsomes isolated from strains expressing CPR1/C4H
      or CPR2/C4H enhanced C4H activities approximately 10-fold relative to the C4H
      only control strain, and catalyzed NADPH-dependent cytochrome c reduction. The
      divergent CPR isoforms (CPR1 and CPR2/3) contained entirely different N-terminal
      sequences, which are conserved in other plant CPRs and are diagnostic for two
      distinct classes of CPRs within the angiosperms. C-terminal green fluorescent
      protein fusions to CPR1 and CPR2 were constructed and expressed in both yeast and
      Arabidopsis. The fusion proteins expressed in yeast retained the ability to
      support C4H activity and, thus, were catalytically active. Both CPR::green
      fluorescent protein fusion proteins were strictly localized to the endoplasmic
      reticulum in transgenic Arabidopsis. The lack of localization of either isoform
      to chloroplasts, where P450s are known to be present, suggests that an
      alternative P450 reduction system may be operative in this organelle. Transcripts
      for the three poplar CPR genes were present ubiquitously in all tissues examined,
      but CPR2 showed highest expression in young leaf tissue.

PMID- 12481068
TI  - Nitric oxide improves internal iron availability in plants.
AB  - Iron deficiency impairs chlorophyll biosynthesis and chloroplast development. In
      leaves, most of the iron must cross several biological membranes to reach the
      chloroplast. The components involved in the complex internal iron transport are
      largely unknown. Nitric oxide (NO), a bioactive free radical, can react with
      transition metals to form metal-nitrosyl complexes. Sodium nitroprusside, an NO
      donor, completely prevented leaf interveinal chlorosis in maize (Zea mays) plants
      growing with an iron concentration as low as 10 microM Fe-EDTA in the nutrient
      solution. S-Nitroso-N-acetylpenicillamine, another NO donor, as well as gaseous
      NO supply in a translucent chamber were also able to revert the iron deficiency
      symptoms. A specific NO scavenger, 2-(4-carboxy-phenyl)-4,4,5,5
      tetramethylimidazoline-1-oxyl-3-oxide, blocked the effect of the NO donors. The
      effect of NO treatment on the photosynthetic apparatus of iron-deficient plants
      was also studied. Electron micrographs of mesophyll cells from iron-deficient
      maize plants revealed plastids with few photosynthetic lamellae and rudimentary
      grana. In contrast, in NO-treated maize plants, mesophyll chloroplast appeared
      completely developed. NO treatment did not increase iron content in plant organs,
      when expressed in a fresh matter basis, suggesting that root iron uptake was not
      enhanced. NO scavengers 2-(4-carboxy-phenyl)-4,4,5,5-tetramethylimidazoline-1
      oxyl-3-oxide and methylene blue promoted interveinal chlorosis in iron-replete
      maize plants (growing in 250 microM Fe-EDTA). Even though results support a role
      for endogenous NO in iron nutrition, experiments did not establish an essential
      role. NO was also able to revert the chlorotic phenotype of the iron-inefficient
      maize mutants yellow stripe1 and yellow stripe3, both impaired in the iron uptake
      mechanisms. All together, these results support a biological action of NO on the
      availability and/or delivery of metabolically active iron within the plant.

PMID- 12481069
TI  - Genetic and physiological analysis of germination efficiency in maize in relation
      to nitrogen metabolism reveals the importance of cytosolic glutamine synthetase.
AB  - We have developed an approach combining physiology and quantitative genetics to
      enhance our understanding of nitrogen (N) metabolism during kernel germination.
      The physiological study highlighted the central role of glutamine (Gln)
      synthetase (GS) and Gln synthesis during this developmental process because a
      concomitant increase of both the enzyme activity and the amino acid content was
      observed. This result suggests that Gln is acting either as a sink for ammonium
      released during both storage protein degradation and amino acid deamination or as
      a source for amino acid de novo synthesis by transamination. In the two parental
      lines used for the quantitative genetics approach, we found that the increase in
      Gln occurred earlier in Io compared with F(2), a result consistent with its
      faster germinating capacity. The genetic study was carried out on 140 F6
      recombinant inbred lines derived from the cross between F(2) and Io. Quantitative
      trait locus mapping identified three quantitative trait loci (QTLs) related to
      germination trait (T50, time at which 50% of the kernels germinated) that explain
      18.2% of the phenotypic variance; three QTLs related to a trait linked to
      germination performance, kernel size/weight (thousand kernels weight), that
      explain 17% of the phenotypic variance; two QTLs related to GS activity at early
      stages of germination that explain 17.7% of the phenotypic variance; and one QTL
      related to GS activity at late stages of germination that explains 7.3% of the
      phenotypic variance. Coincidences of QTL for germination efficiency and its
      components with genes encoding cytosolic GS (GS1) and the corresponding enzyme
      activity were detected, confirming the important role of the enzyme during the
      germination process. A triple colocalization on chromosome 4 between gln3 (a
      structural gene encoding GS1) and a QTL for GS activity and T50 was found;
      whereas on chromosome 5, a QTL for GS activity and thousand kernels weight
      colocalized with gln4, another structural gene encoding GS1. This observation
      suggests that for each gene, the corresponding enzyme activity is of major
      importance for germination efficiency either through the size of the grain or
      through its faster germinating capacity. Consistent with the possible
      nonoverlapping function of the two GS1 genes, we found that in the parental line
      Io, the expression of Gln3 was transiently enhanced during the first hours of
      germination, whereas that of gln4 was constitutive.

PMID- 12481070
TI  - Comparative molecular and functional analyses of the tobacco cyclin-dependent
      kinase inhibitor NtKIS1a and its spliced variant NtKIS1b.
AB  - In all eukaryotes, cell cycle progression is controlled by cyclin-dependent
      kinases (CDKs) whose activity is regulated at several levels including inhibition
      by CDK inhibitors. Here, we report a comparative molecular and functional
      analysis of the tobacco (Nicotiana tomentosiformis) CDK inhibitor, NtKIS1a, and
      its spliced variant, NtKIS1b. The C-terminal end of NtKIS1a shares strong
      sequence similarity with mammalian CIP/KIP inhibitors, which is not the case for
      NtKIS1b. Consistent with this, NtKIS1a but not NtKIS1b inhibits in vitro the
      kinase activity of CDK/cyclin complexes, and tobacco (Nicotiana tabacum) D-type
      cyclins and an A-type CDK are NtKIS1a, but not NtKIS1b, interacting partners.
      Although both NtKIS1a and NtKIS1b transcripts are mainly found in flowers and
      more precisely in stamens, NtKIS1b transcript levels are cell cycle regulated,
      whereas those of NtKIS1a remain constant during the cell cycle. NtKIS1a and
      NtKIS1b fused to fluorescent proteins are localized in the nucleus when
      transiently expressed in onion epidermal cells. Furthermore, there is no
      competition for their nuclear localization when they are simultaneously
      overexpressed. In vitro competition toward CDK kinase activity suggests that
      NtKIS1b is a strong competitor of NtKIS1a. Arabidopsis plants overexpressing
      NtKIS1a-green fluorescent protein (GFP) or NtKIS1b-GFP fusion proteins were
      obtained. In these plants, the fusion proteins are still localized in the
      nucleus. Interestingly, NtKIS1a-GFP-overexpressing plants display strong
      morphological modifications and a reduced CDK kinase activity, whereas NtKIS1b
      GFP-overexpressing plants display a wild-type phenotype including a wild-type CDK
      kinase activity. Our results strongly suggest that the inhibition of the kinase
      activity is responsible for the phenotypic modifications.

PMID- 12481071
TI  - Genetic complexity of cellulose synthase a gene function in Arabidopsis
      embryogenesis.
AB  - The products of the cellulose synthase A (CESA) gene family are thought to
      function as isoforms of the cellulose synthase catalytic subunit, but for most
      CESA genes, the exact role in plant growth is still unknown. Assessing the
      function of individual CESA genes will require the identification of the null
      mutant phenotypes and of the gene expression profiles for each gene. Here, we
      report that only four of 10 CESA genes, CESA1, CESA2, CESA3, and CESA9 are
      significantly expressed in the Arabidopsis embryo. We further identified two new
      mutations in the RADIALLY SWOLLEN1 (RSW1/CESA1) gene of Arabidopsis that obstruct
      organized growth in both shoot and root and interfere with cell division and cell
      expansion already in embryogenesis. One mutation is expected to completely
      abolish the enzymatic activity of RSW1(CESA1) because it eliminated one of three
      conserved Asp residues, which are considered essential for beta
      glycosyltransferase activity. In this presumed null mutant, primary cell walls
      are still being formed, but are thin, highly undulated, and frequently
      interrupted. From the heart-stage onward, cell elongation in the embryo axis is
      severely impaired, and cell width is disproportionally increased. In the embryo,
      CESA1, CESA2, CESA3, and CESA9 are expressed in largely overlapping domains and
      may act cooperatively in higher order complexes. The embryonic phenotype of the
      presumed rsw1 null mutant indicates that the RSW1(CESA1) product has a critical,
      nonredundant function, but is nevertheless not strictly required for primary cell
      wall formation.

PMID- 12481072
TI  - Light-dependent death of maize lls1 cells is mediated by mature chloroplasts.
AB  - We reported previously the isolation of a novel cell death-suppressing gene from
      maize (Zea mays) encoded by the Lls1 (Lethal leaf spot-1) gene. Although the
      exact metabolic function of LLS1 remains elusive, here we provide insight into
      mechanisms that underlie the initiation and propagation of cell death associated
      with lls1 lesions. Our data indicate that lls1 lesions are triggered in response
      to a cell-damaging event caused by any biotic or abiotic agent or intrinsic
      metabolic imbalance--as long as the leaf tissue is developmentally competent to
      develop lls1 lesions. Continued expansion of these lesions, however, depends on
      the availability of light, with fluence rate being more important than spectral
      quality. Double-mutant analysis of lls1 with two maize mutants oil-yellow and
      iojap, both compromised photosynthetically and unable to accumulate normal levels
      of chlorophyll, indicated that it was the light harvested by the plant that
      energized lls1 lesion development. Chloroplasts appear to be the key mediators of
      lls1 cell death; their swelling and distortion occurs before any other changes
      normally associated with dying cells. In agreement with these results are
      indications that LLS1 is a chloroplast-localized protein whose transcript was
      detected only in green tissues. The propagative nature of light-dependent lls1
      lesions predicts that cell death associated with these lesions is caused by a
      mobile agent such as reactive oxidative species. LLS1 may act to prevent reactive
      oxidative species formation or serve to remove a cell death mediator so as to
      maintain chloroplast integrity and cell survival.

PMID- 12481073
TI  - Auxin and ethylene response interactions during Arabidopsis root hair development
      dissected by auxin influx modulators.
AB  - The plant hormones auxin and ethylene have been shown to play important roles
      during root hair development. However, cross talk between auxin and ethylene
      makes it difficult to understand the independent role of either hormone. To
      dissect their respective roles, we examined the effects of two compounds,
      chromosaponin I (CSI) and 1-naphthoxyacetic acid (1-NOA), on the root hair
      developmental process in wild-type Arabidopsis, ethylene-insensitive mutant ein2
      1, and auxin influx mutants aux1-7, aux1-22, and double mutant aux1-7 ein2. Beta
      glucuronidase (GUS) expression analysis in the BA-GUS transgenic line, consisting
      of auxin-responsive domains of PS-IAA4/5 promoter and GUS reporter, revealed that
      1-NOA and CSI act as auxin uptake inhibitors in Arabidopsis roots. The frequency
      of root hairs in ein2-1 roots was greatly reduced in the presence of CSI or 1
      NOA, suggesting that endogenous auxin plays a critical role for the root hair
      initiation in the absence of an ethylene response. All of these mutants showed a
      reduction in root hair length, however, the root hair length could be restored
      with a variable concentration of 1-naphthaleneacetic acid (NAA). NAA (10 nM)
      restored the root hair length of aux1 mutants to wild-type level, whereas 100 nM
      NAA was needed for ein2-1 and aux1-7 ein2 mutants. Our results suggest that
      insensitivity in ethylene response affects the auxin-driven root hair elongation.
      CSI exhibited a similar effect to 1-NOA, reducing root hair growth and the number
      of root hair-bearing cells in wild-type and ein2-1 roots, while stimulating these
      traits in aux1-7and aux1-7ein2 roots, confirming that CSI is a unique modulator
      of AUX1.

PMID- 12481074
TI  - Ethylene synthesis regulated by biphasic induction of 1-aminocyclopropane-1
      carboxylic acid synthase and 1-aminocyclopropane-1-carboxylic acid oxidase genes
      is required for hydrogen peroxide accumulation and cell death in ozone-exposed
      tomato.
AB  - We show that above a certain threshold concentration, ozone leads to leaf injury
      in tomato (Lycopersicon esculentum). Ozone-induced leaf damage was preceded by a
      rapid increase in 1-aminocyclopropane-1-carboxylic acid (ACC) synthase activity,
      ACC content, and ethylene emission. Changes in mRNA levels of specific ACC
      synthase, ACC oxidase, and ethylene receptor genes occurred within 1 to 5 h.
      Expression of the genes encoding components of ethylene biosynthesis and
      perception, and biochemistry of ethylene synthesis suggested that ozone-induced
      ethylene synthesis in tomato is under biphasic control. In transgenic plants
      containing an LE-ACO1 promoter-beta-glucuronidase fusion construct, beta
      glucuronidase activity increased rapidly at the beginning of the O(3) exposure
      and had a spatial distribution resembling the pattern of extracellular H(2)O(2)
      production at 7 h, which coincided with the cell death pattern after 24 h.
      Ethylene synthesis and perception were required for active H(2)O(2) production
      and cell death resulting in visible tissue damage. The results demonstrate a
      selective ozone response of ethylene biosynthetic genes and suggest a role for
      ethylene, in combination with the burst of H(2)O(2) production, in regulating the
      spread of cell death.

PMID- 12481075
TI  - Control of demand-driven biosynthesis of glutathione in green Arabidopsis
      suspension culture cells.
AB  - We have investigated what limits demand-driven de novo glutathione (GSH)
      biosynthesis in green Arabidopsis suspension culture cells. GSH is the most
      abundant low-molecular weight thiol in most plants and can be quantified using
      monochlorobimane to fluorescently label GSH in live cells. Progress curves for
      labeling reached a plateau as all the cytoplasmic GSH was conjugated. In the
      presence of excess monochlorobimane, a second, almost linear phase of labeling
      was observed, after a lag of 2 to 3 h, that was then maintained for an extended
      period. The increase in fluorescence was shown to be because of de novo GSH
      biosynthesis by high-performance liquid chromatography analysis and was
      eliminated by DL-buthionine-[S,R]-sulfoximine, a specific inhibitor of GSH
      biosynthesis, or reduced by inhibitors of transcription and translation. The rate
      of GSH biosynthesis during the linear phase was 8.9 +/- 1.4 nmol g fresh weight(
      1) min(-1) and was not affected by addition of glutamate, glycine, or cysteine,
      the immediate precursors needed for GSH biosynthesis. Likewise, the synthesis
      rate was not affected by pretreatment with aminotriazole, menadione, jasmonic
      acid, or cadmium, all of which cause oxidative stress and up-regulate expression
      of GSH biosynthetic genes. The lag phase was markedly reduced by aminotriazole
      and menadione and marginally by jasmonic acid, suggesting the system was primed
      to react faster after mild stress. In contrast to the other feeding experiments,
      exclusion of SO(4)(2-) from the medium abolished the second phase completely.
      This suggests demand-driven GSH biosynthesis is directly coupled to uptake of
      SO(4)(2-) and that the linear increase in fluorescence reflects flux through the
      entire SO(4)(2-) assimilation pathway.

PMID- 12481077
TI  - Humic acids isolated from earthworm compost enhance root elongation, lateral root
      emergence, and plasma membrane H+-ATPase activity in maize roots.
AB  - Earthworms (Eisenia foetida) produce humic substances that can influence plant
      growth by mechanisms that are not yet clear. In this work, we investigated the
      effects of humic acids (HAs) isolated from cattle manure earthworm compost on the
      earliest stages of lateral root development and on the plasma membrane H(+)
      ATPase activity. These HAs enhance the root growth of maize (Zea mays) seedlings
      in conjunction with a marked proliferation of sites of lateral root emergence.
      They also stimulate the plasma membrane H(+)-ATPase activity, apparently
      associated with an ability to promote expression of this enzyme. In addition,
      structural analysis reveals the presence of exchangeable auxin groups in the
      macrostructure of the earthworm compost HA. These results may shed light on the
      hormonal activity that has been postulated for these humic substances.

PMID- 12481076
TI  - Proteomics of light-harvesting proteins in different plant species. Analysis and
      comparison by liquid chromatography-electrospray ionization mass spectrometry.
      Photosystem I.
AB  - The light-harvesting proteins (Lhca) of photosystem I (PSI) from four monocot and
      five dicot species were extracted from plant material, separated by reversed
      phase high-performance liquid chromatography (HPLC) and subsequently identified
      on the basis of their intact molecular masses upon on-line hyphenation with
      electrospray ionization mass spectrometry. Although their migration behavior in
      gel electrophoresis was very similar, the elution times among the four antenna
      types in reversed-phase-HPLC differed significantly, even more than those
      observed for the light-harvesting proteins of photosystem II. Identification of
      proteins is based on the good agreement between the measured intact molecular
      masses and the values calculated on the basis of their nucleotide-derived amino
      acid sequences, which makes the intact molecular masses applicable as intact mass
      tags. These values match excellently for Arabidopsis, most probably because of
      the availability of high-quality DNA sequence data. In all species examined, the
      four antennae eluted in the same order, namely Lhca1 > Lhca3 > Lhca4 > Lhca2.
      These characteristic patterns enabled an unequivocal assignment of the proteins
      in preparations from different species. Interestingly, in all species examined,
      Lhca1 and Lhca2 were present in two or three isoforms. A fifth antenna protein,
      corresponding to the Lhca6 gene, was found in tomato (Lycopersicon esculentum).
      However PSI showed a lower heterogeneity than photosystem II. In most plant
      species, Lhca2 and Lhca4 proteins are the most abundant PSI antenna proteins. The
      HPLC method used in this study was found to be highly reproducible, and the
      chromatograms may serve as a highly confident fingerprint for comparison within a
      single and among different species for future studies of the PSI antenna.

PMID- 12481078
TI  - Expression and biochemical properties of a ferredoxin-dependent heme oxygenase
      required for phytochrome chromophore synthesis.
AB  - The HY1 gene of Arabidopsis encodes a plastid heme oxygenase (AtHO1) required for
      the synthesis of the chromophore of the phytochrome family of plant
      photoreceptors. To determine the enzymatic properties of plant heme oxygenases,
      we have expressed the HY1 gene (without the plastid transit peptide) in
      Escherichia coli to produce an amino terminal fusion protein between AtHO1 and
      glutathione S-transferase. The fusion protein was soluble and expressed at high
      levels. Purified recombinant AtHO1, after glutathione S-transferase cleavage, is
      a hemoprotein that forms a 1:1 complex with heme. In the presence of reduced
      ferredoxin, AtHO1 catalyzed the formation of biliverdin IXalpha from heme with
      the concomitant production of carbon monoxide. Heme oxygenase activity could also
      be reconstituted using photoreduced ferredoxin generated through light
      irradiation of isolated thylakoid membranes, suggesting that ferredoxin may be
      the electron donor in vivo. In addition, AtHO1 required an iron chelator and
      second reductant, such as ascorbate, for full activity. These results show that
      the basic mechanism of heme cleavage has been conserved between plants and other
      organisms even though the function, subcellular localization, and cofactor
      requirements of heme oxygenases differ substantially.

PMID- 12481079
TI  - Germanium does not substitute for boron in cross-linking of rhamnogalacturonan II
      in pumpkin cell walls.
AB  - Boron (B)-deficient pumpkin (Cucurbita moschata Duchesne) plants exhibit reduced
      growth, and their tissues are brittle. The leaf cell walls of these plants
      contain less than one-half the amount of borate cross-linked rhamnogalacturonan
      II (RG-II) dimer than normal plants. Supplying germanium (Ge), which has been
      reported to substitute for B, to B-deficient plants does not restore growth or
      reduce tissue brittleness. Nevertheless, the leaf cell walls of the Ge-treated
      plants accumulated considerable amounts of Ge. Dimeric RG-II (dRG-II) accounted
      for between 20% and 35% of the total RG-II in the cell walls of the second to
      fourth leaves from Ge-treated plants, but only 2% to 7% of the RG-II was cross
      linked by germanate (dRG-II-Ge). The ability of RG-II to form a dimer is not
      reduced by Ge treatment because approximately 95% of the monomeric RG-II
      generated from the walls of Ge-treated plants is converted to dRG-II-Ge in vitro
      in the presence of germanium oxide and lead acetate. However, dRG-II-Ge is
      unstable and is converted to monomeric RG-II when the Ge is removed. Therefore,
      the content of dRG-II-Ge and dRG-II-B described above may not reflect the actual
      ratio of these in muro. (10)B-Enriched boric acid and Ge are incorporated into
      the cell wall within 10 min after their foliar application to B-deficient plants.
      Foliar application of (10)B but not Ge results in an increase in the proportion
      of dRG-II in the leaf cell wall. Taken together, our results suggest that Ge does
      not restore the growth of B-deficient plants.

PMID- 12481080
TI  - Auxin regulation of the gibberellin pathway in pea.
AB  - The auxin indole-3-acetic acid (IAA) has been shown to promote the biosynthesis
      of the active gibberellin (GA(1)) in shoots of pea (Pisum sativum). We used
      northern analysis to investigate the timing of IAA-induced changes in transcript
      levels of PsGA3ox1 (Mendel's LE), PsGA2ox1, PsGA2ox2, and PsGA20ox1, key genes
      for the later stages of GA(1) biosynthesis and metabolism in pea. Rapid (2-4 h)
      changes occurred in the transcript levels of PsGA3ox1, PsGA2ox1, and PsGA2ox2
      after treatment with IAA. [(14)C]GA(1) metabolism studies in decapitated shoots
      indicated that IAA inhibits GA(1) deactivation, consistent with the suppression
      of PsGA2ox1 (SLN) transcript levels by IAA. Studies with the sln mutant also
      indicated that PsGA2ox1 activity is involved in GA(1) deactivation in decapitated
      shoots. Culture of excised internode tissue in the presence of auxin clearly
      demonstrated that internode tissue is a site of GA(1) biosynthesis per se.
      Excised internode tissue cultured in the presence/absence of cycloheximide showed
      that de novo protein synthesis is required for IAA-induced increases in PsGA3ox1
      transcript levels. Auxin dose response studies indicated that IAA concentration
      is a critical determinant of GA(1) biosynthesis over 1 to 2 orders of magnitude,
      and a range of auxins was shown to affect the GA pathway.

PMID- 12481081
TI  - Effect of ethylene pathway mutations upon expression of the ethylene receptor
      ETR1 from Arabidopsis.
AB  - The ethylene receptor family of Arabidopsis consists of five members, one of
      these being ETR1. The effect of ethylene pathway mutations upon expression of
      ETR1 was examined. For this purpose, ETR1 levels were quantified in mutant
      backgrounds containing receptor loss-of-function mutations, ethylene-insensitive
      mutations, and constitutive ethylene response mutations. Ethylene-insensitive
      mutations of ETR1 resulted in a posttranscriptional increase in levels of the
      mutant receptor. Treatment of seedlings with silver, which leads to ethylene
      insensitivity, also resulted in an increase in levels of ETR1. Loss-of-function
      mutations of ETR1 resulted in both transcriptional and posttranscriptional
      changes in levels of the receptor. Most other ethylene pathway mutations,
      including a newly isolated T-DNA insertion mutation in the gene encoding the
      ethylene receptor ERS1, had relatively minor effects upon the expression of ETR1.
      Our results indicate that mutations in ETR1 can affect expression at the
      posttranscriptional level, and suggest that these posttranscriptional changes may
      contribute to the phenotypes observed in the mutants. Our results also refine the
      model on how mutations in ethylene receptors are able to confer dominant ethylene
      insensitivity upon plants.

PMID- 12481082
TI  - Temperature response of mesophyll conductance. Implications for the determination
      of Rubisco enzyme kinetics and for limitations to photosynthesis in vivo.
AB  - CO(2) transfer conductance from the intercellular airspaces of the leaf into the
      chloroplast, defined as mesophyll conductance (g(m)), is finite. Therefore, it
      will limit photosynthesis when CO(2) is not saturating, as in C3 leaves in the
      present atmosphere. Little is known about the processes that determine the
      magnitude of g(m). The process dominating g(m) is uncertain, though carbonic
      anhydrase, aquaporins, and the diffusivity of CO(2) in water have all been
      suggested. The response of g(m) to temperature (10 degrees C-40 degrees C) in
      mature leaves of tobacco (Nicotiana tabacum L. cv W38) was determined using
      measurements of leaf carbon dioxide and water vapor exchange, coupled with
      modulated chlorophyll fluorescence. These measurements revealed a temperature
      coefficient (Q(10)) of approximately 2.2 for g(m), suggesting control by a
      protein-facilitated process because the Q(10) for diffusion of CO(2) in water is
      about 1.25. Further, g(m) values are maximal at 35 degrees C to 37.5 degrees C,
      again suggesting a protein-facilitated process, but with a lower energy of
      deactivation than Rubisco. Using the temperature response of g(m) to calculate
      CO(2) at Rubisco, the kinetic parameters of Rubisco were calculated in vivo from
      10 degrees C to 40 degrees C. Using these parameters, we determined the
      limitation imposed on photosynthesis by g(m). Despite an exponential rise with
      temperature, g(m) does not keep pace with increased capacity for CO(2) uptake at
      the site of Rubisco. The fraction of the total limitations to CO(2) uptake within
      the leaf attributable to g(m) rose from 0.10 at 10 degrees C to 0.22 at 40
      degrees C. This shows that transfer of CO(2) from the intercellular air space to
      Rubisco is a very substantial limitation on photosynthesis, especially at high
      temperature.

PMID- 12481083
TI  - Acclimation of rice photosynthesis to irradiance under field conditions.
AB  - Acclimation to irradiance was measured in terms of light-saturated photosynthetic
      carbon assimilation rates (P(max)), Rubisco, and pigment content in mature field
      grown rice (Oryza sativa) plants in tropical conditions. Measurements were made
      at different positions within the canopy alongside irradiance and daylight
      spectra. These data were compared with a second experiment in which acclimation
      to irradiance was assessed in uppermost leaves within whole-plant shading regimes
      (10% low light [LL], 40% medium light [ML], and 100% high light [HL] of full
      natural sunlight). Two varieties, japonica (tropical; new plant type [NPT]) and
      indica (IR72) were compared. Values for Rubisco amount, chlorophyll a/b, and
      P(max) all declined from the top to the base of the canopy. In the artificial
      shading experiment, acclimation of P(max) (measured at 350 microL L(-1) CO(2))
      occurred between LL and ML for IR72 with no difference observed between ML and
      HL. The Rubisco amount increased between ML and HL in IR72. A different pattern
      was seen for NPT with higher P(max) (measured at 350 microL L(-1) CO(2)) at LL
      than IR72 and some acclimation of this parameter between ML and HL. Rubisco
      levels were higher in NPT than IR72 contrasting with P(max). Comparison of data
      from both experiments suggests a leaf aging effect between the uppermost two leaf
      positions, which was not a result of irradiance acclimation. Results are
      discussed in terms of: (a) acclimation of photosynthesis and radiation use
      efficiency at high irradiance in rice, and (b) factors controlling photosynthetic
      rates of leaves within the canopy.

PMID- 12481084
TI  - Polyphenolic allelochemicals from the aquatic angiosperm Myriophyllum spicatum
      inhibit photosystem II.
AB  - Myriophyllum spicatum (Haloragaceae) is a highly competitive freshwater
      macrophyte that produces and releases algicidal and cyanobactericidal
      polyphenols. Among them, beta-1,2,3-tri-O-galloyl-4,6-(S)-hexahydroxydiphenoyl-D
      glucose (tellimagrandin II) is the major active substance and is an effective
      inhibitor of microalgal exoenzymes. However, this mode of action does not fully
      explain the strong allelopathic activity observed in bioassays. Lipophilic
      extracts of M. spicatum inhibit photosynthetic oxygen evolution of intact
      cyanobacteria and other photoautotrophs. Fractionation of the extract provided
      evidence for tellimagrandin II as the active compound. Separate measurements of
      photosystem I and II activity with spinach (Spinacia oleracea) thylakoid
      membranes indicated that the site of inhibition is located at photosystem II
      (PSII). In thermoluminescence measurements with thylakoid membranes and PSII
      enriched membrane fragments M. spicatum extracts shifted the maximum temperature
      of the B-band (S(2)Q(B)(-) recombination) to higher temperatures. Purified
      tellimagrandin II in concentrations as low as 3 microM caused a comparable shift
      of the B-band. This demonstrates that the target site of this inhibitor is
      different from the Q(B)-binding site, a common target of commercial herbicides
      like 3-(3,4-dichlorophenyl)-1,1-dimethylurea. Measurements with electron
      paramagnetic resonance spectroscopy suggest a higher redox midpoint potential for
      the non-heme iron, located between the primary and the secondary quinone electron
      acceptors, Q(A) and Q(B). Thus, tellimagrandin II has at least two modes of
      action, inhibition of exoenzymes and inhibition of PSII. Multiple target sites
      are a common characteristic of many potent allelochemicals.

PMID- 12481085
TI  - Molecular characterization of an Arabidopsis acyl-coenzyme a synthetase localized
      on glyoxysomal membranes.
AB  - In higher plants, fat-storing seeds utilize storage lipids as a source of energy
      during germination. To enter the beta-oxidation pathway, fatty acids need to be
      activated to acyl-coenzyme As (CoAs) by the enzyme acyl-CoA synthetase (ACS; EC
      6.2.1.3). Here, we report the characterization of an Arabidopsis cDNA clone
      encoding for a glyoxysomal acyl-CoA synthetase designated AtLACS6. The cDNA
      sequence is 2,106 bp long and it encodes a polypeptide of 701 amino acids with a
      calculated molecular mass of 76,617 D. Analysis of the amino-terminal sequence
      indicates that acyl-CoA synthetase is synthesized as a larger precursor
      containing a cleavable amino-terminal presequence so that the mature polypeptide
      size is 663 amino acids. The presequence shows high similarity to the typical
      PTS2 (peroxisomal targeting signal 2). The AtLACS6 also shows high amino acid
      identity to prokaryotic and eukaryotic fatty acyl-CoA synthetases.
      Immunocytochemical and cell fractionation analyses indicated that the AtLACS6 is
      localized on glyoxysomal membranes. AtLACS6 was overexpressed in insect cells and
      purified to near homogeneity. The purified enzyme is particularly active on long
      chain fatty acids (C16:0). Results from immunoblot analysis revealed that the
      expression of both AtLACS6 and beta-oxidation enzymes coincide with fatty acid
      degradation. These data suggested that AtLACS6 might play a regulatory role both
      in fatty acid import into glyoxysomes by making a complex with other factors,
      e.g. PMP70, and in fatty acid beta-oxidation activating the fatty acids.

PMID- 12481086
TI  - Molecular analysis of a bifunctional fatty acid conjugase/desaturase from tung.
      Implications for the evolution of plant fatty acid diversity.
AB  - The seed oil derived from the tung (Aleurites fordii Hemsl.) tree contains
      approximately 80% alpha-eleostearic acid (18:3delta(9cis,11trans,13trans)), an
      unusual conjugated fatty acid that imparts industrially important drying
      qualities to tung oil. Here, we describe the cloning and functional analysis of
      two closely related Delta(12) oleate desaturase-like enzymes that constitute
      consecutive steps in the biosynthetic pathway of eleostearic acid. Polymerase
      chain reaction screening of a tung seed cDNA library using degenerate
      oligonucleotide primers resulted in identification of two desaturases, FAD2 and
      FADX, that shared 73% amino acid identity. Both enzymes were localized to the
      endoplasmic reticulum of tobacco (Nicotiana tabacum cv Bright-Yellow 2) cells,
      and reverse transcriptase-polymerase chain reaction revealed that FADX was
      expressed exclusively within developing tung seeds. Expression of the cDNAs
      encoding these enzymes in yeast (Saccharomyces cerevisiae) revealed that FAD2
      converted oleic acid (18:1delta(9cis)) into linoleic acid (18:2delta(9cis,12cis))
      and that FADX converted linoleic acid into alpha-eleostearic acid. Additional
      characterization revealed that FADX exhibited remarkable enzymatic plasticity,
      capable of generating a variety of alternative conjugated and delta(12)
      desaturated fatty acid products in yeast cells cultured in the presence of
      exogenously supplied fatty acid substrates. Unlike other desaturases reported to
      date, the double bond introduced by FADX during fatty acid desaturation was in
      the trans, rather than cis, configuration. Phylogenetic analysis revealed that
      tung FADX is grouped with delta(12) fatty acid desaturases and hydroxylases
      rather than conjugases, which is consistent with its desaturase activity.
      Comparison of FADX and other lipid-modifying enzymes (desaturase, hydroxylase,
      epoxygenase, acetylenase, and conjugase) revealed several amino acid positions
      near the active site that may be important determinants of enzymatic activity.

PMID- 12481087
TI  - The involvement of a multicopper oxidase in iron uptake by the green algae
      Chlamydomonas reinhardtii.
AB  - In the unicellular green algae Chlamydomonas reinhardtii, high-affinity uptake of
      iron (Fe) requires an Fe(3+)-chelate reductase and an Fe transporter. Neither of
      these proteins nor their corresponding genes have been isolated. We previously
      identified, by analysis of differentially expressed plasma membrane proteins, an
      approximately 150-kD protein whose synthesis was induced under conditions of Fe
      deficient growth. Based on homology of internal peptide sequences to the
      multicopper oxidase hephaestin, this protein was proposed to be a ferroxidase. A
      nucleotide sequence to the full-length cDNA clone for this ferroxidase-like
      protein has been obtained. Analysis of the primary amino acid sequence revealed a
      putative transmembrane domain near the amino terminus of the protein and
      signature sequences for two multicopper oxidase I motifs and one multicopper
      oxidase II motif. The ferroxidase-like gene was transcribed under conditions of
      Fe deficiency. Consistent with the role of a copper (Cu)-containing protein in Fe
      homeostasis, growth of cells in Cu-depleted media eliminated high-affinity Fe
      uptake, and Cu-deficient cells that were grown in optimal Fe showed greatly
      reduced Fe accumulation compared with control, Cu-sufficient cells. Reapplication
      of Cu resulted in the recovery of Fe transport activity. Together, these results
      were consistent with the participation of a ferroxidase in high-affinity Fe
      uptake in C. reinhardtii.

PMID- 12481088
TI  - The maize gene terpene synthase 1 encodes a sesquiterpene synthase catalyzing the
      formation of (E)-beta-farnesene, (E)-nerolidol, and (E,E)-farnesol after
      herbivore damage.
AB  - Maize (Zea mays) emits a mixture of volatile compounds upon attack by the
      Egyptian cotton leafworm (Spodoptera littoralis). These substances, primarily
      mono- and sesquiterpenes, are used by parasitic wasps to locate the lepidopteran
      larvae, which are their natural hosts. This interaction among plant, lepidopteran
      larvae, and hymenopteran parasitoids benefits the plant and has been termed
      indirect defense. The committed step in the biosynthesis of the different
      skeletal types of mono- and sesquiterpenes is catalyzed by terpene synthases, a
      class of enzymes that forms a large variety of mono- and sesquiterpene products
      from prenyl diphosphate precursors. We isolated a terpene synthase gene, terpene
      synthase 1 (tps1), from maize that exhibits only a low degree of sequence
      identity to previously identified terpene synthases. Upon expression in a
      bacterial system, the encoded enzyme produced the acyclic sesquiterpenes, (E)
      beta-farnesene, (E,E)-farnesol, and (3R)-(E)-nerolidol, the last an intermediate
      in the formation of (3E)-4,8-dimethyl-1,3,7-nonatriene. Both (E)-beta-farnesene
      and (3E)-4,8-dimethyl-1,3,7-nonatriene are prominent compounds of the maize
      volatile blend that is emitted after herbivore damage. The biochemical
      characteristics of the encoded enzyme are similar to those of terpene synthases
      from both gymnosperms and dicotyledonous angiosperms, suggesting that catalysis
      involves a similar electrophilic reaction mechanism. The transcript level of tps1
      in the maize cv B73 was elevated after herbivory, mechanical damage, and
      treatment with elicitors. In contrast, the increase in the transcript level of
      the tps1 gene or gene homolog in the maize cv Delprim after herbivory was less
      pronounced, suggesting that the regulation of terpene synthase expression may
      vary among maize varieties.

PMID- 12481089
TI  - Cloning and expression of the gene for soybean hydroxyisourate hydrolase.
      Localization and implications for function and mechanism.
AB  - The gene encoding hydroxyisourate hydrolase, a novel ureide-metabolizing enzyme,
      has been cloned from soybean (Glycine max). The gene encodes a protein that is
      560 amino acids in length and contains a 31-amino acid signal sequence at the N
      terminus that is not present in the mature protein. The presence of two SKL
      motifs near the C terminus suggests that the protein resides in the peroxisome.
      This expectation is borne out by results from immunogold electron microscopy,
      which revealed that hydroxyisourate hydrolase was localized in the peroxisomes of
      uninfected root nodules. The gene encoding hydroxyisourate hydrolase was
      expressed in Escherichia coli, and soluble, catalytically active enzyme was
      purified to homogeneity. Sequence analysis revealed considerable homology with
      members of the beta-glucosidase family of enzymes. Two glutamate residues, E199
      and E408, align with the conserved glutamates that play catalytic roles in the
      beta-glucosidases. However, the other residues that have been identified by
      crystallography to interact directly with the substrates in beta-glucosidases are
      not conserved in hydroxyisourate hydrolase. The E199A and E408A hydroxyisourate
      hydrolase mutants were devoid of detectable catalytic activity. Analysis of
      transcripts for hydroxyisourate hydrolase demonstrated that its level of
      expression was highest in the nodule; mRNA was detectable 12 d after infection
      and increased until 21 d postinfection, then declined. In a similar manner,
      immunodetection of hydroxyisourate hydrolase indicated preferential localization
      in the nodule; the amount of protein detected was maximal at 21 d postinfection.
      The pattern of expression of hydroxyisourate hydrolase matched that of urate
      oxidase, and supports the hypothesis that hydroxyisourate hydrolase plays a role
      in ureide metabolism.

PMID- 12481090
TI  - Phosphorylation of the D1 photosystem II reaction center protein is controlled by
      an endogenous circadian rhythm.
AB  - The light dependence of D1 phosphorylation is unique to higher plants, being
      constitutive in cyanobacteria and algae. In a photoautotrophic higher plant,
      Spirodela oligorrhiza, grown in greenhouse conditions under natural diurnal
      cycles of solar irradiation, the ratio of phosphorylated versus total D1 protein
      (D1-P index: [D1-P]/[D1] + [D1-P]) of photosystem II is shown to undergo
      reproducible diurnal oscillation. These oscillations were clearly out of phase
      with the period of maximum in light intensity. The timing of the D1-P index
      maximum was not affected by changes in temperature, the amount of D1 kinase
      activity present in the thylakoid membranes, the rate of D1 protein synthesis, or
      photoinhibition. However, when the dark period in a normal diurnal cycle was cut
      short artificially by transferring plants to continuous light conditions, the D1
      P index timing shifted and reached a maximum within 4 to 5 h of light
      illumination. The resultant diurnal oscillation persisted for at least two cycles
      in continuous light, suggesting that the rhythm is endogenous (circadian) and is
      entrained by an external signal.

PMID- 12481091
TI  - The sac mutants of Chlamydomonas reinhardtii reveal transcriptional and
      posttranscriptional control of cysteine biosynthesis.
AB  - Algae and vascular plants are cysteine (Cys) prototrophs. They are able to
      import, reduce, and assimilate sulfate into Cys, methionine, and other organic
      sulfur-containing compounds. Characterization of genes encoding the enzymes
      required for Cys biosynthesis from the unicellular green alga Chlamydomonas
      reinhardtii reveals that transcriptional and posttranscriptional mechanisms
      regulate the pathway. The derived amino acid sequences of the C. reinhardtii
      genes encoding 5'-adenylylsulfate (APS) reductase and serine (Ser)
      acetyltransferase are orthologous to sequences from vascular plants. The Cys
      biosynthetic pathway of C. reinhardtii is regulated by sulfate availability. The
      steady-state level of transcripts and activity of ATP sulfurylase, APS reductase,
      Ser acetyltransferase, and O-acetyl-Ser (thiol) lyase increase when cells are
      deprived of sulfate. The sac1 mutation, which impairs C. reinhardtii ability to
      acclimate to sulfur-deficient conditions, prevents the increase in accumulation
      of the transcripts encoding these enzymes and also prevents the increase in
      activity of all the enzymes except APS reductase. The sac2 mutation, which does
      not affect accumulation of APS reductase transcripts, blocks the increase in APS
      reductase activity. These results suggest that APS reductase activity is
      regulated posttranscriptionally in a SAC2-dependent process.

PMID- 12481092
TI  - Differential regulation of RNA levels of gibberellin dioxygenases by photoperiod
      in spinach.
AB  - Previous work with spinach (Spinacia oleracea) has shown that the level of
      gibberellin (GA) 20-oxidase is strongly up-regulated by long days (LD). In the
      present work, the effect of photoperiod on expression of other GA dioxygenases
      was investigated and compared with that of GA 20-oxidase. Two GA 2-oxidases and
      one GA 3-oxidase were isolated from spinach by reverse transcription-polymerase
      chain reaction with degenerate primers and by 5'- and 3'-rapid amplification of
      cDNA ends. As determined by high-performance liquid chromatography with on-line
      radioactivity detection, the SoGA3ox1 gene product catalyzed 3beta-hydroxylation
      of GA(9) to GA(4) and GA(20) to GA(1). The SoGA2ox1 and the SoGA2ox2 gene
      products catalyzed 2beta-hydroxylation of GA(9) to GA(51) and GA(20) to GA(29).
      The product of GA(20) metabolism by SoGA3ox1 was identified as GA(1) by gas
      chromatography-mass spectrometry, whereas the products of GA(1) and GA(20)
      metabolism by SoGA2ox1 and SoGA2ox2 were identified as GA(8) and GA(29),
      respectively. SoGA2ox1 also metabolized GA(53) to GA(97). The levels of SoGA20ox1
      transcripts were greatly increased in all organs tested in LD conditions, but the
      levels of SoGA3ox1 transcripts were only slightly increased in blades and
      petioles. A decrease in the levels of the SoGA2ox1 transcripts in young leaves
      and tips in LD conditions is opposite to the expression pattern of the SoGA20ox1.
      Expression of SoGA20ox1 in petioles and young leaves was strongly up-regulated by
      a supplementary 16 h of light, but the levels of SoGA3ox1 and SoGA2ox1
      transcripts did not change. It is concluded that regulation and maintenance of
      GA(1) concentration in spinach are primarily attributable to changes in
      expression of SoGA20ox1.

PMID- 12481093
TI  - Tip-growing cells of the moss Ceratodon purpureus Are gravitropic in high-density
      media.
AB  - Gravity sensing in plants and algae is hypothesized to rely upon either the mass
      of the entire cell or that of sedimenting organelles (statoliths). Protonemata of
      the moss Ceratodon purpureus show upward gravitropism and contain amyloplasts
      that sediment. If moss sensing were whole-cell based, then media denser than the
      cell should prevent gravitropism or reverse its direction. Cells that were
      inverted or reoriented to the horizontal displayed distinct negative gravitropism
      in solutions of iodixanol with densities of 1.052 to 1.320 as well as in bovine
      serum albumin solutions with densities of 1.037 to 1.184 g cm(-3). Studies using
      tagged molecules of different sizes and calculations of diffusion times suggest
      that both types of media penetrate through the apical cell wall. Estimates of the
      density of the apical cell range from 1.004 to 1.085. Because protonemata grow
      upward when the cells have a density that is lower than the surrounding medium,
      gravitropic sensing probably utilizes an intracellular mass in moss protonemata.
      These data provide additional support for the idea that sedimenting amyloplasts
      function as statoliths in gravitropism.

PMID- 12481094
TI  - Plasma membrane aquaporins play a significant role during recovery from water
      deficit.
AB  - The role of plasma membrane aquaporins (PIPs) in water relations of Arabidopsis
      was studied by examining plants with reduced expression of PIP1 and PIP2
      aquaporins, produced by crossing two different antisense lines. Compared with
      controls, the double antisense (dAS) plants had reduced amounts of PIP1 and PIP2
      aquaporins, and the osmotic hydraulic conductivity of isolated root and leaf
      protoplasts was reduced 5- to 30-fold. The dAS plants had a 3-fold decrease in
      the root hydraulic conductivity expressed on a root dry mass basis, but a
      compensating 2.5-fold increase in the root to leaf dry mass ratio. The leaf
      hydraulic conductance expressed on a leaf area basis was similar for the dAS
      compared with the control plants. As a result, the hydraulic conductance of the
      whole plant was unchanged. Under sufficient and under water-deficient conditions,
      stomatal conductance, transpiration rate, plant hydraulic conductance, leaf water
      potential, osmotic pressure, and turgor pressure were similar for the dAS
      compared with the control plants. However, after 4 d of rewatering following 8 d
      of drying, the control plants recovered their hydraulic conductance and their
      transpiration rates faster than the dAS plants. Moreover, after rewatering, the
      leaf water potential was significantly higher for the control than for the dAS
      plants. From these results, we conclude that the PIPs play an important role in
      the recovery of Arabidopsis from the water-deficient condition.

PMID- 12481095
TI  - A rice mutant defective in Si uptake.
AB  - Rice (Oryza sativa) accumulates silicon (Si) in the tops to levels up to 10.0% of
      shoot dry weight, but the mechanism responsible for high Si uptake by rice roots
      is not understood. We isolated a rice mutant (GR1) that is defective in active Si
      uptake by screening M(2) seeds (64,000) of rice cv Oochikara that were treated
      with 10(-3) M sodium azide for 6 h at 25 degrees C. There were no phenotypic
      differences between wild type (WT) and GR1 except that the leaf blade of GR1
      remained droopy when Si was supplied. Uptake experiments showed that Si uptake by
      GR1 was significantly lower than that by WT at both low and high Si
      concentrations. However, there was no difference in the uptake of other nutrients
      such as phosphorus and potassium. Si concentration in the xylem sap of WT was 33
      fold that of the external solution, but that of GR1 was 3-fold higher than the
      external solution at 0.15 mM Si. Si uptake by WT was inhibited by metabolic
      inhibitors including NaCN and 2,4-dinitrophenol and by low temperature, whereas
      Si uptake by GR1 was not inhibited by these agents. These results suggest that an
      active transport system for Si uptake is disrupted in GR1. Analysis of F(2)
      populations between GR1 and WT showed that roots with high Si uptake and roots
      with low Si uptake segregated at a 3:1 ratio, suggesting that GR1 is a recessive
      mutant of Si uptake.

PMID- 12481096
TI  - Cloning and sequencing of cDNAs for hypothetical genes from chromosome 2 of
      Arabidopsis.
AB  - About 25% of the genes in the fully sequenced and annotated Arabidopsis genome
      have structures that are predicted solely by computer algorithms with no support
      from either nucleic acid or protein homologs from other species or expressed
      sequence matches from Arabidopsis. These are referred to as "hypothetical genes."
      On chromosome 2, sequenced by The Institute for Genomic Research, there are
      approximately 800 hypothetical genes among a total of approximately 4,100 genes.
      To test their expression under various growth conditions and in specific tissues,
      we used six cDNA populations prepared from cold-treated, heat-treated, and
      pathogen (Xanthomonas campestris pv campestris)-infected plants, callus, roots,
      and young seedlings. To date, 169 hypothetical genes were tested, and 138 of them
      are found to be expressed in one or more of the six cDNA populations. By
      sequencing multiple clones from each 5'- and 3'-rapid amplification of cDNA ends
      (RACE) product and assembling the sequences, we generated full-length sequences
      for 16 of these genes. For 14 genes, there was one full-length assembly that
      precisely supported the intron-exon boundaries of their gene predictions, adding
      only 5'- and 3'-untranslated region sequences. However, for three of these genes,
      the other assemblies represent additional exons and alternatively spliced or
      unspliced introns. For the remaining two genes, the cDNA sequences reveal major
      differences with predicted gene structures. In addition, a total of six genes
      displayed more than one polyadenylation site. These data will be used to update
      gene models in The Institute for Genomic Research annotation database ATH1.

PMID- 12481097
TI  - Transcriptome changes for Arabidopsis in response to salt, osmotic, and cold
      stress.
AB  - To identify genes of potential importance to cold, salt, and drought tolerance,
      global expression profiling was performed on Arabidopsis plants subjected to
      stress treatments of 4 degrees C, 100 mM NaCl, or 200 mM mannitol, respectively.
      RNA samples were collected separately from leaves and roots after 3- and 27-h
      stress treatments. Profiling was conducted with a GeneChip microarray with probe
      sets for approximately 8,100 genes. Combined results from all three stresses
      identified 2,409 genes with a greater than 2-fold change over control. This
      suggests that about 30% of the transcriptome is sensitive to regulation by common
      stress conditions. The majority of changes were stimulus specific. At the 3-h
      time point, less than 5% (118 genes) of the changes were observed as shared by
      all three stress responses. By 27 h, the number of shared responses was reduced
      more than 10-fold (< 0.5%), consistent with a progression toward more stimulus
      specific responses. Roots and leaves displayed very different changes. For
      example, less than 14% of the cold-specific changes were shared between root and
      leaves at both 3 and 27 h. The gene with the largest induction under all three
      stress treatments was At5g52310 (LTI/COR78), with induction levels in roots
      greater than 250-fold for cold, 40-fold for mannitol, and 57-fold for NaCl. A
      stress response was observed for 306 (68%) of the known circadian controlled
      genes, supporting the hypothesis that an important function of the circadian
      clock is to "anticipate" predictable stresses such as cold nights. Although these
      results identify hundreds of potentially important transcriptome changes, the
      biochemical functions of many stress-regulated genes remain unknown.

PMID- 12481098
TI  - cDNA cloning, heterologous expressions, and functional characterization of
      malonyl-coenzyme a:anthocyanidin 3-o-glucoside-6"-o-malonyltransferase from
      dahlia flowers.
AB  - In the flowers of important ornamental Compositae plants, anthocyanins generally
      carry malonyl group(s) at their 3-glucosyl moiety. In this study, for the first
      time to our knowledge, we have identified a cDNA coding for this 3-glucoside
      specific malonyltransferase for anthocyanins, i.e. malonyl-coenzyme
      A:anthocyanidin 3-O-glucoside-6"-O-malonyltransferase, from dahlia (Dahlia
      variabilis) flowers. We isolated a full-length cDNA (Dv3MaT) on the basis of
      amino acid sequences specifically conserved among anthocyanin acyltransferases of
      the versatile plant acyltransferase family. Dv3MaT coded for a protein of 460
      amino acids. Quantitative real-time PCR analyses of Dv3MaT showed that the
      transcript was present in accordance with the distribution of 3MaT activities and
      the anthocyanin accumulation pattern in the dahlia plant. The Dv3MaT cDNA was
      expressed in Escherichia coli, and the recombinant enzyme was purified to
      homogeneity and characterized. The recombinant Dv3MaT catalyzed the regiospecific
      transfer of the malonyl group from malonyl-coenzyme A (K(m), 18.8 microM) to
      pelargonidin 3-O-glucoside (K(m), 46.7 microM) to produce pelargonidin 3-O-6"-O
      malonylglucoside with a k(cat) value of 7.3 s(-1). The other enzymatic profiles
      of the recombinant Dv3MaT were closely related to those of native anthocyanin
      malonyltransferase activity in the extracts of dahlia flowers. Dv3MaT cDNA was
      introduced into petunia (Petunia hybrida) plants whose red floral color is
      exclusively provided by cyanidin 3-O-glucoside and 3,5-O-diglucoside. Thirteen
      transgenic lines of petunia were found to produce malonylated products of these
      anthocyanins (11-63 mol % of total anthocyanins in the flower). The spectral
      stability of cyanidin 3-O-6"-O-malonylglucoside at the pHs of intracellular
      milieus of flowers was significantly higher than that of cyanidin 3-O-glucoside.
      Moreover, 6"-O-malonylation of cyanidin 3-O-glucoside effectively prevented the
      anthocyanin from attack of beta-glucosidase. These results suggest that
      malonylation should serve as a strategy for pigment stabilization in the flowers.

PMID- 12481099
TI  - Convergence of calcium signaling pathways of pathogenic elicitors and abscisic
      acid in Arabidopsis guard cells.
AB  - A variety of stimuli, such as abscisic acid (ABA), reactive oxygen species (ROS),
      and elicitors of plant defense reactions, have been shown to induce stomatal
      closure. Our study addresses commonalities in the signaling pathways that these
      stimuli trigger. A recent report showed that both ABA and ROS stimulate an NADPH
      dependent, hyperpolarization-activated Ca(2+) influx current in Arabidopsis guard
      cells termed "I(Ca)" (Z.M. Pei, Y. Murata, G. Benning, S. Thomine, B. Klusener,
      G.J. Allen, E. Grill, J.I. Schroeder, Nature [2002] 406: 731-734). We found that
      yeast (Saccharomyces cerevisiae) elicitor and chitosan, both elicitors of plant
      defense responses, also activate this current and activation requires cytosolic
      NAD(P)H. These elicitors also induced elevations in the concentration of free
      cytosolic calcium ([Ca(2+)](cyt)) and stomatal closure in guard cells. ABA and
      ROS elicited [Ca(2+)](cyt) oscillations in guard cells only when extracellular
      Ca(2+) was present. In a 5 mM KCl extracellular buffer, 45% of guard cells
      exhibited spontaneous [Ca(2+)](cyt) oscillations that differed in their kinetic
      properties from ABA-induced Ca(2+) increases. These spontaneous [Ca(2+)](cyt)
      oscillations also required the availability of extracellular Ca(2+) and depended
      on the extracellular potassium concentration. Interestingly, when ABA was applied
      to spontaneously oscillating cells, ABA caused cessation of [Ca(2+)](cyt)
      elevations in 62 of 101 cells, revealing a new mode of ABA signaling. These data
      show that fungal elicitors activate a shared branch with ABA in the stress signal
      transduction pathway in guard cells that activates plasma membrane I(Ca) channels
      and support a requirement for extracellular Ca(2+) for elicitor and ABA
      signaling, as well as for cellular [Ca(2+)](cyt) oscillation maintenance.

PMID- 12481100
TI  - Cloning of beta-primeverosidase from tea leaves, a key enzyme in tea aroma
      formation.
AB  - A beta-primeverosidase from tea (Camellia sinensis) plants is a unique
      disaccharide-specific glycosidase, which hydrolyzes aroma precursors of beta
      primeverosides (6-O-beta-D-xylopyranosyl-beta-D-glucopyranosides) to liberate
      various aroma compounds, and the enzyme is deeply concerned with the floral aroma
      formation in oolong tea and black tea during the manufacturing process. The beta
      primeverosidase was purified from fresh leaves of a cultivar for green tea (C.
      sinensis var sinensis cv Yabukita), and its partial amino acid sequences were
      determined. The beta-primeverosidase cDNA has been isolated from a cDNA library
      of cv Yabukita using degenerate oligonucleotide primers. The cDNA insert encodes
      a polypeptide consisting of an N-terminal signal peptide of 28 amino acid
      residues and a 479-amino acid mature protein. The beta-primeverosidase protein
      sequence was 50% to 60% identical to beta-glucosidases from various plants and
      was classified in a family 1 glycosyl hydrolase. The mature form of the beta
      primeverosidase expressed in Escherichia coli was able to hydrolyze beta
      primeverosides to liberate a primeverose unit and aglycons, but did not act on 2
      phenylethyl beta-D-glucopyranoside. These results indicate that the beta
      primeverosidase selectively recognizes the beta-primeverosides as substrates and
      specifically hydrolyzes the beta-glycosidic bond between the disaccharide and the
      aglycons. The stereochemistry for enzymatic hydrolysis of 2-phenylethyl beta
      primeveroside by the beta-primeverosidase was followed by (1)H-nuclear magnetic
      resonance spectroscopy, revealing that the enzyme hydrolyzes the beta
      primeveroside by a retaining mechanism. The roles of the beta-primeverosidase in
      the defense mechanism in tea plants and the floral aroma formation during tea
      manufacturing process are also discussed.

PMID- 12481101
TI  - The elicitor cryptogein blocks glucose transport in tobacco cells.
AB  - Cryptogein is a 10-kD protein secreted by the oomycete Phytophthora cryptogea
      that induces a hypersensitive response on tobacco (Nicotiana tabacum var. Xanthi)
      plants and a systemic acquired resistance against various pathogens. The mode of
      action of this elicitor has been studied using tobacco cell suspensions. Our
      previous data indicated that within minutes, cryptogein signaling involves
      various events including changes in ion fluxes, protein phosphorylation, sugar
      metabolism, and, eventually, cell death. These results suggested that transport
      of sugars could be affected and, thus, involved in the complex relationships
      between plant and microorganisms via elicitors. This led us to investigate the
      effects of cryptogein on glucose (Glc) uptake and mitochondrial activity in
      tobacco cells. Cryptogein induces an immediate inhibition of Glc uptake, which is
      not attributable to plasma membrane (PM) depolarization. Conversely, cryptogein
      induced valine uptake is because of PM depolarization. Inhibition of the PM Glc
      transporter(s) was shown to be mediated by a calcium-dependent phosphorylation
      process, and is independent of active oxygen species production. This inhibition
      was associated with a strong decrease in O(2) uptake rate by cells and a large
      mitochondrial membrane depolarization. Thus, inhibition of Glc uptake accompanied
      by inhibition of phosphorylative oxidation may participate in hypersensitive cell
      death. These results are discussed in the context of competition between plants
      and microorganisms for apoplastic sugars.

PMID- 12481102
TI  - Biosynthesis of UDP-xylose. Cloning and characterization of a novel Arabidopsis
      gene family, UXS, encoding soluble and putative membrane-bound UDP-glucuronic
      acid decarboxylase isoforms.
AB  - UDP-xylose (Xyl) is an important sugar donor for the synthesis of glycoproteins,
      polysaccharides, various metabolites, and oligosaccharides in animals, plants,
      fungi, and bacteria. UDP-Xyl also feedback inhibits upstream enzymes (UDP-glucose
      [Glc] dehydrogenase, UDP-Glc pyrophosphorylase, and UDP-GlcA decarboxylase) and
      is involved in its own synthesis and the synthesis of UDP-arabinose. In plants,
      biosynthesis of UDP-Xyl is catalyzed by different membrane-bound and soluble UDP
      GlcA decarboxylase (UDP-GlcA-DC) isozymes, all of which convert UDP-GlcA to UDP
      Xyl. Because synthesis of UDP-Xyl occurs both in the cytosol and in membranes, it
      is not known which source of UDP-Xyl the different Golgi-localized
      xylosyltransferases are utilizing. Here, we describe the identification of
      several distinct Arabidopsis genes (named AtUXS for UDP-Xyl synthase) that encode
      functional UDP-GlcA-DC isoforms. The Arabidopsis genome contains five UXS genes
      and their protein products can be subdivided into three isozyme classes (A-C),
      one soluble and two distinct putative membrane bound. AtUxs from each class, when
      expressed in Escherichia coli, generate active UDP-GlcA-DC that converts UDP-GlcA
      to UDP-Xyl. Members of this gene family have a large conserved C-terminal
      catalytic domain (approximately 300 amino acids long) and an N-terminal variable
      domain differing in sequence and size (30-120 amino acids long). Isoforms of
      class A and B appear to encode putative type II membrane proteins with their
      catalytic domains facing the lumen (like Golgi-glycosyltransferases) and their N
      terminal variable domain facing the cytosol. Uxs class C is likely a cytosolic
      isoform. The characteristics of the plant Uxs support the hypothesis that unique
      UDP-GlcA-DCs with distinct subcellular localizations are required for specific
      xylosylation events.

PMID- 12481104
TI  - Balancing terror and freedom.

PMID- 12481103
TI  - Both vegetative and reproductive actin isovariants complement the stunted root
      hair phenotype of the Arabidopsis act2-1 mutation.
AB  - The ACT2 gene, encoding one of eight actin isovariants in Arabidopsis, is the
      most strongly expressed actin gene in vegetative tissues. A search was conducted
      for physical defects in act2-1 mutant plants to account for their reduced fitness
      compared with wild type in population studies. The act2-1 insertion fully
      disrupted expression of ACT2 RNA and significantly lowered the level of total
      actin protein in vegetative organs. The root hairs of the act2-1 mutants were 10%
      to 70% the length of wild-type root hairs, and they bulged severely at the base.
      The length of the mutant root hairs and degree of bulging at the base were
      affected by adjusting the osmolarity and gelling agent of the growth medium. The
      act2-1 mutant phenotypes were fully rescued by an ACT2 genomic transgene. When
      the act2-1 mutation was combined with another vegetative actin mutation, act7-1,
      the resulting double mutant exhibited extensive synergistic phenotypes ranging
      from developmental lethality to severe dwarfism. Transgenic overexpression of the
      ACT7 vegetative isovariant and ectopic expression of the ACT1 reproductive actin
      isovariant also rescued the root hair elongation defects of the act2-1 mutant.
      These results suggest normal ACT2 gene regulation is essential to proper root
      hair elongation and that even minor differences may cause root defects. However,
      differences in the actin protein isovariant are not significant to root hair
      elongation, in sharp contrast to recent reports on the functional nonequivalency
      of plant actin isovariants. Impairment of root hair functions such as nutrient
      mining, water uptake, and physical anchoring are the likely cause of the reduced
      fitness seen for act2-1 mutants in multigenerational studies.

PMID- 12481105
TI  - Biotechnology. Retreat from Torrey Mesa: a chill wind in ag research.

PMID- 12481106
TI  - Air pollution. Counting the cost of London's killer smog.

PMID- 12481107
TI  - High energy physics. Particle trap confirms antimatter shuffle.

PMID- 12481108
TI  - Genetic modification. Europe prepares for arrival of GM foods.

PMID- 12481109
TI  - Climate. River flow could derail crucial ocean current.

PMID- 12481110
TI  - Report seeks answers to marine mystery.

PMID- 12481111
TI  - Comparative genomics. Tunicate genome shows a little backbone.

PMID- 12481112
TI  - Research infrastructure. NSF urged to boost spending on facilities.

PMID- 12481113
TI  - Patenting life. Canadian high court rejects OncoMouse.

PMID- 12481114
TI  - Gene therapy. RAC's advice: proceed with caution.

PMID- 12481115
TI  - Planetary science. How a pair marries for the eons.

PMID- 12481116
TI  - Gene therapy. The strange case of chimeraplasty.

PMID- 12481117
TI  - Gene therapy. Pioneering papers under the microscope.

PMID- 12481118
TI  - Frontiers of science. A bridge across the Mideast divide.

PMID- 12481119
TI  - Sea-floor ecosystems. Trawling's a drag for marine life, say studies.

PMID- 12481120
TI  - Ethics. Fair benefits for research in developing countries.

PMID- 12481121
TI  - Neuroscience. Mental models and musical minds.

PMID- 12481122
TI  - Materials science. Nanocubes and nanoboxes.

PMID- 12481123
TI  - Development. Fishing out a new heart.

PMID- 12481124
TI  - Immunology. Catalytic antibody bridges innate and adaptive immunity.

PMID- 12481125
TI  - Ultracold matter. The quest for superfluidity in Fermi gases.

PMID- 12481127
TI  - Glaciology. Ice sheets on the move.

PMID- 12481126
TI  - Behavioral ecology. The economics of animal cooperation.

PMID- 12481128
TI  - Antioxidants in photosynthesis and human nutrition.
AB  - The harnessing of solar energy by photosynthesis depends on a safety valve that
      effectively eliminates hazardous excess energy and prevents oxidative damage to
      the plant cells. Many of the compounds that protect plant cells also protect
      human cells. Improving plant resistance to stress may thus have the beneficial
      side effect of also improving the nutritional quality of plants in the human
      diet. The pathways that synthesize these compounds are becoming amenable to
      genetic manipulation, which may yield benefits as widespread as improved plant
      stress tolerance and improved human physical and mental health.

PMID- 12481129
TI  - A green algal apicoplast ancestor.

PMID- 12481131
TI  - The cortical topography of tonal structures underlying Western music.
AB  - Western tonal music relies on a formal geometric structure that determines
      distance relationships within a harmonic or tonal space. In functional magnetic
      resonance imaging experiments, we identified an area in the rostromedial
      prefrontal cortex that tracks activation in tonal space. Different voxels in this
      area exhibited selectivity for different keys. Within the same set of
      consistently activated voxels, the topography of tonality selectivity rearranged
      itself across scanning sessions. The tonality structure was thus maintained as a
      dynamic topography in cortical areas known to be at a nexus of cognitive,
      affective, and mnemonic processing.

PMID- 12481130
TI  - The draft genome of Ciona intestinalis: insights into chordate and vertebrate
      origins.
AB  - The first chordates appear in the fossil record at the time of the Cambrian
      explosion, nearly 550 million years ago. The modern ascidian tadpole represents a
      plausible approximation to these ancestral chordates. To illuminate the origins
      of chordate and vertebrates, we generated a draft of the protein-coding portion
      of the genome of the most studied ascidian, Ciona intestinalis. The Ciona genome
      contains approximately 16,000 protein-coding genes, similar to the number in
      other invertebrates, but only half that found in vertebrates. Vertebrate gene
      families are typically found in simplified form in Ciona, suggesting that
      ascidians contain the basic ancestral complement of genes involved in cell
      signaling and development. The ascidian genome has also acquired a number of
      lineage-specific innovations, including a group of genes engaged in cellulose
      metabolism that are related to those in bacteria and fungi.

PMID- 12481132
TI  - Increasing river discharge to the Arctic Ocean.
AB  - Synthesis of river-monitoring data reveals that the average annual discharge of
      fresh water from the six largest Eurasian rivers to the Arctic Ocean increased by
      7% from 1936 to 1999. The average annual rate of increase was 2.0 +/- 0.7 cubic
      kilometers per year. Consequently, average annual discharge from the six rivers
      is now about 128 cubic kilometers per year greater than it was when routine
      measurements of discharge began. Discharge was correlated with changes in both
      the North Atlantic Oscillation and global mean surface air temperature. The
      observed large-scale change in freshwater flux has potentially important
      implications for ocean circulation and climate.

PMID- 12481133
TI  - Soil warming and carbon-cycle feedbacks to the climate system.
AB  - In a decade-long soil warming experiment in a mid-latitude hardwood forest, we
      documented changes in soil carbon and nitrogen cycling in order to investigate
      the consequences of these changes for the climate system. Here we show that
      whereas soil warming accelerates soil organic matter decay and carbon dioxide
      fluxes to the atmosphere, this response is small and short-lived for a mid
      latitude forest, because of the limited size of the labile soil carbon pool. We
      also show that warming increases the availability of mineral nitrogen to plants.
      Because plant growth in many mid-latitude forests is nitrogen-limited, warming
      has the potential to indirectly stimulate enough carbon storage in plants to at
      least compensate for the carbon losses from soils. Our results challenge
      assumptions made in some climate models that lead to projections of large long
      term releases of soil carbon in response to warming of forest ecosystems.

PMID- 12481134
TI  - Shape-controlled synthesis of gold and silver nanoparticles.
AB  - Monodisperse samples of silver nanocubes were synthesized in large quantities by
      reducing silver nitrate with ethylene glycol in the presence of poly(vinyl
      pyrrolidone) (PVP). These cubes were single crystals and were characterized by a
      slightly truncated shape bounded by [100], [110], and [111] facets. The presence
      of PVP and its molar ratio (in terms of repeating unit) relative to silver
      nitrate both played important roles in determining the geometric shape and size
      of the product. The silver cubes could serve as sacrificial templates to generate
      single-crystalline nanoboxes of gold: hollow polyhedra bounded by six [100] and
      eight [111] facets. Controlling the size, shape, and structure of metal
      nanoparticles is technologically important because of the strong correlation
      between these parameters and optical, electrical, and catalytic properties.

PMID- 12481135
TI  - Short-lived nuclides in hibonite grains from Murchison: evidence for solar system
      evolution.
AB  - Records of now-extinct short-lived nuclides in meteorites provide information
      about the formation and evolution of the solar system. We have found excess 10B
      that we attribute to the decay of short-lived 10Be (half-life 1.5 million years)
      in hibonite grains from the Murchison meteorite. The grains show no evidence of
      decay of two other short-lived nuclides-26Al (half-life 700,000 years) and 41Ca
      (half-life 100,000 years)-that may be present in early solar system solids. One
      plausible source of the observed 10Be is energetic particle irradiation of
      material in the solar nebula. An effective irradiation dose of approximately 2 x
      10(18) protons per square centimeter with a kinetic energy of >/=10
      megaelectronvolts per atomic mass unit can explain our measurements. The presence
      of 10Be, coupled with the absence of 41Ca and 26Al, may rule out energetic
      particle irradiation as the primary source of 41Ca and 26Al present in some early
      solar system solids and strengthens the case of a stellar source for 41Ca and
      26Al.

PMID- 12481136
TI  - Heart regeneration in zebrafish.
AB  - Cardiac injury in mammals and amphibians typically leads to scarring, with
      minimal regeneration of heart muscle. Here, we demonstrate histologically that
      zebrafish fully regenerate hearts within 2 months of 20% ventricular resection.
      Regeneration occurs through robust proliferation of cardiomyocytes localized at
      the leading epicardial edge of the new myocardium. The hearts of zebrafish with
      mutations in the Mps1 mitotic checkpoint kinase, a critical cell cycle regulator,
      failed to regenerate and formed scars. Thus, injury-induced cardiomyocyte
      proliferation in zebrafish can overcome scar formation, allowing cardiac muscle
      regeneration. These findings indicate that zebrafish will be useful for
      genetically dissecting the molecular mechanisms of cardiac regeneration.

PMID- 12481137
TI  - Experimental identification of downhill protein folding.
AB  - Theory predicts the existence of barrierless protein folding. Without barriers,
      folding should be noncooperative and the degree of native structure should be
      coupled to overall protein stability. We investigated the thermal unfolding of
      the peripheral subunit binding domain from Escherichia coli's 2-oxoglutarate
      dehydrogenase multienzyme complex (termed BBL) with a combination of
      spectroscopic techniques and calorimetry. Each technique probed a different
      feature of protein structure. BBL has a defined three-dimensional structure at
      low temperatures. However, each technique showed a distinct unfolding transition.
      Global analysis with a statistical mechanical model identified BBL as a downhill
      folding protein. Because of BBL's biological function, we propose that downhill
      folders may be molecular rheostats, in which effects could be modulated by
      altering the distribution of an ensemble of structures.

PMID- 12481138
TI  - Maintenance of serological memory by polyclonal activation of human memory B
      cells.
AB  - Production of antibodies can last for a lifetime, through mechanisms that remain
      poorly understood. Here, we show that human memory B lymphocytes proliferate and
      differentiate into plasma cells in response to polyclonal stimuli, such as
      bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies
      to recall antigens are produced in vivo at levels proportional to the frequency
      of specific memory B cells, even several years after antigenic stimulation.
      Although antigen boosting leads to a transient increase in specific antibody
      levels, ongoing polyclonal activation of memory B cells offers a means to
      maintain serological memory for a human lifetime.

PMID- 12481139
TI  - Rainfall variability, carbon cycling, and plant species diversity in a mesic
      grassland.
AB  - Ecosystem responses to increased variability in rainfall, a prediction of general
      circulation models, were assessed in native grassland by reducing storm frequency
      and increasing rainfall quantity per storm during a 4-year experiment. More
      extreme rainfall patterns, without concurrent changes in total rainfall quantity,
      increased temporal variability in soil moisture and plant species diversity.
      However, carbon cycling processes such as soil CO2 flux, CO2 uptake by the
      dominant grasses, and aboveground net primary productivity (ANPP) were reduced,
      and ANPP was more responsive to soil moisture variability than to mean soil water
      content. Our results show that projected increases in rainfall variability can
      rapidly alter key carbon cycling processes and plant community composition,
      independent of changes in total precipitation.

PMID- 12481140
TI  - Role of melanopsin in circadian responses to light.
AB  - Melanopsin has been proposed as an important photoreceptive molecule for the
      mammalian circadian system. Its importance in this role was tested in melanopsin
      knockout mice. These mice entrained to a light/dark cycle, phase-shifted after a
      light pulse, and increased circadian period when light intensity increased.
      Induction of the immediate-early gene c-fos was observed after a nighttime light
      pulse in both wild-type and knockout mice. However, the magnitude of these
      behavioral responses in knockout mice was 40% lower than in wild-type mice.
      Although melanopsin is not essential for the circadian clock to receive photic
      input, it contributes significantly to the magnitude of photic responses.

PMID- 12481141
TI  - Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting.
AB  - The master circadian oscillator in the hypothalamic suprachiasmatic nucleus is
      entrained to the day/night cycle by retinal photoreceptors. Melanopsin (Opn4), an
      opsin-based photopigment, is a primary candidate for photoreceptor-mediated
      entrainment. To investigate the functional role of melanopsin in light resetting
      of the oscillator, we generated melanopsin-null mice (Opn4-/-). These mice
      entrain to a light/dark cycle and do not exhibit any overt defect in circadian
      activity rhythms under constant darkness. However, they display severely
      attenuated phase resetting in response to brief pulses of monochromatic light,
      highlighting the critical role of melanopsin in circadian photoentrainment in
      mammals.

PMID- 12481142
TI  - Discounting and reciprocity in an Iterated Prisoner's Dilemma.
AB  - The Iterated Prisoner's Dilemma (IPD) is a central paradigm in the study of
      animal cooperation. According to the IPD framework, repeated play (repetition)
      and reciprocity combine to maintain a cooperative equilibrium. However,
      experimental studies with animals suggest that cooperative behavior in IPDs is
      unstable, and some have suggested that strong preferences for immediate benefits
      (that is, temporal discounting) might explain the fragility of cooperative
      equilibria. We studied the effects of discounting and strategic reciprocity on
      cooperation in captive blue jays. Our results demonstrate an interaction between
      discounting and reciprocity. Blue jays show high stable levels of cooperation in
      treatments with reduced discounting when their opponent reciprocates, but their
      levels of cooperation decline in all other treatment combinations. This suggests
      that stable cooperation requires both reduced discounting and reciprocity, and it
      offers an explanation of earlier failures to find cooperation in controlled
      payoff games.

PMID- 12481143
TI  - Renal processing of albumin in diabetes and hypertension in rats: possible role
      of TGF-beta1.
AB  - BACKGROUND/AIMS: Recent studies show that albuminuria may be the result of
      changes in post-glomerular cellular uptake and processing of albumin. This study
      aims to determine whether this processing is disrupted in diabetes and/or
      hypertension. METHODS: Diabetes (d) was induced using streptozotocin in
      spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY)
      and studied after 8, 16 and 24 weeks of disease. Intact albumin excretion was
      determined by radioimmunoassay. Total albumin was determined by [(14)C]albumin.
      Lysosomal activity was determined by dextran sulfate desulfation. Renal TGF-beta1
      and transforming growth factor-beta1 inducible gene-h3 mRNA (betaig-h3)
      expression was determined by real time RT-PCR. RESULTS: SHR-c rats exhibited an
      increase in intact albuminuria without significant change in total albumin
      excretion (intact plus albumin-derived peptides). For WKY-d rats, intact
      albuminuria developed initially, followed by an increase in total albumin
      excretion primarily in the form of albumin peptides (peptiduria). SHR-d rats
      exhibited both increases in peptiduria and intact albuminuria. There was no
      increase in glomerular permeability at 24 weeks for polydisperse [(3)H]Ficoll in
      all groups. Increased renal TGF-beta1 and betaig-h3 expression was correlated
      with a decrease in dextran sulfate desulfation and increased intact albuminuria
      independent of peptiduria. CONCLUSION: Increased albumin excretion in
      hypertension and/or diabetes is manifested in different forms independent of
      glomerular permeability.

PMID- 12481144
TI  - Renal replacement in end-stage renal disease patients over 75 years old.
AB  - BACKGROUND: Over the last decade, the age of dialysis patients has been
      increasing steadily in several units in Canada. Our main objective was to assess
      prevalence, co-morbidity and outcome of ESRD patients over 75 years old at the
      beginning of dialysis treatment in our center. As a group, they were compared to
      younger dialysis patients treated simultaneously. METHODS: In the last 5 years,
      all cases beginning dialysis in our institution who were above 75 years of age
      were reviewed, as well as cases aged between 50 and 60 years who started dialysis
      during the same period. Between January 1996 and December 2000, among a total of
      429 new chronic dialysis patients, 67 ESRD patients over 75 years (15.6%) and 66
      patients between 50 and 60 years (15.4%) began dialysis treatment. RESULTS-
      PRIMARY AND SECONDARY: Diabetes was present in 37% of elderly and in 56% of the
      younger patients. Younger patients had been referred earlier to our nephrologists
      than the older ones (42 vs. 27%). Elderly were more frequently treated by
      hemodialysis than peritoneal dialysis (81 vs. 19%) when compared to their younger
      counterparts (65 vs. 35%). Long-term catheters for hemodialysis were used more
      often in elderly patients. No renal transplantation were performed in older
      patients while 7 younger patients received a renal graft. Survival rates after 1
      and 3 years were, respectively, 93 and 74% for patients between 50 and 60 years,
      whereas it decreased to 80 and 45% for those over 75 years (p = 0.002). More than
      50% of patients older than 75 years died within 2 years after starting dialysis;
      their mean survival was 31 months; patients starting dialysis between 50 and 60
      years survived on the average 44 months during the study period. According to the
      multivariate logistic regression model, risk factors for increased mortality in
      the older group were: number of hospitalization days during the past 3 months (OR
      34.8, 95% CI 8.3-145.7, p < 0.001) and lower weight (OR 16.6, 95% CI 2.0-139.0, p
      = 0.001). CONCLUSION: We may conclude that, in our hands, life expectancy of
      patients who began dialysis above 75 years is significantly shorter than for
      patients for whom dialysis is initiated between age 50 and 60 years, especially
      if they have a low weight, lose weight and/or require hospitalization.

PMID- 12481145
TI  - Erythropoietin therapy in pre-dialysis patients with chronic renal failure: lack
      of need for parenteral iron.
AB  - BACKGROUND: During erythropoietin therapy, scant information exists regarding the
      optimal target percent saturation of transferrin (TSAT), ferritin and the mode
      and amount of iron supplementation in pre-dialysis patients with anemia due to
      chronic kidney disease (CKD). HYPOTHESIS: Pre-dialysis CKD patients may have
      different needs for iron supplementation than end-stage renal disease subjects
      during erythropoietin therapy. METHODS: Retrospective analysis of pre-dialysis
      CKD subjects (n = 31) treated with erythropoietin at our institution. RESULTS: In
      this population our results showed that target hematocrit (33-36%) was achievable
      with erythropoietin (mean subcutaneous dose 86 +/- 17 [SD] units/kg/week) without
      parenteral iron therapy. The hematocrit increased from a mean baseline value of
      28.4 +/- 2.7 to 33.6 +/- 3.4% at time 1 (4-9 weeks, p < 0.0001), and to 37.7 +/-
      4.5% at time 2 (10-20 weeks, p < 0.0001). The hemoglobin concentration increased
      from 9 +/- 0.9 g/dl at baseline to 10.7 +/- 1.1 g/dl at time 1 (p < 0.0001) and
      to 12 +/- 1.5 g/dl at time 2 (p < 0.0001). Subgroup analyses of patients
      prescribed <200 mg oral elemental iron per day (n = 10), those with TSAT <20%
      and/or ferritin <100 ng/ml (n = 19), and those prescribed erythropoietin <80
      units/kg/week (n = 12), all showed a significant increase in hematocrit and
      hemoglobin. CONCLUSIONS: Our data show that pre-dialysis CKD subjects respond
      adequately to erythropoietin at or lower than recommended erythropoietin doses
      without parenteral iron. This response extends even to subgroups with TSAT and/or
      ferritin levels deemed to indicate iron deficiency in CKD subjects, and may be
      due to lack of existence of functional iron deficiency in this group of patients.

PMID- 12481146
TI  - Silent cerebral infarction in hemodialysis patients.
AB  - BACKGROUND: Cerebrovascular diseases are very common in hemodialysis (HD)
      patients. Silent cerebral infarction (SCI) has not been investigated in HD
      patients although it may be a significant risk factor for cerebrovascular
      diseases. HYPOTHESIS: Chronic renal failure may be an independent risk factor for
      SCI and cerebrovascular diseases. METHODS: Cranial magnetic resonance imaging
      (MRI) was performed on 123 HD patients without symptomatic cerebrovascular
      disease and on 52 control subjects. We investigated the prevalence of SCI and
      performed cross-sectional study using multiple logistic analysis to assess the
      relationship between SCI and the risk factors. RESULTS: The prevalence of SCI was
      significantly higher in HD patients than in the healthy control group (60
      patients (48.8%) vs. 5 patients (9.6%), chi(2) = 22.4, p < 0.0001). Multiple
      logistic regression analysis with all subjects showed that independent risk
      factors of SCI were chronic renal failure, hypertension, smoking and age (R(2) =
      0.468, p < 0.0001). In only the HD patient group, age and smoking were shown to
      be independent risk factors of SCI (R(2) = 0.378, p < 0.0001) while HD duration
      and hypertension were not. CONCLUSIONS: The findings of the present study
      indicate that chronic renal failure maintained by hemodialysis increases the
      prevalence of SCI and that age and smoking habits are also significantly
      associated with SCI in HD patients.

PMID- 12481147
TI  - Effects of an acute dose of L-arginine during coronary angiography in patients
      with chronic renal failure: a randomized, parallel, double-blind clinical trial.
AB  - BACKGROUND: Contrast media (CM) are nephrotoxic and might further worsen renal
      function in patients with chronic renal failure. L-Arginine, the substrate of
      nitric oxide, protects kidney function and may improve endothelial function in
      patients with coronary artery disease. HYPOTHESIS: Acute administration of L
      arginine in a subset of patients with combined coronary artery disease and
      impaired kidney function during coronary angiography might prevent superimposed
      acute renal failure. METHODS: A double-blind study of patients with mild/moderate
      chronic renal failure (Cr >1.7 mg/dl) undergoing coronary angiography (meglumine
      ioxaglate) was conducted. Patients received either L-arginine (300 mg/kg) or
      placebo and were followed for 48 h. Cardiac hemodynamic parameters, renal
      function and nitric oxide production were sequentially recorded. RESULTS--PRIMARY
      AND SECONDARY: Both groups experienced a decrease of creatinine clearance 48 h
      following the procedure (p < 0.05). Creatinine levels slightly increased
      following the administration of L-arginine (p < 0.05) but not in the placebo
      treated group. No changes of systemic and cardiac pressures, total peripheral
      resistance or cardiac output were recorded within and between the treatment and
      placebo groups. CONCLUSION: CM injection causes an impairment of renal function.
      Addition of intravenous L-arginine during cardiac catheterizations in patients
      with chronic renal failure does not prevent CM-induced nephrotoxicity and does
      not affect endothelial dysfunction in the particular population studied by the
      authors, i.e. patients with coronary artery disease (CAD) of various degrees, or
      suspicion of CAD and chronic mild renal failure.

PMID- 12481148
TI  - Profile of interdialytic blood pressure in hemodialysis patients.
AB  - BACKGROUND AND METHODS: Hypertension is a common problem in hemodialysis (HD).
      However, its behavior during the interdialytic period is not completely known and
      is infrequently monitored in clinical practice. Thus, for better understanding of
      interdialytic blood pressure (BP), we analyzed the interdialytic blood pressure
      profile using 44-hour ambulatory blood pressure monitoring (ABPM) data in 71
      unselected, stable HD patients. RESULTS: There was an increase in BP during the
      interdialytic period (awake day 1: 135/84 +/- 23/14 mm Hg; awake day 2: 140/86 +/
      22/15 mm Hg, p < 0.05; sleep day 1: 130/77 +/- 24/15 mm Hg; sleep day 2: 136/80
      +/- 24/15 mm Hg, p < 0.05). The correlation between the average 44-hour BP and
      interdialytic weight gain (IDWG) was not significant (r = -0.07 for systolic BP
      and r = -0.09 for diastolic BP). The number of non-dipper patients was high, 77%
      on interdialytic day 1 and 83% on interdialytic day 2 for systolic BP.
      Uncontrolled hypertension (average 44 h BP > or =135/85 mm Hg) was diagnosed in
      58 (55%) patients. Patients with uncontrolled hypertension had higher pre- and
      posthemodialysis BP, higher BP on each interdialytic day and night, and higher
      night/day diastolic BP ratio on the second interdialytic day. These patients were
      also taking a greater number of vasoactive medications (1.5 vs. 0.6 in those with
      controlled BP, p = 0.001). There were no significant differences related to kt/V,
      hematocrit, or weekly erythropoietin dose between patients with controlled or
      uncontrolled BP. Hemodialysis shift assignment (morning or afternoon) did not
      impact on BP levels or diurnal profile. CONCLUSION: In HD patients, interdialytic
      BP is often poorly controlled, there is a progressive rise in BP, and a trend
      toward loss of nocturnal decline in BP as the interdialytic period progresses.
      Further research is needed to determine whether treatment directed to
      interdialytic BP changes can alter outcomes in HD patients.

PMID- 12481149
TI  - Treatment of anemia with darbepoetin alfa administered de novo once every other
      week in chronic kidney disease.
AB  - BACKGROUND/AIMS: Darbepoetin alfa is an erythropoiesis-stimulating protein that
      works via the same mechanism and has a threefold longer serum half-life than
      recombinant human erythropoietin (rHuEPO). The objective of this study was to
      evaluate extending the dosing interval of darbepoetin alfa to once every other
      week administration for the treatment of anemia in patients with chronic kidney
      disease (CKD) not requiring dialysis who were naive to rHuEPO therapy. METHODS:
      This was a multi-center, open-label study. Seventy-six rHuEPO-naive patients were
      enrolled to receive darbepoetin alfa (0.75 microg/kg) once every other week for
      up to 24 weeks. Doses were titrated to achieve and maintain a hemoglobin target
      of 11.0 to 13.0 g/dl. RESULTS: Ninety-seven percent (95% CI: 0.92, 1.00) of
      patients completing 24 weeks of treatment achieved a hemoglobin response. The
      median time to response was 5 weeks (range 1-25 weeks). The median darbepoetin
      alfa dose at the time of response was 60 microg(range 30-130 microg). Darbepoetin
      alfa was safe and well tolerated, and no antibodies to darbepoetin alfa were
      detected. CONCLUSION: These results demonstrate the utility of darbepoetin alfa
      administered once every other week in rHuEPO-naive CKD patients. This new
      treatment paradigm may allow for more widespread management of anemia in patients
      with CKD.

PMID- 12481150
TI  - Polymorphic genes for kinin receptors, nephropathy and blood pressure in type 2
      diabetic patients.
AB  - BACKGROUND/AIMS: There is evidence that hereditary predisposition contributes to
      the development of diabetic nephropathy and hypertension. Polymorphisms in the
      genes for bradykinin receptors (B(1)R and B(2)R) were found to be associated with
      decreased risk of the development of end-stage renal disease. This study examines
      whether B(1)R G(-699)C and B(2)R C(181)T polymorphisms are associated with
      microalbuminuria or overt nephropathy, or blood pressure variation in type 2
      diabetic subjects. METHODS: B(1)R and B(2)R polymorphisms were determined in 153
      type 2 diabetic patients with microalbuminuria, 132 with overt nephropathy
      (macroalbuminuria or chronic renal failure), and 161 patients with
      normoalbuminuria despite diabetes duration longer than 10 years. RESULTS:
      Distributions of the examined polymorphisms did not differ between patients with
      microalbuminuria or overt nephropathy, compared to normoalbuminuric control
      subjects. Patients carrying the B(2)R T allele had lower DBP, compared with non
      carriers: 83.6 +/- 12.0 vs. 87.4 +/- 12.1 mm Hg, p < 0.05. Among patients not
      receiving ACEI, both SBP and DBP was significantly lower in B(2)R T allele
      carriers, compared to non-carriers (137.2 +/- 20.3 vs. 146.5 +/- 21.7 mm Hg, and
      80.3 +/- 11.9 vs. 85.8 +/- 11.6 mm Hg, p < 0.05). CONCLUSIONS: Examined
      polymorphisms are not associated with the increased risk of incipient or overt
      nephropathy in type 2 diabetic patients. B(2)R C(181)T polymorphism may
      contribute to blood pressure variation in these subjects.

PMID- 12481151
TI  - Impact of birth weight on familial aggregation of end-stage renal disease.
AB  - BACKGROUND: Birth weight (BW) and family history (FH) of end-stage renal disease
      (ESRD) have been shown to have an independent association with development of
      subsequent ESRD. This study was undertaken to determine the effects of BW (low BW
      suggesting a congenital reduction in functional nephron number) on the observed
      familial aggregation of ESRD. METHODS: Cases were identified from the ESRD
      Network 6 "Family History of ESRD" Study and BW was determined from birth
      certificate records maintained at the Office of Vital Records, South Carolina
      Department of Health and Environmental Control. BW and FH of ESRD data were
      available in 387 patients who initiated dialysis therapy between 1993 and 1997.
      Multiple logistic regression analysis was performed to assess the risk of low BW
      (<2,500 g) and high BW (> or =4,000 g) on FH of ESRD. RESULTS: A FH of ESRD in
      first or second-degree relatives was present in 24% of cases. No significant
      differences were observed in the frequency of a positive FH of ESRD in those with
      low BW compared to those with normal BW. There was a significant reduction in the
      prevalence of a FH of ESRD in those with high BW, compared to those with a normal
      BW (risk ratio 0.32, CI 0.11-0.94). CONCLUSION: The clustering of either high BW
      or low BW within multiply affected ESRD families does not account for the
      observed familial aggregation of ESRD. In addition, high BW was associated with a
      reduced familial aggregation of ESRD.

PMID- 12481152
TI  - Serotonin and apoptosis: studies on rat lymphocytes.
AB  - OBJECTIVE: The apoptogenic potential of serotonin (5-hydroxytryptamine) on
      mitogen-stimulated lymphocytes was studied in primary cultures of rat spleen
      cells, in two sets of experiments. METHODS: Apoptosis was measured by morphologic
      criteria and flow cytometry. RESULTS: In both assays, serotonin, at a
      concentration producing half-maximal inhibition of lymphocyte proliferation,
      significantly increased the basal levels of apoptosis. CONCLUSION: An apoptotic
      mechanism should be taken into account when considering immunoinhibition induced
      by serotonin.

PMID- 12481153
TI  - Chronic fatigue syndrome: what role does the autonomic nervous system play in the
      pathophysiology of this complex illness?
AB  - Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800000
      Americans of all ages, races and socioeconomic groups and both genders. The
      etiology and pathophysiology of CFS are unknown, yet studies have suggested an
      involvement of the autonomic nervous system (ANS). A symposium was organized in
      December 2000 to explore the possibility of an association between ANS
      dysfunction and CFS, with special emphasis on the interactions between ANS
      dysfunction and other abnormalities noted in the immune and endocrine systems of
      individuals with CFS. This paper represents the consensus of the panel of experts
      who participated in this meeting.

PMID- 12481154
TI  - Triiodothyronine modulates extracellular matrix-mediated interactions between
      thymocytes and thymic microenvironmental cells.
AB  - OBJECTIVES: Thyroid hormones exert immunomodulatory activities and the thymus is
      one of their target organs. We previously showed that triiodothyronine (T(3))
      modulates thymic hormone production and extracellular matrix (ECM) expression by
      mouse thymic epithelial cells (TEC). This concept is enlarged herein by studying
      the effects of T(3) in human TEC preparations including primary cultures derived
      from thymic nurse cell complexes, as well as human and murine TEC lines. METHODS
      AND RESULTS: We observed that in all cases, ECM ligands and receptors (such as
      fibronectin, laminin, VLA-5 and VLA-6) are enhanced in vitro, as ascertained by
      immunocytochemistry, ELISA and cytofluorometry. Moreover, thymocyte adhesion to
      these TEC preparations is augmented by T(3). Interestingly, TEC-thymocyte
      adhesion is also upregulated when thymocytes from T(3)-treated mice adhere to
      untreated TEC cultures. Such an enhancing effect of T(3) upon TEC-thymocyte
      interactions is likely due to the increase in the expression of ECM ligands and
      receptors, since it is prevented when T(3)-treated TEC cultures are incubated
      with anti-ECM antibodies prior to the adhesion assay. We then tested whether T(3)
      could modulate interactions between thymocytes and nonepithelial
      microenvironmental cells, exemplified herein by the phagocytic cells of the mouse
      thymic reticulum. In fact, in vitro treatment of these cells with T(3) increases
      ECM ligands and receptors and augments their ability to adhere to thymocytes.
      Lastly, using immunochemistry-based assays, we showed the presence of the nuclear
      T(3) receptor in all thymic microenvironmental cell preparations. CONCLUSION: Our
      data show that T(3) upregulates ECM-mediated heterocellular interactions of
      thymocytes with distinct thymic microenvironmental cells, in both humans and
      mice.

PMID- 12481155
TI  - Effect of nutritional stress on the hypothalamo-pituitary-gonadal axis in the
      growing male rat.
AB  - BACKGROUND/OBJECTIVE: Nutritional dwarfing (ND) consists of a decrease in weight
      and height gain and delayed onset of puberty. The aim of the present
      investigation was to study the modifications induced in male rats by the
      nutritional stress of a mere 20% reduction in food intake which, however, started
      immediately after weaning. MATERIALS AND METHODS: At weaning, male Wistar rats
      were divided into two groups: Control (C) and ND. C rats were fed ad libitum with
      a balanced rodent diet. ND received 80% of the diet consumed by C for 4 weeks
      (T4); then they were fed ad libitum for another 4 (T8) and 8 weeks (T12). The
      rats were studied at T0, T4, T8 and T12 for the effects of nutritional stress and
      refeeding on nutritional status, body composition, hypothalamic-pituitary-gonadal
      axis, and sperm morphology and concentration. RESULTS: ND body weight and length
      diminished vs. C (p < 0.001). ND body fat percentage decreased 40% (p < 0.001)
      without change in the percentage of body protein content. The hypothalamic
      content of LHRH did not change. However, FSH, LH and testosterone serum levels
      had significantly decreased (p < 0.001) at T4 in ND rats. A 48.4 % decrease in
      serum leptin in the ND group was observed at T4 (p < 0.05). The absolute
      testicular and seminal vesicle weight was significantly decreased by ND at T4 (p
      < 0.001). At T4 the percentage of anomalies of caudal spermatozoa increased in
      about 64% (p < 0.001) of ND vs. C rats, despite the unchanged sperm
      concentrations. All parameters normalized during refeeding. CONCLUSION: In this
      model, a decrease in leptin due to nutritional stress could be responsible, at
      least in part, for the inhibition of reproductive function. Refeeding normalized
      all parameters studied.

PMID- 12481156
TI  - Lateralization and catecholaminergic neuroimmunomodulation: prazosin, an
      alpha1/alpha2-adrenergic receptor antagonist, suppresses interleukin-1 and
      increases interleukin-10 production induced by lipopolysaccharides.
AB  - OBJECTIVE: The brain has previously been shown to asymmetrically modulate
      neurochemical, neuroendocrine and immune responses to lipopolysaccharides (LPS).
      As these responses are reversed by a chemical sympathectomy, it can be
      hypothesized that the asymmetry in the functioning of the sympathetic nervous
      system may be one of the mechanisms by which the brain hemispheres asymmetrically
      modulate immune reactivity. METHODS: The effects of prazosin, an alpha1/alpha2
      adrenergic receptor antagonist, on the production of interleukin (IL)-1beta and
      IL-10 induced by LPS was studied in mice selected for their paw preference.
      RESULTS: Two hours after intraperitoneal injection of 5 microg of LPS, plasma
      levels of IL-1beta were higher in right-pawed mice as compared to left-pawed or
      ambidextrous animals. No lateralization effect was observed for LPS-induced
      plasma IL-10 levels. Prazosin, 10 mg/kg, injected intraperitoneally half an hour
      before LPS, reduced plasma levels of IL-1beta and abolished the effect of
      lateralization. By contrast, prazosin drastically increased plasma levels of IL
      10 in response to LPS and the production of corticosterone in untreated controls.
      CONCLUSIONS: These results suggest that the catecholaminergic modulation of
      immune reactivity depends on lateralization. This work further demonstrates that
      prazosin is endowed with anti-inflammatory properties that may be considered side
      effects of this drug, which is widely prescribed in the treatment of
      hypertension.

PMID- 12481157
TI  - Recombinant human prolactin improves antitumor effects of murine natural killer
      cells in vitro and in vivo.
AB  - OBJECTIVE: To verify the effect of prolactin on natural killer (NK) cells in vivo
      and its implications for NK cell immunotherapy. METHODS: Recombinant human
      prolactin (rhPRL; 30 microg, i.p.) was administered to BALB/c mice and severe
      combined immunodeficiency (SCID) mice 1 day before harvesting splenocytes for
      (51)Cr release assay to examine the effects of rhPRL on NK cells of normal mice.
      rhPRL (10 microg, i.p., every other day for a total of 5 injections) was
      administered to BALB/c mice after syngeneic bone marrow transplantation (SBMT) to
      determine its effects on NK cell reconstitution. CT26 tumor cells were injected
      into BALB/c mice intravenously on day 0, and interleukin (IL)-15-cocultured
      activated syngeneic NK cells (IL-15-NK) from SCID mice were intravenously
      injected into tumor-bearing BALB/c mice on day 1. The improvement of
      antimetastasis effects and survival of tumor-bearing mice by rhPRL were checked.
      RESULTS: BALB/c and SCID mice receiving one rhPRL injection exhibited a
      significant increase in cellular cytotoxicity against YAC-1 target tumor cells;
      the specific lysis was enhanced from 12.5 to 17.3% in BALB/c mice and from 27.8
      to 51.2% in SCID mice. BALB/c mice continuously receiving rhPRL injections
      exhibited significant increases in NK cell (DX5-positive) contents and
      cellularity in both the bone marrow and spleen in the SBMT model. The bone marrow
      NK cell contents were improved from 1.53 to 3.13% after rhPRL injection. NK cells
      from SCID mice were then cultured with recombinant human IL-15 (rhIL-15; 6000
      IU/ml), rhPRL (10 ng/ml) or rhIL-15 plus rhPRL for 25 days. The cytotoxicity and
      cellularity were enhanced by rhPRL when tested on day 10, when comparing the rhIL
      15 plus rhPRL group with the rhIL-15 group or rhPRL group, respectively. In the
      adoptive cellular immunotherapy study, the IL-15-NK plus IL-15 plus rhPRL group
      showed significantly lower numbers of lung metastases and longer survival than
      the IL-15-NK plus IL-15 group; the mean survival interval was prolonged from 31.5
      to 53.7 days. CONCLUSION: These results indicate that rhPRL is possibly an
      important regulator of NK cells and a potential biologic product for
      immunotherapy.

PMID- 12481158
TI  - Pituitary adenylate-cyclase-activating polypeptide expression in the immune
      system.
AB  - Although pituitary adenylate-cyclase-activating polypeptide (PACAP) is a
      multifunctional and pleiotropic neuropeptide with many different immunomodulatory
      properties, investigations of its source in lymphoid organs are scarce. The
      present report contributes to the knowledge on the origin and synthesis of this
      peptide in immune cells of the lymphoid organs and peritoneum using
      immunohistochemistry, immunocytochemical staining, Western blot and RT-PCR
      methods. Our study reveals PACAP immunoreactivity in the thymus, spleen and lymph
      nodes. Cytochemical results show that PACAP is present in thymocytes, lymphocytes
      and plasma cells from the spleen and lymph nodes. Western blot analysis showed a
      band corresponding to PACAP for all lymphoid organs studied. mRNA appears in both
      double (CD4+CD8+)- and single-positive (CD4+CD8-, CD4-CD8+) thymocytes and in T
      subsets and B cells from the spleen and lymph nodes. In addition, PACAP mRNA is
      expressed in lymphocytes, but not in macrophages from peritoneal suspensions. Our
      findings show that PACAP produced by lymphocytes could be added to the growing
      list of mediators shared by nervous, endocrine and immune systems. Moreover,
      PACAP could be considered as a lymphocyte-derived cytokine in the central and
      peripheral lymphoid organs acting on lymphocytes and stromal cells.

PMID- 12481159
TI  - Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal
      tumorigenesis.
AB  - Cancers of the gastrointestinal tract, including the liver, bile ducts, and
      pancreas, constitute the largest group of malignant tumors. Colorectal cancer is
      one of the most common neoplastic diseases in Western countries and one of the
      leading causes of cancer-related deaths. Inactivation of the adenomatous
      polyposis coli (APC) tumor-suppressor gene during early adenoma formation is
      thought to be the first genetic event in the process of colorectal carcinogenesis
      followed by mutations in oncogenes like K-Ras and tumor-suppressor genes like
      p53. Identification of the interaction of APC with the proto-oncogene beta
      catenin has linked colorectal carcinogenesis to the Wnt-signal transduction
      pathway. The main function of APC is thought to be the regulation of free beta
      catenin in concert with the glycogen synthase kinase 3beta (GSK-3beta) and Axin
      proteins. Loss of APC function, inactivation of Axin or activating beta-catenin
      mutations result in the cellular accumulation of beta-catenin. Upon translocation
      to the nucleus beta-catenin serves as an activator of T-cell factor (Tcf)
      dependent transcription leading to an increased expression of several specific
      target genes including c-Myc, cyclin D1, MMP-7, and ITF-2. While APC mutations
      are almost exclusively found in colorectal cancers, deregulation of Wnt/beta
      catenin/Tcf signaling is also common in other gastrointestinal and extra
      gastrointestinal human cancers. In a fraction of hepatocellular carcinomas the
      Wnt pathway is deregulated by inactivation of Axin or stabilizing mutations of
      beta-catenin. The majority of hepatoblastomas and a group of gastric cancers also
      carry beta-catenin mutations. Clearly, this pathway harbors great potential for
      future applications in cancer diagnostics, staging, and therapy.

PMID- 12481160
TI  - Healing of duodenal ulcers is not impaired by indomethacin or rofecoxib, the
      selective COX-2 inhibitor, in rats.
AB  - BACKGROUND/AIM: Studies have demonstrated an important role for endogenous PG and
      NO in the healing of chronic gastric ulcers. We investigated the effects of COX
      and NOS inhibitors on the healing of duodenal ulcers, in comparison with gastric
      ulcers, in rats. METHODS: Gastric and duodenal ulcers were induced by serosal
      application of acetic acid (0.1 ml of 100% acetic acid) for 60 and 20 s,
      respectively. Indomethacin (a nonselective COX inhibitor) or rofecoxib (a
      selective COX-2 inhibitor) was given p.o. once daily for 14 days from 3 days
      after ulcer induction, while N(G)-nitro-L-arginine methyl ester (L-NAME: a
      nonselective NOS inhibitor) or aminoguanidine (a relatively selective iNOS
      inhibitor) was given s.c. twice daily during this period. RESULTS: Both gastric
      and duodenal ulcers induced by acetic acid healed spontaneously within 17 days to
      a minimal size. Daily administration of indomethacin or rofecoxib significantly
      delayed the healing of gastric but not duodenal ulcers. In contrast, the healing
      of both gastric and duodenal ulcers was delayed by repeated administration of
      either L-NAME or aminoguanidine. Ulceration markedly increased the PGE(2) content
      of the ulcerated mucosa in both the stomach and duodenum, and the increased PG
      biosynthetic response was inhibited by either indomethacin or rofecoxib in both
      tissues. The expression of both COX-2 and iNOS mRNAs was upregulated in the
      ulcerated mucosa of the stomach and duodenum. CONCLUSION: These results suggest
      that COX-2/PG is actively involved in the healing of gastric but not duodenal
      ulcers, although the mRNA for COX-2 is expressed in the duodenal mucosa after
      ulceration, as potently as in the gastric mucosa. In contrast, NO produced by
      both cNOS and iNOS plays a role in the healing of both gastric and duodenal
      ulcers.

PMID- 12481162
TI  - Nitric oxide releasing aspirin protects the gastric mucosa against stress and
      promotes healing of stress-induced gastric mucosal damage: role of heat shock
      protein 70.
AB  - BACKGROUND/AIM: Nitric oxide (NO) releasing nonsteroidal anti-inflammatory drugs
      do not cause gastric mucosal damage, despite inhibition of the cyclooxygenase
      activity to a similar extent as conventional nonsteroidal anti-inflammatory drugs
      that induce such damage. We compared the effects of native aspirin (ASA) with
      those of NO-releasing ASA (NO-ASA) on the development and healing of acute
      gastric lesions induced by water immersion and restraint stress (WRS) and the
      mucosal expression of heat shock protein 70 (HSP70). METHODS: Wistar rats
      received: (1). vehicle; (2). ASA (40 mg/kg i.g), and (3). NO-ASA (2.5-40 mg/kg
      i.g.), followed 0.5 h later by 3.5 h of WRS with or without glyceryl trinitrate,
      the donor of NO, and carboxy-PTIO, a NO scavenger. Healing of WRS lesions was
      assessed 0-24 h after termination of WRS. Number of gastric lesions, gastric
      mucosal blood flow (GBF), malondialdehyde (MDA) content, and RT-PCR expression of
      HSP70 mRNA were determined. RESULTS: WRS caused typical bleeding erosions that
      were aggravated by aspirin and this was accompanied by a fall in the GBF and a
      significant rise in the mucosal MDA concentrations. In contrast, NO-ASA, which
      raised significantly the luminal content of NO(x), reduced number of WRS lesions
      and mucosal MDA levels while increasing significantly the GBF. These protective
      and hyperemic effects of NO-ASA against WRS lesions were mimicked by addition of
      glyceryl trinitrate to native ASA and significantly attenuated by carboxy-PTIO
      added to NO-ASA. HSP70 mRNA was significantly upregulated by WRS, and this was
      significantly attenuated by ASA, but not by NO-ASA. NO-ASA decreased
      significantly the MDA content and induced overexpression of HSP70 mRNA during
      healing of WRS lesions. CONCLUSION: NO-ASA exhibits mucosal protective and
      healing effects against WRS-induced gastric lesions due to the release of NO,
      which induces gastric hyperemia, and the attenuation of lipid peroxidation and
      counteracts the inhibition of HSP70 expression induced by native ASA.

PMID- 12481161
TI  - Eradication therapy with rabeprazole versus omeprazole in the treatment of active
      duodenal ulcer.
AB  - BACKGROUND: Rabeprazole has been demonstrated to be a potent antisecretory agent
      and has been shown to be clinically effective in the treatment of acid-related
      diseases. AIMS: It was to determine the efficacy of rabeprazole at 20 and 40 mg
      in addition to amoxicillin and clarithromycin in the treatment of active
      Helicobacter pylori-positive duodenal ulcers compared with omeprazole 40 mg.
      PATIENTS AND METHODS: One hundred and twenty-seven patients were randomised into
      three treatment groups: 40 patients were treated with rabeprazole 40 mg daily, 42
      patients with rabeprazole 20 mg daily and 45 patients with omeprazole 40 mg daily
      for 10 days. All patients received amoxicillin 1 g twice a day and clarithromycin
      500 mg twice a day for 5 days. All patients were re-assessed at least 4 weeks
      after the end of the treatment. RESULTS: According to the intention-to-treat
      (ITT) protocol, ulcer healing was observed in 90% of patients in the rabeprazole
      40 group, in 85.7% in the rabeprazole 20 group and in 93.3% in the omeprazole 40
      group. We observed H. pylori eradication in 90% ITT in the rabeprazole 40 group,
      in 80.9% ITT in the rabeprazole 20 group and in 88.8% ITT in the omeprazole 40
      group. Statistical analysis did not show significant differences among the three
      groups. CONCLUSIONS: A 10-day rabeprazole 20 mg regimen represents an efficacious
      and safe regimen for H. pylori eradication and ulcer healing.

PMID- 12481163
TI  - Anti-saccharomyces cerevisiae antibodies in patients with inflammatory bowel
      disease and their first-degree relatives: potential clinical value.
AB  - Anti-Saccharomyces cerevisiae antibodies (ASCA) have been described as specific
      markers in Crohn's disease and their healthy first-degree relatives. 171 patients
      with Crohn's disease, their 105 first-degree relatives, 145 patients with
      ulcerative colitis and 101 first-degree relatives of patients with ulcerative
      colitis, 50 patients with infectious enterocolitis and 100 healthy controls were
      tested for ASCA employing the ELISA technique. When compared with the healthy
      controls (p < 0.0001) and patients with infectious enterocolitis (p < 0.0001) the
      prevalence of ASCA was significantly increased in patients with Crohn's disease
      and their first-degree relatives (p < 0.01). Further significant differences
      concerning the frequency of ASCA within the different groups of our study
      population were not observed. In particular, ASCA were not found in increased
      prevalence in infectious enterocolitis. These observations are compatible with a
      role of ASCA as a marker of genetic predisposition to Crohn's disease.

PMID- 12481164
TI  - Long-term follow-up of celiac adults on gluten-free diet: prevalence and
      correlates of intestinal damage.
AB  - BACKGROUND AND AIMS: Celiac disease is the most common severe food intolerance in
      the Western world and is due to gluten ingestion in genetically susceptible
      children and adults. Intestinal biopsy is the golden standard for evaluation of
      mucosal damage associated with celiac disease. Gluten-free diet is the key
      treatment for celiac disease. Data on the long-term control of celiac disease are
      few and limited to small series of patients. The study reports data on the
      control of celiac disease and on its correlates in a large cohort of celiac
      adults during long-term treatment with gluten-free diet. METHODS: The study
      cohort comprises 91 men and 299 women having undergone treatment with a gluten
      free diet for at least 2 years and with complete records for visits at the time
      of diagnosis of celiac disease (baseline). Data collection included gender, age,
      education, weight, bowel habit, blood hemoglobin, plasma albumin and cholesterol,
      serum antiendomysium antibodies (EMA), dietary compliance to gluten-free diet
      (coded as good, low, or very low), and intestinal damage at biopsy (coded as
      absent, mild, or severe). RESULTS: The duration of follow-up was 6.9 +/- 7.5
      years (mean +/- SD, range 2-22 years). At follow-up visit, intestinal damage was
      absent in 170 patients (43.6%), mild in 127 (32.6%), and severe in 93 (23.8%). At
      follow-up, intestinal damage was significantly associated with dietary
      compliance, EMA, and plasma albumin (follow-up value and change value from
      baseline to follow-up). Baseline education significantly predicted dietary
      compliance and intestinal damage at follow-up. CONCLUSIONS: Celiac disease is
      often poorly controlled in the majority of patients on long-term treatment with a
      gluten-free diet as demonstrated by intestinal biopsy. Lack of adherence to
      strict gluten-free diet is the main reason of poorly controlled disease in
      adults. Laboratory and clinical information have a high positive predictive value
      and low negative predictive value for intestinal damage on long-term treatment.
      Dietary compliance as assessed by interview is the best marker of celiac disease
      control due to low cost, noninvasivity, and strong correlation with intestinal
      damage.

PMID- 12481165
TI  - Vasoactive intestinal polypeptide and gastrin-releasing peptide attenuate hepatic
      microvasculatory disturbances following intestinal ischemia and reperfusion.
AB  - BACKGROUND/AIMS: In addition to the primarily affected small bowel, intestinal
      ischemia and reperfusion (IIR) also leads to a marked decrease in hepatic
      microcirculation. The aim was to determine the potentially protective effect of
      the vasoactive hormones vasoactive intestinal polypeptide (VIP) and gastrin
      releasing peptide (GRP) on hepatic microcirculation following IIR. METHODS: Using
      a rat model, three animal groups were subjected to 40 min of intestinal ischemia,
      two of which were infused with either VIP or GRP (n = 12 each). Following
      reperfusion, hepatic intravital microscopy was performed. Portal venous
      perfusion, activities of serum glutamate pyruvate transaminase and alkaline
      phosphatase, mucosal injury in the small intestine and the expression of
      antioxidant enzymes glutathione peroxidase, copper-zinc-superoxide dismutase (Cu
      Zn-SOD), glutathione reductase and catalase (CAT) in the liver were investigated.
      RESULTS: Infusion of either VIP or GRP improved hepatic microcirculation and bile
      flow when compared with the untreated IIR group. VIP and GRP increased portal
      venous blood flow during reperfusion. VIP reduced the extent of mucosal damage
      resulting from IIR. GRP caused a decrease in expression of CAT and Cu-Zn-SOD,
      whereas VIP simply reduced CAT expression. CONCLUSION: This study indicates that
      vasoactive hormones may attenuate intestinal and hepatic injuries and circulatory
      disturbances following IIR.

PMID- 12481166
TI  - Pancreatic panniculitis in an 88-year-old man with neuroendocrine carcinoma.
AB  - Pancreatic panniculitis is a rare complication that occurs in 0.3-3% of patients
      with pancreatic diseases. Most of the cases reported to date were associated with
      adenocarcinoma and acute or chronic pancreatitis. We here present an 88-year-old
      man who was admitted to our institution with a nonfunctional neuroendocrine
      carcinoma of the pancreas. He subsequently developed pancreatic panniculitis and
      arthritis. Treatment with octreotide did not have an effect neither on
      progression of the carcinoma nor on development of new skin lesions. Two months
      after the diagnosis of pancreatic panniculitis had been made, the patient died
      from progressing carcinoma. A review of the literature shows that there is no
      congruent hypothesis for the pathogenesis of pancreatic panniculitis. Vascular
      damage seems to induce lipolysis by pancreatic enzymes. This eventually leads to
      fat necrosis. The diversity of disorders that can go along with pancreatic
      panniculitis suggests an unspecific damage of pancreatic tissue as a first step
      in the chain of events.

PMID- 12481167
TI  - Adverse outcomes of endoscopic retrograde cholangiopancreatography.
AB  - Endoscopic retrograde cholangiopancreatography (ERCP) has evolved from a
      diagnostic tool into a primarily therapeutic procedure for a variety of biliary
      and pancreatic problems. ERCP can, however, cause a wide range of short-term
      complications, including pancreatitis, hemorrhage, and perforation. In general,
      complications appear to be associated primarily with patient-related factors and
      the technical skill of the endoscopist. Overall, the risk factors for
      complications include suspected sphincter of Oddi dysfunction and technique
      related variables, such as difficult cannulation, precut sphincterotomy in
      inexperienced hands, failure to achieve drainage, and percutaneous transhepatic
      biliary access. Reviewed here are specific risk factors for post-ERCP
      pancreatitis and hemorrhage. A risk-factor assessment may be useful to help the
      endoscopist decide whether or not to perform ERCP and aids in making decisions
      regarding the techniques to be used. The principal strategies to reduce
      complications of ERCP include improving the training and education of
      endoscopists regarding risk factors; avoiding marginally indicated ERCP and
      preferentially using alternative imaging techniques; making referrals to advanced
      centers for complex or high-risk cases; and, in due course, concentrating ERCP
      practices among fewer endoscopists performing more ERCPs.

PMID- 12481168
TI  - Gastrointestinal imaging update: swallowing disorders and sphincter of Oddi
      dysfunction.
AB  - This update focuses on swallowing disorders and sphincter of Oddi dysfunction.
      Anatomy and physiology of swallowing are described, as are the signs, symptoms,
      and etiology of swallowing disorders. The imaging of these patients, particularly
      with videofluoroscopic swallowing study and fiberoptic endoscopic examination of
      swallowing, is then discussed. Sphincter of Oddi dysfunction as a cause of
      postcholecystectomy syndrome as well as its classification is described. This is
      followed by an explanation of the roles of fatty meal sonography and
      hepatobiliary scintigraphy in patients with sphincter of Oddi dysfunction,
      particularly type II and type III.

PMID- 12481169
TI  - Evaluation of chronic diarrhea in patients with human immunodeficiency virus
      infection.
AB  - Chronic diarrhea is a common problem for patients with human immunodeficiency
      virus infection, especially those with advanced disease. The extent of evaluation
      and whether to do flexible sigmoidoscopy, colonoscopy, and/or upper endoscopy
      have been areas of significant debate. Based upon the marked improvement in long
      term survival since the introduction of highly active antiretroviral therapy, a
      comprehensive evaluation is currently justified. A stepwise approach to the
      evaluation of chronic diarrhea appears to be the best approach. The first step is
      a history, with a focus on any association between the onset of diarrhea and the
      institution of protease inhibitor therapy, which is associated with significant
      diarrhea in many patients. If there is no temporal association with
      antiretroviral therapy, the next step is examination of stool for bacterial and
      protozoal pathogens. If the stool studies are negative, the next step is to
      proceed to colonoscopy. Flexible sigmoidoscopy alone has been noted to miss up to
      39% of cases of cytomegalovirus colitis. The inclusion of ileoscopy and biopsy of
      the terminal ileum during colonoscopy has a significant yield for
      microsporidiosis, which may obviate the need for upper endoscopy. The highest
      yield can be expected in patients with fever, weight loss, and a CD4 count of
      under 200 cells/mm3, especially those with a CD4 count less than 50 cells/mm3.

PMID- 12481170
TI  - Esomeprazole: update and clinical review.
AB  - The U.S. Food and Drug Administration's Nonprescription Drugs Advisory Committee
      and Gastroenterological Drugs Advisory Committee recommended approval of
      omeprazole as an over-the-counter treatment of heartburn in patients who have at
      least two episodes of heartburn each week. The consumer studies that have been
      conducted indicate that the majority of patients understand the proposed labeling
      and could use the proposed label to determine if the omeprazole therapy was
      appropriate for them. Esomeprazole is an effective agent in the treatment of
      gastroesophageal reflux disease (GERD) and erosive esophagitis. Newer studies
      continue to support its efficacy and safety in the treatment of these conditions.
      Several of the most recent studies have included comparisons with other proton
      pump inhibitors. The results of these studies indicate that all the proton pump
      inhibitors are effective in treating GERD and erosive esophagitis and that some
      patients would benefit from esomeprazole therapy.

PMID- 12481171
TI  - Clinical implications of new information on colorectal cancer genes.

PMID- 12481172
TI  - Outcomes of liver transplantation in patients with obesity and patients with
      inflammatory bowel disease.

PMID- 12481173
TI  - Does Helicobacter pylori infection increase the risk for NSAID-associated ulcers?

PMID- 12481174
TI  - Evidence-based dentistry.

PMID- 12481175
TI  - Lost in trousers.

PMID- 12481177
TI  - Further statistics in dentistry. Part 4: Clinical trials 2.
AB  - The principles which underlie a well-designed clinical trial were introduced in a
      previous paper. The trial should be controlled (to ensure that the appropriate
      comparisons are made), randomised (to avoid allocation bias) and, preferably,
      blinded (to obviate assessment bias). However, taken in isolation, these concepts
      will not necessarily ensure that meaningful conclusions can be drawn from the
      study. It is essential that the sample size is large enough to enable the effects
      of interest to be estimated precisely, and to detect any real treatment
      differences.

PMID- 12481178
TI  - Dietary advice in dental practice.
AB  - This paper aims to provide dental health professionals with practical advice to
      pass on to patients about diet and dental health. Sugars are the most important
      dietary factor contributing to dental caries. Different foods carry different
      dental health risks; those containing non-milk, extrinsic sugars are potentially
      the most damaging. In the UK, sugared soft drinks and confectionery contribute
      approximately 50% to total intake of non-milk extrinsic sugars. Patients should
      be encouraged to reduce the frequency of intake of sugary foods. Intake of acidic
      foods and drinks contributes to dental erosion and consumption of such foods
      should also be limited. Dietary advice to dental patients should be positive and
      personalized if possible and can be in line with dietary recommendations for
      general health. These are to increase the consumption of starchy staple foods (eg
      bread, potatoes and unsweetened cereals), vegetables and fruit and to reduce the
      consumption of sugary and fatty foods.

PMID- 12481179
TI  - Ectopic salivary gland tissue in the anterior mandible: a case report.
AB  - Ectopic salivary gland inclusions in the mandible are a rare phenomenon.
      Classically as described by Stafne they have been found in the posterior
      mandibular region. Cases affecting the anterior mandible are even more unusual.
      We report a case of ectopic salivary gland tissue in the anterior mandible. In
      our discussion we emphasise the need for a thorough history, examination and
      relevant investigations. Mandibular radiolucencies can prove a pitfall for the
      unwary.

PMID- 12481180
TI  - A view from the bodies corporate. 2. OrthoWorld 2000 Ltd.
AB  - North London may seem an unlikely venue for a discussion about orthodontics which
      takes us as far afield as South Africa and the USA, but Edgware is where I find
      the head office of OrthoWorld. At the time of writing OrthoWorld are the only
      specialist body corporate in the UK. I am meeting Dr. Morris Fine, Director of
      Operations, a quietly spoken orthodontist - and still practising - with what
      turns out to be strong views and clear convictions. OrthoWorld had its beginnings
      'four and a half years ago. Three of us started the venture, an orthodontist, an
      ex-dentist and a business man'. Morris Fine is the orthodontist, and the other
      two of the triumvirate are Jack and Reuben Shapiro respectively. Morris Fine
      tells that they 'had headed up a successful media company in South Africa before
      turning their attention to orthodontics in the UK.'

PMID- 12481184
TI  - General dental practitioners' knowledge of and attitudes towards evidence based
      practice.
AB  - AIMS: To assess general dental practitioners' understanding of, and attitudes
      towards, evidence based practice (EBP). SUBJECTS: A random sample of general
      dental practitioners currently practising in the North West of England. METHOD: A
      cross-sectional survey using self administered, structured, postal questionnaires
      in January 2001. RESULTS: A majority of the respondents had some understanding of
      technical terms associated with EBP. Only 29% (60/204) could correctly define the
      term EBP. When faced with clinical uncertainties 60% (122/204) of general dental
      practitioners turned to friends and colleagues for help and advice. Eighty one
      percent of respondents were interested in finding out further information about
      EBP (165/204). Barriers to its use included a lack of available time and
      financial constraints. CONCLUSIONS: EBP is not a concept that every dentist is
      familiar with, however, the general dental practitioners surveyed were
      enthusiastic and expressed a desire to find out more information on EBD. It
      appears to be the right time for an educational program targeted at GDPs to
      enhance their knowledge and use of EBD in everyday practice.

PMID- 12481185
TI  - Evaluation of the efficacy of Alpron disinfectant for dental unit water lines.
AB  - AIMS: To assess the efficacy of a disinfectant, Alpron, for controlling microbial
      contamination within dental unit water lines. METHODS: The microbiological
      quality of water emerging from the triple syringe, high speed handpiece, cup
      filler and surgery hand wash basin from six dental units was assessed for
      microbiological total viable counts at 22 degrees C and 37 degrees C before and
      after treatment with Alpron solutions. RESULTS: The study found that the use of
      Alpron disinfectant solutions could reduce microbial counts in dental unit water
      lines to similar levels for drinking water. This effect was maintained in all
      units for up to six weeks following one course of treatment. In four out of six
      units the low microbial counts were maintained for 13 weeks. CONCLUSIONS:
      Disinfectants may have a short term role to play in controlling microbial
      contamination of dental unit water lines to drinking water quality. However, in
      the longer term attention must be paid to redesigning dental units to discourage
      the build up of microbial biofilms.

PMID- 12481191
TI  - BMS-204352: a potassium channel opener developed for the treatment of stroke.
AB  - During ischemic stroke, a fatal biochemical cascade that results in neuronal
      hyperexcitability is initiated when neurons at risk are exposed to excessive
      excitatory amino acids and pathologically high levels of intracellular calcium
      (Ca(2+)). Therefore, neuroprotectants including NMDA-antagonists and blockers of
      voltage-gated Ca(2+) channels have been proposed as novel strategies for stroke
      treatment. Since potassium channels are key players in the control of neuronal
      excitability, and activation of neuronal potassium channels decrease excitability
      and neurotransmitter release, a novel approach for targeting acute ischemic
      stroke has been to develop openers of neuronal potassium channels. Bristol-Myers
      Squibb is developing BMS-204352, a fluoro-oxindole potassium channel opener, as a
      potential neuroprotectant for the treatment of acute ischemic stroke. BMS-203252
      is a potent and effective opener of two important subtypes of neuronal potassium
      channels, the calcium-activated, big-conductance potassium channels (K(Ca)
      channels) and voltage-dependent, non-inactivating potassium channels known as
      KCNQ channels. BMS-204352 (0.3 mg/kg, i.v.) significantly reduced cortical
      infarct volume in a model of permanent occlusion of the middle cerebral artery
      (MCA) in spontaneous hypertensive rats (SHR), as compared to vehicle when
      administered 2 h post-occlusion. At doses from 1 microg/kg to 1 mg/kg i.v., BMS
      204352 produced a significant reduction in cortical infarct volume in
      normotensive Wistar rats. In healthy humans, single and multiple i.v. doses of
      BMS-204352 (0.001 to 0.2 mg/kg) were safe, well-tolerated and without psychomotor
      function effects. Multiple doses of BMS-204352 (0.1-2 mg/kg i.v.) administered
      within 48 h after stroke onset were well tolerated in patients in Phase II
      studies, designed to evaluate safety, tolerability and pharmacokinetics. No
      clinically significant differences in organ toxicity or adverse effects were
      found, and total clearance and volume of distribution were independent of dose.
      BMS-204352 failed to show superior efficacy in acute stroke patients compared to
      placebo in a Phase III study that included 1978 patients at 200 centers
      worldwide.

PMID- 12481190
TI  - YM872: a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5
      methylisoxazole-4-propionic acid receptor antagonist.
AB  - This review focuses on the in vitro and in vivo neuropharmacology of YM872, a
      potential neuroprotective agent currently undergoing clinical trials in the
      United States (trial name: AMPA Receptor Antagonist Treatment in Ischemic Stroke 
      ARTIST). Its neuroprotective properties in rats and cats with induced focal
      cerebral ischemia are described. YM872, [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro
      1,2,3,4-tetrahydroquinoxalin-1-yl]-acetic acid monohydrate, is a selective,
      potent and highly water-soluble competitive alpha-amino-3-hydroxy-5
      methylisoxazole-4-propionic acid (AMPA) receptor antagonist. YM872 has a potent
      inhibitory effect on [(3)H]AMPA binding with a K(i) value of 0.096 microM. In
      contrast, YM872 has very low affinity for other ionotropic glutamate receptors.
      The solubility of YM872 is approximately 500 to 1000 times higher than that of
      the other competitive AMPA antagonists: YM90K, NBQX, or CNQX. The neuroprotective
      efficacy of YM872 was investigated in rats and cats subjected to permanent
      occlusion of the left middle cerebral artery. The animals were assessed either
      histologically or neurologically following ischemia. In rats with occluded middle
      cerebral artery (MCAO) YM872, by i.v. infusion, significantly reduced infarct
      volume measured at 24 h and 1 week after ischemia. Significant neuroprotection
      was maintained even when drug administration was delayed for up to 2 h after
      ischemia. In addition, YM872 significantly improved neurological deficit measured
      at 1 week after ischemia. In cats with MCAO YM872, by i.v. infusion, dose
      dependently reduced infarct volume at 6 h after ischemia. YM872 produced no
      behavioral abnormalities and was not nephrotoxic. The evidence for the
      neuroprotective efficacy of YM872 suggests its therapeutic potential in the
      treatment of acute stroke in humans.

PMID- 12481192
TI  - Duloxetine pharmacology: profile of a dual monoamine modulator.
AB  - Dysregulation within central monoaminergic systems is believed to underlie the
      pathology of depression. Drugs that selectively inhibit the reuptake of central
      monoamines have been used clinically to alleviate symptoms of depressive
      illnesses. Duloxetine, a novel compound currently under investigation for the
      treatment of depression, binds selectively with high affinity to both
      norepinephrine (NE) and serotonin (5-HT) transporters and lacks affinity for
      monoamine receptors within the central nervous system. It has been suggested that
      dual inhibition of monoamine reuptake processes may offer advantages over other
      antidepressants currently in use. In preclinical studies, duloxetine mimics many
      physiologic effects of antidepressants. Consistent with other antidepressants,
      duloxetine, by acute administration, elevates extracellular monoamine levels,
      while by chronic administration it does not alter basal monoamine levels. Like
      the selective serotonin reuptake inhibitor, fluoxetine, by microiontophoretic
      application, duloxetine inhibits neuronal cell firing. However, in comparison
      with fluoxetine, duloxetine is a more potent serotonin reuptake inhibitor.
      Furthermore, in behavioral experiments, duloxetine attenuates immobility in
      forced swim tests in animal models of depression to a greater extent than several
      other commonly used antidepressants. In a six-week open label uncontrolled study,
      duloxetine was evaluated in patients with a history of depression. Duloxetine was
      effective in treating depression as determined by marked reduction in Hamilton
      Depression Rating scores. Adverse effects reported during duloxetine treatment
      were minor and similar to those of other antidepressants. In an eight-week
      multicenter, double-blind, placebo-controlled study in patients with a major
      depressive disorder, duloxetine was effective as an antidepressant, particularly
      in patients with greater symptom severity. Only limited data are available
      regarding the pharmacokinetic profile of duloxetine in humans, although a half
      life of 10 to 15 h has been reported. Studies conducted in healthy human subjects
      confirm the preclinical profile of duloxetine as an inhibitor of 5-HT and NE
      reuptake. Taken together, existing data suggest that duloxetine is a novel and
      effective antidepressant.

PMID- 12481193
TI  - Buprenorphine: an analgesic with an expanding role in the treatment of opioid
      addiction.
AB  - Buprenorphine, a long-acting opioid with both agonist and antagonist properties,
      binds to mu-opioid (OP(3)), kappa-opioid (OP(2)), delta-opioid (OP(1)), and
      nociceptin (ORL-1) receptors. Its actions at these receptors have not been
      completely characterized, although buprenorphine is generally regarded as a mu
      opioid receptor partial agonist and a kappa-opioid receptor antagonist. Its
      pharmacology is further complicated by an active metabolite, norbuprenorphine.
      Although buprenorphine can be used as an analgesic agent, it is of greater
      importance in the treatment of opioid abuse. Because of its partial agonist
      activity at mu-opioid receptors and its long half-life, buprenorphine has proven
      to be an excellent alternative to methadone for either maintenance therapy or
      detoxification of the opioid addict. Although buprenorphine may ultimately prove
      to be superior to methadone in the maintenance of the pregnant addict, its
      effects on the developing fetus must be carefully evaluated.

PMID- 12481194
TI  - Dihydroetorphine: a potent analgesic: pharmacology, toxicology, pharmacokinetics,
      and clinical effects.
AB  - Dihydroetorphine (DHE) is one of the strongest analgesic opioid alkaloids known;
      it is 1000 to 12000 times more potent than morphine. Several in vitro and in vivo
      studies have shown that DHE is a selective mu-opioid receptor (OP(3)) agonist
      that also binds and activates all human recombinant mu-, delta-, and kappa-opioid
      receptors (OP(3), OP(1), and OP(2)). The onset of the analgesic effect of DHE in
      rodents is rapid, 5 to 15 min after parenteral administration; the duration of
      action is short, the analgesic effect disappears within 120 min after
      administration. By oral administration much higher doses of DHE are required to
      produce analgesic effects. These characteristics are accounted for by the
      pharmacokinetic properties of DHE in the rat, namely, by rapid distribution of
      DHE from the injection site to the brain and rapid metabolism by glucuronidation
      in the gut and liver followed by elimination into the bile. Continuous infusion
      and repeated administration of DHE lead to the development of tolerance to
      analgesia, physical dependence, and a rewarding effect in normal rats but not in
      animals with formalin-induced inflammation. Although formalin-induced
      inflammation is only one type of pain stimulus, these findings suggest that DHE
      addiction would be observed only in the case of pain-free conditions. Clinical
      reports in China show that sublingual doses of DHE, 20 to 180 microg, produce a
      potent analgesic effect with only mild side effects, including dizziness,
      somnolence, nausea, vomiting, constipation, and shortness of breath. To improve
      the short-lasting effect following sublingual administration, transdermal
      delivery of DHE via a patch has been investigated. The patch formulation of DHE
      produces continuous analgesic effect with minimal physical dependence and
      rewarding effect in rats suffering from chronic pain. This patch formulation,
      which is very suitable for DHE, may be viable for the treatment of severe pain
      and is likely to improve patients' quality of life.

PMID- 12481195
TI  - Nicotinic cholinergic modulation: galantamine as a prototype.
AB  - Nicotinic acetylcholine receptor pharmacology is becoming increasingly important
      in the clinical symptomatology of neurodegenerative diseases in general and of
      cognitive and behavioral aspects in particular. In addition, the concept of
      allosteric modulation of nicotinic acetylcholine receptors has become a research
      focus for the development of therapeutic agents. In this review the scientific
      evidence for changes in nicotinic acetylcholine receptors in Alzheimer's disease
      is described. Within this context, the pharmacology of galantamine, a recently
      approved drug for cognition enhancement in Alzheimer's disease, is reviewed along
      with preclinical studies of its efficacy on learning and memory. Galantamine
      modestly inhibits acetylcholinesterase and has an allosteric potentiating ligand
      effect at nicotinic receptors. The data collected in this review suggest that the
      unique combination of acetylcholinesterase inhibition and nicotinic acetylcholine
      receptor modulation offers potentially significant benefits over
      acetylcholinesterase inhibition alone in facilitating acetylcholine
      neurotransmission.

PMID- 12481196
TI  - Special issue dedicated in memory of Dr. Edward H. Ahrens, Jr.
AB  - This special issue of the "Cardiovascular Drug Reviews" is dedicated in memory of
      Dr. Edward H. Ahrens, Jr., who died on Dec. 9th, 2000 at the Princeton Medical
      Center in New Jersey at the age of 85. Dr. Ahrens was the Director of the Lipid
      Metabolism Laboratory at the Rockefeller University. Dr. Alexander Scriabine
      conceived the idea for the issue at the special memorial symposium held at the
      Rockefeller University on Feb. 05, 2002 under the auspices of The New York Lipid
      and Vascular Biology Research Club. Dr. Ahrens was the first president of the
      club. He started this club with Drs. Howard Eder and DeWitt Goodman. Dr. Eder
      thought that it would be a fitting attribute to honor one of the founding fathers
      of the club by hosting a memorial symposium. I, as the President of the club for
      that academic year, had no hesitation in accepting the proposal. This year will
      be the 40th anniversary of the club and its continued success provides a glimpse
      of the fine legacy left behind by Dr. Ahrens. Dr. Ahrens also played a pivotal
      role in the establishment of the Journal of Lipid Research. This is the 43rd year
      of the journal and in this commemorative issue we are reproducing a review he
      wrote for the 25th anniversary of the journal. I was never personally acquainted
      with Dr. Ahrens. However, I am honored that I got this opportunity to pay tribute
      to a great scientist whose work has contributed immensely to the progress of
      lipid research. He was a person who touched many lives and still continues to do
      so. My involvement in the remembrance of Dr. Ahrens shows that science not only
      impacts your contemporaries but also generations that follow you. Scientific
      research is a journey where you can leave your trails behind and be remembered
      for your work long after your departure from this world. Dr. Ahrens contributed
      immensely to the understanding of cholesterol metabolism. In the early stages of
      his career he showed that phospholipids solubilize fat in the blood. Now we know
      that a monolayer of phospholipids surrounds the neutral lipid core of cholesterol
      esters and triglycerides in lipoproteins. This monolayer contains proteins,
      called apolipoproteins, which play a major role in lipoprotein catabolism.
      Lipoproteins are the major vehicles that transport triglycerides and cholesterol
      in the plasma. He also described a new form of primary biliary cirrhosis
      characterized by the presence of xanthomas and hyperlipidemia with normal
      translucent plasma. Subsequently, his group at the Rockefeller Institute
      developed methods for the separation of lipids using silicic acid columns,
      isolated highly unsaturated long chain fish oil fatty acids using gas-liquid
      chromatography, standardized techniques to study sterol metabolism, and
      introduced the concept of using beta-sitosterolemia as an internal marker for
      cholesterol balance studies. These studies revealed that individuals show a
      reproducible response to a given regimen when studied over time. In contrast,
      different individuals may respond differently to the same regimen. Throughout his
      career, Dr. Ahrens championed metabolic studies in humans and has passionately
      argued for the continuation of such investigations. Dr. Ahrens also left behind
      trails of "graduates." Several of them are currently prominent scientists in
      their own fields. In this issue, Drs. Davignon and Samuel share their feelings
      for him in the form of "Remembrance" and "Curriculum Vitae." Dr. Salen has
      submitted a preview of his research progress towards the understanding of
      sitosterolemia. Dr. Hudgins and associates have acknowledged the efforts of Dr.
      Ahrens in binding LDL apheresis technique to the United States of America and
      have previewed the use of this procedure in the treatment of hypercholesterolemic
      patients. The contributions of these and other graduates will keep his legacy
      alive for a long time to come. We are truly grateful for this opportunity to pay
      homage to such a distinguished scientist.

PMID- 12481200
TI  - LDL Apheresis: an effective and safe treatment for refractory
      hypercholesterolemia.
AB  - Through the efforts of Edward H. Ahrens, LDL apheresis became available for the
      treatment of patients, often with familial hypercholesterolemia, who have no
      alternative therapy for severely elevated LDL cholesterol levels. In the U.S.,
      the FDA has approved this treatment for individuals on maximum diet and drugs
      with an LDL cholesterol greater than 300 mg/dL or greater than 200 mg/dL with
      coronary artery disease. Unlike plasmapheresis, apolipoprotein B-containing
      lipoproteins (LDL, Lp(a), and VLDL) are selectively removed by heparin
      precipitation or columns containing dextran sulfate cellulose or antibodies to
      apolipoprotein B. The acute lowering of LDL-cholesterol by a typical 2 - 3 h
      treatment is up to 80%, and the time-averaged lowering in the 1 to 2 week
      interval between treatments is up to 50%, with very few side effects. The
      lowering of LDL-cholesterol and other cardioprotective effects of LDL apheresis
      have reduced chest pain, prevented new disability and prolonged life. Whole blood
      compatible columns in development offer the possibility of simpler and less
      expensive treatments.

PMID- 12481199
TI  - Sitosterolemia.
AB  - Sitosterolemia was first described 28 years ago in two sisters. They had
      tendonxanthomas, normal plasma cholesterol levels, and elevated plant sterol
      levels. The high plant sterol levels were shown to be due to the increased
      absorption and delayed removal of plant sterols from the body. The increased
      absorption of plant sterols does not affect cholesterol absorption in these
      patients. However, cholesterol biosynthesis pathway is downregulated and turnover
      rates are reduced. Bile acid binding resins and ileal bypass surgery are
      effective treatments for sitosterolemic patients, whereas statins are
      ineffective. Sitosterolemia is inherited as a recessive trait. Recent studies
      have shown that mutations in ABCG5 and ABCG8 genes contribute to sitosterolemia.
      Most likely, ABCG5 and ABCG8 proteins function as obligate heterodimers and play
      a role in the absorption of plant sterol or control their rate of absorption.

PMID- 12481201
TI  - Update on fenofibrate.
AB  - Fenofibrate is a fibric acid derivative that has been marketed since the mid
      1970's (1998 in the United States). Its active metabolite, fenofibric acid, is
      responsible for the primary pharmacodynamic effects of the drug: reductions in
      total plasma cholesterol, low density lipoprotein cholesterol, triglycerides, and
      very low-density lipoprotein concentrations and increases in high-density
      lipoprotein cholesterol and apolipoproteins AI and AII concentrations. These
      effects are mediated by activation of peroxisome proliferator-activated receptor
      alpha (PPAR(alpha)). The drug has broad spectrum utility, with documented
      efficacy in Fredrickson types IIa, IIb, III, IV, and V hyperlipidemias.
      Fenofibrate is well tolerated, with digestive and musculoskeletal side effects
      similar to those of other fibrates. Results of the initial cardiovascular
      morbidity/mortality outcomes study with fenofibrate (known as DAIS [Diabetes
      Atherosclerosis Intervention Study]) were encouraging vis-a-vis slowing of
      atherosclerotic progression in the coronary vasculature of type II diabetics. The
      results of other ongoing outcome trials are eagerly awaited. These results will
      help to establish the overall place of fenofibrate in the hypolipidemic
      armamentarium.

PMID- 12481202
TI  - Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor.
AB  - Rosuvastatin, a new statin, has been shown to possess a number of advantageous
      pharmacological properties, including enhanced HMG-CoA reductase binding
      characteristics, relative hydrophilicity, and selective uptake into/activity in
      hepatic cells. Cytochrome p450 (CYP) metabolism of rosuvastatin appears to be
      minimal and is principally mediated by the 2C9 enzyme, with little involvement of
      3A4; this finding is consistent with the absence of clinically significant
      pharmacokinetic drug-drug interactions between rosuvastatin and other drugs known
      to inhibit CYP enzymes. Dose-ranging studies in hypercholesterolemic patients
      demonstrated dose-dependent effects in reducing low-density lipoprotein
      cholesterol (LDL-C) (up to 63%), total cholesterol, and apolipoprotein (apo) B
      across a 1- to 40-mg dose range and a significant 8.4% additional reduction in
      LDL-C, compared with atorvastatin, across the dose ranges of the two agents.
      Rosuvastatin has also been shown to be highly effective in reducing LDL-C,
      increasing high-density lipoprotein cholesterol (HDL-C), and producing favorable
      modifications of other elements of the atherogenic lipid profile in a wide range
      of dyslipidemic patients. In patients with mild to moderate hypercholesterolemia,
      rosuvastatin has been shown to produce large decreases in LDL-C at starting
      doses, thus reducing the need for subsequent dose titration, and to allow greater
      percentages of patients to attain lipid goals, compared with available statins.
      The substantial LDL-C reductions and improvements in other lipid measures with
      rosuvastatin treatment should facilitate achievement of lipid goals and reduce
      the requirement for combination therapy in patients with severe
      hypercholesterolemia. In addition, rosuvastatin's effects in reducing
      triglycerides, triglyceride-containing lipoproteins, non-HDL-C, and LDL-C and
      increasing HDL-C in patients with mixed dyslipidemia or elevated triglycerides
      should be of considerable value in enabling achievement of LDL-C and non-HDL-C
      goals in the numerous patients with combined dyslipidemias or metabolic syndrome
      who require lipid-lowering therapy. Rosuvastatin is well tolerated alone, and in
      combination with fenofibrate, extended-release niacin, and cholestyramine, and
      has a safety profile similar to that of currently marketed statins. A large, long
      term clinical trials program is under way to investigate the effects of
      rosuvastatin on atherosclerosis and cardiovascular morbidity and mortality.

PMID- 12481203
TI  - Pioglitazone: cardiovascular effects in prediabetic patients.
AB  - Pioglitazone is the second thiazolidine derivative used clinically in the type 2
      diabetes mellitus (DM). In the prediabetic stage, hyperinsulinemia or insulin
      resistance has been suggested to be closely associated with the oxidative stress.
      The first thiazolidine derivative used to treat DM, troglitazone, is chemically
      related to alpha-tocopherol, a known antioxidant. Troglitazone prevents tissue
      damage, but has been reported to produce hepatotoxicity. Pioglitazone strongly
      increases insulin sensitivity, improves glucose and lipid metabolism and showed
      no evidence of hepatotoxicity. The mechanism of the antidiabetic action of
      pioglitazone involves activation of insulin receptors and/or high affinity for
      peroxisome proliferator-activated receptor gamma (PPARgamma). Hydroxylation of
      the phenyl and pyridine rings in the chemical structure of pioglitazone may
      facilitate the scavenging of hydroxyl radicals. The direct antioxidant effect of
      pioglitazone may contribute to its effect on insulin resistance. The hypoglycemic
      and hypolipidemic effects of pioglitazone are likely to reduce the expression of
      TNFalpha. The reduction in the oxidative stress may lead to the suppression of
      TGFbeta and of collagen accumulation. A decrease in collagen content is likely to
      improve left ventricular diastolic function and distensibility of the aortic
      wall. Reduction in the oxidative stress may prevent the proliferation of vascular
      smooth muscle cells and contribute to the decrease in the aortic wall stiffness.

PMID- 12481204
TI  - The use of capture-recapture methods in public health.

PMID- 12481205
TI  - Using the two-source capture-recapture method to estimate the incidence of acute
      flaccid paralysis in Victoria, Australia.
AB  - OBJECTIVE: To estimate the incidence and the completeness of ascertainment of
      acute flaccid paralysis (AFP) in Victoria, Australia, in 1998-2000 and to
      determine its common causes among children aged under 15 years. METHODS: : The
      two-source capture-recapture method was used to estimate the incidence of cases
      of AFP and to evaluate case ascertainment in the routine surveillance system. The
      primary and secondary data sources were notifications from this system and
      inpatient hospital records, respectively. FINDINGS: The routine surveillance
      system indicated that there were 14 cases and the hospital record review
      identified 19 additional cases. According to the two-source capture-recapture
      method, there would have been 40 cases during this period (95% confidence
      interval (CI) = 29-51), representing an average annual incidence of 1.4 per
      100000 children aged under 15 years (95% CI = 1.1- 1.7). Thus case ascertainment
      based on routine surveillance was estimated to be 35% complete. Guillain-Barre
      syndrome was the commonest single cause of AFP. CONCLUSIONS: Routine surveillance
      for AFP in Victoria was insensitive. A literature review indicated that the
      capture-recapture estimates obtained in this study were plausible. The present
      results help to define a target notification rate for surveillance in settings
      where poliomyelitis is not endemic.

PMID- 12481206
TI  - Rapid assessment method for prevalence and intensity of Loa loa infection.
AB  - OBJECTIVE: To assess the validity of observations on eye worm and Calabar
      swellings for the rapid assessment of the prevalence and intensity of loiasis at
      the community level. METHOD: A total of 12895 individuals over the age of 15
      years living in 102 communities in Cameroon and Nigeria took part in the study. A
      standardized questionnaire was administered to participants from whom finger
      prick blood samples were collected and examined for Loa loa microfilariae. Rapid
      assessments of the prevalence and intensity of loiasis were made on the basis of
      a history of eye worm or Calabar swellings. FINDINGS: There was a strong
      correlation between the indices of the rapid assessment procedures and the
      parasitological indices of L. loa endemicity. The rapid assessment indices were
      effective in diagnosing high-risk communities (sensitivity 94-100%; specificity
      66-92%). The highest sensitivity (100%) and specificity (92%) were obtained with
      a rapid assessment procedure based on a history of eye worm lasting 1-7 days
      together with confirmation by the guided recognition of a photograph of adult L.
      loa in the eye. CONCLUSION: Rapid assessment of the prevalence and intensity of
      loiasis at the community level can be achieved using a procedure based on the
      history of eye worm lasting 1-7 days together with confirmation by the guided
      recognition of a photograph of an adult L. loa in the eye.

PMID- 12481207
TI  - Model-based estimates of risks of disease transmission and economic costs of
      seven injection devices in sub-Saharan Africa.
AB  - OBJECTIVE: To investigate and compare seven types of injection devices for their
      risks of iatrogenic transmission of bloodborne pathogens and their economic costs
      in sub-Saharan Africa. METHODS: Risk assumptions for each device and cost models
      were constructed to estimate the number of new hepatitis B virus (HBV) and human
      immunodeficiency virus (HIV) infections resulting from patient-to-patient,
      patient-to-health care worker, and patient-to-community transmission. Costs of
      device purchase and usage were derived from the literature, while costs of direct
      medical care and lost productivity from HBV and HIV disease were based on data
      collected in 1999 in Cote d'Ivoire, Ghana, and Uganda. Multivariate sensitivity
      analyses using Monte Carlo simulation characterized uncertainties in model
      parameters. Costs were summed from both the societal and health care system
      payer's perspectives. FINDINGS: Resterilizable and disposable needles and
      syringes had the highest overall costs for device purchase, usage, and iatrogenic
      disease: median US dollars 26.77 and US dollars 25.29, respectively, per
      injection from the societal perspective. Disposable-cartridge jet injectors and
      automatic needle-shielding syringes had the lowest costs, US dollars 0.36 and US
      dollars 0.80, respectively. Reusable-nozzle jet injectors and auto-disable needle
      and syringes were intermediate, at US dollars 0.80 and US dollars 0.91,
      respectively, per injection. CONCLUSION: Despite their nominal purchase and usage
      costs, conventional needles and syringes carry a hidden but huge burden of
      iatrogenic disease. Alternative injection devices for the millions of injections
      administered annually in sub-Saharan Africa would be of value and should be
      considered by policy-makers in procurement decisions.

PMID- 12481208
TI  - Effect of interpregnancy interval on risk of spontaneous preterm birth in Emirati
      women, United Arab Emirates.
AB  - OBJECTIVE: To investigate whether a short interpregnancy interval is a risk
      factor for preterm birth in Emirati women, where there is a wide range of
      interpregnancy intervals and uniformity in potentially confounding factors.
      METHODS: A case-control design based on medical records was used. A case was
      defined as a healthy multiparous Emirati woman delivering a healthy singleton
      spontaneously before 37 weeks of gestation between 1997 and 2000, and a control
      was defined as the next eligible similar woman delivering after 37 weeks of
      gestation. Women were excluded if there was no information available about their
      most recent previous pregnancy or if it had resulted in a multiple or preterm
      birth. Data collected from charts and delivery room records were analysed using
      the STATA statistical package. All variables found to be valid, stable and
      significant by univariate analysis were included in multivariate logistic
      regression analysis. FINDINGS: There were 128 cases who met the eligibility
      criteria; 128 controls were selected. Short interpregnancy intervals were
      significantly associated with case status (P<0.05). The multivariate adjusted
      odds ratios for the 1st, 2nd, and 4th quartiles of interpregnancy interval
      compared with the lowest-risk 3rd quartile were 8.2, 5.4, and 2.0 (95% confidence
      intervals: 3.5-19.2, 2.4-12.6, and 0.9- 4.5 respectively). CONCLUSION: A short
      interpregnancy interval is a risk factor for spontaneous preterm birth in Emirati
      women. The magnitude of the risk and the risk gradient between exposure quartiles
      suggest that the risk factor is causal and that its modification would reduce the
      risk of preterm birth.

PMID- 12481209
TI  - Mortality patterns in the Russian Federation: indirect technique using widowhood
      data.
AB  - OBJECTIVE: The Russian mortality crisis of the early 1990s attracted considerable
      attention, but information on possible covariates of mortality is lacking, and
      concerns have been raised about the validity of official mortality data. To help
      elucidate the determinants of mortality, we examined whether indirect demographic
      techniques could be used to study mortality in countries such as the Russian
      Federation, where mortality data are inadequate, using input data independent
      from official vital statistics. METHODS: A national sample of the population was
      interviewed (n = 1600, response rate = 67%). Participants who had ever been
      married (82% of the sample) were asked about the date of birth and vital status
      of their first spouse. Spousal mortality was then estimated indirectly for the
      531 men and 710 women for whom valid data were available. FINDINGS: The estimated
      risk of death between the ages of 35-69 years was 57% for male spouses and 17%
      for female spouses. Corresponding figures derived from national data for 1990
      were 52% and 25% for the Russian Federation, and 31% and 20% for the United
      Kingdom. According to spouses' reports, 38% of their husbands died from
      cardiovascular disease, 22% from cancer, and 14% from injuries and accidents.
      Mortality of male spouses was inversely related to the education level of their
      wives, and the age-adjusted hazard ratios for death from all causes, compared to
      primary education, were 0.77 for secondary education and 0.57 for university
      education (trend P = 0.03). Mortality was also inversely related to ownership of
      household items, but not to size of settlement, pride in Russia, membership in
      the Soviet Communist Party, nationality or self-assessed social status.
      CONCLUSIONS: Although the indirect estimates were imprecise (partly owing to the
      small population size of the study), and mortality in women was probably
      underestimated (owing to many factors, including poorer reporting by males and
      high male mortality), our results are nevertheless consistent with the mortality
      pattern observed in official mortality data. The indirect technique thus appears
      to be a useful tool to study the determinants of mortality in the Russian
      Federation and other populations, where reliable or sufficiently extensive data
      are not available.

PMID- 12481210
TI  - Evaluation of the micro-CATT, CATT/Trypanosoma brucei gambiense, and LATEX/T b
      gambiense methods for serodiagnosis and surveillance of human African
      trypanosomiasis in West and Central Africa.
AB  - OBJECTIVE: To evaluate the performance of serological tests using dried blood on
      filter-papers (micro-card agglutination test for trypanosomiasis (micro-CATT))
      performed under field and laboratory conditions and using whole blood ((CATT/T.b.
      gambiense) (wb-CATT) and latex agglutination (LATEX/T.b. gambiense) (wb-LATEX))
      for the serodiagnosis and surveillance of human African trypanosomiasis in West
      and Central Africa. METHODS: We evaluated the micro-CATT, wb-CATT and wb-LATEX
      methods in Cote d'Ivoire and the Central African Republic by screening 940
      people. Sensitivity and specificity were calculated for each serological test;
      only patients with the confirmed presence of trypanosomes in the blood or lymph
      aspirate were considered true positives. Positive and negative predictive values
      were also calculated. FINDINGS: Each of the tests showed a lower sensitivity in
      the Central African Republic than in Cote d'Ivoire. CONCLUSION: The results
      confirmed the efficiency of the classic wb-CATT to detect sleeping sickness
      patients. The micro-CATT method can be used for human African trypanosomiasis
      surveillance if the test is performed on the same day as the blood collection, or
      if samples are stored at 4 degrees C. Otherwise, micro-CATT can be used when
      absolute sensitivity is not required. wb-LATEX should only be used for high
      specificity screening.

PMID- 12481211
TI  - Risk of death following pregnancy in rural Nepal.
AB  - OBJECTIVE: To investigate the length of time following pregnancy during which the
      risk of mortality was elevated among women in rural Nepal. METHODS: An analysis
      was performed of prospective data on women participating in the control group of
      a large, population-based trial. Weekly visits were made for three years to 14805
      women aged 14-45 years. Pregnancy and vital status were assessed. A total of 7325
      pregnancies were followed. Mortality during and following pregnancy, expressed on
      a person-time basis, was compared to referent mortality unrelated to pregnancy
      (52 weeks after pregnancy) in the same cohort. FINDINGS: The relative risk (RR)
      of death during pregnancy but before the onset of labour was 0.93 (95% confidence
      interval (CI): 0.38-2.32). During the perinatal period, defined as lasting from
      the onset of labour until seven days after outcome, the RR of death was 37.02
      (95% CI: 15.03-90.92). The RR for 2 to 6 weeks, 7 to 12 weeks, and 13 to 52 weeks
      after pregnancy were 4.82, 2.59 and 1.01 with 95% CI of 1.77-13.07, 0.81-8.26 and
      0.40-2.53, respectively. The RR of death was 2.21 (95% CI. 1.03-4.71) during the
      conventional maternal mortality period (pregnancy until 6 weeks after outcome).
      It was 2.26 (95% CI: 1.05-4.90) when the period was extended to 12 weeks after
      pregnancy outcome. CONCLUSION: The risk of mortality associated with pregnancy
      should be assessed over the first 12 weeks following outcome instead of over the
      first 6 weeks.

PMID- 12481212
TI  - How will the reduction of tariffs and taxes on insecticide- treated bednets
      affect household purchases?
AB  - One of the steps called for in the fight against malaria is the removal of
      tariffs and taxes on insecticide-treated bednets (ITNs), netting materials, and
      insecticides, with a view to reducing the retail prices of ITNs and thus
      increasing utilization. In this paper we develop an approach for analysing the
      extent to which reform of tariff and tax policy can be expected to increase ITN
      purchases. We consider the following questions: (1). How much does the retail
      price of ITNs change if tariffs and taxes are reduced or eliminated? (2). How
      responsive is consumer demand to changes in the retail price of ITNs? Data on the
      price elasticity of demand for ITNs are very limited. Nevertheless, they suggest
      that ITN demand is not highly responsive to lower prices if household preferences
      are held constant. The reduction in retail prices associated with the removal of
      tariffs and taxes depends on the structure of the market in individual countries.
      In Nigeria, reducing the tariff on insecticides from 42% to zero and the tariff
      on netting materials from 40% to 5% is expected to increase ITN purchases by 9
      27%, depending on the elasticity used. Country-specific information about market
      structure and cost conditions is needed if predictions are to be made as to how a
      specific policy change will affect ITN purchases.

PMID- 12481213
TI  - Emergency medical care in developing countries: is it worthwhile?
AB  - Prevention is a core value of any health system. Nonetheless, many health
      problems will continue to occur despite preventive services. A significant burden
      of diseases in developing countries is caused by time-sensitive illnesses and
      injuries, such as severe infections, hypoxia caused by respiratory infections,
      dehydration caused by diarrhoea, intentional and unintentional injuries,
      postpartum bleeding, and acute myocardial infarction. The provision of timely
      treatment during life-threatening emergencies is not a priority for many health
      systems in developing countries. This paper reviews evidence indicating the need
      to develop and/or strengthen emergency medical care systems in these countries.
      An argument is made for the role of emergency medical care in improving the
      health of populations and meeting expectations for access to emergency care. We
      consider emergency medical care in the community, during transportation, and at
      first-contact and regional referral facilities. Obstacles to developing effective
      emergency medical care include a lack of structural models, inappropriate
      training foci, concerns about cost, and sustainability in the face of a high
      demand for services. A basic but effective level of emergency medical care
      responds to perceived and actual community needs and improves the health of
      populations.

PMID- 12481214
TI  - Immunosuppression induced by ultraviolet radiation: relevance to public health.

PMID- 12481215
TI  - Systemic alteration induced in mice by ultraviolet light irradiation and its
      relationship to ultraviolet carcinogenesis. 1977.
AB  - Chronic irradiation of mice with ultraviolet (UV) light produces a systemic
      alteration of an immunologic nature. This alteration is detectable in mice long
      before primary skin cancers induced by UV light begin to appear. The alteration
      results in the failure of UV-irradiated mice to reject highly antigenic,
      transplanted UV-induced tumors that are rejected by unirradiated syngeneic
      recipients. The immunologic aspect of this systemic alteration was demonstrated
      by transferring lymphoid cells from UV-irradiated mice to lethally x-irradiated
      recipients. These recipients were unable to resist a later challenge with a
      syngeneic UV-induced tumor, whereas those given lymphoid cells from normal donors
      were resistant to tumor growth. Parabiosis of normal mice with UV-irradiated
      mice, followed by tumor challenge of both parabionts with a UV-induced tumor,
      resulted in the growth of the challenge tumors in both WV-irradiated and
      unirradiated mice. Splenic lymphocytes from tumor-implanted UV-treated mice were
      not cytotoxic in vitro against UV-induced tumors, whereas under identical
      conditions cells from tumor-implanted, unirradiated mice were highly cytotoxic.
      Our findings suggest that repeated UV irradiation can circumvent an immunologic
      mechanism that might otherwise destroy nascent UV-induced primary tumors that are
      strongly antigenic.

PMID- 12481216
TI  - Twenty-five years of essential medicines.

PMID- 12481217
TI  - Vaccine-associated paralytic polio in India.

PMID- 12481218
TI  - Malaria and mosquito genomes sequenced, but funding falls short.

PMID- 12481219
TI  - Malaria takes its constant toll: a postcard from Kenya.

PMID- 12481220
TI  - Argentina's health system devastated but health workers rally.

PMID- 12481221
TI  - South Africa takes first steps to provide antiretrovirals.

PMID- 12481226
TI  - SCAR Radiologic Technologist Survey: analysis of technologist workforce and
      staffing.
AB  - One of the greatest dilemmas facing medical imaging departments today is the
      worsening personnel crisis in the radiologic technologist (RT) workforce. As the
      volume and complexity of medical imaging studies continues to increase, an
      unprecedented imbalance exists between RT supply and demand. A number of
      etiologic factors have been postulated to contribute to this RT shortage
      including decreasing morale, perceived inadequacies in compensation, decreasing
      number of training programs, and limitations in the career ladder. Previous
      studies have cited improved technologist productivity as imaging departments
      successfully transition from film-based to filmless operation. This study was
      undertaken to address the impact of digital technologies (information systems,
      PACS, digital radiography) on technologist productivity, in an attempt to
      determine whether these technologies can be used to positively affect the
      existing RT workforce imbalance. A total of 112 facilities participated in this
      nationwide study, with representation of imaging providers that paralleled the
      demographic profile of the marketplace as a whole. Survey results indicate the
      existing RT staffing shortage is greatest within academic and rural-based
      hospitals and is most severe in the area of general radiography, which accounts
      for 65-70% of imaging department volumes. For general radiography alone,
      respondents report an average shortage of 2 RT full-time equivalents (FTE's) per
      institution, when comparing the number of budgeted RT FTE's versus the actual
      number of RT FTE's. Preliminary results indicate that at this time, RT staffing
      shortages are not affected by the presence or absence of digital information
      technologies. Additional research is planned through a five-year longitudinal
      data collection, to better delineate the complex relationship that exists between
      implementation of digital technologies and RT staffing.

PMID- 12481227
TI  - SCAR Radiologic Technologist Survey: analysis of the impact of digital
      technologies on productivity.
AB  - As medical reimbursements continue to decline, increasing financial pressures are
      placed upon medical imaging providers. This burden is exacerbated by the existing
      radiologic technologist (RT) crisis, which has caused RT salaries to trend
      upward. One strategy to address these trends is employing technology to improve
      technologist productivity. While industry-wide RT productivity benchmarks have
      been established for film-based operation, little to date has been published in
      the medical literature regarding similar productivity measures for filmless
      operation using PACS. This study was undertaken to document the complex
      relationship between technologist productivity and implementation of digital
      radiography and digital information technologies, including PACS and
      hospital/radiology information systems (HIS/RIS). A nationwide survey was
      conducted with 112 participating institutions, in varying degrees of digital
      technology implementation. Technologist productivity was defined as the number of
      annual exams performed per technologist full-time equivalent (FTE). Productivity
      analyses were performed among the different demographic and technology profile
      groups, with a focus on general radiography, which accounts for 65-70% of imaging
      department volumes. When evaluating the relationship between technologist
      productivity and digital technology implementation, improved productivity
      measures were observed for institutions implementing HIS/RIS, modality worklist,
      and PACS. The timing of PACS implementation was found to have a significant
      effect on technologist productivity measures, with an initial 10.8% drop in
      productivity during the first year of PACS implementation, followed by a 27.8%
      increase in productivity beyond year one. This suggests there is a "PACS learning
      curve" phenomenon, which should be considered when institutions are planning for
      PACS implementation.

PMID- 12481228
TI  - Workflow optimization: current trends and future directions.
AB  - In an attempt to maximize productivity within the medical imaging department,
      increasing importance and attention is being placed on workflow. Workflow is the
      process of analyzing individual steps that occur during a single event, such as
      the performance of an MRI exam. The primary focus of workflow optimization within
      the imaging department is automation and task consolidation, however, a number of
      other factors should be considered including the stochastic nature of the
      workload, availability of human resources, and the specific technologies being
      employed. The purpose of this paper is to determine the complex relationship that
      exists between information technology and the radiologic technologist, in an
      attempt to determine how workflow can be optimized to improve technologist
      productivity. This relationship takes on greater importance as more imaging
      departments are undergoing the transition from film-based to filmless operation.
      A nationwide survey was conducted to compare technologist workflow in film-based
      and filmless operations, for all imaging modalities. The individual tasks
      performed by technologists were defined, along with the amount of time allocated
      to these tasks. The index of workflow efficiency was determined to be the
      percentage of overall technologist time allocated to image acquisition, since
      this is the primary responsibility of the radiologic technologist. Preliminary
      analysis indicates technologist workflow in filmless operation is enhanced when
      compared with film-based operation, for all imaging modalities. The specific
      tasks that require less technologist time in filmless operation are accessing
      data and retake rates (due to both technical factors and lost exams).
      Surprisingly, no significant differences were reported for the task of image
      processing, when comparing technologist workflow in film-based and filmless
      operations. Additional research is planned to evaluate the potential workflow
      gains achievable through workflow optimization software, improved systems
      integration, and automation of advanced image processing techniques.

PMID- 12481230
TI  - Idiopathic hyperammonemia following an unrelated cord blood transplant for
      mucopolysaccharidosis I.
AB  - Bone marrow transplantation (BMT) has been shown to reverse or stabilize some
      manifestations of mucopolysaccharidosis I (Hurler syndrome). Idiopathic
      hyperammonemia (IHA) is a rare complication of solid organ and BMT that is
      characterized by elevated serum ammonia, normal liver enzymes, and abrupt onset
      of neurologic deterioration. We present the case of a 14-month-old male patient
      with Hurler syndrome who developed fatal IHA (ammonia = 2297 micromol/L) 31 days
      after a cord blood transplant. A complete autopsy was performed, with examination
      of both frozen and formalin-fixed paraffin-embedded (FFPE) tissues using a
      variety of special stains and electron microscopy. Hyperammonemia was documented
      by analysis of antemortem serum and postmortem cerebrospinal and vitreous fluid.
      Other causes of hyperammonemia, including Reye syndrome, were excluded.
      Histologic changes included centrilobular microvesicular steatosis of the liver
      and storage product present in multiple organs. The highly water-soluble
      mucopolysaccharide (MPS) storage product was best identified by colloidal iron
      staining of FFPE and unfixed air-dried fresh frozen liver sections. Alcian blue
      stains failed to convincingly demonstrate MPS in any of the liver sections. This
      is the first published report, to our knowledge, of IHA in a posttransplant
      patient younger than 18 years old or following transplantation for Hurler
      syndrome. Demonstration of the hepatic centrilobular microvesicular steatosis
      characteristic of IHA was complicated by the diffuse storage of MPS within the
      liver. MPS storage can be best detected in the liver using colloidal iron
      staining. Oil-red-O staining may be useful to document microvesicular steatosis
      in cases with a clinical history of hyperammonemia following solid organ or BMT.
      Determining if certain subsets of children are at increased risk for IHA requires
      further study.

PMID- 12481231
TI  - Incidence of autopsy findings in unexpected deaths of children and adolescents.
AB  - Studies in various settings reveal that a significant percentage of autopsies
      demonstrate findings that were not previously clinically diagnosed. In the
      pediatric and adolescent age group, forensic examinations comprise a large
      percentage of total autopsies performed. We hypothesized that a similar number of
      previously undiagnosed findings would be present in this population and thus
      reviewed a series of autopsy reports from the Medical Examiners Office in the
      Arkansas Crime Laboratory. During 1997 through 1999, we performed 439 complete
      forensic autopsies on children and adolescents (age range 1 day to 19 years;
      median 18 months). Previously undiagnosed lesions were found in 173 (39%). Of
      these subjects, 68 (39%) had clinically significant pathology, 60 (35%) had
      insignificant pathology, and 45 (26%) had pathology of undetermined significance.
      Thirty-six subjects had lesions expected from a previously diagnosed condition.
      Of the total number of lesions found, 168 were inflammatory, 58 were congenital
      anomalies (48 unexpected), and 88 comprised miscellaneous other conditions.
      Infants <6 months of age were significantly more likely to have a previously
      undiagnosed lesson than children > 6 months (P <0.0001). Previously undiagnosed
      findings, mostly inflammatory, occur relatively frequently in pediatric and
      adolescent forensic autopsies and are more likely to occur in infants.

PMID- 12481233
TI  - Buoyancy regulation and the potential for vertical migration in the oceanic
      cyanobacterium trichodesmium.
AB  - Diel protein and carbohydrate content in Trichodesmium thiebautii was measured to
      evaluate the relationship to buoyancy status. Carbohydrate:protein ratio was the
      best predictor of buoyancy and fit a cosine curve with increasing values during
      the day and decreasing values at night in cycles that paralleled observed diel
      buoyancy patterns. This ratio also increased in short-term experiments as a
      function of light and increased in parallel with decreasing positive buoyancy. We
      used changes in this ratio to estimate the potential for vertical migration.
      Whereas limited vertical excursions in the upper 70 m are possible, deeper
      migrations appear unlikely unless respiration rates decrease significantly. N:P
      ratios in sinking and floating colonies were used to test for the P acquisition
      at depth (vertical migration). We noted that pooled N:P ratios were not
      significantly different between sinking and ascending colonies (N:P = 65.6 and
      66.3, respectively) collected along the northern Australian coast, much like
      published results from north of Hawaii. Highly significant differences (p
      <0.0001) were observed in the western Gulf of Mexico between sinking and
      ascending colonies (N:P = 87.0 and 43.5, respectively) and provide the best
      direct evidence to date of vertical migration for P acquisition. Our
      physiological data on compositional changes during buoyancy reversals suggest a
      complex relationship between light and nutrients. It appears likely that light
      and P metabolism interact to regulate the vertical extent of migrations, with
      deep vertical migration regulated by P metabolism superimposed on a mixed-layer
      light-driven migration. The variability in N:P ratios suggests that care should
      be taken in assuming buoyancy reversals always result in P acquisition in this
      oceanic cyanobacterium.

PMID- 12481234
TI  - Two endophytic fungi in different tissues of scots pine buds (Pinus sylvestris
      L.).
AB  - Two fungal species were isolated with different frequencies from pine tissue
      cultures originating from buds. One species was detected in 33.1% of the cultures
      initiated in March, and another was present in 1.7% of cultures initiated in
      June. Based on analyses of phylogenetic and physiological characteristics these
      fungi were identified as Hormonema dematioides (isolated in March) and
      Rhodotorula minuta (isolated in June). Probes targeted towards the 18S rRNA of H.
      dematioides and R. minuta were made. When in situ hybridizations were performed
      on pine bud tissue, R. minuta was detected inside the cells of meristematic
      tissue in 40% of the samples, in contrast to H. dematioides, which was not found
      in this tissue. Using light microscopy, H. dematioides was found to be localized
      in the scale tissues of the buds. Fungal endophytes have previously been detected
      in scale tissues, but not in the meristematic tissues of buds. The habitats of
      these fungi may reflect their different roles in the plant.

PMID- 12481235
TI  - Early prevention of obesity and cardiovascular diseases.
AB  - SUMMARY: The prevalence of nutrition related diseases increased exponentially
      during the last decades. Risk factors are acquired early in life. Preventive
      measures include a longer duration of breast-feeding and measures of prevention
      and health promotion early in childhood. These measures should be undertaken by
      all persons having influence on the development of children.

PMID- 12481236
TI  - [Hepatocellular carcinoma: rising incidence of hepatitis C virus-associated cases
      at a university clinic in Germany].
AB  - BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC) ranks eighth among
      malignant tumors worldwide. Western countries belong to areas of low HCC
      prevalence, but incidence of HCC is rising. The aim of the present, retrospective
      study was to determine changes in the incidence rates and risk factors for HCC in
      Germany based on the data of a single center. PATIENTS AND METHODS:
      Epidemiological data of 205 consecutive patients with HCC (163 males, 42 females,
      mean age 64+/-1 years), admitted to the University clinic Dusseldorf between
      January 1988 and December 2001, were evaluated. For comparison this time period
      was divided into two equal intervals (1988 - 1994 and 1995 - 2001). RESULTS: The
      number of newly diagnosed HCC has more than doubled in the years 1995 - 2001
      compared to the years 1988 - 1994. Chronic hepatitis C (HCV), hepatitis B (HBV),
      and chronic alcohol abuse accounted for almost 80 % of HCC. The number of HCV
      associated HCC increased from 31.0 % in the years 1990 - 1995 to 44.6 % (p <
      0.04) in the years 1996 - 2001, whereas the proportion of HBV-associated HCC
      decreased. There were no changes in the Okuda tumor stage, tumor diameter and
      alpha-fetoprotein levels at the time of HCC diagnosis throughout the years 1988 -
      2001. More than 65 % of HCC were non-resectable at the time of HCC diagnosis due
      to tumor diameter or number of tumor lesions. CONCLUSION: Screening for HCC,
      possibly rising in its incidence, should be further improved, taking into account
      that chronic HCV infection is the major risk factor for HCC in Germany.

PMID- 12481237
TI  - [Acute pancreatitis caused by atrial fibrillation?].
AB  - HISTORY: We report three male patients who had atrial fibrillation with a rapid
      and irregular ventricular rate, aged 60, 69 and 70 years, respectively, in whom
      development of acute pancreatitis occurred simultaneously with other ischaemic
      events. INVESTIGATIONS: One of these patients simultaneously suffered from a
      transient ischaemic attack (TIA), another developed a stroke and an infarction of
      the spleen, while the third one had a splenic infarction and an embolism in the
      region of the mesenteric arteries. Two patients had paroxysmal atrial
      fibrillation, while the third suffered from ischemic cardiomyopathy with chronic
      atrial fibrillation. DIAGNOSIS AND TREATMENT: Oedematous pancreatitis occurred in
      one patient while, in the two others, the diagnosis of severe necrotizing
      pancreatitis was made. CONCLUSION: Atrial fibrillation is the most common
      sustained arrhythmia encountered in clinical practice and a recognized risk
      factor for the development of peripheral embolism, which often takes the form of
      an ischaemic stroke. It is a major cause of stroke, especially in the elderly.
      Because of the simultaneous occurrence of thromboembolic events in all three
      patients, an ischaemic cause for the acute pancreatitis can be assumed with a
      high degree of probability. This is one of the first reports of acute ischaemic
      pancreatitis probably caused by microembolization secondary to atrial
      fibrillation. Because of the relatively frequent occurrence of atrial
      fibrillation, this factor deserves increased attention in the differential
      diagnosis of supposedly idiopathic pancreatitis.

PMID- 12481238
TI  - [Granulocytic sarcoma of the tonsils associated with myelodysplastic syndrome].
AB  - HISTORY AND ADMISSION FINDINGS: A 60-year-old man with anaemia was found to have
      a myelodysplastic syndrome (MDS) which was classified as refractory anemia with
      ringsideroblasts (RAEB). Because of severe fever the patient was hospitalized.
      Waldeyer's throat ring revealed signs of acute inflammation. LABORATORY FINDINGS:
      Indicated severe anemia and thrombocytopenia. Leucocytes were 8000/ml with a
      pathological shift to the left (1920/ml blasts). CRP (4.7 g/dl) and BSG (59/91mm)
      were abnormal. An axial CT of the neck showed a left sided paratonsillar abscess.
      DIAGNOSIS AND THERAPY: The tonsillitis was treated with antibiotics. Persistent
      fever up to 39.8 degrees C suggested resistance to therapy. After three weeks the
      patient developed septicemia and died. Autopsy revealed MDS with excess of blasts
      in transformation (RAEBT-t). Granulocytic sarcoma was found in the throating
      where there was no paratonsillar abscess. Generalized miliary tuberculosis was
      proved at autopsy, explaining the continuous fever resistant to antibiotic
      treatment. CONCLUSION: Granulocytic sarcoma is rarely associated with
      myelodysplastic syndrome. Deficiency in the immune system may facilitate the
      occurrence of miliary tuberculosis.

PMID- 12481239
TI  - [Usefulness of new methods in transtelephone electrocardiographic monitoring].

PMID- 12481240
TI  - [Changing perspectives of parenteral nutrition in cancer patients. Rational and
      clinical implications].

PMID- 12481241
TI  - [Ethical decisions at the end of life: principles, uncertainties, perspectives].

PMID- 12481242
TI  - [Agreement on loss of national health insurance coverage on leaving group
      practice--decision of the federal court 22 July 2002--II ZR 265/00].

PMID- 12481243
TI  - [Physician availability in the hospital: may the employer determine the time
      frame? Decision of the federal court 31 January 2002--6 AZR].

PMID- 12481244
TI  - [Embolism prevention in atrial fibrillation with heparin?].

PMID- 12481245
TI  - [Drug use by patients in old age and nursing homes in comparison with patients in
      ambulatory care needing no nursing care--response].

PMID- 12481249
TI  - Transactivation of ErbB1 and ErbB2 receptors by angiotensin II in normal human
      prostate stromal cells.
AB  - BACKGROUND: Heparin-binding epidermal growth factor-like growth factor (HB-EGF)
      is synthesized primarily in the stromal compartment of the human prostate and may
      regulate stromal as well as epithelial cell growth and survival. The primary
      cognate HB-EGF receptor, ErbB1, has been shown recently to be transactivated by G
      protein coupled receptors (GPCRs) through regulated proteolytic cleavage of the
      membrane-bound, precursor form of HB-EGF. Previous studies have demonstrated that
      human prostate tissue, especially tissue from benign prostatic hyperplasia (BPH),
      has high angiotensin converting enzyme activity, and a high density of
      angiotensin (Ang) receptors in periurethral stromal cells. Because the pressor
      peptide Ang II signals through GPCRs, we tested the possibility that Ang II could
      transactivate ErbB1/ErbB2 in human prostate stromal (hPS) cells. METHODS: Primary
      and early passage hPS cells were used as an in vitro model. Cells were stimulated
      by recombinant HB-EGF or Ang II and total cell lysates were harvested for
      immunoprecipitation and Western blot. Cell growth was measured by [(3)H]thymidine
      incorporation assay and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl
      tetrazoliumbromide (MTT) assay. RESULTS: Ang II receptors AT1 and AT2 were
      expressed in hPS cells. ErbB1 and ErbB2 receptors were activated by HB-EGF.
      Furthermore, Ang II was able to transactivate both ErbB1 and ErbB2, and this
      transactivation activity could be abolished by pretreatment with [Glu-52]
      diphtheria toxin/CRM197, a specific inhibitor of HB-EGF bioactivity. Consistent
      with its transactivation activity, Ang II modestly promoted hPS cell growth and
      this effect was abolished by pretreatment with the ErbB1 antagonist AG1478.
      CONCLUSION: These experiments suggest a regulatory role for Ang II in the
      prostate stroma and implicate the endogenous stromal growth factor HB-EGF as a
      mediator of Ang II signaling in the prostate.

PMID- 12481250
TI  - Differential expression of specific FGF ligand and receptor isoforms during
      angiogenesis associated with prostate cancer progression.
AB  - BACKGROUND: The aim of this study was to elucidate how changes in temporal and
      spatial expression patterns of individual components of the fibroblast growth
      factor (FGF) signaling axis correlate with prostate cancer-associated
      angiogenesis to contribute to the progression of this disease. METHODS: The
      temporal and spatial expression patterns of specific FGF ligands and receptors
      were characterized by immunoblot, in situ hybridization, and immunohistochemical
      analyses in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model.
      RESULTS: We detected expression of high molecular weight isoform of FGF-2 in PIN
      lesions and detected both high and low molecular weight isoforms of FGF-2 in
      advanced tumors. Expression of the mRNA encoding the FGFR1iiib isoform was found
      to be specifically and differentially expressed in tumor vasculature in TRAMP but
      was not detected in prostate-associated vasculature in nontransgenic mice.
      Expression of the FGFR2iiic isoform was observed to be elevated in the epithelial
      component of PIN lesions in TRAMP mice. CONCLUSION: By using the TRAMP model, the
      expression of FGFR1iiib in intraductal vasculature and expression of FGF-2
      protein were found to be concomitant with the emergence of PIN. These
      observations implicate specific changes in the FGF axis with the initiation and
      progression of prostate cancer and underscore the utility of animal models to
      identify specific molecular changes in early disease.

PMID- 12481251
TI  - Stromal/epithelial interactions of murine prostatic cell lines in vivo: a model
      for benign prostatic hyperplasia and the effect of doxazosin on tissue size.
AB  - BACKGROUND: One of the major constraints in elucidating the mechanisms involved
      in the etiology of benign prostatic hyperplasia (BPH) is the lack of suitable
      model systems that are readily manipulable in vitro and in vivo. To address this
      issue, we have used murine prostatic cell lines to establish a novel in vivo
      model for studying prostatic cell interactions. METHODS: Luminal, basal, and
      smooth muscle (SM) cell lines were inoculated alone or in combinations under the
      renal capsule of intact or castrated male mice, and the growth and composition of
      prostatic tissue in the absence or presence of doxazosin was determined. RESULTS:
      Both the luminal and basal cell lines reconstituted prostatic tissue if co
      inoculated under the renal capsule with normal SM cells, whereas none of the
      lines formed significant tissue when inoculated alone. Luminal cells produced and
      secreted prostatic secretory products. The growth of prostatic tissue formed from
      co-inoculation of basal and SM cells was androgen responsive. In addition, a
      significant reduction in prostatic tissue was noted in animals treated with
      doxazosin. CONCLUSION: We have established an in vivo model that uses prostatic
      epithelial and SM cell lines for investigating cellular interactions between
      epithelial and SM cells that regulate prostatic growth and function. This model
      will be useful for delineating the mechanisms by which prostatic cells interact
      and in determining the efficacy of new approaches aimed at interfering with
      prostatic stromal/epithelial interactions that result in abnormal cellular
      proliferation.

PMID- 12481252
TI  - Opposite effects of unmodified prolactin and a molecular mimic of phosphorylated
      prolactin on morphology and the expression of prostate specific genes in the
      normal rat prostate.
AB  - BACKGROUND: In the current study, we have investigated the individual roles of
      unmodified, wild-type prolactin (WT PRL) and a molecular mimic of phosphorylated
      prolactin (S179D PRL) in the normal rat prostate. METHODS: In the first animal
      experiment, recombinant WT PRL and S179D PRL were delivered to adult male rats at
      a rate of 14 microg/kg per day for 3 weeks. In the second animal experiment, two
      subcutaneous (200 microg/kg) injections of long-acting forms of the two PRLs were
      given to adult male rats on day 1 and day 22 for a total of 5.5 weeks of
      treatment. RESULTS: The different forms of PRL had opposite effects on the normal
      rat prostate, independently of androgens. WT PRL promoted morphologic changes in
      prostate epithelium consistent with preparation for cell proliferation, whereas
      S179D PRL produced morphologic evidence of a more differentiated epithelium.
      Northern blot analysis of expression of the two major prostate specific proteins,
      prostatein and probasin, showed that WT PRL decreased, whereas S179D PRL
      increased, the expression of the mRNAs for these two proteins. At the same time,
      S179D PRL reduced both testosterone and dihydrotestosterone levels. CONCLUSION:
      We conclude that PRL is an important modulator of normal rat prostate biology and
      that different forms of PRL have specific functions. The molecular mimic of
      phosphorylated PRL, S179D PRL, is the most important in terms of epithelial cell
      differentiation.

PMID- 12481253
TI  - ALCAM/CD166 is up-regulated in low-grade prostate cancer and progressively lost
      in high-grade lesions.
AB  - BACKGROUND: Activated leukocyte cell adhesion molecule (ALCAM, CD166) is
      expressed in various tissues, including malignant melanoma, prostate cancer cell
      lines, and prostate cancer. We aimed to clarify the expression patterns of ALCAM
      in normal and malignant prostate tissue. METHODS: RNA from 54 matched pairs of
      microdissected prostate tissue (tumor and normal) was hybridized to a custom
      built 4K GeneChip. Frozen section immunohistochemistry was used to confirm the
      ALCAM expression. RESULTS: Chip-based transcript analysis revealed an up
      regulation of ALCAM in prostate cancer in 22% of cases. Immunohistochemistry
      showed a focally raised ALCAM expression in 81% and a decreased expression in 19%
      of cases. These expression patterns correlated significantly with Gleason tumor
      grade: ALCAM up-regulation was found in most low-grade tumors (Gleason grade 1
      3), whereas down-regulation occurred preferentially in high-grade tumors (Gleason
      grade 4 and 5), although up-regulation of ALCAM expression was preserved in two
      Gleason grade 5 tumors. CONCLUSION: ALCAM expression is commonly disturbed in
      prostate cancer, which might indicate a role of ALCAM in the progression of this
      disease.

PMID- 12481254
TI  - Inhibition of the enzymatic activity of prostate-specific antigen by boric acid
      and 3-nitrophenyl boronic acid.
AB  - BACKGROUND: Prostate specific antigen (PSA) is a well-established marker of
      prostate cancer, but it can also degrade extracellular matrix proteins such as
      fibronectin and could be involved in tumor progression and metastasis. In this
      study, we have addressed the use of boric acid and 3-nitrophenyl boronic acid
      (NPBA) as PSA inhibitors in vitro. METHODS: The inhibition of PSA by boric acid
      was studied by using specific fluorogenic substrates. Fibronectin, a biologically
      relevant substrate for PSA, was used as a substrate in a zymographic assay, and
      the degradation of fibronectin by PSA in the presence of boric acid and NPBA was
      followed by Western Blot. RESULTS: Low concentrations of boric acid partially
      inhibited the proteolytic activity of PSA toward a synthetic fluorogenic
      substrate. Also, by Western blot, we have found significant inhibition in the
      proteolysis of fibronectin by PSA in the presence of boric acid as well as NPBA.
      Results indicate that the boronated compounds used in this study can be used for
      the modulation of PSA activity. CONCLUSION: PSA activity is inhibited in vitro by
      boric acid and NPBA. If degradation of fibronectin by PSA were, in fact, an
      important step in the progression of prostate cancer, then borate-induced
      inhibition of PSA activity should help reduce the development and proliferation
      of prostate carcinomas.

PMID- 12481255
TI  - Allelic imbalance in hereditary and sporadic prostate cancer.
AB  - BACKGROUND: In this study, we evaluate the pattern of allelic imbalance (AI) in
      both sporadic prostate cancer (SPC) and hereditary prostate cancer (HPC) at loci
      that frequently show allelic imbalance in sporadic prostate cancer, or are
      believed to have a putative role in the disease. METHODS: DNA obtained from 35
      sporadic tumors and 46 hereditary tumors were tested for AI, by using a panel of
      35 microsatellite markers. RESULTS: Chromosomal regions that display high
      frequencies of AI (>or=30%) in HPC include 1q, 5q, 7q, 8p, 13q, 16q, 17q, 18q,
      and 20q. In SPC, high frequencies of AI were found at 5q, 7q, 8p, 10q, 13q. Main
      differences (delta >or= 20%) in AI between HPC and SPC were at 1q, 10q, 17q, 18q,
      and 20q. CONCLUSION: AI at the prostate cancer susceptibility loci HPC1, PCaP,
      and HPC20 was seen more often in HPC compared with SPC. It appears that there are
      marked differences in the pattern of AI between sporadic and hereditary PCa.

PMID- 12481256
TI  - Acute hypoxia increases the aggressive characteristics and survival properties of
      prostate cancer cells.
AB  - BACKGROUND: Androgen withdrawal, the standard therapeutic strategy for advanced
      prostate cancer, induces a rapid reduction of blood flow to prostate and prostate
      cancer tissues and the concomitant onset of a hypoxic environment in these
      tissues. To establish whether hypoxia-responsiveness (by means of the action of
      hypoxia inducible factor [HIF] -1alpha protein) might affect the tumorigenic or
      survival properties of prostate cancer cells, we studied how acute exposure of
      cultured human prostate cancer cells (LNCaP cell line) to hypoxia might alter
      their pattern of gene expression and their in vitro behavior. METHODS: LNCaP
      cultures were placed in a hypoxia chamber for up to 24 hr and were compared with
      control (normoxic) cells for the expression of gene products by Western blotting
      and semiquantitative reverse transcription-polymerase chain reaction techniques.
      RESULTS: Exposure of LNCaP cells to acute hypoxia activated a typical cellular
      hypoxia response characterized by up-regulation of HIF-1alpha and vascular
      endothelial growth factor protein expression. In contrast, expression of
      differentiation-specific proteins (prostate specific antigen and androgen
      receptor) or proliferative-regulatory proteins (c-myc, cyclin D1, p27) were down
      regulated by hypoxia. Some of these latter changes (reduction of c-myc and cyclin
      D expression) were not accompanied by corresponding reduction of mRNAs and were
      abrogated by a proteosome inhibitor (MG132), suggesting that their loss was
      associated with their increased degradation rather than through transcriptional
      controls. The phosphorylation of Akt/protein kinase B and its downstream target,
      forkhead protein, was highly up-regulated by hypoxia, and cells exposed to
      transient periods of hypoxia became significantly less sensitive to an apoptotic
      stimulus (exposure to phorbol ester) when compared with normoxic cells.
      CONCLUSION: This study demonstrates that even acute hypoxia has the potential to
      drastically alter the growth, differentiation characteristics, and apoptotic
      sensitivity of a prostate cancer cell.

PMID- 12481257
TI  - Soy isoflavonoid equol modulates the growth of benign and malignant prostatic
      epithelial cells in vitro.
AB  - BACKGROUND: The dietary consumption of high levels of soy has been linked to
      reduced risks for prostate cancer (PC) in Asians and vegetarians. In vitro
      studies have focused on the two most abundant isoflavones in soy, genistein and
      daidzein. However, daidzein is differentially metabolized by gut microflora in
      humans, yielding compounds with very different bioactivities and half-lives.
      Asians are significantly more likely to produce the metabolite equol than
      Caucasians, suggesting its role in the prevention of PC. We hypothesize that
      equol is a bioactive metabolite that exerts direct antiproliferative effects on
      prostatic epithelial cells. METHODS: Benign and malignant prostatic epithelial
      cells were treated in vitro with equol, genistein, and daidzein by using the
      range of concentrations found in the prostatic fluids of Asians consuming soy.
      Growth and cell cycle distribution were analyzed over time. RESULTS: After 9 days
      of treatment, equol inhibited growth of benign human prostatic epithelial cells
      (PrEC) by 37% at 10(-6) M and 80% at 10(-5) M. Although genistein also had
      profound effects, daidzein appeared only one tenth as potent as equol. Equol and
      daidzein caused an accumulation of cells in G0/G1, whereas genistein arrested
      cells in G2/M. The isoflavonoids demonstrated differential effects on the
      established PC cell lines 22Rv1, LNCaP, LAPC-4, PC-3, and DU 145. PC-3 cells
      showed the greatest resistance. CONCLUSION: Equol is a biologically active
      metabolite of daidzein that has potent antiproliferative effects on benign and
      malignant prostatic epithelial cells at concentrations that can be obtained
      naturally through dietary soy consumption.

PMID- 12481259
TI  - Background-free, fast protein staining in sodium dodecyl sulfate polyacrylamide
      gel using counterion dyes, zincon and ethyl violet.
AB  - A background-free, fast protein staining method in polyacrylamide gel
      electrophoresis using an acidic dye, zincon (ZC) and a basic dye, ethyl violet
      (EV) is described. It is based on the counterion dye staining technique that
      employs two oppositely charged dyes to form an ion-pair complex in staining
      solution. The selective binding of free dye molecules to proteins in acidic
      solution produces bluish violet-colored bands. It is a rapid and end-point
      staining procedure, involving only fixing and staining steps that are completed
      in 1-1.5 h. The detection limit of this method is 8-15 ng of protein that is
      comparable to the sensitivity of the colloidal Coomassie Brilliant Blue G (CBBG)
      stain. Due to its sensitivity and speed, this stain may be more practical than
      any other dye-based stains for routine laboratory purposes.

PMID- 12481260
TI  - Detection of submicrogram quantities of glycosaminoglycans on agarose gels by
      sequential staining with toluidine blue and Stains-All.
AB  - A sensitive method has been developed for the visualization of nonradiolabelled
      glycosaminoglycans resolved by agarose gel electrophoresis using staining with
      toluidine blue followed by Stains-All procedure. This method, which can detect as
      little as 10 ng of a single species, can be used to stain a few micrograms of a
      complex polysaccharide mixture. The combination of agarose gel electrophoresis
      and sequential toluidine blue/Stains-All staining can be applied to the analysis
      of all the complex glycosaminoglycans (i.e., heparin, heparan sulfate,
      chondroitin/dermatan sulfate) and nonsulfated polyanions (i.e., hyaluronate,
      defructosylated capsular polysaccharide K4) as well as to comparisons of
      specificities of the glycosaminoglycan-degrading enzymes and the identification
      and quantification of the contaminations of other polysaccharides within
      glycosaminoglycan preparations with great sensitivity (about 0.1%). Furthermore,
      this method can be used to stain low-molecular-mass fractions and
      oligosaccharides derived from the natural polyanions, such as heparin. This
      procedure may be particularly valuable in situations where the availability of
      glycosaminoglycan is very limited.

PMID- 12481261
TI  - Revisiting electroblotting of immobilized pH gradient gels: a new protocol for
      studying post-translational modification of proteins.
AB  - Currently, one of the most important techniques in proteome analysis is two
      dimensional electrophoresis that is widely used for separation of thousands of
      different protein spots. Nevertheless, characterization of special aspects in
      protein patterns, e.g., separation of protein isoforms generated by post
      translational modifications, requires individual detection methods, e.g.,
      immunoblotting. Blotting of proteins after fractionation in immobilized pH
      gradients has always caused some problems. In this paper we present an optimized
      protocol for immunoblotting after isoelectric focusing using immobilized pH
      gradient (IPG) strips cast on Net-Fix as an internal support that is permeable to
      electric current. The focusing procedure can be carried out in commonly used IPG
      systems, e.g., the IPGphor by Amersham Biosciences, where electrically assisted
      rehydration can be performed. This may be of interest for many laboratories,
      because the same system as used for the first dimension of two-dimensional
      polyacrylamide gel electrophoresis (2-D PAGE) is involved. As an example, we
      describe separation and detection of up to seven isoforms of recombinant
      erythropoietin beta using semidry blotting of IPG strips and visualization by
      chemiluminescence detection.

PMID- 12481262
TI  - Evaluation of a potential epigenetic biomarker by quantitative methyl-single
      nucleotide polymorphism analysis.
AB  - Tumorigenesis is characterized by alterations of methylation profiles including
      loss and gain of 5-methylcytosine. Recently, we identified a single CpG, which
      seemed to be consistently hypomethylated in pilocytic astrocytomas but not in
      other gliomas. To evaluate its applicability as a biomarker, we examined its
      methylation status in a large panel of gliomas (n = 97). Methylation-dependent
      DNA sequence variation may be considered a kind of single nucleotide polymorphism
      (methylSNP). MethylSNPs can be easily converted into common SNPs of the C/T type
      by sodium bisulfite treatment of the DNA and afterwards subjected to conventional
      SNP typing. We adapted SnaPshot trade mark and Pyrosequencing trade mark to
      determine the methylation of our test CpG in a quantitative manner. The adapted
      methods, called SNaPmeth and PyroMeth, respectively, gave nearly identical
      results, however data obtained with PyroMeth showed less scattering. Furthermore,
      the integrated software for allele frequency determination from Pyrosequencing
      could be used directly for data analysis while SnaPmeth data had to be exported
      and processed manually. Although data did not confirm our previous result of a
      preferential hypomethylation of the tested CpG in pilocytic astrocytomas, we
      consider quantitative methylSNP analysis by SNaPmeth or PyroMeth a favorable
      alternative to existing high-throughput methylation assays. It combines single
      CpG analysis with accurate quantitation and is amenable to high throughput.

PMID- 12481263
TI  - Complete mitochondrial DNA sequence of a tadpole shrimp (Triops cancriformis) and
      analysis of museum samples.
AB  - The complete mitochondrial DNA (mtNDA) of the tadpole shrimp Triops cancriformis
      was sequenced. The sequence consisted of 15,101 bp with an A+T content of 69%.
      Its gene arrangement was identical with those sequences of the water flea
      (Daphnia pulex) and giant tiger prawn (Penaeus monodon), whereas it differed from
      that of the brine shrimp (Artemia franciscana) in the arrangement of its genes
      for tRNAs. Phylogenetic analysis revealed T. cancriformis to be more closely
      related to the water flea than to the brine shrimp and giant tiger prawn. We also
      compared the 16S rRNA sequences of five formalin-fixed tadpole shrimps that had
      been collected in five different locations and stored in a museum. The sequence
      divergence was in the range of 0-1.51%, suggesting that those samples were
      closely related to each other.

PMID- 12481264
TI  - BRCA1 mutation screening using restriction endonuclease fingerprinting-single
      strand conformation polymorphism in an automated capillary electrophoresis
      system.
AB  - Efficient mutation scanning techniques are needed for the rapid detection of
      novel disease-associated mutations and rare-sequence variants of putative
      importance. The large size of the breast cancer 1 gene (BRCA1) and the many
      mutations found throughout its entire coding sequence make screening for
      mutations in this gene particularly challenging. We have developed a method for
      screening exon 11 of the BRCA1 gene based on restriction enzyme digestion of
      fluorescence-labeled polymerase chain reaction (PCR) products followed by single
      strand conformation polymorphism (SSCP) using an automated capillary
      electrophoresis system, denoted capillary restriction endonuclease fingerprinting
      (REF)-SSCP electrophoresis. Using this strategy on a control set of samples, we
      were able to detect 17 of 18 known sequence alterations. The method was then
      applied to screen 73 Norwegian females with family histories of breast and/or
      ovarian cancer. A total of 172 sequence alterations were detected, including
      substitutions, insertions, and deletions. One novel substitution of unknown
      function was identified. Sequencing of all samples negative in the capillary REF
      SSCP system gave no additional mutations confirming the high sensitivity of the
      described methodology. Capillary REF-SSCP electrophoresis appeared as a
      technically convenient technique, requiring amplification of fewer PCR fragments
      than traditional SSCP. The novel strategy allows high-throughput mutation
      scanning without radioactive labeling and polyacrylamide gel electrophoresis
      (PAGE).

PMID- 12481265
TI  - Analysis of benzo[a]pyrene diol epoxide-DNA adducts by capillary zone
      electrophoresis- electrospray ionization-mass spectrometry in conjunction with
      sample stacking.
AB  - Benzo[a]pyrene diol epoxide (BPDE) was reacted in vitro with (2'
      deoxy)nucleotides and with calf thymus DNA. The modified DNA was enzymatically
      hydrolyzed to the 5'-monophosphate nucleotides using deoxyribonuclease I (DNA-ase
      I), nuclease P1 and snake venom phosphodiesterase (SVP). Most of the unmodified
      nucleotides were removed using solid phase extraction (SPE) in a polystyrene
      divinylbenzene copolymer. Three adducts could be detected and identified using
      capillary zone electrophoresis(negative)-ion electrospray ionization-mass
      spectrometry (CZE-(-)-ESI-MS) in conjunction with sample stacking. This way, not
      only a BPDE-dGMP adduct [(M-H)(-) at m/z 648], a well-known nucleotide adduct,
      could be retrieved, but also a BPDE-dAMP [(M-H)(-) at m/z 632] and a BPDE-dCMP
      adduct [(M-H)(-) at m/z 608] could be detected for the first time. The presence
      of the prominent ion at m/z 195 (the deoxyribose-phosphate ion) in the three low
      energy collision-activated decomposition (CAD) spectra indicated that the adducts
      were formed through base-alkylation. CZE-positive ion ESI-MS/MS experiments were
      performed to obtain further information on base-alkylation. The absence of the
      loss of NH(3) from the nucleobase in each CAD spectrum points to an alkylated
      exocyclic NH(2) position of the nucleobase. So, the three adducts could be
      identified as BPDE-N(2)-dGMP, BPDE-N(6)-dAMP and BPDE-N(4)-dCMP using CZE-ESI-MS
      and CZE-ESI-MS/MS.

PMID- 12481266
TI  - Study of urinary nucleosides as biological marker in cancer patients analyzed by
      micellar electrokinetic capillary chromatography.
AB  - Thirteen normal and modified nucleosides, primarily degradation products of
      transfer ribonucleic acid (tRNA), were evaluated as potential tumor markers for
      cancer patients. Their urinary concentrations were determined by means of
      micellar electrokinetic capillary chromatography (MEKC) in the urine from 54
      healthy adults and 70 cancer patients, then quantitatively expressed as a
      function of creatinine excretion. It was found that urinary nucleosides for
      cancer patients were on the average significantly higher than those for healthy
      controls, however, no significant differences were found between male and female
      or between different ages. Based on 13 urinary nucleoside concentrations,
      principal component analysis (PCA) could be used to classify 72% of cancer
      patients from the healthy controls. The present study shows that the precise
      measurement of urinary nucleosides by MEKC in combining with PCA technique may
      provide a clinically useful approach for diagnosis of cancer.

PMID- 12481267
TI  - An ionic liquid coating for determination of sildenafil and UK-103,320 in human
      serum by capillary zone electrophoresis-ion trap mass spectrometry.
AB  - Ionic liquid (IL) was covalently bonded onto the silica capillary surface and the
      electroosmotic flow was reversed over a pH range of 3.5 to 7. Sildenafil (SL) and
      its metabolite UK-103,320 (UK) in human serum were detected by solid-phase
      extraction followed by capillary zone electrophoresis-mass spectrometry analysis.
      The running buffer contained 10 mM acetic acid adjusted to pH 4.5 with 1 M
      ammonia, and the separating voltage was set to -25 kV. The adsorption of the
      analytes onto the bare capillary wall was eliminated by the IL coating and the
      drugs were baseline-separated within 14 min with detection limits (S/N = 3) of 14
      and 17 ng/mL for SL and UK, respectively. The method developed showed good
      intraday precision in terms of relative standard deviation (RSD) with respect to
      migration time (RSD </= 0.76%, n = 5) and peak area (RSD </= 3.4%, n = 5); the
      relative coefficients of linear regression for both targets were better than 0.99
      within linear dynamic range (SL: 50-600 ng/mL; UK: 40-400 ng/mL). Satisfactory
      interday precision was obtained with respect to the slope of the regression (RSD
      </= 4.21%, n = 9) and the migration time (RSD </= 1.1%, n = 9). The IL coating
      could be used with stable electroosmotic flow (RSD = 2.78%, n = 10) for at least
      80 h.

PMID- 12481268
TI  - Capillary zone electrophoresis study of cyclodextrin--lipoic acid host-guest
      interaction.
AB  - Lipoic acid is a naturally occurring compound which is being widely investigated
      for its therapeutic effects in the treatment or prevention of a variety of
      diseases associated with oxidative injury, particularly diabetes. The diversity
      of therapeutic applications of lipoic acid requires an appropriate formulation to
      control its bioavailability, site-targeting delivery and to overcome its inherent
      chemical instability. In this regard, cyclodextrins (CDs) are ideally suitable
      due to their well-documented ability to include in their cavity proper guest
      molecules and protect them from physical or chemical damages. Lipoic acid forms
      1:1 inclusion complexes with betaCD as shown in a previous report of an extended
      investigation that also indicated the suitability of capillary zone
      electrophoresis (CZE) for the study of such host-guest interactions. In view of
      these possible applications, we extended the CZE analysis to determine the
      strength of binding, in a pH 9 phosphate buffer, of lipoic acid with other CD
      derivatives such as alphaCD, gammaCD and the alkylated derivatives of betaCD,
      namely (2-hydroxypropyl)-beta-CD (HPbetaCD), and heptakis(2,3,6-tri-O-methyl)
      beta-CD (TMbetaCD). Once established that the easily available betaCD is the most
      suitable receptor for lipoic acid, we set up and here describe a simple and
      reliable procedure for the quantitative determination of lipoic acid in
      commercial dietary supplement tablets containing also other active substances and
      excipients.

PMID- 12481269
TI  - Enantioseparation of chiral aromatic amino acids by capillary electrophoresis in
      neutral and charged cyclodextrin selector modes.
AB  - Simultaneous enantioseparations of 15 racemic aromatic amino acids and L-mimosine
      for their chiral discrimination were achieved by neutral selector-modified
      capillary electrophoresis (CE) and by charged selector-modified CE. Among the
      diverse cyclodextrins (CDs) examined, hydroxypropyl (HP)-alpha-CD as the neutral
      selector and highly sulfated (HS)-gamma-CD as the charged selector provided best
      chiral environments of different enantioselectivities. Fairly good enantiomeric
      resolutions were achieved with the HP-alpha-CD mode except for racemic 6-hydroxy
      3,4-dihydroxyphenylalanine, threo-3,4-dihydroxyphenylserine and homophenylalanine
      while high-resolution separations of all the enantiomeric pairs were achieved in
      the HS-gamma-CD mode except that L-mimosine was not detected and a partial
      resolution (0.6) for threo-3,4-dihydroxyphenylserine enantiomers. Relative
      migration times to that of internal standard under the respective optimum
      conditions were characteristic of each enantiomer with good precision (% RSD: 0.7
      3.8), thereby enabling to cross-check the chemical identification of aromatic
      amino acids and also their chiralities. The method linearity was found to be
      adequate (r> 0.99) for the chiral assay of the aromatic amino acids investigated.
      When applied to extracts of three plant seeds, nonprotein amino acids such as L
      mimosine (42 nug/g) from Mimosa pudica Linne, and L-3,4-dihydroxyphenylalanine
      (268 nug/g) from Vicia faba were positively detected along with L-tryptophan, L
      phenylalanine and L-tyrosine.

PMID- 12481270
TI  - Proteomic analysis of rat brain tissue: comparison of protocols for two
      dimensional gel electrophoresis analysis based on different solubilizing agents.
AB  - The present study reports a comparison of recently described solubilizing
      methods, to set up a simple protocol for obtaining two-dimensional (2-D) gel
      electrophoresis maps of brain tissue. Different protocols were used for preparing
      rat brain homogenates and the resulting maps were compared by image analysis.
      Three different detergents, two delipidation methods, and introduction of a
      fractionation step based on different protein solubility in surfactants, were
      evaluated. When using efficient zwitterionic detergents (3-[(3
      cholamidopropyl)dimethylamino]-1-propanesulfonate, CHAPS; amidosulfobetaine 14,
      ASB-14), the patterns obtained by direct loading of total extracts were
      qualitatively overlapping with patterns obtained from fractionated samples. In
      contrast, a weaker nonionic agent (Nonidet P-40, NP-40) produced a different
      protein pattern in the collected fractions. Delipidation did not improve the
      results for all the different extraction methods. Immunoblots performed with
      antibodies recognizing cytosolic and membrane-spanning proteins, which were
      detected as nondegraded spots, showed that membrane proteins with intermediate
      molecular mass could be recovered. We suggest, as a simple and efficient method
      for preparing rat brain maps, the homogenization in a solution containing an
      efficient zwitterionic surfactant, which allows to solubilize cytosolic and
      membrane proteins in a single step. Alternatively, a fractionation can be carried
      out on samples homogenized by a weak solubilizing agent, a more labor-intensive
      effort resulting in a larger number of proteins on two maps.

PMID- 12481271
TI  - Proteome analysis of human liver tumor tissue by two-dimensional gel
      electrophoresis and matrix assisted laser desorption/ionization-mass spectrometry
      for identification of disease-related proteins.
AB  - Hepatocellular carcinoma (HCC) is a common malignancy worldwide and is a leading
      cause of death. To contribute to the development and improvement of molecular
      markers for diagnostics and prognostics and of therapeutic targets for the
      disease, we have largely expanded the currently available human liver tissue maps
      and studied the differential expression of proteins in normal and cancer tissues.
      Reference two-dimensional electrophoresis (2-DE) maps of human liver tumor tissue
      include labeled 2-DE images for total homogenate and soluble fraction separated
      on pH 3-10 gels, and also images for soluble fraction separated on pH 4-7 and pH
      6-9 gels for a more detailed map. Proteins were separated in the first dimension
      by isoelectric focusing on immobilized pH gradient (IPG) strips, and by 7.5-17.5%
      gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
      gels in the second dimension. Protein identification was done by peptide mass
      fingerprinting with delayed extraction-matrix assisted laser
      desorption/ionization-time of flight-mass spectrometry (DE-MALDI-TOF-MS). In
      total, 212 protein spots (117 spots in pH 4-7 map and 95 spots in pH 6-9)
      corresponding to 127 different polypeptide chains were identified. In the next
      step, we analyzed the differential protein expression of liver tumor samples, to
      find out candidates for liver cancer-associated proteins. Matched pairs of
      tissues from 11 liver cancer patients were analyzed for their 2-DE profiles.
      Protein expression was comparatively analyzed by use of image analysis software.
      Proteins whose expression levels were different by more than three-fold in at
      least 30% (four) of the patients were further analyzed. Numbers of protein spots
      overexpressed or underexpressed in tumor tissues as compared with nontumorous
      regions were 9 and 28, respectively. Among these 37 spots, 1 overexpressed and 15
      underexpressed spots, corresponding to 11 proteins, were identified. The
      physiological significance of the differential expressions is discussed.

PMID- 12481272
TI  - Comparison of ethanol-soluble proteins from different rye (Secale cereale)
      varieties by two-dimensional electrophoresis.
AB  - The major storage proteins from six rye varieties, grown under the same
      conditions in 1997 and 1998 in Ronhave, Denmark, were analyzed by two-dimensional
      (2-D) polyacrylamide gel electrophoresis. The proteins were extracted from ground
      rye kernels with 70% ethanol and separated by 2-D electrophoresis. The gels were
      scanned, compared using ImageMaster software and the data sets were analyzed by
      principal component analysis (PCA) using THE UNSCRAMBLER software. Afterwards
      MATLAB was used to make a cluster analysis of the varieties based on PCA. The
      analysis of the gels showed, that the protein patterns (number of different
      proteins and their isoelectric points and molecular weights) from the six rye
      varieties were different. Based on the presence of unique cultivar-specific spots
      it was possible to differentiate between all six varieties if the two harvest
      years were investigated separately. When the results were combined from the two
      years five varieties could be differentiated. The results from the PCA confirmed
      the finding of the unique spots and cluster analysis was made in order to
      illustrate the results. The combination of the results from 2-D electrophoresis
      and other grain characteristics showed that one protein spot was located close to
      the parameters bread volume and bread height.

PMID- 12481273
TI  - Gerbils of a seizure-sensitive strain have a mitochondrial inner membrane protein
      with different isoelectric points from those of a seizure-resistant strain.
AB  - The distribution of proteins in the cerebral cortex of a seizure-sensitive (SS)
      strain of gerbil and its seizure-resistant (SR) counterpart was profiled using
      two-dimensional gel electrophoresis. A series of proteins of similar molecular
      weight (around 83 kDa) showed small but consistent differences in their
      isoelectric point (pI) with indistinguishable profiles of distribution between
      the two strains. Amino acid sequences of peptides produced by limited proteolysis
      of each protein in the spots from the strains were identical or highly homologous
      to those of mitofilin, a mitochondrial inner membrane protein (IMMT) in humans.
      Analysis of cDNA sequences revealed the proteins of these spots to be gerbil
      mitofilin-like proteins (gIMMT), with a few base substitutions between SS and SR
      strains, in particular within a region near a putative transmembrane domain that
      is highly conserved in humans and gerbils. The amino acid at the site was acidic,
      Glu in humans and Asp in the strain SR of gerbil and a neutral, Asn in strain SS.
      In addition to these base substitutions, production of multiple species of mRNA
      for gIMMT by alternative splicing was observed.

PMID- 12481277
TI  - Theory of DNA electrophoresis (approximately 1999-2002(1/2)).
AB  - Over the last two decades, the introduction of new methods such as pulsed-field
      gel electrophoresis and capillary array electrophoresis has made it possible to
      map and sequence entire genomes, including our own. The development of these
      experimental methods has been helped by the progress of theoretical and
      computational sciences, and the interactions between these three modi operandi of
      modern science are still pushing the limits of our technologies. We now see a
      clear trend towards proteomics and microfluidic (even nanofluidic!) devices. In
      this review, we take a look at the progress of the field over the last 3 years
      using the glasses of the theoretical scientist and focusing mostly on new ideas
      and concepts. About a dozen different subfields are discussed and reviewed. We
      conclude by giving a commented list of some of the best review articles published
      over the last 2-3 years.

PMID- 12481278
TI  - Peak broadening in microchip electrophoresis: a discussion of the theoretical
      background.
AB  - A review on peak (band, zone) broadening in electromigration separation methods
      is presented, mainly covering articles published between the begining of 2000 and
      middle of 2002. Most attention is drawn to work dealing with microchip
      electrophoresis performed in micrototal analysis systems (microTAS) or the lab-on
      a-chip, but many of the results are significant for capillary zone
      electrophoresis in general. The paper reviews the theoretical background of the
      peak dispersion due to the geometry of the separation channel, the transversal
      nonhomogeneity of the electroosmootic flow, and electromigration dispersion
      (sample overload) connected with the occurrence of the system zones (system
      peaks, system eigenpeaks).

PMID- 12481279
TI  - Theory of electroosmotic flow, retention and separation efficiency in capillary
      electrochromatography.
AB  - This article reviews recent progress that has taken place in the past decade
      (1992-2002) in the areas of understanding of flow of ions, buffers, as well as
      neutral and charged sample components through open channels and porous media.
      Though, primarily dealing with open capillaries and packed columns that are often
      used in capillary electrochromatography (CEC), these fundamental concepts are
      applicable to the evolving area of separations on a microchip.

PMID- 12481280
TI  - Recent advances in capillary isoelectric focusing: 1997-2001.
AB  - The methodological developments in the field of capillary isoelectric focusing
      (CIEF) published between 1997-2001 are reviewed as a continuation of the previous
      review by Rodriguez-Diaz et al. (Electrophoresis 1997, 18, 2134-2144). The
      applications are summarized and the progress in CIEF technologies, including
      experimental setup with coated and uncoated capillaries, remedies for the
      presence of salts in samples, additives to reduce precipitation of samples during
      the focusing process, calibration of the pH gradients, issues of reproducibility,
      carrier ampholyte-free CIEF, and a computer simulation of focusing process are
      discussed. Developments of IEF separations in fabricated microchannels and the
      advances in detection schemes, i.e., imaging, fluorescence and chemiluminescence,
      are summarized. The progress in micropreparation was noted, and the massive works
      for two-dimensional separations are described for the coupling with size
      exclusion chromatography and mass spectrometry, in which the developments aimed
      at proteomics are discussed separately. The applications for the detection of
      noncovalent complexes and the separations of microorganisms are reviewed.

PMID- 12481281
TI  - Recent progress in capillary isotachophoresis.
AB  - This article is a continuation of previous reviews and summarizes the progress of
      analytical capillary isotachophoresis since 2000. Papers reviewed include
      methodological and instrumental aspects as well as analytical applications.
      Included are also papers using isotachophoresis and/or isotachophoretic
      principles as part of multidimensional separation schemes.

PMID- 12481282
TI  - Recent advances in nonaqueous capillary electrophoresis.
AB  - Nonaqueous capillary electrophoresis is undergoing rapid development. The scope
      of the investigations has clearly expanded, covering both basic studies and
      analytical applications. This review provides a comprehensive overview at the
      current status of the technique. Special attention is given to theoretical,
      methodological, and technical challenges, and the achievements of capillary
      electrophoresis in nonaqueous media are demonstrated with reference to recent
      applications.

PMID- 12481283
TI  - Recent advances and trends in capillary electrophoresis of inorganic ions.
AB  - Capillary electrophoresis (CE) continues its invasion into the domain of
      inorganic analysis. This review summarizes the progress and significant
      developments of CE of inorganic ions over the first two years of the new century.
      As manifested by the substantial number of published articles, this field is
      still witnessing a growing activity of many separation scientists. To provide an
      in-depth treatment of fundamental and methodological aspects of inorganic ion
      analysis by CE, an extensive fraction of the relevant literature is covered
      whereas only most innovative application reports are briefly considered. Most of
      the recent advancements have focused on CE system modernization designed to
      improve a limited detection sensitivity, which still remains a major obstacle to
      overcome in order to ensure the method's wider practical acceptance. Attention is
      also given to how and in which directions the future research could be performed
      to implement CE in routine inorganic analysis.

PMID- 12481284
TI  - Micellar electrokinetic chromatography: current developments and future.
AB  - This review highlights recent methodological and instrumental advances in
      micellar electrokinetic chromatography (MEKC). Enhancements in sensitivity and
      selectivity of the technique through the use of on-line preconcentration
      approaches (stacking and sweeping) and nonconventional pseudostationary phases,
      namely nonionic and zwitterionic surfactants, mixed micelles and polymers, are
      discussed in detail. Laser-induced fluorescence and mass spectrometry, as
      alternatives to UV-absorption detection, have been covered to evaluate their
      advantages and limitations when applied to analysis in an MEKC format. Some
      thoughts on future directions in this area such as in-capillary reactions, coated
      capillaries and MEKC on microchips are also presented.

PMID- 12481285
TI  - Derivatization trends in capillary electrophoresis: an update.
AB  - This survey as a sequel of two earlier reports gives an overview of recent
      developments, starting from 1999, in the use of derivatization protocols in
      capillary electrophoretic (CE) analysis. Derivatization is mainly used for
      enhancement of the detection sensitivity in CE, for which a combination of
      fluorescence labeling and laser-induced fluorescence detection is favorable.
      Moreover, especially in the field of saccharide assay, derivatization to
      introduce charge into the molecule, is common. Derivatization procedures are
      classified in tables, focused on precapillary, on-line, on-capillary and
      postcapillary arrangements and divided in sections concerning the functional
      group that is derivatized. The most frequently reported groups are amines and the
      reducing end of (oligo)saccharides, but thiols, carbonyl and carboxyl groups,
      steroids and inorganic ions have also been reported about. Other reasons for
      derivatization are to enhance chiral separation, introduction of a suitable
      charge into the molecule or to improve mass spectrometric detection. The use of
      derivatization techniques for special cases, such as the analysis of
      neurotransmitters, insulin antibodies and mitochondria has also been incorporated
      as well as a study on the adsorption of proteins onto capillary walls during CE
      in which derivatization plays a role.

PMID- 12481286
TI  - Polymeric monolithic stationary phases for capillary electrochromatography.
AB  - This review summarizes the contributions of a number of groups working in the
      rapidly growing area of monolithic columns for capillary electrochromatography
      (CEC), with a focus on those prepared from synthetic polymers. Monoliths have
      quickly become a well-established stationary phase format in the field of CEC.
      The simplicity of their in situ preparation method as well as the good control
      over their porous properties and surface chemistries make the monolithic
      separation media an attractive alternative to capillary columns packed with
      particulate materials. A wide variety of approaches as well as materials used for
      the preparation of the monolithic stationary phases are detailed. Their excellent
      chromatographic performance is demonstrated by numerous separations of different
      analytes.

PMID- 12481287
TI  - Recent progress in adsorbed stationary phases for capillary
      electrochromatography.
AB  - This review surveys the recent progress in the adsorbed stationary phases for
      capillary electrochromatography (CEC). Adsorption-based methods for preparation
      of stationary phase are novel approaches in CEC, which allow rapid and facile
      preparing stationary phases with desirable selectivity onto an open-tubular fused
      silica capillary, a bare-silica or ion-exchange packed column or a monolithic
      silica or polymer column. A variety of adsorbing agents have been developed as
      adsorbed stationary phases, including ionic long-chain surfactant, protein,
      peptide, amino acid, charged cyclodextrin (CD), basic compound, aliphatic ionene,
      and ion-exchange latex particle. The adsorbed stationary phases have been applied
      to separation of neutral, basic and acidic organic compounds, inorganic anions
      and enantiomers. They have also been applied to on-line sample concentration,
      fast separation and study of the competitive binding of enantiomers with protein.

PMID- 12481288
TI  - Advances in sol-gel based columns for capillary electrochromatography: sol-gel
      open-tubular columns.
AB  - The development of sol-gel open-tubular column technology in capillary
      electrochromatography (CEC) is reviewed. Sol-gel column technology offers a
      versatile means of creating organic-inorganic hybrid stationary phases. Sol-gel
      column technology provides a general approach to column fabrication for
      microseparation techniques including CEC, and is amenable to both open-tubular
      and monolithic columns. Direct chemical bonding of the stationary phase to the
      capillary inner walls provides enhanced thermal and solvent stability to sol-gel
      columns. Sol-gel stationary phases inherently possess higher surface area, and
      thus provide an effective one-step alternative to conventional open-tubular
      column technology. Sol-gel column technology is applicable to both silica-based
      and transition metal oxide-based hybrid stationary phases, and thus, provides a
      great opportunity to utilize advanced material properties of a wide range of
      nontraditional stationary phases to achieve enhanced selectivity in analytical
      microseparations. A wide variety of stationary phase ligands can be chemically
      immobilized on the capillary inner surface using a single-step sol-gel procedure.
      Sol-gel chemistry can be applied to design stationary phases with desired
      chromatographic characteristics, including the possibility of creating columns
      with either a positive or a negative charge on the stationary phase surface. This
      provides a new tool to control electroosmotic flow (EOF) in the column. Column
      efficiencies on the order of half a million theoretical plates per meter have
      been reported for sol-gel open-tubular CEC columns. The selectivity of sol-gel
      stationary phases can be easily fine-tuned by adjusting the composition of the
      coating sol solution. Open-tubular columns have significant advantages over their
      packed counterparts because of the simplicity in column making and hassle-free
      fritless operation. Open-tubular CEC columns possess low sample capacity and low
      detection sensitivity. Full utilization of the analytical potential of sol-gel
      open-tubular columns will require a concomitant development in the area of high
      sensitivity detection technology.

PMID- 12481289
TI  - Recent progress in the development, characterization and application of polymeric
      pseudophases for electrokinetic chromatography.
AB  - This review article details the development, characterization and application of
      polymeric materials as pseudostationary phases for electrokinetic chromatography
      over the past two years. Recent developments in cationic polymers and anionic
      siloxane, acrylamide and polymerized surfactants (micelle polymers) are reviewed.
      Also reviewed is recent progress in the development and characterization of
      chiral polymeric phases for chiral separations by electrokinetic chromatography,
      and application of a polymeric pseudophase with electrospray ionization mass
      spectrometric detection.

PMID- 12481290
TI  - Recent progress in enantiomeric separation by capillary electrochromatography.
AB  - Recent progress in enantiomeric separations by capillary electrochromatography
      (CEC) is reviewed. The development of simple and robust CEC column technologies
      plays an important role for popularization of CEC. During the last several years,
      various approaches for the preparation of enantioselective columns have been
      reported. Currently, the monolithic column technology (continuous beds)
      represents the most advanced approach for the preparation of CEC columns. The
      development of new chiral stationary phase used for CEC is another important
      issue in this field. Fundamental investigations on electrochromatographic
      behaviors of various CSPs are necessary in order to understand the separation
      mechanism and thus improve the separation performance. Some chiral stationary
      phases performed better under nonaqueous CEC conditions than reversed-phase
      conditions. Coupling CEC with mass spectrometry (MS) provides a powerful tool for
      enantiomeric separation. Finally, some applications of enantiomeric separation by
      CEC are summarized.

PMID- 12481291
TI  - Enantiomer migration order in chiral capillary electrophoresis.
AB  - Enantiomer migration order (EMO) in chiral capillary electrophoresis (CE)
      represents a challenging issue, referred to in less than 20% of the articles on
      CE enantioseparations. This review article will (i) illustrate the actuality of
      the topic, (ii) discuss some technical problems related to EMO in CE
      enantioseparations, (iii) examine the principal differences between CE and other
      separation techniques from the viewpoint of enantiomer elution order, (iv)
      demonstrate the potential for a designed reversal of EMO in CE, and (v) emphasize
      the importance of studying EMO for better understanding of chiral CE as well as
      its more effective application. Along with CE, the results obtained by other
      instrumental techniques such as nuclear magnetic resonance (NMR) spectroscopy,
      mass spectrometry (MS), X-ray crystallography, as well as molecular modeling
      calculations will be shortly discussed. Rather than referring to all published
      examples of the opposite migration order of enantiomers in CE, the emphasis will
      be on general aspects. Recently, the reversal of the EMO was described in detail
      in a book chapter (Chankvetadze, B., Capillary Electrophoresis in Chiral
      Analysis, Wiley & Sons, Chichester, UK 1997, Chapter 12) as well as in three
      review articles.

PMID- 12481292
TI  - Chiral capillary electrophoresis-mass spectrometry: modes and applications.
AB  - A review is presented to highlight several approaches for coupling capillary
      electrophoresis (CE) and electrospray ionization-mass spectrometry (ESI-MS) for
      analysis of chiral compounds. A short discussion of commercially available CE-MS
      instruments and interface design is followed by a detail review on various modes
      of chiral CE-MS. In general, for each CE-MS mode, the capabilities, applications
      and limitations for chiral analysis have been pointed out. The first mode, chiral
      capillary zone electrophoresis-mass spectrometry (CZE-MS) in which neutral
      derivatized cyclodextrins (CDs) are used is possible using either column coupling
      with voltage switching or a partial-filling technique (PFT). However, some
      applications of direct coupling of CZE-MS mode are also reported. The second mode
      is a chiral electrokinetic chromatography-mass spectrometry (EKC-MS) in which a
      charged chiral selector such as a sulfated beta-CD or a vancomycin could be
      conveniently employed. This is because these chiral selectors have a
      significantly higher countercurrent electrophoretic mobility which prevents the
      entrance of these selectors into the mass spectrometer. The combination of
      counter-migration and PFT demonstrates that this synergism could be successfully
      applied to chiral analysis of a broader range of compounds. It is well-known that
      the on-line coupling of micellar electrokinetic chromatography to mass
      spectrometry (MEKC-MS) is problematic because the high surface activity and
      nonvolatile nature of conventional surfactant molecules lower the electrospray
      ionization efficiency. However, a recent report demonstrates that this
      hyphenation is now possible with the use of molecular micelles. Various MEKC-ESI
      MS parameters that can be used to optimize both chiral resolution and ESI
      response are discussed. Finally, two recent examples that demonstrate the
      feasibility of using either open-tubular or packed chiral CEC with MS are
      reviewed. This survey will attempt to cover the state-of-the-art on various modes
      of CE-MS from 1998 up to 2002.

PMID- 12481294
TI  - What cardiovascular defect does my prenatal mouse mutant have, and why?
AB  - Since the advent of mouse targeted mutations, gene traps, an escalating use of a
      variety of complex transgenic manipulations, and large-scale chemical mutagenesis
      projects yielding many mutants with cardiovascular defects, it has become
      increasingly evident that defects within the heart and vascular system are
      largely responsible for the observed in utero lethality of the embryo and early
      fetus. If a transgenically altered embryo survives implantation but fails to be
      born, it usually indicates that there is some form of lethal cardiovascular
      defect present. A number of embryonic organ and body systems, including the
      central nervous system, gut, lungs, urogenital system, and musculoskeletal system
      appear to have little or no survival value in utero (Copp, 1995). Cardiovascular
      abnormalities include the failure to establish an adequate yolk-sac vascular
      circulation, which results in early lethality (E8.5-10.5); poor cardiac function
      (E9.0-birth); failure to undergo correct looping and chamber formation of the
      primitive heart tube (E9.0-11.0); improper septation, including division of the
      common ventricle and atria and the establishment of a divided outflow tract
      (E11.0-13.0); inadequate establishment of the cardiac conduction system (E12.0
      birth); and the failure of the in utero cardiovascular system to adapt to adult
      life (birth) and close the interatrial and aorta-pulmonary trunk shunts that are
      required for normal fetal life. Importantly, the developmental timing of
      lethality is usually a good indicator of both the type of the cardiovascular
      defect present and may also suggest the possible underlying cause/s. The purpose
      of this review is both to review the literature and to provide a beginner's guide
      for analysing cardiovascular defects in mouse mutants.

PMID- 12481295
TI  - Cre-loxp fate-mapping of Pax6 enhancer active retinal and pancreatic progenitors.
AB  - Pax6 plays important roles in the control of ocular and pancreatic development.
      We identified a 450 bp Pax6 enhancer that contains two interacting sequences: a
      274 bp fragment sufficient for expression in retinal progenitors and an adjacent
      156 bp fragment required for expression in pancreatic progenitors. Since this
      enhancer is only transiently expressed during embryogenesis, a Cre-loxP fate
      mapping strategy was used to investigate the developmental potential of these
      progenitors. Surprisingly, the labeled retinal precursors predominantly gave rise
      to horizontal cells, indicating a cell lineage role in horizontal cell
      differentiation. In the pancreas, all enhancer-specific cells were restricted to
      endocrine and ductal cell lineages. This result lends support to a model whereby
      Pax6-expressing progenitors contribute to the adult pancreatic islets and ducts.
      The progenitor cell-specificity of this enhancer will be useful in studies that
      require either cell-specific expression or conditional gene inactivation in these
      cell populations.

PMID- 12481296
TI  - Histone deacetylase dHDAC4 is involved in segmentation of the Drosophila embryo
      and is regulated by gap and pair-rule genes.
AB  - Histone deacetylases (HDACs) are catalytic subunits of multiprotein complexes
      that are targeted to specific promoters through their interaction with different
      transcriptional repressors causing silencing of the corresponding genes. This
      study describes the isolation of dHDAC4, a novel, catalytically active class II
      Drosophila histone deacetylase, and the analysis of its role in embryonic
      development. In early embryos, dHDAC4 is expressed in several phases. Initial
      ubiquitous expression becomes localized to an anterior domain, then evolves into
      a pair-rule-like and finally into a segment-polarity-like pattern. Suppression of
      dHDAC4 during early embryogenesis by double-stranded RNA interference led to
      segmentation defects. Analysis of dHDAC4 expression in gap and pair-rule gene
      mutants demonstrated that hunchback, knirps, and giant activate, while even
      skipped suppresses dHDAC4 expression. These data revealed dHDAC4 involvement in
      the segmentation regulatory pathway and suggested complex transcriptional
      regulation as a potential mechanism that controls its expression.

PMID- 12481297
TI  - Podocyte-specific expression of cre recombinase in transgenic mice.
AB  - We report a transgenic mouse line that expresses Cre recombinase exclusively in
      podocytes. Twenty- four transgenic founders were generated in which Cre
      recombinase was placed under the regulation of a 2.5-kb fragment of the human
      NPHS2 promoter. Previously, this fragment was shown to drive beta-galactosidase
      (beta-gal) expression exclusively in podocytes of transgenic mice. For analysis,
      founder mice were bred with ROSA26 mice, a reporter line that expresses beta-gal
      in cells that undergo Cre recombination. Eight of 24 founder lines were found to
      express beta-gal exclusively in the kidney. Histological analysis of the kidneys
      showed that beta-gal expression was confined to podocytes. Cre recombination
      occurred during the capillary loop stage in glomerular development. No evidence
      for Cre recombination was detected in any of 14 other tissues examined.

PMID- 12481298
TI  - Consequences of knocking out BMP signaling in the mouse.
AB  - During the past two decades, a significant amount of data has been accumulated
      revealing the intriguing functions of bone morphogenetic proteins (BMPs) in all
      aspects of embryonic development and organogenesis. Numerous genes encoding BMPs,
      BMP receptors, and their downstream signal transducers have been mutated in the
      mouse through targeted mutagenesis. This review focuses on what is known about
      the role of BMP signaling in gastrulation, mesoderm formation, left-right
      asymmetry, neural patterning, skeletal and limb development, organogenesis, and
      gametogenesis as revealed by BMP-signaling mutants.

PMID- 12481299
TI  - Introduction of cell markers into germ layer tissues of the mouse gastrula by
      whole embryo electroporation.
AB  - We have optimized the technique of electroporation for introducing genetic
      markers into cells of the gastrulating mouse embryo to follow cell fates, tissue
      movement, and lineage differentiation. Using a plate-needle electrode combination
      and specific route of plasmid delivery, labeling could be targeted to discrete
      regions of the epiblast or the endoderm of the late gastrula. Among the various
      types of fluorescent and chromogenic reporter constructs tested, those driven by
      CMV promoter are efficient and strong expression can be detected as soon as 2-3 h
      after electroporation. The efficacy of marking cell lineages by CRE-mediated
      activation of reporters proved to be inefficient for tracking cell lineages due
      to an obligatory 8-9-h lag from the electroporation of constructs to the
      expression of reporter. This significant time lag also raises concern of the
      temporal precision at which tissue- or stage-specific knock-out or activation of
      genetic activity may be achieved by the Cre-loxP mechanism.

PMID- 12481300
TI  - Inducible site-specific recombination in myelinating cells.
AB  - To explore the function of genes expressed by myelinating cells we have developed
      a model system that allows for the inducible ablation of predetermined genes in
      oligodendrocytes and Schwann cells. The Cre/loxP recombination system provides
      the opportunity to generate tissue-specific somatic mutations in mice. We have
      used a fusion protein between the Cre recombinase and a mutated ligand-binding
      domain of the human estrogen receptor (CreER(T)) to obtain inducible, site
      specific recombination. CreER(T) expression was placed under the transcriptional
      control of the regulatory sequences of the myelin proteolipid protein (PLP) gene,
      which is abundantly expressed in oligodendrocytes and to a lesser extent in
      Schwann cells. The CreER(T) fusion protein translocated to the nucleus and
      mediated the recombination of a LacZ reporter transgene in myelinating cells of
      PLP/CreER(T) mice injected with the synthetic steroid tamoxifen. In untreated
      animals CreER(T) remained cytoplasmic, and there was no evidence of
      recombination. The PLP/ CreER(T) animals should be very useful in elucidating and
      distinguishing a particular gene's function in the formation and maintenance of
      the myelin sheath and in analyzing mature oligodendrocyte function in
      pathological conditions.

PMID- 12481301
TI  - Cytokine, chemokine, and matrix metalloproteinase response after sulfur mustard
      injury to weanling pig skin.
AB  - Cutaneous exposure to sulfur mustard [bis(2-chloroethyl) sulfide; SM] produces a
      delayed inflammatory skin response and severe tissue injury. Pig skin has organ
      similarities to human skin that is characterized by the content and types of
      epidermal lipids, the density of hair follicles and presence of sweat glands,
      which together afford penetration of topically applied compounds, complex
      inflammatory responses, and subsequent wound healing. The goal of this study was
      to identify in vivo proinflammatory biomarkers of the SM porcine skin injury
      within 72 h after SM challenge, using the weanling pig model. Changes in gene
      expression of inflammatory mediators were examined at 3, 6, 24, 48, and 72 h,
      using subtraction library analyses and by quantitation of selected transcripts by
      reverse transcription-polymerase chain reaction (RT-PCR). Sequence analysis of
      subtraction libraries identified up-regulation of IL-8 at 24, 48, and 72 h. No
      other specific proinflammatory gene transcripts were isolated from the libraries.
      Specific transcript RT-PCR analysis showed increased production of interleukin
      1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), and matrix
      metalloproteinase-9 (MMP-9, gelatinase B) mRNA levels in response to SM exposure.
      Tumor necrosis factor-alpha (TNF-alpha) expression was only slightly increased
      and no change in the levels of expression was observed for monocyte
      chemoattractant protein-1 and MMP-2. This study identifies the main
      proinflammatory mediators involved in SM-induced skin injury in a weanling pig
      model. The results suggest transcriptional activity in the inflammatory response
      proteins IL-8, IL-6, IL-1beta, and MMP-9 and modest changes in TNF-alpha that
      together produce inflammation and contribute to the pathogenesis of SM
      dermatotoxicity. Therefore, drugs preventing SM-induced inflammation should be
      prime candidates for medical intervention to lessen collateral inflammation
      associated with tissue destruction.

PMID- 12481302
TI  - Melatonin inhibits the contractile effect of vanadate in the isolated pulmonary
      arterial rings of rats: possible role of hydrogen peroxide.
AB  - The effect and possible mechanism of action of vanadate on the isolated pulmonary
      arterial rings of normal rats were studied. Pulmonary arterial rings contracted
      in response to vanadate (0.1-1 mM) in a concentration-dependent manner.
      Preincubation of the pulmonary arterial rings with 1 mM melatonin significantly
      reduced the contractile effect of vanadate by more than 60%. Furthermore,
      addition of hydrogen peroxide (50 microM) or enzymatic generation of hydrogen
      peroxide by the addition of glucose oxidase (10 U/mL) to the medium containing
      glucose produced remarkable increases in the pulmonary arterial tension, 46.2 +/-
      7.3 and 78.7 +/- 9.7 g tension/g tissue, respectively. Similarly, incubation of
      the pulmonary arterial rings with 1 mM melatonin significantly reduced the
      contractile responses of the arterial rings to hydrogen peroxide and
      glucose/glucose oxidase to 25.7 +/- 2.9 and 24.7 +/- 4.4 g tension/g tissue,
      respectively. Vanadate, in vitro, significantly stimulated the oxidation of NADH
      by xanthine oxidase, and the rate of oxidation was increased by increasing either
      time or vanadate concentration. Similarly, addition of melatonin to a reaction
      mixture containing xanthine oxidase and vanadate significantly inhibited the rate
      of NADH oxidation in a concentration-dependent fashion. The results of the
      present study indicated that vanadate induced contraction in the isolated
      pulmonary arterial rings, which was significantly reduced by melatonin.
      Furthermore, the contractile effect of vanadate on the pulmonary arterial rings
      may be attributed to the intracellular generation of hydrogen peroxide.

PMID- 12481303
TI  - 4-Hydroxytamoxifen sulfation metabolism.
AB  - Tamoxifen (TAM) is an important chemotherapeutic agent for the treatment of
      breast cancer. It has also been shown to decrease breast cancer incidence in
      healthy women at high risk for the disease. The increased risk of endometrial
      cancer in women has raised concerns in the use of the drug. Tamoxifen has also
      been shown to be a potent hepatocarcinogen in rats. The oxidative metabolites of
      TAM include alpha-hydroxytamoxifen (alpha-OH-TAM) and 4-hydroxytamoxifen (4-OH
      TAM). The studies on the sulfation of these metabolites are very limited. It has
      been reported that alpha-OH-TAM is a substrate for rat hydroxysteroid
      sulfotransferase a (STa). Our studies on the sulfation of 4-OH-TAM demonstrated
      that 4-hydroxytamoxifen can be sulfated by human liver and human intestinal
      cytosols. Human phenol-sulfating sulfotransferase and human estrogen
      sulfotransferase are the major enzymes for the sulfation of 4-OH-TAM. Human
      dopamine-sulfating sulfotransferase also has sulfation activity for 4-OH-TAM. In
      contrast, rat liver and intestine cytosols have no detectable sulfation activity
      for 4-OH-TAM. The results suggest that the alpha-OH-TAM sulfation pathway leads
      to bioactivation of TAM, and the 4-OH-TAM sulfation pathway leads to
      detoxification of TAM. This agrees with the fact that TAM is more toxic for rats
      than for human beings.

PMID- 12481304
TI  - Biochemical characteristics of purified beef liver NADPH-cytochrome P450
      reductase.
AB  - NADPH-cytochrome P450 reductase, an obligatory component of the cytochrome P450
      dependent monooxygenase system, was purified to electrophoretic homogeneity from
      beef liver microsomes. The purification procedure involved the ion exchange
      chromatography of the detergent-solubilized microsomes on first and second DEAE
      cellulose columns, followed by 2',5'-ADP Sepharose affinity chromatography.
      Further concentration of the enzyme and removal of Emulgen 913 and 2'-AMP were
      accomplished on the final hydroxylapatite column. The enzyme was purified 239
      fold and the yield was 13.5%. Monomer molecular weight of the enzyme was
      estimated to be 76000 +/- 3000 (N = 5) by SDS-PAGE. The absolute absorption
      spectrum of beef reductase showed two peaks at 455 and 378 nm, with a shoulder at
      478 nm, characteristics of flavoproteins. The effects of cytochrome c
      concentration, pH, and ionic strength on enzyme activity were studied. Reduction
      of cytochrome c with the enzyme followed Michaelis-Menten kinetics, and the
      apparent K(m) of the purified enzyme was found to be 47.7 microM for cytochrome c
      when the enzyme activity was measured in 0.3 M potassium phosphate buffer (pH
      7.7). Stability of cytochrome c reductase activity was examined at 25 and 37
      degrees C in the presence and absence of 20% glycerol. The presence of glycerol
      enhanced the stability of cytochrome c reductase activity at both temperatures.
      Sheep lung microsomal cytochrome P4502B and NADPH-cytochrome P450 reductase were
      also purified by the already existing methods developed in our laboratory. Both
      beef liver and sheep lung reductases were found to be effective in supporting
      benzphetamine and cocaine N-demethylation reactions in the reconstituted systems
      containing purified sheep lung cytochrome P4502B and synthetic lipid,
      phosphatidylcholine dilauroyl.

PMID- 12481305
TI  - Use of [125I]4'-iodoflavone as a tool to characterize ligand-dependent
      differences in Ah receptor behavior.
AB  - We have synthesized [(125)I]4'-iodoflavone to study Ah receptor (AhR)-ligand
      interactions by a class of AhR ligands distinct from the prototypic ligand
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). This radioligand allows the
      comparison of AhR-ligand interactions using a ligand that differs in AhR
      affinity, and yet has the same radiospecific activity as [(125)I]2-iodo-7,8
      dibromodibenzo-p-dioxin. Specific binding of [(125)I]4'-iodoflavone with the AhR
      was detected as a single radioactive peak ( approximately 9.7 S) following
      density sucrose gradient analysis. Cytosolic extracts from both Hepa 1 and HeLa
      cells were used as the source of mouse and human AhR, respectively. A
      approximately 6.7 S form of radioligand-bound Ah receptor was detected in the
      high salt nuclear extracts of both cell lines. In HeLa cells approximately
      twofold more [(125)I]4'-iodoflavone-AhR 6 S complex, compared with [(125)I]2-iodo
      7,8-dibromodibenzo-p-dioxin, was recovered in nuclear extracts. A comparison of
      the ability of 4'-iodoflavone and TCDD to cause time-dependent translocation of
      AhR-yellow fluorescent protein revealed that 4'-iodoflavone was more efficient at
      enhancing nuclear accumulation of the receptor. These results suggest that
      [(125)I]4'-iodoflavone is a particularly useful and easily synthesized ligand for
      studying the AhR.

PMID- 12481306
TI  - The roles of cytochrome b5 in cytochrome P450 reactions.
AB  - Cytochrome b(5), a 17-kDa hemeprotein associated primarily with the endoplasmic
      reticulum of eukaryotic cells, has long been known to augment some cytochrome
      P450 monooxygenase reactions, but the mechanism of stimulation has remained
      controversial. Studies in recent years have clarified this issue by delineating
      three pathways by which cytochrome b(5) augments P450 reactions: direct electron
      transfer of both required electrons from NADH-cytochrome b(5) reductase to P450,
      in a pathway separate and independent of NADPH-cytochrome P450 reductase;
      transfer of the second electron to oxyferrous P450 from either cytochrome b(5)
      reductase or cytochrome P450 reductase; and allosteric stimulation of P450
      without electron transfer. Evidence now indicates that each of these pathways is
      likely to operate in vivo.

PMID- 12481307
TI  - A dynamic role for the Ah receptor in cell signaling? Insights from a diverse
      group of Ah receptor interacting proteins.
AB  - The aryl hydrocarbon (Ah) receptor (AhR) is a member of the basic helix-loop
      helix PER-ARNT-SIM (PAS) transcription factor family. Consistent with the notion
      that PAS proteins are biological sensors, AhR binding to Ah toxicants induces or
      represses transcription of a wide range of genes and results in a cascade of
      toxic responses. However, an endogenous role for AhR in development and
      homeostasis is supported by (1) the discovery of low affinity, endogenous
      ligands; (2) studies demonstrating a role for the receptor in development of
      liver and vascular systems, that were established using mice lacking AhR
      expression; and (3) the presence of functional dioxin-responsive elements in
      promoter regions of genes involved in cellular growth and differentiation. A
      large body of recent literature has implicated AhR in multiple signal
      transduction pathways. AhR is known to interact with signaling pathways that are
      mediated by estrogen receptor and other hormone receptors, hypoxia, nuclear
      factor kappaB, and retinoblastoma protein. In addition, AhR complexes may affect
      cellular signaling through interactions with various other regulatory and
      signaling proteins, including PAS heterodimerization partners (ARNT), chaperone
      and immunophilin-like proteins (e.g. HSP90, XAP2/ARA9/AIP, p23), protein kinases
      and phosphatases (e.g. tyrosine kinases, casein kinase 2, protein kinase C), and
      coactivators (e.g. SRC-1, RIP 140, CBP/p300). Here we summarize the types of
      molecular cross talk that have been identified between AhR and cell signaling
      pathways.

PMID- 12481315
TI  - How important is parity violation for molecular and biomolecular chirality?
AB  - Parity violation leads to energy differences delta(pv)H(o)(0)=N(A)delta(pv)E of
      enantiomers in the femtojoule to picojoule per mole range. Recently introduced
      methods of electroweak quantum chemistry predict such energy differences to be
      one to two orders of magnitude larger than previously accepted-but still very
      small. How can such small energies be measured and what are the consequences for
      our understanding of molecular chirality, biomolecular homochirality, and perhaps
      fundamental physics? The review gives some tentative answers to these questions.
      We discuss the current status of theory and some of the current experimental
      approaches.

PMID- 12481316
TI  - Actin-binding marine macrolides: total synthesis and biological importance.
AB  - Marine organisms produce a fascinating range of structurally diverse secondary
      metabolites, which often possess unusual and sometimes unexpected biological
      activities. This structural diversity makes these marine natural products
      excellent molecular probes for the investigation of biochemical pathways.
      Recently, a number of novel and stereochemically complex macrolides, having a
      large macrolactone (22- to 44-membered) ring, that interact with the actin
      cycloskeleton have been isolated from different marine sources. Actin, like
      tubulin, is a major component of the cytoskeleton and has important cellular
      functions. Although the details of these interactions are still under
      investigation, these marine macrolides are becoming increasingly important as
      novel molecular probes to help elucidate the cellular functions of actin. Owing
      to their potent antitumor activities, these compounds, for example the
      aplyronines, also have potential for preclinical development in cancer
      chemotherapy. Their appealing molecular structures, with an abundance of
      stereochemistry, and biological significance, coupled with the extremely limited
      availability from the marine sources, have stimulated enormous interest in the
      synthesis of these compounds. This review summarizes the biological properties of
      these unusual marine natural products and features the recently completed total
      syntheses of swinholide A, scytophycin C, aplyronine A, mycalolide A--all of
      these being potent cytotoxic agents that target actin--and a diastereoisomer of
      ulapualide A. Rather than detailing each individual step of these multistep total
      syntheses, the different synthetic strategies, key reactions, and methods adopted
      for controlling the stereochemistry are compared.

PMID- 12481317
TI  - What is a discovery? Carbon skeletal rearrangements as counter-examples to the
      rule of minimal structural change.

PMID- 12481318
TI  - Efficient, racemization-free peptide coupling of N-alkyl amino acids by using
      amino acid chlorides generated in situ--total syntheses of the cyclopeptides
      cyclosporin O and omphalotin A.

PMID- 12481319
TI  - New principles of protein structure: nests, eggs--and what next?

PMID- 12481320
TI  - Preparation of resolved fourfold symmetric amphiphilic helices using chiral
      metallacrown building blocks.

PMID- 12481321
TI  - Novel synthetic approach to trinuclear 3d-4f complexes: specific exchange of the
      central metal of a trinuclear zinc(II) complex of a tetraoxime ligand with a
      lanthanide(III) ion.

PMID- 12481322
TI  - The structure of neutral proline.

PMID- 12481323
TI  - Lewis acidity in transition-metal-doped microporous aluminophosphates.

PMID- 12481324
TI  - Total synthesis of (+/-)-wortmannin.

PMID- 12481325
TI  - Concise enantioselective synthesis of (+)-FR66979 and (+)-FR900482:
      dimethyldioxirane-mediated construction of the hydroxylamine hemiketal.

PMID- 12481326
TI  - Facile construction of N-hydroxybenzazocine: enantioselective total synthesis of
      (+)-FR900482.

PMID- 12481327
TI  - Total synthesis of (+/-)-FR66979.

PMID- 12481328
TI  - Polymer-supported C2-symmetric ligands for palladium-catalyzed asymmetric allylic
      alkylation reactions.

PMID- 12481329
TI  - An efficient one-pot enantio- and diastereoselective synthesis of heterocycles.

PMID- 12481330
TI  - General synthesis of semiconductor chalcogenide nanorods by using the monodentate
      ligand n-butylamine as a shape controller.

PMID- 12481331
TI  - Electron-transfer dynamics of cytochrome C: a change in the reaction mechanism
      with distance.

PMID- 12481332
TI  - Enantiopure beta-hydroxy morpholine amides from terminal epoxides by
      carbonylation at 1 atm.

PMID- 12481333
TI  - Mutually induced formation of host-guest complexes between p-sulfonated
      calix[8]arene and photolabile cholinergic ligands.

PMID- 12481334
TI  - New ferrocenyl ligands with broad applications in asymmetric catalysis.

PMID- 12481335
TI  - A remarkable 14-nuclear Re(8)(V) Ag(I)(6) coordination oligomer derived from a 2D
      (Re(2)(V) Ag(I)(2))n coordination polymer with D-penicillaminate.

PMID- 12481336
TI  - Using mass spectrometry to characterize self-assembled monolayers presenting
      peptides, proteins, and carbohydrates.

PMID- 12481337
TI  - A method for determining the difference in relative apicophilicity of carbon
      containing substituents of 10-P-5 phosphoranes.

PMID- 12481338
TI  - Preferential location of Ge atoms in polymorph C of beta zeolite (ITQ-17) and
      their structure-directing effect: a computational, XRD, and NMR spectroscopic
      study.

PMID- 12481339
TI  - Solid-state NMR studies of MCM-41 supported with a highly catalytically active
      cluster.

PMID- 12481340
TI  - Low-temperature destruction of chlorinated hydrocarbons over lanthanide oxide
      based catalysts.

PMID- 12481341
TI  - Selective isomerization of a terminal olefin catalyzed by a ruthenium complex:
      the synthesis of indoles through ring-closing metathesis.

PMID- 12481342
TI  - The structure of the peroxo species in the TS-1 catalyst as investigated by
      resonant Raman spectroscopy.

PMID- 12481343
TI  - Pd0-catalyzed three-component tandem double-addition-cyclization reaction:
      stereoselective synthesis of cis-pyrrolidine derivatives.

PMID- 12481344
TI  - Catalytic electronic activation: indirect "Wittig" reaction of alcohols.

PMID- 12481345
TI  - A straightforward detection of deprotonated conformers of malonic acid by solid
      state 13C NMR spectroscopy.

PMID- 12481346
TI  - Unparalleled rates for the activation of aryl chlorides and bromides: coupling
      with amines and boronic acids in minutes at room temperature.

PMID- 12481347
TI  - A new entry to the stereoselective introduction of an ethynyl group by a radical
      reaction: synthesis of the potential antimetabolite 2'-deoxy-2'-C-ethynyluridine.

PMID- 12481348
TI  - Stereoselective total synthesis of mucocin, an antitumor agent.

PMID- 12481349
TI  - Structure of a drug-induced DNA T-bulge: implications for DNA frameshift
      mutations.

PMID- 12481350
TI  - Traceless solid-phase synthesis of 2-aminothiazoles: receptor tyrosine kinase
      inhibitors with dual selectivity for Tie-2 and VEGFR-2.

PMID- 12481351
TI  - [Pd3(InCp*)4(mu2-InCp*)4]: three linearly arranged palladium atoms wrapped into a
      fluxional shell of eight InCp* ligands.

PMID- 12481352
TI  - Total synthesis of amphidinolide T4.

PMID- 12481353
TI  - Tuning PCR specificity by chemically modified primer probes.

PMID- 12481354
TI  - Detection of individual p53-autoantibodies by using quenched peptide-based
      molecular probes.

PMID- 12481355
TI  - Long-distance magnetic interaction between a Mn(III)Mn(IV) (S=1/2) core and an
      organic radical: a spectroscopic model for the S(2)Y(Z). state of photosystem II.

PMID- 12481356
TI  - Real-time single-molecule imaging of the formation and dynamics of coordination
      compounds.

PMID- 12481357
TI  - Low-temperature synthesis of single-crystal germanium nanowires by chemical vapor
      deposition.

PMID- 12481358
TI  - Experimental observation and confirmation of icosahedral W@Au12 and Mo@Au12
      molecules.

PMID- 12481359
TI  - Synthesis and characterization of lanthanide hydroxide single-crystal nanowires.

PMID- 12481363
TI  - Court ruling casts shadow on Missouri RN.

PMID- 12481364
TI  - Slash and burn redux. Hunter Group still bottom-line feeding.

PMID- 12481365
TI  - RNs make gains.

PMID- 12481366
TI  - Direct hit. Nurses win with targeted ads.

PMID- 12481367
TI  - No longer in denial. Interview by Pamela Rohland.

PMID- 12481368
TI  - Nothing succeeds like exce$$.

PMID- 12481369
TI  - Nursing a nation. Interview by Diana Reiss-Koncar.

PMID- 12481370
TI  - Living, and dying, with. AIDS.

PMID- 12481372
TI  - Ingredients in pharmaceutical preparations: a problem not value.

PMID- 12481373
TI  - Pharmacotechnical characterization and effectiveness testing of a proposed
      emulsion for the treatment of dry skin.
AB  - One of the most important objectives of the Pharmaceutical Industry is the
      development of new excipients as well as the optimization of other more
      traditional ones. Also, the investigation of new active substances able to
      prevent, palliate or treat the cutaneous dehydration is another of the most
      important of their objectives. Both tendencies are implanted in this experimental
      work: we propose an emulsion formulated with the base--Neo PCL' (25%), NMF
      (Lactil', 5%) and a peculiar active--Honey of Rosemary (15%). The working scheme
      is as follows: 1) Pharmacotechnical Characterization--organoleptic
      characteristics, Photomicrograph Study, Type of Emulsion, pH, Rheology; 2)
      Stability Study by means of accelerated tests based on temperature and
      centrifugation; 3) Effectiveness Study by applying of non-invasive assessment
      techniques. An emulsified dermopharmaceutical form is obtained (O/W) with a
      satisfactory organoleptic characteristics and eudermic pH (5.2), attributable to
      the acid character of Honey. From the rheological study, a very good results are
      obtained: viscosity (T = 408.8.D0.549), structural recuperation (30%) and
      thixotropy (AD1/AD2 = 1.36). On the other hand, from the effectiveness results
      (corneometric--P.I.120 = 43.2%- and sebumetric--E.I. = 33-144 mg/cm2-), a high
      level of moisturizing is deduced, which is attributable to the synergic action of
      both Lactil' and Honey. Finally, the proposed emulsion would serve as a treatment
      for all type of dry skin.

PMID- 12481374
TI  - Biological and chemical quality control of spermicidal raw material nonoxynol-9
      and nonoxynol-9 containing vaginal contraceptive (ABF contraceptive film):
      determination of spermicidal activity and assay of nonoxynol-9.
AB  - The paper presents a routine biological and chemical quality control of nonoxynol
      9 raw material and pharmaceutical formulation containing nonoxynol-9 (ABF
      contraceptive film). The biological control performed based on the determination
      and comparison of the spermicidal activities different dilutions of the standard
      raw materials solution and assay raw material or nonoxynol-9 pharmaceutical
      formulation solution on the human or breeding bull sperm using a modified Sander
      Cramer method. The test preparations of the nonoxynol-9 raw materials or
      pharmaceutical formulation should show equal or higher spermicidal activity than
      the standard. The spermicidal activity should not be lower than dilution 1:90.
      The chemical control is performed based on the determination and comparison of
      nonoxynol-9 content in the standard raw material solution and assay raw material
      or nonoxynol-9 pharmaceutical formulation solution using UV-spectrophotometric
      method determining and comparing the absorbances at the maximum absorbance
      wavelength (275 nm). The content of nonoxynol-9 in the raw material assay
      solution or pharmaceutical formulation (ABF contraceptive film) should be within
      90-110% of the declared value.

PMID- 12481375
TI  - Analysis of the drugs, applied for the treatment of the patients, hospitalized in
      a urological department, by pharmacological groups.

PMID- 12481376
TI  - Asthma, drug medication and noncompliance.
AB  - According to the new concepts, asthma is a chronic disease of the upper
      respiratory tracts, caused by different cells, including the mastocits and
      eozinofils. The patients that are suffering from episodic, frequent, or chronic
      asthma are participating very energetic in the treatment--they have to know and
      control the symptoms of their disease and also to possess technical skills to
      perform the treatment. METHODOLOGY: Between March 1 and July 31, 1999, 30
      patients [19 women and 11 men, mean age 35 years (range 2.50 to 65)], followed at
      the Clinic for Allergic Diseases of the University hospital "Aleksandrovska",
      Medical University of Sofia, Bulgaria, were interviewed blindly in order to
      assess their compliance with pharmacologic therapy. All patients were suffering
      from different types of asthma. RESULTS: The level of compliance among the
      studied group of patients is 86%. In comparison with the literary data where the
      level of non-compliance is 20% the obtained level is lower--14%. The reasons for
      non-compliance according to the patients are: the appearance of ADRs, the high
      prize of the drugs, the hard application of the drug form.

PMID- 12481377
TI  - Synthesis and CNS activities of 2-methyl/5-chloro-8-(3-substituted
      propoxy)quinolines.
AB  - In the present study, a series of 2-methyl/5-choloro-8-(3-substituted propoxy)
      quinolines were synthesized. The compounds were characterized by IR, 1H-NMR and
      elemental analysis. The compounds were investigated for anticonvulsant and
      decrease in the elevated motor activity by introceptive chemical stimuli
      (amphetamine antagonistic activity) at the dose level of 80 and 160 mg/kg.
      Compounds 2, 10, 11, 12 and 13 exhibited significant anticonvulsant and
      amphetamine antagonistic activity. Compounds 2 and 11 exhibited highest
      anticonvulsant and amphetamine activity respectively.

PMID- 12481378
TI  - Sustaining pattern of phenformin hydrochloride using various polymers and waxes.
AB  - The present study was carried out to formulate matrix tablets of phenformin
      hydrochloride. Granules of phenformin HCl were prepared by using ethyl cellulose,
      eudragit RS 100, gum acacia, carnauba wax, stearyl alcohol, glyceryl monostearate
      and triethanol amine. Thus the granules were compressed and fourteen tablets
      formulations were prepared. All the physical parameters of granules and matrix
      tablets were studied including compatibility study. One commercial timed
      disintegration capsule was also included for study and comparison. The results of
      in vitro studies showed that sustained release matrix tablet might be prepared
      using carnauba wax, stearyl alcohol, triethanol amine and magnesium stearate.

PMID- 12481379
TI  - Comparative study between culture media employed in sterility test.
AB  - The sterility test aims at the contact of a product with a culture medium, as a
      way of detecting the possible presence of viable microorganisms in products which
      have been submitted to a sterilization process and/or to aseptic processing.
      Since the official introduction of the methodology, in 1932, several culture
      media have been proposed and adopted, in a constant attempt to offer conditions
      which support the growth of as many contaminants as possible. This work aimed at
      a comparative evaluation of the efficiency of microbial contaminants detection in
      the different types of culture media employed in sterility tests. The study led
      to the conclusion that the culture media recommended by the pharmacopoeia
      compendia, soybean casein digest and fluid thioglycollate, present the best
      results in microorganisms detection. Besides, the microbial strains, as well as
      microbial suspension density, recommended by the main pharmacopoeias to verify
      culture media growth promoting capacity, have also proved suitable for use.

PMID- 12481380
TI  - Thioglycolic acid and pyrazole derivatives of 4(3H)-quinazolinone: synthesis and
      antimicrobial evaluation.
AB  - New derivatives of 4(3H)-quinazolinone were synthesized and evaluated for their
      antibacterial and antifungal activity. The derivatives are: 3-Aryl-2-[3-aryl-1
      (carboxymethylthio)-3-oxopropyl)]-4(3H)-quinazolinones 2a-f; 3-Aryl-2-(3-aryl-1H
      pyrazol-5-yl)-4(3H)-quinazolinones 3a-f; 3-Aryl-2-(1,3-diaryl-1H-pyrazol-5-yl)
      4(3H)-quinazolinones 4a-f; 3-Aryl-2-(3-aryl-1-thiocarbamoyl-1H-pyrazol-5-yl)
      4(3H)-quinazolinones 5a-f; 3-Aryl-2-[3-aryl-1-(carboxymethylthio)-3
      hydroxyiminopropyl)]-4(3H)- quinazolinones 6a-f; and 3-Aryl-2-[3-aryl-1
      (carboxymethy- lthio)-3-thiocarbamoyliminopropyl)]-4(3H)-quinazolinones 7a-f.
      Some of the tested compounds showed activity comparable to that of the standard
      references used.

PMID- 12481381
TI  - Enteric-coated insulin capsules: a combination with or a replacement of oral
      hypoglycaemic drugs.
AB  - The hypoglycaemic effect of Eudragit S100 enteric-coated insulin capsules
      containing sodium salicylate as an absorption promoter, oral hypoglycaemic
      tablets sulphonylurea (e.g. doanil 5 mg) and metformin (e.g. glucophage 500 mg)
      was studied in hyperglycaemic beagle dogs. The effect of the combinations of
      insulin capsules + doanil, insulin capsules + glucophage and the combination of
      doanil + glucophage is also studied. The results show that the enteric-coated
      insulin capsules produced the same results as the glucophage tablets with respect
      to Cmax, AUC and relative hypoglycaemia. While, doanil tablets produced non
      significant lowering (P > 0.05) of Cmax and a significant less (P < 0.05) AUC
      compared to that produced by insulin capsules and lower (P < 0.001) RH compared
      to that of insulin capsules or glucophage tablets. The combination of glucophage
      and doanil tablets resulted in synergistic effect producing 59 +/- 9.27%
      reduction in plasma glucose levels by 4h and significantly higher (P < 0.001) AUC
      and RH compared to either of the tablets alone. The combination of insulin
      capsules and doanil tablets produced only 16% lowering in plasma glucose levels
      by 6h and significantly (P < 0.001) lower AUC and RH compared to the combination
      of glucophage + doanil. The combination of insulin capsules and glucophage
      tablets produced about 38% reduction in plasma glucose levels and significantly
      (P < 0.001) higher AUC and RH compared to either glucophage, doanil tablets or
      enteric coated insulin capsules alone. The results show that enteric-coated
      insulin capsules can be a replacement of either of the oral hypoglycemic drugs.
      In addition, the combination of the insulin capsules and glucophage tablets could
      be a good therapy to Type II diabetic patients that not controlled properly by
      oral hypoglycemic drugs.

PMID- 12481382
TI  - In vitro antimicrobial interactions of arthemeter with some 4-quinolones.
AB  - Bacterial infections often co-exist with acute malarial attacks. The effect of
      combining arthemeter (a new antimalarial) with some commonly used 4-quinolones
      (ciprofloxacin, pefloxacin, norfloxacin and nalidixic acid) was investigated in
      vitro with a view to providing data for the design of drug regimens for the
      treatment of such infections. While arthemeter demonstrated no antibacterial
      activity whatsoever against any of the test microorganisms (E. coli and Staph.
      aereus), the 4-quinolones shared marked activity. Comparative analyses of the
      activity of each quinolone alone and in combination with arthemeter showed 0%
      43.8%, 44.9% and -12.2% change in the minimum inhibitory concentration (MIC) of
      nalidixic acid pefloxacin, ciprofloxacin and norfloxacin respectively against E.
      coli and -17.5%, 22.3% 35.8% and 50.9% change in the MICs of the same respective
      drugs against Staph. aureus. These changes in MIC were statistically significant
      (Pf0.05). With respect to infections caused by E. coli and E. coli, the
      combination of artemether with ciprofloxacin or pefloxacin proves to be a
      rational chemotherapeutic regimen when such infection co-exist with malaria.

PMID- 12481383
TI  - Synthesis, characterization and antifungal activities of some
      benzenesulphonylamino acid derivatives.
AB  - Condensation of benzenesulphonyl chloride (1) with a series of amino acids
      afforded benzenesulphonylamino acids (2a-d). Esterification of the derivatives
      (2a-d) in methanol gave the corresponding benzensulphonylamino acid methylesters
      (3a-d), which condensed with o-aminophenol and o-phenylene diamine to give the
      benzoxazoles (4a-d) and benximidazoles (5a-d) respectively. Hydrazinolysis of the
      methyl esters (3a-d) afforded the hydrazide derivatives (6a-d). The 1,2
      diazeridine derivatives (7a-d) can be prepared by the reaction of hydrazides (6a
      d) with alpha-chloroacetylchloide. Schiff's bases (10a-d) were achieved by the
      condensation of p-chlorobenzaldehyde with the hydrazides (6a-d). Condensation of
      Schiff's bases (10a-d) with p-chlorophenyldiazonium chloride afforded the
      formazan derviatives (11a-d). The hydrazides (6a-d) were reacted with
      acetylethylacetate to give 3-methyl-2-pyrazoline-2-one derivatives (8a-d), which
      condensed with p-chlorobenzaldehyde to give 4-arylidino-3-methyl-2-pyrazoline-2
      one derivatives (9a-d). All derivatives (2-11) were tested against: A. flavus, A.
      parasiticus, A. alutaceus and F. moniliforme. Some of the derivatives showed
      promising results against the tested fungi.

PMID- 12481384
TI  - Antituberculosis agents. VI. Activity of a new ciprofloxacin derivative against
      Mycobacterium avium and some drug-resistant strains of Mycobacterium
      tuberculosis.
AB  - The in vitro antimycobacterial activity of a new quinolone derivative, 1a
      containing 2-(2-furyl)-2-oxoethyl group at N-4 position of piperazine ring of
      Ciprofloxacin was tested for efficacy in vitro in TB-infected macrophage model
      (EC90 = 3.25 micrograms/ml and EC99 > 12.5 micrograms/ml). The MIC values of 1a
      were determined against M. tuberculosis strains resistant to Isoniazid (MIC =
      1.56 micrograms/ml), Rifampin (MIC = 1.56 micrograms/ml), Ethambutol (MIC = 0.78
      microgram/ml), Kanamycin (MIC = 0.78 microgram/ml) and Ciprofloxacin (MIC > 25
      micrograms/ml). Furthermore, the MIC and selectivity index (SI) of 1a were
      evaluated against M. avium. Also, in this study the minimum bactericidal
      concentration (MBC) of 1a was determined against M. tuberculosis H37Rv (MBC =
      6.25 micrograms/ml) and strain resistant to Rifampim (MBC = 25 micrograms/ml) and
      Isoniazid (MBC = 25 micrograms/ml).

PMID- 12481385
TI  - [Symposium on "Renal failure in the elderly" Juan-les-Pin, September 21-22,
      2001].

PMID- 12481386
TI  - [Sixth Immunopathology Clinic Day, Paris, May 31, 2002].

PMID- 12481387
TI  - [Are blood markers of hepatic fibrosis available in clinical practice?].

PMID- 12481388
TI  - [Treatment of hepatitic C virus infection after the French 2002 Consensus
      Conference].

PMID- 12481389
TI  - [Usefulness in clinical practice of noninvasive measurement of colloids osmotic
      pressure-capillary pulmonary pressure gradient in the management of acute
      dyspnea].
AB  - BACKGROUND: Increased pulmonary capillary pressure (PAWP) and decreased serum
      colloid osmotic pressure (COP) are important factors in pulmonary edema (PE)
      formation. The aim of this study was to evaluate the clinical usefulness of
      noninvasive determination of COP, PAWP and COP-PAWP gradient in patients with
      acute dyspnea. METHODS: Thirty four patients presenting with PE, 19 with
      preserved left ventricular systolic function (Ia) and 15 with depressed systolic
      function (Ib), and 26 patients presenting with acute pulmonary diseases (II) were
      enrolled. COP was estimated using Landis and Pappenheimer formula (COP = 2.1 x P
      + 0.16 x P2 + 0.009 x P3, P: serum total protein concentration). PAWP was
      measured by transthoracic Doppler echocardiography using E/Vp and 1000/(2 x IPT +
      Vp) Doppler indexes. RESULTS: The mean value of the gradient was 0.5 +/- 5, 1.7
      +/- 3.4 and 10.4 +/- 4.7 mmHg in Ia, Ib and II respectively (P < 0.001 Ia and Ib
      vs II). PAWP was higher in Ia and Ib than in II (P < 0.001). However,
      hypoalbuminemia with COP < or = 18 mmHg was observed in 63% of patients in Ia as
      compared to those in Ib (7%) and II (8%). CONCLUSIONS: Severe hypoalbuminemia
      frequently contributes to PE formation in the presence of normal left ventricular
      systolic function. A COP-PAWP gradient value lower than 6 mmHg is highly
      predictive of the diagnosis of acute heart failure in these patients presenting
      with acute dyspnea.

PMID- 12481390
TI  - [Characteristics of autoimmune hemolytic anemia in adults: retrospective analysis
      of 83 cases].
AB  - PURPOSE: To describe the main characteristics and outcome of adult's acquired
      immune hemolytic anemias (AIHA). To analyse the relevance of the complementary
      tests performed for the search of an underlying disease. METHODS: Retrospective
      (1980-2000) monocentric study. INCLUSION CRITERIA: age above 16, AIHA defined by
      an hemoglobin level below 12 g/dl in men and 11 g/dl in women, with hemolysis
      and/or a positive direct Coombs test and/or the presence of cold agglutinins
      (threshold 1/500) and/or in the absence of any other cause. RESULTS: Eighty three
      patients included (56 women and 27 men), with a mean age of 56 years (+/- 22) at
      AIHA onset including: 72 patients (87%) with warm antibody AIHA and 11 (13%) with
      cold agglutinin disease. The mean follow-up was 48 months (median 22 months).
      Among the 72 patients with warm antibody AIHA, the specificity of autoantibodies
      was: IgG + complement (43%), IgG (32%) or complement alone (25%); cold
      agglutinins (titre from 1/60 to 1/512) were detected in 15 (20%) of the patients.
      Antinuclear antibodies were detected (threshold: 1/80) in 33% of the cases.
      Hypogammaglobulinemia on serum protein electrophoresis (SPE) was significantively
      associated with the presence of an underlying non-Hogkin lymphoma (NHL). The CT
      scan of the the chest and abdomen which was performed in 50% of the patients,
      showed abnormalities other than a spleen enlargement in 25% of the cases. The
      medullar biopsy (MB) was abnormal in 7 of 26 cases (27%) but lead by itself to
      the diagnosis of NHL in a single case. Thrirty seven (51%) of warm antibody AIHA
      cases were finally considered to be "secondary" to an underlying disease namely:
      NHLs (n = 14), Hogkin's disease (n = 1) connective tissue disease (CTD) (n = 14),
      drug-induced AIHA (n = 3), miscellaneous (n = 5). In 6 out of 14 cases (43%) of
      NHL's associated AIHA, the onset of AIHA precedes the NHL from 22 to 66 months.
      The response rates to different therapeutic regimens did not significatively
      differ when "secondary" and "idiopathic" AIHA were compared. Overall, 13 patients
      (15.6%) died mainly from infectious complications (n = 5) or an underlying NHL (n
      = 5). CONCLUSIONS: In more than half of the cases AIHA are associated with an
      underlying disease and AIHA may precede the onset of a NHL for a long period. In
      the absence of a clinically apparent underlying disorder, testing for the
      presence of antinuclear antibodies, a SPE and a CT-scan must be systematic.
      Conversely, if no abnormalities are found, the relevance of a systematic MB at
      AIHA onset seems very low.

PMID- 12481391
TI  - [Risk factors for venous thromboembolism in hospitalized patients in internal
      medicine: case-control study of 150 patients].
AB  - BACKGROUND: Risk factors for the thrombo-embolic disease are not yet completely
      validated in medical setting. Indeed, there is a lack of scientific data
      concerning their prevalence and their thrombogenic weight. METHODS: We carried
      out a prospective case-control study in an internal medicine unit where general
      acute pathologies are recruited. We have included two patients without thrombosis
      for each patient admitted for a thrombo-embolic event. In all patients, at
      admission, clinical and biological risk factors for thromboembolism were
      systematically analysed in a physiopathological and chronological way. RESULTS:
      450 patients were included during the 27 months period of the study. Among these
      patients, 150 were hospitalised for a deep venous thrombosis of the leg or/and a
      pulmonary embolism. Height risk factors have demonstrated their high thrombogenic
      potential: paralysis of the legs (OR = 13; 95% CI: 1.4 to 5.1), post-thrombotic
      syndromes (OR = 13; CI: 1.7 to 4.3), extrinsic compressions (OR = 8; CI: 1.3 to
      5.4), pregnancy (OR = 6; CI: 1.2 to 6), malignancy occurred one year before (OR =
      4; CI: 1.1 to 6.7), personal history of deep vein thrombosis (OR = 3; CI: 1.6 to
      4.5), varicosity (OR = 2.5; CI: 1.2 to 6.1) and venous insufficiency (OR = 1.7;
      CI: 1 to 7.4). Four parameters, generally considered as risk factors, didn't
      prove here their pathogenic power: the age over 60, obesity (BMI > 27), bedrest
      and the presence of an on-going malignancy. CONCLUSIONS: Only risk factors with
      high thrombogenic power (as paralysis or extrinsic compression for example) could
      be identified by this kind of study performed in polypathological patients. In
      this particular population, usually recognised risk factors as age, obesity and
      bedrest are not determinant parameters for the thomboembolic risk evaluation.

PMID- 12481392
TI  - [Nasal septal perforation and systemic disease].
AB  - INTRODUCTION: Nasal septal perforations are mainly due to trauma. Our review
      highlights systemic diseases leading to this disorder. CURRENT KNOWLEDGE AND KEY
      POINTS: Various systemic diseases may be responsible of nasal septal perforation:
      Wegener's granulomatosis, systemic lupus erythematosus, antiphospholipid
      syndrome, sarcoidosis, cryoglobulinaemia. But, very few data are available about
      the frequency of septum nasal perforation in each disease. Clinical
      manifestations are numerous and not specific: obstruction, epistaxis, postnasal
      discharge, whistling, crusting. Asymptomatic forms are frequent. Biopsy of nasal
      septum is poorly useful for the diagnosis except when granuloma or vasculitis is
      found. Pathophysiologic mechanisms of nasal septal perforation are ischemic,
      infectious or inflammatory. FUTURE PROSPECTS AND PROJECTS: Systemic disease may
      be suspected in unclear nasal septal perforation. More, in systemic disease, even
      when symptoms are absent, intranasal examination is required.

PMID- 12481393
TI  - [Pregnancy-related hypertension].
AB  - PURPOSE: Hypertension occurs in 10 to 15 p cent of pregnancies. Among them, 10 to
      20% also have proteinuria. This situation defines preeclampsia, and involves a
      serious threat on fetal and even maternal prognosis. Presence of the hepatic
      (HELLP) syndrome still severely worsens the prognosis. CURRENT KNOWLEDGE AND KEY
      POINTS: Pathophysiology of preeclampsia is based on a very early abnormality of
      placentation, leading to insufficient blood supply to the feto-placental unit. At
      the maternal level, the main consequence of placental ischemia is generalized
      endothelial dysfunction, responsible for systemic vasoconstriction and clotting
      abnormalities. In such a context, lowering blood pressure with drugs is quite
      inefficient, or even harmful. The prognosis of this disease is mainly related to
      the pertinence of obstetrical management. FUTURE PROSPECTS AND PROJECTS: An early
      preventive strategy is the most logical approach of preeclampsia, its modalities
      remain under discussion.

PMID- 12481394
TI  - [Biceps crural myositis after an insect bite].
AB  - INTRODUCTION: It can be difficult to diagnose focal muscular disease. We report a
      case of crural biceps focal myositis after an insect bite. DISCUSSION: We then
      discuss diagnostics of one or a small number of muscle injury. Focal inflammatory
      myositis has been described. We emphasize the role of pathology. In our case,
      pathological examination rules out inflammatory or tumoral disease and access
      likely toxical etiology. Muscle injury can appear, most frequently around the
      bite of venomous animal. CONCLUSION: Hymenopters are often responsible for such
      stings in France. Venoms are toxic for muscle cells membrane.

PMID- 12481395
TI  - [Difficulties in diagnosing an aortic arch thrombus].
AB  - INTRODUCTION: Thrombosis of the aortic arch is a rare and often underdiagnosed
      source of peripherical arterial embolic events. EXEGESIS: We report a case with a
      non-typical initial clinical presentation of polyarteritis nodosa. A mobile
      thrombus in the aortic arch was secondarily suspected when disseminated arterial
      embolism appeared. Transthoracic echocardiography failed twice to diagnosticate
      the source of embolism. The diagnosis was only performed with transesophageal
      echocardiography and confirmed by computed tomography and magnetic resonance
      imaging of the thoracic aorta. The thrombus completely disappeared after six
      months of oral anticoagulant therapy. CONCLUSION: Although rare, this diagnosis
      mustn't be disregarded in an etiologic view of recurrent and disseminated
      peripherical ischemic events (even clinically silent ones) under penalty of
      detrimental functional consequences due to a delayed diagnosis.

PMID- 12481396
TI  - [Polyarthritis of every color...].

PMID- 12481397
TI  - [Dysarthria during irinotecan administration].

PMID- 12481398
TI  - [T-cell lymphocytosis associated with thymoma and myasthenia].

PMID- 12481399
TI  - [Interferons: cytokines usually used as drugs].

PMID- 12481400
TI  - [The interferons: pharmacology, mechanism of action, tolerance and side effects].
AB  - BACKGROUND: Interferons are a recombinant form of endogenous interferon. By
      inducing the release of intracellular enzymes such as 2'5' oligoadenylate
      synthetase and double stranded RNA dependent protein kinase, the drug causes
      degradation of viral messenger RNA and inhibits protein synthesis. MAIN POINTS:
      Interferons are cytokines efficient in the treatment of infections diseases.
      Three main types are described as alpha, beta and gamma depending on their
      antigenic specificity. They have antiviral activity, antiproliferative and
      immunomodulation properties in response to a viral infection or other enzyme
      inducers. Furthermore, they increase expression of major histo-compatible complex
      antigens, increase natural killer and cytotoxic T cell activity, cytokine
      induction and production of endogenous interferon. Adverse effects frequently
      occur but are generally wild and reversible at current dosages. The
      pharmacokinetics of interferons have been fairly well described. The decline in
      serum concentrations is rapid after intravenous administration. The volume of
      distribution approximates 20-60% of bodyweight. Terminal elimination half lives
      range from 4-16 hrs, 1-2 hrs and 25-35 min for alpha, beta, gamma respectively.
      Intra-muscular and subcutaneous administration of interferons alpha and beta
      results in protracted but fairly good absorption > 80% for interferon alpha to
      70% for interferon gamma. Pegylated interferon safety and pharmacodynamic
      profiles were comparable. Pegylated interferon demonstrated delayed clearance
      compared with non-pegylated interferon, consistent with once-weekly
      administration. The severity of adverse effects is dose dependent. Most patients
      treated have an influenza like syndrome within 2-8 hrs of drug administration.
      Other effects such as fatigue, lethargy, anorexia are usually dose limiting.
      Neuropsychiatric reactions may also become dose limiting. Interferon induced the
      formation of serum neutralizing antibodies in approximately 10-20% of treated
      patients. PERSPECTIVES: The development of pegylated forms, a greater
      understanding of action mechanisms, and the combination with other therapies
      should reinforce the place of interferons in the therapeutic arsenal.

PMID- 12481401
TI  - [Role of interferons in the treatment of hepatitis B and hepatitis C virus
      infections].
AB  - BACKGROUND: Since the discovery of hepatitis C (HCV), the efficacy of treatment
      has significantly progressed using standard mono-therapy: with Interferon alpha
      (IFN) during six months we obtained approximately 10% sustained response and
      currently with the association of pegylated IFN and Ribavirin a 55% sustained
      response was achieved. CURRENT POSITION AND MAJOR POINTS: HCV infection continues
      to present therapeutic problems which have not entirely been solved, mainly
      related to clinical and biological tolerance, and non-responders. Moreover, the
      care of patients with extra-hepatic localization, cirrhotic patients, as well as
      therapeutic problems of co-infected HIV-HCV patients. As regards hepatitis B
      (HBV) new effective treatments against this virus have appeared, IFN then
      nucleoside analogs, some of which are available in France (i.e. lamivudine,
      adefovir, dipovoxil). The main objective of chronic hepatitis B treatment is to
      obtain the complete inhibition of the HBV virus by Hbe-antigen antibody
      seroconversion which would therefore significantly increase patient survival. In
      this article the advantages and disadvantages of the different treatments are
      assessed. FUTURE PERSPECTIVES: Despite the considerable and rapid progress
      obtained in the therapeutic treatment of infection due to HCV and HBV a number of
      unknown factors remain, which warrants further trials, in particular to evaluate
      the efficacy as well as the tolerance of the antiviral agent association.

PMID- 12481402
TI  - [Interferons and neurologic diseases].
AB  - PURPOSES: Therapeutic strategies using interferons in neurology are limited to
      multiple sclerosis. In this disease, only beta interferons are used and now
      considered as a first line treatment in the relapsing-remitting forms of the
      disease. MAIN POINTS: Beta interferons have reduced the relapse rate by
      approximately 3% and also reduced the risk of disability progression. They have
      also favorably influenced the brain lesions on MRI. Numerous data have stressed
      the importance of starting treatment as early as possible. In the secondary form
      of the disease, the impact of beta interferons are still discussed. In some
      clinical endpoints, a dose-response has been demonstrated, probably related to
      the frequency of injections. Side effects are acceptable despite the high
      frequency of flu-like syndrome. PERSPECTIVES: Recent data argue for beta
      interferon treatment after the first demyelinating episode in subjects at risk
      for early new relapses. In some patients, in cases of treatment failure,
      combination strategies, including beta interferons, should be addressed in the
      near future. Interferons were also tested with disappointing results in other
      neuro-inflammatory disorders, such as chronic inflammatory demyelinating
      neuropathies.

PMID- 12481403
TI  - [Interferons and hematology].
AB  - BACKGROUND: IFN alpha are cytokines used for a number of years in the treatment
      of certain hemopathies, i.e. of a myeloid and lymphoid etiology. IFN alpha are a
      family of polypeptides produced by eukaryote cells in response to various
      stimulant agents. The first trials using this cytokine in humans were carried out
      by H. Strander in the years 1965-1970. IFN alpha contain anti-viral, anti
      proliferative and immunomodulatory properties. The access of clinicians to IFN
      alpha molecules, in addition to elements produced by genetic engineering for
      approximately the past 20 years, has permitted a number of therapeutic trials to
      be carried out. In hematology the clinical interest of IFN alpha was primarily in
      chronic myeloid and lymphoid proliferating syndromes. Certain indications have to
      date been well demonstrated. However, the impact of IFN alpha on therapeutic care
      of certain hemopathies as compared to conventional treatment remains
      controversial. At the same time, the frequency of side effects from treatment
      with IFN alpha and its cost should be taken into consideration. CURRENT POSITION
      AND MAJOR POINTS: The therapeutic trials carried out over the past ten years have
      proven the interest of IFN alpha in, essentially, two diseases: on one hand
      chronic myeloid leukemia with the acquisition of cytogenetic remission and on the
      other malignant non-Hodgkin's follicular type lymphoma. However, as regards other
      hemopathies the place of IFN alpha remains debatable. PERSPECTIVES: The future of
      IFN alpha use in the treatment of hemopathies appears to be linked to its
      association with new treatments, an association, however, where its efficacy and
      superiority should be demonstrated. This is the case in chronic myeloid leukemia
      where IFN alpha could be associated with aracytine or the inhibitors of tyrosine
      kinase. Also, in the treatment of malignant non-Hodgkin's lymphomas as well as
      the studies concerning the association between IFN alpha and monoclonal
      antibodies, in particular antibody anti-CD 20.

PMID- 12481404
TI  - [Interferons and malignant melanoma].
AB  - BACKGROUND: Alpha interferon is currently used in the treatment of malignant
      melanoma mainly as adjuvant therapy at the first stage of the illness (primary
      tumor) and at the second stage (lymph node invasion). CURRENT POSITION AND MAIN
      POINTS: At metastatic stage, interferon alpha has no adverse indication when used
      alone. However, studies are on going to assess its potential synergistic effect
      combined with chemotherapy and its interest for maintaining clinical response.
      Beta and gamma interferon have no adverse indication in the treaTment of
      malignant melanoma. PERSPECTIVE: Although its action has been mainly demonstrated
      on relapse free survival, and the impact on quality of life remains important,
      additional new studies will be required to confirm its interest as adjuvant
      therapy for melanoma. In addition, the future use of pegylated interferon which
      would permit a reduction in the number of injections is of a significant
      interest.

PMID- 12481405
TI  - [Interferons and Behcet's disease].
AB  - BACKGROUND: Behcet's disease is a vasculitis of unknown origin. Various
      therapeutic agents have been proposed. Interferon alpha 2a or 2b appear to be the
      most promising. CURRENT KNOWLEDGE AND KEY POINTS: Numerous anecdotal reports and
      some short series have shown the efficacy of interferon in some cases previously
      resistant to conventional therapy, particularly to immunosuppressors. Posology,
      depending on the author, may vary from three million three times a week to 18
      million three times a week. Interferon alpha is useful in cases of ocular, muco
      cutaneous and articular involvement. Data is lacking for digestive, vascular and
      neurological manifestations. FUTURE PROSPECTS AND PROJECTS: Multicenter trials
      will nevertheless be required to determine the duration of therapy, risk of
      relapses, associated therapy and the optimal time to commence interferon
      treatment.

PMID- 12481406
TI  - [Interferon-alpha and auto-immunity].
AB  - PURPOSE: To assess the role of endogenous interferon alpha (IFN) in auto-immune
      experimental models and human diseases, and to evaluate its iatrogenic potential
      as a therapeutic agent. MAIN POINTS: IFN is a cytokine involved in cellular
      immunity, that promotes both differentiation of dendritic cells and the TH1
      pathway. Auto-immune side-effects of recombinant IFN depend on IFN dosage and the
      pathology concerned. The spectrum extends from occurrence of auto-antibodies in
      an asymptomatic patient to overt disease such as systemic lupus. Antigenic
      targets of auto-antibodies are diverse: blood cells coagulation factors,
      immunoglobulin, hormones, intrinsic factor, intracellular components. Thyroiditis
      is the most frequently reported auto-immune disease occurring during IFN
      treatment, including hypothyroidism, hyperthyroidism or a bi-phasic pattern.
      Currently, true incidence of thyroiditis remains debated. It appears very low
      (under 1%) in hepatologic series using low-dose IFN. The fact that auto-immunity
      may be related to the treated disease--before use of IFN--must also be addressed:
      e.g. antinuclear factors and anti-DNA antibodies in chronic myeloid leukemia or
      anti-actin and anti-LKM antibodies in chronic C hepatitis. FUTURE PROSPECTS:
      Recombinant alpha interferon appears more as a trigger than a de novo inducer of
      auto-immune disorders. Its use as an immunomodulator agent should be treated with
      caution.

PMID- 12481407
TI  - [Do the interferons have an antifibrotic action? The internist's point of view].
AB  - PURPOSE: The antifibrotic action of interferon alpha on the liver is now
      established in hepatitis C (cf. article by T. Poynard). Numerous in vitro
      experimental evidences may lead people into believing in the efficacy of
      interferon gamma in patients with mucous membrane and pulmonary fibrosis. CURRENT
      KNOWLEDGE AND KEY POINTS: A randomized study has confirmed the efficacy of
      interferon gamma in the idiopathic pulmonary fibrosis, probably by an anti TGF
      beta action. Several open studies have shown the efficacy of interferon gamma in
      patients with post-radiation cutaneous fibrosis (Chernobyl survivors, sequelae of
      radiotherapy for cancer). In systemic sclerosis, several teams have shown that
      interferon gamma reduced collagen synthesis by sclerodermic fibroblasts in vitro.
      Four open studies have also confirmed the efficacy of interferon gamma in
      systemic sclerosis. In our experience concerning 20 patients with diffuse
      systemic sclerosis, the five years survival with long term therapy was 85% and we
      observed an improvement in the cutaneous suppleness in 40% of these cases. There
      was no serious side effect. FUTURE PROSPECTS AND PROJECTS: These encouraging
      results need to be confirmed by large randomized studies in pulmonary fibrosis
      and systemic sclerosis. Other indications should be assessed, particularly extra
      cutaneous radiation sequelae and in systemic fibrosis (retroperitoneal,
      mediastinal and cervical).

PMID- 12481408
TI  - [Do the interferons have an antifibrotic action? The hepatologist's point of
      view].
AB  - INTRODUCTION: Major progress in the treatment of hepatitis C has been achieved in
      the last ten years with an obvious histologic impact. The last approved regimen
      combines ribavirin (10.6 mg per kg) with pegylated interferon (1.5 microgram per
      kg) which permits to obtain improvement of necrosis and inflammation in 73% of
      patients with only 8% of fibrosis worsening. CURRENT KNOWLEDGE AND KEYS POINTS:
      Reversibility of post hepatitis C cirrhosis is now well documented. However, this
      reversibility has been observed mainly in young cirrhotic patients, particularly
      in those with sustained virologic response. For older patients with decompensated
      cirrhosis the reversibility has not been established. Interferon alpha directly
      or indirectly is indeed an effective anti-fibrotic agent in chronic hepatitis C.
      The indirect anti-fibrotic effect through the antiviral effect has been
      considerably improved by the pegylation and the association with ribavirin.

PMID- 12481409
TI  - The antisignaling agent SC-alpha alpha delta 9, 4-(benzyl-(2-[(2,5
      diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)- 2-decanoylaminobutyric acid,
      is a structurally unique phospholipid analogue with phospholipase C inhibitory
      activity.
AB  - Phospholipids and lipid second messengers mediate mitogenic signal transduction
      and oncogenesis, but there have been few successful examples of small molecules
      that affect biologically important phospholipid metabolism. Here we investigated
      the actions of a previously described antitumor agent, 4-(benzyl-(2-[(2,5
      diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)- 2-decanoylaminobutyric acid
      (SC-alpha alpha delta 9), which has antisignaling properties, on phospholipases.
      Although SC-alpha alpha delta 9 had been shown to be a potent and selective
      inhibitor of the Cdc25 family of dual-specificity phosphatases, many of its
      cellular effects are not readily reconciled with phosphatase inhibition.
      Molecular modeling studies suggested that SC-alpha alpha delta 9 shared several
      structural features with membrane phospholipids. Enzyme inhibition studies in
      vitro revealed that SC-alpha alpha delta 9 was a potent inhibitor of
      phospholipase C (PLC; IC50 = 25 microM) but did not inhibit phospholipase D
      activity at concentrations up to 100 microM. In H-ras (Q61L)-transformed Rat-1
      fibroblasts with constitutively elevated levels of phosphorylated extracellular
      signal-regulated kinase (Erk), SC-alpha alpha delta 9 inhibited both
      proliferation and oncogenic Erk activation at concentrations that inhibited PLC
      in vitro. A SC-alpha alpha delta 9 congener that lacked antiproliferative
      activity also did not inhibit PLC in vitro. In the PLC-dependent scratch wound
      healing model, SC-alpha alpha delta 9 was 10-fold more potent than the
      phosphatidylcholine-specific PLC inhibitor D-609. We propose that the structural
      resemblance of SC-alpha alpha delta 9 to phospholipids allows it to inhibit
      cellular PLC, thereby providing a possible molecular mechanism for SC-alpha alpha
      delta 9's effects on oncogenic Erk activation.

PMID- 12481410
TI  - Combination therapy with AG-490 and interleukin 12 achieves greater antitumor
      effects than either agent alone.
AB  - Constitutive activation of Janus kinases (JAKs) and signal transducers and
      activators of transcription (STAT) occurs at very high frequency in various
      hematopoietic malignancies and solid tumors. It has been demonstrated that the
      tyrosine kinase inhibitor, AG-490, selectively blocks JAK activity and completely
      eliminates leukemia cells in a severe combined immunodeficient (SCID) mouse
      model. Because many cytokines, including interleukin (IL)-12, have been shown to
      signal through JAK/STAT pathways, AG-490 may inhibit cytokine-based cancer
      therapy. In this study, we evaluated the effects of AG-490 on IL-12 functional
      signaling and IL-12-mediated antitumor response in vivo. Previous studies have
      established the critical roles of macrophages and IFN-gamma in mediating IL-12
      induced antitumor effects. Our results show that in vivo administration of AG-490
      causes tumor cell apoptosis but does not inhibit IL-12-mediated macrophage
      activation and IFN-gamma production by lymphocytes. Furthermore, our data
      indicate that combined therapy with AG-490 and IL-12-induces greater antitumor
      effects than either agent alone in a murine myeloma tumor model. These results
      suggest that JAK/STAT inhibitors deserve further investigation for use with IL-12
      therapy in treating human cancers with elevated JAK/STAT activity.

PMID- 12481411
TI  - Design, synthesis, and biological evaluation of a dual tumor-specific motive
      containing integrin-targeted plasmin-cleavable doxorubicin prodrug.
AB  - The design, synthesis, and initial biological evaluation of a doxorubicin prodrug
      that contains a dual tumor specific moiety, which allows enhanced tumor
      recognition potential, is reported. Both a tumor-specific recognition site and a
      tumor selective enzymatic activation sequence are incorporated in the prodrug.
      The first tumor-specific sequence is the bicyclic CDCRGDCFC (RGD-4C) peptide that
      selectively binds alpha v beta 3 and alpha v beta 5 integrins. These integrins
      are highly overexpressed on invading tumor endothelial cells. The second tumor
      specific sequence is a D-Ala-Phe-Lys tripeptide that is selectively recognized by
      the tumor-associated protease plasmin, which is involved in tumor invasion and
      metastasis. An aminocaproyl residue was incorporated as a spacer between the two
      peptide sequences, whereas a self-eliminating 4-aminobenzyl alcohol spacer was
      inserted between the plasmin substrate and doxorubicin. Although the prodrug
      showed a decreased binding affinity as compared with the unconjugated reference
      peptide, it was still a potent ligand for alpha v beta 3 and alpha v beta 5
      integrin receptors. The synthesized construct also possessed plasmin substrate
      properties as demonstrated by doxorubicin release from 1 upon incubation with
      plasmin. The release of doxorubicin from 1 was not complete, possibly related to
      low prodrug solubility. In vitro prodrug 1 showed plasmin-dependent cytotoxicity
      for endothelial cells and HT1080 fibrosarcoma cells. On the basis of these in
      vitro results, derivatives of 1 with improved water solubility are considered
      good candidates for additional development and in vivo evaluation of this dual
      targeting concept.

PMID- 12481412
TI  - Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes
      apoptosis, and enhances sensitivity of small cell lung cancer cells to
      chemotherapy.
AB  - A promising therapeutic alternative to inhibition of growth factor receptors is
      the inhibition of downstream signal transduction pathways. Such an approach may
      be especially important in tumors that can use signals from multiple growth
      factor receptors for growth and survival. Both stem cell factor (SCF) and insulin
      like growth factor (IGF)-I, components of prominent small cell lung cancer (SCLC)
      autocrine loops, as well as FCS, can potently activate phosphatidylinositol 3
      kinase (PI3K)-Akt signaling, albeit with different kinetics. SCF-induced PI3K-Akt
      activation occurs rapidly but fades within 60 min; IGF-I and FCS-induced
      activation persists for at least 6 h. SCF and IGF-I-mediated growth was potently
      inhibited by LY294002 in proportion to its ability to inhibit
      phosphatidylinositol 3-kinase (PI3K)-Akt signaling. A panel of six SCLC cell
      lines grown in 10% FCS was also very sensitive to LY294002, with average IC50 and
      LD50 of 5 and 25 microM, respectively. These drug concentrations suppressed the
      growth of the MRC-5 pulmonary fibroblast cell line and primary bronchial
      epithelial cells but did not induce significant cell death. Because LY294002 can
      also inhibit PI3K-related enzymes, we confirmed the role of the PI3K-Akt pathway
      in SCLC using doxycycline-regulated expression of a dominant-negative (kinase
      dead) and a constitutively active (CA; myristolated) Akt allele. Expression of
      dominant-negative Akt, which could only be achieved at relatively low levels,
      completely inhibited growth in the absence of exogenous growth factors and
      inhibited SCF-mediated growth but had no effect on IGF-I-mediated growth at the
      expression levels attained. Expression of CA Akt markedly augmented growth in the
      absence of exogenous growth factors but had minimal effect on growth in the
      presence of saturating concentrations SCF or IGF-I. Because PI3K-Akt signaling is
      known to promote survival under apoptotic stresses, we determined the effect of
      this pathway on SCLC sensitivity to etoposide. LY294002 potentiated the effect of
      low concentrations of etoposide in inhibiting growth and inducing apoptosis. The
      effect of low concentrations of LY294002 could largely be reversed by expression
      of CA Akt, suggesting that it was mediated by inhibition of Akt signaling.
      Expression of CA Akt by itself also induced resistance to etoposide-mediated
      apoptosis. Taken together, these data demonstrate that PI3K-Akt signaling
      promotes SCLC growth, survival, and chemotherapy resistance. Therefore, selective
      inhibitors of PI3K or Akt could potentially be useful as novel therapeutic agents
      in the treatment of SCLC.

PMID- 12481413
TI  - Transmission of apoptosis in human colorectal tumor cells exposed to
      capecitabine, Xeloda, is mediated via Fas.
AB  - We developed an original in vitro model dedicated to the exploration of molecular
      pharmacology of the new oral fluoropyrimidine capecitabine (Xeloda). More
      specifically, in this report, we investigated whether apoptosis induced by
      capecitabine was mediated by the Fas/FasL system. To achieve this goal, a
      specific in vitro coculture model mixing hepatoma and human colorectal cell line
      was used. A bystander effect was observed between HepG2 and LS174T cells treated
      with capecitabine. Besides this, Xeloda showed a 7-fold higher cytotoxicity and
      markedly stronger apoptotic potential in thymidine phosphorylase (TP)-transfected
      LS174T-c2 cells. The striking enhancement of thymidylate synthase inhibition that
      we observed in cells with high TP activity was most probably at the origin of the
      potentiation of capecitabine antiproliferative efficacy. In addition, this
      increase of sensitivity was accompanied by a strong overexpression of the CD95
      Fas receptor on the cell surface. Both Fas and FasL mRNA expression were
      triggered after exposing TP+ cells to the drug. This implication of Fas in Xeloda
      induced apoptosis was next confirmed by using antagonistic anti-Fas and anti-FasL
      antibodies that proved to reverse capecitabine antiproliferative activity, thus
      highlighting the key role that Fas could play in the optimization of an antitumor
      response to fluoropyrimidine drugs. Our data, therefore, show that TP plays a key
      role in the capecitabine activity and that the Fas/FasL system could be
      considered as a new determinant for Xeloda efficacy.

PMID- 12481414
TI  - Lipoxygenase inhibitors attenuate growth of human pancreatic cancer xenografts
      and induce apoptosis through the mitochondrial pathway.
AB  - Several studies have suggested that high dietary fat intake, particularly
      essential fatty acids, is associated with pancreatic cancer development and
      growth. Our previous studies have demonstrated that blockade of either the 5
      lipoxygenase (LOX) or 12-LOX pathway of arachidonic acid metabolism inhibited
      pancreatic cancer cell proliferation and induced apoptosis. This study
      investigated the underlying mechanisms for LOX inhibitor-induced apoptosis and
      the potential of LOX inhibitors as antipancreatic cancer agents using the athymic
      mice xenograft model. Apoptosis of pancreatic cancer cells induced by LOX
      inhibitors (including the nonselective LOX inhibitor nordihydroguaiaretic acid,
      the 5-LOX inhibitor Rev-5901, and the 12-LOX inhibitor baicalein) was confirmed
      by growth inhibition, annexin V binding, and terminal deoxynucleotidyl
      transferase-mediated nick end labeling assay in MiaPaCa-2 and AsPC-1 human
      pancreatic cancer cells. Expression of the antiapoptotic proteins Bcl-2 and Mcl-1
      was significantly decreased after LOX inhibitor treatment while that of the
      proapoptotic protein bax was increased. LOX inhibitors also markedly induced the
      release of cytochrome c from mitochondria into the cytosol. Caspase-9, caspase-7,
      and caspase-3 but not caspase-8 were activated after treatment, concomitant with
      cleavage of the capase-3 substrate poly(ADP-ribose) polymerase. In vivo studies
      in the athymic mice xenograft model also confirmed the growth inhibitory effect
      and induction of apoptosis by these LOX inhibitors in pancreatic cancer. In
      conclusion, LOX inhibitors block pancreatic cancer cell proliferation and induce
      apoptosis through the mitochondrial pathway both in vivo and in vitro. LOX
      inhibitors are likely to be valuable for the treatment of human pancreatic
      cancer.

PMID- 12481415
TI  - Histone deacetylase inhibitors all induce p21 but differentially cause tubulin
      acetylation, mitotic arrest, and cytotoxicity.
AB  - By preventing deacetylation of histones, histone deacetylase inhibitors (HDIs)
      transcriptionally induce p21. Here we show that the HDIs sodium butyrate (Bu),
      trichostatin A (TSA) and depsipeptide (FR901228) all induced p21, but only TSA
      and FR901228 caused mitotic arrest (in addition to arrest in G1 and G2). The
      ability to cause mitotic arrest correlated with the higher cytotoxicity of these
      compounds. Although causing mitotic arrest, TSA and FR901228 (unlike paclitaxel)
      did not affect tubulin polymerization. Unlike FR9012208, TSA caused acetylation
      of tubulin at lysine 40; both soluble tubulin and microtubules were acetylated.
      Whereas the induction of p21 reached a maximum by 8 h, tubulin was maximally
      acetylated after only 1 h of TSA treatment. Tubulin acetylation was detectable
      after treatment with 12-25 ng/ml TSA although acetylation plateaued at 50 ng/ml
      TSA, coinciding with G2-M arrest, appearance of cells with a sub-2N DNA content,
      poly(ADP-ribose) polymerase cleavage, and rapid cell death. We conclude that HDIs
      have differential effects on non-histone deacetylases and that rapid acetylation
      of tubulin caused by TSA is a marker of nontranscriptional effects of TSA.

PMID- 12481416
TI  - O6-benzylguanine-mediated enhancement of chemotherapy.
AB  - We have previously demonstrated (A. E. Pegg, Cancer Res., 50: 6119-6129, 1990)
      that O6-benzylguanine (O6-BG) enhances nitrosourea, temozolomide, and
      cyclophosphamide activity in malignant glioma xenografts growing in athymic nude
      mice. More recently, we have demonstrated (V. J. Patel et al., Clin. Cancer Res.,
      6: 4154-4157, 2000; P. Pourquier et al., Cancer Res., 61: 53-58, 2001) that the
      combination of temozolomide plus irinotecan (CPT-11) displays a schedule
      dependent enhancement of antitumor activity secondary to trapping of
      topoisomerase I by O6-methylguanine residues in DNA. These studies suggested that
      there might be favorable therapeutic interactions between O6-BG and combinations
      of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus cyclophosphamide or
      temozolomide plus CPT-11, respectively. Our present results indicate that the
      combination of cyclophosphamide plus BCNU plus O6-BG produces growth delays
      modestly-to-markedly-superior to combinations of cyclophosphamide with BCNU.
      Although the combination of temozolomide and CPT-11 reveals a marked increase in
      activity compared with either agent used alone, the addition of O6-BG to this
      combination dramatically increased the growth delay of the O6-alkylguanine-DNA
      alkyltransferase (AGT)-positive malignant glioma D-456 MG. These results suggest
      that a Phase I trial of CPT-11 plus temozolomide plus O6-BG in AGT-positive
      tumors may be an important intervention to maximize the therapeutic benefits of
      the combination of CPT-11 and temozolomide.

PMID- 12481417
TI  - Intratumoral injection of interleukin-12 plasmid DNA, either naked or in complex
      with cationic lipid, results in similar tumor regression in a murine model.
AB  - Effective eradication of established tumors and generation of a lasting systemic
      immune response is an important goal for cancer gene immunotherapy. The method of
      gene delivery may also be critical for the generation of an effective antitumor
      response. We compared the level of transgene expression and antitumor activity of
      two different interleukin (IL)-12 DNA preparations (naked DNA versus DNA lipid
      complex). Established murine adenocarcinoma (CT26) and renal cell carcinoma
      (Renca) tumors in BALB/c mice were treated by direct intratumoral injection of a
      nonviral plasmid DNA vector encoding the murine IL-12 (mIL-12) gene, either alone
      (naked) or in complexes with cationic lipid. Both treatments resulted in the same
      percentage (87%) of mice undergoing a complete tumor regression of the CT26
      tumor. For the Renca tumor model, complete tumor regression was observed in 67
      and 75% of animals treated with naked mIL-12 DNA and mIL-12 DNA plus lipid,
      respectively. Mice that were rendered tumor free for > 50 days by mIL-12 gene
      therapy rejected a subsequent challenge of parental tumor cells but not of an
      unrelated, syngeneic tumor. The marked reduction of tumor growth in tumor-bearing
      mice treated with mIL-12 cDNA was associated with the augmentation of tumor
      specific cytotoxic T cells, enhanced production of IFN-gamma in spleen and lymph
      node cells, and increased splenomegaly and lymphadenopathy. The CD8+: CD4+ ratio
      in tumor-infiltrating lymphocytes was significantly increased in the tumor
      bearing mice treated with mIL-12 DNA alone and mIL-12 cDNA plus lipid as compared
      with a control vector-treated group. These results indicate that direct
      intratumoral gene transfer with naked nonviral IL-12 DNA provides an effective
      and simple method for the treatment of murine tumors, suggesting an approach for
      clinical application.

PMID- 12481419
TI  - Translation initiation in cancer: a novel target for therapy.
AB  - Translation initiation is regulated in response to nutrient availability and
      mitogenic stimulation and is coupled with cell cycle progression and cell growth.
      Several alterations in translational control occur in cancer. Variant mRNA
      sequences can alter the translational efficiency of individual mRNA molecules,
      which in turn play a role in cancer biology. Changes in the expression or
      availability of components of the translational machinery and in the activation
      of translation through signal transduction pathways can lead to more global
      changes, such as an increase in the overall rate of protein synthesis and
      translational activation of the mRNA molecules involved in cell growth and
      proliferation. We review the basic principles of translational control, the
      alterations encountered in cancer, and selected therapies targeting translation
      initiation to help elucidate new therapeutic avenues.

PMID- 12481418
TI  - Cancer chemopreventive activity of Xanthohumol, a natural product derived from
      hop.
AB  - Characterization and use of effective cancer chemopreventive agents have become
      important issues in public health-related research. Aiming to identify novel
      potential chemopreventive agents, we have established an interrelated series of
      bioassay systems targeting molecular mechanisms relevant for the prevention of
      tumor development. We report anticarcinogenic properties of Xanthohumol (XN), a
      prenylated chalcone from hop (Humulus Iupulus L.) with an exceptional broad
      spectrum of inhibitory mechanisms at the initiation, promotion, and progression
      stage of carcinogenesis. Consistent with anti-initiating potential, XN potently
      modulates the activity of enzymes involved in carcinogen metabolism and
      detoxification. Moreover, XN is able to scavenge reactive oxygen species,
      including hydroxyl- and peroxyl radicals, and to inhibit superoxide anion radical
      and nitric oxide production. As potential antitumor-promoting mechanisms, it
      demonstrates anti-inflammatory properties by inhibition of cyclooxygenase-1 and
      cyclooxygenase-2 activity and is antiestrogenic without possessing intrinsic
      estrogenic potential. Antiproliferative mechanisms of XN to prevent
      carcinogenesis in the progression phase include inhibition of DNA synthesis and
      induction of cell cycle arrest in S phase, apoptosis, and cell differentiation.
      Importantly, XN at nanomolar concentrations prevents carcinogen-induced
      preneoplastic lesions in mouse mammary gland organ culture. Because XN is easily
      cyclized to the flavanone isoxanthohumol, activities of both compounds were
      compared throughout the study. Together, our data provide evidence for the
      potential application of XN as a novel, readily available chemopreventive agent,
      and clinical investigations are warranted once efficacy and safety in animal
      models have been established.

PMID- 12481420
TI  - The apoptotic effect of HA14-1, a Bcl-2-interacting small molecular compound,
      requires Bax translocation and is enhanced by PK11195.
AB  - HA14-1 is a small molecular compound that was identified based on the structure
      of Bcl-2. HA14-1 interacts with Bcl-2 and inhibits the antiapoptotic effect of
      Bcl-2. We investigated the mechanism of HA14-1-induced apoptosis and found that
      HA14-1 induces translocation of Bax from cytosols to the mitochondria. Cells
      deficient in Bax were much more resistant to HA14-1-induced apoptosis, suggesting
      that Bax is required for this process. A pan-caspase inhibitor failed to inhibit
      the apoptotic effect of HA14-1, indicating that this is through a caspase
      independent pathway. To eliminate the effect of cytosolic Bax, we incubated cell
      free mitochondria with HA14-1 to study its effect on cytochrome c release. HA14-1
      was ineffective in causing cytochrome c release from the purified mitochondria.
      However, the combination of HA14-1 and PK11195, an antagonist of peripheral
      benzodiazepine receptor of the mitochondria, enhanced the cytochrome c release by
      HA14-1. The combination of PK11195 and HA14-1 could therefore serve as a
      potentially useful approach to enhance apoptosis in cancer.

PMID- 12481421
TI  - Inhibition of the phosphatidylinositol 3'-kinase-AKT pathway induces apoptosis in
      pancreatic carcinoma cells in vitro and in vivo.
AB  - The phosphatidylinositol 3'-kinase (PI3k)-AKT survival pathway is activated in
      many malignancies. We observed constitutive AKT phosphorylation (on S473)
      consistent with pathway activation in seven of nine human pancreatic carcinoma
      cell lines in vitro. Exposure of the cells to two structurally distinct
      inhibitors of PI3k (worthmannin and LY294002) resulted in a dose-dependent
      induction of apoptosis in six of seven of the cell lines that displayed
      constitutive AKT phosphorylation but not in either of the cell lines that did
      not. The mitogen-activated protein/extracellular signal-regulated kinase kinase
      mitogen-activated protein kinase inhibitor PD98059 also induced apoptosis in two
      of the cell lines, including one of the LY294002-insensitive lines (AsPC-1).
      Exposure of orthotopic L3.6pl pancreatic tumors to LY294002 resulted in dose
      dependent inhibition of tumor growth, and decreased peritoneal and liver
      metastases, effects that were associated with an inhibition of AKT
      phosphorylation and increased terminal deoxynucleotidyl transferase-mediated nick
      end labeling staining characteristic of apoptosis. Furthermore, a suboptimal dose
      of LY294002 (25 mg/kg) produced additive inhibition of tumor growth when combined
      with a suboptimal dose of gemcitabine (62 mg/kg). Together, our results establish
      that the PI3k/AKT pathway is constitutively activated in a majority of human
      pancreatic cancer cell lines and establish that the pathway is a promising target
      for therapeutic intervention.

PMID- 12481422
TI  - Intratumor administration of interleukin 13 receptor-targeted cytotoxin induces
      apoptotic cell death in human malignant glioma tumor xenografts.
AB  - Apoptosis is not only essential for homeostasis in normal cells but also in
      cancer cells, in which it is associated with cell death mechanisms caused by
      novel therapeutics. We have previously reported that interleukin-13 receptors (IL
      13R) are constitutively overexpressed on a majority of human malignant glioma
      cell lines and primary cell cultures. In addition, we have reported that IL-13
      cytotoxin, comprised of human IL-13 and a mutated form of Pseudomonas exotoxin,
      is highly and specifically cytotoxic to these cells and can lead to pronounced
      antitumor activity in malignant glioma tumors in animal models. However, the
      molecular mechanisms of tumor cytotoxicity induced by IL-13 cytotoxin are poorly
      understood. In this study, we demonstrate that glioma tumors undergo apoptotic
      cell death on intratumoral administration of IL-13 cytotoxin. This conclusion was
      made based on (a) time-dependent induction of several proapoptotic molecules,
      such as caspases (caspase-3, -8, and -9) in tumors; (b) cleavage of procaspase-3
      and poly(ADP-ribose) polymerase (PARP); and (c) the release of cytochrome c from
      mitochondria to the cytosol on injection of IL-13 cytotoxin in U251 glioblastoma
      tumors established in immunodeficient animals. These indicators of two major
      pathways of apoptosis were detected in tumors even though IL-13 cytotoxin was no
      longer present in tumors. In addition, we found that inducible nitric oxide was
      expressed in tumors in a time-dependent manner with primary localization in
      infiltrating phagocytes after treatment with IL-13 cytotoxin. These studies
      demonstrate that IL-13 cytotoxin mediates apoptotic death of glioma cells,
      resulting in regression of established tumors. Our studies will help unravel the
      molecular pathways of cell death associated with tumor regression and provide
      additional insight and define apoptosis as possible surrogate marker of tumor
      response.

PMID- 12481423
TI  - A novel mechanism by which N-(4-hydroxyphenyl)retinamide inhibits breast cancer
      cell growth: the production of nitric oxide.
AB  - N-(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells;
      however, the molecular basis by which 4-HPR induces apoptosis is not well
      understood. In breast cancer cells, nitric oxide (NO) is predominantly an
      apoptotic inducer. Apoptotic agents, such as phorbol ester, tumor necrosis factor
      alpha, and peptide hormones, have been shown to increase NO production in breast
      cancer cells. Therefore, we hypothesized that the production of No is vital for 4
      HPR to induce apoptosis in breast cancer cells. We found that 4-HPR induced NO
      production in a dose-dependent manner in all of the breast cancer cell lines
      tested. The degree of growth inhibition and apoptotic induction by 4-HPR was
      directly correlated with the amount of NO produced. To prove that NO is essential
      for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a
      competitive NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), and 4
      HPR, L-NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO
      is crucial for 4-HPR to induce its apoptotic effects in breast cancer cells. IFNs
      and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer
      cells. Both IFN-gamma and TAM enhanced the ability of 4-HPR to induce NO
      production in breast cancer cells, which was correlated with increased apoptosis.
      Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial
      NOS (NOSIII). When combined with 4-HPR, IFN-gamma and TAM enhanced NOSII
      expression. Thus, we have identified a novel mechanism by which 4-HPR induces
      apoptosis in breast cancer cells, i.e., by increasing NOS expression to induce NO
      production.

PMID- 12481424
TI  - Glycoinositol phospholipid-anchored interleukin 2 but not secreted interleukin 2
      inhibits melanoma tumor growth in mice.
AB  - Whereas cancer immunotherapy with interleukin (IL) 2 and/or other cytokines has
      proved effective in activating immune responses against tumor cells, the major
      obstacle with the use of these cytokines in cancer patients is their severe side
      effects when delivered systemically at high doses. In an effort to overcome this
      problem, in the present study, a fusion protein containing human IL-2 and a
      glycoinositol phospholipid (GPI) anchor sequence of decay accelerating factor was
      generated. When expressed by transfected cells, these fusion proteins were
      presented on the cell surface in the GPI-anchored form as demonstrated by
      fluorescence-activated cell sorter and ELISA analyses. This GPI-anchored IL-2 is
      highly functional as indicated by significantly increased T-cell infiltration in
      tumor masses. Immunohistochemical analysis of tumor cells isolated from
      experimental tumors indicated that a local high level of IL-2 was achieved by GPI
      anchored IL-2. More importantly, when injected into mice i.v., the growth of
      these B16F0 melanoma cells that were engineered to express this fusion protein
      was significantly inhibited. In contrast, the inhibition of secreted IL-2 on
      tumor growth was not observable in this study. These studies may provide a novel
      approach to locally deliver high doses of cytokines for cancer immunotherapy.

PMID- 12481425
TI  - Cell proliferation in the normal mouse mammary gland and inhibition by
      phenylbutyrate.
AB  - Ovarian hormones have a pivotal role in the control of proliferation in the
      mammary gland, and cumulative life-time exposure to ovarian hormones is known to
      be a determinant of breast cancer risk. We have shown previously that a p.o.
      active, long-acting butyrate analogue, sodium phenylbutyrate (PB), reduced
      proliferation in normal and malignant human breast cells in culture and reduced
      expression of ovarian hormone receptors, suggesting that PB had cellular effects
      consistent with decreasing breast cancer risk. The aim of this study was to
      determine the in vivo effects of PB in the normal mammary gland on epithelial
      cell proliferation, estrogen receptor alpha (ER alpha) expression, and cyclin D1
      expression. BALB/c mice were treated with PB, delivered by mini-osmotic pumps,
      for 7 days. Moderate (250 mg/kg/day) and high (500 mg/kg/day) PB treatment
      resulted in a decrease in proliferation in mammary epithelial cells (P < 0.001),
      determined by bromodeoxyuridine incorporation. Analysis of ER alpha
      immunostaining revealed a significant reduction in moderate- and high-treatment
      groups (P = 0.01 and P = 0.02), and expression of cyclin D1 was virtually ablated
      (P < 0.001). Histone deacetylase inhibition is a known mechanism of butyrate
      action, and consistent with this, PB increased levels of acetylated histone H3 in
      the mammary gland. In summary, PB decreased proliferation in the mammary gland in
      vivo at clinically achievable doses. Decreased proliferation was accompanied by
      changes in the levels of ER alpha and cyclin D1. These data show that PB
      modulates parameters thought to be involved in the carcinogenic process in the
      normal mammary gland, and compounds in this class may therefore be useful
      candidates for breast cancer chemoprevention.

PMID- 12481426
TI  - Prediction of chemosensitivity for patients with acute myeloid leukemia,
      according to expression levels of 28 genes selected by genome-wide complementary
      DNA microarray analysis.
AB  - To identify genes involved in the sensitivity of acute myeloid leukemia (AML)
      cells to chemotherapy, we monitored gene-expression profiles of cancer cells from
      76 AML patients using a cDNA microarray consisting of 23,040 genes. We identified
      63 genes that were commonly overexpressed and 372 genes suppressed in AML.
      Because these genes represent key molecules for disclosing the molecular
      mechanisms of AML, they may be potential targets for drug development. We also
      found 28 that revealed different expression levels between good and poor
      responders to chemotherapy and appeared to be associated with chemosensitivity.
      On that basis, we developed a "Drug Response Scoring" system that was correlated
      well with individual sensitivity to an anticancer drug regimen. Among the 44
      cases with positive drug-response scores by our definition, 40 achieved complete
      remission after treatment, whereas the only 3 of the 20 cases with negative
      scores responded well to the treatment. An ability to predict chemosensitivity
      should eventually lead to achievement of our goal of "personalized therapy."

PMID- 12481427
TI  - Development of p53 protein transduction therapy using membrane-permeable peptides
      and the application to oral cancer cells.
AB  - Recent studies suggest that several proteins can transverse biological membranes
      through protein transduction. The protein transduction domains of these proteins,
      10-16 residues long, have been identified as critical domains for the protein
      transduction. Poly-arginine peptide also has the ability of protein transduction.
      Here, we show that the protein delivery system using 11 poly-arginine peptides
      (11R) is a powerful tool for the transduction of the biologically active tumor
      suppressor protein, p53, to suppress the proliferation of oral cancer cells. The
      11R-fused p53 proteins (11R-p53) effectively penetrated across the plasma
      membrane of the cancer cells and translocated into the nucleus. The proteins
      induced the activity of the p21/WAF promoter and inhibited the proliferation of
      human oral cancer cells, in which the p53 gene was mutated. The effect was
      equivalent to that of the adenovirus-mediated p53 gene transduction system.
      Moreover, 11R-p53 enhanced the cisplatin-dependent induction of apoptosis of the
      cells. These data suggest that this protein transduction method may become a
      promising cancer therapy.

PMID- 12481428
TI  - X-linked inhibitor of apoptosis (XIAP) blocks Apo2 ligand/tumor necrosis factor
      related apoptosis-inducing ligand-mediated apoptosis of prostate cancer cells in
      the presence of mitochondrial activation: sensitization by overexpression of
      second mitochondria-derived activator of caspase/direct IAP-binding protein with
      low pl (Smac/DIABLO).
AB  - The resistance to Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis
      inducing ligand (TRAIL)-mediated apoptosis could be overcome by treatment with
      subtoxic concentrations of actinomycin D (Act D) in prostate tumor cells.
      Furthermore, the sensitization to Apo2L/TRAIL-mediated apoptosis by Act D
      positively correlated with selective down-regulation of X-linked inhibitor of
      apoptosis (XIAP). In this study, we examined whether second mitochondria-derived
      activator of caspase/direct inhibitor of apoptosis-binding protein with low pl
      (Smac/DIABLO), a known inhibitor of apoptosis (IAP)-neutralizing protein,
      sensitizes resistant prostate tumor cells to Apo2L/TRAIL-mediated apoptosis. The
      prostate tumor cell line CL-1 was treated with Apo2L/TRAIL, Act D, or a
      combination of the two. The apoptosis-mediated signaling pathway was examined by
      Western blotting and flow cytometry. Furthermore, CL-1 cells transfected with the
      anti-IAP inhibitor Smac/DIABLO were examined for sensitivity to Apo2L/TRAIL.
      Whereas Apo2L/TRAIL induced the release of cytochrome c and endogenous
      Smac/DIABLO in the CL-1 tumor cells, the cytosolic levels of both molecules were
      not sufficient to induce apoptosis. Transient transfectants with a Smac/DIABLO
      cDNA encoding a neutralizing inhibitor of IAPs were sensitized to Apo2L/TRAIL
      mediated apoptosis. The sensitization to Apo2L/TRAIL by Smac/DIABLO
      overexpression was a result of synergistic activation of caspases-3, -9, and -8.
      Treatment of the Smac/DIABLO transient transfectant with Apo2L/TRAIL enhanced the
      release of Smac/DIABLO from mitochondria and led to reduction of IAP family
      proteins (XIAP, c-IAP1, and c-IAP2). These results show that Smac/DIABLO can
      sensitize CL-1 tumor cells to Apo2L/TRAIL-mediated apoptosis. Thus, up-regulation
      of Smac/DIABLO and sensitization to Apo2L/TRAIL-mediated apoptosis are of
      potential clinical application in the immunotherapy of drug-/Apo2L/TRAIL
      resistant tumors.

PMID- 12481429
TI  - Distinct effects of methylseleninic acid versus selenite on apoptosis, cell
      cycle, and protein kinase pathways in DU145 human prostate cancer cells.
AB  - Selenium has been implicated as a promising chemopreventive agent for prostate
      cancer. Whereas the anticancer mechanisms have not been clearly defined, one
      hypothesis relates to selenium metabolites, especially the monomethyl selenium
      pool, generated under supranutritional selenium supplementation. To explore
      potential molecular targets for mediating the chemopreventive activity, we
      contrasted the effects of methylseleninic acid (MSeA), a novel precursor of
      methylselenol, versus sodium selenite, a representative of the hydrogen selenide
      metabolite pool, on apoptosis execution, cell cycle distribution, and selected
      protein kinases in DU145 human prostate cancer cells. Exposure of DU145 cells to
      3 microM MSeA led to a profound G1 arrest at 24 h, and exposure to greater
      concentrations led to not only G1 arrest, but also to DNA fragmentation and
      caspase-mediated cleavage of poly(ADP-ribose) polymerase (PARP), two biochemical
      hallmarks of apoptosis. Immunobiot analyses indicated that G1 arrest induced by
      the subapoptogenic doses of MSeA was associated with increased expression of
      p27kip1 and p21cip1, but apoptosis was accompanied by dose-dependent decreases of
      phosphorylation of protein kinase AKT and extracellular signal-regulated kinase
      (ERK1/2) in the absence of any phosphorylation change in p38 mitogen-activated
      protein kinase (p38MAPK) and c-Jun NH2-terminal kinase (JNK1/2). In contrast,
      selenite exposure caused S-phase arrest and caspase-independent apoptotic DNA
      fragmentation, which were associated with decreased expression of p27kip1 and
      p21cip1 and increased phosphorylation of AKT, JNK1/2, and p38MAPK. Although
      apoptosis induction by MSeA exposure was not sensitive to superoxide dismutase
      added into the cell culture medium, cell detachment and DNA nucleosomal
      fragmentation induced by selenite exposure were greatly attenuated by this
      enzyme, supporting a chemical mediator role of superoxide for these processes.
      Despite a temporal relationship of AKT and ERK1/2 de-phosphorylation changes
      before the onset of PARP cleavage in MSeA-exposed cells, experiments with
      phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 did not show an
      enhancing effect of specific blocking of AKT on MSeA-induction of PARP cleavage.
      Taken together, exposure of DU145 cells to MSeA versus selenite induced
      differential patterns of cell cycle arrest and apoptosis execution as well as
      distinct patterns of effects on AKT, ERK1/2, JNK1/2, and p38MAPK phosphorylation
      and p27kip1 and p21cip1 expression. Multiple molecular pathways are likely
      differentially targeted by selenium metabolite pools to mediate cancer
      chemoprevention.

PMID- 12481430
TI  - A novel indolocarbazole, ICP-1, abrogates DNA damage-induced cell cycle arrest
      and enhances cytotoxicity: similarities and differences to the cell cycle
      checkpoint abrogator UCN-01.
AB  - DNA damaging agents such as cisplatin arrest cell cycle progression at either G1,
      S, or G2 phase, although the G1 arrest is only seen in cells expressing the wild
      type p53 tumor suppressor protein. We have reported that 7-hydroxystaurosporine
      (UCN-01) overcomes S and G2 phase arrest and enhances the cytotoxicity of
      cisplatin. Abrogation of arrest appears to be selective for cells defective in
      p53 and therefore provides a potential, tumor-targeted therapy. Unfortunately,
      UCN-01 binds avidly to human plasma proteins, limiting access to the tumor. A
      screen of related indolocarbazoles identified analogues with both beneficial and
      undesirable properties. This led to a synthetic program to develop a novel
      analogue rationally designed to overcome the obstacles observed with the other
      analogues. We report the synthesis and analysis of a novel analogue, ICP-1. This
      analogue abrogated S and G2 phase arrest and enhanced cytotoxicity induced by
      cisplatin only in p53 defective cells. ICP-1 also abrogated arrest and enhanced
      cell killing induced by the topoisomerase I inhibitor SN38. Analysis of proteins
      that regulate cell cycle arrest suggest both drugs inhibit checkpoint kinases
      Chk1 and/or Chk2. In contrast to UCN-01, checkpoint abrogation by ICP-1 was only
      slightly inhibited by human plasma. UCN-01 and ICP-1 differed significantly in
      other regards. UCN-01 potently enhanced the activity of 1-beta-D
      arabinofuranosylcytosine in both p53 wild-type and mutant cells, whereas ICP-1
      was inactive in this combination. This property of UCN-01 was independent of its
      ability to inhibit protein kinase C because more specific inhibitors of protein
      kinase C failed to enhance cell killing induced by 1-beta-D
      arabinofuranosylcytosine. High concentrations of UCN-01 also inhibit C-TAK1 that
      results in S phase-arrested cells directly entering mitosis, but this property
      was not observed with ICP-1. Hence, ICP-1 appears to be a more selective
      inhibitor of the S and G2 cell cycle checkpoint than previously studied analogues
      and is worthy of study in preclinical tumor models.

PMID- 12481431
TI  - Selenium compounds inhibit I kappa B kinase (IKK) and nuclear factor-kappa B (NF
      kappa B) in prostate cancer cells.
AB  - Selenium compounds are potential chemopreventive agents for prostate cancer.
      There are several proposed mechanisms for their anticancer effect, including
      enhanced apoptosis of transformed cells. Because the transcription factor nuclear
      factor-kappa B (NF-kappa B) is often constitutively activated in tumors and is a
      key antiapoptotic factor in mammalian cells, we tested whether selenium inhibited
      NF-kappa B activity in prostate cancer cells. In our work, we used sodium
      selenite and a novel synthetic compound, methylseleninic acid (MSeA), that served
      as a precursor of the putative active monomethyl metabolite methylselenol. We
      found that both selenium forms inhibited cell growth and induced apoptosis in
      DU145 and JCA1 prostate carcinoma cells. Sodium selenite and MeSeA, at the
      concentrations that induced apoptosis, inhibited NF-kappa B DNA binding induced
      by tumor necrosis factor-alpha and lipopolysaccharide in DU145 and JCA1 prostate
      cells. Both compounds also inhibited kappa B. Luciferase reporter activity in
      prostate cells. A key to NF-kappa B regulation is the inhibitory kappa B (I kappa
      B) proteins that in response to diverse stimuli are rapidly phosphorylated by I
      kappa B kinase complex, ubiquitinated, and undergo degradation, releasing NF
      kappa B factor. We showed that sodium selenite and MSeA inhibited I kappa B
      kinase activation and I kappa B-alpha phosphorylation and degradation induced by
      TNF-alpha and lipopolysaccharide in prostate cells. NF-kappa B blockage by I
      kappa B-alpha d.n. mutant resulted in the sensitization of prostate carcinoma
      cells to apoptosis induced by selenium compounds. These results suggest that
      selenium may target the NF-kappa B activation pathway to exert, at least in part,
      its cancer chemopreventive effect in prostate.

PMID- 12481432
TI  - Efficacy of a glutathione S-transferase pi-activated prodrug in platinum
      resistant ovarian cancer cells.
AB  - Human ovarian carcinoma cells (C70 and C200) made resistant to cisplatin from
      A2780 cells demonstrated an approximately 20-fold resistance to the drug. These
      same cell lines showed no collateral resistance (as compared with the wild-type)
      to a novel glutathione S-transferase pi-activated prodrug [gamma-glutamyl-alpha
      amino-beta[2-ethyl-N,N,N',N'-tetrakis (2-chloroethyl) phosphorodiamidate]
      sulfonyl-propionyl-(R)-(-) phenylglycine; TLK286]. Previous results have shown a
      direct correlation between levels of GST pi expression and cytotoxicity for
      TLK286 (L. A. Rosario et al., Mol. Pharmacol., 58: 167-174, 2000.). However,
      protein levels of the isozyme were identical in wild-type C70 and C200 cell
      lines. In analyzing the DNA repair capacity of C70 and C200, an altered
      expression of the DNA-dependent protein kinase (DNA-PK) complex (catalytic
      subunit DNA-PKcs, and the heterodimers Ku70 and Ku80) was found. In C70 and C200
      cells, DNA-PKcs was overexpressed at both the transcript and protein levels,
      whereas amounts of Ku70 and Ku80 were higher only at the level of protein
      expression. TLK286 in either its parent or activated form inhibited the catalytic
      kinase activity of purified DNA-PK with an IC50 value of approximately 1 microM.
      Coimmunoprecipitation of Ku70 after TLK286 treatment of purified DNA-PK and C70
      cells showed a drug-induced destabilization of the protein-protein interaction
      between the catalytic subunit and the Ku heterodimer. Overall, these results
      implicate inhibition of DNA-PK as a component of TLK286 cytotoxicity and provide
      a rationale for its use in the clinical management of cisplatin-resistant ovarian
      cancer.

PMID- 12481433
TI  - MDM2 does not influence p53-mediated sensitivity to DNA-damaging drugs.
AB  - MDM2 inhibits transactivation properties of the tumor suppressor protein p53 by
      binding to and facilitating proteasomal degradation of p53. Because MDM2 targets
      p53 for degradation, it was anticipated that cells that overexpress MDM2 would
      not contain functional wild-type p53 (wtp53). However, p53 and MDM2 in cells with
      damaged DNA can become phosphorylated, and their binding to each other can become
      inhibited. Thus, p53 remains functional and induces apoptosis of damaged cells.
      Here we report the results of experiments designed to investigate whether MDM2
      amplification and overexpression can inhibit p53-mediated chemosensitivity to DNA
      damaging drugs. Two cell lines in which MDM2 is amplified, NB-1691 and Rh18, were
      transduced with an adenoviral expression vector for p53 (Ad.p53). Although
      functional wtp53 was detected, no change in chemosensitivity was observed,
      suggesting that endogenous wtp53 may have been active in the MDM2-amplified
      cells. The adenoviral vector Ad.MDM2 was used to generate MDM2 expression in a
      rhabdomyosarcoma cell line, Rh30-CI.27, engineered to express inducible wtp53.
      When p53 expression was induced, cells became chemosensitive to actinomycin D in
      the presence or absence of MDM2 expression; this result suggests that MDM2 cannot
      inhibit p53-mediated chemosensitivity. There was no evidence of a reduced amount
      of MDM2-p53 binding after drug exposure, but the remaining unbound wtp53 may be
      functional and capable of potentiating cytotoxicity. In conclusion, MDM2
      expression is important in inhibiting p53 function during tumor development but
      not during the DNA damage-mediated cytotoxic response.

PMID- 12481434
TI  - Comparative study of the importance of multidrug resistance-associated protein 1
      and P-glycoprotein to drug sensitivity in immortalized mouse embryonic
      fibroblasts.
AB  - Multidrug resistance-associated protein 1 and P-glycoprotein are major ATP
      binding cassette transporters that function as efflux pumps and confer resistance
      to a variety of structurally unrelated anticancer agents. To evaluate the
      comparative importance of these transporters with respect to anticancer agents,
      we established and characterized SV40-immortalized [mrp1(-/-)] (KO), [mdr1a/1b(-/
      )] (DKO), and combined [mrp1 (-/-), mdr1a/1b(-/-)] (TKO) deficient fibroblast
      lines derived from primary embryonic fibroblasts of knockout mice. Western blot
      analyses demonstrated that KO and DKO fibroblasts exhibited similar levels of P
      glycoprotein and mrp1, respectively, to that of wild-type (WT) fibroblasts. In
      addition, semiquantitative reverse transcription-PCR measurements of other
      multidrug resistance-associated protein (mrp) family members demonstrated that
      TKO fibroblasts displayed expression profiles of mrps 2-7 comparable to that of
      WT fibroblasts. These results indicate that loss of mrp1, P-glycoprotein, or both
      transporters does not cause overt compensatory changes in the expression of the
      other determined transporters. Using cell viability and calcein accumulation
      assays, we demonstrated that KO and DKO fibroblasts exhibited a low to moderate
      increase in sensitivity to vincristine and etoposide and in calcein accumulation
      compared to WT fibroblasts, whereas TKO fibroblasts displayed a markedly enhanced
      sensitivity to these agents and further elevated calcein accumulation.
      Furthermore, verapamil, an inhibitor of both mrp1 and P-glycoprotein,
      significantly sensitized WT fibroblasts to both vincristine and etoposide while
      having no effect on the sensitivity of TKO cells to these agents. Collectively,
      these findings indicate that mrp1 and P-glycoprotein are major determinants of
      drug sensitivity in immortalized mouse embryonic fibroblasts. They also suggest
      the existence of a compensatory mechanism by which the loss of one transporter
      can be functionally offset by the other in the transport of common drug
      substrates.

PMID- 12481435
TI  - Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared
      with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant.
AB  - Imatinib (Glivec; STI571) is an ATP-competitive kinase inhibitor of c-Abl,
      BCR/ABL, c-Kit, and platelet-derived growth factor receptor. Overexpression or
      constitutive activation of Kit by mutations have been associated with various
      malignancies. Mutations in the intracellular juxtamembrane region of Kit (e.g.,
      V560G) are common in gastrointestinal stromal tumors and have been linked to poor
      prognosis. Mutations in the kinase domain of Kit (e.g., D816V) have been detected
      in mastocytosis, acute myeloid leukemia, and germ-cell tumors. To determine the
      sensitivity of Kit mutants to Imatinib in the same cellular background, wild-type
      Kit (WTKit), V560GKit and D816VKit were expressed in FDC-P1 cells. Growth of
      FDC(WTKit) was inhibited by Imatinib with GI50 (a concentration of drug at which
      50% inhibition of growth occurs) of 0.1-0.2 microM but FDC(V560GKit) were more
      sensitive to Imatinib with a GI50 of 0.01-0.025 microM and FDC(D816VKit) were
      resistant to Imatinib with a GI50 greater than 5 microM. The naturally occurring
      isoforms of c-Kit did not differ in their sensitivity to Imatinib.
      Immunoprecipitation and Western blot analysis indicated that 1 microM Imatinib
      reduced phosphorylation of WTKit and completely blocked phosphorylation of
      V560GKit but did not affect D816VKit phosphorylation. In signaling studies,
      addition of stem cell factor (SCF) induced phosphorylation of ERK and Akt by
      WTKit, and ERK, Akt and STAT3 by V560GKit, which were all blocked by Imatinib.
      Imatinib also blocked the constitutive activation of Akt and STAT3 by V560GKit
      but had no affect on the constitutive activation of ERK, Akt, and STAT3 by
      D816VKit. Overall, these findings demonstrate the increased susceptibility of the
      Kit juxtamembrane mutant, V560G, and the resistance of the kinase domain mutant,
      D816V, to Imatinib compared with WTKit.

PMID- 12481436
TI  - Inhibition of mitogen-activated protein kinase activity of human lymphocytes
      after oral administration of Oltipraz.
AB  - Several preclinical studies indicated that Oltipraz appears to be one of the most
      potent cancer chemopreventive agents. Pharmacological studies in humans provided
      substantial amounts of information related to doses and schedules. Oltipraz has
      been reported to induce phase II drug-metabolizing enzymes. However, its
      chemopreventive activity suggests that it may also interact with cellular
      processes associated with cancer cell growth and proliferation. During a clinical
      trial designed to monitor eventual Oltipraz toxicity in high-risk population for
      development of lung cancer, we performed companion studies related to cell
      proliferation. Human lymphocytes were chosen as surrogate tissue to assess the in
      vivo effects of Oltipraz on cell signaling pathways involved in cell
      proliferation. The results of this study demonstrate that Oltipraz markedly
      inhibited the activation state of the extracellular signal-regulated kinases of
      the mitogen-activated protein kinase family of kinases in lymphocytes of subjects
      treated with two different doses and schedules of Oltipraz. Individual variations
      were observed that were not related to Oltipraz dosing or schedule of
      administration. The results from this study indicate that lymphocytes could be
      used as surrogate tissue for the development of biomarkers for studies of
      anticarcinogenic agents.

PMID- 12481437
TI  - Attenuated recombinant vaccinia virus expressing oncofetal antigen (tumor
      associated antigen) 5T4 induces active therapy of established tumors.
AB  - The human oncofetal antigen 5T4 (h5T4) is a transmembrane glycoprotein
      overexpressed by a wide spectrum of cancers, including colorectal, ovarian, and
      gastric, but with a limited normal tissue expression. Such properties make 5T4 an
      excellent putative target for cancer immunotherapy. The murine homologue of 5T4
      (m5T4) has been cloned and characterized, which allows for the evaluation of
      immune intervention strategies in "self-antigen" in vivo tumor models. We have
      constructed recombinant vaccinia viruses based on the highly attenuated and
      modified vaccinia virus ankara (MVA strain), expressing h5T4 (MVA-h5T4), m5T4
      (MVA-m5T4), and Escherichia coli LacZ (MVA-LacZ). Immunization of BALB/c and
      C57BL/6 mice with MVA-h5T4 and MVA-m5T4 constructs induced antibody responses to
      human and mouse 5T4, respectively. C57BL/6 and BALB/c mice vaccinated with MVA
      h5T4 were challenged with syngeneic tumor line transfectants, B16 melanoma, and
      CT26 colorectal cells that express h5T4. MVA-h5T4-vaccinated mice showed
      significant tumor retardation compared with mice vaccinated with MVA-LacZ or PBS.
      In active treatment studies, inoculation with MVA-h5T4 was able to treat
      established CT26-h5T4 lung tumor and to a lesser extent B16.h5T4 s.c. tumors.
      Additionally, when C57BL/6 mice vaccinated with MVA-m5T4 were challenged with B16
      cells expressing m5T4, resulting growth of the tumors was significantly retarded
      compared with control animals. Furthermore, mice vaccinated with MVA-m5T4 showed
      no signs of autoimmune toxicity. These data support the use of MVA-5T4 for tumor
      immunotherapy.

PMID- 12481438
TI  - Induction of thymidine phosphorylase in both irradiated and shielded,
      contralateral human U87MG glioma xenografts: implications for a dual modality
      treatment using capecitabine and irradiation.
AB  - In the United States, tumors of the central nervous system remain the third
      leading cancer-related cause of death in young adults with a median survival time
      of < 1 year. A recent case study suggested that Capecitabine (a novel,
      fluoropyrimidine prodrug) may be effective in the treatment of brain metastases.
      Pharmacogenomic studies have correlated the antitumor response to Capecitabine
      with the expression of the drug metabolizing enzymes thymidine phosphorylase (TP)
      and dihydropyrimidine dehydrogenase (DPD). In the current study, we examined TP
      and DPD expression in normal human brain tissues and in glioblastoma multiforme,
      the most common and malignant type of brain tumor. Because previous reports
      suggest a tumor necrosis factor (TNF)-alpha-mediated increase in TP expression
      after irradiation (a current standard of care for glioblastoma multiforme), we
      also examined the effect of irradiation on the expression of TP, DPD, and TNF
      alpha in both irradiated and lead-shielded contralateral U87MG glioma xenografts
      within the same animal. Expression levels were determined using real-time
      quantitative PCR as described previously. Results demonstrate an approximately 70
      fold increase in TP mRNA levels 4 days after irradiation, relative to initial
      control levels. Interestingly, TP mRNA in the lead-shielded tumors (contralateral
      to irradiated tumors) increased approximately 60-fold by day 10 relative to
      initial control levels. Elevated TP levels were sustained for 20 days in
      irradiated xenografts but began to decrease after 15 days in the
      shielded/contralateral tumors, returning to baseline by 20 days. TP mRNA levels
      in normal mouse liver were unaltered, suggesting a tumor-associated effect. TNF
      alpha mRNA levels did not increase after irradiation; therefore, mRNA expression
      of 11 additional cytokines [interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL
      5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, and IFN-gamma] in both the irradiated
      and shielded xenografts was quantitated. Results demonstrated increased levels of
      IFN-gamma, IL-10, and IL-1 alpha by 6.3-, 3.7-, and 1.6-fold, respectively, in
      irradiated tumors only. DPD mRNA levels did not change after irradiation. The
      tumor-associated induction of TP in irradiated and lead-shielded tumors within
      the same animal may have significant implications for the combined modality
      treatment of cancer patients with Capecitabine in conjunction with radiotherapy
      and may apply to the treatment of distant tumors and or metastatic disease.

PMID- 12481439
TI  - Overcoming immune tolerance to cancer by heat shock protein vaccines.
AB  - Heat shock proteins (HSPs) are a large family of inducible but also ubiquitously
      and constitutively expressed protein chaperones involved in assisting protein
      folding and unfolding in the cells. The realization of the immunological
      significance of HSPs came from the observation that tumor cell-derived HSPs could
      immunize against tumors, although there were no structural differences between
      HSPs from normal cells and from cancer cells. Studies of this puzzle have
      uncovered two unique immunological properties of HSPs. One is their ability to
      associate and present antigenic fingerprints/peptides of cells to MHC antigens.
      The other is their ability to activate dendritic cells (DCs), which are the most
      efficient antigen-presenting cells. These surprising immunological attributes of
      HSPs are now the basis for a number of already completed clinical trials for
      cancer immunotherapy. Because DCs orchestrate both innate and adaptive immunity,
      the findings that HSPs can modulate the functions of DCs may have fundamental
      implications. We hypothesize that HSPs are at the forefront in counterbalancing T
      cell tolerance to tumor-associated antigens and thus play pivotal roles in
      antitumor immunity in vivo.

PMID- 12481440
TI  - [Recent topics on ethical issues in psychiatry, mental care and welfare].
AB  - This lecture focuses on several ethical issues on psychiatry research and
      psychiatric practice. The most important issue in ethics is informed consent in
      both the national guidelines on ethics in genomic study and epidemiological
      studies determined by the Ministry of Health, Welfare and Labor, Ministry of
      Education, Culture, Sports, Science and Technology and Ministry of Economy, Trade
      and Industry. They recommend researchers to obtain consent from subjects making
      free voluntary decisions after they are fully provided with the necessary
      information and explanation. The guidelines on ethics in genomic study strongly
      recommend organizing an ethical committee committed by several extramural members
      from the fields of law, social or human sciences. On the other hand, the
      guidelines on ethics in epidemiological study provide how to obtain informed
      consent in detail according to how projects are carried out. Strict requirements
      of informed consent tend to inhibit medical research conduct, in particular a
      research on post-mortem brain, which is one of the important research areas for
      elucidation of pathogenesis and pathophysiology of mental disorders. Recently a
      new trend to organize a brain bank by donation of the patient who has given
      consent before death. This is a proper way to collect post-mortem brain
      overcoming the ethical problems and it is our hope that this trend will develop
      in our country. Disclosure of medical records to patients is one of the most
      recent and debated issues in psychiatric practices. In 1999, the Ministry of
      Health and Welfare started investigations on whether medical records should be
      disclosed to patients. The report of the committee strongly recommends
      accelerating the disclosure of medical records. Responding to this report,
      several medical organizations issued a guideline. Recently, we carried out a
      questionnaire survey on the disclosure rate of medical records in the psychiatric
      departments of both medical school hospitals and national mental hospitals, where
      special committees have been organized to determine the disclosure of the medical
      records when a patient demands it officially. Contrary to our expectation the
      rate of disclosure demands was very low in both medical schools and national
      mental hospitals. The average number was only less than one case in medical
      schools, and less than 0.5 cases in national mental hospitals. It was speculated
      that patient requests demanding the disclosure of the records are mostly managed
      by the doctor in charge without consulting the special committee. Looking back
      the process of debate on the disclosure of medical records, several important
      issues, such as notice of diagnosis, informed consent, management of records,
      standardization of medical records, financial support to establish management
      system of medical records and so on, remain to be further examined thoroughly.

PMID- 12481441
TI  - [Social phobia: east and west].
AB  - The condition corresponding to social phobia, named taijin-kyofu (taijin: in
      relation to people, kyofu: phobia), has been widely known since the early 1930s
      in Japan. As there had been few reports on social phobia in Western countries
      until DSM-III was introduced in 1980, taijin-kyofu had long been considered as a
      unique condition existing only in Japan. After DSM-III, it was realized that
      taijin-kyofu included two types of social phobia (SP). The first one meets the
      diagnostic criteria for social phobia described in DSM-IV and ICD-10 (type 1 SP).
      On the other hand, the clinical manifestations of the second type of social
      phobia (type II SP) are not covered by the same criteria. Mori et al. reported
      that out of 152 patients with SP, 92 were classified as type I and 60 as type II
      cases. In 1977, I published a small book on taijin-kyofu dealing with 100
      subjects, most of whom belonged to type II SP. Reviewing the complaints of type
      II SP patients, we can point out 4 characteristics; 1. Firm belief in the
      existence of serious shortcomings (such as flushing, bodily odors). 2. Its
      existence is intuitively perceived by patients from the behavior, actions and
      gestures of other people around them. 3. These defects make others to feel
      unpleasant and therefore must be corrected or removed. 4. No other symptoms
      appear in the long follow-up period of time. Predominant targets of their phobias
      are as follows, flushing in 22, eye contact in 15, showing one's odd attitude in
      18, body dysmorphia in 5, bodily odors in 28, multiple fears in 3 and anxiety
      about others' attitude in 9 cases. Out of 100 subjects, 76 were male and 24 were
      female. Their sufferings started often in the low teens, most frequently in the
      high teens, and next in the early 20s and much less afterwards. Although avoidant
      personality disorder is often comorbid with SP, character traits in childhood of
      more than half of them were active and only 13 cases were timid and introverted.
      Most of them were brought up in ordinary homes. Morita-oriented psychotherapy
      combined with anxiolytic drugs was carried out. The outcome after the average of
      10.6 times interview sessions showed complete or almost complete recovery in 27
      cases, considerable improvement in 55 and no apparent changes in 18 cases. It has
      been argued that socio-cultural tradition in Japan where more value is placed on
      thoughtfulness for others than on self-assertion, more on emotional intimacy than
      on logical explanation, more on human trust than on laws can be one factor for
      the development of type II SP. But Lee of Korea reported that 119 out of 315 SP
      cases presented type II features. It is expected that similar condition is found
      in countries other than Japan and Korea. In 1993, I published the English edition
      of my old Japanese book. In its preface, I wrote; My purpose for providing an
      English translation of this book is to pose a simple question to psychiatrists
      and clinical psychologists outside of Japan, "Do you see these kinds of patients
      in your country or not?".

PMID- 12481442
TI  - Teaching mental health skills to general practitioners and medical officers.
AB  - David Goldberg opened by describing the research that had led up to the present
      WPA teaching package. Early research had demonstrated that many psychological
      illnesses were not detected in primary care settings (Goldberg & Huxley 1980;
      ibid 1992), and these findings have been replicated in 14 centres round the
      world, with broadly similar results (Ustun & Sartorius 1995). We have found that
      in the UK the problem is not defects in factual knowledge, but not having
      clinical skills to assist in the management of mental disorders in general
      medical settings. The clinical skills needed in primary care are seldom taught in
      medical schools, and cannot be learned by listening to a lecture: it is necessary
      to practice them after they have been demonstrated. To do this it is convenient
      to break complex clinical skills down into their components: these are called
      "micro-skills", and we will deal later with the way in which these are taught.
      The most powerful method for improving mental health skills in this setting is to
      provide doctors with feedback--either video or audio--of their interview with
      real patients. The emphasis of such teaching must be on the interview techniques
      used by the doctor, rather than the clinical problems displayed by the particular
      patient being interviewed (Gask et al 1991). The problem with this is that video
      feedback teaching of the necessary type is not always available, so we have
      developed videotapes that we can send out to distant locations, and which focus
      the attention of both local tutor and postgraduates on what should be learned.
      Because it is essential that most of the teaching is done by the live teacher
      rather than the videotape, there are always several "discussion points" so that
      postgraduates can ask questions, or describe their own way of dealing with
      particular situations. The videotapes are supplied together with teaching notes
      for the tutor, power points slides which can be adapted to suit local conditions,
      "role plays" to allow postgraduates to practice each skill they wish to learn,
      and other support materials. There is also a paper written by ourselves in
      association with Norman Sartorius, who has encouraged us to prepare the teaching
      package under the auspices of the WPA. Linda Gask described the process of
      teaching specific 'microskills', by working through how the skills necessary for
      the management of people who present in primary and general medical settings have
      been described and taught in the UK (see box 1). A model of the strategies and
      skills to be [figure: see text] taught was first developed utilizing the
      experience professionals and teachers from both primary care and mental health. A
      videotape was produced in which the skills to be acquired were demonstrated by
      real primary care doctors in role-played interviews with the addition of
      subtitles to label particular skills. The videotape is then utilised in a group
      teaching session to model the specific component skills of the model or
      'microskills' to the participants in order to demonstrate exactly how the
      strategies of the model are applied in a real consultation. Watching the
      videotape will not however change behaviour. To do this, it is necessary to role
      play brief scenarios so that the professional is able to practice the actual
      words he or she would use. This role-play work may be carried out in pairs, with
      one doctor playing the professional and the other playing the patient, or in
      threes, with the addition of an observer who ensures that the participants keep
      to the task. At the end of the role-play all participants provide feedback. These
      methods are described in much more detail in Gask (1999). Finally, there is also
      the possibility of videotaping one of these role-played interviews and teaching
      on this tape with the group as a whole. The specific skills and methods required
      to do this are described in much more detail along with the research evidence for
      these methods in Gask (1998). Our approach to facilitating the group in the
      exercise of videofeedback teaching is summarised in box 2.

PMID- 12481443
TI  - [Panic disorder and theories of neurosis].
AB  - In early 1960's, psychopharmacologist DF Klein cut out from anxiety neurosis a
      drug-responsive acute anxiety syndrome, later named panic disorder in the
      Research Diagnostic Criteria (RL Spitzer et al. 1978). Nowadays, many authors
      tend to consider panic disorder a clinical entity with biologically determined
      causes distinct from psychodynamic aetiology. The author keeps a reserved
      distance from this trend. Japanese psychiatrist M. Morita, described in 1928
      paroxysmal anxiety neurosis, symptomatically identical to panic disorder. This
      anxiety neurosis is related to the mental life of individuals who have a
      particular temperament, i.e., nervous, introverted, and easily trapped in a
      vicious circle of mental activities. Spontaneous panic consists of an evoked
      dreadful feeling connected with some dreadful life event buried in the mind and
      its crescendo is vivid escalation due to a vicious circle of mental activities.
      Many psychoanalysts have proven that neurotic symptoms, including spontaneous
      panic and phobic avoidance, derive from inner conflict and unconscious process.
      American psychoanalyst JC Nemiah, reported in a meeting a spontaneous panic case.
      During his psychoanalytically-oriented interview, the patient revealed violently
      aggressive impulses related to the panic. Nemiah explained the nature of the
      causes of panic anxiety in this case in terms of psychodynamic concepts. The
      attendants, biologically-oriented researchers of panic disorder, criticized
      Nemiah: there was no scientific evidence in his method of proof and explanation.
      Discussion in the meeting revealed that the epistemology of the attendants and
      that of Nemiah were totally different, the former tending to see a panic attack
      as a biological phenomenon in the world of matter and energy, and the latter
      tending to see panic anxiety as a phenomenon of mental life in the world of
      meaning and information. In the treatment of panic disorder cases, especially
      chronic cases frequently seen in daily practice, we psychiatrists can not help
      regarding neurotic symptoms as closely related to the mental life of the patient
      and resorting to psychodynamic considerations.

PMID- 12481444
TI  - [Recurrent retrieval of the core episode referred to as the onset of
      schizophrenia--psychopathological study on the autobiographical memory of the
      onset of the illness].
AB  - OBJECTIVE: In this study, we explore the onset of psychotic episodes in
      schizophrenia. Patients with schizophrenia have sometimes reported specific life
      events at the period of onset. For example: "It started on my 22nd birthday. From
      that day onward, my life was colored with extremes of happiness and tragedies",
      or "It was when I was playing with a cat in the park of S temple that I realized
      suddenly that my 'I'-ness had completely changed." In each case, patients
      referred to a specific event as a critical moment when the meaning of selfness
      and the surrounding world had changed. Interestingly, these moments were reported
      repeatedly throughout the history of their illnesses. We termed these clinical
      phenomena "Recurrent retrieval of the core episode referred to as the onset of
      schizophrenia" and investigated their psychopathologic implication. METHOD: The
      autobiographical memory of nine schizophrenic patients with "Recurrent retrieval
      of the core episode referred to as the onset of schizophrenia" was investigated.
      Four representative cases are described in detail. Samples of subjective
      statements were collected from medical records and analyzed. RESULTS: 1) Form and
      content of the statement: Patients clearly referred to a specific moment in their
      life. They usually reported that their image of self or the world had completely
      changed. The content of their reports were always about the same theme. 2)
      Chronological pattern of the repetition: Although the reported life event
      occurred just before onset, the reminiscence usually occurred not only at the
      beginning of the refractory period but also at the beginning of the recovery
      period. Patients did not report such events when they were stable. In the
      refractory period, distinct symptoms of schizophrenia were observed after the
      reminiscence. In the recovery period, the reminiscence was accompanied by minor
      physical symptoms, such as fever elevation or gastrointestinal dysfunction. 3)
      Subjective characteristics of repetitive reminiscence: In the refractory period,
      patients relived the onset of schizophrenia by reporting it reminiscently. They
      were excited, in a state of high-tension, or feeling oppressed. In contrast, in
      the recovery period, they reported the critical moment in an emotionally stable
      state, and even recollected it with humor. They were able to maintain some
      emotional distance from the reminiscence. 4) Predictive factor on prognosis:
      Reminiscence in the recovery period predicted a good prognosis. Seven of nine
      such cases were in remission. Two patients with whom the reminiscence was
      observed only in the refractory period were chronically ill. Therefore, two
      patterns of repetitive reminiscence of the critical moment should be
      discriminated. DISCUSSION: 1. The statements of patients were developed on the
      possibility that the critical event had not happened. Therefore, it can be
      postulated that their statements reconstructed a temporality open to any possible
      future: the moment just before the critical event might not have happened. The
      proper temporality associated with repetitive reminiscence should be
      distinguished from that of repetition of a traumatic memory in post-traumatic
      stress disorder. 2. From a therapeutic viewpoint, it is important to know to whom
      the discourse of the patient was addressed. In the refractory period, patients
      reported the repetitive reminiscence to anyone in a non-discriminating fashion.
      In contrast, in the recovery period, their discourse on the reminiscence was
      directed to a particular person with whom they were in close contact. The
      structure of the latter discourse was similar to that of neurotic patients in
      that they both demand acceptance from others. That is, the discourse structure of
      our patients was drastically changed in the recovery period. Reconstruction of
      the critical moment found in the recovery period was accomplished by the
      patient's discourse directed to another person, one from whom they could realize
      self-acceptance.

PMID- 12481445
TI  - [Sympathetic block in dogs by a local anesthetic with addition of clonidine].
AB  - BACKGROUND: The aim of this study is to examine the duration and magnitude of
      vasodilating effect induced by sympathetic block with the addition of different
      concentrations of clonidine to mepivacaine. METHODS: In dogs, mean arterial
      pressure (MAP), heart rate (HR), and right as well as left brachial artery blood
      flow (BABF) were measured before and after stellate ganglion block (SGB) used as
      sympathetic block. The experimental protocol was designed as follows: 1) Group 1:
      left SGB using 0.5% mepivacaine 1 ml (n = 6), 2) Group 2: left SGB using the
      addition of clonidine 0.5 microgram to 0.5% mepivacaine 1 ml (n = 6), 3) Group 3:
      left SGB using the addition of clonidine 5 micrograms to 0.5% mepivacaine 1 ml (n
      = 6). RESULTS: MAP showed no significant change throughout the study in the
      groups 1 and 2. In the group 3, MAP was lower than that of the group 1. HR showed
      no significant change throughout the study in the three groups. Left BABF
      increased significantly after left SGB in the three groups. The duration of
      increased BABF in the group 2 was the longest, and that in the group 3 was the
      shortest among them. Right BABF after left SGB decreased significantly throughout
      the study in the three groups, and the magnitude of the decrease in BABF in the
      group 3 was the highest among them. CONCLUSION: Sympathetic block with the
      addition of clonidine to local anesthetics increases both duration and magnitude
      of its vasodilating effect. However, sympathetic block with the addition of
      higher doses of clonidine to local anesthetics may induce shorter duration and
      lower magnitude of vasodilating effect compared with local anesthetics alone.

PMID- 12481446
TI  - [Effects of olprinone hydrochloride on intraocular pressure and ocular blood flow
      in patients after cardiac surgery under cardiopulmonary bypass].
AB  - BACKGROUND: We evaluated the effect of olprinone hydrochloride on intraocular
      pressure (IOP) and ocular blood flow in patients after cardiac surgery under
      cardiopulmonary bypass (CPB). METHODS: Nine patients after cardiac surgery under
      CPB were investigated. We measured IOP of the left eye using tonometer (Tonopen
      XL, BIO RAD, Osaka), and mean blood flow velocity in the left ophthalmic artery
      (Vm) and calculated the pulsatility index in the left ophthalmic artery (PI)
      using 2 MHz Doppler ultrasound system (Multidop P, DWL, Germany). After baseline
      measurement, the olprinone hydrochloride loading dosage was increased from 0.15
      to 0.3 microgram.kg-1.min-1 every 60 minutes. The intraocular pressure and ocular
      blood flow were measured at each point. RESULTS: IOP and PI decreased
      significantly, and Vm increased significantly at the infusion rate of 0.3
      microgram.kg-1.min-1 from baseline. There was a significant linear correlations
      between IOP and Vm. CONCLUSION: We demonstrated that olprinone hydrochloride led
      to a decrease in IOP and an increase in ocular blood flow in patients after
      cardiac surgery under CPB.

PMID- 12481447
TI  - [Evaluation of preoperative anxiety in patients with and without premedication].
AB  - BACKGROUND: The purpose of this investigation was to determine whether
      elimination of premedication before general anesthesia affects preoperative
      anxiety. METHODS: Subjects were assigned to one of two groups: a sedative group
      (0.5 mg midazolam i.m., n = 111) or a no-premedication group (n = 98). We used
      patients' responses to a questionnaire to compare the no-premedication group and
      the sedative group. RESULTS: Eighty-three percent of patients in the no
      premedication group entered the operating room ambulatory. The responses
      concerning preoperative anxiety were not different between the two groups. There
      was a high rate of recall of the conversation before anesthesia induction in the
      no-premedication group, and most of these patients replied that making
      conversation before general anesthesia was beneficial to them. Increases in heart
      rate and blood pressure at the point of entrance to operating room were observed
      in the no-premedication group, but the degrees of increase were not considered
      clinically important. CONCLUSION: We conclude that elimination of premedication
      does not increase anxiety in comparison with patients receiving sedatives, but
      makes patients feel comfortable by way of preoperative conversation. Elimination
      of premedication also makes ambulatory entrance possible, both improving safety
      with respect to patient identification and reducing the demand on nursing.

PMID- 12481448
TI  - [Changes in acid-base balance and blood lactate levels during radio frequency
      ablation conducted for the treatment of hepatocellular carcinomata in patients
      with liver cirrhosis].
AB  - BACKGROUND: Radio frequency ablation (RFA) has recently received increasing
      attention as an effective minimally invasive approach for the treatment of
      hepatocellular carcinomata (HCCs). However, we experienced a patient with liver
      cirrhosis (LC, Child-Pugh class B) in whom severe lactic acidosis developed
      during RFA conducted for the treatment of a HCC (-4.5 cm in diameter). This case
      prompted us to reevaluate possible injurious effects of RFA on non-tumorous liver
      tissues in the vicinity of its target in LC patients. METHODS: Intraoperative
      changes in acid-base balance and blood lactate levels, and postoperative changes
      in serum transaminases were investigated in LC (Child-Pugh class A) patients
      undergoing either laparotomic RFA (for the treatment of HCCs [diameter < 3 cm])
      or partial hepatectomy (with the aid of the Pringle's manuever), and non-LC
      patients undergoing pancreatectomy. RESULTS: During the intraoperative period,
      significant lactic acidosis developed only in the patients undergoing
      hepatectomy. Core temperature significantly increased following the RFA.
      Postoperative increases in the transaminases observed in the patients undergoing
      hepatectomy were far larger than those observed in the patients undergoing either
      RAF or pancreatectomy. CONCLUSION: RFA, conducted for the treatment of smaller
      HCCs, appears to be minimally invasive even in the presence of LC (Child-Pugh
      class A).

PMID- 12481449
TI  - [Anesthetic management of four cases of craniotomy with alternate monitoring of
      motor and somatosensory evoked potentials].
AB  - We experienced four cases of craniotomy in which motor evoked potential (MEP) and
      somatosensory evoked potential (SEP) were monitored alternately. Anesthesia was
      induced with propofol and fentanyl, and it was maintained with continuous
      infusion of propofol. Intermittently, propofol and fentanyl were administered as
      needed. Inhalation of 66% nitrous oxide did not prolong latency, but
      significantly reduced the amplitude of MEP. We could obtain the largest amplitude
      of MEP using five consecutive stimuli of which duration and frequency were 0.5
      milliseconds and 500 Hz, respectively. Anesthetic management using propofol and
      fentanyl is useful for craniotomy with monitoring of MEP and SEP.

PMID- 12481450
TI  - [Re-bleeding during embolization of ruptured cerebral aneurysms by Guglielmi
      detachable coil].
AB  - Intra-aneurysmal embolization by Guglielmi detachable coil (GDC) is becoming an
      important method in treatment of intracranial aneurysm. However, intraoperative
      bleeding remains an essential problem. We reviewed our anesthesia records in
      patients treated with GDC embolization. Ninety four cases of ruptured cerebral
      aneurysms were treated with GDC embolization, including 59 females and 35 males.
      Their ages ranged from 21 to 88, with mean age of 67 years. Preoperative Hunt and
      Hess grading scales were 1 in 3 cases, 2 in 31, 3 in 40, 4 in 16 and 5 in 4.
      Intraoperative re-bleeding occurred in 3 cases. These were confirmed by
      extravasation in angiography or by increased HDA in CT. Each case has berry
      aneurysm. Acute hypertension at re-bleeding was treated with nicardipine as well
      as by increasing dose of anesthetic, and hemostasis was obtained by hypotension
      and reversal of heparin with protamine. After disappearance of extravasation, the
      procedures were continued. Anesthesia was maintained with fentanyl-propofol in 1
      case and sevoflurane in 2 cases. Direct hemostasis is impossible during
      endovascular surgery and management of systemic circulation by an
      anesthesiologist is necessary.

PMID- 12481451
TI  - [Two cases of intraoperative awareness during intravenous anesthesia with
      propofol in morbidly obese patients].
AB  - We experienced two cases of intraoperative awareness during intravenous
      anesthesia with propofol and fentanyl in morbidly obese patients. The rates of
      propofol infusion were calculated according to the adjusted body weights, or
      reduced intentionally as obese patients are generally believed to require lower
      doses of propofol compared with non-obese patients. Our postoperative analysis by
      simulations using the anesthesia records showed that, when the simulation was
      based on real body weight, the blood/effect-site concentrations of propofol in
      both patients would have been below the necessary levels to keep the patients
      unconscious during the operation, but when the simulation was based on adjusted
      body weight, those concentrations might have been within the necessary range to
      maintain an adequate hypnotic level. We propose that the rate of propofol
      infusion should be the same in obese and non-obese patients and should be
      calculated according to the real body weight not to the adjusted body weight.

PMID- 12481452
TI  - [Successful intravenous administration of low dose ketamine for pain caused by
      erythromelalgia: report of a case].
AB  - A 15-year-old female complained of reddening, edema, and pain in her hands and
      feet. The symptoms were relieved upon cooling. From these findings, a diagnosis
      of erythromelalgia was made. Because none of the oral medication prescribed by
      dermatologist was effective, the patient was consulted to our department. A low
      dose of ketamine, a drug considered to be effective for intractable pain, was
      administered intravenously and the pain subsided significantly. Furthermore, the
      pain became completely controllable with a combination of intramuscular ketamine
      injection and other oral medication.

PMID- 12481453
TI  - [Spinal anesthesia with bupivacaine for a patient with a history of severe leg
      pain after intrathecal dibucaine].
AB  - An 87-year-old man was scheduled for the 11th transurethral bladder tumor
      resection (TURBT). He had a history of non-active syphilis for 21 years, diabetes
      mellitus for 7 years, and severe emphysema. Preoperative physical examination of
      the lower extremities, revealed loss of knee-jerk reflex, and loss of vibratory
      and proprioceptive perception. Four years previously, he underwent TURBT twice
      under spinal anesthesia with dibucaine, which caused severe leg pain during
      anesthesia. Therefore, subsequent TURBTs (eight times) were performed under
      general anesthesia with tracheal intubation, which frequently caused
      postoperative respiratory distress. Recently, bupivacaine, less neurotoxic than
      dibucaine, was on the market in Japan for use in spinal anesthesia. Therefore we
      planned spinal anesthesia using 0.5% bupivacaine, 2.0 ml. This time, he did not
      complain of leg pain during anesthesia, and postoperative conditions were
      satisfactory. We can conclude that bupivacaine is very useful for spinal
      anesthesia especially in patients with a history of leg pain by spinal anesthesia
      with dibucaine.

PMID- 12481454
TI  - [Anaphylactoid reaction to dibucaine during spinal anesthesia].
AB  - A 71-year-old man with a history of allergic rhinitis for 6 years received spinal
      anesthesia using 2 ml of 0.3% dibucaine for transurethral prostatectomy. Two
      months previously he had undergone prostate biopsy and cystoscopy under spinal
      anesthesia with isobaric bupivacaine uneventfully. Forty five minutes after
      injection of dibucaine he complained of itching in the periorbital area, and
      developed tremor and muscle rigidity followed by loss of consciousness. Soon
      after, his blood pressure decreased to 40 mmHg, and erythema appeared over his
      body. Symptoms were relieved by epinephrine, hydrocortisone and antihistamine
      agents, but ten minutes after the treatment he again developed hypotension and
      erythema. Continuous infusion of epinephrine was needed for complete relief of
      symptoms. An intradermal test with 0.3% dibucaine carried out 6 days after
      surgery demonstrated a 12 x 8 mm wheal with flare. Although anaphylactic reaction
      to an amide local anesthetic has been reported to be quite rare, this is the 7th
      case report of anaphylactic reaction to dibucaine used for spinal anesthesia in
      Japan.

PMID- 12481455
TI  - [A case of shoulder pain following right basilic vein catheterization].
AB  - We have experienced a case of total laryngectomy with graft of the rectus
      abdominis muscle skin flap because of the recurrent lingual cancer. Just before
      the operation, we used right basilic vein for introduction of a central venous
      catheter. Right shoulder pain occurred on the first postoperative day. After the
      operation, we found that the catheter from the right basilic vein was inserted to
      the right jugular vein. We pulled out it and inserted another catheter from the
      left subclavian vein. Shoulder pain diminished and then pyrexia and symptom of
      infection diminished. After recatheterization, shoulder pain was suspected to be
      the result of frozen shoulder. We should be aware that shoulder pain could occur
      by immobility of upper extremities when basilic venous catheter is in place.

PMID- 12481456
TI  - [Anesthetic management of a patient with Evans syndrome--benefit of perioperative
      hemodilutional autologous blood transfusion].
AB  - The combination of idiopathic thrombocytopenic purpura and autoimmune hemolytic
      anemia is termed Evans syndrome. We experienced the anesthetic management of a
      patient with this syndrome undergoing laparoscopic splenectomy. After induction
      of general anesthesia using thiamylal, fentanyl and vecuronium, hemodilutional
      autologous transfusion was employed to minimize the immune hemolytic process
      against the transfused blood throughout the surgical procedure. The anesthetic
      course was uneventful, and neither massive hemorrhage nor any complications
      related to bleeding occurred. We therefore recommend the use of hemodilutional
      autologous transfusion for the anteshetic management of patients with Evans
      syndrome.

PMID- 12481457
TI  - [Development of severe lactic acidosis during radio frequency ablation conducted
      for the treatment of hepatocellular carcinomata in a patient with liver
      cirrhosis].
AB  - A 60-year-old male with liver cirrhosis (Child-Pugh class B) underwent
      laparotomic radio frequency ablation for the treatment of a solitary
      hepatocellular carcinoma (-4.5 cm in diameter). Severe lactic acidosis (base
      excess < -12 mEq.l-1, lactate > 150 mg.dl-1) developed during the intraoperative
      period, when neither his hemodynamics nor arterial oxygenation was significantly
      impaired. The blood loss was small (-200 g), and the serum hemoglobin level was
      maintained -10 g.dl-1 during the procedure. There was no evidence for impairment
      of either peripheral perfusion or renal function. In addition, there was no
      evidence for development of either splanchnic ischemia or diabetic ketoacidosis.
      Thus, the acidosis appeared to be caused by significant impairment of liver
      function possibly resulting from the ablation (total ablation time = -60 min).
      The core temperature increased rapidly (-1.5 degrees C/60 hr) immediately after
      the ablation was started, suggesting that a large amount of heat was produced in
      the ablated area and/or that the vicinity of the ablated area was richly supplied
      by blood flow. As a result, intact liver cells in the vicinity of the tumor
      probably suffered from thermal injuries. In conclusion, depending on preoperative
      liver function, ablated area, and/or blood flow in the vicinity of ablated area,
      the ablation may become significantly invasive.

PMID- 12481458
TI  - [Perioperative management for nephrectomy using combined spinal-epidural
      anesthesia with sedation in a patient with cerebral palsy under maintenance
      hemodialysis].
AB  - A 43-year-old man (166 cm, 53.5 kg) with cerebral palsy on maintenance
      hemodialysis underwent a right nephrectomy for gross hematuria under combined
      spinal-epidural anesthesia (CSEA) with sedation. The patient suffered from
      hemiplegia, speech disturbance and low intelligence (approximately 6 years and 8
      months). Following premedication with midazolam 4 mg, he was calm and
      cooperative. An analgesic level below T 10 was obtained by spinal (L 4-5)
      anesthesia using plain 0.5% bupivacaine 4 ml. Further cephalad spread (below T 3)
      was secured by bolus (7 ml) and continuous (8.5 ml.h-1) administration of 2%
      mepivacaine for thoracic epidural (T 10-11) anesthesia. Intravenous sedation
      (midazolam 0.08 mg.kg-1.h-1 and pentazocine 0.24 mg.kg-1.h-1) with 2 l.min-1
      oxygen via nasal cannula was given during surgery. The operation and anesthesia
      times were 216 min and 330 min, respectively. Intraoperative bleeding was 1,158 g
      and the extracted kidney weighted 2,333 g. Following a prompt recovery with
      exclamation at the end of surgery, a bolus dose of epidural buprenorphine 0.2 mg
      combined with droperidol 2.5 mg was administered. Three hours after surgery,
      sleep was induced by brotizolam 0.25 mg orally. We accomplished a giant
      nephrectomy under CSEA with sedation in a patient with cerebral palsy receiving
      hemodialysis. Sufficient premedication using midazolam was profitable for CSEA in
      mental-retarded patient.

PMID- 12481459
TI  - [Anesthetic management of a patient with Young-Simpson syndrome].
AB  - Young-Simpson syndrome (YSS) is a rare malformation syndrome characterized
      peculiar facies, congenital hypothyroidism, congenital heart disease, and
      postnatal growth deficiency. A 3-year-old boy with YSS underwent tracheostomy for
      respiratory failure under general anesthesia using sevoflurane, nitrous oxide and
      oxygen. Although he was assumed to be difficult for intubation due to
      micrognathia and macroglossia, tracheal intubation was done without difficulty.
      No complications were observed during the 40 minutes of the operation.

PMID- 12481461
TI  - [Living with the diagnosis of malignant hyperthermia].
AB  - This is the summary of a special lecture presented by a malignant hyperthermia
      (MH) patient at 24th Japanese Symposium of Malignant Hyperthermia in Yamagata
      City (August 25, 2001). Thirteen years ago, he developed acute crisis of MH on
      general anesthesia for tonsillectomy and was diagnosed as MH-susceptible (MHS)
      with muscle biopsy test. His personal troublesome experiences related to MHS,
      i.e. local anesthesia, sports under hot environment etc., have presented him with
      many difficulties and problems to be solved in actual life after discharge from
      hospital. He hoped in the lecture for advances in noninvasive diagnosis for MHS
      and safe anesthetic method for MHS-patients. Important missions of
      anesthesiologists include consultation of the medical problems of MHS patients
      and supporting their safety in daily life.

PMID- 12481460
TI  - [Mechanical supports for stunned myocardium after esophagectomy].
AB  - Coronary vasospasm can cause a wide spectrum of clinical syndromes ranging from
      transient myocardial ischemia to irreversible infarction. A 72-year-old male
      patient had intense vasospasms intraoperatively, which led to stunned myocardium.
      Though MB fraction of creatine kinase after the spasms was almost within normal
      limits, postoperative transcutaneous echocardiogram showed diffuse hypokinesis of
      heart wall motion. He developed low output syndrome, acute respiratory distress
      syndrome and acute renal failure. He was treated with mechanical supports (intra
      aortic balloon pumping, high frequency oscillatory ventilation, and continuous
      hemodiafiltration), in addition to intravenous administration of cathecolamines,
      on the first postoperative day. It took 6 days to wean the patient from these
      mechanical supports and catecholamine infusion. This case suggests stunned
      myocardium after coronary vasospasm, despite the rapid disappearing ST elevation,
      and of importance of mechanical supports for the circulatory failure.

PMID- 12481462
TI  - [Perioperative mortality and morbidity in the year 2000 in 520 certified training
      hospitals of Japanese Society of Anesthesiologists: with a special reference to
      age--report of Japanese Society of Anesthesiologists Committee on Operating Room
      Safety].
AB  - Perioperative mortality and morbidity in Japan for the year 2000 were studied
      retrospectively. Committee on Operating Room Safety of Japanese Society of
      Anesthesiologists (JSA) sent confidential questionnaires to 794 Certified
      Training Hospitals of JSA and received answers from 67.6% of the hospitals. We
      analyzed their answers with a special reference to the age group. The total
      number of anesthetics available for this analysis was 910,757. All cases were
      divided into 7 age groups; group A (< 1 months), group B (< 12 months), group C
      (< 5 years), group D (< 18 years), group E (< 65 years), group F (< 85 years),
      and group G (> 85 years). The incidences of all critical events including cardiac
      arrest, severe hypotension, and severe hypoxemia were 70.04, 42.06, 17.79, 15.57,
      21.14, 39.66, and 44.65 per 10,000 in patients with group A, B, C, D, E, F, and
      G, respectively. The overall mortality rates (death during anesthesia and within
      7th postoperative day) were 26.94, 5.91, 1.88, 2.57, 5.23, 11.98, and 17.50 per
      10,000 anesthetics in patients with group A, B, C, D, E, F, and G, respectively.
      The incidences of cardiac arrest were 28.29, 8.54, 3.56, 2.57, 5.08, 10.27, and
      11.47 per 10,000 in patients with group A, B, C, D, E, F, and G, respectively.
      The mortality rates after cardiac arrest were 18.86, 4.60, 1.26, 1.57, 2.77,
      5.50, and 6.64 in patients with group A, B, C, D, E, F, and G, respectively. The
      incidence of all critical events, the incidence of cardiac arrest, and the
      overall mortality rate were much higher in group A than in other groups, but much
      lower than those in 1999. The incidences of all critical events and the mortality
      rate after cardiac arrest were lowest in group C. Mortality and morbidity due to
      all kinds of causes including anesthetic management, intraoperative events, co
      existing diseases, and operation were as follows. The incidences of all critical
      events attributable to co-existing disease were the highest in these four groups,
      and 32.33, 13.80, 5.86, 4.43, 7.50, 15.34, and 21.72 per 10,000 in patients with
      group A, B, C, D, E, F, and G, respectively. The incidences of all critical
      events attributable to anesthetic management were 13.47, 16.43, 6.28, 3.86, 4.08,
      6.87, and 6.64 per 10,000 in patients with group A, B, C, D, E, F, and G,
      respectively. The incidence of cardiac arrest in group A was much more
      attributable to co-existing disease and operation than other causes. The
      incidences of cardiac arrest attributable to anesthetic management were 0.00,
      1.97, 0.63, 0.29, 0.38, 0.74, and 1.81 per 10,000 in patients with group A, B, C,
      D, E, F, and G, respectively. Its mortality rate in each group was 0.00, 0.00,
      0.21, 0.14, 0.06, 0.04, or 0.00. There were eleven cases of death or vegetative
      state due to anesthetic management, like improper management of airway and
      overdose of anesthetics. Some of them were preventable with the
      anesthesiologists' effort in protocol development and skilled assistance.

PMID- 12481463
TI  - [Image of the month. Phyllodes tumor of the breast].

PMID- 12481464
TI  - [How I treat ... the athlete's foot and its non-mycotic cutaneous pathology].
AB  - Skin and nails of the foot of sport practitioners of various disciplines are
      subjected to the effects of benign but invalidating pathologies. Microtraumatisms
      are frequently involved. Beside dermatomycoses and onychomycoses, a dozen of
      typical disorders are identified.

PMID- 12481465
TI  - [Clinical case of the month. Type A aortic dissection after valve replacement].
AB  - The risk for aortic dissection or further dilation of the ascending aorta exists
      after aortic valve replacement. We present a case of acute aortic dissection
      following replacement of the aortic valve. The management and treatment of
      dilated ascending aorta associated with aortic valve disease are reviewed and
      discussed.

PMID- 12481466
TI  - [Autoimmunity in endocrinology: general principles].
AB  - The thymus is a crucial meeting place between the major systems of cell-to-cell
      communication, the nervous, the endocrine and the immune systems. More
      specifically, the thymus is the site for establishment of central T cell self
      tolerance of neuroendocrine principles. The different factors--genetic,
      environmental, sexual--that intervene in the pathogenesis of autoimmune
      endocrinopathies are briefly reviewed here. Current research try to evidence that
      a thymic dysfunction, a defect in central self-tolerance could play an important
      role in the development of organ-specific autoimmune diseases, or cell-specific
      such as type 1 diabetes.

PMID- 12481467
TI  - [Efficacy and safety of acetaminophen-codeine in the treatment of pain].
AB  - The treatment of acute or chronic pain of variable intensity and origin, is
      efficiently achieved by the association of paracetamol and codeine. At a dose of
      1000 mg paracetamol and 60 mg of codeine, this association is considered one of
      the most efficient as compared to other analgesics of level II in the OMS
      classification, like tramadol.

PMID- 12481469
TI  - [The tuberous breast: a review].
AB  - The tuberous breast is one of the most challenging problem in breast surgery.
      Pediatricians, gynaecologists and plastic surgeons are particularly concerned
      with the treatment of these young patients. A good assessment of the pathology
      and a precise knowledge of the surgical procedures are keypoints for a successful
      treatment. A case report will precede a literature overview of this very complex
      problem.

PMID- 12481468
TI  - [Hereditary neuropathy with pressure hypersensitivity or tomaculous neuropathy].
AB  - Hereditary neuropathy liability to pressure palsies is characterized by recurring
      accesses of painless paralysis at the level of various nerves likely to be
      compressed. This affection remains underdiagnosed because of its usually benign
      course, sometimes without any symptom. The diagnosis is supported by clinical and
      electrophysiological data associated with, in the majority of patients, a
      deletion of one of the alleles coding for protein PMP 22 on the level of the
      locus 17p11.2.

PMID- 12481470
TI  - [Skin and its daily chronobiological clock].
AB  - Some cutaneous functions of importance are governed by periodical variations
      according to the nycthemeral timing. Similarly to other organs, the skin is under
      the influence of a coherent organisation of circadian and nythemeral rhythms
      modulating various biological cycles which usually display a wide amplitude. The
      cutaneous biorhythms in humans suggest that during daylight the skin boosts
      diverse protective functions with regard to environmental threats. In the evening
      and at night, the skin increases its renewal and diverse metabolic processes.
      Biorhythms in the skin which are in line with the organism's needs, merit to be
      recognized. Chronophysiology, chronopathology and clinical chronopharmacology may
      help reach optimal therapeutic decisions.

PMID- 12481471
TI  - [About some "anatomic anthroponyms"].
AB  - Daily in our practice we use terms of anatomy. Some of these terms are directly
      linked to the name of their discoverer. Very often, we ignore or have forgotten
      the history of these anatomists. The author, with a short repertory refreshes our
      memory.

PMID- 12481472
TI  - [How I investigate ... Alport's syndrome by skin biopsy. When the skin speaks for
      the kidney].
AB  - Alport's syndrome is a severe hereditary renal disease. Type IV collagen is
      abnormal in its molecular composition both in the kidneys and the skin.
      Immunohistochemistry performed on a conventional skin biopsy allows to prove the
      diagnosis in the affected subjects and in healthy women exhibiting the mutation
      on a single X chromosome.

PMID- 12481473
TI  - [Info-congress. Study of the prevention of type 1 diabetes with nicotinamide:
      positive lessons of a negative clinical trial (ENDIT)].
AB  - ENDIT ("European Nicotinamide Diabetes Intervention Trial") is a large placebo
      controlled randomised clinical trial that aimed at studying the efficacy of
      nicotinamide in the prevention of type 1 diabetes mellitus among first-degree
      relatives of type 1 diabetic patients with positive islet cell antibodies (ICA).
      The results presented at the last congress of the European Association for the
      Study of Diabetes (EASD) in Budapest do not evidence any significant difference
      in the risk of developing overt diabetes mellitus in the patients treated with
      nicotinamide (n = 274) as compared to those receiving placebo (n = 275) after 5
      years of follow-up. Despite these negative results, positive lessons could be
      drawn from ENDIT: 1) the feasibility of a large long-standing multicentre
      European trial in a difficult research area; 2) the importance of large
      randomised controlled clinical trials to bring the evidence requested by
      "Evidence-Based Medicine"; 3) the predictive value of various risk markers to
      progress toward type 1 diabetes in first-degree relatives, especially the number
      of positive auto-antibodies; and 4) the urgent need to continue intensive
      research in this important field of preventive medicine.

PMID- 12481474
TI  - Neuro-anniversary 2002.

PMID- 12481475
TI  - The neuroscience of Helmholtz and the theories of Johannes Muller. Part 2:
      Sensation and perception.
AB  - In this, our continuation paper on Helmholtz and Muller, we examine Helmholtz's
      contributions to sensation and perception, with emphasis on his extension and
      modification of Muller's theory of specific nerve energies. The material is again
      presented in biographical-chronological context. We also examine Helmholtz's
      views on depth and space perception, and his empirical theory of knowledge, which
      are also compared to Muller's views. It will be shown that Helmholtz remained
      stimulated by the thoughts and doctrines of Johannes Muller in the sensory
      perceptual part of his career, which began early in the 1850s and ended with his
      death. Nevertheless, Helmholtz's own experiments and new discoveries by others
      sometimes led him to quite different conclusions.

PMID- 12481476
TI  - From photography to cinematography: recording movement and gait in a neurological
      context.
AB  - The major challenge of photography has been freezing movement, to transform it
      into a fixed image or series of images. Very soon, photographers became
      interested in movement itself and tried to use photography as a tool to analyze
      movement. At the early stages, physicians interested in movement, perhaps
      surprisingly, made important technical contributions. Mecanisme de la physionomie
      humaine, by Duchenne, the first book with physiological experiments illustrated
      by photographs, is a landmark in this historical development. At the Salpetriere,
      thanks to Charcot, photography officially entered clinical neurology. Medical
      journals with photographs were actively developed by Bourneville. Londe
      established a clinical photographic laboratory and published the first book on
      medical photography. The study of animal and human movement by Muybridge and
      Marey in the 1880s led to chronophotography and later cinematography. Clinicians
      such as Dercum and Richer took advantage of these new techniques to study
      pathological movement and gait in neurological diseases.

PMID- 12481477
TI  - Historical development of the dopamine hypothesis of schizophrenia.
AB  - This review examines the history of discoveries that contributed to development
      of the dopamine hypothesis of schizophrenia. The origin of the hypothesis is
      traced to the recognition that neuroleptic drugs interfere with brain dopamine
      function. This insight was derived from two distinct lines of research. The first
      line originated from the discovery in 1956 that reserpine depletes brain
      serotonin. This finding resulted in a sequence of studies that led to the
      discovery that brain dopamine is involved in neuroleptic-induced extrapyramidal
      motor disturbances. The second line of research was aimed at determining the
      mechanism of action of psychomotor stimulants. This research produced evidence
      that stimulants directly or indirectly activate brain dopamine receptors. Because
      nonreserpine neuroleptics such as chlorpromazine block stimulant-induced
      movement, these findings suggested that neuroleptics were dopamine antagonists.
      Most previous accounts of the development of the dopamine hypothesis of
      schizophrenia emphasize the first line of research and ignore the second.

PMID- 12481478
TI  - Otto Wernicke on developmental dyslexia.
AB  - The first paper on developmental dyslexia to come from outside Europe was
      published in 1903 by Otto Wernicke, an Argentinean ophthalmologist. In addition
      to adding some details to previous descriptions of the disorder, his thoughtful
      contribution challenged the assumptions of early British authors.

PMID- 12481479
TI  - A note on Marinus of Alexandria.

PMID- 12481480
TI  - Lorenz Heister and the challenge of trepanation: a neurosurgical case study from
      the 18th century.
AB  - In the 18th century, medical practice was essentially based on communication.
      Cranial trepanation, however, was usually performed on an unconscious person.
      Here the dialogue ceased. It was the only operation which had to be attempted
      without the positive consent of the patient. Thus trepanation challenged the
      surgeon's skill not only with its intricate surgical practice, but also with its
      unusual social setting. The present paper illustrates possible ways out of the
      "trap of trepanation" by interweaving two points of view. On the one hand, a
      general account is given on the basis of surgical publications written by Lorenz
      Heister and his contemporaries. On the other, the unpublished sources of the
      Heister correspondence serve to reconstruct the case of Heinrich Wilhelm
      Bachmann, a German merchant who fell victim to a traffic accident and underwent
      trepanation in 1753. The case study shows how the physician in charge
      counterbalanced the patient's inability to communicate by strengthening the
      remaining network of professionals, and ultimately confirming his decisions by
      use of the post-mortem.

PMID- 12481481
TI  - Early account relating head pain to cervical spinal disorders.

PMID- 12481482
TI  - Ansa hypoglossi or ansa cervicalis? That is the question....

PMID- 12481483
TI  - The origin of the term plasticity in the neurosciences: Ernesto Lugaro and
      chemical synaptic transmission.
AB  - The Italian psychiatrist Ernesto Lugaro can be regarded as responsible for
      introducing the term plasticity into the neurosciences as early as 1906. By this
      term he meant that throughout life the anatomo-functional relations between
      neurons can change in an adaptive fashion to enable psychic maturation, learning,
      and even functional recovery after brain damage. Lugaro's concept of plasticity
      was strongly inspired by a neural hypothesis of learning and memory put forward
      in 1893 by his teacher Eugenio Tanzi. Tanzi postulated that practice and
      experience promote neuronal growth and shorten the minute spatial gaps between
      functionally associated neurons, thus facilitating their interactions. In
      addition to discovering the cerebellar cells known by his name and advancing
      profound speculations about the functions of the glia, Lugaro lucidly foresaw the
      chemical nature of synaptic transmission in the central nervous system, and was
      the first to propose the usage of the terms "nervous conduction" and "nervous
      transmission" in their currently accepted meaning.

PMID- 12481484
TI  - [Guidelines for the management of bone and joint infections due to methicillin
      resistant staphylococci].
AB  - Bone and joint infections are a group of complicated diseases with high
      morbidity. Emerging resistant microorganisms and the use of prosthetic devices
      have increased the difficulty in the medical treatment of patients. The purpose
      of these guidelines is to offer information on the management of bone and joint
      infections (post-invasive septic arthritis, chronic osteomyelitis and infected
      arthroplasty) produced by methicillin resistant staphylococci. They are oriented
      to physicians dedicated to internal medicine, infectious diseases, trauma and
      orthopedist surgeons as well as to everybody interested in this issue. The
      guidelines mainly point to the rational use of diagnostic methods and describe
      the new treatment modalities. A group of experts analyzed the different
      strategies for diagnosing and treating bone and joint infections due to
      methicillin resistant staphylococci and attempted at setting a level of evidence
      level and the strength of each recommendation.

PMID- 12481485
TI  - [New therapeutic strategies with teicoplanin].
AB  - Teicoplanin is a glycopeptide antibiotic with similar spectrum to vancomycin.
      However, unlike this drug, teicoplanin can be administered by i.v. or i.m. route
      once daily thanks to its long half-life (88 to 182 hours). This pharmacokinetic
      characteristic is particularly interesting in infections that require extended
      antimicrobial therapy, where new therapeutic strategies may be considered. Long
      term treatment with teicoplanin proved effective in the treatment of bone and
      joint infections due to methicillin-resistant staphylococci. Teicoplanin
      administered three times a week yields comparable clinical efficacy than daily
      administration with considerably improved cost-effectiveness. This aspect merits
      special attention, particularly when evaluating prolonged outpatient antibiotic
      therapy regimens. For synergic effects it is possible to associate teicoplanin
      with other antibiotics. Chronic suppressive antibiotic therapy with teicoplanin
      may be an alternative in carefully selected patients, particularly those carrying
      prosthetic devices.

PMID- 12481486
TI  - [Methicillin resistant Staphylococcus].
AB  - The pathogenic potential of Staphylococcus aureus is well known as well as its
      role both in nosocomial and community-acquired infections. When penicillin was
      introduced by mid '40s, S. aureus was almost 94% susceptible to this drug.
      Widespread resistance to penicillin developed in the '50s, followed by resistance
      to semi synthetic penicillins in the '60s and '70s. Since then, strains of
      methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulase
      negative staphylococci have spread worldwide. The prevalence of methicillin
      resistant S. aureus varies geographically. In our country it reaches nearly 50%.
      Methicillin resistance in Staphylococci develops due to an additional penicillin
      binding protein, PBP2a, which is encoded by gene mecA, the responsible of
      methicillin resistance. Methicillin resistance in Staphylococcus aureus and in
      coagulase-negative staphylococci represents a serious problem both for the
      microbiologist and the physician. A special feature of methicillin resistance is
      its heterogeneous nature with different levels of resistance. Most clinical
      isolates show a heterogeneous pattern under routine growth conditions. The high
      prevalence of methicillin-resistant staphylococci compromises the use of semi
      synthetic penicillins for empiric treatments in many institutions, thus
      increasing the use of vancomycin. Until 1996, glycopeptides were almost
      universally active against S. aureus but it was then that the first glycopeptide
      intermediate S. aureus (GISA) was described and isolated in Japan, followed by
      France and USA. The exact mechanism involved has not been elucidated yet,
      although vancomycin resistance is associated with increased wall synthesis.

PMID- 12481487
TI  - [Teicoplanin in the prophylaxis of surgical infections and bacterial
      endocarditis].
AB  - Antibiotic prophylaxis has become a standard of care in all surgical categories,
      since its impact in reducing the incidence of post-operative infections has now
      been well established. Antibiotic prophylaxis should target expected pathogens.
      Glycopeptide-based regimens have been considered a choice for surgical
      procedures, since Gram-positive bacteria are the pathogens most commonly isolated
      from wound infections. In orthopedics, cardiac, vascular and other clean surgical
      procedures, staphylococci (S. aureus and coagulase-negative staphylococci) are
      responsible for 70-90% of post-surgical infections. The isolation of methicillin
      resistant strains has also risen to alarmingly high rates. This article focuses
      on the results of clinical trials on the efficacy of teicoplanin as prophylaxis
      in clean surgical procedures.

PMID- 12481488
TI  - [Teicoplanin in the treatment of bone and joint infections due to methicillin
      resistant staphylococci. Experience in adult patients].
AB  - We retrospectively evaluated 89 episodes of bone and joint infections due to
      methicillin-resistant staphylococci: 56 chronic osteomyelitis (CO), 10 septic
      arthritis (SA) and 23 infections associated to arthroplasties (IAA). We analyzed
      the efficacy of Teicoplanin (T) in three times a week or daily administration
      schemes and adequate surgery (AS). Also, we determined cost savings derived from
      outpatient parenteral antibiotic therapy (OPAT). The overall efficacy of T in CO
      and both in cases with and without implants, was higher when antibiotic therapy
      was associated to AS (86 vs. 46%, p = 0.001; 100 vs. 33%, p = 0.0049 and 76 vs.
      50%, p = 0.09). All SA were cured. The overall efficacy of T was higher in IAA
      with implant removal vs. surgical debridement (100 vs. 54%, p = 0.045). In all
      cases, T was similarly effective when administered three times a week vs. daily
      administration, when associated to AS. The savings derived from OPAT were 897
      days/bed and USS 179,400. Adverse effects were few and light (8 episodes, 9%).
      The results obtained are similar to those published in the literature and show
      that T administered daily or in a three times a week scheme and associated to AS,
      is effective and safe for the treatment of bone and joint infections. The savings
      derived from OPAT, mainly related to reduced hospitalization, are significant in
      these pathologies, which usually require long treatment periods.

PMID- 12481489
TI  - [Role of teicoplanin in the ambulatory treatment of infections in children due to
      gram-positive microorganisms].
AB  - Infections caused by Gram-positive bacteria remain a major cause of morbidity and
      mortality. Teicoplanin is a glycopeptide antibiotic with similar spectrum to
      vancomycin. Easy administration and dosage encourage its use in children,
      particularly due to its long half-life which allows single daily dose regimens.
      We evaluated the efficacy of teicoplanin in severe infections in children due to
      Gram-positive organisms. We retrospectively analyzed 171 children with proven or
      suspected Gram-positive infection treated with teicoplanin between January 1996
      and December 2000. Of them, 166 cases were valuable for clinical assessment.
      Staphylococcus aureus (72) and coagulase-negative staphylococci (38) were the
      most frequent pathogens isolated. Osteoarthritis (35) and catheter-related
      infections (31) were the predominant clinical foci. The cure and improvement
      rates were 88% (150 patients) and 5% (9 patients) respectively. There were 7 (4%)
      cases of therapeutic failure. Mean treatment duration was 10 +/- 34.3 days
      (range: 1-205). Adverse events were registered in 11 patients (6%, 15 adverse
      events). In this study population, teicoplanin was safe and effective in the
      ambulatory treatment of severe Gram-positive infections in children.

PMID- 12481490
TI  - [Pharmacokinetic characteristics and antimicrobial spectrum of teicoplanin].
AB  - Teicoplanin is a glycopeptide antibiotic with similar spectrum to vancomycin. Its
      long half-life permits administration in a single daily dose. The adverse effects
      of teicoplanin are less frequent than those of vancomycin. Rash and local
      intolerance are the most frequent. Staphylococcus aureus, coagulase-negative
      staphylococci and Enterococcus sp. are susceptible to teicoplanin. Clinical data
      have shown teicoplanin to be less nephrotoxic than vancomycin when combined with
      amino glycosides. Teicoplanin, alone or in combination with additional
      antibacterial drugs, has proven to be effective in the treatment of several Gram
      positive infections, such as sepsis, bone and joint infections, endocarditis and
      skin and soft tissue infections. Clinical efficacy was obtained in more than 90%
      of the patients treated. Similar data have been reported in adults, children and
      elderly patients. Due to its easy administration and dosage, teicoplanin is a
      treatment of choice for outpatient parenteral therapies.

PMID- 12481491
TI  - [The clinic osteology, a necessity or an atavism?].

PMID- 12481492
TI  - [Repercussion of age on management of neoplastic patients in an Internal Medicine
      Service].
AB  - AIM: To determine whether age is a factor affecting the management of patients
      diagnosed with neoplastic disease in an internal medicine service. PATIENTS AND
      METHODS: Prospective study of 388 patients diagnosed with cancer in the internal
      medicine service of a large public health teaching hospital. We evaluated
      clinical characteristics, diagnostic procedures, types and stage of neoplasm,
      referral after hospital discharge and treatment. A comparative study based on age
      was performed between patients 65 years older and patients under this age.
      RESULTS: The 388 cancer patients accounted for 12% of hospital admissions in our
      service. Among the total, 62% were > or = 65 years old. Constitutional syndrome,
      the most frequently associated symptom and the main reason for the consultation,
      was more common in the > or = 65-year-old group. Lung cancer was predominant in
      men and hematologic neoplasms in women. Patients > or = 65 were referred more
      frequently to internal medicine physicians, general practitioners and home
      palliative assistance services (p < 0.05) and they received only palliative
      treatment in a greater percentage of cases (50% vs. 37%, p = 0.001). CONCLUSIONS:
      The incidence of neoplasms in our service was high (12%), with a considerable
      percentage of patients in advanced phases of the disease (83%). Age was not
      related to diagnostic methods nor was it determinant in the staging, but it did
      have repercussions on treatment; patients > or = 65 received palliative treatment
      alone more often than younger patients.

PMID- 12481493
TI  - [Nosocomial infection/colonization of the respiratory tract caused by
      Acinetobacter baumannii in an Internal Medicine ward].
AB  - BACKGROUND: To present the epidemiology of the outbreak and the description of
      patients with infection or colonization of the respiratory tract caused by A.
      baumannii in an Internal Medicine ward. METHODS: 20 consecutively patients
      hospitalized in the Internal Medicine ward were studied during 18 months with
      isolation of multiresistant A. baumanni in respiratory tract specimens with or
      without clinical signs of infection. RESULTS: Starting on an index case, that was
      a patient coming from other hospital with diagnosis of nosocomial Acinetobacter
      pneumonia, we detected 20 patients. The age of the patients ranged from 48 to 95
      years, with a mean of 71.4 years. Eighty percent were males. The clinical
      features were similar: advanced age, with chronic diseases (35 percent diabetics,
      45 percent with chronic lung diseases), and use of broad-spectrum antibiotics
      agents, fundamentally third generation cephalosporin (70 percent), clarithromycin
      (55 percent) and quinolones (30 percent). 75 percent of patients were in the same
      ward. Eight (40 percent) of the patients with chronic lung diseases were subjects
      with COPD, two with asthma and chronic glucocorticoids treatment, and one with a
      sleep apnea. In four cases the isolation was considered a colonization. The mean
      stay was 26.15 days, and the mortality 40 percent. CONCLUSIONS: The nosocomial
      infection caused by Acinetobacter baumannii is responsible of a high morbi
      mortality between the patients hospitalized in an Internal Medicine ward, and
      produce an increase in length of stay. It is necessary a combination of control
      measures to prevent the transmission in the hospital and the outbreak of new
      multiresistant strains.

PMID- 12481494
TI  - [Cost-effectiveness analysis of Ramipril treatment of patients at high-risk of
      cardiovascular events in Spain].
AB  - INTRODUCTION AND OBJECTIVES: The cost-effectiveness of adding ramipril to the
      regular treatment of patients at high risk of suffering cardiovascular events was
      calculated. METHODS: A retrospective pharmacoeconomic model was used. The
      clinical data were obtained from a randomized clinical trial of 9,297 patients
      (the HOPE study). Information about resource use and the associated costs was
      obtained from Spanish sources. The analysis was undertaken from the perspective
      of the National Health System, focusing on drug costs and the primary and
      secondary complications of cardiovascular events. RESULTS: The incremental cost
      per life-year gained in the base case was 10,329 euros (6% discount rate). A
      sensitivity analysis showed that the results were more sensitive to changes in
      estimated post-trial life expectancy than to any other variable. The estimated
      number of cases of myocardial infarction, stroke, or cardiovascular death
      prevented in five years ranged from 19,000 to 39,000. CONCLUSIONS: The addition
      of Ramipril to the conventional treatment of patients at high cardiovascular risk
      is cost-effective and less expensive per life-year gained than several treatments
      currently financed by the Spanish National Health System.

PMID- 12481495
TI  - [Acute hepatic failure in a teaching hospital: a review of 20 cases in the past
      seven years].
AB  - Acute liver failure (ALF) is a medical emergency which entails a multisistemic
      affectation almost always. Twenty cases of ALF have been reviewed in a teaching
      hospital with active liver transplantation programme. A high percentage of
      patients with alcohol abuse was observed although these patients did not have
      previously known hepatic damage. Although microbiological, toxicological and
      anatomopatological studies were performed in all cases, an important difficulty
      for establishing the etiologic agent was observed. We observed a worse prognosis
      in those patients older than 40, those with grade IV encephalophaty and those
      that did not undergo a liver transplantation. Most patients needed UCI attention
      and more than half died.

PMID- 12481496
TI  - [Bilateral primary adrenal lymphoma: an unusual presentation].
AB  - A case of primary adrenal bilateral non-Hodgking lymphoma, with depressed adrenal
      reserve is presented. This rare neoplasm causes rapid evolution and fatal outcome
      in most cases. In our patient, lethal outcome was associated with severe
      hypercalcemia and refractary hypotension. Many other complications are due to
      tumoral lysis syndrome associated with high steroid doses in adrenal
      insufficiency. This rare entity must be included in the differencial diagnosis of
      adrenal masses, uni or bilateral, because early diagnostic is important for
      preventing complications, potentially lethals and for improving survival. Image
      thecnics and ultrasound-guided or computed-tomography-guided FNA, are best
      diagnostic methods, but in many cases, definitive diagnostic is obtained by
      necropsy.

PMID- 12481497
TI  - [Anaplastic large cell lymphoma. Report of an unusual case].
AB  - An anaplastic large cell lymphoma which fulfills all the criteria required for
      its inclusion among the soft tissue forms is reported. We point out in this case,
      in addition to its low frequency in adults, the severe systemic involvement of
      the disorder with out generalization, the lack of expression of the ALK1 protein,
      frequently positive in the generalized forms and the absence of response to
      polichiomiotherapy. We think that this case emphasizes the heterogenicity if the
      disorder on the clinical pathologycal relation ship of this kind of lymphomas.

PMID- 12481498
TI  - [Multivisceral infarcts are complication of invasive aspergillosis].
AB  - Aspergillus fumigatus is one of the species of Aspergillus that causes
      aspergillosis. The clinical picture of invasive-disseminated aspergillosis is
      generally characterized by fever and respiratory distress that usually follows a
      fatal course. This form of intensive aspergillosis is suffered by severely
      immunossuppressed patients. There is another clinical form of severe
      aspergillosis, aortic aspergillosis, that appears after cardiac surgery. We
      present two cases of invasive aspergillosis complicated by multiple visceral
      infarcts involving the liver, spleen, kidneys, pancreas, thiroid and brain.
      Infarcts were confirmed in necropsy and appeared to be caused by an overwhelming
      amount of intravascular hiphae, which were observed in the infarcted areas acting
      forming septic embolus. We believe that multi-visceral infarcts are an
      underestimated complication of invasive aspergillosis. Given the progressive
      increase in the population of immunossuppressed patients, clinicians have to
      aware of all the possible presentations of invasive aspergillosis.

PMID- 12481499
TI  - [Treatment of hepatocellular carcinoma].
AB  - Hepatocellular carcinoma develops in more of 90% of patients in the setting of
      cirrhosis. The increasing prevalence seems related with the wide-spread
      distribution of hepatitis C virus infection, as 80% of cases arise on chronic
      infection caused by this agent. Either conventional resection or orthotopic liver
      transplantation are often curative but suitable for few patients, If the surgical
      approach is not adequate, percutaneous ablation using ethanol injection or
      radiofrequency current may be considered. However, only 15-20% of patients can
      benefit from these therapies. Chemoembolization is considered when the previous
      options are contra-indicated but benefits on survival are still a matter of
      debate. The impact of new agents as tamoxifen, interferon o diverse
      chemotherapies on both survival and symptoms also remains to be stablished.

PMID- 12481500
TI  - [Hematological abnormalities in patients with systemic lupus erythematosus].
AB  - Haematological abnormalities are frequently encountered in patients with systemic
      lupus erythematosus (SLE). Anaemia is the most common hematological abnormality
      in SLE, it is multifactorial. The most common form of anaemia is that of chronic
      disease, and it is relate with inflammatory cytokines. Other tips of anaemia are:
      iron deficiency anaemia, autoimmune haemolytic anaemia, pure red cell aplasia.
      Leucopenia is related to neutropenia and/or lymphopenia. Thrombocytopenia is
      common, autoimmune and associated with a decreased survival. The presence of
      antiphospholipid antibodies increase risk of thrombosis in patients with SLE.

PMID- 12481501
TI  - [Acute myocardial infarction in a pregnant woman due to a coronary artery
      dissection].

PMID- 12481503
TI  - [Pruritus and hypercalcemia as presentation of sarcoidosis].

PMID- 12481502
TI  - [Abdominal pain and necrobacillosis].

PMID- 12481504
TI  - [Bilateral lung tuberculosis and over-infection by Hafnia alvei].

PMID- 12481505
TI  - [Carcinoma of the colon associated to ectopic ACTH secretion].

PMID- 12481506
TI  - [Doxazosin and urinary incontinence].

PMID- 12481507
TI  - [Hypokalemic paralysis as presentation of thyrotoxicosis].

PMID- 12481508
TI  - [Atypical manifestation of metastatic melanoma].

PMID- 12481509
TI  - [Hepatic failure secondary to hepatitis due to amoxicillin-clavulanic acid.
      Treatment with corticoids].

PMID- 12481510
TI  - [Clinical and neurological aspects of schizophrenia. The disease structure of
      schizophrenia].

PMID- 12481511
TI  - [How do clozapine and co. work? Pharmacologic mechanisms of atypical
      neuroleptics].

PMID- 12481512
TI  - [Important to atypical antipsychotics: pharmacokinetics, interaction potential
      and therapeutic drug monitoring].

PMID- 12481513
TI  - [Fewer adverse effects! Treatment with atypical neuroleptics].

PMID- 12481514
TI  - [The contribution of clinical pharmacy: optimization of administration in
      schizophrenic disorders].

PMID- 12481515
TI  - [Expensive but nevertheless cost effect? Pharmacoeconomics of atypical
      neuroleptics].

PMID- 12481516
TI  - [Continuous subcutaneous infusion in palliative care, an undervalued method].
AB  - Three patients, 2 men aged 55 and 54 years and a woman aged 86 years, were
      admitted to hospital for treatment of symptoms resulting from terminal disease
      (pain, agitation, nausea etc.). In all three patients, continuous subcutaneous
      infusion (CSI) of medication was successfully used to control the symptoms.
      Compared with intravenous infusion, the technique of CSI is easy to learn and is
      associated with fewer complications. Its reliability and ease-of-use make it a
      technique that can be used not only in a hospital setting, but also in general
      practice and nursing homes. Medication used in palliative care (e.g. morphine,
      haloperidol, metoclopramide, levomepromazine, midazolam) can often be
      administered safely by CSI. In palliative care, where goals should be
      accomplished with minimal burden to the patient, CSI must be considered the
      technique of choice in patients who are unable to swallow their medication.

PMID- 12481517
TI  - [Nutrition and health].
AB  - In this issue the journal publishes the first of a series of articles on
      nutrition and health. Dutch investigators have contributed to food research since
      the work of Eijkman and co-workers on vitamins at the end of the nineteenth
      century. During the last forty years, food research has moved towards
      investigating the role of nutrients in the prevention of diseases with a long
      latency and in specific population groups, e.g. the elderly and people with
      hypertension or obesity. More recent research has focused on enriched food
      products and biotechnologically manufactured nutritional elements. The series
      will discuss subjects such as dietary reference intakes, dietary infections,
      dietary requirements of the elderly and patients in hospitals and rehabilitation
      institutions, and the beneficial and detrimental effects of alcohol consumption.
      This will enable the clinician to provide answers to patients' questions
      regarding their diet and to recommend a healthy diet.

PMID- 12481518
TI  - [Nutrition and health--recommendations of the Health Council of the Netherlands
      regarding energy, proteins, fats and carbohydrates].
AB  - The present report of the Health Council of the Netherlands, entitled 'Dietary
      reference intakes: energy, proteins, fats and digestible carbohydrates' is the
      second of a series of updated and revised recommendations in which the emphasis
      has shifted from nutritional deficiencies to the risks for some chronic diseases
      caused by the affluent nutrition of the 'developed' Western countries. The
      recommendation for total fat differs between people with an optimum weight and
      those who are overweight. The range for normal intake, from 20 to 40 energy per
      cent, has been enlarged due to a higher upper threshold. For persons who are
      already overweight, the narrower range from 20 to 30/35 energy percent has been
      maintained. Due attention should be given to the fatty acid composition of the
      fat and the favourable effects of unsaturated fatty acids on some chronic
      diseases, particularly coronary heart disease. The adequate intake of alpha
      linolenic acid has been raised to 1 energy per cent while maintaining linoleic
      acid at 2 energy per cent. The benefits of the n-3-polyunsaturated fatty acids
      from fish are emphasised. Trans fatty acids should be limited to 1 energy per
      cent. The recommendation of 50 to 40 energy per cent for digestible carbohydrates
      from birth to old age is lower than in foreign recommendations. The estimate is
      derived from the production of endogenous glucose. No specific effects on chronic
      diseases are known. The recommended dietary allowances for protein are lower than
      those in the previous Dutch recommendation. They are now in line with most
      recommendations in other countries. With respect to the energy requirement, an
      abnormal level of physical activity should be reflected in a correction factor on
      the normal energy consumption.

PMID- 12481519
TI  - [Nutrition and health--fish fatty acids against fatal coronary heart disease].
AB  - There are strong indications that eating (fatty) fish or n-3 fatty acids from
      fish reduces the risk of fata coronary heart disease (CHD). Observational studies
      in the general population show that consumption of moderate amounts of fish or n
      3 fatty acids from fish are associated with a lower risk of fatal coronary heart
      disease and in particular sudden cardiac death. The most plausible hypothesis is
      that n-3 fatty acids reduce the risk of CHD mortality via anti-arrhythmic
      effects. Two clinical intervention trials show that prescription of fish or n-3
      fatty acids to patients with prior myocardial infarction is effective in
      preventing mortality due to CHD. Ongoing trials will have to prove the
      effectiveness of a low dose of n-3 fatty acids and show that the underlying
      mechanism involves a protective effect against life-threatening arrhythmias. In
      addition to other recommendations for a healthier diet and lifestyle, consumption
      of one or two fatty fish meals a week is a highly effective and safe measure to
      reduce CHD mortality in both the general population and patients.

PMID- 12481520
TI  - [Diagnostic image (115). A comatose woman after a car collision. Subdural 'contre
      coup'-hematoma without cranial fracture, with brain edema, and crowding].
AB  - A 70-year-old woman was hit by a truck from her right side when riding her
      bicycle. CT revealed contre-coup severe brain injury.

PMID- 12481521
TI  - [Non-fatal rupture of a cocaine packet in a man with the 'bodypacker' syndrome].
AB  - A 24-year-old patient was admitted to the intensive care unit because he had
      swallowed about 20 cocaine packets 48 hours before admission; he also complained
      of abdominal cramps, perspiration and dizziness. The patient reported that he had
      not defecated since swallowing the packets. Abdominal X-ray revealed only
      coprotasis. On conservative therapy with bowel irrigation, two packets were
      eliminated, after which a second abdominal X-ray revealed several cocaine packets
      in the colon. Four days afterwards, the cocaine packets in the colon had not
      progressed despite adequate bowel irrigation. The patient now showed signs of
      mild cocaine intoxication (hallucinations and tachycardia). It was therefore
      decided to perform a laparotomy. Via a sigmoidotomy, 7 intact packets were
      removed; another 3 had already ruptured and were empty. The rupture of 3 cocaine
      packets in this patient was probably not fatal because of the sedation with
      midazolam and because the patient had diarrhoea as a result of the extensive
      irrigation, so that a large proportion of the cocaine was probably not absorbed.
      This case also shows that the presence of foreign bodies cannot be established
      adequately by an abdominal X-ray if there is coprostasis.

PMID- 12481522
TI  - [Information provision for the biomedical sciences in the Netherlands faces an
      uncertain future].
AB  - The availability of biomedical information in the Netherlands is largely
      guaranteed by the libraries of the eight medical faculties and related university
      hospitals together with the Netherlands Institute for Scientific Information
      Services (Dutch acronym: NIWI). The acquisition of biomedical journals has always
      been coordinated at a national level. Up until now the NIWI has played a central
      role in filling in the gaps left by the other collections. It also functions as a
      national archive and a main document delivery centre. The NIWI receives financial
      support from the Dutch government to perform these tasks. Recently, NIWI
      announced that it intends to terminate its acquisition and document delivery
      service for the biomedical sciences. The remaining eight libraries foresee a
      number of negative effects if no alternatives to the present NIWI service are
      developed. We are of the opinion that this situation necessitates a national,
      biomedical information strategy.

PMID- 12481523
TI  - [Information provision for the biomedical sciences in the Netherlands remains
      safe guarded].
AB  - In view of the rapid development of electronic journals covering the biomedical
      sciences, the Netherlands Institute for Scientific Information Services has
      decided to review its document delivery services. The Institute will cancel all
      of its journal subscriptions at the end of 2002. This will not affect services
      provided to users of the library. Requests for documents from the collection will
      continue to be honoured. Cooperation with other European libraries, in particular
      with the German Central Library of Medicine in Cologne, will ensure continued
      access to a broad collection of journals. However, users will need to ensure that
      they prepare themselves for the world of digital journals. Document delivery is
      seen as a substitute for fully-fledged digital access.

PMID- 12481524
TI  - [More care for a limited budget; a case for a better use of the efficiency
      criteria].
AB  - A systematic consideration of the cost-effectiveness in decisions concerning the
      financing and implementation of healthcare technologies would contribute to the
      efficiency of the Dutch healthcare system. This consideration applies to the
      initial decision to finance a project, the periodic testing of this on the basis
      of practice data and the policy to promote a cost-effective approach in daily
      practice (via practice guidelines). Bearing in mind that the government has
      decided to allocate few additional resources to healthcare, it should undertake
      measures to ensure the systematic use of such information in these steps. The
      National Institute for Clinical Excellence (NICE) in the United Kingdom can serve
      as an example, where broadly supported guidelines are drawn up with systematic
      attention for the cost-effectiveness and the implications for healthcare. Within
      this context the question arises as to whether a Dutch variant of NICE is needed.

PMID- 12481525
TI  - [The budget control function of the Drug Reimbursement System].

PMID- 12481526
TI  - [Surgical treatment of primary hyperparathyroidism: minimally invasive if
      possible, conventional neck exploration if necessary].

PMID- 12481527
TI  - [Aplasia cutis congenita in 4 infants].

PMID- 12481528
TI  - [From gene to disease; a defect in the regulation of protein production leading
      to vanishing white matter].

PMID- 12481530
TI  - [Introduction to the theme. Competence to make decisions in the elderly].

PMID- 12481531
TI  - [Competence to make decisions: the psychology of deliberate decision making].
AB  - This paper examines the psychological structure of mental competence, conceived
      of as competence in deliberate decision making. Analysis of that structure may be
      useful in understanding mental incompetence, as it occurs among some elderly
      persons. Mental competence not only depends on a number of cognitive abilities,
      such as foreseeing consequences, but also on the intactness of emotions, insight
      in one's own emotions, and abilities for emotion regulation.

PMID- 12481532
TI  - [Mental competence and elderly care].
AB  - Competence or decision-making capacity are concepts, which are far from clear
      cut. The normative consequences of an incapacity-judgment in elderly care require
      a balanced approach, which takes into consideration the risk of misuse in the
      context of the justification of interventions that are applied without consent of
      the patient. In this article a number of central issues in the debate on decision
      making capacity are discussed. The different criteria, which are proposed to
      assess capacity, are discussed as well as the development of instruments in order
      to objectify capacity. It is concluded that the common approach towards decision
      making capacity, which is strongly cognitive-oriented, is inadequate. A number of
      relevant aspects remain underexposed within this approach. A broader approach is
      explored, which takes into account the role of emotions, identity, and dialogue
      and deliberation. The different approaches are illustrated by way of a case
      example.

PMID- 12481533
TI  - [The assessment of competence in cognitively impaired elderly persons: a closer
      look at the vignette method].
AB  - This article focuses on the assessment of competence of elderly persons both with
      and without cognitive impairment. In total 113 patients of a geriatric clinic
      were interviewed. Competence was assessed by using two clinical vignettes,
      representing respectively a hypothetical treatment situation with mild
      consequences (endoscopy) and one with severe consequences (operation for colon
      cancer). Competence was evaluated using the following standards: the ability to
      evidence a choice, the ability to understand a situation, the ability to reason
      about a choice, and the ability to appreciate a situation. In the vignette with
      mild consequences, elderly persons with cognitive impairment performed
      significantly worse on understanding, reasoning and appreciation than elderly
      persons without cognitive impairment. In the vignette with severe consequences,
      elderly persons with cognitive impairment performed significantly worse only on
      understanding as compared to elderly persons without cognitive impairment. No
      differences were found for reasoning and appreciation between the cognitively
      impaired and non-impaired elderly persons. We conclude that competence is less
      limited by cognitive impairment when assessed in a treatment situation with
      severe consequences. Therefore, the use of hypothetical vignettes should be
      carefully reconsidered.

PMID- 12481534
TI  - [Mental competence and long term care: an uncomfortable relationship].
AB  - Competency is an important concept in medical ethics as well as in law. It refers
      to the moral principles of self-determination and autonomy, which are of central
      importance in the ethics of health care. These moral principles also prevail in
      nursing home care. Societal prejudice concerning nursing home patients suggests
      that the inhabitants of a nursing home are almost by definition incompetent. We
      assert that such prejudice rests on certain societal delusions and
      misinterpretations of incompetency five of which are subsequently analysed. Next
      we discuss the dominant conception of competency in terms of decisional capacity.
      This conception is predominantly oriented towards cognitive abilities and
      underplays affective capacities. We confront this dominant conception with an
      alternative proposal of competency in terms of 'the capacity to value', which--to
      our opinion--more properly reflects nursing home practice concerning questions of
      competency. Finally we address the limitations of any concept of competency or
      decisional capacity in relation to the moral issues of 'good care' for demented
      elderly. As an alternative we draw attention to the moral perspective of the
      'ethics of care'.

PMID- 12481535
TI  - [Advanced directives. Legal and practical aspects of negative instructions
      concerning medical treatment].
AB  - The right of a competent patient to stipulate in advance of possible non
      competence, medical treatment he does not want, is based on the fundamental legal
      principle that a person cannot be medically treated without his informed consent.
      It is in Dutch law a strong and almost unqualified right. There are indications
      in the international literature, however, that advance directives in many cases
      may not have much influence on medical treatment at the end of life. Very little
      is known about the social practice of advance directives in the Netherlands.

PMID- 12481536
TI  - [Second evaluation BOPZ (Special Survey in Psychiatric Hospitals): from BOPZ to
      WGBO (The Medical Treatment Agreement)?].

PMID- 12481537
TI  - [Veterinary medicine in the 21st century: a liberal or commercial profession?].

PMID- 12481538
TI  - [Ferrets in veterinary practice].
AB  - Ferrets (Mustela putorius furo) show up with increasing frequency in veterinary
      practice. Originally domesticated for hunting of rodents and rabbits, they became
      very popular pets which require legal permission though and the further
      fulfillment of various husbandry needs. Ferrets have to be maintained on a high
      protein diet which in practice is often done with commercial feline products.
      Physical examination is similar to dogs and cats whereas the frequent occurrence
      of non-specific symptoms require further diagnostic investigation including blood
      sampling, radiology, ultrasound or exploratory laparatomy. The preferred
      anaesthetic method is the direct face mask induction and maintenance using
      isoflurane without pramedication. Special attention of veterinarians has to be
      paid to canine distemper vaccination, the specialized reproduction physiology of
      the females (jills) which can develop, if unmated, a persistent oestrus with
      fatal consequences of hyperestrogenism, as well as the frequent occurrence of
      further endocrine disorders, congestive cardiomyopathy and gastrointestinal
      diseases.

PMID- 12481539
TI  - [Anesthesia and analgesia of small mammals. Part 1: Preparation, premedication
      and general anesthesia].
AB  - In today's society small rodents and rabbits are increasingly kept as pets.
      Anaesthesia is necessary for numerous reasons and proves to be a challenge for
      many veterinarians. Following surgical intervention analgesia is frequently
      neglected. This article reviews the preparation of small mammals for anaesthesia,
      the choice of anaesthetics and the possibilities of perioperative care including
      monitoring, complications, fluid therapy and analgesia.

PMID- 12481540
TI  - [Anaesthesia and analgesia of small mammals. Part 2: Intra- and postoperative
      care].

PMID- 12481541
TI  - [Anesthesia and analgesia of ornamental birds].
AB  - Pet birds are frequently viewed as difficult patients for anaesthesia. The
      present paper revises the current anaesthetic procedures for injectable and
      inhalant anaesthetics. Currently the method of choice for the anaesthesia of pet
      birds is the isoflurane inhalation anaesthesia. Special emphasis is given to the
      preanaesthetic preparations. Fasting is shorter for pet birds than for mammals.
      Anaesthetized birds are at special risk for hypothermia. Methods for the
      prevention of heat loss are given. The use of analgesics are recommended both for
      welfare reasons but also because of the possibility to reduce the concentration
      of inhalation anaesthetics and therefore the amount of possible exposure of
      personnel to waste gases.

PMID- 12481542
TI  - Bone growth stimulators. New tools for treating bone loss and mending fractures.
AB  - In the new millennium, humans will be traveling to Mars and eventually beyond
      with skeletons that respond to microgravity by self-destructing. Meanwhile in
      Earth's aging populations growing numbers of men and many more women are
      suffering from crippling bone loss. During the first decade after menopause all
      women suffer an accelerating loss of bone, which in some of them is severe enough
      to result in "spontaneous" crushing of vertebrae and fracturing of hips by
      ordinary body movements. This is osteoporosis, which all too often requires
      prolonged and expensive care, the physical and mental stress of which may even
      kill the patient. Osteoporosis in postmenopausal women is caused by the loss of
      estrogen. The slower development of osteoporosis in aging men is also due at
      least in part to a loss of the estrogen made in ever smaller amounts in bone
      cells from the declining level of circulating testosterone and is needed for bone
      maintenance as it is in women. The loss of estrogen increases the generation,
      longevity, and activity of bone-resorbing osteoclasts. The destructive osteoclast
      surge can be blocked by estrogens and selective estrogen receptor modulators
      (SERMs) as well as antiosteoclast agents such as bisphosphonates and calcitonin.
      But these agents stimulate only a limited amount of bone growth as the unaffected
      osteoblasts fill in the holes that were dug by the now suppressed osteoclasts.
      They do not stimulate osteoblasts to make bone--they are antiresorptives not bone
      anabolic agents. (However, certain estrogen analogs and bisphosphates may
      stimulate bone growth to some extent by lengthening osteoblast working lives.) To
      grow new bone and restore bone strength lost in space and on Earth we must know
      what controls bone growth and destruction. Here we discuss the newest bone
      controllers and how they might operate. These include leptin from adipocytes and
      osteoblasts and the statins that are widely used to reduce blood cholesterol and
      cardiovascular damage. But the main focus of this article is necessarily the
      currently most promising of the anabolic agents, the potent parathyroid hormone
      (PTH) and certain of its 31- to 38-aminoacid fragments, which are either in or
      about to be in clinical trial or in the case of Lilly's Forteo [hPTH-(1-34)]
      tentatively approved by the Food and Drug Administration for treating
      osteoporosis and mending fractures.

PMID- 12481543
TI  - Using GFP--ligand fusions to measure receptor-mediated endocytosis in living
      cells.
AB  - Recombinant DNA technology has enabled the production of many types of chimeric
      proteins containing heterologous functional domains that have served a variety of
      useful capacities for cell biology research. Among proteins gaining wide use as a
      fusion partner is Aequorea victoria green fluorescent protein (GFP). GFP has been
      employed by numerous groups as a reporter gene for cell transfection and as an
      autofluorescent tag by recombinant fusion to foreign sequences. Here we describe
      the use of GFP as a tag for ligands, and provide examples of how purified
      recombinant GFP-ligand fusion proteins may be used to detect ligand-receptor
      interactions, including receptor-mediated endocytosis. Both its utility and
      limitations are discussed.

PMID- 12481544
TI  - Mitochondrial energy dissipation by fatty acids. Mechanisms and implications for
      cell death.
AB  - For most cell types, fatty acids are excellent respiratory substrates. After
      being transported across the outer and inner mitochondrial membranes they undergo
      beta-oxidation in the matrix and feed electrons into the mitochondrial energy
      conserving respiratory chain. On the other hand, fatty acids also physically
      interact with mitochondrial membranes, and possess the potential to alter their
      permeability. This occurs according to two mechanisms: an increase in proton
      conductance of the inner mitochondrial membrane and the opening of the
      permeability transition pore, an inner membrane high-conductance channel that may
      be involved in the release of apoptogenic proteins into the cytosol. This article
      addresses in some detail the mechanisms through which fatty acids exert their
      protonophoric action and how they modulate the permeability transition pore and
      discusses the cellular effects of fatty acids, with specific emphasis on their
      role as potential mitochondrial mediators of apoptotic signaling.

PMID- 12481545
TI  - Trinucleotide repeat disease. The androgen receptor in spinal and bulbar muscular
      atrophy.
AB  - It has been more than 10 years since the discovery that the expansion of a simple
      CAG trinucleotide repeat within the coding region of the androgen receptor gene
      leads to the motor neuronopathy spinal and bulbar muscular atrophy (SBMA). A
      flurry of investigation into this and the other, more recently discovered,
      polyglutamine diseases has led to an understanding of many aspects of the
      molecular pathogenesis of this family of diseases. A characteristics pathological
      feature of the polyglutamine diseases is the occurrence in affected neurons of
      ubiquitinated aggregates; such aggregates also contain, among others, proteins
      involved in the folding and degradation of the mutant proteins. Aggregates
      themselves are likely not directly cytotoxic, but rather mark the accumulation of
      all or part of the mutant protein. Furthermore, aggregation occurs because of the
      inefficient clearance of the mutant protein by the ubiquitin-proteasome pathway
      for protein degradation. These findings are common to the polyglutamine diseases
      and reflect the general problem of folding/degrading expanded polyglutamines. In
      SBMA, the altered metabolism of the androgen receptor is ligand dependent. How
      the accumulation of the mutant protein causes neuronal dysfunction and disease is
      not well understood, but several cellular processes have been implicated.
      Although these findings provide insight into the toxic function of the expanded
      polyglutamine protein, additional investigations have led to the finding that
      intrinsic AR transactivational function is somewhat diminished in the presence of
      the expanded polyglutamine; this likely leads to the partial androgen
      insensitivity that characterizes patients with SBMA. The recent development of
      useful animal and cell models of SBMA will lead to increased understanding of
      disease pathogenesis, as well as to the development of new and better therapeutic
      strategies.

PMID- 12481546
TI  - Human prostacyclin receptor.
AB  - Prostacyclin, a member of the eicosanoid family of lipid mediators, is the major
      product of arachidonic acid metabolism formed in the marcovascular endothelium.
      It is a potent vasodilator, antithrombotic, and antiplatelet agent that mediates
      it effects through a membrane-associated receptor termed the IP. Cloning of the
      cDNA for IP, from human and other species, indicated its membership of the G
      protein-coupled receptor superfamily and has allowed detailed examination of the
      signaling and regulatory pathways utilized by this receptor. This article
      examines the current state of knowledge of the IP, its signaling and regulation,
      and its biological role in vivo and examines the possible existence of multiple
      PGI2 receptor sites.

PMID- 12481547
TI  - Sterol regulatory element-binding protein family as global regulators of lipid
      synthetic genes in energy metabolism.
AB  - Sterol regulatory element-binding proteins (SREBPs) have been established as
      lipid synthetic transcription factors for cholesterol and fatty acid synthesis.
      SREBPs are synthesized as membrane-bound precursors with their N-terminal active
      portions entering the nucleus to activate target genes after proteolytic cleavage
      in a sterol-regulated manner. This cleavage step is regulated by a putative
      sterol-sensing molecule, SREBP-activating protein (SCAP), that forms a complex
      with SREBPs and traffics between the rough endoplasmic reticulum and Golgi. DNA
      cis-elements that SREBPs bind, originally identified as sterol-regulatory
      elements (SREs), now expands to a variety of SRE-like sequences and some of E
      boxes, which makes SREBPs eligible to regulate a wide range of lipid genes.
      Animal experiments including transgenic and knockout mice suggest that three
      isoforms, SREBP-1a, -1c, and -2, have different roles in lipid synthesis. In
      differentiated tissues and organs, SREBP-1c is involved in fatty acid, whereas
      SREBP-2 plays a major role in regulation of cholesterol synthesis. SREBP-1a is
      expressed in growing cells, providing both cholesterol and fatty acids that are
      required for membrane synthesis. SREBP-1c seems to be a mediator for
      insulin/glucose signaling to lipogenesis, and could be involved in insulin
      resistance, remnant lipoproteins, and fatty livers. Future studies in this field
      will certainly focus on understanding the molecular mechanisms sensing cellular
      sterol and energy states leading to the activation of SREBP-mediated gene
      transcription.

PMID- 12481548
TI  - Brassinosteroids. Plant counterparts to animal steroid hormones?
AB  - Brassinosteroids are polyhydroxylated derivatives of common plant membrane
      sterols such as campesterol. They occur throughout the plant kingdom and have
      been shown by genetic and biochemical analyses to be essential for normal plant
      growth and development. Numerous reviews have detailed the recent progress in our
      understanding of the biosynthesis, physiological responses, and molecular modes
      of action of brassinosteroids. It is clear that like their animal steroid
      counterparts, brassinosteroids have a defined receptor, can regulate the
      expression of specific genes, and can orchestrate complex physiological responses
      involved in growth. This review summarizes the current status of BR research,
      pointing out where appropriate the similarities and differences between the
      mechanism of action of brassinosteroids and the more thoroughly studied animal
      steroid hormones.

PMID- 12481549
TI  - Endocannabinoids and their actions.
AB  - Endocannabinoids are a new class of lipid mediators, which includes amides and
      esters of long-chain polyunsaturated fatty acids. Anandamide (I) and 2
      arachidonoylglycerol (II) are the main endogenous agonists of cannabinoid
      receptors, able to mimic several pharmacological effects of delta 9
      tetrahydrocannabinol (III), the active principle of Cannabis sativa preparations
      such as hashish and marijuana. The pathways leading to the synthesis and release
      of anandamide and 2-arachidonoylglycerol from neuronal and nonneuronal cells are
      rather uncertain. Instead, evidence has accumulated showing that the activity of
      these compounds at their specific receptors is limited by cellular uptake through
      a specific membrane transporter, followed by intracellular degradation by a fatty
      acid amide hydrolase. Here, the endocannabinoids and the endocannabinoid-like
      compounds most relevant for human physiology will be discussed, along with the
      synthetic and degradative pathways of anandamide and 2-arachidonoylglycerol and
      their molecular targets on the cell surface. The main actions of the
      endocannabinoids in human cells and tissues will also be reviewed, focusing on
      the activities most recently discovered in the central nervous system and in the
      periphery.

PMID- 12481550
TI  - Endomorphins and related opioid peptides.
AB  - Opioid peptides and their G-protein-coupled receptors (delta, kappa, mu) are
      located in the central nervous system and peripheral tissues. The opioid system
      has been studied to determine the intrinsic mechanism of modulation of pain and
      to develop uniquely effective pain-control substances with minimal abuse
      potential and side effects. Two types of endogenous opioid peptides exist, one
      containing Try-Gly-Gly-Phe as the message domain (enkephalins, endorphins,
      dynorphins) and the other containing the Tyr-Pro-Phe/Trp sequence (endomorphins-1
      and -2). Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has high mu receptor affinity
      (Ki = 0.36 nM) and remarkable selectivity (4000- and 15,000-fold preference over
      the delta and kappa receptors, respectively), was isolated from bovine and human
      brain. In addition, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), isolated from the same
      sources, exhibited high mu receptor affinity (Ki = 0.69 nM) and very high
      selectivity (13,000- and 7500-fold preference relative to delta and kappa
      receptors, respectively). Both opioids bind to mu-opioid receptors, thereby
      activating G-proteins, resulting in regulation of gastrointestinal motility,
      manifestation of antinociception, and effects on the vascular systems and memory.
      To develop novel analgesics with less addictive properties, evaluation of the
      structure-activity relationships of the endomorphins led to the design of more
      potent and stable analgesics. Opioidmimetics and opioid peptides containing the
      amino acid sequence of the message domain of endomorphins, Tyr-Pro-Phe/Trp, could
      exhibit unique binding activity and lead to the development of new therapeutic
      drugs for controlling pain.

PMID- 12481551
TI  - Leptin and melanocortin signaling in the hypothalamus.
AB  - The regulation of body weight in humans is coordinated by the interplay between
      food intake and energy expenditure. The identification of the adipocyte-secreted
      hormone leptin as a key regulator on both of these processes has shed new light
      on the pathways involved in their regulation. Indeed, mutations in the gene's
      encoding leptin and its cognate receptor cause severe obesity in humans. Leptin's
      actions are mediated principally by target neurons in the hypothalamus where it
      acts to alter food intake, energy expenditure, and neuroendocrine-function.
      Recently, it has become clear that a number of critical neuropeptides are
      regulated by leptin in the hypothalamus. Among these is the proopiomelanocortin
      (POMC)-derived peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), which
      is produced in the arcuate nucleus and is a potent negative regulator of food
      intake. Like leptin, mutations in POMC or in central melanocortin receptors lead
      to obesity in humans. Thus, an understanding of the mechanisms by which the
      leptin and melanocortin pathways signal in the hypothalamus is critical in order
      to begin to clarify the pathways involved in regulating body weight in humans.

PMID- 12481552
TI  - Function and regulation of cytosolic molecular chaperone CCT.
AB  - Molecular chaperones are a group of proteins that assists in the folding of newly
      synthesized proteins or in the refolding of denatured proteins. The cytosolic
      chaperonin-containing t-complex polypeptide 1 (CCT) is a molecular chaperone that
      plays an important role in the folding of proteins in the eukaryotic cytosol.
      Actin, tubulin, and several other proteins are known to be folded by CCT, and an
      estimated 15% of newly translated proteins in mammalian cells are folded with the
      assistance of CCT. CCT differs from other chaperonin family proteins in its
      subunit composition, which consists of eight subunit species comprising the CCT
      16-mer double-ring-like complex. CCT preferentially recognizes quasinative (or
      partially folded) intermediates, whereas its Escherichia coli homologue GroEL
      recognizes more unfolded intermediates, especially those displaying hydrophobic
      surfaces. Molecular evolutionary analyses have suggested that each subunit
      species has a specific function in addition to contributing to a common ATPase
      activity. Consistent with this view, it has been suggested that each subunit
      recognizes specific substrate proteins (or their parts) and that they
      collectively modulate the ATPase activity of the complex. The overall expression
      of CCT in mammalian cells is primarily dependent on cell growth, but each subunit
      exhibits an individual patterns of expression. Recent progress in CCT research is
      reviewed, focusing particularly on CCT function and expression. From these
      observations, the possible roles of the distinct subunits in CCT-assisted folding
      in the eukaryotic cytosol are discussed.

PMID- 12481553
TI  - Herbal factors in the treatment of autoimmunity-related habitual abortion.
AB  - Deterioration in the balance of T helper-1 (Th1)/T helper-2 (Th2) during
      pregnancy may cause complications such as habitual abortion. Two types of
      immunity-related abortion are, at present, recognized. One is caused by
      autoimmune disorders as exemplified by the antiphospholipid antibody syndrome, in
      which the Th1/Th2 balance is excessively shifted to polarization of Th2. The
      other is caused by alloimmune fetal-maternal disorder, a condition associated
      with increased serum activity of Th1 cytokines. In Japan, herbal medicines such
      as Sairei-to (Sai) and Tokishakuyaku-san (Toki), which are prepared in granule
      forms and are manufactured, have been used in the treatment of these immunity
      related habitual abortions and were reported to be clinically effective for these
      patients. The clinical effect of these herbal medicines can be explained by how
      they function in the maternal immune system. Sai and Toki enhance Th1 cytokine
      release from peripheral blood mononuclear cells (PBMCs) and might suppress the
      production of autoantibodies from B cells. However, Sai and Toki do not affect
      cytokine release from decidual mononuclear cells (DMCs), which are directly in
      contact with fetal trophoblasts. These herbal medicines might not enhance the
      killer activity of DMCs. Thus, the differential effects of Toki and Sai on the
      release of Th1/Th2 cytokines from PBMCs and DMCs may reveal the rationale for the
      use of these medicines in the treatment of autoimmunity-related habitual
      abortion.

PMID- 12481554
TI  - Vitamin D receptor and retinoid X receptor interactions in motion.
AB  - Vitamin D receptor (VDR) and retinoid X receptor (RXR) are members of the nuclear
      receptor superfamily and they bind target DNA sequences as heterodimers to
      regulate transcription. This article surveys the latest findings regarding the
      roles of dimerizing RXR in VDR function and emphasizes potential areas for future
      developments. We first highlight the importance of dimerization with RXR for both
      the ligand-independent (hair growth) and ligand-dependent functions of VDR
      (calcium homeostasis, bone development and mineralization, control of cell growth
      and differentiation). Emerging information regarding the regulatory control of
      dimerization based on biochemical, structural, and genetic studies is then
      presented. Finally, the main focus of this article is a new dynamic perspective
      of dimerization functions, based on recent research with fluorescent protein
      chimeras in living cells by microscopy. These studies revealed that both VDR and
      RXR constantly shuttle between the cytoplasm and the nucleus and between
      subnuclear compartments, and showed the transient nature of receptor--DNA and
      receptor--coregulator interactions. Because RXR dimerizes with most of the
      nuclear receptors, regulation of receptor dynamics by RXR has a broad
      significance.

PMID- 12481555
TI  - Electron paramagnetic resonance for quantitation of nitric oxide in aqueous
      solutions.

PMID- 12481556
TI  - In vitro detection of nitric oxide and nitroxyl by electron paramagnetic
      resonance.

PMID- 12481557
TI  - Iron dithiocarbamate as spin trap for nitric oxide detection: pitfalls and
      successes.

PMID- 12481558
TI  - Advanced spin trapping of vascular nitric oxide using colloid iron
      diethyldithiocarbamate.

PMID- 12481559
TI  - Simultaneous detection of pO2 and NO by electron paramagnetic resonance.

PMID- 12481560
TI  - Electron paramagnetic resonance studies of nitric oxide in living mice.

PMID- 12481561
TI  - Measuring end products of nitric oxide in vivo.
AB  - The methods we have presented are suitable for measuring end products of the NO
      pathway in biological fluids. In particular, the first part of this article
      demonstrated how standard methods could be improved to increase the sensitivity
      of NO measurements in biological methods. In addition, we showed two
      possibilities for the estimation of NO formation in higher species, as NO
      standard measurements in these species are often not reliable to detect changes
      of the NO pathway.

PMID- 12481562
TI  - Guide for the use of nitric oxide (NO) donors as probes of the chemistry of NO
      and related redox species in biological systems.

PMID- 12481563
TI  - Amperometric measurement of nitric oxide using a polydemethylsiloxane-coated
      electrode.

PMID- 12481564
TI  - Nitric oxide monitoring in hippocampal brain slices using electrochemical
      methods.

PMID- 12481565
TI  - Electrochemical detection of physiological nitric oxide: materials and methods.
AB  - Advances in the electroanalytical technology of NO detection make it possible to
      detect the release of robust concentrations of NO from living systems under
      pathological or pharmacological conditions. However, technical improvements
      should enable the construction of research instruments with one or two orders of
      magnitude improvement in both detection limit and temporal resolution. Such
      instruments would be capable of revealing physiological NO production and could
      help quantify the correlations between NO levels and health or disease,
      ultimately leading to important applications in biomedical research and clinical
      medicine.

PMID- 12481566
TI  - Detection of nitric oxide production by fluorescent indicators.

PMID- 12481567
TI  - Specific analysis of nitrate and nitrite by gas chromatography/mass spectrometry.

PMID- 12481569
TI  - Gas-phase oxidation and disproportionation of nitric oxide.

PMID- 12481568
TI  - Griess method for nitrite measurement of aqueous and protein-containing samples.

PMID- 12481570
TI  - Detection and quantification of nitric oxide (NO) synthase-independent generation
      of NO.
AB  - Nitric oxide formation in ischemia-reperfusion injury can be identified and
      measured directly using EPR of nitroso-heme complexes comprising NO bound to
      either Mb or Hb-Fe2+. This article described the successful use of this method to
      detect and quantify the generation of NO formed independently of nitric oxide
      synthase in ischemia-reperfusion injury to skeletal muscle. The quantification of
      nitroso-heme complexes using EPR is recommended in ischemia-reperfusion studies
      of either skeletal or cardiac muscle that aim to characterize the role of nitric
      oxide.

PMID- 12481571
TI  - Nitric oxide-dependent vasodilation in human subjects.

PMID- 12481572
TI  - Antioxidant and diffusion properties of nitric oxide in low-density lipoprotein.

PMID- 12481573
TI  - Measurements of redox control of nitric oxide bioavailability.
AB  - The assay outlined in this article have been employed successfully by ourselves
      and many other investigators to assess endothelial NO production under conditions
      in which the redox status of the cell has been manipulated. Table I contains
      expected changes in each of the assays (compared to the control state) that one
      would expect to see for specific perturbations in the NO-cGMP axis in endothelial
      cells. Used in combination, these assays can provide considerable insight into
      the effect of cellular redox status on NO bioactivity and provide the
      investigator with a good starting point for further mechanistic studies.

PMID- 12481574
TI  - Reactions of S-nitrosothiols with L-ascorbic acid in aqueous solution.

PMID- 12481575
TI  - Nitrosothiols and S-nitrosohemoglobin.

PMID- 12481576
TI  - Nitrosothiol processing by platelets.

PMID- 12481577
TI  - Nitric oxide-activated glutathione Sepharose.

PMID- 12481578
TI  - Measurement of protein nitration and S-nitrosothiol formation in biology and
      medicine.

PMID- 12481579
TI  - S-glutathionylation of NF-kappa B subunit p50.

PMID- 12481580
TI  - Intercellular signaling mediated by nitric oxide in human glioblastoma cells.

PMID- 12481581
TI  - L-arginine metabolism in Trypanosoma cruzi in the regulation of programmed cell
      death.

PMID- 12481582
TI  - Measurement of mitochondrial respiratory thresholds and the control of
      respiration by nitric oxide.
AB  - The methods described serve to illustrate not only the importance of measuring
      NO. thresholds in mitochondria and cells, but also highlight many of the
      considerations that must be taken when making such measurements. These include
      the presence of O2, the source of NO., the precise design of the apparatus, and
      experimental conditions, such as buffer composition, light level, and
      temperature. When all these factors are considered, accurate interpretations of
      the role of NO. in controlling mitochondrial function can be made. Such
      experiments can provide insight into the intricate nature of the interaction
      between NO. and mitochondria and the variations in this system that can occur
      under both physiological and pathological conditions.

PMID- 12481583
TI  - Determination of nitric oxide-induced effects on tissue levels of glutathione and
      mitochondrial membrane potential.

PMID- 12481585
TI  - Characterization of mitochondrial nitric oxide synthase.

PMID- 12481584
TI  - Pharmacological regulation of mitochondrial nitric oxide synthase.

PMID- 12481586
TI  - Peroxynitrite formation from biochemical and cellular fluxes of nitric oxide and
      superoxide.

PMID- 12481587
TI  - Evaluation of antioxidant activity using peroxynitrite as a source of radicals.

PMID- 12481588
TI  - Peroxynitrite reactions with heme and heme-thiolate (P450) proteins.

PMID- 12481589
TI  - Gas chromatography/mass spectrometry assay for 3-nitrotyrosine.

PMID- 12481590
TI  - Quantitation and localization of tyrosine nitration in proteins.

PMID- 12481591
TI  - Neuronal nitric oxide synthases in brain and extraneural tissues.

PMID- 12481592
TI  - Visualization and distribution of neuronal nitric oxide synthase-containing
      neurons.

PMID- 12481593
TI  - Quantitative measurement of endothelial constitutive nitric oxide synthase.

PMID- 12481594
TI  - Quantitation of expressed message for inducible nitric oxide synthase.
AB  - Methodology for the analysis of expressed message has evolved rather rapidly
      since the early 1990s and will undoubtedly continue to evolve with new
      technology. cRNA standards are a useful tool, which allow for absolute rather
      than relative quantification of an expressed message. Selecting an appropriate
      sequence(s) for analysis has become even more important as techniques have
      evolved from Northern hybridization where possible multiple hybridization bands
      can be observed to real-time Rt-PCR approaches where only a signal is recorded.
      NOS2 presents a particular problem in this regard because of the high
      conservation of sequence with NOS1 and NOS3, as well as the existence of both
      multiple genes and splice variants, which may be of experimental importance.

PMID- 12481595
TI  - Inducible nitric oxide synthase knockout mouse and low-density lipoprotein
      oxidation.
AB  - We have presented experimental procedures that examine macrophage-mediated LDL
      oxidation using Ham's F-10 medium. By comparing iNOS-/- and iNOS+/+ macrophages,
      an antioxidant effect for NO and a prooxidant effect for IFN-gamma were
      demonstrated. The methods outlined here should allow for the investigation on the
      mechanism of in vitro LDL oxidation and how the macrophage-mediated LDL oxidation
      process is affected by various factors, one of which was the effect of iNOS
      induction by IFN-gamma.

PMID- 12481596
TI  - Nitric oxide and resolution of inflammation.

PMID- 12481597
TI  - John M. Eisenberg Patient Safety Awards. Individual lifetime achievement:
      Julianne M. Morath, RN, MS.
AB  - BACKGROUND: This article provides a brief biography of Julianne M. Morath,
      describes the scope and impact of her patient safety initiatives at Children's
      Hospitals and Clinics in Minneapolis and St Paul, and includes an interview in
      which Morath responds to questions about challenges to patient safety and medical
      accident reduction. BIOGRAPHY IN BRIEF: With a 25-year career spanning the
      spectrum of health care, Morath has served in leadership positions in health care
      organizations in Minnesota, Rhode Island, Ohio, and Georgia. LEADERSHIP AT THE
      FRONT LINE: Morath joined Children's Hospitals and Clinics in 1999 and launched a
      major patient safety initiative that put Children's on the map. Elements of the
      initiative included a culture of learning, patient safety action teams, open
      discussion of medical accidents and error, blameless reporting, and a full
      accident disclosure policy. AN INTERVIEW WITH JULIE MORATH: As the greatest
      challenge to leadership ownership of the patient safety initiative, Morath cites
      the need to confront the myths of the medical system and to develop the awareness
      of the issues of patient safety. She believes that clinicians on the front lines
      will be convinced that patient safety isn't "just another fad of the month" when
      leadership action is disciplined and aligns with what is being espoused. She
      advises other leaders of health care organizations interested in establishing a
      culture of safety to start with a personal and passionate belief that harm-free
      care is possible, to commit to informed action, and to identify and develop
      champions throughout the organization and medical staff.

PMID- 12481598
TI  - John M. Eisenberg Patient Safety Awards. Advocacy: the Lexington Veterans Affairs
      Medical Center.
AB  - BACKGROUND: After the Veterans Affairs Medical Center (VAMC) in Lexington,
      Kentucky, lost two major malpractice cases in the mid-1980s, leaders started
      taking a more proactive approach to identifying and investigating incidents that
      could result in litigation. An informal risk management team met regularly to
      discuss litigation-prone incidents. During one in-depth review, the team learned
      that a medication error had caused the patient's death. Although the family would
      probably never have found out, the team decided to honestly inform the family of
      exactly what had happened and assist in filing for any financial settlement that
      might be appropriate. This decision evolved into an organization wide full
      disclosure policy and procedure. DISCLOSURE POLICY AND PROCEDURE: The Lexington
      VAMC's policy on full disclosure includes informing patients and/or their
      families of adverse events known to have caused harm or injury to the patient as
      a result of medical error or negligence. The disclosure includes discussions of
      liability and also includes apology and discussion of remedy and compensation.
      RESULTS: Full disclosure is the right thing to do and the moral and ethical thing
      to do. Moreover, doing the right thing actually seems to have mitigated the
      financial repercussions of inevitable adverse events that result in injury to
      patients. As reported in 1999, Lexington VAMC was in the top quarter of medical
      centers for number of tort claims filed but was in the lowest quarter for
      malpractice payouts resulting from these torts.

PMID- 12481599
TI  - John M. Eisenberg Patient Safety Awards. Research: David W. Bates, MD, MSc,
      Brigham and Women's Hospital. Interview by Steven Berman.
AB  - Dr Bates discusses the challenges and rewards of computerized physician order
      entry and other information technology applications and describes current work in
      improving medication safety across clinical settings.

PMID- 12481600
TI  - John M. Eisenberg Patient Safety Awards. System innovation: Veterans Health
      Administration National Center for Patient Safety.
AB  - BACKGROUND: In 1998 the Veterans Health Administration (VHA) created the National
      Center for Patient Safety (NCPS) to lead the effort to reduce adverse events and
      close calls systemwide. NCPS's aim is to foster a culture of safety in the
      Department of Veterans Affairs (VA) by developing and providing patient safety
      programs and delivering standardized tools, methods, and initiatives to the 163
      VA facilities. A NOVEL APPROACH: To create a system-oriented approach to patient
      safety, NCPS looked for models in fields such as aviation, nuclear power, human
      factors, and safety engineering. Core concepts included a non-punitive approach
      to patient safety activities that emphasizes systems-based learning, the active
      seeking out of close calls, which are viewed as opportunities for learning and
      investigation, and the use of interdisciplinary teams to investigate close calls
      and adverse events through a root cause analysis (RCA) process. Participation by
      VA facilities and networks was voluntary. NCPS has always aimed to develop a
      program that would be applicable both within the VA and beyond. KEY ACTION ITEMS
      AND RESULTS RELATED TO RCA: NCPS's full patient safety program was tested and
      implemented throughout the VA system from November 1999 to August 2000. Program
      components included an RCA system for use by caregivers at the front line, a
      system for the aggregate review of RCA results, information systems software,
      alerts and advisories, and cognitive acids. Following program implementation,
      NCPS saw a 900-fold increase in reporting of close calls of high-priority events,
      reflecting the level of commitment to the program by VHA leaders and staff.

PMID- 12481601
TI  - John M. Eisenberg Patient Safety Awards. System innovation: Concord Hospital.
AB  - BACKGROUND: The Cardiac Surgery Program at Concord Hospital (Concord, NH)
      restructured clinical teamwork for improved safety and effectiveness on the basis
      of theory and practice from human factors science, aviation safety, and high
      reliability organization theory. A team-based, collaborative rounds process--the
      Concord Collaborative Care Model--that involved use of a structured
      communications protocol was conducted daily at each patient's bedside. METHODS:
      The entire care team agreed to meet at the same time each day (8:45 AM to 9:30
      AM) to share information and develop a plan of care for each patient, with
      patient and family members as active participants. The cardiac surgery team
      developed a structured communications protocol adapted from human factors
      science. To provide a forum for discussion of team goals and progress and to
      address system-level concerns, a biweekly system rounds process was established.
      RESULTS: Following implementation of collaborative rounds, mortality of Concord
      Hospital's cardiac surgery patients declined significantly from expected rates.
      Satisfaction rates of open heart patients scores were consistently in the 97th
      99th percentile nationally. A quality of work life survey indicated that in every
      category, providers expressed greater satisfaction with the collaborative care
      process than with the traditional rounds process. Practice patterns in the
      Cardiac Surgery Program at Concord Hospital have changed to a much more
      collaborative and participatory process, with improved outcomes, happier
      patients, and more satisfied practitioners. A culture of continuous program
      improvement has been implemented that continues to evolve and produce benefits.

PMID- 12481602
TI  - [Cytopathological effect of Bacillus thuringiensis israelensis endotoxins on the
      intestines of Aedes aegypti mosquito larvae].
AB  - The dynamics of pathological changes in the intestine of Aedes aegypti larvae
      under the influence of toxins Cry11A and Cry4B produced by Bacillus thuringiensis
      israelensis was studied by means of electron microscope. Most significant
      ultrastructure changes in the intestine of the second instar larvae were observed
      in the midgut. The cytoplasm of cells disintegrated, and elongated lacunae
      appeared. The number of microvilli decreased, or they disappeared in the result
      of destruction. The peritrophic membrane displaced to the lumen of midgut. Any
      changes in epithelial cells and cuticle in time of foregut and hindgut were not
      observed in a comparison to control. The toxin Cry4B caused the most effective
      destruction of the midgut epithelium.

PMID- 12481603
TI  - [Reason for fluctuation in the demographic structure of the taiga tick population
      (Ixodidae) in dark conifer-leaf forests of Kemchug Upland].
AB  - It was found out, that mean ratio of unfed taiga ticks Ixodes persulcatus having
      a life cycle of 3-5 and 6 years counts respectively (N = 6) 33.6, 52.8, 13.2 and
      0.4%. Data on absolute number of I. persulcatus individuals in the process of
      onthogenesis is given. It is shown, that mortality of different unfed stages
      increases from larva to imago. In the autumn-winter period, the mean ratio of
      eliminated individuals counted 16% of larvae, 20% of nymphs, and 38 of imago. The
      mortality in the spring-summer period caused mainly by the deficit of hosts and
      counted for these stages 3, 82 and 98% respectively. Engorged ticks successfully
      undertake unfavorable conditions both in the spring-summer and autumn-winter
      periods. Their mean mortality in the period from feeding to moulting does not
      exceed 12%.

PMID- 12481604
TI  - [Dynamics of infection of Fringilla coelebs chaffinch nestlings with feather
      mites (Acari: Analgoidea)].
AB  - A process of infecting the chaffinch nestlings Fringilla coelebs with three
      analgoid feather mites, Analges passerinus L., 1758, Monojoubertia microphylla
      (Robin, 1877), and Pteronyssoides striatus (Robin, 1977), commonly occurred on
      this bird species was investigated. 15 nests contained totally 65 nestlings, from
      2 to 6 individuals in a brood, have been examined from the day of hatching till
      11th day. Observations were held in the neighbourhood of the bird banding station
      "Rybachy" (Russia, Kaliningrad Province) in June of 1982. Number of mites on
      alive nestlings taken temporarily from their nest was counted by means of
      binocular lens under the magnification x12.5 and x25. The nestlings receive the
      mites from the chaffinch female during the night time, when the female sits
      together with the young birds and heats them. In the condition of this prolonged
      direct contact the mites migrate from the female onto the nestlings. As it was
      shown in our study of seasonal dynamics of mites on the chaffinch (Mironov,
      2000), the chaffinch female only gives its mites to young generation and looses
      about three quarter of its mite micropopulation during the nesting period (June),
      hile in the chaffinch males the number of mites continues to increase during all
      summer. The infections with three feather mite species happen in the second part
      of the nestling's stay in the nest. The starting time of this process, its
      intensity, and sex and age structure of mite micropopulations on the nestlings
      just before their leaving the nest are different in the mite species examined.
      These peculiarities of feather mite species are determined by the biology of
      examined species, and first of all by their morphological characteristic and
      specialisation to different microhabitats, i.e. certain structural zones of
      plumage. Pteronyssoides striatus (Pteronyssidae) is rather typical mite
      specialised to feathers with vanes. In adult birds with completely developed
      plumage this species occupies the ventral surface of the big upper coverts of
      primary flight feathers. This species appears on the chaffinch nestlings in a
      significant number on 7th day. The mites occupy the basal parts of primary flight
      feathers represented in that moment by the rods only. They sit on practically
      open and smooth surface of this microhabitat, which is uncommon for them, because
      the vanes of the big upper coverts are not yet open and also represented by thin
      rods. During the period of the last 5 days (from 7 to 11th day) the mean number
      of mites per one nestling increases from 2.3 +/- 0.5 to 17.1 +/- 1.8 mites. Just
      before the day, when the nestling leave the nest, the tritonymphs absolutely
      predominate (82.4%) in the micropopulation of P. striatus. Analges passerinus
      (Analgidae) is specialised to live in the friable layer formed by numerous not
      engaged thread barbles of the down feathers and basal parts of the body covert
      feathers. Mites have special hooks on legs used for hard attaching to the barbles
      and for fast moving in the friable layer of feathers. On the chaffinch nestlings,
      these mites appear usually on 8th day, when the rod-like body covert feathers
      begin to open on apices and form short brushes; however some individuals occur on
      the skin of nestlings even on 6th day. The mean number of mites per nestling on
      the 11th day reaches 16.5 +/- 1.4 individuals. The micropopulation of A.
      passerinus is represented on the nestlings mainly by the females (45.5%),
      tritonymphs (23.6%) and males (11.5%). Monojobertia microphylla
      (Proctophyllodidae) is a typical dweller of feathers with large vanes. Mites of
      this species commonly occupy the ventral surface of primary and secondary flight
      feathers and also respective big upper covert feathers of wings. M. microphylla
      appears on the nestlings in a significant number (7.1 +/- 1.2 mites) on 9th day,
      only when the primary flight feathers already have short vanes about 10 mm in
      length. In next three days the number of mites increases very fast and reaches on
      11th day 60.3 +/- 5.7 mites per nestling. In the micropopulation of this species,
      the tritonymphs count 38.3%, and the quota of males and females is 25.3% each.
      The migration of this species goes most intensively, than in two other species.
      An analitic selection of logistic curves shows, that the increasing of mite
      number during the process of infection with three mite species may be most
      adequately described by the sigmoid curves with clearly recognizable levels of
      saturation, which can be theoretically reached. Indeed, the number of mite
      individuals being able to migrate onto the nestlings is limited by their number
      on a respective chaffinch female. In a contrast, the increasing of plumage
      indices, for instance the length of flight feathers, has almost linear character
      during the period of observation. The beginning of mite migration is determined
      by the development of respective microhabitats in the plumage of nestlings, or at
      least by the development of certain structure elements of plumage, where mites
      are able to attach for a while, before that moment, when the nestlings will
      develop the plumage completely and begin to fly. In three mite species examined,
      the process of infection was performed by older stages, namely by the imago
      and/or tritonymphs. This can be explained by two reasons. On the one hand, the
      older stages are most active in their movement, resistible and able to survive
      successfully on new host individuals. On the other hand, the older stage are
      ready for the reproduction or will be ready after one moulting. The older stages
      of mites can quickly create a large and self-supporting micropopulations on the
      birds, therefore this strategy ensures a successful subsequent existence of the
      parasite species. In cases, when mites (A. passerinus, M. microphylla) migrate
      into the respective microhabitats structurally corresponding to their normal
      microhabitats on adult birds, the micropopulations of these mite species include
      a significant or dominant quota of females and males. When the normal
      microhabitat is not yet formed, feather mites migrate into neighboring structure
      elements of plumage, where they can survive and wait for the development of
      normal microhabitat, to which they are well adapted. Therefore, in the case of P.
      striatus, its micropopulations on the chaffinch nestlings are represented mainly
      by the tritonymphs.

PMID- 12481605
TI  - [Histopathological changes in lizard skin (Reptilia: Lacertidae) in feeding
      places of ticks of the genus Ixodes (Acari: Ixodidae)].
AB  - Histopathological changes in a skin of Lacerta agilis in the places of attachment
      and feeding of nymphs of Ixodes pacificus and I. ricinus were investigated. The
      mouthparts of ticks are surrounded by the fibrin cone and collagen capsula formed
      by their hosts. Ticks of these species do not produce the cement. A proliferation
      stage of skin inflammation is expressed, the large collagen capsula is formed as
      the result of proliferation. Neutrophils and eosinophils predominate in the
      inflammate cell infiltrate.

PMID- 12481606
TI  - [Morphological variablility in the chigger mite species Neotrombicula sympatrica
      (Acariformes: Trombiculidae) from Kyrgyzstan].
AB  - Aberrations (quantitative chaetotactic deviations, i.e. decreasing or increasing
      of setae numbers and variations in arrangement of setae) and anomalies
      (qualitative chaetotactic deviations, for example, partial reduction of scutum,
      shortening of a seta more than 1.5-2 times, merging of setae) were recorded for
      13 taxonomically important morphological structures in the chigger mite species
      Neotrombicula sympatrica Stekolnikov, 2001. 3308 specimens were studied as a
      total. 17.2% of them had various morphological deviations. The most common types
      of aberrations were observed in the number and positions of genualae I (94
      specimens), AM seta (79 spec.) and sternal setae (77 spec.). The aberrations of
      sternal and coxal setae were usually interrelated: the sternal seta was
      "transferred" from the sternal area onto the coxa, or the other way round take
      place. The specimens having aberrations of sternal setae were twice as numerous
      as the specimens with aberrations of coxal setae (77 against 35). The specimens
      with aberrations of dorsal setae and mastitarsala were very rare (2 spec. each).
      Among anomalies, the presence of nude galeal seta (91 spec.) and scutal anomalies
      (66 spec.) were prevalent. The most frequently one form of deviation only was
      observed in one specimen of N. sympatrica. Nevertheless, the specimens
      simultaneously having several aberrations or anomalies were also found. 17 types
      of such combinations were observed, that counts 20.6% of all specimens with
      deviations. Symmetric deviations, namely the presence of two nude galeal setae
      (31 spec.), presence of 2 genualae on both legs I (4 spec.), presence of 2 AM (2
      spec.) and symmetric reduction of scutal angles (1 spec.), sometimes cause
      troubles in diagnostics. The quarter of variance in N. sympatrica and in the
      species N. monticola Schluger et Davydov, 1967 formerly studied by the author
      turned out as almost identical. The specimens with deviations counted 14.5% of
      all studied specimens in the latter species. However, the structures of variance
      in these species is different. In N. monticola, the aberrations of humeral setae
      were dominant (71.6%) (Kharadov, Chirov, 2001), while in N. sympatrica, the
      aberrations of other structures were prevalent: genualae I (24.8%), AM (20.9%)
      and sternal setae (20.4%).

PMID- 12481607
TI  - [Comparative study of the sensory system in gamasid mites Rhinonyssus
      rhinolethrum, Rh. subrhinolethrum and Ptilonyssus motacillae (Mesostigmata:
      Gamasina: Rhinonyssidae), parasites in the nasal cavity of birds].
AB  - Sensillae of the tarsal receptor complex, palpal organ, and body chaetom were
      examined by means of scanning electron microscopy in three endoparasitic gamasid
      mites: Rhinonyssus rhinolethrum, Rh. subrhinolethrum and Ptilonyssus motacillae,
      the parasites of Anser albifrons, Anas crecca, and Motacilla alba, respectively.
      In the tarsal sensory complex, the scale of reduction of the olfactory sensilla
      reflects the adaptation of gamasid mites to cavernous parasitism. The topography
      of this sensilla is specific at generic and species taxonomic levels. In the
      palpal sensory organ, the number and scale of reduction of two main sensilla
      types depend on peculiarities of places of blood-sucking.

PMID- 12481608
TI  - [Policlithrum ponticum sp. n. (Monogenea: Gyrodactylidae: Polyclithrinae) from
      Mugil cephalus from the Black Sea and problems of suprageneric systematics of the
      gydrodactylids].
AB  - Polyclithrum ponticum sp. n. is described and P. mugilini Rogers, 1967 is
      redescribed. Both monogenean species are parasites of Mugil cephalus in the Black
      Sea. The new species differs from P. mugilini, P. alberti and P. boegeri by the
      lesser size of anchors, while it is distinguished from P. corallense by the
      larger size of these structures. P. ponticum sp. n. differs from all formerly
      described species by the greater length of dorsal connective bar. In both species
      from the Black Sea, "ear-like" structures situated near the external roots of
      anchors are described for the first time. It is suggested, that these structures
      take part in longitudinal, two-lobe folding of the haptor. The process of opening
      the haptor is probably performed by the additional bars of the haptor (bars 2 and
      3 after: Rogers, 1967), joined to each other and with the anchors. The fifth pair
      of additional bars (Ernst e. a., 2000) derives from the "beard" of ventral
      connective bar and is united with its basal part. The sixth pair of additional
      bars (Ernst e. a., 2000) is considered as a typical "ribs" of the haptor, and
      therefore the "ribs" are represented by three pairs. Differences between marginal
      hooks of P. ponticum sp. n. and P. mugilini are insignificant, that probably
      depends on the presence of "ribs" of the haptor. Based on the subdivision of
      marginal hooks into two groups, the presence of additional supporting structure
      in the haptor, and the presence of the seminal receptacle, it is suggested that
      the subfamily Polyclithrinae Rogers, 1967 should include the genera Polyclithrum
      Rogers, 1967, Swingleus Rogers, 1969, Macrogyrodactylus Mamlberg, 1959, and
      probably Fundulotrema Hargis, 1955. Based on such characters as the lack of the
      anchors, the presence of suckers in the haptor, and ovipositing of eggs, it seems
      to be expedient to use the following taxa in systematics of gyrodactylids:
      Isancistrinae Fuhrmann, 1928 (genera Isancistrum, Anacanthocotyle);
      Gyrdicotylinae Vercammen-Grandjean, 1960 (Gyrdicotyle) and Ooegyrodactylinae
      Harris, 1983 (genera Phanerothecium, Ooegyrodactylus, Nothogyrodactylus,
      Hyperopletes).

PMID- 12481609
TI  - [Impact of microsporidia on hormonal balance in insect hosts].
AB  - Microsporidia (M) is a phylum of protists parasitizing obligatory in animal
      cells. Long way of adaptation of M to intracellular parasitism resulted in
      establishment of quite close relationships between the parasite and its host.
      Different species of M induce in their hosts symptoms similar to those caused by
      misbalance of juvenile hormone (JH) and ecdysone. M infection leads to pathology
      of different hormone-dependent functions such as cell differentiation and
      specialization, molting, metamorphosis, diapause and reproduction of insects. The
      signs of hormonal dysfunction evidence for elevated titer of JH in M-infected
      insects. Two possible explanation of this could be offered: JH secretion by M or
      specific influence of the parasites on the insect endocrine systems. Impact on
      insect endogenous JH titer by M could be mediated by affection of secretory
      activity of corpora allata or by suppression of enzymatic degradation of JH.
      According to different hypotheses, insect hormonal status during microsporidiosis
      could be modified by a) insect host stress-reaction, b) exhaustion of insect host
      reserves, characteristic for acute phase of the disease, c) destruction of
      infected insect cells and tissues during mass sporogenesis of M. Data found in
      literature and provided by our experiments evidence for presence of JH analogues
      or juvenilizing substance in the extracts of M spores. From detailed examination
      of pathological process it is also seen that juvenilizing effect of M infection
      is usually restricted to the invaded regions of tissues (i.e. expressed locally)
      but not a systemic one. Ability of M to modify morpho-functional features of
      infected tissues at the level of hormonal regulation is undoubtfully a prominent
      adaptation for stabilizing "microsporidia-insect" parasite-host systems.

PMID- 12481610
TI  - [Cephalic region damage in the nemertean Lineus ruber by the orthonectid Intoshia
      linei].
AB  - Previous investigators believed, that the plasmodia of Intoshia linei can affect
      all part of nemerteans body except the cephalic lobe. Our results indicate that
      in strongly infected worms mature plasmodia can settle inside of the cephalic
      region and form the large conglomerates. Common places of plasmodia localization
      in hosts are not only the tegument, connective tissue, gonads, muscles of body
      wall and proboscis, but also the nervous tissue. We found a lot of the mature
      plasmodia in all four lobes of the nemerteans brain and in the lateral nerve
      trunks. Furthermore the plasmodia can settle in the cerebral organs, in the walls
      of blood lacunae and rhynchcoel. In spite of the strong invasion of the cephalic
      lobe we have never observed a plasmodial outgrowths in the tegument of this
      region. This phenomena can be explained by the assumption, that plasmodia usually
      intrude into the cephalic region relatively late and have no time to form
      outgrowths up to the moment when starts the emission of adult males and females
      in the rest parts of nemertean body. Moreover, single parasite cells were
      repeatedly found in the host tissue near the mature plasmodium. These cells had
      few cytoplasm and large vesicular nuclei, which were very similar in size to the
      nuclei of the host cells. General morphology of single cells was very similar to
      the generative cells of the plasmodium. At present, the function of these cells
      is not evident, but we believe, they appearance is concerned with the
      proliferation of plasmodiuma and agglomeration of the parasite in the body of
      Lineus ruber.

PMID- 12481611
TI  - [Development of Paragonimus westermani ichunensis in a reservoir host].
AB  - Experimental observations showed, that the muscle larva stage of the trematodes
      Paragonimus westermani ichunensis located in a reservoir host can enlarge its
      body size. A rate of growth in trematode individuals varied both among different
      host animals and within one host specimens. When rodents are infected with such
      muscle larvae, the individuals with the size exceeding 1.15 x 0.33 mm invade into
      the lungs oh host, while smaller individuals secondarily migrate to muscles.

PMID- 12481612
TI  - Optimizing health of individuals with tetraplegia.
AB  - People surviving spinal cord dysfunction with tetraplegia (SCDT) are returning
      earlier to their communities with the assistance of long-term health care
      providers (LTHP). However, the prevalence of rehospitalization following
      rehabilitation of persons with spinal cord dysfunction is high, with rates
      ranging from 19% to 57%. Rehospitalization is costly, both financially and
      personally, and may be preventable. Current literature suggests that education of
      the LTHP is essential to prevent rehospitalization of persons with SCDT. The
      Health Maintenance Education program was developed to optimize individual and
      societal outcomes of persons with SCDT through improvement of long-term health
      care. An educational program was designed for persons with SCDT and their LTHP;
      namely, community health nurses (registered nurses, licensed practical nurses),
      home health aides, personal care assistants, and family care providers. The
      program included three distinct educational phases, including a 1-day workshop, a
      collaborative home visit, and ongoing support and follow-up for 1 year.
      Satisfaction surveys indicated favorable responses to the overall program.
      Individual results of the program include improved knowledge, acquired resources,
      and updated equipment for the person with tetraplegia and the caregiver.
      Educational materials related to the management of persons with SCDT were
      provided to home care agencies for education of employees.

PMID- 12481613
TI  - Challenges to communication: supporting the patients with SCI with their
      diagnosis and prognosis.
AB  - This article discusses some of the common dilemmas that nurses experience when
      communicating with patients who have recently sustained a spinal cord injury.
      Drawing on the literature, this article highlights that the nurse's role in
      giving bad news is unique. Nurses are often in the position of clarifying
      information as patients become aware of their limitations. This awareness prompts
      the need for support for both patients and their families. Nurses must interact
      with patients during their adjustment to their losses, and this requires good
      communication skills. The experiences of other health professionals, particularly
      physicians, are helpful in providing guidance for nurses who reinforce
      information regarding the patient's diagnosis/prognosis. They must continue to
      interact with patients during their adjustment to their losses, and this requires
      good communication skills. This article offers insight into problems as well as
      strategies to assist nurses in developing their communication skills.

PMID- 12481614
TI  - Hurricane: evacuating an SCI unit.

PMID- 12481615
TI  - Redefining power wheelchairs.

PMID- 12481616
TI  - AASCIN's research priorities.

PMID- 12481617
TI  - Security in the midst of uncertainty.

PMID- 12481618
TI  - "The day I took my last dive": a patient's viewpoint after SCI.

PMID- 12481619
TI  - [Role of partial nephrectomy in the treatment of kidney cancer].
AB  - Incidental finding of small renal carcinoma by radiologic exams (ultrasound,
      computed tomography, MRI) performed for non urological purposes raises
      therapeutic and management problems (therapeutic abstinence and surveillance,
      partial or radical nephrectomy). Radical nephrectomy is recognized as a curative
      treatment for renal cell carcinoma. However, partial nephrectomy was suggested
      for renal cell carcinoma of solitary functional kidney or bilateral tumors in
      order to avoid dialysis or renal transplantation. The debate remains open for the
      small renal carcinomas with a normal controlateral kidney. Is partial nephrectomy
      an adequate treatment or rather perform radical nephrectomy? The present study
      was performed to analyse the published literature on the subject.

PMID- 12481620
TI  - [Surgical aspects of kidney transplantation in children (study of 148 cases)].
AB  - OBJECTIVE: Kidney transplantation is the best treatment for end-stage renal
      disease. This procedure is by now routinely used and permits children survival
      and rehabilitation. We describe the surgical complications of kidney graft in our
      paediatric experience. MATERIALS AND METHODS: From April 1987 to August 2000, 175
      kidney transplantation were proceeded in the department of urology and
      transplantation in Edouard Herriot Hospital (Lyon). Twenty-nine kidneys (17%)
      were from living related donors and 146 (83%) were from cadaveric donors. We
      evaluated 148 kidney transplantation (132 patients) in 79 male and 53 female
      children. Mean age was ten years (range: seven months to 18 years). Twelve
      allografts were from living related donors and 136 cadaveric donors. RESULTS:
      Twelve patients died of various medical complications. One patient was lost of
      sight. Surgical complications were postoperative bleeding, lymphocele, urologic
      and digestive troubles. The rest of our patients had uneventful evolution.
      CONCLUSION: A general commitment is the only way to promote organ donation and
      enable patients with terminal renal failure to have access to renal
      transplantation.

PMID- 12481621
TI  - [Psoas abscess: 12 case reports].
AB  - Psoas abscess are rare. Primitives or secondary their clinical diagnosis is
      difficult. Imagery and especially computed tomography is fundamental. Treatment
      associates antibiotherapy and drainage. This drainage can be percutaneous or
      surgical (open surgery). The authors analyze in a retrospective way 12 cases of
      abscess of the psoas.

PMID- 12481622
TI  - [Small cell carcinoma of the prostate: a case report].
AB  - Pure small cells carcinoma of the prostate is a rare tumour with a pejorative
      forecast. We report a case of neuroendocrine small cells carcinoma developed at a
      68 years old patient. This tumour expressed a positive marking immunohistochimic
      with chromogranin A, the rate of PSA was on the other hand normal (2.9 ng/ml).
      The patient was treated by chemotherapy associating etoposide and cisplatinium
      and external radiotherapy. He is deceased 4 months afterwards.

PMID- 12481623
TI  - [Perineo-transpubic approach to the management of posterior urethral post
      traumatic rupture].
AB  - OBJECTIVE: To study the place of the perineal-trans-pubic approach in the
      treatment of the posterior urethral post-traumatic rupture operated late, and to
      evaluate its results. PATIENTS AND METHODS: Twenty-four patients whose had a
      total posterior urethral post-traumatic rupture were treated in our department in
      a stage of urethral strictures. All patients underwent perineal transpubic
      urethroplasty. In this study we detailed a technique description of the approach
      and a clinical evaluation of our results. RESULTS: This technique allows having a
      direct approach of the posterior urethra, to perform a tension free end to end
      urethral suture. The backward is about 3 years. We assessed 3 cases of recurrent
      urethral strictures. The cases of erectile dysfunction assessed were mainly
      related to the initial pelvic trauma. Finally this approach had not orthopaedic
      squall in all cases. CONCLUSIONS: Comparing to others, the perineal transpubic
      approach is the best one to manage the posterior urethral injuries treated with
      late. It gives a satisfactory results with a few disadvantages.

PMID- 12481624
TI  - [Intrascrotal inflammatory pseudotumor (a case report)].
AB  - We report one case of intrascrotal inflammatory tumour in a 12 year-old boy. The
      clinical symptomatology was a tumoral rise in the right scrotal volume. The rate
      of biological markers was normal. A testicular neoplasm was highly suspected in
      scrotal ultrasound and CT scan. A radical orchidectomy was accomplished and
      histological examination revealed a peritesticular inflammatory tumor without
      neoplasm. The clinical and imaging findings of the tumor are discussed.

PMID- 12481625
TI  - [Local recurrence of paratesticular rhabdomyosarcoma].
AB  - We report an uncommon case of scrotal recurrence of embryonal paratesticular
      rhabdomyosarcoma in 19 year old man after 3 years later. The diagnosis was
      suspected clinically and confirmed by histopathology study after resection of the
      scrotal tumor. About this case, the authors discuss the diagnosis and the
      management of this tumor.

PMID- 12481626
TI  - [Laparoscopic spermatic vessel ligation in the treatment of varicocele: report of
      129 procedures].
AB  - With the improvement of laparoscopic techniques in the hands of urologists, a
      minimally invasive therapy can be offered to patients. We report retrospectively
      our experience in the laparoscopic treatment of varicoceles. A total of 93
      patients with 129 varicoceles were treated by a laparoscopic approach, the mean
      age was 29 years (12-47), with 57 left varicoceles and 36 bilateral varicoceles.
      Indications for treatment were infertility in 51 patients and pain in 42 cases.
      The mean duration of the operation was 40 min (25-85) for bilateral varicoceles,
      and 24 min (15-65) for left varicoceles. All our patients were operated the day
      of their admission and 52 patients left the hospital 8 h after the intervention.
      We report 2 incidents with conversion to open surgery in one case. The pregnancy
      rate after surgery in patients with infertility was 21%, the recurrence rate was
      4%. Laparoscopic spermatic vein ligation in the treatment of varicocele is a
      minimally invasive procedure, simple, fast and is not a contraindication for
      other procedures in case of recurrence.

PMID- 12481627
TI  - [Study of urogenital fistulas in the Ivory Coast at the end of the 20th century.
      Results of 70 cases].
AB  - The urogenital fistulas (UGF), mostly in Africa and particularly in Ivory Coast,
      still represent a great flail nowadays. However, the authors notice, through a
      study of 70 cases done in Ivory Coast over (ten) 10 years, that a relative
      decrease of the impact of the urogenital fistulas troubles still remains a
      serious affection of young women who can give birth. They are about 30 years old
      and more; that is to say primipares (44.28%) but over all multipares (54.28%) and
      poor ones (100%). Most cases are obstetrical causes which expose those women to
      genital mutilations (25.71%) linked to birth giving difficulties which also bring
      about many dead born (14.11%) and divorces (20%).

PMID- 12481628
TI  - [Staphylococci as uropathogens-frequency of isolation in hospitalized patients
      and sensitivity to antimicrobial agents].
AB  - For a period of 24 months (1997-1999) were isolated 266 clinically significant
      staphylococcal strains, S. aureus, 36 (13.5%) and 230 (86.5%) coagulase negative
      staphylococci (CNS) from urines of hospitalised patients (over 14 years) with
      UTI. The most frequently isolated strains from CNS was S. haemolyicus, 110 (47.8)
      strains, followed by S. saprophyticus 47 (20.4%) strains and S. epidermidis 18
      (7.8%). The susceptibility of the isolates to 13 antimicrobial agents was
      determined by agar dilution method (NCCLS). From the isolated 36 strains S.
      aureus, 24 were sensitive and 12 were resistant to methicillin. From 230 CNS, 105
      strains showed sensitivity and 125 strains resistance to methicillin. All
      staphylococci were sensitive to vancomycin and most of them (over 95%) to
      amikacin and rifampin. It was established a considerable difference between the
      sensitivity of methicillin-sensitive and methicillin-resistant staphylococci. The
      established resistance accompanied with high rate percentage methicillin
      resistance requires careful consideration to antimicrobial therapy of
      staphylococcal urinary tract infections (UTI).

PMID- 12481629
TI  - Unsafe disposal of medical waste: a threat to the community and environment.

PMID- 12481630
TI  - Role of dexamethasone in acute bacterial meningitis in adults.
AB  - OBJECTIVE: To evaluate the role of dexamethasone as adjunctive therapy in adult
      acute bacterial meningitis (ABM) in two groups of patients treated with
      antibiotics alone or a combination of antibiotics and dexamethasone. DESIGN:
      Systematic sampling interventional open cohort study. SETTING: Department of
      Medicine (Medical Unit II), Jinnah Postgraduate Medical Centre, Karachi.
      PATIENTS: Sixty eight patients aged 12-85 years admitted in Medical Unit II and
      diagnosed to have ABM. Patients were divided into two groups. Group A received
      anti-microbial therapy for 14 days (a combination of benzyl penicillin 6 million
      units I/V 6 hourly and chloramphenicol 1 gm I/V 6 hourly) and group B received
      the same antimicrobial therapy with dexamethasone 0.6 mg/kg/day in 3 divided
      doses for 4 days. MAIN OUTCOME MEASURES: Differences in mortality and morbidity
      in the two groups and differences in the CSF inflammatory parameters between the
      two groups of patients. RESULTS: There was early resolution of fever, headache
      and altered consciousness in group B as compared to group A. Cranial nerves
      involvement was lower in group B. There was no difference in the occurrence of
      other focal neurological deficits between the two groups. CSF inflammatory
      parameters (glucose, protein and WBC count) were significantly better in group B
      by day 5. No complications attributable to dexamethasone were seen in group B.
      CONCLUSION: There was early resolution of symptoms and CSF inflammatory
      parameters in the group that received dexamethasone as adjuvant therapy.
      Mortality was lower in the group treated with dexamethasone but the difference
      was not statistically significant. Dexamethasone should be administered to all
      adults patients with ABM.

PMID- 12481631
TI  - Health needs of clients as reported by medical practitioners from two districts
      of Sindh.
AB  - OBJECTIVE: To identify the major health and reproductive health problems for
      which people consult local medical practitioners. METHODOLOGY: Forty-one
      practitioners completed a self-administered questionnaire. A startified purposive
      sample of practitioners was selected by asking the community members from various
      towns and rural areas to identify practitioners who have most busy practices and
      are perceived as providing quality care. RESULTS: Nine of the forty-one
      practitioners were females. Twenty-two were consulted mainly by women and another
      seventeen by an equal number of women and men. Practitioners pointed to
      malnutrition, malaria, gastrointestinal and respiratory tract problems as being
      the most common ailments. They identified menstrual problems, malnutrition among
      pregnant women, burning micturition and vaginal discharge as the most common
      reproductive health problems of their clients. Only 16 medical practitioners said
      that they diagnosed someone in the last one-month as suffering from sexually
      transmitted infections. CONCLUSION: The survey helped in developing an
      understanding of health issues from provider perspective. Findings indicate a
      concordance between what has been revealed by previous population based studies
      in similar situations and to what health problems practitioners pointed as
      common. While a comprehensive needs-assessment requires surveys and qualitative
      interviews with communities, consultations with relatively fewer medical
      practitioners could also provide a quick and fair approximation of priority
      health problems in the area.

PMID- 12481632
TI  - Cancer patterns in Karachi division (1998-1999).
AB  - OBJECTIVE: A minimal cancer incidence data for Karachi, the largest city of
      Pakistan, is being presented here, for the years 1998-1999. The city has a
      population of 9,802,134; males 5,261,712 (52.6%) and females 4,540,422 (47.4%);
      census 1998. METHODOLOGY: A predominantly mixed (passive and active) registration
      system has evolved in Karachi, the data sources being the hospitals within the
      Karachi Division. The reported/retrieved cancer data sets at the Karachi Cancer
      Registry are checked, coded, computerised in an analytical format and analysed.
      RESULTS: The incident cancer cases registered in Karachi, during the 2-year
      period, 1st January 1998 to 31st December 1999 were analysed. The age
      standardised incidence rate (ASR) of cancer, all sites was 132.4/100,000 for the
      males. Cancer of the lung 10.8%; ASR 17.3 was the most frequently recorded
      malignancy, followed by oral cavity 10.5%; ASR 13.2 and larynx 5.0%; ASR 7.4. The
      age-standardised incidence rate (ASR) of cancer, all sites was 133.0/100,000 in
      the females. Cancer of the breast, 32.0%; ASR 40.7 was the most frequently
      recorded malignancy, followed by oral cavity 8.1%; ASR 11.7 and gall bladder
      3.6%; ASR 5.5. CONCLUSION: The present data has been calculated with an estimated
      15-20% probable under ascertainment. Tobacco-associated cancers in Karachi were
      responsible for 38.3% of the tumours diagnosed amongst the males. Two principal
      cancers, breast and oral cavity were responsible for 40.1% of the cancers in
      females. A rare finding was the high incidence of gall bladder cancer in the
      females. At present it is difficult to determine whether this indicates a genuine
      high risk or a selection bias. A continuous process of cancer registration to
      study the trends in the incidence and an adequate cancer control program are
      possible and essential for Pakistan and can be based on the pattern being
      practiced in Karachi.

PMID- 12481633
TI  - Acute myeloid leukemia in children in Pakistan: an audit.
AB  - OBJECTIVE: To see the clinical features and treatment of children with Acute
      Myeloid Leukemia (AML) in Pakistan. SETTING: Tertiary referral at a specialist
      Hematology/Oncology center. METHODS: Retrospective, chart-based review of
      children (less than 14 years) admitted to the hospital with a diagnosis of AML
      between January 1987 and August 1997. RESULTS: A total of 23 patients were
      admitted. There were 18 males and 5 females. The mean age was 8 +/- 5 years. M3
      was the commonest morphological subtype (43%). Twenty-two percent of the patients
      presented with hyperleucocytosis (TLC > 100 x 10(9)/L) and 95% with an elevated
      LDH (> 548 IU/L). Pneumonia at presentation was seen in 29%. Of 23 patients 14
      were evaluable for responses. Six patients died early (43%); 3 before starting
      the chemotherapy and 3 during the induction chemotherapy, 8/11 (73%) patients
      entered remission. The median survival was 9 months. CONCLUSION: The pediatric
      patients with acute myeloid leukemia present with advanced disease. There is a
      high early death rate (within 28 days of diagnosis). The long-term outcome was
      inferior to that reported in the literature.

PMID- 12481634
TI  - Prevalence of smoking among Karachi population.
AB  - AIMS: To determine the prevalence of smoking in Karachi population and compare it
      with previous studies to see if any change has occurred in this addiction.
      SETTING: Cross sectional survey in 5 districts of Karachi, using a questionnaire.
      SUBJECTS AND METHODS: Apparently healthy subjects from 25 areas covering 5
      districts of Karachi were interviewed regarding their smoking habits, ethnic
      origin, socioeconomic strata and the education level. Two modes of interview were
      adopted, one was a house to house and the other was interview at public places.
      RESULTS: Previous studies showed a 21-32.3% prevalence of smoking which is almost
      similar to 32.7% seen in this study. In the present study highest frequency of
      smoking was seen in college going male students belonging to 21-25 years while in
      females majority were graduates belonging to 26-30 years age group. The age at
      which most cases acquired this habit was between 15-25 years and in majority it
      was introduced by friends. Although most knew that smoking was hazardous for
      health and many cases did make an attempt to quit but very few were able to get
      rid of this addiction. CONCLUSION: Over the past few decades not much change has
      been seen in the frequency of smoking in our population. Stronger anti smoking
      campaigns using press and other media are required to improve public awareness.

PMID- 12481635
TI  - Use of esophageal self expandable metal stents--the local experience.

PMID- 12481636
TI  - Squamous cell carcinoma of true vocal cords (T1) lesion metastasis to lung--a
      case report.

PMID- 12481637
TI  - Takayasu's arteritis presenting as ischemic stroke--case report.

PMID- 12481638
TI  - Macular hemorrhage secondary to increased intrathoracic pressure and difficult
      intubation.

PMID- 12481639
TI  - View box case--6. Giant cell tumor.

PMID- 12481640
TI  - Knowledge about sexually transmitted infections among young Pakistani men.

PMID- 12481641
TI  - The utilization of services of health care providers among patients presenting to
      family physicians at a teaching hospital in Karachi, Pakistan.
AB  - OBJECTIVE: To study the utilization of services of Health care providers among
      patients presenting to Family Physicians in a teaching hospital in Karachi.
      METHODOLOGY: It was a cross sectional study. A questionnaire was developed to
      collect patient's utilization of services of health care providers. The
      investigators administered the questionnaire to 387 patients, after purpose of
      the study was explained, written consent was taken and confidentiality was
      assured. RESULTS: The study population included more females than males, with
      average age of 32.6 years. The majority were married, well educated, in private
      and government service, were students or housewives. We found that 383(99%),
      141(36.4%), 88(22.7%) and 45(11.6%) of the respondents had used services of
      allopaths, homeopaths, hakims and spiritual healers respectively. It is important
      to consider that these patients had come for allopathic treatment, thus
      exhibiting preference for it. The five main ailments for consulting health care
      providers differed, suggesting the perception in the mind of patients that
      certain ailments are better treated by particular system of treatment than the
      others. Studies are needed to explore this area further. The main reasons for
      consultation with particular health care provider were the recommendation of
      others or the perceived effectiveness of the practitioners. The reasons cited for
      non-consultation with health care providers were the lack of belief in them or
      lack of effectiveness of their treatment. Three hundred seventy nine (98%), 259
      (67%), 174 (45%) and 249 (64.4%) of patients were willing to consult allopaths,
      homeopaths, hakims and spiritual healers again respectively, if unwell in future.
      CONCLUSION: We found a substantial utilization of services of complimentary
      medicine practitioners among patients seeking allopathic treatment. Further study
      on the utilization and organization of services offered by health care providers
      is required.

PMID- 12481642
TI  - Anorexic behaviour and attitudes among female medical and nursing students at a
      private university hospital.
AB  - OBJECTIVE: To study the anorexic behaviour and attitude among female medical and
      nursing students in a tertiary care hospital. SUBJECTS AND METHODS: A cross
      sectional survey to determine the proportion of anorexic behaviour among female
      medical and nursing students at The Aga Khan University Hospital Karachi was
      conducted. A multistaged sampling technique was utilized in which our study
      population was first divided according to field of enrollment (medical or nursing
      school) and then stratified by class. Within each stratum, we used convenience
      sampling due to time and availability constraints. We utilized a modified Eating
      Attitudes Test (EAT-26) to collect data. The Eating Attitude Test is probably the
      most widely used standardized measure of symptoms characteristic of eating
      disorders, including anorexia nervosa. RESULTS: A total of 180 female students
      were interviewed. Ninety-four (52.2%) were medical students and 86 (47.8%) were
      nursing students. Among the 94 medical students, 26 (27.7%) were from first year,
      14 (14.9%) from second year, 15 (16.0%) from third year, 20 (21.3%) from fourth
      year and 19 (20.2%) from the final year of medical college. Among the 86 nursing
      students 34 (39.5%) were from first year, 23 (26.7%) from second year, 27 (31.4%)
      from third year and 2 (2.4%) from fourth year. The proportion of anorexic
      behaviour among medical students was 8.0%, 7.1% and 20.0% in first, third and
      fourth years respectively. No individuals with anorexic behaviour were found in
      second and fifth years. The total proportion of anorexic behaviour among female
      health care students was 21.7%. CONCLUSION: Results showed a 21.7% prevalence of
      anorexic behaviour, a figure much higher than that reported in similar studies
      conducted in Asia. We also found that the proportion was much higher among female
      nursing students as compared to female medical students. A previous visit to a
      psychiatrist for reasons other than eating disorders was found to be associated
      with anorexic behaviour.

PMID- 12481643
TI  - Health research investments: a challenge for National Public Health Associations.
      .

PMID- 12481644
TI  - [Skin layer thickness at the ear of the domesticated pig , with special reference
      to the use of the ear integument for human dermatological research].
AB  - Based on a shrinkage-free methodical approach (special plastic resin embedding,
      frozen section technique) and histological routine staining, the thickness of the
      different skin layers was measured from 15 regions of the outer and the inner
      side of the porcine auricle. Mean thickness values were for the str. corneum: 19
      microns outside/20 microns inside, vital epidermis without ridges: 52 microns
      outside/56 microns inside, dermis: 1175 microns outside/1112 microns inside,
      hypodermis: 1024 microns outside/741 microns inside, perichondrium: 295 microns
      outside/220 microns inside. When both sides of the auricle were compared, it
      became obvious that the outer side generally had a thicker dermis (1140-1290
      microns) and hypodermis (780-1150 microns), whereas the inner side had a thicker
      vital epidermis (50-60 microns) and deeper epidermal ridges (145-165 microns).
      The results are discussed with regard to corresponding findings from the human
      skin, and one region of the outer side of the porcine auricle is recommended as
      suitable for human dermatological research.

PMID- 12481645
TI  - [Morphological and immunohistochemical studies in testes of normal and
      cryptorchid boars].
AB  - Scrotal (n = 66), inguinal (n = 7) and abdominal (n = 36) testes from pigs
      differing in age (from 1 day to 4 years) were collected after slaughtering or by
      castration, fixed in 4% formalin and examined by light microscopy. The expression
      of vimentin, desmin, alpha-actin and PCNA was detected by immunohistochemical
      technique. Histologically no differences between scrotal and cryptorchid testes
      are obvious during the prepubertal period, until the age of 10-12 weeks, but with
      the onset of puberty degenerative alterations (Sertoli-cell-only morphology,
      giant cells) in dystopic testes occur. Additionally the differentiation of the
      interstitial cells is disturbed in abdominal testes resulting in a deviating
      expression pattern of alpha-actin. The Sertoli cells show different distribution
      patterns (basal, perinuclear, apical) of vimentin depending on the position of
      the testis and the age of the animal.

PMID- 12481646
TI  - [Complications after implantation of a modular total hip prostheses compared with
      fixed head prostheses].
AB  - 164 total hip prostheses of different manufacturers were implanted over an 8-year
      period. Clinical records were evaluated with a complication rate of 29.0% (42 of
      145 joints) or 31.7% (39 of 123 dogs). The complications encountered in dogs that
      received the modular hip prosthesis (Biomecanique, Bretigny-sur-orge, France)
      amounted to 16.3% (15 of 92), dogs that received a fixed head prosthesis (5
      different manufactures) had 39% complications (28 of 72). Although the
      complication rate was influenced by different surgeons (n = 5) with different
      system predelictions and a different learning curve it was obvious that luxations
      (n = 6 of 10) and stem fractures (n = 5) more often occurred with the fixed head
      prosthesis systems. These stem fractures might be due to implant material failure
      or due to improper cementation followed by fatigue material failure. Femur
      fracture or infection were encountered with both prosthesis systems.

PMID- 12481647
TI  - [Diagnostic validity of palpation in horses with back problems].
AB  - There is a regularly high proportion of x-ray findings indicating a pathological
      deterioration of the equine vertebral column which do not correlate with the
      clinical symptoms. Therefore, palpation remains one of the most important
      clinical examination methods to determine whether or not a horse is suffering
      from back pain. The aim of this study was to check the validity of palpation
      results of horses with an assumed back problem. The palpation results of 167
      horses were evaluated in retrospect: If the palpation proceeds under following
      conditions, positive palpation results agree with an primary back problem in
      about 100% of cases: 1. Hind limb lameness, being the most likely reason for
      misleading positive palpation results, has to be ruled out. 2. Only reproducible
      painful behavior is allowed to be interpreted as positive. Under these conditions
      a negative palpation result is correct in about 72% of cases. For the examiner it
      is important to keep in mind that an apparent Kissing Spine-Syndrome can exist
      without being palpable. By means of clinical examination it is not always
      possible to distinguish between painful and normal reactions. In doubtful cases
      diagnosis can be made by a "diagnostic therapy", or better by scintigraphy.

PMID- 12481648
TI  - Melanocytoma and myxoma-tumours of the limbs in cattle.
AB  - Two cases of myxoma and one case of melanocytoma of enormous size in three aged
      cows are described. The conditions had a clinically benign course, and there was
      no physical evidence of metastasis in the regional lymph nodes. All cases were
      cured by surgical excision.

PMID- 12481650
TI  - [The helminth fauna of indigenous white storks (Ciconia ciconia)].
AB  - 120 carcasses of white storks originating from the federal countries Saxonia
      Anhalt and Brandenburg where examined between 1994 and 2000 for internal
      parasites. The established parasite spectrum consisted of 8 trematode
      (Tylodelphis excavata, Chaunocephalus ferox, Cathemasia hians, Echinostoma
      revolutum, Echinoparyphium sp., Monilifer spinulosus, Ignavia ciconiae and
      Brachylaimus sp.), 4 cestode (Anomotaenia discoidea and 3 Hymenolepidae species)
      and at least 3 nematode species (Capillaria spp., Syngamus palustris and
      Contracaecum microcephalum). 5 of the helminths are considered to be stork
      specific. Considering host age groups the highest percentage of infected birds
      was found in adults.

PMID- 12481649
TI  - [The occurrence of Echinococcus multilocularis in red foxes in lower Saxony:
      identification of a high risk area by spatial epidemiological cluster analysis].
AB  - There is considerable interest in the spatial distribution of Echinococcus
      multilocularis in red foxes (Vulpes vulpes L.), because this parasite causes the
      zoonoses of alveolar echinococcosis which is potentially of high fatality rate.
      High risk areas are known from France, Switzerland and the Swabian Alb in Germany
      for a long time. In this work, the spatial scan statistic is introduced as an
      instrument for identification and localisation of high risk areas, so called
      disease clusters in spatial epidemiology. The use of the spatial scan statistic
      along with data about the distribution of the parasite in 5365 red foxes in Lower
      Saxony, that were collected during 1991 to 1997, led to the identification of
      another high risk area. The relative risk for this disease cluster is
      approximated by RR = 5.03 (CI0.95(RR) = [4.27; 6.58]) for the period of 1991 to
      1994 and by RR = 4.45 (CI0.95(RR) = [3.53; 5.59]) for the period of 1994 to 1997,
      respectively.

PMID- 12481651
TI  - [The myocardial thickness in budgerigars (Melopsittacus undulatus) and Australian
      king parrots (Alisterus s. scapularis)].
AB  - Due to lack of reference values an objective assessment of myocardial dilatation
      and hypertrophy in cage and aviary birds so far is not possible. Therefore the
      thickness of the myocardium of the left and the right ventricle of the heart of
      14 budgerigars (Melopsittacus undulatus) and 5 Alisterus parrots (Alisterus s.
      scapularis) of both sexes was examined according to a standard protocol to
      establish morphometric data and first reference values. In order to compare the
      results of birds of different sizes all data were set in relation to the size of
      the bird's body (length of the sternum). Results of different zones were compared
      by means of statistical methods within one species. Besides that a comparison
      between the two species was performed. Only minor significant differences could
      be noticed.

PMID- 12481652
TI  - [The development of the relationship between sow and piglet in the domestic pig-
      a sociobiological observation].
AB  - The nursing and suckling behaviour of the domestic pig is a complex social
      behavioural interaction aimed to ensure the milk flow from the sow to the
      piglets. Ultimately caused theoretical frameworks from basic ethology and/or
      sociobiology are increasingly used to explain such social behavioural patterns.
      The present paper gives a short survey of ethophysiological aspects of the
      nursing and suckling behaviour in domestic pigs and, thereafter, discusses the
      development and consequences of some parts of the suckling behaviour and the
      maternal lactation performance in terms of a possible parent-offspring and
      weaning conflict. It is concluded that--additional to proximately caused
      mechanisms--the ontogeny of domestic pigs can be interpreted with such
      principles. In housing systems allowing the animals more control over their
      behaviour (e.g. their investment) ultimate causes should be more considered.
      Especially the pathways on which the ultimate strategies become effective via
      proximate mechanisms do not seem to be understood in total and require specific
      research. However, it is suggested that effective improvements of welfare, health
      and productivity can only be reached with the knowledge and integration of both
      ultimate and proximate causes of behaviour.

PMID- 12481653
TI  - Effect of Tween 80 and monensin on ruminal fermentation of the diet containing
      70% wheat straw treated by white-rot fungus in artificial rumen.
AB  - The objective of this study was to investigate the effect of Tween 80 and
      monensin on rumen fermentation of the diet containing 70% wheat straw treated by
      white-rot fungus Pleurotus tuber-regium (TWS-PT) and 30% barley in artificial
      rumen (RUSITEC). The RUSITEC consisted of four fermentation vessels (V1, V2, V3,
      V4): V1 was without additives (control), V2 received daily 10 mg of monensin, V3
      received daily 0.5% Tween 80 (vol.wt-1) and V4 involved the combination of 10 mg
      of monensin with 0.5% Tween 80 (vol.wt-1). After an adaptation period (6 days)
      the fermentation parameters were determined for six consecutive days. Tween 80
      did not affect the rumen fermentation of the diet consisting 70% TWS-PT and 30%
      barley in RUSITEC. Monensin affected the rumen fermentation of the diet by the
      decreased degradability of DM, neutral detergent fiber (NDF), acid detergent
      fiber (ADF), hemicellulose, cellulose (p < 0.001), the decrease of methane
      production (p < 0.001) and the higher proportion of propionate within the
      volatile fatty acids (p < 0.001) in comparison to control. Tween 80 did not
      improve the potency of monensin. Only some indices of the increase mol% of
      propionate (about 3.4%) and the decrease of methane production (about 0.47
      mmol.day-1) were found by using Tween 80 plus monensin in comparison to use of
      monensin alone.

PMID- 12481654
TI  - [Significance and application of vitamin E in broilers and laying hens,
      especially during supplementation with fish oil].
AB  - Vitamin E is necessary as an antioxidant, as a regulator of the transcription and
      of the activity of enzymes as well as an activator of the immune system.
      Supplements of 150-300 mg/kg feed stimulate the activity of the immune system. A
      content of vitamin E of 200 mg/kg feed in the last three weeks of fattening
      increases the content in the tissues and stabilises the meat quality. A
      supplement of fish oil (3%) increases the content of fish fatty acids in the yolk
      and necessitates an addition of 60 mg vitamin E/kg feed. The content of vitamin E
      in the tissues of chicks at hatch is dependent of that in the yolk. A supplement
      of 250 mg vitamin E/kg feed diminishes the decrease in egg production in heat
      stress. Recommendations for an optimal supply with vitamin E are given.

PMID- 12481655
TI  - Association of diabetes mellitus and chronic hepatitis C infection.

PMID- 12481656
TI  - Diabetes mellitus is equally frequent in chronic HCV and HBV infection.
AB  - OBJECTIVE: To see the association of type 2 diabetes mellitus (Type 2 DM) in
      patients suffering from chronic HBV or HCV related liver disease. SETTING:
      Patients were selected from the gastroenterology OPD of the medical research
      centre, diabetic controls from private diabetes clinic and healthy controls from
      the blood bank of the hospital. METHODS: Patients with chronic liver disease had
      HBV, HCV tested using ELISA and blood sugar using a glucometer mostly as a 2 hour
      post prandial sample. Healthy controls had their sugar and ALT checked while
      donating blood and HBV, HCV were checked routinely. In diabetic controls, blood
      sample was taken as sera stored for HBV,HCV and ALT and later tested in batches.
      A random sugar of > or = 200 mg/dl was taken as diabetes. RESULTS: Of 400 patient
      with chronic liver disease 302 had HCV and 98 HBV infection. Diabetes was found
      in 24.5% HCV and 19.4% HBV related cases (not significant). Out of 410 healthy
      controls 18 were HCV and 17 HBV positive. Diabetes was found in only 1 (5.6%) HCV
      positive control and none of the HBV positive controls. Of 196 diabetics 10
      (5.1%) were HCV positive and none HBV positive. Diabetes was more frequent in
      patients having liver cirrhosis than in those having chronic hepatitis (P <
      0.01). CONCLUSION: Diabetes is equally frequent in both HBV and HCV related
      disease but is significantly more in those with chronic liver disease than in
      controls. The pancreatic damage secondary to extrahepatic viral replication
      appears to be the major cause but genetic factors also need to be explored.

PMID- 12481657
TI  - Need and duration of antibiotic therapy in clean and clean contaminated
      operations.
AB  - OBJECTIVE: To define the need and duration of prophylactic antibiotic
      administration in clean and clean contaminated surgery in the prevailing
      operating theatre environment in Karachi. SETTING: Surgical Department of Hamdard
      University Hospital and three other private hospitals in Karachi. METHODS: One
      hundred consecutive patients undergoing elective clean and clean contaminated
      surgery were recruited from October 2000 to October 2001. Patients were admitted
      either a day prior to surgery or on the day of surgery, depending on the nature
      of procedure. Prophylaxis was provided by single dose of antibiotic at induction.
      The rest of the pre-operative preparation was done in standard way. Patients were
      discharged home as dictated by the nature of the operation and social
      circumstances. Wounds were examined for Surgical Site Infection (SSI) on day 4
      and day 11. Patients who had post-operative pyrexia or signs of SSI were given
      extended antibiotic treatment for 5 days or until resolution of infection.
      RESULTS: Four out of 8 patients who developed SSI required extended antibiotic
      treatment. CONCLUSION: Single dose prophylactic antibiotic therapy is
      satisfactory in our surgical environment. This practice would be efficient, cost
      effective and prevent the emergence of nosocomial infections in a developing
      country such as Pakistan with extremely limited health care resources.

PMID- 12481658
TI  - Characterization of pathogenic mutations in 21-hydroxylase gene of Pakistani
      patients with congenital adrenal hyperplasia and their family members--a
      preliminary report.
AB  - OBJECTIVE: To characterize specific mutations within the 21-hydroxylase gene
      (CYP21-B) using ARMS-PCR assay in patients with congenital adrenal hyperplasia
      (CAH) and to compare it with that reported in other populations. SUBJECTS AND
      METHODS: Five families, having an index case with CAH diagnosed on the basis of
      clinical and biochemical findings volunteered to give blood samples for analysis.
      A strategy, based on ARMS-PCR (Amplified Refractory Mutation System) was employed
      for the detection of mutations in 21-hydroxylase gene. The products of ARMS-PCR
      were resolved on agarose gels and the PCR products were visualized over ultra
      violet illumination. RESULTS: Twenty-six specimens were analyzed for common point
      mutations in the 21-hydroxlase genes at the nucleotide positions 659, 1004 and
      1688. Seven samples belonged to index cases with CAH. Of these 7, the assigned
      sex was male in 5 and female in 2 cases. However, genotypic sex was 3 males and 4
      females. The mean age was 8 months in 5 cases while the median 17-OH Progesterone
      levels was 273.2 ng/ml. Vomiting, precocious puberty and ambiguous genitalia were
      the presenting features in 2, 1 and 4 cases respectively. Analysis for mutation
      at 659, 100 and 1688 was performed on 7 index cases and the family members of 5
      index cases. The mutation analysis for the family members of index case 6 and 7
      was not performed due to non-availability of their blood specimens. Index case
      No. 1, 4 and 7 showed homozygosity for splice mutations at nucleotide position
      659, intron 2 with a sequence change of A to G, while the index case No. 2 and 6
      showed heterozygosity for the same mutation. No mutation was found at 659, 1004
      or 1688 in index case No. 3 and 4 at the analyzed nucleotide position. Nineteen
      family members of Case Nos. 1-5 were also analyzed for the same mutations.
      (Family No. 1, 2, 3, 4 and 5 included 3, 2, 7, 4 and 5 members respectively).
      These included 8 males and 11 females. All were asymptomatic. Both the parents of
      index case 1 and 4 were heterozygous at 659 while the father of index case No. 2
      was heterozygous at 659 and mother was normal. CONCLUSION: Our results
      demonstrated the A to G transition at nucleotide 659 causing aberrant splicing,
      reported for some other populations as the most commonly identified point
      mutations. All cases were appropriately assigned to paternal or maternal
      chromosomes.

PMID- 12481659
TI  - Mini cholecystectomy now a day stay surgery: anaesthetic management with multi
      modal analgesia.
AB  - OBJECTIVE: To develop anaesthetic techniques for mini cholecystectomy in a day
      care set up. METHODS: Fifty patients in ASA grade I and II scheduled for
      minicholecystectomy were selected. They were given Inj. Ketoralac 30 mg
      intramuscular 45 minutes prior to surgery. Inj. pethidine 0.5 mg/kg intravenous
      was given at induction and Inj. bupivacaine 0.5% plain 10 ml was infiltered into
      the wound at the end of surgery. RESULTS: The mean age was 43.4 +/- 6.1 years
      with a preponderance of females (41 of 51). Thirty eight belonged to ASA grade I
      and 12 were in ASA grade II. Mean duration of surgery was 28.8 +/- 5.1 minutes.
      Size of minicholecystectomy incision was 3.9 +/- 0.4 cms. Two patients required
      additional opioid peroperatively, while two patients were given opioids post
      operatively. They were discharged from the PACUI at aldrete score > or = 9 at
      61.4 +/- 6.3 minutes while 47 patients were discharged from PACU II at PADSS
      score 7 > = or 9,172.1 +/- 11.4 minutes after surgery. The incidence of nausea
      was 6% with confidence interval of 95% range (5.0-23.3). Three patients were
      admitted. None of our patients required a readmission. CONCLUSION:
      Miinicholecystectomy as a day care procedure is safe, with good pain relief
      facilitating mobility and recovery with multimodal pain management strategy.

PMID- 12481660
TI  - Utility of participatory rural appraisal for health needs assessment and
      planning.
AB  - BACKGROUND: While poverty and lack of life opportunities are root causes of a
      high burden of disease and infant and maternal mortality, inadequate health care
      contributes heavily. Often those who are left without care are those who need it
      most. Existing health services are managed without taking into account acceptance
      and need perspectives. This further reduces the effectiveness of and equity in
      health care. In order to guide the planning of reproductive health services by a
      national NGO, health needs were assessed in a district in Sindh using a
      combination of participatory rural appraisal (PRA) and qualitative and
      quantitative research methods. PRA is considered as a better framework to assess,
      analyse and develop programs with communities. OBJECTIVE: The objective of PRA
      was to initiate community involvement and to understand the needs of health care
      from a community perspective. METHODOLOGY: PRA was conducted with groups of men
      and women from three rural areas in a district of Sindh, Pakistan using a life
      cycle framework. The community members identified various stages of their life
      with the associated health issues. RESULTS: This research was empowering to
      community members as it facilitated community involvement. The respondents took
      charge of the process of identification of health needs at PRA sessions. PRA
      helped identify health problems considered prevalent and important by the
      community. More importantly, it helped potential service providers and the
      community to initiate community involvement in planning. CONCLUSION: PRA is not
      only an effective tool for assessment and analysis of health issues but also a
      vehicle to promote community involvement. Additionally, participatory methods
      contribute to understand the context of quantitative data generated for planning
      purposes.

PMID- 12481661
TI  - Comparability and Quality Control in Cancer Registration; Karachi (data
      monitoring 1995-2001).
AB  - INTRODUCTION: Comparability and Quality Control in Cancer Registration remains an
      essential component of standardisation of cancer incidence data. The information
      provided by registries is used as a base-line data for cancer control and cancer
      research. As such misleading information will encourage fictious cancer patterns
      with over or under registration of some cancer sites. METHODOLOGY: The
      registration in Karachi started in 1995 and was confined to a single district of
      Karachi, the South District. Since 1998 the registration has extended to Karachi
      Division. For both the data sets, recommendations of the International Agency for
      Research on Cancer (IARC) and the International Association of Cancer Registries
      (IACR) have been followed to assure comparability and Quality Control of the
      results. RESULTS: The 2 data sets from Karachi show well-recorded demographic
      details of cases. Age was not a true indicator of validity in our case, as we
      have approximate ages of patients aggregated around quintiles and decades. All
      the cancer cases were reported from a minimum of 3 sources. Microscopic
      verifications (MV) were high. Cancers with the highest histological verification
      (HV) were those located in easily accessible sites e.g. breast, oral cavity and
      cervix. The age specific incidence rates (ASR) for Karachi South, all sites (1995
      1999) was 148.1 males and 175.5 females. The same for Karachi Division (1998-99)
      was 132.4 males and 133.0 females. CONCLUSION: The cancer data in 1995 during the
      initial phase of registration was incomplete and suffered from inaccuracies
      associated with a lack of awareness in early years of registration. By the year
      2001, the data (1995-1999) showed improved completion and accuracy. The incidence
      rates have shown no dramatic changes during the past 2 years. The malignancies
      also show a stable pattern, despite the possibility of under-registration of
      clinically diagnosed cases. The microscopic verification is high compared with
      the world region and similar to those observed in developed countries. This may
      be due to the widely available diagnostic facilities in Karachi and should
      therefore be considered an indicator of validity of registered data.

PMID- 12481662
TI  - Maternal health care in a rural area of Pakistan.
AB  - OBJECTIVE: The need for effective strategies for delivery of healthcare to rural
      women is paramount and requires a study of maternal perceptions and experiences
      of the healthcare system. METHOD: This article describes knowledge, attitudes and
      practices regarding obstetric healthcare in a rural area of Pakistan. This is a
      cross sectional survey of a rural area of district Hyderabad, Pakistan. A
      multistage sample of 1,150 households was drawn from a population of 247,257
      living in 30,653 households. Structured KAP questionnaires regarding maternal
      health were administered to male and female respondents in study household.
      RESULTS: A total of 1,178 married women and 1,146 married men were interviewed.
      The mean age of female respondents was 29 +/- 6 years. At the time of the
      interview 20% women were pregnant. Sixty-one percent women received antenatal
      care during their last pregnancy. The most frequent antenatal care providers were
      female doctors (55%). Majority (67%) of women had delivered at home with the
      assistance of traditional birth attendants (TBAs). Overall less than 40% of
      respondents could correctly identify signs of obstetric complications. Thirty
      eight percent women experienced obstetric complications during their last
      pregnancy. Estimated annual maternal mortality ratio (MMR) was 689/100,000 live
      births. CONCLUSION: Women have inadequate access to obstetric care due to limited
      healthcare options and poor knowledge of obstetric complications. This can be
      corrected by improving services and increasing overall maternal health awareness
      in the community.

PMID- 12481663
TI  - Methicillin resistant Staphylococcus aureus: a multicentre study.
AB  - OBJECTIVE: To determine the frequency of Methicillin resistance Staphylococcus
      aureus infection in major cities of Pakistan. SETTING: Various laboratories of
      the country with one as the central Laboratory. MATERIALS AND METHODS: Seven
      hundred and ninety two consecutive clinical isolates of Staphylococcus aureus
      were collected from 8 laboratories all over Pakistan i.e. Karachi, Peshawar,
      Lahore, Sukkhur, Islamabad, Quetta, and Mirpur, Azad Kashmir. Antibiotic
      sensitivity was done by Kirby Bauer disc diffusion method and MIC of Vancomycin
      was determined by 'E' test. RESULTS: Forty two percent of the isolates were found
      to be Methicillin resistant staphylococcus aureus (MRSA) while no Vancomycin
      resistance was encountered. CONCLUSION: Methicillin resistant Staphylococcus
      aureus (MRSA) are seen in the local population with frequencies varying between 2
      61% highest incidence is seen in the major cities of the country. Fortunately no
      Vancomycin resistant Staphylococcus has been isolated from any of the major
      cities.

PMID- 12481664
TI  - Prevalence of parasitic infections in a rural area of Karachi, Pakistan.
AB  - OBJECTIVE: To find the prevalence of human intestinal pathogenic parasites.
      SETTING: The study was conducted in Konkor, Gadap, District East, Karachi.
      METHODS: After taking the verbal consent, all the villagers, selected by area
      sampling technique were interviewed by a structured questionnaire and then each
      person in the house was provided with a clean, plastic container to collect the
      stool samples. Samples were examined using normal saline, iodine preparation and
      zinc floatation technique where appropriate. RESULTS: Out of 263 residents 185
      tested for intestinal parasites and 88 (47.5%) had pathogenic parasites. The
      distributions of parasites were Giardia lamblia 50% and Entamoeba histolytica
      48.86%. Statistically none of the socio-demographic variables were associated
      except education and age group. CONCLUSION: In the light of the study result it
      is concluded that there is a high prevalence of parasitic infection in the
      community and an intervention strategy including health education program should
      be designed and implemented to control parasitic infections.

PMID- 12481665
TI  - Prince of Lyallpur.
AB  - Prince Masud Khan was a leader of psychoanalytical movement in its halcyon days.
      His name is given by many in the profession in the same breath as Freud, Klein
      and Winnicot. Despite his aristocratic background, handsome and charismatic
      personality and distinguished achievements as an academic and clinician, to the
      English he remained a Pakistani and nobody knows him in Pakistan. This article is
      an attempt to examine Prince Masud's work, personality and some of the issues
      behind his absence from our collective conscience.

PMID- 12481666
TI  - Acute lung injury/acute respiratory distress syndrome.

PMID- 12481667
TI  - View box case--7. Salter-Harris type-II fracture.

PMID- 12481668
TI  - Pragmatic solutions for problems in the undergraduate medical programmes in
      Pakistan.
AB  - Reforms in the Pakistani undergraduate medical education have remained elusive
      for decades. An attempt is made to highlight the importance of research-oriented
      education and problem-based learning to Pakistani medical schools. Possible
      causes are analyzed and implementable solutions are suggested with appropriate
      references from literature search. An innovative "Research Ladder" approach to
      implementing a research-oriented curriculum that culminates in attainment of a
      combined MBBS-BRS degree is also proposed. In the end, techniques for making
      existing lecture-based learning more interactive are suggested.

PMID- 12481669
TI  - Direct coronary stenting: the way to go in Pakistan.

PMID- 12481670
TI  - Experience of direct coronary stenting at National Institute of Cardiovascular
      Diseases.
AB  - OBJECTIVE: To assess the efficacy, safety and advantage of direct coronary
      stenting versus traditional angioplasty and stenting. METHODS: From May 2000 to
      June 2001, 486 patients underwent PTCA procedure. One hundred fifteen (24%) were
      considered candidates for direct stenting. Out of 150 coronary lesions, 119 (79%)
      had direct coronary stenting. In 5% patients stent could not be passed across the
      lesion. These stents were withdrawn without stent damage and after predilatation
      the same were successfully deployed. RESULTS: Primary success rate was 95%.
      Angiographically assessed success was achieved in all patients with immediate
      TIMI 111 flow in 97%. The vessels directly stented were LAD 53%, RCA 27% and LCX
      18%. Two saphenous vein grafts were also directly stented. The coronary lesions
      stented were type A 36%, B1 54% and B2 10%. In borderline lesions IVUS was used
      for quantification of stenosis. There was no in-hospital death, MI or emergency
      CABG. Compared to traditional stenting there was 46% reduction in procedure time,
      62% reduction in radiation exposure time and 35% decrease in use of contrast
      media. There was also significant (18%) cost benefit in direct stenting.
      CONCLUSION: This study supports the view that direct coronary stenting is
      feasible and a safe procedure in our population with additional benefits of cost
      reduction by 18%. We recommend direct stenting in appropriately selected
      patients.

PMID- 12481671
TI  - The obesity pandemic--implications for Pakistan.
AB  - BACKGROUND: Adverse health outcomes are associated with overweight and obesity.
      In February 2000, the WHO Regional Office for the Western Pacific, the
      International Association for the Study of Obesity and the International Obesity
      Task Force published provisional recommendations for adults for the Asia-Pacific
      region: overweight at Body Mass Index (BMI) > or = 23 and obesity at BMI > or =
      25. METHODS: Data from the National Health Survey of Pakistan, 1990-94 were
      reanalyzed using BMI cut-offs recommended for Asians to reassess prevalence of
      overweight and obesity in the adult Pakistani population. RESULTS: Prevalence of
      obesity (BMI > or = 25) in 25-44 year olds in rural areas was 9% for men and 14%
      for women; in urban areas, prevalence was 22% and 37% for men and women,
      respectively. For 45-64 year olds, prevalence was 11% for men and 19% for women
      in rural areas, and 23% and 40% in urban areas for men and women, respectively.
      Obesity prevalence was directly associated with SES, regardless of residence.
      CONCLUSION: In South Asia, including Pakistan, social and environmental changes
      are occurring rapidly, with increasing urbanization, changing lifestyles, higher
      energy density of diets, and reduced physical activity. The coexistence of
      underweight in early life with obesity in adults may presage both a higher
      prevalence and incidence for noncommunicable diseases (NCDs) such as hypertension
      and diabetes. Use of BMI > or = 23 for overweight, and BMI > or = 25 for obesity,
      may provide a more accurate determination of the health of Pakistanis, especially
      in those with more than one risk factor for NCDs.

PMID- 12481672
TI  - Drug sensitivity pattern of cholera in children.
AB  - OBJECTIVE: To study the drug sensitivity pattern of cholera in children. SETTING:
      DTU of Civil Hospital, Karachi. PATIENTS AND METHODS: All children age 2 months
      to 15 years attending Diarrhoea Treatment Unit (DTU) with acute onset of
      diarrhoea and dehydration were screened for cholera. Stool samples were collected
      in alkaline peptone and those positive for cholera had their antibiotic
      sensitivity determined. RESULTS: Of 846 stool specimens, 161 were positive for V.
      Cholera. All were sensitive to third generation cephalosporins and quinolones, 98
      100% to nalidixic acid, 82-86% to chloramphenicol and 67-75% to doxycycline and
      all were resistant to cotrimaxazole. CONCLUSION: Cholera can be treated with
      nalidixic acid or chloramphenical in young children while doxycycline for older
      children. Cotrimoxazole is not effective. Efforts should be done for
      identification and surveillance of cholera cases, along with change of
      sensitivity pattern of Vibrio cholera.

PMID- 12481673
TI  - Neonatal sepsis: high antibiotic resistance of the bacterial pathogens in a
      neonatal intensive care unit in Karachi.
AB  - OBJECTIVE: To study the bacterial pathogens causing neonatal sepsis and their
      sensitivity pattern so that guidelines can be prepared for empirical antibiotic
      therapy. SETTING: The study was conducted in the neonatal intensive care unit
      (NICU) at PNS Shifa (Naval Hospital), Karachi during January 1997 to June 1999.
      METHODS: Blood specimens for culture were drawn from 520 newborns admitted in a
      NICU with sepsis. The specimens were inoculated into brain heart infusion broth.
      Subcultures were performed on days 1, 2, 3, 5, 7 and 10. The isolates were
      identified by standard biochemical tests. Antibiotic resistance pattern of the
      isolates was studied by Modified Kirby Baur disc diffusion technique. RESULTS: A
      total of 212 organisms were isolated. These included Staphylococcus aureus (n =
      65), Klebsiella pneumoniae (n = 73), Acinetobacter baumannii (n = 23),
      Escherichia coli (n = 22), Enterobacter cloacae (n = 18), Citrobacter diversus (n
      = 5), Pseudomonas aeruginosa (n = 4) and group B Streptococcus (n = 2). On
      antibiotic sensitivity testing, 61.54% of Staphylococcus aureus isolates were
      found to be methicillin resistant. Susceptibility to the other common drugs was
      also quite low while 89.23% of these were susceptible to amikacin and 100% to
      vancomycin. More than 90% gram negative rods were resistant to ampicillin and co
      trimoxazole. Resistance to gentamicin was as high as 90.4% for Klebsiella
      pneumoniae; 60.87% for Acinetobacter baumannii. Resistance to the third
      generation cephalosporins and the quinolone tested (ciprofloxacin) varied between
      25-75%. Majority of the isolates were susceptible to meropenem and amikacin.
      CONCLUSION: In view of the isolation of highly antibiotic resistant organisms,
      vancomycin in combination with amikacin or a carbapenem is the drug of choice for
      empirically treating neonatal sepsis.

PMID- 12481674
TI  - CSF oligoclonal bands in multiple sclerosis.
AB  - OBJECTIVE: To study the significance of oligoclonal bands in neurological
      disorders, specifically in Multiple Sclerosis (MS). METHODS: The study was
      designed to assess the sensitivity and specificity of the test methodology of CSF
      electrophoresis by performing the retrospective analysis of CSF samples sent for
      oligoclonal bands (OCB). A total of 603 samples were received by the Clinical
      Laboratories, Department of Pathology of The Aga Khan University, during a period
      of 54 months (January 1993-June 1997). All of these samples were analyzed by
      performing CSF protein electrophoresis. One hundred thirty three out of 603
      samples showed evidence of OCB. Out of these, 24 patients were registered with
      Section of Neurology, Department of Medicine, The Aga Khan University Hospital.
      These 24 patients were finally selected for analysis. Relevant clinical details
      such as age, sex and clinical presentations were recorded. RESULTS: Fifteen (62%)
      out of 24 patients with positive OCB were diagnosed as cases of MS. Four (17%)
      patients were diagnosed to have subacute sclerosing panencephalitis (SSPE). Five
      (21%) patients were having other inflammatory neurological disorders. CONCLUSION:
      The overall relative sensitivity and specificity for multiple sclerosis were
      found to be 100% and 62.5% respectively. Lack of specificity was attributed to
      the fact that OCB were positive in other neurological disorders as well.

PMID- 12481675
TI  - Influence of prokinetics on the gastrointestinal transit and residence times of
      activated charcoal.
AB  - OBJECTIVE: To find the effects of prokinetics, saline cathartics and different
      charcoal doses on the gastrointestinal transit and residence times of activated
      charcoal (AC). SETTING: Five undergraduate volunteers of College of Health
      Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria, were
      studied. METHODS: After an overnight fast, the volunteers were given 10 g and 20
      g AC with and without saline cathartics, in a simple cross-over design in which
      the subjects served as their own control. In another experiment, the volunteers
      received 10 g AC and magnesium sulphate, with propantheline (as bromide 15 mg),
      metoclopramide (as hydrochloride 10 mg), placebo liquid or identical placebo
      capsule. Gastrointestinal transit and residence times of AC were recorded.
      RESULTS: Increase in the dose of AC significantly (P < 0.05) decreased the
      transit, but not the residence time of AC. Addition of saline cathartics (Na2SO4
      and MgSO4) decreased both the transit and residence times of AC significantly (P
      < 0.05). Also, administration of propantheline, but not metoclopramide, produced
      a significant (P < 0.05) decrease in both the transit and residence times of AC.
      The transit and residence times were statistically (P < 0.05) different in both
      the magnesium sulphate group, as well as in the placebo liquid and placebo
      capsule groups. CONCLUSION: Cathartic efficiency is enhanced by alteration of
      gastrointestinal motility with propantheline.

PMID- 12481676
TI  - Prevalence of diabetes, impaired fasting glucose and associated risk factors in a
      rural area of Baluchistan province according to new ADA criteria.
AB  - OBJECTIVE: To assess the prevalence of impaired fasting glucose (IFG) and
      diabetes in an adult rural population on the basis of fasting blood glucose (FBG)
      alone using American Diabetic Association (ADA) criteria and to assess the
      prevalence of and association between selected risk factors such as obesity,
      family history of diabetes and hypertension. MATERIALS AND METHODS: Sixteen
      randomly selected villages from the Lasbella district of Baluchistan were
      included in this study. One month before the survey a team visited the areas; all
      the households located in the selected areas were approached and the family
      members aged 25 or above, who were available and willing to participate in the
      study, were recruited. On the day of survey anthroprometric and blood pressure
      measurements were taken; interviews were conducted to obtain demographic
      information and health history and fasting blood samples were collected. The
      blood samples were transported to the laboratory and analysed using "GOD-PAP"
      Enzymatic Colorimetric test method. RESULTS: A total of 670 males and 1362
      females were studied. Prevalence rate of diabetes using the ADA fasting criteria
      was 6.3% while the prevalence rate in males was 10.1% and in females was 4.3%.
      The prevalence rate of impaired fasting glucose was 4.2% in males and 2.3% in
      females. Overall prevalence of obesity between diabetics vs non-diabetics was 22%
      vs 16%, for hypertension 12.9% vs 6.5% and for positive family history of
      diabetes 1.6% vs 0.9% was higher among diabetics as compared to non diabetics;
      the difference of these parameters was statistically significant only among
      females (P < 0.01). CONCLUSION: The results of this study suggest the need of
      continual use of OGTT for screening people at high risk of developing diabetes
      and perhaps also for diagnosing diabetes.

PMID- 12481677
TI  - Tumor-induced hypercalcemia: predictors of early mortality.
AB  - OBJECTIVE: To delineate the demographics and predictors of early mortality
      associated with tumor-induced hypercalcemia (TIH) amongst cancer patients in
      Pakistan. SETTING: A tertiary care hospital in Pakistan. PATIENTS AND METHODS:
      Retrospective analysis of patients with cancers, presenting with TIH and admitted
      to the hospital between January 1988 and December 1997, was carried out. RESULTS:
      Eighty-four patients (56 males and 28 females) were diagnosed to have TIH. The
      mean age at the time of presentation was 55 +/- 14 years. Twenty-five percent of
      the patients each had multiple myeloma and hepatocellular carcinoma whereas 20%
      of the patients had underlying breast cancer. Other malignancies included lung
      cancer, gall bladder cancer and colorectal carcinomas. Univariate analysis
      revealed male sex (p < 0.04), underlying diagnosis other than multiple myeloma (p
      < 0.025) and a high TLC (p < 0.05) at presentation, as predictors of an early
      mortality. CONCLUSION: Multiple myeloma, hepatoma and breast carcinoma were
      common cancers causing TIH. One-third patients died within first few days. Male
      sex, a high white cell count and an underlying diagnosis other than multiple
      myeloma predicted early mortality.

PMID- 12481678
TI  - Nutrition education in the undergraduate medical curriculum at the Aga Khan
      University, Karachi, Pakistan.

PMID- 12481679
TI  - Practicing prevention: handwashing.

PMID- 12481680
TI  - Faecal empyema.

PMID- 12481681
TI  - Disseminated histoplasmosis in an immunocompetent host.

PMID- 12481682
TI  - Neurocytoma - a rare intraventricular tumor.

PMID- 12481683
TI  - View box case-8. Ilio-cecal tuberculosis.

PMID- 12481684
TI  - Superstitions regarding health problems in different ethnic groups in Karachi.
AB  - OBJECTIVE: To find out the superstitions regarding health problems in different
      ethnic groups, their implications over the socio-economic development of that
      group and to what extent can those superstitions be related to their level of
      literacy. METHODS: The study was a questionnaire-based survey, 20 subjects from
      each ethnic group were selected by cluster sampling of residential areas where
      that particular group has its highest concentration, making a total of 100
      subjects. RESULTS: It was found that most people (73%) do have some superstitious
      beliefs. Fifty percent of people believe in them as a part of culture and
      tradition, another 25% got them from their elders. No significant difference was
      found between different racial groups (p value = 0.9). According to literacy
      rate, 73.5% of literate community and 94.1% illiterate community were found to
      have superstitions. The occupation of the breadwinner of family didn't have a
      significant impact over the belief in superstitions (p value = 0.6). CONCLUSION:
      Majority of our population believes in superstitions, which are more common in
      illiterates. These superstitions not only predict health seeking behaviour of a
      person but also play a major role in shaping the response of a community to any
      health intervention program. Without the knowledge of these superstitions,
      effective community participation cannot be achieved.

PMID- 12481685
TI  - Quasi-periodic behaviour in a model for the lithium-induced, electrical
      oscillations of frog skin.
AB  - The fact that oscillations can be induced in studies of the maintenance of the
      electrical potential of frog skin by addition of lithium allowed evaluation of
      several parameters fundamental to the functioning of the system in vivo (e.g.
      relative volumes of internal compartments, characteristic times of ionic
      exchanges between compartments). A realistic model was thus proposed under the
      form of a set of ordinary differential equations. In the past, numerical
      simulations using such a model reproduced the periodic experimental oscillations
      and was able to provide an explanation for the global synchronised oscillations
      of the whole skin. In that paper, new numerical simulations reproduce the non
      periodic oscillations which were observed two decades ago, but not reproduced by
      the model. Moreover, the dynamical process under which all the local oscillators
      are synchronised is explained in terms of a tangent bifurcation.

PMID- 12481687
TI  - [Mevalonolactone: a volatile compound produced by Psammotettix alienus (Dhb)].
AB  - The interaction between the aphid Rhopalosiphum padi (L.) and the leafhopper
      Psammotettix alienus was investigated in the laboratory. The leafhoppers, when
      physically separated from aphid but with a common air supply, caused a reduction
      in aphid offspring production. One of the hypotheses to explain this result is
      that volatile compounds might be responsible for the effect on the aphid
      reproduction. To verify this hypothesis, leafhopper static headspace was
      subjected to GC-MS (gas chromatography-mass spectrometry) analyses. An original
      compound was identified in the leafhopper headspace as mevalonolactone (Mev) and
      was found to be produced only by adults. This is the first report of Mev released
      in the headspace of either an insect or living organisms in general. Two other
      new compounds in insects were also identified in both leafhopper nymphs and
      adults: 2-(2-hydroxypropoxy)-1-propanol and 3,3'-oxybis-2-butanol.

PMID- 12481688
TI  - [Identification of the intraclonal variability of date-palm vitro-plants grown
      via organogenesis from in vitro cultures: morphological study].
AB  - The greater rhythm of the degradation of the Morocco palm plantation implies a
      repopulation with vitroplants. To estimate the behaviour of those vitroplants, a
      morphological study of clones of date palm, obtained via organogenesis from
      primordial leaves surrounding the shoot tip of young offshoots, was carried out
      on 92 vitroplants arising from three cultivars (Boufeggous, Jihel and Bouskri)
      and two sairs (Sair 16 bis and 35). The results of the Principal Components
      Analysis (PCA) of 34 morphological variables of vegetative and reproductive
      apparatus and those of the hierarchical classification allowed us to show an
      intraclonal heterogeneity of these vitroplants within each cultivar and sair. A
      certain number of characters was selected as being the most discriminating. These
      characters can be useful in the study of vitroplants genetic conformity with
      regard to the parents.

PMID- 12481686
TI  - [Cytotoxic effects of lead on the endocrine and exocrine sexual function of
      pubescent male and female rats. Demonstration of apoptotic activity].
AB  - This study deals with the impact of chronic exposure to lead on male and female
      fertility in rats. Male and female rats (3 months old) were fed on commercial
      tablets (SICO, Sfax). For drinking, some rats were given distilled water (T =
      controls), the other ones were given distilled water enriched with lead acetate,
      either 3 (P1 group) or 6 mg ml-1 (P2 group), for 15, 30, 45, 60 or 90 days. In
      male rats, absolute and relative weights of testis, epididymis, prostate and
      seminal vesicles were found to significantly decrease at day 15 in the P2 group
      and at day 45 in the P1 group. However, at day 60, these absolute and relative
      weights returned to control values. Lead-induced pathological changes in
      spermatogenesis were observed at day 15 by histological study: arrest of cell
      germ maturation, changes in the Sertoli cells, and presence of apoptotic cells
      revealed by borated toluidine blue in the testis. Presence of lead deposits was
      observed after histochemical staining using sodium rhodizonate. Serum
      testosterone level was found to be lowered at day 15 in both (P1) and (P2)
      groups, to display a peak at day 60, then to return to controls values, in spite
      of the continuation of the treatment. In female rats, absolute and relative
      weights of ovary and uterus were found unchanged. The vaginal smears practiced in
      females revealed the oestrus phase in all groups. Exposed females were mated with
      control males, and fecundity was assessed 15 days later by counting the number of
      pregnancies and the number of concepti per pregnancy. Fertility was found to be
      reduced in females of P1 and P2 groups as compared to control females (T group).
      Lead level in blood was found to be poorly correlated with the level of
      poisoning, whereas lead accumulation in tail was found to be dose-dependent.
      Therefore, lead accumulation in tail appears as a more reliable biomarker of
      exposure to lead. In summary, our study shows that chronic exposure to lead
      causes a double sexual disorder in rats: first, disorder deals with the hormonal
      function, which is affected at the early stages of poisoning, but is rapidly
      corrected; second, disorder deals with the genital tract, affecting the testis
      and the ovary, resulting in a reduced fertility in both P1 and P2 females, in
      spite of the presence of a normal oestrus. The cytotoxic effect of lead in males
      seems to be related to an apoptotic process.

PMID- 12481689
TI  - The importance of being ordered: improving NMR structures using residual dipolar
      couplings.
AB  - Residual dipolar couplings arise from small degrees of alignment of molecules in
      a magnetic field. Most biomolecules lack sufficient intrinsic magnetic
      susceptibility anisotropies for practical purposes; however, alignment can be
      achieved using dilute aqueous phospholipid mixtures, colloidal suspensions of rod
      shaped viruses, complex phases of surfactant systems and strained gels. The
      stability of the liquid crystalline phases varies with respect to temperature
      range, pH variation and time and is critically dependent on sample composition
      and experimental conditions. The magnitude of the residual dipolar couplings
      depends upon the degree of ordering and allows the determination of the
      corresponding inter-nuclear vectors with respect to the molecule's alignment
      frame. Inclusion of dipolar constraints into NMR structure calculations leads to
      improved precision and accuracy of the resulting structures, especially in cases
      where the information content provided by traditional NOE constraints is limited.
      In addition, rapid evaluation of backbone protein folds and determination of the
      relative orientations of individual components in multi-molecular complexes have
      become feasible. Dipolar coupling based strategies may well emerge as the most
      critical developments, in establishing NMR as a valuable and competitive
      methodology in the structural genomics initiative.

PMID- 12481690
TI  - Atherina punctata and Atherina lagunae (Pisces, Atherinidae), new species in the
      Mediterranean Sea. 1. Biometric investigations of three Atherinid species.
AB  - Discriminative canonical analysis of 87 biometric parameters in the marine and
      lagoon atherinids of 'Atherina boyeri' complex from the Mediterranean Sea helps
      defining three distinct atherinid groups: marine punctuated, marine unpunctuated
      and lagoon atherinids. Each atherinid group constitutes a clearly independent
      original entity. Besides, each one is a more or less heterogeneous group with
      geographical disparities, characterising specimen collected from France and
      Tunisia. Concordance of biometric, biochemical and genetic results as well help
      define two new species of atherinids: Atherina punctata = punctuated marine
      atherinids, and Atherina lagunae = atherinids living in lagoon environments.

PMID- 12481691
TI  - Higher-level relationships of caenophidian snakes inferred from four nuclear and
      mitochondrial genes.
AB  - Higher-level caenophidian snake relationships are inferred from sequence analyses
      of one nuclear gene (C-mos) and three mitochondrial genes (12S rRNA, 16S rRNA and
      ND4). Caenophidians, which are haenophidian closest relatives, have an Asiatic
      origin. An African clade comprising atractaspidids, psammophiines,
      'lamprophiines' and 'pseudoxyrhophiines' is identified. We discern no
      evolutionary trend such as an improvement of the venom apparatus with a linear
      progression from the absence of a venom system to the presence of a front-fanged
      one. The venom apparatus is contemporary with the origin of colubroids and its
      absence in a few lineages results from secondary losses. The front-fanged venom
      system appeared three times independently. The active diurnal foraging mode
      (associated with a high metabolic rate) appears in a derived position among
      colubroids.

PMID- 12481692
TI  - Genotypic influences on metabolic alterations during inflammation and the
      nutritional outcome.

PMID- 12481693
TI  - Fatty acids and gene expression related to inflammation.

PMID- 12481694
TI  - Nutritional modulation of gut inflammation.

PMID- 12481695
TI  - How valid is the concept of antioxidants and cell injury?

PMID- 12481696
TI  - Optimizing intravenous supply of functional lipid components.

PMID- 12481697
TI  - Optimization of dietary protein intake during aging.

PMID- 12481698
TI  - Vitamin and antioxidant supplementation: critical evaluation of clinical
      outcomes.

PMID- 12481700
TI  - Timing of nutritional support.

PMID- 12481699
TI  - Trace elements: contribution to the efficacy of nutritional support.

PMID- 12481701
TI  - Signaling factors for gut adaptation.

PMID- 12481702
TI  - Parenteral versus enteral nutrition: can we get rid of the myths?

PMID- 12481703
TI  - Specialized nutrition support in the critically ill: for whom and when?

PMID- 12481704
TI  - The primary target of nutritional support: body composition or muscle function?

PMID- 12481705
TI  - Body composition in pediatrics to geriatrics: a lesson for nutritional
      monitoring.

PMID- 12481706
TI  - Efficacy of nutritional support: evidence-based nutrition and cost-effectiveness.

PMID- 12481707
TI  - Nutritional intervention: what of the future?

PMID- 12481708
TI  - Timely nutritional support: thoughts for the future.

PMID- 12481709
TI  - Tumor physiology and resistance to chemotherapy: repopulation and drug
      penetration.

PMID- 12481710
TI  - The role of membrane transporters in cellular resistance to anticancer nucleoside
      drugs.

PMID- 12481711
TI  - MDR and MRP gene families as cellular determinant factors for resistance to
      clinical anticancer agents.

PMID- 12481712
TI  - The glutathione system in alkylator resistance.

PMID- 12481713
TI  - The role of signal transduction pathways in drug and radiation resistance.

PMID- 12481714
TI  - Mechanisms of repair of interstrand crosslinks in DNA.

PMID- 12481715
TI  - DNA repair in resistance to bifunctional alkylating and platinating agents.

PMID- 12481716
TI  - Leukemic cell insensitivity to cyclophosphamide and other oxazaphosphorines
      mediated by aldehyde dehydrogenase(s).

PMID- 12481717
TI  - Mechanisms of resistance against cyclophosphamide and ifosfamide: can they be
      overcome without sacrificing selectivity?

PMID- 12481718
TI  - Cellular mechanisms of cyclophosphamide resistance: model studies in human
      medulloblastoma cell lines.

PMID- 12481719
TI  - Mechanisms of drug resistance in AML.

PMID- 12481721
TI  - Modification of radiosensitivity following chemotherapy exposure: potential
      implications for combined-modality therapy.

PMID- 12481720
TI  - Biochemical and molecular mechanisms of cisplatin resistance.

PMID- 12481722
TI  - Clinical pharmacology of melphalan and its implications for clinical resistance
      to anticancer agents.

PMID- 12481723
TI  - Pharmacological considerations of primary alkylators.

PMID- 12481724
TI  - Genomic approaches to clinical drug resistance.

PMID- 12481725
TI  - Radiologic imaging in gastroenterology. Introduction.

PMID- 12481726
TI  - Endovascular intervention for the treatment of acute arterial gastrointestinal
      hemorrhage.
AB  - The treatment of arterial gastrointestinal hemorrhage continues to evolve.
      Currently, most interventional radiologists approach bleeding both in the upper
      and lower gastrointestinal tract with intention to treat. Embolization has
      replaced local vasoconstrictive therapy as the catheter-based treatment of choice
      in many hospitals. Coaxial microcatheters have simplified embolotherapy and
      enabled lower gastrointestinal bleeding to be treated safely and effectively.

PMID- 12481727
TI  - Enteroclysis and computed tomography enteroclysis.
AB  - Enteroclysis, the most detailed radiologic examination of the small bowel, can be
      a challenge for both patient and radiologist. This article broadly outlines the
      principal technical features of the standard enteroclysis procedure and discusses
      its diagnostic advantages and indications, as well as its limitations and
      difficulties. A comparative assessment of computed tomography-enteroclysis and
      the emerging magnetic resonance adaptation complements the survey of current
      approaches to radiologic small bowel diagnostics.

PMID- 12481728
TI  - Update on magnetic resonance cholangiopancreatography.
AB  - MRCP is a useful tool in the diagnosis of a wide variety of pathologic entities
      including congenital anomalies, biliary obstruction and stricture, biliary
      calculi, pancreatitis, neoplasms, and trauma. ERCP and MRCP both have important
      roles in the management of patients with suspected pancreaticobiliary disease.
      Knowledge of the advantages and disadvantages of each technique is needed to
      determine the appropriate work-up of patients with these pathologies.

PMID- 12481729
TI  - Virtual colonoscopy. Potential clinical applications of a new technique.
AB  - The potential role of virtual colonoscopy is not limited to colorectal cancer
      screening, although that is its greatest potential. Same-day VC should be offered
      for patients undergoing an incomplete colonoscopy. Conversely, faster, more
      accurate interpretation by the radiologist on the same day as a VC should lead to
      the consideration by the gastroenterologist of same-day colonoscopy for patients
      with a suspicious, significantly sized polyp.

PMID- 12481730
TI  - Computed tomography and magnetic resonance imaging evaluation of liver cancer.
AB  - Focal liver lesions occur commonly and with varying histology, each requiring
      radically different management. There are a multitude of imaging modalities
      currently being used for detecting and characterizing focal liver neoplasms. The
      primary modalities include ultrasonography, computed tomography (CT), magnetic
      resonance imaging (MRI), and rarely, angiography. CT and MRI have benefited from
      rapid technologic advances, and MRI, in particular, from the advent of new
      contrast agents.

PMID- 12481731
TI  - Intestinal obstruction role of CT.
AB  - CT has significantly advanced the evaluation of small and large bowel
      obstruction, especially in the acute situation where high-grade or possibly
      strangulating obstruction is being encountered. Any physician involved in
      evaluating patients with bowel distention and abdominal pain where obstruction
      becomes a distinct diagnostic possibility should be aware of the attributes and
      limitations of this modality to provide the best patient care. New technological
      advances will hopefully limit radiation exposure and provide even more definitive
      information in the diagnosis of bowel obstruction.

PMID- 12481732
TI  - Ultrasonography.
AB  - Diagnostic sonography is experiencing a breath-taking period of technological
      advancement. Ultrasound contrast agents, new imaging techniques, and handheld
      instruments will play a role in facilitating more diagnostic power in high-end
      imaging and insuring more widespread use of diagnostic sonography in medicine in
      general.

PMID- 12481733
TI  - Endorectal ultrasound and magnetic resonance imaging in rectal cancer staging.
AB  - The majority of rectal cancers have local disease only at presentation, but
      despite meticulous surgery, a number of factors will influence outcome.
      Preoperative identification of adverse prognostic factors provides a rational
      basis for selecting preoperative therapy. Thin section MRI can influence
      preoperative therapeutic algorithms by T and N staging, demonstrating
      operability, and the potential risk of circumferential margin involvement.
      Endosonography may contribute to this, but has a greater role in determining
      intramural invasion for early tumors. The assessment of residual tumor after
      chemoradiotherapy remains difficult; PET scanning has been used in this situation
      [32], but has not been compared with MRI and is unlikely to show only residual
      cells with extensive fibrosis.

PMID- 12481734
TI  - The role of positron emission tomography in gastrointestinal imaging.
AB  - Although the use of PET in studies of the gastrointestinal tract is still
      relatively new, its value is clear. The future will provide a better definition
      of the indications for PET, refinement of the technology, and its relative value
      compared with other modalities such as peptide and antibody imaging, CT, MR
      imaging, and US.

PMID- 12481735
TI  - Endoscopic ultrasound.
AB  - Indications and the clinical utility of endosonography have evolved as new
      technology, such as linear array echoendoscopes and EUS-guided fine needle
      aspiration, has emerged. The most noteworthy of the EUS applications are for
      cancer staging; including rectal, pancreatic, lung, and esophageal malignancies.
      There is little doubt that EUS is a powerful tool for cancer imaging, but its
      clinical impact in patient care and management has yet to be validated in
      prospective outcome studies. Other imaging modalities such as positron emission
      tomography (PET), dual-phased helical CT, and MR imaging technology will
      undoubtedly provide increasingly accurate diagnostic and staging information for
      gastrointestinal diseases. EUS imaging alone may assume a less significant role
      in relation to these noninvasive modalities in the future. EUS-guided FNA, as
      well as therapeutic EUS applications, will likely continue to expand in scope and
      play an important role in clinical medicine for many years to come.

PMID- 12481736
TI  - Multidetector-row CT and volumetric imaging of pancreatic neoplasms.
AB  - Multidetector-row CT provides excellent visualization of the pancreas and
      peripancreatic structures, yielding information that is crucial for detecting
      pancreatic neoplasms and accurately determining their staging. This new
      technology enables the acquisition of large volumetric data sets to create high
      quality curved planar reformations that clearly depict the common bile duct, the
      pancreatic duct, and the peripancreatic vasculature. Additionally, curved planar
      reformations highlight critical anatomic and pathologic relationships which are
      useful for surgical planning in patients with resectable disease.

PMID- 12481737
TI  - Imaging and intervention in the gastrointestinal tract in children.
AB  - Vascular and interventional techniques have become an integral component of
      modern pediatric healthcare. Minimally invasive procedures of the
      gastrointestinal tract now comprise a large part of any active pediatric
      interventional practice. Magnetic resonance cholangiopancreatography offers a
      reliable, non-invasive means to evaluate patients with possible pancreatic or
      biliary pathology. This article reviews treatment of esophageal strictures and
      placement of gastronomy and gastrojejunostomy tubes and discusses new
      developments. Placement of percutaneous cecostomy tubes is a relatively new
      procedure that creatively uses the techniques developed for placement of
      percutaneous gastronomy tubes. This procedure offers significant benefits and
      lasting positive lifestyle changes for patients suffering from fecal
      incontinence. Liver biopsy in high-risk patients can be performed safely using
      measures designed to significantly decrease the risk of post-biopsy hemorrhage,
      such as track embolization or the transjugular approach.

PMID- 12481738
TI  - The deification and deconstruction of doctors.

PMID- 12481739
TI  - Physicians & NPs: the business relationship needs repair.

PMID- 12481740
TI  - From eye drops to intraocular surgery.

PMID- 12481741
TI  - Doctors of chiropractic: current scope of practice.

PMID- 12481742
TI  - The 2002 psychologist prescribing law in New Mexico: the psychiatrists'
      perspective.
AB  - In March 2002 New Mexico passed the first state statute permitting the
      development of a process leading to prescriptive authority for doctoral level
      psychologists who obtain requisite training and certification. This article
      reviews the background of these events, the political processes by which this
      expanded scope of practice for psychologists evolved, the current state of
      regulatory discussions regarding this statute, forecasts of the practical impact
      of this legislation on practitioner patterns, and prospects for the future.

PMID- 12481743
TI  - The 2002 psychologist prescribing law in New Mexico: the psychologists'
      perspective.

PMID- 12481744
TI  - Psychologist prescribing: the issues in Maryland.

PMID- 12481745
TI  - Art, artists, and arthritis.

PMID- 12481746
TI  - Bioterrorism treatment information.

PMID- 12481747
TI  - Salt: data and speculation.

PMID- 12481748
TI  - The straw men of the salt lobby.

PMID- 12481749
TI  - Ventricular repolarization in diabetes mellitus: still much to learn.

PMID- 12481750
TI  - Diabetic autonomic neuropathy. Cardiac sympathetic "dysinnervation," QT interval
      prolongation, and mortality.

PMID- 12481751
TI  - Bibliography. Current world literature. Paediatric urology.

PMID- 12481753
TI  - General thoracic surgery and science: it all takes time.

PMID- 12481752
TI  - Bibliography. Current world literature. Andrology, sexual dysfunction,
      infertility.

PMID- 12481754
TI  - ACOG committee opinion. Nonsurgical diagnosis and management of vaginal agenesis.
      Number 274, July 2002. Committee on Adolescent Health Care. American College of
      Obstetrics and Gynecology.
AB  - Vaginal agenesis occurs once in every 4,000-l0,000 females. The most common cause
      of vaginal agenesis is congenital absence of the uterus and vagina, which is also
      referred to as mullerian aplasia, mullerian agenesis, or Mayer-Rokitansky-Kuster
      Hauser syndrome. The condition usually can be managed nonsurgically with the use
      of successive dilators if it is correctly diagnosed and the patient is
      sufficiently motivated. Besides correct diagnosis, effective management also
      includes evaluation for associated congenital, renal, or other anomalies and
      careful psychologic preparation of the patient before any treatment or
      intervention. If surgery is preferred a number of approaches are available; the
      most common is the Abbe-McIndoe operation.

PMID- 12481755
TI  - ACOG practice bulletin. Thyroid disease in pregnancy. Number 37, August 2002.
      American College of Obstetrics and Gynecology.
AB  - Because thyroid disease is the second most common endocrine disease affecting
      women of reproductive age, obstetricians often care for patients who have been
      previously diagnosed with alterations in thyroid gland function. In addition,
      both hyperthyroidism and hypothyroidism may initially manifest during pregnancy.
      Obstetric conditions, such as gestational trophoblastic disease or hyperemesis
      gravidarum, may themselves affect thyroid gland function. This document will
      review the thyroid-related pathophysiologic changes created by pregnancy and the
      maternal-fetal impact of thyroid disease.

PMID- 12481756
TI  - ACOG practice bulletin. Perinatal care at the threshold of viability. Number 38,
      September 2002. American College of Obstetrics and Gynecology.
AB  - The survival rate for extremely preterm or extremely low-birth-weight (LBW)
      newborns born at the threshold of viability (25 or fewer completed weeks of
      gestation) improved in the early 1990s, largely as the result of a greater use of
      assisted ventilation in the delivery room and surfactant therapy. Increased use
      of antenatal and neonatal corticosteroids also may have influenced survival
      rates. However, this improvement in survival has not been associated with an
      equal improvement in morbidity. The incidence of chronic lung disease, sepsis,
      and poor growth remains high and may even have increased. There is concern that
      the treatment of extremely preterm and extremely LBW newborns may result in
      unforeseen effects into adulthood, and that the neurodevelopmental outcome and
      cognitive function of extremely preterm and extremely LBW infants may be
      suboptimal. The purpose of this document is to describe the potential
      consequences of extremely preterm birth and to provide clinical management
      guidelines based on the best available data.

PMID- 12481757
TI  - ACOG committee opinion. Obstetric management of patients with spinal cord
      injuries. Number 275, September 2002. Committee on Obstetric Practice. American
      College of Obstetrics and Gynecology.
AB  - Effective rehabilitation and modern reproductive technology may increase the
      number of women considering pregnancy who have spinal cord injuries (SCIs). It is
      important that obstetricians caring for these patients are aware of the specific
      problems related to SCIs. Autonomic dysreflexia is the most significant medical
      complication seen in women with SCIs,and precautions should be taken to avoid
      stimuli that can lead to this potentially fatal syndrome. Women with SCIs may
      give birth vaginally, but when cesarean delivery is indicated adequate anesthesia
      (spinal or epidural if possible) is needed.

PMID- 12481758
TI  - Comments on the use of the startle reflex in psychopharmacological challenges:
      impact of baseline startle on measurement of fear-potentiated startle.

PMID- 12481759
TI  - From the Centers for Disease Control and Prevention. Preventive-care practices
      among persons with diabetes--United States, 1995 and 2001.

PMID- 12481761
TI  - From the Centers for Disease Control and Prevention. Progress toward global
      dracunculiasis eradication, June 2002.

PMID- 12481760
TI  - From the Centers for Disease Control and Prevention. Influenza and pneumococcal
      vaccination levels among persons aged > or = 65 years--United States, 2001.

PMID- 12481762
TI  - Clinical trials integrity: a CRO perspective.
AB  - When contract research organizations (CROs) were first formed, pharmaceutical
      companies outsourced to them only certain aspects of the conduct of their
      clinical trials. At first CROs were highly specialized entities, providing, for
      example, either biostatistical advice, clinical research associates who monitored
      investigational sites for regulatory compliance, or regulatory support.
      Gradually, full service CROs emerged, offering a full range of services for
      clinical trials, including the selection of investigators and investigational
      sites, assistance with patient recruitment, safety surveillance and reporting,
      site audits, and data management and biostatistics. This evolving relationship
      between CROs and the pharmaceutical and medical device industries has resulted in
      CROs assuming more and more of the regulatory and ethical risks and
      responsibilities inherent in the conduct of clinical trials. In this full service
      role, CROs, unlike sponsors, are not interested in the outcome of study, but like
      sponsors, are subject to heavy regulation by the federal government, must follow
      applicable state laws, must respect international guidelines, and are obliged to
      follow their own operating procedures. Moreover, they are judged by the industry
      on the basis of the scope and quality of services provided, including the degree
      of adherence to the research protocol, regulatory requirements, and timelines;
      the quality of the professional working relationships with investigators and
      institutions, both academic and community-based; and the validity of the data.
      Further, CROs are subject to comprehensive audits by sponsoring companies, FDA,
      and other regulatory authorities. For all these reasons, CROs are being tasked
      with strict vigilance of all stages of the clinical trial process to ensure that
      the laws, regulations, and industry standards designed for the protection of
      human subjects and data integrity are maintained.

PMID- 12481763
TI  - Many universities do teach professionalism.

PMID- 12481764
TI  - Nurses should adopt a better political stance.

PMID- 12481765
TI  - Abandoning patients is never good conduct.

PMID- 12481766
TI  - Medical devices; reclassification of the cutaneous carbon dioxide and the
      cutaneous oxygen monitor. Final rule.
AB  - The Food and Drug Administration (FDA) is reclassifying the cutaneous carbon
      dioxide (PcCO2) monitor from class II (performance standards) into class II
      (special controls). FDA is also reclassifying the cutaneous oxygen (PcO2) monitor
      for an infant patient who is not under gas anesthesia from class II (performance
      standards) into class II (special controls) and is reclassifying the cutaneous
      oxygen (PcO2) monitor for all other uses from class III (premarket approval) into
      class II (special controls). Elsewhere in this issue of the Federal Register, FDA
      is announcing the availability of the guidance document entitled "Class II [[Page
      76679]] Special Controls Guidance Document: Cutaneous Carbon Dioxide (PcCO2) and
      Oxygen (PcO2) Monitors; Guidance for Industry and FDA" that will serve as the
      special control for the devices. These reclassifications are taken on the
      agency's own initiative based on new information. These actions are 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), the Food and Drug Administration Modernization Act of
      1997 (FDAMA), and the Medical Device User Fee and Modernization Act.

PMID- 12481767
TI  - Are new laws needed to protect human subjects?

PMID- 12481768
TI  - Investigators, industry, and the heuristic device: ethics, patent law, and
      clinical innovation.

PMID- 12481769
TI  - The ethics of editorializing.

PMID- 12481770
TI  - What is your diagnosis? Secondary syphilis.

PMID- 12481771
TI  - What is your diagnosis? Infantile fibrosarcoma.

PMID- 12481772
TI  - What is your diagnosis? Canalicular adenoma.

PMID- 12481773
TI  - What is your diagnosis? Desmoplastic melanocytic nevus.

PMID- 12481774
TI  - What is your diagnosis? Lupus profundus.

PMID- 12481775
TI  - What is your diagnosis? Bacterial dermatitis due to Corynebacterium species.

PMID- 12481776
TI  - What is your diagnosis? Cutaneous infection with Fusarium.

PMID- 12481777
TI  - What is your diagnosis? Kaposi's sarcoma, lymphangioma-like variant.

PMID- 12481778
TI  - What is your diagnosis? Granulomatus slack skin syndrome.

PMID- 12481779
TI  - Mother-to-child HIV transmission and ARVs.

PMID- 12481780
TI  - Adverse events reporting--the tip of an iceberg.
AB  - NIH data indicate that annually seven million human subjects are enrolled in
      research sponsored by NIH alone. In addition, there are sixteen federal agencies
      and numerous departments outside NIH conducting experiments with human subjects.
      Moreover, the pharmaceutical industry spends $26 billion on research (compared to
      $16 billion for NIH), thus, the total number of human subjects enrolled in
      research for both the public and private sectors can be estimated as high as
      nineteen million. I present data on the potential magnitude of adverse events in
      the United States among human subjects enrolled in research that appear to be
      unreported and unaccounted for. We obtained data from the Office for Human
      Research Protections (OHRP) through the Freedom of Information Act for the years
      1990 to August 2000 regarding all Institutional Incident Reports (IRPTs) and a
      list of Compliance Oversight Branch Investigations (COBIs) involving Multiple
      Project Assurances (MPAs). In the ten years of reporting for nearly seventy
      million human subjects, there were only 878 IRPTs and 41 investigations. From the
      incident reports to OHRP, 44% involved adverse events. Those projects
      investigated for Multiple Project Assurances violations (41 such investigations)
      showed that 51% were suspended or terminated. The number of deaths reported to
      OHRP in ten years for the seventy million human subjects is merely eight. The
      anticipated number of deaths among the general population in seventy million
      (assuming subject's duration in trials is one month) is 51,000. The number of
      suicides and attempted suicides alone among the seventy million expected research
      subjects can be anticipated to be about 5,000. Therefore, the number of expected
      deaths should have been between 5,000 and 51,000. These numbers and percentages
      represent minimal numbers since they are not a result of random audits or
      investigations, but a result of self-reporting or an exogenous complaint. Despite
      the fact that these are conservative estimates, they represent a significant
      problem. The purpose of this paper is to present the potential boundaries and
      magnitude of the problem in the current use of human subjects in research. This
      is a call for responsible institutions to undertake a thorough evaluation of the
      problem in order to obtain accurate information. For the immediate future, strong
      actions need to be taken to increase the protection of human subjects enrolled in
      research. This precautionary policy is prudent in light of recent revelations and
      data from this investigation.

PMID- 12481781
TI  - Balancing public health and civil liberties.

PMID- 12481782
TI  - Recalcitrant chronic low back and leg pain--a new theory and different approach
      to management.
AB  - The management of chronic low back and leg pain has always provided a challenge
      for therapists. This paper examines the influence of a repetitive movement such
      as walking as a possible causative factor of chronic low back pain. Diminished
      shock absorption and limited hip extension and external rotation are hypothesized
      to affect the mobility of the lumbar spine. These compensatory changes can result
      in lumbar spine dysfunction. Treatment must therefore be directed not only at
      increasing the mobility of the hips and thoracic spine, but also the stability of
      the lumbar spine. Sometimes however, the symptoms can be exacerbated by
      treatment, so the neural tissue needs to unloaded to optimize the treatment
      outcome. This can be achieved by taping the buttock and down the leg following
      the dermatome to shorten the inflamed tissue.

PMID- 12481783
TI  - A long-term review of the treatment of patients with Ewing's sarcoma in one
      institution (EJSO 2001; 27: 569-73).

PMID- 12481784
TI  - Unisexual clones: lizards and corals.

PMID- 12481785
TI  - Industry-government collaboration.

PMID- 12481786
TI  - Medicine in the Noise Age: what can we believe?

PMID- 12481787
TI  - Liver resection for metatastic non-colorectal non-neuroendocrine hepatic
      neoplasms.

PMID- 12481788
TI  - Understanding sacroiliac joint movement as a guide to the management of a patient
      with unilateral low back pain.

PMID- 12481789
TI  - Physician duties in the conduct of human subject research.
AB  - In this article, I examine a skeptical argument against the possibility of
      ethically justifying risky human subject research (rHSR). That argument asserts
      that such research is unethical because it holds the possibility of wronging
      subjects who are harmed and whose consent to participate was less than fully
      voluntary. I conclude that the skeptical argument is not in the end sufficient to
      undermine the ethical foundation of rHSR because it fails to take account of the
      special positive duty researchers owe their clients and future patients. Although
      the skeptical argument is defeated, it exacts certain novel concessions from the
      pro-research position. Of particular importance are the admissions (a) that
      researchers presumptively owe a fiduciary duty to research subjects, (b) that
      because the most important risks of rHSR are unknown and unquantifiable that duty
      must be explicitly waived by all subjects before they participate in any
      protocol, and (c) that such waivers must be made by individuals who satisfy
      objective criteria of competence for giving fully voluntary consent. The
      implementation of procedures responsive to these concerns might have a dampening
      effect on the conduct of research. However, the article concludes with a
      consideration of the likely benefits to researchers and society of a more
      cautious ethical regime.

PMID- 12481790
TI  - The Course Approval Board of the Manipulation Association of Chartered
      Physiotherapists.

PMID- 12481791
TI  - van Ruth S, Bronkhorst MWGA, van Coeverden F, Zoetmulder FAN. Peritoneal benign
      cystic mesothelioma: a case report and review of literature. Eur J Surg Oncol
      2002; 28(2): 192-5.

PMID- 12481792
TI  - Bibliography.

PMID- 12481793
TI  - Axillary recurrence after sentinel node biopsy for operable breast cancer.

PMID- 12481794
TI  - The therapeutic misconception, beneficence, and respect.
AB  - In order to provide benefits to society, human medical trials must place subjects
      at risk of harm. This activity is thought to be justified in part by the consent
      of the subjects involved. But, studies have shown that most such consents are
      based on a therapeutic misconception (TM); the false belief of subjects that
      their researchers will act as their personal physicians (seeking their benefit
      and protecting them from harm), rather than placing them at risk of harm for the
      good of others. Toleration by researchers of the TM in their subjects is a form
      of "informational manipulation" that renders consent procedures disrespectful to
      subject autonomy. Consent obtained from subjects who labor under a TM is neither
      voluntary nor informed; as long as they have not been disabused of the TM, the
      action they take in enrolling in a trial is not the one they intend nor is it
      autonomously chosen. Changes in consent procedures should be adopted to ensure
      that all subjects are aware inter alia that (a) the health interests of future
      patients (as well as the researchers' and their sponsors' financial interests)
      may be more important to researchers than the interest of a subject in his or her
      health, and (b) normal subjects neither understand nor believe this when told.
      Close attention to the response of prospective subjects to this information
      should allow for the exclusion of all but the truly altruistic. However, the
      result of conscientious implementation of such policies would likely be that
      human medical research could no longer be conducted on more than a minimal level.

PMID- 12481795
TI  - Prophylaxis of menstrual migraine with triptans: problems and possibilities.
AB  - Menstruation is a prominent, predictable attack trigger for many women with
      migraine. If abortive therapy of menstrual attacks is ineffective, prophylactic
      therapy is used to prevent attacks or render them shorter and less resistant to
      acute therapy. Interest is increasing in the use of triptan medications for the
      prophylaxis of menstrual migraine, and clinical trials to evaluate this approach
      are underway. Potential problems with triptan prophylaxis of menstrual migraine
      that deserve attention include the lack of consensus on the definition of
      menstrual migraine and the difficulty in making a reliable diagnosis of the
      disorder. Unconvincing demonstrations of efficacy and unresolved cost and safety
      concerns should temper enthusiasm for their use in this manner. Further studies,
      using a consistent definition of menstrual association and employing diary
      validation of the diagnosis, are needed to determine the efficacy of the triptans
      in women who consistently experience migraine attacks associated with
      menstruation. Triptans would have to show compelling advantages over other
      therapy to be a plausible prophylactic treatment for menstrual migraine.

PMID- 12481796
TI  - Empirically supported ethical research practice: the costs and benefits of
      research from the participants' view.
AB  - Researchers and institutional review boards are routinely called upon to evaluate
      the cost-benefit status of proposed research protocols that involve human
      participants. Often these assessments are based on subjective judgments in the
      absence of empirical data. This reliance on subjective judgments is of particular
      concern for studies involving clinical samples where unfounded assumptions may
      adversely affect research progress or clinical outcomes. The Reactions to
      Research Participation Questionnaire (RRPQ) was designed to address this
      shortcoming and to help promote ethical decision making about research practice.
      The present study describes development of the RRPQ and presents a series of
      exploratory and confirmatory analyses investigating its structure. Based on these
      findings, a revised version of the instrument and suggestions for future research
      are presented. This approach provides a foundation for scientifically informed
      protection of human subjects.

PMID- 12481797
TI  - Principles, property rights, and profits: historical reflections on
      university/industry relations.

PMID- 12481799
TI  - A perspective of an overseas nurse.

PMID- 12481798
TI  - Current issues in clinical research and the development of new pharmaceuticals.
AB  - As a normal part of the drug development process, U.S. pharmaceutical companies
      conduct many thousands of clinical trials each year. Only after a reasonable
      assurance of safety is made can the drug be given to patients who have the
      underlying medical condition that the drug is designed to treat. Patient welfare
      is assured by adhering to the Food and Drug Administration's interpretation of
      the "common rule" if the data will be used to support a licensing application. 21
      CFR Part 50 sets forth the regulations along with the principles of informed
      consent and the use of institutional review boards (IRBs) that assure patients'
      rights are protected. Any potential conflict of interest on the part of a
      clinical investigator must be reported to the FDA. Pharmaceutical companies
      extensively monitor ongoing clinical trials for compliance with appropriate
      regulations. The recent revision of the Declaration of Helsinki governing placebo
      controlled clinical trials may adversely impact drug development.

PMID- 12481800
TI  - Debate over Intrasite Gel continues.

PMID- 12481801
TI  - A 1-year, three-couple expedition as a crew analog for a Mars mission.
AB  - This study assessed the intrapersonal and interpersonal functioning of a three
      couple expedition group that included a 2 1/2-year-old child which was ice-locked
      on a boat in the High Arctic during a major portion of the expedition.
      Personality assessment indicated that team members were generally well adjusted,
      scoring relatively higher on well-being and achievement and relatively lower on
      stress reactivity. Weekly mood ratings showed that the group exhibited
      significantly higher positive than negative affect. Reported negative events were
      relatively most frequent at the beginning of the Arctic stay and toward the end
      of the darkness period and were lowest during the initial darkness interval. The
      period of darkness had both a salutary and negative impact. A highly important
      means of coping with stress was seeking emotional support from one's partner.
      Selection of couples with strong bonds with their partner appears to be one
      viable approach for crew selection for long-duration missions.

PMID- 12481802
TI  - Calcium is involved in the gravitactic orientation in colorless flagellates.
AB  - The colorless flagellate Astasia longa shows a pronounced negative gravitaxis.
      The calcium fluorescence indicator Calcium Crimson was used to detect changes of
      the intracellular calcium concentration during gravitactical orientation. Astasia
      shows an increase of the fluorescence after a lag phase of about 10 s, a maximum
      after about 30 s and a decrease to the basic level within 60 s during gravitactic
      reorientation. The observed change in fluorescence corresponds to an almost
      doubling of the initial free calcium concentration. The influence of inhibitors,
      known to impair gravitaxis, on the calcium concentration of Astasia longa was
      tested. Addition of caffeine, an inhibitor of phosphodiesterase, increases, while
      addition of gadolinium, an inhibitor of mechanosensitive ion channels decreases
      the fluorescence signal. While gravitactic stimulation of caffeine-treated cells
      resulted in a kinetics of fluorescence intensity changes comparable to control
      cells the addition of gadolinium inhibited any calcium concentration change.
      Dynamic fluorescence imaging was used during a sounding rocket experiment (MAXUS
      3 campaign). Different accelerations interrupted by microgravity intervals were
      applied to Astasia cells. The cells show an increase in the calcium signal upon
      acceleration and a decrease during the microgravity state. The results strongly
      reemphasize the working model of gravitaxis which is based on the activation of
      mechano-sensitive ion channels as one of the primary events in signal perception.

PMID- 12481803
TI  - Physiological parameters of gravitaxis in the flagellate Euglena gracilis
      obtained during a parabolic flight campaign.
AB  - The unicellular freshwater flagellate Euglena gracilis and its close relative
      Astasia longa show a pronounced negative gravitaxis. Previous experiments
      revealed that gravitaxis is most likely mediated by an active physiological
      mechanism in which changes of the internal calcium concentration and the membrane
      potential play an important role. In a recent parabolic flight experiment on
      board an aircraft (ESA 29th parabolic flight campaign), changes of
      graviorientation, membrane potential and the cytosolic calcium concentration upon
      changes of the acceleration (between 1 x g(n), 1.8 x g(n), microgravity) were
      monitored by image analysis and photometric methods using Oxonol VI (membrane
      potential) and Calcium Crimson (cytosolic calcium concentration). The parabolic
      flight maneuvers performed by the aircraft resulted in transient phases of 1.8 x
      g(n) (about 20 s), microgravity (about 22 s) followed by 1.8 x g(n) (about 20 s).
      A transient increase in the intracellular calcium concentration was detected from
      lower to higher accelerations (1 x g(n) to 1.8 x g(n) or microgravity to 1.8 x
      g(n)). Oxonol VI-labeled cells showed a signal, which indicates a depolarization
      during the transition from 1 x g(n) to 1.8 x g(n), a weak repolarization in
      microgravity followed by a rapid repolarization in the subsequent 1 x g(n) phase.
      The results show good coincidence with observations of recent terrestrial and
      space experiments.

PMID- 12481804
TI  - Water cycles in closed ecological systems: effects of atmospheric pressure.
AB  - In bioregenerative life support systems that use plants to generate food and
      oxygen, the largest mass flux between the plants and their surrounding
      environment will be water. This water cycle is a consequence of the continuous
      change of state (evaporation-condensation) from liquid to gas through the process
      of transpiration and the need to transfer heat (cool) and dehumidify the plant
      growth chamber. Evapotranspiration rates for full plant canopies can range from
      ~1 to 10 L m-2 d-1 (~1 to 10 mm m-2 d-1), with the rates depending primarily on
      the vapor pressure deficit (VPD) between the leaves and the air inside the plant
      growth chamber. VPD in turn is dependent on the air temperature, leaf
      temperature, and current value of relative humidity (RH). Concepts for developing
      closed plant growth systems, such as greenhouses for Mars, have been discussed
      for many years and the feasibility of such systems will depend on the overall
      system costs and reliability. One approach for reducing system costs would be to
      reduce the operating pressure within the greenhouse to reduce structural mass and
      gas leakage. But managing plant growth environments at low pressures (e.g.,
      controlling humidity and heat exchange) may be difficult, and the effects of low
      pressure environments on plant growth and system water cycling need further
      study. We present experimental evidence to show that water saturation pressures
      in air under isothermal conditions are only slightly affected by total pressure,
      but the overall water flux from evaporating surfaces can increase as pressure
      decreases. Mathematical models describing these observations are presented, along
      with discussion of the importance for considering "water cycles" in closed
      bioregenerative life support systems.

PMID- 12481805
TI  - Near-term lander experiments for growing plants on Mars: requirements for
      information on chemical and physical properties of Mars regolith.
AB  - In order to support humans for long-duration missions to Mars, bioregenerative
      Advanced Life Support (ALS) systems have been proposed that would use higher
      plants as the primary candidates for photosynthesis. Hydroponic technologies have
      been suggested as the primary method of plant production in ALS systems, but the
      use of Mars regolith as a plant growth medium may have several advantages over
      hydroponic systems. The advantages for using Mars regolith include the likely
      bioavailability of plant-essential ions, mechanical support for plants, and easy
      access of the material once on the surface. We propose that plant biology
      experiments must be included in near-term Mars lander missions in order to begin
      defining the optimum approach for growing plants on Mars. Second, we discuss a
      range of soil chemistry and soil physics tests that must be conducted prior to,
      or in concert with, a plant biology experiment in order to properly interpret the
      results of plant growth studies in Mars regolith. The recommended chemical tests
      include measurements on soil pH, electrical conductivity and soluble salts, redox
      potential, bioavailability of essential plant nutrients, and bioavailability of
      phytotoxic elements. In addition, a future plant growth experiment should include
      procedures for determining the buffering and leaching requirements of Mars
      regolith prior to planting. Soil physical tests useful for plant biology studies
      in Mars regolith include bulk density, particle size distribution, porosity,
      water retention, and hydraulic conductivity.

PMID- 12481806
TI  - Potential integration of wetland wastewater treatment with space life support
      systems.
AB  - Subsurface-flow constructed wetlands for wastewater treatment and nutrient
      recycling have a number of advantages in planetary exploration scenarios: they
      are odorless, relatively low labor and low energy, assist in purification of
      water and recycling of atmospheric CO2, and can directly grow some food crops.
      This article presents calculations for integration of wetland wastewater
      treatment with a prototype ground-based experimental facility ("Mars on Earth")
      supporting four people showing that an area of 4-6 m2 may be sufficient to
      accomplish wastewater treatment and recycling. Discharge water from the wetland
      system can be used as irrigation water for the agricultural crop area, thus
      ensuring complete reclamation and utilization of nutrients within the
      bioregenerative life support system. Because the primary requirements for wetland
      treatment systems are warm temperatures and lighting, such bioregenerative
      systems can be integrated into space life support systems because heat from the
      lights may be used for temperature maintenance in the human living environment.
      Subsurface-flow wetlands can be modified for space habitats to lower space and
      mass requirements. Many of its construction requirements can eventually be met
      with use of in situ materials, such as gravel from the Mars surface. Because the
      technology does not depend on machinery and chemicals, and relies more on natural
      ecological mechanisms (microbial and plant metabolism), maintenance requirements
      (e.g., pumps, aerators, and chemicals) are minimized, and systems may have long
      operating lifetimes. Research needs include suitability of Martian soil and
      gravel for wetland systems, system sealing and liner options in a Mars base, and
      determination of wetland water quality efficiency under varying temperature and
      light regimes.

PMID- 12481807
TI  - Airtight sealing a Mars base.
AB  - Atmospheric leakage from a Mars base would create a demand for continuous or
      periodic replenishment, which would in turn require extraction or mining for
      oxygen and other gases from local resources and attendant equipment and energy
      requirements for such operations. It therefore becomes a high priority to
      minimize leakage. This article quantifies leak rates as determined by the size of
      holes and discusses the implications of pressure for structural configuration.
      The author engineered the sealing of Biosphere 2 from which comparisons are
      drawn.

PMID- 12481808
TI  - Light, plants, and power for life support on Mars.
AB  - Regardless of how well other growing conditions are optimized, crop yields will
      be limited by the available light up to saturation irradiances. Considering the
      various factors of clouds on Earth, dust storms on Mars, thickness of atmosphere,
      and relative orbits, there is roughly 2/3 as much light averaged annually on Mars
      as on Earth. On Mars, however, crops must be grown under controlled conditions
      (greenhouse or growth rooms). Because there presently exists no material that can
      safely be pressurized, insulated, and resist hazards of puncture and
      deterioration to create life support systems on Mars while allowing for
      sufficient natural light penetration as well, artificial light will have to be
      supplied. If high irradiance is provided for long daily photoperiods, the growing
      area can be reduced by a factor of 3-4 relative to the most efficient irradiance
      for cereal crops such as wheat and rice, and perhaps for some other crops. Only a
      small penalty in required energy will be incurred by such optimization. To obtain
      maximum yields, crops must be chosen that can utilize high irradiances. Factors
      that increase ability to convert high light into increased productivity include
      canopy architecture, high-yield index (harvest index), and long-day or day
      neutral flowering and tuberization responses. Prototype life support systems such
      as Bios-3 in Siberia or the Mars on Earth Project need to be undertaken to test
      and further refine systems and parameters.

PMID- 12481809
TI  - Swiss chard: a salad crop for the space program.
AB  - Salad greens will be among the first crops grown on lunar or planetary space
      stations. Swiss chard (Beta vulgaris L.) is an important candidate salad crop
      because it is high yielding and rich in vitamins and minerals. Five Swiss chard
      cultivars were grown in the greenhouse under two light levels for 13 weeks to
      compare cumulative yields from weekly harvests, mineral composition, and to
      evaluate sensory attributes as a salad green. The varieties Large White Ribbed
      (LWR) and Lucullus (LUC) were the highest yielding in both light regimes. LWR was
      the shortest of the cultivars requiring the least vertical space. LWR also
      received the highest sensory ratings of the five cultivars. LWR Swiss chard
      should be considered as an initial test variety in food production modules.

PMID- 12481810
TI  - Enzyme-based CO2 capture for advanced life support.
AB  - Elevated CO2 levels in air can lead to impaired functioning and even death to
      humans. Control of CO2 is critical in confined spaces that have little physical
      or biological buffering capacity (e.g., spacecraft, submarines, or aircraft). A
      novel enzyme-based contained liquid membrane bioreactor was designed for CO2
      capture and certain application cases are reported in this article. The results
      show that the liquid layer accounts for the major transport resistance. With
      addition of carbonic anhydrase, the transport resistance decreased by 71%.
      Volatile organic compounds of the type and concentration expected to be present
      in either the crew cabin or a plant growth chamber did not influence carbonic
      anhydrase activity or reactor operation during 1-day operation. Alternative sweep
      method studies, examined as a means of eliminating consumables, showed that the
      feed gas could be used successfully in a bypass mode when combined with medium
      vacuum pressure (-85 kPa) to achieve CO2 separation comparable to that with an
      inert sweep gas. The reactor exhibited a selectivity for CO2 versus N2 of 1400:1
      and CO2 versus O2 is 866:1. The CO2 permeance was 1.44 x 10(-7) mol m-2 Pa-1 s-1
      (4.3 x 10(-4) cm3 cm-2 s-1 cmHg-1) at a feed concentration of 0.1% CO2. These
      data show that the enzyme-based contained liquid membrane is a promising
      candidate technology that may be suitable for NASA applications to control CO2 in
      the crew or plant chambers.

PMID- 12481811
TI  - A management information system to study space diets.
AB  - A management information system (MIS), including a database management system
      (DBMS) and a decision support system (DSS), was developed to dynamically analyze
      the variable nutritional content of foods grown and prepared in an Advanced Life
      Support System (ALSS) such as required for long-duration space missions. The DBMS
      was designed around the known nutritional content of a list of candidate crops
      and their prepared foods. The DSS was designed to determine the composition of
      the daily crew diet based on crop and nutritional information stored in the DBMS.
      Each of the selected food items was assumed to be harvested from a yet-to-be
      designed ALSS biomass production subsystem and further prepared in accompanying
      food preparation subsystems. The developed DBMS allows for the analysis of the
      nutrient composition of a sample 20-day diet for future Advanced Life Support
      missions and is able to determine the required quantities of food needed to
      satisfy the crew's daily consumption. In addition, based on published crop growth
      rates, the DBMS was able to calculate the required size of the biomass production
      area needed to satisfy the daily food requirements for the crew. Results from
      this study can be used to help design future ALSS for which the integration of
      various subsystems (e.g., biomass production, food preparation and consumption,
      and waste processing) is paramount for the success of the mission.

PMID- 12481812
TI  - Bioregenerative food system cost based on optimized menus for advanced life
      support.
AB  - Optimized menus for a bioregenerative life support system have been developed
      based on measures of crop productivity, food item acceptability, menu diversity,
      and nutritional requirements of crew. Crop-specific biomass requirements were
      calculated from menu recipe demands while accounting for food processing and
      preparation losses. Under the assumption of staggered planting, the optimized
      menu demanded a total crop production area of 453 m2 for six crew. Cost of the
      bioregenerative food system is estimated at 439 kg per menu cycle or 7.3 kg ESM
      crew-1 day-1, including agricultural waste processing costs. On average, about
      60% (263.6 kg ESM) of the food system cost is tied up in equipment, 26% (114.2 kg
      ESM) in labor, and 14% (61.5 kg ESM) in power and cooling. This number is high
      compared to the STS and ISS (nonregenerative) systems but reductions in ESM may
      be achieved through intensive crop productivity improvements, reductions in
      equipment masses associated with crop production, and planning of production,
      processing, and preparation to minimize the requirement for crew labor.

PMID- 12481813
TI  - Permissive hypercapnia.
AB  - There has been increasing recognition that mechanical ventilation can cause acute
      parenchymal lung injury (ventilator-induced lung injury, or VILI) in addition to
      the more widely recognized forms of barotrauma. Furthermore, in patients with
      acute lung injury, this type of injury may cause considerable morbidity and
      mortality. Subsequently, the goals of mechanical ventilation have been altered to
      avoid this outcome. In patients with relatively normal lungs who are receiving
      mechanical ventilation because of neuromuscular dysfunction or impaired conscious
      level or for short-term postoperative support, maintaining normal blood-gas
      tensions without risk of VILI is usually easy. In patients with acute asthma,
      chronic obstructive pulmonary disease, or acute lung injury, however, accepting
      abnormal blood-gas tensions, particularly an elevated PaCO2 (permissive
      hypercapnia), to improve survival and reduce complications is frequently
      necessary. Extensive experience has shown that ventilated patients usually
      tolerate moderate hypercapnia and frequently some degree of hypoxemia in the
      absence of shock, anemia, severe cardiac disease, or other contraindications.

PMID- 12481814
TI  - Tracheal gas insufflation as an adjunct to mechanical ventilation.
AB  - Tracheal gas insufflation (TGI) as an adjunct to mechanical ventilation delivers
      fresh gas into the central airways continuously or in a phasic fashion to improve
      the efficiency of alveolar ventilation or to minimize the ventilatory pressure
      requirements. Recently, TGI has received increasing attention as an adjunctive
      tool for lung-protective mechanical-ventilation strategies. Experimental studies
      in animal and mechanical-lung models have been essential in the quest to
      understand TGI's mechanisms of action and operational characteristics.
      Experimental studies in animal models of lung injury have substantiated the
      potential role of TGI in clinical practice. Currently, the evolution of TGI is
      entering a phase in which overcoming obstacles to clinical implementation may
      lead to the development of commercial systems with more widespread TGI
      application.

PMID- 12481815
TI  - Liquid ventilation.
AB  - In laboratory models, PLV is clearly more effective than conventional ventilation
      alone; however, this advantage has not been observed in any human study. The
      reasons for this are unclear, but the approach to ventilation during PLV may have
      been inappropriate. HFO may require further study or perhaps PLV should be
      combined with nitric oxide or some other vasoactive agent. Additionally,
      perfluorocarbons may need to be aerosolized instead of instilled. Kandler et al.
      recently demonstrated better gas exchange that was sustained for a longer period
      in lavage-injured piglets when a perfluorocarbon was aerosolized. This
      preliminary result demonstrates that there are other options for the delivery of
      perfluorocarbons in the management of critically ill patients. Based on the
      failure of the two trials in adult ARDS patients, however, a long time may pass
      before another human PLV trial is undertaken.

PMID- 12481816
TI  - Surfactant supplementation in the lung.
AB  - Alterations in pulmonary surfactant is an important contributing factor in the
      pathogenesis of ARDS. Surfactant deficiency affects the progression and prognosis
      of ARDS patients and increases the susceptibility of ARDS in patients who are at
      risk for it. Several studies have suggested that the use of exogenous surfactant
      preparations can improve lung function and overall outcome in ARDS patients;
      however, large randomized clinical trials have failed to show any benefit.
      Continued work on surfactant therapy-including efforts to improve the mode of
      delivery, to understand better the pathophysiology of exogenous surfactant, and
      to develop synthetic surfactants that emulate natural ones more closely-will help
      to elucidate its role in ARDS.

PMID- 12481817
TI  - Prone positioning in patients with acute respiratory distress syndrome.
AB  - Acute respiratory distress syndrome (ARDS) is a severe form of respiratory
      failure that is characterized by marked hypoxemia, bilateral infiltrates on chest
      radiograph, and no clinical evidence of left ventricular failure. Mechanical
      ventilation with positive end-expiratory pressure (PEEP) is a cornerstone therapy
      for ARDS patients. Because the fundamental aim of supportive treatment is to
      improve arterial oxygenation, several alternatives to mechanical ventilation with
      PEEP have been used. One of these alternative therapies is prone positioning,
      which has been used safely to improve oxygenation in many patients with ARDS.
      Despite encouraging results, however, the use of prone positioning is not widely
      accepted as an adjunct to therapy in hypoxemic patients because, aside from
      temporarily improving gas exchange, it does not seem to affect the outcome of
      these patients. This article reviews the rationale for using prone positioning in
      ARDS patients who require intubation and mechanical ventilation.

PMID- 12481818
TI  - High-frequency mechanical ventilation principles and practices in the era of lung
      protective ventilation strategies.
AB  - The term high-frequency ventilation is used to describe a heterogeneous group of
      ventilation modes that are characterized by high respiratory frequencies and low
      tidal volumes. The increasing understanding of the pathogenesis of VILI,
      including concepts such as volutrauma and atelectrauma, has led to a renewed
      interest in the role of HFV in lung-protective ventilation strategies. Inherent
      to many modes of HFV are low tidal volumes and small pressure swings during the
      respiratory cycle, which allow for higher mean airway pressures than those safely
      achieved with CMV. This has the potential to reduce lung injury by limiting
      volutrauma, whereas maintaining bigger lung volumes at end-expiration may reduce
      atelectrauma. Of the various forms of HFV, HFO is the only mode with an active
      expiration phase. This characteristic, combined with superior gas conditioning,
      may make HFO a promising ventilatory strategy for adults. Although a significant
      amount of data exists in the literature to support the application of HFO in
      infants and children who have acute respiratory failure, clinical data on the use
      of HFO in adults is only now emerging. Early studies of applying HFO in ARDS
      patients have demonstrated its safety and benefit in terms of oxygenation.
      Additionally, limited data exist on the comparison between HFO and CMV in this
      patient population; however, encouraging preliminary results have been reported.
      The optimum strategy for the application of HFV, including the timing of HFV
      initiation, remains unclear.

PMID- 12481819
TI  - Inhaled nitric oxide.
AB  - Inhaled NO offers a novel therapy for the treatment of pulmonary hypertensive
      diseases and the symptomatic relief of hypoxemia. The use of iNO reduces the
      necessity for ECMO in newborns and infants with acute hypoxemic respiratory
      failure. Proper indications, contraindications, dosing criteria, and implications
      of the toxic actions of NO must be delineated fully. Randomized clinical trials
      of patients with carefully defined, specific acute disease states that are
      characterized by pulmonary hypertension or hypoxemia have not been completed.

PMID- 12481820
TI  - Recruitment maneuvers in acute lung injury.
AB  - Maintaining optimal lung recruitment has a marked effect on the outcome of
      patients who suffer from ARDS. RMs superimposed on mechanical ventilation have
      the potential to recruit atelectatic lungs in the course of general anesthesia;
      however, the physiologic benefits are less evident in ARDS patients who are
      ventilated at low VT values and high PEEP levels. Currently, the following
      technical aspects warrant further investigation: optimal time (the first hours
      after intubation or the first days of ARDS), duration (from 15 seconds to 2
      minutes), mode (continuous positive end-expiratory pressure or pressure
      controlled ventilation with high PEEP), and type of patients (pulmonary versus
      extrapulmonary ARDS). Before the routine implementation of RMs to recruit the
      lungs fully in ARDS patients, clinicians also need more information on side
      effects and contraindications. Although RMs are transient, they may be associated
      with complications such as hypotension, bradycardia, and barotrauma. Moreover,
      further studies are needed to compare the efficacy of periodic high-pressure RMs
      that are superimposed on mechanical ventilation with ventilation using high PEEP
      levels and low VT values without RMs in patients who have early ARDS after
      initial hemodynamic stabilization.

PMID- 12481821
TI  - Helium-oxygen ventilation.
AB  - Because of its low density, the He/O2 mixture markedly affects the dynamics of
      gas-flow, increasing inspiratory and expiratory flows, reducing WOB and
      respiratory acidosis, and relieving dyspnea in various clinical situations
      associated with obstructive airway disease. The magnitude of these changes varies
      according to the proportion of turbulent, transitional, and laminar flow
      conditions. These effects, however, last only as long as the patient breathes the
      He/O2 mixture, because it has no curative effect on the cause of airway
      obstruction. Thus, He/O2 ventilation is mostly useful while awaiting the effects
      of more definitive treatment. Evidence shows that He/O2 ventilation can improve
      pathophysiologic and clinical parameters in spontaneously breathing patients with
      upper airway obstruction, asthma. COPD, bronchopulmonary dysplasia. and
      bronchiolitis. Furthermore. He/O2 ventilation may prove to be a valuable adjunct
      in decompensated COPD patients, during both NIV and conventional mechanical
      ventilation. Despite promising results, however, there are two primary pitfalls
      to He/O2 ventilation. First, the consequences of the physical properties of the
      He/O2 mixture on various ventilator functions, the major differences between
      machines, and the correction factors to apply (if necessary) should be known.
      Second, in this age of cost control, particular attention should be paid to the
      cost-benefit ratio of He/O2 ventilation. Indeed, despite clinical evidence that
      the pathophysiologic principles on which He/O2 ventilation rests can be
      translated into favorable short-term physiologic and subjective effects, there is
      presently no evidence of a significant effect on patient outcome. Hence, before
      He/O2 ventilation can be recommended for widespread use, prospective outcome
      studies should be conducted in patients who suffer from the conditions discussed
      in this article to identify which, if any, are most likely to receive a benefit.
      Meanwhile, the authors recommend that He/O2 ventilation be reserved for patients
      who have a severe condition and who do not respond to the classic validated
      treatment modalities.

PMID- 12481822
TI  - Aerosol medications.
AB  - Aerosol medications are used commonly in mechanically ventilated patients.
      Several classes of drugs with different properties and indications may be given
      by inhalation. In all cases, inhaled therapy's main advantage over the systemic
      route is that, for a given therapeutic response, the drug dose is several-fold
      lower, whereas systemic absorption is negligible. Because of this, the side
      effects are minimized greatly. Additionally, for some medications, the systemic
      route either causes nonacceptable side effects or results in considerably
      inferior therapeutic response, rendering the inhaled route the method of choice
      of drug administration. Bronchodilators, vasoactive drugs, surfactant,
      antibiotics, and helium are some agents that can be inhaled during mechanical
      ventilation.

PMID- 12481823
TI  - Antibiotic and biocide resistance in bacteria: introduction.
AB  - Drug resistance in bacteria is increasing and the pace at which new antibiotics
      are being produced is slowing. It is now almost commonplace to hear about
      methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant
      enterococci (VRE), multi-drug resistance in Mycobacterium tuberculosis (MDRTB)
      strains and multi-drug-resistant (MDR) gram-negative bacteria. So-called new and
      emerging pathogens add to the gravity of the situation. Reduced susceptibility to
      biocides is also apparently increasing, but is more likely to be low level in
      nature and to concentrations well below those used in hospital, domestic an
      industrial practice. A particular problem, however, is found with bacteria and
      other micro-organisms present in biofilms, where a variety of factors can
      contribute to greater insusceptibility compared with cells in planktonic culture.
      Also of potential concern is the possibility that widespread usage of biocides is
      responsible for the selection and maintenance of antibiotic-resistant bacteria.
      The basic mechanisms of action of, and bacterial resistance to, antibiotics are
      generally well documented, although data continue to accumulate about the nature
      and importance of efflux systems. In contrast, the modes of action of most
      biocides are poorly understood and consequently, detailed evaluation of bacterial
      resistance mechanisms is often disappointing. During this Symposium, the
      mechanisms of bacterial resistance to antibiotics and biocides are discussed at
      length. It is hoped that this knowledge will be used to develop newer, more
      effective drugs and biocides that can be better and perhaps, on occasion, more
      logically used to combat the increasing problem of bacterial resistance.

PMID- 12481824
TI  - Exploiting current understanding of antibiotic action for discovery of new drugs.
AB  - The introduction of antibiotics for the chemotherapy of bacterial infections has
      been one of the most important medical achievements of the past 50 years.
      However, the emergence of bacterial resistance to antibiotics undermines the
      therapeutic utility of existing agents, creating a requirement for the discovery
      of new antibacterial drugs. Several drug discovery strategies have emerged,
      including incremental improvements to existing antibiotics by chemical
      manipulation and the search for novel drug targets based on genomic approaches.
      An alternative strategy seeks to exploit opportunities for drug discovery arising
      from an understanding of the mode of action of existing antibiotics. Thus
      biochemical pathways or processes inhibited by antibiotics already in clinical
      use may nevertheless contain key functions that represent unexploited targets for
      further drug discovery. A major benefit of employing pathways or processes that
      are already known to contain drug targets is that proof of principle for drug
      intervention is already established. This approach to drug discovery is
      illustrated by reviewing target sites for existing antibiotics and considering
      how this information might be applied for the discovery of new agents inhibiting
      peptidoglycan synthesis, tRNA synthesis, transcription and DNA replication.

PMID- 12481825
TI  - Bacterial target sites for biocide action.
AB  - Although biocides have been used for a century, the number of products containing
      biocides has recently increased dramatically with public awareness of hygiene
      issues. The antimicrobial efficacy of biocides is now well documented; however,
      there is still a lack of understanding of their antimicrobial mechanisms of
      action. There is a wide range of biocides showing different levels of
      antimicrobial activity. It is generally accepted that, in contrast to
      chemotherapeutic agents, biocides have multiple target sites within the microbial
      cell and the overall damage to these target sites results in the bactericidal
      effect. Information about the antimicrobial efficacy of a biocide (i.e. the eta
      value) might give some useful indications about the overall mode of action of a
      biocide. Bacteriostatic effects, usually achieved by a lower concentration of a
      biocide, might correspond to a reversible activity on the cytoplasmic membrane
      and/or the impairment of enzymatic activity. The bacteriostatic mechanism(s) of
      action of a biocide is less documented and a primary (unique?) target site within
      the cell might be involved. Understanding the mechanism(s) of action of a biocide
      has become an important issue with the emergence of bacterial resistance to
      biocides and the suggestion that biocide and antibiotic resistance in bacteria
      might be linked. There is still a lack of understanding of the mode of action of
      biocides, especially when used at low concentrations (i.e. minimal inhibitory
      concentration (MIC) or sublethal). Although this information might not be
      required for highly reactive biocides (e.g. alkylating and oxidizing agents) and
      biocides used at high concentrations, the use of biocides as preservatives or in
      products at sublethal concentrations, in which a bacteriostatic rather than a
      bactericidal activity is achieved, is driving the need to better understand
      microbial target sites. Understanding the mechanisms of action of biocides serves
      several purposes: (i) it will help to design antimicrobial formulations with an
      improved antimicrobial efficacy and (ii) it will ensure the prevention of the
      emergence of microbial resistance.

PMID- 12481826
TI  - Novel targets for the future development of antibacterial agents.
AB  - Recent advances in DNA sequencing technology have made it possible to elucidate
      the entire genomes of pathogenic bacteria, and advancements in bioinformatic
      tools have driven comparative studies of these genome sequences. These
      evaluations are dramatically increasing our ability to make valid considerations
      of the limitations and advantages of particular targets based on their predicted
      spectrum and selectivity. In addition, developments in gene knockout technologies
      amenable to pathogenic organisms have enabled new genes and gene products
      critical to bacterial growth and pathogenicity to be uncovered at an
      unprecedented rate. Specific target examples in the areas of cell wall
      biosynthesis, aromatic amino acid biosynthesis, cell division, two component
      signal transduction, fatty acid biosynthesis, isopreniod biosynthesis and tRNA
      synthetases illustrate how aspects of the above capabilities are impacting on the
      discovery and characterization of novel antibacterial targets. An example of a
      novel inhibitor of bacterial fatty acid biosynthesis discovered from high
      throughput screening processes is described, along with its subsequent chemical
      optimization. Furthermore, the application and importance of technologies for
      tracking the mode of antibacterial action of these novel inhibitors is discussed.

PMID- 12481827
TI  - Cellular impermeability and uptake of biocides and antibiotics in gram-negative
      bacteria.
AB  - The principal targets for antibacterial agents reside at the cytoplasm and
      cytoplasmic membrane, damage to other structures often arising from initial
      events at these loci. The gram-negative bacteria offer a complex barrier system
      to biocides and antibiotics, regulating, and sometimes preventing, their passage
      to target regions. Routes of entry differ between hydrophobic and hydrophilic
      agents, often with a structure dependency; specialized uptake mechanisms are
      exploited and portage transport can occur for pro-drug antibacterials. Uptake
      isotherms offer insight into the sorption process and can sometimes shed light on
      biocide mechanisms of action. The multi-component barrier system of gram-negative
      bacteria offers opportunities for phenotypic resistance development where
      partitioning or exclusion minimizes the delivery of an antibacterial agent to the
      target site. Active efflux processes are recognized as increasingly relevant
      mechanisms for resistance, potentially offering routes to biocide:antibiotic
      cross-resistance. These mechanisms may be targeted directly in an attempt to
      compromise their role in microbial survival.

PMID- 12481828
TI  - Cellular impermeability and uptake of biocides and antibiotics in gram-positive
      bacteria and mycobacteria.
AB  - Gram-positive bacteria possess a permeable cell wall that usually does not
      restrict the penetration of antimicrobials. However, resistance due to restricted
      penetration can occur, as illustrated by vancomycin-intermediate resistant
      Staphylococcus aureus strains (VISA) which produce a markedly thickened cell
      wall. Alterations in these strains include increased amounts of nonamidated
      glutamine residues in the peptidoglycan and it is suggested that the resistance
      mechanism involves 'affinity trapping' of vancomycin in the thickened cell wall.
      VISA strains have reduced doubling times, lower sensitivity to lysostaphin and
      reduced autolytic activity, which may reflect changes in the D-alanyl ester
      content of the wall and membrane teichoic acids. Mycobacterial cell walls have a
      high lipid content, which is assumed to act as a major barrier to the penetration
      of antimicrobial agents. Relatively hydrophobic antibiotics such as rifampicin
      and fluoroquinolones may be able to cross the cell wall by diffusion through the
      hydrophobic bilayer composed of long chain length mycolic acids and glycolipids.
      Hydrophilic antibiotics and nutrients cannot diffuse across this layer and are
      thought to use porin channels which have been reported in many species of
      mycobacteria. The occurrence of porins in a lipid bilayer supports the view that
      the mycobacterial wall has an outer membrane analogous to that of gram-negative
      bacteria. However, mycobacterial porins are much less abundant than in the gram
      negative outer membrane and allow only low rates of uptake for small hydrophilic
      nutrients and antibiotics.

PMID- 12481829
TI  - Mechanisms of bacterial biocide and antibiotic resistance.
AB  - Resistance to antibiotics is increasingly commonplace amongst important human
      pathogens. Although the mechanism(s) of resistance vary from agent to agent they
      typically involve one or more of: alteration of the drug target in the bacterial
      cell, enzymatic modification or destruction of the drug itself, or limitation of
      drug accumulation as a result of drug exclusion or active drug efflux. While most
      of these are agent specific, providing resistance to a single antimicrobial or
      class of antimicrobial, there are currently numerous examples of efflux systems
      that accommodate and, thus, provide resistance to a broad range of structurally
      unrelated antimicrobials--so-called multidrug efflux systems. Resistance to
      biocides is less common and likely reflects the multiplicity of targets within
      the cell as well as the general lack of known detoxifying enzymes. Resistance
      typically results from cellular changes that impact on biocide accumulation,
      including cell envelope changes that limit uptake, or expression of efflux
      mechanisms. Still, target site mutations leading to biocide resistance, though
      rare, are known. Intriguingly, many multidrug efflux systems also accommodate
      biocides (e.g. triclosan) such that strains expressing these are both antibiotic-
      and biocide-resistant. Indeed, concern has been expressed regarding the potential
      for agents such as triclosan to select for strains resistant to multiple
      clinically-relevant antibiotics. Some of the better characterized examples of
      such multidrug efflux systems can be found in the opportunistic pathogen
      Pseudomonas aeruginosa where they play an important role in the noted intrinsic
      and acquired resistance of this organism to antibiotics and triclosan. These
      tripartite pumps include an integral inner membrane drug-proton antiporter, an
      outer membrane- and periplasm-spanning channel-forming protein and a periplasmic
      link protein that joins these two. Expression of efflux genes is governed
      minimally by the product of a linked regulatory gene that is in most cases the
      target for mutation in multidrug resistant strains hyperexpressing these efflux
      systems. Issues for consideration include the natural function of these efflux
      systems and the therapeutic potential of targeting these systems in combating
      acquired multidrug resistance.

PMID- 12481830
TI  - Active efflux, a common mechanism for biocide and antibiotic resistance.
AB  - Energy-driven drug efflux systems are increasingly recognized as mechanisms of
      antibiotic resistance. Chromosomally located or acquired by bacteria, they can
      either be activated by environmental signals or by a mutation in a regulatory
      gene. Two major categories exist: those systems energized by proton motive force
      and those dependent on ATP. The pumps may have limited or broad substrates, the
      so-called multiple drug resistance pumps, which themselves form a number of
      related families. The multiple antibiotic resistance (mar) locus and mar regulon
      in Escherichia coli and other members of the Enterobacteriaceae is a paradigm for
      a generalized response locus leading to increased expression of efflux pumps. One
      such pump, the AcrAB pump extrudes biocides such as triclosan, chlorhexidine and
      quaternary ammonium compounds as well as multiple antibiotics. In Pseudomonas
      aeruginosa, a number of multidrug efflux pumps export a broad range of
      substrates. Since bacteria expressing these pumps thwart the efficacy of both
      kinds of therapeutic agents which control infectious diseases--biocides which
      prevent transmission of infectious disease agents and antibiotics which treat and
      cure infectious diseases--they are of particular concern. The prudent use of
      antibiotics and biocides will guard against the selection and propagation of drug
      resistant mutants and preserve the efficacy of these valuable anti-infective
      agents.

PMID- 12481831
TI  - Products containing biocides: perceptions and realities.
AB  - The mechanisms of action for chemical germicides and antibiotics for inactivating
      microorganisms are significantly different and methods for determining resistance
      by microorganisms to these agents are also different. Chemical germicides usually
      have multiple targets and the mechanisms for inactivation and resistance are not
      measured in absolute terms but rather in the rapidity with which they reduce
      levels of microorganisms. The term tolerance is much more suited for germicides
      than the term resistance. The mechanism of resistance to chemical germicides is
      often dependent on the concentration of the germicide. At high concentrations
      multiple cellular and metabolic targets are involved, and at low concentrations
      fewer cellular targets. In contrast antibiotics usually have a singular cellular
      or metabolic target and resistance implies the ability of the microorganism to
      grow in the presence of the antibiotic, and in a clinical sense, to initiate or
      continue infection in the presence of the antibiotic. When methods used to assess
      resistance to antibiotics are applied to chemical germicides, inappropriate
      interpretations can be made regarding the ability of microorganisms to develop
      resistance to antibiotics as a result of developing resistance to chemical
      germicides. The use of chemical germicides in health-care institutions and
      especially the home setting has increased in recent years. Although there may be
      an overuse of germicides in these settings the consequence is a cost issue and
      not one that involves the development of antibiotic resistant microorganisms.

PMID- 12481832
TI  - Antibiotic exposure as a risk factor for emergence of resistance: the influence
      of concentration.
AB  - Evolution of antibiotic resistance (AR) is increasingly perceived as a major
      clinical problem. The use of bactericidal antibiotics may protect against this,
      to some extent, by eradication of the pathogen, but the borders between cidal and
      inhibitory activity in the patient are often blurred. In addition, there are
      clinical reasons why eradication of the pathogen may not always be desirable.
      Antibiotic dosing schedules are currently driven by the perception that T > MIC
      and AUIC are the main predictors of outcome for time-dependent and concentration
      dependent antibiotics, respectively. In the context of protecting against
      development of resistance in the pathogen however, peak antibiotic concentration
      and the concept of mutant prevention concentrations may be more important. The
      role of post-antibiotic and sub-MIC effects is more conjectural. Considerations
      of mechanisms of resistance and their relationship to antibiotic dosing schedules
      will also be highlighted. Lastly, the relevance of all this to the development of
      resistance in the normal bacterial flora will be discussed.

PMID- 12481833
TI  - Antimicrobial resistance and the food chain.
AB  - The extent to which antibiotics given to animals contribute to the overall
      problem of antibiotic resistance in man is still uncertain. The development of
      resistance in some human pathogens, such as methicillin-resistant Staphylococcus
      aureus and multi-drug resistant Mycobacterium tuberculosis, is linked to the use
      of antimicrobials in man and there is no evidence for animal involvement.
      However, there are several good examples of transfer of resistant bacteria or
      bacterial resistance genes from animals to man via the food chain. A bacterial
      ecosystem exists with simple and complex routes of transfer of resistance genes
      between the bacterial populations; in addition to transfer of organisms from
      animals to man, there is also evidence of resistance genes spilling back from
      humans into the animal population. This is important because of the amplification
      that can occur in animal populations. The most important factor in the selection
      of resistant bacteria is generally agreed to be usage of antimicrobial agents and
      in general, there is a close association between the quantities of antimicrobials
      used and the rate of development of resistance. The use of antimicrobials is not
      restricted to animal husbandry but also occurs in horticulture (for example,
      aminoglycosides in apple growing) and in some other industrial processes such as
      oil production.

PMID- 12481834
TI  - Clinical significance of the emergence of bacterial resistance in the hospital
      environment.
AB  - Antibiotic resistance is an increasing threat in hospitals and both morbidity and
      mortality from infections are greater when caused by drug-resistant organisms.
      Whilst hospitals are universally blamed for this increase, there is an
      insufficient appreciation of external sources of resistance, such as when
      patients are admitted to hospitals from long-term care facilities in the
      community. The use of antibiotics in family practice and animal husbandry has
      also been linked to drug resistance being encountered in the hospital setting.
      Justifiable hospital antibiotic use, which can be life saving, may lead to
      'collateral damage' with the emergence of resistance in non-target bacteria in
      the bowel, for example, with subsequent spread by cross-infection. At a
      management level, antibiotic resistance can have a significant impact on the
      ability of hospitals to maintain services since cohorting of patients and ward
      closures from outbreaks add to continuing bed shortages and waiting lists.
      Hospital laboratories must review their standard operating procedures since some
      resistance mechanisms may be missed by current methods of antibiotic
      susceptibility testing. With increasing public concern from press reports of
      'multiresistant Staphylococcus aureus killer virus' and other drug-resistant
      organisms, there will inevitably be a push by national authorities for more
      surveillance data on antibiotic resistance; however, the cost-effectiveness of
      different surveillance strategies should be considered. Clinical governance and
      risk management are dominant themes in the National Health Service and hospital
      hygiene and antibiotic resistance are likely to feature prominently in audits
      related to these themes in the near future.

PMID- 12481835
TI  - Biofilms in vitro and in vivo: do singular mechanisms imply cross-resistance?
AB  - Microbial biofilm has become inexorably linked with man's failure to control them
      by antibiotic and biocide regimes that are effective against suspended bacteria.
      This failure relates to a localized concentration of biofilm bacteria, and their
      extracellular products (exopolymers and extracellular enzymes), that moderates
      the access of the treatment agent and starves the more deeply placed cells.
      Biofilms, therefore, typically present gradients of physiology and concentration
      for the imposed treatment agent, which enables the less susceptible clones to
      survive. Such clones might include efflux mutants in addition to genotypes with
      modifications in single gene products. Clonal expansion following subeffective
      treatment would, in the case of many antibiotics, lead to the emergence of a
      resistant population. This tends not to occur for biocidal treatments where the
      active agent exhibits multiple pharmacological activity towards a number of
      specific cellular targets. Whilst resistance development towards biocidal agents
      is highly unlikely, subeffective exposure will lead to the selection of less
      susceptible clones, modified either in efflux or in their most susceptible
      target. The latter might also confer resistance to antibiotics where the target
      is shared. Thus, recent reports have demonstrated that sublethal concentrations
      of the antibacterial and antifungal agent triclosan can select for resistant
      mutants in Escherichia coli and that this agent specifically targets the enzyme
      enoyl reductase that is involved in lipid biosynthesis. Triclosan may, therefore,
      select for mutants in a target that is shared with the anti-E. coli diazaborine
      compounds and the antituberculosis drug isoniazid. Although triclosan may be a
      uniquely specific biocide, sublethal concentrations of less specific
      antimicrobial agents may also select for mutations within their most sensitive
      targets, some of which might be common to therapeutic agents. Sublethal treatment
      with chemical antimicrobial agents has also been demonstrated to induce the
      expression of multidrug efflux pumps and efflux mutants. Whilst efflux does not
      confer protection against use concentrations of biocidal products it is
      sufficient to confer protection against therapeutic doses of many antibiotics. It
      has, therefore, been widely speculated that biocide misuse may have an insidious
      effect, contributing to the evolution and persistence of drug resistance within
      microbial communities. Whilst such notions are supported by laboratory studies
      that utilize pure cultures, recent evidence has strongly refuted such linkage
      within the general environment where complex, multispecies biofilms predominate
      and where biocidal products are routinely deployed. In such situations the
      competition, for nutrients and space, between community members of disparate
      sensitivities far outweighs any potential benefits bestowed by the changes in an
      individual's antimicrobial susceptibility.

PMID- 12481836
TI  - Biocide use in the food industry and the disinfectant resistance of persistent
      strains of Listeria monocytogenes and Escherichia coli.
AB  - AIMS: The aims of the project were threefold: to survey the use of disinfectants
      in the UK food industry; to assess the product and environmental microflora of
      selected food factories for the persistence of Listeria monocytogenes and
      Escherichia coli; and to determine the disinfectant resistance of any persistent
      strains. METHODS AND RESULTS: A survey of the use of disinfectants in the UK food
      industry was undertaken in which a total of 40 sites were visited and a further
      77 postal questionnaires were returned from farms, food manufacture, food
      transport and food retail sites. Quaternary ammonium compounds (QACs) were
      predominantly used, applied in small volumes as a mist. Approximately 30,000
      samples from the product and environment of five chilled food factories were
      examined for L. monocytogenes and E. coli over a 3 year period. A total of 181 L.
      monocytogenes and 176 E. coli isolates were ribotyped to yield 19 and 34
      ribogroups, respectively. Some strains were isolated only from the product, a
      number only from the environment and others from both niches. Some strains were
      seen to be persistent for the duration of the sampling exercise (2-3 years). The
      most common L. monocytogenes and E. coli strains, together with two environmental
      L. monocytogenes strains, were assessed for any resistance to commercial
      disinfectants as compared with a laboratory L. monocytogenes disinfectant testing
      strain. The resistance of the L. monocytogenes and E. coli strains isolated from
      the factory were not significantly different from the laboratory control strain.
      CONCLUSIONS: Persistent strains of L. monocytogenes and E. coli are found in the
      UK food industry, though this persistence is not related to their increased
      susceptibility to the most commonly used disinfectants. SIGNIFICANCE AND IMPACT
      OF THE STUDY: The concept of a persistent microflora in food factories will have
      an impact on the future selection of suitable control options, including the use
      of biocides.

PMID- 12481837
TI  - Introduction of biocides into clinical practice and the impact on antibiotic
      resistant bacteria.
AB  - Biocides and other antimicrobial agents have been employed for centuries. Much
      later, iodine found use as a wound disinfectant, chlorine water in obstetrics,
      alcohol as a hand disinfectant and phenol as a wound dressing and in antiseptic
      surgery. In the early part of the twentieth century, other chlorine-releasing
      agents (CRAs), and acridine and other dyes were introduced, as were some
      quaternary ammonium compounds (QACs, although these were only used as biocides
      from the 1930s). Later still, various phenolics and alcohols, formaldehyde and
      hydrogen peroxide were introduced and subsequently (although some had actually
      been produced at an earlier date) biguanides, iodophors, bisphenols, aldehydes,
      diamidines, isocyanurates, isothiazolones and peracetic acid. Antibiotics were
      introduced clinically in the 1940s, although sulphonamides had been synthesized
      and used previously. After penicillin came streptomycin and other aminoglycosides
      aminocyclitols, tetracyclines, chloramphenicol, macrolides, semi-synthetic beta
      lactams, glycopeptides, lincosamides, 4-quinolones and diaminopyrimidines.
      Bacterial resistance to antibiotics is causing great concern. Mechanisms of such
      resistance include cell impermeability, target site mutation, drug inactivation
      and drug efflux. Bacterial resistance to biocides was described in the 1950s and
      1960s and is also apparently increasing. Of the biocides listed above, cationic
      agents (QACs, chlorhexidine, diamidines, acridines) and triclosan have been
      implicated as possible causes for the selection and persistence of bacterial
      strains with low-level antibiotic resistance. It has been claimed that the
      chronological emergence of qacA and qacB determinants in clinical isolates of
      Staphylococcus aureus mirrors the introduction and usage of cationic biocides.

PMID- 12481838
TI  - Quantitative assessment of risk reduction from hand washing with antibacterial
      soaps.
AB  - The Centers for Disease Control and Prevention have estimated that there are
      3,713,000 cases of infectious disease associated with day care facilities each
      year. The objective of this study was to examine the risk reduction achieved from
      using different soap formulations after diaper changing using a microbial
      quantitative risk assessment approach. To achieve this, a probability of
      infection model and an exposure assessment based on micro-organism transfer were
      used to evaluate the efficacy of different soap formulations in reducing the
      probability of disease following hand contact with an enteric pathogen. Based on
      this model, it was determined that the probability of infection ranged from
      24/100 to 91/100 for those changing diapers of babies with symptomatic
      shigellosis who used a control product (soap without an antibacterial
      ingredient), 22/100 to 91/100 for those who used an antibacterial soap
      (chlorohexadine 4%), and 15/100 to 90/100 for those who used a triclosan (1.5%)
      antibacterial soap. Those with asymptomatic shigellosis who used a non
      antibacterial control soap had a risk between 49/100,000 and 53/100, those who
      used the 4% chlorohexadine-containing soap had a risk between 43/100,000 and
      51/100, and for those who used a 1.5% triclosan soap had a risk between
      21/100,000 and 43/100. The adequate washing of hands after diapering reduces risk
      and can be further reduced by a factor of 20% by the use of an antibacterial
      soap. Quantitative risk assessment is a valuable tool in the evaluation of
      household sanitizing agents and low risk outcomes.

PMID- 12481839
TI  - Significance of biocide usage and antimicrobial resistance in domiciliary
      environments.
AB  - Recent events have raised awareness of the need for effective hygiene in the
      home. Not least is the requirement to reduce antibiotic resistance by reducing
      the need for antibiotic prescribing. Current evidence suggests that improved
      hygiene in the domestic setting could have a significant impact. Recently, it has
      been suggested that widespread biocide usage, particularly in consumer products,
      may be a contributory factor in antibiotic resistance. In developing home hygiene
      policies, however, it is important that biocide use as an integral part of good
      hygiene practice is not discouraged in situations where there is real benefit.
      Although laboratory data indicate possible links, it is necessary to assess
      whether and to what extent biocide exposure could contribute to antibiotic
      resistance in clinical practice. The extent to which reduced susceptibility to
      biocides resulting from biocide exposure could compromise their 'in-use'
      effectiveness must also be considered. Equally, it is important that changes in
      susceptibility induced by biocide exposure are assessed relative to those induced
      by antibiotic exposure or the phenotypic changes induced by 'normal'
      environmental 'stresses'. It is proposed that to be effective, home hygiene
      policy should be based on the concept of risk assessment and risk prevention.
      Using this approach, critical risk situations are identified and appropriate
      hygiene procedures applied to reduce risks. This may involve either soap and
      water cleaning, or cleaning combined with a disinfection process. A 'targeted'
      hygiene approach not only provides the most effective means of preventing
      infectious disease, it also offers a means of addressing concerns about 'too much
      hygiene' and 'too many antibacterials' amongst a public who have lost confidence
      regarding appropriate hygiene for their home environment.

PMID- 12481840
TI  - Susceptibility of antibiotic-resistant cocci to biocides.
AB  - Biocide resistance has hitherto been a poorly studied subject, possibly due to
      the belief that such resistance was rare and clinically insignificant. Various
      recent findings, however, have underlined the importance of biocide resistance as
      a clinically relevant phenomenon. Outbreaks of biocide-resistant organisms in
      hospitals have been described and the genetic mechanism for resistance to
      quaternary ammonium compounds (QACs) in Staphylococcus aureus has now been
      elucidated. Mycobacteria resistant to commonly used endoscope disinfectants are
      now commonly reported and have caused numerous adverse clinical events. Cross
      resistance between triclosan and antituberculous drugs has been demonstrated in
      other strains of mycobacteria. This is related to a common mechanism of action.
      The work presented here describes studies into the biocide resistance of
      antibiotic-resistant cocci and attempts to create biocide-resistant strains in
      vitro. Strains of staphylococci (including methicillin-resistant Staph. aureus
      (MRSA)) and enterococci (including vancomycin-resistant enterococci (VRE)) had
      their susceptibility to biocides assayed using broth macro dilution methods and
      resistant strains were selected by serial subculture on biocide-containing media.
      Mutants were created with relative ease; for instance, triclosan minimal
      bactericidal concentrations (MBCs) increased from 0.002 to 3.12 mg l(-1). Some
      strains of MRSA which have intermediate resistance to glycopeptides were
      demonstrated to have decreased susceptibility to some biocides. Biocide
      resistance amongst enterococci was demonstrated although there was no clear
      correlation between biocide and antibiotic resistance. The exact mechanisms of
      resistance in these strains are still being studied but it is clear that biocide
      resistance is an important clinical phenomenon.

PMID- 12481841
TI  - Susceptibility of antibiotic-resistant gram-negative bacteria to biocides: a
      perspective from the study of catheter biofilms.
AB  - Bacteria resistant to both the agents deployed to prevent infections and those
      used to treat infections would be formidable nosocomial pathogens. The aim of
      this paper is to review the evidence that gram-negative bacteria resistant to
      antibiotics and biocides have emerged and been responsible for catheter
      associated urinary tract infection. A study of patients undergoing intermittent
      bladder catheterization revealed that the frequent application of the antiseptic
      chlorhexidine to the perineal skin prior to the insertion of the catheter was
      effective against the normal gram-positive skin flora but not against the gram
      negative organisms that subsequently colonized this site. Organisms such as
      Providencia stuartii, Pseudomonas aeruginosa and Proteus mirabilis were
      repeatedly isolated from the skin of these patients and inevitably went on to
      cause urinary infections. The minimum inhibitory concentration (MIC) of
      chlorhexidine for many of these strains proved to be 200-800 microg ml(-1)
      compared with the 10-50 microg ml(-1) recorded for reference strains of gram
      negative species. A subsequent survey of over 800 gram-negative isolates from
      urinary tract infections in patients from both hospitals and the community
      revealed that chlorhexidine resistance was not a widespread phenomenon, but was
      restricted to these species and to units where the care of catheterized patients
      involved the extensive use of chlorhexidine. Analysis of the antibiotic
      resistance patterns revealed that the chlorhexidine-resistant strains were also
      multidrug resistant. Other clinical studies also reported catheter-associated
      infections with chlorhexidine- and multidrug-resistant strains of Pr. mirabilis
      when chlorhexidine was being used extensively. This species poses particular
      problems to the catheterized patient. Chlorhexidine thus proved counterproductive
      in the care of catheters and its use in this context has been largely abandoned.
      Suggestions of reintroducing this agent in the form of biocide-impregnated
      catheters should be resisted.

PMID- 12481842
TI  - Antibiotic and biocide resistance in bacteria: comments and conclusions.

PMID- 12481843
TI  - The power issue: determination of KB or Ki from IC50. A closer look at the Cheng
      Prusoff equation, the Schild plot and related power equations.
AB  - INTRODUCTION: The Cheng-Prusoff equation (1973) is often applied to the
      determination of equilibrium dissociation constant (KB) of a competitive
      antagonist when the IC50 value is available. The purpose of this study is to
      illustrate that the slope function (K) of an agonist concentration-response curve
      is critical to the determination of KB values. METHODS: The article describes new
      equations, which incorporate the slope function, consequently yielding more
      accurate estimation of KB values for antagonists, and tests them using simulated
      data. The value of KB was calculated according to the following new power
      equation: KB = IC50/(l + A(K)/Kp) = IC50/[l + (A/EC50)(K)], where IC50 is the
      concentration of the antagonist producing 50% inhibition, A is the concentration
      of the agonist against which the IC50 is being determined and KP is the apparent
      equilibrium dissociation constant of the agonist. RESULTS: The new equation is
      the same as the Cheng-Prusoff equation when the slope function K is exactly
      unity. Application of the equation avoids errors inherent in the use of the Cheng
      Prusoff equation when the slope function of the agonist concentration-response
      curve deviates from unity. The new equation was applicable to slope functions
      less than, equal to or greater than unity. All inhibition curves have a negative
      slope function of 1, indicating that there is only one single receptor population
      even though different slope functions of agonist concentration-response curves
      are involved. The importance of the power function in the Schild plot is
      illustrated by using the equation: log (x(K) - 1) = log B - log KB, where x is
      the concentration ratio and B is the concentration of the antagonist. DISCUSSION:
      This investigation illustrates the application of six power equations for
      accurate estimation of KB values covering situations with different slope
      functions of the agonist concentration-response curves.

PMID- 12481844
TI  - Quantitative whole-body autoradiography in the pharmaceutical industry. Survey
      results on study design, methods, and regulatory compliance.
AB  - INTRODUCTION: Quantitative whole-body autoradiography (QWBA) is a technique used
      to determine the tissue distribution of radiolabeled compounds in laboratory
      animals. This relatively new technique is quickly replacing wet-tissue dissection
      techniques, which, up to now, have been used by the pharmaceutical industry when
      performing tissue distribution studies to develop new drugs and to address
      regulatory compliance needs. In an effort to harmonize QWBA procedures across the
      pharmaceutical industry, the Society for Whole Body Autoradiography (SWBA)
      surveyed its membership to gain insight into the procedures and practices being
      used to perform tissue distribution studies conducted in support of drug
      development. METHODS: The survey polled 29 respondents, who represent
      pharmaceutical companies in the United States, Europe, and Asia. Participants
      answered approximately 50 questions related to study design, applications,
      autoradiography methods, tissue quantitation, and regulatory compliance. RESULTS:
      The survey revealed general consistencies and inconsistencies among the labs that
      responded. Consistencies were related to: isotope use and doses of radioactivity,
      number of animals per time point, exsanguination of animals, freezing methods,
      section thickness, tissue collection lists, section lyophilization, imaging
      technology, blood and calibration standards, tissues and sections sampled for
      quantitation, use of QWBA data for human dosimetry, and QWBA method validation.
      Inconsistencies were related to: number of time points used, euthanasia methods,
      carcass freezing time, microtome calibration, section thickness verification,
      sample collection, validation of commercial standards, use of background
      measurements during calibration, definition of limits of quantitation, reporting
      of extrapolated values, reexposure of section to determine low levels, computer
      system validation, definitions of raw data, audit trail documentation, studies
      performed under Good Laboratory Practices (GLP) vs. non-GLP conditions.
      DISCUSSION: The survey indicated that most labs are now using QWBA to perform
      their tissue distribution studies and that these data have been submitted and
      accepted by regulatory authorities around the world. Procedures and practices
      involved in the design of these studies appear to vary somewhat. An important
      inconsistency found related to the number of time points used to determine the
      pharmacokinetic (PK) parameters for tissues, which may effect the reliability of
      these parameters for use in predicting human exposure to radioactivity during
      human radiolabeled studies. Survey results regarding QWBA methods indicated that
      there is a lot of consistency across surveyed labs; however, there are some
      inconsistent areas that raise regulatory compliance issues and these are related
      to the verification of section thickness, validation of commercial standards and
      their use in quantitation, definitions of limits of quantitation, and
      consideration of background measurements during quantitation. This survey
      provides autoradiographers, managers, and regulators with an important reference
      on the state-of-the art of QWBA and shows that the technique has gained wide
      acceptance across the pharmaceutical industry. However, it also shows that there
      are some key areas, such as inconsistencies in the procedures used for
      quantitation, that investigators may want to probe further to assure that the
      highest quality and most useful studies are performed.

PMID- 12481845
TI  - Methods determining phosphor imaging limits of quantitation in whole-body
      autoradiography rodent tissue distribution studies affect predictions of 14C
      human dosimetry.
AB  - INTRODUCTION: Radioluminography, or phosphor imaging, is often used in rodent
      quantitative whole-body autoradiography (QWBA) studies to determine the tissue
      distribution and pharmacokinetic (PK) parameters of new pharmaceutical entities
      in rodents. The rodent tissue pharmacokinetics information are then used to
      predict human radiation exposure to 14C or 3H during human radioisotope mass
      balance studies. The human dosimetry estimation can be biased by the method used
      to determine the lower limit of quantitation (LOQ) of the phosphor imager. A
      survey of autoradiographers revealed that at least five different methods are
      used to determine phosphor imager LOQ. The objective of this study is to compare
      and evaluate the human dosimetry estimates obtained by applying those five LOQ
      methods to a single set of WBA data. METHODS: Five different phosphor imager LOQ
      determination methods were applied to a single set of QWBA rodent tissue
      distribution data to produce five tissue concentration time profiles. Tissue PK
      parameters were determined for each profile and subsequently used to calculate
      the 14C exposure for a proposed human 14C mass balance study. RESULTS: A
      threefold difference was observed among the five predictions of human 14C
      exposure when the five different phosphor imager LOQ values were applied to the
      initial data set. DISCUSSION: The method chosen to determine the phosphor imaging
      LOQ for QWBA rodent tissue distribution study could impact the human 14C exposure
      estimates. The end result may either under- or overestimate the 14C-tissue
      exposure in humans during radioisotope studies, depending on the method used to
      determine LOQ. We recommend two approaches to reduce the variations in the
      determination of rodent tissue distribution pharmacokinetics: (1) Set more
      sampling time points to cover the terminal phase to obtain more accurate t 1/2
      and (2) use Method 3 or the small sized sampling tool of Method 5 for LOQ
      determinations because it is a balanced approach for both simplicity and
      accuracy.

PMID- 12481846
TI  - Permeability measurement of macromolecules and assessment of mucosal antigen
      sampling using in vitro converted M cells.
AB  - INTRODUCTION: M cells are located in the epithelial layer covering the gut
      associated lymphoid tissue and are responsible for delivery of macromolecules and
      microorganisms to the underlying lymphoid cells. It has been shown that the human
      colonic cell line Caco-2 can be converted to M cells in vitro following coculture
      with isolated lymphocytes from murine Peyer's patches. Studies were undertaken to
      evaluate and characterize the transepithelial transport of select macromolecules
      across these in vitro derived M cells. METHODS: Caco-2 cells were converted to M
      cells as reported previously. The morphology of Caco-2 cells and M cells was
      compared by transmission electron microscopy (TEM). The transport properties of
      macromolecules such as horseradish peroxidase, FITC-conjugated polystyrene beads,
      and radiolabeled dextrans were examined. The activation of murine antigen
      specific T cells following transport of the antigen ovalbumin across the M-cell
      barrier was assessed by measuring cytokine production. RESULTS: M cells were
      shown to be irregular in shape and have fewer and shorter microvilli compared to
      the Caco-2 cell progenitors. These cells were still able to form tight junctions
      and monolayers on polycarbonate membranes. Time-course studies demonstrated that
      the transport of polystyrene beads and large-molecular-weight dextrans at
      physiological temperature across M-cell-containing monolayers was size dependent
      and more rapid than across Caco-2 cell monolayers. The transport of dextrans was
      also shown to be temperature and concentration dependent. Befitting the role of
      the M cell in mucosal defense, protein antigen could be delivered by these cells
      in order to be processed and presented to antigen-specific CD4+ T lymphocytes.
      DISCUSSION: The M-cell permeability model is a functional and practical system
      for evaluating the transport properties of macromolecules and assessing the
      potential for intestinal mucosal antigen sampling to elicit immunological
      responses.

PMID- 12481847
TI  - An improved method for assaying phosphocholine and glycerophosphocholine in mouse
      tissue.
AB  - INTRODUCTION: To measure the levels of phosphocholine (PCh) and
      glycerophosphocholine (GPCh) in the tissues and organs of mice, we developed a
      simple and rapid method using high-performance liquid chromatography (HPLC) with
      electrochemical detection (ECD) and an immobilized enzyme column. METHODS: Under
      our modifications of the separation procedure of Klein et al. [Neurochem. Int. 2
      (1993) 293], PCh and GPCh in the hydrophilic phase of the homogenate samples were
      selectively hydrolyzed into free choline by alkaline phosphatase and a 0.4-N
      perchloric acid solution, respectively, and the resulting hydrolyzed mixtures
      were directly injected into the HPLC system for analysis. RESULTS: The present
      method permits PCh or GPCh assay within 5 min in one chromatographic run.
      Recoveries from tissue samples were 97% for PCh and 101% for GPCh. The
      percentages of the crossover reaction to the authentic PCh and GPCh were 0.4% and
      3.8%, respectively. The within-run coefficients of variation for choline derived
      from PCh and GPCh in the tissue samples were 1.2% and 1.4%, respectively.
      DISCUSSION: The method is effective and has been applied to the measurement of
      PCh and GPCh levels in several tissues of mice.

PMID- 12481848
TI  - A rapid method of determining amphetamine in plasma samples using
      pentafluorobenzenesulfonyl chloride and electron-capture gas chromatography.
AB  - INTRODUCTION: Acute administration of (+)-amphetamine has been used as a model
      for mania in humans since it mimics the physiological, biochemical, and cognitive
      effects seen in mania. A rapid and sensitive method for the determination of
      amphetamine in human plasma samples using gas chromatography with electron
      capture detection was developed in our laboratory to follow the time course of
      amphetamine levels in patients receiving this drug as part of a study using
      amphetamine as a model for mania. METHODS: Blood samples were taken from healthy
      male volunteers at 30, 60, 90, 150, 210, 240, and 480 min after administration of
      25 mg of (+)-amphetamine. Plasma was isolated by centrifugation and used for the
      analysis. This method is a modification of the procedure described by Paetsch et
      al. [J. Chromatogr. 573 (1992) 313] for the determination of amphetamine in rat
      brain tissue. Amphetamine was derivatized under basic conditions using
      pentafluorobenzenesulfonyl chloride (PFBSC) prior to analysis on a gas
      chromatograph equipped with a capillary column and an electron-capture detector.
      The internal standard used was benzylamine. The structure of the amphetamine
      derivative was confirmed using combined gas chromatography-mass spectrometry (GC
      MS). RESULTS: The limit of detection was <1 ng/ml, and the method was linear in
      the 1- to 100-ng range used. Mean amphetamine levels peaked at 3.5 h after drug
      administration, and were 40.8 +/- 1.5 ng/ml at that time. DISCUSSION: This
      procedure produces a stable derivative with excellent chromatographic properties
      and is both simple and reproducible.

PMID- 12481849
TI  - A novel testosterone 6 beta-hydroxylase activity assay for the study of CYP3A
      mediated metabolism, inhibition, and induction in vitro.
AB  - INTRODUCTION: In order to examine CYP3A-mediated metabolism in vitro, a unique
      analytical assay was developed to detect the formation of 63-hydroxytestosterone
      (63-OHT). This assay has been determined to be useful for the study of both
      inhibition- and induction-related drug-drug interactions in vitro and involves
      simple incubation and sample handling procedures. METHODS: A primary and three
      backup sets of analytical conditions were developed to detect interference
      between a test compound and either 6beta-OHT or the internal standard. RESULTS:
      The primary set of conditions was validated with a three-batch validation, and
      the remaining sets of conditions were validated with one-batch validations, all
      in human liver microsomes. The primary assay was also validated with a single
      batch for CYP3A induction studies in primary human hepatocytes. Enzyme kinetic
      parameters of 6beta-OHT formation (Km, Vmax) were determined to be reproducible
      in human liver microsomes. DISCUSSION: Utility of the assay in inhibition studies
      and induction studies, respectively, was confirmed with the test compounds
      ketoconazole and rifampicin. In addition, superiority to existing methods was
      demonstrated in three areas: ease of sample preparation, short run times, and low
      detection limits.

PMID- 12481850
TI  - Radio frequency chaff: the effects of its use in training on the environment.
AB  - Chaff is a radiofrequency countermeasure released by military aircraft, ships,
      and vehicles to confuse enemy radar. Chaff consists of aluminum-coated glass
      fibers ranging in lengths from 0.8 to 0.75 cm and is released in packets of 0.5
      to 100 million fibers. The Department of Defense has determined that use of chaff
      in training is required for maintaining proficiency in the use of this
      countermeasure. At least 500 tons of chaff is released annually during training
      within selected military operating areas in the United States. Concerns have been
      raised about impact on the environment and its potential toxicity to humans,
      livestock, and wildlife. Many of these concerns have been addressed or are being
      researched by the Department of Defense and other agencies, but much of the data
      are unpublished. Herein, the authors summarize the issues and review scientific
      data for the impact of chaff use on humans, animals, and the environment.

PMID- 12481851
TI  - A rapid response toxicity test based on the feeding rate of the tropical
      cladoceran Moinodaphnia macleayi.
AB  - Recent research has reported that the feeding rate of the cladoceran Daphnia
      magna (measured over 24 h) is a sensitive indicator of toxicity. Using a
      methodology similar to that used for D. magna, a feeding test for the Australian
      tropical cladoceran Moinodaphnia macleayi was developed and the sensitivity of
      the test was compared with the currently used reproduction test. The results of
      the study revealed that the feeding rate of M. macleayi was a more sensitive
      indicator of toxicity than reproduction for cadmium; a mean concentration of 1.4
      microg/L caused significant inhibition of feeding (P < or = 0.05), while
      reproduction was significantly reduced at 3.1 microg/L (P < or = 0.05). No
      feeding inhibition was detected when M. macleayi were exposed to copper, despite
      significant mortality. The difference in feeding and reproductive responses of M.
      macleayi to cadmium and copper suggest differing modes of action for the two
      metals. The feeding test was validated on two samples of mine release water
      containing various metals. Results demonstrated that a cladoceran feeding test,
      performed over a 20-h period, was comparable in sensitivity to a reproduction
      test performed over a 5- to 6-day period.

PMID- 12481852
TI  - Essential elements as early indicators of hexavalent chromium nephrotoxicity.
AB  - The kidney is the appropriate critical organ for indicating chronic exposure to
      chromium compounds. The present work investigates the effect of dose-dependent
      hexavalent chromium concentration in various tissues of rats, the disturbances in
      metabolism of zinc and copper in liver and kidney, and histopathological changes
      in kidneys. White Wistar rats were used. Animals were injected intraperitoneally
      at a dose of 0.5 and 5 mg Cr/kg as K2CrO4. The animals were sacrificed after
      single and repeated doses at 24 h after the last injection. Disturbances in the
      metabolism of zinc and copper in the kidney of rats occur when the concentration
      of chromium in this organ attains about 30 microg Cr/g. An increase in urinary
      output of these essential metals is a more sensitive indicator of nephrotoxicity
      than ultrastructural damage of kidney.

PMID- 12481853
TI  - Effects of temperature on the sensitivity of sludge worm Tubifex tubifex Muller
      to selected heavy metals.
AB  - The present study evaluates the effect of temperature on the sensitivity of the
      freshwater tubificid sludge worm Tubifex tubifex Muller to 10 heavy metal ions.
      Metals used in this study were cadmium, chromium, cobalt, copper, iron, lead,
      manganese, mercury, nickel, and zinc. The acute toxicity of these heavy metals
      was studied at 15, 20, 25, and 30 degrees C. The percentage mortality, relative
      toxicity, and EC50 values and their 95% confidence limits from 24 to 96 h were
      determined at varying temperatures. The EC50 values (mg/liter) of metal ions at
      15 degrees C were Hg2+, 0.034; Cu2+, 0.340; Cr6+, 1.846; Zn2+, 10.99; Ni2+,
      25.10; Cd2+, 56; Fe3+, 86.09; Co2+, 239.39; Pb2+, 456.76; and Mn2+, 164.55. At 30
      degrees C the values were Hg2+, 0.014; Cu2+, 0.031; Cr6+, 0.872; Zn2+, 3.37;
      Ni2+, 18; Cd2+, 28.55; Fe3+, 71.26; Co2+, 95.35; Pb2+, 165.22; and Mn2+, 239.39.
      The results indicate that the acute toxicity of cadmium, chromium, cobalt,
      copper, lead, mercury, nickel, and zinc increases with temperature increase. The
      toxicity of manganese was not influenced by temperature, and temperature had
      little effect on iron toxicity. The rank order of toxicity of metal ions at 15,
      20, 25, and 30 degrees C is presented and discussed. It is concluded that
      temperature is an important factor in short-term acute toxicity tests. The study
      indicates that seasonal temperature changes are an important variable in
      determining the amount of heavy metals that may be safely released from metal
      industries and other similar sources into the aquatic environment. Influence of
      temperature on the short- and long-term toxicity of chemicals should be
      considered for establishing appropriate water-quality criteria and standards to
      protect aquatic flora and fauna and human health.

PMID- 12481854
TI  - Effects of long-term low-dose cyanide administration to rats.
AB  - Chronic exposure to cyanide has been associated with development of pancreatic
      diabetes, hypothyroidism, and several neurological diseases in both humans and
      animals. However, there is a limited number of experimental models for these
      pathologies. Thus, in the present study 0, 0.15, 0.3, or 0.6 mg KCN/kg body
      weight/day was administered for 3 months to 26 rats. On the last day, plasma
      samples were obtained for glucose, cholesterol, and thyroidal hormone
      measurement, and the pancreas, thyroids, and whole central nervous system were
      collected for histopathologic study. There were no significant difference in
      plasma concentrations of the substances measured between groups, and no lesions
      were found in the pancrease or thyroid. The CNS of experimental animals revealed
      the presence of spheroids on the ventral horn of the spinal cord, neuron loss in
      the hippocampus, damaged Purkinje cells, and loss of cerebellar white matter. In
      conclusion, cyanide administration could promote neuropathological lesions in
      rats without affecting pancreas or thyroid gland metabolism.

PMID- 12481855
TI  - Detection and determination of aromatic amines as products of reductive splitting
      from selected azo dyes.
AB  - The current environment-friendly regulations concerning textile products ban the
      marketing of textiles dyed with azo dyes capable of reductively splitting
      carcinogenic aromatic amines. The study analyzes seven azo dyes whose chemical
      structure determines various quantities of splitting aromatic amines, such as
      benzidine. For tests, seven commercially available azo dyes with aromatic amines
      in their structure were selected. These included two hazardous dyes: Acid Red 85
      and Direct Blue 6, both capable of reductively splitting carcinogenic benzidine.
      Of the remaining five azo dyes, three--Ponceau SS, Sudan II, and Disperse Yellow
      7--are capable of splitting p-phenylenediamine and aniline, while Mordant Orange
      1 and Disperse Orange 3 can split only p-phenylenediamine. For Acid Red 85 and
      Direct Blue 6, the quantity of benzidine split from them was analyzed, depending
      on the conditions of the reduction process (e.g., in the HPLC method, 104 g/kg of
      dye for reduction in NaOH, and 41 g/kg of dye for reduction in acetate buffer).
      The spectrophotometric method proved useful for preliminary analysis of amine
      content in examined samples. Spectrophotometric analysis may be used to determine
      the total content of amines counted as aniline. A full qualitative and
      quantitative analysis of amines released from azo dyes is possible using high
      performance liquid chromatography (HPLC).

PMID- 12481856
TI  - Protective effect of early and late administration of pralidoxime against
      organophosphate muscle necrosis.
AB  - The objective of the present investigation was to study the protection afforded
      by a single administration of pralidoxime against the muscle necrosis induced by
      the organophosphate compound metamidophos at different times after intoxication.
      The fiber necrosis of the diaphragm muscle was quantified by a morphometric
      technique, comparing the area fraction occupied by necrotic muscle fibers in
      animals that received pralidoxime at different times after intoxication, i.e., 0,
      1, 3, 6, and 12 h. Pralidoxime administration protected metamidophos-induced
      muscle necrosis in all groups studied except for the 12-h group. The earlier the
      administration of pralidoxime the greater the protection against muscle necrosis.
      This protection was not accompanied by complete reactivation of plasma
      cholinesterase activity. Results support the current opinion that pralidoxime
      should be administered as soon as possible after organophosphate intoxication,
      because in addition to reversing the muscarinic effects, early administration of
      pralidoxime also prevents muscle necrosis--which could impair muscular function
      and respiratory condition. The time difference between recovery of plasma
      cholinesterase activity and muscle necrosis protection indicates that this method
      is not completely trustworthy for patient follow-up, since some improvement may
      occur in spite of the low plasma cholinesterase activity.

PMID- 12481857
TI  - Impact of cadmium on liver pigmentary system of the frog Rana ridibunda.
AB  - The liver pigmentary system of the frog Rana ridibunda was investigated after
      exposure to CdCl2. There was a time-dependent alteration in the area occupied by
      pigment cells. Most pigment was melanin, but lipofuscin and ferritin were also
      detected, being similarly increased with time. There was a time-dependent
      increase in the dimensions of pigment cells as a result of forming a cluster of
      more than two pigment cells, the so-called melanomacrophage aggregates (MMC). A
      thin capsule of connective tissue with fibroblast-like cells surrounds some MMCs.
      The various possible roles of MMCs are discussed, for instance, those of
      scavengers of foreign substances, for lowering of metabolic activities to survive
      in an anoxic environment probably caused by cadmium, or as scavenger of cadmium,
      thus playing a protective role against this metal.

PMID- 12481858
TI  - Reduced recruitment in Hyalella azteca (Saussure, 1858) exposed to copper.
AB  - Neonates of the amphipod Hyalella azteca were exposed for a 35-day period in the
      laboratory to a range of copper concentrations, nominally 18 microg/l, 40
      microg/l, 70 microg/l and 260 microg/l. The reproductive status of the population
      was assessed by recording recruitment, the number of precopulatory pairs and
      number of gravid females. At the end of the experiment, the body lengths of
      individuals were measured using image analysis. There was a significant decrease
      in the final population size of H. azteca with increasing copper concentration
      and compared with the control. Copper significantly reduced recruitment of
      juveniles and length composition of the final population and there was also a
      trend toward reduced precopula number with increasing copper concentrations.

PMID- 12481859
TI  - Estrogenic effects from household stoves.
AB  - With the application of a genetically modified yeast, estrogen receptor
      activating compounds were detected in the soot and emission gas of a wood-burning
      household stove. The EC50 value of 17beta-estradiol was divided by the EC50 value
      of soot, and the obtained relative estrogenic value for raw soot was 2.37E-5,
      indicating that soot was about 100,000 times less estrogenic than 17beta
      estradiol. Chemical analysis revealed that alkyl phenol, benzonic acid, and PAHs
      represented the major constituents in the most potent fractions of the soot.
      Along with PAHs, other constituents might also contribute to the estrogenicity of
      soot.

PMID- 12481860
TI  - In vitro toxicity of stimulant soft drinks.
AB  - Some drinks containing natural products with stimulant properties are highly
      consumed among young adults. The market for these drinks has increased in past
      years around the globe, and, although they might be harmless, overdoses or
      combination of these with other drinks could be harmful to the health of some
      consumers in certain circumstances. Samples were obtained at food shops and
      different popular brands were chosen. Cytotoxicity tests used were neutral red
      uptake, total protein content, and tetrazolium assay on Chinese hamster ovary
      cells. Results revealed that tested samples were not cytotoxic; however, studies
      have demonstrated the toxicity of high concentrations of some of these products.
      For this reason, the authors considered it to be of critical importance to
      carryout an in vitro toxicity screening of stimulant soft drinks that are highly
      consumed.

PMID- 12481861
TI  - Developmental effects of ambient UV-B light and landfill leachate in Rana blairi
      and Hyla chrysoscelis.
AB  - This study assessed the effects of ambient UV light on the development of two
      native species of anurans, Rana blairi and Hyla chrysoscelis, during their normal
      breeding season in Oklahoma. Additionally, the effects of ambient UV light and
      water contaminated with landfill leachate in Rana blairi were examined. Embryos
      were collected from the field and distributed equally among replicates of four
      filter treatments of ambient UV light in experimental tubs filled with either
      FETAX solution or landfill leachate diluted to 25, 10, and 5% concentrations.
      Three endpoints (mortality, teratogenesis, and growth) were compared between
      filter treatments. By itself, UV-B caused no significant effects. Leachate at 10
      and 25% concentrations caused 100% mortality across all filter treatments. There
      was a significant interaction between filter treatment and water toxicity at
      leachate concentrations of 5% for both malformation and growth. Increased UV-B
      exposure decreased the malformation rate and increased growth in the leachate
      treatments.

PMID- 12481862
TI  - Benzo[a]pyrene and beta-naphthoflavone mutagenic activation by European eel
      (Anguilla anguilla L.) S9 liver fraction.
AB  - Is Anguilla anguilla L. (eel) liver ethoxyresorufin O-deethylase (EROD) induction
      absolutely necessary in order to convert promutagens as benzo[a]pyrene (BaP) into
      a mutagenic compound? Eels were exposed for 8 h to clean (control) and 0.3 microM
      beta-naphthoflavone (BNF)-contaminated water. The 8-h exposure to 0.3 microM BNF
      brought about a very high EROD induction (10 pmol/min/mg protein) compared to
      control animals (1 pmol/min/mg protein). The Ames test (Maron and Ames, 1983) was
      carried out with Salmonella typhimurium TA 98 strain (TA98 His-) and eel isolated
      S9 liver fraction was used as a metabolic BaP activator. The BaP and BNF dose
      range concentrations tested were 0 (blank), 0.015, 0.08, 0.15, 0.38, 0.75, 1.5,
      3.8, and 7.5 microM/plate and 0 (blank), 0.412, 1.235, 3.704, 11.1, 33.0, and 100
      nM BNF, respectively. A dose-response relationship between BaP concentration and
      mutagenic activity was observed in the presence of S9 fractions in control and
      0.3 microM BNF-exposed eels. Significant positive results, as TA98 His+
      revertants, were observed at 0.38, 0.75, 1.5, 3.8, and 7.5 microM BaP/plate
      induced by BNF S9 fractions. Significant BaP mutagenic activation by liver
      control S9 was detected only at 1.5, 3.8, and 7.5 microM/plate. The BaP 1.5, 3.8,
      and 7.5 microM/plate mutagenic activation by BNF S9 and control S9 were not
      significantly different. Relative to BNF activation, it was only possible to
      detect His+ reversion at 11.1 nM BNF concentration with 0.3 microM BNF-induced
      S9. The above results demonstrate that the eel S9 liver fraction has the capacity
      to biotransform high BaP concentrations and convert it into a mutagenic compound
      with or without previous liver BNF biotransformation induction. The same does not
      apply to low BaP concentrations, where liver S9 induction by BNF is necessary to
      promote mutagenesis.

PMID- 12481863
TI  - Anguilla anguilla L. biochemical and genotoxic responses to benzo[a]pyrene.
AB  - Eels (Anguilla anguilla L.) were exposed for 2, 4, 6, 8, 16, 24, 48, 72, 144, and
      216 h to 0 (control), 0.3, 0.9, and 2.7 microM benzo[a]pyrene (BaP). The
      biotransformation induced by BaP was measured as liver ethoxyresorufin O
      deethylase (EROD) activity and cytochrome P450 content, and compared with the
      genotoxic effects, such as erythrocytic nuclear abnormalities (ENA), and blood
      and liver DNA strand breaks. The liver exhibited a highly significant EROD
      activity increase from 2 up to 216 h exposure to 0.9 and 2.7 microM BaP, whereas
      0.3 microM BaP exposure induced a significant liver EROD increase from 2 up to
      144 h. Liver cytochrome P-450 content was significantly increased at 8 h to 2.7
      microM BaP exposure. Liver DNA integrity was decreased at 16 h, from 8 up to 144
      h and 8 up to 72 h exposure to 0.3, 0.9, and 2.7 microM BaP, respectively. A
      significant decrease in blood DNA integrity was observed at 48, 72, 144 h, from 8
      up to 72, and from 6 up to 72 h exposure to 0.3, 0.9, and 2.7 microM BaP,
      respectively. The A. anguilla L. genotoxic response to BaP, measured as ENA
      induction, was significantly increased at 144 h exposure to 0.3 microM BaP. The
      intermediate BaP concentration tested (0.9 microM) induced a significant three
      fold ENA increase at 48 and 72 h exposure compared to their controls. The highest
      BaP concentration (2.7 microM) induced a significant increase in ENA frequency at
      72, 144 and 216 h exposure.

PMID- 12481864
TI  - Responses of microbial activity and decomposer organisms to contamination in
      microcosms containing coniferous forest soil.
AB  - Soil respiration from microcosms contaminated with pentachlorophenol, 2
      ethanolhexanoate, creosote, CuSO4, and benomyl was measured in order to evaluate
      usefulness of soil microcosms and microbial respiration rate monitoring as a
      toxicity test in soils with high organic matter content. Coniferous forest soil
      and its organisms were used as test objects. In addition, how a short-term low
      temperature period including frost affects respiration dynamics in stressed soils
      was studied, i.e., whether contaminants reduce resistance of the community to
      other (also natural) stresses. In addition, at the end of the experiment, effects
      of contaminants on faunal and microbial community structures were analyzed. Soil
      respiration measurements from the microcosms appeared to be a sensitive parameter
      for testing community-level effects of chemicals in the soil with high organic
      matter content. An 84-day exposure had acute effects, long-term effects, delaying
      effects, and total recovery of community respiration. Direct negative and
      indirect positive effects of chemical contamination on the community of soil
      organisms were found. Responses to contamination of soil respiration rate and
      structure of the soil community were parallel. Addition of pentachlorophenol, 2
      ethanolhexane, and Cu into the soil reduced frost resistance of the decomposer
      community. It was concluded that soil respiration monitoring of artificially
      contaminated soil microcosms seems to be a useful tool for testing community
      level toxic effects of chemicals.

PMID- 12481865
TI  - Juvenile sea bass liver biotransformation and erythrocytic genotoxic responses to
      pulp mill contaminants.
AB  - This research represents the first study concerning liver phase I
      biotransformation induction, measured as cytochrome P-450 (P450) and
      ethoxyresorufin-O-deethylase (EROD), and genotoxic responses, measured as
      erythrocytic micronuclei (EMN) and nuclear abnormalities (ENA), in Dicentrarchus
      labrax L. (sea bass) exposed to pulp and paper mill contaminants. Juvenile sea
      bass were exposed for 6 h to 0 (control) and 0.0125 microM concentrations of the
      resin acids (RAs) abietic acid (AA) and dehydroabietic acid (DHAA) or 7-isopropyl
      1-methylphenanthrene (retene) (Experiment 1). Sea bass were exposed for 6 h to 0
      (control), 0.78, 1.56, 3.12, 6.25, and 12.5% bleached kraft pulp mill
      environmental contaminated water (BKPMECW) collected at the old sewage outlet of
      a pulp and paper industry (Experiment 2). The time-dependent response was studied
      in sea bass at 0, 8, 16, 24, 48, and 72 h exposure to 0.78 and 12.5% BKPMECW
      (Experiment 3). The experimental results demonstrated the presence of genotoxic
      compounds in BKPMECW. AA, DHAA, and retene may be the constituents responsible
      for high BKPMECW genotoxicity, since they induced similar sea bass EMN and ENA
      frequency increases. The BKPMECW, the RAs, and retene failed to significantly
      increase liver EROD activity and P450 content at 6 h. Furthermore, 3.12% BKPMECW,
      0.0125 microM AA, and 0.0125 microM retene significantly decreased liver EROD
      activity. However, P450 was significantly increased from 8 up to 72 h exposure to
      BKPMECW. Therefore, the low or inhibited EROD levels could be a consequence of a
      general membrane disturbance by BKPMECW, RAs, and retene. However, liver ALT
      results indicate significant liver damage or enzyme inhibition only at 8, 16, 48,
      and 72 h exposure to BKPMECW.

PMID- 12481866
TI  - Toxicity of 4-nonylphenol to Tubifex tubifex and Chironomus riparius in 28-day
      whole-sediment tests.
AB  - Concern has been growing recently over the toxicity and the mimicking properties
      of 4-nonylphenol (4NP), the most persistent breakdown product of the nonionic
      surfactant nonylphenol ethoxylates, broadly used in industrial cleaning
      processes. Twenty-eight-day tests were performed to evaluate the toxicity and the
      effects on reproduction of 4NP spiked sediment to the benthic invertebrates
      Tubifex tubifex and Chironomus riparius. 4NP was directly added to the wet
      sediment, avoiding any solvent. The EC50 value for the emergence of chironomids
      was 380 microg 4NP g(-1) dry weight (dw); the EC50 values for the deposition of
      cocoons and the development of young worms were very similar (428 and 420 microg
      g(-1) dw, respectively). Regarding NP estrogenic activity and its effects on
      reproduction and development, no significant differences were noted in the sex
      ratio of the emerged chironomids when exposed to 4NP compared to the controls,
      but the emerged chironomids did not lay eggs at concentrations higher than the
      EC10 (250 microg 4NP g(-1) dw). Furthermore, at concentration of 610 microg 4NP
      g(-1) dw an interference in the development of the gonads of adult worms was
      observed, but it was impossible to determine whether this effect was due to 4NP
      toxicity or to its hormone mimicking properties.

PMID- 12481867
TI  - Repeatability of the submitochondrial particle assay.
AB  - A study assessing the intralaboratory precision of the in vitro submitochondrial
      particle (SMP) electron transfer (ETr) and reverse electron transfer (RET) assays
      was undertaken using the standard reference toxicants, pentachlorophenol (PCP),
      sodium dodecyl sulfate (SDS), and zinc sulfate 7-hydrate (ZnSO4 7H2O). One to
      three trials of each assay were manually conducted daily for at least 5 days with
      each toxicant using commercially available sources of particles and reagents.
      Composite coefficients of variation (CVs) for the ETr assay ranged from 20.6% for
      ZnSO4 to 29.3% for PCP (n > or = 15). Composite CVs for the RET assay ranged from
      6.5% for SDS to 16.5% for PCP (n > or = 15). Comparison of intralaboratory
      results with in-house and published data demonstrates that the precision of both
      of these SMP assays is comparable to that of the more common in vivo, whole
      organism bacterial, invertebrate, and fish toxicity tests.

PMID- 12481868
TI  - Toxicity of cadmium and zinc to encystment of Notocotylus attenuatus (Trematoda:
      Notocotylidae) cercariae.
AB  - The toxicity of cadmium, zinc, and cadmium/zinc mixtures at concentration ranging
      from 100 to 10,000 microg/L was investigated against the encystment strategy of
      free-living metacercarial stages of the parasitic fluke Notocotylus attenuatus.
      Exposure of encysting cercariae caused a reduction in encystment by all metals at
      concentrations of 1000 microg/L or higher. The formation of cyst associations was
      reduced in all metal-polluted test solutions. In addition, there was an increase
      in the number of floating metacercariae (cysts formed when not in contact with
      any surface) at low metal concentrations. The effects of metal toxicity to
      encystment strategy and its influence on transmission to the target host are
      briefly discussed.

PMID- 12481869
TI  - Cellular stress induced in cultured human cells by exposure to sludge extracts
      from water treatment plants.
AB  - Sludge extracts from three water treatment plants, corresponding either to the
      readily water-soluble fraction or to the heavy metal content found in the solid
      fraction were tested separately or in combination on human cultured cells for
      their ability to affect the growth rate and/or to trigger a synthesis of the
      stress-related hsp72 and metallothionein proteins. When given separately, the
      soluble extract or the metal mixture corresponding to the solid fraction of
      sludge failed to exert significant effects on cell growth rate and expression
      level of the stress proteins. However, when given in combination, they were found
      to exert a strong synergistic effect, as they impaired cell growth and induced a
      significant overexpression of both hsp72 and metallothionein. This result points
      out the complex molecular interactions in actual environmental samples when
      acting on biological structures. It underscores the need for biological tests to
      complement chemical analyses in environment monitoring.

PMID- 12481870
TI  - Contamination and distribution of polychlorinated dibenzo-p-dioxins and
      dibenzofurans (PCDD/F) in agriculture fields in Ya-Er Lake area, China.
AB  - The contamination and distribution of polychlorinated dibenzo-p-dioxins and
      dibenzofurans (PCDD/Fs) from two agricultural fields of a heavily polluted lake
      area in China (Ya-Er Lake) are presented. The vertical distribution pattern of
      total PCDD/Fs in soil cores reveals that the maximum concentration was in the
      layer of 20-30 cm. The concentrations in the top layer of soil at the two sites
      were similar (17.48 ng/kg at Site 1 and 18.10 ng/kg at Site 2), but the maximum
      concentration of Site 1 (120.8 ng/kg) was two times higher than that of Site 2
      (64.39 ng/kg). The maximum concentration of PCDD/Fs in mud cores in rice fields
      (0-50 cm) at Sites 1 and 2 was in the layer of 0-10 cm. The maximum PCDD/F
      concentration in the top layer in mud at Site 1 (203.1 ng/kg) was higher than
      that at Site 2 (143.3 ng/kg). Significant correlations were found between the mud
      PCDD/Fs and the organic carbon content (R = 0.9743, P < 0.05 at Site 1; R =
      0.9821, P < 0.05 at Site 2), the two variables being highly correlated (R =
      0.9049, P < 0.05, at Site 1; R = 0.9916, P < 0.05 at Site 2). All correlation
      coefficients were significant at the 95% level. Concentrations were highly
      correlated with organic carbon, indicating that sorption to organic carbon was
      the dominant mechanism. Using principal component analysis, the homologue
      profiles of soil, mud, and plants (rice and radish) were compared. The PCDD/F
      patterns in plants were found not to be correlated to those in soil and mud. This
      suggests that atmospheric deposition may be the main source of PCDD/Fs in rice
      grain. However, mixed exposure involving uptake mechanisms and atmospheric
      deposition is considered main the source of PCDD/F pollution in radishes.

PMID- 12481871
TI  - Transfer of cadmium from plant leaves and vegetable flour to the snail Helix
      aspersa: bioaccumulation and effects.
AB  - Juvenile Helix aspersa snails were exposed for 4 weeks to fresh rape leaves
      (Brassica napus), contaminated by simulating superficial deposits of increasing
      concentrations of cadmium (Cd). The Cd concentration in leaves was 0.1 in control
      and 38.4, 93.1, and 177.2 microg x g(-1) (dry mass) in Cd-treated food. The
      concentration in snail tissues increased with increasing Cd concentrations in the
      food. The bioaccumulation factors ranged from 4.8 (control) to 2.4 (highest
      exposed group), indicating a biomagnification of Cd in this food chain. The
      growth of the snails treated with Cd was reduced by 17, 24, and 43% respectively,
      compared to the control group. Comparison of these results with those obtained
      with snails exposed to similar Cd concentrations in a vegetable flour revealed
      that accumulation and effects were relatively consistent, demonstrating a
      comparable bioavailability of Cd in the two diets. Tests using growing H. aspersa
      snails exposed to metals in flour or fresh leaves can be useful for risk
      assessment purposes.

PMID- 12481872
TI  - Effects of a coastal golf complex on water quality, periphyton, and seagrass.
AB  - The objective of this study was to provide baseline information on the effects of
      a golf course complex on water quality, colonized periphyton, and seagrass
      meadows in adjacent freshwater, near-coastal, and wetland areas. The chemical and
      biological impacts of the recreational facility, which uses reclaimed municipal
      wastewater for irrigation, were limited usually to near-field areas and decreased
      seaward during the 2-year study. Concentrations of chromium, copper, and
      organochlorine pesticides were below detection in surface water, whereas mercury,
      lead, arsenic, and atrazine commonly occurred at all locations. Only mercury and
      lead exceeded water quality criteria. Concentrations of nutrients and chlorophyll
      a were greater in fairway ponds and some adjacent coastal areas relative to
      reference locations and Florida estuaries. Periphyton ash free dry weight and
      pigment concentrations statistically differed but not between reference and non
      reference coastal areas. Biomass of Thalassia testudinum (turtle grass) was
      approximately 43% less in a meadow located adjacent to the golf complex (P <
      0.05). The results of the study suggest that the effects of coastal golf courses
      on water quality may be primarily localized and limited to peripheral near
      coastal areas. However, this preliminary conclusion needs additional supporting
      data.

PMID- 12481873
TI  - DDT homologues and PCBs in eggs of great crested grebe (Podiceps cristatus) and
      mallard (Anas platyrhynchos) from Lake Maggiore (Italy).
AB  - DDT homologues and PCBs were determined in eggs of two stationary species, great
      crested grebe (Podiceps cristatus) and mallard (Anas platyrhynchos), in three
      breeding areas of Lake Maggiore in 1998. As expected, much higher contamination
      levels of both DDTs and PCBs were found in the fish-eating great crested grebe
      than in the mallard. In many eggs these values exceeded the safety thresholds
      proposed for aquatic bird protection. However, no significant correlation could
      be found between the two classes of pollutants and shell thickness in great
      crested grebe eggs. While a DDT manufacturer was detected as the main source of
      DDT pollution in the Lake Maggiore environment, the reason for the surprisingly
      high PCB level remains unknown.

PMID- 12481874
TI  - Correlation of two bioluminescence and one fluorogenic bioassay for the detection
      of toxic chemicals.
AB  - The linear correlation between the EC50 values of 50 substances obtained in
      luminescence bioassays using Vibrio fischeri and Vibrio harveyi and in a
      fluorogenic bioassay using Escherichia coli was investigated. As a result, a
      significant correlation was found between the said values in all three toxicity
      tests. The bioassay using V. harveyi had a sensitivity similar to that of the
      fluorogenic bioassay, and the bioassay using V. fischeri was the least sensitive
      of all. The sensitivity of the three bioassays for each of the tested substances,
      chiefly heavy metals, organic solvents, orgnochlorated compounds, and pesticides,
      differed in the majority of the cases. The three bioassays were quantified using
      the same laboratory apparatus and the data were processed in the same way. The
      possibility of designing a battery of toxicity tests that can be performed using
      the same apparatus but different organisms and parameters is discussed.

PMID- 12481875
TI  - Validation of an ex vivo Xenopus liver slice bioassay for environmental estrogens
      and estrogen mimics.
AB  - A sensitive ex vivo bioassay for detecting environmental estrogens and estrogen
      mimics was developed using Xenopus liver slice culture. Vitellogenin synthesis by
      these cultures was used as biomarker for estrogenic activity of environmental
      water samples. Sensitization of the assay for estrogens and mimics was
      accomplished by employing tissue from animals after in vivo preexposure to
      estrogen. Effects of various tissue culture factors were investigated in order to
      obtain optimum conditions for the bioassay. It was found that endogenous
      vitellogenin and/or estrogen could be "washed out" of cultures and that not only
      uncontaminated males but also estrogen-pretreated males and females can
      successfully be used as bioindicators. Estrogenicity was detected, using the ex
      vivo Xenopus liver slice culture assay, in sewage effluent, lake water, and dam
      water. This article presents an optimized protocol for effective estrogen
      detection in environmental water samples.

PMID- 12481876
TI  - Osteoporosis: disease, risk factor or hype?

PMID- 12481877
TI  - EMEA guidelines for trials in osteoporosis: design implications.
AB  - The design, execution and interpretation of trials that do not contain a placebo
      arm are a challenge. These issues are briefly discussed in the context of the new
      European guidelines for the study of drugs for the indication prevention and
      treatment of postmenopausal osteoporosis.

PMID- 12481878
TI  - Intravenous pamidronate compared with oral alendronate for the treatment of
      postmenopausal osteoporosis.
AB  - There are several options for the treatment of osteoporosis in postmenopausal
      women. One of the options is treatment with bisphosphonates, which are very
      potent inhibitors of osteoclast-mediated bone resorption in vitro and in vivo.
      The most potent bisphosphonates have a nitrogen side chain and can be given
      orally or intravenously (i.v.). In the present study we evaluated retrospectively
      the effect of intravenously administered pamidronate (60 mg monthly) in
      comparison with oral alendronate with regard to bone mineral density (BMD) and
      vertebral fractures. A total of 117 consecutive women aged 46 to 78 years were
      seen in the outpatient clinic because of postmenopausal osteoporosis. Three-year
      follow-up data were available for a total of 45 patients treated with pamidronate
      i.v. and 40 patients on alendronate for at least three years. In the pamidronate
      group mean T score of lumbar spine BMD increased from -3.49 +/- 0.72 to -2.81 +/-
      0.74 SDs after three years of treatment (p < 0.001). In the 40 patients treated
      with alendronate we observed an increase in the T score from -2.95 +/- 0.67 to 
      2.33 +/- 0.74 SDs (p < 0.001) during the same observation period. X-rays of the
      lumbar and thoracic spine were analysed from 25 patients in each group who had
      been treated for at least three years. At baseline nine patients (36%) in the
      pamidronate group had one or more vertebral fractures compared with seven
      patients (28%) in the alendronate group. After three years of treatment no new
      fractures were observed, while only three women in the pamidronate group and two
      in the alendronate group showed a deterioration of one or more pre-existing
      vertebral fractures (p = ns between groups). This retrospective analysis
      demonstrates that monthly intravenous administration of pamidronate is at least
      as good as alendronate taken orally in the treatment of women with postmenopausal
      osteoporosis, with regard to improvement of bone mineral density of the lumbar
      spine. We conclude that it is a good alternative for the more widely used oral
      bisphosphonates as it is effective, well-tolerated and easy to administer.

PMID- 12481879
TI  - Clinical and radiological evolution in patients with pulmonary Langerhans' cell
      histiocytosis.
AB  - BACKGROUND: Pulmonary Langerhans' cell histiocytosis (LCH) is a diffuse, smoking
      related lung disease characterised pathologically by proliferation of abnormal
      Langerhans' cells, cyst formation and vascular abnormalities, and physiologically
      by a decreased diffusing capacity. The aim of this study was to describe our
      experience with pulmonary LCH at our institution during the past 30 years, with
      particular reference to diagnosis and long-term outcome. PATIENTS AND METHODS:
      Seven patients, two men and five women, mean age 33 years (range 26-49 years),
      who had been evaluated for pulmonary LCH, were retrospectively studied. All
      available clinical, diagnostic and pathological data were included. RESULTS: The
      patients presented with symptoms of dyspnoea, cough, pleuritic pain, anorexia and
      fatigue. Chest X-ray and high-resolution computed tomography (HRCT) showed
      bilateral nodular and cystic lesions, with a predilection for the middle and
      upper lung zones. In the majority of patients, lung function tests showed a
      decrease in diffusing capacity. In six patients the diagnosis of pulmonary LCH
      was made after immunohistochemical examination of an open lung biopsy specimen.
      In one patient a confident diagnosis was made radiologically. During serial
      follow-up, median seven years (range 1-28 years), three patients stopped smoking
      and in four patients the tobacco consumption remained unchanged. For the whole
      group the evolution was benign, with all patients being asymptomatic or showing
      improvement in symptoms and regression of radiological signs. CONCLUSION:
      Radiographic studies often provide clues to the diagnosis, but may not obviate
      the need for open lung biopsy in the majority of cases. Our study shows that
      irrespective of smoking cessation, spontaneous regression of symptoms and
      radiological signs and long-term survival are possible.

PMID- 12481880
TI  - Tuberculous dacryoadenitis: a rare manifestation of tuberculosis.
AB  - A 41-year-old Somalian female inhabitant of The Netherlands presented with
      malaise and cervical lymph node swelling. Enlarged mediastinal, hilar and
      abdominal lymph nodes were found on CT scan. Subsequently the left lacrimal gland
      became swollen, accompanied by periostitis of the lateral orbit margin.
      Mycobacterium tuberculosis was cultured from lymph node tissue and the diagnosis
      of tuberculous dacryoadenitis with periostitis was made on CT images and
      histology. All lesions responded well to tuberculostatic treatment. Although
      tuberculous dacryoadenitis is a very rare manifestation of tuberculosis, it is
      still important to recognise this presentation, especially since the incidence of
      tuberculosis continues to increase in Western countries.

PMID- 12481881
TI  - Adult T-cell leukaemia and lymphoma: report of two cases and a brief review of
      the literature.
AB  - Human T-cell lymphotropic virus type 1 (HTLV-1) can cause adult T-cell
      leukaemia/lymphoma (ATLL). Two patients originating from the Caribbean area with
      ATLL are described. The first patient developed respiratory insufficiency due to
      acute T-cell leukaemia. The diagnosis was suspected because of characteristics of
      abnormal lymphocytes in the blood smear. The second patient had lymphadenopathy
      and developed severe hypercalcaemia. Both patients were typical cases of ATLL.
      The pathogenesis, clinical manifestations, pitfalls and treatment of this
      intriguing disease are discussed.

PMID- 12481882
TI  - How to diagnose cardiac tamponade.
AB  - Malignant pericardial effusion is a potentially fatal complication of malignancy
      unless recognised and treated promptly. Patients with this condition are often
      difficult to diagnose. Physical examination, chest radiography and
      electrocardiography have poor diagnostic values in identification of patients
      with pericardial effusion. Echocardiography, which allows rapid confirmation of
      the presence of an effusion and precise assessment of its haemodynamic impact, is
      the gold standard for diagnosis.

PMID- 12481883
TI  - New vessel formation and aberrant VEGF/VEGFR signaling in acute leukemia: does it
      matter?
AB  - Although many patients with acute leukemia achieve a hematological complete
      remission with aggressive intensive therapy protocols, a large proportion shows
      reoccurrence of disease. Novel strategies are warranted. In acute leukemia new
      vessel formation is observed. New vessel formation is the result of angiogenesis
      and vasculogenesis. The degree of neovascularization in the bone marrow is
      correlated with vascular endothelial growth factor (VEGF) expression in the
      leukemic cells. The present review discusses the impact of new vessel formation
      related to acute leukemia, the relation with various angiogenic factors and will
      focus on VEGF/VEGF receptor signaling.

PMID- 12481884
TI  - Drug monitoring of PEG-asparaginase treatment in childhood acute lymphoblastic
      leukemia and non-Hodgkin's lymphoma.
AB  - This is an updated review of the pharmacokinetic profile of PEG-asparaginase (PEG
      ASNase) in childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma
      (NHL). In a total of 271 children undergoing ALL/NHL or relapsed ALL treatment
      according to the Berlin-Frankfurt-Munster (BFM) protocols, drug monitoring of
      ASNase serum activity was performed after PEG-ASNase infusions. From December
      1996 to July 2000, 1667 samples after 362 intravenous administrations of either
      500, 750, 1000 or 2500 IU/m2 PEG-ASNase were analyzed. Three weeks after infusion
      when relating the ASNase activity to the four-dose levels significant differences
      were not observed. Large interpatient variability was seen at each dose level
      resulting in a relevant number of patients not achieving adequate treatment
      intensity. Neither the extent of ASNase pre-treatment nor a prior event of a
      hypersensitivity reaction against unmodified ASNase had any impact on PEG-ASNase
      pharmacokinetics. It is concluded that escalation of the dose of PEG-ASNase did
      not result in a significant prolongation of time with activity values considered
      therapeutic. Depending on the desired endpoint, a second administration of PEG
      ASNase seems to be more favorable than increasing the dose. For a safer
      recommendation, further investigations assessing the pharmacodynamic profile are
      required. Drug monitoring is advisable for early detection of patients with rapid
      elimination in order to ensure maximum treatment intensity.

PMID- 12481885
TI  - Thrombotic thrombocytopenic purpura following stem cell transplantation.
AB  - Thrombotic thrombocytopenic purpura (TTP) occurring after stem cell
      transplantation is poorly understood. The literature is scant and heterogeneous;
      little is known about the condition's pathogenesis except that it appears to
      differ from that of classical or de novo TTP. There are no widely agreed
      diagnostic criteria hence, it is difficult to compare the major findings of the
      relatively small, single centre series that have been reported. The true
      incidence is disputed and risk factors have only recently been evaluated. Plasma
      exchange is commonly employed for the therapy of severe post-transplant TTP but
      there are no data that support its use. This review summarises the state of
      knowledge of post-transplant TTP in 2002, addressing all the aforementioned
      issues and aims to provide the basis for further systematic study of this
      problematic complication of transplant.

PMID- 12481886
TI  - Correlation between the percentages of myeloblasts in bone marrow obtained by
      flow cytometry and manual counting on glass slide smears in 74 hematologic
      patients.
AB  - To investigate reliability of calculating percentage of myeloblasts by flow
      cytometric method, data were obtained from 74 hematologic patients (76 paired
      data). Myeloblast counts obtained by manual count versus flow cytometry were
      compared. Our data show that the percentage of myeloblasts in the bone marrow
      obtained with flow cytometric method correlates well with manual count
      (correlation coefficient is 0.9912). A very high correlation coefficient means
      that reliable percentage of myeloblasts in the bone marrow can be obtained by
      either method alone. Flow cytometry is a useful adjunct (or quality control) to
      validate manual myeloblast count and vice versa.

PMID- 12481887
TI  - Prospective study of indolent non-follicular non-Hodgkin's lymphoma: validation
      of Gruppo Italiano per lo studio dei linfomi (GISL) prognostic criteria for watch
      and wait policy.
AB  - Only recently both the Revised European American Lymphoma (REAL) and World Health
      Organization (WHO) classifications clearly identified indolent non-follicular non
      Hodgkin's lymphoma (NHL) as a distinct group of precise histological entities.
      Therefore, prognostic models, specifically designed for this NHL subset, are
      still lacking. In this study, we prospectically evaluated the prognostic criteria
      proposed by the Gruppo Italiano per lo studio dei linfomi (GISL) to identify
      patients with an indolent non-progressive clinical course, eligible for a watch
      and wait policy within this histological subset defined according to stringent
      criteria of histomorphology and immunophenotype. Fifty-three patients affected
      with small lymphocytic, marginal zone, lymphoplasmacytic lymphoma and lacking at
      presentation the following: B symptoms, bulky disease, anemia, thrombocytopenia,
      diffuse pattern of bone marrow infiltration and short tumor doubling time, were
      registered in a prospective therapeutic GISL trial and addressed to a watch and
      wait program. After 41.3 months of median follow-up, the median progression free
      survival (PFS) was not reached and 73% of cases did not progress. When additional
      variables were considered, in order to improve the prognostic model, it was
      evident that LDH level and the number of extranodal sites were of statistical
      significance in the multivariate analysis. Based on this finding, a prognostic
      score was devised which was able to further identify a small group of patients
      more likely to undergo early progression, and thus suitable for immediate
      treatment. In conclusion, the GISL definition of indolent disease is a reliable
      tool to design the appropriate therapeutic strategy in this histological setting.

PMID- 12481888
TI  - Regional variation in the distribution of subtypes of lymphoid neoplasms in
      India.
AB  - Lymphoid malignancies (LM) are a heterogeneous group of tumours. The relative
      frequencies of the various types of LMs vary across geographic regions. The
      pattern in India shows significant differences from the rest of the world. As
      India is a vast country, we set out to investigate whether there are regional
      differences in the relative frequencies of the various LMs. A total of 562 LMs
      from three different regions in India--Barshi (western India, 102 cases),
      Pondicherry (southern India, 156 cases) and Jaipur (northern India, 304 cases)
      were analysed according to the WHO classification. The non-Hodgkin lymphoma (NHL)
      to Hodgkin disease (HD) ratio was 6.28 in Barshi, 1.26 in Pondicherry and 2.27 in
      Jaipur. The frequency of HD's various subtypes did not significantly differ among
      the three regions. While T-cell NHLs constituted only 12.5% of NHLs at Barshi,
      they accounted for 31 and 27.5% of all NHLs at Pondicherry and Jaipur,
      respectively. There were also notable differences in the specific subtypes of NHL
      between the three different geographic regions in India.

PMID- 12481889
TI  - Phase I study of gemcitabine (difluorodeoxycytidine) in children with relapsed or
      refractory leukemia (CCG-0955): a report from the Children's Cancer Group.
AB  - To determine the maximum tolerated dose (MTD) and assess the toxicity profile and
      pharmacokinetics of weekly gemcitabine infusions in pediatric patients with
      refractory hematologic malignancies. Fourteen patients under 21 years old were
      given infusions of gemcitabine for escalating durations at 10 mg/m2/min weekly
      for three consecutive weeks. Two males and two females were studied at each dose
      level. Pharmacokinetics of the drug's metabolism were measured by high pressure
      liquid chromatography (HPLC) for 24 h after the first dose. Intracellular
      difluorodeoxycytidine triphosphate formation in leukemic blasts was measured in
      selected patients. The MTD of gemcitabine in these patients was 3600 mg/m2/week
      for three consecutive weeks (10 mg/m2/min for 360 min). Hepatotoxicity was the
      dose limiting toxicity. Thirty to fifty percent of patients exhibited fever,
      rash, or myalgia. Rare instances of hypotension and pulmonary toxicity were
      observed. Two of six patients [one acute lymphoblastic leukemia (ALL) and one
      acute myelogenous leukemia (AML)] treated at the MTD had at least M2 marrows,
      although peripheral blood counts did not recover sufficiently for the patients to
      be considered in complete response. Pharmacokinetics of gemcitabine fit a two
      compartment open model with terminal half-life and plasma clearance value of 62
      min and 2.2 l/min/m2, respectively. No gender differences were observed. In
      conclusion, the MTD of gemcitabine was 10 mg/m2/min for 360 min every week for 3
      weeks. This is the recommended phase II dose schedule for children with leukemia.
      The activity of the drug at this schedule in heavily pretreated, refractory
      patients warrants a phase II trial in hematologic malignancies.

PMID- 12481890
TI  - Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis
      acute myeloid leukemia.
AB  - The objective of this work was to determine the safety and efficacy of gemtuzumab
      ozogamicin in patients with poor prognosis acute myeloid leukemia (AML). Patients
      with the following diagnoses/characteristics were treated with 1-3 infusions of
      gemtuzumab ozogamicin at a dose of 9 mg/m2: (1) relapse of AML < or = 6 months of
      first complete remission (CR); (2) AML refractory to chemotherapy at initial
      induction or at first relapse; (3) AML in second or greater relapse; (4) myeloid
      blast crisis of chronic myeloid leukemia (CML); (5) untreated patients > or = 70
      years or > or = 55 years with abnormal cytogenetics (excluding inv 16, t(15;17)
      and t(8;21)) and/or an antecedent hematologic disorder; (6) refractory anemia
      with excess blasts in transformation (RAEBT). Forty-three patients, ages 19-84
      (mean 62), were treated, including 7 patients with untreated AML age > 70 years,
      2 with untreated RAEBT, 14 with AML first salvage (first remission 0-6 months),
      15 with AML > or = second salvage and 14 with myeloid blast phase of CML. The
      overall response rate was 14%, with 4/43 (9%) patients achieving CR and 2/43 (5%)
      achieving CR without platelet recovery. The most significant toxicity was
      neutropenic fever, which occurred in 84% of patients. In conclusion, in patients
      with relapsed/refractory AML, gemtuzumab ozogamicin has a comparable response
      rate to single-agent chemotherapy and may offer a more favorable toxicity
      profile.

PMID- 12481891
TI  - Harvesting of autologous blood stem cells after a mobilising regimen with low
      dose cyclophosphamide.
AB  - Although high-dose cyclophosphamide (HD-CTX) is commonly used as a mobilising
      regimen for autologous peripheral blood stem cell (PBSC) collection, significant
      morbidity and insufficient harvesting may complicate the procedure. Alternative
      regimens and lower doses of cyclophosphamide (CTX) have been investigated as
      possible ways of overcoming these difficulties. Low-dose CTX (1.5 g/m2) was
      administered to 102 lymphoma patients as an autologous PBSC mobilising regimen.
      The collection of 6 x 10(6) CD34+ cells/kg was chosen as the target of the
      apheresis sessions, whereas 3 x 10(6)/kg were considered the minimum necessary to
      perform autologous stem cell transplantation (ASCT) safely. The apheretic
      sessions were started a median of eight days after CTX administration; a median
      of two aphereses was required. More than 6 x 10(6) CD34+ cells/kg were collected
      from 78 patients, between 3 and 6 x 10(6)/kg from 19, and fewer than 3 x 10(6)/kg
      from 5, two of whom underwent bone marrow harvesting and one a successful second
      PBSC harvesting session using the same mobilising regimen. Eighty-two patients
      underwent autografting, six of whom received a second transplant after relapse
      (five using autologous PBSCs coming from the first apheretic course). Low-dose
      CTX proved to be a safe and effective regimen for autologous PBSC mobilization
      and also compared favourably with alternative regimens in terms of the rate of
      harvesting insufficiency. This does not imply that low-dose CTX is the best
      mobilising regimen for all patients, and the identification of prognostic factors
      predicting mobilising potential may help in choosing the best individualised
      regimen.

PMID- 12481892
TI  - A pilot study on feasibility and efficacy of amifostine preceding high-dose
      melphalan with autologous stem cell support in myeloma patients.
AB  - To evaluate feasibility and potential efficacy of amifostine (AMI) in the
      prevention of toxicities associated with high-dose melphalan (MEL), ten myeloma
      patients received AMI 910 mg/m2 in 15 min infusion preceding MEL 200 mg/m2
      followed by stem cell infusion (AMI group). Hematologic and extra-hematologic
      toxicities as well as the need for supportive care observed in the AMI group were
      compared with ten myeloma patients treated in an identical protocol but without
      AMI. Hypotension was the most important adverse event of AMI infusion. No
      differences were observed in the time of engraftment between the AMI group and
      the control group neither was there any difference in the need for supportive
      care. Oral mucositis grade >2 was observed in 30% of the patients in both groups.
      Diarrhea grade >2 occurred only in two AMI patients but in five control patients.
      AMI preceding high-dose MEL is feasible, although adverse events are observed in
      some patients. Whether AMI could reduce the gastrointestinal toxicity associated
      with high-dose MEL can be reliably assessed only in prospective randomized
      trials.

PMID- 12481893
TI  - Haemophilus influenzae type b (Hib) antibody concentrations and vaccination
      responses in patients with chronic lymphocytic leukaemia: predicting factors for
      response.
AB  - We have recently demonstrated a moderate vaccination response rate of 43% against
      Haemophilus influenzae type b (Hib) conjugate vaccine among adult and elderly
      patients with chronic lymphocytic leukaemia (CLL). We now investigated
      demographic and immunological factors predicting the favourable response and
      protective antibody concentrations for Hib conjugate vaccine in CLL. Lower age
      was associated with protective pre- and post-vaccination antibody concentrations.
      High IgG1 and IgA concentrations were also associated with the protective
      efficacy. High IgM, in turn, was the best predictor of a significant vaccination
      response. Again, lower age seemed to be involved in this outcome. Judging from
      these findings, it would seem beneficial to vaccinate all CLL patients with
      conjugate vaccines at the presentation of the disease. Investigations of a new
      pneumococcal conjugate vaccine in CLL are warranted.

PMID- 12481894
TI  - Pretargeted radioimmunotherapy (PRIT) using an antibody-streptavidin fusion
      protein in non-Hodgkin's lymphoma.
AB  - Pretargeted radioimmunotherapy (PRIT) decreases the amount of time that
      radioactivity non-selectively circulates. Our PRIT approach is a multi-step
      method in which a monoclonal antibody is used to target streptavidin to a tumor
      associated antigen and biotin is then used to target 90Y to the streptavidin. A
      genetically engineered antibody streptavidin fusion construct was used to target
      tumor in a patient with non-Hodgkin's lymphoma. Impressive localization of 90Y to
      known and previously unknown areas of adenopathy was observed, thus demonstrating
      that a genetically engineered fusion protein can selectively target lymphoma
      cells as part of a clinically meaningful PRIT strategy.

PMID- 12481895
TI  - Effectiveness of local radiotherapy in primary extranodal marginal zone B-cell
      lymphoma of MALT or MALT lymphoma of conjunctiva: study of four cases.
AB  - Primary lymphomas of the conjunctiva are extremely infrequent and usually belong
      to extranodal marginal zone B-cell lymphoma of MALT or MALT lymphoma.
      Radiotherapy with lens shielding is one of the most employed therapeutic options.
      Four patients with MALT lymphomas of the conjunctiva with complete and maintained
      response to radiotherapy are reported. The effectiveness as well as the lack of
      significant toxicity of radiotherapy are emphasized.

PMID- 12481896
TI  - Microsatellite instability in hematological malignancies.
AB  - The replication error (RER+) phenotype, characterized by microsatellite
      instability (MSI) has been recently related to mutations of genes involved in DNA
      mismatch repair pathway. These genetic alterations were first described in
      hereditary non polyposis colorectal cancer (HNPCC). We examined 44 patients with
      hematological malignancies (27 AML, 9 MDS, 2 CML-BP and 6 T-ALL) for evidence of
      MSI. Twenty seven percent of our patients showed differences for only one marker.
      In four cases (9.1%) MSI was observed in multiple markers and these cases were
      described as RER+ phenotype. Presented data suggest that this phenomenon may play
      a role in at least a subset of patients with hematological malignancies.

PMID- 12481897
TI  - Instability of CAG-trinucleotide repeats in chronic lymphocytic leukemia.
AB  - Anticipation--earlier onset and more severe disease in the offspring generation-
      is a well documented feature of familial chronic lymphocytic leukaemia (CLL). In
      a number of Mendelian diseases, anticipation is caused by expansion of contiguous
      triplets of nucleotides. The severity of disease expression and penetrance is
      related to the extent of the triplet expansion. To investigate whether repeat
      nucleotide repeat expansion is a feature of CLL, the repeat expansion detection
      (RED) technique was applied to samples from 17 patients with familial disease and
      32 patients with early-onset CLL disease. No potentially pathological CAG
      expansions were detected. We conclude that unstable CAG repeat expansion is not a
      feature of CLL and that other processes are likely to be involved in generating
      anticipation in familial forms of the disease.

PMID- 12481898
TI  - Comparative antiproliferative and apoptotic effects of resveratrol, epsilon
      viniferin and vine-shots derived polyphenols (vineatrols) on chronic B
      lymphocytic leukemia cells and normal human lymphocytes.
AB  - Trans-resveratrol, its dimer epsilon-viniferin and two preparations of vineatrol
      (a grape-derived polyphenol fraction isolated from vine-shots extracts) were
      compared for their effects on the proliferation and survival of normal and
      leukemic human lymphocytes. The two different batches of vineatrol (vineatrol 10
      and 25%) was obtained by HPLC fractionation and contained 10 and 25% trans
      resveratrol, respectively. The different polyphenols were added to cultures of
      leukemic cells from chronic B cell malignancies (B-cell chronic lymphocytic
      leukemia, B-CLL or hairy cell leukemia, HCL) or normal peripheral blood-derived
      mononuclear cells (PBMC) as a control. The different polyphenols displayed anti
      proliferative effect on the leukemic cells, as estimated by the observed
      inhibition of tritiated thymidine uptake and the reduction of cell recovery.
      Vineatrol 10% was the most potent whereas vineatrol 25% and resveratrol displayed
      comparable activity, epsilon-viniferin only exhibiting slight effets. The same
      order of potency was observed for their capacity to induce apoptosis in leukemic
      B cells. In contrast, the survival of normal peripheral blood mononuclear cells
      (PBMC) was little affected in the presence of these polyphenolic compounds and
      higher concentrations were required in order to elicit cell death. Polyphenol
      driven apoptosis in chronic leukemic B cells was shown to correlate with an
      activation of caspase 3, a drop in the mitochondrial transmembrane potential, a
      reduction in the expression of the anti-apoptotic protein bcl-2, as well as a
      reduction in the expression of the inducible nitric oxide synthase (iNOS). Our
      data therefore indicate that vine-shoots may be a convenient and natural source
      of material for the purification of resveratrol and other polyphenolic compounds
      of putative therapeutic interest.

PMID- 12481899
TI  - Antisense oligonucleotides complementary to Bax transcripts reduce the
      susceptibility of B-cell chronic lymphocytic leukaemia cells to apoptosis in a
      bcl-2 independent manner.
AB  - Our previous work demonstrated that antisense oligonucleotides complementary to
      Bcl-2 mRNA sequences were able to reduce Bcl-2 protein expression in B-cell
      chronic lymphocytic leukaemia (B-CLL) cells. Furthermore, the reduction in Bcl-2
      expression led to an increase in apoptotic cell death that was associated with an
      increase in Bax expression. In this present study antisense oligonucleotides
      directed towards the Bax translation initiation sequence were employed to
      determine whether Bcl-2 and Bax protein expression were interdependent upon one
      another and whether Bcl-2 antisense-induced apoptosis was mediated through a p53
      dependent cell death pathway. The antisense oligonucleotide down-regulated Bax
      protein expression between 23.7 and 68.8% in the 20 B-CLL samples tested and
      significantly inhibited apoptotic cell death when compared to controls (p =
      0.0001). Furthermore, these changes were independent of Bcl-2 expression
      suggesting that the previously observed increase in Bax expression following
      exposure of B-CLL cells to Bcl-2 antisense oligonucleotides was probably caused
      by the induction of apoptosis rather than a rheostatic response to the reduction
      in Bcl-2 protein expression. This notion was substantiated by the fact that p21
      expression was induced in Bcl-2 antisense-treated B-CLL cells, a finding
      consistent with p53 activation.

PMID- 12481900
TI  - Regulation of alloresponses after bone marrow transplantation using donor T cells
      expressing a thymidine kinase suicide gene.
AB  - Donor T cells have a critical role in promoting engraftment after allogeneic bone
      marrow transplantation (BMT), but also cause graft versus host disease (GVHD). Ex
      vivo T cell depletion has been an effective strategy to reduce GVHD but has been
      associated with impaired alloengraftment and host immunity. Using an MHC
      mismatched murine model, we have examined an alternative approach to GVHD
      prevention whereby donor T cells are selectively eliminated in vivo after BMT
      using transgenic T cells in which a thymidine kinase (TK) suicide gene is
      targeted to the T cell. Lethally irradiated AKR/J (H-2k) mice transplanted with
      TCD C57BL/6 (B6)(H-2b) bone marrow (BM) plus B6 TK+ T cells and then treated with
      GCV post-BMT had significantly less GVHD severity and improved immune
      reconstitution compared to untreated mice, providing proof of principle that this
      strategy could mitigate GVHD. To assess the impact of GCV administration on
      alloengraftment, sublethally irradiated AKR mice were transplanted with TCD B6 BM
      alone or admixed with limiting numbers (5 x 10(5)) of B6 TK+ T cells. When tested
      3-4 weeks post-transplant, control TCD BM mice all rejected their grafts.
      Conversely, > 80% of GCV-treated mice had sustained donor T cell engraftment
      comparable to what was observed in untreated animals. Notably, GCV-treated mice
      were more likely to have mixed T cell chimerism early post-BMT than untreated
      animals, however, nearly all GCV-treated mice progressed to complete donor T cell
      engraftment by 2-3 months post-transplant. Preservation of engraftment was
      critically dependent upon the GCV administration schedule and required that GCV
      be delayed for at least one week post-transplant. These studies demonstrate that
      specific incorporation of a suicide gene into donor T cells is a viable strategy
      that can be employed to reduce GVHD without compromising alloengraftment.

PMID- 12481901
TI  - Telomere length in haemopoietic stem cells can be determined from that of
      mononuclear blood cells or whole blood.
AB  - Telomere length can be used to predict the replicative capacity of haematological
      progenitor cells and may be an important prognostic factor for the onset of
      cellular immune dysfunction. However, such measurements require invasive bone
      marrow (BM) biopsies and laborious stem cell isolations that are impractical in a
      clinical setting. Previous studies have used peripheral blood (PB) cells as an
      indicator of stem cell telomere length without demonstrating a correlation. In
      this study, we examined the telomere length in PB, isolated mononuclear cells
      (MNC) and BM aspirates from each of 19 patients ranging in age from 45 to 81
      years. Correlation analysis confirmed that mean telomere length of BM aspirates
      was equivalent to that of PB (r = 0.85, P < 0.001), or MNC (r = 0.94, P < 0.001).
      Since BM is a heterogeneous population of cells, we have also shown in 13
      separate patients that the mean telomere length in isolated peripheral blood stem
      cell (PBSC) harvests was equivalent to that of isolated CD34+ stem cells (r =
      0.83, P < 0.001). Thus, telomere length in haemopoietic stem cells can be
      determined from that of whole or fractionated PB in future studies of
      haematological disorders.

PMID- 12481902
TI  - Molecular analysis of a new variant of the CBF beta-MYH11 gene fusion.
AB  - The inv(16)(p13q22) is observed in 16% of patients with acute myelogenous
      leukemia (AML). It is classically found in the AML M4Eo subtype, which has
      distinctive morphological abnormalities in the bone marrow including
      myelomonocytic differentiation and an increase in atypical bone marrow
      eosinophils. A gene fusion involving CBFbeta and MYH11 is invariably created by
      the inv(16)(p13q22) and is thought to be a necessary genetic lesion in this form
      of leukemia. The most common fusion point occurs at CBFbeta nucleotide (nt) 495
      and MYH11 nt 1921; however, several rare variants have been described. We report
      a patient with AML M4Eo whose leukemic cells contained two distinct CBFbeta-MYH11
      transcripts, one rare and the other previously undescribed. Both gene fusion
      products were cloned and sequenced and the breakpoints were identified. These
      were at CBFbeta nt 495 and MYH11 nt 994 and CBFbeta nt486 and MYH11 nt 1591. The
      CBFbeta(495)/MYH11(994) fusion is seen in 5-7% of AML M4Eo, while the
      CBFbeta(486)/MYH11(1591) fusion is novel. We postulate that these two fusions
      arose from a single rearranged chromosome 16 by way of alternative splicing.
      These fusions were associated with a good prognosis in this patient. Molecular
      diagnostic facilities should be aware of the existence of the
      CBFbeta(486)/MYH11(1591) variant and its potential association with the
      previously described type E fusion.

PMID- 12481903
TI  - Acute myelogenous leukemia with internal tandem duplication of the Flt3 gene
      appearing or altering at the time of relapse: a report of two cases.
AB  - Detection of Flt3-internal tandem duplication (ITD) in acute myelogenous leukemia
      (AML) blasts at the time of diagnosis is associated with an increased risk of
      leukemia relapse after chemotherapy. In the present report, we describe two
      patients with Flt3-abnormalities that were only detectable at the time of
      relapse. One of the patients had an ITD at the time of diagnosis (duplicated
      region 41-133 numbered from the start of exon 14 plus CGG insertion), but at the
      time of relapse a new abnormality (duplicated region 70-230 plus insertion
      GGGGAGT) was detected as the only Flt3-abnormality. The second patient showed no
      Flt3-ITD at the time of diagnosis, but ITD was detected at the time of relapse
      (duplicated region 12-96, no insertion). Our observations of independent Flt3-ITD
      and the detection of new Flt3-abnormalities at the time of relapse suggest that
      (i) Flt3-gene abnormalities may be even more important in the pathogenesis of
      chemotherapy-resistant AML than suggested from previous studies of newly
      diagnosed AML, and (ii) monitoring of minimal residual disease by using patient
      specific real-time polymerase chain reaction assays for Flt3-abnormalities may
      not be reliable.

PMID- 12481905
TI  - Cavernous sinus involvement by extramedullary plasmacytoma of the sphenoid sinus.
      An argument for the use of adjuvant chemotherapy.
AB  - A 63-year-old man with cavernous sinus involvement from extramedullary
      plasmacytoma (EMP) of the sphenoid sinus is described. Transient resolution of
      retro-orbital headache and continued progression of the locally extensive tumor
      were noted after chemotherapy was given following a poor response to 5400 cGy of
      local irradiation. To determine whether adjunctive chemotherapy will improve the
      outcome of these particular patients, we propose that a randomized trial
      comparing radiotherapy to chemoradiation be conducted.

PMID- 12481904
TI  - Variations in MLL amplification in a patient with acute myeloid leukemia.
AB  - In a 66 years old female patient with acute myeloblastic leukemia (AML) complex
      chromosomal rearrangements involving 11q23 were diagnosed by G-banding and
      confirmed by different fluorescence in situ hybridization (FISH) techniques. The
      amplification of MLL gene differed in various sidelines as shown by locus
      specific probes for 11q23 and 11q13. Complex karyotype rearrangements involving
      deletions del(5)(q31) and del(7)(q31) were verified by multicolor fluorescence in
      situ hybridization (mFISH).

PMID- 12481906
TI  - Langerhans cell histiocytosis in a patient with systemic lupus erythematosus: a
      clonal disease responding to treatment with cladribine, and cyclophosphamide.
AB  - Langerhans cell histiocytosis (LCH) is a rare neoplastic disease of specific
      dendritic cells which belong to the monocyte-macrophage system. The association
      of LCH with autoimmune disease is extremely rare and to our knowledge its
      coexistence with systemic lupus erythematosus (SLE) has not been described so
      far. We report a case of LCH affecting liver, spleen and abdomen lymph nodes,
      which developed in an adult female six years after diagnosis of SLE treated for a
      long time with prednisone. Histology showed infiltration of characteristic
      Langerhans cells with folded, grooved or lobulated nuclei with fine chromatin. In
      the background there were eosinophils, lymphocytes and CD-68-positive
      histiocytes. The neoplastic cells were S100p-immunopositive, but stained
      negatively for CD1a--probably as the result of overfixation of consulted
      material. CD-68 was present mostly in macrophages. Ultrastructurally, the tumour
      cells presented structures consistent with Birbeck granules. Clonal origin of
      neoplastic cells was shown using the HUMARA-PCR assay. The disease was refractory
      to treatment with high doses of prednisone and vincristine but complete response
      was achieved after treatment with caldribine combined with cyclophosphamide.

PMID- 12481907
TI  - EBV associated hemophagocytic syndrome accompanied by central pontine
      myelinolysis.
AB  - The development of central pontine myelinolysis (CPM) has rarely been reported in
      association with hemophagocytic syndromes (HPS). Here we report a unique case of
      Epstein-Barr Virus (EBV)-related HPS which was accompanied with CPM. A 72-year
      old man who had no significant medical history was admitted to our hospital due
      to high fever and progressing dysphasia and dysarthria. Physical examination
      revealed anisocoria of the right pupil, fixed reaction to light, and paralysis of
      the left vagus nerves. Magnetic resonance imaging revealed low signal intensity
      on T1-weighted images and high signal intensity T2-weighted images in the
      patient's central midpontine lesion. Initial work-up showed anemia and
      thrombocytopenia with elevated levels of serum ferritin, lactate dehydrogenase,
      and soluble IL-2 receptor. Bone marrow aspiration revealed hemophagocytosis. The
      EBV genome was detected in the peripheral blood using the polymerase chain
      reaction method. He was diagnosed as having EBV-related HPS and CPM. Despite
      intensive treatment with methylpredonisolone, immunoglobulin, and etoposide, he
      died due to progressive disease and fungal septicemia. The etiology and relation
      between CPM and HPS are discussed.

PMID- 12481908
TI  - Allogeneic bone marrow transplantation in the management of chronic neutrophilic
      leukemia.
AB  - Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder
      characterized by a clonal proliferation of mainly mature neutrophils, which is
      often difficult to differentiate from reactive leukocytosis or other
      myeloproliferative disorders. Treatment to date has focused on disease control
      rather than cure. Once the disease has progressed to a more aggressive leukemia
      there is typically little chance of obtaining a long lasting remission due to the
      older age of most patients as well as the acquisition of multiple poor prognostic
      cytogenetic abnormalities. In this case report we describe a successful sibling
      allogeneic bone marrow transplant in a 60-year-old man with CNL performed while
      he was still in the stable phase of his disease. We propose that even in older
      patients this curative approach may be considered in selected patients at an
      early stage of their disease, similar to the approach taken with chronic
      myelogenous leukemia.

PMID- 12481909
TI  - Diffuse large B-cell non-Hodgkin's lymphoma presenting as Sister Joseph's nodule.
AB  - Traditionally associated with intra-abdominal epithelial tumours, umbilical
      metastases (known eponymously as "Sister Joseph's nodules") are often thought to
      represent advanced malignancy with dismal prognosis. Lymphomas are rare causes of
      umbilical metastases, with no cases reported prior to 1966 and only three cases
      since. We describe a patient who presented with diffuse large B-cell non
      Hodgkin's lymphoma with "signet ring" morphology manifesting as a "Sister
      Joseph's nodule", who had an excellent response to systemic therapy, with no
      detectable disease at 12 months post-completion of therapy. Our experience with
      this patient highlights the need for accurate histological diagnosis in all
      umbilical metastases, and dispels the widely held assumption that "Sister
      Joseph's nodules" represent disseminated malignancy beyond the realm of effective
      therapy. The patient's unusual histology and pattern of disease involvement are
      also discussed.

PMID- 12481910
TI  - Parvovirus-B19 infection preceding acute myeloid leukemia with orbital
      granulocytic sarcoma.
AB  - We report here an unusual presentation of acute nonlymphoblastic leukemia with
      ocular granulocytic sarcoma who was firstly diagnosed iron deficiency anemia and
      acute parvovirus infection induced erythroid hypoplasia. To our knowledge this is
      the first paper of acute myeloblastic leukemia (AML) with granulocytic sarcoma,
      preceded by acute Parvovirus B19 infection.

PMID- 12481911
TI  - Marked thrombocytosis following relapse of acute myeloblastic leukemia associated
      with development of translocation (2;14) (p13;q32).
AB  - Thrombocytosis is a rare finding in acute myeloblastic leukemia (AML). Here, we
      describe a patient with AML who relapsed with marked thrombocytosis. The patient
      was initially diagnosed as having AML (M4) with a low platelet count. The patient
      was started on combination chemotherapy including high-dose etoposide and
      achieved complete remission. However, the patient relapsed six months later with
      an extremely high platelet count (72.5 x 10(4)/microl). Cytogenetic analysis at
      relapse revealed the development of t(2;14)(p13;q32). Despite the repeated
      combination chemotherapy, the patient died with progressive disease. This case
      suggests that the additional chromosomal aberration t(2;14)(p13;q32) may be
      related to abnormal thrombocytosis in AML.

PMID- 12481912
TI  - Successful HLA-identical unrelated allogeneic bone marrow transplantation with a
      very low dose of stem cells for a patient with chronic myeloid leukemia in blast
      crisis.

PMID- 12481913
TI  - Legitimizing fluvial ecosystems as users of water: an overview.
AB  - We suggest that fluvial ecosystems are legitimate users of water and that there
      are basic ecological principles guiding the maintenance of long-term ecological
      vitality. This article articulates some fundamental relationships between
      physical and ecological processes, presents basic principles for maintaining the
      vitality of fluvial ecosystems, identifies several major scientific challenges
      and opportunities for effective implementation of the basic ecological
      principles, and acts as an introduction to three specific articles to follow on
      biodiversity, biogeochemistry, and riparian communities. All the objectives, by
      necessity, link climate, land, and fresh water. The basic principles proposed
      are: (1) the natural flow regime shapes the evolution of aquatic biota and
      ecological processes, (2) every river has a characteristic flow regime and an
      associated biotic community, and (3) aquatic ecosystems are topographically
      unique in occupying the lowest position in the landscape, thereby integrating
      catchment-scale processes. Scientific challenges for the immediate future relate
      to quantifying cumulative effects, linking multidisciplinary knowledge and
      models, and formulating effective monitoring and assessment procedures.
      Additionally, forecasting the ecological consequences of changing water regimes
      is a fundamental challenge for science, especially as environmental issues
      related to fresh waters escalate in the next two to three decades.

PMID- 12481914
TI  - Basic principles and ecological consequences of changing water regimes: riparian
      plant communities.
AB  - Recent research has emphasized the importance of riparian ecosystems as centers
      of biodiversity and links between terrestrial and aquatic systems. Riparian
      ecosystems also belong among the environments that are most disturbed by humans
      and are in need of restoration to maintain biodiversity and ecological integrity.
      To facilitate the completion of this task, researchers have an important function
      to communicate their knowledge to policy-makers and managers. This article
      presents some fundamental qualities of riparian systems, articulated as three
      basic principles. The basic principles proposed are: (1) The flow regime
      determines the successional evolution of riparian plant communities and
      ecological processes. (2) The riparian corridor serves as a pathway for
      redistribution of organic and inorganic material that influences plant
      communities along rivers. (3) The riparian system is a transition zone between
      land and water ecosystems and is disproportionately plant species-rich when
      compared to surrounding ecosystems. Translating these principles into management
      directives requires more information about how much water a river needs and when
      and how, i.e., flow variables described by magnitude, frequency, timing,
      duration, and rate of change. It also requires information about how various
      groups of organisms are affected by habitat fragmentation, especially in terms of
      their dispersal. Finally, it requires information about how effects of hydrologic
      alterations vary between different types of riparian systems and with the
      location within the watershed.

PMID- 12481915
TI  - Basic principles and ecological consequences of changing water regimes on
      nitrogen cycling in fluvial systems.
AB  - Understanding the environmental consequences of changing water regimes is a
      daunting challenge for both resource managers and ecologists. Balancing human
      demands for fresh water with the needs of the environment for water in
      appropriate amounts and at the appropriate times are shaping the ways by which
      this natural resource will be used in the future. Based on past decisions that
      have rendered many freshwater resources unsuitable for use, we argue that river
      systems have a fundamental need for appropriate amounts and timing of water to
      maintain their biophysical integrity. Biophysical integrity is fundamental for
      the formulation of future sustainable management strategies. This article
      addresses three basic ecological principles driving the biogeochemical cycle of
      nitrogen in river systems. These are (1) how the mode of nitrogen delivery
      affects river ecosystem functioning, (2) how increasing contact between water and
      soil or sediment increases nitrogen retention and processing, and (3) the role of
      floods and droughts as important natural events that strongly influence pathways
      of nitrogen cycling in fluvial systems. New challenges related to the cumulative
      impact of water regime change, the scale of appraisal of these impacts, and the
      determination of the impacts due to natural and human changes are discussed. It
      is suggested that cost of long-term and long-distance cumulative impacts of
      hydrological changes should be evaluated against short-term economic benefits to
      determine the real environmental costs.

PMID- 12481916
TI  - Basic principles and ecological consequences of altered flow regimes for aquatic
      biodiversity.
AB  - The flow regime is regarded by many aquatic ecologists to be the key driver of
      river and floodplain wetland ecosystems. We have focused this literature review
      around four key principles to highlight the important mechanisms that link
      hydrology and aquatic biodiversity and to illustrate the consequent impacts of
      altered flow regimes: Firstly, flow is a major determinant of physical habitat in
      streams, which in turn is a major determinant of biotic composition; Secondly,
      aquatic species have evolved life history strategies primarily in direct response
      to the natural flow regimes; Thirdly, maintenance of natural patterns of
      longitudinal and lateral connectivity is essential to the viability of
      populations of many riverine species; Finally, the invasion and success of exotic
      and introduced species in rivers is facilitated by the alteration of flow
      regimes. The impacts of flow change are manifest across broad taxonomic groups
      including riverine plants, invertebrates, and fish. Despite growing recognition
      of these relationships, ecologists still struggle to predict and quantify biotic
      responses to altered flow regimes. One obvious difficulty is the ability to
      distinguish the direct effects of modified flow regimes from impacts associated
      with land-use change that often accompanies water resource development.
      Currently, evidence about how rivers function in relation to flow regime and the
      flows that aquatic organisms need exists largely as a series of untested
      hypotheses. To overcome these problems, aquatic science needs to move quickly
      into a manipulative or experimental phase, preferably with the aims of
      restoration and measuring ecosystem response.

PMID- 12481917
TI  - Section 404 wetland mitigation and permit success criteria in Pennsylvania, USA,
      1986-1999.
AB  - Twenty-three Section 404 permits in central Pennsylvania (covering a wetland age
      range of 1-14 years) were examined to determine the type of mitigation wetland
      permitted, how the sites were built, and what success criteria were used for
      evaluation. Most permits allowed for mitigation out-of-kind, either vegetatively
      or through hydrogeomorphic class. The mitigation process has resulted in a shift
      from impacted wetlands dominated by woody species to less vegetated mitigation
      wetlands, a trend that appears to be occurring nationwide. An estimate of the
      percent cover of emergent vegetation was the only success criterion specified in
      the majority of permits. About 60% of the mitigation wetlands were judged as
      meeting their originally defined success criteria, some after more than 10 years.
      The permit process appears to have resulted in a net gain of almost 0.05 ha of
      wetlands per mitigation project. However, due to the replacement of emergent,
      scrub-shrub, and forested wetlands with open water ponds or uplands, mitigation
      practices probably led to a net loss of vegetated wetlands.

PMID- 12481918
TI  - Riparian livestock exclosure research in the western United States: a critique
      and some recommendations.
AB  - Over the last three decades, livestock exclosure research has emerged as a
      preferred method to evaluate the ecology of riparian ecosystems and their
      susceptibility to livestock impacts. This research has addressed the effects of
      livestock exclusion on many characteristics of riparian ecosystems, including
      vegetation, aquatic and terrestrial animals, and geomorphology. This paper
      reviews, critiques, and provides recommendations for the improvement of riparian
      livestock exclosure research. Exclosure-based research has left considerable
      scientific uncertainty due to popularization of relatively few studies, weak
      study designs, a poor understanding of the scales and mechanisms of ecosystem
      recovery, and selective, agenda-laden literature reviews advocating for or
      against public lands livestock grazing. Exclosures are often too small (<50 ha)
      and improperly placed to accurately measure the responses of aquatic organisms or
      geomorphic processes to livestock removal. Depending upon the site conditions
      when and where livestock exclosures are established, postexclusion dynamics may
      vary considerably. Systems can recover quickly and predictably with livestock
      removal (the "rubber band" model), fail to recover due to changes in system
      structure or function (the "Humpty Dumpty" model), or recover slowly and remain
      more sensitive to livestock impacts than they were before grazing was initiated
      (the "broken leg" model). Several initial ideas for strengthening the scientific
      basis for livestock exclosure research are presented: (1) incorporation of meta
      analyses and critical reviews. (2) use of restoration ecology as a unifying
      conceptual framework; (3) development of long-term research programs; (4)
      improved exclosure placement/ design; and (5) a stronger commitment to collection
      of pretreatment data.

PMID- 12481919
TI  - Residential water consumption, motivation for conserving water and the continuing
      tragedy of the commons.
AB  - This paper explores the effect of the perception of externalities (PE) on
      residential water consumption. Externalities occur when individuals make
      decisions that harm others, without concern for the impact or feeling a need to
      compensate for the harm. The aim of this study was to investigate whether PE
      affects people's motivation to conserve water, and, consequently, the practice of
      residential water consumption. Two hundred eighty Mexican citizens responded to a
      questionnaire investigating how they perceived that other individuals in their
      community wasted water. Respondents were also asked about their motives to
      conserve water, and direct observations of individual water consumption were
      recorded. Results were processed within a structural equations model, which
      revealed that motives to conserve water significantly inhibit water consumption.
      Since the perception of extemalities also inhibits conservation motives, the
      resulting effect of PE on water consumption is positive. This result means that
      the more people perceive that others waste water, the less their conservation
      motives, and, therefore, the more their own water consumption.

PMID- 12481920
TI  - Methods of compliance evaluation for ocean outfall design and analysis.
AB  - Sewage discharge from an ocean outfall is subject to water quality standards,
      which are often stated in probabilistic terms. Monte Carlo simulation (MCS) has
      been used in the past to evaluate the ability of a designed outfall to meet water
      quality standards or compliance guidelines associated with sewage discharges. In
      this study, simpler and less computer-intensive probabilistic methods are
      considered. The probabilistic methods evaluated are the popular mean first-order
      second-moment (MFOSM) and the advance first-order second-moment (AFOSM) methods.
      Available data from the Spaniard's Bay Outfall located on the east coast of New
      foundland, Canada, were used as inputs for a case study. Both methods were
      compared with results given by MCS. It was found that AFOSM gave a good
      approximation of the failure probability for total coliform concentration at
      points remote from the outfall. However, MFOSM was found to be better when
      considering only the initial dilutions between the discharge point and the
      surface. Reasons for the different results may be the difference in complexity of
      the performance function in both cases. This study does not recommend the use of
      AFOSM for failure analysis in ocean outfall design and analysis because the
      analysis requires computational efforts similar to MCS. With the advancement of
      computer technology, simulation techniques, available software, and its
      flexibility in handling complex situations, MCS is still the best choice for
      failure analysis of ocean outfalls when data or estimates on the parameters
      involved are available or can be assumed.

PMID- 12481921
TI  - Comparative influence of forest management and habitat structural factors on the
      abundances of hollow-nesting bird species in subtropical Australian eucalypt
      forest.
AB  - We examined the impact of single-tree selective logging and fuel reduction burns
      on the abundance of hollow-nesting bird species at a regional scale in
      southeastem Queensland, Australia. Data were collected on species abundance and
      habitat structure of dry sclerophyll production forest at 36 sites with known
      logging and fire histories. Sixteen bird species were recorded with most being
      resident, territorial, obligate hollow nesters that used hollows that were either
      small (< 10 cm diameter) or very large (>18 cm diameter). Species densities were
      typically low, but combinations of two forest management and three habitat
      structural variables influenced the abundances of eight bird species in different
      and sometimes conflicting ways. The results suggest that habitat tree management
      for biodiversity in production forests cannot depend upon habitat structural
      characteristics alone. Management histories appear to have independent influence
      (on some bird species) that are distinguishable from their impacts on habitat
      structure per se. Rather than managing to maximize species abundances to maintain
      biodiversity, we may be better off managing to avoid extinctions of populations
      by identifying thresholds of acceptable fluctuations in populations of not only
      hollow-nesting birds but other forest dependent wildlife relative to
      scientifically valid forest management and habitat structural surrogates.

PMID- 12481922
TI  - An environmental assessment of food supply chains: a case study on dessert
      apples.
AB  - The contemporary food system provides consumers with convenience, extensive
      choice, and the year-round availability of fresh produce. In this paper these
      achievements are recognized within the context of the associated environmental
      impacts. While many analyses have considered the energy and material efficiency
      of various options for food production and packaging, very few studies have
      investigated the environmental impacts of the transport components of food supply
      chains. This is surprising, given that the global sourcing of food produce,
      centralized distribution systems, and shopping by car have become prevalent in
      recent decades and have contributed to an increase in the distance between
      producer and consumer or "food miles." In a case study the transport energy
      consumption is calculated for all possible ways in which dessert apples can be
      supplied to the UK consumer. The aim is to assess the environmental performance
      of the predominant fresh produce supply chains and to investigate claims that
      localized systems are more environmentally efficient. The main criteria used to
      compare the environmental efficiency in alternative food supply chains are the
      transport-related fossil-fuel energy consumption and associated carbon dioxide
      emissions. Analysis of the empirical data shows that transportation is now
      responsible for a considerable fraction of the total energy consumption in the
      life cycle of fresh apples, and in most cases exceeds the energy consumed in
      commercial apple cultivation. By developing local production and marketing
      systems for fresh products, transport demand can be reduced and many of the
      environmental impacts associated with existing supply chains can be avoided. The
      results of the study are then discussed in relation to the wider issues of
      transport policy, international trade, food security, and product-related
      environmental information for consumers.

PMID- 12481923
TI  - Factors affecting private forest landowner interest in ecosystem management:
      linking spatial and survey data.
AB  - Many factors influence forest landowner management decisions. This study examines
      landowner decisions regarding participation in ecosystem management activities,
      such as a landscape corridor cutting across their private lands. Landscape
      corridors are recognized worldwide as an important tool in biodiversity
      conservation. For ecosystem management activities to occur in areas dominated by
      a multitude of small private forest landholdings, landowner participation and
      cooperation is necessary. Data from a survey of landowners combined with an
      analysis of their land's spatial attributes is used to assess their interest in
      ecosystem management. Results suggest that spatial attributes are not good
      predictors of an owner's interest in ecosystem management. Other factors such as
      attitudes and opinions about the environment are more effective in explaining
      landowner interest. The results have implications for any land manager using GIS
      data and implementing ecosystem management activities on private forestland.

PMID- 12481924
TI  - Cross-boundary cooperation in a watershed context: the sentiments of private
      forest landowners.
AB  - Ecosystem management and sustainable forestry on mixed ownership landscapes will
      require some level of cross-boundary coordination or management. Oregon's
      experiment with local, voluntary, collaborative forums, called watershed
      councils, is one mechanism to foster cross-boundary management. Fifty
      qualitative, in-depth interviews in three study areas were conducted with
      nonindustrial private forest (NIPF) landowners, watershed council members, and
      agency employees to learn how and why landowners participate (or not) on
      watershed councils. Study areas were located in three different areas of the
      state to reflect different ecological and organizational settings. Our case study
      identified three themes-stewardship ethic, property rights amid uncertainty, and
      action orientation-that were most salient among landowners when deciding to
      participate in their local watershed council. Other factors related to competing
      opportunities were also identified. Our results relate to the social
      psychological antecedents to cooperation of perceived consensus, group identity,
      and legitimacy of authority as well as to applied situations where cross-boundary
      coordination and management are goals.

PMID- 12481925
TI  - Neuroendocrine function and chronic inflammatory stress.
AB  - The factors regulating susceptibility and severity of autoimmune diseases are
      poorly understood. That neuroendocrine factors are critical modulators in this
      regard is self-evident. For example, there are major gender differences in
      susceptibility with women at greater risk than men of, for example, rheumatoid
      arthritis (RA) and multiple sclerosis (MS). The hypothalamo-pituitary-adrenal
      (HPA) axis has rightly attracted a considerable amount of attention. Of
      particular interest has been the hypothesis that susceptibility to autoimmune
      disease may be related to an impaired responsiveness of the HPA axis; that is, an
      inability to mount an appropriate cortisol response with which to down-regulate
      the immune system might allow the immune system to rampage unchecked and attack
      self. This hypothesis links regulation of the release from the adrenal gland of
      the potent anti-inflammatory glucocorticoids to the disease process. Endogenous
      glucocorticoids are crucial for the regulation of the severity of the disease
      process. The hypothesis proposing a link between a hyporesponsive HPA axis and
      susceptibility to disease is compelling. However, evidence from a number of
      sources has suggested that this may not be the entire story and alterations in
      the activity of the HPA axis have not been consistently observed in patients with
      RA. This review will concentrate on recent findings concerning the HPA axis in
      determining susceptibility to, and in regulating the severity of, inflammatory
      processes in autoimmune disease. These studies have revealed that a single
      exposure to endotoxin can confer protection to subsequent development of
      inflammation in an arthritis model in both neonatal and adult rats. Behavioural
      differences within a single population of rats are associated with differences in
      the plasma corticosterone responses to stress. However, relative
      hyporesponsiveness is not reflected by an increase in the severity of
      inflammation. In humans with RA the dexamethasone-corticotrophin-releasing factor
      (CRF) test has revealed two distinct sub-populations of patients. Studies in
      patients with MS have shown that this is not related to depression but rather to
      the severity of the disease. A better understanding of these complex
      neuroendocrine interactions may lead to novel clinical interventions.

PMID- 12481926
TI  - Arterial myogenic properties of the spontaneously hypertensive rat.
AB  - When subject to a transmural pressure gradient resistance arteries develop a
      spontaneous, intrinsically initiated contraction which varies according to the
      pressure stimulus and occurs in the absence of vasoconstrictor agonists. Such
      pressure-dependent active changes in vascular tone are indicative of the vascular
      myogenic response and contribute to autoregulation and the setting of total
      peripheral resistance and hence blood pressure regulation. The myogenic behaviour
      of blood vessels provides the background tone upon which other vasomotor
      influences act. Hypertension is associated with a raised vascular resistance and
      in this article the evidence for increased myogenic activity contributing to the
      raised vascular resistance is reviewed. Although there are some cases that
      provide evidence for exaggerated myogenic responsiveness in resistance arteries
      taken from hypertensive animals it is not possible to conclude that enhanced
      myogenic contractile responses within normal pressure ranges contribute to the
      raised total peripheral resistance. However, the myogenic tone of the resistance
      arteries of the various vascular beds is subject to differing modulatory
      influences in hypertensive animals and their normotensive controls which may
      contribute to the aetiology of hypertension.

PMID- 12481927
TI  - A simple method for generating a blood pressure-unit activity relationship for
      central cardiovascular neurons in the rat.
AB  - One way to identify central cardiovascular neurons is to consider their
      barosensitivity, for example by plotting changes in their single unit activity as
      a function of evoked changes in blood pressure. To simplify the genesis of such
      pressure-activity relationships, a coronary angioplasty catheter was threaded
      into the aorta of anaesthetized rats and the balloon inflated to raise the blood
      pressure mechanically. Here, such a procedure is exemplified for cardiac vagal
      motoneurons in the medulla oblongata in eight rats. This simplification bypasses
      potentially problematic surgery and minimizes deterioration of the animal.

PMID- 12481928
TI  - Early myocardial fibrosis is associated with depletion of vasoactive intestinal
      peptide in rat heart.
AB  - In this study we sought to determine whether early myocardial fibrosis is
      associated with depletion of vasoactive intestinal peptide (VIP) in the heart,
      thereby suggesting a possible pathogenetic role for depletion of myocardial VIP
      levels in the development of fibrosis in the heart. Spontaneously hypertensive
      rats (SHRs) and normotensive control Wistar-Kyoto rats (WKYs) were assigned
      randomly to low, intermediate or high sodium diets and their blood pressure was
      recorded twice weekly for 4 weeks. At the end of this period the rats were
      anaesthetised, blood was sampled for plasma VIP concentration and the hearts were
      harvested for histology and determination of the concentration of VIP in the
      heart. The degree of myocardial fibrosis increased with increasing dietary sodium
      intake in both the WKYs (P < 0.001) and the SHRs (P < 0.01). Myocardial VIP
      concentration decreased with increasing dietary sodium intake in the WKYs (P <
      0.01) and in the SHRs (P < 0.01). There was a negative correlation between
      myocardial VIP concentration and the degree of myocardial fibrosis in both the
      WKYs (P < 0.0005) and the SHRs (P < 0.005). Dietary sodium intake induces
      myocardial fibrosis in a dose-dependent manner. Further, in early myocardial
      fibrosis resulting from increasing dietary sodium intake in both normotensive and
      hypertensive rats the concentration of VIP in the heart was negatively correlated
      with the degree of fibrosis. This suggests a possible role for depletion of VIP
      in the myocardium in the pathogenesis of myocardial fibrosis.

PMID- 12481929
TI  - Myocardial infarction and cardiac remodelling in mice.
AB  - We established a mouse model of cardiac dysfunction due to myocardial infarction
      (MI). For this we ligated the left anterior descending coronary artery in male
      C57BL/6J mice and assessed healing and left ventricular (LV) remodelling at 1, 2
      and 4 days and 1, 2 and 4 weeks after MI. Echocardiography was performed at 1 and
      2 weeks and 1, 2, 4 and 6 months after MI. We found that neutrophil infiltration
      of the infarct border was noticeable at 1-2 days. Marked macrophage infiltration
      occurred at day 4, while lymphocyte infiltration was apparent at 7-14 days.
      Massive proliferation of fibroblasts and collagen accumulation began by day 7-14,
      and scar formation was completed by day 21. LV diastolic dimension increased
      markedly at 2 weeks and remained at the same level thereafter. LV shortening
      fraction decreased significantly at 2 weeks and then slowly decreased. In non
      infarcted areas of the LV, myocyte cross-sectional area and interstitial collagen
      fraction increased progressively, reaching a maximum at 4 months. This study
      provides important qualitative and quantitative information about the natural
      history of cardiac remodelling after MI in mice.

PMID- 12481930
TI  - Renal sympathetic nerves do not modulate renal responses to haemorrhage in
      conscious lambs.
AB  - The present study was designed to investigate the renal responses to hypotensive
      haemorrhage early in life and the role of renal sympathetic nerves in modulating
      these renal responses. To this end, experiments were carried out in conscious,
      chronically instrumented lambs with either intact renal nerves (n = 7, Intact) or
      bilateral renal denervation performed at the time of surgery (n = 5, Denervated).
      Parameters of renal function were measured before and after 20% haemorrhage
      (experiment 1) and 0% haemorrhage (experiment 2), the latter serving as a time
      control. The two experiments were performed in random order at intervals of 24-48
      h. Within 20 min of hypotensive haemorrhage in intact lambs, glomerular
      filtration rate decreased by approximately 60%; this response was not altered by
      renal denervation. Since renal plasma flow remained constant after haemorrhage,
      the filtration fraction also decreased. After 20% haemorrhage, urinary flow rate
      decreased in intact lambs; this response was also not altered by renal
      denervation. Excretion rates of Na+ and K+ as well as urinary osmolality and free
      water clearance were not altered by haemorrhage in either intact or denervated
      lambs. These data provide the first description of renal responses to haemorrhage
      early in life. In addition, the present findings provide new information that
      renal responses to haemorrhage early in life do not appear to be modulated by
      renal sympathetic nerves.

PMID- 12481931
TI  - An arterially perfused decerebrate preparation of Suncus murinus (house musk
      shrew) for the study of emesis and swallowing.
AB  - Arterially perfused, decerebrate preparations of the insectivore, Suncus murinus
      were made to determine whether the emetic reflex could be activated in such a
      preparation using a range of stimuli shown to be emetic in conscious or
      anaesthetised Suncus. Efferent phrenic and vagus nerve activities and
      electromyograms (EMGs) from the temporalis, abdominal oesophagus and trapezius
      muscles were recorded, as well as longitudinal shortening of the oesophagus and
      dorso-ventral movements of the thorax. The preparations swallowed spontaneously
      every 0.6 to 6.5 min. The duration of a swallow was 3.1 +/- 0.3 s (recorded as
      the time taken for the oesophagus to shorten and recover to its resting position)
      and the oesophagus shortened by 3.5 +/- 0.4 mm during a swallow. The emetic
      reflex was activated by electrical stimulation (30 Hz, 10-20 V, 0.2 ms pulse
      width, for 30 s) of abdominal vagal afferents (latency < 30 s) or by arterial
      perfusion with either 40 nM of the capsaicin analogue resiniferatoxin (latency
      1.7 +/- 0.6 min), 6 microM nicotine (latency 1.6 +/- 0.1 min) or 1 microM of the
      phosphodiesterase IV inhibitor CP-80,633 (latency 8.9 +/- 3.9 min). These emetic
      stimuli produced somatic and visceral movements in Suncus preparations indicative
      of activation of the emetic reflex. There were pronounced contractions of the
      thorax that occurred simultaneously with oesophageal shortening and mouth
      opening, separated by thorax expansion and a burst of phrenic nerve activity.
      During emetic-like episodes, oesophageal shortenings were only 0.84 +/- 0.1 s in
      duration, faster than the duration of shortening observed during swallowing (cf.
      swallowing, 3.1 +/- 0.3 s; P < 0.0001). The shortening of the oesophagus during
      emetic-like episodes was 6.2 +/- 0.4 mm, which was greater than the shortening
      seen during swallowing (cf. swallowing, 3.5 +/- 0.4 mm; P < 0.0001). We conclude
      that the emetic reflex can be activated in our Suncus preparations and that this
      non-sentient small adult animal model can now be used to study the
      neurophysiology and pharmacology of swallowing and emesis.

PMID- 12481932
TI  - Expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase slow (SERCA2) isoform in
      regenerating rat soleus skeletal muscle depends on nerve impulses.
AB  - We have examined the influence of innervation on the expression of different
      isoforms of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) in regenerating
      rat slow twitch muscle. The process of degeneration/regeneration was induced by
      injection of bupivacaine into rat soleus muscle under four different conditions:
      (1) in the presence of intact motor nerves, (2) after surgical denervation, (3)
      with nerve impulse conduction blocked by the Na(+)-channel blocker tetrodotoxin
      (TTX), and (4) with the axoplasmic flow blocked by vinblastine. Expression of
      SERCA isoforms was visualized by immunohistochemical and Western blot analysis.
      In regenerating innervated muscle, SERCA1, the isoform normally expressed in fast
      twitch fibres, was present after 5 days and was then progressively replaced by
      SERCA2, the isoform typical of slow twitch fibres. The maximum Ca(2+) uptake,
      measured in single skinned fibres regenerating for 10-21 days, was similar to
      that of slow adult fibres and significantly lower than that of fast adult fibres.
      Denervation or TTX treatment prevented the expression of the SERCA2 isoform.
      Conversely, vinblastine did not affect the expression of SERCA isoforms. These
      data indicate that nerve impulses play a determinant role in the expression of
      the SERCA2 isoform.

PMID- 12481933
TI  - Glucose infusion attenuates muscle fatigue in rat plantaris muscle during
      prolonged indirect stimulation in situ.
AB  - Carbohydrate ingestion increases both endurance time to exhaustion during
      prolonged exercise, and the ability to perform resistance exercise. The
      mechanism(s) underlying the increased performance following glucose ingestion
      remain(s) unclear. The purpose of the present study was to verify the hypothesis
      that glucose infusion could attenuate peripheral muscle fatigue in the
      anaesthetized rat during prolonged indirect electrical stimulation in situ. For
      this purpose the plantaris muscle was electrically stimulated (50 Hz for 200 ms
      every 2.7 s; 5 V; pulse width, 0.05 ms) in situ through the sciatic nerve to
      perform concentric contractions for 60 min while infusing intravenously either
      saline alone (7.25 ml kg(-1) h(-1)), or saline and glucose (1 g kg(-1) h(-1):
      plasma glucose 11 +/- 1.1, vs. 4.9 +/- 0.2 mm with infusion of saline) (8 rats
      per group). Glucose infusion attenuated the reduction in submaximal peak dynamic
      force (55% decrease vs. 70% decrease in rats infused with saline alone, P <
      0.05). In a third group of rats (n = 8), infusion of glucose 30 min after the
      start of stimulation partially restored submaximal peak dynamic force (P < 0.05).
      Maximum dynamic and isometric forces at the end of the period of stimulation were
      also higher (P < 0.05) in rats infused with glucose (4.0 +/- 0.2 and 4.3 +/- 0.2
      N, respectively) than saline alone (3.0 +/- 0.2 and 3.5 +/- 0.2 N, respectively).
      The beneficial effect of glucose infusion on peripheral muscle force during
      prolonged stimulation was not associated with a reduction in muscle glycogen
      utilisation, nor with a reduction of fatigue at the neuromuscular junction, as
      assessed through maximal direct muscle stimulation (200 Hz for 200 ms; 150 V;
      pulse width, 0.05 ms). However, changes in M-wave peak-to-peak amplitude,
      duration and total area suggest that glucose infusion, and/or the associated
      increase in plasma insulin concentration, may prevent the deterioration of
      electrical properties of the muscle fibre membrane.

PMID- 12481934
TI  - Fatigue-induced change in corticospinal drive to back muscles in elite rowers.
AB  - This study examined post-exercise changes in corticospinal excitability in five
      'elite' rowers and six nonrowers. Transcranial magnetic stimulation (TMS) was
      delivered to the motor cortex and bilateral electromyographic (EMG) recordings
      were made from erector spinae (ES) muscles at L3/L4 spinal level and from the
      first dorsal interosseous (FDI) muscle of the dominant hand. Each subject
      completed two exercise protocols on a rowing ergometer: a light exercise protocol
      at a sub-maximal output for 10 min and an intense exercise protocol at maximum
      output for 1 min. A trial of ten magnetic stimuli was delivered before each of
      the protocols and, on finishing exercise, further trials of ten stimuli were
      delivered every 2 min for a 16 min period. Amplitudes of motor-evoked potentials
      (MEPs) in each of the three test muscles were measured before exercise and during
      the recovery period after exercise. The non-rowers showed a brief facilitation of
      MEPs in ES 2 min after light and intense exercise that was only present in the
      elite rowers after intense exercise. In the period 4-16 min after light exercise,
      the mean (+/- S.E.M.) MEP amplitude (relative to pre-exercise levels) was less
      depressed in the elite rowers (79.4 +/- 2.1%) than in the non-rowers (60.9 +/-
      2.5%) in the left ES but not significantly so in the right ES. MEP amplitudes in
      FDI were significantly larger in the elite rowers, averaging 119.0 +/- 3.1% pre
      exercise levels, compared with 101.2 +/- 5.8% in the non-rowers. Pre-exercise MEP
      latencies were no different in the two groups. After light exercise MEP latencies
      became longer in the elite rowers (left ES, 16.1 +/- 0.5 ms; right ES, 16.1 +/-
      0.4 ms; dominant FDI, 23.4 +/- 0.2 ms) than in the non-rowers (left ES, 15.0 +/-
      0.3 ms; right ES, 15.2 +/- 0.3 ms; dominant FDI, 21.5 +/- 0.2 ms). There were no
      differences in MEP depression or latency between elite rowers and non-rowers
      after intense exercise. We conclude that the smaller degree of MEP depression in
      the elite rowers after light exercise reflects less central fatigue within
      corticospinal control pathways than that seen in the non-rowers. The longer
      latency of MEPs seen in the elite rowers may reflect recruitment of more slower
      conducting fatigue-resistant motor units compared with the non-rowers. These
      differences may be because the energy requirements for the non-rowers during
      light exercise are closer to their maximum capacity, leading to more fatigue.
      This notion is supported by the lack of any difference between groups following
      intense exercise when both groups were working at their own maximum.

PMID- 12481935
TI  - The effect of resistive breathing on leg muscle oxygenation using near-infrared
      spectroscopy during exercise in men.
AB  - The effect of added respiratory work on leg muscle oxygenation during constant
      load cycle ergometry was examined in six healthy adults. Exercise was initiated
      from a baseline of 20 W and increased to a power output corresponding to 90% of
      the estimated lactate threshold (moderate exercise) and to a power output
      yielding a tolerance limit of 11.8 min (+/- 1.4, S.D.) (heavy exercise).
      Ventilation and pulmonary gas exchange were measured breath-by-breath. Profiles
      of leg muscle oxygenation were determined throughout the protocol using near
      infrared (NIR) spectroscopy (Hamamatsu NIRO 500) with optodes aligned midway
      along the vastus lateralis of the dominant leg. Four conditions were tested: (i)
      control (Con) where the subjects breathed spontaneously throughout, (ii)
      controlled breathing (Con Br) where breathing frequency and tidal volume were
      matched to the Con profile, (iii) increased work of breathing (Resist Br) in
      which a resistance of 7 cmH2O l(-1) s(-1) was inserted into the mouthpiece
      assembly, and (iv) partial leg blood flow occlusion (Leg Occl), where muscle
      perfusion was reduced by inflating a pressure cuff (approximately 90 mmHg) around
      the upper right thigh. During Resist Br and Leg Occl, subjects controlled their
      breathing pattern to reproduce the ventilatory profile of Con. An approximately 3
      min period with respiratory resistance or pressure cuff was introduced
      approximately 4 min after exercise onset. NIR spectroscopy data for reduced
      haemoglobin-myoglobin (delta[Hb]) were extracted from the continuous display at
      specific times prior to, during and after removal of the resistance or pressure
      cuff. While the delta[Hb] increased during moderate- and heavy-intensity
      exercise, there was no additional increase in delta[Hb] with Resist Br. In
      contrast, delta[Hb] increased further with Leg Occl, reflecting increased muscle
      O2 extraction during the period of reduced muscle blood flow. In conclusion,
      increasing the work of breathing did not increase leg muscle deoxygenation during
      heavy exercise. Assuming that leg muscle O2 consumption did not decrease, this
      implies that leg blood flow was not reduced consequent to a redistribution of
      flow away from the working leg muscle.

PMID- 12481936
TI  - Myocardial response to incremental exercise in endurance-trained athletes:
      influence of heart rate, contractility and the Frank-Starling effect.
AB  - Recent evidence indicates that endurance-trained athletes are able to increase
      their stroke volume (SV) throughout incremental upright exercise, probably due to
      a progressively greater effect of the Frank-Starling mechanism. This is contrary
      to the widely held belief that SV reaches a plateau at a submaximal heart rate
      (irrespective of fitness level), owing to a limitation in the time for diastolic
      filling. The purpose of this investigation was to evaluate whether endurance
      trained athletes rely on a progressively greater effect of the Frank-Starling
      mechanism throughout incremental exercise. A secondary purpose was to evaluate
      the effects of postural position on the cardiovascular responses to incremental
      exercise. Ten male cyclists participated in this investigation. Left ventricular
      function was assessed throughout incremental exercise in the supine and upright
      positions (counterbalanced) using radionuclide ventriculography. Stroke volume
      increased in a linear fashion during incremental exercise in both the upright and
      supine positions. The increases in cardiac output (Q) throughout incremental to
      maximal exercise (in both the supine and upright positions) were significantly
      related to changes in heart rate, myocardial contractility and the Frank-Starling
      mechanism. Percentage changes in end-diastolic volume and SV were significantly
      greater in the upright position versus the supine position, reflecting an
      increased reliance on the Frank-Starling effect to increase Q. We conclude from
      this investigation that highly trained endurance athletes are able to make
      progressively increasing usage of the Frank-Starling effect throughout
      incremental exercise. Postural position has a significant effect on the relative
      contribution of heart rate, myocardial contractility and the Frank-Starling
      mechanism to the increase in Q during exercise conditions.

PMID- 12481937
TI  - Combined oral contraceptives do not influence post-exercise hypotension in women.
AB  - The aim of the present study was to examine the pattern of cardiovascular
      recovery from exercise in 15 women (age, 20.3 +/- 1.4 years; body mass, 61.5 +/-
      4.3 kg) across two phases of oral contraceptive (OC) use: 21 days of consumption
      and 7 days of withdrawal. Cardiovascular recovery was measured in the supine
      position for 60 min following 30 min of exercise at 60% maximal rate of oxygen
      consumption (VO2,max). Central and peripheral haemodynamics were assessed during
      consumption and withdrawal of the OC pill using occlusion plethysmography,
      Doppler flowmetry and echocardiography. Significant hypotension occurred
      following exercise (P < 0.05), returning to baseline values after 60 min. The
      peak hypotension occurred 5 min into recovery. Cardiac output and heart rate were
      elevated for 60 min following exercise (P < 0.05), whilst stroke volume remained
      at baseline values. Heart rate was greater throughout recovery during consumption
      compared to withdrawal (P < 0.05); however, although there was a trend for
      greater responses during consumption, phase of OC use did not affect the other
      central cardiovascular variables (P > 0.05). Post-exercise blood flow parameters
      were not significantly affected by exercise or OC phase; however, calf blood flow
      was greater, and resistance to flow lower during consumption (P > 0.05). The
      pattern of post-exercise fluctuations in cardiovascular parameters may differ
      from those seen in men, whilst oestrogen variation may influence research
      findings.

PMID- 12481938
TI  - Changes in cerebral blood flow during and after 48 h of both isocapnic and
      poikilocapnic hypoxia in humans.
AB  - During acclimatization to the hypoxia of altitude, the cerebral circulation is
      exposed to arterial hypoxia and hypocapnia, two stimuli with opposing influences
      on cerebral blood flow (CBF). In order to understand the resultant changes in
      CBF, this study examined the responses of CBF during a period of constant mild
      hypoxia both with and without concomitant regulation of arterial P(CO2). Nine
      subjects were each exposed to two protocols in a purpose-built chamber: (1) 48 h
      of isocapnic hypoxia (Protocol I), where end-tidal P(O2) (P(ET,O2)) was held at
      60 Torr and end-tidal P(CO2) (P(ET,CO2)) at the subject's resting value prior to
      experimentation; and (2) 48 h of poikilocapnic hypoxia (Protocol P), where
      P(ET,O2) was held at 60 Torr and P(ET,CO2) was uncontrolled. Transcranial Doppler
      ultrasound was used to assess CBF. At 24 h intervals during and after the hypoxic
      exposure CBF was measured and the sensitivity of CBF to acute variations in P(O2)
      and P(CO2) was determined. During Protocol P, P(ET,CO2) decreased by 13% (P <
      0.001) and CBF decreased by 6% (P < 0.05), whereas during Protocol I, P(ET,CO2)
      and CBF remained unchanged. The sensitivity of CBF to acute variations in P(O2)
      and P(CO2) increased by 103% (P < 0.001) and 28% (P < 0.01), respectively, over
      the 48 h period of hypoxia. These changes did not differ between protocols. In
      conclusion, CBF decreases during mild poikilocapnic hypoxia, indicating that
      there is a predominant effect on CBF of the associated arterial hypocapnia. This
      fall occurs despite increases in the sensitivity of CBF to acute variations in
      P(O2)/P(CO2) arising directly from the hypoxic exposure.

PMID- 12481939
TI  - Glucose transporter 1 gene expression is related to thyroid neoplasms with an
      unfavorable prognosis: an immunohistochemical study.
AB  - PURPOSE: An accelerated rate of glucose metabolism mediated by overexpression of
      key regulatory glycolytic enzymes and glucose transporters is among the most
      characteristic biochemical marker of malignant transformed cells. In thyroid
      neoplasms, however, an increased uptake of glucose [measured by 2-[18F]-fluoro-2
      deoxy-D-glucose (FDG) and positron emission tomography (PET)] seems to be
      restricted to more aggressive and high-grade tumors, whereas tumors with
      favorable prognosis demonstrate no significant tracer uptake. We therefore
      studied the expression of glucose transporters in thyroid carcinomas with
      different grades of malignancy. METHODS: Sections of formalin-fixed and paraffin
      embedded tissue obtained from 45 patients with thyroid cancer (5 anaplastic, 20
      papillary and 20 follicular tumors) were investigated. Polyclonal rabbit
      antiglucose transporter antibodies, reactive with glucose transporters 1-5 (GLUT1
      5), were used after heat pretreatment of the sections. Staining was performed by
      the avidin-biotin conjugate immunoperoxidase reaction and evaluated
      semiquantitatively. RESULTS: Expression of GLUT1 transporter on the cell membrane
      was closely related to the grade of malignancy in thyroid neoplasms (Fisher exact
      test p < 0.05). All anaplastic tumors showed a high level of GLUT1 expression in
      the cytoplasm and on the cell membrane. Positive membranous staining in
      differentiated tumors was detected predominantly in neoplasms with unfavorable
      prognosis, e.g., in widely invasive follicular or metastatic tumors, whereas low
      or no immunoreactivity could be seen in well-differentiated tumors or in normal
      thyroid epithelium. CONCLUSIONS: These data indicate that overexpression of GLUT1
      on the cell membrane of thyroid neoplasms is closely related to tumors
      demonstrating a more aggressive biological behavior. Therefore, determination of
      GLUT1 expression in thyroid cancer tissue may be a prognostic marker, and FDG-PET
      may be a helpful technique in identifying patients at a higher risk.

PMID- 12481940
TI  - Peptide scanning for thyrotropin receptor T-cell epitopes in mice vaccinated with
      naked DNA.
AB  - Vaccinating mice with DNA encoding the thyrotropin receptor (TSHR), the major
      autoantigen in Graves' disease, induces memory T cells that secrete interferon
      gamma (IFN-gamma) in response to TSHR antigen. We used a panel of 29 synthetic
      TSHR peptides encompassing the ectodomain and three extracellular loops to
      identify T-cell epitopes after TSHR-DNA vaccination of BALB/c, NOD.H-2h4, and
      AKR/N mice. These strains were chosen because of their previous use in animal
      models of thyroid autoimmunity. In initial studies, challenge of splenocytes with
      TSHR protein induced IFN-gamma and tumor necrosis factor-alpha (TNF-alpha)
      production in all three strains of mice. BALB/c mice recognized three peptides,
      all in the TSHR A subunit. These peptides differed from the four peptides
      recognized by nonobese diabetic (NOD mice NOD H-2h4). Three of the latter were
      also in the A subunit. The fourth was within the intervening C peptide region
      excised on TSHR cleavage into A and B subunits. Because of high and erratic
      responses in AKR/N mice, their TSHR T-cell epitopes could not be determined. In
      summary, we report that TSHR DNA vaccination of BALB/c and NOD.H-2h4 mice, with
      different major histocompatibility complex (MHC) class II genes (I-Ad and I-Ak,
      respectively), recognize restricted, nonoverlapping TSHR T-cell epitopes, nearly
      all in the TSHR A subunit.

PMID- 12481941
TI  - Thymosin beta-10 protein synthesis suppression reduces the growth of human
      thyroid carcinoma cells in semisolid medium.
AB  - Beta-thymosins are structurally related, highly conserved acidic polypeptides,
      originally isolated from calf thymus. We have recently shown that the TB10 gene
      is overexpressed in human thyroid carcinoma cell lines and tissues, particularly
      in undifferentiated thyroid carcinomas, but expressed at an undetectable level in
      normal thyroid cells. The precise role of thymosin beta-10 (TB10) activity in
      maintaining the malignant phenotype of thyroid cell lines is unknown. To
      investigate TB10 function and relevance in a model system we used an antisense
      methodology to suppress TB10 protein synthesis in two human thyroid carcinoma
      cell lines (NPA and ARO). The growth in soft agar of NPA and ARO cells carrying a
      TB10 construct in an antisense orientation was significantly reduced. Conversely,
      anchorage-dependent growth was unchanged in NPA and ARO cells carrying the TB10
      construct in a sense orientation or carrying the backbone vector. TB10 expression
      also affected actin organization. In fact, stress fibers were long and thick in
      ARO cells in which TB10 expression was suppressed by the antisense construct.
      Conversely, they were scarce and short in the vector-transfected ARO cells. These
      data suggest that TB10 plays a critical role in the regulation of anchorage
      independent growth and assembly of actin filaments.

PMID- 12481942
TI  - Genotyping and characterization of two polymorphic microsatellite markers located
      within introns 29 and 30 of the human thyroglobulin gene.
AB  - The purpose of the present work was to characterize two new polymorphic
      microsatellite markers in the thyroglobulin gene. TGrI29 and TGrI30 repeats are
      located within introns 29 and 30, respectively. Genetic studies were carried out
      by using polymerase chain reaction (PCR) followed by denaturing polyacrilamide
      gel electrophoresis. TGrI29 exhibited clearly 4 distinguishable alleles ranging
      from 197 to 203 base pair (bp) in length and TGrI30 showed 8 alleles ranging from
      502 to 542 bp. We characterized the two markers by determinating allele
      frequencies and measures of variation. The heterozygosities (HET) observed of
      TGrI29 and TGrI30 were 0.859 and 0.522, respectively. The polymorphism
      information contents (PIC) were 0.471 and 0.434, respectively. No significant
      differences from Hardy-Weinberg values were found for these two systems. The PCR
      products of each allele were cloned using the pGEM-T Easy vector and directly
      sequenced by Taq polymerase-based chain terminator method. Sequencing analysis
      indicated that both loci are complex repeats, TGrI29 containing two types of
      variable motifs (tc)n and (tg)n, and TGrI30 a tetra-nucleotide tandem units
      (atcc)n. In two TGrI29 alleles and one TGrI30 allele were found two different
      subtypes in each one, with the same molecular weights but different distribution
      of the tandem repeats. In conclusion, both microsatellites analyzed are highly
      informative polymorphic markers and can be used in linkage studies in families
      with congenital hypothyroidism or autoimmunity thyroid diseases.

PMID- 12481943
TI  - Follicular growth of a thyroid carcinoma cell line (KAT-4) with abnormal E
      cadherin and impaired epithelial barrier.
AB  - Loss of the epithelial phenotype is a well-established phenomenon during
      progression of carcinomas to a more malignant state. In the present study, we
      describe a human thyroid tumor cell line (KAT-4), established from a poorly
      differentiated carcinoma, which displays exceptional features. In culture, the
      KAT-4 cells had a fast proliferation rate that was not restricted by high cell
      density, resulting in multilayered growth. Unexpectedly, the cells expressed
      normal levels of epithelial markers, e.g., cytokeratin, occludin, and E-cadherin,
      showed apical-basolateral polarization of the plasma membrane including
      microvilli and junction complexes, and formed intercellular lumens resembling
      thyroid follicles. Yet, when grown on filter, the cells were unable to establish
      a tight paracellular barrier. Moreover, E-cadherin expressed at the cell surface
      consisted of two peptides with abnormal size (135 and 95 kd, respectively) as
      compared to mature E-cadherin (120 kd) in nonneoplastic thyrocytes. Northern blot
      analysis and examination of immunoreactivity, glycosylation, and catenin binding
      suggested that E-cadherin was aberrant because of altered posttranscriptional
      processing. Thus, the KAT-4 thyroid carcinoma cell line has a unique phenotype,
      with maintained epithelial morphology despite dysfunctioning tight junctions,
      abnormal E-cadherin, and loss of contact-inhibited growth, that is not previously
      identified in other wild-type tumor cell lines.

PMID- 12481944
TI  - Calcitonin: the other thyroid hormone.
AB  - Calcitonin was originally discovered as a hypocalcemic factor synthesized by
      thyroid parafollicular C cells. Early experiments demonstrated that calcitonin
      inhibited bone resorption and decreased calcium efflux from isolated cat tibiae
      and subsequent histologic and culture studies confirmed the osteoclast as its
      major site of action. Its potent antiresorptive effect and analgesic action have
      led to its clinical use in treatment of Paget's bone disease, osteoporosis, and
      hypercalcemia of malignancy. This review surveys the cellular and molecular basis
      of these physiologic and clinical actions.

PMID- 12481945
TI  - Hyperthyroidism in ancient Mesopotamia.

PMID- 12481946
TI  - Independent involvement of CD8+ CD25+ cells and thyroid autoantibodies in disease
      severity of Hashimoto's disease.
AB  - Hashimoto's disease (HD) is well known as an autoimmune thyroid disease caused by
      the destruction of the thyroid follicles, and can be diagnosed in the subclinical
      stage with thyroid-specific autoantibodies. However, some patients with HD
      develop hypothyroidism and are treated with thyroxine (severe HD), but most do
      not throughout their lives (mild HD). To clarify the immunologic differences
      between these two groups of patients with HD, we examined serum thyroid
      autoantibodies (antithyroid peroxidase antibodies and antithyroglobulin
      antibodies), CD4+ CD25+ cells that contain regulatory T cells and activated
      helper T cells, and CD8+ CD25+ cells that are activated cytotoxic T cells. There
      was no significant difference in CD4+ CD25+ cells between these HD groups,
      although the proportion of CD25+ cells within CD4+ cells increased in both groups
      as compared to normal controls. The serum titers of the thyroid autoantibodies
      and the proportion of CD25+ cells within CD8+ cells were higher in patients with
      severe HD than in those with mild HD. There was no correlation between these two
      parameters, and a two-dimensional analysis with these parameters differentiated
      these two groups of patients with HD more clearly. These results indicate that
      both thyroid autoantibodies and CD8+ CD25+ cells are independently involved in
      the disease severity of HD and CD4+ CD25+ cells are not related to the severity
      of HD.

PMID- 12481947
TI  - Goiter prevalence and urinary iodide excretion in a formerly iodine-deficient
      region after introduction of statutory lodization of common salt.
AB  - The objective of this epidemiologic study was to determine the volume of the
      thyroid gland as well as urinary iodine excretion in dependence on age and gender
      in a population from an area of low natural iodine supply now receiving iodine
      prophylaxis. In 430 persons from three communities in the province of Carinthia,
      Austria, we determined thyroid volume via sonography as well as urinary iodide
      excretion. As in numerous other European countries, natural iodine supply is
      insufficient in Austria. Therefore, to reduce goiter incidence, iodization of
      common salt with 10 mg potassium iodide (KI) per kilogram of NaCl was made
      mandatory in Austria in 1963 by federal law. In 1990, the amount of iodine
      addition was increased to 20 mg KI per kilogram of NaCl. Our results show that
      mean urinary iodide excretion in the persons investigated was altogether
      satisfactory (males: 163.7 microg of iodine per gram of creatinine; females:
      183.3 microg of iodine per gram of creatinine). Goiter prevalence was 34.3% in
      women and 21.3% in men. An increase in goiter occurrence with age was noted in
      both genders. The increase in goiter prevalence was particularly obvious in the
      age group older than 40, i.e., among those participants who had spent at least a
      certain span of their lives in an area of iodine deficiency. Thus, the most
      likely reason for the persistently high goiter prevalence is not current iodine
      deficit but rather the high number of goiters that had developed previously at
      the time of iodine deficiency and were unable to undergo regression in spite of
      today's comparatively good iodine supply situation.

PMID- 12481948
TI  - Percutaneous ethanol injection efficacy in the treatment of large symptomatic
      thyroid cystic nodules: ten-year follow-up of a large series.
AB  - We present a prospective study on the long-term efficacy of percutaneous ethanol
      injection (PEI) treatment of a large series of symptomatic thyroid cystic nodules
      (STCN). Ninety-eight patients (72 females and 26 males) were treated. The mean
      basal volume of the STCN was 35.3 mL. In 92 of 98 patients PEI treatment induced
      a greater than 50% nodule shrinkage, only 6 of 92 responder patients relapsed at
      a follow-up of 9 years. Moreover, all the patients had a significant clinical
      benefit because a significant reduction of the cyst-associated symptoms was
      recorded. Furthermore, a limited number of sessions was required for the
      treatment of cysts larger than 40 mL (mean +/- standard deviation [SD]: 2.7 +/-
      0.75) demonstrating the feasibility of the procedure also in the treatment of
      large cysts. In conclusion, PEI is an effective and inexpensive procedure with a
      high patient compliance and long-lasting effects in the treatment of cysts larger
      than 40 mL.

PMID- 12481949
TI  - Thyrotropin suppression by thyroid hormone replacement is correlated with
      thyroxine level normalization in central hypothyroidism.
AB  - We have retrospectively studied 41 patients with hypothalamic-pituitary disease
      and central hypothyroidism associated with hypopituitarism. Sixteen patients had
      nonsecreting pituitary macroadenoma, whereas different sellar and suprasellar
      pathologies affected all other patients. Pretreatment thyrotropin (TSH) level
      (mean +/- standard error of the mean [SEM]) was 2.04 +/- 0.25 mU/L (normal, 0.4
      4), and gradually decreased to 0.51 +/- 0.19 mU/L (range, 0.009-3.38) by
      treatment with levothyroxine in a mean dose of 86 +/- 6 microg/d. TSH was
      suppressed by thyroid replacement to less than 0.5 mU/L in 80% of patients. Mean
      baseline free thyroxine (FT4) was 7.55 +/- 0.51 pmol/L (normal, 11.8-24.6) and
      gradually increased with thyroid hormone to 15.19 +/- 1.0 pmol/L, whereas total
      thyroxine (TT4) increased from 57.4 +/- 2.6 to 104.4 +/- 5.0 nmol/L (normal, 77
      154). Mean pretreatment total triiodothyronine (TT3) was 1.44 +/- 0.09 nmol/L
      (normal, 1.1-2.7), and was not altered by treatment. Thyrotropin-releasing
      hormone (TRH) test was performed in 20 patients before thyroid replacement, and
      mean baseline and peak TSH levels were 1.33 +/- 0.3 and 7.14 +/- 1.62 mU/L,
      respectively. In 5 subjects TSH was stimulated to 6 mU/L or more, whereas in 5
      others TSH was not affected. Based on linear regression of logarithm (Ln) TSH
      against FT4, a leftward shift of the TSH/FT4 ratio was demonstrated in patients
      with central hypothyroidism compared to 17 patients with primary hypothyroidism.
      Plotting measurements of TSH against FT4 for 6 individuals with central
      hypothyroidism showed different regression slope for each patient. Suppression of
      TSH by thyroid replacement to levels below 0.1 mU/L predicted euthyroidism in 92%
      of cases, compared to 34% when TSH was above 1 mU/L (p < 0.0001). In conclusion,
      in central hypothyroidism baseline TSH is usually within normal values, and is
      further suppressed by exogenous thyroid hormone as in primary hypothyroidism, but
      to lower levels. Thus, insufficient replacement may be reflected by
      inappropriately elevated TSH levels, and may lead to dosage increment.

PMID- 12481950
TI  - Hashimoto's thyroiditis and Graves' disease associated with retroperitoneal
      fibrosis.
AB  - Retroperitoneal fibrosis is a rare disease of uncertain pathogenesis. However,
      its possible association with several immunopathologic conditions, the
      possibility of systemic involvement by the fibrous process, the presence of
      various autoantibodies, and the frequent response to immunosuppressive treatment
      all support an autoimmune pathogenesis. Riedel's thyroiditis is a rare disease
      the pathogenesis of which is also thought to be immune-mediated based on its
      optimal response to steroids; Riedel's thyroiditis is also frequently reported in
      association with retroperitoneal fibrosis. We describe here two cases of
      autoimmune thyroid disease associated with retroperitoneal fibrosis, the first
      with features of primary myxedema, the second of primary thyrotoxicosis.
      Histology of retroperitoneal fibrosis is documented and it is compatible with an
      immunopathologic condition. Thus, these two cases add further support to the
      hypothesis of an autoimmune pathogenesis of retroperitoneal fibrosis and indicate
      the importance of carefully monitoring for the development of other autoimmune
      disorders, i.e., of the thyroid gland, in patients with retroperitoneal fibrosis.

PMID- 12481951
TI  - The utility of intraoperative parathyroid hormone monitoring with false-positive
      sestamibi scintigraphy.

PMID- 12481952
TI  - Cheap research is likely to be biased.

PMID- 12481953
TI  - Accruing large numbers of patients in primary care trials by retrospective
      recruitment methods.
AB  - There is a need for large scale, pragmatic trials of complementary and
      alternative medicine in a primary care setting to answer questions about the
      'real world' effectiveness of such methods. Randomisation and treatment in such
      trials should be prospective, but retrospective recruitment is possible,
      especially in chronic conditions. This involves contacting patients who have
      previously consulted their GP (identified through GP database searches) rather
      than encouraging GPs to refer patients as they present. We describe a prospective
      randomised trial of acupuncture for chronic headache, currently underway, as an
      example of retrospective recruitment. A pilot study of recruitment and
      recruitment modelling was undertaken. The target sample size was 300, 26% (n =
      36) of general practices approached took part in the study, 32 completed the
      required database search. Practices used diagnostic term searches, prescription
      searches, or a combination of both. On average 1.7% of the total practice
      populations were identified as headache consulters, letters were sent to 4128
      patients. 12% of identified patients were randomised (n = 401). Retrospective
      recruitment methods are feasible for CAM trials in chronic, stable conditions
      modelling can provide accurate data for planning such studies. Retrospective
      recruitment can be more efficient than prospective, further research is required
      on the generalisibility of results from populations recruited in this way.

PMID- 12481954
TI  - An exploratory qualitative study to investigate how patients evaluate
      complementary and conventional medicine.
AB  - OBJECTIVE: We wish to determine the constructs used by patients to evaluate
      conventional and complementary medicine (CAM), prioritise these constructs and
      determine how these characterise patients' choice for CAM and conventional
      medicine. METHODS: A repertory grid technique was employed, in interviews of 20
      patients, 10 from a general practice and 10 from a CAM clinic. RESULTS: CAM was
      used with greater frequency in chronic illness and generated more constructs than
      conventional medicine, although the constructs were similar. The priorities for
      these constructs were different: specificity of treatment and severity of illness
      were prioritised for conventional medicine and lack of science was prioritised
      for CAM. The CAM characteristic most commonly cited was non-chemical. CONCLUSION:
      This exploratory initial study suggests that people use very similar criteria to
      evaluate CAM and conventional medicine. Their choice of treatment was based
      largely on the type of illness from which they were suffering. Further research
      is needed in this area.

PMID- 12481955
TI  - Pregnancy outcome following women's participation in a randomised controlled
      trial of acupuncture to treat nausea and vomiting in early pregnancy.
AB  - OBJECTIVES: Recent studies have concluded that acupuncture is safe in the hands
      of a qualified practitioner. This study assessed the risk of adverse effects of
      acupuncture administered during pregnancy. METHODS: 593 women with nausea and
      vomiting in early pregnancy volunteered to participate in a randomised controlled
      trial, conducted at the Women's and Children's Hospital, in South Australia.
      Patients were given either traditional acupuncture, formula acupuncture, sham
      acupuncture or no acupuncture. OUTCOME MEASURES: Data were collected on perinatal
      outcome, congenital abnormalities, pregnancy complications and the newborn.
      RESULTS: No differences were found between study groups in the incidence of
      perinatal outcome, congenital abnormalities, pregnancy complications and other
      infant outcomes. CONCLUSION: Our findings suggest that no serious adverse effects
      arise from acupuncture administered in early pregnancy.

PMID- 12481956
TI  - Popularity of complementary and alternative medicine in Japan: a telephone
      survey.
AB  - OBJECTIVE: To obtain information on the use of complementary and alternative
      medicine (CAM) in Japan. DESIGN: Nationwide, random-sampled and population
      weighted telephone survey. METHODS: The survey was conducted by a telephone
      survey company in April 2001. The sample size of respondents was 1000. Using a
      region-, gender- and age-weighted sampling table, professional operators called
      respondents with random-digit dialling. Respondents were asked questions about
      their use of CAM in the past 12 months, out-of-pocket expenditures on CAM and
      orthodox Western medicine, reasons for the use of CAM and so on, as well as
      general socio-demographics. RESULTS: The percentage of respondents who had used
      at least one CAM therapy in the past 12 months was greater than those who had
      used orthodox Western medicine (76.0% (95% CI: 73.4-78.6) vs 65.6% (95% CI: 62.7
      68.5). The percentage of use for each CAM therapy was as follows: nutritional and
      tonic drinks (43.1%), dietary supplements (43.1%), health-related appliances
      (21.5%), herbs or over-the-counter Kampo (17.2%), massage or acupressure (14.8%),
      ethical Kampo (Kampo prescribed by medical doctors) (10.0%), aromatherapy (9.3%),
      chiropractic or osteopathy (7.1%), acupuncture and moxibustion (6.7%), homeopathy
      (0.3%), and other therapies (6.5%). Regarding the reasons for the use of CAM,
      60.4% responded that 'the condition was not serious enough to warrant orthodox
      Western medicine', and 49.3% were 'expecting health promotion or disease
      prevention'. Average annual out-of-pocket expenditures of all the 1000
      respondents for CAM were half as much as those for orthodox Western medicine
      (19,080 yen (95% CI: 15,824-22,336) vs 38,360 yen (95% CI: 30,439-46,280)).
      CONCLUSIONS: CAM is very popular in Japan and the expenditures for them are not
      negligible, although there is still an overwhelming dominance of orthodox Western
      medicine with regard to cost, variety of indications, and severity of conditions.

PMID- 12481957
TI  - Survey of the use of complementary and alternative medicine among Turkish cancer
      patients.
AB  - OBJECTIVES: To measure the frequency of use of complementary and alternative
      medicine (CAM) among patients with malignancy undergoing or following
      conventional treatment, to determine demographic characteristics associated with
      the use of CAM, and to find out how benefits, if any, were perceived by patients.
      DESIGN: A 35-item survey questionnaire administered to 305 return patients with
      malignancy. SETTING: Clinical wards of the Oncology and Haematology departments
      of Gulhane Military Medical Academy, Ankara, Turkey. METHODS: Questionnaire-based
      measures of demographics, motives, expectations and effects of using CAM, and
      types and reported perceived benefits of CAM practised on patients with
      malignancy. RESULTS: The majority of return patients (n = 186, 61.0%) used at
      least one CAM practice; and birthplace, educational status, and family type were
      significant factors in such behaviour. CONCLUSIONS: Patients with malignancy born
      in villages, having less education and living in large families were more likely
      to use folk medicine. More than half of those using CAM (n = 99, 53.2%) reported
      as benefits the feelings of either strengthening of the body, being in good
      psychological condition, or the disappearance of several symptoms.

PMID- 12481958
TI  - Complementary cancer care in Southampton: a survey of staff and patients.
AB  - BACKGROUND: Complementary and alternative medicine (CAM) is used by one in ten of
      the UK population yearly and 47% during their lifetime. One-third of cancer
      patients seek some form of CAM treatment during their illness. AIM: To evaluate
      the use of and attitudes to CAM among patients and all healthcare staff in the
      Southampton Cancer Care Directorate (UK). SETTING: The Royal South Hants
      Hospital, Countess Mountbatten and Oakhaven Hospices. METHOD: A questionnaire
      based survey performed between January 2001 and March 2001. RESULTS: Two hundred
      and seventy questionnaires were distributed to patients and 162 responses
      received. The distribution of cancers within this population was generally
      typical of those in the community. Thirty-two percent (n = 52) were receiving
      some form of CAM, half of those receiving CAM were in hospice care. Forty-nine
      percent of those not receiving CAM would like to, and 76% of all patients would
      be prepared to pay for this treatment. The five most popular treatments were
      massage, nutrition, aromatherapy, relaxation and reflexology. While most patients
      expected CAM to palliate their symptoms (n = 149, 92%), some had unrealistic
      expectations that CAM would cure their cancer (n = 13, 8%). Four hundred and
      forty-eight staff questionnaires were distributed and 196 responses were
      received: 148 (75.5%) from nurses. Twenty-one percent of staff responding had CAM
      training and two-thirds would like to receive training. The most popular
      therapies used by staff were the same as those identified by the patients. Ninety
      nine percent of staff and 98.5% of patients wished to see CAM treatments
      introduced into service provision within the Cancer Care Directorate.
      CONCLUSIONS: The use of CAM for cancer care in Southampton is widespread and
      consistent with its use nationally. There is a clearly expressed need for CAM
      treatments by patients and a willingness to pay. Two-thirds of the cancer care
      staff responding wished to receive training in and provide these therapies. There
      are some misconceptions among patients about the role of CAM in cancer care which
      need to be discussed and resolved. We believe that all cancer care units should
      have clear policies on the use of CAM for cancer patients.

PMID- 12481959
TI  - An international scientific conference on complementary, alternative, and
      integrative medicine research.

PMID- 12481960
TI  - An international scientific conference on complementary, alternative, and
      integrative medicine research. Boston, April 2002.

PMID- 12481961
TI  - Long-term ventilation introduction and perspectives.
AB  - An increasing number of patients are receiving prolonged ventilation worldwide.
      The excessive financial burden associated with chronic ventilation hinders
      effective discharge from the intensive care unit to any other alternative site of
      care or to the home. The beneficial outcome of caring for chronic ventilator
      dependent patients relies on the organization of the treatment team, quality of
      the medical and rehabilitative treatment programs, and leadership of the medical
      director. These patients require a highly organized and integrated care plan that
      has sufficient and prolonged administrative oversight to ensure optimum outcome
      and reduce costs.

PMID- 12481962
TI  - Survival of individuals receiving long-term mechanical ventilation.
AB  - The reports published to date support the concept that LTMV can extend life for
      patients with respiratory insufficiency, particularly adults and children with
      neuromuscular and chest wall diseases. The impact of LTMV on survival in patients
      with obstructive lung diseases, such as COPD and bronchiectasis, is less clear
      and deserves further study. For all disease states, research is needed to
      determine the characteristics of patients who are most likely to benefit from
      LTMV and whether one method of ventilation is superior to another. In addition to
      survival, other important outcomes, such as patient satisfaction, quality of
      life, and costs associated with LTMV, should be assessed in future long-term
      studies.

PMID- 12481963
TI  - Physiologic factors predisposing to chronic respiratory failure.
AB  - V(A)/Q mismatching and load/capacity imbalance are the major physiologic
      determinants of chronic respiratory failure. The former underlies lung failure
      and the consequent development of hypoxemia. The latter causes chronic
      ventilatory failure and hypercapnia. This is the consequence of an inefficient
      breathing pattern with lower VT and higher respiratory rate, probably due to the
      "wise choice" of preventing excessive inspiratory effort and eventually
      respiratory muscle fatigue. In many disorders, V(A)/Q mismatching and the
      load/capacity imbalance coexist, particularly in COPD, where the interplay
      between the two pathophysiologically represents the advanced stage of the
      disease. In other disorders, one of the two mechanisms prevails; for example,
      V(A)/Q mismatching in pure lung diseases, and chest wall mechanics in thoracic
      disorders. This has important therapeutic implications because oxygen
      administration can relieve hypoxemia, whereas mechanical ventilation can prevent
      excessive hypercapnia and respiratory acidosis. Although the role of oxygen
      therapy is well established, the role of chronic mechanical ventilation is still
      a matter of debate, particularly in COPD. A major task for future research is to
      achieve the best possible understanding of the pathophysiologic factors
      predisposing to chronic ventilatory failure, to prevent the progression of the
      respiratory diseases to the stage when chronic respiratory failure eventually
      develops.

PMID- 12481964
TI  - Evaluation of candidates for long-term ventilation.
AB  - This article considers the evaluation of patients prior to institution of long
      term ventilation (LTV). LTV has evolved from a concept of necessity ventilation
      to a more satisfactory approach of preventive LTV, enabled by the impressive
      development of noninvasive mechanical ventilation (NIV). Due to its convenience
      and efficacy, and its safety compared with invasive ventilation, NIV has rapidly
      gained popularity among patients with chronic respiratory failure (CRF) requiring
      intermittent ventilatory assistance. Evaluation of candidates for LTV involves
      clinical and laboratory evaluations and sleep monitoring. It includes
      consideration of the etiology of CRF, be it restrictive lung disease, chronic
      obstructive pulmonary disease, obesity or other cause, and considers the
      feasibility of LTV as well as its desirability.

PMID- 12481965
TI  - Choice of ventilator types, modes, and settings for long-term ventilation.
AB  - Ventilator-associated issues are important for optimum short- and long-term
      outcome in patients treated with long-term mechanical ventilation, and may even
      influence compliance. This article discusses the individual choice of type,
      modeand settings ventilators, based on the efficacy of the intervention and
      patient-related factors, such as the patient's comfort and safety. Although this
      strategy may cause some overlap, from a methodological point of view it seems
      reasonable to deal separately with types, modes and different ventilator
      settings.

PMID- 12481966
TI  - Physiologic responses to long-term ventilation.
AB  - Long-term MV, delivered by way of a tracheostomy or noninvasive mask, often is
      indicated in patients with restrictive or neuromuscular pulmonary diseases and
      occasionally in patients with severe obstructive hypercapnic respiratory failure.
      Regardless of the mode of ventilation, respiratory physiology seems to be
      significantly impacted in these patients. Although the effects of ventilation can
      be unpredictable, they often seem to be favorable. Selected patients can develop
      increased sensitivity to hypercapnia, with subsequent improvements in blood gas
      tensions and decreased pulmonary artery pressures, which result in augmented
      cardiac function and greater tolerance to exercise. The patient-ventilator
      interaction, mode of ventilation, and degree of support should be considered when
      managing these patients. For some patients, particularly patients with fibrotic
      lung disease or COPD, chronic MV likely does not alter pathophysiology or improve
      prognosis.

PMID- 12481967
TI  - Where to perform long-term ventilation.
AB  - Given that most VAI prefer to be cared for at home and that their return home is
      the desire of families, health care professionals, and others concerned with
      LTMV, the effort to transform prolonged mechanical ventilation from a hospital
      centered to a home-centered treatment needs to be continued and further
      developed. Nevertheless, the future of high-technology home care will undoubtedly
      be influenced by improvements in quality and containment of costs, as in its
      current status treatment of VAI at home too often leads to family disruption and
      presents a dramatically increasing cost burden. Careful selection of patients,
      closer attention to education and training, and collection of outcome data are
      all factors that presumably will facilitate the development of better-quality and
      cost-saving home care.

PMID- 12481968
TI  - Quality of life and long-term ventilation.
AB  - The interest in measuring HS or QoL in patients with respiratory diseases has
      increased progressively over the last decade, but only recently has it been
      applied to patients with more severe disease (ie, patients with CRF who are
      receiving LTOT or NIPPV). The impact of CRF on the daily life and well being of
      patients can be measured in a number of different ways. There is evidence,
      however, that it is not possible to predict patients' health from surrogate
      measures (eg, spirometry or exercise performance) and that the size of the health
      gain following treatments or interventions cannot be predicted from changes in
      physiologic measurements. Adequate assessments of HS can be measured directly
      only through the use of valid and reliable QoL questionnaires. A range of
      different instruments is available in the literature. The SGRQ and MRF28 have
      been shown to be applicable and reliable in patients on long-term ventilation.

PMID- 12481969
TI  - Costs and reimbursement of long-term ventilation.
AB  - Patients receiving long-term mechanical ventilation present a serious financial
      challenge to hospitals. Depending on the case mix in a particular hospital of
      Medicare, Medicaid, managed-care contract, and fully insured patients, the
      financial picture in most hospitals is bleak. Depending on the level of state
      Medicaid reimbursement, Medicaid losses on these patients vary. Because acute
      care hospitals cannot be reimbursed for chronic ventilator units, hospitals have
      resorted to leasing space to separate entities, which, when separately
      incorporated, accredited, and staffed, can secure waivered status from the PPS
      and can be paid at a per diem rate based on their costs. Hospital patients who
      are ventilator dependent can be transferred to these PPS-waived units. There are
      states where no chronic ventilator facilities exist and where nursing homes do
      not accept ventilator-dependent patients. This situation is serious for the
      hospital if the patient does not have caregivers at home who are capable of
      caring for a ventilator-dependent patient. The problem of the large numbers of
      patients who are ventilated mechanically with endotracheal tubes but who do not
      fall into MDC 4 needs to be addressed by Medicare. Medicare needs to evaluate the
      cost and use of NIV in ICU practice and develop a system to reimburse for this
      modality at a reasonable level under Part A.

PMID- 12481970
TI  - Early parent-child relations and family functioning of preschool boys with
      pervasive hyperactivity.
AB  - This study examined the quality of parent-child relationships and family
      functioning of preschool children with early onset hyperactivity by comparing a
      community sample of 33 pervasively hyperactive preschool boys with a comparison
      sample of 34 boys. Mothers and children were assessed at home on a range of
      interview, parent questionnaire, and observational measures of parenting and
      family functioning. Results of the study showed that higher rates of reported lax
      disciplinary practices, less efficient parental coping, lower rates of father
      child communication, and less synchronous mother-child interactions were
      significantly associated with hyperactivity following statistical adjustment for
      the effects of conduct problems and other confounding factors. The best parenting
      predictor of hyperactivity was maternal coping. The present findings suggest that
      the way in which parents interact with their preschool children may make a unique
      contribution to the development and ongoing behavioral difficulties experienced
      by children with pervasive hyperactivity. Findings also highlight the importance
      of considering the role of fathers in the behavioral development of boys with
      early tendencies to hyperactive and distractible behavior problems.

PMID- 12481971
TI  - Preschoolers at risk for attention-deficit hyperactivity disorder and
      oppositional defiant disorder: family, parenting, and behavioral correlates.
AB  - This community study assigned 129 4-year-olds to groups at risk for attention
      deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), both
      ADHD and ODD, or no problems. Mothers of children at risk for ODD reported more
      family dysfunction, felt less competent as parents, suggested fewer solutions to
      child behavior problems, demonstrated a less assertive approach to child
      management, and reported more child internalizing problems than did mothers of
      children not elevated on ODD symptoms. Mothers of children at risk for ADHD
      reported higher personal depression scores than did those of the non-ADHD
      subgroup. Children at risk for ADHD evidenced the most difficulties in school
      where teachers reported more social behavior, classroom management, and
      internalizing problems relative to other children not at risk for ADHD. When
      solving child management problems, mothers of children in all groups suggested
      twice as many controlling/negative management strategies as positive/preventive
      strategies. In addition, faced with oppositional and conduct problems, mothers of
      children in all groups increased controlling/negative suggestions and decreased
      positive/preventive suggestions. Mothers of girls at risk for ADHD, ODD, and
      ADHD/ODD gave more rewards per positive behavior than did mothers of boys.

PMID- 12481972
TI  - The effects of the Triple P-Positive Parenting Program on preschool children with
      co-occurring disruptive behavior and attentional/hyperactive difficulties.
AB  - Two variants of a behavioral family intervention (BFI) program known as Triple P
      were compared using 87 preschoolers with co-occurring disruptive behavior and
      attentional/hyperactive difficulties. Families were randomly allocated to
      enhanced BFI (EBFI), standard BFI (SBFI), or a waitlist (WL) control group. At
      postintervention both BFI programs were associated with significantly lower
      levels of parent-reported child behavior problems, lower levels of dysfunctional
      parenting, and greater parental competence than the WL condition. The EBFI
      condition was also associated with significantly less observed child negative
      behavior in comparison to the WL. The gains achieved at postintervention were
      maintained at 1-year follow-up. Contrary to predictions, the enhanced program was
      not shown to be superior to the standard program using any of the outcome
      measures at either postintervention or follow-up. Each of the programs produced
      significant reductions in children's co-occurring disruptive behavior and
      attentional/hyperactive difficulties with 80% of the children showing clinically
      reliable improvement in observed negative behavior from preintervention to follow
      up.

PMID- 12481973
TI  - Neurocognitive performance of 5- and 6-year-old children who met criteria for
      attention deficit/hyperactivity disorder at 18 months follow-up: results from a
      prospective population study.
AB  - The aim of this prospective study was to examine whether neurocognitive
      performance of children aged 5-6 years distinguished children who were later
      diagnosed with attention deficit/hyperactivity disorder(ADHD) or "borderline
      ADHD" from children without ADHD after adjustment for behavioral measures and to
      examine the influence of comorbid psychopathology. Out of a general population of
      1,317 children, 366 children were selected on the basis of their scores on the
      Child Behavior Checklist (CBCL). Eighteen months later, the parents were
      interviewed using a standardized child psychiatric interview: 33 children were
      classified as ADHD and 75 children as borderline ADHD, and there were 258
      children without ADHD. Children with rated ADHD were significantly impaired on
      measures of visuomotor ability and working memory compared to children without
      ADHD after adjustment for CBCL results. The performance of borderline ADHD
      children was in between that of children with and without ADHD. In addition, 4
      groups of children were analyzed: 9 ADHD, 24 ADHD with comorbid oppositional
      defiant disorder/conduct disorder (ODD/CD), 59 ODD/CD, and 274 controls. Children
      with rated comorbid ADHD and ODD/CD performed significantly worse on these tasks
      compared to children with rated ODD/CD and control children while they did not
      differ from ADHD children. Our results imply that neurocognitive measures can
      contribute to the early identification of ADHD with and without comorbid ODD/CD.

PMID- 12481974
TI  - Relational and physical victimization within friendships: nobody told me there'd
      be friends like these.
AB  - In past research, relational and physical forms of peer victimization have been
      identified that have been shown to be significantly associated with social
      psychological maladjustment. These forms of victimization, although studied
      primarily within the group peer context, also occur within dyadic relationships
      such as friendships. Gender differences in friend victimization and the
      association between friend victimization and children's social-psychological
      adjustment were examined. Results showed that boys were more physically
      victimized by their friends than were girls. Girls were more relationally than
      physically victimized by their friends. Friend victimization was related to
      adjustment difficulties for both boys and girls; however, friend physical
      victimization was particularly related to boys whereas friend relational
      victimization was particularly related to girls. The implications of these
      findings for future research and intervention with victimized children are
      discussed.

PMID- 12481975
TI  - Assessing aggressive and depressed children's social relations with classmates
      and friends: a matter of perspective.
AB  - This study examined aggressive, depressed, and aggressive-depressed children's
      peer relations from the children's own and from their peers' perspective.
      Participants were 819 fourth through sixth graders (50.2% girls) who were
      assessed twice during the same school year. Measures included children's
      aggression and depression, self-rated and peer-rated social acceptance, number of
      reciprocal friends, and self-rated and friend-rated friendship quality. Analyses
      revealed different patterns, depending on the perspective considered. Depression
      but not aggression was significantly related to difficulties with the peer group
      and with dyadic friends from the children's own perspective, whereas the opposite
      pattern was found according to the peers' view. The co-occurrence of aggression
      and depression entailed significant difficulties with peers regardless of
      perspective. The implications of these results for the links between children's
      aggression and depression and their interpersonal relationships are discussed.

PMID- 12481976
TI  - Patterns of friendship among girls with and without attention
      deficit/hyperactivity disorder.
AB  - Examined patterns of friendship participation, stability, and quality among
      previously unfamiliar, ethnically diverse girls with attention
      deficit/hyperactivity disorder (ADHD; n = 140) and comparison (n = 88) girls,
      aged 6-12 years, who attended 5-week naturalistic summer camps. Each girl
      completed sociometric nominations during Weeks 1, 3, and 5 of the camps;
      friendships were indexed by examining patterns of reciprocal nominations. At each
      assessment point, girls with ADHD had fewer mutual friends and were more likely
      to have no friends. Girls with Combined-type ADHD exhibited difficulties
      maintaining friendships from the beginning to middle of camp, whereas girls with
      Inattentive-type ADHD demonstrated poor friendship stability from the middle to
      end of camp. In general, girls with ADHD had higher levels of negative
      relationship features-including conflict and relational aggression-than did
      comparison girls, but levels of positive relationship features did not differ
      across subgroups. Friendship status predicted positive and negative peer regard,
      controlling for Verbal IQ and diagnostic status. Overall, although girls with
      ADHD were able to make friends to some extent, they differed from comparison
      girls in terms of the likelihood of doing so, the ability to maintain the
      friendships that they did form, and the levels of negative features found in
      their friendships.

PMID- 12481978
TI  - Family expressiveness and parental emotion coaching: their role in children's
      emotion regulation and aggression.
AB  - In this study, we explored the relations between positive and negative family
      expressiveness, parental emotion coaching, child emotion regulation, and child
      aggression. The sample included 120 fourth-grade children and their mothers.
      Mothers completed the Emotion Regulation Checklist, the Family Expressiveness
      Questionnaire, and a portion of the meta-emotion interview to assess their
      awareness and acceptance of, and instruction in managing their child's anger and
      sadness (3 dimensions of parental emotion coaching). Teachers rated each child's
      aggression and completed the Emotion Regulation Checklist for each child. The 3
      dimensions of parental emotion coaching and positive and negative family
      expressiveness were not directly related to child aggression. However, both
      negative family expressiveness and the mother's acceptance of the child's
      negative emotions were indirectly related to child aggression through the child's
      emotion regulation.

PMID- 12481977
TI  - Reactive aggression in boys with disruptive behavior disorders: behavior,
      physiology, and affect.
AB  - This study examined responses to peer provocation in boys ages 9-13 years who met
      symptomatic criteria for ADHD-only, ODD/CD-only, comorbid ADHD/ODD/CD, or no
      diagnosis. Boys participated in a reaction-time game that included standardized
      verbal and behavioral provocation. Their behavioral, physiological, and affective
      responses to this task were measured. Results showed that groups did not differ
      following high levels of provocation because all boys behaved aggressively.
      However, following low provocation boys with comorbid ADHD/ODD/CD had higher
      levels of behavioral aggression, had greater heart rate acceleration, and were
      rated as angrier than all other boys. In addition, boys with comorbid ADHD/ODD/CD
      held a grudge longer than other children. Results suggest that boys with comorbid
      ADHD/ODD/CD are especially reactive to provocation from their peers.

PMID- 12481979
TI  - The metabolic basis of arginine nutrition and pharmacotherapy.
AB  - As an essential precursor for the synthesis of proteins and other molecules with
      enormous biological importance (including nitric oxide, urea, ornithine, proline,
      polyamines, glutamate, creatine, agmatine, and dimethylarginines), arginine
      displays remarkable metabolic and regulatory versatility. Evidence available to
      date provides a sound reason to classify arginine as an essential amino acid for
      young mammals (including parenterally fed human infants) and as a conditionally
      essential amino acid for adults under such conditions as trauma, burn injury,
      massive small-bowel resection, and renal failure. Arginine administration
      reverses endothelial dysfunction, enhances wound healing, prevents the early
      stages of tumorigenesis, and improves cardiovascular, reproductive, pulmonary,
      renal, digestive, and immune functions. Arginine or its effective precursor
      citrulline may hold great promise as a nutritional or pharmacotherapeutic
      treatment for a wide array of human diseases.

PMID- 12481980
TI  - I. Arginine.
AB  - L-Arginine (Arg) is classified as an essential amino acid for birds, carnivores
      and young mammals and a conditionally essential amino acid for adults. It is
      converted by arginase to L-ornithine, a precursor of polyamines and urea, which
      is important in the urea cycle. Arg serves as a precursor for creatine, which
      plays an essential role in the energy metabolism of muscle, nerve and testis and
      accounts for Arg catabolism and for the synthesis of agmatine and proteins. Via
      its ability to increase growth hormone secretion it influences immune function.
      Depending on nutritional status and developmental stage, normal plasma Arg
      concentrations in humans and animals range from 95 to 250 micromol/l. Systemic or
      oral Arg administration has been shown to improve cardiovascular function and
      reduce myocardial ischemia in coronary artery disease patients. It reduces blood
      pressure and renal vascular resistance in essential hypertensive patients with
      normal or insufficient renal function. Although Arg plasma concentrations are not
      altered in hypercholesterolemic individuals, oral or intravenous Arg
      administration can reverse endothelial dysfunction in hypercholesterolemic
      patients and in cigarette smokers. The main importance of Arg is attributed to
      its role as a precursor for the synthesis of nitric oxide (NO), a free radical
      molecule that is synthesized in all mammalian cells from L-Arg by NO synthase
      (NOS). NO appears to be a major form of the endothelium-derived relaxing factor
      (EDRF). NO and EDRF share similar chemical and pharmacological properties and are
      derived from the oxidation of a terminal guanidine group of L-Arg. Various
      mechanisms have been implicated in the defect in vascular relaxation. These
      include, increased diffusional barrier for NO, L-Arg depletion, altered levels of
      reactive oxygen, inactivation of NO by superoxide anions (O2-). The independent
      reactions of O2-, NO and their reaction yielding peroxynitrite are critical in
      the initiation and maintenance of the atherosclerotic state and contribute to the
      defect in vasorelaxation. NO also plays a role as a neurotransmitter, mediator of
      immune response and as signaling molecule. The NO synthesized by iNOS in
      macrophages contributes to their cytotoxic activity against tumor cells, bacteria
      and protozoa. Our aim here is to review on some amino acids with high functional
      priority such as Arg and to define their effective activity in human health and
      pathologies.

PMID- 12481981
TI  - II. Glutamine and glutamate.
AB  - Glutamine and glutamate with proline, histidine, arginine and ornithine, comprise
      25% of the dietary amino acid intake and constitute the "glutamate family" of
      amino acids, which are disposed of through conversion to glutamate. Although
      glutamine has been classified as a nonessential amino acid, in major trauma,
      major surgery, sepsis, bone marrow transplantation, intense chemotherapy and
      radiotherapy, when its consumption exceeds its synthesis, it becomes a
      conditionally essential amino acid. In mammals the physiological levels of
      glutamine is 650 micromol/l and it is one of the most important substrate for
      ammoniagenesis in the gut and in the kidney due to its important role in the
      regulation of acid-base homeostasis. In cells, glutamine is a key link between
      carbon metabolism of carbohydrates and proteins and plays an important role in
      the growth of fibroblasts, lymphocytes and enterocytes. It improves nitrogen
      balance and preserves the concentration of glutamine in skeletal muscle.
      Deamidation of glutamine via glutaminase produces glutamate a precursor of gamma
      amino butyric acid, a neurotransmission inhibitor. L-Glutamic acid is a
      ubiquitous amino acid present in many foods either in free form or in peptides
      and proteins. Animal protein may contain from 11 to 22% and plants protein as
      much as 40% glutamate by weight. The sodium salt of glutamic acid is added to
      several foods to enhance flavor. L-Glutamate is the most abundant free amino acid
      in brain and it is the major excitatory neurotransmitter of the vertebrate
      central nervous system. Most free L-glutamic acid in brain is derived from local
      synthesis from L-glutamine and Kreb's cycle intermediates. It clearly plays an
      important role in neuronal differentiation, migration and survival in the
      developing brain via facilitated Ca++ transport. Glutamate also plays a critical
      role in synaptic maintenance and plasticity. It contributes to learning and
      memory through use-dependent changes in synaptic efficacy and plays a role in the
      formation and function of the cytoskeleton. Glutamine via glutamate is converted
      to alpha-ketoglutarate, an integral component of the citric acid cycle. It is a
      component of the antioxidant glutathione and of the polyglutamated folic acid.
      The cyclization of glutamate produces proline, an amino acid important for
      synthesis of collagen and connective tissue. Our aim here is to review on some
      amino acids with high functional priority such as glutamine and to define their
      effective activity in human health and pathologies.

PMID- 12481982
TI  - The effect of opioid agonists of delta-class DSLET, mu-class DAMGO, kappa-class U
      69593 and an opioid antagonist, naloxone, on MTT activity of NALM-1 leukemic
      cells.
AB  - The effects of synthetic agonists of delta-, mu-, kappa-opioid classes were
      studied on the proliferation of NALM-1 leukemic cells, using the MTT-test. Delta
      opioid DSLET and mu-opioid DAMGO mildly and transiently decreased, in higher
      concentrations, the MTT-activity of NALM-1 cells after 6 h of treatment. The
      kappa-opioid agonist U-69593 mildly suppressed proliferation of NALM-1 cells
      after 48 h of treatment. Naloxone, an opioid receptor antagonist, mildly and
      transiently diminished MTT-activity of NALM-1 cells after 6 h of treatment.
      Treatment with opioid agonists, DAMGO, DSLET, U-69593, and an opioid antagonist
      naloxone for 6, 24, and 48 h, did not trigger DNA fragmentation, which was
      considered as a possible mechanism of action.

PMID- 12481983
TI  - Effect of seabuckthorn on sodium nitroprusside-induced cytotoxicity in murine
      macrophages.
AB  - The present study reports the anti-oxidant activity of alcoholic extracts of leaf
      and fruit of seabuckthorn (SBT) on nitric oxide (NO) induced cytotoxicity in J
      774 macrophages. Sodium nitroprusside (SNP), which generates NO at the
      concentration of 500 microg/ml, induced cytotoxicity as revealed by decreased
      neutral red uptake by macrophages. The cytotoxicity of SNP was attributed to
      enhanced reactive oxygen species (ROS) production, which in turn resulted in
      decrease in anti-oxidant levels. Alcoholic leaf and fruit extracts of SBT at the
      concentration of 500 microg/ml were found to have a significant cytoprotective
      effect against SNP-induced oxidative stress. These extracts inhibited SNP-induced
      cytotoxicity, free radical production and maintained the anti-oxidant status
      identical to that of control cells. The alcoholic fruit extract of SBT was found
      to have significantly higher anti-oxidant activity than leaf extract against SNP
      induced cytotoxicity in murine macrophages.

PMID- 12481984
TI  - Frontotemporal lobar degeneration--tau as a pied piper?
AB  - Frontotemporal lobar degeneration (FTLD) is the second most-common form of
      cortical dementia in the presenium after Alzheimer disease. Clinically three
      disease entities can be distinguished: frontotemporal dementia, semantic
      dementia, and primary progressive aphasia. The underlying neuropathology can be
      classified into disorders with tau pathology (including Pick disease,
      corticobasal degeneration, progressive supranuclear palsy, and familial
      frontotemporal dementia with parkinsonism linked to chromosome 17 - FTDP-17), and
      into disorders that lack tau abnormalities (including dementia lacking
      distinctive histology and motor neuron disease inclusion dementia). The recent
      discovery of tau gene mutations in FTDP-17 brought tau to the center stage, but
      led to the erroneous trend of collectively grouping all forms of FTLD as
      tauopathies. However, clinicopathological and genetic studies strongly suggest
      that the majority of sporadic and familial FTLD cases are not associated with tau
      pathology and/or tau gene mutations. Furthermore, recent studies have linked
      several autosomal dominantly inherited familial frontotemporal dementia cases to
      a variety of gene loci on different chromosomes. Thus, this review is intended to
      summarize our current knowledge about the sporadic and familial FTLD disorders
      that lack tau pathology, and shall further strengthen the view that FTLD is
      heterogeneous, both in terms of clinicopathological phenotypes as well as genetic
      backgrounds.

PMID- 12481985
TI  - Identification of genetic loci affecting mouse-adapted bovine spongiform
      encephalopathy incubation time in mice.
AB  - Prion diseases are fatal neurodegenerative disorders of humans and animals, which
      include bovine spongiform encephalopathy (BSE) and its human form, variant
      Creutzfeldt-Jakob disease (vCJD). They are characterized by a prolonged
      incubation period, which is known to be influenced by polymorphisms in the prion
      protein gene. Previous studies of inbred mice have demonstrated that additional
      genetic loci also contribute to the observed variation in incubation period.
      However, a substantial transmission barrier between cow and mouse complicates
      studies using BSE. As a result, primary transmissions display large variations in
      incubation period and not all animals develop clinical signs of disease. To
      identify quantitative trait loci for BSE without the presence of a transmission
      barrier, we analysed 124 animals from an F2 intercross between CAST/Ei and
      NZW/OlaHsd mice and challenged them intracerebrally with a strain of BSE that was
      passaged twice through C57BL/6OlaHsd mice. Interval mapping identified two highly
      significant linked regions on chromosomes 2 and 11 with peak lod scores of 6.34
      and 4.77, respectively. Composite interval mapping suggests that chromosome 2
      includes three linked quantitative trait loci. Loci in the same position on
      chromosomes 2 and 11 were also identified in a previous study using the same
      mouse cross but infected with Chandler/RML scrapie prions. If these are the same
      loci, it suggests that these loci may be influencing incubation time
      independently of prion strain. This provides hope that it may be possible to
      identify human quantitative trait loci for prion incubation time using mouse
      models that may allow identification of at-risk individuals and the discovery of
      novel therapeutic targets.

PMID- 12481986
TI  - Reduction in the minimum candidate interval in the dominant-intermediate form of
      Charcot-Marie-Tooth neuropathy to D19S586 to D19S432.
AB  - As part of an on-going genomic screen of unlinked Charcot-Marie-Tooth disease
      type 2 (CMT2) families, we identified 11 regions in the genome with lod scores >
      or = 1.0. One of these regions was near the recently identified CMTDI1 locus on
      19q. We show evidence of linkage of DUK 1118 to this region and our data reduce
      the minimum candidate interval for CMTDI1 to the 9-cM interval spanned by D19S586
      and D19S432. We also demonstrate that five additional CMT2 families are unlinked
      to 19q markers, providing further evidence of CMT2 heterogeneity.

PMID- 12481987
TI  - Congenital myasthenia in Brahman calves caused by homozygosity for a CHRNE
      truncating mutation.
AB  - To elucidate the genetic defect in four previously reported related Brahman
      calves with severe myasthenic weakness, we determined the genomic structure of
      the gene encoding the bovine epsilon-subunit (bovCHRNE) of the acetylcholine
      receptor (AChR). Amplification of DNA isolated from paraplast-embedded tissue
      samples from one of the myasthenic calves and subsequent sequencing of all
      bovCHRNE exons revealed a homozygous 20-bp deletion within exon 5 (470del20). The
      deletion causes a frame shift followed by a premature stop codon in the predicted
      bovCHRNE protein. Thus, the 470del20 mutation reported here leads to a non
      functional allele, explaining the impairment of neuromuscular transmission
      observed in the affected Brahman calves. With a survival time limited to only
      several months, the effect on neuromuscular transmission was more pronounced in
      the calves than that observed in humans homozygous for truncating CHRNE
      mutations. This may be due to a different capacity to express the fetal-type AChR
      after birth.

PMID- 12481988
TI  - A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian
      family.
AB  - Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and
      sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is
      currently subdivided into seven types based on genetic localization. These are
      CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21),
      HMNSP (3q13.1), and CMT2F (7q11-q21). Two loci have thus far been identified for
      autosomal recessive CMT2; ARCMT2A (1q21.1-q21.3) and ARCMT2B (19q13.3). Mutations
      in four genes (connexin 32, myelin protein zero, neurofilament-light, and
      kinesin) have been associated with the CMT2 phenotype. We identified a novel
      neurofilament-light missense mutation (C64T) that causes the disease in a large
      Slovenian CMT2 family. This novel mutation shows complete co-segregation with the
      dominantly inherited CMT2 phenotype in our family.

PMID- 12481989
TI  - Multiple founder effects in Japanese families with primary torsion dystonia
      harboring the GAG deletion in the Tor1A (DYT1) gene.

PMID- 12481990
TI  - De novo MECP2 mutation in a 46,XX male patient with Rett syndrome.

PMID- 12481991
TI  - Pseudomonas viridiflava and P. syringae--natural pathogens of Arabidopsis
      thaliana.
AB  - We report the isolation and identification of two natural pathogens of
      Arabidopsis thaliana, Pseudomonas viridiflava and Pseudomonas syringae, in the
      midwestern United States. P. viridiflava was found in six of seven surveyed
      Arabidopsis thaliana populations. We confirmed the presence in the isolates of
      the critical pathogenicity genes hrpS and hrpL. The pathogenicity of these
      isolates was verified by estimating in planta bacterial growth rates and by
      testing for disease symptoms and hypersensitive responses to A. thaliana.
      Infection of 21 A. thaliana ecotypes with six locally collected P. viridiflava
      isolates and with one P. syringae isolate showed both compatible (disease) and
      incompatible (resistance) responses. Significant variation in response to
      infection was evident among Arabidopsis ecotypes, both in terms of symptom
      development and in planta bacterial growth. The ability to grow and cause disease
      symptoms on particular ecotypes also varied for some P. viridiflava isolates. We
      believe that these pathogens will provide a powerful system for exploring
      coevolution in natural plant-pathogen interactions.

PMID- 12481992
TI  - Modulation of defense responses of Malus spp. during compatible and incompatible
      interactions with Erwinia amylovora.
AB  - Erwinia amylovora is the causal agent of fire blight, a disease affecting members
      of subfamily Maloideae. In order to analyze mechanisms leading to compatible or
      incompatible interactions, early plant molecular events were investigated in two
      genotypes of Malus with contrasting susceptibility to fire blight, after
      confrontation with either E. amylovora or the incompatible tobacco pathogen
      Pseudomonas syringae pv. tabaci. Many defense mechanisms, including generation of
      an oxidative burst and accumulation of pathogenesis-related proteins, were
      elicited in both resistant and susceptible genotypes by the two pathogens at
      similar rates and according to an equivalent time course. This elicitation was
      linked with the functional hypersensitive reaction and pathogenicity (hrp)
      cluster of E. amylovora, because an hrp secretion mutant did not induce such
      responses. However, a delayed induction of several genes of various branch
      pathways of the phenylpropanoid metabolism was recorded in tissues of the
      susceptible genotype challenged with the wild-type strain of E. amylovora,
      whereas these genes were quickly induced in every other plant-bacteria
      interaction, including interactions with the hrp secretion mutant. This suggests
      the existence of hrp-independent elicitors of defense in the fire blight pathogen
      as well as hrp-dependant mechanisms of suppression of these nonspecific
      inductions.

PMID- 12481994
TI  - The AVR4 elicitor protein of Cladosporium fulvum binds to fungal components with
      high affinity.
AB  - The interaction between tomato and the fungal pathogen Cladosporium fulvum
      complies with the gene-for-gene system. Strains of C. fulvum that produce race
      specific elicitor AVR4 induce a hypersensitive response, leading to resistance,
      in tomato plants that carry the Cf-4 resistance gene. The mechanism of AVR4
      perception was examined by performing binding studies with 125I-AVR4 on
      microsomal membranes of tomato plants. We identified an AVR4 high-affinity
      binding site (KD = 0.05 nM) which exhibited all the characteristics expected for
      ligand-receptor interactions, such as saturability, reversibility, and
      specificity. Surprisingly, the AVR4 high-affinity binding site appeared to
      originate from fungi present on infected tomato plants rather than from the
      tomato plants themselves. Detailed analysis showed that this fungus-derived, AVR4
      specific binding site is heat- and proteinase K-resistant. Affinity crosslinking
      demonstrated that AVR4 specifically binds to a component of approximately 75 kDa
      that is of fungal origin. Our data suggest that binding of AVR4 to a fungal
      component or components is related to the intrinsic virulence function of AVR4
      for C. fulvum.

PMID- 12481993
TI  - The P34 syringolide elicitor receptor interacts with a soybean photorespiration
      enzyme, NADH-dependent hydroxypyruvate reductase.
AB  - The syringolide receptor P34 mediates avrD-Rpg4 gene-for-gene complementarity in
      soybean. However, the mechanism underlying P34 signal transmission after
      syringolide binding is unknown. In an effort to identify a second messenger for
      P34, soybean leaf proteins were run though a P34-affinity column. A 42-kDa
      protein which specifically bound to the column was identified as a putative plant
      NADH-dependent hydroxypyruvate reductase (HPR) by N-terminal peptide sequencing.
      HPR is an important enzyme involved in the plant photorespiration system.
      Screening of a soybean cDNA library yielded two distinct HPR clones that encoded
      proteins with 97% identity (P42-1 and P42-2). Surprisingly, only P42-2 displayed
      good binding with P34 in a yeast two-hybrid assay, indicating that P42-2, but not
      P42-1, is a potential second messenger for P34. Glycerate and its analogs, which
      are utilized in the photorespiration system, were tested for their inhibitory
      effect on syringolide-induced hypersensitive response (HR) to evaluate the
      biological significance of P42-2. Interestingly, the downstream products of HPR
      (glycerate and 3-phosphoglycerate) inhibited HR but the upstream compounds
      (hydroxypyruvate or serine) did not have a significant effect on HR. These
      results suggest that P42-2 is a primary target for a P34/syringolide complex and
      that P42-2 binding with the complex probably induces HR by inhibiting one or more
      HPR functions in soybean.

PMID- 12481995
TI  - Mutational and transcriptional analysis of the type III secretion system of
      Bradyrhizobium japonicum.
AB  - Sequencing the symbiotic region of Bradyrhizobium japonicum revealed a gene
      cluster (tts) encoding a type III secretion system (TTSS) that is similar to
      those found in Mesorhizobium loti MAFF303099 and Rhizobium strain NGR234. In
      addition to genes that are likely to encode structural core components of the
      TTSS, the cluster contains several open reading frames that are found exclusively
      in rhizobia or that are specific to B. japonicum. Depending on the host,
      mutations within this cluster affected nodulation capacity to different extents.
      One of the genes likely encodes a transcriptional activator (TtsI) of the two
      component regulatory family. Upstream of ttsI, a nod box promoter was identified.
      Expression of ttsI could be induced by genistein. This induction depended on the
      transcriptional activator protein NodW as well as the nodD1nodD2nolA gene region.
      TtsI was found to be involved in transcriptional regulation of the tts gene
      cluster. Sequence comparison revealed a conserved tts box element within putative
      promoter regions of several genes. Here, we propose a model of the regulatory
      cascade leading to the induction of the tts gene cluster.

PMID- 12481996
TI  - Effect of leaf surface waxes on leaf colonization by Pantoea agglomerans and
      Clavibacter michiganensis.
AB  - To evaluate the influence of leaf cuticular waxes on bacterial colonization of
      leaves, bacterial colonization patterns were examined on four glossy maize (Zea
      mays L.) mutants that were altered in their cuticular wax biosynthesis. Mutant
      gl3 was indistinguishable from the wild-type maize in its ability to foster
      colonization by the two bacterial species, Pantoea agglomerans and Clavibacter
      michiganensis subsp. nebraskensis. In contrast, the other three mutants supported
      the development of populations that significantly differed in size from those on
      the wild type. Mutant gl5 gl20 supported smaller populations of P. agglomerans,
      but not C. michiganensis, while mutant gl1 supported larger populations of C.
      michiganensis but not P. agglomerans. Mutant gl4 supported larger populations of
      both bacterial species. The exceptional ability of mutant gl4 to support
      bacterial colonization was hypothesized to result from the lower density of the
      crystalline waxes on gl4 than on the wild type, because a reduced crystal density
      could promote capillary water movement and water trapping among the wax crystals.
      This hypothesis was supported by the demonstration that the mechanical
      introduction of gaps among the wax crystals of the wild-type leaves resulted in
      the establishment of larger P. agglomerans populations on the altered leaves.
      These results provide the first direct evidence that leaf surface waxes affect
      bacterial leaf colonization at various stages of colonization and in a bacterial
      species-dependent manner.

PMID- 12481997
TI  - Analysis of differences between Sinorhizobium meliloti 1021 and 2011 strains
      using the host calcium spiking response.
AB  - In the Rhizobium-legume symbiosis, compatible partners recognize each other
      through an exchange of signals. Plant inducers act together with bacterial
      transcriptional activators, the NodD proteins, to regulate the expression of
      bacterial biosynthetic nodulation (nod) genes. These genes direct the synthesis
      of a lipochito-oligosaccharide signal called Nod factor (NF). NFs elicit an early
      host response, root hair calcium spiking, that is initiated in root hair cells
      within 15 min of NF or live Rhizobium inoculation. We used calcium spiking as an
      assay to compare two closely related strains of Sinorhizobium meliloti, Rm1021
      and Rm2011, derived from the same field isolate. We found that the two strains
      show a kinetic difference in the calcium spiking assay: Rm1021 elicits calcium
      spiking in host root hairs as rapidly as purified NF, whereas Rm2011 shows a
      significant delay. This difference can be overcome by raising expression levels
      of either the NodD transcriptional activators or GroEL, a molecular chaperone
      that affects expression of the biosynthetic nod genes. We further demonstrate
      that the delay in triggering calcium spiking exhibited by Rm2011 is correlated
      with a reduced amount of nod gene expression compared with Rm1021. Therefore,
      calcium spiking is a useful tool in detecting subtle differences in bacterial
      gene expression that affect the early stages of the Rhizobium-legume symbiosis.

PMID- 12481998
TI  - Regulation of the MPG1 hydrophobin gene in the rice blast fungus Magnaporthe
      grisea.
AB  - The hydrophobin-encoding gene MPG1 of the rice blast fungus Magnaporthe grisea is
      highly expressed during the initial stages of host plant infection and targeted
      deletion of the gene results in a mutant strain that is reduced in virulence,
      conidiation, and appressorium formation. The green fluorescent protein-encoding
      allele sGFP was used as a reporter to investigate regulatory genes that control
      MPG1 expression. The MAP kinase-encoding gene PMK1 and the wide domain regulators
      of nitrogen source utilization, NPR1 and NUT1, were required for full expression
      of MPG1 in response to starvation stress. The CPKA gene, encoding the catalytic
      subunit of protein kinase A, was required for repression of MPG1 during growth in
      rich nutrient conditions. During appressorium morphogenesis, high-level MPG1
      expression was found to require the CPKA and NPR1 genes. Expression of a
      destabilized GFP allele indicated that de novo MPG1 expression occurs during
      appressorium formation. Three regions of the MPG1 promoter were identified which
      are required for high-level expression of MPG1 during appressorium formation and
      are necessary for the biological activity of the MPG1 hydrophobin during spore
      formation and plant infection.

PMID- 12481999
TI  - The mitogen-activated protein kinase gene MAF1 is essential for the early
      differentiation phase of appressorium formation in Colletotrichum lagenarium.
AB  - Colletotrichum lagenarium, the causal agent of cucumber anthracnose, invades host
      plants by forming a specialized infection structure called an appressorium. In
      this fungus, the mitogen-activated protein kinase (MAPK) gene CMK1 is involved in
      several steps of the infection process, including appressorium formation. In this
      study, the goal was to investigate roles of other MAPKs in C. lagenarium. The
      MAPK gene MAF1, related to Saccharomyces cerevisiae MPK1 and Magnaporthe grisea
      MPS1, was isolated and functionally characterized. The maf1 gene replacement
      mutants grew normally, but there was a significant reduction in conidiation and
      fungal pathogenicity. The M. grisea mps1 mutant forms appressoria, but conidia of
      the C. lagenarium maf1 mutants produced elongated germ tubes without appressoria
      on both host plant and glass, on which the wild type forms appressoria,
      suggesting that MAF1 has an essential role in appressorium formation on inductive
      surfaces. On a nutrient agar, wild-type conidia produced elongated germ tubes
      without appressoria. The morphological phenotype of the wild type on the nutrient
      agar was similar to that of the maf1 mutants on inductive surfaces, suggesting
      repression of the MAF1-mediated appressorium differentiation on the nutrient
      agar. The cmk1 mutants failed to form normal appressoria but produced swollen,
      appressorium-like structures on inductive surfaces, which is morphologically
      different from the maf1 mutants. These findings suggest that MAF1 is required for
      the early differentiation phase of appressorium formation, whereas CMK1 is
      involved in the maturation of appressoria.

PMID- 12482000
TI  - At Kaiser Permanente Colorado, using practice strategies to combat the manpower
      shortage.

PMID- 12482001
TI  - The state of the pharmacy workforce.

PMID- 12482002
TI  - Job satisfaction top students' priority list.

PMID- 12482003
TI  - Pharmacist services: insurance need not be the only answer.

PMID- 12482004
TI  - The pharmaceutical sciences in America, 1952-2002.

PMID- 12482005
TI  - Drug quality and the origins of APhA:the 1851 convention of pharmaceutists and
      druggists.

PMID- 12482006
TI  - Implementing HIPAA privacy regulations in pharmacy practice.
AB  - A worthy goal of HIPAA is to protect the privacy of patient health information.
      Final regulations for achieving this goal have been issued, and all covered
      entities, including all pharmacies that transmit health information
      electronically, must comply with these regulations by April 14, 2003. Pharmacists
      are strongly advised to begin educating themselves about the HIPAA privacy
      regulations and taking steps toward implementation as soon as possible. Because
      of the complexity of the privacy rule and the lingering ambiguities about how to
      implement the regulations, pharmacies also are encouraged to obtain expert
      guidance and stay up-to-date with the regulations and implementation
      recommendations posted by OCR.

PMID- 12482007
TI  - The continuing challenge of inappropriate prescribing in the elderly: an update
      of the evidence.
AB  - OBJECTIVES: To provide an updated review of the literature on the extent of and
      risk factors for inappropriate prescribing in the elderly. METHODS: A
      comprehensive review of the most recent publications in English assessing
      inappropriate prescriptions for elderly patients in the United States using the
      1997 version of the Beers explicit criteria. The reviewed articles were obtained
      via an electronic search of the MEDLINE database for articles published between
      1997 and 2001 and a manual search through major journals for articles referenced
      in those located through MEDLINE. Search terms were Beers, explicit criteria,
      inappropriate drug use, prescribing, prescriptions, medication use, elderly, and
      health outcomes. RESULTS: Using the updated explicit criteria, a total of 11
      empirical studies were identified, all of which were conducted using
      observational surveys or claims databases. The reported prevalence of elderly
      patients using at least one inappropriately prescribed drug ranged from a high of
      40% for a population of nursing home patients to 21.3% for community-dwelling
      patients over age 65. Propoxyphene, amitriptyline, long-acting benzodiazepines
      (e.g., chlordiazepoxide, diazepam, flurazepam), and dipyridamole are among the
      most commonly occurring inappropriate prescriptions. With a few exceptions, the
      most significant patient-related predictors of inappropriate prescribing include
      polypharmacy, poor health status, and female sex. Other potential risk factors
      include prescribing location, ethnicity, age, and referral status. Limited
      evidence was found of increased health care utilization and poorer quality of
      life resulting from inappropriate drug use in the elderly in Medicare health
      maintenance organization and emergency department settings. CONCLUSION: The
      prevalence of inappropriate prescribing remains alarmingly high for the elderly
      in general and for nursing home residents in particular. This review identified
      some attributes of the elderly groups most vulnerable to inappropriate
      prescribing. Future research should document more evidence regarding the adverse
      impact of inappropriate prescribing on total health care costs and patient health
      outcomes.

PMID- 12482008
TI  - Digitalis: from folklore remedy to valuable drug.

PMID- 12482009
TI  - Evaluation of a pharmaceutical care program for hypertensive patients in rural
      Portugal.
AB  - OBJECTIVES: To evaluate the community pharmacist's capacity to positively
      influence the results of antihypertensive drug therapy through a pharmaceutical
      care program and to determine what factors limit the program. DESIGN: Randomized,
      controlled study. SETTING: Private pharmacy caring for a semiliterate, rural
      Portuguese population. PATIENTS: Random sample of 100 patients with a diagnosis
      of essential hypertension who had been on drug treatment for less than 6 months.
      Patients were randomly assigned to an intervention (n = 50) or a control (n = 50)
      group. INTERVENTION: Individualized health promotion by a research pharmacist
      involving monthly appointments for 6 months to monitor blood pressure; assess
      adherence to treatment; prevent, detect, and resolve drug-related problems
      (DRPs); and encourage nonpharmacologic measures for blood pressure control.
      Control patients received traditional care. MAIN OUTCOME MEASURES: Control of
      blood pressure; decreases in systolic/diastolic blood pressure; number of
      detected, resolved, and prevented DRPs. RESULTS: From the initial sample of 100
      patients, 41 patients in the intervention group and 41 patients in the control
      group completed the longitudinal study. After 6 months, prevalence of
      uncontrolled blood pressure decreased by 77.4% in the intervention group (P <
      .0001) and by 10.3% in the control group (P = .48). Systolic blood pressure fell
      from a mean +/- standard deviation of 152 mm Hg +/- 23 mm Hg to 129 +/- 15 mm Hg
      in intervention patients and 148 +/- 16 mm Hg to 143 +/- 20 mm Hg in control
      patients (P < .001). Twenty-four of 29 (83%) detected actual DRPs were resolved.
      About 40% of potential DRPs were prevented. CONCLUSION: In this rural community,
      a pharmaceutical care program was associated with significant improvements in
      blood pressure control in hypertensive patients.

PMID- 12482010
TI  - Stability of nifedipine in two oral suspensions stored at two temperatures.
AB  - OBJECTIVE: To determine the stability of nifedipine in two oral suspensions
      stored at 4 degrees C and 25 degrees C in plastic prescription bottles over a 3
      month period. DESIGN: Two suspensions were prepared: 1% methylcellulose:simple
      syrup NF (1:13) stored in ten 2 oz bottles; and Ora Plus:Ora Sweet (1:1) at a
      nifedipine concentration of 4 mg/mL also stored in ten 2 oz bottles. Five bottles
      of each formulation were stored at 4 degrees C, and the rest of the bottles were
      stored at 25 degrees C. Three samples were collected from each bottle at 0, 7,
      14, 28, 42, 56, 70, and 91 days and analyzed by a stability-indicating high
      performance liquid chromatography analytic method (n = 15). SETTING: Laboratory.
      RESULTS: At 4 degrees C, the mean concentration of nifedipine was nearly 100%
      that of the original concentration in both the Ora Plus-Ora Sweet and the 1%
      methylcellulose-syrup formulations during the 3-month study period. At 25 degrees
      C, the mean +/- standard deviation concentration of nifedipine was 98.9% +/-
      2.36% of the initial concentration in the Ora Plus-Ora Sweet and 97.4% +/- 2.48%
      in the 1% methylcellulose-syrup formulation over the 3-month period. No changes
      in pH or physical appearance were observed. CONCLUSION: Nifedipine can be
      prepared in two liquid dosage forms and stored for up to 3 months under
      refrigeration or at room temperature.

PMID- 12482011
TI  - Stability of methylprednisolone sodium succinate in autodose infusion system
      bags.
AB  - OBJECTIVE: To evaluate the physical and chemical stabilities of
      methylprednisolone sodium succinate solutions packaged in sterile AutoDose
      Infusion System bags. SETTING: Laboratory. INTERVENTIONS: The test samples were
      prepared by reconstituting the methylprednisolone sodium succinate, adding the
      required amount of drug to the AutoDose Infusion System bags, and diluting to the
      target concentrations of 100 mg/100 mL and 1 gram/100 mL with 0.9% Sodium
      Chloride Injection. MAIN OUTCOME MEASURES: Physical stability and chemical
      stability based on drug concentrations initially and at appropriate intervals
      over periods up to 3 days at 23 degrees C and 30 days at 4 degrees C. RESULTS:
      The admixtures initially were clear when viewed in normal fluorescent room light
      and with a Tyndall beam. Measured turbidity and particulate content were low
      initially and exhibited little change. All samples were essentially colorless
      throughout the study. High-performance liquid chromatography analysis revealed
      some decomposition in the samples. Methylprednisolone sodium succinate exhibited
      about 8% loss after 2 days and about 13% loss after 3 days at 23 degrees C. In
      the samples stored at 4 degrees C, methylprednisolone sodium succinate exhibited
      acceptable stability through 21 days of storage, but losses exceeded 10% after 30
      days. CONCLUSION: Methylprednisolone sodium succinate exhibited physical and
      chemical stabilities consistent with those found in previous studies. The
      AutoDose Infusion System bags did not adversely affect the physical or chemical
      stability of this drug.

PMID- 12482012
TI  - The syringe shield rule: model for practitioner-initiated regulatory reform.
AB  - OBJECTIVE: To implement a performance-based method for maintaining radiation
      exposures to extremities as low as reasonably achievable while handling syringes
      containing radioactive materials. SETTING: University hospital nuclear medicine
      clinic. PRACTICE DESCRIPTION: Nuclear pharmacy and nuclear medicine. PRACTICE
      INNOVATION: The author petitioned the Iowa Department of Public Health to revise
      its prescriptive syringe shield rule to allow for the development of a
      performance-based method while handling syringes containing radioactive material.
      MAIN OUTCOME MEASURES: Following enactment of the revised rule, a new performance
      based policy and guidelines for the use of syringe shields were developed and
      implemented. Extremity exposures for nuclear medicine personnel were monitored in
      the nuclear medicine clinic and evaluated for 6-month periods immediately before
      and after implementation of the new policy and guidelines. RESULTS: The Iowa
      Department of Public Health responded favorably to the author's petition and
      revised its rule to allow performance-based methods. Implementation of the
      performance-based method did not significantly affect extremity exposures.
      CONCLUSION: Practitioner-initiated regulatory reform for revision of a
      prescriptive rule to a performance-based rule can be feasible and practicable.

PMID- 12482013
TI  - Third party reimbursement for pharmacist services: why has it been so difficult
      to obtain and is it really the answer for pharmacy?
AB  - OBJECTIVES: To describe three models of how health insurance coverage can develop
      for health care goods and services and apply them to pharmacist services. Also,
      to raise readers' awareness of the costs/tradeoffs involved in receiving third
      party reimbursements of insurance coverage from a health provider perspective.
      DATA SOURCES: Insurance theory and literature. SUMMARY: The three models for
      developing health insurance coverage are the risk-pooling model, the demand
      model, and the cost containment model. The risk-pooling model does not apply to
      coverage for pharmacist services because the cost of such services is not
      catastrophic and unpredictable. Applying both the demand model and the cost
      containment model to developing coverage for pharmacist services presents some
      challenges, but the demand model has been used more successfully to obtain
      insurance coverage for other health care goods and services. Potential costs and
      tradeoffs to the health care provider associated with insurance coverage are
      higher administrative costs, lower reimbursement rates, and loss of professional
      autonomy. CONCLUSION: If pharmacists want to increase third party coverage for
      their services, the best approach may be to increase patient demand for insurance
      coverage by promoting and charging for pharmacist services. However, pharmacists
      should seriously consider whether the benefits of such coverage for their
      services outweigh the costs.

PMID- 12482014
TI  - Combination antiplatelet therapy: implications for pharmacists.
AB  - OBJECTIVES: To present two case reports of patients who received suboptimal oral
      antiplatelet therapy and to review recent changes in national guidelines for
      management of acute coronary syndromes. DATA SOURCES: Personal observation by the
      authors, and clinical practice guidelines and related clinical trials of the
      American Heart Association and the American College of Cardiology. SUMMARY: The
      American College of Cardiology and the American Heart Association revised the
      guidelines for administration of antiplatelet and anticoagulant therapy in
      patients with unstable angina and non-ST-segment elevation myocardial infarction
      in March 2002. Two cases observed by the authors illustrate the consequences of
      suboptimal antiplatelet therapy when a combination of two antiplatelet drugs
      should have been administered. CONCLUSION: Evidence from recent randomized,
      controlled trials led to changes in the national guidelines for administration of
      oral antiplatelet therapy in patients with acute coronary syndromes. Pharmacists
      should be aware of these changes and counsel patients about appropriate
      administration of antiplatelet drugs.

PMID- 12482015
TI  - Implementing new guidelines to prevent sexually transmitted diseases.

PMID- 12482016
TI  - NHBPEP: working to reduce death and disability from high blood pressure. National
      High Blood Pressure Education Program.

PMID- 12482017
TI  - Rebif offers another option for treating multiple sclerosis.

PMID- 12482018
TI  - Founders of the American Pharmaceutical Association.

PMID- 12482019
TI  - Antioxidant status during cutaneous wound healing in immunocompromised rats.
AB  - The present investigation was undertaken to investigate the endogenous status of
      free radical scavengers during cutaneous wound healing in immunocompromised rats.
      Antioxidant contents and lipid peroxidation product in terms of malondialdehyde
      (MDA) have been monitored in the wound tissues of immunosuppressed rats at
      different time intervals (2, 7 and 14 days) following cutaneous injury. A
      significant increase in MDA content and decrease in glutathione and vitamin C
      content was observed in the skin of immunocompromised rats as compared to control
      subjects. Further, a significant decrease in vitamin C, vitamin E content,
      catalase and glutathione peroxidase activity was observed at 2 days postwounding
      in immunocompromised rats. A significant and time-dependent decrease in
      glutathione content was also observed at 7 and 14 days postwounding. However, the
      healing tissue on 2 and 7 days postwounding exhibited significantly elevated
      superoxide dismutase activity. The MDA content was augmented only at 2 days
      postwounding in immunosuppressed rats. Thus significant alterations in the
      antioxidant profile accompanied by elevated levels of MDA, a marker of free
      radical damage may be contributory to impaired wound healing in immunocompromised
      rats.

PMID- 12482020
TI  - Biochemical and morphological alterations in lungs induced by experimental
      inhibition of fibrinolytic activity.
AB  - The fibrinolytic system is known to play an important role in the protection of
      lung architecture and function. This study investigated the effects on lungs of
      inhibiting the fibrinolytic system using tranexamic acid (TXA). Thirty cats were
      used, 15 experimental and 15 control. TXA was administered intravenously to the
      experimental animals for 3 h at 200 mg/kg (acute) and 7 days at 100 mg/kg
      (chronic). Blood samples were obtained from the carotid artery. The acute dose
      cats were sacrificed at 3 h and 24 h and the chronic dose cats at 8 days. Samples
      of inflated and fixed lung were examined morphologically and their collagen
      contents were determined. Fibrinolytic activity in blood samples was determined
      by fibrinogen degradation products levels, fibrin plate lytic area diameter, and
      the euglobulin lysis time. Hyperemia, lung interstitial oedema, haemorrhaging,
      inflammatory cell infiltration, pneumocyte type II cell proliferation, thrombosis
      and emphysema-related changes, characterized by enlargement of air spaces
      accompanied by destruction of alveolar walls, were observed in experimental cats
      group. None of these alterations except hyperemia and lung interstitial oedema
      were observed in two control animals. Electron microscopy results revealed oedema
      fluid in the interstitium, proliferation of pneumocyte type II cells, thickening
      of the alveolar septa and presence of marked amounts of collagen. Vacuoles were
      seen in the capillary endothelial cells. Elastic tissue was observed as elastic
      masses and partly disrupted, although elastic fibers were not prominent in all
      parts of the interstitium. Collagen content in the chronic dose experimental
      group was significantly higher than in all control and acute dose experimental
      groups. The inhibition of fibrinolytic system appears to have caused the
      emphysematous alterations, alveolar wall destruction and collagen accumulation
      possibly by causing microthromboses leading to mechanical blockage-ischemic
      changes, or by causing secondary fibrinolysis as a result of fibrin degradation
      products affecting local plasminogen activators and proteases. An injury-repair
      process also appears to have occurred.

PMID- 12482021
TI  - Fibronectin expression in proximal tubules from ischemic rat kidneys without
      reperfusion.
AB  - The expression of fibronectin (FN), one of the extracellular matrix proteins, was
      studied in isolated renal proximal tubules in a in vivo rat model of unilateral
      renal ischemia without reperfusion. FN is involved in cell-extracellular matrix
      interactions and defective cell-extracellular matrix interactions have been
      hypothesized to contribute to ischemic renal failure. The expression of FN was
      investigated by reverse transcription-polymerase chain reaction (RT-PCR), Elisa
      and Western blot. Isolated proximal tubules from control and post-ischemic rat
      kidneys were used. ATP, intracellular calcium content, and alkaline phosphatase
      were also measured to describe the effects associated to 40 min of ischemia.
      Control tubules expressed FN. Forty minutes of ischemia promoted diminished ATP
      levels and phosphatase alkaline activity, and increased intracellular calcium in
      isolated proximal tubules. An increased abundance of FN was observed by ischemic
      tubules as compared with control tubules. To determine quantitatively the value
      of FN content, ELISA method was performed. The ischemic tubules also expressed
      higher amount of FN mRNA. Three amplification products were obtained from both
      ischemic and control proximal tubular cDNA. The relative amounts of each of the
      obtained products were the same, strongly suggesting that the augmentation of the
      FN gene transcription during ischemia is not associated to a modification in the
      splicing pattern. Moreover, this expression is increased after 40 min of
      ischemia, not followed by reperfusion.

PMID- 12482022
TI  - Calpain, calpastatin activities and ratios during myocardial ischemia
      reperfusion.
AB  - The purpose of this study was to test the hypothesis that myocardial ischemia
      reperfusion (I/R) is accompanied by an early burst in calpain activity, resulting
      in decreased calpastatin activity and an increased calpain/calpastatin ratio,
      thereby promoting increased protein release. To determine the possibility of a
      'calpain burst' impacting cardiac calpastatin inhibitory activity, rat hearts
      were subjected (Langendorff) to either 45 or 60 min of ischemia followed by 30
      min of reperfusion with and without pre-administration (s.c.) of a cysteine
      protease inhibitor (E-64c). Myocardial function, calpain activities (casein
      release assay), calpastatin inhibitory activity and release of CK, LDH, cTnI and
      cTnT were determined (n = 8 for all groups). No detectable changes in calpain
      activities were observed following I/R with and without E-64c (p > 0.05). Both
      I/R conditions reduced calpastatin activity (p < 0.05) while E-64c pre-treatment
      was without effect, implicating a non-proteolytic event underlying the
      calpastatin changes. A similar result was noted for calpain-calpastatin ratios
      and the release of all marker proteins (p < 0.05). In regard to cardiac function,
      E-64c resulted in transient improvements (15 min) for left ventricular developed
      pressure (LVDP) and rate of pressure development (p < 0.05). E-64c had no effect
      on end diastolic pressure (LVEDP) or coronary pressure (CP) during I/R. These
      findings demonstrate that restricting the putative early burst in calpain
      activity, suggested for I/R, by pre-treatment of rats with E-64c does not prevent
      downregulation of calpastatin inhibitory activity and/or protein release despite
      a transient improvement in cardiac function. It is concluded that increases in
      calpain isoform activities are not a primary feature of l/R changes, although the
      role of calpastatin downregulation remains to be elucidated.

PMID- 12482023
TI  - Mixed lineage kinase 3 inhibits phorbol myristoyl acetate-induced DNA synthesis
      but not osteopontin expression in rat mesangial cells.
AB  - Mixed lineage kinase 3 (MLK 3) (also called SPRK or PTK-1) is a recently
      described member of the family of the mixed lineage kinase subfamily of Ser/Thr
      protein kinases that interacts with mitogen-activated protein kinase pathways. In
      order to test the biological relevance and potential interaction of MLK 3 with
      protein kinase C-mediated signaling pathways, human MLK 3 was stably expressed in
      rat glomerular mesangial cells using a retroviral vector (LXSN) and the effects
      of phorbol myristoyl acetate (PMA) on DNA synthesis and osteopontin mRNA
      expression were examined. In control (vector-transfected) mesangial cells PMA
      increased [3H]-thymidine incorporation in a concentration-dependent manner. In
      mesangial cells stably expressing MLK 3, the PMA-induced increase in [3H]
      thymidine incorporation was significantly reduced (> 50%). However, the PMA
      induced increase in osteopontin mRNA was not affected by MLK 3 expression. To
      determine the mechanisms of these effects, activation of ERK2, JNK1 and p38 in
      response to PMA was examined in both vector and MLK 3 transfected cells. ERK2
      activation was increased several fold by PMA in control cells but was attenuated
      significantly in MLK 3 expressing cells, suggesting that MLK 3 expression in
      mesangial cells can negatively regulate the ERK pathway. PMA had no significant
      effect on JNK and P38 activation, in either vector- or MLK 3-expressing cells.
      PD98059, a MEK inhibitor blocked PMA-induced DNA synthesis without affecting
      osteopontin expression. These results suggest that while protein kinase C
      activation increases cellular proliferation and osteopontin mRNA expression, over
      expression of MLK 3 affects only the PKC-induced DNA synthesis, probably through
      inhibition of ERK. These results also indicate a novel mechanism of growth
      regulation by a member of the mixed-lineage kinase family that might have
      significant therapeutic implications in proliferative glomerulonephritis.

PMID- 12482024
TI  - Interactions of the 18.5 kDa isoform of myelin basic protein with Ca2+
      calmodulin: in vitro studies using gel shift assays.
AB  - The interactions of the 18.5 kDa isoform of myelin basic protein (MBP) with
      calmodulin (CaM) in vitro have been investigated using glutaraldehyde or
      dithiobis[succinimidylpropionate] (DSP) cross-linking, and SDS-polyacrylamide gel
      electrophoresis. The following forms of MBP were used: the natural bovine C1
      charge isomer (bMBP/C1) and a recombinant murine product (rmMBP), and their
      fragments generated by digestion with cathepsin D (EC 3.4.23.5). In physiological
      buffers (10 mM HEPES-NaOH, pH 7.4, 5 mM CaCl2, 0.0035% glutaraldehyde; or 50 mM
      HEPES-NaOH, pH 7.4, 100 mM NaCl, 1 mM CaCl2, 0.0035% DSP), MBP and CaM interacted
      primarily in a 1:1 molar ratio, consistent with previous studies that used 6 M
      urea, i.e. denaturing conditions. Moreover, the appearance of higher-order bands
      (not previously observed) suggested that the mechanism of interaction of the two
      proteins involved a series of relatively complex equilibria, resulting in 2:1
      ratios of MBP to CaM. This observation would explain the cooperativity of
      association inferred from fluorescence studies [13]. Our results demonstrated
      further that the interaction involved the C-terminal domain of MBP, again in a
      primarily 1:1 molar ratio with CaM, consistent with our identification of a CaM
      binding motif at the C-terminus.

PMID- 12482025
TI  - Effect of feeding aqueous extract of Pterocarpus marsupium on glycogen content of
      tissues and the key enzymes of carbohydrate metabolism.
AB  - The Indian traditional system of medicine prescribed plant therapies for diseases
      including diabetes mellitus called madhumeh in Sanskrit. One such plant mentioned
      in Ayurveda is Pterocarpus marsupium (PM). In the present study, aqueous extract
      of PM (1 g/kg PO) was assessed for its effect on glycogen levels of insulin
      dependent (skeletal muscle and liver), insulin-independent tissues (kidneys and
      brain) and enzymes such as glucokinase (GK), hexokinase (HK), and
      phosphofructokinase (PFK). Administration of PM led to decrease in blood glucose
      levels by 38 and 60% on 15th and 30th day of the experiment. Liver and 2-kidney
      weight expressed as percentage of body-weight was significantly increased in
      diabetics (p < 0.0005) vs. normal controls and this alteration in the renal
      weight (p < 0.0005) but not liver weight was normalized by feeding of PM extract.
      Renal glycogen content increased by over 10-fold while hepatic and skeletal
      muscle glycogen content decreased by 75 and 68% in diabetic controls vs. controls
      and these alteration in glycogen content was partly prevented by PM. Activity of
      HK, GK and PFK in diabetic controls was 35,50 and 60% of the controls and PM
      completely corrected this alteration in PFK and only partly in HK and GK.

PMID- 12482026
TI  - Potential role of regucalcin as a specific biochemical marker of chronic liver
      injury with carbon tetrachloride administration in rats.
AB  - The potential sensitivity of liver specific protein regucalcin as a biochemical
      marker of chronic liver injury with carbon tetrachloride (CCl4) administration in
      rats was investigated. CCl4 (10%; 1.0 ml/100 g body wt) was orally given 5 times
      at 3-day intervals to rats, and the animals were killed by bleeding at 3, 6, 18,
      and 30 days after the first administration of CCl4. The body weight of rats was
      significantly lowered 3 and 6 days after CCI4 administration as compared with
      that of control rats administered with corn oil, and then the weight was restored
      at 18 and 30 days. Serum glutamate-oxaloacetate transaminase (GOT) and glutamate
      pyruvate transaminase (GPT) activities were significantly increased 3 days after
      the administration, while a significant increase in serum y
      glutamyltranspeptidase (gamma-GTP) activity was seen at 3 and 6 days after the
      administration. Serum GOT, GPT, and gamma-GTP activities were restored to control
      levels at 18 and 30 days after CCl4 administration. Serum albumin, alpha
      fetoprotein, and ammonium levels were not changed by CCl4 administration.
      Meanwhile, serum regucalcin concentration was markedly increased 3 and 6 days
      after CCl4 administration, and a significant increase in serum regucalcin
      concentration was observed 18 and 30 days after the administration. Liver
      regucalcin mRNA and liver cytosolic regucalcin levels were significantly
      decreased 18 and 30 days after CCl4 administration. Liver content of calcium,
      which intracellular calcium homeostasis is maintained, was significantly
      increased between 3 and 30 days after CCl4 administration. Hepatic mitochondrial
      succinate dehydrogenase activity was significantly increased 30 days after the
      administration. The present study demonstrates that serum regucalcin has a
      potential sensitivity as a specific biochemical marker of chronic liver injury
      with CCl4 administration in rats.

PMID- 12482028
TI  - Human liver AMP-deaminase--oligomeric forms of the enzyme.
AB  - AMP-deaminase (EC 3.5.4.6) is a key enzyme of nucleotide breakdown involved in
      regulation of adenine nucleotide pool in the liver. Mechanisms regulating
      activity of the enzyme are not completely elucidated, till now. In this paper
      experimental data indicating on the potential regulatory significance of changes
      in oligomeric structure of the enzyme are presented. SDS-PAG electrophoresis of
      human liver AMP-deaminase revealed the presence of three enzyme fragments. Only
      largest of them (the protein fragments weighing 68 kDa) reacted immunologically
      with anti- (human liver) AMP-deaminase antibodies. At physiological pH 7.0, in
      the absence of regulatory ligands, reaction catalysed by human liver AMP
      deaminase was strongly dependent on enzyme concentration used, with half
      saturation constant (S0.5) values increasing significantly with the degree of
      enzyme dilution. Preincubation with activated long-chain fatty acids--substances
      promoting dissociation of oligomeric enzymes, inhibited the activity of AMP
      deaminase studied nearly completely. Gel filtration on Sepharose CL-6B column
      demonstrated existence of at least three active oligomeric forms of human liver
      AMP-deaminase. We postulate that oligomeric structure of the enzyme is a factor
      determining regulatory profile of AMP-deaminase studied.

PMID- 12482027
TI  - Rat osseous plate alkaline phosphatase: effect of neutral protease digestion on
      the hydrolysis of pyrophosphate and nitrophenylphosphate.
AB  - Collagenase treatment, commonly used to prepare alkaline phosphatase-rich matrix
      vesicles from epiphyseal cartilage growth plates, seems to affect the integrity
      of this membrane-bound enzyme. Alkaline phosphatase-rich rat osseous plates were
      incubated with 1,000 U/mL collagenase for 3 h, at 37 degrees C and after
      purification on Sepharose 4B, kinetic studies were performed using
      nitrophenylphosphate and pyrophosphate as substrates. The optimum apparent pH for
      the hydrolysis of p-nitrophenylphosphate and pyrophosphate increased from 9.4 to
      10.25 and from 8.0 to 9.0, respectively, as a consequence ofcollagenase
      treatment. In the absence of Mg2+ ions, the enzyme hydrolyzed PNPP with KM =
      322.5 +/- 15.3 microM and V = 965.2 +/- 45.8 U/mg, while in the presence of 2 mM
      Mg2+ ions, V increased 66%. Cobalt (K0.5 = 5.3 +/- 0.3 microM) and manganese
      (K0.5 = 0.72 +/- 0.03 microM) ions stimulated the PNPPase activity of the
      collagenase-treated enzyme, but with a lower apparent affinity when compared with
      that of not-treated enzyme. In the absence of Mg2+ ions pyrophosphate was
      hydrolyzed according to Michaelis-Menten kinetics (KM = 105.1 +/- 6.3 microM and
      V = 64.9 +/- 3.9 U/mg), but site-site interactions (nH = 1.2) were observed in
      the presence of 2 mM Mg2+ ions (V = 110.8 +/- 5.5 U/mg; K0.5 = 42.7 +/- 2.0
      microM). To our knowledge this is the first report showing significant
      alterations on phosphohydrolytic activity and metal binding properties of bone
      alkaline phosphatase due to associated neutral proteases in collagenase
      preparations often used for the isolation of matrix vesicles.

PMID- 12482029
TI  - Mutation of glutamic acid residue 1046 abolishes Jak2 tyrosine kinase activity.
AB  - Jak2 is a member of the Janus family of tyrosine kinases and is known to be
      activated by a wide variety of ligands. Here, we sought to identify amino acid
      residues within Jak2 that are essential for its activation. We provide evidence
      that glutamic acid 1046 (E1046) is one such residue. Using molecular modeling
      algorithms of the Jak2 kinase domain, we identified a putative molecular
      interaction between E1046 and tryptophan 1020 (W1020). Conversion of E1046 to
      either arginine (E 1046R), alanine (E1046A), aspartic acid (E1046D) or glutamine
      (E1046Q) abolished Jak2 kinase activity as measured by autophosphorylation
      assays. Conversion of W1020 to glycine (W1020G) similarly abolished Jak2 kinase
      activity. Finally, we tested the ability of the E1046R mutant to activate the
      Jak/STAT signaling pathway in a ligand-dependent signaling system. The ability of
      angiotensin II to activate the Jak/STAT signaling pathway in cells expressing the
      E1046R mutant was severely compromised as measured by reduced (1) Jak2
      autophosphorylation (2) Jak2 kinase activity (3) AT1/Jak2 co-association (4)
      Stat1 tyrosine phosphorylation and (5) angiotensin Il-mediated gene
      transcription. Thus, these studies demonstrate for the first time, the critical
      role of E1046 in mediating Jak2 activation and its subsequent downstream
      signaling events.

PMID- 12482030
TI  - Hypoglycemic and antihyperglycemic effect of Brassicajuncea diet and their effect
      on hepatic glycogen content and the key enzymes of carbohydrate metabolism.
AB  - Plants in the form of food or other remedial forms have been used for the
      treatment of various human ailments. Diabetes is one such disorder in which
      various form of plants and herbal remedies have been tried. Brassicajuncea (BJ)
      seeds (Rai) are consumed in India as a spice in various food items. Previous
      studies have shown the hypoglycemic effect of this plant in rats. The present
      study was undertaken to study the hypoglycemic and antihyperglycemic of various
      strengths (5, 10 and 15%) of BJ seed diet in alloxan and streptozotocin induced
      diabetes in albino rats. In addition, key enzymes of carbohydrate metabolism
      (glucokinase--EC 2.7.1.1, hexokinase--EC 2.7.1.1, and phosphofructokinase--EC
      2.7.1.11) and hepatic glycogen content was also assessed to understand the
      mechanism of action. BJ diet (10 and 15%) showed significant antihyperglycemic
      effect in alloxan (35 mg/kg) but not in STZ (60 mg/kg) rats. It also failed to
      modulate the hepatic glycogen content and enzyme activities.

PMID- 12482031
TI  - Effects of D-glucose upon D-fructose metabolism in rat hepatocytes: A 13C NMR
      study.
AB  - Isolated hepatocytes from fed rats were exposed for 120 min to D-glucose (10 mM)
      and either D-[1-13C]fructose, D-[2-13C]fructose or D-[6-13C]fructose (also 10 mM)
      in the presence of D2O. The identification and quantification of 13C-enriched D
      fructose and its metabolites (D-glucose, L-lactate, L-alanine) in the incubation
      medium and the measurement of their deuterated isotopomers indicated, by
      comparison with a prior study conducted in the absence of exogenous D-glucose,
      that the major effects of the aldohexose were to increase the recovery of 13C
      enriched D-fructose, decrease the production of 13C-enriched D-glucose, restrict
      the deuteration of the 13C-enriched isotopomers of D-glucose to those generated
      by cells exposed to D-[2-13C]fructose, and to accentuate the lesser deuteration
      of the C, (as compared to C5) of 13C-enriched D-glucose derived from D-[2
      13C]fructose. The ratio between C2-deuterated and C2-hydrogenated L-lactate, as
      well as the relative amounts of the CH3-, CH2D-, CHD, and CD3- isotopomers of 13C
      enriched L-lactate were not significantly different, however, in the absence or
      presence of exogenous D-glucose. These findings indicate that exogenous D-glucose
      suppressed the deuteration of the C1 of D-[I-13C]glucose generated by hepatocytes
      exposed to D-[1-13C]fructose or D-[6-13C]fructose, as otherwise attributable, in
      part at least, to gluconeogenesis from fructose-derived [3-13C]pyruvate, and
      apparently favoured the phosphorylation of D-fructose by hexokinase isoenzymes,
      probably through stimulation of D-fructose phosphorylation by glucokinase.

PMID- 12482032
TI  - Dietary vitamin E and C supplementation prevents fructose induced hypertension in
      rats.
AB  - In fructose-induced hypertension in Wistar-Kyoto (WKY) rats, excess endogenous
      aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+
      channels and increasing cytosolic free calcium and blood pressure. The thiol
      compound N-acetyl cysteine prevents fructose-induced hypertension by binding
      excess endogenous aldehydes and normalizing membrane Ca2+ channels and cytosolic
      free calcium. The aim of the present study was to investigate whether dietary
      supplementation of vitamin E and vitamin C which are known to increase tissue
      glutathione, a storage form of cysteine, prevents this hypertension and its
      associated biochemical and histopathological changes. Starting at 7 weeks of age,
      animals were divided into four groups of six animals each and treated as follows:
      control group, normal diet and normal drinking water; fructose group, normal diet
      and 4% fructose in drinking water; fructose + vitamin E group, diet supplemented
      with vitamin E (34 mg/ kg feed) and 4% fructose in drinking water; fructose +
      vitamin C group, diet supplemented with vitamin C (1,000 mg/kg feed) and 4%
      fructose in drinking water. At 14 weeks, systolic blood pressure, platelet
      [Ca2+]i and kidney and aortic aldehyde conjugates were significantly higher in
      the fructose group. These animals also displayed smooth muscle cell hyperplasia
      in the small arteries and arterioles of the kidneys. Dietary vitamin E and C
      supplementation in fructose-treated WKY rats prevented the increase in systolic
      blood pressure by normalizing cytosolic [Ca2+]i and kidney and aortic aldehyde
      conjugates and preventing adverse renal vascular changes.

PMID- 12482033
TI  - Mechanical overload-induced apoptosis: a study in cultured neonatal ventricular
      myocytes and fibroblasts.
AB  - Apoptosis of cardiac myocytes has been implicated in cardiac dysfunction due to
      chronic hemodynamic overload. Reports on the role of apoptosis in the transition
      from hypertrophy to decompensated heart failure are not unequivocal. In this
      study we analysed the direct relationship between mechanical overload and
      induction of apoptosis in an in vitro model of cultured heart cells. Cyclic
      mechanical stretch was applied to cultured neonatal rat ventricular myocytes and
      fibroblasts. Several indicators of apoptosis were examined, such as morphological
      features, caspase-3 activity and DNA fragmentation. Mechanical strain did not
      induce any significant change in these parameters as compared to non-stretched
      myocytes or fibroblasts. However, administration of staurosporine, a known
      inducer of apoptosis, induced massive apoptosis in myocytes as well as
      fibroblasts. We conclude that this in vitro cell model system lacks a direct link
      between mechanical stretch and apoptosis. The three-dimensional structure
      function relationship of myocardial tissue in the intact heart may elicit stretch
      induced molecular signaling cascades in a much more complex way than in monolayer
      cultures of cardiac cells.

PMID- 12482034
TI  - Time-dependent changes of the susceptibility of cardiac contractile function to
      hypoxia-reoxygenation after myocardial infarction in rats.
AB  - In this study we analyzed the susceptibility of contractile function of the
      myocardium to hypoxia-reoxygenation after infarction. For this purpose, the
      contractility of isolated papillary muscles from rats was studied at high oxygen
      tension (pO2 80 kPa) and during hypoxia (pO2 3 kPa) with subsequent reoxygenation
      at variable intervals between 15 h and 9 weeks after permanent ligation of the
      left coronary artery. Hypoxic exposure reduced the contractile performance of the
      preparations to a similar extent in both groups. Notably, the contractility and,
      in particular, the relaxation rates recovered more completely from hypoxia in the
      hypertrophied myocardium of rats with coronary artery ligation than in sham
      operated (SO) animals. The recovery of contractile function was improved
      maximally between 6 and 9 weeks after myocardial infarction (MI). The lower
      sensitivity of the (post)ischemic myocardium to hypoxia-reoxygenation correlated
      with enhanced left ventricular glutathione peroxidase (GSH-Px) activity (15 h to
      9 weeks post-MI) and 2-3-fold increased expression levels (15 h to 6 weeks post
      MI) of the 72 kDa heat shock protein (HSP72) in the papillary muscles. These
      findings suggest that the greater antioxidant potential and, possibly,
      stimulation of HSPs contribute to the sustained tolerance of the myocardium to
      hypoxia-reoxygenation injury after infarction.

PMID- 12482035
TI  - Scleroderma: what is the reason for the death?

PMID- 12482036
TI  - Disorders of skin barriers: clinical implications.

PMID- 12482037
TI  - How should pemphigus be treated?

PMID- 12482038
TI  - Current treatments and perceptions of genital herpes: a European-wide view.
AB  - A European panel of physicians reviewed the current treatments and perceptions of
      recurrent genital herpes (GH) across the continent. The panel consisted of
      specialists in dermatology and venereology from France, Finland, Germany, Italy,
      Norway, Spain, Sweden and the UK. A wide variety of factors that influence GH
      management were considered, including different health delivery systems, funding
      and cultural differences. The poor awareness of GH among both the general public
      and physicians was highlighted. The effectiveness of GH management was then
      examined from a patient's viewpoint, including the confirmation of the diagnosis,
      information and counselling about GH, as well as prescriptions for treatment. It
      was agreed that both physicians and patients often feel uncomfortable about
      discussing the disease, and that a European-wide effort is needed to re-educate
      patients and physicians about GH. The panel identified clear and unmet needs to
      manage a patient with clinical recurrences and to attempt to reduce the risk of
      GH transmission. Finally, resiquimod, an immune response modifier, was considered
      as a potential treatment option for GH.

PMID- 12482039
TI  - Psychiatric morbidity in vitiligo: prevalence and correlates in India.
AB  - BACKGROUND: Vitiligo, a common pigmentary disorder, is recognized to be
      associated with a high psychiatric morbidity, yet compared to other
      dermatological disorders like leprosy, psoriasis, etc., it has not been subjected
      to detailed evaluation of its psychological consequences. The data from the
      developing countries on this aspect in particular is meager. METHODS: One hundred
      and thirteen cases with vitiligo were evaluated along with 55 healthy controls
      comparable for sociodemographic profile and matched on attitude to appearance
      scale. Clinical details, impact of illness, associated dysfunction and
      psychological morbidity were additionally assessed. RESULTS: Twenty-eight
      patients with vitiligo were found to have psychiatric morbidity, a clinic
      prevalence rate of 25% (95% confidence interval 20.3-29.3%). The majority of the
      cases had a diagnosis of adjustment disorder. Psychiatric morbidity was
      significantly correlated with dysfunction arising out of illness. CONCLUSIONS:
      Vitiligo is associated with high psychiatric morbidity. There is a need to
      develop cross-cultural database on psychosocial aspects and psychiatric morbidity
      associated with vitiligo.

PMID- 12482040
TI  - Onychomycosis: strategies to improve efficacy and reduce recurrence.
AB  - Fungal infections may be difficult to treat for several reasons. It is important
      to obtain the correct diagnosis, and select the appropriate antifungal agent and
      route. General considerations that may be associated with recurrent infections
      are, a genetic predisposition and suboptimal bioavailability of drug, resulting
      in insufficient concentration at the target site. The aetiologic organism, the
      severity of disease, other coexisting diseases, concomitant drug intake, and the
      presence of fungal infection at other sites are some factors that determine the
      choice of antifungal therapy and its route of administration, oral vs. topical
      lacquer. Local factors such as the thickness of the nail, presence of lateral
      onychomycosis, longitudinal spike, dermatophytoma and severe onycholysis are some
      factors that may determine the choice of secondary measures such as mechanical or
      topical treatment. Booster or supplemental therapy may be of benefit when the
      response to initial treatment is poorer than expected and unlikely to result in
      complete response. Steps should be taken to reduce the possibility of recurrence
      once cure has been achieved.

PMID- 12482041
TI  - Repair of acetone- and sodium lauryl sulphate-damaged human skin barrier function
      using topically applied emulsions containing barrier lipids.
AB  - BACKGROUND: It is generally acknowledged that well-formulated moisturizing skin
      care products can restore disturbed barrier function that can be assessed by
      transepidermal water loss (TEWL) measurements. When ceramides and/or other
      barrier lipids are incorporated, it is, however, not always clearly demonstrated
      which ingredients of the formulation exert the beneficial effects. OBJECTIVES: In
      this study the effects of topically applied ceramide-containing mixtures on the
      barrier repair of sodium lauryl sulphate (SLS)- and acetone-induced skin damage
      have been studied in human volunteers. TEWL and stratum corneum hydration
      measurements were carried out. The emulsions applied contained either a mixture
      of two types of ceramides, CerIII and CerIIIB (emulsion 1) or a complete mixture
      of ceramides III, IIIB and VI together with phytosphingosine, cholesterol and the
      free fatty acid linoleic acid (emulsion 2). RESULTS: After SLS damage, it was
      observed that barrier recovery was significantly accelerated by topical
      application (14 days, 2 x/d) of emulsion 2 compared with the results obtained
      with emulsion 1. Corneometrical results were not relevant due to the occurrence
      of scaly fissured skin, failing to provide a good skin/probe contact. Although no
      effect on TEWL could be observed, the improvement of skin hydration after acetone
      treatment and a single application of the emulsions, was significantly more
      positive for emulsion 2 than for emulsion 1. CONCLUSIONS: The investigative
      methods used in this study show that ceramides combined with other skin lipids
      can improve barrier repair after damage.

PMID- 12482042
TI  - Local treatment of chronic cutaneous leg ulcers with recombinant human
      granulocyte-macrophage colony-stimulating factor.
AB  - AIM: To test the efficacy and safety of recombinant granulocyte-macrophage colony
      stimulating factor (rHuGM-CSF) in the treatment of chronic cutaneous leg ulcers.
      METHODS: Five patients with chronic cutaneous leg ulcers were recruited for this
      4-month study using only rHuGM-CSF to treat the ulcers. One patient had a
      neuropathic-diabetic ulcer, and four had long-standing vascular leg ulcers.
      RESULTS: The patient with the neuropathic diabetic ulcer showed complete healing
      after 1 month of treatment. The other four patients with vascular leg ulcers with
      a long history of ulceration had a poor prognosis for healing. The first, with
      three venous ulcerative lesions, presented complete resolution of one ulcer and
      stabilization of the other two; the second and third patients, with large
      vascular ulcers, improved with more then 50% reduction of the mean diameter of
      the ulcers; the fourth patient, with one large venous ulcer, did not show any
      improvement. CONCLUSIONS: Pathogenesis, size and duration of the ulcers seemed to
      be the most important parameters regarding wound repairing capability of rHuGM
      CSF. None of the ulcers increased in size and none of the patients developed
      clinical side-effects or peripheral blood cell count abnormalities during the
      treatment. All the results described were stable after 6 months of follow up. The
      absence of peripheral leucocyte count variation and the size-dependent
      therapeutic effect indicate that the drug exercises local rather than systemic
      actions.

PMID- 12482043
TI  - Pemphigus vulgaris: a review of treatment over a 19-year period.
AB  - BACKGROUND: Pemphigus vulgaris is an autoimmune blistering disease of the skin
      and mucous membranes with a high mortality if left untreated. OBJECTIVE: We
      present a retrospective analysis of 159 patients with pemphigus vulgaris and
      pemphigus vegetans who were admitted to the Department of Dermatology and
      Venereology, Zagreb University Hospital Center (Zagreb, Croatia) from 1980 to
      1998. RESULTS: Female to male ratio was approximately 2:1. The mean age was 53
      years. During the war years in Croatia (1991-95) we noticed a low incidence of
      pemphigus vulgaris, and from 1996 to 1998 the incidence almost doubled. Diagnosis
      was based on histopathology [showing typical pemphigus vulgaris changes in 156
      (98%) patients], indirect immunofluorescence [positive in 122 (77%) patients],
      direct immunofluorescence [positive in 141 (89%) patients], and blister smear
      cytology (Tzanck test) [positive in 115 (72%) patients]. High dosages of
      prednisone (100-150 mg) were given to 129 patients, which was combined with
      azathioprine. Patients with refractory pemphigus vulgaris were treated with
      intramuscular gold (14 patients) and plasmapheresis (five patients). All patients
      were treated with local ointments. The prolonged use of high doses of
      corticosteroids and immunosuppressants caused several complications, in
      particular, steroid diabetes (37 patients), skin infections (26 patients),
      arterial hypertension (23 patients), cardiorespiratory diseases (22 patients),
      sepsis (nine patients), etc. During the hospital treatment, 14 patients died, 10
      during 1980-89 and only four during the 1990-98 period. The main causes of death
      were cardiorespiratory failure (six patients) and sepsis (five patients).
      CONCLUSIONS: Although pemphigus vulgaris is still a life-threatening disease,
      today it can be successfully treated with a combination of immunosuppressive
      agents. Early diagnosis and treatment of pemphigus vulgaris allow a better
      prognosis with lower mortality rates.

PMID- 12482044
TI  - Efficacy of erbium YAG laser-assisted autologous epidermal grafting in vitiligo.
AB  - BACKGROUND: Of the various modalities of therapy available for the treatment of
      vitiligo, a combination of psoralen + ultraviolet A (PUVA) with autologous
      epidermal grafting appears to offer the best results. The erbium YAG laser can be
      used to prepare the recipient site in both punch grafting and suction blister
      grafting. METHODS: In this study 29 subjects, 26 with localized and three with
      generalized stable vitiligo, had received pregrafting PUVA and underwent further
      PUVA starting 2 weeks after surgery until maximal pigmentation was achieved. The
      erbium YAG laser was used on 16 subjects; the recipient site for punch grafting
      was prepared with laser and minigrafts harvested by manual punch were placed into
      the prepared sites. For suction blister grafting, the site was dermabraded with a
      laser and the harvested blister roof (created using suction apparatus) was
      transplanted on to the site. RESULTS: More than two-thirds (68.75%) of the
      subjects who were punch grafted using a laser showed repigmentation of more than
      75%, but only one-half of those who underwent conventional punch grafting showed
      a similar response. All subjects with laser-assisted suction blister grafting
      showed a good response, compared with only 60% of those who underwent
      conventional suction blister grafting. CONCLUSIONS: The results obtained with
      laser-assisted grafting are more satisfactory than those achieved with
      conventional grafting techniques. We found that the repigmentation zones are
      larger (up to 9 mm in the former vs. 3 mm in the latter) and cobblestoning does
      not occur with laser-assisted grafting. Also, the procedure is precise,
      relatively atraumatic and can be performed rapidly even when covering vast areas.

PMID- 12482045
TI  - Dexamethasone pulse therapy in pemphigus.
AB  - Pulse therapy with high-dose glucocorticoids was introduced 20 years ago as a
      treatment modality for autoimmune disease and transplant rejection. The most
      popular dermatological indication for pulse therapy is severe pemphigus. We
      reviewed the sequelae of 14 patients with pemphigus who were treated by pulse
      therapy. Seven of them reached complete remission, although three of them needed
      a new pulse course due to disease flare-up. Adverse events were minor and
      confined to 60% of all patients: temporary facial flushing during pulse
      administration, sleep disturbances during the first night after pulse
      administration, and mood changes occurred during the week of pulse therapy. The
      study showed the possibility of oral instead of an intravenous mute of
      dexamethasone pulse administration, which makes double-blind placebo-controlled
      trials ethically feasible. Fifty per cent of the patients reached complete
      remission. This retrospective study does not allow claims on the steroid-sparing
      effect.

PMID- 12482046
TI  - Bacillary angiomatosis of the scalp in a human immunodeficiency virus-negative
      patient.
AB  - Bacillary angiomatosis (BA) is a recently recognized bacterial infectious disease
      that is mainly seen in patients with the acquired immunodeficiency syndrome. BA
      has rarely been reported in immunocompetent individuals. A case of BA of the
      scalp in an immunocompetent patient, who was human immunodeficiency virus
      seronegative, is reported. The importance of differential diagnosis of this
      lesion is emphasized.

PMID- 12482047
TI  - Temporal arteritis presenting with scalp ulceration.
AB  - We report the case of a 75-year-old-woman who presented with bilateral scalp
      ulcerations and blindness, accompanied by severe headache and scalp tenderness,
      due to bilateral temporal arteritis without systemic involvement. A biopsy taken
      from the border of an ulceration showed evidence of giant cell arteritis. She was
      treated with oral prednisone, 60 mg per day. The ulcerations healed in a few
      weeks but the vision loss was irreversible. This case highlights for temporal
      arteritis the importance of accurate and timely diagnosis as well as the need for
      prompt therapy with systemic steroids in order to avoid major complications,
      namely loss of vision. It also demonstrates that scalp necrosis and ulcerations
      are skin signs associated with a poor prognosis.

PMID- 12482048
TI  - Linear childhood cutaneous lupus erythematosus following Blaschko lines.
AB  - We report a case of a 3-year-old Spanish boy with linear cutaneous lupus
      erythematosus following the lines of Blaschko on his face and neck. Histological
      examination established the diagnosis. Only eight cases of discoid lupus
      erythematosus following the lines of Blaschko have been reported previously.

PMID- 12482049
TI  - Calcinosis cutis universalis.
AB  - We report the case of a 49-year-old female who complained of hardening of the
      skin, with onset about 1.5 years before presentation. The laboratory data showed
      normal biochemistry profile. Routine haematochemical examinations showed slight
      anaemia, an increased erythrocyte sedimentation rate and negative rheumatological
      markers. Calcium excretion in a 24-h urine sample was normal, but the phosphate
      excretion was slightly low. The clinical diagnosis was verified by soft tissue
      ultrasound examination showing subcutaneous calcifications. X-ray examination of
      bones evidenced no abnormal calcification. Mammography revealed deep seated
      bilateral reticular calcifications, even in the axillary region. Histological
      examination showed calcinosis cutis. On these grounds, the diagnosis of
      idiopathic universal calcinosis cutis was made. The authors describe the clinical
      and histological picture and discuss the laboratory findings.

PMID- 12482050
TI  - Pretibial myxoedema associated with Hashimoto's thyroiditis.
AB  - Pretibial myxoedema is a cutaneous mucinosis typically associated with Graves'
      disease, although it may also develop in subjects with non-thyrotoxic thyroid
      pathologies. This report presents a rare case of pretibial myxoedema occurring in
      a 58-year-old woman with biopsy-proven Hashimoto's thyroiditis. The hypothetical
      pathogenetic link between the two disorders is discussed with particular
      attention to the role of thyroid stimulating hormone receptor antibodies.

PMID- 12482051
TI  - Granulomatous folliculitis at sites of herpes zoster scars: Wolf's isotopic
      response.
AB  - Cutaneous eruptions described on herpes zoster scars are variable. We present a
      case of granulomatous folliculitis occurring 4 weeks after an episode of herpes
      zoster infection in a woman with cutaneous T-cell lymphoma. The pathogenesis of
      the lesions remains unclear. The viral genome was detected only in early lesions.

PMID- 12482052
TI  - Malignant eccrine poroma in an unusual location.
AB  - Malignant eccrine poroma is a rare skin appendage tumour, originating from the
      intraepidermal and upper dermal eccrine ducts. The tumour either arises
      spontaneously or develops in a long-standing eccrine poroma, generally in elderly
      people over 60. Clinically, it tends to be a localized lesion, which manifests
      itself as a nodule or ulcerated tumour, favouring extremities. We report an 83
      year-old female with an enlarging and bleeding tumour on her lumbosacral region.
      This lesion first appeared as a small pigmented papule and progressed to an
      erythematous patch with central papular portion and some peripheral pigmentation.
      Histopathology revealed malignant eccrine poroma. Also, immunohistochemically,
      diffuse and intense p53 staining was observed. Regular pigment pattern, brown
      globules and black dots were seen in dermoscopic examination. After performing a
      wide excision, 20 months of follow-up revealed no recurrence or metastasis of the
      tumour. This case represents an unusually located malignant eccrine poroma with
      some pigmentation.

PMID- 12482053
TI  - Acute generalized exanthematous pustulosis induced by ingestion of bamifylline.
AB  - We report a case of acute generalized exanthematous pustulosis (AGEP) in a 64
      year-old woman, associated with the use of bamifylline. To the best of our
      knowledge there have been no previous reports of AGEP induced by the ingestion of
      bamifylline in the medical literature. We, therefore, add this drug to the list
      of causes for AGEP.

PMID- 12482054
TI  - Acne vulgaris as an immune reconstitution syndrome in a patient with AIDS after
      initiation of antiretroviral therapy.

PMID- 12482055
TI  - Report of a case of Muir-Torre syndrome.

PMID- 12482056
TI  - 'Nocardia asteroides' mycetoma of the foot.

PMID- 12482057
TI  - In vitro bactericidal effect of low-dose ultraviolet B in patients with acne.

PMID- 12482058
TI  - Cutaneous granulomas caused by corynebacterium minutissimum in an HIV-infected
      man.

PMID- 12482059
TI  - Erythema multiforme associated with Trichophyton mentagrophytes infection.

PMID- 12482060
TI  - Localized bullous pemphigoid as an unusual complication of radiation therapy.

PMID- 12482061
TI  - Death due to pulmonary tuberculosis in progressive systemic sclerosis.

PMID- 12482062
TI  - Controversies concerning the cure process in patients with pemphigus vulgaris.

PMID- 12482063
TI  - Lichen planopilaris and autoimmune thyroiditis.

PMID- 12482064
TI  - Habituation of the visually evoked potential and its vascular response:
      implications for neurovascular coupling in the healthy adult.
AB  - In the human, visually evoked potentials (VEP) and cerebral oxygenation changes,
      as measured by near-infrared spectroscopy (NIRS), are assessed to elucidate the
      relation between electrophysiological and vascular responses to a checkerboard
      stimulus reversing at 3 Hz. Habituation of either response is analysed on two
      time scales. Within the 1-min stimulation period we find a decrease in P100N135
      component amplitude, closely coupled to a decrease in the amplitude of the
      oxygenation parameters (concentration changes in oxygenated and deoxygenated
      haemoglobin, [oxy-Hb] and [deoxy-Hb]). The N75P100-component amplitude exhibits a
      different behaviour along the 1-min stimulation period. An initial increase is
      overridden by an overall decrease, the latter not reaching statistical
      significance. The analysis across the 13 successive stimulation blocks separated
      by resting periods of equal duration yields a trend for an decrease in the VEP
      components' amplitude, not reflected in the vascular response. When calculating a
      ratio between the amplitude of the P100N135-component and the concentration
      changes in the haemoglobins a "coupling index" of a 0.2 microM decrease in [deoxy
      Hb] and an increase of 0.6 microM in [oxy-Hb] is found per 1 microV increase in
      VEP-component amplitude. The ratio is the same irrespective of its assessment
      from the difference stimulation/ rest or from the habituation effect, i.e., the
      difference between the amplitudes at the beginning and towards the end of the
      stimulation period. Although supporting the notion that the coupling between
      neuronal activation and the vascular response exhibits linear aspects, our
      findings cannot be taken as a proof of such a linearity across all brain regions
      and activation types. On the contrary, tentatively calculating a coupling index
      for the data assessed in the visual system, we intend to stress the necessity to
      assess both neuronal and vascular response to allow for a comparison between
      different systems and conditions in whom neurovascular coupling is expected to be
      altered (Miller et al, 2001; Mechelli et al, 2001).

PMID- 12482065
TI  - An empirical comparison of SPM preprocessing parameters to the analysis of fMRI
      data.
AB  - We present the results from two sets of Monte Carlo simulations aimed at
      evaluating the robustness of some preprocessing parameters of SPM99 for the
      analysis of functional magnetic resonance imaging (fMRI). Statistical robustness
      was estimated by implementing parametric and nonparametric simulation approaches
      based on the images obtained from an event-related fMRI experiment. Simulated
      datasets were tested for combinations of the following parameters: basis
      function, global scaling, low-pass filter, high-pass filter and autoregressive
      modeling of serial autocorrelation. Based on single-subject SPM analysis, we
      derived the following conclusions that may serve as a guide for initial analysis
      of fMRI data using SPM99: (1) The canonical hemodynamic response function is a
      more reliable basis function to model the fMRI time series than HRF with time
      derivative. (2) Global scaling should be avoided since it may significantly
      decrease the power depending on the experimental design. (3) The use of a high
      pass filter may be beneficial for event-related designs with fixed interstimulus
      intervals. (4) When dealing with fMRI time series with short interstimulus
      intervals (<8 s), the use of first-order autoregressive model is recommended over
      a low-pass filter (HRF) because it reduces the risk of inferential bias while
      providing a relatively good power. For datasets with interstimulus intervals
      longer than 8 seconds, temporal smoothing is not recommended since it decreases
      power. While the generalizability of our results may be limited, the methods we
      employed can be easily implemented by other scientists to determine the best
      parameter combination to analyze their data.

PMID- 12482066
TI  - Automatic differentiation of anatomical patterns in the human brain: validation
      with studies of degenerative dementias.
AB  - We compared voxel-based morphometry (VBM) with independent accurate region-of
      interest (ROI) measurements of temporal lobe structures in order to validate the
      usefulness of this fully automated and unbiased technique in Alzheimer's disease
      (AD) and semantic dementia (SD). In AD, ROI analyses appear more sensitive to
      volume loss in the amygdalae, whereas VBM analyses appear more sensitive to right
      middle temporal gyrus and regional hippocampal volume loss. In SD, ROI analyses
      appear more sensitive to left middle and inferior temporal gyrus volume loss,
      whereas VBM appears more sensitive to regional hippocampal volume loss. In
      addition the significance of volume reductions was generally less in VBM owing to
      more stringent corrections for multiple comparisons. In conclusion, the automated
      technique detects a general trend of atrophy similar to that of expertly labeled
      ROI measurements in AD and SD, although there are discrepancies in the ranking of
      severity and in the significance of volume reductions that are more marked in AD.

PMID- 12482067
TI  - Wavelet-aided parametric mapping of cerebral dopamine D2 receptors using the high
      affinity PET radioligand [11C]FLB 457.
AB  - The study of human neuroreceptor systems by means of positron emission tomography
      (PET) and suitable radioligands has proven to be of great importance in research
      on normal brain functions and the pathophysiology and treatment of
      neuropsychiatric disorders. A for long identified goal is to produce detailed
      parametric maps of showing neuroreceptor binding parameters for the entire human
      brain in vivo. The application of wavelet filters has recently been proposed as a
      solution to handle the inherently low signal-to-noise ratio of PET images. In the
      present study we applied the wavelet approach to data obtained from 10 healthy
      subjects who were examined with [11C]FLB 457. This high affinity dopamine D2
      receptor antagonist provides a signal from a range of regions with a hundredfold
      difference in receptor density and should thus be suitable for evaluation of the
      wavelet approach. For cross-validation purposes the data were analysed with four
      methods: a traditional region-of-interest (ROI) based analysis, a pixel-based
      analysis and two variants of wavelet-aided analyses. In both variants the wavelet
      filter was spatially applied, but a two-dimensional filter was used in one case
      and a three-dimensional one in the other. The same linear-graphical binding
      potential (BP) estimation step was used for all methods and the results of the
      three parametric mapping techniques were compared to the reference ROI-based
      method by calculating the average BP of representative ROIs. The pixel-based and
      the two-dimensional-wavelet-based methods yielded highly correlated but
      systematically lower values when compared to the reference ROI-based method. The
      approach utilising three-dimensional wavelet filters yielded BP maps with
      regional averages closely matching the values of the ROI-based method. The
      results show that the combination of three-dimensional spatial wavelet filtering
      with established parameter estimation procedures provides detailed, accurate maps
      of radioligand binding parameters. Such maps can be used for in inter-individual
      or multi-condition comparisons of binding parameters at subregional levels.

PMID- 12482068
TI  - Manual and semiautomated measurement of cerebellar subregions on MR images.
AB  - Previous structural and functional imaging studies suggest that the
      corticocerebellar-thalamic-cortical circuit is dysfunctional in schizophrenia.
      Accurate identification and volumetric measurement of cerebellar subregions are
      essential to the assessment of the cerebellum's role in healthy and disease
      states. Manual parcellation of the cerebellum on MR images was performed with the
      use of guide traces. Guide traces identified relevant fissures and borders in
      several planes, and their intersections with the primary tracing plane were used
      to maintain consistency and accuracy during the parcellation. The cerebellum was
      parcellated into right and left anterior lobes, superior posterior lobes,
      inferior posterior lobes, and corpus medullare. A systematic review of the final
      traces ensured their accuracy. An artificial neural network was trained using a
      novel landmark-warped method to help account for wide variability in structure
      size and location. Overlaps of the manually traced lobes (intersection/union)
      ranged from 0.78 to 0.85 and intraclass correlations (r2) ranged from 0.82 to
      0.94. In a comparison of the semiautomated method with the manual method overlaps
      ranged from 0.83 to 0.88 and intraclass correlations ranged from 0.92 to 0.97.
      For two raters using the semiautomated method overlaps ranged from 0.83 to 0.88
      and intraclass correlations ranged from 0.97 to 0.99. The semiautomated method
      was built on the groundwork of the manual method to produce more reliable results
      in a fraction of the time, making valid measurements possible on a large number
      of subjects.

PMID- 12482069
TI  - Virtual in vivo interactive dissection of white matter fasciculi in the human
      brain.
AB  - This work reports the use of diffusion tensor magnetic resonance tractography to
      visualize the three-dimensional (3D) structure of the major white matter
      fasciculi within living human brain. Specifically, we applied this technique to
      visualize in vivo (i) the superior longitudinal (arcuate) fasciculus, (ii) the
      inferior longitudinal fasciculus, (iii) the superior fronto-occipital
      (subcallosal) fasciculus, (iv) the inferior frontooccipital fasciculus, (v) the
      uncinate fasciculus, (vi) the cingulum, (vii) the anterior commissure, (viii) the
      corpus callosum, (ix) the internal capsule, and (x) the fornix. These fasciculi
      were first isolated and were then interactively displayed as a 3D-rendered
      object. The virtual tract maps obtained in vivo using this approach were faithful
      to the classical descriptions of white matter anatomy that have previously been
      documented in postmortem studies. Since we have been able to interactively
      delineate and visualize white matter fasciculi over their entire length in vivo,
      in a manner that has only previously been possible by histological means,
      "virtual in vivo interactive dissection" (VIVID) adds a new dimension to
      anatomical descriptions of the living human brain.

PMID- 12482070
TI  - The roles of timing and task order during task switching.
AB  - The neural bases of the different processes involved in task switching remain
      poorly identified. Whether distinct brain regions are involved according to the
      overall structure of the task sequence and the predictability of task timing
      during task switching is unknown. To address this question, we used functional
      magnetic resonance imaging and a 2 x 2 factorial design varying timing
      (fixed/random) and task order (predictable/unpredictable). We hypothesized that
      predictable task order should activate brain regions involved in long-term memory
      retrieval because retrieving which task has to be performed constitutes the
      essential part of what subjects can do to prepare before stimulus presentation.
      When examining the "pure" main effects of task order/timing predictability/
      unpredictability, we found that anticipating task order activated the right
      hippocampus, the anterior medial prefrontal cortex, and the posterior cingulate
      cortex, while anticipating task onset timing activated the left middle and
      superior frontal gyrus. Furthermore, task order unpredictability activated the
      intraparietal cortex bilaterally while random relative to fixed timing activated
      the right cerebellum. Interactions between task order and timing were found in a
      network, which included the left frontopolar cortex and the lateral prefrontal
      cortex bilaterally. Specifically, the left frontopolar cortex was more activated
      when both timing and task order were predictable, while the lateral prefrontal
      cortices were more activated when both task order and timing were unpredictable.
      These results indicate a hierarchic organization of the prefrontal cortex along a
      posterioanterior axis as the task becomes more endogenously guided. Finally, we
      found no evidence for specific brain regions involved in task switching because a
      bilateral prefronto-parietal network, which was activated in task switching
      relative to performing each task separately, was no longer activated relative to
      a control condition, which required subjects to maintain two tasks in memory
      without switching between them.

PMID- 12482071
TI  - Frontal and temporal dysfunction of auditory stimulus processing in
      schizophrenia.
AB  - Attention deficits have been consistently described in schizophrenia. Functional
      neuroimaging and electrophysiological studies have focused on anterior cingulate
      cortex (ACC) dysfunction as a possible mediator. However, recent basic research
      has suggested that the effect of attention is also observed as a relative
      amplification of activity in modality-associated cortical areas. In the present
      study, the question was addressed whether an amplification deficit is seen in the
      auditory cortex of schizophrenic patients during an attention-requiring choice
      reaction task. Twenty-one drug-free schizophrenic patients and 21 age- and sex
      matched healthy controls were studied (32-channel EEG). The underlying generators
      of the event-related N1 component were separated in neuroanatomic space using a
      minimum-norm (LORETA) and a multiple dipole (BESA) approach. Both methods
      revealed activation in the primary auditory cortex (peak latency approximately
      100 ms) and in the area of the ACC (peak latency approximately 130 ms). In
      addition, the adapted multiple dipole model also showed a temporal-radial source
      activation in nonprimary auditory areas (peak latency approximately 140 ms). In
      schizophrenic patients, significant activation deficits were found in the ACC as
      well as in the left nonprimary auditory areas that differentially correlated with
      negative and positive symptoms. The results suggest that (1) the source in the
      nonprimary auditory cortex is detected only with a multiple dipole approach and
      (2) that the N1 generators in the ACC and in the nonprimary auditory cortex are
      dysfunctional in schizophrenia. This would be in line with the notion that
      attention deficits in schizophrenia involve an extended cortical network.

PMID- 12482072
TI  - Evaluation of striatal dopamine transporter function in rats by in vivo beta
      [123I]CIT pinhole SPECT.
AB  - Striatal dopamine transporter (DAT) function was evaluated in rats by in vivo
      SPECT-MRI coregistration using the radioligand 2-beta-carbomethoxy-3-beta-(4
      [123I]iodophenyl)tropane (beta-[123I]CIT). The reconstructed transaxial
      resolution of 3.5 mm full width at half-maximum and the system sensitivity of
      0.081 c/s/kBq using a 2.0-mm pinhole collimator aperture provided adequate
      spatial detail and sufficient sensitivity for imaging striatal beta-[123I]CIT
      uptake. SPECT images, coregistered onto a MRI template, showed high accuracy in
      the coronal and transverse planes (maximum mismatch of 1.3 mm). Following
      estimation of the in vivo binding equilibrium of beta-[123I]CIT in the healthy
      rat striatum, we evaluated the 6-hydroxydopamine-induced loss of striatal DAT
      function using beta-[123I]CIT SPECT and MRI coregistration and correlated these
      findings with dopaminergic cell counts in the substantia nigra pars compacta
      using TH immunohistochemistry. A subtotal unilateral DAT deficit was detected by
      beta-[123I]CIT SPECT in all animals which correlated significantly with the cell
      counting of the remaining dopaminergic neurons. beta-[123I]CIT pinhole SPECT
      provides a powerful and widely available tool for in vivo investigations of rat
      striatal DAT function. In contrast to classical autoradiography, the present
      method will be helpful in imaging dynamic changes of neurotransmission in the CNS
      by virtue of serial study designs. Depending on SPECT ligand availability, a wide
      range of other CNS receptors may be imaged as well using the presented in vivo
      technique.

PMID- 12482073
TI  - Stereotaxic localization, intersubject variability, and interhemispheric
      differences of the human auditory thalamocortical system.
AB  - Population (probability) maps of cytoarchitectonically defined cortical maps and
      myeloarchitectonically defined subcortical fiber tracts of the human brain became
      recently available. These maps can be used for the precise anatomical
      localization of activated foci as found in functional imaging studies. The aim of
      this study is to evaluate population maps of the human acoustic radiation (AR)
      for the purpose of brain mapping studies. Thus, a stereotaxic 3-D representation
      of the human AR was computed which includes myeloarchitectonic probabilistic maps
      of AR and its thalamic origin, i.e. the cytoarchitectonically defined medial
      geniculate nucleus (MGN). These maps were compared with earlier, mostly schematic
      drawings of AR and MGN. To generate these maps, the degree of intersubject
      variability of AR and MGN in each stereotaxic position was quantified for the
      standard axes (x, y, and z) of the reference space in a series of 10 adult human
      postmortem brains. The results show that the location and volumes of AR and MGN
      vary considerably between individuals and hemispheres. It is demonstrated that
      this striking degree of spatial variations may lead to structural-functional
      mismatch in brain mapping studies based on the Talairach atlas (discrepancy
      maps). Furthermore, the volumetric measures showed no hemispheric asymmetry for
      AR and MGN. In contrast to earlier maps, our approach provides microanatomically
      defined data as a probabilistic reference system for research in auditory
      structure-function relationships.

PMID- 12482074
TI  - Generators of movement-related cortical potentials: fMRI-constrained EEG dipole
      source analysis.
AB  - To clarify the precise location and timing of the mo tor cortical activation in
      voluntary movement, dipole source analysis integrating multiple constraints wa
      conducted for the movement-related cortical potentia (MRCP). Six healthy subjects
      performed single self paced extensions of the right index finger at about 15
      intervals during EEG and event-related fMRI acquisi tions. EEG was recorded from
      58 scalp electrodes, and fMRI of the entire brain was obtained every 2.6 s.
      Coordinates of the two methods were coregistered us ing anatomical landmarks.
      During dipole source mod eling, a realistic three-layer head model was used as a
      volume conductor. To identify the number of uncorre lated source s in the MRCP,
      principal component (PC analysis was performed, which was consistent with the
      existence of six sources in the left (Lt SM1) and right (Rt SMI) sensorimotor and
      medial frontocentral (MFC) areas. After dipoles were seeded at the acti vated
      spots revealed by fMRI, dipole orientations were fixed based on the
      interpretation of the topography of distribution of the PC. The strength of the
      six dipoles (three dipoles in Lt SMI, two in Rt SMI, and one in MFC) was then
      computed over time. Within the bilat eral SM1, activation of the precentral gyrus
      occurs bilaterally with similar strength from -1.2 s, followed by that of the
      precentral bank from -0.5 s with con tralateral preponderance. Subsequently, the
      postcen tral bank becomes active only on the contralateral side at 0.1 s after
      movement. Activation of the MFC shows timing similar to that of the bilateral
      precentral gyri These deduced patterns of activation are consis tent with
      previous studies of electrocorticography in humans.

PMID- 12482075
TI  - Neural substrates of spoken language rehabilitation in an aphasic patient: an
      fMRI study.
AB  - Little is known about the neural counterparts of speech therapy in aphasic
      patients. An fMRI experiment was performed before and after a specific and
      intensive speech output therapy in RC, a patient with long-lasting speech output
      deficit following a left-sided ischemic lesion. Overt picture naming and
      picture/word rhyming were used as activation tasks in RC and 6 control subjects.
      The naming task concerned the output lexicon deficit to be rehabilitated while
      rhyming referred to preserved levels of processing and was used to control for
      repetition effect. The speech therapy program improved naming performance. By
      comparison to the pattern observed before therapy, the naming task after therapy
      induced a pattern of activation close to that observed in control subjects,
      involving left-sided language areas surrounding the lesion. Speech therapy effect
      was associated with activations in Broca's area and the left supra-marginal
      gyrus, which might reflect a therapy-induced phonological compensatory strategy
      for naming.

PMID- 12482076
TI  - The feasibility of a common stereotactic space for children and adults in fMRI
      studies of development.
AB  - The question of whether pediatric and adult neuroimaging data can be analyzed in
      a common stereotactic space is a critical issue for developmental neuroscience.
      Two studies were performed to address this question. In Study 1, high-resolution
      structural MR brain images of 20 children (7-8 years of age) and 20 young adults
      (18-30 years of age) were transformed to a common space. Overall brain shape was
      assessed by tracing the outer boundaries of the brains in three orientations, and
      more local anatomy was assessed by analysis of portions of 10 selected sulci.
      Small, but consistent, differences in location and variability were observed in
      specific locations of the sulcal tracings and outer-boundary sections. In Study
      2, a computer simulation was used to assess the extent to which the small
      anatomical differences observed in Study 1 would produce spurious effects in
      functional imaging data. Results indicate that, assuming a functional resolution
      of 5 mm in images averaged across subjects, anatomical differences in either
      variability or location between children and adults of the magnitude obperved in
      Study 1 would not negatively affect functional image comparisons. We conclude
      that atlas-transformed brain morphology is relatively consistent between 7- and 8
      year-old children and adults at a resolution appropriate to current functional
      imaging and that the small anatomical differences present do not limit the
      usefulness of comparing child and adult functional images within a common
      stereotactic space.

PMID- 12482077
TI  - Maintenance and manipulation in spatial working memory: dissociations in the
      prefrontal cortex.
AB  - Two experiments were conducted to compare thec ries of the functional
      organization of spatial working memory within the human prefrontal cortex. In
      Experiment I, memory set size for locations was parametrically varied, allowing
      for the assessment of BOLD signal across maintenance requirements. In the sec ond
      experiment, manipulation of spatial information held in working memory was
      contrasted with simple maintenance of that information. Both experiment evoked
      significant activity in a distributed spatia working memory network. Although
      dorsolateral prefrontal activation increased monotonically with memory set size,
      this region was differentially engaged in task conditions involving explicit
      manipulation of in ternal representations. Activation in the superior frontal
      sulcal region was associated with maintenance of spatial information, increasing
      with memory se size. In contrast, ventrolateral prefrontal activation was present
      only at the highest memory set size, possibly due to the differential use of
      organizational strategies with more complex stimuli. These results sup port
      claims that the dorsolateral prefrontal cortex is involved in the manipulation of
      internal representa tions and that the superior frontal sulcal region is involved
      in the maintenance of spatial information but they suggest a complex role for the
      ventrolatera prefrontal region.

PMID- 12482078
TI  - Human amygdala responses to fearful eyes.
AB  - Fearful facial expressions evoke increased neural responses in human amygdala. We
      used event-related fMRI to investigate whether eye or mouth components of a
      fearful face are critical in evoking this increased amygdala activity. In
      addition to prototypical fearful (FF) and neutral (NN) faces, subjects viewed two
      types of chimerical face: fearful eyes combined with a neutral mouth (FN), and
      neutral eyes combined with a fearful mouth (NF). FE faces evoked specific
      responses in left anterior amygdala. FN faces evoked responses in bilateral
      posterior amygdala and superior colliculus. Responses in right amygdala, superior
      colliculus, and pulvinar exhibited significant time x condition interactions with
      respect to faces with fearful eyes (FF, FN) vs neutral eyes (NF, NN). These data
      indicate that fearful eyes alone are sufficient to evoke increased amygdala
      activity. In addition, however, left amygdala displayed discriminatory responses
      to fearful eyes in different configural contexts (i.e., in FF and FN faces).
      These results suggest, therefore, that human amygdala responds to both feature
      specific and configural aspects of fearful facial expressions.

PMID- 12482079
TI  - Linear spatial integration for single-trial detection in encephalography.
AB  - Conventional analysis of electroencephalography (EEG) and magnetoencephalography
      (MEG) often relies on averaging over multiple trials to extract statistically
      relevant differences between two or more experimental conditions. In this article
      we demonstrate single-trial detection by linearly integrating information over
      multiple spatially distributed sensors within a predefined time window. We report
      an average, single-trial discrimination performance of Az approximately 0.80 and
      faction correct between 0.70 and 0.80, across three distinct encephalographic
      data sets. We restrict our approach to linear integration, as it allows the
      computation of a spatial distribution of the discriminating component activity.
      In the present set of experiments the resulting component activity distributions
      are shown to correspond to the functional neuroanatomy consistent with the task
      (e.g., contralateral sensorymotor cortex and anterior cingulate). Our work
      demonstrates how a purely data-driven method for learning an optimal spatial
      weighting of encephalographic activity can be validated against the functional
      neuroanatomy.

PMID- 12482080
TI  - Cortical activation to auditory mismatch elicited by frequency deviant and
      complex novel sounds: a PET study.
AB  - The analysis of auditory deviant events outside the focus of attention is a
      fundamental capacity of human information processing and has been studied in
      experiments on Mismatch Negativity (MMN) and the P3a component in evoked
      potential research. However, generators contributing to these components are
      still under discussion. Here we assessed cortical blood flow to auditory
      stimulation in three conditions. Six healthy subjects were presented with
      standard tones, frequency deviant tones (MMN condition), and complex novel sounds
      (Novelty condition), while attention was directed to a nondemanding visual task.
      Analysis of the MMN condition contrasted with thestandard condition revealed
      blood flow changes in the left and right superior temporal gyrus, right superior
      temporal sulcus and left inferior frontal gyrus. Complex novel sounds contrasted
      with the standard condition activated the left superior temporal gyrus and the
      left inferior and middle frontal gyrus. A small subcortical activation emerged in
      the left parahippocampal gyrus and an extended activation was found covering the
      right superior temporal gyrus. Novel sounds activated the right inferior frontal
      gyrus when controlling for deviance probability. In contrast to previous studies
      our results indicate a left hemisphere contribution to a frontotemporal network
      of auditory deviance processing. Our results provide further evidence for a
      contribution of the frontal cortex to the processing of auditory deviance outside
      the focus of directed attention.

PMID- 12482081
TI  - MRI atlas of the human cerebellar nuclei.
AB  - The differential role of the cerebellar cortex and nuclei has rarely been
      addressed in human lesion and functional brain imaging studies. One important
      reason is the difficulty of defining the localization of the cerebellar nuclei
      and extent of possible lesions based on CT or MR scans. The present MRI
      investigation was specifically designed to study the anatomy of the deep
      cerebellar nuclei. In both basal ganglia and cerebellar nuclei of healthy human
      subjects the amount of iron is high compared to the rest of the brain. Clusters
      of iron are paramagnetic and, therefore, tend to cause local inhomogenities in a
      magnetic field. The iron-induced susceptibility artefacts were used to visualize
      the cerebellar nuclei as hypointensities on MR images. A three-dimensional atlas
      of the dentate (D), interposed (I), and fastigial (F) nuclei is presented in
      standard proportional stereotaxic space coordinates based on findings in a
      healthy 26-year-old female. A three-dimensional axial volume of the cerebellum
      was acquired using a T1-weighted fast low-angle shot (FLASH) sequence on a
      Siemens Sonata 1.5 Tesla MR. To increase the signal to noise ratio the sequence
      was acquired 5 times and averaged. Each volume was registered, resampled to 1.00
      x 1.00 x 1.00-mm3 voxel size and spatially normalized into a standard
      proportional stereotaxic space (the MNI-space) using SPM99. Localization of
      cerebellar nuclei were confirmed by comparison with postmortem MRI and
      histological microsections of another brain.

PMID- 12482082
TI  - Genetic contributions to regional variability in human brain structure: methods
      and preliminary results.
AB  - Twin studies provide one approach for investigating and partitioning genetic and
      environmental contributions to phenotypic variability in human brain structure.
      Previous twin studies have found that cerebral volume, hemispheric volume,
      ventricular volume, and cortical gyral pattern variability were heritable. We
      investigated the contributions of genetic and environmental factors to both
      global (brain volume and lateral ventricular volume) and regional (parcellated
      gray matter) variability in brain structure. We examined MR images from 10 pairs
      of healthy monozygotic and 10 pairs of same-sex dizygotic twins. Regional gray
      matter volume was estimated by automated image segmentation, transformation to
      standard space, and parcellation using a digital atlas. Heritability was
      estimated by path analysis. Estimated heritability for brain volume variability
      was high (0.66; 95% confidence interval 0.17, 1.0) but the major effects on
      lateral ventricular volume variability were common and unique environmental
      factors. We constructed a map of regional brain heritability and found large
      genetic effects shared in common between several bilateral brain regions,
      particularly paralimbic structures and temporal-parietal neocortex. We tested
      three specific hypotheses with regard to the genetic control of brain
      variability: (i) that the strength of the genetic effect is related to gyral
      ontogenesis, (ii) that there is greater genetic control of left than of right
      hemisphere variability, and (iii) that random or fluctuating asymmetry in
      bilateral structures is not heritable. We found no evidence in support of the
      first two hypotheses, but our results were consistent with the third hypothesis.
      Finally, we used principal component (PC) analysis of the genetic correlation
      matrix, to identify systems of anatomically distributed gray matter regions which
      shared major genetic effects in common. Frontal and parietal neocortical areas
      loaded positively on the first PC; some paralimbic and limbic areas loaded
      negatively. Bilateral insula, some frontal regions, and temporal neocortical
      regions functionally specialized for audition and language loaded strongly on the
      second PC. We conclude that large samples are required for powerful investigation
      of genetic effects in imaging data from twins. However, these preliminary re.
      sults suggest that genetic effects on structure of the human brain are regionally
      variable and predominantly symmetric in paralimbic structures and lateral
      temporal cortex.

PMID- 12482083
TI  - Zoomed functional imaging in the human brain at 7 Tesla with simultaneous high
      spatial and high temporal resolution.
AB  - Functional neuroimaging in the human brain using noninvasive magnetic resonance
      methods has the potential of providing highly resolved maps of neuronal
      activation. Decreasing the voxel size and obtaining simultaneously high temporal
      resolution is a major challenge and is mainly limited by sensitivity. Here,
      signal-to-noise gains at high magnetic fields (7 Tesla) and an optimized surface
      coil setup are combined with a novel approach for zoomed functional imaging in
      the visual cortex. For echoplanar imaging, the acquisition time and segmentation
      was shortened fourfold by using a reduced field-of-view. An adiabatic outer
      volume suppression method, BISTRO, was used to obliterate signal outside the area
      of-interest achieving effective suppression even for inhomogeneous B1-fields. A
      single-shot acquisition was performed at submillimeter resolution in the human
      brain, while simultaneously maintaining a high temporal resolution of 125 ms.
      Functional studies with and without field-of-view reduction were performed.
      Activation and percent change maps were compared with respect to spatial extent,
      t values and percentage changes of the BOLD contrast. The detection of functional
      activation was found to be equal within the inter-series variability for the two
      acquisition schemes. Thus, single-trial BOLD responses were detected for the
      first time robustly at a 500 x 500 microm2 in plane and 250 ms temporal
      resolution, significantly expanding the possibilities of event-related functional
      imaging in the human brain. The magnetization transfer effect induced by the
      outer-volume suppression pulses was investigated and found to be increased during
      neuronal activity.

PMID- 12482084
TI  - Systematic regularization of linear inverse solutions of the EEG source
      localization problem.
AB  - Distributed linear solutions of the EEG source localization problem are used
      routinely. Here we describe an approach based on the weighted minimum norm method
      that imposes constraints using anatomical and physiological information derived
      from other imaging modalities to regularize the solution. In this approach the
      hyperparameters controlling the degree of regularization are estimated using
      restricted maximum likelihood (ReML). EEG data are always contaminated by noise,
      e.g., exogenous noise and background brain activity. The conditional expectation
      of the source distribution, given the data, is attained by carefully balancing
      the minimization of the residuals induced by noise and the improbability of the
      estimates as determined by their priors. This balance is specified by
      hyperparameters that control the relative importance of fitting and conforming to
      prior constraints. Here we introduce a systematic approach to this regularization
      problem, in the context of a linear observation model we have described
      previously. In this model, basis functions are extracted to reduce the solution
      space a priori in the spatial and temporal domains. The basis sets are motivated
      by knowledge of the evoked EEG response and information theory. In this paper we
      focus on an iterative "expectation-maximization" procedure to jointly estimate
      the conditional expectation of the source distribution and the ReML
      hyperparameters on which this solution rests. We used simulated data mixed with
      real EEG noise to explore the behavior of the approach with various source
      locations, priors, and noise levels. The results enabled us to conclude: (i)
      Solutions in the space of informed basis functions have a high face and construct
      validity, in relation to conventional analyses. (ii) The hyperparameters
      controlling the degree of regularization vary largely with source geometry and
      noise. The second conclusion speaks to the usefulness of using adaptative ReML
      hyperparameter estimates.

PMID- 12482085
TI  - Discrimination between Alzheimer dementia and controls by automated analysis of
      multicenter FDG PET.
AB  - A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t
      statistics and an automated voxel-based procedure, is presented and validated in
      a large data set comprising 110 normal controls and 395 patients with probable
      Alzheimer's disease (AD) that were studied in eight participating centers. The
      effect of differences in spatial resolution of PET scanners was minimized
      effectively by filtering and masking. In controls FDG uptake declined
      significantly with age in anterior cingulate and frontolateral perisylvian
      cortex. In patients with probable AD decline of FDG uptake in posterior
      cingulate, temporoparietal, and prefrontal association cortex was related to
      dementia severity. These effects were clearly distinct from age effects in
      controls, suggesting that the disease process of AD is not related to normal
      aging. Women with probable AD had significantly more frontal metabolic impairment
      than men. The new indicator of metabolic abnormality in AD-related regions
      provided 93% sensitivity and specificity for distinction of mild to moderate
      probable AD from normals, and 84% sensitivity at 93% specificity for detection of
      very mild probable AD (defined by Mini Mental Score 24 or better). All regions
      related to AD severity were already affected in very mild AD, suggesting that all
      vulnerable areas are affected to a similar degree already at disease onset.
      Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis
      of multicenter FDG PET is feasible, provides insights into AD pathophysiology,
      and can be used potentially as a sensitive biomarker for early AD diagnosis.

PMID- 12482086
TI  - The amygdala response to emotional stimuli: a comparison of faces and scenes.
AB  - As a central fear processor of the brain, the amygdala initiates a cascade of
      critical physiological and behavioral responses. Neuroimaging studies have shown
      that the human amygdala responds not only to fearful and angry facial expressions
      but also to fearful and threatening scenes such as attacks, explosions, and
      mutilations. Given the relative importance of facial expressions in adaptive
      social behavior, we hypothesized that the human amygdala would exhibit a stronger
      response to angry and fearful facial expressions in comparison to other fearful
      and threatening stimuli. Twelve subjects completed two tasks while undergoing
      fMRI: matching angry or fearful facial expressions, and matching scenes depicting
      fearful or threatening situations derived from the International Affective
      Picture System (IAPS). While there was an amygdala response to both facial
      expressions and IAPS stimuli, direct comparison revealed that the amygdala
      response to facial expressions was significantly greater than that to IAPS
      stimuli. Autonomic reactivity, measured by skin conductance responses, was also
      greater to facial expressions. These results suggest that the human amygdala
      shows a stronger response to affective facial expressions than to scenes, a bias
      that should be considered in the design of experimental paradigms interested in
      probing amygdala function.

PMID- 12482087
TI  - An fMRI-constrained MEG source analysis with procedures for dividing and grouping
      activation.
AB  - To analyze neural activity using magnetoencephalography (MEG) and functional
      magnetic resonance imaging (fMRI), we developed a method for fixing equivalent
      current dipoles of MEG in activation areas of fMRI. It includes a procedure for
      dividing large fMRI activation volumes into subvolumes in each of which a dipole
      is placed and another procedure for grouping neighboring dipoles whose temporal
      changes are inseparable based on MEG data. To optimize the procedures'
      parameters, we carried out simulations and found that (1) any single dipole
      within 10 mm from a true source can explain MEG data with a correlation of 94% on
      average for the low signal-to-noise ratio of 3 and (2) a neighboring dipole
      within a few tens of millimeters from the dipole nearest to the true source tends
      to be highly incorporated in explaining MEG data. We applied the method to data
      measured in a language experiment and detected 13 significant sources. The
      results show that the present method is promising for detecting neural activity
      originating from a number of separate neural sources.

PMID- 12482088
TI  - Orthogonal polynomial regression for the detection of response variability in
      event-related fMRI.
AB  - Previous studies using event-related potentials (ERPs) have identified a variety
      of brain regions that respond to rare nontarget distractor stimuli presented in
      the visual oddball task. By contrast, event-related functional magnetic resonance
      imaging (ER-fMRI) studies using similar stimuli have found little or no response
      in these same regions, suggesting that ER-fMRI may be less sensitive than ERPs
      for detecting stimulus-evoked activity. It was hypothesized here that variations
      in ER-fMRI response amplitude evoked by successive stimuli may have reduced
      detection sensitivity in these previous studies. Multiple regression with
      orthogonal polynomials (OPR) was used to increase detection sensitivity by
      employing orthogonal polynomial equations to model such variations in response
      amplitude. ER-fMRI data was collected from 17 subjects during performance of the
      visual oddball task, which included frequent nontarget, rare nontarget
      distractor, and rare target block letter stimuli, to which subjects made a
      speeded button press response. When compared with multiple regression using main
      effect regressors alone, OPR identified an increased volume of significant target
      and distractor evoked main effect response due to reduced error variance. In
      addition, distractor-evoked activity was found to correlate with orthogonal
      polynomial regressors but not main effect regressors across a large volume of
      prefrontal and paralimbic brain regions including dorsal-lateral prefrontal,
      inferior-lateral prefrontal, and cingulate cortex. These results illustrate that
      considerable variability is present in ER-fMRI responses evoked by rare
      distractor stimuli in the oddball task. Such variability can be modeled using
      OPR, leading to increased detection sensitivity and better anatomical
      correspondence between the findings of ER-fMRI and ERP studies.

PMID- 12482089
TI  - Linking actions and their perceivable consequences in the human brain.
AB  - Voluntary action is goal-directed and therefore depends on the ability to learn
      associations between movements and their perceivable consequences. The neural
      substrate of this ability was investigated with H2(15O) positron emission
      tomography (PET). Healthy adults first learned that self-initiated keypresses
      were consistently followed by certain tones (i.e., action effects). During PET
      imaging, participants listened to varied ratios of action-effect tones and
      neutral tones without performing any movement. The caudal supplementary motor
      area and the right hippocampus increased their activity with the frequency of
      action-effect tones, suggesting that both cortical areas play a role in linking
      the consequences of an action and the action itself. This integration process
      represents a highly flexible mechanism that helps to promote the learning,
      automatization, and control of voluntary

PMID- 12482090
TI  - Stereotaxy-based regional brain volumetry applied to segmented MRI: validation
      and results in deficit and nondeficit schizophrenia.
AB  - A method for postprocessing of segmented routine brain MRI studies providing
      automated definition of major structures (frontal, parietal, occipital, and
      temporal lobes; cerebellar hemispheres; and lateral ventricles) according to the
      Talairach atlas is presented. The method was applied to MRI studies from 25
      normal subjects (NV), 14 patients with deficit schizophrenia (DS), and 14 with
      nondeficit schizophrenia (NDS), to evaluate their gray matter and CSF regional
      volumes. The two patient groups did not differ in mean age at illness onset,
      duration of illness, severity of psychotic symptoms, or disorganization; DS had
      more severe avolition and worse social functioning than NDS. For validation
      purposes, brain structures were manually outlined on original MR images in 10
      studies, thus obtaining reference measures. Manual and automated measures were
      repeated 1 month apart to measure reproducibilities of both methods. The
      automated method required less than 1 min/operator per study vs more than 30 min
      for manual assessment. Mean absolute difference per structure between the two
      techniques was 4.8 ml. Overall reproducibility did not significantly differ
      between the two methods. In subjects with schizophrenia, a significant decrease
      in GM and increase in CSF were found. GM loss was confined to frontal and
      temporal lobes. Lateral ventricles were significantly larger bilaterally in NDS
      compared to NV and only on the right in NDS compared to DS. The finding of
      greater structural brain abnormalities in NDS adds to the evidence that deficit
      schizophrenia does not represent just the more severe end of the schizophrenia
      continuum.

PMID- 12482091
TI  - Brain activation during the fist-edge-palm test: a functional MRI study.
AB  - The purpose of our study is to clarify, using functional MRI, brain regions
      activated during the fist-edge-palm task (FEP) compared to relatively simple hand
      motor tasks using either the right or the left hand in right-handed normal
      volunteers. The FEP was introduced to detect a disorder of voluntary movement,
      and it is believed to be closely related to contralateral frontal lobe damage.
      However, this assumption still remains controversial. Ten subjects participated
      in this study. Hand motor tasks were as follows: (1) the FEP, in which the
      subjects were requested to place their hand in three different positions
      sequentially: a fist resting horizontally, a palm resting vertically, and a palm
      resting horizontally; (2) a fist-palm task (FP), in which the subjects were asked
      to clench and unclench their fist alternately; and (3) a control task requiring
      the subjects to knock lightly with their clenched fist. The contralateral
      sensomotor and premotor areas were activated in the FP with the right hand and
      the contralateral sensorimotor, premotor, and supplementary motor areas (SMA)
      were activated in the FP with the left hand. In the FEP with either hand,
      bilateral premotor and left parietal areas and ipsilateral cerebellum were also
      activated as well as contralateral sensorimotor area and SMA. Our results suggest
      that successful performance of the FEP requires the participation of more brain
      areas than FP, which may explain why some patients without frontal lobe damage
      failed to perform the FEP.

PMID- 12482092
TI  - Retrieval of relational information: a role for the left inferior prefrontal
      cortex.
AB  - Neuroimaging studies have implicated different areas of prefrontal cortex and
      medial temporal lobe structures (MTL) in episodic retrieval tasks. However, the
      role of specific regions in particular aspects of episodic memory is still
      unclear. In this experiment we studied changes in regional cerebral blood flow
      (rCBF) associated with relational and nonrelational retrieval of studied pairs of
      words. For relational retrieval, a list of either studied or rearranged pairs was
      presented and subjects (n = 8) were asked to indicate whether pairs had appeared
      on the study list. Under the nonrelational retrieval condition they indicated
      whether one or both words of the pair had appeared on the study list. As compared
      to the baseline condition (looking at a cross-mark), increased rCBF was observed
      in the left inferior prefrontal cortex (LIPFC) for both studied pairs and
      rearranged pairs under the relational retrieval condition. Under the
      nonrelational condition, an increase was observed in right inferior frontal
      gyrus. The MTL showed a trend for increased rCBF in the rearranged-pair
      condition. This increase was probably associated with the encoding that
      accompanies retrieval of novel stimuli. Results suggest that the lateralized
      activation of prefrontal cortex observed in episodic memory tasks may be related
      to the degree of relational processing involved. The LIPFC appears to be
      associated with relational retrieval and the right prefrontal cortex with
      nonrelational retrieval.

PMID- 12482093
TI  - Dissociating sentential prosody from sentence processing: activation interacts
      with task demands.
AB  - Sentence processing was contrasted with processing of syntactic prosody under two
      task conditions in order to examine the representation of these components of
      language and their interaction with working memory load. Twelve adults received
      fMDI scans while they listened to low-pass filtered and unfiltered sentences
      either passively, or during tasks that required subjects to remember and
      recognize information contained in the stimuli. Results indicated that temporal
      activation for prosodic stimuli differed compared to activation for sentence
      stimuli only during passive listening tasks. The inclusion of memory demands was
      associated with frontal activation, which was differentially lateralized for
      sentence and prosodic stimuli. The results demonstrate differential brain
      activation for prosodic vs sentential stimuli which interacts with the memory
      demands placed on the subjects.

PMID- 12482094
TI  - Sustained attention in a counting task: normal performance and functional
      neuroanatomy.
AB  - We examined changes in relative cerebral flood flow (relCBF) using PET during a
      sustained attention paradigm which included auditory stimulation and different
      tasks of mental counting. Ten normal volunteers underwent PET (15O water) during
      a baseline state and under experimental conditions which included listening to
      clicks, serial counting with auditory stimulation, counting with no auditory
      stimulation, and an additional component of working memory and time estimation.
      All subjects performed within normal limits in a battery of neurocognitive tests,
      which included measures of attention and working memory. Both counting with
      auditory stimulation and counting with no auditory stimulation engaged motor
      cortex, putamen, cerebellum, and anterior cingulate. Furthermore, counting with
      no auditory stimulation relative to counting while listening resulted in
      significantly increased relCBF in the inferior parietal, dorsolateral prefrontal,
      and anterior cingulate. The findings obtained in this study support the notion
      that the parietal and dorsolateral prefrontal cortex are involved when time
      estimation and working memory are taking part in a task requiring sustained
      attention.

PMID- 12482095
TI  - Functional magnetic resonance imaging of the human sensorimotor cortex using a
      novel vibrotactile stimulator.
AB  - The purpose of this study was to investigate the fMRI response of the
      sensorimotor cortex to a vibration paradigm produced by a novel vibrotactile
      stimulator. Fifteen contiguous slices covering the sensorimotor cortex parallel
      to the anterior (AC) and posterior commissure (PC) line were obtained with
      echoplanar magnetic resonance imaging at 1.5T. Cortical activity in ten healthy
      subjects (20-45 years) was investigated during vibration (50 Hz) of the palm of
      the right hand and compared to a finger-to-thumb tapping paradigm. For the
      vibration paradigm a mechanically driven vibration head was mounted on the palm
      of the right hand. The new vibration device produces vibration frequencies (1-130
      Hz) and displacement amplitudes (0.5-4 mm) suitable to elicit the tonic vibratory
      reflex. The fMRI measurement during vibratory stimulation revealed activation in
      the pre- and postcentral gyrus in all subjects. These activations were comparable
      to the finger-to-thumb tapping paradigm. The advantages of the new MR compatible
      vibration device include effective transmission of the stimulus and controlled
      vibration frequencies and intensities. These preliminary fMRI results indicate
      that vibration can be an alternative paradigm for the evaluation of sensory and
      motor functions in patients unable to perform active motor paradigms.

PMID- 12482096
TI  - How to avoid spurious cluster validation? A methodological investigation on
      simulated and fMRI data.
AB  - This paper presents an evaluation of a common approach that has been considered
      as a promising option for exploratory fMRI data analyses. The approach includes
      two stages: creating from the data a sequence of partitions with increasing
      number of subsets (clustering) and selecting the one partition in this sequence
      that exhibits the clearest indications of an existing structure (cluster
      validation). In order to achieve that the selected partition is actually the best
      characterization of the data structure, previous studies were directed to find
      the most appropriate validity function(s). In our analysis protocol, we first
      optimize the sequence of partitions according to the given objective function.
      Our study showed that an insufficient optimization of the partition, for one or
      more numbers of clusters, can easily yield a spurious validation result which, in
      turn, may lead the analyst to a misleading interpretation of the fMRI experiment.
      However, a sufficient optimization, for each included number of clusters,
      provided the basis for a reliable, adequate characterization of the data
      Furthermore, it enabled an adequate evaluation of the validity functions. These
      findings were obtained independently for three clustering algorithms
      (representing the hard and fuzzy clustering variant) and three up-to-date cluster
      validity functions. The findings were derived from analyses of Gaussian clusters,
      simulated data sets that mimic typical fMRI response signals, andreal fMRI data.
      Based on our results we propose a number of options of how to configure improved
      clustering tools.

PMID- 12482097
TI  - FMRI-determined language lateralization in patients with unilateral or mixed
      language dominance according to the Wada test.
AB  - Due to the reported variability of the language laterality index (LI) across fMRI
      studies, reliable distinction between patients with unilateral and mixed language
      dominance is currently not possible, preventing clinical implementation of fMRI
      as a replacement for the invasive Wada test. Variability of the LI may be related
      to differences in experimental and control tasks, and statistical methodology.
      The goal of this study was to improve detection power of fMRI for hemispheric
      language dominance by using a combined analysis of four different language tasks
      (CTA), that has previously shown more reliable and robust Lls in groups of normal
      volunteers than individual task analyses (see Ramsey et al). The CTA targets
      brain areas that are common to different language tasks, thereby focusing on
      areas that are critical for language processing. Further advantage of the CTA is
      that it is relatively independent of specific task and control conditions. 18
      patients with typical (i.e., left-sided, n = 11) and atypical (i.e., right-sided
      or mixed, respectively, n = 3 and n = 4) language dominance according to the Wada
      test underwent fMRI (groups respectively denoted as WadaL, WadaR, and WadaM
      patients). Statistical methodology (including thresholding of activity maps) was
      fixed to assure a user-independent approach. CTA yielded better results than any
      of the individual task analyses: it was more robust (on average 2.5 times more
      brain activity was detected due to its higher statistical power) and more
      reliable (concordance for WadaL, WadaM and WadaR patients was respectively 10/11
      (91%), 3/4 (75%), and 2/3 patients (67%)). Overall, a significant correlation was
      observed between frontal and temporoparietal LIs. Remarkably, brain activity for
      WadaM patients was significantly lower than for WadaL or WadaR patients, and a
      dissociation in lateralization was observed between frontal (right-sided) and
      temporoparietal (left-sided) activity in three of four patients. Of the
      individual task analyses, the verb generation task yielded best results for
      patients with unilateral language dominance (same concordance as CTA). However,
      in contrast to CTA results, the verb generation task was unable to identify WadaM
      patients (concordance in one of four patients). In conclusion, the CTA is a
      promising approach for clinical implementation of fMRI for the prediction of
      hemispheric language dominance.

PMID- 12482098
TI  - Proprioception-related evoked potentials: origin and sensitivity to movement
      parameters.
AB  - Reafferent electroencephalography (EEG) potentials evoked by active or passive
      movement are largely dependent on muscle spindle input, which projects to
      postrolandic sensory areas as well as the precentral motor cortex. The origin of
      these proprioception-related evoked potentials has previously been studied by
      using N20-P20 source locations of the median nerve somatosensory evoked potential
      as an landmark for postcentral area 3b. As this approach has yielded
      contradictory findings, likely due to spatial undersampling, we applied dipole
      source analysis on two independently collected sets of high-density EEG data,
      containing the proprioception-related N90 elicited by passive finger movement,
      and the N20-P20 elicited by median nerve stimulation. In addition, the influence
      of movement parameters on the N90 was explored by varying amplitude/duration and
      direction of passive movements. The results showed that the proprioceptive N90
      component was not influenced by movement direction, but had a duration that
      covaried with the duration of the movement. Sources were localized in the
      precentral cortex, located on average 10 mm anterior to the N20-P20 sources. The
      latter result supports earlier claims that the motor cortex is involved in the
      generation of proprioception-related EEG potentials.

PMID- 12482099
TI  - Quantitative cerebral perfusion MRI and CO2 reactivity measurements in patients
      with symptomatic internal carotid artery occlusion.
AB  - Quantitative perfusion MRI is a promising new technique capable of offering
      information on cerebral blood flow (CBF), cerebral blood volume (CBV), and mean
      transit time (MTT). However, it is still unclear how these perfusion parameters
      relate to the underlying physiological indicators and how they compare to
      conventional techniques. The purpose of this study was to investigate how
      quantitative perfusion MRI is related to the cerebrovascular reactivity as
      measured by transcranial Doppler ultrasonography (TCD) in combination with a CO2
      stimulus in patients with a symptomatic occlusion of the internal carotid artery
      (ICA). Thirty-nine patients with transient or minor disabling retinal or
      hemispheric ischemic symptoms and an occlusion of the ICA underwent quantitative
      perfusion MRI and CO2 reactivity measurements by TCD. Perfusion parameters were
      correlated with cerebrovascular reactivity measurements and compared with
      measurements of control subjects. The results of this study show a negative
      correlation between the cerebrovascular reactivity and the time to bolus peak
      (TBP) both for gray (r = -0.26, P = 0.035) and white matter (r = -0.28, P =
      0.026). No correlation between resting CBV, CBF, or MTT and cerebrovascular
      reactivity was found. Our results indicate that an increase in TBP reflects a
      poor development of collateral flow, which is supported by a relatively low CO2
      reactivity in these patients.

PMID- 12482100
TI  - Accurate, robust, and automated longitudinal and cross-sectional brain change
      analysis.
AB  - Quantitative measurement of brain size, shape, and temporal change (for example,
      in order to estimate atrophy) is increasingly important in biomedical image
      analysis applications. New methods of structural analysis attempt to improve
      robustness, accuracy, and extent of automation. A fully automated method of
      longitudinal (temporal change) analysis, SIENA, was presented previously. In this
      paper, improvements to this method are described, and also an extension of SIENA
      to a new method for cross-sectional (single time point) analysis. The methods are
      fully automated, robust, and accurate: 0.15% brain volume change error
      (longitudinal): 0.5-1% brain volume accuracy for single-time point (cross
      sectional). A particular advantage is the relative insensitivity to differences
      in scanning parameters. The methods provide easy manual review of their output by
      the automatic production of summary images which show the results of the brain
      extraction, registration, tissue segmentation, and final atrophy estimation.

PMID- 12482101
TI  - Reduction of excitability ("inhibition") in the ipsilateral primary motor cortex
      is mirrored by fMRI signal decreases.
AB  - Functional magnetic resonance imaging (fMRI) was used to investigate how focal
      cortical inhibition affects the blood oxygen level-dependent (BOLD) signal.
      Phasic low force pinch grip reduces excitability of the ipsilateral primary motor
      cortex. This task was used to study BOLD signal changes during inhibition. Six
      right-handed normal volunteers participated in the study. They were asked to
      perform a right-handed pinch grip repetitively at 1 Hz and 5% of their individual
      maximal voluntary contraction (MVC). Data were acquired with a 1.5 Tesla Magnetom
      and continuous multislice T2*-weighted images. The contralateral primary motor
      cortex (M1) revealed an activation in the knob-shaped hand representation of the
      central sulcus area. More importantly, a decreased (often referred to as
      "negative") BOLD signal in the ipsilateral M1 was observed. We suggest phasic low
      force pinch grip as a reproducible, easy model of focal inhibition. Decreased
      cortical excitability presents as decreased BOLD signal using fMRI.

PMID- 12482102
TI  - Distortion-free diffusion tensor imaging of cranial nerves and of inferior
      temporal and orbitofrontal white matter.
AB  - The main impact of functional neuroimaging has been its ability to locate
      neuronal activity either directly (EEG, MEG) or through the hemodynamic response
      caused by neuronal activity (PET, fMRI). In the past decade functional
      neuroimaging has been extended to investigate how brain regions interact, using
      the concepts of functional and effective connectivity. These concepts are further
      strengthened by estimates of anatomical connectivity of the same subject. A tool
      to determine anatomical connectivity in vivo may be provided by diffusion tensor
      imaging (DTI) methods. These can be used to determine the orientation of fiber
      bundles in white matter on the basis of the diffusion characteristics of water.
      Commonly, DTI data are acquired using echo planar imaging which suffers from
      susceptibility artifacts in orbitofrontal and inferior temporal cortex. Here we
      demonstrate the use of an alternative pulse sequence, diffusion-weighted single
      shot STEAM, for assessing fiber orientation in orbitofrontal cortex and the
      cranial nerves. The scope of DTI needs to be extended to these structures to
      investigate psychiatric disorders in which orbitofrontal pathology or temporo
      frontal disconnection have been postulated.

PMID- 12482103
TI  - The precision of anatomical normalization in the medial temporal lobe using
      spatial basis functions.
AB  - We investigated the accuracy of spatial basis function normalization using
      anatomical landmarks to determine how precisely homologous regions are
      colocalized. We examined precision in terms of: (1) the number of nonlinear basis
      functions used by the normalization procedure; (2) the degree of (Bayesian)
      regularization; and (3) the effect of substituting different templates and how
      this interacted with the number of basis functions. The face validity of spatial
      normalization was assessed as a function of these parameters, using the
      colocalization of homologous landmarks in a test sample of 20 normally developing
      children and 5 children with bilateral hippocampal pathology. Our results suggest
      that when optimal normalization parameters are used, anatomical landmarks in the
      medial temporal lobes are colocalized to within a standard deviation of about 1
      mm. When suboptimal parameters are used this standard deviation can increase up
      to 3 mm. Interestingly the optimal parameters are those that provide a rather
      constrained normalization as opposed to those that optimize intensity matching at
      the expense of rendering the warps "unlikely." The implications of our results,
      for users of voxel-based morphometry, are discussed.

PMID- 12482104
TI  - Retractions.

PMID- 12482106
TI  - Compliance with estrogen replacement therapy: current issues.
AB  - Compliance is now considered to be a major issue in the clinical arena of the
      menopause and hormone replacement management. Recently, the terminology has
      evolved to intimate a closer working relationship between the woman and her
      clinician, but still varies from country to country, as do uptake and
      continuation rates. The literature is conflicting, some papers demonstrating an
      improvement in the situation in recent years, others striking a more pessimistic
      note. Certainly, trends can be identified. Factors are emerging that will
      positively influence long-term adherence, and most studies are consistent in the
      reasons women quote for cessation of therapy. The gulf between medical and
      feminist literature is wide, but we should examine women's viewpoints to enhance
      the profession's understanding of why the perception is one of unnecessary
      medicalization. Market research allows an insight into women's requirements and
      we should learn from other countries, cultures and professions. There is an
      increasing emphasis on communication skills. Counselling and information-giving
      have been recognized to be the key to developing a working relationship with the
      patient, but education for the physician is also necessary if accurate,
      individualized risk-benefit assessments and patient profiling are to be
      effective. Finally, a wider range of treatment options enhance individualization
      for the woman.

PMID- 12482107
TI  - Estrogens and receptors: an evolving concept.
AB  - Estrogens elicit most of their physiological effects through specific nuclear
      receptors (ERalpha and ERbeta), which belong to a superfamily of hormone
      activated transcription factors. They regulate gene expression either through
      direct binding to DNA (as homo- or heterodimers) or via protein-protein
      interactions with other transcription factors. The hormone induces a
      conformational change that creates a new interface for molecules acting as
      transcription intermediary factors. These cofactors bind directly to estrogen
      receptors and mediate transcription activation or repression, usually as part of
      multimolecular complexes, acting either by stabilization of the basal
      transcription machinery or by chromatin remodelling; these involve the activities
      of various enzymes such as histone acetyltransferases and deacetylases. Moreover,
      different types of post-translational modifications (phosphorylation,
      acetylation, ubiquitination) also regulate estrogen receptor stability and/or
      transcriptional activation, and these effects, together with the non-genomic
      effects of estrogens, are important parameters of this signalling pathway.
      Finally, all these processes have their own dynamics, which may lead, depending
      on whether the hormone is provided continuously or as a pulse, to the same or
      different effects according to the end-point and the cell considered.

PMID- 12482108
TI  - Pulsed estrogen therapy: from cellular mode of action to tissue effects.
AB  - Failure to achieve a uniform response to estrogen replacement therapy may be
      related to the dose or route of administration of estrogen. The established
      doctrines of estrogen replacement therapy are under scrutiny. Recent discoveries
      have prompted a complete re-evaluation of estrogen action at the biochemical,
      physiological, and molecular level. Further questions remain as regards the
      correct dose of estrogen. It is becoming clear that individual cell types respond
      differently to different doses of estrogen and, even within a single experimental
      system, a considerable variation in response can be seen. Furthermore, there is
      an evident link between the duration of exposure to estradiol (continuous versus
      pulsed) and cellular behavior. In addition to this, it appears that ligand
      binding has a significant effect on estrogen receptor dynamics. The concept of
      pulsed estrogen therapy has recently been exploited by the introduction of a
      nasal spray delivery system. The administration of estradiol via the nasal mucosa
      is made possible by the use of randomly methylated alpha-cyclodextrin (RAMEB), a
      beta-cyclodextrin which increases the solubility of estradiol. The original
      pulsed plasma concentration time profile of E2 following transnasal
      administration was studied and the results were compared with orally or
      transdermally administered E2. Being dose-proportional, estradiol transnasally
      administered at a dose of 300 microg gave an estimated 24-h systemic exposure to
      exogenous estradiol (area under the curve) close to that of reference treatments.
      It would appear that pulsed estrogen therapy has a different cellular mechanism
      to that of traditional forms of administration. This new concept provides
      reliable dose-dependent exposure to estradiol, avoids the hepatic first-pass
      effect and demonstrates good biological and clinical efficacy. This development,
      linked to our improved understanding of the cellular effects of estrogen, ushers
      in a new era in postmenopausal hormone replacement therapy.

PMID- 12482109
TI  - Pulsed estrogen therapy: relieving climacteric symptoms, preventing
      postmenopausal bone loss.
AB  - Aerodiol with its new mode of action--pulsed estrogen therapy made possible by a
      unique pharmacokinetic profile and an innovative route of administration--acts on
      the full range of climacteric symptoms and on the long-term consequences of
      estrogen deprivation. Four well-designed, international studies investigating the
      efficacy of pulsed estrogen therapy on both the short- and long-term consequences
      of estrogen deprivation were conducted. Climacteric symptoms and their reduction
      were assessed individually and also using the Kupperman index, which is a
      weighted score. Aerodiol produced a significant reduction in the Kupperman index
      and in the occurrence of menopausal symptoms, such as hot flushes and night
      sweats. This reduction appeared to be significant as early as the second week of
      treatment. Moreover, Aerodiol remained effective even among highly symptomatic
      women with more than seven hot flushes per day, and also among smokers. Since it
      avoids hepatic first-pass metabolism, pulsed estrogen therapy also has a
      favorable action on the lipid profile, decreasing lipoprotein(a), apolipoprotein
      B, total cholesterol, and low-density lipoprotein cholesterol. Furthermore,
      Aerodiol is neutral with regard to clotting factors, angiotensinogen and insulin
      levels. The effect of pulsed estrogen therapy on bone has been assessed in both
      the short and the long term. Bone turnover, as measured by markers of resorption
      and formation, was normalized to premenopausal levels after 3 months of treatment
      at a dose of 300 microg/day. Aerodiol, again at the dose of 300 microg/day, is as
      effective as a 50-microg/day transdermal patch in increasing bone mineral density
      (p < 0.001 versus baseline) at the spine and hip after 56 weeks. Finally, data
      collected during the development of Aerodiol have shown that pulsed estrogen
      therapy is at least as effective as 2 mg of oral estrogen or 50 microg of
      transdermal estrogen in relieving climacteric symptoms and preventing
      postmenopausal bone loss.

PMID- 12482110
TI  - Safety and tolerability of pulsed estrogen therapy: key factors for an improved
      compliance.
AB  - Hormone replacement therapy (HRT) is recognized as the 'gold standard' for the
      treatment of the short- and long-term consequences of estrogen deprivation.
      Compliance with HRT is poor, mainly due to side-effects and fear of cancer. Many
      women discontinue the treatment prematurely and will not derive its full benefit.
      This presentation summarizes the results of studies assessing the safety and
      tolerability of pulsed estrogen therapy (Aerodiol) versus conventional estrogen
      therapy. The mammary safety was assessed in well-recognized experimental models.
      In comparison with oral administration, pulsed therapy showed a significantly
      lower rate of tumor induction (p < 0.05) and reduced tumor growth. The
      endometrial safety of Aerodiol was assessed in a long-term study. After 1 year of
      treatment, 311 biopsies could be evaluated: 34% were atrophic, 16% proliferative,
      39% secretory, 4% menstrual and 7% had no endometrial tissue. No cases of
      endometrial hyperplasia or cancer were detected. In a comparative study
      comprising 659 women, a lower frequency of irregular bleeding was reported with
      Aerodiol compared with orally administered estradiol. In two randomized studies,
      the frequency of mastalgia has been found to be significantly lower with Aerodiol
      compared with orally and transdermally administered estradiol. Aerodiol has been
      found to be well-tolerated, with better gynecological acceptability than
      conventional estrogen, and individualization of therapy might increase
      compliance. Intranasally administered estradiol is an attractive alternative for
      many women.

PMID- 12482111
TI  - Estrogen therapy: from women's choice to women's preference.
AB  - The climacteric is not an illness, but the menopause is an event that troubles a
      woman's present life and puts her future life at risk. One would like to think
      that, for the woman of the new millennium, the menopause has simply become what
      it is: a feminine milestone that marks the transition and path to another period
      of life. She appears younger than her mother was at her age, she has given birth
      when she decided to, she has had the number of children she wanted, and her
      social and professional roles are well defined. Nevertheless, none of this makes
      much difference--the 'change of life' is still something difficult to live
      through, a bend to negotiate, each woman going at her own pace, using her own
      means, with the cards that life has already dealt her. Where do we gynecologists
      come in, what part have we to play in our patients' lives? Sometimes, we need to
      be less discreet and ask some of those questions women may have trouble voicing
      aloud. Let us try to help them to talk about their mood changes, the changes in
      their body, and their anxiety about osteoporosis and aging. Shame or fear of
      ridicule are still often among the ideas on the menopause and, by preventing
      honest answers from being given, often modify the scientific statistics on
      menopausal women--especially as women are often at a loss to know which of the
      different opinions to believe. The media air their news, the medical community
      offers its dissent, while friends recount frightening stories. Between the danger
      of offending Mother Nature and the risk of missing out on the progress of
      science, what is the right modus operandi that helps to add quality to the
      quantity of life still there to be enjoyed after the menopause? The doctor
      patient relationship is of the utmost importance here, since an atmosphere of
      confidence and trust is the basis of mutual comprehension. By understanding the
      patient's needs, her desires, and her ways of coping with the situation, the
      physician will enable her to accept the proposed prescription. The mode of
      administration should be proposed and not imposed, offered first as one of many
      possibilities, and should take into account the lifestyle, the private and
      professional situation of the particular woman, and her habits and tastes,
      allowing her a true role in the decision-making process. Observance and
      compliance will therefore naturally follow, with a woman feeling she has been
      listened to and understood as a mature adult, and not as a stupid individual or a
      child. After all, there are not very many medical situations where both patients
      and physicians have such an array of products and routes of administration
      available to them. This was the way patients in the Aerodiol studies were
      considered, and it was also the way that they responded, after the initial
      surprise factor which opened the road to interesting exchanges. Local
      acceptability was graded as good to excellent by the spray users. While the
      Kupperman score was as significantly reduced in both the group that received the
      Aerodiol spray and the group treated via the transdermal route, mastalgia, one of
      those side-effects known to dramatically reduce the acceptability of a treatment,
      was significantly less frequent and user satisfaction was similarly greater at
      week 16 in the Aerodiol group. The approach, as well as the drug itself, seems to
      have been well appreciated, as a great number of patients (66% versus 34% for the
      transdermal route) wanted to continue the treatment after the end of the
      protocol. How else do our patients express their satisfaction if not by their
      compliance (which is, after all, our aim)? Compliance was not a problem with the
      pulsed estrogen therapy and nasal administration of it. The woman's preference
      could well be the doctor's choice, meaning true informed consent from both
      parties.

PMID- 12482112
TI  - Estrogen effects on neuroendocrine function: the new challenge of pulsed therapy.
AB  - A growing body of evidence shows a beneficial effect of hormone replacement
      therapy (HRT) on climacteric symptoms, well-being, and prevention of long-term
      consequences of estrogen deprivation. Nevertheless, only a relatively small
      number of women are users, and the mean duration of treatment is only about 18-24
      months. This evident reluctance to prescribe and use HRT, so-called poor
      compliance, is without doubt not only due to a misunderstanding of the beneficial
      effects of HRT but also (and mainly) due to a discordance between expectations
      and treatment available. In order to improve compliance and to meet the
      expectations of physicians and patients, there is a need for a new treatment.
      This new treatment has to be effective, better tolerated, reassuring for
      physicians and women, convenient, easy to prescribe, easy to use and also
      feminine. 17beta-Estradiol remains the only natural estrogen available. It is
      almost identical to that secreted by the ovaries, is effective on all the
      consequences of estrogen deprivation, and is obviously the one to choose.
      Research on the intimate intracellular mode of action of estrogen is progressing
      on a daily basis. Today, we know that there are different estrogen receptor
      isoforms, that the distribution of these receptors is not uniform among the
      tissues, and that there are different mechanisms of action: genomic and non
      genomic, with rapid (seconds or minutes) or delayed (hours or days) effects.
      Natural hormonal stimulation of target tissues is not a continuous event over the
      day. Up to now, all available forms of estrogen stimulate target cells in a
      continuous fashion over the day and might lead to unsatisfactory reactions.
      Aerodiol, the first-ever pulsed estrogen therapy with its specific mode of
      action, a brief stimulation of estrogen receptors made possible by its unique
      pharmacokinetic profile and its innovative route of administration, represents a
      new approach in the field of HRT. Aerodiol is not only a new route of
      administration but really a new way to treat hormone deficiency. Data collected
      during phase-3 studies provide evidence that Aerodiol is at least as effective as
      continuous therapy such as with oral and transdermal estrogens, is better
      tolerated gynecologically, and may be safer. If we consider that improvement in
      compliance is the key issue of HRT, we have to consider women as decision-makers
      in this process and we have to provide them with something that meets their
      expectations. With two out of three women (66%) choosing Aerodiol to continue
      their treatment for 1 year and 85% of women continuing their treatment after 1
      year, Aerodiol goes at least some way to meeting these.

PMID- 12482113
TI  - Reliability of postal questionnaires for the Glasgow Outcome Scale.
AB  - The purpose of the study was to investigate if a questionnaire sent by mail can
      give a reliable assessment of outcome on the Glasgow Outcome Scale. A
      questionnaire was developed for the Glasgow Outcome Scale (GOS) and a second
      questionnaire for the Extended Glasgow Outcome Scale (GOSE). The questionnaires
      were self-contained and designed to be completed by either a head-injured person
      or a proxy. The questionnaires were studied in two ways: each questionnaire was
      administered twice (at an interval of approximately 2 weeks), and ratings from
      the postal questionnaires were compared to ratings from a structured interview
      conducted by telephone. The four studies were carried out in separate groups of
      head-injured participants consisting of 32-38 individuals. For the test-retest
      comparison, k(w) (quadratic weights) was 0.94 for the GOS questionnaire and 0.98
      for the GOSE questionnaire. For the comparison with the telephone interview, k(w)
      was 0.67 for the GOS and 0.92 for the GOSE. The values of k(w) indicate good
      agreement for all comparisons. We conclude that it is possible to obtain reliable
      outcome data after head injury using postal questionnaires.

PMID- 12482114
TI  - Cerebral endothelial injury in severe head injury: the significance of
      measurements of serum thrombomodulin and the von Willebrand factor.
AB  - Thrombomodulin (TM), which is located in the surface of the endothelium in the
      arteries, veins, and capillaries of major organs such as the brain, lungs, liver,
      kidneys, skeletal muscles, and gastrointestinal tract, is one of several
      indicators of endothelial injury. Von Willebrand factor (vWf), which is
      synthesized by endothelial cells, is also an endothelial specific glycoprotein.
      The serum level of vWf increases in response to various stimuli without
      endothelial injury. An elevated serum level of vWf may suggest endothelial
      activation in severe head injury. We hypothesize that the degree of cerebral
      endothelial activation or injury depends on the type of head injury and that
      measuring the TM and vWf is useful for predicting delayed traumatic intracerebral
      hematoma (DTICH), produced by weakness of the vessel wall, occuring either as a
      direct or indirect effect of head injury. The values of vWf in focal brain injury
      (ranging from 332.5 +/- 52.8% to 361.7 +/- 86.2%) were significantly higher than
      those in diffuse axonal injury from 2 h to 7 days after the injury occurred
      (ranging from 201.6 +/- 59.5% to 242.5 +/- 51.7%). The serum level of TM in focal
      brain injury (ranging from 3.84 +/- 1.54 to 4.12 +/- 1.46 U/mL) was higher than
      that in diffuse axonal injury (ranging from 2.96 +/- 0.63 to 3.67 +/- 1.70 U/mL),
      but these differences were not statistically significant. In patients with DTICH,
      TM was significantly higher than in patients without DTICH (p < 0.01). The
      results of our study demonstrate that the degree of endothelial activation in
      focal brain injury was significantly higher than in diffuse brain injury. In
      addition, the serum level of TM in patients with DTICH was significantly higher
      than in patients without DTICH. These findings suggest that cerebral tissue
      injury is often accompanied by cerebral endothelial activation, and that these
      two phenomena should be distinguished from each other. The levels of serum TM and
      vWf appear to be good indicators of the cerebral endothelial injury and of
      endothelial activation in severe head injury.

PMID- 12482115
TI  - Arachnoid cyst is a risk factor for chronic subdural hematoma in juveniles:
      twelve cases of chronic subdural hematoma associated with arachnoid cyst.
AB  - Chronic subdural hematoma (CSDH) tends to occur in elderly patients with a
      history of mild head injury at a few months prior to the onset of symptoms.
      Intracranial arachnoid cyst is believed to be congenital and sometimes becomes
      symptomatic in pediatric patients. These two distinct clinical entities
      sporadically occur in the same young patient. Twelve of 541 cases of CSDH
      surgically treated in our institution had associated arachnoid cyst. The clinical
      and radiological characteristics of the cases of CSDH associated with arachnoid
      cyst were retrospectively analyzed and compared with those of CSDH without
      arachnoid cyst. Arachnoid cysts were located in the middle fossa (eight cases),
      convexity (two cases), and posterior fossa (two cases). Three cysts were less
      than 20 mm in diameter. The 12 patients with CSDH and arachnoid cyst (mean age
      27.8 +/- 19.7 years) were significantly younger (p < 0.001) than the patients
      with CSDH without arachnoid cyst (69.5 +/- 13.7 years). Five of the 12 patients
      were pediatric cases (< 15 years old). The clinical symptoms were also
      significantly different. The most frequent symptom was headache followed by
      vomiting in the patients with arachnoid cyst, while gait disturbance and
      hemiparesis predominated in patients without arachnoid cyst. Hematoma evacuation
      through burr holes improved the symptoms in all patients with arachnoid cyst. We
      conclude that even a small arachnoid cyst can be a risk factor for CSDH after
      mild head injury in young patients and symptoms of increased intracranial
      pressure are common. Hematoma evacuation is adequate at first operation. If the
      preoperative symptoms persist, additional arachnoid cyst surgery should be
      considered. The present results also suggest that CSDH formation may be preceded
      by subdural hygroma caused by the rupture of arachnoid cyst.

PMID- 12482116
TI  - Cerebral blood flow at one year after controlled cortical impact in rats:
      assessment by magnetic resonance imaging.
AB  - Progressive tissue loss and delayed cognitive deficits are seen in rats during
      the initial year after experimental traumatic brain injury (TBI). As much as 10%
      of parenchymal volume is lost even in the contralateral hemisphere by 1 year
      after controlled cortical impact (CCI) in rats. Progressive declines in cerebral
      blood flow (CBF) are also associated with advanced age and neurodegenerative
      diseases. Surprisingly, the long-term effects of TBI on CBF remain undefined. CBF
      was quantified by continuous arterial spin-labeled magnetic resonance imaging
      (MRI) and measurements of spin-lattice relaxation time in a slice through the
      plane of injury at 1 year after experimental TBI produced by CCI (n = 4) or sham
      surgery (n = 4) in rats. CBF was quantified in six regions of interest (ROIs)
      that were anatomically identified on the control images in each hemisphere and
      included a medial cortical segment (contusion-enriched, beneath the impact site,
      on the ipsilateral side) cortex, hippocampus, thalamus, amygdala/pyriform cortex,
      and hemisphere. At 1 year after injury, CBF was dramatically (96%) reduced in
      structures within the large cystic lesion that was seen in three of four rats and
      variably included cortex and hippocampus. Overall, there was an 80% reduction in
      CBF in the ipsilateral medial cortical segment comparing CCI and sham groups.
      Similarly, 52% and 67% reductions were seen in CBF in the cortical and
      hippocampal ROIs ipsilateral to impact (CCI vs. sham), respectively. These are
      regions both with marked CBF disturbances early after injury and that ultimately
      suffer considerable tissue loss over the 1-year interval. However, at 1 year
      after CCI, CBF was not different from sham in other ROIs, including ipsilateral
      thalamus, or either contralateral hippocampus or hemisphere. We conclude that, at
      1 year after CCI, CBF is reduced in anatomic structures at or near the impact
      site, including injured cortex and hippocampus, and this translates into a
      reduction in hemispheric CBF. However, despite both significant occult tissue
      loss ipsilateral and contralateral to the injury and delayed cognitive deficits,
      widespread reductions in CBF are not observed. This suggests the possibility of
      remodeling or repackaging of the brain that preserves CBF outside of the cystic
      lesion.

PMID- 12482117
TI  - Administration of either anti-intercellular adhesion molecule-1 or a nonspecific
      control antibody improves recovery after traumatic brain injury in the rat.
AB  - Intercellular adhesion molecule-1 (ICAM-1) is an endothelial protein that
      facilitates invasion of leukocytes into the CNS in response to injury or
      inflammation. ICAM-1 expression correlates with the severity of clinical head
      injuries, but its importance in secondary injury events is not fully understood.
      Therefore, we evaluated ICAM-1 expression and the effect of anti-ICAM-1 treatment
      on motor recovery and neutrophil invasion after traumatic brain injury induced
      via the lateral fluid-percussion method in the rat. ICAM-1 was expressed in large
      and small blood vessels within the injured cortex at 10 and 24 h after injury.
      Repeated administration of anti-ICAM-1 antibody (clone 1A29) at 1, 10, and again
      at 24 h after injury significantly improved performance in two of three motor
      tests, compared to saline controls. Equal doses of nonspecific control antibody
      (IgG) also significantly improved motor test scores, compared to saline controls.
      Cortical myeloperoxidase activity, an indicator of neutrophil invasion, was
      significantly reduced 26 h after injury in animals treated with anti-ICAM-1.
      Animals treated with IgG showed a trend toward reduction that did not reach
      significance. These data suggest that ICAM-1 may be involved in neutrophil
      invasion and neurological dysfunction after TBI, but also implicate a role for a
      nonspecific antibody effect in improved functional outcome.

PMID- 12482118
TI  - Cyclooxygenase-2, prostaglandin synthases, and prostaglandin H2 metabolism in
      traumatic brain injury in the rat.
AB  - Inflammatory mediators are important in traumatic brain injury (TBI). The
      objective of the present study was to investigate the expression of
      cyclooxygenase-2 (COX-2), prostaglandin E (PGE) and PGD synthases, and PGH2
      metabolism in two rat models of TBI. Fluid percussion injury (FPI) resulted in
      bilateral induction of COX-2 mRNA in the dentate gyri and the cortex, whereas
      controlled cortical contusion injury (CCC) induced COX-2 mRNA in the ipsilateral
      dentate gyrus and intensely in the cortex as judged by in situ hybridization. The
      induction subsided within 24 h. COX-2 immunoreactivity was detectable in these
      areas and persisted in the ipsilateral cortex for at least 72 h after CCC.
      Regions with COX-2 induction co-localized with TUNEL staining, suggesting a link
      between COX-2 expression and cell damage. COX-2 forms PGH2, which can be
      isomerized to PGD2, PGE2, and PGF2alpha by enzymatic and non-enzymatic
      mechanisms. In situ hybridization showed that mRNA of PGD synthase and microsomal
      PGE synthase were present in the choroid plexus. The microsomal PGE synthase was
      induced bilaterally after FPI and unilaterally after CCC. Liquid chromatography
      mass spectrometry showed that low speed supernatant of normal and traumatized
      cortex and hippocampus transformed PGH2 to PGD2 as main product. PGD2 was
      dehydrated in brain homogenates to biological active compounds, for example, 15
      deoxy-delta12,14-PGJ2. Thus COX-2 increases in certain neurons following TBI
      without neuronal induction of PGD and microsomal PGE synthases, suggesting that
      PGH2 may decompose to PGD2 and its dehydration products by nonenzymatic
      mechanisms or to PGD2 by low constitutive levels of PGD synthase.

PMID- 12482119
TI  - Induction of manganese superoxide dismutase in acute spinal cord injury.
AB  - Free radical-mediated mechanisms of cellular damage have been implicated in the
      early stages of spinal cord injury (SCI). Manganese superoxide dismutase (MnSOD)
      is a potent scavenger of superoxide radicals and likely serves an important
      cytoprotective role in preventing cellular damage after SCI. We have evaluated
      the expression of MnSOD to address its role during the early events of SCI using
      a well-established rat contusion model. Northern analysis showed a rapid
      induction of MnSOD mRNA between 2 and 6 h post injury. Observed time-dependent
      increases in MnSOD message was maximal 6 h post injury over that of MnSOD mRNA
      levels induced by laminectomy alone. Immunoblot and immunohistochemical analysis
      demonstrated increased expression of MnSOD protein 24 h after SCI with
      localization primarily within neurons. Interestingly, laminectomy alone also
      caused an induction of MnSOD gene and protein expression. To evaluate one
      potential mechanism of MnSOD induction, we microinjected the naive spinal cord
      with IL-1beta, which caused a similar fold induction of MnSOD mRNA levels by 6 h
      as observed with SCI, thus implicating it as a potential inducer of MnSOD during
      SCI. In summary, these results demonstrate that this potent cytoprotective
      antioxidant enzyme is rapidly and significantly induced as a consequence of SCI.

PMID- 12482120
TI  - Cationic liposome-mediated GDNF gene transfer after spinal cord injury.
AB  - Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect
      cranial and spinal motoneurons, which suggests potential uses of GDNF in the
      treatment of spinal cord injury (SCI) and motor neuron disease. We examined
      neuroprotective effect of cationic liposome-mediated GDNF gene transfer in vivo
      on axonal regeneration and locomotor function recovery after SCI in adult rats.
      The mixture of DC-Chol liposomes and recombinant plasmid pEGFP-GDNF cDNA was
      injected after SCI. RT-PCR confirmed the increased expression of GDNF mRNA in the
      injected areas at 7 days after injection. The expression of EGFP-GDNF was
      observed in the cells around the injection locus by fluorescence microscope at
      least 4 weeks after injection. Four weeks after GDNF gene transfer, regeneration
      of the corticospinal tracts was assessed using anterograde tract tracing. There
      are more HRP labeling of corticospinal tract axons across the lesion in GDNF
      group compared with control group. In GDNF group, the maximum distance these
      labeled axons extended varied in different animals and ranged from 5 mm to
      approximately 9 mm from the lesion. In control group, no HRP labeled axons
      extended caudal to the lesion. The locomotion function of hindlimbs of rats was
      evaluated using inclined plane test and BBB locomotor scores. The locomotion
      functional scores in GDNF group were higher than that in control group within 1-4
      weeks after SCI (p < 0.05). These data demonstrate that in vivo transfer of GDNF
      cDNA can promote axonal regeneration and enhance locomotion functional recovery,
      suggesting that cationic liposome-mediated delivery of GDNF cDNA may be a
      practical gene transfer method for traumatic SCI treatment.

PMID- 12482121
TI  - Optimal treatment timing to attenuate neuronal apoptosis via Bcl-2 gene transfer
      in vitro and in vivo.
AB  - Although Bcl-2 gene transfer can rescue cells from neuronal apoptosis, the
      temporal relationship between treatment initiation time and effectiveness is
      unknown. The purpose of present study is to investigate the optimal treatment
      timing of Bcl-2 gene transfer in saving cells after neural insults. Bcl-2 gene
      transfer was mediated by recombinant adenovirus carrying human bcl-2 oncogene
      (Adv-Bcl-2). Adenovirus carrying beta-galactosidase gene (Adv-Bgal) served as a
      control. A serum withdrawal model of NSC-19 cell culture was used to induce
      apoptosis in vitro. At various time points before or after serum withdrawal, the
      motor neuron cells (NSC-19 cells) were infected with either Adv-Bcl-2 or Adv
      Bgal. At 72 h after serum withdrawal, the number of apoptotic cells and DNA
      fragmentation were examined to evaluate the effect of Bcl-2 gene transfer. A
      weight-drop spinal cord injury model in rats was used as in vivo model. At
      various time points before or after experimental spinal injury, virus solution,
      including Adv-Bcl-2 or Adv-Bgal, was injected at the spinal cord in injured rats.
      The degree of cord injury was measured at 72 h after injury. TUNEL staining was
      performed to count cells that have undergone DNA damage in sections. Bcl-2
      protein overexpression was confirmed by immunostaining both in vitro and in vivo
      model. In vitro, Adv-Bcl-2 infection produced a less prominent DNA laddering
      pattern. Adv-Bcl-2 infection between 24 h before and 4 h after serum withdrawal
      significantly reduced the apoptotic cell death. In vivo Adv-Bcl-2 injection
      immediately after injury effectively suppressed the injury lesion by blocking DNA
      fragmentation and irreversible cellular injury. Our data demonstrate that earlier
      initiation of Bcl-2 gene transfer can produce improved neural cell rescue
      following neural insults. These results stress important temporal considerations
      in future gene therapy strategies for spinal cord injury.

PMID- 12482122
TI  - Severe cerebral blood flow reduction inhibits nitric oxide synthesis.
AB  - The purpose of this study was to investigate the relationship between cerebral
      blood flow (CBF) and nitric oxide (NO) synthesis using a rat model of transient
      forebrain ischemia of varying severity. Forebrain ischemia was induced for 30 min
      by occlusion of the bilateral common carotid arteries without hemorrhagic
      hypotension. The production of NO end-products (nitrite and nitrate) was measured
      by in vivo microdialysis, and CBF by the hydrogen clearance technique. Ischemia
      induced NO synthesis, although the increase in the quantity of NO end-products
      was not remarkable during the ischemic period but became prominent after
      reperfusion. Such increases were abolished by Nomega-nitro-L-arginine methyl
      ester (L-NAME), although 7-nitroindazole (7-NI) appeared to have only slight
      effects. The production of NO end-products during ischemia increased when the CBF
      during ischemia was less than 60 mL/100 g/min. In animals in which the CBF during
      ischemia was higher than 22.7 mL/100 g/min, the production of NO end-products
      increased gradually after the induction of ischemia and reached a peak during the
      reperfusion period, whereas in other animals in which the CBF during ischemia
      fell below 22.7 mL/100 g/min, the NO end-products decreased during ischemia and
      increased transiently after reperfusion. These results suggest that the increase
      in NO end-products is NO synthase (NOS)-dependent and that most of the increase
      is derived from endothelial NOS. It is also suggested that NO synthesis during
      ischemia is closely related to CBF, and that severe CBF reduction may inhibit NO
      synthesis.

PMID- 12482123
TI  - Correlation of sera TNF-alpha with percentage of bone marrow plasma cells, LDH,
      beta2-microglobulin, and clinical stage in multiple myeloma.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is important for function,
      differentiation, and transformation of B-lymphocytes in multiple myeloma (MM) but
      can also induce apoptosis of myeloma cells. Based on this opposite effect, it is
      very crucial to analyze the correlation of the serum level of TNF-alpha with
      clinical parameters of the patients. In this article, we analyzed 18 MM patients,
      48% male and 52% female, with a mean age of 52 yr (range: 35-81 yr), clinical
      stage I in 21.4%, stage II in 26.4%, and stage III in 52.2% of patients. Patients
      with advanced clinical stage, presence of osteolysis, and elevated lactate
      dehydrogenase (LDH) had a significant difference (Mann-Whitney U-test, p < 0.05)
      in the serum level of TNF-alpha in comparison with those in the early stage,
      without osteolysis, and normal LDH. The correlation of individual values of TNF
      alpha with the percentage of plasma cells in the bone marrow, LDH, beta2
      microglobulin, fibrinogen, and sedimentation rate was significant (p < 0.05).
      However, we have not found a significant correlation between TNF-alpha and
      concentration of hemoglobin, the number of white blood cells or platelets (p >
      0.05). We concluded that our data indicate determination of TNF-alpha as a good
      parameter for estimation of tumor mass presence, among individual patients with
      MM, and may by used for monitoring during application of different therapy
      protocols.

PMID- 12482124
TI  - Lympho-hemopoietic malignancies in India.
AB  - Available information on lympho-hemopoietic malignancies in India is presented.
      The incidence of most cancers, including multiple myeloma, lymphomas, and
      leukemias, is lower compared to that in the West; chronic myelogenous leukemia,
      however, is higher and the incidence of non-Hodgkin's lymphoma (NHL) is rising.
      Most cancers occur at a younger age. Higher frequencies of mixed-cellularity
      Hodgkin's disease, diffuse large-cell NHL and T cell acute lymphoblastic leukemia
      are noted. Most patients present in advanced stages and have poorer prognostic
      factors. Treatment results are comparable if stagewise distribution and poor
      prognostic factors are taken into account.

PMID- 12482125
TI  - Selection of chemotherapy by ex vivo assessment of tumor sensitivity to cytotoxic
      drugs: results of a clinical trial.
AB  - The feasibility of tumor sampling followed by ex vivo assessment of drug
      sensitivity, using the short-term fluorometric microculture cytotoxicty assay
      (FMCA), for selection of chemotherapy was investigated prospectively in patients
      with advanced cancer not amenable to standard treatment. Taxol (175 mg/m2 every 3
      wk) was given to patients with tumor samples being low drug resistant (LDR) to
      Taxol ex vivo, to patients with no LDR drug, and if other drugs were unsuitable.
      The remaining patients received the most optimal drug(s) based on the FMCA
      results. Gastrointestinal cancer was dominating among the 61 eligible patients.
      Tumor sampling was safely performed in 75% by ultrasound-guided core biopsy.
      Eighty-two percent of the patients had Taxol. Five patients (8%) had a partial
      remission and 18 (30%) had stable disease. Tumor response was poorly predicted,
      probably because the Taxol excipient Cremophor EL is cytotoxic exclusively ex
      vivo. However, patients with tumor cells being LDR to at least one drug ex vivo
      lived significantly longer than those with no such drug.

PMID- 12482126
TI  - Cefepime monotherapy as an empirical initial treatment of patients with febrile
      neutropenia.
AB  - Currently, monotherapy is considered a valid alternative to the combination
      antibiotic treatments used for initial, empirical management of febrile
      neutropenia. The advent of new cephalosporins warrants assessment. The aim of
      this study was to prospectively evaluate the effectiveness of cefepime
      monotherapy in the treatment of cancer patients with febrile granulocytopenia (<
      1000 leukocytes/muL and/or < 500 neutrophils/muL). A prospective, multicenter,
      nonrandomized trial was conducted. Initial treatment consisted of iv cefepime, 2
      g every 8 h. If the patient was still febrile after 72 h, amikacin,
      vancomycin/teicoplanin, and amphotericin B were added sequentially. Response was
      evaluated according to EORTC criteria. One hundred twenty episodes were analyzed
      in 81 males and 39 females (median age, 52 yr; range, 15-83). The median
      leukocyte count at the time of diagnosis was 781 microL(-1) (range, 100-2600) and
      the median neutrophil count was 173 microL(-1) (range 0-500). The median duration
      of neutropenia (< 1000 neutrophils/microL) was 4.8 d (range, 3-20). Fifty-two
      episodes (44%) were confirmed microbiologically (42 presented as bacteremia), 31
      with Gram-positive bacteria and 21 with Gram-negative bacteria, 47 (39.3%) were
      confirmed clinically, 16 (13.3%) were considered as probable infections, and 5
      (4.2%) as doubtful infections. Protocol success was achieved in 110 episodes
      (91.7%), 8 (6.6%) were treatment failures, and 2 (1.7%) were not evaluable.
      Ninety-nine episodes (83.3%) were controlled with cefepime monotherapy, with 19
      other episodes requiring additional antibiotics: amikacin in 7 (5.8%), amikacin +
      vancomycin/teicoplanin in 12 (10.1%). Three patients (2,5%) died during an
      episode of neutropenic fever. Cefepime is effective as an initial, empirical
      treatment of febrile neutropenia. The early addition of amikacin and/or
      vancomycin resolves most of the monotherapy failures, which seem somewhat lower
      than with other monotherapies.

PMID- 12482127
TI  - Leptomeningeal infiltration of malignant mesothelioma.
AB  - Mesothelioma is a disease mostly involving the pleura, peritoneum, and
      pericardium. Hematogenously disseminated metastases involving the liver, adrenal
      glands, kidneys, and contralateral lung have been documented in some patients,
      but central nervous system (CNS) involvement, especially as leptomeningeal
      infiltration, is very rare. A 44-yr-old mesothelioma patient admitted to hospital
      with convulsions and diffuse leptomeningeal infiltration was shown with magnetic
      resonance imaging. She had a positive history for environmental asbestos
      exposure. Pleural and axillary lymph node biopsies were consistent with
      mesothelioma. Diffuse leptomeningeal infiltration is the only constant
      radiological finding reported as a diagnostic criteria for CNS involvement and
      histopathological confirmation is usually possible only at autopsy, so clinical
      and radiological diagnosis is essential after exclusion of other possible causes.

PMID- 12482129
TI  - Generalized lymphadenopathy: a rare presentation of disseminated prostate cancer.
AB  - Prostate cancer most often metastases to regional lymph nodes and bones by
      hematogenous or lymphatic spread. Metastases to the supradiaphragmatic nodes are
      rare. A 56-yr-old male smoker with generalized lymphadenopathy was referred to
      our center with the complaints of weight loss of 15 kg and severe back and leg
      pain. On computed tomography of the thorax and abdomen, massive mediastinal,
      intra-abdominal, retroperitoneal, and inguinal lymphadenopathies with
      hydroureteronephrosis of the left kidney were noted. Excisional biopsy of left
      cervical lymph node revealed metastasis of prostatic adenocarcinoma and
      transrectal biopsy of the prostate disclosed poorly differentiated
      adenocarcinoma. Bone marrow aspiration biopsy, done for the differential
      diagnosis of anemia, also showed infiltration with prostate-specific antigen
      positive neoplastic cells. Supradiaphragmatic spread of prostate cancer has been
      postulated to be by a hematogenous route via the vertebral venous system, or
      Batson's plexus, accessible via direct extension from the primary cancer site.

PMID- 12482128
TI  - Solitary esophageal metastasis of breast cancer after 11 years: a case report.
AB  - A patient with dysphagia and a history of breast cancer 11 yr ago was admitted to
      the hospital. A tumor presumably originating from the esophagus was detected. It
      could not be surgically removed and biopsy revealed adenocarcinoma. The patient
      received radiotherapy and chemotherapy consisting of etoposide, adriamycin, and
      cisplatin. An unexpectedly good response was achieved and the possibility of
      metastatic breast cancer was reinvestigated. Biopsy specimens showed positive
      estrogen and progesterone receptor staining. Tamoxifen treatment was started. The
      patient is well after 5 yr following relapse. Solitary esophageal metastasis of
      breast cancer is a rare event, especially after a remission period lasting more
      than a decade. Dysphagia in breast cancer patients should raise the suspicion of
      metastatic disease as well as esophageal cancer and benign strictures.

PMID- 12482130
TI  - Vasoactive intestinal polypeptide-secreting tumor (VIPoma) with liver metastases:
      dramatic and durable symptomatic benefit from hepatic artery embolization, a case
      report.
AB  - Neuroendocrine tumors often manifest an excess production of hormones that create
      severe metabolic abnormalities resulting in significant patient morbidity,
      independent of the tumor burden itself. VIPomas are rare neuroendocrine tumors
      arising from the pancreas and are associated with secretory diarrhea and
      electrolyte disturbances. We present a patient with VIPoma and hepatic metastases
      who had greater than 10 loose stools a day for 4 yr since diagnosis, despite
      debulking surgery, multiple antidiarrheal medications, large doses of octreotide,
      and targeted radioisotope injections. The patient required several
      hospitalizations for treatment of dehydration and electrolyte disturbances,
      despite receiving daily intravenous fluids at home. Hepatic artery embolization
      (HAE) immediately stopped the patient's diarrhea and provided a return to normal
      formed stools without any other symptom-support measures. One year after HAE, the
      patient remains asymptomatic and has returned to a productive life. HAE can be a
      very effective and durable treatment modality for patients with metastatic
      VIPomas (or other neuroendocrine tumors) and who are clinically symptomatic from
      the effects of hormone hypersecretion.

PMID- 12482131
TI  - Microangiopathic hemolysis refractory to plasmapheresis responding to docetaxel
      and cisplatin: a case report.
AB  - We report the case of a 56-yr-old woman with adenocarcinoma of unknown origin
      metastatic to the bone marrow presenting with a thrombotic thrombocytopenic
      purpura-like syndrome refractory to protracted daily plasmapheresis and steroids
      but readily and completely responsive to docetaxel plus cisplatin. Sustained and
      complete response was pathologically confirmed.

PMID- 12482132
TI  - Molecular beacons: fluorogenic probes for living cell study.
AB  - Molecular beacons are a new class of fluorescent probes that can report the
      presence of specific nucleic acids with high sensitivity and excellent
      specificity. In addition to their current wide applications in monitoring the
      progress of polymerase chain reactions, their unique properties make them
      promising probes for the detection and visualization of target biomolecules in
      living cells. This article is focused on our recent research in exploring the
      potential of using molecular beacon for living-cell studies in three important
      areas: the monitoring of mRNA in living cells, the development of ultrasmall
      DNA/RNA biosensors, and the novel approach of combining molecular beacon's signal
      transduction mechanism with aptamer's specificity for real-time protein
      detection. These applications demonstrate molecular beacon's unique properties in
      bioanalysis and bioassay development.

PMID- 12482133
TI  - Predicted alterations in tertiary structure of the N-terminus of Na(+)/K(+)
      ATPase alpha-subunit caused by phosphorylation or acidic replacement of the PKC
      phosphorylation site Ser-23.
AB  - The protein kinase C (PKC)-mediated phosphorylation of the Na(+)/K(+)-ATPase
      alpha-subunit has been shown to play an important role in regulation of the
      Na(+)/K(+)-ATPase activity. In the rat alpha1-subunit, phosphorylation occurs at
      Ser-23 and results in inhibition of the transport function of the Na(+)/K(+)
      ATPase, which is mimicked by replacing the Ser-23 by the negatively charged
      glutamic acid or by aspartic acid. Using comparative molecular modeling, we
      investigated whether phosphorylation or acidic replacement at position 23 causes
      a dramatic change in the molecular electrostatic potential at position 23 as a
      result of insertion of a negative charge of the phosphoryl group or Glu per se,
      or whether, alternatively, the modification causes larger-scale conformational
      changes in the N-terminus of the alpha-subunit. The results predict a
      considerable conformational change of the 30-residue stretch around Ser-23 when
      mutated to the residues carrying a net negative charge or being phosphorylated.
      The structural rearrangements occur within the N-terminal helix-loop-helix motif
      with a set of charged residues. This motif has structural homology with one in
      the Ca(2+)-ATPase and may form a function-related structural site in the P-type
      ATPases. Comparative molecular modeling indicates a lengthening of the
      interhelical loop and an order-to-disorder transition by disrupting a helix at
      position 23 because of posphorylation.

PMID- 12482134
TI  - A computational comparison of the atomic models of the actomyosin interface.
AB  - Several atomic models of the actomyosin interface have been proposed based on the
      docking together of their component structures using electron microscopy and
      resonance energy-transfer measurements. Although these models are in approximate
      agreement in the location of the binding interfaces when myosin is tightly bound
      to actin, their relationships to molecular docking simulations based on
      computational free-energy calculations are investigated here. Both rigid-docking
      and flexible-docking conformational search strategies were used to identify free
      energy minima at the interfaces between atomic models of myosin and actin. These
      results suggest that the docking model produced by resonance energy-transfer data
      is closer to a free-energy minimum at the interface than are the available atomic
      models based on electron microscopy. The conformational searches were performed
      using both scallop and chicken skeletal muscle myosins and identified similarly
      oriented actin-binding interfaces that serve to validate that these models are at
      the global minimum. These results indicate that the existing docking models are
      close to but not precisely at the lowest-energy initial contact site for strong
      binding between myosin and actin that should represent an initial contact between
      the two proteins; therefore, conformational changes are likely to be important
      during the transition to a strongly bound complex.

PMID- 12482135
TI  - The dance of actin and myosin: a structural and spectroscopic perspective.
AB  - Actin and myosin interact in a cyclic series of steps linked to the hydrolysis of
      ATP that are representative of an ancient and widespread molecular mechanism.
      Spectroscopic findings are related to the analysis of the actin and myosin
      structures and results from kinetics, fibers, single molecules, electron
      microscopy, genetics, and a variety of other biophysical and biochemical studies
      on actin and myosin to provide an overview of the steps in this molecular
      process. The synthesis of the key findings from these fields reveals a highly
      efficient engine that amplifies subtle changes in the active site into
      unsurpassed molecular displacements. Recent developments in resonance energy
      transfer spectroscopy and X-ray crystallography are enabling a detailed
      elucidation of the stages of a large power stroke that concurs with evidences
      from diverse lines of structural and kinetic inquiry. A complete image of actin
      and myosin motility appears to include twists, tilts, steps, and dynamics from
      both partners that could be described as a molecular dance.

PMID- 12482136
TI  - Circadian rhythm entrainment in flies and mammals.
AB  - Circadian rhythms are a fundamental adaptation of living cells to the daily and
      seasonal fluctuation in light and temperature. Circadian oscillations persist in
      constant conditions; however, they are also phase-adjusted (entrained) by day
      night cycles. It is this entrainability that provides for the proper phasing of
      the program, to the sequence of external changes that it has evolved to exploit.
      Synchronization of circadian oscillators with the outside world is achieved
      because light, temperature, or other external temporal cues, have acute effects
      on the levels of one or more of the clock's components. The consequences are
      ripples through the interconnected molecular loops, leading to a stable phase
      realignment of the endogenous rhythm generator and the external conditions. This
      review summarized the evolving knowledge of the different types, modes, and
      molecular processes of entrainment in flies and mammals.

PMID- 12482137
TI  - Managing the enlarging waiting list.

PMID- 12482138
TI  - Waiting time or wasted time? The case for using time on dialysis to determine
      waiting time in the allocation of cadaveric kidneys.

PMID- 12482139
TI  - EBV viral load monitoring: unanswered questions.

PMID- 12482140
TI  - Laparoscopic donor nephrectomy after seven years.

PMID- 12482141
TI  - What's in the pipeline? New immunosuppressive drugs in transplantation.
AB  - In the pipeline, there are a number of novel immunosuppressive drugs in
      preclinical development or in early clinical trials. The major target of new
      agents are cell-surface molecules important in immune cell interactions
      (especially the costimulatory pathway), signaling pathways that activate T cells,
      T-cell proliferation and trafficking and recruitment of immune cells responsible
      for rejection. The most promising biologic agents include a humanized anti-CD11a
      (anti-LFA1), humanized anti-B7.1/B7.2, a second-generation CTLA4Ig (LEA29Y) and a
      humanized antibody to anti-CD45 RB. Inhibitors of T-cell activation and signaling
      are still in preclinical development. The most interesting inhibitors of T-cell
      proliferation include inhibitors of the Janus protein tyrosine kinase, JAK3, and
      FK778, a leflunomide analog. Chemokines play an important role in rejection by
      virtue of their critical role as regulator of trafficking and activation of
      lymphocytes. Early trials of FTY720, a synthetic small molecule with functional
      homology to sphingosine-1 phosphate leading to lymphocyte sequestration, appear
      very promising; however, enthusiasm for this drug is mitigated by its potential
      cardiac side-effects. Antagonists to several chemokine receptors, including CCR1,
      CXCR3 and CCR5, have been shown to be effective in experimental transplantation
      and are likely to be considered for clinical development.

PMID- 12482142
TI  - On the role of proteasomes in cell biology and proteasome inhibition as a novel
      frontier in the development of immunosuppressants.
AB  - The proteasome, a large protease complex in cells, is the major machinery for
      protein degradation. It was previously considered a humble garbage collector,
      performing housekeeping duties to remove misfolded or spent proteins. Until
      recently, the interests of immunologists in proteasomes were focused largely on
      its role in antigen processing. Its real importance in cell biology has only been
      revealed contemporarily due to the availability of relatively specific
      inhibitors. It has now become increasingly clear that many aspects of immune
      responses highly depend on proper proteasome activity. Recently, a proteasome
      inhibitor has been successfully used to prevent acute as well as ongoing heart
      allograft rejection in mice. Such inhibitors are also efficacious in treating
      several autoimmune diseases, such as arthritis, psoriasis, and probably type I
      diabetes, in animal models. Phase II and III clinical trials of proteasome
      inhibitors in treating various tumors have shown promising results, and the side
      effects of these drugs are tolerable. Therefore, proteasome inhibition represents
      a new and promising frontier in immunosuppressant development.

PMID- 12482143
TI  - Gene expression during acute allograft rejection: novel statistical analysis of
      microarray data.
AB  - High-throughput microarrays promise a comprehensive analysis of complex
      biological processes, yet their applicability is hampered by problems of
      reproducibility and data management. The current study examines some of the major
      questions of microarray use in a well-described model of allograft rejection.
      Using the Brown Norway to Lewis heterotopic heart transplant model, highly
      purified RNA was isolated from cardiac tissue at postoperative days (POD) 3, 5
      and 7 and hybridized onto Affymetrix U34A microarrays. Using the log average
      ratio (LAR), changes in gene expression were monitored at each timepoint and p
      values generated through statistical analysis. Microarray data were verified for
      13 significant transcripts using RT-PCR. Of the 8800 transcripts studied, 2864
      were increased on POD 3, 1418 on POD 5 and 2745 on POD 7. Verifying previous
      studies, many up-regulated genes appeared to be associated with the inflammatory
      process and graft infiltrating cells. Down-regulated transcripts included many
      novel molecules such as SC1 and decorin. LAR analysis provides a useful approach
      to analyze microarray data. Results were reproducible and correlated well with
      both RT-PCR and prior studies. Most importantly, these results provide new
      insights into the pathogenesis of acute rejection and suggest new molecules for
      future studies.

PMID- 12482144
TI  - High incidence of donor-reactive delayed-type hypersensitivity reactivity in
      transplant patients.
AB  - Evidence of transplant recipient cellular sensitization towards donor antigens
      has rarely been directly measured. Rather, sensitization has been generally
      inferred by the presence of detectable allo-reactive or donor-reactive
      antibodies. In this study a newly developed delayed-type hypersensitivity assay
      was used to directly determine the incidence of post-transplant donor-reactive T
      cell sensitization in a large cohort of kidney and simultaneous kidney-pancreas
      recipients. These results were compared with the presence of detectable
      circulating alloantibodies and with patient clinical outcome. We found an
      unexpectedly high incidence (52%) of donor-reactive delayed-type hypersensitivity
      reactivity in our study patients. Donor-reactive delayed-type hypersensitivity
      reactivity occurred at a much higher frequency than detectable alloantibodies
      (20%). Further, we found no correlation between the presence of alloantibodies
      and donor-reactive delayed-type hypersensitivity reactivity. We also found no
      correlation between the development of donor-reactive delayed-type
      hypersensitivity reactivity and the degree of donor and recipient HLA matching.
      Finally, the presence of detectable donor-reactive delayed-type hypersensitivity
      reactivity did not correlate with a worse clinical outcome at the time of these
      analyses. We conclude that in transplant recipients, the presence of circulating
      alloantibodies is a poor indicator of previous T-cell sensitization to donor
      antigens. We also conclude that our current immunosuppression strategies are
      relatively ineffective at blocking T-cell allosensitization, but are very
      effective at blocking the biological consequences of that allosensitization.

PMID- 12482145
TI  - Eversion thrombectomy for portal vein thrombosis during liver transplantation.
AB  - Portal vein thrombosis (PVT) has been seen as an obstacle to orthotopic liver
      transplantation (OLT), but recent data suggest that favorable results may be
      achieved in this group of patients. The aim of this study was to analyze the
      incidence, management, and survival of patients with PVT undergoing primary OLT
      with thrombectomy. Between October 1990 and August 2000, 468 liver
      transplantations were performed in our center and portal vein thrombosis was
      present in 38 patients (8.1%). Preoperative diagnosis, extension, intraoperative
      management, postoperative recurrence of portal vein thrombosis, and 1-year
      actuarial survival rates were retrospectively studied. Preoperative diagnosis was
      made in 17 cases (44.7%). In all patients, portal flow was restored after portal
      vein thrombectomy, followed by usual end-to-end portal anastomosis. All patients
      received preventive low-weight heparin from day 2 to hospital discharge, and then
      aspirin. Rethrombosis was observed in one patient with extended splanchnic
      thrombus. The 1-year actuarial patient survival rate was 83.7%, and did not
      significantly differ from the patients without portal vein thrombosis (86.7%).
      Our results suggest that portal vein thrombosis is often partial and thus
      difficult to diagnose preoperatively: it can be managed successfully during
      surgery by thrombectomy, except when there is complete splanchnic veins
      thrombosis; and it did not affect 1-year survival.

PMID- 12482146
TI  - Improved late graft survival and half-lives in pediatric kidney transplantation:
      a single center experience.
AB  - We evaluated variables associated with improved late graft survival in 290
      children transplanted between 11/1/1984 and 12/31/1997, and who had > 1 year
      graft survival. We studied the following variables: age, gender, race, primary
      disease (diseases prone to recurrence, i.e. hemolytic uremic syndrome, focal
      segmental glomerulosclerosis or oxalosis vs. others), primary vs. retransplant;
      donor source, acute tubular necrosis, acute rejection episodes in the first year,
      transplant era and discharge serum creatinine. Graft half-life was defined as the
      time taken for 1/2 of the grafts functioning at 1 year to fail. There were 205
      living donor and 85 cadaveric transplant. The cumulative graft survival at 5 and
      10 years was 88% and 75% for living donor, and 72% and 46% for cadaveric,
      respectively. Multivariate analyses showed a higher late graft survival to be
      associated with: no acute rejection episodes (risk ratio 0.16, p = 0.0001), age 2
      5 years (risk ratio 0.24, p = 0.0007), living donor (risk ratio 0.46, p = 0.017),
      primary nonrecurrent disease (risk ratio 0.29, p = 0.001), Caucasian race (risk
      ratio 0.40, p = 0.006). A high half-life was seen with living donor transplant
      (21.3 years) and the age group 2-5 years (27.5 years). Further, living donor
      patients with no acute rejection episodes had the best half-life of 37.6 years,
      while children with hemolytic uremic syndrome, focal segmental glomerulosclerosis
      or oxalosis had the lowest overall half-life of 5.6 years. This study finds that
      living donor, no acute rejection episodes, age 2-5 years, Caucasian race and
      having a disease not prone to recurrence are strong predictors of late graft
      survival. Hence, preferential use of living donor and prevention of acute
      rejection episodes in the first year are key variables that can improve long-term
      renal graft survival in children.

PMID- 12482148
TI  - Preemptive strategy for ganciclovir administration against cytomegalovirus in
      liver transplantation recipients.
AB  - In utilizing a preemptive strategy to minimize the occurrence of symptomatic
      cytomegalovirus (CMV) infection following liver transplant, only patients with
      proven CMV activity by direct detection are treated. We applied the following
      preemptive strategy for CMV infection to 49 sequential liver transplant
      recipients between 1998 and 2001. Patients were monitored for CMV activity using
      CMV p65 antigen assay for the first 10 months of the study. Thereafter, we
      changed the detection method to a quantitative PCR for plasma CMV-DNA. All
      patients were monitored post transplant, weekly for the first 3 months and then
      monthly. Only patients with detected CMV activity were treated with ganciclovir.
      Patients were divided into four groups, based on donor (D) and recipient (R) CMV
      status. In seven out of 49 patients (14.3%) CMV activity was detected: four in
      group D+/R-, and three in group D-/R-. Five out of these seven patients had
      asymptomatic CMV infection. Symptomatic CMV infection developed only in two of
      these seven patients, to give total rate of 4.1% (2/49). All seven patients
      developed CMV IgG antibody. 'Transient' CMV replication detected by PCR in five
      patients in group D+/R+ was not defined as infection. No patients developed organ
      invasive CMV disease. The cost of anti-CMV treatment using the preemptive
      strategy was $1000/patient/1st year. Using preemptive strategy, early detection
      of CMV infection was achieved, allowing timely treatment. The use of ganciclovir
      for CMV infection in only 4.3% of the patients should have a positive impact on
      minimizing the risk of ganciclovir-resistant virus, and should reduce the cost of
      CMV prevention strategies.

PMID- 12482147
TI  - Use of EBV PCR for the diagnosis and monitoring of post-transplant
      lymphoproliferative disorder in adult solid organ transplant patients.
AB  - Epstein-Barr virus (EBV) is known to be involved in the majority of patients who
      develop post-transplant lymphoproliferative disorder after solid organ
      transplant. We conducted a retrospective study to determine the utility of
      qualitative and quantitative Epstein-Barr virus polymerase chain reaction (PCR)
      for the diagnosis and monitoring of post-transplant lymphoproliferative disorder
      in adult solid organ transplant patients. Peripheral blood leukocytes obtained
      from 35 adult solid organ transplant patients consecutively referred for
      evaluation of possible post-transplant lymphoproliferative disorder, were tested
      by EBV PCR at the time of initial evaluation and at time points thereafter.
      Eighteen of 35 (51%) patients were ultimately diagnosed with post-transplant
      lymphoproliferative disorder by tissue biopsy. Fifteen of 18 (83%) patients were
      found to have EBER-1 positive tumors by in situ hybridization. EBV PCR was
      positive in 7 of 15 patients, suggesting a sensitivity of 39%. Seventeen patients
      without post-transplant lymphoproliferative disorder and three with EBER-1
      negative post-transplant lymphoproliferative disorder all had negative EBV PCR
      tests, suggesting a specificity of 100%. We observed that declines in EBV DNA
      load were associated with response to therapeutic interventions, such as
      reduction in immunosuppression, rituximab therapy and chemotherapy. We conclude
      that peripheral blood EBV PCR may have a role in the diagnosis and monitoring of
      post-transplant lymphoproliferative disorder in adult solid organ transplant
      patients.

PMID- 12482149
TI  - Long-term (20-37 years) follow-up of living kidney donors.
AB  - Numerous studies with <20 years of follow-up have shown no significant long-term
      consequences of living kidney donation. However, hypertension and proteinuria
      have both been described; it is unknown whether either complication presages
      future kidney dysfunction. Between June 1, 1963, and December 31, 1979, we did
      773 living donor kidney transplants for 715 recipients. We attempted to contact
      all donors to determine long-term outcome regarding their remaining kidney. We
      obtained information on 464 (60%) of the donors. Of these, 84 had died and 380
      were alive; of the 380, 256 returned a questionnaire and 125 sent in current
      laboratory results and/or records of a recent history and physical examination.
      Of the 84 donors who had died, three were known to have had kidney failure. Of
      the 380 still alive, three had abnormal kidney function and two had undergone
      transplantation. The remaining donors had normal kidney function. The rate of
      proteinuria and hypertension was similar to the age-matched general population.
      We conclude that most kidney donors have normal renal function 20-37 years post
      donation. However, some do develop renal dysfunction; some, renal failure. Our
      data underscore the need to develop prospective trials for long-term follow-up of
      kidney donors.

PMID- 12482150
TI  - Immunogenicity of intradermal hepatitis B vaccination in renal transplant
      recipients.
AB  - We investigated intradermal hepatitis B (HBV) vaccination in 24 renal transplant
      recipients who failed to develop hepatitis B surface antibody (anti-HBs) with
      intramuscular (i.m.) vaccination. All patients received recombinant HBV vaccine 5
      microg intradermally every 2 weeks for 8 doses. Nine patients developed
      protective levels of anti-HBs (> 10 miu/mL) and two patients developed low levels
      of anti-HBs (4-6 miu/mL), giving an overall initial response rate of 45.8%. A
      booster of 40 microg was administered intramuscularly after 1 year. All initial
      responders developed an anti-HBs response (322.6 +/- 92.0 miu/mL). In addition,
      four patients who did not respond initially to the intradermal vaccination
      seroconverted after the booster. Responders (62.5%) and nonresponders had
      comparable age, gender, immunosuppressive medications, and duration of
      transplant. In conclusion, renal transplant patients who fail to respond to
      intramuscular HBV vaccination may benefit from intradermal vaccination followed
      by an intramuscular booster.

PMID- 12482151
TI  - Death after graft loss: an important late study endpoint in kidney
      transplantation.
AB  - Traditional study endpoints utilized in renal transplantation have included graft
      survival, and death with a functioning graft. We analyzed the risk factors for
      death after allograft loss (DAGL) among a total of 78564 primary renal
      transplants reported to the United States Renal Data System (USRDS) from 1988 to
      1998. Cox models were used to investigate risk factors for DAGL. Of 15528 deaths,
      10816 occurred before, and 4712 occurred after graft loss. Overall annual
      adjusted death rates were more than 3-fold higher after graft loss as compared to
      before graft loss (9.42% vs. 2.81%). By Cox model, dialysis for more than 2 years
      was associated with a more than 2-fold relative risk for DAGL (RR = 2.2, Cl =
      1.88-2.53), while transplant time was not associated with DAGL. Infection related
      graft losses showed a strong association with DAGL (RR = 1.64, Cl = 1.31-2.07).
      Acute rejection and thrombosis as causes of graft loss were also significantly
      associated with the risk for DAGL (RR = 1.35, Cl = 1.23-1.47 and RR = 1.39, Cl =
      1.39). Patient survival after graft loss is poor. The lack of association between
      DAGL and transplant time, as opposed to the strong relation to pretransplant
      dialysis time, would suggest the adverse effects of previous uremia-mediated
      damage may be contributing to this phenomenon, along with the adverse effects of
      loss of renal function.

PMID- 12482152
TI  - The remission of post-transplant nephrotic syndrome clinicopathologic
      characterization.
AB  - Among 67 renal transplant recipients with nephrotic syndrome (NS), nine episodes
      were reversible in eight patients. Biopsies showed minimal-change disease, focal
      segmental membranous glomerulonephritis and acute glomerulitis, IgA nephropathy
      and acute glomerulitis or thrombotic microangiopathy, and chronic transplant
      nephropathy with or without acute glomerulitis. NS developed 1-4 months post
      transplant in the four patients with minimal-change disease, but later (33-151
      months) in the others. At onset, serum creatinine was normal or elevated.
      Treatment included calcium-channel blockers, angiotensin-converting enzyme
      inhibitors, or both, together with routine antirejection therapy. Remission was
      achieved 4-12 months after onset, when renal function remained normal in four,
      improved in four, and worsened in one. At last follow-up, six patients still had
      remission and functional grafts. One lost graft to chronic transplant nephropathy
      while NS remained in remission. In the remaining patient, proteinuria, which was
      due to chronic transplant glomerulopathy unrelated to the initial minimal-change
      disease-associated NS, recurred 50 months post transplant. Remission of post
      transplant NS is possible. It is often associated with minimal-change diseases
      and less frequently with other glomerular lesions, including acute glomerulitis.
      Reversible post-transplant NS does not have an adverse effect on the renal
      allografts.

PMID- 12482153
TI  - Hand-assisted laparoscopic living-donor nephrectomy as an alternative to
      traditional laparoscopic living-donor nephrectomy.
AB  - The benefits of laparoscopic living-donor nephrectomy (LDN) are well described,
      while similar data on hand-assisted laparoscopic living-donor nephrectomy (HALDN)
      are lacking. We compare hand-assisted laparoscopic living-donor nephrectomy with
      open donor nephrectomy. One hundred consecutive hand-assisted laparoscopic living
      donor nephrectomy (10/98-8/01) donor/recipient pairs were compared to 50 open
      donor nephrectomy pairs (8/97-1/00). Mean donor weights were similar (179.6 +/-
      40.8 vs. 167.4 +/- 30.3 lb; p = NS), while donor age was greater among hand
      assisted laparoscopic living-donor nephrectomy (38.2 +/- 9.5 vs. 31.2 +/- 7.8
      year; p < 0.01). Right nephrectomies was fewer in hand-assisted laparoscopic
      living-donor nephrectomy [17/100 (17%) vs. 22/50 (44%); p < 0.05]. Operative time
      for hand-assisted laparoscopic living-donor nephrectomy (3.9 +/- 0.7 vs. 2.9 +/-
      0.5 h; p < 0.01) was longer; however, return to diet (6.9 +/- 2.8 vs. 25.6 +/-
      6.1 h; p < 0.01), narcotics requirement (17.9 +/- 6.3 vs. 56.3 +/- 6.4h; p <
      0.01) and length of stay (51.7 +/- 22.2 vs. 129.6 +/- 65.7 h; p < 0.01) were less
      than open donor nephrectomy. Costs were similar ($11072 vs. 10840). Graft
      function and 1-week Cr of 1.4 +/- 0.9 vs. 1.6 +/- 1.1 g/dL (p = NS) were similar.
      With the introduction of HALDN, our laparoscopic living-donor nephrectomy program
      has increased by 20%. Thus, similar to traditional laparoscopic donor
      nephrectomy, hand-assisted laparoscopic living-donor nephrectomy provides
      advantages over open donor nephrectomy without increasing costs.

PMID- 12482154
TI  - Post-transplant lymphoproliferative disorder in the United States: young
      Caucasian males are at highest risk.
AB  - We have previously documented Caucasian race and cadaver donor source as risk
      factors for post-transplant lymphoproliferative disorder (PTLD) development in
      recipients registered in the North American Pediatric Renal Transplant
      Cooperative Study (NAPRTCS). We analyzed data from the Scientific Registry of the
      United Network of Organ Sharing (UNOS) (from January 1988 to December 1999) to
      determine risk factors for the development of PTLD in all organ systems and its
      frequency, and we compared these factors to the risk factors in the most recent
      NAPRTCS database (1987-2000). In the UNOS database, PTLD was reported in 2365 of
      205114 organ-transplant recipients (1.2%). PTLD was reported in 3% or more of all
      intestinal and thoracic organ recipients, but in less than 1% of other abdominal
      organ recipients. Recipient age < 18 years, Caucasian race and male gender were
      independent risk factors [Odds Ratios (OR) 2.81, 2.22 and 1.40, respectively, p =
      0.0001], but not cadaver donor source. The combination of all three risk factors
      increased the OR to 8.78. The occurrence of PTLD showed a significant rise per
      year for heart-lung, kidney, kidney-pancreas and liver transplants, but decreased
      significantly for heart transplants (p < 0.001). Similar frequencies of PTLD were
      found in smaller organ-specific registries of heart, intestine, pediatric liver
      and pediatric kidney transplants. The PTLD incidence per year and incidence
      density have increased in recent years. Young Caucasian males are at highest risk
      for PTLD development among solid-organ-transplant recipients. The incidence of
      PTLD is increasing.

PMID- 12482155
TI  - Hospitalizations for total hip arthroplasty after renal transplantation in the
      United States.
AB  - The national incidence of and factors associated with total hip arthroplasty in
      renal transplant recipients has not been reported. We conducted an historical
      cohort study of 42096 renal transplant recipients in the United States between 1
      July 1994 and 30 June 1998. Primary outcomes were associations with
      hospitalizations for a primary discharge code of total hip arthroplasty (ICD9
      procedure code 81.51x) within 3 years after renal transplant using Cox
      regression. Renal transplant recipients had a cumulative incidence of total hip
      arthroplasty of 5.1 episodes/1000 person-years, which is 5-8 times higher than
      reported in the general population. Avascular necrosis of the hip was the most
      frequent primary diagnosis associated with total hip arthroplasty in this
      population (72% of cases). Repeat surgeries were performed in 27% of patients
      with avascular necrosis, vs. 15% with other diagnoses. Total hip arthroplasty was
      more frequent in transplant recipients who were older, African American, or who
      experienced allograft rejection. Mortality after total hip arthroplasty was 0.21%
      at 30 days and 15% at 3 years, similar to the mortality of all transplant
      recipients. The most common indication for total hip arthroplasty after renal
      transplant is avascular necrosis of the hip, in contrast to the general
      population. Although repeat surgeries are common, total hip arthroplasty is well
      tolerated and is not associated with increased mortality in this population.

PMID- 12482156
TI  - The coronary heart disease in-patient experience questionnaire (I-PEQ (CHD)):
      results from the survey of National Health Service patients.
AB  - OBJECTIVE: Analysis of data from the National Survey of Coronary Heart Disease
      patients to develop a core measure of patient experiences of health care. A
      secondary purpose was to determine whether a single summary index figure could be
      generated from the instrument. DESIGN: The data reported here comes from the
      survey of coronary heart disease (CHD) patients, which was the second in the
      programme of National Surveys of National Health Service (NHS) patients. It took
      place during 1999. After an in-patient episode for CHD, questionnaires were
      mailed out to patients with a covering letter and a pre-paid stamped addressed
      envelope. Those patients who did not reply within two weeks of the initial
      mailing were sent a reminder letter and, if this elicited no reply within two
      weeks, they were sent another copy of the questionnaire. SAMPLE: Of the 116,872
      patients who were sent questionnaires, 3399 proved to be ineligible or out-of
      scope to the survey. Responses were gained from 84,310 (74.3% of eligible
      respondents). RESULTS: Reliability analysis supported the existence of seven
      dimensions which seem to be tapping distinct underlying phenomena: hospital
      environment, information and communication, patient involvement, coordination of
      care, discharge and transition, and pain. Higher order factor analysis indicated
      these dimensions constituted one factor and, consequently, can be summed to
      create an index figure. The construct validity of the measure was assessed, and
      it distinguished between groups as was hypothesised. CONCLUSIONS: The dimensions
      of the questionnaire have high internal reliability. Both the dimensions of the
      instrument and the index score were found to have high construct validity. The
      instrument provides a core set of issues that should be covered when assessing
      the quality of care for hospital patients with coronary heart disease.

PMID- 12482157
TI  - Health-related quality of life in asthma: a comparison between the St George's
      Respiratory Questionnaire and the Asthma Quality of Life Questionnaire.
AB  - The aim of the study is to compare the performance of the Juniper Asthma Quality
      of Life Questionnaire (AQLQ) and the St George's Respiratory Questionnaire (SGRQ)
      in a sample of asthmatic patients, representative of a broad spectrum of asthma
      severity. We studied 116 patients with a mean age (SD) of 42.6 (18.3) year.
      Patients were assessed twice, at recruitment and after 2 months, to determine the
      reliability, validity and responsiveness of the AQLQ and the SGRQ. Both
      questionnaires showed good reliability coefficients (> or = 0.70) which reached
      the standards for comparison at individual level (> or = 0.90) in the case of
      activity, impacts and overall SGRQ scores as well as symptoms, activities and
      overall AQLQ scores. Both AQLQ and SGRQ were able to discriminate among groups of
      patients based on asthma severity and control and showed, except for the symptoms
      domain of the SGRQ, large (standardized response means >0.8) and significant
      changes in the group of patients that improved at follow-up. We conclude that the
      AQLQ and SGRQ have shown high reliability and validity and, with the exception of
      the SGRQ symptoms, a high level of responsiveness. In overall terms, not one of
      these instruments seems to behave better than the other.

PMID- 12482158
TI  - Health-related quality of life and healthcare resource utilization by COPD
      patients: a comparison of three instruments.
AB  - The aim of this study was to compare the SF-36 and two disease-specific
      instruments--St. George's Respiratory Questionnaire (SGRQ) and Chronic
      Respiratory Disease Questionnaire (CRDQ) among chronic obstructive pulmonary
      disease (COPD) patients using healthcare utilization data. The three instruments
      were administered twice by telephone interview to 40 COPD patients separated by a
      3-month interval. Healthcare utilization data were obtained for the 3 months
      immediately prior to each administration. Reliabilities for sub-scales on the
      three instruments ranged from 0.70 to 0.90 for the SF-36, from 0.78 to 0.85 for
      the SGRQ, and from 0.64 to 0.91 for the CRDQ. In general, the study sample had
      poor physical health, and somewhat better mental health. None of the demographic
      variables were significantly associated with either health status or utilization.
      Among the three instruments, the SF-36 explained the most variance in healthcare
      utilization. The aggregate scores such as the summary scores of the SF-36 and the
      total score of the SGRQ did not perform as well as the individual sub-scales of
      the respective instruments in explaining the variation in utilization. The
      conclusion that the SF-36 provides the best association to healthcare utilization
      data from among the three instruments studied should be interpreted with caution
      given the small sample size and relatively brief duration of the study.

PMID- 12482159
TI  - Validation of the World Health Organization quality of life instrument in
      patients with HIV infection.
AB  - We studied the reliability and validity of the World Health Organization quality
      of life (WHOQOL) assessment instrument in patients with human immunodeficiency
      virus (HIV) infection. WHOQOL-BREF was used to assess 136 HIV-infected
      outpatients. The results were analyzed and compared with data from 213 healthy
      persons. The Cronbach's alpha for internal consistency ranged from 0.74 to 0.85
      across domains in HIV-infected patients. The test-retest reliability ranged from
      0.64 to 0.79 across domains at average 4-week retest interval. Factor analysis
      identified four major factors: social, psychological, environment, and physical,
      consistent with the four domains of the instrument. The scores of all four
      domains correlated positively with self-evaluated health status and happiness (r
      range: 0.52-0.60 and 0.55-0.73 across domains, respectively), and correlated
      negatively with the number and severity of symptoms (r range: -0.40 to -0.47 and 
      0.41 to -0.52, respectively). The scores of physical, psychological and social
      domains, but not the environment domain, discriminated between healthy persons
      and HIV-infected patients (all p < 0.01). We conclude that the WHOQOL-BREF can be
      a useful quality-of-life instrument in patients with HIV infection.

PMID- 12482160
TI  - Confirmatory factor analysis of the Child Health Questionnaire-Parent Form 50 in
      a predominantly minority sample.
AB  - The Child Health Questionnaire-Parent Form 50 (CHQ-PF50; Landgraf JM et al., The
      CHQ User's Manual. Boston, MA: The Health Institute, New England Medical Centre,
      1996) appears to be a useful method of assessing children's health. The CHQ-PF50
      is designed to measure general functional status and well-being and is available
      in several versions to suit the needs of the health researcher. Several
      publications have reported favorably on the psychometric properties of the CHQ.
      Landgraf et al. reported the results of an exploratory factor analysis at the
      scale level that provided evidence for a two-factor structure representing
      physical and psychosocial dimensions of health. In order to cross-validate and
      extend these results, a confirmatory factor analysis was conducted with an
      independent sample of generally healthy, predominantly minority children. Results
      of the analysis indicate that a two-factor model provides a good fit to the data,
      confirming previous exploratory analyses with this questionnaire. One additional
      method factor seems likely because of the substantial similarity of three of the
      scales, but that does not affect the substantive two-factor interpretation
      overall.

PMID- 12482161
TI  - Factors affecting health related quality of life of patients with inflammatory
      bowel disease.
AB  - Using a disease specific instrument to measure the health related quality of life
      (HRQOL) of patients with inflammatory bowel disease (IBD), it has been shown that
      their perceived HRQOL worsens during active disease. The precise factors involved
      in HRQOL changes reported by these patients are largely unknown. Our aim was to
      elucidate which socio-demographic and health status variables are related with
      HRQOL in IBD patients. To this end, 354 patients with IBD were interviewed. To
      quantify the impairment in the HRQOL, the 36-item version of the inflammatory
      bowel disease questionnaire (IBDQ) was administered to all patients. To explore
      the relation of each individual variable on the HRQOL an univariate analysis by
      using the Spearman correlation, the Mann-Whitney or the Kruskal-Wallis test was
      performed when necessary. Factors significant at the univariate analysis were
      assessed using multiple linear regression modeling with global IBDQ score as the
      dependent factor. RESULTS: Disease type did not predict IBDQ score in the
      univariate nor in the multivariate analysis. Consequently, statistical analysis
      was performed in the global group of 354 patients independently of the type of
      disease. Lower recurrence/year index, longer disease duration, higher level of
      education, symptom activity, male gender and non-necessity of hospitalization all
      predict a better HRQOL (p < 0.05). Factors which remained significant (p < 0.05)
      in the multiple regression modeling were gender, need of hospitalization,
      symptomatic activity, recurrence/year index and education level. CONCLUSIONS:
      Symptomatic activity and socio-demographic variables such as gender and education
      are the most important factors involved in the impairment of HRQOL in patients
      with IBD.

PMID- 12482162
TI  - Investigating correlates of health related quality of life in a low-income sample
      of patients with diabetes.
AB  - OBJECTIVE: We sought to describe and find correlates of health-related quality of
      life among under-served low-income patients in North Carolina with diabetes
      mellitus. METHODS: A telephone survey of 310 patients recording quality of life,
      patient satisfaction, self-reported health, and patient complaints was conducted
      as part of a diabetes care improvement project. Demographic and clinical records
      were available for 249 of these patients: 69% were female, 45% were minority, and
      84% had type 2 diabetes. Ages ranged from 18 to 88 years with a mean of 56.
      Quality of life indices consisted of SF-36 physical functioning, mental health
      and diabetes-39 sub-scores. RESULTS: Comparison to SF-36 norms showed the sample
      had lower sub-scores than expected. The multivariate analysis suggested that
      being within an acceptable metabolic control predicted better quality of life
      physically, mentally, and sexually. Strong associations were detected between
      most sub-scores and complaints involving legs and feet, self-rated vision, and
      hassles in self-management. CONCLUSIONS: The consistent associations between the
      sub-scores and complaints, symptoms, and hassles underscore the strong
      relationship quality of life may share with the severity of diabetes
      complications as well as with psychosocial factors. Significantly lower quality
      of life in this sample highlights the need to improve the care of minority low
      income diabetes patients.

PMID- 12482163
TI  - Validating the Functional Capacity Index as a measure of outcome following blunt
      multiple trauma.
AB  - BACKGROUND: The validity of the Functional Capacity Index (FCI) is evaluated by
      examining its distributional characteristics, its correlation with other well
      known measures of outcome and its ability to discriminate among persons with
      injuries of varying type and severity. METHODS: A telephone survey which included
      the FCI and the SF-36 was administered 1 year post-injury to 1240 blunt trauma
      patients discharged from 12 trauma centers. A subsample of 656 patients also
      completed the Sickness Impact Profile (SIP) by mail. RESULTS: FCI scores
      correlated well with the physical health subscores of the SIP and SF-36. They
      also correlated well with self-reported change in health status and return to
      work. The FCI, when compared to either the SF-36 or the SIP, however, appears to
      discriminate better among patients according to the presence and severity of head
      trauma. CONCLUSIONS: While further testing of the FCI is needed, it holds promise
      as a preference based measure for assessing the physical impact of trauma.

PMID- 12482164
TI  - Responsiveness of the Acne-Specific Quality of Life Questionnaire (Acne-QoL) to
      treatment for acne vulgaris in placebo-controlled clinical trials.
AB  - The Acne-Specific Quality of Life Questionnaire (Acne-QoL) was developed to
      measure the impact of facial acne across four dimensions of patient quality of
      life. The main objective of the current study was to evaluate the responsiveness
      of this instrument. Secondarily, this study provided an opportunity to extend the
      developer's psychometric validation. The Acne-QoL was utilized in two randomized,
      double-blind, placebo-controlled studies of the efficacy of Estrostep
      (norethindrone acetate/ethinyl estradiol) in the treatment of facial acne; a
      total of 296 Estrostep and 295 placebo patients were evaluated. The Acne-QoL was
      completed at the beginning, middle (cycle 3), and end (cycle 6) of the 6-month
      treatment period. The responsiveness of the Acne-QoL was demonstrated through its
      ability to detect both small (baseline to mid-study) and moderate (baseline to
      study end) treatment advantages for Estrostep patients. Confirmatory factor
      analysis supported the subscale structure, and internal consistency estimates
      were excellent. Convergent and discriminant validity were supported by
      correlations between Acne-QoL scores and clinical measures that were both in the
      direction and relative magnitude hypothesized. Finally, item response theory
      analyses confirmed that each item is highly related to its subscale's latent
      construct and that each subscale is sensitive across a broad range of the
      underlying continuum. The results of this evaluation confirm that the Acne-QoL is
      responsive, internally consistent, and valid.

PMID- 12482166
TI  - Bell's palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of
      different etiologies.
AB  - OBJECTIVE: The Copenhagen Facial Nerve Study aims to explain the spontaneous
      course of idiopathic peripheral facial nerve palsy which occurs without any kind
      of treatment. In this study Bell's palsy and idiopathic palsy are considered to
      be synonymous and specify an acute, monosymptomatic, unilateral peripheral facial
      paresis of unknown etiology. MATERIAL AND METHODS: The material includes 2,570
      cases of peripheral facial nerve palsy studied during a period of 25 years. It
      includes 1,701 cases of Bell's palsy and 869 of non-Bell's palsy. In the total
      patient sample, 116 had herpes zoster, 76 were diabetic, 46 were pregnant and 169
      were neonates. A total of 38 different etiologies were observed. At the first
      consultation a standard ENT examination was performed, including a thorough
      description of the grade and localization of the paresis, taste, stapedius reflex
      and nasolacrimal reflex tests and acoustic-vestibular examination. Follow-up was
      done once a week during the first month and subsequently once a month until
      normal function was restored or for up to 1 year. RESULTS: The initial
      examination revealed 30% incomplete and 70% complete palsies. Follow-up showed
      that in 85% of patients function was returned within 3 weeks and in the remaining
      15% after 3-5 months. In 71% of patients normal mimical function was obtained.
      Sequelae were slight in 12% of patients, mild in 13% and severe in 4%.
      Contracture and associated movements were found in 17% and 16% of patients,
      respectively. CONCLUSION: A survey of the literature showed that no kind of
      treatment, including prednisone, was able to give a better prognosis. The use of
      prednisone raises a big ethical problem because no evidence of its efficacy
      exists and the euphoric side-effect induces a false feeling of benefit in the
      patients.

PMID- 12482165
TI  - Validation of a Chinese version of the Epworth sleepiness scale.
AB  - Epworth sleepiness scale (ESS) is widely used to evaluate degree of somnolence
      among Chinese patients with sleep-disordered breathing. Yet no Mandarin-Chinese
      translation has ever reported its validation data. In this study we translated
      and validated the ESS into Mandarin Chinese (CESS). We found, in 31 bilingual
      patients' responses to the CESS and the English ESS obtained 1-2 weeks apart did
      not differ significantly (10.5 +/- 3.7 vs. 9.6 +/- 3.9, p = 0.32, Wilcoxon's
      signed rank test) and were significantly correlated (Spearman's p = 0.67, p =
      0.0004). A total of 359 sleep-disordered breathing subjects were enrolled into
      the validation study in a prospective manner. The CESS showed acceptable internal
      consistency (Cronbach's alpha = 0.81). Thirty out of these patients answered CESS
      twice at an interval of 2-4 weeks, to yield an acceptable level of test-retest
      reliability (p = 0.74, p = 0.001). The respiratory disturbance indices obtained
      from 251 out of 359 subjects were significantly correlated with their CESS scores
      (p = 0.22, p < 0.001). The standard response mean of CESS was 0.86 as obtained
      from 94 out of 359 subjects who had initial control of their symptoms at 3 months
      after radio-frequency palate surgery. We conclude that the CESS is reliable in
      both a linguistic and a test-retest sense, and appears to be valid and sensitive
      to clinical change. The CESS could be used to advantage among other Mandarin
      speaking subjects as a standardised screening test of sleepiness in daily life.

PMID- 12482167
TI  - Amyotrophic lateral sclerosis: pathogenesis, differential diagnoses, and
      potential interventions.
AB  - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive
      neurodegenerative motor neuron disease. The etiology is likely multifactorial,
      involving both genetic and environmental factors. METHOD: Literature review.
      FINDINGS: Motor neuron death is believed to arise from mutations in superoxide
      dismutase 1. Abnormal neurofilament metabolism, glutamate transporter
      dysfunction, and altered responses to growth factors may play a role. These
      discoveries have highlighted possible interventions, several of which have
      subsequently undergone human clinical trials. These include studies of
      antioxidants, antiglutamatergic agents, cyclooxygenase inhibitors, and various
      growth factors. CONCLUSION: Findings are inconclusive, and further investigations
      are underway. At present, nonpharmacologic interventions such as nutritional
      support; physical, speech, and occupational therapy; and respiratory management
      offer the best means of improving quality of life for patients with ALS.

PMID- 12482168
TI  - Amyotrophic lateral sclerosis: practical aspects of care.

PMID- 12482169
TI  - Prevention of urinary tract infection in patients with spinal cord injury.
AB  - BACKGROUND: Urinary tract infection (UTI) is a major cause of morbidity and
      mortality in individuals with spinal cord injury (SCI). Altered voiding dynamics,
      use of urinary drainage catheters, and frequent exposure to antibiotic agents
      predispose individuals with SCI to recurrent episodes of UTI, often with
      resistant organisms. OBJECTIVE: To evaluate the efficacy of various methods of
      UTI prevention in the SCI population. These methods include type of bladder
      management, choice of catheter materials, antiseptic agents, oral antibiotics,
      and experimental approaches. METHODS: Literature review. FINDINGS: Choosing a
      method of bladder management that minimizes the use of a foreign body, yet drains
      the bladder effectively, is the best available means to reduce the risk of UTI.
      The chief drawback to antimicrobial-coated catheters, topical or intravesicular
      antiseptic agents, and prophylactic oral antibiotics is that, over time, bacteria
      become resistant and overcome the obstacles to bladder invasion. Therefore,
      antiinfective catheter materials, antibiotics, and antiseptic agents are not
      beneficial for long-term prevention of UTI in persons with SCI. Novel approaches
      that avoid the use of antimicrobial agents offer hope for patients with recurrent
      UTI, but these techniques are still in the experimental stage. CONCLUSIONS:
      Method of bladder management remains the most influential factor in reducing the
      risk of UTI in persons with SCI. Experimental approaches that inhibit adhesion
      and biofilm formation by uropathogens are promising.

PMID- 12482170
TI  - Spinal cord lesions caused by arteriovenous malformation: clinical course and
      risk of cancer.
AB  - PURPOSE: Patients with nontraumatic myelopathy caused by arteriovenous
      malformation (AVM) are encountered in cohorts of traumatic myelopathy (SCI)
      patients. The study describes the clinical course of SCI secondary to AVM and
      compares the incidence of cancer with that in SCI patients. PARTICIPANTS: Twenty
      three patients with AVM and 219 patients with SCI patients aged 50 years and
      older. METHODS: The 2 groups were described by the character of paralysis and
      compared for the incidence of cancer in a retrospective review of records from
      the index year 1989. RESULTS: Twenty-three patients with AVM became paralyzed,
      with onset from age 22 years to 85 years (mean, 53 years). The presenting
      symptoms were pain (usually back pain), paresthesias, and weakness. The clinical
      picture varied, with evolution of symptoms reported over a wide period ranging
      from minutes to 27 years (median, 6 months). Levels of the spinal cord damage
      were thoracic in 74% of the AVM group vs 40% for the SCI group, P = .004. For
      patients with AVM, grade of paralysis was American Spinal Injury Association D
      (some significant use of the legs) in 26% vs 16% for patients with SCI, P = .38.
      Nine patients with AVM (39%) developed cancer (skin, brain, blood, thyroid,
      liver, bladder, and prostate at age 66 +/- 7 years) with an incidence of 5.92
      cancers/100 patient years. Thirty-five patients with SCI (9%) had cancer (skin,
      blood, lung, bowel, bladder, and prostate, age 67 +/- 5 years) develop at a rate
      of 1.70 cancers/100 patient years, 95% confidence interval = 1.89-6.51 for the
      difference, P = .001. CONCLUSION: Patients with nontraumatic spinal cord lesions
      caused by AVM often present with pain, may have a protracted clinical course, and
      have cancer develop more often than do those with traumatic SCI.

PMID- 12482171
TI  - Prevalence of upper motor neuron vs lower motor neuron lesions in complete lower
      thoracic and lumbar spinal cord injuries.
AB  - OBJECTIVE: To determine the incidence and etiology of lower motor neuron (LMN) vs
      upper motor neuron (UMN) lesions in patients with complete thoracic and lumbar
      spinal cord injuries (SCI). DESIGN: Retrospective chart review. SETTING: A
      regional Model Spinal Cord Injury System center. METHODS: A consecutive sample of
      medical records of patients with lower thoracic and upper lumbar (T7-L3) complete
      SCI admitted from 1979 through 1996 was systematically reviewed. Of the 306
      patients evaluated, 156 subjects met inclusion criteria. The incidence and
      etiology of LMN vs UMN lesions were determined for the following neurologic
      levels: T7-T9, T10-T12, L1-L3. Lesions were classified as LMN, UMN, or mixed on
      the basis of the presence or absence of (1) the bulbocavernosus reflex, (2) lower
      limb deep tendon reflexes below the neurologic level of injury, and (3) the
      Babinski sign. RESULTS: The incidences of LMN, UMN, and mixed lesions in the T7
      T9, T10-T12, and L1-L3 groups were as follows: T7-T9 group (7.3% LMN, 85.5% UMN,
      7.3% mixed), T10-T12 group (57% LMN, 17.7% UMN, 25.3% mixed),L1-L3 group (95.5%
      LMN, 0.0% UMN, 4.5% mixed). Etiology of injury did not significantly influence
      the likelihood of a LMN lesion. CONCLUSIONS: One cannot determine the type of
      lesion (UMN vs LMN) on the basis of the neurological level of injury. A detailed
      clinical examination, including sacral reflexes, is required. This has important
      prognostic and therapeutic implications for bowel, bladder, and sexual function,
      as well as mobility. Distinguishing UMN lesions from LMN lesions is also
      essential for evaluating new interventions in clinical trials for UMN pathology.

PMID- 12482172
TI  - Reliability of cystometrically obtained intravesical pressures in patients with
      neurogenic bladders.
AB  - BACKGROUND AND PURPOSE: Urodynamic studies in patients with neurogenic bladder
      detect and categorize neurourodynamic states, identify the risk for urologic
      sequelae, and determine the necessity for interventions. Because urodynamic
      studies serves as a prognostic indicator and guides patient management, pressure
      measurements during the study must accurately represent bladder function under
      physiologic conditions. Because nonphysiologic bladder filling used during
      conventional urodynamic studies may alter the bladder's accommodative properties,
      we studied how closely the intravesical pressures obtained before filling
      cystometry resembled those obtained during the filling phase of the
      cystometrogram. METHODS: Twenty-two patients (21 men, 1 woman) with neurogenic
      bladders underwent standard urodynamic studies. A 16F triple-lumen catheter was
      inserted into the bladder, and the intravesical pressures were recorded
      (physiologic volume-specific pressures, PVSP). After emptying the bladder, an
      equal volume of normal saline solution was reinfused, and the pressures were
      recorded again (cystometric volume-specific pressure, CVSP). All patients
      underwent routine fluoroscopically assisted urodynamic testing. The PVSP and the
      CVSP were compared using the Wilcoxon signed ranks test. P value of .05 was
      significant. RESULTS: The mean PVSP was 14.5 cmH2O (range, 4-42 cmH2O) and mean
      CVSP was 20.6 cmH2O (range, 6-70 cmH2O). The CVSP was significantly higher than
      the PVSP (P = .01). CONCLUSION: Filling pressures during cystometry (CVSP) were
      significantly higher than the pressures measured at rest (PVSP). This study also
      suggests a strong correlation between PVSP and CVSP.

PMID- 12482173
TI  - Adults with pediatric-onset spinal cord injuries: part 3: impact of medical
      complications.
AB  - OBJECTIVE: To determine the impact of medical complications on adult outcomes of
      individuals with pediatric-onset spinal cord injury (SCI). METHOD: Structured
      interview including standardized measures. PARTICIPANTS: Individuals who
      sustained SCI at age 18 years or younger and were 24 years of age or older at
      interview. OUTCOME MEASURES: A structured interview covering employment,
      independent living and driving, and marriage. Standardized measures include the
      Craig Handicap Assessment and Reporting Technique (CHART), the Short Form (SF
      12), and the Satisfaction with Life Scale (SWLS). RESULTS: Two hundred sixteen
      individuals were interviewed, with a mean age at injury of 14 years and a mean
      age at follow-up of 29 years. Of all the complications, pressure ulcers, severe
      urinary tract infection (UTI), and spasticity had the greatest impact on adult
      outcomes. Pressure ulcers were statistically related to all main outcomes. Severe
      UTI was statistically associated with all the outcomes except for marriage.
      Spasticity was associated with all the measured outcomes, except for marriage and
      life satisfaction. Life satisfaction was most significantly associated with
      severe UTI, pressure ulcers, pain, and respiratory complications. CONCLUSION:
      Medical complications significantly affect adult outcomes of individuals with
      pediatric-onset SCI.

PMID- 12482174
TI  - The thoracic suspension orthosis--a seating option for patients with pressure
      ulcers.
AB  - BACKGROUND/OBJECTIVE: For patients with pressure ulcers, wound healing and
      prevention are important steps in reducing disability. Ulcers that fail to heal
      adequately may interfere with normal sitting. By relieving pressure, the thoracic
      suspension orthosis (TSO) may allow some patients with recurrent pressure ulcers
      to return to sitting and sit for longer periods. METHODS: In this retrospective
      case series, 6 patients with chronic pressure ulcers were managed with TSO. Each
      patient had at least one of the following: (1) severe, non-healing pressure
      ulcers unresponsive to standard therapy, (2) recurrent ulcers requiring multiple
      surgeries, (3) chronic pain associated with sitting, or (4) bilateral lower
      extremity amputation resulting in instability or ischial pain in the seated
      position. RESULTS: Each participant had a favorable functional outcome. Patients
      were able to resume modified sitting. Others were able to sit for longer periods.
      Some have used the TSO for long-term management. CONCLUSIONS: A TSO is an
      additional seating option for patients with chronic pressure ulcer, chronic pain
      associated with sitting, or bilateral lower extremity amputation. It is
      recommended after less restrictive, conservative measures have failed. In some
      patients, it has been used in lieu of extreme surgical measures.

PMID- 12482175
TI  - The impacts of the model SCI system: historical perspective.
AB  - BACKGROUND: The Model Spinal Cord Injury System (MSCIS) program, which began in 1
      970, has had a positive impact on the health and well being of thousands of
      individuals with disabilities. Not only has the program been instrumental in
      improving the delivery of services for individuals with spinal cord injury (SCI),
      but also MSCIS is acknowledged as a leader in the advancement of science and
      practice in SCI rehabilitation. MSCIS is funded by grants awarded in 5-year
      cycles by the National Institute on Disability and Rehabilitation Research. In
      the current cycle (2000-2005), 1 6 SCI programs received funding as "model
      systems." SUMMARY: This series (1) describes the impact of the MSCIS since its
      inception; (2) reviews the national, multicenter data collection effort and its
      effects on the field; (3) reviews the initial goals and objectives of current
      research projects, and (4) forecasts the impact of current work on the field of
      SCI medicine. This introductory article provides an overview for this special
      section, as well as a brief synopsis of the history of the MSCIS program.

PMID- 12482176
TI  - Contributions from the model systems programs to spinal cord injury research.
AB  - OBJECTIVE: To review research developments across the Model Spinal Cord Injury
      Systems (MSCIS) program. DESIGN: Retrospective review of literature and web-based
      information. SETTING AND PARTICIPANTS: MSCIS program in general and its 16
      currently funded centers. RESULTS: The MSCIS centers have been funded since 1970
      by the US Department of Education to conduct research that contributes to the
      lives of persons with spinal cord injury (SCI). A review of this research
      suggests changes across time in terms of methods of investigation used to conduct
      research (eg, from demonstration studies to clinical trials) and selected study
      focuses, reflecting timely national priorities. Although initial studies were
      designed to describe medical factors and necessary treatment immediately after
      injury, most recent studies focus on broader social and environmental issues of
      living with SCI. In addition, a number of current investigations focus on new
      advances in medicine and technology geared toward recovery and increase in
      physical functioning. CONCLUSIONS: Research by the MSCIS has elevated the
      standards of care for SCI and inspired other researchers to develop larger and
      more sophisticated studies bridging the gap between basic and applied sciences
      and has inspired policy makers to continue to fund such needed research.

PMID- 12482177
TI  - Collaborative research in the model spinal cord injury systems: process and
      outcomes.
AB  - OBJECTIVE: To review the way in which collaborative research has been conducted
      under the National Institute on Disability and Rehabilitation Research (NIDRR)
      funded Model Spinal Cord Injury Systems (MSCIS) Program, changes made in that
      process, and significant outcomes. METHODS: A comparison of changes by NIDRR in
      the way collaborative research was competed and funded in the 1 995 and 2001
      competitions. A review of outcomes of the 1 995 collaborative projects was based
      on queries to lead centers. RESULTS: Collaborative research through the model SCI
      systems has been conducted and continues to be conducted through 2 main venues:
      The National Spinal Cord Injury Statistical Center (NSCISC) database, which has
      provided data for a number of collaborative studies, and specifically funded
      proposals for collaborative research. In the 1995 competition for NIDRR funding,
      collaborative research proposals were submitted as part of the Model SCI Systems
      competitive applications. In the 2001 competition, collaborative research was
      parceled out and a separate competition held. There have been a number of
      publications stemming from the 1 995 competition; some of the data from these
      projects are still being explored and used for manuscripts. The outcomes for the
      2001 competition will not be known for several years. CONCLUSIONS: Collaborative
      research has the advantage of generating larger numbers more quickly than any 1
      center can typically generate, producing a more broadly based sample and,
      therefore, generalizable result, and facilitating the use of expertise not always
      available in a single center. Collaborative research activities have been among
      the most productive aspects of the Model Systems program; the change in the way
      this component is competed in the most recent competition is yet to be evaluated
      in terms of its efficacy compared with methods used for funding collaborative
      research in past competitions.

PMID- 12482178
TI  - Overview of the national spinal cord injury statistical center database.
AB  - OBJECTIVE: An evaluation of the history, design, and status of the database of
      the National Spinal Cord Injury Statistical Center (NSCISC) was undertaken to
      identify its continued relevance. RESEARCH DESIGN: A systematic review was
      conducted of goals, content, and quality control procedures, as well as its
      suitability and public availability for conducting future epidemiologic and
      health services research. RESULTS: The NSCISC database contains information on
      approximately 29,000 persons injured since 1973 and treated at any regional model
      spinal cord injury system within 1 year of injury. The NSCISC database is
      structured longitudinally with data collected at discharge, 1 year after injury,
      5 years after injury, and every 5 years thereafter. The database includes
      information on demographics, injury severity, medical complications, surgical
      procedures, types and amounts of therapy, length of stay, charges, and both short
      term and long-term treatment outcomes. Strengths include large sample size, use
      of valid and reliable measures, geographic and patient diversity,
      comprehensiveness, availability of long-term prospective follow-up information,
      good case identification, and rigorous quality control procedures. Limitations
      include lack of population basis, inclusion of only model system patients, losses
      to follow-up, and other missing data. Recent content additions include detailed
      information on each treatment phase, depression, substance abuse, environmental
      barriers to community integration, and patient identifying information. A process
      exists for researchers to gain access to the data. CONCLUSIONS: The database
      remains a valuable resource. Future plans include linkage to other databases to
      enhance research capability, a published research compendium, and development of
      a user's guide to facilitate database usage.

PMID- 12482179
TI  - Clinical activities of the model spinal cord injury system.
AB  - OBJECTIVE: To review clinical activities that have resulted from funding of the
      Model Spinal Cord Injury System (MSCIS). METHODS: Review of the literature and
      responses from Model Systems Centers. RESULTS: Clinical benefits derived from
      MSCIS funding have been classified into 5 different areas: shift of spinal cord
      care from individual centers to care from a "Systems approach"; data collection
      as a stimulus for improved clinical care; service comprehensiveness to improve
      clinical care; research as a stimulus for improved clinical care; and
      dissemination of MSCIS research findings for educational purposes and to improve
      care provided by all SCI centers, including those not funded by the MSCIS.
      CONCLUSION: Many clinical benefits have been derived from the MSCIS program.
      Current research and developments being studied at model systems across the
      nation should continue to lead to new standards of care for persons with SCI.

PMID- 12482180
TI  - Three-year follow-up of an implanted functional electrical stimulation system for
      upright mobility in a child with a thoracic level spinal cord injury.
AB  - PURPOSE: The purpose of this study was to compare the use of a functional
      electrical stimulation (FES) system with the use of knee-ankle-foot orthoses
      (KAFO) for upright mobility over a 3-year period in a child with a spinal cord
      injury (SCI). METHODS: A 13-year-old boy with a T8 complete SCI received a lower
      extremity implanted FES system. Electrodes were implanted for knee extension and
      for hip extension, abduction, and adduction. After training and at annual
      intervals, independence and timeliness in completing 7 upright mobility
      activities with FES and KAFO, as well as stimulated muscle strength, were
      assessed. RESULTS: Results have shown that FES provided independence equal to
      that of KAFO for all activities. Four activities were accomplished more quickly
      with FES, including donning the system, reaching a high object, transferring to a
      high surface, and walking 6 m. A floor-to-stand transfer was faster with KAFO.
      Functional results and stimulated muscle strength have remained stable over the 3
      year period. CONCLUSION: The results indicate that FES can provide function equal
      to or faster than KAFO in a child with a T8 complete SCI and that performance
      with the FES system can remain stable for at least 3 years.

PMID- 12482181
TI  - Re: Slominski M, Aguilera EJ. Atelectasis and mucus plugging in spinal cord
      injury. J Spinal Cord Med. 2001; 24:284-288.

PMID- 12482182
TI  - The European history of psychotraumatology.
AB  - The history of European psychotraumatology shows that opposing cultural, social,
      economic, and political forces have influenced scientific development.
      Inevitably, the theories of traumatic stress reflect the spirit of the age.
      Several of today's controversies were already evident during World War I: the
      risk of reinforcing evacuation and compensation syndromes by legitimising
      diagnostic labels, increased somatization when the psychological nature of the
      trauma or symptom is not understood, and the deleterious effect of treating the
      individual removed from his primary group setting. Towards the end of the
      nineteenth century and the beginning of the twentieth century the study of
      psychic trauma identified important intrapsychic phenomena, and, consequently,
      there was a neglect of the external stressor.

PMID- 12482183
TI  - Silent disaster: a European perspective on threat perception from Chernobyl far
      field fallout.
AB  - Surveys investigated the perceived threat of radioactive fallout and public
      coping following a "silent disaster" (Chernobyl) across Europe. Survey data from
      national representative samples in 12 European countries are compiled, 6 months
      and 2 years after the accident, across 12 countries. Exposure to information
      about the accident, and perception of the consequences of Chernobyl as a health
      threat, were significantly related to the level of fallout in each country.
      Another significant relationship was found between the level of fallout in these
      12 countries and the proportion of respondents who reported having taken
      countermeasures. Information challenges for the authorities are highlighted.

PMID- 12482184
TI  - The Derryhirk Inn incident: the psychological sequelae.
AB  - A major incident occurred in a Northern Ireland bar in March 1997. One hundred
      and fifty customers were held at gunpoint. No one sustained any serious physical
      injury. Six months after the incident 68 individuals were assessed by means of a
      semistructured interview. Higher than expected levels of posttraumatic stress
      disorder (PTSD) were found. The severity of the incident, but not perceived life
      threat, was associated with the development of PTSD. The results of this
      preliminary study show that even in the absence of physical injury, significant
      psychopathology can occur.

PMID- 12482185
TI  - Making sense of repetition phenomena by integrating psychotraumatology and
      psychodynamic psychotherapy.
AB  - Psychotherapy and psychotraumatology share a preoccupation with repetition
      phenomena, manifested as transference, compulsions to repeat, or intrusive
      reexperiencing. Terminological diversity obscures compelling similarities between
      these repetition phenomena and discourages speculation about processes involved
      in their genesis. This paper remedies these oversights by integrating recent
      empirical evidence pertaining to memory with European intellectual traditions
      embraced by its pioneering dynamic psychotherapists. Using dreams as a prototype
      repetition, the phenomenological diversity of repetition phenomena is shown to be
      reconcilable with current evidence about memory encoding, storage, and retrieval.
      Differences in persistence, intensity, pervasiveness, and treatment resilience of
      repetition phenomena are explained using concepts derived from psychological and
      biological sciences. Implications for psychotherapeutic theory, practice, and
      evaluation are considered.

PMID- 12482186
TI  - Workplace trauma and the law.
AB  - The law places increasing responsibilities on organizations to protect its
      workforce from psychological injury. This paper looks at the development of
      British law relating to traumatic stress and explores a growing concern of
      clinicians that the law and the legal processes themselves may increase the
      psychological injury of victims of traumatic stress. The statutory requirement
      for organizations to provide effective support for employees following a
      traumatic incident is enshrined in law. However organizations are confused by the
      conflicting statements on the effectiveness of debriefing and trauma counselling.

PMID- 12482187
TI  - Posttraumatic sequelae in a community hit by an avalanche.
AB  - The posttraumatic sequelae for 104 adult inhabitants from the town of Flateyri,
      Iceland, were studied 10 weeks after an avalanche hit the town killing 20 people.
      Eighty-seven adults from the neighboring town of Thingeyri constituted a control
      group. On the basis of the General Health Questionnaire (GHQ-30), 25% of the
      Flateyri group (twice as many than in Thingeyri) reached a level of psychiatric
      caseness. The most common symptoms were intrusive thoughts and feelings, tension,
      sadness, and anxiety. The loss of family members was associated with
      symptomatology. A high number of former life events correlated more strongly with
      distress symptoms than with the individual appraisal of these events. Distress
      symptoms were related to gender, age, and education.

PMID- 12482188
TI  - German version of Clinician-Administered PTSD Scale.
AB  - This study assessed the reliability of a German translation of the Clinician
      Administered PTSD Scale (CAPS) by using data from 45 survivors of accidents who
      were hospitalized at the department of traumatology of a university hospital.
      Assessments were carried out 5 days (Time 1) and 6 months (Time 2) after the
      accident. Internal consistency proved to be comparable to that of the original
      English version: Cronbach's alpha was .88 at T1 and .92 at T2 for the CAPS total
      score. The CAPS correlated significantly with the validated German version of the
      Impact of Event Scale (IES) (T1: r = .56, T2: r = .78). The data suggest that the
      German version of the CAPS is a reliable instrument for the assessment of
      posttraumatic stress disorder symptomatology in accident victims. Further studies
      are necessary to validate further the questionnaire.

PMID- 12482189
TI  - Genetics of multiple sclerosis: determinants of autoimmunity and
      neurodegeneration.
AB  - Since the first description of multiple sclerosis (MS) as an inheritable disease
      by Eichhorst [1] accumulating epidemiological observations support a genetic
      hypothesis. Population, family and twin studies have revealed that Mendelian
      transmission of a single susceptibility gene would not be compatible with the
      observed patterns of inheritance. Like most other common diseases, MS is a
      complex trait, defined by several genes, each probably exerting a relatively
      small effect. Complex interactions among susceptibility genes and the environment
      are believed to contribute to a predisposition to dysregulation of inflammatory
      pathways, demyelination and tissue degeneration in the central nervous system
      (CNS). Natural history and pathological studies, however, define that MS
      represents a spectrum rather than a single entity of inflammatory demyelination.
      Despite a growing need for identifying molecular markers of biological subtypes
      of MS, only limited information is available for genotype-phenotype correlations.
      Four full genome scans using polymorphic microsatellite markers in nuclear and
      multiplex MS families indicated several chromosomal regions of susceptibility.
      With the recently discovered, highly abundant single nucleotide polymorphisms
      (SNPs) and family-based association methods, the means are now available to
      confine these relatively large regions of interest to candidate genes and
      susceptibility alleles. The currently available SNP maps favor indirect
      association studies based on linkage disequilibrium between marker and disease
      alleles. Here, we review available genetic data in MS, and introduce an
      additional strategy which correlate genetic markers with major biological
      components of the disease such as autoimmunity and neurodegeneration. This
      approach may yield important insights with utility in clinical practice.

PMID- 12482190
TI  - HLA-DRB1 genes and susceptibility to rheumatoid arthritis in three ethnic groups
      from Malaysia.
AB  - Worldwide population studies have generally agreed that rheumatoid arthritis (RA)
      is associated with a group of HLA-DRB1 alleles which share a common amino acid
      sequence at residues 70-74. This represents the first study to investigate the
      association of HLA-DRB1 genes with susceptibility to RA amongst Malay, Chinese
      and Indian ethnic groups in Malaysia. One hundred and thirty three RA patients
      and one hundred and sixty seven healthy controls were recruited. The HLA-DRB1
      alleles were studied using the Phototyping method. The subtypes of HLA-DR4 were
      detected by "high resolution" PCR-SSP DRB1*04 typing techniques. The prevalence
      of HLA-DRB1*0405 was significantly higher in Malay patients with RA than in
      healthy controls (28.9 vs. 8.3%, p = 0.0016, OR = 4.48, 95% CI = 1.26-16.69).
      Similarly, DRB1*0405 was more common in Chinese RA patients than in controls
      (30.0 vs. 6.7%, p = 0.0029, OR = 6.00, 95% CI = 1.67-23.48). In addition,
      DRB1*0901 was a predisposing factor (32.0 vs. 6.7%,p = 0.0015, OR = 6.59, 95% CI
      = 1.85-25.64) and *0301/04 had a protective role (4.0vs. 25.0%, p = 0.00562, OR =
      0.13, 95% CI = 0.02-0.62) in Malaysian Chinese RA. RA in Indians was associated
      with DRB1*1001 (51.1 vs. 8.5%,p = 0.00002, OR = 11.24, 95% CI = 3.13-44.18).
      DRB1*0701 (13.3 vs. 42.6%,p = 0.0022, OR = 2.73, 95% CI = 1.40-5.37) may have a
      protective effect. Therefore, in the Malaysian population, RA is primarily
      associated with the QRRAA motif, and we suggest that genetic factors play a
      crucial role in the pathogenesis of RA, compared to environmental factors.

PMID- 12482191
TI  - Anti-heart antibodies in postpericardiotomy syndrome: cause or epiphenomenon? A
      prospective, longitudinal pilot study.
AB  - OBJECTIVES: To assess the role of anti-heart antibodies (AHA) in
      postpericardiotomy syndrome (PPS) and the timing of their appearance in relation
      to the initial manifestations of PPS. DESIGN AND SUBJECTS: Twenty patients who
      were scheduled to undergo elective coronary artery bypass grafting (CABG) were
      enrolled in a prospective, longitudinal pilot study. METHODS: Serum was sampled
      for AHA on the day prior to surgery and at regular intervalsfollowing surgery in
      all patients. In those who developed PPS, the serum AHA was determined on the day
      that typical clinical manifestations of PPS appeared and at regular intervals
      following the onset of PPS. RESULTS: All patients were negative for AHA on the
      day precedingsurgery. Three(15%) patients developed PPS. Their sera were negative
      for AHA on the day they were diagnosed as sufferingfrom PPS and the sera became
      positive for AHA within 14 days from the time of diagnosis. The intensity of
      immunofluorescence decreased markedly 30 days afterwards and AHA had disappeared
      within 90days after diagnosis of PPS. The other 17 (85%) patients were negative
      for AHA prior to surgery and remained so during the six-month postoperative
      follow-up period. CONCLUSION: The findings of this study suggest that serum AHA
      may not play a causal role inthe pathogenesis of PPS, but may rather be an
      epiphenomenon, reflecting an immune response to pericardial and/or myocardial
      injury.

PMID- 12482192
TI  - Clustering of cases of insulin dependent diabetes (IDDM) occurring three years
      after hemophilus influenza B (HiB) immunization support causal relationship
      between immunization and IDDM.
AB  - OBJECTIVE: The hemophilus vaccine has been linked to the development of
      autoimmune type 1 diabetes, insulin dependent diabetes (IDDM) in ecological
      studies. METHODS: We attempted to determine if the Hemophilus influenza B (HiB)
      vaccine was associated with an increased risk of IDDM by looking for clusters of
      cases of IDDM using data from a large clinical trial. All children born in
      Finland between October 1st, 1985 and August 31st, 1987, approximately 116,000
      were randomized to receive 4 doses of the HiB vaccine (PPR-D, Connaught) starting
      at 3 months of life or one dose starting after 24 months of life. A control
      cohort included all 128,500 children born in Finland in the 24 months prior to
      the HiB vaccine study. Non-obese diabetic prone (NOD) mice were immunized with a
      hemophilus vaccine to determine if immunization increased the risk of IDDM.
      RESULTS: The difference in cumulative incidence between those receiving 4 doses
      and those receiving 0 doses is 54 cases of IDDM/100,000 (P = 0.026) at 7 years,
      (relative risk = 1.26). Most of the extra cases of IDDM appeared in statistically
      significant clusters that occurred in periods starting approximately 38 months
      after immunization and lasting approximately 6-8 months. Immunization with
      pediatric vaccines increased the risk of insulin diabetes in NOD mice.
      CONCLUSION: Exposure to HiB immunization is associated with an increased risk of
      IDDM. NOD mice can be used as an animal model of vaccine induced diabetes.

PMID- 12482193
TI  - Immunoglobulin G autoantibodies against tissue-transglutaminase. A sensitive,
      cost-effective assay for the screening of celiac disease.
AB  - The characterization of target antigens in several autoimmune disorders has made
      it possible to develop antigen-specific immunoassays that are superior in terms
      of sensitivity, specificity, reproducibility and ease of standardization,
      compared to immunohistological methods that are highly subjective, rely on
      skilled technicians and are not applicable to large-scale studies. In the case of
      celiac disease (CD), tissue transglutaminase (tTGase) has been identified as a
      major autoantigen, and antibodies against this molecule are present in most CD
      patients before gluten is removed from diet. In general, anti-tTGase detection
      assays detect the presence of IgA class antibodies, but these immunoglobulins are
      absent among patients with IgA deficiency, a frequent condition in which CD is
      very prevalent. In this report, we have analyzed 64 patients at diagnosis of CD
      for the presence of antibodies against tTGase of both IgA (TGA) and IgG (TGG)
      classes, using anti-IgA antibodies or Protein A, respectively, for the
      immunoprecipitation of 35S labeled, in vitro transcribed and translated human
      recombinant tTGase. In our hands, the TGG assay matches TGA in terms of
      sensitivity (97%) and specificity (100%), and besides, the combination of both
      assays is able to detect antibodies in all patient samples. The method described
      uses only 6 microl of serum, can be adapted to automated large-scale analysis
      and, in combination with other antigens, can be used for the simultaneous
      screening of other autoimmune diseases, like type 1 diabetes mellitus.

PMID- 12482194
TI  - Streptozotocin induced diabetes in minipig: a case report of a possible model for
      type 1 diabetes?
AB  - Studies on the pathogenic process in type 1 diabetes are often performed in
      animal models. Low-dose administration of streptozotocin has been used to induce
      diabetes with pathological alterations similar to human type 1 diabetes in the
      animals. Rodent models are frequently used but there is a need of developing new
      models including larger animals. In this study we wanted to investigate to what
      extent a minipig was sensitive to low-dose streptozotocin for induction of
      diabetes with features of human Type I diabetes. A female Gottingen minipig
      received two low-doses (40 mg/kg) of streptozotocin with an 11-day interval.
      Serum was analysed for the presence of the enzyme glutamic acid decarboxylase,
      isoform 65, (GAD65) and autoantibodies against glutamic acid decarboxylase,
      isoform 65 (GAD65A), isoform 67 (GAD67A), insulinoma antigen 2 (IA-2) and insulin
      (IAA). Pancreas tissue was fixated in formaldehyde and was sent for
      pathoanatomical examination. The minipig became hyperglycaemic after the second
      injection of streptozotocin. The pathoanatomical examination showed atrophy of
      the beta-cell population, depletion of insulin with preserved glucagon content.
      There was no sign of insulitis. Both GAD65 and GAD65A were detected while GAD67A
      and IAA were absent. It is concluded that chronic diabetes developed after low
      dose streptozotocin injection in a female minipig with the characteristics of the
      end stage of type 1 diabetes. This pilot study suggests that minipigs show
      promise as a model to induce diabetes by injections of low-dose streptozotocin.

PMID- 12482195
TI  - HLA study on two Mexican Mestizo families with autoimmune thyroid disease.
AB  - Several studies have been done regarding the genetic susceptibility to autoimmune
      thyroid disease, particularly those related to the role of Major
      Histocompatibility Complex (MHC) genes in the etiology of the disease. In the
      present study, we report class I and class II MHC haplotypes in nine individuals
      affected by Hashimoto thyroiditis and Graves' disease who belong to two distinct
      Mexican families. In one of the families, Hashimoto thyroiditis was associated
      with the Human Leukocyte Antigen (HLA) HLA-DR3 allele whereas in the other family
      the disease was associated with homozygosity for the HLA-DR4 (DRB1*0407), HLA-DQ3
      (DQB1*0302) haplotype. On the other hand, Graves' disease was found to be
      associated in one of the families with HLA-DR2 (DRB1*1501) and in the other with
      homozygosity for the HLA-DR7 (DRB*0701) and HLA-DQ2 (DQB1*0201) haplotype. These
      results confirm that in Mexicans as in other ethnic groups, genes located within
      the MHC region are related to the genetic susceptibility to develop autoimmune
      thyroid disease.

PMID- 12482196
TI  - An antibody to BP 180 kDa antigen is able to induce an increase of intracellular
      Ca2+ concentration in DJM-1 (human squamous cell carcinoma) cells.
AB  - To elucidate the induction of transmembrane signal transduction of keratinocytes
      by bullous pemphigoid (BP) antibodies, we assessed the intracellular Ca2+
      concentration ([Ca2+]i) in DJM-1 cells (a squamous cell carcinoma cell line). The
      time course of fluo-3-fluorescence intensity was investigated, and transient
      increase of fluorescence intensity in DJM-1 cells was observed when the DJM-1
      cells were incubated with rabbit IgG anti-human BP 180kDa antigen (BP 180). No
      increase of fluorescence intensity was observed when the cells were incubated
      with rabbit IgG anti-human BP 230 kDa antigen (BP 230). This transient increase
      of fluorescence intensity was inhibited by U-73122, a specific inhibitor of
      phospholipase C. These results indicate the possibility that an antibody to BP
      180 induces transmembrane signal transduction in keratinocytes.

PMID- 12482197
TI  - Effect of halofuginone on the development of tight skin (TSK) syndrome.
AB  - The end point of pathogenic events in scleroderma is fibrosis of the skin and
      internal organs. Fibrosis in scleroderma results from the over synthesis and
      deposition of collagen in the connective tissue. The morbidity and mortality of
      the scleroderm is very high and presently there is no specific treatment.
      Halofuginone is a drug with great potential for the treatment of scleroderma
      since it inhibits the synthesis of collagen type I by fibroblasts. We have
      studied the in vivo effect of halofuginone in tight skin (TSK) mice that
      spontaneously develop a scleroderma-like disease due to a genetic defect. Our
      results demonstrate that halofuginone prevented the occurrence of skin sclerosis
      when administered to newborn mice and reduced cutaneous hyperplasia when
      administered in adult TSK mice. These effects correlated with a decreased number
      of cells synthesizing collagen gene transcripts and a reduction in the level of
      autoantibodies specific for human target antigens. These results indicate that
      halofuginone may have use as a therapeutic in the treatment of fibrotic disease.

PMID- 12482198
TI  - Inhibition of Fas-mediated apoptosis by antigen: implications for
      lymphomagenesis.
AB  - Apoptotic deletion of expanded B cell populations is essential in avoidance of
      autoimmune disease and immune regulation of some B cell malignancies. The role of
      CD4+ T cells in B cell apoptosis is evident from the high incidence of B cell
      tumors and autoimmunity in patients with T cell diseases such as the acquired
      immune deficiency syndrome (AIDS). We have previously demonstrated that in
      Epstein-Barr Virus (EBV) negative Burkitt's lymphoma (BL), a tumor derived from
      proliferating centroblasts of the germinal center, the malignant lymphocytes can
      be induced to express Fas (CD95) by ligation of CD40 at the B cell surface. Upon
      CD40 engagement, BL cells are sensitized to T-cell derived death signals provided
      by Fas ligand (FasL, CD95L). HBL-3 is a cell line derived from an AIDS-related BL
      in which the tumor IgM binds the human erythrocyte "i" antigen. To determine
      whether Fas-mediated apoptosis of BL cells is reduced in the context of antigen
      to which the tumor IgM binds, we stimulated HBL-3 cells with CD40 ligand (CD40L,
      CD154) in the presence and absence of human erythrocytes expressing the "i"
      antigen, and measured Fas-mediated apoptosis upon exposure to an agonistic anti
      Fas antibody. We observed that HBL-3 cells were sensitized to Fas-mediated death
      by exposure to CD40L. When i+ RBCs were present, Fas-mediated apoptosis in HBL-3
      cells was reduced by greater than 30%. In contrast, there was no reduction in Fas
      mediated apoptosis in the presence of i- (I+) RBCs. These findings demonstrate
      that Fas-mediated deletion of BL cells is inhibited upon surface IgM engagement
      by antigen for which the malignant clone has affinity.

PMID- 12482199
TI  - Eukaryotic chaperonin containing T-complex polypeptide 1 interacts with
      filamentous actin and reduces the initial rate of actin polymerization in vitro.
AB  - We have previously observed that subunits of the chaperonin required for actin
      production (type-II chaperonin containing T-complex polypeptide 1 [CCT]) localize
      at sites of microfilament assembly. In this article we extend this observation by
      showing that substantially substoichiometric CCT reduces the initial rate of
      pyrene-labeled actin polymerization in vitro where eubacterial chaperonin GroEL
      had no such effect. CCT subunits bound selectively to F-actin in cosedimentation
      assays, and CCT reduced elongation rates from both purified actin filament
      "seeds" and the short and stabilized, minus-end blocked filaments in erythrocyte
      membrane cytoskeletons. These observations suggest CCT might remain involved in
      biogenesis of the actin cytoskeleton, by acting at filament (+) ends, beyond its
      already well-established role in producing new actin monomers.

PMID- 12482200
TI  - Surface binding and uptake of heat shock protein 70 by antigen-presenting cells
      require all 3 domains of the molecule.
AB  - The surprisingly efficient uptake of peptide-loaded heat shock proteins (Hsps) by
      antigen-presenting cells (APCs) has been recently associated with a specific
      receptor-ligand-based mechanism, and the identity of at least 1 receptor has been
      determined. In this study, we tested how the domain composition of the stress
      protein affected its surface association and internalization by APCs, and this
      was facilitated by the availability of the 70-kDa human heat shock protein
      (Hsp70) and its various deletion mutants. We show that both these processes
      strictly depend on the presence of all 3 domains of Hsp70. We propose that the
      previously described interdomain interactions as a determinant of a favorable
      conformational status might also govern a sterical adaptation of Hsps to
      components of the internalization machinery.

PMID- 12482201
TI  - Hsp70 expression in thermally stressed Ostrea edulis, a commercially important
      oyster in Europe.
AB  - Synthesis of heat shock proteins (Hsps) in response to elevated temperatures and
      other denaturing agents is a common feature of prokaryotic and eukaryotic cells.
      The heat-induced expression of Hsp70 family members in the gills and mantle of
      Ostrea edulis, a highly valued fisheries resource inhabiting primarily estuarine
      environments, has been studied. O edulis is exposed to a variety of natural and
      anthropogenic stresses in the environment. Two isoforms of about 72 kDa and 77
      kDa were constitutively present in unstressed organisms, reflecting the
      housekeeping function performed by these proteins under normal circumstances.
      Their expression in animals undergoing thermal stress was highly variable, and on
      the average, little change occurred under different experimental conditions. A
      third isoform of about 69 kDa was induced in both tissues after exposure to > or
      = 32 degrees C; its synthesis was detected within 4 hours of poststress recovery
      at 15 degrees C, reaching the maximum expression after 24 hours in the gills and
      after 48 hours in the mantle and declining thereafter. Hsp69 expression was low
      at 38 degrees C, a temperature lethal for about 50% of the individuals tested.
      Densitometric analysis of Western blots revealed that Hsp69 was mostly
      responsible for the significant heat-induced overexpression of Hsp70s in O
      edulis. Comparison with heat shock responses in tissues of Crassostrea gigas
      indicated a similar pattern of Hsp70 expression. In this organism, however, Hsp69
      was induced after exposure to > or = 38 degrees C. We conclude that tissue
      expression of Hsp69 in O edulis, and possibly other bivalves, is an early sign of
      thermal stress; determining whether these changes also correlate with other major
      environmental stresses is the goal of ongoing studies.

PMID- 12482202
TI  - Small glutamine-rich protein/viral protein U-binding protein is a novel
      cochaperone that affects heat shock protein 70 activity.
AB  - Molecular chaperone complexes containing heat shock protein (Hsp) 70 and Hsp90
      are regulated by cochaperones, including a subclass of regulators, such as Hsp70
      interacting protein (Hip), C-terminus of Hsp70 interacting protein (CHIP), and
      Hsp70-Hsp90 organizing factor (Hop), that contain tetratricopeptide repeats
      (TPRs), where Hsp70 refers to Hsp70 and its nearly identical constitutive
      counterpart, Hsc70, together. These proteins interact with the Hsp70 to regulate
      adenosine triphosphatase (ATPase) and folding activities or to generate the
      chaperone complex. Here we provide evidence that small glutamine-rich
      protein/viral protein U-binding protein (SGT/UBP) is a cochaperone that
      negatively regulates Hsp70. By "Far-Western" and pull-down assays, SGT/UBP was
      shown to interact directly with Hsp70 and weakly with Hsp90. The interaction of
      SGT/UBP with both these protein chaperones was mapped to 3 TPRs in SGT/UBP (amino
      acids 95-195) that are flanked by charged residues. Moreover, SGT/UBP caused an
      approximately 30% reduction in both the intrinsic ATPase activity of Hsc70 and
      the ability of Hsc70 to refold denatured luciferase in vitro. This negative
      effect of SGT/UBP on Hsc70 is similar in magnitude to that observed for the
      cochaperone CHIP. A role for SGT/UBP in protein folding is also supported by
      evidence that a yeast strain containing a deletion in the yeast homolog to
      SGT/UBP (delta SGT/UBP) displays a 50-fold reduction in recovery from heat shock
      compared with the wild type parent. Together, these results are consistent with a
      regulatory role for SGT/UBP in the chaperone complex.

PMID- 12482203
TI  - Heat shock protein-27 protects human bronchial epithelial cells against oxidative
      stress-mediated apoptosis: possible implication in asthma.
AB  - Inflammation of the human bronchial epithelium, as observed in asthmatics, is
      characterized by the selective death of the columnar epithelial cells, which
      desquamate from the basal cells. Tissue repair initiates from basal cells that
      resist inflammation. Here, we have evaluated the extent of apoptosis as well as
      the Hsp27 level of expression in epithelial cells from bronchial biopsy samples
      taken from normal and asthmatic subjects. Hsp27 is a chaperone whose expression
      protects against oxidative stress. We report that in asthmatic subjects the basal
      epithelium cells express a high level of Hsp27 but no apoptotic morphology. In
      contrast, apoptotic columnar cells are devoid of Hsp27 expression. Moreover, we
      observed a decreased resistance to hydrogen peroxide-induced apoptosis in human
      bronchial epithelial 16-HBE cells when they were genetically modified to express
      reduced levels of Hsp27.

PMID- 12482204
TI  - Stress protection by a fluorescent Hsp27 chimera that is independent of nuclear
      translocation or multimeric dissociation.
AB  - A chimeric protein consisting of enhanced green fluorescent protein (EGFP) fused
      to the N-terminus of human Hsp27 conferred stress protection in human A549 lung
      carcinoma and murine L929 cells that were stably transfected to express the
      chimera constitutively. The resultant protection was comparable with that in the
      same cell lines when they were transfected to express corresponding levels of
      Hsp27. Unlike L929 cells, A549 cells exhibit endogenous Hsp27 expression, whose
      expression was inhibited in proportion to the amount of fluorescent chimera
      expressed, suggesting that the A549 cells recognized the latter as Hsp27.
      Upregulation of Hsp27 or chimeric Hsp27 in all transfected cell lines (stable or
      transient transfection) caused no measurable change in cellular glutathione
      levels, indicating that glutathione played no role in the stress protection
      associated with either protein. Chimeric Hsp27 had a monomeric molecular weight
      of 55 kDa (that of Hsp27 plus EGFP) in both cell types and formed a 16-mer
      complex twice as massive as that formed by Hsp27. Heat shock or sodium arsenite
      induced phosphorylation of both chimeric Hsp27 and Hsp27, which resulted in the
      disaggregation of Hsp27 multimers in both cell types and disaggregation of 20% of
      the chimeric multimers in L929 cells. But chimeric Hsp27 multimers did not
      disaggregate after stress in A549 cells. Epifluorescence and confocal microscopy
      demonstrated that chimeric Hsp27 was restricted to the cytoplasm under normal
      growth conditions and after heat shock in all cells. This study supports the
      conclusions that Hsp27 stress protection requires neither its translocation into
      the nucleus nor the dissociation of its multimeric complex. Furthermore, it
      demonstrates that fluorescent chimeras of heat shock proteins can be functional
      and used to observe the protein's distribution within living cells.

PMID- 12482207
TI  - 2002 Wolff Award. 5 -HT2A receptor activation and nitric oxide synthesis: a
      possible mechanism determining migraine attacks.
AB  - OBJECTIVE: To determine the effect of the 5-HT2A receptor in control of spinal
      nociception, cerebral circulation, and nitric oxide synthase (nNOS) expression in
      trigeminovascular neurons. BACKGROUND: The plasticity of the 5-HT2A receptor is a
      possible factor determining the course of migraine. Up-regulation of this
      receptor has been demonstrated to correlate with the increasing frequency of
      migraine attacks and may underlie the development of chronic daily headache.
      METHODS: Adult male Wistar rats were divided into groups receiving the 5-HT2A
      agonist, 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), nitroglycerin, or
      normal saline. The tail flick test and chemical nociception-evoked Fos-expression
      in dorsal horn neurons were used as indicators of nociception. Regional cerebral
      blood flow was monitored using laser Doppler flowmetry. Expression of Fos and
      nNOS was studied using immunohistochemical method. RESULTS: Administration of DOI
      led to the shortening of tail flick latency (1.3 +/- 0.2 and 7.2 +/- 0.6 seconds
      for DOI-treated and control groups, respectively). The number of Fos
      immunoreactive neurons was also greater in the DOI-treated group compared with
      the control group. DOI also produced long-lasting cerebral hyperemia (123% of
      baseline value) associated with the enlargement of perivascular nNOS
      immunoreactive nerve fibers and increased nNOS-immunoreactive neurons in
      trigeminal ganglia and trigeminal nucleus caudalis. These findings resembled
      those observed in the rats exposed to nitroglycerin. CONCLUSION: Our results
      suggest that activation of the 5-HT2A receptor leads to an enhancement of NO
      production in trigeminovascular pathway. NO may trigger migraine attacks by
      inducing cerebral vasodilation and sensitizing the perivascular nociceptors and
      central nociceptive neurons in trigeminovascular system. Up-regulation of this
      pronociceptive receptor can increase headache attacks and contributes to the
      development of chronic daily headache.

PMID- 12482205
TI  - Hsp70 and thermal pretreatment mitigate developmental damage caused by mitotic
      poisons in Drosophila.
AB  - To assess the ability of the heat-inducible molecular chaperone heat-shock
      protein 70 (Hsp70) to mitigate a specific developmental lesion, we administered
      the antimicrotubule drugs vinblastine (VB) and colchicine (COL) to larvae of
      Drosophila engineered to express differing levels of Hsp70 after heat
      pretreatment (HP). VB and COL decreased survival during metamorphosis, disrupted
      development of the adult eye and other structures as well as their precursor
      imaginal disks, and induced chromosome nondisjunction in the wing imaginal disk
      as indicated by the somatic mutation and recombination test (SMART) assay. Hsp70
      inducing HP reduced many of these effects. For the traits viability, adult eye
      morphology, eye imaginal disk morphology, cell death in the eye imaginal disks,
      and single and total mutant clone formation in the SMART assay, HP reduced the
      impact of VB to a greater extent in Drosophila with 6 hsp70 transgenes than in a
      sister strain from which the transgenes had been excised. Because the extra-copy
      strain has higher levels of Hsp70 than does the excision strain but is otherwise
      almost identical in genetic background to the excision strain, these outcomes are
      attributable to Hsp70. The hsp70 copy number had a variable interaction with HP
      and COL administration.

PMID- 12482206
TI  - An Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where?
AB  - Mortalin/mthsp70/PBP74/Grp75 (called mortalin hereafter), a member of the Hsp70
      family of chaperones, was shown to have different subcellular localizations in
      normal and immortal cells. It has been assigned to multiple subcellular sites and
      implicated in multiple functions ranging from stress response, intracellular
      trafficking, antigen processing, control of cell proliferation, differentiation,
      and tumorigenesis. The present article compiles and reviews information on the
      multiple sites and functions of mortalin in different organisms. The relevance of
      its differential distributions and functions in normal and immortal cell
      phenotypes is discussed.

PMID- 12482208
TI  - Chronic daily headache: identification of factors associated with induction and
      transformation.
AB  - BACKGROUND: Chronic daily headache (CDH) is one of the more frequently
      encountered headache syndromes at major tertiary care centers. The analysis of
      factors related to the transformation from episodic to chronic migraine (CM) and
      to the de novo development of new daily persistent headache (NDPH) remain poorly
      understood. OBJECTIVES: To identify somatic factors and lifestyle factors
      associated with the development of CM and NDPH. METHODS: We used a randomized
      case-control design to study the following groups: 1) CM with analgesic overuse
      (ARH), n = 399; 2) CM without analgesic overuse, n = 158; and 3) NDPH, n = 69.
      These groups were compared with two control groups: 1) episodic migraine, n =
      100; and 2) chronic posttraumatic headache (CPTH); n = 65. Associated medical
      conditions were assessed. We investigated the case groups for any association
      with somatic or behavioral factors. Data were analyzed by the two-sided Fischer's
      exact test, with the odds ratio being calculated considering a 95% confidence
      interval using the approximation of Woolf. RESULTS: When the active groups were
      compared with the episodic migraine group, the following associations were found:
      1) ARH: hypertension and daily consumption of caffeine; 2) CM: allergies, asthma,
      hypothyroidism, hypertension, and daily consumption of caffeine; and 3) NDPH:
      allergies, asthma, hypothyroidism, and consumption of alcohol more than three
      times per week. The following associations were found when comparing the active
      groups with CPTH: 1) ARH: asthma and hypertension; 2) CM: allergies, asthma,
      hypothyroidism, hypertension, and daily consumption of caffeine; and 3) NDPH:
      allergies, asthma, hypothyroidism, and consumption of alcohol more than three
      times per week. CONCLUSIONS: Several strong correlations were obtained between
      patients with specific types of CDH and certain somatic conditions or behaviors;
      some have not been previously described. Transformation of previously episodic
      headache or development of a NDPH thus may be related to certain medical
      conditions and behaviors beyond the frequently incriminated precipitant analgesic
      overuse. As similar results were obtained when CPTH was used as a control, the
      correlation is more complex than simple comorbidity.

PMID- 12482209
TI  - Effects of fluoxetine on habituation of pattern reversal visually evoked
      potentials in migraine prophylaxis.
AB  - OBJECTIVE: To investigate the effects of fluoxetine in migraine prophylaxis on
      habituation of visually evoked potentials. BACKGROUND: Habituation of pattern
      reversal visually evoked potentials was found to be abnormal in migraine between
      attack, and this abnormality was most likely due to serotonergic pathway
      dysfunction in the brain stem. METHODS: One hundred nineteen subjects were
      included in the study: 40 healthy volunteers and 79 migraineurs not taking any
      prophylactic migraine medication (44 without aura and 35 with aura). Visually
      evoked potentials in migraineurs were recorded in the headache-free interval.
      Amplitude change of the visually evoked potentials (N1-P1) was measured between
      the first and fifth block of 50 sequential averagings during continuous
      stimulation at 3.1 Hz. All migraineurs were placed on fluoxetine 20 mg/day for
      prophylaxis of migraine. One month later, visually evoked potentials were
      recorded again. RESULTS: Mean amplitude changes in the fifth block expressed as
      percentages of the first block were -13.4% +/- 19.2% in healthy volunteers, 9.8%
      +/- 23.3% in migraine without aura, and 4.4% +/- 8.7% in migraine with aura
      during the baseline period. The difference was significant between migraineurs
      and healthy volunteers (both P= 0.0001), but not between migraineur groups. After
      treatment, amplitude changes were -9.3% +/- 14.5% in migraine without aura and 
      10.1% +/- 11.5% in migraine with aura. Habituation pattern tended to normalize
      with prophylactic treatment, and mean amplitude changes were not significant
      between migraineurs and healthy volunteers (both P = 0.4). CONCLUSIONS: We
      concluded that the fluoxetine prophylaxis corrects the interictal deficit of
      habituation in migraineurs.

PMID- 12482210
TI  - Platelet serotonin measures in migraine.
AB  - OBJECTIVE AND BACKGROUND: Serotonergic mechanisms play an important role in the
      pathogenesis of headache. To search for potential indicators of altered serotonin
      homeostasis in migraine, we have investigated three parameters of the platelet
      serotonin (5HT) system, platelet serotonin level (PSL), platelet serotonin uptake
      (PSU), and monoamine oxidase (MAO-B) activity, in a group of 55 patients with
      migraine and in 81 healthy controls. METHODS: After platelet separation, PSL was
      determined fluorimetrically; PSU was measured by incubating aliquots of platelet
      rich plasma with six concentrations of 14C-5-HT for 60 seconds at 37 degrees C,
      followed by vacuum filtration; platelet MAO-B activity (toward kynuramine as a
      substrate) was determined fluorimetrically. RESULTS: Values of the investigated
      measures, in patients versus controls, amounted to (mean +/- SD) 608 +/- 166 vs.
      591 +/- 184 ng/10(9) platelets for PSL, 139 +/- 25 vs. 142 +/- 25 pmol 5HT/10(8)
      platelets/minute for Vmax of PSU, 376 +/- 62 vs. 404 +/- 72 nM for Km of PSU, and
      15.8 +/- 5.1 vs. 14.3 +/- 5.7 nmol product/10(8) platelets/60 minutes for
      velocity of MAO-B. Mentioned parameters did not show statistical differences
      between patients and controls, with exception of a small difference in Km of PSU,
      reaching significance (P<0.01). After subgrouping of patients according to
      diagnosis (migraine with aura, migraine without aura, and migraine attack) and
      gender, no differences retained significance. CONCLUSIONS: Our results indicate
      the absence of a measurable disturbance in 5HT homeostasis in migraine, as shown
      by platelet 5HT parameters, and they question the suitability of the use of
      mentioned blood elements in this regard.

PMID- 12482211
TI  - Central cholinergic challenging of migraine by testing second-generation
      anticholinesterase drugs.
AB  - The antinociceptive activity of donepezil, a novel cholinesterase inhibitor, was
      investigated in the mouse hot plate test. Donepezil (5 to 10 mg kg(-1) i.p.)
      induced a dose-dependent antinociception that reached its maximum effect 15
      minutes after injection. Donepezil antinociception was prevented by the
      antimuscarinic drug scopolamine. At analgesic doses, donepezil did not alter
      gross animal behavior. These results indicate that donepezil is endowed by
      muscarinic antinociceptive properties, suggesting this compound as a potential
      therapeutic approach for the treatment of painful pathologies. Therefore, we
      investigated donepezil's effect in migraine. Donepezil (5 mg per os, evening
      assumption) was effective as a prophylatic agent in patients suffering from
      migraine with or without aura by reducing the number of hours with pain, the
      number of attacks, and the severity of the pain attack. The efficacy of donepezil
      was compared with that of the beta-blocker propranolol (40 mg bid per os),
      showing higher activity. Response rates of a large-sized open study devoid of
      entry criteria regarding migraine subtypes suggest the drug as an excellent
      prophylactic compound for migraine in general practice. Clinical results also
      indicate that the activation of the cholinergic system can represent a novel
      prophylactic approach to migraine.

PMID- 12482212
TI  - Effects of the headache state on objective and perceived performance.
AB  - The reduced ability to perform tasks is generally reported by those who
      experience headache. However, in an experimental study, participants reporting
      onset of headache chose more ambitious tasks than participants remaining headache
      free. The purpose of this study was to reevaluate the objective ambition of
      subjects with headache onset, and to determine if perceptions of expended effort
      and performance accuracy contributed to this seemingly maladaptive behavior.
      These effects were evaluated while controlling for headache proneness. A
      nonclinical sample was used. Measures of ambition, performance accuracy,
      perceived effort, and perceived accuracy for a headache-developing group (n = 25)
      and a sex-matched, headache-free group (n = 25) were compared during a series of
      mental arithmetic problems. Ambition among participants after headache onset was
      significantly higher than for the control group. There was little indication that
      inaccurate perceptions of effort or accuracy contributed to the observed
      heightened ambition. However, perceived accuracy was poorer for the headache
      developing group after onset of a headache state. Headache proneness did not
      eliminate the significance of any relationship between objective or subjective
      performance and headache state.

PMID- 12482213
TI  - The burden of illness associated with headache disorders among young adults in a
      representative cohort study.
AB  - This study investigated the functional impairment (work and social functioning
      and general health status) associated with migraine and tension-type headache
      (TTH) among young adult members of the Dunedin Multidisciplinary Health and
      Development Study. Using criteria based on the International Headache Society
      classificatory system, the 1-year prevalence for migraine headache was 7.4%, TTH
      was 11.1%, and combined headache (coexisting migraine and TTH) was 4.3%. All
      comparisons were against a health control group (headache free) and a diagnostic
      control group (individuals without headache currently using medication for
      asthma). Although those suffering from migraine and combined headache had the
      most severe impairment in work- and social-related activities, those with TTH
      reported significantly poorer social and mental health functioning and poorer
      emotional and physical functioning while performing everyday roles than did
      headache-free controls. Study members with combined headache had the poorest self
      reported health, with significantly lower ratings on physical, vitality, and
      mental health measures than asthmatics currently using medication. The pervasive
      impairment reported across multiple life domains among young headache sufferers
      illustrates the significant burden of illness associated with headache disorders.

PMID- 12482214
TI  - Prevalence of migraines in NCAA division I male and female basketball players.
      National Collegiate Athletic Association.
AB  - OBJECTIVE: The purpose of this study was to describe the overall prevalence of
      migraines within National Collegiate Athletic Association Division I men's and
      women's basketball players. In addition, the prevalence of migraines was
      determined across gender and ethnic groups for the same sample. BACKGROUND:
      Although numerous studies have assessed the prevalence of migraines within the
      general population, college students, professional groups, industrial/work place
      settings, and overseas populations, little has been done with athletes. To the
      best of our knowledge, no study of the incidence of migraines in athletes has
      been previously conducted. It has also been reported that migraines cause
      depression, insomnia, fatigue, anorexia, nausea, and vomiting, all of which might
      hinder athletic performance. Sports medicine clinicians and researchers also
      agree that migraines in athletes are probably underreported and often
      misdiagnosed. METHODS: Seven hundred ninety-one Division I men and women
      basketball players representing 51 colleges and universities were mailed a
      previously validated survey asking questions about headaches. All surveys were
      analyzed with a validated diagnostic algorithm consistent with the International
      Headaches Society's (IHS) criteria for headache diagnosis. Descriptive statistics
      were used to report the prevalence rate for gender and ethnic groups, as well as
      the entire sample. Chi-square tests were performed (P = 0.05) to determine if
      there were any differences in the prevalence of migraines among gender and ethnic
      groups. RESULTS: Results showed that 2.9% (n = 23 of 791) of the total sample was
      classified as having migraines meeting IHS guidelines. In addition, 0.9% (n = 3
      of 332) of men and 4.4% (n = 20 of 459) of women were classified as having
      migraines meeting IHS guidelines. Additionally, results showed that women
      reported migraines (chi2 = 8.140, P = 0.004) more often than men. When comparing
      the prevalence rates of migraines between ethnic groups, results showed that
      Caucasians had a rate of 3.3% (n = 14 of 429), whereas African Americans had a
      rate of 3.1% (n = 9 of 287). There was no significant difference found between
      ethnic groups in migraine prevalence (chi2 = 2.491, P = 0.2888). CONCLUSIONS: In
      conclusion, it was found that the prevalence of migraines in National Collegiate
      Athletic Association Division I men's and women's basketball players was
      generally less than in the general population, that women showed an increased
      prevalence of migraines when compared with men, and that Caucasians and African
      Americans did not differ in prevalence of migraines.

PMID- 12482215
TI  - Upper and lower cluster headache: clinical and pathogenetic observations in 608
      patients.
AB  - OBJECTIVE, BACKGROUND, AND METHODS: Ever since it was proposed by Ekbom and
      Kugelberg back in 1968 on the basis of the different location of head pain during
      attacks, the differentiation of cluster headache into an upper syndrome (US) and
      a lower syndrome (LS) has been regarded as a purely academic distinction. To
      evaluate whether this differentiation is indeed well founded and to understand
      its possible significance in the light of current pathogenetic knowledge, we
      rigorously applied Ekbom and Kugelberg's classification criteria to a sample of
      608 patients with cluster headache (CH; 440 men and 168 women), including 483
      with episodic CH, 69 with chronic CH, and 56 with CH periodicity undetermined.
      RESULTS: Of these patients, 278 could be classified as US sufferers and 330 as LS
      sufferers. Our data analysis showed statistically significant clinical
      differences between the two syndromes: pain location was more common in the
      ocular, temporal, and nuchal regions among LS sufferers; in addition, patients
      with LS reported not only a higher rate of autonomic symptoms, but also a higher
      predominance of nasal congestion, ptosis, and forehead and facial sweating among
      these symptoms. CONCLUSIONS: Based on current anatomofunctional knowledge and on
      the most recent pathogenetic findings, we believe that changes in hypothalamic
      activity posteroinferiorly may lead to activation of the caudal part of the
      spinal trigeminal nucleus by way of the hypothalamus, midbrain, and trigeminal
      nerve fibers and consequently to activation of the trigeminovascular system with
      a different location in the two syndromes. More specifically, there seems to be a
      larger and more extensive involvement of the subnucleus caudalis in LS compared
      with US, where only its ventrocaudal portions are likely to be affected.

PMID- 12482216
TI  - Intravenous propofol in the treatment of refractory headache.
AB  - We analyzed the results of treating patients who had chronic daily headaches that
      were refractory to standard medications with repetitive low-dose boluses of
      intravenous propofol (2,6-diisopropylphenol). Patients were treated over a 1-year
      period at Thomas Jefferson University Hospital. A total of 18 patients were
      treated a total of 21 times. Over 90% of patients had at least some headache
      relief after treatment. The headache cycle was broken in eight patients. There
      were no complications. Intravenous propofol is safe and effective when used under
      monitored conditions and should be considered for patients who have refractory
      chronic daily headache and have failed other interventions.

PMID- 12482217
TI  - Labetalol for prophylactic treatment of intractable migraine during pregnancy.
AB  - Headaches tend to improve in the majority of migraineurs during pregnancy, but
      some patients report a worsening of migraine and present a management challenge
      because of the restrictions of pharmacotherapy during pregnancy. Treatment
      options become even more limited for pregnant migraineurs who develop
      preeclampsia. Labetalol was tried successfully in reducing the frequency,
      duration, and intensity of migraine attacks in a pregnant woman with
      preeclampsia. There were no significant side effects and the patient delivered a
      healthy baby without complications.

PMID- 12482218
TI  - Auditory hallucinations associated with migraine.
AB  - OBJECTIVE: Two children experienced auditory hallucinations during migraine (one
      with migraine without aura and one with migraine with aura). These hallucinations
      only occurred during headache. BACKGROUND: Auditory hallucinations are rarely
      reported in patients with migraine. These patients often have other psychiatric
      or neurologic disorders such as affective disorder or epilepsy. METHODS: Case
      report and a review of the literature. RESULTS: No other neuropsychiatric
      disorder was identified in either patient at presentation or upon follow-up.
      CONCLUSIONS: Auditory hallucinations can rarely occur in patients with migraine.
      Further study of this association might provide insight to any relationship
      between migraine, auditory hallucinations, and the temporal lobe.

PMID- 12482219
TI  - Headache associated with epileptic seizures: epidemiology and clinical
      characteristics.
AB  - OBJECTIVE: To investigate the incidence and characteristics of seizure-associated
      headaches and the modalities of treatment. BACKGROUND: Systematic investigations
      of the characteristics of seizure-associated headaches are rare. Although data in
      the literature on the incidence of postictal headaches range between 37% and 51%,
      experiences with their treatment are limited and pathophysiological concepts do
      not exist. METHODS: One hundred ten epileptic outpatients from an epilepsy
      referral center participated in a semi-standardized interview about headaches
      associated with epileptic seizures. The characteristics of these patients and of
      15 additionally recruited patients with known postictal headaches were analyzed.
      RESULTS: The incidence of seizure-associated headaches was 43% (n = 47). Forty
      three patients had exclusively postictal headaches. One patient had exclusively
      preictal headaches. Three patients had both pre- and postictal headaches. The
      duration of postictal headaches was longer than 4 hours in 62.5% of the patients.
      In the majority of patients, postictal headaches occurred in more than 50% of the
      seizures. Postictal headaches were treated by self-medication in 19 patients
      (30%). No patient treated headaches according to a medical prescription. In 11
      patients, postictal migraine was untreated. Postictal headaches were associated
      with focal seizures in 23 patients and/or with generalized seizures in 54
      patients. According to the headache classification of the International Headache
      Society, headaches were classified as migraine-type in 34% of patients and as
      tension-type headache in 34% of patients. Headaches could not be classified in
      21% of patients. Patients with and without postictal headaches did not differ as
      to localization of the epileptogenic zone or to the number of prescribed
      antiepileptic drugs. There was no relationship between the localization of the
      epileptogenic focus, localization of the headache, or the headache
      classification. CONCLUSIONS: Headaches associated with partial and generalized
      seizures are frequent and undertreated. Treatment should consider both the
      headache syndrome and the general guidelines for treating primary headaches. The
      pathophysiology of seizure-associated headaches cannot be explained by the
      epileptic syndrome.

PMID- 12482220
TI  - A review of mechanisms of response to pain therapy: why voodoo works.
AB  - A person's response to pain treatment may be due to factors other than the direct
      effect of analgesics. Amelioration of pain is often associated with modalities
      that appear to make no scientific sense. This review outlines the mechanisms of
      pain amelioration other than that by medication. These mechanisms help to explain
      why pain relief may follow the administration of allopathic modalities. Pain is
      modulated, enhanced, or diminished by both cerebral and peripheral mechanisms.
      Cerebral factors include the placebo response, psychological phenomena, and
      conscious cognitive activation. In addition to evoking endogenous opioids, these
      central mechanisms activate antinociceptive pathways beginning in the limbic
      forebrain and relayed in the periaqueductal gray matter to primary afferent
      nociceptive sites in the spinal cord dorsal horn (and medullary nucleus
      caudalis). Obvious peripheral factors that may diminish pain perception are those
      that decrease afferent stimuli. Paradoxically, stimulation of afferent neurons
      may also ameliorate pain by activating spinal or supraspinal inhibitory
      mechanisms. Finally, improvement in pain or other symptoms is often falsely
      attributed to a therapy when remission occurs because the underlying illness has
      run its normal course.

PMID- 12482221
TI  - Borderline personality disorder and the chronic headache patient: review and
      management recommendations.
AB  - BACKGROUND: Physicians and psychologists who treat headache not infrequently
      encounter patients with borderline personality disorder (BPD). BPD patients
      frequently suffer from headache, and often pose special problems in treatment.
      Few guidelines exist for the management of the BPD headache patient. OBJECTIVES:
      To provide an overview of current concepts on BPD, including comorbidity,
      psychopathophysiology, and treatment. To provide an explicit framework for
      managing borderline behavior in patients with chronic headache. METHODS: A
      literature review combined with clinical observations from the tertiary treatment
      of intractable headache in outpatient and inpatient settings. RESULTS: BPD is
      found in almost 2% of the general population, with increased prevalence in
      patients with comorbid psychopathology and substance abuse. Severe headaches and
      migraine appear to be more prevalent in patients with BPD than the general
      population. A reported history of abuse is common, but must be interpreted with
      caution. Recent research has found reduced hippocampal volume in women patients
      with BPD; hypometabolism in the premotor, prefrontal, and anterior cingulate
      cortex, as well as the thalamic, caudate, and lenticular nuclei; and serotonergic
      dysfunction. Opioid medications may have an adverse influence on certain clinical
      features of BPD. Some patients show at least short-term improvement in
      dissociative behavior when given opioid antagonists. Treatment should combine
      appropriate pharmacotherapy with ongoing psychotherapy. Early identification of
      BPD is likely to improve the course of treatment. Treatment often requires
      explicit contracts, consistent limit-setting, confrontation, and communication
      between different treating professionals to avoid "splitting." The recognition
      and management of the doctor's own countertransference is important to successful
      management. Noncompliant patients may need to be terminated from treatment.
      CONCLUSIONS: Specific management guidelines and the use of explicit treatment
      contracts can help sustain patients in treatment, reduce the risk of medication
      abuse, and minimize distress in the treating professional. Headaches and other
      symptoms in patients with BPD can be successfully managed over the course of a
      long-term relationship with clearly defined limits.

PMID- 12482222
TI  - Triptans for migraine management in adolescents.
AB  - OBJECTIVE: To review triptan efficacy and tolerability data for adolescent
      migraine sufferers to assist clinicians in selecting triptans for this age group.
      BACKGROUND: Migraine is a common cause of headache among adolescents. To date, no
      medications, including those with proven headache relief in adults, have been
      approved for treatment of migraine in adolescents. METHODS: Recent triptan
      clinical trials conducted in adolescent migraine sufferers 12 to 17 years of age
      were reviewed and results were summarized. RESULTS: The success of individual
      triptan clinical trials conducted in adolescent appears related to time to
      treatment (1.9 to 6 hours), placebo response (25% to 57%), and day of the week
      (weekday versus weekend). Overall, triptan tolerability in adolescents is similar
      to that reported in adults. CONCLUSION: Study results suggest that the triptan
      class of antimigraine drugs may effectively alleviate migraine in adolescents.
      Future research should address placebo response and earlier treatment paradigms.

PMID- 12482223
TI  - Comparison of therapeutic gain with therapeutic ratio for the assessment of
      selective 5HT(1B/1D) agonist efficacy in migraine.
AB  - OBJECTIVE: Comparison of use of therapeutic gain (TG) and therapeutic ratio (TR)
      for relative assessments of selective 5HT(1B/1D) agonist efficacy in the acute
      treatment of migraine. BACKGROUND: Comparison of selective 5HT(1B/1D) agonist
      efficacy in the acute treatment of migraine is complicated by the impracticality
      of conducting high-quality head-to-head active comparator trials for all
      permutations of drug, dose, and route of administration; the clinical trials that
      are available are usually noncontemporaneous, and have fluctuating active and
      placebo response rates (ARR and PRR, respectively) for the necessarily subjective
      endpoints. The standard primary endpoint is conversion of headache score 2
      (moderate pain) or score 3 (severe pain) into score 0 (no pain) or score 1 (mild
      pain) at a single timepoint (usually 2 or 4 hours postdose). Two principal
      methods have been used for comparison of ARR between studies: TG = ARR - PRR and
      TR = ARR/PRR. Secondary endpoints can be treated in the same way, although the 24
      hour remedication rate is the only secondary endpoint that is subject to
      regulatory authority standardization. Does either TG or TR have an advantage over
      the other? METHODS: Efficacy data were collected from published sources and
      included pain score conversion at 2- and 4-hour, as well as 24-hour remedication
      rates. TG and TR were calculated for each endpoint, as shown above. The ranges of
      these variables were found from all observed measures. Correlations between TG
      and TR were found using least squares methods. The 95% confidence intervals (CI)
      for TG and TR were then found for all clinical trials, and for the whole range of
      observed PRR. RESULTS: Values for TR and TG generally were well correlated for
      pain score conversion at 2 hours postdose (n = 51 clinical trials). Deviations
      from this correlation were greatest for drugs that were evidently very
      efficacious. When standardized for the observed ranges of PRR and ARR, the 95% CI
      for TR were narrower than for TG. A subset of these studies also reported 4-hour
      data (n = 23 clinical trials), but the correlation between TR and TG was again
      good, with narrower 95% CI for TR than TG. For the 24-hour remedication data (n =
      18 trials), PRR was less variable; TR and TG again correlated well, but there was
      little difference in their relative 95% CI. CONCLUSIONS: For comparison of drugs
      in noncontemporaneous studies, when PRR fluctuates, relative ranges for TR are
      narrower than for TG. For assessing single clinical trial results (ie, point
      estimates of efficacy) TR will generally be relatively nearer to its mean than
      TG. For both these reasons, TR is a more robust statistic than TG.

PMID- 12482224
TI  - "Occult" orthostatic headache.

PMID- 12482225
TI  - Triggering migraine in a 20-year-old athletic male.

PMID- 12482226
TI  - Letter to the editor of Headache from the United States Attorney General: a
      comment.

PMID- 12482227
TI  - Fatal ergotism induced by an HIV protease inhibitor.

PMID- 12482228
TI  - A new drug for an old condition?

PMID- 12482229
TI  - Suggestion for another anti-epileptic drug to use for migraine prophylaxis.

PMID- 12482230
TI  - Efficient synthesis of the benzo[a]pyrene metabolic adducts of 2'-deoxyguanosine
      and 2'-deoxyadenosine and their direct incorporation into DNA.
AB  - A new and efficient method is described for the synthesis in gram quantities of
      the benzo[a]pyrene (B[a]P) metabolic adducts of 2'-deoxyguanosine (dG) and 2'
      deoxyadenosine (dA) substituted, respectively, at the N(2)- and N(6)- positions.
      When the racemic form of the tris(benzoyloxy)amine 5 (related to the notoriously
      carcinogenic epoxydiol 2) is coupled with the bromoinosine derivative 6 by means
      of a Buchwald-Hartwig reaction, the expected pair of diastereomers, 7 and 8, is
      obtained in high (combined) yield. Selective deblocking of this mixture then gave
      cleanly the pair of diastereomers 9. These were used in the synthesis of a series
      of DNA oligomers via their 5'-O-DMT-3'-O-phosphoramidites (10) using standard
      automated methods. Coupling efficiencies were 94-98% at the point of introduction
      of the xeno-2'-deoxynucleoside, and in all cases the mixtures of the two
      diastereomeric oligomers (DMT-off stage) were easily separated by HPLC. By a
      similar sequence of reactions beginning with 5 and the protected 6-bromopurine 2'
      deoxynucleoside 11, it was possible with equal efficiency to introduce the N(6)
      modified diastereomers (16) of dA into oligomeric DNA. Circular dichroism
      measurements were used to establish the fundamental configurations at the xeno-2'
      deoxynucleoside site for each of the oligomers. Mass spectral data in both the dG
      and the dA series confirmed the presence of the xeno-2'-deoxynucleoside in the
      oligomers. This was complemented by enzymatic degradation of one of the oligomers
      from each of the series. In both of these cases, after HPLC separation, circular
      dichroism measurements on the reisolated xenonucleoside also confirmed its
      presence in the oligomer.

PMID- 12482231
TI  - Correlations of nitrenium ion selectivities with quantitative mutagenicity and
      carcinogenicity of the corresponding amines.
AB  - There is a correlation (r(adj)(2) = 0.5491-0.6338) of quantitative mutagenicity,
      log m, for a series of heterocyclic (HCAs) and carbocyclic (AAs) aromatic amines
      in Salmonella typhimurium TA 98 (18 amines) and TA 100 (15 amines) vs log S, the
      log of the azide/solvent selectivity of the corresponding nitrenium ion.
      Monocyclic aromatic amines, MAAs, are less mutagenic than other amines of similar
      log S. Multiple variable linear regression analysis led to a two parameter
      regression model, significant at the 95% confidence level for both variables,
      that includes log S and a ring index variable, I(rings), that is 0 for MAAs and 1
      for all other amines. These models have r(adj)(2) = 0.8448 for TA 98, and 0.8927
      for TA 100. Inclusion of a third variable, Clog P, increases r(adj)(2) to 0.8913
      for TA 98 and 0.9011 for TA 100. This model is significant at the 95% confidence
      level for all variables for TA 98, but only for two of the three variables for TA
      100. The confidence level is 80% for Clog P in TA 100. Quantitative
      carcinogenicity data in mice and rats are more weakly correlated with log S
      (r(adj)(2) = 0.5357 for 12 amines in mice, r(adj)(2) = 0.4216 for 10 amines in
      rats). Several two parameter regression models, all containing Clog P and one
      containing log S, adequately correlate the mouse data.

PMID- 12482232
TI  - Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice.
AB  - Hepatic injury induced by various toxic agents, including acetaminophen (APAP),
      has been attributed, in part, to the production of proinflammatory cytokines and
      other mediators by resident Kupffer cells within the liver. However, recent
      evidence from our laboratory has demonstrated that hepato-protective factors,
      such as interleukin (IL)-10 and cyclooxygenase-derived mediators, are also
      upregulated in response to hepatic damage to help protect against exacerbated
      injury, and Kupffer cells have been suggested to be a source of these modulatory
      factors. In other models, Kupffer cells also serve important regulatory functions
      in pathophysiological states of the liver. Therefore, we reevaluated the role of
      Kupffer cells in a murine model of APAP-induced liver injury using liposome
      entrapped clodronate (liposome/clodronate) as an effective Kupffer cell-depleting
      agent. We show that in contrast to pretreatment of mice with a widely used
      macrophage inhibitor, gadolinium chloride, which did not deplete Kupffer cells
      but moderately protected against APAP-induced hepatotoxicity as reported
      previously, the intravenous injection of liposome/clodronate caused nearly
      complete elimination of Kupffer cells and significantly increased susceptibility
      to APAP-induced liver injury as compared with mice pretreated with empty
      liposomes. This increased susceptibility was apparently unrelated to the
      metabolism of APAP since liposome/clodronate pretreatment did not alter APAP
      protein adduct levels. Instead, Kupffer cell depletion by liposome/clodronate led
      to significant decreases in the levels of hepatic mRNA expression of several
      hepato-regulatory cytokines and mediators, including IL-6, IL-10, IL-18 binding
      protein and complement 1q, suggesting that Kupffer cells are a significant source
      for production of these mediators in this model. Our findings indicate that, in
      addition to their protoxicant activities, Kupffer cells can also have an
      important protective function in the liver through the production of a variety of
      modulatory factors which may counteract inflammatory responses and/or stimulate
      liver regeneration.

PMID- 12482233
TI  - Computational studies on biphenyl derivatives. Analysis of the conformational
      mobility, molecular electrostatic potential, and dipole moment of chlorinated
      biphenyl: searching for the rationalization of the selective toxicity of
      polychlorinated biphenyls (PCBs).
AB  - With the objective to understand how the pattern and degree of chlorination
      influence on the properties of the title molecules, a computational study on
      biphenyl and all the chlorinated biphenyls (from 1 to 10 chlorine atoms, 209
      congeners) has been undertaken. The study includes conformational searches (and
      further refinement by molecular dynamics simulations) and the ab initio
      calculation of the molecular electrostatic potential (MEP) and the dipole moments
      for all the congeners. The most significant property is the MEP, finding a good
      correlation between the MEPs and the substitution pattern on chlorinated
      biphenyls. The most toxic congeners possess highly positive values of
      electrostatic potential on the aromatic rings and highly negative values of
      electrostatic potential on the chlorine atoms. Additionally, we have found that
      the toxic congeners possess conformations with low dipole moments, a fact that
      may be linked to the ready accumulation on the adipose tissue. The results on the
      geometry and electrostatic properties of chlorinated biphenyls can be useful to
      rationalize their selective toxicities.

PMID- 12482234
TI  - Specificity of ethephon as a butyrylcholinesterase inhibitor and phosphorylating
      agent.
AB  - Butyrylcholinesterase (BChE) is inhibited by the plant growth regulator (2
      chloroethyl)phosphonic acid (ethephon) as observed 25 years ago both in vitro and
      in vivo in rats and mice and more recently in subchronic studies at low doses
      with human subjects. The proposed mechanism is phosphorylation of the BChE active
      site at S198 by ethephon dianion. The present study tests this hypothesis
      directly using [(33)P]ethephon and recombinant BChE (rBChE) with single amino
      acid substitutions and further evaluates if BChE is the most sensitive esterase
      target in vitro and with mice in vivo. [(33)P]Ethephon labels purified rBChE but
      not enzymatically inactive diethylphosphoryl-rBChE (derivatized at S198 by
      preincubation with chlorpyrifos oxon) or several other esterases and proteins.
      Amino acid substitutions that greatly reduce rBChE sensitivity to ethephon are
      G117H and G117K in the oxyanion hole (which may interfere with hydrogen bonding
      between glycine-N-H and ethephon dianion) and A328F, A328W, and A328Y (perhaps by
      impeding access to the active site gorge). Other substitutions that do not affect
      sensitivity are D70N, D70K, D70G, and E197Q which are not directly involved in
      the catalytic triad. The effect of pH and buffer composition on inhibition
      supports the hypothesis that ethephon dianion is the actual phosphorylating agent
      without activation by divalent cations. Human plasma BChE in vitro and mouse
      plasma BChE in vitro and in vivo are more sensitive to ethephon than any other
      esterases detected by butyrylthiocholine or 1-naphthyl acetate hydrolysis in
      native-PAGE. All mouse liver esterases observed are less sensitive than plasma
      BChE to ethephon in vitro and in vivo. More than a dozen other esterases examined
      are 10-100-fold less sensitive than BChE to ethephon. Thus, BChE inhibition
      continues to be the most sensitive marker of ethephon exposure.

PMID- 12482235
TI  - Extract of motorcycle exhaust particles induced macrophages apoptosis by calcium
      dependent manner.
AB  - Large survey and experiments have reported that environment pollutants from
      fossil fuel combustion would cause immune system deleterious by enhancement of
      allergic reaction and damage to respiratory tract. In this study, we reported
      that the extract of motorcycle exhaust particles (MEP) might affect the immune
      system by inducing cell apoptosis on macrophages. The motorcycle exhaust
      particles were collected from a two-stoke engine and their cytotoxic effect on
      macrophages was investigated. We found MEP is cytotoxic and induced apoptosis in
      RAW 264.7 cells, murine peritoneal macrophage, and rat alveolar macrophage.
      Pretreatment with mitochondria permeability transition inhibitor (cyclosporin A),
      intracellular (BAPTA-AM) and extracellular (EGTA) Ca(2+) chelator, and
      antioxidants (NAC, GSH, catalase, SOD) attenuated the MEP-induced cell apoptosis,
      and BAPTA-AM was the most effective one. Utilized Fura-2/AM loaded RAW 264.7
      cells to directly detect the change of intracellular Ca(2+) concentration
      ([Ca(2+)](i)), we found that MEP could induce a sustained increase of
      [Ca(2+)](i). The raise of [Ca(2+)](i) induced by MEP could be completely blocked
      by the intracellular Ca(2+) chelator, BAPTA-AM, however, only partially inhibited
      by the extracellular Ca(2+) chelator, EGTA. These results suggested that both
      influx of extracellular Ca(2+) and release of Ca(2+) from the internal storage
      were involved. We also found that MEP caused a decrease of mitochondria membrane
      potential and an increase of oxidative stress in RAW 264.7 cells. In conclusion,
      we found that the particles, collected from the motorcycle exhaust, contain
      chemicals that will induce apoptosis of macrophage in calcium-dependent manner.

PMID- 12482236
TI  - Studies on hydrolytic and oxidative metabolic pathways of anhydroecgonine methyl
      ester (methylecgonidine) using microsomal preparations from rat organs.
AB  - During smoking of cocaine-base (crack), anhydroecgonine methyl ester (AEME,
      methylecgonidine) is formed in large amounts as a pyrolysis product of cocaine
      and is absorbed in the lungs. The metabolism of AEME was studied in the present
      investigation using microsome preparations from rat liver, lung, kidney, and
      brain. Potential metabolites of AEME were synthesized and used as substrate to
      complement the experiments. Analysis of the incubation mixtures was performed
      using gas chromatography-mass spectrometry and nanoelectrospray multiple-stage
      mass spectrometry. Screening for metabolites was focused on postulated oxidative
      pathways, chemical and enzymatic hydrolysis, and ethanol dependent
      transesterification as known from cocaine metabolism. Enzymatic hydrolysis of
      AEME to anhydroecgonine (AE), which was inhibited by sodium fluoride, was found
      in all microsomal preparations. Liver microsomes exhibited the highest activity,
      brain microsomes the lowest. Anhydronorecgonine methyl ester (ANEME) and
      anhydroecgonine methyl ester N-oxide were identified as AEME metabolites of liver
      and lung microsomes only. In the presence of ethanol AEME was metabolized to
      anhydroecgonine ethyl ester and anhydronorecgonine ethyl ester. Further
      metabolism of AE or ANEME was not observed. No N-hydroxy-anhydronorecgonine
      derivatives were found which could represent precursors of cytotoxic metabolites
      as known to be formed from cocaine.

PMID- 12482237
TI  - Identification of adducts derived from reactions of (1-chloroethenyl)oxirane with
      nucleosides and calf thymus DNA.
AB  - (1-Chloroethenyl)oxirane is a major mutagenic metabolite of chloroprene, an
      important large-scale petrochemical used in the manufacture of synthetic rubbers.
      The reactions of (1-chloroethenyl)oxirane with 2'-deoxyguanosine, 2'
      deoxyadenosine, 2'-deoxycytidine, thymidine, and calf thymus DNA have been
      studied in aqueous buffered solutions. The adducts from the nucleosides were
      isolated by reversed-phase HPLC, and characterized by their UV absorbance and
      (1)H and (13)C NMR spectroscopic and mass spectrometric features. The reaction
      with 2'-deoxyguanosine gave one major adduct, N7-(3-chloro-2-hydroxy-3-buten-1
      yl)-guanine (dGI), and eight minor adducts which were identified as
      diastereoisomeric pairs of N1-(3-chloro-2-hydroxy-3-buten-1-yl)-2'-deoxyguanosine
      (dGII, dGIII), N3,N7-bis(3-chloro-2-hydroxy-3-buten-1-yl)-guanine (dGIV, dGV),
      N7,N9-bis(3-chloro-2-hydroxy-3-buten-1-yl)-guanine (dGVI, dGVII), and N1,N7-bis(3
      chloro-2-hydroxy-3-buten-1-yl)-guanine (dGVIII, dGIX). The reaction of 2'
      deoxyadenosine with (1-chloroethenyl)oxirane gave two adducts: N1-(3-chloro-2
      hydroxy-3-buten-1-yl)-2'-deoxyadenosine (dAI) and N(6)-(3-chloro-2-hydroxy-3
      buten-1-yl)-2'-deoxyadenosine (dAII). The adduct dAII was shown to arise via a
      Dimroth rearrangement of adduct dAI. The HPLC analyses of the reaction mixtures
      of (1-chloroethenyl)oxirane with 2'-deoxycytidine and thymidine showed the
      formation of one major product in each reaction. The adduct from 2'-deoxycytidine
      was identified as N3-(3-chloro-2-hydroxy-3-buten-1-yl)-2'-deoxyuridine (dCI)
      derived by alkylation at N-3 followed by deamination. The adduct from thymidine
      was identified as N3-(3-chloro-2-hydroxy-3-buten-1-yl)-thymidine (TI). Reaction
      of (1-chloroethenyl)oxirane with calf thymus DNA gave all of the adducts observed
      from the individual nucleosides except dGII and dGIII. However, there was
      selectivity for the formation of dGI and dCI. The adduct levels in DNA were 9,630
      (dGI), 240 (dCI), 83 (dAI), 6 (dAII), and 28 (TI) pmol/mg DNA, respectively. The
      preferred formation of dCI may be relevant to chloroprene mutagenesis.

PMID- 12482238
TI  - Mechanism-based inactivation of cytochromes P450 2E1 and 2E1 T303A by tert-butyl
      acetylenes: characterization of reactive intermediate adducts to the heme and
      apoprotein.
AB  - The kinetics for the inactivation of cytochrome P450 2E1 and the mutant P450 2E1
      T303A by tert-butyl acetylene (tBA) and tert-butyl 1-methyl-2-propynyl ether
      (tBMP) were investigated. The two acetylenes inactivated the 7-ethoxy-4
      (trifluoromethyl)coumarin (7-EFC) O-deethylation activity of purified rabbit
      P450s 2E1 and 2E1 T303A in a reconstituted system in a time-, concentration-, and
      NADPH-dependent manner. The K(I) values for the inactivation of P450s 2E1 and 2E1
      T303A by tBA were 1.0 and 2.0 mM, the k(inact) values were 0.20 and 0.38 min(
      )(1), and the t(1/2) values were 3.5 and 1.8 min, respectively. The K(I) values
      for the tBMP-inactivated P450s were 0.1 and 1.0 mM, the k(inact) values were 0.12
      and 0.07 min(-)(1), and the t(1/)(2) values were 5.9 and 10.2 min, respectively.
      Losses in enzyme activity occurred with concurrent losses in the P450 CO spectrum
      and P450 heme, which were accompanied by the appearance of two different tBA- or
      tBMP-modified heme products in each inactivated sample. LC-MS analysis of the
      adducts showed masses of 661 or 705 Da, consistent with the mass of an iron
      depleted heme plus the masses of a tBA or tBMP reactive intermediate and one
      oxygen atom, respectively. Only the tBA-inactivated P450 2E1 revealed a tBA
      adducted apoprotein with an increase in mass of 99 Da, corresponding to the mass
      of tBA plus one oxygen atom. Surprisingly, the inactivation, CO spectral and heme
      loss, and heme adduct formation of the tBA-inactivated T303A mutant were
      completely reversible after dialysis. In addition, metabolism of para-nitrophenol
      was not compromised by the tBA-inactivated T303A mutant. Therefore, our studies
      on the inactivation of P450s 2E1 and 2E1 T303A by tBA and tBMP suggest the
      existence of three distinct mechanisms for inactivation, among which includes a
      novel, reversible heme alkylation that has not been previously described with
      P450 enzymes.

PMID- 12482239
TI  - Mutagenic spectrum of butadiene-derived N1-deoxyinosine adducts and N6,N6
      deoxyadenosine intrastrand cross-links in mammalian cells.
AB  - Reactive metabolites of 1,3-butadiene, including 1,2-epoxy-3-butene (BDO),
      1,2:3,4-diepoxybutane (BDO(2)), and 3,4-epoxy-1,2-butanediol (BDE), form both
      stable and unstable base adducts in DNA and have been implicated in producing
      genotoxic effects in rodents and human cells. N1 deoxyadenosine adducts are
      unstable and can undergo either hydrolytic deamination to yield N1 deoxyinosine
      adducts or Dimroth rearrangement to yield N(6) adducts. The dominant point
      mutation observed at AT sites in both in vivo and in vitro mutagenesis studies
      using BD and its epoxides has been A --> T transversions followed by A --> G
      transitions. To understand which of the butadiene adducts are responsible for
      mutations at AT sites, the present study focuses on the N1 deoxyinosine adduct at
      C2 of BDO and N(6),N(6)-deoxyadenosine intrastrand cross-links derived from
      BDO(2). These lesions were incorporated site-specifically and stereospecifically
      into oligodeoxynucleotides which were engineered into mammalian shuttle vectors
      for replication bypass and mutational analyses in COS-7 cells. Replication of
      DNAs containing the R,R-BDO(2) intrastrand cross-link between N(6) positions of
      deoxyadenosine yielded a high frequency (59%) of single base substitutions at the
      3' adducted base, while 19% mutagenesis was detected using the S,S-diastereomer.
      Comparable studies using the R- and S-diastereomers of the N1 deoxyinosine adduct
      gave rise to approximately 50 and 80% A --> G transitions with overall mutagenic
      frequencies of 59 and 90%, respectively. Collectively, these data establish a
      molecular basis for A --> G transitions that are observed following in vivo and
      in vitro exposures to BD and its epoxides, but fail to reveal the source of the A
      --> T transversions that are the dominant point mutation.

PMID- 12482240
TI  - Detection and characterization of a glutathione conjugate of ochratoxin A.
AB  - The ability of the carcinogenic mycotoxin ochratoxin A (OTA) to react with
      reduced glutathione (GSH) has been assessed using electrospray ionization (ES)-MS
      techniques. On the basis of the assumption that OTA undergoes biotransformation
      into the reactive quinone species OTQ (6), a synthetic sample of the reduced form
      of OTQ (6), hydroquinone OTHQ (5), was prepared and photoreacted with 6 M equiv
      of GSH to yield an authentic sample of the conjugate 8 that was definitively
      identified by mass spectrometry, UV-vis spectroscopy and NMR. With the authentic
      sample of 8 in hand, it was demonstrated that the same conjugate is produced from
      reaction of 100 microM OTA (1) in the presence of 5 mM GSH following incubation
      for 1 h with either horseradish peroxidase (HRP)/H(2)O(2), rat liver microsomes
      (RLM)/NADPH or free Fe(II). In each of these oxidative systems the conjugate 8
      was generated in less than 1% yield and the parent OTA molecule is poorly
      metabolized. Comparison of the peak area ratio of the conjugate 8 to that for the
      hydroxyOTA metabolite from the RLM/NADPH system implied that the conjugate was
      produced at a rate of approximately 1-3 pmol min(-)(1) (mg of protein)(-)(1).
      These studies are the first to demonstrate that OTA undergoes biotransformation
      to a reactive intermediate [OTQ (6)] that covalently reacts with GSH to yield the
      conjugate 8. The biological implications of the reactivity of OTA toward GSH are
      discussed.

PMID- 12482241
TI  - Determining the site of spin trapping of the equine myoglobin radical by combined
      use of EPR, electrophoretic purification, and mass spectrometry.
AB  - Although myoglobin protein radicals are thought important intermediates in
      peroxide-induced toxicity, the site of spin trapping of this radical in equine
      myoglobin using the trap 3,5-dibromo-4-nitrosobenzene sulfonate (DBNBS) is
      unclear. We have combined EPR, electrophoretic adduct purification, and mass
      spectrometry approaches to unambiguously determine the site of trapping to be Tyr
      103 and suggest that reports of trapping at Trp-7 or Trp-14 may be due to
      nonradical addition to proteolytically derived Trp-containing peptides with
      DBNBS. The technique developed here of combining electrophoretic separation of
      DBNBS adducts with MS of resultant peptides will also allow proteomic-like
      approaches to determining identities and sites of radical formation and
      translocation on complex mixtures of proteins.

PMID- 12482242
TI  - Influence of local duplex stability and N6-methyladenine on uracil recognition by
      mismatch-specific uracil-DNA glycosylase (Mug).
AB  - To maintain genomic integrity, DNA repair enzymes continually remove damaged
      bases and lesions resulting from endogenous and exogenous processes. These repair
      enzymes must distinguish damaged bases from normal bases to prevent the
      inadvertent removal of normal bases, which would promote genomic instability. The
      mechanisms by which this high level of specificity is accomplished are as yet
      unresolved. One member of the uracil-DNA glycosylase family of repair enzymes,
      Escherichia coli mismatch-specific uracil-DNA glycosylase (Mug), is reported to
      distinguish U:G mispairs from U:A base pairs based upon specific contacts with
      the mispaired guanine after flipping the target uracil out of the duplex.
      However, recent studies suggest other mechanisms for base selection, including
      local duplex stability. In this study, we used the modified base N6-methyladenine
      to probe the effect of local helix perturbation on Mug recognition of uracil. N6
      Methyladenine is found in E. coli as part of both the mismatch repair and
      restriction-modification systems. In its cis isomer, N6-methyladenine
      destabilizes hydrogen bonding by interfering with pseudo-Watson-Crick base
      pairing. It is observed that the selection of uracil by Mug is sequence dependent
      and that uracil residues in sequences of reduced thermostability are
      preferentially removed. The replacement of adenine by N6-methyladenine increases
      the frequency of removal of the uracil residue paired opposite the modified
      adenine. These results are in accord with suggestions that local helix stability
      is an important determinant of base recognition by some DNA repair enzymes and
      provide a potential strategy for identifying the sequence location of modified
      bases in DNA.

PMID- 12482243
TI  - Structure-toxicity relationships for aliphatic chemicals evaluated with
      Tetrahymena pyriformis.
AB  - Quantitative structure-activity relationships were developed for the toxicity
      data of 500 aliphatic chemicals tested in the two-day Tetrahymena pyriformis
      population growth impairment assay. These chemicals represented a number of
      structural classes spanning a variety of mechanisms of toxic action including
      narcoses and electrophilic mechanisms. A series of quantitative structure
      toxicity models correlating toxic potency [log(IGC(50)(-1))] with a limited
      number of mechanistically interpretable descriptors were developed for
      toxicological domains within the data set. The descriptors included the 1
      octanol/water partition coefficient (log K(ow)) (for hydrophobicity) and the
      energy of the lowest unoccupied molecular orbital (E(lumo)) to quantify
      electrophilic reactivity. Neutral (nonpolar) narcosis was well modeled by the
      equation [log(IGC(50)(-1)) = 0.723(0.140) (log K(ow)) - 1.79(0.031); n = 215,
      r(2) (adj.) = 0.926, s = 0.274, r(2) (pred.) = 0.925]. Chemical classes fitting
      this domain included saturated alcohols, ketones, nitriles, esters, and sulfur
      containing compounds. When the neutral narcotic chemicals were combined with
      diester narcotics, carboxylic sodium salts, Schiff-based forming aldehydes,
      electrophilic compounds capable of acting by a S(N)2 mechanism, and
      proelectrophiles, the model [log(IGC(50)(-1)) = 0.45(0.014) (log K(ow)) - 0.342
      (0.035) (E(lumo)) - 1.11(0.05); n = 353, r(2) (adj.) = 0.859, s = 0.353, r(2)
      (pred.) = 0.857] provided a good fit to the data. The model [log(IGC(50)(-1)) =
      0.273(0.018) (log K(ow)) - 0.116(0.056) (E(lumo)) - 0.558(0.054); n = 35, r(2)
      (adj.) = 0.873, s = 0.141, r(2) (pred.) = 0.838] provided an excellent fit of the
      data for compounds containing a carboxyl [RC(=O)O] group. The toxicity of
      aliphatic amines [RCN] was modeled by the equation [log(IGC(50)(-1)) =
      0.676(0.048) (log K(ow)) - 1.23(0.08) n = 30, r(2) (adj.) = 0.873, s = 0. 336,
      r(2) (pred.) = 0.848]. The potency of saturated aliphatic isothiocyanates was a
      constant (0.0202 mM). Aliphatic chemicals that did not model well by equations
      involving log K(ow) and E(lumo) included amino alcohols and alpha-haloactivated
      compounds.

PMID- 12482244
TI  - Comparative study on the bioactivation mechanisms and cytotoxicity of Te-phenyl-L
      tellurocysteine, Se-phenyl-L-selenocysteine, and S-phenyl-L-cysteine.
AB  - Tellurium compounds are effective antioxidants and chemoprotectors, even more
      active than their selenium and sulfur analogues. In addition to these properties,
      some selenium compounds, such as selenocysteine Se-conjugates, possess
      significant chemopreventive and antitumor activities, and selenol metabolites are
      considered as active species. In the present study, we have synthesized Te-phenyl
      L-tellurocysteine and evaluated its bioactivation and cytotoxicity. The
      activities of this compound were compared with those of the corresponding
      selenium and sulfur analogues. Te-Phenyl-L-tellurocysteine is bioactivated into
      its corresponding tellurol, as detected by GC-MS, by cysteine conjugate beta
      lyase and amino acid oxidase, analogously to what has been shown previously for
      Se-phenyl-L-selenocysteine. The rate of beta-elimination may reflect the bond
      strength of the corresponding C-S, C-Se, and C-Te bond. Bioactivation of Te
      phenyl-L-tellurocysteine and its selenium and sulfur analogues by oxidative
      enzymes was evaluated by measuring NADPH-dependent activation of hepatic mGST and
      inhibition of EROD. Te-Phenyl-L-tellurocysteine and Se-phenyl-L-selenocysteine
      displayed strong and time-dependent mGST activation, while S-phenyl-L-cysteine
      resulted in no significant activation. Te-Phenyl-L-tellurocysteine was also a
      strong inhibitor of EROD activity. In addition to EROD inhibition, Te-phenyl-L
      tellurocysteine was the strongest inhibitor of several human cytochrome P450
      isoenzymes followed by Se-phenyl-L-selenocysteine, while S-phenyl-L-cysteine was
      the weakest inhibitor. Interestingly, Te-phenyl-L-tellurocysteine selectively
      inhibited cytochrome P450 1A1 directly, which is, for example, responsible for
      the activation of several procarcinogens. Preliminary cytotoxicity studies with
      Te-phenyl-L-tellurocysteine in freshly isolated rat hepatocytes showed a time
      dependent depletion of GSH and LDH leakage comparable with the relatively
      nontoxic drug paracetamol, while the selenium and sulfur analogues were nontoxic
      toward rat hepatocytes. In conclusion, because the chemopreventive and antitumor
      activities of selenium compounds are thought to be mediated via their selenol
      metabolites and tellurium compounds might be even more active than selenium
      compounds, tellurocysteine Te-conjugates might be an interesting novel class of
      prodrugs for the formation of biologically active tellurols.

PMID- 12482245
TI  - Site-specific mutagenesis in Escherichia coli by N2-deoxyguanosine adducts
      derived from the highly carcinogenic fjord-region benzo[c]phenanthrene 3,4-diol
      1,2-epoxides.
AB  - Although there have been numerous studies of site-specific mutagenesis by dGuo
      adducts of benzo[a]pyrene diol epoxides (B[a]P DEs), the present study represents
      the first example of site-specific mutagenesis by dGuo adducts of the highly
      carcinogenic benzo[c]phenanthrene 3,4-diol 1,2-epoxides (B[c]Ph DEs). The eight
      adducts that would result from cis- and trans-opening at C-1 of four optically
      active isomers of B[c]Ph DEs by the N(2)-amino group of dGuo were incorporated
      into 5'-TTCGAATCCTTCCCCC (context III) and 5'-GGGGTTCCCGAGCGGC (context IV) at
      the underlined site. These modified oligonucleotides along with unmodified
      controls were ligated into single-stranded M13mp7L2, which were then used to
      transfect SOS-induced Escherichia coli. Upon replication of the lesions in each
      of the two sequence contexts, mutational analysis of the progeny was performed by
      differential hybridization. For the 16 adducts, the mutation frequencies varied
      over 2 orders of magnitude with a reasonably even distribution (0.4-1% for three
      adducts, 1-2% for six adducts, 3-7.4% for five adducts, and one adduct each at 11
      and 39%). For all but this last adduct, the mutation frequency for a given B[c]Ph
      DE adduct was less than for its B[a]P analogue with the same stereochemistry in
      the same sequence. For the vectors containing adducts with S configuration at the
      site of attachment of the hydrocarbon to the dGuo base, the main base
      substitution was G --> T followed by G --> A. In contrast, for the vectors
      containing adducts with R configuration, the main base substitution was G --> A.
      The most notable observation in the present study is the low frequency of
      mutations induced by the B[c]Ph DE-dGuo adducts relative to their B[a]P
      counterparts. A possible structural basis for this difference is proposed.

PMID- 12482246
TI  - DNA damage induced by methylated trivalent arsenicals is mediated by reactive
      oxygen species.
AB  - Arsenic is a human carcinogen; however, the mechanisms of arsenic's induction of
      carcinogenic effects have not been identified clearly. We have shown previously
      that monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) are
      genotoxic and can damage supercoiled phiX174 DNA and the DNA in peripheral human
      lymphocytes in culture. These trivalent arsenicals are biomethylated forms of
      inorganic arsenic and have been detected in the urine of subjects exposed to
      arsenite and arsenate. We show here by molecular, chemical, and physical methods
      that reactive oxygen species (ROS) are intermediates in the DNA-damaging
      activities of MMA(III) and DMA(III). Using the phiX174 DNA nicking assay we found
      that the ROS inhibitors Tiron, melatonin, and the vitamin E analogue Trolox
      inhibited the DNA-nicking activities of both MMA(III) and DMA(III) at low
      micromolar concentrations. The spin trap agent 5,5-dimethyl-1-pyrroline-N-oxide
      (DMPO) also was effective at preventing the DNA nicking induced by MMA(III) and
      DMA(III). ESR spectroscopy studies using DMPO identified a radical as a ROS
      intermediate in the DNA incubations with DMA(III). This radical adduct was
      assigned to the DMPO-hydroxyl free radical adduct on the basis of comparison of
      the observed hyperfine splitting constants and line widths with those reported in
      the literature. The formation of the DMPO-hydroxyl free radical adduct was
      dependent on time and the presence of DMA(III) and was completely inhibited by
      Tiron and Trolox and partially inhibited by DMSO. Using electrospray mass
      spectrometry, micromolar concentrations of DMA(V) were detected in the DNA
      incubation mixtures with DMA(III). These data are consistent with the conclusions
      that the DNA-damaging activity of DMA(III) is an indirect genotoxic effect
      mediated by ROS-formed concomitantly with the oxidation of DMA(III) to DMA(V).

PMID- 12482247
TI  - Mitogen-activated protein kinases contribute to reactive oxygen species-induced
      cell death in renal proximal tubule epithelial cells.
AB  - Extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases
      (JNK/SAPK), and p38 mitogen-activated protein kinase (MAPK) were all rapidly
      activated in a ROS-dependent manner during 2,3,5-tris-(glutathion-S
      yl)hydroquinone (TGHQ)-mediated oxidative stress and oncotic cell death in renal
      proximal tubule epithelial cells (LLC-PK1). TGHQ-induced phosphorylation of
      ERK1/2 and JNK MAPKs required epidermal growth factor receptor (EGFR) activation,
      whereas p38 MAPK activation was EGFR independent. In contrast to their
      established roles in cell survival, TGHQ-activated ERK1/2 and p38 MAPK (but not
      JNK) appear to contribute to cell death, since inhibition of ERK1/2 or p38 MAPKs
      with PD098059 or SB202190 respectively, attenuated TGHQ-mediated cell death. TGHQ
      increased AP-1 and NFkappaB DNA-binding activity, but whereas pharmacological
      inhibition of ERK1/2 or p38 MAPKs attenuated AP-1 DNA binding activity, it
      potentiated TGHQ-mediated NFkappaB activation. Consistent with a role for
      NFkappaB activation in the cytoprotective response to ROS in renal epithelial
      cells, an anti-NFkappaB peptide SN50 suppressed the protective effects of ERK
      inhibition (PD098059 treatment). The data provide evidence that the activation of
      MAPKs by ROS in renal epithelial cells plays an important role in oncotic cell
      death, and NF-kB is involved in the cytoprotective effects of PD098059.

PMID- 12482248
TI  - Characterization of the dehydro-guanidinohydantoin oxidation product of guanine
      in a dinucleotide.
AB  - The study of the biological consequences of oxidative damage to DNA requires the
      characterization of DNA lesions at a molecular level. The oxidation of guanine in
      the dinucleoside monophosphate, d(GpT), by a metal-oxo porphyrin produces a
      dehydro-guanidinohydantoin derivative. The (1)H NMR spectrum of this oxidized
      guanine derivative is reported. The structure was confirmed by the chemical
      transformation of the dehydro-guanidinohydantoin derivative into a linear
      oxaluric acid derivative upon hydrolysis at ambient temperature. The proposed
      mechanism of formation of the dehydro-guanidinohydantoin derivative is in
      agreement with the labeling experiments performed with H(2)(18)O.

PMID- 12482250
TI  - Trans Tasman links and beyond.

PMID- 12482251
TI  - Refractive index of the crystalline lens in young and aged eyes.
AB  - BACKGROUND: When the ageing crystalline lens is modelled on the basis of a
      constant equivalent lens, the changes in ocular dimensions would lead to an
      increase in power of the order of two dioptres. A comparable increase in myopia
      is usually not evident with increasing age and this inconsistency has been
      referred to as the lens paradox. It has been proposed that this paradox can be
      resolved if the refractive index is modelled as a gradient refractive index. The
      purpose of this paper was to study differences in the equivalent, gradient and
      surface refractive index of the crystalline lens between a young and old age
      group. METHODS: Biometric data was collected for 96 subjects: 48 young adults
      with an age range 19 to 31 years (mean 22.10 +/- 2.93 years) and 48 old adults
      with an age range 49 to 61 years (mean 53.88 +/- 3.88 years). The equivalent
      refractive index was determined for each subject by paraxial ray tracing and a
      merit function based on refractive error and Purkinje image height. The
      refractive index gradient was determined by modelling the crystalline lens as a
      bi-elliptical iso-indicial structure in a three-surface Gullstrand-Emsley
      schematic eye and a merit function based on the surface power, the gradient
      refractive index power and the equivalent power of the lens. The central
      refractive index of the lens was assumed to be 1.406. RESULTS: The differences
      between the groups included a decrease in the mean equivalent refractive index
      from 1.427 +/- 0.007 to 1.418 +/- 0.006, an increase in surface refractive index
      from 1.386 +/- 0.007 to 1.394 +/- 0.006 with a concurrent change in the gradient
      refractive index profile. The refractive index changes maintained a constant mean
      lens power in each group. CONCLUSIONS: The so-called 'lens paradox' whereby an
      increase in the power of the crystalline lens does not lead to an increase in
      myopia is resolved by a decrease in the equivalent refractive index of the lens
      or when modelled as a gradient refractive index structure, by an increase in the
      surface refractive index and an associated change in gradient for an assumed
      central refractive index of 1.406.

PMID- 12482252
TI  - Field restriction and vignetting in contact lenses with opaque peripheries.
AB  - BACKGROUND: Some previous researchers have shown empirically that visual fields
      can be restricted by contact lenses with opaque and semi-opaque peripheral zones.
      However, there has been no formal statement of the optical theory behind such
      restriction. METHODS: Calculations are made of fields of view with opaque
      periphery contact lenses, based on paraxial theory and meridional finite ray
      tracing in the Gullstrand-Emsley schematic eye. RESULTS: This analysis shows that
      paraxial theory is adequate for predicting 'half fields of full illumination' for
      ocular pupil diameters smaller than six millimetres, although paraxial estimates
      of 'half total field' can substantially underestimate those obtained by finite
      ray tracing for a wide range of ocular pupil sizes. Therefore finite ray tracing
      may be a more appropriate method of calculating half total field. 'Total field'
      will be smaller with smaller ocular pupils and smaller contact lens apertures. A
      clinical method is suggested for assessing total field with such contact lenses
      in situ. The analysis applied to opaque periphery contact lenses is extended to
      the semi-opaque periphery contact lenses used for cosmetic alteration of eye
      appearance. CONCLUSION: Semi-opaque periphery contact lenses will decrease
      retinal illuminance most at regions outside those tested by previous empirical
      static perimetry studies.

PMID- 12482253
TI  - Age dependence of ocular biometric measurements under cycloplegia with
      tropicamide and cyclopentolate.
AB  - BACKGROUND: Cyclopentolate continues to be the cycloplegic of choice for
      refracting young children, although many studies of ocular biometry promote the
      use of tropicamide. METHODS: To clarify the role of drug type in biometric
      measurements, cycloplegia was induced in two disparate age groups using
      cyclopentolate and tropicamide on two separate occasions. Refraction, phakometry
      and A-scan ultrasonography measurements were made on two groups of Tibetan
      children resident in Nepal. RESULTS: Cyclopentolate produced significantly more
      cycloplegia in the younger group, which was supported by phakometry measurements.
      However, in clinical terms, the difference between the measurements was not
      significant. CONCLUSION: We conclude that although cyclopentolate is more
      effective than tropicamide in relaxing accommodation in young children, the use
      of a local anaesthetic prior to instillation of tropicamide produces refractive
      data virtually equivalent to that of cyclopentolate, regardless of the age group
      measured. However, biometric measurements may be susceptible to greater error
      when near fixation targets are used during phakometry procedures.

PMID- 12482254
TI  - Visual performance requirements for post-PRK police recruits.
AB  - BACKGROUND: New Zealand Police regulations (1996) allow the unaided visual acuity
      requirement of 6/12 to be achieved following refractive surgery (except radial
      keratotomy or keratoplasty) provided applicants also achieve normal (95 per cent
      confidence limit data from the literature): glare disability, contrast
      sensitivity, and low luminance visual acuity, one year or more after treatment.
      METHODS: To confirm the limits adopted, 80 young normal adults were subjected to
      the tests in the regulations. To examine the operation of the current standards,
      the results of 34 post-photorefractive keratectomy (post-PRK) police applicants
      are reported. Glare disability was the loss of high contrast visual acuity (VA)
      with the Mentor Brightness Acuity Tester at medium intensity. Contrast
      sensitivity (CS) was examined using both Melbourne Edge Test thresholds and the
      VA difference between high and low contrast Bailey-Lovie charts. Low luminance VA
      was measured using high contrast Bailey-Lovie charts viewed through a one per
      cent transmittance filter. RESULTS: The 95 per cent confidence limits found for
      normal performance were as follows. Glare disability: no more than 10 letters
      worse than VA without glare. Contrast sensitivity: no more than 12 letters
      difference between high contrast and low contrast letter acuity together with an
      edge contrast threshold of not less than 20 dB (CS = 100). These results were
      close to the values adopted for the current standard. The 95 per cent confidence
      limit for low luminance VA was a loss of 24 letters (almost five lines) and not
      the three lines of loss estimated from the literature. Two of the 34 post-PRK
      applicants failed. One was unable to achieve 6/6 acuity with best refraction. The
      second could not meet the low luminance VA limit (loss no more than three lines).
      No failures have been due to glare disability or poor contrast sensitivity even
      though one applicant had obvious corneal haze.

PMID- 12482255
TI  - Visibility of protective helmets worn by forestry workers.
AB  - BACKGROUND: High visibility helmets must be worn by forestry workers in New
      Zealand for protection and as conspicuous 'clothing' to alert workers to the
      presence and location of other workers. The colours yellow-green (fluorescent
      yellow-green) and 'watermelon' (fluorescent pink) are used and both appear to be
      conspicuous. To solve a controversy, we investigated which helmet colour is more
      visible for use in a forest setting for workers having normal or defective colour
      vision. METHOD: We obtained threshold angular sizes for two-millimetre square
      samples of helmet material presented against a textured background containing
      colours representative of those found in the foliage and bark of the most common
      forest type (Pinus Radiata). Observers with normal colour vision (n = 22) and
      with deutan (n = 8) and protan (n = 6) defects participated. Subjects with mild
      colour vision defects were excluded. RESULTS: The yellow-green colour was
      significantly more visible than the pink for the normal (p +/- 0.001) and protan
      (p +/- 0.05) observers. For the deutan observers the pink helmet colour was
      significantly more visible (p +/- 0.01). The median equivalent outdoor detection
      distances were for normal observers 400 m (pink) and 500 m (yellow-green); for
      protan observers 185 m (pink) and 500 m (yellow-green); and for deutan observers
      550 m (pink) and 450 m (yellow-green). CONCLUSIONS: The yellow-green helmet can
      be detected at large distances by all observers. The yellow-green helmet has
      greater reflectance and therefore greater luminance contrast. The pink helmet
      colour can be confused with green forest background colours by observers with
      protan defects. For some observers with a protan colour vision defect, detection
      distances for the pink helmet colour are less than half of normal detection
      distances.

PMID- 12482256
TI  - A strong nexus between teaching and research.

PMID- 12482257
TI  - Christmas tree cataract.

PMID- 12482258
TI  - The effect of monovision contact lens wear on driving performance.
AB  - BACKGROUND: A number of studies have highlighted the problems with driving
      reported by wearers of monovision contact lens corrections. In this study, we
      wished to investigate this further, by determining whether driving performance as
      measured on the open road under daytime conditions is worse when drivers wear
      their monovision contact lenses compared to their habitual correction. METHODS:
      Thirteen subjects with healthy eyes and corrected visual acuity of 6/6 were
      selected. Each had worn monovision contact lenses for at least three months. All
      subjects had their driving performance assessed while driving their own vehicles
      on an open road course, with both monovision contact lenses and their other
      habitual correction (spectacles or unaided). RESULTS: No statistically
      significant differences were found in driving performance when subjects wore
      their monovision contact lenses compared to when they wore their habitual
      distance correction. CONCLUSIONS: The results indicate that monovision does not
      adversely affect driving performance in daylight hours for adapted wearers.
      However, limitations in the study design are acknowledged, including the
      relatively small sample size, lack of standardisation of the habitual correction
      and the use of adapted wearers. Future studies are recommended to investigate
      these issues further.

PMID- 12482259
TI  - The accreditation of university teachers: an optometric viewpoint.
AB  - The issue of whether university teachers should be required to gain a formal
      teaching qualification is currently under debate. In the United Kingdom, the
      development of an accreditation system for university teachers is well advanced.
      In the future, Australian university teachers may be required to either: 1. prove
      their teaching competency 2. undertake teaching courses as part of their
      induction program. Of the current full-time academic staff of the optometry
      schools in Australia and New Zealand, about 15 per cent have undertaken
      university courses on higher education teaching: two of 10, one of 12, one of six
      and one of six for the optometry schools at the Queensland University of
      Technology, The University of New South Wales, The University of Melbourne and
      The University of Auckland, respectively. In terms of undergraduate optometry
      students' views, of those who responded (43 per cent of QUT third and fourth year
      students) to a survey on a range of teaching and learning issues, 20 out of 26
      thought that a teaching qualification should be a requirement, while only six
      thought that it was not necessary. It has been suggested that an accredited
      training system is one way of ensuring that university teachers have the skills
      to deal with a dynamic teaching environment and the challenges of the future. The
      quality of teaching in universities has particular relevance to the optometric
      profession both in terms of undergraduate students and postgraduate experiences.

PMID- 12482260
TI  - Clinical evaluation of patient tolerance to autorefractor prescriptions.
AB  - BACKGROUND: In clinical optometric practice, autorefractors are used as an
      objective measure of refractive error prior to subjective refraction. We evaluate
      the clinical efficacy of autorefractor measurements by determining whether
      spectacles can be prescribed from autorefractor results. METHODS: Forty-seven
      subjects were randomly allocated spectacles using prescriptions determined either
      by an optometrist or from an autorefractor in a double-blind protocol. Subjects
      wore each prescription for two weeks and completed an oral questionnaire
      following each period of wear. The questionnaire assessed both pairs of spectacle
      lenses in terms of visual performance and ocular comfort. RESULTS: The level of
      negative responses to all questions was higher for spectacles based on the
      autorefractor findings than for those based on the optometrist's prescriptions.
      Having reported initial discomfort, many subjects indicated that they had adapted
      to the spectacle lenses over a two-week period. CONCLUSIONS: Our results suggest
      that, in a clinical environment, subjective refraction produces a more accurate
      and acceptable spectacle prescription than an autorefractor.

PMID- 12482261
TI  - Effect of an intervening screen on accommodation to a distant object.
AB  - Background: An intervening screen has been suggested to induce an inward shift of
      accommodation when viewing a distant object. This is an example of the Mandelbaum
      effect. However, there have been no objective measures of the magnitude of this
      effect in this particular situation. Methods: Accommodation was recorded with an
      infra-red optometer, while subjects (n = 16) viewed a distant letter target with
      or without an intervening screen. Screens were placed near the individual dark
      focus distance or at 50 cm. In a second experiment the contrast of the distant
      target was varied and subjects (n = 5) viewed the target directly or through a
      screen placed near the individual dark focus distance. Results: In the main
      experiment, the Mandelbaum effect was not significantly different from zero and
      was less than 0.5 D in every subject. In addition, accommodation was not more
      variable when viewing through the screen. However, it may be that some subjects
      do demonstrate a Mandelbaum effect while others do not. The individual dark focus
      level did not predict susceptibility to the Mandelbaum effect for a screen at the
      dark focus. Subjects reported their perceptions of the tasks and some noted
      changes in the perceived distances of objects when viewing through a screen. In
      the second experiment, the Mandelbaum effect (< 0.6 D) did not vary with distant
      target contrast. Conclusions: When viewing a distant object through a screen
      there is a small (< 0.6 D) or negligible inward shift of accommodation.

PMID- 12482262
TI  - Corneal shape in hyperopia.
AB  - Background: A trend towards decreased peripheral corneal flattening with
      increasing myopia has recently been demonstrated. The present study was conducted
      to determine whether corneal asphericity also varies significantly with hyperopic
      refractive error. Methods: Thirty-five eyes with spherical equivalent refractive
      error ranging from -0.37 D to +6.00 D were examined. A conicoid equation was
      fitted to videokeratoscopic (Topographic Modeling System) data and corneal
      asphericity and apical radius of curvature values were calculated for each
      subject. Axial length measurements were made using a hand-held biometric ruler.
      Keratometry was also performed on each eye. Results: The relationship between
      corneal asphericity (Q) and spherical equivalent refractive error was not
      statistically significant (p = 0.7419). In addition, no association could be
      demonstrated between Q and corneal radius of curvature or between Q and axial
      length. Corneal radius of curvature was positively correlated with axial length
      (r = 0.367, p = 0.0298). Axial length was found to decrease as hyperopic
      refractive error increased (r = 0.753, p = 0.0001). Conclusions: For hyperopic
      eyes, corneal asphericity does not appear to be significantly correlated with
      refractive error, a finding that is at variance with previous data for myopic
      eyes showing an association between these two variables. The results suggest that
      there may be differences between hyperopic and myopic eyes with regard to the
      anterior segment changes that occur during refractive error development.

PMID- 12482263
TI  - A subluxated intraocular lens.

PMID- 12482264
TI  - The importance of our journal.

PMID- 12482266
TI  - Obituary: Joyce Schultz.

PMID- 12482265
TI  - Hearing and vision impairments affect the everyday lives of healthy older
      Australians.

PMID- 12482267
TI  - Prescribing near magnification for low vision patients.
AB  - Most patients with low vision request help with reading. Despite improvements in
      the assessment of visual functions, determining the appropriate magnification for
      reading still often involves a trial and error approach. Recent research has
      shown that with accurate and systematic assessments of vision, the required
      magnification can be predicted but this magnification needs to be much higher
      than has been previously recommended. This paper presents a systematic approach
      to enable practitioners to determine the power of a near addition or simple
      magnifier needed to assist patients with mild or moderate low vision who may
      present seeking help for reading. Guidelines for appropriate referral to low
      vision services are also provided.

PMID- 12482268
TI  - A review of argon and selective laser trabeculoplasty as primary treatments of
      open-angle glaucoma.
AB  - It is generally accepted within the ophthalmic community that medical therapy is
      the preferred primary treatment in open-angle glaucoma, followed by laser
      trabeculoplasty if the medical therapy is unsuccessful, with surgery employed
      more as an end-stage option when these avenues have been exhausted. This review
      discusses the efficacy of argon laser trabeculoplasty, alone and in comparison
      with medical therapy as a primary treatment of glaucoma. It will also discuss the
      new laser technique, selective laser trabeculoplasty.

PMID- 12482269
TI  - RGP fitting philosophies for keratoconus.
AB  - Rigid gas permeable (RGP) lenses are the choice of vision correction for most
      keratoconic patients. Various fitting philosophies and different lens designs are
      available and the question of which technique is the most appropriate is a
      controversial issue in the field of contact lens practice. This article reviews
      the different philosophies with respect to their rationale, optical performance
      and physiological influence on the cornea. The 'three-point-touch' approach is
      now the most widely-accepted corneal lens fitting philosophy in clinical
      practice. It provides a well-distributed pressure between the cone apex and the
      relatively normal peripheral cornea but other philosophies such as apical bearing
      and apical clearance also have advantages. Having considered the advantages and
      disadvantages of each philosophy, a variant of the three-point-touch appears to
      be a practical solution. Practitioners can fit keratoconic patients with a three
      point-touch tending towards apical clearance to allow for disease progression and
      unexpected lack of follow-up. Wearing time, visual acuity and comfort are also
      important issues to be considered as all of these are essential to constitute a
      successful contact lens fitting.

PMID- 12482270
TI  - Is there a hyperopic shift in myopic eyes during the presbyopic years?
AB  - BACKGROUND: Studies of age-related changes in myopia during the presbyopic years
      have produced contradictory results. Some studies have shown that myopic eyes
      undergo a hyperopic shift after the age of 40 or 45 years, whereas others have
      provided evidence for a myopic shift. In this paper, we report the results of
      both a cross-sectional study and a retrospective longitudinal study of age
      related changes in refraction during the presbyopic years. METHODS: In the cross
      sectional study, refractive error data were tabulated for the right eyes of 559
      patients over the age of 45 years, who had been examined during a 17-month period
      in an established optometric practice. In the longitudinal study, we tabulated
      refractive error data on 100 myopes, 100 hyperopes and 100 emmetropes, who had
      been examined for periods varying from 10 to 26 years after age 40, all of whom
      had 6/6 visual acuity at all examinations. RESULTS: In the cross-sectional study,
      the prevalence of myopia during the later presbyopic years was found to be
      greater when eyes with all visual acuities were included than when only eyes with
      acuity of 6/6 or better were considered. In the longitudinal study, it was found
      that almost all hyperopic and emmetropic eyes showed an age-related hyperopic
      shift; but only a small proportion of myopic eyes shifted toward hyperopia, with
      others remaining relatively stable and still others increasing in myopia.
      DISCUSSION AND CONCLUSIONS: We suggest that when healthy myopic, hyperopic, or
      emmetropic eyes shift in the hyperopic direction, it is because of an age-related
      decrease in the gradient index of the lens; but when healthy myopic eyes shift in
      the myopic direction, it is because of axial elongation that more than
      compensates for the decrease in the gradient index of the lens. Another possible
      cause of a myopic shift, even for eyes having 6/6 visual acuity, is the presence
      of early, sub-clinical nuclear sclerosis.

PMID- 12482271
TI  - Acuity predictions from visually evoked potential to checkerboard pattern
      reversal stimuli: the effect of reversal rate.
AB  - INTRODUCTION: A pattern reversal stimulus (check size 5.5 minutes of arc) was
      used to elicit the visually evoked potential (VEP). METHODS: The peak to trough
      amplitude of the VEP wave was measured and compared to subjective visual acuity
      (Landolt C). The recordings were made at three, six and 12 pattern reversals per
      second. RESULTS: The correlation between VEP amplitude and visual acuity was
      found to decrease at higher temporal frequencies. The decrease is not confined to
      the use of a television system reversing checkerboard pattern stimulus as
      suggested by previous workers. DISCUSSION: It may well be concerned with a change
      in processing of the visual information as could be expected at these higher
      frequencies.

PMID- 12482273
TI  - Recent Advances in the Management of Primary Open-angle Glaucoma: Reply to O'Shea
      et al.

PMID- 12482274
TI  - Has the 'McDonalds' contact lens resulted in the demise of the contact lens
      practitioner?

PMID- 12482272
TI  - Recent Advances in the Management of Primary Open-angle Glaucoma.

PMID- 12482275
TI  - Aetiology and management of choroidal folds.
AB  - Choroidal folds are known to be associated with a wide variety of pathological
      conditions, such as central serous retinopathy, choroidal naevi, tumours and
      papilloedema. They may also occur with surgical procedures, especially when
      hypotony of the globe occurs, such as following cataract surgery, laser therapy
      and from post-operative choroidal oedema or inflammation. However, choroidal
      folds are idiopathic in the majority of cases and can be associated with benign
      conditions, such as hypermetropia and optic disc drusen. Numerous patterns and
      orientations of choroidal folds are possible, with some authors suggesting that
      typical presentations are associated with particular pathological conditions.
      They may be seen as dark and light streaks on ophthalmoscopy (often more defined
      with red-free viewing) but are more apparent and differentiated from retinal
      folds by fluorescein angiography. The aetiology of choroidal folds appears to be
      linked to a combination of an anatomical attachment of Bruch's membrane to the
      underlying choriocapillaris and congestion of the choriocapillaris. This paper
      reviews aspects of the differential diagnosis of choroidal folds with guidelines
      for optometric management. Several case reports are presented to demonstrate some
      of the clinical features of choroidal folds.

PMID- 12482276
TI  - Preliminary tear film measurements of tolerant and non-tolerant contact lens
      wearers.
AB  - BACKGROUND: The relationship between contact lens intolerance and tear stability,
      tear quantity, distribution and consistency has yet to be clearly established. In
      this study, we have examined the tear film of several tolerant and non-tolerant
      soft contact lens wearers. We aimed to develop a number of clinical and
      biochemical techniques to establish a correlation between one or more factors
      leading to contact lens intolerance. METHODS: Subjects were separated by their
      self-described tolerance to contact lens wear. Five tolerant and five non
      tolerant subjects were chosen. A McMonnies symptomatology questionnaire was used
      to ascertain subject history, while non-invasive tear break-up time (TBUT)
      examined tear stability. Basal tear collection was performed using glass
      capillary tubes, the tear flow rate was measured and one dimensional gel
      electrophoresis used to analyse protein differences. RESULTS: Non-tolerant
      subjects experienced primary symptoms, such as dryness and grittiness, more often
      than tolerant subjects (p = 0.007). The TBUT of non-tolerant lens wearers was
      also reduced (average of seven seconds) compared to tolerant lens wearers (p <
      0.002). Tolerant lens wearers had a longer more stable tear film with an average
      TBUT of 20 seconds and this correlated with a fast tear flow rate (p < 0.04).
      Protein gel electrophoresis showed that some subjects who were non-tolerant to
      lens wear had variations in their tear protein profiles compared to tolerant
      subjects. CONCLUSION: These preliminary results demonstrate that clinical and
      biochemical tear profiles can be used to differentiate subjects with good lens
      wear tolerance from those who may be non-tolerant to lens wear.

PMID- 12482277
TI  - Viewing distance with minimum heterophoria.
AB  - BACKGROUND: The purposes of this study are to determine the viewing distance with
      minimum heterophoria and its relationship with refractive error and the resting
      position of accommodation. METHODS: The heterophoria and the accommodation
      responses of 36 optometry students (25 emmetropes and 11 myopes) were tested.
      Heterophoria was measured with the Free-Space Heterophoria Card at five different
      viewing distances (25 cm, 33 cm, 50 cm, 100 cm and 300 cm). The dioptric viewing
      distance with minimum heterophoria for each individual was estimated from the
      graph, where heterophoria in prism dioptres was plotted against viewing distance
      in centimetres. The Canon R-1 autore-fractor was used to determine the
      accommodation response at six different viewing distances (25 cm, 33 cm, 50 cm,
      100 cm, 300 cm and 600 cm). The resting position of accommodation for each
      individual was estimated from the graph where the accommodative stimulus in
      dioptres was plotted against the accommodative response in dioptres. RESULTS: The
      dioptric viewing distance with minimum heterophoria ranges from 0.003 D to 0.65 D
      in emmetropes and ranges from 0.03 D to 2.36 D in myopes. There is no difference
      in the dioptric viewing distance with minimum heterophoria between myopes and
      emmetropes. Our results show a possible but not significant correlation between
      the dioptric viewing distance with minimum heterophoria and the resting position
      of accommodation. CONCLUSIONS: The viewing distance with minimum heterophoria is
      not affected by refractive error (stable early-onset myopia) and is poorly
      correlated with the resting position of accommodation.

PMID- 12482278
TI  - Practitioner trial of SOLA Percepta progressive lenses.
AB  - INTRODUCTION: SOLA has conducted a trial of patient acceptance of the Percepta
      lens with optometrists independently selected by Australia's Independent
      Optometrists (AIO), which helped organise the study. METHODS: Twenty-eight
      optometrists each recruited approximately five patients who were prescribed the
      lens. These patients were the next patients who would normally be prescribed a
      progressive lens. Ultimately, 125 patients were recruited. RESULTS: Approximately
      82 per cent of the ratings of lens wear were either 'good' or 'excellent' with a
      further nine per cent 'adequate'. Those patients who were not satisfied with the
      lens showed adaptation problems or had difficulties with the width of near vision
      available to them. Thirty-one of these patients (25 per cent) were prior wearers
      of single vision lenses for distance or near (or both) and therefore it was not
      surprising to hear them voice concern over near vision performance. The majority
      of patients (45 per cent) recruited into the study were previously wearing
      progressive lenses and the high success rate in this study reflected a successful
      change into a new lens type. CONCLUSION: The Percepta lens provides a well
      accepted solution to the visual needs of patients. Patients had difficulty with
      computer use but rated the Percepta lens highly for clarity of vision and for
      driving.

PMID- 12482279
TI  - Ocular injury due to bungee jumping.
AB  - BACKGROUND: Bungee jumping is a well-established recreational activity in New
      Zealand and Australia which may be associated with injuries to the eyes and other
      tissues. CASE HISTORY: A patient with a retinal haemorrhage which resulted from
      bungee jumping is reported and the clinical characteristics described.
      DISCUSSION: There have been several reports of injury due to bungee jumping. The
      types of ocular injury are reviewed and the aetiological theories discussed.

PMID- 12482280
TI  - Contact lens status in ametropia correction: a prospective study.
AB  - BACKGROUND: Optical devices such as spectacles and contact lenses have been used
      to correct ametropia for many years. Recently, surgical means of correction such
      as photorefractive keratectomy have been introduced. All of these forms of
      correction are readily available in Saudi Arabia. The purpose of this study was
      to determine the proportion of contact lens use in ametropia correction. This
      survey also presents an insight into patient satisfaction with their correction
      and their willingness to change to another form of correction in the future. This
      will serve as a guide for eye care practitioners and manufacturers. METHOD: Five
      hundred and seventy four subjects responded to questionnaires randomly
      distributed among hospital patients, students and staff of King Saud University.
      RESULTS: Data revealed that spectacle wearers constituted 74.5 per cent of the
      sample population, followed by contact lens wearers (21.8 per cent) and those who
      had undergone photorefractive keratectomy (3.7 per cent). On the whole, 50 per
      cent of the population sample would change to another form of correction. Among
      contact lens wearers, 9.5 per cent would prefer to change to PRK and 0.4 per cent
      to spectacles, while 17.9 per cent of spectacle wearers would consider changing
      to contact lenses. CONCLUSION: Contact lenses constitute a minor proportion of
      ametropia corrections. Spectacles remain the most popular form of ametropia
      correction at the moment, but for the future, there is greater tendency towards
      contact lenses and PRK.

PMID- 12482281
TI  - Megalopapilla.
AB  - INTRODUCTION: Optic discs can show a variety of congenital malformations, mostly
      due to incomplete development. CASE STUDY: The subject of this report is a
      particularly rare abnormality, known as megalopapilla, in which the optic disc is
      significantly larger than usual.

PMID- 12482282
TI  - Granular dystrophy of the cornea.
AB  - BACKGROUND: Granular corneal dystrophy is the commonest of the dystrophies and
      usually results in visual disability in the fourth or fifth decades. CASE
      HISTORY: A patient with granular corneal dystrophy is reported and the clinical
      characteristics described. DISCUSSION: The classical clinical features and the
      pathology and management of granular dystrophy are reviewed. Two unusual
      variations of the corneal dystrophy, namely, juvenile granular dystrophy and
      Avellino dystrophy, which is a concurrence of the features of granular and
      lattice dystrophies, are also described.

PMID- 12482283
TI  - A unique research institute.

PMID- 12482284
TI  - Considerations in the routine assessment and treatment of anisometropic
      amblyopia.
AB  - Anisometropic amblyopia has traditionally been treated by direct occlusion with
      or without refractive correction of the anisometropia. This treatment has
      generally been considered so successful that practitioners prescribe occlusion
      for a time and consider treatment complete when visual acuity is no longer
      improving. The aetiology of anisometropic amblyopia, addressing the functional
      deficits of the amblyopic system and patient compliance issues, are important to
      the success of amblyopia treatment in anisometropia and are briefly reviewed in
      this paper. We propose that, while each case of anisometropic amblyopia may have
      slightly different attributes, initially they should all be treated with
      occlusion and full-time spectacle correction. Some presentations may be
      responsive to individual treatment strategies to correct binocular functions such
      as stereopsis, accommodative response and fusional vergences.

PMID- 12482285
TI  - Cataract development in the GalKO mouse.
AB  - BACKGROUND: Deletion of the gene for the enzyme alpha-(1,3) galactosyltransferase
      in the BalbC mouse generates the GalKO mouse, an animal which develops early
      bilateral cataract. The cause is not obvious. As part of studies to elucidate the
      mechanism involved, we have examined the rate of development and the location of
      opacities. METHODS: The development of cataract was monitored through daily
      observations on more than 200 animals from 50 litters. The first appearance of
      opacity was noted as well as the time at which the cataract was mature. Slitlamp
      photography was used to determine the location of the opacity. RESULTS: Without
      exception, every animal developed bilateral cataract. A white pinhead opacity was
      observed in one eye at an average age of 36 to 37 days and in the second eye, one
      to two days later. There was no apparent preference for either eye or for gender.
      Rapid progression to full opacities occurred, on average, within seven to eight
      days. Slitlamp photography revealed early nuclear and posterior cortical changes
      as well as fibre folds and swollen sutures. CONCLUSIONS: The GalKO mouse cataract
      appears to be an autosomal dominant trait. The nature and rapidity of the lens
      changes are indicative of severe biochemical alterations resulting in osmotic
      cataracts. It is possible this may be a novel cataract model.

PMID- 12482286
TI  - Sorsby's fundus dystrophy: what does TIMP3 tell us about general mechanisms
      underlying macular degeneration?
AB  - INTRODUCTION: Mutations in tissue inhibitor of metalloproteinases-3 (TIMP3) gene
      result in the rare autosomal dominant disease Sorsby's fundus dystrophy (SFD),
      which shows striking similarities to age-related macular degeneration (ARMD).
      METHODS: Current research is reviewed and suggests that these mutations result in
      the accumulation of TIMP3 in Bruch's membrane resulting in decreased turnover of
      the extracellular matrix and consequent thickening of Bruch's membrane. DNA
      analysis of ARMD patients has failed to show any significant mutations in the
      coding-regions of TIMP3. However, this should not be taken to imply that TIMP3 is
      not affected in the disease, as another possibility is that levels of TIMP3 might
      be elevated by other mechanisms. CONCLUSION: The finding that TIMP3 levels are
      elevated in simplex retinitis pigmentosa in the absence of coding mutations begs
      for a revaluation of its role in other retinal conditions such as ARMD.

PMID- 12482287
TI  - Steroid adduct formation with lens crystallins.
AB  - BACKGROUND: Development of steroid cataract is a likely outcome following
      prolonged exposure to glucocorticoids. It has been suggested that formation of
      steroid-protein adducts is a key event in this lens opacification. In order to
      explore this possibility, we have monitored the reaction of bovine lens proteins
      with glucocorticoids and examined the effects of adduct formation on their
      structures. METHODS: Bovine lens proteins were incubated with high (10(-4) M) and
      low (10(-8) M) concentrations of dexamethasone or prednisolone for up to 56 days
      at 37 degrees Celsius. Changes in molecular size and solubility of the
      crystallins and their polypeptide subunits were examined using gel permeation
      chromatography and SDS gel electrophoresis. Conformational changes were assessed
      with the aid of tryptophan fluorescence spectroscopy and oxidation was monitored
      by measuring protein sulphydryl content. RESULTS: Covalent incorporation of
      glucocorticoids was observed for all crystallins with relative reactivities for
      alpha-: beta-: gamma-crystallin of 20: 5: 1. The maximum incorporated was one
      steroid molecule per 40 to 50 subunits of alpha-crystallin. The proportions and
      sizes of the soluble crystallins and their subunits were unchanged. Protein
      sulphydryl contents decreased by eight to 10 per cent more than controls but no
      intermolecular disulphide bonds were detected. There were no alterations in
      tryptophan microenvironments. CONCLUSIONS: Steroids form adducts with lens
      proteins, in particular alpha-crystallin, but it appears unlikely that this
      reaction is responsible for steroid cataract formation.

PMID- 12482289
TI  - An important contribution to public health.

PMID- 12482288
TI  - Twenty-five years of progress: reflections of the NVRI directors 1973-1998.

PMID- 12482290
TI  - Optometry, public health and diabetes.

PMID- 12482291
TI  - Non-retinal ocular changes in diabetes.
AB  - Diabetes is the major cause of legal blindness in people of working age. There
      are other non-retinopathic ocular changes that can also have a very significant
      impact on vision. This review examines the effects of diabetes mellitus on the
      cornea, the lens and the optic nerve and also its effects on vision.

PMID- 12482292
TI  - Diagnosing diabetes mellitus.
AB  - Diagnosing diabetes mellitus by well-defined, objectively established, laboratory
      criteria is a relatively recent occurrence. Diabetes was not defined by any
      laboratory criteria until urine glucose could be measured last century. The use
      of blood tests for glucose did not develop until well into this century. The
      discovery of insulin, the wider use of the hypodermic syringe for venesection and
      the development of micro methods for laboratory analysis permitted the
      development of blood tests in diagnosing diabetes. The use of insulin to keep
      young diabetic subjects alive, albeit with elevated glucose levels, lead to the
      discovery of the association of retinopathy and elevated plasma glucose. This
      lead to efforts to diagnose diabetes in as mild a form as possible using the oral
      glucose tolerance test, to prevent such complications occurring. Determining what
      glucose levels were normal or abnormal then became an issue. Studies of the Pima
      Indians of Arizona eventually lead to objective definitions of diabetes that have
      been further refined in the past few years. We also now understand how
      retinopathy and other diabetes complications may develop. It is the glucose
      itself 'sticking' to proteins (advanced glycosylation end products) that does the
      damage. The future holds the promise that genetic diagnoses for diabetes and its
      complications may lead to the total prevention of diabetes and its effects.

PMID- 12482293
TI  - The optometrist's role in the multidisciplinary diabetes team: towards a more
      holistic approach.
AB  - Diabetes is a chronic and costly disease, which is increasingly affecting
      Australians of all ages. It imposes a personal and public health threat. Every
      health care provider will encounter numerous people with diabetes in the course
      of practice and will have the opportunity to influence the course of diabetes in
      individual patients. Optometrists have recognised technical training and
      expertise in detecting diabetic eye disease but can also be effective in helping
      to improve overall diabetes outcomes by adopting strategies which can assist in:
      1. the earlier detection of undiagnosed diabetes, 2. earlier referral to
      appropriate services for people with established diabetes and who may be
      experiencing problems and 3. greater patient awareness of recommendations for
      optimal diabetes care. This article provides an overview of the way diabetes
      services are currently provided in Australia and the role of non-medical
      providers in the management of diabetes. Suggestions are made for greater
      involvement of optometrists as members of the multi-disciplinary diabetes team.

PMID- 12482294
TI  - Diabetic retinopathy: classification, description and optometric management.
AB  - BACKGROUND: Diabetes mellitus is an important cause of visual loss, which can be
      moderated by treatment at specific stages of diabetic retinopathy. Existing
      monitoring for retinopathy has been shown to fall short of ideal, resulting in
      unnecessary visual loss. Using appropriate guidelines, optometrists should be
      well-placed to contribute to the management of patients having diabetic eye
      disease. METHOD: The underlying pathology of diabetic retinopathy is reviewed as
      a basis for recognising the various stages of diabetic retinopathy, including
      macular oedema and risk of progression of disease. These stages are detailed in
      terms of classification, prevalence and appropriate examination techniques. An
      illustrated guide summarises these features and provides a suggested management
      regimen for continued monitoring, reporting, referral and ongoing management by
      optometrists. CONCLUSIONS: The majority of optometrists have the diagnostic
      skills and the clinical equipment required for efficient monitoring of diabetic
      retinopathy. Inclusion of optometrists in the team providing health services for
      diabetes is an economic and practical solution to improving the primary eye care
      of people having diabetes and ensuring a significant reduction of unnecessary
      visual loss caused by diabetic retinopathy.

PMID- 12482295
TI  - Diabetes mellitus: the general practitioner's perspective.
AB  - Diabetes mellitus is a disease of modern society. It has been estimated that
      there are 700,000 people in Australia with diabetes, 50 per cent of whom are not
      aware of it. Type 2 diabetes in particular is on the increase and is sinister.
      The concern is the serious complications, especially those of the ocular fundi
      leading to deterioration of vision, of kidney function, neurological function and
      the heart. The general practitioner, assisted by share care, must aim to maintain
      optimal glycaemic control and control of blood pressure and serum lipids. Optimal
      management to prevent complications involves a team approach. The optometrist has
      an important role in competent screening of the ocular fundi of all patients
      having an eye examination.

PMID- 12482296
TI  - Diabetes and diabetic retinopathy in indigenous Australians.
AB  - The health status of indigenous Australians is significantly poorer than that of
      other Australians. One of the major health problems for this population is type 2
      diabetes which has been reported to have much higher prevalence rates than those
      in the rest of the Australian population. The significance of diabetes as a
      health issue has recently been reinforced by its inclusion as one of the six
      National Health Priorities. The recently developed National Diabetes Strategy is
      now in its implementation phase. Diabetic retinopathy is an important
      complication of diabetes. However, its prevalence within the indigenous
      population of Australia is not well documented. In this paper, we give a brief
      overview pertaining to this topic and include two case reports to illustrate some
      of the specific issues related to the management of diabetic retinopathy in this
      population.

PMID- 12482297
TI  - A review of current research on the effect of diabetes mellitus on the eye.
AB  - It is estimated that almost one million Australians will have diabetes by the
      year 2000. Of those with diabetes a significant proportion will have eye-related
      conditions, the most debilitating being diabetic retinopathy. Appropriate
      identification and treatment can result in prevention of visual loss and
      blindness. The importance of diabetes as a cause of blindness in our community is
      realised by the commencement of a national program by the National Health and
      Medical Research Council to develop clinical practice guidelines for the
      management of diabetic retinopathy. The development of these guidelines was based
      on available evidence following an extensive review of the literature up to May
      1996. This review is a summary of our advances in research on the effect of
      diabetes on various aspects of the eye and vision over the past two years. This
      review is a compilation of articles of research on the effect of diabetes on
      various aspects of the eye and vision. As a result of the enormous amount of
      effort and work by scientists and clinicians around the world, as well as space
      restrictions, the review covers the past two years only. Although every effort
      has been made to include as many research articles as possible, not all articles
      of research are covered. It is intended that this review provide an overview of
      the latest trends in research, particularly relating to new techniques and
      methods in the study of diabetes in ocular tissue as well as the new theories in
      the development of ocular damage to each of the tissue.

PMID- 12482298
TI  - Treatment of diabetic retinopathy.
AB  - Diabetic retinopathy is a major public health problem and it remains the leading
      cause of blindness in people of working age (20 to 65 years). Several important
      clinical trials have given us the evidence base to provide clinical practice
      guidelines for management of this disease. With full implementation of existing
      technology, it should be possible to greatly improve visual outcomes for people
      with diabetes. There are two keys to maintaining vision in people with diabetes.
      First, achieving good long-term metabolic control of diabetes will limit the
      development and progression of diabetic retinopathy. Second, ensuring early
      detection of diabetic retinopathy by regular (two-yearly at least) screening
      examinations will allow timely referral for application of retinal
      photocoagulation. This paper will review the ophthalmologist's treatment of
      diabetic retinopathy with emphasis on the role of photocoagulation.

PMID- 12482299
TI  - Diabetes mellitus: a brief history, epidemiology, definition and classification.
AB  - Diabetes mellitus is a systemic disease of great significance to optometrists.
      This review includes a brief history of the key discoveries in the understanding
      of diabetes from ancient times and a summary of the present knowledge of diabetes
      with respect to prevalence, epidemiology and major complications. The currently
      accepted classification of diabetes mellitus includes the major categories of
      type 1 and type 2 diabetes, specific diabetes types and gestational diabetes. The
      definition of diabetes has also been revised recently. The new diagnostic
      criterion for diabetes mellitus is a confirmed fasting plasma glucose equal to or
      greater than 7.0 mmol/L, with a reduced reliance on the role of oral glucose
      tolerance testing.

PMID- 12482300
TI  - Secretory immunoglobulin A in tears:functions and changes during contact lens
      wear.
AB  - INTRODUCTION: Secretory immunoglobulin A (sIgA) is the predominant immunoglobulin
      in tears. The role of sIgA in defending the eye against pathogens has not been
      established clearly. There have been conflicting reports about the effect of
      contact lens wear on the concentration of sIgA in tears. This study was conducted
      to elucidate the role of sIgA in ocular defence and to determine the effect of
      contact lens wear on sIgA concentration. METHODS: Tears were collected from
      contact lens wearers and non-wearers using micro-capillary tubes. The
      concentration of sIgA was evaluated using an in-house ELISA. The specificity of
      sIgA to a strain of P. aeruginosa was examined using a fluorescent assay and the
      ability of neutrophils to phagocytose sIgA coated bacteria were assessed by plate
      counts. RESULTS: Tears contained sIgA that reacted to P. aeruginosa. P.
      aeruginosa coated with sIgA was phagocytosed by the neutrophils. The level of
      sIgA and the level of sIgA specific to P. aeruginosa in the tears of contact lens
      wearers were significantly reduced. CONCLUSIONS: These results indicate that
      contact lens wear significantly alters the level of sIgA in tears which may lead
      to changes in the ability of the ocular surface to defend itself against
      potential pathogens.

PMID- 12482301
TI  - The characteristics of corneal staining in successful daily and extended
      disposable contact lens wearers.
AB  - PURPOSE: The aim of this investigation was to measure levels of corneal staining
      in successful daily and extended wearers of disposable hydrogel contact lenses.
      METHODS: Twenty-four subjects on a daily wear (DW) schedule and 20 subjects on an
      extended wear (EW) schedule were examined at six-monthly intervals over a two
      year period. Subjects wore two types of disposable hydrogel lenses. Measurements
      were taken from the eye wearing an etafilcon A contact lens only. The cornea was
      divided into five equally sized zones and the extent and depth of corneal
      staining were assessed on a zero to four scale. RESULTS: The overall levels of
      corneal staining were low with median values below or equal to grade 0.5 in all
      groups. There was no difference in the extent, depth or geographical distribution
      of corneal staining between the DW and EW groups. Staining was more frequently
      recorded in the superior and inferior areas of the cornea than in the central,
      nasal or temporal regions (Pearson's Chi-Square, p < 0.10). CONCLUSIONS: The mode
      of wear with disposable contact lenses is not a contributing factor to the amount
      of corneal staining seen in successful wearers. Low levels of corneal staining
      should be expected in successful DW and EW wearers.

PMID- 12482302
TI  - Conversion factor for comparison of data from Humphrey and Medmont automated
      perimeters.
AB  - Background: Clinical experience has shown that the sensitivity indices reported
      by the Humphrey Field Analyser (HFA) are generally higher than those given by the
      Medmont Automated Perimeter (M600). It is the purpose of this paper to determine
      a conversion factor for the two perimeters and to confirm this prediction using
      clinical data. Theory predicted that HFA(sensitivity) - 5 dB = M600(sensitivity).
      Methods: Sensitivity versus eccentricity profiles were measured over the central
      visual field on 10 young subjects using both perimeters. Results: Both the HFA
      and the M600 operate within the realms of the Weber law and measure similar Weber
      fractions. The sensitivity profiles had similar slopes (about -0.2 dB/degree) and
      were separated by about six decibels with the HFA reporting higher sensitivity
      values. This result confirmed the theoretical prediction. Conclusion: The
      difference in threshold sensitivities between the two perimeters is a result of
      differences in scaling factors and instrument luminances. A suggested clinical
      conversion factor is to subtract 5 dB from the HFA data to approximate those of
      the M600.

PMID- 12482303
TI  - Salzmann's nodular degeneration of the cornea.
AB  - Salzmann's nodular degeneration is a rare condition characterised by elevated
      bluish-white to grey sub-epithelial nodules in the cornea. This paper presents
      two case reports of this corneal disorder and discusses appropriate management
      strategies.

PMID- 12482304
TI  - Free-floating vitreous cysts.

PMID- 12482305
TI  - Posterior polymorphous dystrophy.

PMID- 12482306
TI  - Experimental study of visual training effects in shooting initiation.
AB  - INTRODUCTION: The present study was conducted to investigate the influence of
      specific visual training in shooting initiation performance. METHODS: Seventy-one
      first-year university students were divided randomly into two groups. The
      experimental group followed a nine-session shooting training program that
      included technical, physical and psychological components, along with specific
      visual exercises. The control group followed the same program with one
      difference: this group received theoretical lectures on psychological training
      techniques instead of doing visual exercises. Pre- and post-test results were
      obtained for shooting, concentration, saccades and visual acuity. RESULTS:
      Statistical analysis indicated significant gains in the four mentioned variables
      for the experimental group. The control group also showed significant differences
      in the three first variables but no significant improvement in visual acuity. No
      significant differences in shooting performance were observed between groups.
      CONCLUSIONS: The effect of vision training on sports initiation performance is
      still not clear. It cannot be assumed that the improvement is transferable to the
      performance of precision shooting at the stage of sports initiation.

PMID- 12482307
TI  - Iridoschisis.
AB  - Iridoschisis is a rare condition in which a localised area of iris stroma is
      cleaved in two with the anterior atrophic portion disintegrating into fibrils.
      The most common presentation of iridoschisis is as an age-related iris atrophy in
      association with glaucoma. The association includes angle-closure glaucoma, angle
      recession glaucoma and open-angle glaucoma. A finding of iridoschisis is a
      warning to the clinician to assess the patient for pre-existing glaucoma and to
      monitor for glaucomatous changes as it is unclear if iridoschisis is a cause or
      an effect of raised intraocular pressure (IOP).

PMID- 12482308
TI  - Editorial.

PMID- 12482310
TI  - Tribute: Professor Barry Leighton Cole AO retires.

PMID- 12482309
TI  - Optometry: an evidence-based clinical discipline.

PMID- 12482311
TI  - Clinical testing of contrast thresholds using a commercial television monitor
      system.
AB  - Background: The Medmont AT-20 has incorporated a contrast threshold test using a
      predetermined letter size that can be applied in clinical settings. This paper
      describes a pilot study that evaluates this technology and the effects of certain
      parameters on test outcomes. Methods: A photometric calibration of the test was
      performed to define the relationship between the AT-20 scale and Weber contrast
      (W%). We determined the effects of repeated measures (precision), target size
      (6/6 to 6/96), viewing duration (50 to 1,000 msec), defocus (+0.50 to +1.50 DS)
      and a macula scotoma on thresholds. The accuracy of the staircase (PEST)
      procedure was evaluated with and without false-negative responses. Results: The
      AT-20 scale has an almost linear relationship to a logarithmic transformation of
      W% and provides a suitable measure of contrast threshold. In the absence of
      monitor calibration, threshold uncertainty could be as great as 0.22 log units
      (W%) compared with published norms. We found that threshold variability averaged
      +/- 7.1 AT-20 scale units (95 per cent limits of agreement) and was proportional
      to threshold magnitude. One dioptre of defocus decreased thresholds by about one
      log unit (W%) for a 6/24 target. We propose that a 6/24 letter shown for 500 msec
      should provide a useful target for most clinical settings. The PEST procedure can
      yield endpoints in 47 (+/-12) seconds, is robust to false negative (FN) responses
      and gives abnormal thresholds in the presence of a macula scotoma. Conclusions:
      The Medmont AT-20 contrast test provides a useful clinical measure of contrast
      threshold. With calibration, the test could also be applied to research projects.

PMID- 12482312
TI  - A comparative study of the corneal endothelium in vertebrates.
AB  - INTRODUCTION: In vertebrates, a corneal endothelium is essential for the
      maintenance of corneal transparency in a variety of environments, including
      aerial, terrestrial and aquatic. Knowledge of the surface structure of the
      corneal endothelium may assist our understanding of this unique tissue and its
      evolutionary development. Except for humans and some mammals, there have been few
      studies of other vertebrates, particularly the unique Australian species.
      METHODS: The field emission scanning electron microscope was used to study the
      corneal endothelium in representatives of four vertebrate classes: Teleostei
      (five species), Reptilia (two species), Aves (four species) and Mammalia (three
      species), including Marsupialia (two species). Endothelial cell densities were
      calculated from micrographs using computer-based image analysis. RESULTS: The
      cell densities varied considerably from 1,900 +/- 197 cells per mm(2) for the
      bream to 11,734 +/- 1,687 cells per mm(2) for the emu. Most of the corneal
      endothelia were similar to those reported for mammals. However, in some species
      such as the koala, the pattern was irregular. Some endothelial cells in birds
      possessed cilia. CONCLUSIONS: The shape of the corneal endothelial cells of
      vertebrates is typically a mixture of hexagonal and pentagonal cells, in which
      the cell borders are irregular and interdigitating. An exception is the koala, in
      which the cells were markedly irregular. Many of the cells have surface
      microvilli but only in the birds are cilia found in the centre of many
      endothelial cells. In spite of the range of corneal environments, there are no
      systematic differences in the cell densities of the various classes and species.

PMID- 12482313
TI  - Management of patients with narrow angles and acute angle-closure glaucoma.
AB  - BACKGROUND: Acute closure of the anterior chamber angle can have catastrophic
      consequences for vision when it occurs in an unsupervised situation. Visual
      debilitation is much less likely to result when angle-closure occurs in a well
      controlled environment that allows appropriate management. Therefore, it is
      desirable for optometrists to undertake a complete ocular health assessment,
      including mydriatic fundus examination, on patients who have narrow anterior
      chamber angles, provided that appropriate precautions and procedures are
      followed. CASE REPORT: We report on the case of a 59-year-old white female whose
      anterior chamber angles closed in response to mydriatic drops instilled during an
      optometric examination. Her optic discs and visual field results from before and
      four years after the angle-closure attack do not show any significant changes.
      CONCLUSION: We conclude that the optimal standard of care for patients presenting
      to an optometric practice, and who are subsequently found to have narrow anterior
      chamber angles, includes pupillary dilatation to allow stereoscopic visualisation
      of the optic nerve head. Precautions must be followed to ensure that, in the
      unlikely event of an ensuing angle-closure episode, the attack occurs under
      clinically supervised conditions.

PMID- 12482314
TI  - Pituitary adenoma presenting with visual complications.
AB  - A pituitary adenoma is a benign tumour of the pituitary gland. The anatomical
      position and pathological expansion of a pituitary adenoma characteristically
      results in a bitemporal visual field defect which may or may not be apparent to
      the affected individual. The patient described in this report did not realise
      that a visual field loss was present until he presented for a routine eye
      examination. Optometrists, together with medical practitioners, can help diagnose
      patients with brain tumours. Automated perimeters can facilitate the
      optometrist's role.

PMID- 12482315
TI  - Evidence for non-selective colour channel involvement in diabetic eyes especially
      after laser treatment.
AB  - PURPOSE: We consider the hypothesis that proliferative diabetes produces
      selective lossof colour channels. We also consider the possibility that laser
      treatment for this condition does not affect macula function. METHODS: We tested
      for the possibility of a selective colour channel involvement in 35 eyes of 33
      cases of proliferative diabetes by considering the outcomes of saturation and hue
      testing before and after pan-retinal photocoagulation (PRP). Saturation testing
      was achieved with the Sahlgren Saturation Test (SST) and hue testing was via the
      Farnsworth-Munsell 100 (FM100) hue test. Our results were compared to a recent
      model1 that was developed to predict the saturation processing of diseased eyes.
      RESULTS: All diabetic eyes with normal hue (FM100) scores passed the saturation
      test (SST). Most pre-treatment eyes (29 of 35 or 83 per cent) failed the FM100
      hue test but only 16 of 35 (46 per cent) failed the saturation test. Following
      laser treatment, 97 per cent of eyes were abnormal on the FM100 hue test but only
      seven per cent failed the saturation test. CONCLUSION: Untreated diabetic eyes
      with proliferative retinopathy show losses of both hue and saturation processing.
      The nature of this relationship is consistent with that modelled assuming
      moderate and asymmetric non-selective losses in both chromatic and luminance
      channels. Laser treatment (PRP) appears to produce a paradoxical normalisation in
      saturation percepts in the presence of deteriorating hue scores. We find that
      this outcome is consistent with a more severe generalised reduction of
      sensitivity in both the chromatic and luminance processes and conclude that pan
      retinal photocoagulation results in these unexpected macula changes.

PMID- 12482316
TI  - Low vision perspectives on glaucoma.
AB  - INTRODUCTION: Glaucoma is one of the major causes of visual impairment,
      especially in the older population. The aim of this paper is to examine the
      demographics of patients with glaucoma-induced visual impairment. METHOD: Visual
      rehabilitation information was analysed for 590 visually impaired patients
      attending the multi-disciplinary low vision clinic at Kooyong in Melbourne. Data
      collected included age, subjective assessment of glare, mobility and visual
      needs, visual acuity (at distance and near), contrast sensitivity, visual field
      loss or disruption and magnifiers prescribed. An assessment was also made of the
      patients' psychological status and the members of the multi-disciplinary team
      involved in their rehabilitation was noted. RESULTS: Glaucoma was the primary
      cause of visual loss in 8.5 per cent of patients and was a secondary contributor
      to visual impairment in 5.9 per cent. The mean distance visual acuity was 6/38
      and peak contrast sensitivity was 10 dB. Sixty-four per cent of glaucoma patients
      had magnifiers prescribed to help them achieve their visual needs, which were to
      read newspapers in the majority of cases. CONCLUSIONS: In the management of low
      vision patients, it is important to understand the eye disease causing the visual
      impairment and its effects. The glaucoma sufferer must be treated as a whole
      person. The psychological state and the need for services such as welfare and
      mobility training must be considered to enable him or her to enjoy an improved
      quality of life.

PMID- 12482317
TI  - Reliability of the response AC/A ratio determined using nearpoint autorefraction
      and simultaneous heterophoria measurement.
AB  - BACKGROUND: Clinicians frequently assess the accommodative convergence to
      accommodation (AC/A) ratio using near phoria measurements and accommodative
      stimuli. The purpose of this study was to evaluate the repeatability of AC/A
      ratio measurements and to compare the response AC/A ratio to stimulus AC/A ratios
      determined two different ways. METHODS: Heterophorias and accommodative responses
      to different stimuli were measured simultaneously on eight subjects at two
      visits. A Canon Auto Ref R-1 autorefractor was used to measure accommodative
      response, while vergence posture was measured using the modified Thorington
      heterophoria technique. These results were used to calculate response-slope,
      stimulus-slope and stimulus-gradient AC/A ratios and the means of these ratios
      for each session were compared. Correlations between the response AC/A ratios and
      the stimulus AC/A ratios were calculated. RESULTS: The mean response AC/A ratios
      for the two sessions were 3.8 prism dioptres per dioptre for each session. The
      correlation between the slope-determined ratios was 0.56, and between the
      response-slope and the stimulus-gradient AC/A ratios the correlation was -0.03.
      The regression equation for the slope-determined AC/A ratios was calculated.
      CONCLUSIONS: Means for the two sessions were not significantly different for any
      of the AC/A ratios. The response-slope and stimulus-slope AC/A ratios had a
      moderately significant correlation and a predictive regression equation was
      determined. The stimulus-gradient AC/A ratios were not correlated with the
      response-slope AC/A ratios.

PMID- 12482318
TI  - Randot stereoacuity norms in a population of Saudi Arabian children.
AB  - BACKGROUND: The onset and development of stereoacuity in children have been
      investigated by several authors. In addition to the study of those aspects of
      stereopsis, it is also important to collect normative data, which can be applied
      in the clinical setting. The purpose of this study was to establish Randot
      stereoacuity norms using a Saudi Arabian children population. METHOD: The Randot
      stereo test was used to measure stereoacuity for 791 male primary school children
      (aged six to 12 years) with normal vision. A battery of tests was used to
      establish that each child had normal eyes and vision prior to the stereoacuity
      measurement. RESULTS: The range of stereoacuities for all the age groups at 40 cm
      was 70 to 20 seconds of arc, except for the nine-year-old children in whom the
      range was 50 to 20 seconds of arc. More than one half (57.5 per cent) of the
      children achieved 29 seconds of arc. The mean stereoacuity for all of the
      children was 25.32 seconds of arc with a standard deviation of 9.93 seconds of
      arc. The mean stereoacuity for the children decreased from 29.11 seconds of arc
      at six years to 23.61 seconds of arc at 11 years. An inter-subject variation in
      stereoacuity development was observed. CONCLUSION: This paper provides normative
      data for Randot stereoacuity for children. The range and mean values presented
      here will be useful as reference data for clinical diagnosis of normalcy or
      otherwise of stereoacuity in children of similar ages when the Randot stereo test
      is used.

PMID- 12482319
TI  - Profile of a low vision clinic population.
AB  - BACKGROUND: Causes of low vision and types of low vision devices (LVDs)
      prescribed in other low vision clinics have been studied extensively. Similar
      studies have not been conducted in Malaysia. This paper reports the results of a
      retrospective study of 573 patients seen at the Universiti Kebangsaan Malaysia
      Malaysian Association for the Blind (UKM-MAB) low vision clinic in Kuala Lumpur.
      METHODS: The record cards of 573 patients seen at the UKM-MAB clinic over 10
      years were examined and the following information extracted: date of first
      consultation, age, sex, cause of visual impairment as diagnosed by an
      ophthalmologist and types of low vision devices (LVDs) prescribed. RESULTS: The
      majority of patients were from the younger age groups with 423 (73.8 per cent)
      less than 50 years of age. Three hundred and ninety-five (68.9 per cent) of the
      subjects were males and 178 (31.1 per cent) female. The main causes of low vision
      were congenital structural defects including nystagmus among patients in the zero
      to 29 years age group, retinitis pigmentosa among the 30 to 59 years age group
      and age-related macular degeneration (ARM) among those over 60 years of age.
      CONCLUSIONS: Since the majority of the patients were from the younger age group
      the main causes of low vision were congenital and hereditary diseases. Three
      hundred and forty-one (59.5 per cent) patients seen at the low vision clinic
      accepted the use of LVDs.

PMID- 12482320
TI  - Acute posterior multifocal placoid pigment epitheliopathy (APMPPE).
AB  - A 20-year-old female presented with distorted vision after a viral illness and
      was found to have acute posterior multifocal placoid pigment epitheliopathy
      (APMPPE). This case is described with presenting signs and symptoms and the final
      outcome. The general features and aetiology of APMPPE are discussed.

PMID- 12482321
TI  - Fourth nerve palsy with monovision.
AB  - The fourth cranial nerve is the most vulnerable cranial nerve. Its damage gives
      rise to a vertical ocular deviation and usually the patient comes with a right
      head-tilt. The Parks-Bielschowsky three-step test is a simple and useful test for
      identifying the paretic extraocular muscle, giving rise to such a vertical ocular
      deviation. A case of long-standing fourth nerve palsy in a 45-year-old woman is
      reported. Monovision spectacles were prescribed to give the patient satisfactory
      distant and near vision.

PMID- 12482322
TI  - Competency standards for entry-level to the profession of optometry 1997.

PMID- 12482323
TI  - Ultrasound velocity in the aqueous and vitreous humours of the one-humped camel
      (Camelus Dromedarius).
AB  - BACKGROUND: There are no previous reports on the velocity of ultrasound through
      the aqueous and vitreous humours of the one-humped camel. This information is
      required for determination of the depth of the aqueous and vitreous chambers and
      therefore the axial length. This knowledge together with other, yet to be
      determined, ocular dimensions will ultimately be used in drawing up a schematic
      eye for the camel. This will provide a tool for studying the visual capability of
      this animal. METHOD: A-mode ultrasonography was used to determine the velocity of
      sound through the aqueous and vitreous fluids of the one-humped camel. The fluids
      were obtained from freshly enucleated eyes. RESULTS: The average velocity of
      ultrasound through 20 aqueous and 22 vitreous humour samples kept at 20 degrees
      Celsius was 1,499 +/- 23 m/s and 1,497 +/- 24 m/s, respectively. CONCLUSION: We
      recommend that at 20 degrees Celsius a common value of 1,498 m/s should be
      adopted as the velocity of ultrasound through the aqueous and vitreous humours of
      the one-humped camel. This value is slower than in humans but similar to that of
      the cow and pig.

PMID- 12482324
TI  - Role of conserved Asp293 of cytochrome P450 2C9 in substrate recognition and
      catalytic activity.
AB  - Human cytochrome P450 2C9 (CYP2C9) is important in the metabolism of non
      steroidal anti-inflammatory compounds such as diclofenac, the antidiabetic agent
      tolbutamide and other clinically important drugs, many of which are weakly
      acidic. Multiple sequence alignment of CYPs identified CYP2C9 Asp(293) as
      corresponding to Asp(301) of CYP2D6, which has been suggested to play a role in
      the binding of basic substrates to the latter enzyme. Replacement of Asp(293)
      with Ala (D293A) decreased activity by more than 90%, and led to an approx. 3- to
      10-fold increase in K (m) values for the three test substrates tolbutamide,
      dextromethorphan and diclofenac. Conservative replacement of the carboxyl side
      chain in a Glu (D293E) mutant produced no significant changes in K (m) values and
      slight increases in k (cat) values. Changes in regiospecificity were observed for
      both the Ala and Glu substitutions; low levels of both dextromethorphan O- and N
      demethylation were observed in the D293A mutant, whereas increased preference for
      O-demethylation was observed for the D293E mutant. Expression of constructs
      coding for Asn (D293N) and Gln (D293Q) substitutions failed to form a P450
      correctly. Our analysis suggests a structural role for the carboxyl side chain of
      Asp(293) in CYP2C9 substrate binding and catalysis. The conservation of an Asp
      residue in other CYP families in a position equivalent to Asp(293) indicates a
      common mechanism for maintaining the active-site architecture.

PMID- 12482325
TI  - The anti-apoptotic effect of leukotriene D4 involves the prevention of caspase 8
      activation and Bid cleavage.
AB  - We have shown in a previous study that leukotriene D(4) (LTD(4)) signalling
      increases cell survival and proliferation in intestinal epithelial cells [Ohd,
      Wikstrom and Sjolander (2000) Gastroenterology 119, 1007-1018]. This is highly
      interesting since inflammatory conditions of the bowel are associated with an
      increased risk of developing colon cancer. The enzyme cyclo-oxygenase 2 (COX-2)
      is important in this context since it is up-regulated in colon cancer tissues and
      in tumour cell lines. Treatment with the COX-2-specific inhibitor N -(2
      cyclohexyloxy-4-nitrophenyl)methane sulphonamide has been shown previously to
      cause apoptosis in intestinal epithelial cells. In the present study, we
      attempted to elucidate the underlying mechanisms and we can now show that a
      mitochondrial pathway is employed. Inhibition of COX-2 causes release of
      cytochrome c, as shown by both Western-blot and microscopy studies, and as with
      apoptosis, this is significantly decreased by LTD(4). Since previous studies
      showed increased Bcl-2 levels on LTD(4) stimulation, we further studied apoptotic
      regulation at the mitochondrial level. From this we could exclude the involvement
      of the anti-apoptotic protein Bcl-X(L) as well as its pro-apoptotic counterpart
      Bax, since they are not expressed. Furthermore, the activity of the pro-apoptotic
      protein Bad (Bcl-2/Bcl-X(L)-antagonist, causing cell death) was completely
      unaffected. However, inhibition of COX-2 caused cleavage of caspase 8 into a 41
      kDa fragment associated with activation and caused the appearance of an activated
      15 kDa fragment of Bid. This indicates that N -(2-cyclohexyloxy-4
      nitrophenyl)methane sulphonamide-induced apoptosis is mediated by the activation
      of caspase 8, via generation of truncated Bid, and thereafter release of
      cytochrome c. Interestingly, LTD(4) not only reverses the effects induced by
      inhibition of COX-2 but also reduces the apoptotic potential by lowering the
      basal level of caspase 8 activation and truncated Bid generation.

PMID- 12482326
TI  - Preparation of name and address data for record linkage using hidden Markov
      models.
AB  - BACKGROUND: Record linkage refers to the process of joining records that relate
      to the same entity or event in one or more data collections. In the absence of a
      shared, unique key, record linkage involves the comparison of ensembles of
      partially-identifying, non-unique data items between pairs of records. Data items
      with variable formats, such as names and addresses, need to be transformed and
      normalised in order to validly carry out these comparisons. Traditionally,
      deterministic rule-based data processing systems have been used to carry out this
      pre-processing, which is commonly referred to as "standardisation". This paper
      describes an alternative approach to standardisation, using a combination of
      lexicon-based tokenisation and probabilistic hidden Markov models (HMMs).
      METHODS: HMMs were trained to standardise typical Australian name and address
      data drawn from a range of health data collections. The accuracy of the results
      was compared to that produced by rule-based systems. RESULTS: Training of HMMs
      was found to be quick and did not require any specialised skills. For addresses,
      HMMs produced equal or better standardisation accuracy than a widely-used rule
      based system. However, accuracy was worse when used with simpler name data.
      Possible reasons for this poorer performance are discussed. CONCLUSION: Lexicon
      based tokenisation and HMMs provide a viable and effort-effective alternative to
      rule-based systems for pre-processing more complex variably formatted data such
      as addresses. Further work is required to improve the performance of this
      approach with simpler data such as names. Software which implements the methods
      described in this paper is freely available under an open source license for
      other researchers to use and improve.

PMID- 12482327
TI  - Quantifying robustness of biochemical network models.
AB  - BACKGROUND: Robustness of mathematical models of biochemical networks is
      important for validation purposes and can be used as a means of selecting between
      different competing models. Tools for quantifying parametric robustness are
      needed. RESULTS: Two techniques for describing quantitatively the robustness of
      an oscillatory model were presented and contrasted. Single-parameter bifurcation
      analysis was used to evaluate the stability robustness of the limit cycle
      oscillation as well as the frequency and amplitude of oscillations. A tool from
      control engineering--the structural singular value (SSV)--was used to quantify
      robust stability of the limit cycle. Using SSV analysis, we find very poor
      robustness when the model's parameters are allowed to vary. CONCLUSION: The
      results show the usefulness of incorporating SSV analysis to single parameter
      sensitivity analysis to quantify robustness.

PMID- 12482329
TI  - Highlights from: 27th congress of the European Society for Medical Oncology.
      Nice, France. October 18-22, 2002.

PMID- 12482330
TI  - Lack of benefit of 5-fluorouracil-based adjuvant chemotherapy in colorectal
      cancer with microsatellite instability.

PMID- 12482331
TI  - Pathologic prognostic factors in the recurrence of rectal cancer.
AB  - For rectal cancer, local recurrence following surgical treatment is a grave
      complication that occurs in as many as 25% of cases. Pathological examination of
      the surgical resection specimen plays a primary role in assessing both the
      surgery- and tumor-related factors that contribute to the risk of recurrence.
      Among the tumor-related factors, stage has long been considered the single most
      accurate indicator of survival. However, recent evidence strongly suggests that
      the most powerful predictor of both local recurrence and overall outcome in the
      absence of distant metastatic disease is the macroscopic quality of the
      mesorectum in the resection specimen and the proximity of the tumor to the
      circumferential (radial) resection margin. Additional pathologic features have
      been shown to have stage-independent prognostic significance in colorectal cancer
      and may help to further define risk of adverse outcome. Such features include:
      tumor grade; histologic type; extent of extramural penetration by tumor; neural,
      venous, and/or lymphatic invasion; tumor border configuration; tumor budding; and
      host lymphoid response. The predictive value of tumor-specific molecular features
      is currently under investigation and may help to further improve prognostication
      and refine individual patient management in rectal cancer.

PMID- 12482332
TI  - Perspectives on the role of sequential or combination chemotherapy for first-line
      and salvage therapy in advanced colorectal cancer.
AB  - Metastatic colorectal cancer is a major cause of cancer-related mortality.
      Surgical resection of all known metastatic disease can be curative in selected
      patients. The majority of patients, however, require the consideration of
      systemic chemotherapy as optimal palliative treatment for their diseases. Using
      new effective chemotherapeutic agents such as irinotecan and oxaliplatin has
      resulted in a clear and clinically significant improvement in survival for
      patients with metastatic colorectal cancer. The optimal sequences and
      combinations of these agents as initial and salvage chemotherapy along with 5
      fluorouracil (5-FU) and leucovorin are controversial. It seems clear that it is
      important for all patients to have access to all 3 drugs at some point in their
      therapy for optimal results. Recent randomized trials of first-line chemotherapy
      for metastatic colorectal cancer in which patients were likely to have access to
      all 3 effective drugs demonstrated median survivals of 18-20 months. This
      compares favorably to median survivals of approximately 12 months for patients
      treated with 5-FU-based regimens alone prior to the availability of effective
      salvage therapy. A small but meaningful number of patients might develop
      resectable disease with curative intent as the result of significant tumor
      response to combination chemotherapy. Herein, we review recent developments in
      combination and sequential chemotherapy for metastatic colorectal cancer and the
      implications for the optimal treatment in these patients.

PMID- 12482333
TI  - Systemic chemotherapy for metastatic colorectal cancer: reasons to combine.

PMID- 12482334
TI  - Randomized phase II trial of embolization therapy versus chemoembolization
      therapy in previously treated patients with colorectal carcinoma metastatic to
      the liver.
AB  - Locoregional therapies are useful in treating patients with colorectal cancer
      metastatic to the liver. A prospective randomized phase II trial of hepatic
      artery embolization versus hepatic artery chemoembolization was conducted to
      evaluate the response rates and toxicities of these therapies in the second-line
      setting. Patients were required to have biopsy-proven adenocarcinoma of the colon
      or rectum metastatic to the liver, with the liver as the sole or predominant site
      of metastatic disease. All patients had measurable disease and had failed at
      least one prior systemic chemotherapy treatment for metastatic disease. Patients
      were randomized to receive either embolization therapy with polyvinyl alcohol
      foam (Ivalon) administered as a single agent or chemoembolization using polyvinyl
      alcohol foam mixed with 750 mg/m2 of 5-fluorouracil and 9 million units of
      interferon. Drugs and embolic material were administered via the hepatic artery
      as a slurry with polyvinyl alcohol foam. Fifty eligible patients were enrolled.
      There were 24 patients in the chemoembolization arm and 26 in the embolization
      arm. Sixty-four percent of patients in both treatment arms had the liver as the
      sole metastatic site. The most common National Cancer Institute common toxicity
      criteria grade 3/4 toxicities were diarrhea (17%) and hepatic toxicity (8%).
      There was 1 (4%) treatment-related mortality due to a hepatic abscess. Four
      patients (15.4%) treated with embolization had a partial response (PR), and 5
      patients (20.8%) treated with chemoembolization had a PR. The median survival for
      all patients was 11 months (95% confidence interval [CI], 8-15 months). Survival
      in patients with extrahepatic disease was 8 months (95% CI, 6-10 months).
      Survival in patients with liver-only metastases was 15 months (95% CI, 10-17
      months). Embolization of the liver as second-line therapy in patients with liver
      predominant metastases is safe and effective. Median survivals are comparable to
      other second-line therapies

PMID- 12482335
TI  - Chemoembolization is effective as second-line therapy in patients with colorectal
      carcinoma metastatic to the liver.

PMID- 12482336
TI  - Combination of 5-fluorouracil and irinotecan on modulation of thymidylate
      synthase and topoisomerase I expression and cell cycle regulation in human colon
      cancer LoVo cells: clinical relevance.
AB  - This study was designed to explore the possible interaction of 5-fluorouracil (5
      FU) and 7-ethyl-10-hydroxycamptothecin (SN-38) in vitro. Human colon cancer LoVo
      cells were treated in both a dose- and time-dependent manner using clinically
      relevant concentrations of and exposure to 5-FU and/or SN-38. The expression of
      thymidylate synthase (TS), topoisomerase I, and cell cycle kinetics were
      evaluated by Western blot analysis and flow cytometry, respectively. Cytotoxicity
      was evaluated by MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium
      bromide) assay. The cytotoxic effects of combination treatment were determined by
      median effect analysis. Topoisomerase I expression was downregulated following 12
      hours of exposure to treatment, and topoisomerase I expression recovered 8 hours
      after SN-38 was removed. The TS expression was decreased following 24 hours of 5
      FU and it remained at reduced levels for > 24 hours after removal of 5-FU. SN-38
      induced an arrest at S/G2/M phase, reaching its maximum effect at 12 hours. This
      cell cycle arrest was reversed 24 hours after SN-38 was removed. 5-FU induced an
      arrest at the S phase, and maximum arrest occurred at 12 hours and lasted for >
      48 hours. After 12 hours of sequential SN-38, LoVo cells were arrested in S
      phase, thereby potentiating the effect of 5-FU. Cytotoxicity studies confirmed
      the synergistic interaction between 5-FU and irinotecan. These findings suggest
      that the proper sequencing of 5-FU/irinotecan depends on regulation of
      topoisomerase I, and cell cycle kinetics

PMID- 12482337
TI  - [Changes of protein tyrosine phosphorylation in erythrocyte band 3 glucose-6
      phosphate dehydrogenase deficiency].
AB  - OBJECTIVE: To explore the hemolytic mechanism of glucose-6-phosphate
      dehydrogenase (G6PD) deficient erythrocytes in the view of phosphorylation of
      membrane protein. METHODS: The alternation of membrane protein phosphorylation
      and the effect of dithiothreitol (DTT) on protein phosphorylation were analysed
      by Western blot technique. The activity of phosphotyrosine phosphatase (PTPs) was
      determined by using p-nitrophenyl phosphate as substrate. RESULTS: Tyrosine
      phosphorylation of band 3 protein was obviously enhanced in G6PD-deficient
      erythrocytes. The activity of PTPs was low compared to the normal erythrocytes.
      The level of phosphotyrosine in G6PD-deficient erythrocytes incubated with DTT
      was almost the same as in those without DTT. The results were consistent with the
      activity of PTPs. CONCLUSIONS: PTPs activity reduction and tyrosine
      phosphorylation enhancement induced by oxidation in G6PD deficiency play an
      important role in erythrocytes hemolysis. However, the alternation of thiol group
      is not the only factor affecting the activity of PTPs in G6PD-deficient
      erythrocytes.

PMID- 12482338
TI  - [Ex vivo expansion of CD34(+) CD59(+) cells from bone marrow of paroxysmal
      nocturnal hemoglobinuria patients].
AB  - OBJECTIVE: To study the separation, purification and ex vivo expansion of
      CD(34)(+) CD(59)(+) cells from patients with paroxysmal nocturnal hemoglobinuria
      (PNH), and explore the new treatment for the PNH patients. METHODS: CD(34)(+)
      CD(59)(+) cells were selected from the bone marrow mononuclear cells of PNH
      patients by means of immunomagnetic microbead-flow cytometry two step sorting
      method, followed by ex vivo expansion of the cells with combination of
      hematopoietic factors for two weeks. RESULTS: The best combination for the ex
      vivo expansion was SCF + IL-3 + IL-6 + FL + Tpo + Epo, and the seventh day was
      the most suitable time for the best harvest when the CD(34)(+) CD(59)(+) cells
      were 22.42 +/- 3.73 fold expanded. After ex vivo expansion, the cells remained
      CD(59) positive and potent capacity of colony formation, but their potentialities
      to multilineage differentiation were decreased. CONCLUSION: The present study
      shows that ex vivo expansion of CD(34)(+) CD(59)(+) cells from PNH patients might
      promise the possibility of performing ABMT or APBSCT clinincally for the
      patients.

PMID- 12482339
TI  - [Study of lymphocyte subsets and its activated-molecules in patients with
      paroxysmal nocturnal hemoglobinuria].
AB  - OBJECTIVE: To investigate the relationship between subsets of lymphocytes and
      between its activated status and the clinical manifestations in patients with
      PNH, and to unfold immunological mechanism in the pathogenesis of PNH. METHODS:
      The peripheral blood mononuclear cells (PBMNC) from 18 PNH patients and 20
      controls were separated into two subpopulations using anti-CD(59) monoclonal
      antibody combined with goat-anti-mouse IgG immunomagnetic beads. CD(3)(+),
      CD(4)(+) and CD(8)(+) lymphocyte subsets were detected by flow cytometry. In 6
      newly diagnosed patients, phenotypes associated with T cell activation such as
      CD(28)(+)/CD(4)(+) or CD(8)(+) cells, CD(8)(+) CD(38)(+) cells, and HLA
      DR(+)/CD(4)(+) or CD(8)(+), and NK (CD(3)(-) CD(16)(+)) cells were detected in
      the peripheral blood. RESULT: Patients with PNH showed significantly increased
      CD(3)(+) CD(8)(+)/CD(3)(+) CD(4)(+) ratio as compared with controls (1.22 +/-
      0.51 vs 0.86 +/- 0.27, P < 0.05), and the CD(3)(+) CD(8)(+)/CD(3)(+) CD(4)(+)
      ratio in CD(59)(-) PBMC was higher than that in CD(59)(+) PBMC (2.31 +/- 1.56 vs
      0.62 +/- 0.27, P < 0.05). The ratios of CD(4)(+) CD(28)(+)/CD(4)(+) markedly
      decreased and CD(8)(+)HLA-DR(+)/CD(8)(+) increased. CONCLUSION: Patients with PNH
      appear to have abnormalities in their lymphocytes. Increased ratios of CD(3)(+)
      CD(8)(+)/CD(3)(+) CD(4)(+) and HLA-DR(+) CD(8)(+)/CD(8)(+) lymphocytes as well as
      declined ratio of CD(4)(+) CD(28)(+)/CD(4)(+) lymphocytes might be involved in
      the pathogenesis of PNH.

PMID- 12482340
TI  - [Role of Th1 cell in the pathogenesis of aplastic anemia].
AB  - OBJECTIVE: To detect the quantity, proportion and function of producing cytokines
      of Th1 and Th2 cells in aplastic anemia (AA) patients and their contribution to
      the hematopoietic failure. METHODS: (1) Eleven patients with severe aplastic
      anemia (SAA) at diagnosis were observed by Marsh's method for the CFU-E, BFU-E
      and CFU-GM before and after depletion of CD(4)(+) T lymphocytes from bone marrow
      mononuclear cells (BMMNC); (2) Th1 (CD(4)(+) IFN-gamma(+)) and Th2 (CD(4)(+) IL
      4(+)) cells in peripheral blood mononuclear cells (PBMNC) of 21 SAA patients and
      17 normal controls were counted by FACS. (3) mRNA expression of IFN-gamma and IL
      4 gene in unstimulated BMMNC from 16 SAA patients, 11 chronic aplastic anemia
      (CAA) patients, 26 other hematological diseases patients and 11 normal controls
      were measured by reverse transcriptase polymerase chain reaction (RT-PCR).
      RESULT: (1) CFU-E, CFU-GM and BFU-E increased significantly after depletion of
      CD(4)(+) T lymphocytes from BMMNC of SAA patients. (2) The percentage of IFN
      gamma producing CD(4)(+) T cell (Th1) of SAA patients was significantly higher
      than that of controls, the percentages of IL-4 producing CD(4)(+) T cells (Th2)
      had no difference between SAA patients and normal controls. (3) IFN-gamma mRNA
      was detected in unstimulated BMMNC in 13 of 16 SAA patients, 6 of 11 CAA patients
      and one of 6 paroxysmal nocturnal hemoglobinuria (PNH) patients. The IFN-gamma
      mRNA was not detected in unstimulated BMMNC of 11 normal controls and other
      hematological diseases patients. CONCLUSIONS: Disbalance of CD(4)(+) T
      lymphocytes subsets and increases in quantity and IFN-gamma producing function of
      Th1 cells might be important for the development of bone marrow failure in AA and
      in distinguishing AA from other kinds of pancytopenic diseases.

PMID- 12482341
TI  - [Clinical analysis of 185 patients with polycythemia vera].
AB  - OBJECTIVE: To understand the clinical feature and natural course of polycythemia
      vera (PV). METHODS: The clinical symptoms, signs, laboratory examination and
      prognosis of 185 patients with PV were analysed. RESULTS: There are 122 males and
      63 females. The mean age was (52.7 +/- 14.1) years. The mean hemoglobin level was
      (208.3 +/- 21.2) g/L. Pancytosis was displayed in 74 (40%) cases, excess of red
      blood cells in 33 (17.8%), excess of red blood cells and granulocytes in 67
      (36.2%) and excess of red blood cell and platelets in 11 (5.9%). Splenomegaly was
      found in 123 (66.5%) patients and hepatomegaly in 30 (16.2%). Quantitative assess
      of serum Epo was done in 25 patients. The level was low in 16 (64.2%) and normal
      in 9 (36.0%). Hematopoietic progenitor culture yields was elevated in 11
      patients, endogenous erythroid colonies (EEC) formation was found in 10 cases
      (90.9%). Eighty two patients (44.3%) had 101 attacks of vascular thrombotic
      incidents, 7 patients developed myelofibrosis (MF). Secondary cancer occurred in
      1 patient. Two patients died of thrombosis. CONCLUSION: PV is an elderly adult
      myeloproliferative disease with a high frequency of thrombosis. EEC can be found
      out in PV patients. The serum Epo level is not increased in PV patients. The main
      sequelae of PV is MF.

PMID- 12482342
TI  - [Expression of cell adhesion molecules in acute leukemia cell].
AB  - OBJECTIVE: To investigate the role of cell adhesion molecule in the development
      and extramedullary infiltration (EI) of acute leukemia. METHODS: The expressions
      of neural cell adhesion molecule (NCAM) gene, intercellular adhesion molecule-1
      (ICAM-1) and vascular cell adhesion molecule (VCAM-1) genes in 25 acute leukemia
      patients bone marrow cells were detected by microarray and reverse transcriptase
      polymerase chain reaction (RT-PCR). RESULTS: The expressions of NCAM, ICAM-1 and
      VCAM-1 gene were significantly higher in acute leukemia cells and leukemia cells
      with EI than in normal tissues and leukemia cells without EI, respectively, both
      by cDNA microarray and by RT-PCR. CONCLUSION: The cDNA microarray is a powerful
      technique in analysis of acute leukemia cells associated genes. High expressions
      of cell adhesion molecule genes might be correlated with leukemia pathogenesis
      and infiltration of acute leukemia cell.

PMID- 12482343
TI  - [CD40 ligandization promotes IL-6 and Flt3 ligand production of bone marrow
      stromal cells].
AB  - OBJECTIVE: To analyze the expression of the CD(40) and its ligand (CD(40)L) on
      bone marrow stromal cells (BMSC), and investigate interleukin-3 (IL-3), IL-6,
      Flt3 ligand (FL) and stem cell factor (SCF) production of BMSC after stimulated
      with CD(40) agonistic monoclonal antibody (5C11) and its role in the regulation
      of hematopoiesis. METHODS: BMSC were freshly isolated from adult bone marrow. The
      expression of CD(40) on these cells was determined with flow cytometry, the
      concentrations of IL-3, IL-6, FL and SCF in the supernatant at 24, 48 and 72
      hours after BMSC cultured with 5C11 at a dose of 20 micro g/ml were determined by
      the ELISA assay. After BMSC incubated with 5C11 for 24 hours, the supernatant was
      collected and cultured with purified cord blood CD(34)(+) cells for 7 days under
      37 degrees C in a fully humidified atmosphere supplement with 5% CO(2). Colony
      formation assay and Annexin V assay were employed to determine the proliferation
      and apoptosis of the CD(34)(+) cells. RESULTS: BMSC expressed CD(40) and the
      production of IL-6 and FL increased after stimulated with 5C11 while IL-3 and SCF
      had no change. The supernatant collected from the stimulated BMSC promoted
      proliferation of CD(34)(+) cells, increased the CFU-GM yields and had anti
      apoptosis effects. CONCLUSION: CD(40) ligandization on BMSC increased the
      production of IL-6 and FL and promoted the proliferation of CD(34)(+) cells. The
      couple CD(40)/CD(40)L may be involved in the control of hematopoiesis via
      modulation of the cytokine network in the bone marrow.

PMID- 12482344
TI  - [Type I antithrombin deficiency due to 13389G deletion in antithrombin gene].
AB  - OBJECTIVE: To identify the gene mutation of a kindred with type I antithrombin
      deficiency. METHODS: All of the seven exons and intron-exon boundaries of
      antithrombin gene were analysed by PCR and direct sequencing of amplified PCR
      products from the propositus. RESULTS: A 13389G deletion in exon 6 was
      characterized in propositus, and this mutation led to frameshift. CONCLUSION:
      This is a novel mutation, which can cause antithrombin deficiency and thrombosis.

PMID- 12482345
TI  - [Establishment and biological characteristics of human multiple myeloma cell line
      CZ-1].
AB  - OBJECTIVE: To establish a multiple myeloma (MM) cell line and analyze its
      biological characteristics. METHODS: Mononuclear cells isolated from the
      peripheral blood (PB) and bone marrow (BM) of an advanced MM patient (lambda
      light chain type) were incubated by liquid cell culture, cell morphology was
      analyzed by Wright-Giemsa-staining and cytochemical staining, immunophenotyping
      by flow cytometry, cytogenetic analysis by chromosome RHG-banding method.
      Quantitative fluorescent polymerase chain reaction was used to detect EBV DNA.
      RESULTS: The established cell line could survive and proliferate in the presence
      of feeder cells or conditioned medium. The cells secreted lambda light chain and
      were negative for EBV. The Wright-Giemsa-staining showed typical plasmablast or
      plasma cell morphology. The cytochemical staining of the cells showed the
      following reactivity pattern: positive for acid phosphatase, negative for
      myeloperoxidase. The immunoprofile of the cells was concordant with that of MM
      cells: positive for CD(10), CD(28), CD(38), CD(138), CD(56), CD(49d), CD(44),
      CD(54) and CD(58), negative for CD(19), CD(40), CD(95), CD(95)L, CD(34), CD(2)
      and CD(5). The cytogenetic analysis showed complex chromosome abnormality of i
      (1q +), 8q +, 13q +, i (17q), i (18q) and + M. There was no difference in
      morphology, immunophenotype and cytogenetics between cells from PB and BM.
      CONCLUSION: A MM cell line secreting lambda light chain named CZ-1, was
      established. The cells from both PB and BM have the same biological
      characteristics.

PMID- 12482346
TI  - [Therapeutic effectiveness of thalidomide to multiple myeloma and its mechanism].
AB  - OBJECTIVE: To observe the effective mechanism and side effects of thalidomide to
      multiple myeloma (MM). METHODS: Ten cases of MM were studied, of which 3 were
      previously untreated and 7 refractory or relapsed. Bone marrow microvascular
      density (MVD) was detected by factor-VIII related antigen and CD(34)
      immunohistological staining and serum concentration of vascular endothelial
      growth factor (VEGF) before and after treatment was determined by ELISA. The
      initial dosage of thalidomide was 100 approximately 200 mg/d with a weekly
      escalation of 50 mg/d to 450 approximately 650 mg/d. The therapeutic
      effectiveness is classified into partial remission, improvement and uneffective
      according to the decrease of serum M protein and bone marrow myeloma cells.
      Anemia, renal function and blood electrolytes were also observed. RESULTS: Before
      treatment, MVD was 73.32 +/- 28.80 and 32.30 +/- 12.50 in MM and control group,
      respectively, (P < 0.01). MVD in MM group decreased to 56.12 +/- 19.34 after
      treatment, and was of significant difference (P < 0.05) as compared to the
      pretreatment value. However, there was still a significant difference as compared
      to control (56.12 +/- 19.34 vs 32.30 +/- 12.50, P < 0.01). The concentration of
      VEGF significantly decreased after treatment [from (178.23 +/- 26.56) ng/L to
      (78.48 +/- 19.98) ng/L, P < 0.01)]. The total effective rate was 70%. There were
      no serious side effects. CONCLUSION: MVD and VEGF concentration were decreased
      obviously by thalidomide treatment. The dosage of 450 approximately 650 mg/d
      might be effective in refractory or initial MM.

PMID- 12482347
TI  - [Study on the biological activity and molecular mechanism of IFNalpha on human
      myeloma cell line Sko-007].
AB  - OBJECTIVE: To investigate the biological activity and molecular mechanism of
      interferon alpha (IFNalpha) on human myeloma cell line Sko-007. METHODS: The
      effect of IFNalpha on the growth of Sko-007 cells was measured by MTT assay.
      Cells cycle distribution and the expression of two IL-6 receptor chains (IL-6R
      and gp130) on Sko-007 cell surface in the absence or presence of IFNalpha were
      monitored by FACS analysis. The activation state of protein kinase ERK, which is
      involved in Ras/MAPK signal transduction pathway mediating cell survival and
      proliferation, and the expression of anti-apoptotic Bcl-2 family proteins-Bcl-2,
      Bcl-x(L) and Mcl-1 in Sko-007 cells with or without IFNalpha were determined by
      immunoblot assay. RESULT: IFNalpha arrested Sko-007 cell cycle progression. After
      stimulation with IFNalpha, an obvious increase in G(0)/G(1) phase (41.1%-->84.1%)
      and decrease in S phase (57.1%-->13.3%) of Sko-007 cell cycle distribution can be
      observed. Moreover, the proliferation of Sko-007 cells was dramatically inhibited
      in the presence of IFNalpha, with a maximal inhibitory rate up to 88%. In
      addition, the expression of gp130 on cell surface, the activation of protein
      kinase ERK and the expression of Bcl-2 and Bcl-x(L) were all down-regualted in
      IFNalpha-stimulated Sko-007 cells. CONCLUSION: The inhibitory effect of IFNalpha
      on the proliferation of Sko-007 cells was mediated by gp130 down-regulation,
      degradation of Bcl-2 family anti-apoptotic proteins and inhibition of ERK
      activation.

PMID- 12482348
TI  - [Thalidomide inhibits the angiogenic activity of culture supernatants of multiple
      myeloma cell line].
AB  - OBJECTIVE: To investigate the pro-angiogenic effects of several multiple myeloma
      (MM) cell line culture supernatants on human bone marrow endothelial cell (HBMEC)
      proliferation, migration, and capillary formation, and the anti-angiogenic
      effects of thalidomide. METHODS: HBMEC was cultured in the presence of MM cell
      lines (IM9, XG1, U266 and MOLP-5) supernatants. Proliferation and migration of
      HBMEC were determined, capillary-like tubule formation of HBMEC was examined in
      fibrin and Matrigel. The inhibiting effect of thalidomide was investigated by
      adding it into myeloma cell line culture supernatants. Vascular endothelial
      growth factor (VEGF) was measured by ELISA. RESULTS: (1) MM cell lines culture
      supernatants promoted HBMEC proliferation and migration. (2) In fibrin and
      Matrigel, capillary-like tubule network formation promoted by the supernatants.
      (3) All of these effects could be inhibited by thalidomide. (4) This effect was
      not related to VEGF in the supernatants. CONCLUSIONS: MM cell line promote
      proliferation, migration and tubule formation by secreting VEGF or other several
      cytokines. Thalidomide can inhibit these effects.

PMID- 12482349
TI  - [Immunophenotype and differential diagnosis of Hodgkin's lymphoma].
AB  - OBJECTIVE: To study the immunophenotype and differential diagnosis of Hodgkin's
      lymphoma (HL). METHOD: Fifty six cases originally diagnosed as HL were re
      evaluated according to lymphoma classification of WHO 2000 on paraffin sections
      using SP immunohistochemistry. RESULTS: Among the 56 cases, 47 met the WHO
      criteria for HL, 8 were NHL and 1 metastatic tumor. Of the 47 HL cases, 2 were
      nodular lymphocyte predominant HL (NLPHL), 43 classical Hodgkin's lymphoma (CHL)
      and 2 unclassified HL, and of the 8 cases reclassified as NHL, 6 were T-cell rich
      B-cell lymphoma (TCRBCL) and 2 anaplastic large cell lymphoma (ALCL). In NLPHL
      cases, L&H cells were CD(20)(+), CD(15)(-) and CD(30)(-); CD(57)(+) cells and
      small B-lymphocytes predominated the background infiltration. Diagnostic R-S
      cells and other tumor cells in 43 cases of CHL were positive for CD(30) (100%),
      CD(15) (81%) and CD(20) (7%). Six cases of TCRBCL were negative for CD(15) and
      CD(30). Two cases of ALCL were positive for CD(30), ALK-1 and CD(3), and negative
      for CD(15) and CD(20). The reactive inflammatory infiltration in CHL and TCRBCL
      was rich in TIA-1 positive cytotoxic lymphocytes, and CD(57)(+) cells were rarely
      encountered. CONCLUSION: Combining the immunophenotype of tumor cells and
      background cells with morphologic criteria are more helpful for classification of
      HL, and discrimination between NLPHL, CHL and TCRBCL.

PMID- 12482350
TI  - [Allogeneic bone marrow transplantation for the treatment of Bruton disease].
AB  - OBJECTIVE: To explore the efficacy of allogeneic bone marrow transplantation
      (allo-BMT) for the treatment of Bruton disease. METHODS: HLA-matched sibling bone
      marrow transplantation was performed for the treatment of 2 cases of X-linked
      agammaglobulinemia. One of them received allo-BMT twice. RESULTS: Recovery of
      hematopoiesis was gained at day 20 and day 13 after allo-BMT in the two cases
      respectively. Serum immunoglobin rose gradually to normal level in three months.
      Their humoral immuno-system was reconstituted and life quality improved. These
      two patients are still in disease-free survival for 13 and 2 years respectively.
      There was no serious graft-versus-host-disease. CONCLUSION: Stem cell
      transplantation is a choice for the treatment of Bruton disease.

PMID- 12482351
TI  - [Synergic effect of heparan sulfate and cytokines on in vitro growth of human
      umbilical cord blood hematopoietic cells].
AB  - OBJECTIVE: To explore the synergic effect of heparan sulfate (HS) and cytokines
      on the growth of human umbilical cord blood (UCB) hematopoietic cells. METHODS:
      Hematopoietic cells from human UCB were cultured with (1) cytokines (rhIL-3, rhIL
      1beta, rhIL-6 and SCF) or (2) SN (supernatant from cultured human marrow stromal
      cells) and cytokines, or (3) SN, or (4) HS and cytokines. Cellular proliferation,
      CFU-GM yields and changes of cell immunophenotype were observed. RESULTS:
      Hematopoietic cell proliferation reached peak at the 14th day. The number of
      total nucleated cells increased 134.5-, 171.3-, 81.5- and 167.2-fold in (1), (2),
      (3) and (4) groups, respectively, at the 21th day, the (3) group significantly
      decreased. CD(34)(+) cells increased at the 7th day and reached peak, at the 14th
      day with a percentage of 68.4%, 82.5%, 69.8% and 79.3%, and at the 21th day
      56.2%, 71.7.%, 12.3% and 73.3%, respectively. CD(33)(+) cells reached peak at the
      14th day and increased by 80.2%, 68.6%, 81.6% and 70.3%, respectively, and
      remained these levels at the 21th day. CD(38)(+) cells increased by 66.6%, 73.8%,
      70.4% and 71.9% at the 7th day and remained this level at the 14th and the 21th
      day. From the first week of culture, the percentage of CFU-GM increased in all of
      the four groups, at the second week of culture, it increased by 250%, 279%, 217%
      and 273%, and at the third week still increased by 151%, 240%, 145% and 231%,
      respectively. CONCLUSION: The combination of SN and cytokines have a synergic
      effect in promoting proliferation of hematopoietic cell from human UCB. The
      synergic effect remained the same when SN was replaced by heparan sulfate.

PMID- 12482352
TI  - [Initial division behavior of cord blood hematopoietic stem cells depends on
      microenvironment].
AB  - OBJECTIVE: The influence of the mimic hematopoietic microenvironment and adhesion
      factor on the initial divisional behavior of human cord blood hematopoietic
      progenitors was studied in the culture system with certain cytokines. METHODS:
      (1) CD(34)(+) CD(38)(-) single cell was sorted by FACS. (2) The stem cell
      supporting stromal feeder layer AFT024 and single adhesive factor fibronectin
      (Fn) were used in the culture system and their influence on the initial division
      was observed. RESULTS: (1) In the presence of the combined cytokines, the
      CD(34)(+) CD(38)(-) human cord blood cells displayed fixed fraction of quiescent,
      slow and fast division, and asymmetric division. (2) There was no influence of
      adhesive factor itself on initial division of CD(34)(+) CD(38)(-) cells. (3) The
      hematopoietic microenvironment mimicked by AFT024 promoted CD(34)(+) CD(38)(-)
      cells to proliferate extensively and undergo more asymmetric division.
      CONCLUSIONS: (1) CD(34)(+) CD(38)(-) cells are heterogeneous and composed of
      various subpopulations with different initial proliferative behavior, including
      asymmetric division. (2) The hematopoietic microenvironmental mimicked by AFT024
      supports the hematopoietic progenitors better than cytokines and single adhesion
      factor do, for their proliferation extensively and preservation the self-renewal
      capacity.

PMID- 12482353
TI  - [The relationship of beta-fibrinogen gene polymorphisms and ischaemic
      cardiocerebral vascular disease].
AB  - OBJECTIVE: To analyze the frequency of beta-fibrinogen (beta-Fg) gene -455G/A, 
      148C/T and 448G/A polymorphism, fibrinogen molecular reactivity and their
      association with plasma fibrinogen levels in health adults, myocardial infarction
      and cerebral infarction disease. METHODS: The beta-Fg gene -455G/A, -148C/T and
      448G/A polymorphisms were analyzed by restriction fragment length polymorphism
      (RFLP). Fibrinogen molecular reactivity was analyzed for the conversion kinetics
      of fibrinogen into fibrin by a computer assistant procedure. Plasma fibrinogen
      levels were determined by Clauss method. RESULTS: The frequencies of -455A, 
      148T, 448A allele in health adults were 0.185, 0.194 and 0.192, in myocardial
      infarction disease 0.295, 0.318 and 0.307, in cerebral infarction disease 0.177,
      0.193 and 0.182, respectively. The frequencies of -455A, -148T, 448A alleles in
      myocardial infarction disease were apparently higher than that of health adults.
      There were close linkage between -455G, -148C and 448G or -455A, -148T and 448A,
      the correspondence was over 98%. There are no differences in the plasma
      fibrinogen levels of the three polymorphisms in two genotype groups. The
      fibrinogen molecular reactivity was significantly increased in cardiocerebral
      vascular disease and related with plasma fibrinogen level. CONCLUSION: The three
      polymorphisms loci are strong linkage disequilibrium. There are no significant
      differences in the plasma fibrinogen levels of the three polymorphisms in two
      genotype groups. The frequencies of -455A, -148T, 448A alleles in myocardial
      infarction disease were apparently higher than that of health adults. It suggest
      that there was no association between beta-Fg gene -455G/A, -148C/T and 448G/A
      polymorphisms and plasma fibrinogen levels, but did in myocardial infarction
      disease. The fibrinogen molecular reactivity was significantly increased in
      cardiocerebral vascular disease and related with plasma fibrinogen level.

PMID- 12482354
TI  - [Study on plasma coagulation factor VII (FVII) levels and polymorphisms of FVII
      gene in patients with coronary heart disease].
AB  - OBJECTIVE: To investigate the plasma levels of coagulation factor VII (FVII) and
      polymorphisms of FVII gene in patients with coronary heart disease (CHD), and
      evaluate the effect of plasma FVII levels and FVII gene polymorphisms on CHD.
      METHODS: Plasma FVIIa, FVII: Ag and FVIIc were measured and polymorphisms of FVII
      gene were analyzed in 149 control cases and 60 CHD cases, including 33 acute
      myocardial infarction (AMI) cases by a combination of polymerase chain reaction
      restriction fragment length polymorphism (PCR-RFLP) and agarose gel
      electrophoresis. RESULTS: FVIIa, FVIIc in AMI group were significantly higher
      than that in control group, but FVII: Ag wasn't. There were no significant
      difference in plasma FVIIa, FVII: Ag and FVIIc between CHD and control group. The
      IVS7 genotypic frequency in AMI group was significantly different from that in
      control group. There was no significant difference in genotypic frequencies and
      allelic frequencies in other polymphism sites. FVII: Ag was significantly higher
      in -402A homozygote than that in -402G homozygote. CONCLUSIONS: Increased FVII
      levels, especially FVIIa and FVIIc in plasma, may contribute to coronary artery
      thrombosis. There was significant difference in IVS7 genotype frequency between
      control and AMI groups, but the rest weren't significantly different. FVII: Ag
      was significantly higher in -402A homozygote than that in -402G homozygote.
      Polymorphism of -402 G/A may play an indirect role in AMI by regulating plasma
      FVII levels.

PMID- 12482355
TI  - [Participation of bonth splenic CD(5)(+) and CD(5)(-) B lymphocytes in production
      of platelet glycoprotein-specific autoantibodies in chronic ITP].
AB  - OBJECTIVE: To investigate the percentage of splenic CD(5)(+) B lymphocytes in
      chronic idiopathic thrombocytopenic purpura (IT) and the impact of splenic
      CD(5)(+) and CD(5)(-) B lymphocytes on the production of platelet glycoprotein
      (GP)-specific autoantibodies. METHODS: Splenic CD(5)(+) B lymphocytes were
      identified by two-color flow cytometric analysis in eight patients. Four of the
      eight patients displayed plasma autoantibodies against both GPIIb/IIIa and
      GPIb/IX, and their splenic B lymphocytes were separated by Ficoll-Hypaque density
      gradient and sheep erythrocyte, and further purified by magnetic activate cell
      separation (MACS). Purified CD(5)(+) and CD(5)(-) B lymphocytes were cultured
      separately with or without staphylococcus aureus cowan I (SAC). GP specific
      autoantibodies in culture supernatants were measured by modified monoclonal
      antibody immobilization of platelet antigen assay (MAIPA). RESULTS: The
      percentage of splenic CD(5)(+) B lymphocytes in ITP patients was slightly higher
      than that in control with no statistical significance. MACS purified splenic
      CD(5)(+) and CD(5)(-) B lymphocytes from three out of four ITP patients produced
      high levels of anti-GPIIb/IIIa and anti-GPIb/IX antibodies. Culture supernatants
      of CD(5)(+) B lymphocytes from the other patient showed positive reaction only in
      GPIb/IX MAIPA. Culture supernatant of CD(5)(-)B lymphocytes from the same patient
      were double positive in both GPIIb/IIIa and GPIb/IX MAIPA. CONCLUSIONS: Both
      splenic CD(5)(+) and CD(5)(-) B lymphocytes produce platelet GP-specific
      autoantibodies in chronic ITP with similar antibody spectrum and titer, and may
      all play a role in the autoimmune pathogenesis of ITP.

PMID- 12482356
TI  - [In vitro expression of human factor VIII gene induced by sodium butyrate].
AB  - OBJECTIVE: To explore the effect and mechanism of sodium butyrate on expression
      of human clotting factor VIII in vitro. METHODS: Mouse NIH/3T3 cell line was
      transfected with recombinant plasmid vector pRC/RSV-BDD-hFVIII, which enclosed B
      domain deleted (760aa approximately 1 639aa) human factor VIII cDNA (BDD-hFVIII
      cDNA). Then cells were incubated in Dulbecco's modification of Eagle's medium
      (DMEM) containing sodium butyrate for 24 hours, hFVIII: C and hFVIII: Ag in the
      cell culture medium were measured by ELISA assay and one-stage method,
      respectively. In addition, the effect of sodium butyrate on transcription of cDNA
      encoding the whole hFVIII, heavy and light chain of hFVIII was also investigated
      by means of run-on assay. RESULTS: After stimulation of sodium butyrate, the
      levels of hFVIII: C and hFVIII: Ag increased 70% than those of control. Run-on
      assay showed that sodium butyrate enhanced the transcription of cDNA which
      encoded heavy chain of hFVIII. CONCLUSION: Sodium butyrate can improve the
      expression of hFVIII through enhancing the transcription of hFVIII heavy chain
      encoding cDNA. It demonstrated that sodium butyrate had potential utility in
      inducing the expression of hFVIII in vitro.

PMID- 12482357
TI  - [Relationship between HLA-DRB1 alleles and idopathic thrombocytopenic purpura in
      children].
AB  - OBJECTIVE: To study the relationship between HLA-DRB1 alleles and idiopathic
      thrombocytopenic purpura (ITP) in children. METHODS: PCR-SSO was used to identify
      DRB1 alleles of 42 children with ITP. Among them, anti-GPIIb/IIIa and anti
      GPIb/IX autoantibody were detected in 36 cases by modified monoclonal antibody
      specific immobilization of platelet antigens (MAIPA). RESULTS: (1) Compared with
      healthy controls, HLA-DRB1 * 17 was significantly increased (relative risk =
      2.76, P < 0.05, etiologic factor = 0.106 4) and HLA-DRB1 * 1202 decreased
      (relative risk = 0.20, P < 0.025, prophylactic factor = 0.761 6) in children with
      ITP. (2) In comparison with patients with good response to steroids and IgG
      therapy, HLA-DRB1 * 11 was significantly increased (P < 0.025) in patients with a
      poor response, furthermore, most (5/6) of HLA-DRB1 * 11-positive patients were
      female teen-ager. (3) Twenty-seven patients (75%) had anti-GPIIb/IIIa and
      seventeen (47.22%) had anti-GPIb/IX autoantibodies, the positivity rates of both
      anti-GPIIb/IIIa (P = 0.02) and anti-GPIb/IX (P = 0.01) were associated with HLA
      DRB1 * 02. However, the pos./itivity rates of autoantibodies between refractory
      and non-refractory patients showed no significant difference. CONCLUSION: (1) The
      DRB1 * 17 seems to predict susceptibility to ITP in children, while DRB1 * 1202
      appears to be protective to against ITP. (2) The DRB1 * 11 plays an important
      role in resistance to steroid and IgG therapy in children with ITP. (3) It seems
      that the response to the antigenic epitope of GPIIb/IIIa and GPIb/IX is
      restricted by DRB1 * 02, while the presence of the autoantibodies couldn't
      predict prognosis. Our preliminary findings indicate that genetic factors
      influence the clinical course of ITP, but its exact mechanism needs to be further
      investigated.

PMID- 12482358
TI  - [In vitro study of the apoptosis effect of DNR on HL-60 cells and its
      relationship with ROS, CER and NF-kappaB].
AB  - OBJECTIVE: To study the effect of DNR on HL-60 cells apoptosis in vitro and the
      related mechanism. METHODS: The apoptosis of HL-60 was observed by microscope,
      flow cytometry (FCM) and DNA electrophoresis and various apoptosis-associated
      proteins expression by immunocytochemistry (IC) and FCM assays; the changes of
      apoptosis in HL-60 cells treated with DNR or suppressors PDTC or FB1 were also
      observed. RESULTS: When treated with 0.2 approximately 2.0 micro mol/L DNR, the
      percentage of apoptotic HL-60 cells increased with the dose increasing and the
      time extending, and the typical apoptotic cells and the appearance of apoptotic
      DNA ladder were observed. It was shown that after treatment with 1 micro mol/L
      DNR, the fluorescence intensity index (FI) of both bcl-2 and c-myc in HL-60 cells
      decreased, the FI of Bax, caspase-3 increased at 2 h, but decreased at 5 h, the
      FI of NF-kappaB increased. After adding PDTC, the apoptosis percentage of HL-60
      cells decreased, but FB1 didn't present these effect. CONCLUSION: It suggested
      from the results that at certain concentration, DNR can induce the apoptosis of
      HL-60 cells in vitro. The mechanism was supposed by suppressing the expression of
      bcl-2 and c-myc and activating the expression of Bax and caspase-3, NF-kappaB and
      ROS had the marked correlation with the apoptosis process, but the ceramide
      synthase wasn't associated with it.

PMID- 12482359
TI  - [Cloning of Ig Fab genes of patients with chronic B lymphocytic leukemia and
      sequences analysis of their variable regions].
AB  - OBJECTIVE: Sequences analysis of Ig variable regions from the peripheral blood
      mononuclear cells (PBMC) of patients with chronic B lymphocytic leukemia.
      METHODS: Total RNA was isolated from PBMC of patients with chronic B lymphocytic
      leukemia, oligo-dT-primed cDNA was synthesized from RNA. The cDNA was amplified
      by Taq DNA polymerase with a set of specific 5' primers corresponding to Ig FR1
      and 3' primers corresponding to CH1 (C micro /C) or CL (Ckappa/Clambda), the PCR
      products of variable regions of Ig heavy (IgH) and light (IgL) chains were
      sequenced by ABI PRISM Dye terminator cycle sequencing ready reaction kit and ABI
      PRISM 310 Genetic Analyzer. The gene homology of variable regions of IgH and IgL
      chains was compared by using DNA tools 5.1 system and "the international
      immunogenetics database". RESULTS: Four light chains and 3 heavy chains were
      amplified from 4 and 3 patients respectively. Homology analysis of the sequences
      of 4 light chains and 3 heavy chains were performed by DNA tools system. The
      sequences of light chains are high homologous. And the sequences of heavy chains
      are quite different. The homologous analysis of the sequences of variable region
      by using "the international immunogenetics database" showed that the sequences
      were higher homologous to idiotype gene of some B lymphocytic leukemia. Four VL
      genes belong to human Ig Vkappa subgroup I, 2 of 3 VH genes belong to VH3 family
      and 1 belongs to VH5 family. CONCLUSION: Ig genes have idiotype and same disease
      may have same idiotype.

PMID- 12482360
TI  - [Preparation and characterization of a single chain antibody fragment of mAb SZ
      21 against platelets GPIIIa].
AB  - OBJECTIVE: To prepare a single chain antibody (ScFv) of mAb SZ-21 against
      platelet GPIIIa for its future clinical application. METHODS: The expression
      vector pET20b-SZ-21ScFv was constructed and the fusion protein was expressed in
      E. coli BL21 (DE3) PlysS. The activated fusion protein was obtained after a
      series of purification steps, including cell breakage, inclusion body
      solubilization, His-bind resin affinity chromatography and protein refolding.
      RESULTS: The fusion protein yields were up to 21% of the total amount of bacteria
      protein. The ScFv fragment could inhibit ADP-induced platelets aggregation in a
      dose-dependent manner in vitro and the maximal inhibition rate was obtained at a
      concentration of 20 micro g/ml. It also reacted with endothelial cells as
      detected by flow cytometry. Moreover, the ScFv fragment was able to inhibit the
      binding of fibrinogen to platelet. CONCLUSION: The SZ-21ScFv fragment had the
      activity to inhibit platelets aggregation and the binding of fibrinogen to
      platelet, being potentially useful for the treatment of thrombotic diseases.

PMID- 12482361
TI  - [A cross-sectional study of personality dysfunction among students of first-grade
      senior high schools in Beijing].
AB  - OBJECTIVE: To test validity and reliability of Personality Diagnostic
      Questionnaire-fourth vision (PDQ-4) and a self-report DSM-IV axis-II personality
      disorder (PD) assessing instrument as well as to study the prevalence of
      personality dysfunction among students of first grade senior high schools in
      Beijing. METHODS: Among 100 PD patients, 91 non-PD patients with mental disorder,
      and 100 normal people, sensitivity, specificity and consistency were tested by
      ICD-10 criteria. By means of stratified cluster sampling, 10 039 students from 25
      senior high schools in urban and rural in Beijing were studied using PDQ-4.
      RESULTS: PDQ-4 had high sensitivity and moderate specificity for most axis II
      disorders when compared with ICD-10. Among different samples, PDQ-4 yielded
      various levels of sensitivity and specificity. Meanwhile, the test-retest
      consistency was 92.2%. Among 130 adults, the total PDQ-4 score was 18.9 +/- 9.8.
      The score in males was 20.6 +/- 10.1, versus 17.1 +/- 9.2 in females with
      significant difference (t = 2.09, P < 0.05). Scores in different age groups were
      21.5 +/- 10.5 in age 16 - 25, 16.9 +/- 11.3 in age 26 - 35, 16.4 +/- 9.7 in age
      36 - 45, 16.2 +/- 7.9 in age 46 - 55, and 20.0 +/- 7.8 in age 56 and over
      respectively. No statistical significant difference of scores at age groups was
      found (F = 2.07, P > 0.05). Among 9 547 students, the total PDQ-4 score was 25.4
      +/- 9.6, being significantly higher than that of adult sample. The prevalence of
      personality dysfunction was 5.6%. Regarding the distribution of personality
      dysfunction in gender, residential area, and type of school, data showed that the
      prevalence rates were higher in males, rural area and lower-ranking schools.
      CONCLUSION: PDQ-4 can be used as a PD screen tool in psychiatric institutions and
      community settings. The distributions of personality dysfunction in Beijing were
      significantly different on gender, residential area and type of schools.
      Attention should be paid to personality dysfunction during adolescence.

PMID- 12482362
TI  - [The impact of depressive symptoms on psychological and physical outcomes: a 5
      year follow-up study of elderly at the community level].
AB  - OBJECTIVE: To explore the impact of depressive symptoms on psychological and
      physical outcomes among elderly living in the residential areas. METHODS: A five
      years follow-up survey of health outcome was carried out among people aged 55
      years or above in community without dementia. The outcome measurements included
      CES-D (center for epidemiological survey, depression scale), MMSE (mini-mental
      state examination), ADL (activity of daily living), LSIA (life satisfaction index
      A), index of physical disease and self-rated health questionnaire. A multiple
      regression analysis was administered to explore the correlation between
      depressive symptoms and indices of psychological and physical outcomes. RESULTS:
      (1) Data from 2 927 subjects having completed two surveys were analyzed. Baseline
      data showed significant distribution difference of MMSE, ADL, gender and
      education among the four CES-D score levels. (2) No significant correlation
      between CES-D score at baseline and MMSE, ADL, LSIA score at five-year follow up
      was found after controlling the age, gender, educational level and baseline score
      of MMSE and ADL. (3) Self-rated general health and memory change were
      significantly correlated to baseline CESD score under controlling the effects of
      other baseline variables. (4) The score of CESD was found to be a significant
      predictor for risks of physical disease and mortality by logistic regression
      model. The odds ratios were 1.52 (95% CI: 1.19 - 1.95) and 2.68 (95% CI: 1.41 -
      5.06) respectively. CONCLUSION: Depressive symptoms play an important role on
      both psychological and physical health outcomes among elderly living in the
      community.

PMID- 12482363
TI  - [The prevalence of epilepsy in rural Jinshan in Shanghai].
AB  - OBJECTIVE: To study the prevalence of epilepsy in Jinshan--a rural area of
      Shanghai and to provide data for development of protocol on prevention and
      therapy of epilepsy. METHODS: Stratified cluster sampling was used in Zhujing
      town, Jinshan district, Shanghai in 2000. In a door to door survey, all
      inhabitants in the study area were interviewed on seizures using a standardized
      protocol to include all new cases with epilepsy. RESULTS: The crude prevalence of
      epilepsy was 3.11 per thousand among the population size of 48,628 and the
      adjusted prevalence was 3.62 per thousand with 3.65 per thousand in male and 2.50
      per thousand in female. The prevalence rates of males were more than that of
      females in both places. Two peaks of epilepsy prevalence in Jinshan district
      Shanghai were noticed: in the age groups of 10 - 30 years old and older than 60
      years. The highest prevalence appeared in rural area was 3.70 per thousand, much
      higher than that 2.45 per thousand in town. CONCLUSION: The prevalence of
      epilepsy in this district was lower than that in other districts of China.

PMID- 12482364
TI  - [Obesity at different ages and endometrial cancer risk factors in urban Shanghai,
      China].
AB  - OBJECTIVE: To study the relationship between obesity at different ages and the
      risk of endometrial cancer in urban Shanghai, China. METHODS: In a population
      based case-control study conducted in urban Shanghai, in-person interviews and
      anthropometric measurements were completed for 497 women at age 30 to 69 and an
      equal number of controls frequency-matched to cases on age distribution. All
      cases were newly diagnosed with endometrial cancer from January 1, 1997 to June
      30, 2000. Unconditional logistic regression model was employed to estimate the
      adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of the obesity at
      different ages. RESULTS: After adjustment for some potential confounding
      variables, neither adolescent height nor weight was significantly related to
      endometrial cancer. Obesity in adulthood, except around 20 years old, was
      associated with elevated risks, with odds ratios for the highest versus lowest
      quartile of body mass index (BMI) being 1.5 (95% CI: 1.0 - 2.1), 1.7 (95% CI: 1.2
      - 2.4), 1.9 (95% CI: 1.3 - 2.8) and 1.7 (95% CI: 1.0 - 2.7) at ages 30, 40, 50
      and 60, respectively. Weight gain of more than 7.5 kg at different 10-year
      intervals in adulthood were associated with increased risk of endometrial cancer,
      whereas only weight gain more than 15% of initial weight from 40 to 50 years old
      significantly related to the risk. Only weight loss from ages 20 to 30 was
      inversely associated with endometrial cancer risk (OR = 0.4, 95% CI: 0.2 - 0.8).
      Current body weight, BMI and waist-to-hip ratio (WHR) were independent risk
      factors to endometrial cancer while standing height and sitting-to-standing
      height ratio were unrelated to the risk of endometrial cancer. CONCLUSION:
      Results indicated that adolescent obesity was unrelated to endometrial cancer.
      General obesity in adulthood, as well as body fat distribution, were associated
      with the risk of endometrial cancer independently. Weight changes before and
      after age 30 had different effects on the risk of endometrial cancer.

PMID- 12482365
TI  - [Trend analyses in the incidence of acute intracerebral hemorrhage events and
      acute cerebral infarction events in urban areas in Beijing].
AB  - OBJECTIVE: To study the trends of incidence on acute intracerebral hemorrhage
      events and acute cerebral infarction events in the population aged 25 - 74 in
      urban areas of Beijing from 1984 to 1999. METHODS: In monitoring the trends and
      determinants in the cardiovascular disease (MONICA) project and subsequent study,
      acute intracerebral hemorrhage events and acute cerebral infarction events were
      registered in a standardized way in men and women aged 25 to 74 years from 1984 -
      1999. RESULTS: Both intracerebral hemorrhage attack rates decreased but cerebral
      infarction attack rates increased significantly; The proportion of intracerebral
      hemorrhage events in stroke events decreased from 42.0% to 16.0% while the
      proportion of cerebral infarction events in stroke events increased from 55.8% to
      81.6%, the changes in incidences of acute intracerebral hemorrhage events and
      acute cerebral infarction events in various age groups were different.
      CONCLUSION: Cerebral infarction was the most important risk causing stroke, so
      prevention of cerebral infarction should be strengthened in the area.

PMID- 12482366
TI  - [Study on the relation between iodine nutrition of pregnant women in different
      occasions and thyroid function of their neonates].
AB  - OBJECTIVE: To study iodine nutrition of pregnant women in different occasions and
      thyroid function of their neonates. METHODS: Urinary iodine of pregnant women and
      their serum T(3), T(4), FT(3), FT(4) were determined by chloric acid-digestion
      thermostatic assay and RIA, TSH determination by IRMA; neonatal umbilical cord
      blood TSH was determined by ELISA. RESULTS: Median urinary iodine of pregnant
      women were 206.3 microg/L, 161.4 microg/L, 203.3 microg/L at 10 - 14 (first
      occasion), 23 - 27 (second occasion) and 39 - 40 (third occasion) week but the
      percentage that lower than 100 microg/L were 14.6%, 17.1%, 11.1% respectively.
      Serum T(3), T(4) of pregnant women was significantly higher than those women of
      premarital health inspection (PHIW, P < 0.001). The difference of serum T(3),
      T(4) of pregnant women at 10 - 14 and 39 - 40 week was not significant. Serum
      FT(3), FT(4) of pregnant women at 39 - 40 week were 2.61 +/- 0.47 pmol/L and 5.50
      +/- 1.57 pmol/L respectively. The difference of serum TSH concentration at third
      occasion and first occasion of pre-pregnancy was significant but the difference
      of TSH frequency distribution in three groups was not significant (chi(2) =
      1.138, P > 0.5). Blood TSH median neonatal umbilical cord was 1.99 mU/L but the
      percentage that higher than 5 mU/L was 9.4%. CONCLUSION: For those areas with
      high iodized salt coverage, pregnant women had had sufficient iodine supplement
      and good thyroid function. The percentage of neonates from iodine sufficient
      pregnant women with TSH > 5 mU/L was lower than 10%. Using the normal range of
      nonpregnant FT(3) and FT(4) to estimate the thyroid function of pregnant women
      could cause mis diagnosis.

PMID- 12482367
TI  - [Epidemiological study on childhood asthma aged 0 to 14, in Kaifeng city].
AB  - OBJECTIVE: To understand childhood asthma from age 0 to 14 in Kaifeng city and
      the relevant risk factors, effects of therapy and costs. METHODS: Eleven thousand
      children aged 0 to 14 were chosen in Gulou area, Shunhe area using cluster
      sampling. RESULTS: (1) The overall prevalence of childhood asthma was 1.16% sex
      ratio 1.72:1. Significant difference was found among every age group (P < 0.001),
      with the highest from 0 to 3, the prevalence rate in industrial area was
      significantly higher than that of residential area, with a ratio of 2.13:1 (P <
      0.001). (2) Major relevant factors were found to be: history of hypersensitivity,
      upper respiratory infection and family history; while nationalities, history of
      contact with pets were not found to be related to childhood asthma (P > 0.05).
      (3) The expenditure was significantly different between non-specific therapy and
      specified therapy (P < 0.001). Among those children with asthma, 89.8% did not
      get specified treatment and the average expenditure was 2,375.2 Yuan per year,
      which was 10.2% of accepted specified therapy, namely under GINA program, with
      average expenditure 653.68 Yuan every year. CONCLUSION: The result of this study
      provided scientific basis for child asthma prevention and cure in this area.

PMID- 12482368
TI  - [Discovery of two sub-types of Hantanvirus in Anhui mountain areas].
AB  - OBJECTIVE: To investigate the existence of hemorrhagic fever with renal syndrome
      (HFRS) foci in high mountains and forest areas. METHODS: A survey was conducted
      in the areas of 1 400 meter altitude in Dabie mountain and of 1,600 meter
      altitude in Wannan mountain in the mid 1990's using methods related to
      epidemiology, geographic-epidemiology, serum epidemiology, pathogenic and
      molecular epidemiology. RESULTS: Two strains of HFRS viruses were isolated from
      pulmonary tissues of Rattus niviventer and both of them were identified as A
      types. The analysis of the nuclei sequence showed that there were significant
      differences between both sub types and HTN 76-118. CONCLUSION: It was confirmed
      that there were HFRS foci in the areas with 2 strains possible new sub-types of
      HFRS.

PMID- 12482369
TI  - [Dissemination of insertion sequences IS605, IS606 among clinical isolates of
      Helicobacter pylori in China].
AB  - OBJECTIVE: To study the distribution of IS605, IS606 among clinical isolates of
      Helicobacter pylori in China. METHODS: A total of 104 H.pylori strains isolated
      from 5 different geographic regions in China were analyzed by PCR and dot-blot.
      RESULTS: Forty-two strains out of the 104 isolates from 5 regions in China were
      found containing IS605 with 19 containing IS606. The frequency (66%) of IS605
      positive strains from Yunnan province was higher than that from other areas. The
      different distribution of IS606 was neither associated with geographical regions
      nor with the presence of IS605 but IS606 were associated with the different
      clinical outcomes. However, the two reading frames ORFA and ORFB of IS605 were
      constantly coexisting. CONCLUSION: In China, IS605 and IS606 of H. pylori were
      widely existing but the presence of IS605 in H. pylori might be associated with
      geographic origin.

PMID- 12482370
TI  - [Study on the association between smoking behavior and dopamine receptor D2 gene
      polymorphisms among lung cancer cases].
AB  - OBJECTIVE: To investigate the possible association between dopamine D2 receptor
      (DRD2) TaqI A and TaqI B genotypes as well as smoking behavior and the risk of
      lung cancer among Chinese Han people. METHODS: PCR was used to perform genotyping
      on peripheral WBC DNA from 326 lung cancer patients and 326 age, sex and
      ethnicity-matched healthy controls. Subjects were interviewed to obtain relevant
      information and lifetime history of tobacco use. RESULTS: There were no
      statistically significant differences in the distribution of DRD2 genotypes
      between lung cancer cases and controls. The DRD2 genotypes and smoking status
      showed no correlation among cases and among controls as well. However, among
      controls, the frequency of the DRD2 * A2/A2 genotype in smokers who smoked > or =
      25 cigarettes/day appeared to be higher than that in those who smoked < 25
      cigarettes/day (42.5% versus 26.1%, P = 0.047). A similar trend was also found
      for the DRD2 * B2/B2 genotype, which was linked to the DRD2 * A2/A2 genotype,
      although the difference was not significant (40.0% versus 26.1%, P = 0.091). In
      contrast to controls, no association was found between the DRD2 genotypes and
      smoking among lung cancer cases. CONCLUSION: Our results suggested that DRD2 *
      A2/A2 genotype might be associated with a greater smoking intensity in Chinese.
      Further studies are needed to confirm this preliminary finding.

PMID- 12482371
TI  - [Study on the Relationship between susceptibility of stomach neoplasm cancer and
      polymorphism of inducible nitric oxide synthase gene].
AB  - OBJECTIVE: To study the relationship between polymorphism of inducible Nitric
      Oxide Synthase (iNOS) gene and the susceptibility of intestinal type stomach
      cancer and stomach cardia cancer in Chinese people. METHODS: A community-based
      case-control study was designed. Ninety-three intestinal type of stomach cancer
      and 50 stomach cardia cancer patients with endoscopy and pathology diagnosis were
      identified as cases. Two hundred and forty-six controls served as controls.
      RESULTS: C-->T polymorphism was found in exon 16 of iNOS gene, which changed the
      coding amino acid from serine to leucine, and formed a recognition site
      identified by Tsp 509 I restriction enzyme (we called it C-->T polymorphism). The
      T allele gene frequency in the control group was 13.21%. No statistically
      significant difference was found between C-->T polymorphism alone and the
      increased susceptibility to intestinal stomach cancer or stomach cardia cancer. A
      significant type 2 multiplicative interaction was found in increasing both the
      risk of intestinal stomach cancer and stomach cardia cancer when both C-->T
      polymorphism and tobacco smoking exposure existed. An additive interaction model,
      which showed statistically significant difference, was found to increase only the
      risk of stomach cardia cancer when CagA antibody shared negative but C-->T
      polymorphism occurred. CONCLUSION: C-->T polymorphism of iNOS gene was considered
      as one of the possible susceptible genes, which specifically increased the risk
      of tobacco-related but CagA negative types of intestinal stomach cancer and
      stomach cardia cancer.

PMID- 12482372
TI  - [A survey on the status of lipid-lowering therapy in 180 hypercholesterolemic
      patients].
AB  - OBJECTIVE: To determine the percentage of hypercholesterolemic patients who had
      met the criteria as total cholesterol (TC) and low-density lipoprotein
      cholesterol (LDL-C), defined by the Chinese National Recommendations for
      Prevention and Treatment of Dyslipidemia. METHODS: Adult patients with
      hypercholesterolemia, who had been receiving the same lipid-lowering therapy for
      at least 2 months, were enrolled. Lipid levels were determined at the time of
      enrollment, to assess whether the patients' lipid levels had reached the criteria
      for treatment. Patients' cardiovascular risk factors and lipid-lowering
      treatments were also collected. RESULTS: One hundred and eighty patients with
      mean age of 65.8 were studied. Of these, 6.7% had no risk factors and no definite
      disease of atherosclerosis (low-risk group), 65.5% had risk factors but no
      documented atherosclerosis (high-risk group), and 27.8% had established
      atherosclerosis diseases or diabetes mellitus. Overall, only 44% of patients
      achieved both TC and LDL-C target levels. The success rates were higher among low
      and high-risk groups than that among patients with atherosclerosis or diabetes
      mellitus. The relationship between four different lipid-lowering drug therapies
      and successful patient outcome was also investigated. The success rates were
      51.8% for simvastatin, 42.9% for pravastatin, 31.6% for fluvastatin, 12.5% for
      other drugs respectively. CONCLUSION: More than half of the hypercholesterolemic
      patients receiving lipid-lowering therapy had not achieved TC and LDL-C target
      levels. Data from this study indicated that a significant gap still existed
      between dyslipidemia prevention principles and clinical practices, suggesting
      that more aggressive treatment of dyslipidemia is needed.

PMID- 12482373
TI  - [Study on a test of screening to predict stroke-using cerebral vascular
      hemodynamic indexes].
AB  - OBJECTIVE: To evaluate efficacy and optimal cut-off-point through cerebral
      vascular hemodynamic indexes (CVHI) examination to predict stroke. METHODS: A
      number of 20,333 people at 35 years old and over were checked by CVHI and
      accumulative score was calculated according to the value of detected indexes.
      Risk factors of stroke were investigated simultaneously. One hundred and sixty
      eight patients with stroke occurred during 4-year following up. Typical syndromes
      and signs stroke were used as golden standard to evaluate screening efficacy of
      CVHI. RESULTS: Score of optimal cut-off-point of cerebral vascular hemodynamic
      indexes was under 75 in ROC curve analyses. Sensitivity, specificity, accuracy,
      positive and negative predictive values, positive and negative likelihood ratios
      as well as Youden's index for predicting stroke within 4 years after examination
      were found to be 87.50%, 67.70%, 67.86%, 2.21%, 99.85%, 2.71, 0.18 and 0.55
      respectively. Sensitivity and positive predict values for predicting cerebral
      vascular thrombosis were superior to predicting cerebral hemorrhage. Positive
      predicting value in risk exposure population was higher than that of overall
      population. Coefficiency of variation of cerebral vascular hemodynamic
      examination was 4.03%. The agreement rate of examination between two physicians
      was 97.62% and Kappa value was 0.94. CONCLUSION: The score of optimal cut-off
      point of cerebral vascular hemodynamic indexes examination was 75. Both Efficacy
      and reliability for predicting stroke seemed to be good, especially for
      predicting cerebral vascular thrombosis.

PMID- 12482374
TI  - [Cost-minimization analysis of two methods during the prevention of dental fear
      during caries filling treatments].
AB  - OBJECTIVE: To determine the economic effects on the prevention of dental fear
      (DF) by pre-operation-education or local anesthesia method during the process of
      tooth filling. METHODS: One hundred and fifty school children of age 7 to 12,
      participating in this study, suffered from occlusal caries on their mandibular
      first molars. They were divided into 3 groups, with 25 boys and 25 girls each.
      Group A (pre-operation-education) was showed video tape on caries to,
      familiarized with clinic environment, including dental chairs and instruments;
      Group B (local anesthesia) received injection of 1.8 ml of 2% lidocaine for local
      anesthesia about 15 minutes before treatment; Group C (blank) received no
      intervention for DF. Thereafter, all subjects received same filling treatment.
      During that process, each DF case was evaluated blindly based on Venham's
      clinical ratings of anxiety and cooperation. Cost-minimization analysis was then
      studied. RESULTS: Significant difference was found between groups, but not
      between group A and B in DF rate (5/50, 9/50 and 21/50, chi(2) = 15.503 1, P =
      0.000 4). The costs of each case in 3 groups were 83.99 Yuan, 87.09 Yuan and
      87.76 Yuan respectively. CONCLUSION: Between pre-operation-education and local
      anesthesia methods, the former was worth promoted for it's better clinical effect
      in DF prevention with lower cost.

PMID- 12482375
TI  - Modulation of the cryopreservation cap: elevated survival with reduced dimethyl
      sulfoxide concentration.
AB  - The development of cryopreservation (CP) strategies has traditionally focused on
      the cellular chemo-osmometric characteristics attendant to the freeze-thaw
      process. This approach coupled with a limited understanding of cellular
      physiological and biochemical responses to the CP process often yields sub
      optimal cell survival. Recently, we have reported on the benefits of the
      utilization of an intracellular-like preservation solution, HypoThermosol (HTS),
      as well as incorporating a molecular approach to improving CP outcome [In Vitro
      Cell. Dev. Biol. Anim. 36(4) (2000) 262]. We now report on the elucidation of a
      cryoprotective agent (CPA)-dependent survival limit (cap) associated with
      standard CP methodologies. We further demonstrate an elevation and shift in the
      CP cap through the utilization of HTS coupled with a reduction in CPA levels
      necessary to achieve "successful" cell preservation. METHODS: Human fibroblasts,
      keratinocytes, hepatic, and renal cells were cryopreserved in a standard fashion
      (approximately 1 degrees C min-1 cooling and storage in LN2) in culture media
      (serum-free) or HTS with varying levels of dimethyl sulfoxide (Me2SO). Samples
      were allowed to recover for 24-h prior to survival assessment. Survival was
      assessed using alamarBlue (metabolic activity indicator) and calcien-AM (membrane
      integrity stain) in comparison with non-frozen controls. RESULTS: (1) A limit in
      cell survival was identified following CP in media-based CP solutions yielding a
      cell-type specific CPA-dependent survival limit, (2) peak cell survival resulted
      in the identification of "optimal" Me2SO concentrations for CP of each cell type,
      (3) incorporation of HTS as the carrier medium at typical Me2SO concentrations
      substantially elevated survival, and (4) utilization of HTS allowed for the
      successful preservation of all systems examined at significantly reduced Me2SO
      levels. CONCLUSION: The data presented in this study illustrate that the
      utilization of HTS as the carrier medium during CP facilitated a significant
      improvement in efficacy at reduced Me2SO levels. Further, the utilization of HTS
      offers the potential for successful Me2SO-free CP. These findings may prove
      significant to the advancement in the development of cell-based clinical
      therapies by providing an improved biocompatible CP methodology.

PMID- 12482376
TI  - Osmotic parameters of cells from a bioengineered human corneal equivalent and
      consequences for cryopreservation.
AB  - A human corneal equivalent is under development with potential applications in
      pharmaceutical testing, biomedical research, and transplantation, but the ability
      to distribute this engineered tissue, depends on successful cryopreservation.
      Tissue recovery after exposure to conditions during cryopreservation depends on
      the response of its constituent cells to the changing environment as ice forms
      and solutes concentrate. This study defines the osmotic properties that define
      the rate of water movement across the plasma membrane of isolated human corneal
      endothelial, stroma, and epithelial cells. Cells were transferred from an
      isotonic (300 mosm/kg) to an anisotonic (150-1500 mosm/kg) solution at constant
      temperature, and cell volumes monitored using an electronic particle counter.
      Histograms describing cell volume changes over time after anisosmotic exposure
      allowed calculation of hydraulic conductivity (L(p)) and osmotically inactive
      volume fraction (V(b)). Experimental values for L(p) at 4, 13, 22, and 37 degrees
      C were used to determine the Arrhenius activation energy (E(a)). The L(p) for
      endothelial, stroma, and epithelial cells at 37 degrees C was 1.98+/-0.32,1.50+/
      0.30, and 1.19+/-0.14 microm/min/atm, and the V(b) was 0.28, 0.27, and 0.41,
      respectively. The E(a) for endothelial, stroma, and epithelial cells was 14.8,
      12.0, and 14.1 kcal/mol, respectively, suggesting the absence of aqueous pores.
      These osmotic parameters and temperature dependencies allow simulation of osmotic
      responses of human corneal cells to cryopreservation conditions, allowing amount
      of supercooling to be calculated to indicate the likelihood of intracellular
      freezing. Simulations show that differences in the osmotic parameters for the
      constituent cells in the bioengineered cornea result in significant implications
      for cryopreservation of the engineered corneal equivalent.

PMID- 12482377
TI  - Characterization of cryopreserved human Langerhans cells.
AB  - Epidermal Langerhans cells are potent antigen-presenting cells in the epidermis.
      The establishment of a cryopreservation method for human Langerhans cells would
      greatly contribute to our ability to successfully conduct various experiments
      dealing with Langerhans cells. Since Langerhans cells are known to be sensitive
      to cold injury, there have been no reports concerning the cryopreservation of
      Langerhans cells. We have investigated the effect of cryopreservation on the
      function and phenotype of human Langerhans cells. Langerhans cells from human
      foreskins were isolated with the immunomagnetic microbead method using monoclonal
      antibodies for CD1a. Langerhans cells were cryopreserved in the presence of
      dimethylsulfoxide (DMSO) 10% and fetal calf serum 90%. Cryopreserved Langerhans
      cells were phenotypically assessed by flowcytometry using monoclonal antibodies
      to HLA-DR and CD1a. The ultrastructures of the Langerhans cells were compared
      using electron microscopy. An autologous T cell stimulation test was performed to
      compare the functions of cryopreserved Langerhans cells and fresh Langerhans
      cells. The viability of the cryopreserved Langerhans cells was able to be
      maintained at more than 90%. Cryopreserved Langerhans cells expressed high levels
      of HLA-DR and CD1a antigens and stimulated autologous T cells to an extent almost
      identical to that obtained from fresh Langerhans cells. These findings indicate
      that the cryopreservation of human Langerhans cells could lead to a breakthrough
      in various experiments dealing with human Langerhans cells.

PMID- 12482378
TI  - Cryopreservation of peripheral blood mononuclear cells does not significantly
      affect the levels of spontaneous apoptosis after 24-h culture.
AB  - Studies performed with malaria patients living in endemic areas are frequently
      conducted in laboratories located hundreds of kilometer away from research
      centers, due to the difficulties in performing the assays in field conditions.
      Thus, we considered the potential indication of cryopreservation of peripheral
      blood mononuclear cells (PBMC), in most fieldwork, and decided to evaluate the
      effect of cryopreservation of PBMC on spontaneous apoptosis. The membrane
      integrity of PBMC was tested using three previously described protocols of
      cryopreservation. Cell samples were obtained from 19 healthy volunteers.
      Percentage of apoptotic nuclei in short-term PBMC cultures was determined by a
      sensitive method using 7-aminoactinomycin D followed by flow cytometry. Our
      results indicate that although cryopreservation can to some extent affect
      lymphocyte membrane integrity rates, flow cytometry analysis showed that
      frequencies of spontaneous apoptosis in cryopreserved cells were not
      significantly modified after 24-h culture. It is concluded that cryopreserved
      PBMC could be used for measuring spontaneous apoptosis and therefore, could be
      employed for the study of populations living in areas distant from research
      centers, allowing the comparative evaluation of samples obtained at different
      time.

PMID- 12482379
TI  - Lipid unsaturation determines the interaction of AFP type I with model membranes
      during thermotropic phase transitions.
AB  - We have previously shown that antifreeze protein (AFP) type I from winter
      flounder interacts with the acyl chains of lipids in model membranes containing a
      mixture of dimyristoylphosphatidylcholine (DMPC) and the plant thylakoid lipid
      digalactosyldiacylglycerol (DGDG), most likely through hydrophobic interactions.
      By contrast, in studies with pure phospholipid membranes, no such interaction was
      seen. DGDG is a highly unsaturated lipid, which renders these studies quite
      different from the previous studies of AFP-membrane interaction where the lipids
      were saturated or trans-unsaturated. Therefore, it seemed possible that either
      the digalactose headgroups or the unsaturated DGDG acyl chains, or both, may be
      important for interactions of membranes with AFP type I. To distinguish between
      these possibilities, we catalytically hydrogenated the DGDG to obtain a
      galactolipid with completely saturated fatty acyl chains. The results with the
      hydrogenated DGDG were strikingly different from those obtained previously with
      the unsaturated DGDG; the clear binding of AFPs to the bilayer appeared to be
      lost. Nevertheless, the temperature-dependent folding of AFP type I was inhibited
      in the presence of liposomes containing either the unsaturated or the
      hydrogenated DGDG. The results indicate that the liposomes and protein still
      interact, even following hydrogenation of the acyl chains, perhaps at the
      membrane-solution interface.

PMID- 12482380
TI  - The effect of liposomes on thermotropic membrane phase transitions of bovine
      spermatozoa and oocytes: implications for reducing chilling sensitivity.
AB  - We have examined the effects of combinations between egg-phosphatidylcholine
      (EPC) or dipalmitoylphosphatidylcholine (DPPC) liposomes with either bovine
      spermatozoa or oocytes on cellular chilling sensitivity, lipid phase transition
      temperature (T(m)), and the ability of the oocytes to develop to the blastocyst
      stage. Spermatozoa and oocytes were exposed to EPC and DPPC liposomes at various
      temperatures (spermatozoa: 4, 12, 16, and 25 degrees C; oocytes: 4, 16, and 32
      degrees C). The membrane integrity of the spermatozoa-control group decreased
      significantly following exposure to 16 or 12 degrees C, compared to ambient
      temperature (25 degrees C). In contrast, the EPC-sperm group had a greater
      resistance to chilling at each temperature and showed a decline in membrane
      integrity only at the lowest temperatures investigated. However, the DPPC-sperm
      group was injured significantly at all temperatures tested. Similar to the sperm,
      oocytes from the control group that were exposed to 16 degrees C were injured
      more severely than oocytes that were electrofused with EPC or DPPC liposomes. The
      membrane integrity of the oocytes at 16 degrees C that were electrofused with
      either EPC or DPPC liposomes was approximately the same as the control group held
      at 32 degrees C (normalized to 100%), compared to 46% in the control group at 16
      degrees C (P<0.01). The transition temperatures of the sperm and oocyte membranes
      revealed different T(m) for the different liposome treatments. All groups had a
      significantly higher cleavage rate, as well as increased blastocyst formation
      when oocytes were exposed to temperatures above or below their T(m). We suggest
      that the T(m) of spermatozoa or oocytes can be changed by spontaneous association
      or electrofusion of liposomes with cellular membranes and, consequently, the
      chilling sensitivity can be altered. The resulting possibility is that embryo
      development after cryopreservation could be improved with such a method.

PMID- 12482381
TI  - Biochemical stabilization enhances red blood cell recovery and stability
      following cryopreservation.
AB  - Glycerolized red blood cells (RBC) are approved for long-term cryopreservation.
      However, the need to remove the glycerol cryoprotectant prior to transfusion has
      limited the usefulness of this cryopreservation method. This report describes
      using non-cryoprotectant biochemical stabilization techniques to substitute for
      the standard glycerol cryoprotectant. The glycerolized RBC method was compared to
      a newly developed LC-V method that combines transfusable cryoprotectants
      (hydroxyethyl starch and dextran) and specific non-cryoprotectant biochemical
      stabilizers (nicotinamide, nifedipine, and flurbiprofen). Results demonstrate
      that the biochemical stabilizers significantly reduce cryopreservation-induced
      hemolysis compared to cryopreservation in their absence and that thaw hemolysis
      levels approach those of standard 40% (w/v) glycerolized RBC (3.1+/-0.2% for 40%
      glycerol compared to 8.7+/-0.9% for the LC-V protocol). Furthermore, LC-V
      cryopreserved RBC exhibit a significantly enhanced post-thaw stability compared
      to glycerolized RBC as determined by osmotic fragility index (0.557+/-0.034 for
      40% glycerol compared to 0.478+/-0.016 for the LC-V protocol). Analysis of
      biochemically stabilized RBC proteins revealed a transient translocation of
      carbonic anhydrase to the membrane fraction. However, the enhanced RBC recovery
      and stability could not be attributed to this event. Finally, DSC analysis
      demonstrated that the biochemical stabilizers of the LC-V process were not
      functioning as surrogate cryoprotectants in that they did not affect the quantity
      or quality of ice formed. Overall, this work demonstrates that cryopreservation
      induced RBC damage may be corrected or prevented through specific biochemical
      stabilization and represents a significant step toward a directly transfusable
      cryopreserved RBC product.

PMID- 12482382
TI  - Cryosurgical changes in the porcine kidney: histologic analysis with thermal
      history correlation.
AB  - Advances in minimally invasive renal cryosurgery have renewed interest in the
      relative contributions of direct cryothermic and secondary vascular injury
      associated ischemic cell injury. Prior studies have evaluated renal cryolesions
      seven or more days post-ablation and postulated that vascular injury is the
      primary cell injury mechanism; however, the contributions of direct versus
      secondary cell injury are not morphologically distinguishable during the
      healing/repair stage of a cryolesion. While more optimal to evaluate this issue,
      minimal acute (< or = 3 days) post-ablation histologic data with thermal history
      correlation exists. This study evaluates three groups of porcine renal
      cryolesions: Group (1) in vitro non-perfused (n = 5); Group (2) in vivo 2-h post
      ablation perfused (n = 5); and Group (3) in vivo 3-day post-ablation perfused (n
      = 6). The 3.4 mm argon-cooled cryoprobe's thermal history included a 75 degrees
      C/min cooling rate, -130 degrees C end temperature, 60 degrees C/min thawing
      rate, and 15-min freeze time. An enthalpy-based mathematical model with a 2-D
      transient axisymmetric numerical solution with blood flow consideration was used
      to determine the thermal history within the ice ball. All three groups of
      cryolesions showed histologically similar central regions of complete cell death
      (CD) and transition zones of incomplete cell death (TZ). The CD had radii of 1.4,
      1.1, and 1.0 cm in the non-perfused, 2-h and 3-day lesions, respectively.
      Capillary thrombosis was present in the 2-h perfused cryolesions with the
      addition of TZ arteriolar/venous thrombosis in the 3-day perfused lesions.
      Thermal modeling revealed the outer CD boundary in all three groups experienced
      similar thermal histories with an approximately -20 degrees C end temperature and
      2 degrees C/min cooling and thawing rates. The presence of similar CD histology
      and in vitro/in vivo thermal histories in each group suggests that direct
      cryothermic cell injury, prior to or synchronous with vascular thrombosis, is a
      primary mediator of cell death in renal cryolesions.

PMID- 12482383
TI  - Osmometric behavior of mouse oocytes in the presence of different intracellular
      sugars.
AB  - In order to successfully cryopreserve oocytes using low concentrations of
      intracellular sugars, it is important to characterize their osmotic response in
      the presence of these intracellular sugars. In the present study, murine (B6D2F1)
      oocytes were microinjected with 0.8M glucose, trehalose or stachyose solutions to
      achieve an intracellular concentration equivalent to 0.1M, and then exposed to
      hypertonic solutions of increasing strength by supplementing an isotonic solution
      with 0.2, 0.3, 0.5, and 0.7 M of trehalose. Analysis of volumetric response of
      microinjected oocytes showed that the oocytes behaved as ideal osmometers in the
      presence of intracellular sugars and satisfied the Boyle van't Hoff relationship.
      Extrapolation of the osmotically inactive fraction (V macro b) from the Boyle
      van't Hoff relationship yielded values of 0.188+/-0.028, 0.212+/-0.042, 0.197+/
      0.044, and 0.211+/-0.042 for control, glucose, trehalose and stachyose-injected
      oocytes, respectively. The present data revealing osmometric behavior of mouse
      oocytes in the presence of different intracellular sugars are important for the
      optimization of cryopreservation protocols using sugars.

PMID- 12482384
TI  - Reversible self-polymerizing high T(g) lyoprotectants.
AB  - One mode of action of protectants in the storage of biological materials is by
      promoting the formation of a vitrified state on cooling or drying. In the case of
      preservation by drying, the glassy material comprises a low water content mixture
      of protectant and organic material. The protectant must on drying form a glassy
      state of glass transition temperature (T(g)) above the desired storage
      temperature. However, in some applications it must also be easily transported
      through cell membranes and this restricts the choice to a relatively limited
      number of small molecules, which typically exhibit very low glass transition
      temperatures. In this work we describe a self-polymerizing protectant comprising
      an inorganic salt and a small hydroxy functional molecule such as glycerol. This
      forms co-ordinate polymer chains of high T(g) on drying but rapidly depolymerizes
      into the original components on rehydration. The polymerization process is
      general for polyhydroxy compounds including glucose and related compounds.

PMID- 12482385
TI  - Recombinantly engineered human proteins: transforming the treatment of psoriasis.
AB  - Psoriasis is a chronic, inflammatory disease with lesions that produce
      considerable physical discomfort and often lead to substantial disruption in
      patients' daily activities. The use of currently available, nonspecific, systemic
      immunosuppressive therapies for patients with moderate to severe psoriasis is
      limited by an inability to maintain disease remission safely. Advances in
      recombinant DNA technology paralleled with increased understanding of the
      immunopathology of psoriasis have led to the development of numerous biologic
      agents for the treatment of this disease. These new biologic therapies target
      specific steps in psoriasis pathology, including direct effects on T cells, T
      cell activation, T cell migration, and cellular production and secretion of
      cytokines. By selectively targeting the activities of T cells that are directly
      involved in psoriasis pathogenesis, these novel agents offer improved safety
      profiles and enhanced efficacy. In this article, the mechanisms of T cell
      pathogenicity that guided the development of these new biologic therapies are
      reviewed along with clinical data on the progress of these agents.

PMID- 12482386
TI  - Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells
      following repeated encounters with the same antigenic stimulus.
AB  - Induction of telomerase, the enzyme that extends telomeres, accompanies human T
      lymphocyte activation. Nevertheless, high proportions of memory T cells with
      shortened telomeres are present in vivo during HIV infection and aging. To
      elucidate the long-term telomerase dynamics in human T cells, longitudinal
      analyses were performed on T cells subjected to repeated encounters with an
      allogeneic cell line in long-term culture. Whereas CD4(+) and CD8(+) T cells
      showed similarly dramatic increases in telomerase activity following primary
      stimulation, by the fourth stimulation, telomerase activity was nearly
      undetectable in the CD8(+) subset, but remained high in the CD4(+) subset. In
      addition, we document the dependence of antigen-specific telomerase inducibility
      on CD28 and that the decline in telomerase activity parallels the loss of CD28
      expression. These findings suggest stringent telomerase regulation in human T
      cells, a property that may ultimately contribute to telomere shortening, finite
      replicative potential, and loss of control over certain pathogens.

PMID- 12482387
TI  - NK cell-mediated lysis of autologous HCMV-infected skin fibroblasts is highly
      variable among NK cell clones and polyclonal NK cell lines.
AB  - Lysis of human cytomegalovirus (HCMV)-infected fibroblasts by autologous natural
      killer (NK) cells was examined in vitro. For NK cell clones, receptor expression
      was determined at the level of mRNA and cell-surface protein and compared to the
      lysis of HCMV AD169 strain-infected fibroblasts in which HLA class I was >70%
      downregulated. The clones ranged broadly in their ability to lyse AD169-infected
      fibroblasts, correlating neither with the expression of inhibitory KIR, leukocyte
      inhibitory receptor-1, or CD94:NKG2A receptors nor with the number of different
      inhibitory KIR expressed per clone. Some lines of polyclonal NK cells
      preferentially lysed AD169-infected cells and similarly lysed fibroblasts
      infected with mutant virus RV798, which lacks the genes for downregulating HLA
      class I. These results demonstrate that NK cell lysis of HCMV-infected autologous
      fibroblasts is more complex than a simple missing-self mechanism involving
      downregulation of HLA class I and failure to engage inhibitory self-specific KIR.

PMID- 12482388
TI  - Evaluation of antigen-based heteropolymer for treatment of systemic lupus
      erythematosus in a nonhuman primate model.
AB  - Autoantibodies that react with double-stranded DNA (dsDNA) are a hallmark for
      diagnosis of systemic lupus erythematosus (SLE) and are also considered the
      pathogenic subset that is most associated with lupus nephritis. As an agent to
      remove the pathogenic dsDNA antibodies from the circulation of SLE patients, we
      are developing an antigen-based heteropolymer (AHP). The AHP consists of a
      monoclonal antibody to the complement receptor (CR1) cross-linked to salmon
      testis dsDNA to effect clearance of anti-DNA antibodies by binding them to
      erythrocyte CR1. Utilizing a cynomolgus monkey model for SLE in which we infused
      plasma from SLE patients containing a high titer of high-avidity anti-dsDNA
      antibody, we have evaluated the safety and efficacy of AHP infusion. The results
      demonstrate that AHP rapidly (within 2 min of infusion) binds to monkey
      erythrocytes without causing any toxicological effects. We also demonstrate that
      human Ig (G+M) antibodies are rapidly bound to the AHP-erythrocyte complex. These
      events are mirrored in their kinetics by a substantial drop in the level of high
      avidity dsDNA antibody in the plasma.

PMID- 12482389
TI  - DNA microarray analysis reveals novel gene expression profiles in collagen
      induced arthritis.
AB  - Global gene expression was analyzed in early and late collagen-induced arthritis
      (CIA). Of 8734 cDNAs analyzed, 330 were induced and 55 downregulated greater than
      twofold in early or late disease. Hierarchical clustering of these 385 cDNAs
      demonstrated five distinct expression patterns differentiating early from late
      disease and correlating with histopathologic changes in the paw. Of the 385
      cDNAs, 185 are known, characterized genes, the majority of which are not
      described as playing a role in arthritis. However, several of these genes are
      involved in pathological processes relating to arthritis, including apoptosis,
      inflammation, and cellular proliferation. One interesting gene, follistatin-like
      gene, is highly expressed along the margin of contact between inflammatory
      synovial pannus and eroding bone, suggesting a role in joint destruction. These
      results demonstrate that global gene expression profiles distinguish early and
      late CIA and reveal several genes novel to arthritis the further characterization
      of which will advance our understanding of arthritis.

PMID- 12482390
TI  - Activation of human neutrophils by the pollutant sodium sulfite: effect on
      cytokine production, chemotaxis, and cell surface expression of cell adhesion
      molecules.
AB  - We have previously demonstrated that the pollutant sodium sulfite (Na(2)SO(3))
      possesses some proinflammatory properties. This study was conducted in order to
      elucidate how this environmentally significant chemical can alter human
      neutrophil cell physiology. Using sensitive ELISAs, we found that Na(2)SO(3)
      induces the total (intra- and extracellular fractions) production of interleukin
      12 (IL-12) and IL-8 but not TNF-alpha, IL-1alpha, or IL-4. IL-8 levels were
      significantly increased in both fractions while the levels of IL-12 were
      significantly increased only in the extracellular milieu. In contrast, IL-1Ra
      levels were significantly decreased in both fractions when cells were treated at
      the highest Na(2)SO(3) concentration (10 mM). Despite the fact that Na(2)SO(3)
      was found to increase IL-8 production, it does not induce neutrophil chemotaxis
      in vitro. Cell surface expression of CD18, CD11a, CD11b, CD11c, CD50, and CD54
      was not affected by Na(2)SO(3) treatment. We conclude that Na(2)SO(3) is a
      modulator of cytokine production but that it does not alter either chemotaxis or
      cell surface expression of the tested molecules. Our results attest to the
      importance of systematically monitoring cytokine production from both
      intracellular and extracellular fractions in pollutant-induced neutrophils, since
      this could lead to different interpretations.

PMID- 12482391
TI  - Prostatein or steroid binding protein (PSBP) induces experimental autoimmune
      prostatitis (EAP) in NOD mice.
AB  - In a previous study, we showed that nonobese diabetic (NOD) mice, a strain that
      present an inherited predisposition to develop both spontaneous and induced
      autoimmune lesions, are susceptible to the induction of experimental autoimmune
      prostatitis (EAP), developing a severe inflammatory reaction in the prostate,
      accompanied by humoral and T-cell-mediated responses. In this study we asked
      whether the protein steroid binding protein (PSBP) or prostatein (a major
      autoantigen in the rat model of EAP) is a potential autoantigen in the NOD mouse
      model and examined the ability of purified PSBP to induce EAP in this strain. Our
      results indicate clearly that NOD male mice react immunologically to PSBP by
      developing lymphocytic inflammatory lesions in prostatic tissue and producing
      both a cellular- and humoral-specific autoimmune response. But our results
      suggest also the existence of other prostatic autoantigens present only in total
      prostate extract. Such additional antigens could enhance the autoimmune response
      and result in more severe forms of inflammation. We also analyzed the respective
      contributions of MHC antigens and CD4/CD8 T-cell subsets in NOD mice lacking
      expression of beta 2-microglobulin (NOD.beta2m degrees/degrees) or MHC class II
      beta chain (NOD.Abeta degrees/degrees) and demonstrate an essential role for
      CD4(+) T cells in the development of EAP in the NOD model. In conclusion, we
      demonstrate that PSBP is an autoantigen recognized by the NOD immune system,
      capable of generating humoral and cellular autoimmune responses and of inducing
      EAP. Moreover, using selected knock-out NOD mice we demonstrate an essential role
      for CD4(+) T cells in the development of EAP.

PMID- 12482392
TI  - In vivo activation of myelin oligodendrocyte glycoprotein-specific T cells in
      healthy control subjects.
AB  - Autoreactive T cells are present in healthy subjects but are assumed not to
      induce overt disease due to lack of exposure to autoantigen or because of immune
      regulation. In EAE, activation of myelin protein-specific T cells is a crucial
      step in disease induction. In this study, we evaluated whether myelin
      oligodendrocyte glycoprotein (MOG)-reactive T cells had been activated in vivo
      using peripheral blood mononuclear cells from neurologically healthy subjects. In
      vitro assays used either memory, CD45RO(+), or naive, CD45RA(+) T-cell
      populations. MOG-reactive T cells were isolated from 7 of 10 subjects.
      Unexpectedly, a substantial number of MOG-reactive T cells were isolated from the
      CD45RO(+), memory T-cell subset in 6 subjects. The majority of these T cells
      generated gamma interferon in excess of IL-4, expressed VLA-4, and produced nerve
      growth factor. These findings demonstrate that a substantial proportion of MOG
      reactive T cells from some subjects have been activated in vivo without resulting
      in clinical disease.

PMID- 12482393
TI  - Influence of IVIg therapy on autoantibody titers to desmoglein 1 in patients with
      pemphigus foliaceus.
AB  - Pemphigus foliaceus (PF) is an autoimmune skin disease characterized by the
      presence of a pathogenic autoantibody to desmoglein 1, an epidermal cadherin
      molecule. Antibody titers to the desmoglein 1 protein can be used to monitor
      disease activity and severity in patients with PF. The purpose of this study is
      to report the influence of IVIg therapy on anti-desmoglein 1 antibody titers, in
      eight patients with severe PF, over a period of 18 consecutive months on each
      patient. This prospective study consisted of eight patients with severe
      widespread active PF at the time of entry into the study. The levels of
      autoantibody to desmoglein 1 were measured by an ELISA, at monthly intervals.
      Sera of all eight had high titers of the autoantibody to desmoglein 1, prior to
      initiating of IVIg therapy. A statistically significant reduction in the
      autoantibody titer index to desmoglein 1 was seen after 4 months of IVIg therapy.
      All eight patients were observed to have a progressive decline in autoantibody
      titer index while they were receiving IVIg. Patients on IVIg therapy had
      nondetectable titers after a mean period of 13 months and continued to remain in
      a serological remission for an additional observation period of 5 months. In the
      context of this study, autoantibody titers to desmoglein 1 can be used to monitor
      the serological response to treatment in patients with PF. Patients receiving
      IVIg therapy achieve serological remission.

PMID- 12482394
TI  - T-cell antigen receptor peptides inhibit signal transduction within the membrane
      bilayer.
AB  - Previous studies have shown that a synthetic peptide (core peptide, CP)
      corresponding to a 9-amino-acid region in the transmembrane domain of the alpha
      subunit of the T-cell antigen receptor (TCR) can suppress T-cell function in
      vitro and in vivo. The aim of these experiments was to determine the cellular
      site and molecular mechanism of CP inhibition in T cells. The cytochrome c
      sensitive TCR-expressing hybridoma (2B4) was stimulated with pigeon cytochrome c
      antigen, anti-CD3 crosslinking, or PMA and ionomycin, in the presence or absence
      of CP, and the resulting IL-2 produced was measured in a bioassay using an IL-2
      dependent cell line (CTLL-2). In the presence of CP, IL-2 production was
      inhibited following antigen-induced stimulation. By contrast, when stimulated
      with cross-linking antibodies to the CD3 complex or with PMA and ionomycin, both
      of which activate T cells downstream of the TCR antigen recognition site, CP had
      no effect on IL-2 production. These experiments suggest that CP interferes with
      TCR function by inhibiting T-cell activation at the transmembrane/receptor level.
      In addition, we show that CP inhibits early TCR signal transduction events such
      as TCR zeta chain phosphorylation following stimulation with either antigen or
      anti-CD3-crosslinking antibodies, although this is unlikely to be the mechanism
      leading to the reduced IL-2 production.

PMID- 12482395
TI  - SDF-1alpha regulates HIV-1-gp120-induced changes in CD79b surface expression and
      Ig production in activated human B cells.
AB  - Binding of HIV-1 glycoprotein (gp120) to activated B cells of HIV-infected and
      HIV-uninfected subjects induces increased cell proliferation, cAMP generation,
      immunoglobulin (Ig) production and downregulation of the invariant chain, CD79b,
      of the B-cell receptor. We present evidence that the stromal cell-derived factor
      1alpha (SDF-1alpha), itself a B-cell stimulant, reversed gp120-driven
      downregulation of CD79b in CD40- and IL-4-activated purified HIV-1 seronegative
      human peripheral blood B cells. SDF-1alpha augmented gp120-induced Ig production,
      downregulated CXCR4 receptor expression, and alone, exerted no effect on CD79b
      surface expression, reversed the gp120-induced downregulation of CD79b. These SDF
      1alpha-modulated B-cell responses were specifically abrogated by an anti-SDF
      1alpha antibody. These data suggest that SDF-1alpha plays an important regulatory
      role in the altered B-cell responses seen in HIV-1 infection. Further, these
      findings may enhance the understanding of the pathophysiology of HIV-1 infection
      and suggest a strategy utilizing SDF-1alpha or related molecules as an anti-HIV
      therapy.

PMID- 12482396
TI  - The role of apoptosis in the antigen-specific T cell hyporesponsiveness of
      paracoccidioidomycosis patients.
AB  - Paracoccidioidomycosis is a deep endemic mycosis associated with an antigen
      specific immunodeficiency. To examine the role of apoptosis in this
      immunodeficiency, peripheral blood mononuclear cells (PBMC) of patients with
      paracoccidioidomycosis and controls were stimulated with the main antigen of
      Paracoccidioides brasiliensis (gp43) and an unrelated fungal antigen (from
      Candida albicans, CMA) and analyzed for annexin V and propidium iodide staining
      by flow cytometry. Control PBMC proliferated well with both antigens. Patients'
      PBMC proliferated only with CMA, but presented higher levels of apoptosis with
      gp43 and CMA than in their own unstimulated cultures. Moreover, gp43-triggered
      apoptosis in control PBMC was lower than in those of the patients. Thus, patient
      but not control gp43-stimulated T cells apparently remained anergized and
      subsequently underwent apoptosis. While CMA-induced apoptosis is likely triggered
      by activation-induced cell death, this is apparently not the case in gp43-induced
      apoptosis because of the lack of cell cycling and IL-2 in the gp43-stimulated
      cultures. However, higher IL-10 levels were found in gp43-stimulated patient PBMC
      cultures. Addition of a neutralizing anti-IL-10 antibody to the cultures resulted
      in increased apoptosis levels only in gp43-stimulated patient PBMC cultures. Our
      results suggest that apoptosis plays a role in the patients' antigen-specific
      hyporesponsiveness and that IL-10 may have an antiapoptotic role.

PMID- 12482397
TI  - A peptide based on an anti-DNA autoantibody downregulates matrix
      metalloproteinases in murine models of lupus.
AB  - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the
      increased production of autoantibodies and by T cell dysfunction associated with
      general clinical manifestations. A model of induced experimental SLE by the
      immunization with the human monoclonal anti-DNA 16/6Id(+) autoantibody and a
      model of the SLE-prone mice (NZB x NZW)F1 were used in the present study. Two
      peptides based on the complementarity determining regions (CDR) 1 and 3 of a
      murine monoclonal anti-DNA 16/6Id(+) autoantibody were shown to ameliorate
      spontaneous and induced SLE in mice. We demonstrate here that levels of matrix
      metalloproteinase (MMP)-3 and MMP-9 were elevated in plasma and kidneys of SLE
      afflicted mice. Levels of both MMP-3 and MMP-9 were elevated in kidneys of mice
      with the 16/6Id induced experimental SLE already in the early phases of disease
      development. However, increased levels of only MMP-3 were detected in the plasma
      at the early stages of disease, while MMP-9 activity was elevated later, when
      clinical manifestations were already observed. Treatment of SLE-afflicted mice,
      with the CDR1-based peptide that ameliorates disease manifestations in mice, led
      to a reduction in MMP-9 activity and in MMP-3 protein levels both in plasma and
      in kidneys. We thus suggest that these enzymes may play a pathogenic role in the
      disease and may serve as markers for the determination of disease progression or
      amelioration.

PMID- 12482398
TI  - Genomic imbalances in drug-resistant T-cell acute lymphoblastic CEM leukemia cell
      lines.
AB  - Ten T-cell acute lymphoblastic (T-ALL) CEM cell lines selected for resistance
      toward methotrexate (CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, CEM/MTX5000PGA,
      CEM/MTXR1, CEM/MTXR2, and CEM/MTXR3), doxorubicin (CEM/ADR5000), vincristine
      (CEM/VCR1000), or hydroxyurea (CEM/HUR90), respectively, and parental drug
      sensitive CCRF-CEM cells were analyzed using comparative genomic hybridization.
      Most genomic imbalances were not specific for drug resistance, as they were found
      in both parental and drug-resistant lines. Three aberrations were common to all
      or most cell lines analyzed: dim(5q35), dim(9p21p24), and enh(20q). We were
      concerned on those imbalances which were specifically present in drug-resistant
      but not in drug-sensitive cells. All methotrexate-resistant cell lines were
      characterized by an enhancement or an amplification of 5q13. The methotrexate
      resistance-conferring dihydrofolate reductase (DHFR) gene is located at this
      locus. Gain of DHFR was verified by PCR analyses. CEM/MTX60PGA, CEM/MTX140LV,
      CEM/MTX1500LV, and CEM/MTX5000PGA showed enh(14q21qter) and CEM/MTX5000PGA
      amp(5p13p15.2). These two loci harbor the methylenetetrahydrofolate dehydrogenase
      (MTHFD1) and 5'-methyltetrahdrofolate-homocysteine methyltransferase reductase
      (MTRR) genes, both of which are involved in folate metabolism. Their gain
      indicates a role in methotrexate resistance. A loss of 4q35 was found in
      CEM/MTXR2, CEM/MTXR3, and CEM/ADR5000 where the proapoptotic caspase-3 gene is
      located. The thioredoxin (TXN) locus 9q31 was enhanced in CEM/ADR5000 and
      CEM/MTX5000PGA cells. 2p22pter was increased in hydroxyurea-resistant CEM/HUR90
      cells. Ribonucleotide reductase polypeptide M2 (RRM2), which confers resistance
      to hydroxyurea, resides at this locus. Other specific genomic imbalances in drug
      resistant cell lines were dim(1p36.5), enh(4p), dim(8p22pter), enh(12p13),
      dim(17p), enh(18q12), enh(21q22.2), dim(21q22.2), and dim(22q13). All genomic
      imbalances were subjected to hierarchical cluster analysis and clustered image
      mapping to identify profiles of chromosomal aberrations in the cell lines. The
      obtained dendrograms allowed separation of imbalances common to all or most cell
      lines from other more individual aberrations. Furthermore, methotrexate-resistant
      cell lines clustered together. Our future efforts will be directed toward those
      imbalances which implicate still unknown candidate drug resistance genes.

PMID- 12482399
TI  - Structural effects of the local anesthetic bupivacaine hydrochloride on the human
      erythrocyte membrane and molecular models.
AB  - The interaction of the local anesthetic bupivacaine with the human erythrocyte
      membrane and molecular models is described. The latter consisted of isolated
      unsealed human erythrocyte membranes (IUM), large unilamellar vesicles (LUV) of
      dimyristoylphosphatidylcholine (DMPC), and phospholipid multilayers built-up of
      DMPC and dimyristoylphosphatidylethanolamine (DMPE), representatives of
      phospholipid classes located in the outer and inner monolayers of the human
      erythrocyte membrane, respectively. Optical and scanning electron microscopy
      revealed that bupivacaine induced erythrocyte spheroechinocytosis. According to
      the bilayer couple hypothesis, this result implied that bupivacaine inserted in
      the outer monolayer of the erythrocyte membrane. Experiments performed on IUM and
      DMPC LUV by fluorescence spectroscopy and X-ray diffraction on DMPC and DMPE
      multilayers confirmed this result. Changes in the molecular organization of
      membranes alter lipid-protein interactions and induce functional perturbation of
      membrane proteins such as Na(+) channels. Since local anesthetics may control the
      influx of Na(+) into the human erythrocyte, in order to relate the structural
      perturbations induced by bupivacaine in these systems to Na(+) transport, the
      interaction of this anesthetic with isolated toad skin was also studied.
      Electrophysiological measurements indicated a significant decrease in the
      potential difference and in the short-circuit current of the skin after the
      application of the anesthetic, reflecting inhibition of the active transport of
      ions. These results suggest that bupivacaine-induced conformational changes of
      the lipid molecules alter the lipid-protein boundaries of the outer moiety of the
      erythrocyte membrane, thus interfering with the function of neighboring sodium
      channels.

PMID- 12482400
TI  - Psoralen and UVA light: an in vitro investigation of multiple immunological
      mechanisms underlying the immunosuppression induction in allograft rejection.
AB  - Photopheresis (ECP) is a novel immunomodulatory therapy effectively used to treat
      several T-cell-mediated diseases and to reverse allograft rejection after organ
      transplantation. It consists of infusion of UVA-irradiated autologous leukocytes
      collected by apheresis and extracorporeally incubated with 8-methoxypsoralen (8
      MOP). In this study we explored the potential immunological events for
      therapeutic efficacy of photopheresis in preventing allograft rejection by
      evaluating in vitro the combined effects of 8-MOP and UVA (PUVA) on multiple
      immunological parameters, such as induction of apoptosis, production of soluble
      mediators, and expression of cell antigens. Peripheral blood mononuclear cells
      (PBMCs) obtained from healthy subjects were treated with 8-MOP and UVA at the
      same doses as those clinically used in ECP. We demonstrate that PUVA treatment
      induced leukocyte hyporesponsiveness and a decrease in expression of co
      stimulatory and adhesion molecules as well as of cytokine levels. Additionally,
      PUVA treatment induced apoptosis in both mononuclear cells (possibly through the
      Fas/FasL system and/or the CD38 pathway) and purified monocytes. In conclusion,
      our work focuses attention on the initial phase of immune response and identifies
      some new targets of therapy (e.g., costimulatory molecules) able to trigger final
      effects underlying therapeutic efficacy of photopheresis.

PMID- 12482401
TI  - High prevalence of the 55-bp deletion (c.1263del55) in exon 9 of the
      glucocerebrosidase gene causing misdiagnosis (for homozygous N370S (c.1226A > G)
      mutation) in Spanish Gaucher disease patients.
AB  - Gaucher disease (GD) is the most frequent lysosomal storage disease, caused by
      mutations in the acid beta-glucosidase gene (GBA). The c.1226A > G (N370S)
      mutation is associated with non-neuronopathic disease (type 1). However, we have
      observed some discrepancy between genotype and phenotype in Spanish Gaucher
      disease patients homozygous for the c.1226A > G mutation. A deletion of 55 bp in
      the exon 9 GBA gene, corresponding to the deleted portion of the beta-glucosidase
      pseudogene, has been previously reported as a cause of erroneous assignment of
      1226G/1226G homozygous patients when the genotype has been performed by PCR
      assay. We had originally identified 25 (out of 124) unrelated Gaucher disease
      patients as being putative homozygotes for the c.1226A > G mutation. By means of
      a new PCR-based assay, we were able to distinguish between the true homozygous
      patients and the carriers of the 55-bp deletion in exon 9 of the GBA gene. The 55
      bp deletion was detected in 10 out of 25 samples (40%) [7 with the 55-bp
      deletion, 1 RecTL, 1 RecNciI (both including the deletion) and one
      rearrangement]. Such a high prevalence in this sample suggests that this allele
      can be more common than expected among GD patients.

PMID- 12482402
TI  - Prevalence and penetrance of HFE mutations in 4865 unselected primary care
      patients.
AB  - Two HFE gene mutations, C282Y and H63D, underlie the vast majority of cases of
      hereditary hemochromatosis. We performed a cross-sectional primary care-based
      study to determine the allele frequency of the C282Y and H63D mutations and the
      penetrance of each of the affected genotypes defined by their presence. Patients
      had previously undergone transferrin saturation (TS) testing. A total of 4865
      unselected frozen serum samples were analyzed to determine serum ferritin (SF)
      levels. Genomic DNA isolated from these samples was analyzed for the C282Y and
      H63D HFE mutations. Homozygotes for each mutation and compound heterozygotes were
      evaluated to determine clinical penetrance. The allele frequency of C282Y was
      0.0507 among Caucasian and 0.0067 among African Americans; that of H63D was
      0.1512 and 0.0263, respectively. TS was > or =55% in 83% of individuals with
      C282Y/C282Y, 14.5% of C282Y/H63D, and 5% of H63D/H63D; SF was > or =300 microG/L
      in 42, 9, and 5% of these genotypes, respectively. None of the 12 C282Y
      homozygotes had cardiac dysfunction or hepatic cirrhosis. Only 9/129 (7%)
      individuals with the genotypes C282Y/H63D or H63D/H63D had a SF > or =300
      microG/L; many had explanations other than iron overload that accounted for this
      increase. Thus, the prevalence of the common HFE mutations is the same in our
      population as previously described. TS screening would detect most C282Y
      homozygotes but not the other two genotypes. The penetrance of C282Y/C282Y is
      significant. The biochemical penetrance of H63D/H63D and C282Y/H63D is modest and
      the clinical penetrance is low.

PMID- 12482403
TI  - Induction of fetal hemoglobin by propionic and butyric acid derivatives:
      correlations between chemical structure and potency of Hb F induction.
AB  - Short-chain fatty acids (C2-C9) induce fetal hemoglobin synthesis in primary cell
      cultures, primates, and patients. We carried out experiments to test whether
      relationships exist between chemical structure and the Hb F-inducing potential of
      several short-chain fatty acid derivatives. BFUe cultures were performed in the
      presence of propionic and butyric congeners, covering the full spectrum of
      substitutions of these molecules, including polar and non-polar groups, esters,
      and double bonds. We found that the fetal hemoglobin inducibility is related to
      the chemical structure of the inducing compound. This structure-activity relation
      depends on the length of carbon chain, the nature of the substitutions, and the
      position of more potent substitutions on the carbon chain. It appears that
      substitutions enhancing the inducibility of these compounds are (with decreasing
      potency): methyl > phenyl > hydroxy >> amino groups. Placement of these
      substitutions at a position distal to the carboxyl group enhances gamma-globin
      inducibility. Presence of the carboxyl group is prerequisite for gamma-globin
      inducibility.

PMID- 12482404
TI  - Comprehensive analysis of blood coagulation pathways in teleostei: evolution of
      coagulation factor genes and identification of zebrafish factor VIIi.
AB  - It is not clear how the complex mammalian coagulation pathways evolved from an
      entirely dissimilar invertebrate coagulation cascade. Comprehensive analysis of
      pro-coagulant factors and their regulators is lacking in early vertebrates to
      discern the mechanism of evolution of these genes from the invertebrates. To
      elucidate the coagulation pathways found in early vertebrates, zebrafish
      cDNAs/gene orthologues for major coagulant, anticoagulant, and fibrinolytic
      proteins were identified and characterized by homology to mammalian sequences. We
      found that zebrafish carry all hemostatic genes present in mammals, providing
      evidence that the coagulation system of teleosts is nearly identical to mammals.
      Zebrafish factor VII and X genes were identified and analyzed to reveal a novel
      factor VII-like gene flanked by the factor VII and factor X genes. This gene
      encodes a protein homologous to factor VII, but lacks critical residues for
      factor VII activity. Expression of the factor VII-like protein (named factor
      VIIi) demonstrated that it functions as an inhibitor of blood coagulation in
      biochemical assays using zebrafish or human plasmas. Analysis of intergenic DNA
      between the zebrafish VII/VIIi/X gene cluster and a Drosophila trypsin gene
      cluster revealed significant homology, and based upon these data, we propose a
      model for a rapid evolution of coagulation factors from the invertebrates.

PMID- 12482405
TI  - Bone marrow-derived CD45+ and CD45- cells reside in skeletal muscle.
AB  - In this report we examined the kinetics of accumulation in muscle tissue of donor
      derived CD45+ and CD45- cells from one to several weeks post-bone marrow
      transplantation. Only after hemopoiesis is fully reconstituted are CD45+ cells
      recovered from muscle tissue in proportions similar to ones we reported earlier
      in non-transplanted mice. Furthermore, using marked donor bone marrow cells, we
      document that in addition to CD45+ cells, donor-derived CD45- cells with certain
      phenotypic characteristics progressively accumulate in muscle post
      transplantation. The turnover rate and physiologic roles of these populations in
      muscle are unclear and require further study.

PMID- 12482406
TI  - Protein C pathway impairment in nonsymptomatic cigarette smokers.
AB  - Increased risk of thrombosis in cigarette smokers implies the existence of an
      underlying prethrombotic state. It is known that oxidative damage to the
      endothelium surface occurs in chronic smokers. Protein C activation takes place
      mostly on the endothelium of small vessels and the anticoagulant activity of
      protein C requires the presence of lipid membranes that are vulnerable to
      oxidation. Our objective was to analyze the relationship between smoking and
      plasma levels of activated protein C, protein C zymogen, activated protein C
      complexed with serpins, total and free protein S, C4b-binding protein, and
      thrombomodulin, as well as fibrinogen, fibrinopeptide A, and protease-cleaved
      antithrombin III. Of the 189 plasma donors used in this study 83 were
      nonsymptomatic smokers (age range 20-44 years, women/men ratio = 1.13) and 106
      were healthy nonsmokers (age range 22-59 years, women/men ratio = 1.36). Smokers
      had 23.3% lower circulating activated protein C than nonsmokers (p = 0.003) and
      the differences were more pronounced in males than in females. Protein C levels
      were also significantly lower in smokers than in nonsmokers (p = 0.034).
      Correlations were negative between the intensity of smoking and circulating
      activated protein C levels (r = -0.31, p = 0.004) and between smoking and the
      ratio of activated protein C to protein C zymogen (r = -0.37, p = 0.001).
      Positive correlations were found between smoking intensity and fibrinogen (r =
      0.21, p = 0.042), or fibrinopeptide A (r = 0.219, p = 0.034). Other parameters
      tested did not show a statistically significant dose-response for the number of
      cigarettes smoked. Cigarette smoke dose-dependent hypercoagulability due to
      acquired activated protein C deficiency could contribute to the increased risk of
      thrombosis in smokers.

PMID- 12482407
TI  - Commentary: Juvenile hemochromatosis in a Spanish family (by Montes-Cano et al.).

PMID- 12482409
TI  - Identification of potential regulatory elements in the human immunoglobulin loci.
AB  - In this post-genomic era, it is necessary to formulate specific questions and
      develop bioinformatics tools to understand the vast amounts of information stored
      in DNA sequence. Using the combinatorial pattern discovery algorithm called
      Teiresias developed by the Bioinformatics and Pattern Discovery Group at IBM, we
      have identified novel conserved motifs present in the immunoglobulin loci. In the
      human VH promoter regions, two new putative regulatory elements have been
      implicated in basal transcriptional regulation of immunoglobulin. In the
      intergenic regions of the immunoglobulin constant region genes segments, elements
      were identified that are absent in similar regions of the Igbeta gene. Since the
      expression patterns of Igbeta and the Ig genes are similar such elements may have
      functions in activities specific to the Ig genes such as somatic hypermutation.
      These elements represent V gene-specific motifs identified through the use of a
      pattern discovery algorithm.

PMID- 12482410
TI  - Constitutive expression of the Fas receptor and its ligand in adult human bone
      marrow: a regulatory feedback loop for the homeostatic control of hematopoiesis.
AB  - Fas ligand (FasL) mediated apoptosis in the bone marrow may contribute to
      suppression of hematopoiesis in myelodysplastic syndromes (MDS) and in aplastic
      anemia, and also to the regulation of normal erythropoiesis. To identify
      potential effector and target cells in this regulatory pathway, we examined the
      constitutive expression of Fas receptor (Fas) and FasL (total and cell-surface)
      in myeloid and lymphoid cells and subsets of CD34+ cells in normal healthy adult
      human bone marrow using multiparameter flow cytometry. A high proportion of CD34+
      cells constitutively expressed cell-surface FasL. However, none of the CD34+
      cells expressed Fas alone. A reciprocal gradient of expression of FasL and Fas
      was observed in subsets of CD34+ cells: as compared to primitive CD34+/HLA-DR(-)
      (DR(-)) cells, a higher proportion of committed CD34+/HLA-DR(++) (DR(++)) cells
      expressed FasL but fewer expressed Fas; the expression of both molecules was
      intermediate in CD34+/HLA-DR(dim) cells. Also, the intensity of FasL expression
      was higher in DR(++) than in DR(-) cells. These results suggest that the
      homeostatic regulation of myelopoiesis in normal bone marrow is mediated via an
      autoregulatory feedback loop by myeloid cells and progenitors themselves, at
      least partly via the Fas-FasL pathway. This notion is also consistent with our
      recent observation that overexpression of FasL by myeloid cells in MDS correlates
      directly with anemia, transfusion requirements, and shorter survival, an example
      of dysregulation of this pathway.

PMID- 12482411
TI  - Juvenile hemochromatosis in the southeastern United States: a report of seven
      cases in two kinships.
AB  - We report clinical and genetic characteristics of seven juvenile hemochromatosis
      (JH) patients (six females, one male) in two unrelated kinships from the
      southeastern U.S. All had severe iron overload. Mean age at diagnosis was 20 +/-
      5 years (range 8-23 years). In six patients, the mean age at onset of signs and
      symptoms attributable to iron overload was 15 +/- 2 years (12-18 years); an 8
      year-old girl had no symptoms. Six of the seven patients had hypogonadotrophic
      hypogonadism, two had severe cardiomyopathy, seven had hepatomegaly, two had
      hepatic cirrhosis, and five had hyperpigmentation. Two of four siblings with JH
      also had Hashimoto thyroiditis. One patient with severe cardiomyopathy improved
      with therapeutic phlebotomy, medical therapy for congestive heart failure, and a
      permanent pacemaker; the other died before phlebotomy was initiated. Estimates of
      average daily iron absorption before phlebotomy-induced iron depletion were 2.3,
      3.1, and 1.7 mg in a male and two females, respectively. Both parents of four
      siblings with JH were heterozygous at two Ch1q loci (D1S1156, D1S2344); each of
      the four affected siblings was homozygous at both loci. An unaffected sib was
      heterozygous at D1S1156. One patient was heterozygous for HFE H63D, five others
      did not have HFE C282Y or H63D, and one was unavailable for testing. We conclude
      that JH occurs in the southeastern U.S. It is likely that JH allele(s) in at
      least one of the present kinships occur(s) on Ch1q, and presumably this
      represents a mutation(s) of the same gene localized to Ch1q in Italian and Greek
      JH kindreds. The present cases do not have HFE genotypes typical of
      hemochromatosis diagnosed in adults. Hashimoto thyroiditis, linked to Ch6p in
      many kinships, did not segregate with JH alleles on Ch1q in the present kinship.

PMID- 12482412
TI  - Chitotriosidase deficiency in survivors of Candida sepsis.
AB  - The existence of chitotriosidase, a human chitinolytic enzyme, hydrolyzes
      artificial chitotrioside substrates, but its specific function in humans is
      unknown. The homologous chitinases have an anti-fungal action in plants. In
      patients with Gaucher disease, chitotriosidase activity is markedly elevated and
      is a marker for response to specific treatment. In all populations, 6% of
      individuals are enzyme deficient but completely healthy. It was hypothesized that
      chitotriosidase deficient persons may be more vulnerable to fungal infections.
      Thus, the objective of the study was to ascertain the prevalence of homozygosity
      for the mutation of chitotriosidase among survivors of Candida sepsis. The
      prevalence of homozygosity among survivors was similar to that in the normal
      population. Although the cohort is the largest of its kind, since only survivors
      were tested, further studies should include all patients with Candida sepsis for
      comparison of survival rates among deficient versus sufficient individuals, and
      thereby elucidate if this enzyme has an anti-fungal function in man. Several
      theories are considered to explain the results.

PMID- 12482413
TI  - Distinct domain responses of R-state human hemoglobins A, C, and S to anions.
AB  - Anionic regulation of hemoglobin (Hb) is of increasing interest for the design of
      Hb-based oxygen carriers. Even "external" amino-acid substitutions can alter the
      nature and extent of anionic control. This was shown by evaluation of the anion
      sensitivities of liganded, R-state, forms of HbA, HbC (beta6 Glu --> Lys) and HbS
      (beta6 Glu --> Val). The beta6 mutants differ in the anion-sensitivity of their
      central cavities, alpha1beta2 interfaces, and heme and beta93 Cys environments.
      The mutant Hbs also exhibit increased anion-dependent oxidation and surface
      denaturation. Moreover, differential chloride effects on oxygen binding by Hbs C,
      S compared to HbA occur after R-state stabilization by fluoresceination of beta93
      Cys. It is concluded that the "external" substitutions in the mutant Hbs have
      structural consequences that are propagated to varying extents to other domains
      as a result of anion binding, and that these anion-dependent changes may underlie
      mechanisms leading to the observed increase in oxidation propensity and surface
      denaturation.

PMID- 12482414
TI  - A novel splice variant of fibroblast growth factor receptor 2 in human leukemia
      HL-60 cells.
AB  - Fibroblast growth factor receptors (FGFRs) genes have been shown to be
      translocated in multiple myeloma (MM) and myeloproliferative disorder (MPD),
      indicating an important role for the FGFRs in hematologic malignancies. Here, we
      describe a novel splice variant of FGFR2 (FGFR2AT-I) arising from skipping exons
      7-10 in human myeloid leukemia HL-60 cells, encoding a FGFR2 in which the Ig-like
      III domain is deleted while the remainder of the mature molecule is fused in
      frame to the transmembrane and COOH-terminal cytoplasmic kinases. Binding assays
      demonstrated that the FGFR2AT-I was able to bind FGF1, FGF2, and FGF7, leading to
      loss of ligand binding specificity. Furthermore, overexpression of FGFR2AT-I
      resulted in increased AKT and MAPK activation, conferring a survival advantage.
      Taken together, these findings indicate that the dysregulation of FGFRs' function
      by aberrant mRNA splicing contributes to tumor progression.

PMID- 12482415
TI  - Small, low nanomolar, noncovalent thrombin inhibitors lacking a group to fill the
      'distal binding pocket'.
AB  - Use of a chlorophenoxyacetamide P1 group with a pyridinone acetamide P2/P3 gave
      an exceptionally potent thrombin inhibitor (K(i)=40 pM). Truncation of the
      molecule at the N-terminus gave unique, low nanomolar, non-covalent thrombin
      inhibitors which do not have a group to fill thrombin's 'distal binding pocket'.
      A co-crystal structure indicates the importance of an intramolecular hydrogen
      bond between the P1 side chain and P1/P2 amide link in this series.

PMID- 12482416
TI  - Highly potent and selective alphaVbeta3-receptor antagonists: solid-phase
      synthesis and SAR of 1-substituted 4-amino-1H-pyrimidin-2-ones.
AB  - Solid-phase synthesis and SAR of alpha(V)beta(3)-receptor antagonists based on a
      N(1)-substituted 4-amino-1H-pyrimidin-2-one scaffold are described. The most
      potent compounds exhibited IC(50) values towards alpha(V)beta(3) in the nano- to
      subnanomolar range and high selectivity versus related integrins like
      alpha(IIb)beta(3). For selected examples efficacy in functional cellular assays
      was demonstrated.

PMID- 12482417
TI  - alpha1-Adrenoceptor antagonists. 5. Pyridazinone-arylpiperazines. Probing the
      influence on affinity and selectivity of both ortho-alkoxy groups at the
      arylpiperazine moiety and cyclic substituents at the pyridazinone nucleus.
AB  - Our previous work on pyridazinone-arylpiperazine derivatives suggested some
      structural features that a compound should have to show high affinity and good
      selectivity for alpha(1) adrenoceptors (AR) with respect to alpha(2)-AR.
      Accordingly, two classes of new alkoxyphenylpiperazinylheptylpyridazinones were
      designed and synthesized to evaluate the effect of the alkoxy substituent on
      affinity and selectivity. As expected, affinity increased with larger alkoxy
      groups. Affinity values are all comparable with that of the reference compound
      (prazosin), with the exception of compound 1c found 4.5-fold more active than
      prazosin.

PMID- 12482418
TI  - New arylpiperazine derivatives with high affinity for alpha1A, D2 and 5-HT2A
      receptors.
AB  - A series of novel long-chain arylpiperazines bearing a coumarin fragment was
      synthesized and the compounds were evaluated for their affinity at alpha(1), D(2
      )and 5-HT(2A) receptors. Most of the new compounds showed high affinity for the
      three types of receptors alpha(1A), D(2) and 5-HT(2A) which depends,
      fundamentally, on the substitution of the N(4) of the piperazine ring. From the
      series emerged compound 6, which had an haloperidol-like profile at D(2) and
      5HT(2A) receptors (pK(i) values of 7.93 and 6.76 respectively). The higher
      alpha(1A) receptor affinity (pA(2)=9.07) of this compound could contribute to a
      more atypical antipsychotic profile than the haloperidol.

PMID- 12482419
TI  - A new series of potent benzodiazepine gamma-secretase inhibitors.
AB  - A new series of benzodiazepine-containing gamma-secretase inhibitors with
      potential use in the treatment of Alzheimer's disease is disclosed. Structure
      activity relationships of the pendant hydrocinnamate side-chain which led to the
      preparation of highly potent inhibitors are described.

PMID- 12482420
TI  - New highly active taxoids from 9beta-dihydrobaccatin-9,10-acetals. Part 3.
AB  - We synthesized novel water-soluble and orally active taxane analogues, 7-deoxy
      9beta-dihydro-9,10-O-acetal taxanes. Cytotoxicities of the synthetic compounds
      were greater than those of paclitaxel and docetaxel, especially against resistant
      cancer cell lines expressing P-glycoprotein. In addition, some compounds showed
      potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po
      administration.

PMID- 12482421
TI  - Design, synthesis and antifungal activity of a novel water soluble prodrug of
      antifungal triazole.
AB  - A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has
      been identified from its parent, the novel antifungal agent RO0094815 (2). The
      prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which
      undergoes enzymatic activation followed by spontaneous chemical degradation to
      release 2. Prodrug 1 showed high chemical stability and water solubility and
      exhibited strong antifungal activity against systemic candidiasis and
      aspergillosis as well as pulmonary aspergillosis in rats.

PMID- 12482422
TI  - Synthesis of 2-substituted-pyrrolidinethiourea derivatives and their antagonist
      effect on vanilloid receptor.
AB  - Four pyrrolidine derivatives were prepared by the formation of a 5-membered ring
      based on capsazepine. Among them, the two carbon extended derivatives, 4a
      (IC(50)=55 microM) and 4b (IC(50)=3 microM), both showed different levels of
      antagonist activity against the vanilloid receptor in a (45)Ca(2+)-influx assay.

PMID- 12482423
TI  - [18F]FMDAA1106 and [18F]FEDAA1106: two positron-emitter labeled ligands for
      peripheral benzodiazepine receptor (PBR).
AB  - We synthesized and evaluated N-(5-fluoro-2-phenoxyphenyl)-N-(2
      [(18)F]fluoromethyl-5-methoxybenzyl)acetamide ([(18)F]-FMDAA1106) and N-(5-fluoro
      2-phenoxyphenyl)-N-(2-[(18)F]fluoroethyl-5-methoxybenzyl)acetamide
      ([(18)F]FEDAA1106) as two potent radioligands for peripheral benzodiazepine
      receptors (PBR). [(18)F]FMDAA1106 and [(18)F]FEDAA1106 were respectively
      synthesized by fluoroalkylation of the desmethyl precursor DAA1123 with
      [(18)F]FCH(2)I and [(18)F]FCH(2)CH(2)Br. Ex vivo autoradiograms of
      [(18)F]FMDAA1106 and [(18)F]FEDAA1106 binding sites in the rat brains revealed
      that a high radioactivity was present in the olfactory bulb, the highest PBR
      density region in the brain.

PMID- 12482424
TI  - Identification of TNF-alpha inhibitors from a split-pool library based on a
      tyrosine-proline peptidomimetic scaffold.
AB  - The design and synthesis of a combinatorial library based on a 4-aryloxyproline
      scaffold with tyrosine as the aryl portion is described. The 1728 member library
      was prepared using the split-pool method to generate pools of compounds.
      Screening of the library components as mixtures followed by deconvolution led to
      the discovery of novel inhibitors of TNF-alpha induced apoptosis.

PMID- 12482425
TI  - Novel inhibitors of neuronal nitric oxide synthase with potent antioxidant
      properties.
AB  - A series of hybrid compounds possessing an nNOS pharmacophore linked to an
      antioxidant fragment has been synthesized. Among them, compound 8d, a propofol
      derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12
      microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS
      selectivity (67.5). This shows that nNOS was able to accommodate very bulky
      groups such as di-tert-butyl or di-iso-propyl phenol in its active site.

PMID- 12482426
TI  - Affinity labeling of the nuclear vitamin D receptor with nonsteroidal alkylating
      agents.
AB  - Synthesis of an affinity alkylating non steroidal mimic of 1alpha,25
      dihydroxyvitamin D(3) and its radiolabeled counterpart is presented. We also
      report the affinity labeling of the VDR-ligand binding domain (VDR-LBD) with this
      analogue.

PMID- 12482427
TI  - 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent
      kinases 1 and 2.
AB  - The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso
      pyrimidine-2,6-diamine (IC(50) vs cdk1/cyclinB1=2.9+/-0.1 microM and IC(50) vs
      cdk2/cyclinA3=2.2+/-0.6 microM), was used as the basis for the design of a series
      of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and
      evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1
      and 2 is described and the structure-activity relationships relating to NU6027
      have been probed. Simple alkoxy- or cycloalkoxy-groups at the O(4)-position were
      tolerated, with the 4-(2-methylbutoxy)-derivative (IC(50) vs cdk1/cyclinB1=12+/-2
      microM and cdk2/cyclinA3=13+/-4 microM) retaining significant activity.
      Substitutions at the N(6) position were not tolerated. Replacement of the 5
      nitroso substituent with ketone, oxime and semicarbazone groups essentially
      abolished activity. However, the derivative bearing an isosteric 5-formyl group,
      2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity
      (IC(50) vs cdk1/cyclinB1=35+/-3 microM and cdk2/cyclinA3=43+/-3 microM). The X
      ray crystal structure of the 5-formyl compound bound to cdk2 has been determined
      to 2.3A resolution. The intramolecular H-bond deduced from the structure with
      NU6027 bound to cdk2 is not evident in the structure with the corresponding
      formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5
      nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future
      structure-activity studies for cyclin-dependent kinase inhibitors in this series.

PMID- 12482428
TI  - Anti-hyperlipidemic sesquiterpenes and new sesquiterpene glycosides from the
      leaves of artichoke (Cynara scolymus L.): structure requirement and mode of
      action.
AB  - The methanolic extract from the leaves of artichoke (Cynara scolymus L.) was
      found to suppress serum triglyceride elevation in olive oil-loaded mice. Through
      bioassay-guided separation, sesquiterpenes (cynaropicrin, aguerin B, and
      grosheimin) were isolated as the active components together with new
      sesquiterpene glycosides (cynarascolosides A, B, and C). The oxygen functional
      groups at the 3- and 8-positions and exo-methylene moiety in alpha-methylene
      gamma-butyrolactone ring were found to be essential for the anti-hyperlipidemic
      activity of guaiane-type sesquiterpene. In addition, inhibition of gastric
      emptying was shown to be partly involved in anti-hyperlipidemic activity.

PMID- 12482429
TI  - Synthesis of non-competitive inhibitors of sphingomyelinases with significant
      activity.
AB  - A series of short-chain analogues of N-palmitoylsphingosine-1-phosphate, modified
      by replacement of the phosphate and the long alkenyl side chain with
      hydrolytically stable difluoromethylene phosphonate and phenyl, respectively,
      were prepared to study the structure-activity relationship for inhibition of
      sphingomyelinase. The study revealed that inhibition is highly dependent upon the
      stereochemistry of the asymmetric centers of the acylamino moiety, and resulted
      in identification of a non-competitive inhibitor with the same level of
      inhibitory activity of schyphostatin, the most potent of the few known small
      molecular inhibitors of sphingomyelinase.

PMID- 12482430
TI  - Syntheses of sphingosine-1-phosphate stereoisomers and analogues and their
      interaction with EDG receptors.
AB  - Sphingosine-1-phosphate (S1P) is considered to be an important regulator of
      diverse biological processes acting as a natural ligand to EDG receptors. As a
      preliminary study to develop potent and selective agonist and antagonist for EDG
      receptors, we report synthesis of S1P stereoisomers and analogues and their
      binding affinities to EDG-1, -3, and -5.

PMID- 12482431
TI  - Dihydropyrimidinones--a new class of anti-staphylococcal antibiotics.
AB  - We report the synthesis and pharmacological evaluation of new derivatives of
      natural dipeptide antibiotic TAN-1057 A, B. In the course of this program, we
      identified novel analogues of the natural product that display similar
      antibacterial activity and showed improved tolerability.

PMID- 12482432
TI  - beta-Homolysine oligomers: a new class of Trojan carriers.
AB  - We describe the design, synthesis and cell-membrane translocation properties of a
      series of beta-peptides with the general sequence fluorescein-Adoa-(beta
      homolysine)(n)-NH(2), n=5-8 and Adoa=8-amino-3,6-dioxaoctanoic acid. These beta
      peptides are able to cross the cytoplasmic membrane and accumulate in the nucleus
      of mammalian cells.

PMID- 12482433
TI  - Methylphosphonate LNA: a locked nucleic acid with a methylphosphonate linkage.
AB  - Synthesis of an oligonucleotide containing one methylphosphonate locked nucleic
      acid (LNA) thymine monomer using the phosphoramidite approach is described. The
      binding affinity of this 9-mer methylphosphonate LNA towards complementary DNA
      and RNA oligonucleotides was increased compared to the reference DNA, but
      decreased compared to the reference LNA. In the 9-mer sequence context studied,
      introduction of a single methylphosphonate LNA monomer, contrary to a single LNA
      monomer, efficiently inhibits 3'-exonucleolytic degradation.

PMID- 12482434
TI  - Design and synthesis of novel PPARalpha/gamma/delta triple activators using a
      known PPARalpha/gamma dual activator as structural template.
AB  - Using a known dual PPARalpha/gamma activator (5) as a structural template, SAR
      evaluations led to the identification of triple PPARalpha/gamma/delta activators
      (18-20) with equal potency and efficacy on all three receptors. These compounds
      could become useful tools for studying the combined biological effects of
      PPARalpha/gamma/delta activation.

PMID- 12482435
TI  - Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid.
AB  - A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed
      and prepared. These compounds exhibited either selective activity as RXR agonists
      or pan-agonists on one or more of each of the RAR and RXR isoforms. The most
      potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good
      antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI
      8226.

PMID- 12482436
TI  - The preparation of (S)-aspartate semi-aldehyde appropriate for use in biochemical
      studies.
AB  - We report two three-step syntheses of (S)-aspartate semi-aldehyde, an important
      synthetic and biosynthetic precursor, from diprotected aspartic acid. The first
      synthesis proceeds via a thioester, the second via a Weinreb amide. Each route
      yields pure (S)-aspartate semi-aldehyde in excellent yield. (S)-Aspartate semi
      aldehyde prepared in this manner has proved appropriate as a substrate for
      detailed enzyme studies.

PMID- 12482437
TI  - Discovery of a series of (4,5-dihydroimidazol-2-yl)-biphenylamine 5-HT7 agonists.
AB  - A novel (4,5-dihydroimidazol-2-yl)-biphenylamine series of 5-HT(7) agonist
      compounds was developed from a structurally related lead compound 1. The newly
      discovered series is exemplified by compound 2 that possesses high affinity for 5
      HT(7) receptors and shows intrinsic agonist activity in functional assays. This
      new series has significant alpha(1) and alpha(2) activities perhaps due to the
      presence of the 2-aminoimidazoline moiety.

PMID- 12482438
TI  - p38MAP kinase inhibitors. Part 1: design and development of a new class of potent
      and highly selective inhibitors based on 3,4-dihydropyrido[3,2-d]pyrimidone
      scaffold.
AB  - A new class of p38 antagonists based on 3,4-dihydropyrido[3,2,-d]pyrimidine
      scaffold has been developed. These inhibitors exhibit unprecedented selectivity
      towards p38 over other very closely related kinases. Compounds 25, 33, and 34
      were identified as benchmark analogues for follow-up studies. They show good
      potency for enzyme inhibition and excellent functional activity.

PMID- 12482439
TI  - Design and synthesis of potent, orally bioavailable dihydroquinazolinone
      inhibitors of p38 MAP kinase.
AB  - The development of potent, orally bioavailable (in rat) and selective
      dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These
      analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by
      Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C
      7 piperidinyl substituents led to the identification of 15i which gave excellent
      suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM)
      and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).

PMID- 12482440
TI  - A novel solid support for synthesis of oligonucleotide 3'-phosphorothioate
      monoesters.
AB  - A new reagent immobilized on solid support allowing for solid-phase synthesis of
      oligonucleotides with a 3'-terminal phosphorothioate monoester is described. The
      support is compatible with phosphoramidite chemistry for automated
      oligonucleotide synthesis. Final deprotection with ammonia under standard
      conditions leads to oligonucleotide 3'-terminal phosphorothioate.

PMID- 12482441
TI  - Development of a presynaptic 5-HT1A antagonist.
AB  - A new 5-HT(1A) silent antagonist 14 (5-HT(1A) IC(50)=2.2 nM) antagonizes the
      effects of agonists on reciprocal forepaw treading behavior, on neuronal firing
      in the rat dorsal raphe, and on 5-HT(1A) release in the raphe and hippocampus.
      While 14 alone was inactive in the social interaction paradigm, it completely
      reversed the social interaction activity of the serotonergic compounds
      (buspirone, 1, and 2).

PMID- 12482442
TI  - CRF ligands via Suzuki and Negishi couplings of 3-pyridyl boronic acids or
      halides with 2-benzyloxy-4-chloro-3-nitropyridine.
AB  - A series of imidazo[4,5-b]pyridines with a 7-(3-pyridyl) substituent is described
      as high affinity CRF receptor ligands. Individual analogues were synthesized from
      key intermediates obtained via palladium-catalyzed coupling of 3-pyridyl zinc or
      boronic acid organometallic intermediates with 2-benzyloxy-4-chloro-3
      nitropyridine 12.

PMID- 12482443
TI  - The synthesis of NPPB and NPBB by reductive amination and the effects of these
      compounds on K+ channels of the alga Nitella hookeri.
AB  - This paper communicates a new synthesis of the ion channel inhibitors NPPB and
      NPBB using a simple reductive amination sequence. The synthesised compounds were
      found to reduce channel amplitude of a K(+) channel present in cytoplasmic
      droplets of Nitella hookeri.

PMID- 12482444
TI  - Design and synthesis of factor Xa inhibitors and their prodrugs.
AB  - In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3,
      a series of potent and novel cyclic diimide amidine compounds has been
      identified. In efforts to improve their oral bioavailability, replacement of the
      amidine group with methyl amidrazone gives compounds of moderate potency (14,
      IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds
      show good oral bioavailability in rats and dogs. High plasma level of prodrug 26
      and significant concentration of active drug 26a were obtained upon oral
      administration of prodrug 26 in rats.

PMID- 12482445
TI  - Synthesis and evaluation of phosphoramidate amino acid-based inhibitors of
      sialyltransferases.
AB  - Several phosphoramidate analogues of CMP-N-acetylneuraminic acid were prepared
      for evaluation as inhibitors of alpha-2,3- and alpha-2,6-sialyltransferase.
      Central to the synthesis was the oxidative coupling of an amino acid ester with
      an H-phosphonate to construct the phosphoramidate linkage. All compounds
      synthesized were weak inhibitors of both of the sialyltransferases as determined
      by an HPLC-based inhibition assay.

PMID- 12482446
TI  - Rosmarinic acid.
AB  - Rosmarinic acid is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid.
      It is commonly found in species of the Boraginaceae and the subfamily Nepetoideae
      of the Lamiaceae. However, it is also found in species of other higher plant
      families and in some fern and hornwort species. Rosmarinic acid has a number of
      interesting biological activities, e.g. antiviral, antibacterial,
      antiinflammatory and antioxidant. The presence of rosmarinic acid in medicinal
      plants, herbs and spices has beneficial and health promoting effects. In plants,
      rosmarinic acid is supposed to act as a preformed constitutively accumulated
      defence compound. The biosynthesis of rosmarinic acid starts with the amino acids
      L-phenylalanine and L-tyrosine. All eight enzymes involved in the biosynthesis
      are known and characterised and cDNAs of several of the involved genes have been
      isolated. Plant cell cultures, e.g. from Coleus blumei or Salvia officinalis,
      accumulate rosmarinic acid in amounts much higher than in the plant itself (up to
      36% of the cell dry weight). For this reason a biotechnological production of
      rosmarinic acid with plant cell cultures has been proposed.

PMID- 12482447
TI  - A flavonol O-methyltransferase from Catharanthus roseus performing two sequential
      methylations.
AB  - Protein extracts from dark-grown cell suspension cultures of Catharanthus roseus
      (Madagascar periwinkle) contained several O-methyltransferase (OMT) activities,
      including the 16-hydroxytabersonine O-methyltransferase (16HT-OMT) in indole
      alkaloid biosynthesis. This enzyme was enriched through several purification
      steps, including affinity chromatography on adenosine agarose. SDS-PAGE of the
      purified protein preparation revealed a protein band at the size expected for
      plant OMTs (38-43 kDa). Mass spectrometry indicated two dominant protein species
      of similar mass in this band, and sequences of tryptic peptides showed
      similarities to known OMTs. Homology-based RT-PCR identified cDNAs for four new
      OMTs. Two of these cDNAs (CrOMT2 and CrOMT4) encoded the proteins dominant in the
      preparation enriched for 16HT-OMT. The proteins were closely related (73%
      identity), but both shared only 48-53% identity with the closest relatives found
      in the public databases. The enzyme functions were investigated with purified
      recombinant proteins after cDNA expression in Escherichia coli. Unexpectedly,
      both proteins had no detectable 16HT-OMT activity, and CrOMT4 was inactive with
      all substrates investigated. CrOMT2 was identified as a flavonoid OMT that was
      expressed in dark-grown cell cultures and copurified with 16HT-OMT. It
      represented a new type of OMT that performs two sequential methylations at the 3'
      and 5'-positions of the B-ring in myricetin (flavonol) and dihydromyricetin
      (dihydroflavonol). The resulting methylation pattern is characteristic for C.
      roseus flavonol glycosides and anthocyanins, and it is proposed that CrOMT2 is
      involved in their biosynthesis.

PMID- 12482449
TI  - Sterol composition of mycelia of the plant pathogenic ascomycete Leptosphaeria
      maculans.
AB  - Analysis of sterols in mycelia of the ascomycete, Leptosphaeria maculans by gas
      chromatography-mass spectrometry revealed that ergosterol comprised 95% of the
      total sterols, with eight other sterols comprising the remaining 5%. Six of these
      latter sterols were putative precursors of ergosterol and their presence
      suggested a pathway for ergosterol biosynthesis in this fungus. Ergosterol
      biosynthesis in fungi is inhibited by the triazole antifungal agent flutriafol.
      When L. maculans was grown in the presence of flutriafol, ergosterol content
      decreased while two 14 alpha-methylated sterols, 24-methylene dihydrolanosterol
      and obtusifoliol, accumulated.

PMID- 12482448
TI  - Initial steps of the peroxidase-catalyzed polymerization of coniferyl alcohol
      and/or sinapyl aldehyde: capillary zone electrophoresis study of pH effect.
AB  - Capillary zone electrophoresis has been used to monitor the first steps of the
      dehydrogenative polymerization of coniferyl alcohol, sinapyl aldehyde, or a
      mixture of both, catalyzed by the horseradish peroxidase (HRP)-H(2)O(2) system.
      When coniferyl alcohol was the unique HRP substrate, three major dimers were
      observed (beta-5, beta-beta, and beta-O-4 interunit linkages) and their initial
      formation velocity as well as their relative abundance varied with pH. The beta-O
      4 interunit linkage was thus slightly favored at lower pH values. In contrast,
      sinapyl aldehyde turned out to be a very poor substrate for HRP except in basic
      conditions (pH 8). The major dimer observed was the beta,beta'-di-sinapyl
      aldehyde, a red-brown exhibiting compound which might partly participate in the
      red coloration usually observed in cinnamyl alcohol dehydrogenase-deficient
      angiosperms. Finally, when a mixture of coniferyl alcohol and sinapyl aldehyde
      was used, it looked as if sinapyl aldehyde became a very good substrate for HRP.
      Indeed, coniferyl alcohol turned out to serve as a redox mediator (i.e. "shuttle
      oxidant") for the sinapyl aldehyde incorporation in the lignin-like polymer. This
      means that in particular conditions the specificity of oxidative enzymes might
      not hinder the incorporation of poor substrates into the growing lignin polymer.

PMID- 12482450
TI  - Transformations of testosterone and related steroids by Botrytis cinerea.
AB  - Botrytis cinerea (strain AM235) was used to investigate the transformations of
      testosterone and related steroids. It was found that the position and
      stereochemistry of the introduced hydroxyl group, as well as the yield of
      products, depended on the structure of the substrate. Botrytis cinerea converts
      the examined substrates mainly to 7 alpha-hydroxy derivatives. 1
      Dehydrotestosterone was also significantly hydroxylated at a 14 alpha-position.

PMID- 12482451
TI  - The biochemical origin of pentenol emissions from wounded leaves.
AB  - Large releases of 1-penten-3-ol (pentenol) and 1-penten-3-one (pentenone) were
      recently observed from a variety of leaves subjected to freeze-thaw damage in the
      presence of oxygen. In order to understand the biochemical origins of these
      volatiles, soybean leaf extracts were used to determine if the formation of
      pentenol and pentenone can be explained by known O(2)-dependent lipoxygenase
      (LOX) reactions. Enzymatic formation of these C5 volatiles was found to be
      dependent on alpha-linolenic acid or the 13(S)-hydroperoxide of alpha-linolenic
      acid [13(S)-HPOT] and blocked by LOX inhibitors. Five soybean leaf LOX isozyme
      genes (VLXA, VLXB, VLXC, VLXD, and VLXE) were then expressed in Escherichia coli
      and used in in vitro incubations with 13(S)-HPOT to test for volatile formation.
      Each of the LOX isozymes catalyzed the formation of low levels of pentenol, but
      not pentenone. It therefore seems likely that the C5,13-cleavage activity of LOX
      is the direct source of abundant pentenol and the indirect source of pentenone
      observed upon leaf wounding.

PMID- 12482452
TI  - 3 beta,13-dihydroxylated C20 gibberellins from inflorescences of Rumex acetosa L.
AB  - Using full scan GC-MS a wide range of gibberellins (GAs) was identified in the
      young inflorescences of the dioecious species Rumex acetosa L., consistent with
      the ubiquitous early 13-hydroxylation pathway in both male and female plants. In
      addition, R. acetosa is the first species in which all three 3beta,13
      dihydroxylated C(20)-GAs-GA(18), GA(38) and GA(23)-have been identified in the
      same organism, suggesting an early 3beta,13-dihydroxylation biosynthesis pathway
      in this species. Authentic GA(18), GA(38) and GA(23) were synthesized and their
      effects and that of GA(1), a GA common to both pathways, on the time to
      inflorescence emergence was investigated. GA(1) accelerated the emergence of
      inflorescences in both male and female plants. In addition some evidence for
      biological activity per se of the C(20)-GA(38) was obtained.

PMID- 12482453
TI  - Volatile emissions of eastern hemlock, Tsuga canadensis, and the influence of
      hemlock woolly adelgid.
AB  - The volatile emissions of eastern hemlock, Tsuga canadensis Carriere, were
      identified and quantified using standard and chiral gas chromatography and mass
      spectrometry. All of the identified compounds were monoterpenes, and included
      alpha-pinene, myrcene, tricyclene, camphene, alpha-phellandrene, beta-pinene,
      limonene, beta-phellandrene, terpinolene, and bornyl acetate. alpha-Pinene,
      myrcene, and camphene comprised greater than 75% by mass of the total release.
      Infestation by the exotic insect, hemlock woolly adelgid (HWA, Adelges tsugae
      Annand), resulted in an increased release rate of monoterpenes from branch tips.
      Release rate was negatively correlated to the amount of the branch tip sample
      that was new growth, suggesting that release rate is greater from previous-year
      foliage. Additionally the percent composition of the volatile profile is slightly
      altered by infestation, with alpha-pinene comprising 57% of volatiles from
      infested foliage and 66% from uninfested foliage.

PMID- 12482454
TI  - Aluminum-induced oxidative stress in maize.
AB  - The relation between Al-toxicity and oxidative stress was studied for two inbred
      lines of maize (Zea mays L.), Cat100-6 (Al-tolerant) and S1587-17 (Al-sensitive).
      Peroxidase (PX), catalase (CAT) and superoxide dismutase (SOD) activities were
      determined in root tips of both lines, exposed to different Al(3+) concentrations
      and times of exposure. No increases were observed in CAT activities in either
      line, although SOD and PX were found to be 1.7 and 2.0 times greater than initial
      levels, respectively, in sensitive maize treated with 36 microM of Al(3+) for 48
      h. The results indicate that Al(3+) induces the dose- and time dependent
      formation of reactive oxygen species (ROS) and subsequent protein oxidation in
      S1587-17, although not in Cat100-6. After exposure to 36 microM of Al(3+) for 48
      h, the formation of 20+/-2 nmol of carbonyls per mg of protein was observed in
      S1587-17. The onset of protein oxidation took place after the drop of the
      relative root growth observed in the sensitive line, indicating that oxidative
      stress is not the primary cause of root growth inhibition. The presence of Al(3+)
      did not induce lipid peroxidation in either lines, contrasting with the
      observations in other species. These results, in conjunction with the data
      presented in the literature, indicate that oxidative stress caused by Al may harm
      several components of the cell, depending on the plant species. Moreover, Al(3+)
      treatment and oxidative stress in the sensitive maize line induced cell death in
      root tip cells, an event revealed by the high chromatin fragmentation detected by
      TUNEL analysis.

PMID- 12482455
TI  - Fatty acid variations in symbiotic dinoflagellates from Okinawan corals.
AB  - The fatty acid composition of polar lipids and triacylglycerols was determined in
      different morphophysiological types of symbiotic dinoflagellates (SD) isolated
      from the hydrocoral Millepora intricata and the scleractinian corals Pocillopora
      damicornis, Seriatopora caliendrum, Seriatopora hystrix and Stylophora pistillata
      from a fringing reef of Sesoko Island, Okinawa, Japan. The distribution of the
      fatty acids among the morphophysiologically distinct types of SD reported in
      these corals makes it possible to readily distinguish one type of SD from the
      other. Moreover, differences were found both in polar lipids and
      triacylglycerols. The polar lipids of SD from M. intricata showed a very
      distinctive fatty acid profile. A combination of large proportions of 18:4 (n-3),
      18:5 (n-3), 22:5 (n-6), and 22:6 (n-3) and negligible amounts of 20:4 (n-6), and
      20:5 (n-3) in SD from M. intricata was particularly noteworthy. The fatty acid
      profiles of SD from P. damicornis and SD isolated from S. caliendrum and S.
      hystrix differed in the proportion of 18:4 (n-3) and 22:6 (n-3). It is suggested
      that fatty acids might provide useful information on possible taxonomic
      differences among symbiotic dinoflagellates. It is assumed that biochemical
      differences can reflect the genetic diversity of the morphophysiological types of
      SD associated with several species of hermatypic corals from this region.

PMID- 12482456
TI  - Cytotoxic triterpenes from the twigs of Celtis philippinensis.
AB  - Two triterpene esters, 3beta-trans-sinapoyloxylup-20(29)-en-28-ol (1) and 3beta
      trans-feruloyloxy-16 beta-hydroxylup-20(29)-ene (2), were isolated as cytotoxic
      constituents from the chloroform-soluble extract of the twigs of Celtis
      philippinensis, along with five known triterpenes, 3beta-O-(E)-feruloylbetulin
      (3), 3beta-O-(E)-coumaroylbetulin (4), betulin (5), 20-epibryonolic acid (6), and
      ursolic acid (7). The structures of 1 and 2 were assigned from their 1D and 2D
      NMR spectroscopic data. All isolates were evaluated for cytotoxicity against
      several human cancer cell lines.

PMID- 12482457
TI  - Antimicrobial constituents from the rhizomes of Rheum emodi.
AB  - The bioassay-guided chemical examination of the rhizomes of R. emodi resulted in
      the isolation of two new oxanthrone esters, revandchinone-1, revandchinone-2, a
      new anthraquinone ether revandchinone-3 and a new oxanthrone ether, revandchinone
      4. Their structures were established based on spectroscopic and degradative
      evidence. Occurrence of oxanthrone ether is reported for the first time. The anti
      bacterial and anti fungal activity of the isolates is studied.

PMID- 12482458
TI  - Chemical composition and antibacterial activities of the essential oils of Lippia
      chevalieri and Lippia multiflora from Burkina Faso.
AB  - The chemical composition of the essential oils of Lippia chevalieri and Lippia
      multiflora obtained from the air-dried leaves by hydrodistillation were analysed
      using GC and GC-MS. L. chevalieri and L. multiflora belonged to thymol/p-cymene/2
      phenyl ethyl propionate and thymol/p-cymene/thymyl acetate chemotypes,
      respectively. The essential oils were also tested against 09 strains using a
      broth microdilution method. The Gram-negative bacteria were the most sensitive.
      The essential oil of L. multiflora was the most active.

PMID- 12482459
TI  - Inhibition of LPS-induced NO production by the oleogum resin of Commiphora
      wightii and its constituents.
AB  - Three new (1-3) and five known compounds (4-8) were isolated from the oleogum
      resin of Commiphora wightii (Arnott.) Bhanol. Their structures were elucidated by
      spectroscopic and chemical methods. The MeOH extract and the EtOAc-sol. fraction
      were found to demonstrate significant inhibition of NO formation in
      lipopolysaccharide (LPS)-activated murine macrophages J774.1 in vitro (IC(50)
      values of 16.4 and 12.8 microg/ml, respectively). When compared with curcumin
      (IC(50) value of 12.3 microM), Z- and E-Guggulsterones (4 and 5, respectively)
      were the most potent inhibitors of NO production (IC(50) values of 1.1 and 3.3
      microM, respectively), followed by myrrhanol A (7) and myrrhanone A (8) (IC(50)
      values of 21.1 and 42.3 microM, respectively). Guggulsterone-M (1) and its
      didehydro derivative (2) were weak inhibitors, while guggulsterols I (6) and Y
      (3) were inactive (IC(50) >500 microM).

PMID- 12482460
TI  - Antioxidant flavonoids from leaves of Polygonum hydropiper L.
AB  - Ten flavonoid compounds were isolated from the dried leaves of Polygonum
      hydropiper L. (Laksa leaves), and identified as 3-O-alpha-L-rhamnopyranosyloxy
      3',4',5,7-tetrahydroxyflavone; 3-O-beta-D-glucopyranosyloxy-4',5,7
      trihydroxyflavone; 6-hydroxyapigenin; 6"-O-(3,4,5-trihydroxybenzoyl) 3-O-beta-D
      glucopyranosyloxy-3', 4', 5, 7-tetrahydroxyflavone; scutillarein; 6
      hydroxyluteolin; 3',4',5,6,7-pentahydroxyflavone; 6-hydroxyluteolin-7-O-beta-D
      glucopyranoside; quercetin 3-O-beta-D-glucuronide; 2"-O-(3,4,5-trihydroxybenzoyl)
      quercitrin; quercetin. Evaluation of the antioxidative activity, conducted in
      vitro, by using electron spin resonance (ESR) and ultraviolet visible (UV-vis)
      spectrophotometric assays, showed that these isolated flavonoids possess strong
      antioxidative capabilities. Measurement of the Trolox equivalent antioxidant
      capacity (TEAC) values, against ABTS (2,2'-azinobis(3-ethyl-benzo-thiazoline-6
      sulphonic acid) radicals and phenyl-tert-butyl nitrone (PBN) azo initiator (AI)
      also showed strong anti-oxidative activity. The most powerful of the antioxidants
      was 2"-O-(3,4,5-trihydroxybenzoyl) quercitrin (galloyl quercitrin). A combination
      of two flavonoid compounds was tested for synergistic anti-oxidative capacity,
      but no significant improvement was observed.

PMID- 12482461
TI  - Malonylated flavonol glycosides from the petals of Clitoria ternatea.
AB  - Three flavonol glycosides, kaempferol 3-O-(2"-O-alpha-rhamnosyl-6"-O-malonyl)
      beta-glucoside, quercetin 3-O-(2"-O-alpha-rhamnosyl-6"-O-malonyl)-beta-glucoside,
      and myricetin 3-O-(2",6"-di-O-alpha-rhamnosyl)-beta-glucoside were isolated from
      the petals of Clitoria ternatea cv. Double Blue, together with eleven known
      flavonol glycosides. Their structures were identified using UV, MS, and NMR
      spectroscopy. They were characterized as kaempferol and quercetin 3-(2(G)-
      rhamnosylrutinoside)s, kaempferol, quercetin, and myricetin 3-neohesperidosides,
      3-rutinosides, and 3-glucosides in the same tissue. In addition, the presence of
      myricetin 3-O-(2"-O-alpha-rhamnosyl-6"-O-malonyl)-beta-glucoside was inferred
      from LC/MS/MS data for crude petal extracts. The flavonol compounds identified in
      the petals of C. ternatea differed from those reported in previous studies.

PMID- 12482462
TI  - 5H-furan-2-ones from fungal cultures of Aporpium caryae.
AB  - Four furanones 1-4 with an unusual skeleton containing an acetylene unit, named
      aporpinones, were isolated from the culture of the basidiomycete Aporpium caryae
      and their structures were elucidated by spectroscopic methods. Compounds 3 and 4
      showed weak to moderate antibacterial activity against Bacillus subtilis,
      Staphylococcus aureus and Escherichia coli.

PMID- 12482464
TI  - Disturbances in hypothalamo pituitary adrenal and thyroid axis identify different
      sleep EEG patterns in major depressed patients.
AB  - This study was aimed at investigating the relationships between sleep EEG
      abnormalities and hypothalamo pituitary adrenal (HPA) and hypothalamo pituitary
      thyroid (HPT) disturbances in major depressive disorder. Post dexamethasone (DXM)
      cortisol levels and the dual TSH response to 08:00 h and 23:00 h TRH
      administration were determined after a 2 weeks wash-out period in a group of 113
      DSM-IV major depressed patients (72 females aged 44.3+/-13.0 and 41 males aged
      45.7+/-11) who were consecutively admitted to undergo sleep EEG recordings. Post
      DXM cortisolemia, 08:00 and 23:00 post-TRH TSH values, time spent in rapid eye
      movement sleep (REMS), in slow wave sleep (SWS), and in stage 2 as well as time
      awake after sleep onset were introduced in a principal component (PC) analysis.
      The four 3 PC scores explaining up to 74% of the data set were further calculated
      for each patients and used in a cluster analysis. A three-cluster solution was
      retained. Controlling for the effects of age and gender, patients belonging to
      these three clusters could clearly be differentiated on the basis of their
      neuroendocrine responses and on their sleep EEG profiles. Compared to the two
      other clusters, cluster I (n=26) patients showed the most severe sleep continuity
      disturbances. Post-DXM cortisol escape and sleep architecture disturbances
      (consisting of a shortening of REMS latency and a decreased SWS) identified
      patients belonging to cluster II (n=39). Patients in cluster III (n=48) had the
      lowest TSH response to TRH and the less marked sleep EEG alteration. Clinical or
      demographic variables were unable to differentiate the three clusters. Our
      results suggest that different biological dysfunctions could each underlie
      particular neuroendocrine and sleep EEG disturbances in major depression.

PMID- 12482465
TI  - Place of chronic insomnia in the course of depressive and anxiety disorders.
AB  - BACKGROUND: Insomnia is frequent in the general population and is often related
      to a psychiatric illness. However, little is known about how the chronicity of
      insomnia affects this relation and how often subjects with chronic insomnia have
      antecedents of psychiatric disorders. METHODS: A total of 14,915 subjects aged
      from 15 to 100 years representative of the general population of the United
      Kingdom, Germany, Italy, and Portugal were interviewed by telephone using the
      Sleep-EVAL system. The questionnaire assessed current psychiatric disorders
      according to the DSM-IV classification and a series of questions assessed the
      psychiatric history. Insomnia was considered as chronic when it lasted for 6
      months or more. RESULTS: The prevalence for insomnia accompanied with impaired
      daytime functioning was 19.1% and significantly increased with age. More than 90%
      of these subjects had a chronic insomnia. About 28% of subjects with insomnia had
      a current diagnosis of mental disorders and 25.6% had a psychiatric history. A
      DSM-IV insomnia disorder was found in 6.6% of the sample. Presence of severe
      insomnia, diagnosis of primary insomnia or insomnia related to a medical
      condition, and insomnia that lasted more than one year were predictors of a
      psychiatric history. In most cases of mood disorders, insomnia appeared before (>
      40%) or in the same time (> 22%) than mood disorder symptoms. When anxiety
      disorders were involved, insomnia appeared mostly in the same time (>38%) or
      after (> 34%) the anxiety disorder. CONCLUSIONS: The study shows that psychiatric
      history is closely related to the severity and chronicity of current insomnia.
      Moreover, chronic insomnia can be a residual symptom of a previous mental
      disorder and put these subjects to a higher risk of relapse.

PMID- 12482466
TI  - Habitual binge/purge behavior influences circulating ghrelin levels in eating
      disorders.
AB  - Previous studies have reported that fasting plasma ghrelin concentrations play an
      important role in the pathophysiology of eating disorders. The purpose of this
      study was to examine the relationship between plasma ghrelin levels and frequency
      of abnormal eating behaviors, nutritional parameters in eating disorders. Fasting
      blood samples were obtained in 40 female anorexia nervosa (AN) patients, 21
      restricting type (AN-R) and 19 binge-eating/purging type (AN-BP), in 31 bulimia
      nervosa (BN) patients, 18 purging type (BN-P) and 13 non-purging type (BN-NP), in
      15 female healthy volunteers (control) before the initiation of active treatment.
      The fasting plasma ghrelin concentrations in all subjects were negatively
      correlated with nutritional parameters such as body mass index, percent body fat
      and serum cholinesterase concentration. The mean plasma ghrelin level in BN-P was
      higher than that in both BN-NP and controls despite similar nutritional
      parameters. The plasma ghrelin levels in both AN-R and AN-BP did not differ from
      BN-P despite difference of nutritional parameters. For both AN-BP and BN-P
      patients with habitual binge/purge behavior, there were significant correlations
      among plasma ghrelin values, frequencies of binge/purge cycles and serum amylase
      values. In BN-NP, there were no significant correlations among plasma ghrelin
      values, frequencies of binge-eating episodes and serum amylase values. These
      results suggest that habitual binge/purge behavior may have some influence on
      circulating plasma ghrelin levels in both BN-P and AN-BP. Habitual binge/purge
      cycles with vomiting as opposed to binge-eating episodes without vomiting may
      have a greater influence on fasting plasma ghrelin concentration in eating
      disorders.

PMID- 12482467
TI  - Enhanced intensity dependence as a marker of low serotonergic neurotransmission
      in borderline personality disorder.
AB  - Dysfunction of central serotonergic activity has been assumed in patients with
      borderline personality disorder (BPD) characterized by a prominent impulsive
      behavioral style. Following the high serotonergic innervation of the primary
      auditory cortex, there is increasing evidence of the intensity dependence of
      auditory evoked potentials (AEP), especially the N1/P2 component, indicating
      serotonergic neurotransmission in animals and humans. 15 females who met the IPDE
      criteria for BPD and a group of comparative healthy females (controls) completed
      extensive personality questionnaires which gave special regard to impulsiveness.
      We obtained event-related AEP through the application of various loudness
      stimuli. We examined the relevant N1/P2 amplitude of the tangential dipole of the
      auditory evoked response using dipole source analysis. The augmentation of the
      N1/P2 amplitude of tangential dipole source activity with rising stimulus
      intensity was significantly pronounced in BPD as opposed to controls, accompanied
      by a reduction in N1 and P2 latencies. The strong loudness dependency of AEP
      correlated with aspects of impulsiveness. These data imply reduced inhibiting
      control over cortical sensory processing in BPD. Our findings contribute a
      further argument to the hypothesis of low serotonergic neurotransmission in BDP
      and may point to a trait character of impulsiveness in this personality disorder.

PMID- 12482468
TI  - Preference for higher sucrose concentrations in cocaine abusing-dependent
      patients.
AB  - BACKGROUND: Animal studies suggest that preference for relatively high
      concentrations of sweet solutions and lack of control over sweet solution
      consumption is related to a preference for alcohol over water. There also is
      evidence in humans that alcoholics prefer high concentration sweet solutions.
      This study was designed to determine whether patients with cocaine use disorder
      also prefer high concentrations of sweet solutions. METHODS: Sixteen patients
      with cocaine abuse/dependency were compared with 16 inpatient controls with an
      affective disorder as to their preferences for increasing concentrations of
      sucrose solutions. Patients were administered aqueous sucrose solutions ranging
      from 0.05 to 0.83 M. They were then asked to rate their degree of preference for,
      and the degree of sweetness of each solution. RESULTS: Cocaine abusing/dependent
      patients significantly more often preferred the highest sucrose concentration
      (0.83 M). CONCLUSIONS: The above information suggests that cocaine
      abusing/dependent patients, like alcoholics, and in contrast to inpatient
      controls, share a preference for high concentrations of sucrose.

PMID- 12482469
TI  - Differential effects of antipsychotics on expression of antioxidant enzymes and
      membrane lipid peroxidation in rat brain.
AB  - Typical and atypical antipsychotics significantly differ in their
      neurotransmitter receptor affinity profiles, and their efficacy and side effects
      in schizophrenic patients. Typical antipsychotics have been found to increase the
      oxidative (i.e. free radical-mediated) cellular injury in rats. Since
      schizophrenia also involves oxidative injury, the understanding of differential
      effects of these antipsychotics on expression of antioxidant enzymes and
      oxidative injury may be very critical. The effect of chronic exposure of
      haloperidol (HAL), a typical antipsychotic, was compared to effects of
      risperidone (RIS) or clozapine (CLZ) or olanzapine (OLZ), atypical antipsychotics
      on antioxidant defense enzymes and lipid peroxidation in the rat brain. The
      levels of antioxidant enzymes and hydroxyalkenals (HAEs) were measured in rat
      brain cytosol and fatty acids were measured in brain cell membranes. Chronic HAL
      treatment for both 45 and 90 days significantly decreased manganese-superoxide
      dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT)
      activity with parallel marked increase in (HAEs), a marker of lipid peroxidation
      in rat brain. The levels of enzymatic activity very well correlated with the
      levels of enzyme proteins indicating that the changes were probably in the
      expression of net protein. However, RIS, CLZ and OLZ treatments did not produce
      any alterations in the levels of antioxidant enzymes and HAEs, both after 45 and
      90 days. There were no alterations in the levels of saturated as well as
      polyunsaturated fatty acids in brain membranes. These findings indicate that
      chronic administration of HAL, but none of the studied atypicals induce oxidative
      stress by persistent changes in the levels of antioxidant enzymes and cause
      membrane lipid peroxidation.

PMID- 12482470
TI  - Differential effects of fluoxetine and imipramine on the phosphorylation of the
      transcription factor CREB and cell-viability.
AB  - It has been shown that antidepressants increase the expression of CREB (cAMP
      response-element-binding-protein) and BDNF (brain derived neurotrophic factor) in
      vivo. Apparently inconsistent to these survival-promoting properties for many
      years antidepressants are known to induce apoptosis in various cell types in
      vitro. In the present study we evaluated if the antidepressants imipramine and
      fluoxetine are capable to influence the translational expression and
      phosphorylation of CREB (pCREB) in cells known to be apoptosis-inducible by
      antidepressants. We therefore used jurkat cells and quantified apoptosis via
      propidiumiodid-staining and FACS-analysis. CREB-expression and -phosphorylation
      was quantified via western blot. Both antidepressants induced apoptosis within 24
      h. Fluoxetin starts to induce significant apoptosis at a concentration of 20
      microM, whereas imipramine at 100 microM. At these concentrations both
      antidepressants also increased the phosphorylation of CREB within 6 h. But even
      in concentrations to low to induce apoptosis both antidepressants still increased
      CREB-phosphorylation. Treating cells with lowest concentrations only imipramine
      revealed an increase of CREB-phosphorylation after long-time treatment over 3
      weeks. In all experiments overall CREB-expression remained unchanged. In
      conclusion our experiments indicate that antidepressants are capable to increase
      CREB-phosphorylation without induction of apoptosis depending on concentration
      and duration of treatment. We further assume that antidepressants induce CREB
      phosphorylation via signal transduction pathways that are different from those
      inducing apoptosis.

PMID- 12482471
TI  - Unique design issues in clinical trials of patients with bipolar affective
      disorder.
AB  - Two National Institute of Mental Health-sponsored meetings of experts on bipolar
      illness (in 1989 and 1994) noted a paucity of clinical psychopharmacological
      trials in this illness which has now extended over the past two decades. One of
      the reasons elucidated for this neglect was a lack of agreement in the field as
      to what constituted an optimal clinical trial design, consequently resulting in
      low-priority scores for funding of studies in bipolar illness. In this paper, we
      note some of the characteristics of bipolar illness that make it particularly
      difficult to study and find such agreed upon trial designs. Some of the assets
      and liabilities of the well-accepted traditional parallel group, placebo
      controlled, randomized clinical trial (RCT) are reviewed, and a series of other
      potential design options, such as crossover, enrichment, off-on-off-on (B-A-B-A),
      and N-of-1 trials, are discussed that may help to better address some of the
      unique clinical characteristics of bipolar illness. Finally, a variety of
      statistical approaches to analyzing data in off-on-off-on trial designs, and in
      helping to predetermine necessary durations of clinical trials in individual
      patients with bipolar disorders, are suggested. Acceptance of a wider variety of
      clinical trial designs may help facilitate the funding and accelerate the
      acquisition of new data on treatment of bipolar illness.

PMID- 12482472
TI  - Operationalizing DSM-IV criteria for PMDD: selecting symptomatic and asymptomatic
      cycles for research.
AB  - While diagnostic criteria for premenstrual syndromes (PMS) exist, studies rarely
      state how these criteria are operationally applied. We examined the consequences
      of application of different operational methods for DSM-IV criteria for
      premenstrual dysphoric disorder (PMDD) to individual cycles in women with PMS and
      controls. PMDD criteria require the presence of both certain types or numbers of
      symptoms (5/11 symptoms present premenstrually, at least one being one of four
      mood symptoms) and certain phenomenal characteristics (present premenstrually,
      absent postmenstrually, causing interference premenstrually). We identified
      individual cycles as symptomatic or asymptomatic by applying criteria that
      operationalized the required phenomenal elements of PMDD according to four
      severity thresholds: literal (i.e. present or absent), 30%, 50%, 70%. Data
      examined were Daily Rating Form symptom scores from two symptomatic menstrual
      cycles both in 25 women with PMS and 25 controls. Literal thresholds correctly
      identified 28% of symptomatic and 4% of asymptomatic cycles, compared with 86 and
      70% identification with a 30% threshold, 60 and 86% with a 50% threshold, and 0
      and 100% with a 70% threshold. An "optimal" combination of 30% thresholds for
      premenstrual symptomatology and premenstrual interference and a 50% threshold for
      postmenstrual symptomatology correctly identified 92% of symptomatic cycles in
      women with PMS and 72% of asymptomatic cycles in controls. Different criteria for
      cycle inclusion yield markedly different sample compositions. No single
      operational threshold of the phenomenal features maximizes selection of both
      symptomatic and asymptomatic cycles, largely consequent to the ubiquity of
      postmenstrual symptoms and premenstrual "interference" even in women without PMS.
      At the very least, the method for operationalizing DSM-IV criteria should be
      described in studies of PMDD.

PMID- 12482473
TI  - Increased concentration of corticosteroid-binding globulin due to antidepressant
      treatment with amitritpyline, but not paroxetine.

PMID- 12482474
TI  - Trace level determination of trichloroethylene from liver, lung and kidney
      tissues by gas chromatography-magnetic sector mass spectrometry.
AB  - Trichloroethylene (TCE) is a common industrial chemical that has been heavily
      used as a metal degreaser and a solvent for the past 100 years. As a result of
      the extensive use and production of this compound, it has become prevalent in the
      environment, appearing at over 50% of the hazardous waste sites on the US EPA's
      National Priorities List (NPL). TCE exposure has been linked to neurological
      dysfunction as well as to several types of cancer in animals. This paper
      describes the development and validation of a gas chromatography-mass
      spectrometry (GC-MS) method for the quantitation of trace levels of TCE in its
      target tissues (i.e. liver, kidney and lungs). The limit of quantitation (5
      ng/ml) is substantially lower than currently published methods for the analysis
      of TCE in tissues. The % RSD and % Error for the assay falls within the
      acceptable range (<15% for middle and high QC points and <20% for low QC points),
      and the recovery is high from all tissues (>79%).

PMID- 12482475
TI  - High-performance liquid chromatographic assay with ultraviolet spectrometric
      detection for the evaluation of inhibitors of secretory phospholipase A(2).
AB  - A non-radioactive spectrometric assay for the evaluation of inhibitors of
      pancreatic group IB and non-pancreatic group IIA secretory phospholipase A(2)
      (sPLA(2)) is described. Mixed-micelles consisting of 1 mM of a 1-palmitoyl-2
      oleoyl-sn-glycero-3-phosphoglycerol and 6 mM of sodium deoxycholate were used as
      substrate. The enzyme activity was determined directly without any sample clean
      up by measuring the sPLA(2)-mediated oleic acid release with reversed-phase HPLC
      and UV-detection at 200 nm. The known sPLA(2) inhibitors MJ33 and AR-C 67047MI
      were analyzed in this assay for their inhibitory potency. While MJ33 revealed
      only a very weak inhibition of group IB and IIA sPLA(2) at the highest test
      concentration (33 microM), AR-C 67047MI proved to be a potent inhibitor of both
      enzymes with IC(50)-values of 0.36 and 0.14 microM, respectively.

PMID- 12482476
TI  - Determination of ximelagatran, an oral direct thrombin inhibitor, its active
      metabolite melagatran, and the intermediate metabolites, in biological samples by
      liquid chromatography-mass spectrometry.
AB  - Analytical methods for the determination of ximelagatran, an oral direct thrombin
      inhibitor, its active metabolite melagatran, and intermediate metabolites,
      melagatran hydroxyamidine and melagatran ethyl ester, in biological samples by
      liquid chromatography (LC) positive electrospray ionization mass spectrometry
      (MS) using selected reaction monitoring are described. Isolation from human
      plasma was achieved by solid-phase extraction on octylsilica. Analytes and
      isotope-labelled internal standards were separated by LC utilising a C(18)
      analytical column and a mobile phase comprising acetonitrile-4 mmol/l ammonium
      acetate (35:65, v/v) containing 0.1% formic acid, at a flow-rate of 0.75 ml/min.
      Absolute recovery was approximately 80% for ximelagatran, approximately 60% for
      melagatran ethyl ester and >90% for melagatran and melagatran hydroxyamidine.
      Limit of quantification was 10 nmol/l, with a relative standard deviation <20%
      for each analyte and <5% above 100 nmol/l. Procedures for determination of these
      analytes in human urine and breast milk, plus whole blood from rat and mouse are
      also described.

PMID- 12482477
TI  - Cellobiose and lactulose coupled with mannitol and determined using ion-exchange
      chromatography with pulsed amperometric detection, are reliable probes for
      investigation of intestinal permeability.
AB  - Lactulose/mannitol and cellobiose/mannitol tests are currently used in the
      investigation of intestinal permeability (IP) in many gastrointestinal diseases.
      The aim of this study was to produce a good technique for the determination and
      comparison of the above-mentioned sugar probes to overcome the problem caused by
      the presence of significant glycosuria in patients affected by particular
      metabolic disorders such as diabetes mellitus. Tests were performed in 25 healthy
      volunteers, using either cellobiose (Ce) (5 g) and mannitol (Ma) (2 g), or
      lactulose (La) (5 g) and mannitol (2 g), given as oral isosmolar loads. Sugars
      were recovered in urine collected for 5 h. Analysis was carried out by using
      anion-exchange chromatography (AEC) with pulsed amperometric detection (PAD).
      Baseline separation of the above carbohydrates was achieved within 13 min by
      using a Carbopac PA-100 column and linear gradient elution. Carbohydrate
      quantification was performed by an internal standard method. The calibration
      curve for each sugar is linear to 40 mM. The limit of sugar detection is 0.01 mM.
      Recovery of sugar probes is between 98.2 and 100%. The %La, %Ce, %Ma in urine
      were evaluated and their ratios (Ce/Ma and La/Ma) were calculated. No significant
      difference in IP parameters were shown (La/Ma to Ce/Ma 0.018+/-0.014 vs. 0.012+/
      0.007; the attendant probability of the null hypothesis being P=0.0714). Ce/Ma
      and/or La/Ma tests result similarly reliable in the clinical investigation of IP
      and the described new method is also helpful in urine even with high glucose
      concentration, without any interference.

PMID- 12482478
TI  - Quantification of clarithromycin, its 14-hydroxy and decladinose metabolites in
      rat plasma, gastric juice and gastric tissue using high-performance liquid
      chromatography with electrochemical detection.
AB  - A rapid, selective and sensitive HPLC assay has been developed for the
      simultaneous analysis of clarithromycin, its 14-hydroxy-clarithromycin
      metabolite, and its decladinose acid degradation product, in small volumes of rat
      gastric juice aspirate, plasma and gastric tissue. Sample were extracted with n
      hexane/2-butanol (4:1) and the internal standard was roxithromycin. A Kromasil
      ODS 5 micrometer(75x4.6 mm I.D.) column was used with a mobile phase consisting
      of acetonitrile/aqueous phosphate buffer (pH 7, 0.086 M) (45:55 v/v). The column
      temperature was 30 degrees C and coulometric detection was used at 850 mV using a
      screen voltage of 600 mV. The analysis time was less than 8 min. The limits of
      quantitation for clarithromycin, 14-OH clarithromycin and decladinose
      clarithromycin were 0.15 microgram ml(-1) or lower in plasma (0.05 ml); 0.16
      microgram ml(-1) or lower in gastric juice (0.2 ml); and 0.51 microgram g(-1) or
      lower for gastric tissue (0.25 g). The method was linear up to at least 20.3,
      15.4 and 12.5 microgram ml(-1) for clarithromycin, 14-OH-clarithromycin and
      decladinose, respectively, in gastric juice aspirate and plasma and up to 40.6,
      30.9 and 25.0 microgram g(-1) in gastric tissue. The assay was applied to the
      measurement of clarithromycin, 14-OH-clarithromycin and, for the first time,
      decladinose clarithromycin in pharmacokinetic studies of gastric transfer of
      clarithromycin in individual rats.

PMID- 12482479
TI  - Simple and accurate determination of bisphenol A in red blood cells prepared with
      basic glycine buffer using liquid chromatography-electrochemical detection.
AB  - For an accurate determination of bisphenol A (BPA) in red blood cells (RBC), the
      effect of pH on the concentration of BPA was investigated. Also, BPA recovery
      using ferric heme, methemoglobin (metHb) and hematin, were investigated to
      confirm whether BPA binds to ferric heme. BPA recovery in hemolysate was high at
      alkaline pH and was very low at acidic pH where oxyHb changed to metHb. BPA
      recovery decreased dose-dependently in metHb and hematin, but inorganic iron ions
      did not influence the recovery. These results suggested that BPA could be bound
      to ferric heme in RBC. The use of glycine-NaOH buffer (pH 11) as well as plasma
      had the highest recovery (97%). BPA was not detected in red blood cells of
      healthy adult volunteers (n=6). In sheep blood contaminated with BPA, BPA was
      detected in both plasma and RBC (10 times lower than in plasma), indicating that
      BPA could have migrated from plasma into RBC.

PMID- 12482480
TI  - Determination of clozapine, and its metabolites, N-desmethylclozapine and
      clozapine N-oxide in dog plasma using high-performance liquid chromatography.
AB  - Clozapine and its two major metabolites, N-desmethylclozapine and clozapine N
      oxide were quantified using a high-performance liquid chromatographic method with
      UV detection in dog plasma following a single dose of clozapine. The analysis was
      performed on a 5-micrometer Hypersil CN (CPS-1; 250x4.6 mm) column. The mobile
      phase consisted of acetonitrile-water-1 M ammonium acetate (50:49:1, v/v/v),
      which was adjusted to pH 5.0 with acetic acid. The detection wavelength was 254
      nm. A liquid-liquid extraction technique was used to extract clozapine and its
      metabolites from dog plasma. The recovery rates for clozapine, N
      desmethylclozapine, and the internal standard (I.S.) were close to 100% using
      this method. The recovery rate for clozapine N-oxide (62-66%) was lower as
      expected because it is more polar. The quantitation limits for clozapine,
      clozapine N-oxide, and N-desmethylclozapine were 0.11, 0.05 and 0.05 microM,
      respectively. Intra-day reproducibility for concentrations of 0.1, 1.0 and 5.0
      microM were 10.0, 4.4 and 4.2%, respectively, for N-oxide; 11.2, 4.3 and 4.9%,
      respectively, for N-desmethylclozapine; and 10.8, 2.2 and 4.9%, respectively, for
      clozapine. Inter-day reproducibility was <15% for clozapine N-oxide, <8% for N
      desmethylclozapine and <19% for clozapine. This simple method was applied to
      determine the plasma concentration profiles of clozapine, N-desmethylclozapine
      and clozapine N-oxide in dog following administration of a 10 mg/kg oral dose of
      clozapine.

PMID- 12482481
TI  - Determination of urinary 12(S)-hydroxyeicosatetraenoic acid by liquid
      chromatography-tandem mass spectrometry with column-switching technique: sex
      difference in healthy volunteers and patients with diabetes mellitus.
AB  - We developed a determination method for human urinary 12-hydroxyeicosatetraenoic
      acid (12-HETE) using LC-MS-MS. This method, which includes simple extraction and
      detection in the SRM mode, allows precise and accurate determination of 12-HETE.
      There was a significant sex difference in urinary 12-HETE levels. Chiral analysis
      of 12-HETE using LC-MS-MS with column-switching technique revealed that the major
      enantiomer was 12(S)-HETE. Furthermore, the urinary level in patients with
      diabetes mellitus (DM) was analyzed. The present in vivo findings indicate that
      there could be difference in production of 12(S)-HETE between genders and 12(S)
      HETE may play a role in the pathogenesis of DM.

PMID- 12482482
TI  - Liquid chromatographic-mass spectrometric method for the determination of alpha
      ,beta-arteether in rat serum.
AB  - This study reports the development and validation of a sensitive and selective
      assay method for the determination of alpha-,beta-arteether in rat serum by
      liquid chromatography-mass spectrometry. The mobile phase was composed of
      methanol-0.1 mM sodium acetate (pH 5) (80:20%) at a flow-rate of 1 ml min(-1) and
      chromatographic separations were achieved on a Ultracarb, 5 ODS 20, Phenomenex
      column (5 micrometer, 30 mmx4.6 mm I.D.). The total effluent from the column was
      split so that one-tenth was injected into the electrospray LC-MS interface. ESI
      MS analysis was carried out using a Micromass Quattro II Triple Quadrupole Mass
      Spectrometer equipped with an electrospray source. The MS analysis was carried
      out at a cone voltage of 52 V with a scan range of 100-400 Da. The analytes were
      quantified from the [M+Na](+) ion chromatograms of alpha-,beta-arteether at m/z
      335 and artemisinin at m/z 305. A simple liquid-liquid extraction with 2x2 ml n
      hexane was used to isolate alpha-,beta-arteether from rat serum. The method was
      validated in terms of recovery, linearity, accuracy and precision (within- and
      between-assay variation). The recovery from spiked control samples ranged from
      88.41 to 96.17% with a maximum CV of 10.8% for alpha-arteether and 69.83-79.69%
      with a maximum CV of 17.06% for beta-arteether. Linearity in serum was observed
      over the range 20-320 ng ml(-1). Percent bias (accuracy) was well within the
      acceptable range. Within- and between-assay precision were less than 15%. The
      assay method described here is being applied to study the pharmacokinetics of
      CDRI developed intramuscular formulation Emal (alpha-/beta-arteether in the ratio
      of 30:70) in rats. The method is sensitive enough to monitor alpha-,beta
      arteether up to 24 h after a single 30 mg kg(-1) i.m. dose.

PMID- 12482483
TI  - Development and characterization of an immunoaffinity column for the selective
      extraction of bisphenol A from serum samples.
AB  - An immunoaffinity column (IAC) was developed by covalently coupling polyclonal
      antibodies against estrogenic bisphenols to CNBr-activated Sepharose 4B. The IAC
      showed high affinity for bisphenol A, while phenol was barely retained. Proteins
      in the sample matrix showed little nonspecific adsorption on the column. The best
      binding solvent for bisphenol A was found to be 0.01 mol l(-1) phosphate-buffered
      saline (PBS) and the optimal operating temperature was 4 degrees C. The bound
      bisphenol A could be quantitatively recovered by 1 ml of methanol-water (80:20)
      with an average recovery of 91.8% and a relative standard deviation of 7.1%
      (n=6). The immunoaffinity column has been successfully used for the isolation and
      purification of bisphenol A from serum samples.

PMID- 12482484
TI  - Simultaneous determination of six urinary porphyrins using liquid chromatography
      tandem mass spectrometry.
AB  - A liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method without
      sample pretreatment was developed and validated for determination of porphyrins
      in samples of canine urine. Acidified urine samples were directly injected into
      the LC-MS system and a gradient elution program was applied. The mass
      spectrometer was operated in the multi-reaction monitoring (MRM) mode and six
      porphyrins were detected with excellent sensitivity and selectivity. The lower
      limits of quantification were 0.014 nmol/mL for mesoporphyrin IX, coproporphyrin
      I, 5-carboxylporphyrin, 6-carboxylporphyrin and 7-carboxylporphyrin, and 0.029
      nmol/mL for uroporphyrin I. Good ln-quadratic responses of calibration standards
      over the range 0.01 to 1.0 nmol/mL for mesoporphyrin IX, coproporphyrin I, 5
      carboxylporphyrin, 6-carboxylporphyrin and 7-carboxylporphyrin, and 0.02 to 1.0
      nmol/mL for uroporphyrin I were demonstrated. This method should be easily
      adapted through cross-validation for use in determining the effects of chemicals
      and pharmaceuticals on the urinary excretion profile of porphyrins in preclinical
      studies with other species, and in assisting the diagnosis of porphyria in
      clinical studies.

PMID- 12482485
TI  - Development of a liquid chromatography-mass spectrometry method for monitoring
      the angiotensin-converting enzyme inhibitor lisinopril in serum.
AB  - In this study, a sensitive, specific, precise and accurate method for lisonopril
      quantitative determination in human serum was developed and validated. The method
      comprises lisinopril isolation from serum by means of solid-phase extraction
      followed by its quantification by liquid chromatography-mass spectrometry.
      Chromatographic separation was performed at 55 degrees C on Kromasil C(18) 5
      micrometer 250x3.2 mm HPLC column with mobile phase composed of 50 mM ammonium
      formate buffer (pH 3)-acetonirile-methanol (72:7:21, v/v/v). A Finnigan AQA
      benchtop mass spectrometer with a pneumatically assisted electrospray (ES)
      interface and a single quadrupole mass filter was used to detect and quantify
      lisinopril in column effluent. Ion signals were acquired by selected ion
      monitoring of the protonated lisinopril ion m/z=406.5 (M+1). The detector
      response was linear with r>0.9993 in the investigated concentration range 6-150
      ng/ml. The mean recovery of lisinopril from serum samples was 88%. The limit of
      quantitation for lisinopril was 6 ng/ml with a signal-to-noise ratio at this
      concentration level S/N=34.75+/-3.9 (n=4).

PMID- 12482486
TI  - Enantioselective determination of metoprolol acidic metabolite in plasma and
      urine using liquid chromatography chiral columns: applications to
      pharmacokinetics.
AB  - Enantioselective separations on chiral stationary phases with or without
      derivatization were developed and compared for the HPLC analysis of (+)-(R)- and
      (-)-(S)-metoprolol acidic metabolite in human plasma and urine. The enantiomers
      were analysed in plasma and urine without derivatization on a Chiralcel OD-R
      column, and in urine after derivatization using methanol in acidic medium on a
      Chiralcel OD-H column. The quantitation limits were 17 ng of each enantiomer/ml
      plasma and 0.5 microgram of each enantiomer/ml urine using both methods. The
      confident limits show that the methods are compatible with pharmacokinetic
      investigations of the enantioselective metabolism of metoprolol. The methods were
      employed in a metabolism study of racemic metoprolol administered to a patient
      phenotyped as an extensive metabolizer of debrisoquine. The enantiomeric ratio
      (+)-(R)/(-)-(S)-acid metabolite was 1.1 for plasma and 1.2 for urine. Clearances
      were 0.41 and 0.25 l/h/kg, respectively, for the (+)-(R)- and (-)-(S)
      enantiomers. The correlation coefficients between the urine concentrations of the
      acid metabolite enantiomers obtained by the two methods were >0.99. The two
      methods demonstrated interchangeable application to pharmacokinetics.

PMID- 12482487
TI  - Gas chromatographic-mass spectrometric detection of 2- and 3-hydroxy fatty acids
      as methyl esters from soil, sediment and biofilm.
AB  - Hydroxy fatty acids (OH-FAs) can be used in the characterization of microbial
      communities, especially Gram-negative bacteria. We prepared methyl esters of 2-
      and 3-OH-FAs from the lipid extraction residue of soil, sediment, and biofilm
      samples without further purification or derivatization of hydroxyl groups. OH-FA
      methyl esters were analyzed using a gas chromatograph equipped with a mass
      selective detector (GC-MS). The ions followed in MS were m/z 103 for 3-OH-FAs and
      m/z 90 and M-59 for 2-OH-FAs. The rapid determination of 3- and 2-OH-FAs
      concomitantly with phospholipid fatty acids provided more detailed information on
      the microbial communities present in soil, sediment, and drinking water biofilm.

PMID- 12482488
TI  - Lansoprazole quantification in human plasma by liquid chromatography-electrospray
      tandem mass spectrometry.
AB  - An analytical method based on liquid chromatography with positive ion
      electrospray ionization (ESI) coupled to tandem mass spectrometry detection was
      developed for the determination of lansoprazole in human plasma using omeprazole
      as the internal standard. The analyte and internal standard were extracted from
      the plasma samples by liquid-liquid extraction using diethyl-ether
      dichloromethane (70:30; v/v) and chromatographed on a C(18) analytical column.
      The mobile phase consisted of acetonitrile-water (90:10; v/v)+10 mM formic acid.
      The method has a chromatographic total run time of 5 min and was linear within
      the range 2.5-2000 ng/ml. Detection was carried out on a Micromass triple
      quadrupole tandem mass spectrometer by Multiple Reaction Monitoring (MRM). The
      intra- and inter-run precision, calculated from quality control (QC) samples, was
      less than 3.4%. The accuracy as determined from QC samples was less than 9%. The
      method herein described was employed in a bioequivalence study of two capsule
      formulations of lansoprazole.

PMID- 12482489
TI  - Validated method for the determination of risperidone and 9-hydroxyrisperidone in
      human plasma by liquid chromatography-tandem mass spectrometry.
AB  - Since the first entry of risperidone on to the market in the early 1990s,
      investigation of the pharmacokinetic behaviour of the compound for which the
      availability of a bioanalytical method was a condition sine qua non, has received
      considerable attention. Most of the published methods, however, did not reach the
      level of sensitivity and selectivity which can be obtained today since the
      evolution of liquid chromatography-tandem mass spectrometry (LC-MS-MS) towards a
      routine technique in the bioanalytical laboratory. Therefore, we developed and
      validated a new LC-MS-MS method for the determination of risperidone and its
      active metabolite 9-hydroxyrisperidone in human plasma. This paper describes in
      detail the bioanalytical procedure and summarizes the validation results
      obtained. In addition, it focuses on the pitfalls one might encounter when
      developing similar assays. Despite the particular physicochemical characteristics
      of risperidone and 9-hydroxyrisperidone, the LC-MS-MS method enabled the
      quantification of both compounds down to 0.1 ng/ml. The method uses a sample
      preparation step by solid-phase extraction at pH 6 using a mixed-mode phase. In a
      short chromatographic run, separation of 9-hydroxyrisperidone from the minor
      metabolite 7-hydroxyrisperidone is achieved. Detection takes place by
      (turbo)ionspray tandem mass spectrometry in the positive ion mode. The validated
      concentration range is from 0.100 to 250 ng/ml, using 500 microliter of sample,
      with accuracy (bias) and precision (coefficient of variation) being below 15%.
      Although new developments in equipment will allow us to further improve and speed
      up the method, the assay reported can be used as a routine method to support a
      wide range of pharmacokinetic studies.

PMID- 12482490
TI  - High-performance liquid chromatographic method for determination of amodiaquine,
      chloroquine and their monodesethyl metabolites in biological samples.
AB  - A high-performance liquid chromatographic method for determination of amodiaquine
      (AQ), desethylamodiaquine (DAQ), chloroquine (CQ) and desethylchloroquine (DCQ)
      in human whole blood, plasma and urine is reported. 4-(4-Dimethylamino-1
      methylbutylamino)-7-chloroquinoline was used as internal standard. The drugs and
      the internal standard were extracted into di-isopropyl ether as bases and then re
      extracted into an acidic aqueous phase with 0.1 M phosphate buffer at pH 4.0 for
      AQ samples and at pH 2.5 for CQ filter paper samples. A C(18) column was used and
      the mobile phase consisted of methanol-phosphate buffer (0.1 M, pH 3)-perchloric
      acid (250: 747.5:2.5, v/v). The absorbance of the drugs was monitored at 333 nm
      and no endogenous compound interfered at this wavelength. The limit of
      quantification in whole blood, plasma and urine was 100 nM for AQ and DAQ (sample
      size 100 microliter) as well as for CQ and DCQ in blood samples dried on filter
      paper. For 1000 microliter AQ and DAQ samples, the limit of quantification was 10
      nM in all three biological fluids. The within-assay and between-assay
      coefficients of variations were always <10% at the limits of quantification.
      Plasma should be preferred for the determination of AQ and DAQ since use of whole
      blood may be associated with stability problems.

PMID- 12482491
TI  - Direct stereoselective assay of fluoxetine and norfluoxetine enantiomers in human
      plasma or serum by two-dimensional gas-liquid chromatography with nitrogen
      phosphorus selective detection.
AB  - A method was developed and validated for the direct enantioselective assay of
      fluoxetine and norfluoxetine in human plasma or serum by two-dimensional
      capillary gas-liquid chromatography (GC). A Rtx-1 fused-silica capillary (15
      mx0.25 mm I.D., 1.0 micrometer film thickness) and a hydrodex-beta-6-TBDM fused
      silica capillary (25 mx0.25 mm I.D., 0.25 micrometer film thickness) were used. A
      three-step liquid-liquid extraction was used for sample preparation with
      fluvoxamine and nisoxetine as internal standards. The method provided linear
      calibration between about 5 and 250 ng/ml for (R)- and (S)-fluoxetine as well as
      15 and 250 ng/ml for (R)- and (S)-norfluoxetine. The limits of detection were
      about 1.5 and 6 ng/ml, respectively. Intra-day precision (coefficient of
      variation) was estimated as being between 5.4 and 12.7% at plasma levels of 25,
      100 and 200 ng/ml for the four enantiomers. Inter-day precision was between 5.3
      and 9.1% at 100 ng/ml. The enantioselective separation of some racemic
      psychopharmaceuticals was tested with various cyclodextrin GC-capillaries.
      Advantages and disadvantages of direct enantioselective GC are discussed for the
      assay of racemic psychopharmaceuticals. Samples from a patient who was treated
      with racemic fluoxetine were measured. In agreement with literature, plasma
      levels of the (R)-enantiomers of fluoxetine and norfluoxetine were considerably
      decreased in comparison to the (S)-enantiomers.

PMID- 12482492
TI  - Simultaneous quantitative determination of the HIV protease inhibitors indinavir,
      amprenavir, ritonavir, lopinavir, saquinavir, nelfinavir and the nelfinavir
      active metabolite M8 in plasma by liquid chromatography.
AB  - A simple HPLC method that quantitates all six currently available protease
      inhibitors and the nelfinavir active metabolite M8 in one assay is presented. A
      500-microliter plasma sample was treated by liquid-liquid extraction with a
      mixture of heptane and ethyl acetate. After evaporation, the residue was
      redissolved in sodium dihydrogenphosphate and acetonitrile and washed twice with
      heptane. Chromatography was performed with an analytical C(18) column.
      Ultraviolet detection at 210 and 239 nm was used. The present method is
      associated with high accuracy and low imprecision in the concentration range of
      25-5000 ng/ml of all six protease inhibitors and M8. This makes it suitable for
      monitoring purposes.

PMID- 12482493
TI  - Detection of bacterial pathogen DNA using an integrated complementary metal oxide
      semiconductor microchip system with capillary array electrophoresis.
AB  - In this paper, we show an integrated complementary metal oxide semiconductor
      (CMOS)-based microchip system with capillary array electrophoresis (CAE) for the
      detection of bacterial pathogen amplified by polymerase chain reaction (PCR). In
      order to demonstrate the efficacy of PCR reaction for the heat-labile toxin
      producing enterotoxigenic Escherichia coli (E. coli), which causes cholera-like
      diarrhea, 100 bp DNA ladders were injected along with the PCR product.
      Poly(vinylpyrrolidone) (PVP) was used as the separation medium and provided
      separation resolution which was adequate for the identification of PCR product.
      The miniaturized integrated CMOS microchip system with CAE has excellent
      advantages over conventional instrumental systems for analysis of bacterial
      pathogens such as compactness, low cost, high speed, and multiplex capability.
      Furthermore, the miniaturized integrated CMOS microchip system should be
      compatible with a variety of microfabricated devices that aim at more rapid and
      high-throughput analysis.

PMID- 12482494
TI  - Determination of midecamycin by capillary zone electrophoresis with
      electrochemical detection.
AB  - Capillary zone electrophoresis was employed for the determination of midecamycin
      using an end-column amperometric detection with a carbon fiber micro-disk bundle
      electrode at a constant potential of +1.15 V vs. saturated calomel electrode. The
      optimum conditions of separation and detection are 1.00x10(-3) mol l(-1)
      Na(2)HPO(4)-3.49x10(-4) mol l(-1) NaOH (pH 11.4) for the buffer solution, 20 kV
      for the separation voltage, 5 kV and 5 s for the injection voltage and the
      injection time, respectively. The limit of detection is 5.0x10(-7) mol l(-1) or
      0.41 fmol (S/N=3). The linear range of the calibration curve is 1.00x10(-6)
      1.00x10(-3) mol l(-1). The relative standard deviation is 1.4% for the migration
      time and 4.9% for the electrophoretic peak current. The method could be applied
      to the determination of midecamycin in human urine. In this case, a separation
      voltage of 14 kV was used.

PMID- 12482495
TI  - Gas chromatography-mass spectrometry profile of urinary organic acids of Wistar
      rats orally treated with ozonized unsaturated triglycerides and ozonized
      sunflower oil.
AB  - The main products in the ozonolysis of unsaturated triglycerides or vegetable
      oils are peroxides, aldehydes, Criegee ozonides and carboxylic acids. Some of
      these compounds are present in different concentrations in the biological fluids.
      The aim of this work is to study, using gas chromatography-mass spectrometry (GC
      MS), the organic acid excretion in urine of rats orally treated with ozonized
      sunflower oil (OSO), ozonized triolein or ozonized trilinolein. Oral
      administration of OSO to Wistar rats has produced changes in the urinary content
      of dicarboxylic organic acids. Among others heptanedioic (pimelic acid) and
      nonanedioic acids (azelaic acid) were the major increased dicarboxylic acids
      found. The urinary dicarboxylic acid profiles of rats which received ozonized
      triolein only showed an increase in heptanedioic and nonanedioic acids. However,
      when ozonized trilinolein is applied, the profile is similar to that obtained
      when OSO is administered. A biochemical mechanism is proposed to explain the
      formation of dicarboxylic acids from ozonated unsaturated triglycerides.

PMID- 12482496
TI  - Clinical implications of antigen transfer mechanisms from malignant to dendritic
      cells. exploiting cross-priming.
AB  - Expansion and activation of cytolytic T lymphocytes bearing high-affinity T-cell
      receptors specific for tumor antigens is a major goal of active cancer
      immunotherapy. Physiologically, T cells receive promitotic and activating signals
      from endogenous professional antigen-presenting cells (APC) rather than directly
      from malignant cells. This phenomenon fits with the broader concept of cross
      presentation that earlier was demonstrated for minor histocompatibility and viral
      antigens. Many mechanisms have been found to be capable of transferring antigenic
      material from malignant cells to APC so that it can be processed and subsequently
      presented by MHC class I molecules expressed on APC. Dendritic cells (DC) are
      believed to be the most relevant APC mediating cross-presentation because they
      can take up antigens from apoptotic, necrotic, and even intact tumor cells. There
      exist specific molecular mechanisms that ensure this transfer of antigenic
      material: 1) opsonization of apoptotic bodies; 2) receptors for released heat
      shock proteins carrying peptides processed intracellularly; 3) Fc receptors that
      uptake immunocomplexes and immunoglobulins; and 4) pinocytosis. DC have the
      peculiar capability of reentering the exogenously captured material into the MHC
      class I pathway. Exploitation of these pieces of knowledge is achieved by
      providing DC with complex mixtures of tumor antigens ex vivo and by agents and
      procedures that promote infiltration of malignant tissue by DC. The final outcome
      of DC cross-presentation could be T-cell activation (cross-priming) but also, and
      importantly, T-cell tolerance contingent upon the activation/maturation status of
      DC. Artificial enhancement of tumor antigen cross-presentation and control of the
      immune-promoting status of the antigen-presenting DC will have important
      therapeutic implications in the near future.

PMID- 12482497
TI  - Tissue microarrays for miniaturized high-throughput molecular profiling of
      tumors.
AB  - New high-throughput screening technologies such as complementary (cDNA)
      microarrays allow identification of hundreds of candidate genes in one
      experiment. To prioritize the leads obtained in such studies, it is necessary to
      analyze a large number of tissues for candidate gene expression. Tissue
      microarray (TMA) technology greatly facilitates such analyses. In this method,
      hundreds of minute tissue samples (0.6-mm diameter) can be placed on one
      microscope glass slide. The TMA approach allows simultaneous analysis of all
      tissues with in situ methods (immunohistochemistry, fluorescence in situ
      hybridization, RNA in situ hybridization) of all tumors in one experiment under
      highly standardized conditions. TMAs are not restricted to solid tumors but can
      be manufactured from a variety of other sources, including cell lines,
      xenografts, and hematologic tissues. In addition to tumor type-specific
      applications that comprise large numbers of one particular tumor type with
      extensive histopathologic and clinical data, TMAs are well suited for large-scale
      molecular epidemiologic studies. For example, genes of interest can be analyzed
      in multitissue TMAs containing a variety of different human normal tissues and
      tumor entities. Once tumor types are identified, where a given molecular
      alteration plays a role, the clinical significance of this molecular alteration
      can be investigated on tumor-specific TMAs. Thus, TMA technology allows
      miniaturized high-throughput molecular epidemiologic studies. The TMA technique
      will markedly accelerate the transition from basic research to clinical
      applications.

PMID- 12482498
TI  - Role of human interleukin-9 as a megakaryocyte potentiator in culture.
AB  - OBJECTIVE: This study investigated the effect of interleukin-9 (IL-9) on the
      proliferation and differentiation of human colony-forming unit megakaryocytic
      progenitor cells (CFU-Meg). MATERIALS AND METHODS: Peripheral blood-derived
      CD34(+)IL-6R(-) cells were sorted and cultured in the presence of IL-9,
      erythropoietin (Epo), stem cell factor (SCF), and thrombopoietin (TPO) alone or
      in combination. The number of pure and mixed megakaryocyte colonies, the size of
      pure megakaryocyte colonies, the ploidy distribution of megakaryocytes, and
      proplatelet formation were investigated. RESULTS: Apart from TPO, no single
      factor could support CFU-Meg-derived colony formation, but each two-factor
      combination among IL-9, Epo, and SCF supported a few CFU-Meg colonies.
      Interestingly, the combination of Epo+SCF+IL-9 induced four to six times as many
      CFU-Meg colonies as any of the two-factor combinations. Neutralizing monoclonal
      antibodies (mAbs) for IL-9 receptor and c-kit completely abolished this
      synergistic effect. In contrast, addition of neutralizing anti-c-Mpl or anti
      CXCR4 Abs did not influence colony formation, indicating that this synergistic
      effect was independent of TPO or SDF-1. Moreover, the endogenous production of
      TPO by cultured CD34(+)IL-6R(-) cells in the presence of Epo+SCF+IL-9 was ruled
      out by reverse transcriptase polymerase chain reaction for TPO mRNA.
      Interestingly, the combination of TPO, Epo, SCF, and IL-9 supported the largest
      number of pure and mixed megakaryocyte colonies, suggesting that this combination
      of cytokines might recruit primitive megakaryocytic as well as multipotential
      progenitors. This combination also potently enhanced proplatelet formation
      compared with TPO alone or a combination of Epo, SCF, and IL-9. CONCLUSION: This
      study demonstrated for the first time that human IL-9 can potentiate human
      megakaryocytopoiesis in the presence of Epo and/or SCF.

PMID- 12482500
TI  - Agonists to the A3 adenosine receptor induce G-CSF production via NF-kappaB
      activation: a new class of myeloprotective agents.
AB  - OBJECTIVE: The aim of this study was to evaluate the effect of CF101, a synthetic
      agonist to the A3 adenosine receptor (A3AR), on the production of granulocyte
      colony-stimulating factor (G-CSF). The ability of CF101 to act as a
      myeloprotective agent in chemotherapy-treated mice was tested. METHODS: CF101 was
      administered orally to naive mice and its effect was studied on blood cell counts
      (coulter counter), serum G-CSF level (ELISA), bone marrow colony-forming cells
      (soft agar culture), and splenocytes' ability to produce ex vivo G-CSF. Protein
      extract was prepared from splenocytes and Western blot analysis was carried out
      to evaluate expression level of key proteins. In an additional set of
      experiments, CF101 was administered to mice 48 hours after cyclophosphamide
      treatment and blood cell counts as well as serum G-CSF levels were monitored.
      RESULTS: Oral administration of CF101 to naive mice led to the elevation of serum
      G-CSF levels, an increase in absolute neutrophil counts (ANC), and bone marrow
      colony-forming cells. Splenocytes derived from these mice produced higher G-CSF
      level than controls. The molecular mechanisms underlying the events prior to G
      CSF production included the upregulation of NF-kappaB and the upstream kinases
      phosphoinositide 3-kinase (PI3K), protein kinase B/Akt (PKB/Akt), and IKK.
      Accelerated recovery of white blood cells and neutrophil counts were observed in
      cyclophosphamide-treated mice following CF101 administration. CONCLUSION: CF101
      induced upregulation of the PI3K/NF-kappaB pathway leading to G-CSF production,
      resulting in myeloprotective effect in cyclophosphamide-treated mice.

PMID- 12482499
TI  - Isolation and characterization of runxa and runxb, zebrafish members of the runt
      family of transcriptional regulators.
AB  - OBJECTIVE: The AML/RUNX family of transcription factors plays important roles in
      hematopoiesis, neurogenesis, bone development, and segmentation in vertebrate
      embryos. The aim of this study was to isolate runt-related genes in a genetically
      and embryologically exploitable system, the zebrafish, and characterize their
      function during hematopoietic development. MATERIALS AND METHODS: Two runt
      related genes were isolated by degenerate PCR and standard library screening, and
      a radiation hybrid panel, T51 RH, was used to resolve their chromosomal
      localization. In situ hybridization demonstrated their expression whereas their
      transcriptional activity was assessed using an AML1-responsive reporter gene in
      the MLA 144 T-cell line. RESULTS: We isolated the zebrafish runxa and runxb
      cDNAs, which encode proteins highly homologous to the human and murine Runx1
      (AML1) and Runx3 (AML2) proteins. In contrast to a recent report, we detected
      runxa expression in both hematopoietic and neural tissues of the developing
      zebrafish. runxa transcripts first appear during segmentation in bilateral
      mesodermal cells that coexpress one of the earliest blood and endothelial cell
      markers, scl/tal-1. By 24 hours postfertilization (hpf), runxa transcripts are
      seen in the ventral wall of the dorsal aorta. Hematopoietic runxa expression is
      lost in cloche mutants, which are defective in blood and endothelial cell
      formation. runxb transcripts are seen in nonhematopoietic domains. Both Runxa and
      Runxb transactivate an AML1-responsive human promoter in hematopoietic cells.
      Genomic localization studies demonstrate that runxa is located on linkage group 1
      (LG1), and the runxb gene is located on LG13. CONCLUSIONS: Our gene expression
      analysis strongly suggests that both the functional and spatial aorta-gonad
      mesonephros (AGM) region has been conserved throughout evolution. Our runxa
      spatiotemporal expression data shed light on the role of vertebrate Runx1/AML1 in
      primitive vs definitive hematopoietic development.

PMID- 12482501
TI  - Accelerated telomere length shortening in granulocytes: a diagnostic marker for
      myeloproliferative diseases.
AB  - OBJECTIVE: The telomere in mature myeloid cells derived from abnormal progenitor
      cells of myeloproliferative diseases (MPDs) may shorten more rapidly than that in
      T lymphocytes, which are considered to be derived from normal clones. To test
      this hypothesis, we measured telomere lengths in granulocytes and T lymphocytes
      from patients with MPDs and compared them with those from normal individuals.
      MATERIALS AND METHODS: Granulocytes and T lymphocytes were separated from the
      peripheral blood of 65 patients with MPDs (25 chronic myelogenous leukemia [CML],
      16 polycythemia vera, 19 essential thrombocythemia, 5 chronic idiopathic
      myelofibrosis) and 35 normal individuals. Genomic DNA from each cell fraction was
      subjected to Southern blot hybridization to determine the mean telomere length.
      RESULTS: Telomere lengths in granulocytes from patients with MPDs were
      significantly shorter than those from normal individuals (vs CML, p = 0.002; vs
      other MPDs, p < 0.0001). However, there was no statistical difference in telomere
      length in T lymphocytes between MPD patients and normal individuals (vs CML, p =
      0.35; vs other MPDs, p = 0.85). DeltaTRF (terminal restriction fragment) in
      patients with MPDs, which is defined as the difference in telomere length between
      granulocytes and T lymphocytes, was significantly longer than that in normal
      individuals. CONCLUSIONS: The results support the disease theory that MPDs result
      from extensive proliferation of myeloid progenitor cells, leading to accelerated
      telomere length shortening in mature granulocytes. An increase in DeltaTRF over
      the standard value (>1.74 kb) may be useful for discriminating leukocytosis due
      to MPDs from reactive leukocytosis.

PMID- 12482502
TI  - Autologous lymphocytes inhibit hemopoiesis in long-term culture in patients with
      myelodysplastic syndrome.
AB  - OBJECTIVE: The current therapy of myelodysplastic syndrome (MDS) is
      unsatisfactory and comprises mainly supportive treatment or antileukemic
      chemotherapy. Recent studies about successful immunosuppressive therapy suggest
      an autoimmune mechanism in subtypes of myelodysplastic syndrome. PATIENTS AND
      METHODS: To investigate this hypothesis, bone marrow mononuclear cells (MNC) from
      15 patients with low-grade MDS, refractory anemia, and refractory anemia with
      ringed sideroblasts (RA and RARS), and from 7 normal donors were depleted of
      CD2(+), CD5(+), and CD7(+) lymphocytes using magnetic cell sorting. Depleted and
      nondepleted MNC were seeded onto irradiated allogeneic bone marrow stroma and the
      generation of colony-forming-cells (CFC), the clonal origin of hemopoietic
      progenitor cells in long-term bone marrow culture (LTC), was compared. RESULTS:
      The capacity of MNC from 7 healthy donors to generate hemopoiesis remained
      unchanged in the lymphocyte-depleted LTC. In contrast, cultures initiated with
      lymphocyte-depleted MNC from patients with RA and RARS exhibited a significantly
      increased generation of CFC compared with the corresponding nondepleted cultures.
      Microsatellite analysis in 6 patients revealed that a significantly increased
      number of CFC grown in lymphocyte-depleted LTC showed no allelic loss, suggesting
      an outgrowth of normal hemopoietic cells. CONCLUSION: These results provide a
      rationale for the recently described successful treatment of MDS with
      immunosuppressive therapy. We suggest that in certain subtypes of MDS the
      residual normal hemopoiesis is suppressed by autoimmune mechanisms, eventually
      allowing the expansion of the abnormal clone.

PMID- 12482503
TI  - Levels of E2A protein expression in B cell precursors are stage-dependent and
      inhibited by stem cell factor (c-kit ligand).
AB  - OBJECTIVE: The E2A-encoded proteins E47 and E12 are crucial to the development of
      pro-B and pre-B cells. The expression of E2A protein and mRNA during early B
      lymphopoiesis was determined and effects of stem cell factor (SCF; Steel factor;
      c-kit ligand) on E2A expression were evaluated. MATERIALS AND METHODS: Ex vivo
      murine pro-B cells and pre-B cells were isolated and in vitro B cell precursors
      were derived after culture of bone marrow with rmIL-7. Levels of E2A proteins
      were determined by Western analysis and mRNA by RT-PCR. E2A expression in vitro
      was also assessed in cultures supplemented with IL-7 +/- recombinant murine SCF
      (rmSCF), insulin-like growth factor-1 (rhIGF-1), or Flt3-ligand (rhFlt3-L).
      Turnover of E2A proteins was assessed following cycloheximide treatment. RESULTS:
      Ex vivo, pro-B cells had lower E47 protein levels than did pre-B cells but had
      comparable E2A mRNA levels. E2A protein, but not mRNA, levels were reduced in pro
      B cells upon culture in vitro with IL-7 + rmSCF. This was associated with
      increased turnover of E2A proteins. In contrast, culture with IL-7 + IGF-1 or
      Flt3-L had minimal effects on E2A protein levels. CONCLUSION: Pre-B cells
      expressed higher levels of E2A protein than did pro-B cells and this mainly
      resulted from posttranscriptional regulation. Exogenous SCF inhibited E2A
      protein, but not mRNA, expression in cultured B cell precursors, possibly by
      increasing E2A protein turnover. The capacity to respond to SCF may influence the
      levels of E2A during B-cell development.

PMID- 12482504
TI  - NF-kappaB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin
      gene expression.
AB  - OBJECTIVE: The aim of this study was to further define the signal transduction
      pathways leading to hypoxia-inducible factor-1 (HIF-1) erythropoietin (EPO) gene
      expression. MATERIALS AND METHODS: Human hepatocellular carcinoma cells (Hep3B)
      were exposed to hypoxia (1% oxygen) and examined for mRNA expression, as well as
      gene transactivation with RT-PCR and luciferase reporter gene assays,
      respectively. RESULTS: Treatment with LY294002 (a selective pharmacological
      inhibitor of phosphatidylinositol 3-kinase) significantly inhibited EPO protein
      and mRNA expression in Hep3B cells exposed to hypoxia for 24 hours, while
      treatment with PD098059 or SB203580 (selective pharmacological inhibitors of the
      MEK and p38 mitogen-activated protein kinase pathways, respectively) had no
      significant effects. The activity of AKT, a downstream target of PI3K, was
      increased by hypoxia and was also inhibited by LY294002. Genetic inhibition of
      AKT resulted in significant inhibition of NF-kappaB and HIF-1-mediated
      transactivation, as well as EPO gene expression, in response to hypoxia.
      Overexpression of constitutively active AKT resulted in increased NF-kappaB and
      HIF-1 transactivation. The selective inhibitor of NF-kappaB, pyrrolidine
      dithiocarbamate (PDTC), significantly blocked HIF-1 protein expression.
      Inhibition of NF-kappaB with a superrepressor dominant negative IkappaBalpha
      genetic construct also significantly blocked NF-kappaB and HIF-1 transactivation,
      as well as EPO gene expression. CONCLUSION: We propose a key role for NF-kappaB
      in EPO gene regulation in response to hypoxia.

PMID- 12482506
TI  - Limiting dilution analysis for estimating the frequency of hematopoietic stem
      cells: uncertainty and significance.
AB  - The ability to predict accurately the number of hematopoietic stem cells (HSCs)
      in a graft is important for the success of HSC transplantation. Limiting dilution
      analysis (LDA) in vitro and in vivo is widely used to enumerate HSCs. However,
      there have been few attempts to standardize this approach. Particularly, the role
      of statistical and experimental errors in the performance and evaluation of LDA
      has received little attention. Since these errors directly affect the
      interpretation, validity, and significance of the LDA results, we have here
      performed a systematic analysis of the contribution of different types of
      errors.Long-term culture-initiating cells (LTC-IC) in the bone marrow of C57BL/6
      (B6) mice were measured. Experiments were designed to exclude systematically
      different types of experimental errors. Computer simulations were performed to
      estimate the statistical error. Analysis of 137 LTC-IC assays showed 2.8 +/- 1.06
      LTC-IC per 10(5) cells in the bone marrow of B6 mice. The major components of the
      uncertainty were derived from variations introduced by performing the experiments
      at different time points and by the statistical error. Surprisingly, operator
      errors and mouse-to-mouse error, including age and sex of the animals,
      contributed little to the overall uncertainty. As expected, the errors were found
      to decrease when increasing numbers of replica were analyzed. A computer program
      was developed to assist with the optimal design of the assay. The analysis
      presented here provides rational strategies for standardizing the experimental
      design and for gauging the accuracy of LDA-based HSC measurements.

PMID- 12482505
TI  - A role for the Fas/Fas ligand apoptotic pathway in regulating myeloid progenitor
      cell kinetics.
AB  - Bone marrow from wild-type mice and mice with mutated Fas (lpr) or mutated Fas
      ligand (gld) was used to investigate the role of the Fas/FasL system in the
      regulation of myeloid progenitor cell kinetics.Granulocyte-macrophage colony
      forming cells (CFU-GM) were measured by a standard colony assay and the
      proliferative activity of CFU-GM was measured by replating primary colonies and
      observing secondary colony formation. Fas expression was restored to lpr mouse
      bone marrow cells by retrovirus-mediated gene transfer and gld mouse marrow cells
      were treated with soluble FasL. Wild-type marrow cells were treated with YVAD (a
      caspase inhibitor) or anti-Fas monoclonal antibodies. There were greater
      frequencies of myeloid progenitor cells (CFU-GM) in lpr and gld mouse marrow
      compared to wild-type (WT) marrow (p = 0.0008). The proliferative capacity of CFU
      GM was also significantly greater for lpr and gld CFU-GM compared to WT CFU-GM (p
      = 0.0003 and 0.0001, respectively). Retrovirus-mediated restoration of Fas into
      lpr marrow, and provision of soluble FasL (sFasL) to gld CFU-GM reduced CFU-GM
      proliferation to WT levels. Treatment of WT CFU-GM with YVAD or anti-FasL
      monoclonal antibody increased CFU-GM proliferation to the levels found in lpr and
      gld CFU-GM. YVAD significantly increased and anti-Fas significantly reduced the
      proliferative capacity of human CFU-GM (p = 0.015 and 0.04, respectively).Fas,
      FasL, and caspase activation may play an important role in regulating myeloid
      progenitor cell kinetics.

PMID- 12482507
TI  - Flk1+ cells derived from mouse embryonic stem cells reconstitute hematopoiesis in
      vivo in SCID mice.
AB  - OBJECTIVE: Embryonic stem (ES) cells are pluripotent and can differentiate into
      any cell type, including the hematopoietic lineage. We examined whether
      hematopoietic progenitor cells derived from ES cells reconstitute hematopoiesis
      in irradiated SCID mice. MATERIALS AND METHODS: ES cells (E14.1, H2K(b)) were
      cultured for 4 days in semisolid medium containing methylcellulose. Irradiated
      SCID mice were used as recipients of hematopoietic progenitor cells. Cell surface
      antigen expression was analyzed by flow cytometry. The spleens of the recipient
      mice were studied by hematoxylin and eosin staining and immunohistochemical
      staining. RESULTS: After cell culture of ES cells in methylcellulose for 4 days,
      the cells expressing Flk1 (VEGF receptor 2), a tentative marker of
      hemangioblasts, were increased, whereas cells expressing CD31 (PECAM-1) and E
      cadherin (nonmesodermal adhesion molecule) were dramatically reduced. Flk1+ cells
      expressed c-kit predominantly. Circulating leukocytes and thrombocytes were
      increased in irradiated SCID (H2K(d)) mice transplanted with ES cell-derived
      Flk1+ cells compared with vehicle-injected control mice. H2K(b+) and VE
      cadherin(+) vascular endothelial cells were prominent in spleens of the recipient
      mice. Flow cytometric analysis demonstrated that H2K(b+) cells were increased in
      the bone marrow of recipient mice. In addition, Flk1+ cells accompanying enhanced
      c-kit expression preferentially repopulated in the bone marrow, and leukopoiesis
      and thrombopoiesis of the recipient mice were evident. CONCLUSION: The Flk1+
      hematopoietic cells derived from ES cells reconstitute hematopoiesis in vivo and
      may become an alternative donor source for bone marrow transplantation.

PMID- 12482508
TI  - Differentiative potential of human metanephric mesenchymal cells.
AB  - OBJECTIVE: To evaluate the ability of mesenchymal cells derived from
      nonhematopoietic organs to form blood and other tissues in vitro and in vivo.
      MATERIALS AND METHODS: Because of its mesodermic derivation, human fetal kidney
      was used as a source of mesenchymal cells. Two populations of kidney cells were
      studied at a nonclonal level: a crude preparation, and an adherent fraction that
      was derived from the first by propagation in vitro (MNMC). Both populations were
      transplanted into sheep fetuses and analyzed at intervals for the presence of
      human cells in different organs by flow cytometry, PCR, immunohistochemistry, and
      in situ hybridization. Secondary transplantation studies were performed using
      human hematopoietic cells obtained from the bone marrow (BM) of primary
      recipients. RESULTS: MNMC were Thy-1(+), CD51(+), CD44(+), CD45(-), and
      vimentin(+), a phenotype consistent with that of metanephric mesenchyme. The
      crude population displayed the same phenotype but was contaminated with 0.4%
      CD34(+)CD45(+) cells. Cells with hepatocyte-like morphology and phenotype were
      obtained from the MNMC after culture in specific inducing media. After
      transplantation, both populations of cells produced multilineage hematopoietic
      engraftment and gave rise to CD34(+) cells. Successful hematopoietic engraftment
      in secondary recipients demonstrated the generation of long-term engrafting
      hematopoietic stem cells from MNMC. PCR analysis confirmed human hematopoietic
      engraftment and revealed that human cells were also present within other organs.
      Liver sections of transplanted animals contained human albumin-producing
      hepatocyte-like cells. CONCLUSION: A human metanephric mesenchymal cell
      population simultaneously gave rise to human blood and liver-like cells,
      suggesting that mesenchymal cells may represent a broad population of putative
      stem cells in multiple adult organs.

PMID- 12482511
TI  - The use of substrate engineering in biohydroxylation.
AB  - In the biohydroxylation of nonactivated carbon atoms, substrate engineering has
      been found to be a very useful and simple means to influence substrate acceptance
      and the regioselectivity and stereoselectivity of this transformation. Recently,
      this methodology has been applied to the hydroxylation of a large number of
      compounds including cycloalkane carboxylic acids, ketones, amines, amides and
      alcohols.

PMID- 12482512
TI  - Methods to increase enantioselectivity of lipases and esterases.
AB  - Lipases and esterases are frequently used in the synthesis of optically pure
      compounds; however, natural enzymes do not always show sufficiently high
      enantioselectivity. Variation of the structure of the substrates, modification of
      the reaction system or protein engineering (e.g. the expression of pure enzymes,
      rational design or directed evolution) are strategies that can be employed to
      improve the distinction between two enantiomers or enantiotopic groups.

PMID- 12482513
TI  - The production of fine chemicals by biotransformations.
AB  - Today, biocatalysis is a standard technology for the production of chemicals. An
      analysis of 134 industrial biotransformations reveals that hydrolases (44%) and
      redox biocatalysts (30%) are the most prominent categories. Most products are
      chiral (89%) and are used as fine chemicals. In the chemical industry, successful
      product developments involve on average a yield of 78%, a volumetric productivity
      of 15.5 g/(L.h) and a final product concentration of 108 g/L. By contrast, the
      pharmaceutical industry focuses on time-to-market. The implications of this for
      future research and development on biocatalysis are discussed.

PMID- 12482514
TI  - Biotransformations using prokaryotic P450 monooxygenases.
AB  - Recent studies on microbial cytochrome P450 enzymes have covered several new
      areas. Advances have been made in structure-function analysis and new non
      enzymatic/electrochemical systems for the replacement of NAD(P)H in biocatalysis
      have been developed. Furthermore, the properties of some enzymes have been re
      engineered by site-directed mutagenesis or by methods of directed evolution and
      new P450s have been functionally expressed and characterized. It is thought that
      a combination of these approaches will facilitate the use of isolated P450
      monooxygenases in biocatalysis.

PMID- 12482515
TI  - Enzyme catalysis in ionic liquids.
AB  - Ionic liquids offer new possibilities for the application of solvent engineering
      to biocatalytic reactions. Although in many cases ionic liquids have simply been
      used to replace organic solvents, they have often led to improved process
      performance. Unlike conventional organic solvents, ionic liquids possess no vapor
      pressure, are able to dissolve many compounds, and can be used to form two-phase
      systems with many solvents. To date, reactions involving lipases have benefited
      most from the use of ionic liquids, but the use of ionic liquids with other
      enzymes and in whole-cell processes has also been described. In some cases,
      remarkable results with respect to yield, (enantio)selectivity or enzyme
      stability were observed.

PMID- 12482516
TI  - Screening for novel enzymes for biocatalytic processes: accessing the metagenome
      as a resource of novel functional sequence space.
AB  - Historically, biotechnology has missed up to 99% of existing microbial resources
      by using traditional screening techniques. Strategies of directly cloning
      'environmental DNA' comprising the genetic blueprints of entire microbial
      consortia (the so-called 'metagenome') provide molecular sequence space that
      along with ingenious in vitro evolution technologies will act synergistically to
      bring a maximum of available sequence-space into biocatalytic application.

PMID- 12482519
TI  - Antibody discovery: the use of transgenic mice to generate human monoclonal
      antibodies for therapeutics.
AB  - Technical advances made in the 1980s and early 1990s resulted in monoclonal
      antibodies that are now approved for human therapy. Novel transgenic mouse
      strains provide a powerful technology platform for creating fully human
      monoclonal antibodies as therapeutics; ten such antibodies have entered clinical
      trials since 1998 and more are in preclinical testing. Improved transgenic mouse
      strains provide a powerful technology platform for creating human therapeutics in
      the future.

PMID- 12482517
TI  - Dynamic kinetic resolutions and asymmetric transformations by enzymes coupled
      with metal catalysis.
AB  - The combination of enzyme and metal catalysis is described as a useful method for
      the synthesis of optically active compounds. A key feature of this new
      methodology is the use of metal catalysts for the in situ racemization of
      enzymatically unreactive enantiomers in the enzymatic resolution of racemic
      substrates. So far, two combinations - lipase-ruthenium and lipase-palladium -
      have been developed for the efficient dynamic kinetic resolution of alcohols and
      amines. The use of these combinations has also been extended to catalysis of the
      asymmetric transformation of ketones, their enol acetates, and ketoximes. In most
      cases, enzyme-metal combination catalysis has provided good yields and high
      optical purities.

PMID- 12482520
TI  - Antibody discovery: phage display.
AB  - Phage display has proven to be a robust and convenient technology for the
      selection of high-quality human antibodies from diverse libraries. Besides
      enabling the identification of antibodies in a fast, high-throughput mode, which
      allows comprehensive protein expression analyses, phage display has been used to
      identify a fully human therapeutic antibody presently undergoing the regulatory
      process for market approval.

PMID- 12482521
TI  - Pharmacokinetics and biodistribution of genetically engineered antibodies.
AB  - The engineering of monoclonal antibodies has created a new generation of
      pharmaceuticals with the desired pharmacokinetics and biodistribution properties.
      For radioimmunotherapy and radioscintigraphy, optimum tumor targeting can be
      achieved using engineered constructs that provide high antigen affinity and
      specificity, effective tumor penetration, circulation properties that allow high
      tumor uptake with acceptable doses to the normal tissues, and fast clearance
      allowing low background. Recent advances have made possible the development of
      antibodies with these properties.

PMID- 12482522
TI  - Monoclonal antibodies as therapeutics in oncology.
AB  - The specificity of antibodies has been harnessed to target cancer cells and the
      first therapeutic antibodies for use in oncology are now finding application in
      the clinic. Studies are currently under way to develop new and improved
      antibodies. Recent developments have been made in the identification of novel
      targets, including the use of genomic and proteomic technologies. Several methods
      are also being developed to enhance antibody efficacy.

PMID- 12482523
TI  - Monoclonal antibodies in immune and inflammatory diseases.
AB  - The era of monoclonal antibody-based therapeutics has arrived. Monoclonal
      antibodies of high quality targeting almost any antigen can now be engineered and
      manufactured in large quantities. In the clinic, monoclonal antibodies are
      proving to be safe and effective for the treatment of a wide range of diseases
      including rheumatoid arthritis, Crohn's disease, spondyloarthropathies, psoriasis
      and allograft rejection.

PMID- 12482524
TI  - Anti-R7V antibodies as therapeutics for HIV-infected patients in failure of
      HAART.
AB  - Many attempts to use therapeutic antibodies to treat HIV have been unsuccessful
      owing to the high variability of the viral proteins, the multiplicity of the
      cellular targets, and the conformational changes of the gp120 glycoprotein during
      cell binding. A new concept of identifying a cellular antigen associated with the
      HIV envelope was investigated. The characterized epitope, R7V, is responsible for
      the formation of antibodies protective against HIV in non-progressor patients.
      The purified anti-R7V antibodies neutralize all HIV isolates, including the
      escape mutants after highly active antiretroviral therapy, creating a new
      therapeutic tool for the treatment of HIV-infected patients.

PMID- 12482525
TI  - Antibody manufacture in transgenic animals and comparisons with other systems.
AB  - Various forms of recombinant monoclonal antibodies are being used increasingly,
      mainly for therapeutic purposes. The isolation and engineering of the
      corresponding genes is becoming less of a bottleneck in the process; however, the
      production of recombinant antibodies is itself a limiting factor and a shortage
      is expected in the coming years. Milk from transgenic animals appears to be one
      of the most attractive sources of recombinant antibodies. None of the production
      systems presently implemented (CHO cells, insect cells infected by baculovirus,
      or transgenic animals and plants) has yet been optimized. This review describes
      the advantages of using milk for antibody production in comparison with the other
      systems.

PMID- 12482526
TI  - Monoclonal antibody manufacturing in transgenic plants--myths and realities.
AB  - The number and types of antibodies expressed in plants has increased steadily
      since the first reports of this accomplishment in the 1980s, illustrating the
      versatility of plants as a production system for antibodies. Many recent reviews
      have detailed the antibody forms that have been derived from plant expression
      systems. This contribution focuses on the remaining challenges to develop plant
      derived therapeutic antibodies into products, and some of the progress that is
      being made in addressing these challenges.

PMID- 12482527
TI  - Confronting parasites from Canada.

PMID- 12482528
TI  - Frontiers in research on parasitic protozoa.
AB  - Frontiers in research on parasitic protozoa was the theme of the Autumn Symposium
      of the British Section of the Society of Protozoologists, held 2 September 2002,
      in London, UK.

PMID- 12482529
TI  - Tsetse control: the next 100 years.
AB  - An international meeting on tsetse control was held 9-10 September 2002, in
      Edinburgh, UK.

PMID- 12482534
TI  - Multiple reproductive processes in Blastocystis.

PMID- 12482535
TI  - Natural host range is not a valid taxonomic character.

PMID- 12482536
TI  - Hot topic or hot air? Climate change and malaria resurgence in East African
      highlands.
AB  - Climate has a significant impact on malaria incidence and we have predicted that
      forecast climate changes might cause some modifications to the present global
      distribution of malaria close to its present boundaries. However, it is quite
      another matter to attribute recent resurgences of malaria in the highlands of
      East Africa to climate change. Analyses of malaria time-series at such sites have
      shown that malaria incidence has increased in the absence of co-varying changes
      in climate. We find the widespread increase in resistance of the malaria parasite
      to drugs and the decrease in vector control activities to be more likely driving
      forces behind the malaria resurgence.

PMID- 12482537
TI  - A response to the aim of eradicating tsetse from Africa.
AB  - An ambitious plan to eradicate tsetse, and therefore tsetse-transmitted
      trypanosomiases, from Africa was launched at the 36th Organization of African
      Unity summit meeting (Togo, July 2000) in a bold attempt to re-focus attention on
      one of Africa's greatest scourges. This plan involves the use of the sterile
      insect technique to achieve final eradication in areas where the fly is
      suppressed by more conventional methods (such as traps and targets). In this
      article, the current aims of this project are questioned on historical,
      ecological, logistical and financial grounds.

PMID- 12482538
TI  - Malaria transmission, sex ratio and erythrocytes with two gametocytes.
AB  - Transmission of haemospororin parasites (phylum Apicomplexa) needs the
      fertilization of at least one female by one male gamete within the bloodmeal of a
      suitable vector. Male and female gamete precursors (gametocytes) in Plasmodium
      and Haemoproteus parasites are normally alone inside the erythrocytes of the
      vertebrate host, but they also occur in male-female pairs in single erythrocytes.
      These paired gametocytes could enhance transmission success by facilitating the
      encounter between the female and male gametes when inside the midgut of the
      vector. Further study of these particular infections could provide new insights
      into the biology of and control strategies for haemospororin parasites.

PMID- 12482539
TI  - The endocytic apparatus of the kinetoplastida. Part II: machinery and components
      of the system.
AB  - Endocytic systems within eukaryotic cells are a diverse set of intracellular
      transport pathways responsible for uptake, recycling, interaction with the
      exocytic system and degradation of molecules. Each of these pathways requires the
      interaction of distinct protein components that function in macromolecule
      sorting, control of transport rates and in membrane biogenesis. In the second of
      two articles on kinetoplastida endocytosis, the endocytic system in Trypanosoma
      brucei is considered as a model, and the molecules that control this system and
      the protein components of the endocytic pathway are discussed. We also consider
      novel mechanisms for sorting that have been proposed to operate in trypanosomes.

PMID- 12482540
TI  - The comparative pathogenesis of neosporosis.
AB  - Since its first description in dogs in 1984, the protozoan parasite Neospora
      caninum has been found to infect a wide range of animals, worldwide. In cattle,
      N. caninum has particular significance as a cause of abortion in which
      persistence of infection in the mother, recrudescence of the parasite during
      pregnancy, and the vulnerability of the placenta and foetus to invasion are
      important features. This article discusses how Neospora invades cells, how it
      infects and causes disease in several animal species, and particularly how it has
      evolved a special niche in cattle and dogs that ensures its survival.

PMID- 12482541
TI  - Trichinellosis in China: epidemiology and control.
AB  - The first outbreak of human trichinellosis in China, according to official
      national publication, was registered in Tibet in 1964. Since then, more than 500
      outbreaks, numbering 25161 cases with 240 deaths, have been recorded. However,
      this reported quantity is probably highly underestimated because adequate
      diagnostic techniques might not have been available in the whole area. Moreover,
      infection in animals is widespread over China, with the prevalence of pig
      trichinellosis being as high as 4% in some provinces. The estimated situation of
      trichinellosis in China highlights the necessity not only for its control, but
      also for the government to elaborate new regulations and guidelines for animal
      inspection.

PMID- 12482545
TI  - Vascular collagens: spotlight on the role of type VIII collagen in atherogenesis.
AB  - Collagens play a central role in maintaining the integrity and stability of the
      undiseased as well as of the atherosclerotic vessel wall. An imbalanced
      metabolism may lead to uncontrolled collagen accumulation reducing vessel wall
      velocity, frequently resulting in arterial occlusion or thrombosis. A reduced
      production of collagen and its uncontrolled degradation may affect the stability
      of the vessel wall and especially of the atherosclerotic plaques by making them
      prone to rupture and aneurysm. This review presents an overview on the four
      groups of vascular collagens and on their role in atherogenesis. The major focus
      was to highlight the extraordinary role and importance of the short chain network
      forming type VIII collagen in the extracellular matrix of undiseased arteries and
      of atherosclerotic plaques. The molecular structure of type VIII collagen, its
      cellular origin, its implication in atherogenesis, its temporal and spatial
      expression patterns in human and experimental models of atherogenesis, the
      factors modulating its expression, and--not at least--its potential function is
      discussed.

PMID- 12482546
TI  - Patterns of oxidized epitopes, but not NF-kappa B expression, change during
      atherogenesis in WHHL rabbits.
AB  - Oxidative modification of lipoproteins plays an important role in atherogenesis.
      We investigated a variety of different oxidatively modified epitopes
      (malondialdehyde (MDA)-2, hydroxynonenal (HNE)-7, peroxynitrite, hypochlorite, EO
      6) in parallel and compared normal vessel wall, early and advanced
      atherosclerotic lesions in WHHL rabbits. Early atherosclerotic lesions showed
      abundant intracellular staining in macrophages for all ox-epitopes, apo B and apo
      E; advanced lesions showed a more prominent peri- and extracellular staining for
      ox-epitopes, which tended to colocalize more with apo B than apo E. Hypochlorite
      modified epitopes showed intense staining in all types of lesions, followed by
      MDA-2. Early and advanced atherosclerotic lesions differed significantly in that
      early stages revealed abundant cellular positivity for EO-6 and weak staining for
      HNE-7 modified proteins whereas the opposite was observed in advanced lesions.
      Nuclear factor-kappa B (NF-kappa B) was nearly exclusively detected in
      macrophages with no difference between early and advanced lesions. We conclude
      that hypochlorite-modified epitopes are abundantly present at all stages of
      atherogenesis. EO-6 might be a marker for early, HNE-7 a marker for advanced
      lesions. Colocalization of ox-epitopes with apolipoproteins further supports that
      oxidation of lipoproteins is one of the key mechanisms in atherogenesis. Chronic
      stable expression and activation of NF-kappa B could be a useful target for
      therapeutic interventions.

PMID- 12482547
TI  - Green tea catechins inhibit the cultured smooth muscle cell invasion through the
      basement barrier.
AB  - Epidemiological studies suggest that green tea consumption is associated with a
      reduced risk of cardiovascular disease. Antioxidative properties of green tea
      flavonoids, catechins, have been believed to be involved in the antiatherogenic
      effect of green tea, since catechins inhibit low density lipoprotein oxidation.
      The migration of vascular smooth muscle cells (SMCs) from the tunica media to the
      subendothelial region is a key event in the development and progression of
      atherosclerosis and post-angioplasty vascular remodeling. Matrix
      metalloproteinases (MMPs) play a key role in these processes of SMC migration. In
      the present study, we investigated the effect of catechins on the gelatinolytic
      activity of MMP-2 that was derived from cultured bovine aortic SMCs. We also
      investigated the effect of catechins on the SMC invasion through the
      reconstituted basement membrane barrier. A major constituent of green tea
      catechins, (-)-epigallocatechin gallate (EGCG), inhibited the gelatinolytic
      activity of MMP-2 and concanavalin A (ConA)-induced pro-MMP-2 activation without
      the influence of membrane-type MMP expression in SMCs. EGCG also inhibited the
      SMC invasion through the basement membrane barrier in a concentration-dependent
      manner without any influence of SMC migration across the basement membrane
      protein thin-coated filter. The antagonistic effects of other catechins, namely (
      )-epigallocatechin (EGC) and (-)-epicatechin gallate (ECG), on gelatinolytic
      activity of MMP-2, ConA-induced pro-MMP-2 activation, or PDGF-BB-directed SMC
      invasion were much less pronounced than those of EGCG. Also, (+)-catechin and (-)
      epicatechin failed to show any effect. These findings may suggest that the anti
      invasive and anti-metalloproteinase activities involve at least part of the anti
      atherogenic action of catechin in accordance with the antioxidant properties of
      catechin.

PMID- 12482548
TI  - Scavenger receptor BI (SR-BI) mediates a higher selective cholesteryl ester
      uptake from LpA-I compared with LpA-I:A-II lipoprotein particles.
AB  - Scavenger receptor class B, type I (SR-BI) mediates the selective uptake of high
      density lipoprotein- (HDL-) associated cholesteryl esters (CE), i.e. lipid uptake
      independent from HDL holo-particle internalisation. This pathway contributes to
      the HDL-mediated CE delivery to the liver. From human plasma HDL, two major
      lipoprotein subfractions can be isolated: one contains apolipoprotein (apo) A-I
      and apo A-II (LpA-I:A-II) as dominant protein components, whereas in the other
      population apo A-II is absent (LpA-I). In this investigation the role of SR-BI in
      selective CE uptake from HDL, LpA-I and LpA-I:A-II was explored. HDL(3) (d=1.125
      1.21 g/ml), LpA-I and LpA-I:A-II were isolated from human plasma and radiolabeled
      in the protein (125I) as well as in the CE moiety ([3H]). Baby hamster kidney
      (BHK) cells were stably transfected with the full-length human SR-BI cDNA and
      these cells demonstrate SR-BI expression in immunoblots. In contrast, no SR-BI
      protein was detectable in control BHK cells (vector). To investigate lipoprotein
      uptake, cells incubated (37 degrees C, 4 h) in medium containing radiolabeled
      HDL(3), LpA-I or LpA-I:A-II and finally cellular tracer content was determined.
      For both types of BHK cells, the rate of apparent lipoprotein particle uptake
      according to the lipid tracer ([3H]) was in substantial excess over that due to
      the protein tracer (125I) demonstrating selective CE uptake ([3H]-(125)I) from
      HDL(3), LpA-I and LpA-I:A-II. SR-BI expression increased cellular selective CE
      uptake from labeled HDL(3) up to 24-fold. In BHK cells without SR-BI expression,
      selective CE uptake was higher from LpA-I compared with LpA-I:A-II. Analogously,
      in BHK cells with SR-BI expression, the rate of selective CE uptake was higher
      from LpA-I compared with LpA-I:A-II. In summary, SR-BI significantly increases
      selective CE uptake from HDL(3), LpA-I and LpA-I:A-II. Concerning HDL
      subfractions, the rate of SR-BI-mediated selective CE uptake is greater from LpA
      I compared with LpA-I:A-II and this result suggests that SR-BI preferentially
      facilitates the CE transfer from LpA-I lipoprotein particles to cells.

PMID- 12482549
TI  - The atheroprotective effect of 17 beta-estradiol is not altered in P-selectin- or
      ICAM-1-deficient hypercholesterolemic mice.
AB  - The mechanisms that mediate the atheroprotective properties of estrogens remain
      obscure. In the present study, we evaluated the involvement of the adhesion
      molecule P-selectin, intercellular adhesion molecule (ICAM-1) and vascular cell
      adhesion molecule (VCAM-1) in the atheroprotective effect of estrogens in murine
      models evaluating early steps of atherosclerosis. First, we studied the effect of
      17 beta-estradiol (E2) administration for 12 weeks on fatty streak constitution
      at the root aorta of ovariectomized female mice deficient in apolipoprotein E
      (apoE) alone or deficient in both apoE and either P-selectin or ICAM-1. Compared
      with respective placebo groups, E2 significantly prevented the development of
      fatty streak, to a similar extent in all three genotypes (-70.0% in apoE(-/-), 
      77.4% in apoE(-/-) P-selectin(-/-), and -77.1% in apoE(-/-) ICAM-1(-/-)). Second,
      the endothelial expression of VCAM-1 at the root aorta was assessed by
      immunohistochemistry in either placebo or E2-treated ovariectomized C57BL/6
      female mice fed an atherogenic diet. Compared with placebo, E2 treatment resulted
      in a 31.8% decrease of VCAM-1 endothelial expression at this lesion-prone site
      (P=0.03). These results demonstrate that P-selectin and ICAM-1 are not involved
      in the atheroprotective effect of estrogens, and suggest that VCAM-1 could play a
      role in this process.

PMID- 12482550
TI  - Effects of polymorphisms of methionine synthase and methionine synthase reductase
      on total plasma homocysteine in the NHLBI Family Heart Study.
AB  - The metabolism of homocysteine requires contributions of several enzymes and
      vitamin cofactors. Earlier studies identified a common polymorphism of
      methylenetetrahydrofolate reductase that was associated with mild
      hyperhomocysteinemia. Common variants of two other enzymes involved in
      homocysteine metabolism, methionine synthase and methionine synthase reductase,
      have also been identified. Methionine synthase catalyzes the remethylation of
      homocysteine to form methionine and methionine synthase reductase is required for
      the reductive activation of the cobalamin-dependent methionine synthase. The
      methionine synthase gene (MTR) mutation is an A to G substitution, 2756A-->G,
      which converts an aspartate to a glycine codon. The methionine synthase reductase
      gene (MTRR) mutation is an A to G substitution, 66A-->G, that converts an
      isoleucine to a methionine residue. To determine if these polymorphisms were
      associated with mild hyperhomocysteinemia, we investigated subjects from two of
      the NHLBI Family Heart Study field centers, Framingham and Utah. Total plasma
      homocysteine concentrations were determined after an overnight fast and after a 4
      h methionine load test. MTR and MTRR genotype data were available for 677 and 562
      subjects, respectively. The geometric mean fasting homocysteine was unrelated to
      the MTR or MTRR genotype categories (AA, AG, GG). After a methionine load, a weak
      positive association was observed between change in homocysteine after a
      methionine load and the number of mutant MTR alleles (P-trend=0.04), but this
      association was not statistically significant according to the overall F
      statistic (P=0.12). There was no significant interaction between MTR and MTRR
      genotype or between these genotypes and any of the vitamins with respect to
      homocysteine concentrations. This study provides no evidence that these common
      MTR and MTRR mutations are associated with alterations in plasma homocysteine.

PMID- 12482551
TI  - Quantitative measurement of carotid intima-media roughness--effect of age and
      manifest coronary artery disease.
AB  - Atherosclerotic changes of the common carotid artery (CCA) may appear like
      irregularities of the intima-media thickness (abbreviated as IM roughness) in B
      mode ultrasound. The purposes of the present study were to investigate whether
      the CCA IM roughness changes with age and differs between individuals presumed to
      be healthy and patients with coronary artery disease (CAD). METHODS AND RESULTS:
      Based on a new automatic identification (AI) program, the segmental intima-media
      thickness (IMT) and IM roughness of the CCA far wall were measured in B-mode
      images of 15 younger and 22 older volunteers presumed to be healthy, and 46
      patients with known CAD. The mean and maximum CCA IMT were lowest in the young
      group (0.55+/-0.05; 0.65+/-0.06 mm), higher in the older group (0.77+/-0.16;
      0.87+/-0.18 mm) and highest in CAD patients (0.88+/-0.18; 1.01+/-0.27 mm) (P<0.01
      among all groups). The CCA IM roughness was greatest by far in the CAD patients
      (0.075+/-0.02 mm; P<0.01 vs. both groups) and increased only slightly with age
      (younger: 0.035+/-0.008 mm; older: 0.040+/-0.014 mm; P<0.05). Areas under the
      curve (AUC) of receiver-operating characteristic curves (ROC) predicting patients
      with CAD were higher for the CCA IM roughness (0.80) than for the mean (0.66) and
      maximum IMT (0.71). CONCLUSIONS: It is suggested that the CCA IM roughness
      increases with age, and helps to discriminate between individuals presumed to be
      healthy and patients with manifest CAD better than the CCA mean and maximum IMT.

PMID- 12482552
TI  - Westernization of lifestyle markedly increases carotid intima-media wall
      thickness (IMT) in Japanese people.
AB  - To illustrate the impact of westernization of lifestyle on the development of pre
      clinical atherosclerosis in Japanese people, we compared risk factors for
      atherosclerosis such as serum lipids, blood pressure, BMI, insulin resistance,
      and smoking habits between non-diabetic native Japanese and non-diabetic Japanese
      Americans. Two hundred and twenty two non-diabetic Japanese Americans living in
      Hawaii and 271 non-diabetic Japanese living in Hiroshima, Japan were studied.
      Carotid intima-media wall thickness (IMT) was measured in all subjects by one
      physician. For all measurements the same ultrasound instrumentation was used.
      Although no significant differences were seen in serum total cholesterol (TC),
      triglycerides, or LDL-cholesterol (LDL-C) levels between the two groups in the
      1998 study, previous to 1998 these three parameters were significantly higher in
      Japanese Americans than native Japanese in our study which has spanned the past
      20 years. IMT was significantly greater in Japanese Americans than native
      Japanese (1.20+/-0.03 mm vs. 0.98+/-0.03 mm, (mean+/-S.E.) respectively;
      P<0.0001). Moreover Japanese Americans reach an IMT of 1.1 mm at age 50, whereas
      the native Japanese reach this value at age 70. These observations indicate more
      rapid atherosclerosis progression in Japanese Americans. Based on our IMT
      measurements, the status and the estimated progression of atherosclerosis in
      Japanese Americans is increased. Since IMT is a validated endpoint for assessment
      of atherosclerotic disease risk, it can be concluded that Japanese Americans are
      at increased risk for cardiovascular disease.

PMID- 12482553
TI  - Chylomicron particle size and number, factor VII activation and dietary
      monounsaturated fatty acids.
AB  - This study evaluated the effects of substituting dietary saturated fatty acids
      (SFAs) with monounsaturated fatty acids (MUFAs) on postprandial chylomicron
      (triacylglycerol (TAG), apolipoprotein B-48 (apo B-48) and retinyl ester (RE)),
      chylomicron particle size and factor VII (FVII) response when subjects were given
      a standard meal. In a controlled sequential design, 51 healthy young subjects
      followed an SFA-rich diet (Reference diet) for 8 weeks after which half of the
      subjects followed a moderate MUFA diet (n=25) and half followed a high MUFA diet
      (n=26) for 16 weeks. Fasting lipoprotein and lipid measurements were evaluated at
      baseline and at 8-week intervals during the Reference and MUFA diets. In 25 of
      the subjects (n=12 moderate MUFA, n=13 high MUFA), postprandial responses to a
      standard test meal containing RE and 13C-tripalmitin were investigated at the end
      of the Reference and the MUFA diet periods. Although there were no differences in
      the postprandial lipid markers (TAG, RE, 13C-TAG) on the two diets, the
      postprandial apo B-48 response (incremental area under the curve (IAUC)) was
      reduced by 21% on the moderate MUFA diet (NS) and by 54% on the high MUFA diet
      (P<0.01). The postprandial peak concentrations of apo B-48 were reduced by 33% on
      the moderate MUFA diet (P<0.01) and 48% on the high MUFA diet (P<0.001). Fasting
      values for factor VII activity (FVIIc), activated factor VII (FVIIa) or factor
      VII antigen (FVIIag) did not differ significantly when subjects were transferred
      from Reference to MUFA diets. However, the postprandial increases in coagulation
      FVII activity (FVIIc) were 18% lower and of activated FVII (FVIIa) were 17% lower
      on the moderate MUFA diet (NS). Postprandial increases in FVIIc and FVIIa were
      50% (P<0.05) and 29% (P<0.07) lower on the high MUFA diet and the area under the
      postprandial FVIIc response curve (AUC) was also lower on the high MUFA diet
      (P<0.05). Significantly higher ratios of RE:apo B-48 (P<0.001) and 13C-palmitic
      acid:apo B-48 (P<0.01) during both MUFA diets suggest that the CMs formed carry
      larger amounts of dietary lipids per particle, reflecting an adaptation to form
      larger lipid droplets in the enterocyte when increased amounts of dietary MUFAs
      are fed. Smaller numbers of larger chylomicrons may explain attenuated activation
      of factor VII during the postprandial state when the background diet is rich in
      MUFA.

PMID- 12482554
TI  - Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet,
      fibrinolytic and vascular function in hypertensive type 2 diabetic patients.
AB  - BACKGROUND: Type 2 diabetes and hypertension are both associated with an
      increased risk of atherothrombosis. We assessed whether purified eicosapentaenoic
      acid (EPA) and docosahexaenoic acid (DHA) from fish oil have differential effects
      on platelet, fibrinolytic and vascular function in patients with both conditions.
      METHODS: In a double-blind placebo-controlled trial of parallel design, 59
      treated-hypertensive Type 2 diabetic men and postmenopausal women, were
      randomised to 4 g/day of EPA, DHA or olive oil (placebo) for 6 weeks. Collagen
      and PAF-stimulated platelet aggregation, collagen-stimulated thromboxane release
      (TXB2), plasma tPA and PAI-1 antigens, von Willebrand factor, p-selectin, and
      flow-mediated and glyceryl-trinitrate-mediated dilatation of the brachial artery,
      were examined before and at the end of intervention. RESULTS: Thirty-nine men and
      12 women aged 61.2+/-1.2 year completed the study. Relative to placebo, DHA but
      not EPA supplementation significantly reduced collagen aggregation (16.9%,
      P=0.05) and TXB2 (18.8%, P=0.03). There were no significant changes in either PAF
      stimulated platelet aggregation, fibrinolytic function or vascular function in
      either the EPA or DHA group relative to placebo. CONCLUSION: Highly purified DHA
      may be a more effective anti-thrombotic agent than EPA. However, longer-term
      studies assessing morbidity and mortality are needed in order to establish if DHA
      contributes to reducing CHD amongst Type 2 diabetic patients with treated
      hypertension.

PMID- 12482555
TI  - Differential contribution of testosterone and estradiol in the determination of
      cholesterol and lipoprotein profile in healthy middle-aged men.
AB  - The role of endogenous sex steroids in the association between male gender and
      cardiovascular risk remains unclear. We performed a cross-sectional analysis of
      the role of endogenous testosterone (T) and estradiol (E2), as well as their
      respective biologically active fractions, in the determination of lipids and
      lipoproteins in an occupation-based cohort of 715 healthy middle-aged men. Serum
      T, sex hormone binding globulin (SHBG) and E(2) were measured by immunoassays;
      free T (FT) and free E2 (FE2) were calculated using a validated equation. Serum
      total cholesterol (Chol), HDL-cholesterol (HDL-Chol), apolipoproteins A1 (ApoA1),
      B (ApoB), E (ApoE), ApoE phenotype, lipoprotein a (Lpa), fibrinogen, C-reactive
      protein (CRP), systolic (SBP) and diastolic blood pressure (DBP) were assessed.
      Serum levels of T and FT, correlated positively with HDL-Chol and ApoA1 with
      Spearman correlation coefficients, partialised for age and body mass index (BMI),
      ranging between 0.14 and 0.17 (P<0.001); FT was associated with total Chol and
      ApoB levels (r=0.12 for both T and FT; P<0.01). After adjustment for age and BMI,
      both serum E2 and FE2 levels correlated significantly with ApoE (r=0.25 and
      r=0.26 for E2 and FE2, respectively; P<0.001). Free and total E2 were associated
      with both SBP and DBP with correlation coefficients partialised for age and BMI
      ranging between 0.11 and 0.13 (P<0.01). No correlation was found between any of
      the studied sex steroids, fibrinogen, Lpa or CRP. In multiple linear regression
      analyses, T was the most important independent hormonal determinant of HDL-Chol
      levels, when E2, SHBG and exogenous factors were considered in the model
      (P<0.01), whereas E2 contributed mostly in the determination of ApoE levels
      (P<0.001) and SBP (P<0.01). When FT and FE2 were considered in multivariate
      analyses as independent hormonal variables, FT was the most significant predictor
      of HDL-Chol (P<0.01) and ApoB (P<0.01) concentrations. Moreover, in the same
      multivariate model, ApoE (P<0.001) concentration as well as SBP (P<0.001) was
      most affected by FE2 levels in comparison with FT. In conclusion, our findings do
      suggest a differential role of T and E2 in the determination of traditional
      cardiovascular risk factors in healthy middle-aged men. In the determination of
      both HDL-Chol and ApoB levels endogenous (F)T may be involved, whereas (F)E2 may
      contribute to the determination of ApoE levels in this study group of 715 healthy
      middle-aged men. Regarding the observational design of the study, the
      physiological relationship of the observed associations between sex steroids and
      cardiovascular risk factors remains to be unravelled.

PMID- 12482556
TI  - Plasma fibrinogen explains much of the difference in risk of coronary heart
      disease between France and Northern Ireland. The PRIME study.
AB  - The incidence of coronary heart disease is higher in Northern Ireland than in
      France. These differences have not been adequately explained. We have
      investigated the associations of plasma fibrinogen concentration and factor VII
      activity with the incidence of coronary heart disease in a prospective cohort
      study involving 10600 men aged 50-59 living in four regions (Lille, Strasbourg,
      and Toulouse in France, Belfast in Northern Ireland). Baseline fibrinogen and
      factor VII were measured in 9489 men free of coronary heart disease at entry
      (7167 in France and 2322 in Northern Ireland). Over 5 years of follow-up, 161
      participants developed myocardial infarction (MI) or coronary death (100 in
      France and 61 in Belfast) and 151 developed angina pectoris (94 in France and 57
      in Belfast). The risk of future coronary events was 1.9 times higher in Belfast
      than in France (95% confidence interval: 1.5-2.4). Baseline mean levels of
      fibrinogen were significantly higher in Belfast than in France and they were
      higher in participants who experienced coronary events compared with those who
      did not in both countries. The age-adjusted relative risk of coronary heart
      disease associated with a rise of one standard deviation in fibrinogen level was
      1.56 (95% confidence interval: 1.29-1.95, P<0.0001) in the whole cohort. This
      association remained significant after adjustment for other cardiovascular risk
      factors (relative risk:1.36; 95% confidence interval: 1.14-1.68; P<0.0001). There
      was no clear geographical variation in factor VII and no significant association
      between factor VII levels and the risk of coronary events was observed. Classic
      risk factors explained 25% of the excess risk of coronary heart disease in
      Belfast compared with France, while fibrinogen alone accounted for 30%. These
      findings add to the epidemiological evidence that elevated fibrinogen is a major
      risk factor for coronary heart disease.

PMID- 12482558
TI  - Sequence and functional changes in a putative enhancer region upstream of the
      apolipoprotein(a) gene.
AB  - Two enhancer regions upstream of the apolipoprotein(a) (apo(a)) gene were
      amplified and sequenced from subjects who were known to express abnormally high
      or low amounts of lipoprotein(a) (Lp(a)). No base changes were found in the DHII
      region situated 28 kb from the apo(a) gene. Three common base substitutions were
      found in the DHIII region about 20 kb from the gene. One, an A to G change at
      position -1230, increased the activity of reporter-gene constructs approximately
      2.5-fold. The other two, a C to A change at -1617 and a G to T change at -1712,
      decreased reporter activity by 30 and 40%, respectively. The sites at -1230 and 
      1617 were in linkage disequilibrium with each other and also with a polymorphic
      site near the DHII enhancer and sites in the apo(a) promoter and gene. The rarer
      G variant at -1230 was associated with smaller alleles. After correcting for the
      effect of allele size, values of Lp(a) concentration for alleles associated with
      the G variant at -1230 were 70% higher than those associated with the more common
      A variant. In contrast, the corrected values for alleles associated with the rare
      T variant at -1712 were 40% lower than those associated with the common G
      variant. Thus, overall the changes observed in this enhancer could influence
      apo(a) gene transcription up to 4-fold and could provide a significant
      contribution to the variation in Lp(a) concentrations in plasma.

PMID- 12482557
TI  - Plasma homocysteine in subjects with familial combined hyperlipidemia.
AB  - Familial combined hyperlipidemia (FCH) is characterised by hypercholesterolemia
      and/or hypertriglyceridemia and associated with an increased risk of
      cardiovascular disease (CVD). The plasma lipid and lipoprotein levels in subjects
      with FCH are relatively moderately elevated and do not fully explain the
      increased risk of CVD. Hyperhomocysteinemia is a disorder of methionine
      metabolism and also a well-known independent risk factor for CVD. We investigated
      whether subjects with FCH have higher plasma homocysteine concentrations than
      controls, and whether homocysteine contributes to the increased risk of CVD in
      FCH. Furthermore we evaluated whether parameters of lipid and lipoprotein
      metabolism and/or insulin resistance are associated with the homocysteine level.
      In total 667 subjects, including 161 subjects with FCH, 109 spouses who
      referenced as control group and 397 normolipidemic relatives were studied. FCH
      was defined by the presence of plasma total cholesterol and/or triglyceride
      levels above the 90th percentile adjusted for age and gender. The mean
      homocysteine concentration of the FCH group did not significantly differ from the
      control group. The risk for CVD due to hyperhomocysteinemia in subjects with FCH
      was not higher than in subjects without FCH. No associations were observed
      between plasma homocysteine concentration and plasma lipid and lipoprotein
      levels, including small dense low density lipoprotein, nor between homocysteine
      concentration and insulin resistance.

PMID- 12482559
TI  - Strong decrease of high sensitivity C-reactive protein with high-dose
      atorvastatin in patients with type 2 diabetes mellitus.
AB  - OBJECTIVE: Statins are known to reduce CRP concentrations, but whether high doses
      are more effective is not known. METHODS: In a prospective double-blind
      multicenter study in 186 DM2 patients without manifest coronary artery disease
      and with dyslipidemia, the effect of a 30-week treatment with 10 and 80 mg
      atorvastatin or placebo on the reduction of hs-CRP levels was measured. RESULTS:
      Median CRP levels increased with 6.6% in the placebo group and were reduced by 15
      and 47%, respectively, with atorvastatin 10 and 80 mg (P<0.001; significantly
      different from 10 mg atorvastatin and from placebo (P<0.001). Variation in IL-6
      and plasma lipids associated for 21 and 8%, respectively, with variation in CRP
      levels (P<0.001 and P=0.01). Of patients with a baseline CRP level above an
      arbitrary threshold of 3.0 mg/l, 56% in the 80 mg atorvastatin group reached a
      level of less than 3.0 mg/l, versus 23% randomized to 10 mg atorvastatin (P<0.01)
      and 17% in the placebo group (P<0.005). CONCLUSIONS: In DM2 patients high dose
      atorvastatin induced a strong reduction in CRP levels. The decrease in CRP was
      mainly independent of effects on lipid lowering and changes in IL-6 levels. The
      pleiotropic effect of high-dose atorvastatin on inflammation could add to its
      cardioprotective effect in high-risk patients.

PMID- 12482560
TI  - The determination of carotid intima medial thickness in adults--a population
      based twin study.
AB  - INTRODUCTION: Although cardiovascular events are known to cluster in families it
      is unclear the extent to which atherosclerosis per se is genetically determined.
      The aim of this study was to assess the heritability of carotid intima media
      thickness (IMT) measurements, a surrogate marker of early atherosclerosis, using
      a population-based twin study methodology. METHODS: B-mode carotid artery
      ultrasound images were acquired on 264 twin subjects (142 monozygotic (MZ); mean
      age 54.3 years and 122 dizygotic (DZ); mean age 51.7 years). An estimate of
      genetic determination, heritability, was calculated for the IMT parameters before
      and after correction for confounding variables. RESULTS: An increased carotid IMT
      was associated with known cardiovascular risk factors (total cholesterol r=0.24,
      P<0.001 and systolic blood pressure r=0.42, P<0.001) and with a history of
      coronary events (0.79+/-0.12 vs. 0.72+/-0.14, P=0.01). Carotid IMT measurements
      demonstrated a familial influence (intra-class correlation of 0.54 for MZ vs.
      0.39 for DZ) but no specific genetic determination (heritability estimate 0.31,
      P=0.15). CONCLUSION: Within a normal population carotid IMT is under a familial,
      but not genetic influence. The mechanism of genetic control over cardiovascular
      events may not be mediated through atherosclerotic load as measured by IMT.

PMID- 12482561
TI  - Hyperhomocysteinemia and vitamin B-12 deficiency are more striking in Syrians
      than in Germans--causes and implications.
AB  - Hyperhomocysteinemia is an accepted risk factor for coronary artery disease, but
      the determining factors are not fully understood. We investigated
      hyperhomocysteinemia and vitamin deficiency in Syrian coronary patients and
      apparently healthy Syrian and German controls. We enrolled 273 Syrian patients
      with angiographically confirmed stenosis, along with 159 Syrian and 75 German
      controls. Plasma total homocysteine (HCY), cystathionine, methylmalonic acid
      (MMA), vitamin B-6, B-12, folate, lipids, apolipoproteins and
      methylenetetrahydrofolate reductase (C677T-MTHFR) mutation were analysed. There
      was a very high prevalence of hyperhomocysteinemia (>12 micromol/l) in Syrians
      (patients 61%, controls 44%, Germans 16%) together with functional vitamin B-12
      deficiency diagnosed by elevated MMA (patients 49%, controls 47%, Germans 3%),
      which was in contrast to the low frequency of decreased serum vitamin B-12 (12%
      in patients, 7% in Syrian controls). The HCY concentration in German controls was
      lower than in Syrians, median 8.8 vs. 11.3 micromol/l. The vitamin B-12
      deficiency induces folate trapping; higher levels of folate are needed to prevent
      hyperhomocysteinemia. Germans achieved the HCY level of < or =12 micromol/l at
      significantly lower folate concentrations > or =4.4 ng/ml, than Syrians with
      normal MMA (> or =16.7 nmol/l folate) or Syrians with high MMA (> or =23.3 nmol/l
      folate). Smoking and homozygous state for C677T-MTHFR mutation contributed to
      hyperhomocysteinemia. We could confirm that the reasons for hyperhomocysteinemia
      in Syrians were in fact mostly related to a relative folate deficiency, which is
      due to a vitamin B-12 shortage. Vitamin B-12 deficiency induces folate trapping.
      Besides lifestyle, other presently unknown factors may contribute to
      hyperhomocysteinemia and vitamin B-12 deficiency in Syrians.

PMID- 12482562
TI  - Micronized fenofibrate normalizes the enhanced lipidemic response to a fat load
      in patients with type 2 diabetes and optimal glucose control.
AB  - This study evaluated the postprandial (PP) response to an oral fat load in 28
      male patients with type 2 diabetes (mean HbA1c of 5.1%), all receiving metformin
      and performing physical exercise, compared with healthy subjects. The effects of
      micronized fenofibrate (200 mg once daily) on triglycerides (TG) and retinyl
      palmitate (RP) responses, lipoprotein mass concentrations, post-heparin lipase
      activities and coagulation factors were investigated after a 16-week double
      blind, placebo-controlled period. Higher and delayed TG response after the oral
      fat load (P<0.001) corresponding to increases in both intestinally and endogenous
      TG-rich lipoproteins and lower lipoprotein lipase (LPL) activity 30 and 60 min
      post-heparin injection (P<0.05) were observed in the patients as compared with
      controls. Fasting PAI-1 activity, 6 h PP Factor VII and PAI-1 activities were
      higher in patients (P=0.036, P=0.032 and P=0.017, respectively). After
      fenofibrate treatment, TG and RP responses and peak LPL activity were no more
      significantly different from controls at baseline. Compared with placebo, fasting
      TG-rich lipoproteins and HDL(3) mass concentrations were significantly lower and
      higher, respectively; PP chylomicrons and very low density lipoprotein (VLDL)
      mass concentrations were lower; fasting and PP fibrinogen levels were
      significantly reduced after fenofibrate treatment. Diabetes control was unchanged
      throughout the study. Fenofibrate normalized the abnormal PP response and
      improved the fasting lipoprotein abnormalities in patients with type 2 diabetes
      and optimal glucose control.

PMID- 12482563
TI  - Hormone replacement therapy use is associated with a lower occurrence of carotid
      atherosclerotic plaques but not with intima-media thickness progression among
      postmenopausal women. The vascular aging (EVA) study.
AB  - BACKGROUND: Information on the impact of hormone replacement therapy (HRT) on
      carotid atherosclerosis is limited. Moreover, transdermal estrogens have not been
      investigated. METHODS: We examined association of HRT use with
      ultrasonographically assessed carotid atherosclerotic plaque occurrence and mean
      common carotid artery intima-media thickness (CCA-IMT) progression. Within the
      Vascular Aging (EVA) Study, a community-based cohort, 815 postmenopausal women
      aged 59-71 have been followed during 4 years. Among these women, 166 had already
      used HRT. RESULTS: Women who had ever used HRT experienced a lower occurrence of
      plaques (8.6 versus 19.1%, P=0.003). After adjustment for the main cardiovascular
      risk factors, odds-ratio for plaque occurrence was 0.41 (95% confidence interval
      0.21-0.78, P=0.01) among ever users of HRT compared with never users. When
      transdermal route of estrogen administration was used, adjusted odds-ratio was
      0.66 (95% confidence interval 0.47-0.99, P=0.04). The progression of IMT, which
      was measured at a plaque-free site and adjusted on initial levels of CCA-IMT did
      not differ between ever and never users of HRT. It was 0.011 mm per year among
      ever users and 0.012 mm per year among never users (P=0.61). CONCLUSION: These
      data suggest that HRT use may prevent the development of atherosclerotic plaques
      in postmenopausal women, especially when estrogens are administered by
      transdermal route.

PMID- 12482564
TI  - Role of IgG-seropositivity to Chlamydia pneumoniae in early thrombotic events
      after coronary stent placement.
AB  - AIMS: Since infection of endothelial or smooth muscle cells with Chlamydia
      pneumoniae increased expression of tissue factor and plasminogen activator
      inhibitor I (PAI-1), C. pneumoniae might be involved in triggering acute
      thrombotic events in patients with coronary artery disease. Therefore, we
      explored a potential relationship between IgG-seropositivity to C. pneumoniae and
      early thrombotic events after coronary stent placement. METHODS AND RESULTS: In a
      prospective randomized placebo-controlled study 1010 patients with successful
      coronary stent placement received roxithromycin or placebo for 4 weeks after
      coronary stent placement, which showed no effect of roxithromycin on early
      thrombotic events, as expected. Venous blood samples were collected from patients
      immediately before treatment. Plasma was analyzed for C. pneumoniae-specific IgG
      antibody levels by microimmuno-fluorescence. Thrombotic events were defined as
      death, non-fatal myocardial infarction, or urgent target vessel reintervention
      within 30 days after stent placement. We found no significant difference
      concerning the frequency of early thrombotic events in patients positive or
      negative for C. pneumoniae-specific antibodies. If patients were stratified
      according to their antibody levels, again no significant difference in the
      frequency of thrombotic events was observed. CONCLUSION: Our findings do not
      suggest a role of C. pneumoniae in the development of early complications after
      stent placement.

PMID- 12482565
TI  - Prevalence and phenotypic spectrum of cholesteryl ester transfer protein gene
      mutations in Japanese hyperalphalipoproteinemia.
AB  - A patient with cholesteryl ester transfer protein (CETP) deficiency presents with
      marked hyperalphalipoproteinemia (HALP). To investigate the contribution of CETP
      deficiency to the cause of HALP (HDL-C> or =1.94 mmol/l, 75 mg/dl), we
      investigated the CETP activities and the prevalence of genetic CETP mutations
      among 624 Japanese HALP subjects. The subjects were screened for four known
      genetic CETP mutations (intron 14 splicing defect (In14), exon 15 missense
      mutation (Ex15), intron 10 splicing defect (In10) and exon 6 nonsense mutation
      (Ex6)). We found the frequency of the patients with reduced CETP activity (<75%
      of normal controls) to be 55.5 and 64.1% in a high HDL group (1.94< or =HDL
      C<2.59 mmol/l) and a marked HALP group (HDL-C> or =2.59 mmol/l, 100 mg/dl),
      respectively. At least one of the four mutations was identified in 65.7% of
      subjects with reduced CETP activities and 57.5% of subjects with marked HALP. The
      In14 and Ex15 mutations were very common in HALP subjects and the frequency of
      In10 mutation and Ex6 mutation was quite low. To investigate the impact of
      genetic CETP mutation on the phenotypes, we compared the plasma lipid levels and
      CETP activities between the subjects with two common mutations. All In14
      homozygotes showed marked HALP, while marked HALP is less frequent (64.3%) in
      Ex15 homozygotes. HDL-C levels in Ex15 heterozygotes were significantly higher
      than those of In14 heterozygotes, suggesting the mutation has dominant negative
      effects on CETP activity in vivo. Some cases with In14 (5.7%) or Ex15 (7.2%)
      mutation showed low HDL-C levels. We conclude that CETP deficiency is a major
      cause of HALP; nevertheless CETP deficiency is not necessarily HALP.

PMID- 12482566
TI  - Atorvastatin and the dyslipidemia of early renal failure.
AB  - Information about lipid abnormalities and the effect of lipid lowering therapy in
      the early stage of renal disease is limited, while preventive treatment in this
      stage might be much more beneficial. Lipid profiles and risk factors were
      assessed in 150 consecutive, non-diabetic patients. Preventive therapy consisted
      of cholesterol-reduced diet and atorvastatin 10 mg daily. Patients were
      considered at risk for cardiovascular disease if LDL-cholesterol was >2.6 mmol/l
      in the case of manifest cardiovascular disease (n=28) or when they had manifest
      cardiovascular risk factors (n=105) or if LDL was >3.5 mmol/l (n=17). A total of
      128 patients (85%) had increased LDL. In men <60 years and women <40 years, total
      cholesterol was higher than in the general population. Linear regression analysis
      showed a decreased creatinine clearance to be significantly associated with the
      lipid profile. For a 10 ml/min decrease of creatinine clearance, a 0.085 increase
      of the total cholesterol to HDL ratio was observed (P=0.005). In similar
      analyses, proteinuria was strongly associated with cholesterol and triglycerides.
      An increase of 0.28 of the total cholesterol/HDL ratio was observed for each gram
      per 24 h proteinuria (P<0.001). On atorvastatin 10 mg daily, 30 of 60 treated
      patients had achieved their target LDL value. On average, LDL-cholesterol was
      reduced by 39% and triglycerides by 18%. No patient had to interrupt their
      treatment because of adverse side-effects. In conclusion, the majority of
      patients had an elevated LDL and other lipid abnormalities. Short-term therapy
      with atorvastatin and a cholesterol lowering diet appears to be safe and
      effective. It is probably useful to determine the lipid profile in patients with
      renal failure already in an early phase and to start lipid lowering treatment as
      soon as abnormalities are found.

PMID- 12482567
TI  - PAPP-A, a novel marker of unstable plaque, is not influenced by hypolipidemic
      treatment in contrast to CRP.

PMID- 12482568
TI  - Atorvastatin reduces expression of leukocyte adhesion molecules in patients with
      hypercholesterolemia.

PMID- 12482569
TI  - Statins and homocysteine.

PMID- 12482570
TI  - Pathogenic roles for Epstein-Barr virus (EBV) gene products in EBV-associated
      proliferative disorders.
AB  - Epstein-Barr virus (EBV) is associated with a still growing spectrum of clinical
      disorders, ranging from acute and chronic inflammatory diseases to lymphoid and
      epithelial malignancies. Based on a combination of in vitro and in vivo findings,
      EBV is thought to contribute in the pathogenesis of these diseases. The different
      EBV gene expression patterns in the various disorders, suggest different EBV
      mediated pathogenic mechanisms. In the following pages, an overview of the
      biology of EBV-infection is given and functional aspects of EBV-proteins are
      discussed and their putative role in the various EBV-associated disorders is
      described. EBV gene expression patterns and possible pathogenic mechanisms are
      discussed. In addition, expression of the cellular genes upregulated by EBV in
      vitro is discussed, and a comparison with the in vivo situation is made.

PMID- 12482571
TI  - Changes in apoptosis during the development of colorectal cancer: a systematic
      review of the literature.
AB  - The development of colorectal cancer is characterised by an accumulation of
      molecular genetic alterations causing disorders in cell growth, differentiation
      and apoptosis. Although changes in apoptosis with colorectal cancer development
      have been studied extensively, a clear consensus of opinion has not yet emerged.
      In this review, the literature about changes in the frequency and distribution of
      apoptosis in tissue sections of normal and neoplastic colorectal tissues was
      reviewed systematically. Using a PUBMED search, 53 relevant articles were
      identified. Data from these studies are discussed with respect to the following
      aspects: methods used to detect apoptotic cell death; frequency and locoregional
      distribution of apoptosis in normal mucosa, adenomas and carcinomas; the
      correlation between levels of apoptosis and proliferation and the prognostic
      significance of the degree of apoptosis in colorectal cancer. Possible underlying
      mechanisms of dysregulation of apoptosis are discussed briefly. Finally, possible
      therapeutic implications of knowledge of the molecular regulation of apoptosis
      are discussed and potential options for further research are suggested.

PMID- 12482572
TI  - Radiation-associated cardiovascular disease.
AB  - As the number of cancer survivors grows because of advances in therapy, it has
      become more important to understand the long-term complications of these
      treatments. This article presents the current knowledge of adverse cardiovascular
      effects of radiotherapy to the chest. Emphasis is on clinical presentations,
      recommendations for follow-up, and treatment of patients previously exposed to
      irradiation. Medline literature searches were performed, and abstracts related to
      this topic from oncology and cardiology meetings were reviewed. Potential adverse
      effects of mediastinal irradiation are numerous and can include coronary artery
      disease, pericarditis, cardiomyopathy, valvular disease and conduction
      abnormalities. Damage appears to be related to dose, volume and technique of
      chest irradiation. Effects may initially present as subclinical abnormalities on
      screening tests or as catastrophic clinical events. Estimates of relative risk of
      fatal cardiovascular events after mediastinal irradiation for Hodgkin's disease
      ranges between 2.2 and 7.2 and after irradiation for left-sided breast cancer
      from 1.0 to 2.2. Risk is life long, and absolute risk appears to increase with
      length of time since exposure. Radiation-associated cardiovascular toxicity may
      in fact be progressive. Long-term cardiac follow-up of these patients is
      therefore essential, and the range of appropriate cardiac screening is discussed,
      although no specific, evidence-based screening regimen was found in the
      literature.

PMID- 12482573
TI  - Is there still a role for neoadjuvant therapy in breast cancer?
AB  - The role of neoadjuvant chemotherapy in locally advanced breast cancer is firmly
      established. There is now also an emerging role for neoadjuvant systemic therapy
      in the treatment of operable breast cancer. There is good evidence that the
      chances of breast conserving surgery can be increased with this approach and
      results of randomised studies indicate that survival is at least as good with
      neoadjuvant as with adjuvant chemotherapy. Similar clinical data are emerging
      with neoadjuvant endocrine therapy. For the future, there are important potential
      advantages in having an in vivo measure of chemosensitivity rather than blindly
      treating micrometastatic disease in the adjuvant setting. Clinical response to
      neoadjuvant treatment, and in particular complete pathological response, are
      predictors of subsequent outcome. Pathological involvement of axillary nodes
      following neoadjuvant therapy portends a poor prognosis. The potential for
      biological surrogate markers of response to predict for long-term outcome may
      allow individualisation of systemic treatment and the rapid assessment of new
      drugs in early breast cancer.

PMID- 12482574
TI  - Homocamptothecins: potent topoisomerase I inhibitors and promising anticancer
      drugs.
AB  - Homocamptothecins (hCPTs) represent a new generation of antitumor agents
      targeting DNA topoisomerase I. The expanded seven-membered lactone E-ring that
      characterizes hCPTs enhances the plasma stability of the drug and reinforces the
      inhibition of topoisomerase I compared with conventional six-membered CPTs. hCPTs
      are more efficient than the CPTs at promoting cleavage at T/G sites and induce
      additional cleavage at C/G sites. Compound BN80765 and its difluoro analogue
      diflomotecan (DN80915) are potent cytotoxic agents and efficiently induce
      apoptosis in tumor cells. They display strong antiproliferative activities
      against specific tumor types. Diflomotecan is remarkably efficient at inhibiting
      the growth of human colon cancer cells in vivo and, administered orally, it also
      shows superior activities against human prostate cancers compared with the
      benchmark products topotecan (TPT) and irinotecan (IRT). Diflomotecan has entered
      phase I clinical testing and antitumor activity has been observed in patients.
      This 9,10-difluoro-hCPTs derivative is one of the most promising new members of
      the 'tecan' family. This review summarizes the recent discoveries in the
      topoisomerase I field and presents the different camptothecin (CPT) analogues
      currently evaluated as anticancer agents. The specific properties of hCPTs are
      highlighted.

PMID- 12482575
TI  - Psycho-oncology in a united Europe--changes and challenges.
AB  - The paper provides an overview on the 11th scientific conference of the European
      Society for Psycho-Oncology (ESPO), which took place in June 2001, at Heidelberg,
      Germany. The main topics discussed during the conference were: (1) the state of
      the art of research on the effects of psychological interventions in cancer
      patients; (2) psychosocial aspects in the new field of cancer genetics; (3)
      recent developments in Quality of Life research; (4) Psycho-Oncology from an
      European perspective; and (5) children and cancer. The conference gave an
      impressive picture of the many achievements Psycho-Oncology in Europe has
      accomplished during the last years, in the clinical and scientific domain. With
      recent biomedical innovations Psycho-Oncology is facing new challenges. Despite
      these achievements limitations have become apparent. Identifying these
      limitations, future aims can be outlined. Among these, there is the need for
      methodological refinement, as well as for proof of clinical relevance of research
      results, in order to narrow the gap between research and practice.

PMID- 12482576
TI  - A mechano-chemical model for energy transduction in cytochrome c oxidase: the
      work of a Maxwell's god.
AB  - Cytochrome c3 has a central role in the energetics of Desulfovibrio sp., where it
      performs an electroprotonic energy transduction step. This process uses a network
      of cooperativities, largely based on anti-Coulomb components, resulting from a
      mechano-chemical energy coupling mechanism. This mechanism provides a model
      coherent with the data available for the redox chemistry of haem a of cytochrome
      c oxidase and its link to the activation of protons. A crucial feature of the
      model is an anti-Coulomb effect that sets the stage for a molecular ratchet,
      ensuring vectoriality for the redox-driven localised movement of protons across
      the membrane, against an electrochemical gradient.

PMID- 12482577
TI  - Activity of the A3 adenosine receptor gene promoter in transgenic mice:
      characterization of previously unidentified sites of expression.
AB  - Sites of A3 adenosine receptor gene expression have not been fully explored nor
      has this gene's promoter activity been confirmed in vivo. Transgenic mice were
      generated in which 2.3 kb upstream of the transcriptional start site of the mouse
      A3 adenosine receptor was coupled to a beta-galactosidase reporter gene.
      Selective transgene expression was detected in testis and brain as well as at
      other sites in which A3 adenosine receptor message has not been previously
      reported, including retinal ganglion cells and smooth muscle cells of the
      cerebrospinal vasculature. Our study suggests that this promoter may be useful in
      the selective targeting of gene expression to specific tissues.

PMID- 12482578
TI  - Interaction of nebulin SH3 domain with titin PEVK and myopalladin: implications
      for the signaling and assembly role of titin and nebulin.
AB  - Skeletal muscle nebulin is thought to determine thin filament length and regulate
      actomyosin interaction in a calcium/calmodulin or S100 sensitive manner. We have
      investigated the binding of nebulin SH3 with proline-rich peptides derived from
      the 28-mer PEVK modules of titin and the Z-line protein myopalladin, using
      fluorescence, circular dichroism and nuclear magnetic resonance techniques. Of
      the six peptides studied, PR2 of titin (VPEKKAPVAPPK) and myopalladin MyoP2
      (646VKEPPPVLAKPK657) bind to nebulin SH3 with micromolar affinity (approximately
      31 and 3.4 microM, respectively), whereas the other four peptides bind weakly
      (>100 microM). Sequence analysis of titins reveals numerous SH3 binding motifs
      that are highly enriched in the PEVK segments of titin isoforms. Our findings
      suggest that titin PEVK and myopalladin may play signaling roles in targeting and
      orientating nebulin to the Z-line during sarcomere assembly.

PMID- 12482579
TI  - Introduction of a Na+/H+ antiporter gene from Atriplex gmelini confers salt
      tolerance to rice.
AB  - We engineered a salt-sensitive rice cultivar (Oryza sativa cv. Kinuhikari) to
      express a vacuolar-type Na+/H+ antiporter gene from a halophytic plant, Atriplex
      gmelini (AgNHX1). The activity of the vacuolar-type Na+/H+ antiporter in the
      transgenic rice plants was eight-fold higher than that in wild-type rice plants.
      Salt tolerance assays followed by non-stress treatments showed that the
      transgenic plants overexpressing AgNHX1 could survive under conditions of 300 mM
      NaCl for 3 days while the wild-type rice plants could not. These results indicate
      that overexpression of the Na+/H+ antiporter gene in rice plants significantly
      improves their salt tolerance.

PMID- 12482580
TI  - Increased expression of vascular endothelial growth factor in placentas of
      p57(Kip2) null embryos.
AB  - Placentas of mice lacking p57(Kip2) expression have trophoblastic hyperplasia. To
      elucidate the mechanism underlying this phenomenon, we studied expression of two
      angiogenic factors, vascular endothelial growth factor (VEGF) and placenta growth
      factor (PlGF). Immunohistochemical analysis with anti-VEGF antibodies indicated
      that VEGF expression was stronger and more clearly detectable in placentas of
      p57(Kip2) null embryos compared to wild-type placentas. PlGF showed no
      significant differences between placentas of p57(Kip2) null and wild-type
      embryos. In quantitative analysis, placentas of p57(Kip2) null embryos showed
      higher VEGF messenger (m)RNA and protein levels than did wild-type placentas.
      PlGF mRNA and protein levels were not significantly different. These findings
      suggest that VEGF is involved in the hyperplasia that occurs in placentas of
      p57(Kip2) null embryos.

PMID- 12482581
TI  - Antioxidants induce different phenotypes by a distinct modulation of signal
      transduction.
AB  - Antioxidants are known to exert a preventive activity against degenerative
      diseases. Here, we investigated the mechanism of action of three antioxidants:
      resveratrol, which causes differentiation of HL-60 cells, and hydroxytyrosol and
      pyrrolidine dithiocarbamate which, in the same model system, activate apoptosis.
      The expression profile of hydroxytyrosol-treated cells showed the up-regulation
      of several genes, including c-jun and egr1. Pyrrolidine dithiocarbamate activates
      both genes, while resveratrol increases uniquely egr1. A selective modulation of
      signalling pathway explained this finding. All antioxidants up-regulate Erk1/2,
      while only hydroxytyrosol and pyrrolidine dithiocarbamate activate c-Jun N
      terminal kinase (JNK). Since JNK induces apoptosis by Bcl-2 phosphorylation, we
      investigated this event. Bcl-2 phosphorylation was increased by hydroxytyrosol
      and pyrrolidine dithiocarbamate and not by resveratrol. Our results indicate that
      the different phenotypical effects of antioxidants correlate with modulation of
      selective transduction pathways.

PMID- 12482582
TI  - Critical switch of the metabolic fluxes by phosphofructo-2-kinase:fructose-2,6
      bisphosphatase. A kinetic model.
AB  - A kinetic model for the bifunctional enzyme, phosphofructo-2-kinase:fructose-2,6
      bisphosphatase, is analysed by application of the graph-theoretical method,
      considering comparable levels for all participants. Certain elementary reactions,
      distributed on the enzyme surface, are considered to be co-ordinated in a single
      conformational transition (a model of parallel molecular operations). The method
      allows us to identify in the kinetic scheme its destabilising sub-scheme as a
      branched cycle of elementary reactions. Under certain conditions this sub-scheme
      induces critical phenomena (bistability or oscillations). The computer
      calculations for the estimated parameter values fit well the experimental
      observations for this system. The model explains the periodic or bistable
      counterphase changes of the two opposing activities of this enzyme, observed
      after glucose perfusion of rat hepatic enzyme samples, and predicts drastic
      critical changes in kinetic behaviour induced by small external signals. The
      model also shows the necessity of the phosphoryl intermediate in the mechanism of
      the bisphosphatase for the critical kind of kinetic behaviour.

PMID- 12482583
TI  - Molecular characterization of a two-domain form of the neuronal voltage-gated P/Q
      type calcium channel alpha(1)2.1 subunit.
AB  - We characterized the neuronal two-domain (95kD-alpha(1)2.1) form of the
      alpha(1)2.1 subunit of the voltage-gated calcium channels using genetic and
      molecular analysis. The 95kD-alpha(1)2.1 is absent in neuronal preparations from
      CACNA1A null mouse demonstrating that alpha(1)2.1 and 95kD-alpha(1)2.1 arise from
      the same gene. A recombinant two-domain form (alpha(1AI-II)) of alpha(1)2.1
      associates with the beta subunit and is trafficked to the plasma membrane.
      Translocation of the alpha(1AI-II) to the plasma membrane requires association
      with the beta subunit, since a mutation in the alpha(1AI-II) that inhibits beta
      subunit association reduces membrane trafficking. Though the alpha(1AI-II)
      protein does not conduct any voltage-gated currents, we have previously shown
      that it generates a high density of non-linear charge movements [Ahern et al.,
      Proc. Natl. Acad. Sci. USA 98 (2001) 6935-6940]. In this study, we demonstrate
      that co-expression of the alpha(1AI-II) significantly reduces the current
      amplitude of alpha(1)2.1/beta(1a)/alpha(2)delta channels, via competition for the
      beta subunit. Taken together, our results demonstrate a dual functional role for
      the alpha(1AI-II) protein, both as a voltage sensor and modulator of P/Q-type
      currents in recombinant systems. These studies suggest an in vivo role for the
      95kD-alpha(1)2.1 in altering synaptic activity via protein-protein interactions
      and/or regulation of P/Q-type currents.

PMID- 12482584
TI  - Properties of the chaperonin complex from the halophilic archaeon Haloferax
      volcanii.
AB  - The halophilic archaeon Haloferax volcanii has three genes encoding type II
      chaperonins, named cct1, cct2 and cct3. We show here that the three CCT proteins
      are all expressed but not to the same level. All three proteins are further
      induced on heat shock. The CCT proteins were purified by ammonium sulphate
      precipitation, sucrose gradient centrifugation and hydrophobic interaction
      chromatography. This procedure yields a high molecular mass complex (or
      complexes). The complex has ATPase activity, which is magnesium dependent, low
      salt-sensitive and stable to at least 75 degrees C. Activity requires high levels
      of potassium ions and was reduced in the presence of an increasing concentration
      of sodium ions.

PMID- 12482585
TI  - Identification of neuropeptide FF-related peptides in human cerebrospinal fluid
      by mass spectrometry.
AB  - Several neuropeptide FF (NPFF)-related peptides, known as modulators of the
      opioid system, have been previously characterized in bovine and rodent brain.
      Reverse-phase high pressure liquid chromatography (HPLC) fractions of a human
      with normal pressure hydrocephalus cerebrospinal fluid (CSF), co-migrating with
      NPFF-related synthetic peptides, were characterized by capillary HPLC coupled on
      line to nanospray ion trap tandem mass spectrometry. Two peptides present in the
      pro-NPFF(A) precursor, NPAF (AGEGLNSQFWSLAAPQRF-NH2) and NPSF (SLAAPQRF-NH2),
      were identified. The monitoring of NPFF-related peptides in human CSF can be
      helpful to understand their roles in pain sensitivity.

PMID- 12482586
TI  - Localisation and regulation of the eIF4E-binding protein 4E-BP3.
AB  - The cap-binding protein eIF4E-binding protein 3 (4E-BP3) was identified some
      years ago, but its properties have not been investigated in detail. In this
      report, we investigated the regulation and localisation of 4E-BP3. We show that
      4E-BP3 is present in the nucleus as well as in the cytoplasm in primary T cells,
      HEK293 cells and HeLa cells. 4E-BP3 was associated with eIF4E in both cell
      compartments. Furthermore, 4E-BP3/eIF4E association in the cytoplasm was
      regulated by serum or interleukin-2 starvation in the different cell types.
      Rapamycin did not affect the association of eIF4E with 4E-BP3 in the cytoplasm or
      in the nucleus.

PMID- 12482588
TI  - A directional electron transfer regulator based on heme-chain architecture in the
      small tetraheme cytochrome c from Shewanella oneidensis.
AB  - The macroscopic and microscopic redox potentials of the four hemes of the small
      tetraheme cytochrome c from Shewanella oneidensis were determined. The
      microscopic redox potentials show that the order of reduction is from hemes in
      the C-terminal domain (hemes 3 and 4) to the N-terminal domain (heme 1),
      demonstrating the polarization of the tetraheme chain during reduction. This
      makes heme 4 the most efficient electron delivery site. Furthermore, multi-step
      reduction of other redox centers through either heme 4 or heme 3 is shown to be
      possible. This has provided new insights into the two-electron reduction of the
      flavin in the homologous flavocytochrome c-fumarate reductase.

PMID- 12482587
TI  - Relationship between protein kinase C and derepression of different enzymes.
AB  - The PKC1 gene in the yeast Saccharomyces cerevisiae encodes for protein kinase C
      which is known to control a MAP kinase cascade consisting of different kinases:
      Bck1, Mkk1 and Mkk2, and Mpk1. This cascade affects the cell wall integrity but
      the phenotype of pkc1Delta mutants suggests additional targets that have not yet
      been identified [Heinisch et al., Mol. Microbiol. 32 (1999) 671-680]. The
      pkc1Delta mutant, as opposed to other mutants in the MAP kinase cascade, displays
      defects in the control of carbon metabolism. One of them occurs in the
      derepression of SUC2 gene after exhaustion of glucose from the medium, suggesting
      an involvement of Pkc1p in the derepression process that is not shared by the
      downstream MAP kinase cascade. In this work, we demonstrate that Pkc1p is
      required for the increase of the activity of enzymatic systems during the
      derepression process. We observed that Pkc1p is involved in the derepression of
      invertase and alcohol dehydrogenase activities. On the other hand, it seems not
      to be necessary for the derepression of the enzymes of the GAL system. Our
      results suggest that Pkc1p is acting through the main glucose repression pathway,
      since introduction of an additional mutation in the PKC1 gene in yeast strains
      already presenting mutations in the HXKII or MIG1 genes does not interfere with
      the typical derepressed phenotype observed in these single mutants. Moreover, our
      data indicate that Pkc1p participates in this process through the control of the
      cellular localization of the Mig1 transcriptional factor.

PMID- 12482589
TI  - PEGylation of microspheres generates a heterogeneous population of particles with
      differential surface characteristics and biological performance.
AB  - Surface PEGylation of polystyrene microspheres with methoxy-poly(ethylene glycol)
      5000 (mPEG-5000) generated a heterogeneous population of entities that differed
      in surface characteristics and in vitro biological performance (phagocytosis and
      complement activation). Surface heterogeneity was determined by hydrophobic
      interaction chromatography, measurements of particle electrophoretic mobility in
      a defined field and adlayer thickness of the projected mPEG chains. The particle
      population separation by hydrophobic interaction chromatography demonstrated a
      remarkable linear relationship between the particle zeta potential and
      phagocytosis by J774 A1 macrophage-like cells. Microsphere populations bearing a
      predominant surface of mPEG molecules as high-density mushroom-brush intermediate
      and/or brush configuration were most resistant to phagocytosis and activated the
      human complement system poorly. Conversely, those populations with predominant
      surface mPEGs in a mushroom regime were potent activators of the complement
      system and were prone to phagocytosis. Therefore, surface heterogeneity explains
      why a fraction of intravenously injected 'long-circulating' nanoparticles is
      cleared rapidly by macrophages of the reticuloendothelial system. Hydrophobic
      interaction chromatography can readily assess the extent of surface heterogeneity
      of PEGylated particulate drug delivery systems and pre-select particles with
      optimal retention times in the blood. These observations may also be relevant
      with respect to successful surface camouflaging of cells, drug depots and
      implantable devices.

PMID- 12482590
TI  - Brown adipocytes are novel sites of expression and regulation of adiponectin and
      resistin.
AB  - Adiponectin and resistin, two recently identified adipocyte-specific secretory
      factors, are able to modulate insulin actions in target tissues. To investigate
      their expression and hormonal regulation in brown adipocytes, we used the brown
      adipocyte cell line T37i, which, beside uncoupling protein expression, secretes
      leptin. Adiponectin and resistin mRNA were detected as a function of cell
      differentiation. Both transcripts were expressed at relatively high levels in
      differentiated T37i cells, reaching maximal levels on day 7, while resistin
      expression drastically fell afterwards. These stable transcripts (t(1/2)>8 h)
      were differentially regulated by factors involved in insulin responsiveness.
      Insulin and thiazolidinedione, a peroxisome proliferator-activated receptor gamma
      agonist, stimulated resistin expression two- to four-fold in differentiated T37i
      cells, whereas adiponectin mRNA levels increased 1.5-2-fold. In contrast,
      dexamethasone and isoproterenol reduced by two-fold the level of adiponectin and
      resistin transcripts in differentiated T37i cells. This study provides the first
      direct evidence that differentiated brown adipocytes are endocrine cells capable
      of expressing adiponectin and resistin. The complex hormonal regulation of their
      expression in brown adipocytes clearly differs from that reported in white
      adipose tissue, pointing to differential physiological and pathophysiological
      implications of brown fat in energy homeostasis.

PMID- 12482591
TI  - Cdc42 and Rac1 are necessary for autotaxin-induced tumor cell motility in A2058
      melanoma cells.
AB  - Autotaxin (ATX) is a strong motogen that can increase invasiveness and
      angiogenesis. In the present study, we investigated the signal transduction
      mechanism of ATX-induced tumor cell motility. Unlike N19RhoA expressing cells,
      the cells expressing N17Cdc42 or N17Rac1 showed reduced motility against ATX. ATX
      activated Cdc42 and Rac1 and increased complex formation between these small G
      proteins and p21-activated kinase (PAK). Furthermore, ATX phosphorylated focal
      adhesion kinase (FAK) that was not shown in cells expressing dominant negative
      mutants of Cdc42 or Rac1. Collectively, these data strongly indicate that Cdc42
      and Rac1 are essential for ATX-induced tumor cell motility in A2058 melanoma
      cells, and that PAK and FAK might be also involved in the process.

PMID- 12482592
TI  - 14-3-3 binding to the IGF-1 receptor is mediated by serine autophosphorylation.
AB  - The phosphoserine-binding 14-3-3 proteins have been implicated in playing a role
      in mitogenic and apoptotic signaling pathways. Binding of 14-3-3 proteins to
      phosphoserine residues in the C-terminus of the insulin-like growth factor-1
      receptor (IGF-1R) has been described to occur in a variety of cell systems, but
      the kinase responsible for this serine phosphorylation has not been identified
      yet. Here we present evidence that the isolated dimeric insulin-like growth
      factor-1 receptor kinase domain (IGFKD) contains a dual specific (i.e.
      tyrosine/serine) kinase activity that mediates autophosphorylation of C-terminal
      serine residues in the enzyme. From the total phosphate incorporation of
      approximately 4 mol per mol kinase subunit, 1 mol accounts for serine phosphate.
      However, tyrosine autophosphorylation proceeds more rapidly than
      autophosphorylation of serine residues (t(1/2) approximately 1 min vs. t(1/2)
      approximately 5 min). Moreover, dot-blot and far-Western analyses reveal that
      serine autophosphorylation of IGFKD is sufficient to promote binding of 14-3-3
      proteins in vitro. The proof that dual kinase activity of IGFKD is necessary and
      sufficient for 14-3-3 binding was obtained with an inactive kinase mutant that
      was phosphorylated on serine residues in a stoichiometric reaction with the
      catalytically active enzyme. Thus, the IGF-1R itself might be responsible for the
      serine autophosphorylation which leads to recognition of 14-3-3 proteins in vivo.

PMID- 12482593
TI  - An expanded V2 receptor retention signal.
AB  - Following ligand-promoted internalization the human type 2 vasopressin receptor
      (hV2R) is not recycled to the cell surface after removal of the agonist. A
      retention motif consisting of a serine triplet present in the cytoplasmic tail
      was previously found to require for retention, but serine 357, and threonines
      359, 360 located upstream were not examined. Evidence is now presented that
      substitution of these amino acids did not change V2 internalization although it
      reduced the levels of arginine vasopressin (AVP)-induced phosphorylation as
      compared to the wild type (WT). Contrary to the WT hV2R, these mutant receptors
      were recycled to the cell surface after a 2 h incubation in the absence of AVP
      identifying these changed residues as additional members of the retention motif
      of the hV2R.

PMID- 12482594
TI  - The gene for domains rearranged methyltransferase (DRM2) in Arabidopsis thaliana
      plants is methylated at both cytosine and adenine residues.
AB  - The methylation patterns of cytosine and adenine residues in the Arabidopsis
      thaliana gene for domains rearranged methyltransferase (DRM2) were studied in
      wild-type and several transgene plant lines containing antisense fragments of the
      cytosine DNA-methyltransferase gene METI under the control of copper-inducible
      promoters. It was shown that the promoter region of the DRM2 gene is mostly
      unmethylated at the internal cytosine residue in CCGG sites whereas the 3'-end
      proximal part of the gene coding region is highly methylated. The DRM2 gene was
      found to be also methylated at adenine residues in some GATC sequences. Cytosine
      methylation in CCGG sites and adenine methylation in GATC sites in the DRM2 gene
      are variable between wild-type and different transgenic plants. The induction of
      antisense METI constructs with copper ions in transgene plants in most cases
      leads to further alterations in the DRM2 gene methylation patterns.

PMID- 12482595
TI  - In vivo activation of the constitutive androstane receptor beta (CARbeta) by
      treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S).
AB  - We investigated whether dehydroepiandrosterone (DHEA) or DHEA-sulfate (S)
      affected the activities of nuclear receptors, with special reference to
      constitutive androstane receptor beta (CARbeta). Administration of DHEA or DHEA-S
      enhanced the DNA binding of hepatic nuclear extracts to responsive elements for
      the retinoic acid receptor, the retinoic acid receptor beta 2 and the peroxisome
      proliferator activated receptor. The bound complexes were shown to be the CARbeta
      RXR heterodimer by antibody-supershift assays. The expression of a target gene of
      CARbeta, Cyp2b10, was increased in liver by DHEA or DHEA-S treatment, suggesting
      that DHEA or DHEA-S actually activated CARbeta in vivo. It was suggested that the
      metabolic conversion of DHEA, DHEA-S to CARbeta ligands could occur in vivo and
      the metabolites could regulate the expression of CARbeta target gene expression.
      Our results provide new insights into the in vivo relationship between DHEA/DHEA
      S and CARbeta activation.

PMID- 12482596
TI  - Identification of the region of AT2 receptor needed for inhibition of the AT1
      receptor-mediated inositol 1,4,5-triphosphate generation.
AB  - Increase in the intracellular inositol triphosphate (IP3) levels in Xenopus
      oocytes in response to expression and activation of rat angiotensin II (Ang II)
      receptor AT1 was inhibited by co-expression of rat AT2 receptor. To identify
      which region of the AT2 was involved in this inhibition, ability of three AT2
      mutants to abolish this inhibition was analyzed. Deletion of the C-terminus of
      the AT2 did not abolish this inhibition. Replacing Ile249 in the third
      intracellular loop (3rd ICL) of the AT2 with proline, corresponding amino acid in
      the AT1, in the mutant M6, resulted in slightly reduced affinity to [125I]Ang II
      (K(d)=0.259 nM), however, did not abolish the inhibition. In contrast, replacing
      eight more amino acids in the 3rd ICL of the AT2 (at positions 241-244, 250-251
      and 255-256) with that of the AT1 in the mutant M8, not only increased the
      affinity of the AT2 receptor to [125I]Ang II (K(d)=0.038 nM) but also abolished
      AT2-mediated inhibition. Interestingly, activation of the M8 by Ang II binding
      also resulted in increase in the intracellular IP(3) levels in oocytes. These
      results imply that the region of the 3rd ICL of AT2 spanning amino acids 241-256
      is sufficient for the AT2-mediated inhibition of AT1-stimulated IP3 generation.
      Moreover, these nine mutations are also sufficient to render the AT2 with the
      ability to activate phospholipase C.

PMID- 12482597
TI  - A dispensable peptide from Acidithiobacillus ferrooxidans tryptophanyl-tRNA
      synthetase affects tRNA binding.
AB  - The activation domain of class I aminoacyl-tRNA synthetases, which contains the
      Rossmann fold and the signature sequences HIGH and KMSKS, is generally split into
      two halves by the connective peptides (CP1, CP2) whose amino acid sequences are
      idiosyncratic. CP1 has been shown to participate in the binding of tRNA as well
      as the editing of the reaction intermediate aminoacyl-AMP or the aminoacyl-tRNA.
      No function has been assigned to CP2. The amino acid sequence of
      Acidithiobacillus ferrooxidans TrpRS was predicted from the genome sequence.
      Protein sequence alignments revealed that A. ferrooxidans TrpRS contains a 70
      amino acids long CP2 that is not found in any other bacterial TrpRS. However, a
      CP2 in the same relative position was found in the predicted sequence of several
      archaeal TrpRSs. A. ferrooxidans TrpRS is functional in vivo in Escherichia coli.
      A deletion mutant of A. ferrooxidans trpS lacking the coding region of CP2 was
      constructed. The in vivo activity of the mutant TrpRS in E. coli, as well as the
      kinetic parameters of the in vitro activation of tryptophan by ATP, were not
      altered by the deletion. However, the K(m) value for tRNA was seven-fold higher
      upon deletion, reducing the efficiency of aminoacylation. Structural modeling
      suggests that CP2 binds to the inner corner of the L shape of tRNA.

PMID- 12482598
TI  - CCl4-induced acute liver injury in mice is inhibited by hepatocyte growth factor
      overexpression but stimulated by NK2 overexpression.
AB  - Hepatocyte growth factor (HGF) inhibits acute liver injury. NK2 acts as an
      antagonist to HGF in vitro, but its in vivo function has reached no consensus
      conclusions. We have investigated in vivo effects of HGF and NK2 on CCl4-induced
      acute liver injury. Elevation of the serum alanine aminotransferase level and
      extension of centrilobular necrosis were inhibited in HGF transgenic mice but
      were promoted in NK2 transgenic mice. Hepatocyte proliferation after liver injury
      was not inhibited in NK2 transgenic mice. Thus, this study indicates that HGF
      inhibits liver injury, and NK2 antagonizes HGF on liver injury, however, NK2 may
      not antagonize HGF on hepatocyte proliferation.

PMID- 12482599
TI  - The tertiary amine local anesthetic dibucaine binds to the membrane skeletal
      protein spectrin.
AB  - The quinoline-based tertiary amine dibucaine has been shown to bind the membrane
      skeletal protein spectrin with a dissociation constant of 3.5x10(-5) M at 25
      degrees C. Such binding is detected by monitoring the quenching of the tryptophan
      fluorescence intensity with increasing concentrations of dibucaine only and not
      with the benzene-based local anesthetics procaine, tetracaine and lidocaine.
      Binding of dibucaine also indicated changes in the tertiary structure of spectrin
      indicated by a circular dichroism spectrum in the near-UV region due to
      absorption of the aromatic side chains. The thermodynamic parameters associated
      with the binding indicated the interaction of dibucaine and spectrin to be
      enthalpy-driven and insensitive to an increase in the ionic strength of the
      buffer.

PMID- 12482600
TI  - The protease core of the muscle-specific calpain, p94, undergoes Ca2+-dependent
      intramolecular autolysis.
AB  - Limb girdle muscular dystrophy type 2A is linked to a skeletal muscle-specific
      calpain isoform known as p94. Isolation of the intact 94-kDa enzyme has been
      difficult to achieve due to its rapid autolysis, and uncertainty has arisen over
      its Ca2+-dependence for activity. We have expressed a C-terminally truncated form
      of the enzyme that comprises the protease core (domains I and II) along with its
      insertion sequence, IS1, and N-terminal leader sequence, NS. This 47-kDa p94I-II
      mini-calpain was stable during purification. In the presence of Ca2+, p94I-II
      cleaved itself within the NS and IS1 sequences. Mapping of the autolysis sites
      showed that NS and IS1 have the potential to be removed without damage to the
      protease core. Ca2+-dependent autolysis must be an intramolecular event because
      the inactive p94I-II C129S mutant was not cleaved by incubation with wild-type
      p94I-II. In addition, the rate of autolysis of p94I-II was independent of the
      concentration of the enzyme.

PMID- 12482601
TI  - Singlet oxygen production in herbicide-treated photosystem II.
AB  - Photo-generated reactive oxygen species in herbicide-treated photosystem II were
      investigated by spin-trapping. While the production of .OH and O2-* was herbicide
      independent, 1O2 with a phenolic was twice that with a urea herbicide. This
      correlates with the reported influence of these herbicides on the redox
      properties of the semiquinone QA-* and fits with the hypothesis that 1O2 is
      produced by charge recombination reactions that are stimulated by herbicide
      binding and modulated by the nature of the herbicide. When phenolic herbicides
      are bound, charge recombination at the level of P+*Pheo-* is thermodynamically
      favoured forming a chlorophyll triplet and hence 1O2. With urea herbicides this
      pathway is less favourable.

PMID- 12482602
TI  - Stimulation of adhesion molecule expression by Helicobacter pylori and increased
      neutrophil adhesion to human umbilical vein endothelial cells.
AB  - Helicobacter pylori upregulates endothelial adhesion molecules but the pattern is
      unclear. Human umbilical vein endothelial cells (HUVEC) were exposed to control
      medium or H. pylori 60190. Binding of monoclonal antibodies against P-selectin, E
      selectin, vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion
      molecule-1 (ICAM-1) was determined using enzyme-linked immunosorbent assay.
      Binding of polymorphonuclear leukocytes to HUVEC was determined on cells exposed
      as above. After 6 h exposure to H. pylori, there were 30%, 124%, 167% and 100%
      increases in P-selectin, E-selectin, VCAM-1 and ICAM-1 levels and a 400% increase
      in polymorphonuclear leukocyte adhesion in HUVEC exposed to H. pylori. Effects of
      incubation for other intervals between 0 and 18 h are also described. H. pylori
      exerts some of its effects on gastric mucosa via gastric vasculature. This study
      gives insight into the pattern of H. pylori-associated endothelial adhesion
      molecule upregulation.

PMID- 12482603
TI  - Reliability of transmembrane predictions in whole-genome data.
AB  - Transmembrane prediction methods are generally benchmarked on a set of proteins
      with experimentally verified topology. We have investigated if the accuracy
      measured on such datasets can be expected in an unbiased genomic analysis, or if
      there is a bias towards 'easily predictable' proteins in the benchmark datasets.
      As a measurement of accuracy, the concordance of the results from five different
      prediction methods was used (TMHMM, PHD, HMMTOP, MEMSAT, and TOPPRED). The
      benchmark dataset showed significantly higher levels (up to five times) of
      agreement between different methods than in 10 tested genomes. We have also
      analyzed which programs are most prone to make mispredictions by measuring the
      frequency of one-out-of-five disagreeing predictions.

PMID- 12482604
TI  - Meltrin beta mini, a new ADAM19 isoform lacking metalloprotease and disintegrin
      domains, induces morphological changes in neuronal cells.
AB  - Meltrin beta (ADAM19) is a metalloprotease-disintegrin expressed in the
      peripheral nervous system and other organs during embryogenesis. We report here
      an alternatively spliced isoform, meltrin beta mini, that lacks the prodomain,
      metalloprotease and disintegrin domains. A comparison of the cDNA and genomic
      sequences suggested the existence of a new exon. This isoform was detected in
      murine dorsal root ganglion and neuronal cell lines by RT-PCR. Overexpression of
      meltrin beta mini but not meltrin beta induced neurite outgrowth in neuronal
      cells. These studies suggest that the novel meltrin beta isoform has a distinct
      function related to neurogenesis.

PMID- 12482605
TI  - A high-affinity competitive inhibitor of type A botulinum neurotoxin protease
      activity.
AB  - The peptide N-acetyl-CRATKML-amide is an effective inhibitor of type A botulinum
      neurotoxin (BoNT A) protease activity [Schmidt et al., FEBS Lett. 435 (1998) 61
      64]. To improve inhibitor binding, the peptide was modified by replacing cysteine
      with other sulfhydryl-containing compounds. Ten peptides were synthesized. One
      peptide adapted the structure of captopril to the binding requirements of BoNT A,
      but it was a weak inhibitor, suggesting that angiotensin-converting enzyme is not
      a good model for BoNT A inhibitor development. However, replacing cysteine with 2
      mercapto-3-phenylpropionyl yielded a peptide with K(i) of 330 nM, the best
      inhibitor of BoNT A protease activity reported to date. Additional modifications
      of the inhibitor revealed structural elements important for binding and supported
      our earlier findings that, with the exception of P1' arginine, subsites on BoNT A
      are not highly specific for particular amino acid side chains.

PMID- 12482606
TI  - Identification and characterization of single-domain thiosulfate
      sulfurtransferases from Arabidopsis thaliana.
AB  - Sulfurtransferases/rhodaneses (ST) are a group of enzymes widely distributed in
      all three phyla that catalyze the transfer of sulfur from a donor to a thiophilic
      acceptor substrate. All ST contain distinct structural domains, and can exist as
      single-domain proteins, as tandemly repeated modules in which the C-terminal
      domain bears the active site, or as members of multi-domain proteins. We
      identified several ST in Arabidopsis resembling the C-terminus of the Arabidopsis
      two-domain ST1 and the single-domain GlpE protein from Escherichia coli. Two of
      them (accession numbers BAB10422 and BAB10409) were expressed in E. coli and
      purified. Both proteins showed thiosulfate-specific ST enzyme activity.

PMID- 12482607
TI  - Functional characterization of GcpE, an essential enzyme of the non-mevalonate
      pathway of isoprenoid biosynthesis.
AB  - The gcpE gene product controls one of the terminal steps of isoprenoid
      biosynthesis via the mevalonate independent 2-C-methyl-D-erythritol-4-phosphate
      (MEP) pathway. This pathway is utilized by a variety of eubacteria, the plastids
      of algae and higher plants, and the plastid-like organelle of malaria parasites.
      Recombinant GcpE protein from the hyperthermophilic bacterium Thermus
      thermophilus was produced in Escherichia coli and purified under dioxygen-free
      conditions. The protein was enzymatically active in converting 2-C-methyl-D
      erythritol-2,4-cyclodiphosphate (MEcPP) into (E)-4-hydroxy-3-methyl-but-2-enyl
      diphosphate (HMBPP) in the presence of dithionite as reductant. The maximal
      specific activity was 0.6 micromol x min(-1) x mg(-1) at pH 7.5 and 55 degrees C.
      The kcat value was 0.4 s(-1) and the K(m) value for HMBPP 0.42 mM.

PMID- 12482608
TI  - LytB protein catalyzes the terminal step of the 2-C-methyl-D-erythritol-4
      phosphate pathway of isoprenoid biosynthesis.
AB  - Recombinant LytB protein from the thermophilic eubacterium Aquifex aeolicus
      produced in Escherichia coli was purified to apparent homogeneity. The purified
      LytB protein catalyzed the reduction of (E)-4-hydroxy-3-methyl-but-2-enyl
      diphosphate (HMBPP) in a defined in vitro system. The reaction products were
      identified as isopentenyl diphosphate and dimethylallyl diphosphate. A
      spectrophotometric assay was established to determine the steady-state kinetic
      parameters of LytB protein. The maximal specific activity of 6.6+/-0.3 micromol x
      min(-1) x mg(-1) protein was determined at pH 7.5 and 60 degrees C. The k(cat)
      value of the LytB protein was 3.7+/-0.2 s(-1) and the K(m) value for HMBPP was
      590+/-60 microM.

PMID- 12482609
TI  - Nitric oxide induces neutral ceramidase degradation by the ubiquitin/proteasome
      complex in renal mesangial cell cultures.
AB  - The neutral ceramidase is a key enzyme in the regulation of cellular ceramide
      levels. Previously we have reported that stimulation of rat renal mesangial cells
      with nitric oxide (NO) donors leads to an inhibition of neutral ceramidase
      activity which is due to increased degradation of the enzyme. This and the
      concomitant activation of the sphingomyelinase results in an amplification of
      ceramide levels. Here, we show that the NO-triggered degradation of neutral
      ceramidase involves activation of the ubiquitin/proteasome complex. The specific
      proteasome inhibitor lactacystin completely reverses the NO-induced degradation
      of ceramidase protein and neutral ceramidase activity. As a consequence, the
      cellular amount of ceramide, which drastically increases by NO stimulation, is
      reduced in the presence of lactacystin. Furthermore, ubiquitinated neutral
      ceramidase accumulates after NO stimulation. In summary, our data clearly show
      that the ubiquitin/proteasome complex is an important determinant of neutral
      ceramidase activity and thereby regulates the availability of ceramide.

PMID- 12482610
TI  - p80 ROKalpha binding protein is a novel splice variant of CRMP-1 which associates
      with CRMP-2 and modulates RhoA-induced neuronal morphology.
AB  - Using antibody against the Rho binding domain of ROKalpha, two neuronal
      phosphoproteins of 62 and 80 kDa were co-immunoprecipitated from brain extracts.
      Peptide analysis revealed their identity as collapsin response mediator proteins
      (CRMPs); p62 was CRMP-2 whereas p80 was a novel splice form of CRMP-1 with an
      extended N-terminus. p80 CRMP-1 was able to complex with CRMP-2, suggesting that
      p80 CRMP-1 and CRMP-2 form oligomers. CRMP-2 was the major substrate of ROK. p80
      CRMP-1 interacted with the kinase domain of ROKalpha, resulting in inhibition of
      the catalytic activity towards other substrates. Over-expression of p80 CRMP-1
      and CRMP-2 together counteracted the effects of RhoA on neurite retraction, an
      effect enhanced by mutation of the ROK phosphorylation site in CRMP-2. p80 CRMP-1
      and CRMP-2 may be modulators of RhoA-dependent signaling, through interaction
      with and regulation of ROKalpha.

PMID- 12482611
TI  - Mouse Apg10 as an Apg12-conjugating enzyme: analysis by the conjugation-mediated
      yeast two-hybrid method.
AB  - Autophagosome formation is a central event in macroautophagy. The Apg12-Apg5
      conjugate, which is essential in this process, is generated by a ubiquitin-like
      protein conjugation system. In yeast, Apg12, following activation by the E1-like
      Apg7, forms a thioester with Apg10 (E2-like). Apg12 is finally conjugated to Apg5
      via an isopeptide bond. The possible requirement of an E3-like protein for the
      conjugation, however, has not yet been confirmed. The Apg12 system is conserved
      among eukaryotes, although a mammalian counterpart of Apg10 has not yet been
      identified. Here, we report the identification and characterization of the mouse
      Apg10 ortholog. A yeast two-hybrid screen using the mouse Apg5 (mApg5) as bait
      identified a novel protein with 19% identity to yeast Apg10. We designated this
      protein mouse Apg10 (mApg10). We demonstrated by a modified yeast two-hybrid
      assay that mApg10 mediates the conjugation of mApg12 and mApg5. The in vivo
      interaction of mApg12 with mApg10 in HeLa cells suggests that mApg10 is an Apg12
      conjugating enzyme, likely serving as an Apg5-recognition molecule in the Apg12
      system. This novel two-hybrid method, which we have named 'conjugation-mediated
      yeast two-hybrid', proves to be a simple and useful technique with which to
      analyze protein-protein conjugation.

PMID- 12482612
TI  - Microbead display by in vitro compartmentalisation: selection for binding using
      flow cytometry.
AB  - In vitro compartmentalisation in an emulsion was used to physically link proteins
      to the DNA that encodes them via microbeads. These microbeads can be selected for
      catalysis, or, as demonstrated here, for binding. Genes encoding a peptide
      containing an epitope (haemagglutinin) were enriched to near purity from a 10(6)
      fold excess of genes encoding a different peptide by two rounds of selection
      using flow cytometry, indicating approximately 1000-fold enrichment per round.
      Single beads can be isolated using flow sorting and the single gene on the bead
      amplified by polymerase chain reaction. Hence, the entire process can be
      performed completely in vitro.

PMID- 12482613
TI  - Uncoupling protein and alternative oxidase of Dictyostelium discoideum:
      occurrence, properties and protein expression during vegetative life and
      starvation-induced early development.
AB  - In this study we show that mitochondria of Dictyostelium discoideum contain both
      alternative oxidase (AOX) and uncoupling protein (UCP). AOX was stimulated by
      purine mononucleoside and was monomeric. UCP was stimulated by free fatty acids
      and was poorly sensitive to GTP. Both proteins collaborated in energy dissipation
      when activated together. AOX expression in free-living ameboid cells decreased
      strongly from exponential to stationary phase of growth but much less during
      starvation-induced aggregation. In contrast, UCP expression was constant in all
      conditions indicating permanent need. Our results suggest that AOX could play a
      role in cell differentiation, mainly by protecting prespore cells from programmed
      cell death.

PMID- 12482614
TI  - The PLP-dependent biotin synthase from Escherichia coli: mechanistic studies.
AB  - Biotin synthase (BioB), an iron-sulfur enzyme, catalyzes the last step of the
      biotin biosynthesis pathway. The reaction consists in the introduction of a
      sulfur atom into two non-activated C-H bonds of dethiobiotin. Substrate radical
      activation is initiated by the reductive cleavage of S-adenosylmethionine
      (AdoMet) into a 5'-deoxyadenosyl radical. The recently described pyridoxal 5'
      phosphate-bound enzyme was used to show that only one molecule of AdoMet, and not
      two, is required for the formation of one molecule of biotin. Furthermore 5'
      deoxyadenosine, a product of the reaction, strongly inhibited biotin formation,
      an observation that may explain why BioB is not able to make more than one
      turnover. However this enzyme inactivation is not irreversible.

PMID- 12482615
TI  - Hepatocyte growth factor: from diagnosis to clinical applications.
AB  - Hepatocyte growth factor (HGF), initially identified and molecularly cloned as a
      potent mitogen of primary cultured hepatocytes, has multiple activities in a
      variety of tissues during the course of development and also in various disease
      states. HGF plays key roles in the attenuation of disease progression as an
      intrinsic repair factor. It is also evident that HGF levels are regulated under
      different conditions, for example, during the course of pregnancy, aging, and
      disease. This review focuses on the levels of HGF in normal and
      pathophysiological situations and examines the relationships between HGF levels
      and disease, disease stage, and disease prognosis. The clinical potential of HGF
      as a treatment for subjects with various diseases is also given attention.

PMID- 12482616
TI  - Specimen materials, target values and commutability for external quality
      assessment (proficiency testing) schemes.
AB  - BACKGROUND: The objective of external quality assessment is to evaluate clinical
      acceptability of laboratory results. It is desirable to evaluate intermethod
      harmonization and traceability to a reference system. METHODS: Conventional
      matrix-modified processed materials are used in most programs, because they can
      be produced in large quantities, can have multiple abnormal analytes in the same
      vial and have excellent stability. The principal limitation of these materials is
      non-commutability which makes them unsuitable for traceability or harmonization
      evaluation. Peer group evaluation is used which allows an individual laboratory
      to confirm appropriate use of a measurement technology and a manufacturer to
      monitor uniformity in their calibration transfer process. Authentic clinical
      specimen pools provide commutability but are limited by the quantity available
      and number of analytes at pathologic levels in the same vial. Hybrid approaches
      have used authentic clinical specimen pools in conjunction with non-commutable
      processed materials to determine method-specific matrix-corrected target values
      which have enabled evaluation of traceability to reference methods. CONCLUSIONS:
      Conventional processed materials are limited by non-commutability. Pooled
      clinical specimens are limited by availability. When used together, external
      quality assessment can evaluate traceability to reference systems and
      harmonization between test procedures.

PMID- 12482617
TI  - Validation of an inductively coupled plasma-mass spectrometry method to quantify
      tungsten in human plasma. Determination of percentage binding to plasma proteins.
AB  - BACKGROUND: The aim of this paper was to validate an inductively coupled plasma
      mass spectrometry (ICP-MS) method to quantify tungsten in human plasma and to
      study its percentage binding to plasma proteins. METHODS: This method was
      validated with respect to accuracy, precision, selectivity and limits of
      quantification and of detection according to Good Laboratory Practice Guidelines.
      Calibration curves were obtained in the range 10-500 ng/ml. The extent of plasma
      protein binding was determined by ultrafiltration in the range 40-2000 ng/ml.
      RESULTS: A significant matrix effect was observed. The linearity of this method
      was statistically proven. Precision ranged from 0.76% to 6.49%, and accuracy from
      97% to 102%. The lower limit of quantification (LLOQ) was 10 ng/ml. The mean
      percentage of unbound fraction was 89%. CONCLUSIONS: The results obtained
      indicate that the method described fulfills the accuracy and precision
      requirements necessary to carry out pharmacokinetic studies in man.

PMID- 12482618
TI  - Validation of an ESI-MS/MS screening method for acylcarnitine profiling in urine
      specimens of neonates, children, adolescents and adults.
AB  - BACKGROUND: Acylcarnitine (AC) profiling in dried blood spots by means of
      electrospray ionisation tandem mass spectrometry (ESI-MS/MS) has proven to be a
      useful method in neonatal screening, able to detect inborn errors of fatty acid
      oxidation, amino acid, organic acid and carnitine metabolism. Furthermore, this
      method is becoming increasingly applied in selective screening and in prenatal
      and postmortal diagnostics of inborn metabolic disorders, where urine is commonly
      used as specimen of interest. We therefore developed and validated a butylation
      method of acylcarnitine profiling in urine by ESI-MS/MS without previous
      chromatographic separation. METHODS: Random urine specimens were used for
      investigation of the analytical imprecision of the method. Recovery, precision
      and linearity were determined using methanolic standard solutions of free
      carnitine, octanoylcarnitine and palmitoylcarnitine at various concentrations.
      RESULTS: The mean coefficients of variation of within-run and run-to-run analysis
      of these analytes were found between 10% and 20% and demonstrated that the method
      fulfills the analytical requirements within the relevant ranges of concentration.
      Creatinine-related and age-related reference values of free carnitine and the ACs
      (C2-C18) were established. The definite discrimination was possible between
      patients with fatty acid oxidation disorders, organic acidurias, and healthy
      controls. The AC profiles from patients with various specific disorders were
      diagnostically helpful during acute deterioration and even during conditions of
      well-compensated metabolic state. CONCLUSION: The method used in this study is
      suitable both for selective screening and for confirmation of diagnosis with the
      advantage of high-throughput quantitative measurement.

PMID- 12482619
TI  - Simultaneous determination of percentage of Lens culinaris agglutinin-reactive
      alpha-fetoprotein and alpha-fetoprotein concentration using the LiBASys clinical
      auto-analyzer.
AB  - BACKGROUND: Lens culinaris agglutinin (LCA)-reactive alpha-fetoprotein (AFP-L3)
      percentage of total AFP concentration [(AFP-L3/total AFP)x100] has been used as
      an effective marker for earlier diagnosis, for assessment of therapeutic effects
      and for predicting the prognosis of hepatocellular carcinoma (HCC). METHODS: A
      new clinical automatic analyzer, the "LiBASys", and an assay kit for the
      simultaneous determination of AFP-L3 percentage and concentration of AFP in human
      serum were developed. LiBASys performed automatic re-measurement and also met
      stat samples. Both AFP-L3 percentage and AFP concentration were calculated
      simultaneously and printed out continuously every 3.4 min per test. RESULTS: A
      linear dose-response relationship was observed up to 1000 ng/ml AFP
      concentration. The detection limit and functional sensitivity of LCA-nonreactive
      AFP (AFP-L1) and AFP-L3 concentrations were 0.4 and 0.8 ng/ml, and 0.4 and 1.0
      ng/ml, respectively. Interassay CVs of AFP-L3 percentage and AFP concentration
      ranged from 2.8% to 13.4% and 2.6% to 4.6%, respectively. Assay results exhibited
      good correlations with those of commercially available lectin-affinity
      electrophoresis (r=0.984) for AFP-L3 percentage and with the RIA method (r=0.999)
      for AFP concentration. CONCLUSIONS: This method simultaneously yields both
      qualitative and quantitative results for AFP-L3 percentage and AFP concentration.

PMID- 12482620
TI  - New IFCC reference procedures for the determination of catalytic activity
      concentrations of five enzymes in serum: preliminary upper reference limits
      obtained in hospitalized subjects.
AB  - Consensus among clinical chemists has dictated a change in reference temperature
      for enzyme catalytic concentrations from 30 to 37 degrees C. Consequently,
      International Federation of Clinical Chemistry (IFCC) reference procedures have
      been redefined at the latter temperature. Acceptance in practice of these new
      procedures requires well-established reference values and clinical decision
      limits, but the establishment of reference values is complex. Therefore, as a
      provisional approach and to facilitate early application of the new IFCC
      procedures, we report our experience gained with them in the transfer of values
      from the consensus methods used hitherto in Germany to the new procedures. The
      preliminary upper reference limits were determined for catalytic activity
      concentrations of the enzymes alanine aminotransferase (ALT), aspartate
      aminotransferase (AST), creatine kinase (CK), gamma-glutamyltransferase (gamma
      GT) and lactate dehydrogenase (LDH) in human sera. Since enzyme measurements are
      almost always made on sera from non-ambulant subjects, we have used hospital
      patients aged 17 years and older as the subjects of our study. The catalytic
      activity concentrations obtained by measurements with the German consensus
      methods for the respective enzyme were chosen in combination with additional
      enzymes of similar diagnostic relevance to classify patients' samples as part of
      the respective reference collective. Measurements for the determination of the
      upper reference limits were performed manually by use of the primary reference
      procedures at the measurement temperature 37 degrees C according to IFCC, and
      also by employing mechanized measurements adapted to the reference procedures.
      The upper reference limits were calculated as the 97.5th percentile of the
      reference collectives and determined separately for women and men: ALT: 34 U/l
      (female) and 45 U/l (male); AST: 31 U/l (female) and 35 U/l (male); CK: 145 U/l
      (female) and 171 U/l (male); gamma-GT: 38 U/l (female) and 55 U/l (male); LDH:
      247 U/l (female) and 248 U/l (male).

PMID- 12482621
TI  - Search for new urinary biochemical markers of collagen degradation in man.
AB  - BACKGROUND: In the human body, collagen degradation produces various fragments
      released from the extracellular matrix, which end up in the urine as pyridinium
      cross-links, either free or bound to peptides or sugars. METHODS: We developed a
      high-performance liquid chromatography (HPLC) technique, which measures not only
      free pyridinoline (Pyr) and deoxypyridinoline (Dpyr), but also glucosyl
      galactosyl-pyridinoline (glc-gal-pyr) and four still unidentified bound
      pyridinolines. Assuming that in Paget's disease of bone and in growing children
      the cross-links (CL) mainly originate from bone tissue, whereas after spinal cord
      injury their high excretion rather reflects the degradation of non-osseous
      collagen, we compared the urinary output of seven different cross-links, among
      which four had not been described before. RESULTS: Our results show that one of
      those, which we called CL1, is essentially originating from bone and is more
      specific in this respect than Dpyr, whereas glc-gal-pyr also reflects the
      degradation of non-osseous collagen. The best indicator of non-bone collagen
      degradation was CL3, one of the newly discovered cross-links. CONCLUSIONS: In
      conclusion, we demonstrate that new sensitive pyridinoline cross-links can be
      identified and assayed in human urine and that their specificity helps to
      distinguish diseases related to bone collagen from those in which other forms of
      collagen are involved.

PMID- 12482622
TI  - Alteration in plasma levels of nonprotein sulfhydryl compounds and S
      nitrosothiols in chronic renal failure patients.
AB  - BACKGROUND: Uremia is accompanied by the elevated nitric oxide (NO) synthesis,
      and it has not yet been established how this influences the levels of nonprotein
      sulfhydryl compounds (NPSH) and formation of S-nitrosothiols (SNT). METHODS: Our
      study was designed to determine plasma levels of SNT and NPSH in chronic renal
      failure (CRF) patients, who were hemodialysed (HD) or were not on hemodialysis
      treatment (ND), and in the control group. RESULTS: In ND patients, the plasma
      levels of SNT were significantly increased (11.25+/-2.08 nmol/ml, p<0.01), while
      NPSH levels were simultaneously decreased (66.67+/-15.0 nmol/ml, p<0.05) in
      comparison with the control subjects (SNT: 8.75+/-2.08 nmol/ml, NPSH: 86.66
      nmol/ml). In HD patients, plasma concentration of SNT before hemodialysis was
      significantly lower than in the control group (0.150+/-0.042 nmol/mg protein vs.
      control: 0.175+/-0.075 nmol/mg protein), and no significant change was observed
      after dialysis (0.142+/-0.058 nmol/mg protein, p<0.05). The level of NPSH in HD
      patients before dialysis was significantly decreased in comparison with the
      control subjects, both, when the results were calculated per 1 ml of plasma
      (45.96+/-17.87 nmol/ml) and per 1 mg of protein (0.70+/-0.25 nmol/mg protein). In
      the postdialysis samples, NPSH rose (79.15+/-22.9 nmol/ml, p<0.001 which
      corresponds to 1.30+/-0.55 nmol/mg protein, p<0.001) as compared to the level
      before dialysis. CONCLUSIONS: Firstly, plasma SNT level was found to be increased
      in CRF patients who were not treated with hemodialysis, while in HD patients, it
      dropped below the control values. It indicates that hemodialysis disturbs an
      equilibrium of reactions involved in S-nitrosothiols formation most probably by
      removing low molecular weight S-nitrosylating compounds. Secondly, the increased
      level of NPSH after each hemodialysis session indicates reestablished antioxidant
      capacity of plasma and suggests the existence of dialysable compounds, which via
      unknown mechanism become responsible for the decreased level of thiols.

PMID- 12482623
TI  - Elevated cell-free serum DNA detected in patients with myocardial infarction.
AB  - BACKGROUND: Cell-free DNA is detectable in the circulation. Increased cell-free
      DNA has been detected in cancer patients and individuals with trauma. We want to
      know whether patients with myocardial infarction (MI) also have increased cell
      free DNA in their blood. METHODS: We used a QIAamp blood kit for DNA extraction
      from serum and the PicoGreen DNA kit for quantification. DNA patterns of serum
      DNA were established by gel electrophoresis on 2.5% metarphor gel. RESULTS: The
      average serum DNA in MI patients (N=55) was 511+/-398 ng/ml, more than 10-fold
      higher than normal (36.3+/-23.8 ng/ml, n=274). Patients with increased CK-MB
      (>4%) were associated with highly increased concentrations of cell-free DNA
      (93.4%). There was no correlation between the concentration of cell-free DNA and
      the concentrations of CK-MB, troponin I and C-reactive protein. In serial
      specimens, we found that the cell-free DNA rose early, but peaked behind CK-MB. A
      slightly diffused DNA ladder could be found with pooled cell-free DNA from MI
      patients by electrophoresis with the smallest DNA band at only a few hundred base
      pairs. CONCLUSIONS: Cell-free DNA in MI patients is increased in patients
      diagnosed with MI, and may complement troponin and CK-MB in a multiple marker
      test format.

PMID- 12482624
TI  - Lipid peroxidation in cerebral tumors.
AB  - BACKGROUND: Serum and tissue concentrations of tumor markers or some metabolites
      are considered to be helpful in diagnosis and follow-up of the central nervous
      system (CNS) disease. However, markers currently available are not sufficiently
      sensitive and specific to be used as actual diagnostic tools. Differentiation
      between the malignant and benign lesions of the CNS is very important, both for
      determining the optimum therapeutic approach and to predict morbidity and
      mortality of the disease. Accurate diagnosis of a malignant disease is mostly
      performed through a surgical resection and histopathologic evaluation. Free
      oxygen radicals (FOR) are thought to take part in oncogenesis and cellular
      differentiation. We explored whether FORs can be used as diagnostic tumor
      markers. METHODS: We investigated the concentration of malondialdehyde (MDA) in
      the serum and tumor tissue of patients with glial tumor. We have studied 30
      patients with malign glial tumor (grades III and IV astrocytoma), 30 patients
      with low grade glial tumor, 28 healthy individuals, and 10 patients with
      nontumorous lesions (lobectomy for epilepsy). RESULTS: Patients with CNS tumors
      showed higher serum MDA concentration compared to control groups (epilepsy
      patients and healthy subjects). These patients had a higher tumor tissue MDA
      concentration compared to lobectomy tissue from epilepsy patients. Serum and
      tissue MDA concentrations were also higher in the malignant glial tumor group
      compared to the low grade glial tumor group. CONCLUSIONS: Although not specific,
      tissue and serum concentrations of FORs can be used as a marker to detect the
      presence and grade of CNS tumors. Further studies are needed to determine the
      optimum cutoff value for use of serum and tissue MDA concentrations in brain
      tumors.

PMID- 12482625
TI  - Blood lead concentrations in children: new ranges.
AB  - BACKGROUND: Lead exposure in young children may have adverse neurodevelopmental
      effects. Currently, an increased blood lead concentration is defined as >or=10
      microg/dl for males and females of all ages, including children younger than 6
      years. Using a large hospital population (n=11145), we define more specific
      ranges for pediatric blood lead concentrations. METHODS: Pediatric blood lead
      concentrations were determined (atomic absorption spectrophotometry) on patient
      samples accrued from January 2001 to June 2002, and the data was analyzed
      employing the Hoffman approach. RESULTS: For lead, the 2.5th and 97.5th
      percentiles for subjects aged 0 to 12 months were 2.3 to 4.7 microg/dl for
      females and 1.8 to 4.9 microg/dl for males. The 97.5th percentiles increased for
      the 1-2 years age group both for females (5.2 microg/dl) and males (5.6
      microg/dl). There was a significant decrease in blood lead concentrations after
      age 10 years, the 97.5th percentile being 4.4 microg/dl in both female and male
      subjects. The values in all corresponding age groups were similar for females and
      for males. The medians of all age groups were similar for females and for male
      subjects. CONCLUSION: The blood lead concentrations are much lower compared to
      previously published data.

PMID- 12482626
TI  - Detection of IgG-bound lipoprotein(a) immune complexes in patients with coronary
      heart disease.
AB  - BACKGROUND: LDL-immune complexes (IC) have a powerful pathogenic role for
      inducing foam cell formation in vitro more efficiently than any other known
      mechanism. Studies have also shown that plasma LDL-IC concentration is a powerful
      marker for the development of atherosclerosis. The structure, fatty acid
      composition and antioxidant concentrations of Lp(a) and LDL are quite similar.
      The same oxidation pattern has also been described for both lipoproteins.
      Modified forms of Lp(a), some resembling oxidized Lp(a), have been identified in
      human atheromatous lesions. The existence of autoantibodies against MDA-Lp(a) in
      vivo is also presented. Therefore, we suppose that Lp(a) might trigger an immune
      response leading to the production of autoantibodies and subsequently to the
      formation of immune complexes. This study examined the existence of IgG-bound
      Lp(a)-IC and investigated its value as a risk factor for the development of
      atherosclerosis. METHODS: We developed two "sandwich" ELISAs for measuring plasma
      Lp(a)-IC and LDL-IC concentrations, using anti-human IgG(Fab) as the capture
      antibody, and quantitating with monoclonal anti-apo(a) or anti-apoB enzyme
      conjugate. Their concentrations were studied in 160 patients with coronary heart
      disease (CHD) and 290 control subjects. RESULTS: Plasma TC, LDL-C, TG and apoB
      concentrations in CHD patients were all significantly increased, whereas HDL-C
      and apoAI concentrations were decreased. The Lp(a) concentrations in the patients
      with CHD were also significantly different from those of control (262.4+/-220.0
      vs. 211.3+/-199.4 mg/l, P<0.005). Plasma Lp(a)-IC (2.24+/-1.71 vs. 1.62+/-1.50
      AU, P<0.0001) and LDL-IC (2.77+/-1.29 vs. 1.40+/-0.92 AU, P<0.0001)
      concentrations in patients with CHD were both significantly higher than those of
      control. The relationships between Lp(a)-IC, LDL-IC concentrations and other
      lipid traits in all the studied subjects (n=450) were carried out. LDL-IC
      concentrations were positively correlated with LDL-C, apoB, TC, TG and Lp(a)
      concentrations, while negatively correlated with HDL-C and apoAI concentrations,
      respectively. Similarly, Lp(a)-IC concentrations were positively correlated with
      Lp(a), LDL-C, apoB and TC concentrations, while negatively correlated with HDL-C
      and apoAI concentrations, respectively. Furthermore, a significantly positive
      relation between LDL-IC and Lp(a)-IC concentrations was also found (r=0.313,
      P<0.0001). CONCLUSIONS: We report the existence of Lp(a)-IC in both the plasma of
      patients with CHD and control subjects. Lp(a)-IC concentration increases in the
      CHD patients.

PMID- 12482627
TI  - Asian and Siberian ginseng as a potential modulator of immune function: an in
      vitro cytokine study using mouse macrophages.
AB  - BACKGROUND: Ginseng is a widely used herbal product in China, other Asian
      countries, and in the Unites States. There is a traditional belief that ginseng
      stimulates immune functions. In this study, the innate effects of Asian and
      Siberian ginsengs on cytokines and chemokines produced by cultured macrophages
      were examined. MATERIALS AND METHODS: The effects of Asian and Siberian ginseng
      on cytokines and chemokines produced by cultured macrophages were examined. Mouse
      macrophages (J774A.1) were incubated with Asian or Siberian ginseng at varying
      concentrations (1, 10, 100, and 1000 microg/ml) for 24 h and then harvested for
      RNA isolation. The expression levels of IL-1beta, IL-12, TNF-alpha, MIP-1 alpha,
      and MIP-2 mRNA were measured by quantitative PCR. RESULTS: Our data showed that
      Asian ginseng induced a statistically significant increase in IL-12 expression at
      both mRNA and protein levels. However, the minor twofold increase is probably
      biologically insignificant. No significant increase of IL-12 by Siberian ginseng
      was observed at any dose level studied. No significant change in IL-1beta, IL-15,
      TNF-alpha, or MIP-1alpha mRNA was observed by either Asian or Siberian ginseng
      treatment. CONCLUSIONS: Our data showed statistically significant differential
      regulation of IL-12 by Asian ginseng. Siberian ginseng did not show a
      statistically significant increase. We conclude that both Asian ginseng and
      Siberian ginseng cannot significantly stimulate innate macrophage immune
      functions that influence cellular immune responses. Therefore, contrary to the
      popular belief, Asian and Siberian ginseng may not stimulate immune function.

PMID- 12482628
TI  - Lipid-lowering efficacy of hesperetin metabolites in high-cholesterol fed rats.
AB  - BACKGROUND: Hesperetin is a naturally occurring flavonoid that has hypolipidemic
      properties. METHODS: Male rats were fed a 1 g/100 g high-cholesterol diet for 5
      weeks along with hesperetin (0.02%, 0.066 mmol/100 g diet) and hesperetin
      metabolites. The hesperetin metabolites, m-hydroxycinnamic acid (m-HC), 3,4
      dihydroxyphenylpropionic acid (3,4-DHPP), and 3-methoxy-4-hydroxycinnamic acid
      (ferulic acid), were supplemented based on an equivalent amount of hesperetin.
      RESULTS: The supplementation of hesperetin and its metabolites significantly
      lowered the plasma total cholesterol and triglyceride concentrations compared to
      the control group. The hepatic HMG-CoA reductase and acyl-CoA:cholesterol
      acyltransferase (ACAT) activities were significantly lower in the hesperetin and
      its metabolite supplemented groups than in the control group. The excretion of
      acidic sterol was significantly higher in the hesperetin, m-HC, 3,4-DHPP, and
      ferulic acid supplemented groups than in the control group. CONCLUSIONS: These
      results demonstrated that the hesperetin metabolites played as potent a role as
      hesperetin in plasma lipid-lowering activities in vivo, and further suggest that
      cholesterol biosynthesis and esterification were concomitantly reduced by
      hesperetin and its metabolites, as indicated by the decreased HMG-CoA reductase
      and ACAT activities.

PMID- 12482629
TI  - Clinical significance of serum total sialic acid in cholangiocarcinoma.
AB  - BACKGROUND: High levels of serum total sialic acid (TSA) have been reported in
      cholangiocarcinoma (CCA) patients. In this study, the clinical value and possible
      cause of increased total sialic acid in the serum in cholangiocarcinoma patients
      were examined. METHODS: Total sialic acid was determined in 172 serum and 25
      tumor tissue samples taken from cholangiocarcinoma patients using the periodate
      thiobarbituric acid method. RESULTS: The total sialic acid content of the tumor
      tissue was significantly greater than that of the serum and not related to the
      concentration found in the serum. The serum total sialic acid was not correlated
      with age, sex, body mass index, blood group, tumor location, tumor stage,
      metastatic condition, histological types and survival of the patients. The
      increased total sialic acid in the serum had a significant correlation with serum
      MUC5AC mucin, alkaline phosphatase and the CA19-9, and the numbers of white blood
      cell and neutrophils. CONCLUSIONS: The concentration of serum sialic acid was not
      associated with clinicopathologic features or the tumor burden. The glycoproteins
      secreted from the tumor and inflammatory cells might be responsible for the
      increased total sialic acid in the serum in these patients.

PMID- 12482630
TI  - Development of an automated photometric assay for serum lithium and use of
      binding equilibrium expressions to optimize results.
AB  - BACKGROUND: A spectrophotometric serum lithium assay and relevant reaction
      equilibria used in the assay development are described. METHODS: The dye, 7-nitro
      2,12-dicarboxyl-16,17-dihydro-5H,15H-dibenzo[b,i]
      [1,11,4,5,7,8]dioxatetraazacyclotetradecine reacts rapidly with Li(+) in alkaline
      water/dimethylsulfoxide with an absorbance change. Sodium binds weakly, thus
      presenting potential inaccuracy from varying endogenous sodium. To minimize this
      problem, excess sodium ion was added from reagents. This diminishes the signal
      from lithium binding, thus lowering sensitivity, requiring selection of reagent
      sodium concentration for proper balance of performance characteristics.
      Absorptivities and binding constants were determined. Description of competing
      equilibria by an explicit cubic equation was used to predict sensitivity and
      effects of varying endogenous Na(+) concentration as functions of added NaCl.
      RESULTS: Concentration-absorbance data were satisfactorily predicted by the cubic
      equation, equilibrium constants, and absorptivities. Li(+) binds 300 times more
      tightly than Na(+). Interference was minimized, while sufficient sensitivity for
      needed precision was retained. A full evaluation is summarized separately in this
      issue. CONCLUSIONS: Explicit description of the competitive binding was
      successfully used to develop an automated liquid reagent assay for Li(+) with
      acceptable accuracy and precision.

PMID- 12482631
TI  - Clinical performance characteristics of a new photometric lithium assay: a
      multicenter study.
AB  - BACKGROUND: Therapeutic monitoring of lithium is important because of its narrow
      therapeutic range and therapeutic index, low protein binding and single route of
      elimination. We characterized a new photometric method that avoids the
      specialized requirements of ion-specific electrode (ISE), atomic absorption and
      flame emission methods. METHODS: Minimum detectable concentration (MDC),
      linearity and calibration drift over 65 days were determined. Within-run, between
      run and total imprecision were assessed over 20 days in accordance with NCCLS
      EP5. Interference studies were conducted for 46 endogenous and exogenous
      compounds. Two production lots of the new photometric method (LI) were compared
      on the Dimension(R) RxL system and two ISE methods [Ciba Corning (n=124) and
      DuPont (n=131)], an established photometric method (Vitros) 950 system; n=63) and
      atomic absorption (Thermo-Jerell Ash; n=63). RESULTS: The MDC was 0.04 mmol/l.
      Linearity was demonstrated from 0.12 to 5.8 mmol/l by the regression equation:
      observed=(1.01 x expected)-0.0005 mmol/l, S(y/x)=0.03 mmol/l, r=0.999. Drift for
      the lithium calibrators over the 65-day study period was <5%, except for the
      lowest calibrator, which showed 0.04 mmol/l drift. None of the 46 potential
      interfering substances showed greater than a 6.5% difference between control and
      test solutions. ISE method comparisons showed the following: LI=(1.08 x Ciba
      Corning ISE)-0.15 mmol/l, S(y/x)=0.05, r=0.999, and LI=(1.03 x DuPont ISE)+0.00
      mmol/l, S(y/x)=0.06 mmol/l, r=0.999. Comparison of the LI method with the atomic
      absorption and Vitros system showed proportionality error <10%. Bias between the
      LI method and atomic absorption was 7%, substantially less than that documented
      in proficiency surveys for the Vitros and other systems. No lot-to-lot or site-to
      site differences were observed. CONCLUSION: This new photometric method is an
      attractive alternative for Li measurement and is adaptable to instruments having
      spectrophotometric capability.

PMID- 12482632
TI  - Set theory in diagnostic reasoning.
AB  - BACKGROUND: Regarding diagnostic reasoning, the currently taught Bayesian theory
      is a form of hypothetical-deduction reasoning. Using set theory, we offer
      syllogism reasoning instead of hypothetical-deductive reasoning and establish an
      online diagnostic expert system model based on this diagnostic methodology.
      METHODS: Concepts of set theory were employed to demonstrate diagnostic
      reasoning. ASP, Vbscript and Microsoft Access were used to establish the expert
      system and data of 50 cases from Shanghai pulmonary hospital were put into the
      program to test its efficiency. CONCLUSION: Diagnostic procedure is type of
      syllogism rather than hypothetical-deductive reasoning.

PMID- 12482633
TI  - Expression of TIMP-1 in Pichia pastoris. Selection of an anti-TIMP-1 specific
      single-chain Fv antibody from a large non-immune library.
AB  - To quantitate tissue inhibitor of metalloproteinase (TIMP)-1 in biological
      samples, a strategy for isolation of monoclonal antibodies was applied that
      employs a phage-displayed single-chain Fv (scFv). In order to obtain sufficient
      amounts of TIMP-1 to use as an antigen, high-level expression in Pichia pastoris
      was achieved under the control of the AOX-1 promotor. Purified protein antigen
      was then used for panning to achieve enrichment of specific phage from naive scFv
      library. In five subsequent panning rounds, antibody fragments that display
      specificity to TIMP-1 were selected. Regions encoding scFv were subcloned into a
      vector allowing production of scFv-alkaline phosphatase (AP) fusion proteins. Two
      such conjugates displaying dose-dependent reactivity with TIMP-1 were isolated
      and characterised, providing the basis for the construction of a TIMP-1
      quantitation assay based entirely on recombinant proteins.

PMID- 12482634
TI  - Angiotensin II type 1 receptor gene polymorphism and essential hypertension in
      Serbian population.
AB  - Essential hypertension is considered to be a multifactorial trait resulting from
      the combined influence of environmental and genetic determinants. Due to the
      controversial results about the role of the ATR1 gene locus in hypertension and
      understanding that ethnic origin should be carefully considered in studying the
      association between gene polymorphism and disease etiology, we investigated the
      role of A1166C polymorphism in Serbian hypertensives. A total of 298 subjects,
      100 hypertensive and 198 normotensive, age- and sex-matched controls, were
      included in this study. All subjects were genotyped for the A1166C polymorphism
      in ATR1 gene using allele-specific PCR-based technique. There were significant
      differences in both allele and genotype frequencies between hypertensive and
      normotensive male subjects (p<0.05). There is significant association between
      hypertension and CC genotype (CC vs. AC+AA OR=2.56, p=0.04) in the males only.
      These results suggest that a genetic variant of the ATR1 gene locus influences
      the risk of essential hypertension in the sex-specific manner in the Serbian
      population.

PMID- 12482635
TI  - Effect of vitamin C supplementation on reduced glutathione and malondialdehyde in
      patients with acute myocardial infarction.

PMID- 12482636
TI  - Extracellular matrix maturation in the left ventricle of normal and diabetic
      swine.
AB  - The main objective of this study is to determine the transmural distribution of
      extracellular matrix (ECM) collagen and maturation in non-diabetic and diabetic
      hearts. The Yucatan miniature swine heart ECM was analyzed in eight
      streptozotocin (STZ) induced diabetic pigs (Diabetic-Swine) and age matched
      normal control pigs (Nondiabetic-Swine). After 12 weeks of STZ induced diabetes,
      transmural biopsies were obtained from the left ventricular free wall divided
      into subendocardial, mid- and subepicardial layers. Collagen concentration and
      maturation were measured by RP-HPLC determination of hydroxyproline (Hyp) and
      content of hydroxylysylpyridinoline (HP) cross-links, respectively. Results
      showed a significant elevation in arterial glucose (P<0.05) and reduction in
      arterial plasma insulin levels in the Diabetic-Swine. Hyp concentration was
      significantly greater (P<0.05) in the subendocardial layers in both the Diabetic
      and Nondiabetic animals. The HP cross-link content was significantly greater
      (17%) in the Diabetic-swine subendocardial layer compared to Nondiabetic-Swine
      (P<0.05), but not in other layers. In summary, the accumulation and/or increase
      in HP cross-link content in the Diabetic-Swine subendocardial layer suggests that
      myocardial fibrosis may be greater in this specific region.

PMID- 12482637
TI  - Gender difference in vascular and platelet reactivity to thromboxane A(2)-mimetic
      U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive,
      hyperinsulinemic) diabetic rats.
AB  - We examined the hypothesis that gender differences exist in platelet and vascular
      reactivity in type-2 diabetes mellitus, using Zucker fatty diabetic rats of both
      sexes and their lean littermates. Type-2 diabetes is characterized by excessive
      platelet production of TXA(2), which is thrombogenic. Testosterone up-regulates
      platelet TXA(2) receptors and the aggregation response to thromboxane mimetics.
      Conversely, estrogen increases vascular nitric oxide (NO) production and inhibits
      platelet aggregation. Hemodynamic studies were undertaken with the determination
      of dose-response curve for MAP and renal cortical blood flow (RCF) in response to
      U46619, angiotensin-II, phenylephrine and endothelin-1, as well as the systemic
      hemodynamic response to acetylcholine and L-NG nitro-arginine methylester (L
      NAME). Platelet aggregation response was evaluated using whole blood impedance
      aggregometry. There were significant gender differences in the systemic blood
      pressure and RCF response to TXA(2)-mimetic U46619 and angiotensin-II (P<0.02,
      ANOVA) but not to phenylephrine or endothelin-1. Male rats exhibited a
      paradoxical hypotensive response to U46619 (-18+/-11 mmHg) compared with a peak
      pressor response of +6+/-1 mmHg in female rats (P<0.01, ANOVA). The male rats
      exhibited an attenuated systemic vasodilator response (P<0.001, ANOVA) to
      acetylcholine (fall in MAP in male diabetic rats being -24+/-8 mmHg, compared
      with a fall of -50+/-8 mmHg in females), but a greater rise in the renal cortical
      resistance in response to NO inhibition by L-NAME (P<0.03) compared with the
      female rats. Both the slope (46+/-2) and the peak magnitude of the U46619-induced
      whole blood platelet aggregation (13+/-1) ohms were significantly higher (P<0.01,
      ANOVA) in male (n=10) compared with female diabetic rats (n=8) (29+/-0.8 slope,
      10.0+/-0.8 ohms, respectively). Thus, the male diabetic Zucker rats exhibited an
      impaired response to vasoconstrictors (U46619 and angiotensin-II) and to
      endothelial (NO)-mediated vasodilation. The male gender may therefore be
      associated with the greater prothrombotic activity and a worse impairment of
      endothelial reactivity in the type-2 diabetic state.

PMID- 12482639
TI  - Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in the
      Dalmatian population.
AB  - Several studies have found a relationship between polymorphisms of the vitamin D
      receptor gene (VDR) and development of type 1 diabetes (T1DM). The meaning of
      this observation remains unclear and its relevance must be checked in different
      population samples. To examine the association of VDR polymorphisms and
      susceptibility to T1DM in the Dalmatian population of South Croatia we studied
      134 individuals with type 1 diabetes and 132 control subjects. VDR genotyping was
      performed using PCR and BsmI, ApaI and TaqI restriction enzymes. Data were
      analysed using the chi(2)-test. The genotype combination which conferred
      strongest susceptibility to T1DM was BBAAtt (P=0.002). Interestingly, the BAt
      haplotype was found to be a risk factor in a German population, the only European
      population tested thus far. Our results indicate that VDR polymorphisms are
      associated with increased risk of T1DM in the Dalmatian population of South
      Croatia and warrant further studies.

PMID- 12482638
TI  - Role of protein kinase C-angiotensin II pathway for extracellular matrix
      production in cultured human mesangial cells exposed to high glucose levels.
AB  - The intrarenal renin-angiotensin system has been implicated in the pathogenesis
      of diabetic nephropathy. This study investigates the mechanisms for glucose
      induced increase in angiotensin II (AII) production by human mesangial cells
      (MCs) in relation to protein kinase C (PKC). We also examine whether locally
      produced AII mediates extracellular matrix protein production in high-glucose
      conditions. Human MCs were cultured in 5 or 33 mmol/l glucose for 8 days, and
      were incubated with or without 5 mmol/l GFX, a PKC inhibitor, 0.1 micromol/l
      candesartan cilexetil (CC), a specific type 1 AII receptor antagonist, for
      another 24 h. In addition, MCs grown in 5 mmol/l glucose were incubated with 0.1
      micromol/l phorbol-12,13-dibutyrate (PDBu) for 24 h. AII, TGF-beta1, fibronectin
      and type IV collagen in the culture media were measured by ELISA. The amount of
      AII secreted from MCs exposed to high-glucose levels was significantly greater
      (P<0.01) than that in normal glucose levels. The increase in AII production was
      completely prevented by GFX. The addition of PDBu mimicked the effect of glucose
      on AII production. The glucose-induced increases in the production of TGF-beta1,
      fibronectin and type IV collagen were partially, but significantly restored
      (P<0.01) by CC, while GFX totally abolished these effects of glucose. These
      results suggest that elevated glucose levels stimulate AII production via
      mechanisms dependent on glucose-induced PKC activation in human MCs, and that
      locally produced AII partly mediates the increase in mesangial matrix synthesis
      in high-glucose conditions.

PMID- 12482640
TI  - Acarbose in the treatment of elderly patients with type 2 diabetes.
AB  - AIMS: To study the effect of acarbose, an alpha-glucosidase inhibitor, on
      glycemic control in elderly patients with type 2 diabetes. METHODS: Elderly
      patients with type 2 diabetes treated with diet alone were randomly treated in a
      double-blind fashion with placebo (n=99) or acarbose (n=93) for 12 months.
      RESULTS: After 12 months of therapy, there was a statistically significant
      difference in the change in glycated haemoglobin (HbA(1c)) (-0.6%) in the
      acarbose group versus placebo, as well as in the incremental post-prandial
      glucose values (-2.1 mmol h/l) and mean fasting plasma glucose (-0.7 mmol/l).
      Although there was no effect of acarbose on insulin release, there was a clear
      effect of acarbose to decrease relative insulin resistance (-0.8) (HOMA method).
      In addition, acarbose was generally well tolerated and safe in the elderly; most
      discontinuations were due to gastrointestinal side effects such as flatulence and
      diarrhea. There were no cases of hypoglycemia reported, and no clinically
      relevant changes in laboratory abnormalities or vital signs during the study.
      CONCLUSIONS: Acarbose improves the glycemic profile and insulin sensitivity in
      elderly patients with type 2 diabetes who are inadequately controlled on diet
      alone.

PMID- 12482641
TI  - The effect of repaglinide on insulin secretion and oxidative stress in type 2
      diabetic patients.
AB  - The effect of repaglinide on insulin secretion and oxidative stress was evaluated
      in type 2 diabetic patients in a randomized, controlled, open-label trial. Forty
      six patients were treated for 2 months with repaglinide, added to either diet
      (n=21) or metformin (n=25). A control group of 29 patients, matched for age,
      weight and glycaemic control, on either diet (n=13) or metformin (n=16) was also
      followed-up. Phases of insulin secretion (first-FPIS and second-SPIS) ware
      studied during IVGTT. Total serum antioxidant capacity and serum superoxide
      dismutase (SOD) activity were measured to assess oxidative stress. HbA(1c)
      decreased significantly in the repaglinide-treated group (P=0.01), the difference
      being significant compared with the control group (P=0.01). FPIS increased
      significantly after repaglinide (P<0.001). The area under the curve (AUC) for
      FPIS increased significantly (P<0.001), while the AUC for SPIS and for total
      insulin secretion did not change. Insulin secretion remained unchanged after 2
      months in the control group. There was a significant increase after repaglinide
      in total serum antioxidant capacity (P<0.05) and serum SOD activity (P<0.0004);
      the difference compared to the control group being significant (P<0.002). Our
      results demonstrate the physiological effect of repaglinide on endogenous insulin
      secretion in a controlled, randomized, open-label study-there is a rise only in
      FPIS, which is the main beta-cell defect in type 2 diabetes mellitus. This
      improvement in glycaemic control was accompanied by a beneficial effect on
      oxidative stress in diabetes mellitus.

PMID- 12482642
TI  - Prospective study of enteroviral infections and development of beta-cell
      autoimmunity. Diabetes autoimmunity study in the young (DAISY).
AB  - OBJECTIVE: To determine whether there is association between infection with
      enteroviruses and beta-cell autoimmunity in children at elevated risk of
      developing type 1 diabetes. BACKGROUND: Recent prospective and case-control
      studies of children who are at high risk of developing type 1 diabetes have
      suggested that enterovirus (EV) infections are a risk factor for beta-cell
      autoimmunity and type 1 diabetes. METHODS: A nested matched case-control study of
      incident cases of beta-cell autoimmunity within two prospective cohorts of
      genetically high-risk children (cases=26, controls=39). EV infection was detected
      by PCR of serum, saliva and rectal swab samples. RESULTS: Prior to autoimmunity
      conversion (or the equivalent age in controls), 11.5% of cases and 17.9% of
      controls were positive for EV infection. EV was detected in 19.5% of cases and
      25.6% of controls over the whole follow-up period. Conditional logistic
      regression gave no evidence that the frequency of EV infection was associated
      with beta-cell autoimmunity. There was a trend for the mean number of EV
      infections found in EV-positive cases (2.2/case) to be higher than in EV-positive
      controls (1.2/control, P=0.08). However, there were no multiple infections prior
      to conversion in either cases or controls. CONCLUSIONS: There is no evidence from
      this study that EV infection is a risk factor for development of beta-cell
      autoimmunity. Further study is needed to assess whether persistent or repeated EV
      infections occur frequently in individuals with beta-cell autoimmunity.

PMID- 12482643
TI  - Lipoprotein(a) level and lipids in type 2 diabetic patients and their
      normoglycemic first-degree relatives in type 2 diabetic pedigrees.
AB  - We investigated alterations of serum levels of Lp(a) and lipid profiles in type 2
      diabetic patients and their normoglycemic first-degree relatives to evaluate the
      potential genetic association among these subjects. Serum Lp(a), triglycerride
      (TG), total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C), and
      low density lipoprotein (LDL-C) levels were analyzed in 62 type 2 diabetic
      patients and 67 normoglycemic first-degree relatives from 29 type 2 diabetic
      pedigrees, and 45 healthy controls without family histories of diabetes.
      Dyslipidemia was observed in diabetics and their normoglycemic first-degree
      relatives. While higher serum TG levels were observed in both type 2 diabetics
      and their first-degree relatives than those in controls, higher TG levels in
      diabetics were found when compared with those in first-degree relatives.
      Meanwhile, lower serum HDL-C levels were observed in both type 2 diabetic
      patients and their first-degree relatives than those in controls. No significant
      difference of serum TC and LDL-C levels was found among the three groups. On the
      other hand, we did not observe significant differences of serum Lp(a) levels
      between type 2 diabetic patients and normoglycemic first-degree relatives, nor
      were any significant differences observed between diabetic patients and healthy
      controls (24.6+/-19.9 vs. 25.8+/-21.2, and 21.3+/-20.5 mg/dl). Although the
      average serum Lp(a) levels were similar in all subgroups, we did observe a
      positive correlation of Lp(a) between type 2 diabetic patients and their
      offspring (r=0.448, P<0.01), suggesting a potential genetic control for Lp(a)
      levels in type 2 diabetics families.

PMID- 12482644
TI  - Impaired beta-cell function and insulin sensitivity in Japanese subjects with
      normal glucose tolerance.
AB  - The development of type 2 diabetes mellitus is characterized by both impaired
      beta-cell function and increasing insulin resistance. To clarify the roles of
      them in developing type 2 diabetes, we evaluated insulin resistance by HOMA-IR
      and insulin secretion by HOMA beta-cell in 453 Japanese subjects whose fasting
      plasma glucose (FPG) and HbA(1c) levels were within normal range. HOMA beta-cell
      was found to decrease in the over 30 years groups, while HOMA-IR increased with
      body mass index (BMI). To analyze the reserve capacity of insulin secretion and
      insulin sensitivity, the 67 of them, who underwent a standard oral glucose
      tolerance test and were diagnosed with normal glucose tolerance (NGT), were
      divided into four degrees of BMI age-adjusted to 50 years. They were compared for
      insulinogenic index and ISI composite proposed by Matsuda and DeFronzo across the
      range of BMI. ISI composite was significantly less in the highest BMI group,
      while insulin secretion did not increase in the higher BMI groups. The subjects
      with higher BMI had remarkably lower insulinogenic indices than those with lower
      BMI. These data suggest that insulin secretory reserve is insufficient to
      compensate for increased insulin resistance in Japanese people with NGT at about
      50 years of age.

PMID- 12482645
TI  - Evaluation of a single serological screening of dairy herds for Neospora caninum
      antibodies.
AB  - Twenty-one dairy herds with a history of Neospora caninum-associated abortions
      were used for a longitudinal serological study. A total of 1,676 animals were
      blood sampled 3 times and used to evaluate a single serological screening for N.
      caninum antibodies. The results of the first serological screening were compared
      with the results based on three consecutive samples, whereby two or more positive
      or negative test results per animal were considered to determine its serological
      status as positive or negative, respectively. In both test regimes 95.3% of the
      animals had the same interpretation, of which 33.9% were seropositive, and 61.3%
      seronegative. Relative sensitivity of one-time sampling compared to three
      consecutive samplings was 94.7%, while relative specificity was 95.6%. Relative
      specificity differed between herds. Predictive values positive and negative of
      one-time sampling were 92.4 and 97%, respectively. The agreement between one-time
      sampling and three consecutive samplings, kappa, was 0.90. For evaluation of
      discrepant results age distribution and pedigree data were used to provide clues
      regarding likelihood of transmission. Age clustering of seropositive animals was
      interpreted to indicate a point source infection. Daughter-mother relationships
      were used for the interpretation of congenital infections. The proportion of
      congenital infection decreased with increasing parity of the mother. Seropositive
      heifers had 80% congenitally infected offspring, while in older cows 66% of the
      offspring was congenitally infected, possibly due an increased immunity to
      transplacental infection with age. It is concluded that a single serological
      screening of a whole herd in connection with an analysis of age distribution and
      pedigree data is a rapid and valid method to interpret the serologic status of
      individual animals and to study the mode of transmission of N. caninum.

PMID- 12482646
TI  - PCR-RFLP using Ssu-rDNA amplification as an easy method for species-specific
      diagnosis of Trypanosoma species in cattle.
AB  - A single polymerase chain reaction (PCR)-restriction fragment length polymorphism
      (RFLP) assay was used to characterise all important bovine trypanosome species.
      This is the first report of a sensitive pan-trypanosome PCR assay amplifying all
      species including T. vivax to a comparable extent using a single primer pair. A
      semi-nested PCR approach resulted in the detection of one T. congolense
      trypanosome genome/40 microl of blood, applied as buffy coat on filter paper.
      Restriction enzyme analysis using Msp1 and Eco571 gave a clear distinction
      between T. congolense, T. brucei, T. vivax and T. theileri. Several subgroups
      within the T. congolense group could be distinguished but no differences between
      the species belonging to the subgenus Trypanozoon or between T. simiae and T.
      theileri could be found. The use of MboII restriction enzyme allowed
      differentiation between T. simiae and T. theileri. The potential of the essay to
      be used as a suitable diagnostic tool is discussed.

PMID- 12482647
TI  - Dynamics and responsiveness of T-lymphocytes in secondary lymphoid organs of
      rabbits developing immunity to Eimeria intestinalis.
AB  - Primary infection with Eimeria intestinalis confers very effective immunity
      against further infections in rabbits. This study was designed to determine the
      onset of the immune response in primary-infected rabbits and to characterise the
      immune status of protected rabbits. Variations in kinetics of CD4+ and CD8+ T
      cell subpopulations were followed after primary infection at the intestinal sites
      of penetration (duodenum) and development (ileum), in mesenteric lymph nodes
      (MLN) and in the spleen. The response against the parasite was measured by
      specific lymphocyte proliferation in the spleen and MLN and by determining
      specific IgG titres in serum. The mucosal immune response was strong after
      primary infection and was characterised by (i) transient increase in the
      percentages of intestinal CD4+ lymphocytes and MLN CD8+ lymphocytes 14 days PI
      and (ii) strong increase in the percentages of intestinal CD8+ lymphocytes from
      14 days PI persisting throughout further infections. Extensive infiltration of
      the lamina propria with CD8+ lymphocytes was observed 14 days PI. The specific
      proliferative response started between 7 and 14 days PI in MLN but remained
      undetectable in spleens for up to 21 days, in contrast to "immunised" rabbits.
      The fact that systemic immune responses were low after primary infection, in
      contrast to indicators of mucosal immune responsiveness, suggests that protection
      of rabbits against E. intestinalis infection is due to an effective mucosal
      immune response, and that systemic responses that increase after successive
      infections are only reflections of repeated encounters with parasite antigens.

PMID- 12482648
TI  - High prevalence of Giardia detected in cats by PCR.
AB  - Microscopy, PCR and a Giardia CELISA test were used to determine the prevalence
      of Giardia in 40 faecal samples obtained from domestic cats in the Perth
      metropolitan area. A prevalence of 5, 80 and 60% was found by the tests,
      respectively. The results show that more sensitive techniques such as PCR may be
      necessary, and may yield more reliable results, in the detection of low levels of
      Giardia in domestic cats.

PMID- 12482649
TI  - Indirect ELISA for the detection of antibodies against Opisthorchis felineus
      (Rivolta, 1884) and Metorchis bilis (Braun, 1790) in foxes.
AB  - Serological investigations focused on the detection of specific opisthorchiid
      liver fluke antibodies in silver foxes (Vulpes vulpes fulva). Animals were
      experimentally infected with Opisthorchis felineus (nos. 1 and 2) and Metorchis
      bilis (nos. 3-8) by feeding fish with a counted number of metacercariae. Four
      foxes remained as non-infected negative controls (nos. 9-12). For the indirect
      ELISA, an excretory-secretory antigen was produced by in vitro cultivation of O.
      felineus and M. bilis adults isolated from livers of experimentally infected
      hamsters. Immunoglobulin G (IgG) seroconversion against homologous antigen took
      place between weeks 2 and 6 postinfection (p.i.) and foxes remained seropositive
      up to the end of the trial at week 41 p.i. In contrast, IgG titres against
      heterologous antigen remained significantly lower and stayed near the cut-off.
      All infected animals excreted opisthorchiid eggs, starting between weeks 2 and 4
      p.i. The number of liver flukes found at necropsy was relatively low, except in
      one fox that was sacrificed at the week 11 p.i. These results suggest that the
      ELISA is a suitable tool for the detection of specific O. felineus and M. bilis
      antibodies in the fox.

PMID- 12482650
TI  - Amphidial structure of ivermectin-resistant and susceptible laboratory and field
      strains of Haemonchus contortus.
AB  - The development of anthelmintic resistance by nematode parasites is a growing
      problem for veterinarians, pet owners, and producers. The intensive use of the
      macrocyclic lactones for the treatment of a variety of parasitic diseases has
      hastened the development of resistance to this family of parasiticides. As a
      result, resistance to ivermectin, moxidectin, nemadectin, and doramectin by
      Haemonchus contortus has been documented throughout the world. Sensory neurons
      located in the cephalic end of nematodes are in close contact with the external
      environment. Through these neurons, important chemical and thermal cues are
      gathered by the parasite. Examination of serial electron micrographs of
      ivermectin-susceptible and ivermectin-resistant H. contortus allows for
      comparison of neuronal structure, arrangement of neurons within the amphidial
      channel, and distance of the tip of the dendritic processes to the amphidial
      pore. The latter of these characteristics provides a useful means by which to
      compare the association between the neurons and the external environment of the
      worm. Comparison of parental laboratory strains of ivermectin-susceptible strains
      of H. contortus with related selected, ivermectin-resistant strains and with a
      wild-type ivermectin-susceptible field strain of H. contortus from Louisiana
      reveal that the ivermectin-resistant worms examined have markedly shorter sensory
      cilia than their ivermectin-susceptible parental counterparts. Additionally, the
      amphidial neurons of ivermectin-resistant worms are characterized by generalized
      degeneration and loss of detail, whereas other neurons outside of the channels,
      such as the labial and cephalic neurons, are normal in structure. These findings
      raise a number of questions regarding the relationship between amphidial
      structure and ivermectin resistance as well as the role of amphids as a means of
      entry for ivermectin. While shortened amphidial sensilla are associated with
      ivermectin resistance, it remains unclear if such a structural modification
      facilitates survival of nematodes exposed to macrocyclic lactones.

PMID- 12482651
TI  - Chemotherapy of surra in horses and mules with diminazene aceturate.
AB  - During June-July 2000, an outbreak of surra occurred on an equine breeding farm
      in Khonkaen Province, Thailand. Forty-two percent of pregnant mares aborted or
      gave stillbirth and 40% (19/47) of horses and 10% (1/10) of mules died from
      surra. In August 2000 Trypanosoma evansi were detected in the remaining animals
      (28 horses and nine mules) on the farm by blood smear and/or the haematocrit
      centrifuge technique. All animals were treated with diminazene aceturate at 3.5
      mg/kg body weight by intramuscular injection on days 0 and 41 of the study. Blood
      samples of eight randomly selected horses and mules were collected on days 0, 1
      and once a week until day 56 and examined for T. evansi by various
      parasitological techniques. The sera were tested for antibodies against T. evansi
      using an indirect enzyme linked immunosorbent assay (ELISA).The results revealed
      that diminazene aceturate at 3.5 mg/kg appeared to be effective in the first
      treatment of horses and mules infected with T. evansi. Parasites were cleared
      from the peripheral blood of horses on days 1 and 7 and mules on days 1 and 14.
      Thereafter the number of positive animals increased. After the second treatment,
      50% of horses and 25% of mules were still positive to surra 24 h after treatment
      demonstrating that diminazene had no protective effect. Mild to severe toxicity
      of diminazene was seen in the horses and mules after injection.

PMID- 12482652
TI  - Susceptibility to IVM in a field strain of Haemonchus contortus subjected to four
      treatments in a closed sheep-goat flock in Kenya.
AB  - Susceptibility to IVM (IVM) of "strain A" Haemonchus contortus which had been
      exposed to IVM four times over a 2-year period was compared to IVM susceptibility
      of "strain C" H. contortus which had no prior field exposure to IVM, by in vivo
      and in vitro methods. In vivo, the percentage reduction in faecal egg counts
      (FEC) and the total worm counts (TWC) were compared between control animals
      (lambs and kids) and animals treated with low dose IVM (20 microg/kg). In vitro
      susceptibility to IVM was evaluated by larval migration inhibition (LMI) after
      the two strains of H. contortus were exposed to different concentrations of IVM.
      The dose response, measured as the proportion of larvae inhibited from migrating,
      was used to estimate LD(50). Although differences in response to IVM in the in
      vivo determinations were not significant, "strain A" H. contortus had a
      significantly higher LD(50) than "strain C" in the LMI assay. Coincident with the
      conduct of the in vivo experiment, it was observed that "strain A" H. contortus
      established and survived better than "strain C" in the control lambs.

PMID- 12482653
TI  - Reappearance and global spread of variants of influenza B/Victoria/2/87 lineage
      viruses in the 2000-2001 and 2001-2002 seasons.
AB  - Two antigenically and genetically distinct lineages of influenza B viruses,
      represented by the reference strains B/Victoria/2/1987 and B/Yamagata/16/1988,
      have cocirculated in humans since at least 1983. Between 1992 and 2000, Victoria
      lineage viruses were detected only in eastern Asia. From March to September of
      2001 and during the 2001-2002 influenza season, Victoria lineage viruses were
      detected for the first time in a decade in several countries including Canada,
      USA, Italy, Netherlands, Norway, Philippines, India, and Oman. Phylogenetic
      analysis of the hemagglutinin (HA) gene of these viruses revealed that the
      viruses fell into two distinct clades: one group, represented by the reference
      strain B/Hong Kong/330/2001, contained viruses sharing three signature amino
      acids, Arg116, Asn121, and Glu164, while the other group of viruses, represented
      by B/Oman/16296/2001, shared Thr121 compared to the previous reference strain,
      B/Shandong/7/97. A number of the viruses in the latter group have been found to
      be reassortants having a Victoria lineage HA and a Yamagata lineage NA. In the
      current 2001-2002 season, Victoria-like viruses have now been associated with
      outbreaks in Asia, Europe, and North America. The reemergence of these Victoria
      lineage viruses worldwide, the fact that the majority of the B/Victoria-like
      isolates have poor cross-reactivity to B/Sichuan/379/99-like viruses in current
      vaccines, and the lack of exposure of young children in many areas of the world
      to these viruses has resulted in a World Health Organization Northern Hemisphere
      recommendation for the inclusion of a B/Victoria-like strain in vaccines for the
      2002-2003 influenza season.

PMID- 12482654
TI  - Evidence against Ebola virus sGP binding to human neutrophils by a specific
      receptor.
AB  - The issue of whether Ebola secretory glycoprotein (sGP) binds to human
      neutrophils via the IgG Fc receptor IIIb (FcgammaRIIIb, CD16b) or other receptors
      has been controversial. To clarify this, FACS analysis, an sGP absorption assay,
      and direct binding of (125)I-sGP to neutrophils were performed. Results from FACS
      analysis demonstrated that limited washing conditions leads to the nonspecific
      formation of immune complexes on the neutrophil surface and this, but not a
      specific interaction between sGP and CD16b, is responsible for the previous
      observations. An sGP absorption assay also demonstrated that sGP is not
      specifically bound but is nonspecifically proteolysed by proteases released from
      neutrophils. Finally, there was no difference in (125)I-sGP binding to
      neutrophils compared to other control cell types. Taken together, these results
      demonstrate that neutrophils do not express a specific receptor for Ebola virus
      sGP. It is unlikely that sGP plays a role in the Ebola virus pathogenesis through
      interfering with the innate immunity by targeting neutrophils.

PMID- 12482655
TI  - Recovery of paramyxovirus simian virus 5 with a V protein lacking the conserved
      cysteine-rich domain: the multifunctional V protein blocks both interferon-beta
      induction and interferon signaling.
AB  - The V protein of the Paramyxovirus simian virus 5 (SV5) is a multifunctional
      protein containing an N-terminal 164 residue domain that is shared with the P
      protein and a distinct C-terminal domain that is cysteine-rich and which is
      highly conserved among Paramyxoviruses. We report the recovery from Vero cells
      [interferon (IFN) nonproducing cells] of a recombinant SV5 (rSV5) that lacks the
      V protein C-terminal specific domain (rSV5VDeltaC). In Vero cells rSV5VDeltaC
      forms large plaques and grows at a rate and titer similar to those of rSV5. In
      BHK or CV-1 cells rSV5VDeltaC forms small plaques and grows poorly. However, even
      when grown in Vero cells rSV5VDeltaC reverts to pseudo-wild-type virus in four to
      five passages, indicating the importance of the V protein for successful
      replication of SV5. Whereas rSV5 grows in many cell types with minimal cytopathic
      effect (CPE), rSV5VDeltaC causes extensive CPE in the same cell types. To
      overcome the antiviral state induced by IFN, many viruses have evolved mechanisms
      to counteract the effects of IFN by blocking the production of IFN and abrogating
      IFN signaling. Whereas rSV5 blocks IFN signaling by mediating the degradation of
      STAT1, rSV5VDeltaC does not cause the degradation of STAT1 and IFN signaling
      occurs through formation of the ISGF3 transcription complex. Furthermore, we find
      that rSV5 infection of cells prevents production of IFN-beta. The transcription
      factor IRF-3 which is required for transcription of the IFN-beta gene is not
      translocated from the cytoplasm to the nucleus in rSV5-infected cells. In
      contrast, in rSV5VDeltaC-infected cells IRF-3 is localized predominantly in the
      nucleus and IFN-beta is produced. By using ectopic expression of IRF-3, it was
      shown that after dsRNA treatment and expression of the V protein IRF-3 remained
      in the cytoplasm, whereas after dsRNA treatment and expression of the P protein
      (which lacks the C-terminal cysteine-rich domain) IRF-3 was localized
      predominantly in the nucleus. Thus, SV5 blocks two distinct pathways of the
      innate immune response, both of which require the presence of the C-terminal
      specific cysteine-rich domain of the multifunctional SV5 V protein.

PMID- 12482656
TI  - The V proteins of simian virus 5 and other paramyxoviruses inhibit induction of
      interferon-beta.
AB  - In this article we show that the paramyxovirus SV5 is a poor inducer of
      interferon-beta (IFN-beta). This inefficient induction is a consequence of the
      expression of an intact viral V protein. In the absence of the viral V protein
      cysteine-rich C-terminal domain, IFN-beta mRNA is strongly induced and the
      transcription factors NF-kappaB and IRF-3 are activated significantly. The V
      protein can work in isolation from SV5 to block intracellular dsRNA signaling.
      The mechanism of block to dsRNA signaling is distinct from that previously
      observed for blocking IFN signaling in that proteolysis of candidate factors
      cannot be detected, and furthermore, the respective blocks require distinct
      protein domains. Blocking of the induction of IFN-beta by dsRNA requires the C
      terminal cysteine-rich domain, a feature that is highly conserved among
      paramyxoviruses. We demonstrate that the V proteins from other paramyxoviruses
      have equivalent functions and speculate that limiting the yield of IFN-beta
      during infection may be a general property of paramyxoviruses.

PMID- 12482657
TI  - SHIV-KB9 infection of rhesus monkeys does not always cause disease-contribution
      of host immune factors and thymic output.
AB  - Simian-human immunodeficiency virus (SHIV) infection in the macaque is a model of
      HIV pathogenesis. KB9, a molecular clone of SHIV 89.6P, induced rapid and
      profound CD4(+) T cell loss in rhesus monkeys, followed by partial recovery in
      some. We describe another clinical outcome after intravenous SHIV-KB9 inoculation
      in two of six infected rhesus macaques: lack of signs of immunodeficiency with
      sustained CD4(+) T cell counts, despite virus load levels similar to those of the
      animals with CD4(+) lymphocyte decline. To dissect the role of host factors in
      determining pathogenicity of this viral clone, humoral and cellular immune
      responses were studied. Differences in CD8(+) T cell effector responses and
      activation profiles and in thymic output, but not in specific antibody
      production, were observed in animals with different disease outcomes during acute
      infection. Thymic involvement may thus be a critical factor in determining
      disease progression.

PMID- 12482658
TI  - Polypyrimidine-tract-binding protein affects transcription but not translation of
      mouse hepatitis virus RNA.
AB  - Polypyrimidine-tract-binding protein (PTB) has been shown to bind specifically to
      the 5' ends of mouse hepatitis virus (MHV) RNA and its complementary strand. To
      further characterize the function of PTB in MHV replication, we generated
      dominant-negative mutant cell lines that express a full-length PTB or a truncated
      form of PTB, which includes only the N-terminal half of the protein, retaining
      its protein-dimerization domain. The truncated form of PTB was localized in the
      cytoplasm, whereas the full-length PTB was present mainly in the nucleus. The
      truncated form can interact with the full-length PTB in vitro. We observed that
      both the full-length and the truncated PTB, when overexpressed, functioned in a
      dominant-negative manner in MHV replication. However, the truncated form
      exhibited more severe effects on syncytia formation, virus production, and
      synthesis of viral RNA and viral proteins. To clarify the precise function of PTB
      in MHV replication, we dissociated the processes of viral transcription from
      translation by transfecting different types of MHV defective-interfering (DI) RNA
      that contain various reporter genes into these stable cell lines. Transcription
      of the DI RNA during MHV infection was greatly inhibited in these cell lines,
      indicating that PTB modulates MHV transcription. In contrast, translation of the
      DI RNA was not affected by PTB depletion in in vitro translation in rabbit
      reticulocyte lysate or by PTB overexpression in in vivo translation experiments
      in MHV-infected cells. Given that PTB interacts with the viral N protein, which
      is one of the components of the MHV replication complex, PTB may exert its
      function on viral replication/transcription by association with viral RNA as well
      as other viral and cellular factors in the replication complex.

PMID- 12482659
TI  - Interaction of human papillomavirus type 16 L2 with cellular proteins:
      identification of novel nuclear body-associated proteins.
AB  - Two structural proteins form the Papillomavirus (PV) capsids. While the functions
      of the major structural protein L1 are well established, the exact functions for
      the minor structural protein L2 are much less well defined, except for some
      information on a role in viral entry and maturation of infectious virions. To
      gain more insight in the function of L2 we used the yeast two hybrid system with
      the Human Papillomavirus (HPV) 11 L2 and HPV16 L2 as bait proteins to isolate
      putative cellular interaction partners. We identified four proteins interacting
      with L2 proteins of at least two different HPV types and this interaction was
      confirmed in vitro by pull-down assays. Further evidence for this interaction was
      obtained by in vivo localization studies. Two of the proteins, the previously
      described PATZ and a novel protein, designated PLINP, were localized in discrete
      nuclear domains and colocalized with L2. The third protein, designated PMSP, is a
      newly identified cytoplasmic protein which was recruited to nuclear dots when
      coexpressed with L2. The fourth protein interacting with HPV16, 11 and 1 L2, the
      tubular-nephritis antigen related protein (TIN-Ag-RP), shows a cytoplasmic as
      well as a membrane bound subcellular distribution. Taken together, our data
      indicate that L2 of HPVs with different phenotypes interacts with several
      cellular host proteins, recruits one of them to the nucleus, and is complexed
      with at least three cellular proteins in specific nuclear domains. These findings
      suggest an HPV type-independent modulatory function of L2 on host-cell functions
      that involves discrete nuclear domains and alteration of the subcellular
      distribution of cellular proteins. The interacting cellular proteins identified
      may play a role in the viral life cycle and establishment of viral persistence.

PMID- 12482660
TI  - Inducible system in human hepatoma cell lines for hepatitis C virus production.
AB  - We cloned the complete complementary DNA of an isolate of the hepatitis C virus,
      HCV-S1, into a tetracycline-inducible expression vector and stably transfected it
      into two human hepatoma cell lines, Huh7 and HepG2. Twenty-six Huh7 and two HepG2
      positive clones were obtained after preliminary screening. Two Huh7 (SH-7 and -9)
      and one HepG2 (G-19) clones were chosen for further characterisation. Expression
      of HCV proteins in these cells accumulated from 6 h to 4 days posttreatment. Full
      length viral plus-strand RNA was detected by Northern analyses. Using RT-PCR and
      ribonuclease protection assay, we also detected the synthesis of minus-strand HCV
      RNA. Plus- and minus-strand viral RNA was still detected after treatment with
      actinomycin D. Indirect immunofluorescence staining with anti-E2, NS4B, and NS5A
      revealed that these proteins were mostly localised to the endoplasmic reticulum
      (ER). Culture media from tet-induced SH-9 cells was separated on sucrose density
      gradients and analysed for the presence of HCV RNA. Viral RNA levels peaked at
      two separate ranges, one with a buoyant density of 1.08 g/ml and another from
      1.17 to 1.39 g/ml. Electron microscopy demonstrated the presence of subviral-like
      particles (approximately 20-25 nm in diameter) in the cytoplasm of SH-9 and G-19
      cells, which were positively labelled by anti-HCV core antibodies. Anti-E2
      antibodies strongly labelled cytoplasmic vesicular structures and some viral-like
      particles. Complete viral particles of about 50 nm which reacted with anti-E2
      antibodies were observed in the culture media of tet-induced SH-9 cells following
      negative staining. Supernatant from tet-treated SH-9 cells was found to infect
      nai;ve Huh7 and stable Huh7-human CD81 cells.

PMID- 12482661
TI  - DNA-binding activity of the Streptococcus thermophilus phage Sfi21 repressor.
AB  - The cloned Streptococcus thermophilus phage Sfi21 repressor open reading frame
      (orf) 127 gp protects a cell against superinfection with the homologous
      temperate, but not against virulent phages. As demonstrated by DNase protection
      assay and gel shift experiments, the repressor binds to a 25-bp operator site
      located upstream of the repressor gene. A second sequence-related operator was
      identified 265 bp apart at the 3'-end of orf 75, the topological equivalent of a
      cro repressor gene. The replacement of a bp at the middle or at the right side of
      the operator decreased substantially the affinity of the repressor for the
      operator. In gel shift assays, the 75 gp did not bind DNA from the genetic switch
      region. However, when increasing amounts of orf 75 gp containing cell extracts
      were added to orf 127 gp containing cell extracts, the repressor could no longer
      bind its operator site.

PMID- 12482662
TI  - Diversity and evolution of the envelope gene of dengue virus type 1.
AB  - The genetic diversity and phylogenetic relationships of a collection of strains
      of dengue virus type 1 (DV-1), isolated from different parts of the world, were
      investigated. Phylogenetic trees derived from the complete sequence of the E gene
      of 44 strains suggested the existence of five genetic types defined by a maximum
      nucleotide divergence within each group of 6%. The 22 strains from America were
      classified into a single genetic type that included strains associated either
      with classical dengue or hemorrhagic dengue episodes. Using a maximum likelihood
      procedure based on a single rate with dated tips model and substitution rates
      calculated at the third codon position, evolution of the five DV-1 genotypes was
      shown to conform to a molecular clock. The average rate of evolution was
      estimated to be approximately 16.2 x 10(-4) substitutions/third codon position
      site/year. Using this estimate, divergence among the DV-1 genotypes was
      calculated to have occurred approximately 100 years ago. Very low average value
      of the ratio of nonsynonymous-to-synonymous nucleotide substitutions, relative to
      the respective sites (0.046), indicated that the evolution of the E gene of the
      DV-1 is subject mostly to purifying selection.

PMID- 12482663
TI  - Species-specific effects of HIV-1 Nef-mediated MHC-I downmodulation.
AB  - In vitro studies have revealed that human immunodeficiency virus-1 (HIV-1) Nef
      functionally interacts with amino acid residues in the cytoplasmic tail of major
      histocompatibility complex class I (MHC-I) molecules, reducing their expression
      on the cell surface and protecting them from cytotoxic T lymphocyte (CTL) lysis.
      To obtain a better understanding of Nef's effects in vivo, it would be helpful to
      have a mouse model system. However, it is not known whether Nef will affect
      murine MHC-I proteins. We find that Nef downmodulates human MHC-I HLA-A2 more
      efficiently than murine MHC-I molecules in HeLa cells and that Nef does not
      function efficiently in murine endothelial cells. Studies with chimeric molecules
      indicate that the MHC-I cytoplasmic tail is primarily responsible for species
      specific differences. However, there are also effects attributable to the
      extracellular domain.

PMID- 12482664
TI  - Passive transfer of serum antibodies induced by BBG2Na, a subunit vaccine, in the
      elderly protects SCID mouse lungs against respiratory syncytial virus challenge.
AB  - Respiratory syncytial virus (RSV) is responsible for severe low respiratory tract
      infections in young infants and the elderly. To investigate whether BBG2Na, a
      recombinant subunit vaccine comprising aa 130-230 of the RSV G protein, induced
      protective Abs in subjects over 60 years during phase II clinical trial, pre- and
      postimmunization sera of individuals immunized with BBG2Na or placebo were
      transferred into SCID mice before RSV challenge. These sera dose-dependently
      reduced lung RSV titers. However at some points of serial dilutions,
      postimmunization sera of BBG2Na-immunized subjects only were significantly more
      efficient than the corresponding preimmunization sera, in agreement with the
      induction of an increased Ab response against multiple epitopes on RSV-A G
      protein. Thus, BBG2Na is immunogenic in the elderly and confers passive
      protection in mice after serum transfer. To our knowledge, this is the first
      description of protective Abs induced by a subunit vaccine in human.

PMID- 12482665
TI  - Replication of HIV-1 deleted Nef mutants in chronically immune activated human T
      cells.
AB  - Lymphocytes (PBMC) obtained from blood of HIV-sera negative Ethiopian immigrants
      (ETH) were highly susceptible to HIV-1 infection in vitro with no need for
      stimulation by mitogens. As the HIV nef gene product has been shown to enhance
      viral replication in stimulated primary lymphocytes, we investigated in this work
      the role of Nef in viral replication in the ETH cells. Lymphocytes obtained from
      ETH individuals supported high replication of wild-type HIV-1 and low but
      significant replication level of the two deleted Nef mutants (encode truncated
      Nef proteins consisting only of either the first 35 or the first 86 amino acids
      of Nef). In contrast, no replication was observed in nonactivated cells obtained
      from non-ETH individuals. After activation of the PBMC from ETH individuals with
      PHA, replication of both wild-type strains and the two deleted Nef mutant viruses
      further increased. The CD4(+) T cells of ETH individuals exhibited elevated
      levels of the surface activation markers CD45RO and HLA-DR, compared with T cells
      derived from non-ETH group. Likewise, expression of the chemokine receptors CCR5
      and CXCR4 on these cells was higher in the ETH group than in the non-ETH group.
      Replication of HIV-1 wild-type and the isogenic-deleted Nef mutants was
      significantly correlated with the proportion of ETH cells expressing CD45RO and
      the chemokine receptors. This study suggests that HIV-1 may respond differently
      to several activation states characteristic of T cells. One activation state,
      defined by chronically activated lymphocytes from ETH individuals, is permissive
      to the wild-type HIV-1 and, to a lesser degree, to the Nef mutants. Further
      activation of these cells by exogenous stimuli enhances replication of the virus.
      Our results support the notion that Nef enhances the basal level of T cell
      activation and consequently, viral replication.

PMID- 12482666
TI  - Nairobi sheep disease virus, an important tick-borne pathogen of sheep and goats
      in Africa, is also present in Asia.
AB  - Nairobi sheep disease (NSD) virus is the prototype of the tick-borne NSD
      serogroup, genus Nairovirus, family Bunyaviridae. It is highly pathogenic for
      sheep and goats, causes disease in humans, and is widespread throughout East
      Africa. Ganjam virus has caused disease in goats and humans in India. Due to
      their occurrence on different continents and association with different ticks,
      these viruses were considered distinct despite serologic cross-reactivity. Their
      S RNA genome segments and encoded nucleocapsid proteins were found to be 1590
      nucleotides and 482 amino acids in length and differed by only 10 and 3% at
      nucleotide and amino acid levels, respectively. Genetic and serologic data
      demonstrate that Ganjam virus is an Asian variant of NSD virus. These viruses
      were phylogenetically more closely related to Hazara virus than Dugbe virus.

PMID- 12482667
TI  - Deficient dimerization of human immunodeficiency virus type 1 RNA caused by
      mutations of the u5 RNA sequences.
AB  - The human immunodeficiency virus type 1 (HIV-1) virion contains two copies of
      genomic RNA that are noncovalently attached along a region at their 5' ends, in
      which two contact sites have been observed by electron microscopy. One of these
      sites is believed to be the stem-loop 1 (SL1) sequence which serves as the
      dimerization initiation site (DIS), and the other site, closer to the 5' end of
      the viral RNA, may involve the R or U5 RNA sequences. In this study, we present
      biochemical evidence showing that alteration of the U5 RNA sequence in the
      context of full-length viral RNA leads to diminished dimerization of virion RNA.
      In particular, two stretches of GU-rich sequences, which are located at
      nucleotides (nt) 99 to 108 and nt 112 to 123 within U5, were either deleted or
      substituted with exogenous sequences. The mutated viruses thus generated all
      exhibited deficient RNA dimerization. This dimerization deficit was not corrected
      by second-site mutations that preserved local RNA structures, such as the poly(A)
      hairpin, and was overcome to only a limited extent by compensatory mutations
      within Gag; these mutations were identified after long-term culture of the
      relevant mutant viruses in permissive cell lines and were able to restore viral
      infectiousness and RNA packaging to wild-type levels. Therefore, these GU
      sequences do not regulate RNA dimerization by the formation of local secondary
      structures nor by the maintenance of efficient viral RNA packaging; instead, they
      may mediate direct RNA-RNA interactions in the dimer structure. In contrast,
      mutation of palindrome 5'-AAGCUU-3', which resides within R and crowns the
      poly(A) hairpin, did not affect either RNA dimerization or RNA packaging.

PMID- 12482668
TI  - Characterization of a novel human endogenous retrovirus, HERV-H/F, expressed in
      human leukemia cell lines.
AB  - We have identified and characterized a human endogenous retrovirus (HERV) gag
      transcript in the human pre-B cell leukemia line Reh. The transcript was found to
      be a splice product of a structurally intact HERV element located on chromosome
      6q13. Its primer binding site is complementary to phenylalanine (F) tRNA, common
      for the HERV-F family, but the overall genome sequence is closely related to the
      HERV-H family. The retroviral sequence was therefore designated HERV-H/F. The
      HERV element shows a distinct mRNA expression pattern among hematopoietic cancer
      cell lines with expression in some leukemia-derived cell lines of B-lymphoid and
      myeloid origin. No expression was observed in normal human tissues, indicating a
      cancer-specific expression pattern. The 5' long terminal repeat (LTR) was tested
      for promoter activity in HERV-H/F expressing and nonexpressing cell lines. The
      cell specificity of the LTR-mediated reporter gene expression did not
      conclusively correlate with endogenous virus expression, indicating that the
      transcription regulation of this gene is not alone dependent on cell-specific
      activity of transcription factors.

PMID- 12482669
TI  - Signaling pathways triggered by HIV-1 Tat in human monocytes to induce TNF-alpha.
AB  - In this study we investigated the signaling pathways triggered by Tat in human
      monocyte to induce TNF-alpha. In monocytes, the calcium, the PKA, and the PKC
      pathways are highly implicated in the expression of cytokine genes. Thus, these
      three major signaling pathways were investigated. Our data show that (i) PKC and
      calcium pathways are required for TNF-alpha production, whereas the PKA pathway
      seems to be not involved; (ii) downstream from PKC, activation of NFkappaB is
      essential while ERK1/2 MAP kinases, even though activated by Tat, are not
      directly involved in the pathway signaling leading to TNF-alpha production.

PMID- 12482670
TI  - Sequence diversity of the capsid gene and the nonstructural gene NS2B of dengue-3
      virus in vivo.
AB  - Previously, we studied the envelope (E) gene of dengue virus and reported that
      dengue-3 virus is present as a quasispecies. To investigate the extent of
      intrahost sequence variation of other dengue viral genes, we examined in this
      study the capsid (C) gene and the nonstructural gene, NS2B, derived directly from
      plasma dengue viruses from 18 confirmed dengue-3 patients. Using reverse
      transcription-PCR, multiple clones of a 360-nucleotide region covering the C gene
      and of a 404-nucleotide region covering the NS2B gene from each patient were
      completely sequenced and analyzed. Our findings of the intrahost sequence
      variation of the C and the NS2B genes (mean pairwise p-distance: 0.12 to 1.02%,
      and 0.16 to 1.20%, respectively) demonstrate the quasispecies structure of dengue
      virus in vivo. A linear relationship was found between the extent of sequence
      variation of the C and NS2B proteins, suggesting that intrahost sequence
      variation of dengue-3 virus is likely to reflect genetic drift. The extent of
      intrahost sequence variation observed is in the same range as that of acute human
      immunodeficiency virus or hepatitis C virus infection, indicating that the random
      mutation frequency of dengue virus is similar to that of other RNA viruses in
      vivo. Consistent with a previous report of the E gene, the observations of genome
      defective clones in both the C and the NS2B genes (3.9 and 5.0% of the clones,
      respectively) suggest a higher frequency of defective viruses in vivo. These
      findings would add to our understanding of the evolution of dengue-3 virus.

PMID- 12482671
TI  - Persistence of simian varicella virus DNA in CD4(+) and CD8(+) blood mononuclear
      cells for years after intratracheal inoculation of African green monkeys.
AB  - Simian varicella virus (SVV) DNA was detected in blood mononuclear cells (MNCs)
      of adult African green monkeys 7 days to 23 months after intratracheal
      inoculation with 10(3) plaque forming units. Infectious virus was not detected in
      MNCs at 14 months postinfection (p.i.), and electron microscopic (EM) analysis of
      MNCs from two monkeys 21 months p.i. did not reveal virus particles. Real-time
      quantitative PCR analysis of DNA from blood MNCs taken at multiple intervals from
      SVV-infected monkeys M7 and M8 revealed a 10- to 100-fold decrease, but not
      clearance of SVV DNA in MNCs between 11 and 17 months p.i. Thereafter, the SVV
      DNA copy number did not decrease further between 17 and 23 months p.i. PCR
      analysis of MNCs sorted by flow cytometry revealed SVV DNA in T cells (CD4(+),
      CD8(+)) and B cells (CD20(+)), but not in monocyte-macrophages (CD14(+)), 10 days
      p.i. At 11 and 23 months p.i., SVV DNA was found exclusively in CD4(+) and CD8(+)
      T cells. Whether the detection of SVV DNA in CD4(+) and CD8(+) MNCs many months
      after the resolution of acute varicella reflects continued infection of these
      cells that began at the time of acute varicella or represents infection acquired
      by MNCs trafficking through infected tissues is unknown.

PMID- 12482672
TI  - A pregenomic RNA sequence adjacent to DR1 and complementary to epsilon influences
      hepatitis B virus replication efficiency.
AB  - Hepatitis B virus (HBV) possesses a 3.2-kb partially double-stranded DNA genome
      that is generated inside the nucleocapsid by the reverse transcription of the 3.5
      kb pregenomic viral transcript. The initial steps in viral replication involve
      the recognition of an encapsidation signal termed epsilon (epsilon) at the 5'-end
      of the pregenomic RNA by the HBV polymerase. The polymerase-bound pregenomic RNA
      is subsequently incorporated into an immature nucleocapsid particle and minus
      strand HBV DNA synthesis is initiated utilizing the bulge region of epsilon as a
      template and a tyrosine residue in the amino-terminal region of the polymerase as
      a primer. Three nucleotides complementary to the 3'-end of the bulge region of
      epsilon are synthesized and subsequently translocated with the polymerase
      molecule to the acceptor site located in the DR1 sequence present at the 3'-end
      of the pregenomic RNA. Using mutagenesis analysis, a sequence element designated
      phi (phi) located upstream of the 3' DR1 sequence has been identified that is
      complementary to epsilon and is important for efficient viral replication. This
      element may bring the 3' DR1 sequence into proximity with the three nucleotide
      primer synthesized at the bulge of epsilon and facilitate primer translocation to
      the 3' DR1 acceptor sequence. Sequence elements with similar proximity to the 3'
      DR1 sequences and complementarity to epsilon are present in the woodchuck
      hepatitis virus (WHV) and duck hepatitis B virus (DHBV), suggesting the phi
      regulatory element may be phylogenetically conserved due to its functional
      importance in hepadnavirus minus-strand DNA synthesis.

PMID- 12482673
TI  - Experience-dependent changes in dendritic arbor and spine density in neocortex
      vary qualitatively with age and sex.
AB  - Male and female Long-Evans hooded rats were placed in the complex environments
      for 3 months either at weaning (22 days), in young adulthood (120 days), or in
      senescence (24 months). The dendritic morphology of both the apical and basilar
      fields of layer III pyramidal cells was analyzed in both parietal and visual
      cortex. There were two novel results. First, although spine density was increased
      significantly with complex-housing in adulthood, it was decreased significantly
      by the same housing during development. Second, dendritic length was increased in
      both parietal and occipital cortex at all ages in males and was increased in
      adult females as well, but juvenile females showed no change in dendritic length
      in the occipital cortex and only a small effect on the apical field in parietal
      cortex. Thus, there are qualitative differences in the changes in spine density
      at different ages and the dendritic changes in response to complex versus
      isolated housing vary with sex, and in females, the changes vary with age as
      well. These results may explain some of the apparent inconsistencies in reports
      of spine and dendrite changes in the literature.

PMID- 12482674
TI  - Decursin from Angelica gigas mitigates amnesia induced by scopolamine in mice.
AB  - We previously reported that a total methanolic extract of the underground part of
      Angelica gigas Nakai (Umbelliferae) (here-in-after abbreviated AG) significantly
      inhibited acetylcholinesterase (AChE) activity. We characterized 12 coumarin
      derivatives including both decursin and decursinol from extracts of AG. In this
      study, we evaluated the anti-amnestic activity of decursin, a major coumarin
      constituent isolated from AG, in vivo using ICR mice with amnesia induced by
      scopolamine (1 mg/kg body weight, s.c.). Decursin, when administered to mice at 1
      and 5 mg/kg body weight i.p., significantly ameliorated scopolamine-induced
      amnesia as measured in both the passive avoidance test and the Morris water maze
      test. Moreover, decursin significantly inhibited AChE activity by 34% in the
      hippocampus of treated mice. These results indicate that decursin may exert anti
      amnestic activity in vivo through inhibition of AChE activity in the hippocampus.

PMID- 12482675
TI  - Ontogenetic dissociation between habit learning and recognition memory in
      capuchin monkeys (Cebus apella).
AB  - The performance of young and adult capuchin monkeys (Cebus apella) on a
      Concurrent Discrimination Learning (CDL) test and a Delayed Non-Matching to
      Sample (DNMS) task were investigated. Results indicate that all subjects were
      able to learn the CDL test with 20-pairs simultaneously and retain this
      stimulus/reward association within 24-h interval. In contrast, young subjects did
      not perform the DNMS task with the same proficiency as adults. While adults'
      scores were above chance across all memory test delays, the young capuchin
      monkeys performed the test by chance level. These results support the hypothesis
      that these two tasks require different cognitive processes mediated by two
      independent neural systems with a differentiated ontogenetic development.
      Moreover, they provide evidence that this dissociation occurs not only in humans
      and Old World monkeys but also in the New World capuchin monkeys indicating that
      this species can be a valuable alternative model for investigations of the
      neurobiological basis of memory.

PMID- 12482676
TI  - Discriminative taste aversion learning: a learning task for older chickens.
AB  - The study of learning and memory using the chicken model has relied on three
      learning paradigms, passive avoidance learning, imprinting and the pebble floor
      task. Passive avoidance learning and imprinting have been used predominantly in
      very young chickens and cannot be used to access learning and memory in older
      chickens. We have established a new behavioural learning paradigm, Discriminative
      Taste Aversion Learning (DTAL), that can be used with both young and older
      animals. The task requires chickens to discriminate between food crumbs dyed
      either red or yellow with one colour being associated with the aversive tasting
      substance, methylanthranilate. Learning can be tested at various times after the
      training session by presenting chickens with the coloured food crumbs without an
      aversive taste. Both chickens tested at 5 and 15 days post-hatch learned to avoid
      the aversive crumbs. Furthermore, the protein synthesis inhibitor anisomycin (30
      mM; 10 microl per hemisphere) injected into the intermediate medial hyperstriatum
      ventrale 15 min pre-training or 45 min post-training blocked long-term memory for
      the DTAL task when tested 24 h later. Memory for the task was unaffected by
      anisomycin injection 120 min post-training or in control animals injected with
      saline at similar times. The timing of the cellular processes of protein
      synthesis needed for consolidation of the DTAL appears to be similar to those
      described for the other behavioural paradigms in young chickens.

PMID- 12482677
TI  - Sex differences in spatial and non-spatial Y-maze performance after chronic
      stress.
AB  - Chronic restraint is known to alter hippocampal CA3 dendritic morphology and
      spatial memory in male rats. The present study examined whether female rats,
      which exhibit different anatomical adaptations to chronic stress than those of
      males, would also show spatial memory impairments. Male and female Sprague-Dawley
      rats were restrained for 6 h/day for 21 days, a time frame previously
      demonstrated to cause hippocampal CA3 dendritic atrophy. The day after the last
      restraint session, rats were tested on a Y-maze, a habituation task that can be
      used to assess spatial memory. Chronic stress impaired Y-maze performance in both
      sexes without affecting levels of locomotion as measured by total arm entries in
      the first minute. However, Y-maze performance of stressed females improved in 2-5
      min when chronically stressed males continued to show poor Y-maze performance.
      The enhanced Y-maze performance of chronically stressed females occurred when
      total arm entries were higher compared to the entries made by males. Therefore,
      correlations were performed between total arm entries and spatial memory in 1 and
      2-5 min. In the first minute when control females demonstrated functional spatial
      memory, female controls with the lowest locomotor levels exhibited the best
      performance. The correlations for stressed females were not significant, and
      neither were the correlations for any group in 2-5 min. Overall, these results
      show important sex differences in response to chronic stress with females
      exhibiting an ability to recover quickly from deficits in Y-maze performance.

PMID- 12482678
TI  - Rapidly learned song-discrimination without behavioral reinforcement in adult
      male zebra finches (Taeniopygia guttata).
AB  - Zebra finches communicate via several distinct vocalizations, of which song is
      the most studied. Behavioral observations indicate that adults are able to
      discriminate among the songs of different conspecific individuals. In the wild,
      zebra finches live in structured but mobile colonies, and encounter new
      individuals on a frequent basis. Thus it seems plausible that adult finches might
      have the capacity to recognize and remember new songs they encounter on a single
      day, but this has never been directly tested. Here we devised a simple
      observational assay to determine whether adult male zebra finches show
      recognition of a song they have heard repeatedly from taped playbacks, over a
      single three hour period the day before. We quantified the rate of production of
      six discrete behaviors (short calls, contact calls, singing, short hops, long
      hops, and beak swipes) made by adult male zebra finches as they listened to the
      playbacks. At the onset of song playback, all birds suspended these behaviors and
      sat silently-occasionally moving their heads. Then, after a measurable period
      ("response latency"), the birds resumed these activities. We observed that the
      response latency was long (approximately 10 min) when birds were hearing a
      particular song for the first time. The response latency was much shorter
      (approximately 1-2 min) when the birds had heard the same song the day before.
      Thus, functional song memories must result from as little as 3 h of passive song
      exposure. These results suggest that ongoing song learning may play a natural
      role in the daily life of adult zebra finches, and provide a behavioral reference
      point for studies of molecular and physiological plasticity in the adult auditory
      system.

PMID- 12482679
TI  - Exposure to novelty enhances retrieval of very remote memory in rats.
AB  - Rats were trained in a one-trial step-down inhibitory avoidance task at the age
      of 3 months and tested for retention 1 day later, or 3, 6, 9, 12, 15, and 19
      months later, i.e., when the animals were 3, 6, 9, 12, 15, 18, or 22 months of
      age. Retrieval performance declined with time and was undetectable in the last
      two age groups. Exposure to an unrelated novel environment (a square box lined
      with black plastic) 1 h before retention testing enhanced retrieval at all ages,
      regardless of the decline in the level of test session performance. The effect
      cannot be explained by an anxiogenic effect of the novelty box, or by an
      influence of novelty on locomotion or exploration, or by a nonspecific influence
      of exposure to novelty on step-down latency in the inhibitory avoidance
      apparatus.

PMID- 12482680
TI  - Exposure to a retrieval cue in rats induces changes in regional brain glucose
      metabolism in the amygdala and other related brain structures.
AB  - Pre-test exposure to training-related cues is known to improve subsequent
      retention performance. To identify brain regions engaged in processes promoted by
      retrieval cues, a brain imaging approach using the [6-14C]glucose
      autoradiographic technique was used. Sprague-Dawley rats trained in a brightness
      discrimination avoidance task were submitted to different cueing conditions after
      a 1- or a 21-day training-to-test interval (TTI). Animals were either non-cued,
      cued with a box, or cued with a box and the light that served as a discriminative
      stimulus. Effects of the different cueing conditions on retention performance or
      on metabolic activity in 58 different brain regions were investigated. Rats cued
      with the light exhibited a subsequent improvement of their retention performance
      relative to controls, when tested at the 1- but not 21-days TTI, confirming our
      previous results. At the 1-day retention interval, a comparison between rats cued
      with the box and rats cued with the box and the light showed that the light cue
      significantly increased glucose uptake in a neuronal network composed of the
      lateral, basal, and central nuclei of the amygdala, the anterior and
      suprachiasmatic hypothalamic nuclei, the nucleus accumbens, the medial septum,
      and the insular cortex. In contrast, at the 21-day retention interval, both
      groups demonstrated similar cerebral metabolic activity. The present results
      indicate that exposure to a light cue increased metabolic activity in the
      previously mentioned brain structures only when the light acted as an effective
      retrieval cue, suggesting an involvement of this network in the processes
      triggered by a retrieval cue. Arguments are provided supporting the notion that
      the amygdala may play a key role in these processes. Whether the amygdala is a
      part of a neural network involved in retrieval processes or in neuromodulating
      systems that favour the efficacy of retrieval processes is also discussed.

PMID- 12482681
TI  - Estrogen treatment alleviates NMDA-antagonist induced hippocampal LTP blockade
      and cognitive deficits in ovariectomized mice.
AB  - Estrogen is implicated in hippocampus-dependent spatial learning as well as
      structural organization and electrophysiological properties of the rat
      hippocampus but little is known about its mechanisms of action in mice. In this
      study, we investigated pharmacologically whether estrogen interacts with the
      hippocampal N-methyl-D-aspartate (NMDA) receptors in ovariectomized mice as
      postulated for rats. Female C57BL/6J mice were ovariectomized at 5 months, and 2
      weeks before testing at 12 months, half of them received subcutaneous estrogen
      pellets containing 0.18 mg of 17 beta-estradiol. The competitive NMDA-antagonist,
      3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), was
      administered at 5.0 and 10.0 microM to block induction of long-term potentiation
      (LTP) in the hippocampal slice and intraperitoneally at 0.5, 2.0, and 5.0 mg/kg
      to impair spatial learning in the water maze. Estrogen treatment shifted the dose
      response curve to CPP in both experiments. First, 10 microM CPP blocked the
      initiation of LTP in all mice, but 5 microM only in ovariectomized non-estrogen
      treated mice. Second, final level of acquisition and probe trial performance in
      the water maze were less affected by high doses of CPP in the estrogen-treated
      ovariectomized mice than in non-treated group. In control tests for motor side
      effects, estrogen treatment did not reduce the tendency of CPP to decrease
      locomotor activity in the open field and impair balance on a rotating rod, and
      estrogen by itself decreased swimming speed as did CPP, but these effects did not
      interact. Our findings support the notion that estrogen treatment increases the
      number of active NMDA-receptors in the mouse hippocampus.

PMID- 12482682
TI  - Sex-related impairment of memory for emotional events with beta-adrenergic
      blockade.
AB  - On the basis of recent evidence indicating a sex-related lateralization of
      amygdala function in memory for emotional events, together with substantial
      evidence suggesting hemispheric specialization in processing global (central)
      versus local (detail) aspects of a situation, and the established dependence of
      the amygdala's memory modulating function on beta-adrenergic receptor activation,
      we predicted differential effects of a beta-adrenergic receptor antagonist
      (propranolol) on long-term memory for an emotionally arousing story in men and
      women. Specifically, we predicted that, relative to placebo, propranolol would
      impair memory for information central to the story line, but not memory for
      peripheral story details in men. Conversely, propranolol would impair memory for
      peripheral details, but not for central information in women. Here we confirm
      this prediction with a novel analysis of data from our two published studies of
      propranolol's effect on memory for an emotionally arousing story. These findings
      demonstrate a sex-related impairment of memory for emotional information by beta
      adrenergic blockade. Additionally, they provide support for the hypothesis that,
      in this paradigm, emotional arousal enhances long-term memory for central
      information in men via activation of right amygdala/hemisphere function, and
      enhances long-term memory for peripheral details in women via activation of left
      amygdala/hemisphere function.

PMID- 12482683
TI  - Electrolytic, but not neurotoxic, lesions to the lateral tegmental tract increase
      acoustic startle amplitude and reduce startle stimulus-induced freezing.
AB  - Startle amplitude and startle stimulus-induced freezing (an index of fear) were
      measured in a standard acoustic startle response (ASR) paradigm in male Sprague
      Dawley rats. Groups with electrolytic lesions to the lateral tegmental tract
      (LTG) or with axon-sparing lesions to the area around LTG made with the
      neurotoxin NMDA were compared with vehicle-injected or sham operated control
      groups on these response measures. Replicating previous results (Leaton &
      Brucato, 2001), electrolytic lesions to LTG significantly reduced freezing and
      produced a persistent 300% increase in ASR amplitude compared with all other
      groups. The NMDA lesions had no effect on freezing or on ASR amplitude compared
      with the controls. In additional testing the rats with electrolytic lesions to
      LTG did not differ from controls in the acquisition or retention of context
      freezing using a footshock unconditioned stimulus. The data made a small, but
      necessary, step in further clarifying two pathways that modify ASR. The source of
      the descending pathway that provides tonic inhibition of the sensory input to the
      ASR circuitry is not within the LTG. The ascending pathway that carries the fear
      inducing dimensions of the acoustic stimulus to the amygdala by way of the medial
      geniculate nucleus does not have an intermediate synapse in the area within LTG.

PMID- 12482684
TI  - NR2B downregulation in a forebrain region required for avian vocal learning is
      not sufficient to close the sensitive period for song learning.
AB  - The neural changes that limit the sensitive period for avian song development are
      unknown, but neurons in a forebrain region critical for song learning, the lMAN,
      exhibit experience-driven changes in NMDAR subunit expression that could regulate
      sensitive period closure. Specifically, NR2B levels in lMAN decrease during song
      acquisition, potentially reducing synaptic plasticity by decreasing NMDAR EPSC
      duration and/or affecting NMDAR-coupled intracellular cascades. While rearing
      birds in isolation extends the sensitive period and also delays the developmental
      changes in NR2B expression and NMDAR physiology, recent work indicates that a
      transition to faster NMDAR currents does not preclude further song learning.
      However, NR2B mRNA expression in isolates remains elevated beyond the age at
      which NMDAR currents shorten, leaving open the possibility that NR2B levels
      regulate closure of the sensitive period through effects other than those
      mediated by NMDAR current duration. To determine whether the experience-driven
      decrease in NR2B expression in lMAN closes the sensitive period, we promoted this
      change in gene expression either by treating isolation-reared zebra finches
      briefly with testosterone (T-isolates) or by allowing males limited access to
      conspecific song (pre-exposed isolates). We then assessed if these birds could
      acquire song from tutors after the normal close of the sensitive period. Despite
      a normal decline in NR2B expression, T-isolate and pre-exposed isolate birds
      learned tutor songs heard from d65-90, while normally reared birds did not. These
      findings suggest that the normal decline in NR2B expression with lMAN is not
      sufficient for sensitive period closure.

PMID- 12482685
TI  - Does the radial arm maze necessarily test spatial memory?
AB  - Since its design 25 years ago (Olton & Samuelson, 1976), the eight-arm radial
      maze has become very popular and is now widely used to assess spatial memory in
      rodents. Two versions of the full-baited maze protocol are present in the
      literature: with or without confinement between the visit of each arm. The
      confinement was introduced by Olton himself as early as 1977 (Olton, Collison, &
      Werz, 1977) to eliminate stereotypic behaviors that he had previously observed.
      It is widely regarded that the confinement prevents rodents from developing these
      response patterns, and as such it is considered an improved procedure to test
      spatial memory. Surprisingly, to the best of our knowledge, no study has been
      especially designed to demonstrate the efficacy of the confinement in blocking
      the stereotypic behaviors of the animals. The present study compares the
      strategies of rats trained with or without a confinement procedure. The results
      show that, after nine days of training, rats submitted to a 5- or a 10-s
      confinement reach the same level of performance as rats without confinement. The
      confinement totally prevents stereotypic behaviors like clockwise serial
      searching strategies which are often observed without confinement. Even a 0-s
      confinement is sufficient to prevent clockwise strategies, but rats seem to
      develop other stratagems which do not imply spatial memory. Furthermore, rats
      previously trained without confinement are unable to perform the task when
      confinement is introduced on a test day. In contrast, rats previously trained
      with confinement perform the task correctly when the confinement is no longer
      present. Thus, without confinement, good levels of performance can be achieved
      without precise spatial representations.

PMID- 12482686
TI  - The role of the amygdala in conditioned flavor preference.
AB  - Long-Evans rats with control or amygdala lesions were tested in a conditioned
      flavor preference task. Half of the rats in each lesion group received an
      unsweetened grape-flavored solution on odd-numbered days and a sweetened cherry
      flavored solution on even-numbered days. The remaining rats received a sweetened
      grape-flavored solution on odd-numbered days and an unsweetened cherry-flavored
      solution on even-numbered days. The appropriate solution was presented once a day
      for 15 min to each rat in the homecage. After six days of testing, each rat
      received unsweetened cherry and grape flavored solutions simultaneously for 15
      min daily across four days. When the two unsweetened flavored solutions were
      presented simultaneously control rats showed a significant preference for the
      flavor that was sweetened during training compared to the unsweetened solution.
      However, amygdala-lesioned rats did not show a preference. The data suggest that
      the amygdala may be critically involved in mediating reward-based conditioned
      flavor preference.

PMID- 12482687
TI  - Modulation of taste-induced Elk-1 activation by identified neurotransmitter
      systems in the insular cortex of the behaving rat.
AB  - Taste consumption activates the extracellular responsive kinases 1-2 (ERK1-2) and
      the transcription factor Elk-1 in the insular cortex (IC) of the behaving rat.
      ERKs activation, an obligatory step for the encoding of long- but not short-term
      memory, was shown to be regulated by multiple neurotransmitter systems in the IC.
      Here I show, by the use of local microinfusions of pharmacological agents into
      the IC of the behaving rat, that a set of similar systems is required for the
      taste-induced activation of Elk-1. N-Methyl-D-aspartate (NMDA), glutamate
      metabotropic (mGlu), ionotropic AMPA/kainate (AMPA), muscarinic, and dopaminergic
      receptors, which all contribute to the acquisition of taste memory, are also
      responsible for Elk-1 activation. However, blockade of the beta-adrenergic
      transmission does not affect Elk-1 activation. I also show that the basal level
      of Elk-1 activation in cortex is mainly maintained by GABAergic transmission.
      Thus, the formation of taste memory triggers the activation of Elk-1 in the IC of
      the behaving rat via selected neurotransmitter and neuromodulatory systems.

PMID- 12482688
TI  - Application of REDOR subtraction for filtered MAS observation of labeled backbone
      carbons of membrane-bound fusion peptides.
AB  - Clean MAS observation of 13C-labeled carbons in membrane-bound HIV-1 and
      influenza fusion peptides was made by using a rotational-echo double-resonance
      spectroscopy (REDOR) filter of directly bonded 13C-15N pairs. The clean filtering
      achieved with the REDOR approach is superior to filtering done with sample
      difference spectroscopy. In one labeling approach, the peptide had labels at a
      single 13C carbonyl and its directly bonded 15N. The resulting chemical shift
      distribution of the filtered signal is used to assess the distribution of local
      secondary structures at the labeled carbonyl. For the influenza peptide, the Leu
      2 carbonyl chemical shift distribution is shown to vary markedly with lipid and
      detergent composition, as well as peptide:lipid ratio, suggesting that the local
      peptide structure also has a strong dependence on these factors. Because most
      carboxylic- and amino-labeled amino acids are commercially available, this REDOR
      approach should have broad applicability to chemically synthesized peptides as
      well as bacterially synthesized proteins. In a second labeling approach, the HIV
      1 fusion peptide had U-13C, 15N labeling over three sequential residues. When a
      1.6 ms REDOR dephasing time is used, only backbone 13C signals are observed. The
      resulting spectra are used to determine spectral linewidths and to assess
      feasibility of assignment of uniformly labeled peptide.

PMID- 12482691
TI  - Magnesium chloride: an efficient 13C NMR relaxation agent for amino acids and
      some carboxylic acids.
AB  - A series of amino acids and carboxylic acids were determined by 13C NMR
      spectroscopy. The results showed that addition of 3 M MgCl(2), led to shortening
      of relaxation time and 13C NMR integral area of samples was well proportional to
      the number of carbon atoms with reliability more than 95%. So MgCl(2) is proposed
      as an efficient relaxation agent for analysis of amino acids and some carboxylic
      acids.

PMID- 12482692
TI  - 3D HSQC-HSQMBC--increasing the resolution of long-range proton-carbon correlation
      experiments.
AB  - A 3D HSQC-HSQMBC experiment is proposed for increasing the separation of proton
      carbon long-range correlation cross peaks, the lack of which is occasionally seen
      in corresponding 2D experiments. It is aimed at complex molecules with many
      protonated carbons exhibiting a narrow spread of 13C chemical shifts e.g.,
      complex carbohydrates. It does not yield long-range correlation of quaternary
      carbons. An extra indirectly detected 1H dimension of this experiment provides
      additional separation of long-range correlation cross peaks by utilising the
      chemical shifts of protons directly attached to 13C. Evolution of single-quantum
      coherences throughout the entire pulse sequence ensures that the cross peaks are
      inphase pure absorption singlets in both indirectly detected dimensions, thus
      maximising the resolution and sensitivity of the experiment. Partial signal
      cancellation can be expected due to the antiphase character of peaks in the
      directly detected dimension. The intensity of cross peaks depends on the length
      of a single long-range evolution interval and values of both active and passive
      long-range coupling constants of each carbon. The 3D HSQC-HSQMBC experiment
      provided high quality long-range correlation spectra of a 2 mg pentasaccharide
      sample in 27 h. The technique can also be used for measurement of long-range
      heteronuclear coupling constants from pure antiphase multiplets in the directly
      detected dimension.

PMID- 12482693
TI  - Automated correction of unwanted phase jumps in reference signals which corrupt
      MRSI spectra after eddy current correction.
AB  - A commonly applied step in the postprocessing of gradient localized proton MR
      spectroscopy, is correction for eddy current effects using the water signal as a
      reference. However, this method can degrade some of the metabolite signals, in
      particular if applied on proton MR spectroscopic imaging data. This artifact
      arises from the water reference signal in the presence of a second signal which
      resonates close to the main water resonance. The interference of both resonances
      will introduce jumps in the phase of the reference time domain signal. Using this
      phase for eddy current correction will result in a ringing artifact in the
      frequency domain of the metabolite signal over the whole frequency range. We
      propose a moving window correction algorithm, which screens the phase of
      reference signals and removes phase jumps in time domain caused by interference
      of signals from multiple spin systems. The phase jumps may be abrupt or gradually
      distributed over several time data points. Because the correction algorithm only
      corrects time data points which contain phase jumps, the phase is minimally
      disrupted. Furthermore, the algorithm is automated for large datasets, correcting
      only those water reference signals which are corrupted. After correction of the
      corrupted reference signals, normal eddy current correction may be performed. The
      algorithm is compared with a method which uses a low-pass filter and tested on
      simulated data as well as on in vivo proton spectroscopic imaging data from a
      healthy volunteer and from patients with a brain tumor.

PMID- 12482694
TI  - Device for aeration and mixing of cell and organelle suspensions during NMR
      experiments.
AB  - A device for aeration and mixing of cell or organelle suspensions in a vertical
      bore NMR magnet is described. Multiple external sensors (e.g., ion-selective
      electrodes) may be immersed in the suspension within the bore of the magnet. The
      sensors are positioned to avoid noise due to contact with gas bubbles and
      proximity to the probe head. The required sample volume is minimised. The modular
      design of components permits the use of the device in magnets of various internal
      dimensions, or with probe heads of different sample tube diameter, by
      modification of the simpler components of the assembly.

PMID- 12482696
TI  - The effect of Hartmann-Hahn mismatching on polarization inversion spin exchange
      at the magic angle.
AB  - The effect of the Hartmann-Hahn mismatch delta = omega(eff)-omega(1S) during
      polarization inversion spin exchange at the magic angle (PISEMA) has been
      investigated, where omega(eff) and omega(1S) represent the amplitudes of the 1H
      effective spin-locking field at the magic angle and the 15N RF spin-locking
      field, respectively. During the PISEMA evolution period, the exact Hartmann-Hahn
      match condition (i.e., delta = 0) yields a maximum dipolar scaling factor of
      0.816 for PISEMA experiments, while any mismatch results in two different
      effective fields for the first and second half of each frequency switched Lee
      Goldburg (FSLG) cycle. The mismatch effect on the scaling factor depends strongly
      on the transition angle from one effective field to the other within each FSLG
      cycle as well as on the cycle time. At low RF spin-lock amplitudes in which the
      FSLG cycle time is relatively long, the scaling factor rapidly becomes smaller as
      omega(1S) becomes greater than omega(eff). On the other hand, when omega(1S) <
      omega(eff), there is relatively little effect on the scaling factor with
      variation in delta. As a result, the presence of RF inhomogeneities may
      significantly broaden the line-width in the dipolar dimension because of the
      mismatch effect. Higher RF spin-lock amplitudes result in a relatively small
      variation for the scaling factor. Furthermore, ramped amplitude of the 15N RF
      spin-lock field in synchronization with the flip-flop of the FSLG sequence
      minimizes the transition angle between the two effective fields within the FSLG
      cycle. It is shown experimentally that such a ramped amplitude not only gives
      rise to the same scaling factor but also results in a narrower dipolar line-width
      in comparison with the rectangular amplitude.

PMID- 12482697
TI  - High capacity production of >65% spin polarized xenon-129 for NMR spectroscopy
      and imaging.
AB  - A rubidium spin exchange optical pumping system for high capacity production of
      >65% spin polarized 129Xe gas is described. This system is based on a fiber
      coupled multiple laser diode array capable of producing an unprecedented 210 W of
      circularly polarized light at the pumping cell with a laser line width of 1.6 nm.
      The 129Xe nuclear spin polarization is measured as a function of flow rate,
      pumping cell pressure, and laser power for varying pumping gas compositions. A
      maximum 129Xe nuclear polarization of 67% was achieved using a 0.6% Xe mixture at
      a Xe flow rate of 2.45 sccm. The ability to generate 12% polarized 129Xe at rates
      in excess of 1L-atm/h is also demonstrated. To achieve production of 129Xe gas at
      even higher polarization will rely on further optimization of the pumping cell
      and laser beam geometries in order to mitigate problems associated with
      temperature gradients that are encountered at high laser power and Rb density.

PMID- 12482698
TI  - Euclidian distance-weighted smoothing for quantitative MRI: application to
      intervoxel anisotropy index mapping with DTI.
AB  - During the computation of intervoxel anisotropy features, the inclusion of both
      eigenvalues and eigenvectors reduces the effect of noise, but spatial averaging
      blurs the resulting maps. We propose a new adaptive technique that uses data
      dependent weights in the averaging process so that the influence of each neighbor
      in the local window is proportional to the similarity of characteristics of the
      neighbor considered to those of the reference central voxel. This likeness
      criterion is based on the multidimensional Euclidian distance using the entire
      available multispectral information contained in the diffusion-weighted images.
      This solution is controlled by a single parameter beta that results from a
      compromise between edge-preserving and noise-smoothing abilities. This Euclidian
      distance-weighted technique is a generic solution for filtering noise during
      parametric reconstruction. It was applied to map anisotropy using an intervoxel
      lattice index (LI) from experimental images of mouse brain in vivo and achieves
      noise reduction without distorting small anatomical structures. We also show how
      to employ in the discrimination scheme the images not used in the estimation of
      the considered feature.

PMID- 12482700
TI  - Electron spin-lattice relaxation in radicals containing two methyl groups,
      generated by gamma-irradiation of polycrystalline solids.
AB  - The effects of methyl rotation on electron spin-lattice relaxation times were
      examined by pulsed electron paramagnetic resonance for the major radicals in
      gamma-irradiated polycrystalline alpha-amino isobutyric acid, dimethyl-malonic
      acid, and L-valine. The dominant radical is the same in irradiated dimethyl
      malonic acid and alpha-amino isobutyric acid. Continuous wave saturation recovery
      was measured between 10 and 295 K at S-band and X-band. Inversion recovery, echo
      detected saturation recovery, and pulsed electron-electron double resonance
      (ELDOR) data were obtained between 77 and 295 K. For the radicals in the three
      solids, recovery time constants measured by the various techniques were not the
      same, because spectral diffusion processes contribute differently for each
      measurement. Hyperfine splitting due to the protons of two methyl groups is
      resolved in the EPR spectra for each of the samples. Pulsed ELDOR data were
      obtained to characterize the spectral diffusion processes that transfer
      magnetization between hyperfine lines. Time constants were obtained for electron
      spin-lattice relaxation (T(1e)), nuclear spin relaxation (T(1n)), cross
      relaxation (T(x1)), and spin diffusion (T(s)). Between 77 and 295 K rapid cross
      relaxation (deltaM(s) = +/- 1, deltaM(I) = -/+ 1) was observed for each sample,
      which is attributed to methyl rotation at a rate that is approximately equal to
      the electron Larmor frequency. The large temperature range over which cross
      relaxation was observed suggests that methyl groups in the radical and in the
      lattice, with different activation energies for rotation, contribute to the rapid
      cross-relaxation. Activation energies for methyl and amino group rotation between
      160 and 1900 K (1.3-16 kJ/mol) were obtained by analysis of the temperature
      dependence of 1/T(1e) at S-band and X-band in the temperature intervals where the
      dynamic process dominates T(1e).

PMID- 12482702
TI  - Quantification of B0 homogeneity variation with head pitch by registered three
      dimensional field mapping.
AB  - In this study, we quantify the extent to which B(0) homogeneity in adult humans
      is dependent on head pitch relative to the B(0) vector. Three-dimensional, whole
      brain B(0) field maps were acquired in five normal subjects for three generalized
      head pitch angles. Optimal first- and second-order shimming of the experimental
      B(0) maps were simulated numerically. The spatial B(0) distribution within the
      brain was analyzed following automated volumetric co-registration of all data.
      Increasing head pitch improves both the resonance offset and local homogeneity in
      the inferior frontal lobes, but introduces inhomogeneities in other regions of
      the brain which cannot be compensated by first-order shimming but are further
      improved by second-order shimming.

PMID- 12482703
TI  - Reciprocity and sensitivity of opposed-solenoid endovascular MRI probes.
AB  - Several forms of catheter-mounted "inside-out" probes for endovascular imaging
      have been proposed in the literature. The "opposed-solenoid" structure has been
      studied in relatively little detail, although it has some potential advantages
      over the others. Using a small water sample as a voxel, we measure point by point
      the spatial variation of the sensitivity and the rf field strength of such a
      probe, and connect the two by the reciprocity relation. By itself, the
      corresponding plot provides a nice example of the reciprocity relation at work;
      and for the characterization of the probe it gives a check on data quality. The
      results can be understood from simple considerations and agree well with the
      sensitivity observed in the image of a phantom.

PMID- 12482706
TI  - Enhanced spectral resolution in immobilized peptides and proteins by combining
      chemical shift sum and difference spectroscopy.
AB  - A two-dimensional correlation experiment is introduced that records the sum and
      difference chemical shift of two scalar or dipolar coupled nuclei. Statistical
      results indicate that the suggested pulse scheme can significantly increase the
      possibility of separating chemical shift contributions due to residue type and
      backbone conformation in immobilized peptides and proteins. Experimental
      applications demonstrate the theoretical concept and lead to the predicted
      resolution enhancement between different amino acid types and among protein
      residues of different secondary structure.

PMID- 12482707
TI  - Early steps in the formation of neural tissue in ascidian embryos.
AB  - Ascidians are simple invertebrate chordates whose lineage diverged from that of
      vertebrates at the base of the chordate tree. Their larvae display a typical
      chordate body plan, but are composed of a remarkably small number of cells.
      Ascidians develop with an invariant cell lineage, and their embryos can be easily
      experimentally manipulated during the cleavage stages. Their larval nervous
      system is organised in a similar way as in vertebrates but is composed of less
      than 130 neurones and around 230 glial cells. This remarkable simplicity offers
      an opportunity to understand, at the cellular and molecular levels, the ontogeny
      and function of each neural cell. Here, we first review the organisation of the
      ascidian nervous system and its lineage. We then focus on the current
      understanding of the processes of neural specification and patterning before and
      during gastrulation. We discuss these advances in the context of what is
      currently known in vertebrates.

PMID- 12482709
TI  - A novel invertebrate trophic factor related to invertebrate neurotrophins is
      involved in planarian body regional survival and asexual reproduction.
AB  - Trophic factors are a heterogeneous group of molecules that promote cell growth
      and survival. In freshwater planarians, the small secreted protein TCEN49 is
      linked to the regional maintenance of the planarian central body region. To
      investigate its function in vivo, we performed loss-of-function and gain-of
      function experiments by RNA interference and by the implantation of microbeads
      soaked in TCEN49, respectively. We show that TCEN49 behaves as a trophic factor
      involved in central body region neuron survival. In planarian tail regenerates,
      tcen49 expression inhibition by double-stranded RNA interference causes extensive
      apoptosis in various cell types, including nerve cells. This phenotype is rescued
      by the implantation of microbeads soaked in TCEN49 after RNA interference. On the
      other hand, in organisms committed to asexual reproduction, both tcen49 mRNA and
      its protein are detected not only in the central body region but also in the
      posterior region, expanding from cells close to the ventral nerve chords. In some
      cases, the implantation of microbeads soaked in TCEN49 in the posterior body
      region drives organisms to reproduce asexually, and the inhibition of tcen49
      expression obstructs this process, suggesting a link between the central nervous
      system, TCEN49, regional induction, and asexual reproduction. Finally, the
      distribution of TCEN49 cysteine and tyrosine residues also points to a common
      evolutionary origin for TCEN49 and molluscan neurotrophins.

PMID- 12482708
TI  - SHP-2 mediates target-regulated axonal termination and NGF-dependent neurite
      growth in sympathetic neurons.
AB  - The tyrosine phosphatase SHP-2 has been implicated in a variety of signaling
      pathways, including those mediated by neurotrophins in neurons. To examine the
      role of SHP-2 in the development of sympathetic neurons, we inhibited the
      function of SHP-2 in transgenic mice by overexpressing a catalytically inactive
      SHP-2 mutant under the control of the human dopamine beta-hydroxylase promoter.
      Expression of mutant SHP-2 did not influence the survival, axon initiation, or
      pathfinding abilities of the sympathetic neurons. However, mutant SHP-2
      expression resulted in an overproduction of sympathetic fibers in sympathetic
      target organs. This was due to interference with SHP-2 function, as
      overexpression of wild type SHP-2 had no such effect. In vitro, NGF-dependent
      neurite growth was inhibited in neurons expressing mutant SHP-2 but not in those
      expressing wild type SHP-2. Mutant (but not wt) SHP-2 expression also inhibited
      NGF-stimulated ERK activation. The NGF-dependent survival pathway was less
      affected than the neurite growth pathway. Our results suggest that NGF-regulated
      axon growth signals, and to a lesser degree survival signals, are mediated
      through a SHP-2-dependent pathway in sympathetic neurons. The increased
      sympathetic innervation in target tissues of neurons expressing mutant SHP-2 may
      result from interference with normal "stop" signals dependent on signaling by
      gradients of NGF.

PMID- 12482710
TI  - Caenorhabditis elegans cog-1 locus encodes GTX/Nkx6.1 homeodomain proteins and
      regulates multiple aspects of reproductive system development.
AB  - The development of the reproductive system in Caenorhabditis elegans is a well
      established model system for patterning and organogenesis. We report the
      characterization of the cog-1 gene, mutations in which cause novel phenotypes in
      late patterning in vulval lineages, establishment of the vulva-uterine
      connection, development and function of the spermathecal-uterine junction, and
      the development of vas deferens-proctodeal connection in the male. We
      positionally cloned cog-1 and found that it encodes a homeobox protein most
      similar to the mammalian GTX and Nkx6.1 proteins. Analysis of cog-1 transcripts
      revealed that cog-1 is likely a complex locus with two promoters. Two mutant
      alleles of cog-1 differentially affect alternative transcripts and cause
      different phenotypes, suggesting that the two forms of cog-1 have distinct
      functions in C. elegans.

PMID- 12482711
TI  - Ray-interray interactions during fin regeneration of Danio rerio.
AB  - Teleost fin ray bifurcations are characteristic of each ray in each fin of the
      fishes. Control of the positioning of such morphological markers is not well
      understood. We present evidence suggesting that the interray blastema is
      necessary for a proper bifurcation of each ray during regeneration in Danio rerio
      (Hamilton-Buchanan) (Cyprinidae, Teleostei). We performed single ray ablations,
      heterotopical graftings of ray fragments and small holes in lateral rays which do
      not normally bifurcate, to generate recombinants in which the lateral rays are
      surrounded with ectopic interrays originating from different positions within the
      tail fin. These ray-interray recombinants do now bifurcate. Furthermore, we show
      that the interray tissue and surrounding epidermis can modulate the length of the
      ray. These results stress the role of the interray in inducing bifurcations of
      the ray blastema as well as modulating ray morphogenesis in general. In addition,
      gene expression analysis under these experimental conditions suggests that msxA
      and msxD expression in the ray and interray epidermis is controlled by the ray
      blastema and that bmp4 could be a candidate signal involved in these inductions.

PMID- 12482713
TI  - Migration of zebrafish spinal motor nerves into the periphery requires multiple
      myotome-derived cues.
AB  - In vertebrate embryos, spinal motor neurons project through segmentally
      reiterated nerves into the somites. Here, we report that zebrafish secondary
      motor neurons, which are similar to motor neurons in birds and mammals, depend on
      myotomal cues to navigate into the periphery. We show that the absence of
      myotomal adaxial cells in you-too/gli2 embryos severely impairs secondary motor
      axonal pathfinding, including their ability to project into the somites.
      Moreover, in diwanka mutant embryos, in which adaxial cells are present but fail
      to produce cues essential for primary motor growth cones to pioneer into the
      somites, secondary motor axons display similar pathfinding defects. The
      similarities between the axonal defects in you-too/gli2 and diwanka mutant
      embryos strongly suggest that pathfinding of secondary motor axons depends on
      myotome-derived cues, and that the diwanka gene is a likely candidate to produce
      or encode such a cue. Our experiments also demonstrate that diwanka plays a
      central role in the migration of primary and secondary motor neurons, suggesting
      that both neural populations share mechanisms underlying axonal pathfinding. In
      summary, we provide compelling evidence that myotomal cells produce multiple
      signals to initiate and control the migration of spinal nerve axons into the
      somites.

PMID- 12482714
TI  - Dlx5 is a positive regulator of chondrocyte differentiation during endochondral
      ossification.
AB  - The process of endochondral ossification in which the bones of the limb are
      formed after generation of cartilage models is dependent on a precisely regulated
      program of chondrocyte maturation. Here, we show that the homeobox-containing
      gene Dlx5 is expressed at the onset of chondrocyte maturation during the
      conversion of immature proliferating chondrocytes into postmitotic hypertrophying
      chondrocytes, a critical step in the maturation process. Moreover, retroviral
      misexpression of Dlx5 during differentiation of the skeletal elements of the
      chick limb in vivo results in the formation of severely shortened skeletal
      elements that contain excessive numbers of hypertrophying chondrocytes which
      extend into ectopic regions, including sites normally occupied by immature
      chondrocytes. The expansion in the extent of hypertrophic maturation detectable
      histologically is accompanied by expanded and upregulated domains of expression
      of molecular markers of chondrocyte maturation, particularly type X collagen and
      osteopontin, and by expansion of mineralized cartilage matrix, which is
      characteristic of terminal hypertrophic differentiation. Furthermore, Dlx5
      misexpression markedly reduces chondrocyte proliferation concomitant with
      promoting hypertrophic maturation. Taken together, these results indicate that
      Dlx5 is a positive regulator of chondrocyte maturation and suggest that it
      regulates the process at least in part by promoting conversion of immature
      proliferating chondrocytes into hypertrophying chondrocytes. Retroviral
      misexpression of Dlx5 also enhances formation of periosteal bone, which is
      derived from the Dlx5-expressing perichondrium that surrounds the diaphyses of
      the cartilage models. This suggests that Dlx5 may be involved in regulating
      osteoblast differentiation, as well as chondrocyte maturation, during
      endochondral ossification.

PMID- 12482712
TI  - Transcriptional integration of competence modulated by mutual repression
      generates cell-type specificity within the cardiogenic mesoderm.
AB  - The way in which spatially patterned cellular identities are generated is a
      central question of organogenesis. In the case of Drosophila heart formation, the
      cardiac progenitors are specified in precise mesodermal positions, giving rise to
      multiple cell types in a highly ordered arrangement. Here, we study the
      mechanisms by which positional information conveyed by signaling pathways and a
      combinatorial code of activating and repressing transcription factors work
      together to confine the expression of the homeobox gene even-skipped (eve) to a
      small region of the dorsal mesoderm. By manipulating both expression patterns and
      binding sites for transcription factors, we show that a complex combination of
      regulatory activities converge on a single enhancer of eve to generate precisely
      targeted gene expression within the cardiac mesoderm. In particular, ladybird
      early (lbe), a homeobox gene expressed adjacent to eve, restricts the positive
      actions of factors downstream of wingless, decapentaplegic, and ras to generate
      the eve pattern. Mutation of a Lbe binding site causes dramatic expansion of
      expression and abolishes the responsiveness to repression by lbe. Conversely,
      eliminating eve in the mesoderm expands lbe expression into the normal eve
      expressing territory, suggesting that mutual repression between eve and lbe is
      essential for delineating the spatial patterns of gene expression that specify
      cell types within the cardiac mesoderm.

PMID- 12482715
TI  - Discrimination of the roles of MPF and MAP kinase in morphological changes that
      occur during oocyte maturation.
AB  - Maturing amphibian oocytes undergo drastic morphological changes, including
      germinal vesicle breakdown (GVBD), chromosome condensation, and spindle formation
      in response to progesterone. Two kinases, maturation-promoting factor (MPF) and
      mitogen-activated protein kinase (MAPK), are involved in these changes, but their
      precise roles are unknown. Unlike in Xenopus oocytes, discrimination of the
      functions of MAPK and MPF in Rana oocytes is easy owing to the lack of pre-MPF.
      We investigated the roles of these kinases by careful observations of chromosomes
      and microtubules in Rana oocytes. MPF and MAPK activities were manipulated by
      treatment with progesterone, c-mos mRNA, or cyclin B mRNA in combination with
      MAPK kinase inhibitors. Activation of one kinase without activation of the other
      induced only limited events; GVBD was induced by MPF without MAPK, and
      reorganization of microtubules at GVBD was induced by MAPK without MPF, but other
      events were not induced. In contrast, coactivation of MPF and MAPK by injection
      of c-mos and cyclin B mRNA promoted almost all of the morphological changes that
      occur during maturation without progesterone, indicating that these are
      controlled by cooperation of MPF and MAPK. The results revealed the functions of
      MAPK and MPF in each process of sequential morphological changes during oocyte
      maturation.

PMID- 12482716
TI  - Auto/cross-regulation of Hoxb3 expression in posterior hindbrain and spinal cord.
AB  - The complex and dynamic pattern of Hoxb3 expression in the developing hindbrain
      and the associated neural crest of mouse embryos is controlled by three separate
      cis-regulatory elements: element I (region A), element IIIa, and the r5 enhancer
      (element IVa). We have examined the cis-regulatory element IIIa by transgenic and
      mutational analysis to determine the upstream trans-acting factors and mechanisms
      that are involved in controlling the expression of the mouse Hoxb3 gene in the
      anterior spinal cord and hindbrain up to the r5/r6 boundary, as well as the
      associated neural crest which migrate to the third and posterior branchial arches
      and to the gut. By deletion analysis, we have identified the sequence
      requirements within a 482-bp element III482. Two Hox binding sites are identified
      in element III482 and we have shown that in vitro both Hoxb3 and Hoxb4 proteins
      can interact with these Hox binding sites, suggesting that auto/cross-regulation
      is required for establishing the expression of Hoxb3 in the neural tube domain.
      Interestingly, we have identified a novel GCCAGGC sequence motif within element
      III482, which is also required to direct gene expression to a subset of the
      expression domains except for rhombomere 6 and the associated neural crest
      migrating to the third and posterior branchial arches. Element III482 can direct
      a higher level of reporter gene expression in r6, which led us to investigate
      whether kreisler is involved in regulating Hoxb3 expression in r6 through this
      element. However, our transgenic and mutational analysis has demonstrated that,
      although kreisler binding sites are present, they are not required for the
      establishment or maintenance of reporter gene expression in r6. Our results have
      provided evidence that the expression of Hoxb3 in the neural tube up to the r5/r6
      boundary is auto/cross-regulated by Hox genes and expression of Hoxb3 in r6 does
      not require kreisler.

PMID- 12482717
TI  - The origin of mesoderm in phoronids.
AB  - Descriptive studies of phoronid development have concluded that the mesoderm of
      these animals originates from the endoderm during gastrulation. This
      interpretation has been tested by labeling one blastomere of 4- through 16-cell
      embryos and examining the position and germ layers occupied by the labeled clones
      of cells in the larva. No 2 injections gave rise to identical clones of cells,
      suggesting that the cleavage program does not generate cells of unique identity
      and that cell fates are established at later developmental time points. In many
      cases, a relatively large sector composed of ectodermal cells was labeled. When
      these labeled cells were adjacent to the mouth or anus of the larva, muscle and
      mesenchyme cells originated from the labeled clones. Under these circumstances,
      nerve cells also originated from these labeled sectors. These labeling studies
      also showed that endodermal cells can give rise to mesodermal and neural cells.
      These results suggest that nerve and muscle cells are induced to form at
      ectodermal-endodermal boundaries from both germ layers. These marking experiments
      also confirmed the observation that nerve cells originate both from the apical
      organ and the trunk region and show for the first time that the intestine
      originates by ingression of posterior ectoderm.

PMID- 12482718
TI  - Neuronal differentiation from postmitotic precursors in the ciliary ganglion.
AB  - In the chick ciliary ganglion, neuronal number is kept constant between St. 29
      and St. 34 (E6-E8) despite a large amount of cell death. Here, we characterize
      the source of neurogenic cells in the ganglion as undifferentiated neural crest
      derived cells. At St. 29, neurons and nonneuronal cells in the ciliary ganglion
      expressed the neural crest markers HNK-1 and p75(NTR). Over 50% of the cells were
      neurons at St. 29; of the nonneuronal cells, a small population expressed glial
      markers, whereas the majority was undifferentiated. When placed in culture,
      nonneuronal cells acquired immunoreactivity for HuD, suggesting that they had
      commenced neuronal differentiation. The newly differentiated neurons arose from
      precursors that did not incorporate bromodeoxyuridine. To test whether these
      precursors could undergo neural differentiation in vivo, purified nonneuronal
      cells from St. 29 quail ganglia were transplanted into chick embryos at St. 9-14.
      Subsequently, quail cells expressing neuronal markers were found in the chick
      ciliary ganglion. The existence of this precursor pool was transient because
      nonneuronal cells isolated from St. 38 ganglia failed to form neurons. Since all
      ciliary ganglion neurons are born prior to St. 29, these results demonstrate that
      there are postmitotic neural crest-derived precursors in the developing ciliary
      ganglion that can differentiate into neurons in the appropriate environment.

PMID- 12482721
TI  - Gastrointestinal neuropharmacology: identification of therapeutic targets.

PMID- 12482722
TI  - Intrinsic nerve circuits of the gastrointestinal tract: identification of drug
      targets.
AB  - Advances in understanding the pathophysiological role of neurotransmitters and
      neurotransmitter receptors that are expressed by neurons of the intrinsic
      circuits of the intestine will aid the selection of new drug targets for
      therapeutic compounds. The major components of the intrinsic circuits for
      motility, secretion and blood flow control in the small and large intestines have
      been identified in recent years, although the intrinsic circuits in the stomach
      are still not adequately determined. In the guinea-pig small intestine, where
      circuits have been most accurately defined, there are 14 functionally identified
      neuron types, each with a characterised pharmacology of transmission.

PMID- 12482723
TI  - Pharmacology of synaptic transmission in the enteric nervous system.
AB  - Recent data indicate that there are multiple mechanisms mediating fast and slow
      synaptic excitation in the enteric nervous system. However, these data also
      suggest that both the neurotransmitters and the receptors mediating fast and slow
      synaptic transmission in the myenteric plexus are organized in a polarity-
      (ascending versus descending) and pathway- (excitatory versus inhibitory)
      specific manner.

PMID- 12482724
TI  - Pharmacology of transmission to gastrointestinal muscle.
AB  - The identity of excitatory and inhibitory neurotransmitters is well established.
      Excitatory motor neurons synthesize and release acetylcholine and tachykinins,
      which act through postjunctional muscarinic M2 and M3 or tachykinin NK1 and NK2
      receptors, respectively, to induce smooth muscle contraction. A residual
      excitatory component is mediated by ATP acting on P2X1 receptors. Conversely,
      inhibitory motor neurons express nitric oxide synthase and vasoactive intestinal
      peptide (VIP), which together with ATP, induce a coordinated muscle relaxation.
      The receptors involved in the inhibitory effects of ATP and VIP are unknown.
      Likewise, the relationships between inhibitory signals triggered by NO and those
      mediated by VIP need to be clarified. Recent evidence obtained using receptor
      knockout mice have confirmed the involvement of the above-mentioned excitatory
      transmitters but have revealed an unexpected complexity in the nitrergic
      transmission, where the effects of NO are manifested only in the presence of
      carbon monoxide. Interstitial cells of Cajal (ICC) are being recognized as
      targets of intestinal motor neurons; therefore, the signaling mechanisms are
      probably integrated by these cells before being transmitted to smooth muscle.
      Challenges in future years will be to identify the physiological role of the
      various excitatory and inhibitory components, and to understand the relative
      importance of neurotransmitter receptors expressed on ICC and smooth muscle
      cells.

PMID- 12482726
TI  - Abdominal vagal afferent neurones: an important target for the treatment of
      gastrointestinal dysfunction.
AB  - Vagal afferents are extensively distributed in the digestive tract from the
      oesophagus to the colon. They are involved in the reflex control of normal
      gastrointestinal (GI) tract function (e.g. secretion and motility) as well as
      reflexes more characteristic of diseases such as functional dyspepsia and
      gastroesophageal reflux disease (e.g. vomiting, disordered lower esophageal
      sphincter relaxation and gastric accommodation). They are also implicated in
      signalling non-painful sensations (e.g. nausea and early satiety) associated with
      disease. A variety of receptors has been identified on vagal afferents, which can
      either enhance (e.g. 5-HT3, CCK1, VR1 and NK1 receptors) or reduce (e.g. ghrelin,
      leptin, k-opioid and GABAB receptors) activity, offering a range of potential
      therapeutic targets. Commonly used laboratory species (e.g. rat and mouse) lack
      an emetic reflex, and the implications of this for models of upper GI disorders
      have been explored in the light of expanding knowledge of the neuropharmacology
      of the emetic reflex implicating glutamate, prostanoids, cannabinoids and
      substance P. Additional pathophysiological roles for vagal afferents (e.g. in
      thermoregulation, arousal and fatigue) are being investigated, raising the
      intriguing possibility of the vagus as a target in non-GI disorders.

PMID- 12482725
TI  - The pharmacology of gastrointestinal nociceptive pathways.
AB  - The principal conscious sensations that arise from the gastrointestinal tract are
      discomfort and pain. Chronic visceral discomfort and pain are generally managed
      poorly with currently available pharmacological agents. Receptors and ion
      channels present on extrinsic visceral primary afferent (sensory) neurons are
      targets for the development of new pharmacological strategies for control of
      visceral pain.

PMID- 12482727
TI  - Controlling the excitability of IPANs: a possible route to therapeutics.
AB  - Recent studies have shown that intrinsic primary afferent neurons (IPANs) express
      a much larger range of ionic currents than non-sensory neurons of the enteric
      nervous system. These ionic currents can be modulated by neurotransmitters that
      are synaptically released onto the soma (unlike cranial and spinal sensory
      neurons). The membrane receptors and ionic channels that are involved in the
      sensory transduction processes of IPANS are beginning to be defined. IPANS can
      move between a large range of excitability states that are influenced by
      neurotransmitters and hormones. An additional cause of variability in
      excitability is the actions of inflammatory mediators. It is becoming apparent
      that the variation in excitability of IPANS might play a critical role in
      determining the physiological state of the intestine.

PMID- 12482728
TI  - Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract.
AB  - Recent identification of novel appetite-regulating hormones has revealed the
      complex interactions between these humoral factors in the regulation of feeding
      behavior in mammals. One such hormone is ghrelin, which is a natural ligand of
      the orphan growth hormone secretagogue receptor. Ghrelin was first purified from
      rat stomach and is able to stimulate growth hormone release from pituitary cells.
      Ghrelin is a peptide of 28 amino acids, in which Ser3 is modified by an n
      octanoic acid. This modification is essential for the activity of ghrelin. The
      peptide regulates food intake by acting on the hypothalamic arcuate nucleus,
      which is a region known to control food intake. Thus, gastric ghrelin is an
      endogenous regulator of feeding behavior that is found in both peripheral tissues
      and the central nervous system.

PMID- 12482729
TI  - Neuroimmune and epithelial interactions in intestinal inflammation.
AB  - The gastrointestinal tract contains the most extensive immune system in the body
      as well as the largest and most diverse collection of nerves outside of the
      central nervous system. These systems are continuously involved in ongoing
      physiological activities of the bowel and they play an active role in
      pathophysiological processes. It is becoming increasingly clear that intestinal
      inflammation involves a dynamic interplay between at least three different cell
      systems: immune cells, neurons and mucosal epithelial cells. A wide array of
      signalling molecules, including cytokines, neurotransmitters and neurotrophic
      factors mediate the exchange of information between these cells. Neuroimmune
      epithelial interactions that take place in the wall of the gut explain many of
      pathophysiological features of intestinal inflammation.

PMID- 12482730
TI  - Drugs targeting functional bowel disorders: insights from animal studies.
AB  - Increased understanding of gastrointestinal pathophysiology in functional bowel
      disorders is leading to improved focus on relevant enteric, vagal and spinal
      afferent nervous systems, and targets operating on these systems. These targets
      include receptors for tachykinins, motilin, ghrelin, corticotropin-releasing
      factor and somatostatin.

PMID- 12482732
TI  - Pharmacotherapeutics and the endocrine system: blocking, replacing and exploiting
      nature's magic bullets.

PMID- 12482731
TI  - Drugs targeting functional bowel disorders: lessons from drug trials.
AB  - Recent insights in the field of functional gastrointestinal disorders have opened
      the way for novel pharmacological treatments directed at the central nervous
      system or peripheral targets. Now, universally accepted guidelines on therapeutic
      trial design and in the conduct and reporting of results of large clinical trials
      in these functional disorders are required. Several lessons have been learned
      from recent clinical and pharmacological trials of novel agents in irritable
      bowel syndrome and diabetic dyspepsia. Approaches that carefully characterize the
      pharmacokinetics, mechanism of action and pharmacodynamics of a drug, and that
      select subgroups of patients after a thorough understanding of the drug's
      effects, should facilitate and enhance the likelihood of accurate assessment of
      potential therapies.

PMID- 12482733
TI  - Parathyroid hormone as a therapeutic agent.
AB  - Recent advances in the use of parathyroid hormone as a therapeutic agent include
      a controlled trial that assessed vertebral and non-vertebral fracture risk
      reduction in women, trials in men, and assessment of treatment on cortical and
      trabecular bone structure. The occurrence of osteosarcoma in long-term toxicology
      studies in rats is briefly reviewed.

PMID- 12482734
TI  - Anabolic strategies in critical illness.
AB  - Critical illness precipitates a marked catabolic response, with protein wasting
      and loss of lean body mass. Prolongation of this response leads to impaired
      immunity, poor wound healing, loss of intestinal barrier function and muscle
      weakness, thereby increasing morbidity and perhaps mortality. Conventional
      nutritional support only partially ameliorates this process. Disappointingly,
      specific anabolic and anticatabolic strategies have so far met with only limited
      success, although recent findings, in particular studies demonstrating the
      potential value of aggressive insulin therapy and the administration of growth
      hormone secretagogues, have been encouraging.

PMID- 12482735
TI  - Implantable closed-loop glucose-sensing and insulin delivery: the future for
      insulin pump therapy.
AB  - Although subcutaneous insulin infusion from portable pumps is the current optimal
      therapy for type 1 diabetic patients, implantable pumps using the intraperitoneal
      route allow increased blood glucose stability and lowered incidence of severe
      hypoglycemia. Subcutaneously implanted enzymatic glucose sensors provide
      continuous interstitial glucose monitoring, but this may differ from the real
      time blood glucose levels. Preliminary investigations of intravascular enzymatic
      sensors demonstrate their clinical acceptability and accuracy and the possibility
      of developing closed-loop insulin delivery by combination with implantable pumps.

PMID- 12482736
TI  - Dissatisfaction with thyroxine therapy - could the patients be right?
AB  - In some patients with hypothyroidism, symptoms of ill health persist despite
      thyroxine treatment. It is unclear whether this arises from comorbidity or
      because standard thyroxine replacement is in some way inadequate for some
      individuals. Some patients feel better if they take a slightly excessive dose of
      thyroxine, but this carries a potential risk of adverse cardiac and skeletal
      effects. There are conflicting data on whether combined
      thyroxine/triiodothyronine treatment is preferable to thyroxine alone in
      dissatisfied patients.

PMID- 12482737
TI  - Glucocorticoid resistance - what is known?
AB  - It has become apparent in recent years that the glucocorticoid receptor is not a
      simple on/off switch, but instead orchestrates subtle and complex interactions
      between large numbers of proteins. This more sophisticated understanding awaits a
      unifying concept that will explain mechanisms of glucocorticoid resistance and
      allow new approaches to enhancing sensitivity.

PMID- 12482738
TI  - The future of growth hormone antagonists.
AB  - Pegvisomant is the only available member of a new class of drugs: the growth
      hormone receptor antagonists. It has a proven efficacy in antagonising the
      effects of growth hormone in acromegalic patients that is better than any of the
      currently available treatment modalities. Its safety profile looks encouraging,
      although more long-term safety data are needed. Potential indications for
      pegvisomant in diabetology and oncology again looks very promising, but the
      optimism is almost entirely built upon favourable data from pre-clinical studies,
      whereas data from human studies are not yet available.

PMID- 12482739
TI  - Calcimimetics: therapeutic potential in hyperparathyroidism.
AB  - Calcium homeostasis is essential for the normal function of many organ systems.
      The recently cloned extracellular calcium-sensing receptor plays a central role
      in this process and thus represents an important target for therapeutic agents
      aimed at treating disorders of calcium metabolism. Compounds, such as the
      phenylalkylamines NPS 568 and AMG 073, act as agonists of calcium at this
      receptor. These calcimimetic agents hold promise as potential treatments for
      diseases of parathyroid hyperfunction, such as primary and secondary
      hyperparathyroidism.

PMID- 12482740
TI  - Treatment of orthostatic hypotension.
AB  - Orthostatic hypotension (OH) is a fall in blood pressure after assuming an
      upright position. Whereas asymptomatic patients usually need no treatment, the
      majority of symptomatic patients can be cured by avoidance of trigger mechanisms
      and the use of physical countermaneuvers and non-pharmacological interventions.
      Several pharmacological therapies are available and generally fludrocortisone and
      midodrine are the drugs of first choice. Recently, highly individualized therapy
      with ambulatory norepinephrine therapy was able to mobilize otherwise immobile
      patients.

PMID- 12482741
TI  - New uses of bisphosphonates: osteogenesis imperfecta.
AB  - Osteogenesis imperfecta is a heterogeneous group of inherited disorders chiefly
      affecting type I collagen, resulting in bone fragility responsible for a host of
      recurrent fractures. Limb and spine deformities, growth failure and restricted
      mobility are the end-result in severe cases. Cyclical intermittent intravenous
      infusions of pamidronate, a potent inhibitor of bone resorption, have yielded
      substantial improvement in chronic pain, bone mineral density, fracture rate and
      mobility without significant side effects. The role of growth hormone and bone
      marrow transplantation in the treatment of osteogenesis imperfecta is still
      unresolved. Newer, theoretically more potent bisphosphonates are currently being
      tested in this potentially crippling condition.

PMID- 12482742
TI  - Molecular mechanisms involved in the regulation of the endothelial nitric oxide
      synthase.
AB  - The endothelial nitric oxide synthase (eNOS), the expression of which is
      regulated by a range of transcriptional and posttranscriptional mechanisms,
      generates nitric oxide (NO) in response to a number of stimuli. The
      physiologically most important determinants for the continuous generation of NO
      and thus the regulation of local blood flow are fluid shear stress and pulsatile
      stretch. Although eNOS activity is coupled to changes in endothelial cell Ca(2+)
      levels, an increase in Ca(2+) alone is not sufficient to affect enzyme activity
      because the binding of calmodulin (CaM) and the flow of electrons from the
      reductase to the oxygenase domain of the enzyme is dependent on protein
      phosphorylation and dephosphorylation. Two amino acids seem to be particularly
      important in regulating eNOS activity and these are a serine residue in the
      reductase domain (Ser(1177)) and a threonine residue (Thr(495)) located within
      the CaM-binding domain. Simultaneous alterations in the phosphorylation of
      Ser(1177) and Thr(495) in response to a variety of stimuli are regulated by a
      number of kinases and phosphatases that continuously associate with and
      dissociate from the eNOS signaling complex. eNOS associated proteins, such as
      caveolin, heat shock protein 90, eNOS interacting protein, and possibly also
      motor proteins provide the scaffold for the formation of the protein complex as
      well as its intracellular localization.

PMID- 12482743
TI  - Importance of the renal medullary circulation in the control of sodium excretion
      and blood pressure.
AB  - The control of renal medullary perfusion and the impact of alterations in
      medullary blood flow on renal function have been topics of research interest for
      almost four decades. Many studies have examined the vascular architecture of the
      renal medulla, the factors that regulate renal medullary blood flow, and the
      influence of medullary perfusion on sodium and water excretion and arterial
      pressure. Despite these studies, there are still a number of important unanswered
      questions in regard to the control of medullary perfusion and the influence of
      medullary blood flow on renal excretory function and blood pressure. This review
      will first address the vascular architecture of the renal medulla and the
      potential mechanisms whereby medullary perfusion may be regulated. The known
      extrarenal and local systems that influence the medullary vasculature will then
      be summarized. Finally, this review will present an overview of the evidence
      supporting the concept that selective changes in medullary perfusion can have a
      potent influence on sodium and water excretion with a long-term influence on
      arterial blood pressure regulation.

PMID- 12482744
TI  - Mouse gene targeting in cardiovascular physiology.

PMID- 12482745
TI  - The adrenal response of neonates to hypoxia.

PMID- 12482746
TI  - Addressing leptin resistance.

PMID- 12482747
TI  - Method of leptin dosing, strain, and group housing influence leptin sensitivity
      in high-fat-fed weanling mice.
AB  - High-fat diets are reported to induce resistance to peripherally administered
      leptin. In an attempt to develop a model of juvenile diet-induced obesity, mice
      were weaned onto high-fat diet. Male and female, 35-day-old, C57BL/6J high-fat
      (45% kcal fat) diet-fed mice housed individually on grid floors did not decrease
      food intake or body weight in response to intraperitoneal (30 microg), lateral
      ventricle (5 microg), or third ventricle (0.5 microg) injections of leptin. Body
      weight and fat were significantly reduced by 13-day intraperitoneal infusions of
      10 microg leptin/day, which doubled circulating leptin. Leptin infusion also
      reduced body fat in weanling, high-fat diet-fed NIH Swiss mice. Group housing
      mice on bedding prevented loss of fat in high-fat diet-fed male and female NIH
      Swiss and female C57BL/6J mice. These results indicate that peripherally infused
      leptin reduces fat in part by increasing thermogenesis and that inhibition of
      food intake in high-fat diet-fed mice requires either chronic activation of
      central leptin receptors or is independent of receptors that inhibit feeding in
      response to an acute central injection of leptin.

PMID- 12482748
TI  - Angiotensin receptors contribute to blood pressure homeostasis in salt-depleted
      SHR.
AB  - This study evaluated the contribution of angiotensin peptides acting at various
      receptor subtypes to the arterial pressure and heart rate of adult 9-wk-old male
      conscious salt-depleted spontaneously hypertensive rats (SHR). Plasma ANG II and
      ANG I in salt-depleted SHR were elevated sevenfold compared with peptide levels
      measured in sodium-replete SHR, whereas plasma ANG-(1-7) was twofold greater in
      salt-depleted SHR compared with salt-replete SHR. Losartan (32.5 micromol/kg), PD
      123319 (0.12 micromol. kg(-1). min(-1)), [d-Ala(7)]ANG-(1-7) (10 and 100
      pmol/min), and a polyclonal ANG II antibody (0.08 mg/min) were infused
      intravenously alone or in combination. Combined blockade of AT(2) and AT((1-7))
      receptors significantly increased the blood pressure of losartan-treated SHR (+15
      +/- 1 mmHg; P < 0.01); this change did not differ from the blood pressure
      elevation produced by the sole blockade of AT((1-7)) receptors (15 +/- 4 mmHg).
      On the other hand, sole blockade of AT(2) receptors in losartan-treated SHR
      increased mean arterial pressure by 8 +/- 1 mmHg (P < 0.05 vs. 5% dextrose in
      water as vehicle), and this increase was less than the pressor response produced
      by blockade of AT((1-7)) receptors alone or combined blockade of AT((1-7)) and
      AT(2) receptors. The ANG II antibody increased blood pressure to the greatest
      extent in salt-depleted SHR pretreated with only losartan (+11 +/- 2 mmHg) and to
      the least extent in salt-depleted SHR previously treated with the combination of
      losartan, PD-123319, and [d-Ala(7)]ANG-(1-7) (+7 +/- 1 mmHg; P < 0.01). Losartan
      significantly increased heart rate, whereas other combinations of receptor
      antagonists or the ANG II antibody did not alter heart rate. Our results
      demonstrate that ANG II and ANG-(1-7) act through non-AT(1) receptors to oppose
      the vasoconstrictor actions of ANG II in salt-depleted SHR. Combined blockade of
      AT(2) and AT((1-7)) receptors and ANG II neutralization by the ANG II antibody
      reversed as much as 67% of the blood pressure-lowering effect of losartan.

PMID- 12482749
TI  - Cerebral leucine uptake and protein synthesis in the near-term ovine fetus:
      relation to fetal behavioral state.
AB  - Behavioral/sleep state activity may impact on synthetic processes within the
      brain, thus accounting for the developmental change in such activity and
      suggesting a role in the brain's growth and development. We have therefore
      determined the cerebral uptake of leucine and [(14)C]leucine during continuous
      tracer infusion as measures of leucine metabolism in relation to behavioral state
      activity, as well as the regional flux of leucine into brain tissue in the ovine
      fetus near term. The cerebral fractional protein synthetic rate and the absolute
      protein synthetic rate averaged approximately 20%/day and approximately 1 g/day,
      respectively, as measured for the whole brain, which is considerably higher than
      anticipated protein accretion and indicates a high rate of protein turnover with
      protein synthesis closely linked to protein degradation. Measures of protein
      synthesis were significantly higher in the pituitary gland, which may be
      attributed to the active synthesis and export of peptide hormones from this
      region. Cerebral leucine and [(14)C]leucine uptakes averaged approximately 630
      and approximately 1,000 nmol. 100 g(-1). min(-1), with the latter higher than
      leucine unidirectional flux and thus supporting a degree of leucine oxidation by
      the brain. Cerebral leucine metabolism as studied was affected by behavioral
      state activity, with uptake measurements for both leucine and [(14)C]leucine
      significantly increased during the high-voltage electrocortical/non-rapid eye
      movement state by 1.7-fold and 2.8-fold, respectively, indicating that protein
      synthesis and degradation must also be increased at this time, and supporting a
      role for behavioral state activity in the brain's growth and development.

PMID- 12482750
TI  - PepN, the major Suc-LLVY-AMC-hydrolyzing enzyme in Escherichia coli, displays
      functional similarity with downstream processing enzymes in Archaea and eukarya.
      Implications in cytosolic protein degradation.
AB  - Succinyl-Leu-Leu-Val-Tyr-7-amido-4-methylcoumarin (Suc-LLVY-AMC), a fluorogenic
      endopeptidase substrate, is used to detect 20 S proteasomal activity from Archaea
      to mammals. An o-phenanthroline-sensitive Suc-LLVY-AMC hydrolyzing activity was
      detected in Escherichia coli although it lacks 20 S proteasomes. We identified
      PepN, previously characterized as the sole alanine aminopeptidase in E. coli, to
      be responsible for the hydrolysis of Suc-LLVY-AMC. PepN is an aminoendopeptidase.
      First, extracts from an ethyl methanesulfonate-derived PepN mutant, 9218, did not
      cleave Suc-LLVY-AMC and L-Ala-para-nitroanilide (pNA). Second, biochemically
      purified PepN cleaves a wide variety of both aminopeptidase and endopeptidase
      substrates, and L-Ala-pNA is cleaved more efficiently than other substrates.
      Studies with bestatin, an aminopeptidase-specific inhibitor, suggest differences
      in the mechanisms of cleavage of aminopeptidase and endopeptidase substrates.
      Third, PepN hydrolyzes whole proteins, casein and albumin. Finally, an E. coli
      strain with a targeted deletion in PepN also lacks the ability to cleave Suc-LLVY
      AMC and L-Ala-pNA, and expression of wild type PepN in this mutant rescues both
      activities. In addition, we identified a low molecular weight Suc-LLVY-AMC
      cleaving peptidase in Mycobacterium smegmatis, a eubacteria harboring 20 S
      proteasomes, to be an aminopeptidase homologous to E. coli PepN, by mass
      spectrometry analysis. "Sequence-based homologues" of PepN include well
      characterized aminopeptidases, e.g. Tricorn interacting factors F2 and F3 in
      Archaea and puromycin-sensitive aminopeptidase in mammals. However, our results
      suggest that eubacterial PepN and its homologues displaying aminoendopeptidase
      activities may be "functionally similar" to enzymes important in downstream
      processing of proteins in the cytosol: Tricorn-F1-F2-F3 complex in Archaea and
      TPPII/Multicorn in eukaryotes.

PMID- 12482751
TI  - Expression of dominant-negative Fas-associated death domain blocks human
      keratinocyte apoptosis and vesication induced by sulfur mustard.
AB  - DNA damaging agents up-regulate levels of the Fas receptor or its ligand,
      resulting in recruitment of Fas-associated death domain (FADD) and autocatalytic
      activation of caspase-8, consequently activating the executioner caspases-3, -6,
      and -7. We found that human epidermal keratinocytes exposed to a vesicating dose
      (300 microm) of sulfur mustard (SM) exhibit a dose-dependent increase in the
      levels of Fas receptor and Fas ligand. Immunoblot analysis revealed that the
      upstream caspases-8 and -9 are both activated in a time-dependent fashion, and
      caspase-8 is cleaved prior to caspase-9. These results are consistent with the
      activation of both death receptor (caspase-8) and mitochondrial (caspase-9)
      pathways by SM. Pretreatment of keratinocytes with a peptide inhibitor of caspase
      3 (Ac-DEVD-CHO) suppressed SM-induced downstream markers of apoptosis. To further
      analyze the importance of the death receptor pathway in SM toxicity, we utilized
      Fas- or tumor necrosis factor receptor-neutralizing antibodies or constructs
      expressing a dominant-negative FADD (FADD-DN) to inhibit the recruitment of FADD
      to the death receptor complex and block the Fas/tumor necrosis factor receptor
      pathway following SM exposure. Keratinocytes pretreated with Fas-blocking
      antibody or stably expressing FADD-DN and exhibiting reduced levels of FADD
      signaling demonstrated markedly decreased caspase-3 activity when treated with
      SM. In addition, the processing of procaspases-3, -7, and -8 into their active
      forms was observed in SM-treated control keratinocytes, but not in FADD-DN cells.
      Blocking the death receptor complex by expression of FADD-DN additionally
      inhibited SM-induced internucleosomal DNA cleavage and caspase-6-mediated nuclear
      lamin cleavage. Significantly, we further found that altering the death receptor
      pathway by expressing FADD-DN in human skin grafted onto nude mice reduces
      vesication and tissue injury in response to SM. These results indicate that the
      death receptor pathway plays a pivotal role in SM-induced apoptosis and is
      therefore a target for therapeutic intervention to reduce SM injury.

PMID- 12482752
TI  - Interactions between p300 and multiple NF-Y trimers govern cyclin B2 promoter
      function.
AB  - The CCAAT box is one of the most common elements in eukaryotic promoters and is
      activated by NF-Y, a conserved trimeric transcription factor with histone-like
      subunits. Usually one CCAAT element is present in promoters at positions between 
      60 and -100, but an emerging class of promoters harbor multiple NF-Y sites. In
      the triple CCAAT-containing cyclin B2 cell-cycle promoter, all CCAAT boxes,
      independently from their NF-Y affinities, are important for function. We
      investigated the relationships between NF-Y and p300. Chromatin
      immunoprecipitation analysis found that NF-Y and p300 are bound to the cyclin B2
      promoter in vivo and that their binding is regulated during the cell cycle,
      positively correlating with promoter function. Cotransfection experiments
      determined that the coactivator acts on all CCAAT boxes and requires a precise
      spacing between the three elements. We established the order of in vitro binding
      of the three NF-Y complexes and find decreasing affinities from the most distal
      Y1 to the proximal Y3 site. Binding of two or three NF-Y trimers with or without
      p300 is not cooperative, but association with the Y1 and Y2 sites is extremely
      stable. p300 favors the binding of NF-Y to the weak Y3 proximal site, provided
      that a correct distance between the three CCAAT is respected. Our data indicate
      that the precise spacing of multiple CCAAT boxes is crucial for coactivator
      function. Transient association to a weak site might be a point of regulation
      during the cell cycle and a general theme of multiple CCAAT box promoters.

PMID- 12482753
TI  - Protein unfolding is not a prerequisite for endoplasmic reticulum-to-cytosol
      dislocation.
AB  - We examined the effects of protein folding on endoplasmic reticulum (ER)-to
      cytosol transport (dislocation) by exploiting the well-characterized
      dihydrofolate reductase (DHFR) domain. DHFR retains the capacity to bind folate
      analogues in the lumen of microsomes and in the ER of intact cells, upon which it
      acquires a conformation resistant to proteinase K digestion. Here we show that a
      Class I major histocompatibility complex heavy chain fused to DHFR is still
      recognized by the human cytomegalovirus-encoded glycoproteins US2 and US11,
      resulting in dislocation of the fusion protein from the ER in vitro and in vivo.
      A folded state of the DHFR domain does not impair dislocation of Class I MHC
      heavy chains in vitro or in living cells. In fact, a slight acceleration of the
      dislocation of DHFR heavy chain fusion was observed in vitro in the presence of a
      folate analogue. These results suggest that one or more of the channels used for
      dislocation can accommodate polypeptides that contain a tightly folded domain of
      considerable size. Our data raise the possibility that the Sec61 channel can be
      modified to accommodate a folded DHFR domain for dislocation, but not for
      translocation into the ER, or that a channel altogether distinct from Sec61 is
      used for dislocation.

PMID- 12482754
TI  - Functional analysis of the nucleotide binding domain of membrane-associated
      guanylate kinases.
AB  - Membrane-associated guanylate kinases (MAGUKs) regulate cellular adhesion and
      signal transduction at sites of cell-cell contact. MAGUKs are composed of modular
      protein-protein interaction motifs including L27, PDZ, Src homology (SH) 3, and
      guanylate kinase domains that aggregate adhesion molecules and receptors. Genetic
      analyses reveal that lethal mutations of MAGUKs often occur in the guanylate
      kinase domain, indicating a critical role for this domain. Here, we explored
      whether GMP binding to the guanylate kinase domain regulates MAGUK function.
      Surprisingly, and in contrast to previously published studies, we failed to
      detect GMP binding to the MAGUKs postsynaptic density-95 (PSD-95) and CASK. Two
      amino acid residues in the GMP binding pocket that differ between MAGUKs and
      authentic guanylate kinase explain this lack of binding, as swapping these
      residues largely prevent GMP binding to yeast guanylate kinase. Conversely, these
      mutations restore GMP binding but not catalytic activity to PSD-95. Protein
      ligands for the PSD-95 guanylate kinase domain, guanylate kinase-associated
      protein (GKAP) and MAP1A, appear not to interact with the canonical GMP binding
      pocket, and GMP binding does not influence the intramolecular SH3/guanylate
      kinase (GK) interaction within PSD-95. These studies indicate that MAGUK proteins
      have lost affinity for GMP but may have retained the guanylate kinase structure
      to accommodate a related regulatory ligand.

PMID- 12482755
TI  - Voltage-dependent anion channels control the release of the superoxide anion from
      mitochondria to cytosol.
AB  - Several reactions in biological systems contribute to maintain the steady-state
      concentrations of superoxide anion (O(2)*-) and hydrogen peroxide (H(2)O(2)). The
      electron transfer chain of mitochondria is a well documented source of H(2)O(2);
      however, the release of O(2)*- from mitochondria into cytosol has not been
      unequivocally established. This study was aimed at validating mitochondria as
      sources of cytosolic O(2)*-, elucidating the mechanisms underlying the release of
      O(2)*- from mitochondria into cytosol, and assessing the role of outer membrane
      voltage-dependent anion channels (VDACs) in this process. Isolated rat heart
      mitochondria supplemented with complex I or II substrates generate an EPR signal
      ascribed to O(2)*-. Inhibition of the signal in a concentration-dependent manner
      by both manganese-superoxide dismutase and cytochrome c proteins that cannot
      cross the mitochondrial membrane supports the extramitochondrial location of the
      spin adduct. Basal rates of O(2)*- release from mitochondria were estimated at
      approximately 0.04 nmol/min/mg protein, a value increased approximately 8-fold by
      the complex III inhibitor, antimycin A. These estimates, obtained by quantitative
      spin-trapping EPR, were confirmed by fluorescence techniques, mainly
      hydroethidine oxidation and horseradish peroxidase-based p-hydroxyphylacetate
      dimerization. Inhibitors of VDAC, 4'-diisothiocyano-2,2'-disulfonic acid stilbene
      (DIDS), and dextran sulfate (in a voltage-dependent manner) inhibited O(2)*-
      production from mitochondria by approximately 55%, thus suggesting that a large
      portion of O(2)*- exited mitochondria via these channels. These findings are
      discussed in terms of competitive decay pathways for O(2)*- in the intermembrane
      space and cytosol as well as the implications of these processes for modulating
      cell signaling pathways in these compartments.

PMID- 12482756
TI  - Structure of human FIH-1 reveals a unique active site pocket and interaction
      sites for HIF-1 and von Hippel-Lindau.
AB  - The master switch of cellular hypoxia responses, hypoxia-inducible factor 1 (HIF
      1), is hydroxylated by factor inhibiting HIF-1 (FIH-1) at a conserved asparagine
      residue under normoxia, which suppresses transcriptional activity of HIF-1 by
      abrogating its interaction with transcription coactivators. Here we report the
      crystal structure of human FIH-1 at 2.8-A resolution. The structural core of FIH
      1 consists of a jellyroll-like beta-barrel containing the conserved ferrous
      binding triad residues, confirming that FIH-1 is a member of the 2-oxoglutarate
      dependent dioxygenase family. Except for the core structure and triad residues,
      FIH-1 has many structural deviations from other family members including N- and C
      terminal insertions and various deletions in the middle of the structure. The
      ferrous-binding triad region is highly exposed to the solvent, which is connected
      to a prominent groove that may bind to a helix near the hydroxylation site of HIF
      1. The structure, which is in a dimeric state, also reveals the putative von
      Hippel-Lindau-binding site that is distinctive to the putative HIF-1-binding
      site, supporting the formation of the ternary complex by FIH-1, HIF-1, and von
      Hippel-Lindau. The unique environment of the active site and cofactor-binding
      region revealed in the structure should allow design of selective drugs that can
      be used in ischemic diseases to promote hypoxia responses.

PMID- 12482758
TI  - Identification of a novel protein with guanylyl cyclase activity in Arabidopsis
      thaliana.
AB  - Guanylyl cyclases (GCs) catalyze the formation of the second messenger guanosine
      3',5'-cyclic monophosphate (cGMP) from guanosine 5'-triphosphate (GTP). While
      many cGMP-mediated processes in plants have been reported, no plant molecule with
      GC activity has been identified. When the Arabidopsis thaliana genome is queried
      with GC sequences from cyanobacteria, lower and higher eukaryotes no unassigned
      proteins with significant similarity are found. However, a motif search of the A.
      thaliana genome based on conserved and functionally assigned amino acids in the
      catalytic center of annotated GCs returns one candidate that also contains the
      adjacent glycine-rich domain typical for GCs. In this molecule, termed AtGC1, the
      catalytic domain is in the N-terminal part. AtGC1 contains the arginine or lysine
      that participates in hydrogen bonding with guanine and the cysteine that confers
      substrate specificity for GTP. When AtGC1 is expressed in Escherichia coli, cell
      extracts yield >2.5 times more cGMP than control extracts and this increase is
      not nitric oxide dependent. Furthermore, purified recombinant AtGC1 has Mg(2+)
      dependent GC activity in vitro and >3 times less adenylyl cyclase activity when
      assayed with ATP as substrate in the absence of GTP. Catalytic activity in vitro
      proves that AtGC1 can function either as a monomer or homo-oligomer. AtGC1 is
      thus not only the first functional plant GC but also, due to its unusual domain
      organization, a member of a new class of GCs.

PMID- 12482757
TI  - Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge
      with the clathrin pathway in early endosomes and form microdomains for recycling.
AB  - We have previously demonstrated that glycosphingolipids are internalized from the
      plasma membrane of human skin fibroblasts by a clathrin-independent, caveolar
      related mechanism and are subsequently transported to the Golgi apparatus by a
      process that is dependent on microtubules, phosphatidylinositol 3-kinase, Rab7,
      and Rab9. Here we characterized the early steps of intracellular transport of a
      fluorescent glycosphingolipid analog, BODIPY-lactosylceramide (LacCer), and
      compared this to fluorescent transferrin (Tfn), a well established marker for the
      clathrin pathway. Although these two markers were initially internalized into
      separate vesicles by distinct mechanisms, they became co-localized in early
      endosomes within 5 min. These results demonstrate that glycosphingolipid
      containing vesicles derived from caveolar-related endocytosis fuse with the
      classical endosomal system. However, in contrast to Tfn, internalization and
      trafficking of LacCer was independent of Rab5a, a key regulator of transport to
      early endosomes. By taking advantage of the monomer/excimer properties of the
      fluorescent lipid analog, we were also able to visualize LacCer segregation into
      distinct microdomains of high (red emission) and low (green emission)
      concentrations in the early endosomes of living cells. Interestingly, the high
      concentration "red" microdomains co-localized with fluorescent Tfn upon exit from
      early endosomes and passed through Rab11-positive "recycling endosomes" prior to
      being transported back to the plasma membrane. These results together with our
      previous studies suggest that glycosphingolipids internalized by caveolar
      endocytosis are rapidly delivered to early endosomes where they are fractionated
      into two major pools, one that is transported via late endosomes to the Golgi
      apparatus and the other that is returned to the plasma membrane via the recycling
      compartment.

PMID- 12482759
TI  - Plasma homocysteine is regulated by phospholipid methylation.
AB  - Mild hyperhomocysteinemia is an independent risk factor for cardiovascular
      disease. Homocysteine, a non-protein amino acid, is formed from S
      adenosylhomocysteine and partially secreted into plasma. A potential source for
      homocysteine is methylation of the lipid phosphatidylethanolamine to
      phosphatidylcholine by phosphatidylethanolamine N-methyltransferase in the liver.
      We show that mice that lack phosphatidylethanolamine N-methyltransferase have
      plasma levels of homocysteine that are approximately 50% of those in wild-type
      mice. Hepatocytes isolated from methyltransferase-deficient mice secrete
      approximately 50% less homocysteine. Rat hepatoma cells transfected with
      phosphatidylethanolamine N-methyltransferase secrete more homocysteine than wild
      type cells. Thus, phosphatidylethanolamine N-methyltransferase is an important
      source of plasma homocysteine and a potential therapeutic target for
      hyperhomocysteinemia.

PMID- 12482760
TI  - Activation imbalances in lumbar spine muscles in the presence of chronic low back
      pain.
AB  - Paraspinal electromyographic (EMG) activity was recorded bilaterally from three
      lumbar levels during 30-s isometric trunk extensions [40 and 80% of maximum
      voluntary contraction (MVC)] in 20 healthy men and 14 chronic low back pain
      patients in pain. EMG parameters indicating neuromuscular fatigue and
      contralateral imbalances in EMG root-mean-square amplitude and median frequency
      were analyzed. Patients in pain showed less fatigue than controls at both
      contraction levels and produced only 55% of their MVC. Patients in pain likely
      did not produce a "true" maximum effort. A low MVC estimate would mean lower
      absolute contraction levels and less neuromuscular fatigue, thus explaining lower
      scores in the patients. Contralateral root-mean-square amplitude imbalances were
      present in both categories of subjects although such imbalances, when averaged
      across lumbar levels, were significantly larger in patients. Median frequency
      imbalances were significantly larger in the patients, at segmental as well as
      across lumbar levels. These results suggest that the presence of pain in these
      patients caused a redistribution of the activation behavior between synergistic
      muscles of the lumbar back.

PMID- 12482761
TI  - Effects of paranasal sinus ostia and volume on acoustic rhinometry measurements:
      a model study.
AB  - We used pipe models to investigate the effects of paranasal sinus ostium size and
      paranasal sinus volume on the area-distance curves derived by acoustic rhinometry
      (AR). Each model had a Helmholtz resonator or a short neck as a side branch that
      simulated the paranasal sinus and sinus ostium. The AR-derived cross-sectional
      areas posterior to the ostium were significantly overestimated. Sinus volume
      affected the AR measurements only when the sinus was connected via a relatively
      large ostium. The experimental area-distance curve posterior to the side branch
      showed pronounced oscillations in association with low-frequency acoustic
      resonances in this distal part of the pipe. The experimental results are
      discussed in terms of theoretically calculated "sound-power reflection
      coefficients" for the pipe models used. The results indicate that the effects of
      paranasal sinuses and low-frequency acoustic resonances in the posterior part of
      the nasal cavity are not accounted for in the current AR algorithms. AR does not
      provide reliable information about sinus ostium size, sinus volume, or cross
      sectional area in the distal parts of nasal cavity.

PMID- 12482762
TI  - Role played by purinergic receptors on muscle afferents in evoking the exercise
      pressor reflex.
AB  - The exercise pressor reflex is believed to be evoked, in part, by multiple
      metabolic stimuli that are generated when blood supply to exercising muscles is
      inadequate to meet metabolic demand. Recently, ATP, which is a P2 receptor
      agonist, has been suggested to be one of the metabolic stimuli evoking this
      reflex. We therefore tested the hypothesis that blockade of P2 receptors within
      contracting skeletal muscle attenuated the exercise pressor reflex in decerebrate
      cats. We found that popliteal arterial injection of pyridoxal phosphate-6
      azophenyl-2',4'-disulfonic acid (PPADS; 10 mg/kg), a P2 receptor antagonist,
      attenuated the pressor response to static contraction of the triceps surae
      muscles. Specifically, the pressor response to contraction before PPADS averaged
      36 +/- 3 mmHg, whereas afterward it averaged 14 +/- 3 mmHg (P < 0.001; n = 19).
      In addition, PPADS attenuated the pressor response to postcontraction circulatory
      occlusion (P < 0.01; n = 11). In contrast, popliteal arterial injection of CGS
      15943 (250 micro g/kg), a P1 receptor antagonist, had no effect on the pressor
      response to static contraction of the triceps surae muscles. In addition,
      popliteal arterial injection of PPADS but not CGS-15943 attenuated the pressor
      response to stretch of the calcaneal (Achilles) tendon. We conclude that P2
      receptors on the endings of thin fiber muscle afferents play a role in evoking
      both the metabolic and mechanoreceptor components of the exercise pressor reflex.

PMID- 12482763
TI  - Heat stress attenuates air bubble-induced acute lung injury: a novel mechanism of
      diving acclimatization.
AB  - Diving acclimatization refers to a reduced susceptibility to acute decompression
      sickness (DCS) in individuals undergoing repeated compression-decompression
      cycles. We postulated that mechanisms responsible for the acclimatization are
      similar to that of a stress preconditioning. In this study, we investigated the
      protective effect of prior heat shock treatment on air embolism-induced lung
      injury and on the incidence of DCS in rats. We exposed rats (n = 31) to a
      pressure cycle that induced signs of severe DCS in 48% of the rats, greater wet
      to-dry ratio (W/D) of lung weight compared with the control group (5.48 +/- 0.69
      vs. 4.70 +/- 0.17), and higher protein concentration in bronchoalveolar lavage
      (BAL) fluid (362 +/- 184 vs. 209 +/- 78 mg/l) compared with the control group.
      Rats with DCS expressed more heat shock protein 70 (HSP70) in the lungs than
      those without signs of disease. Prior heat shock (n = 12) increased the
      expression of HSP70 in the lung and attenuated the elevation of W/D of lung
      weight (5.03 +/- 0.17) after the identical decompression protocol. Prior heat
      shock reduced the incidence of severe DCS by 23%, but this failed to reach
      statistical significant (chi(2) = 1.94, P = 0.163). Venous air infusion (1.0
      ml/40 min) caused profound hypoxemia (54.5 +/- 3.8 vs. 83.8 +/- 3.2 Torr at
      baseline; n = 6), greater W/D of lung weight (5.98 +/- 0.45), and high protein
      concentration in BAL fluid (595 +/- 129 mg/l). Prior heat shock (n = 6) did not
      alter the level of hypoxemia caused by air embolism, but it accelerated the
      recovery to normoxemia after air infusion was stopped. Prior heat shock also
      attenuated the elevation of W/D of lung weight (5.19 +/- 0.40) and the increase
      in BAL protein (371 +/- 69 mg/l) in air embolism group. Our results showed that
      the occurrence of DCS after rapid decompression is associated with increased
      expression of a stress protein (HSP70) and that prior heat shock exposure
      attenuates the air bubble-induced lung injury. These results suggest that bubble
      formation in tissues activates a stress response and that stress preconditioning
      attenuates lung injury on subsequent stress, which may be the mechanism
      responsible for diving acclimatization.

PMID- 12482764
TI  - Effect of a divided caffeine dose on endurance cycling performance, postexercise
      urinary caffeine concentration, and plasma paraxanthine.
AB  - This study compared the effects of a single and divided dose of caffeine on
      endurance performance and on postexercise urinary caffeine and plasma
      paraxanthine concentrations. Nine male cyclists and triathletes cycled for 90 min
      at 68% of maximal oxygen uptake, followed by a self-paced time trial (work
      equivalent to 80% of maximal oxygen uptake workload over 30 min) with three
      randomized, balanced, and double-blind interventions: 1) placebo 60 min before
      and 45 min into exercise (PP); 2) single caffeine dose (6 mg/kg) 60 min before
      exercise and placebo 45 min into exercise (CP); and 3) divided caffeine dose (3
      mg/kg) 60 min before and 45 min into exercise (CC). Time trial performance was
      unchanged with caffeine ingestion (P = 0.08), but it tended to be faster in the
      caffeine trials (CP: 24.2 min and CC: 23.4 min) compared with placebo (PP: 28.3
      min). Postexercise urinary caffeine concentration was significantly lower in CC
      (3.8 micro g/ml) compared with CP (6.8 micro g/ml). Plasma paraxanthine increased
      in a dose-dependent fashion and did not peak during exercise. In conclusion,
      dividing a caffeine dose provides no ergogenic effect over a bolus dose but
      reduces postexercise urinary concentration.

PMID- 12482765
TI  - Effects of nonspecific beta-adrenergic stimulation and blockade on blood
      coagulation in hypertension.
AB  - A hypercoagulable state might contribute to increased atherothrombotic risk in
      hypertension. The sympathetic nervous system is hyperactive in hypertension, and
      it regulates hemostatic function. We investigated the effect of nonspecific beta
      adrenergic stimulation (isoproterenol) and blockade (propranolol) on clotting
      diathesis in hypertension. Fifteen hypertensive and 21 normotensive subjects
      underwent isoproterenol infusion in two sequential, fixed-order doses of 20 and
      then 40 ng. kg(-1). min(-1) for 15 min/dose. Thirteen subjects were double-blind
      studied after receiving placebo or propranolol (100 mg/day) for 5 days each. In
      hypertensive subjects, isoproterenol elicited a dose-dependent increase in plasma
      von Willebrand factor (vWF) antigen [F(2,34) = 5.02; P = 0.032] and a decrease in
      D-dimer [F(2,34) = 4.57; P = 0.040], whereas soluble tissue factor remained
      unchanged. Propranolol completely abolished the increase in vWF elicited by
      isoproterenol [F(1,12) = 10.25; P = 0.008] but had no significant effect on
      tissue factor and D-dimer. In hypertension, vWF is readily released from
      endothelial cells by beta-adrenergic stimulation, which might contribute to
      increased cardiovascular risk. However, beta-adrenergic stimulation alone may not
      be sufficient to trigger fibrin formation in vivo.

PMID- 12482766
TI  - Human pulmonary vascular response to 4 h of hypercapnia and hypocapnia measured
      using Doppler echocardiography.
AB  - Hypercapnia has been shown in animal experiments to induce pulmonary
      hypertension. This study measured the sensitivity and time course of the human
      pulmonary vascular response to sustained (4 h) hypercapnia and hypocapnia. Twelve
      volunteers undertook three protocols: 1) 4-h euoxic (end-tidal Po(2) = 100 Torr)
      hypercapnia (end-tidal Pco(2) was 10 Torr above normal), followed by 2 h of
      recovery with euoxic eucapnia; 2) 4-h euoxic hypocapnia (end-tidal Pco(2) was 10
      Torr below normal) followed by 2 h of recovery; and 3) 6-h air breathing
      (control). Pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by
      using Doppler echocardiography via the maximum tricuspid pressure gradient during
      systole. Results show progressive changes in pressure gradient over 1-2 h after
      the onset or offset of the stimuli, and sensitivities of 0.6 to 1 Torr change in
      pressure gradient per Torr change in end-tidal Pco(2). The human pulmonary
      circulatory response to changes in Pco(2) has a slower time course and greater
      sensitivity than is commonly assumed. Vascular tone in the normal pulmonary
      circulation is substantial.

PMID- 12482767
TI  - Acute hypoxia prolongs the apnea induced by right atrial injection of capsaicin.
AB  - Inspiratory central drive is augmented by acute hypoxia that leads to a
      hyperventilation, but it is inhibited by capsaicin (Cap)-induced stimulation of
      pulmonary C fibers (PCFs) that produces an expiratory apnea. We hypothesized that
      acute hypoxia should shorten or eliminate the Cap-induced apnea. The ventilatory
      responses to bolus injection of Cap (0.2-0.5 microg) into the right atrium before
      and during acute hypoxia (10% O(2) for approximately 1 min; Hypoxia+Cap) were
      compared in anesthetized and spontaneously breathing rats. We found that Cap
      injection during acute hypoxia produced an extremely long-lasting apnea (69.67 +/
      11.97 s) that was 16-fold longer than the apnea induced by Cap alone (expiratory
      duration = 4.37 +/- 0.53 s; P < 0.01). A similar prolonged apnea was also
      observed during hypoxia in anesthetized guinea pigs. Bilateral vagotomy abolished
      apneic responses to Cap both before and during hypoxia. Subsequent recording of
      single-fiber activity of PCFs (PCF(A)) showed that acute hypoxia did not
      significantly affect baseline PCF(A) but that it doubled PCF(A) responses to Cap
      via increasing both the firing rate (3.34 +/- 0.76 to 7.65 +/- 1.32 impulses/s; P
      < 0.05) and burst duration (1.12 +/- 0.18 to 2.32 +/- 0.31 s; P < 0.05). These
      results suggest that acute hypoxia augments PCF-mediated inspiratory inhibition
      and thereby leads to an extremely long-lasting apnea. This interaction is
      partially due to hypoxic sensitization of PCF response to Cap.

PMID- 12482768
TI  - Colchicine attenuates left ventricular hypertrophy but preserves cardiac function
      of aortic-constricted rats.
AB  - To investigate the effects of colchicine on left ventricular (LV) function and
      hypertrophy (LVH) of rats subjected to constriction of transverse aorta (TAoC),
      we evaluated SO (sham operated, vehicle; n = 25), SO-T (sham operated, colchicine
      0.4 mg/kg body wt ip daily; n = 38), TAoC (vehicle; n = 37), and TAoC-T (TAoC,
      colchicine; n = 34) on the 2nd, 6th, and 15th day after surgery. Colchicine
      attenuated LVH of TAoC-T compared with TAoC rats, as evaluated by ratio between
      LV mass (LV(M)) and right ventricular mass, LV wall thickness, and average
      diameter of cardiac myocytes. Systolic gradient across TAoC ( approximately 45
      mmHg), LV systolic pressure, LV end-diastolic pressure, and rate of LV pressure
      increase (+dP/dt) were comparable in TAoC-T and TAoC rats. However, the baseline
      and increases of LV systolic pressure-to-LV(M) and +dP/dt-to-LV(M) ratios induced
      by phenylephrine infusion were greater in TAoC-T and SO-T compared with SO rats.
      Baseline and increases of +dP/dt-to-LV(M) ratio were reduced in TAoC compared
      with SO rats. TAoC rats increased polymerized fraction of tubulin compared with
      SO, SO-T, and TAoC-T rats. Our results indicate that colchicine treatment reduced
      LVH to pressure overload but preserved LV function.

PMID- 12482769
TI  - S1P induces FA remodeling in human pulmonary endothelial cells: role of Rac,
      GIT1, FAK, and paxillin.
AB  - Sphingosine 1-phosphate (S1P) enhances human pulmonary endothelial monolayer
      integrity via Rac GTPase-dependent formation of a cortical actin ring (Garcia et
      al. J Clin Invest 108: 689-701, 2001). The mechanisms underlying this response
      are not well understood but may involve rapid redistribution of focal adhesions
      (FA) as attachment sites for actin filaments. We evaluate the effects of S1P on
      the redistribution of paxillin, FA kinase (FAK), and the G protein-coupled
      receptor kinase-interacting proteins (GITs). S1P induced Rac GTPase activation
      and cortical actin ring formation at physiological concentrations (0.5 microM),
      whereas 5 microM S1P caused prominent stress fiber formation and activation of
      Rho and Rac GTPases. S1P (0.5 microM) stimulated the tyrosine phosphorylation of
      FAK Y(576), and paxillin was linked to FA disruption and redistribution to the
      cell periphery. Furthermore, S1P induced a transient association of GIT1 with
      paxillin and redistribution of the GIT2-paxillin complex to the cell cortical
      area without affecting GIT2-paxillin association. These results suggest a role of
      FA rearrangement in S1P-mediated barrier enhancement via Rac- and GIT-mediated
      processes.

PMID- 12482770
TI  - Short-term plasticity of descending synaptic input to phrenic motoneurons in
      rats.
AB  - Respiratory afferent stimulation can elicit increases in respiratory motor output
      that outlast the period of stimulation by seconds to minutes [short-term
      potentiation (STP)]. This study examined the potential contribution of spinal
      mechanisms to STP in anesthetized, vagotomized, paralyzed rats. After C(1) spinal
      cord transection, stimulus trains (100 Hz, 5-60 s) of the C(1)-C(2) lateral
      funiculus elicited STP of phrenic nerve activity that peaked several seconds
      poststimulation. Intracellular recording revealed that individual phrenic
      motoneurons exhibited one of three different responses to stimulation: 1)
      depolarization that peaked several seconds poststimulation, 2) depolarization
      during stimulation and then exponential repolarization after stimulation, and 3)
      bistable behavior in which motoneurons depolarized to a new, relatively stable
      level that was maintained after stimulus termination. During the STP, excitatory
      postsynaptic potentials elicited by single-stimulus pulses were larger and
      longer. In conclusion, repetitive activation of the descending inputs to phrenic
      motoneurons causes a short-lasting depolarization of phrenic motoneurons, and
      augmentation of excitatory postsynaptic potentials, consistent with a
      contribution to STP.

PMID- 12482771
TI  - Selected contribution: skeletal muscle capillarity and enzyme activity in rats
      selectively bred for running endurance.
AB  - To attempt to explain the difference in intrinsic (untrained) endurance running
      capacity in rats selectively bred over seven generations for either low (LCR) or
      high running capacity (HCR), the relationship among skeletal muscle capillarity,
      fiber composition, enzyme activity, and O(2) transport was studied. Ten females
      from each group [body wt: 228 g (HCR), 247 g (LCR); P = 0.03] were studied at 25
      wk of age. Peak normoxic maximum O(2) consumption and muscle O(2) conductance
      were previously reported to be 12 and 33% higher, respectively, in HCR, despite
      similar ventilation, arterial O(2) saturation, and a cardiac output that was <10%
      greater in HCR compared with LCR. Total capillary and fiber number in the medial
      gastrocnemius were similar in HCR and LCR, but, because fiber area was 37% lower
      in HCR, the number of capillaries per unit area (or mass) of muscle was higher in
      HCR by 32% (P < 0.001). A positive correlation (r = 0.92) was seen between
      capillary density and muscle O(2) conductance. Skeletal muscle enzymes citrate
      synthase and beta-hydroxyacyl-CoA dehydrogenase were both approximately 40%
      higher (P < 0.001) in HCR (12.4 +/- 0.7 vs. 8.7 +/- 0.4 and 3.4 +/- 0.2 vs. 2.4
      +/- 0.2 mmol. kg(-1). min(-1), respectively), whereas phosphofructokinase was
      significantly (P = 0.02) lower in HCR (27.8 +/- 1.2 vs. 35.2 +/- 2.5 mmol. kg(
      1). min(-1)) and hexokinase was the same (0.65 +/- 0.04 vs. 0.65 +/- 0.03 mmol.
      kg(-1). min(-1)). Resting muscle ATP, phosphocreatine, and glycogen contents were
      not different between groups. Taken together, these data suggest that, in rats
      selectively bred for high-endurance exercise capacity, most of the adaptations
      for improved O(2) utilization occur peripherally in the skeletal muscles and not
      in differences at the level of the heart or lung.

PMID- 12482772
TI  - Fever induction by localized subcutaneous inflammation in guinea pigs: the role
      of cytokines and prostaglandins.
AB  - In guinea pigs, dose-dependent febrile responses can be induced by injection of a
      high (100 micro g/kg) or low (10 micro g/kg) dose of bacterial lipopolysaccharide
      (LPS) into artificial subcutaneously implanted Teflon chambers. In this fever
      model, LPS does not enter the systemic circulation from the site of localized
      tissue inflammation in considerable amounts but causes a local induction of the
      proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6),
      which can be measured in lavage fluid collected from the chamber area. Only in
      response to the high LPS dose, small traces of TNF are measurable in blood
      plasma. A moderate increase of circulating IL-6 occurs in response to
      administration of both LPS doses. To investigate the putative roles of TNF and
      prostaglandins in this fever model, a neutralizing TNF binding protein (TNF-bp)
      or a nonselective inhibitor of cyclooxygenases (diclofenac) was injected along
      with the high or low dose of LPS into the subcutaneous chamber. In control
      groups, both doses of LPS were administered into the chamber along with the
      respective vehicles for the applied drugs. The fever response to the high LPS
      dose remained unimpaired by treatment with TNF-bp despite an effective
      neutralization of bioactive TNF in the inflamed tissue area. In response to the
      low LPS dose, there was an accelerated defervescence under the influence of TNF
      bp. Blockade of prostaglandin formation with diclofenac completely abolished
      fever in response to both LPS doses. In conclusion, prostaglandins seem to be
      essential components for the manifestation of fever in this model.

PMID- 12482773
TI  - Cardiovascular and splenic responses to exercise in humans.
AB  - To investigate splenic erythrocyte volume after exercise and the effect on
      hematocrit- and hemoglobin-based plasma volume equations, nine men cycled at an
      intensity of 60% maximal O(2) uptake for 5-, 10-, or 15-min duration, followed by
      an incremental ride to exhaustion. The reduction in spleen volume, calculated
      using (99m)Tc-labeled erythrocytes, was not significantly different among the
      three submaximal rides (5 min = 28%, 10 min = 30%, 15 min = 36%; P = 0.26). The
      incremental ride to exhaustion resulted in a 56% reduction in spleen volume,
      which recovered to baseline levels within 20 min. Plasma catecholamines were
      inversely related to spleen volume after exercise (r = 0.70-0.84; P < 0.0001).
      There were no differences in red cell or total blood volume pre- to postexercise;
      however, a significant reduction in plasma volume was observed (18.9%; P < 0.01).
      There was no difference between the iodinated albumin and the hematocrit and
      hemoglobin methods of assessing plasma volume changes. These results suggest that
      the spleen regulates its volume in response to an intensity-dependent signal, and
      plasma catecholamines appear partially responsible. Splenic release of
      erythrocytes has no effect on indirect measures of plasma volume.

PMID- 12482774
TI  - Risk assessment in coronary artery surgery.

PMID- 12482775
TI  - Heart research and ancient Greek medicine.

PMID- 12482776
TI  - Coarctation of the aorta in adults: do we need surgeons?

PMID- 12482777
TI  - Aortic dissection extending to both carotid arteries.

PMID- 12482778
TI  - Dissection of the aorta: a new approach.
AB  - There are two generally proposed causes of dissection of the aorta: (1) cleavage
      caused by blood entering the tear; and (2) haemorrhage that dissects the media
      and tear secondary to the cleavage. Using analysis of pressures and forces, this
      article shows that, on some occasions, these mechanisms alone cannot be
      responsible for causing aortic dissection

PMID- 12482779
TI  - Assessment of myocardial viability: using coronary pressure and flow after acute
      myocardial infarction.

PMID- 12482780
TI  - Pituitary apoplexy following anticoagulation for acute coronary syndrome.

PMID- 12482781
TI  - Histopathology of coronary in-stent restenosis following gamma brachytherapy.
AB  - The histopathology of in-stent restenosis (ISR) following gamma brachytherapy is
      described. Such histology has not been reported previously. An 82 year old man
      presented with recurrent ISR three months after gamma brachytherapy to an area of
      ISR within a native circumflex vessel. The recurrent ISR was treated with
      directional coronary atherectomy; the histopathology of this directional coronary
      atherectomy specimen is discussed. These histopathological examinations showed
      abundant extracellular matrix material. Surprisingly, there was a relatively
      small cellular (myofibroblastic) component, with an absence of endothelial cells
      and little evidence of active proliferation. ISR after gamma brachytherapy may be
      a pathologically distinct entity.

PMID- 12482783
TI  - A novel form of spontaneous coronary vasospasm: bead-like vasospasm in an elderly
      man.

PMID- 12482782
TI  - Therapeutic inhibition of tumour necrosis factor alpha in patients with heart
      failure: cooling an inflamed heart.
AB  - Heart failure is a systemic disorder characterised by tissue hypoxia and
      secondary organ dysfunction which occurs in response to various myocardial
      insults that include ischaemia, viral infections, and toxins. In addition to
      maladaptive neurohumoral activation, heart failure is associated with an
      inflammatory state that appears to have a detrimental effect on cardiac function
      and prognosis. This has led to the suggestion that anti-inflammatory
      interventions may have therapeutic potential in the symptomatic and prognostic
      treatment of patients with heart failure. This review considers the role of
      inhibition of the cytokine tumour necrosis factor alpha in the treatment of heart
      failure.

PMID- 12482784
TI  - Coronary risk factors predicting early and late coronary deaths.
AB  - OBJECTIVE: To study the time related association of a single measurement of
      coronary risk factors with coronary heart disease (CHD) deaths occurring during a
      very long follow up period in a population sample of middle aged men. DESIGN,
      SETTING, AND METHODS: Age, systolic blood pressure, serum total cholesterol,
      physical activity at work, body mass index, and cigarette smoking were measured
      once in 1622 CHD-free men aged 40-59 belonging to the Italian rural cohorts of
      the seven countries study. During 35 years of follow up 214 men died from CHD
      (sudden death and definite myocardial infarction). Seven partitioned proportional
      hazards models were solved, one for each independent five year block of follow
      up, to predict the risk of CHD death. RESULTS: The seven, five year partitioned
      hazard functions were cumulated and smoothed for each risk factor. The resulting
      curves showed a regularly increasing time trend in risk for coronary deaths as a
      function of age, serum cholesterol, systolic blood pressure, and cigarette
      smoking and a regularly decreasing risk for physical activity. The curves fit
      straight lines, with large squared correlation coefficients ranging from 0.92
      0.97. This suggests a relatively constant strength in the association of risk
      factor levels with events, which are predicted whatever the length of time after
      risk factors were measured. These findings were not altered by adding to the
      models risk factor changes preceding the quinquennium of death. CONCLUSION: A
      single measurement of some coronary risk factors in middle aged men maintains a
      regular and almost monotonic relation with the occurrence of CHD deaths during 35
      years of follow up.

PMID- 12482785
TI  - Factors associated with survival to hospital discharge among patients
      hospitalised alive after out of hospital cardiac arrest: change in outcome over
      20 years in the community of Goteborg, Sweden.
AB  - OBJECTIVE: To describe the change in survival and factors associated with
      survival during a 20 year period among patients suffering from out of hospital
      cardiac arrest and being hospitalised alive. PATIENTS: All patients hospitalised
      alive in the community of Goteborg after out of hospital cardiac arrest between 1
      October 1980 and 1 October 2000 were included. METHODS: Patient data were
      prospectively computerised with regard to factors at resuscitation. Data on
      medical history and hospitalisation were retrospectively recorded. Patients were
      divided into two groups (the first and second 10 year periods). SETTING:
      Community of Goteborg, Sweden. RESULTS: 5505 patients suffered from cardiac
      arrest during the time of the survey. Among them 1310 patients (24%) were
      hospitalised alive. Survival (discharged alive) was 37.5% during the first part
      and 35.1% during the second part (NS). The following were independent predictors
      of an increased chance of survival: ventricular fibrillation/tachycardia as the
      first recorded rhythm (odds ratio (OR) 3.46, 95% confidence interval (CI) 2.36 to
      5.07); witnessed arrest (OR 2.50, 95% CI 1.52 to 4.10); bystander initiated
      cardiopulmonary resuscitation (OR 2.00, 95% CI 1.42 to 2.80); the patient being
      conscious on admission to hospital (OR 6.43, 95% CI 3.61 to 11.45); sinus rhythm
      on admission to hospital (OR 1.53, 95% CI 1.12 to 2.10); and treatment with
      lidocaine in the emergency department (OR 1.64, 95% CI 1.16 to 2.31). The
      following were independent predictors of a low chance of survival: age > 70 years
      (median) (OR 0.65, 95% CI 0.47 to 0.88); atropine required in the emergency
      department (OR 0.35, 95% CI 0.16 to 0.75); and chronic treatment with diuretics
      before hospital admission (OR 0.59, 95% CI 0.43 to 0.81). CONCLUSION: There was
      no improvement in survival over time among initial survivors of out of hospital
      cardiac arrest during a 20 year period. Major indicators for an increased chance
      of survival were initial ventricular fibrillation/tachycardia, bystander
      cardiopulmonary resuscitation, arrest being witnessed, and the patient being
      conscious on admission. Major indicators for a lower chance were high age,
      requirement for atropine in the emergency department, and chronic treatment with
      diuretics before cardiac arrest.

PMID- 12482786
TI  - Effect of diabetes on serum potassium concentrations in acute coronary syndromes.
AB  - OBJECTIVES: To compare serum potassium concentrations in diabetic and non
      diabetic patients in the early phase of acute coronary syndromes. BACKGROUND:
      Acute phase hypokalaemia occurs in response to adrenergic activation, which
      stimulates membrane bound sodium-potassium-ATPase and drives potassium into the
      cells. It is not known whether the hypokalaemia is attenuated in patients with
      diabetes because of the high prevalence of sympathetic nerve dysfunction.
      METHODS: Prospective cohort study of 2428 patients presenting with acute coronary
      syndromes. Patients were stratified by duration of chest pain, diabetic status,
      and pretreatment with beta blockers. RESULTS: The mean (SD) serum potassium
      concentration was significantly higher in diabetic than in non-diabetic patients
      (4.3 (0.5) v 4.1 (0.5) mmol/l, p < 0.0001). Multivariate analysis identified
      diabetes as an independent predictor of a serum potassium concentration in the
      upper half of the distribution (odds ratio 1.66, 95% confidence interval 1.38 to
      2.00). In patients presenting within 6 hours of symptom onset, there was a
      progressive increase in plasma potassium concentrations from 4.08 (0.46) mmol/l
      in patients presenting within 2 hours, to 4.20 (0.47) mmol/l in patients
      presenting between 2-4 hours, to 4.24 (0.52) mmol/l in patients presenting
      between 4-6 hours (p = 0.0007). This pattern of increasing serum potassium
      concentration with duration of chest pain was attenuated in patients with
      diabetes, particularly those with unstable angina. Similar attenuation occurred
      in patients pretreated with beta blockers. CONCLUSION: In acute coronary
      syndromes, patients with diabetes have significantly higher serum potassium
      concentrations and do not exhibit the early dip seen in non-diabetics. This may
      reflect sympathetic nerve dysfunction that commonly complicates diabetes.

PMID- 12482787
TI  - Cumulative risk assessment in unstable angina: clinical, electrocardiographic,
      autonomic, and biochemical markers.
AB  - OBJECTIVES: To determine the incremental value of clinical data, troponin T, ST
      segment monitoring, and heart rate variability for predicting outcome in patients
      with non-ST elevation acute coronary syndromes. METHODS: Prospective cohort study
      of 304 consecutive patients. Baseline clinical and electrocardiographic data were
      recorded, serial blood samples were obtained for troponin T assay, and 48 hour
      Holter monitoring was performed for ST segment and heart rate variability
      analysis. End points were cardiac death and non-fatal myocardial infarction
      during 12 months' follow up. RESULTS: After 12 months, 7 patients had died and 21
      had had non-fatal myocardial infarction. The risk of an event was increased by
      troponin T > 0.1 microg/l, T wave inversion on the presenting ECG, Holter ST
      shift, and a decrease in the standard deviation of 5 minute mean RR intervals.
      Positive predictive values of individual multivariate risk were low; however,
      analysis of all multivariate risk markers permitted calculation of a cumulative
      risk score, which increased the positive predictive value to 46.9% while
      retaining a negative predictive value of 96.9%. CONCLUSION: A cumulative approach
      to risk stratification in non-ST elevation coronary syndromes successfully
      identifies a group in whom the risk of cardiac death or non-fatal myocardial
      infarction approaches 50%.

PMID- 12482788
TI  - Pulmonary arteriovenous fistula.

PMID- 12482789
TI  - Mode of death in heart failure: findings from the ATLAS trial.
AB  - OBJECTIVE: To investigate markers that predict modes of death in patients with
      chronic heart failure. DESIGN: Randomised, double blind, three period,
      comparative, parallel group study (ATLAS, assessment of treatment with lisinopril
      and survival). PATIENTS: 3164 patients with mild, moderate, or severe chronic
      heart failure (New York Heart Association functional class II-IV). INTERVENTIONS:
      High dose (32.5 or 35 mg) or low dose (2.5 or 5 mg) lisinopril once daily for a
      median of 46 months. MAIN OUTCOME MEASURES: All cause mortality, cardiovascular
      mortality, sudden death, and chronic heart failure death related to prognostic
      factors using competing risks analysis. Mode of death was classified by trialists
      and by an independent end point committee. RESULTS: Age, male sex, pre-existing
      ischaemic heart disease, increasing heart rate, creatinine concentration, and
      certain drugs taken at randomisation were markers of increased risk of all cause
      mortality and cardiovascular death. There were risk markers for sudden death that
      were different from the risk markers for death from chronic heart failure. Low
      systolic blood pressure at baseline, raised creatinine, reduced serum sodium or
      haemoglobin, and increased heart rate were associated with chronic heart failure
      death. Use of beta blockers or antiarrhythmic agents (mainly amiodarone) was
      associated with a reduced risk of sudden death, whereas long acting nitrates and
      previous use of angiotensin converting enzyme inhibitors were markers for
      increased risk. CONCLUSIONS: The use of competing risks analysis on the data from
      the ATLAS study has identified variables associated with certain modes of death
      in heart failure patients. This approach to analysing outcomes may make it
      possible to predict which patients might benefit most from particular therapeutic
      interventions.

PMID- 12482792
TI  - High prevalence of left ventricular systolic and diastolic asynchrony in patients
      with congestive heart failure and normal QRS duration.
AB  - OBJECTIVE: To study the possible occurrence of left ventricular (LV) systolic and
      diastolic asynchrony in patients with systolic heart failure (HF) and narrow QRS
      complexes. DESIGN: Prospective study. SETTING: University teaching hospital.
      PATIENTS: 200 subjects were studied by echocardiography. 67 patients had HF and
      narrow QRS complexes (< or = 120 ms), 45 patients had HF and wide QRS complexes
      (> 120 ms), and 88 served as normal controls. INTERVENTIONS: Echocardiography
      with tissue Doppler imaging was performed using a six basal, six mid-segmental
      model. MAIN OUTCOME MEASURES: Severity and prevalence of systolic and diastolic
      asynchrony, as assessed by the maximal difference in time to peak myocardial
      systolic contraction (T(S)) and early diastolic relaxation (T(E)), and the
      standard deviation of T(S) (T(S)-SD) and of T(E) (T(E)-SD) of the 12 LV segments.
      RESULTS: The mean (SD) maximal difference in T(S) (controls 53 (23) ms v narrow
      QRS 107 (54) ms v wide QRS 130 (51) ms, both p < 0.001 v controls) and in T(S)-SD
      (controls 17.0 (7.8) ms v narrow QRS 33.8 (16.9) ms v wide QRS 42.0 (16.5) ms,
      both p < 0.001 v controls) was prolonged in the narrow QRS group compared with
      normal controls. Similarly, the maximal difference in T(E) (controls 59 (19) ms v
      narrow QRS 104 (71) ms v wide QRS 148 (87) ms, both p < 0.001 v controls) and in
      T(E)-SD (controls 18.5 (5.8) ms v narrow QRS 33.3 (27.7) ms v wide QRS 48.6
      (30.2) ms, both p < 0.001 v controls) was prolonged in the narrow QRS group. The
      prevalence of systolic and diastolic asynchrony was 51% and 46%, respectively, in
      the narrow QRS group, and 73% and 69%, respectively, in the wide QRS group.
      Stepwise multiple regression analysis showed that a low mean myocardial systolic
      velocity from the six basal LV segments and a large LV end systolic diameter were
      independent predictors of systolic asynchrony, while a low mean myocardial early
      diastolic velocity and QRS complex duration were independent predictors of
      diastolic asynchrony. CONCLUSIONS: LV systolic and diastolic mechanical
      asynchrony is common in patients with HF with narrow QRS complexes. As QRS
      complex duration is not a determinant of systolic asynchrony, it implies that
      assessment of intraventricular synchronicity is probably more important than QRS
      duration in considering cardiac resynchronisation treatment.

PMID- 12482791
TI  - Heart failure and the aging population: an increasing burden in the 21st century?
AB  - BACKGROUND: Despite an overall decline in age adjusted mortality from coronary
      heart disease in developed countries, the number of patients with heart failure
      may be increasing. OBJECTIVE: To project the future burden of heart failure in
      Scotland from contemporary epidemiological data. METHODS: Scotland, like many
      industrialised countries, has an aging though numerically stable population (5.1
      million). Current estimates of prevalence, general practice (GP) consultation
      rates, and hospital admission rates related to heart failure were applied to the
      whole Scottish population. These estimates were then projected over the period
      2000 to 2020, on an age and sex specific basis, using expected changes in the age
      structure of the Scottish population. RESULTS: There are currently estimated to
      be 40 000 men and 45 000 women aged > or = 45 years with heart failure in
      Scotland. On the basis of population changes alone, these figures will rise in
      men and women by 2300 (6%) and 1500 (3%) by year 2005, and by 12 300 (31%) and
      7800 (17%) in the longer term (2020), respectively. On the same basis, the annual
      number of male and female GP visits is likely to rise by 6400 (6%) and 2500 (2%)
      by year 2005, and by 35 200 (40%) and 17 300 (16%) in the longer term (124 000
      and 126 000 visits), respectively. In the year 2000 about 3500 men and 4300 women
      in Scotland had an incident hospital admission for heart failure. By the year
      2020 these figures are likely to increase by 52% (1800 more) and 16% (717 more)
      in men and women, respectively. If recent trends in short term case fatality
      rates continue to improve, the number of men who survive this event will increase
      by 59% (1700 more). Overall, by 2020 the annual number of male and female
      hospital admissions associated with a principal diagnosis of heart failure is
      expected to increase by 34% (from 5500 to 7500) and by 12% (from 7800 to 8500),
      respectively. CONCLUSIONS: Unless rapid and major changes occur in the incidence
      of heart failure, the burden of this disorder will continue to increase in both
      primary and secondary care over the next two decades. The greatest increase is
      likely to occur in men. Future health service planning must take this into
      account.

PMID- 12482793
TI  - Fragile left atrial thrombus successfully treated with anticoagulants.

PMID- 12482794
TI  - Effects of glucose-insulin-potassium infusion on chronic ischaemic left
      ventricular dysfunction.
AB  - BACKGROUND: Glucose-insulin-potassium (GIK) infusion improves cardiac function
      and outcome during acute ischaemia. OBJECTIVE: To determine whether GIK infusion
      benefits patients with chronic ischaemic left ventricular dysfunction, and if so
      whether this is related to the presence and nature of viable myocardium. METHODS:
      30 patients with chronic ischaemic left ventricular dysfunction had dobutamine
      echocardiography and were given a four hour infusion of GIK. Segmental responses
      were quantified by improvement in wall motion score index (WMSI) and peak
      systolic velocity using tissue Doppler. Global responses were assessed by left
      ventricular volume and ejection fraction, measured using a three dimensional
      reconstruction. Myocardial perfusion was determined in 15 patients using contrast
      echocardiography. RESULTS: WMSI (mean (SD)) improved with dobutamine (from 1.8
      (0.4) to 1.6 (0.4), p < 0.001) and with GIK (from 1.8 (0.4) to 1.7 (0.4), p <
      0.001); there was a similar increment for both. Improvement in wall motion score
      with GIK was observed in 55% of the 62 segments classed as viable by dobutamine
      echocardiography, and in 5% of 162 classed as non-viable. There was an increment
      in peak systolic velocity after both dobutamine echocardiography (from 2.5 (1.8)
      to 3.2 (2.2) cm/s, p < 0.01) and GIK (from 3.0 (1.6) to 3.5 (1.7) cm/s, p <
      0.001). The GIK effects were not mediated by changes in pulse, mean arterial
      pressure, lactate, or catecholamines, nor did they correlate with myocardial
      perfusion. End systolic volume improved after GIK (p = 0.03), but only in 25
      patients who had viable myocardium on dobutamine echocardiography. CONCLUSIONS:
      In patients with viable myocardium and chronic left ventricular dysfunction, GIK
      improves wall motion score, myocardial velocity, and end systolic volume,
      independent of effects on haemodynamics or catecholamines. The response to GIK is
      observed in areas of normal and abnormal perfusion assessed by contrast
      echocardiography.

PMID- 12482795
TI  - Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic
      characteristics and optimal therapeutic strategies to prevent sudden death.
AB  - OBJECTIVE: To investigate the clinical outcome, ECG characteristics, and optimal
      treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), a
      malignant and rare ventricular tachycardia. PATIENTS AND METHODS: Questionnaire
      responses and ECGs of 29 patients with CPVT were evaluated. Mean (SD) age of
      onset was 10.3 (6.1) years. RESULTS: The initial CPVT manifestations were syncope
      (79%), cardiac arrest (7%), and a family history (14%). ECGs showed sinus
      bradycardia and a normal QTc. Mean heart rate during CPVT was 192 (30) beats/min.
      Most cases were non-sustained (72%), but 21% were sustained and 7% were
      associated with ventricular fibrillation. The morphology of CPVT was polymorphic
      (62%), polymorphic and bidirectional (21%), bidirectional (10%), or polymorphic
      with ventricular fibrillation (7%). There was 100% inducement of CPVT by
      exercise, 75% by catecholamine infusion, and none by programmed stimulation. No
      late potential was recorded. Onset was in the right ventricular outflow tract in
      more than half the cases. During a follow up of 6.8 (4.9) years, sudden death
      occurred in 24% of the patients, 7% of whom had anoxic brain damage. Autosomal
      dominant inheritance was seen in 8% of the patients' families. beta Blockers
      completely controlled CPVT in only 31% of cases. Calcium antagonists partially
      suppressed CPVT in autosomal dominant cases. CONCLUSIONS: CPVT may arise in
      certain distinct areas but the prognosis is poor. The onset of CPVT may be an
      indication for an implanted cardioverter-defibrillator.

PMID- 12482796
TI  - Assessment of myocardial viability using coronary zero flow pressure after
      successful angioplasty in patients with acute anterior myocardial infarction.
AB  - OBJECTIVES: To investigate the relation between coronary flow reserve (CFR),
      coronary zero flow pressure (Pzf), and residual myocardial viability in patients
      with acute myocardial infarction. DESIGNS: Prospective study. SETTING: Primary
      care hospital. PATIENTS: 27 consecutive patients with acute anterior myocardial
      infarction. MAIN OUTCOME MEASURES: F-fluorodeoxyglucose (FDG) positron emission
      tomography (PET) was used in 27 patients who underwent successful intervention
      within 12 hours of onset of a first acute anterior myocardial infarction. Within
      three days before discharge they had < 25% stenosis in the culprit lesion as
      determined by angiography 24 (3) days after acute myocardial infarction. Pzf and
      the slope index of the flow-pressure relation (SIFP) were calculated from the
      simultaneously recorded aortic pressure and coronary flow velocity signals at
      peak hyperaemia.%FDG was quantified by comparing FDG uptake in the infarct
      myocardium with FDG uptake in the normal myocardium. RESULTS: There was a
      correlation between %FDG and CFR, where y = -1.477x + 62.517, r = -0.072 (NS).
      There was also a correlation between %FDG and SIFP, where y = -0.975x + 60.542, r
      = -0.045 (NS), and a significant correlation between %FDG and Pzf, where y = 
      0.98x + 85.108, r = -0.696 (p < 0.001). CONCLUSIONS: CFR does not correlate with
      FDG-PET at the time of postreperfusion evaluation of residual myocardial
      viability. The parameter that correlates best with residual myocardial viability
      is Pzf and this may be a useful index for predicting patient prognosis.

PMID- 12482797
TI  - Complete occlusion of the abdominal aorta with a solitary kidney.

PMID- 12482800
TI  - First human use of a new PFM "Babystent".

PMID- 12482798
TI  - The adult patient with native coarctation of the aorta: balloon angioplasty or
      primary stenting?
AB  - OBJECTIVE: To compare results of dilatation of native coarctation of the aorta
      with and without stent implantation. DESIGN: Open, observational, non-randomised
      study. PATIENTS: 54 consecutive adult patients: 32 with balloon angioplasty alone
      (group 1) and 22 with stent placement (group 2). INTERVENTIONS: Balloon
      dilatation from 1995 to 1997; dilatation with Palmaz stent placement from 1997 to
      1999. MAIN OUTCOME MEASURES: The primary end point was a composite index of
      failure including heart related death, a residual gradient of > 20 mm Hg, the
      need of reintervention, and aneurysm formation. RESULTS: Peak systolic gradient
      (mean (SD)) was reduced both in group 1 (from 63.3 (22.8) to 10.7 (10.8) mm Hg, p
      < 0.001) and group 2 (from 63.9 (20.8) to 2.7 (4.3) mm Hg, p < 0.001), but Delta
      change was significantly greater in group 2. A residual gradient of > 10 mm Hg
      was shown to be the best cut off point to separate risk groups, representing a
      hazard ratio (HR) of 9.59 compared with a residual gradient of < or = 10 mm Hg
      (95% confidence interval (CI) 1.92 to 47.8). From multivariate Cox regression
      analysis, the only risk marker was the residual gradient (HR 8.9, 95% CI 1.2 to
      63.0). The type of the coarctation and the use of stent were the factors
      associated with a residual gradient of < or = 10 mm Hg. CONCLUSIONS: Mid term
      outcome in adult patients with native aortic coarctation receiving percutaneous
      treatment is strongly related to the immediate residual gradient. When treating
      these cases, efforts should be made to obtain gradients under 10 mm Hg, either by
      angioplasty alone or by placing a stent. Patients with discrete aortic
      coarctation have similar mid term results when the immediate residual gradient is
      < or = 10 mm Hg despite the implantation of a stent. To achieve these gradients,
      patients with hypoplastic isthmus or tubular coarctation should be treated with
      primary stenting. Further studies including exercise tests and non-invasive
      imaging are still needed before definitive conclusions can be drawn.

PMID- 12482801
TI  - Mechanism of lumen enlargement with direct stenting versus predilatation
      stenting: influence of remodelling and plaque characteristics assessed by
      volumetric intracoronary ultrasound.
AB  - OBJECTIVE: To compare the effects of arterial remodelling and plaque
      characteristics on the mechanisms of direct stenting and predilatation stenting.
      Direct stenting has become routine in some laboratories and differs technically
      from predilatation stenting. METHODS: Pre- and post-interventional volumetric
      intravascular ultrasound (IVUS) was undertaken in 30 patients with direct
      stenting and in 30 with predilatation stenting of non-calcified native coronary
      lesions, using the same stent design and stent length. Lumen, vessel (external
      elastic membrane (EEM)), and plaque (plaque + media) volumes were calculated.
      Remodelling was determined by comparing the EEM area at the centre of the lesion
      with the EEM areas at proximal and distal reference sites. Plaque eccentricity
      was defined as the thinnest plaque diameter to the thickest plaque diameter
      ratio. Plaque composition was characterised as soft, mixed, or dense. RESULTS:
      All volumetric IVUS changes were similar in the two groups. Pre-intervention
      remodelling remained uninfluenced after direct stenting, but was neutralised
      after predilatation stenting. Eccentric lesions responded to intervention by a
      greater luminal gain owing to greater vessel expansion in direct stenting. Plaque
      composition influenced luminal gain in direct stenting, the gain being greatest
      in the softest plaques; in predilatation stenting, luminal gain was equivalent
      but vessel expansion was greater for "dense" plaque and plaque reduction greater
      for "soft" plaque. CONCLUSIONS: In non-calcified lesions, the mechanisms of lumen
      enlargement after direct or predilatation stenting are significantly influenced
      by atherosclerotic remodelling, plaque eccentricity, and plaque composition.

PMID- 12482804
TI  - Tumour necrosis factor alpha concentration and collateral flow in patients with
      coronary artery disease and normal systolic left ventricular function.

PMID- 12482802
TI  - Transoesophageal atrial pacing combined with transthoracic two dimensional
      echocardiography: experience in patients operated on with arterial switch
      operation for transposition of the great arteries.
AB  - OBJECTIVE: To assess the feasibility, safety, and diagnostic accuracy of
      transoesophageal atrial pacing stress echocardiography (TAPSE) combined with two
      dimensional transthoracic echocardiography (TTE) for evaluation of coronary
      perfusion in patients undergoing arterial switch operation for transposition of
      the great arteries. DESIGN: TAPSE combined with TTE was performed at the end of
      cardiac catheterisation. An ischaemic response was defined as > 1.5 mm horizontal
      or downsloping ST segment depression or as a new or worsened wall motion
      abnormality. The results were compared with results of coronary angiography.
      SETTING: Tertiary referral centre for paediatric cardiology and cardiac surgery.
      PATIENTS: 25 patients, mean (SD) age 29.5 (19) months, mean (SD) weight 12.5
      (3.4) kg. MAIN OUTCOME MEASURES: Target heart rate (200 beats/min) was attained
      in 22 of 25 (88%) patients. Electrocardiographic ischaemic changes occurred in 4
      of 25 (16%) and wall motion abnormalities in 3 of 25 (12%). Coronary obstructions
      were found in 2 of 25 (8%) patients. RESULTS: The test was feasible in all
      patients, without clinical complications requiring treatment. Compared with
      coronary angiography, the test had a sensitivity and a specificity of 100% and
      95%, respectively, for the echocardiographic stress, and of 100% and 91%,
      respectively, for the electrocardiographic stress. The negative predictive value
      was 100% for both the echocardiographic and the electrocardiographic stress
      tests. The positive predictive value was 66% for the echocardiographic stress and
      50% for the electrocardiographic stress tests. CONCLUSIONS: In these patients
      TAPSE combined with TTE was feasible and safe and apparently an accurate
      diagnostic method for evaluation of coronary perfusion. Patients with a negative
      test may have a low likelihood of major coronary abnormalities and may not
      require coronary angiography.

PMID- 12482805
TI  - The risk model of choice for coronary surgery in the UK.

PMID- 12482806
TI  - Imaging of a huge atrial myxoma.

PMID- 12482807
TI  - Timing of surgery in mitral regurgitation.

PMID- 12482808
TI  - Pacing for atrial fibrillation.

PMID- 12482809
TI  - Stress echocardiography.

PMID- 12482811
TI  - Catheter ablation of sinoatrial re-entry tachycardia in a 2 month old infant.
AB  - Successful catheter ablation of sinoatrial re-entry tachycardia in an infant has
      not been previously reported. This procedure is described in a 2 month old boy
      with tachycardia induced cardiomyopathy.

PMID- 12482812
TI  - Sisters with atypical Fabry's disease with complete atrioventricular block.
AB  - A 56 year old woman with severe right heart failure and complete atrioventricular
      block was referred to hospital for further examination. Symptoms and signs
      suggestive of Fabry's disease, such as corneal opacities, acroparaesthesias,
      hypohidrosis, and angiokeratoma, were not noted. Echocardiography showed a
      diffuse hypertrophic left ventricular wall and paradoxical movement of the
      interventricular septum. Cardiac catheterisation showed restrictive-type
      ventricular dysfunction. Left ventricular endomyocardial biopsy showed central
      vacuolar degeneration of myocytes with inclusion bodies, which had a concentric
      lamellar configuration under electron microscopy. This finding is specific for
      Fabry's disease. The patient's elder sister had experienced an almost identical
      clinical course and histological findings of myocardial cells on necropsy. In
      conclusion, two sisters were encountered displaying interesting cases of atypical
      Fabry's disease. Symptoms began with complete atrioventricular block and
      histological myocardial findings were specific for Fabry's disease.

PMID- 12482813
TI  - Unruptured congenital aneurysm of the left sinus of Valsalva in an adult with
      complex left heart malformations.
AB  - A 26 year old man who presented with the first signs of right heart failure was
      found to have a large congenital aneurysm of the aortic sinus of Valsalva and of
      the left coronary sinus. These were combined with left heart anomalies in the
      form of a bicuspid aortic valve, a rare variant of a persistent left superior
      vena cava with blood flow from the left atrium through the brachiocephalic vein
      into the superior vena cava and a kink in the aortic arch. An aortic coarctation
      had been corrected with a patch 12 years earlier. Although the aneurysm was not
      perforated and there were no clinical signs of infarction, the aneurysm was
      resected prophylactically and the left coronary artery was reinserted through a
      bypass with a Gore-Tex conduit. The case is noteworthy because this diagnosis is
      very rare and its early treatment may prevent several complications. The clinical
      features, treatment, and outcome are discussed.

PMID- 12482814
TI  - Coronary artery aneurysm with a fistulous connection to the right atrium
      mimicking a sinus of Valsalva aneurysm.
AB  - Coronary artery aneurysms are uncommon and may be complicated by rupture,
      thromboembolic phenomenon, and more rarely fistulation into one of the cardiac
      chambers. This case report highlights the difficulty in making a preoperative
      diagnosis of a coronary artery aneurysm that has fistulated into the right
      atrium, and lists possible differential diagnoses.

PMID- 12482815
TI  - Do PAI-1 and vitronectin promote or inhibit neointima formation? The exact role
      of the fibrinolytic system in vascular remodeling remains uncertain.

PMID- 12482816
TI  - Microarray analysis of neointima: flowing toward a clear future.

PMID- 12482817
TI  - Aortic aneurysms: It's all about the stress.

PMID- 12482818
TI  - Oxidized LDL autoantibodies, endothelial dysfunction, and transplant-associated
      arteriosclerosis.

PMID- 12482819
TI  - Nonnuclear actions of estrogen.
AB  - Estrogen has long been observed to endow cardiovascular protective effects, as
      evidenced by sex-specific differences in the incidence of hypertensive and
      coronary artery disease, the development of atherosclerosis, and myocardial
      remodeling after infarction. To exert its tissue-specific effects, the classic
      estrogen receptor (ER) functions as a ligand-dependent transcription factor.
      However, there is growing evidence that in response to 17beta-estradiol and
      heterologous signals, the ER can also mediate signaling cascades at the membrane
      and in the cytoplasm via various second messengers, such as receptor-mediated
      protein kinases. This review summarizes the current understanding of nonnuclear
      ER signaling and discusses the relevance to eliciting the beneficial
      cardiovascular effects of estrogen. These include vasodilation, inhibition of
      response to vessel injury, limiting myocardial injury after infarction, and
      attenuating cardiac hypertrophy. Defining the full repertoire of ER function
      promises to expose novel, highly specific targets for pharmacological
      interventions and may ultimately lead to the primary and secondary prevention of
      cardiovascular diseases.

PMID- 12482820
TI  - The reactive adventitia: fibroblast oxidase in vascular function.
AB  - The vascular adventitia is activated in a variety of cardiovascular disease
      states and has recently been shown to be a barrier to nitric oxide bioactivity.
      Vascular fibroblasts produce substantial amounts of NAD(P)H oxidase-derived
      reactive oxygen species (ROS) that appear to be involved in fibroblast
      proliferation, connective tissue deposition, and perhaps vascular tone. However,
      the physiological and pathophysiological roles of the adventitia have not been
      extensively studied, possibly because of its location in large blood vessels
      remote from the vascular endothelium. In recent years, substantial information
      has been gathered on pathways leading to oxidase activation in smooth muscle
      cells and fibroblasts and the downstream signaling pathways leading to
      hypertrophy and proliferation. A clearer understanding of the molecular
      mechanisms involved will likely lead to therapeutic strategies aimed at
      preventing vascular dysfunction in diseases such as atherosclerosis, in which
      these pathways are activated.

PMID- 12482821
TI  - N-cadherin upregulation and function in response of smooth muscle cells to
      arterial injury.
AB  - OBJECTIVE: Smooth muscle cell migration is critical to neointimal formation after
      arterial injury. The purpose of this study was to elucidate the regulation and
      functional significance of cell-cell adhesion via adherens junctions during this
      process. METHODS AND RESULTS: Using balloon catheter injury of rat carotid
      artery, we showed that neointimal formation is accompanied by dramatic but
      transient upregulation of intimal N-cadherin and associated catenins, proteins
      that mediate adhesion at adherens junctions. Upregulation was demonstrated by
      immunofluorescence microscopy and by immunoblotting, and it coincided with
      evidence of phenotypic modulation of smooth muscle cells. Similar upregulation
      was observed when postconfluent cultures of porcine aortic smooth muscle cells
      were subjected to linear denuding injuries. Furthermore, treatment of wounded
      cultures with a blocking antibody against the extracellular domain of the N
      cadherin protein significantly suppressed the repair of wounds. CONCLUSIONS: N
      cadherin and associated proteins are dynamically regulated during neointimal
      formation and provide evidence that this regulation is important for migratory
      repair. Therefore, N-cadherin may provide a novel target for therapies that are
      directed toward intimal proliferative disorders, including restenosis and
      vascular bypass graft failure.

PMID- 12482822
TI  - Plasminogen activator inhibitor 1 and vitronectin protect against stenosis in a
      murine carotid artery ligation model.
AB  - OBJECTIVE: We previously reported that plasminogen activator inhibitor 1 (PAI-1),
      in the presence of vitronectin (VN), inhibits thrombin activity in vitro.
      Furthermore, we demonstrated in human atherosclerotic plaques the colocalization
      of thrombin, PAI-1, and VN, as well as activity of thrombin and PAI-1. Here, we
      show that PAI-1 is a local thrombin inhibitor in vivo. METHODS AND RESULTS: We
      used the murine carotid artery ligation model to assess the role of PAI-1 and VN
      in stenosis by using PAI-1-deficient (PAI-1(-/-)) and VN(-/-) mice. Ligation
      resulted in a smooth muscle cell (SMC)-rich intima without infiltrating cells. We
      show that PAI-1(-/-) and VN(-/-) mice generate a larger intima than wild-type
      mice as the result of more extensive SMC proliferation, as evidenced by cell
      counting and staining for proliferating cell-nuclear antigen. CONCLUSIONS: In PAI
      1(-/-) mice, excessive intima formation is prevented by the thrombin-specific
      inhibitor hirudin. Finally, immunohistochemical analysis revealed PAI-1, VN, and
      (pro)thrombin antigen in intimal lesions. Our observations are compatible with
      inhibition of thrombin-mediated SMC proliferation by PAI-1/VN complexes.

PMID- 12482823
TI  - PlA polymorphism of integrin beta 3 differentially modulates cellular migration
      on extracellular matrix proteins.
AB  - OBJECTIVE: Cell migration is central to multiple physiological and pathologic
      processes and involves interactions between integrins on the cell surface and the
      extracellular matrix. The Leu33Pro (PlA) polymorphism of integrin beta3 has been
      reported to be associated with a greater rate of restenosis after angioplasty, a
      process involving endothelial and smooth muscle cell migration. We have addressed
      the possibility that the Leu33Pro polymorphism could modify the migratory
      behavior of Chinese hamster ovary (CHO) cells expressing the beta3-containing
      integrin complexes. METHODS AND RESULTS: Haptotactic migratory responses of CHO
      alpha(IIb)beta3 cells to fibronectin and vitronectin were not statistically
      different between the Leu33 and Pro33 cells. However, CHO cells with the Pro33
      (PlA2) polymorphism had an enhanced haptotactic migratory response to fibrinogen
      and von Willebrand Factor. This enhanced migration (1) could be blocked by the
      alpha(IIb)beta3-complex-specific neutralizing mAb 10E5, by 7E3, a neutralizing
      mAb specific for the beta3 integrin, and by the alpha(IIb)beta3-blocking peptide
      Integrilin; (2) was not observed with a CHO cell line expressing an activating
      beta3 Cys435 to Ala mutation; and (3) was attributable to increased activity of
      mitogen-activated protein kinase and cyclooxygenase. CHO cell lines expressing
      the Pro33 isoform of alpha(v)beta3 had an enhanced haptotactic migratory response
      to vitronectin and osteopontin but not fibrinogen. CONCLUSIONS: The Leu33Pro
      polymorphism alters the migratory behavior of cells on extracellular matrix
      substrates, and the alpha subunit influences the substrate specificity of this
      genetic effect.

PMID- 12482824
TI  - Oxidized LDL-induced smooth muscle cell proliferation involves the EGF
      receptor/PI-3 kinase/Akt and the sphingolipid signaling pathways.
AB  - OBJECTIVE: Oxidized low-density lipoprotein (oxLDL)-induced smooth muscle cell
      (SMC) proliferation requires the coactivation of various signaling pathways,
      namely sphingomyelin/ceramide/sphingosine-1-phosphate, epithelial growth factor
      receptor (EGFR), and phosphoinositide 3-kinase (PI-3K) pathways. This study aimed
      to clarify the respective role and the hypothetical cross-talk between
      sphingomyelin/ceramide/sphingosine-1-phosphate, EGFR, and PI-3K/Akt pathways in
      the balance between mitogenic and cytotoxic effects elicited by oxLDL. METHODS
      AND RESULTS: Coimmunoprecipitation experiments and the use of inhibitors and
      dominant-negative mutant showed that oxLDL-induced PI-3K activation is dependent
      on EGFR. PI-3K activation is independent of the
      sphingomyelin/ceramide/sphingosine-1-phosphate pathway, because PI-3K inhibition
      by LY294002 or dominant-negative Deltap85 mutant does not abrogate sphingomyelin
      hydrolysis, and, conversely, the use of permeant C2-ceramide and of N,N-dimethyl
      sphingosine, a sphingosine kinase inhibitor, does not alter PI-3K activity.
      Activation of Akt/PKB by oxLDL requires PI-3K, as shown by the inhibition by
      LY204002 and in Deltap85 SMC. The inhibition of Akt/PKB by PI-3K inhibitor
      LY204002 or by overexpression of kinase-dead Akt shifted the mitogenic effect of
      oxLDL toward apoptosis, thus suggesting that the PI-3K/Akt pathway acts as a
      survival pathway. CONCLUSIONS: SMC proliferation elicited by moderate
      concentrations of oxLDL involves the sphingomyelin/ceramide/sphingosine-1
      phosphate pathway, which leads to extracellular regulated kinase 1/2 activation
      and DNA synthesis, and the EGFR/PI-3K/Akt pathway, which prevents the apoptotic
      effect of oxLDL.

PMID- 12482825
TI  - Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to
      endothelial dysfunction.
AB  - OBJECTIVE: We tested the hypothesis that deficiency of cellular glutathione
      peroxidase (GPx-1) enhances susceptibility to endothelial dysfunction in mice
      with moderate hyperhomocysteinemia. METHODS AND RESULTS: Mice that were wild type
      (Gpx1+/+), heterozygous (Gpx1+/-), or homozygous (Gpx1-/-) for the mutated Gpx1
      allele were fed a control diet or a high-methionine diet for 17 weeks. Plasma
      total homocysteine was elevated in mice on the high-methionine diet compared with
      mice on the control diet (23+/-3 versus 6+/-0.3 micromol/L, respectively;
      P<0.001) and was not influenced by Gpx1 genotype. In mice fed the control diet,
      maximal relaxation of the aorta in response to the endothelium-dependent dilator
      acetylcholine (10(-5) mol/L) was similar in Gpx1+/+, Gpx1+/-, and Gpx1-/- mice,
      but relaxation to lower concentrations of acetylcholine was selectively impaired
      in Gpx1-/- mice (P<0.05 versus Gpx1+/+ mice). In mice fed the high-methionine
      diet, relaxation to low and high concentrations of acetylcholine was impaired in
      Gpx1-/- mice (maximal relaxation 73+/-6% in Gpx1-/- mice versus 90+/-2% in
      Gpx1+/+ mice, P<0.05). No differences in vasorelaxation to nitroprusside or
      papaverine were observed between Gpx1+/+ and Gpx1-/- mice fed either diet.
      Dihydroethidium fluorescence, a marker of superoxide, was elevated in Gpx1-/-
      mice fed the high-methionine diet (P<0.05 versus Gpx1+/+ mice fed the control
      diet). CONCLUSIONS: These findings demonstrate that deficiency of GPx-1
      exacerbates endothelial dysfunction in hyperhomocysteinemic mice and provide
      support for the hypothesis that hyperhomocysteinemia contributes to endothelial
      dysfunction through a peroxide-dependent oxidative mechanism.

PMID- 12482826
TI  - Depolarization of endothelial cells enhances platelet aggregation through
      oxidative inactivation of endothelial NTPDase.
AB  - OBJECTIVE: The objective of this study was to investigate whether depolarization
      of cultured endothelial cells (human umbilical vein endothelial cells, HUVECs)
      affects their ectonucleotidase activity through superoxide (O2-) production.
      METHODS AND RESULTS: Depolarization by the cation channel gramicidin (100 nmol/L)
      or tetrabutylammonium chloride (1 mmol/L) induced O2- release from HUVECs (n=4),
      which was decreased by superoxide dismutase (SOD, 500 U/mL). The activity of
      endothelial ectonucleotidases was assessed by the production of inorganic
      phosphate from ADP, which was decreased by chronic depolarization by 25% (n=6,
      P<0.05) and the amount of AMP derived from ADP in the presence of the 5'
      nucleotidase inhibitor alpha,beta-methylene-5'-diphosphate (100 micromol/L). AMP
      was decreased by chronic depolarization from 0.54+/-0.16 to 0.39+/-0.11
      micromol/min/mg protein (n=6, P<0.05). This was abolished in the continuous
      presence of SOD (n=6). NTPDase protein was predominantly expressed in HUVECs
      (n=4). Protein abundance, viability of cells, and apoptosis rates were not
      altered by depolarization (n=10). Only in the presence of depolarized HUVECs, but
      not with control cells or with HUVECs depolarized in the presence of SOD, did 5
      micromol/L of ADP cause irreversible platelet aggregation. Increases in
      transmural pressure induced endothelial depolarization in intact hamster small
      arterioles. CONCLUSIONS: Depolarization causes the endothelial production of O2-,
      which inhibits the activity of endothelial ectonucleotidases. Increases in
      transmural pressure induce endothelial depolarization. In chronically
      hypertensive diseases, depolarization might favor platelet aggregation.

PMID- 12482827
TI  - Expression profiling identifies 147 genes contributing to a unique primate
      neointimal smooth muscle cell phenotype.
AB  - OBJECTIVE: This study represents the first in an effort to systematically
      characterize different intimas by using expression array analysis. METHODS AND
      RESULTS: We compared smooth muscle cells (SMCs) of the neointima formed 4 weeks
      after aortic grafting with those from normal aorta and vena cava from cynomolgus
      monkeys. Hybridization to cDNA arrays identified subsets of 147 and 45 genes
      differentially expressed in the neointima versus the aorta and vena cava,
      respectively. The expression pattern differentiating neointima from aortic SMCs
      was characterized largely by suppression. Only 13 genes were induced in the
      neointima: 7 encoded matrix proteins (6 collagens and 1 versican) and 2 encoded
      inducers of matrix synthesis (osteoblast-specific factor-2/Cbfa1 and connective
      tissue growth factor). The genes suppressed most in the neointima included the
      regulator of G-protein signaling-5, SPARClike-1/hevin, and nonmuscle myosin heavy
      chain-B. A smaller gene set differentiated the neointima from the vena cava. Most
      were induced (39 of 45 genes), and overlap with the neointima-aorta set was
      significant (10 of 13 genes). Array results were validated with Northern
      analysis, in situ hybridization, or immunohistochemistry. CONCLUSIONS: These data
      underscore the importance of matrix synthesis in neointimal maturation, and novel
      genes, newly associated with neointimal SMCs (regulator of G-protein signaling-5
      and osteoblast-specific factor-2/Cbfa1), have raised new hypotheses regarding the
      pathogenesis of intimal hyperplasia.

PMID- 12482828
TI  - Flow loading induces macrophage antioxidative gene expression in experimental
      aneurysms.
AB  - OBJECTIVE: Reactive oxygen species may act as proinflammatory mediators in
      abdominal aortic aneurysm (AAA) disease. Flow loading increases antioxidative
      enzyme expression and limits reactive oxygen species production in vascular
      smooth muscle cells in vitro, limits experimental AAA enlargement in rodent
      models, and is indirectly associated with reduced clinical AAA risk. We attempted
      to determine the mechanism or mechanisms by which flow loading limits AAA
      enlargement. METHODS AND RESULTS: Rodent AAAs were flow loaded via femoral
      arteriovenous fistula creation. Aortic wall shear stress and relative wall strain
      were significantly higher in flow-loaded rodents. Flow loading reduced AAA
      diameter by 26% despite evidence of flow-mediated aortic enlargement proximal to
      the aneurysmal segment. Messenger RNA from AAA tissue was harvested for cDNA
      labeling and hybridization to a 384-clone DNA microarray. Twenty-nine genes were
      differentially expressed (relative intensity/relative intensity of control ratio
      >1.5 and <0.67) in flow-loaded compared with normal flow AAA tissue, including
      heme oxygenase 1 (HO-1). Increased HO-1 expression was confirmed via reverse
      transcriptase-polymerase chain reaction. Immunohistochemistry localized HO-1
      expression to infiltrative macrophages. alpha-Tocopherol was found to be as
      effective as flow loading in limiting AAA enlargement. Flow loading and alpha
      tocopherol therapy reduced AAA reactive oxygen species production. CONCLUSIONS:
      Flow loading may attenuate AAA enlargement via wall shear or strain-related
      reductions in oxidative stress.

PMID- 12482829
TI  - Gene expression profiling of apoptosis-related genes in human atherosclerosis:
      upregulation of death-associated protein kinase.
AB  - OBJECTIVE: Apoptosis substantially affects the cellularity and integrity of
      atherosclerotic plaques. It remains, however, unclear which key regulatory genes
      are involved. In this study, cDNA expression arrays were used to analyze
      transcript levels of 205 apoptosis-related genes in human carotid endarterectomy
      specimens versus nonatherosclerotic mammary arteries. METHODS AND RESULTS:
      Seventeen genes with a 2- to 5-fold relative expression difference were
      identified. One of the most apparent changes in human plaques was the
      overexpression of death-associated protein (DAP) kinase ( approximately 5-fold),
      a positive mediator of apoptotic cell death. Differential expression of DAP
      kinase mRNA in human plaques relative to mammary arteries was confirmed by
      quantitative reverse-transcription polymerase chain reaction. Western blotting
      and immunohistochemistry demonstrated enhanced levels of DAP kinase protein in
      the plaque with negligible expression in non-atherosclerotic vessels. DAP kinase
      was located predominantly in foam cells of smooth muscle cell (SMC) origin.
      Uptake of aggregated LDL by cultured aortic SMCs as well as exposure of SMCs to
      the short-chain acyl ceramide derivative N-hexanoyl-D-sphingosine (C6-ceramide)
      upregulated DAP kinase both at the mRNA and protein level. CONCLUSIONS: Our data
      demonstrate that cDNA array technology can identify novel genes that might
      participate in cell death pathways underlying atherogenesis.

PMID- 12482830
TI  - Differential gene expression in vascular smooth muscle cells in primary
      atherosclerosis and in stent stenosis in humans.
AB  - OBJECTIVE: We sought to identify differentially expressed genes in human in stent
      stenosis (ISS) to provide insights into the mechanism of disease. METHODS AND
      RESULTS: Using representation difference analysis, we examined differential gene
      expression between cultured normal human medial vascular smooth muscle cells
      (VSMCs) and cells from primary atherosclerotic plaques or ISS sites. Specific
      groups of genes were overexpressed in ISS and plaque VSMCs, including cell cycle
      regulatory proteins and cell matrix and contractile proteins. Differential
      expression was validated by virtual Northern analysis, reverse transcriptase
      polymerase chain reaction, in situ hybridization, and immunohistochemistry. All
      ISS genes were expressed by normal intima and had even higher expression in
      primary plaque VSMCs. CONCLUSIONS: ISS VSMCs have a stable gene expression
      profile reflecting an intimal pattern, intermediate between normal medial and
      primary plaque VSMCs. Differential expression profiling may identify markers of
      disease that are overexpressed in ISS and also help elucidate the origin of the
      ISS lesion.

PMID- 12482831
TI  - Cytochrome b558-dependent NAD(P)H oxidase-phox units in smooth muscle and
      macrophages of atherosclerotic lesions.
AB  - OBJECTIVE: Despite studies implicating superoxide anion-producing oxidases in
      atherosclerosis, their characteristics, expression, and regulation in cells of
      lesions are poorly understood. We examined the following: (1) whether cytochrome
      b558-dependent NAD(P)H oxidase-phox peptides are expressed by intimal smooth
      muscle cells (iSMCs) and macrophages of human aortic atherosclerotic lesions and
      their regulation and (2) whether cytochrome b558-dependent NAD(P)H oxidase
      represents a major NAD(P)H oxidase in iSMCs. METHODS AND RESULTS: Using a
      combination of immunochemical and reverse transcription-polymerase chain reaction
      procedures, we demonstrate that p22(phox) and gp91(phox) (cytochrome b558)
      expression in normal intima was restricted to a quarter of the iSMCs. In fatty
      streaks, a similar fraction of iSMCs expressed cytochrome b558, whereas
      macrophages also expressed low levels of p47(phox) and p67(phox). In fibrofatty
      lesions, the majority of iSMCs expressed the cytochrome b558 subunits; p67(phox)
      was also detected. Macrophages and macrophage-derived foam cells expressed the 4
      phox subunits that constitute superoxide-producing cytochrome b558-dependent
      NAD(P)H oxidase. These were upregulated by transforming growth factor-beta1 and
      interferon-gamma. Aortic lesions also expressed Thox1 and Nox4, and although
      their expression also increases with lesion severity, their expression is less
      frequent than that of gp91(phox). CONCLUSIONS: In human aortic fibrofatty
      lesions, a cytochrome b558-dependent NAD(P)H oxidase appears to be a major iSMC
      and macrophage oxidase whose expression is upregulated by cytokines.

PMID- 12482832
TI  - Circulating autoantibodies to oxidized LDL correlate with impaired coronary
      endothelial function after cardiac transplantation.
AB  - OBJECTIVE: The oxidative modification of low density lipoprotein (LDL) may play a
      role in the pathogenesis of transplant-associated arteriosclerosis. Oxidized LDL
      (OxLDL) is immunogenic as well as atherogenic, and the level of autoantibodies to
      OxLDL has been taken as an index of the oxidant state of LDL. Because endothelial
      dysfunction is key in the initiation of transplant-associated arteriosclerosis,
      we postulated that the level of OxLDL autoantibody is associated with the degree
      of impairment of coronary endothelial function. METHODS AND RESULTS: Coronary
      endothelium-dependent dilation was assessed by using intracoronary acetylcholine
      and endothelium-independent dilation by nitroglycerin in 36 cardiac transplant
      recipients within 1 year of transplantation. The coronary responses to
      acetylcholine ranged from -37% (vasoconstriction) to 31% (vasodilation), and the
      responses to nitroglycerin ranged from 0% to 42% (vasodilation). The coronary
      vasomotor response to acetylcholine was significantly and inversely related to
      OxLDL autoantibody levels (r=-0.43, P<0.01) but not LDL levels (r=-0.04, P=0.83)
      or circulating OxLDL levels detected by monoclonal antibody EO6 (r=-0.27,
      P=0.11). The coronary artery response to nitroglycerin was not related to levels
      of OxLDL autoantibodies, LDL, or EO6 (all P=NS). CONCLUSIONS: Autoantibodies to
      OxLDL are increased in patients with coronary endothelial dysfunction in the
      first year after cardiac transplantation. The oxidative modification of LDL by
      inducing endothelial dysfunction in cardiac transplant recipients may be a
      critical step in the atherogenic effects of LDL and may provide a potential
      target for therapy.

PMID- 12482833
TI  - Expression of G2A, a receptor for lysophosphatidylcholine, by macrophages in
      murine, rabbit, and human atherosclerotic plaques.
AB  - OBJECTIVE: Lysophosphatidylcholine (LPC), a major phospholipid component of
      oxidized low density lipoprotein, has been demonstrated to induce multiple
      functional alterations of vasculature that are potentially involved in
      atherosclerosis. Recently, an orphan G-protein-coupled receptor, G2A, has been
      identified as a high-affinity receptor for LPC. Although it has been demonstrated
      that G2A is expressed predominantly in lymphoid tissues and lymphocytes, there
      are no reports to determine whether G2A is expressed in atherosclerotic lesions
      and cardiovascular cells. METHODS AND RESULTS: Immunohistochemistry with an anti
      G2A antibody revealed that G2A was expressed predominantly by macrophages within
      atherosclerotic lesions at the aortic root of apolipoprotein E-deficient mice and
      the thoracic aortas of Watanabe heritable hyperlipidemic rabbits. In
      atherosclerotic plaques of human coronary arterial specimens, G2A was expressed
      by macrophages within the lipid-rich plaques, whereas no immunoreactivity of G2A
      was observed in fibrous plaques where macrophages did not exist. Reverse
      transcription-polymerase chain reaction analysis demonstrated that G2A mRNA was
      highly expressed in human and murine monocytes/macrophages. The expression of G2A
      protein was detected in human and murine monocytes/macrophages by immunoblotting.
      CONCLUSIONS: These findings demonstrate that monocytes/macrophages abundantly
      express G2A and suggest that G2A may play a role in the formation and progression
      of atherosclerotic lesions.

PMID- 12482834
TI  - Blood pressure increase and incidence of hypertension in relation to inflammation
      sensitive plasma proteins.
AB  - OBJECTIVE: The reasons for the relationship between inflammation-sensitive plasma
      proteins (ISPs) and incidence of cardiovascular diseases are poorly understood.
      This study explored the hypothesis that ISPs are associated with future
      hypertension and age-related blood pressure increase. METHODS AND RESULTS: Blood
      pressure and plasma levels of fibrinogen, alpha1-antitrypsin, haptoglobin,
      ceruloplasmin, and orosomucoid were determined in 2262 healthy men aged 35 to 50
      years, initially without treatment for hypertension. The cohort was re-examined
      after 15.7 (+/-2.2) years. Incidence of hypertension and blood pressure increase
      was studied in relation to number of elevated proteins (ie, in the top quartile)
      at baseline. Among men without treatment for hypertension at follow-up, mean (+/
      SD) increase in systolic blood pressure was 18.8+/-17, 19.2+/-17, 19.3+/-17, and
      22.1+/-18 mm Hg, respectively, for men with 0, 1, 2, and > or =3 elevated
      proteins (P for trend=0.02, adjusted for confounders). The corresponding values
      for pulse pressure increase was 15.5+/-14, 15.8+/-14, 17.4+/-14, and 17.8+/-15 mm
      Hg, respectively (P=0.02). Incidence of hypertension (> or =160/95 mm Hg or
      treatment) and future blood pressure treatment showed similar associations with
      ISPs. Increase in diastolic blood pressure showed no association with ISPs.
      CONCLUSIONS: Plasma levels of ISPs are associated with a future increase in blood
      pressure. This could contribute to the relationship between ISP levels and
      cardiovascular disease.

PMID- 12482835
TI  - Remodeling of small intramyocardial coronary arteries distal to a severe
      epicardial coronary artery stenosis.
AB  - OBJECTIVE: Impaired coronary blood flow (CF) or flow reserve with incomplete and
      delayed recovery of left ventricular (LV) function after revascularization is
      common in severe ischemic LV dysfunction. The underlying mechanism is not fully
      known. We studied structural changes of small intramyocardial coronary arteries
      (SIMCAs) in a pig model of chronic coronary stenosis, testing the hypothesis that
      microvascular remodeling develops distally to a severe epicardial coronary artery
      stenosis. METHODS AND RESULTS: A total of 24 pigs were studied in 3 groups. Left
      anterior descending coronary stenosis was created to reduce CF by a mean of
      approximately 30%, producing severe regional systolic dysfunction without
      infarction. The stenosis was maintained for 7 days in 6 pigs (Group 1) and for 4
      weeks in 12 pigs (Group 2). The control group (Group 3) consisted of 6 pigs with
      the same surgical procedures but without stenosis. The wall thickness (WTa) and
      lumen (L) diameter of SIMCA were measured, and the ratio of WTa/L and lumen
      area/total vessel area (% lumen) were calculated. The composition of the arterial
      wall was studied with cell proliferation markers Ki67 and BrdU. The immediate
      reduction in CF after the creation of the stenosis was similar in both study
      groups, but after the first week, CF decreased significantly (P<0.05) when the
      stenosis was maintained (group 2). The left anterior descending stenosis caused
      regional LV dysfunction in all pigs (groups 1 and 2). After 4 weeks of stenosis
      with chronic myocardial hibernation (group 2), but not after 1 week (group 1),
      WTa and WTa/L increased and L decreased significantly in the chronic hibernating
      region located distally to the stenosis, compared with both the control (group 3)
      and the normal region in the same pig. The mean % lumen of SIMCA per pig
      correlated with the CF reduction (r=0.92, P<0.001) and with myocardial fibrosis
      (r=0.82, P<0.01) in the 4-week stenosis group. Ki67- and BrdU-positive cells were
      increased in the wall of SIMCA in Group 1 and 2 compared with the control group
      (P<0.01 for each). The proliferated cells were stained positively with smooth
      muscle alpha-actin antibody. CONCLUSION: In the chronic ischemic, hibernating
      myocardial region distal to a flow-limiting epicardial coronary stenosis, the
      small intramyocardial coronary arteries undergo remodeling, with an increase in
      wall thickness and a decrease in lumen. These structural changes may further
      restrict blood flow to ischemic myocardium and may account for the
      pathophysiologic impairment of CF or flow reserve after revascularization, which
      leads to delayed or incomplete recovery of myocardial function.

PMID- 12482836
TI  - In the elderly, interleukin-6 plasma levels and the -174G>C polymorphism are
      associated with the development of cardiovascular disease.
AB  - OBJECTIVE: Interleukin (IL)-6-mediated inflammation is involved in cardiovascular
      disease (CVD). We assessed IL-6 levels and the -174G>C genotype in a case-control
      study of men and women (average age 73 years) within the Cardiovascular Health
      Study. METHODS AND RESULTS: Cases included incident angina, myocardial infarction
      (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A
      control group and a group free of subclinical CVD were used for comparison. The 
      174C allele was associated with higher C-reactive protein (11% higher, P=0.02),
      fibrinogen (3% higher, P=0.02), and IL-6 (5% higher; P=0.16). IL-6 was associated
      with increased atherosclerosis when the control group was compared with the group
      free of subclinical CVD. No further association with CVD events was found when
      case groups were compared with the control group. Compared with its absence,
      presence of the -174C allele was associated with risk of MRI infarcts (odds ratio
      1.5). CONCLUSIONS: IL-6 levels differentiated those with subclinical CVD from
      those without. Although the -174C allele was not associated with incident events,
      associations of the genotype with inflammation and MRI infarcts, combined with
      the plasma IL-6 results, suggest that IL-6 may chronically predispose an
      individual to develop atherosclerosis.

PMID- 12482837
TI  - Quantitative trait loci influencing blood and liver cholesterol concentration in
      rats.
AB  - OBJECTIVE: The LEW/OlaHsd and BC/CpbU rat inbred strains differ markedly in blood
      and hepatic cholesterol levels before and after a cholesterol-rich diet. To
      define loci controlling these traits and related phenotypes, an F2 population
      derived from these strains was genetically analyzed. METHODS AND RESULTS: For
      each of the 192 F2 animals, phenotypes were determined, and genomic DNA was
      screened for polymorphic microsatellite markers. Significant quantitative trait
      loci (QTLs) were detected for basal serum cholesterol level on chromosome 1
      (D1Rat335-D1Rat27: total population, lod score 9.6; females, lod score 10.3) and
      chromosome 7 (D7Rat69: males, lod score 4.1), for postdietary serum cholesterol
      level on chromosome 2 (D2Rat69: total population, lod score 4.4) and chromosome
      16 (D16Rat6-D16Rat44: total population, lod score 3.3), for postdietary serum
      phospholipid level on chromosome 11 (D11Rat10: total population, lod score 4.1;
      females, lod score 3.6), and for postdietary serum aldosterone level on
      chromosome 1 (D1Rat14: females, lod score 3.7) and chromosome 18 (D18Rat55
      D18Rat8: females, lod score 2.9). In addition, QTLs with borderline significance
      were found on chromosomes 3, 5 to 11, 15, and 18. CONCLUSIONS: QTLs involved in
      blood and/or hepatic cholesterol concentrations (or related phenotypes) in the
      rat were identified. This contributes to the value of the rat as an animal model
      in studies researching the role of cholesterol in the pathogenesis of
      atherosclerosis and other cholesterol-related diseases.

PMID- 12482838
TI  - Apolipoprotein E and lipoprotein lipase increase triglyceride-rich particle
      binding but decrease particle penetration in arterial wall.
AB  - OBJECTIVE: Liver-derived apolipoprotein E (apoE) decreases atherosclerosis
      without altering the circulating concentrations of plasma lipoproteins. We
      evaluated the effects of apoE and lipoprotein lipase (LpL) on the interactions of
      triglyceride-rich particles (TGRPs) in the arterial wall. METHODS AND RESULTS:
      Quantitative fluorescence microscopy was used to study the interactions of TGRPs
      (25- to 35-nm diameter) in the arterial wall. Carotid arteries were harvested
      from rats, placed in a perfusion chamber, and perfused with fluorescently labeled
      TGRPs. In the absence of apoE or LpL, 1,1'-dioctadecyl-3,3,3',3'
      tetramethylindocarbocyanine-TGRP (100 microg neutral lipid/mL) was poorly
      retained in the arterial wall. The addition of either apoE (10 microg/mL) or LpL
      (10 microg/mL) increased TGRP accumulation 220% and 100%, respectively. This
      effect was attenuated by heparin (10.0 IU/mL). Histological analyses of cross
      sections from these vessels demonstrate that in the absence of apoE or LpL, there
      is deep penetration of lipid into the arterial wall. With the addition of either
      apoE or LpL, arterial wall penetration of TGRP is blocked. CONCLUSIONS: These
      results demonstrate that although apoE and LpL increase arterial wall
      accumulation of TGRPs, these proteins also reduce the penetration of TGRPs into
      the arterial wall. We postulate that this may represent a novel antiatherogenic
      property of apoE and LpL.

PMID- 12482839
TI  - Mast cell tryptase degrades HDL and blocks its function as an acceptor of
      cellular cholesterol.
AB  - OBJECTIVE: In human atherosclerotic lesions, degranulated mast cells are found in
      the vicinity of macrophage foam cells. Mast cell granules contain tryptase, a
      tetrameric serine protease requiring glycosaminoglycans for stabilization. No
      endogenous inhibitors have been described for tryptase, and the physiological
      functions of the enzyme are poorly understood. Here, we investigated the effects
      of human tryptase on the integrity of high density lipoprotein (HDL)3 and on its
      ability to release cholesterol from cultured mouse macrophage foam cells. METHODS
      AND RESULTS: Incubation of HDL3 with tryptase led to degradation of its
      apolipoproteins. Tryptase predominantly degraded a quantitatively minor
      subfraction of HDL3 that is lipid poor, exhibits electrophoretic pre-beta
      mobility, and contains either apolipoprotein A-I or apolipoprotein A-IV as its
      sole apolipoprotein. Moreover, tryptase caused functional changes in HDL3 by
      destroying its ability to promote high-affinity efflux of cholesterol from
      macrophage foam cells, ie, the pre-beta-HDL-dependent component of the process.
      Human aortic proteoglycans increased the ability of tryptase to proteolyze HDL3,
      suggesting that the proteoglycan-rich extracellular matrix of the arterial intima
      provides an appropriate environment for the extracellular actions of tryptase.
      CONCLUSIONS: By depleting pre-beta-HDL, mast cell tryptase may impair the initial
      step of reverse cholesterol transport and will then favor cellular accumulation
      of cholesterol during atherogenesis.

PMID- 12482840
TI  - Increased platelet-collagen interaction associated with double homozygosity for
      receptor polymorphisms of platelet GPIa and GPIIIa.
AB  - OBJECTIVE: There is considerable controversy regarding the clinical role of the
      single-nucleotide polymorphisms (SNPs) of the platelet glycoprotein receptor GPIa
      C807T and the Pl(A1/A2) of GPIIIa as cardiovascular risk factors. We hypothesized
      that two combined SNPs in their homozygous prothrombotic forms could clarify
      their pathophysiological impact. METHODS AND RESULTS: We identified a family with
      a striking history of premature cardiovascular events and a high frequency of the
      prothrombotic form of the two SNPs. From this family, the platelets of a healthy,
      27-year-old propositus with this double homozygosity were compared with three
      matched male neutral gene variant controls. The propositus had shortened PFA-100
      closure times and an increased platelet aggregation response to collagen.
      Platelet deposition to collagen was augmented under the blood flow conditions of
      a high shear rate model (1600 s(-1)). Platelet adhesion on collagen monomers was
      induced in a static system, leading to the promotion of subsequent procoagulant
      activity. CONCLUSIONS: The combined homozygous prothrombotic SNPs of GPIa and
      GPIIIa are associated with an increased platelet-collagen interaction and
      procoagulant activity that can be readily demonstrated in several independent
      systems. Our patient may serve as a useful model for the functional consequences
      of two combined, potentially procoagulant, platelet SNPs.

PMID- 12482841
TI  - Characterization of the association of tissue factor pathway inhibitor with human
      placenta.
AB  - OBJECTIVE: Tissue factor pathway inhibitor (TFPI) is an endothelial-associated
      inhibitor of blood coagulation. Because the mechanism for attachment of TFPI to
      endothelium is not clear, we investigated its association with human placenta.
      METHODS AND RESULTS: Western blots demonstrate that treatment with
      phosphatidylinositol-specific phospholipase C (PIPLC) removes more placental TFPI
      than either PBS or heparin, a finding confirmed by immunohistochemistry. The
      amounts of heparin-releasable and PIPLC-releasable TFPI activity on placental
      endothelium were measured in placentas from 5 individuals. PIPLC removes >10-fold
      more TFPI activity from the placental fragments than 10 U/mL heparin and >100
      fold more than 1 U/mL heparin. Pretreatment of the placental fragments with PIPLC
      increases the amount of heparin-releasable TFPI by approximately 3-fold. An
      antibody specific for the C-terminal region of TFPI recognizes PIPLC-releasable
      TFPI in Western blots. CONCLUSIONS: GPI-anchored TFPI is the predominant form on
      placental endothelium. Heparin-releasable TFPI likely represents only a small
      portion of the total TFPI on endothelium that remains attached to cell-surface
      glycosaminoglycans after cleavage of the GPI anchor by endogenous enzymes. The
      predominance of GPI-anchored TFPI suggests that heparin infusion does not
      significantly redistribute TFPI within the vasculature. The intact C-terminus in
      GPI-anchored TFPI indicates it is not directly attached to a GPI anchor. Rather,
      it most likely associates with endothelium by binding to a GPI-anchored protein.

PMID- 12482842
TI  - Periprocedural kinetics in serum levels of cytokines and adhesion molecules in
      elective PTCA and stent implantation: impact on restenosis.

PMID- 12482843
TI  - Genetic association studies.

PMID- 12482844
TI  - Thrombospondin-2 polymorphism is associated with a reduced risk of premature
      myocardial infarction.
AB  - OBJECTIVE: Recently, polymorphisms in thrombospondin (THBS) genes coding for THBS
      1 (N700S), THBS-2 (T>G substitution in 3'-untranslated region), and THBS-4
      (A387P) genes were proposed to modulate the risk of premature coronary artery
      disease (CAD) or myocardial infarction (MI). It was our objective to verify this
      hypothesis in an independent cohort. METHODS AND RESULTS: We performed a case
      control study among patients (n=503) referred to our institution for symptomatic
      CAD that occurred before the age of 50 years and a group of age- and sex-matched
      population-based controls free of CAD (n=1071). The THBS-1 variant allele was not
      associated with an altered risk of premature CAD or MI. Homozygosity for the THBS
      2 variant allele and the THBS-4 variant (387P) allele was significantly
      associated with a reduced risk of premature MI compared with wild-type
      individuals (OR=0.44, 0.24 to 0.84 and OR=0.43, 0.22 to 0.85, respectively). The
      latter observation is in contrast with a previous report, although confidence
      intervals overlap. CONCLUSIONS: We conclude that a relationship between the THBS
      1 N700S polymorphism and premature CAD is unlikely. For the THBS-4 A387P
      polymorphism, additional studies are required to elucidate its role in premature
      CAD. Finally, we conclude that the THBS-2 polymorphism is associated with a
      reduced risk of premature MI.

PMID- 12482845
TI  - Tetratricopeptide repeat motif-mediated Hsc70-mSTI1 interaction. Molecular
      characterization of the critical contacts for successful binding and specificity.
AB  - Murine stress-inducible protein 1 (mSTI1) is a co-chaperone that is homologous
      with the human Hsp70/Hsp90-organizing protein (Hop). Guided by Hop structural
      data and sequence alignment analyses, we have used site-directed mutagenesis, co
      precipitation assays, circular dichroism spectroscopy, steady-state fluorescence,
      and surface plasmon resonance spectroscopy to both qualitatively and
      quantitatively characterize the contacts necessary for the N-terminal
      tetratricopeptide repeat domain (TPR1) of mSTI1 to bind to heat shock cognate
      protein 70 (Hsc70) and to discriminate between Hsc70 and Hsp90. We have shown
      that substitutions in the first TPR motif of Lys(8) or Asn(12) did not affect
      binding of mSTI1 to Hsc70, whereas double substitution of these residues
      abrogated binding. A substitution in the second TPR motif of Asn(43) lowered but
      did not abrogate binding. Similarly, a deletion in the second TPR motif coupled
      with a substitution of Lys(8) or Asn(12) reduced but did not abrogate binding.
      These results suggest that mSTI1-Hsc70 interaction requires a network of
      interactions not only between charged residues in the TPR1 domain of mSTI1 and
      the EEVD motif of Hsc70 but also outside the TPR domain. We propose that the
      electrostatic interactions in the first TPR motif made by Lys(8) or Asn(12)
      define part of the minimum interactions required for successful mSTI1-Hsc70
      interaction. Using a truncated derivative of mSTI1 incapable of binding to Hsp90,
      we substituted residues on TPR1 potentially involved in hydrophobic contacts with
      Hsc70. The modified protein had reduced binding to Hsc70 but now showed
      significant binding capacity for Hsp90. In contrast, topologically equivalent
      substitutions on a truncated derivative of mSTI1 incapable of binding to Hsc70
      did not confer Hsc70 specificity on TPR2A. Our results suggest that binding of
      Hsc70 to TPR1 is more specific than binding of Hsp90 to TPR2A with serious
      implications for the mechanisms of mSTI1 interactions with Hsc70 and Hsp90 in
      vivo.

PMID- 12482846
TI  - Differential SERM effects on corepressor binding dictate ERalpha activity in
      vivo.
AB  - Selective estrogen receptor modulators (SERMs) show differential effects upon
      ERalpha activation function 1 (AF-1). Tamoxifen allows strong ERalpha AF-1
      activity, whereas raloxifene allows less and ICI 182,780 (ICI) allows none. Here,
      we show that blockade of corepressor histone de-acetylase (HDAC) activity
      reverses the differential inhibitory effect of SERMs upon AF-1 activity in MCF-7
      cells. This suggests that differential SERM repression of AF-1 involves HDAC
      dependent corepressors. Consistent with this, ICI and raloxifene are more potent
      than tamoxifen in promoting ERalpha-dependent sequestration of progesterone
      receptor-associated corepressors. Moreover, ICI and raloxifene are more efficient
      than tamoxifen in promoting ERalpha binding to the corepressor N-CoR in vivo and
      in vitro. An ERalpha mutation (537X) that increases N-CoR binding in the presence
      of all SERMs blocks AF-1 activity. An ERalpha mutation (L379R) that decreases N
      CoR binding increases AF-1 activity in the presence of ICI and raloxifene and
      reverses the effect of the 537X mutation. The 537X and L379R mutations also alter
      the ligand preference of ERalpha action at AP-1 sites and C3 complement, an
      action that also involves AF-1. Together, our results suggest that differential
      SERM effects on corepressor binding can explain differences in SERM effects on
      ERalpha activity. We propose a model for differential effects of SERMs on N-CoR
      binding.

PMID- 12482847
TI  - Hormone-sensitive lipase is a cholesterol esterase of the intestinal mucosa.
AB  - The identity of the enzymes responsible for lipase and cholesterol esterase
      activities in the small intestinal mucosa is not known. Because hormone-sensitive
      lipase (HSL) catalyzes the hydrolysis of acylglycerols and cholesteryl esters, we
      sought to determine whether HSL could be involved. HSL mRNA and protein were
      detected in all segments of the small intestine by Northern and Western blot
      analyses, respectively. Immunocytochemistry experiments revealed that HSL was
      expressed in the differentiated enterocytes of the villi and was absent in the
      undifferentiated cells of the crypt. Diacylglycerol lipase and cholesterol
      esterase activities were found in the different segments. Analysis of gut from
      HSL-null mice showed that diacylglycerol lipase activity was unchanged in the
      duodenum and reduced in jejunum. Neutral cholesterol esterase activity was
      totally abolished in duodenum, jejunum, and ileum of HSL-null mice. Analysis of
      HSL mRNA structure showed two types of transcripts expressed in equal amounts
      with alternative 5'-ends transcribed from two exons. This work demonstrates that
      HSL is expressed in the mucosa of the small intestine. The results also reveal
      that the enzyme participates in acylglycerol hydrolysis in jejunal enterocytes
      and cholesteryl ester hydrolysis throughout the small intestine.

PMID- 12482848
TI  - The conserved glutamine-rich region of chick csal1 and csal3 mediates protein
      interactions with other spalt family members. Implications for Townes-Brocks
      syndrome.
AB  - Members of the spalt family of zinc finger-containing proteins have been
      implicated in development and disease. However, very little is known about the
      molecular function of spalt proteins. We have used biochemical approaches to
      characterize functional domains of two chick spalt homologs, csal1 and csal3. We
      show that csal1 and csal3 proteins repress transcription and that they can
      interact with each other. Furthermore, we found that truncated chick spalt
      proteins, similar to the truncated spalt protein expressed in the human
      congenital disorder Townes-Brocks syndrome, affect the nuclear localization of
      full-length spalt. Our findings have implications for the understanding of Townes
      Brocks syndrome and the role of spalt genes in normal development. We propose
      that truncated spalt can exert a dominant negative effect and is able to
      interfere with the correct function of full-length protein, by causing its
      displacement from the nucleus. This could affect the transcriptional repressor
      activity of spalt and DNA binding. Spalt protein truncations could also affect
      the function of other spalt family members in various tissues.

PMID- 12482849
TI  - Identification of oligomerization and drug-binding domains of the membrane fusion
      protein EmrA.
AB  - Many pathogenic Gram-negative bacteria possess tripartite transporters that
      catalyze drug extrusion across the inner and outer membranes, thereby conferring
      resistance. These transporters consist of inner (IMP) and outer (OMP) membrane
      proteins, which are coupled by a periplasmic membrane fusion (MFP) protein.
      However, it is not know whether the MFP translocates the drug between the
      membranes, by acting as a channel, or whether it brings the IMP and OMP together,
      facilitating drug transfer. The MFP EmrA has an elongated periplasmic domain,
      which binds transported drugs, and is anchored to the inner membrane by a single
      alpha-helix, which contains a leucine zipper dimerization domain. Consistent with
      CD and hydrodynamic analyses, the periplasmic domain is predicted to be composed
      of a beta-sheet subdomain and an alpha-helical coiled-coil. We propose that EmrA
      forms a trimer in which the coiled-coils radiate across the periplasm, where they
      could sequester the OMP TolC. The "free" leucine zipper in the EmrA trimer might
      stabilize the interaction with the IMP EmrB, which also possesses leucine zipper
      motifs in the putative N- and C-terminal helices. The beta-sheet subdomain of
      EmrA would sit at the membrane surface adjacent to the EmrB, from which it
      receives the transported drug, inducing a conformational change that triggers the
      interaction with the OMP.

PMID- 12482850
TI  - Structural determinants of procryptdin recognition and cleavage by matrix
      metalloproteinase-7.
AB  - The bactericidal activity of mouse Paneth cell alphadefensins, or cryptdins, is
      dependent on processing of cryptdin precursors (pro-Crps) by matrix
      metalloproteinase-7 (MMP-7) (Wilson, C. L., Ouellette, A. J., Satchell, D. P.,
      Ayabe, T., Lopez-Boado, Y. S., Stratman, J. L., Hultgren, S. J., Matrisian, L.
      M., and Parks, W. C. (1999) Science 286, 113-117). To investigate the mechanisms
      of pro-Crp processing by this enzyme, recombinant pro-Crp4, a His-tagged chimeric
      pro-Crp (pro-CC), and site-directed mutant precursors of each were digested with
      MMP-7, and the cleavage products were analyzed by NH(2)-terminal peptide
      sequencing. Proteolysis of pro-Crp4 with MMP-7 activated in vitro bactericidal
      activity to the level of the mature Crp4 peptide by cleaving pro-Crp4 at Ser(43)
      downward arrow Ile(44) and Ala(53) downward arrow Leu(54) in the proregion and
      near the Crp4 peptide NH(2) terminus between Ser(58) downward arrow Leu(59).
      Because the Crp4 NH(2) terminus occurs at Gly(61), not Leu(59), MMP-7 is
      necessary but insufficient to complete the processing of Crp4. Crp activating
      proteolysis at S58 downward arrow L59 was unaffected by I44S/I44D or L54S/L54D
      loss-of-function mutations in pro-Crp4, and a (L59S)-pro-CC mutant was cleaved
      normally at Ser(43) downward arrow Val(44) and Ser(53) downward arrow Leu(54)
      sites but not at the peptide NH(2) terminus. C57BL/6 mice contain an abundant
      (L59S)-Crp4 mutant peptide with Leu(54) at its NH(2) terminus resulting from
      Ala(53) downward arrow Leu(54) cleavage and loss-of-function at the Ser(58)
      downward arrow Ser(59) cleavage site. Thus, alpha-defensins resulting from
      mutations at MMP-7 cleavage sites exist in mouse populations. A pro-CC substrate
      containing both L54S and L59S mutations resisted cleavage at Ser(43) downward
      arrow Val(44) completely, showing that cleavage at one or both downstream sites
      must precede proteolysis at Ser(43) downward arrow Val(44). These findings show
      that MMP-7 activation of pro-Crps can occur without proteolysis of the proregion,
      and prosegment fragmentation depends, at least in part, on the release of the Crp
      peptide from the precursor.

PMID- 12482851
TI  - The PrP-like protein Doppel binds copper.
AB  - Doppel (Dpl) is a glycosylphosphatidylinositol-anchored protein expressed in the
      testis. It exhibits 26% sequence identity with the prion protein (PrP) but lacks
      the octarepeat region implicated as the major copper-binding domain. Contrary to
      expectations, Cu(II) induced a 26% reduction in the intrinsic fluorescence of
      Dpl(27-154) and a calculated K(d) for a single-site model of 0.16 +/- 0.08
      microm. Other metals had minimal effects on fluorescence quenching. Matrix
      assisted laser desorption ionization mass spectrometry of a Dpl peptide revealed
      binding of copper (but not other metals) to the helical alphaB/B'-loop-alphaC
      subregion of Dpl. Fluorescence quenching and equilibrium dialysis analyses of
      this Dpl(101-145) peptide were compatible with a binding site of K(d) = 0.4
      microm. Diethylpyrocarbonate footprinting (Qin, K., Yang, Y., Mastrangelo, P.,
      and Westaway, D. (2002) J. Biol. Chem. 277, 1981-1990) of Dpl(27-154) defined one
      residue/molecule was protected by copper from diethylpyrocarbonate adduct
      formation, and reiteration of this analysis with Dpl(101-145) suggested that
      His(131) may contribute to Cu(II) binding. Taken together, our data indicate that
      the alpha-helical region of mouse Dpl possesses a selective copper-binding site
      with a submicromolar K(d) and perhaps one or more lower affinity sites. Although
      metallated forms of Dpl might exist in vivo, analyses of Tg(Dpl)10329 mice were
      inconsistent with reports that Dpl expression is associated with increased
      carbonylation and nitrosylation of brain proteins. Thus, rather than comprising
      an important source of free radical damage, copper binding may serve to modulate
      the activity, stability, or localization of the Dpl protein.

PMID- 12482852
TI  - Kinetic studies of the uracil phosphoribosyltransferase reaction catalyzed by the
      Bacillus subtilis pyrimidine attenuation regulatory protein PyrR.
AB  - The PyrR protein from Bacillus subtilis and many other bacteria is a bifunctional
      protein. Its primary function is the regulation of expression of pyrimidine
      biosynthetic (pyr) genes by binding to specific sites on pyr mRNA in a uridine
      nucleotide-dependent manner and altering the folding of downstream RNA to promote
      termination of transcription. PyrR also catalyzes the uracil
      phosphoribosyltransferase (UPRTase) reaction even though it bears little amino
      acid sequence similarity to other bacterial UPRTases. The PyrR-catalyzed UPRTase
      reaction obeyed a Ping Pong steady state kinetic pattern under all conditions
      examined, but no catalysis of [(14)C]uracil-UMP and [(32)P]PP(i)
      phosphoribosylpyrophosphate exchange reactions could be detected. Steady state
      equations for Ordered Bi Bi mechanisms for PyrR that include a kinetically
      irreversible conformational change after binding of PRPP but before uracil
      binding were shown to account for the Ping Pong pattern of the enzyme. This
      mechanism was supported by the following experimental observations. The reverse
      reaction was extremely slow with a catalytic rate constant 3300 times smaller
      than for the forward reaction. Patterns of product inhibition of the forward
      reaction were consistent with a version of the irreversible conformational change
      model in which PyrR returns to the unliganded conformation before dissociation of
      UMP and were inconsistent with several other kinetic mechanisms. UMP and
      phosphoribosylpyrophosphate were shown by equilibrium dialysis to bind to free
      PyrR (dissociation constants of 27 +/- 3 and 18 +/- 2 microm, respectively), but
      uracil and PP(i) did not bind at equilibrium concentrations up to 750 microm. We
      propose that the conformational change kinetic model developed for PyrR can also
      account for numerous other reports of Ping Pong kinetics for various
      phosphoribosyltransferases that do not form the phosphoribosyl-enzyme
      intermediate predicted by classic Ping Pong kinetics.

PMID- 12482853
TI  - Evidence that peroxisome proliferator-activated receptor alpha is complexed with
      the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2.
AB  - The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand
      inducible transcription factor, which belongs to the nuclear receptor
      superfamily. PPARalpha mediates the carcinogenic effects of peroxisome
      proliferators in rodents. In humans, PPARalpha plays a fundamental role in
      regulating energy homeostasis via control of lipid metabolism. To study the
      possible role of chaperone proteins in the regulation of PPARalpha activity, a
      monoclonal antibody (mAb) was made against PPARalpha and designated as 3B6/PPAR.
      The specificity of mAb 3B6/PPAR in recognizing PPARalpha was tested in
      immunoprecipitations using in vitro translated PPAR subtypes. The mAb 3B6/PPAR
      recognized PPARalpha, failed to bind to PPARbeta or PPARgamma, and is efficient
      in both immunoprecipitating and visualizing the receptor on protein blots. The
      immunoprecipitation of PPARalpha in mouse liver cytosol using mAb 3B6/PPAR has
      resulted in the detection of two co-immunoprecipitated proteins, which are heat
      shock protein 90 (hsp90) and the hepatitis B virus X-associated protein 2 (XAP2).
      The concomitant depletion of PPARalpha in hsp90-depleted mouse liver cytosol was
      also detected. Complex formation between XAP2 and PPARalpha/FLAG was also
      demonstrated in an in vitro translation binding assay. hsp90 interacts with
      PPARalpha in a mammalian two-hybrid assay and binds to the E/F domain. Transient
      expression of XAP2 co-expressed with PPARalpha resulted in down-regulation of a
      peroxisome proliferator response element-driven reporter gene activity. Taken
      together, these results indicate that PPARalpha is in a complex with hsp90 and
      XAP2, and XAP2 appears to function as a repressor. This is the first
      demonstration that PPARalpha is stably associated with other proteins in tissue
      extracts and the first nuclear receptor shown to functionally interact with XAP2.

PMID- 12482854
TI  - Identification of two mammalian reductases involved in the two-carbon fatty acyl
      elongation cascade.
AB  - The de novo synthesis of fatty acids occurs in two distinct cellular
      compartments. Palmitate (16:0) is synthesized from acetyl-CoA and malonyl-CoA in
      the cytoplasm by the enzymes acetyl-CoA carboxylase 1 and fatty acid synthase.
      The synthesis of fatty acids longer than 16 carbons takes place in microsomes and
      utilizes malonyl-CoA as the carbon source. Each two-carbon addition requires four
      sequential reactions: condensation, reduction, dehydration, and a final reduction
      to form the elongated fatty acyl-CoA. The initial condensation reaction is the
      regulated and rate-controlling step in microsomal fatty acyl elongation. We
      previously reported the cDNA cloning and characterization of a murine long chain
      fatty acyl elongase (LCE) . Overexpression of LCE in cells resulted in the
      enhanced addition of two-carbon units to C12-C16 fatty acids, and evidence was
      provided that LCE catalyzed the initial condensation reaction of long chain fatty
      acid elongation. The remaining three enzymes in the elongation reaction have not
      been identified in mammals. Here, we report the identification and
      characterization of two mammalian enzymes that catalyze the 3-ketoacyl-CoA and
      trans-2,3-enoyl-CoA reduction reactions in long and very long chain fatty acid
      elongation, respectively.

PMID- 12482855
TI  - Human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene.
AB  - Increased mammary epithelial expression of the human growth hormone (hGH) gene is
      associated with the acquisition of pathological proliferation. We report here
      that autocrine hGH production by human mammary carcinoma cells increased the
      expression and transcriptional activity of the homeobox domain containing protein
      HOXA1. Forced expression of HOXA1 in human mammary carcinoma cells resulted in
      increased total cell number primarily by the promotion of cell survival mediated
      by the transcriptional up-regulation of Bcl-2. HOXA1 also abrogated the apoptotic
      response of mammary carcinoma cells to doxorubicin. Forced expression of HOXA1 in
      mammary carcinoma cells, in a Bcl-2-dependent manner, resulted in dramatic
      enhancement of anchorage-independent proliferation and colony formation in soft
      agar. Finally, forced expression of HOXA1 was sufficient to result in the
      oncogenic transformation of immortalized human mammary epithelial cells with
      aggressive in vivo tumor formation. Herein, we have therefore provided a
      molecular mechanism by which autocrine hGH stimulation of human mammary
      epithelial cells may result in oncogenic transformation.

PMID- 12482856
TI  - Up-regulation of CD14 in liver caused by acute ethanol involves oxidant-dependent
      AP-1 pathway.
AB  - Ethanol is known to cause both tolerance and sensitization to endotoxin
      (lipopolysaccharide). It is also known that ethanol modulates the expression and
      activity of several intracellular signaling molecules and transcription factors
      in monocytes and Kupffer cells, the resident hepatic macrophages. Expression of
      CD14, the endotoxin receptor, is up-regulated following chronic exposure to
      endotoxin and ethanol. Ethanol-induced oxidative stress is important in the
      regulation of transcription factor activation and cytokine production by Kupffer
      cells. Thus, it was hypothesized that acute ethanol increases CD14 expression
      through a mechanism dependent upon oxidant production. This hypothesis was tested
      by overexpression of superoxide dismutase via recombinant adenovirus. Mice were
      infected with adenovirus (3 x 10(9) plaque-forming units, intravenously)
      containing either Cu,Zn superoxide dismutase (Ad.SOD1) or beta-galactosidase
      (Ad.lacZ), which caused significant expression of Cu,Zn-SOD in hepatocytes and
      Kupffer cells. Three days post-infection, mice were given saline or ethanol (5
      g/kg, intragastrically). A significant increase in CD14 mRNA was observed 3 h
      after ethanol, and this increase was almost completely blocked in mice
      overexpressing Cu,Zn-SOD. Additionally, overexpression of SOD also blunted
      ethanol-induced activation of redox-sensitive transcription factors NFkappaB and
      AP-1 and production of cytokines. However, only inhibition of AP-1 with dominant
      negative TAK1 but not NFkappaB by dominant-negative IkappaBalpha significantly
      blunted ethanol-induced increases in CD14, suggesting that AP-1 is important for
      CD14 transcriptional regulation. It is also shown here that NADPH oxidase is
      important in the increase in CD14 due to ethanol. Moreover, these data suggest
      that acute ethanol causes sensitization to endotoxin through mechanisms dependent
      upon oxidative stress.

PMID- 12482857
TI  - Factors governing nonoverlapping substrate specificity by mitochondrial inner
      membrane peptidase.
AB  - At least three peptidases are involved in cleaving presequences from imported
      mitochondrial proteins. One of the peptidase, the inner membrane peptidase, has
      two catalytic subunits, Imp1p and Imp2p, which are structurally related but
      functionally distinct in the yeast Saccharomyces cerevisiae. Whereas both
      subunits are members of the type I signal peptidase family, they exhibit
      nonoverlapping substrate specificities. A clue to the substrate specificity
      mechanism has come from our discovery of the importance not only of the -1 and -3
      residues in the signal peptides cleaved by Imp1p and Imp2p but also the +1 cargo
      residues attached to the signal peptides. We specifically find that Imp1p prefers
      substrates having a negatively charged residue (Asp or Glu) at the +1 position,
      whereas Imp2p prefers substrates having the Met residue at the +1 position. We
      further suggest that the conformation of the cargo is important for substrate
      recognition by Imp2p. A role for the cargo in presequence recognition
      distinguishes Imp1p and Imp2p from other type I signal peptidases.

PMID- 12482858
TI  - Evidence for a role of p38 kinase in hypoxia-inducible factor 1-independent
      induction of vascular endothelial growth factor expression by sodium arsenite.
AB  - Recently we have demonstrated that sodium arsenite induces the expression of
      hypoxia-inducible factor 1alpha (HIF-1alpha) protein and vascular endothelial
      growth factor (VEGF) in OVCAR-3 human ovarian cancer cells. We now show that
      arsenic trioxide, an experimental anticancer drug, exerts the same effects. The
      involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase
      (MAPK) pathways in the effects of sodium arsenite was investigated. By using
      kinase inhibitors in OVCAR-3 cells, both effects of sodium arsenite were found to
      be independent of phosphatidylinositol 3-kinase and p44/p42 MAPKS but were
      attenuated by inhibition of p38 MAPK. A role for p38 in the regulation of HIF
      1alpha and VEGF expression was supported further by analysis of activation
      kinetics. Experiments in mouse fibroblast cell lines, lacking expression of c-Jun
      N-terminal kinases 1 and 2, suggested that these kinases are not required for
      induction of HIF-1alpha protein and VEGF mRNA. Unexpectedly, sodium arsenite did
      not activate a HIF-1-dependent reporter gene in OVCAR-3 cells, indicating that
      functional HIF-1 was not induced. In agreement with this hypothesis, up
      regulation of VEGF mRNA was not reduced in HIF-1alpha(-/-) mouse fibroblast cell
      lines. Altogether, these data suggest that not HIF-1, but rather p38, mediates
      induction of VEGF mRNA expression by sodium arsenite.

PMID- 12482859
TI  - Phosphoenolpyruvate-dependent tubulin-pyruvate kinase interaction at different
      organizational levels.
AB  - Evidence for the direct binding of pyruvate kinase to tubulin/microtubule and for
      the inhibitory effect of phosphoenolpyruvate on tubulin-enzyme hetero-association
      were provided by surface plasmon resonance and pelleting experiments. Electron
      microscopy revealed that pyruvate kinase induces depolymerization of paclitaxel
      stabilized microtubules into large oligomeric aggregates and bundles the tubules
      in a salt concentration-dependent manner. The C-terminal "tail"-free microtubules
      did not bind pyruvate kinase, suggesting the crucial role of the C-terminal
      segments in the binding of kinase. Immunoblotting and polymerization experiments
      with cell-free brain extract revealed that pyruvate kinase specifically binds to
      microtubules, the binding of pyruvate kinase impedes microtubule assembly, and
      phosphoenolpyruvate counteracts the destabilization of microtubules induced by
      pyruvate kinase. We also showed by immunostaining the juxtanuclear localization
      of pyruvate kinase in intact L929 cells and that this localization was influenced
      by treatments with paclitaxel or vinblastine. These findings suggest that the
      distribution of the enzyme may be controlled by the microtubular network in vivo.

PMID- 12482860
TI  - Crystal structure of human protein-tyrosine phosphatase SHP-1.
AB  - SHP-1 is a cytosolic protein-tyrosine phosphatase that behaves as a negative
      regulator in eukaryotic cellular signaling pathways. To understand its regulatory
      mechanism, we have determined the crystal structure of the C-terminal truncated
      human SHP-1 in the inactive conformation at 2.8-A resolution and refined the
      structure to a crystallographic R-factor of 24.0%. The three-dimensional
      structure shows that the ligand-free SHP-1 has an auto-inhibited conformation.
      Its N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive
      conformation, which supports that the phosphatase activity of SHP-1 is primarily
      regulated by the N-SH2 domain. In addition, the C-SH2 domain of SHP-1 has a
      different orientation from and is more flexible than that of SHP-2, which enables
      us to propose an enzymatic activation mechanism in which the C-SH2 domains of
      SHPs could be involved in searching for phosphotyrosine activators.

PMID- 12482861
TI  - Mouse MIM, a tissue-specific regulator of cytoskeletal dynamics, interacts with
      ATP-actin monomers through its C-terminal WH2 domain.
AB  - The WH2 (WASP homology domain-2) is a small actin monomer-binding motif and is
      found in many proteins that regulate the actin cytoskeleton, including the beta
      thymosins, ciboulot, WASP, and verprolin/WIP (WASP-interacting protein). In
      sequence database searches we identified a novel mouse protein containing a WH2
      domain in its C-terminal region. This mouse gene also shows strong sequence
      homology to human MIM (Missing in Metastasis), a cDNA fragment that is present in
      non-metastatic but absent in metastatic bladder cancer cell lines. Northern blot
      and in situ hybridizations show that MIM is strongly expressed in the developing
      neurons and skeletal and cardiac muscles in mouse embryos. In adult mice, the
      strongest expression of MIM mRNA is in liver, outer layers of the kidney, and in
      the Purkinje cells of the brain. Recombinant MIM protein interacts with actin
      monomers and inhibits actin filament nucleation in vitro. However, the MIM/ATP-G
      actin complex can participate in actin filament assembly at the barbed end. MIM
      binds ATP-G-actin with a higher affinity (K(D) = 0.06 microm) than ADP-G-actin
      (K(D) = 0.3 microm) and inhibits the nucleotide exchange on actin monomers. Site
      directed mutagenesis demonstrates that the actin monomer-binding site resides in
      the C-terminal WH2 domain of MIM. Overexpression of mouse MIM in NIH 3T3 cells
      results in the disappearance of actin stress fibers and appearance of abnormal
      actin filament structures. These data show that MIM is an ATP-G-actin binding
      protein that regulates cytoskeletal dynamics in specialized mammalian cell-types.

PMID- 12482862
TI  - Disulfide folding pathways of cystine knot proteins. Tying the knot within the
      circular backbone of the cyclotides.
AB  - The plant cyclotides are a fascinating family of circular proteins that contain a
      cyclic cystine knot motif. The knotted topology and cyclic nature of the
      cyclotides pose interesting questions about folding mechanisms and how the
      knotted arrangement of disulfide bonds is formed. In the current study we have
      examined the oxidative refolding and reductive unfolding of the prototypic
      cyclotide, kalata B1. A stable two-disulfide intermediate accumulated during
      oxidative refolding but not in reductive unfolding. Mass spectrometry and NMR
      spectroscopy were used to show that the intermediate contained a native-like
      structure with two native disulfide bonds topologically similar to the
      intermediate isolated for the related cystine knot protein EETI-II (Le-Nguyen,
      D., Heitz, A., Chiche, L., El Hajji, M., and Castro B. (1993) Protein Sci. 2, 165
      174). However, the folding intermediate observed for kalata B1 is not the
      immediate precursor of the three-disulfide native peptide and does not accumulate
      in the reductive unfolding process, in contrast to the intermediate observed for
      EETI-II. These alternative pathways of linear and cyclic cystine knot proteins
      appear to be related to the constraints imposed by the cyclic backbone of kalata
      B1 and the different ring size of the cystine knot. The three-dimensional
      structure of a synthetic version of the two-disulfide intermediate of kalata B1
      in which Ala residues replace the reduced Cys residues provides a structural
      insight into why the two-disulfide intermediate is a kinetic trap on the folding
      pathway.

PMID- 12482863
TI  - Essential role of the unusual DNA-binding motif of BAG-1 for inhibition of the
      glucocorticoid receptor.
AB  - The co-chaperone BAG-1 is involved in the regulation of steroid hormone
      receptors, including the glucocorticoid receptor (GR). More recently, BAG-1 was
      found in the nucleus where it decreases GR transactivation. Moreover, nonspecific
      DNA binding of BAG-1 has been reported. We discovered that of the N-terminal part
      of BAG-1M, the first 8 amino acids are sufficient for DNA binding, containing a
      stretch of three lysines and a stretch of three arginines. Changing the spacing
      between these stretches had no effect on DNA binding. Surprisingly, this small,
      nonsequence-specific DNA binding domain was nonetheless necessary for the
      inhibitory function of BAG-1 for GR-dependent transcription, whereas the
      following serine- and threonine-rich E(2)X(4) repeat domain was not. Mutational
      analysis of these two domains revealed that only mutants retaining DNA binding
      capability were able to down-regulate GR-mediated transactivation. Intriguingly,
      lack of DNA binding could not be functionally rescued by BAG-1M harboring a point
      mutation abolishing interaction with hsp70. Thus, DNA binding and hsp70
      interaction are required in cis. We propose that the nonsequence-specific DNA
      binding protein BAG-1 acts at specific chromosomal loci by interacting with other
      proteins.

PMID- 12482864
TI  - The cartilage-specific fibronectin isoform has a high affinity binding site for
      the small proteoglycan decorin.
AB  - Binding of fibronectin to the small proteoglycan decorin plays an important role
      in cell differentiation and cell migration. The cartilage-specific (V+C)(-)
      fibronectin isoform, in which nucleotides that normally encode the protein
      segments V, III(15), and I(10) are spliced out, is one of the major splice
      variants present in cartilage matrices. Full-length and truncated cDNA constructs
      were used to express recombinant versions of fibronectin. Results demonstrated
      that the (V+C)(-) isoform has a higher affinity for decorin. Dissociation
      constants for decorin and fibronectin interaction were calculated to be 93 nm for
      the V(+)C(+) isoform and 24 nm and 223 nm for (V+C)(-) fibronectin. Because
      heparin competed with decorin competitively, binding of decorin to fibronectin
      likely occurs at a heparin-binding region. We propose that alternative splicing
      of the V and C regions changes the global conformation of fibronectin in such a
      way that it opens an additional decorin-binding site. This conformational change
      is responsible for the higher affinity of the (V+C)(-) fibronectin isoform for
      decorin.

PMID- 12482865
TI  - The N-terminal region of the transmembrane domain of human erythrocyte band 3.
      Residues critical for membrane insertion and transport activity.
AB  - We studied the role of the N-terminal region of the transmembrane domain of the
      human erythrocyte anion exchanger (band 3; residues 361-408) in the insertion,
      folding, and assembly of the first transmembrane span (TM1) to give rise to a
      transport-active molecule. We focused on the sequence around the 9-amino acid
      region deleted in Southeast Asian ovalocytosis (Ala-400 to Ala-408), which gives
      rise to nonfunctional band 3, and also on the portion of the protein N-terminal
      to the transmembrane domain (amino acids 361-396). We examined the effects of
      mutations in these regions on endoplasmic reticulum insertion (using cell-free
      translation), chloride transport, and cell-surface movement in Xenopus oocytes.
      We found that the hydrophobic length of TM1 was critical for membrane insertion
      and that formation of a transport-active structure also depended on the presence
      of specific amino acid sequences in TM1. Deletions of 2 or 3 amino acids
      including Pro-403 retained transport activity provided that a polar residue was
      located 2 or 3 amino acids on the C-terminal side of Asp-399. Finally, deletion
      of the cytoplasmic surface sequence G(381)LVRD abolished chloride transport, but
      not surface expression, indicating that this sequence makes an essential
      structural contribution to the anion transport site of band 3.

PMID- 12482866
TI  - Expression of hypoxia-inducible factors in the peri-implantation mouse uterus is
      regulated in a cell-specific and ovarian steroid hormone-dependent manner.
      Evidence for differential function of HIFs during early pregnancy.
AB  - Increased uterine vascular permeability and angiogenesis are hallmarks of
      implantation and placentation. These events are profoundly influenced by vascular
      endothelial growth factor (VEGF). We previously showed that VEGF isoforms and
      VEGF receptors are expressed in the uterus, suggesting the role of VEGF in
      uterine vascular permeability and angiogenesis required for implantation and
      decidualization. We have recently shown that estrogen promotes uterine vascular
      permeability but inhibits angiogenesis, whereas progesterone stimulates
      angiogenesis with little effect on vascular permeability. However, the mechanism
      of differential steroid hormonal regulation of uterine angiogenesis remains
      unresolved. Oxygen homeostasis is essential for cell survival and is primarily
      mediated by hypoxia-inducible factors (HIFs). These factors are intimately
      associated with vascular events and induce VEGF expression by binding to the
      hypoxia response element in the VEGF promoter. HIFalpha isoforms function by
      forming heterodimers with the aryl hydrocarbon nuclear translocator (ARNT) (HIF
      beta) family members. There is very limited information on the relationship among
      HIFs, ARNTs, and VEGF in the uterus during early pregnancy, although the role of
      HIFs in regulating VEGF and angiogenesis in cancers is well documented. Using
      molecular and physiological approaches, we here show that uterine expression of
      HIFs and ARNTs does not correlate with VEGF expression during the preimplantation
      period (days 1-4) in mice. In contrast, their expression follows the localization
      of uterine VEGF expression with increasing angiogenesis during the
      postimplantation period (days 5-8). This disparate pattern of uterine HIFs,
      ARNTs, and VEGF expression on days 1-4 of pregnancy suggests HIFs have multiple
      roles in addition to the regulation of angiogenesis during the peri-implantation
      period. Using pharmacological, molecular, and genetic approaches, we also
      observed that although progesterone primarily up-regulates uterine HIF-1alpha
      expression, estrogen transiently stimulates that of HIF-2alpha.

PMID- 12482867
TI  - Differential regulation of a hyperthermophilic alpha-amylase with a novel (Ca,Zn)
      two-metal center by zinc.
AB  - The crystal structure of the alpha-amylase from the hyperthermophilic archaeon
      Pyrococcus woesei was solved in the presence of three inhibitors: acarbose, Tris,
      and zinc. In the absence of exogenous metals, this alpha-amylase bound 1 and 4
      molar eq of zinc and calcium, respectively. The structure reveals a novel,
      activating, two-metal (Ca,Zn)-binding site and a second inhibitory zinc-binding
      site that is found in the -1 sugar-binding pocket within the active site. The
      data resolve the apparent paradox between the zinc requirement for catalytic
      activity and its strong inhibitory effect when added in molar excess. They
      provide a rationale as to why this alpha-amylase, in contrast to commercially
      available alpha-amylases, does not require the addition of metal ions for full
      catalytic activity, suggesting it as an ideal target to maximize the efficiency
      of industrial processes like liquefaction of starch.

PMID- 12482868
TI  - Twists, knots, and rings in proteins. Structural definition of the cyclotide
      framework.
AB  - In recent years an increasing number of miniproteins containing an amide-cyclized
      backbone have been discovered. The cyclotide family is the largest group of such
      proteins and is characterized by a circular protein backbone and six conserved
      cysteine residues linked by disulfide bonds in a tight core of the molecule.
      These form a cystine knot in which an embedded ring formed by two of the
      disulfide bonds and the connecting backbone segment is threaded by a third
      disulfide bond. In the current study we have undertaken high resolution
      structural analysis of two prototypic cyclotides, kalata B1 and cycloviolacin O1,
      to define the role of the conserved residues in the sequence. We provide the
      first comprehensive analysis of the topological features in this unique family of
      proteins, namely rings (a circular backbone), twists (a cis-peptide bond in the
      Mobius cyclotides) and knots (a knotted arrangement of the disulfide bonds).

PMID- 12482869
TI  - Identification of a critical ankyrin-binding loop on the cytoplasmic domain of
      erythrocyte membrane band 3 by crystal structure analysis and site-directed
      mutagenesis.
AB  - The cytoplasmic domain of erythrocyte membrane band 3 (cdb3) serves as a center
      of membrane organization, interacting with such proteins as ankyrin, protein 4.1,
      protein 4.2, hemoglobin, several glycolytic enzymes, a tyrosine phosphatase, and
      a tyrosine kinase, p72(syk). The crystallographic structure of the cdb3 dimer has
      revealed that residues 175-185 assume a beta-hairpin loop similar to a putative
      ankyrin-binding motif at the cytoplasmic surface of the Na(+)/K(+)-ATPase. To
      test whether this hairpin loop constitutes an ankyrin-binding site on cdb3, we
      have deleted amino acids 175-185 and substituted the 11-residue loop with a Gly
      Gly dipeptide that bridges the deletion without introducing strain into the
      structure. Although the deletion mutant undergoes the same native conformational
      changes exhibited by wild type cdb3 and binds other peripheral proteins normally,
      the mutant exhibits no affinity for ankyrin. This suggests that the exposed beta
      hairpin turn indeed constitutes a major ankyrin-binding site on cdb3. Other
      biochemical studies suggest that ankyrin also docks at the NH(2) terminus of band
      3. Thus, antibodies to the NH(2) terminus of cdb3 block ankyrin binding to the
      cdb3, and ankyrin binding to cdb3 prevents p72(syk) phosphorylation of cdb3 at
      its NH(2) terminus (predominantly at Tyr-8). However, a truncation mutant of cdb3
      lacking the NH(2)-terminal 50 residues displays the same binding affinity as wild
      type cdb3. These data thus suggest that the NH(2) terminus of cdb3 is proximal to
      but not required for the cdb3-ankyrin interaction.

PMID- 12482870
TI  - Characterization of sorCS1, an alternatively spliced receptor with completely
      different cytoplasmic domains that mediate different trafficking in cells.
AB  - We previously isolated and sequenced murine sorCS1, a type 1 receptor containing
      a Vps10p-domain and a leucine-rich domain. We now show that human sorCS1 has
      three isoforms, sorCS1a-c, with completely different cytoplasmic tails and
      differential expression in tissues. The b tail shows high identity with that of
      murine sorCS1b, whereas the a and c tails have no reported counterparts. Like the
      Vps10p-domain receptor family members sortilin and sorLA, sorCS1 is synthesized
      as a proreceptor that is converted in late Golgi compartments by furin-mediated
      cleavage. Mature sorCS1 bound its own propeptide with low affinity but none of
      the ligands previously shown to interact with sortilin and sorLA. In transfected
      cells, about 10% of sorCS1a was expressed on the cell surface and proved capable
      of rapid endocytosis in complex with specific antibody, whereas sorCS1b presented
      a high cell surface expression but essentially no endocytosis, and sorCS1c was
      intermediate. This is an unusual example of an alternatively spliced single
      transmembrane receptor with completely different cytoplasmic domains that mediate
      different trafficking in cells.

PMID- 12482871
TI  - Variations in the response of mouse isozymes of adenylosuccinate synthetase to
      inhibitors of physiological relevance.
AB  - Vertebrates have acidic and basic isozymes of adenylosuccinate synthetase, which
      participate in the first committed step of de novo AMP biosynthesis and/or the
      purine nucleotide cycle. These isozymes differ in their kinetic properties and N
      leader sequences, and their regulation may vary with tissue type. Recombinant
      acidic and basic synthetases from mouse, in the presence of active site ligands,
      behave in analytical ultracentrifugation as dimers. Active site ligands enhance
      thermal stability of both isozymes. Truncated forms of both isozymes retain the
      kinetic parameters and the oligomerization status of the full-length proteins.
      AMP potently inhibits the acidic isozyme competitively with respect to IMP. In
      contrast, AMP weakly inhibits the basic isozyme noncompetitively with respect to
      all substrates. IMP inhibition of the acidic isozyme is competitive, and that of
      the basic isozyme noncompetitive, with respect to GTP. Fructose 1,6-bisphosphate
      potently inhibits both isozymes competitively with respect to IMP but becomes
      noncompetitive at saturating substrate concentrations. The above, coupled with
      structural information, suggests antagonistic interactions between the active
      sites of the basic isozyme, whereas active sites of the acidic isozyme seem
      functionally independent. Fructose 1,6-bisphosphate and IMP together may be
      dynamic regulators of the basic isozyme in muscle, causing potent inhibition of
      the synthetase under conditions of high AMP deaminase activity.

PMID- 12482872
TI  - Zinc-induced decrease of the thermal stability and regeneration of rhodopsin.
AB  - Zinc is present at high concentrations in the photoreceptor cells of the retina
      where it has been proposed to play a role in the visual phototransduction
      process. In order to obtain more information about this role, the study of the
      effect of zinc on several properties of the visual photoreceptor rhodopsin has
      been investigated. A specific effect of Zn(2+) on the thermal stability of
      rhodopsin, obtained from bovine retinas and solubilized in dodecyl maltoside
      detergent, in the dark is reported. The thermal stability of rhodopsin in its
      ground state (dark state) is clearly reduced with increasing Zn(2+)
      concentrations (0-50 microm Zn(2+)). The thermal bleaching process is accelerated
      in the presence of Zn(2+) with k rate constants, at 55 degrees C, of 0.028 +/-
      0.002 min(-1) (0 microm Zn(2+)) and 0.056 +/- 0.003 min(-1) (50 microm Zn(2+)),
      corresponding to t(12) values of 24.4 +/- 1.6 min and 11.8 +/- 0.1 min,
      respectively. Thermodynamic parameters derived from Arrhenius plots show a
      significant E(a) increase at 50 microm Zn(2+) for the process, with deltaG++
      decrease and increase in deltaH++ and deltaS++ possibly reflecting conformational
      rearrangements and reordering of water molecules. The stability of the
      metarhodopsin II intermediate is also decreased and changes in the metarhodopsin
      II decay pathway are also detected. The extent of rhodopsin regeneration in vitro
      is also reduced by zinc. These effects, specific for zinc, are also seen for
      rhodopsin in native disc membranes, and may be relevant to the suggested role of
      Zn(2+) in normal and pathological retinal function.

PMID- 12482873
TI  - Cyclin D3 is a cofactor of retinoic acid receptors, modulating their activity in
      the presence of cellular retinoic acid-binding protein II.
AB  - Ligand-induced transcription activation of retinoic acid (RA) target genes by
      nuclear receptors (retinoic acid (RAR) and retinoid X (RXR) receptors) depends on
      the recruitment of coactivators. We have previously demonstrated that the small
      15-kDa cellular RA-binding protein II (CRABPII) is a coactivator present in the
      RA-dependent nuclear complex. As identifying cell-specific partners of CRABPII
      might help to understand the novel control of RA signaling, we performed a yeast
      two-hybrid screen of a hematopoietic HL-60 cDNA library using human CRABPII as
      bait and have subsequently identified human cyclin D3 as a partner of CRABPII.
      Cyclin D3 interacted with CRABPII in a ligand-independent manner and equally
      bound RAR alpha, but not RXR alpha, and only in the presence of RA. We further
      show that cyclin D3 positively modulated RA-mediated transcription through
      CRABPII. Therefore, cyclin D3 may be part of a ternary complex with CRABPII and
      RAR. Finally, we show that cyclin D3 expression paralleled HL-60 differentiation
      and arrest of cell growth. These findings led us to speculate that control of
      cell proliferation during induction of differentiation may directly involve, at
      the transcriptional level, nuclear receptors, coactivators, and proteins of the
      cell cycle in a cell- and nuclear receptor-specific manner.

PMID- 12482874
TI  - Transcriptional adaptation to cystic fibrosis transmembrane conductance regulator
      deficiency.
AB  - Cystic fibrosis, the most commonly inherited lethal pulmonary disorder in
      Caucasians, is caused by mutations in the cystic fibrosis transmembrane
      conductance regulator gene (CFTR). To identify genomic responses to the presence
      or absence of CFTR in pulmonary tissues in vivo, microarray analyses of lung
      mRNAs were performed on whole lung tissue from mice lacking (CFTR(-)) or
      expressing mouse CFTR (CFTR(+)). Whereas the histology of lungs from CFTR(-) and
      CFTR(+) mice was indistinguishable, statistically significant increases in the
      relative abundance of 29 and decreases in 25 RNAs were identified by RNA
      microarray analysis. Of RNAs whose expression was consistently altered by the
      absence of CFTR, functional classes of genes influencing gene transcription,
      inflammation, intracellular trafficking, signal transduction, and ion transport
      were identified. RNAs encoding the transcription factor CCAAT enhancer-binding
      protein (CEBP) delta and interleukin (IL) 1beta, both known to regulate CFTR
      expression, were induced, perhaps indicating adaptation to the lack of CFTR. RNAs
      mediating lung inflammation including calgranulin-S100 family members, IL-1beta
      and IL-4, were increased. Likewise, expression of several membrane transport
      proteins that interact directly with CFTR were increased, suggesting that CFTR
      protein complexes initiate genomic responses. Absence of CFTR influenced the
      expression of genes modulating diverse pulmonary cell functions that may
      ameliorate or contribute to the pathogenesis of CF.

PMID- 12482875
TI  - The first putative transmembrane segment of subunit c" (Vma16p) of the yeast V
      ATPase is not necessary for function.
AB  - The yeast vacuolar ATPase (V-ATPase) contains three proteolipid subunits: c
      (Vma3p), c' (Vma11p), and c" (Vma16p). Each subunit contains a buried glutamate
      residue that is essential for function, and these subunits are not able to
      substitute for each other in supporting activity. Subunits c and c' each contain
      four putative transmembrane segments (TM1-4), whereas subunit c" is predicted to
      contain five. To determine whether TM1 of subunit c" serves an essential
      function, a deletion mutant of Vma16p was constructed lacking TM1 (Vma16p-Delta
      TM1). Although this construct does not complement the loss of Vma3p or Vma11p, it
      does complement the loss of full-length Vma16p. Vacuoles isolated from the strain
      expressing Vma16p-Delta TM1 showed V-ATPase activity and proton transport greater
      than 80% relative to wild type and displayed wild type levels of subunits A and
      a, suggesting normal assembly of the V-ATPase complex. These results suggest that
      TM1 of Vma16p is dispensable for both activity and assembly of the V-ATPase. To
      obtain information about the topology of Vma16p, labeling of single cysteine
      containing mutants using the membrane-permeable reagent 3-(N
      maleimidylpropionyl)biocytin (MPB) and the -impermeable reagent 4-acetamido-4'
      maleimidylstilbene-2,2'-disulfonic acid (AMS) was tested. Both the Cys-less form
      of Vma16p and eight single cysteine-containing mutants retained greater than 80%
      of wild type levels of activity. Of the eight mutants tested, two (S5C and S178C)
      were labeled by MPB. MPB-labeling of S5C was blocked by AMS in intact vacuoles,
      whereas S178C was blocked by AMS only in the presence of permeabilizing
      concentrations of detergent. In addition, a hemagglutinin epitope tag introduced
      into the C terminus of Vma16p was recognized by an anti-hemagglutinin antibody in
      intact vacuolar membranes, suggesting a cytoplasmic orientation for the C
      terminus. These results suggest that subunit c" contains four rather than five
      transmembrane segments with both the N and C terminus on the cytoplasmic side of
      the membrane.

PMID- 12482877
TI  - Stearoyl-CoA desaturase inhibits ATP-binding cassette transporter A1-mediated
      cholesterol efflux and modulates membrane domain structure.
AB  - Liver X receptor/retinoid X receptor (LXR/RXR) transcription factors have been
      found to induce a number of genes involved in the regulation of cellular
      cholesterol efflux, including the ATP-binding cassette transporter A1 (ABCA1),
      which mediates the active efflux of cellular cholesterol and phospholipids to
      extracellular acceptors, such as apolipoprotein A-I (apoA-I). In a screen for
      macrophage LXR/RXR target genes, we identified stearoyl-CoA desaturases 1 and 2
      (Scd1 and Scd2), and subsequently tested the hypothesis that SCD activity might
      modulate cellular cholesterol efflux. In HEK 293 cells co-transfection of ABCA1
      with either SCD1 or SCD2 inhibited ABCA1-mediated cholesterol efflux but not
      phospholipid efflux. In Chinese hamster ovary (CHO) cells with moderate stable
      overexpression of SCD1, cholesterol efflux to apoA-I was inhibited by 73%,
      whereas phospholipid efflux and ABCA1 protein levels were unchanged. In contrast,
      cholesterol efflux to HDL(2), which is not dependent on ABCA1, was increased 2
      fold in CHO-SCD1 cells. The effect of SCD on cholesterol efflux to apoA-I was
      independent of acyl-CoA:cholesterol acyltransferase (ACAT) activity. SCD activity
      led to an increased content of plasma membrane monounsaturated fatty acids (18:1)
      at the expense of saturated fatty acids (18:0). As shown by confocal microscopy,
      SCD overexpression led to a decrease of Triton X-100-resistant domains in the
      plasma membrane, indicating a decrease in membrane-ordered regions. The data
      suggest that SCD changes membrane organization and depletes a specific pool of
      membrane cholesterol supporting ABCA1-mediated efflux, whereas increasing
      availability of cholesterol for passive efflux by HDL(2). ABCA1-mediated
      cholesterol and phospholipid efflux may be uncoupled in pathological states
      associated with high SCD activity, as in hyperinsulinemic obese mice, or in
      animals treated with LXR activators.

PMID- 12482876
TI  - The small ubiquitin-like modifier (SUMO) protein modification system in
      Arabidopsis. Accumulation of SUMO1 and -2 conjugates is increased by stress.
AB  - Small ubiquitin-like modifier (SUMO) is a member of the superfamily of ubiquitin
      like polypeptides that become covalently attached to various intracellular target
      proteins as a way to alter their function, location, and/or half-life. Here we
      show that the SUMO conjugation system operates in plants through a
      characterization of the Arabidopsis SUMO pathway. An eight-gene family encoding
      the SUMO tag was discovered as were genes encoding the various enzymes required
      for SUMO processing, ligation, and release. A diverse array of conjugates could
      be detected, some of which appear to be SUMO isoform-specific. The levels of
      SUMO1 and -2 conjugates but not SUMO3 conjugates increased substantially
      following exposure of seedlings to stress conditions, including heat shock,
      H(2)O(2), ethanol, and the amino acid analog canavanine. The heat-induced
      accumulation could be detected within 2 min from the start of a temperature
      upshift, suggesting that SUMO1/2 conjugation is one of the early plant responses
      to heat stress. Overexpression of SUMO2 enhanced both the steady state levels of
      SUMO2 conjugates under normal growth conditions and the subsequent heat shock
      induced accumulation. This accumulation was dampened in an Arabidopsis line
      engineered for increased thermotolerance by overexpressing the cytosolic isoform
      of the HSP70 chaperonin. Taken together, the SUMO conjugation system appears to
      be a complex and functionally heterogeneous pathway for protein modification in
      plants with initial data indicating that one important function may be in stress
      protection and/or repair.

PMID- 12482878
TI  - Essential role of caveolae in interleukin-6- and insulin-like growth factor I
      triggered Akt-1-mediated survival of multiple myeloma cells.
AB  - Caveolae, specialized flask-shaped lipid rafts on the cell surface, are composed
      of cholesterol, sphingolipids, and structural proteins termed caveolins;
      functionally, these plasma membrane microdomains have been implicated in signal
      transduction and transmembrane transport. In the present study, we examined the
      role of caveolin-1 in multiple myeloma cells. We show for the first time that
      caveolin-1, which is usually absent in blood cells, is expressed in multiple
      myeloma cells. Analysis of myeloma cell-derived plasma membrane fractions shows
      that caveolin-1 is co-localized with interleukin-6 receptor signal transducing
      chain gp130 and with insulin-like growth factor-I receptor. Cholesterol depletion
      by beta-cyclodextrin results in the loss of caveola structure in myeloma cells,
      as shown by transmission electron microscopy, and loss of caveolin-1 function.
      Interleukin-6 and insulin-like growth factor-I, growth and survival factors in
      multiple myeloma, induce caveolin-1 phosphorylation, which is abrogated by pre
      treatment with beta-cyclodextrin. Importantly, inhibition of caveolin-1
      phosphorylation blocks both interleukin-6-induced protein complex formation with
      caveolin-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1
      pathway. beta-Cyclodextrin also blocks insulin-like growth factor-I-induced
      tyrosine phosphorylation of insulin-responsive substrate-1 and downstream
      activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. Therefore,
      cholesterol depletion by beta-cyclodextrin abrogates both interleukin-6- and
      insulin-like growth factor-I-triggered multiple myeloma cell survival via
      negative regulation of caveolin-1. Taken together, this study identifies caveolin
      1 and other structural membrane components as potential new therapeutic targets
      in multiple myeloma.

PMID- 12482879
TI  - Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis.
AB  - The human genomic sequencing effort has revealed the presence of a large number
      of Rho GTPases encoded by the human genome. Here we report the characterization
      of a new family of Rho GTPases with atypical features. These proteins, which were
      called Miro-1 and Miro-2 (for mitochondrial Rho), have tandem GTP-binding domains
      separated by a linker region containing putative calcium-binding EF hand motifs.
      Genes encoding Miro-like proteins were found in several eukaryotic organisms from
      Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster to
      mammals, indicating that these genes evolved early during evolution.
      Immunolocalization experiments, in which transfected NIH3T3 and COS 7 cells were
      stained for ectopically expressed Miro as well as for the endogenous Miro-1
      protein, showed that Miro was present in mitochondria. Interestingly,
      overexpression of a constitutively active mutant of Miro-1 (Miro-1/Val-13)
      induced an aggregation of the mitochondrial network and resulted in an increased
      apoptotic rate of the cells expressing activated Miro-1. These data indicate a
      novel role for Rho-like GTPases in mitochondrial homeostasis and apoptosis.

PMID- 12482880
TI  - The mycotoxin penicillic acid inhibits Fas ligand-induced apoptosis by blocking
      self-processing of caspase-8 in death-inducing signaling complex.
AB  - Upon engagement with Fas ligand (FasL), Fas rapidly induces recruitment and self
      processing of caspase-8 via the adaptor protein Fas-associated death domain
      (FADD), and activated caspase-8 cleaves downstream substrates such as caspase-3.
      We have found that penicillic acid (PCA) inhibits FasL-induced apoptosis and
      concomitant loss of cell viability in Burkitt's lymphoma Raji cells. PCA
      prevented activation of caspase-8 and caspase-3 upon treatment with FasL.
      However, PCA did not affect active caspase-3 in FasL-treated cells, suggesting
      that PCA primarily blocks early signaling events upstream of caspase-8
      activation. FasL-induced processing of caspase-8 was severely impaired in the
      death-inducing signaling complex, although FasL-induced recruitment of FADD and
      caspase-8 occurred normally in PCA-treated cells. Although PCA inhibited the
      enzymatic activities of active recombinant caspase-3, caspase-8, and caspase-9 at
      similar concentrations, PCA exerted weak inhibitory effects on activation of
      caspase-9 and caspase-3 in staurosporine-treated cells but strongly inhibited
      caspase-8 activation in FasL-treated cells. Glutathione and cysteine neutralized
      an inhibitory effect of PCA on caspase-8, and PCA bound directly to the active
      center cysteine in the large subunit of caspase-8. Thus, our present results
      demonstrate that PCA inhibits FasL-induced apoptosis by targeting self-processing
      of caspase-8.

PMID- 12482881
TI  - Slowing muscle atrophy: putting the brakes on protein breakdown.

PMID- 12482882
TI  - The history of contraction of the wrist flexors can change cortical excitability.
AB  - Voluntary contractions induce thixotropic changes in intrafusal muscle fibres and
      hence, by induction or removal of "slack", the background discharge and
      sensitivity of spindle endings to stretch is altered. This study assessed whether
      such changes also altered the "excitability" of the motor cortex. Eleven subjects
      performed a series of voluntary conditioning contractions of the wrist flexors
      designed to remove slack in the intrafusal fibres (contract and test at
      intermediate length, termed "contract-test") or to introduce slack (contract at
      long length and test at intermediate length, termed "contract-long"). Surface
      electromyographic recordings were made from one wrist flexor, flexor carpi
      radialis. Subjects relaxed after each contraction, and 10 s later a test stimulus
      was applied to elicit a tendon tap response, H-reflex, or motor-evoked potential
      (MEP) to transcranial magnetic stimulation in the flexor carpi radialis. Each of
      the three test stimuli was applied during 15 consecutive pairs of contractions
      ("contract-long" and "contract-test"). Three subjects repeated the protocol using
      transmastoid electrical stimulation as the test stimulus to evoke a
      cervicomedullary motor-evoked potential (CMEP). For the group of subjects, after
      conditioning contractions designed to induce slack there was a significant
      reduction in the amplitude of the tendon reflex, no significant change in the H
      reflex, and a small but significant reduction in the amplitude of the MEP. In one
      subject the CMEP was significantly reduced, while it was unchanged in two others.
      In the absence of corresponding changes in the H-reflex (or CMEP), changes in the
      size of the response to motor cortical stimulation suggest that the level of
      motor cortical "excitability" changes according to naturally induced variations
      in the discharge of muscle spindle afferents.

PMID- 12482883
TI  - The relation between charge movement and transport-associated currents in the rat
      GABA cotransporter rGAT1.
AB  - Most cotransporters characteristically display two main kinds of electrical
      activity: in the absence of organic substrate, transient presteady-state currents
      (I(pre)) are generated by charge relocation during voltage steps; in the presence
      of substrate, sustained, transport-associated currents (I(tr)) are recorded.
      Quantitative comparison of these two currents, in Xenopus oocytes expressing the
      neural GABA cotransporter rGAT1, revealed several unforeseen consistencies
      between I(pre) and I(tr), in terms of magnitude and kinetic parameters. The decay
      rate constant (r) of I(pre) and the quantity of charge displaced to an inner
      position in the transporter (Q(in)(0)) depended on voltage and ionic conditions.
      Saturating GABA concentrations, applied under the same conditions, suppressed
      I(pre) (i.e. Q(in)( infinity ) = 0) and produced a transport-associated current
      with amplitude I(tr) = Q(in)(0)r. At non-saturating levels of GABA, changes of
      I(tr) were compensated by corresponding variations in Q(in), such that I(pre) and
      I(tr) complemented each other, according to the relation: I(tr) = (Q(in)(0) -
      Q(in)) r. Complementarity of magnitude, superimposable kinetic properties and
      equal dependence on voltage and [Na(+)](o) point to the uniqueness of the charge
      carrier for both processes, suggesting that transport and charge migration arise
      from the same molecular mechanism. The observed experimental relations were
      correctly predicted by a simple three-state kinetic model, in which GABA binding
      takes place after charge binding and inward migration have occurred. The model
      also predicts the observed voltage dependence of the apparent affinity of the
      transporter for GABA, and suggests a voltage-independent GABA binding rate with a
      value around 0.64 microM(-1) s(-1).

PMID- 12482884
TI  - Modulation of homomeric and heteromeric KCNQ1 channels by external acidification.
AB  - The I(KS) K(+) channel plays a major role in repolarizing the cardiac action
      potential. It consists of an assembly of two structurally distinct alpha and beta
      subunits called KCNQ1 and KCNE1, respectively. Using two different expression
      systems, Xenopus oocytes and Chinese hamster ovary cells, we investigated the
      effects of external protons on homomeric and heteromeric KCNQ1 channels. External
      acidification (from pH 7.4 to pH 5.5) markedly decreased the homomeric KCNQ1
      current amplitude and caused a positive shift (+25 mV) in the voltage dependence
      of activation. Low external pH (pH(o)) also slowed down the activation and
      deactivation kinetics and strongly reduced the KCNQ1 inactivation process. In
      contrast, external acidification reduced the maximum conductance and the
      macroscopic inactivation of the KCNQ1 mutant L273F by only a small amount. The
      heteromeric I(KS) channel complex was weakly affected by low pH(o), with minor
      effects on I(KS) current amplitude. However, substantial current inhibition was
      produced by protons with the N-terminal KCNE1 deletion mutant Delta11-38. Low
      pH(o) increased the current amplitude of the pore mutant V319C when co-expressed
      with KCNE1. The slowing of I(KS) deactivation produced by low pH(o) was absent in
      the KCNE1 mutant Delta39-43, suggesting that the residues lying at the N-terminal
      boundary of the transmembrane segment are involved in this process. In all, our
      results suggest that external acidification acts on homomeric and heteromeric
      KCNQ1 channels via multiple mechanisms to affect gating and maximum conductance.
      The external pH effects on I(Kr) versus I(KS) may be important determinants of
      arrhythmogenicity under conditions of cardiac ischaemia and reperfusion.

PMID- 12482885
TI  - Activation of a PTX-insensitive G protein is involved in histamine-induced
      recombinant M-channel modulation.
AB  - The M-type potassium current (I(M)) plays a dominant role in regulating membrane
      excitability and is modulated by many neurotransmitters. However, except in the
      case of bradykinin, the signal transduction pathways involved in M-channel
      modulation have not been fully elucidated. The channels underlying I(M) are
      produced by the coassembly of KCNQ2 and KCNQ3 channel subunits and can be
      expressed in heterologous systems where they can be modulated by several
      neurotransmitter receptors including histamine H(1) receptors. In HEK293T cells,
      histamine acting via transiently expressed H(1)R produced a strong inhibition of
      recombinant M-channels but had no overt effects on the voltage dependence or
      voltage range of I(M) activation. In addition, the modulation of I(M) by
      histamine was not voltage sensitive, whereas channel gating, particularly
      deactivation, was accelerated by histamine. Non-hydrolysable guanine nucleotide
      analogues (GDP-beta-S and GTP-gamma-S) and pertussis toxin (PTX) treatment
      demonstrated the involvement of a PTX-insensitive G protein in the signal
      transduction pathway mediating histamine-induced I(M) modulation. Abrogation of
      the histamine-induced modulation of I(M) by expression of a C-terminal construct
      of phospholipase C (PLC-beta1-ct), which buffers activated Galpha(q/11) subunits,
      implicates this G protein alpha subunit in the modulatory pathway. On the other
      hand, abrogation of the histamine-induced modulation of I(M) by expression of two
      constructs which buffer free betagamma subunits, transducin (Galphat) and a C
      terminal construct of a G protein receptor kinase (MAS-GRK2-ct), implicates
      betagamma dimers in the modulatory pathway. These findings demonstrate that
      histamine modulates recombinant M-channels in HEK293T cells via a PTX-insensitive
      G protein, probably Galpha(q/11), in a similar manner to a number of other G
      protein-coupled receptors. However, histamine-induced I(M) modulation in HEK293T
      cells is novel in that betagamma subunits in addition to Galpha(q/11) subunits
      appear to be involved in the modulation of KCNQ2/3 channel currents.

PMID- 12482886
TI  - Two forms of electrical resonance at theta frequencies, generated by M-current, h
      current and persistent Na+ current in rat hippocampal pyramidal cells.
AB  - Coherent network oscillations in the brain are correlated with different
      behavioural states. Intrinsic resonance properties of neurons provide a basis for
      such oscillations. In the hippocampus, CA1 pyramidal neurons show resonance at
      theta (theta) frequencies (2-7 Hz). To study the mechanisms underlying theta
      resonance, we performed whole-cell recordings from CA1 pyramidal cells (n = 73)
      in rat hippocampal slices. Oscillating current injections at different
      frequencies (ZAP protocol), revealed clear resonance with peak impedance at 2-5
      Hz at approximately 33 degrees C (increasing to approximately 7 Hz at
      approximately 38 degrees C). The theta-resonance showed a U-shaped voltage
      dependence, being strong at subthreshold, depolarized (approximately -60 mV) and
      hyperpolarized (approximately -80 mV) potentials, but weaker near the resting
      potential (-72 mV). Voltage clamp experiments revealed three non-inactivating
      currents operating in the subthreshold voltage range: (1) M-current (I(M)), which
      activated positive to -65 mV and was blocked by the M/KCNQ channel blocker XE991
      (10 microM); (2) h-current (I(h)), which activated negative to -65 mV and was
      blocked by the h/HCN channel blocker ZD7288 (10 microM); and (3) a persistent
      Na(+) current (I(NaP)), which activated positive to -65 mV and was blocked by
      tetrodotoxin (TTX, 1 microM). In current clamp, XE991 or TTX suppressed the
      resonance at depolarized, but not hyperpolarized membrane potentials, whereas
      ZD7288 abolished the resonance only at hyperpolarized potentials. We conclude
      that these cells show two forms of theta-resonance: "M-resonance" generated by
      the M-current and persistent Na(+) current in depolarized cells, and "H
      resonance" generated by the h-current in hyperpolarized cells. Computer
      simulations supported this interpretation. These results suggest a novel function
      for M/KCNQ channels in the brain: to facilitate neuronal resonance and network
      oscillations in cortical neurons, thus providing a basis for an oscillation-based
      neural code.

PMID- 12482887
TI  - O2-sensitive K+ channels in immortalised rat chromaffin-cell-derived MAH cells.
AB  - The regulation of K(+) channels by O(2) levels is a key link between hypoxia and
      neurotransmitter release in neuroendocrine cells. Here, we examined the effects
      of hypoxia on K(+) channels in the immortalised v-myc, adrenal-derived HNK1(+)
      (MAH) cell line. MAH cells possess a K(+) conductance that is sensitive to
      Cd(2+), iberiotoxin and apamin, and which is inhibited by ~24 % when exposed to a
      hypoxic perfusate (O(2) tension 20 mmHg). This conductance was attributed to high
      conductance Ca(2+)-activated K(+) (BK) and small-conductance Ca(2+)-activated
      K(+) (SK) channels, which are major contributors to the O(2)-sensitive K(+)
      conductance in adrenomedullary chromaffin cells. Under low [Ca(2+)](i) conditions
      that prevented activation of Ca(2+)-dependent K(+) conductances, a rapidly
      activating and slowly inactivating K(+) conductance, sensitive to both TEA and 4
      aminopyridine (4-AP), but insensitive to 100 nM charybdotoxin (CTX), was
      identified. This current was also reduced (by ~25 %) when exposed to hypoxia. The
      hypoxia-sensitive component of this current was greatly attenuated by 10 mM 4-AP,
      but was only slightly reduced by 10 mM TEA. This suggests the presence of delayed
      rectifier O(2)-sensitive channels comprising homomultimeric Kv1.5 or
      heteromultimeric Kv1.5/Kv1.2 channel subunits. The presence of both Kv1.5 and
      Kv1.2 alpha-subunits was confirmed using immunocytochemical techniques. We also
      demonstrated that these K(+) channel subunits are present in neonatal rat
      adrenomedullary chromaffin cells in situ. These data indicate that MAH cells
      possess O(2)-sensitive K(+) channels with characteristics similar to those
      observed previously in isolated chromaffin cells, and therefore provide an
      excellent model for examining the cellular mechanisms of O(2) sensing in
      adrenomedullary chromaffin cells.

PMID- 12482889
TI  - Freshly isolated bovine coronary endothelial cells do not express the BK Ca
      channel gene.
AB  - Recent reports have suggested that different types of Ca(2+)-activated K(+)
      channels may be selectively expressed either in the vascular endothelial cells
      (ECs) or smooth muscle cells (SMCs) of a single artery. In this study, we
      directly compared mRNA, protein and functional expression of the high-conductance
      Ca(2+)-activated K(+) (BK(Ca)) channel between freshly isolated ECs and SMCs from
      bovine coronary arteries. Fresh ECs and SMCs were enzymatically isolated, and
      their separation verified by immunofluorescent detection of alpha-actin and
      platelet/endothelium cell adhesion molecule (PECAM) proteins, respectively.
      Subsequently, studies using a sequence-specific antibody directed against the
      pore-forming alpha-subunit of the BK(Ca) channel only detected its expression in
      the SMCs, whereas PECAM-positive ECs were devoid of the alpha-subunit protein.
      Additionally, multicell RT-PCR performed using cDNA derived from either SMCs or
      ECs only detected mRNA encoding the BK(Ca) alpha-subunit in the SMCs. Finally,
      whole-cell recordings of outward K(+) current detected a prominent iberiotoxin
      sensitive BK(Ca) current in SMCs that was absent in ECs, and the BK(Ca) channel
      opener NS 1619 only enhanced K(+) current in the SMCs. Thus, bovine coronary SMCs
      densely express BK(Ca) channels whereas adjacent ECs in the same artery appear to
      lack the expression of the BK(Ca) channel gene. These findings indicate a cell
      specific distribution of Ca(2+)-activated K(+) channels in SMCs and ECs from a
      single arterial site.

PMID- 12482888
TI  - Expression of a calpastatin transgene slows muscle wasting and obviates changes
      in myosin isoform expression during murine muscle disuse.
AB  - Muscle wasting is a prominent feature of several systemic diseases, neurological
      damage and muscle disuse. The contribution of calpain proteases to muscle wasting
      in any instance of muscle injury or disease has remained unknown because of the
      inability to specifically perturb calpain activity in vivo. We have generated a
      transgenic mouse with muscle-specific overexpression of calpastatin, which is the
      endogenous inhibitor of calpains, and induced muscle atrophy by unloading
      hindlimb musculature for 10 days. Expression of the transgene resulted in
      increases in calpastatin concentration in muscle by 30- to 50-fold, and
      eliminated all calpain activity that was detectable on zymograms. Muscle fibres
      in ambulatory, transgenic mice were smaller in diameter, but more numerous, so
      that muscle mass did not differ between transgenic and non-transgenic mice. This
      is consistent with the role of the calpain-calpastatin system in muscle cell
      fusion that has been observed in vitro. Overexpression of calpastatin reduced
      muscle atrophy by 30 % during the 10 day unloading period. In addition,
      calpastatin overexpression completely prevented the shift in myofibrillar myosin
      content from slow to fast isoforms, which normally occurs in muscle unloading.
      These findings indicate that therapeutics directed toward regulating the calpain
      calpastatin system may be beneficial in preventing muscle mass loss in muscle
      injury and disease.

PMID- 12482890
TI  - Regulation of Cl--HCO3- exchangers by cAMP-dependent protein kinase in adult rat
      hippocampal CA1 neurons.
AB  - The contributions of HCO(3)(-)-dependent, DIDS-sensitive mechanisms to the
      maintenance of steady-state pH(i), and the regulation of their activities by cAMP
      dependent protein kinase (PKA), were investigated in CA1 neurons with the H(+)
      sensitive fluorophore, BCECF. The addition of HCO(3)(-)/CO(2) to neurons with
      "low" (pH(i) < or = 7.20) and "high" (pH(i) > 7.20) initial pH(i) values under
      Hepes-buffered conditions, increased and decreased steady-state pH(i),
      respectively. Conversely, under HCO(3)(-)/CO(2)-buffered conditions, DIDS caused
      pH(i) to decrease and increase in neurons with low and high initial pH(i) values,
      respectively. In the presence, but not the absence, of HCO(3)(-), the PKA
      inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate (Rp-cAMPS; 50 microM)
      evoked DIDS-sensitive increases and decreases in pH(i) in neurons with low and
      high initial pH(i) values, respectively. In contrast, in neurons with low initial
      pH(i) values, activation of PKA with the Sp isomer of cAMPS (Sp-cAMPS; 25 microM)
      elicited increases in pH(i) that were smaller in the presence than in the absence
      of HCO(3)(-), whereas in neurons with high initial pH(i) values, Sp-cAMPS-evoked
      rises in pH(i) were larger in the presence than in the absence of HCO(3)(-); the
      differences between the effects of Sp-cAMPS on pH(i) under the different
      buffering conditions were attenuated by DIDS. Consistent with the possibility
      that changes in the activities of HCO(3)(-)-dependent, DIDS-sensitive mechanisms
      contribute to the steady-state pH(i) changes evoked by the PKA modulators, in
      neurons with initial pH(i) values < or = 7.20, Rp-cAMPS concurrently inhibited
      Na(+)-independent Cl(-)-HCO(3)(-) exchange and stimulated Na(+)-dependent Cl(-)
      HCO(3)(-) exchange; in contrast, Sp-cAMPS concurrently stimulated Na(+)
      independent Cl(-)-HCO(3)(-) exchange and inhibited Na(+)-dependent Cl(-)-HCO(3)(
      ) exchange. Data from a limited number of neurons with initial pH(i) values >
      7.20 suggested that the directions of the reciprocal changes in anion exchange
      activities (inhibition or stimulation) evoked by Rp- and Sp-cAMPS may be opposite
      in cells with low vs. high resting pH(i) values. Taken together, the results
      indicate that the effects of modulating PKA activity on steady-state pH(i) in rat
      CA1 neurons under HCO(3)(-)/CO(2)-buffered conditions reflect not only changes in
      Na(+)-H(+) exchange activity but also changes in Na(+)-dependent and Na(+)
      independent Cl(-)-HCO(3)(-) exchange activity that, in turn, may be dependent
      upon the initial pH(i).

PMID- 12482891
TI  - Cellular mechanisms of orexin actions on paraventricular nucleus neurones in rat
      hypothalamus.
AB  - Using whole-cell patch clamp techniques we have examined the cellular mechanisms
      underlying the effects of orexin A (OX-A) on electrophysiologically identified
      magnocellular and parvocellular neurones in the rat hypothalamic paraventricular
      nucleus (PVN). The majority of magnocellular neurones (67 %) showed concentration
      dependent, reversible depolarizations in response to OX-A. These effects were
      abolished in tetrodotoxin (TTX), suggesting them to be indirect effects on this
      population of neurones. OX-A also caused increases in excitatory postsynaptic
      current (EPSC) frequency and amplitude in magnocellular neurones. The former
      effects were again blocked in TTX while increases in mini-EPSC amplitude
      remained. Depolarizing effects of OX-A on magnocellular neurones were also found
      to be abolished by kynurenic acid, supporting the conclusion that these effects
      were the result of activation of a glutamate interneurone. Parvocellular neurones
      (73 % of those tested) also showed concentration-dependent, reversible
      depolarizations in response to OX-A. In contrast to magnocellular neurones, these
      effects were maintained in TTX, indicating direct effects of OX-A on this
      population of neurones. Voltage clamp analysis using slow voltage ramps
      demonstrated that OX-A enhanced a non-selective cationic conductance with a
      reversal potential of -40 mV in parvocellular neurones, effects which probably
      explain the depolarizing effects of this peptide in this subpopulation of PVN
      neurones. These studies have identified separate cellular mechanisms through
      which OX-A influences the excitability of magnocellular and parvocellular PVN
      neurones.

PMID- 12482892
TI  - Rapid non-genomic inhibition of ATP-induced Cl- secretion by dexamethasone in
      human bronchial epithelium.
AB  - A non-genomic antisecretory role for dexamethasone at low concentrations (0.1 nM
      to1 microM) is described in monolayers of human bronchial epithelial cells in
      primary culture and in a continuous cell line (16HBE14o- cells). Dexamethasone
      produced a rapid decrease of [Ca(2+)](i) (measured with fura-2
      spectrofluorescence) to a new steady-state concentration. After 15 min exposure
      to dexamethasone (1 nM), [Ca(2+)](i) was reduced by 32 +/- 11 nM (n = 7, P <
      0.0001) from a basal value of 213 +/- 36 nM (n = 7). We have shown previously
      that aldosterone (1 nM) also produces a rapid fall in [Ca(2+)](i); however, after
      the decrease in [Ca(2+)](i) induced by dexamethasone, subsequent addition of
      aldosterone did not produced any further lowering of [Ca(2+)](i). The rapid
      response to dexamethasone was insensitive to pretreatment with cycloheximide and
      unaffected by the glucocorticoid type II and mineralocorticoid receptor
      antagonists RU486 and spironolactone, respectively. The rapid [Ca(2+)](i)
      decrease induced by dexamethasone was inhibited by the Ca(2+)-ATPase pump
      inhibitor thapsigargin (1 microM), the adenylate cyclase inhibitor MDL
      hydrochloride (500 microM) and the protein kinase A inhibitor Rp-adenosine 3',5'
      cyclic monophosphorothioate (200 microM), but was not affected by the protein
      kinase C inhibitor, chelerythrine chloride (0.1 microM). Treatment of 16HBE14o-
      cell monolayers with dexamethasone (1 nM) inhibited the large and transient
      [Ca(2+)](i) increase induced by apical exposure to ATP (10(-4) M). Dexamethasone
      (1 nM) also reduced by 30 % the Ca(2+)-dependant Cl(-) secretion induced by
      apical exposure to ATP (measured as the Cl(-)-sensitive short-circuit current
      across monolayers mounted in Ussing chambers). Our results demonstrate, for the
      first time, that dexamethasone at low concentrations inhibits Cl(-) secretion in
      human bronchial epithelial cells. The rapid inhibition of Cl(-) secretion induced
      by the synthetic glucocorticoid is associated with a rapid decrease in
      [Ca(2+)](i) via a non-genomic mechanism that does not involve the classical
      glucocorticoid or mineralocorticoid receptor. Rather, it is a result of rapid non
      genomic stimulation of thapsigargin-sensitive Ca(2+)-ATPase, via adenylate
      cyclase and protein kinase A signalling.

PMID- 12482893
TI  - Distinct effect of actin cytoskeleton disassembly on exo- and endocytic events in
      a membrane patch of rat melanotrophs.
AB  - We used the cell-attached mode of patch-clamp technique to measure discrete
      attofarad steps in membrane capacitance (C(m)), reporting area changes in the
      plasma membrane due to unitary exocytic and endocytic events. To investigate the
      role of the actin cytoskeleton in elementary exocytic and endocytic events,
      neuroendocrine rat melanotrophs were treated with Clostridium spiroforme toxin
      (CST), which specifically depolymerises F-actin. The average amplitude of
      exocytic events was not significantly different in control and in CST-treated
      cells. However, the amplitude of endocytic events was significantly smaller in
      CST-treated cells as compared to controls. The frequency of exocytic events
      increased by 2-fold in CST-treated cells relative to controls. In control cells
      the average frequency of exocytic events (upsilon;(exo)) was lower than the
      frequency of endocytic events (upsilon;(endo)) with a ratio
      upsilon;(exo)/upsilon;(endo) < 1. In the toxin treated cells, the predominant
      process was exocytosis with a ratio (upsilon;(exo)/upsilon;(endo) > 1). To study
      the coupling between the two processes, the slopes of regression lines relating
      upsilon;(exo) and upsilon;(endo) in a given patch of membrane were studied. The
      slopes of regression lines were similar, whereas the line intercepts with the y
      axis were significantly different. The increased frequency of unitary exocytic
      events in CST-treated cells is consistent with the view, that the actin
      cytoskeleton acts as a barrier for exocytosis. While the disassembly of the actin
      cytoskeleton diminishes the size of unitary endocytic events, suggesting an
      important role of the actin cytoskeleton in determining the size of endocytic
      vesicles, the coupling between exocytosis and endocytosis in a given patch of
      membrane was independent of the state of the actin cytoskeleton.

PMID- 12482894
TI  - Determinants of relaxation rate in rabbit skinned skeletal muscle fibres.
AB  - The influence of Ca(2+)-activated force, the rate of dissociation of Ca(2+) from
      troponin C (TnC) and decreased crossbridge detachment rate on the time course of
      relaxation induced by flash photolysis of diazo-2 in rabbit skinned psoas fibres
      was investigated at 15 degrees C. The rate of relaxation increased as the diazo-2
      chelating capacity (i.e. free [diazo-2]/free [Ca(2+)]) increased. At a constant
      diazo-2 chelating capacity, the rate of relaxation was independent of the pre
      photolysis Ca(2+)-activated force in the range 0.3-0.8 of maximum isometric
      force. A TnC mutant that exhibited increased Ca(2+) sensitivity caused by a
      decreased Ca(2+) dissociation rate in solution (M82Q TnC) also increased the
      Ca(2+) sensitivity of steady-state force and decreased the rate of relaxation in
      fibres by approximately twofold. In contrast, a TnC mutant with decreased Ca(2+)
      sensitivity caused by an increased Ca(2+) dissociation rate in solution (NHdel
      TnC) decreased the Ca(2+) sensitivity of steady-state force but did not
      accelerate relaxation. Decreasing the rate of crossbridge kinetics by reducing
      intracellular inorganic phosphate concentration ([P(i)]) slowed relaxation by
      approximately twofold and led to two phases of relaxation, a slow linear phase
      followed by a fast exponential phase. In fibres, M82Q TnC further slowed
      relaxation in low [P(i)] conditions by approximately twofold, whereas NHdel TnC
      had no significant effect on relaxation. These results are consistent with the
      interpretation that the Ca(2+)-dissociation rate and crossbridge detachment rate
      are similar in fast-twitch skeletal muscle, such that decreasing either rate
      slows relaxation, but accelerating Ca(2+) dissociation has little effect on
      relaxation.

PMID- 12482895
TI  - Role of the flocculus in mediating vestibular nucleus neuron plasticity during
      vestibular compensation in the rat.
AB  - We investigated the role of the cerebellar flocculus in mediating the adaptive
      changes that occur in the intrinsic properties of brainstem medial vestibular
      nucleus (MVN) neurons during vestibular compensation. Ipsi-lesional, but not
      contra-lesional, flocculectomy prevented the compensatory increase in intrinsic
      excitability (CIE) that normally occurs in the de-afferented MVN neurons within 4
      h after unilateral labyrinthectomy (UL). Flocculectomy did not, however, prevent
      the down-regulation of efficacy of GABA receptors that also occurs in these
      neurons after UL, indicating that these responses of the MVN neurons to
      deafferentation are discrete, parallel processes. CIE was also abolished by intra
      floccular microinjection of the metabotropic glutamate receptor (mGluR)
      antagonist AIDA, and the protein kinase C inhibitor bisindolymaleimide I (BIS-I).
      The serene-threonine kinase inhibitor H-7 had no effect when microinjected at the
      time of de-afferentation, but abolished CIE if microinjected 2 h later. These
      cellular effects are in line with the recently reported retardatory effects of
      BIS-I and H-7 on behavioural recovery after UL. They demonstrate that the
      increase in intrinsic excitability in MVN neurons during vestibular compensation
      is cerebellum dependent, and requires mGluR activation and protein
      phosphorylation in cerebellar cortex. Furthermore, microinjection of the
      glucocorticoid receptor (GR) antagonist RU38486 into the ipsi-lesional flocculus
      also abolished CIE in MVN neurons. Thus an important site for glucocorticoids in
      facilitating vestibular compensation is within the cerebellar cortex. These
      observations ascribe functional significance to the high levels of GR and 11-beta
      HSD Type 1 expression in cerebellum.

PMID- 12482896
TI  - Quantitative responses of spinothalamic lamina I neurones to graded mechanical
      stimulation in the cat.
AB  - Nociceptive spinothalamic tract (STT) neurones in lamina I of the lumbosacral
      spinal cord of anaesthetized cats were characterized by recording their responses
      to graded mechanical stimulation with controlled forces of 10-120 g and probes of
      5.0, 0.5 and 0.1 mm(2) contact area. Neurones were identified by antidromic
      activation from the contralateral thalamus, and cells that responded to noxious
      stimulation were categorized as either nociceptive specific (NS, n = 20) or as
      polymodal nociceptive (HPC, responsive to heat, pinch and cold, n = 19) based on
      their responses to quantitative thermal stimuli. The mean responses of the 39
      units increased linearly as stimulus intensity increased, and the population
      stimulus-response curves evoked by each of the three probes were all
      significantly different from each other. Thresholds were 45 g for the 5.0 mm(2)
      probe, 30 g for the 0.5 mm(2) probe and 20 g for the 0.1 mm(2) probe. Further
      analysis showed that the NS neurones encoded both stimulus intensity and area
      (probe size) significantly better than HPC neurones in terms of their thresholds
      to individual probes, their peak discharge rates, their suprathreshold
      responsiveness and their ability to discriminate the three different probe sizes.
      These differences are consistent with the known differences between the
      mechanical encoding properties of A-fibre nociceptors, which provide the dominant
      inputs to NS neurones, and C-fibre nociceptors, which are the dominant inputs to
      HPC cells. Comparison of the stimulus-response curves of NS and HPC neurones
      indicated that the discharge of NS neurones better match the psychophysics of
      mechanical pain sensations in humans than the discharge of the HPC neurones do.
      Our findings support the view that NS neurones have a prominent role in
      mechanical pain and sharpness, and they corroborate the concept that the lamina I
      STT projection comprises several discrete channels that are integrated in the
      forebrain to generate qualitatively distinct sensations.

PMID- 12482897
TI  - Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3
      kinase-driven activation of BK channels.
AB  - The obese gene product, leptin is an important circulating satiety factor that
      regulates energy balance via its actions in the hypothalamus. However, leptin
      receptors are also expressed in brain regions not directly associated with energy
      homeostasis, such as the hippocampus. Here, leptin inhibits hippocampal neurones
      via activation of large conductance Ca(2+)-activated K(+) (BK) channels, a
      process that may be important in regulating neuronal excitability. We now show
      that leptin receptor labelling is expressed on somata, dendrites and axons, and
      is also concentrated at synapses in hippocampal cultures. In functional studies,
      leptin potently and reversibly reduces epileptiform-like activity evoked in lean,
      but not leptin-resistant Zucker fa/fa rats. Furthermore, leptin also depresses
      enhanced Ca(2+) levels evoked following Mg(2+) removal in hippocampal cultures.
      The ability of leptin to modulate this activity requires activation of BK, but
      not K(ATP), channels as the effects of leptin were mimicked by the BK channel
      activator NS-1619, and inhibited by the BK channel inhibitors, iberiotoxin and
      charybdotoxin. The signalling mechanisms underlying this process involve
      stimulation of phosphoinositide 3-kinase (PI 3-kinase), but not mitogen-activated
      protein kinase (MAPK), as two structurally unrelated inhibitors of PI 3-kinase,
      LY294002 and wortmannin, blocked the actions of leptin. These data indicate that
      leptin, via PI 3-kinase-driven activation of BK channels, elicits a novel
      mechanism for controlling neuronal excitability. As uncontrolled excitability in
      the hippocampus is one underlying cause of temporal lobe epilepsy, this novel
      action of leptin could provide an alternative therapeutic target in the
      management of epilepsy.

PMID- 12482898
TI  - Active and passive membrane properties of rat sympathetic preganglionic neurones
      innervating the adrenal medulla.
AB  - The intravascular release of adrenal catecholamines is a fundamental homeostatic
      process mediated via thoracolumbar spinal sympathetic preganglionic neurones (AD
      SPN). To understand mechanisms regulating their excitability, whole-cell patch
      clamp recordings were obtained from 54 retrogradely labelled neonatal rat AD-SPN.
      Passive membrane properties included a mean resting membrane potential, input
      resistance and time constant of -62 +/- 6 mV, 410 +/- 241 MOmega and 104 +/- 53
      ms, respectively. AD-SPN were homogeneous with respect to their active membrane
      properties. These active conductances included transient outward rectification,
      observed as a delayed return to rest at the offset of the membrane response to
      hyperpolarising current pulses, with two components: a fast 4-AP-sensitive
      component (A-type conductance), contributing to the after-hyperpolarisation (AHP)
      and spike repolarisation; a slower prolonged Ba(2+)-sensitive component (D-like
      conductance). All AD-SPN expressed a Ba(2+)-sensitive instantaneous inwardly
      rectifying conductance activated at membrane potentials more negative than around
      -80 mV. A potassium-mediated, voltage-dependent sustained outward rectification
      activated at membrane potentials between -35 and -15 mV featured an atypical
      pharmacology with a component blocked by quinine, reduced by low extracellular pH
      and arachidonic acid, but lacking sensitivity to Ba(2+), TEA and intracellular
      Cs(+). This quinine-sensitive outward rectification contributes to spike
      repolarisation. Following block of potassium conductances by Cs(+) loading, AD
      SPN revealed the capability for autorhythmicity and burst firing, mediated by a T
      type Ca(2+) conductance. These data suggest the output capability is dynamic and
      diverse, and that the range of intrinsic membrane conductances expressed endow AD
      SPN with the ability to generate differential and complex patterns of activity.
      The diversity of intrinsic membrane properties expressed by AD-SPN may be key
      determinants of neurotransmitter release from SPN innervating the adrenal
      medulla. However, factors other than active membrane conductances of AD-SPN must
      ultimately regulate the differential ratio of noradrenaline (NA) versus
      adrenaline (A) release secreted in response to various physiological and
      environmental demands.

PMID- 12482899
TI  - The effects of ischaemic preconditioning, diazoxide and 5-hydroxydecanoate on rat
      heart mitochondrial volume and respiration.
AB  - Studies with different ATP-sensitive potassium (K(ATP)) channel openers and
      blockers have implicated opening of mitochondrial K(ATP) (mitoK(ATP)) channels in
      ischaemic preconditioning (IPC). It would be predicted that this should increase
      mitochondrial matrix volume and hence respiratory chain activity. Here we confirm
      this directly using mitochondria rapidly isolated from Langendorff-perfused
      hearts. Pre-ischaemic matrix volumes for control and IPC hearts (expressed in
      microl per mg protein +/- S.E.M., n = 6), determined with (3)H(2)O and
      [(14)C]sucrose, were 0.67 +/- 0.02 and 0.83 +/- 0.04 (P < 0.01), respectively,
      increasing to 1.01 +/- 0.05 and 1.18 +/- 0.02 following 30 min ischaemia (P <
      0.01) and to 1.21 +/- 0.13 and 1.26 +/- 0.25 after 30 min reperfusion. Rates of
      ADP-stimulated (State 3) and uncoupled 2-oxoglutarate and succinate oxidation
      increased in parallel with matrix volume until maximum rates were reached at
      volumes of 1.1 microl ml(-1) or greater. The mitoK(ATP) channel opener, diazoxide
      (50 microM), caused a similar increase in matrix volume, but with inhibition
      rather than activation of succinate and 2-oxoglutarate oxidation. Direct addition
      of diazoxide (50 microM) to isolated mitochondria also inhibited State 3
      succinate and 2-oxoglutarate oxidation by 30 %, but not that of palmitoyl
      carnitine. Unexpectedly, treatment of hearts with the mitoK(ATP) channel blocker
      5-hydroxydecanoate (5HD) at 100 or 300 microM, also increased mitochondrial
      volume and inhibited respiration. In isolated mitochondria, 5HD was rapidly
      converted to 5HD-CoA by mitochondrial fatty acyl CoA synthetase and acted as a
      weak substrate or inhibitor of respiration depending on the conditions employed.
      These data highlight the dangers of using 5HD and diazoxide as specific
      modulators of mitoK(ATP) channels in the heart.

PMID- 12482900
TI  - Smooth muscle membrane potential modulates endothelium-dependent relaxation of
      rat basilar artery via myo-endothelial gap junctions.
AB  - The release of endothelium-derived relaxing factors, such as nitric oxide (NO),
      is dependent on an increase in intracellular calcium levels ([Ca(2+)](i)) within
      endothelial cells. Endothelial cell membrane potential plays a critical role in
      the regulation of [Ca(2+)](i) in that calcium influx from the extracellular space
      is dependent on membrane hyperpolarization. In this study, the effect of
      inhibition of vascular smooth muscle delayed rectifier K(+) (K(DR)) channels by 4
      aminopyridine (4-AP) on endothelium-dependent relaxation of rat basilar artery to
      acetylcholine (ACh) was assessed. ACh-evoked endothelium-dependent relaxations
      were inhibited by N-(Omega)-nitro-L-arginine (L-NNA) or 1H-[1,2,4]oxadiazolo[4,3
      a]quinoxalin-1-one (ODQ), confirming a role for NO and guanylyl cyclase. 4-AP
      (300 microM) also suppressed ACh-induced relaxation, with the maximal response
      reduced from approximately 92 to approximately 33 % (n = 11; P < 0.01). However,
      relaxations in response to exogenous NO, applied in the form of authentic NO,
      sodium nitroprusside or diethylamineNONOate (DEANONOate), were not affected by 4
      AP treatment (n = 3-11). These data are not consistent with the view that 4-AP
      sensitive K(DR) channels are mediators of vascular hyperpolarization and
      relaxation in response to endothelium-derived NO. Inhibition of ACh-evoked
      relaxation by 4-AP was reversed by pinacidil (0.5-1 microM; n = 5) or 18beta
      glycyrrhetinic acid (18betaGA; 5 microM; n = 5), indicating that depolarization
      and electrical coupling of the smooth muscle to the endothelium were involved. 4
      AP caused depolarization of both endothelial and vascular smooth muscle cells of
      isolated segments of basilar artery (mean change 11 +/- 1 and 9 +/- 2 mV,
      respectively; n = 15). Significantly, 18betaGA almost completely prevented the
      depolarization of endothelial cells (n = 6), but not smooth muscle cells (n = 6)
      by 4-AP. ACh-induced hyperpolarization of endothelium and smooth muscle cells was
      also reduced by 4-AP, but this inhibition was not observed in the combined
      presence of 4-AP and 18betaGA. These data indicate that 4-AP can induce an
      indirect inhibition of endothelium-dependent relaxation in the rat basilar artery
      by electrical coupling of smooth muscle membrane depolarization to the
      endothelium via myo-endothelial gap junctions.

PMID- 12482901
TI  - Phase-disparity coding in extrastriate area 19 of the cat.
AB  - Binocular interactions were investigated in area 19 of the anaesthetized cat
      using dichoptically presented phase-shifted static spatial frequency gratings
      that flickered at a fixed temporal rate. More than two-thirds of the binocular
      cells showed phase specificity to static phase disparities leading to either
      summation or facilitation interactions. This proportion of spatial disparity
      selectivity was higher than that shown for the same area (one-third of the units)
      when drifting light bars or drifting spatial frequencies were used to create
      disparities. The range of phase disparities encoded by binocular cells in area 19
      is inversely related to the optimal spatial frequency of the dominant eye. Thus,
      cells in this area are tuned to coarse spatial disparities which, as supported by
      behavioural studies, could reflect its involvement in the analysis of
      stereoscopic pattern having gross disparities but devoid of motion cues. Because
      of the nature of its interconnections with numerous visual cortical areas, area
      19 could serve as a way station where stereoscopic information could be first
      analysed and sent to other higher order areas for a complete representation of
      three-dimensional objects.

PMID- 12482903
TI  - Nicotinic ACh receptor subtypes on gastrointestinally projecting neurones in the
      dorsal motor vagal nucleus of the rat.
AB  - To determine the predominant nicotinic ACh receptor (nAChR) located on neurones
      in the dorsal motor nucleus of the vagus (DMV) that project to the
      gastrointestinal tract, we used the rat brainstem slice preparation and whole
      cell recordings of DMV neurones identified by retrograde DiI tracing to
      pharmacologically characterize nAChRs. Pressure ejection of acetylcholine (ACh,
      250 microM for 200 ms) from a patch pipette placed approximately 10-20 microm
      from the surface of the recorded cell produced an inward current in most DMV
      neurones sampled. The average currents for neurones projecting to the fundus,
      antrum and caecum were 149 +/- 38 (n = 25), 115 +/- 18 (n = 29) and 117 +/- 23 pA
      (n = 6), respectively. Blockade of the alpha7 subtype of nAChR with either alpha
      bungarotoxin (alpha-BGT) or methyllycaconitine (MLA) counteracted 60-75 % of the
      ACh-evoked current in DMV neurones projecting to the fundus, antrum and caecum.
      In neurones projecting to the fundus and the antrum, currents resistant to alpha
      BGT were significantly blocked by dihydro-beta-erythroidine (10-20 nM), an
      antagonist of the alpha4beta2 subtype of nAChR. In neurones projecting to the
      caecum, currents resistant to alpha-BGT were significantly depressed by a low
      concentration of mecamylamine (1 microM). Cytisine (100 microM), an agonist of
      nAChRs that contain the alpha7 or the beta4 subunit, evoked significant currents
      in caecum-projecting neurones that were previously exposed to alpha-BGT. In
      contrast, cytisine had no effect on DMV neurones previously exposed to alpha-BGT
      that project to the fundus or antrum. Our data indicate that the prevailing nAChR
      subtype in DMV neurones projecting to the GI tract is the alpha7 subtype. In
      addition, we obtained evidence for the co-expression of the alpha4beta2 nAChR
      subtype on DMV neurones projecting to the fundus and antrum, and the alpha3beta4
      nAChR subtype on DMV neurones projecting to the caecum.

PMID- 12482902
TI  - Cessation of activity in red nucleus neurons during stimulation of the medial
      medulla in decerebrate rats.
AB  - The pontine oral reticular nucleus, gigantocellular reticular nucleus (Gi) and
      dorsal paragigantocellular nucleus (DPGi) of the medulla are key elements of a
      brainstem-reticulospinal inhibitory system that participates in rapid eye
      movement (REM) sleep atonia. Our recent study has shown that excitation of these
      brainstem nuclei in decerebrate rats inhibits locus coeruleus cells and the
      midbrain locomotor region neurons related to muscle tone facilitation. In the
      present study we have examined the influences of electrical and chemical
      stimulation of Gi and DPGi inhibitory sites on the activity of neurons located in
      the magnocellular part of the red nucleus (RMC), a cell group that participates
      in both the tonic and phasic regulation of motor output. A total of 192 RMC
      neurons were recorded in precollicular-premammillary decerebrate rats with muscle
      rigidity and induced locomotion. Thirty-three RMC neurons were identified
      antidromically as rubrospinal (RMC-spinal) cells by stimulation of the
      contralateral dorsolateral funiculus at the L2 level. A total of 141 RMC neurons
      (88.7 %) and all RMC-spinal neurons were inhibited during electrical stimulation
      of Gi and DPGi inhibitory sites. This cessation of activity was correlated with
      bilateral muscle atonia or blockage of locomotion. Six RMC cells (3.8 %) were
      excited (224 +/- 50 %, n = 6, minimum = 98, maximum = 410, P < 0.05) and 11 cells
      (7 %) gave no response to Gi and DPGi stimulation. Microinjections of kainic acid
      (100 microM, 0.2 microl) into Gi and DPGi inhibitory sites, previously identified
      by electrical stimulation, produced a short-latency (35 +/- 3.5 s, n = 11)
      decrease of rigid hindlimb muscle tone and inhibition of all tested RMC (n = 7)
      and RMC-spinal (n = 5) neurons. These results, combined with our recent published
      data, suggest that inhibition of motor function during activation of the
      brainstem inhibitory system is related to both the descending inhibition of
      spinal motoneurons and suppression of activity in supraspinal motor facilitatory
      systems. These two mechanisms acting synergistically may cause generalized motor
      inhibition during REM sleep and cataplexy.

PMID- 12482904
TI  - Opioid-resistant respiratory pathway from the preinspiratory neurones to
      abdominal muscles: in vivo and in vitro study in the newborn rat.
AB  - We report that after spontaneous breathing movements are stopped by
      administration of opioids (opioid-induced apnoea) in neonatal rats, abdominal
      muscles continue to contract at a rate similar to that observed during periods of
      ventilation. Correspondingly, in vitro bath application of a mu opioid receptor
      agonist suppresses the activity of the fourth cervical root (C4) supplying the
      diaphragm, but not the rhythmic activity of the first lumbar root (L1)
      innervating the abdominal muscles. This indicates the existence of opioid
      resistant rhythmogenic neurones and a neuronal pathway transmitting their
      activity to the abdominal motoneurones. We have investigated this pathway by
      using a brainstem-spinal cord preparation of the neonatal rat. We identified
      bulbospinal neurones with a firing pattern identical to that of the L1 root.
      These neurones were located caudal to the obex in the vicinity of the nucleus
      retroambiguus. Resting potentials ranged from -49 to -40 mV (mean +/- S.D. -44.0
      +/- 4.3 mV). The mean input resistance was 315.5 +/- 54.8 MOmega. The mean
      antidromic latency from the L1 level was 42.8 +/- 4.4 ms. Axons crossed the
      midline at the level of the cell body. The activity pattern of the bulbospinal
      neurones and the L1 root consisted of two bursts per respiratory cycle with a
      silent period during inspiration. This pattern is characteristic of
      preinspiratory neurones. We found that 11 % of the preinspiratory neurones
      projected to the area where the bulbospinal neurones were located. These
      preinspiratory neurones were found in the rostral ventrolateral medulla close
      (200-350 microm) to the ventral surface at the level of the rostral half of the
      nucleus retrofacialis. Our data suggest the operation of a disynaptic pathway
      from the preinspiratory neurones to the L1 motoneurones in the in vitro
      preparation. We propose that the same pathway is responsible for rhythmic
      activation of the abdominal muscles during opioid-induced apnoea in the newborn
      rat.

PMID- 12482905
TI  - Stretch reflex gain in cat triceps surae muscles with compliant loads.
AB  - The triceps surae (TS) stretch reflex was measured in decerebrate cats during
      crossed extensor stimulation (tonic contractions) and after spinalization during
      rhythmic locomotor activity. The TS reflex force in response to a short pulse
      stretch measured during tonic contractions at low level of background activity
      was greater than when more background activity was present at the time of
      application of stretch. In contrast, the reflex force measured during rhythmic
      contractions was very small at low level of background force (flexion phase) and
      increased at moderate and high levels of background activity (extension phase).
      Thus, even in reduced preparations, a task modulation of the stretch reflex
      occurs. Throughout the experimental procedure, the torque motor used to stretch
      the muscles behaved like a spring of a preset compliance (from isometric to very
      compliant). A reflex model was used to simulate the responses obtained
      experimentally. The gain of the stretch reflex loop was estimated for each load
      condition and both behavioural tasks. The reflex loop gain was significantly
      larger as the compliance of the external load increased for both tonic and
      rhythmic contractions, although to a lesser extent in the phasically activated
      muscles. During rhythmic locomotor contractions the gain was less than 1,
      assuring stability of the system. In contrast, during tonic contractions against
      a compliant load the gain exceeded 1, consistent with the instability
      (oscillations, clonus) seen at times under these load conditions. However, the
      high gain and instability was only transient, since repeated stretch reduced the
      gain. Thus, non-linearities in the system assured vigorous responses at the onset
      of perturbations, but then weaker responses to ongoing perturbations to reduce
      the chance of feedback instability (clonus).

PMID- 12482906
TI  - Direct measurement of human ankle stiffness during quiet standing: the intrinsic
      mechanical stiffness is insufficient for stability.
AB  - During quiet standing the human "inverted pendulum" sways irregularly. In
      previous work where subjects balanced a real inverted pendulum, we investigated
      what contribution the intrinsic mechanical ankle stiffness makes to achieve
      stability. Using the results of a plausible model, we suggested that intrinsic
      ankle stiffness is inadequate for providing stability. Here, using a piezo
      electric translator we applied small, unobtrusive mechanical perturbations to the
      foot while the subject was standing freely. These short duration perturbations
      had a similar size and velocity to movements which occur naturally during quiet
      standing, and they produced no evidence of any stretch reflex response in soleus,
      or gastrocnemius. Direct measurement confirms our earlier conclusion; intrinsic
      ankle stiffness is not quite sufficient to stabilise the body or pendulum. On
      average the directly determined intrinsic stiffness is 91 +/- 23 % (mean +/-
      S.D.) of that necessary to provide minimal stabilisation. The stiffness was
      substantially constant, increasing only slightly with ankle torque. This
      stiffness cannot be neurally regulated in quiet standing. Thus we attribute this
      stiffness to the foot, Achilles' tendon and aponeurosis rather than the activated
      calf muscle fibres. Our measurements suggest that the triceps surae muscles
      maintain balance via a spring-like element which is itself too compliant to
      guarantee stability. The implication is that the brain cannot set ankle stiffness
      and then ignore the control task because additional modulation of torque is
      required to maintain balance. We suggest that the triceps surae muscles maintain
      balance by predictively controlling the proximal offset of the spring-like
      element in a ballistic-like manner.

PMID- 12482907
TI  - ANChors away: an actin based mechanism of nuclear positioning.
AB  - Mechanisms for nuclear migration and nuclear anchorage function together to
      control nuclear positioning. Both tubulin and actin networks play important roles
      in nuclear positioning. The actin cytoskeleton has been shown to position nuclei
      in a variety of systems from yeast to plants and animals. It can either act as a
      stable skeleton to anchor nuclei or supply the active force to move nuclei. Two
      C. elegans genes and their homologues play important roles in these processes.
      Syne/ANC-1 anchors nuclei by directly tethering the nuclear envelope to the actin
      cytoskeleton, and UNC-84/SUN functions at the nuclear envelope to recruit
      Syne/ANC-1.

PMID- 12482908
TI  - Making sense of latent TGFbeta activation.
AB  - TGFbeta is secreted as part of a latent complex that is targeted to the
      extracellular matrix. A variety of molecules, 'TGFbeta activators,' release
      TGFbeta from its latent state. The unusual temporal discontinuity of TGFbeta
      synthesis and action and the panoply of TGFbeta effects contribute to the
      interest in TGF-beta. However, the logical connections between TGFbeta synthesis,
      storage and action are obscure. We consider the latent TGFbeta complex as an
      extracellular sensor in which the TGFbeta propeptide functions as the detector,
      latent-TGFbeta-binding protein (LTBP) functions as the localizer, and TGF-beta
      functions as the effector. Such a view provides a logical continuity for various
      aspects of TGFbeta biology and allows us to appreciate TGFbeta biology from a new
      perspective.

PMID- 12482909
TI  - Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)
      induced vascular endothelial growth factor (VEGF/VPF) transcription.
AB  - Hepatocyte growth factor (HGF/SF)-induced expression of vascular endothelial
      growth factor (VEGF/VPF) has been implicated in paracrine amplification of
      angiogenesis, contributing to angiogenic responses during inflammation, wound
      healing, collateral formation and tumor growth. We have shown previously that
      HGF/SF-mediated VEGF/VPF expression by keratinocytes is primarily dependent on
      transcriptional activation, and we mapped the HGF/SF-responsive element to a GC
      rich region between bp -88 and -65. Sp1-like factors bind to this element
      constitutively; however the VEGF/VPF promoter is transactivated by HGF/SF in the
      absence of induced binding activity. In experimental approaches to clarify
      molecular mechanisms of Sp1-dependent VEGF/VPF gene transcription, neither HGF/SF
      dependent changes in nuclear expression nor in relative DNA binding activity of
      Sp family members to the indicated element were observed. Thus, HGF/SF was
      hypothesized to induce VEGF/VPF gene transcription via increased transactivation
      activity of Sp1 owing to biochemical modification. In immunoprecipitation
      studies, HGF/SF was found to increase the amount of serine-phosphorylated Sp1,
      revealing a likely mechanism of HGF/SF-induced VEGF/VPF expression, as
      phosphorylation may enhance the transcriptional activity of Sp1. The contribution
      of different signaling molecules to HGF/SF-induced VEGF/VPF transcription was
      demonstrated by the use of chemical inhibition, of expression of kinase-deficient
      signaling proteins, and by the use of antisense oligonucleotides. Herein, we
      provide evidence that PI 3-kinase, MEK1/2 and PKC-zeta play a significant role in
      HGF/SF-induced VEGF/VPF promoter activation. Together, our results elucidate a
      critical pathway of paracrine amplification of angiogenesis, suggesting that
      HGF/SF-induced Sp1 phosphorylation may activate VEGF/VPF promoter activity that
      requires the contribution of distinct signaling molecules.

PMID- 12482910
TI  - Differential localization of WAVE isoforms in filopodia and lamellipodia of the
      neuronal growth cone.
AB  - The formation and extension of filopodia in response to an extracellular stimulus
      by guidance cues determine the path of growth cone advance. Actin-filament
      bundling and actin polymerization at the tips supply the driving force behind the
      formation and elongation. We tried to clarify how signals in response to
      extracellular cues are transformed to induce filopodial generation and extension.
      Observations on the formation process of filopodia at growth cones in the
      neuroblastoma cell line NG108 showed that WAVE (WASP (Wiskott-Aldrich syndrome
      protein)-family verprolin homologous protein) isoforms played crucial and
      distinct roles in this process. WAVE1 was continuously distributed along the
      leading edge only and was not found in the filopodia. WAVE2 and WAVE3 discretely
      localized at the initiation sites of microspikes on the leading edge and also
      concentrated at the tips of protruding filopodia. We further found that WAVE
      isoforms localized at the filopodial tips through SHD (SCAR homology domain),
      next to its leucine zipper-like motif. Furthermore, time-lapse observations of
      filopodial formation in living cells showed that WAVE2 and WAVE3 were
      continuously expressed at the tips of filopodia during elongation. These results
      indicate that WAVE2 or WAVE3 may guide the actin bundles into the filopodia and
      promote actin assembly at the tips.

PMID- 12482911
TI  - Phosphoinositide-3-kinase-independent contractile activities associated with
      Fcgamma-receptor-mediated phagocytosis and macropinocytosis in macrophages.
AB  - Previous studies have shown that Fcgamma receptor (FcR)-mediated phagocytosis and
      macropinocytosis in macrophages consist of two dissociable activities: a
      phosphoinositide 3-kinase (PI3K)-independent extension of phagocytic cups and a
      PI3K-dependent contractile mechanism that closes phagosomes and ruffles into
      intracellular organelles. Here, we identify an additional contractile activity
      that persists in the presence of the PI3K inhibitor wortmannin. ML-7, an
      inhibitor of myosin-light-chain kinase (MLCK), inhibited FcR-mediated
      phagocytosis, macropinocytosis and cell movements associated with ruffling.
      Scanning electron microscopy demonstrated a striking difference in morphology
      between phagocytic cups in the different inhibitors: whereas phagocytic cups of
      control cells and wortmannin-treated cells conformed closely to particles and
      appeared to have constricted them, the phagocytic cups in cells treated with ML-7
      were more open. Video microscopy of macrophages expressing green-fluorescent
      protein (GFP)-actin fusions revealed that bound IgG-opsonized erythrocytes were
      squeezed during phagosome formation and closure. In ML-7, GFP-actin-rich
      protrusions extended outward but failed to squeeze particles. Moreover, in
      contrast to the effects of PI3K inhibitors, ML-7 markedly reduced ruffle
      movement, and perturbed circular ruffle formation. These PI3K-independent myosin
      II-based contractile activities that squeeze phagocytic cups and curve ruffles
      therefore represent a third component activity of the actin cytoskeleton during
      phagocytosis and macropinocytosis.

PMID- 12482912
TI  - Regulation of meiotic progression by the meiosis-specific checkpoint kinase Mek1
      in fission yeast.
AB  - During the eukaryotic cell cycle, accurate transmission of genetic information to
      progeny is ensured by the operation of cell cycle checkpoints. Checkpoints are
      regulatory mechanisms that block cell cycle progression when key cellular
      processes are defective or chromosomes are damaged. During meiosis, genetic
      recombination between homologous chromosomes is essential for proper chromosome
      segregation at the first meiotic division. In response to incomplete
      recombination, the pachytene checkpoint (also known as the meiotic recombination
      checkpoint) arrests or delays meiotic cell cycle progression, thus preventing the
      formation of defective gametes. Here, we describe a role for a meiosis-specific
      kinase, Mek1, in the meiotic recombination checkpoint in fission yeast. Mek1
      belongs to the Cds1/Rad53/Chk2 family of kinases containing forkhead-associated
      domains, which participate in a number of checkpoint responses from yeast to
      mammals. We show that defects in meiotic recombination generated by the lack of
      the fission yeast Meu13 protein lead to a delay in entry into meiosis I owing to
      inhibitory phosphorylation of the cyclin-dependent kinase Cdc2 on tyrosine 15.
      Mutation of mek1(+) alleviates this checkpoint-induced delay, resulting in the
      formation of largely inviable meiotic products. Experiments involving ectopic
      overexpression of the mek1(+) gene indicate that Mek1 inhibits the Cdc25
      phosphatase, which is responsible for dephosphorylation of Cdc2 on tyrosine 15.
      Furthermore, the meiotic recombination checkpoint is impaired in a cdc25
      phosphorylation site mutant. Thus, we provide the first evidence of a connection
      between an effector kinase of the meiotic recombination checkpoint and a crucial
      cell cycle regulator and present a model for the operation of this meiotic
      checkpoint in fission yeast.

PMID- 12482913
TI  - Furrow microtubules and localized exocytosis in cleaving Xenopus laevis embryos.
AB  - In dividing Xenopus eggs, furrowing is accompanied by expansion of a new domain
      of plasma membrane in the cleavage plane. The source of the new membrane is known
      to include a store of oogenetically produced exocytotic vesicles, but the site
      where their exocytosis occurs has not been described. Previous work revealed a V
      shaped array of microtubule bundles at the base of advancing furrows. Cold shock
      or exposure to nocodazole halted expansion of the new membrane domain, which
      suggests that these microtubules are involved in the localized exocytosis. In the
      present report, scanning electron microscopy revealed collections of pits or
      craters, up to approximately 1.5 micro m in diameter. These pits are evidently
      fusion pores at sites of recent exocytosis, clustered in the immediate vicinity
      of the deepening furrow base and therefore near the furrow microtubules. Confocal
      microscopy near the furrow base of live embryos labeled with the membrane dye FM1
      43 captured time-lapse sequences of individual exocytotic events in which
      irregular patches of approximately 20 micro m(2) of unlabeled membrane abruptly
      displaced pre-existing FM1-43-labeled surface. In some cases, stable fusion
      pores, approximately 2 micro m in diameter, were seen at the surface for up to
      several minutes before suddenly delivering patches of unlabeled membrane. To test
      whether the presence of furrow microtubule bundles near the surface plays a role
      in directing or concentrating this localized exocytosis, membrane expansion was
      examined in embryos exposed to D(2)O to induce formation of microtubule monasters
      randomly under the surface. D(2)O treatment resulted in a rapid, uniform
      expansion of the egg surface via random, ectopic exocytosis of vesicles. This
      D(2)O-induced membrane expansion was completely blocked with nocodazole,
      indicating that the ectopic exocytosis was microtubule-dependent. Results
      indicate that exocytotic vesicles are present throughout the egg subcortex, and
      that the presence of microtubules near the surface is sufficient to mobilize them
      for exocytosis at the end of the cell cycle.

PMID- 12482914
TI  - Differential usage of two in-frame translational start codons regulates
      subcellular localization of Arabidopsis thaliana THI1.
AB  - Arabidopsis thaliana THI1 is encoded by a single nuclear gene and directed
      simultaneously to mitochondria and chloroplasts from a single major transcript.
      In vitro transcription/translation experiments revealed the presence of two
      translational products by the differential usage of two in-frame translational
      start codons. The coupling site-specific mutations on the THI1 encoding sequence
      with green fluorescent protein (GFP) gene fusions showed that translation
      initiation at the first AUG directs translocation of THI1 to chloroplasts.
      However, when translation starts from the second AUG, THI1 is addressed to
      mitochondria. Analysis of the translation efficiency of thi1 mRNA revealed that
      the best context for translation initiation is to use the first AUG. In addition,
      a suboptimal context in the vicinity of the second AUG initiation codon, next to
      a stable stem-and-loop structure that is likely to slow translation, has been
      noted. The fact that translation preferentially occurs in the first AUG of this
      protein suggests a high requirement for TH1 in chloroplasts. Although the
      frequency of upstream AUG translation is higher, according to the first AUG rule,
      initiation at the second AUG deviates significantly from Kozak's consensus. It
      suggests leaky ribosomal scanning, reinitiation or the internal entry of
      ribosomes to assure mitochondrial protein import.

PMID- 12482915
TI  - Lipopolysaccharides from Legionella and Rhizobium stimulate mouse bone marrow
      granulocytes via Toll-like receptor 2.
AB  - Lipopolysaccharide (LPS) derived from enterobacteria elicit in several cell types
      cellular responses that are restricted in the use of Toll-like receptor 4 (TLR4)
      as the principal signal-transducing molecule. A tendency to consider
      enterobacterial LPS as a prototypic LPS led some authors to present this
      mechanism as a paradigm accounting for all LPSs in all cell types. However, the
      structural diversity of LPS does not allow such a general statement. By using
      LPSs from bacteria that do not belong to the Enterobacteriaceae, we show that in
      bone marrow cells (BMCs) the LPS of Rhizobium species Sin-1 and of three strains
      of Legionella pneumophila require TLR2 rather than TLR4 to elicit the expression
      of CD14. In addition, exposure of BMCs from TLR4-deficient (C3H/HeJ) mice to the
      lipid A fragment of the Bordetella pertussis LPS inhibits their activation by the
      Legionella lipid A. The data show selective action of different LPSs via
      different TLRs, and suggest that TLR2 can interact with many lipid A structures,
      leading to either agonistic or specific antagonistic effects.

PMID- 12482916
TI  - Control of Cajal body number is mediated by the coilin C-terminus.
AB  - Cajal bodies (CBs) are nuclear suborganelles implicated in the post
      transcriptional maturation of small nuclear and small nucleolar RNAs. The number
      of CBs displayed by various cell lines and tissues varies, and factors that
      control CB numbers within a given cell have yet to be described. In this report,
      we show that specific regions within the C-terminus of coilin, the CB marker
      protein, are responsible for regulating the number of nuclear foci. Despite the
      fact that the coilin N-terminal domain is responsible for its self
      oligomerization activity, truncation or mutation of predicted sites of
      phosphorylation in the conserved C-terminal region leads to a striking alteration
      in the number of nuclear bodies. Similarly, coilin constructs from various
      species display differential propensities to form nuclear foci when expressed in
      heterologous backgrounds. We mapped the domain responsible for this variability
      to the coilin C-terminus utilizing chimeric proteins. Furthermore, the activities
      responsible for regulating coilin self-association must reside in the nucleus, as
      constructs lacking critical nuclear localization sequences fail to form foci in
      the cytoplasm. Factors controlling the putative signal transduction cascade that
      phosphorylates coilin are also discussed. The results point to a model whereby
      phosphorylation of the coilin C-terminus regulates the availability of the N
      terminal self-interaction domain.

PMID- 12482918
TI  - Evidence of a role for Munc18-2 and microtubules in mast cell granule exocytosis.
AB  - Compound exocytosis of inflammatory mediators from mast cells requires SNARE and
      a series of accessory proteins. However, the molecular steps that regulate
      secretory granule movement and membrane fusion as well as the role of the
      cytoskeleton are still poorly understood. Here, we report on our investigation of
      the role of syntaxin-binding Munc18 isoforms and the microtubule network in this
      process. We found that mast cells express Munc18-2, which interacts with target
      SNAREs syntaxin 2 or 3, as well as Munc18-3, which interacts with syntaxin 4.
      Munc18-2 was localised to secretory granules, whereas Munc18-3 was found on the
      plasma membrane. Increased expression of Munc18-2 and derived peptides containing
      an interfering effector loop inhibited IgE-triggered exocytosis, while increased
      expression of Munc18-3 showed no effect. Munc18-2 localisation on granules is
      polarised; however, upon stimulation Munc18-2 redistributed into forming
      lamellipodia and persisted on granules that were aligned along microtubules, but
      was excluded from F-actin ruffles. Disruption of the microtubule network with
      nocodazole provoked Munc18-2 redistribution and affected mediator release. These
      findings suggest a role for Munc18-2 and the microtubule network in the
      regulation of secretory granule dynamics in mast cells.

PMID- 12482917
TI  - Secretory ribonucleases are internalized by a dynamin-independent endocytic
      pathway.
AB  - Cytosolic internalization is a requirement for the toxicity of secretory
      ribonucleases. Here, we investigate the mechanism of internalization of Onconase
      (ONC), a toxic protein, and ribonuclease A (RNase A), a nontoxic homolog.
      Microscopy studies indicate that both ribonucleases readily bind to the cell
      surface and are internalized via acidic vesicles. Blocking dynamin-dependent
      endocytosis prevents transferrin internalization but does not hinder RNase A
      internalization. ONC and G88R RNase A, which is a toxic variant, demonstrate
      enhanced cytotoxicity in the absence of clathrin- and dynamin-mediated
      endocytosis. The cytosolic entry of ribonucleases does not require an acidic
      environment or transport to the ER and probably occurs from endosomes. Thus,
      common proteins - secretory ribonucleases - enter the cytosol by a pathway that
      is distinct from that of other known toxins.

PMID- 12482919
TI  - Polycomb group gene silencing proteins are concentrated in the perichromatin
      compartment of the mammalian nucleus.
AB  - Human Polycomb group (PcG) proteins are involved in cell-type-dependent
      epigenetic gene silencing in an evolutionarily conserved manner. We have analysed
      the subnuclear localisation of these regulatory proteins in two different human
      cell lines and in rat liver tissue by means of light and electron
      immunomicroscopy using specific antibodies. We find that the PcG proteins HPC2,
      HPH1, BMI1 and RING1 are highly concentrated in the perichromatin compartment,
      situated at the surface of condensed chromatin domains. This compartment was
      demonstrated earlier to be the nuclear site where most pre-mRNA synthesis takes
      place. Interestingly, these PcG proteins are virtually absent from the interior
      of condensed chromatin areas. The present observations therefore show that
      transcriptionally active and PcG-silenced loci occur within the same spatially
      limited nuclear domain. Our novel high-resolution data strongly support the idea
      that epigenetic PcG-mediated gene silencing is a local event, rather than
      affecting large chromatin domains. In addition to being associated with the
      perichromatin region, PcG proteins also occur in the interchromatin space.
      Implications of these observations for higher order chromatin structure and for
      the mechanisms of PcG-mediated gene silencing are discussed.

PMID- 12482920
TI  - RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX.
AB  - The function of DAXX, a highly conserved mammalian gene, has remained
      controversial; this is due, in part, to its identification in a variety of yeast
      two-hybrid screens. Targeted deletion in the mouse revealed that DAXX is
      essential for embryonic development. Furthermore, the increased levels of
      apoptosis observed in Daxx-knockout embryos and embryonic stem cell lines
      suggested that DAXX functions in an anti-apoptotic capacity. In contrast,
      overexpression studies showed that DAXX may promote apoptosis. Additional studies
      showed that, when overexpressed, DAXX could function as a transcriptional
      repressor. To clarify these matters, we have used RNAi to deplete endogenous DAXX
      and thereby assess DAXX function in cell lines previously tested in
      overexpression studies. Increased apoptosis was observed in DAXX-depleted cells,
      showing DAXX to be anti-apoptotic. The apoptosis induced by the absence of DAXX
      was rescued by Bcl-2 overexpression. In addition, transcriptional derepression
      was observed in RNAi-treated cells, indicating the ability of endogenous DAXX to
      repress gene expression and allowing for the identification of novel targets of
      DAXX repression, including nuclear factor kappaB (NF-kappaB)- and E2F1- regulated
      targets. Thus, depletion of DAXX by RNAi has verified the crucial role of
      endogenous DAXX as an anti-apoptotic regulator, and has allowed the
      identification of probable physiological targets of DAXX transcriptional
      repression.

PMID- 12482921
TI  - CaM kinase IIalpha mediates norepinephrine-induced translocation of cytosolic
      phospholipase A2 to the nuclear envelope.
AB  - Several growth factors, hormones and neurotransmitters, including norepinephrine,
      increase cellular calcium levels, promoting the translocation of cytosolic
      phospholipase A(2) to the nuclear envelope. This study was conducted to
      investigate the contributions of the calcium-binding protein calmodulin and of
      calcium-calmodulin-dependent protein kinase II to cytosolic phospholipase A(2)
      translocation to the nuclear envelope elicited by norepinephrine in rabbit aortic
      smooth-muscle cells. Norepinephrine caused cytosolic phospholipase A(2)
      accumulation around the nuclear envelope as determined from its
      immunofluorescence; cytosolic phospholipase A(2) translocation was blocked by
      inhibitors of calmodulin and calcium-calmodulin-dependent protein kinase II or
      calcium-calmodulin-dependent protein kinase IIalpha antisense oligonucleotide.
      Calmodulin and calcium-calmodulin-dependent protein kinase II inhibitors did not
      prevent cytosolic calcium increase but attenuated cytosolic phospholipase A(2)
      phosphorylation caused by norepinephrine or ionomycin. In vascular smooth-muscle
      cells reversibly permeabilized with beta-escin and treated with alkaline
      phosphatase, norepinephrine failed to cause cytosolic phospholipase A(2)
      phosphorylation and translocation to the nuclear envelope; these effects of
      norepinephrine were minimized by the phosphatase inhibitor okadaic acid.
      Recombinant cytosolic phospholipase A(2) phosphorylated by purified calcium
      calmodulin-dependent protein kinase II, but not unphosphorylated or
      dephosphorylated cytosolic phospholipase A(2), introduced into permeabilized
      vascular smooth-muscle cells in the absence of calcium accumulated around the
      nuclear envelope. These data suggest that norepinephrine-induced translocation of
      cytosolic phospholipase A(2) to the nuclear envelope is mediated by its
      phosphorylation by calcium-calmodulin-dependent protein kinase II and that
      calcium alone is insufficient for cytosolic phospholipase A(2) translocation to
      the nuclear envelope in rabbit vascular smooth-muscle cells.

PMID- 12482922
TI  - External Ca2+ is predominantly used for cytoplasmic and nuclear Ca2+ increases in
      fertilized oocytes of the marine bivalve Mactra chinensis.
AB  - Oocytes of the marine bivalve Mactra chinensis are spawned and arrested at the
      germinal vesicle stage (first meiotic prophase) until fertilization, without
      undergoing a process called oocyte maturation. As is the case of other animals, a
      fertilized oocyte of the bivalve displays increases in intracellular free Ca(2+).
      We have clarified here the spatiotemporal patterns and sources of the
      intracellular Ca(2+) changes at fertilization. Shortly after insemination,
      increased Ca(2+) simultaneously appeared at the whole cortical region of the
      oocyte and spread inwardly to the center, attaining the maximal Ca(2+) levels
      throughout the oocyte, including the cytoplasm and nucleus. The initial maximal
      Ca(2+) peak was followed by a submaximal plateau phase of cytoplasmic and nuclear
      Ca(2+) elevations, which persisted for several minutes. The nuclear envelope
      began to break down shortly before the termination of the plateau phase. These
      sperm-induced Ca(2+) changes were inhibited by suppression of the influx of
      external Ca(2+) from seawater but not by disturbance of the release of internal
      Ca(2+) from inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)]-sensitive stores,
      suggesting that the increased Ca(2+) is from an external source. In contrast to
      the situation observed at fertilization, an oocyte artificially stimulated with
      serotonin (5-hydroxytryptamine, 5-HT) displayed repetitive Ca(2+) transients,
      each of which started from one cortical region and propagated across the oocyte
      as a Ca(2+) wave. The 5-HT-induced Ca(2+) transients persisted even in the
      absence of external Ca(2+). Experiments with caged Ins(1,4,5)P(3) revealed that
      Ca(2+) release from Ins(1,4,5)P(3)-sensitive stores is another pathway that is
      sufficient to trigger meiosis reinitiation from the first prophase. These results
      demonstrate that Mactra oocytes can potentially use two different Ca(2+)
      mobilizing pathways: Ca(2+) influx producing a centripetal Ca(2+) wave from the
      whole cortex and Ca(2+) release from Ins(1,4,5)P(3)-sensitive stores producing a
      point-source propagating Ca(2+) wave. However, it seems likely that the Ca(2+)
      influx pathway is predominantly activated at fertilization.

PMID- 12482923
TI  - Alpha5beta1 integrin mediates strong tissue cohesion.
AB  - Integrins and cadherins are considered to have distinct and opposing functions.
      Integrins are traditionally cited for their role in cell-substratum interactions,
      whereas cadherins are thought to mediate strong intercellular cohesion. Together,
      these adhesion systems play crucial roles in a wide variety of cellular and
      developmental processes including cell migration, morphology, differentiation and
      proliferation. In this manuscript we present evidence that integrins possess the
      ability to mediate strong intercellular cohesion when cells are grown as 3D
      aggregates. Much of the data elucidating the role of integrins as mediators of
      cell-extracellular matrix (ECM) interactions have been generated using
      conventional cell culture techniques in which cells are plated onto ECM-coated 2D
      surfaces. In vivo, cells are embedded in a 3D meshwork of ECM proteins. We
      hypothesized that, within this meshwork, integrin-ECM interactions may impart
      cohesivity to an aggregate of cells by linking adjacent cells together. To test
      this hypothesis, we transfected Chinese hamster ovary (CHO-B2) cells to express
      alpha5beta1 integrin and found that these cells formed compact, spherical
      aggregates. We measured aggregate cohesivity using tissue surface tensiometry, a
      novel technique that quantifies cell-cell cohesivity of spheroids under
      physiological conditions. We determined that alpha5beta1 integrin is capable of
      conferring strong cohesivity (sigma=8.22+/-0.68 dynes/cm) to aggregates of alpha5
      integrin-transfected cells. This cohesion was found to be independent of cadherin
      expression and was significantly greater than the cohesivity conferred onto CHO
      B2 cells transfected with N-cadherin (sigma=3.14+/-0.20 dynes/cm, P</=0.0001), a
      more traditional cell-cell cohesion system. Fibronectin-null CHO cells that
      express alpha5beta1 integrin but do not secrete endogenous fibronectin do not
      form aggregates in fibronectin-depleted medium. Addition of increasing amounts of
      exogenous dimeric fibronectin to these cells resulted in a dose-dependent
      compaction. However, compaction failed to occur in the presence of fibronectin
      monomers. These data indicate that fibronectin is required for alpha5beta1
      mediated compaction and that the dimeric structure of fibronectin is essential
      for this process. Additionally, aggregate formation of the alpha5 integrin
      transfectants was inhibited by an RGD peptide thus confirming alpha5beta1
      integrin specificity. Collectively, these data confirm our hypothesis that
      alpha5beta1 integrin acts through fibronectin to link adjacent cells together,
      thus promoting strong intercellular cohesion in 3D cellular aggregates.

PMID- 12482924
TI  - Analysis of the interactions between BP180, BP230, plectin and the integrin
      alpha6beta4 important for hemidesmosome assembly.
AB  - Hemidesmosomes (HDs) are multi-protein complexes that promote stable adhesion of
      epithelial cells to the underlying extracellular matrix. We assessed the
      interactions between different hemidesmosomal components with each other, mapped
      the binding sites and studied the importance of these interactions for HD
      assembly in yeast two-hybrid and cell-transfection assays. The results show that:
      (1) bullous pemphigoid antigen (BP) 180 binds not only to BP230, but also to
      plectin. The interactions between these proteins are facilitated by the Y
      subdomain in the N-terminal plakin domain of BP230 and plectin, and residues 145
      230 of the cytoplasmic domain of BP180; (2) different, but overlapping, sequences
      on BP180 mediate binding to beta4, which, in turn associates with BP180 via its
      third fibronectin type III repeat; (3) sequences in the N-terminal extremity of
      BP230 mediate its binding to beta4, which requires the C-terminal end of the
      connecting segment up to the fourth FNIII repeat of the beta4 subunit. (4)
      Finally, cell-transfection studies showed that the localization of BP230 into
      hemidesmosome-like structures depends on its Z-Y subdomains as well as on the
      availability of BP180. By having further uncovered interactions between various
      hemidesmosomal components, mapped the involved binding sites and dissected a
      hierarchy of interactions relevant for their topogenic fate, our findings give
      novel insights into the molecular organization of hemidesmosomes.

PMID- 12482925
TI  - A dominant negative form of the AAA ATPase SKD1/VPS4 impairs membrane trafficking
      out of endosomal/lysosomal compartments: class E vps phenotype in mammalian
      cells.
AB  - SKD1 is a member of the family of ATPases associated with cellular activities
      whose yeast homologue Vps4p has been implicated in endosomal/vacuolar membrane
      transports. When a mutant of SKD1 that lacks ATPase activity [SKD1(E235Q)] was
      overexpressed in mammalian cells, it induced a dominant negative phenotype
      characterized by aberrant endosomal structures (denoted as E235Q compartments).
      Expression of SKD1(E235Q) caused an accumulation of basolateral recycling
      receptors, such as asialoglycoprotein receptor and low-density lipoprotein in
      polarized hepatocytes and Madin-Darby canine kidney cells, respectively, in E235Q
      compartments. In addition, SKD1(E235Q) also abrogated, via endosomes, transport
      to the trans-Golgi network, as indicated by an accumulation of TGN38 in E235Q
      compartments. Three lines of evidence further demonstrated that SKD1 participates
      in the membrane transport from early endosomes to late endosomes/lysosomes: (1) a
      redistribution of a late endosomal and lysosomal membrane protein endolyn in
      E235Q compartments; (2) an inhibition of epidermal growth factor receptor
      degradation, due to an accumulation of the receptors in E235Q compartments; and
      (3) a mis-sorting of and defect in the proteolytic processing of newly
      synthesized cathepsin D. An intriguing finding was that the expression of
      SKD1(E235Q) caused the number of lysosomes to decrease (to one-sixth of control
      numbers) but their size to increase (2.4-fold larger in diameter than control
      lysosomes). Indeed, an ultrastructural analysis revealed that the expression of
      SKD1(E235Q) causes an accumulation of hybrid organelles formed by direct fusion
      between late endosomes and lysosomes. We conclude that SKD1 regulates multiple
      steps of membrane transport out of early endosomes and the reformation of
      lysosomes from a hybrid organelle.

PMID- 12482926
TI  - COPII proteins are required for Golgi fusion but not for endoplasmic reticulum
      budding of the pre-chylomicron transport vesicle.
AB  - The budding of vesicles from endoplasmic reticulum (ER) that contains nascent
      proteins is regulated by COPII proteins. The mechanisms that regulate lipid
      carrying pre-chylomicron transport vesicles (PCTVs) budding from the ER are
      unknown. To study the dependence of PCTV-ER budding on COPII proteins we examined
      protein and PCTV budding by using ER prepared from rat small intestinal mucosal
      cells prelabeled with (3)H-oleate or (14)C-oleate and (3)H-leucine. Budded (3)H
      oleate-containing PCTVs were separated by sucrose density centrifugation and were
      revealed by electron microscopy as 142-500 nm vesicles. Our results showed the
      following: (1) Proteinase K treatment did not degrade the PCTV cargo protein,
      apolipoprotein B-48, unless Triton X-100 was added. (2) PCTV budding was
      dependent on cytosol and ATP. (3) The COPII proteins Sar1, Sec24 and Sec13/31 and
      the membrane proteins syntaxin 5 and rBet1 were associated with PCTVs. (4)
      Isolated PCTVs were able to fuse with intestinal Golgi. (5) Antibodies to Sar1
      completely inhibited protein vesicle budding but increased the generation of
      PCTV; these changes were reversed by the addition of recombinant Sar1. (6) PCTVs
      formed in the absence of Sar1 did not contain the COPII proteins Sar1, Sec24 or
      Sec31 and did not fuse with the Golgi complex. Together, these findings suggest
      that COPII proteins may not be required for the exit of membrane-bound
      chylomicrons from the ER but that they or other proteins may be necessary for
      PCTV fusion with the Golgi.

PMID- 12482927
TI  - Discovery of lipid peroxidation products formed in vivo with a substituted
      tetrahydrofuran ring (isofurans) that are favored by increased oxygen tension.
AB  - Free radicals have been implicated in the pathogenesis of an increasing number of
      diseases. Lipids, which undergo peroxidation, are major targets of free radical
      attack. We report the discovery of a pathway of lipid peroxidation that forms a
      series of isomers in vivo that are characterized by a substituted tetrahydrofuran
      ring structure, termed isofurans (IsoFs). We have proposed two distinct pathways
      by which IsoFs can be formed based on 18O2 and H2 18O labeling studies.
      Measurement of F2-isoprostanes (IsoPs), prostaglandin F2-like compounds formed
      nonenzymatically as products of lipid peroxidation, is considered one of the most
      reliable approaches for assessing oxidative stress status in vivo. However, one
      limitation with this approach is that the formation of IsoPs becomes limited at
      high oxygen tension. In contrast, the formation of IsoFs becomes increasingly
      favored as oxygen tension increases. IsoFs are present at readily detectable
      levels in normal fluids and tissues, and levels increase dramatically in CCl4
      treated rats, an animal model of oxidant injury. The ratio of IsoFs to IsoPs in
      major organs varies according to normal steady-state tissue oxygenation. In
      addition, IsoFs show a marked increase early in the course of hyperoxia-induced
      lung injury, whereas IsoPs do not significantly increase. We propose that
      combined measurement of IsoFs and IsoPs should provide a more reliable index of
      oxidant stress severity than quantification of either alone because of the
      opposing modulation of the two pathways by oxygen tension, which can vary widely
      in different organs and disease states.

PMID- 12482928
TI  - More antibody with less antigen: can immunogenicity of attenuated live virus
      vaccines be improved?
AB  - New or improved vaccines against viruses such as influenza, parainfluenza types 1
      3, measles, dengue, and respiratory syncytial virus would prevent an enormous
      burden of morbidity and mortality. Vaccines or vaccine candidates exist against
      these viral diseases, but all could potentially be improved if the immunogenicity
      of the vaccine could be enhanced. We found that the immunogenicity in primates of
      a live-attenuated vaccine candidate for parainfluenza virus type 3, an enveloped
      RNA virus that is an important etiologic agent of pediatric respiratory tract
      disease, could be enhanced by expression of granulocyte-macrophage colony
      stimulating factor (GM-CSF) from an extra gene inserted into the genome of a cDNA
      derived virus. Expression of GM-CSF by the live attenuated recombinant virus did
      not per se affect the level of pulmonary viral replication in rhesus monkeys
      after topical administration, which was 40-fold lower than that of WT
      parainfluenza virus type 3. Despite that, the expressed extra gene augmented the
      virus-specific serum antibody response to a level that was (i) 3- to 6-fold
      higher than that induced by the same virus with an unrelated RNA insert of equal
      length and (ii) equal to the response induced by nonattenuated WT virus. In
      addition, topical immunization with the attenuated virus expressing GM-CSF
      induced a greater number of virus-specific IFN-gamma-secreting T lymphocytes in
      the peripheral blood of monkeys than did immunization with the control virus
      bearing an unrelated RNA insert. These findings show that the immunogenicity of a
      live-attenuated vaccine virus in primates can be enhanced without increasing the
      level of virus replication. Thus, it might be possible to develop live-attenuated
      vaccines that are as immunogenic as parental WT virus or, possibly, even more so.

PMID- 12482930
TI  - Direct imaging of nanoscale magnetic interactions in minerals.
AB  - The magnetic microstructure of a natural, finely exsolved intergrowth of
      submicron magnetite blocks in an ulvospinel matrix is characterized by using off
      axis electron holography in the transmission electron microscope. Single-domain
      and vortex states in individual blocks, as well as magnetostatic interaction
      fields between them, are imaged at a spatial resolution approaching the nanometer
      scale. The images reveal an extremely complicated magnetic structure dominated by
      the shapes of the blocks and magnetostatic interactions. Magnetic superstates, in
      which clusters of magnetite blocks act collectively to form vortex and
      multidomain states that have zero net magnetization, are observed directly.

PMID- 12482929
TI  - Chemical complementation: a reaction-independent genetic assay for enzyme
      catalysis.
AB  - A high-throughput assay for enzyme activity has been developed that is reaction
      independent. In this assay, a small-molecule yeast three-hybrid system is used to
      link enzyme catalysis to transcription of a reporter gene in vivo. Here we
      demonstrate the feasibility of this approach by using a well-studied enzyme
      catalyzed reaction, cephalosporin hydrolysis by the Enterobacter cloacae P99
      cephalosporinase (beta-lactam hydrolase, EC ). We show that the three-hybrid
      system can be used to read out cephalosporinase activity in vivo as a change in
      the level of transcription of a lacZ reporter gene and that the wild-type
      cephalosporinase can be isolated from a pool of inactive mutants by using a lacZ
      screen. The assay has been designed so that it can be applied to different
      chemical reactions without changing the components of the three-hybrid system. A
      reaction-independent high-throughput assay for protein function should be a
      powerful tool for protein engineering and enzymology, drug discovery, and
      proteomics.

PMID- 12482931
TI  - Modularity and reshuffling of Snail and Slug expression during vertebrate
      evolution.
AB  - Gene duplication has been a major mechanism for increasing genomic complexity and
      variation during evolution. The evolutionary history of duplicated genes has been
      poorly studied along the vertebrate lineage. Here, we attempt to study that
      history by analyzing the expression of two members of the Snail family, Snail and
      Slug, in representatives of the major vertebrate groups. We find a surprising
      degree of variability in a subset of the expression sites for both genes in
      different species. Although some of the changes can be explained by
      neofunctionalization or subfunctionalization, others imply reciprocal changes in
      the expression of the two genes and the reappearance of expression in sites lost
      earlier in evolution. Because these changes do not fit easily into current
      models, we need to invoke additional mechanisms acting on enhancer elements to
      distribute expression domains and functions of duplicated genes unequally during
      evolution.

PMID- 12482932
TI  - Common denominator of Cu/Zn superoxide dismutase mutants associated with
      amyotrophic lateral sclerosis: decreased stability of the apo state.
AB  - More than 100 point mutations of the superoxide scavenger Cu/Zn superoxide
      dismutase (SOD; EC ) have been associated with the neurodegenerative disease
      amyotrophic lateral sclerosis (ALS). However, these mutations are scattered
      throughout the protein and provide no clear functional or structural clues to the
      underlying disease mechanism. Therefore, we undertook to look for folding-related
      defects by comparing the unfolding behavior of five ALS-associated mutants with
      distinct structural characteristics: A4V at the interface between the N and C
      termini, C6F in the hydrophobic core, D90A at the protein surface, and G93A and
      G93C, which decrease backbone flexibility. With the exception of the disruptive
      replacements A4V and C6F, the mutations only marginally affect the stability of
      the native protein, yet all mutants share a pronounced destabilization of the
      metal-free apo state: the higher the stability loss, the lower the mean survival
      time for ALS patients carrying the mutation. Thus organism-level pathology may be
      directly related to the properties of the immature state of a protein rather than
      to those of the native species.

PMID- 12482933
TI  - Polyphosphate kinase (PPK2), a potent, polyphosphate-driven generator of GTP.
AB  - An enzyme that uses inorganic polyphosphate (poly P) as a donor to convert GDP to
      GTP has been purified 1,300-fold to homogeneity from lysates of Pseudomonas
      aeruginosa PAOM5. Poly P chains of 30-50 residues are optimal; those of 15-700
      residues can also serve. GDP is preferred over ADP among nucleoside diphosphate
      acceptors. This nucleoside diphosphate kinase (NDK) activity resides in the same
      protein isolated for its synthesis of poly P from GTP and designated PPK2 in an
      accompanying report. The reaction that synthesizes poly P and the reaction that
      utilizes poly P differ in their kinetic features. Especially notable is the
      catalytic potency of the NDK activity, which is 75-fold greater than that of poly
      P synthesis. PPK2 appears in the stationary phase of growth and reaches NDK
      levels of 5-10% that of the classic NDK; both kinase activities may figure in the
      generation of the guanosine precursors in the synthesis of alginate, an
      exopolysaccharide essential for the virulence of P. aeruginosa.

PMID- 12482934
TI  - High-throughput screening for evidence of association by using mass spectrometry
      genotyping on DNA pools.
AB  - To facilitate positional cloning of complex trait susceptibility loci, we are
      investigating methods to reduce the effort required to identify trait-associated
      alleles. We examined primer extension analysis by matrix-assisted laser
      desorptionionization time-of-flight mass spectrometry to screen single-nucleotide
      polymorphisms (SNPs) for association by using DNA pools. We tested whether this
      method can accurately estimate allele frequency differences between pools while
      maintaining the high-throughput nature of assay design, sample handling, and
      scoring. We follow up interesting allele frequency differences in pools by
      genotyping individuals. We tested DNA pools of 182, 228, and 499 individuals
      using 16 SNPs with minor allele frequencies 0.026-0.486 and allele frequency
      differences 0.001-0.108 that we had genotyped previously on individuals and 381
      SNPs that we had not. Precision, as measured by the average standard deviation
      among 16 semidependent replicates, was 0.021 +/- 0.011 for the 16 SNPs and 0.018
      +/- 0.008 for the 291381 SNPs used in further analysis. For the 16 SNPs, the
      average absolute error in predicting allele frequency differences between pools
      was 0.009; the largest errors were 0.031, 0.028, and 0.027. We determined that
      compensating for unequal peak heights in heterozygotes improved precision of
      allele frequency estimates but had only a very minor effect on accuracy of allele
      frequency differences between pools. Based on these data and assuming pools of
      500 individuals, we conclude that at significance level 0.05 we would have 95%
      (82%) power to detect population allele frequency differences of 0.07 for control
      allele frequencies of 0.10 (0.50).

PMID- 12482935
TI  - The promoter of IL-18 binding protein: activation by an IFN-gamma -induced
      complex of IFN regulatory factor 1 and CCAAT/enhancer binding protein beta.
AB  - The IL-18 binding protein (IL-18BP) is a circulating inhibitor of the
      proinflammatory cytokine IL-18. It is constitutively expressed in mononuclear
      cells, and elevated expression is induced by IFN-gamma. In this study, we
      characterized the IL-18BP promoter. We first showed that induction is at the
      transcriptional level and requires de novo protein synthesis. The IL-18BP
      promoter resides within 1.6 kb DNA upstream of the first exon and includes at
      least six regulatory elements. We identified in the basal promoter a gamma
      activated sequence (GAS) proximal to the transcription start site (base 1),
      followed by an IFN regulatory factor 1 response element (IRF-E) and two
      CCAATenhancer binding protein beta (CEBPbeta) sites, all of which are essential
      for basal promoter activity. Furthermore, GAS and IRF-E were essential for IFN
      gamma-induced transcription. Indeed, sera of IRF-1-deficient mice lacked basal
      and IFN-gamma-induced IL-18BP. We found that after induction of IRF-1 by IFN
      gamma, it formed a complex with CEBPbeta, which bound to the IRF-E and GAS
      containing proximal DNA. In contrast, the IFN-gamma-induced signal transducer and
      activator of transcription 1 dimer did not associate with this GAS. In addition,
      we identified a silencer element and a distal enhancer at bases -1081 to -1272,
      which was also physically associated with IRF-1. The IRF-1-CEBPbeta complex
      described here probably plays a fundamental role in regulating additional IFN
      gamma-responsive genes.

PMID- 12482936
TI  - A molecular switch underlies a human telomerase disease.
AB  - Telomerase is a ribonucleoprotein (RNP) required for maintenance of telomeres.
      Although up-regulated telomerase activity is closely linked to the cellular
      immortality characteristic of late stage carcinogenesis, recently, mutations in
      the telomerase RNA gene in humans have been associated with dyskeratosis
      congenita and aplastic anemia, both typified by impaired haemopoietic function.
      These mutations include base changes in a highly conserved putative telomerase
      RNA pseudoknot. Here, by using in vitro telomerase assays, NMR, and UV absorbance
      melting analyses of model oligonucleotides designed to form a "trans-pseudoknot,"
      we describe functional, structural, and energetic properties of this structure.
      We demonstrate that the pseudoknot domain exists in two alternative states of
      nearly equal stability in solution: one is the previously proposed pseudoknot
      formed by pairing P3 with the loop domain of P2b, and the other is a structured
      P2b loop alone. We show that the two-base mutation (GC1078 --> AG) present in one
      gene copy in a family with dyskeratosis congenita abrogates telomerase activity.
      This mutation hyperstabilizes the P2b intraloop structure, blocking pseudoknot
      formation. Conversely, when the P3 pseudoknot pairing is hyperstabilized by
      deleting a conserved bulge in P3, telomerase activity also decreases. We propose
      that the P2bP3 pseudoknot domain acts as a molecular switch, and interconversion
      between its two states is important for telomerase function. Phylogenetic
      covariation in the P2b and P3 sequences of 35 species provides a compelling set
      of "natural" compensatory base pairing changes supporting the existence of the
      crucial molecular switch.

PMID- 12482937
TI  - A genome-wide screen for methyl methanesulfonate-sensitive mutants reveals genes
      required for S phase progression in the presence of DNA damage.
AB  - We performed a systematic screen of the set of approximately 5,000 viable
      Saccharomyces cerevisiae haploid gene deletion mutants and have identified 103
      genes whose deletion causes sensitivity to the DNA-damaging agent methyl
      methanesulfonate (MMS). In total, 40 previously uncharacterized alkylation damage
      response genes were identified. Comparison with the set of genes known to be
      transcriptionally induced in response to MMS revealed surprisingly little overlap
      with those required for MMS resistance, indicating that transcriptional
      regulation plays little, if any, role in the response to MMS damage. Clustering
      of the MMS response genes on the basis of their cross-sensitivities to
      hydroxyurea, UV radiation, and ionizing radiation revealed a DNA damage core of
      genes required for responses to a broad range of DNA-damaging agents. Of
      particular significance, we identified a subset of genes that show a specific MMS
      response, displaying defects in S phase progression only in the presence of MMS.
      These genes may promote replication fork stability or processivity during
      encounters between replication forks and DNA damage.

PMID- 12482938
TI  - Three mutations in sterol-sensing domain of SCAP block interaction with insig and
      render SREBP cleavage insensitive to sterols.
AB  - We report the isolation and characterization of a new line of mutant Chinese
      hamster ovary cells, designated SRD-5, that are resistant to 25HC, a potent
      suppressor of cleavage of sterol regulatory element-binding proteins (SREBPs) in
      mammalian cells. In SRD-5 cells, SREBPs are cleaved constitutively, generating
      transcriptionally active nuclear SREBP even in the presence of sterols. Sequence
      analysis of SREBP cleavage-activating protein (SCAP) transcripts from SRD-5 cells
      revealed the presence of a mutation in one SCAP allele that results in
      substitution of a conserved Leu by Phe at amino acid 315 within the sterol
      sensing domain. Sterols fail to inhibit the packaging of SREBPSCAP(L315F)
      complexes into budding vesicles in vitro. Sterols also fail to induce binding of
      SCAP(L315F) to insig-1 or insig-2, two proteins that function in the sterol
      mediated retention of SREBPSCAP complexes in the endoplasmic reticulum. Similar
      findings were observed for SCAP(D443N) and SCAP(Y298C), both of which cause a
      sterol-resistant phenotype. Thus, three different point mutations, each within
      the sterol-sensing domain of SCAP, prevent sterol-induced binding of SCAP to
      insig proteins and abolish feedback regulation of SREBP processing by sterols.

PMID- 12482939
TI  - Dynamic assembly of MinD into filament bundles modulated by ATP, phospholipids,
      and MinE.
AB  - Accurate positioning of the division septum at the equator of Escherichia coli
      cells requires a rapid oscillation of MinD ATPase between the polar halves of the
      cell membrane, together with the division inhibitor MinC, under MinE control. The
      mechanism underlying MinD oscillation remains poorly understood. Here, we
      demonstrate that purified MinD assembles into protein filaments in the presence
      of ATP. Incubation with phospholipid vesicles further stimulates MinD
      polymerization. Addition of purified MinE in the presence of lipids promotes
      bundling of MinD filaments as well as their disassembly through activation of
      MinD ATPase. MinE thus provokes a net decay in the steady-state MinD polymer
      mass. Taken together, our results suggest that reversible MinD assembly modulated
      by MinE underlies the dynamic processing of positional information in E. coli to
      identify precisely the nascent site for cell division.

PMID- 12482940
TI  - Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3
      deficient mice.
AB  - Epstein-Barr virus-induced gene 3 (EBI3) is a widely expressed IL-12p40-related
      protein that associates as a heterodimer with either IL-12p35 or an IL-12p35
      homologue, p28, to create a new cytokine (IL-27). To define the function of EBI3
      in vivo, we generated knockout mice in which the ebi3 gene was targeted by
      homologous recombination. EBI3-/- mice exhibited normal numbers of both naive and
      mature CD4+ and CD8+ T cells and B cells, but markedly decreased numbers of
      invariant natural killer T cells (iNKT) as defined by staining with an alpha
      galactosylceramide (alphaGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/-
      mice exhibited decreased IL-4 and, to a lesser extent, IFN-gamma production after
      alphaGalCer stimulation in vitro. A sustained decrease in IL-4 production was
      also observed in EBI3-/- mice after alphaGalCer stimulation in vivo in contrast
      to IFN-gamma production, which was only transiently decreased under such
      stimulation. Notably, EBI3-/- mice were resistant to the induction of
      immunopathology associated with oxazolone-induced colitis, a colitis model
      mediated primarily by T helper (Th) 2-type cytokine production by iNKT cells. In
      contrast, trinitrobenzene sulfonic acid-induced colitis, a predominantly Th1
      mediated colitis model, was unaffected. Thus, EBI3 plays a critical regulatory
      role in the induction of Th2-type immune responses and the development of Th2
      mediated tissue inflammation in vivo, which may be mediated through the control
      of iNKT cell function.

PMID- 12482941
TI  - A possible substrate for dopamine-related changes in mood and behavior:
      prefrontal and limbic effects of a D3-preferring dopamine agonist.
AB  - Dopamine can induce fascinating, complex human behavioral states, including
      disinhibition, euphoria, or elaborate stereotypies, whereas dopamine deficiency
      can cause anxiety or sadness. Limited data suggest that these phenomena may
      involve dysfunction of orbital frontal cortex, cingulate cortex, or ventral
      striatum. The dopamine D3 receptor (D3R) has an anatomic distribution that
      suggests it could mediate these effects, but almost no data directly demonstrate
      the regional functional effects of D3R activation. We used quantitative positron
      emission tomography (PET), [15O]water, and the D3-preferring dopamine agonist
      pramipexole to identify D3-mediated regional cerebral blood flow (rCBF) responses
      in living primates. We studied seven normal baboons ventilated with 70% nitrous
      oxide, and analyzed results voxelwise in a common atlas space. At clinically
      relevant doses, pramipexole produced statistically robust decreases in rCBF in
      bilateral orbitofrontal cortex, thalamus, operculum, posterior and anterior
      (subgenual) cingulate cortex, and insula (in decreasing order of significance).
      Cortical areas related to movement were relatively unaffected, and rCBF did not
      change in cerebellum or visual cortex. The dose-response curve and duration of
      pramipexole's effects suggest that these rCBF responses indicate functional
      effects of a D3-preferring agonist. A D2-preferring agonist studied under the
      same conditions produced a quantitatively different pattern of responses. We
      conclude that a dopamine D3 receptor agonist preferentially affects brain
      activity in prefrontal and limbic cortex, and speculate that dopamine's effects
      on these regions via D3Rs may mediate some of the known psychiatric complications
      of dopamine deficiency or excess.

PMID- 12482942
TI  - Differential modulation of synaptic transmission by neuropeptide Y in rat
      neocortical neurons.
AB  - Neuropeptide Y (NPY) is widely expressed throughout the nervous system and is
      known to reduce excitatory (but also inhibitory) synaptic transmission in many
      CNS areas, leading to the proposal that it is an endogenous antiepileptic agent.
      In the neocortex, where NPY is present in gamma-aminobutyric acid (GABA)ergic
      interneurons, its effects on inhibitory and excitatory synaptic activities have
      not been completely explored. Here we report that NPY application elicits a long
      lasting decrease in evoked excitatory postsynaptic current amplitude and a
      delayed, long-lasting increase in the amplitude of evoked monosynaptic inhibitory
      postsynaptic current (IPSC) in layer V pyramidal neurons of rat neocortex. The
      novel, late, NPY-mediated increase of inhibitory synaptic transmission is caused
      by modulation of Ca2+-dependent GABA release onto pyramidal neurons, as it was
      accompanied by an increase in Ca2+-dependent miniature IPSC frequency. NPY
      decreased evoked monosynaptic IPSCs in GABAergic interneurons, indicating that
      this neuropeptide has differential effects on different neuronal subtypes in the
      neocortex. Each of these NPY actions would decrease excitability in cortical
      circuits, a result that has important implications for both physiological
      neocortical operations as well as pathophysiological epileptiform activities.

PMID- 12482943
TI  - Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons
      inhibits luteinizing hormone pulses in transgenic rats.
AB  - Experiments in the GT1 gonadotropin-releasing hormone (GnRH) cell line have shown
      that the cAMP signaling pathway plays a central role in regulating the
      excitability of the cells. Lowering cAMP levels by expressing the constitutively
      active cAMP-specific phosphodiesterase PDE4D1 in GT1 cells inhibited spontaneous
      Ca2+ oscillations and intrinsic pulsatile GnRH secretion. To address the role of
      cAMP levels in endogenous GnRH neurons, we genetically targeted expression of
      PDE4D1 (P) to GnRH neurons in transgenic rats (R) by using the GnRH gene
      promoterenhancer regions (G). Three lines of transgenic rats, GPR-2, -4, and -5,
      were established. In situ hybridization and RT-PCR studies demonstrated that
      transgene expression was specifically targeted to GnRH neurons. Decreased
      fertility was observed in female but not in male rats from all three lines. The
      mean luteinizing hormone (LH) levels in ovariectomized rats were significantly
      reduced in the GPR-4 and -5 lines but not in the GPR-2 line. In castrated male
      and female GPR-4 rats, the LH pulse frequency was dramatically reduced. Six of
      twelve GPR-4 females studied did not ovulate and had polycystic ovaries. The
      remaining six females ovulated, but the magnitude of the preovulatory LH surge
      was inhibited by 63%. These findings support the hypothesis that cAMP signaling
      may play a central role in regulating excitability of GnRH neurons in vivo. The
      GPR-4 line of transgenic rats provides a genetic model for the understanding of
      the role of pulsatile gonadotropin release in follicular development.

PMID- 12482944
TI  - Distribution of nitric oxide synthase in normal and cirrhotic human liver.
AB  - Chronic liver disorders represent a serious health problem, considering that 300
      million people worldwide are hepatitis B virus carriers, and 8,000-10,000
      patients per year, in the U.S. alone, die as a result of liver failure caused by
      hepatitis C infection. Nitric oxide synthase (NOS) regulates hepatic vasculature;
      however, the patterns of expression and activity of NOS proteins in healthy and
      diseased human livers are unknown. Sections of diseased (n = 42) and control
      livers (n = 14) were collected during orthotopic liver transplants and partial
      hepatectomy. The diseased sections included alcoholic cirrhosis, viral hepatitis,
      cholestasis, acute necrosis, and uncommon pathologies including alpha(1)-anti
      trypsin disorder. The endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal
      NOS (nNOS) were studied by using the citrulline assay, Western immunoblot,
      immunohistochemistry, and in situ hybridization. The systemic generation of
      plasma NO metabolites was measured by HPLC. In control livers, Ca(2+)-dependent
      and -independent NOS activities were identified by Western analysis as eNOS and
      iNOS, respectively. The eNOS was uniformly distributed in the hepatocytes and
      also detected in the endothelium of hepatic arteries, terminal hepatic venules,
      sinusoids, and in biliary epithelium. The iNOS was detected in hepatocytes and
      localized mainly in the periportal zone of the liver acinus. This pattern of
      distribution of eNOS and iNOS in normal liver was confirmed by in situ
      hybridization. In diseased livers, there was a significant increase in Ca(2+)
      independent NOS with the corresponding strong appearance of iNOS in the cirrhotic
      areas. The eNOS was translocated to hepatocyte nuclei. Thus, eNOS and iNOS
      proteins are differentially expressed in healthy human liver, and this expression
      is significantly altered in cirrhotic liver disorders.

PMID- 12482945
TI  - Premonitory patterns of seismicity months before a large earthquake: five case
      histories in Southern California.
AB  - This article explores the problem of short-term earthquake prediction based on
      spatio-temporal variations of seismicity. Previous approaches to this problem
      have used precursory seismicity patterns that precede large earthquakes with
      "intermediate" lead times of years. Examples include increases of earthquake
      correlation range and increases of seismic activity. Here, we look for a
      renormalization of these patterns that would reduce the predictive lead time from
      years to months. We demonstrate a combination of renormalized patterns that
      preceded within 1-7 months five large (M > or = 6.4) strike-slip earthquakes in
      southeastern California since 1960. An algorithm for short-term prediction is
      formulated. The algorithm is self-adapting to the level of seismicity: it can be
      transferred without readaptation from earthquake to earthquake and from area to
      area. Exhaustive retrospective tests show that the algorithm is stable to
      variations of its adjustable elements. This finding encourages further tests in
      other regions. The final test, as always, should be advance prediction. The
      suggested algorithm has a simple qualitative interpretation in terms of
      deformations around a soon-to-break fault: the blocks surrounding that fault
      began to move as a whole. A more general interpretation comes from the phenomenon
      of self-similarity since our premonitory patterns retain their predictive power
      after renormalization to smaller spatial and temporal scales. The suggested
      algorithm is designed to provide a short-term approximation to an intermediate
      term prediction. It remains unclear whether it could be used independently. It
      seems worthwhile to explore similar renormalizations for other premonitory
      seismicity patterns.

PMID- 12482946
TI  - Dicer is required for chromosome segregation and gene silencing in fission yeast
      cells.
AB  - RNA interference is a form of gene silencing in which the nuclease Dicer cleaves
      double-stranded RNA into small interfering RNAs. Here we report a role for Dicer
      in chromosome segregation of fission yeast. Deletion of the Dicer (dcr1+) gene
      caused slow growth, sensitivity to thiabendazole, lagging chromosomes during
      anaphase, and abrogated silencing of centromeric repeats. As Dicer in other
      species, Dcr1p degraded double-stranded RNA into approximately 23 nucleotide
      fragments in vitro, and dcr1Delta cells were partially rescued by expression of
      human Dicer, indicating evolutionarily conserved functions. Expression profiling
      demonstrated that dcr1+ was required for silencing of two genes containing a
      conserved motif.

PMID- 12482947
TI  - cAMP-independent role of PKA in tonicity-induced transactivation of tonicity
      responsive enhancer/ osmotic response element-binding protein.
AB  - Hypertonicity-induced increase in activity of the transcription factor tonicity
      responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP)
      protects renal cells by increasing transcription of genes, including those
      involved in increased accumulation of organic osmolytes. We previously showed
      that hypertonicity increases transactivating activity of TonEBP/OREBP. Assay with
      a binary GAL4 transactivation system showed that the 984 C-terminal amino acids
      of TonEBP/OREBP (amino acids 548-1531) contain a tonicity-dependent
      transactivation domain (TAD). Also, amino acids 548-1531 undergo tonicity
      dependent phosphorylation, and some inhibitors of protein kinases reduce the
      tonicity-dependent transactivation. In the present studies we examined the role
      of protein kinase A (PKA). RESULTS: (i) An inhibitor of PKA (H89) reduces
      tonicity-dependent increases in transactivation, ORE/TonE reporter activity, and
      induction of aldose reductase and betaine transporter mRNAs. (ii) Overexpression
      of the catalytic subunit of PKA (PKAc) increases transactivation activity of
      amino acids 548-1531 and activity of an ORE/TonE reporter. The increases are much
      greater under isotonic than under hypertonic conditions. (iii) A dominant
      negative PKAc reduces activity of an ORE/TonE reporter. (iv) PKAc activity
      increases with tonicity but cAMP does not. (v) TonEBP/OREBP and PKAc
      coimmunoprecipitate. (vi) amino acids 872-1271, including N- and C-terminal
      polyglutamine stretches, demonstrate tonicity-dependent transactivation, albeit
      less than amino acids 548-1531, and a similar role for PKA. CONCLUSIONS: (i) PKA
      plays an important role in TonEBP/OREBP activation of tonicity-dependent gene
      expression; (ii) PKA activation of TonEBP/OREBP appears to be cAMP-independent;
      and (iii) amino acids 872-1271 are sufficient for tonicity-dependent
      transactivation of TonEBP/OREBP.

PMID- 12482948
TI  - Interaction of pollinators and herbivores on plant fitness suggests a pathway for
      correlated evolution of mutualism- and antagonism-related traits.
AB  - Different kinds of plant-animal interactions are ordinarily studied in isolation,
      yet considering the combined fitness effects of mutualistic and antagonistic
      interactions is essential to understanding plant character evolution. Functional,
      structural, or phylogenetic associations between attractive and defensive traits
      may be nonadaptive or result from correlational selection on sets of herbivory-
      and pollination-linked traits. Nonadditivity of fitness effects of mutualists and
      antagonists, a requisite for correlational selection, was experimentally tested
      in the field. We created experimental populations of the insect-pollinated
      perennial herb, Helleborus foetidus, at 16 different locations distributed among
      three regions in the Iberian Peninsula. Plants experienced one of four possible
      selective regimes generated by independently weakening the effects of pollinators
      and herbivores (flower and fruit predators) according to a two-way fully
      factorial design. Effects were assessed in terms of number of next-generation
      offspring recruited per mother plant under natural field conditions. Differences
      among H. foetidus plants in the strength of their interactions with pollinators
      and herbivores translated into differential fitness, as measured in terms of
      recruited offspring, and subsequent changes in plant population densities. A
      strong, geographically consistent nonadditivity in the fitness consequences of
      pollinators and herbivores was found also. Plants possessing the particular
      combination of "traits" simultaneously enhancing pollination and escape from
      herbivores enjoyed a disproportionate fitness advantage over plants possessing
      any of the other three possible "trait" combinations. Results suggest a simple,
      possibly widespread ecological pathway favoring the adaptive correlated evolution
      of mutualism- and antagonism-related plant traits in pollinator-dependent plants
      suffering intense flower and fruit herbivory.

PMID- 12482949
TI  - Cleavage of polycystin-1 requires the receptor for egg jelly domain and is
      disrupted by human autosomal-dominant polycystic kidney disease 1-associated
      mutations.
AB  - Polycystin-1 plays an essential role in renal tubular morphogenesis, and
      disruption of its function causes cystogenesis in human autosomal-dominant
      polycystic kidney disease (ADPKD). We demonstrated that polycystin-1 undergoes
      cleavage at G protein coupled receptor proteolytic site in a process that
      requires the receptor for egg jelly domain. Most of the N-terminal fragment
      remains tethered at the cell surface, although a small amount is secreted. PKD1
      associated mutations in the receptor for egg jelly domain disrupt cleavage,
      abolish the ability of polycystin-1 to activate signal transducer and activator
      of transcription-1, and induce tubulogenesis in vitro. We conclude that the
      cleavage of polycystin-1 is likely essential for its biologic activity.

PMID- 12482950
TI  - Discovery of sulfated metabolites in mycobacteria with a genetic and mass
      spectrometric approach.
AB  - The study of the metabolome presents numerous challenges, first among them being
      the cataloging of its constituents. A step in this direction will be the
      development of tools to identify metabolites that share common structural
      features. The importance of sulfated molecules in cell-cell communication
      motivated us to develop a rapid two-step method for identifying these metabolites
      in microorganisms, particularly in pathogenic mycobacteria. Sulfurcontaining
      molecules were initially identified by mass spectral analysis of cell extracts
      from bacteria labeled metabolically with a stable sulfur isotope (34SO 4 2-). To
      differentiate sulfated from reduced-sulfur-containing molecules, we employed a
      mutant lacking the reductive branch of the sulfate assimilation pathway. In these
      sulfur auxotrophs, heavy sulfate is channeled exclusively into sulfated
      metabolites. The method was applied to the discovery of several new sulfated
      molecules in Mycobacterium tuberculosis and Mycobacterium smegmatis. Because a
      sulfur auxotrophic strain is the only requirement of the approach, many
      microorganisms can be studied in this manner. Such genetic engineering in
      combination with stable isotopic labeling can be applied to various metabolic
      pathways and their products.

PMID- 12482951
TI  - A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and
      P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat.
AB  - P2X3 and P2X2/3 receptors are highly localized on peripheral and central
      processes of sensory afferent nerves, and activation of these channels
      contributes to the pronociceptive effects of ATP. A-317491 is a novel non
      nucleotide antagonist of P2X3 and P2X2/3 receptor activation. A-317491 potently
      blocked recombinant human and rat P2X3 and P2X2/3 receptor-mediated calcium flux
      (Ki = 22-92 nM) and was highly selective (IC50 >10 microM) over other P2
      receptors and other neurotransmitter receptors, ion channels, and enzymes. A
      317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ganglion
      neurons. Blockade of P2X3 containing channels was stereospecific because the R
      enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and
      P2X2/3 receptors. A-317491 dose-dependently (ED50 = 30 micromolkg s.c.) reduced
      complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was
      most potent (ED50 = 10-15 micromolkg s.c.) in attenuating both thermal
      hyperalgesia and mechanical allodynia after chronic nerve constriction injury.
      The R-enantiomer, A-317344, was inactive in these chronic pain models. Although
      active in chronic pain models, A-317491 was ineffective (ED50 >100 micromolkg
      s.c.) in reducing nociception in animal models of acute pain, postoperative pain,
      and visceral pain. The present data indicate that a potent and selective
      antagonist of P2X3 and P2X2/3 receptors effectively reduces both nerve injury and
      chronic inflammatory nociception, but P2X3 and P2X2/3 receptor activation may not
      be a major mediator of acute, acute inflammatory, or visceral pain.

PMID- 12482952
TI  - The Forkhead Box m1b transcription factor is essential for hepatocyte DNA
      replication and mitosis during mouse liver regeneration.
AB  - The Forkhead Box (Fox) proteins are an extensive family of transcription factors
      that shares homology in the winged helix DNA-binding domain and whose members
      play essential roles in cellular proliferation, differentiation, transformation,
      longevity, and metabolic homeostasis. Liver regeneration studies with transgenic
      mice demonstrated that FoxM1B regulates the onset of hepatocyte DNA replication
      and mitosis by stimulating expression of cell cycle genes. Here, we demonstrate
      that albumin-promoter-driven Cre recombinase-mediated hepatocyte-specific
      deletion of the Foxm1b Floxed (fl) targeted allele resulted in significant
      reduction in hepatocyte DNA replication and inhibition of mitosis after partial
      hepatectomy. Reduced DNA replication in regenerating Foxm1b(-/-) hepatocytes was
      associated with sustained increase in nuclear staining of the cyclin-dependent
      kinase (Cdk) inhibitor p21(Cip1) (p21) protein between 24 and 40 h after partial
      hepatectomy. Furthermore, increased nuclear p21 levels and reduced expression of
      Cdc25A phosphatase coincided with decreases in Cdk2 activation and hepatocyte
      progression into S-phase. Moreover, the significant reduction in hepatocyte
      mitosis was associated with diminished mRNA levels and nuclear expression of
      Cdc25B phosphatase and delayed accumulation of cyclin B1 protein, which is
      required for Cdk1 activation and entry into mitosis. Cotransfection studies
      demonstrate that FoxM1B protein directly activated transcription of the Cdc25B
      promoter region. Our present study shows that the mammalian Foxm1b transcription
      factor regulates expression of cell cycle proteins essential for hepatocyte entry
      into DNA replication and mitosis.

PMID- 12482953
TI  - Transcriptional modulation of bacterial gene expression by subinhibitory
      concentrations of antibiotics.
AB  - Antibiotics such as erythromycin and rifampicin, at low concentrations, alter
      global bacterial transcription patterns as measured by the stimulation or
      inhibition of a variety of promoter-lux reporter constructs in a Salmonella
      typhimurium library. Analysis of a 6,500-clone library indicated that as many as
      5% of the promoters may be affected, comprising genes for a variety of functions,
      as well as a significant fraction of genes with no known function. Studies of a
      selection of the reporter clones showed that stimulation varied depending on the
      nature of the antibiotic, the promoter, and what culture medium was used; the
      response differed on solid as compared with liquid media. Transcription was
      markedly reduced in antibiotic-resistant hosts, but the presence of mutations
      deficient in stress responses such as SOS or universal stress did not prevent
      antibiotic-induced modulation. The results show that small molecules may have
      contrasting effects on bacteria depending on their concentration: either the
      modulation of bacterial metabolism by altering transcription patterns or the
      inhibition of growth by the inhibition of specific target functions. Both
      activities could play important roles in the regulation of microbial communities.
      These studies indicate that the detection of pharmaceutically useful natural
      product inhibitors could be effectively achieved by measuring activation of
      transcription at low concentrations in high-throughput assays using appropriate
      bacterial promoter-reporter constructs.

PMID- 12482954
TI  - A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking
      and maturation but normal ligand-induced signaling.
AB  - Notch receptors are single transmembrane receptors that contain a large number of
      epidermal growth factor-like repeats (EGF repeats) in their extracellular
      domains. Mutations in the EGF repeats of the human Notch 3 receptor lead to the
      vascular dementia disease Cerebral Autosomal Dominant Arteriopathy with
      Subcortical Infarcts and Leukoencephalopathy (CADASIL). The vast majority of
      CADASIL mutations are missense mutations removing or inserting cysteine residues
      in the EGF repeats, but it is not yet clear whether these mutations primarily
      affect receptor trafficking, maturation, andor signaling. To address this issue,
      we have generated and analyzed stable cell lines expressing either wild-type
      murine Notch 3 (mNotch 3) or the mutant mNotch 3(R142C), which corresponds to the
      prevalent CADASIL form of Notch 3, Notch 3(R141C) in humans. We find that a lower
      proportion of mNotch 3(R142C) is expressed in the site 1-cleaved configuration,
      and that reduced amounts of mNotch 3(R142C) appear at the cell surface, as
      compared with wild-type mNotch 3. This observation is accompanied by a higher
      propensity for mNotch 3(R142C) to form intracellular aggregates, which may be a
      result of increased accumulation or slowed transport in the secretory pathway. In
      contrast to the impaired cell surface expression, mNotch 3(R142C) signals equally
      well in response to Delta 1 and Jagged 1 as wild-type mNotch 3. Taken together,
      these data suggest that trafficking and localization rather than signaling of
      mNotch 3 are affected in mNotch 3(R142C).

PMID- 12482955
TI  - A systematic approach to reconstructing transcription networks in
      Saccharomycescerevisiae.
AB  - Decomposing regulatory networks into functional modules is a first step toward
      deciphering the logical structure of complex networks. We propose a systematic
      approach to reconstructing transcription modules (defined by a transcription
      factor and its target genes) and identifying conditionsperturbations under which
      a particular transcription module is activateddeactivated. Our approach
      integrates information from regulatory sequences, genome-wide mRNA expression
      data, and functional annotation. We systematically analyzed gene expression
      profiling experiments in which the yeast cell was subjected to various
      environmental or genetic perturbations. We were able to construct transcription
      modules with high specificity and sensitivity for many transcription factors, and
      predict the activation of these modules under anticipated as well as unexpected
      conditions. These findings generate testable hypotheses when combined with
      existing knowledge on signaling pathways and protein-protein interactions.
      Correlating the activation of a module to a specific perturbation predicts links
      in the cell's regulatory networks, and examining coactivated modules suggests
      specific instances of crosstalk between regulatory pathways.

PMID- 12482956
TI  - Transcriptional repression of peri-implantation EMX2 expression in mammalian
      reproduction by HOXA10.
AB  - HOXA10 is necessary for mammalian reproduction; however, its transcriptional
      targets are not completely defined. EMX2, a divergent homeobox gene, is necessary
      for urogenital tract development. In these studies we identify and characterize
      the regulation of EMX2 by HOXA10. By using Northern analysis and in situ
      hybridization, we found that EMX2 is expressed in the adult urogenital tract in
      an inverse temporal pattern from HOXA10, suggestive of a negative regulatory
      relationship. Constitutive expression of HOXA10 diminished EMX2 mRNA, whereas
      blocking HOXA10 through the use of antisense resulted in high EMX2 mRNA
      expression. Deletional analysis of the EMX2 5' regulatory region revealed that a
      150-bp element mediated transcriptional repression when cotransfected with
      pcDNA3.1/HOXA10 in transient-transfection assays. Binding of HOXA10 protein to
      this element was demonstrated by electrophoretic mobility shift assay and further
      localized to a consensus HOXA10 binding site within this element by DNase I
      footprinting. Site-directed mutagenesis abolished binding, as well as the
      negative transcriptional regulation. Transcriptional activation of empty
      spiracles, the Drosophila ortholog of EMX2, by Abdominal-B (HOXA10 ortholog) has
      been previously demonstrated. These findings demonstrate conservation of the
      transcription factor-target gene relationship, although the direction of
      regulation is reversed with possible evolutionary implications.

PMID- 12482957
TI  - Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial
      endothelial cells: implications for modulating arteriogenesis and angiogenesis.
AB  - Notch and its ligands play critical roles in cell fate determination. Expression
      of Notch and ligand in vascular endothelium and defects in vascular phenotypes of
      targeted mutants in the Notch pathway have suggested a critical role for Notch
      signaling in vasculogenesis and angiogenesis. However, the angiogenic signaling
      that controls Notch and ligand gene expression is unknown. We show here that
      vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor
      can induce gene expression of Notch1 and its ligand, Delta-like 4 (Dll4), in
      human arterial endothelial cells. The VEGF-induced specific signaling is mediated
      through VEGF receptors 1 and 2 and is transmitted via the phosphatidylinositol 3
      kinase/Akt pathway but is independent of mitogen-activated protein kinase and Src
      tyrosine kinase. Constitutive activation of Notch signaling stabilizes network
      formation of endothelial cells on Matrigel and enhances formation of vessel-like
      structures in a three-dimensional angiogenesis model, whereas blocking Notch
      signaling can partially inhibit network formation. This study provides the first
      evidence for regulation of Notch/Delta gene expression by an angiogenic growth
      factor and insight into the critical role of Notch signaling in arteriogenesis
      and angiogenesis.

PMID- 12482958
TI  - The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation
      factor 4A binding protein that inhibits translation.
AB  - Pdcd4 is a novel transformation suppressor that inhibits tumor promoter-induced
      neoplastic transformation and the activation of AP-1-dependent transcription
      required for transformation. A yeast two-hybrid analysis revealed that Pdcd4
      associates with the eukaryotic translation initiation factors eIF4AI and eIF4AII.
      Immunofluorescent confocal microscopy showed that Pdcd4 colocalizes with eIF4A in
      the cytoplasm. eIF4A is an ATP-dependent RNA helicase needed to unwind 5' mRNA
      secondary structure. Recombinant Pdcd4 specifically inhibited the helicase
      activity of eIF4A and eIF4F. In vivo translation assays showed that Pdcd4
      inhibited cap-dependent but not internal ribosome entry site (IRES)-dependent
      translation. In contrast, Pdcd4(D418A), a mutant inactivated for binding to
      eIF4A, failed to inhibit cap-dependent or IRES-dependent translation or AP-1
      transactivation. Recombinant Pdcd4 prevented eIF4A from binding to the C-terminal
      region of eIF4G (amino acids 1040 to 1560) but not to the middle region of
      eIF4G(amino acids 635 to 1039). In addition, both Pdcd4 and Pdcd4(D418A) bound to
      the middle region of eIF4G. The mechanism by which Pdcd4 inhibits translation
      thus appears to involve inhibition of eIF4A helicase, interference with eIF4A
      association-dissociation from eIF4G, and inhibition of eIF4A binding to the C
      terminal domain of eIF4G. Pdcd4 binding to eIF4A is linked to its transformation
      suppressing activity, as Pdcd4-eIF4A binding and consequent inhibition of
      translation are required for Pdcd4 transrepression of AP-1.

PMID- 12482959
TI  - The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis.
AB  - The yeast Sir2p protein has an essential role in maintaining telomeric and mating
      type genes in their transcriptionally inactive state. Mammalian cells have a very
      large proportion of their genome inactive and also contain seven genes that have
      regions of homology with the yeast sir2 gene. One of these mammalian genes,
      sir2alpha, is the presumptive mammalian homologue of the yeast sir2 gene. We set
      out to determine if sir2alpha plays a role in mammalian gene silencing by
      creating a strain of mice carrying a null allele of sir2alpha. Animals carrying
      two null alleles of sir2alpha were smaller than normal at birth, and most died
      during the early postnatal period. In an outbred background, the sir2alpha null
      animals often survived to adulthood, but both sexes were sterile. We found no
      evidence for failure of gene silencing in sir2alpha null animals, suggesting that
      either SIR2alpha has a different role in mammals than it does in Saccharomyces
      cerevisiae or that its role in gene silencing in confined to a small subset of
      mammalian genes. The phenotype of the sir2alpha null animals suggests that the
      SIR2alpha protein is essential for normal embryogenesis and for normal
      reproduction in both sexes.

PMID- 12482961
TI  - Zinc finger protein sall2 is not essential for embryonic and kidney development.
AB  - SALL/Sall is a mammalian homolog of the Drosophila region-specific homeotic gene
      spalt (sal), and heterozygous mutations in SALL1 in humans lead to Townes-Brocks
      syndrome. We earlier reported that mice deficient in Sall1 die in the perinatal
      period and that kidney agenesis or severe dysgenesis are present. We have now
      generated mice lacking Sall2, another Sall family gene. Although Sall2 is
      expressed mostly in an overlapping fashion versus that of Sall1, Sall2-deficient
      mice show no apparent abnormal phenotypes. Morphology and gene expression
      patterns of the mutant kidney were not affected. Mice lacking both Sall1 and
      Sall2 show kidney phenotypes comparable to those of Sall1 knockout, thereby
      demonstrating the dispensable roles of Sall2 in embryonic and kidney development.

PMID- 12482960
TI  - Phenotypic analysis of Meltrin alpha (ADAM12)-deficient mice: involvement of
      Meltrin alpha in adipogenesis and myogenesis.
AB  - Meltrin alpha (ADAM12) is a metalloprotease-disintegrin whose specific expression
      patterns during development suggest that it is involved in myogenesis and the
      development of other organs. To determine the roles Meltrin alpha plays in vivo,
      we generated Meltrin alpha-deficient mice by gene targeting. Although the number
      of homozygous embryos are close to the expected Mendelian ratio at embryonic days
      17 to 18, ca. 30% of the null pups born die before weaning, mostly within 1 week
      of birth. The viable homozygous mutants appear normal and are fertile. Most of
      the muscles in the homozygous mutants appear normal, and regeneration in
      experimentally damaged skeletal muscle is unimpeded. In some Meltrin alpha
      deficient pups, the interscapular brown adipose tissue is reduced, although the
      penetrance of this phenotype is low. Impaired formation of the neck and
      interscapular muscles is also seen in some homozygotes. These observations
      suggest Meltrin alpha may be involved in regulating adipogenesis and myogenesis
      through a linked developmental pathway. Heparin-binding epidermal growth factor
      like growth factor (HB-EGF) is a candidate substrate of Meltrin alpha, and we
      found that TPA (12-O-tetradecanoylphorbol-13-acetate)-induced ectodomain shedding
      of HB-EGF is markedly reduced in embryonic fibroblasts prepared from Meltrin
      alpha-deficient mice. We also report here the chromosomal locations of Meltrin
      alpha in the mouse and rat.

PMID- 12482962
TI  - Targeted disruption of the murine zyxin gene.
AB  - Zyxin is an evolutionarily conserved protein that is concentrated at sites of
      cell adhesion, where it associates with members of the Enabled (Ena)/vasodilator
      stimulated phosphoprotein (VASP) family of cytoskeletal regulators and is
      postulated to play a role in cytoskeletal dynamics and signaling. Zyxin
      transcripts are detected throughout murine embryonic development, and the protein
      is widely expressed in adults. Here we used a reverse genetic approach to examine
      the consequences of loss of zyxin function in the mouse. Mice that lack zyxin
      function are viable and fertile and display no obvious histological abnormalities
      in any of the organs examined. Because zyxin contributes to the localization of
      Ena/VASP family members at certain subcellular locations, we carefully examined
      the zyxin(-/-) mice for evidence of defects that have been observed when Ena/VASP
      proteins are compromised in the mouse. Specifically, we evaluated blood platelet
      function, nervous system development, and skin architecture but did not detect
      any defects in these systems. Zyxin is the founding member of a family of
      proteins that also includes the lipoma preferred partner (LPP) and thyroid
      receptor-interacting protein 6 (TRIP6). These zyxin family members display
      patterns of expression that significantly overlap that of zyxin. Western blot
      analysis indicates that there is no detectable upregulation of either LPP or
      TRIP6 expression in tissues derived from zyxin-null mice. Because zyxin family
      members may have overlapping functions, a comprehensive understanding of the role
      of these proteins in the mouse will require the generation of compound mutations
      in which multiple zyxin family members are simultaneously compromised.

PMID- 12482963
TI  - Yeast Isw1p forms two separable complexes in vivo.
AB  - There are several classes of ATP-dependent chromatin remodeling complexes, which
      modulate the structure of chromatin to regulate a variety of cellular processes.
      The budding yeast, Saccharomyces cerevisiae, encodes two ATPases of the ISWI
      class, Isw1p and Isw2p. Previously Isw1p was shown to copurify with three other
      proteins. Here we identify these associated proteins and show that Isw1p forms
      two separable complexes in vivo (designated Isw1a and Isw1b). Biochemical assays
      revealed that while both have equivalent nucleosome-stimulated ATPase activities,
      Isw1a and Isw1b differ in their abilities to bind to DNA and nucleosomal
      substrates, which possibly accounts for differences in specific activities in
      nucleosomal spacing and sliding. In vivo, the two Isw1 complexes have overlapping
      functions in transcriptional regulation of some genes yet distinct functions at
      others. In addition, these complexes show different contributions to cell growth
      at elevated temperatures.

PMID- 12482964
TI  - Sam68 enhances the cytoplasmic utilization of intron-containing RNA and is
      functionally regulated by the nuclear kinase Sik/BRK.
AB  - Cells normally restrict the nuclear export and expression of intron-containing
      mRNA. In many cell lines, this restriction can be overcome by inclusion of cis
      acting elements, such as the Mason-Pfizer monkey virus constitutive transport
      element (CTE), in the RNA. In contrast, we observed that CTE-mediated expression
      from human immunodeficiency virus Gag-Pol reporters was very inefficient in 293
      and 293T cells. However, addition of Sam68 led to a dramatic increase in the
      amount of Gag-Pol proteins produced in these cells. Enhancement of CTE function
      was not seen when a Sam68 point mutant (G178E) that is defective for RNA binding
      was used. Additionally, the effect of Sam68 was inhibited in a dose-dependent
      manner by coexpression of an activated form of the nuclear kinase Sik/BRK that
      hyperphosphorylated Sam68. RNA analysis showed that cytoplasmic Gag-Pol-CTE RNA
      levels were only slightly enhanced by the addition of Sam68, compared to a 60- to
      70-fold increase in the levels of Gag-Pol protein expression. Thus, in this
      system, Sam68 functioned to enhance the cytoplasmic utilization of RNA containing
      the CTE. These results suggest that Sam68 may interact with specific RNAs in the
      nucleus to provide a "mark" that affects their cytoplasmic fate. They also
      provide further evidence of links between signal transduction and RNA
      utilization.

PMID- 12482965
TI  - AKT-independent protection of prostate cancer cells from apoptosis mediated
      through complex formation between the androgen receptor and FKHR.
AB  - Recent studies suggested that the protection of cell apoptosis by AKT involves
      phosphorylation and inhibition of FKHR and related FOXO forkhead transcription
      factors and that androgens provide an AKT-independent cell survival signal in
      prostate cancer cells. Here, we report receptor-dependent repression of FKHR
      function by androgens in prostate cancer cells. Transcriptional analysis
      demonstrated that activation of the androgen receptor caused an inhibition of
      both wild-type FKHR and a mutant in which all three known AKT sites were mutated
      to alanines, showing that the repression is AKT independent. In vivo and in vitro
      coprecipitation studies demonstrated that the repression is mediated through
      protein-protein interaction between FKHR and the androgen receptor. Mapping
      analysis localized the interacting domains to the carboxyl terminus between amino
      acids 350 and 655 of FKHR and to the amino-terminal A/B region and the ligand
      binding domain of the receptor. Further analysis demonstrated that the activated
      androgen receptor blocked FKHR's DNA binding activity and impaired its ability to
      induce Fas ligand expression and prostate cancer cell apoptosis and cell cycle
      arrest. These studies identify a new mechanism for androgen-mediated prostate
      cancer cell survival that appears to be independent of the activity of the
      receptor on androgen response element-mediated transcription and establish FKHR
      and related FOXO forkhead proteins as important nuclear targets for both AKT
      dependent and -independent survival signals in prostate cancer cells.

PMID- 12482966
TI  - The leucine zipper motif of the Drosophila AF10 homologue can inhibit PRE
      mediated repression: implications for leukemogenic activity of human MLL-AF10
      fusions.
AB  - In a screen for Drosophila genes that interfere with transcriptional repression
      mediated by the Polycomb group of genes, we identified a dominant mutation
      affecting the Alhambra (Alh) gene, the fly homologue of the human AF10 gene. AF10
      has been identified as a fusion partner of both MLL and CALM in infant leukemias.
      Both fusion proteins retain the leucine zipper domain of AF10 but not its PHD
      domain. We show here that, while the full-length ALH protein has no activity on
      Polycomb group-responsive elements (PREs), overexpression of the isolated ALH
      leucine zipper domain activates several PREs. Within the ALH full-length protein,
      the PHD domain inhibits the PRE deregulation mediated by the leucine zipper
      domain. This deregulation is conserved in the human AF10 leucine zipper domain,
      which confers the same activity on an oncogenic MLL-AF10 fusion protein expressed
      in Drosophila melanogaster. These data reveal new properties for the leucine
      zipper domain and thus might provide new clues to understanding the mechanisms by
      which AF10 fusion proteins in which the PHD domain is lost might trigger
      leukemias in humans.

PMID- 12482967
TI  - The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt
      5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling.
AB  - Wnt signaling controls a variety of developmental processes. The canonical
      Wnt/beta-catenin pathway functions to stabilize beta-catenin, and the
      noncanonical Wnt/Ca(2+) pathway activates Ca(2+)/calmodulin-dependent protein
      kinase II (CaMKII). In addition, the Wnt/Ca(2+) pathway activated by Wnt-5a
      antagonizes the Wnt/beta-catenin pathway via an unknown mechanism. The mitogen
      activated protein kinase (MAPK) pathway composed of TAK1 MAPK kinase kinase and
      NLK MAPK also negatively regulates the canonical Wnt/beta-catenin signaling
      pathway. Here we show that activation of CaMKII induces stimulation of the TAK1
      NLK pathway. Overexpression of Wnt-5a in HEK293 cells activates NLK through TAK1.
      Furthermore, by using a chimeric receptor (beta(2)AR-Rfz-2) containing the ligand
      binding and transmembrane segments from the beta(2)-adrenergic receptor
      (beta(2)AR) and the cytoplasmic domains from rat Frizzled-2 (Rfz-2), stimulation
      with the beta-adrenergic agonist isoproterenol activates activities of endogenous
      CaMKII, TAK1, and NLK and inhibits beta-catenin-induced transcriptional
      activation. These results suggest that the TAK1-NLK MAPK cascade is activated by
      the noncanonical Wnt-5a/Ca(2+) pathway and antagonizes canonical Wnt/beta-catenin
      signaling.

PMID- 12482968
TI  - Activating signal cointegrator 2 belongs to a novel steady-state complex that
      contains a subset of trithorax group proteins.
AB  - Many transcription coactivators interact with nuclear receptors in a ligand- and
      C-terminal transactivation function (AF2)-dependent manner. These include
      activating signal cointegrator 2 (ASC-2), a recently isolated transcriptional
      coactivator molecule, which is amplified in human cancers and stimulates
      transactivation by nuclear receptors and numerous other transcription factors. In
      this report, we show that ASC-2 belongs to a steady-state complex of
      approximately 2 MDa (ASC-2 complex [ASCOM]) in HeLa nuclei. ASCOM contains
      retinoblastoma-binding protein RBQ-3, alpha/beta-tubulins, and trithorax group
      proteins ALR-1, ALR-2, HALR, and ASH2. In particular, ALR-1/2 and HALR contain a
      highly conserved 130- to 140-amino-acid motif termed the SET domain, which was
      recently implicated in histone H3 lysine-specific methylation activities. Indeed,
      recombinant ALR-1, HALR, and immunopurified ASCOM exhibit very weak but specific
      H3-lysine 4 methylation activities in vitro, and transactivation by retinoic acid
      receptor appears to involve ligand-dependent recruitment of ASCOM and subsequent
      transient H3-lysine 4 methylation of the promoter region in vivo. Thus, ASCOM may
      represent a distinct coactivator complex of nuclear receptors. Further
      characterization of ASCOM will lead to a better understanding of how nuclear
      receptors and other transcription factors mediate transcriptional activation.

PMID- 12482969
TI  - Tsg101 is essential for cell growth, proliferation, and cell survival of
      embryonic and adult tissues.
AB  - Tumor susceptibility gene 101 (Tsg101) was identified in a random mutagenesis
      screen for potential tumor suppressors in NIH 3T3 cells. Altered transcripts of
      this gene have been detected in sporadic breast cancers and many other human
      malignancies. However, the involvement of this gene in neoplastic transformation
      and tumorigenesis is still elusive. Using gene targeting, we generated
      genetically engineered mice with a floxed allele of Tsg101. We investigated
      essential functions of this gene in vivo and examined whether the loss of
      function of Tsg101 results in tumorigenesis. Conventional knockout mice were
      generated through Cre-mediated excision of the first coding exon in the germ line
      of mouse mammary tumor virus (MMTV)-Cre transgenic mice. The complete ablation of
      Tsg101 in the developing embryo resulted in death around implantation. In
      contrast, mammary gland-specific knockout mice developed normally but were unable
      to nurse their young as a result of impaired mammogenesis during late pregnancy.
      Neither heterozygous null mutants nor somatic knockout mice developed mammary
      tumors after a latency of 2 years. The Cre-mediated deletion of Tsg101 in primary
      cells demonstrated that this gene is essential for the growth, proliferation, and
      survival of mammary epithelial cells. In summary, our results suggest that Tsg101
      is required for normal cell function of embryonic and adult tissues but that this
      gene is not a tumor suppressor for sporadic forms of breast cancer.

PMID- 12482970
TI  - Induction of apoptosis by sphingoid long-chain bases in Aspergillus nidulans.
AB  - Sphingolipid metabolism is implicated to play an important role in apoptosis.
      Here we show that dihydrosphingosine (DHS) and phytosphingosine (PHS), two major
      sphingoid bases of fungi, have potent fungicidal activity with remarkably high
      structural and stereochemical specificity against Aspergillus nidulans. In fact,
      only naturally occurring DHS and PHS are active. Further analysis revealed that
      DHS and PHS induce rapid DNA condensation independent of mitosis, large-scale DNA
      fragmentation, and exposure of phosphatidylserine, all common morphological
      features characteristic of apoptosis, suggesting that DHS and PHS induce
      apoptosis in A. nidulans. The finding that DNA fragmentation requires protein
      synthesis, which implies that an active process is involved, further supports
      this proposition. The induction of apoptosis by DHS and PHS is associated with
      the rapid accumulation of reactive oxygen species (ROS). However, ROS are not
      required for apoptosis induced by DHS and PHS, as scavenging of ROS by a free
      radical spin trap has no effect. We further demonstrate that apoptosis induced by
      DHS and PHS is independent of metacaspase function but requires mitochondrial
      function. Together, the results suggest that DHS and PHS induce a type of
      apoptosis in A. nidulans most similar to the caspase-independent apoptosis
      observed in mammalian systems. As A. nidulans is genetically tractable, this
      organism should be an ideal model system for dissecting sphingolipid signaling in
      apoptosis and, importantly, for further elucidating the molecular basis of
      caspase-independent apoptosis.

PMID- 12482971
TI  - Iron status in mice carrying a targeted disruption of lactoferrin.
AB  - Lactoferrin is a member of the transferrin family of iron-binding glycoproteins
      present in milk, mucosal secretions, and the secondary granules of neutrophils.
      While several physiological functions have been proposed for lactoferrin,
      including the regulation of intestinal iron uptake, the exact function of this
      protein in vivo remains to be established. To directly assess the physiological
      functions of lactoferrin, we have generated lactoferrin knockout (LFKO(-/-)) mice
      by homologous gene targeting. LFKO(-/-) mice are viable and fertile, develop
      normally, and display no overt abnormalities. A comparison of the iron status of
      suckling offspring from LFKO(-/-) intercrosses and from wild-type (WT)
      intercrosses showed that lactoferrin is not essential for iron delivery during
      the postnatal period. Further, analysis of adult mice on a basal or a high-iron
      diet revealed no differences in transferrin saturation or tissue iron stores
      between WT and LFKO(-/-) mice on either diet, although the serum iron levels were
      slightly elevated in LFKO-/- mice on the basal diet. Consistent with the
      relatively normal iron status, in situ hybridization analysis demonstrated that
      lactoferrin is not expressed in the postnatal or adult intestine. Collectively,
      these results support the conclusion that lactoferrin does not play a major role
      in the regulation of iron homeostasis.

PMID- 12482972
TI  - Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments
      that confers protein stability and subnuclear localization.
AB  - The mixed-lineage leukemia gene (MLL, ALL1, HRX) encodes a 3,969-amino-acid
      nuclear protein homologous to Drosophila trithorax and is required to maintain
      proper Hox gene expression. Chromosome translocations in human leukemia disrupt
      MLL (11q23), generating chimeric proteins between the N terminus of MLL and
      multiple translocation partners. Here we report that MLL is normally cleaved at
      two conserved sites (D/GADD and D/GVDD) and that mutation of these sites
      abolishes the proteolysis. MLL cleavage generates N-terminal p320 (N320) and C
      terminal p180 (C180) fragments, which form a stable complex that localizes to a
      subnuclear compartment. The FYRN domain of N320 directly interacts with the FYRC
      and SET domains of C180. Disrupting the interaction between N320 and C180 leads
      to a marked decrease in the level of N320 and a redistribution of C180 to a
      diffuse nuclear pattern. These data suggest a model in which a dynamic post
      cleavage association confers stability to N320 and correct nuclear
      sublocalization of the complex, to control the availability of N320 for target
      genes. This predicts that MLL fusion proteins of leukemia which would lose the
      ability to complex with C180 have their stability conferred instead by the fusion
      partners, thus providing one mechanism for altered target gene expression.

PMID- 12482974
TI  - Critical role of histone methylation in tumor suppressor gene silencing in
      colorectal cancer.
AB  - The mechanism of DNA hypermethylation-associated tumor suppressor gene silencing
      in cancer remains incompletely understood. Here, we show by chromatin
      immunoprecipitation that for three genes (P16, MLH1, and the O(6)-methylguanine
      DNA methyltransferase gene, MGMT), histone H3 Lys-9 methylation directly
      correlates and histone H3 Lys-9 acetylation inversely correlates with DNA
      methylation in three neoplastic cell lines. Treatment with the histone
      deacetylase inhibitor trichostatin A (TSA) resulted in moderately increased Lys-9
      acetylation at silenced loci with no effect on Lys-9 methylation and minimal
      effects on gene expression. By contrast, treatment with the DNA methyltransferase
      inhibitor 5-aza-2'-deoxycytidine (5Aza-dC) rapidly reduced Lys-9 methylation at
      silenced loci and resulted in reactivation for all three genes. Combined
      treatment with 5Aza-dC and TSA was synergistic in reactivating gene expression
      through simultaneous effects on Lys-9 methylation and acetylation, which resulted
      in a robust increase in the ratio of Lys-9 acetylated and methylated histones at
      loci showing dense DNA methylation. By contrast to Lys-9, histone H3 Lys-4
      methylation inversely correlated with promoter DNA methylation, was not affected
      by TSA, and was increased moderately at silenced loci by 5Aza-dC. Our results
      suggest that reduced H3 Lys-4 methylation and increased H3 Lys-9 methylation play
      a critical role in the maintenance of promoter DNA methylation-associated gene
      silencing in colorectal cancer.

PMID- 12482973
TI  - An Rpb4/Rpb7-like complex in yeast RNA polymerase III contains the orthologue of
      mammalian CGRP-RCP.
AB  - The essential C17 subunit of yeast RNA polymerase (Pol) III interacts with Brf1,
      a component of TFIIIB, suggesting a role for C17 in the initiation step of
      transcription. The protein sequence of C17 (encoded by RPC17) is conserved from
      yeasts to humans. However, mammalian homologues of C17 (named CGRP-RCP) are known
      to be involved in a signal transduction pathway related to G protein-coupled
      receptors, not in transcription. In the present work, we first establish that
      human CGRP-RCP is the genuine orthologue of C17. CGRP-RCP was found to
      functionally replace C17 in Deltarpc17 yeast cells; the purified mutant Pol III
      contained CGRP-RCP and had a decreased specific activity but initiated
      faithfully. Furthermore, CGRP-RCP was identified by mass spectrometry in a highly
      purified human Pol III preparation. These results suggest that CGRP-RCP has a
      dual function in mammals. Next, we demonstrate by genetic and biochemical
      approaches that C17 forms with C25 (encoded by RPC25) a heterodimer akin to
      Rpb4/Rpb7 in Pol II. C17 and C25 were found to interact genetically in
      suppression screens and physically in coimmunopurification and two-hybrid
      experiments. Sequence analysis and molecular modeling indicated that the C17/C25
      heterodimer likely adopts a structure similar to that of the archaeal RpoE/RpoF
      counterpart of the Rpb4/Rpb7 complex. These RNA polymerase subunits appear to
      have evolved to meet the distinct requirements of the multiple forms of RNA
      polymerases.

PMID- 12482975
TI  - Novel p27(kip1) C-terminal scatter domain mediates Rac-dependent cell migration
      independent of cell cycle arrest functions.
AB  - Hepatocyte growth factor (HGF) signaling via its receptor, the proto-oncogene
      Met, alters cell proliferation and motility and has been associated with tumor
      metastasis. HGF treatment of HepG2 human hepatocellular carcinoma cells induces
      cell migration concomitant with increased levels of the p27(kip1) cyclin-cdk
      inhibitor. HGF signaling resulted in nuclear export of endogenous p27 to the
      cytoplasm, via Ser-10 phosphorylation, where it colocalized with F-actin.
      Introduction of transducible p27 protein (TATp27) was sufficient for actin
      cytoskeletal rearrangement and migration of HepG2 cells. TATp27 mutational
      analysis identified a novel p27 C-terminal domain required for cell migration,
      distinct from the N-terminal cyclin-cyclin-dependent kinase (cdk) binding domain.
      Loss or disruption of the p27 C-terminal domain abolished both actin
      rearrangement and cell migration. The cell-scattering activity of p27 occurred
      independently of its cell cycle arrest functions and required cytoplasmic
      localization of p27 via Ser-10 phosphorylation. Furthermore, Rac GTPase was
      necessary for p27-dependent migration but alone was insufficient for HepG2 cell
      migration. These results predicted a migration defect in p27-deficient cells.
      Indeed, p27-deficient primary fibroblasts failed to migrate, and reconstitution
      with TATp27 rescued the motility defect. These observations define a novel role
      for p27 in cell motility that is independent of its function in cell cycle
      inhibition.

PMID- 12482976
TI  - Targeting the MEF2-like transcription factor Smp1 by the stress-activated Hog1
      mitogen-activated protein kinase.
AB  - Exposure of Saccharomyces cerevisiae to increases in extracellular osmolarity
      activates the stress-activated Hog1 mitogen-activated protein kinase (MAPK),
      which is essential for cell survival upon osmotic stress. Yeast cells respond to
      osmotic stress by inducing the expression of a very large number of genes, and
      the Hog1 MAPK plays a critical role in gene transcription upon stress. To
      understand how Hog1 controls gene expression, we designed a genetic screen to
      isolate new transcription factors under the control of the MAPK and identified
      the MEF2-like transcription factor, Smp1, as a target for Hog1. Overexpression of
      SMP1 induced Hog1-dependent expression of osmoresponsive genes such as STL1,
      whereas smp1Delta cells were defective in their expression. Consistently,
      smp1Delta cells displayed reduced viability upon osmotic shock. In vivo
      coprecipitation and phosphorylation studies showed that Smp1 and Hog1 interact
      and that Smp1 is phosphorylated upon osmotic stress in a Hog1-dependent manner.
      Hog1 phosphorylated Smp1 in vitro at the C-terminal region. Phosphorylation of
      Smp1 by the MAPK is essential for its function, since a mutant allele unable to
      be phosphorylated by the MAPK displays impaired stress responses. Thus, our data
      indicate that Smp1 acts downstream of Hog1, controlling a subset of the responses
      induced by the MAPK. Moreover, Smp1 concentrates in the nucleus during the
      stationary phase, and the lack of SMP1 results in cells that lose viability in
      the stationary phase. Localization of Smp1 depends on HOG1, and consistently,
      hog1Delta cells also lose viability during this growth phase. These data suggest
      that Smp1 could be mediating a role for the Hog1 MAPK during the stationary
      phase.

PMID- 12482977
TI  - LXXLL-related motifs in Dax-1 have target specificity for the orphan nuclear
      receptors Ad4BP/SF-1 and LRH-1.
AB  - The orphan receptor Ad4BP/SF-1 (NR5A1) is a constitutive activator, and its
      activity is repressed by another orphan receptor, Dax-1 (NR0B1). In the present
      study, we investigated the molecular mechanisms underlying this repression by Dax
      1. Yeast two-hybrid and transient-transfection assays confirmed the necessity of
      three LXXLL-related motifs in Dax-1 for interaction with and repression of
      Ad4BP/SF-1. In vitro pull-down experiments confirmed that Dax-1 interacts with
      Ad4BP/SF-1 and also with LRH-1 (NR5A2). The target specificity of the LXXLL
      related motifs was indicated by the observations that Ad4BP/SF-1, ERalpha
      (NR3A1), LRH-1, ERR2 (NR3B2), and fly FTZ-F1 (NR5A3) interacted through their
      ligand binding domains with all the LXXLL-related motifs in Dax-1 whereas HNF4
      (NR2A1) and RORalpha (NR1F1) did not. Transcriptional activities of the receptors
      whose DNA binding domains (DBDs) were replaced by the GAL4 DBD were repressed by
      Dax-1 to various levels, which correlated with the strength of interaction. Amino
      acid substitutions revealed that Ad4BP/SF-1 and LRH-1 preferentially interact
      with L(+1)XXLL-related motifs containing serine, tyrosine, serine, and threonine
      at positions -2, +2, +3, and +6, respectively. Taken together, our results
      indicate that the specificities of LXXLL-related motifs in Dax-1 based on their
      amino acid sequences play an important role in regulation of orphan receptors.

PMID- 12482978
TI  - Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment
      of histone deacetylase 1 to their conserved ELM2 domain.
AB  - mi-er1 (previously called er1) was first isolated from Xenopus laevis embryonic
      cells as a novel fibroblast growth factor-regulated immediate-early gene. Xmi-er1
      was shown to encode a nuclear protein with an N-terminal acidic transcription
      activation domain. The human orthologue of mi-er1 (hmi-er1) displays 91%
      similarity to the Xenopus sequence at the amino acid level and was shown to be
      upregulated in breast carcinoma cell lines and tumors. Alternative splicing at
      the 3' end of hmi-er1 produces two major isoforms, hMI-ER1alpha and hMI-ER1beta,
      which contain distinct C-terminal domains. In this study, we investigated the
      role of hMI-ER1alpha and hMI-ER1beta in the regulation of transcription. Using
      fusion proteins of hMI-ER1alpha or hMI-ER1beta tethered to the GAL4 DNA binding
      domain, we show that both isoforms, when recruited to the G5tkCAT minimal
      promoter, function to repress transcription. We demonstrate that this repressor
      activity is due to interaction and recruitment of a trichostatin A-sensitive
      histone deacetylase 1 (HDAC1). Furthermore, deletion analysis revealed that
      recruitment of HDAC1 to hMI-ER1alpha and hMI-ER1beta occurs through their common
      ELM2 domain. The ELM2 domain was first described in the Caenorhabditis elegans
      Egl-27 protein and is present in a number of SANT domain-containing transcription
      factors. This is the first report of a function for the ELM2 domain, highlighting
      its role in the regulation of transcription.

PMID- 12482979
TI  - Novel transcriptional potentiation of BETA2/NeuroD on the secretin gene promoter
      by the DNA-binding protein Finb/RREB-1.
AB  - The basic helix-loop-helix protein BETA2/NeuroD activates transcription of the
      secretin gene and is essential for terminal differentiation of secretin-producing
      enteroendocrine cells. However, in heterodimeric complexes with its partner basic
      helix-loop-helix proteins, BETA2 does not appear to be a strong activator of
      transcription by itself. Mutational analysis of a proximal enhancer in the
      secretin gene identified several cis-acting elements in addition to the E-box
      binding site for BETA2. We identified by expression cloning the zinc finger
      protein RREB-1, also known to exist as a longer form, Finb, as the protein
      binding to one of the mutationally sensitive elements. Finb/RREB-1 lacks an
      intrinsic activation domain and by itself did not activate secretin gene
      transcription. Here we show that Finb/RREB-1 can associate with BETA2 to enhance
      its transcription-activating function. Both DNA binding and physical interaction
      of Finb/RREB-1 with BETA2 are required to potentiate transcription. Thus,
      Finb/RREB-1 does not function as a classical activator of transcription that
      recruits an activation domain to a DNA-protein complex. Finb/RREB-1 may be
      distinguished from coactivators, which increase transcription without sequence
      specific DNA binding. We suggest that Finb/RREB-1 should be considered a
      potentiator of transcription, representing a distinct category of transcription
      regulating proteins.

PMID- 12482980
TI  - Carcinoembryonic antigen-related cell adhesion molecule 10 expressed specifically
      early in pregnancy in the decidua is dispensable for normal murine development.
AB  - The carcinoembryonic antigen (CEA) family consists of a large group of
      evolutionarily and structurally divergent glycoproteins. The murine CEACAM9 and
      CEACAM11-related proteins as well as the pregnancy-specific glycoproteins (PSG)
      are secreted members of the CEA family which are differentially expressed in
      fetal trophoblast cell populations during placental development. PSG are
      essential for a successful pregnancy, possibly by protecting the semiallotypic
      fetus from the maternal immune system. In contrast, Ceacam10 mRNA, coding for a
      protein identical in structure with CEACAM11-related proteins, is expressed in
      the maternal decidua surrounding the implantation site of the conceptus only
      during early stages of gestation between day 6.5 and day 10.5 postcoitum. To
      determine its role during murine development, we inactivated Ceacam10. Ceacam10(
      /-) mice developed, like the previously established Ceacam9(-/-) mice,
      indistinguishably from wild-type littermates with respect to sex ratio, weight
      gain, and fertility. However, a small but significant reduction of the litter
      size by 23% was observed in Ceacam10(-/-) matings. Furthermore, combining the
      Ceacam9 and Ceacam10 null alleles, both located on chromosome 7, by meiotic
      recombination and subsequent mating of heterozygotes carrying both knockout
      alleles on one chromosome yielded wild-type and double knockout offspring at the
      expected Mendelian ratio. Taken together, both Ceacam10 and Ceacam9, alone or in
      combination, are not essential for either murine placental and embryonic
      development or for adult life.

PMID- 12482981
TI  - The internal ribosome entry site-mediated translation of antiapoptotic protein
      XIAP is modulated by the heterogeneous nuclear ribonucleoproteins C1 and C2.
AB  - The X-chromosome-linked inhibitor of apoptosis, XIAP, is the most powerful and
      ubiquitous intrinsic inhibitor of apoptosis. We have shown previously that the
      translation of XIAP is controlled by a potent internal ribosome entry site (IRES)
      element. IRES-mediated translation of XIAP is increased in response to cellular
      stress, suggesting the critical role for IRES translation during cellular stress.
      Here, we demonstrate that heterogeneous nuclear ribonucleoproteins C1 and C2
      (hnRNPC1 and -C2) are part of the RNP complex that forms on XIAP IRES.
      Furthermore, the cellular levels of hnRNPC1 and -C2 parallel the activity of XIAP
      IRES and the overexpression of hnRNPC1 and -C2 specifically enhanced translation
      of XIAP IRES, suggesting that hnRNPC1 and -C2 may modulate XIAP expression. Given
      the central role of XIAP in the regulation of apoptosis these results are
      important for our understanding of the control of apoptosis.

PMID- 12482982
TI  - The Drosophila SNR1 (SNF5/INI1) subunit directs essential developmental functions
      of the Brahma chromatin remodeling complex.
AB  - The Drosophila melanogaster Brahma (Brm) complex, a counterpart of the
      Saccharomyces cerevisiae SWI/SNF ATP-dependent chromatin remodeling complex, is
      important for proper development by maintaining specific gene expression
      patterns. The SNR1 subunit is strongly conserved with yeast SNF5 and mammalian
      INI1 and is required for full activity of the Brm complex. We identified a
      temperature-sensitive allele of snr1 caused by a single amino acid substitution
      in the conserved repeat 2 region, implicated in a variety of protein-protein
      interactions. Genetic analyses of snr1(E1) reveal that it functions as an
      antimorph and that snr1 has critical roles in tissue patterning and growth
      control. Temperature shifts show that snr1 is continuously required, with
      essential functions in embryogenesis, pupal stages, and adults. Allele-specific
      genetic interactions between snr1(E1) and mutations in genes encoding other
      members of the Brm complex suggest that snr1(E1) mutant phenotypes result from
      reduced Brm complex function. Consistent with this view, SNR1(E1) is stably
      associated with other components of the Brm complex at the restrictive
      temperature. SNR1 can establish direct contacts through the conserved repeat 2
      region with the SET domain of the homeotic regulator Trithorax (TRX), and
      SNR1(E1) is partially defective for functional TRX association. As truncating
      mutations of INI1 are strongly correlated with aggressive cancers, our results
      support the view that SNR1, and specifically the repeat 2 region, has a critical
      role in mediating cell growth control functions of the metazoan SWI/SNF
      complexes.

PMID- 12482983
TI  - Two different Drosophila ADA2 homologues are present in distinct GCN5 histone
      acetyltransferase-containing complexes.
AB  - We have isolated a novel Drosophila (d) gene coding for two distinct proteins via
      alternative splicing: a homologue of the yeast adaptor protein ADA2, dADA2a, and
      a subunit of RNA polymerase II (Pol II), dRPB4. Moreover, we have identified
      another gene in the Drosophila genome encoding a second ADA2 homologue (dADA2b).
      The two dADA2 homologues, as well as many putative ADA2 homologues from different
      species, all contain, in addition to the ZZ and SANT domains, several
      evolutionarily conserved domains. The dada2a/rpb4 and dada2b genes are
      differentially expressed at various stages of Drosophila development. Both dADA2a
      and dADA2b interacted with the GCN5 histone acetyltransferase (HAT) in a yeast
      two-hybrid assay, and dADA2b, but not dADA2a, also interacted with Drosophila
      ADA3. Both dADA2s further potentiate transcriptional activation in insect and
      mammalian cells. Antibodies raised either against dADA2a or dADA2b both
      immunoprecipitated GCN5 as well as several Drosophila TATA binding protein
      associated factors (TAFs). Moreover, following glycerol gradient sedimentation or
      chromatographic purification combined with gel filtration of Drosophila nuclear
      extracts, dADA2a and dGCN5 were detected in fractions with an apparent molecular
      mass of about 0.8 MDa whereas dADA2b was found in fractions corresponding to
      masses of at least 2 MDa, together with GCN5 and several Drosophila TAFs.
      Furthermore, in vivo the two dADA2 proteins showed different localizations on
      polytene X chromosomes. These results, taken together, suggest that the two
      Drosophila ADA2 homologues are present in distinct GCN5-containing HAT complexes.

PMID- 12482984
TI  - Inhibition of stress-inducible kinase pathways by tumorigenic mutant p53.
AB  - More than 50% of human cancers contain p53 gene mutations and as a result
      accumulate altered forms of the full-length p53 protein. Although certain tumor
      types expressing mutant p53 protein have a poor prognostic process, the precise
      role of mutant p53 protein in highly malignant tumor cells is not well defined.
      Some p53 mutants, but not wild-type p53, are shown here to interact with Daxx, a
      Fas-binding protein that activates stress-inducible kinase pathways. Interaction
      of Daxx with p53 is highly dependent upon the specific mutation of p53.
      Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of
      the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH(2)
      terminal kinase. Mutant p53 forms complexes with Daxx in cells, and consequently,
      mutant p53 is able to rescue cells from Daxx-dependent inhibition of
      proliferation. Thus, the accumulation of mutant p53 in tumor cells may contribute
      to tumorigenesis by inhibiting stress-inducible kinase pathways.

PMID- 12482985
TI  - Mediator and p300/CBP-steroid receptor coactivator complexes have distinct roles,
      but function synergistically, during estrogen receptor alpha-dependent
      transcription with chromatin templates.
AB  - Ligand-dependent transcriptional activation by nuclear receptors involves the
      recruitment of various coactivators to the promoters of hormone-regulated genes
      assembled into chromatin. Nuclear receptor coactivators include histone
      acetyltransferase complexes, such as p300/CBP-steroid receptor coactivator (SRC),
      as well as the multisubunit mediator complexes ("Mediator"), which may help
      recruit RNA polymerase II to the promoter. We have used a biochemical approach,
      including an in vitro chromatin assembly and transcription system, to examine the
      functional role for Mediator in the transcriptional activity of estrogen receptor
      alpha (ERalpha) with chromatin templates, as well as functional interplay between
      Mediator and p300/CBP during ERalpha-dependent transcription. Using three
      different approaches to functionally inactivate Mediator (immunoneutralization,
      immunodepletion, and inhibitory polypeptides), we find that Mediator is required
      for maximal transcriptional activation by ligand-activated ERalpha. In addition,
      we demonstrate synergism between Mediator and p300/CBP-SRC during ERalpha
      dependent transcription with chromatin templates, but not with naked DNA. This
      synergism is important for promoting the formation of a stable transcription
      preinitiation complex leading to the initiation of transcription. Interestingly,
      we find that Mediator has an additional distinct role during ERalpha-dependent
      transcription not shared by p300/CBP-SRC: namely, to promote preinitiation
      complex formation for subsequent rounds of transcription reinitiation. These
      results suggest that one functional consequence of Mediator-ERalpha interactions
      is the stimulation of multiple cycles of transcription reinitiation.
      Collectively, our results indicate an important role for Mediator, as well as its
      functional interplay with p300/CBP-SRC, in the enhancement of ERalpha-dependent
      transcription with chromatin templates.

PMID- 12482986
TI  - Activator-independent functions of the yeast mediator sin4 complex in
      preinitiation complex formation and transcription reinitiation.
AB  - RNA polymerase II (Pol II) Mediator plays an essential role in both basal and
      activated transcription. Previously, subunits of the Sin4 Mediator complex (Sin4,
      Pgd1, Gal11, and Med2) have been implicated in both positive and negative
      transcriptional regulation. Furthermore, it was proposed that this subcomplex
      constitutes an activator-binding domain. A yeast nuclear-extract system was used
      to investigate the biochemical role of the Sin4 complex. In contrast to previous
      findings, we found at least two general activator-independent roles for the Sin4
      complex. First, mutations in sin4 and pgd1 destabilized the Pol II-Med complex,
      leading to a reduced rate and extent of preinitiation complex (PIC) formation
      both in the presence and absence of activators. Although reduced in amount
      compared with the wild type, PICs that are formed lacking the Sin4 complex are
      stable and can initiate transcription normally. Second, mutation of pgd1 causes
      partial disruption of the Sin4 complex and leads to a defect in transcription
      reinitiation. This defect is caused by dissociation of mutant Mediator from
      promoters after initiation, leading to nonfunctional Scaffold complexes. These
      results show that function of the Sin4 complex is not essential for transcription
      activation in a crude in vitro system but that it plays key roles in the general
      transcription mechanism.

PMID- 12482987
TI  - Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during
      hypoxia.
AB  - A classical cellular response to hypoxia is a cessation of growth. Hypoxia
      induced growth arrest differs in different cell types but is likely an essential
      aspect of the response to wounding and injury. An important component of the
      hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1)
      transcription factor. Although this transcription factor is essential for
      adaptation to low oxygen levels, the mechanisms through which it influences cell
      cycle arrest, including the degree to which it cooperates with the tumor
      suppressor protein p53, remain poorly understood. To determine broadly relevant
      aspects of HIF-1 function in primary cell growth arrest, we examined two
      different primary differentiated cell types which contained a deletable allele of
      the oxygen-sensitive component of HIF-1, the HIF-1alpha gene product. The two
      cell types were murine embryonic fibroblasts and splenic B lymphocytes; to
      determine how the function of HIF-1alpha influenced p53, we also created double
      knockout (HIF-1alpha null, p53 null) strains and cells. In both cell types, loss
      of HIF-1alpha abolished hypoxia-induced growth arrest and did this in a p53
      independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF
      1alpha genes have completely lost the ability to alter the cell cycle in response
      to hypoxia. In addition, we have found that the loss of HIF-1alpha causes an
      increased progression into S phase during hypoxia, rather than a growth arrest.
      We show that hypoxia causes a HIF-1alpha-dependent increase in the expression of
      the cyclin-dependent kinase inhibitors p21 and p27; we also find that
      hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1alpha dependent.
      These data demonstrate that the transcription factor HIF-1 is a major regulator
      of cell cycle arrest in primary cells during hypoxia.

PMID- 12482988
TI  - Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated
      protein kinase.
AB  - p38 mitogen-activated protein (MAP) kinases play an important role in the
      regulation of cellular responses to all kinds of stresses. The most abundant and
      broadly expressed p38 MAP kinase is p38alpha, which can also control the
      proliferation, differentiation, and survival of several cell types. Here we show
      that the absence of p38alpha correlates with the up-regulation of one of its
      upstream activators, the MAP kinase kinase MKK6, in p38alpha(-/-) knockout mice
      and in cultured cells derived from them. In contrast, the expression levels of
      the p38 activators MKK3 and MKK4 are not affected in p38alpha-deficient cells.
      The increase in MKK6 protein concentration correlates with increased amounts of
      MKK6 mRNA in the p38alpha(-/-) cells. Pharmacological inhibition of p38alpha also
      up-regulates MKK6 mRNA levels in HEK293 cells. Conversely, reintroduction of
      p38alpha into p38alpha(-/-) cells reduces the levels of MKK6 protein and mRNA to
      the normal levels found in wild-type cells. Moreover, we show that the MKK6 mRNA
      is more stable in p38alpha(-/-) cells and that the 3'untranslated region of this
      mRNA can differentially regulate the stability of the lacZ reporter gene in a
      p38alpha-dependent manner. Our data indicate that p38alpha can negatively
      regulate the stability of the MKK6 mRNA and thus control the steady-state
      concentration of one of its upstream activators.

PMID- 12482989
TI  - The stalling of transcription at abasic sites is highly mutagenic.
AB  - Abasic (AP) sites represent one of the most frequently formed lesions in DNA.
      Here, we examine the consequences of the stalling of RNA polymerase II at AP
      sites in DNA in Saccharomyces cerevisiae. A severe inhibition of transcription
      occurs in strains that are defective in the removal of AP sites and that also
      lack the RAD26 gene, a homolog of the human Cockayne syndrome group B (CSB) gene,
      and, importantly, a dramatic rise in mutagenesis is incurred in such strains.
      From the various observations presented here, we infer that the stalling of
      transcription at AP sites is highly mutagenic.

PMID- 12482990
TI  - Control of the replicative life span of human fibroblasts by p16 and the polycomb
      protein Bmi-1.
AB  - The polycomb protein Bmi-1 represses the INK4a locus, which encodes the tumor
      suppressors p16 and p14(ARF). Here we report that Bmi-1 is downregulated when WI
      38 human fibroblasts undergo replicative senescence, but not quiescence, and
      extends replicative life span when overexpressed. Life span extension by Bmi-1
      required the pRb, but not p53, tumor suppressor protein. Deletion analysis showed
      that the RING finger and helix-turn-helix domains of Bmi-1 were required for life
      span extension and suppression of p16. Furthermore, a RING finger deletion mutant
      exhibited dominant negative activity, inducing p16 and premature senescence.
      Interestingly, presenescent cultures of some, but not all, human fibroblasts
      contained growth-arrested cells expressing high levels of p16 and apparently
      arrested by a p53- and telomere-independent mechanism. Bmi-1 selectively extended
      the life span of these cultures. Low O(2) concentrations had no effect on p16
      levels or life span extension by Bmi-1 but reduced expression of the p53 target,
      p21. We propose that some human fibroblast strains are more sensitive to stress
      induced senescence and have both p16-dependent and p53/telomere-dependent
      pathways of senescence. Our data suggest that Bmi-1 extends the replicative life
      span of human fibroblasts by suppressing the p16-dependent senescence pathway.

PMID- 12482991
TI  - betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105
      serines 927 and 932.
AB  - NF-kappaB1 p105 functions both as a precursor of NF-kappaB1 p50 and as a
      cytoplasmic inhibitor of NF-kappaB. Following the stimulation of cells with tumor
      necrosis factor alpha (TNF-alpha), the IkappaB kinase (IKK) complex rapidly
      phosphorylates NF-kappaB1 p105 on serine 927 in the PEST region. This
      phosphorylation is essential for TNF-alpha to trigger p105 degradation, which
      releases the associated Rel/NF-kappaB subunits to translocate into the nucleus
      and regulate target gene transcription. Serine 927 resides in a conserved motif
      (Asp-Ser(927)-Gly-Val-Glu-Thr-Ser(932)) homologous to the IKK target sequence in
      IkappaBalpha. In this study, TNF-alpha-induced p105 proteolysis was revealed to
      additionally require the phosphorylation of serine 932. Experiments with IKK1(-/
      ) and IKK2(-/-) double knockout embryonic fibroblasts demonstrate that the IKK
      complex is essential for TNF-alpha to stimulate phosphorylation on p105 serines
      927 and 932. Furthermore, purified IKK1 and IKK2 can each phosphorylate a
      glutathione S-transferase-p105(758-967) fusion protein on both regulatory serines
      in vitro. IKK-mediated p105 phosphorylation generates a binding site for
      betaTrCP, the receptor subunit of an SCF-type ubiquitin E3 ligase, and depletion
      of betaTrCP by RNA interference blocks TNF-alpha-induced p105 ubiquitination and
      proteolysis. Phosphopeptide competition experiments indicate that betaTrCP binds
      p105 more effectively when both serines 927 and 932 are phosphorylated.
      Interestingly, however, betaTrCP affinity for the IKK-phosphorylated sequence on
      p105 is substantially lower than that on IkappaBalpha. Thus, it appears that
      reduced p105 recruitment of betaTrCP and subsequent ubiquitination may contribute
      to delayed p105 proteolysis after TNF-alpha stimulation relative to that for
      IkappaBalpha.

PMID- 12482993
TI  - Nonvascular interventions of the urinary tract.
AB  - Nonvascular intervention of the urinary tract is a well-established uroradiologic
      subspecialty, which is more important for avoiding invasive open surgery in the
      age of rising demand about the value of less invasive treatment. Various kinds of
      nonvascular intervention are recently performed under image-guidance and are as
      follows: percutaneous nephrostomy, percutaneous nephrostolithotomy, percutaneous
      dilatation of the urinary tract, sclerotherapy for renal cysts, percutaneous
      catheter drainage, percutaneous foreign body retrieval and biopsy. Percutaneous
      nephrostomy is a basic technique to provide a direct access to urinary tract,
      which makes it possible to perform other interventional procedures. Although
      nonvascular intervention may produce some complications, it is generally
      considered to be less invasive than open surgery and has advantages such as short
      hospital stay, early return to normal life and therefore economic savings. This
      review is described to help clinicians easily understand the procedures,
      indications, techniques, and complications with figures of cases the authors
      experienced.

PMID- 12482992
TI  - A novel domain within the DEAD-box protein DP103 is essential for transcriptional
      repression and helicase activity.
AB  - Members of the DEAD-box family of helicases, distinguished by a core
      characteristic sequence of Asp-Glu-Ala-Asp, are expressed in a wide range of
      prokaryotes and eukaryotes and exhibit diverse cellular functions, including DNA
      transcription, recombination and repair, RNA processing, translation, and
      posttranslational regulation. Although ubiquitous, the function of most DEAD-box
      proteins is unknown. We and others have recently cloned DP103, which harbors
      conserved DEAD-box, helicase, and ATPase domains in its N terminus. DP103 (also
      termed Gemin3 and DDX20) interacts with SF-1, SMN, EBNA2, and EBNA3C in mammalian
      cells. Here we demonstrate that a discrete domain within the nonconserved C
      terminal region of DP103 directly interacts with SF-1. This domain exhibits an
      autonomous repression function and is necessary and sufficient for repressing the
      transcriptional activity of SF-1. Furthermore, intact DP103 exhibits helicase
      activity. Importantly, the C-terminal domain is obligatory but not sufficient for
      this unwinding activity of DP103. Together, our results support a novel paradigm
      for transcriptional repression and demonstrate the bifunctional role of the C
      terminal domain of DP103.

PMID- 12482995
TI  - Prediction of left ventricular peak ejection velocity by preceding and
      prepreceding RR intervals in atrial fibrillation: a new method to adjust the
      influence between two intervals.
AB  - In atrial fibrillation, cardiac performance is dependent on both preceding RR (RR
      1) and prepreceding RR (RR-2) intervals. However, relative contributions were not
      well defined. Left ventricular outflow peak ejection velocity (Vpe) was measured
      by echocardiography from 21 patients. The relation between RR-1 and Vpe could be
      divided into two zones; steep slope in short RR-1 intervals (< or =0.5 sec) and
      plateau in long RR-1 intervals (> 0.5 sec). RR-2 had a weak negative association
      with Vpe. The mean squared correlation coefficient (r2) between RR-2 and Vpe was
      0.15 +/-0.13 and improved to 0.29+/-0.21 (p<0.001), when coordinates with RR-1 <
      or =0.5 sec were excluded. The RR-1 was positively associated with Vpe. The mean
      r2 between RR-1 and Vpe was 0.52+/-0.17 and improved to 0.72+/-0.11 (p<0.001),
      when adjusted by RR-2. Simple linear regression analysis showed that mean RR
      interval, age, fractional shortening (FS), and mean peak velocity were negatively
      correlated with modified r2 between RR-2 and Vpe. Multiple stepwise regression
      analysis revealed that mean RR interval (r2=0.32) and FS (r2=0.16) were
      significant. In summary, simple modification could improve the relationship of
      both RR-1 and RR-2 with cardiac performance. RR-2 might play a more role in
      cardiac performance than previously expected, and when cardiac function was
      impaired.

PMID- 12482994
TI  - In vitro activity of gemifloxacin against recent clinical isolates of bacteria in
      Korea.
AB  - Gemifloxacin is an enhanced-affinity fluoroquinolone with broad-spectrum
      antibacterial activity. In Korea, resistant bacteria are relatively more
      prevalent than in other industrialized countries. In this study, we studied the
      in vitro activities of gemifloxacin, gatifloxacin, moxifloxacin, levofloxacin,
      ciprofloxacin, and other commonly used antimicrobial agents against 1,689
      bacterial strains isolated at four Korean university hospitals during 1999-2000.
      Minimum inhibitory concentrations (MICs) were determined using the agar dilution
      method of National Committee for Clinical Laboratory Standards. Gemifloxacin had
      the lowest MICs for the respiratory pathogens: 90% of Streptococcus pneumoniae,
      Moraxella catarrhalis, and Haemophilus influenzae were inhibited by 0.06, 0.03,
      and 0.03 mg/L, respectively. Gemifloxacin was more active than the other
      fluoroquinolones against methicillin-susceptible Staphylococcus aureus, coagulase
      negative staphylococci, streptococci, and Enterococcus faecalis. The MIC90s of
      gemifloxacin for Klebsiella oxytoca, Proteus vulgaris, and non-typhoidal
      Salmonella spp. were 0.25, 1.0, and 0.12 mg/L, respectively, while those for
      other Gram-negative bacilli were 4-64 mg/L. In conclusion, gemifloxacin was the
      most active among the comparative agents against Gram-positive species, including
      respiratory pathogens isolated in Korea.

PMID- 12482997
TI  - Circulating IL-8 and IL-10 in euthyroid sick syndromes following bone marrow
      transplantation.
AB  - It is generally agreed that euthyroid sick syndromes (ESS) are associated with an
      increased production of cytokines. However, there has been scarce data on the
      relationship thyroid hormone changes and cytokines among the patients undergoing
      bone marrow transplantation (BMT). Because interleukin-8 (IL-8) has been
      identified as a potent proinflammatory and interleukin-10 (IL-10) as an
      antiinflammatory cytokine, we studied the relation between thyroid hormone
      parameters and these cytokines following BMT. We studied 80 patients undergoing
      allogeneic BMT. Serum T3 decreased to nadir at post-BMT 3 weeks. Serum T4 was the
      lowest at the post-BMT 3 months. Serum TSH sharply decreased to nadir at 1 week
      and gradually recovered. Serum free T4 significantly increased during 3 weeks and
      then returned to basal level. Mean levels of serum IL-8 significantly increased
      at 1 week after BMT. Mean levels of serum IL-10 significantly increased until 4
      weeks after BMT. No significant correlation was found between serum thyroid
      hormone parameters and cytokines (IL-8, IL-10) after adjusting steroid doses
      during the entire study period. In conclusion, ESS developed frequently following
      allogeneic BMT and cytokine levels were increased in post-BMT patients. However,
      no significant correlation was found between serum thyroid hormone parameters and
      these cytokines.

PMID- 12482996
TI  - The skeletal site-differential changes in bone mineral density following bone
      marrow transplantation: 3-year prospective study.
AB  - Loss of bone mass is usually detected after bone marrow transplantation (BMT)
      during the early post-transplant period. However, little is known about the long
      term effects of BMT on bone metabolism. We have prospectively investigated 11
      patients undergoing BMT. Bone mineral density (BMD) was measured before BMT, and
      1, 2, and 3 yr after BMT. Serum markers of bone turnover were serially measured
      before BMT and 1, 2, 3, 4, and 12 weeks, 6 months, and 1 yr after BMT. The mean
      change in the lumbar spine (L2-4) BMD, calculated as the percent change from the
      baseline to the level at 1, 2, and 3 yr was -4.7% (NS), -1.1% (NS), and +6.4%
      (p<0.05), respectively. The mean change in the total proximal femur BMD from the
      baseline to the level at 1, 2, and 3 yr was -8.5% (p<0.01), -8.7% (p<0.05) and 
      5.6% (p<0.05), respectively. In summary, there was little decline in lumbar BMD
      at 1 yr following BMT and gradual recovery until 3 yr. In contrast, femoral BMD
      decreased much more than the lumbar area at 1 yr and did not recover until 3 yr.
      The mechanism of skeletal site-selective differences in the changes of BMD needs
      to be elucidated.

PMID- 12482998
TI  - Nasal eosinophilic inflammation contributes to bronchial hyperresponsiveness in
      patients with allergic rhinitis.
AB  - There are increasing evidences that allergic rhinitis (AR) may influence the
      clinical course of asthma. We conducted methacholine challenge test and nasal
      eosinophils on nasal smear to patients with allergic rhinitis in order to
      investigate the mechanism of connecting upper and lower airway inflammation in 35
      patients with AR during exacerbation. The methacholine concentration causing a
      20% fall in FEV1 (PC20) was used as thresholds of bronchial hyperresponsiveness
      (BHR). Thresholds of 25 mg/dL or less were assumed to indicate BHR. All patients
      had normal pulmonary function. Significant differences in BHR were detected in
      the comparison of patients with cough or postnasal drip and without cough or
      postnasal drip. There were significant differences of PC20 between patients with
      cough or postnasal drip and those without cough or postnasal drip (3.41+/-3.59
      mg/mL vs 10.2+/-1.2 mg/mL, p=0.001). The levels of total IgE were higher in
      patients with seasonal AR than in patients with perennial AR with exacerbation
      (472.5+/-132.5 IU/L vs. 389.0+/-70.9 IU/L, p<0.05). Nasal eosinophils were
      closely related to log PC20 (r=-0.65, p<0.01). These findings demonstrated that
      nasal eosinophilic inflammation might contribute to BHR in patients with AR.

PMID- 12482999
TI  - Interleukin-1beta induces MUC2 gene expression and mucin secretion via activation
      of PKC-MEK/ERK, and PI3K in human airway epithelial cells.
AB  - Interleukin 1beta(IL-1beta), a proinflammatory cytokine, is related with
      inflammatory diseases and it up-regulates MUC2 gene expression and mucin
      secretion. This study was designed to investigate the signal transduction pathway
      of the IL-1beta-mediated MUC2 gene expression and mucin secretion in human airway
      epithelial cells. In cultured human airway NCI-H292 epithelial cells, the steady
      state of the mRNA level of MUC2 gene expression and mucin secretion induced by IL
      1beta were determined by reverse transcriptase-polymerase chain reaction (RT
      PCR), enzyme immunoassay, and immunoblot analysis. To observe the signal pathway
      of the IL-1beta-mediated MUC2 gene expression and mucin secretion, we used
      several specific inhibitors. PD98059 (MEK/ERK inhibitor) suppressed IL-1beta
      mediated MUC2 gene expression and mucin secretion, while SB203580 (p38 inhibitor)
      did not. Ro31-8220 (PKC inhibitor) inhibited IL-1beta-mediated MUC2 gene
      expression and mucin secretion. It inhibited ERK phosphorylation, but did not
      inhibit p38 phosphorylation. LY294002 (PI3K inhibitor) also suppressed MUC2
      expression, but did not inhibit any MAPKs phosphorylation. These results suggest
      that the IL-1beta-mediated MUC2 gene expression and mucin secretion in NCI-H292
      cells are regulated through activation of the PKC-MEK/ERK pathway, and that PI3K
      is also involved in the IL-1beta-mediated MUC2 gene expression and mucin
      secretion.

PMID- 12483000
TI  - Prognostic factors of the long-term survival after transjugular intrahepatic
      portosystemic shunt in the treatment of gastric and esophageal variceal bleeding.
AB  - Transjugular intrahepatic portosystemic shunt (TIPSS) is a promising method of
      treatment for gastric or esophageal variceal bleeding. This study was performed
      to determine the prognostic factors contributing to the survival of patients
      after TIPSS for gastric or esophageal variceal bleeding. One hundred and fifty
      five patients who underwent TIPSS between September 1991 and March 2001 were
      followed up by clinical examination, upper gastrointestinal endoscopy, and Duplex
      sonography. The mean portohepatic pressure gradient prior to TIPSS was 20.5+/
      9.93 mmHg and dropped to 10.7+/-6.62 mmHg after TIPSS (p<0.001). The cumulative
      survival rate was 75.1% at 6 months, 66.6% at 1 yr, 58.4% at 2 yr, and 38.1% at 5
      yr. Survival after TIPSS was inversely related to the Child-Pugh classification
      (p<0.05). The rebleeding rate was 18.3% at 6 months, 21.0% at 1 yr, 32.8% at 2
      yr, and 53.1% at 5 yr. The causes of deaths were hepatic failure (53.5%),
      recurrent variceal bleeding (11.6%), pneumonia (4.6%), sepsis (3.5%), hepatic
      encephalopathy (2.3%), and unknown (17.4%). Multivariate analysis (Cox
      proportional hazard model) revealed that the Child-Pugh classification and age
      were statistically significant independent prognostic factors. In conclusion,
      TIPSS is an effective method of treatment for variceal bleeding in cases where
      other treatment modalities including endoscopic therapy are unsuccessful and the
      most important prognostic factors are preprocedural hepatic reserve (Child-Pugh
      class) and age.

PMID- 12483001
TI  - Glutamine on the luminal microbial environment after massive small bowel
      resection.
AB  - To evaluate the oral glutamine (GLN) on the luminal microbes and bacterial
      translocation (BT) in short bowel, 45 Wistar rats were utilized in three groups;
      A (control), and B and C (short bowel, 85% of small bowel resected). The group A
      was fed with elemental diet (EmD), B with EmD+2% glycine, and C with EmD+2% GLN.
      The groups B and C were isocaloric and isonitrogenous. Wet weight, DNA, protein,
      and histomorphometry of the mucosa and parallel microbial culture from cecal
      contents, caval blood, and tissue blocks of the liver, spleen, and mesenteric
      lymph nodes were performed on the 5th, 10th, and 15th day. Mucosal growth was
      higher in group C than B. Colony forming units (CFU) from cecal contents
      increased more in group B than in C. BTs in A, B, and C were 7/15, 8/15, and
      2/15, respectively. Total CFUs in blood and tissues were 5.8 X 10(4)/g, 5.5 X
      10(6)/g, and 1.8 X 10(4)/g, respectively. As for BT, the most frequent organism
      was Klebsiella in A (79.3%), but E. coli in B and C (94.2% and 55.6%). GLN seems
      to suppress luminal microbes, and reduces BT in short bowel due to enforced
      barrier function and proliferation of the mucosa.

PMID- 12483002
TI  - The clinical features of Behcet's disease in Yongdong districts: analysis of a
      cohort followed from 1997 to 2001.
AB  - This study was undertaken to evaluate the clinical features of a cohort of
      Behcet's disease (BD) followed up from January 1997 to July 2001 in Yongdong
      districts in Korea, and to compare the results with the literature. Overall
      features of clinical manifestations were similar to those described in the
      literature. However, the frequency of gastrointestinal (GI) ulcerations was much
      higher than those of other Korean studies. The Korean studies including ours
      revealed a lower frequency of vascular lesions and epididymitis compared with
      studies of other countries. The most common site and pattern of inflammatory
      arthritis were knees and monoarticular involvement, respectively. In addition, in
      most patients, the ocular lesions involved the posterior uveal tract, and the
      terminal ileum and cecum were the most common sites of GI involvement. Patients
      with ocular lesions or GI lesions showed a good prognosis during the follow-up.
      The HLA-B51 antigen was positive in 50.7% of patients, and it was more commonly
      found in patients with a familial BD.

PMID- 12483003
TI  - Analysis of depression in continuous ambulatory peritoneal dialysis patients.
AB  - It is well known that depression and sense of hopelessness worsen the quality of
      life in end-stage renal disease (ESRD) patients receiving dialysis. However, the
      characteristics of depression in continuous ambulatory peritoneal dialysis (CAPD)
      patients have not been analyzed in detail. We performed this study to investigate
      the severity of depression and the factors affecting depression in CAPD patients.
      With 96 CAPD patients, we evaluated each patient's depressive mood and
      hopelessness with CES-D (Center for Epidemiologic Studies Depression) scale and
      Beck Hopelessness Scale. We also evaluated the degree of stress of each patient
      with internal individual stress scale. Most CAPD patients experienced severe
      depression compared with the general population. Their depression was better
      explained by psychological factors, such as stress and sense of hopelessness,
      than by demographic or physical factors. On the basis of these findings, we
      suggest that the treatment of depression in CAPD patients might be possible by
      modulation of psychological factors.

PMID- 12483004
TI  - Increased microfilaments in hepatocytes and biliary ductular cells in cholestatic
      liver diseases.
AB  - To assess the extent of microfilaments in cholestatic liver diseases we examined
      the cytoplasmic microfilaments in intrahepatic and extrahepatic cholestasis in
      man by electron microscopy. Study subjects were two patients with drug-induced
      intrahepatic cholestasis, three patients with intrahepatic cholestasis due to
      viral hepatitis, four patients with extrahepatic cholestasis due to stones of the
      common bile duct and two patients with primary biliary cirrhosis. Two biopsied
      specimens from patients without clinical or histological evidence of liver
      disease served as noncholestatic controls. The microfilaments in hepatocytes and
      biliary ductular cells were significantly increased in cholestasis compared with
      those in non-cholestatic controls. Well developed bundles of microfilaments were
      noted around the pericanalicular ectoplasm and seemed to be parallel to plasma
      membrane of the hepatocytes in cholestasis. In cholestasis, there were increased
      bundles of microfilaments around the periluminal region, lateral cell wall, and
      nucleus of biliary ductular cells. Two patterns of microfilaments bundles (fine
      microfilamentous network and spindle-shaped dense or clusters of microfilaments)
      were associated with cholestasis. The clustered form of microfilaments also
      seemed to be clearly associated with intracytoplasmic vacuoles containing bile
      salts. In conclusion, the increase of microfilaments in hepatocytes and biliary
      ductular cells may be the consequence of various forms of cholestasis. Further
      studies are needed to clarify the functional significance of increased
      microfilaments in cholestasis.

PMID- 12483005
TI  - Correlation of mutation and immunohistochemistry of p53 in hepatocellular
      carcinomas in Korean people.
AB  - The degree of correlation between sequencing and immunohistochemisty (IHC) for
      detecting mutations of p53 has not been well established in human hepatocellular
      carcinoma (HCC). We analyzed 36 HCCs from Korean people for p53 mutation at exons
      4-10 by PCR-SSCP and sequencing, and compared the results with the IHC
      positivity. p53 mutations were identified in 7 out of 36 HCCs (19.4%). These
      mutations were found widely throughout exons 4-8. No mutation was detected in
      codon 249. Among the 7 mutations, 6 missense mutations were detected in 15 HCCs
      with > or =5% immunoreactive tumor cells and one nonsense mutation was in 21 HCCs
      with <5% immunoreactive tumor cells. The sensitivity for p53 mutation was 85.7%
      (6/7), the specificity 69.0% (20/29), the predictive value of positive IHC 40.0%
      (6/15), and the predictive value of negative IHC 95.2% (20/21). Two missense
      mutations were detected in 25 cases with <10% immunoreactive tumor cells.
      Predictive values of both positive IHC and negative IHC were higher in > or =5%
      overexpression group than in > or =10% overexpression group or >0% overexpression
      group. This study suggests that 5% immunoreactivity is a reliable
      immunohistochemical threshold value to detect p53 mutations in HCCs and the
      spectrum of p53 mutations in HCCs in Korean people is different from that of high
      aflatoxin B1 exposure areas.

PMID- 12483006
TI  - Osteonecrosis of the hip in patients with aplastic anemia.
AB  - The incidence and clinical and magnetic resonance imaging features of
      osteonecrosis of the hip were evaluated in patients with aplastic anemia. Two
      hundred and forty-one patients with aplastic anemia were examined using MR
      imaging of bone marrow during the five years from 1994 to 1998. Osteonecrosis of
      the hip was observed on MR imaging in nineteen (15 males and 4 females, mean age
      35 yr) of the 241 patients. It was present in both hips in 14 patients, and there
      were five cases with unilateral occurrence, with a total of 33 involved hips. All
      except for five hips with associated bone marrow edema revealed increased fatty
      marrow conversion in the proximal femoral metaphysis. In nine patients,
      osteonecrosis was detected without any pain. Five patients already had
      osteonecrosis before any medication was administered. Twelve patients received
      antilymphocyte globulin, and seven patients received a low dose of steroids
      before the MR diagnosis of osteonecrosis. Osteonecrosis of the hip frequently
      develops in patients with aplastic anemia (7.9%), associated with fatty marrow
      conversion of the proximal femoral metaphysis.

PMID- 12483007
TI  - Surface expression of P-selectin on platelets is related with clinical worsening
      in acute ischemic stroke.
AB  - Platelet activation has a critical role in arterial disorders. In this study, we
      showed that the upregulation of P-selectin expression on platelets was related
      with clinical worsening in acute ischemic stroke. We serially (within 24 hr, at
      72 hr, and 7 days) measured the expression of P-selectin on platelets in patients
      with acute ischemic stroke (n=45) and investigated the correlation between their
      extents and clinical severity of ischemic stroke. A significant relationship
      between the P-selectin expressions and National Institute of Health Stroke Scale
      (NIHSS) was observed at 72 hr and 7 days after ischemic stroke onset. Patients
      with clinical deterioration showed significantly increased expression of P
      selectin on platelets as compared to those without deterioration. These results
      suggest that the P-selectin expression on platelets may contribute to the
      aggravation of clinical course in acute ischemic stroke. Thus, adequate
      manipulation of activated platelets is an important therapeutic strategy in acute
      ischemic stroke.

PMID- 12483008
TI  - Chemoreduction followed by local therapy and adjuvant chemotherapy for advanced
      intraocular retinoblastoma: a pilot study in a single center.
AB  - Intraocular (IO) retinoblastoma (RB) has traditionally been treated with
      enucleation (ENU) or external beam radiotherapy (EBRT). Recently, clinical trials
      are in progress to cure RB without ENU or EBRT in order to salvage the globe and
      to avoid unacceptable side effects of EBRT. We performed a pilot study to treat
      patients with advanced Reese-Ellsworth (RE) stage IO RB with initial chemotherapy
      (CRx) followed by local therapy (LT) and adjuvant CRx. Ten eyes (8 RE group V, 2
      RE group IV) from 9 patients were enrolled from March 2001 to November 2001. All
      tumors responded to CRx. In 5 of 10 eyes, the RB was enough to be treated with LT
      after chemoreduction. One patient who underwent LT is waiting for ENU due to post
      cryotherapy complication. For a median follow-up of 13 months (8-16 mo), 4 eyes
      that received LT and adjuvant CRx were relapse-free. A patient with bilateral RB
      who failed to be a candidate for LT was rescued with high-dose CRx and
      hematopoietic stem cell transplantation. Consequently, by treating patients
      according to our strategy, we were able to salvage 6 out of 10 eyes without ENU
      or EBRT. These results suggest that chemoreduction followed by LT and adjuvant
      CRx might offer the opportunity to salvage the globe and vision even in patients
      with advanced stage IO RB.

PMID- 12483009
TI  - Parallel technique of endobronchial balloon catheter tamponade for transient
      alleviation of massive hemoptysis.
AB  - Endobronchial balloon tamponade is an alternative method that can be used to
      control massive hemoptysis. Several different techniques have been used for this
      purpose. We describe a new parallel method, in which biopsy forceps introduced
      through a bronchoscope channel is used to grasp a balloon catheter. As the
      bronchoscope is advanced to the bleeding site, the balloon catheter is pulled
      into position, and subsequently inflated. There are several advantages of this
      technique. It needs no specialized catheter or guide wire, the procedure is
      relatively easy to perform, and applicable to other purposes such as introduction
      of an additional suction catheter.

PMID- 12483010
TI  - Chylothorax in Gorham's disease.
AB  - A 25-yr-old woman presented with a right pleural effusion. Destruction of 9th
      through 12th ribs, adjacent vertebral bodies, and transverse processes was noted
      on plain radiograph and a large low-attenuated, irregular shaped mass lesion with
      peripheral rim enhancement, destroying vertebral body and transverse process, was
      revealed on the computed tomographic scan. Magnetic resonance imaging showed high
      signal on T1- weighted image and iso- and low signal on T2-weighted image for the
      mass lesion replacing the vertebral bony cortex and marrow space. An open rib
      biopsy revealed the histopathological changes of Gorham's disease (essential
      osteolysis), even though only bloody fluid filling the empty space and rib and
      vertebral transverse process destruction were grossly observed on operation. Even
      though there was no definite response to radiotherapy and pleurodesis, the
      patient showed stable condition up to 20 months after diagnosis.

PMID- 12483011
TI  - Oropharyngeal angioedema induced by inhaled histamine.
AB  - Inhaled histamine used to measure airway responsiveness produces some side
      effects more frequently than does methacholine. It is possible that the inhaled
      histamine induces the side effects in asthmatics with increased end organ
      responsiveness to histamine. A 56-yr-old woman with chronic idiopathic angioedema
      presented with asthma-like symptoms. Methacholine challenge test was performed,
      with a negative result. Five days later, histamine inhalation test was done. FEV1
      fell by 37% after inhalation of histamine concentration of 8 mg/mL. Immediately
      thereafter, severe angioedema on face, lips, and oropharyngeal area, foreign body
      sensation at throat, and hoarseness occurred. To assess end organ responsiveness
      to histamine, skin prick tests with doubling concentrations of histamine (0.03-16
      mg/mL) were carried out on the forearm of the patient and six age- and sex
      matched asthmatic controls. The wheal areas were measured. The patient showed
      greater skin responses than the controls. Regression analysis showed that the
      intercept and slope were greater than cut-off levels determined from six
      controls. The patient showed an increased skin wheal response to histamine,
      indicating the enhanced end organ responsiveness to histamine, which is likely to
      contribute to the development of the oropharyngeal angioedema by inhaled
      histamine.

PMID- 12483012
TI  - CD4+CD56+CD68+hematopoietic tumor of probable plasmacytoid monocyte derivation
      with weak expression of cytoplasmic CD3.
AB  - Hematopoietic neoplasm coexpressing CD4 and CD56 includes a subset of acute
      myeloid leukemia with myelomonocytic differentiation, plasmacytoid monocyte
      tumor, and other immature hematopoietic neoplasms of undefined origin. Herein, we
      report a CD4+CD56+CD68+ hematopoietic tumor that was thought to be a tumor of
      plasmacytoid monocytes. This case is unique in the absence of accompanying
      myelomonocytic leukemia and the faint expression of cCD3 on the tumor cells. The
      patient was a 22-yr old man presented with multiple lymphadenopathy and an
      involvement of the bone marrow. Tumor cells were large and monomorphic with an
      angulated eosinophilic cytoplasm of moderate amount. Nuclei of most tumor cells
      were eccentric and round with one or two prominent nucleoli. Rough endoplasmic
      reticulum was prominent in electron microscopic examination. Tumor cells
      expressed CD4, CD7, CD10, CD45RB, CD56, CD68, and HLA-DR and were negative for
      CD1a, CD2, sCD3, CD5, CD13, CD14, CD20, CD33, CD34, CD43, CD45RA, TIA-1, S-100,
      and TdT. cCD3 was not detected in the immunostaining using paraffin tissue, but
      was faintly expressed in flow cytometry and immunostaining using a touch imprint
      slide. T-cell receptor gene rearrangement analysis and EBV in situ hybridization
      showed negative results. Cytochemically, myeloperoxidase, Sudan black B, and
      alpha naphthyl butyrate esterase were all negative.

PMID- 12483013
TI  - Cotyledonoid dissecting leiomyoma of the uterus: a case report and review of the
      literature.
AB  - "Cotyledonoid dissecting leiomyoma" or "Sternberg tumor" is a very rare variant
      of smooth muscle tumors with a distinctive gross appearance. We describe a
      similar lesion, probably the sixth reported case, comparing its
      clinicopathological features with those of previous cases. A 26-yr-old
      nulliparous woman underwent laparotomy for a large pelvic mass replacing the
      postero-lateral aspect of the uterus with extension into the left pelvic cavity
      in the form of numerous exophytic congested small nodules. The tumor was removed
      by resection without hysterectomy after frozen section examination.
      Histologically, there were variable sized micronodules of benign smooth muscle
      fascicles, which were separated by fibrous connective tissue with a marked
      hydropic change and rich vascularity. Immunohistochemical and ultrastructural
      studies were helpful for confirmation of the smooth muscle nature, but not useful
      for the definitive diagnosis. Due to bizarre, sarcoma-like gross appearances,
      this type of lesion should be subjected to frozen section examination in order to
      avoid overtreatment and preserve the fertility in young women.

PMID- 12483014
TI  - Mixed tumor of the vagina: a case report.
AB  - We report a case of mixed tumor arising in the lower vaginal wall. The patient
      was a 20-yr-old nullipararous woman. The tumor was relatively well-defined with
      expansile margin, and showed solid sheets or fascicles of stromal-type spindle
      cells and ovoid epithelial cells with sparsely scattered nests of mature squamous
      epithelium and glands lined by mucinous epithelium. Cellular atypia was not
      conspicuous, however, mitosis was counted upto 6 per 10 high power fields. We
      examined this tumor immunohistochemically and ultrastructurally and reviewed the
      articles to identify the histogenesis. Positive reaction for vimenin and
      cytokeratin of stromaltype spindle cells and presence of desmosome-like
      structures and tonofilaments on electron microscopic examination suggested the
      epithelial origin of the stromaltype spindle cells.

PMID- 12483015
TI  - Giant cell tumor originating from the anterior arc of the rib.
AB  - We report a case of giant cell tumor originating from the anterior arc of the
      rib. The tumor and the surrounding chest wall were completely resected, and the
      chest wall defect was covered with Marlex mesh. Giant cell tumor of the bone
      usually originates from the epiphysis of long bones. Even when the tumor occur in
      ribs, it usually occur in the posterior aspect. However, giant cell tumor should
      be included in the differential diagnosis of a tumor originating from the
      anterior arc of the ribs.

PMID- 12483016
TI  - Adult-onset Still's disease with vesiculopustules on the hands and feet.
AB  - Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of
      unknown etiology characterized by an evanescent rash, intermittent spiking high
      fever, arthralgia, and a variety of systemic features. We describe a 46-yr-old
      woman with Still  s disease who presented with a 2-month history of a symmetrical
      vesiculopustular eruptions only on both hands and feet. Skin biopsy specimens of
      both vesicle and pustule revealed fibrin thrombi deposition in the small dermal
      vessels with little inflammation, subepidermal bulla, and ischemic necrosis of
      the overlying epidermis, which were consistent with a vasculopathic reaction. Her
      skin lesions gradually disappeared in response to conventional AOSD therapy, as
      elevated serum ferritin levels, an index of disease activity, decreased. To the
      best of our knowledge, this is the first case of vesiculopustular lesions as a
      skin manifestation of AOSD.

PMID- 12483017
TI  - A Korean family with Arg1448Cys mutation of SCN4A channel causing paramyotonia
      congenita: electrophysiologic, histopathologic, and molecular genetic studies.
AB  - A family with paramyotonia congenita (PC) is presented. At least 10 family
      members were affected in an autosomal dominant inheritance pattern. The proband
      had cold-sensitive muscle stiffness, paradoxical myotonia, and intermittent
      muscle weakness since childhood. The serum level of creatine kinase was mildly
      elevated and short exercise test with cooling revealed a drastic reduction of
      compound muscle action potentials with repetitive discharges. Muscle biopsy
      revealed marked variation in the fiber size and increased internal nuclei. The
      molecular biological study revealed a common missense mutation (Arg1448Cys) at
      the voltage-gated sodium channel gene (SCN4A). The repetitive CMAP discharges
      during short exercise test with cooling observed in the proband has not been
      reported previously. This observation needs to be confirmed among PC patients
      with different mutations. This is the first report on a PC family confirmed by
      the molecular biological technique in Korea.

PMID- 12483018
TI  - Globus pallidus lesions associated with high mountain climbing.
AB  - Acute mountain sickness (AMS) occurs commonly in hikers who are rapidly exposed
      to high altitude environments. Despite the numerous reports of AMS, few studies
      have reported pallidal lesions associated with altitude sickness. A previously
      healthy 49-yr-old Korean patient, after ascent to 4,700 m, suffered symptoms
      consistent with AMS. After returning home, the patient showed changes in
      personality characterized by abulia, indifference, and indecisiveness. T2
      weighted brain magnetic resonance imaging showed high signal lesions involving
      bilateral globus pallidus. Our case suggests that globus pallidus injury should
      be included in the differential diagnosis of patients with personality or
      cognitive change after recovery from AMS.

PMID- 12483019
TI  - Protective action of nipradilol against ischemia-induced retinal damage in rats.
AB  - The purpose of this study was to investigate whether nipradilol, a beta-blocker
      having both vasodilating and alpha(1)-blocking activities, can protect retinal
      cells from the injury induced by ischemia and reperfusion. Rats were anesthetized
      and, after an intravitreal injection of nipradilol, the intraocular pressure was
      raised for 45 min to induce retinal ischemia and reperfusion. Before, and 3 and 7
      days after the ischemia, electroretinograms were recorded. After the ischemia,
      the mean amplitude of the b-waves in rats receiving 5 microl of 1.0 x 10(-6) M
      nipradilol was significantly larger than of controls (injected with phosphate
      buffered saline). Histologically, the reduction in the number of retinal ganglion
      cells (1.0 x 10(-6) M), and the thickness of the inner and outer plexiform layers
      and the inner nuclear layer (1.0 x 10(-6), 10(-7) and 10(-8) M) was suppressed by
      nipradilol. These results indicate that nipradilol protected the retina against
      retinal ischemia and reperfusion and should be considered for therapeutic use in
      cases of transient retinal ischemia.

PMID- 12483020
TI  - Effects of hypoxia on retinal pigmented epithelium cells: protection by
      antioxidants.
AB  - Age-related macular degeneration and other eye diseases, such as diabetic
      retinopathy, are probably linked to the effects of oxygen radicals derived from
      light or metabolic reactions. We have investigated the effects of hypoxia on
      bovine retinal pigmented epithelial cells (RPE) and the response of these cells
      to two antioxidants that have previously shown a beneficial action against free
      radical-linked senescent involution. The main results of the study were as
      follows: (i) Hypoxia induced apoptotic damage on RPE cells, with LDH leakage and
      ATP reduction; (ii) both vitamin C (VC) and N-acetyl-cysteine (NAC) treatment
      protected against hypoxia-induced apoptosis, with less DNA fragmentation. In our
      opinion, these findings justify further experimental and clinical work to
      investigate the role of hypoxia in the mechanisms of age-related RPE injury and
      death as well as the potential of antioxidant administration to prevent or delay
      retinal degenerative processes caused by oxygen-dependent pathophysiological
      conditions.

PMID- 12483021
TI  - Identification of inwardly rectifying potassium channels in bovine retinal and
      choroidal endothelial cells.
AB  - Ion channels were studied using the whole-cell patch clamp technique in bovine
      retinal and choroidal microvascular endothelial cells (MVEC) cultured under the
      same conditions. The two types of MVEC expressed inward currents at
      hyperpolarizing voltage steps and showed small outward currents at depolarizing
      steps. The extrapolated reversal potentials of the inward currents were near to
      the potassium equilibrium potential. Cs(+) and the K(+) channel blocker TEA
      reduced the amplitudes of the currents indicating the selectivity and
      permeability for potassium. This was confirmed by changes of outside K(+)
      concentration shifting the I-V curves to the right. RT-PCR studies revealed the
      presence of mRNA of Kir2.1, an inwardly rectifying K(+) channel, in retinal and
      choroidal MVEC. The profile of the small outward currents is related to the Kv
      family but not identical with the Kv1.4 subtype.

PMID- 12483022
TI  - The efficacy of intravitreal levofloxacin and intravitreal dexamethasone in
      experimental Staphylococcus epidermidis endophthalmitis.
AB  - This study was designed to investigate the efficacy of intravitreal levofloxacin,
      and intravitreal levofloxacin and dexamethasone combined in Staphylococcus
      epidermidis endophthalmitis. Albino rabbits (n = 25), infected with an
      intravitreal inoculum of S. epidermidis (1.0 x 10(5) colony forming units/0.1
      ml), were divided into five groups (n = 5). Groups 1 and 2 received treatment 24
      h after the inoculation, and groups 3 and 4 48 h after the inoculation. No
      treatment was given to the control group. Treatment efficacy was assessed by
      vitreous culture, clinical examination and histopathology. Five days after
      treatment, groups 1 and 2 had significantly lower clinical scores than the
      control group (p = 0.004, p = 0.007). The culture results of the treatment groups
      were sterile. The histopathological scores of the treatment groups were lower
      than the control group (p = 0.007). Studies on retinal toxicity and dose-response
      relation are needed to prove the efficacy of levofloxacin in S. epidermidis
      endophthalmitis.

PMID- 12483023
TI  - Changes in gene expression of ARPE-19 cells in response to vitreous treatment.
AB  - PURPOSES: The purpose of this study is to determine the changes in gene
      expression by a human retinal pigment epithelium (RPE) cell line (ARPE-19) in
      response to vitreous treatment, which induces RPE proliferation and phenotypic
      changes in vitro that mimic the repair response observed in vivo during
      proliferative vitreoretinopathy. METHODS: ARPE-19 cells were grown for more than
      4 weeks and their gene expression studied in: (1) subconfluent cultures treated
      with 50% human vitreous for 72 h; (2) subconfluent cultures without vitreous
      treatment, and (3) a confluent, nondividing monolayer. Total RNA was extracted
      from RPE cells and differential gene expression between each condition was
      determined using gene arrays (Clontech, Palo Alto, Calif., USA). Semiquantitative
      RT-PCR was used to confirm the upregulation of 4 genes related to vitreous
      treatment. In addition, the secretion of 1 of these upregulated gene products,
      monocyte chemotactic protein 1 (MCP-1), was confirmed by ELISA. RESULTS: A
      greater than threefold increase in the expression of mRNA for cell cycle
      regulators, intracellular transducers, cell adhesion proteins, growth factors and
      chemokines was observed following vitreous treatment of the RPE cell line and a
      corresponding decrease in the expression of genes related to apoptosis. RT-PCR
      confirmed the increased gene expression of MCP-1, intercellular adhesion molecule
      1, vascular cell adhesion protein 1 precursor and vascular endothelial growth
      factor in vitreous-treated cells. Immunoassays further showed an increased MCP-1
      secretion by vitreous-treated RPE. CONCLUSIONS: These findings suggest that in
      this in vitro vitreous treatment model, ARPE-19 cells participate in a mock
      repair response by upregulating genes encoding for proteins associated with
      inflammation and wound healing.

PMID- 12483024
TI  - Comparison of free amino acids in aqueous humor of farmed and wild salmon and of
      six species additionally.
AB  - OBJECTIVE: A comparative study was performed in order to identify aqueous humor
      amino acids possibly involved in cataract formation in farmed Atlantic salmon.
      METHODS: Aqueous humor amino acids from farmed salmons with and without cataract
      were compared with levels in wild salmon and other animals of different
      evolutionary levels such as frog, crocodile, turkey, goose, minke whale, and
      cattle. Serum samples from wild and farmed salmon and minke whale were also
      analyzed. RESULTS: The total amino acid concentration was lower in aqueous humor
      obtained from salmon, frog and crocodile compared to birds and mammals. Wild
      salmon had a higher content of amino acids than farmed salmon. Asparagine was
      absent in salmon aqueous humor and serum. Aqueous humor proline was readily
      detectable in wild salmon, birds, whale, and cattle, but not detectable in farmed
      salmon, frog and crocodile. The aqueous humor concentration of taurine was about
      seven- and fifty-fold lower compared to serum in wild and farmed salmon,
      respectively. The corresponding ratio in minke whale was 1:2. CONCLUSIONS: The
      results indicate a blood- aqueous barrier for taurine in farmed salmon. The lower
      total amino acid concentration and low aqueous humor proline concentration in
      farmed salmon should be further investigated.

PMID- 12483025
TI  - Novel noninvasive sensitive determination of tear volume changes in normal cats.
AB  - We describe a novel, high-resolution and noninvasive method for measuring tear
      volume changes in cats. The method entails photographing at the lid margin the
      tear meniscus area defined by instillation of 0.1% fluorescein solution into the
      cul-de-sac. The inferior tear meniscus area was obtained from the digitized
      images with computer-assisted software. The tear meniscus area increased in
      proportion to the saline volume applied into the conjunctival sac, which
      validates the technique. Furthermore, this technique detected with high
      sensitivity previously described increases in tear fluid secretion induced by the
      P2Y(2) agonist. We demonstrate in cats that changes in conjunctival sac tear
      volume can be evaluated by measurement of its inferior tear meniscus area.

PMID- 12483026
TI  - A feasible tool to detect mRNA expression of matrix metalloproteinases and their
      tissue inhibitors in human Tenon's capsule.
AB  - PURPOSE: To determine the mRNA expression of matrix metalloproteinases (MMPs) and
      tissue inhibitors of metalloproteinases (TIMPs) in human specimens of Tenon's
      capsule. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) with
      specific primers for MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 was performed on
      tissue specimens obtained from patients with cataract, rhegmatogenous retinal
      detachment, glaucoma, or diabetes mellitus. RESULTS: Glyceraldehyde phosphate
      dehydrogenase (GAPDH) mRNA transcripts were detected in 26 (76.5%) of 34
      specimens, with almost the same amount of expression in each of these samples.
      Messenger RNA expression of one or more of the MMPs/TIMPs could also be detected
      in all of these 26 samples, but not in any sample without GAPDH expression. MMP
      2, TIMP-1 and TIMP-2 were detected in 25 (96.2%) of the 26 samples with GAPDH
      expression, while MMP-1 and MMP-9 were detected with a lower percentage (34.6 and
      19.2%, respectively). CONCLUSION: The feasibility of RT- PCR with GAPDH as an
      internal standard to determine mRNA transcripts of the MMPs and TIMPs in the
      subconjunctival Tenon's capsule was demonstrated.

PMID- 12483027
TI  - Quantification of simulated corneal haze by measuring back-scattered light.
AB  - The Scheimpflug anterior eye segment analysis system EAS-1000 was modified to
      specifically quantitate the degree of corneal haze. In order to confirm the basic
      measurement performance of the new system, TSPC-3 hazemeter, in vitro experiments
      were conducted. Using white latex microsphere solutions, tests were performed for
      the linearity of the measurements, the influence of slit lamp illuminance and the
      influence of the length of the light path through the latex solution. The
      validity of Beer's law was confirmed, indicating that a sufficiently wide range
      of latex concentrations (haze intensities) can be covered by the hazemeter. The
      scattering intensity measured with the hazemeter showed a significant linear
      correlation with the latex concentration. The obtained scattering intensity was
      directly proportional to the illuminance of the slit lamp. The ratio of
      integrated scattering values was proportional to that of the light path length.
      It was shown that the TSPC-3 hazemeter possesses sufficient capability for a
      quantitative evaluation of corneal haze.

PMID- 12483028
TI  - On the age-related prevalence of anisometropia.
AB  - Data on the prevalence of non-amblyopic anisometropia amongst adults throughout
      the world were tabulated and plotted as a function of age. The global picture
      reveals a systematic rise in the prevalence of anisometropia with age, the fitted
      linear regression having a significant positive slope of 1% (p < 0.0005) for
      every 7 years. The distribution may embrace a juvenile rise and a later, post
      presbyopic one, perhaps due to neuro-senescence.

PMID- 12483029
TI  - Nonlinear component of the electroretinogram recorded from the posterior pole of
      normal and highly myopic human eyes.
AB  - To extract the nonlinear component of the electroretinogram (ERG) from the
      posterior pole (pp) of the human ocular fundus and to evaluate the possibility of
      its clinical application, three types of stimulus modes - double-flash, single
      flash, and delayed single-flash stimuli - were produced using a conventional
      electrophysiological system. A large hexagonal element was presented on a CRT
      monitor, and ppERGs were recorded from 14 normal eyes and 16 eyes of eight highly
      myopic patients. The nonlinear component of the ppERG was obtained by subtracting
      the single-flash ERG and delayed single-flash ERG responses from the double flash
      ERG response. Three peaks were commonly observed in the nonlinear component of
      ppERG, all of which were significantly depressed in patients with high myopia.
      ppERGs that can be obtained using a simple algorithm might be useful in clinical
      applications.

PMID- 12483031
TI  - The role of IL-10 and TGF-beta in the differentiation and effector function of T
      regulatory cells.
AB  - Suppression by T regulatory (Tr) cells is essential for the induction of
      peripheral tolerance. Many types of CD4+ Tr cells have been described in a number
      of systems, and although the precise mechanisms which mediate their effects
      remain to be defined, it is well established that they can suppress immune
      responses via cell-cell interactions and/or the production of interleukin-10 (IL
      10) and transforming growth factor-beta (TGF-beta). Type 1 T regulatory (Tr1)
      cells are defined by their ability to produce high levels of IL-10 and TGF-beta,
      and these cytokines mediate their ability to suppress pathological immune
      responses in the settings of transplantation, allergy and autoimmune disease. Tr1
      cell activity is not necessarily beneficial, and they can also suppress immune
      responses to antigens from tumours and pathogens. In vivo, the differentiation of
      Tr1 cells is likely controlled by certain dendritic cells which promote IL-10
      production and may express tolerogenic costimulatory molecules. Another subset of
      CD4+ Tr cells is defined by constitutive expression of CD25, and although these
      CD4+CD25+ Tr cells appear to suppress via mechanisms which are largely
      independent of cytokines, they may actively promote the differentiation of Tr1
      cells. Many questions about the basic biology of Tr1 cells remain to be answered,
      but the development of therapeutic strategies designed to harness their
      immunoregulatory effects can already be contemplated.

PMID- 12483032
TI  - The immune response to intrinsic and extrinsic allergens: determinants of
      allergic disease.
AB  - A central role for Th2 effector cells in IgE-mediated allergic disease is well
      established. However, the question of why some individuals develop allergic
      disease and others do not remains largely unanswered. Until recently, the
      prevailing view was that the allergic response reflected a shift in the Th1/Th2
      'balance' to favor production of Th2 cytokines and IgE antibody isotype
      switching. Evidence is now emerging to suggest that distinct allergic responses
      cannot be distinguished simply on the basis of type 1 and type 2 cytokine
      profiles. For example, delayed-type hypersensitivity responses to intrinsic
      allergens derived from the dermatophyte fungus Trichophyton are associated with a
      paradoxical increase in Th2 cytokines compared with immediate hypersensitivity
      responses. In contrast, analysis of 'tolerant' responses to extrinsic allergens
      which are induced by specific immunotherapy or high-dose natural exposure to
      inhaled allergen (the modified Th2 response) supports a role for both the Th1
      cytokine IFN-gamma and the regulatory cytokine IL-10. However, IL-10 may also be
      a critical mediator in the allergic response. In this article, we examine how
      analysis of epitope-specific T cell responses may lead to an understanding of how
      T lymphocyte cytokines relate to distinct allergic phenotypes. The relevance of
      Th1/Th2 and regulatory cytokines to development of new allergen-specific
      therapies is also discussed.

PMID- 12483033
TI  - IgE to cross-reactive carbohydrate determinants: analysis of the distribution and
      appraisal of the in vivo and in vitro reactivity.
AB  - BACKGROUND: IgE to cross-reacting carbohydrate determinants has already been
      described by several authors, but their function and distribution are still a
      matter of debate. In previous studies we showed how the presence of IgE to
      bromelain could be a useful and simple marker of the presence of IgE to
      carbohydrate epitopes. METHODS: A survey of 1,831 subjects with a suspected
      allergic respiratory disease has been carried out by detecting IgE to bromelain.
      Data were analysed on the basis of demographical and allergological parameters.
      To find out whether a glycoprotein is capable of triggering an allergic reaction,
      1,076 subjects were also skin tested with several purified molecules bearing
      carbohydrate side chains differing in number, composition and complexity.
      RESULTS: An overall prevalence of 23% of positive IgE to cross-reacting
      carbohydrate determinants was recorded. Prevalence varied when subsets of non
      allergic (5%), non-pollen-allergic (10%), and pollen-allergic (31%) subjects were
      considered. Prevalence further increased in subsets with multiple pollen
      sensitization (71%), and with a previous pollen immunotherapy course (46%),
      whereas minor differences were found in gender and age distribution. Almost all
      the allergenic extracts recorded negative in the skin test gave a positive IgE
      test in vitro. A higher correlation was found mainly with plant-derived
      allergenic extracts, whereas a lower one was recorded with mites and fungi.
      Horseradish peroxidase was the only glycoprotein capable of exerting a positive
      skin test in 21% of the subjects with IgE to cross-reacting carbohydrate
      determinants, 80% of them having IgE to the HRP molecule. CONCLUSIONS: IgE to
      cross-reacting carbohydrate determinants are common among the allergic population
      and the binding to skin test negative allergenic extracts further confirms their
      poor biological activity. Further studies on horseradish peroxidase should be
      carried out to define the role of the glycan side chains in its allergenic
      activity.

PMID- 12483034
TI  - Allergenic relevance of Cupressus arizonica pollen extract and biological
      characterization of the allergoid.
AB  - BACKGROUND: Cupressaceae (cypress) pollens can cause pollinosis in winter.
      However, the lack of specific commercial extracts combined with the early
      pollination period of cypress trees make a precise diagnosis difficult. The need
      for a reliable and effective cypress extract for diagnostic and therapeutic
      purposes is increasingly felt. METHODS: Mixed or single Cupressus arizonica,
      lusitanica and sempervirens pollen extracts precipitated with ammonium sulfate
      (PPT) were compared by direct RAST, RAST inhibition and SDS-PAGE techniques. The
      major allergen of C. arizonica (Cup a 1), purified by anion exchange
      chromatography, was checked by immunoblotting experiments before chemical
      modification, in parallel with a C. arizonica extract, with potassium cyanate
      (KCNO) to obtain a monomeric allergoid. The allergoid extract was characterized
      for its biological, chemico-physical and immunological features by RAST
      inhibition, SDS-PAGE and ELISA assays. RESULTS: Direct RAST, RAST inhibition, and
      SDS-PAGE data indicated that the PPT C. arizonica pollen extract showed the most
      allergenic potential, and it can be considered representative of the Cupressus
      spp. Immunoblotting data confirmed Cup a 1 as a major allergen. RAST inhibition
      and ELISA showed that modified PPT C. arizonica extract had less IgE reactivity
      than the native, non-modified extract, while preserving the immunogenic capacity
      typical for an allergoid. Finally, the SDS-PAGE profile of Cup a 1 allergoid was
      similar to native Cup a 1 allergen, suggesting the modified C. arizonica extract
      shows the characteristics of a monomeric allergoid. CONCLUSIONS: The PPT C.
      arizonica pollen extract shows good in vitro diagnostic potential and its
      chemically modified form offers the features of a monomeric allergoid. It might
      therefore lend itself to the development of a product to be administered by the
      sublingual or oromucosal route for immunotherapy of individuals with cypress
      pollinosis.

PMID- 12483035
TI  - IgG-mediated signal transduction in canine mastocytoma-derived cells.
AB  - BACKGROUND: We have reported canine cutaneous mastocytoma-derived cells named CM
      MC sensitized with monomeric IgG released histamine upon anti-IgG stimulation.
      However, IgG or IgE-mediated signal transduction in the cells remains to be
      examined. METHODS: Monomeric IgG-binding to cells was measured by flow cytometry
      using FITC-anti-IgG. IgG-mediated protein tyrosine phosphorylation was studied by
      Western blotting using anti-phosphotyrosine antibody. We monitored the
      intracellular Ca(2+) concentration ([Ca(2+)](i)) when IgG-primed cells were
      activated with anti-canine IgG. Release of Ca(2+) from intracellular stores was
      analyzed with thapsigargin in the absence of extracellular Ca(2+). The Ca(2+)
      entry via store-operated Ca(2+) channel from the external environment was
      characterized using Ba(2+), Ni(2+) and EGTA. Cells sensitized with canine serum
      abundant in IgG and IgE or heat-inactivated serum were activated by anti-canine
      IgG or anti-canine IgE. The effect of extracellular Ca(2+) and reaction time on
      IgG-mediated histamine release was examined. Staurosporine and ER-27319 were used
      to clarify the IgG-mediated protein tyrosine phosphorylation. RESULTS: Abundant
      IgG-binding sites on the cell were detected by FACS analysis. Anti-IgG induced
      rapid protein tyrosine phosphorylation and [Ca(2+)](i) elevation. When
      extracellular Ca(2+) was excluded by EGTA, a mild and transient increase in
      [Ca(2+)](i) was observed, indicating the release of Ca(2+) from anti-IgG
      sensitive intracellular Ca(2+) stores. The constant Ba(2+) entry from external
      environment proved the Ca(2+) influx occurred mainly via a store-operated Ca(2+)
      channel which was inhibited by Ni(2+) and EGTA. Canine serum-sensitized cells
      showed a rapid and sustained increase in [Ca(2+)](i) upon both anti-IgG and anti
      IgE stimulation. The [Ca(2+)](i) elevation induced by anti-IgE was decreased in
      the cells sensitized with heat-inactivated serum. Histamine release from CM-MCs
      was absolutely dependent on extracellular Ca(2+), and reached equilibrium within
      5 min. Staurosporine inhibited the tyrosine phosphorylation of 38-, 65-, 70-, 80
      kD proteins. ER-27319 inhibited the tyrosine phosphorylation of 38- and 70-kD
      proteins. Staurosporine also inhibited IgG-mediated [Ca(2+)](i) elevation and
      histamine release in a dose-dependent manner. CONCLUSIONS: Canine cutaneous
      mastocytoma-derived (CM-MC) cells were activated by both IgG- and IgE-mediated
      mechanisms. IgG-mediated protein tyrosine phosphorylation and Ca(2+) influx were
      similar to those mediated by IgE. CM-MC cells are useful for the study of
      allergic inflammation caused by IgG-dependent mechanisms.

PMID- 12483036
TI  - Selective inhibition of systemic anti-OVA IgE production in response to oral pre
      treatment with OVA-liposome conjugates.
AB  - BACKGROUND: We have previously reported that intraperitoneal injection with OVA
      liposome conjugates induces OVA-specific and IgE-selective unresponsiveness in
      mice. METHODS: In the present study, the effects of oral pre-treatment with OVA
      liposome conjugates or with plain OVA solution on anti-OVA IgG antibody
      production were investigated in mice after subsequent immunization with alum
      adsorbed OVA. Control mice received only the immunization. RESULTS: The levels of
      serum anti-OVA IgG antibody in mice receiving oral administration of OVA-liposome
      were comparable to those in the control mice. However, in mice receiving oral
      administration of the same dose of plain OVA, levels of serum anti-OVA IgG
      antibody were significantly lower than those in control mice. Surprisingly, anti
      OVA IgE antibody production was completely inhibited in mice receiving oral
      administration of OVA-liposome conjugates. Splenic CD4(+) T cells of mice
      receiving oral administration of OVA-liposome and those of control mice produced
      comparable levels of cytokines, while those of mice receiving oral administration
      of plain OVA solution produced significantly lower levels of cytokines than those
      in the other two groups. CONCLUSION: Orally administered OVA-liposome did not
      affect anti-OVA IgG production but did inhibit anti-OVA IgE antibody production,
      while orally administered OVA solution inhibited production of both IgG and IgE
      antibodies. These results suggest that antigen-liposome conjugates can possibly
      be orally administered in order to control antigen-specific IgE antibody
      production, without affecting IgG antibody production.

PMID- 12483037
TI  - Airway responsiveness and airway remodeling after chronic exposure to procaterol
      and fenoterol in guinea pigs in vivo.
AB  - BACKGROUND: Chronic exposure to fenoterol (FEN), a beta(2)-adrenergic receptor
      (beta(2)-AR) agonist, was shown to induce both airway hyperresponsiveness and
      airway remodeling in experimental animals. OBJECTIVE: We wanted to know the
      effects of chronic exposure to procaterol (PRO), a beta(2)-AR agonist, on airway
      function and structure, because this agent is widely used as a bronchodilator in
      Japan. For comparison, the effects of FEN were also examined. METHODS:
      Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given
      to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents
      was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN
      or vehicle, the dose-response relationship between lung resistance (R(L)) and
      intravenously administered acetylcholine (ACh) was measured. After measuring
      R(L), histological changes in noncartilaginous airway dimensions were evaluated.
      RESULTS: The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present
      study was speculated to be 100 times larger than that of therapeutic dose. ACh
      concentrations causing 2-fold, 10-fold and maximal increases in R(L) were not
      different in 4 groups tested. In the smaller membranous airways (<0.4 mm in
      diameter), but not the larger ones, thickening of adventitial areas was
      significantly greater in animals treated with beta(2)-AR agonists than in control
      animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or
      1 mg/ml FEN, respectively). The degree of the increase was significantly less in
      PRO-treated animals than in FEN-treated animals (p < 0.01). CONCLUSION: Our
      results did not provide any evidence that regular inhalation of PRO at the
      therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge
      amounts of PRO only caused a mild thickening of the adventitial areas, suggesting
      that PRO may be a weak inducer of airway remodeling compared with FEN.

PMID- 12483038
TI  - Identification of highly expressed genes in peripheral blood T cells from
      patients with atopic dermatitis.
AB  - BACKGROUND: Analysis of genes that are differentially expressed in patients with
      atopic dermatitis (AD) and normal individuals will provide important information
      on the underlying molecular pathogenetic mechanisms of AD. METHODS: Transcript of
      freshly isolated peripheral blood T cells from 59 individuals were analyzed with
      a fluorescent differential display (FDD) method. Ninety-two differentially
      expressed genes were identified in this manner. Additionally, real-time
      quantitative RT-PCR was employed to investigate the expression of the FDD
      selected genes and also genes related to T cell function. RESULTS: A number of
      genes, including CC chemokine receptor 4, T cell-specific tyrosine kinase
      (Emt/Itk), integrin beta1, integrin alpha6, IQGAP1 and MAR/SAR DNA-binding
      protein (SATB1), were shown to be more highly expressed in patients with moderate
      and/or severe AD than in controls or patients with mild AD. Because the products
      of these upregulated genes influence chemotaxis, adhesion, migration and Th2
      polarization, it is suggested that in more severe AD, circulating T cells may
      function differently in this regard. Several other genes, the role of which in T
      cell function is currently unknown, were also found to be differentially
      expressed in AD. These included the heat shock protein 40 and vasopressin
      activated calcium-mobilizing receptor 1. CONCLUSION: The upregulated genes
      identified in this work may serve as useful markers for moderate to severe AD as
      opposed to normal or mild AD and also as markers indicating progression to more
      severe AD. Further functional characterization will provide a better
      understanding of the pathophysiology of circulating T cells in AD.

PMID- 12483039
TI  - Relationship between nasal and bronchial responsiveness in perennial allergic
      rhinitic patients with asthma.
AB  - BACKGROUND: The nasal and bronchial mucosa present similarities and most patients
      with asthma also have rhinitis, suggesting the concept of 'one airway one
      disease'. Although many studies may suggest the relationship between nasal and
      bronchial responsiveness in patients with allergic rhinitis and asthma, few
      studies have been published which address this question directly. The aim of this
      study is to investigate whether the relationship between nonspecific nasal and
      bronchial responsiveness exists in perennial allergic rhinitic patients with
      asthma. METHODS: Fifty-one perennial allergic rhinitic patients with the
      definitive or suspected asthma underwent methacholine bronchial provocation tests
      and nasal histamine challenge tests. A slope of the absolute changes in nasal
      symptoms score/log concentrations of histamine was calculated by linear
      regression analysis. A ratio of the final absolute change in nasal symptoms score
      to the sum of all the doses of histamine given to the subject was also
      calculated. The degree of bronchial responsiveness to methacholine was
      categorized as positive bronchial hyperresponsiveness (BHR) if PC(20)
      (provocative concentration of methacholine resulting in 20% fall in FEV(1)) was
      <4 mg/ml, borderline BHR if PC(20) was >or=4 but <or=16 mg/ml, and negative BHR
      if PC(20) was >16 mg/ml. Another index of bronchial responsiveness (BRindex) was
      calculated as the log [(% decline in FEV(1)/log final methacholine concentration
      as mg/dl) + 10]. RESULTS: The geometric means of the slope (4.47 vs. 2.95, p <
      0.05) and the ratio (1.68 vs. 0.54, p < 0.01) were higher in patients with
      positive BHR (n = 23) than in patients with negative BHR (n = 19), respectively.
      The geometric means of the slope (3.50) and the ratio (1.13) in patients with
      borderline BHR (n = 9) were between the two groups, respectively. In all
      patients, the log-slope (r = 0.48, p < 0.001) and the log-ratio (r = 0.51, p <
      0.001) were correlated well with the BRindex, respectively. Even in allergic
      rhinitic patients with definitive asthma, the log-slope was correlated with the
      BRindex (r = 0.39, p < 0.05) or log-PC(20) (r = -0.36, p < 0.05). CONCLUSIONS:
      The nonspecific nasal responsiveness may be related to the nonspecific bronchial
      responsiveness in patients with allergic rhinitis and asthma, which may support
      the viewpoint that allergic rhinitis and asthma represent a continuum of
      inflammation involving one common airway.

PMID- 12483040
TI  - Enhancement of allergic skin wheal responses by microwave radiation from mobile
      phones in patients with atopic eczema/dermatitis syndrome.
AB  - Microwave radiation from mobile phones enhanced skin wheal responses induced by
      house dust mite and Japanese cedar pollen while it had no effect on wheal
      responses induced by histamine in patients with atopic eczema/dermatitis syndrome
      (AEDS). Microwave radiation also increased plasma levels of substance P (SP) and
      vasoactive intestinal peptide (VIP) in patients with AEDS. These results indicate
      that microwave radiation from mobile phones may enhance allergen-induced wheal
      responses in association with the release of SP and VIP. This finding may be
      useful in elucidating the pathophysiology and treatment of AEDS.

PMID- 12483048
TI  - Effect of hyperventilation on extracellular concentrations of glutamate, lactate,
      pyruvate, and local cerebral blood flow in patients with severe traumatic brain
      injury.
AB  - OBJECTIVE: To determine the potential adverse effects of brief periods of
      hyperventilation commonly used for acute neurologic deterioration. DESIGN:
      Prospective clinical trial. SETTING: University medical school. PATIENTS: Twenty
      patients with severe traumatic brain injury. INTERVENTIONS: The effect of 30 mins
      of hyperventilation (mean PaCO2, 24.6 mm Hg) on the extracellular metabolites
      associated with ischemia, and on local cerebral blood flow was studied by using
      microdialysis and local cerebral blood flow techniques. Normal appearing brain
      adjacent to evacuated hemorrhagic contusions or underlying evacuated subdural
      hematomas was studied. Hyperventilation trials were done 24-36 hrs after injury
      and again at 3-4 days after injury. Dialysate concentrations of glutamate,
      lactate, and pyruvate were measured before and for 4 hrs after the
      hyperventilation trials. MEASUREMENTS AND MAIN RESULTS: At 24-36 hrs,
      hyperventilation led to a >or=10% increase in the extracellular concentrations of
      glutamate in 14 of 20 patients, with concentrations in those 14 patients 13.7
      395% above baseline; a >or=10% increase in lactate in 7 of 20 patients (11.6-211%
      above baseline); and a >or=10% increase in the lactate/pyruvate ratio in eight of
      20 patients (10.8-227% above baseline). At 3-4 days after injury, ten of 13
      patients had an increase in glutamate of >or=10%, while only three of 13 patients
      had an increase in extracellular lactate and two of 13 patients had an increase
      in the lactate/pyruvate ratio of this magnitude. The hyperventilation associated
      increases in extracellular glutamate and lactate concentrations were significant
      ( P<.05; one-sample Student's -test) at both time points after injury, as was the
      lactate/pyruvate ratio at 24-36 hrs. A >or=10% decline in local cerebral blood
      flow was observed with hyperventilation in five of 20 patients at 24-36 hrs
      (range, 10.2-18.7% below baseline), and in ten of 13 patients studied at 3-4 days
      (11.3-54% below baseline). There was no correlation with the presence or absence
      of local CO2 vasoresponsivity and increases in the extracellular metabolites at
      either the early or late time points. CONCLUSIONS: In brain tissue adjacent to
      cerebral contusions or underlying subdural hematomas, even brief periods of
      hyperventilation can significantly increase extracellular concentrations of
      mediators of secondary brain injury. These hyperventilation-induced changes are
      much more common during the first 24-36 hrs after injury than at 3-4 days.

PMID- 12483049
TI  - Stroke volumes generated by precordial compression during cardiac resuscitation.
AB  - OBJECTIVES: To quantitate stroke volumes generated by precordial compression
      during cardiopulmonary resuscitation and to determine their relationship to
      coronary perfusion pressure and the success of resuscitation. DESIGN:
      Prospective, observational animal study. SETTING: Medical research laboratory in
      a university-affiliated research and educational foundation. SUBJECTS: Domestic
      pigs. INTERVENTIONS: Ventricular fibrillation was electrically induced in 25
      anesthetized male domestic pigs. After an interval of 7 mins, electrical
      defibrillation was attempted. Failing to reverse ventricular fibrillation in each
      instance, precordial compression was begun coincident with mechanical
      ventilation. MEASUREMENTS AND MAIN RESULTS: Stroke volumes were computed from
      differences between diastolic and systolic areas of the left ventricle by
      utilizing transesophageal echocardiography. Both stroke volumes and coronary
      perfusion pressure were consistently greater in successfully resuscitated
      animals. Progressive decreases in stroke volumes during precordial compression
      were predictive of unsuccessful resuscitation. A linear correlation between
      stroke volume and coronary perfusion pressure (r =.70) was documented.
      CONCLUSION: These observations support the concept that stroke volumes generated
      by precordial compression are quantitatively related to the coronary perfusion
      pressure and to the success of cardiopulmonary resuscitation.

PMID- 12483050
TI  - Inflammation at the insertion site is not predictive of catheter-related
      bloodstream infection with short-term, noncuffed central venous catheters.
AB  - BACKGROUND: Noncuffed, percutaneously inserted central venous catheters (CVCs)
      are widely used and cause at least 250,000 bloodstream infections (BSIs) in U.S.
      hospitals each year. We report a prospective study to determine whether
      inflammation at the insertion site is predictive of CVC-related BSI. METHODS:
      Percutaneously inserted, noncuffed CVCs inserted into the subclavian, internal
      jugular, or femoral vein in two randomized trials during 1998-2000 were
      prospectively studied; most patients were in an intensive care unit. The
      condition of the insertion site was evaluated daily by research nurses,
      quantifying pain (0, 1), erythema (0-2), swelling (0, 1), and purulence (0, 1);
      the lowest possible overall inflammation score was 0 and the highest was 5. CVC
      related BSI was confirmed in each case by demonstrating concordance between
      isolates from the catheter segment and from blood cultures by restriction
      fragment DNA subtyping. RESULTS: Among 1,263 CVCs prospectively studied, 333
      (26.3%) were colonized at removal; of these, 35 catheters (2.7%) caused BSIs (5.9
      per 1000 CVC days). BSIs were caused by coagulase-negative staphylococci (n =
      27), enterococci (n = 4), enteric Gram-negative bacilli (n = 3), or (n = 1). Most
      insertion sites showed little or no inflammation at the time of removal. There
      were no significant differences among mean scores for each inflammatory variable
      examined or overall score among colonized CVCs (0.1 +/- 0.1), catheters causing
      CVC-related BSI (0.2 +/- 0.4), and noncolonized CVCs (0.1 +/- 0.1). The
      sensitivity of local inflammation for diagnosis of CVC-related BSI was dismal (0
      3%). CONCLUSION: Local inflammation is uncommon with infected CVCs, probably
      because most catheter-associated infections are currently caused by coagulase
      negative staphylococci, a pathogen that incites little local or systemic
      inflammation. Whereas overt inflammation of the insertion site should raise
      suspicion of CVC-related BSI caused by or Gram-negative bacilli, especially if
      the patient has fever or other signs of sepsis, in general, site appearance
      cannot be relied on to identify catheter colonization or CVC-related BSI.

PMID- 12483051
TI  - Intensive care unit-acquired infections: is postdischarge surveillance useful?
AB  - OBJECTIVE: To assess the added value of surveying patients after discharge from
      the intensive care unit. DESIGN: Prospective cohort study. SETTING: Medical
      intensive care unit of a large teaching hospital. PATIENTS: All patients admitted
      to the intensive care unit for 48 hrs or more from October 1995 to November 1997.
      MEASUREMENTS AND MAIN RESULTS: We prospectively surveyed 1,068 patients during
      their intensive care unit stay and for 5 days after intensive care unit
      discharge. We detected 554 intensive care unit-acquired infections, yielding an
      infection rate of 70.7 per 1,000 patient days. Of these, only 31 infections
      (5.6%) in 27 patients were detected after intensive care unit discharge. If
      postdischarge surveillance was targeted on patients who had had a central
      vascular catheter while in the intensive care unit, only one infected patient
      would have been missed, but only 554 out of 889 would have been followed up
      (sensitivity, 96.2%; specificity, 38.7%; negative predictive value, 99.7%).
      CONCLUSIONS: Surveillance of all patients discharged from the medical intensive
      care unit is not recommended, as it is resource demanding and allows the
      detection of few additional infections. However, targeted postdischarge
      surveillance could be a rational alternative, and selection criteria need to be
      refined and validated.

PMID- 12483052
TI  - The "air leak" test around the endotracheal tube, as a predictor of
      postextubation stridor, is age dependent in children.
AB  - OBJECTIVES: The airleak test is measured with a manometer as the pressure
      necessary to generate an audible airleak around the endotracheal tube. Our
      objectives were to determine whether the airleak test predicts postextubation
      stridor in children and if age affects its sensitivity and specificity. DESIGN: A
      retrospective study. SETTING: Pediatric intensive care unit. PATIENTS: We studied
      all intubated patients admitted to our pediatric intensive care unit between July
      1998 and December 1999. Patients were excluded if they had acute viral croup,
      tracheal surgery, hypotonic airway, or vocal cord paralysis or if they died
      before extubation. INTERVENTIONS: Medical records were reviewed for patient
      demographics, presence of an airleak on the day of extubation, airleak values,
      presence of postextubation stridor, and extubation failure secondary to upper
      airway obstruction. MEASUREMENTS AND MAIN RESULTS: One hundred and five patients
      met our inclusion criteria and had an airleak test at the time of extubation. In
      children <7 yrs of age, the incidence of postextubation stridor was similar in
      patients with or without an airleak at >20 mm Hg (50% vs. 67.7%; >.05) with a
      sensitivity of 65.6% (95% confidence interval, 46.9-80.8). In children >or=7 yrs
      of age, the incidence of postextubation stridor was greater in patients with an
      airleak at >20 mm Hg (55.5% vs. 5.8%; p=.01) with a sensitivity of 83.3% (95%
      confidence interval, 36.8-99) in predicting postextubation stridor. CONCLUSIONS:
      Our study suggests that the airleak test has a low sensitivity when used as a
      screening test to predict postextubation stridor in young children (<7 yrs old),
      whereas in older children (>or=7 yrs old) the airleak test may predict
      postextubation stridor.

PMID- 12483053
TI  - Sedation during mechanical ventilation: a systematic review.
AB  - OBJECTIVE: A systematic review was performed to determine the most effective
      agent with which to sedate adult patients who have respiratory failure that
      requires mechanical ventilation in the medical intensive care unit. DATA SOURCES:
      A computerized literature search of MEDLINE, a U.S. National Library of Medicine
      online database, from 1966 to August 1998 was conducted. All selected articles
      were reviewed to identify other relevant articles. STUDY SELECTION: Inclusion
      criteria were as follows: a) population-adults with respiratory failure who
      received mechanical ventilation in a medical intensive care unit; b) design
      prospective, randomized controlled trial; c) intervention-sedation; and d)
      primary outcome-successful sedation. DATA EXTRACTION: Of 71 potentially relevant
      articles, only 15 randomized trials fulfilled all four selection criteria. DATA
      SYNTHESIS: Clinical heterogeneity among studies precluded statistical pooling of
      results. CONCLUSIONS: More research is needed to determine the most effective
      agent with which to sedate adult patients who have respiratory failure that
      requires mechanical ventilation in the medical intensive care unit.

PMID- 12483054
TI  - Albumin versus crystalloid prime solution for cardiopulmonary bypass in young
      children.
AB  - OBJECTIVE: To determine the effects of adding 5% albumin to the cardiopulmonary
      bypass prime on perioperative fluid status and fluid management in young
      children. DESIGN: Prospective randomized study. SETTING: Single university
      hospital. PATIENTS: Pediatric patients of <14 kg undergoing cardiac surgery
      requiring cardiopulmonary bypass. INTERVENTIONS: Patients received a 5% albumin
      prime or a crystalloid prime. Perioperative fluid intake, output, and daily
      weights were recorded. Serial hematocrits, colloid osmotic pressures, and serum
      albumins were measured. Outcomes and complications were documented. MEASUREMENTS
      AND MAIN RESULTS: There were 86 patients aged 3 days to 4 yrs; 44 patients had an
      albumin prime and 42 had a crystalloid prime. Patients in the albumin group had a
      net negative fluid balance at the end of cardiopulmonary bypass compared with a
      net positive fluid balance in the crystalloid group. Patients in the albumin
      group had significantly higher serum albumins and colloid osmotic pressures and
      gained less weight postoperatively. However, their hematocrits were lower, and
      more patients in the albumin group received packed red blood cells. By 24 hrs
      postoperatively, there were no differences in colloid osmotic pressures and
      hematocrits between groups, and by the fourth postoperative day, there was no
      difference in weight gain. No differences were found in length of mechanical
      ventilation, intensive care unit or hospital stay, complications, or mortality.
      CONCLUSIONS: Albumin in the prime may attenuate the extravasation of fluid out of
      the vascular space, but it may be associated with an increased transfusion rate.
      The risk/benefit ratio for this intervention warrants further study.

PMID- 12483055
TI  - Survival and quality of life: short-term versus long-term ventilator patients.
AB  - OBJECTIVE: Examine postdischarge mortality, quality of life, and charges for care
      for short-term (>24 and <or=96 hrs of ventilation) and long-term (>96 hrs)
      ventilator patients. DESIGN: Prospective longitudinal descriptive study. SETTING:
      Posthospital discharge follow-up in homes, nursing homes, and rehabilitation
      centers. PATIENTS: Intensive care unit patients who required >24 hrs of
      continuous in-hospital mechanical ventilation were enrolled from February 1997
      through March 1999. Patients living to hospital discharge were followed for 1 yr
      postdischarge. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: A total of 538
      patients were studied. In-hospital mortality was 47.4%, with a 1-yr mortality
      rate of 64.7%; survival analysis showed that the different survival risks for
      short-term and long-term ventilator patients over time were not statistically
      significant. Long-term patients were more likely to be discharged to a nursing
      home (45.2%). Short-term ventilator patients had better overall quality of life
      at all points postdischarge. Charges to produce a long-term survivor were
      significantly higher than for short-term patients; on average $86,360 more
      charges were required to produce a long-term ventilator patient survivor for 1 yr
      postdischarge. CONCLUSIONS: There were no significant demographic or clinical
      differences between short-term and long-term ventilator patients. Our results
      suggest that the likelihood of need for continued care in an extended-care
      facility for months and the risk of death during the first year postdischarge are
      sufficiently common features of this population and need to be included in
      discussions of treatment options with patients and their families.

PMID- 12483056
TI  - Ventilatory care in myasthenia gravis crisis: assessing the baseline adverse
      event rate.
AB  - OBJECTIVE: Myasthenic patients who require mechanical ventilation often develop
      pneumonia or atelectasis. Although there are differences in the prevalence of
      these complications among various institutions, there is no evidence that
      aggressive treatment shortens the course of the myasthenic crisis. We have
      quantified the severity of lung injury and aggressiveness of respiratory
      intervention in myasthenic patients admitted to the neuro-critical care unit.
      DESIGN: We retrospectively identified all mechanically ventilated myasthenic
      patients admitted in our unit between 1990 and 1998. SETTING: Neuro-critical care
      unit of a tertiary care center in an urban area with a large, established,
      regional neuromuscular disease program. PATIENTS: Eighteen myasthenia gravis
      patients with 24 episodes of respiratory failure requiring mechanical
      ventilation. INTERVENTIONS: A novel respiratory intervention index, comprising
      the use of suction, intermittent positive-pressure breathing or bronchodilator
      treatments, sighs, and chest physiotherapy represented the aggressiveness of the
      respiratory treatment. The respiratory intervention index was correlated with the
      lung injury score, used as a measure of lung involvement and other respiratory
      variables. MEASUREMENTS AND MAIN RESULTS Our patients had less atelectasis and
      pneumonia than previously published series (46% vs. 91%), leading to shorter
      mechanical support and neuro-critical care unit stay. The mean respiratory
      intervention index correlated with lung injury score and inversely with forced
      vital capacity. CONCLUSIONS: This study presents an estimate for both severity of
      pulmonary complications and intensity of respiratory therapy in the severe
      myasthenic patient with mechanical ventilatory compromise. Our results suggest
      that aggressive respiratory treatment should be used in myasthenic patients in
      crisis to diminish the risk for prolonged respiratory complications. These
      observations should be validated in a prospective study.

PMID- 12483058
TI  - Tidal volume increases do not affect alveolar mechanics in normal lung but cause
      alveolar overdistension and exacerbate alveolar instability after surfactant
      deactivation.
AB  - OBJECTIVE: We utilized microscopy to measure the impact of increasing tidal
      volume on individual alveolar mechanics (i.e., the dynamic change in alveolar
      size during tidal ventilation) in the living porcine lung. DESIGN: In three
      anesthetized, mechanically ventilated pigs, we observed normal alveoli (n = 27)
      and alveoli after surfactant deactivation by Tween 20 lavage (n = 26) at three
      different tidal volumes (6, 12, and 15 mL/kg). Alveolar area was measured at peak
      inspiration (I) and at end expiration (E) by image analysis and I minus E was
      calculated as an index of alveolar stability (I-Edelta). MEASUREMENTS AND MAIN
      RESULTS: In normal alveoli, increasing tidal volume did not change alveolar area
      at I (6 mL/kg = 9726 +/- 848 microm; 15 mL/kg = 9,637 +/- 884 microm ), E (6
      mL/kg = 9747 +/- 800 microm; 15 mL/kg = 9742 +/- 853 microm ), or I-Edelta (6
      mL/kg = -21 +/- 240 microm; 15 mL/kg = -105 +/- 229 microm ). In contrast, with
      surfactant deactivation, increasing tidal volume significantly increased alveolar
      area at I (6 mL/kg = 11,413 +/- 1032 microm; 15 mL/kg = 13,917 +/- 1214 microm ),
      at E (6 mL/kg = 10,462 +/- 906 microm; 15 mL/kg = 12,000 +/- 1066 microm ), and I
      Edelta (6 mL/kg = 825 +/- 276 microm; 15 mL/kg = 1917 +/- 363 microm ). Moreover,
      alveolar instability (increased I-Edelta) was significantly increased at all
      tidal volumes with altered surface tension when compared with normal alveoli.
      CONCLUSIONS: We conclude that high tidal volume ventilation does not alter
      alveolar mechanics in the normal lung; however, in the surfactant-deactivated
      lung, it causes alveolar overdistension and exacerbates alveolar instability.

PMID- 12483057
TI  - Serum S-100B and interleukin-8 as predictive markers for comparative neurologic
      outcome analysis of patients after cardiac arrest and severe traumatic brain
      injury.
AB  - OBJECTIVE: To compare S-100B and interleukin-8 serum values on scene/at admission
      and 12 hrs later with respect to neurologic long-term outcome 12 months after
      cardiac arrest and return of spontaneous circulation, as well as after severe
      traumatic brain injury. DESIGN: Prospective comparative cohort study. SETTING: On
      scene; intensive care units of a university hospital. PATIENTS: Twenty patients
      with out-of-hospital cardiac arrest. Twenty patients with severe traumatic brain
      injury. INTERVENTIONS: Therapy was adjusted to the standards of modern
      prehospital and intensive care management by physicians who were not involved in
      the study. MEASUREMENTS AND MAIN RESULTS: First median S-100B values of the
      cardiac arrest group (4.42 ng/mL) mounted as high as those of the traumatic brain
      injury group (4.11 ng/mL). Within 12 hrs, S-100B levels significantly decreased
      to 0.75 ng/mL in cardiac arrest patients and to 0.68 ng/mL in traumatic brain
      injury patients but remained significantly elevated compared with the controls
      (0.04 ng/mL). Interleukin-8 levels of the cardiac arrest patients on scene (30.33
      pg/mL) were clearly elevated above normal (12.60 pg/mL) and increased
      significantly to 101.40 pg/mL after 12 hrs. They showed no significant difference
      compared with those of the traumatic brain injury patients (78.75 pg/mL and 96.00
      pg/mL, respectively). Multivariate Cox regression analysis in cardiac arrest
      patients identified only the S-100B level measured 12 hrs after study entry as an
      independent predictor for unfavorable neurologic outcome according to the Glasgow
      Outcome Scale score. In contrast, S-100B as well as interleukin-8 levels
      quantified 12 hrs after admission significantly predicted an unfavorable
      neurologic course in the traumatic brain injury group. CONCLUSIONS: Significantly
      elevated S-100B and interleukin-8 serum levels 12 hrs after cardiac arrest
      suggest that primary brain damage and systemic inflammatory response are
      comparably serious with that of traumatic brain injury. In both collectives,
      increased S-100B values measured 12 hrs after insult correlated well with an
      unfavorable neurologic outcome after 12 months.

PMID- 12483059
TI  - Reduction of cerebral infarction using the third circulation.
AB  - OBJECTIVE: To ascertain whether ventriculosubarachnoid perfusion of the brain
      with an oxygen-carrying nutrient emulsion affects the volume of infarction in
      animals with permanent middle cerebral artery occlusion. DESIGN: Prospective,
      randomized, controlled trial. SETTING: An animal laboratory in a university
      setting. SUBJECTS: Twenty-eight closed colony adult cats weighing between 3.5 and
      4.5 kg. INTERVENTIONS: Cats were assigned randomly into one of three groups:
      untreated surgical controls, artificial cerebrospinal fluid (ACSF) perfused, or
      oxygenated fluorochemical (t-bis perfluorobutylethylene; F44E) nutrient emulsion
      (OFNE) perfused. The formulation used in this study was developed for clinical
      use and is currently being used in a phase 1 clinical trial in patients with
      severe ischemic stroke. Focal cerebral ischemia was induced by permanently
      clipping the middle cerebral artery via the retro-orbital approach. Treatment was
      initiated 90 mins postocclusion and continued for 18 hrs. Animals were killed 1
      hr after the termination of perfusion, the brains were sectioned and stained with
      2,3,5-triphenyltetrazolium chloride, and the infarct area was determined with a
      computer digitizer. MEASUREMENTS AND MAIN RESULTS: There was a significant
      difference in cerebral infarct volume in the OFNE-perfused animals compared with
      the other groups ( p<or=.015). Intracranial pressure was significantly reduced in
      the OFNE-perfused group relative to the surgical control group at 18 hrs (
      P<or=.05). Overall, infarct volume correlated with intracranial pressure measured
      at the end of the treatment period (Spearman rank order, p<.001). CONCLUSIONS:
      Fluorochemical emulsion delivery of oxygen and nutrients directly to the brain by
      means of ventriculocisternal perfusion is a viable treatment alternative for
      cerebral ischemia. In addition, this technique may control elevations in
      intracranial pressure following stroke.

PMID- 12483060
TI  - Evaluation of unfractionated heparin and recombinant hirudin on survival in a
      sustained ovine endotoxin shock model.
AB  - OBJECTIVE: To compare and evaluate the potential benefit of two different
      anticoagulation regimens during endotoxemia in an ovine model. DESIGN: Animal
      prospective randomized and controlled study following preliminary dose-range
      study conforming with the Guide for the Care and Use of Laboratory Animals as
      promulgated by the Council of the American Physiologic Society and reviewed by
      the Ethical Committee for Animal Research of our institution. SETTING:
      Laboratories of anesthesiological investigations and hemostasis, primary care
      university medical center. SUBJECTS: Twenty-two adult sheep of either sex,
      weighing 29-42 kg (mean 35.8 kg), surgically instrumented for chronic studies and
      randomly allocated to receive three different treatment groups: unfractionated
      heparin (40 units.kg.hr; n = 7), recombinant hirudin (500 units.kg.hr; n = 7), or
      saline (nonanticoagulated controls; n = 8). INTERVENTIONS: Ovine model of severe
      endotoxin shock induced by a continuous intravenous endotoxin infusion over 72
      hrs (10 ng.kg.min ). MEASUREMENTS AND MAIN RESULTS: Endotoxin infusion alone
      produced a progressive hypotensive, hyperdynamic shock state with right ventricle
      failure leading to the death of all animals of the control group within 44 hrs
      (median, 12 hrs). Heparin profoundly improved survival rate in this model,
      whereas effective anticoagulation with hirudin did not significantly increase the
      survival rate compared with controls. Animals in the control group died from
      disseminated intravascular coagulation, metabolic acidosis, and hemorrhagic
      pulmonary edema, whereas sheep treated with hirudin died from severe pulmonary
      edema (hypoxemia, increased alveoloarterial oxygen gradient associated with an
      increased wet/dry lung weight ratio) in the absence of disseminated intravascular
      coagulation. CONCLUSIONS: We conclude that systemic anticoagulation with the
      thrombin inhibitor hirudin is without benefit in this sheep model of lethal
      endotoxemia, whereas anticoagulation with heparin affords not only effective
      prevention of endotoxin-induced coagulation disorders but also global protection
      with prevention of respiratory decompensation and thus markedly improves survival
      rate in this situation.

PMID- 12483061
TI  - Differential effects of lowering culture temperature on mediator release from
      lipopolysaccharide-stimulated neonatal rat microglia.
AB  - OBJECTIVE: Therapeutic moderate hypothermia has the potential for neuronal
      protection against brain injury. Microglia, a type of immune-related cell in the
      brain, may play a certain role in neuronal damage subsequent to injury. We
      examined the effects of culture temperature changes from 37 degrees C to 33
      degrees C or 30 degrees C on mediator release, including nitric oxide,
      interleukin-6, and tumor necrosis factor-alpha from lipopolysaccharide-stimulated
      microglia harvested from neonatal rats. DESIGN: Laboratory study. SETTING:
      University medical school. SUBJECTS: Microglial cells isolated from primary
      cultures of rat brains. INTERVENTIONS: The production of nitric oxide was
      measured by a nitrite accumulation method in a culture medium, whereas cytokines,
      interleukin-6, and tumor necrosis factor-alpha were measured by enzyme-linked
      immunosorbent assay. MEASUREMENT AND MAIN RESULTS: At 30 degrees C and 33 degrees
      C, nitric oxide production stimulated by lipopolysaccharide decreased to 10 and
      30% of control (37 degrees C), respectively, 24 hrs after the stimulation, and
      the decrease was sustained for 48 hrs. Interleukin-6 production at 30 degrees C
      and 33 degrees C was also reduced to 30% of control 6 hrs after the activation.
      Such responses lasted throughout the study. However, tumor necrosis factor-alpha
      release at 30 degrees C and 33 degrees C was depressed for only 6 hrs after
      stimulation, followed by subsequent elevation to concentrations similar to those
      at 37 degrees C. Microglial morphologic activation, showing changes from round to
      bipolar, reached a peak at 6 hrs in the 37 degrees C group, returning to round 12
      hrs after lipopolysaccharide application. In 30 degrees C and 33 degrees C, the
      zenith was detected at 6 hrs, with activation remaining even 12 hrs after the
      stimulation, suggesting prolongation of the microglial response to
      lipopolysaccharide, which was inconsistent with changes in tumor necrosis factor
      release. CONCLUSIONS: Decreasing culture temperature inhibits the production of
      nitric oxide and interleukin-6 from activated microglia. Differences were found
      in the degree or time course change between tumor necrosis factor-alpha and the
      other mediators. Also, the time course of morphologic changes in microglia was
      dependent on culture temperature. Further studies are required to define the
      mechanisms for such differences in mediator release from cooled microglia and
      also to clarify the inconsistency between morphologic change and its function in
      the cell.

PMID- 12483062
TI  - Role of serum S100B as an early predictor of high intracranial pressure and
      mortality in brain injury: a pilot study.
AB  - OBJECTIVE: To investigate whether serum S100B is suitable as a sensitive
      biomarker for early prediction of increased intracranial pressure and mortality
      rates after brain injury. DESIGN: A prospective, longitudinal study. SETTING:
      Neurosurgical intensive care unit. PATIENTS: Twenty-one patients with acute brain
      injury and 13 healthy controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN
      RESULTS: We assessed Glasgow Coma Scale score and pupil reaction on admission and
      quantified serum S100B (in-house enzyme-linked immunosorbent assay) and
      intracranial pressure on admission and the subsequent 6 days. Serum S100B
      concentrations on admission and day 1 were significantly higher in patients with
      fatal outcome (p <.05, p<.01, respectively), with a sensitivity of 100% and a
      specificity of 75-83%. Patients with high serum S100B on admission had an eight
      fold and on day 1 a 12-fold increased relative risk of a fatal outcome.
      Subsequent serum S100B values predicted the development of high intracranial
      pressure in patients with traumatic brain injury (p <.01). Patients with high
      intracranial pressure on day 5 had an 11-fold and on day 6 a nine-fold increased
      risk of fatal outcome. CONCLUSIONS: Serum S100B is a sensitive biomarker for
      early prediction of the development of high intracranial pressure and fatal
      outcome following acute brain injury. Monitoring S100B concentrations could
      contribute to early detection of patients at risk of secondary increases in
      intracranial pressure and subsequent mortality. This would allow earlier
      targeting of therapy in selected patients.

PMID- 12483063
TI  - Sepsis gene expression profiling: murine splenic compared with hepatic responses
      determined by using complementary DNA microarrays.
AB  - OBJECTIVE: DNA microarrays allow genome-wide assessment of changes in relative
      messenger RNA abundance and thus can be used to monitor changes in gene
      expression. The aim of this series of experiments was to gain experience in
      sepsis gene expression profiling in a well-accepted model of murine polymicrobial
      abdominal sepsis and begin characterizing (in the parlance of genomics) the
      sepsis "transcriptome." DESIGN: Prospective animal study. SETTING: University
      based animal research facility.SUBJECTS C57BL/6 mice. INTERVENTIONS: After
      induction of general anesthesia, cecal ligation and puncture were performed to
      induce peritonitis and polymicrobial sepsis. The control group had sham
      laparotomy only. Three samples of spleen and liver were collected from septic and
      sham animals at 24 hrs after laparotomy. Changes in expression were measured for
      588 annotated mouse genes by using a commercially available complementary DNA
      microarray kit. MEASUREMENTS AND MAIN RESULTS: Broad-scale gene expression
      profiles were characterized for septic liver and spleen and compared with sham
      controls. The analytical tools used included commercially available software
      packages and a novel analysis program. Very little overlap was observed in the
      septic gene expression profiles of these two organs. Most of the genes identified
      have previously been linked to regulation of the inflammatory response;
      importantly, however, some have not. In addition, hierarchical cluster analysis
      showed that cecal ligation and puncture at 24 hrs induced coordinate expression
      of genes that alter cell signaling and survival pathways in spleen, consistent
      with previously published reports of sepsis-induced splenocyte apoptosis. The
      current limitations of microarray analysis as reflected in these studies are also
      discussed. CONCLUSIONS: Microarray technology provides a powerful new tool for
      rapidly analyzing tissue-specific changes in gene expression induced by sepsis in
      animal models. To our knowledge, these data constitute the first report on the
      use of microarrays to determine the sepsis transcriptome.

PMID- 12483064
TI  - Cyclosporin A ameliorates mitochondrial ultrastructural injury in the ileum
      during acute endotoxemia.
AB  - OBJECTIVE: This study was designed to determine the role, if any, of the
      mitochondrial permeability transition in the pathogenesis of mitochondrial injury
      in a representative systemic organ during the acute phase of endotoxemia. DESIGN:
      A well-established, normotensive feline model was employed to determine whether
      pretreatment with cyclosporin A, a potent inhibitor of the mitochondrial
      permeability transition, reduces the severity of mitochondrial injury in the
      ileum during acute endotoxemia. SETTING: The Ohio State University Medical Center
      research laboratory. SUBJECTS Adult, male conditioned cats. INTERVENTIONS: Volume
      resuscitation and maintenance of acid/base balance and tissue oxygen availability
      were provided, as needed, to minimize the potentially confounding effects of
      tissue hypoxia and/or acidosis on the experimental results. Following isotonic
      saline vehicle (control; n = 6), lipopolysaccharide (3.0 mg/kg, intravenously; n
      = 10), or cyclosporin A (6 mg/kg, intravenously; n = 7) followed in 60 mins by
      lipopolysaccharide (3.0 mg/kg, intravenously) administration, ileal samples were
      obtained at 4 hrs posttreatment, and mitochondrial ultrastructure was assessed.
      Objective comparisons of mitochondrial ultrastructural morphology were performed
      by using digital image analyses. MEASUREMENTS AND MAIN RESULTS: As expected,
      significant mitochondrial injury was apparent in the ileal tissues by 4 hrs
      following LPS treatment, despite maintenance of regional tissue oxygen
      availability. Objective evaluation of mitochondrial morphology demonstrated
      characteristics consistent with high-amplitude swelling. Cyclosporin A
      pretreatment protected against the development of these LPS-induced mitochondrial
      ultrastructural abnormalities, an effect not attributable to the suppression of
      lipopolysaccharide-induced tumor necrosis factor-alpha production. CONCLUSIONS:
      These investigations are the first to demonstrate a protective effect of
      cyclosporin A against mitochondrial injury in a representative systemic organ
      during acute endotoxemia. We propose that mitochondrial injury likely related to
      induction of the mitochondrial permeability transition may participate in the
      pathogenesis of systemic organ injury and organ failures during acute sepsis.

PMID- 12483066
TI  - Fixed-energy biphasic waveform defibrillation in a pediatric model of cardiac
      arrest and resuscitation.
AB  - OBJECTIVE: For adults, 150-J fixed-energy, impedance-compensating biphasic
      truncated exponential (ICBTE) shocks are now effectively used in automated
      defibrillators. However, the high energy levels delivered by adult automated
      defibrillators preclude their use for pediatric patients. Accordingly, we
      investigated a method by which adult automated defibrillators may be adapted to
      deliver a 50-J ICBTE shock for pediatric defibrillation. DESIGN: Prospective,
      randomized study. SETTING: A university-affiliated research institution. SUBJECT:
      Domestic piglets. INTERVENTIONS: We initially investigated four groups of
      anesthetized mechanically ventilated piglets weighing 3.8, 7.5, 15, and 25 kg.
      Ventricular fibrillation was induced with an AC current delivered to the right
      ventricular endocardium. After 7 mins of untreated ventricular fibrillation, a
      conventional manual defibrillator was used to deliver up to three 50-J ICBTE
      shocks. If ventricular fibrillation was not reversed, a 1-min interval of
      precordial compression preceded a second sequence of up to three shocks. The
      protocol was repeated until spontaneous circulation was restored, or for a total
      of 15 mins. In a second set of experiments, we evaluated a 150-J biphasic adult
      automated defibrillator that was operated in conjunction with energy-reducing
      electrodes such as to deliver 50-J shocks. The same resuscitation protocol was
      then exercised on piglets weighing 3.7, 13.5, and 24.2 kg. MEASUREMENTS AND MAIN
      RESULTS: All animals were successfully resuscitated. Postresuscitation
      hemodynamic and myocardial function quickly returned to baseline values in both
      experimental groups, and all animals survived. CONCLUSION: An adaptation of a 150
      J biphasic adult automated defibrillator in which energy-reducing electrodes
      delivered 50-J shocks successfully resuscitated animals ranging from 3.7 to 25 kg
      without compromise of postresuscitation myocardial function or survival.

PMID- 12483065
TI  - Mechanisms of the beneficial effect of adrenomedullin and adrenomedullin-binding
      protein-1 in sepsis: down-regulation of proinflammatory cytokines.
AB  - OBJECTIVE: Our recent study indicates that administration of adrenomedullin (AM)
      in combination with AM-binding protein-1 (AMBP-1) before sepsis (i.e.,
      pretreatment) maintains cardiovascular stability and reduces the mortality rate.
      The aim of the present study was to determine whether administration of AM/AMBP-1
      after the onset of sepsis (posttreatment) has any salutary effects on the septic
      host, and if so, whether AM/AMBP-1 down-regulates proinflammatory cytokines, such
      as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6. DESIGN:
      Prospective, controlled, randomized animal study. SETTING: A university research
      laboratory. SUBJECTS: Male adult Sprague-Dawley rats. INTERVENTIONS: Rats were
      subjected either to polymicrobial sepsis by cecal ligation and puncture or to
      sham operation followed by the administration of normal saline solution (i.e.,
      fluid resuscitation). MEASUREMENTS AND MAIN RESULTS: At 5 hrs after cecal
      ligation and puncture, AM (12 microg/kg body weight) and AMBP-1 (40 microg/kg
      body weight) were administered intravenously over 1 hr. At 20 hrs after cecal
      ligation and puncture (i.e., the late, hypodynamic stage of sepsis), cardiac
      output, stroke volume, total peripheral resistance, systemic oxygen delivery, and
      organ blood flow were determined by radioactive microspheres, and circulating
      concentrations of proinflammatory cytokines were measured using enzyme-linked
      immunosorbent assay kits. Moreover, plasma concentrations of transaminases and
      lactate were measured. The results indicated that administration of AM/AMBP-1 at
      5 hrs after cecal ligation and puncture prevented the decrease in measured
      systemic and regional hemodynamic variables and reduced plasma concentrations of
      tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 at 20 hrs after
      the onset of sepsis. Moreover, administration of AM/AMBP-1 attenuated hepatic
      damage and the increase in plasma lactate and prevented hemoconcentration.
      CONCLUSION: Administration of AM/AMBP-1 may provide a novel approach to the
      treatment of sepsis. Moreover, because AM/AMBP-1 significantly reduced
      circulating concentrations of tumor necrosis factor-alpha, interleukin-1beta, and
      interleukin-6, down-regulation of those proinflammatory cytokines by AM/AMBP-1
      appears to play an important role for the beneficial effects of these agents in
      polymicrobial sepsis.

PMID- 12483067
TI  - Treatment of acute traumatic brain injury in children with moderate hypothermia
      improves intracranial hypertension.

PMID- 12483068
TI  - Propylene glycol accumulation associated with continuous infusion of lorazepam in
      pediatric intensive care patients.
AB  - OBJECTIVE: To determine if propylene glycol accumulates in children receiving
      continuous lorazepam infusion and, if accumulation occurs, to determine if it is
      associated with significant laboratory abnormalities. DESIGN: Prospective study.
      SETTING: A tertiary care pediatric intensive care unit. PATIENTS: Eleven
      intubated pediatric intensive care patients receiving continuous lorazepam
      infusion for sedation. INTERVENTIONS: Propylene glycol accumulation was
      determined by comparing concentrations at baseline, after 48 hrs, and at end of
      therapy. Laboratory abnormalities were determined by comparing serum lactate and
      osmolar gap at baseline, after 48 hrs, and at end of therapy. Correlation between
      the cumulative dose of lorazepam received and the propylene glycol concentration
      measured at the end of therapy was determined. MEASUREMENTS AND MAIN RESULTS:
      Patients aged 1-15 months were studied. Lorazepam infusion rates ranged from 0.1
      to 0.33 mg.kg.hr and lasted 3-14 days. Propylene glycol accumulated significantly
      in patients receiving continuous infusion of lorazepam. The propylene glycol
      concentration increased during the study from 86 +/- 93 microg/mL at baseline to
      763 +/- 660 microg/mL at the end of the study ( p=.038). A statistically
      significant correlation between the cumulative dose of lorazepam received and
      propylene glycol concentration at the end of therapy was demonstrated ( r(2)=.65,
      p<.005). However, the propylene glycol accumulation was not associated with
      significant laboratory abnormalities. Neither serum lactate concentrations nor
      osmolar gap were significantly elevated over baseline. CONCLUSION: Propylene
      glycol accumulated significantly in pediatric intensive care patients receiving
      continuous lorazepam infusion, and propylene glycol concentration correlated with
      the cumulative lorazepam dose the patient received. However, significant
      laboratory abnormalities due to propylene glycol accumulation were not observed.

PMID- 12483069
TI  - Calciphylaxis, proteases, and purpura: an alternative hypothesis for the severe
      shock, rash, and hypocalcemia associated with meningococcal septicemia.
AB  - The hallmarks of severe meningococcal sepsis include the rapid onset of shock,
      purpuric rash, and metabolic derangement, in particular, hypocalcemia. The severe
      ecchymoses and purpura associated with meningococcal sepsis are usually
      attributed to acute thrombotic episodes, attributable to the associated
      procoagulation disorder. An alternative explanation for the rash is a sudden
      extravasation of calcium from the intravascular space into the tissues. We will
      argue that in meningococcal sepsis, cleavage of albumin into fragments by
      protease(s) occurs and these fragments, along with calcium, cross the endothelium
      into the interstitium. The fragmentation of albumin and its loss through the
      endothelium would also provide a more rational explanation for the rapidity of
      the shock and the hypocalcemia that is so characteristic of the disease.

PMID- 12483070
TI  - Inhaled prostacyclin for the treatment of pulmonary hypertension after cardiac
      surgery.
AB  - OBJECTIVE: To describe the effects of inhaled prostacyclin administered after
      cardiopulmonary bypass (CPB) to a patient with severe pulmonary hypertension.
      DESIGN: Case report and literature review. SETTING: Cardiac surgical operating
      rooms and postoperative recovery unit. PATIENTS: A 63-yr-old female who had
      undergone mitral and aortic valve replacement for rheumatic heart disease.
      INTERVENTIONS: Administration of inhaled prostacyclin to decrease pulmonary
      artery pressures and to permit discontinuation of CPB. MEASUREMENTS AND MAIN
      RESULTS: The patient was unable to be removed from CPB because of severe
      pulmonary hypertension precipitating acute right heart failure, despite
      administration of milrinone, norepinephrine, and nitroglycerin infusions. Inhaled
      prostacyclin was started at a dosage of 50 ng/kg/min, and the patient was able to
      be weaned from CPB. The inhaled prostacyclin was continued for 4 days
      postoperatively, with no signs of tolerance or systemic effects. CONCLUSION:
      Inhaled prostacyclin is an effective and selective pulmonary vasodilator at the
      dosage given in this report. Prolonged use is not associated with tolerance or
      systemic effects. The apparatus required for the delivery of inhaled prostacyclin
      is simple, inexpensive, and readily available in most hospitals. A review of the
      literature suggests that inhaled prostacyclin is effective in a number of
      clinical settings and displays comparable efficacy and hemodynamic effects to
      inhaled nitric oxide.

PMID- 12483071
TI  - Project IMPACT: results from a pilot validity study of a new observational
      database.
AB  - OBJECTIVE: The objective of this study was to evaluate the accuracy of the
      information contained in the Project IMPACT database. Project IMPACT is a
      comprehensive database system developed to measure and describe the care of
      intensive care patients. This database is being used by a large group of
      hospitals to help clinicians improve the care of these patients. Data on patient
      demographics, diagnoses, treatment, and outcomes are entered into the Project
      IMPACT database by staff at participating hospitals. This pilot study was a first
      step in assessing the accuracy of these data to determine the usefulness of the
      Project IMPACT database for measuring intensive care unit (ICU) performance and
      patient outcomes. DESIGN: The design of the pilot study was the independent
      abstraction of selected data items from a random sample of ICU patient records
      from two hospitals participating in Project IMPACT. The abstracted data were
      compared with the data existing in the Project IMPACT database for agreement.
      SETTING: Abstraction was performed onsite at the two pilot hospitals by a trained
      abstractor who was not affiliated with either hospital. PATIENTS: Patients whose
      records were abstracted included 45 randomly selected ICU patients at each of the
      two pilot hospitals. MEASUREMENTS AND MAIN RESULTS: Comparison of the Project
      IMPACT data with the independently abstracted data indicated good agreement (80%
      or above) on discrete items, such as type of ICU patient. Poorer agreement (under
      80%) was seen for continuous items (e.g., 24-hr urine output) and coded items
      requiring judgment (e.g., reason for ICU admission). CONCLUSIONS: The pilot study
      showed good internal validity for most of the abstracted variables. High
      agreement rates were observed, regardless of method of original data capture
      (electronic download or manual entry), although agreement was higher for some
      data items that had been electronically downloaded into the Project IMPACT
      database. The results suggest that Project IMPACT is a valuable resource for ICUs
      to collect and evaluate information about treatment and patient outcomes.

PMID- 12483072
TI  - Sepsis- and endotoxemia-generated cytokines do not trigger activation of human
      platelets.
AB  - OBJECTIVE: To analyze the effect of cytokines generated in sepsis and endotoxemia
      (tumor necrosis factor [TNF]-alpha and interleukins [IL]-1beta, -6, and -8) on
      activation of human platelets and to study the effect of cytokines on platelet
      activation in the presence of alpha-thrombin, a potent inducer of coagulation and
      platelet activation generated in sepsis and endotoxemia. DESIGN: flow cytometric
      study of platelet activation induced by cytokines and/or thrombin in the whole
      blood and platelet-rich plasma (PRP) of healthy volunteers. SETTING: Research
      laboratory in a Canadian hospital. SUBJECTS: Nine healthy volunteers recruited
      from laboratory staff. MEASUREMENTS AND MAIN RESULTS: Venous blood samples were
      obtained into acid-citrate-dextrose anticoagulant. Whole blood and PRP were
      diluted with appropriate buffer optimized for analyzing platelet activation by
      flow cytometry. TNF-alpha, IL-1beta, IL-6, and IL-8 were added to blood or PRP in
      concentrations ranging from 1 to 100 ng/mL and incubated for 15 mins at 37
      degrees C in the presence or absence of a submaximal concentration of human alpha
      thrombin (0.025 units/mL). Samples were stained with fluorescent antibodies
      against markers of platelet activation (P-selectin [CD62], lysosomal protein
      [CD63], and fibrinogen and von Willebrand factor receptors [CD41 and CD42b,
      respectively]) and analyzed by flow cytometry. The data obtained show that none
      of these cytokines trigger activation of resting platelets in whole blood or PRP
      and do not modulate the effect of thrombin on platelet activation as measured by
      quantitation of CD62, CD63, and CD42b markers on the platelet surface.
      CONCLUSIONS: Cytokines TNF-alpha, IL-1beta, IL-6, and IL-8, which are extensively
      produced in sepsis and endotoxemia, do not trigger activation of resting human
      platelets directly or indirectly by mediating processes in white or red blood
      cells. The cytokines did not affect thrombin-induced platelet activation.

PMID- 12483073
TI  - Does acute hyperventilation cause cerebral ischemia in severely head-injured
      patients?

PMID- 12483074
TI  - Molecular mechanisms of slime production: a transferable operon explains how a
      saprophyte finds a home.

PMID- 12483075
TI  - Evaluating the outcome from respiratory care.

PMID- 12483076
TI  - Evaluation of brain injury using a blood test: is there a role in clinical
      practice?

PMID- 12483077
TI  - Mitochondrial dysfunction in sepsis: a familiar song with new lyrics.

PMID- 12483078
TI  - Open visiting vs. safety.

PMID- 12483079
TI  - Living with a union contract.

PMID- 12483080
TI  - Succession planning.

PMID- 12483081
TI  - The impact of an advisory board on a parish nurse program.

PMID- 12483082
TI  - Competitors collaborating: creative strategies for addressing the shortage?

PMID- 12483083
TI  - What constitutes successful nurse leadership?: A qualitative approach utilizing
      Kanter's theory of organizational behavior.
AB  - What constitutes successful leadership in today's healthcare environment and what
      are the principal components of an organization that supports the role of the
      nurse leader? To answer these questions, 16 nurse leaders from four acute care
      hospitals were interviewed for their perception of leadership traits that are
      effective in the inpatient hospital setting and types of organizational
      infrastructures that create conditions for job effectiveness. Kanter's theory of
      organizational behavior provided the conceptual framework for this study.
      Leadership effectiveness is linked to having access to opportunity, resources,
      information, and formal and informal power in the work setting. Nurse leaders
      with access to these structures are empowered and successful, which leads to
      enhanced worth and overall organizational achievement. Also, strong central
      beliefs and business astuteness are considered vital attributes in today's
      economically oriented environment.

PMID- 12483084
TI  - The impact of staffing on patient outcomes across specialty units.
AB  - OBJECTIVE: Determine the relationships between nursing staffing and specific
      nurse-sensitive outcomes (central line blood-associated infection, pressure
      ulcer, fall, medication error, and restraint application duration rates) across
      specialty units (cardiac and noncardiac intensive care, cardiac and noncardiac
      intermediate care, and medical-surgical). BACKGROUND: A number of hospital-level
      studies have demonstrated that lower staffing levels are associated with higher
      adverse patient outcomes. However, insufficient insight into unit-level staffing
      relationships is available. Further unit-level inquiry is necessary to fully
      explicate the relationships between staffing and outcomes and to provide
      assistance to nurse administrators as they seek to develop blueprints for
      staffing plans that are linked to quality outcomes. METHODS: Secondary analysis
      of prospective, observational data from 95 patient care units (cardiac intensive
      care, n = 15; noncardiac intensive care, n = 7; cardiac intermediate care, n =
      18; noncardiac intermediate care, n = 12, and medical-surgical, n = 43) across 10
      acute care hospitals. RESULTS: No statistically significant relationships were
      found between central line infection and pressure ulcer rates and staffing across
      specialty units. Significant inverse relationships were present between staffing
      and falls in cardiac intensive care, medication errors in both cardiac and
      noncardiac intensive care units, and restraint rates in the medical-surgical
      units. CONCLUSIONS: Results from this study suggest that the impact of staffing
      on outcomes is highly variable across specialty units; however, when present, the
      relationships are inversely related with lower staffing levels, resulting in
      higher rates of all outcomes.

PMID- 12483085
TI  - Nurse staffing in long-term care facilities.
AB  - This qualitative study provides insight into how nurse administrators in long
      term care facilities make staffing decisions and the factors they consider when
      making those decisions. The provides an evidenced-based framework for nurse
      administrators on how they can organize a comprehensive staffing program for
      their facility.

PMID- 12483086
TI  - Job satisfaction among nurses: a predictor of burnout levels.
AB  - OBJECTIVE: This study assessed the impact of differential levels of job
      satisfaction on burnout among nurses, hypothesizing that higher levels of job
      satisfaction predict lower levels of burnout. BACKGROUND: Social environmental
      factors of the workplace arising from organizational restructuring cost
      containment strategies, diminishing resources, and increasing responsibilities,
      cause highly stressed, burned out nurses to leave the profession. METHODS: This
      study used the Maslach Burnout Inventory (MBI) to measure emotional exhaustion,
      depersonalization, and personal accomplishment. The job satisfaction scale of
      Katzell et al was used to measure overall job satisfaction. Statistical tests for
      significance used were Confirmatory Factor Analysis, Structural Equation
      Modeling, the chi statistic, Root Mean Square Error of Approximation, Goodness of
      Fit Index, and Comparative Fit Index. RESULTS: The findings show that job
      satisfaction has a significant direct negative effect on emotional exhaustion,
      whereas emotional exhaustion has a direct positive effect on depersonalization. A
      significant indirect effect was seen of job satisfaction on depersonalization via
      exhaustion. The path coefficient shows that job satisfaction has both direct and
      indirect effects on burnout, confirming job satisfaction as a significant
      predictor of burnout. IMPLICATIONS: Collaborative efforts between nurses,
      administrators, and educators to research and test practical models to improve
      job satisfaction may work as an antidote to burnout.

PMID- 12483087
TI  - Success.

PMID- 12483088
TI  - Learning effect and measurement variability in frequency-doubling technology
      perimetry in chronic open-angle glaucoma.
AB  - PURPOSE: To prospectively study the learning effects and measurement variability
      in frequency-doubling technology perimetry in glaucoma patients who were well
      practiced in testing with an automated static perimeter. PATIENTS AND METHODS:
      Patients with clinically stable chronic open-angle glaucoma (n = 44) who had
      undergone repeated perimetric testing using a 30-2 full-threshold program with a
      Humphrey perimeter with reliable results were enrolled in the study. The authors
      tested each patient using frequency-doubling technology perimetry. After initial
      examination with the C-20-1 screening program, the N-30 full-threshold program
      was performed three times at 1- to 3-month intervals. RESULTS: Perimetric results
      of the N-30 program improved with repeated testing in both eyes between the first
      and second visits. The average of mean deviation (MD) of the N-30 program
      significantly improved by 0.6 dB ( < 0.001) in the right eye and 0.8 dB ( <
      0.002) in the left eye between the first and second sessions. The sensitivity in
      4 of 19 test points (right eye) and 5 of 19 points (left eye) improved
      significantly at the second sessions, but not the third session. There were no
      significant differences in the FDT results between the second and third sessions
      in both eyes. The standard deviation of the mean MD value for the three sessions
      ranged from 3.8 to 4.0 dB in both eyes. CONCLUSION: Baseline measurements for
      perimetric follow-up with the N-30 full-threshold program in patients with
      glaucoma should be repeated at least twice after testing with the C-20-1
      screening program.

PMID- 12483089
TI  - Neuroprotective effect of memantine in different retinal injury models in rats.
AB  - PURPOSE: To evaluate the neuroprotective effect of memantine, an NMDA receptor
      channel blocker, in two retinal ganglion cell (RGC) injury models in rats.
      METHODS: Neuroprotective effect of memantine was tested in partial optic nerve
      injury and chronic ocular hypertensive models. In the optic nerve injury model,
      memantine (0.1 - 30 mg/kg) was injected intraperitoneally immediately after
      injury. Two weeks later, optic nerve function was determined by measuring
      compound action potential and surviving RGC was determined by retrograde labeling
      with dextran tetramethyl rhodamine. Chronic ocular hypertension was attained by
      laser photocoagulation of episcleral and limbal veins. Memantine (5 or 10 mg/kg)
      was administered continuously each day with an osmotic pump, either immediately
      after or 10 days after first laser photocoagulation, for 3 weeks, after which RGC
      survival was determined. RESULTS: Two weeks after partial optic nerve injury,
      there was approximately 80% reduction in RGC number. Memantine (5 mg/kg) caused a
      twofold increase in compound action potential amplitude and a 1.7-fold increase
      in survival of RGCs, respectively. In the chronic ocular hypertension model there
      was 37% decrease in RGCs after 3 weeks of elevated intraocular pressure.
      Memantine (10 mg/kg daily) reduced ganglion cell loss to 12% when applied
      immediately after first laser photocoagulation, and prevented any further loss
      when applied 10 days after first laser photocoagulation. CONCLUSION: The
      protective effect of memantine suggests that excessive stimulation of NMDA
      receptors by glutamate is involved in causing cell damage in these RGC injury
      models.

PMID- 12483090
TI  - Retinal nerve fiber layer measurement of the Hong Kong chinese population by
      optical coherence tomography.
AB  - PURPOSE: To obtain retinal nerve fiber layer (RNFL) measurements by optical
      coherence tomography in a local, normal Hong Kong Chinese population and to
      identify the correlation of the measurement with age cross-sectionally. METHODS:
      A total of 129 normal Hong Kong Chinese volunteers of different age groups were
      recruited for this study. The RNFL was measured by optical coherence tomography
      (OCT; OCT 2000; Humphrey Instruments, San Leandro, CA). RESULTS: Mean +/- SD
      peripapillary RNFL measurements at the superior, inferior, temporal, and nasal
      regions were 145 +/- 24, 154 +/- 26, 98 +/- 32, and 87 +/- 16 microm,
      respectively. There was a highly significant negative correlation in average RNFL
      measurement with increasing age (3.3 microm per decade, < 0.001). A significant
      negative correlation with increasing age was also identified in the RNFL
      measurements in all the regions ( < 0.05) and decreased at similar extent.
      CONCLUSION: The RNFL thickness of the Hong Kong Chinese population, as measured
      by OCT, appeared to decrease over time. The OCT normative values used for
      determining RNFL measures "outside of normal" should be developed on an age
      specific, or at least age-adjusted, basis.

PMID- 12483091
TI  - Laser peripheral iridoplasty as initial treatment of acute attack of primary
      angle-closure: a long-term follow-up study.
AB  - PURPOSE: To study the long-term clinical course and complications of patients
      with acute primary angle-closure treated with immediate laser peripheral
      iridoplasty followed by laser peripheral iridotomy. PATIENTS AND METHODS:
      Consecutive patients with acute primary angle closure treated with immediate
      laser peripheral iridoplasty, followed by laser peripheral iridotomy, at the
      Prince of Wales Hospital from July 1997 through January 2000 were followed up to
      document the clinical course of their disease and any complications from the
      laser treatment. Visual acuity, intraocular pressure, gonioscopic findings,
      corneal and lens clarity, iris appearance, pupillary reaction, and progression of
      glaucomatous optic neuropathy were evaluated. RESULTS: Thirty eyes of 29 Chinese
      patients with acute primary angle closure treated initially with either argon or
      diode laser peripheral iridoplasty were recruited. The mean follow-up period was
      33.0 +/- 9.3 months. Twenty-one eyes (70%) had no further attack and maintained
      normal intraocular pressure without medications, and 9 eyes (30%) developed
      chronic angle-closure glaucoma with peripheral anterior synechiae. All eyes had
      pigmented laser marks on the peripheral iris, but none had peripheral corneal
      burn. CONCLUSIONS: Long-term follow-up data indicated that 30% of Chinese eyes
      with acute primary angle closure successfully treated with immediate laser
      peripheral iridoplasty followed by laser peripheral iridotomy developed
      peripheral anterior synechiae and an increase in intraocular pressure. There were
      minimal long-term complications on the cornea and the lens from the laser
      treatment.

PMID- 12483092
TI  - Intraobserver reproducibility of a two-dimensional mapping of the optic nerve
      head perfusion.
AB  - PURPOSE: To evaluate the intraobserver reproducibility of a software designed to
      assess retinal blood flow with the Heidelberg Retina Flowmeter (HRF). METHODS:
      Ten subjects were consecutively recruited, and one eye of each patient was
      randomly selected for study. Blood flow measurements were analyzed by using an
      automatic full field perfusion image analysis (AFFPIA) program, which calculates
      the Doppler frequency shift and hemodynamic variables (flow, volume, and
      velocity) for each pixel. The resulting perfusion image is processed with respect
      to underexposed and overexposed pixels, saccades, and retinal vessel tree.
      Intraobserver reproducibility was calculated for the AFFPIA program. All the
      optic nerve heads were horizontally divided into three sections (superior,
      central, and inferior). The retinal blood flow was calculated in the superior and
      inferior section, and each section was further divided into three areas
      (temporal, nasal, and rim). The blood flow was evaluated for each area. RESULTS:
      When the same observer analyzed the same image five times (intraobserver
      intraimage reproducibility), the AFFPIA coefficient of variation ranged from 0.5%
      to 5% in the temporal area, from 0.1% to 5.3% in the nasal area, and from 0.5 to
      28% in the rim area. When the same observer analyzed three different images of
      the same section once (intraobserver interimage reproducibility), the AFFPIA
      coefficient of variation of flow measurements ranged from 1% to 7.3% in the
      temporal area, from 1.5% to 10% in the nasal area, and from 2 to 30% in the rim
      area. CONCLUSION: Retinal blood flow measured by HRF and analyzed by AFFPIA had
      good intraobserver reproducibility. The reproducibility was significantly better
      in the temporal and nasal areas than in the rim area.

PMID- 12483093
TI  - Effect of mild to moderate myopic correction by laser-assisted in situ
      keratomileusis on intraocular pressure measurements with goldmann applanation
      tonometer, tono-pen, and pneumatonometer.
AB  - PURPOSE: To evaluate the effect of mild to moderate myopic correction by laser
      assisted in situ keratomileusis (LASIK) on intraocular pressure (IOP)
      measurements with three tonometers: the Goldmann applanation tonometer, Tono-Pen,
      and pneumatonometer. PATIENTS AND METHODS: In a prospective study of a clinic
      based population undergoing elective LASIK surgery for myopia correction, IOP
      measurements were obtained preoperatively and postoperatively with a Goldmann
      applanation tonometer, Tono-Pen, and pneumatonometer. Central corneal thickness
      and keratometric and astigmatism measurements were also obtained before and after
      surgery. A paired test was used to evaluate the significance of differences
      between preoperative and postoperative IOP measurements with each instrument.
      Linear regression was used to correlate IOP measurements with degree of myopia
      corrected, astigmatism, and central corneal thickness before and after surgery.
      RESULTS: The study included 66 eyes of 34 individuals with a mean preoperative
      refractive error of -5.66 + 2.3 D (mean + SD). The reduction of central corneal
      thickness after LASIK of 0.032 + 0.030 mm (mean + SD) was statistically
      significant ( < 0.0001). However, there was no statistically significant change
      in mean IOP after the procedure with the Goldmann applanation tonometer or the
      Tono-Pen, while the pneumatonometer, was associated with a small but
      statistically significant decrease in mean IOP of 1.1 mm Hg. CONCLUSION: In this
      group of patients with mild to moderate myopia, LASIK had little or no
      statistically significant influence on IOP readings obtained with a Goldmann
      applanation tonometer, Tono-Pen, or pneumatonometer. This finding is in contrast
      to earlier reports of greater amounts of myopic correction, in which significant
      reductions in measured IOP were observed. Further study is needed to determine
      whether a critical amount of corneal change after LASIK is required to have a
      significant effect on IOP measurements.

PMID- 12483094
TI  - A comparative clinical study of latanoprost and isopropyl unoprostone in Japanese
      patients with primary open-angle glaucoma and ocular hypertension.
AB  - PURPOSE: To compare the efficacy and safety of latanoprost versus isopropyl
      unoprostone (unoprostone) in Japanese patients with primary open-angle glaucoma
      (POAG) or ocular hypertension (OH). METHODS: An 8-week, multicenter, randomized,
      comparative study was performed in 48 Japanese patients with POAG or OH. Four
      patients (two in each group) withdrew from the study, but their data were
      included in the safety assessment but not in the intraocular pressure (IOP)
      evaluation. The patients were randomly treated with latanoprost 0.005% once daily
      or unoprostone 0.12% twice daily for 8 weeks. IOP was measured at baseline and 2,
      4, and 8 weeks after treatment. In addition, ocular and systemic adverse events
      were recorded. RESULTS: The baseline IOPs were similar between the latanoprost (n
      = 25) and unoprostone (n = 19) groups (24.3 +/- 2.4 mm Hg vs 23.3 +/- 2.1 mm Hg,
      respectively, = 0.18). The IOP reductions from baseline at 2, 4, and 8 weeks
      after treatment were 5.8 +/- 2.4, 6.6 +/- 2.5, and 6.7 +/- 2.0 mm Hg in the
      latanoprost group, and 3.8 +/- 2.0, 3.5 +/- 2.3, and 3.3 +/- 3.0 mm Hg in the
      unoprostone group, respectively. The IOP reduction in the latanoprost group at 8
      weeks was larger than that in the unoprostone group ( < 0.001, analysis of
      covariance). Five adverse events were observed in 4 (15%) of 27 patients in the
      latanoprost group, and five adverse events were observed in 4 (20%) of 21
      patients in the unoprostone group. There was no difference in the incidence of
      adverse events between groups ( = 0.71). CONCLUSION: Latanoprost produced a
      statistically greater reduction in IOP than unoprostone in Japanese patients with
      POAG or OH.

PMID- 12483095
TI  - An ultrasound biomicroscopic study of the anterior segment in Indian eyes with
      primary angle-closure glaucoma.
AB  - PURPOSE: To evaluate the presence of plateau iris in eyes with primary angle
      closure glaucoma (PACG) after laser peripheral iridotomy by gonioscopy and
      ultrasound biomicroscopy and to evaluate the pathogenesis of this condition by
      comparing the UBM parameters of these eyes with those in normal subjects.
      PATIENTS AND METHODS: This prospective study was carried out in the Glaucoma
      clinic of a tertiary eye care center. A detailed clinical examination including
      applanation tonometry, indentation gonioscopy with a Sussman four-mirror
      gonioscope, and ultrasound biomicroscopic examination in one randomly selected
      eye of 55 patients (55 eyes) with PACG who had undergone laser peripheral
      iridotomy and 22 normal subjects (22 eyes). RESULTS: Among the PACG eyes, 40%
      (22/55) had an open angle (angle opening distance > 130 microns) and 60% (33/55)
      eyes had a narrow angle (angle opening distance <or= 130 microns). A large
      anteriorly placed ciliary process with a narrow ciliary sulcus was found in 9 of
      the 22 eyes with open angle (40.9%), and 22 of the 33 eyes with narrow angles
      (66.66%). Trabecular ciliary process distance was significantly larger in the
      eyes with open angles compared with those with narrow angles ( = 0.001).
      CONCLUSIONS: Plateau iris was common in the clinic population studied. Anteriorly
      directed ciliary processes were seen both in eyes with plateau iris as well as in
      eyes with PACG that had deep anterior chambers after iridotomy.

PMID- 12483096
TI  - Setons and serum IgG titers to silicone.
AB  - PURPOSE: To determine whether exposure to silicone shunts used in refractory
      glaucomas increases serum IgG binding to silicone and whether this response is
      associated with shunt-related complications or poor postoperative intraocular
      pressure control. METHODS: Sera from 12 patients (13 eyes) who had undergone
      placement of silicone seton implants were examined for IgG binding to silicone.
      Patients were monitored postoperatively for the occurrence of complications and
      intraocular pressure elevation (mean duration of exposure to silicone and follow
      up, 25.1 months; range, 2.5-86 months). RESULTS: The levels of serum IgG binding
      in 4 of the 12 patients were two standard deviations above the mean for control
      sera. No patients had titers greater than 46 arbitrary units (AU). Four patients
      developed shunt-related complications; the serum IgG binding to silicone for
      their sera ranged from 24 to 46 AU. Serum IgG binding values were not
      significantly correlated with poor postoperative intraocular pressure control, or
      with a history of autoimmune disease or malignancy, type of glaucoma, previous
      intraocular surgery, or chronic uveitis. CONCLUSIONS: Although elevation of serum
      IgG binding to silicone may be noted in some patients receiving silicone seton
      shunts, individual levels do not seem to predict the development of shunt-related
      complications. Since the number of patients tested, the frequency of elevated IgG
      binding values, and the complication rate were relatively low in this study, it
      is difficult to exclude some clinicopathologic correlations. However, the results
      are in accord with previous studies of silicone ocular devices suggesting that
      clinically significant reactions to silicone ophthalmic implants must be rare
      events, and hence do not necessitate altering the use of these important devices.

PMID- 12483097
TI  - The learning effect in visual field testing of healthy subjects using frequency
      doubling technology.
AB  - PURPOSE: To evaluate the presence, duration and magnitude of a learning effect in
      serial visual field (VF) testing, using the commercially available frequency
      doubling technology (FDT) instrument. PATIENTS AND METHODS: 21 healthy adults
      with no prior VF experience underwent 6 serial VF tests, using the full-threshold
      C-20 program of the Zeiss-Humphrey FDT analyzer, on one randomly chosen eye.
      Tests were spaced at least two days apart. RESULTS: The average mean sensitivity
      was 32.37 +/- 2.6 dB; the average mean deviation (MD) was 1.22 +/- 1.8 dB. The MD
      at the first examination (0.28 +/- 2.1 dB) was significantly poorer than at any
      of the other testing sessions (p<0.003). Similarly, the mean sensitivity at the
      first examination (31.16 +/- 3.0 dB) was significantly lower than any other
      testing session (p<0.004). The proportion of improvement from the first to the
      second session was 63% and 65% of the total improvement, for mean sensitivity and
      MD, respectively. Mean test duration showed a modest reduction, from 4.40 +/- 0.3
      minutes in the first session to 4.17 +/- 0.4 minutes in the last session (p =
      0.023). A sub-analysis comparison of the different VF segments showed a more
      prominent learning effect in the peripheral and nasal visual segments (p<0.0001).
      CONCLUSION: Baseline measurements should best rely on the second testing session,
      since MD and mean sensitivity are somewhat poorer when subjects with no prior VF
      experience are first tested on the FDT instrument. This may be especially true
      for the purpose of following patients over time.

PMID- 12483098
TI  - Unilateral exfoliation syndrome: conversion to bilateral exfoliation and to
      glaucoma: a prospective 10-year follow-up study.
AB  - PURPOSE: This prospective 10-year follow-up study was conducted to examine
      conversion of nonglaucomatous eyes with unilateral exfoliation syndrome (EXS) to
      bilateral EXS and to glaucoma. Risk factors for conversion to a bilateral
      condition and to glaucoma were studied. PATIENTS: Sixty-three nonglaucomatous
      subjects (mean age, 68.6 +/- 6.2 years) with unilateral EXS were enrolled. Of
      these patients, 56 were followed-up (89%). The effects of age, initial
      intraocular pressure (IOP), IOP difference between the fellow eyes, angle
      pigmentation, amount of exfoliation material, pupillary dilatation, optic disc
      topography, and phenylephrine-induced pigmentary dispersion on occasional
      conversion to the bilateral form and to glaucoma were studied by multivariate
      survival analysis. RESULTS: In 10 years, 38% had converted to bilateral EXS.
      Conversion to exfoliation glaucoma (EG) was 32% in the initially exfoliative eyes
      and 38% in the initially nonexfoliative (non-EXS) fellow eyes. Primary open-angle
      glaucoma developed in 3.5% of the non-EXS eyes. In the initially EXS eyes, a
      significant association was found between the initial IOP and conversion to EG
      (relative risk = 1.471, = 0.0001). When initial IOP was removed from the model,
      the pupillary dilatation values (relative risk = 0.488, = 0.035) and the
      differences in IOP between the fellow eyes (relative risk = 1.224, = 0.0181) were
      associated with conversion to EG. None of the factors studied was associated with
      conversion to the bilateral form. CONCLUSION: In unilateral EXS, factors
      associated with conversion to EG were initial IOP, pupillary dilatation value,
      and difference in IOP between the fellow eyes. No risk factors for conversion to
      bilateral EXS were found.

PMID- 12483099
TI  - Nanophthalmia and chronic angle-closure glaucoma.

PMID- 12483100
TI  - Tenon's traction sutures: an aid for trabeculectomy and aqueous drainage device
      implantation.
AB  - PURPOSE: To describe a surgical technique to improve visualization and surgical
      access for trabeculectomy and implantation of aqueous drainage devices. MATERIALS
      AND METHODS: After the corneal traction suture (6-0 polygalactin; S-29 needle) is
      placed, a second suture is passed through Tenon's capsule alone, either at the
      anterior edge of a limbus-based conjunctival flap for trabeculectomy or at the
      incisional edge of a fornix-based conjunctival flap for drainage implant surgery.
      RESULTS: The incision for limbus-based peritomies must be posterior enough to
      take advantage of the posterior thickening of Tenon's capsule when placing the
      traction suture. The use of traction sutures enhances visualization and limbal
      surgical access for trabeculectomy. They also enhance posterior ocular surface
      visualization and aid placement of scleral fixation sutures for securing the
      explants of aqueous drainage devices. CONCLUSIONS: Tenon's traction sutures are
      an aid to visualization and to surgical access during glaucoma filtering surgery.

PMID- 12483101
TI  - Health economics, economic evaluation, and glaucoma.
AB  - Glaucoma has not received a great deal of attention from health economists in the
      past, partly due to the fact that no new treatments have been introduced for some
      time. Economic evaluation is generally performed for new technologies, to assess
      their cost-effectiveness compared with current treatments, to estimate the
      potential changes in the use of health care resources that their introduction may
      produce, and to make decisions about their reimbursement status and formulary
      inclusion. Economic studies in glaucoma have been largely limited to studies
      about cost, because a useful outcome measure has been lacking. Therapy aims at
      reducing intraocular pressure, but the data to estimate the absolute risk of
      vision loss due to high pressure have been lacking. Hence, it has been impossible
      to assess the benefit of treatments in terms of their ability to reduce
      blindness. However, as new out knowledge about these issues increases and more
      data become available, such studies become possible. This review illustrates the
      issues encountered when performing economic evaluation in glaucoma and reviews
      the current economic literature in the field.

PMID- 12483102
TI  - Supraciliochoroidal fluid in the eyes indicates good intraocular pressure control
      despite absence of obvious filtering bleb after trabeculectomy.
AB  - PURPOSE: To examine the presence of supraciliochoroidal fluid (SCF) by ultrasound
      biomicroscopy in posttrabeculectomy eyes that show good intraocular pressure
      (IOP) control despite the absence of an obvious filtering bleb. PATIENTS AND
      METHODS: Eyes were selected retrospectively according to the following criteria:
      IOP < 15 mm Hg, no antiglaucoma medication, no filtering bleb or a flattened bleb
      without microcystic spaces, and no ophthalmoscopic choroidal detachment after
      trabeculectomy with mitomycin C. The SCF was examined using 50-MHz ultrasound
      biomicroscopy (Zeiss-Humphrey). RESULTS: Ultrasound biomicroscopy detected SCF in
      five (63%) of eight eyes that met the study criteria. The extent of SCF in two of
      the eyes was four quadrants and one or two quadrants in three eyes. CONCLUSION:
      The presence of the SCF may explain increased uveoscleral outflow and may
      represent an IOP-lowering mechanism after trabeculectomy with mitomycin C,
      especially when IOP control is good and a filtering bleb is not obvious.

PMID- 12483103
TI  - Central corneal thickness on GAT (Goldman applanation tonometry accuracy).

PMID- 12483105
TI  - PX domain takes shape.
AB  - In recent years, a number of protein domains have been identified that bind
      phosphoinositides and direct proteins to membrane targets. A recent addition to
      this group is the Phox homology or PX domain, a 120-amino acid domain conserved
      from yeast to humans, which is present in proteins involved in cell signaling,
      protein sorting, vesicle fusion, and the assembly of components of the superoxide
      generating system of neutrophils. These domains have varying affinities for
      phosphatidylinositol-3-phosphate (PI(3)P), and PI(3,4) and (4,5) bisphosphates,
      which couple the PI kinase and phosphatase signaling networks to the assembly of
      proteins at membrane surfaces. These PX domains also contain a PXXP motif,
      allowing them to bind to proteins containing Src homology 3 (SH3) domains.

PMID- 12483106
TI  - Regulation of neutrophil function by Rac GTPases.
AB  - Rac plays a central role in regulating neutrophil responses to inflammatory
      signals, including actin remodeling, chemotaxis, and superoxide production by the
      nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Rac-GTP is a
      component of the membrane-assembled NADPH oxidase complex, and new evidence
      suggests that Rac-GTP interacts directly with the oxidase flavocytochrome, in
      addition to binding to the regulatory p67 subunit, to regulate electron transfer
      both independently and cooperatively from NADPH to molecular oxygen. Other new
      studies suggest that Rac-GTP plays a dual role in NADPH oxidase activation, and
      can initiate signaling pathways leading to translocation of cytosolic oxidase
      subunits in addition to functioning in the assembled enzyme complex. Rac
      activation in response to neutrophil chemoattractants may be regulated in large
      part by a newly identified guanine nucleotide exchange factor, P-Rex1, which is
      activated by either phosphatidylinositols or Gbetagamma subunits. Multiple Rac
      GTPase activating proteins are present in neutrophils and may also modulate
      levels of Rac-GTP. The importance of Rac in a broad range of neutrophil functions
      is shown by the variety of defects seen in neutrophils from Rac2 knockout mice
      and from a patient with recurrent infections and a dominant-negative mutation in
      Rac2.

PMID- 12483107
TI  - Structure, organization, and function of glycosphingolipids in membrane.
AB  - A large variety of glycosylation patterns in combination with different ceramide
      structures in glycosphingolipids provide a basis for cell type-specific
      glycosphingolipid pattern in membrane, which essentially reflects the composition
      of glycosphingolipid-enriched microdomains. Functions of glycosphingolipids as
      antigens, mediators of cell adhesion, and modulators of signal transduction are
      all based on such organization. Of particular importance is the assembly of
      glycosphingolipids with signal transducers and other membrane proteins to form a
      functional unit termed a, through which glycosylation-dependent cell adhesion
      coupled with signal transduction takes place. The microenvironment formed by
      interfacing glycosynapses of interacting cells plays a central role in defining
      phenotypic changes after cell adhesion, as occur in ontogenic development and
      cancer progression. These basic functional features of glycosphingolipids in
      membrane can also be considered roles of glycosphingolipids and gangliosides
      characteristic of neutrophils, myelocytes, and other blood cells. A series of
      sialyl fucosyl poly-N-acetylgalactosamine gangliosides without the sialyl-Le
      epitope, collectively termed, have been shown to mediate E-selectin-dependent
      rolling and tethering under dynamic flow with physiologic shear stress
      conditions. Functional roles of myeloglycan in neutrophils during inflammatory
      processes are discussed.

PMID- 12483108
TI  - Neutrophil transendothelial migration and alteration in vascular permeability:
      focus on neutrophil-derived azurocidin.
AB  - Infiltration and accumulation of polymorphonuclear leukocytes within the tissues
      is a hallmark of the acute inflammatory response. A prominent feature of acute
      inflammation is enhanced vascular permeability resulting in edema formation. Such
      changes in vascular permeability have been known to be dependent upon
      polymorphonuclear leukocyte interactions with the vascular endothelium. Careful
      investigation has shown clearly that permeability changes can occur without
      polymorphonuclear leukocyte transendothelial migration, and that
      polymorphonuclear leukocyte migration can occur without permeability alteration.
      The underlying mechanisms of polymorphonuclear leukocyte-stimulated changes in
      endothelial barrier function have remained elusive. Endothelial activation and
      polymorphonuclear leukocyte adhesion to the endothelium are both required for
      polymorphonuclear leukocyte-induced changes in vascular permeability.
      Polymorphonuclear leukocyte-derived azurocidin plays a major role in this
      polymorphonuclear leukocyte-evoked alteration in endothelial permeability.
      Azurocidin is released after activation of polymorphonuclear leukocytes, such as
      after ligation of the major adhesive integrin CD11b/CD18. Understanding how
      polymorphonuclear leukocytes alter vascular permeability may provide targets for
      new drugs for appropriate therapeutic intervention in acute and chronic
      inflammatory diseases. This review focuses on the role of polymorphonuclear
      leukocyte-derived azurocidin in alteration of vascular permeability.

PMID- 12483109
TI  - Update in childhood acute myeloid leukemia: recent developments in the molecular
      basis of disease and novel therapies.
AB  - Childhood acute myeloid leukemia is a heterogeneous group of disorders that
      remains challenging to treat. There are multiple common genetic alterations in
      childhood acute myeloid leukemia. These include chromosomal translocations
      affecting RUNX1-CBFbeta, RARalpha, and MLL. There are known activating mutations
      in the genes for the receptor tyrosine kinases FLT3, KIT, and FMS. As these
      abnormalities are better understood, they are providing important insights into
      the pathogenesis of disease as well as information about prognosis. Although
      intensive chemotherapy remains the mainstay of acute myeloid leukemia therapy,
      long-term cure rates with chemotherapy alone remain approximately 50%, creating
      an urgent need for better therapies. Multiple avenues are being explored in the
      design of new treatments for pediatric acute myeloid leukemia. Targeted therapies
      include targeted antibody therapy; inhibitors of FLT3, KIT, and
      farnesyltransferase; diphtheria toxin conjugated to the granulocyte-macrophage
      colony-stimulating factor; and antisense oligonucleotides. Another area of
      interest is chromatin remodeling and differentiation therapy, including agents
      such as all- retinoic acid, arsenic trioxide, and inhibitors of DNA methylation
      and histone deacetylation. There are also ongoing trials of antiangiogenesis
      agents. Another avenue for novel therapies is immunotherapy with agents such as
      interleukin-2 and tumor vaccines. This article reviews recent advances in
      understanding of the molecular basis for childhood acute myeloid leukemia and the
      design of novel therapies for the treatment of childhood acute myeloid leukemia.

PMID- 12483110
TI  - Role of constitutively activated protein tyrosine kinases in malignant
      myeloproliferative disorders: an update.
AB  - Modern molecular technology helped identify more than 10 protein tyrosine kinases
      related to myeloid malignancies, which allowed the development of small molecule
      inhibitors targeting deregulated protein tyrosine kinase activity. Protein
      tyrosine kinase deregulation can occur as a consequence of fusion gene formation
      because of chromosomal translocations, or as distinct gain-of-function point
      mutations. Although the tyrosine kinase inhibitor imatinib mesylate (Gleevec)
      targeting the ABL protein tyrosine kinase has revolutionized current chronic
      myeloid leukemia therapy, it became rapidly evident that overcoming the multiple
      cellular resistance mechanisms will be very challenging. To develop efficient
      therapeutic alternatives, one must understand the complex signal transduction
      mechanisms involved in transformation by deregulated protein tyrosine kinases.
      This article reviews the most recently identified molecular mechanisms involved
      in cell transformation by the BCR/ABL protein tyrosine kinase fusion and presents
      new members of the increasing family of deregulated protein tyrosine kinases
      involved in myeloproliferative disorders. In addition, the article discusses new,
      promising small molecule protein tyrosine kinase inhibitors and the molecular
      mechanism that may lead to resistance to these drugs. Finally, the article
      highlights putative alternative strategies that could be used to block signal
      transduction pathways of deregulated protein tyrosine kinase activity.

PMID- 12483112
TI  - New developments in anti-tumor efficacy and malignant transformation of human
      natural killer cells.
AB  - For decades, the driving force behind many immunologic studies has been the hope
      of augmenting anti-cancer therapy through targeted immune-based strategies. The
      question remains: can immune cells be successfully manipulated to augment
      chemotherapy and aid in the elimination of malignancy? Such efforts have included
      work with natural killer (NK) cells, large granular lymphocytes that contribute
      to the early innate immune response by nonspecifically killing pathogens, virus
      infected cells, and tumor cells, and by producing important early
      immunoregulatory cytokines such as interferon gamma (IFN-gamma). These qualities
      have made NK cells attractive candidates for therapy aimed at boosting host
      immunity against tumor cells and infectious pathogens. Recent advances in our
      understanding of how NK cells select targets for killing have improved our
      ability to design and test more effective immune-targeted therapies. However, our
      understanding of NK leukemias and lymphomas remains incomplete. NK leukemias and
      lymphomas, while rare, represent a significant challenge to the patients and
      physicians coping with them, as most lack effective treatment strategies. This
      brief review will summarize current directions in NK cell immune therapy and give
      an update on the classification and treatment of NK malignancies.

PMID- 12483111
TI  - Role of neutrophil elastase in bone marrow failure syndromes: molecular genetic
      revival of the chalone hypothesis.
AB  - Two forms of inherited deficiency of neutrophil numbers are cyclic hematopoiesis
      and severe congenital neutropenia. In cyclic hematopoiesis, neutrophil counts
      oscillate opposite monocytes in a 3-week cycle. Severe congenital neutropenia
      consists of static neutropenia and a predisposition to myelodysplasia and acute
      myelogenous leukemia. All cases of cyclic neutropenia and most cases of severe
      congenital neutropenia result from heterozygous germline mutations in the gene
      encoding neutrophil elastase, ela2. Recent work extends the list of neutropenia
      genes to include WASp, Gfi-1, adaptin, and tafazzin. Studies of mosaic patients
      suggest that ela2 mutations act in a cell-autonomous fashion. A hypothetical
      feedback circuit potentially interconnects these genes. Genetic dissection of
      signaling in model organisms along with experimental hematology implicate
      C/EPBepsilon, RUNX1/AML1, Notch family members, LEF1, and Cdc42 as additional
      nodes in this pathway. The authors propose that neutrophil elastase acts as an
      inhibitor of myelopoiesis, substantiating a chalone hypothesis proposed many
      years ago.

PMID- 12483113
TI  - Current challenges in therapy of myelodysplastic syndromes.
AB  - The International Prognostic Scoring System (or, more conveniently, the marrow
      blast percentage) can be used to divide patients with myelodysplasia into those
      with better (International Prognostic Scoring System low/ intermediate-1, or <10%
      blasts) and worse (International Prognostic Scoring System intermediate-2/high,
      or >10% blasts) prognoses. There is no treatment known to produce responses in
      the great majority of patients in either group. Hence, most patients should be
      considered for clinical trials. Exceptions are cases with low serum
      erythropoietin levels or low marrow cellularity; such cases may benefit from
      erythropoietin with or without granulocyte colony-stimulating factor or
      antithymocyte globulin, respectively. A wide variety of new agents are in
      clinical trial. These can be grouped into biologic or targeted, therapies, acute
      myelogenous leukemia-type chemotherapy, and allogeneic stem cell transplants. In
      general, competing risk-to-benefit ratios and consideration of natural histories
      suggest that patients with a better prognosis should receive biologic therapies
      first, with transplant reserved until failure. In higher-risk patients,
      particularly those who are relatively young or have a normal karyotype, acute
      myelogenous leukemia-type chemotherapy or transplant should be considered earlier
      in the course. The advent of nonmyeloablative (mini) transplant protocols has
      extended to 70 to 75 years the age at which transplantation can be performed,
      although the efficacy of such protocols is unknown. Current data do not permit
      recommendation of specific regimens in patients with a better or worse prognosis;
      rather, emphasis should be placed on entry into a clinical trial Finally, because
      other causes of cytopenias are more treatable, the diagnosis of myelodysplastic
      syndrome should depend on more than the presence of dysplasia, unless the
      dysplasia is very severe.

PMID- 12483114
TI  - Genetic basis of Fanconi anemia.
AB  - Fanconi anemia is a rare autosomal recessive disease characterized by bone marrow
      failure, developmental anomalies, a high incidence of myelodysplasia and acute
      nonlymphocytic leukemia, and cellular hypersensitivity to cross linking agents.
      Five of the seven known Fanconi anemia proteins bind together in a complex and
      influence the function of a sixth, FANCD2, which colocalizes with BRCA1 in
      nuclear foci after genotoxic stress. Carboxy-terminal truncating mutations of the
      seventh Fanconi anemia gene, BRCA2, are hypomorphic and lead to FA-D1 and
      possibly FA-B. Because the Fanconi anemia alleles of BRCA2 fail to bind to Rad51
      in response to genotoxic stress and Rad51 therefore fails to localize to nuclear
      damage foci, many investigators in the field suspect that the Fanconi anemia
      pathway supports the integrity of the Rad51 and BRCA1 and BRCA2 pathways as they
      function in homologous recombination repair. Because these abnormalities are
      common to all somatic cells, it is unlikely that dysfunction of this particular
      pathway results in tissue-specific apoptosis of hematopoietic cells. Indeed, at
      least one of the Fanconi anemia proteins, FANCC, exhibits functions in
      hematopoietic cells in addition to its role in the complex. Because FANCC
      protects hematopoietic cells from apoptotic cues in ways that do not require an
      intact heteromeric Fanconi anemia complex, it is reasonable to expect that the
      other Fanconi anemia gene products will have independent cytoplasmic and nuclear
      functions, particularly in hematopoietic and germ cells that seem to rely so
      substantially on an intact portfolio of Fanconi anemia proteins.

PMID- 12483116
TI  - [Introduction. Hearing and vestibular schwannomas].

PMID- 12483117
TI  - [Anatomy of the vestibulo-acoustico-facial neurovascular pedicle. Importance of
      therapeutic management of vestibular schwannomas].
AB  - A perfect knowledge of the anatomy of the vestibuloacusticofacial pedicle is
      required to preserve hearing and facial functions during cerebellopontine angle
      surgery for vestibular schwannoma. A clarification of the anatomy of this
      pedicle, in particular of its blood supply, is presented here, based on a review
      of the available literature, as well as on the author's data issued from
      anatomical dissections on latex-injected fresh specimens, and from radiological
      images of the cerebellopontine angle. The blood supply to the
      vestibuloacusticofacial bundle arises from the meatal loop of the anterior
      inferior cerebellar artery most often exhibited at the porus of the internal
      acoustical meatus. The labyrinthine artery is particularly exposed to injury
      between the cochlear and facial nerves. In addition, dissection in between these
      two nerves is likely to sever vessels directed to these nerves even though the
      labyrinthine artery is not interrupted. Thus, aside from a direct injury to the
      labyrinth, auditory function can be impaired through two distinct ischemic lesion
      types. Although the facial nerve is supplied through three main arterial systems
      (from the labyrinthine, the middle meningeal, and the stylomastoid arteries), its
      labyrinthine portion is more likely to suffer from ischemic damage as it is only
      supplied by meatal arteries. A refinement of our anatomical knowledge of the
      vestibuloacusticofacial pedicle, from a functional point of view, could arise
      from laser Doppler measurements of labyrinthine and facial blood flow during
      surgery, in an attempt to improve our functional preservation rate during
      therapeutic procedures for vestibular schwannoma.

PMID- 12483118
TI  - [Grade I and II vestibular schwannomas: hearing, clinical course. Pre- and
      postoperative aspects].
AB  - We propose a point by point response to the questions raised at this round table
      concerning the spontaneous and postoperative course of grade I and II vestibular
      schwannomas, focusing on hearing function. The questions concerning non-operated
      schwannomas are: For operated schwannomas, the questions are: Spontaneously, 75
      80% of these schwannomas progress significantly with a degradation of hearing
      function in more than half of the cases. We monitor clinical disorders and order
      routine audiometry and MRI. For us, Gardner and Roberson class A or 1 is truly
      useful hearing function. Preservation of truly useful hearing function after
      microsurgery is no better than 10%; satisfactory facial motor function is
      preserved in 70-80% of the cases with grade I, II, or III schwannomas and in more
      than 50% for grade IV schwannomas. Incomplete excision to preserve hearing
      function is compromised by recurrence. We preferably treat the smaller grade I
      schwannomas by radiosurgery to halt tumor progression and attempt to preserve
      hearing function.

PMID- 12483119
TI  - [Imaging findings in 122 cases of Pott's disease].
AB  - Spinal tuberculosis is a frequent skeletal involvement in tuberculosis. We report
      122 cases between 1983 and 1998 of Pott's disease explored by plain radiographies
      in all cases, CT-scan in 22 cases and MRI in 6 cases. The lesion involved one
      localization in 98 cases, two localizations in 9 cases and multiple localizations
      in 15 cases. The usual form associating the discal and vertebral involvement was
      noted in 70%. Unusual forms were seen in 30% of the cases The localizations were:
      posterior arch (20 cases), centrosomatic (10 cases), suboccipital (4 cases) and
      subligamentar (2 cases). In addition, the CT scan noted vertebral lesion with
      soft tissue abscess in all cases and epidural lesion in 9 cases. MRI performed in
      6 cases showed epidural lesions in 4 cases: epiduritis (2 cases) and abscess (2
      cases). The disco-vertebral puncture-biopsy, performed in 12 cases, confirmed the
      diagnosis in 7 cases. The diagnosis of Pott's disease was confirmed biologically
      in 30 cases. Radiographic exploration of Pott's disease is improved by the
      contributions of CT and MRI which can identify sequestra, perilesional sclerosis
      and epidural or soft tissue abscesses. Discovertebral aspiration biopsy provides
      the key to diagnosis.

PMID- 12483120
TI  - [Neurosurgical and endovascular treatment of intracranial aneurysms: a cost
      analysis of two different strategies at the University Hospital of Bordeaux
      (France)].
AB  - BACKGROUND: Rupture of intracranial aneurysms causes major mortality and
      morbidity. Moreover, treatment of this vascular malformation generates high
      medical costs. We compared the cost of two different strategies employed at the
      University of Bordeaux to prevent aneurysms from rebleeding: a classical
      neurosurgical technique consisting in clipping the neck of the aneurysm and a new
      less invasive neuroradiological technique based on embolization using platinum
      coils. METHOD: A micro-cost study was carried out retrospectively from May 1998
      to June 2000) comparing data from 44 patients admitted for ruptured intracranial
      aneurysm: 22 operated patients and 22 patients treated with an endovascular
      approach. Each operated patient was matched with an embolized patient for
      clinical status at admission (World Federation of Neurological Surgeons Scale)
      and complications resulting from cerebral hemorrhage (hydrocephalus, vasospasm,
      rebleeding). RESULTS AND CONCLUSION: Our results showed the same cost for the
      same efficiency . Expenditures are however made differently. The endovascular
      technique allows a shorter hospital stay (8 days less), balancing the high cost
      of single use medical supplies (coils, microcatheters.). The endovascular
      technique has many advantages for the patients, but cannot be successful in all
      types of intracranial aneurysms. Both techniques remain indispensable.

PMID- 12483121
TI  - [Contribution of perfusion magnetic resonance imaging in a patient with cerebral
      ganglioglioma].
AB  - A 48-year-old woman was admitted to the Neurosurgery Department for a large
      frontal lobe tumor revealed by partial seizures. The patient was conscious and
      alert. Neurological examination was normal. MRI study showed a right frontal lobe
      tumor compounded of an anterior solid mass strongly enhanced after gadolinium
      injection and a posterior voluminous cyst with important mass effect. The
      cerebral blood volume (CBV) map showed no area of elevated CBV within the tumor
      consistent with a low-grade tumor. The patient was operated on with a presumed
      diagnosis of anaplastic oligodendroglioma. Postoperative course was uneventful.
      Histopathological examination was consistent with a benign ganglioglioma. The
      patient did not undergo an additional treatment. One year later, the patient was
      healthy and neurological and neuropsychological examination were normal. MRI
      study did not show any recurrence. This case emphazises the relevance of
      perfusion MR imaging in the preoperative workup of glioneuronal and glial tumors.

PMID- 12483122
TI  - [Solitary plasmacytoma of the sphenoid. A case report].
AB  - A rare case of sphenoidal plasmacytoma in a 79 year-old male patient is reported.
      The diagnosis was preoperatively considered because of associated dysproteinemia
      and it was histopathologically confirmed on a transphenoidal biopsy specimen.
      Initial evaluation disclosed no systemic dissemination of the disease and a
      solitary plasmacytoma was diagnosed. Radiotherapy was delivered with subsequent
      clinical improvement and significant tumor reduction was illustrated on follow-up
      imaging studies. Twenty-two months after diagnosis, the patient remains
      asymptomatic without evidence of transformation to multiple myeloma. Only 7
      comparable cases have been reported in the literature. The diagnostic,
      pathological and nosographic features of sphenoid plasmacytomas are discussed.

PMID- 12483123
TI  - [Dedifferentiated chordoma of the skull base. A case report].
AB  - Sarcomatous transformation in chordoma is a very rare condition and has been
      emphasized as a distinct entity because of its more aggressive clinical course.
      Here we describe a case of dedifferentiated chordoma arising from the skull base
      region of an 11-year-old boy, with tumor recurrence within one year. This tumor
      showed features of pleomorphic cell sarcoma with areas more typical of chordoma.
      Most of tumor cells expressed cytokeratin, epithelial membrane antigen, vimentin
      and S-100 protein, thus confirming the diagnosis of dedifferentiated chordoma.

PMID- 12483124
TI  - [Capillary hemangioma of the spinal cord. A new case].
AB  - A 49-year-old man presented with a 8-month history of gait and sphincter
      disturbances. Examination revealed a spastic paraplegia predominant on the left
      limb, associated with decreased tactile sensitivity below T10. MRI showed a right
      posterolateral intramedullary lesion with an isosignal on T1-weighted images and
      a mild hypersignal on T2-weighted images, with an intense contrast enhancement;
      the spinal cord presented with an hypersignal on T2-weighted images. At
      operation, a vascular tumor presented at the spinal cord surface, was well
      demarcated from the parenchyma and was easily removed. Microscopic examination
      showed a capillary hemangioma. Three months later the patient exhibited a motor
      improvement with a right spasticity, deficits in proprioception, without
      sphincter abnormalities. A new MRI showed the disappearance of the hemangioma and
      of the preoperative spinal cord hypersignal. Capillary hemangiomas are unusual on
      nerves or roots. Cases found in the spinal cord are extremely rare: to our
      knowledge, 5 cases have been reported. On MRI, they are easily distinguished from
      cavernous hemangiomas, but microscopic examination is necessary to distinguish
      them from hemangioreticulomas. The postoperative prognosis is generally good.
      However, a report of a multiple location case, on roots and spinal cord, suggests
      the need for long follow-up.

PMID- 12483125
TI  - [Treatment of gastroesophageal reflux: a new frontier for interventional
      endoscopy?].

PMID- 12483126
TI  - [Endoscopic management of biliary and pancreatic ascariasis in Viet-Nam. Report
      of a series of 91 cases].
AB  - AIM: Ascariasis is the most widespread helminthiasis in the world. Biliary and
      pancreatic involvement, frequently encountered in endemic areas, is a serious
      public health problem. Surgical management is often required. The purpose of our
      work was to assess the feasibility of emergency endoscopic treatment of biliary
      and pancreatic ascariasis in the Viet Duc hospital (Hanoi, Vietnam), and to
      evaluate outcome. METHODS: A prospective study conducted over a 3-year period
      included 91 patients with biliary and pancreatic ascariasis. Diagnosis was based
      on clinical findings and abdominal ultrasound and was confirmed by endoscopic
      procedures. RESULTS: The 91 patients, 21 males and 70 females, mean age 41 +/- 17
      years, underwent endoscopic procedures to retrieve the worm. The procedure was
      successful in 89 patients (97.8%). Mild pancreatitis occurred in four patients
      who underwent biliary sphincterotomy. The mean hospital stay was 3.1 days.
      CONCLUSION: Endoscopic management of ascariasis is feasible, with a very low
      morbidity and a high rate of success. With this treatment, hospital stay is
      greatly shortened.

PMID- 12483127
TI  - [Treatment of Crohn's disease with anti-TNF alpha antibodies (infliximab):
      results of a multicentric and retrospective study].
AB  - OBJECTIVE: To evaluate the results of infliximab therapy, an anti-TNF-alpha
      antibody, in patients with severe and refractory Crohn's disease or with
      fistulas, treated outside the setting of a therapeutic trial. METHODS: All
      Crohn's disease patients treated at the Departments of Gastroenterology of the
      University Hospitals of Bordeaux, Nantes, Poitiers, Rennes and Tours were
      retrospectively analyzed. RESULTS: Sixty-nine patients were treated with a total
      of 170 infusions of infliximab, 32 patients being treated for refractory Crohn's
      disease and 37 for fistulas. The median follow-up was 8 months (extremes 1-20).
      An objective response was observed in 79% of refractory Crohn's disease patients
      and 78% of fistulazing patients. A remission was observed in 72% and 70% of the
      patients respectively. Forty-five percent of patients had relapsed within 4
      months (extremes 2-7). Immunosuppressive therapy was associated with a lower
      relapse rate (18% with versus 56% without, P=0.004). Infliximab resulted in a
      steroid-sparing effect in 73% of patients. Forty adverse events, none of severe
      grade, were observed in 22% of the patients, without any influence of steroids or
      immunosuppressive therapy. CONCLUSION: This study confirms that infliximab is
      very effective in steroid-dependent and fistulazing Crohn's disease. Infliximab
      has a steroid-sparing effect and immunosuppressive therapy is associated with a
      reduced relapse rate. Although the tolerance is good in the short term, long term
      safety remains to be established by further studies.

PMID- 12483128
TI  - [Short term complications of endoscopic retrograde cholangiopancreatography].

PMID- 12483129
TI  - [Atheroma and hepatitis C virus].

PMID- 12483130
TI  - [Practical use of genetic markers other than C282Y in iron overload disorders].

PMID- 12483131
TI  - [Acute hepatitis C: a retrospective study of 62 cases].
AB  - OBJECTIVES: Retrospective study of acute hepatitis C cases observed in general
      hospitals. METHODS: Questionnaire sent by mail to members of the Association
      Nationale des Gastroenterologues des Hopitaux Generaux (ANGH) in December, 1997.
      Data were updated in September, 2001. RESULTS: Sixty-two cases were reported in
      40 centers. Patients were predominantly female (58%), the median age was 33 years
      old. Symptoms revealed the disease in 65% of cases (jaundice in 53%) and
      screening in 30%. The main suspected routes of infection were intravenous drug
      use (32%), nosocomial exposure (29%) and professional accidents (11%). Sustained
      viral clearance occurred in 12 out of the 28 patients who were followed without
      treatment for 6 months, in 14 of 30 treated early, and 4 out of 7 treated
      secondarily with interferon alpha alone. No prognostic factor was identified,
      except for a low total dose of interferon in treated patients. CONCLUSIONS: Acute
      hepatitis C is a rare disease, occurring in younger and more often in female
      patients than chronic hepatitis C. Spontaneous cure is not infrequent, and could
      justify a period of simple follow-up before starting treatment. A national
      observatory would help for epidemiologic surveillance and therapeutic studies.

PMID- 12483132
TI  - Chronic viral hepatitis: a prospective factor against atherosclerosis. A study
      with echo-color Doppler of the carotid and femoral arteries and the abdominal
      aorta.
AB  - OBJECTIVE: To evaluate if chronic viral hepatitis may be a protective factor for
      atherosclerosis. METHODS: Echo-doppler of the carotid and femoral arteries and
      the abdominal aorta was used to examine 48 patients with a histological diagnosis
      of chronic viral hepatitis (42 hepatitis C virus-related, 6 hepatitis B virus
      related), with a low degree of activity and preserved hepatic function, and 50
      controls matched for age, sex and exposure to the main risk factors of
      atherosclerosis. RESULTS: The prevalence of atherosclerosis in patients was
      clearly lower than in controls in all investigated sites, although the difference
      was statistically significant only for the carotid arteries. The percentage of
      patients with carotid atherosclerosis was 27% in patients with liver disease and
      56% in controls (P<0.005). Furthermore, and again at the carotid level, the
      patients with liver disease had fewer atheromatous lesions (16 plaques vs. 59;
      P<0.001) than controls as well as a lower degree of vessel stenosis. None of the
      liver disease patients presented with vessel stenosis above 30% vs. 8% of control
      subjects. CONCLUSIONS: Chronic viral hepatitis may help prevent from
      atherosclerosis.

PMID- 12483133
TI  - [Hepatitis B virus genotypes: clinical, epidemiological and therapeutic
      implications].

PMID- 12483134
TI  - [Biliary lithiasis in 2002].

PMID- 12483136
TI  - [Biliary lithiasis].

PMID- 12483137
TI  - [Violent gallbladder-like pain in a cholecystectomized patient].

PMID- 12483138
TI  - [Acute biliary pancreatitis].

PMID- 12483139
TI  - [Interview: questions to Professor Bertrand Millat].

PMID- 12483141
TI  - [Duodenal bleeding revealing a renal cell carcinoma].
AB  - The pancreas is an uncommon site of metastasis from renal cell carcinoma. The
      metastasis is generally diagnosed during the follow-up of patients who underwent
      nephrectomy for renal cell carcinoma. In our observation, duodenal bleeding led
      to the diagnosis of both pancreatic metastasis and renal carcinoma. The diagnosis
      of pancreatic metastasis should be suspected when a pancreatic mass is associated
      with past or synchronous renal carcinoma. The outcome after resection of
      pancreatic metastasis is better than after resection of pancreatic
      adenocarcinoma. Surgical resection of pancreatic metastasis should be considered
      when possible.

PMID- 12483142
TI  - [Juvenile polyposis coli. The usefulness of a genetic study and the role of
      surgical treatment].
AB  - We report two cases of familial juvenile polyposis coli. SMAD4 gene mutation was
      found in our two patients, leading to the definite diagnosis. Colonic cancer
      occurred in the first patient. Long-term outcome was favorable after colectomy.
      In the second patient, prophylactic total colectomy was performed. Rectal
      bleeding, diarrhea, stomach obstruction and vomiting developed during the follow
      up. Proctectomy, distal partial gastrectomy and total gastrectomy were
      successively performed.

PMID- 12483143
TI  - [Acute pancreatitis related to hemobilia complicating hepatocarcinoma].
AB  - Hemobilia is an rare cause of acute pancreatitis. The most frequent causes are
      iatrogenic trauma (percutaneous liver biopsy) and hepatic artery aneurysm. To our
      knowledge, this is the second published case of acute pancreatitis related to
      hemobilia secondary to hepatocarcinoma complicated cirrhosis in a patient treated
      with anticoagulants for a mechanical valvular aortic prosthesis. The clinical
      picture included acute epigastric pain, fever and jaundice. Increased amylase and
      lipase serum activities, and abdominal CT data confirmed the diagnosis of acute
      pancreatitis. Gallstone induced acute pancreatitis was suspected and thus, a
      cholecystectomy was performed. No bile duct stones were found but a clot was
      extracted from the extrahepatic bile duct during surgery. Arterial embolization
      was then performed and repeated 1 and 3 months later for recurrence. The patient
      was asymptomatic eight months later. Hepatic arterial embolization is an
      effective haemostatic treatment for hemobilia, even though, in this case
      treatment had to be repeated because of an anticoagulant therapy.

PMID- 12483144
TI  - [Duodenal polyposis disclosing mantle-cell lymphoma].

PMID- 12483145
TI  - [All digestive tumors expressing c-kit protein are not stromal tumors].

PMID- 12483146
TI  - [Ischemic colitis associated with naratriptan administration].

PMID- 12483147
TI  - [Treatment of lamiduvine-resistant mutant chronic hepatitis B with interferon
      alpha].

PMID- 12483148
TI  - [Specific risks of liver transplantation in patients co-infected with hepatitis C
      virus and human immunodeficiency virus].

PMID- 12483149
TI  - [Chemotherapy in adenocarcinomas of the pancreas].

PMID- 12483150
TI  - [Role of CARD15/Nod2 in the regulation of the host's response to pathogens in
      patients with Crohn's disease].

PMID- 12483151
TI  - [Pathology of the pancreas].

PMID- 12483152
TI  - [Molecular pathways of pancreatic carcinogenesis].
AB  - Pancreatic carcinogenesis is still not well characterized and no specific
      carcinogen has been isolated in humans. Pancreatic adenocarcinoma acquires
      genetic abnormalities with successive modification of genes involved in the
      regulation of cell proliferation and differentiation. The kinetic of genetic
      alterations in pancreatic cancer is not totally elucidated but experimental
      pancreatic cancer induced by BOP in Syrian golden hamster attempts to approach
      this problematic. The activating mutation of the K-ras oncogene on codon 12 seems
      to occur early in pancreatic carcinogenesis regarding the detection of this
      mutation in preneoplastic dysplastic lesions and tumors such as intraductal
      mucinous papillary tumors. Tumor suppressor genes are also inactivated leading
      commonly to the loss of an inhibitory function on cell proliferation. This
      inactivation occurs with gene mutation, deletion or methylation on one chromosome
      arm associated with a loss of heterozygosity: it concerns p53, p16/MTS-1, DPC
      4/SMAD4. We recently characterized the somatostatin receptor SST2 gene as a
      potential suppressor gene for pancreatic carcinoma. The kinetic of these gene
      alterations is unknown in human. At a late stage of tumor development, an
      increase of telomerase activity, an over expression of growth factors and/or
      their receptors (EGF, NGF, gastrin, bombesin), of proangiogenic factors (VEGF,
      FGF, PDGF), of invasiveness factors (metalloproteinases, E-cadherin, urokinase
      and tissue plasminogen activators) occur. All these molecular events contribute
      to the progression and to the metastatic potential of this carcinoma. Recently,
      the identification of human genome and the large scale analysis of transcriptoma
      will certainly authorize a better knowledge of pancreatic carcinogenesis as well
      as the identification of new genetic alterations and new clinical markers.

PMID- 12483153
TI  - [Neoplastic intraepithelial lesions of pancreatic ducts: new entities].
AB  - Intraductal neoplastic lesions of the pancreas have been the focus of recent
      efforts aiming to better characterize several entities. Beside reactive papillary
      hyperplastic lesion of pancreatic ducts whose limits and significance are
      unclear, two different entities, intraductal papillary mucinous neoplasm (IPMN)
      with its variant intraductal oncocytic papillary neoplasm, and pancreatic
      intraepithelial neoplasia (PanIN), the precursors of pancreatic adenocarcinoma
      have been recognized. Each has been carefully described at the microscopic level
      with classification into several grades of dysplasia. IPMNs are intraductal,
      papillary, often diffuse and mucus hypersecreting neoplastic lesions. Mucin
      accumulation gives to the lesion a cystic pattern. Treatment is surgical
      resection of the whole lesion. Intraductal oncocytic papillary neoplasm is a rare
      variant of IPMN. The prognosis of IPMN is globally favorable, but these tumors
      display the risk of malignant transformation into a mucinous or a tubular
      pancreatic adenocarcinoma. Although IPMN can induce symptoms, PanIN are silent
      and always discovered at the vicinity of an invasive adenocarcinoma. The
      usefulness and the reproducibility of the classification of PanIN remain to be
      determined. PanIN classification might resume the different successive steps of
      molecular genetic or epigenetic events associated with the development of a
      pancreatic carcinoma.

PMID- 12483154
TI  - [Endocrine tumors of the pancreas: classification, clinical and molecular
      prognostic factors].
AB  - Pancreatic endocrine tumors are uncommon. Although the great majority of these
      tumors are well differentiated, their malignant potential varies sometimes
      greatly. Thus, a variety of clinicopathologic features have been developed in the
      past to assist in distinguishing pancreatic endocrine tumors with benign,
      indeterminate and aggressive behavior. Recently, a revised classification of
      pancreatic endocrine tumors has been proposed including, in addition to previous
      parameters, the number of mitoses and a Ki-67 index. In this review, the
      potential diagnostic utility of these different criteria is discussed.

PMID- 12483155
TI  - [Persistent hyperinsulinemic hypoglycemia of infancy: the pathologist's
      experience].
AB  - Persistent hyperinsulinemic hypoglycemia of Infancy (PHHI) is characterized by
      episodes of severe hypoglycemia exposing the child to serious neurological
      sequelae. The morphologic pancreatic anomalies observed consist in either a focal
      lesion which can be totally cured by a selective surgical resection, or a diffuse
      and poorly understood lesion of pancreatic tissue, which may appear at first
      glance to be both macroscopically and microscopically normal, the treatment of
      which, requires a near-total pancreatectomy. The studies presented concentrate on
      several pathogenic hypotheses of this latter form of PHHI. We first demonstrate
      that nesidioblastosis, long considered as the original lesion for the diffuse
      form of hyperinsulinism, does indeed exist although it is not specific to this
      disease and does not correspond to a permanent proliferation of endocrine cells.
      We then dismiss the hypothesis of an enhanced B cell mass, as the volume density
      of B cells is not systematically increased in hyperinsulinemic children compared
      to controls. The third hypothesis looking to a decreased D cell mass has to be
      approached with circumspection as the difference in volume density of
      somatostatin cells, which tends to be slightly lower in hypoglycemic children, is
      small and inconsistent. The fourth hypothesis concerns an intrinsic functional
      lesion of the B cells, and is supported by an increased quantity of proinsulin
      detected in the Golgi area as well as by the observation of voluminous nuclei and
      a particularly abundant cytoplasm in certain B cells. These histological
      anomalies are detected on per-operative frozen sections and guide the surgical
      treatment.

PMID- 12483156
TI  - [Uncommon types of chronic pancreatitis].
AB  - Alcoholic chronic pancreatitis and obstructive chronic pancreatitis are the most
      frequent and the better characterized types of pancreatitis. Recent advances in
      biology and genetics have brought new insights into the understanding of rare
      forms of chronic pancreatitis such as tropical chronic pancreatitis, hereditary
      chronic pancreatitis and chronic pancreatitis in cystic fibrosis. Some other rare
      forms of chronic pancreatitis have been identified: eosinophilic chronic
      pancreatitis, chronic pancreatitis after radiotherapy or during hypercalcemia,
      minimal change chronic pancreatitis and chronic pancreatitis associated with gut
      diseases or connectivitis. Recently, a particular form of non alcoholic chronic
      pancreatitis with duct destruction has been described often presenting as a
      pancreatic mass, leading in some cases to surgical resection of the pancreas. New
      insights into the understanding of chronic pancreatitis lead to new
      physiopathological concepts, and many arguments suggest that combined factors may
      lead to chronic inflammatory lesions of the pancreas.

PMID- 12483157
TI  - [Acinar cystic transformation of the pancreas (or acinar cell cystadenoma), a
      rare and recently described entity].
AB  - We report a case of cystic acinar transformation (also known as acinar cell
      cystadenoma) of the pancreas. A 40-year old woman presented 3 episodes of acute
      pancreatitis that revealed a multicystic lesion of the ventral part of the head
      of the pancreas. A Whipple resection was performed. Gross examination of the
      specimen revealed a well-demarcated multiloculated cyst measuring 4 x 2 cm
      without communication with the excretory ducts. The cystic spaces contained a non
      mucinous fluid. Histological analysis showed numerous various sized cysts that
      seemed to develop from microcystic structures in the surrounding acinar tissue.
      The cysts were lined by normal appearing acinar cells, with no atypia, sometimes
      flattened. Acinar cystic transformation is a rare lesion of the pancreas whose
      histogenesis is unknown. It should be distinguished from other lesions such as
      IPMT in order to discuss a surveillance strategy instead of surgical procedure.

PMID- 12483158
TI  - [Endocrine carcinoma of the pancreas revealed by a pseudocyst].
AB  - Pancreatic pseudocysts are the most frequent cystic lesions of the pancreas. They
      always are associated with acute or chronic pancreatitis. We here report the case
      of a pseudocyst of the pancreas associated with obstructive chronic pancreatitis
      and diagnosed in a 47-year-old man without previous history of acute pancreatitis
      and without risk factor. The examination of the surgical specimen resulted in the
      incidental discovery of an obstructive nodule of endocrine carcinoma, measuring 9
      mm in diameter and located immediately at the contact of the pseudocyst. The
      tumor was ill limited and associated with metastatic spread in 2 peripancreatic
      lymph nodes. Immunohistochemical studies showed that 60% of tumor cells expressed
      serotonin. This case report underlines that the diagnosis of pseudocyst must be
      done much cautiously in patients without a clinical history of pancreatitis and
      without risk factor. In most cases, the lesion corresponds to a misdiagnosed
      cystic tumor. Even if the lesion actually corresponds to a pseudocyst, as in the
      present case, an unusual cause, and particularly, an obstructive tumor, must be
      searched for.

PMID- 12483159
TI  - [A clear cell tumor of the pancreas].

PMID- 12483160
TI  - [Macrocystic lesions of the pancreas may be not mucinous cystadenomas!].

PMID- 12483161
TI  - [A pancreatic tumor in a young woman].

PMID- 12483162
TI  - [Fine needle aspiration biopsy of the pancreas].
AB  - In the majority of cases, fine needle aspiration biopsy of the pancreas is used
      to confirm or exclude the presence of malignancy. New therapeutic trials need a
      precise diagnosis before treatment. Material consists of smears, microbiopsy and
      monolayer cytology. Microbiopsies and monolayer cytology can also be used for
      complementary techniques. The sensitivity of the technique is better for solid
      masses than for cystic lesions.

PMID- 12483163
TI  - [Pancreatectomy for adenocarcinoma: prognostic factors, recommendations for
      pathological reports].
AB  - The ductal adenocarcinoma of the pancreas is a tumor with very poor prognosis,
      often diagnosed at an advanced stage of evolution. The surgical resection of the
      tumor is performed in only 15% of the patients but only 10% of them are alive 5
      years later. The bad prognostic factors individualized on surgical specimens are
      the tumor size (>2 cm), lymph node metastases, the poor differentiation of the
      tumor on microscopic examination, the infiltration of the portal vein and
      mesenteric vessels by the tumor, the infiltration of the surgical margins,
      especially the retroperitoneal margin of the tumor. We propose a pre-established
      form including these items for pathological reports of pancreatectomy for
      adenocarcinomas.

PMID- 12483164
TI  - Pharmacological studies on internal mammary artery bypass grafts. Action of
      endogenous and exogenous vasodilators and vasoconstrictors.
AB  - BACKGROUND: The purpose of this experiment was four-fold: 1) to determine the
      effect of currently used cardiovascular drugs on internal mammary artery (IMA)
      vascular tone, 2) to examine IMA reactivity to autacoids and products released
      from aggregating platelets, 3) to compare the vascular reactivity of the right
      versus left IMA, and 4) to determine whether the canine IMA was an acceptable
      physiological model as regards its similarity to the human IMA, which is used
      routinely for coronary artery bypass grafting. METHODS: To study factors that
      modulate the tone of IMA, bypass grafts, right and left canine IMAs were studied
      in vitro in organ chambers (95% O(2)/5% CO(2), pH=7.4). RESULTS: Increasing
      concentrations (10(-9) to 10(-4M)) of the neurotransmitter acetylcholine (ACH)
      and the platelet-derived products adenosine diphosphate (ADP) or serotonin (5-HT)
      induced vasodilatation of contracted right and left IMAs. The vasodilation caused
      by ACH and ADP was endothelium-dependent while serotonin acted directly on the
      vascular smooth muscle. Histamine and bradykinin also induced IMA vasodilation,
      histamine via a direct action on the smooth muscle, and bradykinin through the
      release of nitric oxide (NO). In canine IMAs, the calcium ionophore A23187
      produced endothelium-dependent vasodilation of contracted blood vessels; this
      vasodilation was blocked by N(G)-nitro-L-arginine (10(-4)M), a competitive
      inhibitor of nitric oxide synthesis from L-arginine, and by hemoglobin (10(-5)M).
      Dopamine, dobutamine, and papaverine induced vasodilation of the IMA regardless
      of the presence or absence of an intact intima, while norepinephrine induced
      profound IMA vasoconstriction, which was comparable to contraction to potassium
      ions or the constrictor peptide endothelin. CONCLUSIONS: These experiments
      establish a pharmacological profile of IMA and demonstrate that endogenous and
      exogenous compounds can significantly alter its vascular tone.

PMID- 12483165
TI  - Long-term results after De Vega's tricuspid annuloplasty.
AB  - BACKGROUND: Although some surgeons prefer to use artificial valve rings for
      tricuspid valve annuloplasty, we have mainly performed De Vega's tricuspid
      annuloplasty for functional tricuspid regurgitation, because it is a simple and
      effective technique for reducing tricuspid regurgitation due to annular
      dilatation. We evaluated long-term results of the De Vega's tricuspid
      annuloplasty up to 19 postoperative years. METHODS: Between January 1980 and June
      1999, 408 patients underwent De Vega's tricuspid annuloplasty. Long-term results
      after De Vega's tricuspid annuloplasty were analyzed. RESULTS: There were 14
      (3.4%) early deaths within 30 postoperative days. There were 63 (15.4%) late
      deaths during the follow-up period. The actuarial survival rate at 15 years after
      operation was 74.0%, the 15-year freedom from re-operation was 91.6%, and the 15
      year freedom from all events was 58.7%, respectively. CONCLUSIONS: These results
      suggest that De Vega's tricuspid annuloplasty was an effective and reliable
      procedure of choice for secondary tricuspid regurgitation with annular
      dilatation.

PMID- 12483166
TI  - Fan-shaped expanded polytetrafluoroethylene valve in the pulmonary position.
AB  - BACKGROUND: Residual pulmonary insufficiency remains a problem after transannular
      repair in pediatric patients. We have developed fan-shaped monocuspid and
      bicuspid valves made of expanded polytetrafluoroethylene (ePTFE) membrane for
      repair of right ventricular outflow tract obstruction in patients with tetralogy
      of Fallot. METHODS: We studied 20 patients (mean age, 39.6 months) with tetralogy
      of Fallot. The right ventricular outflow tract was reconstructed with use of a
      short, wide transannular patch and a fan-shaped valve made of 0.1-mm-thick
      expanded ePTFE membrane (PRECLUDE Pericardial Membrane, W.L. Gore & Associates,
      Inc, Flagstaff, AZ). The width of the valve and the outflow patch were
      constructed so that the neopulmonary annulus was approximately 130% the normal
      size. RESULTS: A monocuspid valve was used in 17 patients and a bicuspid valve in
      3. The mean follow-up time was 32.3 months (range, 14.7 to 56.7 months). Right
      ventricular function was well maintained in all patients. Valvular motion
      remained competent in 13 patients (65%). In the remaining 7 (35%), the valve
      became fixed in the open position. Trivial and mild pulmonary insufficiency was
      detected in 10 patients with a competent valve and 7 with an incompetent valve.
      No pressure gradient across the neopulmonary annulus or calcification of the
      expanded ePTFE membrane was detected in any patient. CONCLUSIONS: The fan-shaped
      expanded ePTFE valve is a useful substitute with adequate function in
      transannular right ventricular outflow reconstruction.

PMID- 12483167
TI  - Influence of arteriotomy shape on power losses across in vitro cavopulmonary
      connections.
AB  - BACKGROUND: In the Fontan circulation power supply for maintaining adequate lung
      perfusion via a total cavopulmonary connection is limited. This study, aiming at
      the detection of energy consuming variables, compares the influence of two
      different pulmonary arteriotomy shapes on power losses across cavopulmonary
      connections. METHODS: Two types of surgical junctions of cavopulmonary
      connections were studied in a mock circulation. Firstly a slot-shaped incision
      and secondly an oval-shaped excision within the pulmonary artery was performed.
      The cross sections of native caval veins were sutured end-to-side with the edges
      of the incised and excised pulmonary arteries, respectively. Pressures and flows
      were measured at total flow rates varying from 1200 ml/min to 6000 ml/min and
      power losses calculated. RESULTS: Power losses were, in dependence of total flow,
      10.66-32.64% lower across the oval-shaped junctions if compared to the
      corresponding slot-shaped junctions (p<0.05). CONCLUSIONS: Surgical junctions
      including an oval excision within the pulmonary artery may reduce power losses
      across cavopulmonary connections if compared to simple slot-shaped incisions.
      These findings may have some influence on surgical techniques to improve
      hemodynamics of cavopulmonary connections.

PMID- 12483169
TI  - Plasma hepatocyte growth factor levels after open heart surgery for congenital
      heart disease.
AB  - BACKGROUND: Hepatocyte growth factor (HGF) is a polypeptide which acts
      protectively against endothelial cell dysfunction. A high plasma level of HGF is
      shown when the endothelium is injured. We measured plasma HGF levels during and
      after open heart operations for congenital heart disease, to elucidate its
      involvement with endothelial cell injury. METHODS:  EXPERIMENTAL DESIGN:
      prospective study. SETTING: perioperative setting. PATIENTS: 18 children
      electively operated upon for congenital heart disease using CPB. RESULTS: Plasma
      HGF levels (ng/ml) before cardiopulmonary bypass (CPB) were 0.36+/-0.07 in 10
      children (S-group) who were older and with simpler diseases, and 0.48+/-0.12 in 8
      children (C-group) who were younger and with relatively complex diseases. HGF
      levels significantly increased after CPB, and gradually decreased thereafter.
      Plasma HGF levels 3 and 6 hours after CPB were significantly greater in the C
      group than in the S-group (1.13+/-0.12 vs 1.68+/-0.1 6 3 hours after, and 1.09+/
      0.19 vs 2.35+/-0,43 6 hours after; p<0.05 for both). There were significant
      positive correlations between HGF levels 6 hours after CPB and the duration of
      the CPB, the aortic crossclamping time, and plasma thrombomodulin levels just
      after CPB in all patients (p<0.05 for all). CONCLUSIONS: This data suggests that
      increased HGF levels are associated with endothelial cell injury induced by CPB,
      and that the increases are much greater in younger patients with complex
      anomalies.

PMID- 12483168
TI  - The role of plasma endothelin in the Fontan circulation.
AB  - BACKGROUND: Various vasoactive substances are released during cardiopulmonary
      bypass. They may deteriorate pulmonary circulation after the Fontan operation.
      Effects of plasma endothelin-1 (ET-1), a vasoconstricting peptide, on the Fontan
      circulation have not been investigated. METHODS: Eleven patients (aged 11.1+/-7.5
      years) who underwent the modified Fontan operation (group F) and seven patients
      (aged 9.9+/-6.0 years) who underwent the biventricular repair (group C) were
      studied. Plasma samples were obtained for measuring ET-1 on the first
      postoperative day (Early I), on returning to floor care from the intensive care
      unit (Early II), and during postoperative cardiac catheterization (Late).
      RESULTS: Plasma concentrations of ET-1 increased in group F (Early I, 4.37+/-1.78
      pg/ml; Early II, 4.07+/-1.90 pg/ml) as compared with the basal value of 1.0+/-0.5
      pg/ml. The central venous pressure, which reflects the pulmonary circulatory
      state, soon after the Fontan operation correlated significantly with the
      increased ET-1 concentration (y=1.809 x+6.484; r=0.809; p=0.0026). Although the
      Late ET-1 concentrations in group F were significantly decreased, the central
      venous pressure and the ET-1 concentrations demonstrated a significant
      correlation (y=3.074 x +5.427; r=0.740; p=0.0227). CONCLUSIONS: The increased
      humoral vasoactive substances such as ET-1, which induces pulmonary
      vasoconstriction following the Fontan operation, may have important implications
      for the Fontan circulation.

PMID- 12483171
TI  - Course of serum lipoprotein(a) and acute phase protein levels in patients
      undergoing open heart surgery.
AB  - BACKGROUND: Lipoprotein(a) [Lp(a)] is an important risk factor in the
      pathogenesis of coronary artery disease because of its thrombogenic and
      atherogenic properties. Lp(a) also displays another property by acting as an
      acute phase reactant. METHODS: In this work, the study group consisted of 20 male
      patients having coronary artery bypass under cardiopulmonary bypass (CPB).
      Preoperative and postoperative levels of plasma total cholesterol, triglyceride,
      apolipoprotein A1 (Apo A1), apolipoprotein B (Apo B), alpha-1 antitrypsin (a1
      AT), alpha-2 macroglobulin (alpha 2-MG), alpha-1 acid glycoprotein (alpha 1-AG),
      Lp(a) were measured in all patients one day before and after the 1st, 2nd, 4th,
      and 10th days of CPB. RESULTS: It was observed that the levels of Lp(a) levels
      gradually reached the preoperative levels at the 10th postoperative day period.
      Observed change of the Lp(a) levels was similar to that of the other acute phase
      proteins which are synthesized and released from liver. In contrast, alpha 2-MG
      has shown different behaviour in terms of operative values. The changes observed
      for all these 3 parameters were found to be statistically significant (p<0.01).
      CONCLUSIONS: The data has indicated that Lp(a) levels show similar progress with
      alpha 2-MG levels. It can be concluded that serum levels of Lp(a) after coronary
      arterial bypass decrease depending upon several factors and reach basal levels at
      the end of a 10 day-period of postoperation. The main cause for this decrease
      might result from the contact of blood with foreign surfaces of the heart-lung
      machine.

PMID- 12483170
TI  - Inhibition of systemic inflammatory response with sodium nitroprusside in open
      heart surgery.
AB  - BACKGROUND: A nitric oxide donor, sodium nitroprusside has been reported to
      reduce the inflammatory response during cardiopulmonary bypass (CPB). To
      investigate this, a double-blind and prospective study was conducted. METHODS:
      Twenty patients with multi vessel coronary disease were randomly chosen to form
      study (SNP) and control groups. In the SNP group, 0.5 microg/kg/min sodium
      nitroprusside were administered for 20 min right after the release of the aortic
      crossclamp. Mac-1 (CD11b/CD18) leukocyte adhesion molecule expressions,
      interleukin-6 levels were measured from radial artery blood as well as leukocyte
      and platelet counts in both groups at 6 different time points: a) before
      anesthesia, b) after heparin administration, c) after aortic crossclamp release,
      d) after protamine administration, e) 3 hours after the termination of CPB, f) 24
      hours after the termination of CPB. RESULTS: The increase in Mac-1 expressions
      were not different between the two groups at any time point except the
      measurements after the administration of protamine. At this time point, Mac-1
      expressions were not different between the groups (99.8+/-30.7 vs 134.6+/-95.1%,
      p=0.076), but higher when compared with the preinduction levels. IL-6 levels for
      SNP and control groups was 89+/-43 and 215+/-131 pg/dL, respectively (p=0.016) 3
      hours after the termination of CPB. Twenty-four hours after the termination of
      CPB, IL-6 levels were still significantly higher in the control group (47+/-27 vs
      111+/-68 pg/dL, p=0.039). Leukocyte and platelet counts were not different at any
      time point between the groups. CONCLUSIONS: Systemic inflammatory response in
      patients undergoing CPB can be reduced to a certain level with sodium
      nitroprusside, especially the activation of vascular endothelial cells can be
      inhibited, but activation of leukocytes still takes place.

PMID- 12483172
TI  - 2-Nicotinamidoethyl nitrale (2-NN) protects myocardium in ischemia and
      reperfusion via the protein kinase C pathway.
AB  - BACKGROUND: Several recent studies have suggested an ATP-sensitive potassium
      channel opener (2-nicotinamidoethyl nitrate: 2-NN) may exert a protective effect
      against the myocardial ischemic/reperfusion injury. This study examines the
      effects of 2-NN on intracellular signaling by measuring intracellular cyclic AMP,
      cyclic GMP accumulation and protein kinase C (PKC) activity after 2-NN perfusion.
      METHODS: Ischemia/reperfused hearts were made by LAD occlusion for 30 min
      followed by 30 min of reperfusion in isolated rat hearts. Hearts were pre
      perfused with 0.1 mM 2-NN, 100 nM Calphostin C, or 2-NN plus Calphostin C for 10
      min prior to ischemia. The left ventricular function, cyclic AMP, cyclic GMP and
      LDH were examined to determine the effects of 2-NN on ischemic/reperfusion
      injury. Four separate groups of hearts were stained with a bisindolylmaleimide
      PKC inhibitor conjugated to fluorescein (fim, Teflabs) and PKC activity was
      measured. RESULTS: 2-NN reduced ischemia/reperfusion injury as evidenced by the
      enhanced myocardial functional recovery, decreased LDH release after reperfusion,
      and decreased reperfusion arrhythmias. The PKC inhibitor attenuated myocardial
      functional recovery but not reperfusion arrhythmias. Cyclic AMP levels decreased
      after 10 min of 2-NN perfusion, compared to controls. We observed an increase in
      PKC activity after 2-NN treatment. CONCLUSIONS: These results suggest that PKC
      plays a significant role in the cardioprotective effect of 2-NN on ischemic and
      reperfused myocardium. The anti-arrhythmic effect of 2-NN in the reperfusion
      phase may be linked its action on the ATP-sensitive potassium channel itself
      rather than its effect on PKC activity.

PMID- 12483173
TI  - The protective action of chlorpromazine on the spinal cord of rabbits submitted
      to ischemia and reperfusion is dose-dependent.
AB  - BACKGROUND: Chlorpromazine (CPZ), at high doses, has been shown to protect the
      central nervous system in experimental models of ischemia and reperfusion. The
      purpose of this study was: 1) to investigate the protection afforded by different
      doses of CPZ on the spinal cord of rabbits submitted to ischemia and reperfusion.
      2) to correlate the motor impairment of the hind limbs and the percentage of
      damaged neurons in the anterior horns of the lumbar spinal cord in treated and
      untreated animals. METHODS: Seventy-two New Zealand white rabbits were divided
      into 6 equal groups (n=12): sham operation, control and 4 study groups. Spinal
      cord ischemia was obtained by clamping the abdominal aorta caudally to the renal
      arteries for 30 min, after which it was released and the animals were observed
      for a period of 48 hrs. The control animals received 3 ml/kg of 0.9% NaCl, i.v.,
      10 min before aorta clamping. The experimental animals received CPZ, i.v., at
      doses of 2, 1 and 0.5 mg/kg, 10 min before aorta clamping. In one group 1 mg/kg
      of CPZ was given 10 min before aorta clamping and the same dose was repeated 2
      hrs after the beginning of reperfusion. The spinal cord of the control animals
      and of those who received one CPZ dose of 2 mg/kg was processed for light
      microscopy examination. RESULTS: Motor scores of the hind limbs, graded 0 to 4,
      obtained 48 hrs after the beginning of reperfusion showed that CPZ was effective
      at doses of 2 and 1 mg/kg. No significant difference was observed with the dose
      of 0.5 mg/kg. However, the best results were obtained with the dose of 2 mg/kg
      administered in a fractionated manner. Histological examination revealed that at
      the dose of 2 mg/kg, CPZ protected a significant number of neuronal cells and
      that motor recovery hardly occurred when the number of damaged neurons exceeded
      50%. CONCLUSIONS: 1) The neuroprotective action of CPZ is dose-dependent in the
      ischemic spinal cord of rabbits. The lower protective dose is 1 mg/kg, which is
      too high for human beings. 2) There is an inverse correlation between motor
      recovery and percentage of damaged neurons, and the critical point seems to be
      between 30% and 50%.

PMID- 12483174
TI  - Posterior non-ischemic left ventricular aneurysm. Report of 2 surgical cases.
AB  - Posterior non-ischemic left ventricular aneurysms are unusual aneurysms of
      different etiology that develop adjacent to the mitral valve annulus causing
      mitral regurgitation and progressive heart failure. Surgical correction is
      mandatory and involves repair of the aneurysm along with repair or replacement of
      the mitral valve. Two cases of posterior non-ischemic left ventricular aneurysms
      are reported. Both patients were females (19 and 9 years old) and they presented
      with symptoms of progressive heart failure. Definite diagnosis was made with
      transesophageal echocardiography (TEE) and confirmed with left ventriculography.
      Both patients were successfully treated by surgery. The first patient underwent
      repair of the aneurysm from inside the left ventricle and mitral valve
      replacement. The second patient had resection of the aneurysm through an
      extracardiac route. Both patients are in NYHA class 1, 5 and 4 years respectively
      after their operation with no evidence of mitral valve dysfunction. Posterior non
      ischemic left ventricular aneurysms can securely be diagnosed by TEE and
      angiocardiography. Surgical treatment is mandatory in order to forestall
      potential life threatening cardiovascular events and should be tailored to the
      operative findings.

PMID- 12483175
TI  - Massive purulent pericarditis and cardiac tamponade caused by Staphylococcus
      aureus urosepsis. Case report.
AB  - We experienced a case of purulent pericarditis and cardiac tamponade in a patient
      who presented with acute respiratory failure and urosepsis and ultimately died of
      overwhelming septic shock. Pericardiocentesis yielded 1400 cc of pus; cultures
      grew only Staphylococcus aureus with sensitivities identical to the
      Staphylococcus aureus cultured from the patient's urine. Purulent pericarditis is
      rare and its association only with urosepsis has not been previously reported.
      The case is discussed and the literature reviewed.

PMID- 12483176
TI  - Aorto-right atrial fistula associated with native tricuspid valve endocarditis.
AB  - Abnormal connections between the ascending aorta and the cardiac chambers are
      rare. Most are due to ruptured aneurysms of the sinus of Valsalva. Congenital
      fistulae between the aorta and left atrium are described. We report a case of
      native tricuspid valve endocarditis associated with a fistula between the right
      atrium and the aorta.

PMID- 12483177
TI  - Accessory mitral valve leaflet in an adult with coronary artery disease.
AB  - Accessory mitral valve leaflet is a very rare cause of left ventricular outflow
      tract obstruction. We report a patient presenting this cardiac abnormality who
      undergone cardiac surgery. A 60-year-old man, presented coronary artery disease
      and moderate left ventricular tract obstruction due to accessory mitral valve
      leaflet. The accessory mitral valve leaflet had the typical morphology of a
      parachute-shaped attached partially to the anterior mitral valve leaflet, with
      chordae tendinae attached to: 1) an accessory papillary muscle inserted at the
      free-wall closed to the apex; 2) interconnected with the chordae tendinae of the
      anterior mitral valve leaflet; 3) a second accessory papillary muscle inserted to
      the interventricular septum. He underwent successful coronary revascularization
      of 2 vessels and accessory leaflet excision. A review of 21 cases with accessory
      mitral valve leaflet is reported.

PMID- 12483178
TI  - Primary repair of pulmonary artery sling with double outlet right ventricle and
      distal tracheal stenosis.
AB  - The fate of patients with pulmonary artery sling depends on associated tracheal
      lesions. Distal tracheal stenosis involving the carina frequently results in
      lethal obstruction due to secretion or inflammatory edema. Further-more,
      associated complex cardiac anomalies with excessive pulmonary flow make the
      situation more complicated. We present a case of successful simultaneous one
      stage repair of pulmonary artery sling, double outlet right ventricle and distal
      tracheal obstruction. Pulmonary artery sling was relieved by relocation of the
      left pulmonary artery (left pulmonary artery to main pulmonary artery) and a
      tracheoplasty (resection and end-to-end anastomosis). We advocate early
      aggressive simultaneous repair of pulmonary artery sling with tracheal stenosis
      and concomitant repair of intracardiac anomalies whenever possible.

PMID- 12483179
TI  - Ascending aortic cannulation via left thoracotomy for distal aortic arch aneurysm
      operation.
AB  - We have cannulated the ascending aorta for cardiopulmonary bypass via left
      thoracotomy in order to avoid conventional retrograde perfusion from the femoral
      arteries, which is associated with an increased risk of cerebral embolism. We use
      silk sutures to retract the anterior margin of the opened pericardium from the
      chest wall, which provides good exposure and easy control of the ascending aorta.
      Between July 1997 and November 2000, cannulation proved easy to do and reliable
      in 24 serial patients.

PMID- 12483180
TI  - Stent jail of the renal arteries in stent graft exclusion of AAA. An in vitro
      study of 3 different stent types.
AB  - BACKGROUND: The success of endoluminal stent grafts (ELG) is critically dependent
      on secure proximal fixation of the graft. Different types of stent grafts with
      uncovered proximal portions for transrenal fixation are obtainable. The present
      in vitro study was designed to elucidate how the flow parameters were altered by
      stent jail of the renal arteries with respect to different stent design. METHODS:
      The experiments were performed in an in vitro pulsatile circulation model. An
      aortic segment with bilateral side branches (like renal arteries) constructed of
      an ePTFE graft was perfused in the circulation model. The flow measurements were
      based on the ultrasound transit-time method. By varying the frequency from 30 to
      100 bpm the flow parameters were altered and recorded continuously. Renal stent
      jailing was carried out using different stent types: Gianturco-Z-Stent, Palmaz
      Stent, Powerlink Endologix. RESULTS: The flow in the aortic model increased from
      1100 ml per minute to 3330 ml per minute depending on the pump frequency. In the
      control group without stent jail the renal flow was measured between 240 ml per
      minute up to 810 ml per minute. The ratio of renal flow was between 0.22 and 0.24
      of the aortic flow. In the Palmaz group the ratio was between 0.21 and 0.24, in
      the Gianturco group between 0.23 and 0.25, and in the Powerlink group between
      0.24 and 0.25 (unpaired-"t"-test: n.s.). CONCLUSIONS: The covering of the renal
      arteries and/ or superior mesenteric artery in case of long bared proximal stent
      raises the question whether the stent jail may result in flow reduction in the
      arteries covered or not. The present in vitro study demonstrated that the flow in
      the renal arteries is not decreased by these stent jails.

PMID- 12483181
TI  - Anterior spinal artery syndrome after infrarenal abdominal aortic surgery.
AB  - BACKGROUND: Neurological complications such as paraplegia or paraparesis due to
      spinal cord ischemia has been an unpredictable, devastating event after
      infrarenal abdominal aortic surgery. The aim of our study is to focus the
      importance of this entity and in this connection to review the vascular anatomy
      of the spinal cord, incidence and etiology of spinal cord ischemia, methods of
      prevention, and management of the patient. METHODS: Eight patients were
      identified with spinal cord ischemia manifested by paraplegia or paraparesis
      after 1331 abdominal aortic operations. All the patients who had spinal cord
      ischemia were examined for risk factors. RESULTS: Three anterior spinal artery
      syndrome neurological recovery occurred but 5 of them remained unchanged. Two
      patients died within 30 days of operation. CONCLUSIONS: Complete paraplegia due
      to ischemic spinal cord injury was thought to be caused by interruption of
      critical collateral blood supply to the spinal cord. For this reason avoidance of
      prolonged aortic cross clamp time, hypotension, and its associated low flow to
      the spinal cord, paying attention to prevent atheromatous embolization of
      Adamkiewicz artery and pelvic circulation can prevent this complication. If the
      greater medullary artery is anomalously low from the anatomic localization the
      blood supply of the cord may be inadequate, so this complication cannot be
      avoided.

PMID- 12483182
TI  - Lipo-prostaglandin E1 is absorbed by vascular smooth muscle cells and may enhance
      re-endothelialization of vein grafts.
AB  - BACKGROUND: Enhancement of re-endothelialization inhibits the progression of
      intimal hyperplasia. We investigated uptake of Lipoprostaglandin E(1) (LPGE(1))
      by endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and effects
      of the LPGE(1) on re-endothelialization of vein grafts. METHODS: Primary cultured
      ECs and VSMCs were obtained from mongrel dogs, and incubated in mediums
      containing 0.5, 5, 50, and 250 ng/ml of DiI-LPGE(1) (DLPGE(1)); its uptake was
      visualized by the standard rhodamine excitation, and assessed by flow cytometry.
      In an implantation study, the bilateral femoral veins of 18 animals were
      implanted into the femoral artery, and the animals were given 0.2 microg/kg
      LPGE(1) for 2 weeks. Percentages of EC coverage area of the grafts (%EC) were
      measured by silver nitrate staining at intervals of 3, 7, and 21 days after
      implantation. RESULTS: VSMCs showed significant uptake in all of the mediums
      containing DLPGE(1), whereas the ECs revealed no fluorescence. In flow cytometry,
      histograms of VSMCs showed a specific notch of DLPGE(1), which increased the
      height according to the grade of the concentrations. The notch did not appear in
      the histograms of the ECs incubated with any concentration nor in the VSMCs
      incubated in control medium. These results suggested that LPGE(1) is
      predominantly absorbed by the VSMCs and exuded PGE(1) then acts on the VSMCs
      itself and on ECs alike. The %EC at 7 days was 58.4+/-1.9% in the DLPGE(1) group
      and 31.6+/-6.8% in controls (p<0.05) showing a significant enhancing effect of
      DLPGE(1) on re-endothelialization of the vein grafts. CONCLUSIONS: In an animal
      model, daily administration of LPGE(1) resulted in significant enhancement of
      vein graft re-endothelialization. LPGE(1) was absorbed by the VSMCs, whereas the
      ECs showed no uptake, therefore the enhancement is probably due to a paracrine
      effect of VSMCs.

PMID- 12483183
TI  - Intraoperative intra-arterial urokinase therapy after failed embolectomy in acute
      lower limb ischemia.
AB  - BACKGROUND: Aim of this study is to evaluate the use of intraoperative intra
      arterial urokinase infusion (IIUI) in overcoming residual thrombi after
      thromboembolectomy in acute lower limb ischemia. METHODS:  DESIGN: retrospective
      study over a 3-year period. SETTING: University affiliated hospital. PATIENTS: 21
      patients with acute lower limb ischemia who underwent IIUI after embolectomy (18
      transfemoral, 3 transpopliteal) had failed to achieve adequate distal perfusion.
      Postoperatively, all patients were maintained on full dose heparinization. MAIN
      OUTCOME MEASUREMENTS: complete or partial clot lysis on post-IIUI angiography;
      restoration of pedal pulses and a viable leg at discharge. RESULTS:
      Angiographically, complete and partial lysis was demonstrated in 14 and 3
      patients, respectively. Two patients with prolonged ischemia required fasciotomy.
      One of these eventually had an amputation. Altogether, limb amputations (1 above
      knee, 2 below knee) were necessary in 3 patients. The angiographic appearance of
      lysis correlated well with the restoration of pedal pulses and/or limb viability.
      One patient died of myocardial infarction 3 days after the procedure.
      Postoperatively, there were 5 (24%) wound hematomas of which 1 required surgical
      exploration. Over a mean follow-up period of 8 months (range 1-16), limb salvage
      was sustained in the 17 patients with successful angiographic lysis. CONCLUSIONS:
      IIUI is an effective therapeutic adjunct to failed embolectomy in acute lower
      limb ischemia. Use of this procedure is recommended as part of the routine
      management in such cases.

PMID- 12483184
TI  - Low dose systemic thrombolytic therapy for treatment of deep venous thrombosis.
AB  - BACKGROUND: Thrombolytic therapy is still not used widely for treatment of deep
      vein thrombosis despite its known efficacy. This reluctance to use it stems from
      worries about its hemorrhagic complications. METHODS: In a 4-year period 97
      patients with deep vein thrombosis diagnosed by duplex study were enrolled into
      the study. Fifty patients received streptokinase as a bolus of 250,000 units
      followed by 100,000 units/hr with a maximum of 4,000,000 units and 47 patients
      received anticoagulation with heparin. RESULTS: Minor hemorrhagic complications
      occurred in 2 patients (4%) in the thrombolytic therapy group. An improvement in
      the control duplex study was observed in 56% of the patients in the thrombolytic
      therapy group compared to 5% in the heparin group (p=0.000). The patients treated
      within 4 days of onset of symptoms had significantly higher success rates
      compared to those treated later (p=0.000). Higher success rates were obtained for
      those with either femoral vein or more distal venous thrombosis compared to those
      with iliac vein and vena cava thrombosis (p=0.007). These results show that
      systemic low dose streptokinase achieves significantly higher recanalization
      rates compared to heparin alone. CONCLUSIONS: Hemorrhagic complications at these
      dose levels are within acceptable ranges. Low dose streptokinase regimen could be
      beneficial in patients who present within 4 days of femoral or more distal venous
      thrombosis.

PMID- 12483185
TI  - The circle of Willis in healthy older persons.
AB  - BACKGROUND: The current indication for carotid surgery is based upon the
      percentage of stenosis of the internal carotid artery. This approach shows many
      limitations, one of which is to presume the anatomical completeness of the circle
      of Willis in all patients who are evaluated. On the contrary, there is increasing
      evidence of a great natural variability in the configuration of the circle of
      Willis. METHODS: The aim of the present paper was to investigate, by magnetic
      resonance angiography, the variability of the circle of Willis in a cohort of 118
      healthy older persons. RESULTS: The circle of Willis showed an entirely complete
      configuration in 47% of the subjects, a complete configuration of its anterior
      part in 90% of the subjects, and a complete configuration of its posterior part
      in 48.5% of the subjects. CONCLUSIONS: These findings confirm the great
      variability of the circle of Willis even in healthy older persons and suggest
      that, in indicating carotid surgery, the configuration of the circle of Willis
      should also be taken into account.

PMID- 12483186
TI  - In vivo evaluation of lumbrokinase, a fibrinolytic enzyme extracted from
      Lumbricus rubellus, in a prosthetic vascular graft.
AB  - BACKGROUND: Lumbrokinase (LK) is a fibrinolytic enzyme purified from the
      earthworm Lumbricus rubellus. To investigate the fibrinolytic and antithrombotic
      effects of lumbrokinase, a series of animal experiments were performed. METHODS:
      The Dacron graft (3 mm in diameter, 3 cm in length) were treated with LK via two
      different methods, simple dipping and covalent bonding METHODS: Covalent bonding
      was performed by UV reaction to polyacrylic acid. The grafts were interposed into
      the inferior vena cava of the rabbits and harvested for 5 hours, 1, 2 and 4 weeks
      after the implantation. RESULTS: The LK non-treated graft (n=4) were totally
      occluded with thrombus 5 hours after the implantation. Both types of LK treated
      graft (n=8) were patent 1 week after the implantation. The grafts treated with
      the simple dipping method (n=4) were occluded with thrombus 2 weeks after the
      implantation. The grafts treated with covalent bonding (n=4) were patent 4 weeks
      after the implantation. Ultrastructural analysis of the luminal surface of the
      patent grafts by scanning electron microscopy revealed the thin plasma protein
      layer to be about 5 micro in thickness with platelet adhesions. CONCLUSIONS:
      Lumbrokinase has potential antithrombotic effects in a small diameter vascular
      prosthesis. The covalent bonding method proved to be more effective than the
      simple dipping method.

PMID- 12483187
TI  - Superior mesenteric thrombosis associated with small bowel stricture. Case
      report.
AB  - Intestinal stricture from superior mesenteric vein (SMV) thrombosis is a
      relatively infrequent, though important cause of intestinal obstruction. The
      symptom of intestinal obstruction in a patient with chronic SMV thrombosis should
      be considered as the possibility of bowel stricture. We report 2 cases of small
      bowel stricture that is related to chronic SMV thrombosis which were treated with
      segmental resection of strictured bowel.

PMID- 12483188
TI  - Extraction of right atrial thrombus with inflow-occlusion technique in a patient
      with gastric cancer.

PMID- 12483189
TI  - Keep your buns warm.

PMID- 12483190
TI  - Of hearts & hyperkalemia.

PMID- 12483191
TI  - Response to "After the fall".

PMID- 12483192
TI  - Danger zone. The prehospital assessment & treatment of blunt & penetrating neck
      trauma.

PMID- 12483193
TI  - Precise questions solve dilemma.

PMID- 12483194
TI  - Chill pills. 10 antidotes to EMS stress.

PMID- 12483195
TI  - No more coma cocktails. Using science to dispel myths & improve patient care.
AB  - It should be clear from this discussion that coma cocktails are a bad idea and
      should be immediately abandoned. In fact, the indiscriminate use of the coma
      cocktail may indeed harm patients, EMS has evolved to a point where any EMS
      provider should be able to reasonably determine the most likely cause of coma,
      or, in a worst-case scenario, narrow the cause to but a few possibilities.
      Certainly, patients with bona fide hypoglycemia should receive IV glucose.
      Because the consequences of prolonged hypoglycemia are severe, if there's a doubt
      about whether hypoglycemia is present, then glucose should be empirically
      administered. Naloxone should be used only for those cases in which a narcotic
      overdose appears likely. Similarly thiamine administration should be limited to
      patients suspected of chronic alcohol abuse and who exhibit at least one of the
      three symptoms of WE described above. Flumazenil has no role in the routine
      treatment of coma unless the patient is known to not be benzodiazepine dependent
      and the overdose is known to result only from benzos--two very difficult
      requirements to verify in the back of an ambulance at 2 a.m. Coma cocktails are
      bad medicine. Let's banish them from our EMS armamentarium.

PMID- 12483196
TI  - The new face of blood clotting technology.

PMID- 12483197
TI  - Treading new ground. New stair chair design will save backs.

PMID- 12483199
TI  - Straight shot. Intubating like an anesthesiologist.

PMID- 12483200
TI  - Privacy matters.

PMID- 12483203
TI  - Evolutionarily conserved networks of residues mediate allosteric communication in
      proteins.
AB  - A fundamental goal in cellular signaling is to understand allosteric
      communication, the process by which signals originating at one site in a protein
      propagate reliably to affect distant functional sites. The general principles of
      protein structure that underlie this process remain unknown. Here, we describe a
      sequence-based statistical method for quantitatively mapping the global network
      of amino acid interactions in a protein. Application of this method for three
      structurally and functionally distinct protein families (G protein-coupled
      receptors, the chymotrypsin class of serine proteases and hemoglobins) reveals a
      surprisingly simple architecture for amino acid interactions in each protein
      family: a small subset of residues forms physically connected networks that link
      distant functional sites in the tertiary structure. Although small in number,
      residues comprising the network show excellent correlation with the large body of
      mechanistic data available for each family. The data suggest that evolutionarily
      conserved sparse networks of amino acid interactions represent structural motifs
      for allosteric communication in proteins.

PMID- 12483204
TI  - Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a
      substrate analog.
AB  - Dipeptidyl peptidase IV (DPP-IV/CD26) is a multifunctional type II transmembrane
      serine peptidase. This enzyme contributes to the regulation of various
      physiological processes, including blood sugar homeostasis, by cleaving peptide
      hormones, chemokines and neuropeptides. We have determined the 2.5 A structure of
      the extracellular region of DPP-IV in complex with the inhibitor valine
      pyrrolidide. The catalytic site is located in a large cavity formed between the
      alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain. Both
      domains participate in inhibitor binding. The structure indicates how substrate
      specificity is achieved and reveals a new and unexpected opening to the active
      site.

PMID- 12483205
TI  - Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii
      sporozoite infectivity.
AB  - Plasmodium sporozoites are transmitted through the bite of infected mosquitoes
      and first invade the liver of the mammalian host, as an obligatory step of the
      life cycle of the malaria parasite. Within hepatocytes, Plasmodium sporozoites
      reside in a membrane-bound vacuole, where they differentiate into exoerythrocytic
      forms and merozoites that subsequently infect erythrocytes and cause the malaria
      disease. Plasmodium sporozoite targeting to the liver is mediated by the specific
      binding of major sporozoite surface proteins, the circumsporozoite protein and
      the thrombospondin-related anonymous protein, to glycosaminoglycans on the
      hepatocyte surface. Still, the molecular mechanisms underlying sporozoite entry
      and differentiation within hepatocytes are largely unknown. Here we show that the
      tetraspanin CD81, a putative receptor for hepatitis C virus, is required on
      hepatocytes for human Plasmodium falciparum and rodent Plasmodium yoelii
      sporozoite infectivity. P. yoelii sporozoites fail to infect CD81-deficient mouse
      hepatocytes, in vivo and in vitro, and antibodies against mouse and human CD81
      inhibit in vitro the hepatic development of P. yoelii and P. falciparum,
      respectively. We further demonstrate that the requirement for CD81 is linked to
      sporozoite entry into hepatocytes by formation of a parasitophorous vacuole,
      which is essential for parasite differentiation into exoerythrocytic forms.

PMID- 12483206
TI  - In vivo imaging of transcriptionally active estrogen receptors.
AB  - Through intracellular receptors, estrogens control growth, differentiation and
      function of not only reproductive tissues, but also other systems. Estrogen
      receptors are ligand-dependent transcription factors whose activity is modulated
      either by estrogens, or by alternative intracellular signaling pathways
      downstream of growth factors and neurotransmitters. To determine the dynamics of
      estrogen receptor activity and the dependence of estrogen receptor on 17beta
      estradiol in vivo, we generated a transgenic mouse that expresses a luciferase
      reporter gene under the control of activated estrogen receptors. As expected,
      luciferase activity, monitored with a cooled charged coupled device camera,
      paralleled circulating estrogen levels in reproductive tissues and in liver,
      indicating that the peak transcriptional activity of the estrogen receptor
      occurred at proestrus. In contrast, in tissues such as bone and brain, the peak
      activity of estrogen receptors was observed at diestrus. These tissue-specific
      responses are masked when mice undergo conventional hormone treatment. We also
      demonstrate that estrogen receptors are active in immature mice before gonadal
      production of sex hormones as well as in ovariectomized adult mice. These
      findings emphasize the importance of hormone-independent activation of the
      estrogen receptor, and have implications for the therapeutic use of estrogens,
      such as hormone replacement therapy.

PMID- 12483207
TI  - Circulating activated platelets exacerbate atherosclerosis in mice deficient in
      apolipoprotein E.
AB  - We studied whether circulating activated platelets and platelet-leukocyte
      aggregates cause the development of atherosclerotic lesions in apolipoprotein-E
      deficient (Apoe(-/-)) mice. Circulating activated platelets bound to leukocytes,
      preferentially monocytes, to form platelet-monocyte/leukocyte aggregates.
      Activated platelets and platelet-leukocyte aggregates interacted with
      atherosclerotic lesions. The interactions of activated platelets with monocytes
      and atherosclerotic arteries led to delivery of the platelet-derived chemokines
      CCL5 (regulated on activation, normal T cell expressed and secreted, RANTES) and
      CXCL4 (platelet factor 4) to the monocyte surface and endothelium of
      atherosclerotic arteries. The presence of activated platelets promoted leukocyte
      binding of vascular cell adhesion molecule-1 (VCAM-1) and increased their
      adhesiveness to inflamed or atherosclerotic endothelium. Injection of activated
      wild-type, but not P-selectin-deficient, platelets increased monocyte arrest on
      the surface of atherosclerotic lesions and the size of atherosclerotic lesions in
      Apoe(-/-) mice. Our results indicate that circulating activated platelets and
      platelet-leukocyte/monocyte aggregates promote formation of atherosclerotic
      lesions. This role of activated platelets in atherosclerosis is attributed to
      platelet P-selectin-mediated delivery of platelet-derived proinflammatory factors
      to monocytes/leukocytes and the vessel wall.

PMID- 12483208
TI  - Cytokine traps: multi-component, high-affinity blockers of cytokine action.
AB  - Cytokines can initiate and perpetuate human diseases, and are among the best
      validated of therapeutic targets. Cytokines can be blocked by the use of soluble
      receptors; however, the use of this approach for cytokines such as interleukin
      (IL)-1, IL-4, IL-6 and IL-13 that use multi-component receptor systems is limited
      because monomeric soluble receptors generally exhibit low affinity or function as
      agonists. We describe here a generally applicable method to create very high
      affinity blockers called 'cytokine traps' consisting of fusions between the
      constant region of IgG and the extracellular domains of two distinct cytokine
      receptor components involved in binding the cytokine. Traps potently block
      cytokines in vitro and in vivo and represent a substantial advance in creating
      novel therapeutic candidates for cytokine-driven diseases.

PMID- 12483209
TI  - Essential role of Id2 in negative regulation of IgE class switching.
AB  - Serum concentrations of immunoglobulin E (IgE) in normal circumstances are kept
      much lower than those of other Ig isotypes to avoid allergic reactions. B cells
      lacking Id2 have increased E2A activity, which leads to specific enhancement of
      germline transcription of the immunoglobulin epsilon locus. As a consequence, Id2
      deficient B cells undergo class switch recombination (CSR) to IgE at a much
      higher frequency than wild-type B cells. In contrast, Id2 is induced in wild-type
      B cells by transforming growth factor-beta1 (TGF-beta1) and suppresses IgE CSR.
      Our results provide evidence for the inhibitory and selective role of Id2 in IgE
      CSR in response to TGF-beta1. Id2 might act as molecular safeguard to suppress
      IgE CSR to prevent serious complications such as allergic hypersensitivity during
      the normal course of immune responses.

PMID- 12483210
TI  - IFN-lambdas mediate antiviral protection through a distinct class II cytokine
      receptor complex.
AB  - We report here the identification of a ligand-receptor system that, upon
      engagement, leads to the establishment of an antiviral state. Three closely
      positioned genes on human chromosome 19 encode distinct but paralogous proteins,
      which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3
      (tentatively designated as IL-29, IL-28A and IL-28B, respectively, by HUGO). The
      expression of IFN-lambda mRNAs was inducible by viral infection in several cell
      lines. We identified a distinct receptor complex that is utilized by all three
      IFN-lambda proteins for signaling and is composed of two subunits, a receptor
      designated CRF2-12 (also designated as IFN-lambdaR1) and a second subunit, CRF2-4
      (also known as IL-10R2). Both receptor chains are constitutively expressed on a
      wide variety of human cell lines and tissues and signal through the Jak-STAT
      (Janus kinases-signal transducers and activators of transcription) pathway. This
      receptor-ligand system may contribute to antiviral or other defenses by a
      mechanism similar to, but independent of, type I IFNs.

PMID- 12483211
TI  - Transcriptional activation of retrotransposons alters the expression of adjacent
      genes in wheat.
AB  - Retrotransposons are a principal component of most eukaryotic genomes,
      representing roughly 40% of the human genome and 50-80% of some grass genomes.
      They are usually transcriptionally silent but can be activated under certain
      stresses. Despite their considerable contribution to genome structure, their
      impact on the expression of adjacent genes is not well understood. The steady
      state transcript levels originating from Wis 2-1A retrotransposons are much
      higher in newly synthesized wheat amphiploids (two or more diverged genomes in
      the same nucleus). On activation, both Wis 2-1A long terminal repeats drive the
      readout synthesis of new transcripts from adjacent sequences including the
      antisense or sense strands of known genes. Here we report that activation of
      these antisense or sense transcripts is associated with silencing or activation
      of the corresponding genes, respectively. These data, together with the abundance
      of retrotransposons in genomes and their ability to be activated by various
      signals, support the view of transposons as potential controlling elements.

PMID- 12483212
TI  - Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella
      pneumophila.
AB  - In inbred mouse strains, permissiveness to intracellular replication of
      Legionella pneumophila is controlled by a single locus (Lgn1), which maps to a
      region within distal Chromosome 13 that contains multiple copies of the gene
      baculoviral IAP repeat-containing 1 (Birc1, also called Naip; refs. 1-3). Genomic
      BAC clones from the critical interval were transferred into transgenic mice to
      functionally complement the Lgn1-associated susceptibility of A/J mice to L.
      pneumophila. Here we report that two independent BAC clones that rescue
      susceptibility have an overlapping region of 56 kb in which the entire Lgn1
      transcript must lie. The only known full-length transcript coded in this region
      is Birc1e (also called Naip5).

PMID- 12483213
TI  - Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for
      morphological evolution.
AB  - Morphological alterations have been shown to occur in Drosophila melanogaster
      when function of Hsp90 (heat shock 90-kDa protein 1alpha, encoded by Hsp83) is
      compromised during development. Genetic selection maintains the altered
      phenotypes in subsequent generations. Recent experiments have shown, however,
      that phenotypic variation still occurs in nearly isogenic recombinant inbred
      strains of Arabidopsis thaliana. Using a sensitized isogenic D. melanogaster
      strain, iso-Kr(If-1), we confirm this finding and present evidence supporting an
      epigenetic mechanism for Hsp90's capacitor function, whereby reduced activity of
      Hsp90 induces a heritably altered chromatin state. The altered chromatin state is
      evidenced by ectopic expression of the morphogen wingless in eye imaginal discs
      and a corresponding abnormal eye phenotype, both of which are epigenetically
      heritable in subsequent generations, even when function of Hsp90 is restored.
      Mutations in nine different genes of the trithorax group that encode chromatin
      remodeling proteins also induce the abnormal phenotype. These findings suggest
      that Hsp90 acts as a capacitor for morphological evolution through epigenetic and
      genetic mechanisms.

PMID- 12483214
TI  - Routes to remembering: the brains behind superior memory.
AB  - Why do some people have superior memory capabilities? We addressed this age-old
      question by examining individuals renowned for outstanding memory feats in forums
      such as the World Memory Championships. Using neuropsychological measures, as
      well as structural and functional brain imaging, we found that superior memory
      was not driven by exceptional intellectual ability or structural brain
      differences. Rather, we found that superior memorizers used a spatial learning
      strategy, engaging brain regions such as the hippocampus that are critical for
      memory and for spatial memory in particular. These results illustrate how
      functional neuroimaging might prove valuable in delineating the neural substrates
      of mnemonic techniques, which could broaden the scope for memory improvement in
      the general population and the memory-impaired.

PMID- 12483215
TI  - NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration
      of ERK signaling.
AB  - The intracellular mechanism(s) by which a cell determines the duration of
      extracellular signal-regulated kinase (ERK) activation is not well understood. We
      have investigated the role of STEP, a striatal-enriched tyrosine phosphatase, in
      the regulation of ERK activity in rat neurons. Glutamate-mediated activation of
      NMDA receptors leads to the rapid but transient phosphorylation of ERK in
      cultured neurons. Here we show that activation of NMDA receptors led to
      activation of STEP, which limited the duration of ERK activity as well as its
      translocation to the nucleus and its subsequent downstream nuclear signaling. In
      neurons, STEP is phosphorylated and inactive under basal conditions. NMDA
      mediated influx of Ca(2+), but not increased intracellular Ca(2+) from other
      sources, leads to activation of the Ca(2+)-dependent phosphatase calcineurin and
      the dephosphorylation and activation of STEP. We have identified an important
      mechanism involved in the regulation of ERK activity in neurons that highlights
      the complex interplay between serine/threonine and tyrosine kinases and
      phosphatases.

PMID- 12483216
TI  - Estimating invisible target speed from neuronal activity in monkey frontal eye
      field.
AB  - Working memory involves transient storage of information and the ability to
      manipulate that information for short-range planning and prediction. The
      computational aspect of working memory can be probed using dynamic sensorimotor
      behavior requiring complex stimulus-response mappings. Such a transformation
      occurs when extrapolating the future location of a moving target that is rendered
      temporarily invisible. Estimating the trajectory of an invisible moving target
      requires encoding and storing several target features, including the direction
      and speed of motion. We trained monkeys to make saccades to the estimated
      position of invisible targets moving at various speeds. The activity of neurons
      in the frontal eye field (FEF) was consistently modulated according to the speed
      of target motion. A reconstruction algorithm showed that estimates of target
      speed based on FEF activity were similar to behavioral speed estimates. FEF may
      therefore be involved in updating an internal representation of target trajectory
      for predictive saccades.

PMID- 12483217
TI  - Multisensory representation of limb position in human premotor cortex.
AB  - Using functional magnetic resonance imaging (fMRI) in humans, we identified
      regions of cortex involved in the encoding of limb position. Tactile stimulation
      of the right hand, across the body midline, activated the right parietal cortex
      when the eyes were closed; activation shifted to a left parietofrontal network
      when the eyes were open. These data reveal important similarities between human
      and non-human primates in the network of brain areas involved in the multisensory
      representation of limb position.

PMID- 12483218
TI  - Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant
      mice.
AB  - Blockade of cholinergic neurotransmission by muscarinic receptor antagonists
      produces profound deficits in attention and memory. However, the antagonists used
      in previous studies bind to more than one of the five muscarinic receptor
      subtypes. Here we examined memory in mice with a null mutation of the gene coding
      the M1 receptor, the most densely distributed muscarinic receptor in the
      hippocampus and forebrain. In contrast with previous studies using nonselective
      pharmacological antagonists, the M1 receptor deletion produced a selective
      phenotype that included both enhancements and deficits in memory. Long-term
      potentiation (LTP) in response to theta burst stimulation in the hippocampus was
      also reduced in mutant mice. M1 null mutant mice showed normal or enhanced memory
      for tasks that involved matching-to-sample problems, but they were severely
      impaired in non-matching-to-sample working memory as well as consolidation. Our
      results suggest that the M1 receptor is specifically involved in memory processes
      for which the cortex and hippocampus interact.

PMID- 12483219
TI  - Vimentin is secreted by activated macrophages.
AB  - Vimentin is a widely expressed intermediate filament protein thought to be
      involved mainly in structural processes, such as wound healing. We now
      demonstrate that activated human macrophages secrete vimentin into the
      extracellular space. The maturation of blood-derived monocytes into macrophages
      involves several signalling pathways. We show that secretion of vimentin, which
      is phosphorylated at serine and threonine residues, is enhanced by the
      phosphatase inhibitor okadaic acid and blocked by the specific protein kinase C
      inhibitor GO6983. These findings are consistent with previous observations that
      phosphorylation of vimentin affects its intracellular localization and that
      vimentin is a substrate for protein kinase C (PKC). We also show that the anti
      inflammatory cytokine interleukin-10 (IL-10), which inhibits PKC activity, blocks
      secretion of vimentin. In contrast, the pro-inflammatory cytokine tumour necrosis
      factor alpha (TNF-alpha) can trigger secretion of vimentin. Finally, we found
      that extracellular vimentin is involved in bacterial killing and the generation
      of oxidative metabolites, two important functions of activated macrophages. These
      data establish that vimentin is secreted by macrophages in response to pro
      inflammatory signalling pathways and is probably involved in immune function.

PMID- 12483220
TI  - Yeast epsin-related proteins required for Golgi-endosome traffic define a gamma
      adaptin ear-binding motif.
AB  - Clathrin-coated vesicles (CCVs) are a central component of endocytosis and
      traffic between the trans-Golgi network (TGN) and endosomes. Although endocytic
      CCV formation is well characterized, much less is known about CCV formation at
      internal membranes. Here we describe two epsin amino-terminal homology (ENTH)
      domain-containing proteins, Ent3p and Ent5p, that are intimately involved in
      clathrin function at the Golgi. Both proteins associate with the clathrin adaptor
      Gga2p in vivo; Ent5p also interacts with the clathrin adaptor complex AP-1 and
      clathrin. A novel, conserved motif that mediates the interaction of Ent3p and
      Ent5p with gamma-ear domains of Gga2p and AP-1 is defined. Ent3p and Ent5p
      colocalize with clathrin, and cells lacking both Ent proteins exhibit defects in
      clathrin localization and traffic between the Golgi and endosomes. The findings
      suggest that Ent3p and Ent5p constitute a functionally related pair that co
      operate with Gga proteins and AP-1 to recruit clathrin and promote formation of
      clathrin coats at the Golgi/endosomes. On the basis of our results and the
      established roles of epsin and epsin-related proteins in endocytosis, we propose
      that ENTH-domain-containing proteins are a universal component of CCV formation.

PMID- 12483221
TI  - Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic
      neutralization epitopes.
AB  - The conserved surfaces of the human immunodeficiency virus (HIV)-1 envelope
      involved in receptor binding represent potential targets for the development of
      entry inhibitors and neutralizing antibodies. Using structural information on a
      CD4-gp120-17b antibody complex, we have designed a 27-amino acid CD4 mimic,
      CD4M33, that presents optimal interactions with gp120 and binds to viral
      particles and diverse HIV-1 envelopes with CD4-like affinity. This mini-CD4
      inhibits infection of both immortalized and primary cells by HIV-1, including
      primary patient isolates that are generally resistant to inhibition by soluble
      CD4. Furthermore, CD4M33 possesses functional properties of CD4, including the
      ability to unmask conserved neutralization epitopes of gp120 that are cryptic on
      the unbound glycoprotein. CD4M33 is a prototype of inhibitors of HIV-1 entry and,
      in complex with envelope proteins, a potential component of vaccine formulations,
      or a molecular target in phage display technology to develop broad-spectrum
      neutralizing antibodies.

PMID- 12483222
TI  - A transgene-based, embryo-specific lethality system for insect pest management.
AB  - Biological approaches to insect pest management offer alternatives to pesticidal
      control. In area-wide control programs that cover entire regions, the sterile
      insect technique (SIT) can be used to successfully suppress economically
      important pest species by the mass release of sterilized pest organisms. However,
      conventional sterilization by ionizing radiation reduces insect fitness, which
      can result in reduced competitiveness of the sterilized insects. Here we report a
      transgene-based, dominant embryonic lethality system that allows for generation
      of large quantities of competitive but sterile insects without the need of
      irradiation. The system involves the ectopic expression of a hyperactive pro
      apoptotic gene that causes embryo-specific lethality when driven by the
      tetracycline-controlled transactivator (tTA) under the regulation of a
      cellularization gene enhancer-promoter. We have successfully tested this system
      in Drosophila melanogaster. The embryonic lethality can be suppressed maternally,
      which will allow it to be combined with transgenic female-specific lethality
      systems to raise only vigorous but sterile males.

PMID- 12483223
TI  - Transgenic silkworms produce recombinant human type III procollagen in cocoons.
AB  - We describe the generation of transgenic silkworms that produce cocoons
      containing recombinant human collagen. A fusion cDNA was constructed encoding a
      protein that incorporated a human type III procollagen mini-chain with C
      propeptide deleted, a fibroin light chain (L-chain), and an enhanced green
      fluorescent protein (EGFP). This cDNA was ligated downstream of the fibroin L
      chain promoter and inserted into a piggyBac vector. Silkworm eggs were injected
      with the vectors, producing worms displaying EGFP fluorescence in their silk
      glands. The cocoons emitted EGFP fluorescence, indicating that the promoter and
      fibroin L-chain cDNAs directed the synthesized products to be secreted into
      cocoons. The presence of fusion proteins in cocoons was demonstrated by
      immunoblotting, collagenase-sensitivity tests, and amino acid sequencing. The
      fusion proteins from cocoons were purified to a single electrophoretic band. This
      study demonstrates the viability of transgenic silkworms as a tool for producing
      useful proteins in bulk.

PMID- 12483224
TI  - Immunomodulation of enzyme function in plants by single-domain antibody
      fragments.
AB  - Immunomodulation involves the use of antibodies to alter the function of
      molecules and is an emerging tool for manipulating both plant and animal systems.
      To realize the full potential of this technology, two major obstacles must be
      overcome. First, most antibodies do not function well intracellularly because
      critical disulfide bonds cannot form in the reducing environment of the cytoplasm
      or because of difficulties in targeting to subcellular organelles. Second, few
      antibodies bind to the active sites of enzymes and thus they generally do not
      neutralize enzyme function. Here we show that the unique properties of single
      domain antibodies from camelids (camels and llamas) can circumvent both these
      obstacles. We demonstrate that these antibodies can be correctly targeted to
      subcellular organelles and inhibit enzyme function in plants more efficiently
      than antisense approaches. The use of these single-domain antibody fragments may
      greatly facilitate the successful immunomodulation of metabolic pathways in many
      organisms.

PMID- 12483225
TI  - An efficient protein complex purification method for functional proteomics in
      higher eukaryotes.
AB  - The ensemble of expressed proteins in a given cell is organized in multiprotein
      complexes. The identification of the individual components of these complexes is
      essential for their functional characterization. The introduction of the 'tandem
      affinity purification' (TAP) methodology substantially improved the purification
      and systematic genome-wide characterization of protein complexes in yeast. The
      use of this approach in higher eukaryotic cells has lagged behind its use in
      yeast because the tagged proteins are normally expressed in the presence of the
      untagged endogenous version, which may compete for incorporation into
      multiprotein complexes. Here we describe a strategy in which the TAP approach is
      combined with double-stranded RNA interference (RNAi) to avoid competition from
      corresponding endogenous proteins while isolating and characterizing protein
      complexes from higher eukaryotic cells. This strategy allows the determination of
      the functionality of the tagged protein and increases the specificity and the
      efficiency of the purification.

PMID- 12483226
TI  - IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice.
AB  - Studies in invertebrates have led to the identification of a number of genes that
      regulate lifespan, some of which encode components of the insulin or insulin-like
      signalling pathways. Examples include the related tyrosine kinase receptors InR
      (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues
      of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To
      investigate whether IGF-1R also controls longevity in mammals, we inactivated the
      IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null
      mutants are not viable, we report that Igf1r(+/-) mice live on average 26% longer
      than their wild-type littermates (P < 0.02). Female Igf1r(+/-) mice live 33%
      longer than wild-type females (P < 0.001), whereas the equivalent male mice show
      an increase in lifespan of 16%, which is not statistically significant. Long
      lived Igf1r(+/-) mice do not develop dwarfism, their energy metabolism is normal,
      and their nutrient uptake, physical activity, fertility and reproduction are
      unaffected. The Igf1r(+/-) mice display greater resistance to oxidative stress, a
      known determinant of ageing. These results indicate that the IGF-1 receptor may
      be a central regulator of mammalian lifespan.

PMID- 12483227
TI  - Rhythmic histone acetylation underlies transcription in the mammalian circadian
      clock.
AB  - In the mouse circadian clock, a transcriptional feedback loop is at the centre of
      the clockwork mechanism. Clock and Bmal1 are essential transcription factors that
      drive the expression of three period genes (Per1-3) and two cryptochrome genes
      (Cry1 and Cry2). The Cry proteins feedback to inhibit Clock/Bmal1-mediated
      transcription by a mechanism that does not alter Clock/Bmal1 binding to DNA. Here
      we show that transcriptional regulation of the core clock mechanism in mouse
      liver is accompanied by rhythms in H3 histone acetylation, and that H3
      acetylation is a potential target of the inhibitory action of Cry. The promoter
      regions of the Per1, Per2 and Cry1 genes exhibit circadian rhythms in H3
      acetylation and RNA polymerase II binding that are synchronous with the
      corresponding steady-state messenger RNA rhythms. The histone acetyltransferase
      p300 precipitates together with Clock in vivo in a time-dependent manner.
      Moreover, the Cry proteins inhibit a p300-induced increase in Clock/Bmal1
      mediated transcription. The delayed timing of the Cry1 mRNA rhythm, relative to
      the Per rhythms, is due to the coordinated activities of Rev-Erbalpha and
      Clock/Bmal1, and defines a new mechanism for circadian phase control.

PMID- 12483228
TI  - Regioselectivity of CYP2B6: homology modeling, molecular dynamics simulation,
      docking.
AB  - Human cytochrome P450 (CYP) 2B6 activates the anticancer prodrug cyclophosphamide
      (CPA) by 4-hydroxylation. In contrast, the same enzyme catalyzes N-deethylation
      of a structural isomer, the prodrug ifosfamide (IFA), thus causing severe adverse
      drug effects. To model the molecular interactions leading to a switch in
      regioselectivity, the structure of CYP2B6 was modeled based on the structure of
      rabbit CYP2C5. We modeled the missing 22-residue loop in CYP2C5 between helices F
      and G (the F-G loop), which is not resolved in the X-ray structure, by molecular
      dynamics (MD) simulations using a simulated annealing protocol. The modeled
      conformation of the loop was validated by unconstrained MD simulations of the
      complete enzymes (CYP2C5 and CYP2B6) in water for 70 and 120 ps, respectively.
      The simulations were stable and led to a backbone r.m.s. deviation of 1.7 A
      between the two CYPs. The shape of the substrate binding site of CYP2B6 was
      further analyzed. It consists of three well-defined hydrophobic binding pockets
      adjacent to the catalytic heme. Size, shape and hydrophobicity of these pockets
      were compared to the shapes of the two structurally isomeric substrates. In their
      preferred orientation in the binding site, both substrates fill all three binding
      pockets without repulsive interactions. The distance to the heme iron is short
      enough for 4-hydroxylation and N-deethylation to occur for CPA and IFA,
      respectively. However, if the substrates are docked in the non-preferred
      orientation (such that 4-hydroxylation and N-deethylation would occur for IFA and
      CPA, respectively), one pocket is left empty, and clashes were observed between
      the substrates and the enzyme.

PMID- 12483229
TI  - CoMFA and CoMSIA studies of angiotensin (AT1) receptor antagonists.
AB  - Two 3D-QSAR methods--CoMFA and CoMSIA--were applied to a set of 38 angiotensin
      receptor (AT1) antagonists. The conformation and alignment of molecules were
      obtained by a novel method - consensus dynamics. The representation of biological
      activity, partial charge formalism, absolute orientation of the molecules in the
      grid, and grid spacing were also studied for their effect on the CoMFA models.
      The models were thoroughly validated through trials using scrambled activities
      and bootstrapping. The best CoMFA model had a cross-validated correlation
      coefficient ( q2) of 0.632, which improved with "region focusing" to 0.680. This
      model had a "predictive" r2 of 0.436 on a test series that was unique and with
      little representation in the training set. Although the "predictive" r2 of the
      best CoMSIA model, which included steric, electrostatic, and hydrogen bond
      acceptor fields was higher than that of the best CoMFA model, the other
      statistical parameters like q2, r2, F value, and s were unsatisfactory. The
      contour maps generated using the best CoMFA model were used to identify the
      structural features important for biological activity in these compounds.

PMID- 12483230
TI  - Three-dimensional solution structure of Tropidechis carinatus venom extract
      trocarin: a structural homologue of Xa and prothrombin activator.
AB  - Trocarin belongs to group D of prothrombin activators derived from snake venom of
      Tropidechis carinatus and is a rich non-hepatic source of Xa, the only known
      hepatic prothrombin activator. The structural and functional similarity with Xa
      makes trocarin an interesting target for exploring the structure-functional
      relationship with Xa. Herein we report a predicted complete three-dimensional all
      atom structural model of trocarin equilibrated in explicit water using 4 ns of
      molecular dynamics simulation. The tertiary structure was modeled using the
      structure of human blood coagulation factor Xa. The conformational and structural
      features of trocarin are then compared with the X-ray crystal and solution
      simulation structures of human factor Xa. The modeled structure of trocarin has
      four individual domains (Gla, EGF1, EGF2 and SP) connected along the long axis
      with similar secondary structural elements to Xa. The simulations suggest that
      sodium ion binding in the serine protease domain is impaired in trocarin as
      compared to Xa. In contrast to Xa, for which the sodium ion forms an octahedral
      coordination network that brings two loop regions connecting four anti-parallel
      beta-sheets together, we do not find a similar pattern of network in trocarin. We
      observe that the difference in the binding pattern of sodium ion leads to a
      approximately 2-A "shrinkage" of the beta2 strand (B2), in comparison to human
      Xa, as marked by a shorter distance between 189Asp373 (S1-site residue) and
      195Ser379 (active-site residue) in the B2 strand. We propose that these
      differences may be linked to the experimentally observed lower amidolytic
      activity of trocarin as compared to Xa.

PMID- 12483231
TI  - F+ tunable laser activity and interaction of atomic halogens (F, Cl and Br) at
      the low coordinated surface sites of SrOAb initio and DFT calculations.
AB  - The twofold potential of F+ color centers at the low coordinated surfaces of SrO
      for providing tunable laser activity and adsorption properties for atomic
      halogens (F, Cl and Br) has been investigated using ab initio electronic
      structure calculations. SrO clusters of variable sizes were embedded in simulated
      Coulomb fields that closely approximate the Madelung fields of the host surfaces
      and the nearest neighbor ions to F+ were allowed to relax to equilibrium. Based
      on Stokes shifted optical transition bands and horizontal shifts along the
      configuration coordinate diagrams, the F+ laser activity was found to decrease as
      the coordination number of the surface ions decreases from 5 (flat) to 4 (edge)
      to 3 (corner). An attempt has been made to explain this result in terms of
      Madelung potentials and optical-optical conversion efficiencies. All relaxed
      excited states are deep below the conduction bands of the perfect ground states,
      implying that F+ is a laser-suitable defect. The most laser active flat surface
      is the least probable for relaxed excited state orientational destruction of F+.
      The excited state at the edge has the highest energy, implying exciton (energy)
      transfer to the flat and edge sites. F+ relaxation and defect-formation energies
      increase with increasing surface coordination number. The Glasner-Tompkins
      relation between the fundamental optical absorption of F+ in solids and the
      fundamental absorption of the host crystals can be generalized to include the low
      coordinated surfaces of SrO. The F+ color center changes the nature of halogen
      surface interaction (adsorption energies) from physical adsorption to chemical
      adsorption. The halogen-surface interactions increase with increasing
      electronegativity of the halogen. The calculated adsorption energies can be
      explained in terms of surface electrostatic potentials, and the covalent spin
      pairing mechanism plays a dominant role in determining adsorbate-substrate
      interactions.

PMID- 12483232
TI  - All-ceramic crowns: bonding or cementing?
AB  - Despite the wide variety of all-ceramic systems available today, the majority of
      dental practitioners hesitate to recommend and insert all-ceramic crowns. This
      article regards the nature of the ceramic materials, the principles of bonding
      and adhesion, and the clinical problems of the acid-etch technique for crowns.
      Advantages and disadvantages are discussed, and the influences of different
      factors on the strength of all-ceramic crowns are presented. Finally, the
      conclusion is drawn that conventional cementing of all-ceramic crowns is possible
      when the specific properties of the ceramics are taken into consideration.

PMID- 12483233
TI  - Conventional and adhesive luting cements.
AB  - Luting materials for fixed prosthesis must fulfill special requirements in order
      to retain indirect restorations and fully maintain the integrity of abutments.
      The main requirements (inhibition of plaque accumulation, sealing of interface,
      possible antibacterial effects, acceptable solubility, wear, mechanical
      properties, adhesion, radiopacity, film thickness, type of curing, esthetics,
      storage, and cost) are reviewed to update clinical criteria on the selection of
      suitable materials. It can be concluded that there is no ideal luting material on
      the market. Alleged improvements in the physical data of newer materials do not
      necessarily result in better clinical performance. Only clinical trials can
      confirm the assumed benefits of materials.

PMID- 12483234
TI  - Antibacterial effect of an enamel matrix protein derivative on in vivo dental
      biofilm vitality.
AB  - The purpose of this observer-blind, randomised, five-cell crossover study was to
      examine the antibacterial efficacy of an enamel matrix protein derivative (EMD)
      on established supragingival plaque in vivo. Saline (NaCl) served as a negative
      control solution and chlorhexidine (CHX) as a positive one. Additionally, the
      propylene glycol alginate (PGA) vehicle and the 24% ethylenediaminetetra-acetate
      (EDTA) gel were tested. After professional oral prophylaxis, 14 volunteers
      refrained from all mechanical oral hygiene measures for the following 48 h to
      build up plaque. In randomised order, the following procedures were applied: (a)
      10 ml of CHX (0.2%) or (b) 10 ml of NaCl were used as a mouthrinse for 1 min
      each. In the cases of (c) EMD (Emdogain), (d) PGA, or (e) 24% EDTA (PrefGel), 1
      ml of each were applied with a syringe on the teeth. Two hours after application,
      plaque samples were taken from one upper and one lower molar, and the vitality of
      the biofilm microbiota was examined using the vital fluorescence technique.
      Biofilm vitality (VF%) was lower for EMD, PGA, and CHX by 19% ( P<0.0001), 22% (
      P=0.001), and 35% ( P<0.0001), respectively, than in negative controls. The EDTA
      showed similar vitality values to NaCl and was therefore not able to affect the
      biofilm flora significantly. The EMD and PGA displayed significantly reduced
      biofilm vitality compared to negative controls, which, however, could not reach
      the effect of the positive control (0.2% CHX). The present results demonstrate
      for the first time a direct influence of EMD on the vitality of supragingival
      dental plaque in vivo.

PMID- 12483235
TI  - Correlations between bacterial levels in autologous subgingival plaque and saliva
      of adult Sudanese.
AB  - The aim of this study was to assess levels of oral bacteria and their
      correlations in paired samples of saliva and subgingival plaque in a population
      of adult Sudanese. Whole saliva and pooled subgingival plaque samples from six
      probing sites of one tooth in each jaw were obtained from 56 Sudanese adults
      (mean age 35.2+/-8.9 years). Levels of 24 oral bacteria in the autologous saliva
      and pooled plaque sample of each subject were assessed by DNA probes and
      checkerboard DNA-DNA hybridization. There were significantly ( P< or =0.01)
      higher percentages of subjects with > or =10(5) bacterial cells of Prevotella
      intermedia, Campylobacter rectus, Veillonella parvula, Streptococcus mutans,
      Lactobacillus acidophilus, Streptococcus anginosus, Streptococcus salivarius, and
      Leptotrichia buccalis and significantly ( P< or =0.01) lower percentages with
      Treponema denticola in saliva than in subgingival plaque. The detection
      frequencies at > or =10(6) bacterial cells were significantly higher for
      Selenomonas sputigena, S. anginosus, Streptococcus sanguis, and S. salivarius and
      significantly lower for Porphyromonas gingivalis in saliva than in subgingival
      plaque ( P< or =0.01). Porphyromonas gingivalis, Fusobacterium nucleatum, S.
      sputigena, S. sanguis, and Streptococcus mitis demonstrated significant ( P< or
      =0.05) positive correlations between their levels in plaque and saliva. This
      study indicates that the levels of P. gingivalis, F. nucleatum, S. sputigena, S.
      sanguis, and S. mitis correlate significantly in saliva and subgingival plaque
      and that higher accuracy of detection and assessment of the levels of these
      bacteria in the oral cavity may be achieved by concurrent sampling of saliva and
      subgingival plaque.

PMID- 12483236
TI  - Plaque-inhibiting effect of bioadhesive mucosal tablets containing chlorhexidine
      in a 4-day plaque regrowth model.
AB  - BACKGROUND AND AIM: Compliance in the use of daily oral antiseptics can probably
      be enhanced by prescribing easily-applied bioadhesive tablets which slowly
      release chlorhexidine (CHX). This could also be of use in patients with
      difficulties in rinsing or performing mechanical plaque control. The aim of the
      present study was to evaluate the capacity of bioadhesive tablets containing
      either 30 mg or 40 mg of CHX to inhibit de novo plaque formation. METHOD: In this
      single, examiner-blinded, crossover study, 22 volunteers between 21 and 25 years
      of age refrained from oral hygiene for 4 days. Bioadhesive mucosal tablets
      containing 30 mg or 40 mg of CHX were applied in the canine region. Rinses with a
      0.2% CHX solution and placebo tablets served as controls. Plaque regrowth was
      evaluated with the Quigley-Hein Index modification of Turesky and by an automatic
      image analysis system (AIA) using slides of stained plaque. Rinsing and
      application of the tablets were done under supervision twice daily. RESULTS:
      According to the plaque index, plaque regrowth was significantly inhibited by CHX
      rinses ( P<0.001) and by tablets with 40 mg of CHX ( P<0.02) for all teeth and
      surfaces. Placebo tablets and 30-mg CHX tablets had no plaque-inhibiting effect.
      For taste, the subjects preferred the placebo and the 30-mg tablets more than the
      rinses and 40-mg tablets. In 3/22 of the subjects, superficial mucosal lesions
      were found at the side of application of the 40-mg tablets. Using the AIA system
      for evaluation of plaque regrowth, similar results for plaque inhibition were
      found. CONCLUSION: It can be concluded that bioadhesive mucosal tablets
      containing 40 mg of CHX can inhibit plaque regrowth as well as 0.2% CHX rinses.
      However, unpleasant taste and superficial mucosal lesions are local side effects
      to be considered.

PMID- 12483237
TI  - Oral condition, chemistry of saliva, and salivary levels of Streptococcus mutans
      in thalassemic patients.
AB  - The purpose of this investigation was to determine the oral status in a group of
      patients with thalassemia major (TM). Eighteen TM patients (15 M, three F) and 18
      healthy controls randomly matched for age and sex were examined for dental caries
      using the decayed, missing, and filled teeth (DMFT) index and for oral hygiene
      conditions using the oral hygiene index (OHI)-S. Spontaneous saliva was collected
      from each subject, and the biochemical composition (calcium, phosphorous,
      potassium, sodium, urea) was determined. Furthermore, salivary Streptococcus
      mutans levels were evaluated. Statistical analysis (Student's t-test) were
      performed for means comparison, while independence among categorical variables
      was assessed using the chi(2) test. Fisher's exact test was used when expected
      cell values were less than 5. Dental status (DMFT index) was almost equal in the
      two groups (10.3 in TM vs 9.4 in controls, P=0.34). The occurrence of plaque (OHI
      S 2) was higher in the control group, but no statistically significant
      association was observed between oral hygiene conditions in the two groups
      (Fisher's exact test 0.47, P=0.79). Biochemical saliva composition was very
      similar in the two groups; only the urea concentration was lower in TM, and this
      difference was statistically significant ( P=0.002). The TM patients had an
      increased presence of mutans streptococci at detectable levels. Our findings
      confirm that, although no substantial differences were found between the two
      observed groups, further investigations are needed to determine the theoretical
      risk of oral diseases in thalassemic patients.

PMID- 12483238
TI  - Quantitative determination of salivary components in the pellicle on PMMA denture
      base material.
AB  - The formation of a salivary pellicle is a protective mechanism of the body for
      all surfaces in the oral cavity. The nature of the substrate may influence the
      composition of the pellicle. The aim of this study was to investigate the
      quantitative composition and individual variation of the salivary pellicle formed
      on denture base material (PMMA). Cylindrical specimens of PMMA were carried in
      the mouth and then desorbed with a 0.5-M sodium chloride solution. The solution
      was analysed for total protein, alpha-amylase, total proteases, protease
      inhibitors, secretory immunoglobulin A, immunoglobulin G, peroxidases,
      thiocyanate, lysozyme, and calcium content. All investigated salivary components
      could be found unequivocally in the desorption solution, indicating that a
      salivary pellicle had formed on the surface of the PMMA. Large coefficients of
      variation indicate large individual variations in the adsorbed amounts. The data
      also point to large intraindividual variations for the bound salivary components.
      Only the protease inhibitors revealed a strong positive correlation of the bound
      activity to the salivary activity. It is hypothesised that differences in the
      bound amounts of antimicrobial components might influence the microbial
      colonisation of denture bases and that protease inhibitors could be meaningful
      for the spread of the yeast Candida albicans from denture base material to the
      oral mucosa and thus might be an explanation for different susceptibility to
      denture base stomatitis.

PMID- 12483239
TI  - A prospective, randomized, comparative clinical study of resin composite and
      glass ionomer cement for retrograde root filling.
AB  - OBJECTIVE: To compare the clinical and radiographic treatment outcome of
      retrograde root filling with either dentin-bonded resin composite (Retroplast,
      RP) or glass ionomer cement (Chelon-Silver, CS). STUDY DESIGN: A prospective,
      randomized clinical study of 134 consecutive patients with indication of
      retrograde root filling of an incisor, canine, premolar, or first molar. Either
      RP or CS was chosen at random as retrograde filling material. Either material was
      applied onto the entire resection surface after prepared slightly concave. This
      preparation technique makes a sealing of the entire resection surface possible
      and prevents marginal contraction gaps during polymerization. A total of 122
      patients were available for 1-year follow-up. RESULTS: After 1 year the
      proportion of successful cases was significantly higher in the RP group (73%)
      than in the CS group (31%) (p<0.001). Doubtful healing with a need for a longer
      observation period was seen in 17% of the RP cases and 19% of the CS cases. The
      proportion of failures in the RP group (10%) was significantly lower than that in
      the CS group (50%) (p<0.001). Most of the unsuccessful CS cases failed due to
      loosening of the retrograde filling. CONCLUSIONS: Dentin-bonded RP applied onto
      the entire, slightly concave resection surface is a predictable apical sealant
      characterized by a high success rate. In contrast, retrograde root filling with
      CS results in an unacceptably high failure rate due to insufficient bonding
      strength to the concave resection surface.

PMID- 12483240
TI  - Dyes for caries detection: influence on composite and compomer microleakage.
AB  - The aim of this study was to evaluate the influence of caries-detecting dyes on
      the microleakage of adhesive materials. Sixty cubic class V cavities were
      prepared on buccal and lingual surfaces of 30 human third molars. Coronal margins
      were located in enamel and gingival margins in cementum. The teeth were randomly
      divided into six groups of ten restorations each. Cavities were restored with an
      adhesive system (Single Bond, 3M ESPE, St. Paul, Minn., USA), a compomer (F2000,
      3M ESPE), or a composite resin (Z100, 3M ESPE) according to the manufacturer's
      directions. Acid red dye (Seek, Ultradent, South Jordan, Ut., USA) and basic
      fuchsin dye (Vide Carie, Inodon, Porto Alegre, Brazil) were tested. Control
      groups were prepared without the use of dyes. After 7 days of storage in
      distilled water, the restorations were polished and the teeth were subjected to
      thermal cycling followed by immersion in 2% methylene blue. The teeth were
      sectioned, and microleakage scores were evaluated under magnification (40x). Data
      were submitted to statistical analysis using the nonparametric Kruskal-Wallis
      test. A statistically significant difference ( P<0.05) in microleakage was found
      between the materials in cementum (Z100>F2000) but not in enamel. Control and
      experimental groups using dyes showed similar results. It was concluded that dyes
      for caries detection did not increase microleakage of the adhesive materials
      tested.

PMID- 12483241
TI  - A new approach to evaluating occlusal support by analyzing the center of the bite
      force.
AB  - The aim of this study was to create a standard for occlusal support in the
      diagnosis and evaluation of prosthetic treatment. In experimental occlusion, the
      maximal bite force of eight normal dentates was measured by pressure-sensitive
      film over the whole dentition using splints divided into nine pieces. The
      occlusal contact was altered by exchanging splint pieces according to the
      shortened dental arch concept. The occlusal load center (OLC) was located on a
      graph set up with reference to the size of the individual dental arch. The
      occlusal supporting index (SI) and the rehabilitation index (RI) were calculated
      from the locations of the OLC corresponding to each occlusal contact. Differences
      in numbers and distribution of occlusal stops could clearly be distinguished by
      the location of the OLC. Though the SI showed a strong positive correlation with
      maximal bite force, it is proposed that the number of occlusal stops, or occlusal
      units, provides the most effective index for quantitative parameters of occlusal
      support in clinical use. From the standpoint of bite force, analysis of the RI is
      suggested as a useful method of objectively evaluating the recovery of occlusal
      support with prosthetic treatment.

PMID- 12483242
TI  - Understanding the hypercarcinogenic state in chronic hepatitis: a clue to the
      prevention of human hepatocellular carcinoma.
AB  - Human hepatocellular carcinomas (HCCs) are preceded by chronic hepatitis and
      cirrhosis. Despite a clear viral etiology (hepatitis B virus [HBV] and hepatitis
      C virus [HCV] of human hepatocarcinogenesis, the mechanism is complex and the
      distinct molecular pathway or molecules that explain this phenomenon are not yet
      known. Viral hepatitis, "inflammation-mediated" hepatocarcinogenesis, greatly
      influences the incidence of somatic genetic events in hepatocytes, by increasing
      the number of target cells or the proliferation of once-hit hepatocytes,
      eventually leading to HCC. We propose that hepatitis virus can cause HCC by a
      combination of two mechanisms; (i) cell killing and stimulation of mitosis,
      leading to an accumulation of events necessary for transformation; and (ii) an
      increase in chromosomal instability mediated by induced recombinogeneic
      protein(s) during chronic hepatitis. These conditions may be designated as the
      "hypercarcinogenic state". Our goal is to change the "hypercarcinogenic state" to
      the "normo- or hypocarcinogenic" state and to prevent HCC development.

PMID- 12483243
TI  - Influence of mosapride citrate on gastric motility and autonomic nervous
      function: evaluation by spectral analyses of heart rate and blood pressure
      variabilities, and by electrogastrography.
AB  - BACKGROUND: Mosapride citrate selectively acts on serotonin (5-HT(4)) receptors,
      thus accelerating gastrointestinal motility via acetylcholine. However, few
      studies have evaluated the influence of mosapride citrate on autonomic nervous
      activity and hemodynamics. METHODS: The changes in autonomic nervous activity, QT
      interval, and QT dispersion resulting from the administration of mosapride
      citrate were studied. Blood pressure, electrocardiograms (ECGs), percutaneous
      electrogastrograms (EGGs), and ultrasonography were recorded in 20 healthy adult
      volunteers before and after mosapride citrate (10 mg) was administered. Autonomic
      nervous activity was evaluated by spectral analyses of heart rate and blood
      pressure variabilities. Serial changes in low-frequency components (LF, 0.04-0.15
      Hz), high-frequency components (HF, 0.15-0.40 Hz), and the LF/HF ratio were
      investigated. RESULTS: The mean peak power of EGG increased significantly, from
      86 +/- 34 microV to 131 +/- 49 microV, after the administration of mosapride
      citrate (P < 0.05). Gastric emptying significantly increased after the
      administration of mosapride citrate (P < 0.05). However, neither blood pressure
      nor heart rate changed significantly after the drug was administrated. In
      addition, spectral analyses of heart rate and blood pressure variabilities showed
      no significant changes in autonomic nervous activity parameters, QT intervals, or
      QT dispersions. CONCLUSIONS: Mosapride citrate increased gastric motility and
      emptying without influencing autonomic nervous activity, suggesting that it may
      be very useful for elderly patients or patients with autonomic imbalance.

PMID- 12483244
TI  - Effects of etodolac, a selective cyclooxygenase-2 inhibitor, on the expression of
      E-cadherin-catenin complexes in gastrointestinal cell lines.
AB  - BACKGROUND: Recent studies have shown that cyclooxygenase-2 (COX-2) inhibitors
      may participate in the proliferation of cancer cells. Because the cadherin
      catenin complex is not only a key component of the adherens junction but also has
      been suggested to regulate cell proliferation, modulation of these molecules may
      be a mechanism by which COX-2 activity affects cell proliferation. In this study,
      we evaluated the effect of a COX-2 inhibitor on the proliferation and expression
      of E-cadherin-complexes in gastrointestinal cancer cell lines. METHODS: The
      gastrointestinal cancer cell lines Caco2, HT29, and MKN45 were grown for 24 h in
      the presence and absence of a selective COX-2 inhibitor, etodolac (10(-5), 10(
      4), and 10(-3) M). Cell proliferation was assessed by (3)H-thymidine
      incorporation, and the expression of E-cadherin and catenins was assessed by
      Western blotting, Northern blotting, and immunofluorescence. RESULTS: Etodolac
      induced a significant reduction in cell proliferation in Caco2 and MKN45 cells. E
      cadherin expression was upregulated after stimulation with etodolac in Caco2
      cells, whereas the expression of alpha-, beta-, gamma- and p120-catenins was not
      modified. The expression of E-cadherin mRNA was also upregulated in Caco2 cells,
      and was upregulated also in MKN45 cells, which did not express normal E-cadherin
      protein by the use of a mouse monoclonal antibody against human E-cadherin, HECD
      1 antibody. Immunofluorescence revealed that the increased E-cadherin was
      localized at the cytoplasmic membrane. CONCLUSIONS: The inhibition of cell growth
      by etodolac in Caco-2 cells was associated with a dose-dependent upregulation and
      intense cytoplasmic localization of E-cadherin. No quantitative change in catenin
      expression was found in this phenomenon. These findings suggest that the COX-2
      inhibitor affects the transcription of E-cadherin, or that there may be some
      homeostatic link between the cell cycle and E-cadherin transcription.

PMID- 12483245
TI  - Immunohistochemical analysis of cell cycle-regulating-protein (p21, p27, and Ki
      67) expression in gastroesophageal reflux disease.
AB  - BACKGROUND: The aim of this study was to carry out an immunohistochemical
      analysis of cell cycle-regulating-protein (p21, p27, and Ki-67) expression in
      endoscopic biopsy samples obtained using angled biopsy forceps. METHODS: The
      study was based on the examination of endoscopic esophageal biopsy specimens
      obtained from 46 patients with evidence of reflux and from 10 normal control
      subjects without clinical reflux. RESULTS: The percentage of samples containing
      the lamina propria was 5.7% using standard forceps ( n = 53) and 83.3% using the
      angled forceps ( n= 67). The use of angled forceps allowed the detection of
      inflammatory cell accumulation in the lamina propria even in patients with
      modified Los Angeles (LA) system grades N and M. In normal esophageal mucosa, Ki
      67-positive cells were detected within the lower parts of the basal zone, and p21
      and p27-positive cells were not detected. In samples from grade N and M
      patients, no histological changes were detectable by standard H&E staining.
      However, the area of Ki-67-positive cells was slightly expanded compared with
      normal mucosa, and p21- and p27-positive cells were clearly detectable from the
      lower to middle part of the epithelium. The area of Ki-67-, p21-, and p27
      positive cells tended to expand upward in the epithelium with gastroesophageal
      reflux disease (GERD) severity based on the LA classification grading.
      CONCLUSIONS: The use of angled biopsy forceps allows the evaluation of
      inflammatory responses at the level of the lamina propria and makes it possible
      to assess the expression of cell cycle-regulating proteins in the entire
      epithelium. The evaluation of these responses may be helpful in the diagnosis of
      endoscopically negative GERD.

PMID- 12483246
TI  - Long-term results of seton drainage on complex anal fistulae in patients with
      Crohn's disease.
AB  - BACKGROUND: The aim of this study was to assess the long-term (greater than 2
      years) results of seton drainage on anal fistulae in patients with Crohn's
      disease. METHODS: Between September 1990 and September 1999, 32 patients with
      Crohn's disease underwent seton drainage for complex anal fistulae. The median
      follow-up time in these patients was 62 months (range, 25-133 months). In 10
      patients (31.3%), recurrent perineal abscesses occurred with inlying seton
      drainage, and these were drained by re-insertion of the seton. A Malecot catheter
      was also inserted in 8 patients with recurrence. RESULTS: The overall success
      rate of long-term seton usage was 87.5%. The subsequent associated procedure was
      simple seton removal ( n = 9), secondary core-out fistulectomy ( n = 7), or lay
      open fistulotomy ( n = 4). Eleven patients still had the seton in place.
      Recurrence developed in 3 patients (33%) who underwent simple seton removal and
      in 2 patients (18.2%) who underwent the secondary core-out procedure or
      fistulotomy. At the last follow-up examination, continence had not changed in 28
      (87.5%) of the 32 patients. No change in continence was experienced by 10 of the
      11 patients who underwent secondary fistulotomy or the secondary core-out
      procedure. CONCLUSIONS: Long-term seton drainage for complex anal fistula in
      Crohn's disease is efficacious in both treating sepsis and preserving anal
      sphincter function. A relatively good result was achieved by the secondary core
      out procedure or fistulotomy at the time of seton removal.

PMID- 12483247
TI  - Interferon for treatment of breakthrough infection with hepatitis B virus mutants
      developing during long-term lamivudine therapy.
AB  - BACKGROUND: We aimed to treat patients with chronic hepatitis B on long-term
      treatment with lamivudine who developed lamivudine-resistant hepatitis B virus
      (HBV) mutants along with clinical relapses. METHODS: Of 217 patients with chronic
      hepatitis B who had been treated with lamivudine for 1-6 years, 23 (11%)
      developed lamivudine-resistant hepatitis B virus (HBV) mutants. Seven of them,
      including 1 whose case was previously reported, received interferon (IFN) daily
      for 4 weeks and then two or three times a week thereafter to cope with
      exacerbation of hepatitis. We investigated the efficacy of this IFN therapy in 6
      patients, excluding the 1 previously reported. RESULTS: In 4 patients, HBV DNA
      decreased to below the detectable limit of the branched DNA assay (<0.7 MEq/ml)
      accompanied by normalization of transaminase levels. During IFN therapy, 2
      patients seroconverted to antibody to hepatitis B e antigen (HBeAg) and showed
      normalized transaminase levels. Interferon was required in 7 of the 111 (6%)
      patients with chronic hepatitis B who were positive for HBeAg, but in none of the
      106 who were positive for antibody to HBeAg ( P = 0.014). CONCLUSIONS: The
      efficacy of IFN in controlling virological breakthroughs and exacerbation of
      hepatitis by infection with lamivudine-resistant HBV mutants in patients with
      HBeAg-positive chronic hepatitis B could enhance the versatility of lamivudine,
      which may have to be given to them indefinitely.

PMID- 12483248
TI  - Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein
      with amino-acid substitution.
AB  - BACKGROUND: We hypothesized that mutation of the pancreatic secretory trypsin
      inhibitor ( PSTI) gene may promote a predisposition to pancreatitis, possibly by
      reducing the inhibition of trypsin activity. Based on this hypothesis, we
      performed a biochemical analysis of recombinant PSTI protein. METHODS: The
      trypsin inhibitory activity of the recombinant protein was analyzed. The activity
      of PSTI protein with a point mutation of the most common type: (34)Asn (AAT)-to
      Ser (AGT)(101A>G N34S: N34S) in exon 3, was compared with that of the wild type.
      RESULTS: The function of N34S PSTI remained unchanged under both the usual
      alkaline and acidic conditions compared with the wild-type PSTI. The calcium
      concentration did not affect the activity of recombinant PSTI. The trypsin
      susceptibility of the N34S protein was not increased either. CONCLUSIONS:
      Mechanisms other than the conformational change of PSTI associated with amino
      acid substitution, such as abnormal splicing, may underlie the predisposition to
      pancreatitis in patients with the N34S mutation.

PMID- 12483249
TI  - Significance of measurement of high-sensitivity C-reactive protein in acute
      pancreatitis.
AB  - BACKGROUND: Determination of the severity of acute pancreatitis is difficult in
      the early phase after onset, and we often encounter difficulties in making
      decisions to initiate intensive care during the early phase. Therefore, there is
      real need for a simple and inexpensive method that can precisely evaluate the
      severity of acute pancreatitis. METHODS: In the present study, we measured serum
      C-reactive protein (CRP) levels in 20 patients with acute pancreatitis, using a
      high-sensitivity CRP (hs-CRP) assay method. RESULTS: CRP levels were as low as
      1.0, 0.4, and 0.3 mg/dl in cases 2, 3, and 9, respectively, with severe acute
      pancreatitis. These three patients were hospitalized within 24 h after the onset
      of pancreatitis. Cases 2, 3, and 9 showed high hs-CRP levels, of 209 000, 68 600,
      and 154 000 ng/ml, respectively, and their interleukin (IL)-6 levels were above
      500 pg/ml. The mean hs-CRP level was 222 760 +/- 32 197 ng/ml in patients with
      severe acute pancreatitis and 22 798 +/- 8216 ng/ml in patients with mild to
      moderate pancreatitis, with a significantly higher level in the severe cases.
      Cases 14, 16, and 20, with mild to moderate pancreatitis, had hs-CRP levels of 83
      400, 1800, and 55 400 ng/ml, respectively. CONCLUSIONS: Measurement of hs-CRP
      levels is a simple and inexpensive method. The hs-CRP levels were found to
      significantly increase in the early phase of severe acute pancreatitis,
      suggesting that hs-CRP could possibly serve as an early indicator of the
      progression of acute pancreatitis into a serious state.

PMID- 12483250
TI  - Primary CD56+ T/NK cell lymphoma of the colon.
AB  - Primary T/natural killer (NK) cell lymphoma of the colon is extremely rare.
      Despite the advances in histological and immunophenotypic studies, the diagnosis
      of primary T/NK cell lymphoma of the colon can be delayed because the early
      symptoms and colonoscopic findings may be very similar to those of inflammatory
      bowel diseases such an Crohn's colitis, and most physicians have little available
      information on this group of neoplasms. Moreover, florid nonspecific inflammatory
      infiltrates would not allow characterization of the tumor cells in such an
      inflammatory background. Herein, we describe a patient who initially presented
      with features that were clinically and colonoscopically similar to Crohn's
      colitis. Three months later, he had cecal bleeding and perforation, and primary
      T/NK cell lymphoma of the colon was diagnosed through immunophenotypic and
      genotypic studies of surgical specimens.

PMID- 12483251
TI  - Somatostatinoma of the papilla of Vater with multiple gastrointestinal stromal
      tumors in a patient with von Recklinghausen's disease.
AB  - We report a case of somatostatinoma of the papilla of Vater with multiple
      gastrointestinal stromal tumors in a patient with von Recklinghausen's disease
      (VRD). A 64-year-old woman who had had recurrent attacks of acute pancreatitis
      and cholangitis was found, on gastroduodenal endoscopy, to have a tumor of the
      papilla of Vater and multiple submucosal tumors of the stomach and duodenum.
      Numerous submucosal tumors were observed in the stomach, duodenum, and jejunum,
      and total excision of the papilla of Vater and resection of the duodenal and
      jejunal submucosal tumors was performed. The tumor of the papilla of Vater showed
      the histologic appearance of a dense proliferation of tumor cells in acinar form,
      from the duodenal mucosa to the muscle layer, and psammoma bodies were revealed
      within the tumor. Immunohistologically, the tumor cells were intensely positive
      for somatostatin. The submucosal tumors of the duodenum and jejunum were negative
      for smooth muscle actin, s-100, and neuron-specific enolase (NSE), and positive
      for CD34 and c-kit, and they were diagnosed as gastrointestinal stromal tumors
      (GISTs) according to the strict definition. The only 25 cases of papilla of Vater
      somatostatinoma associated with VRD to have been reported in the English-language
      literature since 1982 are reviewed, as well as our own case.

PMID- 12483252
TI  - Small-bowel hemorrhage caused by cytomegalovirus vasculitis following fulminant
      hepatitis.
AB  - We describe life-threatening vasculitis of the small bowel following fulminant
      hepatitis. A 35-year-old man was admitted to our hospital due to consciousness
      disturbance and jaundice. He was diagnosed with fulminant hepatitis, and
      recovered after intensive medical care that included corticosteroid
      administration and artificial liver support. During reduction of the dosage of
      steroid, massive gastrointestinal hemorrhage occurred from the upper jejunum,
      revealed by arteriography. The hemorrhage could not be stopped, so a portion of
      the ileum, including the bleeding point, was excised. However, the intestinal
      hemorrhage continued from several small ulcers remaining outside the resected
      area. Pathological findings revealed an ulcerative region that was diagnosed as
      cytomegalovirus (CMV) vasculitis. His serum level of CMV (measured by real-time
      detection polymerase chain reaction [PCR]) was high. Ganciclovir therapy was
      started, and manifestations of the CMV infection improved. In addition to CMV,
      PCR assay for hepatitis A virus (HAV), HBV, HCV, Epstein-Barr virus (EBV), human
      herpes virus-6 (HHV-6), and herpes simplex virus (HSV) was performed, but no
      viruses other than CMV were detected. We are the first to report such a case. We
      conclude that the possibility of CMV enteritis should be considered when patients
      present with unexplained fever and gastrointestinal hemorrhage following
      fulminant hepatitis, and we conclude that the early administration of ganciclovir
      should be considered.

PMID- 12483253
TI  - Congenital anomalous connection between the left intrahepatic bile duct and the
      stomach.

PMID- 12483254
TI  - Carcinosarcoma of the gallbladder with chondroid differentiation.
AB  - Carcinosarcoma of the gallbladder is an uncommon neoplasm. We herein report the
      case of a patient with carcinosarcoma of the gallbladder with chondroid
      differentiation, treated by cholecystectomy with liver segmentectomy and lymph
      node dissection for a tumor which occupied the entire gallbladder and spread to
      the liver. Histologically, the tumor contained two distinct components: a mixture
      of both well and poorly differentiated tubular adenocarcinoma and sarcomatoid
      tissue with chondroid differentiation. From a review of the literature, it was
      seen that carcinosarcomas of the gallbladder could be divided into two groups:
      one group with apparent sarcomatous differentiation, such as chondroid, osteoid,
      and rhabdomyosarcomatous differentiation, and the other group, of carcinosarcomas
      with a sarcomatous portion composed of anaplastic spindle cells. Each group had a
      poor prognosis in spite of surgical resection of tumors. Our patient died of
      peritoneal dissemination 7 months after surgery.

PMID- 12483255
TI  - Solid cystic tumor of the pancreas: report of six cases and a review of the
      Japanese literature.
AB  - Although many cases of solid cystic tumor of the pancreas (SCT) have been
      reported, its nature and histogenesis remain controversial. We herein report six
      cases of SCT, including three cases of noncystic type. A review of 22 cases of
      noncystic type SCT, including our 3 cases, was carried out to compare their
      features with those of 173 cases of classic SCT reported in Japan. Noncystic type
      SCTs tend to occur in male patients and are smaller in size and less frequently
      symptomatic, although they show histological characteristics similar to those of
      classic SCTs. The developmental process might be a cause of cyst formation. The
      accumulation and analysis of many, at present, "atypical" cases for clarification
      of its nature, will, it is hoped, lead to a new nomenclature for this condition
      that adequately describes its biological origin.

PMID- 12483256
TI  - Management of adenocarcinoma of the appendix.

PMID- 12483257
TI  - Initial transformed cells of colorectal adenoma: do they occur at the top of the
      crypt?

PMID- 12483258
TI  - Gastrointestinal reflux disease and cell cycle-regulating proteins.

PMID- 12483259
TI  - Remission of breakthrough hepatitis in chronic hepatitis B patients on
      lamivudine.

PMID- 12483261
TI  - Gut barrier dysfunction in patients with acute pancreatitis.

PMID- 12483260
TI  - Cytokine storm in acute pancreatitis.
AB  - Efforts to unravel the events in the evolution of tissue damage in acute
      pancreatitis have shown a number of inflammatory mediators to be involved. The
      pathways of damage are similar, whatever the etiology of pancreatitis, with three
      phases of progression: local acinar injury, systemic response, and generalized
      sepsis. The proinflammatory response is countered by an anti-inflammatory
      response, and an imbalance between these two systems leads to localized tissue
      destruction and distant organ damage. Cytokines lie at the heart of the problem
      and are involved in all aspects of the cascade leading to systemic inflammatory
      response syndrome and multiple organ dysfunction syndrome. This review discusses
      the present knowledge about the role of various mediators in this process, their
      genetic control, and the effects of their modulation. The major proinflammatory
      mediators are tumor necrosis factor, interleukins 1, 6, and 8, platelet
      activation factor, and the chemokines. The major anti-inflammatory factors
      include interleukin 10, and interleukin 1 receptor antagonist. Emerging knowledge
      of new mediators as well as future strategy of damage control is discussed.

PMID- 12483262
TI  - Evidence-based clinical practice guidelines for acute pancreatitis: proposals.
AB  - BACKGROUND/PURPOSE: To provide a framework for clinicians to manage acute
      pancreatitis, evidence-based guidelines have been developed by the Japanese
      Society of Abdominal Emergency Medicine. METHODS: Evidence was collected by a
      systematic search of MEDLINE and Japana Centra Revuo Medicina. A total of 1348
      papers were reviewed and levels of evidence were assessed. Practical
      recommendations were also graded. RESULTS: The present guidelines consist of
      introductions, a summary of recommendations, practice algorithms, definitions,
      epidemiology, diagnosis, severity assessment, and therapy. The main points of
      recommendation in these guidelines are: (1) measuring lipase for the diagnosis of
      acute pancreatitis (recommendation grade [RG], A). (2) The Severity of acute
      pancreatitis should be assessed using a scoring system, such as that of the
      Japanese Ministry of Health and Welfare or Acute Physiology and Chronic Health
      Evaluation (APACHE) II (RG, A). (3) Enhanced computed tomography (CT) should be
      used for assessment of degree of pancreatic necrosis and inflammation (RG, B).
      (4) Prophylactic antibiotic administration should be used for severe pancreatitis
      (RG, A), but not for mild to moderate pancreatitis (RG, D). (5) Gabexate mesilate
      should be used for severe pancreatitis (RG, B). (6) Enteral feeding should be
      used for all pancreatitis (RG, B). (7) Continuous hemodiafiltration and
      continuous arterial infusion of proteinase inhibitor and antibiotics may be of
      benefit (RG, C). (8) Fine-needle aspiration should be done for the diagnosis of
      infectious pancreatic necrosis, and if positive, necrosectomy is indicated (RG,
      A). CONCLUSIONS: These guidelines provide useful information for physicians to
      manage this troublesome disease.

PMID- 12483263
TI  - Management of infection in acute pancreatitis.
AB  - The clinical course of acute pancreatitis varies from a mild, transitory illness
      to a severe, rapidly fatal disease. In about 80% to 90% of cases pancreatitis
      presents as a mild, self-limiting disease with low morbidity and mortality.
      Unlike mild pancreatitis, necrotizing pancreatitis develops in about 15% of
      patients, with infection of pancreatic and peripancreatic necrosis representing
      the single most important risk factor for a fatal outcome. Infection of
      pancreatic necrosis in the natural course develops in the second and third week
      after onset of the disease and is reported in 40% to 70% of patients with
      necrotizing pancreatitis. Just recently, prevention of infection by prophylactic
      antibiotic treatment and assessment of the infection status of pancreatic
      necrosis by fine-needle aspiration have been established in the management of
      severe pancreatitis. Because medical treatment alone will result in a mortality
      rate of almost 100% in patients with signs of local and systemic septic
      complications, patients with infected necrosis must undergo surgical
      intervention, which consists of an organ-preserving necrosectomy combined with a
      postoperative closed lavage concept that maximizes further evacuation of infected
      debris and exudate. However, intensive care treatment, including prophylactic
      antibiotics, reduces the infection rate and delays the need for surgery in most
      patients until the third or fourth week after the onset of symptoms. At that
      time, debridement of necrosis is technically easier to perform, due to better
      demarcation between viable and necrotic tissue compared with necrosectomy earlier
      in the disease. In contrast, surgery is rarely needed in the presence of sterile
      pancreatic necrosis. In those patients the conservative approach is supported by
      the present data.

PMID- 12483264
TI  - Surgical management of severe pancreatitis including sterile necrosis.
AB  - BACKGROUND/PURPOSE: Severe pancreatitis develops in 15% to 20% of patients with
      acute pancreatitis, morphologically characterized by extra- and intrapancreatic
      necrosis and associated with single or multiple organ failure. It is well
      accepted that surgery is indicated in patients with infected pancreatic necrosis.
      However, management of sterile necrosis is still controversial. In a prospective
      study, we evaluated the effect of maximal intensive care unit (ICU) treatment
      combined with prophylactic antibiotics in patients with necrotizing pancreatitis.
      METHODS: A total of 306 consecutive patients with acute pancreatitis were
      hospitalized between November 1993 and August 2001. All patients with necrotizing
      pancreatitis diagnosed by computed tomography received ICU treatment, including
      antibiotics (imipenem/cilastin). Fine-needle aspiration of pancreatic necrosis
      was performed in patients with clinical signs of sepsis, and necrosectomy
      combined with continuous postoperative lavage was indicated when bacterial
      testing demonstrated infection. In the presence of sterile necrosis, surgery was
      only performed when there was no clinical improvement despite maximal ICU
      treatment. RESULTS: Necrotizing pancreatitis was found in 121 patients. Infected
      necrosis was verified in 41 patients (34%) at a mean of 26 days. Four percent of
      patients with sterile necrosis and 95% of patients with infected necrosis were
      operated on. The surgical procedure was successful in 83% of patients as a single
      intervention; relaparotomy had to be performed in only 7 patients (17%).
      Pancreatic abscesses were found in 7 patients; four of these were drained
      interventionally. The overall mortality of the patients with necrotizing
      pancreatitis was 9.9%. The mortality of patients with sterile and infected
      necrosis was 2.5% and 24%, respectively (sterile vs infected; P < 0.01).
      CONCLUSIONS: Due to improved intensive care treatment, including prophylactic
      antibiotics, surgical intervention is usually not indicated in the early course
      of severe acute pancreatitis. Surgery is clearly indicated in patients with
      proven infected necrosis. Patients with sterile necrosis should undergo surgery
      when there is no clinical improvement within 4 weeks of intensive care treatment.
      In the majority of patients a single intervention is sufficient. Reinterventions
      are rare and even in patients with abscess formation are not needed, because
      these can easily be drained interventionally.

PMID- 12483265
TI  - Acute pancreatitis: who needs an operation?

PMID- 12483266
TI  - Hepatobiliary transport of bile acids and organic anions.
AB  - Recent studies have elucidated the mechanism and regulation of hepatic transport
      of bile acids and organic anions. Bile acids are taken up into hepatocytes by
      basolateral transporters, Na+-dependently by Na+/taurocholate cotransporting
      polypeptide (NTCP) and Na+-independently by organic anion transporting
      polypeptide (OATP) families. Organic anions are taken up into hepatocytes by OATP
      families. These compounds are then transported in hepatocytes bound to cytosolic
      binders, and subjected to transport by ATP binding cassette (ABC) transporters at
      the canalicular membrane. Amidated bile acids are excreted into bile by bile salt
      export pump (BSEP), and organic anions and bile acid sulfates and glucuronides
      are excreted by multidrug resistance protein 2 (MRP2). Hepatic transporters are
      downregulated under cholestasis in rats and humans, except for MRP3, a
      basolateral ABC transporter, which is upregulated and may have a role in removing
      bile acids and organic anions from hepatocytes to the blood under cholestatic
      conditions. Nuclear receptors, which bind bile acids, have been shown to regulate
      the expression of hepatic transporters. Farnesoid X receptor (FXR), which
      downregulates CYP7A1, the rate-limiting enzyme of bile acid biosynthesis,
      upregulates BSEP and downregulates NTCP. MRP2 is upregulated by both FXR and
      pregnane X receptor (PXR), which upregulates CYP3A.

PMID- 12483267
TI  - Enteral nutrition in HPB surgery: past and future.
AB  - Perioperative nutrition has, during the past century, been transformed from a
      tool to provide calorie and nitrogen support to a tool to boost the immune system
      and increase resistance to complications. Despite all the progress in medicine
      and surgery, perioperative morbidity, the rate of infections, thrombosis, and the
      development of serosal adhesions has remained the same as long as can be judged,
      or at least during the past 80 years. Most prone to develop complications are
      persons above the age of 65 and persons with depressed immunity. About 80% of the
      immune system is localized in the gastrointestinal tract, which offers great
      opportunities for modulation through enteral nutrition. As the stomach has a
      tendency to develop postoperative paralysis, tube feeding is often necessary. In
      1918, Andresen demonstrated the advantages of enteral nutrition, which already
      started on the operating table. Mulholland and colleagues and Rhoads and co
      workers demonstrated, during the 1940s, certain advantages of enteral tube
      feeding. Also, the works by Alexander, Fischer, and Ryan, and their co-workers
      supported the value of early enteral feeding, and suggested enteral feeding as an
      effective tool to boost the immune system. It was, however, works published in
      the early 1990s, by Moore and colleagues and by Kudsk and colleagues, which made
      surgeons more aware of the advantages of early enteral nutrition. Surgery in the
      hepatobiliary pancreatic field is known to have a high rate of complications.
      Uninterrupted perioperative nutrition, i.e., nutrition during the night before,
      during surgery, and immediately after, offers a strong tool to prevent
      complications. It is essential that the nutrition also provides food for the
      colon, e.g., fiber and healthy bacteria (probiotics) to ferment the fiber and
      boost the immune system.

PMID- 12483268
TI  - Hepatobiliary nutrition: history and future.
AB  - The liver is a master metabolic gland; consequently, liver disease commonly
      results in significant malnutrition. Complex metabolic derangements always
      accompany liver failure, often reflect the magnitude of hepatic insufficiency,
      and are characterized by accentuated catabolism. Nutritional assessment is
      problematic in these patients, because many of the usual indicators of
      nutritional status are altered directly by the hepatic pathophysiology rather
      than, or in addition to, preexisting or subsequent secondary malnutrition. The
      objective of nutritional support in patients with liver failure is to provide
      adequate nutrients to ensure the availability of specific substrates for energy
      and protein synthesis and for normal hepatocyte survival and function, without
      inducing or accentuating encephalopathy or otherwise compounding hepatic
      insufficiency. In the near future, guidelines must be developed for the specific
      nutritional support of patients with fulminant hepatic failure, cholestatic liver
      disease, steatosis, and cirrhosis. Currently, work is underway to develop an
      artificial liver for patients awaiting transplantation; to use genetic
      engineering technology to provide an alternative source of hepatic tissue; and to
      test the utility of various intermediary metabolites for hepatobiliary nutrition
      support. No ideal regimen for nutritional support of all forms of liver failure
      exists, and this also represents a significant challenge for future basic and
      clinical investigations. However, it is mandatory to attempt to maintain optimal
      nutrition in patients with severe liver failure if morbidity and mortality are to
      be reduced and survival is to be maximized.

PMID- 12483269
TI  - Prognosis of hepatocellular carcinoma associated with Child class B and C
      cirrhosis in relation to treatment: a multivariate analysis of 411 patients at a
      single center.
AB  - BACKGROUND/PURPOSE: Given that the prognosis of patients with hepatocellular
      carcinoma (HCC) complicating severe cirrhosis remains uncertain, particularly
      with regard to various therapeutic strategies, we have evaluated the prognosis in
      a series of patients with homogeneous diagnostic and therapeutic histories.
      METHODS: From 1990 to 1998, 411 consecutive HCC patients associated with Child
      class B and class C cirrhosis who did not have lymph node or distant metastasis
      were treated by partial hepatectomy (PH; n = 48), percutaneous ethanol injection
      (PEI; n = 105), transcatheter arterial chemoembolization (TACE; n = 189),
      chemotherapy, or supportive care (chemo/supportive; n = 69). Univariate survival
      curves were estimated. The Cox model, stratified by the treatment groups, was
      used for multivariate analysis. RESULTS: As of January 1999, 305 patients (74.2%)
      had died. Overall median survival was 23.4 months. There were statistically
      significant differences between the survival times of patients receiving PH or
      PEI and TACE, as compared with those receiving chemo/supportive care. According
      to multivariate analysis, the independent predictive survival factors were:
      albumin level (> or = 3.0 g/dl), esophageal varices (i.e., absence), tumor size
      (< or = 3.0 cm), tumor number (solitary), and alpha-fetoprotein (AFP) level (<400
      ng/ml). According to the total number of risk factors and the median survival,
      all patients were divided into four subgroups. For the score 0 group (no risk
      factor group), 3- and 5-year survival rates were 83.1% and 68.0% for PH, and
      87.5% and 62.3% for PEI, respectively. In the score 1-2 group (one or two risk
      factors), survival rates at 3 and 5 years were 53.1% and 40.3% for PH, 54.8% and
      33.2% for PEI, and 35.4% and 22.8% for TACE, respectively. For patients with a
      score of 3 or more, there were no differences among the treatment groups,
      excluding those with chemo/supportive care. CONCLUSIONS: These findings indicate
      that, in HCC patients with complicating Child B and C cirrhosis, PEI and PH
      should be considered first for subgroups of patients with scores (risk factors)
      of 0-2, as an acceptable survival rate was obtained in such patients. Therefore,
      the advantages and disadvantages of these therapies regarding tumor size and
      location should be counterbalanced. In patients with a score of 3 or more, TACE,
      when possible, could be a first choice because of its applicability and its
      adjuvant nature with respect to other therapies such as liver transplantation.

PMID- 12483270
TI  - Detection of serum MMPs in tumor-bearing hamsters.
AB  - BACKGROUND/PURPOSE: Matrix metalloproteinases (MMPs) have been implicated as
      playing an important role in cancer invasion and metastasis. MMPs have been
      identified in various malignancies, including pancreatic duct adenocarcinomas.
      METHODS: We investigated the circulating level of MMP-2 and MMP-9 in sera from
      Syrian golden hamsters into which hamster pancreatic duct adenocarcinoma tissues
      had been transplanted subcutaneously (HPDt hamsters). Northern blot analysis and
      gelatin zymographic analysis were performed to detect the expression of MMPs and
      that of tissue inhibitors of metalloproteinases (TIMPs) in HPDt hamsters.
      RESULTS: Northern analysis revealed overexpression of MMP-2, MMP-9, and TIMP-2
      mRNAs in subcutaneous tumors of HPDt hamsters as compared with normal pancreatic
      tissue. Sera from HPDt hamsters possessed significantly higher levels of serum
      MMP-2 and MMP-9 than control sera, as determined by gelatin zymographic analysis,
      and there was a significant correlation between tumor growth and serum MMP
      levels. CONCLUSIONS: These results indicate that overexpression of MMP mRNAs is
      involved in the progression of pancreatic duct adenocarcinomas, and that MMP
      protein expression in hamster sera is associated with the presence of pancreatic
      duct adenocarcinoma cells. The findings also suggest that serum MMPs could be
      useful markers for monitoring patients with pancreatic duct adenocarcinomas.

PMID- 12483271
TI  - Application of argyrophilic nucleolar organizer region (AgNOR) staining for
      cytology of biliary tract carcinomas.
AB  - PURPOSE/BACKGROUND: Increased numbers of argyrophilic nucleolar organizer region
      (AgNOR) dots reflect higher proliferating activity of malignant cells. METHODS:
      To determine whether AgNOR staining is suitable for cytology of bile in biliary
      diseases as an ancillary diagnostic method, we examined the mean number of AgNOR
      dots (MNA) in cells of both bile smear and tissue sections in 14 benign biliary
      diseases and 25 malignancies of the biliary tract. The malignant diseases
      consisted of 11 gallbladder cancers, 10 bile duct cancers, and 4 ampulla cancers
      in patients who underwent surgical resection. Results of AgNOR staining were
      available in 15 min, and the MNA in the nucleus was counted in 50 cells/specimen.
      RESULTS: The MNAs in malignant cells in bile smear (9.6 +/- 3.8) and tissue
      sections (9.2 +/- 3.5) were significantly higher than those in the corresponding
      cells in benign biliary diseases (4.1 +/- 1.0 and 2.9 +/- 0.8, respectively; P<
      0.01). The MNA of bile smear for both benign and malignant cells correlated
      significantly with that of tissue sections ( r= 0.915; P< 0.0001). When the
      cutoff value of MNA for bile smear was set at 7.0, benign diseases could be
      discriminated from malignancy, and the MNA of 20 (80%) malignant specimens was
      higher than this value. CONCLUSIONS: Our results suggest that the AgNOR dot count
      of cells in bile smears would be a useful diagnostic tool, in combination with
      conventional cytological diagnosis, before and during surgery.

PMID- 12483272
TI  - Altered intestinal morphology and immunity in patients with acute necrotizing
      pancreatitis.
AB  - PURPOSE/BACKGROUND: Impairment of gut barrier function has been demonstrated in
      patients with severe acute pancreatitis and may contribute to the development of
      local and systemic septic complications. The underlying mechanisms, however,
      remain unclear. Against this background, our aims were to investigate the small
      intestinal epithelial morphology and mucosal immunity in patients with severe
      acute pancreatitis. METHODS: Segments of terminal ileum from three patients with
      severe necrotizing acute pancreatitis who underwent pancreatic debridement and
      ileocolic resection for doubtful or evident segmental colonic viability were
      available for the study. Control specimens were available from seven patients who
      underwent gastric bypass and distal ileal resection for morbid obesity. Sections
      were cut and stained with hematoxylin and eosin for the measurement of villous
      height and crypt depth, and with toluidine blue for the determination of mucosal
      mast cell counts. Only adequately oriented specimens were deemed suitable for
      computer-aided image analysis. Results were expressed as the villous height/crypt
      depth ratio (VH/CD) and mucosal mast cell index (ratio of mast cell count/length
      of muscularis mucosa). RESULTS: Microscopy of the small intestine from controls
      was normal. The villous height and VH/CD were significantly reduced in patients
      with acute pancreatitis compared with controls (median, 0.47 mm vs 0.68 mm, and
      1.9 vs 2.8, respectively; P < 0.00001). The mast cell index was significantly
      reduced in patients with acute pancreatitis compared with controls (median, 5.88
      cells/mm vs 8.58 cells/mm; P= 0.001). A positive correlation was observed between
      the mast cell index and the height of the villi ( r= 0.23; P= 0.027).
      CONCLUSIONS: Patients with necrotizing acute pancreatitis have an altered
      intestinal morphology and depleted mucosal mast cells. These factors may
      contribute to the impairment of gut barrier function in patients with severe
      acute pancreatitis.

PMID- 12483273
TI  - Cholangiocarcinoma cells express somatostatin receptor subtype 2 and respond to
      octreotide treatment.
AB  - BACKGROUND/PURPOSE: We investigated the in vitro and in vivo inhibitory effects
      of a somatostatin analogue (octreotide, OCT) on cholangiocarcinoma cell lines.
      METHODS: The reverse transcriptase-polymerase chain reaction (RT-PCR) was
      employed to detect the gene expression of five somatostatin receptor (SSTR)
      subtypes in four cholangiocarcinoma cell lines (RBE, NEC, QBC939, and SSP-25).
      The antiproliferative effects of OCT on these cell lines were determined by means
      of an MTT assay in vitro, as well as in a nude mouse tumor heterograft model in
      vivo. Apoptosis and cell cycles in the cholangiocarcinoma cell lines after OCT
      administration were evaluated by flow cytometry; and the effects of OCT on the
      expression of cyclin E, cyclin-dependent kinase 2 (CDK2), and p27kipl were
      evaluated by Western blots. RESULTS: Only SSTR2 mRNA was detected in these four
      cholangiocarcinoma cell lines. OCT significantly inhibited the proliferation of
      the four cholangiocarcinoma cell lines in vitro ( P < 0.05 vs control), and the
      weights of the QBC939 xenografts in the OCT-treated group were lower than those
      in the control group, but there was no significant difference between them. After
      48-h exposure to 10(3) ng/ml OCT, flow cytometric analysis demonstrated an
      increased number of cells in G0/G1 phase associated with a decreased number of
      cells in G2/M and S phases ( P < 0.01 vs control). Apoptosis was not observed in
      any samples. The expression of p27kipl was promoted by OCT administration, while
      that of cyclin E and that of CDK2 were inhibited. CONCLUSIONS: The results proved
      that OCT inhibits the proliferation of cholangiocarcinoma cells through G0/G1
      cell cycle arrest rather than through the process of apoptosis. These effects are
      partially mediated by enhancing the expression of p27kipl, and decreasing the
      amounts of cyclin E-CDK2 complex.

PMID- 12483274
TI  - Antitumor effect to IL-12 administration into the portal vein on murine liver
      metastasis.
AB  - BACKGROUND/PURPOSE: Interleukin (IL)-12 has been shown to possess potent
      antitumor activity, and an antitumor effect of systemic IL-12 administration has
      been reported in liver metastasis models. METHODS: In this study, we examined the
      usefulness of local IL-12 administration into the portal system in the treatment
      of liver metastasis. First, we confirmed the antitumor effect of recombinant IL
      12 (rIL-12) on MC-38 tumors in an intracutaneous model. In the murine liver
      metastasis model, 1 x 10(5) of MC-38 cells were injected into the portal vein on
      day 0, and the spleen was transpositioned subcutaneously for administration of
      rIL-12 continually into the portal system. From days 3 to 7, 0.1 micro g rIL-12
      was administered intraperitoneally or intrasplenicly, while Hanks' Balanced Salf
      Solution (HBSS) was injected intrasplenicly in the control group. RESULTS: The
      liver weight in the rIL-12 intraperitoneal treatment group (1.88 +/- 0.37 g) and
      that in the rIL-12 intrasplenic treatment group (1.43 +/- 0.21 g) were
      significantly less than that in the HBSS group (2.86 +/- 0.74 g; P < 0.05). The
      numbers of metastatic nodules in the rIL-12 intraperitoneal treatment group (22.3
      +/- 17.1) and in the rIL-12 intrasplenic treatment group (12.4 +/- 13.8) were
      significantly less than that in the HBSS group (137.1 +/- 44.9; P < 0.05).
      Complete regression of the tumor was observed in one of six mice in the rIL-12
      intrasplenic treatment group. This antitumor effect of rIL-12 on MC-38 liver
      metastasis was not observed in interferon (IFN)-gamma knockout mice. Intraportal
      administration of IL-12-transduced fibroblasts, which were syngeneic to C57BL/6
      mice, had an antitumor effect in the MC-38 liver metastasis model. CONCLUSIONS:
      These results suggested that the local administration of IL-12 into the portal
      system would be a useful strategy for the treatment of liver metastasis.

PMID- 12483275
TI  - Unexpected bile duct carcinoma presenting with port-site metastasis after
      laparoscopic cholecystectomy for cholecystolithiasis.
AB  - On March 1, 1999, a 71-year-old woman was diagnosed as having
      cholecystolithiasis, for which she underwent laparoscopic cholecystectomy at a
      local hospital. Intraoperative cholangiography was not performed. No malignant
      lesion was detected in the gallbladder. In March 2000, a subcutaneous tumor was
      pointed out at the port site in her abdomen, and resected. Histological
      examination revealed metastatic adenocarcinoma. On detailed examination,
      endoscopic retrograde cholangiopancreatography (ERCP) revealed a tumor, about 2
      cm in diameter, in the lower bile duct. On June 1, she underwent pylorus
      preserving pancreatoduodenectomy at our institute, and several disseminated
      lesions were detected at the port site and in the abdominal cavity. There have
      been few reports of bile duct carcinoma that developed peritoneal dissemination
      caused by leakage of bile during cholecystectomy. Leakage of bile should be
      prevented during laparoscopic cholecystectomy, even in patients not diagnosed as
      having cancer preoperatively.

PMID- 12483276
TI  - Pancreatic tuberculosis.
AB  - A 63-year-old Japanese man visited our institute with fever of unknown origin.
      Findings on preoperative imaging modalities were consistent with pancreatic
      carcinoma, but a positive tuberculin skin test indicated tuberculosis infection.
      Negative results for MycobacteriumDNA polymerase chain reaction from sputum and
      bone-marrow aspiration biopsy specimens ruled out pulmonary and miliary
      tuberculosis, respectively. Positron emission tomography (PET) with 2-[fluorine
      18]-fluoro-2-deoxy- d-glucose (FDG) showed multiple labeled spots within the
      pancreas body and chest. Distal pancreatectomy was performed with a diagnosis of
      suspected pancreatic carcinoma, but the histological and microbiological
      diagnosis was Mycobacterium infection. A rare case of pancreatic tuberculosis
      evaluated by FDG PET is reported and discussed herein.

PMID- 12483277
TI  - Combined liver and pancreas resection with biochemotherapy for metastatic ocular
      melanoma.
AB  - Systemic therapy alone for metastatic melanoma is relatively ineffective, and
      surgical resection of metastases to a solitary site remains the best single
      treatment to improve survival. While cytoreductive surgery plus chemotherapy play
      a significant role in the management of advanced ovarian cancer, the precise role
      of surgery as an adjunct to systemic therapy for melanoma metastatic to multiple
      sites is not well defined. We report a patient with ocular melanoma metastatic to
      liver and pancreas treated by cytoreductive surgery consisting of mesohepatic
      resection, distal pancreatectomy, and portal node dissection, followed by
      biochemotherapy with dacarbazine and interferon alpha. The concept of
      cytoreductive surgery is reviewed, with particular attention to its use in the
      management of metastatic melanoma. The patient's postoperative course was
      unremarkable and she remains alive and asymptomatic with no detectable disease at
      20 months' follow-up. Cytoreductive surgery as a part of an aggressive
      multidisciplinary approach may play a role in the treatment of cutaneous and
      ocular melanoma metastatic to multiple visceral sites. Data from well-designed,
      innovative clinical trials of cytoreductive surgery and biochemotherapy are
      required to determine the effectiveness of this multidisciplinary approach.

PMID- 12483278
TI  - Lymphoplasmacytic sclerosing pancreatocholangitis successfully treated by
      pancreatoduodenectomy.
AB  - A 68-year-old man complaining of jaundice was admitted to our hospital in October
      1996. Radiological imaging studies, including dynamic computed tomography,
      endoscopic retrograde cholangiography, and angiography, were highly suggestive of
      pancreatic head cancer, and laparotomy was performed on October 25, 1996. On
      gross examination, the pancreas appeared firm, as in chronic pancreatitis, with a
      mass lesion in the pancreatic head measuring 35 x 35 x 25 mm. A pylorus
      preserving pancreatoduodenectomy was carried out. Histological findings were
      characterized by uniform fibrosis with diffuse lymphoplasmacytic infiltration and
      lymph follicles in the thickened wall of the bile duct and in and around the
      pancreas, with acinar atrophy. The histological diagnosis was lymphoplasmacytic
      sclerosing pancreatocholangitis. Approximately 5 years postoperatively, the
      patient was alive and well without adjunctive corticosteroid therapy. This
      positive result suggests that pancreatoduodenectomy may be effective for
      lymphoplasmacytic sclerosing pancreatocholangitis that is localized in the
      pancreatic head.

PMID- 12483279
TI  - Angiotensin IV in the central nervous system.
AB  - The mammalian brain harbors a renin-angiotensin system (RAS), which is
      independent from the peripheral RAS. Angiotensin II is a well-studied member of
      the RAS and exerts most of the known angiotensin-mediated effects on fluid and
      electrolyte homeostasis, autonomic activity, neuroendocrine regulation, and
      behavior. This review summarizes a mass of compelling new evidence for the
      biological role of an active (3-8) fragment of angiotensin II, named angiotensin
      IV. Angiotensin IV binds to a widely distributed binding site in the brain, but
      which is different from the known angiotensin II receptors AT1 and AT2.
      Angiotensin IV has been implicated in a number of physiological actions,
      including the regulation of blood flow, the modulation of exploratory behavior,
      and processes attributed to learning and memory. Furthermore, angiotensin IV may
      also be involved in neuronal development. Collectively, the available evidence
      suggests that angiotensin IV is a potent neuropeptide, involved in a broad range
      of brain functions.

PMID- 12483280
TI  - Evidence that two forms of choline acetyltransferase are differentially expressed
      in subclasses of enteric neurons.
AB  - Cholinergic neurons have been revealed in the enteric nervous system by
      functional and biochemical studies but not by antibodies that provide excellent
      localisation of the synthesising enzyme, choline acetyltransferase (ChAT), in the
      central nervous system. In order to determine whether a newly described
      peripheral form of ChAT (pChAT) is a ChAT enzyme of enteric neurons, we have
      compared pChAT distribution with that of the common form of ChAT, cChAT, by
      quantitative analysis of the co-localisation of pChAT and cChAT with other
      neurochemical markers in enteric neurons of the guinea-pig ileum. We found
      classes of neuron with strong pChAT immunoreactivity (IR) and others with strong
      cChAT-IR. In myenteric ganglia, strong pChAT-IR was in calbindin-positive
      intrinsic primary afferent neurons (IPANs), whereas cChAT-IR of these neurons was
      weak. Calretinin neurons were immunoreactive for cChAT, but not pChAT. Only 4% of
      nitric oxide synthase (NOS) neurons (possibly interneurons) were pChAT
      immunoreactive, similar to observations with cChAT. NOS-immunoreactive inhibitory
      motor neurons stained with neither cChAT nor pChAT antisera. In the submucosal
      ganglia, pChAT-IR was strongly expressed in IPANs (identified by cytoplasmic
      staining for the neuronal nuclear marker, NeuN) and in neuropeptide Y (NPY)
      immunoreactive secretomotor neurons, but not in calretinin-immunoreactive
      neurons. cChAT-IR occurred weakly in submucosal IPANs and also labelled NPY- and
      calretinin-immunoreactive neurons. Submucosal vasoactive-intestinal-peptide
      immunoreactive neurons (non-cholinergic secretomotor neurons) were not reactive
      for either form of ChAT.

PMID- 12483281
TI  - Phosphorylation and subcellular distribution of connexin43 in normal and stressed
      cells.
AB  - We have developed polyclonal antibodies (SA226P) to a peptide of the human
      connexin43 (Cx43) protein between amino acids 271 and 288 containing
      phosphorylated S279 and S282. Antibodies specific for the phosphorylated form of
      the peptide were isolated by double immunoaffinity chromatography and were
      characterised using proteins of the cell line WB-F344, known to contain large
      amounts of Cx43. SA226P recognises specifically the slowest migrating Cx43 band
      in immunoblots of proteins isolated from untreated cells. In immunofluorescence
      experiments SA226P scarcely stains the plasma membrane in untreated cells in
      contrast to a commercial antibody recognising all isoforms of the Cx43 protein.
      EGF or stress treatment of the cells results in a rapid increase in the
      phosphorylated forms of Cx43 as revealed by immunoblotting. Immunofluorescence
      experiments reveal that both phosphorylated and non-phosphorylated Cx43 could be
      found at the plasma membrane. Whether phosphorylation of S279/S282 takes place
      before or after incorporation of Cx43 into the membranes is so far unknown. More
      interestingly, confocal microscopy using our antibodies and a commercial antibody
      recognising all isoforms of Cx43 shows the coexistence of differentially
      phosphorylated forms of the protein at the plasma membrane. Our results indicate
      that MAP kinases erk1/2 are mainly responsible for this phosphorylation, as
      already published. Nevertheless, treatment of the cells with anisomycin, known to
      activate stress kinase p38 but not erk1/2, also results in a weak but
      reproducible Cx43 phosphorylation.

PMID- 12483282
TI  - Differentiation of human alveolar epithelial cells in primary culture:
      morphological characterization and synthesis of caveolin-1 and surfactant protein
      C.
AB  - Human alveolar type II cells were isolated from lung tissue and cultured for
      several days. The morphology of cells was investigated at different time points
      postseeding and the synthesis of alveolar cell-type specific proteins was
      analyzed using different methods. The rationale of the study was to characterize
      a primary cell culture of human alveolar cells for the development of an in vitro
      model studying pulmonary drug delivery. In vitro test systems based on human
      cells are attracting increasing interest as important alternatives to animal
      derived models because possible interspecies differences in alveolar cell biology
      and transport mechanisms cannot be excluded. In our study, both morphological
      characterization and marker protein synthesis of human alveolar cells in culture
      indicate the differentiation of isolated alveolar type II cells into epithelial
      monolayers consisting of alveolar type I-like and alveolar type II-like cells,
      which corresponds to the composition of the alveolar epithelium of the donor
      tissue. By using flow cytometry, immunofluorescence, immunoblotting and reverse
      transcriptase polymerase chain reaction (RT-PCR), we observed a shift in the
      synthesis of important marker proteins. Early cultures were characterized by low
      caveolin-1 and high Sp-C levels. In comparison, the protein biosynthesis of
      alveolar cells switched with time of culture to high caveolin-1 and low Sp-C
      levels. Based on the similarity between human alveolar epithelium and the
      development of our primary alveolar cell culture, we suggest that the culture may
      serve as a suitable model to study epithelial transport or cell biological
      processes in human alveolar cells.

PMID- 12483283
TI  - Evidence that exogenous substances can be phagocytized by alveolar epithelial
      cells and transported into blood capillaries.
AB  - Since the ability of alveolar epithelial cells to ingest inhaled fine particles
      has not been characterized in detail, the present study seeks to evaluate this
      physiological activity. We used a 0.2% suspension of intact or lecithin-coated
      polystyrene latex beads (240 nm in diameter). A 5-ml suspension of intact or
      lecithin-coated latex beads was intratracheally administered to rats using a
      compressor nebulizer. Thereafter, the lungs were perfused intratracheally with
      glutaraldehyde solution and cut into small pieces. The samples were postfixed
      with osmium tetroxide, embedded in epoxy resin and examined under an electron
      microscope. Both lecithin-coated and uncoated beads were incorporated into
      alveolar macrophages. Some of the ingested beads in the alveolar macrophages were
      sequestered within lysosomes. Types I and II alveolar epithelial cells
      selectively incorporated only lecithin-coated beads, which were also observed
      within the cytoplasm of monocytes in the capillary lumen. These findings suggest
      that alveolar epithelial cells can incorporate exogenous particles, which are
      then transferred from the alveoli to intravascular spaces by transcytosis.

PMID- 12483284
TI  - Regulation of peptidase activity in a three-dimensional aggregate model of brain
      tumor vasculature.
AB  - The abnormal vascular system of brain cancers inappropriately expresses membrane
      proteins, including proteolytic enzymes, ultimately resulting in blood
      extravasation. The production of inflammatory mediators, such as cytokines and
      nitric oxide, and tumor hypoxia have been implicated in these effects. We have
      previously shown that the activity of aminopeptidase A is increased in the
      abnormal vascular system of human and rat brain tumors. To study the mechanisms
      regulating the activities of peptidases in cerebral vasculature in brain tumors,
      we have developed a three-dimensional model of differentiated rat brain cells in
      aggregate cultures in which rat brain microvessels were incorporated. The
      secretion of interleukin-6 (IL-6) in the culture medium of aggregates was used as
      an indicator of inflammatory activation. Addition to these aggregates of C6
      glioma cell medium (C6-CM) conditioned under hypoxic or normoxic conditions or
      serum mimicked tumor-dependent hypoxia or conditions of dysfunction of brain
      tumor vasculature. Hypoxic and normoxic C6-CM, but not serum, regulated peptidase
      activity in aggregates, and in particular it increased the activity of
      aminopeptidase A determined using histoenzymography. Serum, but not C6-CM,
      increased IL-6 production, but did not increase aminopeptidase A activity in
      aggregates. Thus soluble glioma-derived factors, but not serum-derived factors,
      induce dysfunctions of cerebral vasculature by directly regulating the activity
      of peptidases, not involving inflammatory activation. Tumor hypoxia is not
      necessary to modulate peptidase activity.

PMID- 12483285
TI  - Melanin-concentrating hormone system in the brain and skin of the cichlid fish
      Cichlasoma dimerus: anatomical localization, ontogeny and distribution in
      comparison to alpha-melanocyte-stimulating hormone-expressing cells.
AB  - Distribution and development of the melanin-concentrating hormone (MCH) system
      were examined by immunocytochemistry of the brain, pituitary gland and skin of
      the South American cichlid fish Cichlasoma dimerus. In adults, the most prominent
      group of MCH-ir perikarya was located in the nucleus lateralis tuberis (NLT).
      Outside the NLT, in the posterior hypothalamic region, a group of small neurons
      was found between the third ventricle and the lateral ventricular recess with
      delicate immunoreactive fibers that did not seem to contribute to the pituitary
      innervation. MCH-ir perikarya were identified at day 4 after hatching (AH) in a
      proliferating zone of the hypothalamic floor. Pituitary innervation could be
      detected at this stage. Another group of small MCH-ir neurons, only detected in
      pre-juvenile stages, originated close to the third ventricle in the medial
      hypothalamic region by day 6 AH. alphaMSH-ir neurons were localized in similar
      regions of the NLT and in the nucleus periventricularis posterior (NPP). Free MCH
      ir neuromasts were detected in the ventral and dorsal skin of larval heads. These
      epidermal sensory organs were in close association with blood vessels and dermal
      melanocytes, suggesting that MCH synthesized in larval skin might act in an
      endocrine way reaching different targets and/or in a paracrine mode regulating
      melanin concentration in dermal melanocytes.

PMID- 12483286
TI  - Immunocytochemical localization and ontogenic development of melanin
      concentrating hormone in the brain of a pleuronectiform fish, the barfin
      flounder.
AB  - Melanin-concentrating hormone (MCH) was first discovered in the pituitary of chum
      salmon because of its role in the regulation of skin pallor. Later, it was found
      that MCH could also play a role as a central neurotransmitter or neuromodulator
      in the brain. However, knowledge of the function of MCH in fish has been
      restricted to certain fish species. Therefore, in the present study, the
      immunocytochemical localization and ontogenic development of MCH in the brain of
      a pleuronectiform fish, the barfin flounder Verasper moseri, were examined to
      obtain a better understanding of this hormone. In adult barfin flounder, MCH
      immunoreactive (ir) neuronal somata were most prevalent in the magnocellular
      neurons of the nucleus tuberis lateralis (NLT), which project to the pituitary.
      In the pituitary, MCH-ir fibers were distributed in the neurohypophysial tissues
      within the pars intermedia and, to a lesser extent, into the pars distalis. MCH
      ir neuronal somata were also present in dorsally projecting parvocellular
      neurons, located more posteriorly in the area above the lateral ventricular
      recess (LVR). LVR-MCH neurons did not seem to project to the pituitary. In the
      brain, MCH-ir fibers were detected not only in the hypothalamus but also in areas
      such as the optic tectum and thalamus. MCH-ir neuronal somata and fibers were not
      detected on the day of hatching. MCH-ir neuronal somata and fibers were first
      detected in the hypothalamus and the pituitary, respectively, 7 days after
      hatching. Subsequently, MCH-ir neuronal somata were observed in the NLT and in
      the area above the LVR 14 days after hatching. The distribution of MCH-ir
      neuronal somata and fibers showed a pattern similar to that in the adult fish 35
      42 days after hatching. These results indicate that MCH neurons were located in
      the NLT and in the area above the LVR and that NLT-MCH neurons project to the
      pituitary. MCH neurons were first detected 7 days after hatching, suggesting that
      MCH plays some physiological role in the early development of barfin flounder.

PMID- 12483287
TI  - Neuropeptide co-localisation in the lepidopteran frontal ganglion studied by
      confocal laser scanning microscopy.
AB  - A comparative study of the co-localisation of three different families of
      neuropeptides, viz. allatostatins of the Y/FXFGL-NH(2) type, Manduca sexta
      allatostatin (Mas-AS) and allatotropin, in the frontal ganglion of lepidopteran
      larvae has been carried out by means of immunocytochemistry and confocal laser
      scanning microscopy. The simultaneous application of three types of fluorochrome
      conjugated antibodies reveals triple co-localisation in an anterodorsal pair of
      neurones in the frontal ganglion of the noctuids Heliothis virescens and
      Lacanobia oleracea. There is no evidence of differential axonal transport, since
      all parts of these neurones show complete co-localisation of all three peptides.
      Prominent axons of the ganglionic neurones project in the recurrent nerve to the
      foregut and stomodeal valve. Over the crop, lateral and sub-lateral branches
      follow the course of circular muscle fibres and terminate in varicosities. All
      three neuropeptides have previously been shown to be myoregulatory on the
      foregut; the Y/FXFGL-NH(2) allatostatins and Mas-AS are inhibitory, whereas
      allatotropin is excitatory. The morphological evidence of co-localisation of
      physiologically antagonistic peptides within the same terminals suggests that an
      extremely complex mechanism controls the contractile activities of the foregut. A
      posterodorsal pair of neurones in the frontal ganglion have prominent axons
      projecting via the frontal connectives to the brain and in the recurrent nerve to
      the stomodeal valve where extensive branching suggests control over the valve
      movements. Studies of another noctuid, Spodoptera frugiperda, and the sphingid,
      M. sexta, show interesting variations in the co-localisation phenomenon.

PMID- 12483289
TI  - Photopigment gene expression and rhabdom formation in the crayfish (Procambarus
      clarkii).
AB  - This study examines the expression of the photopigment gene in the developing
      retina of the freshwater crayfish Procambarus clarkii(Crustacea, Malacostraca,
      Decapoda). Both sense and anti-sense RNA probes were used for in situ
      hybridization (ISH) of whole embryos collected at various stages during
      development. A characteristic of retinal development is the formation of
      screening pigment in the retinular cells of the retinal ommatidia. This
      pigmentation is seen as a band that begins at the lateral side of the retinal
      field and progresses medially. At hatching the retina is approximately 50%
      pigmented. ISH of whole embryos shows that expression of the photopigment gene by
      the retinular cells correlates with the extent of the screening pigment band in
      the retina and with the presence of rhabdoms within the ommatidia. Sections taken
      through embryos after being hybridized indicate that staining is localized in the
      cytoplasm of the retinular cells and in the axonal region below the basement
      membrane. No staining reaction was seen in the rhabdoms of older ommatidia. ISH
      staining was also seen at the anterior midline of the protocerebrum where
      extraretinal photoreceptors have been reported. The data presented here show a
      close correlation of opsin expression within the retinular cells of the ommatidia
      and the formation of the very early rhabdoms, similar to Drosophila. The results
      will be discussed in relation to recent studies in Drosophila that suggest
      rhodopsin plays a role in effecting the organization of the terminal web-like
      cytoskeleton at the base of the developing rhabdom microvilli.

PMID- 12483288
TI  - Expression and localisation of GLUT1 and GLUT12 glucose transporters in the
      pregnant and lactating rat mammary gland.
AB  - Glucose plays a major role in mammary gland function during lactation as it is
      used both as a fuel and as a precursor of milk components. In rats, previous
      studies have shown that the facilitative glucose transporter GLUT1 is expressed
      in mammary epithelial cells. We have used confocal immunofluorescence to localise
      GLUT1 and GLUT12, a recently identified member of the sugar transporter family,
      in pregnant and lactating rat mammary gland. GLUT12 staining was observed in the
      cytoplasm of mammary epithelial cells at day 20 of pregnancy, and at 1 and 6 days
      postpartum. Furthermore, GLUT12 staining was present at the apical plasma
      membrane of epithelial cells during lactation. In contrast, GLUT1 protein
      localised to the cytoplasm and basolateral surface of mammary epithelial cells.
      Forced weaning resulted in decreased cytoplasmic GLUT1 staining intensity, but no
      change in GLUT12 staining. The results suggest a possible role for GLUT12 in the
      metabolism of mammary epithelial cells during pregnancy and lactation.

PMID- 12483290
TI  - Enzymatic, analytical and structural aspects of electron-dense granules in cells
      of Ucides cordatus (Crustacea, Decapoda) hepatopancreas.
AB  - Electron-dense granules (EDGs) are singular structures found in the tissues of
      several vertebrate and invertebrate organisms. Two types of EDGs were observed in
      hepatopancreatic cells of the crab Ucides cordatus: (1) a non-mineralized EDG,
      found mainly inside vacuoles, which reacted positively to acid phosphatase and D
      amino acid oxidase, possibly formed by degradation of lipid membranes, and (2) a
      mineralized EDG surrounded by endoplasmic reticulum membranes that gave a
      positive reaction for glucose-6-phosphatase. In this study we show the fine
      structure and composition of the mineralized EDGs using cytochemistry, analytical
      transmission electron microscopy and field-emission scanning electron microscopy.
      They are formed of microvesicle-like structures that are arranged in concentric
      spherical layers in the most mineralized portions of the granule. Analytical
      microscopy of mineralized EDGs indicated that they are composed of amorphous
      calcium-magnesium phosphate. Isolated EDGs treated with NaOCl lose several
      elements, including P, when compared with EDGs treated with deionized water.
      Removal of the organic matrix by NaOCl induced marked changes in the mineralized
      EDGs, showing that the organic matrix plays an important role in its elemental
      composition and structure.

PMID- 12483291
TI  - Cell culture of mechanoreceptor neurons innervating proleg sensory hairs in
      Manduca sexta larvae, and co-culture with target motoneurons.
AB  - The tip of each proleg in Manduca sexta larvae bears a dense array of
      mechanosensory hairs termed planta hairs (PHs), each innervated by a single
      sensory neuron (termed a PH-SN) located in the underlying epidermis. In the CNS,
      axon terminals of PH-SNs make direct, excitatory, nicotinic cholinergic synapses
      with proleg retractor motoneurons including the accessory planta retractor (APR).
      These synapses mediate a proleg withdrawal reflex, exhibit multiple forms of
      activity-dependent plasticity and weaken during the prepupal peak of
      ecdysteroids. In the present study we developed methods to dissociate PH-SNs from
      the epidermis and culture them alone or with APRs. The PH-SNs were fluorescently
      labeled in situ by introducing dye through the cut hair shaft or by retrograde
      axonal staining. Alternatively, unlabeled PH-SNs were utilized. The epidermis
      beneath the planta hair array was separated from the cuticle, enzymatically
      treated and mechanically dissociated into single cells. PH-SNs were cultured on
      glass coverslips coated with concanavalin A and laminin, in modified Leibovitz's
      IL-15 medium. Supplementation with medium conditioned by an insect cell line
      produced the best results. Dissociated PH-SNs had somatic diameters of ~10 micro
      m and typically bore a stout dendrite consisting of the inner and, occasionally,
      the outer dendritic segment. An axonal stump was sometimes retained. Viable PH
      SNs typically extended new processes and often survived for 2-4 weeks. When co
      cultured, PH-SNs and APRs exhibited robust growth and made close anatomical
      appositions. This culture system provides convenient experimental access to PH
      SNs and may potentially permit sensorimotor synapses to be investigated in vitro.

PMID- 12483292
TI  - Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly
      concordant or discordant F508del homozygous sib pairs.
AB  - Cystic fibrosis (CF) is the most common severe autosomal recessive disease among
      Caucasians and is caused by lesions within the cystic fibrosis transmembrane
      conductance regulator ( CFTR) gene. The variability of CF disease severity
      suggests the effect of modifying factors. Thirty-four highly concordant and
      highly discordant F508del homozygous sib pairs, who have been selected out of a
      group of 114 pairs for extreme disease phenotypes by nutritional and pulmonary
      status, were typed at single nucleotide polymorphisms (SNPs) and short tandem
      repeat polymorphisms (STRPs) in the 24-cM CFTR-spanning region between D7S525 and
      D7S495. Allele frequencies differed significantly at D7S495, located within a 21
      cM distance 3' of CFTR, comparing concordant mildly affected, concordant severely
      affected and discordant sib pairs, as judged by hypothesis-free permutation
      analysis by Monte Carlo simulation. A rare haplotype of two SNPs within the
      leptin gene promotor was found exclusively among the concordant mildly affected
      pairs. All concordant sib pairs shared the paternal F508del chromosome between
      CFTR and D7S495, whilst the cohort of discordant sib pairs inherited equal
      proportions of recombined and non-recombined parental chromosomes. We conclude
      that disease manifestation in CF is modulated by loci in the partially imprinted
      region 3' of CFTR that determine stature, food intake and energy homeostasis,
      such as the Silver-Russel-Syndrome candidate gene region and LEP.

PMID- 12483293
TI  - Three different pathological lesions in the NF1 gene originating de novo in a
      family with neurofibromatosis type 1.
AB  - Three members of a Portuguese family, who exhibited clinical evidence of
      neurofibromatosis type 1 (NF1), were found to possess different heritable and
      pathological mutations in their NF1 genes: a 1.5-Mb deletion spanning the entire
      NF1 gene, a truncating CGA-->TGA transition in exon 22 (R1241X), and a frameshift
      mutation in exon 29 (5406insT). All three lesions occurred de novo and are likely
      to have been generated by different mutational mechanisms. At least two of the
      mutations occurred on different chromosomal backgrounds. The probability of
      finding three non-identical NF1 gene lesions arising de novo in a family with NF1
      is very remote, too low to be readily accepted as mere coincidence. A number of
      possible explanations for this unique finding were therefore explored, but none
      were found to be wholly convincing. This report nevertheless serves as a reminder
      that it is unwise, even in the case of an autosomal dominant condition, to
      extrapolate from the detection of a single mutation in a specific individual to
      assuming an identical molecular genetic aetiology in other clinically affected
      members of the same family.

PMID- 12483294
TI  - Surfactant protein B polymorphism and respiratory distress syndrome in premature
      twins.
AB  - Recent evidence suggests that the susceptibility to respiratory distress syndrome
      (RDS) is partly explained by genetic variation in the surfactant proteins (SP) SP
      A and SP-B. The present study was designed to evaluate the concordance difference
      method and candidate gene analysis, in parallel, for the investigation of genetic
      susceptibility to RDS. We studied 100 same-sex twin pairs with established RDS in
      at least one twin. The difference in RDS concordance rates between the
      monozygotic (MZ) and dizygotic (DZ) twin pairs as evidence of a genetic influence
      was evaluated, and the SP-A and SP-B genes were investigated for potential
      associations with the susceptibility to RDS. The concordance rates of RDS were 54
      and 44% in the MZ and DZ pairs, respectively. The concordance difference of 10%
      was not significant [95% confidence interval (CI) -0.1 to +0.3, P=0.32],
      suggesting a low hereditary impact. However, the SP-B Ile131Thr polymorphism was
      associated with RDS. The threonine allele was associated with an increased risk
      of RDS [odds ratio (OR) 2.2, 95% CI 1.4-3.5, P=0.0014]. This was particularly
      apparent in first-born male infants (OR 6.2, 95% CI 2.4-16.3, P<0.001). The
      degree of prematurity (<32 weeks OR 2.0, 95% CI 1.1-3.7, P=0.021) and birth order
      (second-born OR 3.1, 95% CI 1.3-7.4, P=0.009) were the clinical variables
      affecting the risk of RDS. An association between the SP-B Ile131Thr polymorphism
      and RDS was found. The threonine allele was associated with the risk of RDS,
      particularly in the first-born twin infants. The concordance difference between
      MZ and DZ twin pairs underestimates the genetic impact on the risk of RDS. The
      traditional twin concordance study is insufficient to evaluate genetic
      predisposition to RDS or other diseases that are confounded by the birth order or
      multiple pregnancy in itself.

PMID- 12483295
TI  - A novel locus for autosomal dominant nonsyndromic hearing loss (DFNA44) maps to
      chromosome 3q28-29.
AB  - Hereditary non-syndromic sensorineural hearing loss (NSSHL) is a genetically
      highly heterogeneous group of disorders. Autosomal dominant forms account for up
      to 20% of cases. To date, 39 loci have been identified by linkage analysis of
      affected families that segregate NSSHL forms in the autosomal dominant mode
      (DFNA). Investigation of a large Spanish pedigree with autosomal dominant
      inheritance of bilateral and progressive NSSHL of postlingual onset excluded
      linkage to known DFNA loci and, in a subsequent genome-wide scan, the disorder
      locus was mapped to 3q28-29. A maximum two-point LOD score of 4.36 at theta=0 was
      obtained for marker D3S1601. Haplotype analysis placed the novel locus, DFNA44,
      within a 3-cM genetic interval defined by markers D3S1314 and D3S2418.
      Heteroduplex analysis and DNA sequencing of coding regions and exon/intron
      boundaries of two genes (CLDN16 and FGF12) in this interval did not reveal
      disease-causing mutations.

PMID- 12483296
TI  - Mitochondrial DNA polymorphisms associated with longevity in a Finnish
      population.
AB  - Sequence variation in mitochondrial DNA (mtDNA) may cause slight differences both
      in the functioning of the respiratory chain and in free radical production, and
      an association between certain mtDNA haplogroups and longevity has been
      suggested. In order to determine further the role of mtDNA in longevity, we
      studied the frequencies of mtDNA haplogroups and haplogroup clusters among
      elderly subjects and controls in a Finnish population. Samples were obtained from
      225 persons aged 90-91 years (Vitality 90+) and from 400 middle-aged controls and
      257 infants. MtDNA haplogroups were determined by restriction fragment length
      polymorphism. The haplogroup frequencies of the Vitality 90+ group differed from
      both those of the middle-aged controls ( P=0.01) and the infants ( P=0.00005),
      haplogroup H being less frequent than among the middle-aged subjects ( P=0.001)
      and infants ( P=0.00001), whereas haplogroups U and J were more frequent.
      Haplogroup clusters also differed between Vitality 90+ and both the middle-aged
      subjects ( P=0.002) and infants ( P=0.00001), the frequency of haplogroup cluster
      HV being lower in the former and that of UK and WIX being higher. These data
      suggest an association between certain mtDNA haplogroups or haplogroup clusters
      and longevity. Furthermore, our data appear to favour the presence of
      advantageous polymorphisms and support a role for mitochondria and mtDNA in the
      degenerative processes involved in ageing.

PMID- 12483297
TI  - Novel immunoglobulin superfamily gene cluster, mapping to a region of human
      chromosome 17q25, linked to psoriasis susceptibility.
AB  - Chromosome 17q25 harbors a susceptibility locus for psoriasis ( PSORS2). This
      locus may overlap with loci for atopic dermatitis and rheumatoid arthritis. To
      further refine the location of PSORS2, we genotyped 242 primarily nuclear
      families for 15 polymorphic microsatellites mapping to chromosome 17q23-q25. Non
      parametric linkage analysis revealed a linkage peak lying close to a novel
      cluster of genes from the immunoglobulin (Ig) superfamily. This cluster spans
      >250 kb and harbors five CMRF35-like genes and a sixth inhibitory receptor (
      CMRF35H) with three ITIM motifs that is transcribed in the opposite direction
      from the rest. The Ig domains encoded by these genes are most similar to those of
      the TREM (triggering receptor expressed selectively in myeloid cells) molecules,
      NKp44 and the polymeric immunoglobulin receptor. CMRF35-like genes are only
      expressed in sub-populations of cells of the myeloid lineage. In order to
      investigate the association of this region with psoriasis, we genotyped the
      families for 13 novel microsatellites and 19 SNPs from the region of linkage. A
      maximum NPL of 1.6 ( P=0.05) was obtained within the interval. Two SNP-based
      haplotypes revealed some evidence for association with psoriasis. One spanned
      CMRF35H and includes a non-synonymous polymorphism within CMRF35H (R111Q) (TDT
      P=0.03). The second was a three-locus haplotype lying within the first intron of
      CMRF35A2 ( TREM5) (TDT P=0.04). The novel markers described here will facilitate
      additional linkage and association studies between the CMRF35 family and disease.

PMID- 12483298
TI  - Molecular cloning and characterization of the GATA1 cofactor human FOG1 and
      assessment of its binding to GATA1 proteins carrying D218 substitutions.
AB  - Erythroid and megakaryocytic lineage differentiation and maturation are regulated
      via cooperation between transcription factor GATA1 and its essential cofactor
      friend-of-GATA1 (FOG1). The interaction between these two murine proteins is well
      studied in vitro and depends on the binding of Fog1 to the N-terminal zinc finger
      (N-finger) of Gata1. We identified the human FOG1 gene on chromosome 16q24 and
      found expression mainly in hematopoietic cells and also in several other tissues.
      Sequencing of FOG1 cDNA revealed a 1006 amino-acid protein that contained nine
      zinc fingers, highly homologous to murine Fog1 fingers. The amino acid sequence
      and the GATA1-binding capacity of the human and murine finger 5 are however
      different. Ex vivo binding studies demonstrated that FOG1 interacts with both
      GATA1 and GATA2. We and others have described patients with mutations in the
      GATA1 N-finger (V205 M, D218G, D218Y, or G208S), who suffer from
      macrothrombocytopenia and erythrocyte abnormalities. We now show ex vivo that the
      interaction between GATA1 and FOG1 is indeed disturbed in platelets and
      erythrocytes of those patients carrying D218 GATA1 mutations. The identification
      of the human FOG1 gene will enable the genetic screening of patients with non X
      linked thrombocytopenia and dyserythropoiesis.

PMID- 12483299
TI  - Mal de Meleda (MDM) caused by mutations in the gene for SLURP-1 in patients from
      Germany, Turkey, Palestine, and the United Arab Emirates.
AB  - Mal de Meleda (MDM) or keratosis palmoplantaris transgrediens of Siemens is an
      autosomal recessive skin disorder characterized by diffuse palmoplantar
      keratoderma (PPK) and transgressive keratosis with an onset in early infancy.
      There is no associated involvement of other organs; however, a spectrum of
      clinical presentations with optional and variable features has been described.
      Mutations in the ARS (component B)-81/s gene ( LY6LS) on chromosome 8q24-qter,
      which encodes SLURP-1, have recently been identified in patients with MDM. Here,
      we have analyzed four MDM families for mutations in SLURP-1. In a large
      Palestinian pedigree with multiple consanguinity, patients are homozygous for a
      new mutation that substitutes an arginine for a conserved glycine residue at
      position 86. A different mutation in Turkish patients results in the same amino
      acid exchange. Some remarkable similarities are seen in the clinical picture of
      patients from both families. Patients of an Emirati Bedouin family have a
      homozygous alteration of the translation initiation codon. In a German family
      with no known consanguinity, we have shown pseudodominant inheritance. Three
      affected children and their affected mother are homozygous for the missense
      mutation W15R. Our findings indicate that the MDM type of transgressive PPK is
      caused by SLURP-1 mutations in patients from various origins and demonstrate
      allelic heterogeneity for mutations in SLURP-1.

PMID- 12483300
TI  - Three duplicons form a novel chimeric transcription unit in the pericentromeric
      region of chromosome 22q11.
AB  - Pericentromeric regions of human chromosomes are preferential sites for the
      integration of duplicated DNA, or "duplicons", which often contain gene
      fragments. Although pericentromeric regions appear to be genomic junkyards, they
      could also be the birthplace of new genes with novel functions. We have
      characterized a chimeric transcription unit (cat eye syndrome critical region
      gene 7, CECR7) formed from three duplicons in the pericentromeric region of
      chromosome 22q. CECR7 exons show similarity to sequences on chromosomes 2, 5, 7,
      10, 11, 12, 13, 14, 15, 16, 18, 19, 21, and elsewhere on 22. Based on polymerase
      chain reaction (PCR) analysis of CECR7 duplicon boundaries in various primate
      species, and the sequence divergence between the human duplicons and their
      putative ancestral human loci, CECR7 was probably formed before the separation of
      macaque and is therefore older than most previously reported pericentromeric
      duplicons. Expression of CECR7 was detected by RT-PCR in humans and gorilla
      fibroblasts, but not orangutan, suggesting that expression did not result
      immediately from the formation of this novel transcription unit, or that
      expression was silenced in orangutan following its formation.

PMID- 12483302
TI  - Genomic structure of the human mitochondrial chaperonin genes: HSP60 and HSP10
      are localised head to head on chromosome 2 separated by a bidirectional promoter.
AB  - Although the mitochondrial chaperonin Hsp60 and its co-chaperonin Hsp10 have
      received great attention in the last decade, and it has been proposed that
      mutations and variations in these genes may be implicated in genetic diseases,
      the genome structure of the human HSP60 and HSP10 genes (also known as HSPD1 and
      HSPE1, respectively) has not been firmly established. The picture has been
      confused by the presence of many pseudogenes of both HSP60 and HSP10 and the long
      surviving assumption that the HSP60 gene is intron-less. An earlier report on the
      partial sequence of the human HSP60 gene and the presence of introns has largely
      been overlooked. We present the full sequence of the human HSP60 and HSP10 genes.
      The two genes are linked head to head comprising approximately 17 kb and consist
      of 12 and 4 exons, respectively. The first exon of the human HSP60 gene is non
      coding and the first exon of the human HSP10 gene ends with the start codon.
      Analysis of human and mouse expressed sequence tag sequences in GenBank indicates
      that alternative splicing occurs resulting in HSP60 gene transcripts with
      different exon-1 sequences. By sequencing of the exons, the exon/intron
      boundaries and the region between the two genes in 10 Danish individuals (five
      couples), nine nucleotide variations and one intronic deletion have been detected
      that, by subsequent typing of one child from each couple, have been assigned to
      five haplotypes. The human HSP60 gene has been localised, by radiation hybrid
      mapping, between markers AFMA121YH1 and WI-10756 on chromosome 2. This location
      and the position of two homologous fragments in the Human Genome Assembly are
      consistent with cytogenetic position 2q33.1. Using a luciferase-reporter assay,
      we demonstrate that the region between the two genes functions as a bi
      directional promoter. The transcriptional activity of the promoter fragment in
      the HSP60 direction is approximately twice that in the HSP10 direction under
      normal growth conditions and, upon heat-shock, promoter activity in either
      direction increased by a factor of approximately 12. One of the nucleotide
      variations detected is localised in a putative SP1-transcription-factor-binding
      site in the bidirectional promoter region and analysis of the transcriptional
      activity of the promoter fragment with this variation has shown that it does not
      affect transcription levels both with and without heat-shock.

PMID- 12483301
TI  - Common variations in noncoding regions of the human natriuretic peptide receptor
      A gene have quantitative effects.
AB  - Genetic susceptibility to common conditions, such as essential hypertension and
      cardiac hypertrophy, is probably determined by various combinations of small
      quantitative changes in the expression of many genes. NPR1, coding for
      natriuretic peptide receptor A (NPRA), is a potential candidate, because NPRA
      mediates natriuretic, diuretic, and vasorelaxing actions of the nariuretic
      peptides, and because genetically determined quantitative changes in the
      expression of this gene affect blood pressure and heart weight in a dose
      dependent manner in mice. To determine whether there are common quantitative
      variants in human NPR1, we have sequenced the entire human NPR1 gene and
      identified 10 polymorphic sites in its non-coding sequence by using DNA from 34
      unrelated human individuals. Five of the sites are single nucleotide
      polymorphisms; the remaining five are length polymorphisms, including a highly
      variable complex dinucleotide repeat in intron 19. There are three common
      haplotypes 5' to this dinucleotide repeat and three 3' to it, but the 5'
      haplotypes and 3' haplotypes appear to be randomly associated. Transient
      expression analysis in cultured cells of reporter plasmids with the proximal
      promoter sequences of NPR1 and its 3' untranslated regions showed that these
      polymorphisms have functional effects. We conclude that common NPR1 alleles can
      alter expression of the gene as much as two-fold and could therefore
      significantly affect genetic risks for essential hypertension and cardiac
      hypertrophy in humans.

PMID- 12483303
TI  - Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an
      EBP mutation in a family with X-linked dominant chondrodysplasia punctata.
AB  - X-linked dominant chondrodysplasia punctata (CDPX2) is a skeletal dysplasia
      characterized by stippled epiphyses, cataracts, alopecia and skin lesions,
      including ichthyosis. CDPX2 exhibits a number of perplexing clinical features,
      such as intra- and inter-familial variation, anticipation, incomplete penetrance
      and possible gonadal and somatic mosaicism. Recently, mutations in the gene
      encoding Delta8,Delta7 sterol isomerase/emopamil-binding protein (EBP) have been
      identified in CDPX2. To better understand the genetics of CDPX2, we examined the
      entire EBP gene by direct sequencing in four CDPX2 patients. We found EBP
      mutations in all four patients, including three novel mutations: IVS3+1G>A, Y165C
      and W82C. Surprisingly, a known mutation (R147H) was identified in a patient and
      her clinically unaffected mother. Expression analysis revealed the mutant allele
      was predominantly expressed in the patient, while both alleles were expressed in
      the mother. Methylation analysis revealed that the wild-type allele was
      predominantly inactivated in the patient, while the mutated allele was
      predominantly inactivated in her mother. Thus, differences in expression of the
      mutated allele caused by skewed X-chromosome inactivation produced the diverse
      phenotypes within the family. Our findings could explain some of the perplexing
      features of CDPX2. The possibility that an apparently normal parent is a carrier
      should be considered when examining seemingly sporadic cases and providing
      genetic counseling to CDPX2 families.

PMID- 12483304
TI  - Novel types of COMP mutations and genotype-phenotype association in
      pseudoachondroplasia and multiple epiphyseal dysplasia.
AB  - Mutations in the gene encoding cartilage oligomeric matrix protein ( COMP) cause
      two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal
      dysplasia (MED). More than 40 mutations have been identified; however, genotype
      phenotype relationships are not well delineated. Further, mutations other than in
      frame insertion/deletions and substitutions have not been found, and currently
      known mutations are clustered within relatively small regions. Here we report the
      identification of nine novel and three recurrent COMP mutations in PSACH and MED
      patients. These include two novel types of mutations; the first, a gross deletion
      spanning an exon-intron junction, causes an exon deletion. The second, a
      frameshift mutation that results in a truncation of the C-terminal domain, is the
      first known truncating mutation in the COMP gene. The remaining mutations, other
      than a novel exon 18 mutation, affected highly conserved aspartate or cysteine
      residues in the calmodulin-like repeat (CLR) region. Genotype-phenotype analysis
      revealed a correlation between the position and type of mutations and the
      severity of short stature. Mutations in the seventh CLR produced more severe
      short stature compared with mutations elsewhere in the CLRs ( P=0.0003) and
      elsewhere in the COMP gene ( P=0.0007). Patients carrying mutations within the
      five-aspartates repeat (aa 469-473) in the seventh CLR were extremely short
      (below -6 SD). Patients with deletion mutations were significantly shorter than
      those with substitution mutations ( P=0.0024). These findings expand the mutation
      spectrum of the COMP gene and highlight genotype-phenotype relationships,
      facilitating improved genetic diagnosis and analysis of COMP function in humans.

PMID- 12483305
TI  - Functional polymorphisms in the mineralocorticoid receptor and amirolide
      sensitive sodium channel genes in a patient with sporadic
      pseudohypoaldosteronism.
AB  - Pseudohypoaldosteronism (PHA) is characterized by urinary salt-wasting in infancy
      resulting from a congenital resistance to aldosterone involving the genes for the
      mineralocorticoid receptor (MR) and the amiloride-sensitive sodium channel
      (ENaC). We identified, in a Japanese patient with sporadic PHA, three homozygous
      substitutions in the MR gene: G215-->C215, A754-->G754 (Ile180-->Val180), C938-
      >T938 (Ala241-->Val241), which had previously been reported to occur in healthy
      populations. Luciferase activities induced by MR with either G215-->C215, Ile180-
      >Val180, or Ala241-->Val241 substitution were significantly lower than those for
      wild-type MR with aldosterone at concentrations ranging from 10(-11) to 10(-9) M,
      10(-8) M, or 10(-11) to 10(-6) M, respectively. A homozygous A-->G substitution
      of the donor splice site of alphaENaC intron 4 was found in the patient. The
      corresponding cDNA exhibited a normal structure, suggesting that this
      substitution does not alter the splice. The results suggest that each of three MR
      polymorphisms identified in our patient is functionally and structurally
      heterogeneous. We hypothesize that two or more "functional" polymorphisms, any of
      which exhibits only slight effects on MR or ENaC function and is alone incapable
      causing PHA, may in the right allelic combination induce the negative salt
      conservation characteristic of PHA.

PMID- 12483306
TI  - Sequence analysis of the granulysin and granzyme B genes in familial
      hemophagocytic lymphohistiocytosis.
AB  - Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive
      disorder of immune regulation. Mutations in the gene encoding perforin were
      previously identified in a subset of FHL patients. The present analysis of two
      novel candidate genes, granzyme B and granulysin, by direct sequencing in a total
      of 16 FHL families, disclosed several sequence variations. However, none of these
      sequence variations were associated with the manifestations of FHL. These data do
      not support the notion that granulysin and granzyme B are candidate genes for
      FHL.

PMID- 12483308
TI  - Modulation of integrins and integrin signaling molecules in the pressure-loaded
      murine ventricle.
AB  - Integrins are heterodimeric cell-surface receptors that link the extracellular
      matrix and the intracellular cytoskeleton and function as mechanotransducers.
      Signaling through integrins is important for cell growth, migration, and
      survival. Extracellular matrix is altered in the myocardium during hypertrophic
      induction and the transition to heart failure. The role of integrins in this
      process is poorly understood. Recently, integrin subunits have been identified
      that are dominantly expressed in striated muscle. We tested the hypothesis that
      since integrins are mechanotransducers, their expression and signaling would be
      modulated with murine left ventricular hemodynamic loading. The acute and chronic
      effects of pressure overload on changes in the expression of integrins, as well
      as related integrin-mediated signaling events were studied. Acute pressure
      loading increased phosphorylation of focal adhesion kinase, p42 and p44
      extracellular signal-regulated kinase. Chronic loading: (1) increased expression
      of alpha1, alpha5, and beta1 integrin transcripts and (2) increased protein
      expression of integrin subunits which are dominantly expressed in striated muscle
      (alpha7 and beta1D) both by western blotting and immunofluorescent microscopy.
      These results show that adaptive responses of the myocardium to pressure overload
      include acute modulation of integrin-related signaling molecules and more chronic
      changes effect expression of integrin subunits, including ones dominantly
      expressed in muscle.

PMID- 12483309
TI  - Multiple nicotinic acetylcholine receptor alpha-subunits are expressed in the
      arterial system of the rat.
AB  - Neuronal nicotinic acetylcholine receptors (nAChRs) are hetero- and homopentamers
      built up by nine different alpha-subunits and three different beta-subunits. The
      subtype composition within the receptor determines ligand specificity, affinity
      and cation permeability. In this study we focused on the distribution of the
      ligand binding alpha-subunits in the rat arterial system by means of RT-PCR and
      immunohistochemistry. Subtypes alpha3, alpha5, alpha7 and alpha10 were found to
      be expressed by endothelial cells, suggesting that they are equipped both with
      calcium-preferring (alpha7 homopentamers) and monovalent cation-preferring
      (heteropentamers containing alpha3- and alpha5-subunits) nAChR channels. All
      alpha-subtypes except alpha9 were expressed by vascular smooth muscle cells with
      a highly specific distribution pattern along the vascular tree. While every alpha
      subunit except alpha9 was detected in the thoracic aorta, intrapulmonary arterial
      branches contained only alpha7 immunoreactivity, and other vascular beds held
      intermediate positions with respect to the extent of alpha-subunit expression.
      Current knowledge does not allow to correlate these distribution patterns to
      specific functions, but it can be anticipated that at least some components of
      nAChR-mediated signalling in the arterial wall are highly specific for individual
      arteries.

PMID- 12483310
TI  - Interstitial cells of Cajal, enteric neurons, and smooth muscle and myoid cells
      of the murine gastrointestinal tract express full-length dystrophin.
AB  - A gene located on the X chromosome is responsible for the transcription of
      several mRNA and related dystrophin isoforms. Lack or truncated expression of the
      427-kDa, full-length isoform in skeletal muscle results in Duchenne muscular
      dystrophy (DMD). Patients with DMD, as well as mdx mice, a mutant strain also
      lacking this isoform, show gastrointestinal dismotilities. The present aim was to
      identify the cell types that express full-length dystrophin in the
      gastrointestinal tract. An immunohistochemical study was performed using an
      antibody specific for this isoform, and double labelings were made for
      interstitial cells of Cajal (ICC) identification and to verify whether all
      neurons express full-length dystrophin. Three different fixation procedures were
      used. The results showed that ICC, enteric neurons, and smooth muscle and myoid
      cells expressed full-length dystrophin. In ICC and neurons, dystrophin
      immunoreactive patches were irregularly distributed at the cell contour and
      within the cytoplasm. In smooth muscle and myoid cells, regularly spaced
      dystrophin-immunoreactive bars were located along the cell contour. Labeling
      intensity varied according to fixation procedure. The different subcellular
      distributions of dystrophin immunoreactivity might reflect diverse roles played
      by full-length isoforms in each cell type. Dystrophin loss in cells involved in
      gastrointestinal motility might explain the gastrointestinal symptomatology
      affecting DMD patients and mdx mice.

PMID- 12483311
TI  - Specific visualization of precipitated cerium by energy-filtered transmission
      electron microscopy for detection of alkaline phosphatase in immunoenzymatic
      double labeling of tyrosine hydroxylase and serotonin in the rat olfactory bulb.
AB  - To understand in detail the functional morphology of neuronal circuits it is
      important to identify at the ultrastructural level the incoming axon, its target
      neuron, and members of the signaling cascades involved. This, however, represents
      a formidable task, requiring highly sophisticated electron microscopic multiple
      labeling techniques. To extend available double-labeling procedures such as
      combinations of immunogold and peroxidase methods, an additional, gold- and
      peroxidase-independent procedure would represent a considerable advantage. The
      present investigation therefore aimed to use alkaline phosphatase as the
      immunoenzymatic label at the electron microscopic level via cerium phosphate
      precipitates. To our surprise we found that available techniques, which are well
      established for the visualization of endogenous enzymes in sections from various
      tissues, are not suitable for application to immunocytochemistry. Careful
      characterization of the individual reaction conditions, however, resulted in an
      optimized procedure with largely increased sensitivity. The novel technique
      yields cerium-containing precipitates which are massive enough to allow the
      detection of the immunoenzymatic reaction product in the electron microscope.
      Using the rat olfactory bulb as the model system we showed further that our
      technique allows the combination with the peroxidase/diaminobenzidine system for
      ultrastructural double labeling. For this purpose, the alkaline phosphatase
      product is identified by its cerium content via energy-filtered transmission
      electron microscopy and thereby differentiated from cerium-free peroxidase
      derived precipitates. Doing so, we found that ascending serotoninergic fibers do
      not establish synapses with dopaminergic periglomerular cells in the rat
      olfactory bulb.

PMID- 12483312
TI  - Differential histochemical localization patterns of reduced nicotinamide adenine
      dinucleotide phosphate-diaphorase and neuronal nitric oxide synthase during
      postnatal development of the rat vomeronasal organ.
AB  - The present study was undertaken to examine the localization patterns of
      nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) by enzyme
      histochemistry and neuronal nitric oxide synthase (NOS) by immunohistochemistry
      in the vomeronasal organ of rat from postnatal day 0 for 8 weeks (adult).
      Nicotinamide adenine dinucleotide phosphate-diaphorase activity was not observed
      in the sensory epithelium of the vomeronasal organ at postnatal day 0 (the day of
      birth) and at day 1. At postnatal day 2, NADPH-d activity was observed in several
      vomeronasal neurons and on the surface of the sensory epithelium. From 25 days
      through adulthood, the number of vomeronasal neurons having NADPH-d activity
      increased gradually. On the other hand, neuronal NOS immunoreactivity was not
      observed in the sensory epithelium of the vomeronasal organ in newborns or in the
      adult rat. In this study, it is suggested that the nitric oxide pathway in the
      sensory epithelium of the vomeronasal organ comes into play beyond postnatal day
      3. Moreover, it was found that NADPH-d and neuronal NOS are not colocalized in
      the sensory epithelium of the developing rat vomeronasal organ.

PMID- 12483313
TI  - Functional and structural regression of the rabbit corpus luteum is associated
      with altered luteal immune cell phenotypes and cytokine expression patterns.
AB  - Following attenuation of progesterone production corpora lutea are selectively
      cleared, a process associated with recruitment of macrophages. In the rabbit
      little is known about luteal immune cell phenotypes and expression of cytokines,
      which influence immune cells and resident luteal cells, during luteolysis.
      Consequently, we studied luteal immune cells by immunohistochemistry as well as
      luteal IL-10, TNFalpha, MCP-1, IFN-gamma, and IL-1beta mRNA expression by
      semiquantitative RT-PCR from day 8 to day 20 in pseudopregnant rabbits (d8-d20
      p.hCG). Luteal function was assayed by serum progesterone levels. Functional
      luteolysis commenced by d14 p.hCG as indicated by attenuation of serum
      progesterone levels. X4(+) tissue macrophage levels increased transiently on d12
      and d14 p.hCG, whereas CD5(+) T-cell levels transiently declined on these two
      days. CD68(+) macrophages increased progressively after d16 p.hCG. The luteal
      mRNA level of the anti-inflammatory cytokine IL-10 as well as the mRNA levels of
      the pro-inflammatory cytokines TNFalpha and MCP-1 increased after d16 p.hCG and
      remained elevated up to d20 p.hCG. IFN-gamma and IL-1beta mRNA expression did not
      vary systematically. In summary, luteolysis was associated with an initial
      transient increase of X4(+) macrophages and decrease of CD5(+) T-cells, and later
      recruitment of CD68(+) macrophages. During structural regression pro- and anti
      inflammatory cytokines are upregulated possibly to control immune cell function.

PMID- 12483314
TI  - Cellular signaling during the macrophage invasion by Trypanosoma cruzi.
AB  - We have reported that protein tyrosine kinases play an important role in the
      invasion of Trypanosoma cruzi into primary resident macrophages. In the present
      study we carry out immunofluorescence assays, using monoclonal anti
      phosphotyrosine antibodies, to reveal an accumulation of tyrosine-phosphorylated
      residues at the site of parasite association with the macrophage surface,
      colocalizing with host cell F-actin-rich domains. SDS-PAGE analysis of macrophage
      cell line IC-21 tyrosine phosphoproteins, labeled with [(35)S] L-methionine,
      revealed several peptides with increased levels of phosphorylation upon
      interaction with the parasite. Among them, were detected bands of 140, 120, 112,
      94, 73, 67, and 56 kDa that match the molecular weights of proteins described as
      being tyrosine phosphorylated during events that lead to actin assembly in
      mononuclear phagocytes. The pretreatment of IC-21 macrophages with the tyrosine
      kinase inhibitor tyrphostin 23 inhibited trypomastigote uptake showing that
      tyrosine phosphorylation is important for the parasite penetration in this
      particular cell line. Immunofluorescence microscopy, using antibodies against
      p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase),
      placed this enzyme also in the same sites, in accordance to what is reported for
      phagocytosis. We suggest that once the components of T. cruzi trypomastigotes
      surface are recognized by macrophage receptors, they trigger the activation of a
      tyrosine phosphorylation cascade, PI 3-kinase recruitment, and assembly of actin
      filaments at the site of initial cell-to-cell contact, resembling the events
      described during phagocytosis. These achievements support the model for a
      phagocytic-like actin-dependent invasion mechanism for T. cruzi trypomastigotes
      into macrophages.

PMID- 12483315
TI  - Electroporation of primary neural cultures: a simple method for directed gene
      transfer in vitro.
AB  - Gene transfer into cells of the nervous system is an important method to analyze
      tissue-specific gene functions. Although highest transfection efficiencies are
      generally obtained by viral gene transfer, non-viral methods are attractive
      because they are less labor intensive and more suitable for high throughput
      screening approaches. Here we describe an approach for electroporation-based gene
      transfer into primary neural cells isolated from dissociated murine cerebella.
      Using GFP as reporter molecule, we show that electroporation allows for efficient
      gene transfer into embryonic and postnatal neural cells under highly controlled
      experimental conditions. Furthermore we show that adaptation of electroporation
      parameters allowed for the preferential transfection of subsets of neural cells
      within the mixed primary culture. Using electroporation settings of high voltage
      and low capacitance (500 V/50 microF) we achieved a transfection efficiency of
      about 10% of small neural cells which were identified as granule cells by the
      expression of the granule cell-specific marker NeuN. At electroporation settings
      of 220 V/975 microF, large and stellate-shaped cells that comprised about 10% of
      the GFAP-positive population of astrocytes were preferentially transfected. We
      conclude that electroporation of primary neural cells can be used to target gene
      transfer to subsets of neural cells.

PMID- 12483317
TI  - Clinical findings on the use of long-term heavy tamponades (semifluorinated
      alkanes and their oligomers) in complicated retinal detachment surgery.
AB  - BACKGROUND: Heavy tamponades for pathologies in the lower part of the retina are
      a new development, and different tamponades have recently come into clinical use:
      semifluorinated alkanes (F(6)H(6), F(6)H(8)) and their oligomers (OL62HV).
      METHOD: Nine patients had been operated on using F(6)H(8) (n=5) and by OL62HV
      (n=4). In all cases the reasons for using the tamponades were complicated retinal
      detachments in the lower part. In three cases the use was primary and in six
      cases tamponades were used after reoperations. In all cases the endotamponade was
      removed within 6 weeks. Fluorescein angiography (FLA) was performed in the
      F(6)H(8) group. RESULTS: In the F(6)H(8)group dispersion developed in two of the
      three aphacic patients. In two out of five cases soft epiretinal membranes and
      cellular material could be found between the substance and the lower periphery.
      In two membranes examined by light microscopy, cystic cells and amorphous
      material could be found. In one case (PDRP, aphacic) cyclophotocoagulation had to
      be performed because of persistent elevated IOP. FLA was unremarkable. In the
      OL62HV group, severe recurrent PVR reaction occurred in the lower periphery (2/4)
      and unusual precipitates were observed (4/4). In one case, after a normal
      postoperative period (VA 0.05 after 5 days) an extensive cellular reaction on the
      complete surface of the tamponade occurred. After 5 weeks VA was no light
      perception. During removal of the oligomer unusual adherent cellular components
      were found on the surface of the retina. The retina appeared necrotic, showed
      constricted retinal vessels and there was optic atrophy. Histologically, fluffy
      epiretinal material and a lens capsule obtained from one eye filled with OL62HV
      resembled the appearance with F(6)H(8). CONCLUSION: Heavy endotamponades on the
      basis of semifluorinated alkanes can lead to an unusual biological reaction and
      need further investigation before clinical use.

PMID- 12483318
TI  - Neodymium:YAG laser capsulotomy: a clinical morphological analysis.
AB  - BACKGROUND: There are no prospective controlled trials comparing methods of
      capsulotomy or patterns of capsulotomy openings in similarly graded opacified
      posterior capsules. This paper aims to investigate the effect of various forms of
      posterior capsular opacification (PCO) capsulotomy openings on visual function
      METHODS: Thirty-six eyes of 34 patients had vision tested and posterior capsules
      were digitally photographed. Each patient then underwent Nd:YAG laser
      capsulotomy. Patients returned 1 week later for repeat vision tests and
      photography. Analyses of areas of pearls and fibrosis were performed using the
      EPCO software system. Analyses of size and shape of capsulotomy was also done
      with image analysis software. The capsulotomy characteristics were analysed with
      respect to improvements in vision, taking into consideration the PCO scores.
      RESULTS: No correlation was found between capsulotomy dimensions and visual
      function improvement, even when PCO details were included in the analyses.
      Neither capsulotomy area, eccentricity, nor shape irregularity in the ranges
      measured was found to correlate significantly with eventual visual outcome in
      terms of contrast sensitivity, near and distance visual acuity, or glare
      readings. CONCLUSION: Performing a small capsulotomy (at least 1.5 mm in
      diameter), even if decentred up to 1 mm, may allow for satisfactory visual
      performance as long as the aperture is clear and not obscured by residual
      strands.

PMID- 12483316
TI  - Progress in focus: recent advances in histochemistry and cell biology.
AB  - Advances in histochemical and cell biological techniques enable increasingly
      refined investigations into the cellular and subcellular distribution of specific
      molecules and into their role in dynamic processes; thus progress in these fields
      complements the growing knowledge in genomics and proteomics. The present review
      summarizes recent technical progress and novel applications.

PMID- 12483319
TI  - Macular capillary blood flow velocity by blue-field entoptoscopy in diabetic and
      healthy women during pregnancy and the postpartum period.
AB  - PURPOSE: To study macular capillary blood flow velocity in diabetic and healthy
      women during pregnancy and the postpartum period. METHODS: A prospective study of
      46 pregnant women with insulin-dependent diabetes and 11 healthy pregnant women
      was performed. Macular capillary blood flow velocity was measured by blue-field
      entoptic simulation. Diabetic retinopathy was graded from colour fundus
      photographs. RESULTS: In diabetic women, the macular capillary blood flow
      velocity was 0.94+/-0.27 mm/s (mean +/- SD) during the first trimester, 1.00+/
      0.28 mm/s during the third trimester and 1.03+/-0.24 mm/s 3 months postpartum,
      compared with values of 0.71+/-0.20, 0.77+/-+/-0.20 and 0.82+/-0.19 mm/s,
      respectively, in healthy women (P=0.0026 between groups). Diabetic women with no
      or very mild retinopathy had lower macular capillary blood flow velocities than
      those with more severe retinopathy (P=0.0164), but higher velocities than healthy
      women (P=0.0167). An increase temporally from the first trimester to the
      postpartum period was observed in diabetic women (P=0.0294) but not in healthy
      (P=0.2449) women. CONCLUSIONS: According to our study macular capillary blood
      flow velocity is higher in diabetic than in healthy women during pregnancy and
      the postpartum period. Further, capillary blood flow velocity seems to depend on
      the grade of retinopathy in pregnant diabetic women. These data support the
      concept that capillary hyperperfusion may play a role in the development of
      diabetic retinopathy during pregnancy.

PMID- 12483320
TI  - Isolation of intact lysosomes from human RPE cells and effects of A2-E on the
      integrity of the lysosomal and other cellular membranes.
AB  - BACKGROUND: Accumulation of lipofuscin in RPE cells occurs with age and in
      association with various retinal diseases. Lipofuscin and its major retinoid
      compound and fluorophore A2-E interfere with the cellular metabolism of RPE cells
      in various ways. One of these mechanisms is thought to be related to detergent
      properties of A2-E. METHODS: We isolated pure and intact lysosomes from RPE cell
      cultures and investigated detergent-like effects of the lipofuscin compound A2-E
      on the integrity of lysosomal membrane and other cellular membranes, using
      latency measurements. 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 upon incubations in isotonic media providing the
      base 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. The described methodology to obtain highly purified and
      intact lysosomes from RPE cells provides a suitable tool for investigations on
      compounds affecting lysosomal structure. A2-E was shown to cause desintegration
      of the lysosomal membrane at relatively low concentrations, which may implicate
      an involvement of such mechanism in triggering lipofuscin-induced dysfunction of
      RPE in vivo. Secondary to disintegration of the lysosomal membrane, damage to
      mitochondria might be an additional pathogenic mechanism. CONCLUSIONS: 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, such as age-related macular degeneration.

PMID- 12483321
TI  - Evidence of toxic side effects of perfluorohexyloctane after vitreoretinal
      surgery as well as in previously established in vitro models with ocular cell
      types.
AB  - BACKGROUND: Cases of ocular irritation have been observed after early clinical
      trials using perfluorohexyloctane (F6H8) as endotamponade. In our clinic two of
      three eyes developed severe inflammatory-like reactions after intermediate-term
      tamponade. These cases will be depicted, serving as background for the
      experimental study. To elucidate possible toxic effects of F6H8 on different
      ocular cell types and corneal tissue we applied our previously established in
      vitro models to investigate effects of F6H8 on cultured ocular cells in
      comparison with perfluorodecaline. METHODS: Vitality and proliferation of
      cultured human corneal endothelial cells (HCEC) and human retinal pigment
      epithelial cells (RPE) were measured after incubation with F6H8 or
      perfluorodecaline for up to 5 days. Vitality was evaluated using the Live/Dead
      assay, and proliferation was determined according to BrdU incorporation.
      Additionally the endothelium of donor corneas was incubated with F6H8 for 5 days
      and endothelial cell morphology was documented. RESULTS: After 5 days incubation
      with F6H8, cultures of RPE and HCEC showed significantly lower extinctions for
      vital cells as well as a non-significant decrease in proliferation compared with
      controls. Analysis by means of fluorescence microscopy after treatment with F6H8
      or perfluorodecaline revealed decreased cell densities (F6H8 > perfluorodecaline)
      within contact areas. The endothelium of donor corneas incubated in presence of
      F6H8 developed circumscribed necrotic areas. CONCLUSIONS: Decreased amounts of
      vital cells cannot be explained solely by mechanical effects or nutritional
      deficit due to direct contact, since F6H8 has a lower specific weight than
      perfluorodecaline. The ability of the remaining cells to proliferate revealed
      that they were not irreversibly damaged. Due to the high lipophilicity of F6H8
      interactions with cellular lipoprotein membranes as well as other toxic effects
      have to be considered and should further be investigated prior to clinical use.

PMID- 12483322
TI  - Advanced glycation end products induce choroidal endothelial cell proliferation,
      matrix metalloproteinase-2 and VEGF upregulation in vitro.
AB  - BACKGROUND: Advanced glycation end products (AGEs) are considered to be important
      modulators of angiogenesis and accumulate in choroidal neovascularization (CNV).
      Their effects regarding cells involved in proliferation of CNV [retinal pigment
      epithelial (RPE) cells, Muller cells and choroidal endothelial cells (CECs)] were
      investigated. Furthermore, the effects of AGEs on expression of matrix
      metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) by CECs
      were explored. METHODS: RPE cells, CECs and Muller cells were exposed to AGEs (10
      microg/ml, 50 microg/ml and 100 microg/ml) for a time course of three days in
      their desired medium and proliferation was estimated by a 3-(4,5-dimethylthiazol
      2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. MMP-2 expression of AGE
      stimulated CECs was determined by zymography and reverse-transcription polymerase
      chain reaction (RT-PCR) after 36 h of exposure. Furthermore, VEGF expression of
      AGE-stimulated CECs (50 microg/ml and 100 microg/ml) was determined by RT-PCR
      after an exposure time of 36 h. RESULTS: AGEs in a concentration of 50 microg/ml
      and 100 microg/ml increased the proliferation of CECs (41% vs 46.1%; P<0.005). No
      AGE effect on RPE cell and Muller cell proliferation was seen. AGEs in all
      concentrations used upregulated the VEGF mRNA expression of CECs. Zymography and
      RT-PCR demonstrated the upregulation of MMP-2 by CECs after AGE exposure.
      CONCLUSION: AGEs stimulate CEC proliferation, MMP-2 secretion and VEGF
      upregulation and may be important promoters of CNV formation in exudative AMD in
      vivo.

PMID- 12483324
TI  - Interaction of zinc and vitamin A on the ocular surface.
AB  - PURPOSE: The purpose of this study was to assess morphologically the interaction
      between zinc and vitamin A in their effect on the ocular surface. METHODS: Three
      week-old Wistar Kyoto rats were divided into five groups: group A(+) Zn(+) was
      fed a diet containing both vitamin A and Zn; group A(-) was fed a vitamin A
      deficient diet; group A(-) Zn(+) was given a vitamin A-deficient diet and
      deionized distilled water with Zn; group Zn(-) and group Zn(-) A(+) were fed a Zn
      deficient diet, whereby group Zn(-) A(+) received an intraperitoneal injection of
      vitamin A. Corneas and conjunctivas of each group were examined by electron
      microscopy. RESULTS: The corneas and conjunctivas of group A(-) demonstrated a
      decrease in the number of microvilli in the epithelium. The corneas and
      conjunctivas of group A(-) Zn(+) had a decrease in microvilli but more microvilli
      than those of group A(-). The corneas of group A(-) showed keratinization, but
      those of group A(-) Zn(+) showed no keratinization. In group Zn(-) the microvilli
      on the conjunctiva and cornea were sparse. Group Zn(-) A(+) had a decrease in
      microvilli but more microvilli than group Zn(-). The conjunctivas of group Zn(-)
      A(+) had more goblet cells with granules than did those of group Zn(-).
      CONCLUSION: These results suggest that a synergistic interaction exists between
      vitamin A and zinc for the maintenance of the corneal and conjunctival
      epithelium.

PMID- 12483323
TI  - Functional role of Egr-1 mediating VEGF-induced tissue factor expression in the
      retinal capillary endothelium.
AB  - PURPOSE: To investigate the causal relationship between VEGF and tissue factor
      (TF) expression, and its intracellular signaling in the retinal capillary
      endothelium both in vitro and in vivo. METHODS: TF mRNA and protein expression in
      cultured bovine retinal capillary endothelial cells (BRECs) were detected by RT
      PCR and western blotting. The expression and subcellular localization of Egr-1
      were analyzed by immunocytochemistry and western blotting. Involvement of p44/p42
      MAPK pathway in this signaling was assessed using PD98059. Electrophoretic
      mobility shift assay (EMSA) was performed using human TF Egr-1/Sp-1 overlapping
      promoter region (-85 to -70). Decoy oligonucleotide was transfected into BRECs to
      clarify the critical transcription factor mediating VEGF-induced TF gene
      expression. To evaluate the importance of GC rich region in VEGF-induced TF
      protein expression in rat retinas, Mithramycin was intraperitoneally
      administered. RESULTS: VEGF stimulated TF mRNA and protein expression in cultured
      BRECs, reaching maximal effect after 4 h and 10 h, respectively. VEGF activated
      transcription factor Egr-1 within 60 min. Inactivation of Egr-1 by PD98059
      resulted in the prohibition of VEGF-induced TF gene expression. EMSA revealed the
      increment of Egr-1 binding with TF promoter region by displacing Sp1 after
      treatment with VEGF. Transfection of the Egr-1/Sp-1 overlapping decoy into BRECs
      inhibited VEGF-dependent TF gene expression. Mithramycin almost completely
      suppressed VEGF-induced TF protein expression in retinal capillary system in vivo
      (80%, p<0.01). CONCLUSION: Transcription factor Egr-1, which lies downstream of
      p44/p42 MAPK, critically mediates VEGF-dependent TF expression in the retinal
      capillary endothelium.

PMID- 12483325
TI  - Alteration of the intracellular pH and apoptosis induction in a retinal cell line
      by the AGE-inducing agent glyoxal.
AB  - BACKGROUND: Methylglyoxal and glyoxal, intermediate products of glycation, are
      known to accelerate glycation and the formation of advanced glycation endproducts
      (AGEs). These mechanisms may play a role in the degenerative progression of
      diabetic retinopathy and macular degeneration. The present study was undertaken
      to elucidate the retinal neurotoxicity of the Maillard reaction intermediate
      alpha-oxoaldehyde glyoxal. METHODS: E1A-NR3 is an immortalized retinal cell line
      that manifests specific phenotypes of retinal neurons. These cells were incubated
      with 0 microM (control), 200 microM, 400 microM, and 800 microM glyoxal for
      different lengths of time. For intracellular pH measurements, cells were
      incubated for 30 min with BCECF-AM prior to measurement of the emission ratio at
      two wavelengths. For semiquantitative analysis of the mitochondrial potential,
      cells were incubated for 15 min with 5,5',6,6'-tetrachloro-1,1', 3,3'
      tetraethylbenzimidazolylcarbocyanine iodide (JC-1). For detection of apoptotic
      cells, cultures were incubated for 15 min with YO-PRO-1 iodide.
      Immunohistochemical labeling of cell components, which are indicative for
      apoptosis like active caspase-3 and the caspase cleavage product fractin, was
      performed after fixation. DNA gel electrophoresis was carried out to detect
      apoptotic cell death at the DNA level. RESULTS: Morphological changes in living
      cells after glyoxal incubation showed signs of cell damage, including cell
      membrane blebbing and aggregation of intracellular organelles. Glyoxal produced a
      dose- and time-dependent acidification from physiological pH to pH 7.2. The
      semiquantitative analysis of mitochondrial membrane potential in living control
      cells showed nearly all mitochondria with intact hyperpolarized membranes. One
      hour after the beginning of incubation with 200 microM glyoxal we found most
      mitochondria depolarized but still with an elongated shape and only regional
      swelling. With higher glyoxal concentrations more depolarized mitochondria
      developed blebs and were located around the nucleus. The membrane permeability
      assay with the nucleic acid stain YO-PRO-1 showed increasing cell membrane
      permeability with time and glyoxal dose and, finally, nuclear fragmentation. By
      means of immunohistochemistry we found a glyoxal-induced accumulation of the AGE
      N(epsilon)-(carboxymethyl) lysine in the cytoplasm and nuclei. The cells were
      immunoreactive for active caspase-3 after glyoxal in a dose-dependent manner.
      Neurofilament protein was strongly expressed in controls and disappeared
      gradually with increasing glyoxal concentration. The immunoreactivity for the
      caspase cleavage product fractin was found in most of the cells after 800 microM
      glyoxal. DNA gel electrophoresis showed DNA ladder formation. CONCLUSIONS: The
      ability of glyoxal to induce apoptosis was confirmed by our findings
      demonstrating the time- and dose-dependent acidification of retinal cells. The
      onset of acidification is a hallmark because acidification is a measurable
      cytosolic event that follows the mitochondrial change but precedes caspase
      activation. Therefore, monitoring of pHi can allow one to assess cell stresses
      such as hypoxia, and metabolic stress (AGEs), and to test whether these stresses
      have a cumulative effect on apoptosis induction. Our study showed that
      intracellular pH and mitochondrial potential in living retinal cells are useful
      parameters for monitoring metabolic status in retinal tissue. These findings may
      be relevant in the study of retinal cell death mechanisms associated with age
      related diabetic retinopathy and macular degeneration.

PMID- 12483326
TI  - Severe ocular and orbital toxicity after intracarotid injection of carboplatin
      for recurrent glioblastomas.
AB  - BACKGROUND: Glioblastoma is a malignant tumor that occurs in the cerebrum during
      adulthood. With current treatment regimens including combined surgery, radiation
      and chemotherapy, the average life expectancy of the patients is limited to
      approximately 1 year. Therefore, patients with glioblastoma sometimes have
      intracarotid injection of carcinostatics added to the treatment regimen.
      Generally, carboplatin is said to have milder side effects than cisplatin, whose
      ocular and orbital toxicity are well known. However, we experienced a case of
      severe ocular and orbital toxicity after intracarotid injection of carboplatin,
      which is infrequently reported. CASE: A 58-year-old man received an intracarotid
      injection of carboplatin for recurrent glioblastomas in his left temporal lobe.
      He complained of pain and visual disturbance in the ipsilateral eye 30 h after
      the injection. Various ocular symptoms and findings caused by carboplatin
      toxicity were seen. RESULTS: He was treated with intravenous administration of
      corticosteroids and glycerin for 6 days after the injection. Although the
      intraocular pressure elevation caused by secondary acute angle-closure glaucoma
      decreased and ocular pain diminished, inexorable papilledema and exudative
      retinal detachment continued for 3 weeks. Finally, 6 weeks later, diffuse
      chorioretinal atrophy with optic atrophy occurred and the vision in his left eye
      was lost. CONCLUSION: When performing intracarotid injection of carboplatin, we
      must be aware of its potentially blinding ocular toxicity. It is recommended that
      further studies and investigations are undertaken in the effort to minimize such
      severe side effects.

PMID- 12483327
TI  - Cutaneous melanoma metastasizing to the iris and choroid: a case report.
AB  - BACKGROUND: Cutaneous melanoma is a primary tumour that rarely produces
      intraocular metastases. We report on a 47-year-old woman who was referred to our
      outpatient department because of anisocoria. METHODS: A cutaneous melanoma of the
      upper left arm had been excised 21 months ago with subsequent polychemotherapy
      for lymph node involvement. Visual acuity and intraocular tension were normal.
      The left iris showed a brownish, parapupillary, prominent nodule. In both eyes,
      multiple circumscribed whitish choroidal sub-pigment epithelial tumours were
      observed. RESULTS: General metastasis to lymph nodes, pleura, lungs, mucosa and
      skin was diagnosed. The patient died 2 months later. CONCLUSION: Metastases of
      cutaneous melanoma to the iris are extremely rare. The ophthalmologist may be
      helpful in monitoring treatment by quantitative documentation at follow-up.

PMID- 12483328
TI  - Frontal cephalometric analysis in the evaluation of facial asymmetry in
      torticollis, and outcomes of bipolar release in patients over 6 years of age.
AB  - BACKGROUND: The aim of this study was to investigate the mid-term results of
      bipolar release in congenital muscular torticollis patients over 6 years of age,
      and the efficacy of frontal cephalometric analysis in the determination and
      follow-up of facial asymmetry. METHODS: Twelve patients (9 boys, 3 girls) from 7
      to 12 years of age were included in the study. Bipolar release was performed,
      followed by 5-7 days of traction and 3 months of physiotherapy. Posteroanterior
      cephalometric radiography was performed at the beginning of and after therapy.
      The postural symmetry angle (PSA) was used to determine the presence and severity
      of facial asymmetry. A modified version of Lee et al.'s system was used in
      evaluating the results. RESULTS: The average follow-up period was 3 years and 5
      months. According to the congenital muscular torticollis evaluation system, the
      outcome was excellent in 2 of the patients, good in 6, fair in 2 and poor in 2.
      Asymmetry was not severe in all patients at the beginning of therapy according to
      PSA values, being insignificant in 2, mild in 6, and severe in 4. The PSA results
      of the last examination indicated that severe facial asymmetry persisted in 3
      patients. In 2 of them, PSA values remained within the limits of severe asymmetry
      despite a slight angular correction. DISCUSSION: Congenital muscular torticollis
      patients can benefit from surgical treatment over the age of 6 years. Bipolar
      release is an adequate and complication-free method. Moreover, PSA may be used as
      an objective method in the determination and follow-up of facial asymmetry in
      torticollis patients.

PMID- 12483329
TI  - Occurrence and treatment of nonunion in long bone fractures in children.
AB  - BACKGROUND: Because of favorable local biological factors, nonunion is rarely
      seen in long bone fractures in children, and there are few studies on pediatric
      nonunion in the literature. METHODS: Twenty-six children under 15 years of age
      diagnosed with long bone nonunion were examined, and 19 received treatment.
      Patients with pseudarthrosis due to tumors or congenital causes were excluded
      from the study. The following factors were assessed for each patient: age and
      sex; cause, location, and type of fracture; form of initial treatment; incidence
      of infection and type of bacteria produced; time between fracture and diagnosis;
      and type of nonunion. RESULTS: Twenty-two of the patients had fractures in the
      lower extremities, and 4 in the upper extremities. The femur was the most
      commonly affected bone (12 patients), followed by the tibia (10 patients). The
      average age of the patients was 9.6 years (range 1-15 years). The frequency of
      occurrence increased after the age of 6, and all patients but two were above this
      cutoff age. In each case, there was at least one factor contributing to nonunion,
      such as open reduction and insufficient fixation, open fracture, and infection.
      Of the 19 patients treated, 3 required reoperation. CONCLUSION: In our opinion,
      claims that pediatric nonunion is an extremely rare condition are exaggerated,
      and we do not agree that it is always due to an error in treatment. Nonunion does
      occur in children despite appropriate treatment, especially after the age of 6,
      and it may be resistant to therapy.

PMID- 12483330
TI  - Effects of steroids on femoral diaphyseal intramedullary circulation in rabbits.
AB  - We examined the effect of steroid treatment on the intraosseous femoral
      vasculature in rabbits, with particular emphasis on the morphologic changes in
      bone marrow sinusoids and central veins. Adult rabbits were divided into three
      treatment groups: group A, untreated control; group B, animals were treated with
      intramuscular injections of methylprednisolone acetate (4 mg/kg/week) for 4
      weeks; and group C, rabbits which received injections for 8 weeks. Examination of
      the intraosseous femoral vasculature was performed using microangiography,
      scanning electron micrography using a corrosion cast method, and retrograde
      venography. Bone marrow sinusoids of group C were dilated and the network of
      anastomosed vessels was irregular compared with those of group A. Changes in
      group B were intermediate between the control rabbits and group C. Retrograde
      venography of the central vein showed an irregular course and frequent narrowing
      of the signal. There were no arterial changes in the steroid-treated groups.
      These findings indicate that steroid therapy does not induce arterial ischemia
      but rather intraosseous venous stasis extending from bone marrow sinusoids to the
      central veins. These changes are attributable to bulging or dilatation of
      sinusoids, a rise in intraosseous pressure, and reduced blood flow.

PMID- 12483331
TI  - Scaphoid fracture in the young athlete--therapeutic outcome of internal fixation
      using the Herbert screw.
AB  - BACKGROUND: A fractured scaphoid is a common disabling injury occurring in
      contact sports. This study was designed to evaluate the therapeutic outcome of
      Herbert screw fixation for scaphoid fracture in young athletes. METHODS: Thirty
      athletes with 30 scaphoid fractures were treated. According to the Herbert
      classification, 10 were classified as acute fracture (group I), 6 as fibrous
      union (group II) and 14 as pseudoarthrosis (group III). Twenty scaphoid non
      unions were due to missed diagnosis or unsuccessful immobilisation. RESULTS: Bony
      union was evident at an average of 9.2, 8.0 and 11.9 weeks postoperatively in
      groups I, II and III, respectively, and times for returning to sports were 10.7,
      14.0 and 22.9 weeks. The clinical outcome assessed using the Mayo wrist score was
      excellent in groups I (97.5 points) and II (93.3) and good in group III (85.4).
      CONCLUSION: Early definitive diagnosis and treatment can allow early return to
      sports in young athletes. The Herbert screw technique produces an excellent
      clinical result for scaphoid fracture.

PMID- 12483332
TI  - Surgical treatment of resistant lateral epicondylitis. Follow-up study of 19
      patients after excision, release and repair of proximal common extensor tendon
      origin.
AB  - BACKGROUND: Lateral epicondylitis resistant to conservative treatment is a rare
      yet disabling condition. When diagnosed, it should be treated surgically. The
      appropriate surgical treatment relies on a precise diagnosis, usually based on
      physical examination. Exclusion of other pathologies in the lateral elbow area is
      essential. METHODS: We report on an outcome in a group of 19 consecutive patients
      treated by excision, release, reattachment and repair of the common extensor
      origin. These patients were followed clinically for at least 2 years. RESULTS:
      Eighteen patients reported recovery from pain and a satisfactory subjective
      gaining of strength in their forearm on average 3 and 4 months after the surgery,
      respectively. CONCLUSIONS: The presented treatment method is highly effective in
      the treatment of resistant lateral epicondylitis.

PMID- 12483333
TI  - Unchanged c-Fos expression after extracorporeal shock wave therapy: an
      experimental investigation in rats.
AB  - BACKGROUND: Despite the extensive use of extracorporeal shock wave therapy (ESWT)
      in the therapy of chronic tendopathies, the biological mechanisms of its
      antinociceptive effects are still unclear. METHODS: In this study we addressed
      the question of whether the clinically described, long-lasting effect of ESWT is
      mediated by changes in the activity of spinal cord neurones. As a marker for
      neuronal activity which is also able to interfere with the molecular expression
      pattern of neurones, the expression of the inducible transcription factor c-Fos
      was analysed in the animal model of the rat. Despite application of different
      energy levels, the analysis of c-Fos protein expression at an early (4 h) and
      late (72 h) time point after ESWT revealed no visible changes in immunoreactivity
      in the dorsal horn of the spinal cord. Additionally, there was no change in c-Fos
      protein and its gene expression c-Fos mRNA in the treatment area of the paw.
      RESULTS AND CONCLUSION: We conclude that ESWT with an energy flux dose up to 0.33
      mJ/mm(2)does not modify neuronal activity. Since the application of ESWT showed
      no significant changes in the immunoreactivity of c-Fos, it is therefore unlikely
      that ESWT triggers stimulation-produced analgesia via activation of peripheral
      nerves.

PMID- 12483334
TI  - Posterior transpedicular stabilisation of the infected spine.
AB  - BACKGROUND: Six men and seven women, aged 62 years, bedridden due to back pain
      from a septic spondylitis in the thoracolumbar region and not responding to
      conservative treatment, were operated on with transpedicular stabilisation of the
      affected segments to enhance mobilisation. All patients experienced immediately
      reduced back pain, allowing them to leave their bed and start mobilisation during
      the first postoperative day. At follow-up after a mean of 29 months (range 13-60
      months) only one was using analgesics. RESULTS: Nine of the 11 patients with
      pathological neurology at surgery had improved, none had deteriorated, and all
      were ambulatory without bladder or bowel disturbances. Seven had achieved a solid
      interbody fusion, with a continued radiographic decrease in the spondylitic
      change in the rest, indicating that a progressive interbody fusion was in
      progress. Three individuals had increased kyphosis, a mean of 11 deg compared
      with the postoperative radiographs.

PMID- 12483335
TI  - Spontaneous fusion of 'os acetabuli' after triple pelvic osteotomy.
AB  - In acetabular dysplasia, an overloading of the acetabular rim can cause a stress
      fracture, creating an 'os acetabuli', or a lesion of the acetabular labrum. At
      puberty, the os acetabuli seems to be the epiphysis of the os pubis. We present
      the case of a 14-year-old girl with acetabular dysplasia and spontaneous fusion
      of an 'os acetabuli' after biomechanical correction by triple pelvic osteotomy.
      Our report supports the correctness of the biomechanical principle: reorientation
      of the acetabulum results in a better coverage of the femoral head, reduces the
      stress at the acetabular rim, shifts the os acetabuli out of the stress region,
      and may allow union of the bony fragment with the acetabulum.

PMID- 12483336
TI  - Phalangeal metastasis secondary to an occult breast carcinoma.
AB  - We report a case of a silent, highly malignant tumour of the breast, which
      presented as an atraumatic deformity of the finger secondary to a phalangeal
      metastasis.

PMID- 12483337
TI  - Non-Hodgkin's lymphoma as an unexpected diagnosis in a hip arthroplasty.
AB  - Total hip replacement is routinely performed for osteoarthritis of the hip joint.
      We report a case of Non-Hodgkin's lymphoma as an unexpected diagnosis after
      routine pathological examination of the bone block harvested during total hip
      replacement in an asymptomatic patient. Although controversies exist regarding
      the cost effectiveness of routine specimen evaluation during total hip
      replacement, we suggest that histological analysis of any unusual-looking
      surgical tissues is appropriate and should be performed in all the patients who
      have suspicious surgical findings. To our knowledge, this is the first case of
      lymphoma detected during primary total hip replacement.

PMID- 12483338
TI  - Severe potential consequences of delayed diagnosis in patients with hip
      claudication.
AB  - Delayed diagnosis in patients with hip claudication can lead to severe
      consequences. We report on patients with ischaemic hip claudication which had
      primarily been attributed to coxarthrosis. One patient went through a variety of
      treatments including hip arthroplasty. The second patient had a life-threatening
      abdominal aortic aneurysm (AAA) which remained undiagnosed. Orthopaedic surgeons
      should maintain a high degree of suspicion for vascular disease. Moreover, we
      strongly advocate that all men over 60 years old who seek medical advice for
      whatever reason should be screened once for AAA by ultrasonography.

PMID- 12483339
TI  - Rheumatoid arthritis presenting as an invasive soft-tissue tumour.
AB  - BACKGROUND: We present two patients with advanced rheumatoid arthritis (RA) who
      were diagnosed as having malignant soft-tissue tumours on magnetic resonance
      scanning. They were tertiary referrals to a unit specialising in the management
      of soft-tissue sarcoma. CONCLUSIONS: Both of these tumours subsequently turned
      out to be benign complications of RA. In both of these cases, no mention was made
      on the initial radiological request form of the presence of RA. It is essential
      to give an adequate past medical history when requesting any radiological
      investigation.

PMID- 12483340
TI  - Medial peritalar dislocation.
AB  - In this paper, a case of closed medial subtalar dislocation and accompanying
      talar head fracture in a 22-year-old man which occurred while walking on a
      downhill road is reported. Closed reduction under general anesthesia was
      unsuccessful. The obstacle for closed reduction was determined at surgery for
      open reduction and internal fixation as buttonholing of the talar head through
      the extensor retinaculum. At the 26-month follow-up, he was pain-free in his
      daily activities.

PMID- 12483341
TI  - A rare case of Salmonella osteomyelitis in the humerus as a differential
      diagnosis to a malignant bone tumor.
AB  - Salmonella osteomyelitis without predisposing factors is seldom seen and thus
      difficult to diagnose. We report on a 14-year-old healthy boy with Salmonella
      osteomyelitis which occurred 2 years after trauma. Radical operative debridement
      is recommended. Intravenous ciprofloxacin has proved to be effective because of
      good tissue penetration and sensitivity towards Salmonella.

PMID- 12483342
TI  - Osteopetrosis, femoral fracture, and chronic osteomyelitis caused by
      Staphylococcus aureus small colony variants (SCV) treated by girdlestone
      resection--6-year follow-up.
AB  - Chronic osteomyelitis caused by Staphylococcus aureus small colony variants in
      combination with osteopetrosis is a unique combination of disorders that
      confronted us with major challenges. The therapeutic approach included four
      serial debridements and antimicrobial therapy. The aggressive treatment led to an
      instability of the brittle and hard osteopetrotic bone, and after 11 weeks, a
      fracture of the femoral neck occurred. A salvage procedure of the femur was
      performed, and the cultures obtained during this intervention remained negative.
      At a 6-year follow-up, the girdlestone situation still showed an acceptable
      functional outcome without any recurrence of osteomyelitis.

PMID- 12483343
TI  - Internal architecture of the proximal femur--Adam's or Adams' arch? Historical
      mystery.
AB  - The designation 'Adam Bogen' describing the thick medial cortex of the femoral
      neck is an incorrect term. This arch was described by Robert Adams (1795-1871),
      an outstanding Irish anatomist and surgeon. He was famous mainly for his book on
      gout and the description of disorders of cardiac rhythm, the so-called Adams
      Stokes syndrome. He published his original description in the today unfortunately
      almost forgotten Cyclopaedia of Anatomy and Physiology, Vol. II (London, Longman,
      1836-1839). The main editor of this monumental six-volume work was the famous
      anatomist and surgeon R.B.Todd. This book represents a significant source of
      information on diseases and injuries of the great joints (shoulder, elbow, wrist,
      knee, ankle).

PMID- 12483344
TI  - Device for accurately siting the acetabular component during total hip
      replacement.
AB  - INTRODUCTION: In this paper we describe a device which allows consistent
      acetabular cup placement to reduce post-arthroplasty dislocation. PATIENTS AND
      METHODS: The development of this surgical appliance is traced from the initial
      concept to the construction of a device suitable for clinical trials. The system
      of use is explained. The constraints imposed by the working environment and the
      methods employed to meet the demands imposed by surgical practice are elucidated.
      A clinical trial is described in which the device was used to assist in siting
      acetabular cup placement in ten patients. RESULTS: The accuracy of the ten cup
      placements done using the device was then compared by radiography with the
      accuracy of placement of 17 acetabular cups performed in the standard manner.
      Comparison of the results show a positive benefit arising from using the device.
      CONCLUSIONS: Our initial good results on cup positioning in laboratory studies
      are maintained in a clinical setting, but further modifications could lend to
      even better results.

PMID- 12483345
TI  - Transfemoral implantation of the Wagner SL stem. The abolition of subsidence and
      enhancement of osteotomy union rate using Dall-Miles cables.
AB  - BACKGROUND: The Wagner SL uncemented revision stem has been utilised successfully
      for revision hip surgery where marked loss of proximal bone stock co-exists or
      where there is a periprosthetic fracture. Implanted via the transfemoral
      approach, one significant difficulty appears to be a tendency for implant
      subsidence, which in some cases has been troublesome enough to necessitate early
      revision (usually to a larger prosthesis). METHODS: A change in our operative
      practice allowed us to review the effects of using either wire cerclages or 2.0
      mm Dall-Miles cables for prophylactic wiring of the distal femur. Seventeen
      Wagner SL stems, inserted via the transfemoral approach, were studied in 16
      patients. RESULTS: We found those patients prophylactically wired with Dall-Miles
      cables demonstrated no subsidence in comparison with those in whom heavy wire
      cerclage had been utilised (mean subsidence 6 mm; p=0.001). In addition, we found
      that closure of the proximal osteotomy with wires conferred a more reliable rate
      of union in comparison with those closed with heavy sutures. CONCLUSION: We
      recommend the use of Dall-Miles cables for distal cerclage and osteotomy closure
      for the Wagner prosthesis.

PMID- 12483347
TI  - Mild trigonocephaly with clinical symptoms.

PMID- 12483349
TI  - Clinical value of amplitude-coded colour Doppler sonography in paediatric
      neurosonography.
AB  - OBJECTIVE: The object of this study was to evaluate the potential of amplitude
      coded colour Doppler sonography (aCDS) in paediatric neurosonography from the
      aspects of clinical value and impact. PATIENTS AND METHODS: Sixty neonates,
      infants, and children underwent 72 aCDS investigations after conventional
      ultrasound (US) studies including conventional colour Doppler. Their diagnoses
      included tumours, hydrocephalus and cerebral fluid collections, cerebral vascular
      disorders, cerebral bleeds and hypoxic-ischaemic lesions. The results of aCDS
      were prospectively compared with the findings obtained with conventional US
      findings, with CT/MRI results when available (34 patients with 41
      investigations), with operative findings (7 patients), and with clinical,
      laboratory, EEG and follow-up results. RESULTS: Six patients showed normal
      findings. Fourteen cerebral bleeds were correctly recognised by both conventional
      US and aCDS; plexus haemorrhage was depicted only on aCDS in 4 additional
      neonates. In 4 of 6 patients with tumours and vascular malformations aCDS
      revealed additional information. aCDS improved early detection of focal ischaemic
      lesions in 10 of 13 cases and enabled Duplex sampling in 7 of 9 children with
      diffuse hypoxic brain injury. In 5 of 20 patients with hydrocephalus and/or fluid
      collections aCDS proved helpful (e.g. demonstration of liquor fistula), yielding
      a sensitivity of 93.75%, as against 43.75% for conventional US. CONCLUSION: aCDS
      is helpful in differentiating perfused structures such as a prominent ventricular
      plexus or tumours from structures without perfused vasculature, such as blood
      clots or ischaemic lesions. aCDS can be considered a valuable adjunct in the
      differential diagnosis of haemorrhage and ischaemic lesions as well as of
      vascular malformations and tumours.

PMID- 12483350
TI  - Hydatidosis of central nervous system and its coverings in the pediatric and
      adolescent age groups in Turkey during the last century: a critical review of 137
      cases.
AB  - INTRODUCTION: Hydatid disease is still a major problem in infested areas of the
      world, especially in the rural areas, including Turkey. OBJECTIVE: The objective
      of this review was to analyze the literature on the management of central nervous
      system (CNS) hydatidosis with an emphasis on their specificities in childhood and
      adolescence, with the aim of determining the clinical and neuroradiological
      findings and treatment modalities, medical or surgical, in these age groups.
      MATERIALS AND METHODS: To establish some guidelines for the diagnosis and
      treatment of this controversial condition, publications reported from Turkey in
      national ( n=33) and international ( n=55) journals during the last century and
      databases containing medical literature were used. Strikingly, the numbers of
      articles produced by Turkish authors on CNS hydatidosis have risen tremendously
      during the study period. Although a total of 272 cases of intracranial and
      intraspinal hydatid cysts were reported from Turkey, only 137 cases for which
      detailed information was available were selected for further analysis, in keeping
      with our inclusion and exclusion criteria. RESULTS AND DISCUSSION: Despite the
      inherent limitations, this type of study indicates that the incidence of
      hydatidosis has not decreased in Turkey in recent years. The clinical findings
      were mostly atypical, and it was interesting that 4 patients were described as
      having cerebrovascular occlusive disease and 3 as having symptoms of movement
      disorders. Computed tomography and/or MRI techniques were extremely useful, both
      in reaching the correct diagnosis and for proper surgical management of hydatid
      disease, because of the absence of a pathognomonic clinical picture of this
      disease. The treatment of choice for hydatid disease of the CNS and its coverings
      was complete intact removal of the cyst. In contrast to that in intracranial
      hydatid cysts, however, surgical intervention was palliative, not curative, in
      almost all cases of intraspinal hydatidosis. According to this critical review of
      the literature, CNS hydatidosis is therefore still a life-threatening condition,
      in spite of all the advances in imaging techniques and therapeutic methods. The
      most important factors in prognosis are the localization of the focus of
      infection, rupture and of the cyst and dissemination of its content, and
      treatment modality. At present, surgical intervention preceded by careful
      neuroradiological evaluation remains the best surgical therapy, and this plus
      adjuvant chemotherapy is advocated in some cases as the gold standard for
      therapy.

PMID- 12483351
TI  - Optic sheath schwannomas: report of two cases.
AB  - INTRODUCTION: Schwannomas are benign tumors that arise from Schwann cells in the
      peripheral nervous system. The vestibular division of the VIIIth cranial nerve is
      the nerve segment most commonly affected, the trigeminal nerve root being the
      next most frequently affected. Although schwannomas of other cranial nerves are
      very rare, these nerves do have myelinated sheaths composed of Schwann cells and
      are potential sites for intracranial schwannomas. However, previous studies have
      suggested that the term 'schwannoma' should not be applied in the case of optic
      nerve pathology, although two cases of optic nerve sheath schwannoma have been
      reported to our knowledge. PURPOSE: The purpose of this paper is to report two
      cases of the exceedingly rare entity of optic sheath schwannoma and to discuss
      its histopathogenesis.

PMID- 12483352
TI  - Dendritic architecture of corticothalamic neurons in a rat model of microgyria.
AB  - MATERIALS AND METHODS: Freezing lesions of the sensorimotor cortex resembling
      focal human microgyria were carried out in newborn rats on first postnatal day
      (P1). The fine architecture of dendritic trees of corticothalamic neurons was
      studied in microgyric animals on P90. RESULTS AND DISCUSSION: Compared with
      controls, layer 5 corticothalamic neurons located in the cortex surrounding the
      experimental lesion display longer basal dendrites. This finding is discussed
      with reference to earlier results on dendrites of layer 3 associative neurons,
      which, in contrast to those of corticothalamic neurons, appear to be markedly
      simplified.

PMID- 12483353
TI  - Temporal and spatial patterns of glial differentiation in the surgically induced
      spinal open neural tube defect of chick embryos: astrocytic, radial glial and
      microglial differentiations.
AB  - INTRODUCTION: There are controversies over the pattern of glial differentiation
      in spinal open neural tube defect (ONTD) at the prenatal stage. A surgical model
      of ONTD allows a more precise comparison of glial differentiation between the
      ONTD and control groups than chemical and genetic models. MATERIALS AND METHODS:
      To investigate the influence of ONTDs on the patterns of glial differentiation,
      ONTDs were induced by surgery using Hamburger and Hamilton stage 18 or 19 chick
      embryos. The spinal cord tissues on postoperative days (POD) 5, 7, 10, and 14
      were processed to observe astrocytic, radial glial, and microglial
      differentiations by glial fibrillary acid protein (GFAP), vimentin and ricinus
      communis agglutinin-I (RCA-I) stainings, respectively. Four embryos were assigned
      to subgroups of each POD. Control embryos ( n=4) were staged but the neural tubes
      were not incised. RESULTS: In the control group, GFAP positivity was shown
      faintly at the dorsal midline on embryonic day (E) 10 (corresponding to POD 7),
      in the ventral one-third of the white matter on E 13 and in the whole white
      matter on E 17. Embryos with ONTDs showed earlier and stronger GFAP positivity
      from POD 7-14, especially at the dorsal surface and the adjacent gray matter. In
      the control group, vimentin staining demonstrated a positive reaction at the
      midline with positivity in a faint, radial pattern on E 8 and E 10. This had all
      disappeared by E 13 and 17. In embryos with ONTDs, vimentin positivity was
      enhanced and persisted from POD 5-14. These findings were prominent along the
      dorsal surface of ONTDs. No difference in RCA-I staining was found between the
      control and ONTD groups. CONCLUSION: The results reveal that ONTD promotes
      astrocytic differentiation and prolongs expression of radial glial fibers, which
      seems to be a reaction to the damage caused by exposure of the spinal cord tissue
      to amniotic fluid.

PMID- 12483354
TI  - Postshunt insertion CSF leaks in infants treated by an adjustable valve opening
      pressure reduction.
AB  - OBJECTS: Cerebrospinal fluid (CSF) leakages through the operation wound following
      shunt placement are commonly treated by head elevation when the shunt is patent
      and signs of infection are absent. METHODS AND RESULTS: In two cases in which the
      standard therapy of head elevation failed, the leakage was successfully managed
      by temporary lowering of the opening pressure of the implanted programmable
      valve. Case 1 was that of a preterm baby with repaired meningomyelocele and
      shunted hydrocephalus. A shunt infection made shunt removal necessary. Five days
      after insertion of a new ventriculoperitoneal shunt, transcutaneous CSF flow
      occurred. The CSF leak was cured by a temporary reduction of the opening pressure
      from 70 to 30 mm H(2)0. Case 2 was in a 9-month-old child with shunted
      posthaemorrhagic hydrocephalus. Shunt infection was treated by shunt removal,
      placement of external ventricular drainage, and antibiotics. CSF leakage through
      the operation wound developed 24 h after placement of the new
      ventriculoperitoneal shunt. The CSF leakage was successfully treated by
      temporarily lowering the opening pressure of the valve from 100 to 50 mm H(2)0.
      CONCLUSION: The authors assume that head elevation alone did not generate a
      sufficient difference between the ventricular and the abdominal pressure for the
      selected opening pressure of the valve to be exceeded, with the result that CSF
      flowed around the ventricular catheter and through the operation wound. It is
      believed that reduction of the opening pressure of the valve led to CSF flow
      through the shunt and made siphoning possible, resulting in cessation of the
      transcutaneous CSF flow. The authors propose the prophylactic implantation of a
      programmable valve in children at high risk of postoperative transcutaneous CSF
      leakage.

PMID- 12483355
TI  - True 3D reconstruction for planning of surgery on malformed skulls.
AB  - OBJECTIVES: Since the difficulty associated with surgical planning of
      craniosynostosis is mostly due to the inadequate possibilities for simulation of
      surgery, a new technique for constructing a precise reproduction of a patient's
      malformed skull has been developed. MATERIALS AND METHODS: CT scans of ten
      malformed skulls on a scale of 1:1 and with 1-mm slices have been used to
      reconstruct the skulls in a special resin using a special lathe used in the
      automobile construction industry for formula one engines. This lathe works in the
      opposite way to other lathes: by apposition of material instead of subtraction.
      RESULTS: The anatomical detail of the phantom is of a very high degree. The
      surgical planning it allows has proved highly consistent with reality in all
      cases in which it has been used in the planning before the operation. DISCUSSION
      AND CONCLUSIONS: This technique has made it possible to plan the surgical
      treatment of all patients with craniosynostosis in a highly satisfactory way. It
      has reduced operating times, in addition to which it provides information on
      materials needed, avoiding waste, and is also an excellent teaching method for
      residents.

PMID- 12483356
TI  - A case of I-cell disease (mucolipidosis II) presenting with craniosynostosis.
AB  - CASE REPORT: In this paper, a patient with mucolipidosis II (I-cell disease) is
      described. The initial findings were microcephaly and metopic craniosynostosis.
      He had coarse facial features and dysostosis multiplex. The first child in his
      family had died with severe bone pathology at 5 months of age. CONCLUSION: The
      case is presented to emphasize that craniosynostosis may be the first symptom in
      mucolipidosis II.

PMID- 12483357
TI  - Chronic epidural hematoma with rapid ossification.
AB  - CASE REPORT: The authors present a rare case of ossified chronic epidural
      hematoma. A 13-year-old female patient presented with an ossified chronic
      epidural hematoma. She had sustained a head injury about 10 weeks previously and
      had received conservative care for a delayed-onset epidural hematoma at a local
      hospital. Ossification was identified about 4 weeks after the head injury and
      then progressed rapidly. A chronic epidural hematoma with a thick collagenous
      capsule and newly formed bone was removed 73 days after the head injury.
      CONCLUSION: An epidural hematoma with mild symptoms can be treated
      conservatively. When, however, the hematoma is observed not to be naturally
      absorbed during serial follow-up examinations, surgical removal must be
      considered, even if the patient's condition is good, because this entity carries
      the risk of bone calcification and ossification.

PMID- 12483358
TI  - Successful management of a symptomatic fusiform dilatation of the internal
      carotid artery following surgery of childhood craniopharyngioma.
AB  - INTRODUCTION: The development of fusiform dilatation of internal carotid artery
      is one of the vascular complications that can follow surgery for
      craniopharyngioma and other suprasellar tumours in children, but its pathogenesis
      and the line of management are still controversial. CASE REPORT AND DISCUSSION:
      We report a child who presented with a giant fusiform aneurysm involving the
      supraclinoid portion of the internal carotid artery after total removal of a
      craniopharyngioma and review the literature on related cases. The treatment of
      this phenomenon and its possible pathogenesis are discussed.

PMID- 12483359
TI  - The reversible focal MRI abnormalities in complex partial seizure: technical
      instruction.
AB  - CASE REPORT: A 17-month-old infant girl was admitted with complex partial
      seizures and right side hemiparesis. Five days after the last seizure, MR signal
      changes were observed in the left hemisphere with a cavernous hemangioma in the
      middle temporal gyrus. However, these MR signal changes had normalized 11 days
      after the last seizure, except for the cavernous hemangioma. The scalp EEG
      findings revealed that the epileptic focus was on the mid-temporal gyrus. The
      patient underwent lesionectomy only. Two months after this operation the MR
      showed no signal abnormality. Throughout a 12-month follow-up after surgery the
      patient remained seizure free. DISCUSSION: MR signal changes in seizure patients
      do not always indicate the structural region concerned, but can be transient
      signal changes. They may be due to the propagation of epileptic discharge along
      the association fiber from the seizure focus. However, transient signal changes
      after seizure must be followed up to allow exclusion of a tumor and other
      diseases.

PMID- 12483360
TI  - Spinal extradural angiolipoma, with a literature review.
AB  - INTRODUCTION: Angiolipoma is a benign tumour composed of mature adipocytes
      admixed with abnormal vascular elements. It reportedly accounts for 0.1-0.5% of
      all spinal axis tumours in adults and is extremely rare in children. CASE REPORT:
      This article describes a case of thoracic spinal angiolipoma in a 4-year-old boy,
      who presented with back pain and weakness. The tumour was excised, and the child
      made a remarkable recovery. DISCUSSION: Only five previous cases of extradural
      angiolipoma have been reported in children. The authors review the existing
      literature on the aetiology, pathogenesis, and clinical pathology, and the
      surgical management is discussed.

PMID- 12483361
TI  - Massive subdural haematomas in Menkes disease mimicking shaken baby syndrome.
AB  - INTRODUCTION: Menkes disease is an X-linked inherited disorder of intestinal
      copper absorption resulting in copper deficiency. Cardinal features include hair
      abnormalities, facial dysmorphism, severe neurological impairment, hypothermia,
      arterial anomalies, bone abnormalities and a fatal outcome. CASE REPORT: We
      present a case of Menkes disease complicated by progressive macrocephaly
      following the development of massive subdural haematomas. These lesions
      associated with femoral metaphyseal spurs could be confused with nonaccidental
      injury such as that seen in the shaken baby syndrome. DISCUSSION: This case
      emphasises that Menkes disease, like glutaric aciduria type 1, should be included
      in the differential diagnosis of unexplained subdural haematomas and neurological
      deficits in infants.

PMID- 12483362
TI  - Hypothalamic lipoma adjacent to mamillary bodies.
AB  - INTRODUCTION: Intracranial lipomas are rare lesions of developmental origin. They
      are generally asymptomatic and localized in the midline. However, they may
      occasionally produce neurological symptoms such as seizures. Surgical treatment
      is rarely indicated. CASE REPORT: We report a child with a lipoma that is located
      on the ventral side of the mamillary bodies. The diagnosis was made using
      computerized tomography (CT) and magnetic resonance imaging (MRI). There have
      been no previous reports of lipomas in this location.

PMID- 12483363
TI  - Mastocytosis: current concepts in diagnosis and treatment.
AB  - Mastocytosis consists of a group of disorders characterized by a pathologic
      increase in mast cells in tissues including skin, bone marrow, liver, spleen, and
      lymph nodes. Mastocytosis is a rare disease. Because of this, general
      practitioners have limited exposure to its clinical manifestations, diagnosis,
      classification, and management. Diagnosis of mastocytosis is suspected on
      clinical grounds and is established by histopathologic examination of involved
      tissues such as skin and bone marrow. The most common clinical sign of
      mastocytosis is the presence of typical skin lesions of urticaria pigmentosa.
      Most patients experience symptoms related to mast cell mediator release, and
      prevention of the effects of these mediators on tissues constitutes the major
      therapeutic goal in the management of mastocytosis. Despite recent advances in
      knowledge about the pathophysiology, diagnosis, and classification of
      mastocytosis, a curative treatment for mastocytosis does not now exist.
      Management of patients within all categories of mastocytosis includes: (1) a
      careful counseling of patients (parents in pediatric cases) and care providers,
      (2) avoidance of factors triggering acute mediator release, (3) treatment of
      acute mast cell mediator release, (4) treatment of chronic mast cell mediator
      release, and if indicated (5) an attempt to treat organ infiltration by mast
      cells. The goal of this manuscript is to provide an overview of the mediators
      produced and released by mast cells, the diagnostic criteria for the different
      variants of mastocytosis, and the treatment options currently available.

PMID- 12483364
TI  - Bilateral adrenal swelling as a cause of chest, back, and upper abdominal pain in
      essential thrombocythemia and polycythemia vera is due to microvascular ischemic
      thrombosis rather than to hemorrhage.
AB  - Bilateral massive adrenal swelling (BAS) on computed tomography (CT) scan with no
      enhancement after injection of intravenous contrast media has been observed in
      two completely different clinical settings. On the one hand, BAS is the result of
      ischemic necrosis and subsequent hemorrhagic infarction in patients with sepsis
      and hypotension in critically ill situations. On the other hand, BAS is the
      result of microvascular thrombosis, ischemia, and secondary inflammatory swelling
      in the setting of thrombotic conditions such as antiphospholipid syndrome (APS),
      heparin-induced thrombocytopenia and thrombosis (HITT), and thrombocythemia. In
      this study we present evidence that the etiology of unilateral or BAS in reported
      cases of essential thrombocythemia (ET) and polycythemia vera (PV) is similar to
      the etiology of microvascular circulation disturbances in thrombocythemia caused
      by platelet-mediated inflammation and thrombosis in the peripheral, cerebral,
      and/or coronary endarterial microvascular circulation.

PMID- 12483365
TI  - In vitro response of myelodysplastic megakaryocytopoiesis to megakaryocyte growth
      and development factor (MGDF).
AB  - To evaluate a potential therapeutic role for megakaryocyte growth and development
      factor (MGDF) in myelodysplastic syndromes (MDS) we compared the in vitro
      response of normal and myelodysplastic megakaryopoiesis to MGDF on bone marrow
      mononuclear cells from nine MDS patients and four healthy donors in a short term
      liquid culture system. The cells were incubated with MGDF alone (1 ng/ml, 10
      ng/ml and 100 ng/ml) and in combination with 20 ng/ml stem cell factor, 2 U/ml
      erythropoietin (EPO) and 100 ng/ml interleukin-3 (IL-3). Cytospins were prepared
      after 4 days and 10 days for CD61 APAAP staining. In addition, the ploidy of
      propidium iodide stained CD61 positive cells were detected by flow cytometry. The
      CD61+ cell number significantly increased (13-fold after 4 days, 56-fold after 10
      days of culture) when MGDF (100 ng/ml) was added to the normal bone marrow (NBM)
      cultures (P=0.0003; P=0.0001). In the MDS cultures the absolute number of
      endomitotic cells as well as the percentage of polyploid cells remained
      significantly lower than in NBM after 10 days (P=0.0001). The effect of MGDF on
      polyploidization of MDS cells was significantly dose dependent (P=0.0051). We
      found no correlation between peripheral platelet count, cellularity of the bone
      marrow, number of bone marrow megakaryocytes or FAB-subtype and response to MGDF.
      Additional administration of IL-3 resulted in a left-shift of megakaryopoiesis in
      both groups. Even though the response of myelodysplastic megakaryocytic
      progenitors to MGDF shows inter-individual variations, it is significantly
      impaired overall. Our data suggest that higher doses of MGDF may be able to
      ameliorate thrombocytopenia in a subgroup of MDS patients.

PMID- 12483366
TI  - Filgrastim mobilization and collection of allogeneic blood progenitor cells from
      adult family donors: first interim report of a prospective German multicenter
      study.
AB  - Recombinant human granulocyte colony-stimulating factor (rhG-CSF) mobilized
      peripheral blood progenitor cells (PBPCs) from healthy individuals are a rapidly
      emerging alternative source to bone marrow for allogeneic transplantation.
      Although widely applied in the meantime, only limited information on feasibility
      and safety of mobilization and collection of PBPCs is currently available from
      prospective multicenter studies specifically designed to investigate this
      donation modality. This ongoing multicenter study on the performance as well as
      the short- and long-term safety profile of rhG-CSF-induced mobilization and
      collection of PBPCs was initiated in October 1999. The study is designed to
      recruit a total of 300 healthy family donors who will be followed regularly for a
      period of 5 years after donation. The first interim report presented here
      summarizes results obtained after enrollment of 150 donors from nine German
      institutions. The study protocol allowed the individual choice between two dose
      regimens of rh-CSF (10 micro g/kg per day vs 2x8 micro g/kg per day of donor body
      weight). The primary endpoint was defined as a yield of > or =5x10(6) CD34(+)
      cells/kg of recipient body weight in a single leukapheresis product. This
      endpoint was attained by 50% of donors receiving the lower rhG-CSF dose regimen
      and by 75% of donors with the higher dose regimen ( p<0.0009). A total of 478
      acute adverse events attributable to the mobilization procedure were recorded and
      manifested predominantly as transient bone pain and headaches (80%). No
      persistent hematologic or nonhematologic adverse events have occurred in this
      study so far. Thus, the current experience in a prospective multicenter study
      supports previous single-center and retrospective registry reports in that the
      collection of PBPCs after rhG-CSF mobilization is feasible and associated with
      frequent, but generally mild and acceptable side effects.

PMID- 12483367
TI  - Prognostic factors influencing feasibility of cytogenetic and molecular analysis
      in leukapheresis products in chronic myelogenous leukemia patients.
AB  - Conventional cytogenetic (CC) study and molecular analysis were performed in 150
      leukapheresis products from 36 patients diagnosed with chronic myelogenous
      leukemia who were included in an autologous stem cell transplantation program.
      The aims of the study were to evaluate the effectiveness of these two methods for
      the detection of residual disease in the harvest and to identify the factors
      influencing the number of cycling cells present in the apheresis products.
      Progenitor cell mobilization procedures performed late after diagnosis (>12
      months), a short interval between interferon-alpha discontinuation and
      mobilization (<3.5 months), and an intensive mobilization regimen (idarubicin,
      cytarabine, and etoposide, ICE protocol) were associated with a low probability
      of obtaining 25 metaphases, which was achieved in only 41 instances (25% of the
      samples). In 38 samples, less than ten metaphases were obtained; a peripheral
      blood leukocyte count <1.0x10(9)/l at mobilization and mononuclear cell counts in
      the bag <0.5x10(8)/kg significantly increased the probability to obtain less than
      ten metaphases for CC analysis. Previous interferon-alpha treatment during > or
      =12 months and low mononuclear cell counts in the bag (<0.5x10(8)/kg) increased
      the probability of not obtaining mitosis for cytogenetic analysis. Molecular
      analysis by the polymerase chain reaction (PCR) technique did not give
      discriminate information in the samples not evaluable by cytogenetics due to the
      high frequency of PCR-positive results. We conclude that new techniques such as
      hypermetaphase fluorescence in situ hybridization (FISH), interphase FISH, or
      quantitative PCR need to be routinely employed in the study of leukapheresis
      samples of chronic myelogenous leukemia patients for a better assessment of the
      neoplastic contamination of the infused products.

PMID- 12483368
TI  - Influence of amifostine on reconstitution of lymphocyte subpopulations after
      conventional- and high-dose chemotherapy in patients with germ cell tumor.
AB  - We assessed the influence of amifostine on immune reconstitution after
      conventional-dose paclitaxel, ifosfamide, cisplatin and high-dose carboplatin,
      etoposide and thiotepa followed by autologous peripheral blood progenitor cell
      (PBPC) rescue in patients with germ cell tumor (GCT). A total of 40 patients were
      treated with one cycle of paclitaxel and ifosfamide (TI) followed by granulocyte
      colony stimulating factor (G-CSF) to mobilize PBPC, three cycles of paclitaxel,
      ifosfamide and cisplatin (TIP) and one course of high-dose carboplatin, etoposide
      and thiotepa (CET) plus PBPC rescue. Patients were randomized to receive an
      absolute dose of 500 mg amifostine (group A, n=20) on each day of chemotherapy or
      no amifostine (group B, n=20). Prior to each cycle of chemotherapy, after
      hematologic engraftment from CET, 6 weeks and 3 months after transplantation the
      subpopulations of lymphocytes were phenotyped. Between the two study groups no
      statistically significant differences were observed concerning reconstitution of
      lymphocyte subpopulations. Throughout treatment with TIP or CET lymphocyte counts
      and their subpopulations remained low without severe clinical complications.
      Delayed reconstitution of the CD4(+) cell compartment after PBPC rescue was
      observed in both study groups, but did not result in any severe or atypical
      infections. Treatment with amifostine administered at this dose did not
      significantly influence the reconstitution of lymphocyte subpopulations. Low
      numbers of lymphocytes during chemotherapy and delayed reconstitution of CD4(+)
      cells and other lymphocyte subpopulations after PBPC rescue had no clinical
      relevance for patients with GCT.

PMID- 12483369
TI  - Myelodysplastic syndrome complicated by autoimmune hemolytic anemia: remission of
      refractory anemia following mycophenolate mofetil.
AB  - Autoimmune hemolytic anemia (AIHA) rarely occurs in myelodysplastic syndrome
      (MDS). A 36-year-old Asian female was diagnosed with MDS (refractory cytopenia
      with multilineage dysplasia, RCMD) and complicated by AIHA 7 months later.
      Secondary myelofibrosis developed at the same time. Steroid therapy was
      ineffective and cyclosporin A (CsA) was discontinued due to its neurotoxicity
      with the development of leukoencephalopathy. However, the patient achieved a good
      hematological response after the use of mycophenolate mofetil (MMF, CellCept)
      with a dose of 1 g/day and prednisolone (15 mg/day). Prednisolone was tapered off
      over the next 3 weeks. The patient did not require any blood support 4 weeks
      after the use of MMF and has been hematologically stable for 4 months. To our
      knowledge, this is the first report of using MMF in treating MDS complicated by
      AIHA. MMF might be considered as a salvage therapy for patients with refractory
      anemia complicated by AIHA.

PMID- 12483370
TI  - Exacerbation of antiphospholipid antibody syndrome after treatment of localized
      cancer: a report of two cases.
AB  - Patients with malignancy often present with a variety of coagulation
      abnormalities which may ultimately lead to recurrent arterial and venous
      thromboses. Recently the presence of antiphospholipid antibodies in cancer
      patients has been proposed as one of the potential mechanisms promoting
      hypercoagulability. Here we report two consecutive patients with localized
      tumors, one suffering from breast cancer and another presenting with colorectal
      cancer, who experienced dramatic exacerbation of the antiphospholipid antibody
      syndrome (APAS) within 4 weeks after surgery. In the first patient who had also
      received one course of adjuvant chemotherapy, major ischemic stroke and recurrent
      venous thromboembolism were paralleled by the development of ulcerative livedoid
      vasculitis and pancytopenia, constituting the diagnosis of systemic lupus
      erythematosus with secondary APAS. In the second patient, progressive thrombotic
      occlusion of the superior and inferior vena cava was associated with bilateral
      pulmonary embolism, acute renal failure, and disabling soft tissue edema.
      Although not fulfilling the classic criteria of "catastrophic" APAS, the clinical
      features were life threatening and appeared to be refractory to oral
      anticoagulation with phenprocoumon. In addition, a diagnosis of Trousseau's
      syndrome was unlikely due to missing evidence of gross metastatic disease.
      Besides a suggested treatment strategy comprising high doses of low-molecular
      weight heparin, potential pathogenic mechanisms are discussed in consideration of
      a recently proposed "thrombotic storm," which may cause multiple thromboses after
      an initial provocation in patients with known hypercoagulability.

PMID- 12483372
TI  - Rituximab: a useful drug for a repeatedly relapsed hairy cell leukemia patient.
AB  - We describe a case of complete response in a patient with hairy cell leukemia,
      relapsed after treatment with interferon-alpha, 2'-deoxycoformicin, and 2
      chlorodeoxyadenosine, and then successfully treated with rituximab. A fourfold
      reduction of leukemic cells was observed concomitantly with restoration of normal
      blood count and differential.

PMID- 12483371
TI  - Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) associated with
      antiphospholipid syndrome: case report and literature review.
AB  - Histiocytic necrotizing lymphadenitis (HNL), or Kikuchi-Fujimoto disease, is a
      benign, self-limited disease that predominantly occurs in women. The etiology
      remains undetermined, although a viral or autoimmune hypothesis has been
      suggested. The disease usually emerges with cervical lymphadenopathy with or
      without fever. The diagnosis can be confirmed only by histological findings of
      lymph node biopsy, characterized by necrosis and histiocytic infiltration without
      neutrophils. We report a case of a 28-year-old woman with a medical history of
      two episodes of unexplained pulmonary embolisms (3 and 2 years previously) who
      was admitted to our hospital because of unilateral cervical lymphadenopathy and
      mild fever that presented 1 week before admission. A diagnosis of HNL was
      performed by lymph node biopsy. In parallel, whereas the laboratory tests for
      inherited thrombophilia were negative, a progressive elevated titer of anti
      beta(2) glycoprotein I (GPI) antibodies was established. Because of persistent
      fever, the patient received a short course of corticosteroid therapy and she
      recovered completely from the HNL after 2 months. It is noteworthy that to date
      the patient has displayed an elevated titer of anti-beta(2) GPI antibodies (18
      months after the recovery from the HNL). Thus, considering the previous history
      of venous thrombosis and the presence of antiphospholipid antibodies, the
      diagnosis of primary antiphospholipid syndrome associated with HNL was made. To
      our knowledge, this is the first report in the literature describing
      antiphospholipid syndrome associated with HNL. Moreover, a brief literature
      review is provided with emphasis on the etiology, clinical course, and
      pathogenesis of this rare disease entity.

PMID- 12483373
TI  - Successful treatment of advanced peripheral T-cell lymphoma with an angiocentric
      growth pattern complicated with hemophagocytic syndrome by high-dose chemotherapy
      and autologous peripheral blood stem cell transplantation.
AB  - Peripheral T-cell lymphomas (PTCL) account for about 10% of all lymphomas in
      Western countries, respond poorly to therapy, and have short survival with no
      sustained remission. Furthermore, the complication of hemophagocytic syndrome
      (HPS) sometimes makes the prognosis of this disease extremely worse. We report
      here a case of PTCL with an angiocentric growth pattern complicated with HPS
      successfully treated by high-dose chemotherapy and autologous peripheral blood
      stem cell transplantation. Our case suggests this approach is an excellent
      candidate for the treatment of this disease.

PMID- 12483374
TI  - Intragastric metastasis in a patient with gastric cancer: unusual CT
      manifestation.
AB  - We describe computed tomographic findings of intragastric metastasis in a patient
      with gastric cancer. On computed tomography, the intragastric metastatic lesion
      appeared as an exophytically growing cystic masss with minimal thickening of the
      adjacent gastric wall, thus mimicking an exophytically growing submucosal tumor
      or adenocarcinoma.

PMID- 12483375
TI  - Proximal gastrectomy and jejunal pouch interposition: radiographic evaluation of
      postoperative findings.
AB  - BACKGROUND: We assessed the postoperative findings of proximal gastrectomy and
      jejunal pouch interposition with contrast radiography. METHODS: Eleven patients
      with proximal gastrectomy and jejunal pouch interposition for proximal gastric
      carcinoma underwent contrast radiography. We evaluated the radiographic findings
      of the remnant stomach and interposed jejunal pouch. RESULTS: The interposed
      jejunal pouch showed good expansion, and the motility of the remnant gastric
      antrum was normal in all patients. One patient had significant lumenal narrowing
      of the esophageal pouch anastomotic site. Leak at the anastomotic site was not
      found. Reflux into the esophagus from the pouch was observed in two patients.
      Gastric emptying time was considerably delayed in two patients. CONCLUSION:
      Follow-up upper gastrointestinal series of the proximal gastrectomy and jejunal
      pouch interposition showed different postoperative findings. Awareness of the
      normal and abnormal findings is essential in the accurate postoperative
      evaluation of these patients.

PMID- 12483376
TI  - Idiopathic enteroenteric intussusceptions in adults.
AB  - BACKGROUND: Intestinal intussusception is infrequent in the adult, especially in
      the idiopathic and transitory forms. METHODS: We reviewed the medical records and
      imaging of four patients with seven idiopathic and transitory intestinal
      intussusceptions discovered in the course of barium meal and small bowel follow
      through radiologic studies carried out for nonspecific abdominal pain. RESULTS:
      The patients had nonobstructive intestinal intussusception, with no demonstrable
      underlying cause. Some intussusceptions were resolved by applying pressure to
      separate the pathologic intestinal loop. No complications associated with the
      intussusceptions were found during subsequent follow-up. CONCLUSION: There are
      cases of idiopathic nonobstructive intestinal intussusception in the adult, with
      few or no clinical repercussions that require aggressive medical intervention.

PMID- 12483377
TI  - Completely isolated enteric duplication cyst: case report.
AB  - We present a case of a completely isolated enteric duplication cyst in a 28-year
      old man. Computed tomography showed a large complex cystic mass with curvilinear
      and nodular calcifications near the anterior aspect of the left kidney. It had no
      connection to the pancreas, stomach, small bowel, or large bowel. We found no
      report describing computed tomographic findings of completely isolated enteric
      duplication cyst in the English-language literature.

PMID- 12483378
TI  - Appendiceal mucocele: sonographic findings.
AB  - BACKGROUND: Appendiceal mucocele (AM) is a relatively rare disease, and its
      sonograms (US) have not been sufficiently analyzed. METHODS: We studied the US
      findings of five patients with AM, with special attention to AM size, shape,
      internal echoes, and the mode of back echoes. RESULTS: All five cases showed an
      elongated mass in the lower right abdomen. Internal echoes were present in all
      cases and M-mode US confirmed the movement of those echoes. The echogenecity of
      the lesion changed according to the frequency of the transducer used. Only one
      case showed posterior echo enhancement, and no case showed lateral shadowing.
      CONCLUSION: AM appears as an elongated echo-poor mass without posterior echo
      enhancement. The cyst wall is less distinct than what one would expect for a
      cyst. When encountering such a mass in the lower right abdomen, one should
      strongly suspect an AM. In such cases, appropriate diagnostic and therapeutic
      strategies are especially necessary to prevent rupture that results in
      development of pseudomyxoma peritonei.

PMID- 12483379
TI  - Gadolinium-enhanced MRI with dynamic evaluation in diagnosing the local
      recurrence of rectal cancer.
AB  - BACKGROUND: At early stages, the diagnosis of local recurrence of rectal cancer
      is often difficult and magnetic resonance imaging (MRI) is currently considered
      the most accurate method for diagnosing recurrence. We evaluated the role of
      unhenhanced and gadolinium-enhanced MRI for the diagnosis of local recurrence of
      rectal cancer. METHODS: Thirty-six patients, suspected of having a pelvic
      recurrence of rectal cancer, were evaluated by a high field strength MRI unit.
      Unenhanced spin-echo T1- and T2-weighted sequences and gadolinium-enhanced
      dynamic fast multiplanar spoiled gradient recalled sequences were performed in
      all patients. The dynamic images were re-elaborated with semiquantitative
      postprocessing by plotting intensity-time curves and calculating the percentage
      of signal increase at the end of the first postcontrast dynamic sequence. The
      pelvic lesions were classified as recurrent or not recurrent by applying the
      following diagnostic criteria: (a) morphology and signal intensity of the lesion
      in unenhanced sequences and (b) percentage of enhancement in dynamic enhanced
      sequences. Diagnosis was confirmed by computed tomography-guided needle biopsy
      (12 patients), surgery (four patients), clinical and imaging follow-up (20
      patients). RESULTS: The diagnosis was local recurrence in 15 patients and
      noncancerous lesions in 21 patients. Unenhanced MRI had 80% sensitivity and 86%
      specificity. Analysis of the percentage of enhancement showed 87% sensitivity and
      100% specificity. CONCLUSION: In agreement with the literature, our results
      showed a high sensitivity and specificity for dynamic MRI. This technique thus
      can be considered an important adjunct to unenhanced MRI, especially in selected
      cases in which unenhanced MRI cannot rule out local recurrences. However, these
      results must be validated by further investigations.

PMID- 12483380
TI  - MR rectography evaluation of rectoceles with oral gadopentetate dimeglumine and
      polyethylene glycol solution.
AB  - BACKGROUND: We assessed the value of magnetic resonance (MR) rectography in
      diagnosing rectocele by using a combination of oral gadopentetate dimeglumine and
      polyethylene glycol solutions. METHODS: T1-weighted, breath-hold, fast low-angle
      shot sequences were made in 22 patients in resting and straining states in the
      supine position before and after administration of oral paramagnetic contrast.
      Twelve patients received polyethylene glycol solution in addition to contrast,
      and 10 received contrast only. The pubococcygeal line was the reference used for
      diagnostic measurements. The quality of each sequence was graded. Paired t test,
      chi-square test, and the Kolmogorov-Smirnov test were applied for statistical
      analysis. RESULTS: The results of noncontrast images were inconclusive. There was
      a statistically significant difference between MR imaging diagnosis of rectocele
      in patients in the straining position without and with contrast ( p < 0.05), and
      the difference was more prominent in patients using polyethylene glycol solution
      ( p < 0.001). Using oral contrast plus polyethylene glycol produced significantly
      better MR examinations in the resting and straining positions ( p < 0.05).
      CONCLUSION: The combination of oral contrast and polyethylene glycol solution
      improves the diagnostic value of MR rectography and is particularly useful when
      noncontrast examinations are inconclusive.

PMID- 12483381
TI  - Embolization of visceral pseudoaneurysms with platinum coils and N-butyl
      cyanoacrylate.
AB  - BACKGROUND: We evaluated the efficacy of transcatheter embolization in visceral
      artery pseudoaneurysms with platinum coils and N-butyl-cyano-acrylate (NBCA).
      METHODS: Over the past 7 years, 20 patients were treated by transcatheter
      embolization in the same sitting with diagnostic angiography. Four right hepatic,
      one cystic, two gastroduodenal, one cavernosal artery, three superior mesenteric
      artery branch, and 11 renal artery branch pseudoaneurysms were included in the
      study. RESULTS: Surgery was completely avoided in 19 patients. In the remaining
      patient with a superior mesenteric artery branch pseudoaneurysm, endovascular
      embolization was unsuccessful. Eighteen pseudoaneurysms were thrombosed with coil
      embolization alone. The remaining three pseudoaneurysms needed NBCA embolization.
      Two patients died from sepsis within 5 weeks after embolization. CONCLUSION:
      Emergent diagnosis and treatment are essential in visceral artery pseudoaneurysms
      because of the high rate of death. Transcatheter embolization with platinum coils
      is an efficient, safe treatment of choice. NBCA may be used to avoid proximal
      embolization of the visceral arteries that could not be catheterized selectively
      because of tortuosity, vessel size, or anatomic location.

PMID- 12483382
TI  - Solitary necrotic nodule of the liver: imaging and correlation with pathologic
      features.
AB  - We describe two cases of solitary necrotic nodule of the liver, an uncommon
      nonmalignant lesion that can mimic a metastasis. The nodule appeared hypoechoic,
      or targetlike, on sonography, hypodense without contrast enhancement on computed
      tomography, and hypointense on magnetic resonance imaging, including diffusion
      weighted images. These features, peculiar when considered together, are explained
      by the coagulative type of necrosis.

PMID- 12483383
TI  - Biliary obstruction in metastatic disease: thin-section helical CT findings.
AB  - BACKGROUND: We describe the thin-section helical computed tomographic (CT)
      findings of biliary obstruction caused by metastasis. METHODS: Thin-section
      helical CT (5 mm slice thickness, 1:1 pitch, portal phase) and direct
      cholangiography in 50 consecutive patients with biliary obstruction caused by
      metastases were reviewed retrospectively by three radiologists. The primary sites
      were the stomach ( n = 36), colon ( n = 12), jejunum ( n = 1), and uterus ( n =
      1). The level of biliary obstruction was analyzed with the Bismuth
      classification, and the CT findings of biliary obstruction were classified into
      six types: small (<2 cm) periductal masses, large (>/=2 cm) periductal masses,
      extrinsic compression by a metastatic liver mass, high-attenuation intraductal
      mass, intrapancreatic mass, and no demonstrable lesion. RESULTS: The level of
      biliary obstruction was the hilum in 18 patients (36%), the proximal common duct
      in 20 (40%), the distal common duct in five (10%), and the periampullary area in
      seven (14%). Of 18 hilar obstructions, tumor involvement of the secondary
      confluence of intrahepatic bile ducts was seen in 10 (right in six, left in one,
      and bilateral in three). Periductal masses were seen in 68% (small in 18, large
      in 16). In one patient (2%), a large metastatic mass of the liver resulted in
      extrinsic compression and biliary obstruction. Lesions mimicking primary biliary
      or pancreatic tumor were seen in four, respectively. In seven, we found no
      obstructing lesion on CT. CONCLUSION: Biliary obstruction in patients with known
      primary malignancies can show atypical patterns mimicking primary
      pancreatobiliary malignancies on thin-section helical CT.

PMID- 12483384
TI  - Liver regeneration after living adult right lobe transplantation.
AB  - BACKGROUND: The purpose of this study was to describe liver regeneration in
      patients undergoing living-adult liver transplantation. METHODS: This prospective
      study included 10 donors and eight recipients who had a total of 65 computed
      tomographic (CT) scans. All patients had preoperative CT ( n = 18), and follow-up
      CT scans ( n = 47) were obtained for up to 14 months after transplantation. Liver
      and spleen volumes were measured by hand tracing each organ on the axial portal
      venous phase images. RESULTS: Both donors and recipients showed immediate
      increases in liver volume. However, liver regeneration was significantly faster
      and reached a higher peak in recipients than in donors. Splenic volume in donors
      demonstrated an initial increase followed by a decline, reaching the preoperative
      volume after 1 year. Splenic volume in recipients demonstrated immediate decline
      postoperatively. CONCLUSION: Restoration of liver volume occurred rapidly after
      transplantation, but followed different patterns in donors and recipients.
      Deviation from these patterns warrants further investigation.

PMID- 12483385
TI  - Successful conservative therapy for portal vein thrombosis after living donor
      liver transplantation.
AB  - Portal vein thrombosis remains a significant cause of graft loss in liver
      transplantation. A case with thrombosis at the anastomotic site is described.
      Close follow-up with ultrasound enabled us to treat the patient promptly and
      successfully with anticoagulants.

PMID- 12483386
TI  - Thrombectomy of portal vein thrombosis in living donor liver transplantation.
AB  - We describe a case of living donor liver transplantation where an intrahepatic
      portal vein embolism was detected by intraoperative ultrasonography after the
      completion of portal and arterial anastomoses. The recipient portal vein trunk
      was clamped and the ligature of the graft's right portal branch was released,
      thus maintaining the sole arterial supply. Backward flushing of the portal system
      was achieved, which removed the clot through the reopened right portal branch
      without the need for thrombectomy by Fogarty balloon catheter.

PMID- 12483387
TI  - Portal vein aneurysm of the umbilical portion: imaging features and the
      relationship with portal vein anomalies.
AB  - BACKGROUND: We evaluated the imaging features of portal vein aneurysm occurring
      at the umbilical portion and the relation between portal vein aneurysm of the
      umbilical portion and portal vein anomaly. METHODS: Retrograde analysis was
      performed in 18 patients with portal vein aneurysm of the umbilical portion of
      the portal vein. We analyzed the size, shape, and imaging findings of portal vein
      aneurysm. In addition, we evaluated associated portal vein anomalies,
      specifically, the branching pattern of the intrahepatic portal vein and the
      position of the umbilical portion of the left portal vein. RESULTS: The diameter
      of the portal vein aneurysm ranged from 1.5 to 2.2 cm and the shape of the portal
      vein aneurysm was saccular (n = 14) or fusiform (n = 4). Imaging findings of the
      portal vein aneurysm of the umbilical portion were typical for its vascular
      nature. Portal vein anomalies were seen in eight of 18 patients (44%): the right
      anterior segmental portal vein (n = 7) or the right anterior and posterior
      segmental portal veins (n = 1) originating from the umbilical portion of the left
      portal vein and a rightward deviation of the umbilical portion of the left portal
      vein (n = 4). CONCLUSION: Due to its vascular nature, noninvasive diagnostic
      modalities can enable the detection of portal vein aneurysm of the umbilical
      portion, and there is a close relation between portal vein aneurysm of the
      umbilical portion and portal vein anomaly.

PMID- 12483388
TI  - Extrahepatic cholangiocarcinoma associated with clonorchiasis: CT evaluation.
AB  - BACKGROUND: I evaluated the computed tomographic (CT) features of nine
      pathologically proven cases of cholangiocarcinoma in the extrahepatic bile duct
      associated with clonorchiasis. METHODS: CT scans of nine pathologically proven
      cholangiocarcinoma associated with clonorchiasis were reviewed retrospectively.
      CT scans were analyzed for the following parameters: tumor (detection, location,
      gross morphologic type, contrast enhancement), intrahepatic bile duct
      (dilatation, pattern of dilatation), common bile duct (dilatation, Clonorchis
      sinensis worms), gallbladder (inflammation, C. sinensis worms), invasion of the
      contiguous viscera (pancreas, duodenum, liver), lobar atrophy, and
      lymphadenopathy and metastasis. RESULTS: CT depicted the level and cause of
      obstruction in all nine patients (100%). Contrast enhancement of the tumors
      relative to the liver parenchyma showed isoattenuation in five tumors (55%) and
      hyperattenuation in four tumors (44%). Severe, uniform dilatation of the
      intrahepatic bile duct was identified in six patients (67%) and central
      dilatation was seen in two patients (22%). No evidence of dilatation of the
      intrahepatic bile duct was seen in one patent (11%). Most tumors were located in
      the proximal third of the extrahepatic bile duct ( n = 7, 78%). Male
      preponderance was found ( n = 8, 89%). CONCLUSION: Cholangiocarcinoma associated
      with clonorchiasis was located predominantly in the proximal third of the
      extrahepatic bile duct and detected more readily than nonclonorchiasis-associated
      cholangiocarcinoma.

PMID- 12483390
TI  - Dilatation of the cystic duct in patients with obstructive jaundice.
AB  - BACKGROUND: It is well known that obstructive jaundice causes biliary dilatation,
      but sonographic (US) findings of the cystic duct in patients with obstructive
      jaundice are rarely reported. METHODS: We reviewed US findings in 25 such
      patients. RESULTS: US findings of dilated cystic duct could be divided roughly
      into two patterns: tortuous and tubular. The former pattern was a tortuously
      dilated cystic duct arising from the gallbladder neck, running predominantly
      deeply, turning anteromedially, and then joining the posterior face of the common
      hepatic duct. The latter pattern was a straight dilated cystic duct running
      parallel with the common hepatic duct, giving the appearance of a septated bile
      duct. CONCLUSION: A better understanding of the US findings of dilated cystic
      duct translates into improved biliary US diagnosis.

PMID- 12483389
TI  - Thorotrast-induced cholangiocarcinoma: case report.
AB  - Thorotrast, a contrast medium used extensively before being banned in 1950s,
      delivers a densely ionizing, high linear energy transfer type of radiation that
      predisposes to malignancies. We report a case of peripheral cholangiocarcinoma
      and describe its computed tomographic and magnetic resonance imaging features in
      a patient who developed it 48 years after exposure to Thorotrast.

PMID- 12483391
TI  - Cystic duct remnant carcinoma with widespread invasion along the extrahepatic
      bile duct wall: dynamic CT findings.
AB  - We report a case of remnant cystic duct carcinoma with widespread invasion along
      the common bile duct wall. Thin-slice dynamic computed tomography showed
      circumferential wall thickening of the extrahepatic bile duct (from the common
      hepatic duct to the intrapancreatic common bile duct) and the remnant cystic
      duct. Pathologically, the extrahepatic bile duct wall was thickened due to
      submucosal tumor infiltration by cystic duct papillary adenocarcinoma.

PMID- 12483392
TI  - Carcinoma of the gallbladder associated with clonorchiasis: clinicopathologic and
      CT evaluation.
AB  - BACKGROUND: The computed tomographic (CT) features of three cases with
      pathologically proven adenocarcinoma of the gallbladder associated with
      clonorchiasis. METHODS: CT scans of three cases with pathologically proven
      adenocarcinoma of the gallbladder associated with clonorchiasis were
      retrospectively reviewed. Scans were analyzed for the following parameters: (a)
      gross morphologic pattern (intralumenal mass lesion, mass replacing the
      gallbladder, focal or diffuse wall thickening); (b) contrast enhancement of the
      tumors; (c) associated gallstones or Chlonorchis sinensis worms; (d) direct
      invasion into the liver; (e) metastasis to adjacent viscera (pancreas, duodenum);
      (f) the extrahepatic bile duct (dilatation, metastasis, stone, C. sinensis
      worms); (g) the intrahepatic bile duct (dilatation); and (h) lymphadenopathy and
      metastasis. RESULTS: The gross morphologic pattern of three cases with carcinoma
      of the gallbladder was an intralumenal mass lesion (the least common type),
      whereas the patterns of infiltration and a mass replacing the gallbladder were
      not identified. Mild contrast enhancement of the tumors relative to the liver was
      demonstrated in all patients. Gallstones and C. sinensis worms were not
      visualized in the gallbladder and the extrahepatic bile duct. An unusual
      metastasis to the distal common bile duct and the pancreas was found in this
      series. CONCLUSION: Three cases with adenocarcinoma of the gallbladder associated
      with clonorchiasis showed intralumenal mass lesions within the gallbladder lumen.
      The cause-and-effect relation between clonorchiasis and gallbladder carcinoma is
      discussed.

PMID- 12483393
TI  - Impaired gallbladder function in spinal cord injury on quantitative Tc-99m DISIDA
      cholescintigraphy.
AB  - BACKGROUND: Patients with spinal cord injury (SCI) have increased prevalences of
      gallstones and acute acalculous cholecystitis. A possible explanation for the
      increased prevalence of gallstone disease in SCI patients is decreased
      gallbladder motility causing gallbladder stasis, a known risk factor for
      gallstone disease. We investigated gallbladder function in SCI. METHODS: Twenty
      five normal control subjects and 50 SCI patients were included in this study.
      Gallbladder function was measured by technium 99m-labeled imino-diacetic acid
      analogue (Tc-99m DISIDA) cholescintigraphy and represented by the filling
      fraction (FF) and the ejection fraction (EF). The SCI patients were assigned to
      subgroups: old versus young, female versus male, high- versus low-level injury,
      and long versus short injury duration. RESULTS: Forty-two percent of SCI patients
      had abnormal FFs and 54% of SCI patients had abnormal EFs. Significantly
      decreased FF and EF values were found in SCI patients, especially in those who
      were female and had high-level injuries. CONCLUSION: With the use of quantitative
      Tc-99m DISIDA cholescintigraphy, we found that SCI can significantly impair
      gallbladder function.

PMID- 12483394
TI  - Pancreatic pleural effusion with a pancreaticopleural fistula diagnosed by
      magnetic resonance cholangiopancreatography and cured by somatostatin analogue
      treatment.
AB  - A 69-year-old man with chronic alcoholic pancreatitis developed a left-sided
      massive pleural effusion. Magnetic resonance cholangiopancreatography clearly
      demonstrated the pancreatic cyst and the fistula connecting the cyst with the
      left pleural cavity, resulting in the diagnosis of pancreatic pleural effusion
      with a pancreaticopleural fistula. Conservative somatostatin analogue treatment
      completely eradicated the pancreatic pleural effusion and closed the
      pancreaticopleural fistula.

PMID- 12483395
TI  - Solid and papillary epithelial neoplasm of the pancreas with peritoneal
      metastasis and its recurrence: a case report.
AB  - Solid and papillary epithelial neoplasm of the pancreas is a low-grade malignant
      tumor, generally occurring as a slowly growing upper abdominal mass in a young
      female. With complete excision, the prognosis is good. Malignant behavior with
      metastasis does occur, but the incidence is very low. We report a young woman who
      had this neoplasm in the pancreatic tail with peritoneal seeding and its
      recurrence.

PMID- 12483396
TI  - Value of CT after laparoscopic repair of postsurgical ventral hernia.
AB  - BACKGROUND: We examined computed tomographic (CT) findings after laparoscopic
      repair of postsurgical ventral hernias in patients with and without symptoms.
      METHODS: Meshes were placed laparoscopically in 18 patients for incisional
      ventral hernia repair. CT of the abdominal wall was performed 1, 15, and 30 days
      after repair and when clinical findings indicated the procedure. RESULTS: Scans
      of four patients showed small fluid collections within the abdominal wall between
      the hernia sac and the mesh. These collections resolved within the first 30 days
      without aspiration. Scans of three patients with symptoms 4-8 months later showed
      fluid collections that required multiple aspirations in one patient and a
      recurrent hernia that was repaired laparoscopically in another patient.
      CONCLUSION: Preliminary results suggest that CT is a useful imaging tool in
      patients with laparoscopic repair of incisional vetral hernia. It showed the
      correct site of the mesh, subclinical fluid collections in the abdominal wall,
      and recurrent hernia.

PMID- 12483397
TI  - Benefits of tissue harmonic imaging in the evaluation of abdominal and pelvic
      lesions.
AB  - BACKGROUND: We compared tissue harmonic imaging (THI) and conventional
      ultrasonography to determine whether THI improves image quality and facilitates
      lesion characterization. METHODS: Eighty-nine various abdominal or pelvic lesions
      in 71 patients(34 men and 37 women; age range = 3-90 years, median age = 52
      years) were evaluated with conventional ultrasonography and THI. Examinations
      were performed with frequencies of 2-5 MHz. All the images were stored on a hard
      disk and evaluated separately by three radiologists. RESULTS: According to the
      interpreters, THI improved overall image quality in 67 (74%) to 76 (84%) and
      lesion characterization in 28 (31%) to 36 (40%) of 89 lesions when compared with
      conventional ultrasonography. All three observers agreed that image quality and
      lesion characterization were improved in 62% and 17% of the lesions,
      respectively. Lesion groups containing five or more lesions were compared for any
      difference of improvement in overall image quality and lesion characterization.
      For overall image quality, a significant difference was found ( p < 0.05). For
      lesion characterization, there was no significant difference between groups ( p >
      0.05). CONCLUSION: THI improved overall image quality and lesion
      characterization.

PMID- 12483398
TI  - Musings at the beginning of the hyper-CT era.
AB  - In the past decade, with the introduction and acceptance of helical and
      multidetector computed tomography (CT), CT has gained ascendancy as the
      preeminent imaging examination for most abdominal conditions. However, attention
      must now be directed toward the implications of dose consequent to CT studies.
      Multidetector CT has resulted in thinner and more slices per region of interest,
      more extensive studies as adjacent body regions can be assessed in one breath
      hold, and more pediatric examinations. Dose per slice is greater with
      multidetector CT than with single-slice CT, and the number of examinations
      nationally has risen dramatically. These factors contribute to the radiation
      burden given to patients and the enhancement of risks for morbidity and mortality
      later in life.

PMID- 12483399
TI  - Normal variants and pitfalls in CT of the gastrointestinal and genitourinary
      tracts.

PMID- 12483400
TI  - CT fluoroscopy-guided abdominal interventions.
AB  - Computed tomographic fluoroscopy (CTF) is one of the most recent developments in
      helical computed tomography (CT), which is increasingly being used in
      interventional radiology. The method combines the advantages of CT with the real
      time capabilities of ultrasonography. This article reviews the current clinical
      applications of CTF in the monitoring of abdominopelvic interventions with
      reference to published clinical studies.

PMID- 12483401
TI  - Diuretic contrast-enhanced magnetic resonance urography versus intravenous
      urography for depiction of nondilated urinary tracts.
AB  - Diuretic contrast-enhanced magnetic resonance urography (MRU) is analogous to
      conventional intravenous urography (IVU) and, hence, designated as excretory MRU.
      It is performed with a T1-weighted fast gradient-echo sequence to obtain breath
      hold, dynamic MRU after intravenous injection of low-dose furosemide (5-10 mg)
      and gadolinium (Gd) chelate. The combination of Gd and furosemide is the key for
      achieving a uniform distribution of the contrast material inside the entire
      urinary tract. It provides high-resolution images of nondilated urinary tracts
      and information about the renal function. This pictorial essay reviews the
      technical aspects and practical consideration of diuretic Gd-enhanced MRU and
      underlines its diagnostic capability in comparison with IVU in the depiction of
      nondilated collecting systems. We discuss its potential applications, as in young
      patients with anatomic anomalies, patients with renal transplants, patients
      allergic to iodinated contrast medium, and avoiding multimodality work-up in the
      evaluation of kidney donors and patients with renal and extrarenal tumor
      diseases.

PMID- 12483403
TI  - Conventional measurements of GFR using 51Cr-EDTA overestimate true renal
      clearance by 10 percent.
AB  - It is widely believed that measurement of the area under the plasma clearance
      curve (AUC) following a single intravenous injection of chromium-51 labelled
      ethylene diamine tetra-acetic acid ((51)Cr-EDTA) is a gold standard method for
      determining glomerular filtration rate (GFR). However, there are reports that
      (51)Cr-EDTA may have a significant extrarenal clearance. The aim of this study
      was to identify the non-renal component of (51)Cr-EDTA plasma clearance
      contributing to the AUC measurement of GFR. Seventy healthy postmenopausal women
      (mean age 60 years, range 45-79 years) were injected with 3 MBq (51)Cr-EDTA and
      0.25 MBq iodine-125 labelled human serum albumin and 11 blood samples taken
      between 0 and 4 h through an indwelling venous cannula. For the first 21
      subjects, two complete urine collections were made 0-2 h and 2-4 h after
      injection, and for the final 49 patients, four 1-h urine collections were made.
      The mean (51)Cr-EDTA total plasma clearance was 84 ml/min (range 50-132 ml/min).
      The mean ratio (SEM) of urine to total clearance determined from the cumulative 1
      , 2-, 3- and 4-h data was 0.903 (0.018), 0.891 (0.013), 0.898 (0.011) and 0.899
      (0.010) respectively and remained constant despite the mean urine concentration
      decreasing from 122% to 15%/litre during this period. A least squares fit to data
      from the 238 individual urine collections was used to determine the fraction of
      the total plasma clearance attributable to renal clearance, alpha(0), and the
      residual urine volume, delta V. The results were alpha(0)=0.910 (95% CI: 0.889
      0.932) and delta V=14 ml (95% CI: -4 to +34 ml). The overestimation of the true
      renal clearance of (51)Cr-EDTA by the AUC method is believed to be due to the
      failure of the plasma clearance curve to reach the true terminal exponential by 2
      h after injection as usually assumed. As a result, conventional measurements of
      GFR using (51)Cr-EDTA overestimate the true renal clearance of tracer by
      approximately 10%.

PMID- 12483404
TI  - Safe and effective inhibition of renal uptake of radiolabelled octreotide by a
      combination of lysine and arginine.
AB  - As scintigraphy with [(111)In-DTPA(0)]octreotide has become a standard technique
      in analysing somatostatin receptor-receptor positive lesions such as
      neuroendocrine tumours, a logical next step is peptide receptor radionuclide
      therapy (PRRT). Initial studies on PRRT were performed with high doses of
      [(111)In-DTPA(0)]octreotide, and recently other radionuclides coupled to other
      somatostatin analogues have been used for this purpose. However, the dose
      delivered to the kidney is a major dose-limiting factor. Amino acid solutions
      have previously been used to reduce renal uptake of radioactivity, but these
      solutions have some disadvantages, i.e. their hyperosmolarity and their
      propensity to cause vomiting and metabolic changes. In this study we tested
      various amino acid solutions in patients receiving [(111)In-DTPA(0)]octreotide
      PRRT in order to assess their safety and their capacity to inhibit the renal
      uptake of radioactivity. Patients served as their own non-infused control. Renal
      radioactivity at 24 h following the injection of [(111)In-DTPA(0)]octreotide was
      inhibited by (1) a commercially available amino acid solution (AA) (21%+/-14%,
      P<0.02), (2) by 25 g (17%+/-9%, P<0.04), 50 g (15%+/-13%, P<0.04) or 75 g of
      lysine (44%+/-11%, P<0.001) and (3) by a combination of 25 g of lysine plus 25 g
      of arginine (LysArg) (33%+/-23%, P<0.01). Fluid infusion alone (500, 1,000 or
      2,000 ml of saline/glucose) did not change renal uptake of radioactivity. In
      patients studied with 75 g of lysine (Lys75) and LysArg, serum potassium levels
      rose significantly. Maximal potassium levels were within the toxic range (6.3,
      6.7 and 6.8 mmol/l) in three out of six patients infused with Lys75, whereas with
      LysArg the highest concentration measured was 6.0 mmol/l. Electrocardiographic
      analysis did not reveal significant changes in any of the patients. Vomiting
      occurred in 50% of patients infused with AA, but in only 6% of patients receiving
      no amino acid infusion (controls) and 9% of patients receiving LysArg. We
      conclude that co-infusion of Lys75 or LysArg results in a significant inhibition
      of renal radioactivity in PRRT, allowing higher treatment doses and thus
      resulting in higher tumour radiation doses. Because Lys75 produced serious
      hyperkalaemia, it is not suitable for clinical use. LysArg, however, is effective
      in offering renal protection in PRRT and is safe.

PMID- 12483405
TI  - Anatomically standardised 99mTc-ECD brain perfusion SPET allows accurate
      differentiation between healthy volunteers, multiple system atrophy and
      idiopathic Parkinson's disease.
AB  - The clinical differentiation between typical idiopathic Parkinson's disease (IPD)
      and atypical parkinsonian disorders such as multiple system atrophy (MSA) is
      complicated by the presence of signs and symptoms common to both forms. The goal
      of this study was to re-evaluate the contribution of brain perfusion single
      photon emission tomography (SPET) with anatomical standardisation and automated
      analysis in the differentiation of IPD and MSA. This was achieved by discriminant
      analysis in comparison with a large set of age- and gender-matched healthy
      volunteers. Technetium-99m ethyl cysteinate dimer SPET was performed on 140
      subjects: 81 IPD patients (age 62.6+/-10.2 years; disease duration 11.0+/-6.4
      years; 50 males/31 females), 15 MSA patients (61.5+/-9.2 years; disease duration
      3.0+/-2.2 years; 9 males/6 females) and 44 age- and gender-matched healthy
      volunteers (age 59.2+/-11.9 years; 27 males/17 females). Patients were matched
      for severity (Hoehn and Yahr stage). Automated predefined volume of interest
      (VOI) analysis was carried out after anatomical standardisation. Stepwise
      discriminant analysis with cross-validation using the leave-one-out method was
      used to determine the subgroup of variables giving the highest accuracy for this
      differential diagnosis. Between MSA and IPD, the only regions with highly
      significant differences in uptake after Bonferroni correction were the putamen
      VOIs. Comparing MSA versus normals and IPD, with putamen VOI values as
      discriminating variables, cross-validated performance showed correct
      classification of MSA patients with a sensitivity of 73.3%, a specificity of 84%
      and an accuracy of 83.6%. Additional input from the right caudate head and the
      left prefrontal and left mesial temporal cortex allowed 100% discrimination even
      after cross-validation. Discrimination between the IPD group alone and healthy
      volunteers was accurate in 94% of the cases after cross-validation, with a
      sensitivity of 91.4% and a specificity of 100%. The three-group classification
      (MSA, IPD and healthy volunteers) resulted in an overall accuracy of 86% post
      hoc, with 98% of normals, 78% of IPD and 93% of MSA correctly classified. These
      values were slightly lower after cross-validation: 96% for healthy volunteers,
      77% for IPD and 67% for MSA. In conclusion, using age- and gender-matched healthy
      volunteer data and anatomical standardisation, it is possible to differentiate
      between IPD and MSA with high discriminating power in clinically relevant
      circumstances.

PMID- 12483406
TI  - Clinical validation of simultaneous dual-isotope myocardial scintigraphy.
AB  - Simultaneous dual-isotope (rest thallium-201/stress technetium-99m sestamibi)
      myocardial single-photon emission tomography (SPET) would be an ideal procedure;
      however, (99m)Tc cross-talk on the (201)Tl window hampers its routine use. Photon
      energy recovery (PER) is a spectral deconvolution technique validated for scatter
      and cross-talk removal in phantom studies and a limited series of patients. In
      this study we aimed to validate the technique in 295 patients within a context of
      clinical routine practice. Conventional separate rest (201)Tl myocardial SPET
      data sets were visually compared with simultaneous dual-isotope data sets
      corrected by PER. Conventional separate rest (201)Tl data sets were identical to
      dual PER-corrected (201)Tl data sets in 173 (58.6%) patients. As dual PER (201)Tl
      data sets are corrected for (99m)Tc cross-talk but also for (201)Tl scatter, they
      were compared with separate rest (201)Tl data sets corrected by PER in the 122
      discordant patients. No difference was found in 77 (26.1%) patients. In 26 (8.8%)
      patients, the difference consisted in the presence of a defect on dual PER
      (201)Tl data sets only, mirroring an ischaemic defect on (99m)Tc-sestamibi data
      sets. This difference can be attributed to the influence of stress on the
      kinetics of (201)Tl injected at rest. In the remaining 19 (6.4%) patients, the
      difference between separate and simultaneous PER-corrected data sets was scored
      as mild in 11 and moderate in eight patients and seemed to be related to multiple
      methodological factors. It is concluded that PER correctly removes (99m)Tc cross
      talk. With the addition of an appropriate attenuation correction, the PER
      technique may allow the routine use of simultaneous dual-isotope myocardial
      scintigraphy in the near future.

PMID- 12483407
TI  - SPET/CT image co-registration in the abdomen with a simple and cost-effective
      tool.
AB  - Fusion of morphology and function has been shown to improve diagnostic accuracy
      in many clinical circumstances. Taking this into account, a number of instruments
      combining computed tomography (CT) with positron emission tomography (PET) or
      single-photon emission tomography (SPET) are appearing on the market. The aim of
      this study was to evaluate a simple and cost-effective approach to generate
      fusion images of similar quality. For the evaluation of the proposed approach,
      patients with neuroendocrine abdominal tumours with liver metastases were chosen,
      since the exact superimposition in the abdomen is more difficult than in other
      regions. Five hours following the injection of 110 MBq (111)In-DTPA-octreotide,
      patients were fixed in a vacuum cushion (MED-TEC, Vac-Loc) and investigated with
      helical CT in a mid-inspiration position ( n=14). Directly following the CT, a
      SPET study (SPET1) of the abdominal region was performed without changing the
      position of the patient. A second SPET study (SPET2), 24 h p.i., was acquired
      after repositioning the patient in his or her individually moulded vacuum
      cushion. A total of nine markers suitable for imaging with CT and SPET were fixed
      on the cushion. Datasets were fused by means of internal landmarks (e.g.
      metastases or margin of abdominal organs) or by the external markers. Image
      fusion using external markers was fast and easy to handle compared with the use
      of internal landmarks. Using this technique, all lesions detectable by SPET (
      n=28) appeared exactly superpositioned on the respective CT morphology by visual
      inspection. Image fusion of CT/SPET1 and CT/SPET2 showed a mean deviation of the
      external markers that in the former case was smaller than the voxel size of 4.67
      mm: 4.17+/-0.61 (CT/SPET1; +/-SD) and 5.52+/-1.56 mm (CT/SPET2), respectively.
      Using internal landmarks, the mean deviation of the chosen landmarks was 6.47+/
      1.37 and 7.78+/-1.21 mm. Vector subtraction of corresponding anatomical points of
      the CT and the re-sampled SPET volume datasets resulted in a similar accuracy.
      Vector subtraction of the metastases showed a significantly less accurate
      superimposition when internal landmarks were used ( P<0.001). The vacuum cushion
      did not affect the image quality of CT and SPET. The proposed technique is a
      simple and cost-effective way to generate abdominal datasets suitable for image
      fusion. External markers positioned on the cushion allow for a rapid and robust
      overlay even if no readily identifiable internal landmarks are present. This
      technique is, in principle, also suitable for CT/PET fusion as well as for
      fusions of MRI data with PET or SPET.

PMID- 12483408
TI  - Impact of body habitus on quantitative and qualitative image quality in whole
      body FDG-PET.
AB  - Obtaining consistent high image quality is desirable for clinical positron
      emission tomography (PET). Body morphology may impact image quality. The purpose
      of this study was to define the average and the range of body sizes in patients
      undergoing tumor PET studies in our center and to determine how the body habitus
      affects the statistical and visual quality of PET images. Height, weight, body
      surface area (BSA), and body mass index (BMI) were determined in 101 male and 101
      female patients (group 1) referred for clinical PET. The summed total counts from
      three consecutive transaxial slices on non-attenuation-corrected (NAC) 2D
      fluorine-18 fluorodeoxyglucose (FDG) PET images, which included the largest liver
      section and no lesions, were determined and compared with body morphology and
      injected doses (ID) in a representative group of 30 male and 30 female patients
      (group 2) spanning a range of body morphologies. The visual quality of images was
      also evaluated using a scoring system by three readers. The average height,
      weight, and BSA were greater in male than in female patients, but the average BMI
      was not different between them in group 1. The largest value of weight or BMI was
      more than four times the smallest value in female patients. The total true counts
      were best correlated with ID/weight (mCi/kg) in group 2 ( r=0.929, P<0.0001).
      Intermediate to high total counts (930,000 or more) corresponded to ID/weight of
      0.22 or higher. The average visual score was positively correlated with the total
      counts (rho=0.63, P<0.0001) and with ID/weight (rho=0.68, P<0.0001) on NAC
      images. The image quality in 22 (84.6%) of 26 patients with intermediate to high
      total counts was adequate to good, whereas that in 21 (61.8%) of 34 patients with
      lower total counts was suboptimal. A wide variety of body morphologies was
      observed in patients referred for clinical FDG-PET tumor studies in our center.
      The total counts and average image visual score were negatively correlated with
      weight. Counts in heavy patients were as low as one-fourth those in light
      patients. Adjusting injected FDG dose in each patient on the basis of body weight
      may be more appropriate to achieve consistent PET image quality than giving a
      fixed injected FDG dose.

PMID- 12483409
TI  - Comparison of SUV and Patlak slope for monitoring of cancer therapy using serial
      PET scans.
AB  - The standardized uptake value (SUV) and the slope of the Patlak plot ( K) have
      both been proposed as indices to monitor the progress of disease during cancer
      therapy. Although a good correlation has been reported between SUV and K, they
      are not equivalent, and may not be equally affected by metabolic changes
      occurring during disease progression or therapy. We wished to compare changes in
      tumor SUV with changes in K during serial positron emission tomography (PET)
      scans for monitoring therapy. Thirteen patients enrolled in a protocol to treat
      renal cell carcinoma metastases were studied. Serial dynamic fluorodeoxyglucose
      (FDG) PET scans and computed tomography (CT) and magnetic resonance (MR) scans
      were performed once prior to treatment, once at 36+/-2 days after the start of
      treatment, and (in 7/13 subjects, 16/27 lesions) a third time at 92+/-9 days
      after the start of treatment. This resulted in a total of 33 scans, and 70 tumor
      Patlak and SUV values (one value for each lesion at each time point). SUV and K
      were measured over one to four predefined tumors/patient at each time point. The
      input function was obtained from regions of interest over the heart, combined, if
      necessary, with late blood samples. Over all tumors and scans, SUV and K
      correlated well ( r=0.97, P<0.0001). However, change in SUV with treatment over
      all tumor scan pairs was much less well correlated with the corresponding change
      in K ( r=0.73, P<0.0001). The absolute difference in % change was outside the 95%
      confidence limits expected from previous variability studies in 6 of 43 pairs of
      tumor scans, and greater than 50% in 2 of 43 tumor scan pairs. In four of the six
      cases, the two indices predicted opposing therapeutic outcomes. Similar results
      were obtained for SUV normalized by body weight or body surface area and for SUVs
      using mean or maximum count. Changes in CT and MR tumor cross-product dimensions
      correlated poorly with each other ( r=0.47, P=NS), and so could not be used to
      determine the "correct" PET index. Absolute values of SUV and K correlated well
      over the patient population. However, when monitoring individual patient therapy
      serially, large differences in the % changes in the two indices were occasionally
      found, sometimes sufficient to produce opposing conclusions regarding the
      progression of disease.

PMID- 12483410
TI  - PET-MR image fusion in soft tissue sarcoma: accuracy, reliability and
      practicality of interactive point-based and automated mutual information
      techniques.
AB  - The fusion of functional positron emission tomography (PET) data with anatomical
      magnetic resonance (MR) or computed tomography images, using a variety of
      interactive and automated techniques, is becoming commonplace, with the technique
      of choice dependent on the specific application. The case of PET-MR image fusion
      in soft tissue is complicated by a lack of conspicuous anatomical features and
      deviation from the rigid-body model. Here we compare a point-based external
      marker technique with an automated mutual information algorithm and discuss the
      practicality, reliability and accuracy of each when applied to the study of soft
      tissue sarcoma. Ten subjects with suspected sarcoma in the knee, thigh, groin,
      flank or back underwent MR and PET scanning after the attachment of nine external
      fiducial markers. In the assessment of the point-based technique, three error
      measures were considered: fiducial localisation error (FLE), fiducial
      registration error (FRE) and target registration error (TRE). FLE, which
      represents the accuracy with which the fiducial points can be located, is related
      to the FRE minimised by the registration algorithm. The registration accuracy is
      best characterised by the TRE, which is the distance between corresponding points
      in each image space after registration. In the absence of salient features within
      the target volume, the TRE can be measured at fiducials excluded from the
      registration process. To assess the mutual information technique, PET data,
      acquired after physically removing the markers, were reconstructed in a variety
      of ways and registered with MR. Having applied the transform suggested by the
      algorithm to the PET scan acquired before the markers were removed, the residual
      distance between PET and MR marker-pairs could be measured. The manual point
      based technique yielded the best results (RMS TRE =8.3 mm, max =22.4 mm, min =1.7
      mm), performing better than the automated algorithm (RMS TRE =20.0 mm, max =30.5
      mm, min =7.7 mm) when registering filtered back-projection PET images to MR.
      Image reconstruction with an iterative algorithm or registration of a composite
      emission-transmission image did not improve the overall accuracy of the
      registration process. We have demonstrated that, in this application, point-based
      PET-MR registration using external markers is practical, reliable and accurate to
      within approximately 5 mm towards the fiducial centroid. The automated algorithm
      did not perform as reliably or as accurately.

PMID- 12483411
TI  - FDG-PET for prediction of tumour aggressiveness and response to intra-arterial
      chemotherapy and radiotherapy in head and neck cancer.
AB  - The aim of this study was to evaluate the possible usefulness of fluorine-18
      fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting tumour
      aggressiveness and response to intra-arterial chemotherapy (THP-ADM + 5-FU +
      carboplatin) and radiotherapy in head and neck carcinomas. Twenty patients with
      squamous cell carcinoma (SCC) of the head and neck were included in the study.
      All patients completed the treatment regimen, and each patient underwent two FDG
      PET studies, one prior to and one at 4 weeks after the chemoradiotherapy. For the
      quantitative evaluation of regional FDG uptake in the tumour, standardised uptake
      values (SUVs) with an uptake period of 50 min were used. The pre-treatment SUV
      (pre-SUV) and post-treatment SUV (post-SUV) were compared with
      immunohistologically evaluated tumour proliferative potential (MIB-1 and PCNA),
      tumour cellularity and other parameters including histological grade, tumour size
      and stage, clinical response and histological evaluation after therapy. All
      neoplastic lesions showed high SUVs (mean, 9.75 mg/ml) prior to the treatment,
      which decreased significantly after the therapy (3.41 mg/ml, P<0.01). Pre-SUV did
      not show any correlation with MIB-1, PCNA, cellularity or other parameters.
      However, lower post-SUV was significantly correlated with good histological
      results after therapy (no viable tumour cells, n=16). In comparison with
      moderately differentiated SCCs, well-differentiated SCCs exhibited significantly
      lower post-SUV and a larger difference between pre- and post-SUVs. Lesions with a
      high pre-SUV (>7 mg/ml) showed residual tumour cells after treatment in 4 out of
      15 patients, whereas patients whose lesions showed a low pre-SUV (<7 mg/ml, five
      patients) were successfully treated. Four out of six tumours with a post-SUV
      higher than 4 mg/ml had viable tumour cells, whereas all tumours (14/14) with a
      post-SUV lower than 4 mg/ml showed no viable tumour cells. Computational
      multivariate analysis using multiple regression revealed four factors (MIB-1
      labelling index, cellularity, the number of MIB-1 labelled tumour cells and
      tumour size grade) contributing to pre-SUV and pre-post SUV (difference between
      pre-treatment SUV and post-treatment SUV in each patient) with statistical
      significance. FDG uptake in the tumour might reflect tumour aggressiveness, which
      is closely related to the proliferative activity and cellularity. Pre-treatment
      FDG-PET is useful in predicting the response to treatment, and post-treatment FDG
      PET is of value in predicting residual viable tumours. FDG-PET has a profound
      impact on the treatment strategy for head and neck carcinomas.

PMID- 12483412
TI  - Uptake of [N-methyl-11C]alpha-methylaminoisobutyric acid in untreated head and
      neck cancer studied by PET.
AB  - Amino acid transport system A is expressed strongly in neoplastic cells. [ N
      methyl-(11)C]alpha-Methylaminoisobutyric acid ((11)C-MeAIB) is a recently
      developed tracer for PET studies on system A amino acid transport. (11)C-MeAIB is
      a metabolically stable amino acid analogue which is transported from plasma into
      the tissue by system A. This study evaluated the kinetics of (11)C-MeAIB uptake
      from plasma into tumour tissue and normal tissues in 13 patients with untreated
      head and neck cancer. (11)C-MeAIB uptake in tumour was compared with histological
      grade and proliferative activity. Tracer uptake was quantitated by calculating
      the standardised uptake values (SUVs) and the kinetic influx constants ( K(i))
      using graphical analysis. All tumours accumulated (11)C-MeAIB and were visualised
      clearly. In the graphical analysis, linear plots were achieved; the mean K(i)
      value of tumour was 0.056+/-0.026 min(-1), and the mean SUV was 6.1+/-2.7. A
      close correlation between graphically obtained K(i) and semi-quantitative SUV in
      tumours was found ( r=0.887, P=0.00005). We could not demonstrate a correlation
      between the uptake of (11)C-MeAIB and the grade of malignancy or the
      proliferative index, as assessed using Ki-67 immunohistochemical assay. Head and
      neck cancer can be effectively imaged with (11)C-MeAIB PET. (11)C-MeAIB showed
      active and rapid transport into tumour tissue and salivary glands. Further
      studies on the applicability of (11)C-MeAIB PET for radiation treatment planning
      in the head and neck region and the regulation of system A amino acid transport
      under different metabolic states are warranted.

PMID- 12483413
TI  - Prognostic value of [18F]FDG-PET imaging in small cell lung cancer.
AB  - Positron emission tomography (PET) utilizing fluorine-18 fluorodeoxyglucose (FDG)
      has been used in the evaluation of non-small cell lung cancer (NSCLC). Recently
      its use in the staging of small cell lung cancer (SCLC) has been reported.
      However, the prognostic value of FDG-PET imaging in SCLC has not been studied. We
      performed a retrospective analysis to assess this, with the following hypotheses:
      (1) PET-positive patients would have a less favorable prognosis than PET-negative
      patients and (2) a high standardized uptake value (SUV) would be associated with
      a poor prognosis. Retrospective review of a mixed population of treated and
      untreated patients imaged between 1995 and 2000 was performed. Results of 62
      scans in 46 patients were analyzed. There were 8 untreated and 38 treated
      patients. Findings were correlated with pathology, computed tomography/magnetic
      resonance imaging and clinical data. The sensitivity of PET scanning was 100%
      with pathological correlation. The prognostic value of a positive PET study was
      determined. Overall survival in PET-positive cases was significantly worse than
      that in PET-negative cases ( P=0.0108). Correlation of SUV(max) with survival
      showed a significant negative correlation ( P=0.0021). In the eight untreated
      patients, scans were strongly positive and in all cases the scan results
      concurred with the final clinical stage assigned on the basis of conventional
      methods. We conclude that FDG-PET imaging provides prognostic information in
      treated patients. A positive study and a high SUV(max) are significantly
      associated with poor survival. Additionally, FDG-PET may be helpful in staging
      and follow-up.

PMID- 12483414
TI  - Multitracer study with positron emission tomography in Creutzfeldt-Jakob disease.
AB  - During the period February 1997 to April 2000, 15 patients with clinical symptoms
      of Creutzfeldt-Jakob disease (CJD) were referred to Uppsala University PET
      Centre. Positron emission tomography (PET) was performed to detect characteristic
      signs of the disease, e.g. neuronal death and/or astrocytosis in the brain. The
      examinations were performed in one session starting with oxygen-15 labelled water
      scan to measure regional cerebral blood flow, followed by imaging with the
      monoamine oxidase B inhibitor N-[(11)C-methyl]- L-deuterodeprenyl (DED) to assess
      astrocytosis in the brain and finally imaging with fluor-18 2-fluorodeoxyglucose
      (FDG) to assess regional cerebral glucose metabolism (rCMR(glu)) [corrected].
      Nine of the patients fulfilled the clinical criteria of probable CJD. In eight of
      them, FDG and DED imaging revealed, in comparison with normal controls, a typical
      pattern characterized by a pronounced regional decrease (<2SD) in glucose brain
      metabolism, indicative of neuronal dysfunction; this was accompanied by a similar
      increase (>2SD) in DED binding, indicating astrocytosis. These changes were most
      pronounced in the cerebellum and the frontal, occipital and parietal cortices,
      whereas the pons, the thalamus and the putamen were less affected and the
      temporal cortex appeared unaffected. The cerebral blood flow showed a pattern
      similar to that observed with FDG. In the ninth patient, analysis with DED was
      not possible. The diagnosis of definite CJD according to international consensus
      criteria was confirmed in six of these patients. In one patient with probable
      CJD, protease-resistant prion protein (PrPres) could not be demonstrated. In two
      patients with probable CJD, autopsy was not allowed. Computed tomography and
      magnetic resonance imaging, performed in four and seven of these nine patients
      respectively, showed unspecific, mainly atrophic changes. In six other patients,
      the PET examinations gave a different pattern. In three of them, high rCMR(glu)
      was noticed in parts of the brain, particularly in the temporal lobes and basal
      ganglia, which could suggest encephalitis. One of the patients had Sjogren's
      syndrome, one had paraneoplastic limbic encephalitis and the third recovered
      spontaneously. In the other three patients, the DED binding was normal despite a
      hypometabolic glucose pattern. In conclusion, the PET findings obtained using DED
      and FDG paralleled neuropathological findings indicating neuronal dysfunction and
      astrocytosis, changes that are found in CJD.

PMID- 12483415
TI  - Brain metastases after stereotactic radiosurgery using the Leksell gamma knife:
      can FDG PET help to differentiate radionecrosis from tumour progression?
AB  - Stereotactic radiosurgery (SRS) using the Leksell gamma knife promotes acute and
      chronic local changes in glucose metabolism. We have been able to find very few
      papers on Medline on the subject of assessment of metastases by 2-[(18)F]fluoro-2
      deoxy- D-glucose positron emission tomography (FDG PET) after SRS. The aim of
      this work was to specify the additional value of FDG PET, in comparison with
      magnetic resonance imaging (MRI), in differentiating SRS-induced radionecrosis
      from viable brain metastasis in a clinical setting. Fifty-seven metastases in 25
      patients were treated by SRS. An average of 33 weeks later, all the patients
      underwent FDG PET. At the same time (SD=2 weeks) all the patients underwent MRI.
      The sensitivity, specificity and accuracy of both FDG PET and MRI examinations
      were calculated with reference to clinical and radiological follow-up or
      biopsies. The additional value derived from use of FDG PET after MRI was assessed
      and progression-free survival rates were compared. The difference in progression
      free survival rates between the negative and positive subgroups was significant (
      P=0.0005) for MRI and even more so ( P<0.00001) for FDG PET. Sensitivity,
      specificity and accuracy were 75% (6/8), 93.9% (46/49) and 91.2% (52/57) for FDG
      PET, and 100% (8/8), 65.3% (32/49) and 70.2% (40/57) for MRI. In the subgroup of
      patients with positive or non-diagnostic MRI, the probability of presence of a
      viable tumour was only 32% (8/25). This probability increased to 100% (5/5) when
      subsequent FDG PET was positive and decreased to 11.1% (2/18) when FDG PET was
      negative. The frequency of a viable neoplasm was significantly different (
      P=0.001) in the FDG PET negative and positive subgroups. MRI and FDG PET both
      have an important predictive value for persistent viable metastases after
      treatment by SRS. Neither sensitive but non-specific MRI nor specific but
      insensitive FDG PET is reliable on its own. While FDG PET significantly improved
      the diagnostic accuracy in the subgroup of patients with positive and non
      diagnostic MRI, it provided no additional value in the MRI-negative subgroup.

PMID- 12483416
TI  - Quantifying tumour hypoxia with fluorine-18 fluoroerythronitroimidazole
      ([18F]FETNIM) and PET using the tumour to plasma ratio.
AB  - Fluorine-18 fluoroerythronitroimidazole ([(18)F]FETNIM) is a nitroimidazole
      compound that is potentially useful as a hypoxia marker in positron emission
      tomography (PET) studies of oncological patients. Our aim was to develop a simple
      protocol to quantitate uptake of [(18)F]FETNIM in hypoxic tumours. Dynamic
      imaging data from ten patients with head and neck cancer undergoing [(18)F]FETNIM
      PET was used in simulations and model fits to assess hypoxia marker uptake under
      different levels of blood flow. The distribution volume determined from dynamic
      PET study was compared with simple tumour to plasma and tumour to muscle ratios
      at 90-120 min. In skeletal muscle having a low but variable blood flow [2-6
      ml/(100 gxmin)], differences in hypoxia-specific uptake of [(18)F]FETNIM remain
      small and may be hard to detect with PET. At higher blood flow [>20 ml/(100
      gxmin)], the retention of [(18)F]FETNIM reflects the oxygenation status well and
      results in satisfactory contrast between hypoxic and well-oxygenated tissue. A
      good estimate of tissue hypoxia is accomplished by measuring the tissue to plasma
      [(18)F]FETNIM activity ratio using only a few late time points. The increased
      hypoxia-specific retention of [(18)F]FETNIM in tissues with high blood flow, such
      as malignant tumours, may facilitate application of [(18)F]FETNIM as a hypoxia
      marker in oncological patients. In the assessment of the tumour to non-target
      uptake ratio, plasma is the preferred reference tissue rather than muscle, which
      may show a more heterogeneous tracer uptake not easily controlled for.

PMID- 12483417
TI  - Quantitation of the regional blood flow in the interventricular septum using
      positron emission tomography and nitrogen-13 ammonia.
AB  - The purpose of the present study was to evaluate the effect of spillover of
      activity from the right ventricle (RV) on quantitation of the regional myocardial
      blood flow in the septum. Thirty-one healthy volunteers, 31 patients with
      ischemic heart disease, 7 patients with severe congestive heart failure, and 6
      heart transplant patients underwent positron emission tomography (PET) with
      nitrogen-13 ammonia. Quantitation of the regional myocardial blood flow in the
      septum was performed using both a conventional two-compartment model and a
      previously validated two-compartment model taking RV spillover into account.
      Unaccounted RV spillover resulted in significant underestimation of the regional
      myocardial blood flow in the septum. The amount of underestimation was primarily
      dependent on the magnitude of spillover and the dispersion between the right and
      the left ventricular input functions. In healthy volunteers, the flow error was
      small but significant: on average 6% (range 5%-29%, P<0.00001), compared with 27%
      (range 0%-88%, P<0.002) in the group of patients with severe congestive heart
      failure, who had the most considerable amount of RV spillover. In the group of
      patients with ischemic heart disease and the group of heart transplant patients
      the flow errors were 10% (range 0%-55%, P<0.00001) and 6% (range 1%-19%, P<0.01),
      respectively. It is concluded that flow quantitation in the septum is
      significantly affected by RV spillover, resulting in a considerable
      underestimation of the septal blood flow unless correction is performed.

PMID- 12483418
TI  - PET imaging of somatostatin receptors: design, synthesis and preclinical
      evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide.
AB  - Because of the excellent nuclear properties of fluorine-18 and the growing
      interest in somatostatin receptor (sst) scintigraphy with PET, a novel
      carbohydrated (18)F-labelled sst ligand was developed and preclinically
      evaluated. Synthesis of N(alpha)-(1-deoxy- D-fructosyl)- N(epsilon)-(2
      [(18)F]fluoropropionyl)-Lys(0)-Tyr(3)-octreotate ([(18)F]FP-Gluc-TOCA) was
      completed in approximately 3 h (20%-30% yield). [(19)F]FP-Gluc-TOCA showed no
      affinity to hsst1 and hsst3, moderate affinity to hsst4 (IC(50): 437+/-84 n M)
      and hsst5 (IC(50): 123+/-8.8 n M) and very high affinity to hsst2 (IC(50): 2.8+/
      0.4 n M). As a result of carbohydration, lipophilicity of [(18)F]FP-Gluc-TOCA was
      found to be low (lg P(OW)=-1.70+/-0.02). In mice, the tracer was rapidly cleared
      via renal excretion (kidneys: 8.69%+/-1.09%ID/g) and showed low uptake in liver
      (0.72%+/-0.14%ID/g) and intestine (1.88%+/-0.52%ID/g) and high tumour uptake
      (13.54%+/-1.47%ID/g) (all data at 1 h p.i.). Tumour to non-tumour ratios at 60
      min p.i. reached 25, 19, 7, 1.6 and 56 for blood, liver, intestine, kidney and
      muscle, respectively. A similar biodistribution pattern was observed in
      pancreatic tumour-bearing rats. Tumour uptake in rats was reduced to 36% and 18%
      of control (30 and 60 min) by co-injection of 500 microg Tyr(3)-octreotide,
      demonstrating sst-specific uptake. In a first [(18)F]FP-Gluc-TOCA-PET study of a
      patient with a metastatic carcinoid in the liver the tracer showed superior
      pharmacokinetics, e.g. rapid urinary excretion and low uptake in liver, kidney
      and spleen. Multiple liver lesions (SUVs ranging from 21.4 to 38.0) and
      previously unknown focal uptake in the abdomen (SUV 10.0) were clearly visible.
      This is the first report on PET imaging using an (18)F-labelled sst binding
      peptide; it indicates that [(18)F]FP-Gluc-TOCA offers excellent imaging
      characteristics and allows sst imaging with high tumour to non-tumour contrast.

PMID- 12483419
TI  - Cerebral haemodynamics in patients with hydrocephalus after subarachnoid
      haemorrhage due to ruptured aneurysm.
AB  - Cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) may be reduced in
      patients with normal pressure hydrocephalus (NPH) after subarachnoid haemorrhage
      (SAH). However, little is known about brain circulation in asymptomatic patients
      with ventriculomegaly after SAH. This study investigated CBF and CVR in
      symptomatic and asymptomatic patients with ventriculomegaly to clarify the
      mechanism of NPH. CBF and CVR were investigated in 48 patients with
      ventriculomegaly after SAH due to ruptured aneurysm. Mean CBF of the whole brain
      was measured by first-pass radionuclide angiography using technetium-99m
      hexamethylpropylene amine oxime. CVR was measured as the percentage change from
      the baseline mean CBF value after administration of 500 mg acetazolamide. Thirty
      patients with NPH who responded to shunting had significantly ( P<0.01) reduced
      mean CBF and CVR compared with normal controls. Fourteen asymptomatic patients
      with ventriculomegaly showed significant ( P<0.01) reduction in CVR but no
      difference in mean CBF. Four symptomatic patients who did not respond to shunting
      showed significantly ( P<0.01) reduced mean CBF but had preserved CVR.
      Postoperative mean CBF and CVR increased significantly ( P<0.01) in 21 patients
      who responded to shunting, but showed no significant change in four symptomatic
      patients who did not respond to shunting. Reduction of CBF superimposed on pre
      existing impairment of CVR may be an essential step in the mechanism responsible
      for the manifestation of symptoms of NPH.

PMID- 12483420
TI  - [N-methyl 11C]meta-Hydroxyephedrine positron emission tomography in Parkinson's
      disease and multiple system atrophy.
AB  - Orthostatic hypotension (OH) can be present in idiopathic Parkinson's disease
      (IPD) as well as in atypical parkinsonian syndromes such as multiple system
      atrophy (MSA). According to clinical tests of sympathetic nerve function and
      histopathological data, OH is caused by primarily postganglionic sympathetic
      dysfunction in IPD and by predominantly central and preganglionic degeneration in
      MSA. It has been proposed that this concept of a different underlying
      pathogenesis for OH should be applied in the differential diagnosis of
      parkinsonian disorders, in the form of measurements of sympathetic myocardial
      innervation. In this pilot study, myocardial imaging with [ N-methyl (11)C]meta
      hydroxyephedrine ((11)C-HED) and positron emission tomography (PET) was used as a
      quantitative tool to evaluate the feasibility of such an approach. Seven patients
      were included in the study. Two had MSA and OH, three had probable IPD and OH
      (duration of disease, >3 years), one had probable IPD without OH (disease
      duration, 3 years) and one had possible IPD without OH (disease duration, 2
      years). Ratios of maximal (11)C-HED uptake in the myocardium to that in the liver
      at 5 and 40 min post injection (p.i.) and - based on kinetic modelling - tracer
      influx rates K(1) were calculated. Compared with MSA patients ( n=2), IPD
      patients with OH ( n=3) showed definitely lower uptake ratios at both 5 min p.i.
      (0.39-0.57 vs 0.78-0.79) and 40 min p.i. (0.21-0.60 vs 0.89-1.06), as well as
      lower K(1) values (0.198-0.359 vs 0.384-0.450 min(-1)). The patient with probable
      IPD without OH showed intermediate values (uptake ratio at 5 min: 0.65; uptake
      ratio at 40 min: 0.87; K(1)=0.363). In the patient with possible IPD, values
      (uptake ratio at 5 min: 0.96; uptake ratio at 40 min: 1.04; K(1)=0.400) did not
      differ from those observed in MSA. These results support the hypothesis that
      measurement of myocardial innervation may contribute to the differential
      diagnosis of parkinsonian disorders and suggest a need for quantitative
      pathophysiological imaging, particularly at early stages of disease.

PMID- 12483421
TI  - Biodistribution and radiation dosimetry of [123I]ADAM in healthy human subjects:
      preliminary results.
AB  - [(123)I]ADAM [2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM)]
      has recently been shown to be a very promising imaging ligand for the detection
      of serotonin transporters (SERT) in human brain, because of its high specificity
      for SERT. [(123)I]ADAM has previously been used only for animal studies. In this
      work, we investigated the radiation dosimetry and biodistribution of [(123)I]ADAM
      based on whole-body scans in healthy human volunteers. Following the
      administration of 196+/-20 MBq (range 157-220 MBq) [(123)I]ADAM, serial whole
      body images were performed up to 24 h. Estimates of radiation absorbed dose were
      calculated using the MIRDOSE 3.0 program with a dynamic bladder model. Twelve
      source organs were considered in estimating absorbed radiation doses for organs
      of the body. The highest absorbed organ doses were found to the lower large
      intestine wall (8.3.10(-2) mGy/MBq), kidneys (5.2.10(-2) mGy/MBq), urinary
      bladder wall (4.9.10(-2) mGy/MBq) and thyroid (4.3.10(-2) mGy/MBq). The effective
      dose was estimated to be 2.2.10(-2) mSv/MBq. The results suggest that
      [(123)I]ADAM is of potential value as a tracer for single-photon emission
      tomography imaging of serotonin receptors in humans, with acceptable dosimetry
      and high brain uptake.

PMID- 12483422
TI  - PET study of the [11C]raclopride binding in the striatum of the awake cat:
      effects of anaesthetics and role of cerebral blood flow.
AB  - Cats were trained to stay in a containment box, without developing any signs of
      behavioural stress, while their head was maintained in a position that allowed
      positron emission tomography (PET) experiments to be performed. The binding
      potential for [(11)C]raclopride (BP(raclo)), a radioligand with good specificity
      for dopamine (DA) receptors of the D(2) type, was measured in the striatum and in
      three experimental situations: awake, anaesthetised with ketamine (50 mg kg(-1)
      h(-1); i.m.) and anaesthetised with halothane (1.5%). Non-specific binding was
      evaluated in the cerebellum. In the striatum of both sides, the BP(raclo) was
      unmodified by ketamine anaesthesia when compared with awake animals. In contrast,
      a large increase in BP(raclo) was observed under halothane anaesthesia. The non
      specific binding of [(11)C]raclopride, evaluated in the cerebellum, was also
      unchanged under ketamine anaesthesia but greatly increased under halothane
      anaesthesia. To evaluate whether changes in the cerebral blood flow (CBF)
      resulting from the different experimental situations could be at the root of
      these discrepancies, injections of [(15)O]H(2)O were performed; measurements
      revealed a drastically increased CBF under halothane anaesthesia and a slight
      enhancement under ketamine anaesthesia, when compared with the waking state.
      These results are the first to be obtained on this topic in awake cats, and show
      that the BP(raclo) is greatly dependent on alterations in the CBF.

PMID- 12483423
TI  - Highlights of the 15th annual congress of the European Association of Nuclear
      Medicine, Vienna, 2002.

PMID- 12483426
TI  - Soft tissue metastasis of an osteosarcoma of the humerus in a four-legged
      patient.

PMID- 12483427
TI  - MR imaging of epidural hematoma in the lumbar spine.
AB  - OBJECTIVE: To bring attention to the MR imaging appearance of epidural hematoma
      (EDH) in the lumbar spine as a small mass often associated with disk herniation
      or an acute event. This paper will show our experience with this entity and
      describe criteria for its MR imaging appearance. DESIGN AND PATIENTS: Thirteen
      cases of prospectively diagnosed EDH of the lumbar spine were compared with 12
      cases of prospectively diagnosed prominent epidural extrusion. Our criteria were
      retrospectively evaluated by the two authors for their presence or absence in
      each case. The chi-square test for nominal data was applied. MR imaging criteria
      utilized to distinguish EDH from disk herniation at our institution include: (1)
      signal different from disk, (2) high signal on T1-weighted images, either
      centrally or peripherally, (3) teardrop- or egg-shaped mass, in the sagittal
      plane, (4) size greater than half the vertebral body height in a craniocaudal
      dimension, (5) primarily retrosomatic epidural location, (6) plasticity - the
      mass is seen to conform closely to the contours of bone (e.g., in the lateral
      recess), (7) little or no disk space narrowing unless associated with disc
      herniation. RESULTS: Chi-square analysis demonstrated each criterion to
      significantly differentiate between EDH and extrusion. Only six of 13 EDH cases
      went to surgery in spite of their relatively large size. Two of six patients were
      diagnosed as having epidural clot consistent with hematoma at the time of
      surgery. The four patients who were not diagnosed at surgery revealed only small
      disk herniations or fragments of disk. CONCLUSIONS: The occurrence of EDH is more
      frequent than previously suspected. Spontaneous EDH is frequently associated with
      disk herniation and acute events such as sneezing or coughing. Most cases of
      spontaneous EDH will resolve prior to surgery with only the minority becoming
      chronic in order to be seen at surgery as an encapsulated mass. MR imaging can
      reliably identify EDH and distinguish between EDH and large disk extrusions.

PMID- 12483428
TI  - MR accuracy and arthroscopic incidence of meniscal radial tears.
AB  - OBJECTIVE: A meniscal radial tear is a vertical tear that involves the inner
      meniscal margin. The tear is most frequent in the middle third of the lateral
      meniscus and may extend outward in any direction. We report (1) the arthroscopic
      incidence of radial tears, (2) MR signs that aid in the detection of radial tears
      and (3) our prospective accuracy in detection of radial tears. DESIGN AND
      PATIENTS: Three musculoskeletal radiologists prospectively read 200 consecutive
      MR examinations of the knee that went on to arthroscopy by one orthopedic
      surgeon. MR images were assessed for location and MR characteristics of radial
      tears. MR criteria used for diagnosis of a radial tear were those outlined by
      Tuckman et al.: truncation, abnormal morphology and/or lack of continuity or
      absence of the meniscus on one or more MR images. An additional criterion used
      was abnormal increased signal in that area on fat-saturated proton density or T2
      weighted coronal and sagittal images. Prospective MR readings were correlated
      with the arthroscopic findings. RESULTS: Of the 200 consecutive knee
      arthroscopies, 28 patients had radial tears reported arthroscopically (14%
      incidence). MR readings prospectively demonstrated 19 of the 28 radial tears (68%
      sensitivity) when the criteria for diagnosis of a radial tear were truncation or
      abnormal morphology of the meniscus. With the use of the additional criterion of
      increased signal in the area of abnormal morphology on fat-saturated T2-weighted
      or proton density weighted sequences, the prospective sensitivity was 25 of 28
      radial tears (89% sensitivity). There were no radial tears described in MR
      reports that were not demonstrated on arthroscopy (i.e., there were no false
      positive MR readings of radial tears in these 200 patients). CONCLUSIONS: Radial
      tears are commonly seen at arthroscopy. There was a 14% incidence in this series
      of 200 patients who underwent arthroscopy. Prospective detection of radial tears
      was 68% as compared with arthroscopy when the criteria as outlined by Tuckman et
      al. were used alone. With the use of the additional criterion of increased signal
      in the area of abnormal morphology on fat-saturated T2-weighted and proton
      density weighted sequences, the prospective sensitivity for radial tear detection
      as compared with arthroscopy was 89% in our series. Fat-saturated proton density
      and T2-weighted images greatly improve the detection of radial tears as signal
      intensity changes in radial tears as well as morphologic changes can be utilized
      for the detection of subtle tears.

PMID- 12483429
TI  - Diagnostic utility of FDG PET in multiple myeloma.
AB  - OBJECTIVE: Very little information is available regarding the diagnostic utility
      of positron emission tomography with [(18)F]fluorodeoxyglucose (FDG PET) in
      multiple myeloma. Our objective was to further define the role of FDG PET in the
      clinical assessment of patients with multiple myeloma. DESIGN AND PATIENTS: Nine
      whole-body PET scans (45 min after intravenous administration of 370-555 MBq FDG)
      were performed in six patients (age 38-62 years, 5 males) with multiple myeloma
      for evaluation of the extent of disease at the time of initial diagnosis (n=3)
      and for assessment of therapy response (n=3). Three patients had PET scans both
      before and after therapy. Prior treatments included chemoradiation therapy (n=2)
      and chemotherapy with autologous bone marrow transplantation (n=1). Correlative
      imaging data were available in all patients and included skeletal radiographic
      survey (n=6), bone scan (n=3), and spinal CT or MRI (n=4), and were all obtained
      within 3 months of the PET study. Validation was by clinical or imaging follow
      up. RESULTS: In three patients with both pre- and post-therapy PET scans, PET
      demonstrated a favorable treatment response, by showing a decline in lesion
      metabolic activity (n=1), or progression of disease, by showing development of
      new lesions or higher lesion glucose metabolism (n=2), concordant with the
      clinical evaluation, while the other imaging studies showed no discernible
      interval changes. PET detected multiple hypermetabolic lesions in one patient
      with a negative bone scan and concordant positive skeletal radiographic survey.
      Bone scans underestimated the extent of disease in two other patients in
      comparison with PET. PET also detected a few early marrow lesions with subtle
      radiographic changes while all radiographically aggressive lytic lesions
      corresponded to intense hypermetabolism on PET. CONCLUSION: PET can detect early
      marrow involvement of multiple myeloma and is useful in assessing the extent of
      active disease at the time of initial presentation and in evaluating treatment
      response.

PMID- 12483430
TI  - The value of ultrasound after shoulder arthroplasty.
AB  - OBJECTIVE: This study was undertaken to evaluate whether sonography is a useful
      tool in the diagnosis of soft tissue disorders as a possible cause for discomfort
      and/or pain after shoulder arthroplasty. DESIGN AND PATIENTS: Static and dynamic
      ultrasound examinations were performed in the standard sectional planes on 22
      patients with 25 hemiprostheses and the results were correlated with the clinical
      outcome. The stability was determined in the transverse and frontal planes and
      the clinical results were evaluated according to the Constant and Swanson scores.
      RESULTS: Several pathological changes were detected: rotator cuff lesions,
      subdeltoid bursitis, changes around the long biceps tendon as well as an increase
      in intra-articular volume due to effusion and/or synovitis. The correlation of
      sonographic and clinical results demonstrated that patients with an excellent
      clinical result showed no or only a few pathological findings on sonography
      compared with those with a moderate or poor result. CONCLUSION: Pathological
      changes of the periarticular tissue in the direct neighbourhood of the implant
      can be detected by sonography, which can be recommended as a valuable examination
      technique to evaluate the soft tissue in patients after shoulder arthroplasty.

PMID- 12483431
TI  - Muscle sarcoidosis following malignant lymphoma: diagnosis by MR imaging.
AB  - We report on a case of intramuscular sarcoidosis in a patient with gastric
      malignant lymphoma that had been operated on before, and discuss the role of
      magnetic resonance (MR) imaging in characterizing sarcoid nodules in muscle and
      distinguishing them from lymphoma.

PMID- 12483432
TI  - Sarcoidosis breaching the fascia and mimicking a sarcoma.
AB  - A 55-year-old woman complained of a subcutaneous mass in her left buttock. MR
      images revealed an ill-defined soft tissue mass that crossed the fascia of the
      gluteus maximus muscle. Some surrounding edema was noted. The lesion showed some
      contrast uptake after administration of Gd-DTPA. An excisional biopsy revealed
      sarcoidosis involving both the muscle and subcutaneous tissue across the fascia,
      mimicking a sarcoma.

PMID- 12483433
TI  - Atypical form of active melorheostosis and its treatment with bisphosphonate.
AB  - We present the case of a 38-year-old man in whom extensive bilateral
      melorheostosis was associated with elevated serum alkaline phosphatase, swelling
      of the right foot and progressive deformity of the left hand, left leg and right
      foot. Radiography, computed tomography and bone scintigraphy were performed.
      Following treatment with bisphosphonate (30 mg/day of pamidronate for 6 days)
      infusion, the pain and swelling of his right foot showed improvement and his
      elevated serum alkaline phosphatase decreased.

PMID- 12483434
TI  - Ribbing disease: radiographic and biochemical characterization, lack of response
      to pamidronate.
AB  - Ribbing disease is a rare form of sclerosing dysplasia characterized by benign
      endosteal and periosteal bone growth confined to the diaphyses of the long bones,
      usually the tibiae and femora. The onset is usually after puberty and the most
      common presentation is pain that is usually self-limited, but may progress. The
      etiology and optimal treatment for the disease are unknown. We present the case
      of a 39-year-old Hispanic man with clinical and radiological manifestations of
      Ribbing disease. Radiographs and CT imaging demonstrated typical cortical
      thickening in the mid-diaphyses of the tibiae bilaterally that correlated with
      intense tracer uptake on (99m)Tc-MDP bone scans. MRI demonstrated cortical
      thickening and abnormal marrow signal consistent with marrow edema. Bone marrow
      edema may explain the pain frequently associated with the disease. Multiple serum
      and urine markers of bone metabolism were within normal limits. In an effort to
      ameliorate pain, the patient was treated with the bisphosphonate, pamidronate. In
      spite of treatment, pain increased, requiring additional and larger doses of
      analgesics. Serial radiographs, CT, bone scans, and MRI all demonstrated disease
      progression with pamidronate treatment. In this report we present for the first
      time the finding of bone marrow edema with MRI as well as disease progression
      during intravenous pamidronate treatment.

PMID- 12483435
TI  - Unusual florid skeletal manifestations of primary hyperparathyroidism.
AB  - We report a case of primary hyperparathyroidism (PHPT) with advanced and unusual
      skeletal manifestations--a rare occurrence in developed countries nowadays. The
      literature is briefly reviewed.

PMID- 12483436
TI  - Gorham-Stout disease of the shoulder girdle and cervico-thoracic spine: fatal
      course in a 65-year-old woman.
AB  - A case of Gorham-Stout disease of the shoulder girdle and cervico-thoracic spine
      in a 65-year-old woman is described. The patient presented with progressive
      neurologic symptoms, pain, and deformities of the cervico-thoracic spine as well
      as of her left shoulder following a traumatic shoulder luxation. Since the
      patient had a history of uterine carcinoma, the current disease was clinically
      difficult to differentiate from osteolytic metastases. The results of the
      clinical, radiological and histopathologic examination leading to the diagnosis
      of Gorham-Stout disease are described. Neither attempted surgery nor radiotherapy
      produced clinical improvement and the patient died 1 year after the first
      clinical evaluation.

PMID- 12483437
TI  - Autosomal dominant precocious osteoarthropathy due to a mutation of the cartilage
      oligomeric matrix protein (COMP) gene: further expansion of the phenotypic
      variations of COMP defects.
AB  - We report on a Japanese family of four generations with an autosomal dominant
      precocious osteoarthropathy. The cardinal clinical manifestations of affected
      individuals were painful weight-bearing large joints, which started in late
      childhood or adolescence. The radiological hallmarks included coxa plana, mild
      epiphyseal dysplasia of the knee, and round talar domes with tibiotalar slant in
      childhood, which evolved into degenerative joint diseases in adulthood. The
      disease phenotype was cosegregated with a mutation of the cartilage oligomeric
      matrix protein (COMP) gene in the family members, who underwent molecular
      evaluation. COMP mutations have been reported in a mild form of multiple
      epiphyseal dysplasia (MED), Ribbing type, as well as allied disorders with more
      severe manifestations, such as MED Fairbank type and pseudoachondroplasia. Unlike
      previously reported cases with the Ribbing type, the present patients did not
      have short stature or brachydactyly. This report expands further the phenotypic
      variations of COMP defects.

PMID- 12483439
TI  - Investigation of cerebrovascular disease with MR angiography: comparison of
      volume rendering and maximum intensity projection algorithms--initial assessment.
AB  - We assessed the clinical utility of the volume-rendering (VR) algorithm as a
      postprocessing technique of intracranial magnetic resonance angiography (MRA) for
      the evaluation of cerebrovascular disease in comparison with the maximum
      intensity projection (MIP) algorithm. VR and MIP images were compared with
      digital subtraction angiography (DSA). Volume-rendered views improved the
      perceptibility of intracranial vasculature and consequently augmented diagnostic
      confidence, improved the characterization of underlying vascular pathologies, and
      facilitated image interpretation. Volume rendering has the potential to expand
      the role of cerebral MRA in the diagnostic investigation and treatment planning
      of cerebrovascular disease.

PMID- 12483440
TI  - Intracerebral pH affects the T2 relaxation time of brain tissue.
AB  - Signal changes in activated brain areas are detectable by MRI and MR spectroscopy
      (MRS). Shifts in pH occur during brain activation. Our aim was to investigate the
      relationship between changes in pH and T2 relaxation times. T2 was determined in
      vitro at 24 MHz in various liquids at different pH using a Carr-Purcell-Meiboom
      Gill (CPMG) spin-echo sequence. We also studied five Fisher rats were studied at
      2.4 tesla with a double-tuneable surface coil. After baseline measurements,
      potassium cyanide was injected, producing intracerebral acidosis. Alternating
      series of 1H CPMG spin-echo sequences and 31P spectra were acquired. True T2
      relaxation times were calculated from a CPMG multi-echo train. Changes in
      intracellular pH determined from 31P spectra. In vitro measurements demonstrated
      a correlation between T2 and pH that could be described by a quadratic fit curve.
      Depending on the initial pH, changes of 0.2 induced changes in T2 of up to 150
      ms. In vivo measurements confirmed these findings. After intraperitoneal
      injection of a sublethal dose of cyanide, T2 decreased by about 5% in four cases,
      followed by recovery after 2 h. The in vitro measurements demonstrated that
      changes in pH can lead to significant signal change on T2- or T2*- weighted
      images. The dependence of T2 on pH in vitro was confirmed in vivo; it may
      contribute to signal change in activated brain areas.

PMID- 12483441
TI  - Repeatability of long and short echo-time in vivo proton chemical-shift imaging.
AB  - We carried out long (145 ms) and short (25 ms) echo time spectroscopic imaging of
      the brain (chemical-shift imaging, CSI) on two occasions 1 week apart on 15
      healthy individuals. We found coefficients of variation (CVs) generally in the
      range 10-25% for long and 15-30% for short echo-time measurements. The CVs of
      metabolite ratios were higher by about 5-10%. Limits of agreement (defined as
      mean+/-2 SD of the week 1-week 2 differences) were wider at the shorter echo
      time. The modest repeatability may be due in part to the difficulty of
      repositioning spectroscopic voxels at a scale of 1 mm. The generally higher CVs
      and wider limits of agreement at TE25 ms suggest that the increased spectral
      complexity more than offsets the theoretical advantage of increased signal at
      short echo-times. Analysis of variance general linear modelling of metabolites
      and metabolite ratios showed that, in general, the subject, region of the brain
      and hemisphere were more important than the occasion in explaining the
      variability of results. Unless information on short-T2 metabolites is
      specifically required, better results can probably be achieved with longer echo
      times. The magnitude of the CVs needs to be taken into account in the calculation
      of sample size for cross-sectional or linear studies.

PMID- 12483442
TI  - Eclamptic encephalopathy: MRI, including diffusion-weighted images.
AB  - Eclampsia is a rare condition peculiar to pregnant and puerperal women. We
      analyse imaging features in five patients with eclampsia, and determine whether
      diffusion-weighted imaging (DWI) could differentiate cytotoxic and vasogenic
      oedema in four of them. All were imaged within 4 days of the onset of symptoms.
      We found lesions with a prolonged T2 in the brain of all five patients, in the
      basal ganglia in four, pons in three and posterior cerebral white matter in two.
      Isotropic DWI revealed variable intensity in these regions. The ADC was decreased
      in one, and increased in all the others. The lesion with reduced ADC progressed
      to infarction.

PMID- 12483443
TI  - Spectroscopic magnetic resonance imaging of a tumefactive demyelinating lesion.
AB  - Tumefactive demyelinating lesions can present with features similar, clinically
      and radiologically, to those of brain tumours. Proton MR spectroscopy has been
      increasingly used to characterize intracranial pathology. As the underlying
      pathophysiology of neoplasms is different from that of demyelinating disease, one
      may expect the metabolic composition of neoplasms to be significantly different
      from that of demyelinating lesions. We report a 49-year-old woman in whom the
      neurologic and radiologic findings were highly suggestive of a high-grade brain
      tumor, and the spectroscopic features were sufficiently similar to that of a
      tumor to convince the neurosurgeon to operate. This case emphasizes the need for
      caution when confronted with a patient who presents with a differential diagnosis
      of demyelinating lesion versus neoplasm.

PMID- 12483444
TI  - Extreme, unilateral widening of Virchow-Robin spaces: case report.
AB  - We report a case of extreme, largely unilateral dilatation of Virchow-Robin
      spaces. Fluid-attenuated inversion-recovery images revealed high-signal foci
      adjacent to the dilated spaces, possibly due to chronic ischaemia.

PMID- 12483445
TI  - Ruptured pericallosal aneurysm causing hemorrhage along the fornix.
AB  - We present a 57 year-old man with a pericallosal aneurysm causing parenchymal
      hemorrhage in the preseptal region of the frontal lobe with extension into the
      fornix. We briefly discuss the literature pertaining to ruptured pericallosal
      aneurysms and their bleeding patterns.

PMID- 12483446
TI  - Spinal MR findings in spontaneous intracranial hypotension.
AB  - Whole spine magnetic resonance (MR) imaging was used to evaluate the shape, size,
      signal intensity, and enhancement of the spinal spaces in a series of six
      patients with spontaneous intracranial hypotension (SIH). In all patients varying
      degrees of shrunken dural sacs, expanded extradural spaces with delayed
      homogeneous enhancement, and distended epidural venous plexuses were noted. In
      83% (5/6) of patients, the MR signal of the expanded extradural space was similar
      to that of cerebrospinal fluid; 17% (1/6) showed an excessive fat deposit in the
      epidural space. Sixty-seven percent (4/6) of patients had a visible peridural
      membrane. After relief of the symptoms, one patient (1/4) showed persistence of
      the spinal abnormalities even though the brain abnormalities disappeared. In
      conclusion, the spinal MR findings of SIH, like its brain counterpart, are
      characteristic. In cases with clinical suspicion but without support from brain
      MR imaging, spinal MR imaging may be helpful in establishing the diagnosis.

PMID- 12483447
TI  - Spinal dural involvement in Erdheim-Chester disease: MRI findings.
AB  - There are very few reported cases of Erdheim-Chester disease that document
      involvement of dura at the level of the spinal cord. Among these reports, we know
      of no publication that includes detailed MRI findings. To the best of our
      knowledge, the case presented here is the first published report of this specific
      manifestation of Erdheim-Chester disease that includes detailed MRI findings in
      addition to the related history. Spinal manifestations of Erdheim-Chester disease
      in our patient were at the dorsal and lumbar levels (T1-T6 and T12-T11
      respectively). Both epidural and subdural linear large masses were present,
      causing spinal cord compression at the dorsal level and epidural thickening at
      the lumbar level.

PMID- 12483448
TI  - Multiform cervical melanocytoma: a case report.
AB  - Melanocytomas are very rare benign melanocytic tumors of the central nervous
      system (CNS). We present a case of a cervical melanocytoma diagnosed after trauma
      as a result of persistent neck pain and abnormal neurological examination. Early
      recognition of benign melanocytic lesions of the CNS is important, as a complete
      resection can often lead to cure with no need for further treatment.

PMID- 12483449
TI  - Quality of global e-pharmacies: can we safeguard consumers?
AB  - OBJECTIVE: E-pharmacies are web sites selling prescription-only medicines and
      other products including non-prescription and complementary medicines to
      consumers via the internet. This study aims to evaluate the quality of global e
      pharmacies, discuss whether e-pharmacies support the safe and appropriate use of
      medicines, and consider how we can protect consumers in the future. METHODS: A
      survey of public information published on global e-pharmacy web sites was
      conducted between July and September 2001. We used a meta-search engine,
      Copernic, and the search terms of 'online' or 'internet', and 'pharmacy',
      'pharmacies' and 'medicines' to identify a sampling frame of global e-pharmacies.
      We surveyed all web sites in the sampling frame except those under construction
      or only offering electronic refills, members-only and non-English web sites.
      Survey data included country of origin, range of medicines sold, prescription
      requirements, availability of online medical consultations and pharmacists'
      advice, quality accreditation seals, policies and advertisements. RESULTS: E
      pharmacies operated in at least 13 countries; however, the country of origin
      could not be identified for 22 web sites. Twenty web sites (19%) appeared to
      supply prescription-only medicines with no prescription required. Only 12% of e
      pharmacies displayed quality accreditation seals. We observed information
      published on e-pharmacy web sites that potentially undermines the safe and
      appropriate use of medicines. CONCLUSION: Safeguarding consumers and ensuring the
      quality of web sites that sell medicines across state and national boundaries is
      both complex and difficult. Strategies to improve the quality of e-pharmacies
      include independent third-party regulation of providers, evaluation and
      enforcement of sanctions in cases of dissemination of fraudulent or harmful
      information and practices, self-regulation and consumer education. The
      development of internet regulatory technologies themselves and the resolution of
      jurisdictional issues offer future solutions but international co-operation is
      vital.

PMID- 12483451
TI  - Therapeutic drug monitoring data: risperidone does not increase serum clozapine
      concentration.
AB  - BACKGROUND: Two case reports suggest that serum clozapine concentration may
      increase when risperidone is added to clozapine treatment. However, risperidone
      is not a significant inhibitor of the most important clozapine metabolising
      cytochrome P(450) (CYP) enzymes (e.g. CYP1A2). OBJECTIVE: To study whether serum
      clozapine concentrations are affected by risperidone. METHODS: Intraindividual
      comparison of serum clozapine therapeutic drug monitoring data from 18 patients
      during and without risperidone use. RESULTS: Addition of risperidone (mean +/-SD
      dose 2.9+/-0.9 mg/day, range 2-4 mg/day) to clozapine treatment (mean clozapine
      dose 451+/-207 mg/day) did not result in any significant changes in serum
      clozapine concentration or clozapine concentration/dose (C/D) ratio relative to
      the values without risperidone (mean clozapine dose 437+/-168 mg/day). During
      risperidone use mean serum clozapine concentration was 3% (P=0.75) and C/D ratio
      8% (P=0.46) lower than without concomitant risperidone. The mean ratio
      mu(test)/mu(reference) for clozapine C/D ratios was 0.99 (90% CI 0.82-1.15),
      confidence interval being within the equivalence interval of 0.80-1.25.
      CONCLUSIONS: Risperidone does not affect serum clozapine concentrations to any
      significant degree.

PMID- 12483450
TI  - Differential effects of Saint John's Wort (hypericum perforatum) on the urinary
      excretion of D-glucaric acid and 6beta-hydroxycortisol in healthy volunteers.
AB  - OBJECTIVE: We investigated the effects of treatment with Saint John's wort
      (hypericum perforatum) extract on the urinary excretion of D-glucaric acid, 6beta
      hydroxycortisol, and free cortisol in order to assess the effect of this extract
      on the activity of hepatic xenobiotic metabolizing enzymes. METHODS: Forty-eight
      healthy volunteers (25 male and 23 female) received a daily dose of 1800 mg
      hypericum extract for 14 days. Urinary excretion of D-glucaric acid, 6beta
      hydroxycortisol, and free cortisol was measured in 24-h urine samples on the day
      preceding the initiation of hypericum treatment and after 14 days of treatment. D
      Glucaric acid was measured enzymatically. Cortisol and 6beta-hydroxycortisol were
      quantified using high-performance liquid chromatography with ultraviolet
      detection. RESULTS: Urinary excretion of D-glucaric acid was unaffected after a
      14-day treatment with Saint John's wort extract (26.7 micromol/day vs 27.7
      micromol/day; 95% confidence interval of the difference: -1.9 to 3.8). The
      urinary excretion of 6beta-hydroxycortisol increased from a mean baseline value
      of 254 microg/day to 369 microg/day (P<0.0001) indicating induction of CYP3A.
      While the excretion of free cortisol was unaltered, the ratio of 6beta
      hydroxycortisol to free cortisol changed significantly from 9.9 at baseline to
      14.3 (95% confidence interval of the difference: 2.3-6.5) after Saint John's wort
      treatment. CONCLUSIONS: High-dose treatment with Saint John's wort extract
      induced CYP3A activity in healthy volunteers as evidenced by increased 6beta
      hydroxycortisol excretion. This enzyme induction most likely contributes to the
      decreased bioavailability observed upon co-administration of various drugs with
      Saint John's wort extract. The D-glucuronic acid pathway appeared unaffected by
      Saint John's wort.

PMID- 12483452
TI  - Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for
      tacrolimus.
AB  - OBJECTIVES: To compare the population modelling programs NONMEM and P-PHARM
      during investigation of the pharmacokinetics of tacrolimus in paediatric liver
      transplant recipients. METHODS: Population pharmacokinetic analysis was performed
      using NONMEM and P-PHARM on retrospective data from 35 paediatric liver
      transplant patients receiving tacrolimus therapy. The same data were presented to
      both programs. Maximum likelihood estimates were sought for apparent clearance
      (CL/F) and apparent volume of distribution (V/F). Covariates screened for
      influence on these parameters were weight, age, gender, post-operative day, days
      of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver
      function tests, creatinine clearance, haematocrit, corticosteroid dose, and
      potential interacting drugs. RESULTS: A satisfactory model was developed in both
      programs with a single categorical covariate--transplant type--providing stable
      parameter estimates and small, normally distributed (weighted) residuals. In
      NONMEM, the continuous covariates--age and liver function tests--improved
      modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 l/h,
      CL/F (cut-down liver) = 8.5 l/h and V/F = 565 l in NONMEM, and CL/F = 8.3 l/h and
      V/F = 155 l in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole
      liver) = 17.9 +/- 8.8 l/h, CL/F (cut-down liver) = 11.6 +/- 8.8 l/h and V/F = 712
      +/- 792 l in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 l/h, CL/F (cut-down
      liver) = 8.2 +/- 3.4 l/h and V/F = 221 +/- 164 l in P-PHARM. Marked
      interindividual kinetic variability (38-108%) and residual random error
      (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily
      provided informative graphical presentation of results. NONMEM allowed a wider
      choice of errors for statistical modelling and coped better with complex
      covariate data sets. CONCLUSION: Results from parametric modelling programs can
      vary due to different algorithms employed to estimate parameters, alternative
      methods of covariate analysis and variations and limitations in the software
      itself.

PMID- 12483453
TI  - Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive
      patients presenting with type-2 diabetes mellitus.
AB  - OBJECTIVE: Nisoldipine (N) is a dihydropyridine calcium antagonist marketed as a
      racemic mixture and used for the treatment of hypertension. In the present study,
      we investigated the influence of type-2 diabetes mellitus (DM) on the
      enantioselective pharmacokinetic and dynamic parameters of N. METHODS: Seventeen
      hypertensive patients, nine of them with DM, were investigated in a cross-over
      study with administration of rac-N as coat-core tablets (20 mg day(-1)) or
      placebo for 15 days each. Serial blood samples (0-24 h) were collected on the
      15th day, and 24-h ambulatory blood pressure (BP) monitoring was simultaneously
      evaluated. N enantiomers in plasma samples were analysed using chiral high
      performance liquid chromatography combined with gas chromatography/mass
      spectrometry. The enantiomeric ratios differing from one were evaluated using the
      Wilcoxon test, and the results are reported as means with the 95% confidence
      intervals. A lidocaine (L) test was carried out as an in vivo marker of CYP3A4
      (and CYP1A2) activities. RESULTS: The following differences were observed between
      the (+)-N and (-)-N enantiomers, respectively, in the patients presenting with DM
      (means and ranges): C(max) 3.9 (1.7-6.1) ng ml(-1) versus 0.7 (0.4-1.0) ng ml(
      1), AUC(0-24) 51.5 (29.0-74.0) ng ml(-1) h versus 9.4 (5.9-12.8) ng ml(-1) h, and
      Cl/f 3.6 (1.9-5.4) l h(-1) kg(-1) versus 18.7 (11.7-25.7) l h(-1) kg(-1). The
      Cl/f value of (+)-N was lower (Mann-Whitney test) in patients with DM: 6.0 (4.3
      7.5) l h(-1) kg(-1) versus 3.6 (1.9-5.4) l h(-1) kg(-1). The same observation was
      made for the (-)-N, with Cl/f reaching 38.8 (26.8-51.0) l h(-1) kg(-1) and 18.7
      (11.7-25.7) l h(-1) kg(-1) for the non-diabetic and DM groups, respectively. The
      L test resulted in higher ratios (P < 0.05) of plasma L/MEGX concentrations (30
      min after i.v. L) for DM (11.1 vs 18.6). N significantly reduced systolic and
      diastolic BP (P < 0.05, Wilcoxon test) in all patients investigated relative to
      placebo. No differences in BP reduction were observed between diabetic and non
      diabetic patients. N significantly increased noradrenaline concentrations in
      plasma of both patient groups. The data also demonstrated that the plasma
      concentrations of noradrenaline 30 min after N administration were lower (P <
      0.05) in diabetic (mean 2.86 pmol ml(-1)) than in non-diabetic patients (4.80
      pmol ml(-1)). CONCLUSIONS: The present data permit us to infer that type-2
      diabetes mellitus alters the kinetic disposition of the (+)-N eutomer and (-)-N
      distomer, presumably due to a lower activity of CYP3A4, although it does not
      modify the clinical effect brought about by the reduction in BP.

PMID- 12483454
TI  - 'In vitro' binding of propofol to serum lipoproteins in thyroid dysfunction.
AB  - OBJECTIVE: To determine a regression relationship between the unbound fraction
      (fu percent) of propofol, a highly lipophilic intravenous anaesthetic agent, and
      demographic and biochemical variables in a thyroid dysfunction population.
      METHODS: Serum samples from patients with hypo- (n=33) and hyperthyroidism (n=33)
      and also from healthy volunteers (control group; n=9) were spiked with propofol
      to a total (bound + unbound propofol) concentration of 10 microg/ml. The unbound
      concentration was determined using ultrafiltration followed by high-performance
      liquid chromatography with fluorimetric detection and the unbound fraction
      percent (fu) and the binding ratio [bound/free concentration (B/F)] were
      calculated. Albumin, alpha(1)-acid glycoprotein, cholesterol, triglycerides, HDL,
      LDL, VLDL lipoproteins, and T3 and T4 hormone concentrations were measured. B/F
      has a linear relationship with lipoprotein concentration--unlike that for fu
      which is curvilinear - so, we developed a linear regression model of B/F for
      propofol with the above biochemical variables and with gender. RESULTS: The fu in
      hypothyroidism was significantly lower than in the healthy control (mean +/-
      standard deviation 0.74 +/- 0.13% vs 0.87 +/- 0.12%, P < 0.01) but the fu was no
      different in hyperthyroid subjects than controls (0.94 +/- 0.16% vs 0.87 +/-
      0.12%, P > 0.05). HDL, LDL and VLDL lipoproteins were significant predictors of
      B/F (P < 0.05) and were capable of explaining 54% of the variability in the 'in
      vitro' binding of propofol in thyroid disease. CONCLUSION: These results could
      help explain the interindividual variability in the protein binding of propofol
      in thyroid dysfunction patients and suggest the inclusion of lipoproteins in
      covariate model development for the pharmacokinetic/pharmacodynamic parameters of
      propofol.

PMID- 12483455
TI  - Age- and gender-related differences in carbohydrate concentrations of alpha1-acid
      glycoprotein variants and the effects of glycoforms on their drug-binding
      capacities.
AB  - OBJECTIVE: Alpha(1)-acid glycoprotein (AAG) is a major binding protein for
      neutral and basic drugs because of its great drug affinity. AAG has three main
      genetic variants--F1, S, and A variants. Several attempts have been made to
      elucidate the differences in compositions of the carbohydrate moiety and
      structure-function relationships such as drug-binding differences. However, there
      have been few reports on age- and gender-related differences in compositions or
      concentrations of the carbohydrate moiety of AAG variants. The aim of this study
      was to clarify the age- and gender-related differences in carbohydrate
      concentrations and in drug-binding capacities of AAG glycoforms. METHODS: The
      sera used in this study were obtained from 32 healthy subjects (17 men and 15
      women, aged 16-84 years). The AAG glycoforms were isolated by hydroxyapatite
      chromatography. The binding capacity of AAG to disopyramide (DP), which is a
      basic drug, was determined using the ultrafiltration method. The concentrations
      of N-acetylneuraminic acid (NeuAc) and monosaccharides in AAG were determined
      using high-pH anion-exchange chromatography with pulsed-amperometric detection.
      RESULTS: The mean plasma AAG concentration in the female subjects was
      significantly lower than that in the male subjects (0.67 +/- 0.12 mg/ml, mean +/-
      SD, in females, n = 15, versus 0.81 +/- 0.17 mg/ml in males, n = 17, P < 0.05),
      but no age-related differences were found (0.75 +/- 0.18 mg/ml in young subjects,
      n = 24, versus 0.77 +/- 0.12 mg/ml in older subjects, n = 8, n.s.). However, the
      degree of branching of the glycan chain in the female subjects was significantly
      lower than that in the male subjects (1.61 +/- 0.17 mol/mol, mean +/- SD, in
      females, n = 15, versus 1.75 +/- 0.23 mol/mol in males, n = 17, P < 0.05). There
      was a significant inverse relationship between the binding capacity of AAG to DP
      (Cb/AAG) and the degree of branching of the glycan chain. The binding capacity
      (Cb/AAG) decreased as the degree of branching in AAG glycans increased. The
      binding capacity (Cb/AAG) in the female subjects was significantly higher than
      that in the male subjects (2.79 +/- 0.59 mg/g AAG in females, mean +/- SD, n =
      15, versus 2.37 +/- 0.29 mg/g AAG in males, n = 17, P < 0.05). CONCLUSION. The
      degree of branching of the glycan chain in AAG plays an important role in drug
      binding capacity. Gender-related differences in drug-binding capacity (Cb/AAG)
      may be caused by differences in the ratios of the extent of branching of the
      glycan chain in AAG.

PMID- 12483456
TI  - Expressing effects of osteoporosis interventions in terms of postponing of
      fractures.
AB  - OBJECTIVE: To estimate the effect from an osteoporosis intervention in terms of
      postponement of hip fractures. DESIGN: A Markov model using Nordic data on
      mortality and hip fracture incidence. PATIENTS: Women aged 50 years and older
      with increased risk of hip fracture. INTERVENTION: A hypothetical intervention
      that reduces the risk of hip fracture by 50%. MAIN OUTCOME MEASURES: Postponement
      of hip fractures--that is increase in expected fracture-free survival from
      osteoporosis interventions. RESULTS: A 1-year treatment would on average postpone
      hip fracture by 12 days if therapy were started at the age of 50 years and 23,
      55, 90 or 74 days if the treatment were started at the ages of 60, 70, 80 or 90
      years, respectively. For 10 years of treatment, the benefit was 146, 260, 369,
      373 and 167 days, respectively. The younger the patient, the lower the risk of
      fracture and, consequently, the greater the benefit for those few who actually
      could benefit. CONCLUSIONS: The benefit in terms of average postponement of hip
      fractures from osteoporosis intervention was, other things being equal, greatest
      in women aged 70-90 years. Fracture postponement may represent an alternative to
      risk reductions in expressing the effect of osteoporosis interventions.

PMID- 12483457
TI  - Towards a core curriculum in clinical pharmacology for undergraduate medical
      students in Europe.
AB  - Undergraduate medical education has been under the spotlight for many years in
      Europe. In the United Kingdom the General Medical Council, which validates the
      final medical examination in all UK Medical Schools, has been trying to influence
      the curriculum for at least the last 50 years. Following their publication of the
      document "Tomorrow's Doctors" in 1993 many medical schools in the UK have
      completely changed their curriculum design away from didactic learning and
      towards an integrated problem-orientated or problem-based approach. There has
      been concern that, as the process continues, some of the more traditional
      learning of pharmacology and clinical pharmacology may be lost with nothing to
      replace it. This manuscript describe two ways of developing a core curriculum for
      clinical pharmacology. The first uses a drug orientated approach (almost an
      essential drug list) where drugs are listed according to whether they are
      essential for students to know about with just over 120 chemical entities; and a
      shorter list of drugs that students would be expected to know about but not know
      in any detail. The second approach is a disease-orientated one with three types
      of disease process: a list of 67 disease states that students must know how to
      manage (category M), a list of 158 diseases that students must be able to
      diagnose (category D) and a list of 36 diseases that students should be aware of.
      The disease orientated approach, though designed in one EU country (the UK) has
      been field tested in a second (Germany) with little difficulty in transfer.

PMID- 12483458
TI  - Surgical re-intervention in postoperative peritonitis based on longitudinal
      scoring systems.

PMID- 12483459
TI  - ETB receptor deficiency causes salt-sensitive hypertension.

PMID- 12483461
TI  - Lipoprotein lipase: structure, function, regulation, and role in disease.
AB  - Lipoprotein lipase (LPL) catalyses the hydrolysis of the triacylglycerol
      component of circulating chylomicrons and very low density lipoproteins, thereby
      providing non-esterified fatty acids and 2-monoacylglycerol for tissue
      utilisation. Research carried out over the past two decades have not only
      established a central role for LPL in the overall lipid metabolism and transport
      but have also identified additional, non-catalytic functions of the enzyme.
      Furthermore, abnormalities in LPL function have been found to be associated with
      a number of pathophysiological conditions, including atherosclerosis,
      chylomicronaemia, obesity, Alzheimer's disease, and dyslipidaemia associated with
      diabetes, insulin resistance, and infection. Advances have also been made in
      relating the various domains in the protein to different functions, and in
      understanding the mechanisms that are responsible for the changes in LPL
      expression seen in response to nutritional and other physiological changes, and
      during disease. This review summarises recent findings in relation to the
      structure, function, and regulation of LPL along with its important role in
      disease.

PMID- 12483462
TI  - Mechanisms underlying targeted gene correction using chimeric RNA/DNA and single
      stranded DNA oligonucleotides.
AB  - Chimeric RNA/DNA oligonucleotides and modified single-stranded oligonucleotides
      have been developed for site-specific correction of episomal and chromosomal
      target genes. The gene repair approach relies on specific hybridization of the
      oligonucleotides to the target gene generating a mismatch with the targeted point
      mutation. Restored gene function is anticipated to occur through activation of
      endogenous repair systems that recognize the created mismatch. We present an
      overview of the gene correction results obtained in several target genes by
      employing various oligonucleotide designs and a discussion of the possible
      mechanisms underlying the gene correction techniques. Experimental data suggest
      that modified single-stranded oligonucleotides form intermediate three-stranded
      heteroduplexes involving the human RecA homologue, hRad51, whereas chimeric
      RNA/DNA oligonucleotides may participate in three or four-stranded intermediate
      structures. Protein factors such as hRad52, hRad54, hRPA, and p53 may modulate
      the heteroduplex formation and participate in the activation of the endogenous
      mismatch repair and/or nucleotide excision repair pathway(s). The efficiency of
      the gene correction process may furthermore be influenced by the differential
      recognition of mismatches by repair enzymes and possible sequence context
      effects.

PMID- 12483463
TI  - Novel mutations affecting SRY DNA-binding activity: the HMG box N65H associated
      with 46,XY pure gonadal dysgenesis and the familial non-HMG box R30I associated
      with variable phenotypes.
AB  - The SRY gene (sex-determining region of the Y chromosome) initiates the process
      of male sex differentiation in mammalians. In humans mutations in the SRY gene
      have been reported to account for 10-15% of the XY sex reversal cases. We
      describe here two novel missense mutations in the SRY gene after the screening of
      17 patients, including 3 siblings, with 46,XY gonadal dysgenesis and 4 true
      hermaphrodites. One of the mutations, an A to C transversion within the HMG box,
      causes the N65H substitution and it was found in a patient presenting 46,XY pure
      gonadal dysgenesis. The Escherichia coli expressed SRY(N65H) protein did not
      present DNA-binding activity in vitro. The other mutation, a G to T transversion,
      causes the R30I substitution. This mutation was found in affected and nonaffected
      members of a family, including the father, two siblings with partial gonadal
      dysgenesis, a phenotypic female with pure gonadal dysgenesis, and three
      nonaffected male siblings. The G to T base change was not found in the SRY
      sequence of 100 normal males screened by ASO-PCR. The R30I mutation is located
      upstream to the HMG box, within the (29)RRSSS(33) phosphorylation site. The E.
      coli expressed SRY(R30I) protein was poorly phosphorylated and consequently
      showed reduced DNA-binding capacity in vitro.

PMID- 12483464
TI  - The K121Q polymorphism in the plasma cell membrane glycoprotein 1 gene
      predisposes to early myocardial infarction.
AB  - Elevated plasma cell membrane glycoprotein 1 (PC-1) expression and the frequent
      PC-1 K121Q polymorphism have recently been associated with insulin resistance.
      Since insulin resistance represents an important risk factor for atherosclerotic
      vascular disease and myocardial infarction, we investigated the involvement of
      the PC-1 K121Q polymorphism in the development of myocardial infarction. We
      analyzed two independent series of cardiovascular patients at a defined end-point
      of atherosclerotic vascular disease (those having suffered myocardial infarction)
      for the PC-1 K121Q mutation by a newly developed mutagenic separated PCR assay.
      In both patient groups the presence of the Q allele was significantly associated
      with younger age at the time of first myocardial infarction, suggesting a more
      rapid progression of endothelial dysfunction. In a multivariate analysis carriers
      of the 121Q allele from Vienna and from Central Germany exhibited a 2.6- and a
      4.2-increased odds, respectively, for suffering myocardial infarction within the
      first tertile of age (<51 and <48 years, respectively). Our data indicate that
      the PC-1 121Q allele might predispose independently of other well established
      risk factors for early myocardial infarction. Testing for the PC-1 K121Q
      polymorphism might be valuable in patients with a family history of
      atherosclerotic vascular disease and myocardial infarction.

PMID- 12483465
TI  - Polymorphisms of glycoprotein Ib affect the inhibition by aurintricarboxylic acid
      of the von Willebrand factor dependent platelet aggregation.
AB  - Two polymorphisms of platelet glycoprotein Ib, VNTR and Thr/Met(145), regarded as
      the possible inherited risks factors for thromboembolic complications, have been
      suggested to underlie platelet response to activating stimuli. This study
      examined the functional significance of these polymorphisms in platelet
      reactivity and sensitivity to aurintricarboxylic acid (the antagonist of von
      Willebrand factor, vWF). To evaluate platelet function at low and high flow
      conditions we monitored the ristocetin-induced and vWF-mediated aggregation of
      isolated platelets and the platelet function analyzer collagen/ADP closure time
      (PFA-100 CT(CADP)), which reflects platelets' ability to adhere and aggregate in
      whole blood. Aurintricarboxylic acid significantly reduced ristocetin-induced
      platelet agglutination in a dose-dependent manner (IC(50)=3.5+/-1.9 microM). At
      the concentration of 100 microM it also markedly prolonged PFA-100 CT(CADP) (up
      to 147+/-32 s vs. 94+/-17 s in control). The efficacy of this antagonist in the
      inhibition of vWF-mediated platelet agglutination was approximately 1.5-fold
      higher in the VNTR B/Met145(+) carriers than in VNTR B/Met145(-) carriers (
      P<0.05). Otherwise, no significant differences occurred between VNTR B/Met(145)
      positive and B/Met(145)-negative individuals in the prolongation of closure time
      by ATA. These findings indicate that under certain experimental conditions VNTR-B
      and Met(145) alleles may contribute to the increased platelet sensitivity to some
      antagonists of platelet natural ligands.

PMID- 12483466
TI  - Endothelial nitric oxide synthase genotype modulates the improvement of coronary
      blood flow by pravastatin: a placebo-controlled PET study.
AB  - The objective was to study whether coronary blood flow or its response to
      pravastatin are affected by genetic variation in the endothelial nitric oxide
      synthase (eNOS) gene. Vascular endothelial nitric oxide maintains endothelium
      dependent vasodilatation and also mediates antithrombotic actions. Its formation
      is catalyzed by eNOS, a constitutive enzyme, which has a polymorphic site in
      intron 4 (4a/b). Some clinical studies have suggested an association of the rare
      a-allele of eNOS with coronary artery disease and myocardial infarction. We
      carried out a double-blind placebo-controlled study involving 43 men (aged 35+/-4
      years), who were randomized to receive either 40 mg/day pravastatin ( n=21) or
      placebo ( n=22) for 6 months. Myocardial blood flow was measured by positron
      emission tomography (PET) using (15)O-labeled water. PET was performed at rest
      and after stimulation by adenosine infusion. PET and lipid analyses were carried
      out at baseline and after 6 months. eNOS genotyping was done by PCR. At baseline
      there were no differences in basal or adenosine-stimulated coronary blood flow
      between subjects with either eNOS bb or ba genotypes. At the end of the study
      genotypes reacted differently between pravastatin and placebo groups with respect
      to the change in adenosine-stimulated flow (ANCOVA P=0.008). More specifically,
      after pravastatin treatment the adenosine-stimulated flow increased by 54.5% in
      men with the eNOS ba genotype, whereas in the men with the bb genotype no
      significant change in flow was observed ( P=0.002 for ba versus bb). In the
      placebo group there were no significant changes in blood flow from the baseline
      values ( P=0.916 for ba versus bb). After pravastatin treatment both genotype
      groups showed a similar decrease in serum total cholesterol and low-density
      lipoprotein cholesterol ( P<0.00001 for both). Our results suggest that adenosine
      stimulated myocardial perfusion improves after treatment with pravastatin in
      subjects with the eNOS ba genotype but not in those with the bb genotype. This
      effect is not dependent on the decrease of serum cholesterol.

PMID- 12483468
TI  - The effect of space flight on the production of actinomycin D by Streptomyces
      plicatus.
AB  - The effect of space flight on production of the antibiotic actinomycin D by
      Streptomyces plicatus WC56452 was examined onboard the US Space Shuttle mission
      STS-80. Paired space flight and ground control samples were similarly prepared
      using identical hardware, media, and inoculum. The cultures were grown in defined
      and complex media under dark, anaerobic, thermally controlled (20 degrees C)
      conditions with samples fixed after 7 and 12 days in orbit, and viable residuals
      maintained through landing at 17 days, 15 h. Postflight analyses indicated that
      space flight had reduced the colony-forming unit (CFU) per milliliter count of S.
      plicatus and increased the specific productivity (pg CFU(-1)) of actinomycin D.
      The antibiotic compound itself was not affected, but its production time course
      was altered in space. Viable flight samples also maintained their sporulation
      ability when plated on agar medium postflight, while the residual ground controls
      did not sporulate.

PMID- 12483469
TI  - Selection of Escherichia coli-inhibiting strains of Lactobacillus paracasei
      subsp. paracasei.
AB  - The aim of this study was to select Escherichia coli-inhibiting strains among
      lactic acid bacteria. On the basis of phenotypical and technological
      characteristics, 20 strains of lactic acid bacteria were screened from a total of
      225 isolates, obtained from nine samples of artisanal Caprino d'Aspromonte
      cheese, made from raw goats' milk. The antagonistic activity of these 20 strains
      was detected in plates against three different strains of E. coli. Two strains of
      Lactobacillus paracasei subsp. paracasei showed a marked anti-E. coli activity
      against all three strains tested; the other lactic acid bacteria did not exhibit
      inhibiting activity. The E. coli inhibition can be ascribed to production of
      bacteriocin-like compounds. The use of L. paracasei subsp. paracasei strains to
      increase the safety of the cheeses made from raw milk is recommended because
      these cultures strongly inhibit E. coli, without foreseeable adverse sensory
      changes.

PMID- 12483470
TI  - Dinitrogen oxide production by a mixed culture of nitrifying bacteria during
      ammonia shock loading and aeration failure.
AB  - A number of experiments was conducted in order to establish if N(2)O in the
      exhaust gas from an aerobic consortium of nitrifiers could be used as an
      indicator for monitoring the nitrification process. Laboratory-scale experiments
      with an activated sludge system showed a strong correlation between ammonia shock
      loads and both the concentration of N(2)O and the rate of increase of N(2)O in
      the exhaust gas for shock loads less than 1.60 mg ammonical nitrogen (NH(3)-N)
      per g total suspended solids (TSS). For greater ammonia shock loads, correlation
      was found between build-up of nitrite in the aeration tank and the concentration
      of N(2)O in the exhaust gas from the tank. When subjecting the system to aeration
      failure, a similar pattern was seen, with a correlation between nitrite build-up
      in the aeration tank and increases in the concentration of N(2)O in the exhaust
      gas. The results from this work suggest that the changes in N(2)O concentration
      in the exhaust gas from a nitrifying process may be a useful parameter for
      monitoring such processes.

PMID- 12483471
TI  - Influence of the yeast strain on the changes of the amino acids, peptides and
      proteins during sparkling wine production by the traditional method.
AB  - The influence of five yeast strains on the nitrogen fractions, amino acids,
      peptides and proteins, during 12 months of aging of sparkling wines produced by
      the traditional or Champenoise method, was studied. High-performance liquid
      chromatography (HPLC) techniques were used for analysis of the amino acid and
      peptide fractions. Proteins plus polypeptides were determined by the colorimetric
      Bradford method. Four main stages were detected in the aging of wines with yeast.
      In the first stage, a second fermentation took place; amino acids and proteins
      plus polypeptides diminished, and peptides were liberated. In the second stage,
      there was a release of amino acids and proteins, and peptides were degraded. In
      the third stage, the release of proteins and peptides predominated. In the fourth
      stage, the amino acid concentration diminished. The yeast strain used influenced
      the content of free amino acids and peptides and the aging time in all the
      nitrogen fractions.

PMID- 12483472
TI  - Rapid bacterial counts in metal working fluids.
AB  - A rapid (10 s) automated fluorescent method to estimate viable bacteria in metal
      working fluids (MWF) was compared with dip-slide cultures. The BactiFluor method
      compared favorably with 107 MWF (r=0.99) and with 30 other metal processing
      fluids.

PMID- 12483474
TI  - Possible implications of biocide accumulation in the environment on the
      prevalence of bacterial antibiotic resistance.
AB  - The lethality of biocides depends upon their interaction with a number of
      distinct biochemical targets. This often reflects reactive chemistry for any
      given agent, such as thiol oxidation. Susceptibility may vary markedly between
      different target organisms, and changes within the more sensitive targets can
      alter the inhibitory effect. The multiplicity of potential targets, however,
      usually dictates against the development of overt resistance to concentrations
      used for hygienic applications. Similarly, although changes in cellular
      permeability toward such agents, mediated either by envelope modification or the
      induction of efflux-pumps may reduce susceptibility, they rarely influence the
      outcome of treatments at use-concentration. It has recently been proposed that
      chronic exposure of the environment to biocides used in a variety of commercial
      products might expose some microbial communities to subeffective concentrations
      causing emergence of resistant clones. Such resistance might relate to mutational
      changes in the most susceptible target or to regulatory mutants that cause the
      constitutive expression of certain efflux pumps. Although selection of organisms
      with such modifications is unlikely to influence the effectiveness of the
      biocides, changes in their susceptibility to third-party antibiotics can be
      postulated. This is particularly the case where a cellular target is shared
      between a biocide and an antibiotic, or where induction of efflux is sufficient
      to confer antibiotic resistance in the clinic. Although such linkage has been
      demonstrated in the laboratory in pure culture, it has not been documented in
      environments commonly exposed to biocides. In nature, the effects of chronic
      stressing with biocides are complicated by competition between microbial
      community members that may result in clonal expansion of naturally insusceptible
      clones.

PMID- 12483475
TI  - Binary and mixed population biofilms: time-lapse image analysis and disinfection
      with biocides.
AB  - Simultaneous binary population biofilm formation by a bacterium and filamentous
      fungus was demonstrated by time-lapse image analysis in a flow cell system. The
      accumulation of attached bacterial cells followed an S-shaped graph similar to
      batch culture bacterial growth, with continual attachment, detachment, rotation,
      and movement of bacteria over the surface. An extensive hyphal network formed on
      the surface of the flow cell, protruding into the bulk flow, which subsequently
      detached. Multiple species mixed fungal-bacterial model biofilms were tested for
      isothiazolone biocide susceptibility. Biofilms were less susceptible to biocide
      treatment than planktonic cells of the same organisms. Mixed species biofilms,
      particularly for the bacterial species, offered greater protection against the
      action of the biocide compared to single species biofilms. Microbial loss as a
      result of biocide activity was shown by reduced cell surface coverage in electron
      micrographs.

PMID- 12483476
TI  - A mathematical model of quorum sensing in a growing bacterial biofilm.
AB  - In a process called quorum sensing, bacteria monitor their population density via
      extracellular signaling molecules and modulate gene expression accordingly. This
      paper describes a one-dimensional model of a growing Pseudomonas aeruginosa
      biofilm. Quorum sensing has been included in the model by the addition of
      equations describing the production, degradation, and diffusion of acyl
      homoserine lactones in the biofilm. In order for quorum sensing to initiate near
      the substratum, in accordance with experimental observations, model results
      suggest that cells in oxygen-deficient regions of the biofilm must still be
      synthesizing the signal compound. This result highlights the importance of
      careful study of the relationship between metabolic activity of the bacterium and
      signal synthesis.

PMID- 12483477
TI  - The influence of fluid shear on the structure and material properties of sulphate
      reducing bacterial biofilms.
AB  - Biofilms of sulphate-reducing Desulfovibrio sp. EX265 were grown in square
      section glass capillary flow cells under a range of fluid flow velocities from
      0.01 to 0.4 m/s (wall shear stress, tau(w), from 0.027 to 1.0 N/m(2)). In situ
      image analysis and confocal scanning laser microscopy revealed biofilm
      characteristics similar to those reported for aerobic biofilms. Biofilms in both
      flow cells were patchy and consisted of cell clusters separated by voids. Length
      to-width ratio measurements (l(c):w(c)) of biofilm clusters demonstrated the
      formation of more "streamlined" biofilm clusters (l(c):w(c)=3.03) at high-flow
      velocity (Reynolds number, Re, 1200), whereas at low-flow velocity (Re 120), the
      l(c):w(c) of the clusters was approximately 1 (l(c):w(c) of 1 indicates no
      elongation in the flow direction). Cell clusters grown under high flow were more
      rigid and had a higher yield point (the point at which the biofilm began to flow
      like a fluid) than those established at low flow and some biofilm cell aggregates
      were able to relocate within a cluster, by travelling in the direction of flow,
      before attaching more firmly downstream.

PMID- 12483478
TI  - Action of glutaraldehyde and nitrite against sulfate-reducing bacterial biofilms.
AB  - A continuous flow reactor system was developed to evaluate the efficacy of
      antimicrobial treatments against sulfate-reducing bacterial biofilms. An annular
      reactor operating at a nominal dilution rate of 0.5 h(-1) was fed one-tenth
      strength Postgate C medium diluted in 1.5% NaCl and was inoculated with a mixed
      culture enriched from oilfield-produced water on the same medium. Thin biofilms
      developed in this reactor after 2 days of operation. The activity of these
      biofilms resulted in approximately 50 mg S l(-1) of sulfide at steady state prior
      to biocide treatment. Biocide efficacy was quantified by recording the time
      required for sulfide production to recover following an antimicrobial treatment.
      In a control experiment in which pure water was applied, the time required to
      reach 10 mg S l(-1) sulfide after the treatment was 1.7+/-1.2 h, whereas the time
      to reach this level of sulfide after a pulse dose of 500 mg l(-1) glutaraldehyde
      was delayed to 61+/-11 h. Nitrite treatment suppressed sulfide production as long
      as the nitrite concentration remained above 15 mg N l(-1). Sulfide production
      recovered more rapidly after nitrite treatment than it did after glutaraldehyde
      treatment.

PMID- 12483479
TI  - Biofilm material properties as related to shear-induced deformation and
      detachment phenomena.
AB  - Biofilms of various Pseudomonas aeruginosa strains were grown in glass flow cells
      under laminar and turbulent flows. By relating the physical deformation of
      biofilms to variations in fluid shear, we found that the biofilms were
      viscoelastic fluids which behaved like elastic solids over periods of a few
      seconds but like linear viscous fluids over longer times. These data can be
      explained using concepts of associated polymeric systems, suggesting that the
      extracellular polymeric slime matrix determines the cohesive strength. Biofilms
      grown under high shear tended to form filamentous streamers while those grown
      under low shear formed an isotropic pattern of mound-shaped microcolonies. In
      some cases, sustained creep and necking in response to elevated shear resulted in
      a time-dependent fracture failure of the "tail" of the streamer from the attached
      upstream "head." In addition to structural differences, our data suggest that
      biofilms grown under higher shear were more strongly attached and were cohesively
      stronger than those grown under lower shears.

PMID- 12483480
TI  - Rapid assessment of antimould efficacies of pressure-treated southern pine.
AB  - A membrane-screening method was developed in conjunction with flow cytometric
      (FC) analysis for determining the efficacies of antimould pressure-treatment
      formulations for mould species of cosmetic significance on southern pine.
      Fusarium subglutinans, Aspergillus flavus, Penicillium chrysogenum, and
      Paecilomyces spp. were the predominant moulds colonizing surfaces of the
      variously treated pine stored in sealed plastic bags over 3- to 6-month periods.
      Nylon membranes placed directly on pressure-treated pine and membranes saturated
      with the various formulations were inoculated with the conidia of selected
      moulds. FC analysis of conidia stained with propidium iodide (PI) before and
      after exposure to the pressure-treatment formulations permitted a rapid
      assessment of the inocula and selection of those pressure-treatment formulations
      with probable inhibitory activity versus probable nonactive preparations.
      Recoveries of the fungi from the membranes over 9-14 days were in general
      agreement with the emergence of colonizing fungi on the similarly preserved
      uninoculated pine stored in sealed plastic bags for 6 months. This combination of
      procedures provided for a relatively rapid assessment of preservative
      formulations designed to provide enhanced efficacy against surface mould growth
      on lumber during storage and retail display.

PMID- 12483481
TI  - Effects of anti-odor automobile air-conditioning system products on adherence of
      Serratia marcescens to aluminum.
AB  - Sixteen commercial products for use in automobile air-conditioning systems (ACS),
      most designated for abatement of malodors presumably of microbial origin, were
      examined for their potential to inhibit attachment and to detach cells of the
      Gram-negative bacterium Serratia marcescens on aluminum sections. Numbers of
      attached cells were appreciably reduced (>60%) following immersion in three
      alcohol-type and two acrylic-coating-type products. Several products had
      essentially no effect on the attached cells. Most of the products indicated for
      alleviation of associated microbial odors from ACS provided only short-term
      effects. When products were coated onto aluminum prior to exposure to the cells,
      water-insoluble coatings appeared to provide more consistent inhibition of
      primary adherence of S. marcescens. The differences in degrees of primary
      adherence of a selected strain of S. marcescens to variously treated aluminum
      provided a rapid and reproducible assessment of potential antimicrobial efficacy
      of ACS products.

PMID- 12483491
TI  - Repair of spinal cord injuries: where are we, where are we going?
AB  - Repairing the spinal cord has for a long time been a 'holy grail' for
      neuroscientists. No achievement in neuroscience is more difficult to achieve, and
      none would have the same impact amongst the medical profession and the public.
      Yet no patient has yet benefited from a regeneration therapy. At last sufficient
      progress has been made in the basic science of axon regeneration that treatments
      that would partially repair a spinal injury are imminent. A full repair of spinal
      injury still remains elusive. This review summarises progress to date, and
      suggests ways in which progress towards treatment of spinal injury patients might
      be made.

PMID- 12483495
TI  - Nutritional and immune status following spinal cord injury: a case controlled
      study.
AB  - STUDY DESIGN: Case controlled study. OBJECTIVE: To compare nutritional status and
      immune response in a group of spinal cord injured (SCI) patients with age and
      gender matched non SCI control subjects. METHOD: Thirty past patients of the
      Burwood Hospital Spinal Injuries Unit living locally were enrolled in the study.
      Age and gender matched non SCI control subjects were selected volunteers from
      hospital staff. Nutritional status was assessed by generating a Nutritional Risk
      Score (NRS, Appendix 1) and drawing blood for full blood count, iron studies, red
      blood cell folate, vitamin B12, ferritin, magnesium, and zinc. Immune status was
      assessed by vaccination response index (VRI) to Pneumovax 23 vaccine. RESULTS:
      Full blood count, iron studies, and testing for red blood cell folate, albumin,
      prealbumin, vitamin B12, ferritin, magnesium and zinc were normal range for both
      groups. The SCI group had significantly different median values than controls (P
      < 0.01) for haemoglobin concentration, white blood cell count, albumin,
      prealbumin, serum iron and % saturation. Body Mass Index (weight kg/(height
      cm(2)) was 22.2 (range 15-30) for the SCI group, significantly less than the
      paired control group index of 26 (range 20-32, P = 0.0004). Median NRS for SCI
      patients was 2 (range 0-6), compared to 0 (range 2-4) for paired controls (P <
      0.0001). Scores ranged from 0 to 2 for each of the five NRS components for the
      SCI patients and 0 to 3 for the control group. There was no significant
      difference in the pre- and post-vaccination ratio for IgG, IgA, and IgM response
      to Pneumovax 23 vaccine. CONCLUSION: We have not identified any nutritional or
      immune status abnormality in SCI patients, however the SCI patients have a lower
      value for certain nutritional parameters and BMI. SCI patients however are at
      only slight risk of nutritional problems given their NRS and their lower normal
      values for certain nutritional factors.

PMID- 12483496
TI  - Kinetics and steady-state of VO2 responses to arm exercise in trained spinal cord
      injury humans.
AB  - STUDY DESIGN: Cross-sectional study comparing trained spinal cord injured (SCI)
      subjects (lesion level: L1 - T6) with healthy young subjects (CONT). OBJECTIVE:
      To investigate the kinetics of response in oxygen uptake (VO(2)) in human upper
      body skeletal muscles, nine trained SCI subjects underwent submaximal supine arm
      exercises. METHOD: The SCI subjects underwent an incremental arm exercise test
      until exhaustion. The days after this first round of testing, breath-by-breath
      VO(2) and beat-by-beat heart rate (HR) on- and off-kinetics were determined
      during three repetitions of constant exercise at 50% of VO(2peak). The overall
      time course of response was determined from the half time (t(1/2)). Increased
      capillary blood lactate production (delta[La]b) at the onset of exercise was
      defined as the difference between at rest and at the end of exercise. Cardiac
      output (Q) was measured using the acetylene rebreathing method during the steady
      state of exercise. In accordance with the Fick principle, the difference in
      arterial-venous O(2) content (Ca-vO(2)) was defined as VO(2)/Q. RESULTS: During
      the steady state of the submaximal arm exercise, a more significant increase in
      the steady state of Q was obtained in the CONT subjects than in the trained SCI
      subjects: respectively, 14.9+/-1.4 l/min versus (12.7+/-0.8 l/min). There was no
      difference in the steady state of VO(2) between the two groups; as a result, SCI
      subjects had the greater Ca-v(2). Meanwhile, VO(2) on- and off-kinetics became
      much faster in the trained SCI subjects than in the CONT subjects. In addition,
      t(1/2) HR on-kinetics was not significantly different between the SCI and CONT
      groups. Increased Delta[La]b was closely related to larger t(1/2) VO(2) on
      kinetics (r = 0.624, P < 0.05). CONCLUSION: It is concluded that the acceleration
      of VO(2) on- and off-kinetics in the trained SCI subjects was observed even
      though there was no difference in HR on- and off-kinetics between the SCI and
      CONT groups and a lower steady state of Q in the trained SCI subjects. VO(2)
      kinetics would therefore be the limiting factor in oxidative phosphorylation in
      the upper skeletal muscles, thereby providing a lower lactic O(2)-deficit (ie
      delta[La]b).

PMID- 12483497
TI  - Blood flow response in individuals with incomplete spinal cord injuries.
AB  - STUDY DESIGN: Cross sectional comparison, control group. OBJECTIVE: To determine
      if incomplete spinal cord injured patients (SCI) have an abnormal blood flow
      response to cuff ischemia compared to able-bodied individuals (AB). SETTING:
      Academic institution. METHODS: Blood flow in five chronic incomplete SCI patients
      (C4-C5) and 17 able bodied individuals was measured in the common femoral artery
      using quantitative Doppler ultrasound (GE LogiQ 400CL) at rest and after distal
      thigh cuff occlusion of 2, 4 and 10 min to investigate whether blood flow or
      vascular control were different in SCI's and AB. RESULTS: Blood flow and the
      diameter of the common femoral artery at rest were similar in incomplete SCI and
      AB. Peak flow after 10 min of cuff ischemia (the highest found) was also
      comparable between incomplete SCI and AB. The half-time for recovery of blood
      flow to baseline after 2, 4 or 10 min of ischemia was 50% longer for incomplete
      SCI compared to the AB (P = 0.023). In addition, peak blood flow after 2 and 4
      min of ischemia relative to the maximum, 10 min value (2/10 and 4/10 ratios) was
      lower in incomplete SCI compared to AB (0.65 +/- 0.06 vs 0.76 +/- 0.15, P = 0.029
      and 0.75 +/- 0.10 vs 0.89 +/- 0.11, P = 0.014, respectively). CONCLUSION: This
      study demonstrated that incomplete spinal cord injured patients have impaired
      vascular control seen as a slower return to resting flow after cuff ischemia and
      reduced sensitivity to ischemia relative to maximum flow. However, incomplete SCI
      patients did not demonstrate impaired flow capacity as seen in complete SCI
      patients suggesting that smaller cardiovascular abnormalities are seen with
      incomplete versus complete SCI injury. Impaired vascular control may serve to
      limit exercise capacity and may contribute to increased cardiovascular disease.
      Impaired circulation could contribute to impaired muscle function and poor
      cardiovascular health in incomplete SCI's, although these findings need to be
      replicated in a study with more subjects.

PMID- 12483498
TI  - Reduction of periodic leg movement in individuals with paraplegia following
      aerobic physical exercise.
AB  - PURPOSE: According to the American Association of Sleep Disorders, periodic leg
      movements (PLM) are classified into the group of intrinsic sleep disorders.
      Studies on PLM in individuals with spinal cord injury are very recent. The
      objective of the present study was to assess the efficacy of aerobic training in
      reducing the index/score of PLM in individuals with complete spinal cord injury.
      METHODS: Twelve male volunteers with complete spinal cord injury between T7 and
      T12 were submitted to six polysonographies (PSG Oxford Medilog SAC system; EEG,
      EMG and EOG: (1) basal night, (2) 12 h after a maximum effort test, (3) 36 h
      after a maximum effort test, (4) after 44 days of aerobic physical training, (5)
      12 h after the last training session, and (6) 36 h after the last training
      session. All volunteers participated in a physical training program for 44 days
      using an arm crank ergometer. Data were analyzed statistically by the Wilcoxon
      test, with the level of significance set at alpha5%. RESULTS: The results
      demonstrated a statistically significant reduction (P < or = 0.05) in the
      comparison of first evaluation (35.1 PLM/h) with fifth (12.70 PLM/h) and sixth
      evaluation (18.5 PLM/h). CONCLUSION: This study suggests that a program of
      regular and systematized physical activity promotes an effective reduction of PLM
      in individuals with spinal cord injury.

PMID- 12483499
TI  - Significance of low compliance bladder in cauda equina injury.
AB  - STUDY DESIGN: Prospective investigation using serial urodynamic studies.
      OBJECTIVE: To evaluate type of neurogenic bladder and to observe changes of
      autonomous detrusor contraction (ADC) after the normalization of the compliance
      and capacity of the bladder in cauda equina injury. SETTING: Spinal Cord Injury
      Unit, Yonsei Rehabilitation Hospital, Seoul, Korea. METHODS: Urodynamic studies
      were performed in 50 patients with complete cauda equina injury from trauma with
      an infusion ratio of 30 ml/min. Findings of urodynamic studies and clinical
      features of patients with low compliance were compared with those of the normal
      compliant patients. Fourteen patients with low compliance received oral
      administration of oxybutynin and propiverine and intravesical instillation of
      oxybutynin to increase the compliance and capacity of the bladder, and follow-up
      urodynamic studies to monitor the change were undertaken. RESULTS: Bladder
      compliance was decreased in 14 (28%) patients and normal in 36 (72%) patients.
      There was a significantly long time interval between the onset of injury and the
      initiation of rehabilitative treatment in the neurogenic bladder group with low
      compliance when compared to those of the normal compliance group (P < 0.05).
      Clean intermittent catheterization was used as the voiding method, significantly
      less than the normal compliance group (P < 0.05). ADC was observed in six out of
      fourteen patients with low compliance neurogenic bladder, but none in the normal
      compliance group. Upon the completion of conservative treatment, ADC disappeared
      in four patients whose compliance and capacity of the bladder were normalized on
      follow-up urodynamic studies. CONCLUSION: ADC was only observed in the low
      compliant bladder and as ADC disappeared when compliance and capacity of the
      bladder was normalized; low compliance appeared to be the main cause of ADC. In
      addition, this study supports that the maintenance of compliance of the bladder
      may be the most important factor in the management of neurogenic bladder.

PMID- 12483500
TI  - The increase of reactive oxygen species and their inhibition in an isolated
      guinea pig spinal cord compression model.
AB  - STUDY DESIGN: In vitro studies using isolated guinea pig spinal cord. OBJECTIVES:
      To develop an alternative model using isolated guinea pig spinal cord, which can
      be used to screen antioxidants for in vivo SCI treatment. SETTING: Department of
      Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA. METHODS:
      The compression injury was induced by a constant-displacement of 5-s compression
      of spinal cord using a modified forceps possessing a spacer. Reactive oxygen
      species (ROS) were evaluated using three distinct methods: fluorescence
      microscopy, lipid peroxidation assay, and flow cytometry. RESULTS: The injury
      mediated ROS increases are comparable with other in vivo studies and consistent
      with our previous observation using a similar injury model and measured with
      electrophysiological and anatomical technique. Further, ascorbic acid,
      hypothermia, or the combination of both significantly suppressed superoxide and
      lipid peroxidation. The combination treatment was the most effective when
      compared with ascorbic acid or hypothermia alone. CONCLUSION: This in vitro model
      has the advantage of replicating some of the in vivo conditions while gaining the
      ability to control the experimental conditions. This in vitro model is suitable
      to study the mechanisms of ROS generation and degradation and can also be used to
      critically evaluate the effective suppressor of ROS in the contents of spinal
      cord traumatic injury.

PMID- 12483501
TI  - Self-injurious behavior in children and adolescents with spinal cord injuries.
AB  - STUDY DESIGN: A case report of self-injurious behavior in four children and
      adolescents with spinal cord injuries (SCI). OBJECTIVES: To report a relatively
      unusual complication of pediatric-onset SCI, focusing on the potential role that
      dysesthesia may play in self-injurious behavior. SETTING: A Spinal Cord Injury
      Program in a Children's Hospital in Chicago that serves children from midwestern
      and south-central United States of America. METHOD: Case reports and literature
      review. RESULTS: Case reports are presented of four children or adolescents with
      SCI who exhibited self-injurious behavior. Two of the subjects had symptoms
      consistent with dysesthesia. The self-injurious behavior in these two subjects
      and a very young child responded to treatment with anticonvulsants. The self
      injurious behavior in the fourth patient was probably the result of poor
      technique of using his mouth to move his hands, which responded to conservative
      management including education, occupational therapy and gloves. CONCLUSION: Self
      injurious behavior is a relatively unusual complication of pediatric onset SCI,
      and may be a manifestation of dysesthesia and be responsive to treatment with
      anticonvulsants.

PMID- 12483502
TI  - Rugby union.

PMID- 12483506
TI  - Recent progress on the Ada response for inducible repair of DNA alkylation
      damage.

PMID- 12483507
TI  - Oxidative nucleotide damage: consequences and prevention.
AB  - 8-Oxoguanine (8-oxo-7,8-dihydroguanine) is produced in DNA, as well as in
      nucleotide pools of cells, by reactive oxygen species normally formed during
      cellular metabolic processes. 8-Oxoguanine nucleotide can pair with cytosine and
      adenine nucleotides with an almost equal efficiency, then transversion mutation
      ensues. MutT protein of Escherichia coli and related mammalian protein MTH1
      specifically degrade 8-oxo-dGTP to 8-oxo-dGMP, thereby preventing
      misincorporation of 8-oxoguanine into DNA. The bacterial and mammalian enzymes
      are close in their size and share a highly conserved region consisting of 23
      residues with 14 identical amino acids. Following saturation mutagenesis of this
      region, most of these residues proved to be essential to exert 8-oxo-dGTPase
      activity. Gene targeting was done to establish MTH1-deficient cell lines and mice
      for study. When examined 18 months after birth, a greater number of tumors were
      formed in the lungs, livers, and stomachs of MTH1(-/-) mice, as compared with
      findings in wild-type mice. These proteins protect genetic information from
      untoward effects of threats of endogenous oxygen.

PMID- 12483508
TI  - Enzymology of the repair of free radicals-induced DNA damage.
AB  - A number of intrinsic and extrinsic mutagens induce structural damage in cellular
      DNA. These DNA damages are cytotoxic, miscoding or both and are believed to be at
      the origin of cell lethality, tissue degeneration, ageing and cancer. In order to
      counteract immediately the deleterious effects of such lesions, leading to
      genomic instability, cells have evolved a number of DNA repair mechanisms
      including the direct reversal of the lesion, sanitation of the dNTPs pools,
      mismatch repair and several DNA excision pathways including the base excision
      repair (BER) nucleotide excision repair (NER) and the nucleotide incision repair
      (NIR). These repair pathways are universally present in living cells and
      extremely well conserved. This review is focused on the repair of lesions induced
      by free radicals and ionising radiation. The BER pathway removes most of these
      DNA lesions, although recently it was shown that other pathways would also be
      efficient in the removal of oxidised bases. In the BER pathway the process is
      initiated by a DNA glycosylase excising the modified and mismatched base by
      hydrolysis of the glycosidic bond between the base and the deoxyribose of the
      DNA, generating a free base and an abasic site (AP-site) which in turn is
      repaired since it is cytotoxic and mutagenic.

PMID- 12483509
TI  - Dynamics and diversions in base excision DNA repair of oxidized abasic lesions.

PMID- 12483510
TI  - Uracil in DNA--occurrence, consequences and repair.
AB  - Uracil in DNA results from deamination of cytosine, resulting in mutagenic U : G
      mispairs, and misincorporation of dUMP, which gives a less harmful U : A pair. At
      least four different human DNA glycosylases may remove uracil and thus generate
      an abasic site, which is itself cytotoxic and potentially mutagenic. These
      enzymes are UNG, SMUG1, TDG and MBD4. The base excision repair process is
      completed either by a short patch- or long patch pathway, which largely use
      different proteins. UNG2 is a major nuclear uracil-DNA glycosylase central in
      removal of misincorporated dUMP in replication foci, but recent evidence also
      indicates an important role in repair of U : G mispairs and possibly U in single
      stranded DNA. SMUG1 has broader specificity than UNG2 and may serve as a
      relatively efficient backup for UNG in repair of U : G mismatches and single
      stranded DNA. TDG and MBD4 may have specialized roles in the repair of U and T in
      mismatches in CpG contexts. Recently, a role for UNG2, together with activation
      induced deaminase (AID) which generates uracil, has been demonstrated in
      immunoglobulin diversification. Studies are now underway to examine whether mice
      deficient in Ung develop lymphoproliferative malignancies and have a different
      life span.

PMID- 12483511
TI  - Subpathways of nucleotide excision repair and their regulation.
AB  - Nucleotide excision repair provides an important cellular defense against a large
      variety of structurally unrelated DNA alterations. Most of these alterations, if
      unrepaired, may contribute to mutagenesis, oncogenesis, and developmental
      abnormalities, as well as cellular lethality. There are two subpathways of
      nucleotide excision repair; global genomic repair (GGR) and transcription coupled
      repair (TCR), that is selective for the transcribed DNA strand in expressed
      genes. Some of the proteins involved in the recognition of DNA damage (including
      RNA polymerase) are also responsive to natural variations in the secondary
      structural features of DNA. Gratuitous repair events in undamaged DNA might then
      contribute to genomic instability. However, damage recognition enzymes for GGR
      are normally maintained at very low levels unless the cells are genomically
      stressed. GGR is controlled through the SOS stress response in E. coli and
      through the activated p53 tumor suppressor in human cells. These inducible
      responses in human cells are important, as they have been shown to operate upon
      chemical carcinogen DNA damage at levels to which humans are environmentally
      exposed. Interestingly, most rodent tissues are deficient in the p53-dependent
      GGR pathway. Since rodents are used as surrogates for environmental cancer risk
      assessment, it is essential that we understand how they differ from humans with
      respect to DNA repair and oncogenic responses to environmental genotoxins. In the
      case of terminally differentiated mammalian cells, a new paradigm has appeared in
      which GGR is attenuated but both strands of expressed genes are repaired
      efficiently.

PMID- 12483512
TI  - How DNA lesions are turned into mutations within cells?
AB  - Genomes of all living organisms are constantly injured by endogenous and
      exogenous agents that modify the chemical integrity of DNA and in turn challenge
      its informational content. Despite the efficient action of numerous repair
      systems that remove lesions in DNA in an error-free manner, some lesions, that
      escape these repair mechanisms, are present when DNA is being replicated.
      Although replicative DNA polymerases are usually unable to copy past such
      lesions, it was recently discovered that cells are equipped with specialized DNA
      polymerases that will assist the replicative polymerase during the process of
      Translesion Synthesis (TLS). These TLS polymerases exhibit relaxed fidelity that
      allows them to copy past lesions in DNA with an inherent risk of generating
      mutations at high frequency. We present recent aspects related to the genetics
      and biochemistry of TLS and highlight some of the remaining hot topics of this
      field.

PMID- 12483513
TI  - Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome
      stability.
AB  - DNA double-strand breaks represent the most potentially serious damage to a
      genome and hence, at least two pathways of DNA repair have evolved; namely,
      homologous recombination repair and non-homologous end joining. Defects in both
      rejoining processes result in genomic instability including chromosome
      rearrangements, LOH and gene mutations, which may lead to development of
      malignancies. Nijmegen breakage syndrome is a recessive genetic disorder,
      characterized by elevated sensitivity to ionizing radiation that induces double
      strand breaks, and high frequency of malignancies. NBS1, the product of the gene
      underlying the disease, forms a multimeric complex with hMRE11/hRAD50 nuclease
      and recruits them to the vicinity of sites of DNA damage by direct binding to
      phosphorylated histone H2AX. The combination of the highly-conserved NBS1
      forkhead associated domain and BRCA1 C-terminus domain has a crucial role for
      recognition of damaged sites. Thereafter, the NBS1-complex proceeds to rejoin
      double-strand breaks predominantly by homologous recombination repair in
      vertebrates. This process collaborates with cell-cycle checkpoints at S and G2
      phase to facilitate DNA repair. NBS1 is also associated with telomere maintenance
      and DNA replication. Based on recent knowledge regarding NBS1, we propose here a
      two-step binding mechanism for damage recognition by repair proteins, and
      describe the molecular links to factors for genome stability.

PMID- 12483514
TI  - Homologous repair of DNA damage and tumorigenesis: the BRCA connection.
AB  - Homologous recombination has been recognized in recent years to be an important
      DNA repair pathway in mammalian cells, for such damage as chromosomal double
      strand breaks. Cells mutated for the genes involved in the hereditary breast and
      ovarian cancer susceptibility syndromes, i.e. BRCA1 and BRCA2, show defects in
      DNA repair by homologous recombination, implicating this repair pathway in
      protecting individuals against tumorigenesis. This review summarizes recent
      advances in our understanding of BRCA1 and BRCA2 in DNA repair, as well as
      insight into these proteins gleaned from structure determination of domains of
      these proteins and the broader evolutionary conservation than previously
      appreciated.

PMID- 12483515
TI  - The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans.
AB  - BRCA1 and BRCA2 mutations are estimated to be responsible for the great majority
      of familial breast and ovarian cancers. Much progress has been made toward the
      understanding of the function of these proteins through genetic, biochemical, and
      structural studies. The embryonic lethality encountered in the knockout mouse
      initially hindered the development of mouse models aimed at studying tumor
      suppression. However, mice that harbor hypomorphic Brca1 and Brca2 alleles and
      cre-mediated tissue-specific deletions for Brca1 and Brca2 have been generated.
      Mice deficient for either Brca1 or Brca2 sustain a wide range of carcinoma and
      mammary epithelium deleted for Brca1 or Brca2 is highly susceptible to mammary
      tumorigenesis. Mammary (and other) tumors occur at long latency as compared to
      oncogene-induced mouse tumors. p53 deficiency is highly cooperative with both
      Brca1 and Brca2 in promoting tumorigenesis. Analysis of Brca1-associated mammary
      tumors reveals significant similarities to BRCA1-associated breast cancer in
      regard to high tumor grade, hormone receptor negativity, a high incidence of p53
      mutations and genetic instability.

PMID- 12483516
TI  - RecQ family helicases: roles as tumor suppressor proteins.
AB  - RecQ family DNA helicases are defined as proteins sharing a homologous region
      with Escherichia coli RecQ and are basically regarded as enzymes involved in
      recombination. Humans have five RecQ family members, and deficiencies in three of
      them, BLM, WRN, and RTS, cause Bloom's, Werner's, and Rothmund-Thomson syndromes,
      respectively, each characterized by genomic instability and cancer
      predisposition. In this context, an important function of the RecQ homologs
      appears to be the unwinding of intermediates of recombination, thereby preventing
      its uncontrolled execution. As a consequence, their deficiencies give rise to
      elevated levels of recombination (the hyper-recombination phenotype), which
      result in chromosomal aberrations including loss of heterozygosity, a common
      chromosomal change associated with malignancies. Thus, those helicases qualify as
      caretaker-type tumor suppressor proteins. In addition, BLM and WRN deficiencies
      have been shown to attenuate p53-mediated apoptosis, suggesting that they also
      belong to the gatekeeper class of tumor suppressor proteins.

PMID- 12483517
TI  - Structure and function of nucleases in DNA repair: shape, grip and blade of the
      DNA scissors.
AB  - DNA nucleases catalyze the cleavage of phosphodiester bonds. These enzymes play
      crucial roles in various DNA repair processes, which involve DNA replication,
      base excision repair, nucleotide excision repair, mismatch repair, and double
      strand break repair. In recent years, new nucleases involved in various DNA
      repair processes have been reported, including the Mus81 : Mms4 (Eme1) complex,
      which functions during the meiotic phase and the Artemis : DNA-PK complex, which
      processes a V(D)J recombination intermediate. Defects of these nucleases cause
      genetic instability or severe immunodeficiency. Thus, structural biology on
      various nuclease actions is essential for the elucidation of the molecular
      mechanism of complex DNA repair machinery. Three-dimensional structural
      information of nucleases is also rapidly accumulating, thus providing important
      insights into the molecular architectures, as well as the DNA recognition and
      cleavage mechanisms. This review focuses on the three-dimensional structure
      function relationships of nucleases crucial for DNA repair processes.

PMID- 12483518
TI  - Gene silencing in phenomena related to DNA repair.
AB  - DNA methylation is essential for embryonic development and important for
      transcriptional repression, as observed in several biological phenomena. These
      include genomic imprinting, X-inactivation and carcinogenesis. The basic
      mechanism by which DNA methylation silences transcription is generally
      understood, but there is still much to be learned about how DNA methyltransferase
      is targeted to a specific region of the gene. Silencing by DNA methylation occurs
      at an early stage of carcinogenesis, when the DNA repair genes, MGMT and hMLH1,
      are frequently inactivated, resulting in mutations in key cancer-related genes in
      cells. Mice defective in Mgmt and/or Mlh1 gave clear evidence of the significant
      roles of these proteins in carcinogenesis. Recently, it has been demonstrated
      that DNA methylation is linked to histone methylation in fungi and plants,
      although it remains unknown whether this mechanism occurs in mammalian systems.

PMID- 12483519
TI  - Photolyase/cryptochrome blue-light photoreceptors use photon energy to repair DNA
      and reset the circadian clock.
AB  - Blue light governs a number of cellular responses in bacteria, plants, and
      animals, including photoreactivation, plant development, and circadian
      photoentrainment. These activities are mediated by a family of highly conserved
      flavoproteins, the photolyase/cryptochrome family. Photolyase binds to UV
      photoproducts in DNA and repairs them in a process called photoreactivation in
      which blue light is used to initiate a cyclic electron transfer to break bonds
      and restore the integrity of DNA. Cryptochrome, which has a high degree of
      sequence identity to photolyase, works as the main circadian photoreceptor and as
      a component of the molecular clock in animals, including mammals, and regulates
      growth and development in plants.

PMID- 12483520
TI  - Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B.
AB  - Reactive oxygen species, which are prevalent in mitochondria, cause oxidative DNA
      damage including the mutagenic DNA lesion 7,8-dihydroxyguanine (8-oxoG).
      Oxidative damage to mitochondrial DNA has been implicated as a causative factor
      in a wide variety of degenerative diseases, and in cancer and aging. 8-oxoG is
      repaired efficiently in mammalian mitochondrial DNA by enzymes in the base
      excision repair pathway, including the 8-oxoguanine glycosylase (OGG1), which
      incizes the lesion in the first step of repair. Cockayne syndrome (CS) is a
      segmental premature aging syndrome in humans that has two complementation groups,
      CSA and CSB. Previous studies showed that CSB-deficient cells have reduced
      capacity to repair 8-oxoG. This study examines the role of the CSB gene in
      regulating repair of 8-oxoG in mitochondrial DNA in human and mouse cells. 8-oxoG
      repair was measured in liver cells from CSB deficient mice and in human CS-B
      cells carrying expression vectors for wild type or mutant forms of the human CSB
      gene. For the first time we report that CSB stimulates repair of 8-oxoG in
      mammalian mitochondrial DNA. Furthermore, evidence is presented to support the
      hypothesis that wild type CSB regulates expression of OGG1.

PMID- 12483521
TI  - In vitro chemo- and radio-resistance in small cell lung cancer correlates with
      cell adhesion and constitutive activation of AKT and MAP kinase pathways.
AB  - Most small cell lung cancer (SCLC) patients relapse within 12 months of starting
      combination chemotherapy plus radio-therapy, due to the development of acquired
      chemo- and radio-resistance. This phenomenon relates to the induction of tumour
      differentiation, resulting in apoptosis-resistant, morphologically variant (v
      SCLC) cells, which lack the neuroendocrine expression of classic (c-) SCLC cells.
      In this study spontaneously adherent SCLC sublines were shown by differential
      gene expression analysis to provide an in vitro model of variant differentiation
      in SCLC, with down-regulation of neuroendocrine markers and up-regulation of
      epithelial differentiation markers cyclin D1, endothelin, the cell adhesion
      molecules CD 44 and integrin subunits alpha2, beta3 and beta4. The sensitivity of
      adherent SCLC sublines to etoposide, cyclophosphamide and gamma radiation was
      significantly diminished relative to parent suspension cell lines. Western blot
      analysis using phosphorylation-specific antibodies to Akt and MAP kinase revealed
      markedly elevated activation in adherent SCLC sublines, paralleled by increased
      levels of phosphorylated Bad protein and activated NF-kappaB. Subcultivation of
      the adherent sublines on uncoated surfaces reversed their adherent phenotype
      immediately and under these conditions Akt activity reverted to low levels. These
      results suggest that c-SCLC cells can differentiate spontaneously to v-SCLC and
      that the associated cellular adhesion may trigger Akt-dependent inhibition of
      apoptosis in SCLC cells, thus leading to acquired chemo- and radio-resistance.

PMID- 12483522
TI  - GADD45-induced cell cycle G2-M arrest associates with altered subcellular
      distribution of cyclin B1 and is independent of p38 kinase activity.
AB  - In response to DNA damage, the cell cycle checkpoint is an important biological
      event in maintaining genomic fidelity. Gadd45, a p53-regulated and DNA damage
      inducible protein, has recently been demonstrated to play a role in the G2-M
      checkpoint in response to DNA damage. In the current study, we further
      investigated the biochemical mechanism(s) involved in the GADD45-activated cell
      cycle G2-M arrest. Using the tetracycline-controlled system (tet-off), we
      established GADD45-inducible lines in HCT116 (wild-type p53) and Hela
      (inactivated p53 status) cells. Following inducible expression of the Gadd45
      protein, cell growth was strongly suppressed in both HCT116 and Hela cells.
      Interestingly, HCT116 cells revealed a significant G2-M arrest but Hela cells
      failed to arrest at the G2-M phases, indicating that the GADD45-activated G2-M
      arrest requires normal p53 function. The GADD45-induced G2-M arrest was observed
      independent of p38 kinase activity. Importantly, induction of Gadd45 protein
      resulted in a reduction of nuclear cyclin B1 protein, whose nuclear localization
      is critical for the completion of G2-M transition. The reduced nuclear cyclin B1
      levels correlated with inhibition of Cdc2/cyclin B1 kinase activity.
      Additionally, overexpression of cyclin B1 substantially abrogated the GADD45
      induced cell growth suppression. Therefore, GADD45 inhibition of Cdc2 kinase
      activity through alteration of cyclin B1 subcellular localization may be an
      essential step in the GADD45-induced cell cycle G2-M arrest and growth
      suppression.

PMID- 12483523
TI  - Modulation of cystatin C expression impairs the invasive and tumorigenic
      potential of human glioblastoma cells.
AB  - Increases in the abundance of cathepsin B transcript and protein with increased
      tumor grade and changes in subcellular localization and activity of this enzyme.
      We observed progressive reductions in levels of the protease inhibitor cystatin
      C, an inhibitor of cathepsin B with corresponding increases in the malignancy of
      glioma cell lines, implying an inverse correlation between cystatin C and tumor
      grade. To investigate the role of cystatin C in the invasion of brain tumor
      cells, we stably transfected SNB19 glioblastoma cells with either a 0.4-kb cDNA
      construct of human cystatin C in the sense orientation or an empty vector. Clones
      expressing sense-cystatin C cDNA had higher cystatin C mRNA and protein levels
      than did control cells. Sense-transfected cells were also markedly less invasive
      than control cells in a Matrigel invasion assay and in a coculture assay of SNB19
      spheroids and fetal rat brain aggregates. Finally, the sense-transfected cells
      did not form tumors in nude mice upon intracerebral injection. These results
      strongly implicate cystatin C in the invasiveness of human glioblastoma cells and
      suggest that sense transcripts of cystatin C may prove useful in cancer therapy.

PMID- 12483524
TI  - Evidence that instability within the FRA3B region extends four megabases.
AB  - FRA3B is the most frequently expressed common fragile site localized within human
      chromosomal band 3p14.2, which is frequently deleted in many different cancers,
      including cervical cancer. Previous reports indicate aphidicolin-induced FRA3B
      instability occurs over approximately 500 kb which is spanned by the 1.5 Mb
      fragile histidine triad (FHIT) gene. Recently an HPV16 cervical tumor
      integration, 2 Mb centromeric to the published FRA3B region, has been identified.
      FISH-based analysis with a BAC spanning the integration has demonstrated this
      integration occurs within the FRA3B region of instability. These data suggest
      that the unstable FRA3B region is much larger than previously reported. FISH
      based analysis of aphidicolin-induced metaphase chromosomes allowed for a
      complete characterization of instability associated with FRA3B. This analysis
      indicates that fragility extends for 4 Mb. Within this region are a total of five
      genes, including FHIT. FRA3B gene expression analysis on a panel of cervical
      tumor-derived cell lines revealed that three of the five genes within FRA3B were
      aberrantly regulated. A similar analysis of genes outside of FRA3B indicated that
      the surrounding genes were not aberrantly expressed. These data provide
      additional support that regions of instability associated with CFSs and the genes
      contained within them, may play an important role in cancer development.

PMID- 12483525
TI  - Cisplatin-induced activation of the EGF receptor.
AB  - Cisplatin (CDDP) is an efficient DNA-damaging antitumor agent employed for the
      treatment of various human cancers. CDDP activates nuclear as well as
      cytoplasmatic signaling pathways involved in regulation of the cell cycle, damage
      repair and programmed cell death. Here we report that CDDP also activates a
      membrane-integrated protein, the epidermal growth factor receptor (EGFR). We show
      that EGFR is activated in response to CDDP in various types of cells that
      overexpress the receptor, including transformed human glioma cells and human
      breast tumor cells. CDDP-induced EGFR activation requires its kinase activity, as
      it can be blocked by an EGFR kinase inhibitor or by expression of a kinase dead
      receptor. We also show that CDDP-induced EGFR activation is independent of
      receptor ligand. CDDP induces the activation of c-Src, and EGFR activation is
      blocked by Src-family inhibitor PP1, suggesting that Src kinases mediate CDDP
      induced EGFR activation. We propose that EGFR activation in response to CDDP is a
      survival response, since inhibition of EGFR activation enhances CDDP-induced
      death. These findings show that signals generated by DNA damage can modulate EGFR
      activity, and argue that interfering with CDDP-induced EGFR activation in tumor
      cells might be a useful approach to sensitize these cells to genotoxic agents.

PMID- 12483526
TI  - Lung tumorigenesis associated with erb-B-2 and erb-B-3 overexpression in human
      erb-B-3 transgenic mice is enhanced by methylnitrosourea.
AB  - Erb-B-3 overexpression is associated with poor prognosis in non-small cell lung
      cancer and is often overexpressed in breast cancers. MMTVhuman-erb-B-3 transgenic
      mice were generated to evaluate the impact of erb-B-3 overexpression on lung and
      mammary gland tumorigenesis. These transgenic mice developed a high incidence of
      lung adenocarcinomas but not mammary gland tumors. The tumors overexpressed
      transgenic human [h]-erb-B-3 but also overexpressed endogenous erb-B-2,
      indicating that the heterodimer of h-erb-B-3-erb-B-2 was required for
      proliferative signal transduction to the nucleus. Lung tumor latency was shorter
      and the incidence higher in erb-B-3 transgenic mice treated with the methylating
      agent, methylnitrosourea [MNU]. In MNU treated mice, K-ras activating point
      mutations in codon 12, synergized with h-erb-B-3 in lung tumorogenesis. In
      bitransgenic MMTVrat-erb-B2/MMTV-human-erb-B-3 mice, lung tumor latency was also
      significantly shortened. Unlike over-expression of rat-erb-B-2, overexpression of
      h-erb-B-3 did not alter the incidence or latency of mammary tumors. Coupled erb-B
      2 and erb-B-3 overexpression as well as K-ras activation induced signaling
      through mitogen-activated protein kinase (MAPK). This animal model links erb-B-3
      with lung cancer, suggests that erb-B-2 and erb-B-3 heterodimerization is a
      necessary intermediate, and documents latency shortening by methylating agent
      induced mutation of K-ras. This erb-B-3 mouse lung cancer model will help dissect
      genetic changes in lung tumorigenesis and may be useful for chemoprevention
      studies.

PMID- 12483527
TI  - Neoplastic progression in melanoma and colon cancer is associated with increased
      expression and activity of the interferon-inducible protein kinase, PKR.
AB  - The interferon-inducible, double-stranded RNA (dsRNA)-activated protein kinase,
      PKR, plays key roles in regulation of cell growth and differentiation, and has
      been postulated as a tumor suppressor. Downstream effectors of PKR include the
      translation initiation factor, eIF2alpha, and the transcription factor, NF
      kappaB. We found elevated levels of PKR protein, dsRNA-dependent PKR
      autophosphorylation activity, and phosphorylated eIF2alpha in melanoma cells
      compared to nontransformed melanocytes in culture. Treatment with interferon
      alpha2b further induced PKR expression and activity. Immunohistochemical analysis
      of primary melanomas demonstrated minimal PKR immunoreactivity, but melanoma
      lymph node metastases expressed a high level of PKR protein. Furthermore,
      analysis of colon cancer specimens revealed that transformation from normal
      mucosa to adenomas and carcinomas was coincident with an increase in PKR
      expression. These data do not support the concept of PKR as a classic tumor
      suppressor but instead suggest that PKR upregulation occurs at defined steps in
      cancer progression, probably as a cellular response to neoplasia.

PMID- 12483528
TI  - Androgen-induced expression of endoplasmic reticulum (ER) stress response genes
      in prostate cancer cells.
AB  - Evaluations of androgen regulated gene (ARG) repertoire provide new insights into
      the androgen receptor (AR) mediated signaling at the transcriptional level.
      Definition of ARGs having critical functions in the biology of normal and
      malignant prostate should aid in identifying new bio-markers and therapeutic
      targets for prostate cancer (CaP). Using Affymetrix HuGene FL oligonucleotide
      arrays, temporal expression profiles of ARGs in widely used hormone responsive
      LNCaP cells, were analysed by hierarchical clustering methods and functional
      classification. ARGs in response to different androgen concentrations showed
      temporal co-regulation of genes involved in specific biochemical pathways. This
      study focuses on our new observations of the coordinated androgen induction of
      genes (NDRG1, PDIR, HERPUD1, ORP150) involved in the endoplasmic reticulum (ER)
      stress response pathway. Expression analysis of the two selected ER stress
      responsive genes, NDRG1 and HERPUD1 in primary CaPs revealed a significantly
      reduced tumor associated expression. Intriguing linkage of the androgen signaling
      to ER stress responsive genes, a protective response to protein unfolding or
      protein damage resulting from cellular stress signals, suggests that androgens
      may induce such stress signals in CaP cells. Decreased CaP associated expression
      of two ER stress responsive genes also suggests that possible abrogation of this
      pathway in prostate tumorigenesis.

PMID- 12483529
TI  - The human B-cell lymphoma cell line RC-K8 has multiple genetic alterations that
      dysregulate the Rel/NF-kappaB signal transduction pathway.
AB  - The human large B-cell lymphoma cell line RC-K8 has a rearranged REL locus that
      directs the production of a chimeric protein, termed REL-NRG (Non-Rel Gene). In
      this study, we show that RC-K8 cells have constitutively nuclear heterodimeric
      and homodimeric DNA-binding complexes that consist of p50, REL, and REL-NRG. In
      vitro, IkappaBalpha can block the DNA-binding activity of wild-type REL
      homodimers but not REL-NRG homodimers. In vivo, REL-NRG cannot activate
      transcription of a kappaB site reporter plasmid, suggesting that it is a
      transcription repressing or blocking REL protein. By Western blotting, no
      IkappaBalpha protein can be detected in extracts of RC-K8 cells. The absence of
      IkappaBalpha protein in RC-K8 cells appears to be due to mutations that cause
      premature termination of translation in three of the four copies of the IKBA gene
      in RC-K8 cells. Re-expression of wild-type IkappaBalpha or a super-repressor form
      of IkappaBalpha in RC-K8 cells is cytotoxic; in contrast, expression of a
      dominant-negative form of IkappaB kinase does not affect the growth of RC-K8
      cells. By cDNA microarray analysis, a number of previously identified Rel/NF
      kappaB target genes are overexpressed in RC-K8 cells, consistent with there being
      transcriptionally active REL complexes. Taken together, our results suggest that
      the growth of RC-K8 cells is dependent on the activity of nuclear wild-type REL
      dimers, while the contribution of REL-NRG to the transformed state of RC-K8 cells
      is less clear. Nevertheless, the RC-K8 cell line is the first tumor cell line
      identified with mutations in genes encoding multiple proteins in the Rel/NF
      kappaB signal transduction pathway.

PMID- 12483530
TI  - Activation of N-ras and K-ras induced by interleukin-6 in a myeloma cell line:
      implications for disease progression and therapeutic response.
AB  - Ras is a major signaling molecule activated by interleukin-6. There have been no
      published reports, however, that specifically examine the kinetics and percentage
      of Ras activation in response to IL-6. Model cell lines were used to study
      activation of N- and K-ras induced by IL-6. All of the myeloma cell lines we
      tested express both N-ras and K-ras, but not H-ras. GTP-bound Ras was measured
      and the percentage of the total Ras pool that was activated in response to IL-6
      was calculated. IL-6 is able to transiently activate both N- and K-ras in the
      ANBL6 cell line. In addition, increasing concentrations of IL-6 are able to
      activate increasing levels of both N- and K-ras. One ng/ml of IL-6 is able to
      activate approximately 10% of the N-ras pool and 18% of the K-ras pool. The
      amount of Ras-GTP in the cells correlates with the level of proliferation at low
      levels, but proliferation plateaus when higher levels of Ras-GTP are present.
      Protection from dexamethasone-induced apoptosis correlates with IL-6
      concentration and Ras activation. However, IL-6 enhances apoptosis induced by
      doxorubicin. Interestingly, the ANBL6 cell line transfected with an N-ras12 or a
      K-ras12 gene is protected from doxorubicin-induced apoptosis.

PMID- 12483531
TI  - MdmX inhibits Smad transactivation.
AB  - Mdm2 overexpression confers a growth promoting activity upon cells primarily by
      downregulating the p53 tumor suppressor protein. Nevertheless, Mdm2 deregulation
      has also been implicated in inhibiting TGF-beta growth repression in a p53
      independent manner. Our goal in this study was to examine whether overexpression
      of Mdm2 or MdmX, a Mdm2-related protein, could affect Smad-induced
      transactivation. As downstream signaling elements of the TGF-beta pathway, Smads
      represent one potential target for Mdm2 and MdmX. Here we show that MdmX but not
      Mdm2 is capable of inhibiting Smad induced transactivation. Based on deletion
      mutant analysis, MdmX inhibition of Smad transactivation was independent of the
      p53 and Mdm2 interaction domains, yet required amino acid residues 128-444. Using
      TGF-beta sensitive HepG2 cells, MdmX overexpression was shown to inhibit TGF-beta
      induced Smad transactivation. Additionally, mouse embryo fibroblasts (MEFs)
      lacking p53 and MdmX showed enhanced Smad transactivation when compared to MEFs
      lacking either p53 or p53 and Mdm2. Interestingly, the inhibition of Smad
      transactivation by MdmX could be reversed by p300, a functional co-activator of
      Smads and a necessary factor for Mdm2 nuclear export and did not result from
      altered Smad localization. In vitro studies demonstrate that MdmX binds to p300
      as well as Smad3 and Smad4. Taken together, these results suggest that inhibition
      of Smad-induced transactivation by MdmX occurs by altering Smad interaction with
      its coactivator p300.

PMID- 12483532
TI  - Chemotherapy: targeting the mitochondrial cell death pathway.
AB  - One of the mechanisms by which chemotherapeutics destroy cancer cells is by
      inducing apoptosis. Apoptosis can be activated through several different
      signalling pathways, but these all appear to converge at a single event -
      mitochondrial membrane permeabilization (MMP). This 'point-of-no-return' in the
      cell death program is a complex process that is regulated by the composition of
      the mitochondrial membrane and pre-mitochondrial signal-transduction events. MMP
      is subject to a complex regulation, and local alterations in the composition of
      mitochondrial membranes, as well as alterations in pre-mitochondrial signal
      transducing events, can determine chemotherapy resistance in cancer cells.
      Detecting MMP might thus be useful for detecting chemotherapy responses in vivo.
      Several cytotoxic drugs induce MMP by a direct action on mitochondria. This type
      of agents can enforce death in cells in which upstream signals normally leading
      to apoptosis have been disabled. Cytotoxic components acting on mitochondria can
      specifically target proteins from the Bcl-2 family, the peripheral benzodiazepin
      receptor, or the adenine nucleotide translocase, and/or act by virtue of their
      physicochemical properties as steroid analogues, cationic ampholytes, redox
      active compounds or photosensitizers. Some compounds acting on mitochondria can
      overcome the cytoprotective effect of Bcl-2-like proteins. Several agents which
      are already used in anti-cancer chemotherapy can induce MMP, and new drugs
      specifically designed to target mitochondria are being developed.

PMID- 12483533
TI  - Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation
      of Stat5 and growth of CML cells.
AB  - Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized
      by the BCR-ABL genetic translocation and constitutive activation of the Abl
      tyrosine kinase. Among members of the Signal Transducers and Activators of
      Transcription (STAT) family of transcription factors, Stat5 is activated by the
      Bcr-Abl kinase and is implicated in the pathogenesis of CML. We recently
      identified PD180970 as a new and highly potent inhibitor of Bcr-Abl kinase. In
      this study, we show that blocking Bcr-Abl kinase activity using PD180970 in the
      human K562 CML cell line resulted in inhibition of Stat5 DNA-binding activity
      with an IC(50) of 5 nM. Furthermore, abrogation of Abl kinase-mediated Stat5
      activation suppressed cell proliferation and induced apoptosis in K562 cells, but
      not in the Bcr-Abl-negative myeloid cell lines, HEL 92.1.7 and HL-60. Dominant
      negative Stat5 protein expressed from a vaccinia virus vector also induced
      apoptosis of K562 cells, consistent with earlier studies that demonstrated an
      essential role of Stat5 signaling in growth and survival of CML cells. RNA and
      protein analyses revealed several candidate target genes of Stat5, including Bcl
      x, Mcl-1, c-Myc and cyclin D2, which were down-regulated after treatment with
      PD180970. In addition, PD180970 inhibited Stat5 DNA-binding activity in cultured
      primary leukemic cells derived from CML patients. To detect activated Stat5 in
      CML patient specimens, we developed an immunocytochemical assay that can be used
      as a molecular end-point assay to monitor inhibition of Bcr-Abl signaling.
      Moreover, PD180970 blocked Stat5 signaling and induced apoptosis of STI-571
      (Gleevec, Imatinib)-resistant Bcr-Abl-positive cells. Together, these results
      suggest that the mechanism of action of PD180970 involves inhibition of Bcr-Abl
      mediated Stat5 signaling and provide further evidence that compounds in this
      structural class may represent potential therapeutic agents for CML.

PMID- 12483534
TI  - Coordinating Etk/Bmx activation and VEGF upregulation to promote cell survival
      and proliferation.
AB  - Etk/Bmx, a member of the Tec family of non-receptor tyrosine kinase, is
      characterized by an N-terminal PH domain and has recently been shown to be
      involved in the regulation of various cellular processes, including
      proliferation, differentiation, motility and apoptosis. Since VEGF and the
      activation of its signaling pathway have been implicated in modulating a variety
      of biological responses, we characterized the role of Etk-dependent signaling
      pathways involved in the upregulation of VEGF expression, and explored the
      functional implications of this enhancement in sustaining cell proliferation and
      survival. Using Northern and Western analyses, transient transfections, and
      pharmacological agents, we demonstrate that Etk activation alone is sufficient to
      transcriptionally induce VEGF expression, independent of the previously
      identified hypoxia response element (HRE), in both Pa-4 epithelial and TR-BBB
      endothelial cells under normoxia. In addition, Etk utilizes both MEK/ERK and PI3
      K/Pak1 signaling pathways in concert to activate VEGF transcription.
      Functionally, Etk activation elicits a profound stimulatory effect on TR-BBB cell
      proliferation and formation of capillary-like networks in Matrigel containing
      reduced levels of growth factors. Finally, antisense oligonucleotides against
      either endogenous VEGF or Etk abrogate the proliferation of Etk-activated TR-BBB
      cells, and exogenous VEGF treatment stimulates endogenous Etk tyrosine
      phosphorylation in HUVECs. Taken together, these results indicate that VEGF is
      both an Etk downstream target gene and an Etk upstream activator, constituting a
      reciprocal Etk-VEGF autoregulatory loop. These findings, to our knowledge, are
      the first delineation of a network of positive feedforward signaling pathways
      that converge on the Etk-VEGF axis, causally associating Etk-mediation of VEGF
      induction with enhanced cellular processes in both epithelial and endothelial
      cells.

PMID- 12483535
TI  - Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor
      infiltrating macrophages.
AB  - The specific functions of plasminogen, stromal plasminogen activator, stromal
      plasminogen activator receptor, and stromal plasminogen activator inhibitor in
      the progression of the murine soft tissue sarcoma, T241 were investigated.
      Negation of plasminogen to the tumor blunted the orthotopic growth of the sarcoma
      in syngeneic mice. The reduced tumor growth was associated with a dramatic
      increase in tumor-infiltrating F4/80-positive macrophages and a diminution of
      vessel density, but not with obvious differences in fibrin and collagen
      deposition, or invasiveness of the tumor. Ablation of plasminogen activation by
      the tumor stroma only modestly impaired the prolonged growth of the sarcoma,
      suggesting that tumor cell-produced plasminogen activator is sufficient to
      mediate productive plasminogen activation. Plasminogen facilitated sarcoma
      progression, angiogenesis, and suppression of macrophage infiltration in the
      absence of either stromal urokinase plasminogen activator receptor or stromal
      plasminogen activator inhibitor. These data demonstrate that tumor cell-produced
      plasminogen activator and host plasminogen cooperate to facilitate soft tissue
      sarcoma growth and suppress the accumulation of tumor-infiltrating macrophages.

PMID- 12483536
TI  - Down-regulation of caspase 3 in breast cancer: a possible mechanism for
      chemoresistance.
AB  - Caspase-3 is a member of the cysteine protease family, which plays a crucial role
      in apoptotic pathways by cleaving a variety of key cellular proteins. Caspase-3
      can be activated by diverse death-inducing signals, including the
      chemotherapeutic agents. The purpose of this study was to determine the levels of
      caspase-3 expression in breast tumor samples and to determine whether alterations
      in its expression can affect their ability to undergo apoptosis. Primary breast
      tumor and normal breast parenchyma samples were obtained from patients undergoing
      breast surgery and the expression of caspases-3 was studied. Similarly, normal
      mammary epithelial cells and several established mammary cancer cell lines were
      studied for caspases-3 expression by reverse transcriptase-polymerase chain
      reaction, Northern blot analysis, and Western blot analysis. Approximately 75% of
      the tumor as well as morphologically normal peritumoral tissue samples lacked the
      caspase-3 transcript and caspase-3 protein expression. In addition, the caspases
      3 mRNA levels in commercially available total RNA samples from breast, ovarian,
      and cervical tumors were either undetectable (breast and cervical) or
      substantially decreased (ovarian). Despite the complete loss of caspase-3, the
      expression levels of other caspases, such as caspase-8 and caspase-9, were normal
      in all of the tumor samples studied. The sensitivity of caspase-3-deficient
      breast cancer (MCF-7) cells to undergo apoptosis in response to doxorubicin and
      other apoptotic stimuli could be augmented by reconstituting caspase-3
      expression. These results suggest that the loss of caspases-3 expression may
      represent an important cell survival mechanism in breast cancer patients.

PMID- 12483537
TI  - Curcumin-induced suppression of cell proliferation correlates with down
      regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein
      phosphorylation.
AB  - Cyclin D1 is a proto-oncogene that is overexpressed in many cancers including
      breast and prostate. It plays a role in cell proliferation through activation of
      cyclin-dependent kinases. Curcumin, a diferuloylmethane, is a chemopreventive
      agent known to inhibit the proliferation of several breast and prostate cancer
      cell lines. It is possible that the effect of curcumin is mediated through the
      regulation of cyclin D1. In the present report we show that inhibition of the
      proliferation of various prostate, breast and squamous cell carcinoma cell lines
      by curcumin correlated with the down-regulation of the expression of cyclin D1
      protein. In comparison, the down-regulation by curcumin of cyclin D2 and cyclin
      D3 was found only in selective cell lines. The suppression of cyclin D1 by
      curcumin led to inhibition of CDK4-mediated phosphorylation of retinoblastoma
      protein. We found that curcumin-induced down-regulation of cyclin D1 was
      inhibited by lactacystin, an inhibitor of 26S proteosome, suggesting that
      curcumin represses cyclin D1 expression by promoting proteolysis. We found that
      curcumin also down-regulated mRNA expression, thus suggesting transcriptional
      regulation. Curcumin also inhibited the activity of the cyclin D1 promoter
      dependent reporter gene expression. Overall our results suggest that curcumin
      down-regulates cyclin D1 expression through activation of both transcriptional
      and post-transcriptional mechanisms, and this may contribute to the
      antiproliferative effects of curcumin against various cell types.

PMID- 12483538
TI  - YY1 and NF-Y binding sites regulate the transcriptional activity of the dek and
      dek-can promoter.
AB  - The mammalian protein DEK has been implicated in multiple cellular processes,
      including transcriptional regulation, mRNA processing, and chromatin remodeling,
      and is associated with a number of clinical autoimmune and neoplastic conditions.
      The connection between DEK and cancer exists at multiple levels: (a) the t(6;9)
      chromosomal translocation that characterizes a subtype of acute myelogenous
      leukemia cases results in the formation of a DEK-CAN fusion oncoprotein; (b) a
      fragment of dek cDNA is capable of partially reversing the radiation-sensitive
      phenotype of fibroblasts cultured from ataxia-telangiectasia patients; and (c)
      increased levels of dek mRNA have been found to be associated with hepatocellular
      carcinoma, glioblastoma, and melanoma. Despite the growing list of cancer
      subtypes with a connection to DEK, the factors that mediate its expression have
      yet to be characterized. Here we undertake the analysis of DEK regulation by
      mapping the discrete elements within the proximal promoter that are responsible
      for constitutive transcription of dek in transformed cells. We find that
      functional elements include an inverted CCAAT box and a YY1 consensus binding
      site, and the introduction of point mutations into these sites markedly
      diminishes transcriptional activity. In addition, we identify the transcriptional
      activator NF-Y as a member of the CCAAT-binding complex, and verify binding of
      the transcription factor YY1 at its consensus site in the dek promoter. The
      discovery of NF-Y and YY1 as regulatory determinants of DEK expression is
      consistent with the well-documented roles of these two factors in cellular
      proliferation and transformation.

PMID- 12483539
TI  - A role for SHPS-1/SIRPalpha1 in IL-1beta- and TNFalpha-dependent signaling.
AB  - We investigated the role of SHPS-1/SIRPalpha1 in IL-1beta- and TNFalpha-dependent
      signaling that leads to the activation of Erk 1/2 and Akt. Treatment of Balb3T3
      cells with IL-1beta or TNFalpha activated tyrosine phosphorylation of SHPS-1, its
      association with SHP-2 and the phosphorylation of Erk 1/2 and Akt. PP1, a
      specific inhibitor for the Src family protein tyrosine kinases, strongly
      inhibited tyrosine phosphorylation of SHPS-1 and complex formation of SHPS-1 with
      SHP-2 by IL-1beta. In addition, PP1 substantially inhibited the IL-2beta- and
      TNFalpha-dependent activation of Erk 1/2 and Akt. Exogenous expression of either
      SHPS-1 mutants that lack SHP-2 binding function or a dominant negative mutant of
      SHP-2 markedly inhibited the activation of Erk 1/2 and Akt by IL-1beta, whereas
      wild type SHPS-1 did not. Moreover, IL-1beta-stimulation induced association of
      SHPS-1 with IL-1RAcP, a second subunit of IL-1 receptor, whereas expression of
      SHPS-1 mutant that lack SHP-2 binding function clearly blocked the association
      and tyrosine phosphorylation of endogenous SHPS-1. Taken together, our results
      strongly suggest that activation of Erk 1/2 and Akt by proinflammatory cytokines
      requires tyrosine phosphorylation of SHPS-1 and subsequent association of SHPS-1
      with SHP-2.

PMID- 12483540
TI  - Frequent promoter hypermethylation of the O6-Methylguanine-DNA Methyltransferase
      (MGMT) gene in testicular cancer.
AB  - Testicular germ cell tumours are classified into two major histological
      subgroups, seminomas and nonseminomas. All tumours display several recurrent
      chromosomal aberrations, but few target genes have been identified. Previous
      studies have shown that genome-wide hypermethylation of CpG islands is
      significantly more prevalent in nonseminomas than in seminomas. We have studied
      two potential target genes in testicular cancer. A series of 70 tumours were
      analysed for methylation of CpG sites in the O(6)-methylguanine-DNA
      methyltransferase (MGMT) gene promoter, and in exon 1alpha of the cyclin
      dependent kinase inhibitor 2A gene (CDKN2A). In addition, eight microsatellite
      markers within and flanking these genes at chromosome arms 10q and 9p,
      respectively, were analysed for allelic imbalances. Allele alterations were
      frequently seen at 9p loci (47 out of 70, 67%), but none of the tumours (none out
      of 55) showed methylation of CDKN2A. On the other hand, a high frequency of MGMT
      promoter methylation (32 out of 69, 46%) was found, as well as allelic imbalances
      at 10q markers (50 out of 70, 71%). A significantly higher methylation frequency
      was found in nonseminomas (24 out of 35, 69%) compared to seminomas (eight out of
      33, 24%) (P=0.0003, Fisher's exact test). Immunohistochemical analysis of the
      MGMT protein in a subgroup (n=20) of the testicular tumours supported the
      hypothesis of gene silencing being the functional consequence of the promoter
      methylation. In summary, our data suggest that inactivation of MGMT contributes
      to development of nonseminomatous testicular cancer.

PMID- 12483541
TI  - Microcirculation as a target for the anti-inflammatory properties of statins.
AB  - Statins are inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a
      ubiquitous enzyme critical for the biosynthesis of cholesterol. Because of their
      cholesterol-lowering properties, statins are extensively used in medical
      practice, and large clinical trials have shown that statins effectively reduce
      cardiovascular related morbidity and mortality. In the past 5 years, an
      important, new concept suggesting that the cardioprotective effects of statins
      are not necessarily related to cholesterol-lowering actions has emerged. Indeed,
      in vivo findings have clearly shown that statins exert anti-inflammatory and
      immunomodulatory effects and that they modulate vascular remodeling under
      normocholesterolemic conditions. These pleiotropic properties of statins affect
      important molecules in vascular biology and help preserve endothelial function in
      acute and chronic inflammatory states of the cardiovascular system, including
      coronary and cerebral artery diseases, diabetes, and atherosclerosis. Emerging
      evidence indicates that the microcirculation is a crucial target for the
      pleiotropic actions of statins because of its important role in regulating blood
      flow, leukocyte-endothelium interactions, and vascular remodeling. Accordingly,
      this review focuses on the role that the microcirculation plays in the vascular
      protective action of statins.

PMID- 12483542
TI  - Regulation of in situ skeletal muscle arteriolar tone: interactions between two
      parameters.
AB  - OBJECTIVE: The growing understanding of the complexity of mechanisms regulating
      arteriolar tone demands that a systematic determination of how these processes
      interact to alter diameter be undertaken. This study examined how five mediators
      of skeletal muscle distal arteriolar tone [adenosine concentration, oxygen
      content, alpha-adrenergic activation (norepinephrine), intravascular pressure and
      wall shear rate], taken two parameters at a time, interact to regulate vessel
      diameter. METHODS: The reactivity of distal arterioles of in situ rat cremaster
      muscle after alterations in each of the above mediators was assessed. In
      addition, arteriolar responses to all two-parameter combinations were evaluated
      to determine the effect of altered environment on vascular reactivity to stimuli.
      RESULTS: Arteriolar dilation to adenosine was unaltered by changes in other
      parameters. In contrast, wall shear rate-induced arteriolar dilation was impaired
      by 60-88% after increases in the other parameters. Myogenic reactivity was
      reduced by 28% with elevated O(2) and by 65% with norepinephrine (because of
      vessel closure) and was impaired by 89% with elevated adenosine. O(2)-induced
      arteriolar reactivity was impaired by 56% with increased adenosine and by 44%
      with increased norepinephrine concentration but was largely unaffected by
      elevated intravascular pressure. Adrenergic reactivity was attenuated with
      elevated intravascular pressure (by 69%) and O(2) (by 54%) because of vessel
      closure but was unaltered with elevated adenosine. CONCLUSIONS: These data
      suggest that (1) individual mediators contributing to the regulation of
      arteriolar tone exist within a hierarchy of importance and (2) mechanisms
      regulating arteriolar tone can be impacted by unidentified alterations in other
      processes. Ongoing investigation into interactions between multiple processes
      regulating arteriolar tone will allow for a more integrated understanding of how
      microvessels regulate their diameter.

PMID- 12483543
TI  - Regulation of endothelial cell adhesion molecule expression in an experimental
      model of cerebral malaria.
AB  - OBJECTIVE: Plasmodium falciparum malaria in humans and animal models of this
      disease have revealed changes in the infected host that are consistent with a
      systemic inflammatory response. Although it has been proposed that endothelial
      cell adhesion molecules (CAM) contribute to the adhesive interactions of
      Plasmodium-infected erythrocytes and immune cells with vascular endothelial
      cells, ECAM expression has not been systematically studied in Plasmodium-infected
      animals. METHODS: In this study, the dual radiolabeled monoclonal antibody method
      was used to quantify the expression of different ECAMs (ICAM-1, VCAM-1, P
      selectin, E-selectin) in different regional vascular beds of Plasmodium berghei
      ANKA-inffected mice (PbA), a well-recognized model of human cerebral malaria. The
      roles of T lymphocytes and certain cytokines (TNF-alpha, IL-12, IFN-gamma) in
      mediating the infection-induced expression of ICAM-1 and P-selectin were assessed
      by using relevant mutant mice. RESULTS: Wild-type (WT) mice exhibited highly
      significant increases in the expression of ICAM-1, VCAM-1, and P-selectin (but
      not E-selectin) in all vascular beds on the 6th day of PbA infection. The PbA
      induced upregulation of ICAM-1 was significantly blunted in mice that were either
      deficient in IFN-alpha, IL-12 (but not TNF1b) or T lymphocytes (Rag-1
      deficiency); however, these responses were tissue specific. CONCLUSIONS: These
      findings indicate that vascular endothelial cells in most regional circulations
      assume an inflammatory phenotype and that cytokines and immune cells mediate this
      response in a tissue-specific manner.

PMID- 12483544
TI  - Endothelin-a receptor antagonist treatment improves the periosteal
      microcirculation after hindlimb ischemia and reperfusion in the rat.
AB  - OBJECTIVES: To examine the microcirculatory changes in the rat tibial periosteum
      after hindlimb ischemia and reperfusion and to evaluate the effects of endothelin
      A (ET-A) receptor antagonist therapy in this condition. The healing and
      functioning of vascularized bone autografts depend mainly on the patency of the
      microcirculation, and the activation of ET-A receptors may be an important
      component of the tissue response that occurs during ischemia-reoxygenation
      injuries. METHODS: Wistar rats were subjected to 1 hour of hindlimb ischemia and
      3 hours of reperfusion. The periosteal microcirculation was visualized by
      intravital fluorescence microscopy. The leukocyte rolling and adherence in the
      postcapillary venules and the functional capillary density of the periosteum were
      determined. Two separate groups were treated with the selective ET-A receptor
      antagonist BQ 610 or the novel ET-A receptor antagonist ETR-p1/fl peptide at the
      onset of reperfusion. RESULTS: Reperfusion was accompanied by a significant
      decrease in functional capillary density and by an increase in the primary and
      secondary leukocyte-endothelial cell interactions. ET-A receptor inhibition
      reduced the leukocyte rolling and firm adherence and attenuated the decrease in
      functional capillary density in both treated groups. CONCLUSIONS: ET-1 plays a
      major role in microvascular dysfunction in the periosteum during reperfusion. The
      ET-1-ET-A receptor system might be an important target for tissue salvage therapy
      in transplantation surgery.

PMID- 12483545
TI  - L-arginine and antineutrophil serum enable venular control of capillary perfusion
      in hypercholesterolemic rats.
AB  - OBJECTIVE: The purpose of this study was to investigate and counteract
      dysfunctional control of capillary flow in hypercholesterolemia. Capillary flow
      is controlled by arteriolar tone, which in turn is influenced by mediators
      released from closely paired venules in a mechanism that involves nitric oxide
      (NO). However, venular control of capillary flow is altered with
      hypercholesterolemia. METHODS: Rats were given a normal or high-cholesterol diet
      before measurements of mesenteric capillary red blood cell velocity. The
      arteriolar pathway leading to the capillary was videotaped to measure the percent
      of the surrounding area (within 15 |gmm) that was occupied by a venule (%
      pairing). RESULTS: Venule-paired arterioles were significantly smaller in
      hypercholesterolemia compared with normocholesterolemia, corresponding to slower
      capillary flow. A positive correlation between capillary velocity and % pairing
      observed in normocholesterolemia was not observed during NO synthase inhibition
      or in hypercholesterolemic rats. However, positive correlations between the two
      parameters were found in hypercholesterolemia when the rats were given drinking
      water supplementation of L-arginine or an injection of antineutrophil serum, both
      of which tended to improve velocity in capillaries branching from venule-paired
      arteriolar pathways. CONCLUSIONS: Dysfunctional venular control of capillary
      perfusion in hypercholesterolemia may be a consequence of a neutrophil-mediated
      deficiency of NO.

PMID- 12483546
TI  - Development of mouse cremaster transplantation model for intravital microscopic
      evaluation.
AB  - OBJECTIVE: In this study, we investigated the possibility of transplanting
      cremaster muscle in mice. After transplantation, we measured the microcirculatory
      parameters and compared with the cremaster-control values with no
      transplantation. METHODS: In group 1 (n = 10, C57BL/6N), normal cremaster
      microcirculation parameters were measured without transplantation. In group 2 (n
      = 6), isograft transplantations were performed between C57BL/6N mice. After
      transplantation, standard microcirculatory parameters were measured for 3 hours
      in both groups. RESULTS: The procedure was performed with a 95% success rate and
      75 minutes of ischemia time. Functional capillary perfusion, diameters, and red
      blood cell velocities of the first-, second-, and third-order arterioles and
      veins showed significant decreases in the isograft group within the first 2 hours
      (p < 0.05) but returned to normal values at the third hour. The number of
      rolling, adhering, and transmigrating leukocytes and lymphocytes also showed an
      increase in the isograft group within the first and second hours (p < 0.05,
      compared to cremaster control). CONCLUSIONS: Leukocyte/endothelial interaction
      and hemodynamic parameters of muscle flap circulation displayed the effects of
      ischemia in the isograft group. The cremaster muscle transplantation in mice was
      found to be a reliable and reproducible model offering the unique possibility of
      observing and studying the leukocyte-endothelial interaction during
      ischemia/reperfusion injury and allograft rejection using intravital microscopy.

PMID- 12483547
TI  - A three-pathway pore model describes extensive transport data from Mammalian
      microvascular beds and frog microvessels.
AB  - OBJECTIVE: To show that a three-pathway pore model can describe extensive
      transport data in cat and rat skeletal muscle microvascular beds and in frog
      mesenteric microvessels. METHODS: A three-pathway pore model was used to predict
      transport data measured in various microcirculatory preparations. The pathways
      consist of 4- and 24-nm radii pore systems with a 2.5:1 ratio of hydraulic
      conductivities and a water-only pathway of variable conductivity. The pore sizes
      and relative hydraulic conductivities of the small- and large-pore systems were
      derived from a model fit to reflection coefficient (sigma) data in the cat
      hindlimb. The fraction (alpha(w)) of total hydraulic conductivity (L(p)) or
      hydraulic capacity (L(p)S) contributed by the water-only pathway was uniquely
      determined for each preparation by a fit of the three-pathway model (parameters
      fixed as above) to sigma data measured in that preparation. These parameter
      values were unchanged when the model was used to predict diffusion capacity
      (permeability-surface area product, P(d)S) data in the cat or rat preparations or
      diffusional permeability (P(d)) data in frog microvessels. The values for L(p) or
      L(p)S used to predict diffusional data in each preparation were taken from the
      literature. Predictions of P(d) ratios for solute pairs were also compared with
      experimental data. RESULTS: The three-pathway model closely predicted the trend
      of P(d)S or P(d) experimental data in all three preparations; in general,
      predicted P(d) ratios for paired solutes were quite similar to experimental data.
      For these comparisons, the only parameter varied between these preparations was
      alpha(w). It varied considerably, from 7 to 16 to 41% of total in frog, rat, and
      cat preparations. Individual P(d)S or P(d) experimental data were closely
      predicted in the cat but somewhat overestimated in the frog and rat. This result
      could be due the use of L(p) or L(p)S values in the model that were affected by
      methodological problems. Calculated hydraulic conductivities of the water-only
      pathway in the three preparations were quite similar. CONCLUSIONS: : These
      results support the hypothesis of a common structure of the transmembrane
      pathways in these three, very different, microcirculatory preparations. What
      varies considerably between them is the total number of solute-conducting
      pathways, but not their dimensions, nor the hydraulic conductivities of their
      water-only pathways. Because of the wide variation of alpha(w) among these
      preparations, the ratio of P(d) to L(p) for any solute is not constant, but the
      deviation from constancy may not be detectable because of errors in the
      experimental data.

PMID- 12483548
TI  - ZM323881, a novel inhibitor of vascular endothelial growth factor-receptor-2
      tyrosine kinase activity.
AB  - OBJECTIVE: Vascular endothelial growth factor (VEGF) increases vascular
      permeability and angiogenesis in many pathological conditions including cancer,
      arthritis, and diabetes. VEGF activates VEGF-Receptor 1(VEGF-R1) and VEGF
      Receptor 2 (VEGF-R2), which autophosphorylate to initiate a signaling cascade
      resulting in angiogenesis and increased microvascular permeability. Here we
      describe a novel VEGF-R2 selective inhibitor, ZM323881 (5-[[7-(benzyloxy)
      quinazolin-4-yl]amino]-4-fluoro-2-methylphenol), that is a potent and selective
      inhibitor of VEGF-R2 tyrosine kinase in vitro (IC(50) < 2 nM), compared with
      other receptor tyrosine kinases, including VEGF-R1 (IC(50) > 50 microM). METHODS:
      Endothelial cell proliferation was assayed by (3)H-thymidine incorporation in
      response to VEGF-A +/- ZM323881. The effect of ZM323881 on VEGF-mediated
      permeability was measured in frog microvessels using the Landis Michel technique.
      To ensure that ZM323881 was effective in frogs, western analysis was performed on
      protein extracted from frog lungs incubated in the presence or absence of VEGF-A
      or VEGF-A with ZM323881. RESULTS: ZM323881 inhibits VEGF-A-induced endothelial
      cell proliferation (IC(50) = 8 nM) and VEGF-R2 tyrosine phosphorylation in vitro.
      VEGF-A-mediated increases in vascular permeability in perfused mesenteric
      microvessels in vivo were reversibly abolished by both ZM323881 and the class III
      receptor tyrosine kinase inhibitor PTK787/ZK222584. CONCLUSIONS: These data
      suggest that VEGF-R2 phosphorylation is necessary for VEGF-A-mediated increases
      in microvascular permeability in vivo.

PMID- 12483549
TI  - Viscosity-independent velocity of neutrophils rolling on p-selectin in vitro or
      in vivo.
AB  - OBJECTIVE: To determine whether selectin-mediated leukocyte-rolling velocity in
      inflamed venules in vivo is determined by wall shear rate (WSR) or by wall shear
      stress (WSS). METHODS: WSS was manipulated independently of WSR by altering the
      viscosity of blood plasma in mice with an isovolemic exchange of blood for low-
      or high-viscosity dextran solutions. Rolling of neutrophils or beads coated with
      P-selectin glycoprotein ligand-1 (PSGL-1) was reconstituted on P-selectin
      immobilized on the wall of a parallel plate flow chamber at two different
      viscosities of the perfusion medium. RESULTS: Leukocytes in vivo showed no
      increase in rolling velocity when shear stress was doubled by doubling viscosity.
      Neutrophils in the parallel-plate flow chamber in vitro showed the same
      dependence on WSR as leukocytes in vivo, but bead-rolling velocities correlated
      best with WSS. Rolling leukocytes, but not beads, deformed significantly in shear
      flow, and deformation correlated better with WSS. CONCLUSION: These data suggest
      leukocyte deformation during rolling offsets increased bond breakage at higher
      shear stress. The stable rolling velocity allows sufficient surveillance of the
      endothelial surface, even in venules with high WSS. doi:10.1038/sj.mm.7800165

PMID- 12483550
TI  - Mechanisms of heterogeneous endothelial cytoplasmic calcium increases in venular
      microvessels.
AB  - OBJECTIVE: Localized inflammatory leaky sites form at regions of the microvessel
      wall with the largest increase in endothelial cell cytoplasmic calcium
      concentration, [Ca(2+)](i). We investigated the mechanisms that modulate
      localized increases in [Ca(2+)](i) in individual endothelial cells of
      microvessels after exposure to ATP. METHODS: [Ca(2+)](i) was measured by using
      digital fluorescence microscopy and fura-2 in the endothelial cells forming the
      walls of individually perfused frog mesenteric microvessels. The spread of
      [Ca(2+)](i) from a localized mechanical stimulus was also measured. RESULTS: The
      peak [Ca(2+)](i) after ATP showed marked heterogeneity, ranging from 227 to 1469
      nM from resting values of 69 +/- 5 nM. After depolarization with high-potassium
      solutions, the endothelial cells with the largest peak increase in [Ca(2+)](i)
      had the largest fractional reduction. Localized increases in [Ca(2+)](i) due to
      mechanical stimulus did not spread. CONCLUSION: The key mechanism regulating the
      heterogeneity in initial peak increase in [Ca(2+)](i) is a calcium-dependent
      process regulated by the calcium influx itself. One such mechanism, the calcium
      dependent opening of additional potassium channels leading to membrane
      hyperpolarization and increased driving force for calcium entry through passive
      conductance pathways, accounts for a significant amount of the heterogeneity of
      [Ca(2+)](i) in our experiments. Further investigations of both localized calcium
      influx and membrane potentials in the endothelial cells of intact microvessels in
      both frog and mammals using the imaging methods developed for these
      investigations are needed to understand the formation of localized leaky sites in
      inflamed microvessels.

PMID- 12483553
TI  - Structure and function of cyclin-dependent Pho85 kinase of Saccharomyces
      cerevisiae.
AB  - Yeast Saccharomyces cerevisiae has five cyclin-dependent protein kinases (Cdks),
      Cdc28, Srb10, Kin28, Ctk1, and Pho85. Any of these Cdks requires a cyclin partner
      for its kinase activity and a Cdk/cyclin complex, thus produced, phosphorylates a
      set of specific substrate proteins to exert its function. The cyclin partners of
      Srb10, Kin28, and Ctk1 are Srb11, Ccl1, and Ctk2, respectively. In contrast to
      the fact that each of Srb10, Kin28, and Ctk1 has a single cyclin partner, Cdc28
      and Pho85 are polygamous; Cdc28 has 9 cyclins and Pho85 has 10 cyclins. Among
      these Cdks, Kin28 and Cdc28 are essential Cdks and it is well known that Cdc28
      kinase plays a major role in regulating cell cycle progression. Pho85 is a non
      essential Cdk but its absence causes a broad spectrum of phenotypes such as
      constitutive expression of PHO5, inability to utilize non-fermentable carbon
      sources, defects in cell cycle progression, and so on. Pho85 homologues are
      expanding to higher eukaryotes. Pho85 is most closely related with Cdk5 in terms
      of the amino acid sequence. The functional analysis of the domains of Pho85 also
      supports the close relationship between Pho85 and Cdk5, in which it was shown
      that the method of regulation of these two kinases is similar. Furthermore,
      forced expression of the mammalian CDK5 gene in a pho85Delta strain canceled a
      part of the pho85 defects. In this review, we summarize the functions of both
      Pho85/cyclin kinase and emphasize yeast Pho85 as valuable model systems to
      elucidate the functions of their homologues in other organisms.

PMID- 12483554
TI  - Identification of Acetobacter strains isolated from Indonesian sources, and
      proposals of Acetobacter syzygii sp. nov., Acetobacter cibinongensis sp. nov.,
      and Acetobacter orientalis sp. nov. 
AB  - Forty-six strains of acetic acid bacteria newly isolated from flowers, fruits,
      and fermented foods collected in Indonesia were taxonomically studied. They were
      Gram-negative rods, produced acetic acid from ethanol, oxidized acetate and
      lactate to CO(2) and H(2)O, and had Q-9 as the major ubiquinone system. On the
      basis of DNA-DNA similarity, all strains studied, including type strains and
      reference strains of the genus Acetobacter, were separated into eleven groups
      (Groups I to XI). Of the 46 isolates, two isolates were included in Group II and
      identified as Acetobacter pasteurianus, five in Group IV as A. orleanensis, 16 in
      Group V as A. lovaniensis, five in Group VII as A. indonesiensis, and three in
      Group VIII as A. tropicalis. The remaining 15 isolates constituted three new
      groups based on DNA-DNA similarity; four isolates were included in Group IX, two
      in Group X, and nine in Group XI. No isolates were identified as A. aceti (Group
      I), A. peroxydans (Group III), and A. estunensis (Group VI). Phylogenetic
      analysis based on 16S rDNA sequences of representative strains of the Groups
      indicated belonging to the strains of the genus Acetobacter. On the basis of DNA
      base composition, DNA-DNA similarity, and 16S rDNA sequences, three new species
      of the genus Acetobacter are proposed: Acetobacter syzygii sp. nov. for Group IX,
      Acetobacter cibinongensis sp. nov. for Group X, and Acetobacter orientalis sp.
      nov. for Group XI. The distribution of Acetobacter strains in Indonesia is
      discussed in light of isolation sources.

PMID- 12483555
TI  - Efficient export of alkaline phosphatase overexpressed from a multicopy plasmid
      requires degP, a gene encoding a periplasmic protease of Escherichia coli.
AB  - Escherichia coli DegP is an inducible serine protease which is involved in the
      breakdown of abberant proteins arising in the periplasmic compartment.
      Overexpression of alkaline phosphatase (PhoA) increased transcription of degP by
      twofold. To examine the significance of its induction, we overexpressed PhoA in a
      mutant strain deficient in the degP gene. Upon PhoA overexpression, the degP
      mutant produced a smaller amount of active PhoA, about one half of the enzymatic
      activity of its isogenic wild-type strain, and accumulated a larger amount of its
      precursor, indicating that degP is required for efficient export of overexpressed
      PhoA. Pulse-chase experiment showed that PhoA overexpression in the absence of
      degP causes a severe defect in the export of several proteins tested. Examination
      of the synthesis and the accumulation of the phoA gene products revealed that a
      part of them, synthesized in the wild-type strain, undergoes relatively rapid
      proteolysis and that degP is necessary for such a process. From these results, we
      discuss a possible role of DegP in facilitating protein export under stress
      conditions.

PMID- 12483556
TI  - Taxonomic position of new bacteriocin (nukacin ISK-1) producer isolated from long
      aged Nukadoko.

PMID- 12483557
TI  - Purification and characterization of a chitinase from Trichoderma viride.
AB  - Usukizyme, a commercial enzyme preparation from Trichoderma viride, showed
      multiple chitin- degrading activities. One of these was purified to homogeneity
      by sequential DEAE Sepharose CL-6B, Q-Sepharose FF, and Sephacryl S-100 HR column
      chromatographies. The purified enzyme showed optimum activity at pH 3.5 and 50
      degrees -55 degrees C and was stable in the pH range of 3.5-6.0 and up to 45
      degrees C. It showed higher activity toward chitosan-7B, a 62% deacetylated
      chitosan, as opposed to highly deacetylated chitosan substrates. Products of
      degradation of a 1% (w/v) solution of partially deacetylated chitin (PC-100) were
      purified on CM-Sephadex C-25 and analyzed by HPLC, exo-glycosidase digestion, and
      nitrous acid deamination. The enzyme was unable to split the GlcN-GlcN linkages
      in the substrate. It produced mainly (GlcNAc)(2) and (GlcNAc)(3) along with mixed
      oligosaccharides. When subjected to nitrous acid degradation, some of the mixed
      oligosaccharides produced mainly 2-deoxyglucitol, implying the presence of GlcN
      at the reducing end of the oligosaccharides.

PMID- 12483558
TI  - Evaluation of in vitro antibacterial activity of some disinfectants on
      Escherichia coli serotypes.
AB  - Three disinfectants commonly used in poultry farms (formalin, TH4+, and Virkon-S)
      were chosen for the present study. The effect of disinfectant concentration and
      the duration of exposure to these disinfectants on the survival of Escherichia
      coli serotypes (O114:K-, O86, O55:K39, and O86:K60) were investigated. Formalin
      (0.6%), TH4+ (0.06%), and Virkon (0.5%) all killed the four serotypes within 5
      min of exposure. As the disinfectant concentration decreases, the length of
      exposure time to kill serotype increases. At 0.03%, 0.007%, and 0.03% of
      formalin, TH4+ and Virkon-S concentrations failed to kill the four E. coli
      serotypes within 360 min, respectively. An improvement of the inhibitory effect
      of these disinfectants occurred when added together with the inoculum instead of
      an established population. The influence of formalin, TH4+, and Virkon-S on the
      cell morphology of E. coli O55:K39 was investigated by using transmission
      electron microscopy. Formalin-treated cells exhibited normal cell morphology,
      with the exception that the treated cell was less fimbriated, and more
      destruction of pili increased when formalin concentrations were doubled. Cells
      treated with TH4+ (0.03%) showed destruction of the cell wall and cell surface
      membrane after 5 min. Cell filamentation occurred at 0.015% and increased with
      the increase of exposure time to this drug. Spheroplasts were observed only when
      cells were treated with 0.125% Virkon-S for 60 min, and cell lysis started to
      occur when 0.25% Virkon-S was applied for 15 min. Scanning electron microscope
      study revealed that Virkon-S at 0.03% and TH4+ at 0.007% completely prevented the
      adherence of E. coli O55:K39 serotype to chicken tracheal organ, whereas formalin
      (0.03%) disinfection minimized the adherence of E. coli cells to tracheal
      explants after 360 min of incubation.

PMID- 12483559
TI  - Emendation of Dioszegia with redescription of Dioszegia hungarica and two new
      combinations, Dioszegia aurantiaca and Dioszegia crocea.
AB  - During phylogenetic analyses of hymenomycetous yeasts based on 18S rDNA
      sequences, we found that Bullera armeniaca showed an extremely close phylogenetic
      relationship to Cryptococcus hungaricus. The analyses of internal transcribed
      spacer (ITS) regions of the two yeasts and the phylogenetically related species,
      Bullera aurantiaca and Bullera crocea, showed that B. armeniaca and C. hungaricus
      had identical sequences, indicating that these were conspecific. B. aurantiaca
      and B. crocea also showed high sequence similarity, 97.1% for ITS1, 100% for
      ITS2, and 98.7% for overall ITS regions. A DNA-DNA reassociation experiment
      revealed that B. armeniaca and C. hungaricus were conspecific and B. aurantiaca
      and B. crocea were two distinct species. These species occurred at a
      phylogenetically different lineage from that of Bulleromyces albus (anamorph:
      Bullera alba, type species of Bullera) and Filobasidiella neoformans (anamorph:
      Cryptococcus neoformans, neotype species of Cryptococcus). Based on these
      results, we emend the genus Dioszegia to include both ballistoconidium-forming
      and non-ballistoconidium-forming yeasts and redescribe the species Dioszegia
      hungarica. B. aurantiaca and B. crocea are also transferred to Dioszegia as
      Dioszegia aurantiaca comb. nov. and Dioszegia crocea comb. nov.

PMID- 12483561
TI  - Occurrence of aminopropylhomospermidine as the major cellular polyamine in a
      halophilic, phototrophic alpha proteobacterium, Rhodothalassium salexigens.

PMID- 12483560
TI  - The formation and structures of cystites of Arthrobacter ureafaciens NRIC 0157T
      induced by antibiotics.
AB  - The cystite formation of Arthrobacter ureafaciens NRIC 0157(T) was induced by
      some antibiotics, and the addition of tetracycline at a lag phase was effective
      for cystite formation in YPM liquid medium. Cystites differed from vegetative
      cells in the cell wall structure, protein content, and water content.
      Furthermore, the characteristics and structures of cystites induced by
      tetracycline were similar to those of cystites produced by nutritional imbalance
      in CT medium. Consequently, various triggers would induce cystite formation. It
      is interesting that cystite formation was found in part of the Arthrobacter
      strains and seemed to correlate with the type of peptidoglycan.

PMID- 12483562
TI  - Large production of an aromatic amine, 2-phenylethylamine, in a psychrophilic
      marine bacterium, Psychroflexus torquis.

PMID- 12483564
TI  - Impact of mitochondrial activity on the cell wall composition and on the
      resistance to tannic acid in Saccharomyces cerevisiae.
AB  - In screening for resistance to tannic acid, mutants of Saccharomyces cerevisiae
      with an altered cell wall composition were recently isolated. Here we show that
      these mutants were all respiratory deficient. Cytoplasmic petite mutants isolated
      after ethidium bromide mutagenesis were resistant to tannic acid and had cell
      wall characteristics similar to the mutants isolated by screening for tannic acid
      resistance as shown by the lower sensitivity to zymolyase, a cell wall
      hydrolyzing enzyme, and by a changed sensitivity to calcofluor white, a molecule
      interfering with the cell wall assembly. Reintroducing active mitochondria to a
      tannic-acid-resistant mutant reduced the tannic acid resistance and zymolyase
      resistance to the wild-type level, showing that a mitochondrial mutation was
      responsible for the changes in cell wall composition and in tannic acid
      sensitivity.

PMID- 12483563
TI  - Regulation of the amylolytic and (hemi-)cellulolytic genes in aspergilli.
AB  - Filamentous fungi produce high levels of polysaccharide-degrading enzymes and are
      frequently used for the production of industrial enzymes. Because of the high
      secretory capacity for enzymes, filamentous fungi are effective hosts for the
      production of foreign proteins. Genetic studies with Aspergillus nidulans have
      shown pathway-specific regulatory systems that control a set of genes that must
      be expressed to catabolize particular substrates. Besides the pathway-specific
      regulation, wide domain regulatory systems exist that affect a great many
      individual genes in different pathways. A molecular analysis of various regulated
      systems has confirmed the formal models derived from purely genetic data. In
      general, many genes are subject to more than one regulatory system. In this
      article, we describe two transcriptional activators, AmyR and XlnR, and an
      enhancer, Hap complex, in view of their regulatory roles in the expression of the
      amylolytic and (hemi-)cellulolytic genes mainly in aspergilli. The amyR gene has
      been isolated as a transcriptional activator involved in the expression of
      amylolytic genes from A. oryzae, A. niger, and A. nidulans, and the xlnR gene,
      which has been isolated from A. niger and A. oryzae, activates the expression of
      xylanolytic genes as well as some cellulolytic genes in aspergilli. Both AmyR and
      XlnR have a typical zinc binuclear cluster DNA-binding domain at their N-terminal
      regions. Hap complex, a CCAAT-binding complex, enhances the overall promoter
      activity and increases the expression levels of many fungal genes, including the
      Taka-amylase A gene. Hap complex comprises three subunits, HapB, HapC, and HapE,
      in A. nidulans and A. oryzae as well as higher eukaryotes, whereas HAP complex in
      Saccharomyces cerevisiae and Kluyveromyces lactis has the additional subunit,
      Hap4p, which is responsible for the transcriptional activation. Hap complex is
      suggested to enhance transcription by remodeling the chromatin structure. The
      regulation of gene expression in filamentous fungi of industrial interest could
      follow basically the same general principles as those discovered in A. nidulans.
      The knowledge of regulation of gene expression in combination with traditional
      genetic techniques is expected to be increasingly utilized for strain breeding.
      Furthermore, this knowledge provides a basis for the rational application of
      transcriptional regulators for biotechnological processes in filamentous fungi.

PMID- 12483565
TI  - Roles of MexXY- and MexAB-multidrug efflux pumps in intrinsic multidrug
      resistance of Pseudomonas aeruginosa PAO1.
AB  - To envisage the roles of MexXY- and MexAB-multidrug efflux pumps in the intrinsic
      multidrug resistance of wild-type strain Pseudomonas aeruginosa PAO1, we
      constructed mutants lacking either individual or both efflux pumps. A mutant
      lacking MexXY showed increased susceptibility to aminoglycosides, erythromycin,
      and tetracycline, but not to beta-lactams, chloramphenicol, or quinolones. A
      mutant lacking MexAB showed increased susceptibility to beta-lactams,
      chloramphenicol, and nalidixic acid, but not to aminoglycosides, erythromycin,
      tetracycline, or fluoroquinolones. A mutant lacking both MexXY and MexAB showed
      an increased susceptibility to all antimicrobial agents tested compared with the
      wild type. Very similar results were obtained with a mutant lacking MexAB-OprM
      and a mutant lacking both MexXY and MexAB-OprM. Thus it is clear that OprM is
      essential not only for the function of MexAB, but also for the function of MexXY.
      Furthermore, we found that each pump compensated to some extent for the lack of
      another pump with respect to the common substrates (tetracycline, quinolones, and
      cefpirome). The introduction of a plasmid carrying the mexXY genes into P.
      aeruginosa PAO1 cells increased the resistance to fluoroquinolones. This suggests
      that the mexXY genes could be involved in acquired resistance to fluoroquinolones
      in P. aeruginosa PAO1.

PMID- 12483566
TI  - Phytotoxic chaetoglobosins are produced by the plant pathogen Calonectria
      morganii (anamorph Cylindrocladium scoparium).
AB  - By the application of a bioassay based on cresson seedlings, two phytotoxic
      compounds were isolated by thin-layer chromatography from the culture fluid of a
      Calonectria morganii isolate. The structure of both compounds was elucidated by
      ESI/MS and NMR spectroscopy. According to the Chemical Abstracts database, they
      were identified as chaetoglobosin A and 19-O-acetylchaetoglobosin A, mycotoxins
      originally described for Chaetomium globosum.

PMID- 12483567
TI  - Characterization of intermediate phenotypes induced by chemically undefined
      laboratory media in virulent Bordetella bronchiseptica strains.
AB  - The expression of many virulence factors of Bordetella bronchiseptica is
      regulated by the bvgAS locus and reduced in response to environmental signals
      called modulators. Virulent strains can alternate between virulent (Bvg(+)),
      intermediate (Bvg(i)), and modulated (Bvg(+)mod) phenotypes. Potential vaccine
      antigens can be expressed by Bvg1 strains grown only in the absence of
      modulators. In the present study we evaluated filamentous hemagglutinin (FHA) and
      outer membrane protein (OMP) expression in Bvg(+) B. bronchiseptica strains grown
      in chemically undefined media: nutrient agar (NA), tryptic soy agar (TSA),
      tryptose phosphate broth (TPB), and brain-heart infusion (BHI). Our results
      suggest that TSA and TPB usually induce semimodulation, since Bvg(+) strains
      cultured in these media retained the expression of FHA and virulence-associated
      OMPs in the 30 kDa region, but failed to express other virulence markers such as
      OMPs in the regions of 90 and 200 kDa, though they expressed flagellin
      (avirulence marker). On the other hand, NA and BHI usually induce modulation.
      Thus the assayed chemically undefined media should not be used in vaccine
      production. Semimodulation induced by TSA and TPB can be accurately detected by
      SDS-PAGE Sarkosyl-insoluble OMP-enriched profiles. The reduction or absence of
      OMPs in the regions of 90 and 200 kDa is the most sensitive marker, and in some
      cases the presence of flagellin in intermediate profiles is another trait of the
      Bvg(i) phenotypes. Therefore these markers could be useful for selecting media
      for vaccine production. We also characterized the phenotype of Bvg(+) strains
      grown in Stainer-Scholte broth, an expensive medium, with and without
      glutathione, and we have detected no differences; this is the first attempt to
      reduce the cost of a Bordetella growth medium for veterinary vaccine production.

PMID- 12483568
TI  - Metalloadsorption by Saccharomyces cerevisiae cells expressing invertase
      metallothionein (Suc2-Cup1) fusion protein localized to the cell surface.

PMID- 12483569
TI  - Themes for mushroom exploitation in the 21st century: Sustainability, waste
      management, and conservation.
AB  - Because many natural resources are limited, sustainability becomes an important
      concept in maintaining the human population, health, and environment. Mushrooms
      are a group of saprotrophic fungi. Mushroom cultivation is a direct utilization
      of their ecological role in the bioconversion of solid wastes generated from
      industry and agriculture into edible biomass, which could also be regarded as a
      functional food or as a source of drugs and pharmaceuticals. To make the mushroom
      cultivation an environmentally friendly industry, the basic biology of mushrooms
      and the cultivation technology must be researched and developed. This is very
      true for Lentinula edodes, Volvariella volvacea, and Ganoderma lucidum, which are
      commonly consumed in Asian communities but are now gaining popularity worldwide.
      Besides the conventional method, strain improvement can also be exploited by
      protoplast fusion and transformation. Biodiversity is the key contribution to the
      genetic resource for breeding programs to fulfill different consumer demands. The
      conservation of these mushrooms becomes essential and is in immediate need not
      only because of the massive habitat loss as a result of human inhabitation and
      deforestation, but also because of the introduced competition by a cultivar with
      the wild germ plasm. Spent mushroom compost, a bulky solid waste generated from
      the mushroom industry, however, can be exploited as a soil fertilizer and as a
      prospective bioremediating agent.

PMID- 12483570
TI  - Biochemical and genetic bases of microbial degradation of polychlorinated
      biphenyls (PCBs).
AB  - The microbial degradation of polychlorinated biphenyls (PCBs) has been
      extensively conducted by many workers, and the following general results have
      been obtained. (1) PCBs are degraded oxidatively by aerobic bacteria and other
      microorganisms such as white rot fungi. PCBs are also reductively dehalogenated
      by anaerobic microbial consortia. (2) The biodegradability of PCBs is highly
      dependent on chlorine substitution, i.e., number and position of chlorine. The
      degradation and dehalogenation capabilities are also highly strain dependent. (3)
      Biphenyl-utilizing bacteria can cometabolize many PCB congeners to
      chlorobenzoates by biphenl-catabolic enzymes. (4) Enzymes involved in the PCB
      degradation were purified and characterized. Biphenyl dioxygenase, ring-cleavage
      dioxygenase, and hydrolase are crystallized, and two ring-cleavage dioxygenases
      are being solved by x-ray crystallography. (5) The bph gene clusters responsible
      for PCB degradation are cloned from a variety of bacterial strains. The structure
      and function are analyzed with respect to the evolutionary relationship. (6) The
      molecular engineering of biphenyl dioxygenases is successfully performed by DNA
      shuffling, domain exchange, and subunit exchange. The evolved enzymes exhibit
      wide and enhanced degradation capacities for PCBs and other aromatic compounds.

PMID- 12483571
TI  - Four new species of Kockovaella isolated from plant leaves collected in Vietnam.
AB  - Five ballistoconidiogenous yeast strains, isolated from plant leaves at Cuc
      Phuong National Forest of Ninh Binh, Vietnam, were assigned to the genus
      Kockovaella based on morphological and chemotaxonomical characteristics. They
      represent four new species based on analyses of 18S rDNA sequence, sequences of
      internal transcribed spacer regions, and DNA-DNA reassociation experiments. Four
      new species, Kockovaella calophylli (1 strain), Kockovaella cucphuongensis (2
      strains), Kockovaella litseae (1 strain), and Kockovaella vietnamensis (1 strain)
      are proposed for these strains.

PMID- 12483572
TI  - Simple detection of a yeast mitochondrial DNA-binding protein, Abf2p, on SDS-DNA
      gels.
AB  - Abf2p, a mitochondrial DNA-binding protein of yeast Saccharomyces cerevisiae, was
      selectively detected among mitochondrial nucleoid proteins by SDS-DNA
      polyacrylamide gel electrophoresis (SDS-DNA PAGE) followed by ethidium bromide
      staining. This method is simple and specific for the detection of Abf2p, and it
      may be used to identify an Abf2p-like protein that is present in mitochondrial
      nucleoids from other yeasts.

PMID- 12483573
TI  - Phylogenetic and phenotypic relationships of microorganisms that degrade
      uncoupler compound, 2,4-dinitrophenol.

PMID- 12483574
TI  - Bacterial strategies to inhabit acidic environments.
AB  - Bacteria can inhabit a wide range of environmental conditions, including extremes
      in pH ranging from 1 to 11. The primary strategy employed by bacteria in acidic
      environments is to maintain a constant cytoplasmic pH value. However, many data
      demonstrate that bacteria can grow under conditions in which pH values are out of
      the range in which cytoplasmic pH is kept constant. Based on these observations,
      a novel notion was proposed that bacteria have strategies to survive even if the
      cytoplasm is acidified by low external pH. Under these conditions, bacteria are
      obliged to use acid-resistant systems, implying that multiple systems having the
      same physiological role are operating at different cytoplasmic pH values. If this
      is true, it is quite likely that bacteria have genes that are induced by
      environmental stimuli under different pH conditions. In fact, acid-inducible
      genes often respond to another factor(s) besides pH. Furthermore, distinct genes
      might be required for growth or survival at acid pH under different environmental
      conditions because functions of many systems are dependent on external
      conditions. Systems operating at acid pH have been described to date, but
      numerous genes remain to be identified that function to protect bacteria from an
      acid challenge. Identification and analysis of these genes is critical, not only
      to elucidate bacterial physiology, but also to increase the understanding of
      bacterial pathogenesis.

PMID- 12483575
TI  - Isolation and enzyme determination of Candida tropicalis mutants for DCA
      production.
AB  - Techniques, named two-step enrichment and double-time replica-plating method
      (TEDR), are described that allow a mutated population of Candida tropicalis to be
      enriched efficiently for mutants deficient in the alkane degradation pathway
      (Alk(-)) and to be selected easily for mutants increasing in the DCA
      (dicarboxylic acids) excretion pathway. After C. tropicalis was mutated with
      ethyl methane sulphonate and ultraviolet, the Alk(-) mutants were enriched (the
      first step enrichment, up to eightfold in one round of enrichment) by treatment
      with nystatin in medium SEL1-1. The mutagen-treated cells were then cultured in
      medium YPD containing chlorpromazine for further enriching (the second-step
      enrichment, up to threefold in one round) the mutants with an increasing capacity
      of alpha- and omega-oxidation. On the other hand, the Alk(-) mutants were readily
      isolated by the SEL1 replica-plating method by using alkane or glucose as the
      sole carbon source. A total of 43 Alk(-) mutants were isolated from 2x10(8)
      mutagen-treated cells. In the following steps, by using SEL2 replica plating, the
      screening studies showed that of the 43 Alk(-) mutants, 11 strains could
      accumulate DCA greatly from alkane, and strains 1-12 and 1-3, especially, could
      produce nearly three times as much DCA as the wild-type organism could. The
      results showed that the strains had more cytochrome P450 activity and a higher
      converting capacity of alkane.

PMID- 12483576
TI  - Transfer of 'Thermoactinomyces glaucus' IFO 12530 and 'Thermoactinomyces
      monosporus' IFO 14050 to the genus Saccharomonospora as members of
      Saccharomonospora glauca.
AB  - Two available strains of 'Thermoactinomyces glaucus' and 'Thermoactinomyces
      monosporus', 'T. glaucus' IFO 12530 and 'T. monosporus' IFO 14050, were
      considered not to be members of the genus Thermoactinomyces and that they
      belonged to the genus Saccharomonospora on the basis of the colors of colonies
      and 16S rDNA sequences. Some chemotaxonomic characteristics also showed that the
      two strains belong to the genus Saccharomonospora. The two strains contained meso
      diaminopimelic acid, galactose, and arabinose in the cell wall and MK-9(H(4)) as
      the predominant menaquinone. The genomic DNAs of the two strains had a G+C
      content of 69 mol%. The 16S rDNAs of 'T. glaucus' IFO 12530 and 'T. monosporus'
      IFO 14050 showed only 1 and 2 bp sequence differences, respectively, from that of
      the type strain of Saccharomonospora glauca. Furthermore, the two strains of 'T.
      glaucus' and 'T. monosporus' and the type strain of S. glauca shared identical
      16S-23S rDNA ITS sequences. The levels of DNA-DNA relatedness confirm that the
      two strains of 'T. glaucus' and 'T. monosporus' are members of Saccharomonospora
      glauca. Therefore it is proposed that 'T. glaucus' IFO 12530 and 'T. monosporus'
      IFO 14050 should be considered as strains belonging to Saccharomonospora glauca.

PMID- 12483577
TI  - Phylogenetic identification of n-alkane assimilating Candida yeasts based on
      nucleotide divergence in the 59 end of LSU rDNA gene.
AB  - Phylogenetic relationships of several species within the n-alkane assimilating
      Candida yeasts were investigated by using characters from the nucleotide sequence
      of the variable D1/D2 region at the 5' end of a large-subunit (26S) ribosomal DNA
      (rDNA) gene. First the nucleotide sequences of D1/D2 domain of Candida sp. 1098
      (formerly identified as C. tropicalis 1098) and its dicarboxylic acid-producing
      mutant strain M1210 were investigated. These two nucleotide sequences were
      identical and lacked only one base pair compared with that of C. maltosa CBS 5611
      (type strain), and they were identified as C. maltosa. We then showed that C.
      maltosa IFO 1978 (formerly identified as C. cloacae) and C. maltosa IFO 1975
      (formerly identified as C. subtropicalis) had the same nucleotide sequence and
      had only one base pair substitution compared with C. maltosa CBS 5611 (type
      strain), which is consistent with conventional classification. We also found that
      another widely studied n-alkane assimilating Candida yeast, C. tropicalis pk233,
      to be C. viswanathii.

PMID- 12483578
TI  - Screening and isolation of a cellulolytic and amylolytic Bacillus from sago pith
      waste.

PMID- 12483579
TI  - Expanding world of ballistosporous yeasts: Distribution in the phyllosphere,
      systematics and phylogeny.
AB  - Ecological and systematic aspects of ballistosporous yeasts inhabiting the
      phyllosphere of the Asia-Pacific region were reviewed in the light of recent
      advances. In the past 20 years, the extensive isolation studies of
      ballistosporous yeasts were carried out in the Asia-Pacific region, and the
      following new species were found in the phyllosphere of the main island of Japan,
      of the Ogasawara Islands in the Pacific Ocean, and of Thailand, New Zealand, and
      the Yunnan Province of China: Bensingtonia ingoldii, B. intermedia, B. miscanthi,
      B. naganoensis, B. musae, B. sakaguchii, B. subrosea, B. thailandica, and B.
      yamatoana; Bullera boninensis, B. coprosmaensis, B. hannae, B. huiaensis, B.
      miyagiana, B. mrakii, B. oryzae, B. penniseticola, B. pseudoalba, B. schimicola,
      B. sinensis, B. unica, B. variabilis, and B. waltii; Kockovaella imperatae, K.
      machilophila, K. phaffii, K. sacchari, K. schimae, and K. thailandica;
      Sporobolomyces blumeae, S. coprosmae, S. coprosmicola, S. dimmenae, S.
      draycophyllus, S. falcatus, S. griseoflavus, S. inositophilus, S. lactophilus, S.
      linderae, S. novazealandicus, S. nylandii, S. oryzicola, S. poonsookiae, S.
      ruber, S. sasicola, S. subbrunneus, S. taupoensis, S. vermiculatus, S. xanthus,
      and S. yunnanensis; and Udeniomyces megalosporus. Yeast species containing Q
      10(H(2)), a monohydrated ubiquinone, have long been considered to be rare yeasts;
      however, these yeasts were proved to be common in the tropical and subtropical
      phyllosphere of Asia. The chemotaxonomic and molecular phylogenetic studies based
      on the sequence analysis of 18S rDNA revealed the heterogeneity of
      ballistosporous yeasts, which comprised species with polyphyletic phylogenetic
      origins. A new phylogenetic cluster, Subbrunneus, was newly found in the class
      Urediniomycetes as the fifth phylogenetical cluster of this class, based on the
      analysis of 18S rDNA sequences. The Subbrunneus cluster comprises four
      ballistosporous yeast species found in the phyllosphere of Japan and New Zealand.
      The future perspectives of basidiomycetous yeast systematics are discussed.

PMID- 12483580
TI  - Screening of microbes, isolation, genetic manipulation, and physiological
      optimization of Brevibacterium helvolum to produce and excrete thymidine and
      deoxyuridine in high concentrations.
AB  - Analogues of deoxypyrimidines are used in the treatment of a variety of human
      ailments. Azidothymidine, or AZT, is one such analogue used to treat AIDS.
      Thymidine is the precursor of AZT, and its cost contributes to the high price of
      AZT. Attempts are being made to isolate and genetically manipulate microbes that
      can produce and excrete this compound in high concentrations. To this end, 145
      different microbial species from Zeneca and the American Type Culture Collection
      were screened. Moreover, soil samples were collected from 36 different sites in
      England, and microbes from these samples were isolated and screened. >From
      approximately 25,000 isolates screened as single colonies and from 4,000 in
      liquid cultures, a strain of Brevibacterium helvolum showed the most promising
      results. Pyrimidine metabolic pathways of this bacterium were worked out, the
      isolate was genetically manipulated, and physiological conditions were optimized
      to increase the production of thymidine and deoxyuridine. These mutants of B.
      helvolum are considered to be of commercial importance.

PMID- 12483581
TI  - Evidence for the involvement of a common genetic determinant in the control of
      thallium-resistant (Tl1-R) phenotype and salinity-tolerant phenotype in the
      cyanobacterium Nostoc muscorum.

PMID- 12483582
TI  - Production of ethanol using granulated yeast cells prepared by a spray dryer.

PMID- 12483583
TI  - Isolation and enumeration of marine actinomycetes from seawater and sediments in
      Alexandria.
AB  - Actinomycetes were isolated from near-shore marine sediments and water at four
      different sites in Alexandria. Statistical analysis revealed that variation in
      temperature, pH, and dissolved phosphate were of insignificant values, but that
      variation in total nitrogen and organic matter were significant. The treatment of
      sediments and water samples by heat resulted in a selective reduction of the
      nonactinomycetal heterotrophic microflora. Four selective culture media were used
      for counting actinomycetes in marine water and sediments. The starch nitrate
      medium favored the growth of these microorganisms. The diversity and counts of
      actinomycetes varied with the seasonal variation, and the highest counts were
      detected in dry warm seasons. The numbers of this bacterial group in sediments
      exceeded by far their numbers in seawater. A positive correlation was found
      between population size and location. Actinomycetes were found in the highest
      numbers in the upper layers (0-20 cm depth). In a few cases, the counts of
      actinomycetes showed bimodal maxima 0-20 and 60-100 cm deep. Sediments were the
      best source of marine actinomycetes, and their distribution varied depending on
      the depth from which samples were collected. The ratio of actinomycetes to the
      total microflora ranged from 0.48 to 2.29, depending on location.

PMID- 12483584
TI  - Molecular breeding of yeast with higher metal-adsorption capacity by expression
      of histidine-repeat insertion in the protein anchored to the cell wall.
AB  - A fusion protein of hexa-histidine repeat (His) and glycosylphosphatidylinositol
      (GPI)-anchor region of Saccharomyces cerevisiae Cwp1 with Aspergillus oryzae Taka
      amylase A (TAA) was expressed on the yeast cell surface. The expressed fusion
      protein (TAA-His-Cwp1) was localized on the cell wall and demonstrated amylolytic
      activity. In comparison with the TAA-Cwp1 expressing strain, these cells
      exhibited 1.6- to 2.8-fold higher adsorbing capacity for Cu(2+), Ni(2+), and
      Zn(2+).

PMID- 12483585
TI  - Activity and properties of fumarate reductase in ruminal bacteria.
AB  - Fumarate-reducing bacteria were sought from the main ruminal bacteria.
      Fibrobacter succinogenes, Selenomonas ruminantium subsp. ruminantium, Selenomonas
      ruminantium subsp. lactilytica, and Veillonella parvula reduced fumarate by using
      H(2) as an electron donor. Ruminococcus albus, Prevotella ruminicola, and
      Anaerovibrio lipolytica consumed fumarate, although they did not oxidize H(2). Of
      these bacteria, V. parvula, two strains of Selenomonas, and F. succinogenes had a
      high capacity to reduce fumarate. In all the fumarate-reducing bacteria examined,
      fumarate reductase existed in the membrane fraction. Based on the activity per
      cell mass and the affinity of fumarate reductase to fumarate, these bacteria were
      divided into two groups, which corresponded to the capacity to use H(2): A group
      of bacteria with higher activity and affinity were able to use H(2) as an
      electron donor for fumarate reduction. The bacteria in this group should gain an
      advantage over the bacteria in another group in fumarate reduction in the rumen.
      Cellulose digestion by R. albus was improved by fumarate reduction by S.
      lactilytica as a result of an increased growth of R. albus, which may have been
      caused by the fact that S. lactilytica immediately consumed H(2) produced by R.
      albus. Thus fumarate reduction may play an important role in keeping a low
      partial pressure of H(2) in the rumen.

PMID- 12483586
TI  - Ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)
      inhibits the growth of Escherichia coli at alkaline pH.
AB  - The growth of Escherichia coli was inhibited by ethylene glycol bis (beta
      aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) in a medium of initial pH
      8.8. The growth inhibition was reversed by the addition of CaCl(2). E. coli could
      grow in the presence of EGTA at pH values below 8. The concentration of free
      calcium ions increases with a decrease in medium pH because of a decrease in the
      calcium binding capacity of EGTA. So, although the results suggest that calcium
      ions are essential for the growth of E. coli, the minimum concentration required
      is very low.

PMID- 12483587
TI  - Seasonal microbial community dynamics in a flowerpot-using personal composting
      system for disposal of household biowaste.
AB  - Microbial community dynamics in a flowerpot-using solid biowaste composting
      (FUSBIC) process were monitored seasonally by quinone profiling and conventional
      microbiological methods. The FUSBIC system, which consisted of three flowerpots
      (14 L or 20 L capacity) with 5-6 kg each of a soil-compost mixture (SCM) as the
      primary reactors, was loaded daily with household biowaste from November 1998 to
      October 1999. The monthly average waste reduction rate was 88.2% for the 14-L
      system and 92.5% for the 20-L system on a wet weight basis. The direct total
      microbial count detected in the 14-L primary reactors ranged from 4.5 to
      9.6x10(11) cells.g(-1) of dry wt of SCM, and the viable count of aerobic
      heterotrophic bacteria recovered on agar plates at 28 degrees C varied from 1.9
      to 5.7x10(11) CFU.g(-1) of dry wt. The quinone content of SCM samples from the 14
      L and 20-L systems ranged from 160 to 353 nmol.g(-1) of dry SCM. Ubiquinones,
      unsaturated menaquinones, and partially saturated menaquinones constituted 15.0
      36.4, 14.8-22.0, and 41.8-61.6 mol% of the total content, respectively. The major
      quinone types detected were usually MK-8(H(2)), MK-9(H(2)), and Q-10. Variations
      in quinone profiles were evaluated numerically by using two parameters, the
      dissimilarity index (D) and microbial divergence index (MD(q)). The upper limit
      of seasonal changes in the microbial community structure was about 30% as
      expressed by D values. The MD(q) values calculated ranged from 18 to 22. A
      significant positive correlation was found between seasonal temperature and
      bacterial populations containing partially saturated menaquinones. These results
      indicated that the FUSBIC system contained highly diverse microbial populations
      that fluctuated to some extent depending on seasonal temperature. Members of the
      Actinobacteria were suggested to be the major constituents of the total
      population present.

PMID- 12483588
TI  - Systematic study of the genus Acetobacter with descriptions of Acetobacter
      indonesiensis sp. nov., Acetobacter tropicalis sp. nov., Acetobacter orleanensis
      (Henneberg 1906) comb. nov., Acetobacter lovaniensis (Frateur 1950) comb. nov.,
      and Acetobacter estunensis (Carr 1958) comb. nov. 
AB  - Thirty-one Acetobacter strains obtained from culture collections and 45
      Acetobacter strains isolated from Indonesian sources were investigated for their
      phenotypic characteristics, ubiquinone systems, DNA base compositions, and levels
      of DNA-DNA relatedness. Of 31 reference strains, six showed the presence of
      ubiquinone 10 (Q-10). These strains were eliminated from the genus Acetobacter.
      The other 25 reference strains and 45 Indonesian isolates were subjected to a
      systematic study and separated into 8 distinct groups on the basis of DNA-DNA
      relatedness. The known species, Acetobacter aceti, A. pasteurianus, and A.
      peroxydans are retained for three of these groups. New combinations, A.
      orleanensis (Henneberg 1906) comb. nov., A. lovaniensis (Frateur 1950) comb.
      nov., and A. estunensis (Carr 1958) comb. nov. are proposed for three other
      groups. Two new species, A. indonesiensis sp. nov. and A. tropicalis sp. nov. are
      proposed for the remaining two. No Indonesian isolates were identified as A.
      aceti, A. estunensis, and A. peroxydans. Phylogenetic analysis on the basis of
      16S rDNA sequences was carried out for representative strains from each of the
      groups. This supported that the eight species belonged to the genus Acetobacter.
      Several strains previously assigned to the species of A. aceti and A.
      pasteurianus were scattered over the different species. It is evident that the
      value of DNA-DNA relatedness between strains comprising a new species should be
      determined for the establishment of the species. Thus current bacterial species
      without data of DNA-DNA relatedness should be reexamined for the stability of
      bacterial nomenclature.

PMID- 12483590
TI  - Occurrence of quaternary branched penta-amines in a large sausage-shaped
      thermophilic sulfide-oxidizing bacterium predominated in hot spring sulfur-turf
      bacterial mats.

PMID- 12483589
TI  - Cystite formation of Arthrobacter ureafaciens NRIC 0157(T).
AB  - The cystite formation of Arthrobacter ureafaciens NRIC 0157(T) was studied by the
      use of a newly designed CT medium composed of 2.0% D-glucose, 0.28%
      NH(4)H(2)PO(4), 0.136% K(2)HPO(4) 0.136% KH(2)PO(4), 0.0005% MgSO(4).7H(2)O, and
      0.0007% CaCl(2).2H(2)O. Cystites are drumstick-shaped and oval cells and are
      larger than vegetative cells. Cystites are Gram-negative, whereas vegetative
      cells are Gram-positive by the KOH reaction. The concentration and ratio of K(+)
      and Mg(2+) in CT medium mainly affected the cystite formation. Cystites are
      considered aberrant forms produced by nutritional imbalance.

PMID- 12483591
TI  - Genetic analysis of Bacillus subtilis mutator genes.

PMID- 12483592
TI  - Metabolism of gamma-hexachlorocyclohexane by Arthrobacter citreus strain BI-100:
      Identification of metabolites.
AB  - Growth characteristics of the aerobic bacterial strain Arthrobacter citreus BI
      100 in mineral salts medium with gamma-hexachlorocyclohexane (gamma-HCH) as the
      sole source of carbon and degradation of gamma-HCH by the strain are reported.
      The highest yield of the bacteria is observed at a gamma-HCH concentration of 100
      mg/L. At this concentration, the bacteria entered the exponential phase of growth
      without any lag. At 8 h of growth, no residual HCH, but its metabolites, was
      detectable in the medium. The bacterium attained its stationary phase at 48 h and
      at 72 h; no metabolite of gamma-HCH could be detected by gas chromatography. Six
      metabolic intermediates of gamma-HCH produced by A. citreus BI-100 at different
      periods of growth were characterized by using gas chromatography-mass
      spectrometry and high-performance liquid chromatography, which furnished evidence
      for the presence of gamma-1,3,4,5,6-pentachlorocyclohexene,
      tetrachlorocyclohexene, trichlorocyclohexa-diene, 2-chlorophenol, phenol, and
      catechol, among others.

PMID- 12483593
TI  - Genetic similarity among Cercospora apii-group species and their detection in
      host plant tissue by PCR/RFLP analyses of the rDNA internal transcribed spacer
      (ITS).
AB  - The objective of this study was to determine the genetic relatedness among the
      Cercospora and Pseudocercospora species closely related to Cercospora apii by
      using a polymerase chain reaction/restriction fragment length polymorphism
      (PCR/RFLP) analysis of the internal transcribed spacer (ITS) region. A single PCR
      fragment (about 550 bp) was obtained from all Cercospora species categorized as
      the C. apii-group, Pseudocercospora purpurea, Pseudocercospora conyzae, and
      Pseudocercospora cavarae. Cercospora caricis yielded a 680 bp PCR fragment. The
      similarity in the PCR fragment size and RFLP profiles among the C. apii-group
      isolates, including Pseudocercospora purpurea, and Pseudocercospora conyzae
      strongly suggests that these species are conspecific. Synonymy with C. apii
      (lectotype) at a subspecific rank has been proposed. Amplified ITS regions of
      genomic DNA extracted from spinach leaves showing 12 and 233% leaf spot disease
      symptoms caused by Cercospora beticola yielded two PCR fragments (i.e., one from
      the fungus and one from the host plant) and were resolved by electrophoresis of
      the PCR product in 3% LMP agarose. Digestion of the total PCR product with HinfI
      restriction enzyme yielded RFLP profiles similar to those obtained from amplified
      DNA from the causative agent, C. beticola. The method described in this
      preliminary study offers rapid detection and diagnosis of fungal infections in
      plants for disease prediction and management and screening of plant materials for
      quarantine purposes.

PMID- 12483594
TI  - Cometabolic biodegradation of methyl tert-butyl ether by a soil consortium:
      Effect of components present in gasoline.
AB  - A soil consortium was tested for its ability to degrade reformulated gasoline,
      containing methyl tert-butyl ether (MTBE). Reformulated gasoline was rapidly
      degraded to completion. However, MTBE tested alone was not degraded. A screening
      was carried out to identify compounds in gasoline that participate in
      cometabolism with MTBE. Aromatic compounds (benzene, toluene, xylenes) and
      compounds structurally similar to MTBE (tert-butanol, 2,2-dimethylbutane, 2,2,4
      trimethylpentane) were unable to cometabolize MTBE. Cyclohexane was resistant to
      degradation. However, all n-alkanes tested for cometabolic activity (pentane,
      hexane, heptane) did enable the biodegradation of MTBE. Among the alkanes tested,
      pentane was the most efficient (200 &mgr;g/day). Upon the depletion of pentane,
      the consortium stopped degrading MTBE. When the consortium was spiked with
      pentane, MTBE degradation continued. When the ratio of MTBE to pentane was
      increased, the amount of MTBE degraded by the consortium was higher. Finally,
      diethylether was tested for cometabolic degradation with MTBE. Both compounds
      were degraded, but the process differed from that observed with pentane.

PMID- 12483595
TI  - Characterization by denaturing gradient gel electrophoresis of bacterial
      communities in deep groundwater at the Kamaishi Mine, Japan.
AB  - Bacterial communities in groundwater collected from five different sites at the
      Kamaishi Mine were investigated by using denaturing gradient gel electrophoresis
      (DGGE). The bacterial cells in groundwater were collected on Millipore filters,
      and their nucleic acid was extracted by freeze-thaw cycles. A partial 16S rRNA
      gene was amplified by using a universal primer set by PCR. The PCR products were
      analyzed by DGGE. The band pattern of DGGE was essentially identical between two
      samples obtained from different depths in the same borehole (KH-1). Samples from
      the other sites differed from one another. The partial sequences of 16S rRNA
      genes (about 350 base pairs) isolated from bands were determined and analyzed for
      phylogenetic position. Almost half the sequences from two samples of the KH-1
      belonged to the cluster of spore-forming, gram-positive sulfate reducer,
      Desulfotomaculum. The other bands also were related to those of obligate
      anaerobes. This suggests that the environment in both sites of KH-1 was highly
      anaerobic. Although only a few sequences were retrieved from the other sites,
      they were phylogenetically distanced from known isolates.

PMID- 12483596
TI  - Evolution of male-killing Spiroplasma (Procaryotae: Mollicutes) inferred from
      ribosomal spacer sequences.

PMID- 12483597
TI  - Effect of fungal treatment on composition, tannin levels, and digestibility of
      black locust (Robinia pseudoacacia) leaves.

PMID- 12483598
TI  - Application of the partial 16S rDNA sequence as an index for rapid identification
      of species in the genus Bacillus.
AB  - A comparison of 16S rRNA gene (rDNA) sequences was made among type strains of 69
      Bacillus species approved in the International Journal of Systematic Bacteriology
      (IJSB) until 1998. The results suggested that 5' end region (approx. 275 bp) was
      the hypervariant region (HV region) in the gene and was highly specific for each
      type strain. Furthermore, a sequence analysis of the HV region of Bacillus
      strains revealed that this region was highly conserved within the species. These
      results indicate that the HV region is a useful index for the identification or
      grouping of Bacillus species.

PMID- 12483599
TI  - Chemotaxonomic and phylogenetic analyses of Sphingomonas strains isolated from
      ears of plants in the family Gramineae and a proposal of Sphingomonas roseoflava
      sp. nov. 
AB  - Chemotaxonomic and phylogenetic characteristics of Sphingomonas strains isolated
      from plants of the family Gramineae were investigated. All strains contained the
      monosaccharide (glucuronic acid) type of glycosphingolipid (GSL-1). Most were
      found also to contain the oligosaccharide-type glycosphingolipids. Fatty acid and
      sphingosine profiles of the isolates were identical, although the ratio of the
      contents varies among the isolates. They all contained ubiquinone Q-10, and the
      G1C contents were from 66 to 68%. Phylogenetic analysis using 16S rRNA gene base
      sequences revealed that all the isolates were placed in the phylogenetic group of
      Sphingomonas paucimobilis in the alpha-4 subclass of Proteobacteria. By DNA-DNA
      hybridization experiments, the plant isolates were divided into five genotypic
      groups (groups 1 to 5). The strains of group 5 showed common physiological
      characteristics and formed pink-yellow colored colonies. Based on these results,
      Sphingomonas roseoflava sp. nov. was proposed for that homology group.

PMID- 12483600
TI  - Purification and some properties of a novel chitosanase from Bacillus subtilis
      KH1.
AB  - One of at least two chitosanases secreted in the culture filtrate of Bacillus
      subtilis KH1 was purified by two sequential DEAE Sepharose CL-6B
      chromatographies, followed by Sephacryl S-100 HR gel chromatography. The purified
      enzyme was homogenous as judged by SDS-PAGE. It showed an estimated molecular
      weight and pI of 28,000 and 8.3, respectively. The enzyme drastically reduced the
      viscosity of highly deacetylated chitosan substrates, with the subsequent
      formation of chitooligosaccharides [(GlcN)(n), n=2-6]. No activity toward
      carboxymethylcellulose (CMC), chitobiose (GlcN)(2), or chitotriose (GlcN)(3) was
      detected. Separation and quantification of products of hydrolysis of 10% (w/v)
      solutions of chitooligosaccharides, (GlcN)(n), n=2-6, by HPLC showed the
      splitting of (GlcN) (n), n=4-6, in an endo-splitting manner. Oligomers comprising
      higher units than the starting substrate were also detected, indicating
      transglycosylation activity. The amino terminal sequence of this enzyme (A-G-L-N
      K-D-Q-K-R-R) is identical to that of the chitosanase derived from Bacillus
      pumilus BN262 and to the deduced amino terminal sequences of Bacillus subtilis
      168 and Bacillus amyloliquefaciens UTK chitosanases.

PMID- 12483601
TI  - Negative control of plasmid pSC101 replication by increased concentrations of
      both initiator protein and iterons.
AB  - Increased intracellular concentrations of the initiator protein Rep (or RepA)
      interfere with pSC101 DNA replication, and mutated Rep proteins that result in an
      increase in plasmid copy numbers do not inhibit the replication. A rep mutant
      (rep(inh)) defective in the inhibitory activity was isolated and found to be a
      new high copy number mutant. The inhibitory function of Rep was enhanced by the
      coexistence of directly repeated sequences (DR; iterons) in the replication
      origin region (ori), but not by the inverted repeat sequences (IR) in ori and the
      rep promoter. This synergistic effect of Rep and DR sequences for the replication
      inhibition was dependent on their intracellular concentrations. Considering that
      DR sequences are the specific binding sites of the Rep monomer form, the Rep
      monomer-DR complex might be responsible for the inhibition of the plasmid
      replication. Furthermore, the Rep monomer in the crude cell extracts facilitated
      dimerization of DR DNA fragments by DNA ligase. Neither synergistic inhibitory
      function with DR nor Rep mediated dimerization of DR DNA was observed in high
      copy number mutant Rep proteins. The role of the Rep-iteron complex in the copy
      number control of pSC101 is discussed.

PMID- 12483602
TI  - Morphological variability of colonies of Microcystis morphospecies in culture.
AB  - Serial observations were carried out on cultures of five morphospecies of the
      genus Microcystis Kutzing ex Lemmermann 1907, Microcystis aeruginosa (Kutzing)
      Kutzing, Microcystis ichthyoblabe Kutzing, Microcystis novacekii (Komarek)
      Compere, Microcystis viridis (A. Brown) Lemmermann, and Microcystis wesenbergii
      (Komarek) Komarek in Kondratieva. Many strains maintained colony forms
      characteristic of their morphospecies, and others showed morphological
      variations, some of which were characteristic of other morphospecies. M.
      novacekii displayed several morphotypes including some characteristics of M.
      aeruginosa and M. ichthyoblabe. M. wesenbergii also showed great morphological
      variability and showed morphotypes characteristic of M. aeruginosa. Distinction
      among these morphospecies, therefore, seemed to be obscure or impossible. We
      conclude that the current classification of the genus Microcystis, chiefly based
      on morphological characteristics, is no longer valid and must be reviewed in
      light of our observations that one strain may have various colony forms.

PMID- 12483603
TI  - Pseudosigmoidea: A new genus for a hyphomycete (ATCC 16660) formerly identified
      as Sigmoidea prolifera.
AB  - A new hyphomycetous genus, Pseudosigmoidea, is established with a single species,
      P. cranei, based on ATCC 16660 previously identified as Sigmoidea prolifera. The
      conidial ontogeny of Pseudosigmoidea is enteroblastic, and its conidiogenesis is
      phialidic. On the other hand, Sigmoidea is redescribed with holoblastic conidial
      ontogeny and with conidiogenous cells proliferating sympodially.

PMID- 12483604
TI  - Bacterial degradation of aromatic compounds via angular dioxygenation.
AB  - Dioxygenation is one of the important initial reactions of the bacterial
      degradation of various aromatic compounds. Aromatic compounds, such as biphenyl,
      toluene, and naphthalene, are dioxygenated at lateral positions of the aromatic
      ring resulting in the formation of cis-dihydrodiol. This "normal" type of
      dioxygenation is termed lateral dioxygenation. On the other hand, the analysis of
      the bacterial degradation of fluorene (FN) analogues, such as 9-fluorenone,
      dibenzofuran (DF), carbazole (CAR), and dibenzothiophene (DBT)-sulfone, and DF
      related diaryl ether compounds, dibenzo-p-dioxin (DD) and diphenyl ether (DE),
      revealed the presence of the novel mode of dioxygenation reaction for aromatic
      nucleus, generally termed angular dioxygenation. In this atypical dioxygenation,
      the carbon bonded to the carbonyl group in 9-fluorenone or to heteroatoms in the
      other compounds, and the adjacent carbon in the aromatic ring are both oxidized.
      Angular dioxygenation of DF, CAR, DBT-sulfone, DD, and DE produces the chemically
      unstable hemiacetal-like intermediates, which are spontaneously converted to
      2,2',3-trihydroxybiphenyl, 2'-aminobiphenyl-2,3-diol, 2',3'-dihydroxybiphenyl-2
      sulfinate, 2,2',3-trihydroxydiphenyl ether, and phenol and catechol,
      respectively. Thus, angular dioxygenation for these compounds results in the
      cleavage of the three-ring structure or DE structure. The angular dioxygenation
      product of 9-fluorenone, 1-hydro-1,1a-dihydroxy-9-fluorenone is a chemically
      stable cis-diol, and is enzymatically transformed to 2'-carboxy-2,3
      dihydroxybiphenyl. 2'-Substituted 2,3-dihydroxybiphenyls formed by angular
      dioxygenation of FN analogues are degraded to monocyclic aromatic compounds by
      meta cleavage and hydrolysis. Thus, after the novel angular dioxygenation,
      subsequent degradation pathways are homologous to the corresponding part of that
      of biphenyl. Compared to the bacterial strains capable of catalyzing lateral
      dioxygenation, few bacteria having angular dioxygenase have been reported. Only a
      few degradation pathways, CAR-degradation pathway of Pseudomonas resinovorans
      strain CA10, DF/DD-degradation pathway of Sphingomonas wittichii strain RW1,
      DF/DD/FN-degradation pathway of Terrabacter sp. strain DBF63, and carboxylated DE
      degradation pathway of P. pseudoalcaligenes strain POB310, have been investigated
      at the gene level. As a result of the phylogenetic analysis and the comparison of
      substrate specificity of angular dioxygenase, it is suggested that this atypical
      mode of dioxygenation is one of the oxygenation reactions originating from the
      relaxed substrate specificity of the Rieske nonheme iron oxygenase superfamily.
      Genetic characterization of the degradation pathways of these compounds suggests
      the possibility that the respective genetic elements constituting the entire
      catabolic pathway have been recruited from various other bacteria and/or other
      genetic loci, and that these pathways have not evolutionary matured.

PMID- 12483605
TI  - Isolation of hexavalent chromium-reducing Cr-tolerant facultative anaerobes from
      tannery effluent.
AB  - Several facultative anaerobes tolerant to high levels of chromate (>400 mg/ml)
      were isolated from tannery effluents. These isolates displayed varying degrees of
      Cr(VI) reduction under aerobic and anaerobic conditions at room temperature (24+/
      2 degrees C). Interestingly, eight isolates were efficient in reducing 70% Cr(VI)
      anaerobically. This includes 5 isolates of genus Aerococcus, two isolates of
      Micrococcus and single isolate of genus Aeromonas. These isolates were subjected
      to further characterization for possible use in Cr(VI) detoxification of
      industrial wastes. This is the first report of Aerococcus sp. capable of Cr(VI)
      reduction >70% anaerobically. These bacteria were further checked for tolerance
      to a variety of other heavy metals. Our study indicates the possible use of these
      bacteria in environmental clean up.

PMID- 12483606
TI  - Presence of Butyrivibrio fibrisolvens in the digestive tract of dogs and cats,
      and its contribution to butyrate production.
AB  - Numbers of Butyrivibrio fibrisolvens, a major butyrate-producing bacterium in the
      rumen, in feces of dogs and cats were estimated by competitive PCR. The type IIb
      of B. fibrisolvens, which produces much more lactate than butyrate, was detected
      at the levels (cells per g of feces dry weight) of 2.4x10(3)-9.0x10(5) for dogs
      and 1.7x10(4-)-6.2x10(5) for cats. However, the type I that produces much more
      butyrate than the type IIb was not detected in cat or dog feces (less than
      6.0x10(4) cells per g of feces dry weight). Butyrate production by B.
      fibrisolvens type IIb in feces was estimated to be at most 30% of the butyrate
      production by mixed fecal microbes, which suggested that more butyrate is
      produced by microbes other than B. fibrisolvens in the intestines. Addition of B.
      fibrisolvens ATCC19171 (type I) to a culture of mixed fecal microbes increased
      butyrate production, and OB156 (type IIb) increased lactate production. When both
      the types were added, both the products were increased. Thus, introduction of
      both the types of B. fibrisolvens as a probiotic may increase butyrate and
      lactate production in the large intestine, which is possibly beneficial for the
      maintenance or improvement of the health of dogs and cats.

PMID- 12483607
TI  - Presence of several cellulose-binding proteins in culture supernatant and cell
      lysate of Eubacterium cellulosolvens 5.
AB  - Attempts were made to separate and characterize cellulose-binding proteins (CBPs)
      from both the culture supernatant and cell lysate of Eubacterium cellulosolvens
      5. Once the CBPs were bound to Avicel cellulose, they were then effectively
      eluted with the solution containing 3.2 or 5% sodium dodecyl sulfate (SDS), but
      not eluted with the solution containing various kinds of carbohydrates and
      reagents. Namely, CBPs in both the culture supernatant and cell lysate of the
      bacterium bound tightly and strongly to cellulose. The SDS-polyacrylamide gel
      electrophoresis (SDS-PAGE) of the eluted CBPs indicated that the CBPs contained
      the two major proteins having the molecular weights of approximately 160 and 84
      kilodaltons (kDa) and one sub-major protein having a molecular weight of
      approximately 140 kDa. Zymogram analysis after the SDS-PAGE of the eluted CBPs
      showed that two proteins exhibited the highest levels of carboxymethyl cellulase
      (CMCase) activity corresponding to the molecular weights of approximately 160 and
      90 kDa. A major protein having the molecular weight of approximately 160 kDa
      exhibited a distinct CMCase activity and was designated as CBPE1. Western
      immunoblot analysis indicated that the proteins prepared from 16 representative
      strains of rumen bacteria did not cross-react with rabbit antiserum raised
      against CBPE1. Thus, CBPE1 may be a unique CBP that plays an important role in
      the adhesion of the bacterium to cellulose.

PMID- 12483608
TI  - Complete nucleotide sequence of the catechol metabolic region of plasmid pTDN1.

PMID- 12483609
TI  - Genetic identification of cultured Saccharomyces yeasts from Asia.

PMID- 12483610
TI  - Effects of sodium acetate on the production of stereoisomers of lactic acid by
      Lactobacillus sakei and other lactic acid bacteria.
AB  - Lactobacillus sakei and other lactic acid bacteria were studied on the change of
      the type of stereoisomers (the ratio of L-form to D-form) of lactic acid produced
      in the presence of sodium acetate and under other cultural conditions. Of 49
      strains tested, only L. sakei NRIC 1071(T) and L. coryniformis subsp.
      coryniformis NRIC 1638(T) changed the type in the presence of 50 mm sodium
      acetate compared with the absence of sodium acetate. The type produced by L.
      sakei NRIC 1071(T) was shifted 30% or more from the DL-type to the L-type in the
      presence of 50 mm sodium acetate. L. sakei NRIC 1071(T) produced not only twice
      or more the amount of L-lactic acid but decreased the amount of D-lactic acid
      compared with the absence of sodium acetate. The shift of the DL-type to the L
      type by L. sakei is due to the high production of L-lactic acid and the low
      production of D-lactic acid. The type of stereoisomers produced by 11 L. sakei
      strains was also shifted from the DL-type to the L-type in the presence of 50 mm
      sodium acetate. The shift of stereoisomers by the majority of L. sakei strains
      seems interesting from the viewpoint of the delineation of this species.

PMID- 12483611
TI  - Selection of more appropriate PCR primer pairs for improved efficiency in
      detecting Norwalk-like virus (NLV) RNA.
AB  - A pair of primers, NV35 and NV36, and another pair of primers, NV81 and
      NV82/SM82, are commonly used for polymerase chain reaction (PCR) detection of
      Norwalk-like virus (NLV) genome RNA sequences in authorized test laboratories in
      Japan. However, the efficiency of NLV genome RNA detection with these primer
      pairs has been less than satisfactory. In the present study, we attempted to
      establish more appropriately matched primer pairs for improved detection of NLV
      genome RNA sequences using a combination of primers including NV35, NV36, NV81,
      NV82/SM82, SR33, and SRs (a mixture of 4 primers SR46, SR48, SR50, and SR52). We
      also evaluated appropriate primers for improved reverse transcription of NLV
      genome RNA. Stool samples used for detection of NLV included 18 samples collected
      from NLV-infected patients who ingested oysters (group 1) and 13 samples
      collected from those who did not ingest oysters (group 2). Reverse transcription
      of RNA genome with primer NV35 was less efficient compared with that with primer
      SR33 or NV81. When PCR products obtained with NV35 and NV36 as a pair of primers
      were subjected to gel electrophoresis, a strong extra band was detected compared
      with those obtained with other primer pairs. Since this extra band may represent
      heterodimeric or homodimeric hybrids, or intramolecular hybrids derived from
      these primers, this template-independent hybridization could lower the efficiency
      of primer-dependent polymerase reaction. Of 18 primer pairs, a pair of NV81 and
      SRs provided the best detection of PCR products following reverse transcription
      of NLV RNA with SR33 or NV81. The detection rate was 61% for both reverse
      transcription with SR33 and that with NV81. After reverse transcription using
      SR33 as a primer, nested PCR using a pair of NV81 and SRs following primary PCR
      using a pair of NV81 and NV82/SM82 increased the detection rate to 89% in group 1
      and 100% in group 2.

PMID- 12483612
TI  - Recharacterization of Pseudomonas fulva Iizuka and Komagata 1963, and proposals
      of Pseudomonas parafulva sp. nov. and Pseudomonas cremoricolorata sp. nov.
AB  - Seven Pseudomonas fulva strains obtained from culture collections were
      taxonomically studied. The seven strains were separated into three clusters
      (Clusters I to III) on the basis of 16S rRNA gene sequences, and located
      phylogenetically in the genus Pseudomonas sensu stricto. Further, the strains
      were classified into 4 groups (Groups I to IV) on the basis of DNA-DNA
      similarity. As a result, Cluster I was split into Groups I and II. Group I
      included the type strain of P. fulva and two strains, and levels of DNA-DNA
      similarity ranged from 88 to 100% among the strains. Group II contained two
      strains, and the level between the two strains ranged from 91 to 100%. Group III
      consisted of one strain. Group IV included one strain, and this strain showed a
      high level of DNA-DNA similarity with the type strain of Pseudomonas straminea
      NRIC 0164(T). Clusters II and III corresponded to Groups III and IV,
      respectively. The four groups were separated from one another and from related
      Pseudomonas species at the level from 3 to 45% of DNA-DNA similarity. The strains
      of Groups I, II, and III had ubiquinone 9 as the major quinone. According to
      numerical analysis by the use of 133 phenotypic characteristics, the seven P.
      fulva strains were split into four phenons (Phenons I to IV). The groups by DNA
      DNA similarity corresponded well with the phenons produced by numerical taxonomy,
      and differential characteristics were recognized. Consequently, Group I was
      regarded as P. fulva because the type strain (NRIC 0180(T)) of this species was
      included in this group. Strains in Group II were identified as a new species,
      Pseudomonas parafulva sp. nov., and the type strain is AJ 2129 (=IFO 16636=JCM
      11244=NRIC 0501). NRIC 0181 in Group III was identified as a new species,
      Pseudomonas cremoricolorata sp. nov., and the type strain is NRIC 0181 (=IFO
      16634=JCM 11246). NRIC 0182 in Group IV was identified as P. straminea on the
      basis of the high level of DNA-DNA similarity with the type strain of this
      species.

PMID- 12483613
TI  - Production and characterization of tannase from Bacillus cereus KBR9.
AB  - A tannase-producing soil bacteria has been isolated and identified as Bacillus
      cereus. It can degrade tannic acid and produce maximum tannase (0.22 U/ml) at
      stationary phases of growth (24 h). Maximum growth and enzyme production occurred
      with initial medium pH of 4.5-5.0. Partial purified tannase showed optimum
      activity at pH 4.5 and 40 degrees C. It remains stable up to 30 degrees C and pH
      4.5 to 5.0. The enzyme is salt tolerant, stable up to 2 m of NaCl and retains 82%
      original activity in 3 m.

PMID- 12483614
TI  - Molecular cloning and transcriptional analysis of the alkyl hydroperoxide
      reductase genes from Pseudomonas putida KT2442.
AB  - Pseudomonas putida KT2442TOL (formerly designated TOL), a toluene-resistant
      variant of strain KT2442 constitutively overexpressed several proteins. The most
      abundantly produced 24-kDa soluble protein was found to be similar to AhpC, the
      small subunit of alkyl hydroperoxide reductase. Molecular cloning of the P.
      putida ahpC based on the N-terminal sequence allowed cloning of closely located
      ahpF, the large subunit of alkyl hydroperoxide reductase. The deduced amino acid
      sequences of these genes showed high similarity with corresponding bacterial
      homologues. Results of RNA transcriptional analyses suggested that P. putida ahpC
      and ahpF were co-transcribed. A lower level expression of the ahpF may result
      from an attenuation of transcription by stem-and-loop structures located between
      two genes. oxyR, the known expression regulatory gene of ahpC-ahpF, was
      separately cloned and a point mutation that rendered an amino acid change
      (Phe(106) to Ile) in OxyR was observed. Reverse mutation of the oxyR gene by
      allelic exchange in P. putida KT2442TOL revealed that this mutation was the cause
      of the overexpression. About 50% of the reverse mutated cells lost colony-forming
      ability under toluene, indicating the mutation of oxyR that contributes to
      overexpression of the oxyR-regulated genes has some relationship with the solvent
      resistance, but their contribution was not significant.

PMID- 12483615
TI  - Microbial toxins in plant-pathogen interactions: Biosynthesis, resistance
      mechanisms, and significance.
AB  - In the history of phytopathology, microbial toxins have been the objects of
      extensive studies as possible pathogenicity or virulence factors for the producer
      pathogens. The recent development of molecular genetic techniques provided an
      experimental basis to thoroughly test the role of these secondary metabolites in
      pathogenesis. Some of them did prove to be highly associated with disease
      initiation or enhanced virulence in certain plant-pathogen interactions. In this
      review, we describe recent progresses in the field of plant-pathogen interactions
      focusing on two toxins; i.e., tabtoxin from Pseudomonas syringae and
      trichothecenes from Fusarium and other fungi. These microbial toxins have
      convincingly been shown to play causal roles in plant disease development.
      Studies on the biosynthesis and resistance mechanisms of these producers are
      outlined, and the significance of this knowledge is discussed in relation to
      practical applications in agriculture.

PMID- 12483616
TI  - Aerobic anoxygenic photosynthetic bacteria with zinc-bacteriochlorophyll.
AB  - Naturally occurring chlorophyllous pigments, which function as the cofactor in
      the early photochemical reaction of photosynthesis, have been proven beyond
      question to be magnesium-complexed porphyrin derivatives. Phototrophic organisms
      that use (bacterio)chlorophylls ([B]Chls) containing metals other than Mg were
      unknown for a long time. This common knowledge of natural photosynthesis has
      recently been modified by the striking finding that a novel purple pigment, zinc
      chelated-BChl (Zn-BChl) a, is present as the major and functional pigment in
      species of the genus Acidiphilium. Acidiphilium species are obligately
      acidophilic chemoorganotrophic bacteria that grow and produce photopigments only
      under aerobic conditions. Although the mechanism of photosynthesis with Zn-BChl a
      in Acidiphilium species is similar to that seen in common purple bacteria, some
      characteristic photosynthetic features of the acidophilic bacteria are also
      found. The discovery of natural photosynthesis with Zn-BChl has not only provided
      a new insight into our understanding of bacterial photosynthesis but also raised
      some interesting questions to be clarified. The major questions are why the
      acidophilic bacteria have selected Zn-BChl for their photosynthesis and how they
      synthesize Zn-BChl and express photosynthetic activity with it in their natural
      habitats. In this article we review the current knowledge of the biology of
      Acidiphilium as aerobic photosynthetic bacteria with Zn-BChl a and discuss the
      interesting topics noted above.

PMID- 12483617
TI  - Strain improvement of Aspergillus niger for enhanced lipase production.
AB  - The enhancement of lipase production from Aspergillus niger was attempted by
      ultraviolet (UV) and nitrous acid mutagenesis, and the mutants were selected on
      media containing bile salts. Nitrous acid mutants exhibited increased efficiency
      for lipase production when compared with UV mutants in submerged fermentation.
      The hyperproducing UV and nitrous acid mutants were further subjected to a second
      step of mutagenesis to devise an economical and ecofriendly technique for lipase
      production by the effective use of hydrocarbons. One percent kerosene was found
      to be optimal for lipase production, and one of the mutant strains NAII exhibited
      2.53 times more increased lipase activity than the parental strain did. This
      investigation indicates a possible role for the A. niger mutant strains in the
      biodegradation of oil-polluted environments for the development of ecofriendly
      technologies.

PMID- 12483618
TI  - Isolation of a new Thermoanaerobacterium thermosaccharolyticum strain (FH1)
      producing a thermostable dextranase.
AB  - A Gram-positive spore-forming thermophilic strict anaerobic bacterium, designated
      FH1, was isolated from enrichments at 65 degrees C with dextran as sole carbon
      and energy source. A sequence analysis of the 16S rRNA gene revealed 99.2%
      identity of FH1 to Thermoanaerobacterium thermosaccharolyticum. Furthermore, the
      substrate spectra of both organisms were similar. It was therefore concluded that
      FH1 represents a new strain within the species T. thermosaccharolyticum. The
      optimal growth temperature of strain FH1 was 68 degrees C. The isolated organism
      produced a thermostable and thermoactive dextranase with a native molecular mass
      of approximately 200,000 Da. The enzyme was concentrated from the cell-free
      culture supernatant by ammonium sulfate precipitation. The resulting crude
      dextranase exhibited optimal activity from 65 to 70 degrees C and a pH optimum of
      5.5.

PMID- 12483619
TI  - Induction of 2-amino-D2-thiazoline-4-carboxylic acid hydrolase and N-carbamoyl-l
      cysteine amidohydrolase by S-compounds in Pseudomonas putida AJ3865.
AB  - The induction of 2-amino-Delta(2)-thiazoline-4-carboxylic acid hydrolase (ATCase)
      and N-carbamoylcysteine amidohydrolase (NCCase), both of which are involved in
      the conversion step of 2-amino-Delta(2)-thiazoline carboxylic acid (ATC) to
      cysteine, was studied with Pseudomonas putida AJ3865. We found that L-ATC induced
      L-ATCase and L-NCCase, but that D-ATC induced only L-NCCase, whereas L- or D-NCC
      and thiazoline derivatives did not induce both enzymes. The bacterium showed
      neither D-ATCase nor D-NCCase activities, indicating that the role of L-ATC and D
      ATC was different in the enzyme induction. We also found new inducers, d- and l
      methionine, S-methyl-L-cysteine, cysteic acid, and 2-aminoethane sulfonic acid.
      However, the induction level of both enzymes by new inducers was much lower than
      those by L-ATC and D-ATC. Furthermore, the induction rate of both enzymes was
      synergistically increased only under a combination of D,L-ATC and new inducers. S
      Compounds, however, such as new inducers except S-methyl-L-cysteine, inhibited
      both enzyme activities. This is the first report on the new inducers, synergistic
      induction, and the new inhibitors of L-ATCase and L-NCCase.

PMID- 12483620
TI  - Autolysis and aging of Penicillium chrysogenum cultures under carbon starvation:
      Chitinase production and antifungal effect of allosamidin.
AB  - In carbon-depleted cultures of Penicillium chrysogenum, age-related chitinases
      were shown to play a crucial role in both autolysis and fragmentation as
      indicated by in vivo enzyme inhibition experiments using allosamidin. This
      pseudotrisaccharide even hindered significantly the outgrowth of new hyphal tips
      from the surviving yeastlike fragments after glucose supplementation. The
      antifungal effect of allosamidin on autolyzing P. chrysogenum mycelia was
      fungistatic rather than fungicidal. In growing hyphae, membrane-bound microsomal
      chitinase zymogen(s) were detected, which may be indicative of some
      compartmentalization of these hydrolases. Later, during autolysis, no zymogenic
      chitinase was detected in any enzyme fraction studied, including microsomes.
      These observations may explain the different sensitivity of growing and
      autolyzing mycelia to allosamidin. Chitinases taking part in the age-related
      fragmentation of hyphae and the outgrowth of surviving hyphal fragments seem to
      be potent targets for future antifungal drug research.

PMID- 12483621
TI  - Phenol degradation by yeasts isolated from industrial effluents.
AB  - Yeast strains of the genera Aureobasidium, Rhodotorula and Trichosporon were
      isolated from stainless steel effluents and tested for their ability to utilize
      phenol as the sole carbon source. Fourteen strains grew in the presence of up to
      10 mm phenol. Only the strain Trichosporon sp. LE3 was able to grow in the
      presence of up to 20 mm phenol. An inhibitory effect was observed at
      concentrations higher than 11 mm, resulting in reduction of specific growth
      rates. Phenol degradation was a function of strain, time of incubation and
      initial phenol concentration. All strains exhibited activity of catechol 1,2
      dioxygenase and phenol hydroxylase in free cell extracts from cells grown on
      phenol, suggesting that catechol was oxidized by the ortho type of ring fission.
      Addition of glucose and benzoate reduced the phenol consumption rate, and both
      substrates were used simultaneously. Glucose concentrations higher than 0.25%
      inhibited the induction of phenol oxidation by non-proliferating cells and
      inhibited phenol oxidation by pre-induced cells.

PMID- 12483622
TI  - Intraoperative endosonography enhances laparoscopy-assisted colon pull-through
      for high imperforate anus.
AB  - PURPOSE: The authors used ultrasonographic endoprobes during laparoscopy-assisted
      colon pull-through (LACPT) for the repair of high imperforate anus to confirm the
      pull-through canal was surrounded symmetrically by pelvic floor muscles. METHODS:
      Six patients with high imperforate anus were treated by LACPT (mean age at LACPT,
      8.2 months). An endoscopic (12-MHz, 2.5-mm in diameter) and proctoscopic (7.5
      MHz, 12-mm in diameter) probe were inserted into the proposed route of dissection
      intraoperatively to measure the thickness of the surrounding muscle tissue at at
      least 3 levels: the external anal sphincter, the levator ani muscle sling, and
      the intervening muscle complex. RESULTS: The average thickness of the external
      anal sphincter was 2.3 +/- 0.4 mm anteriorly, 2.4 +/- 0.4 mm on the left, 2.4 +/-
      0.5 mm posteriorly, and 2.6 +/- 0.6 mm on the right. The average thickness of the
      muscle complex was 2.3 +/- 0.6 mm anteriorly, 2.2 +/- 0.5 mm on the left, 2.1 +/-
      0.4 mm posteriorly, and 2.2 +/- 0.5 mm on the right. The average thickness of the
      left crus of the levator ani muscle was 1.8 +/- 0.3 mm, the right crus was 1.9 +/
      0.4 mm, and the rim located posterior to the rectum was 2.0 +/- 0.3 mm. No
      statistically significant difference was found between the measurements taken at
      each level. CONCLUSION: Intraoperative endosonography during LACPT can greatly
      enhance the precision of positioning the pull-through canal.

PMID- 12483623
TI  - Laparoscopy-assisted suction colonic biopsy and intraoperative rapid
      acetylcholinesterase staining during transanal pull-through for Hirschsprung's
      disease.
AB  - BACKGROUND: It is crucial to identify the exact level of transition to normal
      ganglion cells in instances of Hirschprung's disease. This report describes a
      technique for laparoscopy-assisted suction colonic biopsy during transanal pull
      through. METHODS: Laparoscopy-assisted suction colonic biopsy (SCBx) was used in
      12 patients with Hirschsprung's disease affecting the rectosigmoid. Average age
      was 4.4 +/- 2.1 months with a mean operative weight 6.2 +/- 1.0 kg. The pull
      through was performed as the primary operative procedure in 11 patients. Using a
      2-team approach (laparoscopic team and transanal team), the site was chosen for
      transanal suction biopsy and marked externally by the laparoscopic team with a
      silver clip. Biopsies were processed for ganglion cells and rapid AChE technique.
      RESULTS: There were no biopsy-induced perforations. Abnormal biopsies were
      repeated more proximally until ganglion cells were observed. Transanal pull
      through was performed and an open full-thickness biopsy performed to confirm the
      presence of ganglion cells. All procedures were performed successfully.
      CONCLUSIONS: Laparoscopy-assisted SCBx can be used successfully in patients with
      Hirschsprung's disease affecting the rectosigmoid (80% of cases). The technique,
      when used with rapid AChE staining, provides accurate identification of the level
      of normoganglionosis.

PMID- 12483624
TI  - Effective Nissen fundoplication length and bougie diameter size in young children
      undergoing laparoscopic Nissen fundoplication.
AB  - BACKGROUND/PURPOSE: Laparoscopic Nissen fundoplication (LNF) is utilized in the
      management of symptomatic gastroesophageal reflux disease (GERD) in children. An
      effective length of fundoplication and bougie size has never been established in
      infants and children requiring LNF for GERD. To determine this effective
      fundoplication length and appropriate bougie size, we analyzed all patients less
      than 15 kg undergoing LNF for GERD over a 2-year period. METHODS: Data recovered
      retrospectively included age, weight, gender, need for gastrostomy, length of
      postoperative hospitalization, operating time, bougie size, and fundoplication
      length. RESULTS: One hundred patients weighed less than 15 kg (mean, 7.23 kg).
      Mean operating time was 95 minutes (range, 31 minutes to 159 minutes).
      Gastrostomies were placed in 32 patients. Postoperative hospitalization averaged
      1.8 days for elective LNF. Fundoplication length was measured in each patient and
      averaged 2.06 cm. Bougie size varied from 22F to 42F, and the size utilized was
      based on the patient's weight. There were no instances of dysphagia or the need
      for esophageal dilatation postoperatively. Two patients have been seen for
      recurrent symptoms. One patient has required a second LNF, and the other has a
      normal upper gastrointestinal study and pH study. CONCLUSION: This study of LNF
      in small children has shown that resolution of GERD symptoms in most patients can
      be accomplished with an average fundoplication length of approximately 2 cm and a
      graduated bougie size relative to the patient's weight.

PMID- 12483625
TI  - Ad libitum feeding: safely improving the cost-effectiveness of pyloromyotomy.
AB  - BACKGROUND/PURPOSE: Patients undergoing pyloromyotomy traditionally have been
      placed on complex postoperative feeding regimens. The authors evaluated the
      substitution of an ad libitum feeding regimen to determine if it could decrease
      length of hospital stay and cost without increasing the morbidity rate. METHODS:
      Fifty-six consecutive patients undergoing open pyloromyotomy were evaluated. The
      initial 31 patients were treated with a traditional protocol, whereas the next 25
      patients received ad libitum feeding. Time to first full-strength feeding, amount
      and time of any emesis, and time to discharge were recorded. Hospital costs and
      number of readmissions were assessed. RESULTS: Patients in the ad libitum group
      had a statistically significant shorter time to discharge (25.1 hours versus 38.8
      hours), which translated into a savings of $1,290 per patient. Whereas more
      patients in the ad libitum group experienced postoperative emesis (32% v 26%),
      this was not statistically significant. There was no other morbidity and there
      were no readmissions in either group. CONCLUSIONS: Postoperative ad libitum
      feedings resulted in significant decreases in hospital stay and associated costs
      without increasing morbidity. Ad libitum feeding is safe, simple, and cost
      effective, and may offer an avenue for short-stay pyloromyotomy in selected
      patients.

PMID- 12483626
TI  - Gastroschisis: small hole, big cost.
AB  - BACKGROUND/PURPOSE: This study was designed to assess the outcome and financial
      costs incurred for the treatment of gastroschisis. METHODS: A retrospective
      analysis was conducted of all patients with gastroschisis at a single institution
      over the past decade (n = 69). Hospital costs were determined and standardized to
      December 2001 dollars. RESULTS: Of the 69 patients, average gestational age at
      delivery was 35.9 weeks. Thirty-six patients had a primary fascial closure; 33
      had a silo placed. The mean time to first feeding was 22 days and full feeding,
      33 days. Average length of stay was 47 days. There were 3 deaths (2 shortly after
      birth, and one 131 days later owing to sepsis). The average cost of
      hospitalization and physician fees for patients with gastroschisis was $123,200.
      Using multivariate regression analysis, significant variables (P <.05) associated
      with cost of hospitalization were number of operative procedures, ventilatory
      days, male gender, and length of stay. Room expenses (43%), physician fees (15%),
      respiratory and pulmonary care (10%), and supply and devices (10%) made up the
      majority of costs. CONCLUSIONS: Cost of care associated with treatment for
      gastroschisis is high. Strategies designed to reduce cost must limit
      gastrointestinal, respiratory, and operative complications and reduce length of
      stay.

PMID- 12483627
TI  - Surgical complications and outcome of pediatric liver transplantation in Hong
      Kong.
AB  - PURPOSE: The aim of this study was to analyze the early and late results of
      pediatric liver transplantation, with particular reference to complications that
      required surgical or radiologic intervention. METHODS: The records and code
      sheets of children who underwent liver transplantation in the authors'
      institution between September 1993 and December 2001 were reviewed. RESULTS:
      Twenty-nine children (16 boys and 13 girls) underwent 31 liver transplantations
      (23 living donor, 8 cadaveric donor) during the study period. The ages of the
      children ranged from 4 months to 132 months (median, 16 months). Eighteen
      children had complications that required surgical or radiologic interventional
      procedures. Complications included, among others, hepatic vein thrombosis (n = 1,
      3%), hepatic vein stenosis (n = 2, 7%), portal vein thrombosis (n = 2, 7%),
      biliary stricture (n = 3, 10%), bile leakage (n = 2, 7%), hepatic artery
      pseudoaneurysm (n = 1, 3%), jejuno-jejunostomy leakage (n = 1, 3%), graft
      hepatitis (n = 1, 3%), and posttransplant lymphoproliferative disorder (n = 2,
      7%). In addition, 6 children (21%) suffered from intraabdominal bleeding from a
      variety of causes. After appropriate interventions, at a median follow-up of 38
      months (range, 1 to 96 months), patient and graft survival rates were 79% and
      74%, respectively. The retransplantation rate was only 7%. There was no incidence
      of hepatic artery thrombosis. All living donors remain alive and well.
      CONCLUSIONS: Complications are inevitable in pediatric liver transplantation.
      However, with timely recognition and active intervention, a good outcome can be
      achieved.

PMID- 12483628
TI  - Congenital diaphragmatic hernia and hydrops: a lethal association?
AB  - BACKGROUND/PURPOSE: Nonimmune hydrops in the fetus is a finding that often
      portends death. The association and prognosis of fetuses with congenital
      diaphragmatic hernia (CDH) and hydrops is not known. METHODS: A retrospective
      review of all prenatally diagnosed cases and referrals of CDH was performed.
      Variables analyzed included gestational age at diagnosis and delivery, side of
      hernia, presence of associated anomalies and hydrops, and neonatal outcome.
      RESULTS: Since 1993, 474 prenatal referrals for CDH have been made. One hundred
      seventy-five were evaluated; 15 fetuses had hydrops (9%). Five patients had CDH,
      hydrops, and associated lethal anomalies. In the remaining 10 patients, 6 of the
      diaphragmatic defects were right-sided and 4 were left-sided. All except one had
      a major portion of the liver herniated into the chest. Six fetuses had prenatal
      intervention. Five neonates died shortly after birth. There were 5 long-term
      survivors; all received prenatal intervention. CONCLUSIONS: The association of
      CDH and hydrops is rare but often results in fatality. Hydrops appears to be
      associated with liver in the hernia, right-sided lesions, and lethal anomalies.
      Fetal intervention can be performed successfully in patients with CDH and
      hydrops, and may improve long-term survival rate in this group.

PMID- 12483629
TI  - Gastroesophageal reflux after repair of congenital diaphragmatic hernia.
AB  - BACKGROUND/PURPOSE: Mechanisms of postoperative gastroesophageal reflux (GER)
      remain unclarified in congenital diaphragmatic hernia (CDH). The aim of this
      study was to examine clinical features of CDH contributing to GER. METHODS: GER
      was evaluated as esophageal acid exposure measured with 24-hour pH monitoring at
      the average age of 1.7 +/- 0.9 months in 26 survivors of CDH. Correlations
      between the percentage total time pH below 4.0 (reflux index: RI)/number of long
      acid reflux (long reflux) and clinical features were investigated. The subjects
      were divided into 2 groups; group A: RI < or = 4.0% (n = 7) and group B: R
      greater than 4.0% (n = 19). Clinical features were compared between the 2 groups.
      RESULTS: No significant correlation was noted between RI/long reflux and birth
      weight, preoperative AaDO2, duration of artificial ventilation, and dimension of
      the defect. The incidence of direct closure was significantly higher, but use of
      nitric oxide inhalation and a presence of intrathoracic liver lobe herniation
      were significantly lower in group B. There was no significant difference of other
      clinical features indicating the severity of CDH between the 2 groups.
      CONCLUSION: An association of GER is not rare in early infancy after repair of
      CDH, which is influenced by the repair methods.

PMID- 12483630
TI  - Fryns syndrome in children with congenital diaphragmatic hernia.
AB  - PURPOSE: Fryns syndrome is characterized by multiple congenital anomalies
      including Congenital Diaphragmatic Hernia (CDH), and has a reported poor
      prognosis with a survival rate during the neonatal period of approximately 15%.
      This report details the management and outcome of patients with Fryns syndrome
      and CDH. METHODS: Records of all liveborn patients with CDH between 1995 and 2001
      in 83 hospitals were entered into the CDH database. Those with Fryns syndrome
      were reviewed retrospectively. RESULTS: A total of 1,833 patients were entered in
      the database, 23 of these had Fryns (1.3%). All patients experienced early
      distress requiring intubation. Ten patients (43%) were found to have other major
      anomalies. Seven patients underwent surgical repair at an average age of 7.5 days
      (range, 6 hours to 14 days). Mortality rate was 83% compared with 33% of patients
      with unilateral CDH (P =.01). Ten patients died within the first 24 hours. The
      parents of 6 patients withdrew support. Of the 4 survivors, 3 have marked
      developmental delay, whereas the fourth has not yet undergone formal assessment.
      CONCLUSIONS: The prognosis of infants with Fryns syndrome and congenital
      diaphragmatic hernia remains grim. Early genetic counseling and recognition of
      lethal anomalies may assist in determining which patients may survive.

PMID- 12483631
TI  - Surgical decision making in necrotizing enterocolitis and focal intestinal
      perforation: predictive value of radiologic findings.
AB  - BACKGROUND/PURPOSE: Given the current controversy over the appropriate surgical
      management (peritoneal drainage versus exploratory laparotomy) of advanced
      necrotizing enterocolitis and focal intestinal perforation, the authors examined
      the predictive value of radiologic findings. METHODS: The medical records of 80
      infants undergoing exploratory laparotomy for presumed advanced necrotizing
      enterocolitis (NEC) or focal intestinal perforation (FIP) were reviewed.
      Radiologic criteria were evaluated as predictors of NEC (pneumatosis
      intestinalis, portal venous gas) or perforation (free air, gasless abdomen). The
      standard epidemiologic measures were calculated for each criterion. RESULTS: For
      pneumatosis intestinalis, the sensitivity was 44% (n = 27) and specificity, 100%
      (n = 19). For portal venous gas, the sensitivity was 13% (n = 8) and specificity,
      100% (n = 19). The sensitivity and specificity calculated for free air was 52% (n
      = 23) and 92% (n = 33), respectively. The sensitivity and specificity calculated
      for a gasless abdomen was 32% (n = 14) and 92% (n = 33), respectively.
      CONCLUSIONS: While demonstrating high specificity, the radiologic signs
      traditionally associated with NEC and FIP have unexpectedly low sensitivities.
      Although positive radiologic findings are of great predictive value, negative
      radiologic findings acquired while determining the need for and specific type of
      surgical intervention in suspected NEC or FIP must be interpreted with extreme
      caution.

PMID- 12483632
TI  - Laparotomy in very small premature infants with necrotizing enterocolitis or
      focal intestinal perforation: postoperative outcome.
AB  - BACKGROUND/PURPOSE: Laparotomy for peritonitis secondary to necrotizing
      enterocolitis (NEC) or focal intestinal perforation (FIP) has been supplanted by
      peritoneal drainage (PD) as the initial treatment in many institutions. Although
      proponents regard it as a safer alternative, early mortality is cited between 21%
      and 36%, with subsequent laparotomy required for worsening disease in 26% to 83%
      of patients. The current outcomes for initial laparotomy are analyzed and
      compared with those cited for PD. METHODS: A retrospective review of very small
      premature infants less than 1,500 g undergoing laparotomy for NEC or FIP between
      1994 and 2000 was performed. RESULTS: Thirty-five neonates were identified with a
      median weight of 741 g (range, 460 g to 1,415 g) and a median age of 26 weeks
      (range, 23 to 33 weeks). Twelve patients had FIP and 23 had NEC including 5 with
      pan-intestinal necrosis (PIN). No deaths occurred during laparotomy or stoma
      closure. Seven (20%) patients died within the immediate 7-day postoperative
      period. Nine (26%) patients died in the 30-day postoperative period. CONCLUSIONS:
      With current peri-operative management, mortality rates for initial laparotomy
      and PD are comparable. Assessing the extent of disease and removing necrotic
      bowel at initial laparotomy can hasten recovery and eventual discharge while
      enabling informed surgical decision making and advice to parents.

PMID- 12483633
TI  - A possible mechanism for prevention of intestinal programmed cell death after
      ischemia-reperfusion injury by hepatocyte growth factor pretreatment.
AB  - BACKGROUND/PURPOSE: Intestinal ischemia-reperfusion (IR) injury produces necrosis
      and apoptosis resulting in tissue loss. The authors have observed previously that
      pretreatment with hepatocyte growth factor (HGF) attenuates enterocyte apoptosis
      after IR. This study investigated the effects of HGF on tissue levels of caspase
      8, an apoptosis initiator, and caspase-3, an apoptosis effector, in intestinal
      mucosa after IR. METHODS: Thirty rats underwent placement of jugular venous
      catheters connected to osmotic pumps; 15 rats received vehicle, and 15 rats
      received HGF (150 microg/kg/d). After a 48-hour infusion, 5 rats from each group
      underwent either 35 minutes of superior mesenteric artery occlusion alone, or
      ischemia followed by 2 or 6 hours of reperfusion. Mucosal protein was analyzed
      for caspase-8 and caspase-3 activity. DNA fragmentation was used to measure the
      presence of apoptosis. Statistical significance was determined using analysis of
      variance. RESULTS: After 6 hours of reperfusion, caspase-3 activity was increased
      significantly in control animals (P <.05). In HGF-pretreated animals, caspase-8
      and caspase-3 activities were significantly reduced at 6 hours compared with
      control animals (P <.05). CONCLUSION: By preventing the activation of enterocyte
      caspase enzymes, and, thus, reducing apoptosis, HGF may enhance preservation of
      the intestine after IR injury.

PMID- 12483634
TI  - Fetal endoscopic surgery: lessons learned and trends reviewed.
AB  - PURPOSE: Fetal surgery is performed increasingly with minimal access approaches.
      The authors report their experience with fetal endoscopic procedures (fetendo)
      with emphasis on changing techniques and outcome trends. METHODS: All fetal
      endoscopic cases performed at a single institution from January 1996 to August
      2001 were reviewed (n = 66). Cases were examined with respect to year performed,
      type of operation, operative data, and outcome. RESULTS: Twin-twin transfusion
      syndrome (26 cases) and congenital diaphragmatic hernia (35 cases) were the most
      common diseases treated. From 1996 to 2001, there was a decrease in average
      operating time (256 to 127 minutes [P =.0006]), number of ports utilized (3.8 to
      one [P =.00001]), pump volume (28.7 to 2.7 L [P =.00001]), and estimated blood
      loss (408 to 29 mL [P =.008]). In addition, port size changed from 10 mm to 5 mm.
      Chorioamniotic separation (31 of 66), premature rupture of membranes (32 of 66),
      chorioamnionitis (12 of 66), and fetal death (10 of 66) continued to be
      significant complications. CONCLUSIONS: Fetal endoscopic surgery over the last 6
      years has evolved toward shorter operating time, the use of smaller and fewer
      ports, decreased pump fluid exchange, and decreased blood loss, with the types of
      cases centered on twin-twin transfusion syndrome and congenital diaphragmatic
      hernia.

PMID- 12483635
TI  - Malignant germ cell tumors: clinical characteristics, treatment, and outcome. A
      report from the study group for Pediatric Solid Malignant Tumors in the Kyushu
      Area, Japan.
AB  - PURPOSE: This study aims to assess the prognostic factors and optimal treatments
      for malignant germ cell tumors (MGCT) in childhood. METHODS: Among 117 MGCT, the
      clinical features were analyzed. Regarding the histology, there were 89 embryonal
      carcinomas, 13 dysgerminomas, 4 choriocarcinomas, and 11 others. The prognostic
      factors and treatments were assessed based on the 5-year survival rate. RESULTS:
      (1) Stage: 100% for stage I (n = 54), 75.0% for stage II (n = 4), 67.3% for stage
      III (n = 14), and 54.8% for stage IV (n = 33); Unknown: n = 12. (2) Primary site:
      93.4% for the testis (n = 52), 86.7% for the ovary (n = 31), 56.9% for the
      sacrococcygeal (n = 21), and 60.6% for others (n = 12); unknown: n = 1. (3)
      Surgical intervention for primary tumor: 100% for stage I with a complete
      resection (n = 53), 78.4% for stage III, IV with a complete resection (n = 26),
      and 33.3% for stage III, IV with an incomplete resection (n = 21). (4) Type of
      chemotherapy for the stage III and IV: 83.9% for the PVB (cisplatin, vinblastin,
      bleomycin; n = 13), 66.7% for the VAC (vincristine, actinomycin D,
      cyclophosphamide; n = 6), and 47.1% for other regimens (n = 25). CONCLUSIONS: An
      early stage, a diagnosis under 1 year of age and a primary site in the gonads
      were favorable prognosis factors, whereas histologic findings of choriocarcinoma
      and liver or lung metastasis were unfavorable. Radical complete resection alone
      is a sufficient treatment for localized MGCT. The PVB regimen is optimal
      chemotherapy for advanced MGCT; however, high-risk cases still may require more
      aggressive treatment.

PMID- 12483636
TI  - Urinary sulfated bile acids: a new simple urine test for cholestasis in infants
      and children.
AB  - BACKGROUND/PURPOSE: Measurement of urinary sulfated bile acid (USBA) has been
      reported as a simple urine test that reflects the degree of cholestasis. The
      authors report the diagnostic value of this new laboratory test in various
      cholestatic conditions affecting infants and children. METHODS: A urine sample
      was collected from 4 surgical neonates with parenteral nutrition-induced
      cholestasis and 48 patients with biliary atresia (BA). USBA was measured by
      direct enzymatic assay. RESULTS: In 3 patients receiving parenteral nutrition,
      USBA increased with caloric gains. For one surgical patient, a decrease in
      calories because of liver dysfunction resulted in a decrease of USBA, closely
      reflecting the fluctuations of caloric intake. In patients with BA, a significant
      positive correlation was noted between serum bile acid and USBA (r = 0.85; P
      <.01). Ten of 14 febrile episodes in 6 patients with liver dysfunction and
      increased C-reactive protein showed elevated USBA, thus diagnosed as cholangitis.
      Four febrile episodes caused by viral infection showed no elevation of USBA.
      CONCLUSIONS: USBA is a simple and sensitive noninvasive test reflecting the
      degree of cholestasis in infants and children. USBA correlated highly with serum
      bile acid levels and may be helpful in diagnosis of cholestasis caused by
      cholangitis without blood sampling.

PMID- 12483637
TI  - Biliary atresia, the next generation: a review of liver function, social
      activity, and sexual development in the late postoperative period.
AB  - PURPOSE: The current study aimed to establish the management for biliary atresia
      (BA) patients in the late postoperative period. METHODS: Of 165 BA patients
      operated on in the authors' department, 44 patients (16 boys, 28 girls) with a
      follow-up period of more than 15 years were reviewed retrospectively. RESULTS:
      Forty-one of 44 patients (93.2%) currently are employed or highly educated, 7 are
      married, whereas 2 (4.5%) died, and 10 (22.7%) required liver transplantation
      after puberty. Four babies have been born from BA parents without congenital
      anomalies. Four girls conceived 5 times and delivered 3 newborns weighing 2,330
      to 2,474 g including one delivered after transplantation. Maternal portal
      hypertension uniformly deteriorated during pregnancy, and one pregnancy was
      terminated. Menstrual disorder correlated significantly with the biochemical data
      related to liver function at puberty such as serum choline esterase (266 +/- 70.4
      in 19 normal patients v 159 +/- 34.3 IU/L in 9 abnormal patients, P =.00057),
      asparate aminotransferase (42 +/- 30.8 v 96.0 +/- 63.6 IU/L; P =.0031), and serum
      albumin (4.6 +/- 0.4 v 3.9 +/- 0.6 g/dL; P =.013). CONCLUSIONS: The long-term
      survivors of Kasai's operation, with or without liver transplantation, have
      reached the next generation. Transgenerational follow-up and management including
      conception and perinatal care should be required for BA patients.

PMID- 12483638
TI  - Surgical management for intractable cholangitis in biliary atresia.
AB  - BACKGROUND/PURPOSE: The efficacy of antireflux surgical procedures involving the
      Roux-en-Y jejunal limb for cholangitis was evaluated retrospectively in patients
      with biliary atresia (BA). METHODS: From July 1993 to December 2001, 41 patients
      with BA underwent hepatic portojejunostomy with Roux-en-Y reconstruction. Of
      these patients, 11 had intractable cholangitis that was treated by creation of a
      value with or without lengthening of the Roux-en-Y limb. RESULTS: Among the 11
      patients, the first episode of cholangitis occurred within 6 months after
      portojejunostomy in 10 patients and at the age of 4 years in one patient.
      Cholangitis developed at various intervals from once every week to once every 2
      months requiring hospitalization each time. All patients underwent valve creation
      at 2 months to 5 years postoperatively, whereas 2 had an additional lengthening
      of the limb. Cholangitis resolved completely after surgery in all cases. Two
      patients underwent liver transplantation, and the third patient died of an
      unrelated cause. The 8 survivors with native livers are doing well after 1 to 8
      years of follow-up. CONCLUSION: Early surgical intervention could control
      intractable cholangitis in all patients, both delaying the time of liver
      transplantation and improving the quality of life.

PMID- 12483639
TI  - Biliary tract anomalies in thoraco-omphalopagus conjoined twins.
AB  - Thoraco-omphalopagus conjoined twins were separated urgently on the ninth day of
      life because of bowel obstruction and impending intestinal perforation.
      Preoperative studies clarified the cardiac, intestinal, and hepatic parenchymal
      anomalies, but the precise biliary anatomy remained obscure. Operative
      cholangiogram through the single gallbladder visualized only the extrahepatic
      biliary anatomy in twin A. At reoperation for abdominal patch removal,
      exploration in twin A found biliary atresia. Because of the unusual duodenal
      anatomy and extreme short bowel, the authors elected to treat the biliary atresia
      in twin A with an appendix portoenterostomy. Twin B had no gallbladder and a
      profoundly hypoplastic biliary tree. Both twins have normal bilirubin and liver
      function at 18 months of age. The anatomic details of 8 additional cases of
      complex biliary tract anomalies in thoraco-omphalopagus conjoined twins are
      reviewed. In all cases, the complex biliary anatomy has been associated with
      conjoined duodenum. In most cases the preoperative technetium 99m HIDA scan has
      been inconclusive or misleading.

PMID- 12483640
TI  - Engineered fetal cartilage: structural and functional analysis in vitro.
AB  - BACKGROUND/PURPOSE: This study was aimed at characterizing the structure and
      function of engineered fetal cartilage in vitro. METHODS: Chondrocytes from ovine
      specimens of fetal elastic, fetal hyaline, and adult elastic cartilage were
      expanded in culture and their growth rates determined. Cells were seeded onto
      synthetic scaffolds, which were then maintained in a bioreactor. Matrix
      deposition was determined by specific staining and quantitative assays for
      glycosaminoglycans (GAG), type II collagen (CII), and elastin, as well as
      compared with native tissue. Statistical analysis was by analysis of variance
      (ANOVA) and Students' t test, with significance set at P less than.01. RESULTS:
      Fetal elastic chondrocytes grew significantly faster than all other cell types.
      All fetal constructs resembled hyaline cartilage, regardless of the cell source.
      There were significantly higher levels of GAG and CII in fetal versus adult
      constructs, but no significant difference between fetal constructs from different
      sources. Unlike their adult counterparts, fetal constructs had GAG and CII levels
      similar to native tissues. CONCLUSIONS: Fetal chondrocytes can be rapidly
      expanded in culture. Compared with adult constructs, matrix deposition is
      enhanced in engineered fetal cartilage, which closely resembles native tissue,
      regardless of the cell source. Engineered fetal cartilage may be a preferable
      option during surgical reconstruction of select congenital anomalies.

PMID- 12483641
TI  - Successful salvage of a long-standing collapsed lung by bronchoplasty in three
      children.
AB  - BACKGROUND: The authors report successful salvage of the ipsilateral lung by a
      bronchoplastic procedure in 3 patients with a long-standing, totally collapsed
      lung. METHODS: The 3 patients were 1, 5, and 6 years of age, and the left lung
      had been collapsed totally for periods of 13 months to 5 years. The origin of
      atelectasis was congenital in 2 patients and traumatic in one patient.
      Bronchoscopy showed complete obstruction of the left main bronchus. In each
      patient, the left lung was small and appeared as a liverlike organ. Entire length
      of the main bronchus was resected. The left lung was not aerated in spite of
      aggressive bagging through an endotracheal tube inserted into the distal
      bronchial stump. The bifurcation of the upper and lower segmental bronchi was
      anastomosed to the trachea by interrupted sutures. Histology of the resected
      bronchus in the cases of congenital origin showed bronchial rings represented by
      islands of immature cartilage. RESULTS: Chest x-ray showed complete aeration of
      the left lung at 3, 4, and 5 months, respectively, after surgery in the 3
      children. Bronchoscopy disclosed a well-reconstructed airway in all patients. Two
      of the 3 patients have been free from respiratory distress during a 3- to 4-year
      follow-up. The latest patient to have this surgery is undergoing home ventilation
      because of chronic lung disease. CONCLUSIONS: A long-standing collapsed lung in
      children may reexpand if bronchial continuity is restored. Insufficient inflation
      of the lung at surgery is not an indication for pneumonectomy. When at all
      possible, a child's lung should be preserved.

PMID- 12483642
TI  - Methylene blue-stained autologous blood for needle localization and thoracoscopic
      resection of deep pulmonary nodules.
AB  - BACKGROUND/PURPOSE: Video-assisted thoracoscopic surgery (VATS) has used a
      variety of preoperative techniques to localize deep pulmonary nodules including
      wires, plain methylene blue, colored collagen, indigo carmine, India ink, and
      barium. The authors describe their experience with a computed tomography (CT)
      guided localization technique using autologous blood stained with methylene blue.
      METHODS: The authors reviewed retrospectively children who had pulmonary nodules
      localized using CT guidance with a mixture containing 3 mL autologous blood
      stained with 0.3 mL methylene blue. Nodules were resected by standard VATS
      technique. Postoperative chest tube drainage was performed selectively. RESULTS:
      Nineteen procedures were performed in 17 children (average age, 11 years).
      Operating time (range, 21 to 171 minutes) varied depending on the number of
      nodules resected. All resections were diagnostic, and 80% represented malignancy.
      Lesions averaged 0.9 cm in size (range, 0.3 to 3 cm) with an average pulmonary
      depth of 0.8 cm (range, 0.1 cm to 1.8 cm). One patient required conversion to an
      open thoracotomy because of malfunction of the endoscopic stapler. Forty percent
      of the children received chest tubes, and 53% were discharged home the same day.
      CONCLUSION: VATS diagnostic resection of deep pulmonary nodules preoperatively
      localized with methylene blue stained autologous blood is safe and effective.

PMID- 12483643
TI  - Thoracoscopic anterior spinal release and fusion: evolution of a faster, improved
      approach.
AB  - PURPOSE: The aim of this study was to compare the perioperative parameters and
      outcomes of video-assisted thoracoscopic surgery (VATS) with open thoracotomy for
      anterior release and fusion in the treatment of pediatric spinal deformities.
      METHODS: Twenty-six patients treated with VATS anterior spinal release and
      posterior spinal fusion by the authors were reviewed retrospectively. Fourteen
      age- and disease-matched patients who underwent open thoracotomy for anterior
      spinal release and posterior spinal fusion by the same group of surgeons during
      the same time period were evaluated for comparison. Patients whose anterior level
      of exposure extended below the diaphragm were excluded. RESULTS: Blood loss,
      operative transfusion, and length of postoperative chest tube use all were
      decreased in the VATS patients compared with thoracotomy patients (P < or =.05).
      The average operating time for VATS was less than that for thoracotomy but did
      not reach statistical significance. However, operating time was significantly
      shorter in the second 13 VATS patients compared with the first 13 patients. No
      complications specifically related to the VATS approach were identified.
      CONCLUSIONS: The VATS technique is a safe and comparable alternative to open
      thoracotomy. Although there is a learning curve for VATS, greater experience
      could show an advantage in this approach to the anterior spine for the treatment
      of pediatric spinal deformity.

PMID- 12483644
TI  - Fetoscopic treatment for discordant twins.
AB  - BACKGROUND/PURPOSE: In rare instances in monochorionic twin pregnancies, one twin
      can have a discordant anomaly (eg, cystic hygroma). If this twin dies in utero,
      neurologic injury and death can occur in the surviving cotwin. To protect the
      normal twin, the authors developed an approach to separate the circulations and
      ablate the umbilical cord of the abnormal twin. METHODS: From September 1998 to
      February 2001, 6 cases of discordant anomalous twins were diagnosed by prenatal
      ultrasound scan in which the anomaly was lethal or parents desired prenatal
      termination for this abnormal twin. All underwent surgical intervention with
      gestational ages varying from 19 to 24 weeks. RESULTS: Depending on cord
      insertion site and placental anatomy, blood flow was interrupted to the anomalous
      fetus by either radiofrequency ablation (RFA; 2 cases), cord transection (1
      case), or cord transection after laser ablation of communicating vessels (3
      cases). Fetal death occurred in one normal twin 4 days postoperatively. Average
      age at delivery for the 5 surviving fetuses was 34.5 weeks' gestation. On follow
      up, all surviving infants are neurologically intact. CONCLUSION: An otherwise
      normal monochorionic twin threatened by an anomalous cotwin can be salvaged
      successfully with a strategy tailored to interrupt the vascular connections
      between the 2 twins.

PMID- 12483645
TI  - Perineal reconstruction of female conjoined twins.
AB  - BACKGROUND/PURPOSE: Conjoined twins are some of the most challenging patients
      faced by surgeons. Pygopagus and ischiopagus twins present particular
      gastrointestinal and genitourinary reconstructive challenges. This study reviews
      the authors' experience with the perineal reconstruction of these types of
      conjoined twins. METHODS: Retrospective analysis was performed for 3 sets of
      female conjoined twins undergoing separation between 1999 and 2001. Particular
      attention was given to the separation and reconstruction of the distal
      gastrointestinal and urogenital structures. RESULTS: Three sets of female
      conjoined twins underwent successful separation 2 pygopagus, one ischiopagus
      tripus) with 5 surviving infants. The sixth infant died of congenital anomalies
      incompatible with life. Four of the 5 surviving infants had diverting
      enterostomies. Two of these enterostomies have been closed. Perineal
      reconstruction consisted of anoplasty (5 of 5), vaginoplasty (4 of 5), and
      urethroplasty (4 of 5). Although fecal and urinary continence are not completely
      measurable at this age (<3 years), all 5 survivors void spontaneously. Three
      infants with intestinal continuity have apparently normal defecation without the
      need of a bowel regimen. CONCLUSIONS: With careful preoperative planning and a
      multidisciplinary team of pediatric surgeons and urologists, satisfactory
      reconstruction and functional outcome of the female perineum can be achieved in
      conjoined twins.

PMID- 12483646
TI  - Usefulness of endoscopic ultrasonography in the diagnosis of congenital
      esophageal stenosis.
AB  - BACKGROUND/PURPOSE: Endoscopic ultrasonography (EUS) is considered a potentially
      useful tool to investigate structural abnormalities of the esophagus in pediatric
      patients, as in adults. The aim of this study was to evaluate the usefulness of
      EUS for the diagnosis of congenital esophageal stenosis. METHODS: High-frequency
      catheter probe EUS was performed under general anesthesia in 2 patients who had
      congenital esophageal stenosis. RESULTS: A 4-year-old boy with anorectal anomaly
      showed tapered narrowing in the distal esophagus, which was not ameliorated with
      balloon dilatation. High-frequency catheter probe EUS showed hypertrophy of the
      muscular layer in the esophageal wall at the narrowed portion, but no images
      suggested the presence of tracheobronchial remnants. The histologic diagnosis of
      fibromuscular hypertrophy was confirmed at esophagoplasty. A 5-month-old boy with
      Gross C-type esophageal atresia and symptomatic gastroesophageal reflux showed
      tapered narrowing in the middle esophagus on esophagography. The symptoms of
      stenosis were not ameliorated by balloon dilatation performed 4 times. High
      frequency catheter probe EUS showed hyperechoic lesions suggesting cartilage at
      the esophageal narrowing. The diagnosis of tracheobronchial remnants was
      confirmed by the finding of 2 pieces of cartilage in the specimen obtained at the
      time of esophageal resection. CONCLUSION: EUS can be applied to show structural
      abnormalities of the esophageal wall even in pediatric patients with congenital
      esophageal stenosis and is useful for planning the therapeutic strategy.

PMID- 12483647
TI  - Expression of vascular endothelial growth factor and its receptor Flk-1 in human
      neuroblastoma using in situ hybridization.
AB  - BACKGROUND/PURPOSE: Although angiogenic factors may play an important role in the
      biology of neuroblastoma, which frequently spreads hematogenously, the mechanism
      remains unclear. The authors studied tumor progression and invasion from the
      perspective of angiogenesis and sought to understand the features of this type of
      tumor. METHODS: Thirty-one specimens were resected from patients with
      neuroblastoma and the expression of vascular endothelial growth factor (VEGF),
      and its receptor (Flk-1) was examined using immunohistochemistry. The authors
      looked for correlations among the expressions of VEGF and its receptor with
      various clinicopathologic factors. In addition, they examined the expression and
      location of VEGF and Flk-1 mRNA in 10 primary neuroblastoma using in situ
      hybridization. RESULTS: Both in situ hybridization and immunohistochemistry
      showed the presence of VEGF expression within the neuroblastoma cells. We found
      VEGF mRNA in neuroblastoma cells but not vascular endothelial cells according to
      in situ hybridization. Further, Flk-1 mRNA was present both in neuroblastoma
      cells and vascular endothelial cells. The level of VEGF expression was higher in
      unfavorable histology, using the criteria of Shimada, than in favorable
      histology. CONCLUSION: The authors suggest that paracrine and autocrine systems
      are involved in the angiogenesis of neuroblastoma, and the expression of VEGF
      correlates with the prognosis in neuroblastoma.

PMID- 12483648
TI  - Human chorionic gonadotrophin (hCG) stimulates spermatogenesis in immature mice
      in vivo.
AB  - BACKGROUND/PURPOSE: Spermatogenesis in postnatal testes is controlled by the
      hypothalamic-pituitary-gonadal axis. To determine if pituitary hormones can
      induce precocious spermatogenesis once primary spermatocytes (PS) have formed,
      prepubertal mice were treated with human chorionic gonadotrophin (hCG). METHODS:
      Day 12 immature mice (n = 10) were injected every third day with hCG (3 or 6 IU)
      dissolved in 100 microL phosphate-buffered saline (PBS). Control mice (n = 10)
      were either uninjected or injected with 100 microL PBS alone. On day 20 to 22 the
      excised testes were examined histologically with tubule counts. RESULTS: HCG
      treated mice had fewer tubules at stage I (P <.001) and more at stage III than
      the PBS-treated group (P <.001). Mean thickness of the round spermatid layer per
      tubular cross section in the hCG-treated group was significantly increased
      compared with the PBS-treated group (P <.01). Similarly, the percentage of the
      tubules at stage III (containing round spermatids) in the hCG-treated group was
      significantly increased, from 25% to 71%, compared with the PBS-treated group (P
      <.01). With increasing doses of hCG the testosterone levels were significantly
      higher than in controls (P <.01), but hCG did not alter testis weight or
      position. CONCLUSIONS: These results show that hCG stimulates the transformation
      of PS to round spermatids even in immature mouse testes. These findings suggest
      that hCG treatment of prepubertal cryptorchid boys may initiate premature
      spermatogenesis.

PMID- 12483649
TI  - Vascular malformations of the colon in children.
AB  - PURPOSE: The aim of this study was to evaluate clinical, radiologic, surgical,
      and histopathologic characteristics of vascular malformations of the colon (VMC)
      in children. METHODS: Eighteen patients with lower intestinal bleeding (LIB) and
      VMC were included. Clinical data, angiographic features, surgical treatments, and
      histopathologic findings were analyzed. RESULTS: Age of clinical onset was from 1
      week to 16 years. Duration of LIB before diagnosis was from 1 month to 9 years.
      Admission hemoglobin level was 2 to 9 g/dL in 13 patients and in the other 5 was
      normal. Scintigraphy, colonoscopy, and barium enema results were normal or
      suggested a vascular problem. Mesenteric arteriography detected VMC in all 18
      cases. Left hemicolon and rectum were affected in 83% of the cases. VMC were
      resected in 14 patients, 10 were anastomosed or pulled-through, and the other 4
      required an intestinal stoma. Ten patients are asymptomatic, and 4 have minimal
      postoperative bleeding. The histopathologic study made in 15 cases (14 surgical
      specimens and 1 endoscopic biopsy), revealed arterial-venous VMC in 12 and
      arterial-venous-lymphatic VMC in 3 cases. CONCLUSIONS: The identification of VMC
      in children with LIB often is delayed. An early mesenteric arteriography should
      be added to the routine evaluation. Surgical treatment presents a challenge in
      rectal cases. To avoid confusion in the nomenclature a simplified morphologic
      classification is suggested.

PMID- 12483650
TI  - Delayed maturation of interstitial cells of Cajal in meconium obstruction.
AB  - BACKGROUND/PURPOSE: The etiology of meconium obstruction without cystic fibrosis
      is unclear. Interstitial cells of Cajal (ICC) function as pacemakers in gut
      motility and may play a role in the pathophysiology of the disease. METHODS: The
      ICC were examined by immunohistochemical staining with anti-c-kit antibody in the
      bowel walls of 6 neonates who had meconium obstruction without cystic fibrosis,
      and the results were compared with specimens from normal neonates (n = 2).
      RESULTS: Six patients underwent ileostomy between 2 and 15 days after birth, and
      5 of them presented with microcolon. Ganglion cells were present in the ileum and
      colon. Whereas ICC were evenly distributed in the control specimens, they were
      not seen at the time of ileostomy in the colons of 2 patients, and the other 4
      showed scanty distribution in muscle layers. However, ileum showed normal
      distribution of ICC in all patients. The ileostomies were closed between 39 and
      104 days of age, and the ICC distribution was changed to a normal pattern in the
      colons of all 6 patients. Their bowel movements were restored to normal after
      closure. CONCLUSION: The findings of this study suggest that delayed maturity of
      ICC may be a cause of meconium obstruction without cystic fibrosis.

PMID- 12483651
TI  - Signs and symptoms of slow-transit constipation versus functional retention.
AB  - BACKGROUND/PURPOSE: Slow-transit constipation (STC) has been described recently
      in children. This retrospective study correlated symptoms, signs, transit times,
      and immunohistochemistry to determine the diagnostic differences between STC and
      functional fecal retention (FFR). METHODS: One hundred eighty children with
      intractable constipation underwent clinical assessment, nuclear transit study
      (NTS), with or without laparoscopic colonic muscle biopsy. Patients were divided
      by NTS into those with STC and those with FFR. Parents completed questionnaires
      on presenting symptoms. RESULTS: In 161 patients with STC and 19 with FFR, there
      were no differences in gender, gestation, or timing of symptom onset. Over 20%
      had the first meconium delayed more than 24 hours after birth even in FFR (4 of
      19). Bloating and soiling were more common in STC. There were no differences
      between patients with STC but different histology on biopsy. More STC patients
      had soft stools (39%) than FFR (16%), and a lower stool frequency of less than
      once a week (STC 26% compared with 11% FFR). FFR was managed more often with
      medication or diet alone (53%) compared with STC (29%), where enemas, lavage, or
      surgery were more common. CONCLUSIONS: Children with STC showed similar symptoms
      and signs to those with FFR, but more had bloating and soiling, softer stools,
      and longer intervals between bowel actions. Delayed meconium stool beyond 24
      hours after birth was common in both groups. Diagnosis of STC or FFR required NTS
      and was not possible on symptoms alone.

PMID- 12483652
TI  - Laparoscopic placement of the Chait cecostomy device via appendicostomy.
AB  - The authors describe their experience with a series of 11 patients in whom they
      have carried out Chait cecostomy catheter insertion into a laparoscopically
      formed appendicostomy. This technique has several advantages compared with
      percutaneous insertion and we now insert the device at the primary procedure. The
      authors have had one minor complication in their 11 patients, with mean follow-up
      of 8 months. This technique is recommended for the management of refractory
      constipation, for etiologies including spina bifida, anorectal malformation,
      distal intestinal obstruction syndrome, and slow-colonic transit.

PMID- 12483653
TI  - Avoidance of leakage and strictures when creating an invisible conduit for
      antegrade colonic enemas.
AB  - BACKGROUND: Antegrade enemas have been proven to minimize problems with stool
      control for many incontinent patients; however, foreign bodies are unsightly, and
      native tissues have been shown to leak or stricture. METHODS: Using a limited
      laparotomy incision, the appendix or a rolled cecal tube was sutured to the apex
      of the everted umbilical skin using a V-shaped incision. The skin then was
      inverted to hide the mucosa. The cecum was plicated around the base of the
      appendix or cecal tube and then tested by filling the cecum with saline to a
      pressure of 30 cm H2O. RESULTS: Twenty patients (aged 4.8 to 41 years) with fecal
      incontinence caused by imperforate anus (17 cases) and other causes underwent
      this procedure. Two patients had minor strictures that resolved with home
      dilatations, and one cecal tube necrosed, and the patient has refused
      reoperation. One patient had minor prolapse and underwent revision. None of the
      conduits leak. Two patients achieved continence and stopped cannulating their
      stomas. With adjustment and customization of each enema regimen, stool accidents
      are infrequent. Follow-up is 22 +/- 14 (mean +/- SD) months. CONCLUSION: A
      catheterizeable colocutaneous conduit has been developed that allows for an
      invisible, leak-proof, and relatively stricture-free means through which
      antegrade enemas can be given.

PMID- 12483654
TI  - Clinical aspects of intestinal neuronal dysplasia.
AB  - PURPOSE: The aim of this study was to determine the presence of specific clinical
      symptoms in intestinal neuronal dysplasia (IND) and whether it correlates to the
      severity of histopathologic findings. METHODS: A group of 44 severe IND and a
      group of 16 mild IND patients diagnosed by means of a histochemical rectal biopsy
      were compared with a group of 37 patients with functional constipation (FC) with
      normal rectal biopsy results. RESULTS: Patients with severe IND began their
      symptoms at an earlier age than those with mild IND and FC (5.2 +/- 112 months v
      17.5 +/- 23 months and 22.5 +/- 21.8 months, respectively; P <.001). The presence
      of intestinal obstruction symptoms was more frequent in severe IND patients than
      in mild IND and FC patients (45.5% v 18.8% v 2.7%, respectively; P <.001). The
      presence of a fecaloma and soiling were less frequent in the severe IND group
      than in mild IND and FC groups (20.5% v 56.3% v 59.5%, respectively; P <.001 and
      15.9% v 31.3% v 59.5%, respectively; P <.001). Barium enema results showed a
      lower incidence of rectosigmoid distension in severe IND if compared with mild
      IND and FC groups (45.5% v 57.1% v 96.9%; P <.001). Internal sphincter relaxation
      was absent frequently in the severe IND group compared with the FC group (47% v
      26.9%, respectively; P <.05). CONCLUSIONS: Intestinal neuronal dysplasia is a
      distinct histopathologic and clinical entity. Its clinical, radiologic, and
      manometric presentation correlates to the severity of histochemical findings.

PMID- 12483655
TI  - 35th annual meeting of the pacific association of pediatric surgeons.

PMID- 12483656
TI  - Annular pancreas and duodenal stenosis.

PMID- 12483657
TI  - Prognosis of antenatally diagnosed cystic adenomatoid malformation.

PMID- 12483659
TI  - Thomas Tenforde, recipient of the 2001 d'Arsonval award.

PMID- 12483660
TI  - The wonders of magnetism.
AB  - In this acceptance address for the Bioelectromagnetics Society's 2001 d'Arsonval
      Award, Dr. Tenforde reviews the highlights of the nonionizing field aspects of
      his research and scientific service career. These are focused in four areas: (a).
      development and application of microelectrophoretic methods to probe the surface
      chemistry of normal and cancerous cells; (b). research on the biophysical
      mechanisms of interaction and the dosimetry of static and extremely low frequency
      magnetic fields; (c). application of extremely high intensity magnetic fields in
      several spectroscopic methods for probing the detailed structures of large
      biological macromolecules; and (d). development of national and international
      guidelines for the exposure of workers and members of the general public to
      electromagnetic fields with frequencies spanning the entire nonionizing
      electromagnetic spectrum.

PMID- 12483661
TI  - Acute exposure to 50 Hz magnetic fields with harmonics and transient components:
      lack of effects on nighttime hormonal secretion in men.
AB  - The purpose of this study was to examine whether low frequency magnetic field
      (MF) influences nighttime secretion of hormones, particularly melatonin. Ten
      healthy males stayed in the experimental room (2.7 m cube with 3 axis Merritt
      coils) on two separate nights. On one night, subjects were exposed to linearly
      polarized 50 Hz, 20 microT sinusoidal MF with the third (30%) and the fifth (10%)
      harmonics and repetitive transient waves (1 burst/s of 1 kHz waves, exponentially
      attenuated with a duration of 50 ms; initially 100 microT peak), and the other
      night was for blind control. During the nights (2000-0800 h, including sleeping
      time, 2300-0700 h), blood samples were collected from the subjects at 1 h
      intervals for determining the levels of plasma hormones (melatonin, growth
      hormone (GH), cortisol, prolactin) and at 10 min intervals from 2200 to 0200 h
      for observing the GH surge induced by sleep. Statistical analyses revealed no
      significant difference between the 2 nights in the profiles of the four hormones,
      and the result suggested that extremely low frequency (ELF) or intermediate
      frequency (IF) MF to which humans are exposed residentially has no acute effect
      on nighttime secretion of hormones, particularly melatonin.

PMID- 12483662
TI  - No effects of extremely low frequency magnetic fields found on cytotoxic
      activities and cytokine production of human peripheral blood mononuclear cells in
      vitro.
AB  - Several epidemiologic studies have suggested an association between exposure to
      extremely low frequency (ELF) magnetic fields (MFs) and cancer in adults and
      children. A possible target of MFs is the immune system. The effects of the
      exposure to ELF MFs on the immunological functions of human peripheral blood
      mononuclear cells (PBMCs) obtained from healthy male volunteers were assessed by
      measuring the natural killer (NK) and lymphokine activated killer (LAK)
      activities and the production of interferon-gamma (IFN-gamma), tumor necrosis
      factor-alpha (TNF-alpha), interleukin-2 (IL-2), and interleukin-10 (IL-10). The
      PBMCs were exposed to three different MF: linearly polarized (vertical),
      circularly polarized, and elliptically polarized, at 50 and 60 Hz. Magnetic flux
      densities were set at 500, 100, 20, and 2 microT (rms) for vertical field and at
      500 microT (rms) for the rotating fields. Using cytotoxicity assay and enzyme
      linked immunosorbent assay (ELISA) for cytokine production, we could not find any
      effects of ELF MFs on the cytotoxic activities and the cytokines production of
      human PBMCs.

PMID- 12483663
TI  - Calmodulin-dependent cyclic nucleotide phosphodiesterase activity is altered by
      20 microT magnetostatic fields.
AB  - Absorbance measurements at 660 nm of calmodulin (CaM) dependent cyclic nucleotide
      phosphodiesterase activity under cell free conditions indicate that 30-min
      exposures to weak magnetostatic field intensities alters this activity, compared
      to zero magnetic field exposures. This effect depends nonlinearly on the
      concentration of free calcium, with maximum magnetic interaction apparently
      occurring at an optimal Ca(2+) concentration corresponding to 50% activation
      (EC(50)). If one regards Ca(2+)/CaM activation as a switching process, then
      increasing the magnetic field at Ca(2+) levels in excess of optimal acts to bias
      this switch towards lower calcium concentrations. A magnetic dependence has been
      previously reported by others in an homologous system, CaM dependent myosin light
      chain phosphorylation, implying that there may be an underlying magnetic
      interaction that involves the initial Ca(2+)/CaM binding process common to both
      enzymatic pathways. The level of magnetostatic intensity at which this effect is
      observed ( approximately 20 microT) implies that CaM activation may be
      functionally sensitive to the geomagnetic field.

PMID- 12483664
TI  - Biophysical limits on athermal effects of RF and microwave radiation.
AB  - Using biophysical criteria, I show that continuous radiofrequency (RF) and
      microwave radiation with intensity less than 10 mW/cm(2) are unlikely to affect
      physiology significantly through athermal mechanisms. Biological systems are
      fundamentally noisy on the molecular scale as a consequence of thermal agitation
      and are noisy macroscopically as a consequence of physiological functions and
      animal behavior. If electromagnetic fields are to significantly affect
      physiology, their direct physical effect must be greater than that from the
      ubiquitous endogenous noise. Using that criterion, I show that none of a set of
      interactions of weak fields, which I argue is nearly complete on dimensional
      grounds, can affect biology on the molecular scale. Moreover, I conclude that
      such weak fields are quite unlikely to generate significant effects in their
      interactions with larger biological elements such as cells. In the course of that
      analysis, I examine important special examples of electromagnetic interactions:
      "direct" interactions where biology is modified simply by the motion of charged
      elements generated by the electric field; resonance interactions; the effects of
      electrostrictive forces and induced dipole moments; and modifications of radical
      pair recombination probabilities. In each case, I show that it is unlikely that
      low intensity fields can generate significant physiological consequences.

PMID- 12483665
TI  - Effects of electromagnetic radiation of mobile phones on the central nervous
      system.
AB  - With the increasing use of mobile communication, concerns have been expressed
      about the possible interactions of electromagnetic radiation with the human
      organism and, in particular, the brain. The effects on neuronal electrical
      activity, energy metabolism, genomic responses, neurotransmitter balance, blood
      brain barrier permeability, cognitive function, sleep, and various brain diseases
      including brain tumors are reviewed. Most of the reported effects are small as
      long as the radiation intensity remains in the nonthermal range, and none of the
      research reviewed gives an indication of the mechanisms involved at this range.
      However, health risks may evolve from indirect consequences of mobile telephony,
      such as the sharply increased incidence rate of traffic accidents caused by
      telephony during driving, and possibly also by stress reactions which annoyed
      bystanders may experience when cellular phones are used in public places. These
      indirect health effects presumably outweigh the direct biological perturbations
      and should be investigated in more detail in the future.

PMID- 12483666
TI  - Human exposure by mobile phones in enclosed areas.
AB  - Human exposure by mobile phones in enclosed areas such as train carriages,
      elevators, and cars is considered. Equivalent power density and whole body
      specific absorption rate (SAR) are estimated by applying multimode resonant
      cavity theory and a straight forward worst case approach. The results show that
      exceeding the International Commission on Non-Ionizing Radiation Protection
      (ICNIRP) guidelines due to simultaneous use of several mobile phones in enclosed
      areas is highly improbable.

PMID- 12483667
TI  - Testing the effectiveness of small radiation shields for mobile phones.
AB  - Nine small radiation shields made to adhere to the case of mobile phones were
      tested at 914 and 1880 MHz. Five popular products were tested because
      advertisements typically claim they are up to 99% effective in blocking radio
      frequency (RF) radiation emitted from mobile phones. Also, four other
      conceptually unusual products were tested because advertisements typically claim
      they emit oscillations that counteract the RF radiation from mobile phones. Each
      shield was tested on the same mobile phone, and measurements were made to compare
      the absorption of RF energy in the head with and without each shield attached to
      the phone. The phone was positioned against a head model, and an automated
      measurement process was used to determine specific absorption rate (SAR) in the
      same way it is used at Motorola to test the compliance of mobile phones with
      respect to human exposure limits. The location of the peak SAR was not observed
      to change with any of the shields attached to the phone, and the 1 g, peak
      spatial average SAR did not change by any statistically significant amount. These
      results indicate the small shields are ineffective in reducing the exposure of
      the head to RF energy emitted by a mobile phone.

PMID- 12483668
TI  - Comment on "proposed test for detection of nonlinear responses in biological
      preparations exposed to RF energy".

PMID- 12483670
TI  - Motifs in nucleic acids: molecular mechanics restraints for base pairing and base
      stacking.
AB  - In building and refining nucleic acid structures, it is often desirable to
      enforce particular base pairing and/or base stacking interactions. Energy-based
      modeling programs with classical molecular mechanics force fields do not lend
      themselves to the easy imposition of penalty terms corresponding to such
      restraints, because the requirement that two bases lie in or near the same plane
      (pairing) or that they lie in parallel planes (stacking) cannot be easily
      expressed in terms of traditional interactions involving two atoms (bonds), three
      atoms (angles), or four atoms (torsions). Here we derive expressions that define
      a collection of pseudobonds and pseudoangles through which molecular mechanics
      restraints for base pairing and stacking can be imposed. We have implemented
      these restraints into the JUMNA package for modeling DNA and RNA structures.
      JUMNA scripts can specify base pairing with a variety of standard geometries
      (Watson-Crick, Hoogsteen, wobble, etc.), or with user-defined geometries; they
      can also specify stacking arrangements. We have also implemented "soft-core"
      functions to modify van der Waals and electrostatic interactions to avoid steric
      conflicts in particularly difficult refinements where two backbones need to pass
      through one another. Test cases are presented to show the utility of the method.
      The restraints could be adapted for implementation in other molecular mechanics
      packages.

PMID- 12483671
TI  - Conformational analysis by intersection: CONAN.
AB  - As high throughput techniques in chemical synthesis and screening improve, more
      demands are placed on computer assisted design and virtual screening. Many of
      these computational methods require one or more three-dimensional conformations
      for molecules, creating a demand for a conformational analysis tool that can
      rapidly and robustly cover the low-energy conformational spaces of small
      molecules. A new algorithm of intersection is presented here, which quickly
      generates (on average <0.5 seconds/stereoisomer) a complete description of the
      low energy conformational space of a small molecule. The molecule is first
      decomposed into nonoverlapping nodes N (usually rings) and overlapping paths P
      with conformations (N and P) generated in an offline process. In a second step
      the node and path data are combined to form distinct conformers of the molecule.
      Finally, heuristics are applied after intersection to generate a small
      representative collection of conformations that span the conformational space. In
      a study of approximately 97,000 randomly selected molecules from the MDDR,
      results are presented that explore these conformations and their ability to cover
      low-energy conformational space.

PMID- 12483672
TI  - Using PC clusters to evaluate the transferability of molecular mechanics force
      fields for proteins.
AB  - The transferability of molecular mechanics parameters derived for small model
      systems to larger biopolymers such as proteins can be difficult to assess. Even
      for small peptides, molecular dynamics simulations are typically too short to
      sample structures significantly different than initial conformations, making
      comparison to experimental data questionable. We employed a PC cluster to
      generate large numbers of native and non-native conformations for peptides with
      experimentally measured structural data, one predominantly helical and the other
      forming a beta-hairpin. These atomic-detail sets do not suffer from slow
      convergence, and can be used to rapidly evaluate important force field
      properties. In this case a suspected bias toward alpha-helical conformations in
      the ff94 and ff99 force fields distributed with the AMBER package was verified.
      The sets provide critical feedback not only on force field transferability, but
      may also predict modifications for improvement. Such predictions were used to
      modify the ff99 parameter set, and the resulting force field was used to test
      stability and folding of model peptides. Structural behavior during molecular
      dynamics with the modified force field is found to be very similar to
      expectations, suggesting that these basis sets of conformations may themselves
      have significant transferability among force fields. We continue to improve and
      expand this data set and plan to make it publicly accessible. The calculations
      involved in this process are trivially parallel and can be performed using
      inexpensive personal computers with commodity components.

PMID- 12483673
TI  - Transferability of fragmental contributions to the octanol/water partition
      coefficient: an NDDO-based MST study.
AB  - This study examines the transferability of fragmental contributions to the
      octanol/water partition coefficient. As a previous step, we report the
      parameterization of the AM1 and PM3 versions of the MST model for n-octanol. The
      final AM1 and PM3 MST models reproduce the experimental free energy of solvation
      and the octanol/water partition coefficient (log P(ow)) with a root-mean-square
      deviation of around 0.7 kcal/mol and 0.5 (in units of log P), respectively. Based
      on this parameterization, an NNDO-based procedure is presented to dissect the
      free energy of transfer between octanol and water in contributions directly
      associated with specific atoms or functional groups. The application of this
      procedure to a set of representative molecular systems illustrates the dependence
      of the log P(ow) fragmental contribution due to electronic, hydrogen bonding, and
      steric effects, which cannot be easily accounted for in simple additive-based
      empirical schemes. The results point out the potential use of theoretical methods
      to refine the fragmental contributions in empirical methods.

PMID- 12483674
TI  - The intramolecular mechanism for the second proton transfer in triosephosphate
      isomerase (TIM): a QM/FE approach.
AB  - The intramolecular mechanism we earlier proposed [Alagona, G.; Desmeules, P.;
      Ghio, C.; Kollman, P. A. J Am Chem Soc 1984, 106, 3623] for the second proton
      transfer of the reaction catalyzed by triosephosphate isomerase (TIM) is examined
      ab initio at the HF and MP2/6-31+G** levels in vacuo for two conformers of the
      enediolate phosphate (ENEP), with the ethereal oxygen of the phosphate group
      either syn (X), as in the crystal structure, or anti (Y) with respect to the
      enediolate carbonyl O. The barrier height for the intramolecular proton transfer
      occurring in enediolate is very sensitive to electron correlation corrections.
      The MP2 internal energy barrier is much lower than the HF one, while the free
      energy (FE) barrier is even more favorable, indicating that the enzyme presence
      is not requested to speed up that step. An investigation of the dynamical aspects
      of the mechanism, along the pathway from ENEP A (with H on O(1)) to TS and from
      TS to ENEP B (with H on O(2)), was, however, carried out in the presence of the
      enzyme field while using a neutral His-95 with its proton on Ndelta. To perform
      the FE simulations, it was necessary to parametrize in the AMBER force-field the
      ENEP A, TS and B species, whose partial charges have been determined with the
      RESP procedure, with the X and Y arrangements of the phosphate head. Actually,
      the FE/QM approach produced a low barrier and a substantial balance between A and
      B, especially at the MP2 level. The trajectories, analyzed paying a particular
      attention to the positions assumed by His-95 and by the other active site
      residues, put forward somewhat different H-bond patterns around the X or Y
      enediolate phosphate.

PMID- 12483675
TI  - Fast approximate methods for calculating nucleic acid base pair interaction
      energies.
AB  - Interaction enthalpies for six base pairs have been computed at a variety of
      efficient levels of electronic structure theory and compared to experiment. In
      addition to previously defined levels of theory, modified Hamiltonians with
      adjusted parameters in hybrid Hartree-Fock/density functionals and semiempirical
      neglect-of-diatomic-differential-overlap models were examined. Of the pure and
      hybrid density functional levels, mPWPW91/MIDI! performed most satisfactorily, as
      judged by comparison not only to the available experimental data, but also to
      data from more robust electronic structure methods for 22 additional base pairs.
      The low computational cost of the mPWPW91/MIDI! model was further exploited in an
      investigation of various base trimers, tetramers, and one base pentamer. A
      carefully reparameterized semiempirical model, PM3(BP), was able to achieve
      similar levels of accuracy at a still greater savings in terms of computational
      effort.

PMID- 12483676
TI  - Cool walking: a new Markov chain Monte Carlo sampling method.
AB  - Effective relaxation processes for difficult systems like proteins or spin
      glasses require special simulation techniques that permit barrier crossing to
      ensure ergodic sampling. Numerous adaptations of the venerable Metropolis Monte
      Carlo (MMC) algorithm have been proposed to improve its sampling efficiency,
      including various hybrid Monte Carlo (HMC) schemes, and methods designed
      specifically for overcoming quasi-ergodicity problems such as Jump Walking (J
      Walking), Smart Walking (S-Walking), Smart Darting, and Parallel Tempering. We
      present an alternative to these approaches that we call Cool Walking, or C
      Walking. In C-Walking two Markov chains are propagated in tandem, one at a high
      (ergodic) temperature and the other at a low temperature. Nonlocal trial moves
      for the low temperature walker are generated by first sampling from the high
      temperature distribution, then performing a statistical quenching process on the
      sampled configuration to generate a C-Walking jump move. C-Walking needs only one
      high-temperature walker, satisfies detailed balance, and offers the important
      practical advantage that the high and low-temperature walkers can be run in
      tandem with minimal degradation of sampling due to the presence of correlations.
      To make the C-Walking approach more suitable to real problems we decrease the
      required number of cooling steps by attempting to jump at intermediate
      temperatures during cooling. We further reduce the number of cooling steps by
      utilizing "windows" of states when jumping, which improves acceptance ratios and
      lowers the average number of cooling steps. We present C-Walking results with
      comparisons to J-Walking, S-Walking, Smart Darting, and Parallel Tempering on a
      one-dimensional rugged potential energy surface in which the exact normalized
      probability distribution is known. C-Walking shows superior sampling as judged by
      two ergodic measures.

PMID- 12483677
TI  - Inherent speedup limitations in multiple time step/particle mesh Ewald
      algorithms.
AB  - Multiple time step (MTS) algorithms present an effective integration approach to
      reduce the computational cost of dynamics simulations. By using force splitting
      to allow larger time steps for the more slowly varying force components,
      computational savings can be realized. The Particle-Mesh-Ewald (PME) method has
      been independently devised to provide an effective and efficient treatment of the
      long-range electrostatics interactions. Here we examine the performance of a
      combined MTS/PME algorithm previously developed for AMBER on a large polymerase
      beta/DNA complex containing 40,673 atoms. Our goal is to carefully combine the
      robust features of the Langevin/MTS (LN) methodology implemented in CHARMM-which
      uses position rather than velocity Verlet with stochasticity to make possible
      outer time steps of 150 fs-with the PME formulation. The developed MTS/PME
      integrator removes fast terms from the reciprocal-space Ewald component by using
      switch functions. We analyze the advantages and limitations of the resulting
      scheme by comparing performance to the single time step leapfrog Verlet
      integrator currently used in AMBER by evaluating different time-step protocols
      using three assessors for accuracy, speedup, and stability, all applied to long
      (i.e., nanosecond) simulations to ensure proper energy conservation. We also
      examine the performance of the algorithm on a parallel, distributed shared-memory
      computer (SGI Origin 2000 with 8 300-MHz R12000 processors). Good energy
      conservation and stability behavior can be demonstrated, for Newtonian protocols
      with outer time steps of up to 8 fs and Langevin protocols with outer time steps
      of up to 16 fs. Still, we emphasize the inherent limitations imposed by the
      incorporation of MTS methods into the PME formulation that may not be widely
      appreciated. Namely, the limiting factor on the largest outer time-step size, and
      hence speedup, is an intramolecular cancellation error inherent to PME. This
      error stems from the excluded-nonbonded correction term contained in the
      reciprocal-space component. This cancellation error varies in time and introduces
      artificial frequencies to the governing dynamics motion. Unfortunately, we find
      that this numerical PME error cannot be easily eliminated by refining the PME
      parameters (grid resolution and/or order of interpolating polynomial). We suggest
      that methods other than PME for fast electrostatics may allow users to reap the
      full advantages from MTS algorithms.

PMID- 12483678
TI  - MOPED: method for optimizing physical energy parameters using decoys.
AB  - We present a method called MOPED for optimizing energetic and structural
      parameters in computational models, including all-atom energy functions, when
      native structures and decoys are given. The present method goes beyond previous
      approaches in treating energy functions that are nonlinear in the parameters and
      continuous in the degrees of freedom. We illustrate the method by improving
      solvation parameters in the energy function EEF1, which consists of the CHARMM19
      polar hydrogen force field augmented by a Gaussian solvation term. Although the
      published parameters for EEF1 correctly discriminate the native from decoys in
      the decoy sets of Levitt et al., they fail on several of the more difficult decoy
      sets of Baker et al. MOPED successfully finds improved parameters that allow EEF1
      to discriminate native from decoy structures on all protein structures that do
      not have metals or prosthetic groups.

PMID- 12483679
TI  - Catalysis on the coastline: theozyme, molecular dynamics, and free energy
      perturbation analysis of antibody 21D8 catalysis of the decarboxylation of 5
      nitro-3-carboxybenzisoxazole.
AB  - Antibody 21D8 catalyzes the decarboxylation of 5-nitro-3-carboxybenzisoxazole.
      The hapten used was designed to induce an antibody binding site with anion
      binders for the carboxylate, plus a nonpolar environment to accelerate
      decarboxylation. A recent X-ray crystal structure of 21D8 has shown that the
      binding pocket contains an array of both polar and charged residues.
      Nevertheless, 21D8 is able to catalyze a reaction that involves a decrease in
      polarity from reactant to transition state. The origins of this phenomenon were
      explored using various computational strategies-quantum mechanics, theozyme
      models, docking, molecular dynamics, free energy perturbation, and linear
      interaction energy-the combination of which has produced a consistent picture of
      catalysis. By partially desolvating the charged carboxylate, 21D8 manages to
      effect "catalysis on the coastline," without burying the carboxylate in a
      nonpolar region of the binding pocket. The results have implications for that
      broad class of enzyme and antibody catalyzed reactions that involve the
      conversion of a substrate with a relatively localized charge into a transition
      state with a highly dispersed charge.

PMID- 12483680
TI  - Molecular mechanics force-field development for amino acid zwitterions.
AB  - Understanding the conformational flexibility of amino acid zwitterions (ZWs) and
      their associated conformational energies is crucial for predicting their
      interactions in biological systems. Gas-phase ab initio calculations of ZWs are
      intractable. Molecular mechanics (MM), on the other hand, is able to handle large
      systems but lacks the necessary force field parameters to model ZWs. To develop
      force field parameters that are able to correctly model ZW geometries and
      energetics we used a novel combinatorial approach: amino acid ZWs were broken
      down structurally into key functional components, which were parameterized
      separately. Moller-Plesset second-order perturbation calculations on small
      carboxylates, on the glycine cation, and on novel hydrogen bonded systems,
      coupled with available experimental data, were used to generate MM3(2000) ZW
      parameters (Allinger N. L.; Yuh, Y. H.; Lii, J.-H. J Am Chem Soc 1989, 111,
      8551). The MM3 results from this combinatorial approach gave geometries that are
      in good agreement with neutron diffraction experiments, plus their frequencies
      and energies appear to be reasonably modeled. Current limitations and future
      development of MM force fields are discussed briefly.

PMID- 12483681
TI  - Intestinofugal neurons and sympathetic reflexes that bypass the central nervous
      system.

PMID- 12483682
TI  - Synaptic density, convergence, and dendritic complexity of prevertebral
      sympathetic neurons.
AB  - Prevertebral sympathetic ganglia contain a unique population of final motor
      neurons receiving convergent synaptic inputs not only from spinal preganglionic
      neurons, but also from peripheral intestinofugal neurons projecting from the gut.
      We used quantitative confocal and ultrastructural immunohistochemistry to
      determine how this increased synaptic convergence is accommodated by sympathetic
      final motor neurons in the celiac ganglion of guinea pigs. Terminals of
      intestinofugal neurons were identified by their immunoreactivity to vasoactive
      intestinal peptide. Stereologic analyses were based on transects and point counts
      at confocal and ultrastructural levels. The relative amount of dendritic neuropil
      in the medial regions of the ganglion was approximately 2.5 times greater than in
      the lateral regions of the ganglion, consistent with the 2 to 3 times difference
      in average dendritic field size of neurons in these regions. The total numbers of
      boutons and synaptic profiles showed significant positive correlations with the
      relative amount of neuropil in a region. However, the overall density of synaptic
      boutons was twice as high in the medial region of the ganglion compared with the
      lateral regions. Because the relative density of preganglionic synapses was
      similar in each region, this difference was due to the selective projection of
      intestinofugal inputs to neurons in the medial celiac ganglion, where they
      provided 45% of synaptic contacts. These results show that, compared with
      vasoconstrictor neurons, sympathetic neurons regulating gastrointestinal activity
      support a higher number of convergent inputs in two ways: in addition to having
      larger dendritic fields, they also have a twofold higher density of synapses.

PMID- 12483683
TI  - Neuronal development in larval polychaete Phyllodoce maculata (Phyllodocidae).
AB  - The existing view on neuronal development in polychaetes, as undergoing
      neurogenesis beginning in the rudiments of central ganglia and then extending
      peripherally, has been contrasted with the latest findings in molluscs, their
      sister trochozoan group, which show a peripheral to central mode of neurogenesis.
      The current study addresses this issue by examining early neuronal development in
      the polychaete Phyllodoce maculata using immunolabeling against acetylated alpha
      tubulin, serotonin, and the FMRFamide. The first nervous cell was detected 20
      hours before hatching, at the early trochophore stage. A solitary serotonergic
      neuron was located at the posterior-dorsal extreme of the larva and issued
      anterior projecting fibers, which outline the future ventral nerve cords and
      prototroch nerve. Two more serotonergic dorsal peripheral cells and three
      peripheral FMRFamidergic cells appeared soon thereafter. The fibers of these
      early cells formed a scaffolding, which prefigured the future adult nervous
      system (cerebral ganglion, ventral cords, prototroch and esophageal nerve rings)
      in prehatched trochophores. Shortly before hatching, the larval nervous system
      developed, including the apical organ, meridianal nerves in the episphere, and
      posttrochal nerves that innervate the feeding apparatus. After hatching, the
      rudiments of the adult nervous system started to develop along the paths already
      established by the earliest peripheral neurons. Thus, the general strategy of
      neurogenesis in a representative polychaete trochophore appears to resemble that
      of molluscs. The first neuronal cells to appear are peripheral in origin, located
      near the posterior margins of the embryo. Their similar anatomical appearance
      suggests that they share a similar functional role in trochophore development and
      behavior.

PMID- 12483684
TI  - Catecholaminergic innervation of the septum in the frog: a combined
      immunohistochemical and tract-tracing study.
AB  - In the present study, we have investigated the distribution and the origin of the
      catecholaminergic innervation of the septal region in the frog Rana perezi.
      Immunohistochemistry for dopamine and two enzymes required for the synthesis of
      catecholamines, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH)
      revealed a complex pattern of catecholaminergic (CA) innervation in the anuran
      septum. Dopaminergic fibers were primarily present in the dorsal portion of the
      lateral septum, whereas noradrenergic (DBH immunoreactive) fibers predominated in
      the medial septum/diagonal band complex. Catecholaminergic cell bodies were never
      observed within the septum. To determine the origin of this innervation,
      applications of dextran amines, both under in vivo and in vitro conditions, into
      the septum were combined with immunohistochemistry for TH. Results from these
      experiments demonstrated that four catecholaminergic cell groups project to the
      septum: (1) the group related to the zona incerta in the ventral thalamus, (2)
      the posterior tubercle/mesencephalic group, (3) the locus coeruleus, and (4) the
      nucleus of the solitary tract. While the two first groups provide dopaminergic
      innervation to the septum, the locus coeruleus provides the major noradrenergic
      projection. Noradrenergic fibers most likely arise also in the nucleus of the
      solitary tract. The results obtained in Rana perezi are readily comparable to
      those in mammals suggesting that the role of catecholamines in the septum is well
      conserved through phylogeny and that the CA innervation of the amphibian septum
      may be involved in functional circuits similar to those in mammals.

PMID- 12483685
TI  - Fractones and other basal laminae in the hypothalamus.
AB  - The physiological role of basal laminae (BL) and connective tissue (meninges and
      their projections) in the adult brain is unknown. We recently described novel
      forms of BL, termed fractones, in the most neurogenic zone of the adult brain,
      the subependymal layer (SEL) of the lateral ventricle. Here, we investigated the
      organization of BL throughout the hypothalamus, using confocal and electron
      microscopy. New types of BL were identified. First, fractones, similar to those
      found in the lateral ventricle wall, were regularly arranged along the walls of
      the third ventricle. Fractones consisted of labyrinthine BL projecting from SEL
      blood vessels to terminate immediately beneath the ependyma. Numerous processes
      of astrocytes and of microglial cells directly contacted fractones. Second,
      another form of BL projection, termed anastomotic BL, was found between
      capillaries in dense capillary beds. The anastomotic BL enclosed extraparenchymal
      cells that networked with the perivascular cells coursing in the sheaths of
      adjacent blood vessels. Vimentin immunoreactivity was often detected in the
      anastomotic BL. In addition, the anastomotic BL overlying macrophages contained
      numerous fibrils of collagen. We also found that the BL located at the pial
      surface formed labyrinthine tube-like structures enclosing numerous fibroblast
      and astrocyte endfeet, with pouches of collagen fibrils at the interface between
      the two cell types. We suggest that cytokines and growth factors produced by
      connective tissue cells might concentrate in BL, where their interactions with
      extracellular matrix proteins might contribute to their effects on the overlying
      neural tissue, promoting cytogenesis and morphological changes and participating
      in neuroendocrine regulation.

PMID- 12483686
TI  - Saccadic omnipause and burst neurons in monkey and human are ensheathed by
      perineuronal nets but differ in their expression of calcium-binding proteins.
AB  - The extracellular matrix of the brain contains large aggregates of chondroitin
      sulfate proteoglycans (CSPG), which form lattice-like cell coatings around
      distinct neuron populations and are termed perineuronal nets. The function of
      perineuronal nets is not fully understood, but they are often found around
      neurons containing the calcium-binding protein parvalbumin, suggesting a function
      in primarily highly active neurons. In the present paper the distribution of
      perineuronal nets was studied in two functional cell groups of the primate
      oculomotor system with well-known firing properties: 1) the saccadic omnipause
      neurons in the nucleus raphe interpositus (RIP) exhibit a high tonic firing rate,
      which is only interrupted during saccades; they are inhibitory and use glycine as
      a transmitter; and 2) premotor burst neurons for vertical saccades in the rostral
      interstitial nucleus of the medial longitudinal fascicle (RiMLF) fire with high
      frequency bursts during saccades; they are excitatory and use glutamate and/or
      aspartate as a transmitter. In the macaque monkey, both cell populations were
      identified by their parvalbumin immunoreactivity and were studied for the
      presence of perineuronal nets using CSPG antibodies or lectin binding with
      Wisteria floribunda agglutinin. In addition, the expression of another calcium
      binding protein, calretinin, was studied in both cell groups. Double- and triple
      immunofluorescence methods revealed that both omnipause and burst neurons are
      selectively ensheathed with strongly labeled perineuronal nets. Calretinin was
      coexpressed in at least 70% of the saccadic burst neurons, but not in the
      omnipause neurons. Parallel staining of human tissue revealed strongly labeled
      perineuronal nets around the saccadic omnipause and burst neurons, in
      corresponding brainstem regions, which specifically highlighted these neurons
      within the poorly structured reticular formation. These findings support the
      hypothesis that perineuronal nets may provide a specialized microenvironment for
      highly active neurons to maintain their fast-spiking activity and are not related
      to the transmitter or the postsynaptic action of the ensheathed neurons.

PMID- 12483687
TI  - Temporal and spatial profiles of ABCA2-expressing oligodendrocytes in the
      developing rat brain.
AB  - ABCA2 protein belongs to the ABCA subclass of ATP-binding cassette (ABC)
      transporters proposed to exert critical functions in transmembrane transport of
      endogenous lipids. In this study, we found by immunoblot analyses that
      approximately 260 kDa of ABCA2 protein is expressed predominantly in
      oligodendrocytes, and that the expression of the protein is upregulated in the
      brain during maturation, especially between postnatal days 6 and 19. Parallel to
      the changes in expression of ABCA2, immunohistochemical analyses showed rapid
      spatial spread of ABCA2-immunolabeled oligodendrocytes in the brain during this
      period. These temporal and spatial changes in ABCA2 expression were in good
      agreement with findings in myeloarchitectonics reported previously. Further,
      double immunolabeling with ABCA2 and a major structural protein of myelin, myelin
      basic protein, demonstrated that onset of ABCA2 expression in oligodendrocytes
      coincides with the appearance of thick myelin segments immunolabeled with myelin
      basic protein. Because ABCA2 was abundantly expressed in adult cortex in white
      matter and gray matter, coexpression of ABCA2 and a marker for the
      oligodendroglial progenitors NG2 or platelet-derived growth factor alpha receptor
      was investigated. No cells coexpressing ABCA2 and the marker were observed,
      suggesting that ABCA2 is expressed predominantly in myelin-forming
      oligodendrocytes distinct from the adult oligodendroglial progenitors tested.
      These results suggested a role for ABCA2 in membrane transport of substrates such
      as the lipids that are closely linked to myelination processes.

PMID- 12483688
TI  - Palmitoyl protein thioesterase 1 is targeted to the axons in neurons.
AB  - Palmitoyl protein thioesterase 1 (PPT1) is a depalmitoylating enzyme whose
      deficiency leads to infantile neuronal ceroid lipofuscinosis. The disease is
      characterized by early loss of vision and massive neuronal death. Although PPT1
      is expressed in many tissues, a deficiency of PPT1 damages neurons only in the
      cerebral and cerebellar cortexes and retina; other cell types remain relatively
      unaffected. We previously demonstrated that PPT1 is present in the synaptosomes
      and synaptic vesicles of neurons. To understand the crucial role of PPT1 for
      neuronal cells, we further investigated the expression and targeting of PPT1 in
      retinal, hippocampal, and cortical neurons during their maturation in culture. We
      found that PPT1 activity increases by neuronal maturation and is highest in
      retinal neuron cultures. In retinal neurons the expression of PPT1 precedes that
      of the synaptic vesicle protein 2 and synaptophysin, indicating a significant
      role for PPT1 in the early development of neuronal cells. We also found by
      quantitative confocal immunofluorescence microscopy that PPT1 is targeted
      preferably to axons in mature neurons, as indicated by its colocalization with
      the axonal marker microtubule-associated protein 1. In axons PPT1 is targeted
      specifically to axonal varicosities and presynaptic terminals, as indicated by
      its significant colocalization with growth-associated protein 43 and
      synaptophysin. Axonal localization of PPT1 was confirmed by double labeling with
      synaptophysin and postembedding immunoelectron microscopy. The polarized axonal
      targeting of PPT1 may well indicate a role for PPT1 in the exocytotic pathway of
      neurons.

PMID- 12483689
TI  - Somatosensory input to the ventrolateral thalamic region in the macaque monkey:
      potential substrate for parkinsonian tremor.
AB  - In the present study, we determined the anatomic relationships between
      somatosensory and motor pathways within ventrolateral (VL) thalamic nuclei of the
      motor thalamus of macaque monkeys. In labeling experiments, four macaque monkeys
      (Macaca mulatta) received injections of biotinylated dextran amine and wheat germ
      agglutinin conjugated to horseradish peroxidase into the cerebellar nuclei or
      internal segment of the globus pallidus and cervical segments of the spinal cord,
      respectively. Each tracer was visualized in brain sections by sequentially using
      a different chromogen. Labeled terminals were plotted and superimposed on
      adjacent brain sections processed for Nissl substance, acetylcholinesterase, and
      the antigens for calbindin and Cat-301 to reveal thalamic nuclei. The labeled
      cerebellar terminals were distributed throughout the posterior VL (VLp), whereas
      the labeled pallidothalamic terminals were concentrated in the anterior VL and
      the ventral anterior nucleus. The spinothalamic input was directed mostly to the
      ventral posterior complex and cells just caudal to it. In addition, the patches
      of spinothalamic terminations intermingled and partly overlapped with the
      cerebellothalamic, but not with the pallidothalamic terminations within VLp. The
      regions of overlap of somatosensory and cerebellar inputs within the VLp of the
      present study appear to correspond to the reported locations of the tremor
      related cells in parkinsonian patients. Thus, the overlapping spinothalamic and
      cerebellar inputs may provide a substrate for the altered activity of motor
      thalamic neurons in such patients.

PMID- 12483690
TI  - Developmental changes in the expression of growth hormone-releasing hormone and
      pituitary adenylate cyclase-activating polypeptide in zebrafish.
AB  - Growth hormone-releasing hormone (GHRH) and pituitary adenylate cyclase
      activating polypeptide (PACAP) are structurally and functionally related members
      of the glucagon superfamily, a group of hormones important in development,
      growth, and metabolism. Our objectives were to determine the developmental
      expression pattern of the ghrh-pacap1 gene using the zebrafish model. The
      temporal and spatial expression pattern of the ghrh-pacap1 gene was examined by
      RT-PCR and in situ hybridization. In zebrafish, the ghrh-pacap1 mRNA transcript
      was expressed throughout development beginning at the transition between the
      blastula and gastrula periods. During midgastrulation, alternative splicing
      resulted in the generation of a novel transcript lacking the cryptic peptide.
      During the segmentation period, expression was localized to the neural tube,
      developing eye, and neural crest; strong expression was found in the developing
      cerebellum. Later in development, expression was localized in the hatching gland
      and developing pharyngeal arches. The temporal and spatial expression pattern of
      the ghrh-pacap1 transcript suggests that these hormones may modulate patterning
      during development.

PMID- 12483692
TI  - Influence of local complications on capsule formation around model implants in a
      rat model.
AB  - We studied the capsule formation around various filled breast implants and other
      related changes in distant organs (e.g., liver, spleen, lymph nodes) in a rat
      model 3 and 6 months after implantation. Model implants, one per rat, (filled
      with saline, n = 19; silicone, n = 14; cohesive silicone, n = 17; and hydrogel, n
      = 19) were implanted subcutaneous in the lower back of rats. The animals were
      sacrificed regularly after 3 and 6 months of implantation or when wound defects
      occurred. The capsules and organs were examined histologically, and
      immunohistology of the capsules was performed. A monoclonal antibody specific for
      AIF-1 (allograft inflammatory factor 1) was used to detect activated macrophages.
      Wound defects occurred most frequently after implantation of saline and hydrogel
      implants. Increased capsule thickness was associated with increased grade of
      inflammation, fibrosis, and the type of implant filling. There was a significant
      positive correlation between capsule thickness, presence of chronic inflammation,
      and AIF-1-positive macrophages (p < 0.0001), indicating that inflammation plays
      an important role in capsule formation. Remarkably, saline and silicone implants
      (in absence of local complications) cause only a blande slight fibrosis in
      capsules after 6 months of implantation, whereas capsules around cohesive
      silicone implants exhibited a more severe fibrosis with an increased capsule
      thickness. Most importantly, hydrogel seems to be most potent to induce an
      inflammatory infiltrate with AIF-1 expressing macrophages at the implantation
      site, independent of implantation time, and capsules also produced a significant
      increase in thickness after 6 months.

PMID- 12483691
TI  - Olivocochlear innervation in the mouse: immunocytochemical maps, crossed versus
      uncrossed contributions, and transmitter colocalization.
AB  - To further understand the roles and origins of gamma-aminobutyric acid (GABA) and
      calcitonin gene-related peptide (CGRP) in the efferent innervation of the
      cochlea, we first produced in the mouse an immunocytochemical map of the efferent
      terminals that contain acetylcholine (ACh), CGRP, and GABA. Olivocochlear (OC)
      terminals in inner and outer hair cell (IHC and OHC) regions were analyzed
      quantitatively along the cochlear spiral via light-microscopic observation of
      cochlear wholemounts immunostained with antibodies to glutamic acid decarboxylase
      (GAD), vesicular acetylcholine transporter (VAT), or the peptide CGRP. Further
      immunochemical characterization was performed in mice with chronic OC transection
      at the floor of the fourth ventricle to distinguish crossed from uncrossed
      contributions and, indirectly, the contributions of lateral versus medial
      components of the OC system. The results in mouse showed that (1) there are
      prominent GABAergic, cholinergic, and CGRPergic innervations in the OHC and IHC
      regions, (2) GABA and CGRP are extensively colocalized with ACh in all OC
      terminals in the IHC and OHC areas, (3) the longitudinal gradient of OC
      innervation peaks roughly at the 10-kHz region in the OHC area and is more
      uniform along the cochlear spiral in the IHC area, (4) in contrast to other
      mammalian species there is no radial gradient of OC innervation of the OHCs, and
      (5) all OHC efferent terminals arise from the medial OC system and terminals in
      the IHC area arise from the lateral OC system.

PMID- 12483693
TI  - Correlating fibronectin adsorption with endothelial cell adhesion and signaling
      on polymer substrates.
AB  - Fibronectin (Fn) adsorption was studied on different commercial polymer surface
      chemistries, including tissue culture polystyrene (TCPS), bacteriologic
      polystyrene (BPS), fluoropolymer Teflon AF, and poly-L-lactide (PLLA). Antibody
      probes detected the availability of Fn's cell binding domain on adsorbed Fn in
      the competitive presence and absence of bovine serum albumin (BSA). Domain
      availability was highest for Fn adsorbed on TCPS, especially in the presence of
      either serum albumin or dilute serum. Attachment and growth efficiencies for
      human umbilical venous endothelial cells (HUVECs) cultured on surfaces
      preadsorbed with Fn in serum and serum-free media correlated with antibody cell
      binding domain availability: TCPS > BPS, Teflon AF > PLLA. Intracellular
      signaling from the GTPase, RhoA, was highest (RhoA:RhoGDI inhibitor ratio) in
      cells cultured on the Teflon AF surfaces, indicating that despite lower attached
      cell numbers on Teflon AF compared to TCPS, cell signaling remained activated
      after 24 h of growth. Up-regulated cellular Fn mRNA messages, assessed using RT
      PCR techniques, supported HUVECs' producing the endogenous extracellular matrix
      (ECM) protein Fn in order to attach and survive on the suboptimal Teflon AF
      culture surfaces.

PMID- 12483694
TI  - Peptide-modified p(AAm-co-EG/AAc) IPNs grafted to bulk titanium modulate
      osteoblast behavior in vitro.
AB  - Interpenetrating polymer networks (IPNs) of poly(acrylamide-co-ethylene
      glycol/acrylic acid) (p(AAm-co-EG/AAc) applied to model surfaces prevent protein
      adsorption and cell adhesion. Subsequently, IPN surfaces functionalized with the
      RGD cell-binding domain from rat bone sialoprotein (BSP) modulated bone cell
      adhesion, proliferation, and matrix mineralization. The objective of this study
      was to utilize the same biomimetic modification strategy to produce functionally
      similar p(AAm-co-EG/AAc) IPNs on clinically relevant titanium surfaces. Contact
      angle goniometry and X-ray photoelectron spectroscopy (XPS) data were consistent
      with the presence of the intended surface modifications. Cellular response was
      gauged by challenging the surfaces with primary rat calvarial osteoblast (RCO)
      surfaces in serum-containing media. IPN modified titanium and negative control
      (RGE-IPN) surfaces inhibit cell adhesion and proliferation, while RGD-modified
      IPNs on titanium supported osteoblast attachment and spreading. Furthermore, the
      latter surfaces supported significant mineralization despite exhibiting lower
      levels of proliferation than positive control surfaces. These results suggest
      that with the appropriate optimization, this approach may be practical for
      surface engineering of osseous implants.

PMID- 12483695
TI  - Oxygenation of hypoxic region in solid tumor by administration of human serum
      albumin incorporating synthetic hemes.
AB  - Recombinant human serum albumin incorporating synthetic heme (rHSA-FeP) was
      tested for its ability to increase O(2) tension in the hypoxia of the solid tumor
      rat model. By the direct administration of the rHSA-FeP solution (10 mL/kg) via
      the aorta descendens to the ascites hepatoma LY80 tumor on the right femur, the
      O(2) tension of the hypoxic region immediately increased to 3.45 +/- 1.43 Torr,
      which corresponds to a 2.4-fold increase compared to that of the baseline value.
      These high O(2) levels continued for 300 s after the infusion. The rHSA-FeP
      solution can be utilized not only as a red blood cell substitute but also as an
      O(2)-carrying medicine for the effective reoxygenation of the hypoxia solid
      tumor.

PMID- 12483696
TI  - Fabrication of micropored elastomeric film-covered stents and acute-phase
      performances.
AB  - To prevent thrombus formation in the acute phase and restenosis in the subacute
      to chronic phase after stenting of atherosclerotic arteries, we developed a
      covered stent with a micropored elastomeric film, the blood-contacting surface of
      which was coated with a photocured gelatin layer immobilized with heparin.
      Segmented polyurethane (SPU) film (30 microm in wall thickness) as a cover
      material was multiply micropored by excimer laser-directed microprocessing (pore
      diameter, 30 microm; interpore distance, 125 microm). An aqueous mixed solution
      of benzophenone-derivatized gelatin and heparin was coated on the micropored SPU
      film. Upon ultraviolet light irradiation, a thin layer of a gelatin gel
      immobilized with heparin was formed and simultaneously fixed on the SPU film. The
      fully covered stents were assembled by wrapping a balloon-expandable stent with
      gelatin/heparin gel-layered SPU film and subsequently suturing and then gluing.
      To assess the validity of this covered stent in vivo, "half-covered" stents, in
      which half at the distal side was covered with the gel-layered SPU film, was
      implanted in rabbit common carotid arteries (about 3 mm in diameter). After 3
      months of implantation, all the half-covered stents (n = 7) were patent.
      Regardless of the covered or noncovered region of the stents, the entire luminal
      surface of the stents was fully endothelialized and a thin neointimal tissue was
      formed. The potential advantages of a covered stent as designed above are
      discussed.

PMID- 12483697
TI  - Histocompatibility of photocrosslinked polyanhydrides: a novel in situ forming
      orthopaedic biomaterial.
AB  - Cell-polymer interactions in subcutaneous and bony tissue were examined for a
      novel class of in situ forming and surface eroding polyanhydride networks.
      Specifically, photopolymerized disks of several polyanhydride compositions were
      implanted subcutaneously in rats, and the tissue was analyzed for an inflammatory
      response. The compositions elicited varied histological responses, ranging from
      highly active cell layers to moderate fibrous capsules, depending on the
      degrading polymer composition. Furthermore, one composition was photopolymerized
      in a model orthopaedic defect in the proximal tibia. The feasibility of
      photopolymerizing the methacrylated monomers in situ and the adherence of the
      photocrosslinked polyanhydride to the medullary canal were examined.

PMID- 12483698
TI  - Controlling the spatial distribution of ECM components in degradable PEG
      hydrogels for tissue engineering cartilage.
AB  - In developing a scaffold to support new tissue growth, the degradation rate and
      mass loss profiles of the scaffold are important design parameters. In this
      study, hydrogels were prepared by copolymerizing a degradable macromer,
      poly(lactic acid)-b-poly(ethylene glycol)-b-poly(lactic acid) endcapped with
      acrylate groups (PEG-LA-DA) with a nondegradable macromer, poly(ethylene glycol)
      dimethacrylate (PEGDM). The resulting hydrogels exhibited a range of degradation
      behavior and mass loss profiles. Chondrocytes were photoencapsulated in gels
      formulated with 50:50, 25:75, and 15:85 (mol % PEGDM: mol % PEG-LA-DA) and
      cultured for 6 weeks in vitro. The neocartilaginous tissue formed was examined
      biochemically and histologically. After 6 weeks, the DNA content in gels with 75
      and 85% degradable crosslinks was nearly twice that of the DNA content in the 50%
      gels. The total collagen content was significantly higher in the 85% gel [2.4 +/-
      0.8% wet weight (ww)] compared to the 50% gel (0.22 +/- 0.29% ww). In examining
      the neocartilaginous tissue with immunohistochemistry, type II collagen was
      localized in the pericellular region in the 50% gel; however, when increased
      degradation was incorporated into the gel, type II collagen was found throughout
      the neotissue. In summary, the important role of hydrogel degradation in
      controlling and influencing the deposition and distribution of extracellular
      matrix molecules was demonstrated and quantified.

PMID- 12483699
TI  - Plasma-polymerized surfaces for culture of human keratinocytes and transfer of
      cells to an in vitro wound-bed model.
AB  - The aim of this study was to develop plasma-polymerized surfaces suitable for the
      attachment and culture of human keratinocytes and that would allow their
      subsequent transfer to a wound-bed model. Keratinocyte attachment has been
      assessed on a carrier polymer, either untreated or treated with a hydrocarbon
      plasma polymer, collagen I, or carboxylic-acid-containing plasma copolymers. Cell
      attachment was poor on the "bare" carrier polymer and hydrocarbon plasma polymer
      (PP) surfaces. Cell attachment was good and comparable on collagen I-coated
      carrier polymer and carrier polymer plasma coated with carboxylic acid
      functionalities. After 24 h of cell culture, surfaces were inverted so that cells
      were adjacent to a de-epidermalized dermis (DED) for 4 days. After 4 days in
      contact with DED, the surfaces were removed and the level of residual cells and
      cells transferred to DED were assessed using a cell viability assay. Cell
      transfer from the collagen I-coated surface was on the order of 90%. Transfer
      from the carrier polymer surface and the hydrocarbon-coated surface was poor
      while cells cultured on acid-containing surfaces showed high levels of transfer.
      Cell transfer was greatest from those surfaces containing the highest level of
      acid functionality (ca. 21%). Cell transfer was not significantly affected by the
      choice of carrier polymer material although some sample-to-sample variation was
      seen. To determine that plasma-polymerized surfaces could be used clinically,
      selected samples were sterilized with ethylene oxide. Subsequent analysis and
      cell culture indicated that the surface chemistry and cell-transfer capability of
      these plasma-polymerized surfaces were unaffected by the sterilization procedure.
      Plasma-polymerized carboxylic-acid-containing surfaces show great promise in the
      field of wound healing, encouraging keratinocyte attachment and permitting
      keratinocyte transfer to a wound bed.

PMID- 12483700
TI  - Regeneration of serous membrane on gelatin-processed polyglycolic acid (PGA)
      human collagen membrane and its efficacy on the prevention of adhesion.
AB  - We prepared a complex membrane consisting of human amnion-derived collagen
      membrane and polyglycolic acid (PGA), and then gelatin was crosslinked using heat
      on one side of the complex membrane to prepare a membrane that can prevent
      adhesion (gelatin-processed PGA-human collagen membrane). Applying this membrane
      to a rabbit cecum-abdominal-wall-adhesion model, the prevention of adhesion and
      tissue regeneration were investigated. The animals were sacrificed 2 and 12 weeks
      after surgery and then examined. The adhesion scores in the short-term
      observation group (2 weeks after surgery) and long-term observation group (12
      weeks after surgery) were 1.0 +/- 2.4 and 0.8 +/- 2.0, respectively, showing a
      significant prevention of adhesion compared to the control value of 6.3 +/- 2.5
      (p < 0.01). Histologically, gelatin was not absorbed, and outgrowth of connective
      tissue accompanied by capillary blood vessels was observed between the sample and
      the cecum in the short-term observation group. In the long-term observation
      group, the sample was completely absorbed, and serous membrane was regenerated on
      the surface of connective tissue. Based on these findings, it is possible to use
      gelatin-processed PGA-human collagen membrane as a filling material with both an
      adhesion-preventing effect and tissue-regenerating function.

PMID- 12483701
TI  - Comparison of failure characteristics of a range of cancellous bone-bone cement
      composites.
AB  - Over the past decade, orthopedic surgery has embraced an increase in the depth of
      cement penetration into the adjacent cancellous bone structure. The resultant
      interdigitation transforms this zone into a thick layer of continuous
      interpenetrating composite material. The failure behavior of the composite formed
      with a number of potential bone cements with different bonding ability was
      investigated. The cancellous bone-cement composites exhibit considerable
      resistance to crack extension, and in situ optical observation indicates that the
      contribution of the cancellous bone is analogous to that of a typical fiber
      bridging process. The critical stress intensity factor and the work of fracture
      have been used to quantify the failure characteristics of the cancellous bone
      cement composites. The nature of the crack propagation through these cement-bone
      composites was also captured via optical microscopy, and scanning electron
      microscopic images were taken of the failure surfaces. The R-curve behavior, or
      crack extension characteristic, of the cancellous bone-cement composite was also
      determined. The interesting outcome is that the cancellous bone-PMMA (poly
      methylmethacrylate) composite, despite the absence of chemical bonding with bone,
      required the highest energy to fracture. In addition, the dimensional stability
      of the cement has a great effect on the interface.

PMID- 12483702
TI  - Differentiation of human bone-derived cells grown on GRGDSP-peptide bound
      titanium surfaces.
AB  - Various surface modifications have been applied to titanium alloy (Ti-6Al-4V)
      implants, in an attempt to enhance osseointegration; crucial for ideal prosthetic
      fixation. Despite the numerous studies demonstrating that peptide-modified
      surfaces influence in vitro cellular behavior, there is relatively little data
      reporting their effects on bone remodeling. The objective of this article was to
      examine the effects of chemically modifying Ti-6Al-4V surfaces with a common RGD
      sequence, a 15-residue peptide containing GRGDSP (glycine-arginine-glycine
      aspartate-serine-proline), on the modulation of bone remodeling. The expression
      of proteins known to be associated with osseous matrix and bone resorption were
      studied during the growth of human bone-derived cells (HBDC) on these peptide
      modified surfaces. HBDC grown for 7 days on RGD surfaces displayed significantly
      increased levels of osteocalcin, and pro-collagen Ialpha1 mRNAs, compared with
      the production by HBDC grown on the native Ti-6Al-4V. A pattern that was also
      reflected at the protein levels for osteocalcin, type I collagen, and bone
      sialoprotein. Moreover, HBDC grown for 7 and 14 days on RGD-modified Ti-6Al-4V
      expressed significantly higher level of osteoclast differentiation factors and
      lower levels of osteoprotegerin and IL-6 proteins compared with other surfaces
      tested. These results suggest that different chemical treatments of implant
      material (Ti-6Al-4V) surface result in differential bone responses, not only
      their ability to form bone but also to stimulate osteoclastic formation.

PMID- 12483703
TI  - Low permeability biomedical polyurethane nanocomposites.
AB  - In this article we describe our continuing research on a novel nanocomposite
      approach for reducing gas permeability through biomedical polyurethane membranes.
      Nanocomposites were prepared using commercially available poly(urethane urea)s
      (PUU) and two organically modified layered silicates (OLS). Wide-angle X-ray
      diffraction experiments showed that the silicate layer spacing in the
      nanocomposites increased significantly compared with the neat OLS, signifying the
      formation of intercalated PUU/OLS structures. The nanocomposite materials exhibit
      increased modulus with increasing OLS content, while maintaining polymer strength
      and ductility. Water vapor permeability was reduced by about fivefold at the
      highest OLS contents, as a result of PUU/inorganic composite formation.

PMID- 12483704
TI  - Theoretical analysis of adsorption thermodynamics for charged peptide residues on
      SAM surfaces of varying functionality.
AB  - Cellular response to an implant is largely controlled by protein adsorption
      because cells directly interact with the adsorbed protein rather than the implant
      surface. Protein adsorption will occur when the change in Gibbs free energy
      (Delta G) of the system decreases during the adsorption process. Electrostatic
      interactions between charged peptide residues presented by a protein's surface
      and surface functional groups greatly contribute to the Delta G of protein
      adsorption. In this study, semiempirical molecular orbital calculations were used
      to theoretically determine the adsorption enthalpy between charged peptide
      residues [aspartic acid (-1), glutamic acid (-1), and arginine (+1)] and
      functionalized SAM surfaces [methyl, hydroxyl, amine (+1), and carboxylic acid (
      1)]. Additional enthalpic and entropic contributions attributed to water
      restructuring effects were then approximated based on literature values for
      functional group solvation and considered along with the calculated enthalpy
      values to estimate the change in Delta G for each residue/surface system as a
      function of surface separation distance. The results predict long-range
      attraction and repulsion to the opposite and same-charge residue/surface systems,
      respectively, followed by strong short-range repulsion caused by functional group
      dehydration. Short-range repulsion alone was predicted for the charged residues
      on the methyl and hydroxyl surfaces. These results provide a theoretical
      quantitative description of fundamental mechanisms governing protein adsorption
      behavior and provide a basis for the development of a knowledge-based surface
      design approach to control biological response.

PMID- 12483705
TI  - Calcium and phosphate adsorption as initial steps of apatite nucleation on sol
      gel-prepared titania surface.
AB  - Titania powders have been prepared by the sol-gel route from Ti (IV) ethoxide
      under acidic conditions. Adsorption experiments of calcium and phosphate ions on
      gel-derived titania suspensions were performed to suggest a likely initial step
      of apatite growth on its surface. Experiments were performed as a function of
      time and pH at 37 degrees C with and without NaCl present in the suspensions.
      Also, zeta (zeta) potential experiments were performed to determine the kind of
      calcium adsorption. Results suggest that, apparently, calcium and phosphate
      adsorption can act as two different initial steps for apatite growth.

PMID- 12483706
TI  - Preparation of epoxy-SiO2 hybrid sol-gel material for bone cement.
AB  - An organic-inorganic hybrid material, epoxy-SiO(2), was prepared by incorporating
      epoxy structure units covalently into a SiO(2) glass network via the sol-gel
      approach. The precursor was obtained by the reaction of diglycidyl ether of
      bisphenol A (DGEBA) with 3-aminopropyl trimethoxysilane (APTS). The precursor was
      then hydrolyzed and co-condensated with tetraethyl orthosilicate (TEOS) in
      tetrahydrofuran (THF) at room temperature to yield epoxy-SiO(2) hybrid sol-gel
      material having a 50 wt % SiO(2) content. Thermal properties of the hybrid
      material were characterized by differential scanning calorimetry (DSC) and
      thermogravimetric analysis (TGA). The hybrid sol-gel material epoxy-SiO(2) was
      the solid, powder component of bone cement. The liquid component contains bis
      phenol-A glycidyl methacrylate (Bis-GMA), triethyleneglycol dimethacrylate
      (TEGDMA), and methyl methacrylate (MMA) with 25, 55, and 20 vol %, respectively.
      We discuss the comparison between the new epoxy-SiO(2) bone cement and the
      commercial Simplex P bone cement. Mechanical properties such as Young's modulus,
      compressive strength, hardness, and impact strength of the new epoxy-SiO(2) bone
      cement exceeded those of Simplex P bone cement. The tensile and bending strengths
      of the new epoxy-SiO(2) bone cement were approximately the same as those of
      Simplex P bone cement. In order to evaluate the biocompatibility of the new bone
      cement, an MTT test and optical microscopy were conducted in cell culture.
      Results indicated that the new epoxy-SiO(2) bone cement exhibits very low
      cytotoxicity compared with Simplex P bone cement.

PMID- 12483707
TI  - Development of new hydroactive dressings based on chitosan membranes:
      characterization and in vivo behavior.
AB  - Different poly(vinyl alcohol) (PVA)/chitosan lactate (ChL)-blended hydrogels
      containing nitrofurazone as a local anti-infective drug were prepared by the
      phase-inversion technique. The swelling degree, surface free energy, mechanical
      properties, and nitrofurazone release of these membranes were determined. Blood
      compatibility of these systems was evaluated by the open-static platelet adhesion
      test with whole human blood. The results showed that water absorption into the
      PVA/ChL membranes slowed down, governed by the rate at which the dressing
      interacted with the physiological fluid. Swelling degree values up to 200% were
      observed. The rate of release of nitrofurazone seemed to depend on the ChL
      percentage on the blend as well as the pH of the solution. The surface free
      energy values were in the range of 20-30 dynes/cm, which was appropriate for a
      favorable interaction with blood. From the Young's module curve, it could be seen
      that elastic hydrogels were obtained with increment of ChL in the PVA/ChL blends.
      Values of platelet adhesion and whole blood clotting times for the PVA/ChL blends
      as well as the increase of ChL, which appears to reduce the fibrinogen adsorption
      on the PVA/ChL membranes, demonstrated that the blood compatibility of PVP/ChL
      blends is superior to that separated polymers. The results of in vivo experiments
      in rats were in very good agreement with these observations, suggesting that
      PVA/ChL may serve as a new type of potential wound-dressing material.

PMID- 12483708
TI  - Synergistic effect of high-affinity binding and flow preconditioning on
      endothelial cell adhesion.
AB  - The current study examined whether the combined introduction of high-affinity
      avidin-biotin bonds and fibronectin-integrin bonds (i.e., dual ligand treatment)
      would further augment the adhesion of flow-preconditioned endothelial cells to
      model substrates via contributions to the actin cytoskeleton and the formation of
      focal contacts. Human umbilical vein endothelial cells (HUVEC) were grown under
      static conditions or exposed to a flow-preconditioning regimen for 24 h. Cell
      retention was determined by exposure to 75 dynes/cm(2). The combination of flow
      preconditioning and the dual ligand treatment yielded higher cell retention under
      flow compared to the cells adherent via fibronectin-integrin bonds only. This
      increase in adhesion strength correlated with a greater focal contact area.
      Elongation of the HUVEC occurred after exposure to flow preconditioning; however,
      orientation of dual ligand adherent cells was restricted due to the presence of
      the high-affinity ligand. Flow-preconditioned cells showed increased stress fiber
      formation compared to nonconditioned cells although the stress fibers per cell
      for flow-preconditioned cells were the same on both the ligand systems employed.
      The results indicate that enhanced adhesion strength is due to a combination of
      increased focal contact area, stress fiber formation, and cell alignment.

PMID- 12483709
TI  - Structural dependence of apatite formation on titania gels in a simulated body
      fluid.
AB  - The apatite-forming ability of titania gels with different structures has been
      investigated in a simulated body fluid with ion concentrations nearly equal to
      those of human blood plasma. Titania gels with an amorphous structure or with an
      anatase or rutile structure were prepared by the sol-gel process with a
      subsequent heat treatment at various temperatures. The titania gels with an
      amorphous structure did not induce apatite formation on their surfaces in the
      simulated body fluid, whereas gels with an anatase or rutile structure induced
      apatite formation on their surfaces. The deposition of apatite was more
      pronounced on the anatase gels than on the rutile gels. This indicates that a
      specific structure of titania is effective in inducing apatite formation in a
      body environment. Such a specific structure was assumed in this study to be the
      crystalline planar arrangement in the anatase structure, which facilitates
      epitaxy of the apatite crystal.

PMID- 12483710
TI  - Effect of the chemical composition of Ricinus communis polyurethane on rat bone
      marrow cell attachment, proliferation, and differentiation.
AB  - Alterations in the chemical composition of a polymer may be undertaken to improve
      its biological properties. The aim of this study was to investigate the in vitro
      biocompatibility of Ricinus communis polyurethane (RCP) with three different
      chemical compositions: RCPp (pure RCP), RCP+CaCO(3), and RCP+Ca(3)(PO(4))(2). Rat
      bone marrow cells were cultivated under conditions that allowed osteoblastic
      differentiation and were evaluated for cell attachment, cell proliferation, cell
      morphology, total protein content, alkaline phosphatase (ALP) activity, and
      bonelike nodule formation. For the evaluation of attachment, cells were cultured
      for 4 h. After 3 days, cell morphology was evaluated. Cell proliferation was
      evaluated after 7 and 14 days. Total protein content and ALP activity were
      evaluated after 14 days. For bonelike nodule formation, cells were cultured for
      21 days. Data were compared with an analysis of variance and Duncan's multiple
      range test when appropriate. Cell attachment and ALP activity were not affected
      by RCP chemical composition. Proliferation, total protein content, and bonelike
      nodule formation were all affected by RCP chemical composition. These results
      suggest that initial cell events are not affected by RCP chemical composition,
      whereas RCPs blended with calcium carbonate or, better yet, calcium phosphate, by
      favoring events that promote matrix mineralization, are more biocompatible
      materials.

PMID- 12483711
TI  - Effect of chitosan film containing basic fibroblast growth factor on wound
      healing in genetically diabetic mice.
AB  - Basic fibroblast growth factor (bFGF) has been shown to stimulate wound healing.
      However, consistent delivery of bFGF has been problematic. We studied the
      stability of bFGF incorporated into a chitosan film as a delivery vehicle for
      providing sustained release of bFGF. The therapeutic effect of this system on
      wound healing in genetically diabetic mice was determined as a model for treating
      clinically impaired wound healing. A chitosan film was prepared by freeze-drying
      hydroxypropylchitosan (a water-soluble derivative of chitosan) acetate buffer
      solution. Growth factor was incorporated into films before drying by mixing bFGF
      solution with the hydroxypropylchitosan solution. bFGF activity remained stable
      for 21 days at 5 degrees C, and 86.2% of activity remained with storage at 25
      degrees C. Full-thickness wounds were created on the backs of diabetic mice, and
      chitosan film or bFGF-chitosan film was applied to the wound. The wound was
      smaller in after 5 days in both groups, but the wound was smaller on day 20 only
      in the bFGF-chitosan group. Proliferation of fibroblasts and an increase in the
      number of capillaries were observed in both groups, but granulation tissue was
      more abundant in the bFGF-chitosan group. These results suggest that chitosan
      itself facilitates wound repair and that bFGF incorporated into chitosan film is
      a stabile delivery vehicle for accelerating wound healing.

PMID- 12483712
TI  - Biomimetic PMMA-based bone substitutes: a comparative in vitro evaluation of the
      effects of pulsed electromagnetic field exposure.
AB  - Pulsed electromagnetic fields (PEMFs) are known to be effective in the
      stimulation of cultured osteoblasts and in vivo healing of delayed and nonunion
      fractures. In the present in vitro study the effects of PEMFs on osteoblastic
      cell cultures (MG63 human osteoblast-like cells) grown in the presence of poly
      methylmethacrylate (PMMA) and of a biomimetic bone substitute made of a PMMA
      matrix added with alfa-tricalcium phosphate (PMMA+alpha-TCP) were evaluated, to
      assess the biological response at the cell-biomaterial interaction. Cultures were
      stimulated with PEMFs (75 Hz, 2.3 mT, 1.3-ms pulse duration) 12 h/day for 3 days
      and evaluations (MTT, ALP, OC, PICP, TGFbeta-1, IL-6) were performed at 3 and 6
      days. PMMA had a negative effect on osteoblasts, whereas PMMA+alpha-TCP enhanced
      production of ALP, PICP, OC and TGFbeta-1, and reduced IL-6 levels. Cells
      responded positively to PEMF stimulation even when cultured with a poorly
      biocompatible material, such as PMMA. This effect was more evident in the
      presence of PMMA+alpha-TCP (further improvement in proliferation and synthetic
      activity) both at 3 and at 6 days. The properties of PMMA+alpha-TCP look
      promising, and the present results support the use of PEMFs to improve tissue
      response to biomaterials implanted as bone substitutes.

PMID- 12483713
TI  - Type I collagen production by osteoblast-like cells cultured in contact with
      different bioactive glasses.
AB  - Bioactive glasses are silica-based, surface-active bone substitutes that have
      shown good biocompatibility both in bone and in soft tissue and are used in oral
      and maxillofacial bone augmentation. Previous in vitro studies showing that
      bioactive glasses support the growth and maturation of rat osteoblast-like cells
      and promote the expression and maintenance of the osteoblastic phenotype have
      suggested that there is both a solution-mediated and a surface-controlled effect
      on cell activity. In this study, we investigated the behavior of human primary
      osteoblast-like cells cultured in contact with three different bioactive glasses
      and compared them with amorphous silica (SiO2) used in the form of granules. The
      specific activity of alkaline phosphatase determined biochemically was
      significantly higher at 2 and 4 days on the bioactive glass with 46.1 mol %
      silica content (45S5 Bioglass) cultures than in the control cultures and in the
      bioactive gel-glass cultures, which had 60 mol % (58S) and 80 mol % (77S) silica
      content. Osteoblasts synthesize collagen type I, which is subsequently
      mineralized. Immunoblot and biochemical studies showed increased collagen release
      from osteoblast-like cells cultured in contact with bioactive glasses over that
      of controls. Among the three bioactive glasses, 45S5 is the highest inducer of
      osteoblast-like cell collagen release; moreover, mRNA for type I collagen was
      stimulated approximately three- to fivefold after 45S5 treatment. 77S bioactive
      glass similarly increased type I collagen synthesis even though alkaline
      phosphatase was not higher. These results suggest that 45S5 Bioglass not only
      induces osteogenic differentiation of human primary osteoblast-like cells, but
      can also increase collagen synthesis and release. The newly formulated bioactive
      gel-glass 77S seems to have potential applications for tissue engineering,
      inducing increased collagen synthesis.

PMID- 12483714
TI  - Missed opportunities in physician management of glucocorticoid-induced
      osteoporosis?

PMID- 12483715
TI  - Osteoprotegerin, an endogenous antiosteoclast factor for protecting bone in
      rheumatoid arthritis.

PMID- 12483716
TI  - Management of glucocorticoid-induced osteoporosis in patients with rheumatoid
      arthritis: rates and predictors of care in an academic rheumatology practice.
AB  - OBJECTIVE: To examine rheumatologists' management practices for patients with
      rheumatoid arthritis (RA) taking glucocorticoids seen at one academic medical
      rheumatology practice. METHODS: All patients diagnosed with RA making at least 2
      visits to the practice who were noted to be taking glucocorticoids on an index
      visit in January or February 1999 were included in a retrospective chart review.
      RESULTS: Of the 623 eligible patients identified with RA, 236 patients were
      taking glucocorticoids at their index visit and were included in this study. The
      mean daily dosage of prednisone (or its equivalent) was 8.8 mg and the mean
      duration of use during the 2-year chart review was 15.4 months. Twenty-three
      percent of the study population underwent bone densitometry, and 42% were
      prescribed a medication that reduces bone loss (not including calcium and/or
      vitamin D). Calcium and/or vitamin D were noted on the medication lists of 25% of
      patients. Factors associated with not undergoing bone densitometry in adjusted
      logistic models included male patient sex and premenopausal status in women. No
      physician factors were significantly related to performing bone densitometry.
      Variables associated with not receiving prescription treatment of osteoporosis
      were male patient sex, premenopausal status, and having at least 1 comorbid
      condition. CONCLUSION: Patients with RA taking oral glucocorticoids did not
      routinely undergo bone densitometry and/or receive prescription medications for
      osteoporosis. Men and premenopausal women were less likely to undergo bone
      densitometry and to receive a prescription medication for osteoporosis than
      postmenopausal women. Interventions to improve detection and prevention of
      glucocorticoid-induced osteoporosis are necessary.

PMID- 12483717
TI  - Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6
      receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind,
      placebo-controlled, dose-escalation trial.
AB  - OBJECTIVE: To investigate the safety and efficacy of MRA, a recombinant human
      anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody of the IgG1 subclass
      that inhibits the function of IL-6, in patients with established rheumatoid
      arthritis (RA). METHODS: A randomized, double-blind, placebo-controlled, dose
      escalation trial was conducted in 45 patients with active RA, as defined by the
      American College of Rheumatology (ACR) revised criteria. Patients were
      sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5,
      or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR
      20% response criteria at week 2 after treatment. RESULTS: Demographic features
      were similar between treatment groups. At week 2, a significant treatment
      difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients
      (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20%
      improvement. There was no statistically significant difference in the ACR 20%
      response between the other 3 MRA cohorts and placebo at week 2. The mean disease
      activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was
      4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively.
      These mean scores were statistically significantly lower than those in the 0.1-
      and 1-mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The
      erythrocyte sedimentation rate and C-reactive protein values fell significantly
      in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment.
      Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1-, 1-, 5-, and
      10-mg/kg MRA cohorts, respectively) required corticosteroid or disease-modifying
      antirheumatic drug treatment because of active disease before study end. They
      were regarded as nonresponders from the time they received these treatments.
      Diarrhea was the most common adverse event, occurring in 8% of patients. Seven
      patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the
      placebo, 0.1-, 1-, and 10-mg/kg MRA cohorts). There were no serious adverse
      events that were thought to be related to the study drug. CONCLUSION: This is the
      first randomized controlled trial showing that inhibition of IL-6 significantly
      improved the signs and symptoms of RA and normalized the acute-phase reactants.
      Further research with multiple dosing is necessary to define the most appropriate
      therapeutic regimen of MRA in RA.

PMID- 12483718
TI  - Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six
      cases reported to the Food and Drug Administration.
AB  - OBJECTIVE: Etanercept and infliximab are tumor necrosis factor (TNF) antagonists
      that have been recently approved for the treatment of rheumatoid arthritis (RA)
      and Crohn's disease (CD). This study was undertaken to investigate the occurrence
      of lymphoproliferative disorders in patients treated with these agents. METHODS:
      Relevant data in the MedWatch postmarket adverse event surveillance system run by
      the US Food and Drug Administration were reviewed. RESULTS: We identified 26
      cases of lymphoproliferative disorders following treatment with etanercept (18
      cases) or infliximab (8 cases). The majority of cases (81%) were non-Hodgkin's
      lymphomas. The interval between initiation of therapy with etanercept or
      infliximab and the development of lymphoma was very short (median 8 weeks). In 2
      instances (1 infliximab, 1 etanercept), lymphoma regression was observed
      following discontinuation of anti-TNF treatment, in the absence of specific
      cytotoxic therapy directed toward the lymphoma. CONCLUSION: Although data from a
      case series such as this cannot establish a clear causal relationship between
      exposure to these medications and the risk of lymphoproliferative disease, the
      known predisposition of patients with RA and CD to lymphoma, the known excess of
      lymphoma in other immunosuppressed populations, and the known immunosuppressive
      effects of the anti-TNF drugs provide a biologic basis for concern and
      justification for the initiation of additional epidemiologic studies to formally
      evaluate this possible association.

PMID- 12483719
TI  - Induction of apoptosis in rheumatoid synovial fibroblasts by celecoxib, but not
      by other selective cyclooxygenase 2 inhibitors.
AB  - OBJECTIVE: Selective cyclooxygenase 2 (COX-2) inhibitors are now being used as
      antiinflammatory agents that cause fewer gastrointestinal complications, compared
      with other antiinflammatory drugs, in patients with rheumatoid arthritis (RA).
      This study was undertaken to investigate whether selective COX-2 inhibitors could
      induce apoptosis of RA synovial fibroblasts (RASFs). METHODS: RASFs were exposed
      to selective COX-2 inhibitors, i.e., celecoxib, etodolac, meloxicam, nimesulide,
      N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide, and rofecoxib, under
      various conditions. Cell proliferation and cell viability were assessed by
      incorporation of 5-bromo-2'-deoxyuridine and by the 2-(4-iodophenyl)-3-(4
      nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay,
      respectively. Apoptosis was detected by identifying DNA fragmentation. Activation
      of peroxisome proliferator-activated receptor gamma (PPARgamma) was measured by
      the luciferase reporter gene assay with a PPAR response element-driven luciferase
      reporter plasmid and a PPARgamma expression plasmid. RESULTS: Celecoxib strongly
      inhibited the proliferation of RASFs, whereas other selective COX-2 inhibitors
      had little or no effect. In addition, celecoxib reduced the viability of RASFs by
      induction of apoptosis, in a concentration-dependent manner. This action was
      abolished by addition of caspase inhibitors. Interleukin-1beta had a weak
      enhancing effect on celecoxib-induced apoptosis in RASFs. In contrast, other
      selective COX-2 inhibitors at concentrations up to 100 microM did not induce
      apoptosis of RASFs. Indomethacin, a nonselective COX inhibitor, activated
      PPARgamma transcription, while celecoxib did not. CONCLUSION: Celecoxib
      suppressed the proliferation of RASFs by COX-2-independent and PPARgamma
      independent induction of apoptosis. Although the mechanism involved remains
      unclear, celecoxib may have not only antiinflammatory activity, but also a
      disease-modifying effect on rheumatoid synovial proliferation.

PMID- 12483720
TI  - The geometric architecture of the subtalar and midtarsal joints in rheumatoid
      arthritis based on magnetic resonance imaging.
AB  - OBJECTIVE: To compare in vivo the 3-dimensional (3-D) geometric architecture of
      the subtalar and midtarsal joints in normal and rheumatoid arthritic (RA) feet,
      using magnetic resonance imaging (MRI) analysis. METHODS: MRI was performed on 23
      patients with RA, all of whom had disease activity in the subtalar and/or
      midtarsal joints. Image processing techniques were used to create 3-D
      reconstructions of the calcaneus (C), cuboid (c), navicular (N), and talus (T)
      bones. Twenty-four standard architectural parameters were measured from the
      reconstructions and were compared with data from 10 normal subjects. These
      parameters defined both 3-D distance and angular relationships among the 4 bones
      studied. Pattern classification techniques were used to establish a geometric
      architecture foot profile for the RA patients. The degree of individual patient
      fit to the new RA foot profile and to profiles for normal, pes planus, and pes
      cavus foot types was derived. Logistic regression was used to examine the
      relationship of foot architecture to inflammatory disease characteristics and
      physical examination variables. RESULTS: Subtalar or midtarsal pain was reported
      by all 23 patients, and 22 of the 23 patients presented with >/=1 clinical
      feature of pes planovalgus deformity. In 21 patients, ultrasonography revealed
      synovitis at >/=1 tarsal joint or surrounding tendon. In the RA group, the
      normalized distances between the geometric centroids were significantly closer
      for bone pairs Cc and cT and significantly distracted for bone pair CN compared
      with the distances in normal subjects. In RA patients (versus normal subjects),
      the angles subtended at the bone centroids were significantly decreased in 3 bone
      groups (CNc, TCN, and TNc) and significantly increased in 3 bone groups (CcN,
      CcT, NTc). The angles formed between the major principal axes of bone pairs CT
      and cT were significantly increased in RA patients compared with those in normal
      subjects. Pattern classification defined 11 RA feet as having normal structure
      and 12 as having abnormal structure. However, the abnormal feet did not fit
      consistently with structures defined for RA, pes planus, or pes cavus foot types.
      Logistic regression demonstrated that subtalar joint synovitis was the only
      predictive factor for abnormal subtalar and midtarsal architecture (odds ratio
      19.2, 95% confidence interval 1.77-200.0). CONCLUSION: This unique 3-D MRI-based
      technique successfully quantified the effects of RA on the geometric architecture
      of the foot and the patient-specific nature of these changes. This technique can
      be used to provide logical therapy for correction.

PMID- 12483721
TI  - Evidence for increased bone resorption in patients with progressive knee
      osteoarthritis: longitudinal results from the Chingford study.
AB  - OBJECTIVE: Several studies have suggested that increased subchondral bone
      turnover is a determinant of progression of osteoarthritis (OA). To test this
      hypothesis, the level of urinary N-terminal type I collagen telopeptides (NTx)
      and C-terminal type I collagen telopeptides (CTx), which are validated markers of
      bone resorption, was measured at 3 different time points in a subset of patients
      from the Chingford study. METHODS: The original Chingford study population
      comprised 1,003 women. From this group, postmenopausal women not receiving any
      bone-modifying medication who had a baseline knee radiograph and a repeat
      radiograph 4 years later, and for whom a baseline lumbar spine bone mineral
      density (BMD) measurement was available, were identified and separated into 4
      groups as follows: controls (n = 50), progressive OA (n = 71), nonprogressive OA
      (n = 36), and osteoporosis (n = 59). NTx and CTx were measured in urine samples
      collected at baseline, year 1, and year 2. RESULTS: Patient age and years since
      menopause were similar among groups at baseline. As expected, both body mass
      index (BMI) and BMD were lowest in patients with osteoporosis. Median resorption
      marker levels over the 3 time points were 31-87% higher in patients with either
      progressive OA or osteoporosis than in controls and patients with nonprogressive
      OA (P < 0.01, except for levels of CTx in patients with progressive OA versus
      nonprogressive OA). Levels of NTx and CTx did not differ significantly between
      women with progressive OA (defined either by the presence of osteophytes or by
      joint space narrowing) and those with osteoporosis or between controls and women
      with nonprogressive OA. Results were essentially unchanged after adjustment for
      age, BMI, BMD, and past use of hormone replacement therapy, or when NTx and CTx
      values at each time point were analyzed separately. CONCLUSION: Our data
      demonstrate that bone resorption is increased in patients with progressive knee
      OA and is not increased in those with nonprogressive knee OA. The increase in
      bone resorption seen in patients with progressive knee OA is similar to that
      observed in patients with osteoporosis. Altered bone turnover may be a diagnostic
      or therapeutic target in patients with progressive OA.

PMID- 12483722
TI  - Nonrandom evolution of end-stage osteoarthritis of the lower limbs.
AB  - OBJECTIVE: Patients with unilateral hip or knee replacements for end-stage
      osteoarthritis (OA) are at high risk for future progression of OA in other joints
      of the lower extremities, often requiring additional joint replacements. Although
      the risks of future surgery in the contralateral cognate joints (i.e.,
      contralateral hip replacement after an initial hip replacement) have been
      evaluated, the evolution of end-stage hip OA to OA involving the knee joints, and
      vice versa (i.e., noncognate progression) has not been investigated. Because
      characterization of OA progression in noncognate joints may shed light on the
      pathogenesis of multijoint OA, we investigated the pattern of evolution of end
      stage lower extremity OA in a large, clinical cohort. METHODS: Total joint
      replacement (TJR) was selected as a marker of end-stage OA, and a database
      comprising all lower extremity TJRs performed at a large referral center between
      1981 and 2001 was accessed. Of the 5,894 patients identified, 486 patients with
      idiopathic OA who underwent hip replacement and 414 who underwent initial knee
      replacement were analyzed to determine the relative likelihood of subsequent
      TJRs. Patients with the systemic inflammatory arthropathy, rheumatoid arthritis
      (RA), were evaluated as a control population because RA progression is not
      considered to be a primarily mechanically mediated process. RESULTS: The
      contralateral cognate joint was the most common second joint to undergo
      replacement in both the OA and the RA groups. However, in OA patients for whom
      the second TJR was in a noncognate joint, that joint was >2-fold more likely to
      be on the contralateral limb than on the ipsilateral limb (hip to knee P < 0.001;
      knee to hip P = 0.013). In contrast, among the RA cohort, the evolution was
      random and no laterality for noncognate TJR was observed at either the hip or the
      knee (P = 0.782). CONCLUSION: This characterization of end-stage lower extremity
      OA demonstrates that the disease evolves nonrandomly; after 1 joint is replaced,
      the contralateral limb is significantly more likely to show progression of OA
      than is the ipsilateral limb. Thus, OA in 1 weight-bearing joint appears to
      influence the evolution of OA in other joints. The absence of such laterality in
      RA suggests that OA progression may be mediated by extrinsic factors such as
      altered joint loading.

PMID- 12483723
TI  - Functional replacement of oxygen by other oxidants in articular cartilage.
AB  - OBJECTIVE: Articular cartilage chondrocytes consume remarkably little O(2) in
      comparison with most other animal cells; glycolysis forms the principal source of
      ATP in this cartilage. Although not lethal for many days, imposition of anoxia
      immediately lowers intracellular ATP, inhibits rates of glycolysis, and prevents
      articular chondrocytes from producing extracellular matrix macromolecules. This
      study was undertaken to investigate the role of O(2) in articular chondrocyte
      metabolism. METHODS: We examined the effects of oxygen and of several other
      classes of exogenous oxidants, i.e., 1) the dyes methylene blue and 2,6
      dichlorophenol-indophenol, 2) the iron (III) complex ferricyanide, and 3) the
      keto-acids oxaloacetate and pyruvate (and phosphoenolpyruvate, a metabolic
      precursor of pyruvate), on rates of glycolysis and of sulfate incorporation by
      bovine articular cartilage in vitro. RESULTS: Lactate production was lowest under
      conditions of anoxia and was stimulated severalfold by addition of O(2) (air
      saturated medium). Under strict anoxia, other oxidants restored lactate
      production to rates at least comparable with those seen in aerobic controls;
      under aerobic conditions, they had little effect. Oxygen and all of the other
      oxidants examined stimulated sulfate incorporation more strongly than lactate
      production. The compounds that promoted glycolysis and hence sulfate
      incorporation in cartilage under anoxia were themselves reduced; that is, they
      functioned as oxidants in lieu of O(2). CONCLUSION: For normal function,
      articular cartilage appears to require exogenous oxidants to stimulate glycolysis
      and produce ATP and extracellular matrix. Under physiologic conditions, oxygen
      acts as this oxidant, but its role can be adequately assumed by other agents.

PMID- 12483724
TI  - Growth-related oncogene alpha induction of apoptosis in osteoarthritis
      chondrocytes.
AB  - OBJECTIVE: To evaluate the apoptotic effect of the chemokine growth-related
      oncogene alpha (GROalpha), which we recently reported to be up-regulated in
      osteoarthritis (OA) chondrocytes. Chondrocyte apoptosis is considered to be a
      major determinant of cartilage damage in OA, a disease resulting from the
      aberrant production of inflammatory mediators (cytokines and chemokines) and
      effectors (matrix metalloproteinases and reactive oxygen and nitrogen species) by
      chondrocytes. METHODS: We investigated the apoptotic effect of GROalpha on
      isolated human cells and on in vitro-cultured cartilage explants by conventional
      methods (morphology, detection of DNA fragmentation in situ and in solution,
      exposure of phosphatidylserine) and by analysis of "early" biochemical events
      (plasma membrane depolarization, activation of caspase 3, and phosphorylation of
      c-Jun N-terminal kinase/stress-activated protein kinase). RESULTS: We clearly
      demonstrated that GROalpha was able to initiate a series of morphologic,
      biochemical, and molecular changes that led to chondrocyte apoptosis. Moreover,
      we found that additional signals delivered from the extracellular matrix (ECM)
      were essential in the control of chondrocyte susceptibility to GROalpha-induced
      apoptosis, since cell death was detected only when cells were stimulated after
      reestablishment of their proper interactions with the ECM, or in cartilage
      explant samples with reduced ECM, as indicated by decreased Safranin O staining.
      CONCLUSION: GROalpha can induce apoptosis in articular chondrocytes, and the
      induction is dependent upon additional signals from the ECM. These findings are
      relevant to understanding the pathogenesis of OA, in view of the availability of
      the GROalpha chemokine in the joint space in the course of this rheumatic
      disease.

PMID- 12483725
TI  - Induction of advanced glycation end products and alterations of the tensile
      properties of articular cartilage.
AB  - OBJECTIVE: To determine whether increasing advanced glycation end products (AGEs)
      in bovine articular cartilage to levels present in aged human cartilage modulates
      the tensile biomechanical properties of the tissue. METHODS: Adult bovine
      articular cartilage samples were incubated in a buffer solution with ribose to
      induce the formation of AGEs or in a control solution. Portions of cartilage
      samples were assayed for biochemical indices of AGEs and tested to assess their
      tensile biomechanical properties, including stiffness, strength, and elongation
      at failure. RESULTS: Ribose treatment of cartilage induced increases in tissue
      fluorescence, absorbance, and pentosidine content (P < 0.001 for each comparison)
      by amounts similar to those that occur during aging in humans. Ribose treatment
      of cartilage also induced an increase in dynamic modulus (60% increase) and
      strength (35% increase), and a decrease (25% decrease) in strain (P < 0.001 for
      each comparison). CONCLUSION: The concomitant increase in AGEs and alteration of
      tensile properties of cartilage after ribose treatment suggest that aging
      associated changes in AGEs have functional consequences for this tissue. The AGE
      associated increases in strength and stiffness of cartilage may be beneficial by
      counteracting the decreases in these properties that are associated with
      degeneration. Conversely, the AGE-associated decrease in failure length, or
      increase in brittleness, together with increased stiffness may predispose
      cartilage to increased stress concentration, fracture, and aging-associated
      biomechanical dysfunction.

PMID- 12483726
TI  - Up-regulated expression of cartilage intermediate-layer protein and ANK in
      articular hyaline cartilage from patients with calcium pyrophosphate dihydrate
      crystal deposition disease.
AB  - OBJECTIVE: Excess accumulation of extracellular inorganic pyrophosphate (ePPi) in
      aged human cartilage is crucial in calcium pyrophosphate dihydrate (CPPD) crystal
      formation in cartilage matrix. Two sources of ePPi are ePPi-generating
      ectoenzymes (NTPPPH) and extracellular transport of intracellular PPi by ANK.
      This study was undertaken to evaluate the role of NTPPPH and ANK in ePPi
      elaboration, by investigating expression of NTPPPH enzymes (cartilage
      intermediate-layer protein [CILP] and plasma cell membrane glycoprotein 1 [PC-1])
      and ANK in human chondrocytes from osteoarthritic (OA) articular cartilage
      containing CPPD crystals and without crystals. METHODS: Chondrocytes were
      harvested from knee cartilage at the time of arthroplasty (OA with CPPD crystals
      [CPPD], n = 8; OA without crystals [OA], n = 10). Normal adult human chondrocytes
      (n = 1) were used as a control. Chondrocytes were cultured with transforming
      growth factor beta1 (TGFbeta1), which stimulates ePPi elaboration, and/or insulin
      like growth factor 1 (IGF-1), which inhibits ePPi elaboration. NTPPPH and ePPi
      were measured in the media at 48 hours. Media CILP, PC-1, and ANK were determined
      by dot-immunoblot analysis. Chondrocyte messenger RNA (mRNA) was extracted for
      reverse transcriptase-polymerase chain reaction to study expression of mRNA for
      CILP, PC-1, and ANK. NTPPPH and ANK mRNA and protein were also studied in fresh
      frozen cartilage. RESULTS: Basal ePPi elaboration and NTPPPH activity in
      conditioned media from CPPD chondrocytes were elevated compared with normal
      chondrocytes, and tended to be higher compared with OA chondrocytes. Basal
      expression of mRNA for CILP (chondrocytes) and ANK (cartilage) was higher in both
      CPPD chondrocytes and CPPD cartilage extract than in OA or normal samples. PC-1
      mRNA was less abundant in CPPD chondrocytes and cartilage extract than in OA
      chondrocytes and extract, although the difference was not significant. CILP, PC
      1, and ANK protein levels were similar in CPPD, OA, and normal chondrocytes or
      cartilage extracts. Both CILP and ANK mRNA expression and ePPi elaboration were
      stimulated by TGFbeta1 and inhibited by IGF-1 in chondrocytes from all sources.
      CONCLUSION: CILP and ANK mRNA expression correlates with chondrocyte ePPi
      accumulation around CPPD and OA chondrocytes, and all respond similarly to growth
      factor stimulation. These findings suggest that up-regulated CILP and ANK
      expression contributes to higher ePPi accumulation from CPPD crystal-forming
      cartilage.

PMID- 12483727
TI  - Bcl-3 is an interleukin-1-responsive gene in chondrocytes and synovial
      fibroblasts that activates transcription of the matrix metalloproteinase 1 gene.
AB  - OBJECTIVE: To define the role of Bcl-3, a member of the inhibitor of nuclear
      factor kappaB (NF-kappaB) family and a known regulator of NF-kappaB, in
      interleukin-1 (IL-1)-induced matrix metalloproteinase 1 (MMP-1) transcription in
      chondrocytes and synovial fibroblasts. METHODS: SW-1353 cells, a human
      chondrosarcoma cell line, were stimulated with IL-1beta, and the harvested RNA
      was subjected to microarray analysis and quantitative real-time reverse
      transcription-polymerase chain reaction (RT-PCR). The SW-1353 cells were
      stimulated with IL-1 or transfected with a plasmid that constitutively expressed
      Bcl-3, and then MMP-1 messenger RNA (mRNA) expression was assayed by quantitative
      real-time RT-PCR. SW-1353 cells were transfected with antisense oligonucleotides
      to Bcl-3, and IL-1-induced MMP-1 mRNA expression was assayed by quantitative RT
      PCR. SW-1353 cells and rabbit synovial fibroblasts were transfected with a 4.3-kb
      human MMP-1 promoter construct along with Bcl-3 and NF-kappaB1 expression
      constructs, and MMP-1 transcription was assayed. RESULTS: Microarray analysis and
      real-time RT-PCR showed Bcl-3 to be an IL-1beta-responsive gene in SW-1353 cells.
      Exogenous expression of Bcl-3 in SW-1353 cells activated MMP-1 transcription.
      Endogenous Bcl-3 expression was required for IL-1beta induction of MMP-1 gene
      expression. Bcl-3 also activated MMP-1 transcription in primary synovial
      fibroblasts. We showed previously that NF-kappaB1 contributes to IL-1beta
      induction of MMP-1 transcription in stromal cells. We showed here that Bcl-3 can
      cooperate with NF-kappaB1 to activate MMP-1 transcription in SW-1353 cells.
      CONCLUSION: These data define a new role for Bcl-3 in joint cells as an IL-1beta
      responsive early gene involved in cell-mediated cartilage remodeling. Our
      findings implicate Bcl-3 as an important contributor to chronic inflammatory
      disease states, such as osteoarthritis and rheumatoid arthritis.

PMID- 12483728
TI  - Expression of matrix metalloproteinases in articular cartilage of
      temporomandibular and knee joints of mice during growth, maturation, and aging.
AB  - OBJECTIVE: This study examined the involvement of different matrix
      metalloproteinases (MMPs) in articular cartilage in the process of growth,
      maturation, and aging of mice, and compared the temporal changes in the
      expression of MMPs between temporomandibular joints (TMJ) and knee joints.
      METHODS: Homogenates of intact tibial plateau, femoral condyle, and TMJ condyle
      cartilages from animals of different ages were assessed for gelatinase (MMP-2 and
      MMP-9) activity by zymography. The messenger RNA (mRNA) expression of MMPs 1, 2,
      3, 9, and 13 in tibial plateau cartilage was determined by semiquantitative
      reverse transcription-polymerase chain reaction, and immunohistochemistry was
      used to localize MMPs 2, 3, 9, and 13 in the knee joints and TMJ from mice of
      different ages. RESULTS: The pattern of gelatinase (MMP-2 and MMP-9) activity and
      their protein expression as well as that of MMPs 3 and 13 varied with the age of
      the mouse, and differences in expression were observed between the knee and TMJ
      cartilage. The expression of mRNA for the MMPs in the tibial plateau was also age
      related. CONCLUSION: This study demonstrated changes in the protein and mRNA
      expression of MMPs 2, 9, 3, and 13 during growth, maturation, and aging in mice.
      The temporal changes were characteristic of the joint, and distinct differences
      were observed between the TMJ and knee cartilage. The differences in
      temporospatial expression of MMPs between the knee joint and TMJ may be the
      result of differences in load and function of these joints. The information
      provided in this study contributes to a better understanding of the role of these
      MMPs in the maintenance and integrity of cartilage tissue.

PMID- 12483729
TI  - Treatment of systemic lupus erythematosus by inhibition of T cell costimulation
      with anti-CD154: a randomized, double-blind, placebo-controlled trial.
AB  - OBJECTIVE: To evaluate the safety and efficacy of a humanized monoclonal antibody
      against CD154 (IDEC-131) in patients with active systemic lupus erythematosus
      (SLE). METHODS: In this phase II, double-blind, placebo-controlled, multiple
      center, multiple-dose study, 85 patients with mild-to-moderately active SLE were
      randomized to receive 6 infusions of IDEC-131, ranging from 2.5 mg/kg to 10.0
      mg/kg, or placebo over 16 weeks. Efficacy was assessed at week 20, primarily by
      the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and secondarily,
      by multiple measures of disease activity. Safety was assessed through week 28 by
      clinical and laboratory evaluation. Immunogenicity studies were also performed.
      RESULTS: SLEDAI scores improved from the baseline levels of disease activity in
      all groups, including the placebo group. However, these scores were not
      statistically different among the IDEC-131 treatment and placebo groups at week
      20. Evaluations of secondary variables did not indicate significant differences
      between the IDEC-131 treatment and placebo groups. The type and frequency of
      adverse events were similar between the IDEC-131 and placebo groups. CONCLUSION:
      IDEC-131 administered at doses ranging 2.5-10.0 mg/kg over 16 weeks was safe and
      well tolerated in patients with SLE. Efficacy of the drug compared with placebo
      was not demonstrated. There were statistically significant improvements from
      baseline in all groups, including the placebo group.

PMID- 12483730
TI  - RP105-lacking B cells from lupus patients are responsible for the production of
      immunoglobulins and autoantibodies.
AB  - OBJECTIVE: We previously reported that B cells lacking the RP105 molecule, which
      proved to be highly activated B cells, are increased in the peripheral blood of
      patients with systemic lupus erythematosus (SLE). In the present study, we
      attempted to determine whether RP105-negative B cells obtained from SLE patients
      would be capable of producing autoantibodies as well as immunoglobulins. METHODS:
      RP105-positive and RP105-negative B cells, sorted by cell sorter, were cultured
      for 5 days without stimulation, or were stimulated with Staphylococcus aureus
      Cowan 1 strain (SAC) or recombinant interleukin-6 (IL-6). For the assay of
      autoantibodies, RP105-positive and RP105-negative B cells were cultured
      separately for 10 days with anti-CD3 antibody-stimulated T cells. The production
      of immunoglobulins and autoantibodies was determined by enzyme-linked
      immunosorbent assay. RESULTS: We demonstrated that RP105-negative B cells, but
      not RP105-positive B cells, obtained from SLE patients could spontaneously
      produce IgG and IgM in vitro until day 5. SAC and IL-6 enhanced production of IgG
      and IgM by RP105-negative B cells but failed to induce such production by RP105
      positive B cells. The latter cells, however, when cocultured with activated T
      cells in the presence of IL-10, produced IgG, although the amount was very small
      compared with that produced by RP105-negative B cells. Most important, under
      these conditions, anti-double-stranded DNA antibodies were produced only by the
      RP105-negative B cells obtained from SLE patients. CONCLUSION: These data
      indicate that RP105-negative B cells, constituting a subset of B cells in SLE
      patients, are highly activated and may be responsible for the production of
      autoantibodies as well as polyclonal immunoglobulins.

PMID- 12483731
TI  - Identity of the RNase MRP- and RNase P-associated Th/To autoantigen.
AB  - OBJECTIVE: To characterize the molecular identity of the Th/To autoantigen, which
      is targeted by autoantibodies in scleroderma and which is associated with the
      human RNase MRP and RNase P ribonucleoprotein complexes. METHODS: Proteins
      immunoprecipitated by anti-Th/To+ patient antisera from biotinylated total HeLa
      cell extracts were analyzed by immunoblotting. The association of autoantigenic
      proteins with the RNase MRP complex was analyzed by reconstitution experiments
      and ultraviolet crosslinking. The reactivity of patient sera with all known RNase
      MRP/RNase P proteins was analyzed by immunoprecipitation of the individual
      recombinant proteins. RESULTS: The previously defined Th40 autoantigen appeared
      to be identical to the Rpp38 protein. Paradoxically, Rpp38 did not bind to the P3
      domain of the RNase MRP RNA, as suggested by previously published data for Th40,
      and only half of the anti-Th/To+ sera contained anti-Rpp38 reactivity. Two other
      RNase MRP/RNase P subunits, Rpp20 and Rpp25, were found to interact with the P3
      domain. The previously reported 40-kd species associated with this domain
      appeared to consist of Rpp20 and/or Rpp25 associated with a nuclease-resistant
      RNA fragment. Finally, we demonstrated that almost all tested anti-Th/To+ patient
      sera contained autoantibodies to Rpp25 and hPop1, indicating that these proteins
      harbor the most frequently targeted Th/To determinants. CONCLUSION: Our data
      unequivocally define the identity of the Th/To autoantigen and demonstrate that
      Th/To autoepitopes are found on several protein subunits of RNase MRP/RNase P.

PMID- 12483732
TI  - A new conformational epitope generated by the binding of recombinant 70-kd
      protein and U1 RNA to anti-U1 RNP autoantibodies in sera from patients with mixed
      connective tissue disease.
AB  - OBJECTIVE: To establish an enzyme-linked immunosorbent assay (ELISA) using a
      complex of in vitro-transcribed U1 RNA and recombinant 70-kd, A, and C proteins
      (C-ELISA) to detect anti-U1 RNP antibodies reactive in double immunodiffusion
      (DID), but not in ELISA using the proteins alone (P-ELISA). METHODS: Sera from
      196 patients with mixed connective tissue disease were used to test reactivity in
      P- and C-ELISAs, and the specificity of the sera was also tested by DID and
      immunoprecipitation (IP). RESULTS: In P-ELISA, 15 of 196 sera positive for anti
      U1 RNP in DID did not react, while all sera reacted in C-ELISA. The reactivity of
      15 sera to the U1 RNA was tested by IP and ELISA, and only 3 sera reacted with
      the U1 RNA. These results indicated that the increased reactivity in C-ELISA was
      not due to the U1 RNA itself. We confirmed that the 70-kd and A proteins were
      bound directly to the U1 RNA by IP using antibodies to His-tag, and we tested the
      reactivity of the sera to the U1 RNA-70-kd protein complex and the U1 RNA-A
      protein complex by IP. All sera reacted with the U1 RNA-70-kd protein complex,
      and 1 sample reacted with the U1 RNA-A protein complex. CONCLUSION: These results
      suggest that some anti-U1 RNP-positive sera specifically recognize the
      conformational structure altered by the binding of U1 RNA to the proteins, and
      the ELISA using U1 RNA and recombinant proteins is as useful as the DID method
      for detecting anti-U1 RNP antibodies.

PMID- 12483733
TI  - Effects of beta2-glycoprotein I and monoclonal anticardiolipin antibodies in
      platelet interaction with subendothelium under flow conditions.
AB  - OBJECTIVE: To evaluate whether the effect of human monoclonal anticardiolipin
      antibodies (aCL) on platelet interaction with the subendothelium under flow
      conditions is dependent on beta(2)-glycoprotein I (beta(2)GPI). METHODS: Three
      monoclonal IgM aCL with anti-beta(2)GPI activity (TM1B3, GR1D5, and EY2C9)
      obtained from patients with antiphospholipid syndrome, a monoclonal aCL with
      lupus anticoagulant activity but without anti-beta(2)GPI activity (FRO) obtained
      from a patient with a splenic lymphoma, and a control monoclonal IgM without aCL
      activity were used. TM1B3, GR1D5, EY2C9, FRO, and control IgM (30 microg/ml) were
      added to reconstituted blood containing gel-filtered platelets (200 x
      10(9)/liter), factor VIII (100 units/dl), and fibrinogen (1.5 gm/liter). Samples
      were perfused (wall-shear rate 800 seconds(-1)), with and without the addition of
      purified beta(2)GPI (20 microg/ml), through annular chambers containing collagen
      rich denuded vascular segments, and the percentages of surface covered by
      platelets and by thrombi were evaluated. RESULTS: No differences in the
      percentages of surface covered by platelets and by thrombi were observed among
      samples with TM1B3, GR1D5, EY2C9, FRO, and control IgM added when reconstituted
      blood samples without beta(2)GPI were used. However, a significant increase in
      the percentage of surface covered by platelets was observed in the presence of
      TM1B3, GR1D5, and EY2C9 but not in the presence of FRO when samples containing
      beta(2)GPI were used. Increased thrombi formation was induced by TM1B3 and GR1D5
      but not by EY2C9 or FRO in samples with added beta(2)GPI. CONCLUSION: Monoclonal
      aCL require anti-beta(2)GPI activity to promote platelet interaction with the
      subendothelium under flow conditions.

PMID- 12483734
TI  - Induction of cell death by sera from patients with acute brain injury as a
      mechanism of production of autoantibodies.
AB  - OBJECTIVE: To investigate the capacity of blood draining from the central nervous
      system of patients with acute brain injury to induce cell death, and to determine
      whether this phenomenon could be a way to induce the production of
      autoantibodies. METHODS: The induction of cell death of several human leukemia
      cell lines cultured in vitro in the presence of serum collected from the brain or
      the systemic circulation of patients with acute brain injury was analyzed by flow
      cytometry after staining with annexin V and propidium iodide. The percentages of
      apoptotic lymphocytes derived directly from the patients were also quantified. To
      investigate the mechanisms responsible for the induction of cell death, the
      expression of apoptosis-related molecules, as well as the effect of addition of
      several molecules known to interfere with apoptosis, was evaluated in the cell
      cultures. The presence of serum autoantibodies at the time of injury and 6 months
      later was studied. RESULTS: Systemic serum and, especially, serum draining from
      the brain lesions induced the in vitro death of the leukemia cell lines used.
      Moreover, there were higher percentages of ex vivo dead lymphocytes in regional
      blood than in systemic blood 48 hours after injury. These effects seemed to be
      induced by an exogenous and/or endogenous opioid, since they were blocked by the
      opioid antagonist, naloxone. Furthermore, such effects were mediated by an
      increased expression of Bax. Importantly, apoptotic Jurkat cells were bound to
      autoantibodies, and patients with acute brain injury produced serum
      autoantibodies some months after the injury. However, they did not develop a full
      autoimmune disease at that time. CONCLUSION: Serum factors from acute brain
      injuries induce cell death, both in vivo and in vitro. Apoptotic cells and, even
      more so, necrotic cells in acute brain injury are potential sources for
      autoantigen presentation that may stimulate autoimmune responses.

PMID- 12483735
TI  - Infliximab in primary Sjogren's syndrome: one-year followup.
AB  - OBJECTIVE: To evaluate the safety and efficacy of a maintenance regimen of
      infliximab in patients with active primary Sjogren's syndrome (SS) over a 1-year
      period. METHODS: This followup study included 10 of the 16 patients with primary
      SS who participated in a pilot study. Patients who continued to have symptoms
      received additional infusions of infliximab for 1 year. RESULTS: All patients
      completed the 1-year followup for evaluation of efficacy. After 1 year, a
      statistically significant decrease in global and local disease manifestations was
      observed in all 10 patients. Treatment was generally well tolerated, with the
      main side effect being a mild, self-limited infusion reaction. CONCLUSION:
      Sustained improvement of active primary SS may be possible with infliximab
      treatment.

PMID- 12483736
TI  - Linkage and association studies of single-nucleotide polymorphism-tagged tumor
      necrosis factor haplotypes in juvenile oligoarthritis.
AB  - OBJECTIVE: The presence of increased levels of tumor necrosis factor (TNF) in
      serum and synovial fluid of patients and the encouraging outcome of anti-TNF
      therapy have implicated TNFalpha in the etiopathogenesis of juvenile
      oligoarthritis. Although the locus is polymorphic, no study has investigated all
      TNF single-nucleotide polymorphisms (SNPs) with respect to disease. The aim of
      this study was to examine the association of multiple TNF SNPs with juvenile
      oligoarthritis and to construct and analyze SNP-tagged TNF haplotypes. METHODS: A
      total of 144 simplex families consisting of parent and affected child, as well as
      88 healthy, unrelated control subjects were available for study. In these
      individuals, 9 polymorphic positions of TNF were typed by a high-throughput
      genotyping method based on the SNaPshot assay. The chi-square and extended
      transmission disequilibrium tests were used to test for association and linkage,
      respectively. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were also
      calculated. Haplotype-tagging SNPs (htSNPs) for the locus were identified by
      ordering the haplotypes according to their frequencies. RESULTS: The study
      detected association of several TNF SNPs and established linkage of the locus to
      juvenile oligoarthritis. The most significant association observed was between
      the intronic +851 TNF SNP and the persistent oligoarthritis subgroup (OR 3.86,
      95% CI 1.6-9.2). Haplotype data mining showed that only 4 of the 9 SNPs need to
      be typed in order to capture the most frequent TNF haplotypes. CONCLUSION: The
      TNF locus is linked and associated with juvenile oligoarthritis. Information on
      the htSNPs can be useful in genetic studies of diseases in which TNF may be of
      relevance.

PMID- 12483737
TI  - Cigarette smoking as a significant risk factor for digital vascular disease in
      patients with systemic sclerosis.
AB  - OBJECTIVE: Patients with systemic sclerosis (SSc) are at high risk for digital
      vascular complications, including amputation and gangrene. Cigarette smoking is
      an important risk factor for vascular disease in the general population. We
      investigated the influence of cigarette smoking on digital ischemia in patients
      with SSc. METHODS: We studied 101 patients with SSc (87 women and 14 men, median
      age 53 years, median disease duration 13 years). Smoking history was defined in
      terms of current smoking status and total number of pack-years. Digital ischemic
      events were classified as debridement, hospital admission for intravenous (IV)
      administration of vasodilators, and digital amputation. The influence of smoking
      on digital ischemic events was examined using logistic regression, adjusting for
      age, sex, and disease duration. Results are expressed as the odds ratio (OR) and
      95% confidence interval (95% CI). RESULTS: Of the 101 patients, 21 (21%) were
      current smokers, 37 (37%) were ex-smokers, and 43 (43%) had never smoked. After
      adjusting for age, sex, and disease duration, current smokers were significantly
      more likely than never-smokers to have had debridement (OR 4.5, 95% CI 1.1-18.3)
      or admission for IV vasodilators (OR 3.8, 95% CI 1.1-12.9). Patients smoking at
      higher intensity were more likely to require admission for IV vasodilators.
      CONCLUSION: Among patients with SSc, current smokers are 3-4 times more likely
      than never-smokers to incur digital vascular complications. Resources should be
      directed to supporting smoking cessation in patients with SSc.

PMID- 12483738
TI  - Interferon-alpha and ribavirin treatment in patients with hepatitis C virus
      related systemic vasculitis.
AB  - OBJECTIVE: Hepatitis C virus (HCV)-related vasculitis may involve multiple
      organs, including the skin, kidneys, and nervous system, and may be life
      threatening. Although HCV is increasingly recognized as a cause of systemic
      vasculitis, limited data are available regarding the optimal treatment of this
      potentially serious condition. Therefore, we retrospectively analyzed the
      response to treatment in patients with chronic hepatitis C complicated by
      systemic vasculitis who had received antiviral therapy with interferon-alpha
      (IFNalpha) and ribavirin. METHODS: This retrospective study included 27 patients
      with systemic vasculitis and chronic HCV infection. Each patient had received
      treatment with IFNalpha and ribavirin for at least 6 months. The response to
      antiviral treatment was analyzed by comparing clinical, immunologic, and
      virologic data at the time of entry and during followup. Clinical response was
      defined according to the evolution of weight, arthralgia, nervous system, renal
      system, and cutaneous involvement. The virologic and immunologic responses were
      defined by the absence of HCV RNA and the absence of cryoglobulinemia,
      respectively, both 6 months after stopping antiviral therapy and at the end of
      followup. RESULTS: Patients received IFNalpha for a mean +/- SD of 20 +/- 14
      months and ribavirin (at a mean +/- SD dosage of 895 +/- 250 mg/day) for 14 +/-
      12 months. Other treatments included low-dose corticosteroids and plasma
      exchange. After a mean +/- SD followup of 57 +/- 29 months, 25 of 27 patients are
      alive and are being followed up as outpatients. Because of the heterogeneity of
      anti-HCV treatments received, the main results were stratified according to
      patients with 6 months of followup after stopping antiviral treatment (group 1, n
      = 14) and those who were still undergoing antiviral therapy at the time of
      analysis (group 2, n = 13). Nine patients in group 1 had a sustained virologic
      response and were clinical and immunologic complete responders. Four patients in
      group 1 were virologic nonresponders, and 3 of these patients had partial
      clinical and immunologic responses. Overall, 10 patients in group 1 had a
      complete clinical and immunologic response of their vasculitis (all 9 of the
      sustained virologic responders and 1 of the 5 patients who remained viremic). At
      the end of followup, 7 patients in group 2 were negative for HCV RNA; 6 were
      complete clinical responders. Among the other 6 patients in group 2, who had
      persistent viremia, 4 had a partial clinical response. Among the patients in
      group 1, HCV RNA was more often undetectable and genotype 1 was less frequent in
      complete clinical responders compared with partial/nonresponders. Age, sex,
      clinical vasculitic involvement, mean duration or total cumulative dose of
      IFNalpha or ribavirin, and use of steroids or plasmapheresis did not differ
      significantly according to clinical response. CONCLUSION: Treatment with IFNalpha
      and ribavirin can achieve a complete clinical response in most patients with HCV
      related systemic vasculitis. Complete clinical response correlates with the
      eradication of HCV.

PMID- 12483739
TI  - Timing of total joint replacement affects clinical outcomes among patients with
      osteoarthritis of the hip or knee.
AB  - OBJECTIVE: To determine the predictors of outcome in patients with osteoarthritis
      2 years after receiving total hip or knee replacement. METHODS: A prospective
      cohort study of 222 osteoarthritis patients undergoing total hip or knee
      replacement in Boston and Montreal was done. Their postoperative outcomes at 6
      months were previously reported. This followup reports on the outcomes after 2
      years among the 165 patients (74%) who remained. The subjects were divided into 2
      groups according to the median value of their preoperative Western Ontario and
      McMaster Universities Osteoarthritis Index (WOMAC) function score. The Short Form
      36-item physical function subscale and the WOMAC pain and function subscale
      scores were collected at baseline and at 3, 6, and 24 months postoperatively.
      Clinical outcomes were analyzed at 2 years, using descriptive and multiple
      regression analyses. RESULTS: Improvements in pain and function at 2 years were
      similar to those observed at 6 months. Those subjects with the worst function and
      pain at the time of surgery (baseline) had comparatively worse function 2 years
      after surgery. CONCLUSION: In this comparison, the poor outcomes observed at 6
      months following total joint replacement in patients with worse baseline
      functional status persisted after 2 years. Although there are no validated
      indications for when a patient should optimally have total joint replacement,
      these data suggest that timing of surgery may be more important than previously
      realized and, specifically, that performing surgery earlier in the course of
      functional decline may be associated with better outcome.

PMID- 12483740
TI  - The effect of education and income on need and willingness to undergo total joint
      arthroplasty.
AB  - OBJECTIVE: Individuals with lower socioeconomic status (SES) receive less
      arthritis care, including joint arthroplasty. However, no studies have considered
      the expectations or needs of the patients. Our objective was to assess the effect
      of education and income on the potential need for, and the willingness to
      consider hip and knee arthroplasty. METHODS: Through a mail/telephone survey of
      48,218 persons ages 55 years or older residing in 2 areas of Ontario, Canada,
      3,307 individuals with moderate-to-severe hip/knee problems were identified.
      These individuals received a questionnaire to assess education, income, arthritis
      severity, and comorbidity. In a subset of these subjects, we conducted interviews
      to evaluate the willingness to consider arthroplasty, and we also performed
      clinical and radiographic examinations of the joints to validate self-reports of
      arthritis. The potential need for arthroplasty was defined as the presence of
      severe arthritis (as scored by the Western Ontario and McMaster Universities
      Osteoarthritis Index), with no absolute contraindications to surgery. Separate
      logistic regression models examined the independent effects of education and
      income on the potential need for, and definite willingness to consider
      arthroplasty, after controlling for age, sex, and region of residence. Potential
      unmet need was estimated as the proportion of subjects with the need for
      arthroplasty who were not already on a surgery waiting list, who were definitely
      willing to consider arthroplasty, and who had evidence of arthritis by
      examination and radiography. RESULTS: Response rates were at least 72% for all
      questionnaires and interviews. Less education (adjusted odds ratio [OR] 1.57 for
      less than high school versus postsecondary education, 95% confidence interval
      [95% CI] 1.17-2.11) and lower income (adjusted OR 1.83 for </=$20,000 versus
      >$40,000, 95% CI 1.24-2.70) were independently associated with a greater
      likelihood of having the potential need for arthroplasty. Among the subjects with
      potential need, neither education nor income was independently associated with a
      definite willingness to consider arthroplasty. Thus, taking willingness into
      consideration, individuals with less education and/or lower income were more
      likely to have potential unmet need for arthroplasty. CONCLUSION: Persons with
      lower SES had a greater need for, and were equally willing to consider
      arthroplasty, compared with those with higher SES. Thus, observed SES disparities
      in the rates of performed arthroplasties cannot be explained by a lower need or
      less willingness to undergo arthroplasty in those with lower SES.

PMID- 12483741
TI  - De novo CIAS1 mutations, cytokine activation, and evidence for genetic
      heterogeneity in patients with neonatal-onset multisystem inflammatory disease
      (NOMID): a new member of the expanding family of pyrin-associated
      autoinflammatory diseases.
AB  - OBJECTIVE: Neonatal-onset multisystem inflammatory disease (NOMID; also known as
      chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is
      characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss,
      urticarial skin rash, and a characteristic deforming arthropathy. We investigated
      whether patients with this disorder have mutations in CIAS1, the gene which
      causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two
      dominantly inherited disorders with some similarities to NOMID/CINCA syndrome.
      METHODS: Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA
      syndrome and their available parents was screened for CIAS1 mutations by
      automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by
      real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum
      cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein
      expression was assessed by Western blotting of lysates from plastic-adherent
      peripheral blood mononuclear cells. RESULTS: In 6 of the 13 patients, we found 6
      heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel.
      None of these sequence changes was observed in a panel of >900 chromosomes from
      healthy controls. Two distinct nucleotide changes in a single codon in unrelated
      patients resulted in the same amino acid change. In 4 mutation-positive children
      whose parental DNA was available, no mutation was found in the parental DNA,
      supporting the conclusion that the mutations arose de novo. Consistent with the
      recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we
      found evidence of increased IL-1beta, as well as tumor necrosis factor, IL-3, IL
      5, and IL-6, but not transforming growth factor beta, in a mutation-positive
      patient compared with normal controls. CONCLUSION: Our data increase the total
      number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases
      ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to
      NOMID/CINCA syndrome. Mutations in CIAS1 were only found in approximately 50% of
      the cases identified clinically as NOMID/CINCA syndrome, which raises the
      possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1
      receptor blockade may constitute a rational approach to the treatment of
      NOMID/CINCA syndrome.

PMID- 12483742
TI  - Isolation and characterization of bone marrow multipotential mesenchymal
      progenitor cells.
AB  - OBJECTIVE: There is an increased interest in rheumatology in mesenchymal
      progenitor/stem cells (MPCs) and their roles in rheumatic diseases, but little is
      known about the phenotype of these cells in vivo. The aim of this study was to
      isolate and characterize human bone marrow (BM) MPCs. METHODS: Fluorescence
      microscopy was used to identify putative MPCs among adherent BM cells. To purify
      them, a positive selection with antifibroblast microbeads was used, combined with
      fluorescence-activated cell sorting (FACS) for microbead+,CD45(low) cells. A more
      detailed phenotype of these cells was determined using 4-color flow cytometry,
      and standard chondrogenic, osteogenic, and adipogenic assays were used to
      investigate their differentiation potentials. RESULTS: Putative MPCs
      microscopically identified as large, fibroblast-like, D7-FIB+ cells were purified
      using positive selection with D7-FIB-conjugated (antifibroblast) microbeads
      followed by FACS for specifically bound microbead+,CD45(low) cells. These cells
      represented 0.01% of mononuclear cells in the BM. They were uniformly positive
      for CD105, LNGFR, HLA-DR, CD10, CD13, CD90, STRO-1, and bone morphogenetic
      protein receptor type IA (BMPRIA) and were negative for CD14, CD34, CD117, and
      CD133. Only cells with this phenotype could proliferate and produce adherent cell
      monolayers capable of chondrogenic, osteogenic, and adipogenic differentiation.
      D7-FIB- cells in the BM lacked any MPC activity. Uncultured skin fibroblasts had
      a phenotype similar to that of BM MPCs, but were negative for LNGFR, STRO-1, HLA
      DR, and BMPRIA. CONCLUSION: This study shows the distinct phenotype, morphology,
      and method of isolation of BM MPCs. The findings may have implications for
      defining the physiologic roles of MPCs in arthritis, bone diseases, and joint
      regeneration.

PMID- 12483743
TI  - Inhibition of adjuvant-induced arthritis by systemic tissue inhibitor of
      metalloproteinases 4 gene delivery.
AB  - OBJECTIVE: An imbalance in the matrix metalloproteinase:tissue inhibitor of
      metalloproteinases (MMP:TIMP) ratio in favor of MMP appears to be an important
      determinant of tissue damage in arthritis. We undertook this study to explore
      whether reversal of this imbalance in favor of TIMP would alter this process and
      to examine the mechanism of this alteration. METHODS: We administered human TIMP
      4 by electroporation-mediated intramuscular injection of naked DNA using the rat
      adjuvant-induced arthritis (AIA) model. RESULTS: Intramuscular naked TIMP-4 gene
      administration resulted in high circulating TIMP-4 levels and completely
      abolished arthritis development in the rat AIA model. This inhibition was
      associated with significantly decreased MMP activity in the joint tissue as well
      as with significantly decreased serum and tissue tumor necrosis factor alpha
      levels and serum interleukin-1alpha levels compared with animals with arthritis.
      The mutation of cysteine at position 1 of TIMP-4 failed to block the development
      of AIA. CONCLUSION: Our data indicate that TIMP-4 is a potent antiinflammatory
      agent, and that its antiarthritis function may be mediated by MMPs. Arthritis
      inhibiting effects of TIMP-4 may suggest a unique application of this gene
      therapy method for arthritis.

PMID- 12483744
TI  - Peptide-induced suppression of collagen-induced arthritis in HLA-DR1 transgenic
      mice.
AB  - OBJECTIVE: To identify peptides capable of altering the immune response to type
      II collagen (CII) in the context of HLA-DR. METHODS: Immunizing mice transgenic
      for the human HLA-DRB1*0101 immune response gene with CII elicits an arthritis
      (collagen-induced arthritis [CIA]) that resembles rheumatoid arthritis. We have
      previously identified an immunodominant determinant of CII, CII (263-270),
      recognized by T cells in the context of DR1. To produce synthetic peptides with
      the potential of disrupting the DR1-restricted immune response, synthetic analog
      peptides were developed that contain site-directed substitutions in critical
      positions. These peptides were used to treat CIA in DR1 transgenic mice. RESULTS:
      An analog peptide, CII (256-276, N(263), D(266)), that inhibited T cell responses
      in vitro, was identified. When DR1 mice were coimmunized with CII and CII (256
      276, N(263), D(266)), the incidence and severity of arthritis were greatly
      reduced, as was the antibody response to CII. Moreover, CII (256-276, N(263),
      D(266)) was effective in down-regulating the immune responses to CII and
      arthritis, even when administered 2 weeks following immunization with CII. Spleen
      and lymph node cells from CII-immunized mice cultured with CII (256-276, N(263),
      D(266)) in vitro produced increased amounts of interleukin-4 (IL-4) compared with
      cells cultured with the wild-type peptide, CII (256-276). Furthermore, CII (256
      276, N(263), D(266)) was incapable of preventing arthritis in DR1 IL-4(-/-) mice
      (genetically deficient in IL-4). CONCLUSION: These data establish that CII (256
      276, N(263), D(266)) is a potent suppressor of the DR-mediated immune response to
      CII. Its effect is mediated, at least in part, by IL-4. These experiments
      represent the first description of an analog peptide of CII recognized by T cells
      in the context of a human major histocompatibility complex molecule that can
      suppress autoimmune arthritis.

PMID- 12483746
TI  - Investigation of linkage on chromosome 2q and hand and knee osteoarthritis.

PMID- 12483745
TI  - Relief of inflammatory pain in rats by local use of the selective P2X7 ATP
      receptor inhibitor, oxidized ATP.
AB  - OBJECTIVE: Oxidized ATP (oATP) is a selective inhibitor of the P2Z/P2X7 ATP
      receptor for extracellular ATP, which contributes to the antinociceptive effect.
      This study sought to determine the mechanism by which local administration of
      oATP is able to relieve inflammatory pain in arthritic rat paws. METHODS:
      Arthritis was induced in Wistar rats by injections of Freund's complete adjuvant
      into one hind paw. Nociceptive thresholds were measured before and after local
      injection of oATP into the inflamed paws. The influence on pain transmission due
      to the presence of recruited inflammatory cells at the site of inflammation was
      determined by inhibiting the initial phase of their migration (by intravenous
      treatment with fucoidin, which blocks the adhesion molecules of the selectin
      family). ATP intraplantar content was determined in the different experimental
      conditions. Histologic features of the hind paws were evaluated by using the anti
      P2X7 receptor polyclonal antibody. RESULTS: Intraplantar administration of oATP
      into inflamed paws significantly relieved inflammatory pain. The antinociceptive
      effect of oATP was independent of the immune-cell recruitment. ATP levels in
      inflamed tissues were significantly reduced by oATP treatment. A variable
      presence of P2X7 receptors on cutaneous sensory nerves with respect to the
      different treatments was observed. Following oATP treatment, there was a
      reduction in P2X7 expression in the endings of peripheral nerves, as well as in
      endothelial cells. CONCLUSION: Oxidized ATP inhibits inflammatory pain in
      arthritic rats by inhibition of the P2X7 receptor for ATP, which is localized on
      nerve terminals.

PMID- 12483747
TI  - Humanized monoclonal anti-interleukin-6 receptor antibody for treatment of
      intractable adult-onset Still's disease.

PMID- 12483748
TI  - Increased osteoprotegerin and decreased pyridinoline levels in patients with
      ankylosing spondylitis: comment on the article by Gratacos et al.

PMID- 12483749
TI  - The value of rheumatologists to patients with fibromyalgia: comment on the
      presidential address by Weinblatt.

PMID- 12483751
TI  - Increased cutaneous reactions to hydroxychloroquine (Plaquenil) possibly
      associated with formulation change: comment on the letter by Alarcon.

PMID- 12483756
TI  - Safety behind the veil of ignorance.

PMID- 12483753
TI  - Efficacy of tumor necrosis factor alpha blockade for enthesitis in
      spondylarthropathy: comment on the article by Marzo-Ortega et al.

PMID- 12483757
TI  - Estimating the monetary value of health care: lessons from environmental
      economics.
AB  - In the recent past, considerable effort in health economics has been made on
      applying stated preference methods such as contingent valuation and choice
      experiments. Despite this increased use, there is still considerable scepticism
      concerning the value of these approaches. The application of contingent valuation
      in environmental economics has a long history and has been widely accepted.
      Whilst choice experiments were introduced to the environmental and health
      economics literature at a similar time, the wider acceptance of monetary measures
      of benefit in environmental economics has meant that they have also been more
      widely applied. The purpose of this paper is to identify some of the key issues
      and debates that have taken place in the environmental economics literature,
      summarise the state of the art with respect to these issues, and consider how
      health economists have addressed these issues. Important areas for future
      research in health economics are identified.

PMID- 12483758
TI  - A utility-theoretic model for QALYs and willingness to pay.
AB  - Despite the widespread use of quality-adjusted life years (QALY) in economic
      evaluation studies, their utility-theoretic foundation remains unclear. A model
      for preferences over health, money, and time is presented in this paper. Under
      the usual assumptions of the original QALY-model, an additive separable
      presentation of the utilities in different periods exists. In contrast to the
      usual assumption that QALY-weights do solely depend on aspects of health-related
      quality of life, wealth-standardized QALY-weights might vary with the wealth
      level in the presented extension of the original QALY-model resulting in an
      inconsistent measurement of QALYs. Further assumptions are presented to make the
      measurement of QALYs consistent with lifetime preferences over health and money.
      Even under these strict assumptions, QALYs and WTP (which also can be defined in
      this utility-theoretic model) are not equivalent preference-based measures of the
      effects of health technologies on an individual level. The results suggest that
      the individual WTP per QALY can depend on the magnitude of the QALY-gain as well
      as on the disease burden, when health influences the marginal utility of wealth.
      Further research seems to be indicated on this structural aspect of preferences
      over health and wealth and to quantify its impact.

PMID- 12483759
TI  - Assessing and comparing costs: how robust are the bootstrap and methods based on
      asymptotic normality?
AB  - This article addresses and challenges some common perceptions in the statistical
      assessment of costs and cost-effectiveness in health economics. Cost data
      typically exhibit highly skew distributions. Two techniques whose validity does
      not depend on any specific form of underlying distribution are the bootstrap and
      methods based on asymptotic normality of sample means. These methods are
      generally thought to be appropriate for the analysis of cost data. We argue that,
      even when these methods are technically valid, they may often lead to inefficient
      and even misleading inferences. It is important to apply methods that recognise
      the skewness in cost data. We further demonstrate that it may also be important
      to incorporate relevant prior information in a Bayesian analysis.

PMID- 12483760
TI  - Eliciting several willingness to pay in a single contingent valuation survey:
      application to health care.
AB  - The usual implementation of contingent valuation (CV), in the context of
      priorities setting for allocation of public funds in health care, is to develop
      as many surveys as there are programmes, i.e. to perform separate evaluations
      (SE). In the EuroWill project, three health programmes (for heart disease, breast
      cancer and a service of helicopter ambulance) were however simultaneously
      evaluated, i.e. a joint evaluation (JE) was performed. The paper examines the
      issue of the econometric techniques that should be used to estimate WTP values
      obtained in the context of JE by comparing the application of independent OLS
      regressions for each programme versus simultaneous estimations using seemingly
      unrelated regressions (SUR) on data of the French EuroWill survey. It shows that
      separate estimations may lead to misspecifications because they cannot take into
      account that JE exogenously provides a reference structure to the respondent
      which affects the estimates of WTP for each programme. Therefore, the potential
      advantage of JE versus SE as an elicitation technique in CV studies applied to
      health care (to better control the referents used by respondents for evaluating
      different programmes) only holds if simultaneous rather than independent
      techniques are used in the estimation of WTPs.

PMID- 12483761
TI  - Comment on Amartya Sen's 'why health equity'.

PMID- 12483762
TI  - How important are economic factors in choice of medical specialty?
AB  - An ongoing debate exists among health care researchers about the mechanism that
      allocates physicians across medical specialties, and appropriate policy measures
      to correct imbalances that may arise from time to time. Most researchers believe
      that choice of residency program by medical school graduates is key to
      understanding how physicians are distributed across specialties, but there is
      much disagreement about whether economic or non-economic factors are most
      influential in determining this choice. We undertake an empirical investigation
      of two potentially important economic factors: income and leisure. To do so, we
      specify a two way error component regression model to estimate the effects of
      expected earnings and available leisure time, and uncertainty of earnings and
      leisure, on specialty choices of medical residents. Our findings indicate that
      economic factors are an important influence in the specialty choice process; in
      particular, medical residents are attracted to specialties that offer the
      prospect of longer and more certain annual vacations, higher earnings, shorter
      residency programs, and more certain work schedules. Our results suggest that
      employment contracts that provide generous annual vacation time and promise
      regular weekly work schedules may be more effective than increased earnings in
      correcting the current perceived shortage of primary care physicians.

PMID- 12483764
TI  - Proceedings of the 22nd Annual Meeting of the International Society for Clinical
      Biostatistics (ISCB22). Stockholm, Sweden. August 19-23, 2001.

PMID- 12483765
TI  - A comparison of confidence interval methods for the intraclass correlation
      coefficient in cluster randomized trials.
AB  - This study compared different methods for assigning confidence intervals to the
      analysis of variance estimator of the intraclass correlation coefficient (rho).
      The context of the comparison was the use of rho to estimate the variance
      inflation factor when planning cluster randomized trials. The methods were
      compared using Monte Carlo simulations of unbalanced clustered data and data from
      a cluster randomized trial of an intervention to improve the management of asthma
      in a general practice setting. The coverage and precision of the intervals were
      compared for data with different numbers of clusters, mean numbers of subjects
      per cluster and underlying values of rho. The performance of the methods was also
      compared for data with Normal and non-Normally distributed cluster specific
      effects. Results of the simulations showed that methods based upon the variance
      ratio statistic provided greater coverage levels than those based upon large
      sample approximations to the standard error of rho. Searle's method provided
      close to nominal coverage for data with Normally distributed random effects.
      Adjusted versions of Searle's method to allow for lack of balance in the data
      generally did not improve upon it either in terms of coverage or precision.
      Analyses of the trial data, however, showed that limits provided by Thomas and
      Hultquist's method may differ from those of the other variance ratio statistic
      methods when the arithmetic mean differs markedly from the harmonic mean cluster
      size. The simulation results demonstrated that marked non-Normality in the
      cluster level random effects compromised the performance of all methods.
      Confidence intervals for the methods were generally wide relative to the
      underlying size of rho suggesting that there may be great uncertainty associated
      with sample size calculations for cluster trials where large clusters are
      randomized. Data from cluster based studies with sample sizes much larger than
      those typical of cluster randomized trials are required to estimate rho with a
      reasonable degree of precision.

PMID- 12483766
TI  - Modelling tooth emergence data based on multivariate interval-censored data.
AB  - Studies on emergence of (permanent) teeth are published regularly in the dental
      literature. Besides descriptive statistics (mean or median values) on emergence
      times, comparisons between boys and girls are of interest. Gender comparisons are
      intersubject analyses, but also intrasubject questions, like 'Is there a left
      right symmetry with respect to the mean (median) emergence times?' are of
      interest. Studies on emergence times most often are faced with interval-censored
      data. We will extend a GEE-type test proposed by Huster et al. for bivariate
      right-censored data to the multivariate setting with interval-censored data.
      Central to our paper is to provide appropriate statistical models to resolve some
      dental questions on emergence. The analyses are based on data from the
      longitudinal Signal-Tandmobiel study.

PMID- 12483767
TI  - Global goodness-of-fit tests in logistic regression with sparse data.
AB  - The logistic regression model has become the standard analysing tool for binary
      responses in medical statistics. Methods for assessing goodness-of-fit, however,
      are less developed where this problem is especially pronounced in performing
      global goodness-of-fit tests with sparse data, that is, if the data contain only
      a small numbers of observations for each pattern of covariate values. In this
      situation it has been known for a long time that the standard goodness-of-fit
      tests (residual deviance and Pearson chi-square) behave unsatisfactorily if p
      values are calculated from the chi(2)-distribution. As a remedy in this situation
      the Hosmer-Lemeshow test is frequently recommended; it relies on a new grouping
      of the observations to avoid sparseness, where this grouping depends on the
      estimated probabilities from the model. It has been shown, however, that the
      Hosmer-Lemeshow test also has some deficiencies, for example, it depends heavily
      on the calculating algorithm and thus different implementations might lead to
      different conclusions regarding the fit of the model. We present some alternative
      tests from the statistical literature which should also perform well with sparse
      data. Results from a simulation study are given which show that there exist some
      goodness-of-fit tests (for example, the Farrington test) that have good
      properties regarding size and power and that even outperform the Hosmer-Lemeshow
      test. We illustrate the various tests with an example from dermatology on
      occupational hand eczema in hairdressers.

PMID- 12483768
TI  - Simplifying a prognostic model: a simulation study based on clinical data.
AB  - Prognostic models are designed to predict a clinical outcome in individuals or
      groups of individuals with a particular disease or condition. To avoid bias many
      researchers advocate the use of full models developed by prespecifying
      predictors. Variable selection is not employed and the resulting models may be
      large and complicated. In practice more parsimonious models that retain most of
      the prognostic information may be preferred. We investigate the effect on various
      performance measures, including mean square error and prognostic classification,
      of three methods for estimating full models (including penalized estimation and
      Tibshirani's lasso) and consider two methods (backwards elimination and a new
      proposal called stepdown) for simplifying full models. Simulation studies based
      on two medical data sets suggest that simplified models can be found that perform
      nearly as well as, or sometimes even better than, full models. Optimizing the
      Akaike information criterion appears to be appropriate for choosing the degree of
      simplification.

PMID- 12483769
TI  - A graphical sensitivity analysis for clinical trials with non-ignorable missing
      binary outcome.
AB  - Many clinical trials are analysed using an intention-to-treat (ITT) approach. A
      full application of the ITT approach is only possible when complete outcome data
      are available for all randomized subjects. In a recent survey of clinical trial
      reports including an ITT analysis, complete case analysis (excluding all patients
      with a missing response) was common. This does not comply with the basic
      principles of ITT since not all randomized subjects are included in the analysis.
      Analyses of data with missing values are based on untestable assumptions, and so
      sensitivity analysis presenting a range of estimates under alternative
      assumptions about the missing-data mechanism is recommended. For binary outcome,
      extreme case analysis has been suggested as a simple form of sensitivity
      analysis, but this is rarely conclusive. A graphical sensitivity analysis is
      proposed which displays the results of all possible allocations of cases with
      missing binary outcome. Extension to allow binomial variation in outcome is also
      considered. The display is based on easily interpretable parameters and allows
      informal examination of the effects of varying prior beliefs.

PMID- 12483770
TI  - Comparison of tests for categorical data from a stratified cluster randomized
      trial.
AB  - Two features commonly exhibited by randomized trials of health promotion
      interventions are cluster randomization and stratification. Ignoring correlations
      between individuals within clusters can lead to an inflated type I error rate and
      hence a P-value which overstates the significance of the result. This paper
      compares several methods for analysing categorical data from a stratified cluster
      randomized trial. We propose an extension of a method from survey sampling that
      uses the design effect to reduce the effective sample size. We compare this with
      three methods from Zhang and Boos that extend the standard Cochran-Mantel
      Haenszel (CMH) statistic by using appropriate covariance matrices, and with a
      bootstrap method. The comparison is based on empirical type I error rates from a
      simulation study, in which the number of clusters randomized is small, as in most
      public health intervention studies. The method that performs consistently well is
      one of the Zhang and Boos extensions of the standard CMH statistic.

PMID- 12483771
TI  - A weighted Kaplan-Meier estimator for matched data with application to the
      comparison of chemotherapy and bone-marrow transplant in leukaemia.
AB  - Studies on the comparison of transplantation with respect to standard therapy
      present a number of statistical challenges: they are usually not randomized,
      often retrospective (based on registry data) and the treatment assignment is time
      dependent (waiting time to transplant). Matching on known prognostic factors and
      waiting time to transplant can be used to select appropriate samples for the
      analysis. When a variable number of patients treated with conventional therapy
      matches each transplanted patient, the standard estimating and testing procedures
      need to be modified in order to account for the fact that matched data are highly
      stratified, with strata containing a few, possibly censored, observations. A
      weighted version of the Kaplan-Meier estimator, which accounts for a variable
      proportion of matching, is proposed and its statistical properties are studied.
      The problem of the comparison of the survival experience in the two treatment
      groups is also considered. Two tests, based on the distance between the survival
      estimates calculated at a prefixed time point, are examined and their behaviour
      is evaluated through simulations. The procedures proposed here are applied to
      data collected from an Italian study whose aim was the evaluation of bone marrow
      transplant, as compared to intensive chemotherapy, in the cure of paediatric
      acute lymphoblastic leukaemia.

PMID- 12483772
TI  - Multicollinearity in prognostic factor analyses using the EORTC QLQ-C30:
      identification and impact on model selection.
AB  - Clinical and quality of life (QL) variables from an EORTC clinical trial of first
      line chemotherapy in advanced breast cancer were used in a prognostic factor
      analysis of survival and response to chemotherapy. For response, different final
      multivariate models were obtained from forward and backward selection methods,
      suggesting a disconcerting instability. Quality of life was measured using the
      EORTC QLQ-C30 questionnaire completed by patients. Subscales on the questionnaire
      are known to be highly correlated, and therefore it was hypothesized that
      multicollinearity contributed to model instability. A correlation matrix
      indicated that global QL was highly correlated with 7 out of 11 variables. In a
      first attempt to explore multicollinearity, we used global QL as dependent
      variable in a regression model with other QL subscales as predictors. Afterwards,
      standard diagnostic tests for multicollinearity were performed. An exploratory
      principal components analysis and factor analysis of the QL subscales identified
      at most three important components and indicated that inclusion of global QL made
      minimal difference to the loadings on each component, suggesting that it is
      redundant in the model. In a second approach, we advocate a bootstrap technique
      to assess the stability of the models. Based on these analyses and since global
      QL exacerbates problems of multicollinearity, we therefore recommend that global
      QL be excluded from prognostic factor analyses using the QLQ-C30. The prognostic
      factor analysis was rerun without global QL in the model, and selected the same
      significant prognostic factors as before.

PMID- 12483773
TI  - Use of the mean, hot deck and multiple imputation techniques to predict outcome
      in intensive care unit patients in Colombia.
AB  - A cohort of intensive care unit (ICU) patients in 20 Colombian ICUs is used to
      describe the application of three imputation techniques: single, hot deck and
      multiple imputation. These strategies were used to impute the missing data in the
      variables used to construct APACHE II scores, a scoring system for the ICU
      patients that provides an unbiased standardized estimate of the probability of
      hospital death. Imputed APACHE II scores were then used in the APACHE II model to
      estimate adjusted hospital mortality rates. The area under the receiver operating
      characteristic (ROC) curve was used to compare imputation strategies with respect
      to predictive power. While statistically significant differences were found for
      the area under the ROC curve, these differences were not clinically significant.

PMID- 12483774
TI  - Predicting time to prostate cancer recurrence based on joint models for non
      linear longitudinal biomarkers and event time outcomes.
AB  - Biological markers that are both sensitive and specific for tumour regrowth or
      metastasis are increasingly becoming available and routinely monitored during the
      regular follow-up of patients treated for cancer. Obtained by a simple blood
      test, these markers provide an inexpensive non-invasive means for the early
      detection of recurrence (or progression). Currently, the longitudinal behaviour
      of the marker is viewed as an indicator of early disease progression, and is
      applied by a physician in making clinical decisions. One marker that has been
      studied for use in both population screening for early disease and for detection
      of recurrence in prostate cancer patients is PSA. The elevation of PSA levels is
      known to precede clinically detectable recurrence by 2 to 5 years, and current
      clinical practice often relies partially on multiple recent rises in PSA to
      trigger a change in treatment. However, the longitudinal trajectory for
      individual markers is often non-linear; in many cases there is a decline
      immediately following radiation therapy or surgery, a plateau during remission,
      followed by an exponential rise following the recurrence of the cancer. The aim
      of this article is to determine the multiple aspects of the longitudinal PSA
      biomarker trajectory that can be most sensitive for predicting time to clinical
      recurrence. Joint Bayesian models for the longitudinal measures and event times
      are utilized based on non-linear hierarchical models, implied by unknown change
      points, for the longitudinal trajectories, and a Cox proportional hazard model
      for progression times, with functionals of the longitudinal parameters as
      covariates in the Cox model. Using Markov chain Monte Carlo sampling schemes, the
      joint model is fit to longitudinal PSA measures from 676 patients treated at
      Massachusetts General Hospital between the years 1988 and 1995 with follow-up to
      1999. Based on these data, predictive schemes for detecting cancer recurrence in
      new patients based on their longitudinal trajectory are derived.

PMID- 12483775
TI  - Cosmetic dentistry.

PMID- 12483776
TI  - Esthetics in dentistry.

PMID- 12483777
TI  - Esthetic composite resin applications.

PMID- 12483778
TI  - Treatment planning and preparation for porcelain veneers.

PMID- 12483779
TI  - Partial to full coverage coronal restorations.

PMID- 12483780
TI  - Successful implants in the esthetic zone.

PMID- 12483781
TI  - The roke of periodontal plastic surgery in esthetic dentistry.

PMID- 12483782
TI  - Optimal dental and facial esthetics in orthodontics--a multifaceted challenge.
AB  - The role of the orthodontist in resolving the patient's dental and facial
      esthetic concerns is a challenge due to the number of factors to be evaluated.
      The effect of growth and aging, and the existing dental, gingival, dentoalveolar,
      skeletal, and facial soft tissue components mandate a thorough investigation into
      all treatment options and modalities available to reach optimal esthetic goals.
      The orthodontist is further challenged with professional bias and patient bias
      and desires. Mounted study models, facial and intraoral photographs,
      cephalometric evaluation of dentoskeletal relationships, VTOs and STOs for trial
      treatment, computerized imaging, and clinical soft tissue evaluation are
      essential in proper diagnosis, treatment planning, execution of treatment, and
      assessment of post treatment results. With proper planning, the challenge of
      reaching dental and facial esthetic goals can be met without compromising the
      functional occlusal goals, periodontal health, TMJ health, and long term
      stability.

PMID- 12483783
TI  - Identifying the functional and esthetic factors associated with dentofacial
      deformities.

PMID- 12483784
TI  - Oral and maxillofacial pathology case of the month. Hairy leukplakia.

PMID- 12483785
TI  - Pregnancy, X-rays and risks--the radiology dilemma. Response to ethical dilemma
      #41.

PMID- 12483786
TI  - Face to face: a conversation with the Chief Dental Officer for England. Interview
      by Ted Renson.

PMID- 12483787
TI  - Oral cancer: prevention and detection in primary dental healthcare.
AB  - The incidence of oral cancer is rising in the UK. Mortality from the disease
      remains high and survival has not improved significantly in the last 30 years.
      The primary dental health team has an integral role in the delivery of oral
      health promotion and prevention advice and in the early detection of oral
      malignancy and potentially malignant lesions. Both prevention and early detection
      within the general dental practice setting have a potential impact on overall
      incidence, morbidity and mortality from oral cancer. This paper details the
      primary dental healthcare team's roles in delivering smoking cessation and
      alcohol reduction counselling, in the early detection by oral examination, and in
      the process of prompt referral.

PMID- 12483788
TI  - Oral health and heart disease.
AB  - Over the past ten years, a body of evidence has accumulated to suggest that
      aspects of oral health, particularly the extent and severity of periodontal
      disease, may be associated with an increased risk of coronary heart disease
      (CHD). This evidence should be seen against the background of a more general
      interest in the role of chronic infections in vascular disease. There have, for
      example, been suggestions of associations between CHD and a range of bacterial
      and viral agents, including H. pylori, C. pneumoniae, and cytomegalovirus, which
      are involved in persistent infections at various sites around the body. Reviews
      of the evidence for the causality of these relationships between CHD and specific
      organisms have been inconclusive. By comparison, periodontal disease is related
      to a wide and complex range of organisms rather than a single species and
      although the nature of the relationship is still inconclusive, the evidence for
      its validity still persists to some degree. A brief synopsis of the
      epidemiological studies to date and their outcomes is shown in Table 1.

PMID- 12483789
TI  - Direct restorative material use of selected practitioners in the United Kingdom.
AB  - PURPOSE OF THE INVESTIGATION: To investigate, by questionnaire, the direct
      restorative materials used by a sample of practitioners from the United Kingdom.
      BASIC PROCEDURES: A postal questionnaire was distributed to a group of self
      selected practitioners, who volunteered to participate in the study. In all 110
      practitioners participated in the study. MAIN FINDINGS: The most used material
      for the restoration of occlusal (Class I) and approximal (Class II) lesions was
      amalgam with 61% and 73% of practitioners indicating that they used amalgam in
      this situation. Adhesive tooth-coloured materials, specifically composites and
      compomers, were preferred by the majority of practitioners for anterior
      approximal (Class III) and incisal (Class IV) restorations with compomer
      preferred for Class V restorations including non-carious cervical lesions and for
      the restoration of primary teeth. PRINCIPAL CONCLUSIONS: It is concluded that the
      general practitioners surveyed in this study tend to use amalgam for the
      restoration of Class I and II lesions as opposed to resin composite. The majority
      of practitioners in this study used compomers, a relatively new group of
      restorative materials, with little evidence of traditional glass-ionomer cements
      being used routinely.

PMID- 12483790
TI  - Resin-retained bridges re-visited. Part 2. Clinical considerations.
AB  - Resin-retained bridges have been used clinically since the 1970s, and offer a
      more conservative approach to the restoration of edentulous spaces than
      conventional bridgework. They are easy to place, cheap to fabricate and have been
      shown to be cost-effective. Despite this, they are not frequently used in general
      dental practice and they have an undeserved reputation for failure. Since their
      initial introduction, they have undergone a number of changes to their method of
      retention, and the materials used in their construction. This has resulted in a
      predictable, aesthetic restoration which, barring the use of implants, is often
      the treatment of choice where teeth adjacent to an edentulous space are minimally
      or not restored. This article hopes to show the clinical techniques required to
      produce predictable resin-retained bridgework in general practice.

PMID- 12483791
TI  - Availability of domiciliary dental care for the elderly.
AB  - PURPOSES OF THE INVESTIGATION: To find out if local nursing/residential home
      managers are experiencing any problems in obtaining domiciliary dental care for
      residents. To assess the availability of local GDS and CDS dentists for
      domiciliary dental care for the elderly and the range of treatments offered.
      BASIC PROCEDURES: Self-completing postal questionnaires distributed to 148
      dentists and 80 nursing/residential home nurse managers. MAIN FINDINGS: 71% of
      responding dentists undertook domiciliary visits but 43% of these were not
      accepting any new NHS domiciliary patients. Only 21% of those willing to visit
      would undertake any conservative treatment. Seventy per cent of nurse managers
      reported few problems in finding a NHS dentist, but the remaining 30% had found
      it difficult or impossible. Eighty-five per cent would find written guidelines
      helpful. PRINCIPAL CONCLUSIONS: The number of elderly patients keeping natural
      teeth is steadily increasing. The rate of dental caries in institutionalised
      patients is significantly higher than those living in their own homes. The number
      of dentists in the area of this study who are accepting new domiciliary patients
      is rapidly decreasing and only one in five will provide conservative treatment.
      This is a deteriorating situation, which merits further investigation on a
      national scale and subsequent planning to address it.

PMID- 12483792
TI  - The working patterns and retirement plans of general dental practitioners in a
      Midlands Health Authority.
AB  - INTRODUCTION: With the problems of access to NHS primary dental care services in
      the last few years attention has focused on manpower considerations for
      dentistry. MATERIALS AND METHOD: This paper presents the results of a simple
      survey of general dental practitioners in South Staffordshire. RESULTS: The
      response rate was 88%. Most dentists (76%) reported working over 30 hours a week.
      A small number reported working more than 50 hours a week. Woman dentists were
      more likely to report working fewer than 31 hours a week. Younger male dentists
      tended to work longer hours than older male dentists, whereas younger women
      dentists tended to work fewer hours than older women. The reported retirement
      plans suggested that around 16% of dentists in their 40s and 50s were planning to
      retire before 60. CONCLUSION: The findings add weight to the view that woman
      dentists tend to work fewer hours but studies of cohorts are required to examine
      the impact of premature retirement and the reasons behind this apparent gender
      difference.

PMID- 12483793
TI  - Study shows chewing sugarfree gum after meals and snacks helps reduce tooth decay
      by up to 40 per cent.

PMID- 12483794
TI  - Tooth erosion in Ireland.

PMID- 12483795
TI  - Listerine launch dual action defence for teeth and gums.

PMID- 12483796
TI  - Assessment of mercury exposure and malaria in a Brazilian Amazon riverine
      community.
AB  - Small-scale gold mining in the Brazilian Amazon occurs in areas with high rates
      of malaria transmission. Amazonian populations can be exposed to mercury through
      direct contact with the mining process and/or through fish consumption. Because
      of data from experimental studies, we examined the potential for mercury to
      affect host response to malaria. A cross-sectional survey was done in
      Jacareacanga, a riverine community in Para state, in a region of intense alluvial
      gold mining. A sample of 205 persons was selected by cluster sampling from the
      total population of approximately 2000. A brief medical history and exam were
      conducted, malaria slides were obtained, and hair samples were taken to measure
      mercury levels. The average hair mercury level was 8.6 micrograms/g, ranging from
      0.3 to 83.2 micrograms/g. The most important predictors of elevated mercury
      levels were high fish consumption and low income. Although there was no prevalent
      malaria, the odds of reporting a past malaria infection was four times higher for
      those also reporting a history of working with mercury.

PMID- 12483797
TI  - Impact of water supply and sanitation on diarrheal morbidity among young children
      in the socioeconomic and cultural context of Rwanda (Africa).
AB  - This project studied the frequency and intensity of water contamination at the
      source, during transportation, and at home to determine the causes of
      contamination and its impact on the health of children aged 0 to 5 years. The
      methods used were construction of the infrastructure for three sources of potable
      water, administration of a questionnaire about socioeconomic status and
      sanitation behavior, anthropometric measurement of children, and analysis of
      water and feces. The contamination, first thought to be only a function of
      rainfall, turned out to be a very complex phenomenon. Water in homes was
      contaminated (43.4%) with more than 1100 total coliforms/100 ml due to the use of
      unclean utensils to transport and store water. This socioeconomic and cultural
      problem should be addressed with health education about sanitation. The latrines
      (found in 43.8% of families) presented a double-edged problem. The extremely high
      population density reduced the surface area of land per family, which resulted in
      a severe nutritional deficit (15% of the children) affecting mainly young
      children, rendering them more susceptible to diarrhea (three
      episodes/child/year).

PMID- 12483798
TI  - Pesticide illness, farm practices, and neurological symptoms among farm residents
      in Colorado.
AB  - The purpose of this study is to evaluate the association between pesticides and
      neurological symptoms among a population exposed to organophosphate chemicals as
      a result of agricultural use. Chronic sequelae of acute pesticide poisoning from
      organophosphate compounds include a variety of neurological symptoms including
      restlessness, irritability, and trouble sleeping. Individuals who have had an
      acute pesticide poisoning have been reported to suffer a wide range of
      neurological symptoms that occur from weeks to months after the initial episode.
      Data for this study came from a cross-sectional survey of farmers and their
      spouses conducted in an eight-county area in north-eastern Colorado. Neurological
      characteristics were assessed to determine their relationship with previously
      reported pesticide-related illnesses. Symptoms that were significantly associated
      with a previous poisoning were difficulty concentrating [OR 2.07, 95% confidence
      interval (CI) 1.22, 3.50]; relatives noticing person had trouble remembering
      things (OR 2.54, 95% CI 1.47, 4.39); making notes to remember things (OR 2.18,
      95% CI 1.20, 3.97); finding it hard to understand the meaning of newspapers,
      magazines, and books (OR 1.90, 95% CI 1.01, 3.60); felt irritable (OR 1.84, 95%
      CI 1.08, 3.12); felt depressed (OR 2.82, 95% CI 1.65, 4.81); had heart
      palpitations without exertion (OR 2.83, 95% CI 1.22, 6.54); sleeping more than
      usual (OR 3.58, 95% CI 1.95, 6.58); difficulty moving fingers or grasping things
      (OR 2.08, 95% CI 1.06, 3.24); and headaches at least once a week (OR 1.85, 95% CI
      1.06, 3.24). Stepwise regression was used to identify the best explanatory model
      of pesticide-related illness. Variables that were associated with increased odds
      of illness were being male, being depressed, sleeping too much, and using crop
      organophosphates.

PMID- 12483799
TI  - Mercury exposure in Munduruku Indians from the community of Sai Cinza, State of
      Para, Brazil.
AB  - The objective of this cross-sectional study was to evaluate mercury exposure and
      health status among Munduruku Indians from the community of Sai Cinza, State of
      Para, Brazil. The population studied included 330 indians, who submitted to a
      questionnaire, clinical exams, and collection of hair, blood, urine, and feces.
      Mercury was measured in hair and fish. Although no person was found to have overt
      mercury intoxication, the mean levels of mercury in hair were elevated (14.45
      micrograms/g for children from 7 to 12 years old, 15.70 micrograms/g for women
      between 14 and 44 years old, and 14.1 micrograms/g for the remaining population).
      Mercury levels in fish were below levels recommended by the World Health
      Organization, but rates of fish consumption were high. These results place this
      indigenous populations as a group under risk of mercury toxicity from the gold
      production.

PMID- 12483800
TI  - Reference intervals of cadmium, lead, and mercury in blood, urine, hair, and
      nails among residents in Mansoura city, Nile delta, Egypt.
AB  - A random sample of 68 males and 25 females who reside in Mansoura city, Egypt,
      was examined for concentrations of cadmium, lead, and mercury in blood, urine,
      hair, and nails. The effect of gender and smoking on such levels was studied. The
      influence of dental amalgam on the levels of mercury in these biological samples
      was also examined. The results obtained show that only blood lead, which
      increased among males, was affected by gender. Blood levels of cadmium and lead
      as well as hair lead appeared to increase with smoking habit. Mercury levels in
      blood and urine were related to the presence of dental amalgam fillings.
      International comparisons between our results and the corresponding levels in
      other localities in the world showed that there were environmentally related
      variations in terms of cadmium levels in hair, lead levels in blood, urine, hair,
      and nails, and mercury levels in blood, hair, and nails. In conclusion, reference
      intervals of cadmium, lead, and mercury in the biological samples are
      environmentally related parameters. Some factors, such as gender, smoking habit,
      and the presence of dental amalgam fillings, may affect such levels and therefore
      should be considered.

PMID- 12483801
TI  - Modeling annual benzene, toluene, NO2, and soot concentrations on the basis of
      road traffic characteristics.
AB  - The investigation of potential adverse health effects of urban traffic-related
      air pollution is hampered by difficulties encountered with exposure assessment.
      Usually public measuring sites are few and thereby do not adequately describe
      spatial variation of pollutant levels over an urban area. In turn, individual
      monitoring of pollution exposure among study subjects is laborious and expensive.
      We therefore investigated whether traffic characteristics can be used to
      adequately predict benzene, NO2, and soot concentrations at individual addresses
      of study subjects in the city area of Munich, Germany. For all road segments with
      expected traffic volumes of at least 4000 vehicles a day (n = 1840), all vehicles
      were counted manually for a single weekday in 1995. The proportion of vehicles in
      "stop-go" mode, an estimate of traffic jam, was determined. Furthermore, annual
      concentrations of benzene, NO2, and soot from 18 high-concentration sites (means:
      8.7, 65.8, and 12.9 micrograms/m3, respectively) and from 16 school sites with
      moderate concentrations (means: 2.6, 32.2, and 5.7 micrograms/m3, respectively)
      were measured from 1996 to 1998. Statistical analysis of the data was performed
      using components of two different statistical models recently used to predict air
      pollution levels in comparable settings. Two traffic characteristics, traffic
      volume and traffic jam percentage, adequately described air pollutant
      concentrations (R2: 0.76-0.80, P < 0.0001). This study shows that air pollutant
      concentrations can be accurately predicted by two traffic characteristics and
      that these models compare favorably with other more complex models in the
      literature.

PMID- 12483802
TI  - Variation of serum and urine cotinine in passive and active smokers and
      applicability in preconceptional smoking cessation counseling.
AB  - This study assessed the applicability of serum and urine cotinine as a
      biochemical marker of self-reported smoking habits for use in a preconceptional
      smoking cessation program. The variation of serum and urine cotinine over the
      course of the day was investigated in a sample of 21 smokers and 8 passive
      smokers who reported their smoking habits and exposure to smoke daily in a
      questionnaire for 10 consecutive days. Blood and urine samples were collected on
      two sampling days, 1 week apart. Both serum and urine cotinine assay could
      distinguish between passive and active smokers, but not between higher categories
      of smokers (10-19 and > or = 20 cigarettes per day) due to significant
      intersubject overlap. In serum, no significant differences were found between
      morning and afternoon cotinine concentrations on either day, in contrast to urine
      cotinine (with lower excretions observed in the morning). An overall coefficient
      of variation of 22% was observed for both specimens in smokers. Because serum
      cotinine is subject to lower variability over the course of the day, it is more
      practical for use in a clinical setting where appointments are scheduled
      throughout the day in order to confirm smoking status.

PMID- 12483803
TI  - Consumption patterns and why people fish.
AB  - Recreational and subsistence fishing play major roles in the lives of many
      people, although their importance in urban areas is often underestimated. There
      are fish and shellfish consumption advisories in the New York-New Jersey harbor
      estuary, particularly in the waters of the Newark Bay Complex. This paper
      examines fishing behavior, consumption patterns, and the reasons that people fish
      in the Newark Bay Complex. I test the null hypotheses that there are no
      differences among Asians, Blacks, Hispanics, and Whites in consumption patterns
      for fish and crabs and in the reasons that they fish or crab. Most people either
      fished or crabbed, but not both. People who fish and crab ate more grams of crab
      than fish in a given meal; people who crab only consumed more grams of crab at a
      meal than those who fish only consumed of fish. Although 30% or more of the
      people who fished and crabbed in the Newark Bay Complex did not eat their self
      caught fish or crabs 8-25% of the people ate more than 1500 g/month. Some people
      angling in the Newark Bay Complex are eating crabs at a rate well over 1500
      g/month, and about 70% are eating crabs even though there is a total ban on both
      harvest and consumption because of the health risks from dioxin. Consumption
      patterns were negatively correlated with mean income and positively correlated
      with mean age. Most people rated relaxation and being outdoors the highest
      reasons for angling, although on an open-ended question they usually listed
      recreation. There were no ethnic differences in reasons for angling, although
      other studies have shown ethnic differences in consumption. Obtaining fish or
      crabs to eat, give away, trade, or sell were rated low, suggesting that
      consumption advisories fail partly because people are not primarily fishing for
      food.

PMID- 12483805
TI  - Zebra mussels (Dreissena polymorpha) as indicators of freshwater contamination
      with lindane.
AB  - Zebra mussels are common freshwater mollusks in many European lakes and rivers.
      Their abundance, wide distribution, and filtering activity make them good
      candidates to evaluate the contamination of freshwaters with environmental
      contaminants. The purpose of this work was to determine the kinetics of lindane
      in zebra mussels and compare laboratory results with in situ measurements.
      Exposure was conducted in small tanks, under controlled experimental conditions.
      Our results indicated that mussels accumulated lindane with a bioconcentration
      factor around 10. They generally reached equilibrium within 4 days. Elimination
      was rapid but biphasic and the terminal elimination half-life was long (> 168 h).
      Age of the mussels and temperature also affected the kinetics of lindane in
      mussels. In the Lake of Geneva, zebra mussels were sampled and showed that
      mussels accumulated it to significant values (up to 900 ng/g fresh weight)
      depending on the site and period of sampling. The in situ results, together with
      the laboratory exposures, showed that freshwater mussels could be used to monitor
      point sources of pollutants such as lindane over short periods of time (< 1
      week).

PMID- 12483804
TI  - Disruption of male reproductive behavior in threespine stickleback Gasterosteus
      aculeatus exposed to 17 beta-estradiol.
AB  - In past years we have witnessed decreased reproductive capacity in many wildlife
      species due to exposure to chemicals with endocrine-disrupting properties. In
      this laboratory experiment male threespine sticklebacks Gasterosteus aculeatus
      exposed to 17 beta-estradiol (2.0 micrograms/g) dispersed in peanut oil, on days
      1, 7, 14, and 21, showed impaired paternal care compared to control fish that
      were exposed to peanut oil only. There were no differences between the two groups
      in number of males that built nests or in courtship displays. However, exposed
      males started nest building significantly later than control males. This study
      suggests that some but not all essential traits of male reproductive behavior may
      be altered as a result of exposure to 17 beta-estradiol. To reveal harmful
      effects of chemicals with suggested reproductive-disrupting properties it is thus
      important to take a wide variety of variables related to reproductive behavior
      into consideration.

PMID- 12483806
TI  - Carboxymethylcellulose improves the antimutagenic activity of sodium selenite
      against maleic hydrazide in Vicia faba seedlings.
AB  - In this study the genotoxic effects induced by a treatment with different doses
      of sodium selenite in Vicia faba seedlings were evaluated with or without the
      addition of carboxymethylcellulose. A further objective of this study was to
      verify whether the adduct selenite-carboxymethylcellulose was also able to reduce
      the genotoxic damages induced by the herbicide maleic hydrazide, a strong
      mutagenic agent in plants, at a higher extent than selenite alone. The results
      obtained showed a genotoxic activity of sodium selenite at concentrations up to
      8.6 mg L-1. In the treatments with selenite-carboxymethylcellulose, the
      genotoxicity induced by the complex was significantly lower in comparison to how
      much was observed in the treatment with selenite only. When sodium selenite's
      protective activity against the genotoxic effects induced by the herbicide maleic
      hydrazide was tested, a reduction of mutagenic damages was observed at the
      highest application doses of selenite (from 86 mg L-1). The treatments with
      selenite-carboxymethylcellulose resulted in a further increase of selenium
      protective activity, which was observable for all doses used. These findings
      suggest a possible role played by carboxymethylcellulose in the regulation of the
      genotoxic activity of selenium.

PMID- 12483807
TI  - Natural and anthropogenic processes that concentrate Mn in rural and urban
      environments of the lower Mississippi River delta.
AB  - This study evaluated natural processes and projected methylcyclopentadienyl
      manganese tricarbonyl fuel additives as sources of Mn accumulation in the
      environment. Data sets include fresh alluvium and sediments from the lower
      Mississippi River Delta and a soil metal survey of metropolitan New Orleans. The
      (1) railroad Mn, (2) industrial Mn, and (3) dynamic aquifer-stream transfer of Mn
      hypotheses were tested with the Mississippi River Delta data. Friction between Mn
      rich steel wheels and rails contributes Mn (P = 0.017) to the environment,
      supporting (1). Sediment loads of Mn were similar (P = 0.77) upstream and
      downstream from the Louisiana industrial corridor, not supporting (2). The median
      Mn on the alluvium surface (59 mg/kg), in the aquifer (159 mg/kg), and in the
      riverbank aquifer discharge zone (513 mg/kg) support (3) as a mechanism for Mn
      enrichment of clay. The New Orleans soil metal survey data set shows a rural to
      urban increase of fourfold for Mn and three orders of magnitude for Pb. At 1999
      U.S. highway fuel use, 8.3 mg of Mn per L would yield 5000 metric tons of Mn
      annually. If 13% of Mn were emitted, 650 tons of Mn would become aerosols
      annually, while 87% or 4350 tons would remain in engines. The 1999 toxic release
      inventory for Mn shows 370 tons as total emissions compared to the potential of
      390 and 260 tons from vehicles, respectively, in urban and rural areas. A
      precautionary lesson from the use of Pb as a fuel additive is that the use of Mn
      as a fuel additive would be associated with an increased risk for neonates
      exceeding the estimated total tolerable daily intake of 2.1-16.5 micrograms Mn
      (especially in urban inner city environments) because neonates lack fully
      functional hepatic clearance for Mn.

PMID- 12483808
TI  - The combined use of chemical and biochemical markers to assess water quality in
      two low-stream rivers (NE Spain).
AB  - Carps (Cyprinus carpio) and red swamp crayfish (Procambarus clarkii) were sampled
      from two lowstream Mediterranean rivers (Anoia and Cardener) receiving extensive
      urban and industrial waste water discharges. Tissue residues of selected
      pollutants (organochlorinated compounds, polycyclic aromatic hydrocarbons (PAHs))
      were determined in conjunction with different biochemical responses (cytochrome
      P450, phase II enzymes) with the aim of investigating whether resident organisms
      were responsive to changes in water quality. Biota inhabiting those rivers were
      highly exposed to complex mixtures of polychlorobiphenyls and
      dichlorodiphenyltrichloroethanes (up to 19 ng/g w.w.) and PAHs (up to 6097 ng/g
      of hydroxylated PAHs in bile), the highest residues being observed in carps from
      Cardener. This has a reflection on 7-ethoxyresorufin O-deethylase (EROD)
      activity; that in carps from Cardener ranged between 350 and 550 pmol/min/mg
      protein, whereas in carps from Anoia ranged between was 90 and 250 pmol/min/mg
      protein. The highest activity recorded was downstream of the sewage treatment
      plants in both rivers. Phase II enzymes were less sensitive to polutant exposure
      than EROD; nonetheless, both glutathione S-transferase and UDP-glucuronyl
      transferase were higher in carps from Cardener. The results support the
      usefulness of the combined use of chemical and biochemical responses to assess
      and diagnose pollution in highly stressed ecosystems.

PMID- 12483809
TI  - "I stood taller than the rest" ... Hildegard Peplau.

PMID- 12483810
TI  - The future for nursing education: three leaders respond.

PMID- 12483811
TI  - The 60-Second Nurse Educator: Creative strategies to inspire learning.
AB  - Educational content that is presented, attended to, remembered, and reinforced in
      a "fun setting" will have a greater likelihood of being learned. Creative
      strategies integrated throughout the learning environment are effective in
      increasing retention of information. Some obstacles to creative teaching methods
      include lack of class time and preparation time, teaching habits, divergent
      learning styles of students, and devotion to covering all the content in class.
      This article presents "60-second strategies" that can be incorporated into large
      and small classes and clinical teaching. The strategies are quick, easy to
      implement, and transferable to a wide range of teaching topics.

PMID- 12483812
TI  - An academic-business partnership for advancing clinical informatics.
AB  - A jointly funded partnership between the school of nursing at a large midwestern
      university and a premier health care information technology supplier represents a
      pioneering event for education and for the health care information technology
      industry. The impetus for this partnership arose from Institute of Medicine
      reports published in late 1999 and early 2001 addressing the quality, error, and
      waste in the health care system in the United States. The Simulated E-hEalth
      Delivery System (SEEDS) provides opportunities based on best practices in
      education to learn and practice clinical skills in a state-of-the-art environment
      using a live-production, clinical information system designed for care delivery.
      A pilot project that began with a small cohort of baccalaureate nursing students
      has been implemented and extended. SEEDS will also be extended to other health
      professional programs.

PMID- 12483813
TI  - A dual degree model for associate and baccalaureate nursing education.
AB  - The dual degree model shared by an associate degree and baccalaureate nursing
      program allows dual enrollment in both programs and the completion of the
      baccalaureate nursing degree in four academic years with summer enrollment. This
      model outlines a dual course of study that strengthens associate degree nursing
      course work with important general education and nursing foundational courses.

PMID- 12483814
TI  - Evaluating reflective writing for appropriateness, fairness, and consistency.
AB  - Nurse educators are divided about how to best evaluate nursing students'
      reflective writings for evidence of critical thinking. This article reports on a
      study of consistency among faculty in grading writing in reflective journals. The
      results indicate a lack of consensus with regard to evaluation and differences
      among faculty with regard to how they view the purpose of such exercises.

PMID- 12483815
TI  - The theory of critical thinking of nursing.
AB  - Critical thinking is a thought process used by nurses for clinical decision
      making. This descriptive correlational study focused on the relationships among
      critical thinking, decision-making, and clinical nursing expertise during a
      clinical simulation. A midrange theory, developed from Benner (1) and Paul (2),
      states that as novice nurses become experts and develop clinical expertise
      through experience and the acquisition of knowledge, critical thinking is
      developed and used for clinical decision-making. > A convenience sample of 149
      nursing students, graduate nurses, and expert nurses was selected for the study.
      Critical thinking was measured with the Elements of Thought Instrument (ETI) and
      a decision score was calculated. Critical thinking and decision-making increased
      with the level of clinical expertise. Related demographics included college
      credits taken, years in nursing practice, and grade point average. The findings
      were consistent with the midrange Theory of Critical Thinking of Nurses.

PMID- 12483817
TI  - [Epileptic syndromes: general review, especially on syndrome classification].

PMID- 12483816
TI  - Promoting, applying, and evaluating problem-based learning in the undergraduate
      nursing curriculum.
AB  - Since its development in the 1960s, problem-based learning (PBL) has become
      increasingly prominent in nursing education. In 1998, Samford University received
      a grant from the PEW Charitable Trusts to promote, apply, and evaluate PBL in its
      undergraduate curriculum over three years. Nursing faculty approached this
      project with tenacity and enthusiasm. PBL has become integrated into the nursing
      curriculum in clinical and nonclinical courses. Descriptions of its
      implementation in specific courses are provided, and its usefulness in nursing
      education is discussed. Evaluations and test scores indicate that PBL has had a
      positive effect on the students and exceeded the educational outcomes anticipated
      by the faculty.

PMID- 12483818
TI  - [Bening epilepsy of childhood with centrotemporal spikes].

PMID- 12483819
TI  - [Childhood epilepsy with occipital paroxysms].

PMID- 12483820
TI  - [Primary reading epilepsy].

PMID- 12483821
TI  - [Chronic progressive epilepsia partialis continua of childhood nonprogressive
      epilepsia partialis continua].

PMID- 12483822
TI  - [Syndromes characterized by seizures with specific modes of precipitation].

PMID- 12483823
TI  - [Temporal lobe epilepsy].

PMID- 12483824
TI  - [Frontal lobe epilepsy].

PMID- 12483825
TI  - [Parietal lobe epilepsy].

PMID- 12483826
TI  - [Symptomatic occipital lobe epilepsy].

PMID- 12483827
TI  - [Benign familial neonatal convulsion].

PMID- 12483828
TI  - [Benign neonatal convulsion].

PMID- 12483829
TI  - [Benign myoclonic epilepsy in infancy].

PMID- 12483830
TI  - [Childhood absence epilepsy(pyknolepsy)].

PMID- 12483831
TI  - [Juvenile absence epilepsy(JAE)].

PMID- 12483832
TI  - [Juvenile myoclonic epilepsy].

PMID- 12483833
TI  - [Epilepsy with GTCs on awakening].

PMID- 12483835
TI  - [Epilepsies with seizures precipitated by specific modes of activation].

PMID- 12483834
TI  - [Other generalized epilepsies not defined above].

PMID- 12483836
TI  - [West syndrome(infantile spasms)].

PMID- 12483837
TI  - [Lennox-Gastaut syndrome].

PMID- 12483838
TI  - [Myoclonic-astatic epilepsy].

PMID- 12483839
TI  - [Epilepsy with myoclonic absences].

PMID- 12483840
TI  - [Early myoclonic encephalopathy(EME)].

PMID- 12483841
TI  - [Early-infantile epileptic encephalopathy with suppression-burst].

PMID- 12483842
TI  - [Aicardi syndrome].

PMID- 12483843
TI  - [Lissencephaly].

PMID- 12483844
TI  - [Pachygyria].

PMID- 12483845
TI  - [Neurocutaneous syndrome(tuberous sclerosis and Sturge-Weber syndrome)].

PMID- 12483846
TI  - [Subcortical band heterotopia].

PMID- 12483847
TI  - [Congenital bilateral perisylvian syndrome].

PMID- 12483848
TI  - [Hemimegalencephaly].

PMID- 12483849
TI  - [Focal cortical dysplasia].

PMID- 12483850
TI  - [Microdysgenesis].

PMID- 12483851
TI  - [Metabolic disorder of carbohydrate].

PMID- 12483852
TI  - [Inborn errors of amino acid metabolism and convulsions].

PMID- 12483853
TI  - [Organic acid disorders: cerebral organic acidemia].

PMID- 12483854
TI  - [Vitamin dependency].

PMID- 12483855
TI  - [Lysosomal disorders].

PMID- 12483856
TI  - [Mitochondrial disease].

PMID- 12483857
TI  - [Epilepsy due to inborn errors of metabolism].

PMID- 12483858
TI  - [Unverricht-Lundborg disease].

PMID- 12483859
TI  - [Dentatorubral-pallidoluysian atrophy].

PMID- 12483860
TI  - [Juvenile onset Huntington's disease: correlation with progressive myoclonus
      epilepsy].

PMID- 12483861
TI  - [Neonatal seizures].

PMID- 12483862
TI  - [Severe myoclonic epilepsy in infancy].

PMID- 12483863
TI  - [Epilepsy with continuous spikes and waves during slow sleep].

PMID- 12483864
TI  - [Acquired epileptic aphasia(Landau-Kleffner syndrome)].

PMID- 12483865
TI  - [Sleep grand mal epilepsy].

PMID- 12483866
TI  - [Febrile convulsion].

PMID- 12483867
TI  - [Seizures due to acute metabolic or toxic factors such as alcohol, drugs,
      eclampsia, nonketotic hyperglycemia, etc].

PMID- 12483868
TI  - [Neocortical epilepsy].

PMID- 12483869
TI  - [Status epilepticus].

PMID- 12483870
TI  - [Photosensitivity syndrome].

PMID- 12483871
TI  - [Myoclonic epilepsies of early childhood].

PMID- 12483872
TI  - [Symptomatic partial epilepsy with secondary bilateral synchrony].

PMID- 12483873
TI  - [Lafora disease].

PMID- 12483874
TI  - [Jansky-Bielschowsky disease].

PMID- 12483875
TI  - [Spielmeyer-Vogt-Sjogren disease].

PMID- 12483876
TI  - [Kufs' disease].

PMID- 12483877
TI  - [MERRF].

PMID- 12483878
TI  - [Severe myoclonic epilepsy in infancy].

PMID- 12483880
TI  - [Hereditary metabolic disease with neonatal seizures].

PMID- 12483879
TI  - [Infantile-onset refractory grand mal epilepsy with variable seizures].

PMID- 12483881
TI  - [Inherited metabolic disorders accompanied with epileptic manifestations].

PMID- 12483882
TI  - [Inherited metabolic diseases associated with West syndrome].

PMID- 12483883
TI  - [ESES syndrome].

PMID- 12483884
TI  - [Nonconvulsive status epilepticus with epileptic negative myoclonus(NSENM)].

PMID- 12483885
TI  - [Atypical benign partial epilepsy(ABPE)].

PMID- 12483886
TI  - [Benign adult familial myoclonic epilepsy(BAFME)].

PMID- 12483887
TI  - [Sleep-related epilepsy].

PMID- 12483888
TI  - [Electrical status epilepticus induced by sleep].

PMID- 12483889
TI  - [Progressive epilepsy with mental retardation(PEMR)].

PMID- 12483890
TI  - [Autosomal dominant nocturnal frontal lobe epilepsy(ADNFLE)].

PMID- 12483891
TI  - [Episodic ataxia with myokymia].

PMID- 12483892
TI  - [Episodic ataxia without myokymia].

PMID- 12483893
TI  - [Paroxysmal kinesigenic choreoathetosis].

PMID- 12483894
TI  - [Paroxysmal dystonic choreoathetosis].

PMID- 12483895
TI  - [Choreoathetosis/spasticity/episodic(CSE)].

PMID- 12483896
TI  - [Autosomal dominant epilepsy with febrile seizures plus].

PMID- 12483897
TI  - [Eyelid myoclonia with absences (EMA)].

PMID- 12483898
TI  - [Migrating partial seizures in infancy].

PMID- 12483899
TI  - [Dual pathology and coexistence in epilepsy].

PMID- 12483900
TI  - [Hypothalamic hamartoma(gelastic seizure)].

PMID- 12483901
TI  - [Early-onset benign occipital seizure susceptibility syndrome(EBOSS)].

PMID- 12483902
TI  - [Familial temporal lobe epilepsy].

PMID- 12483903
TI  - [Postoperative de novo psychosis in epileptic patients after temporal lobectomy].

PMID- 12483904
TI  - [Epilepsy and personality].

PMID- 12483905
TI  - [Mental retardation and disturbance of cognitive function].

PMID- 12483906
TI  - [Psychotic episodes and chronic psychoses with epilepsy].

PMID- 12483907
TI  - [Pseudoseizures].

PMID- 12483908
TI  - [Syncope].

PMID- 12483909
TI  - [Breath-holding spell].

PMID- 12483910
TI  - [Migraine(basilar migraine, hemiplegic migraine, CADSIL)].

PMID- 12483911
TI  - [Startle disease].

PMID- 12483912
TI  - [Sleep-wake disorders to be differentiated from epileptic seizures].

PMID- 12483913
TI  - Testing your diagnostic skills #64. Case No 1. Squamous cell carcinoma.
      Histoplasmosis. Blastomycosis.

PMID- 12483914
TI  - Testing your diagnostic skills #64. Case No 2. Odontogenic koratocyst.

PMID- 12483915
TI  - The Aqualizer's role.

PMID- 12483916
TI  - Splint therapy questions.

PMID- 12483917
TI  - A new technique for placement of posterior composite.

PMID- 12483918
TI  - Two decades of progress.

PMID- 12483919
TI  - Periodontology.

PMID- 12483920
TI  - Pediatric dentistry.

PMID- 12483921
TI  - Endodontics.

PMID- 12483922
TI  - Prosthodontics.

PMID- 12483923
TI  - Digital technologies.

PMID- 12483924
TI  - Restorative dentistry.

PMID- 12483925
TI  - Oral surgery.

PMID- 12483926
TI  - Implant dentistry.

PMID- 12483927
TI  - Aesthetic  dentistry.

PMID- 12483929
TI  - The process is important in autoclaving.

PMID- 12483928
TI  - Oral cancer facts.

PMID- 12483930
TI  - The hygiene department. From the doctor's perspective.

PMID- 12483931
TI  - Preserving a full-arch reconstruction.

PMID- 12483932
TI  - Dental management of sleep disorders.

PMID- 12483934
TI  - The interdisciplinary referral.

PMID- 12483933
TI  - Contemporary restoration of Class II caries. Direct posterior composites.

PMID- 12483935
TI  - Seventh-generation adhesive systems.

PMID- 12483936
TI  - Surgical crown lengthening for enhanced clinical success.

PMID- 12483937
TI  - Digital photography enables better soft tissue screening, diagnosis, and case
      acceptance.

PMID- 12483938
TI  - Gaining crown or bridge retention. An alternative to surgical crown lengthening.

PMID- 12483939
TI  - Conservative aesthetic treatment of dark necrotic teeth. Efficient internal
      bleaching.

PMID- 12483940
TI  - Diagnosis and management of nondental toothache.

PMID- 12483941
TI  - A desensitizing technique that really works.

PMID- 12483942
TI  - Stand and deliver. Fast track your staff to accountability and exceptional
      performance.

PMID- 12483943
TI  - Clinical dentistry and the Internet. A marriage made in heaven?

PMID- 12483944
TI  - The collapsed athlete.
AB  - Athletic collapse is rare, but personnel caring for athletes at sporting events
      must be prepared for it. Most cases are nonfatal and, with proper management, can
      have good outcomes. Medical personnel should expect the typical causes of
      athletic collapse that occur at the events they are covering, but rare causes
      should also be anticipated.

PMID- 12483945
TI  - Acute shoulder and elbow dislocations in the athlete.
AB  - Dislocations of the elbow are less common than shoulder dislocations. The primary
      treatment is conservative, with a conscious effort toward early mobilization.
      Recurrence is rare, and improvement in function and motion can be expected for up
      to 1 year. Operative treatment should be reserved for baseball pitchers and cases
      of complex instability.

PMID- 12483946
TI  - Fractures and tendon injuries of the athletic shoulder.
AB  - Athletic injuries in the shoulder range from a routine strain or sprain to a
      potentially disabling fracture or tendon rupture. The level of sports
      participation plays an important role in diagnosis and treatment. The
      nonprofessional athlete may be more likely to sustain injuries secondary to under
      training or improper technique. The professional athlete may be capable of play
      under much higher velocities and applied loads and, therefore, may be subject to
      higher energy trauma than the amateur athlete. In addition to standard treatment
      considerations, return to play time must also be decided. Decisions regarding
      definitive treatment may be modulated depending on an athlete's desire to return
      to his or her previous level of competition.

PMID- 12483947
TI  - Traumatic elbow injuries in the athlete.
AB  - Traumatic injuries to the elbow are not uncommon in the athlete. A fall onto the
      out-stretched arm may result in fracture of the radial head, dislocation of the
      elbow, or other injuries about the joint. Strength training and contact sports
      may cause rupture of the biceps or triceps tendon at the elbow. It is important
      for the sports medicine physician to become familiar with injury patterns about
      the elbow in athletes and treatment options. This article will be devoted to a
      summary of classification, diagnosis, and treatment considerations for selected
      traumatic athletic injuries of the elbow.

PMID- 12483948
TI  - Neurovascular trauma in athletes.
AB  - Injuries to neurovascular structures are not the most common injuries seen in
      athletes and for this reason may often be overlooked. Additionally, diagnosis and
      management may be more difficult because of inexperience with these injuries. The
      majority of acute sports-related neurovascular injuries are associated with
      contact sports such as rugby, wrestling, ice hockey, and especially football.
      These injuries most commonly occur about the shoulder girdle and brachial plexus,
      with "burners" syndrome being the most common. Less common injuries include
      thoracic outlet syndrome, effort-induced thrombosis, axillary artery occlusion,
      and peripheral nerve injuries, as well as compression syndromes involving the
      axillary, suprascapular, and long thoracic nerves.

PMID- 12483949
TI  - Acute wrist injuries in the athlete.
AB  - The athlete represents a special population in which injuries can occur either
      from a single acute traumatic event or as part of a continuum of overuse that
      leads to osseous or soft tissue failure. The spectrum of overuse with
      superimposed acute trauma makes the evaluation of the upper extremity in the
      competitive athlete more challenging. The expectation of this population for
      quick, full, painless recovery, coupled with the desire to return to the sport
      that caused the injury, makes the treatment difficult as well. This article will
      discuss athletic injuries of the forearm and wrist with an emphasis on
      evaluation, treatment, and criteria for return to play.

PMID- 12483950
TI  - Athletic hand injuries.
AB  - Hand injuries are among the most common injuries arising from athletic
      participation. Suboptimal outcomes from poorly treated athletic hand injuries can
      produce functionally disabling injuries. Careful assessment and, when needed,
      radiographic studies are critical for the accurate and complete diagnoses of hand
      injuries. Carefully thought out modifications may accelerate the time for return
      to competition. A thorough understanding of these many variables can enable the
      physician to minimize time lost without compromising care.

PMID- 12483951
TI  - Acute athletic trauma to the hip and pelvis.
AB  - Athletic trauma to the hip and pelvis is rare; however, as football players hit
      harder and skiers ski faster, the incidence of high-energy hip and pelvis trauma
      can be expected to increase. As the energy of the injury increases, so do the
      associated risks. Therefore, a thorough understanding of on-field recognition and
      management is a necessary addition to the armamentarium of the sports medicine
      physician.

PMID- 12483952
TI  - Knee fractures in the athlete.
AB  - Sports-related fractures of the knee, although uncommon, do occur during athletic
      participation. The assessment and management of each fracture type have been
      emphasized in this article to provide a guideline for treating these acute knee
      injuries to a successful return to sports-specific competition. Anatomic fracture
      reduction is necessary to have optimal joint function in the knee as well as
      stability of fracture for early joint motion, promote bone healing, and avoid
      traumatic arthritis. This is especially crucial to the injured athlete, as
      residual deficits of the knee can greatly affect performance. Selection of low
      profile implants at the time of surgery to prevent soft tissue irritation and
      possible implant removal must also be considered with the return to athletic
      activity.

PMID- 12483953
TI  - The acute management of soft tissue injuries of the knee.
AB  - The acute management of soft tissue injuries of the knee requires knowledge of
      the injury mechanism, physical findings, and results of adjunctive tests. Knee
      dislocations, fractures, and extensive soft tissue injury requires immediate and
      thoughtful treatment. All injuries are afforded the benefit of the basic
      principles of rest, ice, compression, and elevation until definitive treatment is
      carried out.

PMID- 12483954
TI  - Traumatic foot and ankle injuries in the athlete.
AB  - Unrecognized and inappropriately managed foot and ankle injuries can lead to
      significant long-term functional disability. As many of the above injuries are
      frequently diagnosed late or not even considered because of the benign appearance
      of the foot or radiograph, it behooves the sports medicine physician to carefully
      assess the foot and obtain appropriate radiographs, including stress views as
      needed. Although quick return to athletic play is among the goals of treatment
      for the elite athlete, this must be tempered by the fact that certain injuries
      require significantly greater time for complete recovery. A functional
      rehabilitation program is the best means to rapidly return the player to
      competition and while prolonging the athletic career.

PMID- 12483955
TI  - [Contrary views on the 35 hour work week].

PMID- 12483956
TI  - [Explosion at the AZF factory, one year later. Interview by Christian Bourdeux].

PMID- 12483957
TI  - [Anthropology. Out of the necessity to understand others].

PMID- 12483958
TI  - [Understanding those "crazy foreigners"].

PMID- 12483959
TI  - [Role of culture in psychopathology].

PMID- 12483960
TI  - [Mediation, an absolute necessity].

PMID- 12483961
TI  - [Globalization and ordering of cultures].

PMID- 12483963
TI  - [The good, the bad, the ugly?].

PMID- 12483962
TI  - [Chronicle of ordinary violence].

PMID- 12483964
TI  - Elevated platelet counts and thrombocytosis in erythema nodosum leprosum.
AB  - Changes in peripheral blood platelet counts associated with the onset of
      symptomatic erythema nodosum leprosum (ENL) were studied by comparing, in each
      patient, the value obtained on the day thalidomide therapy commenced with the
      average of the three preceding values. In the 11 patients studied, the mean
      platelet count rose from 235 to 322 x 10(3)/mm3, p < 0.001. In 3, the platelet
      count was above the normal limit, qualifying as thrombocytosis, in 7 the rise was
      appreciable, and in 2 it was negligible. In the 3 patients studied 1-2 weeks
      after beginning thalidomide, the mean count was 414 x 10(3)/mm3. Counts obtained
      after 3 or more weeks of thalidomide therapy were within normal limits. This
      study provided no direct evidence as to the mechanism responsible for the
      elevated platelet count, but mediation by interleukin-6 (IL-6) was concluded to
      be an attractive hypothesis, consistent with prior studies of IL-6 in reactive
      thrombocytosis and of IL-6 in ENL.

PMID- 12483965
TI  - Combined 12-month WHO/MDT MB regimen and Mycobacterium w. vaccine in
      multibacillary leprosy: a follow-up of 136 patients.
AB  - A total of 136 patients with BI > or = 2 having been followed up for at least 2
      years or more were included in the analyses. Seventy-seven out of 136 patients
      had completed three years follow up. All patients were given WHO/MDT MB regimen
      for 12 months and additionally 4 doses of Mycobacterium w. vaccine at 3-month
      intervals. The age of the patients varied from 6 to 77 years (mean 34 +/- 11.3
      years) and they had the disease varying from 3 months to 7 years (mean = 1.9 +/-
      1.4 years). The mean of the BI before starting treatment was 3.6 +/- 1.3. At the
      end of 2 years follow-up, a total of 54 patients out of the 136 (39.7%) had
      become smear-negative. A larger proportion of patients, 39/46 (84.8%) with BI of
      < or = 3 had become smear-negative, whereas, only 10/32 (31.3%) patients with BI
      between 3.1 to 4 and 5/58 (8.6%) highly bacillated patients having initial BI > 4
      had become smear-negative at the end of 2 years. Out of the 77 patients who were
      available for follow up at 3 years, 30/33 (90.9%) patients with BI of < or = 3,
      15/20 (75%) patients with BI between 3.1 to 4 and 13/24 (54.2%) patients having
      initial BI > 4, respectively, had attained smear negativity. Reactions occurred
      more frequently after 6 months of therapy and over a period of time their
      frequency gradually decreased, however, they continued to occur even two years
      after RFT. During the course of MDT and thereafter in follow up 4.6% and 1.3% of
      the patients developed new deformities or an increase in the existing grade of
      deformities, respectively. Three relapses (2 in LL and 1 in BL) occurred in
      patients having initial BI of > 4. One patient relapsed in the second year and
      the other two relapsed in the third year of follow up and were successfully
      treated with reintroduction of the same MDT MB regimen. Local ulceration healing
      with scar formation and regional lymphadenopathy were the only local reactions to
      the vaccine seen in 47/136 (34.5%) patients. All the patients showed
      histopathological improvement in the form of a gradual reduction of granuloma
      fraction. Although the results of this limited period follow up are satisfactory,
      a long-term follow-up in larger number of patients will settle the issue of
      safety and efficacy of shortened MDT MB regimen and the place of immunotherapy
      with M. w. vaccine in multibacillary patients.

PMID- 12483967
TI  - The effect of exogenous peroxidase on the evolution of murine leprosy.
AB  - Mycobacterium lepraemurium (MLM) is a successful parasite of murine macrophages;
      in vitro, this microorganism infects macrophages without triggering these cells'
      ability to produce either the reactive oxygen intermediaries (ROI) or the
      reactive nitrogen intermediaries (RNI), and ends up lodging within these cells,
      that, in addition, do not contain myeloperoxidase (MPO). In this study, we
      analyzed the effect of exogenous peroxidase on the evolution of murine leprosy.
      Bacilli were intraperitoneally injected, either alone (MLM) or precoated with
      horseradish peroxidase (MLM-PO), into two different groups of mice. At two-week
      intervals, the groups were blood-sampled to measure the levels of antibodies to
      protein- or lipid-MLM antigens. The extent of the disease was also assessed by
      looking at the histopathologic changes that occurred both in the liver and the
      spleen of the infected animals. We found that the animals injected with MLM-PO
      developed a disease that evolved at a slower pace than the disease that occurred
      in the animals injected with intact MLM. The difference between groups, both in
      terms of antibody levels and histological changes, was clearly evident at the
      intermediate stages of the disease (2 to 2.5 months), but was not so obvious at
      the more advanced stage of 3 months. Several possibilities to explain how the PO
      coated bacilli might have regained their infectiousness are discussed. Lowering
      the infective dose of MLM and MLM-PO from 5 x 10(7) bacilli to 5 x 10(6) bacilli
      would, probably, have resulted in a different outcome of the disease: more
      extended in the MLM-group than in the MLM-PO group.

PMID- 12483966
TI  - Effect of hsp65 DNA vaccination carrying immunostimulatory DNA sequences (CpG
      motifs) against Mycobacterium leprae multiplication in mice.
AB  - A DNA expressing hsp65 of Mycobacterium leprae (pACB/hsp65) was constructed by
      using a vector containing immunostimulatory DNA sequences (pACB). At 12 weeks
      post-immunization, spleen cells from BALB/cA mice immunized with pACB/hsp65,
      produced a significantly higher amount of IFN-gamma than mice immunized with pACB
      in the absence of any in vitro stimulation, and further enhanced its production
      upon secondary in vitro stimulation with M. leprae lysate and hsp65. On the other
      hand, while production of IL-12 was observed in mice immunized with pACB/hsp65 12
      weeks before, the cytokine production was inhibited by in vitro secondary
      stimulation with M. leprae or hsp65. At 18 weeks post-immunization, the
      production of both IFN-gamma and IL-12 was apparently down-regulated, but that of
      IL-10 was up-regulated. IL-10 seemed to suppress the IFN-gamma and IL-12
      productions, because their production was recovered by neutralization of IL-10
      with anti-IL-10 mAb. Furthermore, when the efficiency of pACB/hsp65 as a vaccine
      against M. leprae was evaluated in vivo, the mice immunized with pACB/hsp65
      suppressed the multiplication of subsequently challenged M. leprae. These results
      suggest that a DNA containing M. leprae-derived hsp65 and immunostimulatory
      sequences might be a potent vaccine candidate against M. leprae infection.

PMID- 12483969
TI  - Bullous reaction in leprosy: a rare phenomenon.

PMID- 12483968
TI  - Phenolic glycolipid-1 (PGL-1) in Buruli ulcer lesions. First demonstration by
      immuno-histochemistry.
AB  - Buruli ulcer, caused by Mycobacterium ulcerans, is emerging as the third most
      common mycobacterial disease after leprosy and tuberculosis in some tropical
      regions. Although a toxin of the polyketide family is central to the pathogenesis
      of the disease, there are still several parameters that need clarification. Among
      them and of crucial interest are the curative drug treatment and the test for
      early detection of the disease. In this study, we used mouse monoclonal
      antibodies, raised against synthetic sugars of the terminal trisaccharide of M.
      leprae PGL-1, to detect the immunoreactivity of this antigen in tissue infected
      with M. ulcerans. Thirty specimens of skin tissue from Buruli ulcer patients (3
      plaques, 10 nodules, 1 ulcerated nodule, 7 deep ulcer beds and 9 ulcers in
      healing) were obtained from Ghana. Eighty-three percent of the submitted cases
      were compatible with the lesions of Buruli ulcer. AFB were positive in 33% of
      plaques, 40% of nodules, 44% of actives ulcers and 22% of the ulcer in healing
      stage. Immunohistochemically, phenolic glycolipid-1 (PGL-1) was detected in all
      AFB-positive cases. This observation implies that Mycobacterium ulcerans may
      express an M. leprae PGL-1-like substance and should tentatively emulate research
      to further characterize such a substance. The search for an early diagnostic tool
      for the Buruli disease may benefit from such investigations.

PMID- 12483970
TI  - Cholinesterase in leprosy nerves: a preliminary report.

PMID- 12483971
TI  - Hansen's disease mimicking palmoplantar keratoderma.

PMID- 12483972
TI  - A comparative study of ocular side effects of pulse steroid therapy versus long
      term oral steroid therapy in steroid responsiveness dermatoses.

PMID- 12483973
TI  - Borderline tuberculoid leprosy and alopecia areata involving scalp.

PMID- 12483974
TI  - [Possibilities and limits of epidemiologic surveillance at the local level
      towards health surveillance].
AB  - The aim of this study is to describe and analyze Epidemiological Surveillance
      activities (ES) developed in a Health Care Unit and to identify their adherence
      to recommended Health Surveillance (HS) strategies. A checklist with the
      activities recommended by the Ministry of Health was used to conduct interviews
      with health professionals involved in ES activities. The data obtained from these
      interviews showed that Epidemiological Surveillance activities are limited to the
      notification and control of infectious diseases, and the nurses' labor is
      characterized by bureaucratic tasks. This shows that further discussion about
      Health Surveillance strategies is necessary to find ways to better implement them
      in health services.

PMID- 12483975
TI  - [Home care for the elderly: profile of the formal caregiver -- Part II].
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 the offer of these people's work and the shortage literature on
      its profile, we developed a study with 41 advertisers that offered their 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 to the second objective.

PMID- 12483976
TI  - [Changes in life-style, needs and difficulties faced by caregivers of AIDS
      patients in home care].
AB  - This study aimed at delineating the social and demographic profile of 17 home
      caregivers for AIDS patients, identifying the alterations occurring in their life
      style and detecting the main needs and doubts presented by them when assisting a
      person living with AIDS at home, as well as the difficulties stemming from the
      disease and the care given by them. We identified that the introduction of
      HIV/AIDS within the family generates a crisis situation and awakens many negative
      feelings in caretakers. An alteration in life routine takes place and there is
      also an overload of tasks to be carried out. The main difficulties of caretakers
      are related to taking care of the patient at home in addition to financial and
      emotional difficulties. We have shown the need for more effective orientation as
      to protection measure while caring for the patient. We have also pointed out the
      importance of orientation and educational actions to be given by health
      professionals, during which nurses' participation in home assistance/visits is
      essential.

PMID- 12483977
TI  - [The process of caring for burned patients: cultural significance attributed by
      relatives].
AB  - This study aimed at investigating the cultural meanings attributed by relatives
      to their participation in the process of delivering care to burned people;
      identifying the care strategies focused on by relatives during their
      participation in the care process. Data were collected by means of semi
      structured interviews with 25 relatives of burned patients admitted in a Unit for
      Burned and by participant observation. The results of this study show that the
      perspective of giving care to a burned person has two dimensions: a physical
      dimension and a moral one; and generates mainly fear.

PMID- 12483978
TI  - [Relationship between dialysis solution and symptomatic arterial hypotension
      observed during hemodialysis sessions in patients with chronic kidney failure].
AB  - This prospective study was designed to evaluate hypotension in a group of 21 end
      stage renal disease patients (ESRD) on hemodialysis, with syntomatic low blood
      pressure. The arterial blood pressure was recorded at 4 consecutive dialysis
      sessions, two at 35 degrees C and two at 37 degrees C dialysate temperature. In
      both situations, systolic and diastolic pressures, measured during dialysis, were
      different from the pre-dialysis value, with progressive lowering up to the end of
      the procedure. Cold dialysis did not protect from lowering the blood pressure in
      an amount similar to that occurring at 37 degrees C.

PMID- 12483979
TI  - [Developing the care proposed by Leininger with a person in dialysis treatment].
AB  - Study of a ethnographic approach, type case study. Describing a person's bearer
      of chronic renal inadequacy accompaniment, with adhesion deficit to the
      treatment. The theoretical presupposition had the model SUNRISE proposed by
      Leininger. It's presented the Mr. Light and the involved sceneries. Described.
      Influences economical, social, cultural, technological and educational in the
      process of taking care. After the identification of the systems of health, were
      decided the actions of taking care through the maintenance, accommodation and
      restoration. The study possibilited effective interventions for the behaviors of
      non adherence. The referencial in continuous and lingering processes of care,
      favoured by the proximity between nurse and attended person.

PMID- 12483980
TI  - [Cardiorespiratory arrest in the intensive care unit: theoretical considerations
      on factors related with iatrogenic events].
AB  - The attendance of Cardiopulmonary Resuscitation (CPR) demands rapidity,
      efficiency, scientific knowledge and technical ability. Still, an adequate infra
      structure is vital as well as the accomplishment of an harmonic and synchronized
      work and team performance, in order to promote the patient's backup. Iatrogenic
      factors related to attendance of CPR in the Intensive Care Unit may be due to
      professional inexperience, insufficient staff and problems with material or
      equipments. Thus, the team must be prepared to assist the patient efficiently, as
      resuscitation should restore the life process and not prolong the death process.

PMID- 12483981
TI  - [Motor capacities involved in the psychomotor skills of the cardiopulmonary
      resuscitation technique: recommendations for the teaching-learning process].
AB  - It is a bibliographic study about the identification of the motor capacities
      involved in the psychomotor skills of the cardiopulmonary resuscitation (CPR)
      which aims to obtain subsidies to the planning of the teaching-learning process
      of this skill. It was found that: the motor capacities involved in the
      psychomotor skill of the CPR technique are predominantly cognitive and motor,
      involving 9 perceptive-motor capacities and 8 physical proficiency capacities.
      The CPR technique is a psychomotor skill classified as open, done in series and
      categorized as a thin and global skill and the teaching-learning process of the
      CPR technique has an elevated degree of complexity.

PMID- 12483982
TI  - [Teaching staff, student, and performance evaluation in nursing administration at
      nursing schools in Brazil].
AB  - The objective of this study was to analyze the theoretical references related to
      the performance evaluation process, establishing their correlation to different
      pedagogical lines. These references constitute the foundation for the analysis of
      data being collected and studied. This study is part of a broader project,
      currently in progress, whose objective is to determine how to evaluate teachers,
      students and achievement in courses dealing with content related to Nursing
      Administration at the graduate and undergraduate levels in Brazil. We hope to be
      contributing to a clearer and better understanding of this concrete reality, and
      of the performance evaluation process in light of the changes in the teaching of
      such courses.

PMID- 12483983
TI  - [Impact of non-verbal communication of professors in the class room -- view of
      nursing professors].
AB  - In the interaction teacher-student, the teacher has an important paper and his
      good acting depends mainly on the conscience and ability that he has in the
      communication, the nonverbal. This work had as objective to verify the
      educational of Nursing, the knowledge and the importance attributed to the
      nonverbal signs in its interaction in class room close to. It is an exploratory
      study, in the qualitative line and 25 teachers were interviewed in the Nursing
      School of USP, in October to December of 1999. As results, we could verify that
      facilitators of the interaction are considered in class room: some teacher's
      characteristics, student's characteristics, the contact regularity, the type of
      exposed content and the own communication.

PMID- 12483984
TI  - [Evaluation of nursing notes based on the nursing process].
AB  - This is a retrospective study that analyzed the nursing notations in a
      Specialized Unit which develops the care to the patient based on Nursing Process.
      The data were collected through two promptuaries utilizing instrument constructed
      for this purpose. Aspects which valuate appearance and content were considered in
      the analysis. The nursing assistant was distinguished in the results considering
      the bigger number of extensive and not very specific notations, and in the
      registrations achieved by the nurse, it was observed a bigger number of legible
      and objective notations. By expressing the Nursing work, greater investments must
      be made to become more objective and full the nursing notations.

PMID- 12483985
TI  - [Living the inexorability of time and its changes with losses and possibilities:
      women in climacteric].
AB  - This research deals with the experience of women in climacterium. Symbolic
      interactionism and Grounded Theory were the theoretical and methodological
      framework of the study. Its objectives were to understand: how the experience of
      the climacterium is defined by the women; what were the psychosocial processes of
      interaction lived by the women; and to develop a theoretical model representing
      the experience of the women in climacterium. The strategies used to collect the
      data were participant observation and open ended interviews. The subjects were
      women in the age group of 45 to 60. The sample was of 30 women. The study
      revealed that the climacterium experience may be constituted of two phenomena:
      REJECTING CHANGES which is characterized by the women as a moment of loss and
      TRYING TO COPE WITH CHANGES, which represents the moment construction of new
      concepts with possibilities of reconstruction of life. Supported by these two
      phenomena, the central category was generated: LIVING THE INEXORABILITY OF TIME
      AND ITS CHANGES WITH LOSSES AND POSSIBILITIES which is fundamental to the
      generation of the theoretical model representing the experience of women in
      climacterium.

PMID- 12483986
TI  - [Perception of adolescent mothers on paternal participation in pregnancy, birth,
      and child rearing].
AB  - Paternal participation in adolescents' pregnancy is little discussed. Although
      the absence of the partner is pointed out as one of the problems due to it. This
      research had the aim to ascertain, under the perspective of mothers who gave
      birth at an early age, the participation of a father during gestation, birth, and
      raising of his child in the first months of life. In order to record data, two
      categories have been devised: experiencing pregnancy and valuing a
      partner/father's presence and participation.

PMID- 12483987
TI  - [The experience of institutionalized children].
AB  - The aim of this study was to know the experience of the institutionalized child
      and was guided by the theoretical referential of the "Symbolic Interactionism"
      and by the methodological referential of the "Grounded Theory". The data had been
      collected in two stages: the first one understood group activities and second
      stage consisted of personal interviews. The results had shown that the
      institutionalization occurred for abandonment and reject of the parents or for
      legal decision as a measure of child protection, having as context the poverty of
      its family. The child's experience is conflicting in relation to being
      institutionalized, because while he/she perceives the necessity of material gain,
      they miss their family, their home, their friends, and simply life outside.

PMID- 12483988
TI  - Role of receptor revision in forming a B cell repertoire.

PMID- 12483989
TI  - Bacterial protease treatment of natural rubber latex alters its primary
      immunogenicity in a mouse model of sensitization.
AB  - The purpose of the present investigation was to determine whether enzyme-treated
      (ET)-NRL is less immunogenic than untreated NRL in a BALB/c mouse model of
      primary in vivo sensitization following repeated subcutaneous injections with the
      aqueous phase of ammoniated NRL or ET-NRL. Mice immunized with NRL produced IgE
      against NRL and ET-NRL, indicating that protease treatment did not completely
      destroy IgE antibody epitopes. In contrast, ET-NRL-immunized mice did not produce
      IgE against either NRL or ET-NRL, suggesting that enzyme treatment reduced the
      number of antigenic polypeptides associated with NRL below the threshold for
      sensitization. Thelper-lymphocytes from NRL-immunized mice proliferated and
      produced IL-4 when stimulated in vitro with polypeptides from NRL, but not ET
      NRL. In contrast, Thelper-lymphocytes from ET-NRL-immunized mice were
      nonresponsive to ET-NRL or NRL. We conclude that lack of IgE production by ET-NRL
      immunized mice is likely related to a lack of T-cell help in the form of IL-4,
      rather than enzyme digestion of IgE antibody epitopes. These data indicate that
      there is an immunologic rationale for production of enzyme-treated NRL-containing
      medical devices.

PMID- 12483990
TI  - Characterization of monocyte-derived dendritic cells in recent-onset diabetes
      mellitus type 1.
AB  - Dendritic cells (DC) may play an important role in the immunopathogenesis of type
      1 diabetes mellitus (DM-1). In this study, we have analyzed phenotypical changes
      during cytokine-driven maturation from CD14+ monocytes to mature DC and DC
      dependent T-cell stimulation in recent-onset pediatric DM-1 patients and healthy
      controls. DC maturation was monitored by flow cytometric analyses for the
      expression of surface markers (HLA-DR, CD1a, CD40, CD80, CD86, CD83, CD14, CD32,
      mannose-receptor, and CD11c). Flow cytometric analysis of isolated peripheral
      blood monocytes did not reveal apparent differences between patients and
      controls. During DC maturation no obvious differences in the expression patterns
      of surface markers over time or evidence for maturation impairments in DM-1
      patients could be appreciated. Solely, a marginal, but significant, transient
      down-regulation of CD1a on Day 3 (mean MDFI 3.82 vs 7.25; P = 0.021), which was
      accompanied by an increase of IL-6, could be observed. The comparison of mature
      DCs (Day 10) between patients and controls indicated no significant differences,
      except for CD83 (mean MDFI 1.7 vs 1.5; P = 0.042) and CD80 (mean MDFI 15.92 vs
      12.73; P = 0.042). Moreover, no difference in T-cell stimulatory capacity was
      seen. In conclusion, our analysis of a cohort of recent-onset DM-1 patients and
      controls does not support a role for disease-related alterations in cytokine
      driven maturation of monocyte-derived DC.

PMID- 12483991
TI  - Red blood cell transfusions are associated with alterations in self-reactive
      antibody repertoires of plasma IgM and IgG, independent of the presence of a
      specific immune response toward RBC antigens.
AB  - Immunization to allogeneic RBC antigens occurs in transfused patients, and may be
      associated with the development of RBC-destructive antibodies directed against
      autologous RBC. The present study investigates the effect of transfusion of
      allogeneic RBC on self-reactive antibody repertoires, independent of the presence
      of a specific immune response directed toward RBC antigens. Antibody repertoires
      of IgM and IgG in plasma of hematological patients prior to starting a
      transfusion regime and of hematological patients receiving regular transfusions
      of leukocyte-depleted RBC were analyzed using quantitative immunoblotting on a
      panel of antigens derived from tissue and cell extracts, followed by
      multiparametric statistical treatment of the data. Multiparametric statistical
      analysis discriminated between self-reactive antibody repertoires of patients
      prior to starting a transfusion regime and those receiving regular RBC
      transfusions (IgM, 0.0001 < P < 0.0244/IgG, 0.0002 < P < 0.0088, depending on the
      tissue extract), whereas antibody repertoires of plasma IgM and IgG toward
      bacterial antigens were similar between groups of patients (P > 0.05). We
      conclude that the challenge of the immune system with allogeneic RBC antigens
      influences self-reactive antibody repertoires of plasma IgM and IgG, independent
      of the presence of a specific immune response toward RBC antigens.

PMID- 12483992
TI  - Visualization of the transfer reaction: tracking immune complexes from
      erythrocyte complement receptor 1 to macrophages.
AB  - Immune complexes (IC) bound to human erythrocytes (E) via complement receptor 1
      (CR1) are transferred to phagocytes in the liver and spleen. In an in vitro model
      system using bispecific mAb reagents (antigen-based heteropolymers) to link IC to
      E, we have made time-lapse movies in which fluorescently labeled IC cross the E
      human macrophage interface and remain associated with the macrophage. Both these
      movies and fixed-time experiments reveal transfer intermediates in which IC hinge
      E to macrophages. Examination of model macrophages after transfer indicates that
      the majority of IC are on the surface at short times (2 min) but are internalized
      at long times (1-4 h). More than half of the surface IC colocalize with CR1 at 2
      min. This evidence supports a model in which CR1-bound IC provide a secure
      linkage between E and macrophages, allowing rearrangements of the macrophage
      surface necessary for release of CR1, and IC, from the E.

PMID- 12483993
TI  - Immunomodulation of experimental colitis via caloric restriction: role of Nk1.1+
      T cells.
AB  - Inflammatory bowel diseases are immune-mediated disorders. Dietary restriction
      and NK1.1+ liver-associated lymphocytes (LAL) are considered to be involved in
      immunomodulation of autoimmune diseases. Our aim was to evaluate the effect of
      caloric restriction on experimental colitis and to determine NK1.1+ LAL function
      in immunoregulation. Experimental colitis was induced in C57 black mice by
      intracolonic instillation of trinitrobenzene sulfonic acid. Caloric restriction
      to 60% of the daily requirement was started 2 weeks prior to, or simultaneously
      with, colitis induction and continued throughout the study. Control mice were fed
      ad libitum. Colitis was assessed by standard clinical and macroscopic scores. To
      determine the mechanism involved in immunomodulation, liver lymphocytes were
      isolated and analyzed for NK1.1+ T-cell markers by FACS. T-cell function was
      evaluated by T-cell proliferation. Serum cytokines were measured by ELISA.
      Dietary restriction to 60% markedly ameliorated experimental colitis in both
      groups. These mice gained weight and showed improved macroscopic parameters of
      colitis. NK1.1+ LAL numbers increased fourfold and NKT cytotoxicity twofold in
      caloric-restricted mice. The antigen-specific T-cell proliferation index
      decreased (from 4.45 in controls to 1.15), and IFN-gamma and IL-12 serum levels
      decreased (from 290 to 200 pg and from 122 to 53 pg, respectively) in caloric
      restricted mice. Our conclusion was that dietary restriction induced
      immunomodulation of experimental colitis and ameliorated the disease. This effect
      was mediated via an increase in NK1.1+ T lymphocytes, which may play a critical
      role in keeping the T-cell balance in immunoregulation.

PMID- 12483994
TI  - Activation of complement components and reduced regulator expression in alcohol
      induced liver injury in the rat.
AB  - The purpose of this study was to evaluate the possible contribution of complement
      mediated inflammation to the development of alcoholic liver disease. Male Wistar
      rats were fed ethanol by liquid diet in a model that results in continuous
      ethanol intoxication and induces early signs of alcoholic liver injury. After a
      six-week study period liver samples were analyzed for the deposition of
      complement components (C1, C3, and C8) and expression of cell membrane-bound
      regulators (Crry and CD59). Activation of the homologous complement system in
      vitro was tested by treating frozen liver sections with normal rat serum (NRS).
      Immunohistochemical analysis showed deposits of C8 in the liver sections of
      ethanol-treated rats. When frozen liver sections from these rats were treated
      with NRS, periportal deposition of both C3 and C8, but only slight C1 deposition,
      was observed. Immunohistochemical and Western blot analysis both revealed a
      reduced expression of the complement regulators Crry and CD59. These results
      suggest an induction of complement-activating capacity in the liver after chronic
      ethanol treatment. Lack of C1 deposition in the lesions suggests that complement
      activation occurs primarily via the alternative pathway. The reduced expression
      of the critical complement regulatory proteins Crry and CD59 may sensitize the
      liver to complement-mediated damage.

PMID- 12483995
TI  - Isotypes and antigenic profiles of pemphigus foliaceus and pemphigus vulgaris
      autoantibodies.
AB  - In this study we systematically characterized isotype profiles and antigenic and
      tissue specificity of antidesmoglein autoantibodies from patients with pemphigus
      foliaceus (PF) and pemphigus vulgaris (PV) using enzyme-linked immunoabsorbent
      assays (ELISA), indirect immunofluorescence (IIF) staining, and immunoblotting
      (IB). In PF, we found that IgG1 antidesmoglein-1 (Dsg1) reacts with a linear
      epitope(s) on the ectodomain of Dsg1, while its IgG4 counterpart recognizes a
      conformational epitope(s). These two subclasses of anti-Dsg1 are both capable of
      recognizing tissues from monkey esophagus and adult human skin, but IgG1 is not
      able to react with mouse skin, which may explain why this isotype of anti-Dsg1
      failed to induce PF-like lesions in the passive transfer animal model. In mucosal
      PV patients, we found that both IgG1 and IgG4 only recognized monkey esophagus
      tissue by IIF, except in one patient, indicating that these antibodies react with
      a unique conformational epitope(s) that is present in mucosal but not skin
      tissue. In generalized PV, IgG1 anti-Dsg3 autoantibodies appeared to recognize a
      linear epitope(s) on the Dsg3 ectodomain. In contrast, IgG4 anti-Dsg3 antibodies
      recognized both linear and conformational epitopes on the Dsg3 molecule.
      Interestingly, the IgG1 anti-Dsg3 antibodies failed to react with human and mouse
      skin tissues, suggesting that this subclass of autoantibodies may not play an
      essential role in the development of PV suprabasilar lesions. In summary, we
      conclude that this study further elucidates the pathological mechanisms of PF and
      PV autoantibodies by revealing their distinct isotype and antigenic profiles.
      This information may help us to better understand the autoimmune mechanisms
      underlying the development of pemphigus.

PMID- 12483996
TI  - Purine nucleoside phosphorylase deficiency: a new case report and identification
      of two novel mutations (Gly156A1a and Val217Ile), only one of which (Gly156A1a)
      is deleterious.
AB  - Purine nucleoside phosphorylase (PNP) deficiency results in an autosomal
      recessive immunodeficiency disease characterized by initial involvement of
      cellular immunity and neurological manifestations with subsequent abnormalities
      of humoral immunity. The initial presentation and clinical course has varied
      widely in the relatively few published cases. The molecular basis has been
      reported in only 10 patients, precluding evaluation of phenotype-genotype
      relationships. We now report clinical, immunologic, and molecular findings in a
      new case of relatively early onset that emphasizes hypotonia and developmental
      delay as early manifestations. The patient carried two novel missense mutations
      (Gly56A1a and Val217Ile) on the same allele in apparent homozygosity. Expression
      of each of the mutant enzymes in vitro demonstrated that the Gly156A1a mutation
      abolished enzyme activity while the Val217Ile mutation was without obvious effect
      and is therefore a normal variant. Such "normal" polymorphisms might be
      associated with a variable response to the immunosuppressive PNP inhibitors
      currently in clinical trials.

PMID- 12483997
TI  - Proatherogenic and proinflammatory properties of immune complexes prepared with
      purified human oxLDL antibodies and human oxLDL.
AB  - Immune complexes (IC) prepared with human low density lipoprotein (LDL) and
      rabbit LDL antibodies induce foam cell transformation of human macrophages and
      activate the release of proinflammatory mediators by human macrophages and THP-1
      cells. Because the affinity of human oxidized LDL (oxLDL) antibodies is lower
      than that of rabbit antibodies, IC formed with human antibodies could have
      limited pathogenic potential. Immune complexes prepared with human oxidized LDL
      (oxLDL) and purified human oxLDL antibodies (predominantly of the IgG1 and IgG3
      isotypes) were presented to THP-1 cells using two protocols previously described
      in studies of the properties of LDL-IC prepared with rabbit antibodies.
      OxLDL/human oxLDL antibody IC immobilized by adsorption to red blood cells (RBC)
      induced the release of significantly higher levels of TNF from THP-1 cells (872
      313 pg/ml) than oxLDL adsorbed to RBC (461-75.6 pg/ml) and caused a higher degree
      of cholesterol ester accumulation in the same cells (5.4-0.77 in cells incubated
      with IC-coated RBC vs 1.99-1.16 in oxLDL-coated RBC). Insoluble IC prepared with
      oxLDL/human oxLDL antibody were even more effective in promoting intracellular
      accumulation of cholesterol in THP-1 cells (total cholesterol = 53.8-13.5 and
      cholesterol esters = 24.0-7.2 mg/l in THP-1 cells incubated with insoluble IC
      (200 micrograms) vs total cholesterol = 32.4-8.2 and cholesterol esters = 7.7 +/-
      2.8 micrograms/l in THP-1 cells incubated with an identical concentration of
      oxLDL) and also induced the release of TNF. Thus we have demonstrated that IC
      prepared with human oxLDL and human oxLDL antibodies have the same atherogenic
      and proinflammatory properties as IC prepared with human LDL and rabbit LDL
      antibodies. This strongly supports the concept that modified LDL-IC present in
      circulation and/or tissues play an important pathogenic role in arteriosclerosis.

PMID- 12483998
TI  - Generation of monocyte-derived dendritic cells in patients with hereditary
      hemochromatosis.
AB  - Hereditary hemochromatosis (HH) is a common genetic disease with autosomal
      recessive transmission and is characterized by a dysregulation of iron
      metabolism, leading to serum iron overload and its progressive accumulation in
      most body tissues. The effects of HH on the immune system include altered
      lymphocytosis and functions of monocytes. Moreover, monocytes can differentiate
      into dendritic cells (DCs), which play crucial roles in the immune response
      (capture, processing, and presentation of antigen to effector T cells) and this
      process was shown to be impaired in several pathologies. The aim of this study
      was to determine whether the monocytes from HH patients still displayed the
      ability to differentiate into DCs. To that purpose, purified monocytes from
      healthy donors and HH patients were cultured in the appropriate medium. The
      results showed no phenotypic and functional differences, at both the immature and
      the mature stages. Furthermore, our work reports altered lymphocytosis with
      expanded CD8+CD28- T cell subset. These monocyte-derived DCs could therefore be a
      solid vector for DC-based immunotherapy and a powerful tool for investigating the
      immune regulatory loops and especially the biological relevance of the expanded
      CD8+CD28- T cells since this population has also been described as suppressor T
      cells.

PMID- 12483999
TI  - Assessing cardiovascular risk in children: the Jackson, Mississippi CRRIC Study.
AB  - According to the NHANES III study, obesity, a cardiovascular risk factor, is now
      an epidemic in the United States. An estimated 97 million adults and one in five
      children between 6 and 17 are overweight. The purpose of this pilot study was to
      determine the prevalence of cardiovascular risk factors among a group of 3rd,
      4th, and 5th graders at two randomly chosen elementary schools in Jackson,
      Mississippi. The sample consisted of 246 ethnic minority children. Results
      revealed that 16% of the boys had systolic blood pressures at or above the 90th
      percentile for sex and age and 13% had abnormally high diastolic blood pressures.
      For girls, 8% exhibited systolic blood pressures and 21% had diastolic blood
      pressures at or above the 90th percentile. Body mass index (BMI) levels revealed
      that 39% of the boys and 49% of the girls had BMIs at or above the 85th
      percentile for age and sex.

PMID- 12484000
TI  - Racial identity from an African Amercian perspective.
AB  - Mortality and morbidity rates for African Americans remain high. Many of the
      contributing factors to these deaths may be associated with lifestyle. Research
      has shown that racial identity influences the lifestyles of African Americans.
      Racial identity includes the adoption of personal behaviors and identification
      with a group of people with similar characteristics. Clarifying the notion of
      racial identity may lead to a better understanding of how racial identity
      influences health behaviors. The purpose of this study was to explore racial
      identity from a qualitative perspective. A focus group of African Americans
      residing in a metropolitan (n = 12) city of the United States was used for data
      collection. Seventy-five percent of the sample were female (n = 16) with a mean
      age of 43 years (s.d. = 7.26) and a range of 36 to 54 years of age. After
      analyses of the data, three themes emerged. These themes were "Racial Identity
      When Growing Up," "Becoming Aware of Racial Differences," and "Present Racial
      Identity." Sub-themes of each were explored in detail.

PMID- 12484001
TI  - Tuberculosis screening in an at-risk immigrant Hispanic population in Baltimore
      city: an academic health center/local health department partnership.
AB  - Tuberculosis (TB) is endemic and epidemic throughout the world. More people will
      die of TB this year then in any previous year in modern history. However, in the
      United States successful TB control programs have resulted in low morbidity and
      low mortality here. Globalization and immigration threatens this control
      potentially bringing the infection to a here-to-fore complacent United States.
      This article describes a unique partnership between a community health program of
      a School of Nursing and a local health department chest clinic to find, screen
      and treat a population of Hispanic immigrants otherwise difficult to reach
      because of legal, language, cultural and socioeconomic barriers. Working through
      community organizations and limiting, and/or eliminating cultural barriers
      accomplished a high level of screening and treatment in a population with a
      significant incidence of latent tuberculosis infection. The program was of great
      satisfaction to the students and faculty involved; the personnel of a seriously
      under-financed health department and the community participants involved.

PMID- 12484002
TI  - Cultural implications in the management of grief and loss.
AB  - As culturally unique individuals, our culture impacts and even dictates our
      responses to normal events of daily living. We are frequently unaware of the way
      we value time, perceive spatial boundaries, and communicate with others. Health
      care professionals must be culturally sensitive to all individuals. Culturally
      diverse nursing care acknowledges the individual's cultural uniqueness and
      incorporates a variety of approaches to provide culturally sensitive care. This
      paper will discuss culturally diverse health care with a client experiencing
      grief and loss.

PMID- 12484003
TI  - [A case of locally extended rectal cancer responding to intra-arterial infusion
      therapy via the internal iliac artery].
AB  - Chemotherapy with combined administration of 5-FU and l-Leucovorin has been
      reported to be effective for advanced rectal cancer. A 61-year-old woman with a
      huge, locally extended advanced rectal cancer was treated with intra-arterial
      infusion therapy via internal iliac artery. Catheters were inserted from the
      bilateral femoral arteries to the opposite internal iliac arteries and the
      bilateral upper and lower gluteal arteries and lateral sacral artery were
      embolized with a metallic coil. The port was positioned under the skin of her
      lower abdominal wall. The chemotherapy regimen was 5-FU (500 mg/body) and l
      Leucovorin (250 mg/m2), administered over 5 hours once weekly to bilateral
      reservoirs through an infuser pump. After 5 sessions of the chemotherapy, the
      perineal pain decreased and the patient no longer needed morphine. Following 34
      administrations (at 10 months) of this regimen, reductions of tumor size on
      pelvic CT and CEA level were confirmed. Side effects of the intra-arterial
      infusion chemotherapy were pygal dermatitis, leg desensitization, infection of
      circumferential reservoir and obstruction of the catheter due to flection were
      observed. Local intra-arterial infusion chemotherapy via the internal iliac
      artery appears to be effective for local advanced rectal cancer.

PMID- 12484005
TI  - [A case of intrahepatic bile duct necrosis following hepatic arterial infusion
      chemotherapy].
AB  - A 51-year-old man underwent partial hepatectomy in July 2000 for metastatic liver
      tumor after gastrectomy for gastric cancer. He received seven cycles of hepatic
      arterial infusion with mitomycin C 20 mg during induced hypertension with
      angiotensin II from October 2000 to April 2001. His body temperature sometimes
      rose above 38 degrees C in June and jaundice appeared in August 2001. Blood
      biochemistry tests showed an elevated value of alkaline phosphatase, gamma
      glutamyl transpepsidase and total bilirubin. Based on an enhanced CT scan of the
      liver showing a low-density area along intrahepatic biliary tracts and hepatic
      arteriography showing stenosis of the proper hepatic artery, we diagnosed bile
      duct necrosis and hepatic necrosis. Bile duct necrosis is a serious complication
      in arterial infusion chemotherapy, and the infusion chemotherapy should be
      suspended or the dose should be reduced for patients with abnormalities shown by
      hepato-biliary function tests.

PMID- 12484004
TI  - [Intra-arterial chemotherapy with gemcitabine (GEM) for unresectable pancreatic
      cancer].
AB  - PURPOSE: Most patients with pancreatic cancer are unresectable because of local
      invasion and liver metastasis at the time of diagnosis. To date, no treatment has
      had a significant impact on this disease. To deliver a high concentration of drug
      to the cancer, intra-arterial chemotherapy with GEM was performed in two patients
      with unresectable advanced cancer. PATIENTS AND METHODS: One patient, a 70-year
      old man with liver metastasis, was treated with arterial infusion of GEM 1,000
      mg/body. Another patient, a 55-year-old woman with local invasion and distant
      metastatic lymphadenopathy, was given intra-arterial infusion of GEM 400 mg and
      intra-venous infusion of GEM 1,000 mg/body. The patients were given GEM weekly
      for 3 weeks followed by a week of rest. RESULTS: In the first patient, the pain
      went away and CEA was decreased for 6 months. After that, the patient died due to
      intra-abdominal dissemination within 4 months. In the other patient, the pain
      went away. Tumor markers, such as CEA and CA19-9, were normalized and primary
      pancreatic cancer was reduced locally. The patient currently has a metastatic
      liver tumor, but she has had a significant improvement in performance status.
      CONCLUSION: Intra-arterial chemotherapy with GEM may be tolerated in patients
      with unresectable pancreatic cancer.

PMID- 12484006
TI  - [A case of postoperative hepatic metastasis from gastric cancer responding to
      hepatic arterial infusion chemotherapy of paclitaxel].
AB  - A 70-year-old man underwent total gastrectomy for advanced gastric cancer in
      January 2000. He was treated with UFT of 300 mg/day after surgery. In December
      2000, liver metastasis was detected. In January 2001, treatment was switched to
      oral administration of TS-1 at 100 mg/day. In April 2001, there were no
      extrahepatic lesions. However, the metastatic liver focus showed progression of
      the disease (PD). TS-1 was discontinued. In May 2001, a hepatic arterial
      injection reservoir was inserted. Thereafter, arterial injection chemotherapy
      with 5-FU was administered. However, in November, liver dysfunction was
      exacerbated, and computed tomography (CT) revealed PD. Therefore, in December,
      the above chemotherapy was switched to arterial injection of paclitaxel at 100
      mg, which was administered once a week for 3 weeks and discontinued for the
      subsequent week. In March 2002, hepatopathy had subsided at the end of the 4th
      course, the performance status (PS) improved and CT revealed a minor response. In
      June 2002, the condition deteriorated to PD. However, there were no side effects
      other than alopecia. During the administration period, treatment at the
      outpatient clinic could be safely performed. These findings suggest that hepatic
      arterial injection therapy with paclitaxel for liver metastasis after surgery for
      gastric cancer is a useful second line for 5-FU-resistant patients.

PMID- 12484007
TI  - [A case report of intra-hepatic arterial infusion of mitomycin C with degradable
      starch microspheres for liver metastases of sigmoid colon carcinoma].
AB  - A 46-year-old man underwent polypectomy of sigmoid colon in January 1996. The
      adenocarcinoma invaded the submucosal layer, and sigmoidectomy and D2 lymph node
      dissection were performed one month later. Follow-up CT revealed liver
      metastases, and partial hepatectomy was performed in January 1998. Afterward,
      weekly high dose intra-hepatic arterial chemotherapy (5-FU: 1,000 mg/body) was
      performed 41 times, but CT revealed multiple liver metastases in October 1998.
      Therefore, intra-hepatic arterial infusion of mitomycin C (MMC) with degradable
      starch microspheres (DSM) was given in November 1998. As follow-up CT revealed
      that the liver metastases were growing, partial hepatectomy was performed again
      in March 1999. No carcinoma was seen in the resected liver. After the second
      hepatectomy, intra-hepatic arterial infusion of MMC with DSM was performed five
      times. No evidence of recurrence has been seen. Intra-hepatic arterial infusion
      of MMC with DSM is recommended for liver metastases of colorectal cancer as a
      second line treatment.

PMID- 12484008
TI  - [A report of two cases in which radiation therapy was effective for distant lymph
      node metastases after curative resection of gastric cancer].
AB  - Long-term survival is difficult after manifestation of distant lymph node
      metastasis following curative resection for advanced gastric cancer. Two patients
      who achieved long survival with linac therapy after curative treatment of gastric
      cancer, are reported. Case 1: 45 years old, male. Distal gastrectomy with D2
      dissection was carried out for such gastric cancer as L.M, less.Post.Ant, fType
      3, T2 (MP), fStage II, on July 13, 1994. As paraaortic lymph nodes metastases was
      observed with CT examination on October 12, 1995, irradiation therapy using linac
      was conducted, and CR was achieved. Though Virchow's lymph nodes metastases was
      followed that episode, PR was achieved with 4,750 cGy of linac therapy. Finally,
      however, the patient died with metastases to lung and bone on May 19, 2002. Case
      2: 62 years old, male. Distal gastrectomy with D2 + No.8p and also No.16b1
      interaorticocaval dissection was conducted for such advanced gastric cancers as
      M, less, fType 3, T3 (SE), fStage III B on June 7, 1995. Paraaortic lymph nodes
      metastases were observed through CT examination on October 12, 1995. Irradiation
      therapy using linac resulted in CR. Virchows lymph node metastasis, which
      appeared on December 12, 1997, was also treated with 5,000 cGy of linac, and CR
      was also achieved. The patient is surviving today without recurrence.

PMID- 12484009
TI  - [Evaluation of intra-arterial infusion chemotherapy for liver metastasis from
      gastric cancer FEM--combination therapy of 5 FU, Epirubicin and MMC].
AB  - OBJECTIVE: We evaluated the effectiveness of FEM (5-FU, Epirubicin, MMC) therapy.
      SUBJECTS: One hundred ten cases of liver metastasis from gastric cancer were
      collected from January, 1977 until June, 2001 (synchronous: 74 cases,
      asynchronous: 36 cases). Twenty-nine cases were H1, 20 cases were H2 and 61 cases
      were H3. METHODS: The patients were divided into the following groups: Group A:
      Resection of the primary lesion and hepatic resection (n = 9); Group A1: Hepatic
      resection only (5 cases), Group A2: Hepatic resection and intra-arterial infusion
      (4 cases). Group B: Resection of the primary lesion (n = 67); Group B1: Resection
      of the primary lesion only (46 cases), Group B2: Intra-arterial infusion (21
      cases). In Groups A2 and B2, FEM therapy was applied to A2a (3 cases) and B2a (8
      cases). Non-FEM therapy was applied to A2b (1 case) and B2b (13 cases). Group C
      consisted of 34 cases in which resection of the primary lesion was not
      undertaken. Survival rates were then compared. RESULTS: One-year survival rates
      and 50% survival period for each group were as follows: Group A: 33%, 5.9 months;
      Group B: 22%, 4.8 months; and Group C: 6%, 3.9 months, respectively. Five
      patients from Groups A2a and B2a survived for one year or longer. CONCLUSION: 1.
      The prognosis with liver metastasis from gastric cancer, even with a number of
      therapies, is not promising. 2. Resection of the primary lesion along with
      hepatic intra-arterial infusion therapy (in addition to hepatic resection),
      especially in combination with FEM therapy, provided an extended survival.

PMID- 12484010
TI  - [Effect of hepatic arterial infusion chemotherapy for liver metastasis from
      gastric cancer].
AB  - We performed hepatic arterial infusion (HAI) chemotherapy for 4 patients with
      advanced gastric cancer who had undergone curative resection except for liver
      metastasis. The main antineoplastic drugs were 5-fluorouracil (5-FU), mitomycin C
      (MMC) and cisplatin (CDDP). A catheter was inserted into the hepatic artery by
      interventional radiological techniques in 3 patients and operatively in 1
      patient. The response rate for 4 patients was 75% (CR2, PR1, PD1). The adverse
      events were Grade 3/4 nausea and/or vomiting in 2 cases. The HAI chemotherapy was
      effective and useful for patients with advanced gastric cancer who had no
      unresectable lesions except for liver metastasis.

PMID- 12484011
TI  - [Evaluation of hepatic resection for metachronous liver metastases from gastric
      cancer].
AB  - To evaluate the effect of hepatic resection for metachronous liver metastases
      after resection of gastric cancer, the clinicopathological factors of gastric
      cancer, state of liver metastasis, surgical procedures for liver metastasis, and
      remote survival were studied. Between 1989 and 2001, 30 consecutive patients
      underwent hepatic resections (36 resections) for metachronous liver metastases.
      The patients included 25 men and 5 women, and the median age was 60 years old
      (range 46-86 years old). As for curability, curative A/curative B was 10/20, and
      H0/H1/H2 was 25/3/2. The mean period from initial surgery to the liver resection
      was 19.3 months (range 6.3-65.2 months), and the liver metastatic conditions were
      H1 for 27 patients and H2 for 9 patients. By number of liver metastases, 27
      patients had 1 lesion, 24 patients had 2, and 5 patients had more than 3 lesions.
      Twenty-nine patients were negative and 7 were positive for lymph node metastasis.
      A partial resection was performed for 13 patients, a subsegmentectomy for 3
      patients, a segmentectomy for 7 patients, a lobectomy for 8 patients, and an
      extended lobectomy for 5 patients. For all patients except those who had other
      causes of death, the overall mean survival time was 702 days and the 5-year
      survival rate was 26.4%. There were four 5-year survivors after hepatic
      resection. In conclusion, the main prognostic factor after resection of
      metachronous liver metastases was the existence of lymph node metastasis, and the
      remote survival of patients with abdominal para-aortic lymph node recurrence was
      poor. The type of liver resection was not a predictor of survival. The resection
      of liver recurrence was evaluated clinically, but we should maintain strict
      criteria and select adequate surgical procedures.

PMID- 12484012
TI  - [Resection made possible following hepatic arterial infusion in 2 cases of
      hepatic metastases from colorectal cancer].
AB  - Of 66 examples of hepatic metastases from colorectal cancer, 30 cases in which
      resection was performed had 3- and 5-year cumulative survival rates of 66.7% and
      56.8%, while in 36 cases in which resection was not possible, the percentages
      were 8.7% and 2.9%, respectively. In two of the latter cases, resection was
      possible following WHF (5-FU 1,000 mg/m2 5 h qw). Case 1: A 58-year-old male,
      with rectal cancer and multiple metastases (H3, synchronous). Arterial infusion
      was performed 21 times, with the total volume of 5-FU administered being 31.5 g.
      The size of the lesions was reduced and hepatic resection was performed. The
      patient later died due to local recurrence and intra-abdominal lymph node
      metastases. He had survived 2 years and 11 months following hepatic resection and
      was free from recurrence of hepatic metastases. Case 2: An 82-year-old female,
      with cancer of the ascending colon, sigmoidal colon and multiple hepatic
      metastases (H3, metachronous). Arterial infusion was performed 16 times, with the
      total amount of 5-FU administered being 20 g. A lowering of CEA levels and
      reduction of tumor size were achieved, and hepatic resection was performed. Seven
      months following hepatic resection, CEA levels are normal and no distant
      metastases or recurrence in the residual liver have been found: possibly a
      complete cure. Even among cases of unresectable hepatic metastases from
      colorectal cancer, there are some in which resection is possible following
      hepatic arterial infusion chemotherapy, with the possibility of complete cure.

PMID- 12484013
TI  - [Hepatectomy and intraarterial infusion chemotherapy for liver metastasis from
      colorectal cancer].
AB  - Hepatectomy and intraarterial chemotherapy for liver metastasis from colorectal
      cancer have been performed in our department. Intraarterial infusion chemotherapy
      has also been performed for unresectable liver metastasis. One hundred twenty
      seven cases of liver metastasis from colorectal cancer were studied. The cases
      were divided into groups according to radicability of the original colorectal
      cancer, whether or not hepatectomy was performed, and whether or not they
      received intraarterial chemotherapy. Group I is cur C of origin. Group II is cur
      A or B without hepatectomy. Group III is cur A or B with hepatectomy. Each group
      was divided into a group without intraarterial chemotherapy (A) and a group with
      it (B). IA 23 cases, IB 13 cases, IIA 14 cases, IIB 21 cases, IIIA 28 cases, and
      IIIB 28 cases. The survival rate of group III was better than that of group II.
      The survival rate of group II was better than that of group I. There was no
      significant difference in survival rates between IA and IB. The survival rate of
      group IIB was significantly better than that of group IIA. The survival rate of
      group IIIB was significantly better than that of group III A. Hepatectomy and
      intraarterial chemotherapy after hepatectomy for liver metastasis from colorectal
      cancer were effective.

PMID- 12484014
TI  - [5-FU pharmacokinetic study of 5-FU hepato-arterial infusion with oral UFT].
AB  - 5-FU hepato-arterial infusion (HAI) is powerful chemotherapy for liver metastases
      of colorectal cancers. Event though hepatic lesions are controlled by 5-FU HAI,
      we have found that extra-hepatic lesions are the limiting factor for colorectal
      cancer patients. General chemotherapy is necessary in addition to 5-FU HAI. The
      chemotherapy of 5-FU venous infusion plus oral UFT is called "pharmacokinetic
      modulating chemotherapy (PMC)." This protocol is very effective for colorectal
      cancers, because UFT reduces the rate of metabolism of infused 5-FU. We studied
      the plasma 5-FU concentration at the time of weekly high dose 5-FU HAI plus oral
      UFT. The plasma concentration of 5-FU in 5-FU HAI plus UFT is 1.5-6 times as high
      as with 5-FU HAI only. 5-FU concentration in the liver tissue is likely to be
      much higher at the time of 5-FU HAI. 5-FU HAI plus oral UFT can be more effective
      for not only liver metastases but also for extra-hepatic lesions than 5-FU HAI
      alone.

PMID- 12484015
TI  - [Evaluation of intra-arterial infusion chemotherapy for liver metastasis from
      colorectal cancer].
AB  - We evaluated the effect of intra-arterial infusion chemotherapy for liver
      metastasis from colorectal cancer. Of 405 patients undergoing colectomy in our
      department from July 1993 to February 2002, 38 had liver metastasis. We performed
      catheterization intra-operatively or postoperatively, and intra-arterial infusion
      chemotherapy was given for liver metastasis from colorectal cancer. Thirty-eight
      patients were treated with four different arterial infusion courses that mainly
      consisted of 5-FU. The 5-year survival rate was 8%. Maximal survival period was
      68 months, and mean survival was 22 months. The effective rate was 20% Intra
      arterial infusion chemotherapy was a useful treatment for liver metastasis from
      colorectal cancer. Resection of the liver metastasis was the first choice for
      operative liver metastases from colorectal cancer, and we performed intra
      arterial infusion chemotherapy for patients postoperatively or patients with non
      operative liver metastasis.

PMID- 12484016
TI  - [Hepatic arterial infusion of IL-2 and chemotherapy for unresectable liver
      metastasis from colorectal cancer].
AB  - We administered interleukin (IL)-2 with mitomycin C (MMC) and 5-fluorouracil (5
      FU) by hepatic arterial infusion for the treatment of liver recurrence from
      colorectal cancer. The regimen consisted of continuous hepatic arterial infusion
      of IL-2 (7 x 10(5) JRU/day)/5-FU (250 mg/day) for 4 weeks. After those 4 weeks, a
      weekly hepatic arterial infusion of IL-2 (2.1 x 10(6) JRU)/5-FU (250 mg) was
      performed more than 4 weeks. MMC (4 mg) was given as a bolus weekly. This therapy
      resulted in partial response (PR) in one case, progressive disease (PD) in one
      case, and no change (NC) in one case. The toxicity of the therapy was a slight in
      all cases. We herein report 3 patients treated with hepatic arterial infusion of
      IL-2 with MMC and 5-FU for liver recurrence from colorectal cancer. This therapy
      may be a new strategy for metastatic colorectal cancer.

PMID- 12484017
TI  - [Evaluation of hepatic arterial infusion chemotherapy with levofolinate (l-LV)
      and 5-fluorouracil (5-FU) for multiple liver metastases from colorectal cancer].
AB  - We evaluated the effect of hepatic arterial infusion chemotherapy with
      levofolinate (l-LV) and 5-fluorouracil (5-FU) for multiple liver metastases from
      colorectal cancer. All patients received drugs on an outpatient basis every six
      weeks, followed by no medication for two weeks. In this regimen levofolinate (200
      mg/m2) was administered for two hours and 5-fluorouracil (500 mg/m2) was
      administered for thirty minutes as a bolus. A complete response was obtained in
      five patients and a partial response in five patients; the overall response rate
      was 40%. All patients could receive this therapy on an outpatient basis because
      no patient had side effects of Grade 3 or over. It is suggested that our protocol
      may be useful for improvement of outcome.

PMID- 12484018
TI  - [Complications related to hepatic arteria infusion chemotherapy for liver
      metastasis].
AB  - Complications from hepatic arterial infusion chemotherapy were analyzed in 27
      cases with liver metastasis from colorectal cancer from December 1994 to April
      2002 in our department. The method used to place the catheter was laparotomy (LP)
      in 11 patients, intervention radiology (IVR) in 16 patients. Complications
      resulting in interruption of therapy occurred in 7 (26%) patients, and the IVR
      method was associated with a lower rate of complications than the LP method. The
      complications with the LP method were 3 (11%) cases of hepatic arterial
      occlusion, and 2 (7.4%) cases of catheter tip dislocation. The best indwelling
      route for the catheter thus seems to be the IVR method. The IVR method is our
      first choice for all patients now.

PMID- 12484019
TI  - [Reasonable approach for prophylactic hepatic arterial infusion chemotherapy
      after potentially curative surgery for colorectal liver metastases].
AB  - The authors discuss the reasonable management of implantable ports and catheters
      after cessation of adjuvant hepatic arterial infusion (HAI) chemotherapy
      following curative resection of colorectal liver metastases. Local recurrence in
      the residual liver was observed in only 4 patients of thirty-two patients (13%).
      Although heparin administration into the port was regularly performed in 17
      patients to prevent its occlusion, the ports were successfully maintained in only
      9 patients at a median time of 11.8 months postoperatively, and only one patient
      received further regional chemotherapy for recurrent disease. These findings
      indicate that heparin administration to maintain the port brings little benefit.
      In the most recent 3 cases, we used a new Piolax W Spiral catheter and removed
      the catheter and port after cessation of adjuvant chemotherapy. No complication
      related to the procedure occurred, and patients' quality of life was well
      preserved, suggesting that this approach for HAI is reasonable and beneficial.

PMID- 12484020
TI  - [A case of postoperative liver metastasis of alpha-fetoprotein producing gastric
      cancer successfully treated with intrahepatic chemotherapy (adriamycin,
      cisplatin, irinotecan hydrochloride)].
AB  - There are only a few reports demonstrating effective regimens for AFP-producing
      gastric cancer. We report a case of alpha-fetoprotein (AFP)-producing gastric
      cancer successfully treated with postoperative intrahepatic chemotherapy,
      together with a review of the literature. A 63-year-old man was diagnosed as
      having multiple liver metastases 6 months following total gastrectomy for type 2
      gastric cancer. Serum AFP level was markedly elevated at 291.4 ng/ml although the
      level was not determined at the time of gastrectomy. Twenty cycles of
      intrahepatic arterial infusion with adriamycin, cisplatin, and irinotecan
      hydrochloride resulted in a 93% decrease in the liver metastases along with
      normalization of the serum AFP level. These results suggest that this regimen is
      worth trying for patients with liver metastasis from AFP-producing gastric
      cancer.

PMID- 12484021
TI  - [Pulmonary resection for metastatic colorectal cancer].
AB  - We reviewed the clinical courses of 25 patients who underwent pulmonary resection
      for metastatic lesions from colorectal cancer between January 1991 and December
      2001. The cumulative survivals at 3 and 5 years were 72% and 63%, respectively.
      Sex, site of the primary tumor, presence of extrapulmonary metastases, disease
      free interval, location of pulmonary metastases (PM), number of PM, size of PM,
      mode of operation, pre-thoracotomy serum carcinoembryonic antigen level, and post
      thoracotomy chemotherapy were not found to be statistically significant
      prognostic factors. Age (70 years < or =) was a predictor of a shorter survival
      duration by univariate analysis (p = 0.02). Recurrence was observed in 19
      patients, 11 of which were lung recurrences. Eight patients underwent repeated
      pulmonary resection. The median survival in these 8 patients was 23 months after
      second pulmonary operation. Surgical treatment for pulmonary metastases from
      colorectal cancer in selected patients might improve prognosis.

PMID- 12484022
TI  - [Limits of surgical therapy for pulmonary metastasis from breast cancer].
AB  - Sixteen cases of first pulmonary metastasis from breast cancer were reexamined.
      There was no significant difference between the operated and non-operated cases.
      The prognoses of both groups were unfavorable due to aggravation of the lung,
      including the pleural focus or other distant metastases. We found a surgical
      benefit in only selected cases such as comparatively advanced breast cancers with
      long disease-free intervals, and cases in which the differentiation with the
      primary lung cancer was difficult. We recommend a mildly invasive operation using
      video-assisted thoracic surgery in these cases.

PMID- 12484023
TI  - [Case report--a patient who has survived more than 4 years with repeated
      resection for bilateral adrenal metastasis from hepatocellular carcinoma].
AB  - We report a patient with bilateral adrenal metastasis from hepatocellular
      carcinoma (HCC) who has survived for a long period as a result of repeated
      resection. A 55-year-old male patient with C type hepatitis underwent
      transcatheter arterial chemo-embolization (TACE) for HCC in November 1997. There
      was no recurrence in the liver, but left adrenal metastasis was detected in
      January 1998, followed by right adrenal metastasis in November 1998. We performed
      surgical resection for bilateral adrenal metastasis in March 1999. The
      histological diagnosis was well approximately moderately differentiated
      hepatocellular carcinoma. A recurrence in the right adrenal gland was detected
      eight months later. As there was no distant metastasis, we performed re-operation
      in December 1999. Recurrence in the liver was detected in October 2000 and was
      treated by TACE. He has survived more than 4 years since the first detection of
      adrenal metastasis. We conclude that surgical treatment is useful for patients
      with adrenal metastasis who have no distant viable lesion.

PMID- 12484024
TI  - [Comparison of percutaneous microwave coagulation area under interruption of
      hepatic arterial blood flow with that under hepatic arterial and venous blood
      flow for hepatocellular carcinoma].
AB  - The study subjects were 49 patients with hepatocellular carcinoma. Twenty-nine
      patients underwent hepatic arterial blood flow block via thrombosis of the cancer
      bearing area with a gelatin sponge, while the other 20 patients underwent a
      combination of hepatic arterial block and partial blood flow block of the portal
      vein with a hepatic venous balloon. Percutaneous microwave coagulation therapy
      (PMCT) was performed on these patients according to the type of hepatic blood
      flow block, and the diameters of the coagulation areas in the two groups were
      compared using CT images taken under portal venography. The 29 patients who
      underwent hepatic arterial block (A-PMCT) had a mean tumor diameter of 19.2 +/- 8
      mm, while the 20 patients who underwent hepatic arterial and hepatic venous block
      (AV-PMCT) had a mean tumor diameter of 25.3 +/- 8.3 mm. PMCT was performed at 60
      W. The mean coagulation time and the mean coagulation diameter were 4.2 +/- 1.1
      min and 36.3 +/- 12.3 mm, respectively, for the A-PMCT group and 5.5 +/- 1.8 min
      and 43.9 +/- 9.8 mm, respectively, for the AV-PMCT group. A comparison of the
      coagulation diameters indicated that the AV-PMCT group had a significantly
      greater coagulation area than the A-PMCT group (p < 0.05).

PMID- 12484025
TI  - [Examination of percutaneous microwave coagulation and radiofrequency ablation
      therapy for metastatic liver cancer].
AB  - Percutaneous microwave coagulation therapy (PMCT) and radio frequency ablation
      therapy (RFA) as treatments for metastatic liver cancer were examined. PMCT or
      RFA was administered for 18 metastatic liver cancer lesions (primary lesion: 11
      colon rectal cancer, one esophagus cancer, one thyroid cancer, one pancreatic
      cancer, one pheochromocytoma) in 16 patients from July 1999 to March 2002. RFA
      was performed 1 time for 12 minutes in principle, using a Cool-tip RF system from
      Radionics. Patients had a mean age of 58.8 years and the mean diameter of the
      neoplasms was about 22 mm. Critical complications were not seen. The rate of
      partial recurrence was 35.3% as of March, 2002, in an average observation period
      of 7.3 months. On the other hand, with the medical treatment for the
      hepatocellular carcinoma provided during this period, the rate of partial
      recurrence was 14.8%. The treatment of metastatic liver cancer by PMCT and RFA is
      associated with a high rate of a recurrence as compared with hepatocellular
      carcinoma, and needs to be examined to discover ways of adaptation and
      improvement of the technology.

PMID- 12484026
TI  - Intraarterial cellular immunotherapy for patients with inoperable liver
      metastases of esophageal cancer.
AB  - PURPOSE: We report 2 patients with refractory liver metastatic tumor after
      esophagectomy for advanced esophageal cancer, who responded markedly to
      locoregional cellular immunotherapy by repeated intraarterial infusions of
      autologous tumor cell-activated T lymphocytes (AuTL), even after they failed the
      standard chemotherapy of cisplatin (CDDP) and 5-fluorouracil (5-FU). METHODS:
      AuTL administrations were made through the hepatic artery via a subcutaneous
      reservoir located at the right upper leg. Six injections were administered to
      both patients, repeated at 2-week intervals. The total number of administered T
      cells reached 2.4 x 10(9) and 3.1 x 10(9), respectively. RESULTS: A 39% and 51%
      regression in each infused field, compared with the size of liver tumor before
      treatment, was observed by computed tomography (CT) scan in patient 1 and 2,
      respectively. The responses continued up to the 10th and 11th month after the
      intraarterial infusion, confirmed by follow-up CT scan. The adverse effects of
      intraarterial immunotherapy were tolerable, with grade 1-2 fever and nausea in
      each patient. CONCLUSIONS: Clinical regression of liver metastases of esophageal
      cancer was observed in both patients who received this intraarterial cellular
      immunotherapy. Liver metastases of esophageal cancer may be controlled
      effectively and safely by repeating the intraarterial AuTL infusion as a
      locoregional immunotherapy over a long period.

PMID- 12484027
TI  - [Studies of the effectiveness and optimal administration of repeated
      intraperitoneal chemotherapy for peritoneal dissemination from gastric cancer].
AB  - The optimal interval for drug administration was examined for repeated
      intraperitoneal chemotherapy (IPC). The subjects were 31 patients who underwent
      curative surgical resection excluding P1 or CY1 factor, followed by IPC. IPC was
      carried out 180 times in total, and the intervals were divided into three groups:
      2-week interval 45 times, 3-week interval 10 times and 4-week or greater interval
      94 times. The optimal method of drug administration was evaluated from the
      therapeutic outcome and the development of adverse effects with each interval
      time. The cytology of ascites obtained via an i.p. port was examined before each
      drug administration, and those with a negative change (CY0) were judged as
      responders. The adverse effects in the patients receiving drugs at 2-week
      intervals were grade 1 or 2, although the incidence was high compared with other
      patients. All responders obtained a negative change in CY within six courses. At
      present, we conclude that it is reasonable for IPC to be carried out six times at
      2-week intervals.

PMID- 12484028
TI  - [Pharmacologic study of intraperitoneal paclitaxel in gastric cancer patients
      with peritoneal dissemination].
AB  - This study was designed to evaluate the pharmacokinetics and toxicity of
      paclitaxel administered via an intraperitoneal (i.p.) route for patients with
      gastric cancer. Fourteen patients with peritoneal dissemination were entered in
      the trial. Three distinct dose levels from 120 to 180 mg/body were studied. A
      major pharmacokinetic advantage (550-2,000 fold) for peritoneal cavity exposure
      compared with the systemic compartment was seen following intraperitoneal
      delivery of paclitaxel. The dose-limiting toxicity was found to be abdominal pain
      at 180 mg/body. Grade 2 toxicity included 1 episode of neutropenia and grade 1
      toxicities included 1 case of finger-numbness and 2 of alopecia. We conclude that
      intraperitoneal paclitaxel administration is well tolerated and provides a
      peritoneal pharmacokinetic advantage for the treatment of peritoneal
      dissemination.

PMID- 12484029
TI  - [Effectiveness of continuous hyperthermic peritoneal perfusion for the peritoneal
      dissemination of gastric cancer].
AB  - We investigated the effectiveness of continuous hyperthermic peritoneal perfusion
      (CHPP) for the peritoneal dissemination of gastric cancer. A total 124 patients
      with advanced gastric cancer were enrolled in this study. Prophylactic CHPP (P
      CHPP) was performed in 45 patients who had macroscopic serosal invasion without
      peritoneal dissemination, and 79 patients without CHPP were a control group.
      Therapeutic CHPP (T-CHPP) was performed in 21 patients with peritoneal
      dissemination, and 52 patients without CHPP were a control group. There was no
      significant difference in 5 year survival between patients treated and not
      treated with P-CHPP. Univariate analysis showed that location of tumor, tumor
      diameter, and lymph node metastasis influenced prognosis, but there was no
      prognostic factor in the Cox proportional regression hazard model. There was no
      significant difference in 5-year survival between patients treated and not
      treated with T-CHPP. Univariate analysis showed that degree of peritoneal
      dissemination and adjuvant chemotherapy influenced prognosis, and the Cox
      proportional regression hazard model showed that the macroscopic types and degree
      of peritoneal dissemination affected prognosis. In the patients with CHPP, the
      incidences of respiratory failure and renal failure were each statistically
      greater than in the patients undergoing CHPP.

PMID- 12484030
TI  - [Significance of peritonectomy for peritonitis carcinomatosis].
AB  - We analyzed patients who underwent multimodal treatment with peritonectomy as an
      aggressive treatment for peritonitis carcinomatosis. Peritonectomy was treated in
      eighteen cases (eleven gastric cancer, seven colon cancer). Out of these eighteen
      cases, nine were initial operation, six were recurrence after first operation and
      three were for relief after palliative operation for peritoneal dissemination.
      Five cases of recurrence included ileus. Of all eighteen patients, ten had
      received preoperative chemotherapies. Peritonectomy made complete resection
      possible principle, and the procedure included resection of the primary lesion,
      subtotal colectomy and peritonectomy. An intestinal stoma was needed in nine
      cases, consequently. All patients cases underwent continuous hyperthermic
      peritoneal perfusion (CHPP). Early postoperative peritoneal chemotherapy was
      given in five cases. By peritonectomy for a first time operation, macroscopically
      complete resection was possible in six cases. In relief and recurrence cases few
      tumor cells remained in five cases. Ileus due to peritoneal carcinomatosia was
      eliminated in all cases, and caloric intake became possible. Fourteen cases had
      postoperative complication (morbidity 78%), and treatment-related death occurred
      in three cases (mortality 17%). It became possible to resect even the peritoneal
      dissemination that was inoperable by conventional surgery, and improvement of QOL
      was achieved by peritonectomy in cases of carcinomatous peritonitis. However,
      postoperative care is important since aggression becomes more intense.

PMID- 12484031
TI  - [Multidisciplinary therapy for peritoneal dissemination using peritonectomy].
AB  - An aggressive approach to peritoneal dissemination involves peritonectomy
      procedures combined with preoperative intraperitoneal chemotherapy,
      intraoperative chemo-hyperthermia, and postoperative systemic chemotherapy. We
      have been performing multimodal therapy consisting of peritonectomy plus
      perioperative chemotherapy for the treatment of patients with peritoneal
      dissemination. Fifty-seven patients with established peritoneal dissemination
      from gastric cancer (n = 32), colon cancer (n = 17), ovarian cancer (n = 7), and
      mesothelioma (n = 1) have been treated with peritonectomy and intraoperative
      chemo-hyperthermia. Five-year survival rates of patients with gastric and colon
      cancer were 18% and 38%, respectively. Among various clinical factors, complete
      tumor resection was the most significant prognostic factor, and the prognosis of
      patients who underwent complete cytoreduction was significantly better than those
      who received incomplete cytoreduction. A multimodal therapy consisting of
      perioperative chemotherapy and peritonectomy with complete cytoreduction may be
      the most powerful method to treat patients with established peritoneal
      dissemination.

PMID- 12484032
TI  - [Efficacy of intraperitoneal chemotherapy for advanced Borrmann type IV gastric
      carcinoma].
AB  - We report four patients with advanced Borrmann type IV gastric carcinoma, in whom
      intraperitoneal chemotherapy with low-dose CDDP and 5-FU plus MMC via a
      peritoneal port was effective against peritoneal metastasis. However, none of the
      four patients survived for a long period. During treatment, they were followed on
      an outpatient basis and received intraperitoneal chemotherapy biweekly with good
      control of peritoneal metastasis. The ratio of the outpatient follow-up period
      was more than 50% in all these patients. Intraperitoneal chemotherapy may be
      effective for controlling peritoneal metastasis of advanced Borrmann type IV
      gastric carcinoma, and contribute to maintaining the patient's quality of life.

PMID- 12484033
TI  - [Pharmacokinetic study of CPT-11, SN-38 and SN-38 glucuronide in the ascites,
      plasma and bile after intraperitoneal administration of CPT-11].
AB  - We studied the pharmacokinetics of CPT-11 with intraperitoneal administration in
      a patient with a PTCD tube. The patient had advanced gastric cancer with
      peritoneal metastasis. CPT-11 was administrated in a dose of 40 mg and the
      intraperitoneal, plasma and bile levels of CPT-11, SN-38 and SN-38 glucuronide
      (SN-38 GLU) were measured periodically. The results showed that the periodical
      concentration pattern of CPT-11, SN-38 and SN-38 GLU in the bile was closely
      related to that of CPT-11 in the abdominal cavity.

PMID- 12484034
TI  - [A novel sustained release system for aqueous cis-platinum].
AB  - The authors devised a novel sustained release system for aqueous cis-platinum
      (CDDP) to study in vitro the degradability of the carrier materials and the
      release profile of the CDDP. We first prepared fibrin hydrogels with clinically
      used biomedical materials, and irradiated the gels with ultraviolet (UV)-rays to
      form gradually degradable drug carriers. We then loaded aqueous CDDP into the
      carriers under negative pressure. These prepared materials were incubated in
      fibrinolytic test medium at 37 degrees C for the in vitro studies. The UV
      irradiated materials slowly degraded and dissolved within 10-15 days, while non
      UV-treated carriers disintegrated in 4-5 days. Each carrier showed a sustained
      release of CDDP. Most of the CDDP delivered was revealed to be the protein
      binding (larger than 10 kDa) form. Free-CDDP was almost nil. The antineoplastic
      efficacies of this new drug delivery system developed using an original technique
      are now being investigated.

PMID- 12484035
TI  - [A study of the oncolytic effect of a newly designed CDDP system on an
      experimental animal model with carcinomatous ascites].
AB  - We provided a novel cancer chemotherapeutic system for the treatment of
      locoregional cancer lesions, e.g. malignant peritonitis and pleuritis. The
      carriers were prepared with fibrin hydrogel clots (FCs) and hemostatic gelatin
      powder (Gp) using an original technique, after which cis-platinum (CDDP) was
      loaded into the carriers. In in vitro tests, the new carrier gradually degraded
      in 10-15 days in our fibrinolytic systems and the release of CDDP from the
      carrier continued for the same period. The CDDP delivered in the incubation
      medium was mainly the protein-bound type, and the released CDDP inhibited the
      proliferation of AH-130 ascitic hepatoma. To evaluate antineoplastic activities
      in vivo, we placed CDDP-loaded carriers into the abdominal cavities of AH-130
      cancer-bearing rats. Seven of 8 cancer-bearing animals treated with our CDDP
      systems survived for more than 5 weeks, and evidence of malignancy completely
      disappeared. These surviving rats were then challenged with AH-130 cells. Four of
      5 repeatedly challenged rats survived for more than 7 months and revealed no
      evidence of recurrence of the cancer. All other rats died of cachexia with
      massive ascites and metastases within 2 weeks. Thus, our newly devised system
      exhibited a sustained release of CDDP with possible antineoplastic efficacy in an
      experimental animal model with carcinomatous ascites.

PMID- 12484036
TI  - [Pharmacological study on levofolinate in intraperitoneal leucovorin-5-FU
      chemotherapy].
AB  - We report the pharmacological findings on levofolinate after the intraperitoneal
      administration of leucovorin-5-FU. Levofolinate 300 mg/saline 500 ml and 5-FU 750
      mg/saline 500 ml were administered intraperitoneally over 1.5 h. The plasma and
      intraperitoneal concentrations of levofolinate at 0, 0.5, 1, 2, 4, 8, 22(20) h
      after the administration were evaluated at 6 points with HPLC analysis. The
      intraperitoneal levofolinate concentration went up as high as 100 micrograms/ml
      and remained above 10 micrograms/ml over 8 hours. This suggested that
      intraperitoneal administration elevated the portal vein and abdominal lymphatic
      levofolinate levels. Intraperitoneal levofolinate-5-FU is a promising protocol
      for gastro-intestinal cancers.

PMID- 12484037
TI  - [Clinical application of PGA-tube for regeneration of intrapelvic nerves during
      extended surgery for intrapelvic recurrent rectal cancer].
AB  - For the regeneration of injured peripheral nerves, we have devised a PGA-tube
      that is composed of a tube of polyglycolic acid containing collagen sponge. This
      PGA-tube was applied clinically to reconstruct a peripheral nerve that had been
      resected during extended surgical resection of for intrapelvic recurrent rectal
      cancer. Four months after the surgical resection, the function of the left hip
      joint has improved remarkably, whereas the function had been lost just after the
      operation. It is suggested that the PGA-tube will be useful for regeneration of
      peripheral nerves that are resected during operation for intrapelvic malignancy.

PMID- 12484038
TI  - [Treatment of tracheobronchial malignant tumors using a new high power diode
      contact laser (GaAlAs) system].
AB  - We treated ten patients with tracheobronchial malignant tumors using a new high
      power diode contact laser (GaAlAs) system (DIOMED 25, OLYMPUS) with a flexible
      bronchofiberscope (OLYMPUS BF IT200 or BF IT240). The total energy of the high
      power diode laser was 811 J, with a range of 64-3,960 J. With this method 85.7
      percent of the symptoms such as dyspnea and hemoptysis were improved, and there
      was no incidence of massive hemorrhage or serious respiratory failure. The
      results confirmed the usefulness and safety of this method of treatment for
      obstructive lesions due to tracheobronchial polypoid malignant tumor and bleeding
      of the tracheobronchial tree.

PMID- 12484039
TI  - [Chemoradiotherapy using platinum analogs/5-FU for advanced esophageal cancer].
AB  - We evaluated the efficacy of concurrent chemoradiotherapy (CRT) using
      cisplatin/nedaplatin and 5-FU for advanced esophageal cancer. Thirteen patients
      with locally advanced esophageal cancer (T4 cases) and 3 with recurrence of
      esophageal cancer were treated with radiotherapy (40-70 Gy) and 5-FU combined
      with cisplatin/nedaplatin concurrently. T4 patients who obtained down-staging by
      CRT also underwent esophagectomy. A complete response was obtained in one case,
      partial response in 8 cases, and no change in 7 cases. The overall response rate
      was 56.3%. A pathological complete response was obtained in one case in which
      curative resection was performed after CRT. Bone marrow suppression was observed
      in 68.8% and grade 3 and 4 bone marrow suppression was observed in 43.8%.
      Concurrent CRT using cisplatin/nedaplatin and 5-FU for advanced esophageal cancer
      has a high response rate and patients obtaining down-staging by CRT as a
      neoadjuvant therapy have a chance for long survival after curative resection in
      locally advanced cases.

PMID- 12484040
TI  - [A case of cardiac cancer for which radiation therapy was effective in improving
      stenosis of the esophagogastric junction].
AB  - The patient was a seventy-seven-year old woman, who was diagnosed with advanced
      gastric cancer with stenosis of the esophagocardiac junction. Her cancer was
      diagnosed as Stage IV (T3N3H0P3M0). As there was no indication for surgery,
      radiation therapy (Linac electron beam, 1.8 Gy/day, total 50.4 Gy) was selected
      to improve the stenosis, after which she was able to eat food. Subjective
      complaints such as nausea and vomiting were also decreased, promoting her QOL. We
      conclude that radiation therapy treatment can be a treatment option for far
      advanced cardiac cancer.

PMID- 12484041
TI  - [Intraoperative radiotherapy (IORT) for unresectable stage IVb pancreatic
      cancer].
AB  - We evaluated the efficacy of IORT for unresectable Stage IVb (Japan Pancreas
      Society classification) pancreatic cancer. Twelve patients were treated with
      IORT, 17 with external beam radiotherapy (ERT) and 17 with chemotherapy (CHT, 8
      patients doxorubicin-based, 7 patients 5-FU-based). Survival, hospital-free
      survival and pain relief were compared among the three groups. In the IORT group,
      7 patients underwent bypass surgery, 3 celiac plexus blockade, 3 ERT, 2
      hyperthermia and 2 CHT. In the ERT group, 1 patient underwent bypass surgery, 7
      hyperthermia and 14 CHT. Distant metastases were more frequently found in the CHT
      group than in the IORT group. Median survival and median hospital-free survival
      were 208 and 79 days in the IORT group, 125 and 32 days in the ERT group and 76
      and 9 days in the CHT group, respectively. Pain relief was obtained in 45% (5/11)
      of symptomatic patients after IORT and in 27% (4/15) after ERT. No patient (0/13)
      in the CHT group experienced pain relief. In conclusion, our experience suggests
      that IORT can reduce pain and improve QOL in patients with unresectable
      pancreatic cancer.

PMID- 12484042
TI  - [Liver and lung abscess after thoracoscopic microwave coagulation therapy for
      hepatocellular carcinoma].

PMID- 12484043
TI  - [Transdiaphragmatic radiofrequency ablation of malignant liver tumors].
AB  - The majority of patients with primary or metastatic liver tumors are not
      candidates for resection because of the size, location, or multifocality of their
      tumors, or because of inadequate hepatic function related to cirrhosis.
      Radiofrequency ablation (RFA) is an evolving technique for treating patients with
      unresectable primary or metastatic liver cancers. After obtaining the approval of
      our institutional review board for this study, 12 patients with HCC and 6
      patients with metastatic liver tumors were treated using the LeVeen RF ablation
      system at the Department of Surgery of Osaka National Hospital between March 2000
      and February 2002. Informed consent was obtained from all patients. Ultrasound
      guided RFA was done during open surgery. In 12 patients, RFA was performed during
      laparotomy, while in 6 patients it was done transdiaphragmatically during
      thoracotomy. All treated tumors showed complete necrosis on imaging after the
      completion of RFA. After a median follow-up period of 288 days, the tumor had
      recurred in 5 out of 18 patients, and the median overall survival rate was 362
      days. No deaths or major complications occurred in these 18 patients. Liver
      function tests (ALT, AST, GGT) that were elevated after RFA returned to baseline
      in most patients by day 7. In 5 patients who underwent RFA at laparotomy, bile
      leakage and liver abscess developed. There were no cases of bile duct injury or
      liver abscess in the patients receiving transdiaphragmatic RFA. In conclusion,
      transdiaphragmatic RFA during thoracotomy is a safe, well-tolerated, effective
      treatment for unresectable hepatic malignancies.

PMID- 12484044
TI  - [Clinicopathological analysis of two patients with local recurrence after
      microwave coagulation therapy for liver metastases from colorectal cancer].
AB  - We analyzed the clinicopathological factors in two cases of local recurrence
      after a disease-free interval (DFI) of more than 12 months following microwave
      coagulation therapy (MCT) for liver metastases from colorectal cancer. Case 1: A
      local recurrence was diagnosed at 14 months after MCT for a liver metastasis of
      20 mm in diameter from rectal cancer. Following liver resection, the patient
      remains alive without recurrence at 9 months. Case 2: A local recurrence was
      diagnosed at 19 months after MCT for a liver metastasis of 20 mm in diameter from
      rectal cancer. After MCT, the patient remains alive without recurrence at 36
      months. CONCLUSION: We treated two patients with local recurrence who have more
      than 12 months' DFI after MCT for liver metastases from colorectal cancer. MCT or
      liver resection was performed as a curative therapy in these cases. Caution is
      recommended for local recurrence at more than 12 months after MCT for liver
      metastases from colorectal cancer.

PMID- 12484045
TI  - [An autopsy case of sepsis following radiofrequency ablation (RFA) for metastatic
      liver carcinoma after bile duct reconstruction].
AB  - An autopsy case of sepsis following radiofrequency ablation (RFA) for metastatic
      liver carcinoma after bile duct reconstructive operation is reported. A 72-year
      old man underwent pylorus-preserving pancreaticoduodenectomy and reconstruction
      with the Suzuki-method (PD-III) for extrahepatic bile duct cancer in October
      1998. A metastatic lesion was recognized in the liver (S3) in November 2001.
      Percutaneous RFA was performed for a recurrent lesion. A metastatic lesion was
      recognized again in the same segment in February 2002. Percutaneous RFA was
      performed again on February 26 and March 12. The patient was discharged without
      hemorrhage, infection, or hepatic failure on March 22. He complained of general
      fatigue on March 26. He was diagnosed with liver abscess, sepsis, acute renal
      failure, and disseminated intravascular coagulation, and received intensive care,
      but died on April 1. The autopsy revealed liver necrotic abscess at the RFA locus
      and multiple microabscesses of the liver, heart, and kidney.

PMID- 12484046
TI  - [Radiofrequency ablation for hepatocellular carcinoma].
AB  - We performed radiofrequency ablation (RFA) for 14 patients with hepatocellular
      carcinoma (HCC) between May 2001 and March 2002. The underlying hepatic disease
      was type C liver cirrhosis in all patients. Seven patients had a solitary lesion,
      and 7 patients had multiple lesions. RFA was chosen for the primary tumor in 5
      cases and for a recurrent tumor in 9 cases. Three cases of well differentiated
      HCC were included. Transcatheter arterial embolization (TAE) was performed in 10
      cases simultaneously. Nine patients received RFA under general anesthesia (open
      laparotomy: 5 cases, transthoracic: 1 case, CT guided: 2 cases, US guided: 1
      case) and 5 patients under local anesthesia (CT guided: 2 cases, US guided: 3
      cases). RFA was performed for 12 minutes in each session and the mean number of
      sessions per patient was 3.2. Excellent ablation was achieved in all cases
      according CT evaluation, and no additional therapy was needed. No recurrences
      have been found in any cases so far. RFA for HCC achieved excellent therapeutic
      effect in combination with other therapies as multimodal therapy.

PMID- 12484047
TI  - [A promising new procedure: laparoscopic devascularization for hepatocellular
      carcinoma with extra-hepatic feeding arteries].
AB  - We have developed a new therapeutic modality: laparoscopic devascularization
      (LDEV) for hepatocellular carcinoma (HCC). Thirteen patients with HCC were
      treated with LDEV from March 1998 to March 2002. All LDEV procedures were
      performed under laparoscopic surgery using laparoscopic coagulating shears (LCS),
      endo-clip and endo-GIA. To prevent recanalization of extra-hepatic feeding
      arteries, we always add local ablation therapy (LAT) intraoperatively. The
      results are as follows. 1. The right gastroepiploic artery in 11 patients, right
      gastric artery in 1 and right inferior phrenic artery in 2 were devascularized.
      2. The amount of intraoperative bleeding ranged 5-150 g and the operating time
      for devasculalization ranged 5-50 min, with an average of 30 min. 3. LAT was also
      performed in all cases. 4. No complications occurred. 5. A recurrent feeding
      artery developed in only one case (8%). 6. Nine patients are living (6-52,
      average 27 months) and 4 have died (5-28, average 16 months).

PMID- 12484048
TI  - [Expression of Fas and induction of apoptosis by anti-Fas monoclonal antibody in
      human bile duct carcinoma cells, and enhancement of induction of apoptosis by IFN
      gamma].
AB  - We investigated the expression of Fas, the induction of apoptosis by anti-Fas
      monoclonal antibody CH-11, and the effect of IFN-gamma on the induction of
      apoptosis in human bile duct carcinoma cells HuCCT1 and HuH28. Fas was expressed
      in 21.7% and 30.9% of HuCCT1 and HuH28 cells, respectively. Pretreatment with IFN
      gamma increased the Fas expression by 17.6% in HuCCT1 cells. However, IFN-gamma
      did not affect the expression of Fas in HuH28 cells. In HuCCT1 and HuH28 cells
      treated with CH-11, the peak corresponding to that of positive control cells was
      detected with the TUNEL method by FCM. The condensation and fragmentation of the
      nucleus, and the apoptotic body were observed as morphological changes specific
      to apoptosis. CH-11 dose-dependently reduced HuCCT1 and HuH28 cell counts by up
      to 16.4% and 71.7%, respectively on day 3. Interferon-gamma attenuated the
      reduction of HuCCT1 cell counts by 12.8% on day 3. However, IFN-gamma had no
      effect on HuH28 cell counts. These results suggest that Fas was expressed,
      apoptosis was induced by CH-11 and the induction of apoptosis was enhanced by IFN
      gamma in human bile duct carcinoma cells.

PMID- 12484049
TI  - [Growth suppression of subcutaneous tumor by CT26 expressing NK4 in syngeneic
      mice].
AB  - An HGF antagonist, NK4, inhibits not only invasion and metastasis of tumor cells
      driven by HGF-Met receptor binding, but also tumor angiogenesis. To address the
      antitumor activities of NK4, we investigated the biological behaviors of CT26
      transfected with the NK4 gene (CT26-NK4) in vitro and in vivo. In the in vitro
      assay, the invasion in MOCK transfected cells (control) was stimulated by HGF;
      however, in CT26-NK4 cells, these effects were completely inhibited. In the in
      vivo assay, the tumor growth of CT26-NK4 was strongly suppressed and the survival
      of CT26-NK4 tumor-bearing mice was significantly prolonged. Immunohistochemical
      analysis revealed that while proliferating cells (PCNA immunostaining) of CT26
      NK4 tumors were weakly suppressed, the micro-vessel number (CD31/PECAM-1
      immunostaining) in those tumors was significantly suppressed as compared with the
      control tumors. In conclusion, NK4 exerts potent antitumor effects via anti
      angiogenesis rather than inhibition of biological events of tumor cells
      stimulated by HGF.

PMID- 12484050
TI  - [High concentration of E-cadherin in portal drainage vein of colorectal cancer
      patients may predict metachronous liver metastasis].
AB  - AIMS: Liver metastasis is the most common recurrence after curative surgery for
      colorectal cancer. Adjuvant chemotherapy such as hepatic arterial infusion or
      intensive systemic infusion may protect against metastatic tumor formation in the
      liver, but conversely have some adverse effects on patients. Therefore, the
      patients with a high risk of liver metastasis after curative resection should be
      selected for the chemotherapy. Portal blood samples of tumor drainage vein were
      obtained during operation from 148 colorectal cancer patients (Dukes' A: 41, B:
      41, C: 33, D: 33) in our institutes from August 1998 to June 2001. Serum E
      cadherin concentration (ng/ml) was estimated using an ELISA kit according to the
      manufacturer's instructions (Takara Shuzo Co.). After at least 6 months follow
      up, each patient's status regarding recurrence was re-examined, as were the sites
      of any recurrences. Serum E-cadherin concentration in each Dukes' stage at the
      primary operation was as follows: A: 1,664.0, B: 1,974.6, C: 2,270.8, D: 3,123.1.
      In these follow-up periods, 21 patients developed metastatic tumor (liver: 13,
      extrahepatic: 8) and 95 did not. The average E-cadherin concentration in each
      group was as follows: liver: 3,585.6, extrahepatic: 2,261.8, no metastasis:
      1,848.4 (p < 0.01 as shown in Figure 4). If the cut-off point is set at 3,000
      ng/ml, liver metastasis can be predicted with sensitivity of 62.1%, specificity
      of 90.3%, and positive predictive value of 64.3%. High levels (> 3,000 ng/ml) of
      serum E-cadherin in portal blood may predict metachronous liver metastasis after
      curative surgery.

PMID- 12484051
TI  - [Hepatic recurrence after prophylactic hepatic arterial infusion of 5
      fluorouracil for Dukes' C colorectal cancer--correlation with the expression of
      dihydropyrimidine dehydrogenase in the primary tumor].
AB  - PURPOSE: The purpose of this study was twofold: (1) to disclose the intermediate
      outcome of a non-randomized trial of prophylactic hepatic arterial infusion
      chemotherapy (PHAI) for curatively resected Dukes' C colorectal cancer performed
      between November 1996 and April 2000, and (2) to examine the relationship between
      the expression of dihydropyrimidine dehydrogenase (DPD) in tumor tissue and the
      efficacy of this chemotherapy. PATIENTS AND METHODS: The oncological outcomes
      were compared between patients (n = 28) receiving PHAI (5-FU: 500 mg/body/w x 50
      cycles) plus oral administration of UFT-E (400 mg/body/day, for 24 months) and
      those (n = 21) receiving UFT-E alone. The levels of tumoral DPD were determined
      in a total of 43 patients (n = 25, PHAI group; n = 18, control group) by an
      enzyme-linked immunosorbent assay. RESULTS: Seven (25%) in the PHAI group and
      four (19%) in the control group developed liver metastasis postoperatively. The
      liver metastasis-free survival was not different between the groups (p = 0.94).
      When the analysis was restricted to patients who developed liver metastasis, the
      duration from surgery to detecting liver metastasis tended to be longer in the
      PHAI group (p = 0.09). In addition, the overall survival tended to be better in
      the PHAI group (p = 0.12). In the control group, the level of DPD was higher in
      patients who developed liver metastases (n = 4) than in those who did not (n =
      14, p = 0.04). However, in the PHAI group, the level of DPD was not different
      regardless of the occurrence of liver metastases (p = 0.30). CONCLUSIONS: These
      results suggest that (1) PHAI is unlikely to improve the prognosis of Dukes' C
      patients remarkably, and (2) the efficacy of this regimen cannot be predicted by
      determining the levels of tumoral DPD.

PMID- 12484052
TI  - [Screening of novel biomarkers for the detection of intraperitoneally
      disseminated cancer cells using human cDNA microarray].
AB  - In this study, we performed a global analysis of the differential gene expression
      of a gastric cancer cell line established from a primary main tumor (SNU-1) and
      that of other cell lines established from the metastasis to the peritoneal cavity
      (KATO-III, SNU-5, SNU-719, MKN45P, HS39). The application of a high-density cDNA
      microarray method made it possible to analyze the expression of approximately
      21,168 genes. Our examinations of KATO-III, SNU-5, SNU-719, MKN45P, and HS39
      showed that several genes were up-regulated in addition to expression of sequence
      tags (ESTs). The analysis revealed altered up-regulation of CD44 (cell adhesion),
      CEA, 14-3-3, Ubiquitin A and several kinds of ESTs in gastric cancer cells from
      malignant ascites. We then analyzed these gastric cancer cell lines with Northern
      blots and observed preferential up-regulation of these selected genes in cells
      prone to peritoneal dissemination. RT-PCR 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 new insights into the study of human gastric cancer peritoneal
      dissemination.

PMID- 12484053
TI  - [Preoperative diagnostic laparoscopy with local anesthesia and lavage telomerase
      activity for advanced gastric cancer].
AB  - A pretherapeutic staging system to design operative or neoadjuvant treatments in
      gastric cancer is needed. In this study, a simple staging system based on
      diagnostic laparoscopic findings under local anesthesia to define a treatment was
      developed. This study was conducted with 68 patients with advanced gastric
      cancer. All the patients had been diagnosed as more than T3, or were suspected to
      have peritoneal seeding. Preoperative diagnostic laparoscopy under local
      anesthesia was performed in the operation room. After insertion of the trocars,
      the abdominal cavity was inspected, and biopsy and/or abdominal lavage sampling
      was performed. Patients were allocated into three stages based on laparoscopic
      and histopathologic findings. Twenty-eight out of 68 patients were diagnosed as
      P1, 34 patients as P0CY0 and 6 as P0CY1. Based on these results, 57 patients
      underwent operation. The accuracy rate of diagnosis was 95% in the P category,
      and 93% in the CY category. Lavage telomerase activity was examined on 10
      patients with P0CY0 gastric cancer. Two out of 10 were positive for this
      activity, and both of them had died due to peritoneal recurrence within a year
      after operation. In conclusion, the proposed diagnostic laparoscopic staging
      system is a simple and reproducible method for selection of a suitable therapy.
      It is considered that diagnostic laparoscopy under local anesthesia is a useful
      preoperative examination in cases of advanced gastric cancer. Moreover lavage
      telomerase activity may be a more sensitive predictor of peritoneal recurrence
      than lavage cytology.

PMID- 12484054
TI  - [The introduction of preoperative staging laparoscopy and molecular diagnosis of
      peritoneal lavages for the treatment of advanced gastric cancer].
AB  - In this study, intra-peritoneal chemotherapy was performed for advanced gastric
      cancer with serosal invasion. We assessed the efficacy of the chemotherapy using
      quantitative genetic diagnosis with peritoneal lavages collected before and after
      chemotherapy at staging laparoscopy and/or gastrectomy. Cases in which genetic
      diagnosis of peritoneal lavages showed negative results, or changed from positive
      to negative after chemotherapy, had a good prognosis. On the other hand, cases in
      which genetic diagnosis showed positive results after chemotherapy had worse
      prognosis. Intra-peritoneal chemotherapy may be indicated for patients with a
      positive genetic diagnosis only and cases becoming negative as a result of this
      therapy may have a better prognosis.

PMID- 12484055
TI  - [A clinical scoring system may identify good candidates for hepatic arterial
      infusion chemotherapy after hepatic resection for colorectal cancer].
AB  - The significance of hepatic arterial infusion chemotherapy (HAI) for the
      prognosis of metastatic colorectal cancer is controversial. We applied a clinical
      scoring system to find good candidates for HAI after hepatic resection. Ninety
      four consecutive cases of hepatic metastases resected at a single institute were
      analyzed retrospectively. The cases were divided into 4 subgroups: those with a
      low risk score (0-2 points) with and without HAI and those with a high risk score
      (3-5 points) with and without HAI. The number of cases and the cumulative 5 year
      survival rate of each case were as follows: low risk score with HAI (n = 17)
      64.1%, low risk score without HAI (n = 25) 27.4%, high risk score with HAI (n =
      28) 16.9%, and high risk score without HAI (n = 24) 14.7%, respectively. These
      results suggest that hepatic resection with HAI seemed to contribute to the
      outcome for selected cases. The clinical scoring system may identify good
      candidates for HAI as well as predict recurrence after hepatic resection for
      metastatic colorectal cancer.

PMID- 12484056
TI  - [Staging laparoscopy for advanced gastric cancer].
AB  - Staging laparoscopy was carried out for 12 cases of advanced primary gastric
      cancer to evaluate the condition of peritoneal seeding. Peritoneal seeding was
      indicated in five cases. Abdominal lavage sampling was positive in six cases.
      Among six cases with positive cytology, surgery was adopted in three cases to
      lessen bleeding or stricture. Chemotherapy were carried out for the other three
      cases. Radical lymph node resection was carried out in six cases without
      peritoneal seeding. Laparoscopic observation was easier and more feasible under
      general anesthesia than local anesthesia. Preoperative staging laparoscopy for
      advanced gastric carcinoma can evaluate the condition of peritoneal seeding.
      Based on the results, a suitable treatment plan for each patient can be
      determined.

PMID- 12484057
TI  - [Detection of sentinel lymphatic region with activated carbon particles in lymph
      node dissection for colorectal cancer].
AB  - Sentinel node navigation surgery (SNNS) for gastrointestinal cancer has been
      examined using various methods, but the SN concept has not been established. For
      18 patients who had colorectal cancer without macroscopic nodal metastases, we
      had attempted to detect sentinel lymph nodes (SNs) with activated carbon
      particles and investigate the existence of nodal metastases histologically. SNs
      were detected in 17 of 18 patients. Thus activated carbon particles are a useful
      tracer for SN detection. Three patients had microscopic nodal metastases, and two
      had nodal metastases in SNs. Although the remaining patient was a false negative
      case which had nodal metastases in non-SNs only, the nodal metastases were within
      the sentinel lymphatic region (SLR) which includes SNs. It is considered possible
      to safely perform minimally invasive lymphadenectomy for colorectal cancer
      without macroscopic nodal metastases, by means of SLR dissection using activated
      carbon particles.

PMID- 12484058
TI  - [Is sentinel lymph node navigation useful for laparoscopic gastrectomy].
AB  - The aim of this paper is to assess the usefulness of sentinel lymph node
      navigation for laparoscopic gastrectomy. The standard lymph node dissection for
      gastric cancer is a D2 dissection. D2 dissection and sentinel lymph node biopsy
      can be performed with laparoscopic gastrectomy as well as with open surgery.
      Sentinel lymph node navigation surgery for gastric cancer has not yet been
      established, but once a strong consensus is reached we will be able to perform
      the laparoscopic gastrectomy safely.

PMID- 12484059
TI  - [Usefulness of CT arteriography for transcatheter peripancreatic arterial
      embolization to patients with advanced pancreatic cancer].
AB  - We reported previously the clinical benefit of hepatic and splenic arterial
      infusion chemotherapy (HSAIC) for patients with advanced pancreatic cancer alter
      transcatheter peripancreatic arterial embolization (TPPAE). TPPAE has two
      therapeutic purposes: (1) preparation for effective arterial infusion
      chemotherapy, and (2) transcatheter arterial embolization (TAE) against pancreas
      head cancer. The present paper describes the advantage of CT arteriography in
      performing TPPAE for advanced pancreatic cancer. CTA was useful in identifying
      the arterial blood supply in pancreatic cancer, especially blood vessels branched
      off from the supramesenteric artery (SMA). Since the anti-tumor effect of TPPAE
      against pancreas head cancer is dependent mainly on whether the blood supply from
      SMA could be shut off, it is suggested that CTA is useful to evaluate the
      embolization effect of TPPAE.

PMID- 12484060
TI  - [Usefulness of CT-angiography for superselective intra-arterial chemotherapy for
      advanced head and neck cancers].
AB  - Eighteen N3 cases, fourteen skullbase invasion cases and twenty-six cases of
      paranasal sinus cancer with orbital invasion were treated by superselective intra
      arterial chemotherapy using CDDP and sodium thiosulfate to preserve the organs
      and to improve poor prognosis. In these patients, 100-150 mg/m2 of CDDP was
      administered weekly to each feeding artery of the tumor superselectively at 5
      mg/m. CT-arteriography (CTA) was used to diagnosis all feeding arteries of
      advanced cancers before infusing CDDP. Twenty-three of 26 cases with orbital
      invasion were treated with preservation of the eyeball. In three cases with
      extirpation of the eyeball CTA was not used in the treatment, and CDDP was
      infused into only the maxillary artery excluding the transverse facial artery. In
      skullbase invasion cases, the number of complete responses (CR) was 8/14, and
      that of partial responses (PR) was 6/14. Feeding arteries originating from the
      external carotid artery were found in 10 of all 14 cases by CTA, and four cases
      in which blood supply was from both carotid arteries were all anterior skullbase
      invasion cases. Ten cases with superselective intra-arterial chemotherapy
      originating from only the external carotid artery were significantly better
      responders than four cases originating from both carotid arteries. In N3 cases,
      feeding arteries were found in more than three arteries by CTA and the overall
      survival rate was 55%, calculated by the Kaplan-Meier method. CTA is a very
      efficient method for diagnosing all feeding arteries of advanced cancers in the
      superselective intra-arterial chemotherapy.

PMID- 12484061
TI  - [Evaluation of diagnostic imagings of liver metastases].
AB  - With the advent of various therapeutic modalities for the management of
      metastatic liver tumor, the task of pretreatment imaging has become more
      demanding. US and CT are non-invasive, and the most widely used techniques for
      pretreatment imaging, but they are far from optimal. Recently, the most sensitive
      pretreatment imaging modality for the depiction of focal liver lesions is CT
      during arterial portography (CTAP); however, it is an invasive procedure with an
      established risk of false-positive results. CT and MRI are the sensitivities of
      these techniques have recently been improved with the development of
      multidetector CT, contrast agents for MRI that specifically accumulate in the
      liver, and other advances. Superparamagnetic iron oxide (Feridex) has been
      developed as a liver-specific particulate MRI contrast agent that is taken up by
      the Kupffer cells of the liver. Rational selection of appropriate modalities for
      a given purpose requires familiarity with the characteristics of each modality.
      The aim of the present study was to evaluate the sensitivities of diagnostic
      modalities in the pre- and post-treatment periods of metastatic liver tumor.
      Feridex-enhanced MRI (Ferumoxide MRI) is more sensitive than enhanced CT and MRI
      in the depiction of metastatic liver tumor. In terms of the ability to visualize
      residual tumor after MCT, dynamic MRI was superior to enhanced CT and Ferumoxide
      MRI. In conclusion, combined Ferumoxide MRI and dynamic MRI is a noninvasive
      method and clinically useful since it can change the therapeutic approach.

PMID- 12484062
TI  - [Evaluation of the diagnostic efficacy of SPIO enhanced MRI in patients with
      focal hepatic lesions--comparison with CECT and CTAP].
AB  - The aim of this study was to compare the diagnostic efficacy of superparamagnetic
      iron oxide (SPIO)-enhanced MRI for the detection and diagnostic accuracy of focal
      liver lesions with helical contrast enhanced CT (CECT) and CT during arterial
      portography (CTAP). Thirty-nine patients (25 men and 14 women, mean age 63.5
      years) were examined by SPIO-MRI and triple-phase CECT. Eleven of them were also
      examined by CTAP. There were a total of 96 confirmed focal hepatic lesions, 61
      metastatic cancers in 18 patients and 35 hepatocellular carcinomas (HCCs) in 21
      patients. Final diagnosis was established by operation in 25 cases, by biopsy in
      7 cases, and by progression of disease on follow-up examination in the other 7
      cases. The sensitivity of SPIO-MRI for HCC detection was almost equal to CECT,
      but that of SPIO-MRI for metastatic cancer detection, especially cancers smaller
      than 1 cm in size, was significantly superior to CECT. The sensitivity of SPIO
      MRI for both HCC and metastatic cancer detection was almost equal to that of
      CTAP, but the specificity of SPIO-MRI for detection of both lesions was
      significantly superior to that of CTAP because CTAP produced a higher incidence
      of false-positive findings. In conclusion, SPIO-MRI could take the place of CTAP
      as a non-invasive excellent modality to determine the distribution of hepatic
      lesions preoperatively. SPIO-MRI could also be a useful modality to follow liver
      metastasis postoperatively in patients with advanced digestive cancers.

PMID- 12484063
TI  - [Analysis of effect of dextran sulfate on cancer cells].
AB  - Peritoneal recurrence is one of the critical problems that occurs after surgery
      for gastrointestinal cancers. Since no curative treatment has been established
      for peritoneal recurrence, many efforts have been made to develop an effective
      method for preventing such recurrence. We focused on dextran sulfate, an anti
      cell-adherence agent, to prevent peritoneal metastasis. Our previous studies in
      vitro and in vivo clarified that dextran sulfate prevents cancer cells from
      adhering to plastic flasks and the abdominal wall. In this study, we investigated
      the effects of dextran sulfate on cancer cells from the viewpoint of the cell
      cycle. Changes in gene expression caused by dextran sulfate were analyzed by cDNA
      microarrays. Analysis by cDNA microarray revealed the decreased expression of the
      genes essential to the progression of G1 and S phases. Our results indicate that
      dextran sulfate suppresses progression of the cell cycle as well as cell
      adhesion, suggesting that dextran sulfate could be used as an antimetastatic
      agent. Anti-cell-adherence agents with such mechanisms of action could be
      effective drugs for treatment during and after operation to prevent peritoneal
      metastases induced by surgical operation.

PMID- 12484064
TI  - [Functional analysis of peritoneal lymphoid tissues by GFP expression in mice-
      possible application for targeting gene therapy against peritoneal
      dissemination].
AB  - It is important to develop an efficient adjuvant therapy for the prevention of
      the postoperative peritoneal recurrence of gastrointestinal cancers such as
      gastric cancer or pancreatic cancer. Milky sports (MS) are peritoneal lymphoid
      tissues broadly distributed on the peritoneal tissues such as the omentum,
      mesentery, or Douglas pouch, and are the selective implantation sites of
      disseminated cancer cells. In this study, we introduced GFP gene into various
      cancer cell lines and host-derived cells such as peritoneal macrophages and
      dendritic cells by adenovirus vetor and injected them i.p. into mice. We then
      investigated the sites of GFP expression on the peritoneum by fluorescence
      microscopy. The results showed that green fluorescence was detected specifically
      for the MS sites that stained black with activated carbon particles (CH40),
      despite the differences in the cell type injected. These findings indicate that
      1) the physioanatomical characteristics of MS may play an essential role in the
      formation of the initial disseminated lesions at MS, and 2) the host-derived
      cells accumulating near MS may be available as carriers of a therapeutic gene in
      intraperitoneal gene therapy against peritoneal dissemination.

PMID- 12484065
TI  - [Intrinsic angiotensin II-generating system in human pancreatic cancer tissues].
AB  - To clarify whether an intrinsic angiotensin II-generating system exists in human
      advanced pancreatic cancer tissues, we measured angiotensin II concentration and
      angiotensin converting enzyme (ACE) activity in tissues of normal pancreas,
      pancreatic cancers, colon cancers and hepatocellular carcinomas. After the
      surgically resected specimens were homogenized, angiotensin II concentration and
      ACE activity in tissues were measured using the florisil method and Kasahara's
      method, respectively. Tissue angiotensin II levels in pancreatic cancers (n = 13)
      were significantly higher than those of normal pancreas (n = 7), colon cancers (n
      = 7), or hepatocellular carcinomas (n = 7). However, there was no significant
      difference in tissue ACE activity between them. This study provides in vivo
      evidence of ACE-independent angiotensin II-generating system in human pancreatic
      cancer tissues and suggests that this locally-formed angiotensin II influences
      the microenvironment of pancreatic cancer tissues in a paracrine fashion.

PMID- 12484066
TI  - [A patient with diffuse peritoneal metastases of GIST who was administered
      STI571].
AB  - We report a patient with diffuse peritoneal metastases of GIST who was
      administered STI571 (a tyrosine kinase inhibitor). She was a 45-year-old woman
      who underwent surgery for a mass that was suspected to be an ovarian tumor. The
      postoperative diagnosis was GIST developing from the small intestine. Two years
      later, multiple peritoneal metastases were noted and a complete macroscopic
      resection was done. Six months after the second operation, she needed a third
      operation and complete macroscopic resection was repeated. Only 4 months after
      the third operation, she underwent a fourth operation. We resected massive
      peritoneal metastases, but diffuse metastases remained. Therefore, we started to
      administer STI571 at 400 mg/day. She has been free from peritoneal masses for 9
      months after the fourth operation. We recommend STI571 for uncontrolled diffuse
      peritoneal metastases of GIST.

PMID- 12484067
TI  - [Short-term intraperitoneal infusion of cisplatin and OK-432 for a case of
      malignant mesothelioma of the peritoneum].
AB  - A case of malignant mesothelioma of the peritoneum successfully treated with
      short-term intraperitoneal chemotherapy is reported. A 67-year-old woman
      underwent laparotomy for ascending colon cancer. During, laparotomy, numerous
      mucoid nodules were found on the peritoneal surface, even though the colonic
      tumor did not invade the serosa. Ileocecal resection (D1) with partial
      omentectomy was performed. Intraperitoneal infusion with cisplatin (200 mg) was
      started immediately after surgery and additional cisplatin (150 mg) was
      administered with OK-432 (30KE). The serum level of CA125 rapidly decreased after
      the chemotherapy, and was normalized 3 months postoperatively. The histological
      diagnosis of the peritoneal lesions was malignant mesothelioma of the peritoneum
      (diffuse type). The patient is living without any evidence of recurrence 10
      months postoperatively. These results suggest that this short-term chemotherapy
      is worth trying in cases of malignant mesothelioma of the peritoneum.

PMID- 12484068
TI  - [A case of ovarian cancer in which a remarkable effect was seen with low-dose
      CDDP intratumoral injection of CPT-11].
AB  - We treated an ovarian cancer patient in whom low-dose CDDP intratumoral injection
      with CPT-11 therapy was very effective. The patient was a 63-year-old woman. She
      showed symptoms of peritonitis. Carcinomatous peritonitis was suspected on
      abdominal CT scan and tumor markers were at high levels (CA125 10,827 U/ml, SLX
      82 U/ml). At laparotomy, massive ascites (3,000 ml), omental cakes and
      disseminated peritoneal tumors were revealed. Her uterus and adnexa were not
      enlarged. The omental tumor and ovaries were biopsied and revealed serous
      adenocarcinoma. The patient was treated with combined chemotherapy of CDDP and
      CPT-11. CDDP (20 mg/day) was administered by intraperitoneally for 3 days, and
      CDDP (10 mg/day) was administered by intratumoral injection (percutaneous for
      omental tumor) for 5 days. CPT-11 (40 mg/day) was administered twice a week. As a
      result, marked shrinkage of the tumors was confirmed. This low-dose CDDP
      intratumoral injection with CPT-11 may be effective for such omental tumors with
      carcinomatous peritonitis.

PMID- 12484069
TI  - [A case of carcinomatous enterodermal fistula successfully treated with arterial
      infusion chemotherapy].
AB  - We report a 74-year-old male patient with a carcinomatous enterodermal fistula
      after residual gastrectomy, who responded to arterial infusion chemotherapy. The
      patient was administered 10 mg/body cisplatin (CDDP) and 1,000 mg/body 5
      fluorouracil (5-FU) through an injection port every week. After 13 weeks, the
      fistula was closed and viable cancer cells had disappeared without any side
      effects. After 1 month, however, the fistula re-opened and viable cancer cells
      appeared again.

PMID- 12484070
TI  - [Combination chemotherapy with intra-perioneal infusion of CDDP and continuous
      intravenous infusion of 5-FU for peritoneal metastasis in gastric cancer-
      analysis of long-term survivors].
AB  - In order to evaluate the utility of combination chemotherapy with intra
      peritoneal infusion of CDDP and continuous intravenous infusion of 5-FU, we
      performed this therapy in 23 primary gastric cancer patients with peritoneal
      metastasis. CDDP was administered intraperitoneally at a dose of 70 mg/m2 over 2
      hours on day 1, and 5-FU was continuously administered intravenously at a dose of
      700 mg/m2 for 5 consecutive days from day 1, respectively. This treatment was
      given twice. Median survival time with this treatment was 343 days, and the depth
      of invasion was selected as an independent prognostic factor according to
      multivariate analysis. Five patients (21.7%) have survived more than 3 years.
      Major toxicities were less than Grade 2 except for two patients with each anemia
      (Grade 3) and venous thrombosis (Grade 3), respectively. This regimen appears to
      be feasible and effective for gastric cancer patients with peritoneal metastases.
      Long term survival may be obtained in patients without adjacent organ invasion.

PMID- 12484071
TI  - [Repeated intraperitoneal injection of low-dose CDDP for gastric cancer with
      ascites owing to peritonitis carcinomatosa].
AB  - We attempted treating 5 patients with ascites from peritonitis carcinomatosa of
      gastric carcinoma using TS-1 as systemic chemotherapy, and repeated
      intraperitoneal injection of low-dose CDDP for the carcinomatous ascites. TS-1
      was administered in the usual manner and repeated intraperitoneal injection of
      CDDP (10 mg/body) dissolved in physiological saline 20-500 ml was given with an
      implantable reservoir. In 3 patients, the carcinomatous ascites disappeared, and
      in 2 other patients they decreased remarkably. As a result, the QOL and PS of all
      patients were improved. Serum concentration of CDDP suggested that weekly
      repeated intraperitoneally injected CDDP not only has an effect on peritonitis
      carcinomatosa, but also functions as a modulator for 5-FU.

PMID- 12484072
TI  - [A case of liver metastasis from anorectal malignant melanoma treated by
      chemoembolization].
AB  - Anorectal malignant melanoma is relatively rare and its prognosis is very poor
      because of distant metastasis via the blood or lymphatic vessels. This paper
      reports a case of liver metastasis from anorectal malignant melanoma treated by
      chemoembolization. A 68-year-old man was admitted to our hospital because
      abdominal enhanced computed tomography revealed multiple liver metastases.
      Angiography also revealed metastasis, so a chemoembolization with nedaplatin was
      performed. Two months later some lesions fell into necrosis but new ones
      appeared, and the same treatment was performed another three times. Accessory
      vessels from the inferior diaphragma artery developed and prevented these
      treatments. The patient died from the progress of metastases to the liver, bone
      and skin three years and two months after the operation, or one year and three
      months after the liver recurrence. The chemoembolization showed some effects on
      liver metastases from malignant melanoma, but they were temporary.

PMID- 12484073
TI  - [A case of multiple liver metastases from breast cancer in which we confirmed
      disappearance of cancer cells after hepatic resection following hepatic arterial
      infusion chemotherapy].
AB  - A 46-year-old woman underwent right mastectomy for stage IIA breast cancer in
      1993. Six years and 8 months after this operation, she was diagnosed as having
      multiple liver metastasis form the breast cancer. An intra-arterial catheter was
      inserted percutaneously into the hepatic artery and she was given hepatic
      arterial infusion chemotherapy and general chemoendocrine therapy. The metastatic
      liver tumors were gradually reduced in size and tumor markers returned to the
      normal range. However, tumor size was unchanged after February 2001. After
      obtaining her informed consent from the patient, we performed hepatic resection
      in December 2001. Histopathologically, three scars were observed and no tumor
      cell was found. She has been free from recurrence to date. This case suggests
      that chemoendocrine therapy including hepatic arterial infusion chemotherapy is
      effective for breast cancer patients with liver metastasis.

PMID- 12484074
TI  - [Three cases of multiple liver metastases of carcinoid tumor responding to
      hepatic arterial infusion chemotherapy using degradable starch microspheres].
AB  - We describe three patients with multiple liver metastases of carcinoid tumor who
      received hepatic arterial infusion chemotherapy using degradable starch
      microspheres (DSM). A partial response was obtained in all cases, and no side
      effects were observed. We believe that this chemotherapy was an effective
      treatment for unresectable liver metastases of carcinoid tumor.

PMID- 12484075
TI  - [Hepatic arterial infusion of high-dose 5-FU to liver metastases--case reports of
      6 patients with abnormal laboratory data on liver function].
AB  - Six patients with metastatic liver cancer (H3) and abnormal laboratory data for
      liver function underwent intra-hepatic arterial infusion (H.A.I.) therapy of high
      dose 5-FU (1 g/body/day, 6 days/week, 1q for 2 patients, 2q for 4 patients, with
      at least a one week interval). No serious side effects were observed in any case.
      Even in 2 cases with suspicious partial obstruction of the portal vein, no
      remarkable change in liver function was observed after high dose 5-FU H.A.I.
      therapy. Four patients who received 12 g of 5-FU showed a reduction in the
      abnormal data after a short transient rise in some cases. In 2 cases the
      reduction rate was high and the laboratory data were normalized in 3 months. A
      long PR was obtained in these cases. The other 2 cases, on the other hand, showed
      a low reduction rate and the liver function relapsed in a week. Tumor markers
      also returned to previous levels in a short period. These findings together imply
      that the reduction rate of abnormal liver function data might predict the
      efficacy of high dose 5-FU H.A.I. therapy.

PMID- 12484076
TI  - [Hepatic metastases from alpha-fetoprotein producing colorectal cancer that
      responded remarkably to transcatheter arterial chemo-embolization].
AB  - Although alpha-fetoprotein (AFP)-producing colorectal cancer is extremely rare,
      its potential for liver metastasis is high and the prognosis of the patient is
      very poor. We report a case of metastatic liver tumor from an AFP producing
      sigmoid colon cancer that was successfully treated with transcatheter arterial
      chemo-embolization (TACE). A 48-year-old female was admitted to our hospital
      complaining of anal bleeding, and was diagnosed as harboring a type 2 advanced
      tumor with two metastatic lesions in the lateral segment of the liver. Serum AFP
      measured 948.2 ng/ml before surgery. We performed sigmoidectomy and lateral
      segmentectomy of the liver. Pathological examination revealed moderately
      differentiated adenocarcinoma both in the primary and the metastatic lesions, and
      AFP-stain positive nests were seen on immunohistochemical staining. The serum AFP
      value returned to normal soon after the surgery. Five months later, a recurrent
      lesion was discovered in the right lobe of liver, and it was surgically removed.
      Another 4 months later, multiple liver metastases were recognized and the
      patient's serum AFP level was found to be 593.3 ng/ml. For the re-recurrent
      hepatic lesions of 5.5 cm in diameter, she underwent two courses of TACE using
      Lipiodol and epirubicin hydrochloride. Following the treatment, the tumor shrank
      rapidly and almost disappeared. The patient has been in good health for 24 months
      since the last TACE, and the serum AFP level has been within the normal range.

PMID- 12484077
TI  - [Hepatic arterial infusion with irinotecan for the colorectal cancer patient with
      liver metastasis--a case report].
AB  - A 53-year-old woman who had been treated for rectal cancer was admitted to our
      hospital with edema, abdominal distension, and general fatigue. Abdominal CT
      showed multiple liver metastases and paraaortic lymph node metastases. After she
      was administered irinotecan by hepatic arterial infusion, the liver metastases
      decreased and paraaortic lymph node metastases were remarkably reduced in size.

PMID- 12484078
TI  - [Audit of the safety of hepatic arterial infusion of degradable starch
      microspheres (DSM). Adriamycin (ADM).mitomycin C (MMC) on aged patients with
      liver metastases of colorectal cancer].
AB  - The purpose of this study was to clarify the safety of hepatic arterial infusion
      of degradable starch microspheres (DSM).adriamycin (ADM).mitomycin C (MMC) on
      aged patients with liver metastases of colorectal cancer. A total of 19 patients
      who received this therapy (DSM: 600 mg or less, ADM: 30 mg, and MMC: 10 mg) three
      times or more every three weeks were included. Changes in laboratory data and
      frequency of the occurrence of the adverse effects were compared between patients
      aged 75 (n = 5) or more and those aged 74 or less (n = 14). There were no
      significant differences in changes in the leukocyte counts, AST, ALT, and c
      reactive protein levels between the groups. The frequency of adverse effects also
      was not different between the groups. These results suggests that this therapy is
      feasible with acceptable safety even in patients aged 75 years or more.

PMID- 12484079
TI  - [A case report of hepatocellular carcinoma with portal thrombus responding to
      hepatic arterial infusion chemo-lipiodolization].
AB  - A 73-year old man with multiple hepatocellular carcinomas underwent 4
      transarterial chemoembolizations, but a tumor thrombus appeared in the left
      portal vein. The tumor sizes in segments 4 and 5 were 4.0 cm and 2.4 cm,
      respectively. The serum levels of AFP and PIVKA-II were 14,991 ng/ml and 15,944
      mAU/ml, respectively. The tumor was 5-FU palpable in the epigastric region. Four
      ml of SMANCS and 4 ml of Lipiodol were injected to proper hepatic artery using
      the Seldinger technique. In addition, epirubicin (20 mg), MMC (4 mg) and Lipiodoi
      (2 ml) were injected into a proper hepatic artery via a reservoir every 3 weeks.
      The tumor was not palpable, and the tumor markers were markedly reduced after 2
      months. The evaluation of response to the treatment was a partial response 3
      months and 6 months later. Chemo-lipiodolization was very useful for advanced
      hepatocellular carcinoma with portal vein thrombus.

PMID- 12484081
TI  - [A case of esophageal cancer successfully treated by chemoradiotherapy after
      resection for multiple liver metastasis of sigmoid colon cancer].
AB  - The patient was a 56-year-old man. Colonoscopic findings showed a cancerous
      lesion of the sigmoid colon and we performed curative sigmoidectomy. Four months
      after the operation, abdominal CT scan revealed multiple metastatic lesions in
      the liver. We performed lateral segmentectomy and partial resection of the S4,
      S6, S8 segments and cannulation for hepatic arterial infusion chemotherapy.
      Continuous hepatic arterial infusion chemotherapy with 5-FU (1,000 mg/body/day)
      was performed for two weeks as a postoperative adjuvant chemotherapy. Immediately
      after the therapy, endoscopic examination for upper digestive tract showed a 0
      lpl type cancer lesion in the middle of the thoracic esophagus. Concurrent
      chemoradiotherapy with low-dose FP was efficacious and a complete response was
      obtained. The patient has survived for nine months after the operation without
      any sign of recurrence. It is suggested that concurrent chemoradiotherapy an
      effective treatment for esophageal cancer.

PMID- 12484080
TI  - [Resection of pancreatic cancer and simultaneous lung metastasis--a case report
      of successful in tumor dormancy mainly by postoperative 5-fluorouracil-based
      chemotherapy].
AB  - A 48-year-old male patient was admitted to our institution with left
      hypochondralgia. Preoperative serum CEA was 504 ng/ml. Under a radiological
      diagnosis of simultaneous double cancer of the pancreas and lung, resection was
      performed. Pathological study revealed primary pancreatic cancer with lung
      metastasis. After the operation, serum CEA fell to 55 ng/ml. Seventeen months
      later, bowel obstruction occurred and serum CEA was 140 ng/ml. One course of
      systemic chemotherapy, using the combination of CDDP, 5-FU and Leucovorin, was
      successful. After another three months, however, the same clinical symptoms
      occurred. With no response to the prior chemotherapy regimen, surgery was
      undertaken and a mass at the mesentery was removed. Fifty-nine months have passed
      since the initial operation and the patient is free of disease, though his serum
      CEA is around 50 ng/ml. In conclusion, there are cases of pancreatic cancer in
      which tumor dormancy can be achieved by postoperative 5-FU based chemotherapy.

PMID- 12484082
TI  - [Airway stent for airway obstruction caused by esophageal carcinoma].
AB  - The result of airway stent and adjuvant therapy for airway obstruction caused by
      advanced esophageal carcinoma was evaluated. In Tokyo Metropolitan Ohkubo
      Hospital, four cases of esophageal carcinoma with airway obstruction were treated
      by tracheo-bronchial stent. Two were primary cases and the others were recurrent
      cases. Three of the patients demonstrated progressive dyspnea due to airway
      obstruction, and the other complained of bloody discharge. An ultraflex non
      covered stent was used cases. After insertion of the airway stent. The patients'
      dyspnea improved immediately. One patient was discharged without adjuvant
      treatment, and died of the cancer one month later. Adjuvant treatment was adopted
      in the other three cases. The size of the tumor decreased, but fistula formation
      was observed in two cases. An airway stent is an effective treatment with
      immediate results for dyspnea caused by airway obstruction. Adjuvant treatment
      after stent placement is often associated with fistula formation. It should be
      considered carefully.

PMID- 12484083
TI  - [A case of pyloric or antral malignant stenosis treated with arterial infusion
      chemotherapy and palliative therapy--self-expandable metal stents through
      gastrostomy].
AB  - The patient is a 62-year-old woman. She had type 3 advanced stomach cancer that
      was judged to have caused complete stricture of the pylorus, and to be
      inoperable. She received percutaneous endoscopic gastrostomy (PEG) for
      decompression. She also received arterial infusion chemotherapy with 5-FU,
      methotrexate (MTX) and cisplatin (CDDP). As a result, the pylorus stricture was
      reduced somewhat. We tried a self-expandable metal stent (EMS) after obtaining
      informed consent. A guide-wire passed in gastrostomy was introduced to the
      pyloric or antral stenosis manually under x-ray fluoroscopy and endoscopy. Next
      the EMS was introduced to the position of the stenosis over the positioned guide
      wire, and then it was released. The EMS did not migrate after placement and the
      quantity of meals she could consume was considerably improved. She could take
      meals for three months after stenting. Bypass procedure is often performed for
      patients with advanced stomach cancer with pylorus stricture, but we thought we
      could help the patient maintain a good quality of life (QOL) by pylorus stenting
      in combination with arterial infusion chemotherapy.

PMID- 12484085
TI  - [A case of breast reconstruction with a rectus abdominis musculocutaneus flap
      following re-lumpectomy for local recurrence of breast cancer after breast
      conserving therapy].
AB  - A 42-year-old woman underwent breast conserving operation with irradiation for
      Stage I (T1 N0 M0) breast cancer at the 12 o'clock axis of her right breast. At
      six years after surgery, a solitary local recurrent tumor (1.2 cm in diameter)
      was found at the 2 o'clock axis of her right breast. No metastases were found at
      other sites. By the desire of the patient to conserve her breast, we performed re
      lumpectomy with surgical margin (2 cm) and reconstructed with a rectus abdominis
      musculocutaneus flap to fill the large defect of breast tissue. One year and 5
      months after surgery, the patient was doing well without recurrence, and was
      satisfied with the cosmetic effect.

PMID- 12484084
TI  - [Recurrence of right breast cancer at the thoracic wall successfully treated with
      intra-arterial infusion of doxorubicin hydrochloride--a case report].
AB  - We report a recurrent case of breast cancer successfully treated with intra
      arterial infusion of doxorubicin hydrochloride (ADM) combined with systemic CAF
      therapy. The patient, a 37-year-old woman, was diagnosed with a recurrence at the
      thoracic wall 55 months after curative resection for right breast cancer. She was
      treated with intra-arterial infusion chemotherapy of ADM, 30 mg, combined with
      systemic CAF therapy of cyclophosphamide, 100 mg from days 1 to 14, ADM, 30 mg on
      days 1 and 8, and 5-fluorouracil, 500 mg on days 1 and 8, as one course. Two
      courses of the treatment resulted in a complete response of the tumor. This
      result suggests that local and systemic chemotherapy could be effective for the
      treatment of local recurrence of breast cancer.

PMID- 12484086
TI  - [A case of metastatic vaginal tumor of rectal cancer].
AB  - The majority of vaginal metastases from extra-genital tumors are from colorectal
      cancer. A case of metastases to the vagina from a huge rectal carcinoma is
      described. A 55-year-old woman was admitted to the hospital because of a barium
      ileus after upper GI. Further examination revealed that she had a huge rectal
      carcinoma. Hartmann's operation combined with resection of the right ureter,
      posterior wall of the uterus and left ovary was performed. Postoperative
      chemoradiotherapy was performed with 60 Gy of irradiation to the small pelvis
      with 500 mg/day continuous infusion of 5-FU. After 18 months, she had genital
      bleeding. Digital examination revealed a vaginal tumor and metastasis of the
      rectal carcinoma to the vagina was confirmed histologically. Abdominoperineal
      resection of the rectum and vagina combined with simple total hysterectomy and
      bilateral salpingo-oophorectomy was performed. Thirty-three months after
      operation, there is no sign of recurrence.

PMID- 12484087
TI  - [A case of stage IV diffusely infiltrating colon cancer treated by surgical
      resection and chemoradiation therapy].
AB  - A 62-year-old male patient presented at the hospital because of left lower
      abdominal tumor. Based on preoperative examination and biopsy results, he was
      diagnosed with stage IV diffusely infiltrating colon cancer (scirrhous type) with
      paraaortic lymph node metastases. He underwent sigmoidectomy with D1 lymph node
      dissection and received systemic infusion of 5-FU 750 mg and l-LV 300 mg once a
      week. This chemotherapy produced no change in response in the paraaortic lymph
      node metastases for a long time. One year later, there were distant lymph node
      metastases including left inguinal and Virchow's lymph node, and systemic
      infusion of CPT-11 was performed. In addition, left inguinal lymph node was
      treated with irradiation therapy (total 50 Gy). The patient died of multiple
      organ failure 18 months after the operation. It is known that the prognosis in
      cases of diffusely infiltrating colorectal cancer is extremely poor. However,
      this case might suggest that intensive therapies with surgery and chemoradiation
      are useful in maintaining quality of life and improving survival.

PMID- 12484088
TI  - [Endoscopic local injection of anticancer drugs bound to carbon particles for
      treatment of advanced rectal cancer, when surgical treatment was
      contraindicated].
AB  - Generally, patients with advanced rectal cancer in whom surgical treatment is
      contraindicated receive radiation or chemotherapy. In such patients, we have
      administered local injection of methotrexate and mitomycin C bound to activated
      carbon particles. Four patients received intratumoral injection of the dosage
      formulation (total dose 100-400 mg of methotrexate or 8-32 mg of mitomycin C)
      under colonofiberscope. After the treatment, bleeding and pain were lessened in
      all 4 patients. In two patients, the tumor markedly decreased in size and there
      was no regrowth prior to death 12-14 months after the treatment. In another
      patient, bleeding and pain disappeared until the patient died of pulmonary and
      liver metastases. The fourth patient is alive without regrowth 5 months after
      treatment. Side effects were not severe.

PMID- 12484089
TI  - [A case report of advanced huge hepatocellular carcinoma (H.C.C.) accompanied by
      tumor embolism to the inferior caval vein (Vv3) that was treated with surgical
      extended right lobectomy after multimodal therapy].
AB  - We performed multimodal therapy for a huge hepatocellular carcinoma with tumor
      embolism (Vv3), for which excision was judged impossible. After treatment, a
      hepatectomy to the primary lesion was finally carried out and long-term survival
      was achieved. A 52-years-old man with right lateroabdominal pain had a huge
      occupied hepatocellular carcinoma that was detected in October 2000. A tumor
      embolism, which invaded the inferior vena cava, was also seen. The residual liver
      was judged to have insufficient capacity for a right hepatic lobectomy. A
      percutaneous transhepatic portal embolism (PTPE) was carried out against the
      right portal vein to increase in the left lobe capacity. The chemo-radiotherapy
      (36 Gy to the right hepatic vein and systemic administration of CDDP) and
      transcatheter arterial chemoembolization were added to the feeding arteries of
      the hepatic tumor. When a decrease in the postcaval vein tumor embolism was
      observed, the extended right hepatic lobectomy was performed. The postoperative
      course was good, and the patient was discharged from the hospital on
      postoperative day 41. Though lung metastasis and new lesions in left lobe were
      seen in a recurrence, two years and ten months since the start of the systemic
      chemotherapy. This case suggested that even if a huge liver cancer with vascular
      invasion is judged impossible to excise, multimodal therapy with the aim of
      surgical treatment helps retain the possibility to later chose hepatectomy for
      the primary lesion and improve prognosis.

PMID- 12484090
TI  - [Hepatocellular carcinoma recurrence in PEI site--a case report].
AB  - The patient was 63-year-old male. Abdominal CT revealed a tumor at S2/S3, which
      led to a diagnosis of hepatocellular carcinoma, in April 1998. On April 15, 1998
      transcathetereal arterial embolization was performed and on May 11, 1998
      percutaneous ethanol injection therapy was given, but a viable lesion remained.
      On July 2, 1998, partial resection of S2/S3 was performed. There was an
      intrahepapic metastatic lesion at Glisson's site of the main tumor, which was
      suspected of implantation. In December 2000, the patient had a high AFP level,
      and a recurrent tumor was observed at S3 on abdominal CT. In June 2001, S3
      subsegmentectomy was performed, because the recurrent tumor existed in the
      Glisson S3 area.

PMID- 12484091
TI  - [Treatment of hepatocellular carcinoma--partial hepatic resection under hand
      assisted laparoscopic surgery and local ablation therapy with ethanol and radio
      frequency].
AB  - A 76-year old female patient with chronic B type hepatitis had HCC expanding into
      the extra-hepatic space. In July 2001, we safely performed partial hepatic
      resection under hand-assisted laparoscopic surgery (HALS). Three months after the
      treatment, computed tomography of the liver revealed HCC close to the first
      branch of right portal vein and bile duct. Although we performed transcatheter
      arterial chemoembolization (TACE) for the tumor, this treatment was not
      effective. So we treated percutaneous ethanol injection therapy (PEIT) for the
      tumor area neighboring Glisson's capsule and radiofrequency ablation therapy
      (RFA) for the tumor. After this treatment the tumor showed no viability on
      dynamic CT, and there was no liver infarction or damage to the bile duct. Four
      months after the final treatment, enhanced CT revealed no viable lesion, and
      serum alpha-fetoprotein level was declining toward the normal range. We conclude
      that selection of an applicable treatment and approach is of importance for safe
      and effective therapy.

PMID- 12484092
TI  - [A case of postoperative multiple hepatic metastasis from gastric cancer
      successfully treated by percutaneous microwave coagulation therapy and hepatic
      arterial infusion chemotherapy].
AB  - A 61-year-old male who underwent radical resection for gastric cancer was
      diagnosed with multiple hepatic metastasis 2 years and 2 months after the
      surgery. He first underwent percutaneous microwave hepatic coagulation therapy
      with segmental hepatic blood flow occlusion and obtained complete coagulation of
      the main tumor. Consecutively, he received hepatic arterial infusion chemotherapy
      (FAP: 5-FU, cisplatin, adriamycin) against residual multiple hepatic tumors.
      These hepatic recurrent lesions disappeared completely after 3 sessions of
      arterial infusion chemotherapy. At present, this patient is alive with no
      recurrent lesions, 1 year and 6 months from the beginning of treatment for
      hepatic metastasis. Recently, we tried hepatic arterial infusion chemotherapy
      (FAP) in four cases in which the recurrence from gastric cancer was not only in
      the liver but elsewhere. The response rate (CR and PR) was 75% and no major side
      effects were observed. In conclusion, some cases can obtain longer survival if
      the multimoderate therapy including hepatic arterial infusion chemotherapy (FAP)
      and microwave coagulation therapy are effective.

PMID- 12484093
TI  - [A case report of primary hepatic carcinoid with lymph node metastasis--treatment
      of hepatic arterial infusion to post-reoperative liver and radiation to
      metastasis of para-aortic lymph nodes].
AB  - We report a case of primary liver carcinoid. A 50-year-old woman had undergone
      left nephrectomy six years earlier for renal cell carcinoma. She developed
      abdominal pain. CT scans showed a low-density area in the lateral segment of the
      liver and lymph node swelling to the left of the abdominal aorta. Angiography
      showed a hypovascular tumor. After lateral segmentectomy and examination of the
      gastrointestinal tract, we diagnosed primary liver carcinoid. Unfortunately, the
      tumor recurred at multiple sites in the residual liver about 9 months after the
      first operation. She underwent further liver resection and microwave coagulation
      therapy. At that time, lymph node biopsy confirmed metastatic carcinoid. We began
      hepatic arterial chemotherapy for the residual liver and radiation therapy for
      the para-aortic lymph nodes (total 45 Gy). During chemotherapy, no recurrence was
      seen. At 11 months after reoperation, however, multiple liver metastases occurred
      with severe liver dysfunction and jaundice. She died about 24 months after the
      first liver resection.

PMID- 12484094
TI  - [A case of metastatic gastric cancer treated with CDDP plus TS-1 and surgical
      resection].
AB  - Advanced gastric cancer (AGC) with liver metastasis has a poor prognosis. We
      encountered a case of AGC with multiple liver metastasis treated with
      chemotherapy and surgery. CASE: A 54-year-old male. He was admitted to our
      hospital with epigastric pain. Gastrointestinal fiberscope examination revealed
      gastric cancer. A CT scan showed regional and para-aortic lymph node (LN)
      swelling and multiple hepatic metastasis in the left hepatic lobe. The serum CEA
      level was 100.6 ng/dl. He was administered 4 courses of CDDP (100 mg (day 8
      i.v.)) plus TS-1 (120 mg/day day 1-21 p.o.). After the chemotherapy, CT showed a
      reduction of liver metastasis and disappearance of the LN swelling. The serum CEA
      levels were normalized. Distal gastrectomy, partial hepatectomy, and microwave
      coagulation therapy were performed. After operation, he was administered 4
      courses of CDDP/TS-1 additionally. Surgery may be one of therapeutic option for
      AGC with liver metastasis that has responded to chemotherapy, as in the present
      case.

PMID- 12484095
TI  - [A case of gastric cancer associated with synchronous liver metastasis
      successfully treated with combination therapy of systemic and hepatic arterial
      infusion chemotherapy].
AB  - A 56-year-old man who underwent distal gastrectomy at another hospital was
      admitted to our hospital because of advanced gastric cancer with synchronous
      liver metastasis. As we considered that the metastatic liver tumor was
      unresectable one, an intra-arterial catheter was inserted and weekly chemotherapy
      including methotrexate (MTX) (intra-venous) and 5-fluorouracil (5-FU) (intra
      arterial) was started. The metastatic liver tumor was gradually reduced and
      resulted in partial response (PR) after 12 courses. Eight months later, the size
      of the metastatic liver tumor increased and lung metastasis occurred, so we
      started a new regimen of chemotherapy using CPT-11 (intra-venous) and CDDP (intra
      arterial). After 4 courses of this regimen, we gained PR both in the metastatic
      liver and lung tumor. This case indicates that the combination therapy of
      systemic and hepatic arterial infusion chemotherapy is a treatment option in
      cases of advanced gastric cancer with liver metastasis.

PMID- 12484096
TI  - [Treatment of colorectal cancer--hepatic metastases].
AB  - The aim of this study was to evaluate the effect of the local therapy for
      colorectal liver metastases on overall survival. Seventy-two patients who had
      resected liver metastases from colorectal cancer during the period from 1982 to
      2001 were evaluated for survival. There was no significant difference in overall
      survival by either surgical method for colorectal liver metastases or
      postoperative arterial infusion chemotherapy. However, the 5-year survival rate
      of resected metachronous liver metastases with postoperative arterial infusion
      chemotherapy was 44.9%, and that for patients with no extra hepatic metastases
      was 57.4%. Patients who have metachronous liver metastases from colorectal cancer
      should therefore be considered for postoperative arterial infusion chemotherapy.
      It is necessary to improve the outcome for cases that have extra hepatic
      metastases.

PMID- 12484097
TI  - Asthma is a serious disease....

PMID- 12484098
TI  - Is the "virtual school nurse" for your community?

PMID- 12484099
TI  - Supreme court rules on student drug testing.

PMID- 12484100
TI  - Choosing where we're going by knowing where we are: results of the 2002
      membership survey.

PMID- 12484101
TI  - Publish or perish. Implications for holistic nursing.

PMID- 12484102
TI  - The use of complementary therapies.

PMID- 12484103
TI  - A descriptive study of the interactive guided imagery experience.
AB  - The purpose of this Study was to describe the experience of participating in
      Interactive Guided Imagery (IGI) from the perspective of clients. A qualitative
      descriptive design guided the research. Ten clients who had engaged in IGI, each
      with an R.N., IGI-certified practitioner, composed the sample. To explore
      participants' perceptions of their IGI experience, data were gathered through
      semistructured, in-depth interviews. Data analysis was carried out through data
      coding, categorizing, and subcategorizing; thematic synthesis; and structuring of
      relationships. Six primary themes emerged to compose the description of the
      experience of participating in IGI: the client's lived experience, use of a
      nonordinary state of consciousness, the guide, the guide-client relationship,
      influencing factors, and the results of IGI use. Based on the primary themes and
      their interrelationships, a model of the IGI experience was developed. The
      description and the model of the IGI experience provide the basis for further
      nursing knowledge development of the IGI modality.

PMID- 12484104
TI  - Prayer after stroke. Its relationship to quality of life.
AB  - Research has documented that recovery from a stroke is stressful, often
      necessitating significant coping efforts. Difficult life events such as stroke
      may encourage patients to reexamine spiritual aspects of life, and the challenges
      associated with stroke can promote spiritual growth and development. Because of
      the life-changing experience of stroke, spiritual practices may assist patients
      in finding meaning and wholeness through the confidence they offer. The purpose
      of this article is to report how 8 patients used prayer after stroke as a coping
      strategy to improve self-efficacy and quality of life after stroke. A qualitative
      approach using the long interview method was employed to expand on spiritual
      practices expressed through prayer as a way of coping after stroke. Potential
      strategies are suggested for nurses that address patients' spiritual needs.

PMID- 12484105
TI  - Effects of integrating therapeutic touch into a cognitive behavioral pain
      treatment program. Report of a pilot clinical trial.
AB  - The purpose of this study was to investigate the effects of offering Therapeutic
      Touch (TT) as an adjunct to cognitive behavioral therapy (CBT) for people with
      chronic pain. Patients were randomized to relaxation training (control group) or
      TT plus relaxation (experimental). Subsequently, all participants attended a CBT
      program. Preprogram and postprogram data were examined to identify patterns of
      change in pain intensity, self-efficacy, unitary power, disability, and perceived
      distress. In addition, patterns of attrition were examined. Patients in this
      study who were randomized to receive TT fared better in terms of enhanced self
      efficacy and unitary power, as well as having lower attrition rates. Trends
      associated TT with less distress and disability. This pilot study suggests that
      offering TT as an adjunct to CBT may help to improve clinical outcomes, reduce
      program attrition, and promote unitary power in those who suffer with chronic
      pain.

PMID- 12484106
TI  - Exploring the meaning of spirituality with aging adults in Appalachia.
AB  - This phenomenological study explored the meaning of spirituality in the lives of
      aging adults in Appalachia. Forty adult volunteers in varying states of health
      ranging in age from 59 to 94 years participated in focus groups. Through open
      ended questions, respondents described their perceptions of spirituality,
      spirituality, and health, and the role of spirituality in helping them cope.
      Themes that emerged from the data were a conviction that God exists and acts in
      the lives of persons, calls them to action, and is a source of connection in
      times of loss. Spirituality positively affects attitude, particularly as health
      declines. Respondents expected respectful and empathic health care providers who
      would meet their physical needs and be concerned about their spiritual needs.
      Spirituality was of paramount importance in the lives of these elders; thus,
      health care providers must consciously include spirituality in assessments and
      interventions. Nursing curricula must prepare students to provide spiritual care.

PMID- 12484107
TI  - Inadequate nursing care in an emergency care unit in Sweden. Lack of a holistic
      perspective.
AB  - The aim of this case study has been to analyze factors that hinder the provision
      of adequate nursing care in one emergency care unit (ECU). The research question
      was, What are the conditions that explain the provision of inadequate nursing
      care in an ECU with reported problems concerning caring attitudes? The design of
      the study was exploratory and interpretive within a hermeneutic tradition. Nurses
      were interviewed, and field notes were made from participant observations of
      routine work and staff meetings. An interpreted whole revealed a lack of a
      holistic perspective. The difficulty of these nurses in accomplishing a holistic
      perspective seemed to be due to overvaluation of measurable tasks, such as
      medical interventions, and undervaluation of nonmeasurable tasks, such as caring.
      As a consequence, caring interventions failed to strengthen the nurses' self
      esteem in the same high degree as medical tasks.

PMID- 12484108
TI  - A spiritual health community seminar based on religious commitment research.
AB  - There is a need for spiritual health seminars at the work site and through
      hospital and other community venues. This article describes how the authors
      prepared for and conducted seminars in their community. The research demonstrates
      that religious commitment may play a beneficial role in an individual's health.
      Once the authors were armed with this research and a fundamentally sound and
      practical program, they were able to assist individuals in their community in
      designing and initiating their own individual spiritual health workouts, which
      may then influence their physical and mental health. In this way, the authors
      were able to apply holistic principles of spirit, mind, and body.

PMID- 12484109
TI  - Nutrition and cancer: a complex relationship.

PMID- 12484110
TI  - Some methodological issues in nutritional epidemiology.

PMID- 12484111
TI  - A new method for calibration of long-term dietary intake by repeated short-term
      measurements.

PMID- 12484112
TI  - Potential use of the Web to improve dietary habits--the ECP Diet Web-1 Project.

PMID- 12484113
TI  - Comparison of telephone versus face-to-face interviews in the assessment of
      dietary intake by the 24-hour recall EPIC SOFT programme--the Norwegian
      calibration study.

PMID- 12484114
TI  - The role of correlated errors in the multivariate analysis of dietary data.

PMID- 12484115
TI  - Do cross-check questions improve food frequency questionnaire data?

PMID- 12484116
TI  - Dietscan: a common approach for analysing dietary patterns.

PMID- 12484117
TI  - Demographics and socio-economic differences in adherence to the Mediterranean
      dietary pattern in Spain.

PMID- 12484118
TI  - Compliance with the urine marker PABAcheck in cancer epidemiology studies.

PMID- 12484119
TI  - Differences in calculating fibre intake of a British diet when applying the
      British, Danish and French food composition tables.

PMID- 12484120
TI  - Validity of the Italian EPIC questionnaire to assess past diet.

PMID- 12484121
TI  - Comparable nutrient intake across countries is only possible through
      standardization of existing food composition tables.

PMID- 12484122
TI  - Do dietary patterns actually vary within the EPIC study?

PMID- 12484123
TI  - Using multiple imputation methods to estimate relative risks in small EPIC lung
      cancer subsets.

PMID- 12484124
TI  - Socio-economic determinants for participation in the Danish EPIC Diet, Cancer and
      Health cohort.

PMID- 12484125
TI  - Adjustment for smoking in lung cancer analyses in the EPIC cohort.

PMID- 12484126
TI  - A European case-only study on familial breast cancer.

PMID- 12484127
TI  - Follow-up of the ORDET cohort, Lombardy Cancer Registry, 1987-1997.

PMID- 12484128
TI  - The Melbourne Collaborative Cohort Study.

PMID- 12484129
TI  - Nutrition and cancer prevention in Australia: a national collaboration to promote
      the evidence.

PMID- 12484130
TI  - Nutrition and cancer prevention: working together to promote healthy eating.

PMID- 12484131
TI  - Epidemiological studies of cereals, fruit and vegetables.

PMID- 12484132
TI  - Vegetable, fruit and cereal consumption and gastric cancer risk.

PMID- 12484133
TI  - Vegetables and fruits and lung cancer.

PMID- 12484134
TI  - Plant foods and the risk of colorectal cancer in Europe: preliminary findings.

PMID- 12484135
TI  - Carbohydrate consumption in 10 European countries.

PMID- 12484136
TI  - Vegetable and fruit consumption in the EPIC cohorts from 10 European countries.

PMID- 12484137
TI  - Consumption of soy products in 10 European countries.

PMID- 12484138
TI  - Consumption of soy products among European consumers of a health-conscious diet.

PMID- 12484139
TI  - Dietary and lifestyle characteristics of meat-eaters, fish-eaters, vegetarians
      and vegans.

PMID- 12484140
TI  - Consumption of wild vegetables in the EPIC cohort of Ragusa (Sicily).

PMID- 12484141
TI  - Plasma vitamin C, cancer mortality and incidence in men and women: a prospective
      study.

PMID- 12484142
TI  - How vegetables are eaten in Italy EPIC centres: still setting a good example?

PMID- 12484143
TI  - Fruit and vegetable consumption and risk of cancer of the digestive tract: meta
      analysis of published case-control and cohort studies.

PMID- 12484144
TI  - Subregional variations of dietary consumption and incidences of cancers in
      southern France.

PMID- 12484145
TI  - Mortality and fresh fruit consumption.

PMID- 12484146
TI  - Validation study of soya intake and plasma isoflavone levels among British women.

PMID- 12484147
TI  - Fruit and vegetable intake and chronic disease risk in Portugal.

PMID- 12484148
TI  - Fruit and vegetable consumption and colorectal cancer incidence.

PMID- 12484149
TI  - Diet and the risk of cancers of the lung, oral cavity and pharynx, and larynx: a
      population-based case-control study in north-east Italy.

PMID- 12484150
TI  - Dietary factors and epithelial cell exfoliation in the human colon.

PMID- 12484151
TI  - Alcoholic beverages and smoking.

PMID- 12484152
TI  - Alcohol and risk of cancer of the upper gastrointestinal tract: first analysis of
      the EPIC data.

PMID- 12484153
TI  - Alcohol consumption and breast cancer risk. Preliminary results of the EPIC
      cohort.

PMID- 12484154
TI  - Smoking and diet quality in teenage girls: are they related?

PMID- 12484155
TI  - Alcohol consumption and oxidative damage.

PMID- 12484156
TI  - Effect of smoking on the association between alcohol consumption and cancer
      mortality among middle-aged Japanese men: JPHC Study Cohort I.

PMID- 12484157
TI  - Trends in self-reported past alcohol intake from 1950 to 1995 observed in eight
      European countries participating in the European Investigation into Cancer and
      Nutrition (EPIC) project.

PMID- 12484158
TI  - Alcohol consumption in EPIC cohorts from ten European countries.

PMID- 12484159
TI  - Meat, fish and dairy products.

PMID- 12484160
TI  - Meat cooking and cancer risk.

PMID- 12484161
TI  - Fish and cancer.

PMID- 12484162
TI  - Dairy foods and colorectal cancer: epidemiological evidence.

PMID- 12484163
TI  - Prostate cancer: rates in Europe, dietary hypotheses, and plans for EPIC.

PMID- 12484164
TI  - Very-long-chain omega-3 fatty acids as markers for habitual fish intake in Spain.

PMID- 12484165
TI  - Conjugated linoleic acid and the risk of breast cancer.

PMID- 12484166
TI  - Red meat and colorectal cancer risk: the effect of dietary iron and haem on
      endogenous N-nitrosation.

PMID- 12484167
TI  - Mercury intake associated with fish consumption in a cohort of Gipuzkoa, Basque
      Country, Spain.

PMID- 12484168
TI  - Meat consumption in Europe--results from the EPIC study.

PMID- 12484169
TI  - Consumption of added fats and oils in EPIC.

PMID- 12484170
TI  - Plasma concentrations of fatty acids in nine European countries: cross-sectional
      study within the European Prospective Investigation into Cancer and Nutrition
      (EPIC).

PMID- 12484171
TI  - Use of high-temperature cooking methods in preparation of meat and fish in
      European countries.

PMID- 12484172
TI  - Variability in fish consumption in 10 European countries.

PMID- 12484173
TI  - Meat consumption and colorectal cancer risk: an estimate of attributable and
      preventable fractions.

PMID- 12484174
TI  - Serum fatty acids and risk of breast cancer in a nested case-control study of the
      New York University Women's Health Study.

PMID- 12484175
TI  - Dietary factors and multiple myeloma. Case-control study in Belgrade.

PMID- 12484176
TI  - Body weight, physical activity and cancer.

PMID- 12484177
TI  - Anthropometry, physical activity and cancer of the breast and colon.

PMID- 12484178
TI  - Leisure-time sport physical activity and dietary intake of foods in Spain.

PMID- 12484179
TI  - Energy intake, energy expenditure and BMI influence the risk of endometrial
      cancer in a prospective study in Norway.

PMID- 12484180
TI  - Prevalence of overweight, general and central obesity in 50- to 64-year-olds
      involved in the EPIC cohort.

PMID- 12484181
TI  - BMI and smoking status in the EPIC cohorts.

PMID- 12484182
TI  - Colorectal cancer associated with BMI, physical activity, diabetes, and blood
      glucose.

PMID- 12484183
TI  - BMI throughout life, intake of vitamin supplements and oral cancer in Spain.

PMID- 12484184
TI  - Adolescent BMI and cancer risk.

PMID- 12484185
TI  - Physical activity in the EPIC cohort in Italy.

PMID- 12484186
TI  - Hormones and breast cancer.

PMID- 12484187
TI  - Possible mechanisms relating diet to colorectal cancer risk.

PMID- 12484188
TI  - Androgenic hormones and prostate cancer risk: status and prospects.

PMID- 12484189
TI  - Nutrition, energy balance and colon cancer risk: the role of insulin and insulin
      like growth factor-I.

PMID- 12484190
TI  - The effect of diet on serum insulin-like growth-factor-I and its main binding
      proteins.

PMID- 12484191
TI  - Diet and postmenopausal breast cancer in Portugal.

PMID- 12484192
TI  - Use of hormonal therapy for menopause in nine European countries.

PMID- 12484193
TI  - Plasma bile acids and risk of breast cancer.

PMID- 12484194
TI  - Age at menarche in relation to adult height in the EPIC cohort.

PMID- 12484195
TI  - The 1944-1945 Dutch famine and age at natural menopause--the value and validity
      of individual exposure assessment.

PMID- 12484196
TI  - Effects of maternal age at birth on breast cancer risk factors in daughters. A
      hypothesis on the role of oocyte, mitochondrial-related chromosomal instability.

PMID- 12484197
TI  - Bone mineral density and subsequent risk of prostate cancer in the NHANES-1
      follow-up.

PMID- 12484198
TI  - Reliability and validity of direct radioimmunoassays for measurement of
      postmenopausal serum androgens and estrogens.

PMID- 12484199
TI  - Food and carcinogenesis.

PMID- 12484200
TI  - Phytoestrogens and breast cancer risk: review of the epidemiological evidence.

PMID- 12484201
TI  - n-3 fatty acids and breast cancer.

PMID- 12484202
TI  - Novel plant-derived anticarcinogens.

PMID- 12484203
TI  - Plant polysaccharides, meat and colorectal cancer.

PMID- 12484204
TI  - Dietary catechins and cancer incidence: the Iowa Women's Health Study.

PMID- 12484205
TI  - Micronutrients and ovarian cancer: an Italian case-control study.

PMID- 12484206
TI  - Micronutrients and the risk of colorectal adenomas: a case-control study in Sao
      Paulo, Brazil.

PMID- 12484207
TI  - Biocide residues in healthy food as risk factors.

PMID- 12484208
TI  - Daidzein and genistein intakes in England (the EPIC Norfolk cohort).

PMID- 12484209
TI  - Sources of selected vitamins in a sample of the Italian population.

PMID- 12484210
TI  - The effects of an isoflavone intervention on the urinary excretion of hormone
      metabolites in premenopausal women.

PMID- 12484211
TI  - Bracken fern (Pteridium aquilinum) ingestion and oesophageal and stomach cancer.

PMID- 12484212
TI  - Ranking chemopreventive agents on rat colon carcinogenesis.

PMID- 12484213
TI  - Anti-tumour-promoting action of Allium constituents.

PMID- 12484214
TI  - Purified and endogenous phytic acid in wheat bran affects early biomarkers of
      colon cancer risk.

PMID- 12484215
TI  - Indigestible carbohydrates which reduce colon tumour incidence in Min mice may
      interfere with the local immune response.

PMID- 12484216
TI  - Analysis of oxidized and nitrated proteins in plasma and tissues as biomarkers
      for exposure to reactive oxygen and nitrogen species.

PMID- 12484217
TI  - Beneficial effect of an antioxidant micronutrient-enriched food on DNA damage:
      experimental study in rats using a modified comet assay in total blood.

PMID- 12484218
TI  - Peroxyl radical-scavenging activity of beverages in vitro, especially of tea,
      coffee and wine.

PMID- 12484219
TI  - Micronutrients and the regulation of cancerous cell growth and death: effect of
      sulforaphane, an isothiocyanate from broccoli.

PMID- 12484220
TI  - Lack of chemoprevention of indole-3-carbinol in N-methyl-N-nitrosourea-induced
      mammary carcinogenesis in rats.

PMID- 12484221
TI  - Interaction of dietary beta-carotene and alpha-linolenic acid: effect on
      promotion of experimental mammary tumours.

PMID- 12484222
TI  - Effects of conjugated linoleic acid on adenoma formation in the ApcMin mouse.

PMID- 12484223
TI  - Geraniol, a component of plant essential oils, sensitizes human colon cancer
      cells to 5-fluorouracil treatment.

PMID- 12484224
TI  - Could apigenin metabolism explain the estrogenic effect of this flavonoid in the
      female immature rat?

PMID- 12484225
TI  - Animal tissue components may be anticarcinogenic.

PMID- 12484226
TI  - Diet modulates the genotoxicity of IQ (2-amino-3-methylimidazo[4,5-f]quinoline)
      in rats associated with a human faecal flora.

PMID- 12484227
TI  - IQ (2-amino-3-methylimidazo[4,5-f]quinoline)-induced aberrant crypt foci and
      colorectal tumour development in rats fed two different carbohydrate diets.

PMID- 12484228
TI  - L-methionine supplementation accelerates tumour growth and shifts the
      phospholipid derivative pattern in a murine model of malignant melanoma. A proton
      HRMAS NMR spectroscopy study.

PMID- 12484229
TI  - Simple sugars modulate the development of aberrant crypt foci in rat colon during
      post-initiation.

PMID- 12484230
TI  - Colonic luminal contents (faecal water) induce COX-2.

PMID- 12484231
TI  - DIANA trials on diet and endogenous hormones.

PMID- 12484232
TI  - Lack of effect of a low-fat high-carbohydrate diet on ovarian hormones in
      premenopausal women: results from a randomized trial.

PMID- 12484234
TI  - Effect of fibre and calcium supplementation on adenoma recurrence and growth.

PMID- 12484233
TI  - The SU.VI.MAX trial on antioxidants.

PMID- 12484235
TI  - Polyps and vegetables (and fat, fibre): the polyp prevention trial.

PMID- 12484236
TI  - DNA adducts and the protective role of fruits and vegetables.

PMID- 12484237
TI  - Malondialdehyde-DNA adducts in relation to diet and disease risk--a brief
      overview of recent results.

PMID- 12484238
TI  - Meat intake, metabolic genes and colorectal cancer.

PMID- 12484239
TI  - Expression of cytochrome P450 enzymes in human colon.

PMID- 12484240
TI  - Role of EPHX genotype in the associations of smoking and diet with colorectal
      adenomas.

PMID- 12484241
TI  - NQO1 and mEH exon 4 (mEH4) gene polymorphisms, smoking and colorectal cancer
      risk.

PMID- 12484242
TI  - The role of folic acid and vitamin B12 in colorectal carcinogenesis in
      genetically different individuals--design of a study.

PMID- 12484243
TI  - Diet and K-ras mutations in colorectal cancer.

PMID- 12484244
TI  - Dietary factors, genetic susceptibility and somatic mutations in colorectal
      cancer: a prospective study.

PMID- 12484245
TI  - Diet and truncating APC mutations in sporadic colon tumours.

PMID- 12484246
TI  - Cruciferous vegetable intake, GSTM1 genotype and lung cancer risk in a non
      smoking population.

PMID- 12484247
TI  - Risk factors, genetic predisposition and mutations in the VHL gene in sporadic
      renal cell carcinoma: The Netherlands Cohort Study.

PMID- 12484248
TI  - Trends in foods available for consumption: Europe, 1961-1999.

PMID- 12484249
TI  - WHO's strategy on nutrition and noncommunicable diseases prevention.

PMID- 12484250
TI  - The World Cancer Research Fund Expert Report: the next steps.

PMID- 12484251
TI  - A global perspective on food, environment and health, with particular reference
      to diet and cancer.

PMID- 12484252
TI  - The dietary prevention of ischaemic heart disease.

PMID- 12484253
TI  - Malignant tumour follow-up in Italy, 1993-1998.

PMID- 12484254
TI  - Benign neoplasms: a follow-up study in Italy, 1993-1998.

PMID- 12484255
TI  - Age at exposure to the Dutch famine of 1944-1945 has opposing effects on adult
      mammographic density (DY); a study in the DOM cohort.

PMID- 12484256
TI  - Diet, energy intake and breast cancer risk in an Asian country.

PMID- 12484257
TI  - Epidemiological characteristics of colorectal cancer in Vojvodina.

PMID- 12484258
TI  - Diet and colorectal cancer in Portugal.

PMID- 12484259
TI  - Calorie restriction reduces the incidence of radiation-induced myeloid leukaemia.

PMID- 12484260
TI  - Dietary factors and brain tumours in adults: pilot study results of a case
      control investigation in Rio de Janeiro, Brazil.

PMID- 12484261
TI  - Diet and cancer of oral cavity and pharynx: a case-control study in Sao Paulo,
      Brazil.

PMID- 12484262
TI  - Forever a nurse.

PMID- 12484263
TI  - How to make sense of research jargon.

PMID- 12484264
TI  - Effective partnerships. Bringing nursing research alive in the practice setting.

PMID- 12484265
TI  - Nurses' work. Growth and satisfaction.

PMID- 12484266
TI  - Quality practice. Psychiatric nurses in hospital emergency departments.

PMID- 12484280
TI  - H Widenham Maunsell: innovative surgeon.

PMID- 12484282
TI  - Henry Gray and Henry Vandyke Carter: creators of a famous textbook.

PMID- 12484283
TI  - John Hunter's last letter to Edward Jenner.

PMID- 12484285
TI  - William Farr: campaigning statistician.

PMID- 12484286
TI  - Medical radicals in the age of the Enlightenment.

PMID- 12484287
TI  - Churchill in Carthage, 1943: Dr Evan Bedford's war diary.

PMID- 12484306
TI  - Will scientists shape the family of the future?

PMID- 12484307
TI  - Turn off the machines!  A plea for death with dignity.

PMID- 12484308
TI  - The dilemmas of our "biological revolution".

PMID- 12484309
TI  - Ethics committee opinion approved -- involuntary drug treatment of sex offenders.

PMID- 12484310
TI  - Genetic experimentation and the family.

PMID- 12484312
TI  - Disease, illness, sickness, health, healing and wholeness: exploring some elusive
      concepts.

PMID- 12484311
TI  - Nurses' attitudes and behavioral intentions concerning AIDS care.

PMID- 12484313
TI  - The practice of clinical medicine as an art and as a science.

PMID- 12484314
TI  - The use of poetry in health care ethics education.

PMID- 12484315
TI  - Voices to be heard -- The many positions of a physician in Anton Chekhov's short
      story, "A Case History.

PMID- 12484316
TI  - Forced administration of sex-drive reducing medications to sex offenders:
      treatment or punishment?

PMID- 12484317
TI  - The humanities in medical education: context, outcomes and structures.

PMID- 12484318
TI  - Changes to bodily appearance: the aesthetics of deliberate intervention.

PMID- 12484319
TI  - Fundraiser. Musicians record Afro-beat tribute for AIDS charities.

PMID- 12484321
TI  - Europeans investigate resale of AIDS drugs.

PMID- 12484320
TI  - FDA approves new rapid HIV test.

PMID- 12484322
TI  - Appeals court sides with HIV coalition in medical marijuana case.

PMID- 12484323
TI  - Activists give South African government AIDS plan ultimatum.

PMID- 12484324
TI  - Lack of medical expert derails suit for false-positive HIV test.

PMID- 12484325
TI  - DNA mapping. HIV-DNA matching uncovers case of intentional infection.

PMID- 12484326
TI  - High Court rejects challenge of HIV-DNA-matching reliability.

PMID- 12484327
TI  - Prisons. Judge reviews jail oversight in case of HIV-positive inmate.

PMID- 12484328
TI  - HIV-positive resident deemed deportable despite flawed case.

PMID- 12484329
TI  - Court awards $1.1 million for false HIV diagnosis.

PMID- 12484330
TI  - AIDS and hunger force changes in labor force, societal dynamics.

PMID- 12484331
TI  - Metabolic toxicities and HIV.

PMID- 12484332
TI  - The Ticket to Work Program: an update.

PMID- 12484334
TI  - Resistance to anti-HIV medications.

PMID- 12484333
TI  - Hepatitis C: be positively aware of the risk of transmission and treatment.

PMID- 12484335
TI  - Microbicides and HIV prevention.

PMID- 12484336
TI  - Once again, once a day.

PMID- 12484337
TI  - [Spectrum analysis of monophosphates SrMN(PO4)2, where M=Co, Ni].
AB  - The infrared and Raman spectra of triclinic phosphates SrM2(PO4)2 where M = Co,
      Ni have been reported and analysed. The results of a force field calculation for
      SrNi2(PO4)2 are presented.

PMID- 12484338
TI  - Thermal stability of the 248-nm-induced presensitization process in standard H2
      loaded germanosilicate fibers.
AB  - Grating growths through exposure of presensitized standard fibers to KrF light
      were recorded in various experimental condition. It is shown that there exists an
      optimum sensitization fluence at which the efficiency of the sensitization
      process is higher. Isochronal thermal annealing of pre-exposed fibers led to a
      decrease in the sensitization-induced enhancement of photosensitivity. IR
      absorption spectroscopy was carried out in fibers or preform plates to monitor
      the attenuation ascribed to H-bearing species in the same samples. The annealing
      induced decay in photosensitivity cannot be correlated with those of the H
      bearing species in the whole temperature range (110 degrees C-800 degrees C).
      This indicates that the enhancement of photosensitivity comes from the
      transformation of more than one species.

PMID- 12484339
TI  - The evolution of orthodontics. 1962.

PMID- 12484340
TI  - Safeguarding children from fabricated or induced illness. Part 1. Background and
      significance of the new Department of Health guidance.

PMID- 12484341
TI  - Infant feeding and lactational amenorrhea in Sagamu, Nigeria.
AB  - Five hundred and twenty educated, breastfeeding women in Sagamu, Nigeria, were
      observed prospectively in order to describe their infant feeding practices and to
      determine whether any predictors of the return of menses could be identified. The
      women remained amenorrheic for seven months. Compared with similarly selected
      women in other countries, they regularly fed their infants with supplements from
      a very early age, yet breastfeeding frequency and duration did not decline
      dramatically. Semi-solid food was introduced at about four months and such
      supplementation, as well as earlier supplementation with milk/milk-based
      feedings, was associated with the return of menses. The median duration of
      abstinence was about four months but the mean may have been much longer. No woman
      became pregnant until her infant was weaned.

PMID- 12484342
TI  - Proton transfer within the active-site cavity of carbonic anhydrase III.
AB  - The maximal turnover rate of CO2 hydration catalyzed by the carbonic anhydrases
      is limited by proton transfer steps from the zinc-bound water to solution, steps
      that regenerate the catalytically active zinc-bound hydroxide. Catalysis of CO2
      hydration by wild-type human carbonic anhydrase III (HCA III) (k(cat) = 2 ms (
      1)) is the least efficient among the carbonic anhydrases in its class, in part
      because it lacks an efficient proton shuttle residue. We have used site-directed
      mutagenesis to test positions within the active-site cavity of HCA III for their
      ability to carry out proton transfer by replacing various residues with
      histidine. Catalysis by wild-type HCA III and these six variants was determined
      from the initial velocity of hydration of CO2 measured by stopped-flow
      spectrophotometry and from the exchange of 18O between CO2 and H2O at chemical
      equilibrium by mass spectrometry. The results show that histidine at three
      positions (Lys64His, Arg67His and Phe131His) have the capacity to transfer
      protons during catalysis, enhancing maximal velocity of CO2 hydration and 18O
      exchange from 4- to 15-fold compared with wild-type HCA III. Histidine residues
      at the other three positions (Trp5His, Tyr7His, Phe20His) showed no firm evidence
      for proton transfer. These results are discussed in terms of the stereochemistry
      of the active-site cavity and possible proton transfer pathways.

PMID- 12484343
TI  - [Consequences of oocyte dysmorphy on the fertilization rate and embryo
      development after intracytoplasmic sperm injection. A prospective multicenter
      study].
AB  - OBJECTIVES: This prospective study aimed to evaluate the impact of oocyte
      dysmorphy on the fertilization rate and embryonic development rate in an ICSI
      programme. PATIENTS AND METHODS: Three hundred and two couples have been included
      during 302 ICSI cycles, and 1970 oocytes have been studied in 4 ART centres.
      After decoronisation, 18 morphological criteria, including the size and shape of
      the oocyte, the thickness of the zona pellucida, the presence or not of debris in
      the perivitelline space, as well as the appearance of the cytoplasm and polar
      body have been noted. RESULTS: In total 61.3% of the oocytes presented a
      dysmorphy, involving, almost equally, the different oocyte compartments. Among
      the dysmorphic oocytes, half presented more than one anomaly. On average, 9.2% of
      the oocytes were lysed the day after the micro-injection. The oocytes presenting
      an enlarged perivitelline space, or multiple vacuoles had a significantly raised
      lyse rate, 16.3% and 27.8%, respectively. The day after micro-injection, 61.3% of
      the intact oocytes were fertilized. The rate of fertilization was correlated to
      the number of abnormalities per oocyte: 1 anomaly: 64.6%, > or = 3 anomalies:
      54.6%. The oocytes presenting a large perivitelline space had a slightly lowered
      fertilization rate (53.4%). On the other hand, those showing a cytoplasm
      containing refractile bodies had a slightly raised fertilization rate (68.6%). We
      did not see any statistically significant difference between the different types
      of oocytes concerning embryonic development at d2. CONCLUSION: These results
      confirm and contribute new elements with respect to previously published data,
      showing that (i) oocyte morphology little affects fertilization and the first
      stages of embryonic development; (ii) certain dysmorphies, (enlargement of the
      perivitelline space) are specifically deleterious at certain stages in the
      process (lowering the fertilization rate); (iii) certain morphological
      differences (the presence of refringent bodies) are not anomalies, but can
      reflect physiological cellular changes.

PMID- 12484344
TI  - A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset
      Alzheimer disease.
AB  - We studied a Cuban family with presenile dementia (autosomal dominant) consisting
      of 281 members within six generations, the proband descended from a Spanish
      founder. Mean age at onset was 59 years of age. Memory impairment was the main
      symptom in all patients, additionally, ischemic episodes were described in 4 (n =
      18) patients. Neuropathological examination of brain material (1 patient)
      revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. Thirty DNA
      samples were genotyped (regions on chromosome 1, 3, 10, 12, 14, 17, 19, 20, and
      21). A maximum Lod score of 3.79 at theta = 0 was obtained for marker D14S43,
      located in a 9-cM interval in which all patients shared the same haplotype.
      Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A
      (exon 6), which is predicted to cause an amino acid change from leucine to
      methionine in the TMIII of the presenilin 1 protein. The mutation was found to co
      segregate with the disease phenotype and the associated disease haplotype. The C 
      -> A change was not observed in 80 control chromosomes from the Cuban population.
      Leucine at position 174 is highly conserved among species and is identical in
      presenilin 1 and presenilin 2 proteins. We propose the L174 M mutation might lead
      to an abnormal N-terminal and probably C-terminal fragments and malfunction of
      the protein complex. In conclusion, we found a novel PSEN1 mutation in a large
      family with clinical and pathological diagnosis of early onset familial Alzheimer
      disease, which may be relevant for other Hispanic populations.

PMID- 12484345
TI  - Differential effect of diarrhea on FK506 versus cyclosporine A trough levels and
      resultant prevention of allograft rejection in renal transplant recipients.
AB  - Diarrhea is the most frequently reported adverse event in patients treated with
      mycophenolate mofetil. Twenty-six renal transplant patients on a mycophenolate
      mofetil-based immunosuppressive regime with persistent afebrile diarrhea were
      examined. Diarrhea caused a significant rise in FK-506 trough levels despite
      intake of stable doses, necessitating FK-506 dose reductions of 30% to obtain pre
      diarrhea trough levels. In contrast, trough levels of cyclosporine A remained
      stable without dose adjustments. This suggests that absorption and/or metabolism
      is differentially altered for FK506 compared with cyclosporine A in patients with
      diarrhea. In nine patients mycophenolate mofetil was reduced or stopped because
      of persistent diarrhea without identifiable cause. This resulted in end-stage
      renal disease because of chronic rejection in two patients, and in acute
      rejection in two patients, all taking FK506 and steroids. Therefore, dose
      adjustments of FK506 in patients with diarrhea must be carefully monitored,
      especially when doses of mycophenolate mofetil are also reduced.

PMID- 12484347
TI  - Embolization of arteriovenous malformations with Onyx: clinicopathological
      experience in 23 patients.

PMID- 12484348
TI  - Working area and angle of attack in three cranial base approaches: pterional,
      orbitozygomatic, and maxillary extension of the orbitozygomatic approach.

PMID- 12484349
TI  - Childhood accident: swallowing of a pencil.

PMID- 12484350
TI  - Blunt duodenal and pancreatic trauma.

PMID- 12484351
TI  - Microscopic and endoscopic transsphenoidal surgery.

PMID- 12484353
TI  - Delayed surgical resection of central nervous system germ cell tumors.

PMID- 12484352
TI  - Ambient formaldehyde detection with a laser spectrometer based on difference
      frequency generation in PPLN.
AB  - A laser spectrometer based on difference-frequency generation in periodically
      poled LiNbO3 (PPLN) has been used to quantify atmospheric formaldehyde with a
      detection limit of 0.32 parts per billion in a given volume (ppbV) using
      specifically developed data-processing techniques. With state-of-the-art fiber
      coupled diode-laser pump sources at 1083 nm and 1561 nm, difference-frequency
      radiation has been generated in the 3.53-micrometers (2832-cm-1) spectral region.
      Formaldehyde in ambient air in the 1- to 10-ppb V range has been detected
      continuously for nine and five days at two separate field sites in the Greater
      Houston area operated by the Texas Natural Resource Conservation Commission
      (TNRCC) and the Houston Regional Monitoring Corporation (HRM). The acquired
      spectroscopic data are compared with results obtained by a well-established wet
      chemical o-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine (PFBHA) technique.

PMID- 12484354
TI  - Patient-evaluated outcome after surgery for basal meningiomas.

PMID- 12484355
TI  - Alexander Evseevich Braunstein.

PMID- 12484356
TI  - From biochemistry of amino acid metabolism to molecular enzymology. In
      recognition of the 100th anniversary of the birth of A. E. Braunstein, member of
      the academy of sciences of the USSR and the academy of medical sciences of the
      USSR.

PMID- 12484357
TI  - Regulation of oocyte maturation via an inhibitory Gs protein in mice.

PMID- 12484358
TI  - Ethics of embryo stem cell research still questioned.

PMID- 12484359
TI  - Braunstein as a strategist.

PMID- 12484360
TI  - How do multiple pregnancies reduce spontaneous in vivo?

PMID- 12484361
TI  - The enzyme of the life of Alexander Evseevich Braunstein.

PMID- 12484362
TI  - [Vitamin B12 deficiencies in adults: current data].

PMID- 12484363
TI  - Screening for domestic violence. Review is not an excuse for clinicians to ignore
      abuse.

PMID- 12484364
TI  - [Cannabis and nifluril].

PMID- 12484365
TI  - Screening for domestic violence. Screening for partner violence makes a
      difference and saves lives.

PMID- 12484366
TI  - Screening for domestic violence. Balanced approach is needed.

PMID- 12484367
TI  - Screening for domestic violence. Doctor's duty of confidentiality may not be in
      patient's or community's interest.

PMID- 12484368
TI  - Screening for domestic violence. Routine questioning of patients attending
      emergency departments may help in assessing local violence.

PMID- 12484369
TI  - Screening for domestic violence. Safe healthcare system needs to be in place.

PMID- 12484370
TI  - Chromatin folding and gene expression.

PMID- 12484371
TI  - The NHS, the private sector, and the virtual asylum. Misconceptions are naive.

PMID- 12484373
TI  - The NHS, the private sector, and the virtual asylum. No lessons have been learnt.

PMID- 12484374
TI  - Selected pages of the history of Soviet biochemistry.

PMID- 12484375
TI  - Association between competing interests and conclusions. Reasons for relation are
      also interesting.

PMID- 12484376
TI  - Diabetics fare well in surgery, study says.

PMID- 12484377
TI  - Several hospital traits linked to two pneumonia care quality indicators.

PMID- 12484378
TI  - PET scans improve management decisions, reduce unnecessary surgery in recurrent
      colorectal cancer.

PMID- 12484379
TI  - Studies describe prevalence of blindness, visual impairment among U.S. Hispanics.

PMID- 12484380
TI  - Treating head injuries. Studies of efficacy of medical and surgical interventions
      are urgently needed.

PMID- 12484381
TI  - Treating head injuries. Neurostimulants may be piece in brain injury
      rehabilitation puzzle.

PMID- 12484383
TI  - Rehabilitation Practice through Science and Research. Abstracts of the 79th
      annual meeting of the American Congress of Rehabilitation Medicine and the 9th
      annual meeting of the American Society of Neurorehabilitation. October 3-6, 2002.
      Philadelphia, Pennsylvania, USA.

PMID- 12484382
TI  - Treating head injuries. Psychiatric aspects of head injury need to be taken into
      consideration.

PMID- 12484385
TI  - Coping with negative test results in patch testing.

PMID- 12484386
TI  - Procedures for supplying fragrance information to dermatologists.

PMID- 12484387
TI  - Iodopropynyl butylcarbamate as a preservative.

PMID- 12484388
TI  - Allergic contact dermatitis caused by phenylephrine eyedrops.

PMID- 12484389
TI  - Clothing tag pruritus.

PMID- 12484390
TI  - Effect of maternal confidence on breastfeeding duration: an application of
      breastfeeding self-efficacy theory.
AB  - BACKGROUND: Although much research has focused on identifying factors that
      influence breastfeeding initiation and duration, many high-risk factors are
      nonmodifiable demographic variables. Predisposing factors for low breastfeeding
      duration rates that are amenable to supportive interventions should be
      identified. The purpose of this study was to assess the effect of maternal
      confidence (breastfeeding self-efficacy) on breastfeeding duration. METHOD: A
      prospective survey was conducted with 300 women in the last trimester of
      pregnancy recruited from the antenatal clinic of a large metropolitan hospital in
      Brisbane, Australia. Telephone interviews were conducted at 1 week and 4 months
      postpartum to assess infant feeding methods and breastfeeding confidence using
      the Breastfeeding Self-Efficacy Scale. RESULTS: Although 92 percent of
      participants initiated breastfeeding, by 4 months postpartum almost 40 percent
      discontinued and only 28.6 percent were breastfeeding exclusively; the most
      common reason for discontinuation was insufficient milk supply. Antenatal and 1
      week Breastfeeding Self-Efficacy Scale scores were significantly related to
      breastfeeding outcomes at 1 week and 4 months. Mothers with high breastfeeding
      self-efficacy were significantly more likely to be breastfeeding, and doing so
      exclusively, at 1 week and 4 months postpartum than mothers with low
      breastfeeding self-efficacy. CONCLUSIONS: Maternal breastfeeding self-efficacy is
      a significant predictor of breastfeeding duration and level. Integrating self
      efficacy enhancing strategies may improve the quality of healthcare that
      healthcare professionals deliver and may increase a new mother's confidence in
      her ability to breastfeed, and to persevere if she does encounter difficulties.

PMID- 12484391
TI  - The right to die versus the right to live--who decides? The long and wandering
      road to a legislative solution.

PMID- 12484392
TI  - Prophylaxis against venous thromboembolic disease: costs and controversy.

PMID- 12484393
TI  - The road to consensus: considerations for the safe use and prescribing of COX-2
      specific inhibitors.

PMID- 12484394
TI  - A quality use of medicines program for continuity of care in therapeutics from
      hospital to community.

PMID- 12484395
TI  - A quality use of medicines program for continuity of care in therapeutics from
      hospital to community.

PMID- 12484396
TI  - [Abstracts of the 77th Annual Meeting of the French Society of Surgical
      Orthopedics and Traumatology].

PMID- 12484397
TI  - The ever-widening gap between the science of artificial reproductive technology
      and the laws which govern that technology.

PMID- 12484398
TI  - In the shadow of "death with dignity": medicine and cultural quandaries of the
      vegetative state.
AB  - In this paper I address one site of technological development and cultural
      production, the permanent or persistent comatose condition and the institutions
      and practices that enable this life form to exist. As with other medical sites of
      ambiguity and change under recent scrutiny by anthropologists, the locations in
      which comatose bodies thrive are those in which the routinization of technology
      use in the clinic and a legitimating social and economic context come together to
      permit and create a further remapping of the notions of "life" and "person." I
      explore the new forms of knowledge, practice, and the body that are created at
      this site and how they are negotiated, and I discuss how the shifting
      understanding of "culture" and "nature" both have an impact on and are informed
      by American quandaries about approaching death. I argue that beings who are
      neither fully alive, biologically dead, nor "naturally" self-regulating, yet who
      are sustained by modern medical practice, destabilize the existing social order
      in ways that are different from other hybrid forms.

PMID- 12484399
TI  - Abstracts of the 6th International Symposium on Predictive Oncology and
      Intervention Strategies. Paris, France, 9-12 February 2001.

PMID- 12484400
TI  - Ethics of psychological research: new policies; continuing issues; new concerns.
AB  - The implementation over the past year within Canadian universities of the new Tri
      Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS)
      ushers in a new era in the oversight of the ethics of psychological research in
      Canada. Although these new policies apply to all human research, our interest in
      how they apply to psychology, primarily to deception, undergraduate subject
      pools, and other continuing concerns. Why have the granting agencies decided that
      government regulation of research ethics is necessary and what is the
      relationship between federal regulations and discipline codes? The history of
      CPA's involvement in protecting psychology's interests in the final revisions to
      the TCPS is recounted. In spite of what has been achieved, many psychologists
      feel that the TCPS has created new concerns for the discipline. Although there is
      the potential for startup problems, it is in our collective and individual best
      interests to make the policy work, thereby ensuring that escalation of government
      regulation or legislation will not be pursued.

PMID- 12484402
TI  - Abstracts of the 43rd Annual Conference of the Indian Society of Gastroenterology
      in association with the Indian Association for the Study of the Liver and Society
      of Gastrointestinal Endoscopy of India. Cochin, November 20-26, 2002.

PMID- 12484401
TI  - The role of the psychologist in determining competence for assisted
      suicide/euthanasia in the terminally ill.
AB  - This paper discusses the history of assisted suicide/euthanasia and public
      attitudes in Canada; discusses depression in the terminally ill and the potential
      role of the psychologist in the assisted suicide/euthanasia process; and
      specifically addresses the importance of determining competence in terminally ill
      patients. One area in which the services of psychologists have not been used to
      their fullest potential is in the care of the terminally ill, particularly in
      helping them make end-of-life decisions. It is very important that individuals
      making end-of-life decisions be used to assessed for mental disorders in order to
      ensure that they are able to make competent decisions. If assisted suicide and
      euthanasia were to become legalized, psychologists should be involved in the
      assessment process in order to determine competency.

PMID- 12484403
TI  - The battle against reproductive rights: the impact of the Catholic church on
      abortion law in both international and domestic arenas.

PMID- 12484404
TI  - Racism in psychiatry: paradigm lost--paradigm regained.
AB  - Racism and psychiatry have been 'linked' in the public imagination, largely
      because psychiatry is seen as an instrument of social control, and racism as a
      different form of oppression which permeates society at large. Racism in
      psychiatry is often believed to be the mediating factor in cases of 'psychiatric
      misdiagnosis' and 'mismanagement.' Misdiagnosis includes underdiagnosis and
      overdiagnosis; this can account for the non-delivery of appropriate treatments
      because of an erroneous diagnostic label. In some instances this leads to a
      deferred intervention, or in some ethnic groups, help-seeking is delayed for
      unnecessarily long periods. Racism is not a recent phenomenon. The blunt
      application of the word 'racism' perpetuates conceptual confusion about what is
      meant by the term, what processes are taking place, how much of the processes are
      institutionalized or individual and to what degree individuals are aware of the
      impact of their actions. We propose a way of understanding racism in psychiatric
      practice, and suggest that within such a framework, the therapist/professional
      and the patient can work together towards improving patient care.

PMID- 12484405
TI  - Dead daddies: issues in postmortem reproduction.

PMID- 12484406
TI  - A theological response to physician-assisted suicide.

PMID- 12484408
TI  - [Primary intraosseous rhabdomyosarcoma: a case of pelvic localization].

PMID- 12484407
TI  - European best practice guidelines for renal transplantation. Section IV: Long
      term management of the transplant recipient.

PMID- 12484409
TI  - [Correction of the article: "Nailing with a long gamma nail in sub-trochanteric
      and trochanteric-diaphyseal femoral fractures in adults].

PMID- 12484410
TI  - First, do no harm.

PMID- 12484411
TI  - [Are autopsies still useful?].

PMID- 12484412
TI  - [On the opportunity to revitalize pathology museums].

PMID- 12484413
TI  - [The reason why it was possible to perform a large number of autopsies in
      Trieste].

PMID- 12484414
TI  - [The triennial electoral assembly of the Italian Society for Gynecologic
      Pathology].

PMID- 12484415
TI  - Responses of the ultimobranchial gland to vitamin D3 treatment in freshwater mud
      eel, Amphipnous cuchia, kept in different calcium environments.
AB  - Freshwater mud eel, Amphipnous cuchia, were injected intraperitoneally daily with
      100 ng of vitamin D3/100 g body weight and maintained in media containing either
      no calcium or different calcium concentrations. The eels were killed after 1, 3,
      5, 10 and 15 days following the treatment and their serum calcium levels were
      measured. The ultimobranchial glands were fixed and processed using the routine
      paraffin method for histological studies. The results of the present study
      indicate that vitamin D3 can induce hypercalcaemia in eels kept in different
      calcium environments. Also, the ultimobranchial glands became hyperactive
      following vitamin D3 treatment. It is concluded that in mud eels, the gland has a
      calcium-regulating function.

PMID- 12484416
TI  - The muscles of mastication in the caspian seal (Phoca caspica).
AB  - The muscles of mastication and their related skull characters in the Caspian seal
      (Phoca caspica) were anatomically examined and compared with those of the Baikal
      (Phoca sibirica) and ringed (Phoca hispida) seals. A well-developed masseter
      muscle was observed in the Caspian seal, whereas the temporal muscle consisted of
      thin bundles. The skull of the Caspian seal possessed the same thin frontal bone
      and the dorso-ventrally developed zygomatic arch found in the Baikal seal that
      are required to install the enlarged eyeball into the orbit. The temporal bone
      was not robust, and the digastric muscle was well-developed in the ventral space
      of the auditory bulla. The present results suggest that the skull form of the
      Caspian seal has changed morphologically from its ringed seal-like ancestors, and
      suggest that the evolutionary strategy of the muscles of mastication in the
      Caspian seal is principally consistent with that of the Baikal seal.

PMID- 12484417
TI  - Morphological investigation of carotid body and its arteries in rabbits.
AB  - The purpose of this study was to determine the morphology of the rabbit carotid
      body and its artery at the light microscopy level. The carotid body was situated
      between the internal and external carotid arteries after the bifurcation point of
      the common carotid artery. The carotid body was usually found to be a single,
      ovoid tissue mass but, in some cases it consisted of two or three parts. More
      carotid bodies were supplied by a single carotid body artery (glomic artery)
      which arose from the common carotid artery or the internal or external carotid
      arteries near the bifurcation point of the common carotid artery. In only one
      case were there two arteries which arose from opposite sides of the external
      carotid artery at its origin. There was a distinguishable sinus (glomic sinus) at
      the origin of the glomic artery. This artery had a thin wall with elastic laminae
      in the sinus area which become thinner distal to the sinus.

PMID- 12484418
TI  - The renal structure in an Asian elephant (Elephas maximus).
AB  - The renal structure of a female Asian elephant (Elephas maximus) was observed in
      both macroscopic and light microscopic levels. The left kidney was elongated
      ellipse in shape, whereas the right appeared round. The left kidney was 31 cm in
      cranio-caudal length, 21 cm in medio-lateral length, and 2950 g in weight. The
      right kidney was 34 cm in cranio-caudal length, 22 cm in medio-lateral length,
      and 3250 g in weight. The external appearance showed the six separated renal
      lobes in both sides of the kidney. The four pairs of the lobes were fused in the
      deepest region in both sides of kidney, so we considered it as an incompletely
      lobated kidney in this species. We observed the proximal and distal urinary
      tubules in histological sections. Many renal corpuscles consisted of the
      glomerulus and Bowman's capsule. Many mesangial cells and some podocytes were
      confirmed in each glomerulus; however, Bowman's capsules were larger than those
      in other mammalian species.

PMID- 12484419
TI  - Expression of cytokeratin 18 during pre- and post-natal porcine lung development.
AB  - The expression pattern of the intermediate filament protein cytokeratin 18 (CK
      18) is described during pre- and post-natal development of the porcine lung using
      a monoclonal antibody against human CK 18. Lungs from 16 foetuses in
      pseudoglandular, canalicular, saccular and alveolar stages of lung development
      and lungs from 12 pigs ranging in age from birth to 49 days after birth were
      studied by immunohistochemistry. In the early pseudoglandular stage of
      development (day 70 of gestation) all the columnar epithelial cells lining the
      tubular endbuds strongly expressed CK 18 predominantly in the apical cell
      compartment. A modest staining was found in the more cuboidal cells of the
      canalicular stage (day 80 of gestation) where the labelling occurred as a
      distinct positive rim at the apical cell membrane in most of the cells lining the
      canaliculi. In 96- and 100-day-old foetuses, parts of the gas exchanging area
      were formed as terminal sacs by extreme attenuation of the epithelium. In this
      stage, CK 18 was clearly detectable in the flat type I as well as in the cuboidal
      type II alveolar epithelial cells. A marked change of the CK 18 expression
      pattern occurred during formation of the alveoli by septal outgrowth and
      maturation of the epithelium in 105- and 111-day-old foetuses. Differentiated
      type I cells no longer expressed CK 18, whereas type II cells were still
      labelled. Moreover, a specific change in the subcellular distribution pattern
      from the luminal periphery in immature porcine type II cells to a cytoplasmic
      localization in differentiated type II cells could be observed. Our investigation
      additionally demonstrated that the epithelium of bronchi, bronchioli and terminal
      bronchioli expressed CK 18 in all pre- and post-natal developmental stages. From
      the 96 days of gestation onwards the epithelial cells of developing bronchial
      glands were also labelled. Our results clearly show that during porcine lung
      development profound changes in the cellular expression pattern of CK 18 occur
      and that CK 18 can be regarded as a selective marker for differentiated porcine
      alveolar type II cells from the 105th day of gestation onwards. We also assume
      that the intermediate filament CK 18 could be of significance in the maturation
      process of the type II alveolar cells.

PMID- 12484420
TI  - Gross and microscopic observations on the lingual structure of the Florida
      Manatee Trichechus manatus latirostris.
AB  - The tongue of the Florida manatee (Trichechus manatus latirostris) was studied
      macroscopically, light and electron microscopically. The tongue was slender,
      muscular and firmly fixed in the oral cavity; only the cranial tip was free and
      mobile. Numerous filiform papillae were distributed over the dorsal surface of
      the rostral tongue. Multiple raised, round fungiform-like papillae were
      distributed over most of the dorsum. Typical fungiform papillae were restricted
      to the lateral margins of the tongue. Foliate papillae, presenting as multi
      fossulate openings, were noted on the caudolateral margins. Open pits were
      located on the dorsocaudal surface and lateral walls. Microscopic examination
      showed that most of the lingual dorsum was covered with a thick stratified
      squamous epithelium. Open pits led to well-developed mucous salivary glands.
      Glands within the foliate papillae were mostly mucous, although some seromucous
      glands were present. Taste buds were restricted to the epithelium of the foliate
      papillae. Throughout the tongue, striated muscle was abundant below the
      epithelium. Blood vessels, lymph channels and nerve fibres were freely
      distributed throughout the intermuscular stroma. Nerve fibres reacted positively
      with neurone specific enolase (NSE) antibody throughout the tongue, including
      nerve bundles, glands and taste buds. Clear to translucent vacuoles were found
      juxtaposed to nuclei in the stratum spinosum in the foliate papillae epithelium.

PMID- 12484421
TI  - Lymphocyte proliferation in lymphoid organs of the dromedary camel using the
      monoclonal antibody MIB-5 against the proliferation-associated nuclear epitope Ki
      67.
AB  - Detection of proliferating lymphocytes is useful for studying immune reactions
      and for the prognosis of tumours of lymphocyte origin. Markers detecting
      proliferating cells are lacking in the dromedary camel. This study deals with the
      immunohistochemical detection of the Ki-67 proliferation-associated nuclear
      epitope using MIB-5 in frozen sections from spleens, different lymph nodes and
      haemal nodes of eight camels (0.5-12 years old). Frozen sections from rat spleens
      were labelled in parallel with camel tissue as a positive control. Large numbers
      of cells expressing the Ki-67 epitope were localized in germinal centres of all
      lymphoid organs tested. A few cells were found in the periarterial lymphoid
      sheath and the red pulp of the spleen, also in the lymphatic cords of the lymph
      nodes and the haemal nodes. There were no obvious differences in respect to the
      age of the animals. The Ki-67 epitope is well expressed by proliferating cells in
      camel lymphoid organs. MIB-5 can be applied to identify this epitope and will be
      a useful marker for cell production in immune reactions.

PMID- 12484422
TI  - Morphological studies on Meckel's diverticulum in geese (Anser anser domesticus).
AB  - This study was carried out to reveal the morphological features of Meckel's
      diverticulum (MD) in geese. For this purpose, a total of 36 adult healthy geese
      of both sexes, 50-52 weeks of age, were used. The mean weight of MD in male was
      found to be significantly larger than that of female. It was located a little
      distal to the midpoint of the small intestine in both sexes. It had a lot of
      lymphoid tissues, the simple columnar epithelium and a small number of crypts,
      and was a lack of villi, and its muscularis mucosae was very thin. Results from
      this study are thought to throw light on future studies on MD and proper
      diagnosis of pathological disorders related to it, and to contribute considerably
      to the present anatomical knowledge on MD in geese.

PMID- 12484423
TI  - Long-term degeneration and regeneration of the rabbit facial nerve blocked with
      conventional lidocaine and bupivacaine solutions.
AB  - The alterations due to the long-term degeneration and regeneration of the rabbit
      facial nerve were investigated. The facial nerve was blocked with conventional
      lidocaine and bupivacaine solutions. The rabbits were sacrificed and facial
      nerves were removed 2, 4, 6 and 8 weeks after the administration of normal
      saline, lidocaine and bupivacaine. The samples were then processed for electron
      microscopic observation. Degenerations were seen 2-4 weeks after the injection of
      normal saline, lidocaine and bupivacaine. In the normal saline group the
      regeneration process was observed after 6 weeks, whereas in the lidocaine and
      bupivacaine groups this process was first noticed after 8 weeks. In the lidocaine
      and bupivacaine groups, regeneration was not completed at the end of 8 weeks;
      however, it was faster in the bupivacaine group. Bupivacaine is therefore
      suggested as the drug of choice for neural blockade as it caused less damage and
      a faster regeneration.

PMID- 12484424
TI  - Prenatal thyroid gland in sheep with regard to the presence of isthmus.
AB  - We studied the embryonal thyroid gland in 18 foetuses of sheep of Slovac merino
      breed by light microscopy in the period from 32nd to 36th day of evolution. We
      found that in the majority of sheep foetuses, the thyroid gland consists of two
      separate lobes and their structure was the same during the afore-mentioned
      period. Parenchyma, composed of solid cell networks or cell groups in the form of
      nests, was irregularly divided by septa, containing embryonal blood vessels.
      Almost all cases of this experiment showed slight asymmetry of lobes. In one case
      the asymmetry reached a considerable proportion - nearly the length of one lobe.
      Glandular isthmus was presented in only eight cases from 18 foetuses. We did not
      find fibrous isthmus in any case.

PMID- 12484425
TI  - Growth marks observation: preferential techniques and teeth for ageing of Spanish
      red deer (Cervus elaphus hispanicus).
AB  - A total of 207 teeth belonging to 53 deer (Cervus elaphus hispanicus) from Sierra
      Morena (South of Spain) were analysed using histological thin sections and/or
      polished thick sections. Growth marks were observed in dentine and cementum of
      incisors, molars and canines. Tooth, region of the tooth, and type of preparation
      giving the best performance in terms of sharpness and interpretation ease of the
      growth marks, when used for Spanish deer ageing, were identified. The tissue
      chosen for the study was the cellular cementum of the inter-radicular pad from
      molars and the acellular cementum of the root from incisors, both observed
      through longitudinal cuts. Histological sections obtained with a conventional
      microtome were optimal for a reliable identification of the first growth marks.
      In sections thicker than 15 microm the first rest line, when observed in cementum
      can be confused with the cementum-dentine junction; whereas in the polished
      sections from molars it will not appear at all. Dentine interpretation was more
      difficult. Its observation should only be accomplished using cross-sections of
      the molar root. Secondary or accessory marks were visible in every tooth, being
      those from the molar pad the easiest to distinguish. Canines were the less
      suitable teeth for this study.

PMID- 12484426
TI  - Histomorphological changes in the oviduct epithelium of the rabbit during early
      pregnancy.
AB  - In this study, we determined the histomorphological changes in different regions
      of the oviduct (fimbriae, infundibulum, ampullae and isthmus) during early
      pregnancy (days 1-4) of the rabbit. It was observed that the number of secretory
      cells (PAS-positive cells) diminished in the fimbriae during the first 4 days of
      pregnancy with the corresponding increase in the number of non-secretory cells
      (PAS-negative cells). In contrast, there was an increase in the number of PAS
      positive cells in the isthmus during early pregnancy. In both the infundibulum
      and the ampullae the number of PAS-positive cells was increased on day 3. A
      significant decrease in the height of the epithelium was observed in the fimbriae
      during early pregnancy. On the contrary, a significant increase in this parameter
      was observed in the isthmus during the first 3 days of pregnancy. A slight
      decrease in the height of the epithelium was observed in the infundibulum on day
      4 of pregnancy, while in the ampullae it was significantly increased on days 1
      and 3. The overall results indicate that during early pregnancy there is a
      selective modification in the histomorphological characteristics of the different
      regions of the rabbit oviduct.

PMID- 12484427
TI  - Morphology of the dorsal lingual papillae in the Japanese macaque and Savanna
      monkey.
AB  - The dorsal lingual surfaces of infant Japanese macaque (Macaca fuscata) and adult
      savanna monkey (Cercopithecus aethiopus) were examined by scanning electron
      microscopy. Filiform, fungiform, foliate and vallate papillae were found. The
      filiform papillae were distributed over the entire dorsal surface of the tongue.
      The fungiform papillae were round in shape, and more densely distributed on the
      lingual apex. The foliate papillae were seen on the dorsolateral aspect of the
      tongue. The three vallate papillae were arranged like a triangle with the apex of
      the triangle directing caudally. Each papilla was surrounded by a groove. The
      rudiments of the fungiform, foliate and vallate papillae were visible earlier
      than those of the filiform papillae.

PMID- 12484428
TI  - A study of the immunohistochemical localization of the progesterone and oestrogen
      receptors in the magnum of the immature ostrich, Struthio camelus.
AB  - The immunolocalization of the progesterone (PR) and oestrogen receptors (OR), in
      the magnum of the immature ostrich, was investigated during periods of ovarian
      activity and inactivity. In the immature ostrich, with an active ovary, numerous
      well-developed tubular glands were present in the lamina propria. Significantly,
      PR immunostaining was strong in the surface epithelium and tubular glands of
      these birds. In contrast, weak staining for the PR was observed in the surface
      epithelium of birds with inactive ovaries. Tubular gland formation, in these
      birds, was indicated by bud-like invaginations of the surface epithelium.
      Oestrogen receptor immunoreactivity was negligible in both birds with active and
      inactive ovaries. These findings suggest that steroid hormones, produced by the
      active ovary of the immature ostrich, influence the differentiation of the
      magnum. Furthermore, the action of these steroid hormones appears to be mediated
      through the PR.

PMID- 12484429
TI  - Dohi Memorial Lecture. New aspects of cutaneous mosaicism.
AB  - The concept of cutaneous mosaicism has today been proven at the cellular level in
      at least fifteen different skin disorders. We can distinguish five different
      patterns of mosaicism, including the phylloid pattern and the lateralization
      pattern. Etiologically, cutaneous mosaics can be divided into two large
      categories, epigenetic mosaicism and genomic mosaicism. All forms of epigenetic
      mosaicism known so far, including the various patterns of X-inactivation, appear
      to be caused by the action of retrotransposons. A new concept is functional
      autosomal mosaicism transmittable through the action of retrotransposons, which
      has been described in mice and dogs and may explain, for example, the familial
      occurrence of pigmentary mosaicism along the Blaschko lines in human skin. Among
      the examples of mosaicism of autosomal lethal mutations, phylloid hypomelanosis
      is a recently recognized neurocutaneous entity caused by mosaic trisomy 13.
      Possible examples of a type 2 segmental manifestation now include at least
      fifteen different autosomally dominant skin disorders. This phenomenon is most
      frequently found in glomangiomatosis, cutaneous leiomyomatosis, and disseminated
      superficial actinic porokeratosis. Recently proposed examples of didymosis (twin
      spotting) include cutis tricolor, paired patches of excessive or absent
      involvement in Darier disease, and didymosis aplasticosebacea characterized by
      coexistent aplasia cutis congenita and nevus sebaceus. To the list of possible
      examples of paradominant inheritance, cutis marmorata telangiectatica congenita
      and speckled lentiginous nevus syndrome have now been added. Revertant mosaicism
      giving rise to unaffected skin areas in autosomally recessive cutaneous traits
      will certainly likewise be recognized more often when clinicians are bearing this
      concept in mind. Such cases can be taken as examples of "natural gene therapy".

PMID- 12484430
TI  - The Japanese version of Skindex-16: a brief quality-of-life measure for patients
      with skin diseases.
AB  - A practical quality-of-life measure applicable to patients with skin diseases is
      necessary. Recently developed dermatological quality-of-life measures must be
      translated and adapted for use in cultures other than the ones in which they were
      created. In this study, we translated and adapted culturally into Japanese a skin
      disease-specific, brief quality-of-life measure, Skindex-16, and studied its
      reliability and validity. Forward-and back-translations of Skindex-16 were
      carried out. Six doubtful items as well as the term "skin condition" required a
      second forward- and back-translation to reach satisfactory agreement with the
      original instrument. Cross-cultural adaptation and cross-sectional questionnaire
      studies were then performed to evaluate the reliability and validity of the
      instrument. One hundred patients and 30 healthy adults responded to the Japanese
      version. The internal-consistency reliability of the final Japanese version of
      Skindex-16 was high (range of Cronbach's alpha for each scale, symptoms,
      emotions, and functioning, was 0.83-0.92). The Japanese version showed construct
      and content validity. As hypothesized, scores for dermatological patients were
      higher than those for healthy persons (mean global scores 36 +/- 23 vs 1 +/- 2, p
      < 0.001) and scores for patients with inflammatory diseases were higher than
      those for patients with isolated skin lesions (mean global scores 48 +/- 21 vs 22
      +/- 17, p < 0.001), indicating a poorer quality of life. Most patients' responses
      to an open-ended question about their skin disease were similar to those of the
      American responders and were addressed according to the items. In conclusion, we
      have developed a semantically equivalent translation of Skindex-16 into Japanese.
      It is a reliable and valid measure of the effects of skin disease on the quality
      of life in Japanese patients.

PMID- 12484431
TI  - Initial recruitment of interferon-gamma-producing CD8+ effector cells, followed
      by infiltration of CD4+ cells in 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced
      murine contact hypersensitivity reactions.
AB  - Contact hypersensitivity (CHS) is an antigen-specific, T-cell-mediated skin
      reaction in sensitized individuals. Recent studies have demonstrated that the
      murine CHS reaction to 2,4-dinitrofluorobenzene (DNCB) is mediated by CD8+ T
      cells and down-regulated by CD4+ T cells. We studied cellular events and
      functions of infiltrating cells in CHS reactions to 2,4,6-trinitro-1
      chlorobenzene (TNCB) in the skin and draining lymph nodes (LN) of BALB/c mice and
      compared them with the CHS reaction to a house dust mite antigen,
      Dermatophagoides farinae (Df). Mice were sensitized with TNCB or Df antigens, and
      CHS reactions elicited with the corresponding antigens were examined
      immunohistologically. Cytokines produced by individual cells isolated from the
      CHS reactions were analyzed by flow cytometry, and the expression of cytokine
      mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR).
      Results demonstrated that the intensity of TNCB-elicited CHS skin reactions
      reached its peak at 24 hr after elicitation and decreased gradually. Flow
      cytometric analysis of isolated cells from the TNCB-elicited CHS reactions
      demonstrated that the infiltrating cells were composed of approximately 25% CD4+
      and CD8+ cells at 12, 24, and 36 hr after challenge, although infiltrating cells
      became dense at 36 hr by histological observation. The percentage of IFN-gamma
      producing CD8+ cells (Tc1) in the cell fractions reached its peak at 12 hr and
      decreased gradually. The peak infiltration of IFN-gamma-producing CD4+ cells (Th
      1) was observed at 24 hr. IL-4-producing cells, however, were always below 5% in
      the cell fractions. The RT-PCR method demonstrated that IFN-gamma mRNA was
      detected in the TNCB-elicited skin reactions at 12, 18 and 24 hr after
      elicitation, became weak at 48 hr, and disappeared at 72 hr. No IL-4 mRNA was
      detected from 12 to 72 hr. In the draining LN cells, however, the percentages of
      both IFN-gamma-producing CD8+ (Tc1) and CD4+ cells (Th1) decreased 12 to 36 hr
      after TNCB elicitation. CHS reactions of Df antigens were predominantly composed
      of infiltrations of CD4+ cells in to the skin, associated with the expression of
      IL-4 mRNA from 12 to 48 hr after elicitaion. The expression of IFN-gamma mRNA was
      detected at 48 hr or later. Our findings indicate that the CHS skin reaction to
      TNCB is induced by early recruitment of IFN-gamma-producing CD8+ effector cells
      (Tcl), followed by infiltration of IFN-gamma-producing CD4+ cells (Th1), whereas
      IL-4-producing T cells (Th2) induce the early CHS response to Df antigens.

PMID- 12484432
TI  - Rapid effects of olopatadine hydrochloride on the histamine-induced skin
      responses.
AB  - Olopatadine hydrochloride is one of the second-generation nonsedating
      antihistamines that are used for treating allergic disorders such as urticaria,
      rhinitis, and atopic dermatitis. We examined the inhibitory effects of this drug
      on the flare and wheal responses induced by histamine iontophoresis at 30, 60,
      and 90 min after oral administration in a double-blind, cross-over, and placebo
      controlled study. Olopatadine hydrochloride significantly inhibited the histamine
      induced flare and wheal responses as early as 60 min after oral administration
      when compared with placebo. Significant inihibitory effects of olopatadine
      hydrochloride on the itch responses were seen at 90 min after administration.
      Thus, olopatadine hydrochloride exhibited a very rapid and potent antihistamine
      effect on the histamine-induced skin responses.

PMID- 12484433
TI  - PDGF-BB induces MAP kinase phosphorylation and VEGF expression in neurofibroma
      derived cultured cells from patients with neurofibromatosis 1.
AB  - Neurofibromas of neurofibromatosis 1 (NF1) are highly vascular. Because the
      number of PDGF beta receptors in neurofibroma-derived cultured cells (NF-derived
      cells) has been reported to be increased, we tested whether platelet-derived
      growth factor BB (PDGF-BB) could induce expression of vascular endothelial growth
      factor (VEGF) in NF-derived cells. When analysed by reverse transcription
      polymerase chain reaction, VEGF mRNA expression was found to be stimulated by
      PDGF-BB and TGF-beta1. Those growth factors stimulated the secretion of VEGF from
      NF-derived cells. PDGF-BB furthermore induced the mitogen-activated protein
      kinase phosphorylation in NF-derived cells from patients with NF1. In conclusion,
      PDGF-BB stimulated VEGF secretion in NF-derived cells, and this stimulation is
      probably important in neurofibroma hypervascularization.

PMID- 12484434
TI  - A monoclonal antibody established from the immunization of basal cell carcinoma
      (BCC) tissues reacts to the intercellular space of BCC and hair follicles.
AB  - To detail the histogenetic relationship between basal cell carcinoma (BCC) and
      hair follicles, a monoclonal antibody, coded as MMKB-1 and established from
      immunization of mice by human basal cell carcinoma (BCC) tissues, was
      immunohistochemically studied in tissues of BCC and squamous cell carcinoma (SCC)
      of the skin, as well as in normal human skin tissues. On 1M-NaCl-split normal
      human skin tissues, it reacted against both the epidermal and the dermal sides of
      the basement membrane zone (BMZ). This monoclonal antibody reacted to the BMZ and
      intercellular space (ICS) of the solid, superficial, and fibrosing types of BCC
      cell nests, but, in SCC tumor cell nests, it reacted exclusively to the BMZ.
      Immunoelectron microscopic studies revealed that the corresponding antigen of the
      monoclonal antibody was distributed in the hemidesmosomes and the anchoring
      fibrils along the BMZ of the normal human skin and the desmosomes of the BCC cell
      nest. The monoclonal antibody also reacted to the ICS of the lower outer root
      sheath and hair matrix. We discussed the histogenesis of BCC and hair follicles,
      referring to the results of the staining patterns of MMKB-1 monoclonal antibody
      and to other studies suggesting a histogenetic relationship between BCC and hair
      follicles.

PMID- 12484435
TI  - Evaluation of cosmetic tattooing in localised stable vitiligo.
AB  - Thirty patients with localised stable vitiligo were selected from the Out Patient
      Department for cosmetic tattooing. Of them, 19 cases (63.3%) had skin patches, 9
      cases (30%) had mucosal patches, and 2 cases (6.7%) had both skin and mucosal
      involvement. After complete clinical evaluation, cosmetic tattooing was performed
      on these patients, and they were followed up for 6 months. As results, 23 cases
      (76.7%) had excellent color matching, 2 cases (6.7%) had good color matching, and
      5 cases (16.6%) had pigment shedding. Excellent results were seen in all mucosal
      patches. Dark complexion cases showed better results than fair complexion ones.

PMID- 12484436
TI  - Erythema gyratum repens responding to cetirizine hydrochloride.
AB  - We report a case of erythema gyratum repens (EGR) in a 59-year-old man with
      inoperable pancreatic cancer and liver metastasis. The patient had a widespread
      erythema with concentric marginal band spreading in waves over the trunk and
      extremities. Numerous vesicles were seen on the margin of the erythema. The skin
      lesions were severely pruritic, and his peripheral blood showed marked
      eosinophilia. He also had palmoplantar hyperkeratosis. A biopsy specimen of the
      erythema disclosed spongiosis, microvesicles filled with eosinophils,
      infiltration of eosinophils into the epidermis, and a perivascular infiltrate in
      the dermis. The skin lesions and pruritus cleared quickly after the
      administration of cetirizine hydrochloride.

PMID- 12484437
TI  - Schnitzler's syndrome with IgG kappa gammopathy.
AB  - A seventy-year-old man with a variant type of Schnitzler's syndrome is reported.
      Physical examination showed pruritic urticarial lesions on the extremities,
      arthralgia of knee joints, and intermittent fever. Laboratory investigations
      revealed a high level of IgG, an increased enythrocyte sedimentation rate,
      urinary Bence-Jones protein, and an M-bow in serum protein electrophoresis, which
      was shown to be a monoclonal IgG kappa type. Histological examination showed
      perivascular neutrophil and lymphocytic infiltration into the upper dermis and
      diffuse neutrophilic infiltration in the middle dermis. One of the clinical
      features of typical Schnitzler's syndrome is IgM macroglobulinemia, and this is a
      very rare case of this syndrome with IgG gammopathy.

PMID- 12484438
TI  - Notalgia paresthetica with a significant increase in the number of intradermal
      nerves.
AB  - Notalgia paresthetica is an isolated mononeuropathy involving the skin over or
      near the scapula. The cause remains unknown. We histologically observed a
      significant increase in the number of dermal nerves in a case of notalgia
      paresthetica. Immunohistochemical examination using a neural marker, S-100,
      positively stained the nerves. Interestingly, a biopsy from perilesional skin
      also showed an abnormal nerve proliferation.

PMID- 12484439
TI  - Aneurysmal fibrous histiocytoma showing transition from factor XIIIa-positive to 
      negative.
AB  - A 39-year-old woman visited us because of a subcutaneous induration on her
      forehead of 7 months' duration. The tumor was tender, firm, and colored blue
      black. Microscopically, the tumor was composed of fibroblastic and histiocytic
      cells showing no atypicality. In some part intra- or extracellular haemosiderin
      was diffusely seen. There were some blood-filled spaces of varying size without
      endothelial lining. From these findings, this case was diagnosed as aneurysmal
      fibrous histiocytoma (AFH), a variant form of dermatofibroma. Immunohistochemical
      analysis showed that factor XIIIa-positive histiocytic cells were distributed in
      the area without haemosiderin, but such cells were absent in the area with its
      deposition. Furthermore, the cells near the blood-filled space showed transition
      from factor XIIIa-positive to -negative, suggesting that the stromal instability
      induced by the attenuation of factor XIII may lead the formation of the blood
      filled spaces in AFH.

PMID- 12484440
TI  - Primary cutaneous T-cell-rich B-cell lymphoma in a zosteriform distribution
      associated with Epstein-Barr virus infection.
AB  - T-cell-rich B-cell lymphoma (TRBL) is a lately recognized B-cell lymphoma variant
      characterized by a minor population of neoplastic B cells existing in a
      background of predominant polyclonal T cells. We report an 86-year-old man with
      primary cutaneous TRBL associated with Epstein-Barr (EB) virus infection.
      Clinically, palpable scaly erythemas were distributed in a zosteriform pattern on
      the right abdomen. Histologically, massive cellular infiltrates were located in
      the upper- and mid-dermis. Higher magnification showed that the cellular
      infiltration was composed mainly of abnormal mononuclear, large lymphoid cells
      with clear cytoplasm and scattered mitoses and small lymphocytes, which
      represented in excess of 75% of all the infiltrating cells. Immunohistochemical
      staining revealed that the large cells were positive for the B cell marker, CD20,
      but negative for the T cell marker, CD3. On the other hand, the small cells were
      positive for CD3, but negative for CD20. Polymerase chain reaction (PCR) revealed
      EB virus DNA in the skin lesion. Primary cutaneous TRBL has only been reported in
      15 cases worldwide. To our knowledge, this is the first case of primary cutaneous
      TRBL in a zosteriform distribution reported in the literature and the second case
      of primary cutaneous TRBL associated with the EB virus infection. We postulate
      that the EB virus may be a contributory pathogenetic event leading to monoclonal
      B-cell proliferation.

PMID- 12484441
TI  - A case of striated muscle hamartoma on the cheek.

PMID- 12484442
TI  - A case of squamous cell carcinoma arising in a pilonidal sinus.

PMID- 12484443
TI  - Seasonal changes in spermatogenesis of the Japanese lesser horseshoe bat,
      Rhinolophus cornutus from a morphological viewpoint.
AB  - Seasonal changes in spermatogenesis of Japanese lesser horseshoe bats,
      Rhinolophus cornutus, captured in Aomori Prefecture (Japan) were examined by
      light microscopy. In March, the seminiferous tubules revealed almost no lumen.
      The seminiferous epithelium consisted of Sertoli cells and spermatogonia. The
      interstitium occupied a relatively large area. In June, the seminiferous tubules
      gradually increased in diameter. Lumen was clearly seen at the center of
      seminiferous tubules. Mitotic figures of spermatogonia and spermatocytes were
      occasionally recognized. Interstitium occupation was still abundant. In August,
      the diameter of seminiferous tubules maximized. The interstitium occupied only a
      small area. Active spermatogenesis was obvious at this time. Released spermatozoa
      were frequently observed within the expanded lumen. In October, although
      spermatogenesis was still active, the diameter of seminiferous tubules tended to
      decrease in size. In December, active spermatogenesis completely disappeared. The
      diameter of tubules greatly decreased. In most cases, the seminiferous epithelium
      contained only Sertoli cells and spermatogonia. Thus, spermatogenesis in Japanese
      lesser horseshoe bats occurs from the middle or late summer to the middle autumn
      in Aomori Prefecture. In epididymal tracts, aggregated spermatozoa were
      recognized throughout the year. The cytoplasm of all Leydig cells in the
      interstitium was positive for 3beta-hydroxysteroid dehydrogenase throughout the
      year.

PMID- 12484444
TI  - Effects of thalidomide, cytochrome P-450 and TNF-alpha on angiogenesis in a three
      dimensional collagen gel-culture.
AB  - The anti-angiogenic effects of thalidomide were examined in mouse aortae grown in
      a three-dimensional collagen gel-culture. In our in vitro model, (+/-)
      thalidomide and (-)-thalidomide exhibited no anti-angiogenic effects. On the
      other hand, when the culture was treated with thalidomide plus cytochrome P-450,
      both types of thalidomides significantly inhibited angiogenesis. Co
      administration of 100 microg/ml thalidomide plus 200 microg/ml cytochrome P-450
      inhibited angiogenesis more strongly than thalidomide plus cytochrome P-450 at
      other concentrations (10 microg/ml + 200 microg/ml and 100 microg/ml + 20
      microg/ml). To study the relation between the anti-angiogenic effect and TNF
      alpha, we also evaluated the concentration of TNF-alpha in the culture medium. We
      found that the concentration of TNF-alpha was correlated to the strength of the
      anti-angiogenic effect. The inhibition of angiogenesis by thalidomide and
      cytochrome P-450 takes place through a suppression of TNF-alpha and involves the
      metabolism of the thalidomide.

PMID- 12484445
TI  - Fiber arrangements of cutaneous and muscular rami in cervical nerves of the rat-
      regarding conception of the spinal nerve stratum-structure.
AB  - Fluorescence tracers DiO and DiI were applied to compare fiber arrangements of
      cutaneous and muscular rami in the proximal region of anterior and posterior
      branches of cervical nerves. Results show that a ventrodorsal relationship of
      cervical nerves is observed in gross level; however, fiber arrangements of
      cutaneous and muscular rami differ in anterior branches according to distance
      from the anterior root and dorsal root ganglia. That is, the fibers have a
      scattering course (no ventrodorsal relationship) in distal regions. Moreover,
      just before entering anterior roots, the motor fibers of muscular ramus run
      through the ventral part and sensory fibers of muscles and fibers of cutaneous
      ramus run through the dorsal part and intersect with motor fibers of the
      posterior muscular ramus. In contrast with the anterior one, in posterior
      branches of cervical nerves, cutaneous and muscular rami fibers are very
      regularly arranged in the distal and proximal region. Based on these results, the
      ventrodorsal relationship of fiber arrangements could exist in posterior branches
      and proximal region of anterior branches. Present results differ with those of
      the spinal nerve stratum-structure; therefore, they are insufficient to elucidate
      the relationship of peripheral nerves by conception of spinal nerve stratum
      structure.

PMID- 12484446
TI  - SEM study on the dorsal lingual surface of the large flying fox, Pteropus
      vampyrus.
AB  - The dorsal lingual surface of the large flying foxes were examined by scanning
      electron microscopy. Filiform, fungiform and vallate papillae were observed. The
      filiform papillae were distributed over the entire dorsal surface of the tongue.
      The filiform papillae notably differed in morphology by their location on the
      tongue and could be classified into 6 types: 1) scale-like, 2) giant trifid, 3)
      small crown-like, 4) large crown-like, 5) long conical and 6) short conical
      papillae. The fungiform papillae were present rounded bodies on the anterior 2/3
      of the tongue. The large flying foxes showed the triangular arrangement of the
      three vallate papillae, with the apex of the triangle directed posteriorly. These
      findings indicate that the tongue of the large flying bat is similar to that of
      the lesser dog-faced fruit bat.

PMID- 12484447
TI  - Ultrastructure and function of Sertoli cell processes in the Korean native goat.
AB  - The ultrastructure of Sertoli cell in the testes of Korean native goats was
      investigated by scanning and transmission electron microscopy to elucidate the
      relationship between germ cell and Sertoli cell processes in the spermiogenetic
      cycle. Type-A Sertoli cells at stage V of the spermiogenetic cycle and type-B
      Sertoli cells at stage VII of the spermiogenetic cycle were used for analysis.
      Morphologically, the Sertoli cell processes were classified into sheet-like and
      slender cord-like processes. The sheet-like process originated solely from the
      Sertoli cell column while the slender cord-like process projected either from the
      Sertoli cell column or the sheet-like process. Periodic acid (PA)
      thiocarbohydrazide (TCH)-silver protein (SP)-physical development (PD)-positive
      granules were found diffusively both in the sheet-like and slender cord-like
      processes near the round spermatid, whereas they had accumulated near the head of
      the elongated spermatid. The morphological variation and glucoconjugate
      histochemical reaction of the Sertoli cell processes reflect nourishment,
      movement and transformation of the spermatogenic cells in accordance with
      spermiogenesis.

PMID- 12484448
TI  - Synthesis and anti-HIV activity of [d4U]-[trovirdine analogue] and [d4T]
      [trovirdine analogue] heterodimers as inhibitors of HIV-1 reverse transcriptase.
AB  - A series of eleven heterodimers containing both a nucleoside analogue (d4U, d4T)
      and a non-nucleoside type inhibitor (Trovirdine analogue) were synthesized and
      evaluated for their ability to inhibit HIV replication. Unfortunately, the (N
      3)d4U-Trovirdine conjugates (9a-e) and (N-3)d4T-Trovirdine conjugates (10a-f)
      were found to be inactive suggesting that the two individual inhibitor compounds
      do not bind simultaneously in their respective sites.

PMID- 12484449
TI  - Interaction of distamycin A and netropsin with quadruplex and duplex structures:
      a comparative 1H-NMR study.
AB  - Homonuclear NMR techniques have been used to investigate the interactions of the
      minor groove binding agents distamycin A (Dist-A) and the related drug netropsin
      (Net) with three quadruplexes characterized by different groove widths:
      [d(TGGGGT)]4 (Q1), [d(GGGGTTTTGGGG)]2 (Q2), and d(GGGGTTGGGGTGTGGGGTTGGGG) (Q3).
      Netropsin has been found to be in a fast chemical exchange with all three kinds
      of quadruplexes, whereas Dist-A interacts tightly with Q1 and, at a less extent,
      with Q2. In order to determine the degree of selectivity of Dist-A for two-
      rather than four-stranded DNA, we titrated with Dist-A an equimolar solution of
      Ql and the duplex d(CGCAAATTTGCG)2 (D). This comparative 1H-NMR study allowed us
      to conclude that Dist-A and, consequently, Net possess higher affinity for duplex
      DNA.

PMID- 12484450
TI  - Synthesis of 5-(2,2'-bipyridinyl and 2,2'-bipyridinediiumyl)-2'-deoxyuridine
      nucleosides: precursors to metallo-DNA conjugates.
AB  - The synthesis of 2,2'-bipyridinyl-2'-deoxyuridine metal-chelator nucleosides
      (Bipy-dU) with either ethynyl or ethylenyl linkers was now been accomplished.
      These new nucleosides will permit the construction of a number of corresponding
      metallo-DNA conjugates where many types of metals can be complexed to the 2,2'
      bipyridinyl chelator group and the resulting metallo-dU conjugates incorporated
      into DNA oligonucleotides. Additionally this paper also reports the synthesis of
      a di-N-alkylated bipyridinediiumyl-2'-deoxyuridine nucleoside (Bipy(2+)-dU) with
      an ethylenyl linker. The Bipy(2+)-dU nucleoside was found to decompose under
      basic conditions precluding its use in standard automated DNA-synthesis by the
      phosphoramidite method. No such restrictions apply to the two Bipy-dU nucleosides
      reported here for use as metal chelators.

PMID- 12484451
TI  - Two efficient polymeric chemical platforms for oligonucleotide microarray
      preparation.
AB  - In this report we describe two robust procedures for oligonucleotide microarray
      preparation based on polymeric coatings. The proposed chemical approaches
      include: 1) a glass functionalisation step with appropriate silanes (gamma
      aminopropyltriethoxysilane-APTES or 3-glycidoxypropyltrimethoxysilane-GOPS), 2) a
      coating step using polymers (poly-L-Lysine or poly(acrylic acid-co-acrylamide)
      copolymer) covalently bound to the modified glass and 3) a surface activation
      step to allow for the attachment of amino-modified oligonucleotides. Results
      obtained using these chemistries in oligo microarray preparation show: 1) an
      overall high loading capacity and availability to hybridisation against targets,
      2) a good uniformity, 3) resistance to consecutive probing/ stripping cycles, 4)
      stability to thermal cycles, 5) effectiveness in hybridisation-mediated mutation
      detection procedures and 6) the possibility to perform enzymatic reactions, such
      as ligation.

PMID- 12484452
TI  - Syntheses of novel substituted-boranophosphate nucleosides.
AB  - A number of substituted (borano) nucleic acids, 3'-[diethylphosphite(cyano,
      carboxy, or carbamoyl) borano] deoxynucleosides (3a-4c) and 5'
      [diethylphosphite(cyano or carboxy) borano] deoxynucleosides (6a-7d) were
      prepared by a variety of synthetic procedures. The syntheses of the
      pyrophosphates (2a-2c), as precursors for 3a-4c, are also described.

PMID- 12484453
TI  - Synthesis and hybridization properties of RNA containing 8-chloroadenosine.
AB  - 8-Chloroadenosine (8-Cl-Ado) has shown potential as a chemotherapeutic agent for
      the treatment of multiple myeloma and certain leukemias. 8-Cl-Ado treatment leads
      to a decrease in global RNA levels and incorporation of the analog into cellular
      RNA in malignant cells. To investigate the effects of 8-Cl-Ado modifications on
      RNA structure and function, an 8-Cl-Ado phosphoramidite and controlled-pore glass
      support were synthesized and used to introduce 8-Cl-Ado at internal and 3'-
      terminal positions, respectively. RNA oligonucleotides containing 8-chloroadenine
      (8-Cl-A) residues were synthesized and hybridized with complementary RNA strands.
      Circular dichroism spectroscopy of the resulting RNA duplexes revealed that the
      modified nucleobase does not perturb the overall A-form helix geometry. The
      thermal stabilities of 8-Cl-Ado modified duplexes were determined by UV thermal
      denaturation analysis and were compared with analogous natural duplexes
      containing standard and mismatched base pairs. The 8-Cl-Ado modification
      destabilizes RNA duplexes by approximately 5 kcal/mole, approximately as much as
      a U:U mismatched base pair. The duplex destabilization of 8-Cl-A may result from
      perturbation of Watson-Crick base pairing induced by conformational preferences
      of 8-halogenated nucleosides.

PMID- 12484454
TI  - ASMS members John Fenn and Koichi Tanaka share Nobel: the world learns our
      "secret". American Society for Mass Spectrometry.

PMID- 12484455
TI  - Evaluation of the role of multiple hydrogen bonding in offering stability to
      negative ion adducts in electrospray mass spectrometry.
AB  - An experimental approach, electrospray mass spectrometry (ES-MS), and a
      theoretical approach employing computer modeling, have been used to characterize
      the interaction between small inorganic anions and neutral analyte molecules that
      form anionic adduct species in negative mode ES mass spectrometry. Certain
      anionic adducts of small saccharides (e.g., alpha-D-glucose, sucrose) have shown
      exceptional stability in ES mass spectra even when internal energies are raised
      at high "cone" voltages. Computer modeling studies reveal that multiple hydrogen
      bonding strengthens the interaction between these neutral molecules and the
      attaching anion. The equilibrium structures and stabilization energies of these
      anionic adducts have been evaluated by semi-empirical, ab initio, and density
      functional theory (DFT) methods. Chloride anion is found to be capable of forming
      "bridging" hydrogen bonds between monosaccharide rings of polysaccharides
      resulting in the stabilization of chloride adducts, thus reducing the tendency
      for the glycosidic bond to decompose. Moreover, the tendency for various hydroxyl
      hydrogens on saccharide molecules to dissociate in the form of HA (A-, anion)
      during decomposition of anionic adducts, thereby forming [M - H]-, has also been
      evaluated by computer modeling.

PMID- 12484456
TI  - A high voltage RF oscillator for driving multipole ion guides.
AB  - A high voltage RF oscillator circuit has been designed and constructed for
      driving multipole ion guides. The circuit is tunable from 500 kHz to 1.5 MHz by
      changing a capacitor and provides 0-1000 V(p-p) that is controlled by a 0-10 V
      input using a negative feedback circuit. This inexpensive circuit uses a set of
      high voltage transistors oscillating in tandem and does not require tuning of the
      resonance drive frequency as the oscillator automatically resonates at the (LC)(
      1/2) frequency. Matrix-assisted laser desorption/ionization-Fourier transform
      mass spectrometry (MALDI-FTMS) mass spectra were acquired using this tunable RF
      oscillator circuit to allow transmission of protein ions in the 8.5-39 kDa range
      through the quadrupole ion guide from the ion source to the mass analyzer.

PMID- 12484457
TI  - Hydrogen/deuterium exchange of hydrophobic peptides in model membranes by
      electrospray ionization mass spectrometry.
AB  - We demonstrate here that the hydrogen/deuterium solvent exchange (HDX) properties
      of the transmembrane fragment of the M2 protein of Influenza A (M2-TM)
      incorporated into lipid vesicles or detergent micelles can be studied with
      straightforward electrospray (ESI) and nanospray mass spectrometry (MS)
      configurations provided that key factors, including sample preparation
      techniques, are optimized. Small unilamellar vesicle preparations were obtained
      by solubilizing dimyristoyl phosphatidylcholine (DMPC) and the M2-TM peptide in
      aqueous solution with n-octyl-beta-D-glycopyranoside, followed by dialysis to
      remove the detergent. Electron microscopy experiments revealed that subsequent
      concentration by centrifugation introduced large multilamellar aggregates that
      were not compatible with ESI-MS. By contrast, a lyophilization-based
      concentration procedure, followed by thawing above the liquid crystal transition
      temperature of the lipid component, maintained the liposome size profile and
      yielded excellent ion fluxes in both ESI-MS and nano-ESI-MS. Using these methods
      the global HDX profile of M2-TM in aqueous DMPC vesicles was compared with that
      in methanol, demonstrating that several amide sites were protected from exchange
      by the lipid membrane. We also show that hydrophobic peptides can be detected by
      ESI-MS in the presence of a large molar excess of the detergent Triton X-100. The
      rate of HDX of M2-TM in Triton X-100 micelles was faster than that in DMPC
      vesicles but slower than when the peptide had been denatured in methanol. These
      results indicate that the accessibility of backbone amide sites to the solvent
      can be profoundly affected by membrane protein structure and dynamics, as well as
      the properties of model bilayer systems.

PMID- 12484458
TI  - Alkali chloride cluster ion dissociation examined by the kinetic method:
      heterolytic bond dissociation energies, effective temperatures, and entropic
      effects.
AB  - Branching ratios have been measured as a function of collision energy for the
      dissociation of mass-selected chloride-bound salt cluster ions, [Rb-35Cl-Mi]+,
      where Mi = Na, K, Cs. The extended version of the kinetic method was used to
      determine the heterolytic bond dissociation energy (HBDE) of Rb-Cl. The measured
      value of 480.8 +/- 8.5 kJ/mol, obtained under single collision conditions, agrees
      with the HBDE value (482.0 +/- 8.0 kJ/mol), calculated from a thermochemical
      cycle. The observed effective temperature of the collisionally activated salt
      clusters increases with laboratory-frame collision energy under both single- and
      multiple-collision conditions. Remarkably, the effective temperatures under
      multiple collision conditions are lower than those recorded under single
      collision conditions at the same collision energy, a consequence of the inability
      of the triatomic ions to store significant amounts of internal energy. Laboratory
      frame kinetic energy to internal energy transfer (T-->V) efficiencies range from
      3.8 to 13.5%. For a given cluster ion, the T-->V efficiency decreases with
      increasing collision energy. Many features of the experimental results are
      accounted for using MassKinetics modeling (Drahos and Vekey, J. Mass Spectrom.
      2001, 36, 237).

PMID- 12484459
TI  - Optimization of experimental parameters for electron capture dissociation of
      peptides in a Fourier transform mass spectrometer.
AB  - This paper describes our effort in optimizing the experimental parameters for
      electron capture dissociation (ECD) of peptides in a commercially available
      Fourier-transform mass spectrometer. Using a built-in electrically heated
      filament electron gun, it was demonstrated that good quality ECD spectra of
      peptides (MW < 2500) could be obtained by irradiating the isolated peptide
      molecule-ions with a short pulse (50 ms) of low-energy (3-6 eV) electrons. In
      addition, we have also demonstrated that pulsing of inert cooling gas (argon)
      could further improve the intensity of the ECD-induced fragment ions. Due
      presumably to the influence of the strong magnetic field on the trajectories of
      electrons, the distance between the electron gun and the trapped-ion cell (i.e.,
      108 mm versus 20 mm) was found to have little influence on the efficiency of the
      ECD process(es). From a systematic study on the impact of the filament heating
      current, filament bias voltage, and electron irradiation time on the intensities
      of precursor ions and various fragment ions, it was postulated that subsequent
      capture of electrons by the fragment ions, i.e., neutralization of the fragment
      ions, might be a significant event for limiting the intensity of the fragment
      ions.

PMID- 12484460
TI  - Fragmentation pathway studies of oligonucleotides in matrix-assisted laser
      desorption/ionization mass spectrometry by charge tagging and H/D exchange.
AB  - The desorption and decompositions of synthesized oligonucleotides bearing fixed
      charge sites have been investigated by linear, delayed-extraction, reflecting and
      post-source decay mode matrix-assisted laser desorption/ionization (MALDI) mass
      spectrometry. In contrast to the conventional [M + H]+ forms of unmodified
      molecules where a proton is likely attached to a nucleobase, here the charge is
      fixed at one of the termini. In this case the observed fragment ions always
      incorporate the charge-tag. H/D exchange experiments provide no evidence for
      intramolecular migration of protons on the phosphate backbone to initiate the
      fragmentation event. New unique pathways of proton migration from the ribose have
      been elucidated and are rationalized by a charge-remote fragmentation pathway.

PMID- 12484461
TI  - Location of abasic sites in oligodeoxynucleotides by tandem mass spectrometry and
      by a chemical cleavage initiated by an unusual reaction of the ODN with MALDI
      matrix.
AB  - We describe two approaches employing electrospray ionization (ESI) tandem mass
      spectrometry (MS/MS) and matrix assisted laser desorption/ionization (MALDI) post
      source decay (PSD) for determining the location of an abasic site in modified
      oligodeoxynucleotides (ODNs). With MS/MS, we found both complementary fragment
      ions (a(n)' and w(n)') produced at the abasic site were predominant in the mass
      spectra and allowed the location to be determined. Under MALDI conditions, most
      ODNs carrying an abasic site are singly charged, and PSD gives predominately
      w(n)' ions at the abasic sites, revealing their location. We also describe
      another approach for identifying and locating abasic sites in model ODNs; namely,
      an "in situ" derivatization coupled with MALDI mass spectrometry (MS). In
      general, an ODN n-mer containing an abasic site at the m-th position from the 5
      terminus can react with the matrix component, anthranilic acid, to form a Schiff
      base. The adduct upon MALDI breaks into 3' and 5' fragments (w(n-m), b(m), a(m),
      d(m-1)) at the abasic site, revealing its location. ESI MS methods are also
      applicable for detecting the hydrazone derivatives of abasic sites, and the
      fragmentation of hydrazones shows the location of the abasic site.

PMID- 12484462
TI  - Unexpected fragmentation of beta-substituted meso-tetraphenylporphyrins induced
      by high-energy collisional activation.
AB  - The protonated molecules and radical cations of meso-tetraphenylporphyrins with
      beta-pyrrolic substituents, when formed by fast atom bombardment (FAB) and
      subjected to high-energy collisions, give rise to unexpected fragment ions. The
      reaction involves hydrogen migration from the ortho position of the phenyl ring
      to the a atom of the substituent, with formation of an intramolecular, six
      membered ring. The process is analogous to condensed-phase cyclizations described
      for the same type of compounds. The fragmentation requires the presence of a
      double bond in the substituent group attached to the pyrrolic ring. A
      rearrangement process involving anchimeric assistance by the phenyl group
      (analogous to an ortho effect) is proposed for the formation of these ions.

PMID- 12484463
TI  - Thermal dissociation of the protein homodimer ecotin in the gas phase.
AB  - The influence of charge on the thermal dissociation of gaseous, protonated,
      homodimeric, protein ecotin ions produced by nanoflow electrospray ionization
      (nanoES) was investigated using the blackbody infrared radiative dissociation
      technique. Dissociation of the protonated dimer, (E2 + nH)(n+) congruent to
      E2(n+) where n = 14-17, into pairs of monomer ions is the dominant reaction at
      temperatures from 126 to 175 degrees C. The monomer pair corresponding to the
      most symmetric charge distribution is preferred, although 50-60% of the monomer
      product ions correspond to an asymmetric partitioning of charge. The relative
      abundance of the different monomer ion pairs produced from E2(14+), E2(15+), and
      E2(16+) depends on reaction time, with the more symmetric charge distribution
      pair dominating at longer times. The relative yield of monomer ions observed late
      in the reaction is independent of temperature indicating that proton transfer
      between the monomers does not occur during dissociation and that the different
      monomer ion pairs are formed from dimer ions which differ in the distribution of
      charge between the monomers. For E2(17+), the yield of monomer ions is
      independent of reaction time but does exhibit slight temperature dependence, with
      higher temperatures favoring the monomers corresponding to most symmetric charge
      distribution. The charge distribution in the E2(15+) and E2(16+) dimer ions
      influences the dissociation kinetics, with the more asymmetric distribution
      resulting in greater reactivity. In contrast, the charge distribution has no
      measurable effect on the dissociation kinetics and energetics of the E2(17+)
      dimer.

PMID- 12484464
TI  - Identification and localization of the fatty acid modification in ghrelin by
      electron capture dissociation.
AB  - Electron capture dissociation (ECD) has been demonstrated to be an effective
      fragmentation technique for characterizing the site and structure of the fatty
      acid modification in ghrelin, a 28-residue growth-hormone-releasing peptide that
      has an unusual ester-linked n-octanoyl (C8:0) modification at Ser-3. ECD cleaves
      21 of 23 possible backbone amine bonds, with the product ions (c and z* ions)
      covering a greater amino acid sequence than those obtained by collisionally
      activated dissociation (CAD). Consistent with the ECD nonergodic mechanism, the
      ester-linked octanoyl group is retained on all backbone cleavage product ions,
      allowing for direct localization of this labile modification. In addition, ECD
      also induces the ester bond cleavage to cause the loss of octanoic acid from the
      ghrelin molecular ion; the elimination process is initiated by the capture of an
      electron at the protonated ester group, which is followed by the radical-site
      initiated reaction known as alpha-cleavage. The chemical composition of the
      attached fatty acid can be directly obtained from the accurate Fourier transform
      ion cyclotron resonance (FTICR) mass measurement of the ester bond cleavage
      product ions.

PMID- 12484465
TI  - Alkali cation attachment to derivatized fullerenes studied by matrix-assisted
      laser desorption/ionization.
AB  - The complexation of alkali metal ions with amphiphilic fullerene derivatives has
      been investigated by matrix-assisted laser desorption/ionization (MALDI) time-of
      flight (TOF) mass spectrometry. The formation of analyte ions occurs via two
      competing mechanisms including electron transfer from matrix-derived ions and
      metal ion attachment. The interplay of these processes has been examined by laser
      fluence dependent sample activation and by variation of the target composition.
      The attachment of metal ions has been established as the gentler and thus more
      efficient route towards the formation of intact analyte ions. Investigations into
      the metal ion complexation have been conducted to reveal the reactivity order of
      the alkali metals in these reactions and to elucidate the influence of structural
      differences of the analytes, as well as to unravel effects caused by the anionic
      counter ion of the metal. The experimental data have been derived by two
      complementary approaches. Competing reactants were either studied simultaneously,
      so that the product distribution would provide direct insight into the reactivity
      pattern, and/or product distributions were obtained in a large variety of
      separate experiments and normalized for reliable comparison. It has been found
      that the extent to which complexation is observed follows the charge density
      order of the alkali metal ions. The structural features of the fullerene-attached
      ligands were of profound influence on the attachment of the metal ion, inducing
      enhanced selectivity for the complexation with less reactive metals. The metal
      ion attachment is reduced with the use of smaller anionic counter ions.
      Rationalization of these findings is provided within the framework of the
      mechanisms of ion formation in MALDI.

PMID- 12484466
TI  - 2001 Achievement Award of the IEEE Ultrasonics, Ferroelectrics, and Frequency
      Control Society. Eric L. Adler. Institute of Electrical and Electronics
      Engineers.

PMID- 12484467
TI  - 2000 Outstanding Paper Award of the IEEE Ultrasonics, Ferroelectrics, and
      Frequency Control Society. Institute of Electrical and Electronics Engineers.

PMID- 12484468
TI  - The origin of the piezoelectric effect in pyroelectric crystals.
AB  - The physical mechanism of piezoelectricity arising in crystals of all
      pyroelectric classes is described and discussed in detail. The piezoelectric
      effect of these crystals is postulated to be a consequence of changes in their
      spontaneous polarization under the impact of external forces (electric fields,
      mechanical stresses). This study shows which piezoelectric coefficients do exist
      in pyroelectric crystals. Both the direct piezoeffect--generation of electric
      polarization under mechanical stresses--and the inverse piezoeffect--crystal
      deformations caused by the application of an electric field--are considered.
      Specifically, the analysis performed suggests that crystals of classes 6, 4, and
      3 may lack d14 and d25 piezo modules, the existence of which is, in principle,
      allowed by the symmetry of the crystals, but which do not actually exist because
      of the accidental cancellation of requisite "piezo-generating" elastic compliance
      coefficients.

PMID- 12484469
TI  - Elastic and piezoelectric properties of La3Ga5SiO14 and La3Ga5.5Ta0.5O14: an
      application of resonant ultrasound spectroscopy.
AB  - The electromechanical properties of La3Ga5SiO14 (LGS) and La3Ga5.5Ta0.5O14 (LGT)
      have been studied at room temperature on 25 samples using resonant ultrasound
      spectroscopy (RUS). The RUS method facilitates simultaneous determination of all
      independent elastic and piezoelectric constants of a sample within the same
      frequency range and yields sample parameters with high internal consistency.
      Consequently, the spread of the experimental results presented here is
      significantly lower than the scatter of literature data obtained by different
      experimental techniques.

PMID- 12484470
TI  - Continuous time transfer using GPS carrier phase.
AB  - The Astronomical Institute of the University of Berne is hosting one of the
      Analysis Centers (AC) of the International GPS Service (IGS). A network of a few
      GPS stations in Europe and North America is routinely analyzed for time transfer
      purposes, using the carrier phase observations. This work is done in the
      framework of a joint project with the Swiss Federal Office of Metrology and
      Accreditation (METAS). The daily solutions are computed independently. The
      resulting time transfer series show jumps of up to 1 ns at the day boundaries. A
      method to concatenate the daily time transfer solutions to a continuous series
      was developed. A continuous time series is available for a time span of more than
      4 mo. The results were compared with the time transfer results from other
      techniques such as two-way satellite time and frequency transfer. This
      concatenation improves the results obtained in a daily computing scheme because a
      continuous time series better reflects the characteristics of continuously
      working clocks.

PMID- 12484471
TI  - Determination of ZnO temperature coefficients using thin film bulk acoustic wave
      resonators.
AB  - Thin film bulk acoustic wave (BAW) resonators have been the subject of research
      in RF microelectronics for some time. Much of the interest lay in utilizing the
      resonators to design filters for wireless applications. Some of the major
      advantages BAW devices present over other filter technologies in use today
      include size reduction and the possibility of on-chip integration. As the
      technology matures, the necessity to more fully characterize the performance of
      the devices and to develop more accurate models describing their behavior is
      apparent. In this investigation, the effects that temperature variations have on
      1.8-2.0 GHz zinc oxide (ZnO)-based solidly mounted BAW resonators (SMRs) are
      studied. The average temperature coefficients of the series and parallel resonant
      frequencies of the fabricated devices are found to be -31.5 ppm/degrees C and 
      35.3 ppm/degrees C, respectively. The slight decrease in separation between the
      two resonant frequencies with temperature implies there is slightly less
      effective coupling with increased temperature. No definite trend is found
      describing the behavior of the quality factor (Q) of the resonator with
      temperature variations. With little temperature coefficient data for thin film
      ZnO available in the literature, the importance of an accurate model is evident.
      The resonator device performance is simulated using Ballato's electronic circuit
      model for acoustic devices on a SPICE-based platform. By virtue of the comparison
      between the predicted and measured device response, various material parameters
      are extracted.

PMID- 12484472
TI  - Second-order theories for extensional vibrations of piezoelectric crystal plates
      and strips.
AB  - An infinite system of two-dimensional (2-D) equations for piezoelectric plates
      with general symmetry and faces in contact with vacuum is derived from the 3-D
      equations of linear piezoelectricity in a manner similar to that of previous
      work, in which an infinite system of 2-D equations for plates with electroded
      faces was derived. By using a new truncation procedure, second-order equations
      for piezoelectric plates with faces in contact with either vacuums or electrodes
      are extracted from the aforementioned infinite systems of equations,
      respectively. The second-order equations for plates with or without electrodes
      are shown to predict accurate dispersion curves by comparing to the corresponding
      curves from the 3-D equations in a range up to the cut-off frequencies of the
      first symmetric thickness-stretch and the second symmetric thickness-shear modes
      without introducing any correction factors. Furthermore, a system of 1-D second
      order equations for strips with rectangular cross section is deduced from the 2-D
      second-order equations by averaging variables across the narrow width of the
      plate. The present 1-D equations are used to study the extensional vibrations of
      barium titanate strips of finite length and narrow rectangular cross section.
      Predicted frequency spectra are compared with previously calculated results and
      experimental data.

PMID- 12484473
TI  - Extensional, thickness-stretch and symmetric thickness-shear vibrations of
      piezoceramic disks.
AB  - A set of two-dimensional (2-D), second-order approximate equations for
      extensional, thickness-stretch and symmetric thickness-shear vibrations of
      piezoelectric ceramic plates with electroded faces is extracted from the infinite
      system of 2-D equations deduced previously. The new truncation procedure
      developed recently is used for it improves the accuracy of calculated dispersion
      curves. Closed-form solutions are obtained for free vibrations of circular disks
      of barium titanate. Dispersion curves calculated from the present approximate 2-D
      equations are compared with those obtained from the 3-D equations, and the
      predicted resonance frequencies are compared with experimental data. Both
      comparisons show good agreement without any corrections. The frequencies of the
      edge modes calculated from the present 2-D equations are very close to the
      experimental data. Furthermore, mode shapes at various frequencies are calculated
      in order to identify the frequency segments of the spectrum at which one of the
      coupled modes--i.e., the radial extension (R), edge mode (Eg), thickness-stretch
      (TSt), and symmetric thickness-shear (s.TSh)--is predominant.

PMID- 12484474
TI  - Diffraction of horizontally polarized ultrasonic plane waves on a periodically
      corrugated solid-liquid interface for normal incidence and Brewster angle
      incidence.
AB  - The theory, and the use at normal incidence, of shear-vertically polarized waves
      (with polarization vector in the plane containing the incident wave vector and
      the normal on the interface) using the mode conversion method has been tackled by
      others. Here we develop the theory for shear-horizontally polarized incident
      waves (with polarization vector perpendicular to both the normal on the interface
      and the incoming wave vector). We take into account normal incidence as well as
      oblique incidence. For normal incidence, we discover the generation of Love
      waves. If oblique incidence is considered, we discover the existence of a
      Brewster angle of incidence, comparable with the Brewster angle in optics, in
      which a diffraction grating can be used as a polarization filter.

PMID- 12484475
TI  - Determination of the acoustic output of a harmonic scalpel.
AB  - The acoustic output of a harmonic scalpel was experimentally determined, and both
      the airborne ultrasound and the ultrasound transmitted in water were taken into
      account. The sound pressure level of airborne ultrasound was measured with a
      microphone and an artificial head, so that the free-field value and the sound
      level at the entrance at the bottom of the cavum conchae of the ear could be
      determined. The derived output power in water was obtained from a hydrophone
      measurement. The results were strongly influenced by cavitation effects, and it
      is shown that the power values with and without cavitation differ by more than a
      factor of 5. The measurement of acoustic output parameters forms the basis for
      describing the performance of the devices and for an assessment of the risk of
      harmful bioeffects on both the operator and the patient.

PMID- 12484476
TI  - Characterization of reperfused infarcted myocardium from high-frequency
      intracardiac ultrasound imaging using homodyned K distribution.
AB  - Myocardial changes caused by infarction/reperfusion (contraction band necrosis,
      hemorrhage, edema, etc.) may result in an increased scatterer density and a
      variation in scatterer arrangement. This paper, for the first time, models most
      of the scattering conditions resulting from the interaction of ultrasound and
      normal/reperfused infarcted myocardium using the homodyned K distribution.
      Furthermore, this method is used to characterize the change in scatterer density
      by calculating the effective scatterer number per resolution cell. The
      reliability and the effects of attenuation and scan conversion on effective
      scatterer number estimation are discussed. We used in vivo data acquired using
      high-frequency intracardiac ultrasound imaging (8.5 MHz) from the left and right
      ventricles of open-chest pigs in an acute infarction/reperfusion model. The
      results show that the homodyned K distribution describes the statistical
      distribution of backscattered signal from both normal and abnormal myocardium. A
      significant increase in scatterer density occurs in the infarcted region after
      reperfusion compared with the same region at baseline (normal myocardium prior to
      occlusion). The scatterer density of the normal region does not change
      significantly after reperfusion. We conclude that the homodyned K distribution
      may characterize normal and reperfused infarcted myocardium using high-frequency
      intracardiac ultrasound images.

PMID- 12484477
TI  - Development and characterization of a vitreous mimicking material for radiation
      force imaging.
AB  - In many medical ultrasound applications tissue-mimicking phantoms are of
      fundamental importance for the performance of controlled experiments.
      Traditionally, such phantoms have been constructed using gelatin and agar gels.
      Although the use of these materials has become standard, few alternative
      materials have not been fully explored. In this paper, we present a protocol
      developed in our laboratory that reliably produces very soft, acrylamide-based
      phantoms that can mimic both acoustical and mechanical characteristics of the
      vitreous body of the eye. Following the described protocol, a series of phantoms
      were constructed ranging in acrylamide concentration from 1.60% to 1.70%.
      Measurements across the series yielded attenuation coefficients of 0.067-0.140
      dB/cm/MHz, depending on acrylamide concentration. Speed of sound ranged between
      1499 and 1510 m/s, also depending on acrylamide concentration. Published values
      for the vitreous gel indicate an attenuation of 0.10 dB/cm/MHz and a speed of
      sound of 1510 m/s, making our phantoms an excellent analog of this tissue. One
      application of these acrylamide phantoms is to test the efficacy of the Kinetic
      Acoustic Vitreoretinal Examination (KAVE), a tool developed in our laboratory
      with the potential to aid in the diagnosis of vitreoretinal disorders. KAVE
      utilizes acoustic radiation force to generate small, localized displacements
      within the vitreous-mimicking gel. These localized displacements are quantified
      to yield maximum displacement, relative elasticity, and relative viscosity
      images. We present KAVE images of a set of four phantoms with different gel
      concentrations. Although B-mode and relative viscosity images exhibit no
      significant differences, maximum displacement, and relative elasticity images
      clearly differentiate gels of different concentrations. Maximum displacements
      ranged between 30 and 5 microns, depending on acrylamide concentration. The
      results presented in this paper show that soft gel phantoms can be produced in a
      range of elasticities not previously reported, and that these phantoms are useful
      for testing ultrasound instruments designed for evaluation of the vitreous gel.
      Furthermore, the use of acrylamide-based gels may also offer a valuable and
      attractive alternative for many other ultrasound applications.

PMID- 12484478
TI  - An integrated compliant balloon ultrasound catheter for intravascular strain
      imaging.
AB  - An integrated compliant balloon ultrasound catheter was developed to allow
      greater deformations in strain imaging with intravascular ultrasound. A 64
      element circumferential array was placed inside a compliant silicone balloon
      catheter to capture real-time, phase-sensitive radio frequency (RF) data during
      deformation experiments. Strains over 40% could be applied to normal arterial
      wall tissue with intracatheter pressures as low as 200 kPa (2 atm). Strain images
      of a hard-soft rubber phantom, thrombus, and fibrotic plaque were produced using
      the integrated balloon ultrasound catheter. Results show that this catheter can
      apply large deformations at low pressures and image various vascular pathologies
      ex vivo. Potentially, it can serve as a multifunctional, intravascular
      therapeutic device to guide angioplasty and stent deployment.

PMID- 12484479
TI  - Characterization of aortic microstructure with ultrasound: implications for
      mechanisms of aortic function and dissection.
AB  - Specific ultrasonic tissue characterization parameters were correlated with the
      three-dimensional architecture and material properties (density, compressibility,
      size, and orientation) of aortic elastic elements at the microscopic level. The
      medial layer of 10 samples of normal canine aorta were insonified in vitro
      utilizing acoustic microscopy from 30 to 44 MHz. The following quantitative
      indexes exhibited substantial anisotropic elastic behavior in radial (R),
      circumferential (C), and longitudinal (L) directions: backscatter coefficient
      (R:0.9 +/- 0.2; C:0.008 +/- 0.0008; LL:0.0077 +/- 0.0008 sr(-1) cm(-1));
      frequency dependence of backscatter (R:3.3; C:1.4; L:1.5); attenuation
      coefficients 1(R:105 +/- 22; L:135 +/- 13; C:131 +/- 14 dB/cm). Thus, the
      ultrasonic indexes are anisotropic: equivalent in the C and L directions, but
      markedly different in the R direction. These data are indicative of an aortic
      microstructure that interacts with ultrasonic waves as thin sheet-like elastic
      layers instead of independent elastin fibers. This specific sheet-like
      organization of elastin microfibers may function to limit shear injury to
      concentric aortic lamellae and prevent aortic dissection. The marked anisotropic
      behavior of normal aortas suggests that ultrasound may be useful for
      nondestructive characterization of vascular integrity.

PMID- 12484480
TI  - A Gaussian framework for modeling effects of frequency-dependent attenuation,
      frequency-dependent scattering, and gating.
AB  - For a wide range of applications in medical ultrasound, power spectra of received
      signals are approximately Gaussian. It has been established previously that an
      ultrasound beam with a Gaussian spectrum propagating through a medium with linear
      attenuation remains Gaussian. In this paper, Gaussian transformations are derived
      to model the effects of scattering (according to a power law, as is commonly
      applicable in soft tissues, especially over limited frequency ranges) and gating
      (with a Hamming window, a commonly used gate function). These approximations are
      shown to be quite accurate even for relatively broad band systems with fractional
      bandwidths approaching 100%. The theory is validated by experiments in phantoms
      consisting of glass particles suspended in agar.

PMID- 12484481
TI  - Modeling ultrasonic compression wave absorption during the seeded crystallization
      of copper (II) sulphate pentahydrate from aqueous solution.
AB  - Ultrasonic compression wave absorption is investigated as a means to monitor the
      seeded crystallization of copper (II) sulphate pentahydrate from aqueous
      solution. Simple models are applied to predict crystal yield, crystal size
      distribution, and the changing nature of the continuous phase. The Allegra-Hawley
      scattering formulation is used to simulate ultrasonic absorption as
      crystallization proceeds. Experiments confirm that simulated attenuation is in
      agreement with measured results.

PMID- 12484482
TI  - Distortion cancellation performance of miniature delay filters for feed-forward
      linear power amplifiers.
AB  - The technique of feed-forward amplitude control has been widely used in the
      linearization of power amplifiers for wireless communication systems. In this
      technique, an error signal due to third order intermodulation distortion (IMD) is
      extracted, amplified, and used to correct the delayed main line distorted signal.
      For example, a miniature prototype base station for the Global System for Mobile
      Communications/Code Division Multiple Access (GSM/CDMA) cellular system uses feed
      forward amplifiers with bulky and expensive coaxial cables, about 20 feet in
      length, to provide about 25 ns of delay. This paper shows alternate space-saving
      approaches of achieving these delays using three different types of delay
      filters: electromagnetic interdigital/lumped (<2.5"), ceramic (<1.8"), and ladder
      type surface acoustic wave (SAW) (0.15"). The delay lines introduce phase and
      amplitude imbalance and delay mismatch in the linearization loop due to
      fabrication tolerances. These adversely affect the IMD cancellation. Using an RF
      system simulation tool, this paper critically compares the IMD cancellation
      performance achieved using the three technologies. Simulation results show that
      the optimization of delay mismatch can achieve the desired cancellation more
      easily than other parameters. It is shown that, if the critical system parameter
      (phase deviation from linearity), is maintained at <2.5 degrees peak-to-peak over
      a 20 MHz bandwidth in the frequency range 855 MHz to 875 MHz, one can achieve 25
      dB of IMD cancellation performance. This paper concludes with the suggestion of a
      set of realistic specifications for a miniature delay filter for the low power
      loop of the feed-forward amplifier.

PMID- 12484483
TI  - Capacitive micromachined ultrasonic transducers: next-generation arrays for
      acoustic imaging?
AB  - Piezoelectric materials have dominated the ultrasonic transducer technology.
      Recently, capacitive micromachined ultrasonic transducers (CMUTs) have emerged as
      an alternative technology offering advantages such as wide bandwidth, ease of
      fabricating large arrays, and potential for integration with electronics. The aim
      of this paper is to demonstrate the viability of CMUTs for ultrasound imaging. We
      present the first pulse-echo phased array B-scan sector images using a 128
      element, one-dimensional (1-D) linear CMUT array. We fabricated 64- and 128
      element 1-D CMUT arrays with 100% yield and uniform element response across the
      arrays. These arrays have been operated in immersion with no failure or
      degradation in performance over the time. For imaging experiments, we built a
      resolution test phantom roughly mimicking the attenuation properties of soft
      tissue. We used a PC-based experimental system, including custom-designed
      electronic circuits to acquire the complete set of 128 x 128 RF A-scans from all
      transmit-receive element combinations. We obtained the pulse-echo frequency
      response by analyzing the echo signals from wire targets. These echo signals
      presented an 80% fractional bandwidth around 3 MHz, including the effect of
      attenuation in the propagating medium. We reconstructed the B-scan images with a
      sector angle of 90 degrees and an image depth of 210 mm through offline
      processing by using RF beamforming and synthetic phased array approaches. The
      measured 6-dB lateral and axial resolutions at 135 mm depth were 0.0144 radians
      and 0.3 mm, respectively. The electronic noise floor of the image was more than
      50 dB below the maximum mainlobe magnitude. We also performed preliminary
      investigations on the effects of crosstalk among array elements on the image
      quality. In the near field, some artifacts were observable extending out from the
      array to a depth of 2 cm. A tail also was observed in the point spread function
      (PSF) in the axial direction, indicating the existence of crosstalk. The relative
      amplitude of this tail with respect to the mainlobe was less than -20 dB.

PMID- 12484484
TI  - Radio-frequency plasma treatment improves the growth and attachment of
      endothelial cells on poly(methyl methacrylate) substrates: implications in tissue
      engineering.
AB  - The aim of this study was to improve the biocompatibility of poly(methyl
      methacrylate) (PMMA) substrates for possible applications in corneal prostheses
      or in micro-carrier cell culture systems. PMMA substrates were exposed to radio
      frequency (RF) argon and nitrogen plasmas for 5 and 10 min each. The PMMA films
      were examined by Fourier transform infrared (FT-IR) spectroscopy, to characterize
      the surface changes after plasma exposure. Plasma treatment in general was found
      to decrease the water contact angle of PMMA, thus increasing its hydrophilicity.
      There was also an associated increase in the work of adhesion of plasma-treated
      PMMA substrates. PMMA substrates exhibited differential properties towards
      endothelial cell (CPA-47) growth. The untreated PMMA surface did not support
      endothelial growth, compared with both polystyrene (TCPS) and plasma-treated
      PMMA, while plasma (PL): PMMA exhibited growth rates slightly lower than the TCPS
      control, as assessed by [3H]thymidine incorporation profiles. The compatibility
      and growth supportive properties of PL : PMMA were further confirmed by an MTT
      assay, which showed preserved cellular viability and mitochondrial activity of
      the cells. Confocal microscopic visualization of cells with fluorescence-labeled
      vimentin showed normal organization of the cytoskeletal fibers, indicating
      appropriate attachment to the substrate. Cells growing on PL: PMMA maintained
      their functionality, as seen from Factor VIII expression. Taken collectively, the
      findings of this study point out the suitability of RF plasma treatment in
      inducing desirable changes in PMMA substrates, so as to improve their ability to
      support the growth and attachment of endothelial cells.

PMID- 12484485
TI  - Grafting sulfobetaine monomer onto the segmented poly(ether-urethane) surface to
      improve hemocompatibility.
AB  - Polyurethanes are widely used as blood-contacting biomaterials, due to their good
      biocompatibility and mechanical properties. Nevertheless, their blood
      compatibility is still not adequate for more demanding applications. Surface
      modification is an effective way to improve the hemocompatibility for
      biomaterials. The purpose of the present study was to synthesize a novel
      nonthrombogenic biomaterial by modifying the surface of polyurethane. Ozonization
      was used to introduce active peroxide groups onto the segmented poly(ether
      urethane) (SPEU) film surface and graft polymerization of N,N'-dimethyl
      (methacryloyloxyethyl) ammonium propanesulfonate (DMAPS), a sulfobetaine
      structure, onto the ozone-activated SPEU surface was conducted. The SPEU-g-PDMAPS
      film was characterized by ATR-FTIR, XPS, and contact angle measurements. ATR-FTIR
      and XPS confirmed the graft polymerization. The grafted film possessed a
      relatively hydrophilic surface, as revealed by contact angle measurement. The
      blood compatibility of the grafted films was evaluated by a platelet-rich plasma
      (PRP) adhesion study and scanning electron microscopy, using SPEU film as the
      reference. No platelet adhesion was observed for the grafted films incubated with
      PRP at 37 degrees C for 60 and 180 min. This new sulfobetaine structure grafted
      biomaterial might have potential for biomedical applications.

PMID- 12484486
TI  - L-tyrosine-based backbone-modified poly(amino acids).
AB  - Tyrosine-based pseudo-peptide polymers, first introduced in 1987 by Kohn and
      Langer, have been identified for potential biomaterial applications. These
      materials combine the desired polypeptide properties of biocompatibility,
      biodegradability, non-toxicity, and non-immunogenicity with good processing
      properties including solubility, thermal stability, and moldability which arise
      from alternating non-amide bonds along the polymer backbone. This paper focuses
      on the analysis of two such polymers based on the natural amino acid L-tyrosine.
      Starting from L-tyrosine and its deaminated analogue, 3-(4-para-hydroxy)
      phenylpropionic acid, a diphenolic structure containing an amide linkage, was
      synthesized following standard procedures of peptide synthesis. This diphenolic
      structure was then used as a monomer to synthesize a polyiminocarbonate using a
      cyanogen bromide-initiated reaction and a polycarbonate using a triphosgene
      initiated reaction. The polyiminocarbonate has iminocarbonate linkages and the
      polycarbonate has carbonate linkages alternating with amide linkages in the
      respective polymer backbone. Analytical studies were performed regarding the
      feasibility of the reaction procedures, the physical properties of the polymers,
      and their degradation processes, to gain insight into the potential biomaterial
      applications of these polymers. These results independently reaffirm the studies
      published by Kohn et al. working on similar polymeric systems.

PMID- 12484487
TI  - Non-connected versus interconnected macroporosity in poly(2-hydroxyethyl
      methacrylate) polymers. An X-ray microtomographic and histomorphometric study.
AB  - Poly(2-hydroxyethyl methacrylate) (pHEMA) has potentially broad biomedical
      applications: it is biocompatible and has a hardness comparable to bone when bulk
      polymerized. Porous biomaterials allow bone integration to be increased,
      especially when the pores are interconnected. In this study, three types of
      porogens (sugar fibers, sucrose crystals, and urea beads) have been used to
      prepare macroporous pHEMA. The pore volume and interconnectivity parameters of
      the porosity were measured by X-ray microtomography and image analysis. Sucrose
      crystals, having a high volumetric mass, gave large pores that were located on
      the block sides. Urea beads and sugar fibers provided pores with the same star
      volume (2.65 +/- 0.46 mm3 and 2.48 +/- 0.52 mm3, respectively) but which differed
      in interconnectivity index, fractal dimension, and Euler-Poincares number. Urea
      beads caused non-connected porosity, while sugar fibers created a dense labyrinth
      within the polymer. Interconnectivity was proved by carrying out surface
      treatment of the pHEMA (carboxymethylation in water), followed by von Kossa
      staining, which detected the carboxylic groups. Carboxymethylated surfaces were
      observed on the sides of the blocks and on the opened or interconnected pores.
      The disconnected pores were unstained. Macroporous polymers can be prepared with
      water-soluble porogens. X-ray microtomography appears a useful tool to measure
      porosity and interconnectedness.

PMID- 12484488
TI  - Synthesis and characterization of glycolide, L-lactide, and PDMS-based
      terpolymers as a support for cell cultures.
AB  - Poly(lactic acid)/poly(glycolic acid)/poly(dimethylsiloxane) (PLGA/TEGOMER)
      terpolymers have been synthesized by the ring-opening polymerization of L-lactide
      and glycolide with alpha,omega-amine-terminated poly(dimethylsiloxane)
      prepolymer, using stannous octoate as a catalyst. The resulting terpolymers were
      characterized by various analytical techniques including size exclusion
      chromatography, 1H-nuclear magnetic resonance (1H-NMR), Fourier transform
      infrared spectroscopy, and differential scanning calorimetry. The data showed
      that the terpolymers presented an amorphous structure. The glass transition
      temperature decreased with increasing TEGOMER unit content. For in vitro
      degradation studies, porous films were fabricated using a solvent-casting,
      particulate leaching technique. Degradation of the PLGA/TEGOMER terpolymer was
      studied in phosphate-buffered saline at pH 7.4 and 37 degrees C. The degradation
      was followed by intrinsic viscosity, mass loss, and molecular weight
      measurements, and 1H-NMR spectroscopy. The mass loss after 55 days was 76% for
      the PLGA/TEGOMER (71/24/5) sample. Cell growth experiments using Swiss 3T3
      fibroblasts demonstrated that PLGA/TEGOMER terpolymer matrices allow the
      attachment and growth of cells.

PMID- 12484489
TI  - Synthesis and biological properties of antitumor-active conjugates of ADR with
      dextran.
AB  - Three kinds of polymeric adriamycin (ADR) conjugates of dextran were synthesized,
      namely a dextran-Gly-Leu-Gly-ADR (DGLGA) conjugate with a lysosomally degradable
      tripeptide spacer group, a dextran-Gly-Leu-Gly-ADR-galactosamine (DGLGA-Ga)
      conjugate with a targeting moiety of galactosamine on DGLGA, and a dextran-C6H10
      ADR (DC6A) conjugate with a hexamethylen spacer group. The content of the ADR
      moiety in the polymeric-drug conjugate was about 3 mol%. Enzyme hydrolysis of
      DGLGA and DC6A was carried out by incubation with papain. The total amount of ADR
      released after 48 h was 43 mol% for DGLGA and less than 1 mol% for DC6A. In an in
      vitro cytotoxicity experiment, the DGLGA-Ga conjugate has higher cytotoxic
      efficacy than the other conjugates for incubation with Hep-3B cells and
      consequently, the capability of targeting hepatoma cells of the galactosamine
      residue was determined. In contrast, for the incubation with SiHa cells of these
      conjugates, there was no significant cytotoxicity effect. The in vivo cytotoxic
      efficacy of each conjugate (20 mg ADR equiv./kg) against CT-26 mice colon cells
      implanted subcutaneously in Balb-C mice was studied. The DGLGA conjugate
      generated the best therapeutic effect with the presence of long-term survival
      (LTS) at day 50 (2/6).

PMID- 12484490
TI  - Synthesis and characterization of nitric oxide generative polyrotaxane.
AB  - L-Arginine was immobilized into a supramolecular-structured polyrotaxane to
      examine the generation of nitric oxide, with a view to improving antithrombosis
      and the blood compatibility of polymeric biomaterials. L-Arginine was immobilized
      to the hydroxyl groups of alpha-cyclodextrins in the polyrotaxane via an ester
      linkage, and the nitric oxide generation and L-arginine release behavior were
      characterized. L-Arginine-immobilized polyrotaxane was insoluble in water, but
      was found to generate nitric oxide when placed in Tris-HCI buffer supplemented
      with activators. L-Arginine-immobilized polyrotaxane exhibited sustained nitric
      oxide generation for a period of 250 h. L-Arginine was completely released by non
      enzymatic hydrolysis from 200 h to 700 h, with a lag-time for the first 200 h.
      Consequently, after the generation of nitric oxide and the release of L-arginine
      from the L-arginine-immobilized polyrotaxane, the residual component will be a
      polyrotaxane with superior biocompatibility and mechanical properties. These
      results suggest that L-arginine-immobilized polyrotaxane can be useful in a wide
      range of medical applications, including use as a nitric oxide generative system
      for antithrombosis, coating and blending materials of hydrophobic extracorporeal
      circuits, and implantable catheters.

PMID- 12484491
TI  - Synthesis and characterization of elastic PLGA/PCL/PLGA tri-block copolymers.
AB  - Various ABA-type tri-block copolymers composed of poly(L-lactide) (PLA) or poly
      (lactide-co-glycolide) (PLGA) as the side A block and poly(epsilon-caprolactone)
      (PCL) as the middle B block were synthesized to produce rapidly degrading elastic
      matrices useful for tissue engineering scaffolds. The terminal di-hydroxyl groups
      in PCL-diol (MW 2000) were used as the initiator for the ring-opening
      polymerization of L-lactide or D,L-lactide and glycolide, employing stannous
      octoate as a catalyst. A series of copolymers were synthesized by varying the
      chain length and monomer composition of the PLA (PLGA) block, while the chain
      length of the PCL block was fixed. It was found that PLGA/PCL/PLGA copolymers
      with a MW of 10000 and lactide/glycolide ratios of 50/50 and 75/25 demonstrated
      desirable mechanical properties of elasticity (Young's modulus 26.0 and 19.8 MPa)
      and showed controllable degradability over a 2-month period depending on the
      monomer composition.

PMID- 12484492
TI  - Poor response of ovaries with endometrioma previously treated with cystectomy to
      controlled ovarian hyperstimulation.
AB  - PURPOSE: To compare ovarian response to controlled ovarian hyperstimulation (COH)
      between normal ovaries and ovaries previously treated surgically for unilateral
      ovarian endometrioma. METHODS: From January 1996 to December 2001, 32 patients
      with unilateral ovarian endometrioma previously treated surgically underwent 38
      cycles of COH. Their records were reviewed retrospectively. The number of
      dominant follicles observed on the day of hCG injection and the number of eggs
      retrieved from the diseased and the normal ovaries in each patient were compared.
      RESULTS: The numbers of dominant follicles from diseased and normal ovaries were
      1.9 +/- 1.5 and 3.3 +/- 2.1, respectively (P < 0.001). During ovum pick up, the
      numbers of eggs retrieved from diseased and normal ovaries were 2.9 +/- 2.6 and
      6.1 +/- 4.1, respectively (P < 0.0001). For diseased ovaries, 21.1% (8/38) had no
      dominant follicles, while only 7.9% (3/38) of normal ovaries lacked dominant
      follicles. The clinical pregnancy rate and the implantation rate per embryo
      transfer were 33.3 and 17.6%. CONCLUSIONS: Surgery for ovarian endometrioma may
      damage ovarian reserve. It potentially results in poor ovarian response to COH,
      compared to the response of the contralateral normal ovary in the same
      individual.

PMID- 12484493
TI  - Zona thinning with a noncontact diode laser in ICSI embryos from women of
      advanced age.
AB  - PURPOSE: The objective of this study was to determine if the zona thinning (ZT)
      technique improved the rates of implantation and clinical pregnancy for patients
      aged > or = 38 years submitted to an ICSI program. METHODS: A total of 100
      patients submitted to ICSI and aged > or = 38 years were divided in a prospective
      and randomized manner into two groups: Group I - patients submitted to ZT (n =
      50); a laser diode with 1.48 microm wavelength (Fertilaser) was used for the ZT
      procedure with 1-2 irradiations of 10 ms applied to four different positions on
      the zona pellucida (ZP) of each embryo to thin 60-90% of the ZP (each point with
      a 15-20 microm length of ZT). Group II - patients with no ZT (n = 50). In both
      groups, embryo transfer was performed on the second or third day. RESULTS: The
      age of Group I patients (39.8 +/- 1.3) did not differ (p = 0.67) from that of
      Group II patients (40 +/- 1.9). The number of oocytes retrieved at metaphase II
      from Group I (6.4 +/- 4.2) and Group II (6.8 +/- 5) was similar (p = 0.94).
      Normal fertilization rates and cleavage rates were similar (p = 0.78 and p =
      0.63, respectively) for Group I (71.5 +/- 22% and 96.7 +/- 11%) and Group II
      (73.5 +/- 19.7% and 96 +/- 11%, respectively). The number of embryos transferred
      was similar (p = 0.53) for the two groups (Group I = 3.1 +/- 1.3; Group II = 2.9
      +/- 1.1). The thickness of the ZP of Group I embryos (16.9 +/- 2.4 microm) did
      not differ (p = 0.97) from that of Group II embryos (16.9 +/- 2.3 microm). The
      rates of embryo implantation and clinical pregnancy per embryo transfer were
      similar (p = 0.67, p = 0.61) for Group I (7 and 16%, respectively) and for Group
      II (8.2 and 22%, respectively). CONCLUSIONS: These results suggest that ZT in the
      population aged > or = 38 years may have no impact on ICSI success rates.
      However, this conclusion is limited to a situation in which length of the laser
      ZT was < or = 20 microm and the laser was applied to four different positions.

PMID- 12484494
TI  - Testicular sonography in men with Klinefelter syndrome shows irregular
      echogenicity and blood flow of high resistance.
AB  - PURPOSE: Klinefelter syndrome is the most common chromosomal aberration among
      azoospermic men. We wanted to compare testicular echogenicity and intratesticular
      arterial blood in men with this syndrome versus men with normal sperm parameters.
      METHODS: Testicular sonography including Doppler imaging, was performed as part
      of the infertility workup in 26 men with Klinefelter syndrome as well as in 26
      men with normal sperm parameters. RESULTS: In men with Klinefelter syndrome,
      sonography of the testicular parenchyma revealed a heterogeneous irregular
      pattern with spread hyper- and hypoechoic foci. Doppler sonography resulted in
      waveforms of high impedance patterns, reflecting intratesticular blood flow of a
      high resistance. In men with normal sperm parameters testicular echogenicity was
      of an almost homogeneous regular pattern. In these men, intratesticular blood
      flow typically exhibited a pattern of low vascular resistance. CONCLUSIONS: The
      study demonstrates that testicular echogenicity as well as intratesticular blood
      flow are different in men with Klinefelter syndrome versus men with normal sperm
      parameters.

PMID- 12484495
TI  - Comparison of intrabursal transfer of spermatozoa, a new method for artificial
      insemination in mice, with intraoviductal transfer of spermatozoa.
AB  - PURPOSE: The objective of this paper was to compare the in vivo fertilizing
      abilities of fresh epididymal spermatozoa with a new method of artificial
      insemination in mice, so-called "intrabursal transfer of spermatozoa (ITS),"
      which requires transfer of spermatozoa into a space near the infundibulum between
      the ovary and ovarian bursa of superovulated females, and the previous method, so
      called "intraoviductal transfer of spermatozoa (IOTS)," especially as regards
      sperm number and capacitation. METHODS: Spermatozoa freshly isolated from B6C3F1
      males were injected into superovulated B6C3F1 females on E 0.4 (10:00 AM) by the
      IOTS or ITS method. Embryos at two-cell stage were collected from the females 1
      day after injection and their morphology was scored. Some females were allowed to
      survive at midgestational stages and inspected for development of normal fetuses.
      RESULTS: When 1 microL of a sperm suspension containing uncapacitated 1 x 10(5)
      spermatozoa freshly isolated from B6C3F1 males was injected by the IOTS or ITS
      method, normal two-cell embryos were recovered from the females at rates ranging
      from 14 to 23% with each method. This rate was much lower than that (93% on
      average) for embryos obtained by natural mating. Neither injection of 1 x 10(3)
      or 1 x 10(4) spermatozoa nor induction of capacitation improved in vivo
      fertilization rate. In both cases, females given spermatozoa exogenously yielded
      midgestational fetuses (E 12.5-13.5) with average litter sizes between 2.5 and
      2.8. CONCLUSION: ITS was comparable to IOTS with the conditions used. These two
      methods will be valuable for artificial insemination in mice for propagation of
      offspring from particular transgenic or mutant lines that are difficult to breed,
      although further attempts to improve in vivo fertilization ability are required.

PMID- 12484496
TI  - Tissue sampling technique affects accuracy of karyotype from missed abortions.
AB  - PURPOSE: To determine if careful specimen selection and washing of tissue from
      first trimester missed abortion products of conception specimens increases the
      sensitivity of routine cytogenetics in detecting aneuploidy. METHODS:
      Retrospective review of cytogenetics results from tissue from dilation and
      curettage for missed abortion in a university fertility practice between 1998 and
      2001. A technique of careful selection and washing of the specimen was
      implemented in July 1999. Results from before (n = 15) and after (n = 41) this
      change were compared. Cytogenetics reports from other physicians using the same
      laboratory were used for comparison (n = 59). RESULTS: The percentage of 46XX
      results was significantly decreased in the test group when compared to historical
      and community controls: 29% vs. 73% and 56% respectively. The percentage of
      aneuploid results was significantly higher in the test group at 61% vs. 7% and
      36% in the historical and community controls respectively. CONCLUSION: Thorough
      separation and cleaning of villi prior to sending missed abortion specimens
      significantly increases sensitivity of conventional cytogenetics for detecting
      aneuploidy by decreasing maternal contamination.

PMID- 12484497
TI  - Do lunar cycles influence in vitro fertilization results?
AB  - PURPOSE: Our objective was to investigate the lunar influence on IVF-ET outcomes.
      METHODS: Between 1992 and 1999 we have completed 7572 preprogrammed IVF-ET
      treatment cycles with the same stimulation protocol in two outpatient units.
      (Vienna, Austria and Budapest, Hungary) Multiple regression (SAS; proc Logistic)
      and two separate analyses were performed on pregnancy rates using a harmonic
      sinoidal trend based on the synodic and anomalistic lunar cycles respectively.
      RESULTS: The overall pregnancy rate was 30.9%. The amplitude of harmonic
      sinoidal, trend for the synodic lunar cycles was chi2 = 1.63,2d.f., p = 0.44 and
      chi2 = 6.27,2d.f., p = 0.044 for the anomalistic moon periods. For the
      anomalistic lunar months the amplitude of harmonic sinoidal trend was borderline
      in terms of higher pregnancy rates with the moon in Perigee. CONCLUSION: The
      cause of seasonal changes in IVF-ET outcomes is probably very complex. Our
      results indicate that lunar influence may only be one of the contributing
      factors. Further studies are needed to clarify unexplained fluctuations of
      pregnancy outcomes.

PMID- 12484498
TI  - Successful birth after transfer of blastocysts derived from oocytes of
      unstimulated woman with regular menstrual cycle after IVM approach.
AB  - PURPOSE: To report a delivery after transfer of blastocysts derived from eggs
      collected following in vivo HCG priming in a patient with regular menstrual
      cycles undergoing in vitro maturation (IVM) program. METHODS: A woman had regular
      menstrual cycle and had experience of ovarian hyperstimulation syndrome (OHSS)
      during a previous conventional IVF-ET cycle. The patient was primed with 10,000
      IU HCG 36 h before egg retrieval. After oocyte collection, the maturity of
      oocytes was evaluated and immature oocytes were cultured in IVM medium. The
      matured oocytes were fertilized with husband sperm, and normal fertilized eggs
      were cultured to blastocysts stage until embryo transfer in uteri. RESULTS: Three
      MII-stage and 13 GV-stage oocytes were collected from the patient. Three mature
      oocytes were fertilized by conventional IVF. All three fertilized oocytes were
      developed to blastocysts. Immature oocytes were matured in vitro and insemination
      was carried out by ICSI. Out of eight fertilized zygotes, two developed to
      blastocyst stage. Transfer of three expanded blastocysts on Day 6 resulted in
      pregnancy in the patient and one healthy baby was born. CONCLUSIONS: This report
      provides an approach to treat infertile women with regular menstrual cycle and
      high risk of OHSS.

PMID- 12484499
TI  - CD44 in cancer.
AB  - CD44 is a multistructural and multifunctional cell surface molecule involved in
      cell proliferation, cell differentiation, cell migration, angiogenesis,
      presentation of cytokines, chemokines, and growth factors to the corresponding
      receptors, and docking of proteases at the cell membrane, as well as in signaling
      for cell survival. All these biological properties are essential to the
      physiological activities of normal cells, but they are also associated with the
      pathologic activities of cancer cells. Experiments in animals have shown that
      targeting of CD44 by antibodies, antisense,and CD44-soluble proteins markedly
      reduces the malignant activities of various neoplasms, stressing the therapeutic
      potential of anti-CD44 agents. Furthermore, because alternative splicing and
      posttranslational modifications generate many different CD44 sequences,
      including, perhaps, tumor-specific sequences, the production of anti-CD44 tumor
      specific agents may be a realistic therapeutic approach. However, in many cancers
      (renal cancer and non-Hodgkin's lymphomas are exceptions), a high level of CD44
      expression is not always associated with an unfavorable outcome. On the contrary,
      in some neoplams CD44 upregulation is associated with a favorable outcome. Even
      worse, in many cases different research grows analyzing the same neoplastic
      disease reached contradictory conclusions regarding the correlation between CD44
      expression and disease prognosis, possibly due to differences in methodology.
      These problems must be resolved before applying anti-CD44 therapy to human
      cancers.

PMID- 12484500
TI  - Hypersensitivity pneumonitis.
AB  - Hypersensitivity pneumonitis (HP) is a group of immunologically mediated lung
      diseases caused by the inhalation of environmental agents in susceptible
      individuals. Most HP patients are non-smokers and have been exposed to organic
      dusts from vegetable or animal products. Some HP cases are associated with
      exposures to relatively simple chemical compounds. HP may present as an acute,
      subacute, or chronic disease and may follow various clinical courses. The type of
      exposure is thought to be more important in the clinical outcome than the nature
      of the antigen. A diagnosis of HP is often considered on the basis of clinical
      history of exposure with resulting respiratory symptoms, but the definitive
      diagnosis requires a constellation of clinical, radiologic, laboratory, and
      pathologic findings. The characteristic histologic triad in HP includes
      bronchiolitis, interstitial lymphocytic infiltration, and granulomas; however,
      biopsy in HP cases may lack the diagnostic triad and manifest as nonspecific
      interstitial pneumonia (NSIP). Avoiding exposure to the offending antigen(s) is
      usually sufficient to resolve symptoms and physiological abnormalities. Pulmonary
      fibrosis and physiological abnormalities occurring in chronic HP may be
      irreversible. Steroid therapy is helpful for symptomatic relief, but probably
      does not affect the long-term prognosis. Type III and type IV hypersensitivity
      reactions are involved in the pathogenesis; alveolar macrophages and T cells (Th
      1 type) play a central role in the immune responses after antigen exposure via
      their increased interaction and secretion of regulatory mediators.

PMID- 12484501
TI  - Proposition of a feasible protocol to evaluate salt sensitivity in a population
      based setting.
AB  - Although a variety of techniques have been devised to assess salt sensitivity,
      most have proven cumbersome from a methodological perspective. We therefore
      attempted to develop a 2-week method by which participants could be tested in an
      outpatient setting without requirement of a strict dietary regimen. In this
      method, subjects take 140 mEq of an NaCl supplement per day for 1 week and 25 mg
      of hydrochlorothiazide daily for another week while maintaining their customary
      diet. In our first trial, 8 healthy volunteers submitted to this method, as well
      as to a widely-used rapid volume expansion and contraction protocol. Blood
      pressure measurements, blood sampling and 24-h urine collection were performed
      before, in the middle of, and after each intervention. There was a fair
      correlation (r = 0.69) between the two protocols with respect to the changes in
      mean blood pressure (deltaMBP), a measure of salt sensitivity. In our second
      trial, we tested the method on 82 Japanese subjects who had never been treated
      with antihypertensive drugs. DeltaMBP was significantly correlated with plasma
      renin activity (PRA) during salt loading (r = 0.52, p < 0.0001) and with the
      changes in atrial natriuretic peptide (deltaANP) (r = -0.34, p = 0.0018). When
      total subjects were divided into two subgroups by age, a similar tendency of
      correlation was observed. Age, PRA during salt loading, deltaANP, and delta
      norepinephrine were proven to be significant predictors of salt sensitivity and
      accounted for 46% of the deltaMBP variances. Based on these results, the dietary
      method presented here seems to be applicable for a population-based survey. Our
      preliminary data also suggest that PRA and ANP would be of predictive value in
      the salt sensitivity test.

PMID- 12484502
TI  - Impact of multiple risk factor clustering on the elevation of blood pressure.
AB  - A family history of hypertension, obesity, diabetes mellitus,
      hypercholesterolemia, and hypertriglyceridemia have all been associated with risk
      of hypertension. We retrospectively conducted a longitudinal study in a large
      screened cohort to explore the effect of the clustering of these five risk
      factors on the elevation of blood pressure (BP) in normotensive subjects at
      baseline. The study group comprised 4,857 normotensive subjects not treated with
      antihypertensive drugs (systolic BP < 140 mmHg, diastolic BP < 90 mmHg, 3,111 men
      and 1,746 women) who were followed up from 1997 to 1999. By 1999, 360 subjects
      had BP at the hypertensive level (systolic BP > or = 140 mmHg or diastolic BP >
      or = 90 mmHg). The incidence of subjects whose BP became hypertensive was 37 per
      1,000 person-years. After adjusting for age, sex, systolic BP and other clinical
      factors, multiple logistic analysis showed that the relative risk of BP elevation
      was 1.49 (95% Cl: 1.09 to 2.05) in subjects with one risk factor; 1.65 (95% Cl:
      1.15 to 2.27) in those with two risk factors; 1.42 (95% Cl: 0.91 to 2.32) in
      those with three; and 4.86 (95% Cl: 2.58 to 9.16) in those with four or more when
      compared with subjects with no risk factors. Multiple regression analysis showed
      that the number of risk factors was positively correlated with an increase in BP
      from 1997 to 1999; the regression coefficient was 0.51 (p = 0.001) for increase
      in systolic BP, and 0.31 (p = 0.008) for increase in diastolic BP after adjusting
      for age and sex. In conclusion, clustering of risk factors significantly
      predicted the development of hypertension.

PMID- 12484503
TI  - Possible roles of angiotensin II-forming enzymes, angiotensin converting enzyme
      and chymase-like enzyme, in the human aneurysmal aorta.
AB  - Aortic aneurysm is a chronic degenerative condition associated with
      atherosclerosis. Recent studies have revealed that angiotensin (Ang) II plays
      important roles in atherosclerosis. In this study, to investigate the
      relationship between aortic aneurysm and Ang II, we measured the activities of
      the angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and
      chymase-like enzyme, in human aneurysmal and control aortae. Aneurysmal aortic
      specimens were obtained from 16 aneurysm patients and control aortic specimens
      were obtained from 16 patients who underwent coronary artery bypass surgery (8
      patients in each group were administered ACE inhibitors). The ACE and chymase
      like enzyme activities were determined using extracts from vascular tissues. Both
      the ACE and chymase-like enzyme activities in the aneurysmal aortae were
      significantly higher than those in the control aortae (p < 0.01). In the patients
      treated with ACE inhibitors, the ACE activity in the aneurysmal aortae tended to
      be low, but the chymase-like enzyme activity tended to be high. In the aneurysmal
      aortae, the chymase-like enzyme activity in the adventitia was significantly
      higher than that in the intimal or medial layers (p < 0.01), while differences in
      ACE activity were not observed. Our results suggest that increases in local Ang
      II formation induced by chymase-like enzymes may play important roles in the
      pathogenesis of aneurysmal formation.

PMID- 12484504
TI  - Long-term treatment with eicosapentaenoic acid improves exercise-induced
      vasodilation in patients with coronary artery disease.
AB  - We have previously shown that long-term treatment with eicosapentaenoic acid
      (EPA) improves endothelium-dependent vasodilation of the atherosclerotic arteries
      in both animals and humans. The aim of the present study was to examine whether
      EPA treatment also improves metabolic vasodilation evoked by exercise in patients
      with coronary artery disease (CAD). Forearm blood flow (FBF) was measured by
      strain gauge plethysmography in 10 patients with stable CAD, before and 3 months
      after oral treatment with EPA (1,800 mg/kg). FBF was measured at rest and during
      intra-arterial infusion of acetylcholine or sodium nitroprusside, before and
      after intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA, an inhibitor
      of nitric oxide (NO) synthesis). A rhythmic handgrip exercise was also performed
      for 3 min before and after L-NMMA, and FBF was measured for 3 min just after the
      handgrip exercise. These protocols were repeated after the long-term treatment
      with EPA for 3 months. The long-term treatment with EPA significantly improved
      the FBF responses to acetylcholine (p < 0.01), which was significantly reduced by
      acute administration of L-NMMA (p < 0.01). By contrast, the EPA treatment did not
      affect the endothelium-independent responses to sodium nitroprusside. Metabolic
      increases in FBF caused by the handgrip exercise were not significantly decreased
      by L-NMMA before the EPA treatment. The EPA treatment significantly augmented the
      exercise-induced increases in FBF (p < 0.05) and L-NMMA acutely abolished this
      augmentation (p < 0.01). These results indicate that long-term treatment with EPA
      improves both endothelium-dependent and exercise-induced forearm vasodilations in
      patients with CAD and that NO is substantially involved in the EPA-induced
      improvement of the FBF responses in patients with CAD.

PMID- 12484505
TI  - Role of genetic polymorphism in the SA gene on the blood pressure and prognosis
      of renal function in patients with immunoglobulin A nephropathy.
AB  - The SA gene has been shown to be much more highly expressed in the kidneys of
      spontaneously hypertensive rats than in the corresponding wild-type strain.
      Genetic polymorphism of this gene has been shown to play a role in human
      hypertension, although the details of this association remain controversial. We
      investigated the possible associations between SA gene polymorphism and both
      hypertension and the prognosis of renal function in patients with immunoglobulin
      A nephropathy (IgAN). Genomic DNA was isolated from the peripheral blood of 367
      individuals, including 274 patients with histologically proven IgAN and 100
      controls without any history of renal disease. The SA genotype was determined by
      polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP)
      with Pst I. The frequencies of genotypes and alleles were not different between
      the patients with IgAN and those without renal disease. In the group without
      renal disease, the SA gene polymorphism was not associated with hypertension.
      However, in the patients with IgAN the A1 allele frequency was significantly
      higher in the hypertensives than in the normotensives. The renal survival of the
      patients with the A2 allele tended to be better than that of those without the A2
      allele. The findings thus suggest that SA gene polymorphism may be associated
      with the renal prognosis of IgAN through its effect on blood pressure. Further,
      they suggest that the sensitivity to this gene polymorphism increases in patients
      with renal injury.

PMID- 12484506
TI  - Relative long-term effects of spironolactone in conjunction with an angiotensin
      converting enzyme inhibitor on left ventricular mass and diastolic function in
      patients with essential hypertension.
AB  - It has been reported that treatment with an angiotensin-converting enzyme (ACE)
      inhibitor is not adequate to suppress aldosterone, and we previously demonstrated
      that adding spironolactone to an ACE inhibitor may have beneficial effects on
      left ventricular hypertrophy (LVH) in selected patients with essential
      hypertension (EH). We have extended our previous short-term study, and addressed
      the relative long-term clinical effects of spironolactone and an ACE inhibitor in
      patients with EH who have LVH. Twenty patients with EH and concomitant LVH
      participated in this study. Subjects were treated with either an ACE inhibitor
      alone (group 1: 10 patients) or an ACE inhibitor plus spironolactone at the dose
      of 25 mg (group 2: 10 patients) for 60 weeks. The baseline clinical and
      echocardiographic characteristics of the two groups were similar. Final values of
      blood pressure were also similar between the two groups. The LV mass index (LVMI)
      decreased significantly in both groups, but the extent of reduction was
      significantly greater in group 2 at 60 weeks. The early peak to atrial peak
      filling velosities ratio (E/A ratio) was significantly increased to a similar
      extent in both groups. Serum procollagen type III amino-terminal peptide (PIIINP)
      was significantly decreased in group 2, but not in group 1. In group 2, there was
      a statistically significant correlation between the changes in LVMI and PIIINP.
      In conclusion, adding spironolactone to therapy with an ACE inhibitor for 60
      weeks may have beneficial effects in patients with EH and concomitant LVH. Our
      study strongly suggests the possibility that attenuation of the effects of
      cardiac aldosterone in patients with EH by treatment with spironolactone and an
      ACE inhibitor may become a new goal for the prevention and regression of cardiac
      hypertrophy.

PMID- 12484507
TI  - Polymorphism of the angiotensin converting enzyme gene and blood pressure in a
      Japanese general population (the Shigaraki Study).
AB  - Recent studies have described a linkage between angiotensin converting enzyme
      (ACE) gene polymorphism and hypertension in a large number of hypertensive sibs.
      Moreover, among Japanese, the DD genotype of the ACE gene has been reported to be
      a genetically predisposing factor for hypertension in a large general population.
      However, there is some controversy regarding the association between the ACE
      insertion/deletion (I/D) polymorphism and systemic hypertension. Therefore, we
      examined the influence of the ACE I/D polymorphism in a random Japanese
      population. The participants were 2,892 subjects (1,110 males: mean age, 58.4 +/-
      15.5; 1,782 females: mean age, 56.2 +/- 15.7) who underwent medical examinations
      in 1999 in Shigaraki, a suburban town located in an urban area in Shiga
      prefecture. Among them, 2,395 subjects (917 males: mean age, 58.0 +/- 15.7; 1478
      females: mean age, 56.3 +/- 15.6) who gave their informed consent for genetic
      analysis were enrolled in the present study. Every year since 1991, we have
      repeatedly performed medical examinations in Shigaraki. ACE genotypes were
      determined by polymerase chain reaction (PCR) methods. Logistic analysis revealed
      that age (p < 0.001; odds ratio = 1.091), body mass index (BMI) (p < 0.001; odds
      ratio = 1.211), and family history of hypertension (p < 0.001; odds ratio =
      0.371) were associated with hypertension (systolic blood pressure greater than
      140 mmHg and diastolic greater than 90 mmHg). There was no association between
      ACE polymorphism and blood pressure. There were also no significant differences
      in blood pressure among males or females across the three genotypes. Moreover, in
      an analysis of 1,484 subjects (549 males: mean age, 62.8 +/- 12.1; 935 females:
      mean age, 61.2 +/- 12.6) who were followed-up since 1991, there was no
      association between ACE polymorphism and changes in blood pressure (p = 0.3905).
      We conclude that ACE polymorphism does not appear to have any significant
      association with blood pressure, changes in blood pressure or sex in Japanese
      subjects, who have a more homogeneous genetic background than any other group
      reported to date.

PMID- 12484509
TI  - Epidemiologic study of the association of low-Km mitochondrial acetaldehyde
      dehydrogenase genotypes with blood pressure level and the prevalence of
      hypertension in a general population.
AB  - In Japanese and other Asians, the prevalence of genetically decreased
      mitochondrial aldehyde dehydrogenase (ALDH2) activity is higher than in
      Caucasians. The aim of this study was to elucidate the relation between ALDH2
      genotypes and blood pressure levels or hypertension in Japanese. After obtaining
      informed consent for genetic analysis from 917 men and 1,478 women who lived in a
      mountainous farming region near Kyoto and who were free from cardiovascular
      disease and liver dysfunction, the authors identified the ALDH2 genotype in all
      subjects. Differences in blood pressure level among genotypes were then compared
      by analysis of covariance, and the relation between genotypes and hypertension
      was also analyzed by logistic regression analysis. The frequencies of genotypes
      *1/*1, *1/*2, and *2/*2 were 44.7%, 46.9% and 8.4% in men, and 50.1%, 43.2% and
      6.8% in women, respectively. In men, systolic and diastolic blood pressures
      tended to decrease in the order of *1/*1>*1/*2>*2/*2. However, adjustment for
      confounding factors including alcohol consumption resulted in the disappearance
      of significance. Logistic regression analysis adjusted for the same confounding
      factors for men showed that the odds ratios (OR) of being hypertensive in the *2
      allele to not having *2 allele were 0.67 (95% confidence interval (CI): 0.47
      0.96). However, in the subgroup analyses, this relation was not observed in the
      group having a below-median level of alcohol consumption (OR = 0.92; 95% CI: 0.53
      1.62) or in the group not taking antihypertensive agents (OR = 0.77; 95% CI: 0.52
      1.15). Furthermore, we did not observe any relation between the ALDH2/*2 allele
      and hypertension in women (OR = 1.07; 95% CI: 0.80-1.42). The results suggest
      that there may be no causal relation between hypertension and the ALDH2 genotype
      per se, after excluding for some confounding factors, especially for alcohol
      drinking.

PMID- 12484508
TI  - Antiproteinuric effects of combined antihypertensive therapies in patients with
      overt type 2 diabetic nephropathy.
AB  - Combined antihypertensive therapy plays a crucial role in achieving targeted
      blood pressure reductions and renoprotection. We therefore compared the
      antihypertensive and antiproteinuric effects of combined therapy with either a
      calcium channel blocker (CCB) plus an angiotensin II receptor blocker (ARB) or an
      angiotensin converting enzyme inhibitor (ACE-I) plus an ARB in patients with type
      2 diabetes mellitus complicated by overt nephropathy and mild to moderate
      hypertension. After a 12-week dietary control period, diabetic patients with
      mildly to moderately impaired renal function were randomly assigned to either a
      CCB (amlodipine 5 mg once daily) or an ACE-I (temocapril 2 mg once daily) for 12
      weeks (monotherapy period). Both groups then received add-on therapy with an ARB
      (candesartan 4 mg once daily) for an additional 12 weeks. During the monotherapy
      period, blood pressure was decreased equally well in both groups. Daily urinary
      protein excretion remained unchanged in the CCB-treated group (control period,
      4.0 +/- 1.8 g/day vs. CCB period, 4.1 +/- 1.9 g/day; ns; n = 8), but decreased in
      the ACE-I-treated group (control period, 4.3 +/- 1.8 g/day vs. ACE-I period, 3.5
      +/- 1.7 g/day; p < 0.05; n = 9). After the combined therapy period, blood
      pressure was decreased to the same degree in both groups. Although ARB plus CCB
      significantly reduced urinary protein excretion (to 3.5 +/- 1.5 g/day; p < 0.05
      vs. control period; n = 8), a more profound reduction was achieved with ARB plus
      ACE-I (to 2.6 +/- 1.3 g/day; p < 0.01 vs. control period; n = 9). Monotherapy
      with the ACE-I increased the serum potassium concentration, and this elevation
      was sustained after addition of the ARB. In contrast, the serum potassium
      concentration was not influenced by monotherapy with the CCB, but was
      significantly increased after addition of the ARB. A decreased hematocrit was
      observed in the ARB plus ACE-I group. The present study suggests that combined
      antihypertensive therapy with either a CCB plus an ARB or an ACE-I plus an ARB
      exerts an antiproteinuric effect in patients with type 2 diabetic nephropathy
      with mildly impaired renal function. Although the latter combination had a more
      profound effect, it was associated with an increased serum potassium
      concentration and worsening of renal anemia. Thus, the combination of a CCB and
      an ARB should be the first line antihypertensive therapy in those with overt
      diabetic nephropathy. The long-term efficacy of these combined antihypertensive
      therapies will need to be further addressed in a future study.

PMID- 12484510
TI  - Selection of the dose of angiotensin converting enzyme inhibitor for patients
      with diabetic nephropathy depends on the presence or absence of left ventricular
      hypertrophy.
AB  - The coexistence of hypertension increases cardiovascular risks and the rate of
      deterioration of renal function for diabetic patients. For patients with left
      ventricular hypertrophy (LVH), the use of an angiotensin converting enzyme (ACE)
      inhibitor is known to be effective and well tolerated and to be protective
      against chronic renal insufficiency (CRI). However, serious adverse reactions to
      ACE inhibitors, such as the rapid deterioration of renal function, have been
      reported, making physicians hesitant to use these agents. To resolve this
      dilemma, we compared changes in renal function and left ventricular function and
      the safety and effectiveness of benazepril, an ACE inhibitor, in patients with
      diabetic nephropathy, with or without LVH. The age, sex, duration of diabetes,
      levels of blood pressure and blood glucose and rates of creatinine clearance
      (CrCl) were compared between 36 diabetic patients with LVH and 36 matched
      diabetic patients without LVH. The rates of CrCl in all patients were between 14
      and 35 ml/min, and all patients received an ACE inhibitor before enrollment. The
      group comprised 43 men and 29 women, with a mean age of 56 +/- 4 years. These
      patients were divided into three groups, each of which was subdivided into a
      group with and a group without LVH. Group I (without LVH) or I-L (with LVH)
      received a half dose of benazepril (2.5 mg daily), Group II (without LVH) or II-L
      (with LVH) received a normal daily dose of 5 mg benazepril, and Group III
      (without LVH) or III-L (with LVH) discontinued the administration of the ACE
      inhibitor. The follow-up period was 1 year and, during the study, blood pressure
      was maintained at less than 140/90 mmHg. If the blood pressure control was not
      satisfactory, benidipine, a calcium antagonist, and/or furosemide, a loop
      diuretic, and/or guanabenz, a central acting antihypertensive agent, were
      administered. In the diabetic patients with LVH, the administration of a normal
      dose of benazepril inhibited the decline of renal function and cardiac function
      (CrCl: 24.2 +/- 1.5 to 22.0 +/- 2.5 ml/min; EF (ejection fraction): 56 +/- 3 to
      54 +/- 6%) compared to the other two groups. In patients without LVH, a half dose
      of benazepril preserved renal function (23.4 +/- 2.6 to 22.0 +/- 3.1 ml/min; EF:
      54 +/- 3 to 56 +/- 3%). Discontinuation of the administration of ACE inhibitor
      led to the further progression of renal dysfunction and decreases in EF in
      patients with or without LVH. Our results provide some indications for the use of
      ACE inhibitors in diabetic patients when renal dysfunction and/or cardiac
      hypertrophy are present.

PMID- 12484511
TI  - An interaction between systolic blood pressure and angiotensin-converting enzyme
      gene polymorphism on carotid atherosclerosis.
AB  - The insertion/deletion (I/D) polymorphism of the human angiotensin-converting
      enzyme (ACE) gene is a major determinant of circulating ACE activity, with the D
      allele being associated with higher ACE levels than the I allele. Thus, chronic
      exposure to high levels of circulating and tissue ACE may well predispose to
      vascular wall thickening and atherosclerosis. However, the effect of the ACE gene
      on carotid atherosclerosis remains controversial. We investigated the association
      between ACE gene I/D polymorphism and risk factor-dependent augmentation of
      carotid arterial remodeling in subjects with several risk factors for
      atherosclerosis. We evaluated sclerotic lesions of the common carotid artery with
      intima-media thickness (IMT) by ultrasonography in 184 patients (mean age +/- SD,
      67 +/- 14 years old) and studied whether any risk factor-gene interactions were
      associated with carotid atherosclerosis. Out of the 184 subjects, 71 had the ACE
      II genotype, 87 the ID genotype and 26 the DD genotype. There was no significant
      difference in IMT among the three ACE genotypes. In total subjects, multiple
      regression analysis showed that age, total-cholesterol (T-C), and HDL-cholesterol
      (HDL-C) were significantly associated with IMT. However, the association between
      risk factors and IMT was genotype-specific. Systolic blood pressure (SBP) and HDL
      C were significantly associated with IMT in ACE D carriers (DD+ID), but not in
      subjects with the ACE II genotype. Similarly, T-C was significantly associated
      with IMT only in subjects with the ACE II genotype. A general linear model of the
      interaction between the ACE genotype and the conventional risk factors showed
      that the SBP-ACE genotype interaction were significantly associated with IMT (F =
      7.915; p = 0.005). This finding further supports the idea that analysis of risk
      factor-gene interaction could be a useful tool for deriving specific predictive
      information about the development of atherosclerosis.

PMID- 12484512
TI  - Relationship between changes in serum leptin levels and blood pressure after
      weight loss.
AB  - Insulin resistance is thought to raise blood pressure. Recently, a significant
      positive relationship between mean blood pressure and plasma leptin levels, but
      there have been no reports dealing with the relationship between blood pressure
      and either insulin resistance or serum leptin levels after weight loss. In the
      present work, we attempted to clarify the relationship between changes in blood
      pressure and either the serum leptin level or the insulin level in 102 moderately
      obese females (mean body mass index (BMI), 29.5 +/- 0.5 kg/m2; age, 47.0 +/- 0.9)
      during a 3 month period. No differences in age, fat-mass, homeostasis model
      assessment (HOMA), the summation of insulin (sigmaIRI), plasma renin activity
      (PRA) or 24 h norepinephrine excretion (24hU-NE) were observed between the
      hypertensive (HT) group (n = 31) and normotensive (NT) group (n = 71) before
      weight loss, but the basal serum leptin was significantly higher in the HT (16.8
      +/- 1.1 ng/ml) than in the NT group (15.2 +/- 0.8 ng/ml), after adjusting for
      abdominal total fat. After a 3 month weight reduction program, the total
      abdominal fat, serum leptin and sigmaIRI significantly decreased in both groups.
      The systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly
      decreased from 144/84 to 130/77 mmHg only in the HT but not in the NT group. The
      PRA decreased in both groups, while the 24hU-NE significantly decreased only in
      the HT group. The changes in the leptin level were significantly correlated with
      the changes in both sigmaIRI and HOMA after weight loss in the two groups,
      respectively. Finally, a statistically significant positive correlation was
      observed between the changes in the leptin and the changes in the mean blood
      pressure (MBP) (r = 0.412, p < 0.05) only in the HT group. Multiple regression
      analysis revealed that the changes in MBP were independently associated with the
      changes in 24hU-NE and the changes in either sigmaIRI or HOMA in all subjects.
      However, a statistically significant positive correlation was observed between
      the changes in MBP and the changes in leptin levels even after adjusting for the
      total abdominal fat, 24hU-NE and either sigmaIRI or HOMA (both expressed as a
      percentage of the baseline value) in a multiple regression analysis only in the
      HT group. These results suggest that leptin may play a role in the
      pathophysiology of obese hypertension.

PMID- 12484513
TI  - Plasma levels of adrenomedullin and atrial and brain natriuretic peptides in the
      general population: their relations to age and pulse pressure.
AB  - Adrenomedullin (AM) and atrial and brain natriuretic peptides (ANP and BNP) exert
      vasodilator and natriuretic actions and are thought to share roles in
      counteracting the progression of hypertension or heart failure as circulating or
      locally-acting hormones. However, little data is available with regard to their
      roles in subjects who have no apparent cardiovascular diseases. The present study
      was carried out to identify the factors that affect plasma levels of AM, ANP and
      BNP in the general population. We measured the plasma levels of AM, ANP and BNP
      in 184 local residents who had a scheduled regular health checkup, and compared
      the findings with those for other clinical parameters. Univariate analyses showed
      that the plasma levels of AM, ANP and BNP were significantly correlated with age.
      The plasma levels of ANP and BNP were also significantly correlated with systolic
      blood pressure (SBP) and with pulse pressure (PP), an indicator of the stiffness
      of the great vessels. Multivariate analyses conducted using a stepwise method
      revealed that age was a significant, independent variable for the plasma levels
      of AM, ANP and BNP. In addition, PP was a significant factor for the plasma
      levels of ANP and BNP, while the plasma AM was significantly associated with body
      mass index (BMI). Thus, the plasma levels of AM, ANP and BNP all increased in
      association with aging, and those of ANP and BNP increased in association with
      PP, suggesting possible relationships between the plasma levels and age-related
      changes in the cardiovascular system.

PMID- 12484514
TI  - Hypertension attenuates the efficacy of hypoglycemic therapy for preserving
      coronary flow reserve in patients with type 2 diabetes.
AB  - Impairment of coronary flow reserve (CFR) in patients with type 2 diabetes has
      been generally demonstrated; however, there have been few studies investigating
      CFR in cases of relatively well-controlled diabetes, in distinction to the
      influence of hypertension. The purpose of the present study was to evaluate the
      influence of diabetes and hypertension upon CFR in relatively well-controlled
      patients. This study included 12 healthy controls (C group) and 57 patients with
      type 2 diabetes (DM) and/or essential hypertension who were divided into three
      groups as follows: patients with DM (DM group; n = 24), patients with essential
      hypertension (HT group; n = 15), and patients with both DM and essential
      hypertension (DM+HT group; n = 18). We excluded patients with evidence of
      coronary artery disease and/or left ventricular hypertrophy. We performed
      transthoracic Doppler recording of diastolic coronary flow velocity (CFV) in the
      left anterior descending coronary artery at rest and after maximal vasodilation
      by adenosine infusion (140 microg/kg/min for 3 min) CFR was defined as the ratio
      of hyperemic to averaged basal peak CFV. The CFR (2.92 +/- 0.46) of the DM group
      was not decreased compared to that of the C group (2.96 +/- 0.58), although the
      CFR of the HT (2.33 +/- 0.25) and DM+HT (2.35 +/- 0.25) groups were significantly
      reduced. Left ventricular mass index, relative wall thickness, and diastolic
      function were worse in the HT and DM+HT groups than in the C and DM groups.
      Subjects with concentric left ventricular remodeling had a lower CFR than those
      with normal left ventricular geometry. In conclusion, adequate hyperglycemic
      control prevented the progression of coronary microcirculatory disturbance, but
      concomitant hypertension attenuated the effect.

PMID- 12484515
TI  - Distinct modulation of superficial and juxtamedullary arterioles by prostaglandin
      in vivo.
AB  - Renal afferent (AFF) and efferent arteriolar (EFF) responsiveness to angiotensin
      II (ANG II) in superficial and juxtamedullary nephrons in vivo remains
      undetermined, nor has it been clarified what role intrarenal
      autocrines/paracrines play in modulating the renal microvascular response. The
      present study characterized the responsiveness to ANG II (1-30 ng/kg/min) of AFF
      and EFF of canine superficial and juxtamedullary nephrons under pentobarbital
      anesthesia, using intravital CCD-videomicroscopy that allowed direct in vivo
      visualization of the renal microcirculation. Furthermore, the effect of
      prostaglandins (PG) and nitric oxide (NO) on ANG II-induced tone was examined. In
      superficial nephrons, ANG II induced a similar dose-dependent constriction of
      both AFF (46 +/- 5% constriction) and EFF (53 +/- 3%). In juxtamedullary
      arterioles, ANG II induced a dose-dependent constriction of EFF, whereas AFF
      responses were diminished (17 +/- 4% vs. 37 +/- 4% at 10 ng/kg/min). The PG
      inhibition by indomethacin enhanced the ANG II-induced constriction of
      juxtamedullary AFF, whereas no augmentation was observed in other arterioles. In
      contrast, NO inhibition by nitro-L-arginine methylester (L-NAME) enhanced the ANG
      II-induced constriction, with greater augmentation in juxtamedullary AFF and EFF.
      Finally, renal interstitial PG and nitrite/nitrate contents were greater in the
      medulla than the superficial cortex under basal and ANG II-stimulated conditions.
      Taken together, the results of the intravital CCD-videomicroscopy reveal that the
      renal microvascular action of ANG II had both zonal (juxtamedullary vs.
      superficial nephrons) and segmental (AFF vs. EFF) heterogeneity under the present
      experimental conditions. This heterogeneity was associated with a difference in
      the intrarenal production of prostaglandin E2 (PGE2) and NO; PGE2 contributed to
      segmental and zonal differences whereas NO was responsible for the zonal
      heterogeneity in arteriolar responsiveness.

PMID- 12484516
TI  - Transforming growth factor-beta expression in cardiovascular organs in stroke
      prone spontaneously hypertensive rats with the development of hypertension.
AB  - Transforming growth factor (TGF)-beta activity is involved in several
      cardiovascular diseases owing to its effects on the growth of vascular smooth
      muscle cells and induction of extracellular matrix formation. We evaluated
      expression of TGF-beta in cardiovascular organs from stroke-prone spontaneously
      hypertensive rats (SHR-SP) which show severe cardiovascular damages with the
      development of hypertension. Twelve-week-old Wistar-Kyoto (WKY)/Izm rats and SHR
      SP/Izm were loaded with 1% salt for 4 weeks. Aorta, heart and kidney were removed
      and evaluated histologically by hematoxylin-eosin staining. Expression of TGF
      beta1 mRNA was evaluated by reverse transcription and polymerase chain reaction
      analysis in mRNA extracted with oligo dT-cellulose. Expression of TGF-beta1
      protein was evaluated by Western blot analysis and immunohistochemical study in
      renal cortex. Whereas expression of TGF-beta1 mRNA was detected only in the heart
      of SHR-SP before salt loading, it was detected in the aorta, left ventricle of
      heart and renal cortex from both rat strains, and it was stronger in the renal
      cortex of SHR-SP than in the renal cortex of WKY rats. Expression of TGF-beta1
      protein was markedly higher in the renal cortex of SHR-SP than in the renal
      cortex of WKY rats after salt loading. TGF-beta was localized at glomeruli and
      capillary arteries in the renal cortex, and immunostaining was stronger in SHR-SP
      than in WKY rats. Expression of TGF-beta1 was increased in glomeruli and
      capillaries of the renal cortex with the development of hypertension in SHR-SP.
      These results implicate TGF-beta in the renal damage observed in hypertension.

PMID- 12484517
TI  - Impact of exercise and angiotensin converting enzyme inhibition on tumor necrosis
      factor-alpha and leptin in fructose-fed hypertensive rats.
AB  - The aim of this study was to evaluate the effects of moderate-intensity regular
      exercise and/or an angiotensin converting enzyme (ACE) inhibition on tumor
      necrosis factor-alpha (TNF-alpha) and glucose and lipid metabolism parameters.
      Spontaneously hypertensive rats (SHRs) were fed a fructose-rich diet during 16
      weeks of either exercise training (Ex group: 20 m/min, 0% grade, 60 min/day, 5
      days/week), administration of an ACE inhibitor (TM group: temocapril, 10
      mg/kg/day), or a combination of both (TM+Ex group). The systolic blood pressure
      was reduced exclusively in the TM and TM+Ex group. Epididymal fat pads (EPI)
      weighed less in the TM+Ex group than in the single-treatment (TM) group. The
      serum leptin level was significantly and directly correlated with the EPI weight
      (p < 0.001). The TNF-alpha content per gram of EPI was the highest in the TM+Ex
      group. In addition, the EPI TNF-alpha level was negatively correlated with both
      the EPI weight and the serum leptin level (p < 0.001, respectively). In contrast,
      the TNF-alpha level of skeletal muscles was identical among the groups. The
      extensor digitorum longus had a significantly higher abundance of TNF-alpha
      protein than the soleus muscle. These data indicate that the local TNF-alpha
      expression is tissue-specific, and that upregulation of TNF-alpha in EPI by
      exercise training and/or ACE inhibition may have contributed to the reduction in
      fat cell volume via the induction of apoptosis and/or the regulation of metabolic
      homeostasis.

PMID- 12484518
TI  - Cyclooxygenase-2 inhibitors attenuate increased blood pressure in renovascular
      hypertensive models, but not in deoxycorticosterone-salt hypertension.
AB  - COX-2 is an inducible cyclooxygenase (COX) that has been reported to be expressed
      in the macula densa and surrounding cortical thick ascending limb in normotensive
      rats. The present study assessed the contribution of COX-2 in three different rat
      models of hypertension, each characterized by a different activation of the renal
      renin-angiotensin system. Mean blood pressure (MBP) in the rat 2 kidney-1 clip
      (2K1C) model was significantly reduced with a COX-2 selective inhibitor, NS-398
      (10 mg/kg, p.o., twice a day) (vehicle-administered rats (n = 8): 154 +/- 6 mmHg;
      NS-398-administered rats (n = 5): 128 +/- 10 mmHg). By contrast, a COX-1
      selective inhibitor, mofezolac, did not lower MBP. Increased plasma renin
      activity (23 +/- 8 ng/kg/h (n = 6) vs. sham operation, 2.4 +/- 0.9 ng/kg/h (n =
      4)) was markedly reduced to 6.8 +/- 2.7 ng/ml/h (n = 5) by NS-398, but not by
      mofezolac. The development of 1 kidney-1 clip (1K1C) hypertension was also
      inhibited by NS-398 (vehicle (n = 12): 133 +/- 1 mmHg; NS-398 (n = 7): 122 +/- 3
      mmHg) accompanied by a reduction in plasma renin activity (3.0 +/- 0.3 ng/ml/h, n
      = 4) to 1.0 +/- 0.2 ng/ml/h (n = 5). The COX-2 inhibitor increased urinary
      excretions in the 1K1C model, but not in the 2K1C model. In a deoxycorticosterone
      acetate (DOCA)-salt model, plasma renin activity was markedly suppressed to less
      than 0.3 ng/ml/h. The COX-2 inhibitor caused no significant changes in MBP,
      plasma renin activity, or urinary excretion, suggesting that COX-2 made a lesser
      contribution in this model. Increased expression of COX-2 mRNA and protein was
      observed in the kidneys of 1K1C and 2K1C rats, but not in DOCA-salt rats. These
      results suggest that COX-2 plays a significant role in the development of 2K1C
      and 1K1C renovascular hypertension, in addition to making a substantial
      contribution to the diuretic effect in the 1K1C model.

PMID- 12484519
TI  - The effects of antihypertensive agents on the survival rate of polycystic kidney
      disease in Han:SPRD rats.
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is the most common
      hereditary renal disorder in humans. Hypertension is one of the major
      complications, and its control might affect the renal survival and disease
      mortality. Suitable antihypertensive agents have been discussed based on clinical
      and animal studies, but no definitive conclusion has been reached. Generally,
      therefore, all antihypertensives are indiscriminately treated as if providing the
      same level of blood pressure control. In this study, the blood pressure control
      of two antihypertensives was investigated using a rat model of ADPKD in humans.
      Twenty-four male Hannover-Sprague Dawley (Han:SPRD) rats were divided into three
      groups: a group receiving amlodipine (6 mg/day), a group receiving benazepril (6
      mg/day) and an untreated control group. Blood pressure, body weight, and urinary
      protein excretion were regularly measured up to week 52. Amlodipine and
      benazepril significantly decreased blood pressure and urinary protein excretion
      to the same degree. Moreover, a remarkably prolonged survival rate was observed
      in both groups (at week 52, the survival rate was 25% in controls, 50% in the
      amlodipine group, and 50% in the benazepril group). Examination at autopsy
      revealed that enlarged cysts were prevalent in the renal tissue of both
      experimental all three groups, suggesting that the cystic disease had reached the
      end-stage in all the animals. In conclusion, both amlodipine and benazepril
      significantly improved blood pressure control, urinary protein excretion, and
      survival rate, possibly due to their enhancement of renal survival.

PMID- 12484520
TI  - Successfully treated "accelerated" renovascular hypertension with intravascular
      stenting.
AB  - A 76-year-old man developed progressive renal dysfunction with refractory
      hypertension. Bilateral renal artery stenosis due to atherosclerosis was
      revealed. Both the hypertension and renal dysfunction were improved by
      percutaneous transluminal renal angioplasty with stenting. Based on the rapidly
      progressive elevation of plasma renin activity and the improvement of both renal
      dysfunction and hypertension after stenting, this was considered a case of
      "accelerated" renovascular hypertension. There have been an increasing number of
      patients with bilateral renal artery stenosis due to atherosclerosis. The present
      case reminds us that a rapid progression of renal dysfunction suggests, in
      addition to besides rapidly progressive glomerulonephritis with crescent
      formation, bilateral renal artery stenosis, the incidence of which is on the
      rise. In the present case, angioplasty with stenting was effective for blood
      pressure control and preservation of renal function.

PMID- 12484521
TI  - Alu-repeat polymorphism in the gene coding for tissue-type plasminogen activator
      and the risk of hypertension in a Chinese Han population.
AB  - Accumulating data support an association between hypertension and impaired
      fibrinolytic potential abnormalities in endogenous fibrinolysis. The present
      study examined whether there was an association between essential hypertension
      and either a polymorphism in the gene coding for t-PA or the plasma concentration
      of t-PA antigen. Chinese hypertensive subjects (n = 126) and normotensive
      controls (n = 102; sex- and age-matched with hypertensives) were recruited from
      among the outpatients of FuWai Hospital. The distributions of the II, ID, and DD
      genotypes of the t-PA gene in hypertensive patients (0.15, 0.49, 0.36) were
      similar to those in control subjects (0.11, 0.51, 0.38; p = 0.626). No
      significant difference in overall allele frequencies was found between the
      hypertension and control groups (p = 0.656). The allelic frequencies were in
      Hardy-Weinberg equilibrium. There was no evidence of an association between the
      level of t-PA antigen and risk of hypertension. Thus, in this case control study,
      neither the presence of the insertion allele of the Alu-repeat polymorphism of
      the t-PA nor the level of t-PA antigen were associated with the risk of essential
      hypertension.

PMID- 12484522
TI  - Genetic sexing strains in medfly, Ceratitis capitata, sterile insect technique
      programmes.
AB  - The introduction of genetic sexing strains (GSS) into medfly, Ceratitis capitata
      (Wiedemann), sterile insect technique (SIT) programmes started in 1994 and it was
      accompanied by extensive evaluation of the strains both in field cages and in
      open field situations. Two male-linked translocation systems, one based on pupal
      colour, wp, and the other based on temperature sensitivity, tsl, have been used
      in medfly SIT programmes and they have quite different impacts on mass rearing
      strategy. In strains based on tsl, female zygotes are killed using high
      temperature and for wp strains, female and male pupae are separated based on
      their colour. In all these systems the colony females are homozygous for the
      mutation requiring that the mutation is not too deleterious and the males are
      also semi-sterile due to the presence of a male-linked translocation. Managing
      strain stability during large-scale mass rearing has presented some problems that
      have been essentially solved by selecting particular translocations for GSS and
      by the introduction of a filter rearing system (FRS). The FRS operates by
      removing from the colony any recombinant individuals that threaten the integrity
      of the strain. The use of GSS opens up the possibility of using the SIT for
      suppression as opposed to eradication and different radiation strategies can be
      considered. Some of the many field trials of the strains that were carried out
      before the strains were introduced into operational programmes are reviewed and
      an overview is given of their current use.

PMID- 12484523
TI  - Sex determination in flies, fruitflies and butterflies.
AB  - Sex determination mechanisms, differing in their modality, are widely represented
      in all the various animal taxa, even at the intraspecific level. Within the
      highly diversified Class Insecta, Drosophila has been used to unravel the
      mechanistic molecular and genetic interactions that are involved in sex
      determination. Indeed, the molecularly characterized genes of the Drosophila sex
      determination hierarchy X:A > Sxl > tra > dsx have been fruitful starting points
      in the cloning of homologous genes from other insect species. This cascade seems
      to control sex determination in all Drosophila species. However, no sex-specific
      regulatory Sxl homologues have been isolated from the Mediterranean fruitfly
      (medfly), Ceratitis capitata, the housefly, Musca domestica, Chrysomya rufifacies
      nor from the distantly related phorid fly Megaselia scalaris. Moreover, all these
      other species use primary signals different from the intricate X:A counting
      system of Drosophila. However, dsx homologues isolated from these and other
      dipteran species as well as from the silkmoth, Bombyx mori, share a conserved sex
      specific regulation based on alternative splicing. An understanding of the sex
      determination mechanisms in insects that are of agricultural or public health
      importance may help in the development of improved methods for their control
      using the sterile insect technique.

PMID- 12484524
TI  - The evolution of sex determination systems in dipteran insects other than
      Drosophila.
AB  - The multitude of sex determination mechanisms displayed in dipteran insects has
      usually been described in terms of variations on a single principle in which the
      primary signal of the primitive pathway consists of a single allelic difference
      at one locus. Evolution of sex determination mechanisms is thought to have
      occurred by the addition of genes below the top gene of the pathway. The
      elucidation of the complex sex determination pathway of Drosophila melanogaster,
      as well as recent evidence that the basal genes of the pathway seem to be
      conserved across metazoan genera both in structure and, to a lesser degree, in
      function, points towards the possibility that sex determination pathways may have
      evolved from the bottom-up. Further to this is the question of whether the
      dominant male-determining factor, M, which is found in a number of insect
      species, represents part of the ancient sex determination pathway or is a later
      addition to the pathway. This, together with the possibility that the M factors
      found in numerous dipteran insect species may have a common origin, is discussed.
      The similarities of the sex determination pathways under the control of M and the
      implications in relation to the construction of genetic sexing strains for
      biological control are also discussed.

PMID- 12484525
TI  - Genetic and cytogenetic analysis of the olive fruit fly Bactrocera oleae
      (Diptera: Tephritidae).
AB  - The genetic and cytogenetic characteristics of one of the major agricultural
      pests, the olive fruit fly Bactmcera oleae, are presented here. The mitotic
      metaphase complement of this insect consists of six pairs of chromosomes
      including one pair of heteromorphic sex chromosomes, with the male being the
      heterogametic sex. The analysis of the polytene complements of three larval
      tissues, the fat body, the salivary glands and the Malpighian tubules of this
      pest has shown (a) a total number of five long chromosomes (10 polytene arms)
      that correspond to the five autosomes of the mitotic nuclei and a heterochromatic
      mass corresponding to the sex chromosomes, (b) the constancy of the banding
      pattern of the three somatic tissues, (c) the absence of a typical chromocenter
      as an accumulation of heterochromatin, (d) the existence of reverse tandem
      duplications, and (e) the presence of toroid tips of the chromosome arms. The in
      situ hybridization of genes or DNA sequences to the salivary gland polytene
      chromosomes of B. oleae provided molecular markers for all five autosomes and
      permitted the establishment of chromosomal homologies among B. olea, B. tryoni
      and Ceratitis capitata. The heat shock response of B. oleae, as revealed by heat
      inducible puffing and protein pattern, shows a higher thermotolerance than
      Drosophila melanogaster.

PMID- 12484526
TI  - Polytene chromosomes as tools in the genetic analysis of the Mediterranean fruit
      fly, Ceratitis capitata.

PMID- 12484527
TI  - Recombination between homologous autosomes in medfly (Ceratitis capitata) males:
      type-1 recombination and the implications for the stability of genetic sexing
      strains.
AB  - The sterile insect technique (SIT) is an environmentally safe technology to
      control insect pests. To improve this technology, genetic sexing strains (GSS)
      have been developed for the Mediterranean fruit fly, Ceratitis capitata. Such
      strains are based on Y-autosome translocations linking a selectable marker to the
      male sex and their long-term stability, especially under large-scale mass rearing
      conditions, is threatened by genetic recombination in the heterozygous males. We
      have measured male recombination in order to be able to construct GSS that are
      more stable. Our results show that male recombination occurs at very low
      frequencies, that is, below 1% per generation. Furthermore, recombination in
      medfly males occurs premeiotically. By selecting strains where the Y-autosome
      translocation breakpoint and the selectable marker are closely linked, the
      deleterious effects of recombination on the stability of GSS can be minimized. In
      such strains recombination is reduced by ca. 80% as compared to previously
      studied GSS. Although recombinants still occur at very low frequencies they still
      pose a threat to the integrity of the sexing system if they possess a selective
      advantage. Under mass rearing condition such recombinants will accumulate
      according to their relative fitness and additional measures, such as improved
      mass rearing strategies, are required to preserve the accuracy of the sexing
      system. As a conclusion it is shown that current GSS are stable enough to allow
      mass rearing at levels exceeding 1000 million male medflies per week.

PMID- 12484528
TI  - Genetic stability of sexing strains based on the locus sw of Ceratitis capitata.
AB  - This report deals with the process of improving the stability of medfly,
      Ceratitis capitata, genetic sexing strains (GSS) based on the sw mutation on
      chromosome 2. This gene affects the rate of development as well as the eye colour
      and iridescence. The improved sexing strains were produced by mapping sw with
      deletions and then inducing and screening for new translocations with breakpoints
      close to the marker. The stability was assessed in large populations over many
      generations. Twenty-two new Y-2 translocations were identified and polytene
      chromosome analysis was performed to locate breakpoints. The translocation
      strains were ranked according to the distance of their breakpoints from sw. The
      map position of sw is region 20D on 2R. As data on the stability of the 22
      strains accumulated, Cast 191 was shown to be the most promising as no
      recombination between sw and the male sex was found. After rearing the strain for
      22 generations under semi-mass rearing conditions, with a population size of
      15,000 adults and scoring 1000 flies per generation, only one such event was
      detected (estimated frequency = 3.1 x 10(-6)). Further tests are being carried
      out with this strain to assess its suitability as a genetic sexing strain for
      medfly Sterile insect technique (SIT).

PMID- 12484529
TI  - Towards a male-only release system for SIT with the Queensland fruit fly,
      Bactrocera tryoni, using a genetic sexing strain with a temperature-sensitive
      lethal mutation.
AB  - Flies that are homozygous for the recessive autosomal mutation bent wings have a
      limited ability to fly and are less tolerant of high temperatures than normal
      flies in both the egg and puparial stages. The differences between the mutant and
      normal flies were found sufficient to be the basis of a genetic sexing strain.
      Genetic sexing strains were created using translocations of the autosome bearing
      the wild-type allele of bent wings (chromosome 2) to the Y chromosome, and
      crossing male flies carrying the translocation to mutant bent wings females. In
      the resulting strain, the females were homozygous for the bent wings mutation and
      the males were phenotypically normal for wing characters. Several translocations
      were recovered after irradiation, but only one translocation involving chromosome
      2 was both stable and expressed in a stock that was vigorous enough for long-term
      viability. Unfortunately, all stocks containing the translocation showed high
      levels of temperature-dependent lethality, including, inexplicably, both males
      and females. Translocation stocks showing this effect included bent wings,
      another second chromosome mutation, white marks, and an otherwise normal stock.
      This phenomenon is probably rare, as it has not been reported before. It is
      likely that bent wings could be suitably used with another translocation.

PMID- 12484530
TI  - Mass rearing of temperature sensitive genetic sexing strains in the Mediterranean
      fruit fly (Ceratitis capitata).
AB  - Genetic sexing strains (GSS) based on the temperature sensitive lethal (tsl)
      mutation are being used to produce sterile male medflies for large scale sterile
      insect technique (SIT) programmes for this pest. The use of male-only strains
      increases the overall efficiency of the technique. Currently more than 1.4
      billion sterile male-only pupae are produced per week in different facilities
      around the world. Due to the mutations used to construct these strains, that is,
      translocations and selectable markers, they require different and more careful
      mass rearing procedures than do bisexual strains (BSS). The basic rearing
      technology has been developed and can be used to produce only males on a
      predictable basis to a level of 99.9% accuracy. If specific rearing procedures
      are followed, then tsl-based GSS has a rearing efficiency that is equal to that
      of a BSS and it is already know that males produced by the tsl-based GSS are of
      equal quality to males produced by BSS. Based on current rearing technology the
      cost of production of male pupae is about the same for both types of strain. This
      is due to the large colony that is required for the tsl-based GSS. This paper
      discusses the considerations that need to be taken into account during mass
      rearing of GSS and identifies the most efficient production processes that are
      currently available.

PMID- 12484531
TI  - Improving male mating competitiveness and survival in the field for medfly,
      Ceratitis capitata (Diptera: Tephritidae) SIT programs.
AB  - The success of the sterile insect technique (SIT) depends critically upon mating
      between released sterilized males and wild females. In Hawaii, improvements in
      the efficiency of sterile males were attempted on two separate fronts--mating
      enhancement and survival improvement. In the former, two methods have been
      investigated--selective breeding and aromatherapy. In the latter, flies which
      survived in field cages for several days were selected and bred to produce
      progeny with enhanced survival ability compared to control flies. Regarding
      mating selection, standard laboratory-reared males that successfully mated with
      wild females in field cages were allowed to breed. F1 offspring were inbred, then
      the selection procedure was repeated for four additional cycles. In the
      aromatherapy procedure, laboratory-reared males were exposed to ginger root oil
      for several hours 1 day prior to testing in field cages. Compared to controls,
      the selected flies improved the mating competitiveness of male flies ca. 3-fold,
      irradiation reduced this increase to ca. 2.5-fold. Exposing the selected, hybrid
      strain raised the fitness of the lab males to ca. 9-fold that of wild males. In
      the ongoing survival selection study, we have obtained lines in which the
      selected males survived ca. 2-fold better than laboratory control males over
      several days in an outdoor field cage, with food and water provided. The goal is
      to combine the traits of higher survival and mating ability into a single strain
      for SIT release.

PMID- 12484532
TI  - Genetic differentiation, gene flow and the origin of infestations of the medfly,
      Ceratitis capitata.
AB  - The genetic structure of natural populations of the economically important
      dipteran species Ceratitis capitata was analysed using both biochemical and
      molecular markers. This revealed considerable genetic variation in populations
      from different geographic regions. The nature of this variation suggests that the
      evolutionary history of the species involved the spread of individuals from the
      ancestral African populations through Europe and, more recently, to Latin
      America, Hawaii and Australia. The observed variation can be explained by various
      evolutionary forces acting differentially in the different geographic areas,
      including genetic drift, bottleneck effects, selection and gene flow. The
      analysis of the intrinsic variability of the medfly's genome and the genetic
      relationships among populations of this pest is a prerequisite for any control
      programme.

PMID- 12484533
TI  - Prospects for using genetic transformation for improved SIT and new biocontrol
      methods.
AB  - The genetic manipulation of non-drosophilid insect species is possible by the
      creation of recombinant DNA constructs that can be integrated into host genomes
      by several transposon-based vector systems. This technology will allow the
      development and testing of a variety of systems that can improve existing
      biological control methods, and the development of new highly efficient methods.
      For programs such as sterile insect technique (SIT), transgenic strains may
      include fluorescent protein marker genes for detection of released insects, and
      conditional gene expression systems that will result in male sterility and female
      lethality for genetic sexing. Conditional expression systems include the yeast
      GAL4 system and the bacterial Tet-off and Tet-on systems that can, respectively,
      negatively or positively regulate expression of genes for lethality or sterility
      depending on a dietary source of tetracycline. Importantly, strains for male
      sterility must also incorporate an effective system for genetic sexing, since
      typically, surviving females would remain fertile. Models for the use of these
      expression systems and associated genetic material come from studies in
      Drosophila and, while many of these systems should be transferable to other
      insects, continued research will be necessary in insects of interest to clone
      genes, optimize germ-line transformation, and perform vector stability studies
      and risk assessment for their release as transgenic strains.

PMID- 12484534
TI  - Spectrophotometric determination of acyclovir in some pharmaceutical
      formulations.
AB  - A simple and reliable spectrophotometric method has been developed for the
      determination of acyclovir in pharmaceutical formulations. The method is based on
      its oxidative coupling reaction with 3-methylbenzothiazolin-2-one hydrazone
      (MBTH) in the presence of FeCl3 as an oxidant to produce deep-green colored
      species measurable at 616 nm. The absorbance-concentration plot is linear over
      the range 20-200 microg ml(-1) with minimum detectability of 1.06 microg ml(-1)
      (4.71 x 10(-6) M). The molar absorptivity was 9.41 x 10(2) l mol(-1) cm(-1) with
      correlation coefficient (n = 7) of 0.9998. The different experimental parameters
      affecting the development and stability of the color were studied carefully and
      optimized. The proposed method was applied successfully to the determination of
      acyclovir in its dosage forms. The percentage recoveries +/-SD (n = 9) were 98.63
      +/- 0.34, 99.61 +/- 0.58, 99.35 +/- 0.58 and 99.72 +/- 0.86 for tablets,
      ophthalmic ointment and cream, respectively. A proposal of the reaction pathway
      was presented.

PMID- 12484535
TI  - Spiro[1,2,4-benzotriazine-3(4H),4'-(1'-substituted)piperidines] and related
      compounds as ligands for sigma receptors.
AB  - As analogues of some conformationally restricted spiropiperidine derivatives
      which are endowed with high affinity for sigma1 receptor, a set of 16 spiro[1,2,4
      benzotriazine-3(4H),4'-(1'-substituted)piperidines] and congeneric compounds was
      prepared and tested for affinity to sigma1 receptor subtype. All N-arylalkyl
      substituted derivatives exhibited high affinity for the relevant receptor, with
      Ki in the low nanomolar range. Affinity for sigma2 subtype (assayed only for a
      few representative compounds) was from one to three order of magnitude lower.
      Spiro[1,2,4-benzotriazine-3(4H),4'-(1'-benzyl)piperidine] (2), with a ratio Ki
      sigma2/Ki sigma1 = 7000 should represent the most selective sigma1 ligand so far
      described.

PMID- 12484536
TI  - The effect of glycyrrhizin on the release rate and skin penetration of diclofenac
      sodium from topical formulations.
AB  - The influence of glycyrrhizin extracted from Glycyrrhiza glabra var. glandulifera
      (licorice roots) on the percutaneous absorption of diclofenac sodium from sodium
      carboxymethylcellulose (NaCMC) gels or oil-in-water (o/w) emulsion was
      investigated. Skin permeation experiments were carried out using excised
      abdominal rat skin. The results showed that the efficiency of glycyrrhizin as an
      enhancer agent is greater in gel formulations than it is in the emulsions. The
      enhancer with the concentration of 0.1% w/w in gel increased diclofenac sodium
      flux value to tenfold compared with the control gel.

PMID- 12484537
TI  - Synthesis and pharmacology of 3-hydroxy-delta2-isoxazoline-cyclopentane analogues
      of glutamic acid.
AB  - The synthesis and pharmacology of two potential glutamic acid receptor ligands
      are described. Preparation of the bicyclic 3-hydroxy-delta2-isoxazoline
      cyclopentane derivatives (+/-)-7 and (+/-)-8 was accomplished via 1,3-dipolar
      cycloaddition of bromonitrile oxide to suitably protected 1-amino-cyclopent-3
      enecarboxylic acids. Their structure was established using a combination of 1H
      NMR spectroscopy and molecular mechanics calculations carried out on the
      intermediate cycloadducts (+/-)-11 and (+/-)-12. Amino acid derivatives (+/-)-7
      and (+/-)-8 were assayed at ionotropic and metabotropic glutamic acid receptor
      subtypes and their activity compared with that of trans-ACPD and cis-ACPD. The
      results show that the replacement of the omega-carboxylic group of the model
      compounds with the 3-hydroxy-delta2-isoxazoline moiety abolishes or reduces
      drastically the activity at the metabotropic glutamate receptors. Conversely, on
      passing from cis-ACPD to derivative (+/-)-8, the agonist activity at NMDA
      receptors is almost unaffected.

PMID- 12484538
TI  - Investigations on the synthesis and pharmacological properties of 4-alkoxy-2-[2
      hydroxy-3-(4-aryl-1-piperazinyl)propyl]-6-methyl-1H-pyrrolo[3,4-c]pyridine
      1,3(2H)-diones.
AB  - Synthesis of 2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl] derivatives of 4-alkoxy
      6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (8-12) is described. The
      chlorides used in the above synthesis can exist in two isomeric forms: chain (18
      20) and cyclic (19a, 20a). The compounds 8-12 exhibited potent analgesic activity
      which was superior than that of acetylsalicylic acid in two different tests. Most
      of the investigated imides suppressed significantly spontaneous locomotor
      activity in mice.

PMID- 12484539
TI  - Antimycobacterial activity of 5-arylidene derivatives of hydantoin.
AB  - The synthesis of various 5-arylidene-2-thiohydantoins and results of the primary
      assay in vitro for their antimycobacterial activity is reported. Eight of those
      compounds exhibited > 90% inhibition of Mycobacterium tuberculosis growth and for
      them the minimum inhibitory concentrations, cytotoxicity (IC50) and the
      selectivity index values were determined. The most active structure, (5Z)-5-(1,1'
      biphenyl-4-ylmethylene)-2-thioxoimidazolidin-4-one, showed MIC = 0.78 microg/ml.
      For all compounds log P and log D (pH 6.5) values were calculated.

PMID- 12484540
TI  - Rigid analogues of buspirone and gepirone, 5-HT1A receptors partial agonists.
AB  - Rigid analogues of buspirone and gepirone, 5-HT1A receptors partial agonists,
      were obtained. The compounds exhibited very low affinity to the receptors. Their
      structural features resembled to a large extent the arrangement of the respective
      structural elements found in the solid state of buspirone and in the theoretical
      structure of NAN-190 (5-HT1A postsynaptic antagonist) rigid analogue exhibiting
      high affinity to the receptor. The obtained results would thus suggest that the
      bioactive conformation of buspirone might not be the extended one. That would
      additionally suggest that either both groups of compounds could occupy different
      areas at the receptor binding sites (or bind to different receptor states) or the
      constrained structure of 2 does not represent well 5-HT1A receptor binding site
      requirements.

PMID- 12484541
TI  - Physicochemical compatibility between thiocolchicoside injections (Miotens) and
      pharmaceutical products frequently used for combined therapy.
AB  - Thiocolchicoside (Miotens), a muscle relaxant agent, is frequently administered
      in association regimen with other drugs, such as anti-inflammatory drugs or
      vitamins. The aim of this study was to investigate the physicochemical
      compatibility between thiocolchicoside (Miotens) and other injectable drugs
      frequently used in association. Physicochemical properties of thiocolchicoside
      mixtures with different drugs, including colour, clarity, pH and drug content
      were observed or measured before and after (3 h) mixing at room temperature.
      Results show that the association of Miotens with different anti-inflammatory
      drugs and vitamins does not cause, up to 3 h from mixing, any significant
      variation in the physicochemical parameters mentioned above. In conclusion the
      results obtained demonstrated the physicochemical compatibility of
      thiocolchicoside (Miotens) with diverse anti-inflammatory drugs and vitamins.

PMID- 12484542
TI  - Chromatographic determination of clotrimazole, ketoconazole and fluconazole in
      pharmaceutical formulations.
AB  - High-performance liquid chromatographic technique has been developed for the
      determination or some azolcsantifungals namely, clotrimazole (CZ), ketoconazole
      (KZ) and fluconazole (FZ), in pure forms and in pharmaceutical formulations. The
      proposed HPLC-method can be successfully applied as a stability indicating method
      for the determination of CZ in presence of its acid degradation products; viz (2
      chlorophenyl)-diphenyl methanol and imidazole. The analyzed drugs were separated
      on a reversed-phase column [Bondapak C18 (10 microm, 25 cm x 4.6 mm, i.d.)] using
      a mobile phase containing acetonitrilc+25 mM trishydroxymeihyl aminomethane in
      phosphate butter (pH 7) = 55:45 (v/v), with UV-detection at 260 nm. The
      differences in the retention times (tR) of the three azoles permit their use as
      internal standard for each other. In addition, a coupled TLC-densitometric method
      has been also applied as a stability indicating method to separate and quantify
      CZ alone or in presence of byproducts impurities and/or its acid degradation
      products. The TLC-fractionation was performed on a precoated silica gel F254
      plates using a solvent system consisting of chloroform+acetone+ammonia (25%)
      (7:1:0.1, by volumes), CZ was well separated from its acid degradation products
      and quantified by densitometric scanning at 260 nm.

PMID- 12484543
TI  - Different geometric shaped hydrogel theophylline tablets: statistical approach
      for estimating drug release.
AB  - The objective of this study was to develop a mathematical equation for the
      calculation of drug release from different shaped matrix tablets. By this way,
      release rate related to the geometric shape could be predicted with the help of
      the developed mathematical equation. So, drug release could be estimated before
      the dissolution. Hydroxypropylmethylcellulose (HPMC) E50 as polymer and
      theophylline as active substance were used in the matrix tablets prepared for
      this purpose. Matrix tablets in three different geometrical shapes, namely in
      triangular, cylindrical and half-spherical forms were prepared by using two
      different drug-polymer ratio (1:0.5, 1:1) and diluent's in three different
      percentages (0, 20, 40%). Using rotating paddle and basket methods reported in
      USP XXIII carried out the release rate studies of these tablets. The Higuchi
      square-root time model best described the dissolution data. Differential scanning
      calorimetry (DSC) analysis was performed to identify any solid-state inactivation
      of the drug. The practical benefit of this work is to improve mathematical
      equation that can be used to predict accurately the required composition and in
      order to achieve the desired release profiles of different geometric shaped
      tablets. By using this equation new pharmaceutical products can be easily
      improved.

PMID- 12484544
TI  - Structural proteomics: lessons learnt from the early case studies.
AB  - The genomics efforts have identified a large number of novel genes and thus
      provided a pool of interesting but not functionally characterized target
      proteins. It has been suggested that structural proteomics will significantly
      impact the success rate of functional characterization of such identified genes
      and proteins by providing structure-function hypotheses by fold and feature
      recognition and analysis. Structural proteomics initiatives, both in academic and
      industrial settings, are today generating protein structures at an unprecedented
      rate although relatively few large-scale efforts have been displayed in the
      public domain. However, a number of individual studies have provided a 'road-map'
      for selected approaches that hold the promise to significantly impact the process
      of deriving function from structure.

PMID- 12484545
TI  - Simultaneous determination of metronidazole and miconazole in pharmaceutical
      dosage forms by RP-HPLC.
AB  - A reversed-phase high performance liquid chromatography (RP-HPLC) method with UV
      detection is described for the simultaneous determination of metronidazole and
      miconazole in pharmaceutical dosage forms. Chromatography was carried out on a
      C18 reversed-phase column, using a mixture of methanol-water (40+60, v/v) as a
      mobile phase, at a flow rate of 1.0 ml min(-1). Sulfamethoxazole was used as an
      internal standard and detection was performed using a diode array detector at 254
      nm. The method produced linear responses in the concentration ranges 10-70 and 1
      20 microg ml(-1) with detection limits 0.33 and 0.27 microg ml(-1) for
      metronidazole and micanozole, respectively. This procedure was found to be
      convenient and reproducible for analysis of these drugs in ovule dosage forms.

PMID- 12484546
TI  - Changes in glutathione-related enzymes in tumor-bearing mice after cisplatin
      treatment.
AB  - The effect of cisplatin on five glutathione-related enzymes was studied in liver,
      kidney, and Dalton lymphoma cells of tumor-bearing mice. In liver, the activities
      of glutathione S-transferase, glutathione peroxidase, catalase, and superoxide
      dismutase decreased approximately 30-40%, 60-67%, 35-50% and 70-80% respectively,
      while glutathione reductase increased about 36-45% after cisplatin treatment. In
      kidney, catalase activity decreased by 47-82% at all time points (24-96 h) of
      cisplatin treatment, while glutathione S-transferase activity decreased
      significantly (approximately 24%) mainly at 72 h of treatment. An increase in
      glutathione reductase (approximately 1.5-2.5 times), glutathione peroxidase
      (significant at 24 h, 47%), and superoxide dismutase (approximately 15-60%) was
      noted in kidney after the treatment. In Dalton lymphoma cells, the activities of
      glutathione S-transferase, glutathione peroxidase, and catalase decreased very
      distinctly (approximately 2-5, 2-5 and 5-11 times, respectively) at all time
      points, but glutathione reductase decreased significantly only at 72 h of
      cisplatin treatment. Interestingly, the superoxide dismutase activity in Dalton
      lymphoma cells increased initially at 24-48 h and then decreased (approximately
      60%) during later periods (72-96 h) of treatment. Cisplatin treatment caused a
      decrease in glutathione level in Dalton lymphoma cells (approximately 14-20%) and
      kidney (approximately 18-28%) but no change in liver. In view of the results, a
      definite correlation with the changes in glutathione concentrations and enzymatic
      activities in a tissue could not be firmly derived. It is suggested that the
      changes in various glutathione-related enzymes and glutathione levels in the
      tissues of the host during cisplatin-mediated chemotherapy could affect cellular
      antioxidant defense potential, which may play an important contributory role in
      cisplatin-mediated toxicity, particularly nephrotoxicity, and anticancer activity
      in the host.

PMID- 12484547
TI  - Nicotinamide "protects" resting lymphocytes exposed to hydrogen peroxide from
      necrosis but not from apoptosis.
AB  - The aim of this work was to investigate the relationship between mechanisms of
      DNA repair and apoptosis induced by oxidative stress (H2O2) in human lymphocytes.
      Using the comet assay, fluorescent microscopy, and DNA electrophoresis, we
      studied the DNA damage induced by hydrogen peroxide (H2O2) treatment, the time
      and the amount of repair of strand breaks, the type of cell death, and the
      influence of inhibitors of repair (nicotinamide). When lymphocytes were treated
      with H2O2, we observed an increased in necrosis compared to apoptosis. However,
      when nicotinamide (which inhibits DNA repair) was added, the mode of death
      reversed to increased apoptosis. These results indicate that nicotinamide
      "protects" resting lymphocytes exposed to H2O2 from necrosis but not from
      apoptosis.

PMID- 12484548
TI  - Comet assay evaluation of DNA single- and double-strand breaks induction and
      repair in C3H10T1/2 cells.
AB  - Ionizing radiation is a potent inducer of DNA damage because it causes single-
      and double-strand breaks, alkali-labile sites, base damage, and crosslinks. The
      interest in ionizing radiation is due to its environmental and clinical
      implications. Single-strand breaks, which are the initial damage induced by a
      genotoxic agent, can be used as a biomarker of exposure, whereas the more
      biologically relevant double-strand breaks can be analyzed to quantify the extent
      of damage. In the present study the effects of 137CS gamma-radiation at doses of
      1, 5, and 10 Gray on DNA and subsequent repair by C3H10T1/2 cells (mouse embryo
      fibroblasts) were investigated. Two versions of the comet assay, a sensitive
      method for evaluating DNA damage, were implemented: the alkaline one to detect
      single-strand breaks, and the neutral one to identify double-strand breaks. The
      results show a good linear relation between DNA damage and radiation dose, for
      both single-strand and double-strand breaks. A statistically significant
      difference with respect to controls was found at the lowest dose of 1 Gy.
      Heterogeneity in DNA damage within the cell population was observed as a function
      of radiation dose. Repair kinetics showed that most of the damage was repaired
      within 2 h after irradiation, and that the highest rejoining rate occurred with
      the highest dose (10 Gy). Single-strand breaks were completely repaired 24 h
      after irradiation, whereas residual double-strand breaks were still present. This
      finding needs further investigation.

PMID- 12484549
TI  - Cytotoxic effects of the polyamine oxidase inactivator MDL 72527 to two human
      colon carcinoma cell lines SW480 and SW620.
AB  - N1,N4-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527) was considered to be a
      selective inactivator of FAD-dependent tissue polyamine oxidase. Recently MDL
      72527 was reported to induce apoptosis in transformed hematopoietic cells through
      lysosomotropic effects. Since it is the only useful inhibitor of polyamine
      oxidase available at present, the re-evaluation of its properties seemed
      important. Human colon carcinoma-derived SW480 cells and their lymph node
      metastatic derivatives (SW620) were chosen for our study because they differ in
      various aspects of polyamine metabolism but have similar polyamine oxidase
      activities. MDL 72527 inhibited cell growth in a concentration-dependent manner,
      depleted intracellular polyamine pools, and caused the accumulation of N1-acetyl
      derivatives of spermidine and spermine. SW620 cells were more sensitive to the
      drug than were SW480 cells. At 150 micromol/L MDL 72527, SW620 cells accumulated
      in S-phase of the cell cycle, showed decreased polyamine transport rate, and
      showed no increase of polyamine N1-acetyltransferase activity. In contrast, SW480
      cells were not arrested in a particular phase of the cell cycle, showed enhanced
      polyamine uptake, and showed a mild induction of acetyltransferase. The results
      suggest that MDL 72527 retains its value as a selective tool in short-term
      experiments only at concentrations not exceeding those necessary for the
      inactivation of polyamine oxidase. At concentrations above 50 micromol/L and at
      exposure times longer than 24 h, it may derange cell functions nonspecifically,
      and thus blur the results of studies intended to elucidate polyamine oxidase
      functions.

PMID- 12484550
TI  - Phospholipid matrix as a target for sulfur mustard (HD): NMR study in model
      membrane systems.
AB  - Although the interactions of sulfur mustard (HD) with nucleic acids and proteins
      have been well studied, the toxic interactions with the membrane matrix and
      specially the phospholipid bilayer have so far been poorly investigated. We have
      used several NMR techniques to study these interactions: 1H NMR to observe the
      localization of HD in membranes of small unilamellar vesicles (SUV) of lecithin;
      31P NMR to verify the hypothesis of pore formation in membranes of large
      unilamellar vesicles (LUV); and pseudo solid state 31P and 2H NMR to analyze the
      dynamic consequences of the presence of HD in multilayer dispersions of
      dimyristoylphosphatidylcholine (DMPC). Immediate and late modifications of the
      DMPC-HD complexes have been observed at the macroscopic and microscopic levels.
      After intoxication, HD is spontaneously incorporated into the membrane and
      locates at the level of the chain methylene groups. This incorporation occurs
      without formation of pores in the membrane. The presence of HD in the
      phospholipid dispersion differentially increases the membrane fluidity depending
      upon the level involved. Weak at the superficial level (phosphate group), this
      increase is dose-dependent on progression into the membrane. This increase is
      related to a lowering of transition temperature when measured at the chain level.
      Macroscopically, HD induces dose- and time-dependent modifications of the DMPC-HD
      complexes, leading to the formation of an optically transparent gel. This gel
      formation is confirmed at a microscopic level, where all structures disappear
      after intoxication.

PMID- 12484551
TI  - Implication of distinct proteins in cadmium uptake and transport by intestinal
      cells HT-29.
AB  - The mechanisms of intestinal absorption have not been clearly elucidated for
      cadmium, a toxic metal. In this work, we show the implication of distinct
      proteins in cadmium transport, and the transport step where these proteins are
      involved. We first validated the HT-29 model by evaluating nontoxic doses of
      cadmium (ranging from 1 to 20 micromol/L), and by quantifying metal uptake and
      transepithelial transport. The time-course of 1 micromol/L cadmium uptake at pH
      7.5 showed three steps: a rapid one during the first 4 min, probably due to
      cadmium binding to the membrane; a slower one, characterized by Km of 1.65+/-0.54
      micromol/L and Vmax of 3.9+/-0.3 micromol/min per mg protein; and a third,
      corresponding to slow accumulation that was not equilibrated even after 48 h of
      cadmium exposure. Intracellular metallothionein content following 1 or 5
      micromol/L cadmium exposure showed a significant increase after 6 h of exposure,
      and was not equilibrated even after 72 h, allowing cadmium accumulation. After 24
      h of exposure, metallothionein content was 5-fold, 14-fold, 26-fold, and 50-fold,
      respectively, for cells grown in the presence of 1, 5, 10, and 20 micromol/L
      cadmium, compared to control cells. The second step of uptake, characterized by
      carrier-mediated transport, was markedly increased at pH 5.5, compared to pH 7.5,
      and strongly inhibited by the metabolic inhibitor dinitrophenol. Moreover Nramp2
      transporter cDNA was present in HT-29 cells. These data suggest the involvement
      of a proton-coupled transporter, which may be the divalent cation transporter
      Nramp2 (natural resistance-associated macrophage protein 2). Cadmium uptake was
      also inhibited by copper, zinc, and para-chloromercuribenzenesulfonate (pCMBS),
      but not by verapamil or ouabain. Taken together, our results indicate that
      cadmium could enter HT-29 cell by Nramp2 proton-coupled active transport and by
      diffusion, and accumulates in the cell as long as it binds to metallothionein.
      Cadmium toxicity could depend partly on the activity of Nramp2, and partly on
      metallothionein content.

PMID- 12484552
TI  - Tricyclic antidepressants prevent the differentiation of monocytes into
      macrophage-like cells in vitro.
AB  - The investigation was designed to determine whether the two tricyclic
      antidepressant agents (TCAs) clomipramine and imipramine and the selective
      reuptake inhibitor citalopram affect differentiation of human monocytes to
      macrophage-like cells (MAC-LCs). We established primary adherent cultures of
      peripheral blood monocytes and monitored their morphology, capacity for
      phagocytosis and antigen expression during transformation to MAC-LCs. As
      expected, maturation of monocytes to MACs is accompanied by changes in
      morphology, elevated expression of the antigens CD16 and CD51 and an increase in
      the percentage of phagocytic cells. Treatment of cells with the TCAs clomipramine
      (40 micromol/L) or imipramine (100 micromol/L) and with citalopram (100
      micromol/L), for 11 days resulted in the following observations: (1) monocytes
      treated with TCAs never developed the morphology characteristic of the MAC-LCs;
      (2) TCAs reduced the percentage of phagocytic cells; (3) TCAs had little
      influence on the expression of CD14, CD16, CD51, and HLA-DR. However, when added
      after monocyte differentiation into MAC-LCs, citalopram and clomipramine no
      longer reduced the percentage of phagocytic cells and these effects were not
      simply due to irreversible cytotoxicity. Thus clomipramine, imipramine, and
      citalopram inhibit differentiation of human monocytes into MAC-LCs in vitro, but
      in a reversible manner.

PMID- 12484553
TI  - Rapid induction of cataract by a single intraperitoneal administration of N
      methyl-N-nitrosourea in 15-day-old Sprague-Dawley (Jcl: SD) rats.
AB  - Cataract was induced by a single intraperitoneal injection of N-methyl-N
      nitrosourea (MNU) in 15-day-old Sprague-Dawley (Jcl: SD) rats. The threshold dose
      of MNU required for cataract induction in a 3-4 week time period was 70 mg/kg; 60
      mg/kg was ineffective. Males and females were both equally affected. Mature
      cataract as confirmed histologically by degeneration, swelling, vacuolation,
      liquefaction of the lens fibers, and formation of Morgagni-like water vacuoles
      was seen in 80% (8/10), 70% (7/10) and 90% (9/10) of 100, 80 and 70 mg/kg MNU
      treated rats, respectively, 4 weeks after dosing (43 days of age). At this time
      point, lens epithelial apoptosis was only rarely seen, but proliferating cell
      nuclear antigen (PCNA) labeled atypical nuclei with vacuolated lens fibers and
      macrophage migration were present within the injured lens. Cataracts were the
      only lesions induced by MNU and there were no other intra- or extraocular lesions
      seen. The dosing and timing schedule for the MNU administration in rats used in
      the present study is effective in rapidly causing cataract to occur.

PMID- 12484554
TI  - The ratio of polymorphonuclear leucocytes (PMN) to non-PMN cells--a novel method
      of assessing acute lung inflammation.
AB  - Polymorphonuclear leucocyte (PMN) numbers are an indicator of the degree of acute
      lung inflammation. However, there is no standardized system for accurately
      quantifying their numbers in tissue sections. Also, the effect of lung inflation
      on the quantification of PMN's is usually overlooked. Lung specimens obtained
      from clinical biopsies are usually deflated, while inflated lung tissue is
      commonly used in experimental studies. We report a method, which is independent
      of the degree of inflation, for measuring the degree of PMN infiltration in the
      both inflated and non-inflated lungs. Using light microscopy, we counted the
      numbers of PMN and non-PMN cells in 240 fields from each of five inflated and
      five non-inflated lung sections and calculated a ratio of PMN: non-PMN cells (the
      PMN ratio). The effect on accuracy and precision of number of fields counted was
      investigated by randomly selecting 200, 160, 80 or 40 readings from the original
      240 fields. The mean PMN ratio, its 95% confidence interval (CI) and the
      coefficient of variation (CV) were calculated for each of the four levels of
      sampling. Both CI and CV increased as the number of readings decreased. Inflated
      lung tissue had consistently higher values for CV compared to non-inflated lung.
      In practice, we recommend that for both inflated and non-inflated lungs, 80-160
      fields (approximate 0.23-0.45 mm2 of absolute area evaluated) need to be counted
      to yield a PMN ratio with acceptable accuracy and precision. The PMN ratio
      provides a simple and objective way of quantifying the degree of acute
      inflammation in clinical histopathology and experimental toxicology studies
      involving lungs. It is suitable for use in research of lung inflammation, and as
      an accessory diagnostic tool and an objective descriptor for clinical
      histopathology.

PMID- 12484555
TI  - Ethylnitrosourea-induced apoptosis in primordial germ cells of the rat fetus.
AB  - Ethylnitrosourea (ENU) is a simple alkylating agent. It induces gene mutations in
      fetal primordial germ cells (PGCs), and a high incidence of congenital
      malformations is also found in the offspring of male mice treated with ENU at the
      embryonic stage. It is also reported that decreases in the fertility rate and
      weights of the testis and ovary were found in the offspring from dams treated
      with ENU. In this study, we analyzed the occurrence of apoptotic cell death and
      the expression of p53 protein which is thought to play an important role in the
      DNA damage-induced apoptosis after administration of ENU to pregnant rats on day
      13 of gestation to obtain a clue for clarifying the toxic effect of ENU on PGCs.
      Apoptotic cells increased in PGCs in fetal gonads from 3 h after treatment. The
      number of apoptotic PGCs peaked at 6 h and gradually decreased towards 24 h after
      treatment. On the other hand, p53-positive PGCs increased from I h after
      treatment, prior to the induction of apoptosis. The number of p53-positive PGCs
      peaked at 3 h and returned to the control level at 24 h after treatment. These
      results suggest that ENU induces apoptosis in rat fetal PGCs immediately after
      its administration to dams and excess cell death by apoptosis may have a close
      relation to the later occurrence of decreases in the fertility rate and gonadal
      weight. Moreover, a possible involvement of p53 is suggested in the ENU-induced
      apoptosis in PGCs.

PMID- 12484556
TI  - Effects of methimazole pretreatment on cerulein induced acute pancreatitis in
      rats.
AB  - BACKGROUND: Many interrelationships exist between the thyroid gland and the
      gastrointestinal tract. Several past and recent studies have shown that the
      thyroid gland profoundly influences the structure and function of the exocrine
      pancreas in the rat. In the present study we investigated the effect of
      methimazole (METZ), an antithyroid drug, on cerulein induced acute pancreatitis
      (AP) in rats. METHODS: Rats were divided into 3 groups (10-12 weeks age, 200-250
      g weight, n: 10). Group B was made hypothyroid with methimazole 5 mg/kg daily for
      10 days and the others were untreated euthyroid groups. After 10 days, acute
      pancreatitis was induced with four doses of 20 microg/kg body weight of cerulein
      administered s.c at hourly intervals in group A and B while the control group C
      was given 4 doses of I ml saline. Pancreas wet weight (mg), plasma amylase
      activity (IU/l) and pancreatic histology were used as endpoints to quantify the
      severity of the AP. RESULTS: Plasma tri-iodothyronine (T3) (ng/dl) and thyroxine
      (T4) (microg/dl) levels were significantly reduced after METZ treatment for 10
      days (p < 0.01). METZ pretreatment reduced significantly the cerulein induced
      increase in pancreatic weight (1,205 +/- 12 mg in METZ treated AP group versus
      1,617 +/- 14 mg in AP group, p < 0.05) and the rise in amylase activity (7,078 +/
      816 IU/l in METZ treated AP group versus 8,611 +/- 830 IU/l in AP group p <
      0.05). CONCLUSION: METZ reduces the severity of cerulein induced AP in rats. This
      effect might be through its antithyroid property.

PMID- 12484557
TI  - Polymicrobial sepsis induces organ changes due to granulocyte adhesion in a
      murine two hit model of trauma.
AB  - INTRODUCTION: Polytrauma patients, who develop organ dysfunction, have often
      undergone multiple subsequent insults ("hits"). The sequence of organs that show
      a dysfunction mostly is lung, liver, kidney and heart. The aim of the present
      study was to investigate whether a second hit after trauma induces organ changes.
      Furthermore, it was of interest to identify possible pathogenic mediators such as
      polymorphonuclear granulocytes (PMN) and cytokines. For this purpose, a two hit
      model of systemic damage in mice was developed. Sepsis was induced by caecal
      ligation and puncture (CLP), which was preceded 48 hours by a femur fracture, the
      most common fracture of long bones in trauma patients. This fracture was combined
      with a haemorrhagic shock. METHODS: In both mouse groups studied, a standardized
      femur fracture was produced using a blunt guillotine device with a weight of 500
      g. This was followed by a haemorrhagic shock with substitution of ringer's
      lactate after 1 hour. In the study group, CLP was induced by puncturing the
      caecum using a 21G needle. As a control, sham animals underwent a laparotomy
      without CLP. Both groups were sacrificed after 48 or 96 hours. Clinical
      parameters were investigated on a daily basis to evaluate the animals' status.
      Lung, liver and kidney morphology was studied by light microscopy. PMN adhesion
      was determined by counting the number of adherent PMN per 100 microm of
      endothelium. Serum levels of TNF-alpha were measured after 48 and 96 hours.
      RESULTS: In the group submitted to laparotomy, all animals survived. The
      induction of polymicrobial sepsis by CLP resulted in an 85% (34/40) mortality
      within 96 hours after surgery (p < 0.05). The induction of a polymicrobial sepsis
      resulted in a significantly steady worsening of the clinical situation compared
      to the sham animals (p < 0.05). Lung morphology demonstrated significant changes
      at the end of the experimental period after 96 h in the two hit group. The
      alveolar septa were thickened and in all lungs haemorrhagic foci were observed.
      The number of PMN adhering to the pulmonary endothelium significantly increased
      at 96 hours. Some of the liver specimens in the two hit group showed focal
      hydropic degeneration and PMN infiltration. No kidney pathology was observed.
      This result coincided with an increase in TNF-alpha serum levels. DISCUSSION: A
      new rodent model mimicking the situation in the polytraumatized patient was
      developed. Although the animals showed minimal organ manifestation, a high
      percentage died probably due to cytokinemia. Furthermore, the increased TNF-alpha
      levels may lead to increased adhesion of PMN in the lung venules. This adhesion
      developed four days after the second hit. This might be the initial step for the
      development of extensive lung lesions in later phases. This model represents the
      SIRS more than MODS. This is a model for devolopment of posttraumatic disease due
      to cytokinemia and less for chronic multiple organ dysfunction and failure.

PMID- 12484558
TI  - Effects of thiocolchicine on axonal cytoskeleton of the rat peroneus nerve.
AB  - Thiocolchicine is a colchicine-derivative used in the therapy of some diseases
      and extensively studied in the field of oncological research as antimitotic
      agent. Here we studied the activity of thiocolchicine on the cytoskeleton of the
      peroneus nerve, performing a histological and ultrastructural analysis. We
      observed a decrease in mean myelinated fiber area in thiocolchicine-treated rats
      in comparison to controls; this was due to a decrease in mean axoplasm area,
      while myelin thickness was constant. In the ultrastructural analysis a decrease
      in microtubule density and an increase in neurofilaments were found; moreover,
      the myelinated fibers seemed to be more affected in comparison to the
      unmyelinated axons. These findings are in agreement with the capability of
      binding to microtubule skeleton shared by all the colchicinoids.

PMID- 12484559
TI  - Gastroprotective effects of honey and glucose-fructose-sucrose-maltose mixture
      against ethanol-, indomethacin-, and acidified aspirin-induced lesions in the
      rat.
AB  - The gastric cytoprotective properties of natural honey (monofloral and polyfloral
      specimens) and of a glucose-fructose-sucrose-maltose mixture (GFSM) was evaluated
      in the rat using absolute ethanol, indomethacin and acidified acetylsalicylic
      acid (ASA-HCl) as necrotising agents. Prior gastric administration of honey (2.5
      g/kg) to animals induced a net reduction of hemorrhagic lesions length of the
      mucosa. Protection of the stomach elicited by both types of honey and GFSM was
      almost total against ethanol-induced lesions. Similar results were also observed
      when using ASA-HCl except that the percent protection was 87%. The percent
      reduction of indomethacin-induced gastric lesions was variable according to the
      nature of the test solution: GFSM mixture (41.1%) < polyfloral honey (55.2%) <
      monofloral honey (64.0%). Perfusion of the stomach with isotonic honey resulted
      in (1) a 70% reduction of the area of the lesions caused by ethanol, (2) the
      failure to prevent the transmural potential difference fall induced by ethanol,
      (3) an increase of basal and histamine-stimulated acid secretion. These results
      suggest that sugar rich solutions (GFSM and honey) may prevent gastric damage by
      a mechanism involving the release of some protective agents.

PMID- 12484560
TI  - In vitro investigation of a standardized dried extract of Citrullus colocynthis
      on liver toxicity in adult rats.
AB  - A standardized extract of Citrullus colocynthis used as an oral natural laxative
      in folk medicine was tested for its influence on liver function parameters in
      vitro. Cytochrome P450 (CYP) dependent production of reactive oxygen species
      (ROS) under the influence of Citrullus colocynthis extract was investigated by
      means of stimulated lipid peroxidation (LPO), H2O2 formation and amplified
      chemiluminescence in rat liver microsomes. In rat liver 9000 x g supernatants 4
      monooxygenase reactions mediated by different CYP forms were measured. Putative
      hepatotoxic effects of Citrullus colocynthis extract were measured by means of
      potassium and GSH concentrations in and LDH leakage from precision-cut rat liver
      slices. For possible hepatoprotective effects the influence of the extract on
      carbon tetrachloride-induced changes of these parameters was investigated.
      Citrullus colocynthis extract in concentrations higher than 10 microg/ml
      incubation mixture proved to inhibit lipid peroxidation and ROS-production as
      well as CYP1A-, 2B- and 3A-dependent reactions with typical substrates. In
      contrast, H2O2 production was not reduced under the influence of the extract, a
      slight but significant increase was seen. Citrullus colocynthis extract was found
      to be free of hepatotoxic effects in concentrations up to 100 microg/ml
      incubation mixture when liver slices were incubated in William's medium E for 22
      hours. All viability parameters used were not influenced by the extract of
      Citrullus colocynthis. Carbon tetrachloride induced hepatotoxicity could not be
      prevented or alleviated. Moreover, the damage was sometimes enhanced by higher
      extract concentrations.

PMID- 12484561
TI  - Inhibition of human renal acid phosphatases by nephrotoxic micromolar
      concentrations of fluoride.
AB  - Fluoride is considered to be a nephrotoxic substance, due to the association of
      50-180 microM serum concentrations of fluoride with dose-related, subclinical to
      overt clinical renal impairment. At these concentrations the cellular targets of
      fluoride in renal tissue remain unknown. Fluoride at micromolar concentrations
      inhibits some enzymes including phosphatases. Here the effects of fluoride on a
      recently characterized acid phosphatase complex present only in a few human
      tissues were studied. This enzyme complex consists of alkaline fixation-resistant
      beta-glycerophosphatase and tartrate-resistant a-naphthyl phosphatase, and these
      are different from activities of known types of acid phosphatase and specific
      phosphatases. In kidney, strong activities for this complex are detected only in
      the endothelium of the afferent arterioles and in glomeruli. It appeared that
      alkaline fixation-resistant and lysosomal acid phosphatase activities were
      significantly inhibited in afferent arterioles and glomeruli by 75 microM
      fluoride. Tartrate-resistant activity was significantly inhibited by greater
      concentrations (250 microM). Inhibition of acid phosphatases in the afferent
      arterioles and glomeruli may be one renal target of fluoride nephrotoxicity.
      Although the physiological substrates of this acid phosphatase complex are
      unknown, its specific and restricted location may indicate a role in regulation
      of renal circulation.

PMID- 12484562
TI  - Dorsal skin responses to topical application with hydrogen peroxide in Mini and
      Wistar rats.
AB  - Mini rats (Jcl: WistarTGN(ARGHGEN) 1Nts) (MRs) are Wistar rat (WR)-derived
      transgenic rats in which the expression of growth hormone (GH) gene is suppressed
      under the presence of antisense RNA transgene. In order to evaluate the effects
      of GH-deficiency on the acute injury by external stimuli, the dorsal skin
      responses to a single topical application with 20% hydrogen peroxide (HPO), one
      of the environmental oxidative stressors, were histologically compared between
      male MRs and WRs of 8 weeks old, whose hair cycle was under the telogen phase. As
      a result, formation of granulation tissues, reepithelialization and regrowth of
      hair follicles were delayed in MRs compared with WRs. While hair follicles of MRs
      of this age are under a long-lasting telogen phase after their 2nd cycle, a new
      hair cycle started not only in the HPO-applied area but also in the solvent
      applied area with a little time lag. These findings suggest that GH-deficiency
      may influence the skin responses to the external chemical stimuli.

PMID- 12484563
TI  - Metallothionein in liver-biopsies from patients with different diseases.
AB  - Metallothioneins (MT) are ubiquitous found in eukaryotic organism. MT have a
      potential for metal-storage and protect the cells against stress. On the genomic
      level, proinflammatory cytokines like interleukin-6 and transition metals like
      copper cause induction of MT. Therefore, an estimation of MT in liver-biopsies
      from patients with different diseases probably could help in identifying acute
      phase reactions and processes which lead to increased copper. We investigated
      paraffin embedded liver biopsies from 170 patients and 13 control biopsies from
      cases of sudden death. Tissue was stained with a primary antibody against MT and
      a peroxidase technique was used to make results visible. A grading was performed
      using an immunoreactive score (IRS from 0-24) and by computer-aided measurement
      of the optical density (OD) of the stained tissue slides. Patients with
      cholestasis (IRS: 12.1 +/- 2.8, n = 11), autoimmune (10.6 +/- 3.1, n = 7) or
      inflammatory bowel diseases (IBD) (13.3 +/- 5.1, n = 4) and lymphoma (9.8 +/-
      5.8, n = 21) showed marked increases in MT compared to the controls (5.2 +/- 2.8,
      n = 13). Patients with chronic hepatitis B or C or chronic alcoholic abuse had no
      elevation of MT. Furthermore, no correlation was found between histological
      damage and amount of MT except in cases of cholestasis, in which increased MT was
      observed. Results by OD confirmed the findings. In summary, we were able to
      demonstrate a clear increase of MT content in liver-biopsies in proinflammatory
      and cholestatic conditions. Marked elevation in patients with systemic diseases
      (like autoimmune-, IBD and lymphoma) seems to be best explained by an acute-phase
      induction of MT by proinflammatory cytokines. This could help in identifying
      these conditions in liver biopsies.

PMID- 12484564
TI  - Helium (argon) plasma coagulation in neurosurgery. morphology of tissue damage
      and reparation.
AB  - Plasma coagulation, used in some neurosurgical operative settings, is currently
      under experimental investigation for the precise assessment of the kind and
      extent of tissue damage. We established a standardised trial to investigate the
      effects of helium (argon) plasma coagulation - H(A)PC - on rat brain tissue. The
      tissue reactions were observed with common methods of morphology including
      immunohistology and electron microscopy. A time dependent profile of the tissue
      reactions was performed from day 1 after operation up to 6 weeks. The tissue
      reaction consisted of clearly demarcated concentric zones. The depth of the
      lesion was about 1 mm maximally, at the beginning. Reparative forces acted at
      variance both in the different layers and at the edges versus the center of the
      damage. A manifold but reproducible picture emerges in the various compartments
      allowing the study of different aspects of organisation and/or elimination of
      tissue components. This study has demonstrated that a defined circumscribed and
      reproducible small lesion can be performed with H(A)PC. As in other areas of
      surgery, this technique has proven to be minimally traumatic. Clinical
      application of this technique in neurosurgery is therefore promising. In
      addition, H(A)PC lesions are obviously best suited for morphological studies of
      early and late reparative reactions in cells and tissues.

PMID- 12484565
TI  - The Big Eye in the 21st century: the role of electron microscopy in modern
      diagnostic neuropathology.
AB  - Electron microscopy (EM) remains a powerful and even essential tool in modern
      diagnostic neuropathology. tumors are still encountered that defy histological or
      immunohistochemical classification, and EM can often provide answers in these
      cases. Tumors of the CNS for which EM is useful include unusual or atypical
      variants of meningioma, ependymoma, and schwannoma; oligodendroglioma-like tumors
      composed of small "clear" cells; and small "blue cell" tumors of childhood. EM is
      of great value in identifying site of origin for metastatic adenocarcinomas of
      unknown origin-an under-recognized and under-utilized potential for this
      technique. EM is useful in the diagnosis of peripheral nerve sheath tumors and
      gastrointestinal autonomic nerve tumors. EM is also important in the evaluation
      of certain congenital, inherited and metabolic diseases-including ceroid
      lipofuscinoses, CADASIL syndrome, certain myopathies, and mitochondrial
      encephalomyopathies--and of certain toxic and drug-induced peripheral
      neuropathies. An important application of EM is its utility in initiating a
      workup of an atypical tumor or metabolic condition, for which clinical and
      histological clues point in no obvious direction. In these situations, EM may
      provide either an answer outright (including answers to questions not asked) or
      important clues that guide further workup and narrow the range of diagnostic
      possibilities.

PMID- 12484567
TI  - Immunohistochemical and ultrastructural study of gap junction proteins connexin26
      and 43 in human arachnoid villi and meningeal tumors.
AB  - Human arachnoid villi and meningiomas are known to have gap junctions formed by
      connexin (Cx) proteins. We examined the expression and localization of Cxs in
      normal human arachnoid villi and meningeal tumors (meningiomas and
      hemangiopericytomas) by immunohistochemistry and Western blots. In arachnoid
      villi, strong immunopositivity for connexin26 (Cx26) and connexin43 (Cx43) was
      detected in the cap cell layer, cap cell cluster, and central core. They were
      weakly expressed in the fibrous capsule. In meningiomas they were strongly
      expressed in the meningotheliomatous area and weakly positive in the fibrous
      area. None of them were expressed in hemangiopericytomas. By immunoelectron
      microscopy, Cx26 and Cx43 were distributed on the cell membranes in arachnoid
      villi and meningiomas. In the Western blots in arachnoid villi and meningiomas,
      Cx26 and Cx43 were shown at bands with molecular weights of 26 kD and 42-47 kD,
      respectively. The degree of positivity for Cxs was different between subtypes of
      meningiomas. These findings suggest that expression of Cx26 and Cx43 might be
      related to the differentiation of the arachnoid villi and meningiomas, and
      exhibit the different origin of various subtypes of meningiomas. We proposed that
      Cx expression is one of the useful markers for the differentiation of meningioma
      and hemangiopericytoma.

PMID- 12484566
TI  - Selective neurofibrillary degeneration of the hippocampal CA2 sector is
      associated with four-repeat tauopathies.
AB  - The CA2 sector of the hippocampus is relatively resistant to neurofibrillary
      tangles in aging and Alzheimer disease; however, some cases have selective
      neurofibrillary degeneration in CA2 with sparing of the more vulnerable CA1
      sector. Cases such as this do not fit in the Braak and Braak staging scheme and
      can be considered to have an atypical pattern of neurofibrillary degeneration. We
      identified 24 atypical cases with an average age at death of 78.6 +/- 1.4 yr and
      average Braak stage of 3.2 +/- 0.4 and describe their pathologic and genetic
      characteristics with Gallyas silver staining, immunohistochemistry for tau and
      alphaB-crystallin, as well as apolipoprotein-E (ApoE) and tau genotyping. Three
      cases were excluded from further analysis due to presence of hippocampal
      sclerosis. All but 1 of the remaining 21 atypical cases were four-repeat (4R)
      tauopathies, including progressive supranuclear palsy, corticobasal degeneration,
      and argyrophilic grain disease (AGD). Remarkably, 19 of the 21 atypical cases
      were pure or mixed cases of AGD. The ApoE epsilon4 allele frequency was similar
      to normal controls, while there was a trend for an increased frequency of the
      extended tau H1 haplotype in atypical cases. Selective neurofibrillary
      degeneration in CA2 sector of the hippocampus is not widely recognized, but when
      detected should suggest the possibility of a 4R-tauopathy, particularly AGD.

PMID- 12484568
TI  - Long-term accumulation of amyloid-beta in axons following brain trauma without
      persistent upregulation of amyloid precursor protein genes.
AB  - Brain trauma has been shown to be a risk factor for developing Alzheimer disease
      (AD), and AD-like plaques containing amyloid-beta (Abeta) peptides have been
      found in the brain shortly following trauma. Here, we evaluated the effects of
      brain trauma on the accumulation of Abeta and expression of amyloid precursor
      protein (APP) genes (APP695 and APP751/ 770) over 1 yr in a non-transgenic rodent
      model. Anesthetized male Sprague-Dawley rats were subjected to parasagittal fluid
      percussion brain injury of moderate severity (2.5-2.9 atm) or sham treatment and
      their brains were evaluated at 2, 4, 7, 14 days, and 1, 2, 6, 12 months following
      injury. Immunohistochemical analysis detected only weak Abeta staining by 2 wk
      following injury. However, by 1 month to 1 yr following injury, strong
      immunoreactivity for Abeta was found in damaged axons throughout the thalamus and
      white matter. Western blot analysis confirmed the accumulation of Abeta peptides
      in tissue from injured brains. Although in situ hybridization demonstrated an
      increased gene expression of APP751/770 surrounding the cortical lesion at 2 to 7
      days following injury, this expression returned to baseline levels at all
      subsequent time points and no increase in the expression of APP695 was detected
      at any time point. These results demonstrate that long-termAbeta accumulation in
      damaged axons can be induced in a non-transgenic rodent model of brain trauma.
      Surprisingly, the extent of this Abeta production appeared to be dependent on the
      maturity of the injury, but uncoupled from the gene expression of APP. Together,
      these data suggest a mechanism that may contribute to long-term neurodegeneration
      following brain trauma.

PMID- 12484569
TI  - Astrocytic deformity and globular structures are characteristic of the brains of
      patients with aceruloplasminemia.
AB  - Aceruloplasminemia is an interesting disease, the study of which helps elucidate
      how iron-induced oxidative stress is involved in neuronal cell death. In order to
      study the neuropathological characteristics associated with oxidative stress, we
      scrutinized the brains of 5 patients with aceruloplasminemia histopathologically
      and immunohistochemically. The pathological findings were essentially similar in
      all patients. In the frontal cortices, iron deposition and neuronal cell loss
      were trivial, but in the basal ganglia (especially in the caudate nucleus and
      putamen), severe iron overload and extensive neuronal loss were noted. Iron
      deposition was more prominent in the astrocytes than in the neurons in both
      regions. 4-hydroxynonenal (HNE), one of the most physiologically active lipid
      peroxides, was strongly detected on neurons and astrocytes by immunostaining.
      Markedly deformed astrocytes were observed in the striatum. These astrocytes were
      similar to Alzheimer type 1 astrocytes. Globular structures were seen in
      proportion to the degree of iron deposition. They clearly reacted with anti-glial
      fibrillary acidic protein (GFAP) and anti-S-100 antibodies and contained glial
      fibril-like filaments, but showed no or only faint immunoreactivity to antibodies
      for neuronal marker proteins, such as neurofilament and synaptophysin. Therefore,
      the globular structures presumably originated from astrocytes. The structures
      also reacted positively to anti-HNE and anti-ubiquitin antibodies. We conclude
      that astrocytic deformities and globular structures are characteristic
      neuropathological features of aceruloplasminemia and are closely linked to iron
      overload and subsequent oxidative stress.

PMID- 12484570
TI  - High-throughput molecular profiling of high-grade astrocytomas: the utility of
      fluorescence in situ hybridization on tissue microarrays (TMA-FISH).
AB  - Due to recent biological and technical advances, the list of potentially useful
      candidate genes is rapidly expanding in the study of brain tumors. However,
      traditional methods of screening individual genes in individual samples are slow
      and tedious, often with consumption of precious resources after only a few
      experiments. This study evaluates the feasibility of high-throughput molecular
      analysis using fluorescence in situ hybridization (FISH) on glioma tissue
      microarrays (TMA). A single microarray paraffin block was constructed using 65
      WHO grade III and IV astrocytomas, sampled in duplicate with 0.6-mm-diameter
      punch cores. FISH was used to detect common alterations, such as EGFR
      amplification, chromosome 7, 9, and 10 aneusomies and deletions of 1p, 19q, PTEN,
      DMBT1, and p16. Of 585 hybridization sets, 508 (87%) yielded interpretable data,
      with hybridization failure in 33 (5.5%) and dislodged tissue in 44 sets (7.5%),
      respectively. Glioblastomas harbored significantly more alterations than
      anaplastic astrocytomas, with the overall frequencies of alterations similar to
      those reported using other techniques. The overall concordance rate between
      paired tumor core samples was 93%. We conclude that TMA-FISH is an efficient and
      reliable method for detecting molecular alterations in high-grade astrocytomas.

PMID- 12484571
TI  - Neuropathological changes in a mouse model of progressive myoclonus epilepsy:
      cystatin B deficiency and Unverricht-Lundborg disease.
AB  - Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a
      recessively inherited neurodegenerative disease caused by loss-of-function
      mutations in the gene encoding cystatin B, a cysteine protease inhibitor. Mice
      with disruptions in this gene display myoclonic seizures, progressive ataxia, and
      cerebellar pathology closely paralleling EPMI in humans. To provide further
      insight into our understanding of EPM1, we report pathological findings in brains
      from cystatin B-deficient mice. In addition to confirming the loss of cerebellar
      granular cell neurons by apoptosis, we identified additional neuronal apoptosis
      in young mutant mice (3-4 months old) within the hippocampal formation and
      entorhinal cortex. In older mutant mice (16-18 months old), there was also
      gliosis most marked in the presubiculum and parasubiculum of the hippocampal
      formation, as well as the entorhinal cortex, neocortex, and striatum.
      Furthermore, widespread white matter gliosis was also noted, which may be a
      secondary phenomenon. Within the cerebral cortex, cellular atrophy was a
      prominent finding in the superficial neurons of the prosubiculum. Finally, we
      show that mutant mice in either a "seizure-prone" or "seizure-resistant" genetic
      background display similar neuropathological changes. These findings indicate
      that neuronal atrophy is an important consequence of cystatin-B deficiency
      independent of seizure events, suggesting a physiological role for this protein
      in the maintenance of normal neuronal structure.

PMID- 12484572
TI  - Genetic alterations commonly found in diffusely infiltrating cerebral gliomas are
      rare or absent in pleomorphic xanthoastrocytomas.
AB  - Pleomorphic xanthoastrocytoma (PXA) is a rare, usually well-circumscribed and
      superficially located neoplasm that preferentially arises in the cerebral cortex
      of children and young adults. The molecular aberrations that are associated with
      these tumors have not been studied systematically so far. We here report on a
      molecular genetic analysis of 62 PXAs (46 PXAs of World Health Organization [WHO]
      grade II and 16 PXAs with anaplastic features) for alterations of 5 candidate
      genes known to be frequently aberrant in diffusely infiltrating astrocytic
      gliomas, i.e. TP53, CDKN2A (p16(INK4a)), CDK4, MDM2, and EGFR. Only 3 PXAs (5%)
      carried a TP53 mutation. None of the 62 PXAs had lost both copies of the CDKN2A
      gene. The CDK4, MDM2, or EGFR genes were not amplified in any of the tumors.
      Fourteen PXAs were additionally analyzed for loss of heterozygosity (LOH) at
      microsatellite markers located on the chromosomes/chromosomal arms 1, gp, 9p, 10,
      17, 19q, and 22q. Two PXAs (14%) had LOH at all informative markers on 9p, while
      1 PXA demonstrated an interstitial area of allelic imbalance between D22S533 and
      D22S417 at 22q11.2-q13.3. Further analysis of 10 PXAs for inactivation of the
      CDKN2A. p14(ARF), and CDKN2B (p15(INK4b)) genes on 9p21 did not reveal any
      homozygous deletion, mutation, promoter hypermethylation, or complete loss of
      mRNA expression. Taken together, our results indicate that the chromosomal and
      genetic aberrations in PXAs are different from those typically associated with
      the diffusely infiltrating astrocytic and oligodendroglial gliomas. These genetic
      differences likely contribute to the more favorable behavior of PXAs and may be
      helpful for the molecular differential diagnosis of cerebral gliomas.

PMID- 12484573
TI  - Circulating autoantibodies recognize and bind dying neurons following injury to
      the brain.
AB  - While it is known that autoimmune cells can protect against cell damage following
      traumatic injury of the brain, the role of autoantibodies in brain injury is less
      clear. Here we present evidence in adult rats that following a cortical lesion of
      the brain, circulating IgG autoantibodies bind to dying neurons in the vicinity
      of the lesion. At intervals that ranged from 4 h to 7 days after making a
      unilateral lesion of visual cortex, we observed neurons near the lesion that were
      immunopositive for rat IgG. Many of these IgG-positive neurons were in advanced
      stages of degeneration. The magnitude of the immunostaining observed was directly
      proportional to the percent reactivity to rat IgG of the antibodies that were
      used. Preadsorption of the antibodies with rat serum eliminated the
      immunostaining. In addition, immunostaining for serum albumin in sections through
      the cortical lesion was negative, supporting the conclusion that the positive
      staining for IgG does not result from the passive diffusion of serum proteins
      into injured cells. Instead, the evidence presented here strongly suggests that
      naturally occurring IgG autoantibodies bind specifically to dying neurons in the
      injured brain. We propose that this autoantibody binding may participate in the
      phagocytosis and removal of injured neurons.

PMID- 12484574
TI  - A review of techniques for liver resection.
AB  - BACKGROUND: There has been a significant increase in the number of hepatic
      resections performed. The aim of this review was to assess available techniques
      for liver resection and their application. METHODS: A literature review was
      performed based on a Medline search to identify articles on liver resection.
      Keywords included liver resection, liver neoplasm, cancer, colorectal metastases
      and hepatocellular carcinoma. RESULTS: Improved understanding of the segmental
      anatomy of the liver has resulted in the evolution of liver resection. The
      development of new approaches to the biliovascular tree, combined with clamping
      to produce ischaemic demarcation, has been important in demonstrating segmental
      boundaries for resection. The combination of methods of vascular control such as
      the Pringle manoeuvre and techniques of parenchymal resection such as ultrasonic
      dissection allows hepatic resection with minimal blood loss and morbidity.
      CONCLUSIONS: Application of refined techniques for liver resection by specialised
      units allows liver resection to be performed on both normal and cirrhotic livers
      with low morbidity and mortality.

PMID- 12484575
TI  - Duration of symptoms and spread of colorectal cancer: a short history does not
      mean early disease.
AB  - The 5-year survival rates for colorectal cancer are generally lower in the UK
      than other European countries. In an attempt to improve prognosis, central
      government has stipulated that patients with suspicious symptoms ought to be seen
      within 2 weeks of referral from a primary care physician. In order to evaluate
      whether symptom duration affects stage at presentation of colorectal cancer, a
      retrospective analysis of all patients presenting over a 2-year period to a large
      district general hospital was performed. There was no significant difference (P =
      0.885) in Dukes' staging in patients with symptoms lasting less or more than 6
      months. Though seeing patients with symptoms suspicious of colorectal cancer in
      specialist out-patient clinics within 2 weeks of presentation to the primary care
      physician would probably reduce the number of patients presenting as an
      emergency, it is unlikely to improve prognosis. Thus funds diverted towards the 2
      week wait are probably best utilised for other procedures such as colonoscopy and
      for improving care once the diagnosis of cancer has been made. Diagnosis of
      colorectal cancer at an earlier stage is best achieved by screening of the
      population.

PMID- 12484576
TI  - The fourteen-day rule and colorectal cancer.
AB  - OBJECTIVE: To examine the effect of the fourteen-day rule on the colorectal
      service of a district general hospital. METHODS: Prospective audit of all
      patients referred by general practitioners to the colorectal service of a
      district general hospital serving a population of approximately 300,000 people.
      The main outcome measures were: (i) mean interval in days from referral to first
      clinic appointment; (ii) first clinic appointment to diagnosis; and (iii) overall
      interval from referral to diagnosis. RESULTS: There was a change in the referral
      pattern with greater numbers of 'fourteen-day rule' and urgent referrals than
      expected (P < 0.001). The mean time interval from referral to diagnosis was
      reduced (P < 0.01). This was due to a reduction in the wait for a first clinic
      appointment (P < 0.01). The wait between first appointment and diagnosis was
      unchanged (P < 0.05). Waiting times for patients referred as 'routine' or whose
      GPs did not specify a priority also improved. CONCLUSIONS: The 'fourteen-day
      rule' with respect to colorectal cancer has reduced waiting times for a first
      appointment to see a specialist. Further improvements will require additional
      resources to reduce the delay for investigations. The effect on long-term
      survival remains to be seen.

PMID- 12484577
TI  - Surgical specialist registrars can safely perform resections for carcinoma of the
      rectum.
AB  - AIM: To assess morbidity, mortality and cancer-related outcomes after supervised
      rectal resection for cancer by surgical specialist registrars (SpRs). PATIENTS: A
      total of 205 consecutive patients (115 male; median age 64 years [range, 24-90
      years]) under the care of six consultant surgeons, who underwent elective rectal
      resection of their rectal cancer between 1995-1999 were studied. The modified
      Dukes' stages were A in 28 patients (13%), B in 47 (21%), C in 103 (51%), and D
      in 30 (15%). RESULTS: Sixty-eight patients (35 males) of mean age 64 years
      (range, 38-82 years) underwent supervised resection (60 anterior resections. 8
      abdomino-perineal resections) by a SpR. Of these, 7 (10%) were modified Dukes'
      stage A, 16 (22%) stage B, 37 (54%) stage C, and 8 (13%) stage D. Postoperative
      morbidity (SpRs 32% versus consultants 41%; P = 0.25) and mortality (SpRs 3%
      versus consultants 6%; P = 0.1) were comparable with consultant outcomes. Local
      recurrence rates (SpRs 9% versus consultants 9%; P = 0.5) and crude survival
      (SpRs 64% versus consultants 61%; P = 0.31) were also comparable after a median
      follow-up of 48 months (range, 24-72 months). CONCLUSION: Operative and cancer
      related outcomes are not compromised by supervised SpR resections of rectal
      cancer in selected patients.

PMID- 12484578
TI  - Hunterian lecture. Laparoscopic transabdominal pre-peritoneal (TAPP) repair of
      groin hernia: one surgeon's experience of a developing technique.

PMID- 12484579
TI  - Wroblewski wedge augmentation for recurrent posterior dislocation of the Charnley
      total hip replacement.
AB  - We analysed 68 cases of acetabular augmentation using the Wroblewski wedge for
      recurrent posterior dislocation of Charnley total hip replacements inserted
      through a posterior approach. The follow-up was done by postal questionnaire in
      living patients or by thorough search of case notes in the dead. All hips were
      followed up either until death or a minimum of 2 years. The average follow-up for
      the surviving successful group was 35.3 months. Out of 68 hips, 52 (76%) had no
      further dislocation at a mean follow-up of 35.3 months (range, 24-95 months). An
      additional 4 hips became stable after one closed reduction for a re-dislocation.
      After a second augmentation, 5 more hips were stabilised. Wroblewski wedge
      augmentation is a simple and effective procedure and should be considered before
      embarking on major revisions in recurrent posterior dislocations in the elderly
      with no obvious cause for instability.

PMID- 12484580
TI  - Informed consent for total hip arthroplasty: does a written information sheet
      improve recall by patients?
AB  - OBJECTIVE: To ascertain whether a written information sheet is acceptable to
      patients and improves recall of the consent interview. DESIGN: Prospective
      randomised controlled study using questionnaires, comparing a group of patients
      given information in a written sheet with appropriate explanation to a group
      given verbal information alone. SETTING: A specialist orthopaedic surgery unit.
      PATIENTS: The test group was 126 patients undergoing revision or primary total
      hip arthroplasty; 65 patients were given information verbally, 61 patients were
      given written information. OUTCOME MEASURE: Patients' recall of information
      given, tested with a questionnaire completed on admission (mean of 18 days
      later). RESULTS: The patients receiving written information scored significantly
      higher (48% correct answers) than the patients receiving verbal information (38%
      correct answers). CONCLUSIONS: Written information sheets contribute to the
      process of informed consent. As patients' recall of information is generally
      poor, the sheets may also be useful medicolegally, as a permanent record of what
      was discussed.

PMID- 12484581
TI  - The experience and training of British general surgeons in trauma surgery for the
      abdomen, thorax and major vessels.
AB  - BACKGROUND: The report Better Carefor the Severely Injured [London: The Royal
      College of Surgeons of England and the British Orthopaedic Association; 2000]
      states that an experienced general surgeon trained in the techniques required to
      perform life-saving emergency surgery is vital in the management of major trauma.
      The experience and training of general surgeons in the UK in the management of
      trauma to the abdomen, thorax and major vessels has never been assessed. METHOD:
      Postal questionnaire sent to UK general surgical consultants and Higher Surgical
      Trainees (HSTs). RESULTS: A total of 854 (48%) questionnaires were completed. Of
      respondents, 85% believe that major trauma should be directed to hospitals that
      provide a dedicated trauma service. Of non-vascular specialists, 43% felt their
      training was adequate to manage vascular trauma and only one-third of general
      surgical consultants felt adequately prepared to manage acute cardiothoracic
      injuries. The median number of trauma laparotomies undertaken annually was 2 for
      blunt injury and 1 for penetrating injury. Of HSTs, 21% had not performed a
      splenectomy for trauma and 44% had no experience of packing for liver injuries.
      CONCLUSIONS: There is limited experience and training in the surgical management
      of torso trauma in the UK. Implementation of the recommendations from Better Care
      for the Severely Injured will be hampered unless steps are taken to maximise
      experience and improve training.

PMID- 12484582
TI  - Abdominal aortic aneurysm and gastrointestinal disease: should synchronous
      surgery be considered?
AB  - BACKGROUND: Abdominal aortic aneurysm (AAA) is relatively common in an age group
      in which other abdominal pathologies have an increasing incidence. The co
      existence of an aneurysm with a second intra-abdominal pathology presents a
      difficult management problem for the surgeon. Synchronous aortic and
      gastrointestinal surgery is often avoided due to the perceived higher risk of
      infection of the vascular prosthesis. METHODS: Cases of synchronous AAA repair
      with a second gastrointestinal/biliary procedure were identified from the
      operative records of a single vascular surgeon working in a district general
      hospital. RESULTS: Eight cases were identified over a 10-year period, comprising
      3 large bowel resections, 2 cholecystectomies and 3 upper gastrointestinal
      operations as the second synchronous procedure. No graft infections were recorded
      in this group and there was one death within 30 days. CONCLUSIONS: From our
      experience and a review of the available literature we conclude that synchronous
      aortic and gastrointestinal surgery should be considered when urgent surgery for
      both conditions is indicated.

PMID- 12484583
TI  - The influence of histological diagnosis on the postoperative complication rate
      following trans-urethral resection of prostate (TURP).
AB  - BACKGROUND: A number of studies have shown that the early mortality following
      TURP is higher for patients with prostate cancer than those with benign disease.
      This study examines the effect of the histological diagnosis on the predischarge
      complication rate following TURP. METHODS: Information on the postoperative,
      predischarge complications of 3036 patients, who underwent TURP over the last
      decade at our institution, was collated from the urology department database
      (AuditBase for Windows). The information on this database is collected
      prospectively, at the point of care and validated at monthly audit meetings.
      Statistical analyses were performed using chi2 and difference of proportion where
      n > 60. Statistical significance was taken as P < 0.05. RESULTS: The
      postoperative, predischarge major complication rate for patients with benign
      disease was 2.1%. This was not statistically different from the 2.3% complication
      rate seen in patients with malignant disease. Patients suffering a postoperative
      complication stayed in hospital significantly longer than those who had a
      straightforward postoperative course (P < 0.001); however, patients with
      malignant histology suffering a postoperative complication did not stay
      statistically significantly longer than those with benign histology suffering a
      postoperative complication (P < 0.1). CONCLUSIONS: Patients undergoing TURP for
      prostate cancer do not suffer more postoperative, predischarge complications or
      stay in hospital longer than patients undergoing TURP for benign disease.

PMID- 12484584
TI  - An investigation into the sensitivities of translocating bacteria to a
      prophylactic antibiotic regimen.
AB  - INTRODUCTION: It is well established that bacterial translocation is associated
      with a significant increase in septic morbidity. The purpose of this study was to
      determine the antibiotic sensitivities of translocating bacteria on the basis
      that this information may influence antibiotic prophylaxis in surgical patients.
      METHODS: Routine microbiological techniques were used to assess the antibiotic
      sensitivities of those bacteria cultured from a mesenteric lymph node harvested
      at laparotomy in a large series of patients. RESULTS: Culture of the mesenteric
      lymph nodes yielded growth in 51 out of a total of 447 patients studied (11.4%).
      The isolates from 40 patients, a total of 60 organisms, were available for
      sensitivity testing. The most common species grown was Escherichia coli (48% of
      isolates). Thirty-three patients (83%) grew organisms sensitive to the antibiotic
      prophylaxis used, but there was no significant difference in the incidence of
      postoperative septic complications between these patients and those in whom
      resistant bacteria were grown (39% versus 29%, P = 0.64 Fisher's Exact test mid
      P). CONCLUSIONS: The majority of translocating bacteria are sensitive to the
      prophylactic antibiotics commonly used in patients undergoing laparotomy.
      However, the occurrence of postoperative septic morbidity is independent of this
      variable.

PMID- 12484585
TI  - Is day case surgery the key to basic surgical training?
AB  - The logbooks of 5 senior house officers (SHOs) were audited to determine
      progression of surgical skills on a single vascular firm. Total surgical
      experience and, in particular, experience in varicose vein and arterio-venous
      fistula surgery, performed in the day-case unit (DCU), were examined. Trainees
      were divided into those undertaking their first surgical SHO post (group 1, n =
      2) and those who had had previous surgical exposure (group 2, n = 3) on the basic
      surgical training rotation. SHOs were exposed to a mean of 273 (+/- 41 SD)
      operative cases in 6 months. Emergency work comprised 15% (+/- 7%) of workload.
      Day cases accounted for 35% (+/- 3%) of elective workload. A mean of 66 (+/- 5)
      varicose vein and AVF cases were undertaken in the DCU. This represented 82% (+/-
      6%) of day-case operative experience for the firm. SHOs undertook 12 (+/- 6)
      VV/AVF cases unassisted, 35 (+/- 5) cases with senior assistance, and 20 (+/- 11)
      as first assistance in the DCU. All SHOs progressed to being able to perform
      arterial bypass and amputation (with senior assistance) during their time on the
      firm. There was no significant difference in experience or progression to major
      vascular surgery between group 1 and group 2 in this study except in lower limb
      amputation procedures. It is concluded that vascular surgical firms can provide a
      good introduction to surgical skills. Most experience as first operator was
      gained in the DCU and we suggest that those undergoing basic surgical training
      might benefit from an attachment to the DCU early in their rotations.

PMID- 12484586
TI  - Diagnosis of facial bone fractures.

PMID- 12484587
TI  - Circumumbilical incision for Ramstedt's pyloromyotomy.

PMID- 12484588
TI  - Centralisation of holding screws during external fixation.

PMID- 12484589
TI  - Thimble-assisted Burch colposuspension.

PMID- 12484590
TI  - Looking for bleeders in the pelvis.

PMID- 12484591
TI  - 'Collar-and-cuff' sling for the positioning of the ipsilateral arm on the
      fracture table.

PMID- 12484592
TI  - Tissue protector for tibial intramedullary nailing.

PMID- 12484593
TI  - Response to paper on: Suturing: a lost art by MS Khan, SD Bann, A Darzi, PEM
      Butler Ann R Coll Surg Engl 2002; 84: 278-9.

PMID- 12484594
TI  - Techniques by Caruana and Singh and Khanduja et al.

PMID- 12484595
TI  - Laparoscopic procedures are associated with a significant risk of digital nerve
      injury for general surgeons.

PMID- 12484596
TI  - Misting of eye protection during surgery.

PMID- 12484597
TI  - Response to article by GS Arul & RD Spicer: Ecthyma gangraenosum--a trap for the
      unwary.

PMID- 12484598
TI  - Technique evolution for facial paralysis reconstruction using functioning free
      muscle transplantation--experience of Chang Gung Memorial Hospital.
AB  - The author performed facial reanimation by using functioning free muscle
      transplantation in 116 cases from 1986 to 2000. Three consecutive five-year
      periods are presented in relation to each stage of the author's technical
      improvement. The first five years bulkiness and asymmetrical smiling with weak
      gum exposure were encountered and required correction. The second five years was
      a period of technical improvement, but with residual deformities. The third five
      year period was one of technique refinement. The author extended the utility of
      the gracilis for different and more challenged problems, such as the use of a
      muscle plus skin two-unit composite flap connected by the septoperforator
      nutrients, not only for facial reanimation but also for intra-oral contracture
      release or extra-oral facial soft tissue and skin deficits replacement.

PMID- 12484599
TI  - The three-stage concept to optimize the results of microsurgical reanimation of
      the paralyzed face.
AB  - From the authors three-dimensional video analyses they had to learn that the
      advantages of a one-stage procedure is outweighed by far by the disadvantages. A
      three-stage concept to a one-stage procedure was preferred for the following
      reasons: 1. Safety of having a cross-face nerve graft to cover the distance from
      the healthy facial nerve to the nerve of the muscle transplant without problems
      and without the danger of tension on the nerve suture line because of shortage of
      the muscle nerve. 2. Independence of anatomical variations like a very proximal
      muscle hilus in the latissimus dorsi muscle e.g., resulting in a too short muscle
      nerve. 3. Only face-lift incisions are necessary without the need of an
      additional incision in the nasolabial fold while using a cross-face nerve graft.
      4. Freedom of positioning the muscle graft on the paralyzed side with free choice
      of the position of the transplant hilus. 5. The superficial temporal vessels can
      be used for microvascular anastomoses. 6. Prevention of a scar in the
      submandibular region with its tendency of hypertrophy, especially if it is
      connected to the preauricular incision. Different functional territories of one
      muscle transplant for eye closure and for smile is only possible in combination
      with two cross-face nerve grafts. Further on the three-dimensional video analysis
      showed clearly that Final surgical corrections for improvement of the static and
      dynamic symmetry should be performed. when the muscle transplant or the
      transposed muscle have gained their final functional result, which is often not
      before one or one and a half year after muscle transplantation. Therefore a three
      stage concept is needed for the majority of patients. Detailed analyses of the
      movements in the different regions and the comparison of both sides clarify
      preoperatively the indication for the operative techniques to be used, and
      describe exactly the improvement of the overall result. It is not only possible
      to show, eg, the better positioning of the alar of the nose by a nasolabial
      dermal suspension plasty on the paralyzed side in millimeter, but also the
      influence on the relation of all the different points in the face (Fig. 5). The
      comparison of the right and the left side gives exact data on the symmetry of the
      face on rest and during the different movements. Of course, also qualities of
      facial reanimation like prevention of mass movements or synkinesias are detected
      in the three-dimensional graphs of all the points at the same time or in the
      repeated reviews of the original movement in the original video sequence. In
      conclusion, three-dimensional video analysis of facial movements became an
      important tool for online planning of operative procedures for the individual
      patient, and an excellent tool for comparative studies of different operative
      concepts and alternative operative techniques within a standardized registry of
      one center treating facial palsy or within international multicenter studies.

PMID- 12484600
TI  - Basic science behind functioning free muscle transplantation.
AB  - Free muscle transfer is now a feasible procedure in several fields of
      reconstructive surgery. In this article, basic science behind clinical free
      muscle transfer, including essential aspects like donor muscle selection (type of
      blood supply, architecture of fibers, fiber length, and muscle volume), donor
      nerve selection, placement and routing of muscle, tension of muscle at suturing,
      postoperative monitoring of muscle circulation, postoperative reinnervation, and
      rehabilitation are discussed in detail.

PMID- 12484601
TI  - Mobius and Mobius-like patients: etiology, diagnosis, and treatment options.
AB  - The surgical goal in Mobius patients is far more modest and differs from patients
      with unilateral developmental facial paralysis. It is impossible to restore a
      true smile in these mask-like, expressionless faces. Despite sophisticated
      microneurovascular transplantations, movement can only be restored along one
      vector and enhanced firmness in the cheeks, thus multiple differentiated facial
      animation is not achievable. A detailed neurological evaluation can identify
      possible motor donors or residual function, which can be used for additional
      dynamic restorations. Due to the multiple cranial nerve involvement a thorough
      clinical and electrophysiological examination is mandatory. In addition,
      electromyographic survey of the potential motor donors is very helpful to avoid
      weak wasted regeneration and prevent further downgrading of function. Because of
      the variety of cranial nerves involved in Mobius' syndrome, a standard procedure
      for dynamic restoration cannot and should not be promoted; instead, a careful
      preoperative objective and quantitative assessment should guide the
      reconstructive surgeon to the optimal reconstruction strategy. Useful movement
      can be restored in afflicted patients that may signal physical and psychological
      rehabilitation.

PMID- 12484602
TI  - Result of microvascular gracilis transplantation for facial paralysis-personal
      series.
AB  - Clinical series of segmental gracilis microvascular transplantation for the
      treatment of long-standing facial paralysis. Discussion on the evaluation of
      results and some data obtained from this series.

PMID- 12484603
TI  - Aesthetic considerations in facial reanimation.
AB  - The treatment results of facial paralysis have improved within the last two
      decades with the introduction of new techniques for neuromuscular reconstruction.
      However, many patients still complain of aesthetic imbalance impairment after
      treatment. This article presents some complementary procedures that can be used
      to improve the appearance of the face either isolated in incomplete palsies, or
      after the completion of reconstructive procedures in complete paralysis. The
      procedures are divided according to anatomical areas--forehead, eyelids, middle
      third of the face, and the lower lip.

PMID- 12484604
TI  - Treatment of weakness of the lower lip depressor.
AB  - Weakness of the lower lip is an embarrassment for the subject, and in the act of
      normal speech the depressor is activated and produces a functional asymmetry with
      the paralyzed side. A number of methods have been used to improve balance by
      paralyzing the active side or increasing the power of the paralyzed side. The
      author presents his experience with these methods and provides an algorithm for
      treatment.

PMID- 12484605
TI  - The treatment of unilateral and bilateral facial palsy using free muscle
      transfers.
AB  - A 25-year experience in the treatment of unilateral and bilateral facial palsies
      is presented. The advent of crossed facial nerve grafts and revascularized muscle
      grafts gives a high proportion of facial reanimation. The choice for the muscle
      graft is the pectoralis minor. The latissimus dorsi can be used in unfavorable
      cirumstances or in bilateral facial palsies. Although recovery of movement is
      high, the search for refinement and symmetry continues. This article encapsulates
      the author's philosophy in trying to achieve these goals.

PMID- 12484606
TI  - Cross-facial and functional microvascular muscle transplantation for longstanding
      facial paralysis.
AB  - Functional results continue to improve with advancing microsurgical techniques
      and monitoring to detect and correct problems within minutes [47]. However,
      failures do occur, even when one can project a 98% survival for the transplant.
      Figs. 9 and 10 show two of our early cases that were fortunately salvaged with a
      second microvascular transplant. Evaluation of the result is a continuing
      challenge--anatomically, physiologically, and psychologically [37]. If one can
      remove the stigma or stigmata of facial paralysis in the patient's mind. success
      has been achieved (Fig. II) [48].

PMID- 12484607
TI  - Cellular precursors of the coronary arteries.
AB  - Coronary vessels develop from a primary vascular network that differentiates in
      the subepicardium through a process of vasculogenesis, that is, self-assembly of
      mesenchymal vascular progenitors. Further growth of the subepicardial vascular
      plexus through a complex process of angiogenesis, vascular remodeling, and
      arterialization of specific branches gives rise to the definitive coronary
      system. This report is intended to summarize current knowledge on the origin of
      the coronary vascular progenitors and to provide new insights suggested by recent
      findings. It has been established that the mesenchymal precursors of the vascular
      smooth muscle cells and the adventitial fibroblasts originate from an epithelial
      mesenchymal transformation of the epicardial mesothelium. We report herein
      experimental evidence that the precursors of the coronary endothelium are also
      epicardium-derived cells (EPDCs). The evidence shown includes co-localization of
      mesothelial and endothelial molecular markers as well as cell lineage studies
      performed through direct labeling of the epicardial cells. If this proposal is
      confirmed, the early EPDCs might be found to have a competence similar to that
      shown by the recently discovered bipotential vascular progenitor cells, which are
      able to differentiate into endothelium or smooth muscle depending on their
      exposure to VEGF or PDGF-BB. It is conceivable that the earliest EPDCs
      differentiate into endothelial cells in response to myocardially secreted VEGF,
      while subsequent EPDCs, recruited by the nascent capillaries via PDGFRbeta
      signaling, differentiate into percytes and smooth muscle cells.

PMID- 12484608
TI  - Role of growth factors in coronary morphogenesis.
AB  - This communication briefly reviews the role of angiogenic growth factors in
      myocardial vessel formation during development. The earliest signs of
      vascularization are the migration and differentiation of angioblasts from the
      epicardium and subepicardium into the myocardium. A regulator of this process is
      vascular endothelial growth factor (VEGF), which is probably triggered by
      hypoxia. The subsequent formation of vascular tubes is regulated by multiple
      growth factors: VEGF family members, fibroblast growth factors (FGFs), and
      angiopoietins and their receptors. Our studies on explanted quail hearts reveal
      that these growth factors are interdependent. We also have shown that a harmonic
      interplay of growth factors characterizes early postnatal development in rats.
      Neutralizing antibodies to either basic FGF (bFGF) or VEGF inhibit capillary
      formation, whereas arteriolar growth is markedly inhibited by bFGF, but not VEGF,
      neutralizing antibodies. Arteriolar diameter is also increased when anti-bFGF and
      anti-VEGF are administered in combination. Thus, the hierarchical development of
      the arteriolar vasculature depends on both of these growth factors; however, the
      establishment of arterioles, as reflected by length density, is dependent on bFGF
      but not on VEG. Finally, stretch of cardiac myocytes and endothelial cells serves
      as a stimulus for increases in growth factor and receptor proteins. We have shown
      that cyclic stretch of either cell type increases VEGF, and that endothelial
      cells respond to stretch by up-regulation of VEGF receptor-2 (VEGFR-2), and Tie-2
      receptor. These results indicate that both mechanical and metabolic factors are
      primary stimuli for coronary angiogenesis.

PMID- 12484609
TI  - The role of the epicardium and neural crest as extracardiac contributors to
      coronary vascular development.
AB  - At species-specific times in embryonic development, the pro-epicardial organ
      appears as an outcropping of the mesothelial body wall, near the sinus venosus
      liver region. The pro-epicardial vesicles attach to the myocardium, flatten, and
      join to form the epicardium. The epicardium shows epithelial-mesenchymal
      transformation: cells detach from the epithelium, fill the subepicardial space,
      and invade the heart tube. Epicardium-derived cells migrate as far as the core of
      the endocardial cushions, which differentiate into the atrioventricular valve
      leaflets. In the cardiac wall, other epicardium-derived cells differentiate into
      interstitial fibroblasts and adventitial and smooth muscle cells of the coronary
      arteries. Using neural crest tracings in mouse embryos (Wnt1-Cre-lacZ), we
      studied the patterning of cardiac neural crest cells during development.
      Participation of neural crest cells in the formation of the vascular media could
      not be excluded, although epicardium-derived cells have hitherto been considered
      responsible for formation of the coronary arterial smooth muscle cells. The
      endothelial cells of the coronary network derive mostly from the endothelium of
      the sinus venosus-liver region by vasculogenesis and angiogenesis. However, an
      epicardium-derived cell origin of some endothelial cells cannot be ruled out. The
      coronary vasculature is closely related to the differentiating Purkinje network,
      but isolated epicardium-derived cells are also associated with Purkinje cells.
      After ablating the pro-epicardial organ in quail embryos, we found severe
      malformations in the myocardial architecture, leading to the hypothesis that
      epicardium-derived cells give instructive signals to the myocardium for proper
      differentiation of the compact and the trabeculated compartments.

PMID- 12484611
TI  - Coronary artery anomalies--current clinical issues: definitions, classification,
      incidence, clinical relevance, and treatment guidelines.
AB  - The study of coronary artery anomalies would benefit from the clarification of
      various fundamental issues, including the definitions, classification, incidence,
      pathophysiologic mechanisms, and clinical relevance of each anomaly. The greatest
      challenge is to identify the abnormality and determine its clinical relevance so
      that appropriate treatment can be instituted. Currently, the coronary anatomy is
      essentially defined by the features of the (conductive) epicardial coronary tree
      and its dependent territory. Therefore, one must consider all the possible and
      observed variations in anatomic features that are used to describe the coronary
      arteries. We propose that the left anterior descending, circumflex, and right
      coronary arteries be considered the essential elementary units of coronary
      anatomy. We also suggest that the coronary arteries be defined not by their
      origin or proximal course, but by their intermediate and distal segments or
      dependent microvascular bed. A strict classification system is necessary before
      meaningful data can be gathered about the incidence of coronary anomalies. With
      respect to clinical relevance, the greatest challenge is presented by anomalies
      that only occasionally cause critically severe clinical events and are otherwise
      compatible with a normal life. In such cases, it is not known whether the
      specific features of a given anomaly cause adverse clinical consequences, or
      whether additional episodic factors are required. To correlate subclassifiable
      anatomic and functional features with clinical events and prognoses, a large,
      multicenter database, relying on prospective, coordinated protocols, is urgently
      needed. In the absence of established official guidelines, we present practical
      protocols for diagnosing and treating coronary anomalies.

PMID- 12484610
TI  - Coronary arteriogenesis and differentiation of periarterial Purkinje fibers in
      the chick heart: is there a link?
AB  - In the following review, we outline the cellular ontogeny and time course of
      coronary artery development within the vertebrate heart. Our eventual focus will
      be the potential role of arteriogenesis in the differentiation of a subset of
      specialized conduction cells in the chick heart. We begin by briefly outlining
      early heart formation, showing how the outermost layer of the looped, tube heart-
      the epicardium--is of extracardiac origin and provides the progenitor cells to
      the entire vascular bed. Subsequently, we summarize the events of coronary
      arterial development that follow epicardialization. Finally, we discuss work in
      the chick that indicates how arteries form pioneering, directional conduits
      through ventricular tissue, adjacent to which myocardial cells differentiate to
      form the most peripheral component of the avian conduction system--a network of
      periarterial Purkinje fibers.

PMID- 12484612
TI  - Congenital heart defects and coronary anatomy.
AB  - Coronary artery anomalies are a well recognized feature of many cardiac
      malformations and have been catalogued in a number of reviews. This overview
      concentrates on 1) the interplay between congenital heart defects and coronary
      morphogenesis, examining how some of the embryology fits with the experiments of
      nature encountered in clinical practice; and 2) the influence of coronary anatomy
      on patient management. This overview uses, as examples, pulmonary atresia with
      intact ventricular septum, complete and congenitally corrected transpositions of
      the great arteries, and tetralogy of Fallot.

PMID- 12484614
TI  - Surgical treatment of coronary artery anomalies: report of a 37 1/2-year
      experience at the Texas Heart Institute.
AB  - The surgical treatment of coronary artery anomalies continues to evolve. The most
      common coronary artery anomalies requiring surgical intervention include coronary
      artery fistulae, anomalous pulmonary origins of the coronary arteries, and
      anomalous aortic origins of the coronary arteries. The choice of surgical
      intervention for each type of coronary anomaly depends on several anatomic,
      physiologic, and patient-dependent variables. As surgical techniques have
      progressed, outcomes have continued to improve, however, controversy still exists
      about many aspects of the proper management of patients who have these coronary
      artery anomalies. We reviewed the surgical treatment of 178 patients who
      underwent surgery for the above-mentioned types of coronary artery anomalies at
      the Texas Heart Institute from December 1963 through June 2001. On the basis of
      this experience, we discuss historical aspects of the early treatment of these
      anomalies and describe their present-day management.

PMID- 12484615
TI  - Can stent-angioplasty be a valid alternative to surgery when revascularization is
      indicated for anomalous origination of a coronary artery from the opposite sinus?
AB  - When intervention is indicated for anomalous origination of a coronary artery
      from the opposite sinus, stent-angioplasty may seem more attractive than coronary
      artery bypass grafting. However, in the case of anomalous origination of a
      coronary artery from the opposite sinus, the anatomy is quite different from that
      encountered in atherosclerotic disease, and stent-angioplasty would involve
      unusual challenges, both in technique and prognostic outcomes. We illustrate
      these points by presenting the 2 first cases in which intervention was indicated
      because of severe symptoms. We conclude from this preliminary study that coronary
      artery bypass grafting should still be considered the preferred (although
      unproven) method of revascularization in patients who have symptomatic anomalous
      origination of a coronary artery from the opposite sinus. Until adequate data
      have been gathered to evaluate the late results of stent-angioplasty in these
      patients (in comparison with the results of surgical and medical treatment), the
      procedure should be performed only in selected patients, enrolled in prospective,
      controlled studies.

PMID- 12484613
TI  - Systolic compression of epicardial coronary and intramural arteries in children
      with hypertrophic cardiomyopathy.
AB  - It has been suggested that systolic compression of epicardial coronary arteries
      is an important cause of myocardial ischemia and sudden death in children with
      hypertrophic cardiomyopathy. We examined the associations between sudden death,
      systolic coronary compression of intra- and epicardial arteries, myocardial
      perfusion abnormalities, and severity of hypertrophy in children with
      hypertrophic cardiomyopathy. We reviewed the angiograms from 57 children with
      hypertrophic cardiomyopathy for the presence of coronary and septal artery
      compression; coronary compression was present in 23 (40%). The left anterior
      descending artery was most often affected, and multiple sites were found in 4
      children. Myocardial perfusion abnormalities were more frequently present in
      children with coronary compression than in those without (94% vs 47%, P = 0.002).
      Coronary compression was also associated with more severe septal hypertrophy and
      greater left ventricular outflow gradient. Septal branch compression was present
      in 65% of the children and was significantly associated with coronary
      compression, severity of septal hypertrophy, and outflow obstruction.
      Multivariate analysis showed that septal thickness and septal branch compression,
      but not coronary compression, were independent predictors of perfusion
      abnormalities. Coronary compression was not associated with symptom severity,
      ventricular tachycardia, or a worse prognosis. We conclude that compression of
      coronary arteries and their septal branches is common in children with
      hypertrophic cardiomyopathy and is related to the magnitude of left ventricular
      hypertrophy. Our findings suggest that coronary compression does not make an
      important contribution to myocardial ischemia in hypertrophic cardiomyopathy;
      however, left ventricular hypertrophy and compression of intramural arteries may
      contribute significantly.

PMID- 12484616
TI  - TIA--treacherously inaccurate acronym.

PMID- 12484617
TI  - Minilaparotomy for aortoiliac occlusive disease: preliminary results.
AB  - This prospective study was designed to establish the feasibility of
      minilaparotomy for aortobifemoral bypass, and its effect on intraoperative and
      postoperative variables. A minilaparotomy has potential benefits for the patient,
      including smaller size of the surgical wound, reduced risk of infection, shorter
      postoperative intubation, decreased postoperative pain, earlier discharge, and a
      smaller, aesthetically more acceptable postoperative scar. Moreover, reoperation
      is less hazardous, because the peritoneum is not completely dissected. From the
      beginning of June 1999 through the end of September 2001, we used a
      minilaparotomy in 33 patients with aortoiliac occlusive disease. Obesity and
      prior abdominal surgery were regarded as contraindications to the operation. One
      patient required conversion to a full laparotomy because of intraoperative
      bleeding. Another patient developed wound infection. There were no deaths. The
      technique has proved safe, effective, and aesthetically acceptable to the
      patient. To date, no study has compared a median laparotomy with a minimally
      invasive alternative for the surgical treatment of aortoiliac occlusive disease.
      Prospective randomized trials are needed to determine whether minilaparotomy is
      the superior technique for treatment of aorto-occlusive disease.

PMID- 12484618
TI  - Meandering right pulmonary vein to the left atrium and inferior vena cava: the
      first case with associated anomalies.
AB  - We report a case of a healthy, asymptomatic 6-year-old boy in whom an anomalous
      right pulmonary vein was noted to drain into both the inferior vena cava and left
      atrium in association with findings consistent with scimitar syndrome. The
      anomalous pulmonary vein took a very circuitous route through the lungs before
      draining into the left atrium, a condition previously termed "meandering
      pulmonary vein." To aid in the diagnosis, cardiovascular magnetic resonance
      imaging and magnetic resonance angiography were used to delineate this complex
      course and the connection of the anomalous pulmonary vein. To our knowledge, this
      is the 1st reported case of a meandering pulmonary vein with dual drainage to the
      inferior vena cava and left atrium in association with other anomalies.

PMID- 12484619
TI  - Rare chronic gastric volvulus associated with left atrial and mediastinal
      compression.
AB  - We report a case of chronic gastric volvulus associated with left atrial
      compression in a 75-year-old woman who presented with chest pain, shortness of
      breath, and hypotension after elective hemiarthroplasty of the left hip. The
      patient's medical history included a paraesophageal hernia and gastric volvulus
      diagnosed in 1997 but left untreated. The present diagnosis of gastric volvulus
      was made on the basis of a chest radiograph and subsequent computed tomography.
      Echocardiography showed the volvulus compressing the left atrium. Surgery to
      repair the defect was successful, and there were no operative or postoperative
      complications. A review of the world medical literature revealed that gastric
      volvulus is rarely reported to cause hemodynamic compromise or compression of the
      heart and mediastinal structures.

PMID- 12484620
TI  - Surgical management of entrapped percutaneous transluminal coronary angioplasty
      hardware.
AB  - Entrapment and fracture of coronary angioplasty hardware are rare complications
      of percutaneous coronary artery interventions; however, when such incidents
      occur, they frequently require surgical management. Percutaneous retrieval should
      be attempted before surgical retrieval unless hemodynamic stability is a problem.
      Surgical intervention should focus on grafting the affected coronary vessel(s)
      and ensuring that there is no hardware in the aortic root that could serve as a
      nidus for thrombus formation. We present 3 cases from our recent experiences of
      entrapped, fractured hardware.

PMID- 12484621
TI  - Giant hydatid cyst in the interventricular septum of a pregnant woman.
AB  - A 25-year-old woman, pregnant for 38 weeks, was admitted to our clinic with
      dyspnea. Transthoracic echocardiography revealed a large cyst that originated
      from the left side of the interventricular septum, decreasing left ventricular
      volume and almost entirely obstructing the left ventricular outflow tract.
      Cardiac magnetic resonance imaging confirmed a grade 1 hydatid cyst, which
      measured 61 x 59 x 66 mm. The cyst was excised after cesarean section.
      Extirpation required the creation of a small septal defect, which we closed
      without a patch, by suturing the septum directly to the left ventricular wall.
      The patient was discharged without symptoms. The case reported here is of
      particular interest not only because a hydatid cyst is rarely seen in the
      interventricular septum, but because a giant hydatid cyst obstructing the left
      ventricular outflow tract is very rare in pregnancy.

PMID- 12484622
TI  - Giant eustachian valve with echocardiographic appearance of divided right atrium.
AB  - The eustachian valve is an embryologic remnant of the valve of the inferior vena
      cava. It may be prominent in some individuals, but the echocardiographic
      appearance of a divided right atrium, as the consequence of a large eustachian
      valve, is extremely rare. Herein we describe an unusual giant eustachian valve
      with an echocardiographic appearance of a septal structure dividing the right
      atrium into 2 separate chambers. This abnormality should be differentiated from
      cor triatriatum dexter, a very rare cardiac malformation for which it could be
      mistaken.

PMID- 12484623
TI  - Pear-shaped multiple iliac artery aneurysms.

PMID- 12484624
TI  - Delayed traumatic aortic rupture into the esophagus.

PMID- 12484625
TI  - Cardiology's 10 greatest discoveries.

PMID- 12484626
TI  - Cardiology's 10 greatest discoveries.

PMID- 12484627
TI  - Cardiology's 10 greatest discoveries.

PMID- 12484628
TI  - Malarial anemia.

PMID- 12484629
TI  - Sicklemia with multi-organ failure syndrome and thrombotic thrombocytopenic
      purpura.
AB  - Acute multi-organ failure syndrome is a rare and life-threatening complication of
      patients with sickle cell disease. The syndrome appears to be reversed with
      prompt, aggressive exchange transfusion therapy. It has been attributed to
      widespread vascular occlusion due to micro-vascular red cell sickling. We present
      a case of severe multi-organ failure in a patient with sickle thalassemia and
      mild clinical course, who had clinical and laboratory features consistent with
      thrombotic thrombocytopenic purpura (TTP). The dramatic response to therapy with
      plasma exchange, a treatment often effective in TTP, suggests a similarity in
      pathophysiology of micro-vascular occlusion and multi-organ failure in sickle
      cell disease.

PMID- 12484630
TI  - Molecular spectrum of alpha-thalassemia in Tunisia: epidemiology and detection at
      birth.
AB  - We present the characterization of the molecular spectrum and frequency data of
      alpha-thal (thal) defects in Tunisia, and an evaluation of the efficacy and
      limitations of Hb Bart's (gamma4) measurement for the screening of alpha-thal at
      birth. Cord blood samples were collected from two different areas: the northeast
      of the country, an area where Hb H (beta4) disease frequently occurs, and Tunis,
      the capital city, representative of the average Tunisian population. From the
      first group, 110 samples with Hb Bart's and/or microcytosis at birth were
      selected from 1270 randomly collected samples. Two additional population samples,
      one from the same northeastern region (n = 90), the other from Tunis (n = 104)
      were collected randomly. Nine common deletional alpha-thal defects and
      nondeletional mutations were screened. In the northeastern samples, selected for
      the presence of Hb Bart's and microcytosis, the -alpha3.7 deletion was the most
      common defect (4.5% allele frequency) followed by a polyadenylation (poly A)
      signal mutation (1.8%), the five nucleotide (nt) deletion and the -alpha4.2
      deletion (both 0.9%). The African polymorphism (G-->TCGGCCC at position 7238 and
      T-->G at 7174) was found with an allele frequency of 11% in the selected
      northeastern samples. In the random population samples, the overall alpha-thal
      allele frequency was 4% in the northeast region, against 2% in the average
      Tunisian population. The +14 (G-->C) polymorphism in the 5'UTR (untranslated
      region) of the alpha2 gene and the African polymorphism in the second intron of
      the same gene, were found in 3.5% of the alleles. No alpha0-thal alleles were
      found among the 304 blood samples studied at the DNA level during this survey.

PMID- 12484631
TI  - Polar bear hemoglobin and human Hb A0: same 2,3-diphosphoglycerate binding site
      but asymmetry of the binding?
AB  - Polar bear (Ursus maritimus) hemoglobin (Hb) shows a low response to 2,3
      diphosphoglycerate (2,3-DPG), compared to human Hb A0, even though these proteins
      have the same 2,3-DPG-binding site. In addition, polar bear Hb shows a high
      response to chloride and an alkaline Bohr effect (deltalog P50/deltapH) that is
      significantly greater than that of human Hb A0. The difference in sequence Pro
      (Hb A0)-->Gly (polar bear Hb) at position A2 in the A helix seems to be critical
      for reduced binding of 2,3-DPG. Our results also show that the A2 position may
      influence not only the flexibility of the A helix, but that differences in
      flexibility of the first turn of the A helix may affect the unloading of oxygen
      for the intrinsic ligand affinities of the alpha and beta chains. However,
      preferential binding to either chain can only take place if there is appreciable
      asymmetric binding of the phosphoric effector. Regarding this point, 31P NMR data
      suggest a loss of symmetry of the 2,3-DPG-binding site in the deoxyHb-2,3-DPG
      complex.

PMID- 12484632
TI  - Importance of helices A and H in oxygen binding differences between bovine and
      human hemoglobins.
AB  - Human and bovine hemoglobins (Hbs) exhibit several functional differences. They
      have a similar oxygen affinity in the presence of 2,3-diphosphoglycerate (2,3
      DPG); however, bovine Hb has a greatly diminished 2,3-DPG effect, which itself is
      chloride dependent. The question is to determine whether these differences have a
      common structural origin, or whether they evolved in an independent fashion. The
      decreased 2,3-DPG effect can be partially reproduced by mutations at the effector
      binding sites, substituting the betaNA1 valine-NA2 histidine present in human Hb
      with a methionine. While changes of human Hb at these sites could provoke the
      bovine characteristic of the lower 2,3-DPG effect, the oxygen affinities of these
      mutated Hbs were not as low as that of the bovine Hb. Modifications responsible
      for tertiary structural modifications of helix A in human Hb might help shift the
      N-terminal methionine position, thereby locking helix A in place. We replaced the
      residues proline beta5(A2), arginine beta104(G6), and tyrosine beta130(H8) of
      human Hb by the residues present in bovine beta-globin, namely alanine, lysine,
      and phenylalanine, respectively. These mutations did not allow us to obtain a low
      oxygen affinity recombinant Hb (rHb). This indicates that other factors also
      influence oxygen binding and the effects are only partially coupled.

PMID- 12484633
TI  - A novel beta-globin variant: Hb Pocos de Caldas [beta 61(E5)Lys-->Gln].

PMID- 12484634
TI  - Hb Manawatu [alpha 37(C2)Pro-->Leu]: a new mildly unstable mutation at an
      invariant proline residue.

PMID- 12484635
TI  - Hb Colima [beta 49(CD8)Ser-->Cys]: a new hemoglobin variant.

PMID- 12484636
TI  - Hb Rampa [alpha 95(G2)pro-->Ser (alpha 2)] in a family of European ancestry: DNA
      analysis confirms the CCG-->TCG mutation at codon 95 of the alpha 2-globin gene;
      clinical and laboratory features.

PMID- 12484637
TI  - Hb Rio Claro is caused by a mutation at the 33rd position of the beta-globin
      chain.

PMID- 12484638
TI  - Considering the significance of ancestry through the prism of mixed-race
      identity.
AB  - People of mixed ancestry promise to be a significant percentage of the population
      of the United States in the 21st century. This article describes a qualitative
      study of 20 older mixed-race adults of African-American-white and Asian-American
      white ancestries and focuses on how the participants construct identity. Using
      grounded theory methodology, racial identity did not emerge as a singular,
      distinct entity in this study, and five dimensions of racial identity were
      observed. Significant differences in patterns of identity dimensions were noted
      for the two mixed groups. Implications for nursing practice are discussed.

PMID- 12484639
TI  - Racism as a source of health disparity in families with children with attention
      deficit hyperactivity disorder.
AB  - Although poverty and health are inextricably linked, one cannot assume that
      simple poverty and low socioeconomic status are the primary causes of health
      disparity among racial groups. Examining the roles of racism and discrimination
      in access to health care and in the health experiences of people of color is
      fundamental to the goal of eliminating health disparities by 2010. Data from
      ethnic minority groups on how race influences health and health care services are
      absent from much of the nursing research literature. This article explores racism
      as a source of health disparity and discusses methodological implications for
      research, using attention deficit hyperactivity disorder (ADHD) research as an
      example.

PMID- 12484640
TI  - Evolving values in community-based long-term care services for Japanese
      Americans.
AB  - This study used grounded theory to explore how long-term care services are
      perceived and what factors influence family caregiving and long-term care service
      utilization choices among Japanese Americans. Family and generational
      perspectives elucidated a dialectic between forces of integration into the
      broader culture, and reconnection with the culture of origin within the context
      of powerful ethnically based historical and generational experiences. This study
      describes the evolution of the values underlying service delivery and family
      expectations and demonstrates the dynamic relationships among cultural
      expectations, historical context, and service evolution for a group of members
      involved in the caregiving experience.

PMID- 12484641
TI  - African-American spirituality: a concept analysis.
AB  - Culturally competent care for African Americans requires sensitivity to
      spirituality as a component of the cultural context. To foster understanding,
      measurement, and delivery of the spiritual component of culturally competent
      care, this article presents an evolutionary concept analysis of African-American
      spirituality. The analysis is based on a sample of multidisciplinary research
      studies reflecting spirituality of African Americans. Findings indicate that
      African-American spirituality involves quintessential, internal, external,
      consoling, and transformative attributive dimensions. Findings are considered in
      relation to previous conceptual analyses of spirituality and suggest that
      defining attributes of African-American spirituality are both global and
      culturally prominent. Implications for practice and research are discussed.

PMID- 12484642
TI  - Understanding adolescent depression in ethnocultural context.
AB  - Asian-American adolescents often are regarded as a "model minority" and as being
      less likely to experience depression than adolescents of other ethnic groups.
      African-American adolescents are more often diagnosed with schizophrenia than
      depression. Do these epidemiologic phenomena reflect the real facts, or are these
      just artifacts shaped by cultural bias or insensitivity prevailing in this
      society? This article explores the diagnostic bias resulting in misdiagnosis of
      adolescent depression and reviews the role of culture/ethnicity in mental health
      and the ethnocultural variations in depression among African-American, Hispanic
      American, and Asian-American adolescents. By discussing the issues, this article
      guides nurses to enhance cultural competence in nursing care.

PMID- 12484643
TI  - Experimental autoimmune labyrinthitis: assessment of molecular size of
      autoantigens in fractions of inner ear proteins eluted on the Mini Whole Gel
      Eluter.
AB  - In order to determine the molecular size of the causative autoantigens of
      experimental autoimmune labyrinthitis, crude inner ear antigen was separated into
      14 fractions and the constituent molecules were identified by means of sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis using the Mini Whole Gel
      Eluter. The mean total protein recovery was approximately 66%. Sensitization with
      55-65 kDa proteins induced the highest number of infiltrating cells among the
      fractions and sensitization with 38-45 kDa proteins induced the second highest
      number of inflammatory cells. These results suggest that 38-45 kDa and 55-65 kDa
      proteins are the causative autoantigens of experimental autoimmune labyrinthitis.

PMID- 12484644
TI  - Steroid perfusion of the inner ear for sudden sensorineural hearing loss after
      failure of conventional therapy: a pilot study.
AB  - The aim of this study was to determine if high-dose delivery of
      methylprednisolone to the round window can improve hearing after the failure of
      conventional treatment for sudden sensorineural hearing loss (SSHL). In 6
      patients with SSHL an Intraear microcatheter was placed in the round window niche
      and methylprednisolone (62.5 mg/ml) was infused at a rate of 10 microl/h for 8-10
      days. Audiometric assessments (including measurement of speech discrimination)
      were made at presentation, either every day or every other day during treatment
      and 5 days after the completion of perfusion. Perfusion of methylprednisolone was
      beneficial for all 6 patients, with a 16.25-25 dB improvement in hearing
      threshold. A dramatic improvement in speech discrimination was also noted in all
      patients. In conclusion, methylprednisolone perfused at the level of the round
      window membrane resulted in significant recovery of hearing function after the
      failure of standard treatment of SSHL.

PMID- 12484645
TI  - Effects of early auditory deprivation and stimulation on auditory brainstem
      responses in the rat.
AB  - The purpose of this study was to investigate the effect of auditory sound
      deprivation or stimulation on auditory brainstem responses (ABRs) during the
      maturation period of the rat auditory system. At postnatal day (PND) 21, 40
      newborn Norway Brown male rats were categorized into 3 groups: (i) an auditory
      deprivation group in which a bilateral average conductive hearing loss of 27 dB
      was induced; (ii) an auditory activation group exposed to 65-90 dB sound pressure
      level; and (iii) a control group. ABR recordings were made on PND 84. In order to
      compare group differences in interpeak latency (IPL), sensation level (SL),
      defined as stimulus intensity above threshold, was used. IPL measurements and
      analysis were restricted to the 20-60 dB SL range. No differences were observed
      in the IPLs of peaks I-IV between the three groups. Small, but not statistically
      significant, differences in mean estimated IPLs of peaks I-IV were shown in the
      ranges > 50 dB SL and < 25 dB SL. Possible confounding factors explaining the
      apparent discrepancy between these results and those of other animal studies are
      reviewed.

PMID- 12484646
TI  - Localization of gamma-aminobutyric acid A receptor subunits in the rat spiral
      ganglion and organ of Corti.
AB  - Gamma-aminobutyric acid (GABA) is thought to be the major inhibitory
      neurotransmitter in the central nervous system. Although it is distributed in the
      olivo-cochlear bundles, which constitute the mammalian cochlear efferent system,
      its function in the cochlea is still obscure. In this study, we investigated the
      localization of GABAa receptor subunits (alpha1-6, beta1-3, gamma) in the rat
      cochlea in order to determine the role of GABA in the cochlea. Most spiral
      ganglion cells were intensely immunolabeled with all the anti-GABAa receptor
      subunit antibodies. In the organ of Corti, punctate immunoreactivities were
      observed in inner hair cell regions corresponding to the distribution of GABA.
      These data suggest that GABAa receptor was present in afferent nerve terminals in
      inner hair cell regions, and that GABA regulated afferent nerve transmission
      contacting efferent nerve endings by means of the axo-dendritic synapse function.

PMID- 12484647
TI  - Cochlear implantation without mastoidectomy: the pericanal electrode insertion
      technique.
AB  - OBJECTIVE: A new minimally invasive cochlear implantation method with direct
      electrode insertion through the external auditory canal (EAC) is presented.
      MATERIAL AND METHODS: Surgery begins with a retroauricular skin incision. The
      bony surface of the mastoid plane behind the ear is dissected free and the skin
      of the EAC is elevated together with the posterior part of the tympanic membrane.
      Cochleostomy is performed through the EAC with a microdrill anterior to the round
      window. A rim is drilled into the postero-superior region of the bony EAC
      immediately above the incus towards the outer border of the EAC and connected to
      the retroauricular surface by a short tunnel. The implant device is placed in the
      usual retroauricular area. The electrode is inserted through the tunnel and rim
      into the tympanic cavity and pushed into the cochleostomy hole. The electrode is
      immobilized in the rim using glass ionomer cement and covered with bone dust.
      After placement of the ground electrode, the retroauricular incision is closed.
      The tympano-meatal flap is replaced and a dressing is put into the EAC. RESULTS:
      The new method has been applied thus far in 15 adults and pre-adolescent deaf
      patients (8 females, 7 males). A MED-EL Combi 40 + device was used in 14 patients
      and a Nucleus CI24M in 1. Pericanal electrode insertion was easy, with insertion
      depths into the cochlea of > or = 30 mm with the MED-EL and of 20 mm with the
      Nucleus device. There were no surgical complications, infections or electrode
      extrusions during postoperative observation periods ranging from 6 months to > 2
      years. The functional results were comparable to those obtained with cochlear
      implantation via mastoidectomy. The pericanal electrode insertion technique has
      several advantages, the most important being that the danger of facial nerve
      damage is minimized and that the operating time is reduced by up to 50%.
      CONCLUSION: Cochlear implantation with pericanal electrode insertion is a simple,
      fast and particularly safe option which may replace the classical transmastoidal
      cochlear implantation method in adults and older children.

PMID- 12484648
TI  - Air-exposed tissue culture of human middle ear epithelium and meatal epidermis: a
      method to study the advancing front of cholesteatoma.
AB  - The suitability of an air-exposed culture model consisting of a collagen matrix
      was investigated for constructing an advancing front (AF) of human middle ear
      epithelium (MEE) and meatal epidermis (ME). Three different culture settings were
      used: (i ) MEE; (ii) ME; and (iii) AF (MEE + ME). Small tissue biopsies were
      placed on a fibroblast-populated collagen matrix and grown at the air-liquid
      interface. After 3 weeks of culture, the MEE and ME outgrowth was differentiated.
      Light, scanning electron and transmission electron microscopy showed no visible
      differences compared to native MEE and ME. Cytokeratin 8 and cytokeratin 10
      expressions were comparable to the expression seen in the native MEE and ME
      tissues. Proliferation, which was demonstrated by the expression of Ki-67, was
      present in the basal layers of cultured MEE and ME. A double layer of cells in
      which the ME covered the MEE formed the AF. In the AF, the MEE and ME showed the
      same morphological and immunohistochemical characteristics as in their native
      tissues. The results of the study show that this in vitro system is a well
      defined model system offering the possibility to study the effects of external
      stimuli on the different epithelia of the AF involved in the pathogenesis of
      cholesteatoma.

PMID- 12484649
TI  - Expression of the p53 and nm23 genes in cholesteatoma.
AB  - OBJECTIVE: To evaluate the roles of p53 and nm23 genes in cholesteatoma. MATERIAL
      AND METHODS: The results of p53 and nm23 immunostainings were compared between 28
      cholesteatoma samples and 13 control skin samples obtained from the external
      acoustic canal. RESULTS: There were no correlations between p53 staining and
      either gender or type of cholesteatoma (p < 0.05). The mean numbers of p53
      positive cells in the unpaired cholesteatoma and skin specimens were 23.1 +/-
      43.5 and 1 +/- 1.9, respectively and this difference was not statistically
      significant (z = -1.531; p = 0.2). The mean numbers of p53-positive cells in the
      paired cholesteatoma and skin specimens were 3.8 +/- 6.1 and 29 +/- 56.9,
      respectively and this difference was also not statistically significant (t = 
      1.078; p = 0.3). Cholesteatoma showed no nm23 positivity. CONCLUSION: The
      mechanisms relating to the expression of p53 and nm23 genes are not associated
      with the occurrence of cholesteatoma.

PMID- 12484650
TI  - Audiologic evidence for further genetic heterogeneity at DFNA2.
AB  - A large American family has been mapped to the DFNA2 locus. However, mutation
      screening of CX31 and KCNQ4, the two genes associated with deafness at this
      locus, did not identify any mutations. The purpose of this report was to
      characterize the otologic and audiometric phenotype of this large American family
      with non-syndromic, autosomal-dominant sensorineural hereditary hearing
      impairment (HHI). Anamnestic data were obtained, pure-tone audiometry was
      performed and transient-evoked otoacoustic emissions were recorded. The findings
      in affected family members were compared to those in unaffected family members
      and to the respective p50 thresholds of the normal age-matched population.
      Mutational analysis of the CX26 gene was also performed. The affected members of
      this family demonstrated progressive symmetric sensorineural hearing impairment.
      The hearing loss was downward sloping, with mild-to-moderate loss in the low and
      mid frequencies and severe-to-profound loss in frequencies > 4,000 Hz. The onset
      of disease was predominantly in the first or early in the second decade. Hearing
      impairment progressed at approximately 1 dB per year across all frequencies.
      Transient-evoked otoacoustic emissions revealed a minimal response over all
      frequencies in affected members but robust responses in all unaffected members.
      Mutation in the CX26 gene was not present. The affected frequencies observed in
      this family were similar to those in the original family mapped to DFNA2;
      however, the age of onset of disease was different and the hearing loss
      progressed at a slower rate. Therefore, this family provides clinical evidence of
      genetic heterogeneity at the DFNA2 locus and can serve as a model for age-related
      hearing loss.

PMID- 12484651
TI  - Current perspectives on the treatment of nasal polyposis: a Swedish opinion
      report.
AB  - This Swedish study group has examined the current knowledge of nasal polyposis
      with emphasis on different treatment modalities. Polyposis is a multifactorial
      disease that exists for decades in the majority of cases. Different types of
      treatment must be considered, focusing on the underlying disease. However, as we
      only know the specific origin of polyposis in a minority of cases, treatment is
      usually symptomatic. When making a thorough evaluation of different treatment
      strategies, it is obvious that there is a real need for more controlled treatment
      studies which would make the scientific ground more stable when it comes to
      suggesting medical, surgical or combined treatments.

PMID- 12484652
TI  - Bacterial adherence to pharyngeal cells: in vitro studies with alpha-haemolytic
      streptococci and Haemophilus influenzae.
AB  - We examined the adherence to pharyngeal cells of alpha-haemolytic Streptococci
      (AHS) and Haemophilus influenzae, representing normal flora and otitis media (OM)
      pathogens, respectively. The bacteria were incubated with epithelial cells
      brushed from the tonsils, adenoid or tubal orifice of children and adults.
      Adherence varied among the clinical isolates of AHS and H. influenzae. AHS
      adhered better to epithelial cells from a child compared with those sampled from
      an adult. The bacteria adhered better to cells from the tubal orifice compared
      with those sampled from the adenoid. The selective attachment of AHS to certain
      cells but not to others could not be correlated to apoptotic/necrotic cells
      versus viable cells. Incubation of epithelial cells with an isolate of AHS with
      good inhibitory activity against OM pathogens showed almost no adherence of
      bacteria to the epithelial cells after 12 and 24 h of incubation. If, however, an
      isolate of AHS with weak inhibitory activity was incubated with the cells, the
      bacteria that were attached to the epithelial cells from the beginning showed
      overgrowth in the broth and increasing attachment to the cells after 12 and 24 h.
      Thus the inhibitory activity of AHS could also affect the adherence of potential
      pathogens to the mucosal surfaces. The adherence pattern may at least partially
      explain the difference in susceptibility to OM between children and adults.

PMID- 12484653
TI  - Uvulopalatopharyngoplasty versus laser uvulopalatoplasty: prospective long-term
      follow-up of self-reported symptoms.
AB  - No study to date has prospectively compared the results of
      uvulopalatopharyngoplasty (UPPP) and CO2 laser palatal surgery. This study
      investigates and compares outcomes in 121 consecutive patients suffering from
      rhonchopathy, the majority of whom reported apneas. Sixty-one patients underwent
      UPPP and 60 laser uvulopalatoplasty (LUPP). Patients were requested to assess the
      frequency of symptoms associated with obstructive sleep apnea syndrome prior to
      surgery, at 3-month follow-up and 5-8 years postoperatively. All symptoms were
      significantly improved for the two patient groups, both short and long term (p <
      0.01) although short-term results were generally better. However, UPPP was
      superior to LUPP in terms of all clinical effect parameters. Although patients
      treated with UPPP had more severe symptoms preoperatively they also had a better
      long-term outcome. Side-effects such as minor swallowing disturbances were
      frequent, using either surgical modality, but few patients were bothered if
      surgery was successful.

PMID- 12484654
TI  - Diagnosis and classification of salivary neoplasms: pathologic challenges and
      relevance to clinical outcomes.

PMID- 12484655
TI  - Second primary tumors in head and neck cancer patients.

PMID- 12484656
TI  - Microvascular free flaps: a major advance in head and neck reconstruction.

PMID- 12484657
TI  - Release of transforming growth factor beta-1 in a vestibular schwannoma cell
      line.
AB  - Vestibular schwannoma (VS) often displays an irregular growth pattern due to
      factors which remain unknown. In this study, VS cell lines from tissue removed
      during surgery were cultured in order to assess the presence of transforming
      growth factor beta-1 (TGFbeta-1) a multifunctional polypeptide that has different
      pleiotropic effects on various tissues. The antibody-binding inhibition assay
      technique was used. The proliferation rate of VS cell lines in vitro was assessed
      by [3H]thymidine incorporation, with determinations carried out on days 0, 1, 2
      and 4 after removal of fetal calf serum (FCS) from the medium. After 48 h of FCS
      deprivation, cell growth decreased. TGFbeta-1 release also decreased
      progressively 24 h after removing FCS from the medium, reaching an overall
      decrease of 50% after 3 days. The cell culturing procedure appeared suitable for
      VS cells, in that VS cultures were viable for at least 4 months. TGFbeta-1 was
      initially shown to be released in significant amounts, but also to decrease
      progressively to values five times lower after 4 days. These data thus support
      the possibility of a significant association between TGFbeta-1 release and VS
      cell replication.

PMID- 12484658
TI  - "Skip metastases" from head and neck cancers.

PMID- 12484659
TI  - Is the standard radical neck dissection no longer standard?

PMID- 12484660
TI  - Can embryology influence clinicians concerning the "best therapy" for glottic
      cancer?

PMID- 12484661
TI  - Pharmacology: advantages and disadvantages.

PMID- 12484662
TI  - Safe prescribing practices in pregnancy and lactation.
AB  - Midwives and other health care providers face a dilemma when a pregnant woman
      develops a condition that usually is treated with a pharmacologic agent.
      Understanding of basic teratology associated with drugs as well as the FDA
      categorization of agents can assist professionals in recognizing which
      pharmaceuticals should be used or avoided. In addition to reviewing teratology,
      this article addresses the use of common drugs for the treatment of upper
      respiratory conditions, minor pain, gastrointestinal problems, psychiatric
      illnesses, and neurologic disorders. In each category, current evidence is
      presented pertaining to which agents should be recommended for pregnant women.

PMID- 12484663
TI  - The drug development process and the pregnant woman.
AB  - The drug development process in the United States includes extensive pre-clinical
      testing and a series of clinical trials designed to explore the safety and
      efficacy of a new drug entity. As part of this process, animal studies are
      conducted to assess the effects of the new drug on the reproductive process.
      These studies, called developmental and reproductive toxicology studies, form the
      basis for the information included in the current pregnancy subsection of the
      drug label. The new drug's effects on the human fetus are gathered through post
      marketing studies, usually observational registries. There is usually no
      information regarding the dose appropriate for pregnancy. The usual adult dose is
      assumed to be appropriate. Proposed changes to the current pregnancy subsection
      would replace the categories with narrative text, allow more detailed clinical
      management advice, including inadvertent fetal exposure, and provide a summary of
      risks associated with the drug. The sections on fertility, pregnancy and
      lactation would be combined, since they are a continuum. A provision is also
      being made to incorporate information from pharmacokinetic and pharmacodynamic
      studies relevant to pregnancy.

PMID- 12484664
TI  - The penicillins: a review and update.
AB  - The penicillin family is one of the most valuable groups of antibiotics in
      primary care. They are bacteriocidal, well distributed, and highly efficacious
      against susceptible organisms. Development of synthetic penicillins has both
      broadened the spectrum of activity and enhanced the efficacy of these
      medications. However, emergence of resistant bacterial strains has limited the
      usefulness of penicillins in recent years. Nonetheless, penicillins remain the
      drugs of choice for many mild, localized soft tissue infections and are
      particularly important in specific situations during pregnancy. History of
      penicillin allergy does not necessarily prohibit the use of penicillin. In
      patients with a self-reported history of allergy, skin testing often fails to
      elicit signs of a true allergy to penicillin. Failure to prescribe penicillin for
      penicillin-sensitive infections in these patients contributes to the development
      of bacterial resistance. This paper provides a review of the modes of action,
      spectrums of activity, adverse effects for the various classes of penicillin most
      often used in primary care and highlights clinical issues in managing women with
      penicillin allergy.

PMID- 12484665
TI  - Early-onset neonatal group B streptococcal infection: 2002 guidelines for
      prevention.
AB  - In 1996, the Centers for Disease Control and Prevention (CDC) and relevant
      professional organizations jointly released guidelines for prevention of early
      onset neonatal group B streptococcal infections. The guidelines recommended that
      all obstetric providers and institutions providing intrapartum services follow
      one of two strategies. This year, on the basis of multistate surveillance data
      collected since prevention strategies were initiated, the CDC has released
      revised prevention recommendations. This article reviews the new guidelines and
      discusses clinical implications for practice in a variety of settings.

PMID- 12484666
TI  - St. John's wort and oral contraceptives: reasons for concern?
AB  - St. John's wort (Hypericum perforatum) is one of the best-selling herbal remedies
      in the United States. It has been implicated as an inducer of the P450 enzyme
      system, and as such, may cause increased metabolism of certain drugs, including
      oral contraceptives. Women using oral contraceptives have been warned against
      using St. John's wort. To date, there are some case reports but little clinical
      data demonstrating risk of contraceptive failure if they do. This article reviews
      available data and discusses theoretical reasons for concern about possible drug
      herb interactions.

PMID- 12484667
TI  - Clinical uses of mifepristone: an update for women's health practitioners.
AB  - In September 2000, the U.S. Food and Drug Administration (FDA) approved the use
      of mifepristone for the provision of medical abortion. Although mifepristone was
      developed and marketed because of its potential to effect early first-trimester
      medical abortion, it has additional applications to health care, including the
      treatment of gynecologic conditions, cancer, and Cushing's disease. The
      controversial nature of abortion has dominated the publicity about mifepristone.
      The evidence for the safety and efficacy of mifepristone in medical abortion has
      been overshadowed, and many clinicians are unaware of the other potential uses of
      the drug. This article provides a discussion of background information on the
      pharmacology, development of, and research on mifepristone and an update on
      current and potential uses in health care today. Information on the FDA-approved
      regimen and alternative protocols for management of mifepristone in its use in
      abortion care are presented.

PMID- 12484668
TI  - Hormone replacement therapy: short-term versus long-term use.
AB  - Midwives manage health care of women throughout the life cycle including
      prescribing hormone replacement therapy (HRT). This article presents a history of
      research on the use of HRT, as well as risks and benefits. Older research on the
      effects of HRT on heart disease, osteoporosis, and breast cancer is included. The
      results and recommendations of the Women's Health Initiative are examined.

PMID- 12484669
TI  - Addressing the epidemic: pharmacotherapeutic management of diabetes in women.
AB  - Diabetes is epidemic in the United States. More than half of the victims are
      women, and women from vulnerable populations have particularly high rates of
      diabetes. In addition, long-term complications of diabetes are contributing
      factors to poverty, disability, and premature death, and complications of
      diabetes are more common and more serious in women. The provision of health care
      to women with diabetes must include knowledge of the pharmacotherapeutic agents
      used to treat diabetes to provide care that compliments and does not complicate
      diabetes management.

PMID- 12484670
TI  - What do you do when the baby is winking at you? Case report of a face
      presentation.
AB  - Face presentation is an uncommon presentation at birth. The identification of a
      fetus with a hyperextended neck on ultrasound antenatally warrants close scrutiny
      for other anomalies. A fetus who presents as a face presentation in labor that is
      of average estimated fetal weight and has no anomalies in a woman with an
      adequate pelvis is likely to deliver vaginally if the mentum rotates to anterior
      prior to birth. Persistent mentum posteriors are best left alone without manual
      intervention and delivered by cesarean section. Prolonged labor is common. The
      clinician must be patient and closely monitor descent and rotation. Infants born
      as face presentations should be assessed closely after birth for normal
      respiratory transition and the presence of significant pain warranting
      analgesics.

PMID- 12484671
TI  - Post-abortion care.

PMID- 12484672
TI  - Post-abortion care.

PMID- 12484673
TI  - Reduced frequency visits for prenatal care.

PMID- 12484674
TI  - Extramural and/or intramural clinical rotations.

PMID- 12484675
TI  - Are traditional cognitive tests useful in predicting clinical success?
AB  - The purpose of this research was to determine the predictive value of the Dental
      Admission Test (DAT) for clinical success using Ackerman's theory of ability
      determinants of skilled performance. The Ackerman theory is a valid, reliable
      schema in the applied psychology literature used to predict complex skill
      acquisition. Inconsistent stimulus-response skill acquisition depends primarily
      on determinants of cognitive ability. Consistent information-processing tasks
      have been described as "automatic," in which stimuli and responses are mapped in
      a manner that allows for complete certainty once the relationships have been
      learned. It is theorized that the skills necessary for success in the clinical
      component of dental schools involve a significant amount of automatic processing
      demands and, as such, student performance in the clinics should begin to converge
      as task practice is realized and tasks become more consistent. Subtest scores of
      the DAT of four classes were correlated with final grades in nine clinical
      courses. Results showed that the DAT subtest scores played virtually no role with
      regard to the final clinical grades. Based on this information, the DAT scores
      were determined to be of no predictive value in clinical achievement.

PMID- 12484676
TI  - Tutoring in a problem-based curriculum: expert versus nonexpert.
AB  - Many studies have examined whether being an "expert" influences the success of a
      tutor in a problem-based learning curriculum. There are, however, no established
      standards by which to determine expertise. The purpose of this study was to
      examine whether students evaluate expert and nonexpert tutors comparably and to
      determine whether setting different standards to determine expertise influences
      the outcome of the above findings. Tutor evaluations, consisting of eight Likert
      type questions completed by first-, second-, and third-year dental students, were
      analyzed. Tutors were ranked by the authorswithin three different categories of
      expertise based on the highest educational degree they had attained, familiarity
      with the specific subject matter, and previous problem-based learning (PBL)
      experience. Linear regression analyses were then performed between each category
      and student evaluation results. A statistically significant difference was found
      in the way students evaluated experts, but only when expertise was defined by the
      tutor's previous tutorial experience. The findings of this study underscore the
      importance of the retention of dental faculty with PBL experience in a PBL-based
      curriculum.

PMID- 12484677
TI  - Undergraduate basic science preparation for dental school.
AB  - In the Institute of Medicines report Dental Education at the Crossroads, it was
      suggested that dental schools across the country move toward integrated basic
      science education for dental and medical students in their curricula. To do so,
      dental school admission requirements and recommendations must be closely reviewed
      to ensure that students are adequately prepared for this coursework. The purpose
      of our study was twofold: 1) to identify student dentists' perceptions of their
      predental preparation as it relates to course content, and 2) to track student
      dentists' undergraduate basic science course preparation and relate that to DAT
      performance, basic science course performance in dental school, and Part I and
      Part II National Board performance. In the first part of the research, a total of
      ninety student dentists (forty-five from each class) from the entering classes of
      1996 and 1997 were asked to respond to a survey. The survey instrument was
      distributed to each class of students after each completed the largest basic
      science class given in their second-year curriculum. The survey investigated the
      area of undergraduate major, a checklist of courses completed in their
      undergraduate preparation, the relevance of the undergraduate classes to the
      block basic science courses, and the strength of requiring or recommending the
      listed undergraduate courses as a part of admission to dental school. Results of
      the survey, using frequency analysis, indicate that students felt that the
      following classes should be required, not recommended, for admission to dental
      school: Microbiology 70 percent, Biochemistry 54.4 percent, Immunology 57.78
      percent, Anatomy 50 percent, Physiology 58.89 percent, and Cell Biology 50
      percent. The second part of the research involved anonymously tracking
      undergraduate basic science preparation of the same students with DAT scores, the
      grade received in a representative large basic science course, and Part I and
      Part II National Board performance. Using T-test analysis correlations, results
      indicate that having completed multiple undergraduate basic science courses (as
      reported by AADSAS BCP hours) did not significantly (p < .05) enhance student
      performance in any of these parameters. Based on these results, we conclude that
      student dentists with undergraduate preparation in science and nonscience majors
      can successfully negotiate the dental school curriculum, even though the students
      themselves would increase admission requirements to include more basic science
      courses than commonly required. Basically, the students' recommendations for
      required undergraduate basic science courses would replicate the standard basic
      science coursework found in most dental schools: anatomy, histology,
      biochemistry, microbiology, physiology, and immunology plus the universal
      foundation course of biology.

PMID- 12484678
TI  - An evaluation of clinical mock boards and their influence on the success rate on
      qualifying boards.
AB  - An important responsibility of each dental school to its graduating dental
      students is exposure to and evaluation on a mock board that simulates one or more
      of the examinations given by its respective regional testing agencies. An
      introduction to the procedures and environment that will be encountered on a
      qualifying examination will hopefully increase a student's chance for success on
      such a test. The purpose of this study was to test the relationship of the
      various attributes or variables of mock boards given by dental schools in the
      United States and Puerto Rico with results obtained on the regional or state
      qualifying board(s) related to timing, structure, method of evaluation,
      graduation, and remediation. A twenty-item questionnaire was mailed to key
      clinical or curricular deans at fifty-four accredited dental schools. Ninety
      three percent of schools completed and returned the questionnaire. In the sample
      of respondents, the percentages of schools participating in the various
      qualifying exams were: CRDTS = 22 percent; NERB = 42 percent; SRTA = 20 percent;
      WREB = 28 percent; Independents = 24 percent, with a reported overall passing
      rate (greater than or equal to 70) of 58 percent. The median time between the
      mock board and the qualifying board was 7.5 weeks. Results indicated that no
      single aspect of a mock board had a statistically significant effect on the
      outcome of qualifying examinations, resulting in a failure to reject the null
      hypothesis. Such findings may indicate that schools should focus their efforts on
      reassessing the restrictions and requirements imposed upon their students related
      to their mock board. A future study could include surveying recent graduates for
      their opinions of the value of their mock board experiences.

PMID- 12484679
TI  - Predictors of success in dental hygiene education: a six-year review.
AB  - The purpose of this study was to examine the predictive reliability of incoming
      grade point average (GPA), incoming math/science GPA, and Scholastic Aptitude
      Test (SAT) scores in predicting success in dental hygiene education. Success in
      dental hygiene education was defined in terms of Dental Hygiene National Board
      score (N-BRD) and dental hygiene GPA at graduation (DH-GPA). Academic transcripts
      and admissions documents of 134 students comprising the Medical College of
      Georgia dental hygiene classes of 1996-2001 were reviewed. Incoming college GPA
      (1-GPA), incoming college math/science GPA (MS-GPA), total SAT score (T-SAT),
      verbal SAT score (V-SAT), math SAT score (M-SAT), N-BRD score, and DH-GPA were
      documented for each student. A forward, step-wise, multiple linear regression was
      used to analyze the data. I-GPA was the most significant predictor of success.
      Analysis showed that DH-GPA was best predicted by both the I-GPA (p < or = .001)
      and T-SAT (p < or = .004). Only the I-GPA (p < or = .001) was significant in
      predicting N-BRD scores. Data from this study will be used to evaluate the
      admissions process in dental hygiene at the Medical College of Georgia.

PMID- 12484680
TI  - How well prepared are Texas dental hygienists to recognize and report elderly
      abuse?
AB  - The elderly are the nation's fastest-growing population, and the number of elder
      abuse victims has reached epidemic proportions. In Texas, dentists and dental
      hygienists are mandated by law to report suspected abuse. This study surveyed
      Texas dental hygienists regarding elder abuse education received in dental
      hygiene school and post-graduation. Respondents were also asked to self-assess
      their knowledge level in recognizing the six types of elder abuse and to answer
      questions regarding Texas law and mandatory reporting of abuse. A survey designed
      for this study was mailed to 780 Texas licensed dental hygienists, representing
      10 percent of the Texas dental hygiene population. Respondents were selected
      using a computer-generated random sample. A second mailing was sent to
      nonrespondents to prevent response bias. Results were analyzed using Statistical
      Programs for Social Scientists (SPSS). Over one-half of the respondents (56
      percent) stated that abuse education was not part of their dental hygiene school
      curriculum. Only 46 percent of the respondents who replied that abuse education
      had been included in the curriculum were educated on elder abuse. A majority of
      respondents stated they lacked knowledge in recognizing the six types of elder
      abuse, and 81 percent of respondents reported being unknowledgeable about
      reporting elder abuse. The current status of elder abuse education in dental
      hygiene programs and post-graduation is insufficient. Dental hygienists have an
      obligation to become knowledgeable in recognizing and reporting elder abuse in
      order to provide complete care for their patients.

PMID- 12484681
TI  - How do U.S. and Canadian dental schools teach interpersonal communication skills?
AB  - The status of instruction in interpersonal communication was surveyed in forty
      U.S and Canadian dental schools. Key faculty members were identified, and syllabi
      and course descriptions were collected and content-analyzed. The following
      findings were obtained for responding schools: 1) only one-third of schools had
      courses specifically focusing on interpersonal communication; 2) more than half
      of the schools offered these types of courses only during the first two years; 3)
      the most common topics were communication skills, patient interviewing, and
      patient education/consultation; 4) the most frequently used method of teaching
      was lectures; active practice was used less often; 5) written examination was the
      primary instructional evaluation tool, whereas more sophisticated performance
      oriented assessments were used less often; and 6) about half of the teachers did
      not have a D.D.S. degree; those not dentists were primarily psychologists. At
      least eight of the forty dental schools surveyed do not appear to meet the
      accreditation guidelines for predoctoral programs in this area of instruction.
      Some could not identify a faculty member responsible for such instruction.
      Schools offering more extensive instruction were more likely to offer active
      rather than passive teaching and use more sophisticated student evaluation
      strategies. This research suggests a need for reevaluation of teaching in this
      subject area.

PMID- 12484682
TI  - Improving the oral health knowledge of osteopathic medical students.
AB  - Due to a complex set of circumstances including culture, poverty, low educational
      achievement, and limited access to dental care, the oral health of rural
      Appalachians is poorer than that of people in other parts of Kentucky. Limited
      health care dollars go to primary medical care which may be the only contact
      these individuals have with the health care system. Consequently, primary care
      physicians can help improve oral health. The University of Kentucky College of
      Dentistry (UKCD) and the Pikeville College School of Osteopathic Medicine (PCSOM)
      developed an oral health education block for third-year PCSOM students. Eleven
      UKCD faculty and one PCSOM faculty participated in the two-day, sixteen-hour oral
      health curriculum. Knowledge retention data from the post-tests was collected
      four months after the educational program. Students significantly improved their
      performance in six of the topic areas, with performance staying the same in one
      area and dropping significantly in one area. Focus groups were conducted with
      sixteen (two groups of eight) randomly selected students one year after the
      educational program. Students reported using the knowledge and oral exam
      techniques included in the course and felt that it was a valuable addition to
      their curriculum.

PMID- 12484683
TI  - Learning approaches and learning difficulties: a comparison of Indian and Nepali
      dental science students.
AB  - This study explored the difference in learning approaches and difficulties of
      Nepali and Indian undergraduate students of dental science. A locally developed
      inventory was used to measure learning approach and learning difficulties. Data
      collected from 166 Indians and 69 Nepalis were compared. The scores on various
      scales of the inventory indicate that Nepalis are more fearful and less confident
      regarding examination and course completion and have significantly less positive
      perception about academic capability. Indian students scored significantly higher
      on motivation, interest, and deep processing. The language problem was
      significantly greater for Nepali students. Higher percentages of Nepalis
      experienced various academic and nonacademic problems. The study highlights the
      need to consider difference in learning approach among the students of health
      science courses that admit students from different academic, nonacademic, and
      cultural backgrounds.

PMID- 12484684
TI  - Family physicians are the main source of primary health care for the Medicare
      population.

PMID- 12484685
TI  - Additional side effects of ACE inhibitors.

PMID- 12484686
TI  - Food challenge vs. skin antigen testing.

PMID- 12484687
TI  - Migraine headache, evidence-based guidelines, and the AAFP. American Academy of
      Family Physicians.

PMID- 12484688
TI  - Witnessing domestic violence: the effect on children.

PMID- 12484689
TI  - Can melatonin prevent or treat jet lag?

PMID- 12484690
TI  - Information from your family doctor. Jet lag.

PMID- 12484691
TI  - Diagnostic and therapeutic injection of the elbow region.
AB  - Joint injection of the elbow is a useful diagnostic and therapeutic tool for the
      family physician. In this article, the injection procedures for the elbow joint,
      medial and lateral epicondylitis, and olecranon bursitis are reviewed. Persistent
      pain related to inflammatory conditions responds well to injection in the region.
      Indications for elbow joint injection include osteoarthritis and rheumatoid
      arthritis. Corticosteroid injection is an accepted treatment option for medial
      and lateral epicondylitis. Olecranon bursa aspiration and injection are useful
      when that bursa is inflamed. The proper techniques, choice and quantity of
      pharmaceuticals, and appropriate follow-up essential for effective outcomes are
      discussed.

PMID- 12484692
TI  - Lymphadenopathy and malignancy.
AB  - The majority of patients presenting with peripheral lymphadenopathy have easily
      identifiable causes that are benign or self-limited. Among primary care patients
      presenting with lymphadenopathy, the prevalence of malignancy has been estimated
      to be as low as 1.1 percent. The critical challenge for the primary care
      physician is to identify which cases are secondary to malignancies or other
      serious conditions. Key risk factors for malignancy include older age, firm,
      fixed nodal character, duration of greater than two weeks, and supraclavicular
      location. Knowledge of these risk factors is critical to determining the
      management of unexplained lymphadenopathy. In addition, a complete exposure
      history, review of associated symptoms, and a thorough regional examination help
      determine whether lymphadenopathy is of benign or malignant origin. Unexplained
      lymphadenopathy without signs or symptoms of serious disease or malignancy can be
      observed for one month, after which specific testing or biopsy should be
      performed. While modern hematopathologic technologies have improved the
      diagnostic yields of fine-needle aspiration, excisional biopsy remains the
      initial diagnostic procedure of choice. The overall evaluation of
      lymphadenopathy, with a focus on findings suggestive of malignancy, as well as an
      approach to the patient with unexplained lymphadenopathy, will be reviewed.

PMID- 12484693
TI  - Vaccine adverse events: separating myth from reality.
AB  - Vaccines have turned many childhood diseases into distant memories in
      industrialized countries. However, questions have been raised about the safety of
      some vaccines because of rare but serious adverse effects that have been
      attributed to them. Pain, swelling, and redness at the injection site are common
      local reactions to vaccines. Fever and irritability may occur after some
      immunizations. Currently, no substantial evidence links measles-mumps-rubella
      vaccine to autism, or hepatitis B vaccine to multiple sclerosis. Thimerosal is
      being eliminated from routine childhood vaccines because of concerns that
      multiple immunizations with vaccines containing this preservative could exceed
      recommended mercury exposures. Family physicians should be knowledgeable about
      vaccines so that they can inform their patients of the benefits of immunization
      and any proven risks. If immunization rates fall, the incidence of vaccine
      preventable illnesses may rise.

PMID- 12484694
TI  - Management of the acute migraine headache.
AB  - As many as 30 million Americans have migraine headaches. The impact on patients
      and their families can be tremendous, and treatment of migraines can present
      diagnostic and therapeutic challenges for family physicians. Abortive treatment
      options include nonspecific and migraine-specific therapy. Nonspecific therapies
      include analgesics (aspirin, nonsteroidal anti-inflammatory drugs, and opiates),
      adjunctive therapies (antiemetics and sedatives), and other nonspecific
      medications (intranasal lidocaine or steroids). Migraine-specific abortive
      therapies include ergotamine and its derivatives, and triptans. Complementary and
      alternative therapies can also be used to abort the headache or enhance the
      efficacy of another therapeutic modality. Treatment choices for acute migraine
      should be based on headache severity, migraine frequency, associated symptoms,
      and comorbidities.

PMID- 12484695
TI  - Information from your family doctor. What should I know about migraines?

PMID- 12484696
TI  - Upper respiratory tract infection.

PMID- 12484697
TI  - Photo quiz. Darkened distal legs.

PMID- 12484698
TI  - AHRQ releases review of treatments for allergic and nonallergic rhinitis. Agency
      for Healthcare Research and Quality.

PMID- 12484699
TI  - Regulation of transforming growth factor-beta signaling and vascular diseases.
AB  - PURPOSE: Members of the transforming growth factor (TGF)-beta superfamily play
      critical roles in regulation of various cellular functions. Dysregulation of the
      signaling mechanisms of the TGF-beta superfamily proteins is associated with
      clinical diseases such as cancer, fibrotic diseases, and vascular disorders.
      Therefore, understanding these signaling mechanisms may provide us with novel
      ways to develop strategies for treating clinical diseases induced by these
      cytokines. METHODS: This review discusses our current understanding of the
      mechanisms of TGF-beta signaling, focusing on the roles of TGF-beta in regulation
      of vascular wall cells and on the regulation of TGF-beta superfamily signals by
      inhibitory Smads.

PMID- 12484700
TI  - Artificial human corneas: scaffolds for transplantation and host regeneration.
AB  - PURPOSE: To review the development of artificial corneas (prostheses and tissue
      equivalents) for transplantation, and to provide recent updates on our tissue
      engineered replacement corneas. METHODS: Modified natural polymers and synthetic
      polymers were screened for their potential to replace damaged portions of the
      human cornea or the entire corneal thickness. These polymers, combined with cells
      derived from each of the three main corneal layers or stem cells, were used to
      develop artificial corneas. Functional testing was performed in vitro. Trials of
      biocompatibility and immune and inflammatory reactions were performed by
      implanting the most promising polymers into rabbit corneas. RESULTS: Collagen
      based biopolymers, combined with synthetic crosslinkers or copolymers, formed
      effective scaffolds for developing prototype artificial corneas that could be
      used as tissue replacements in the future. We have previously developed an
      artificial cornea that mimicked key morphologic and functional properties of the
      human cornea. The addition of synthetic polymers increased its toughness as it
      retained transparency and low light scattering, making the matrix scaffold more
      suitable for transplantation. These new composites were implanted into rabbits
      without causing any acute inflammation or immune response. We have also
      fabricated full-thickness composites that can be fully sutured. However, the long
      term effects of these artificial corneas need to be evaluated. CONCLUSIONS: Novel
      tissue-engineered corneas that comprise composites of natural and synthetic
      biopolymers together with corneal cell lines or stem cells will, in the future,
      replace portions of the cornea that are damaged. Our results provide a basis for
      the development of both implantable temporary and permanent corneal replacements.

PMID- 12484701
TI  - Proteoglycans in the eye.
AB  - PURPOSE: Various proteoglycans are expressed in ocular tissues. We investigated
      and reviewed the distribution and the potential roles of proteoglycans in cornea,
      trabecular meshwork, and retinal tissues. METHODS: Immunohistochemical studies
      were performed in rat ocular tissues. The concentration of transforming growth
      factor (TGF)-beta2, which regulates the expression of proteoglycans in aqueous
      humor from human glaucomatous eyes, was evaluated by enzyme-linked immunosorbent
      assay (ELISA). In retinal tissues, we examined the localization of 2 soluble
      nervous tissue-specific chondroitin sulfate proteoglycans, neurocan and
      phosphacan, by immunohistochemical analysis, then investigated the effect on the
      neurite outgrowth of cultivated retinal ganglion cells. RESULTS: The expression
      of chondroitin sulfate in stroma was upregulated at early postnatal stages and
      reduced during development in rat eyes. In trabecular meshwork tissues,
      immunohistochemical studies showed the intense expression of decorin. Moreover,
      elevated levels of TGF-beta2 in the aqueous humor from glaucomatous patients were
      observed. In retinal tissues, neurocan and phosphacan were expressed mainly in
      nerve fiber-rich layers during rat postnatal stages. In vitro, the neurite
      extension from retinal ganglion cells was inhibited by neurocan and phosphacan.
      CONCLUSIONS: Soluble extracellular proteoglycans in corneal and trabecular
      meshwork tissues contribute to the stromal transparency in the corneal tissues
      and the resistance of the aqueous humor outflow in trabecular meshwork tissues.
      In retinal tissues, chondroitin sulfate and heparan sulfate proteoglycans are not
      only secreted into the extracellular space of retinal tissues but also expressed
      in the membrane of the retinal cells, contributing to the neural network
      formation and the maintenance of the interphotoreceptor matrix.

PMID- 12484702
TI  - Anatomy and histopathology of human meibomian gland.
AB  - PURPOSE: To investigate histopathologic changes in human meibomian gland.
      METHODS: Human meibomian gland samples were obtained at autopsy from 50 men and
      33 women aged from 17 to 87 years with a mean age (+/- SD) of 61 +/- 13 years.
      Pieces of tarsal plate measuring 3 x 3 mm including meibomian glands were excised
      from the center of both upper eyelids, then fixed and embedded in paraffin.
      Sections 4-microm thick were stained with hematoxylin and eosin and periodic acid
      Schiff. Light microscopy was used to observe any histopathologic changes.
      RESULTS: The following histopathologic changes were observed: (1) cystic
      dilatation of acini and/or ducts, (2) atrophy of acini, (3) basement membrane
      thickening of acini, (4) granulation tissue, and (5) lipogranulomatous
      inflammation. CONCLUSION: Various histopathologic changes were observed in the
      human meibomian gland. Hyperkeratinization of ductal epithelium and atrophy of
      acinar cells may cause meibomian gland dysfunction.

PMID- 12484703
TI  - Evaluation of optical quality of corneas using corneal topographers.
AB  - PURPOSE: To review the evaluation of the optical quality of the cornea by corneal
      topography. METHODS AND RESULTS: Color-coded maps show qualitatively the
      characteristics and severity of irregular astigmatism at the entrance pupil.
      Topographic indices such as the surface regularity index and predicted corneal
      acuity are derived from computation of the corneal power distribution, and they
      are highly correlated with high-contrast visual acuity. Fourier analysis can be
      used to represent the irregular and regular astigmatism components
      simultaneously. Zernike polynomials can be used to calculate higher-order
      wavefront aberrations due to the corneal surface. CONCLUSION: Evaluation of the
      optical properties of the cornea using a corneal topographer is useful for
      assessing quality of vision.

PMID- 12484704
TI  - Effect of herpes simplex virus-1 gD or gD-IL-2 DNA vaccine on herpetic keratitis.
AB  - PURPOSE: To evaluate the efficacy of DNA immunization using herpes simplex virus
      (HSV)-1 gD or gD-IL-2 (chimeric gene of gD and human IL-2) with reference to
      their immune responses and preventive effect on the development of murine
      herpetic stromal keratitis, based on our previous work. METHODS: Plasmids
      containing gD (pHSDneol) or gD-IL-2 (pHDLneol) were constructed, and gD or gD-IL
      2 peptides were purified. BALB/c mice were immunized by hypodermal injection,
      subconjunctival injection, or topical eye drop twice at 7-day intervals. Attained
      anti-HSV immune reaction was estimated, including neutralizing antibody, delayed
      type hypersensitivity (DTH) measured by the swelling of the ear pinna, and
      cytotoxic T lymphocyte (CTL) measured by 51Cr release from MHC-matched target
      cells by splenic and/or local lymph node cells. The corneas of a group of the
      immunized mice were challenged with CHR3 strain of HSV-1 (10 microL of 3 x 10(6)
      PFU/mL) 3 weeks after the last immunization. Clinical signs (stromal and
      epithelial keratitis) were scored. Results. All gD- or gD-lL-2-immunized mice
      developed specific neutralizing antibody. Delayed-type hypersensitivity and CTL
      were obtained in gD DNA- or gD-IL-2 DNA-immunized mice. Chimeric DNA vaccine gD
      IL-2 elicited higher DTH and more vigorous CTL activity. The scores of stromal
      keratitis for all gD- or gD-IL-2-immunized mice were significantly suppressed,
      although those of epithelial keratitis were not. Conclusion. Immunization with gD
      or gD-IL-2 was effective against herpetic stromal keratitis. By focusing
      specifically on high induction of cell-mediated immunity, gD-IL-2 DNA could have
      possible clinical applications against HSV-1 in the future.

PMID- 12484705
TI  - Methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulase
      negative Staphylococcus ocular surface infection efficacy of chloramphenicol eye
      drops.
AB  - PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin
      resistant coagulase-negative Staphylococcus (MR-CNS) are two major multidrug
      resistant pathogens. In this paper we report the prevalence of MRSA and MR-CNS in
      ocular surface infections. METHODS: We investigated the proportion of MRSA and MR
      CNS in bacterial isolates from conjunctiva of elderly patients with and without
      bacterial conjunctivitis. The relationship between conjunctival MRSA carriers and
      general background conditions was studied. We evaluated the efficacy of
      chloramphenicol eye drops in the treatment of MRSA conjunctivitis. We also
      investigated the presence of MRSA and MR-CNS in lid skin and conjunctiva of
      patients with atopic dermatitis. RESULTS: In conjunctival bacterial flora of
      elderly patients the proportion of MRSA in S. aureus was 57%, and the proportion
      of MR-CNS in coagulase-negative Staphylococcus was 25%. Conjunctival MRSA
      carriers were more likely to have anemia, malignant tumor, liver dysfunction, and
      dementia, and to be postoperation and chronically bedridden. The efficacy rate of
      chloramphenicol eye drops in the treatment of MRSA conjunctivitis was 81%. In
      conjunctival sacs of patients with atopic dermatitis, S. aureus was the most
      frequent species (48%), and the proportion of MRSA was 18%. CONCLUSION:
      Methicillin-resistant S. aureus and MR-CNS are widespread in elderly hospitalized
      patients and in patients with atopic dermatitis. Chloramphenicol eye drops were
      useful for the treatment of MRSA ocular surface infections.

PMID- 12484706
TI  - Reactivation and donor-host transmission of herpes simplex virus after corneal
      transplantation.
AB  - PURPOSE: To review our previous studies regarding herpes simplex virus type 1
      (HSV-1) corneal latency in the rabbit lamellar keratoplasty (LK) and penetrating
      keratoplasty (PKP) models. METHODS: Rabbits latently infected with HSV- I
      received allografts from naive rabbits, and naive rabbits received grafts from
      rabbits latently infected with HSV-1. In rabbits undergoing LK, viral shedding in
      tear film and the occurrence of herpetic lesions were investigated for 7 days
      after operation. In rabbits undergoing PKP, latency-associated transcript (LAT)
      positive and -negative HSV- I mutants were used to establish latency. Ninety days
      after PKP, reactivation of HSV-1 was induced by transcorneal iontophoresis of
      epinephrine. Viral shedding was then assessed by tear-film swabbing. Donor
      corneal buttons, recipient corneal rims, and corresponding trigeminal ganglia
      were analyzed for HSV DNA concentration and viral transcription. RESULTS: In
      rabbits undergoing LK, the occurrence of positive tear-film cultures and number
      of days on which corneal epithelial lesions were observed were significantly
      higher in the operated eyes of latently infected rabbits as compared with
      controls. In rabbits undergoing PKP, HSV- I could transmit between host and donor
      tissues both in anterograde and retrograde fashion. LAT-positive virus had a
      significantly greater ability to transmit. Higher concentrations of HSV DNA
      detected in cornea and trigeminal ganglia correlated with active viral
      transcription and higher percentage of viral shedding. CONCLUSION: Corneas from
      latently infected rabbits contain HSV-1 DNA that can replicate and transmit after
      induced reactivation. Our studies provide further evidence for corneal latency of
      this virus.

PMID- 12484707
TI  - Methicillin-resistant Staphylococcus aureus and methicillin-resistant
      Staphylococcus epidermidis infections in the cornea.
AB  - PURPOSE: To describe the incidence and clinical management of corneal infections
      with methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant
      Staphylococcus epidermidis (MRSE). METHODS: The incidence of methicillin
      resistant Staphylococcus (MRS) at the Department of Ophthalmology, Kyoto
      Prefectural University of Medicine, was reviewed during the 5-year period from
      January 1996 to December 2000. Clinical aspects of MRS colonization or infection
      in the eye were investigated. RESULTS: Methicillin-resistant S. aureus or MRSE
      was detected from 30 eyes with ocular diseases; post-keratoplasty (11 eyes),
      ocular surface disorders without operation (9 eyes), and others (10 eyes). Among
      the 30 eyes, 12 manifested keratitis. Eight cases (8 eyes) occurred after
      keratoplasty, including four postoperative cases in patients with Stevens-Johnson
      syndrome, and two bilateral cases (4 eyes) in patients with acute-phase Stevens
      Johnson syndrome. The degree of MRS keratitis was classified into 4 groups:
      asymptomatic carrier or conjunctivitis, intraepithelial infiltrations,
      superficial keratitis, and severe keratitis leading to corneal perforation. All
      cases of keratitis were treated successfully with topical ofloxacin (OFLX),
      vancomycin (VCM), or arbekacin (ABK). CONCLUSION: Factors associated with ocular
      MRS colonization were long-term use of antibiotics and/or steroids, and
      hospitalization. Patients who had undergone keratoplasty or who had Stevens
      Johnson syndrome were at increased risk of MRS keratitis. Superficial stromal
      infiltrations, minimal melting, and minimal stromal scarring are characteristic
      of MRS keratitis. Therapy for MRS keratitis is summarized. Ofloxacin, VCM, and
      ABK are effective in the treatment of MRS keratitis. Vancomycin eye ointment is
      effective as the final choice in serious cases.

PMID- 12484708
TI  - Treatment of the common cold with unrefined echinacea. A randomized, double
      blind, placebo-controlled trial.
AB  - BACKGROUND: Echinacea preparations are widely used to treat the common cold.
      OBJECTIVE: To assess the efficacy of dried, encapsulated, whole-plant echinacea
      as early treatment for the common cold. DESIGN: Randomized, double-blind, placebo
      controlled community-based trial. SETTING: University of Wisconsin-Madison,
      Madison, Wisconsin. PARTICIPANTS: 148 registered students with common colds of
      recent onset. INTERVENTION: An encapsulated mixture of unrefined Echinacea
      purpurea herb (25%) and root (25%) and E. angustifolia root (50%) taken in 1-g
      doses six times on the first day of illness and three times on each subsequent
      day of illness for a maximum of 10 days. MEASUREMENTS: Severity and duration of
      self-reported symptoms of upper respiratory tract infection. RESULTS: No
      statistically significant differences were detected between the echinacea and
      placebo groups for any of the measured outcomes. Trajectories of severity over
      time were nearly identical in the two groups. Mean cold duration was 6.01 days in
      both groups as a whole, 5.75 days in the placebo group, and 6.27 days in the
      echinacea group (between-group difference, -0.52 day [95% CI, -1.09 to 0.22
      days]). After controlling for severity and duration of symptoms before study
      entry, sex, date of enrollment, and use of nonprotocol medications, researchers
      found no statistically significant treatment effect (adjusted hazard ratio, 1.24
      [CI, 0.86 to 1.78]). Multivariable regression models assessing severity scores
      over time failed to detect statistically significant differences between the
      echinacea and placebo groups. CONCLUSION: Compared with placebo, unrefined
      echinacea provided no detectable benefit or harm in these college students who
      had the common cold.

PMID- 12484709
TI  - Results of a prospective study of acute liver failure at 17 tertiary care centers
      in the United States.
AB  - BACKGROUND: Because acute liver failure is rare, related data have been sparse.
      Studies have suggested that viral hepatitis is the most common underlying cause
      of this condition. OBJECTIVE: To describe the clinical features, presumed causes,
      and short-term outcomes of acute liver failure. DESIGN: Prospective cohort study.
      SETTING: 17 tertiary care centers participating in the U.S. Acute Liver Failure
      Study Group. PATIENTS: 308 consecutive patients with acute liver failure,
      admitted over a 41-month period. MEASUREMENTS: Detailed clinical and laboratory
      data collected during hospitalization, including outcome 3 weeks after study
      admission. RESULTS: 73% of patients were women; median age was 38 years.
      Acetaminophen overdose was the most common apparent cause of acute liver failure,
      accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive
      cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of
      cases, and 17% of cases were of indeterminate cause. Overall patient survival at
      3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and
      43% survived without transplantation. Short-term transplant-free survival varied
      greatly, from 68% for patients with acetaminophen-related liver failure to 25%
      and 17% for those with other drug reactions and liver failure of indeterminate
      cause, respectively. Coma grade at admission appeared to be associated with
      outcome, but age and symptom duration did not. CONCLUSIONS: Acetaminophen
      overdose and idiosyncratic drug reactions have replaced viral hepatitis as the
      most frequent apparent causes of acute liver failure. Apparent cause and coma
      grade at admission were associated with outcome. Although transplantation may
      improve patient survival, it was unavailable or unnecessary for most patients.

PMID- 12484710
TI  - Residual venous thrombosis as a predictive factor of recurrent venous
      thromboembolism.
AB  - BACKGROUND: The optimum duration of anticoagulant therapy after an episode of
      deep venous thrombosis (DVT) is controversial. Contributing to the controversy is
      uncertainty about whether residual venous thrombosis, as assessed by repeated
      ultrasonography over time, increases the risk for recurrent thromboembolism.
      OBJECTIVE: To determine the risk for recurrent thromboembolism in patients who
      have persistent residual thrombosis compared with patients who have early vein
      recanalization. DESIGN: Prospective cohort study. SETTING: A university hospital
      in Padua, Italy. PATIENTS: 313 consecutive symptomatic outpatients with proximal
      DVT who received conventional short-term anticoagulation. MEASUREMENTS:
      Ultrasonographic assessment of the common femoral and popliteal veins was
      performed 3 months after acute DVT in all patients and at 6, 12, 24, and 36
      months in patients found to have residual venous thrombosis. Veins were
      considered recanalized if they were 2.0 mm or less in diameter on a single test
      or 3.0 mm or less in diameter on two consecutive tests. Recurrent thromboembolism
      was assessed during a 6-year period. RESULTS: The cumulative incidence of normal
      results on ultrasonography was 38.8% at 6 months, 58.1% at 12 months, 69.3% at 24
      months, and 73.8% at 36 months. Of 58 recurrent episodes, 41 occurred while the
      patient had residual thrombosis. The hazard ratio for recurrent thromboembolism
      was 2.4 (95% CI, 1.3 to 4.4; P = 0.004) for patients with persistent residual
      thrombosis versus those with early vein recanalization. CONCLUSIONS: Residual
      venous thrombosis is an important risk factor for recurrent thromboembolism.
      Ultrasonographic assessment of residual venous thrombosis may help clinicians
      modify the duration of anticoagulation in patients with DVT.

PMID- 12484711
TI  - Prevalence of liver disease in a population of asymptomatic persons with
      hepatitis C virus infection.
AB  - BACKGROUND: The prevalence of significant liver disease in persons with
      asymptomatic hepatitis C virus (HCV) infection is unclear. OBJECTIVE: To
      determine the prevalence and severity of HCV infection in asymptomatic persons.
      DESIGN: Population-based cross-sectional study. SETTING: Northeastern Italy.
      PATIENTS: 4820 apparently healthy Telecom Italy employees or their relatives who
      underwent screening for cardiovascular risk factors. MEASUREMENTS: Initial
      screening for anti-HCV by enzyme-linked immunosorbent assay followed by HCV RNA
      testing by polymerase chain reaction and monitoring of alanine aminotransferase
      levels in viremic persons (92% of viremic persons also had liver biopsies to
      assess their METAVIR scores). RESULTS: 116 persons (2.4% [95% CI, 1.97% to
      2.84%]) were positive for anti-HCV and 85 (1.76% [CI, 1.39% to 2.14%]) were also
      viremic. The ALT level was persistently normal in 39 (46%) of viremic patients
      and elevated in 46 (54%). Significant hepatic histologic abnormalities were
      detected in 19% (CI, 7.21% to 36.4%) of persons with persistently normal ALT
      levels and in 61% (CI, 45.4% to 74.9%) of viremic persons who had elevated ALT
      levels (P < 0.001). The prevalence of HCV infection and number of persons with
      chronic liver fibrosis increased with age (P = 0.003). CONCLUSIONS: Hepatitis C
      is histologically active and progressive in up to 40% of asymptomatic persons
      with HCV infection. The severity of liver disease correlates with abnormal ALT
      levels and increases with age.

PMID- 12484713
TI  - Update in infectious diseases.

PMID- 12484712
TI  - Credentialing complementary and alternative medical providers.
AB  - Since the late 19th century, state legislatures and professional medical
      organizations have developed mechanisms to license physicians and other
      conventional nonphysician providers, establish standards of practice, and protect
      health care consumers by establishing standardized credentials as markers of
      competence. The popularity of complementary and alternative medical (CAM)
      therapies presents new challenges. This article describes the current status of,
      and central issues in, efforts to create models for health care credentialing of
      chiropractors, acupuncturists, naturopaths, massage therapists, and other CAM
      practitioners. It also suggests a strategy of CAM provider credentialing for use
      by physicians, health care administrators, insurance companies, and national
      professional organizations. The credentialing debate reflects fundamental
      questions about who determines which providers and therapies will be accepted as
      safe, effective, appropriate, and reimbursable. More nationally uniform
      credentialing mechanisms are necessary to ensure high standards of care and more
      generalizable clinical research. However, the result of more uniform licensure
      and credentialing may be excessive standardization and a decrease in
      individualization of services. Thus, increased standardization of credentialing
      for CAM practitioners may alter CAM practice substantially. Furthermore, even
      credentialed providers can deliver ineffective therapy. The suggested framework
      balances the desire to protect the public from dangerous practices against the
      wish to grant patients access to reasonably safe and effective therapies.

PMID- 12484714
TI  - Novel insights in the congenital long QT syndrome.
AB  - BACKGROUND: The congenital long QT syndrome is a potentially fatal, inherited
      cardiac syndrome. Early diagnosis and preventive treatment are instrumental to
      prevent sudden cardiac death in patients with the congenital long QT syndrome.
      PURPOSE: To review new insights in genetics and cellular electrophysiology, as
      well as the current understanding of the clinical diagnosis and treatment of the
      congenital long QT syndrome. DATA SOURCES: Authors' personal databases and search
      of PubMed database from 1966 to 2001. STUDY SELECTION: Experimental and clinical
      studies on the congenital long QT syndrome. DATA EXTRACTION: Data from peer
      reviewed studies were manually extracted, classified, and summarized. DATA
      SYNTHESIS: The congenital long QT syndrome is characterized by abnormally
      prolonged ventricular repolarization, which predisposes patients to syncope,
      ventricular arrhythmias, and sudden cardiac death. The recent discovery of
      mutations in genes encoding ion channels has improved our understanding of the
      cellular origin of this condition. The congenital long QT syndrome may result
      from inherited defects in cardiac K+ and Na+ channels, which both result in
      prolongation of the ventricular action potential. The diagnosis is based on
      electrocardiographic and clinical criteria. Genetic screening of symptomatic
      patients or asymptomatic family members may identify patients at risk for life
      threatening ventricular arrhythmias. beta-Blocking agents are the mainstay of
      treatment. Certain patients may also benefit from a pacemaker or implantable
      cardioverter defibrillator. Recent studies suggest that genotype-specific
      treatment of the congenital long QT syndrome will be feasible in the near future.
      CONCLUSIONS: The congenital long QT syndrome is a potentially life-threatening
      condition caused by mutations in genes encoding cardiac ion channels. Better
      understanding of the mechanisms responsible for this condition will guide
      genotype-specific therapy in the near future.

PMID- 12484715
TI  - Smallpox manifestations and survival during the Boston epidemic of 1901 to 1903.
AB  - Clinical records of 243 patients with smallpox consecutively admitted to the
      Southampton Street smallpox hospital in Boston, Massachusetts, during the 1901
      1903 epidemic were reviewed. Smallpox was divided into five categories of varying
      severity; 47% of patients had varioloid, a relatively mild form of the disease
      usually occurring in previously vaccinated individuals with incomplete immunity.
      Survival information is available for 206 patients, of whom 36 (17.5%) died.
      Vaccination status, disease severity, and age were associated with survival,
      whereas sex, birthplace, and race were not. While full recovery often took weeks,
      most deaths occurred 7 to 14 days after the onset of symptoms, and all deaths
      occurred within 18 days of symptom onset. Smallpox was eradicated worldwide in
      1977, but knowledge of the disease is essential because its cause, variola virus,
      is considered a potential biological weapon.

PMID- 12484717
TI  - Echinacea for the common cold: can alternative medicine be evidence-based
      medicine?.

PMID- 12484718
TI  - The healing touch.

PMID- 12484719
TI  - Trust.

PMID- 12484721
TI  - Reporting enrollment in clinical trials.

PMID- 12484722
TI  - Reporting enrollment in clinical trials.

PMID- 12484723
TI  - Reporting enrollment in clinical trials.

PMID- 12484724
TI  - Careful conversation about care at the end of life.

PMID- 12484725
TI  - The risk-benefit profile of commonly used herbal therapies.

PMID- 12484728
TI  - Careful conversation about care at the end of life.

PMID- 12484729
TI  - Careful conversation about care at the end of life.

PMID- 12484730
TI  - Physician involvement in voluntary stopping of eating and drinking.

PMID- 12484732
TI  - Reflections on medical journals.

PMID- 12484734
TI  - Angina caused by calcific constrictive pericarditis.

PMID- 12484735
TI  - Use of antiviral therapy in patients with hepatitis C.

PMID- 12484737
TI  - Foamy macrophage syndrome due to hydroxyethyl starch replacement: a severe side
      effect in plasmapheresis.

PMID- 12484738
TI  - Recertification.

PMID- 12484739
TI  - Summaries for patients. When the heart's electrical system goes haywire: the
      congenital long QT syndrome.

PMID- 12484740
TI  - Summaries for patients. Liver disease in persons with asymptomatic hepatitis C
      virus infection.

PMID- 12484741
TI  - Summaries for patients. Risks for persistent clots in leg veins despite
      treatment.

PMID- 12484742
TI  - Summaries for patients. Acute liver failure in the United States.

PMID- 12484743
TI  - Summaries for patients. Treatment of colds with a capsule form of the herb
      echinacea.

PMID- 12484744
TI  - Careful conversation about care at the end of life.

PMID- 12484745
TI  - Careful conversation about care at the end of life.

PMID- 12484746
TI  - Biosynthesis and trafficking of sphingolipids in the yeast Saccharomyces
      cerevisiae.

PMID- 12484747
TI  - Time-resolved dissociation of the light-harvesting 1 complex of Rhodospirillum
      rubrum, studied by infrared laser temperature jump.
AB  - For the first time, data are presented on the time-resolved disassembly reaction
      of a highly organized membrane protein complex in vitro. The photosynthetic core
      light-harvesting complex of the bacterial strain Rhodospirillum rubrum G9
      consists of 12-16 dimeric subunits that in vivo are associated with the
      photosynthetic reaction center in a ringlike manner. Isolated in a detergent
      solution, its appearance either as a ringlike complex (called B873 and absorbing
      at 873 nm), subunit dimer (called B820 and absorbing at 820 nm), or monomeric
      form (called B777 and absorbing at 777 nm) is strongly temperature-dependent. In
      thermodynamic equilibria between B820 and B873, intermediate-sized complexes have
      also been observed that have absorption maxima around 850 nm. It is unknown
      whether these structures appear as intermediates in the kinetic B820-B873
      (dis)assembly reaction. In this paper disassembly of the light-harvesting complex
      into its dimeric subunits was followed spectroscopically on a time scale up to
      200 ms, upon applying an infrared laser-induced temperature jump. The full
      dissociation process appears to take place on a time scale of tens to hundreds of
      milliseconds, the rates becoming faster at higher starting temperatures. Applying
      the same technique, the dissociation reaction of dimeric subunits into monomers
      also could be established. This dissociation process occurred on a much faster
      time scale and took place within the 500 micros response time of our detection
      system.

PMID- 12484748
TI  - Light-induced trimer to monomer transition in the main light-harvesting antenna
      complex of plants: thermo-optic mechanism.
AB  - The main chlorophyll a/b light-harvesting complex of photosystem II, LHCIIb, has
      earlier been shown to be capable of undergoing light-induced reversible
      structural changes and chlorophyll a fluorescence quenching in a way resembling
      those observed in granal thylakoids when exposed to excess light [Barzda, V., et
      al. (1996) Biochemistry 35, 8981-8985]. The nature and mechanism of this
      unexpected structural flexibility has not been elucidated. In this work, by using
      density gradient centrifugation and nondenaturing green gel electrophoresis, as
      well as absorbance and circular dichroic spectroscopy, we show that light induces
      a significant degree of monomerization, which is in contrast with the
      preferentially trimeric organization of the isolated complexes in the dark.
      Monomerization is accompanied by a reversible release of Mg ions, most likely
      from the outer loop of the complexes. These data, as well as the built-in thermal
      and light instability of the trimeric organization, are explained in terms of a
      simple theoretical model of thermo-optic mechanism, effect of fast thermal
      transients (local T-jumps) due to dissipated photon energies in the vicinity of
      the cation binding sites, which lead to thermally assisted elementary structural
      transitions. Disruption of trimers to monomers by excess light is not confined to
      isolated trimers and lamellar aggregates of LHCII but occurs in photosystem II
      enriched grana membranes, intact thylakoid membranes, and whole plants. As
      indicated by differences in the quenching capability of trimers and monomers, the
      appearance of monomers could facilitate the nonphotochemical quenching of the
      singlet excited state of chlorophyll a. The light-induced formation of monomers
      may also be important in regulated proteolytic degradation of the complexes.
      Structural changes driven by thermo-optic mechanisms may therefore provide plants
      with a novel mechanism for regulation of light harvesting in excess light.

PMID- 12484749
TI  - The C-terminal domain of the epsilon subunit of the chloroplast ATP synthase is
      not required for ATP synthesis.
AB  - The epsilon subunit of the ATP synthases from chloroplasts and Escherichia coli
      regulates the activity of the enzyme and is required for ATP synthesis. The
      epsilon subunit is not required for the binding of the catalytic portion of the
      chloroplast ATP synthase (CF1) to the membrane-embedded part (CFo). Thylakoid
      membranes reconstituted with CF1 lacking its epsilon subunit (CF1-epsilon) have
      high ATPase activity and no ATP synthesis activity, at least in part because the
      membranes are very leaky to protons. Either native or recombinant epsilon subunit
      inhibits ATPase activity and restores low proton permeability and ATP synthesis.
      In this paper we show that recombinant epsilon subunit from which 45 amino acids
      were deleted from the C-terminus is as active as full-length epsilon subunit in
      restoring ATP synthesis to membranes containing CF1-epsilon. However, the
      truncated form of the epsilon subunit was significantly less effective as an
      inhibitor of the ATPase activity of CF1-epsilon, both in solution and bound to
      thylakoid membranes. Thus, the C-terminus of the epsilon subunit is more involved
      in regulation of activity, by inhibiting ATP hydrolysis, than in ATP synthesis.

PMID- 12484750
TI  - Aspergillus aculeatus beta-1,4-galactanase: substrate recognition and relations
      to other glycoside hydrolases in clan GH-A.
AB  - The three-dimensional structure of Aspergillus aculeatus beta-1,4-galactanase
      (AAGAL), an enzyme involved in pectin degradation, has been determined by
      multiple isomorphous replacement to 2.3 and 1.8 A resolution at 293 and 100 K,
      respectively. It represents the first known structure for a polysaccharidase with
      this specificity and for a member of glycoside hydrolase family 53 (GH-53). The
      enzyme folds into a (beta/alpha)(8) barrel with the active site cleft located at
      the C-terminal side of the barrel consistent with the classification of GH-53 in
      clan GH-A, a superfamily of enzymes with common fold and catalytic machinery but
      diverse specificities. Putative substrate-enzyme interactions were elucidated by
      modeling of beta-1,4-linked galactobioses into the possible substrate binding
      subsites. The structure and modeling studies identified five potential subsites
      for the binding of galactans, of which one is a pocket suited for accommodating
      the arabinan side chain in arabinogalactan, one of the natural substrates. A
      comparison with the substrate binding grooves of other Clan GH-A enzymes suggests
      that shape complementarity is crucial in determining the specificity of
      polysaccharidases.

PMID- 12484751
TI  - A unique structural pattern shared by T-cell-activating and abscess-regulating
      zwitterionic polysaccharides.
AB  - In contrast to the conventional dogma that carbohydrates are poorly immunogenic T
      cell-independent antigens, zwitterionic polysaccharides (ZPSs) can significantly
      stimulate T-cell proliferation and regulate abscess formation in bacterial
      infection. Despite their similar biological activities, ZPSs from various
      bacteria are greatly different in primary chemical compositions and building
      block linkages. To identify the common structural features that govern the
      peculiar immunologic activity of ZPSs, we have been determining three-dimensional
      structures of compositionally different ZPSs by NMR spectroscopy and molecular
      mechanics and dynamics calculations. We report here the conformation of type 1
      capsular polysaccharide from the human pathogen Streptococcus pneumoniae (Sp1) to
      be a right-handed helix with repeated zwitterionically charged grooves. We also
      report the striking similarity between the structures of Sp1 and our previously
      determined PS A2 from Bacteroides fragilis. These results support our hypothesis
      that T-cell-activating ZPSs assume similar conformational and charge patterns
      that are recognized by specific receptors and that account for their common
      property as T-cell activators.

PMID- 12484752
TI  - Histone deacetylase-dependent establishment and maintenance of broad low-level
      histone acetylation within a tissue-specific chromatin domain.
AB  - The murine beta-globin locus in adult erythroid cells is characterized by a broad
      pattern of erythroid-specific histone acetylation. The embryonic beta-globin
      genes Ey and betaH1 are located in a approximately 30 kb central subdomain
      characterized by low-level histone acetylation, while the fetal/adult genes
      betamajor and betaminor and the upstream locus control region reside in
      hyperacetylated chromatin. Histone deacetylase (HDAC) inhibitors induce H4
      acetylation at the Ey promoter [Forsberg, E. C., Downs, K. M., Christensen, H.
      M., Im, H., Nuzzi, P. A., and Bresnick, E. H. (2000) Proc. Natl. Acad. Sci.
      U.S.A. 97, 14494-14499], indicating that HDACs maintain low-level H4 acetylation
      at this site. Since little is known about the establishment of broad histone
      modification patterns, we asked whether this mechanism applies only to the
      promoter or to the entire subdomain. We show that the HDAC inhibitor trichostatin
      A induces H4 hyperacetylation at multiple sites within the subdomain in erythroid
      cells. The hematopoietic factors p45/NF-E2, GATA-1, and erythroid kruppel-like
      factor (EKLF), which function through cis elements of the beta-globin locus, were
      not required for induction of H4 hyperacetylation. Analysis of chromatin
      structure within the subdomain revealed low accessibility to restriction
      endonucleases and nearly complete CpG dinucleotide methylation. Induction of H4
      hyperacetylation did not restore hallmark features of transcriptionally active
      chromatin. We propose that an HDAC-dependent surveillance mechanism counteracts
      constitutive histone acetyltransferase (HAT) access, thereby maintaining low
      level H4 acetylation throughout the subdomain.

PMID- 12484753
TI  - Local protein dynamics and catalysis: detection of segmental motion associated
      with rate-limiting product release by a glutathione transferase.
AB  - Glutathione transferase rGSTM1-1 catalyzes the addition of glutathione (GSH) to 1
      chloro-2,4-dinitrobenzene, a reaction in which the chemical step is 60-fold
      faster than the physical step of product release. The hydroxyl group of Y115,
      located in the active site access channel, controls the egress of product from
      the active site. The Y115F mutant enzyme has a k(cat) (72 s(-)(1)) that is 3.6
      fold larger than that of the native enzyme (20 s(-)(1)). Crystallographic
      observations and evidence from amide proton exchange kinetics are consistent with
      localized increases in the degree of segmental motion of the Y115F mutant that
      are coupled to the enhanced rate of product release. The loss of hydrogen bonding
      interactions involving the hydroxyl group of Y115 is reflected in subtle
      alterations in the backbone position, an increase in B-factors for structural
      elements that comprise the channel to the active site, and, most dramatically, a
      loss of well-defined electron density near the site of mutation. The kinetics of
      amide proton exchange are also enhanced by a factor between 3 and 12 in these
      regions, providing direct, quantitative evidence for changes in local protein
      dynamics affecting product release. The enhanced product release rate is proposed
      to derive from a small shift in the equilibrium population of protein conformers
      that permit egress of the product from the active site.

PMID- 12484754
TI  - Effect of phosphorylation on the interdomain interaction of the response
      regulator, NarL.
AB  - DNA binding by the effector domain (NarLC) of the response regulator, NarL, is
      modulated by the phosphorylation state of the receiver domain (NarLN). The
      receiver domain appears to block the site of DNA binding in the nonphosphorylated
      state. Phosphorylation is proposed to disrupt this interaction, causing the
      effector domain to be released and free to bind DNA (Baikalov, I., Schroder, I.,
      Kaczor-Grzeskowiak, M., Grzeskowiak, K., Gunsalus, R. P., and Dickerson, R. E.
      (1996) Biochemistry 35, 11053-61). To better understand this modulation, we
      analyzed the interaction between the two domains in the absence of a polypeptide
      linkage. Using multidimensional NMR, we mapped chemical shift changes that
      occurred during a titration between the two isolated domains. Specific residues
      in NarLC exhibit large chemical shift changes upon the addition of NarLN. These
      residues are primarily at the interface between the two domains as seen in the
      crystal structure. Using the residues with the largest chemical shift changes, we
      observed a dissociation constant of 88 +/- 7 microM. In the presence of 10 mM
      MgCl(2), the affinity is reduced 4-fold to about 350 microM. This work shows that
      the domains interact in trans and that this interaction, while fairly weak,
      provides a way to monitor the energetics of domain-domain interaction in this
      system. Phosphorylation of NarLN by a small-molecule phosphate donor,
      phosphoramidate, decreases this interaction about 25-fold from the
      nonphosphorylated sample. The results support the model that the mechanism of
      activation of NarL involves a disruption of the interdomain interface and
      suggests that the linker is not necessary for the transmission of signal across
      the domain interface. The linker does play a role in increasing the local
      concentration of the domains and therefore increasing the amount of closed
      conformation with respect to the open conformation. We estimate the levels of
      open conformation to be low (about 1%) in the nonphosphorylated state in the
      absence of magnesium ion and much higher in the phospho state (near 50%). This
      modulation of the open or active state via the interaction at the interface may
      also be applicable to other multidomain response regulator proteins.

PMID- 12484755
TI  - Solution structure of a DNA duplex containing mispair-aligned N4C-ethyl-N4C
      interstrand cross-linked cytosines.
AB  - The solution structure of an interstrand cross-linked self-complementary
      oligodeoxynucleotide containing directly opposed alkylated N(4)C-ethyl-N(4)C
      cytosine bases was determined by molecular dynamics calculations guided by NMR
      derived restraints. The undecamer d(CGAAACTTTCG)(2), where C represents directly
      opposed alkylated N(4)C-ethyl-N(4)C cytosine bases, serves as model for the
      cytotoxic cross-links formed by bifunctional alkylating agents used in cancer
      therapy. The structure of the duplex shows the cross-link protruding into the
      major groove. An increase in the diameter of the DNA at the pseudoplatform formed
      by the cross-linked residues creates an A-DNA characteristic hole in the central
      portion of the DNA. This results in a centrally underwound base step and a number
      of subsequent overwinding steps leading to an overall axis bend toward the major
      groove. The structure shows narrowing of both minor and major grooves in the
      proximity of the cross-link. The perturbation leads to preferential intrastrand
      base stacking, disruption of adjacent canonical (A.T) base pairing, and buckling
      of base pairs, the extent of which diminishes with progression away from the
      lesion site. Overall, the distortion induced by the cross-link spreads over three
      base pairs on the 5'- and 3'-sides of the cross-link.

PMID- 12484756
TI  - Human glutathione-dependent formaldehyde dehydrogenase. Structural changes
      associated with ternary complex formation.
AB  - Human glutathione-dependent formaldehyde dehydrogenase plays an important role in
      the metabolism of glutathione adducts such as S-(hydroxymethyl)glutathione and S
      nitrosoglutathione. The role of specific active site residues in binding these
      physiologically important substrates and the structural changes during the
      catalytic cycle of glutathione-dependent formaldehyde dehydrogenase was examined
      by determining the crystal structure of a ternary complex with S
      (hydroxymethyl)glutathione and the reduced coenzyme to 2.6 A resolution. The
      formation of the ternary complex caused the movement of the catalytic domain
      toward the coenzyme-binding domain. This represents the first observation of
      domain closure in glutathione-dependent formaldehyde dehydrogenase in response to
      substrate binding. A water molecule adjacent to the 2'-ribose hydroxyl of NADH
      suggests that the alcohol proton is relayed to solvent directly from the
      coenzyme, rather than through the action of the terminal histidine residue as
      observed in the proton relay system for class I alcohol dehydrogenases. S
      (Hydroxymethyl)glutathione is directly coordinated to the active site zinc and
      forms interactions with the highly conserved residues Arg114, Asp55, Glu57, and
      Thr46. The active site zinc has a tetrahedral coordination environment with
      Cys44, His66, and Cys173 as the three protein ligands in addition to S
      (hydroxymethyl)glutathione. This is in contrast to zinc coordination in the
      binary coenzyme complex where all of the ligands were contributed by the enzyme
      and included Glu67 as the fourth protein ligand. This change in zinc coordination
      is accomplished by an approximately 2.3 A movement of the catalytic zinc.

PMID- 12484757
TI  - Guanine binding site of the Nicotiana glutinosa ribonuclease NW revealed by X-ray
      crystallography.
AB  - Ribonuclease NW (RNase NW), the wound-inducible RNase in Nicotiana glutinosa
      leaves, preferentially cleaves guanylic acid. We expressed the cDNA encoding
      RNase NW in the methylotrophic yeast Pichia pastoris using the expression vector
      pPIC9K, and the resulting recombinant RNase NW (ryRNaseNW) secreted into medium
      was purified to apparent homogeneity using column chromatography. The crystal
      structure of ryRNase NW bound to 5'-GMP was determined at 1.5 A resolution by
      molecular replacement with tomato RNase LE as a search model. The RNase NW
      structurally belongs to the (alpha + beta) class of proteins, having eight
      helices (five alpha-helices and three 3(10) helices) and six beta-strands, and
      its structure is highly similar to those of other plant RNases, including a
      uridylic acid preferential RNase MC1 from bitter gourd seeds. The guanine ring of
      5'-GMP lies in a hydrophobic pocket of the molecular surface composed of Tyr17,
      Tyr71, Ala80, Leu79, and Phe89: the guanine base is sandwiched between aromatic
      side chains of Tyr17 and Phe89. In addition, the guanine base is firmly
      stabilized by a network of hydrogen bonds of the side chains of Gln12 and Thr78,
      as well as of the main chain of Leu79. Therefore, Gln12, Tyr17, Thr78, Leu79, and
      Phe89 are responsible for recognition of the guanine base by RNase NW, findings
      which provide insight into the manner in which RNase NW preferentially cleaves
      guanylic acid.

PMID- 12484758
TI  - Molecular cloning and functional characterization of chicken brain tau: isoforms
      with up to five tandem repeats.
AB  - Tau is a major microtubule-associated protein in mammalian brain, where it exists
      as multiple isoforms that are produced from a single gene by alternative mRNA
      splicing. Here we present the first report on the structure and function of tau
      protein from a nonmammalian vertebrate. In the adult chicken brain, five main tau
      isoforms are expressed. One isoform has three tandem repeats, two isoforms have
      four repeats each, and two isoforms have five repeats each. Similar to mammalian
      tau, some chicken tau isoforms contain an amino-terminal insert of 53 amino
      acids. Unlike mammalian tau, a 34 amino acid insert in the proline-rich region
      upstream of the repeats is alternatively spliced in chicken tau. It is preceded
      by a constitutively expressed sequence of 17 amino acids that is absent in tau
      from human and rodent brains. The expression of chicken tau isoforms and their
      phosphorylation are developmentally regulated, similar to what has been described
      in mammalian brain. Functionally, chicken tau isoforms with five repeats have the
      greatest ability to promote microtubule assembly, followed by isoforms with four
      and three repeats, respectively. The 34 amino acid insert positively influences
      both the rate and the extent of microtubule assembly, whereas the 53 amino acid
      insert only influences the extent of assembly.

PMID- 12484759
TI  - Probing subtle coordination changes in the iron-quinone complex of photosystem II
      during charge separation, by the use of NO.
AB  - The terminal electron acceptor of Photosystem II, PSII, is a linear complex
      consisting of a primary quinone, a non-heme iron(II), and a secondary quinone,
      Q(A)Fe(2+)Q(B). The complex is a sensitive site of PSII, where electron transfer
      is modulated by environmental factors and notably by bicarbonate. Earlier studies
      showed that NO and other small molecules (CN(-), F(-), carboxylate anions) bind
      reversibly on the non-heme iron in competition with bicarbonate. In the present
      study, we report on an unusual new mode of transient binding of NO, which is
      favored in the light-reduced state (Q(A)(-)Fe(2+)Q(B)) of the complex. The
      related observations are summarized as follows: (i) Incubation with NO at -30
      degrees C, following light-induced charge separation, results in the evolution of
      a new EPR signal at g = 2.016. The signal correlates with the reduced state Q(A)(
      )Fe(2+) of the iron-quinone complex. (ii) Cyanide, at low concentrations,
      converts the signal to a more rhombic form with g values at 2.027 (peak) and
      1.976 (valley), while at high concentrations it inhibits formation of the
      signals. (iii) Electron spin-echo envelope modulation (ESEEM) experiments show
      the existence of two protein (14)N nuclei coupled to electron spin. These two
      nitrogens have been detected consistently in the environment of the semiquinone
      Q(A)(-) in a number of PSII preparations. (iv) NO does not directly contribute to
      the signals, as indicated by the absence of a detectable isotopic effect ((15)NO
      vs (14)NO) in cw EPR. (v) A third signal with g values (2.05, 2.03, 2.01)
      identical to those of an Fe(NO)(2)(imidazole) synthetic complex develops slowly
      in the dark, or faster following illumination. (vi) In comparison with the
      untreated Q(A)(-)Fe(2+) complex, the present signals not only are confined to a
      narrow spectral region but also saturate at low microwave power. At 11 K the g =
      2.016 signal saturates with a P(1/2) of 110 microW and the g = 2.027/1.976 signal
      with a P(1/2) of 10 microW. (vii) The spectral shape and spin concentration of
      these signals is successfully reproduced, assuming a weak magnetic interaction (J
      values in the range 0.025-0.05 cm(-)(1)) between an iron-NO complex with total
      spin of (1)/(2) and the spin, (1)/(2), of the semiquinone, Q(A)(-). The different
      modes of binding of NO to the non-heme iron are examined in the context of a
      molecular model. An important aspect of the model is a trans influence of Q(A)
      reduction on the bicarbonate ligation to the iron, transmitted via H-bonding of
      Q(A) with an imidazole ligand to the iron.

PMID- 12484760
TI  - Identifying the lowest electronic states of the chlorophylls in the CP47 core
      antenna protein of photosystem II.
AB  - CP47 is a pigment-protein complex in the core of photosystem II that tranfers
      excitation energy to the reaction center. Here we report on a spectroscopic
      investigation of the isolated CP47 complex. By deconvoluting the 77 K absorption
      and linear dichroism, red-most states at 683 and 690 nm have been identified with
      oscillator strengths corresponding to approximately 3 and approximately 1
      chlorophyll, respectively. Both states contribute to the 4 K emission, and the
      Stark spectrum shows that they have a large value for the difference
      polarizability between their ground and excited states. From site-selective
      polarized triplet-minus-singlet spectra, an excitonic origin for the 683 nm state
      was found. The red shift of the 690 nm state is most probably due to strong
      hydrogen bonding to a protein ligand, as follows from the position of the stretch
      frequency of the chlorophyll 13(1) keto group (1633 cm(-)(1)) in the fluorescence
      line narrowing spectrum at 4 K upon red-most excitation. We discuss how the 683
      and 690 nm states may be linked to specific chlorophylls in the crystal structure
      [Zouni, A., Witt, H.-T., Kern, J., Fromme, P., Krauss, N., Saenger, W., and Orth,
      P. (2001) Nature 409, 739-743].

PMID- 12484761
TI  - Characterization of the redox centers in dimethyl sulfide dehydrogenase from
      Rhodovulum sulfidophilum.
AB  - Dimethyl sulfide dehydrogenase from the purple phototrophic bacterium Rhodovulum
      sulfidophilum catalyzes the oxidation of dimethyl sulfide to dimethyl sulfoxide.
      Recent DNA sequence analysis of the ddh operon, encoding dimethyl sulfide
      dehydrogenase (ddhABC), and biochemical analysis (1) have revealed that it is a
      member of the DMSO reductase family of molybdenum enzymes and is closely related
      to respiratory nitrate reductase (NarGHI). Variable temperature X-band EPR
      spectra (120-122 K) of purified heterotrimeric dimethyl sulfide dehydrogenase
      showed resonances arising from multiple redox centers, Mo(V), [3Fe-4S](+), [4Fe
      4S](+), and a b-type heme. A pH-dependent EPR study of the Mo(V) center in
      (1)H(2)O and (2)H(2)O revealed the presence of three Mo(V) species in
      equilibrium, Mo(V)-OH(2), Mo(V)-anion, and Mo(V)-OH. Above pH 8.2 the dominant
      species was Mo(V)-OH. The maximum specific activity occurred at pH 9.27.
      Comparison of the rhombicity and anisotropy parameters for the Mo(V) species in
      DMS dehydrogenase with other molybdenum enzymes of the DMSO reductase family
      showed that it was most similar to the low-pH nitrite spectrum of Escherichia
      coli nitrate reductase (NarGHI), consistent with previous sequence analysis of
      DdhA and NarG. A sequence comparison of DdhB and NarH has predicted the presence
      of four [Fe-S] clusters in DdhB. A [3Fe-4S](+) cluster was identified in dimethyl
      sulfide dehydrogenase whose properties resembled those of center 2 of NarH. A
      [4Fe-4S](+) cluster was also identified with unusual spin Hamiltonian parameters,
      suggesting that one of the iron atoms may have a fifth non-sulfur ligand. The g
      matrix for this cluster is very similar to that found for the minor conformation
      of center 1 in NarH [Guigliarelli, B., Asso, M., More, C., Augher, V., Blasco,
      F., Pommier, J., Giodano, G., and Bertrand, P. (1992) Eur. J. Biochem. 307, 63
      68]. Analysis of a ddhC mutant showed that this gene encodes the b-type
      cytochrome in dimethyl sulfide dehydrogenase. Magnetic circular dichroism studies
      revealed that the axial ligands to the iron in this cytochrome are a histidine
      and methionine, consistent with predictions from protein sequence analysis. Redox
      potentiometry showed that the b-type cytochrome has a high midpoint redox
      potential (E degrees = +315 mV, pH 8).

PMID- 12484762
TI  - Conserved proline residue at position 189 in cone visual pigments as a
      determinant of molecular properties different from rhodopsins.
AB  - To identify the amino acid residue(s) responsible for the difference in the
      molecular properties between rod and cone pigments, we have prepared chicken
      green mutants where each of the residues (Val77, Gly144, and Pro189) completely
      conserved in the cone pigments was replaced with the residue in the rod pigment
      rhodopsin. Among the mutants, the P189I mutant showed an expression level in
      cultured HEK293 cells and a thermal stability higher than did the wild-type
      chicken green. The mutation caused a reduced decay rate of the meta II
      intermediate, while the mutation of the wild-type chicken rhodopsin at position
      189 (I189P) resulted in an increased decay rate. The additional mutation at
      position 122, the previously reported site where the amino acid residue is one of
      the determinants of the meta II decay rate, converted the meta II decay rate into
      that observed in the wild-type chicken rhodopsin. These results suggest that the
      difference in the meta II decay rate between the chicken green and rhodopsin is
      due to the difference in the amino acid residues at positions 189 and 122. The
      completely conserved nature of proline at position 189 could provide a clue to
      the molecular evolution of the pigments.

PMID- 12484763
TI  - Influence of the protein environment on the properties of a tyrosyl radical in
      reaction centers from Rhodobacter sphaeroides.
AB  - The influence of the local environment on the formation of a tyrosyl radical was
      investigated in modified photosynthetic reaction centers from Rhodobacter
      sphaeroides. The reaction centers contain a tyrosine residue placed approximately
      10 A from a highly oxidizing bacteriochlorophyll dimer. Measurements by both
      optical and electron paramagnetic resonance spectroscopy revealed spectral
      features that are assigned as arising primarily from an oxidized
      bacteriochlorophyll dimer at low pH values and from a tyrosyl radical at high pH
      values, with a well-defined transition that occurred with a pK(a) of 6.9. A model
      based on the wild-type structure indicated that the Tyr at M164 is likely to form
      a hydrogen bond with His M193 and to interact weakly with Glu M173. Substitution
      of Tyr or Glu for His at M193 increased the pK(a) for the transition from 6.9 to
      8.9, while substitution of Gln for His M193 resulted in a higher pK(a) value.
      Substitution of Glu M173 with Gln resulted in loss of the partial formation of
      the tyrosyl that occurs in the other mutants at low pH values. The results are
      interpreted in terms of the ability of the residues to act as proton acceptors
      for the oxidized tyrosine, with the pK(a) values reflecting those of either the
      putative proton acceptor or the tyrosine, in accord with general models of amino
      acid radicals.

PMID- 12484764
TI  - 11-cis-retinal protonated Schiff base: influence of the protein environment on
      the geometry of the rhodopsin chromophore.
AB  - Density functional theory (DFT) calculations based on the self-consistent-charge
      tight-binding approximation have been performed to study the influence of the
      protein pocket on the 3-dimensional structure of the 11-cis-retinal Schiff base
      (SB) chromophore. Starting with an effectively planar chromophore embedded in a
      protein pocket consisting of the 27 next-nearest amino acids, the relaxed
      chromophore geometry resulting from energy optimization and molecular dynamics
      (MD) simulations has yielded novel insights with respect to the following
      questions: (i) The conformation of the beta-ionone ring. The protein pocket
      tolerates both conformations, 6-s-cis and 6-s-trans, with a total energy
      difference of 0.7 kcal/mol in favor of the former. Of the two possible 6-s-cis
      conformations, the one with a negative twist angle (optimized value: -35 degrees
      ) is strongly favored, by 3.6 kcal/mol, relative to the one in which the dihedral
      is positive. (ii) Out-of-plane twist of the chromophore. The environment induces
      a nonplanar helical deformation of the chromophore, with the distortions
      concentrated in the central region of the chromophore, from C10 to C13. The
      dihedral angle between the planes formed by the bonds from C7 to C10 and from C13
      to C15 is 42 degrees. (iii) The absolute configuration of the chromophore. The
      dihedral angle about the C12-C13 bond is +170 degrees from planar s-cis, which
      imparts a positive helicity on the chromophore, in agreement with earlier
      considerations based on theoretical and spectroscopic evidence.

PMID- 12484765
TI  - Insight into the factors influencing the backbone dynamics of three homologous
      proteins, dendrotoxins I and K, and BPTI: FTIR and time-resolved fluorescence
      investigations.
AB  - Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy,
      combined with hydrogen/deuterium exchange technique and time-resolved
      fluorescence spectroscopy, has been used to investigate the changes in structure
      and dynamics that underlie the thermodynamic stability differences observed for
      three closely homologous proteins: dendrotoxins I and K, and bovine pancreatic
      trypsin inhibitor (BPTI). The experiments were performed on proteins under their
      native state and a modified form, obtained by selective reduction of a disulfide
      bond at the surface of the molecule, increasing slightly the backbone flexibility
      without changing the average structure. The data confirmed the high local as well
      as global rigidity of BPTI. In protein K, the exchange process was slow during
      the first 2 h of exchange, presumably reflecting a compact three-dimensional
      conformation, and then increased rapidly, the internal amide protons of the beta
      strands exchanging 10-fold faster than in BPTI or protein I. The most probable
      destabilizing element was identified as Pro32, in the core of the beta-sheet.
      Protein I was found to present a 10% more expanded volume than protein K or BPTI,
      and there is a possible correlation between the resulting increased flexibility
      of the molecule and the lower thermodynamic stability observed for this protein.
      Interestingly, the interior amide protons of the beta-sheet structure were found
      to be as protected against exchange in protein I as in BPTI, suggesting that,
      although globally more flexible than that of Toxin K or BPTI, the structure of
      Toxin I could be locally quite rigid. The structural factors suspected to be
      responsible for the differences in internal flexibility of the two toxins could
      play a significant role in determining their functional properties.

PMID- 12484766
TI  - Structure and dynamics of condensed DNA probed by 1,1'-(4,4,8,8-tetramethyl-4,8
      diazaundecamethylene)bis[4-[[3- methylbenz-1,3-oxazol-2-yl]methylidine]-1,4
      dihydroquinolinium] tetraiodide fluorescence.
AB  - Information on the structure and dynamics of condensed forms of DNA is important
      in understanding both natural situations such as DNA packaging and artificial
      systems such as gene delivery complexes. We have established the fluorescence of
      bisintercalator 1,1'-(4,4,8,8-tetramethyl-4,8-diazaundecamethylene)bis[4-[[3
      methylbenz-1,3-oxazol-2-yl]methylidine]-1,4-dihydroquinolinium] tetraiodide (YOYO
      1) as a novel probe for DNA condensation. When the level of DNA-bound YOYO-1 is
      sufficiently large, condensation by either polyethylenimine (PEI) or the cationic
      detergent cetyltrimethylammonium bromide (CTAB) leads to electronic interaction
      among YOYO-1 molecules bound on the same DNA molecule. This interaction results
      in an excitonic blue shift of the absorption spectra of YOYO-1 and dramatic
      decrease in the fluorescence quantum yield. These observations constitute a
      signature of the condensation of DNA. We further examined the comparative
      properties of DNA condensed by PEI, CTAB, or Co(NH(3))(6)(3+) through the steady
      state and dynamic fluorescence of YOYO-1. Condensation by either PEI or CTAB was
      associated with a blue shift in the absorption spectra of YOYO-1, although the
      magnitude of the shift was larger in the case of PEI when compared to that of
      CTAB. In contrast, condensation by Co(NH(3))(6)(3+) was not associated with a
      measurable shift in the absorption spectra. These results were interpreted as
      signifying the varying level of compactness of the DNA condensates. Quenching of
      fluorescence by acrylamide showed that condensation by all three agents led to an
      increase in the level of solvent exposure of the base pairs. Observation of the
      decay of fluorescence intensity and anisotropy of DNA-bound YOYO-1 showed that
      while condensation by either PEI or CTAB froze the segmental mobility of the
      helix, condensation by Co(NH(3))(6)(3+) enhanced the flexibility of DNA. The
      relevance of our findings to functions such as efficiency of gene delivery is
      discussed.

PMID- 12484767
TI  - Characterization of DNA binding and the cysteine rich region of SRE, a GATA
      factor in Neurospora crassa involved in siderophore synthesis.
AB  - Several homologous genes encoding proteins involved in regulating siderophore
      synthesis in fungi have been isolated, including the sre gene from the
      filamentous fungus Neurospora crassa. We present data that further characterize
      SRE and provide new insights into the regulation of iron homeostasis in
      Neurospora. SRE is a member of the GATA factor family, which is comprised of
      transcription factors that contain either one or two zinc finger motifs that
      recognize and bind to GATA-containing DNA sequences. Results from electrophoretic
      mobility shift assays demonstrate that SRE binds with high affinity to a DNA
      probe containing the iron response element from the sid1 promoter from Ustilago.
      SRE binding to DNA was demonstrated to be zinc-dependent. Moreover, changes in
      the spacing between two GATA sites altered the DNA binding affinity of SRE.
      Mutants of highly conserved cysteine residues present in SRE and homologous
      proteins were created by site-directed mutagenesis. The combined results of
      mobility shift assays, siderophore synthesis assays, and ornithine oxygenase
      enzyme activity determinations demonstrate that these mutants with cysteine
      substitutions have a dominant repressor phenotype.

PMID- 12484768
TI  - Probing the effect of side chains on the conformation and stability of helical
      peptides via isotope-edited infrared spectroscopy.
AB  - The mechanism of helix stabilization or destabilization by different amino acids
      has been the subject of several experimental and theoretical studies; these
      studies suggest that large or bulky side chains may modulate helix stability by
      altering the hydration of the helix backbone. In this paper, we report a
      spectroscopic study to determine the effect of alanine to leucine substitutions
      on the conformation and solvation of specific segments of a model helical
      peptide. A 25-residue, alanine-rich, helical peptide [Ac-(AAAAK)(4)-AAAAY-NH(2)
      (AKA)] and its two leucine variants [Ac-LLLLK-(AAAAK)(3)-AAAAY-NH(2) (LKA) and Ac
      (AAAAK)(4)-LLLLY-NH(2) (AKL)] were characterized by infrared (IR) and electronic
      circular dichroism (ECD) spectroscopies. Introduction of (13)C isotopes into
      specific, consecutive, backbone carbonyls for certain blocks of each of the
      peptides mentioned above allows the IR spectra to be interpreted in terms of the
      conformation and solvation of specific residues within the helix. These isotope
      edited IR spectra of the leucine peptides do not show evidence of a decrease in
      the degree of backbone solvation compared to the alanines, but suggest that the
      peptide may adopt a distorted conformation to accommodate the larger leucine side
      chains at the N-terminus. These experiments demonstrate the power of isotope
      edited IR in dissecting subtle changes in helix conformation at the residue
      level.

PMID- 12484769
TI  - In vitro nucleotide misinsertion opposite the oxidized guanosine lesions
      spiroiminodihydantoin and guanidinohydantoin and DNA synthesis past the lesions
      using Escherichia coli DNA polymerase I (Klenow fragment).
AB  - The low redox potential of 8-oxo-7,8-dihydroguanine (OG), a molecule regarded as
      a marker of oxidative damage in cells, makes it an easy target for further
      oxidation. Using a temperature-dependent method of synthesis, the oxidation
      products of OG, guanidinohydantoin (Gh) and/or its isomer iminoallantoin (Ia) as
      well as spiroiminodihydantoin (Sp), have been site-specifically incorporated into
      DNA oligomers. Single nucleotide insertion and primer extension experiments using
      Escherichia coli Kf exo(-) DNA polymerase were carried out under "standing start"
      and "running start" conditions in various sequence contexts. dAMP and dGMP were
      found to be inserted opposite these OG oxidation products. Steady-state kinetic
      studies show that the Gh/Ia.G base pair yields a lower K(m) value compared to the
      Sp.G pair or X.A (X = Gh/Ia or Sp). Running start experiments using oxidized and
      unoxidized OG-containing templates showed enhanced full extension in the presence
      of all four dNTPs. A sequence preference for efficiency of extension was found
      when Gh/Ia and Sp are present in the DNA template, possibly leading to primer
      misalignment. Full extension is more efficient for the templates containing two
      Gs immediately 3' to the lesions compared to two As. Although these lesions cause
      a significant block for DNA elongation, results show that they are more easily
      bypassed by the polymerase when situated in the appropriate sequence context. UV
      melting studies carried out on duplexes mimicking the template/primer systems
      were used to characterize thermal stability of the duplexes. These experiments
      suggest that both Gh/Ia and Sp destabilize the duplex to a much greater extent
      than OG, with Sp being most severe.

PMID- 12484770
TI  - Translin binding to DNA: recruitment through DNA ends and consequent
      conformational transitions.
AB  - The human translin protein binds a variety of sequences (chromosomal breakpoint
      consensus sequences, their sequence variants, as well as nonbreakpoint sequences
      such as simple AT and GC repeats) at nanomolar protein concentration when short
      single strands ( approximately 20-30mers) are used as DNA targets. The protein,
      which is known to exist as an octamer in its free state, undergoes a
      conformational transition upon binding to short single strands leading either to
      a compaction or to the dissociation of the oligomer. Moreover, the protein
      oligomers tend to aggregate into complexes that get progressively larger as the
      length of the single-stranded DNA target increases. The protein loads onto
      duplexes via the free ends of DNA, generating higher oligomeric complexes as a
      function of protein concentration. Interestingly, the conformation of DNA targets
      encased by translin oligomer is significantly altered such that the single strand
      is rendered hypersensitive to DNase I. Furthermore, the loading of translin
      oligomers leads to tighter clamping of duplex ends. All of these observations,
      taken together, suggest that translin is a bona fide binder of DNA ends, thereby
      subjecting the DNA to a conformation conducive for repair steps during
      translocation events. We discuss the results in the perspective of translin
      biology.

PMID- 12484771
TI  - Ribozyme-catalyzed excision of targeted sequences from within RNAs.
AB  - We demonstrate that a group I intron-derived ribozyme from the opportunistic
      pathogen Pneumocystis carinii can bind an RNA in trans and excise from within it
      an internal segment, resulting in the splicing of the remaining ends of the RNA
      back together (the trans excision-splicing reaction). The reaction is
      intramolecular with regard to substrate. The ribozyme targets its substrate by
      base pairing with two or three noncontiguous regions on the substrate, and the
      reaction occurs through a nucleotide cofactor independent mechanism. The excised
      segment can be as long as 28 nucleotides, or more, and as little as one
      nucleotide. The potential usefulness of this reaction is demonstrated by
      engineering a ribozyme that excises the triplet-repeat expansion region from a
      truncated myotonic dystrophy protein kinase transcript mimic in vitro.

PMID- 12484772
TI  - RNA polymerase alters the mobility of an A-residue crucial to polymerase-induced
      melting of promoter DNA.
AB  - Strand separation in promoter DNA induced by Escherichia coli RNA polymerase is
      likely initiated at a conserved A residue at position -11 of the nontemplate
      strand. Here we describe the use of fluorescence techniques to study the
      interaction of RNA polymerase with the -11 base. Forked DNA templates were
      employed, containing the fluorescent base, 2-aminopurine (2AP), substituted at
      the -11 position in a single-stranded tail comprising the nucleotides on the
      nontemplate strand at which base pairing is disrupted in an RNA polymerase
      promoter complex. We demonstrate that the presence of 2AP instead of an A at
      position -11 has no major effect on the accessibility of DNA to DNase I or
      KMnO(4) in the presence or absence of RNA polymerase, thus justifying the use of
      templates containing the 2AP substitution in the fluorescence studies. A blue
      shift of the 2AP fluorescence emission maximum is observed in the presence of RNA
      polymerase. The results of fluorescence anisotropy decay studies indicate that
      about 60% of the 2AP residues at -11 are immobilized in an RNA polymerase
      complex. This value is in good agreement with the fraction of 2AP-substituted
      templates determined to be in a stable, heparin-resistant complex with RNA
      polymerase. These results are consistent with the residue at -11 being tightly
      bound in a hydrophobic pocket of the enzyme.

PMID- 12484773
TI  - Extended conformation of mammalian translation elongation factor 1A in solution.
AB  - The conformation of mammalian elongation factor eEF1A in solution was examined by
      the small angle neutron scattering and scanning microcalorimetry. We have found
      that in contrast to the bacterial analogue the eEF1A molecule has no fixed rigid
      structure in solution. The radius of gyration of the eEF1A molecule (5.2 nm) is
      much greater than that of prokaryotic EF1A. The specific heat of denaturation is
      considerably lower for eEF1A than for EF1A, suggesting that the eEF1A
      conformation is significantly more disordered. Despite its flexible conformation,
      eEF1A is found to be highly active in different functional tests. According to
      the neutron scattering data, eEF1A becomes much more compact in the complex with
      uncharged tRNA. The absence of a rigid structure and the possibility of large
      conformational change upon interaction with a partner molecule could be important
      for eEF1A functioning in channeled protein synthesis and/or for the well-known
      capability of the protein to interact with different ligands besides the
      translational components.

PMID- 12484774
TI  - Investigation of the structural stability of the human acidic fibroblast growth
      factor by hydrogen-deuterium exchange.
AB  - The conformational stability of the human acidic fibroblast growth factor (hFGF
      1) is investigated using amide proton exchange and temperature-dependent chemical
      shifts, monitored by two-dimensional NMR spectroscopy. The change in free energy
      of unfolding (DeltaG(u)) of hFGF-1 is estimated to be 5.00 +/- 0.09 kcal.mol(
      )(1). Amide proton-exchange rates of 74 residues (in hFGF-1) have been
      unambiguously measured, and the exchange process occurs predominately according
      to the conditions of the EX2 limit. The exchange rates of the fast-exchanging
      amide protons exposed to the solvent have been measured using the clean SEA-HSQC
      technique. The amide proton protection factor and temperature coefficient
      estimates show reasonably good correlation. Residues in beta-strands II and VI
      appear to constitute the stability core of the protein. Among the 12 beta-strands
      constituting the beta-barrel architecture of hFGF-1, beta-strand XI, located in
      the heparin binding domain, exhibits the lowest average protection factor value.
      Amide protons involved in the putative folding nucleation site in hFGF-1,
      identified by quench-flow NMR studies, do not represent the slow-exchanging core.
      Residues in portions of hFGF-1 experiencing high conformational flexibility
      mostly correspond to those involved in receptor recognition and binding.

PMID- 12484775
TI  - Retinol-binding protein-deficient mice: biochemical basis for impaired vision.
AB  - We reported previously that mice lacking plasma retinol-binding protein (RBP) are
      phenotypically normal except that they display impaired vision at the time of
      weaning. This visual defect is associated with greatly diminished eyecup levels
      of retinaldehyde and is reversible if the mutants are maintained for several
      months on a vitamin A-sufficient diet. Here we provide a biochemical basis for
      the visual phenotype of RBP-deficient mice. This phenotype does not result from
      inadequate milk total retinol levels since these are not different for RBP
      deficient and wild-type mice. The eye, unlike all other tissues that have been
      examined, takes up dietary retinol very poorly. Moreover, compared to other
      tissues, the eye displays a strong preference for retinol uptake when retinol is
      delivered bound to RBP. The poor uptake of dietary retinol by the eye coupled
      with its marked ability to take up retinol from RBP, we propose, provides a basis
      for the impaired vision observed in weanling RBP-deficient mice. Further study of
      the mutants suggests that the impaired vision is reversible because the eyes of
      mutant mice slowly acquire sufficient retinol from the low levels of retinol
      present in their circulation either bound to albumin or present in lipoprotein
      fractions. Thus, the eye is unlike other tissues in the body in that it shows a
      very marked preference for acquiring retinol needed to support vision from the
      retinol-RBP complex and is unable to meet adequately its retinol need through
      uptake of recently absorbed dietary retinol. This provides an explanation for the
      impaired vision phenotype of RBP-deficient mice.

PMID- 12484776
TI  - Engineering-specific pharmacological binding sites for peptidyl inhibitors of
      potassium channels into KcsA.
AB  - The bacterial potassium channel, KcsA, can be modified to express a high-affinity
      receptor site for the scorpion toxin kaliotoxin (KTX) by substituting subregion I
      in the P region of KcsA with the one present in the human voltage-gated potassium
      channel Kv1.3 [Legros, C., Pollmann, V., Knaus, H. G., Farrell, A. M., Darbon,
      H., Bougis, P. E., Martin-Eauclaire, M. F., and Pongs, O. (2000) J. Biol. Chem.
      275, 16918-16924]. This approach opened the way to investigate whether sequence
      differences in subregion I of Kv1 channels correlate with the distinct
      pharmacological profiles of peptide inhibitors. A panel of six chimeras between
      KcsA and human Kv1.1-6 were constructed, expressed in Escherichia coli, purified
      to homogeneity, and assessed in filter binding assays using either monoiodo
      tyrosine-KTX ([(125)I]KTX) or monoiodo-tyrosine-hongotoxin(1)(A19Y/Y37F)
      ([(125)I]HgTX(1)(A19Y/Y37F)). The KcsA-Kv1.X chimeras were found to have lower
      affinities for these ligands than the corresponding mammalian Kv1.X channels,
      indicating that other parts of the channels may contribute to binding or that
      subtle structural differences exist between these channels. The properties of the
      KcsA-Kv1.X chimeras were also characterized in surface plasmon resonance
      experiments. KcsA-Kv1.3 chimeras were immobilized on the surface of a sensor chip
      for determining, in real time, binding of the peptides. KTX binding properties to
      immobilized KcsA-Kv1.3 chimera were similar to those determined by filtration
      techniques. Taken together, our results demonstrate that the pharmacological
      profile of peptide toxins can be incorporated into KcsA-Kv1.X chimeras containing
      the subregion I of the corresponding mammalian Kv1.X channels. This innovative
      approach may facilitate the high-throughput screening of ligand libraries aimed
      at the discovery of novel potassium channel modulators.

PMID- 12484777
TI  - The environmental toxin arsenite induces tau hyperphosphorylation.
AB  - Abnormally hyperphosphorylated tau polymers known as paired helical filaments
      constitute one of the major characteristic lesions that lead to the demise of
      neurons in Alzheimer's disease. Here, we demonstrate that the environmental toxin
      arsenite causes a significant increase in the phosphorylation of several amino
      acid residues (Thr-181, Ser-202, Thr-205, Thr-231, Ser-262, Ser-356, Ser-396, and
      Ser-404) in tau, which are also hyperphosphorylated under pathological
      conditions. Complementary phosphopeptide mapping revealed a dramatic increase in
      the (32)P-labeling of many peptides in tau following arsenite treatment. Although
      arsenite activates extracellular-signal regulated kinases-1/-2 and stress
      activated protein kinases, these enzymes did not contribute to the arsenite
      increased phosphorylation, nor did they appear to normally modify tau in vivo.
      Tau phosphorylation induced by arsenite did not involve glycogen synthase kinase
      3 or protein phosphatase-1 or -2, but the activity responsible for tau
      hyperphosphorylation could be inhibited with the protein kinase inhibitor
      roscovitine. The effects of arsenite on the phosphorylation of some tau mutations
      (DeltaKappa280, V337M, and R406W) associated with frontal-temporal dementia with
      parkinsonism linked to chromosome 17 was analyzed. The unchallenged and arsenite
      induced phosphorylation of some mutant proteins, especially R406W, was altered at
      several phosphorylation sites, indicating that these mutations can significantly
      affect the structure of tau in vivo. Although the major kinase(s) involved in
      aberrant tau phosphorylation remains elusive, these results indicate that
      environmental factors, such as arsenite, may be involved in the cascade leading
      to deregulation of tau function associated with neurodegeneration.

PMID- 12484778
TI  - Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels
      in amphibian sympathetic and sensory neurons.
AB  - Mu-conotoxins are a family of peptides from the venoms of predatory cone snails.
      Previously characterized mu-conotoxins preferentially block skeletal muscle
      voltage-gated sodium channels. We report here the discovery (via cloning),
      synthesis, and electrophysiological characterization of a new peptide in this
      family, mu-conotoxin SmIIIA from Conus stercusmuscarum. Although mu-conotoxin
      SmIIIA shares several biochemical characteristics with other mu-conotoxins (the
      arrangement of cysteine residues and a conserved arginine believed to interact
      with residues near the channel pore), it has distinctive features such as the
      absence of hydroxyproline. In voltage-clamped dissociated neurons from frog
      sympathetic and dorsal root ganglia, the peptide inhibited the majority of
      tetrodotoxin-resistant sodium currents irreversibly; in contrast, tetrodotoxin
      sensitive sodium currents were largely unaffected by the peptide. We believe that
      mu-conotoxin SmIIIA is the first specific antagonist of tetrodotoxin-resistant
      voltage-gated sodium channels to be discovered. Thus, the peptide provides a new
      and potentially useful tool to investigate the functional roles of tetrodotoxin
      resistant voltage-gated sodium channels, including those that are found in
      sensory nerves that convey nociceptive information.

PMID- 12484779
TI  - ADAM-9 is an insulin-like growth factor binding protein-5 protease produced and
      secreted by human osteoblasts.
AB  - IGF binding protein-5 (BP-5) is an important bone formation regulator. Therefore,
      elucidation of the identity of IGF binding protein-5 (BP-5) protease produced by
      osteoblasts is important for our understanding of the molecular pathways that
      control the action of BP-5. In this regard, BP-5 protease purified by various
      chromatographic steps from a conditioned medium of U2 human osteosarcoma cells
      migrated as a single major band, which comigrated with the protease activity in
      native PAGE and yielded multiple bands in SDS-PAGE under reducing conditions. N
      Terminal sequencing of these bands revealed that three of the bands yielded amino
      acid sequences that were identical to that of alpha2 macroglobulin (alpha2M).
      Although alpha2M was produced by human osteoblasts (OBs), it was not found to be
      a BP-5 protease. Because alpha2M had been shown to complex with ADAM proteases
      and because ADAM-12 was found to cleave BP-3 and BP-5, we evaluated if one of the
      members of ADAM family was the BP-5 protease. On the basis of the findings that
      (1) purified preparations of BP-5 protease from U2 cell CM contained ADAM-9, (2)
      ADAM-9 is produced and secreted in high abundance by various human OB cell types,
      (3) purified ADAM-9 cleaved BP-5 effectively while it did not cleave other IGFBPs
      or did so with less potency, and (4) purified ADAM-9 bound to alpha2M, we
      conclude that ADAM-9 is a BP-5 protease produced by human OBs.

PMID- 12484780
TI  - Mn2+ is a native metal ion activator for bacteriophage lambda protein
      phosphatase.
AB  - Bacteriophage lambda protein phosphatase (lambdaPP) is a member of a large family
      of metal-containing phosphoesterases, including purple acid phosphatase, protein
      serine/threonine phosphatases, 5'-nucleotidase, and DNA repair enzymes such as
      Mre11. lambdaPP can be activated several-fold by various divalent metal ions,
      with Mn(2+) and Ni(2+) providing the most significant activation. Despite the
      extensive characterization of purified lambdaPP in vitro, little is known about
      the identity and stoichiometry of metal ions used by lambdaPP in vivo. In this
      report, we describe the use of metal analysis, activity measurements, and whole
      cell EPR spectroscopy to investigate in vivo metal binding and activation of
      lambdaPP. Escherichia coli cells overexpressing lambdaPP show a 22.5-fold
      increase in intracellular Mn concentration and less dramatic changes in the
      intracellular concentration of other biologically relevant metal ions compared to
      control cells that do not express lambdaPP. Phosphatase activity assessed using
      para-nitrophenylphosphate as substrate is increased 850-fold in cells
      overexpressing lambdaPP, indicating the presence of metal-activated enzyme in
      cell lysate. EPR spectra of intact cells overexpressing lambdaPP exhibit
      resonances previously attributed to mononuclear Mn(2+) and dinuclear
      [(Mn(2+))(2)] species bound to lambdaPP. Spin quantitation of EPR spectra of
      intact E. coli cells overexpressing lambdaPP indicates the presence of
      approximately 40 microM mononuclear Mn(2+)-lambdaPP and 60 microM [(Mn(2+))(2)]
      lambdaPP. The data suggest that overexpression of lambdaPP results in a mixture
      of apo-, mononuclear-Mn(2+), and dinuclear-[(Mn(2+))(2)] metalloisoforms and that
      Mn(2+) is a physiologically relevant activating metal ion in E. coli.

PMID- 12484781
TI  - New UDP-GlcNAc C4 epimerase involved in the biosynthesis of 2-acetamino-2-deoxy-L
      altruronic acid in the O-antigen repeating units of Plesiomonas shigelloides O17.
AB  - Plesiomonas shigelloides is a ubiquitous waterborne pathogen responsible for
      diseases such as diarrhea and bacillary dysentery, commonly afflicting infants
      and children. This bacterium is endowed with an O-antigen gene cluster consisting
      of 10 consecutive reading frames. One of these, designated wbgU (orf3), has been
      overexpressed and biochemically characterized to show that it encodes a uridine
      diphosphate-N-acetylglucosamine (UDP-GlcNAc) C4 epimerase, only the second
      microbial enzyme characterized to have this activity. Epimerization is an
      equilibrium reaction resulting in a 70:30 ratio of UDP-GlcNAc to uridine
      diphosphate-N-acetylgalactosamine (UDP-GalNAc), irrespective of the initial
      substrate. The K(m) values for UDP-GalNAc and UDP-GlcNAc are 131 microM and 137
      microM, respectively. WbgU is also capable of converting nonacetylated
      derivatives but with much lower efficiency. It contains a tightly bound
      nicotinamide adenine dinucleotide [NAD(H)] molecule and requires no other
      cofactors for activity. We propose here that this enzyme catalyzes the first of
      the three transformations in the biosynthetic pathway of 2-acetamino-2-deoxy-L
      altruronic acid, an unusual sugar present in the O-specific side chains of
      lipopolysaccharide of P. shigelloides O17 and its close relative Escherichia coli
      Sonnei.

PMID- 12484782
TI  - pH and ionic strength dependence of protein (un)folding and ligand binding to
      bovine beta-lactoglobulins A and B.
AB  - Formation of complexes between bovine beta-lactoglobulins (BLG) and long-chain
      fatty acids (FAs), effect of complex formation on protein stability, and effects
      of pH and ionic strength on both complex formation and protein stability were
      investigated as a function of pH and ionic strength by electrophoretic techniques
      and NMR spectroscopy. The stability of BLG against unfolding is sharply affected
      by the pH of the medium: both A and B BLG variants are maximally stabilized
      against urea denaturation at acidic pH and against SDS denaturation at alkaline
      pH. The complexes of BLGB with oleic (OA) and palmitic acid (PA) appear more
      stable than the apoprotein at neutral pH whereas no differential behavior is
      observed in acidic and alkaline media. PA forms with BLG more stable complexes
      than OA. The difference between the denaturant concentration able to bring about
      protein unfolding in the holo versus the apo forms is larger for urea than for
      SDS treatment. This evidence disfavors the hypothesis of strong hydrophobic
      interactions being involved in complex formation. Conversely, a significant
      contribution to FA binding by ionic interactions is demonstrated by the effect of
      pH and of chloride ion concentration on the stoichiometry of FA.BLG complexes. At
      neutral pH in a low ionic strength buffer, one molecule of FA is bound per BLG
      monomer; this ratio decreases to ca. 0.5 per monomer in the presence of 200 mM
      NaCl. The polar heads of bound FA appear to be solvent accessible, and carboxyl
      resonances exhibit an NMR titration curve with an apparent pK(a) of 4.7(1).

PMID- 12484783
TI  - Affinities of the nucleocapsid protein for variants of SL3 RNA in HIV-1.
AB  - Efficient packaging of genomic RNA into new HIV-1 virus particles requires that
      nucleocapsid domains of precursor proteins bind the SL3 tetraloop (G317-G-A-G320)
      from the 5'-untranslated region. This paper presents the affinities of 35 RNA
      variants of SL3 for the mature 55mer NC protein, as measured by fluorescence
      quenching of tryptophan-37 in the protein by nucleobases. The 1:1 complexes that
      form in 0.2 M NaCl have dissociation constants ranging from 8 nM (GGUG) to 20
      microM (GAUA). The highly conserved (GGAG) sequence for the wild type is not the
      most stable (K(d) = 28 nM), suggesting that other selective pressures beyond the
      stability of the complex must be satisfied. The leading requirement for strong
      interaction is for G320, followed closely by G318. Replacing either with U, A, or
      C reduces affinity by a factor of 15-120. NC-domains from multiple proteins
      combine to recognize unpaired G(2)-loci, where two guanines are in close
      proximity. We have previously measured affinities of the NC protein for the
      important stem-loops of the major packaging domain [Shubsda, M. F., Paoletti, A.
      C., Hudson, B. S., and Borer, P. N. (2002) Biochemistry 41, 5276-82]. Comparison
      with the present work shows that the nature of the stem also modulates NC-RNA
      interactions. Placing the G(2)-loci from the apical SL2 or SL1 loops on the SL3
      stem increases affinity by a factor of 2-3, while placing the SL4 loop on the SL3
      stem reduces affinity 50-fold. These results are interesting in the context of
      RNA-protein interaction, as well as for the discovery of antiNC agents for AIDS
      therapy.

PMID- 12484784
TI  - Chemical rescue of proton transfer in catalysis by carbonic anhydrases in the
      beta- and gamma-class.
AB  - Catalysis of the dehydration of HCO(3)(-) by carbonic anhydrase requires proton
      transfer from solution to the zinc-bound hydroxide. Carbonic anhydrases in each
      of the alpha, beta, and gamma classes, examples of convergent evolution, appear
      to have a side chain extending into the active site cavity that acts as a proton
      shuttle to facilitate this proton transfer, with His 64 being the most prominent
      example in the alpha class. We have investigated chemical rescue of mutants in
      two of these classes in which a proton shuttle has been replaced with a residue
      that does not transfer protons: H216N carbonic anhydrase from Arabidopsis
      thaliana (beta class) and E84A carbonic anhydrase from the archeon Methanosarcina
      thermophila (gamma class). A series of structurally homologous imidazole and
      pyridine buffers were used as proton acceptors in the activation of CO(2)
      hydration at steady state and as proton donors of the exchange of (18)O between
      CO(2) and water at chemical equilibrium. Free energy plots of the rate constants
      for this intermolecular proton transfer as a function of the difference in pK(a)
      of donor and acceptor showed extensive curvature, indicating a small intrinsic
      kinetic barrier for the proton transfers. Application of Marcus rate theory
      allowed quantitative estimates of the intrinsic kinetic barrier which were near
      0.3 kcal/mol with work functions in the range of 7-11 kcal/mol for mutants in the
      beta and gamma class, similar to results obtained for mutants of carbonic
      anhydrase in the alpha class. The low values of the intrinsic kinetic barrier for
      all three classes of carbonic anhydrase reflect proton transfer processes that
      are consistent with a model of very rapid proton transfer through a flexible
      matrix of hydrogen-bonded solvent structures sequestered within the active sites
      of the carbonic anhydrases.

PMID- 12484786
TI  - Carbon nanotubes.

PMID- 12484785
TI  - Supramolecular structural constraints on Alzheimer's beta-amyloid fibrils from
      electron microscopy and solid-state nuclear magnetic resonance.
AB  - We describe electron microscopy (EM), scanning transmission electron microscopy
      (STEM), and solid-state nuclear magnetic resonance (NMR) measurements on amyloid
      fibrils formed by the 42-residue beta-amyloid peptide associated with Alzheimer's
      disease (Abeta(1)(-)(42)) and by residues 10-35 of the full-length peptide
      (Abeta(10)(-)(35)). These measurements place constraints on the supramolecular
      structure of the amyloid fibrils, especially the type of beta-sheets present in
      the characteristic amyloid cross-beta structural motif and the assembly of these
      beta-sheets into a fibril. EM images of negatively stained Abeta(10)(-)(35)
      fibrils and measurements of fibril mass per length (MPL) by STEM show a strong
      dependence of fibril morphology and MPL on pH. Abeta(10)(-)(35) fibrils formed at
      pH 3.7 are single "protofilaments" with MPL equal to twice the value expected for
      a single cross-beta layer. Abeta(10)(-)(35) fibrils formed at pH 7.4 are
      apparently pairs of protofilaments or higher order bundles. EM and STEM data for
      Abeta(1)(-)(42) fibrils indicate that protofilaments with MPL equal to twice the
      value expected for a single cross-beta layer are also formed by Abeta(1)(-)(42)
      and that these protofilaments exist singly and in pairs at pH 7.4. Solid-state
      NMR measurements of intermolecular distances in Abeta(10)(-)(35) fibrils, using
      multiple-quantum (13)C NMR, (13)C-(13)C dipolar recoupling, and (15)N-(13)C
      dipolar recoupling techniques, support the in-register parallel beta-sheet
      organization previously established by Lynn, Meredith, Botto, and co-workers
      [Benzinger et al. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 13407-13412; Benzinger
      et al. (2000) Biochemistry 39, 3491-3499] and show that this beta-sheet
      organization is present at pH 3.7 as well as pH 7.4 despite the differences in
      fibril morphology and MPL. Solid-state NMR measurements of intermolecular
      distances in Abeta(1)(-)(42) fibrils, which represent the first NMR data on
      Abeta(1)(-)(42) fibrils, also indicate an in-register parallel beta-sheet
      organization. These results, along with previously reported data on Abeta(1)(
      )(40) fibrils, suggest that the supramolecular structures of Abeta(10)(-)(35),
      Abeta(1)(-)(40), and Abeta(1)(-)(42) fibrils are quite similar. A schematic
      structural model of these fibrils, consistent with known experimental EM, STEM,
      and solid-state NMR data, is presented.

PMID- 12484787
TI  - Carbon nanotubes from organometallic precursors.
AB  - Multiwalled as well as single-walled carbon nanotubes are conveniently prepared
      by the pyrolysis of organometallic precursors such as metallocenes and
      phthalocyanines in a reducing atmosphere. More importantly, pyrolysis of
      organometallics alone or in mixture with hydrocarbons yields aligned nanotube
      bundles with useful field emission and hydrogen storage properties. By pyrolysis
      of organometallics in the presence of thiophene, Y-junction nanotubes are
      obtained in large quantities. The Y-junction tubes have a good potential in
      nanoelectronics. Carbon nanotubes prepared from organometallics are useful to
      prepare nanowires and nanotubes of other materials such as BN, GaN, SiC, and
      Si(3)N(4).

PMID- 12484788
TI  - Multiwall carbon nanotubes: synthesis and application.
AB  - Chemical vapor deposition (CVD) is the most promising synthesis route for
      economically producing large quantities of carbon nanotubes. We have developed a
      low-cost CVD process for the continuous production of aligned multiwall carbon
      nanotubes (MWNTs). Here we report the effects of reactor temperature, reaction
      time, and carbon partial pressure on the yield, purity, and size of the MWNTs
      produced. A simple method for purifying and healing structural defects in the
      nanotubes is described. The dispersion of nanotubes in polymer matrices has been
      investigated as a means of deriving new and advanced engineering materials. These
      composite materials have been formed into fibers and thin films and their
      mechanical and electrical properties determined.

PMID- 12484789
TI  - Fundamental electronic properties and applications of single-walled carbon
      nanotubes.
AB  - Recent scanning tunneling microscopy studies of the intrinsic electronic
      properties of single-walled carbon nanotubes (SWNTs) are overviewed in this
      Account. A brief theoretical treatment of the electronic properties of SWNTs is
      developed, and then the effects of finite curvature and broken symmetry on
      electronic properties, the unique one-dimensional energy dispersion in nanotubes,
      the interaction between local spins and carriers in metallic nanotubes systems,
      and the atomic structure and electronic properties of intramolecular junctions
      are described. The implications of these studies for understanding fundamental
      one-dimensional physics and future nanotube device applications are also
      discussed.

PMID- 12484790
TI  - Molecular electronics with carbon nanotubes.
AB  - Carbon nanotubes have unique properties that make them a most promising system on
      which to base molecular electronics. We briefly review the electrical
      characteristics of carbon nanotubes, and then focus on carbon nanotube field
      effect transistors (CNTFETs). Procedures by which hole-transport, electron
      transport and ambipolar CNTFETs can be fabricated are presented, and their
      electrical characteristics are discussed and compared with those of Si MOSFETs.
      Ways to fabricate arrays of CNTFETs are also demonstrated, and electron and hole
      CNTFETs are integrated to form complementary logic circuits.

PMID- 12484791
TI  - Carbon nanotubes: synthesis, integration, and properties.
AB  - Synthesis of carbon nanotubes by chemical vapor deposition over patterned
      catalyst arrays leads to nanotubes grown from specific sites on surfaces. The
      growth directions of the nanotubes can be controlled by van der Waals self
      assembly forces and applied electric fields. The patterned growth approach is
      feasible with discrete catalytic nanoparticles and scalable on large wafers for
      massive arrays of novel nanowires. Controlled synthesis of nanotubes opens up
      exciting opportunities in nanoscience and nanotechnology, including electrical,
      mechanical, and electromechanical properties and devices, chemical
      functionalization, surface chemistry and photochemistry, molecular sensors, and
      interfacing with soft biological systems.

PMID- 12484792
TI  - Materials science of carbon nanotubes: fabrication, integration, and properties
      of macroscopic structures of carbon nanotubes.
AB  - In this Account, we summarize some of our recent studies on the materials
      properties of the carbon nanotubes (CNTs). The focus is on single-wall carbon
      nanotubes (SWNTs). We describe experiments on synthesis of SWNTs with controlled
      molecular structures and assembly of functional macroscopic structures. In
      addition, we present results on the electron field emission properties of
      macroscopic CNT cathodes.

PMID- 12484793
TI  - Structural characterization of atomically regulated nanocrystals formed within
      single-walled carbon nanotubes using electron microscopy.
AB  - The structural chemistry of nanoscale materials encapsulated within single-walled
      carbon nanotubes (SWNTs) is reviewed. SWNTs form atomically thin channels within
      a restricted diameter range, and their internal van der Waals surfaces regulate
      the growth behavior of encapsulated crystals in a precise fashion, leading to
      atomically regulated growth. The structural properties of these systems are
      largely dictated by the structural chemistry of the bulk material, although
      significant deviations from bulk structures are often observed, with lower
      surface coordinations and substantial lattice distortions.

PMID- 12484794
TI  - Defects in carbon nanotubes.
AB  - Carbon nanotubes are quasi one-dimensional nanostructures with unique eletrical
      prroperties that make them prime candidates for molecular electronics, which is
      certainly a most promising direction in nanotechnology. Early theoretical works
      predicted that the electronic properties of "ideal" carbon nanotubes depend on
      their diameter and chirality. However, carbon nanotubes are probably not as
      perfect as they were once thought to be. Defects such as pentagons, heptagons,
      vacancies, or dopant are found to modify drastically the electronic properties of
      these nanosystems. Irradiation processes can lead to interesting, highly
      defective nanostructures and also to the coalescence of nanotubes within a rope.
      The introduction of defects in the carbon network is thus an interesting way to
      tailor its intrinsic properties, to create new potential nanodevices. The aim of
      the present Acount is to investigate theoretically the effects of different types
      of defects on the electronic properties of carbon nanotubes, and to propose new
      potential applications in nanoelectronics.

PMID- 12484795
TI  - Single nanotube Raman spectroscopy.
AB  - A review is presented on the observation of the resonant Raman spectra from one
      isolated single wall carbon nanotube, focusing on the important structural
      information that is provided by single nanotube spectroscopy including the (n, m)
      determination of the individual tubes. The special sensitivity of the radial
      breathing mode to the (n, m) determination is emphasized, and the corroboration
      of this (n, m) assignment by diameter- and chirality-dependent phenomena in other
      Raman modes, such as the G-band, D-band, and G'-band features is also discussed.
      The significance of single nanotube spectroscopy for future nanotube research in
      general is briefly reviewed.

PMID- 12484796
TI  - Chemical doping of single-wall carbon nanotubes.
AB  - Single-wall carbon nanotubes can be doped, or intercalated, with electron donors
      or acceptors, similar to graphite and some conjugated polymers. The resulting
      materials show many of the same features: enhanced electrical conductivity,
      conduction electron paramagnetism, partial or complete reversibility, and
      cyclability. Reactions may be carried out in vapor or liquid phase, or
      electrochemically. Structural information is sketchy at best, due to the limited
      quality of currently available materials and solvent-related effects. Recent
      developments in coagulation-based fiber extrusion and partially aligned materials
      offer new opportunities for novel material modifications by chemical doping.

PMID- 12484797
TI  - Fluorination of single-wall carbon nanotubes and subsequent derivatization
      reactions.
AB  - This Account focuses on the most recent and systematic efforts in the area of
      functionalization chemistry of the single-wall carbon nanotubes (SWNTs) which
      utilizes direct fluorination for the preparation of "fluoronanonotubes" and their
      subsequent derivatization. The results obtained prove that the addition of
      fluorine drastically enhances the reactivity of the nanotube side walls. The use
      of this strategy as a versatile tool for preparation and manipulation of SWNTs
      with variable side-wall functionalities has been demonstrated. The functionalized
      SWNTs have shown an improved solubility in selected solvents and significantly
      altered electrical, mechanical, and optical properties. An overview of new
      synthetic methods for preparation and a discussion of characterization data for
      the functionalized SWNTs are provided.

PMID- 12484798
TI  - Functionalized carbon nanotubes: properties and applications.
AB  - Carbon nanotubes can be functionalized via amidation and esterification of the
      nanotube-bound carboxylic acids. The solubility of these functionalized carbon
      nanotubes makes it possible to characterize and study the properties of carbon
      nanotubes using solution-based techniques. Representative results concerning the
      solubility, dispersion, defunctionalization, and optical properties of the
      functionalized carbon nanotubes are presented. Several examples for the use of
      functionalized carbon nanotubes in the fabrication of polymeric carbon
      nanocomposites, the probing of nanotube-molecule interactions, and the
      conjugation with biological species are highlighted and discussed.

PMID- 12484799
TI  - Chemistry of single-walled carbon nanotubes.
AB  - In this Account we highlight the experimental evidence in favor of our view that
      carbon nanotubes should be considered as a new macromolecular form of carbon with
      unique properties and with great potential for practical applications. We show
      that carbon nanotubes may take on properties that are normally associated with
      molecular species, such as solubility in organic solvents, solution-based
      chemical transformations, chromatography, and spectroscopy. It is already clear
      that the nascent field of nanotube chemistry will rival that of the fullerenes.

PMID- 12484800
TI  - Generic clozapine: a cost-saving alternative to brand name clozapine?
AB  - As a consequence of its prevalence, early onset and chronicity, schizophrenia
      imposes clinical and economic impediments to healthcare practitioners and society
      alike. Among the many antipsychotics available to treat the symptoms of this
      devastating illness, clozapine has emerged and differentiated itself from the
      others as the agent most efficacious for the treatment of refractory patients.
      Since the patent for Clozaril (Novartis) expired in 1998, three manufacturers of
      generic clozapine have submitted abbreviated new drug applications to the US FDA
      for review and approval to market a generic clozapine product. In each case, the
      US FDA deemed the generic formulations to be bioequivalent to the brand name
      Clozaril. Apart from case reports, industry-sponsored studies have been conducted
      comparing Clozaril with two generic formulations. In one case, a generic
      formulation of clozapine manufactured by Creighton Products Corporation (formerly
      a subsidiary [generic house] of Sandoz Pharmaceuticals) was found to be
      bioequivalent to Clozaril. On the other hand, studies (sponsored by Novartis)
      have challenged the bioequivalence, therapeutic equivalence and
      interchangeability between Clozaril and a generic formulation manufactured by
      Zenith Goldline Pharmaceuticals (now IVAX Corporation). The IVAX Corporation
      sponsored studies refuted these claims citing data from two patient registry
      database studies and one small clinical trial. Apart from a single in-house
      bioequivalence study, no further investigations have been conducted with a third
      generic formulation manufactured by Mylan Pharmaceutical. Although the clinical
      significance of the above discrepancy is obvious, what is less than obvious is
      the pharmacoeconomic implications that arises from this debate. Clearly, if the
      brand name and generic formulations are 'truly' bioequivalent, then the cost
      savings realised would be the difference in acquisition cost. On the other hand,
      if the various formulations are not bioequivalent, then the economic benefits of
      a lower-priced generic formulation may be compromised. In the worst-case
      scenario, if a patient decompensates as a result of switching from Clozaril to a
      generic formulation, the added direct costs (i.e. hospitalisation) and indirect
      cost (i.e. lost productivity) will most certainly offset any cost savings
      resulting from the use of a generic formulation. Until further studies have been
      conducted, we suggest that patients who are treatment refractory and stabilised
      on Clozaril are not switched to a generic formulation. On the other hand, if a
      patient is stabilised on Clozaril and not treatment refractory, then cautious
      switching to a generic formulation may be reasonable. Finally, initiating a
      generic formulation in a 'clozapine-naive' individual would be appropriate. The
      cost implications related to these recommendations will depend on the success or
      failure of treatment.

PMID- 12484801
TI  - Economic evaluations of varicella vaccination programmes: a review of the
      literature.
AB  - Chickenpox infections are generally mild but due to their very high incidence
      among healthy children they give rise to considerable morbidity and occasional
      mortality. With the development of a varicella vaccine in the early 1970s and its
      progressive licensing in many countries, interest in the efficiency of varicella
      immunisation programmes grew. The objective of this review was to discuss the
      methodological aspects and results of published economic evaluations of varicella
      vaccination. From this, we attempted to make recommendations. A computerised
      search was carried out; 17 full economic evaluations of varicella vaccination
      were retrieved. The review identified the methodological divergences and
      similarities between the articles in four areas: study design, epidemiological
      data, economic data and model characteristics. We assessed to what extent the
      applied methods conform to general guidelines for the economic evaluation of
      healthcare interventions and compared the studies' results. The desirability of a
      universal vaccination programme depends on whose perspective is taken. Despite
      variability in data and model assumptions, the studies suggest that universal
      vaccination of infants is attractive to society because large savings occur from
      averted unproductive days for parents. For the healthcare payer, universal
      vaccination of infants does not generate savings. Vaccination of susceptible
      adolescents has been proposed by some authors as a viable alternative; the
      attractiveness of this is highly dependent on the negative predictive value of
      anamnestic screening. Targeted vaccination of healthcare workers and
      immunocompromised individuals appears relatively cost effective. Findings for
      other target groups are either contradictory or provide insufficient evidence for
      any unequivocal recommendations to be made. High sensitivity to vaccine price was
      reported in most studies. This review highlights that some aspects of these
      studies need to be further improved before final recommendations can be made.
      First, more transparency, completeness and compliance to general methodological
      guidelines are required. Second, because of the increasing severity of varicella
      with age, it is preferable and in some cases essential to use dynamic models for
      the assessment of universal vaccination strategies. Third, most studies focused
      on the strategy of vaccinating children only while their results depended heavily
      on disputable assumptions (regarding vaccine effectiveness and impact on herpes
      zoster). Since violation of these assumptions could have important adverse public
      health effects, we suggest pre-adolescent vaccination as a more secure
      alternative. This option deserves more attention in future analyses.

PMID- 12484802
TI  - Advantages of using the net-benefit approach for analysing uncertainty in
      economic evaluation studies.
AB  - No consensus has yet been reached on how to analyse uncertainty in economic
      evaluation studies where individual patient data are available for costs and
      health effects. This paper summarises the available results regarding the
      analysis of uncertainty on the cost-effectiveness plane and argues for using the
      net-benefit approach when analysing uncertainty in cost-effectiveness studies.
      The net-benefit approach avoids the interpretation and statistical problems
      related to the incremental cost effectiveness ratio and implies several
      advantages. First, traditional statistical methods can be used for confidence
      interval estimation and hypothesis testing. Second, calculation of the optimal
      sample size and the power of the study are facilitated allowing the correlation
      between costs and effects to vary within and between patient groups. Third, the
      use of a Bayesian approach to cost-effectiveness analysis is facilitated. Fourth,
      a formal relation between cost-effectiveness acceptability curves and statistical
      inference is provided. Finally, the net-benefit approach gives the Fieller's
      limits of the confidence interval for the incremental cost-effectiveness ratio in
      the cost-effectiveness plane. Based on these advantages the net-benefit approach
      should strongly be considered when analysing uncertainty in cost-effectiveness
      analyses.

PMID- 12484803
TI  - Potential costs and effects of the National Service Framework for Coronary Heart
      Disease in the UK.
AB  - OBJECTIVE: To estimate the costs and effect of implementing the National Service
      Framework for Coronary Heart Disease (CHD) in the UK. DESIGN: Decision trees were
      built on the results from randomised controlled trials on improving coronary
      revascularisation. All costs were presented in UK pounds (1997 values). PATIENTS:
      Each year 6600 new patients with CHD are expected to require revascularisation in
      the UK. INTERVENTIONS: The new patients would be equally divided into those
      undergoing coronary artery bypass grafting (CABG) and those undergoing a
      percutaneous coronary intervention (PCI) i.e., percutaneous transluminal
      angioplasty (PCTA). PTCA could be administered with or without abciximab (a
      glycoprotein IIb/IIIa receptor antagonist), stent, or stent plus abciximab
      (stent+). RESULTS: CABG/stent alone has an incremental cost of more than 115,489
      pounds per additional quality-adjusted life-year (QALY) gained compared with
      CABG/ PTCA+. This high incremental cost is not attractive because if CABG/ stent
      would be added to abciximab (CABG/stent+) its incremental cost-effectiveness
      ratio would be 2529 pounds per extra QALY compared with CABG/stent. Therefore,
      the debate should not be limited to the issue of stents but it should focus on
      the need for administering abciximab in addition to stent. The 5-year direct
      costs of implementing such a strategy in the UK is expected to be 50.6 million
      pounds (1997 values). CONCLUSIONS: Abciximab and probably any glycoprotein
      IIb/IIIa receptor antagonists should be added to any PCI, especially if stents
      are used.

PMID- 12484804
TI  - Comparative cost effectiveness of angiotensin II receptor blockers in a US
      managed care setting: olmesartan medoxomil compared with losartan, valsartan, and
      irbesartan.
AB  - OBJECTIVE: To compare the cost effectiveness of the angiotensin II receptor
      blockers (ARBs) olmesartan medoxomil, losartan, valsartan and irbesartan for the
      treatment of hypertension, from the perspective of a US managed care setting.
      METHODS: The evaluation was based on a recently completed, prospective,
      randomised, double-blind clinical trial comparing the antihypertensive efficacy
      of these agents. Differences in diastolic blood pressure reductions among the
      comparative agents were used to estimate reductions in the annualised risk of
      cardiovascular (CV) and cerebrovascular events using the Framingham model. These
      annualised risks were translated into reductions in healthcare expenditures
      associated with treating CV events covered by managed care in the US. Data
      sources included: the recently published clinical trial of ARB antihypertensive
      efficacy, the Framingham Heart Study and a managed care database. Actual
      reimbursed amounts were used. RESULTS: Based on antihypertensive efficacy data
      versus irbesartan, the use of olmesartan medoxomil is expected to reduce the
      number of new cases of CV disease, resulting in a first-year reduction in cost in
      a cohort of 100,000 patients of 906,000 US dollars. Similarly, a reduction in new
      cases of coronary heart disease (CHD) resulted in a cost reduction of 701,000 US
      dollars; a cost reduction of 196,000 US dollars for fewer myocardial infarctions
      (MI); and a cost reduction of 28,000 US dollars for fewer strokes. Over 5 years,
      these estimates increase to 5,410,000 US dollars for fewer cases of CV disease;
      3,975,000 US dollars for fewer cases of CHD; 1,430,000 US dollars for fewer MI;
      and 497,000 US dollars for fewer strokes. Compared with valsartan, the use of
      olmesartan medoxomil is estimated to reduce by 3,397,000 US dollars the expected
      cost of treating a cohort of 100 000 patients in the first year for fewer cases
      of CV disease; by 2,426,000 US dollars for fewer cases of CHD; by 565,000 US
      dollars for fewer MI; and by 124,000 US dollars for fewer strokes. Over 5 years,
      these estimates increase to 16,231,000 US dollars for CV disease; 11,955,000 US
      dollars for CHD; 4,505,000 US dollars for MI; and 1,741,000 dollars for stroke.
      Compared with losartan, the estimated reduction in first-year cost is 2,969,000
      US dollars for CV disease for the cohort of 100,000 patients; 2,163,000 US
      dollars for CHD; 732,000 US dollars for MI; and 124,000 US dollars for stroke.
      Over 5 years, these estimates increase to 15,149,000 US dollars for CV disease;
      11,107,000 US dollars for CHD; 4,057,000 US dollars for MI; and 1,437,000 dollars
      for stroke. CONCLUSION: Based on comparative antihypertensive efficacy data,
      treatment of hypertensive patients with olmesartan medoxomil instead of the other
      leading ARBs has the potential to reduce overall cost of medical care in a US
      managed care setting.

PMID- 12484805
TI  - Configuration of separability and tests for multipartite entanglement in bell
      type experiments.
AB  - We derive tight quadratic inequalities for all kinds of hybrid separable
      inseparable n-particle density operators on an arbitrary dimensional space. This
      methodology enables us to derive a tight quadratic inequality as tests for full n
      partite entanglement in various Bell-type correlation experiments on the systems
      that may not be identified as a collection of qubits, e.g., those involving
      photons measured by incomplete detectors. It is also proved that when the two
      measured observables are assumed to precisely anticommute, a stronger quadratic
      inequality can be used as a witness of full n-partite entanglement.

PMID- 12484806
TI  - Nucleation, growth, and stabilization of Bose-Einstein condensate vortex
      lattices.
AB  - We give a simple unified theory of vortex nucleation and vortex lattice formation
      in which (i) the thermal cloud plays a crucial role; (ii) the basic process is
      due to growth of the condensate from a rotating thermal cloud, which provides
      gain for certain surface modes of nonzero angular momentum; (iii) vortices appear
      initially as the result of a linear interference between the far fields of the
      condensate and the surface modes; and (iv) the description applies from the
      initiation process up to the final stabilization of the lattice. We have
      simulated the growth of vortex lattices from a rotating thermal cloud, and their
      production using a rotating trap.

PMID- 12484807
TI  - Dynamical horizons: energy, angular momentum, fluxes, and balance laws.
AB  - Dynamical horizons are considered in full, nonlinear general relativity.
      Expressions of fluxes of energy and angular momentum carried by gravitational
      waves across these horizons are obtained. Fluxes are local, the energy flux is
      positive, and change in the horizon area is related to these fluxes. The flux
      formulas also give rise to balance laws analogous to the ones obtained by Bondi
      and Sachs at null infinity and provide generalizations of the first and second
      laws of black-hole mechanics.

PMID- 12484808
TI  - Inflation from quantum geometry.
AB  - Quantum geometry predicts that a universe evolves through an inflationary phase
      at small volume before exiting gracefully into a standard Friedmann phase. This
      does not require the introduction of additional matter fields with ad hoc
      potentials; rather, it occurs because of a quantum gravity modification of the
      kinetic part of ordinary matter Hamiltonians. An application of the same
      mechanism can explain why the present day cosmological acceleration is so tiny.

PMID- 12484809
TI  - Holography and string dynamics in time-dependent backgrounds.
AB  - We study the dynamics of D-branes in a smooth time-dependent background. The
      theory on the branes is a time-dependent noncommutative field theory. We find the
      metric and fluxes that determine the dual holographic closed string theory. This
      provides a concrete example of holography in a cosmological setting.

PMID- 12484811
TI  - Strength of the 18F(p,alpha)15O resonance at Ec.m. = 330 keV.
AB  - Production of the radioisotope 18F in novae is severely constrained by the rate
      of the 18F(p,alpha)15O reaction. A resonance at E(c.m.)=330 keV may strongly
      enhance the 18F(p,alpha)15O reaction rate, but its strength has been very
      uncertain. We have determined the strength of this important resonance by
      measuring the 18F(p,alpha)15O cross section on and off resonance using a
      radioactive 18F beam at the ORNL Holifield Radioactive Ion Beam Facility. We find
      that its resonance strength is 1.48+/-0.46 eV, and that it dominates the
      18F(p,alpha)15O reaction rate over a significant range of temperatures
      characteristic of ONeMg novae.

PMID- 12484812
TI  - Exact level densities for the harmonic oscillator.
AB  - The number of levels of a many-fermion system confined by a harmonic-oscillator
      potential is computed as a function of excitation energy. Because of its exact
      nature, the formalism accounts for effects of shell structure on the level
      density. The method is easily extended to a variety of situations as is
      illustrated with the inclusion of isospin and deformation effects as well as a
      calculation of the number of spurious states.

PMID- 12484813
TI  - Multiphoton pi pulses.
AB  - Multiphoton excitation in a two-level system is exceedingly weak because of small
      multiphoton coupling strengths, large ac Stark shifts, and ionization. I will
      discuss a three-level system in which the ac Stark shift is greatly reduced and
      the multiphoton coupling strength is greatly enhanced over a two-level system, to
      such an extent that multiphoton pi pulses can be produced. I will also present
      two-electron calculations in a model potential, including ionization that shows a
      12-photon pi pulse driven with 800-nm photons. This three-level configuration may
      provide the basis for an amplifying medium in the vacuum ultraviolet, as well as
      multiphoton adiabatic passage and innershell ionization.

PMID- 12484814
TI  - Low-energy monopole modes of a trapped atomic Fermi gas.
AB  - We consider the low energy collective monopole modes of a trapped weakly
      interacting atomic Fermi gas in the collisionless regime. The spectrum is
      calculated for varying coupling strength and chemical potential. Using an
      effective Hamiltonian, we derive analytical results that agree well with
      numerical calculations in various regimes. The onset of superfluidity is shown to
      lead to effects such as the vanishing of the energy required to create a Cooper
      molecule at a critical coupling strength and to the emergence of pair vibration
      excitations. Our analysis suggests ways to experimentally detect the presence of
      the superfluid phase in trapped atomic Fermi gases.

PMID- 12484815
TI  - Competition among molecular fragmentation channels described with Siegert channel
      pseudostates.
AB  - To describe multiple interacting fragmentation continua, we develop a method in
      which the vibrational channel functions obey outgoing wave Siegert boundary
      conditions. This paper demonstrates the utility of the Siegert approach, which
      uses channel energy eigenvalues that possess a negative imaginary part. The
      electron scattering energy in each such channel is rotated upward, giving it an
      equal and opposite imaginary part. This permits a natural inclusion of
      vibrational continua without requiring them to appear as explicit channels in the
      scattering matrix. Calculations illustrate the application of this theory to
      photoionization, photodissociation, and dissociative recombination.

PMID- 12484816
TI  - Controlling the angular momentum composition of a Rydberg electron wave packet.
AB  - Sequences of phase-locked laser pulses have been employed to control the orbital
      angular momentum character of an electron wave packet, which is initially created
      from a superposition of s and d Rydberg series. By an intelligent choice of
      phase, which depends on the excitation energy and the quantum defects, we are
      able to selectively pump down either all or a fraction of one or other angular
      momentum component, and by employing multichannel quantum-defect theory we are
      able to analyze the quantum-state distribution in detail.

PMID- 12484817
TI  - Velocity scaling of ion neutralization in low energy ion scattering.
AB  - The ion fraction P+ is measured for He+ ions scattered by 129 degrees from a Cu
      surface. Both the primary energy and the angles of incidence and of exit are
      varied. From our results we conclude the following: along the incoming and
      outgoing trajectories, neutralization is due to Auger processes and depends on
      the normal velocity component v( perpendicular ) only. At higher energies,
      additional charge exchange is due to collision induced neutralization and
      reionization, both depending on the total ion energy only. Also in this regime P+
      depends on v( perpendicular ), but via a two-valued function of the scattering
      geometry at fixed energy.

PMID- 12484818
TI  - Decay rates and survival probabilities in open quantum systems.
AB  - We provide the first statistical analysis of the decay rates of strongly driven
      3D atomic Rydberg states. The distribution of the rates exhibits universal
      features due to Anderson localization, while universality of the time dependent
      decay requires particular initial conditions.

PMID- 12484819
TI  - Superfluorescence-stimulated photon echoes.
AB  - Two closely spaced 778 nm, 4-ps pulses, two-photon resonant with the 5S-5D
      transition in Rb vapor generate a ground state grating, which later is excited by
      a similar third pulse, producing conical yoked superfluorescence echo on the 5S
      6P, 420-nm transition. The intensity of this emission as a function of the
      relative delay between the leading excitation pulses is governed by the dynamics
      of Doppler dephasing and rephasing. This is the first observation of an echo
      effect induced by a spontaneous relaxation process.

PMID- 12484820
TI  - Chirped femtosecond solitonlike laser pulse form with self-frequency shift.
AB  - Ultrashort laser pulse propagation in a generalized nonconservative system is
      considered. Slopes appearing in the form of the third-order time derivative for
      narrow pulse widths, nonlinear dispersion, and self-frequency shift arising from
      stimulated Raman scattering are taken into account. An exact analytical
      solitonlike solution is presented for a femtosecond solitary laser pulse. The
      stability of the latter has been shown numerically by applying perturbations in
      amplitude and chirp, as well as adding white noise. The results indicate
      stability in a broad parameter range. In addition, we have also found that the
      solution acts as an attractor when starting with a quite arbitrary Gaussian pulse
      as an initial condition.

PMID- 12484821
TI  - Optimal identification of Hamiltonian information by closed-loop laser control of
      quantum systems.
AB  - A closed loop learning control concept is introduced for teaching lasers to
      manipulate quantum systems for the purpose of optimally identifying Hamiltonian
      information. The closed loop optimal identification algorithm operates by
      revealing the distribution of Hamiltonians consistent with the data. The control
      laser is guided to perform additional experiments, based on minimizing the
      dispersion of the distribution. Operation of such an apparatus is simulated for
      two model finite dimensional quantum systems.

PMID- 12484822
TI  - Harmonic measure and winding of conformally invariant curves.
AB  - The exact joint multifractal distribution for the scaling and winding of the
      electrostatic potential lines near any conformally invariant scaling curve is
      derived in two dimensions. Its spectrum f(alpha,lambda) gives the Hausdorff
      dimension of the points where the potential scales with distance r as H
      approximately r(alpha) while the curve logarithmically spirals with a rotation
      angle phi=lambdalnr. It obeys the scaling law
      f(alpha,lambda)=(1+lambda(2))f(alpha)-blambda(2) with alpha=alpha/(1+lambda(2))
      and b=(25-c)/12, and where f(alpha) identical with f(alpha,0) is the pure
      harmonic measure spectrum, and c the conformal central charge. The results apply
      to O(N) and Potts models, as well as to stochastic Lowner evolution.

PMID- 12484823
TI  - Locking-based frequency measurement and synchronization of chaotic oscillators
      with complex dynamics.
AB  - We propose a method for the determination of a characteristic oscillation
      frequency for a broad class of chaotic oscillators generating complex signals. It
      is based on the locking of standard periodic self-sustained oscillators by an
      irregular signal. The method is applied to experimental data from chaotic
      electrochemical oscillators, where other approaches of frequency determination
      (e.g., based on Hilbert transform) fail. Using the method we characterize the
      effects of phase synchronization for systems with ill-defined phase by external
      forcing and due to mutual coupling.

PMID- 12484810
TI  - Search for the production of single sleptons through R-parity violation in pp;
      collisions at square root (s) =1.8 TeV.
AB  - We report the first search for supersymmetric particles via s-channel production
      and decay of smuons or muon sneutrinos at hadronic colliders. The data for the
      two-muon and two-jets final states were collected by the D0 experiment and
      correspond to an integrated luminosity of 94+/-5 pb(-1). Assuming that R parity
      is violated via the single coupling lambda'211, the number of candidate events is
      in agreement with expectation from the standard model. Exclusion contours are
      given in the (m(0),m(1/2)) and (m(x),m(v)) planes for lambda(')(211)=0.09, 0.08,
      and 0.07.

PMID- 12484824
TI  - Relevant length scale of barchan dunes.
AB  - A new experiment can create small scale barchan dunes under water: some sand is
      put on a tray moving periodically and asymmetrically in a water tank, and
      barchans rapidly form. We measure basic morphological and dynamical properties of
      these dunes and compare them to field data. These favorable results demonstrate
      experimentally the relevance of the so-called "saturation length" for the control
      of the dunes physics.

PMID- 12484825
TI  - Epitaxial growth of granular single crystals.
AB  - Compaction from a random-loose-packed to a random-close-packed phase is observed
      when monodisperse granular beds are shaken, but beyond this packing, the system
      freezes up in a jammed structure. Here we report a technique to grow large hard
      sphere granular crystals, with perfect stacking and no defects by means of a "gas
      phase" epitaxial procedure. We study the growth mechanism and provide evidence
      that the observed granular crystallization is driven by gravity and energy
      dissipation.

PMID- 12484826
TI  - Bailout embeddings and neutrally buoyant particles in three-dimensional flows.
AB  - We use the bailout embeddings of three-dimensional volume-preserving maps to
      study qualitatively the dynamics of small spherical neutrally buoyant impurities
      suspended in a time-periodic incompressible fluid flow. The accumulation of
      impurities in tubular vortical structures, the detachment of particles from fluid
      trajectories near hyperbolic invariant lines, and the formation of nontrivial
      three-dimensional structures in the distribution of particles are predicted.

PMID- 12484828
TI  - Analytical description of a neutral-induced tripole vortex in a plasma.
AB  - An analytical description of a stationary triple vortex, observed in a
      cylindrical plasma, is presented. The concentration of neutrals, which is rather
      high in the experiment, turns out to be of crucial importance due to a spatially
      dependent distribution. In the radial direction the neutral concentration is
      paraboliclike, yielding an effective radial force directed towards the axis of
      the system. This neutral force causes the rotation of the plasma in the direction
      which is opposite to the E-->xB--> drift. The stationary triple vortex develops
      for a starting Gaussian-density distribution and a rigid-body rotation of the
      plasma column.

PMID- 12484827
TI  - Heating of thin foils with a relativistic-intensity short-pulse laser.
AB  - K-shell x-ray spectroscopy of sub-100 nm Al foils irradiated by high contrast,
      spatially uniform, 150 fs, Ilambda (2)=2 x 10(18) W microm(2)/cm(2), laser pulses
      is obtained with 500 fs time resolution. Two distinct phases occur: At </=500 fs
      a broad feature comparable to the resonance transitions occurs due to satellites,
      and at >/=500 fs the resonance transitions dominate. Initial satellites arise
      from a large area, high density, low temperature (approximately 100 eV) plasma
      created by fast electrons. Thus, contrary to predictions, a short, high intensity
      laser incident on a thin foil does not create a uniform, hot dense plasma.

PMID- 12484829
TI  - Observation of coherent sheared turbulence flows in the DIII-D Tokamak.
AB  - Time-resolved measurements of the turbulent density flow field in a tokamak
      plasma reveal low-frequency ( approximately 15 KHz), coherent oscillations in the
      poloidal flow, v(theta). These flow oscillations have a long poloidal wavelength
      (m<3) and narrow radial extent (k(r)rho(i) approximately 0.2). The estimated flow
      shearing rate is of the same order of magnitude as the turbulence decorrelation
      rate and may thus regulate the turbulence amplitude. These features are
      consistent with theoretically predicted axisymmetric, self-regulating, sheared
      flows recognized as geodesic acoustic modes.

PMID- 12484830
TI  - Comparison of a low- to high-confinement transition theory with experimental data
      from DIII-D.
AB  - From our recent theory based on the generation of shear flow and field in finite
      beta plasmas, the criterion for bifurcation from low to high confinement mode
      yields a critical parameter proportional to T(e)/square root (L(n)), where T(e)
      is the electron temperature and L(n) is the density scale length. The predicted
      threshold shows very good agreement with edge measurements on discharges
      undergoing low-to-high transitions in DIII-D. The observed differences in the
      transitions with the reversal of the toroidal magnetic field are reconciled in
      terms of this critical parameter. The theory also provides an explanation for
      pellet injection H modes in DIII-D, thereby unifying unconnected methods for
      accomplishing the transition.

PMID- 12484831
TI  - Generation of noninductive current by electron-Bernstein waves on the COMPASS-D
      Tokamak.
AB  - Electron-Bernstein waves (EBW) were excited in the plasma by mode converted
      extraordinary (X) waves launched from the high field side of the COMPASS-D
      tokamak at different toroidal angles. It has been found experimentally that X
      mode injection perpendicular to the magnetic field provides maximum heating
      efficiency. Noninductive currents of up to 100 kA were found to be driven by the
      EBW mode with countercurrent drive. These results are consistent with ray tracing
      and quasilinear Fokker-Planck simulations.

PMID- 12484832
TI  - Anomalous capacitive sheath with deep radio-frequency electric-field penetration.
AB  - A novel nonlinear effect of anomalously deep penetration of an external radio
      frequency electric field into a plasma is described. A self-consistent kinetic
      treatment reveals a transition region between the sheath and the plasma. Because
      of the electron velocity modulation in the sheath, bunches in the energetic
      electron density are formed in the transition region adjacent to the sheath. The
      width of the region is of order V(T)/omega, where V(T) is the electron thermal
      velocity, and omega is the frequency of the electric field. The presence of the
      electric field in the transition region results in a collisionless cooling of the
      energetic electrons and an additional heating of the cold electrons.

PMID- 12484833
TI  - New dynamical mean-field dynamo theory and closure approach.
AB  - We develop a new nonlinear mean field dynamo theory that couples field growth to
      the time evolution of the magnetic helicity and the turbulent electromotive
      force, E. We show that the difference between kinetic and current helicities
      emerges naturally as the growth driver when the time derivative of E is coupled
      into the theory. The solutions predict significant field growth in a kinematic
      phase and a saturation rate/strength that is magnetic Reynolds number
      dependent/independent in agreement with numerical simulations. The amplitude of
      early time oscillations provides a diagnostic for the closure.

PMID- 12484834
TI  - Theoretical evaluation of zirconia and hafnia as gate oxides for si
      microelectronics.
AB  - Parameters determining the performance of the crystalline oxides zirconia (ZrO2)
      and hafnia (HfO2) as gate insulators in nanometric Si electronics are estimated
      via ab initio calculations of the energetics, dielectric properties, and band
      alignment of bulk and thin-film oxides on Si (001). With their large dielectric
      constants, stable and low-formation-energy interfaces, large valence offsets, and
      reasonable (though not optimal) conduction offsets (electron injection barriers),
      zirconia and hafnia appear to have considerable potential as gate oxides for Si
      electronics.

PMID- 12484835
TI  - Segregation in strongly ordering compounds: a key role of constitutional defects.
AB  - For the example of the B2 CoAl(100) surface, we demonstrate that even slight
      deviations from an ordered alloy's ideal stoichiometry in a subsurface region or
      in the bulk can drastically affect its surface composition. By experimental
      surface analysis and first-principles calculations, we show that Co antisite
      atoms segregate to the very surface, driven by the same strong interactions which
      enforce order in the bulk. Our findings are consistent with the lack of antisite
      segregation we found earlier for the much weaker ordering FeAl(100), and resolve
      contradictory reports for NiAl(100).

PMID- 12484836
TI  - Influence of supersaturation on surface structure.
AB  - Using low-energy electron microscopy, we have investigated the influence of an
      external flux on the structure of the Si(111) surface during growth and etching
      at elevated temperatures. We find that varying the adatom supersaturation
      effectively changes the surface free energies of coexisting 7 x 7 and '1 x 1'
      regions of the surface. In response, the boundaries separating the phases adopt a
      new steady-state configuration. The measured configuration can be used to
      quantitatively determine the difference in free energy between the phases,
      Deltagamma. The change in Deltagamma provides a measure of the local
      supersaturation at the surface, and can be interpreted as a change in the phase
      transition temperature.

PMID- 12484837
TI  - Epitaxial growth and erosion on (110) crystal surfaces: structure and dynamics of
      interfacial States.
AB  - We study nonequilibrium interfacial states in multilayer epitaxial growth and
      erosion on rectangular symmetry crystal surfaces. We elucidate a recently
      observed transition between two kinds of rippled states on (110) surfaces. We
      predict several novel interface states intervening, via consecutive transitions,
      between the two rippled states. We predict coarsening laws of the dynamics of the
      rippled and the intervening states on (110) crystal surfaces.

PMID- 12484838
TI  - High resolution atomic force microscopic imaging of the Si(111)-(7 x 7) surface:
      contribution of short-range force to the images.
AB  - Observation of the rest-atom layer of the Si(111)-(7 x 7) surface is performed by
      atomic force microscopy. By detecting the force due to the single chemical
      covalent bond formed between the tip and the sample surface, individual atoms on
      the layer were clearly resolved. Unprecedented high spatial resolution was
      achieved by setting the detection force at a small value and by reducing
      background forces due to the long-range interactions with the small oscillation
      amplitude of the cantilever and sharp probe tip.

PMID- 12484839
TI  - Tunneling electron induced bromine hopping on Si(100)-(2 x 1).
AB  - Tunneling electrons from the tip of a scanning tunneling microscope can be used
      to induce adatom hopping on Br-terminated Si(100)-(2x1) at low current and
      without voltage pulses. Hopping does not occur when electrons tunnel from a
      sample to a tip. The threshold energy is +0.8 V, and tunneling spectroscopy shows
      antibonding Si-Br states 0.8 eV above the Fermi level. Electron capture in these
      states is a necessary condition for hopping, but repulsive adsorbate interactions
      that lower the activation barrier are also required. Such interactions are strong
      near saturation for Br but are insufficient when the coverage is low or when Br
      is replaced by Cl.

PMID- 12484840
TI  - The diffusion-control limit revisited.
AB  - We consider nonequilibrium adsorption to a freshly formed surface. Owing to the
      initial lack of equilibrium, the common diffusion-control assumption is
      inconsistent at small times. A uniform small-time asymptotic approximation is
      constructed for a Langmuir-type system in terms of the small parameter epsilon
      representing the ratio of the respective kinetic and diffusive time scales of the
      problem. The diffusion-control approximation becomes valid only when t>>epsilon.
      The adsorption results are applied to the calculation of the dynamic surface
      tension.

PMID- 12484841
TI  - Exchange monte carlo for molecular simulations with monoelectronic hamiltonians.
AB  - We introduce a general Monte Carlo scheme for achieving atomistic simulations
      with monoelectronic Hamiltonians including the thermalization of both nuclear and
      electronic degrees of freedom. The kinetic Monte Carlo algorithm is used to
      obtain the exact occupation numbers of the electronic levels at canonical
      equilibrium, and comparison is made with Fermi-Dirac statistics in infinite and
      finite systems. The effects of a nonzero electronic temperature on the
      thermodynamic properties of liquid silver and sodium clusters are presented.

PMID- 12484842
TI  - Hybrid density-functional theory and the insulating gap of UO2.
AB  - We report the first calculations carried out with a periodic boundary condition
      code capable of examining hybrid density-functional theory (DFT) for f-element
      solids. We apply it to the electronic structure of the traditional Mott insulator
      UO2, and find that it correctly yields an antiferromagnetic insulator as opposed
      to the ferromagnetic metal predicted by the local spin density and generalized
      gradient approximations. The gap, density of states, and optimum lattice constant
      are all in good agreement with experiment. We stress that this results from the
      functional and the variational principle alone. We compare our results with the
      more traditional approximations.

PMID- 12484843
TI  - Multifunctional composites: optimizing microstructures for simultaneous transport
      of heat and electricity.
AB  - Composite materials are ideally suited to achieve multifunctionality since the
      best features of different materials can be combined to form a new material that
      has a broad spectrum of desired properties. Nature's ultimate multifunctional
      composites are biological materials. There are presently no simple examples that
      rigorously demonstrate the effect of competing property demands on composite
      microstructures. To illustrate the fascinating types of microstructures that can
      arise in multifunctional optimization, we maximize the simultaneous transport of
      heat and electricity in three-dimensional, two-phase composites using rigorous
      optimization techniques. Interestingly, we discover that the optimal three
      dimensional structures are bicontinuous triply periodic minimal surfaces.

PMID- 12484844
TI  - Detecting spin-polarized currents in ballistic nanostructures.
AB  - We demonstrate a mesoscopic spin polarizer/analyzer system that allows the spin
      polarization of current from a quantum point contact in a large in-plane magnetic
      field to be measured. A transverse electron focusing geometry is used to couple
      current from an emitter point contact into a collector point contact. At large in
      plane fields, with the point contacts biased to transmit only a single spin
      (g<e(2)/h), the voltage across the collector depends on the spin polarization of
      the current incident on it. Spin polarizations of >70% are found for both emitter
      and collector at 300 mK and 7 T in-plane field.

PMID- 12484845
TI  - Crossover from symplectic to orthogonal class in a two-dimensional honeycomb
      lattice.
AB  - We have calculated the weak-localization correction to the conductivity for
      disordered electrons in a two-dimensional honeycomb lattice and shown that it can
      be either positive or negative depending on the interaction range of impurity
      potentials. From symmetry considerations, the symplectic class turns out to be
      realized at nonzero temperatures and crossover to the orthogonal class is
      predicted with decreasing temperature.

PMID- 12484846
TI  - From quantum Hall ferromagnetism to huge longitudinal resistance at the 2/3
      fractional quantum Hall state.
AB  - We observe the transition from a spin-unpolarized to a polarized nu=2/3
      fractional quantum Hall state at low currents (<5 nA), recently described in
      terms of quantum Hall ferromagnetism, versus density and parallel magnetic field.
      At larger currents the time and current dependent huge longitudinal resistance
      (HLR) is always initiated at the transition. Transport in the HLR regime is
      linear and the amount of current-induced nuclear polarization in the HLR is
      comparable to the thermal nuclear polarization at approximately 20 mK and 10 T. A
      current-induced disorder in the nuclear polarization is speculated to cause the
      enhanced resistance in the HLR regime.

PMID- 12484847
TI  - Ising quantum Hall ferromagnet in magnetically doped quantum wells.
AB  - We report on the observation of the Ising quantum Hall ferromagnet with Curie
      temperature T(C) as high as 2 K in a modulation-doped (Cd,Mn)Te heterostructure.
      In this system field-induced crossing of Landau levels occurs due to the giant
      spin-splitting effect. Magnetoresistance data, collected over a wide range of
      temperatures, magnetic fields, tilt angles, and electron densities, are discussed
      taking into account both Coulomb electron-electron interactions and s-d coupling
      to Mn spin fluctuations. The critical behavior of the resistance "spikes" at T-
      >T(C) corroborates theoretical suggestions that the ferromagnet is destroyed by
      domain excitations.

PMID- 12484848
TI  - Using single quantum states as spin filters to study spin polarization in
      ferromagnets.
AB  - By measuring electron tunneling between a ferromagnet and individual energy
      levels in an aluminum quantum dot, we show how spin-resolved quantum states can
      be used as filters to determine spin-dependent tunneling rates. We also observe
      magnetic-field-dependent shifts in the magnet's electrochemical potential
      relative to the dot's energy levels. The shifts vary between samples and are
      generally smaller than expected from the magnet's spin-polarized density of
      states. We suggest that they are affected by field-dependent charge
      redistribution at the magnetic interface.

PMID- 12484849
TI  - Anomalous low-field classical magnetoresistance in two dimensions.
AB  - The magnetoresistance of classical two-dimensional electrons scattered by
      randomly distributed impurities is investigated by numerical simulation. At low
      magnetic fields, we find for the first time a negative magnetoresistance
      proportional to |B|. This unexpected behavior is shown to be due to a memory
      effect specific for backscattering events, which was not considered previously.

PMID- 12484850
TI  - Nanoscale imaging of electronic surface transport probed by atom movements
      induced by scanning tunneling microscope current.
AB  - The hopping movements of Cl atoms on a Si(111)-(7 x 7) surface that are enhanced
      by an electron injection from tips of a scanning tunneling microscope (STM)
      exhibit a spatial spread from the electron injection point with an anisotropic
      distribution. The enhanced hopping effect becomes greatest at a sample bias
      voltage being resonant with the Si-Cl antibonding states and also exhibits an
      oscillatory decay with the distance from the injection point characterized by the
      wavelength depending on the bias voltage. All of these facts can be interpreted
      in terms of the coherent expansion of the electron wave packets locally formed at
      the STM tip.

PMID- 12484851
TI  - Magnetization-orientation dependence of the superconducting transition
      temperature in the ferromagnet-superconductor-ferromagnet system: CuNi/Nb/CuNi.
AB  - The superconducting critical temperature (T(c)) of ferromagnet-superconductor
      ferromagnet systems has been predicted to exhibit a dependence on the
      magnetization orientation of the ferromagnetic layers such that T(AP)(c)>T(P)(c)
      for parallel (P) and antiparallel (AP) configurations of the two ferromagnetic
      layers. We have grown CuNi/Nb/CuNi films via magnetron sputtering and confirmed
      the theoretical prediction by measuring the resistance of the system as a
      function of temperature and magnetic field. We find an approximately 25%
      resistance drop occurs near T(c) in Cu0.47Ni0.53(5 nm)/Nb(18)/CuNi(5) when the
      two CuNi layers change their magnetization directions from parallel to
      antiparallel, whereas there is no corresponding resistance change in the normal
      state.

PMID- 12484852
TI  - LiV2O4: frustration induced heavy fermion metal.
AB  - We propose a two-stage spin-quenching scenario for the unusual heavy fermion
      state realized in the mixed valent metal LiV2O4. In this theory, local valence
      fluctuations are responsible for the formation of partially quenched, spin-1 / 2
      moments below room temperature. Frustration of the intersite spin couplings then
      drives the system to produce the heavy Fermi liquid seen at low temperatures. The
      anomalous resistivity and the sign change of the Hall constant can be understood
      naturally within this model, which also predicts a unique symmetry for the heavy
      quasiparticle bands that may be observed in de Haas-van Alphen experiments.

PMID- 12484853
TI  - Absence of an equilibrium ferromagnetic spin-glass phase in three dimensions.
AB  - Using ground state computations, we study the transition from a spin glass to a
      ferromagnet in 3D spin glasses when changing the mean value of the spin-spin
      interaction. We find good evidence for replica symmetry breaking up until the
      critical value where ferromagnetic ordering sets in, and no ferromagnetic spin
      glass phase. This phase diagram is in conflict with the droplet/scaling and mean
      field theories of spin glasses. We also find that the exponents of the second
      order ferromagnetic transition do not depend on the microscopic Hamiltonian,
      suggesting universality of this transition.

PMID- 12484854
TI  - Uniaxial magnetocrystalline anisotropy of metal/semiconductor interfaces:
      Fe/ZnSe(001).
AB  - A theoretical study of the magnetic moments and the in-plane magnetic anisotropy
      of an interface between a cubic ferromagnet and a cubic semiconductor,
      Fe/ZnSe(001), is presented. Theory confirms the observed, much debated, uniaxial
      anisotropy of the iron film. This result is important since the calculations are
      for perfect interfaces with squarelike environments, proving that the fourfolded
      symmetry of the interface Fe atoms is broken beyond the nearest neighboring
      semiconducting layer, effects that are usually assumed small. It is demonstrated
      how the uniaxial anisotropy is produced by the directional covalent bonds at the
      interface, even without atomic relaxations.

PMID- 12484855
TI  - Stimulated light emission in dense fog confined inside a porous glass matrix.
AB  - We report on light amplification through stimulated emission in a dielectrically
      disordered medium. Liquid fragments confined in the solid matrix of porous quartz
      layers result in a random fluctuation of the dielectric function, and dye
      molecules embedded in the voids yield optical gain. The level of opacity is
      tunable by the ambient vapor pressure of the dielectric substance. In the
      multiple scattering regime, a strong intensity enhancement of the dye emission
      accompanied by significant spectral narrowing is observed above the threshold for
      a layer being in the opalescence state.

PMID- 12484856
TI  - Experimental demonstration of a controlled-NOT wave-packet gate.
AB  - We report the experimental demonstration of a controlled-NOT (CNOT) quantum logic
      gate between motional and internal-state qubits of a single ion where, as opposed
      to previously demonstrated gates, the conditional dynamics depends on the extent
      of the ion's wave packet. Advantages of this CNOT gate over one demonstrated
      previously are its immunity from Stark shifts due to off-resonant couplings and
      the fact that an auxiliary internal level is not required. We characterize the
      gate logic through measurements of the postgate ion state populations for both
      logic basis and superposition input states, and we demonstrate the gate coherence
      via an interferometric measurement.

PMID- 12484857
TI  - Organization in lipid membranes containing cholesterol.
AB  - A fundamental attribute of raft formation in cell membranes is lateral separation
      of lipids into coexisting liquid phases. Using fluorescence microscopy, we
      observe spontaneous lateral separation in free-floating giant unilamellar
      vesicles. We record coexisting liquid domains over a range of composition and
      temperature significantly wider than previously reported. Furthermore, we
      establish correlations between miscibility in bilayers and in monolayers. For
      example, the same lipid mixtures that produce liquid domains in bilayer membranes
      produce two upper miscibility critical points in the phase diagrams of
      monolayers.

PMID- 12484858
TI  - Macroion-induced compositional instability of binary fluid membranes.
AB  - Macroion adsorption on a mixed, fluid, lipid membrane containing oppositely
      charged lipids induces local changes in lipid composition at the interaction
      zones, and gradients at their boundaries. Including these effects in the free
      energy of the macroion-dressed membrane we derive its spinodal equation, and show
      that nonideal lipid mixing can lead to (lipid-mediated) attraction between
      macroions and lateral phase separation in the composite membrane. The critical
      nonideality for this transition is substantially smaller than that of the bare
      lipid membrane, decreasing with macroion size and charge. That is, the lipid
      membrane is destabilized by macroion adsorption.

PMID- 12484859
TI  - Stretching and collapse of neutral polymer layers under association with ionic
      surfactants.
AB  - We provide experimental evidence for stretching and collapse of neutral polymer
      layers, already adsorbed at an oil-in-water interface, due to its interaction
      with surfactants. Upon stretching, the first interaction length (2L(0)) follows a
      power law dependence on surfactant concentration ( proportional, variant C(x)(s),
      where x approximately 0.5 for cationic surfactants) and collapses in the presence
      of salt, as a relatively weak power law (C(-y)(s), where y=0.17), in good
      agreement with brush length decay for polyelectrolyte brushes.

PMID- 12484860
TI  - Efficient Eley-Rideal reactions of H atoms with single Cl adsorbates on Au(111).
AB  - Density functional theory is used to construct an interaction model for H atoms
      with Cl over Au(111). Single-adsorbate Eley-Rideal reactions are investigated
      with quantum and quasiclassical methods. The reaction cross sections, amounting
      to 2-3 A(2), are much larger than for HD recombinations on metals. This can be
      traced to the adsorbed Cl being relatively far above the surface, the H-Cl
      interaction prevailing over the H-substrate attraction for a sizable range of
      impact parameters.

PMID- 12484861
TI  - Linear and time-dependent behavior of the gyrotron backward-wave oscillator.
AB  - Formation of axial modes in the gyrotron backward-wave oscillator is examined in
      the perspective of optimum conditions for beam-wave interactions. Distinctive
      linear properties are revealed and interpreted physically. Nonlinear implications
      of these properties (specifically, the role of high-order axial modes) are
      investigated with time-dependent simulations. Nonstationary oscillations exhibit
      self-modulation behavior while displaying no evidence of axial mode competition.
      Reasons for the erratic frequency tuning are investigated and stable tuning
      regimes are identified as a remedy.

PMID- 12484862
TI  - Coloring random graphs.
AB  - We study the graph coloring problem over random graphs of finite average
      connectivity c. Given a number q of available colors, we find that graphs with
      low connectivity admit almost always a proper coloring, whereas graphs with high
      connectivity are uncolorable. Depending on q, we find the precise value of the
      critical average connectivity c(q). Moreover, we show that below c(q) there
      exists a clustering phase c in [c(d),c(q)] in which ground states spontaneously
      divide into an exponential number of clusters and where the proliferation of
      metastable states is responsible for the onset of complexity in local search
      algorithms.

PMID- 12484863
TI  - Extreme self-organization in networks constructed from gene expression data.
AB  - We study networks constructed from gene expression data obtained from many types
      of cancers. The networks are constructed by connecting vertices that belong to
      each others' list of K nearest neighbors, with K being an a priori selected non
      negative integer. We introduce an order parameter for characterizing the
      homogeneity of the networks. On minimizing the order parameter with respect to K,
      degree distribution of the networks shows power-law behavior in the tails with an
      exponent of unity. Analysis of the eigenvalue spectrum of the networks confirms
      the presence of the power-law and small-world behavior. We discuss the
      significance of these findings in the context of evolutionary biological
      processes.

PMID- 12484864
TI  - Extremum statistics in scale-free network models.
AB  - We investigate the statistics of the most connected node in scale-free networks.
      For a scale-free network model with homogeneous nodes, we show by means of
      extensive simulations that the exponential truncation, due to the finite size of
      the network, of the degree distribution governs the scaling of the extreme values
      and that the distribution of maxima follows the Gumbel statistics. For a scale
      free network model with heterogeneous nodes, we show that scaling no longer holds
      and that the truncation of the degree distribution no longer controls the maxima
      distribution.

PMID- 12484865
TI  - Singularities of the mixed state phase.

PMID- 12484867
TI  - Replica field theories, painleve transcendents, and exact correlation functions.
AB  - Exact solvability is claimed for nonlinear replica sigma models derived in the
      context of random matrix theories. Contrary to other approaches reported in the
      literature, the framework outlined does not rely on traditional "replica symmetry
      breaking" but rests on a previously unnoticed exact relation between replica
      partition functions and Painleve transcendents. While expected to be applicable
      to matrix models of arbitrary symmetries, the method is used to treat fermionic
      replicas for the Gaussian unitary ensemble (GUE), chiral GUE (symmetry classes A
      and AIII in Cartan classification) and Ginibre's ensemble of complex non
      Hermitian random matrices. Further applications are briefly discussed.

PMID- 12484868
TI  - Universal behavior of the energy of trapped few-boson systems with large
      scattering length.
AB  - We calculate energy levels of two and three bosons trapped in a harmonic
      oscillator potential with oscillator length a(osc). The atoms are assumed to
      interact through a short-range potential with a scattering length a, and the
      short-distance behavior of the three-body wave function is characterized by a
      parameter theta. For large positive a/a(osc), the energies of states that, in the
      absence of the trap, correspond to three free atoms approach values independent
      of a and theta. For other states, the theta dependence of the energy is strong,
      but the energy is independent of a for |a/a(osc)|>>1.

PMID- 12484869
TI  - Expansion of an interacting fermi gas.
AB  - We study the expansion of a dilute ultracold sample of fermions initially trapped
      in an anisotropic harmonic trap. The expansion of the cloud provides valuable
      information about the state of the system and the role of interactions. In
      particular, the time evolution of the deformation of the expanding cloud behaves
      quite differently depending on whether the system is in the normal or in the
      superfluid phase. For the superfluid phase, we predict an inversion of the
      deformation of the sample, similar to what happens with Bose-Einstein
      condensates. Vice versa, in the normal phase, the inversion of the aspect ratio
      is never achieved, if the mean field interaction is attractive and collisions are
      negligible.

PMID- 12484870
TI  - The Feynman propagator from a single path.
AB  - We show that it is possible to construct the Feynman propagator for a free
      particle in one dimension, without quantization, from a single continuous space
      time path.

PMID- 12484871
TI  - Oscillating superfluidity of bosons in optical lattices.
AB  - Following a suggestion by Orzel et al. [Science 291, 2386 (2001)]], we analyze
      bosons in an optical lattice undergoing a sudden parameter change from the Mott
      to superfluid phase. We introduce a modified coherent states path integral to
      describe both phases. The saddle point theory yields collective oscillations of
      the uniform superfluid order parameter. We calculate its damping rate by phason
      pair emission. In two dimensions the overdamped region largely overlaps with the
      quantum critical region. Measurements of critical dynamics on the Mott side are
      proposed.

PMID- 12484872
TI  - Multispecies pair annihilation reactions.
AB  - We consider diffusion-limited reactions A(i)+A(j)--> (1< or =i<j< or =q) in d
      space dimensions. For q>2 and d> or =2, we argue that the asymptotic density
      decay for such mutual annihilation processes with equal rates and initial
      densities is the same as for single-species pair annihilation A+A-->. In d=1,
      however, particle segregation occurs for all q< infinity. The total density
      decays according to a q dependent power law, rho(t) approximately t(-alpha(q)).
      Within a simplified version of the model alpha(q)=(q-1)/2q can be determined
      exactly. Our findings are supported through Monte Carlo simulations.

PMID- 12484876
TI  - Spin, parity, and nature of the xi(1620) resonance.
AB  - Using a unitary extension of chiral perturbation theory with a lowest-order s
      wave SU(3) chiral Lagrangian we study low-energy meson-baryon scattering in the
      strangeness S=-2 sector. A scattering-matrix pole is found around 1605 MeV which
      corresponds to an s-wave Xi resonance with J(P)=1/2(-). We identify this
      resonance with the Xi(1620) state, quoted by the Particle Data Group with I=1/2
      but with unknown spin and parity. The addition of the S=-2 state to the recently
      computed Lambda(1670), Sigma(1620), and N(1535) states completes the octet of
      J(P)=1/2(-) resonances dynamically generated in this chiral unitary approach.

PMID- 12484877
TI  - High-p(T) Tomography of d+Au and Au+Au at SPS, RHIC, and LHC.
AB  - The interplay of nuclear effects on the p(T)>2 GeV inclusive hadron spectra in
      d+Au and Au+Au reactions at sqrt[s(NN)]=17, 200, and 5500 GeV is compared to
      leading order perturbative QCD calculations for elementary p+p (p+p) collisions.
      The competition between nuclear shadowing, Cronin effect, and jet energy loss due
      to medium-induced gluon radiation is predicted to lead to a striking energy
      dependence of the nuclear suppression/enhancement pattern in A+A reactions. We
      show that future d+Au data can be used to disentangle the initial and final state
      effects.

PMID- 12484873
TI  - Observation of B-->K(0)(S)pi(+)pi(-) and Evidence for B-->K(*+/-)pi(-/+).
AB  - We report on a search for charmless hadronic B decays to the three-body final
      states K(0)(S)h(+)pi(-), K(+)h(-)pi(0), K(0)(S)h(+)pi(0) (h(+/-) denotes a
      charged pion or kaon), and their charge conjugates, using 13.5 fb(-1) of
      integrated luminosity produced near sqrt[s]=10.6 GeV, and collected with the CLEO
      detector. We observe the decay B-->K0pi(+)pi(-) with a branching fraction
      (50(+10)(-9)(stat.)+/-7(syst.))x10(-6) and the decay B-->K(*+)(892)pi(-) with a
      branching fraction (16(+6)(-5)(stat.)+/-2(syst.))x10(-6).

PMID- 12484874
TI  - Dalitz analysis of D0-->K(0)(S)pi(+)pi(-).
AB  - In e(+)e(-) collisions using the CLEO detector, we have studied the decay of the
      D0 to the final state K(0)(S)pi(+)pi(-) with the initial flavor of the D0 tagged
      by the decay D(*+)-->D0pi(+). We use the Dalitz technique to measure the resonant
      substructure in this final state and clearly observe ten different contributions
      by fitting for their amplitudes and relative phases. We observe a K(*)(892)(+)pi(
      ) component which arises from doubly Cabibbo suppressed decays or D0-D0; mixing.

PMID- 12484878
TI  - Observation of double radiative capture on pionic hydrogen.
AB  - We report the first observation of double radiative capture on pionic hydrogen.
      The experiment was conducted at the TRIUMF cyclotron using the RMC spectrometer
      and detected gamma-ray coincidences following pi(-) stops in liquid hydrogen. We
      found the branching ratio for double radiative capture to be [3.05+/-0.27(stat)+/
      0.31(syst)]x10(-5). The measured branching ratio and angle-energy distributions
      support the theoretical prediction of a dominant contribution from the pipi-
      >gammagamma annihilation mechanism.

PMID- 12484879
TI  - Vibration induced electric dipole in a weakly bound molecular complex.
AB  - A strong electric susceptibility is measured as a function of temperature in a
      molecular dimer which is weakly bound by a pair of hydrogen bonds. This system is
      a remarkable example where the dominant term in the susceptibility is due to a
      vibration induced electric dipole. As a consequence, the averaged square of the
      dipole moment varies linearly with the temperature and the susceptibility does
      not follow the usual 1/T Curie law. this spectacular effect demonstrates the
      importance of dynamics to interpret the properties of weakly bound complexes.

PMID- 12484880
TI  - Dynamics of two overlapping spin ensembles interacting by spin exchange.
AB  - We describe linear and nonlinear dynamics of spin-polarized K and 3He ensembles
      interacting by spin exchange. The interactions are dominated by the imaginary
      part of the spin-exchange cross section and each spin species is primarily
      affected by the average magnetization of the other. Operating in a very low
      magnetic field we demonstrate novel dynamics when the electron and nuclear spin
      precession frequencies are nearly matched. We observe transverse damping as well
      as a dynamic instability of the 3He spins interacting with polarized K vapor. We
      also demonstrate operation as a self-compensating comagnetometer, useful for
      tests of CPT violation and other precision measurements.

PMID- 12484881
TI  - Collective cooling and self-organization of atoms in a cavity.
AB  - We theoretically investigate the correlated dynamics of N coherently driven atoms
      coupled to a standing-wave cavity mode. For red detuning between the driving
      field and the cavity as well as the atomic resonance frequencies, we predict a
      light force induced self-organization of the atoms into one of two possible
      regular patterns, which maximize the cooperative scattering of light into the
      cavity field. Kinetic energy is extracted from the atoms by superradiant light
      scattering to reach a final kinetic energy related to the cavity linewidth. The
      self-organization starts only above a threshold of the pump strength and atom
      number. We find a quadratic dependence of the cavity mode intensity on the atom
      number, which demonstrates the cooperative effect.

PMID- 12484882
TI  - Controlled tunneling of cold atoms: from full suppression to strong enhancement.
AB  - Two recent experiments have demonstrated the phenomenon of dynamical tunneling of
      cold atoms interacting with standing electromagnetic waves. We show by
      quantitative calculations that one can achieve a control of the tunneling period
      over an orders of magnitude range by changing the frequency difference of the
      waves by about 10% only. In this narrow parameter region, the mechanism of the
      tunneling oscillations evolves from the two-state to the three-state one. Our
      calculations demonstrate that the change in the underlying mechanism leads to the
      dramatic enhancement of the dynamical tunneling. Moreover, a complete suppression
      of the dynamical tunneling can also be achieved in the cold atom setup.

PMID- 12484883
TI  - Surface aligned ion-molecule reaction: direct observation of initial and final
      ion momenta.
AB  - An ion-molecule reaction has been studied by measuring the momentum of both the
      reactant and the product ions. This is carried out in an ordered molecular film
      of CD3I where electron stimulated desorption causes the reaction CD+3+ CD3I-->
      C2D+5+DI. The close similarity of the normal momentum of CD+3 and C2D+5 indicates
      that a sticky collision occurs in which, to within 10%, the momentum of the
      reactant ion is transferred to the momentum of the product ion. The measurement
      represents the first use of molecularly aligned species to study momentum effects
      in an ion-molecule reaction.

PMID- 12484875
TI  - Measurement of the B(0)-B(0) mixing parameter Deltam(d) using semileptonic B0
      decays.
AB  - We present a measurement of the B0-Bmacr;(0) mixing parameter Deltam(d) using
      neutral B meson pairs in a 29.1 fb(-1) data sample collected at the Upsilon(4S)
      resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-)
      collider. We exclusively reconstruct one neutral B meson in the semileptonic B0-
      >D(*-)l(+)nu decay mode and identify the flavor of the accompanying B meson from
      its decay products. From the distribution of the time intervals between the two
      flavor-tagged B meson decay points, we obtain Deltam(d)=(0.494+/-0.012+/-0.015)
      ps(-1), where the first error is statistical and the second error is systematic.

PMID- 12484884
TI  - Experimental demonstration of continuous variable polarization entanglement.
AB  - We report the experimental transformation of quadrature entanglement between two
      optical beams into continuous variable polarization entanglement. We extend the
      inseparability criterion proposed by Duan et al. [Phys. Rev. Lett. 84, 2722
      (2000)]] to polarization states and use it to quantify the entanglement. We
      propose an elaboration utilizing two quadrature entangled pairs for which all
      three Stokes operators between a pair of beams are entangled.

PMID- 12484885
TI  - Demonstration of a Ni-like Kr optical-field-ionization collisional soft x-ray
      laser at 32.8 nm.
AB  - We report the first experimental demonstration of a Ni-like optical-field
      ionization collisional soft x-ray laser. The amplifying medium is generated by
      focusing a circularly polarized 760 mJ, 30 fs, 10-Hz Ti:sapphire laser beam in a
      few mm cell filled with krypton. We have measured a gain coefficient of 78 cm(-1)
      on the 3d(9)4d 1S0-3d(9)4p(1)P1 transition at 32.8 nm, which is here amplified
      for the first time. This radiation source represents the shortest wavelength
      optical-field ionization collisional soft x-ray laser ever produced. The
      influence of the gas pressure and the pumping energy on the lasing output are
      also presented.

PMID- 12484886
TI  - Highly directive 18.9 nm nickel-like molybdenum x-ray laser operating at 150 mJ
      pump energy.
AB  - We experimentally demonstrate that by longitudinally pumping 2 mm long molybdenum
      preformed plasma with high-intensity 475 fs duration laser pulse, a highly
      directive soft-x-ray laser at 18.9 nm wavelength is generated. The divergence of
      the beam is evaluated to be of the submilliradian order, and only requires a pump
      laser energy of 150 mJ.

PMID- 12484887
TI  - Noise-induced Hopf-bifurcation-type sequence and transition to chaos in the
      lorenz equations.
AB  - We study the effects of noise on the Lorenz equations in the parameter regime
      admitting two stable fixed point solutions and a strange attractor. We show that
      noise annihilates the two stable fixed point attractors and evicts a Hopf
      bifurcation-like sequence and transition to chaos. The noise-induced oscillatory
      motions have very well defined period and amplitude, and this phenomenon is
      similar to stochastic resonance, but without a weak periodic forcing. When the
      noise level exceeds certain threshold value but is not too strong, the noise
      induced signals enable an objective computation of the largest positive Lyapunov
      exponent, which characterize the signals to be truly chaotic.

PMID- 12484888
TI  - Suppression of spatial chaos via noise-induced growth of arrays of spatial
      solitons.
AB  - Domain walls with oscillatory tails are commonplace in models of spatially
      extended nonlinear optical devices. Their interaction and locking at discrete
      distances lead to asymptotically stable spatial disorder. We show that noise in
      the presence of domain walls with oscillatory tails can suppress spatial disorder
      by privileging highly correlated dynamical states consisting of arrays of spatial
      solitons.

PMID- 12484889
TI  - Nonequilibrium probabilistic dynamics of the logistic map at the edge of chaos.
AB  - We consider nonequilibrium probabilistic dynamics in logisticlike maps x(t+1)=1
      a|x(t)|(z), (z>1) at their chaos threshold: We first introduce many initial
      conditions within one among W>>1 intervals partitioning the phase space and focus
      on the unique value q(sen)<1 for which the entropic form S(q) identical with (1-
      summation operator Wp(q)(i))/(q-1) linearly increases with time. We then verify
      that S(q(sen))(t)-S(q(sen))( infinity ) vanishes like t(-1/[q(rel)(W)-1])
      [q(rel)(W)>1]. We finally exhibit a new finite-size scaling, q(rel)( infinity )
      q(rel)(W) proportional, variant W(-|q(sen)|). This establishes quantitatively,
      for the first time, a long pursued relation between sensitivity to the initial
      conditions and relaxation, concepts which play central roles in nonextensive
      statistical mechanics.

PMID- 12484890
TI  - Spatial and temporal coarse graining for dispersion in randomly packed spheres.
AB  - The propagator for molecular displacements P(zeta, t) and its first three
      cumulants were measured for Stokes flow in monodisperse bead packs with different
      sphere sizes d and molecular diffusion coefficients D(m). We systematically
      varied the normalized mean displacement <zeta>/d and diffusion length
      L(D)=sqrt[2D(m)t]/d. The experimental results map onto each other with this
      scaling. For L(D)/d<0.2 the propagator remains non-Gaussian, and thus an
      advection diffusion equation is not obeyed, for mean displacements measured up to
      <zeta>>10d. A Gaussian shape is approached for large mean displacements when
      L(D)>0.3d.

PMID- 12484891
TI  - Long time correlations in lagrangian dynamics: a key to intermittency in
      turbulence.
AB  - Using a new experimental technique, based on the scattering of ultrasounds, we
      perform a direct measurement of particle velocities, in a fully turbulent flow.
      This allows us to approach intermittency in turbulence from a dynamical point of
      view and to analyze the Lagrangian velocity fluctuations in the framework of
      random walks. We find experimentally that the elementary steps in the walk have
      random uncorrelated directions but a magnitude that is extremely long range
      correlated in time. Theoretically, a Langevin equation is proposed and shown to
      account for the observed one- and two-point statistics. This approach connects
      intermittency to the dynamics of the flow.

PMID- 12484892
TI  - Origin of stability in sedimentation.
AB  - Velocity fluctuations and particle concentrations are studied in a liquid
      fluidized bed to investigate the origin of steady state sedimentation. Both the
      velocity fluctuations and the particle concentrations are found to strongly
      depend on height. A flux balance model shows why the bed is stable: velocity
      fluctuations drive a downward particle flux that is compensated by an upward
      particle flux stemming from an excess flow velocity due to the stratification in
      concentration. Our results show that in steady state the magnitudes of the
      fluctuations are related to the degree of stratification.

PMID- 12484893
TI  - Sandpiles with bistable automata rules: towards a minimal model of pedestal
      formation and structure.
AB  - A sandpile with two stable and two unstable ranges of slopes is presented as a
      minimal model for the study of H-mode pedestal formation and dynamics. Pedestals
      are observed to form and expand inward with increasing deposition. Transport
      bifurcation is not critical to pedestal formation, though the pedestal structure
      obtained with a second, hard stability boundary is qualitatively different from
      that found in standard sandpiles. Nonperiodic particle ejection events are
      observed, but do not initiate pedestal collapse. Pedestal formation alters the
      spectrum of transport avalanches.

PMID- 12484894
TI  - Patching and tearing single-wall carbon-nanotube ropes into multiwall carbon
      nanotubes.
AB  - Bundles of single-wall carbon nanotubes (SWCNTs) coalesce forming multiwall
      carbon nanotubes (MWCNTs), containing from two to six nested tubes, under thermal
      treatment at high temperatures [(2200-2400) degrees C]. This structural
      transformation is confirmed by extensive molecular dynamics (MD) simulations. The
      simulations suggest a "patching-and-tearing" mechanism for the single-wall-to
      multiwall transformation underlying the "concerted" coalescence of the tubes that
      begins with their polymerization. Tubes of different sizes and chiralities are
      considered.

PMID- 12484895
TI  - Torsional response and stiffening of individual multiwalled carbon nanotubes.
AB  - We report on the characterization of torsional oscillators which use multiwalled
      carbon nanotubes as the spring elements. Through atomic-force-microscope force
      distance measurements we are able to apply torsional strains to the nanotubes and
      measure their torsional spring constants, and estimate their effective shear
      moduli. The data show that the nanotubes are stiffened by repeated flexing. We
      speculate that changes in the intershell mechanical coupling are responsible for
      the stiffening.

PMID- 12484896
TI  - Charge distribution and stability of charged carbon nanotubes.
AB  - Density-functional calculations of charge distribution on negatively and
      positively charged nanotubes result in charge density profiles characterized by a
      significant increase of charge density at the tube ends. These results are in
      quantitative agreement with classical electrostatic analysis, which assumes
      constant electrostatic potential on the conductive tube surface. At high charging
      levels, the tube ends are observed to be unstable due to Coulomb repulsion. By
      combining ab initio calculations with classical electrostatics, we determine, as
      a function of tube length and geometry of the tube end, the critical voltage
      beyond which nanotubes are unstable.

PMID- 12484897
TI  - Ablation of solids under femtosecond laser pulses.
AB  - We study the basic mechanisms leading to ablation by femtosecond laser pulses
      using molecular dynamics and a simple two-dimensional Lennard-Jones model. We
      demonstrate that the ablation process involves three different mechanisms as a
      function of deposited energy. In particular, it can result from mechanical
      fragmentation, which does not require the system to cross any metastability or
      instability line. The relevance of homogeneous nucleation and vaporization for
      the description of ablation in this regime is also established.

PMID- 12484898
TI  - Electronic structure of the muonium center as a shallow donor in ZnO.
AB  - The electronic structure and the location of muonium centers (Mu) in single
      crystalline ZnO were determined for the first time. Two species of Mu centers
      with extremely small hyperfine parameters have been observed below 40 K. Both Mu
      centers have an axial-symmetric hyperfine structure along with a <0001> axis,
      indicating that they are located at the antibonding (AB(O, parallel )) and bond
      center (BC( parallel )) sites. It is inferred from their small ionization energy
      ( approximately 6 and 50 meV) and hyperfine parameters ( approximately 10(-4)
      times the vacuum value) that these centers behave as shallow donors, strongly
      suggesting that hydrogen is one of the primary origins of n type conductivity in
      as-grown ZnO.

PMID- 12484899
TI  - High-frequency acoustic modes in liquid gallium at the melting point.
AB  - The microscopic dynamics in liquid gallium at melting has been studied by
      inelastic x-ray scattering. We demonstrate the existence of acousticlike modes up
      to wave vectors above one-half of the first maximum of the static structure
      factor, at variance with earlier results from inelastic neutron scattering [F. J.
      Bermejo et al., Phys. Rev. E 49, 3133 (1994)]. Despite structural (extremely rich
      polymorphism) and electronic (mixed valence) peculiarities, the collective
      dynamics is strikingly similar to the one of van der Waals and metallic fluids.
      This result speaks in favor of the universality of the short time dynamics in
      monatomic liquids rather than of system-specific dynamics.

PMID- 12484900
TI  - Strength and elasticity of SiO2 across the stishovite-CaCl2-type structural phase
      boundary.
AB  - Radial x-ray diffraction experiments were conducted under nonhydrostatic
      compression on SiO2 to 60 GPa in a diamond anvil cell. This ratio of differential
      stress to shear modulus t/G is 0.019(3)-0.037(5) at P=15-60 GPa. The ratio for
      octahedrally coordinated stishovite is lower by a factor of about 2 than observed
      in four-coordinated silicates. Using a theoretical model for the shear modulus,
      the differential stress of stishovite is found to be 4.5(1.5) GPa below 40 GPa
      and to decrease sharply as the stishovite-CaCl2-type phase transition boundary is
      approached. Inversion of measured lattice strains provides direct experimental
      evidence for softening of C11-C12.

PMID- 12484901
TI  - From dislocation junctions to forest hardening.
AB  - The mechanisms of dislocation intersection and strain hardening in fcc crystals
      are examined with emphasis on the process of junction formation and destruction.
      Large-scale 3D simulations of dislocation dynamics were performed yielding access
      for the first time to statistically averaged quantities. These simulations
      provide a parameter-free estimate of the dislocation microstructure strength and
      of its scaling law. It is shown that forest hardening is dominated by short-range
      elastic processes and is insensitive to the detail of the dislocation core
      structure.

PMID- 12484902
TI  - Competing classical and quantum effects in shape relaxation of a metallic island.
AB  - Pb islands grown on a Si substrate transform at room temperature from a flattop
      facet geometry into an unusual ring shape. The volume-preserving mass transport
      is catalyzed by the electrical field from the tip of a scanning tunneling
      microscope. The ring morphology results from the competing classical and quantum
      effects in the shape relaxation. The latter is enhanced by the large anisotropy
      of the effective mass, and leads to a sequential strip-flow growth on alternating
      strips of the same facet defined by substrate steps, showing its dynamical impact
      on the stability of a nanostructure.

PMID- 12484903
TI  - Limiting step involved in the thermal growth of silicon oxide films on silicon
      carbide.
AB  - Thermal growth of silicon oxide films on silicon carbide in O2 was investigated
      using oxygen isotopic substitution and narrow resonance nuclear reaction
      profiling. This investigation was carried out in parallel with the thermal growth
      of silicon oxide films on Si. Results demonstrate that the limiting steps of the
      thermal oxide growth are different in these two semiconductors, being diffusion
      limited in the case of Si and reaction limited in the case of SiC. This fact
      renders the growth kinetics of SiO2 on SiC very sensitive to the reactivity of
      the interface region, whose compositional and structural changes can affect the
      electrical properties of the structure.

PMID- 12484904
TI  - Evaporation of free PbS nanoparticles: evidence of the Kelvin effect.
AB  - The size-dependent evaporation of free-spherical PbS nanoparticles has been
      investigated by in-flight sintering of size-classified aerosols. The temperature
      (T(ev)) at which the particle size decreases due to evaporation is found to be
      size dependent and decreases with decreasing particle size. A linear relationship
      between the evaporation temperature and the inverse of the particle size is
      obtained as is the case with size-dependent melting of nanoparticles. This gives
      a direct evidence of the Kelvin effect and allows one to estimate the surface
      energy of nanoparticles. The surface energy of PbS nanoparticles has been found
      to be 2.45 J m(2).

PMID- 12484905
TI  - Epitaxial crystal growth of charged colloids.
AB  - A pattern of repulsive, charged lines is shown to direct three-dimensional (3D)
      crystallization in a system of long-range repulsive, density-matched colloids. At
      volume fractions where the bulk phase behavior leads to bcc crystallization, the
      1D template was found to induce formation of a metastable fcc crystal. The bcc
      crystals were oriented with the (100) or the (110) plane, with twofold twinning,
      parallel to the template. The template further induced prefreezing of the (100)
      plane. At a large mismatch between template and interparticle spacing, 1D strings
      form in the surface layer of a 3D crystal.

PMID- 12484906
TI  - Luttinger-liquid behavior in tunneling through a quantum dot at zero magnetic
      field.
AB  - Thermodynamic and transport properties of a two-dimensional circular quantum dot
      are studied theoretically at zero magnetic field. In the limit of a large
      confining potential, where the dot spectrum exhibits a shell structure, it is
      argued that both spectral and transport properties should exhibit Luttinger
      liquid behavior. These predictions are verified by direct numerical
      diagonalization. The experimental implications of such Luttinger liquid
      characteristics are discussed.

PMID- 12484907
TI  - Size effects in photoemission of one-dimensional metals.
AB  - High-resolution photoemission spectra of an array of one-dimensional (1D)
      metallic chains created on Si(335) reveal characteristic features precluding any
      interpretation within known theoretical models. The origin of this dilemma is
      attributed to imperfections acting as boundaries in 1D systems. A simple model
      calculation including a Coulomb shift in the photoemission final state of chain
      segments yields straight simulations of our spectra and is likely to clarify the
      confusing situation encountered in this field.

PMID- 12484908
TI  - Anderson transition in two-dimensional systems with spin-orbit coupling.
AB  - We report a numerical investigation of the Anderson transition in two-dimensional
      systems with spin-orbit coupling. An accurate estimate of the critical exponent
      nu for the divergence of the localization length in this universality class has
      to our knowledge not been reported in the literature. Here we analyze the SU(2)
      model. We find that for this model corrections to scaling due to irrelevant
      scaling variables may be neglected permitting an accurate estimate of the
      exponent nu=2.73+/-0.02.

PMID- 12484909
TI  - Quantum dot in the Kondo regime coupled to superconductors.
AB  - The Kondo effect and superconductivity are both prime examples of many-body
      phenomena. Here we report transport measurements on a carbon nanotube quantum dot
      coupled to superconducting leads that show a delicate interplay between both
      effects. We demonstrate that the superconductivity of the leads does not destroy
      the Kondo correlations on the quantum dot when the Kondo temperature, which
      varies for different single-electron states, exceeds the superconducting gap
      energy.

PMID- 12484910
TI  - Specific heat of single crystal MgB2: a two-band superconductor with two
      different anisotropies.
AB  - Heat-capacity measurements of a 39 microg MgB2 single crystal in fields up to 14
      T and below 3 K allow the determination of the low-temperature linear term of the
      specific heat, its field dependence, and its anisotropy. Our results are
      compatible with two-band superconductivity, the band carrying the smaller gap
      being isotropic, that carrying the larger gap having an anisotropy of
      approximately 5. Three different upper critical fields are thus needed to
      describe the superconducting state of MgB2.

PMID- 12484911
TI  - Origin of second-order transverse magnetic anisotropy in Mn12-acetate.
AB  - The symmetry breaking effects for quantum tunneling of the magnetization in Mn12
      acetate, a molecular nanomagnet, represent an open problem. We present structural
      evidence that the disorder of the acetic acid of crystallization induces sizable
      distortion of the Mn(III) sites, giving rise to six different isomers. Four
      isomers have symmetry lower than tetragonal and a nonzero second-order transverse
      magnetic anisotropy, which has been evaluated using a ligand field approach. The
      result of the calculation leads to an improved simulation of electron
      paramagnetic resonance spectra and justifies the tunnel splitting distribution
      derived from the field sweep rate dependence of the hysteresis loops.

PMID- 12484912
TI  - Reversal-field memory in the hysteresis of spin glasses.
AB  - We report a novel singularity in the hysteresis of spin glasses, the reversal
      field memory effect, which creates a nonanalyticity in the magnetization curves
      at a particular point related to the history of the sample. The origin of the
      effect is due to the existence of a macroscopic number of "symmetric clusters" of
      spins associated with a local spin-reversal symmetry of the Hamiltonian. We use
      first order reversal curve (FORC) diagrams to characterize the effect and compare
      to experimental results on thin magnetic films. We contrast our results on spin
      glasses to random magnets and show that the FORC technique is an effective
      "magnetic fingerprinting" tool.

PMID- 12484913
TI  - First-order transition between a small gap semiconductor and a ferromagnetic
      metal in the isoelectronic alloy FeSi1-xGex.
AB  - The contrasting ground states of isoelectronic, isostructural FeSi and FeGe are
      explained within an extended local density approximation scheme (LDA+U) by an
      appropriate choice of the Coulomb repulsion U on the Fe sites. A minimal two-band
      model with interband interactions leads to a phase diagram for the alloys FeSi1
      xGex. A mean field approximation gives a first-order transition between a small
      gap semiconductor and a ferromagnetic metal as a function of magnetic field,
      temperature, and concentration x. Unusually the transition from metal to
      insulator is driven by broadening, not narrowing, the bands and it is the
      metallic state that shows magnetic order.

PMID- 12484914
TI  - Scale invariance in disordered systems: the example of the random-field Ising
      model.
AB  - We show by numerical simulations that the correlation function of the random
      field Ising model (RFIM) in the critical region in three dimensions has very
      strong fluctuations and that in a finite volume the correlation length is not
      self-averaging. This is due to the formation of a bound state in the underlying
      field theory. We argue that this nonperturbative phenomenon is not particular to
      the RFIM in 3D. It is generic for disordered systems in two dimensions and may
      also happen in other three-dimensional disordered systems.

PMID- 12484915
TI  - Power propagation in homogeneous isotropic frequency-dispersive left-handed
      media.
AB  - We study transmission at a boundary between a right-handed medium (RHM:
      epsilon>0, mu>0) and a frequency dispersive left-handed medium [LHM:
      epsilon(omega)<0, mu(omega)<0 for some omega], both homogeneous and isotropic. In
      order to account for the dispersion, two types of signal spectra are considered.
      The first consists of two discrete frequencies, while the second is Gaussian.
      Explicit expressions for the time-domain fields are obtained, from which the time
      averaged Poynting vectors and hence power flow vectors are calculated. In both
      cases, we find that waves refract at negative angles at a RHM-LHM interface.

PMID- 12484916
TI  - Electron and orbital correlations in Ca2-xSrxRuO4 probed by optical spectroscopy.
AB  - The optical conductivity spectra of the quasi-two-dimensional Ca2-xSrxRuO4 (0.0<
      or =x< or =2.0) system were investigated. In the Mott insulating state, two
      electron correlation-induced peaks were observed about 1.0 and 1.9 eV, which
      could be explained using the 3-orbital Hubbard model. The low frequency peak
      showed a shift toward higher frequency as temperature was lowered, indicating
      that electron-phonon interactions play an important role in the orbital
      arrangements. From the systematic analysis, it was suggested that the antiferro
      orbital and the ferro-orbital ordering states could coexist.

PMID- 12484917
TI  - Spontaneous emission of europium ions embedded in dielectric nanospheres.
AB  - We measure fluorescence lifetimes of emitters embedded in isolated single
      dielectric nanospheres. By varying the diameters of the spheres from 100 nm to 2
      microm and by modifying their dielectric surrounding, we demonstrate a systematic
      change of paradigm in the spontaneous emission rate, as we cross the border from
      the superwavelength regime of Mie resonances to the nanoscopic realm of Rayleigh
      scattering. Our data show inhibition of the spontaneous emission up to 3 times
      and are in excellent agreement with the results of analytical calculations.

PMID- 12484918
TI  - Ultrafast dephasing of surface plasmon excitation in silver nanoparticles:
      influence of particle size, shape, and chemical surrounding.
AB  - By combination of two special methods, i.e., persistent spectral hole burning and
      laser assisted nanoparticle preparation, the dephasing time T2 of surface plasmon
      excitation in silver nanoparticles was systematically investigated. A strong
      dependence of T2 on the plasmon energy is found which reflects the relevance of
      interband damping and makes necessary a precise control of the particle shape
      when measuring T2. The influence of the reduced dimension on the dephasing
      dynamics was observed as a decrease of T2 with shrinking particle size. In
      addition, for silver nanoparticles on quartz substrates, a considerable amount of
      chemical interface damping was observed.

PMID- 12484919
TI  - Resonant two-magnon Raman scattering and photoexcited States in two-dimensional
      mott insulators.
AB  - We investigate the resonant two-magnon Raman scattering in two-dimensional (2D)
      Mott insulators by using a half-filled 2D Hubbard model in the strong coupling
      limit. By performing numerical diagonalization calculations for small clusters,
      we find that the Raman intensity is enhanced when the incoming photon energy is
      not near the optical absorption edge but well above it, being consistent with
      experimental data. The absence of resonance near the gap edge is associated with
      the presence of background spins, while photoexcited states for resonance are
      found to be characterized by the charge degree of freedom. The resonance
      mechanism is different from those proposed previously.

PMID- 12484920
TI  - Primary processes of laser-induced selective dimer-layer removal on Si(001)
      (2x1).
AB  - Excitation with nanosecond-laser pulses at fluences well below the melt threshold
      removes Si dimers on the Si(001)-(2x1) surface and induces atomic-Si desorption
      through an electronic mechanism. The rate of this photoinduced reaction depends
      superlinearly on the excitation intensity, and is enhanced resonantly at the
      photon energy where the optical transition injects holes into the dimer backbond
      surface-band state. The results reveal the crucial role of surface holes and
      their nonlinear localization in the bond rupture of Si dimers on this surface.

PMID- 12484921
TI  - Picosecond snapshot of the speckles from ferroelectric BaTiO3 by means of x-ray
      lasers.
AB  - A picosecond x-ray laser speckle has been conducted to study the dynamics of a
      disordered surface domain structure (BaTiO3 with 90 degrees c/a domains) as a
      function of temperature for the first time. The transient surface structures
      induced by ferroelectric domains decrease as temperature increases towards the
      Curie temperature T(c) and completely disappear above T(c). The dramatic change
      of the spatial configuration of the c/a domains was observed to occur from a
      temperature 2 degrees C below T(c), near which the average correlated domain size
      at equilibrium decreases as (T(c)-T)(0.37+/-0.02).

PMID- 12484922
TI  - Polarization entanglement purification using spatial entanglement.
AB  - We present a scheme for entanglement purification with linear optics that works
      for currently available parametric down-conversion sources, in contrast to a
      previous scheme [J. W. Pan, Nature (London) 410, 1067 (2001)]] that relied on
      ideal single-pair sources. The present scheme makes use of spatial entanglement
      in order to purify polarization entanglement. Surprisingly, spatial entanglement
      as an additional resource also leads to a substantial improvement in entanglement
      output compared to the previous scheme.

PMID- 12484923
TI  - Tracer studies on f-actin fluctuations.
AB  - We present a study on the fluctuations of semiflexible actin filaments using
      fluorescence videomicroscopy, focusing on the end-to-end fluctuations of single
      filaments. In order to specifically measure the position of the polymer's ends,
      we developed a novel noninvasive method that consists of annealing short end tags
      to the filaments. This allows us to probe polymer fluctuations to a very high
      accuracy. We compared the distribution of the end-to-end distance with recent
      theoretical results, and found excellent agreement. We also studied the dynamics
      of the mean-square end-to-end distance deltaR2(t) and orientation of the ends,
      deltaTheta(2)(t), finding power laws t(3/4) and t(1/4), respectively. Scaling
      behavior for deltaR2(t) is observed over several decades in relaxation time in
      agreement with theoretical results.

PMID- 12484924
TI  - Amorphous solidification in polymer-platelet nanocomposites.
AB  - Computer simulations are used to understand the molecular basis of the rheology
      changes in polymer melts when loaded with platelet filler particles, specifically
      when the polymer and nanofiller interact attractively. With decreasing
      temperature, there is increasing aggregation between chains and filler and an
      increase in the polymer matrix structural relaxation time. These lifetimes are
      predicted to diverge at an extrapolated temperature, which we identify with the
      emergence of an amorphous solid state. Our findings suggest that filled polymers
      are phenomenologically similar to solutions of associating polymers and to
      supercooled liquids near their glass transition.

PMID- 12484925
TI  - Topological transition in aqueous nonionic micellar solutions.
AB  - We have studied the topological transition of the nonionic micelles of a penta
      ethyleneglycol mono n-dodecyl ether (C12E5)/DL-alpha-phosphatidylcholine
      Dimyristoyl (DMPC) mixture in water by light scattering and viscosity
      measurements. The topological transition concentration decreases with an increase
      of the mixing ratio of DMPC to C12E5. The topological transition point is
      strongly affected by defect energies of the end cap (epsilon(1)) and a threefold
      junction (epsilon(3)) and is compared with a recent theoretical study. This
      experimental study shows the first clear evidence for the topological transition
      in a nonionic micellar system resulting from balancing the defect energies.

PMID- 12484926
TI  - Coexistence of regular and irregular dynamics in complex networks of pulse
      coupled oscillators.
AB  - For general networks of pulse-coupled oscillators, including regular, random, and
      more complex networks, we develop an exact stability analysis of synchronous
      states. As opposed to conventional stability analysis, here stability is
      determined by a multitude of linear operators. We treat this multioperator
      problem exactly and show that for inhibitory interactions the synchronous state
      is stable, independent of the parameters and the network connectivity. In
      randomly connected networks with strong interactions this synchronous state,
      displaying regular dynamics, coexists with a balanced state exhibiting irregular
      dynamics. External signals may switch the network between qualitatively distinct
      states.

PMID- 12484927
TI  - Scale-free networks from varying vertex intrinsic fitness.
AB  - A new mechanism leading to scale-free networks is proposed in this Letter. It is
      shown that, in many cases of interest, the connectivity power-law behavior is
      neither related to dynamical properties nor to preferential attachment. Assigning
      a quenched fitness value x(i) to every vertex, and drawing links among vertices
      with a probability depending on the fitnesses of the two involved sites, gives
      rise to what we call a good-get-richer mechanism, in which sites with larger
      fitness are more likely to become hubs (i.e., to be highly connected).

PMID- 12484928
TI  - Statistics of changes in lead node in connectivity-driven networks.
AB  - We study statistical properties of the highest degree, or most popular, nodes in
      growing networks. We show that the number of lead changes increases
      logarithmically with network size N, independent of the details of the growth
      mechanism. The probability that the first node retains the lead approaches a
      finite constant for popularity-driven growth, and decays as N-phi (ln(N)(-1/2),
      with phi=0.08607 em leader, for growth with no popularity bias.

PMID- 12484929
TI  - Comment on "Superheating and supercooling of vortex matter in a Nb single
      crystal: direct evidence for a phase transition at the peak effect from neutron
      diffraction".

PMID- 12484931
TI  - Complex probabilities on R(N) as real probabilities on C(N) and an application to
      path integrals.
AB  - We establish a necessary and sufficient condition for averages over complex
      valued weight functions on R(N) to be represented as statistical averages over
      real, non-negative probability weights on C(N). Using this result, we show that
      many path integrals for time-ordered expectation values of bosonic degrees of
      freedom in real-valued time can be expressed as statistical averages over
      ensembles of paths with complex-valued coordinates, and then speculate on
      possible consequences of this result for the relation between quantum and
      classical mechanics.

PMID- 12484932
TI  - Experimental two-photon, three-dimensional entanglement for quantum
      communication.
AB  - Orbital angular momentum entangled photons emitted by a down-conversion source
      are in higher dimensional entangled states. Here we report the experimental
      confirmation by demonstrating a violation of a generalized Clauser-Horne-Shimony
      Holt-type Bell inequality in three dimensions by more than 18 standard
      deviations. Higher dimensional entangled states allow the realization of new
      types of quantum communication protocols. They also provide a more secure quantum
      cryptography scheme. Therefore our experimental results are likely to have
      applications in future quantum communication technology.

PMID- 12484933
TI  - Dynamical transition from a quasi-one-dimensional Bose-Einstein condensate to a
      Tonks-Girardeau gas.
AB  - We analyze in detail the expansion of a 1D Bose gas after removing the axial
      confinement. We show that during its one-dimensional expansion the density of the
      Bose gas does not follow a self-similar solution. Our analysis is based on a
      nonlinear Schrodinger equation with variable nonlinearity whose validity is
      discussed for the expansion problem, by comparing with an exact Bose-Fermi
      mapping for the case of an initial Tonks-Girardeau gas. For this case, the gas is
      shown to expand self-similarly, with a different scaling law compared to the one
      dimensional Thomas-Fermi condensate.

PMID- 12484934
TI  - Are the laws of entanglement theory thermodynamical?
AB  - We argue that on its face, entanglement theory satisfies laws equivalent to
      thermodynamics if the theory can be made reversible by adding certain bound
      entangled states as a free resource during entanglement manipulation. Subject to
      plausible conjectures, we prove that this is not the case in general, and discuss
      the implications of this for the thermodynamics of entanglement.

PMID- 12484935
TI  - Complete two loop bosonic contributions to the muon lifetime in the standard
      model.
AB  - The last missing correction to the muon lifetime in the standard model at
      O(alpha(2)) coming from gauge and Higgs boson loops is presented. The associated
      contribution to the parameter Deltar in the on-shell scheme ranges from 6x10(-5)
      to -4x10(-5) for Higgs boson masses from 100 GeV to 1 TeV. This result translates
      into a shift of the W boson mass which does not exceed +/-1 MeV in the same range
      and amounts, in particular, to approximately -0.8 MeV for a 115 GeV Higgs boson.

PMID- 12484936
TI  - Higgs-mediated tau-->3micro in the supersymmetric seesaw model.
AB  - Recent observations of neutrino oscillations imply nonzero neutrino masses and
      lepton flavor violation (LFV), most economically explained by the seesaw
      mechanism. Within the context of supersymmetry, LFV among the neutrinos can be
      communicated to the sleptons and from there to the charged leptons. We show that
      LFV can appear in the couplings of the neutral Higgs bosons, an effect that is
      strongly enhanced at large tan(beta. We calculate the branching fraction for tau-
      >3micro and micro-->3e mediated by Higgs and find they can be as large as 10(-7)
      and 5x10(-14), respectively. These modes, along with tau-->mugamma and mu-
      >egamma, can provide key insights into the neutrino mass matrix.

PMID- 12484937
TI  - Delta-->Ngamma in large-N(c) QCD.
AB  - The decay Delta(+)-->pgamma is studied in the 1/N(c) expansion of QCD. The ratio
      of the helicity amplitudes is determined to be
      A(3/2)/A(1/2)=sqrt[3]+O(1/N(2)(c)). Equivalently, the ratio E2/M1 of the
      multipole amplitudes is predicted to be order 1/N(2)(c).

PMID- 12484939
TI  - Coulomb excitation paths of high-K isomer bands in 178Hf.
AB  - Three distinctly different mechanisms are shown to populate the K(pi)=6(+)
      (t(1/2)=77 ns), 16(+) (31 yr), and 8(-) (4 s) isomer bands of 178Hf by Coulomb
      excitation. High spin states of the three isomer bands were populated by Coulomb
      excitation of a hafnium target with a 650 MeV 136Xe beam. Although direct
      population of high-K bands is highly K-forbidden, isomer bands in 178Hf were
      populated up to spins 13(+)(K=6), 20(+)(K=16), and 14(-)(K=8) with in-band gamma
      yields of approximately 10(-4) of the ground state band. The data are consistent
      with a rapid increase in K mixing with increasing spin in the isomer bands.

PMID- 12484940
TI  - Interference effects in the resonant photoemission channels to the Ne+
      2p(4)(1D2)3p 2P, 2D, and 2F states in the Ne 1s excitation region.
AB  - We present measurements of total and partial photoionization cross sections of Ne
      in the 1s excitation region. The total cross section exhibits resonances with
      symmetric profiles, whereas the branching ratios to the Ne+ 2p(4)(1D2)3p 2P, 2D,
      and 2F states present strong oscillations in the interresonance regions. We prove
      that not only the interference between the direct and resonant ionization
      processes but also the interference among the ionization processes via different
      nonisolated resonances are important for this effect.

PMID- 12484941
TI  - Size-selective extended X-ray absorption fine structure spectroscopy of free
      selenium clusters.
AB  - In a recent paper [M. Yao et al., J. Synchrotron Radiat. 8, 542 (2001)]], we
      proposed a new method for the size-selective EXAFS (extended x-ray absorption
      fine structure) of neutral-free clusters, in which not only the x-ray absorption
      process but also the deexcitation processes are utilized as the structural
      information. In order to verify this method experimentally, we have developed the
      synchronous measurements of EXAFS and photoelectron photoion coincidence and
      carried them out for a Se cluster beam by utilizing the third-generation intense
      x-ray source. The EXAFS spectra for Se small clusters have been obtained and
      compared critically with theoretical predictions.

PMID- 12484938
TI  - Q2 evolution of the generalized Gerasimov-Drell-Hearn integral for the neutron
      using a 3He target.
AB  - We present data on the inclusive scattering of polarized electrons from a
      polarized 3He target at energies from 0.862 to 5.06 GeV, obtained at a scattering
      angle of 15.5 degrees. Our data include measurements from the quasielastic peak,
      through the nucleon resonance region, and beyond, and were used to determine the
      virtual photon cross-section difference sigma(1/2)-sigma(3/2). We extract the
      extended Gerasimov-Drell-Hearn integral for the neutron in the range of four
      momentum transfer squared Q2 of 0.1-0.9 GeV2.

PMID- 12484942
TI  - Hyperfine structure of antiprotonic helium revealed by a laser-microwave-laser
      resonance method.
AB  - Using a newly developed laser-microwave-laser resonance method, we observed a
      pair of microwave transitions between hyperfine levels of the (n,L)=(37,35) state
      of antiprotonic helium. This experiment confirms the quadruplet hyperfine
      structure arising from the interaction of the antiproton orbital angular
      momentum, the electron spin and the antiproton spin as predicted by Bakalov and
      Korobov. The measured frequencies of nu(+)(HF)=12.895 96+/-0.000 34 GHz and nu(
      )(HF)=12.924 67+/-0.000 29 GHz agree with recent theoretical calculations on a
      level of 6x10(-5).

PMID- 12484943
TI  - Anisotropic diffusion of light in a strongly scattering material.
AB  - Light transport in a strongly scattering, strongly anisotropic material is
      studied experimentally using both static and time-resolved techniques. Both the
      static and the dynamic results are well characterized by a diffusion equation
      with an anisotropic diffusion tensor and a scalar absorption term. Light diffuses
      4.0 times faster along the uniaxial axis of the material compared with diffusion
      in the orthogonal directions.

PMID- 12484944
TI  - Measuring the phase of spatially coherent polychromatic fields.
AB  - Realistic optical fields are never completely monochromatic and the
      interpretation of the concept of phase is not straightforward. It has been
      pointed out by Wolf that, if a strict condition of spatial coherence is imposed,
      the statistically averaged behavior of a polychromatic field can be described by
      an associated monochromatic wave. We show that, for spatially coherent
      polychromatic optical fields, the measurement of the phase of the second-order
      correlations determines the phase of this associated, spatially coherent field.
      We verify this prediction using a novel interferometric technique for measuring
      the cross-spectral density of a steady-state optical field.

PMID- 12484945
TI  - Steady stokes flow with long-range correlations, fractal fourier spectrum, and
      anomalous transport.
AB  - We consider viscous two-dimensional steady flows of incompressible fluids past
      doubly periodic arrays of solid obstacles. In a class of such flows, the
      autocorrelations for the Lagrangian observables decay in accordance with the
      power law, and the Fourier spectrum is neither discrete nor absolutely
      continuous. We demonstrate that spreading of the droplet of tracers in such flows
      is anomalously fast. Since the flow is equivalent to the integrable Hamiltonian
      system with 1 degree of freedom, this provides an example of integrable dynamics
      with long-range correlations, fractal power spectrum, and anomalous transport
      properties.

PMID- 12484946
TI  - Quantum chaos and 1/f noise.
AB  - It is shown that the energy spectrum fluctuations of quantum systems can be
      formally considered as a discrete time series. The power spectrum behavior of
      such a signal for different systems suggests the following conjecture: The energy
      spectra of chaotic quantum systems are characterized by 1/f noise.

PMID- 12484947
TI  - Stabilizing and tracking unknown steady States of dynamical systems.
AB  - An adaptive dynamic state feedback controller for stabilizing and tracking
      unknown steady states of dynamical systems is proposed. We prove that the steady
      state can never be stabilized if the system and controller in sum have an odd
      number of real positive eigenvalues. For two-dimensional systems, this
      topological limitation states that only an unstable focus or node can be
      stabilized with a stable controller, and stabilization of a saddle requires the
      presence of an unstable degree of freedom in a feedback loop. The use of the
      controller to stabilize and track saddle points (as well as unstable foci) is
      demonstrated both numerically and experimentally with an electrochemical Ni
      dissolution system.

PMID- 12484948
TI  - Granular segregation as a critical phenomenon.
AB  - We present the results of an experimental study of patterned segregation in a
      horizontally shaken shallow layer of a binary mixture of dry particles. An order
      parameter for the segregated domains is defined and the effect of the variation
      of the combined filling fraction, C, of the mixture on the observed pattern
      formation is systematically studied. We find that there is a critical event
      associated with the onset of segregation, at C(c)=0.647+/-0.049, which has the
      characteristics of a continuous phase transition, including critical slowing
      down.

PMID- 12484949
TI  - Adsorption phenomena in the transport of a colloidal particle through a
      nanochannel containing a partially wetting fluid.
AB  - Using molecular dynamics simulations, we study the motion of a closely fitting
      nanometer-size solid sphere in a fluid-filled cylindrical nanochannel at low
      Reynolds numbers. At early times, when the particle is close to the middle of the
      tube, its velocity is in agreement with continuum calculations, despite large
      thermal fluctuations. At later times, partially wetting fluids exhibit novel
      adsorption phenomena: the sphere meanders away from the center of the tube and
      adsorbs onto the wall, and subsequently either sticks to the wall and remains
      motionless on average, or separates slightly from the tube wall and then either
      slips parallel to the mean flow or executes an intermittent stick-slip motion.

PMID- 12484950
TI  - Trapped-particle modes and asymmetry-induced transport in single-species plasmas.
AB  - A new asymmetry-induced transport mechanism in pure electron plasmas is shown to
      be proportional to the damping rate of the corresponding trapped-particle mode,
      with simple scalings for all other parameters. This transport occurs when axial
      particle trapping exists due to variations in the electric or magnetic
      confinement fields. This new transport is strong for even weak unintentional
      trapping (deltaB/B approximately 10(-3)), and may be prevalent in transport
      experiments with magnetic or electrostatic theta asymmetries.

PMID- 12484952
TI  - Microwave saturation of the Rydberg States of electrons on helium.
AB  - We present measurements of the resonant microwave excitation of Rydberg energy
      levels for surface-state electrons on superfluid helium. The temperature
      dependent contribution to the linewidth gamma(T) agrees with theoretical
      predictions and is very small below 700 mK, in the ripplon scattering regime.
      Absorption saturation and power broadening were observed as the fraction of
      electrons in the first excited state was increased to 0.49, close to the thermal
      excitation limit of 0.5. The Rabi frequency Omega was determined as a function of
      microwave power. High values of the ratio Omega/gamma confirm this system as an
      excellent candidate for creating qubits.

PMID- 12484951
TI  - Symmetric inertial-confinement-fusion-capsule implosions in a double-z-pinch
      driven hohlraum.
AB  - An inertial-confinement-fusion (ICF) concept using two 60-MA Z pinches to drive a
      cylindrical hohlraum to 220 eV has been recently proposed. The first capsule
      implosions relevant to this concept have been performed at the same physical
      scale with a lower 20-MA current, yielding a 70+/-5 eV capsule drive. The capsule
      shell shape implies a polar radiation symmetry, the first high-accuracy
      measurement of this type in a pulsed-power-driven ICF configuration, within a
      factor of 1.6-4 of that required for scaling to ignition. The convergence ratio
      of 14-21 is to date the highest in any pulsed-power ICF system.

PMID- 12484953
TI  - Equation of state and pressure induced amorphization of beta-boron from X-ray
      measurements up to 100 GPa.
AB  - The equation of state of boron has been measured up to 100 GPa by single-crystal
      x-ray diffraction with helium as the pressure transmitting medium. Rhombohedral
      beta-boron is the stable structure up to 100 GPa under hydrostatic conditions.
      Nonhydrostatic stress stabilizes a different rhombohedral structure. At about 100
      GPa a pressure-induced amorphization is observed. The amorphous phase can be
      quenched to ambient pressure. An explanation is proposed based on the different
      stability under pressure between intraicosahedra and intericosahedra bonds.

PMID- 12484954
TI  - Adhesion between elastic bodies with randomly rough surfaces.
AB  - I have developed a theory of adhesion between an elastic solid and a hard
      randomly rough substrate. The theory takes into account the fact that partial
      contact may occur between the solids on all length scales. I present numerical
      results for the case where the substrate surface is self-affine fractal. When the
      fractal dimension is close to 2, complete contact typically occurs in the
      macroasperity contact areas. For a fractal dimension larger than 2.5, the area of
      (apparent) contact decreases continuously when the magnification is increased.

PMID- 12484955
TI  - Universality in lattice models of dynamic arrest: introduction of an order
      parameter.
AB  - We introduce an order parameter for dynamical arrest. Dynamically available
      volume (unoccupied space that is available to the motion of particles) is
      expressed as holes for the simple lattice models we study. Near the arrest
      transition the system is dilute in holes, so we expand dynamical quantities in a
      series of hole density. Unlike the situation when presented in particle density,
      all cases of simple models that we examine have a quadratic dependence of the
      diffusion constant on hole density. This observation implies that in certain
      regimes ideal dynamical arrest transitions may possess a hitherto unnoticed
      degree of universality.

PMID- 12484956
TI  - Pressure-induced structural changes in liquid SiO2 from Ab initio simulations.
AB  - First-principles molecular dynamics simulations at constant pressure have been
      used to investigate the mechanisms of compression of liquid SiO2. Liquid SiO2 is
      found to become denser than quartz at a pressure of about 6 GPa, in agreement
      with extrapolations of lower pressure experimental data. The high compressibility
      of the liquid is traced to medium-range changes in the topology of the atomic
      network. These changes consist in an increase of network connectivity caused by
      the pressure-induced appearance of coordination defects.

PMID- 12484957
TI  - Non-Gaussian nature of the alpha relaxation of glass-forming polyisoprene.
AB  - We report quasielastic neutron scattering experiments exploring the alpha
      relaxation in polyisoprene over an unprecedented range in momentum transfer.
      Corroborating and validating earlier molecular dynamics simulations, the
      measurements reveal a crossover from a Gaussian regime of sublinear diffusion to
      a strongly non-Gaussian regime at short distances. We show that a consistent
      interpretation in terms of a distribution of finite jumps underlying the alpha
      process is possible. This model leads to a time-dependent non-Gaussian parameter
      exhibiting all features revealed so far from various simulations.

PMID- 12484958
TI  - Reversible dynamic behavior in catalyst systems: oscillations of structure and
      morphology.
AB  - Exposing vanadium oxide nanoparticles on a Pd(111) surface to reducing conditions
      is shown to cause a spreading of the oxide over the metal until a reduced oxide
      phase covers the entire surface. Reoxidation reverses this process and oxide
      island structures and bare metal patches are reestablished. The physical origin
      of this wetting-dewetting process is revealed at the atomic level by in situ
      variable-temperature scanning tunneling microscopy and in terms of a surface
      oxide phase stability diagram, as calculated by density functional theory as a
      function of the chemical potential of oxygen and the vanadium concentration.

PMID- 12484959
TI  - Universal scaling in transient creep.
AB  - We present experimental evidence that pressure solution creep does not establish
      a steady-state interface microstructure as previously thought. Conversely,
      pressure solution controlled strain and the characteristic length scale of
      interface microstructures grow as the cubic root of time. Transient creep with
      the same scaling is known in metallurgy (Andrade creep). The apparent universal
      scaling of pressure solution transient creep is explained using an analogy with
      spinodal dewetting.

PMID- 12484960
TI  - Materials science of the gel to fluid phase transition in a supported
      phospholipid bilayer.
AB  - We report the results of in situ AFM measurements examining the phase transition
      of bilayers formed from the zwitterionic phospholipid, DMPC, 1,2-dimyristoyl-sn
      glycero-3-phosphocholine, supported on mica. The images show that the fluid to
      gel phase transition process features substantial tearing of the bilayer due to
      the density change between the two phases. The gel to fluid transition is
      strongly affected by the resultant stress introduced into the gel phase, which
      changes the degree of cooperativity, the shape of developing fluid phase regions,
      and the course of the transition.

PMID- 12484961
TI  - Effect of an electric field on the surface tension of a dipolar-quadrupolar fluid
      and its implication for sign preference in droplet nucleation.
AB  - The effect of a uniform electric field on interfacial properties of dipolar
      quadrupolar fluids is investigated by using the density-functional theory. As in
      the case of purely dipolar fluids the (thermodynamic) surface tension is always
      altered by the external field, regardless of the direction of the field. However,
      unlike the purely dipolar fluids, for two given external fields with the same
      strength but exactly opposite direction the magnitude of variation in the surface
      tension is different. This apparent symmetry breaking by reversing the field
      direction suggests a new molecular mechanism to explain the phenomenon of sign
      preference in droplet formation on charged condensation centers.

PMID- 12484962
TI  - Self-assembly of three-dimensional metal islands: nonstrained versus strained
      islands.
AB  - A theoretical model for the Volmer-Weber growth of three-dimensional metal
      islands is proposed, with a dipolar island edge-edge interaction. The existence
      of such an island edge effect makes the island shape dependent on island size.
      Furthermore, it induces a stable island size against coarsening, leading to self
      assembled islands of uniform size. The dependence of the stable island size on
      total film coverage is shown to be different for nonstrained versus strained
      islands, in the regime of strong island-island interaction.

PMID- 12484963
TI  - Higher coverage gas adsorption on the surface of carbon nanotubes: evidence for a
      possible new phase in the second layer.
AB  - We present adsorption isotherm results for Ne, CH4, and Xe on bundles of close
      ended single-wall carbon nanotubes, for coverages above the completion of the
      first layer. We find a small, sharp, substep present in the second-layer data for
      Ne and CH4, and a weaker feature, that produces an isothermal compressibility
      peak, for Xe. The size and location of the feature allows its tentative
      identification as a new, second-layer, one-dimensional phase, in which the atoms
      sit atop high binding energy sites in the second layer.

PMID- 12484964
TI  - Butterfly hysteresis loop at nonzero bias field in antiferromagnetic molecular
      rings: cooling by adiabatic magnetization.
AB  - At low temperatures, the magnetization of the molecular ferric wheel NaFe6
      exhibits a step at a critical field B(c) due to a field-induced level crossing.
      By means of high-field torque magnetometry we observed a hysteretic behavior at
      the level crossing with a characteristic butterfly shape which is analyzed in
      terms of a dissipative two-level model. Several unusual features were found. The
      nonzero bias field of the level crossing suggests the possibility of cooling by
      adiabatic magnetization.

PMID- 12484966
TI  - Conductance distributions in quasi-one-dimensional disordered wires.
AB  - A detailed analysis of the distribution of conductances P(g) of quasi-one
      dimensional disordered wires in the metal-insulator crossover is presented. P(g)
      obtained from a Monte Carlo solution of the Dorokhov, Mello, Pereyra, and Kumar
      (DMPK) scaling equation is in full agreement with "tight-binding" numerical
      calculations of bulk disordered wires. Perturbation theory is shown to be valid
      even for mean dimensionless conductances <g> of the order of 1. In the crossover
      regime <g> <, similar 1, P(g) presents a sharp feature at g=1 which is different
      from that observed in surface disordered wires.

PMID- 12484965
TI  - d Orbital doping into pi charge-ordered molecular insulator.
AB  - A quasi-one-dimensional pi-electron charge-ordered insulator, (DI-DCNQI)2Ag, is
      metallized by Cu doping into the Ag sites. It is found that with doping the
      charge gap is diminished and then disorder-induced insulating nature comes up,
      eventually followed by transition or crossover to a pi-d networked metal. The
      profile of the charge-gap collapse is consistent with the prediction of the
      theory highlighting the interplay between electron correlation and disorder. The
      present doping method is regarded as doping of d orbital, which is different from
      the conventional charge and/or spin doping developed in cuprates and manganites.

PMID- 12484967
TI  - Electrodynamics of a Coulomb glass in n-type silicon.
AB  - Measurements of the complex frequency dependent conductivity of uncompensated n
      type silicon are reported. The experiments are done in the quantum limit, variant
      Planck's over 2pi omega>k(B)T, across a broad doping range on the insulating side
      of the metal-insulator transition. The low energy linear frequency dependence is
      consistent with theories of a Coulomb glass, but discrepancies exist in the
      relative magnitudes of the complex components. At higher energies we observe a
      crossover to a quadratic frequency dependence that is sharper than expected. The
      concentration dependence gives evidence that the Coulomb interaction energy is
      the energy scale that determines this crossover.

PMID- 12484968
TI  - Density-dependent spin polarization in ultra-low-disorder quantum wires.
AB  - There is controversy as to whether a one-dimensional (1D) electron gas can spin
      polarize in the absence of a magnetic field. Together with a simple model, we
      present conductance measurements on ultra-low-disorder quantum wires supportive
      of a spin polarization at B=0. A spin energy gap is indicated by the presence of
      a feature in the range (0.5-0.7)x2e(2)/h in conductance data. Importantly, it
      appears that the spin gap is not constant but a function of the electron density.
      Data obtained using a bias spectroscopy technique are consistent with the spin
      gap widening further as the Fermi level is increased.

PMID- 12484969
TI  - Surface-plasmon-enhanced optical forces in silver nanoaggregates.
AB  - We use extended Mie theory to investigate optical forces induced by and acting on
      small silver nanoparticle aggregates excited at surface plasmon resonance. It is
      shown that single molecules can be trapped at junctions between closely spaced
      nanoparticles, which are simultaneously pulled together by optical forces. These
      effects could significantly influence surface-enhanced Raman scattering and
      related spectroscopies under normal experimental conditions and contribute to
      single-molecule sensitivity.

PMID- 12484970
TI  - Current-driven resonances in magnetic multilayers.
AB  - We describe complex variations in resistance of a Co/Cu multilayer, generated by
      injection of an adjustable dc current density ( approximately 10(9) A/cm(2)) via
      a point contact. We attribute these variations to coupling of current-induced
      spin waves to lattice vibrations, leading especially to current-driven resonant
      excitations of phonons. We propose a simple model to explain the observed
      structured behavior of the variations as a function of the applied current and
      magnetic field.

PMID- 12484971
TI  - NMR investigation of how free composite fermions are at nu=1 / 2.
AB  - NMR measurements of the electron spin polarization (P) have been performed on a
      2D electron system at and around half-filled lowest Landau level. Comparing the
      magnetic field and the temperature dependence of P to models of free and
      interacting composite fermions (CF), the imbalance of spin-up and spin-down CF
      Fermi seas is mapped as a function of Zeeman energy. Independent measurements of
      the CF effective mass, g factor, and Fermi energy are obtained from the thermal
      activation of P in tilted fields. The filling factor dependence of the P for 2 /
      5<nu<2 / 3 reveals a broken particle-hole symmetry for the partially polarized CF
      Fermi sea.

PMID- 12484972
TI  - Origin of the oscillator strength of the triplet state of a trion in a magnetic
      field.
AB  - The dynamics of the spin-triplet trion state, under high magnetic field in a
      GaAs/AlGaAs quantum well, are studied using time resolved spectroscopy. The
      oscillator strength of the triplet transition is shown to rise with increasing
      electron density, in good agreement with a theoretical model where the trion
      interacts with excess electrons in the quantum well. This analysis suggests that
      the spin-triplet trion state, which is expected to be an optically "dark" state,
      is experimentally observable due to the interactions with the excess electrons,
      demonstrating that X- cannot be regarded as an isolated three particle complex.

PMID- 12484973
TI  - New Josephson plasma modes in underdoped YBa2Cu3O6.6 induced by a parallel
      magnetic field.
AB  - The c-axis reflectivity spectrum of underdoped YBa2Cu3O6.6 (YBCO) is measured
      below T(c)=59 K in parallel magnetic fields H parallel CuO2 up to 7 T. Upon
      application of a parallel field, a new peak appears at finite frequency in the
      optical conductivity at the expense of suppression of c-axis condensate weight.
      We conclude that the dramatic change originates from different Josephson coupling
      strengths between bilayers with and without Josephson vortices. We find that the
      400 cm(-1) broad conductivity peak in YBCO gains the spectral weight under
      parallel magnetic field; this indicates that the condensate weight at omega=0 is
      distributed to this peak as well as to the new optical Josephson mode.

PMID- 12484974
TI  - Periodic oscillations of Josephson-vortex flow resistance in
      Bi(2)Sr(2)CaCu(2)O(8+y).
AB  - To study the Josephson-vortex system, we have measured the vortex-flow resistance
      as a function of magnetic field parallel to the ab plane in
      Bi(2)Sr(2)CaCu(2)O(8+y) single crystals. Novel periodic oscillations of the
      vortex-flow resistance have been observed in a wide range of temperatures and
      magnetic fields. The period of the oscillations corresponds to the field needed
      to add "one" vortex quantum per "two" intrinsic Josephson junctions. The flow
      velocity is related to a matching effect between the lattice spacing of Josephson
      vortices along the layers and the width of the sample. These results suggest that
      Josephson vortices form a triangular lattice in the ground state where the
      oscillations occur.

PMID- 12484975
TI  - Detection and implications of a time-reversal breaking state in underdoped
      cuprates.
AB  - We present general symmetry considerations on how a time-reversal breaking state
      may be detected by angle-resolved photoemission using circularly polarized
      photons as has been proposed earlier. Results of recent experiments utilizing the
      proposal in underdoped cuprates are analyzed and found to be consistent in their
      symmetry and magnitude with a theory of the copper oxides. These experiments if
      correct, together with evidence of a quantum critical point and marginal Fermi
      liquid properties near optimum doping, suggest that the essentials of a valid
      microscopic theory of the phenomena in the cuprates may have been found.

PMID- 12484976
TI  - Direct evidence for two-band superconductivity in MgB2 single crystals from
      directional point-contact spectroscopy in magnetic fields.
AB  - We present the results of the first directional point-contact spectroscopy
      experiments in high-quality MgB2 single crystals. Because of the directionality
      of the current injection into the samples, the application of a magnetic field
      allowed us to separate the contributions of the sigma and pi bands to the total
      conductance of our point contacts. By using this technique, we were able to
      obtain the temperature dependency of each gap independent of the other. The
      consequent, strong reduction of the error on the value of the gap amplitude as a
      function of temperature allows a stricter test of the predictions of the two-band
      model for MgB2.

PMID- 12484977
TI  - Striped phase in a quantum XY model with ring exchange.
AB  - We present quantum Monte Carlo results for a square-lattice S=1/2 XY model with a
      standard nearest-neighbor coupling J and a four-spin ring exchange term K.
      Increasing K/J, we find that the ground state spin stiffness vanishes at a
      critical point at which a spin gap opens and a striped bond-plaquette order
      emerges. At still higher K/J, this phase becomes unstable and the system develops
      a staggered magnetization. We discuss the quantum phase transitions between these
      phases.

PMID- 12484978
TI  - Fluctuation-driven quantum phase transitions in clean itinerant ferromagnets.
AB  - The quantum phase transition in clean itinerant ferromagnets is analyzed. It is
      shown that soft particle-hole modes invalidate Hertz's mean-field theory for d<
      or =3. A renormalized mean-field theory predicts a fluctuation-induced first
      order transition for 1<d< or =3, whose stability is analyzed by renormalization
      group techniques. Depending on microscopic parameter values, the first order
      transition can be stable, or be preempted by a fluctuation-induced second order
      transition. The critical behavior at the latter is determined. The results are in
      agreement with recent experiments.

PMID- 12484979
TI  - Local symmetry breaking by impurities and mode splitting in doped SmS.
AB  - We introduce the idea of local symmetry breaking by impurities to explain the
      recently observed splitting of the J=0-->1 propagating excitation in doped Sm1
      xYxS. While preserving the global cubic symmetry of the crystal, Y impurities
      change the local crystal-field environment of each Sm ion from cubic to
      tetragonal, thereby splitting the J=1 triplet into a m(i).J=0 level with energy
      Delta(1) and a m(i).J=+/-1 doublet with energy Delta(2)>Delta(1). A model with a
      randomly oriented quantization axis m(i) fits not only the observed mode
      frequencies but also their intensities, which strongly depends on the wave
      vector.

PMID- 12484980
TI  - Trapped-ion quantum simulator: experimental application to nonlinear
      interferometers.
AB  - We show how an experimentally realized set of operations on a single trapped ion
      is sufficient to simulate a wide class of Hamiltonians of a spin-1/2 particle in
      an external potential. This system is also able to simulate other physical
      dynamics. As a demonstration, we simulate the action of two nth order nonlinear
      optical beam splitters comprising an interferometer sensitive to phase shift in
      one of the interferometer beam paths. The sensitivity in determining these phase
      shifts increases linearly with n, and the simulation demonstrates that the use of
      nonlinear beam splitters (n=2,3) enhances this sensitivity compared to the
      standard quantum limit imposed by a linear beam splitter (n=1).

PMID- 12484981
TI  - Practical scheme for quantum computation with any two-qubit entangling gate.
AB  - Which gates are universal for quantum computation? Although it is well known that
      certain gates on two-level quantum systems (qubits), such as the controlled-not,
      are universal when assisted by arbitrary one-qubit gates, it has only recently
      become clear precisely what class of two-qubit gates is universal in this sense.
      We present an elementary proof that any entangling two-qubit gate is universal
      for quantum computation, when assisted by one-qubit gates. A proof of this result
      for systems of arbitrary finite dimension has been provided by Brylinski and
      Brylinski; however, their proof relies on a long argument using advanced
      mathematics. In contrast, our proof provides a simple constructive procedure
      which is close to optimal and experimentally practical.

PMID- 12484982
TI  - Nanomechanics of microtubules.
AB  - We have determined the mechanical anisotropy of a single microtubule by
      simultaneously measuring the Young's and the shear moduli in vitro. This was
      achieved by elastically deforming the microtubule deposited on a substrate
      tailored by electron-beam lithography with a tip of an atomic force microscope.
      The shear modulus is 2 orders of magnitude lower than the Young's, giving rise to
      a length-dependent flexural rigidity of microtubules. The temperature dependence
      of the microtubule's bending stiffness in the (5-40) degrees C range shows a
      strong variation upon cooling coming from the increasing interaction between the
      protofilaments.

PMID- 12484983
TI  - Stretching single stranded DNA, a model polyelectrolyte.
AB  - The elastic properties of single stranded (ss)DNA, studied by pulling on an
      isolated molecule, are shown to agree with a recent model of ssDNA that takes
      into account base pairings and screened electrostatic repulsion of the
      phosphodiester backbone. By an appropriate physicochemical treatment, the pairing
      interactions were suppressed and ssDNA used as an experimental model for a
      generic polyelectrolyte. The elastic behavior of such an altered ssDNA deviates
      strongly from the behavior of an ideal polymer. This deviation is shown to result
      from the elasticity of the chain and its electrostatic self-avoiding
      interactions.

PMID- 12484984
TI  - Simple approach for charge renormalization in highly charged macroions.
AB  - We revisit the notion of renormalized charge, which is a concept of central
      importance in the field of highly charged colloidal or polyelectrolyte solutions.
      Working at the level of a linear Debye-Huckel-like theory only, we propose a
      versatile method to predict the saturated amount of charge renormalization, which
      is, however, a nonlinear effect arising at strong electrostatic coupling. The
      results are successfully tested against nonlinear Poisson-Boltzmann theory for
      polyions of various shapes (planar, cylindrical, and spherical), both in the
      infinite dilution limit or in confined geometry, with or without added
      electrolyte. Our approach, accurate for monovalent microions in solvents such as
      water, is finally confronted against experimental results on charged colloids and
      B-DNA solutions.

PMID- 12484985
TI  - Dynamics of spiral waves under phase feedback control in a Belousov-Zhabotinsky
      reaction.
AB  - Feedback control of spiral waves by the phases of the spiral tip is investigated
      experimentally in a light-sensitive Belousov-Zhabotinsky reaction. The phases of
      rotation (Psi(r)) and meandering (Psi(m)) of the spiral tip are obtained in real
      time during experiments. It is found that, for both meandering and rigid rotating
      spirals, one can manipulate the spirals to move with any arbitrary paths by the
      feedback signals derived from Psi(r). Synchronization between meandering and
      rotation dynamics can be induced when both Psi(m) and Psi(r) are used
      simultaneously as control signals. Experimental findings are compared well with
      numerical simulations of the Oregonator model.

PMID- 12484986
TI  - Nanostructured cellular networks.
AB  - Au nanocrystals spin-coated onto silicon from toluene form cellular networks. A
      quantitative statistical crystallography analysis shows that intercellular
      correlations drive the networks far from statistical equilibrium. Spin-coating
      from hexane does not produce cellular structure, yet a strong correlation is
      retained in the positions of nanocrystal aggregates. Mechanisms based on
      Marangoni convection alone cannot account for the variety of patterns observed,
      and we argue that spinodal decomposition plays an important role in foam
      formation.

PMID- 12484987
TI  - Theory of nonlinear rheology and yielding of dense colloidal suspensions.
AB  - A first-principles approach to the nonlinear flow of dense suspensions is
      presented which captures shear thinning of colloidal fluids and dynamical
      yielding of colloidal glasses. The advection of density fluctuations plays a
      central role, suppressing the caging of particles and speeding up structural
      relaxation. A mode coupling approach is developed to explore these effects.

PMID- 12484988
TI  - Optimal network topologies for local search with congestion.
AB  - The problem of searchability in decentralized complex networks is of great
      importance in computer science, economy, and sociology. We present a formalism
      that is able to cope simultaneously with the problem of search and the congestion
      effects that arise when parallel searches are performed, and we obtain
      expressions for the average search cost both in the presence and the absence of
      congestion. This formalism is used to obtain optimal network structures for a
      system using a local search algorithm. It is found that only two classes of
      networks can be optimal: starlike configurations, when the number of parallel
      searches is small, and homogeneous-isotropic configurations, when it is large.

PMID- 12484989
TI  - Limit cycles in quantum theories.
AB  - Renormalization group limit cycles and more chaotic behavior may be commonplace
      for quantum Hamiltonians requiring renormalization, in contrast to experience
      based on classical models with critical behavior, where fixed points are far more
      common. We discuss the simplest quantum model Hamiltonian identified so far that
      exhibits a renormalization group with both limit cycle and chaotic behavior. The
      model is a discrete Hermitian matrix with two coupling constants, both governed
      by a nonperturbative renormalization group equation that involves changes in only
      one of these couplings and is soluble analytically.

PMID- 12484990
TI  - Fluctuations of fluctuation-induced casimir-like forces.
AB  - The force experienced by objects embedded in a correlated medium undergoing
      thermal fluctuations-the so-called fluctuation-induced force-is actually itself a
      fluctuating quantity. Using a scalar field model, we compute the corresponding
      probability distribution and show that it is a Gaussian centered on the well
      known Casimir force, with a nonuniversal standard deviation that can be typically
      as large as the mean force itself. The relevance of these results to the
      experimental measurement of fluctuation-induced forces in soft condensed matter
      is discussed, as well as the influence of the finite temporal resolution of the
      measuring apparatus.

PMID- 12484991
TI  - Noise-induced transport with low randomness.
AB  - We study the transport of overdamped Brownian particles in periodic potentials
      subject to a spatially modulated Gaussian white noise. We derive an analytical
      expression for the diffusion coefficient of particles. By means of velocity,
      diffusion coefficient, and their ratio (Peclet number) we discuss (a) symmetric
      potential and modulation of noise intensity and (b) a ratchet profile with strong
      noise modulation. It is shown that state dependent fluctuations may not only
      induce directed transport, but also a pronounced coherence of transport if the
      potential exhibits a strong asymmetry.

PMID- 12484992
TI  - Optical clock with ultracold neutral atoms.
AB  - We demonstrate how to realize an optical clock with neutral atoms that is
      competitive to the currently best single ion optical clocks in accuracy and
      superior in stability. Using ultracold atoms in a Ca optical frequency standard,
      we show how to reduce the relative uncertainty to below 10(-15). We observed atom
      interferences for stabilization of the laser to the clock transition with a
      visibility of 0.36, which is 70% of the ultimate limit achievable with atoms at
      rest. A novel scheme was applied to detect these atom interferences with the
      prospect to reach the quantum projection noise limit at an exceptional low
      instability of 4 x 10(-17) in 1 s.

PMID- 12484993
TI  - r-Process nucleosynthesis without excess neutrons.
AB  - Matter expanding sufficiently rapidly and at high enough entropy per nucleon can
      enter a heavy-element synthesis regime heretofore unexplored. In this extreme
      regime, more similar to nucleosynthesis in the early universe than to that
      typical in stellar explosive environments, there is a persistent disequilibrium
      between free nucleons and abundant alpha particles, which allows heavy r-process
      nucleus production even in matter with more protons than neutrons. This
      observation bears on the issue of the site of the r process, on the variability
      of abundance yields from r-process events, and on constraints on neutrino physics
      derived from nucleosynthesis.

PMID- 12484994
TI  - Measuring neutron-star radii with gravitational-wave detectors.
AB  - Coalescing binary neutron stars (NS) are expected to be an important source of
      gravitational waves (GW) detectable by laser interferometers. We present here a
      simple method for determining the compactness ratio M/R of NS based on the
      observed deviation of the GW energy spectrum from point-mass behavior at the end
      of inspiral. Our method is based on the properties of quasiequilibrium binary NS
      sequences and does not require the computation of the full GW signal h(t).
      Combined with the measurement of the NS masses during inspiral, the determination
      of M/R will allow very strong constraints to be placed on the equation of state
      of dense nuclear matter.

PMID- 12484995
TI  - Observational bounds on quantum gravity signals using existing data.
AB  - We consider a new set of effects arising from the quantum gravity corrections to
      the propagation of fields, associated with fluctuations of the spacetime
      geometry. Using already existing experimental data, we can put bounds on these
      effects that are more stringent by several orders of magnitude than those
      expected to be obtained in astrophysical observations. In fact, these results can
      already be interpreted as questioning the whole scenario of linear (in l(P))
      corrections to the dispersion relations for free fields in Lorentz violating
      theories.

PMID- 12484996
TI  - CP violation in neutrino oscillation and leptogenesis.
AB  - We study the correlation between CP violation in neutrino oscillations and
      leptogenesis in the framework with two heavy Majorana neutrinos and three light
      neutrinos. Among three unremovable CP phases, a heavy Majorana phase contributes
      to leptogenesis. We show how the heavy Majorana phase contributes to Jarlskog
      determinant J as well as neutrinoless double beta decay by identifying a low
      energy CP-violating phase which signals the CP-violating phase for leptogenesis.
      For some specific cases of the Dirac mass term of neutrinos, a direct relation
      between lepton number asymmetry and J is obtained. We also study the effect
      coming from the phases which are not related to leptogenesis.

PMID- 12484997
TI  - CPT violation implies violation of Lorentz invariance.
AB  - A interacting theory that violates CPT invariance necessarily violates Lorentz
      invariance. On the other hand, CPT invariance is not sufficient for out-of-cone
      Lorentz invariance. Theories that violate CPT by having different particle and
      antiparticle masses must be nonlocal.

PMID- 12484999
TI  - Direct CP violation in B-->phiKs and new physics.
AB  - In the presence of large new physics contributions to loop-induced b-->s
      transitions, sizable direct CP violation in B-->phiK decays is expected on
      general grounds. We compute explicitly CP-violating effects using QCD
      factorization and find that, even in the restricted case in which new physics has
      the same penguin structure as the standard model, the rate asymmetry can be of
      the order of 1. We briefly discuss a more general scenario and comment on the
      inclusion of power-suppressed corrections to factorization.

PMID- 12485000
TI  - CP asymmetry in B-->phiK(S) decays in left-right models and its implications for
      Bs decays.
AB  - In left-right models the gluonic penguin contribution to b-->ss;s transition is
      enhanced by m(t)/m(b) due to the presence of (V+A) currents and by large values
      of loop functions. Together those effects may overcome the suppression due to the
      small left-right mixing angle xi less, similar 0.013. Two independent new phases
      in the B-->phiK(S) decay amplitude appearing in a large class of left-right
      models can modify the time-dependent CP asymmetry in this decay mode by O(1) and
      explain the recent BABAR and Belle CP asymmetry measurements in this channel.
      This scenario implies observable deviations from the standard model also in B(s)
      decays which could be measured at Tevatron and LHC.

PMID- 12485002
TI  - Control of light pulse propagation with only a few cold atoms in a high-finesse
      microcavity.
AB  - Propagation of a light pulse through a high-Q optical microcavity containing a
      few cold atoms (N<10) in its cavity mode is investigated experimentally. With
      less than ten cold rubidium atoms launched into an optical microcavity, up to 170
      ns propagation lead time ("superluminal"), and 440 ns propagation delay time
      (subluminal) are observed. Comparison of the experimental data with numerical
      simulations as well as future experiments are discussed.

PMID- 12484998
TI  - Radiative B meson decays into kpigamma and kpipigamma final states.
AB  - We report observations of radiative B meson decays into the K+pi(-)gamma and
      K+pi(-)pi(+)gamma final states. In the B0-->K+pi(-)gamma channel, we present
      evidence for decays via an intermediate tensor meson state with a branching
      fraction of B(B0-->K(*)(2)(1430)(0)gamma)=[1.3+/-0.5(stat)+/-0.1(syst)]x10(-5).
      We measure the branching fraction B(B+-->K+pi(-)pi(+)gamma)=[2.4+/-0.5(stat) +0.4
      0.2(syst)]x10(-5), in which the B+-->K(*0)pi(+)gamma and B+-->K+rho(0)gamma
      channels dominate. The analysis is based on a data set of 29.4 fb(-1) recorded by
      the Belle experiment at the KEKB collider.

PMID- 12485003
TI  - Theory of time-resolved photoelectron imaging: nonperturbative calculation for an
      internally converting polyatomic molecule.
AB  - We present the first calculation of time-resolved photoelectron angular
      distributions for a polyatomic system. Our method takes rotations into exact
      account, treats the laser field nonperturbatively, and computes the electronic
      dynamics from first principles. Our results point to the information content of
      time-resolved photoelectron imaging observables and illustrate the role played by
      the field intensity.

PMID- 12485004
TI  - Theory for the optimal control of time-averaged quantities in quantum systems.
AB  - We present a variational theory for the optimal control of quantum systems with
      relaxation over a finite time interval. In our approach, which is a nontrivial
      generalization of previous formulations and which contains them as limiting
      cases, the optimal control field fulfills a high-order Euler-Lagrange
      differential equation, which guarantees the uniqueness of the solution. We solve
      this equation numerically and also analytically for some limiting cases. The
      theory is applied to two-level quantum systems with relaxation, for which we
      determine quantitatively how relaxation effects limit the control of the system.

PMID- 12485005
TI  - Controlling the cold collision shift in high precision atomic interferometry.
AB  - We present a new method based on a transfer of population by adiabatic passage
      that allows one to prepare cold atomic samples with a well-defined ratio of
      atomic density and atom number. This method is used to perform a measurement of
      the cold collision frequency shift in a laser cooled cesium clock at the percent
      level, which makes the evaluation of the cesium fountain accuracy at the 10(-16)
      level realistic. With improvements, the adiabatic passage would allow
      measurements of density-dependent phase shifts at the 10(-3) level in high
      precision experiments.

PMID- 12485001
TI  - Observation of D+(s)K- and evidence for D+(s)pi- final states in neutral B
      decays.
AB  - We report the first observation of a B meson decay that is not accessible by a
      direct spectator process. The channel B(0)-->D(+)(s)K- is found in a sample of 85
      x 10(6) BB; events, collected with the Belle detector at KEKB, with a branching
      fraction B(B(0)-->D(+)(s)K-)=(4.6(+1.2)(-1.1)+/-1.3) x 10(-5). We also obtain
      evidence for the B0-->D(+)(s)pi(-) decay with branching fraction B(B0-
      >D(+)(s)pi(-))=(2.4(+1.0)(-0.8)+/-0.7) x 10(-5). This value may be used to
      extract a model-dependent value of |V(ub)|.

PMID- 12485006
TI  - Driven production of cold antihydrogen and the first measured distribution of
      antihydrogen states.
AB  - Cold antihydrogen is produced when antiprotons are repeatedly driven into
      collisions with cold positrons within a nested Penning trap. Efficient
      antihydrogen production takes place during many cycles of positron cooling of
      antiprotons. A first measurement of a distribution of antihydrogen states is made
      using a preionizing electric field between separated production and detection
      regions. Surviving antihydrogen is stripped in an ionization well that captures
      and stores the freed antiproton for background-free detection.

PMID- 12485007
TI  - Efficient two-photon light amplification by a coherent biexciton wave.
AB  - A reversible coupling between photon pair states and a long-lived, highly
      coherent biexciton wave in CuCl allows efficient phase-sensitive two-photon
      amplification or attenuation of ultrashort light pulses. We demonstrate a gain of
      350 cm(-1) for a pump intensity of 1 MW/cm(2), nearly 2 orders of magnitude
      higher than that achievable with conventional parametric crystal amplifiers. We
      develop a theoretical model that describes this new type of parametric converter
      where the light pump is replaced by a coherent biexciton wave and show that it is
      well suited for the generation of entangled photons and the squeezing of an
      optical beam with ultrafast time gating.

PMID- 12485008
TI  - Efficient source of single photons: a single quantum dot in a micropost
      microcavity.
AB  - We have demonstrated efficient production of triggered single photons by coupling
      a single semiconductor quantum dot to a three-dimensionally confined optical mode
      in a micropost microcavity. The efficiency of emitting single photons into a
      single-mode traveling wave is approximately 38%, which is nearly 2 orders of
      magnitude higher than for a quantum dot in bulk semiconductor material. At the
      same time, the probability of having more than one photon in a given pulse is
      reduced by a factor of 7 as compared to light with Poissonian photon statistics.

PMID- 12485009
TI  - Curvature instability in passive diffractive resonators.
AB  - We study the stability of localized structures in a passive optical bistable
      system. We show that there is a critical value of the input field intensity above
      which localized structures are unstable with respect to a curvature instability.
      Beyond this instability boundary, a transition from the localized branch of
      solutions to stable hexagons is found.

PMID- 12485010
TI  - Discrete breathers in two-dimensional Josephson-junction arrays.
AB  - We have proposed theoretically and studied numerically the existence of discrete
      breathers (intrinsic localized modes) in the dynamics of a two-dimensional
      Josephson-junction array biased by radio-frequency fields. The solutions are
      linearly stable in the framework of the Floquet theory and robust in the presence
      of thermal fluctuations. We have also discussed the conditions for realizing an
      experimental detection of these modes.

PMID- 12485011
TI  - Bi-laplacian growth patterns in disordered media.
AB  - Experiments in quasi-two-dimensional geometry (Hele-Shaw cells) in which a fluid
      is injected into a viscoelastic medium (foam, clay, or associating polymers) show
      patterns akin to fracture in brittle materials, very different from standard
      Laplacian growth patterns of viscous fingering. An analytic theory is lacking
      since a prerequisite to describing the fracture of elastic material is the
      solution of the bi-Laplace rather than the Laplace equation. In this Letter we
      close this gap, offering a theory of bi-Laplacian growth patterns based on the
      method of iterated conformal maps.

PMID- 12485012
TI  - Active versus passive scalar turbulence.
AB  - Active and passive scalars transported by an incompressible two-dimensional
      conductive fluid are investigated. It is shown that a passive scalar displays a
      direct cascade towards the small scales while the active magnetic potential
      builds up large-scale structures in an inverse cascade process. Correlations
      between scalar input and particle trajectories are found to be responsible for
      those dramatic differences as well as for the behavior of dissipative anomalies.

PMID- 12485013
TI  - Time-resolved phase measurement of a self-amplified free-electron laser.
AB  - We report on the first time-resolved phase measurement on self-amplified
      spontaneous emission (SASE) free-electron laser (FEL) pulses. We observed that
      the spikes in the output of such free-electron laser pulses have an intrinsic
      positive chirp. We also observed that the energy chirp in the electron bunch
      mapped directly into the FEL output. Under certain conditions, the two chirps
      cancel each other. The experimental result was compared with simulations and
      interpreted with SASE theory.

PMID- 12485014
TI  - Sustained stabilization of the resistive-wall mode by plasma rotation in the DIII
      D tokamak.
AB  - Values of the normalized plasma pressure up to twice the free-boundary stability
      limit predicted by ideal magnetohydrodynamic (MHD) theory have been sustained in
      the DIII-D tokamak. Long-wavelength modes are stabilized by the resistive wall
      and rapid plasma toroidal rotation. High rotation speed is maintained by
      minimization of nonaxisymmetric magnetic fields, overcoming a long-standing
      impediment [E. J. Strait, Phys. Rev. Lett. 74, 2483 (1995)]]. The ideal-MHD
      pressure limit calculated with an ideal wall is observed as the operational limit
      to the normalized plasma pressure.

PMID- 12485015
TI  - Ion acceleration during reconnection in MAST.
AB  - Spontaneous acceleration of ions to suprathermal energies is observed during
      magnetic reconnection in the Mega-Ampere Spherical Tokamak (MAST). A high-energy
      tail is observed in the ion-distribution function following each internal
      reconnection event in Ohmic discharges. This phenomenon is explained in terms of
      runaway ion acceleration in the electric field induced by the reconnection.

PMID- 12485016
TI  - Atomic scale mechanism of the transformation of gamma-alumina to theta-alumina.
AB  - gamma-alumina is known to transform to theta-alumina and finally to alpha-alumina
      upon thermal treatment with a catastrophic loss of porosity and catalytic
      activity. First-principles calculations were performed to investigate the atomic
      scale mechanism of the gamma- to theta-alumina transformation. The transformation
      pathways between the two different forms have been mapped out and identified as a
      sequence of Al cation migrations. Different possible Al migration paths may be
      responsible for the experimentally observed formation of domains and twins in
      theta-alumina. The estimated temperature dependence of the conversion rate is in
      excellent agreement with the experimental transformation temperature.

PMID- 12485017
TI  - Self-assembly of nanometer-scale magnetic dots with narrow size distributions on
      an insulating substrate.
AB  - The self-assembly of iron dots on the insulating surface of NaCl(001) is
      investigated experimentally and theoretically. Under proper growth conditions,
      nanometer-scale magnetic iron dots with remarkably narrow size distributions can
      be achieved in the absence of a wetting layer. Furthermore, both the vertical and
      lateral sizes of the dots can be tuned with the iron dosage without introducing
      apparent size broadening, even though the clustering is clearly in the strong
      coarsening regime. These observations are interpreted using a phenomenological
      mean-field theory, in which a coverage-dependent optimal dot size is selected by
      strain-mediated dot-dot interactions.

PMID- 12485018
TI  - Structure characterization and mechanism of growth of PbTe nanocrystals embedded
      in a silicate glass.
AB  - A nanocomposite consisting of PbTe nanocrystals embedded in a silicate glass was
      studied by small-angle x-ray scattering during the early stage of isothermal
      annealing at 793 K. A theoretical function based on a model of spherical PbTe
      nanocrystals surrounded by a Pb and Te depleted shell fits well to all
      experimental curves. The time dependences of the nanocrystal radius and size of
      the depleted shell agree with the prediction of the theory of nucleation and
      growth by the classical mechanism of atomic diffusion.

PMID- 12485019
TI  - Large local deflections of a dynamic crack front induced by intrinsic
      dislocations in brittle single crystals.
AB  - We show that intrinsic dislocations in brittle single crystals can be a source of
      strong local perturbations along the crack path. A theoretical model was
      developed which predicts substantial crack front deflections. Investigating the
      crack surfaces in Si crystals with induced dislocation density of 10(9)-10(10)
      cm(-2) revealed a significant amount of crack front perturbations in the form of
      V-shaped grooves, which were completely missing in dislocation-free Si specimens.
      The measured depths of the perturbations were in the range of 2-20 nm and in
      excellent agreement with the theoretical model.

PMID- 12485020
TI  - Hydrodynamics of binary fluid phase segregation.
AB  - Starting with the Vlasov-Boltzmann equation for a binary fluid mixture, we derive
      an equation for the velocity field u when the system is segregated into two
      phases (at low temperatures) with a sharp interface between them. u satisfies the
      incompressible Navier-Stokes equations together with a jump boundary condition
      for the pressure across the interface which, in turn, moves with a velocity given
      by the normal component of u. Numerical simulations of the Vlasov-Boltzmann
      equations for shear flows parallel and perpendicular to the interface in a phase
      segregated mixture support this analysis. We expect similar behavior in real
      fluid mixtures.

PMID- 12485021
TI  - Element specific surface reconstructions of islands during surfactant-mediated
      growth on Si (111).
AB  - The early stages of surfactant- (As, Sb) mediated homoepitaxial growth on Si
      (111) are examined by scanning tunneling microscopy and extensive ab initio
      calculations of Si(n) clusters (n</=12). The results reveal the different
      microscopic behavior of the two surfactants: On As-covered Si (111), one
      exclusively finds two-dimensional islands with double-layer height which show the
      (1 x 1) terrace structure. On Sb-covered Si (111), the islands show two different
      reconstructions: at the rim of the islands a (1 x 1) structure appears, while in
      the center the (square root 3 x square root 3) terrace structure is observed.

PMID- 12485022
TI  - Ground-state phase diagram of a half-filled one-dimensional extended hubbard
      model.
AB  - The density-matrix renormalization group is used to study the phase diagram of
      the one-dimensional half-filled Hubbard model with on-site (U) and nearest
      neighbor (V) repulsion and hopping t. A critical line V(c)(U) approximately U/2
      separates a Mott insulating phase from a charge-density-wave phase. The formation
      of bound charge excitations for V>2t changes the phase transition from continuous
      to first-order at a tricritical point U(t) approximately 3.7t, V(t)=2t. A
      frustrating effective antiferromagnetic spin coupling induces a bond-order-wave
      phase on the critical line V(c)(U) for U(t)<U less, similar 7t.

PMID- 12485023
TI  - Pseudogaps in an incoherent metal.
AB  - How are the properties of a metal changed by strong inelastic scattering? We
      investigate this question within the two-dimensional t-J model using extended
      dynamical mean field theory and a generalized noncrossing approximation. Short
      ranged antiferromagnetic fluctuations lead to a strongly incoherent single
      particle dynamics, large entropy, and resistance. Close to the Mott transition at
      low hole doping a pseudogap opens, accompanied by a drop in resistivity and an
      increase in the Hall constant for both lower temperatures T and doping levels.
      The behavior obtained bears surprising similarity to properties of the cuprates.

PMID- 12485024
TI  - Extremely small energy gap in the quasi-one-dimensional conducting chain compound
      SrNbO3.41.
AB  - Resistivity, optical, and angle-resolved photoemission experiments reveal unusual
      one-dimensional electronic properties of highly anisotropic SrNbO3.41. Along the
      conducting chain direction, we find an extremely small energy gap of only a few
      meV at the Fermi level. A discussion in terms of typical 1D instabilities
      (Peierls, Mott-Hubbard) shows that neither seems to provide a satisfactory
      explanation for the unique properties of SrNbO3.41.

PMID- 12485025
TI  - Electronic interactions in the expanded metal compound Li-NH3.
AB  - Inelastic x-ray scattering was used to measure the plasmon as a function of
      electron density in liquid lithium ammonia as well as the low temperature solid
      phase. As the electronic density is lowered, electronic correlation effects cause
      the random-phase approximation (RPA) to break down, requiring more advanced
      theoretical treatments. The deviation from RPA becomes greatest at the lowest
      electronic densities. We also see evidence for decreased electronic screening as
      shown by an increase in the strength of the pseudopotential at lower
      concentrations. Plasmon behavior in the solid is similar to that of the heavier
      alkali metals, but surprisingly different than in the liquid.

PMID- 12485026
TI  - Precession and motional slowing of spin evolution in a high mobility two
      dimensional electron gas.
AB  - Optical spin-dynamic measurements in a high-mobility n-doped GaAs/AlGaAs quantum
      well show oscillatory evolution at 1.8 K consistent with a quasi-collision-free
      D'yakonov-Perel'-Kachorovskii regime. Above 5 K evolution becomes exponential as
      expected for collision-dominated spin dynamics. Momentum scattering times
      extracted from Hall mobility and Monte Carlo simulation of spin polarization
      agree at 1.8 K but diverge at higher temperatures, indicating the importance of
      electron-electron scattering and an intrinsic upper limit for the spin-relaxation
      rate.

PMID- 12485027
TI  - Coulomb blockade with dispersive interfaces.
AB  - What quantity controls the Coulomb blockade oscillations if the dot-lead
      conductance is essentially frequency dependent? We argue that it is the
      conductance at the imaginary frequency given by the effective charging energy.
      The latter may be very different from the bare charging energy due to the
      interface-induced capacitance (or inductance). These observations are supported
      by a number of examples, considered from the weak and strong coupling
      (perturbation theory versus instanton calculus) perspectives.

PMID- 12485028
TI  - Electronic density oscillations in gold atomic chains assembled atom by atom.
AB  - Linear Au chains two to 20 atoms long were constructed on a NiAl(110) surface via
      the manipulation of single atoms with a scanning tunneling microscope.
      Differential conductance (dI/dV) images of these chains reveal one-dimensional
      electronic density oscillations at energies 1.0 to 2.5 eV above the Fermi energy.
      The origin of this delocalized electronic structure is traced to the existence of
      an electronic resonance measured on single, isolated Au atoms. Variations in the
      wavelength in dI/dV images of an eleven-atom chain taken at different energies
      revealed an effective electronic mass of 0.4+/-0.1 times the mass of a free
      electron.

PMID- 12485029
TI  - New type of vortex pinning structure effective at very high magnetic fields.
AB  - We report on a new type of correlated nanometer-scale pinning structure observed
      in a melt-processed (Nd0.33Eu0.38Gd0.28)Ba(2)Cu(3)O(y) (NEG-123). It consists of
      NEG/Ba-rich clusters in the stoichiometric NEG-123 matrix forming a lamellar
      array with a period of a few nanometers. These lamellas appear within regular
      twins, thus representing their fine substructure-sometimes straight, sometimes
      wavy. This new material structure correlates well with the significant
      enhancement of pinning at high fields, represented by irreversibility field above
      14 T at 77 K (B parallel c). We believe that the new pinning medium enables one
      to significantly broaden the limits for high-field applications.

PMID- 12485030
TI  - Ehrenfest-time-dependent excitation gap in a chaotic Andreev billiard.
AB  - A semiclassical theory is developed for the appearance of an excitation gap in a
      ballistic chaotic cavity connected by a point contact to a superconductor.
      Diffraction at the point contact is a singular perturbation in the limit variant
      Planck's over 2pi -->0, which opens up a gap E(gap) in the excitation spectrum.
      The time scale variant Planck's over 2pi /E(gap) proportional, variant alpha(
      1)ln( variant Planck's over 2pi (with alpha the Lyapunov exponent) is the
      Ehrenfest time, the characteristic time scale of quantum chaos.

PMID- 12485031
TI  - Nernst coefficient and magnetoresistance in high-T(c) superconductors: the role
      of superconducting fluctuations.
AB  - In high-T(c) cuprates, the Nernst coefficient (nu) as well as the
      magnetoresistance (Deltarho/rho) increases drastically below the pseudogap
      temperature, T(*), which attracts much attention as a key phenomenon in the
      pseudogap region. We study these transport phenomena in terms of the fluctuation
      exchange+T-matrix approximation. In this present theory, the d-wave
      superconducting (SC) fluctuations, which are mediated by antiferromagnetic (AF)
      correlations, become dominant below T(*). We especially investigate the vertex
      corrections both for the charge current and the heat one to keep the conservation
      laws. As a result, the mysterious behaviors of nu and Deltarho/rho are naturally
      explained as the reflection of the enhancement of the SC fluctuation, without
      assuming thermally excited vortices. The present result suggests that the
      pseudogap phenomena are well described in terms of the Fermi liquid with AF and
      SC fluctuations.

PMID- 12485032
TI  - Reentrant vortex lattice transformation in fourfold symmetric superconductors.
AB  - The physics behind the rhombic-->square-->rhombic flux line lattice
      transformation in increasing fields is clarified on the basis of Eilenberger
      theory. We demonstrate that this reentrance observed in LuNi2B2C is due to
      intrinsic competition between the superconducting gap and Fermi surface
      anisotropies. The calculations not only reproduce it but also predict the not yet
      found lock-in transition to a square lattice with different orientation in a
      higher field. In view of the physical origin given, this sequence of transitions
      is rather generic to occur in fourfold symmetric superconductors.

PMID- 12485033
TI  - Free energy and torque for superconductors with different anisotropies of H(c2)
      and lambda.
AB  - The free energy is evaluated for a uniaxial superconductor with the anisotropy of
      the upper critical field, gamma(H)=H(c2,a)/H(c2,c), different from the anisotropy
      of the penetration depth gamma(lambda)=lambda(c)/lambda(a). With increasing
      difference between gamma(H) and gamma(lambda), the equilibrium orientation of the
      crystal relative to the applied field may shift from theta=pi/2 (theta is the
      angle between the field and the c axis) to lower angles and reach theta=0 for
      large enough gamma(H). These effects are expected to take place in MgB2.

PMID- 12485034
TI  - Imaging the magnetic spin structure of exchange-coupled thin films.
AB  - We have investigated the magnetic spin structure of a soft-magnetic film that is
      exchange-coupled to a hard-magnetic layer to form an exchange-spring layer
      system. The depth dependence of the magnetization direction was determined by
      nuclear resonant scattering of synchrotron radiation from ultrathin 57Fe probe
      layers. In an external field a magnetic spiral structure forms that can be
      described within a one-dimensional micromagnetical model. The experimental method
      allows one to image vertical spin structures in stratified media with
      unprecedented accuracy.

PMID- 12485035
TI  - Time-resolved measurement of propagating spin waves in ferromagnetic thin films.
AB  - We measure the propagation of spatially localized spin waves in NiFe thin films
      through local inductive detection of the dynamic magnetization. A pulsed magnetic
      field excites a linear superposition of spin wave modes with a distribution that
      is predominantly driven by the spatial dependence of the in-plane excitation
      field. The results of numerical micromagnetic calculations exhibit excellent
      agreement with experiment and show that a comprehensive account of spatial
      nonuniformity and propagation is necessary to accurately measure the intrinsic
      damping rate.

PMID- 12485036
TI  - Intrinsic inhomogeneities in manganite thin films investigated with scanning
      tunneling spectroscopy.
AB  - Thin films of La0.7Sr0.3MnO3 on MgO show a metal insulator transition and
      colossal magnetoresistance. The shape of this transition can be explained by
      intrinsic spatial inhomogeneities, which give rise to a domain structure of
      conducting and insulating domains at the submicrometer scale. These domains then
      undergo a percolation transition. The tunneling conductance and tunneling gap
      measured by scanning tunneling spectroscopy were used to distinguish and
      visualize these domains.

PMID- 12485037
TI  - First-order phase transition and phase coexistence in a spin-glass model.
AB  - We study the mean-field static solution of the Blume-Emery-Griffiths-Capel model
      with quenched disorder, an Ising-spin lattice gas with random magnetic
      interaction. The thermodynamics is worked out in the full replica symmetry
      breaking scheme. The model exhibits a high temperature/low density paramagnetic
      phase. As temperature decreases or density increases, a phase transition to a
      full replica symmetry breaking spin-glass phase occurs. The nature of the
      transition can be either of the second order or, at temperature below a given
      critical value, of the first order in the Ehrenfest sense, with a discontinuous
      jump of the order parameter, a latent heat, and coexistence of phases.

PMID- 12485038
TI  - Magnetization-direction-dependent local electronic structure probed by scanning
      tunneling spectroscopy.
AB  - Scanning tunneling spectroscopy (STS) of thin Fe films on W(110) shows that the
      electronic structure of domains and domain walls is different. This experimental
      result is explained on the basis of first-principles calculations. A detailed
      analysis reveals that the spin-orbit induced mixing between minority d(xy+xz) and
      minority d(z(2)) spin states depends on the magnetization direction and changes
      the local density of states in the vacuum detectable by STS. As a consequence
      nanometer-scale magnetic structure information is obtained even by using
      nonmagnetic probe tips.

PMID- 12485039
TI  - Correlated vibrational dynamics revealed by two-dimensional infrared
      spectroscopy.
AB  - Two-dimensional infrared (2D IR) spectroscopy has been used to monitor the
      solvent-induced correlated fluctuations in the transition energies of two coupled
      vibrations. The elongation of diagonal and cross peaks in a 2D IR correlation
      spectrum reflects the degree of inhomogeneity in the individual transition
      energies and the correlation between them. Changes in the 2D line shapes as a
      function of a variable waiting period have been successfully reproduced by a
      correlated spectral diffusion model.

PMID- 12485040
TI  - Experimental measurement of the dynamic photothermal effect in Fabry-Perot
      cavities for gravitational wave detectors.
AB  - We report the experimental observation of the frequency dependence of the
      photothermal effect. The measurements are performed by modulating the laser power
      absorbed by the mirrors of two high-finesse Fabry-Perot cavities. The results are
      very well described by a recently proposed theoretical model [M. Cerdonio, L.
      Conti, A. Heidmann, and M. Pinard, Phys. Rev. D 63, 082003 (2001)]], confirming
      the correctness of such calculations. Our observations and quantitative
      characterization of the dynamic photothermal effect demonstrate its critical
      importance for interferometric displacement measurements towards the quantum
      limit, as those necessary for gravitational wave detection.

PMID- 12485041
TI  - Quantum interference of virtual and real amplitudes in a semiconductor exciton
      system.
AB  - By two-color pulse shaping, we simultaneously create virtual and real amplitudes
      for excitons in GaAs quantum wells, and monitor population and amplitude by pump
      probe and four-wave mixing spectroscopies. Excited-state probability amplitude
      can be induced by the off-resonant, virtual excitations as well as by the
      resonant, real excitations. Population modulation in time-domain results from the
      interference between the virtual and real amplitudes, and the modulation depth
      reveals the relative contributions of these two amplitudes. The fact that virtual
      and real amplitudes have a phase difference of 90 degrees is demonstrated
      directly in time-domain.

PMID- 12485042
TI  - Dephasing of atomic tunneling by nuclear quadrupoles.
AB  - Recent experiments revealed a most surprising magnetic-field dependence of
      coherent echoes in amorphous solids. We show that a novel dephasing mechanism
      involving nuclear quadrupole moments is the origin of the observed phenomena.

PMID- 12485043
TI  - Quasideterministic generation of entangled atoms in a cavity.
AB  - We present a scheme to generate a maximally entangled state of two three-level
      atoms in a cavity. The success or failure of the generation of the desired
      entangled state can be determined by detecting the polarization of the photon
      leaking out of the cavity. With the use of an automatic feedback, the success
      probability of the scheme can be made to approach unity.

PMID- 12485045
TI  - Morphology selection of nanoparticle dispersions by polymer media.
AB  - Designable media can control properties of nanocomposite materials by spatially
      organizing nanoparticles. Here we theoretically study particle organization by
      ultrathin polymer films of grafted chains ("brushes"). Polymer-soluble
      nanoparticles smaller than a brush-determined threshold disperse in the film to a
      depth scaling inversely with particle volume. In the polymer-insoluble case,
      aggregation is directed: provided particles are nonwetting at the film surface,
      the brush stabilizes the dispersion and selects its final morphology of giant
      elongated aggregates with a brush-selected width.

PMID- 12485044
TI  - Noise-enhanced human balance control.
AB  - Noise can enhance the detection and transmission of weak signals in certain
      nonlinear systems, via a mechanism known as stochastic resonance. Here we show
      that input noise can be used to improve motor control in humans. Specifically, we
      show that the postural sway of both young and elderly individuals during quiet
      standing can be significantly reduced by applying subsensory mechanical noise to
      the feet. We further demonstrate with input noise a trend towards the reduction
      of postural sway in elderly subjects to the level of young subjects. These
      results suggest that noise-based devices, such as randomly vibrating shoe
      inserts, may enable people to overcome functional difficulties due to age-related
      sensory loss.

PMID- 12485046
TI  - Giant hexagonal superstructures in diblock-copolymer membranes.
AB  - We have observed polymersomes of high genus with their vesicle wall organized on
      the micrometer scale either in a double bilayer connected by a lattice of
      passages or a tubular network with hexagonal symmetry. Experimentally found shape
      classes are identified within a theoretical phase diagram based on the bending
      energy of the polymer membrane. Pronounced morphological changes could be induced
      and controlled by temperature.

PMID- 12485047
TI  - Complex scaling behavior of nonconserved self-organized critical systems.
AB  - The Olami-Feder-Christensen earthquake model is often considered the prototype
      dissipative self-organized critical model. It is shown that the size distribution
      of events in this model results from a complex interplay of several different
      phenomena, including limited floating-point precision. Parallels between the
      dynamics of synchronized regions and those of a system with periodic boundary
      conditions are pointed out, and the asymptotic avalanche size distribution is
      conjectured to be dominated by avalanches of size 1, with the weight of larger
      avalanches converging towards zero as the system size increases.

PMID- 12485048
TI  - Universal power-law decay in Hamiltonian systems?

PMID- 12485050
TI  - Comment on "Anomalous mobility of strongly bound surface species: Cl on GaAs(001)
      c(8 x 2)".

PMID- 12485052
TI  - Beliaev damping of quasiparticles in a Bose-Einstein condensate.
AB  - We report a measurement of the suppression of collisions of quasiparticles with
      ground state atoms within a Bose-Einstein condensate at low momentum. These
      collisions correspond to Beliaev damping of the excitations, in the previously
      unexplored regime of the continuous quasiparticle energy spectrum. We use a
      hydrodynamic simulation of the expansion dynamics, with the Beliaev damping cross
      section, in order to confirm the assumptions of our analysis.

PMID- 12485053
TI  - Interferometer-type structures for guided atoms.
AB  - We experimentally demonstrate interferometer-type guiding structures for neutral
      atoms based on dipole potentials created by microfabricated optical systems. As a
      central element we use an array of atom waveguides being formed by focusing a red
      detuned laser beam with an array of cylindrical microlenses. Combining two of
      these arrays, we realize X-shaped beam splitters and more complex systems like
      the geometries for Mach-Zehnder and Michelson-type interferometers for atoms.

PMID- 12485054
TI  - Polarization of interacting bosons with spin.
AB  - We prove that in the absence of explicit spin-dependent forces one of the ground
      states of interacting bosons with spin is always fully polarized. Generally, this
      state is degenerate with other states, but one can specify the exact degeneracy.
      For T>0, the magnetization and zero-field susceptibility exceed that of a pure
      paramagnet. The results are relevant to experimental work on triplet
      superconductivity and condensation of atoms with spin. They eliminate the
      possibility, raised in some theoretical speculations, that the ground state or
      positive temperature state might be antiferromagnetic.

PMID- 12485055
TI  - Vacuum induced spin-1/2 Berry's phase.
AB  - We calculate the Berry phase of a spin-1/2 particle in a magnetic field
      considering the quantum nature of the field. The phase reduces to the standard
      Berry phase in the semiclassical limit and the eigenstate of the particle
      acquires a phase in the vacuum. We also show how to generate a vacuum induced
      Berry phase considering two quantized modes of the field which has an interesting
      physical interpretation.

PMID- 12485056
TI  - Embedding dissipation and decoherence in unitary evolution schemes.
AB  - Dissipation and decoherence, and the evolution from pure to mixed states in
      quantum physics, are handled through master equations for the density matrix. By
      embedding elements of this matrix in a higher-dimensional Liouville-Bloch
      equation, the methods of unitary integration are adapted to solve for the density
      matrix as a function of time, including the nonunitary effects of dissipation and
      decoherence. The input requires only solutions of classical, initial value time
      dependent equations. Results are illustrated for a damped, driven two-level
      system.

PMID- 12485057
TI  - Ionization rates in a bose-einstein condensate of metastable helium.
AB  - We have studied ionizing collisions in a BEC of metastable He. Measurements of
      the ion production rate combined with measurements of the density and number of
      atoms for the same sample allow us to estimate both the two- and three-body
      contributions to this rate. A comparison with the decay of the atom number
      indicates that ionizing collisions are largely or wholly responsible for the
      loss. Quantum depletion makes a substantial correction to the three-body rate
      constant.

PMID- 12485058
TI  - High-temperature superfluidity of fermionic atoms in optical lattices.
AB  - Fermionic atoms confined in a potential created by standing wave light can
      undergo a phase transition to a superfluid state at a dramatically increased
      transition temperature. Depending upon carefully controlled parameters, a
      transition to a superfluid state of Cooper pairs, antiferromagnetic states or d
      wave pairing states can be induced and probed under realistic experimental
      conditions. We describe an atomic physics experiment that can provide critical
      insight into the origin of high-temperature superconductivity in cuprates.

PMID- 12485059
TI  - E10 and a small tension expansion of m theory.
AB  - A formal "small tension" expansion of D=11 supergravity near a spacelike
      singularity is shown to be equivalent, at least up to 30th order in height, to a
      null geodesic motion in the infinite-dimensional coset space E(10)/K(E10), where
      K(E10) is the maximal compact subgroup of the hyperbolic Kac-Moody group E10(R).
      For the proof we make use of a novel decomposition of E10 into irreducible
      representations of its SL(10,R) subgroup. We explicitly show how to identify the
      first four rungs of the E10 coset fields with the values of geometric quantities
      constructed from D=11 supergravity fields and their spatial gradients taken at
      some comoving spatial point.

PMID- 12485060
TI  - Light gluino, light bottom squark scenario, and LEP predictions.
AB  - The scenario of light gluinos and light sbottoms was advocated to explain the
      discrepancy between the measured and theoretical production of b quarks at the
      Tevatron. This scenario will have model-independent predictions for Z-->qqgg at
      the Z0 pole, and e(+)e(-)-->qqgg at LEPII. We show that the data for Z-->qqg*-
      >qqbb; at LEPI cannot constrain the scenario, because the ratio Gamma(Z-
      >qqgg)/Gamma(Z-->qqg*-->qqbb)=0.15-0.04 for m(g)=12-16 GeV is smaller than the
      uncertainty of the data. However, at LEPII the ratio sigma(e(+)e(-)-
      >qqgg)/sigma(e(+)e(-)-->qqg*-->qqbb) approximately 0.4-0.2 for m(g)=12-16 GeV,
      which may give an observable excess in qqbb events; especially, the 4b events.

PMID- 12485061
TI  - Measurement of B(D+-->K(*0)l(+)nu(l)).
AB  - Using 13.53 fb(-1) of CLEO data, we have measured the ratios of the branching
      fractions R(+)(e),R(+)(mu) and the combined branching fraction ratio R(+)(l),
      defined by R(+)(l)=[B(D+-->K(*0)l(+)nu(l))]/[B(D+-->K-pi(+)pi(+))]. We find
      R(+)(e)=0.74+/-0.04+/-0.05, R(+)(mu)=0.72+/-0.10+/-0.05, and R(+)(l)=0.74+/
      0.04+/-0.05, where the first and second errors are statistical and systematic,
      respectively. The known branching fraction B(D+-->K-pi(+)pi(+)) leads to B(D+-
      >K(*0)e(+)nu(e))=(6.7+/-0.4+/-0.5+/-0.4)%, B(D+-->K(*0)mu(+)nu(mu))=(6.5+/-0.9+/
      0.5+/-0.4)%, and B(D+-->K(*0)l(+)nu(l))=(6.7+/-0.4+/-0.5+/-0.4)%, where the third
      error is due to the uncertainty in B(D+-->K-pi(+)pi(+)).

PMID- 12485063
TI  - Pseudorapidity and centrality dependence of the collective flow of charged
      particles in Au+Au collisions at sqrt[s(NN)]=130 GeV.
AB  - This paper describes the measurement of collective flow for charged particles in
      Au+Au collisions at sqrt[s(NN)]=130 GeV using the PHOBOS detector at the
      Relativistic Heavy Ion Collider (RHIC). The measured azimuthal hit anisotropy is
      presented over a wide range of pseudorapidity (-5.0<eta<5.3) for the first time
      at this energy. The result, averaged over momenta and particle species, is
      observed to reach 7% for peripheral collisions at midrapidity, falling off with
      centrality and increasing |eta|. These results call into question the common
      assumption of longitudinal boost invariance over a large region of rapidity in
      RHIC collisions.

PMID- 12485064
TI  - In-medium modifications of the pipi interaction in photon-induced reactions.
AB  - Differential cross sections of the reactions (gamma,pi(0)pi(0)) and
      (gamma,pi(0)pi(+/-)) have been measured for several nuclei (1H,12C, and (nat)Pb)
      at an incident-photon energy of E(gamma)=400-460 MeV at the tagged-photon
      facility at MAMI-B using the TAPS spectrometer. A significant nuclear-mass
      dependence of the pipi invariant-mass distribution is found in the pi(0)pi(0)
      channel. This dependence is not observed in the pi(0)pi(+/-) channel and is
      consistent with an in-medium modification of the pipi interaction in the I=J=0
      channel. The data are compared to pi-induced measurements and to calculations
      within a chiral-unitary approach.

PMID- 12485065
TI  - Generalized partial dynamical symmetry in nuclei.
AB  - We introduce the notion of a generalized partial dynamical-symmetry for which
      part of the eigenstates have part of the dynamical symmetry. This general concept
      is illustrated with the example of Hamiltonians with a partial dynamical O(6)
      symmetry in the framework of the interacting boson model. The resulting spectrum
      and electromagnetic transitions are compared with empirical data in 162Dy.

PMID- 12485066
TI  - Anomalous natural linewidth in the 2p photoelectron spectrum of SiF4.
AB  - The silicon 2p photoelectron spectra for SiH4, SiF4, and SiCl4 have been analyzed
      to give the natural linewidths of the Si 2p hole states, which reflect the Auger
      decay rates of the states. For SiH4 the measured width of 38 meV is in
      approximate agreement with the prediction of the one-center model (32 meV), but
      that for SiF4 of 79 meV is more than 5 times the value of 14 meV predicted by
      this model. Approximate theoretical calculations indicate that valence electrons
      from the fluorine atoms of SiF4 play an important role in the Auger decay via
      interatomic processes.

PMID- 12485068
TI  - Subwavelength photonic band gaps from planar fractals.
AB  - We show by both experiment and theory that a specific class of planar conducting
      fractals possesses a series of self-similar resonances, leading to multiple gaps
      and pass bands for electromagnetic waves over an ultrawide frequency range. A
      double stack of these fractal patterns exhibits polarization-independent absolute
      gaps over a wide range of incidence angles. These characteristics are retained
      even when the fractal patterns are significantly subwavelength in all dimensions.
      In addition, the transmittance can be modulated by an external current source.

PMID- 12485067
TI  - Correlation between double and nonresonant single ionization.
AB  - We performed simultaneous measurements of electrons and ions produced in Xe
      photoionization driven by an 800-nm, 100-fs laser pulse. The obtained energy and
      angular resolved electron spectra allow the identification of the electronic
      states populated during the ionization. Xe2+ ions appear at the same laser
      intensity as electrons emerging from a nonresonant 9-photon ionization process of
      Xe. Similar to optical tunneling ionization, the nonresonant ionization delivers
      low-energy electrons needed for the formation of Xe2+ by a backscattering
      process.

PMID- 12485062
TI  - Eta photoproduction on the proton for photon energies from 0.75 to 1.95 GeV.
AB  - Differential cross sections for gammap-->etap have been measured with tagged real
      photons for incident photon energies from 0.75 to 1.95 GeV. Mesons were
      identified by missing mass reconstruction using kinematical information for
      protons scattered in the production process. The data provide the first extensive
      angular distribution measurements for the process above W=1.75 GeV. Comparison
      with preliminary results from a constituent quark model support the suggestion
      that a third S11 resonance with mass approximately 1.8 GeV couples to the etaN
      channel.

PMID- 12485069
TI  - Observation of sub-Fourier resonances in a quantum-chaotic system.
AB  - We experimentally show that the response of a quantum-chaotic system can display
      resonance lines sharper than the inverse of the excitation duration. This allows
      us to discriminate two neighboring frequencies with a resolution nearly 40 times
      better than the limit set by the Fourier inequality. Furthermore, numerical
      studies indicate that there is no limit, but the loss of signal, to this
      resolution, opening ways for the development of sub-Fourier quantum-chaotic
      signal processing.

PMID- 12485070
TI  - Observation of the wave function of a quantum billiard from the transverse
      patterns of vertical cavity surface emitting lasers.
AB  - We demonstrate experimentally that the near-field and far-field transverse
      patterns of a large aperture vertical cavity surface emitting laser (VCSEL) can
      be successfully interpreted as a two-dimensional (2D) billiard system. It is
      found that the near-field and far-field transverse patterns of a large aperture
      VCSEL evidently represent the coordinate-space and momentum-space wave functions
      of a 2D quantum billiard, respectively. The result of this paper suggests that
      large aperture VCSELs are potentially appropriate physical systems for the wave
      function study in quantum problems.

PMID- 12485071
TI  - Nature of mechanical instabilities and their effect on kinetic friction.
AB  - It has long been recognized that kinetic friction F(k) between two solids must be
      due to instabilities, sudden "pops" of certain degrees of freedom. Here, such
      pops are studied with a focus on boundary lubrication. The pops' characteristics
      and consequently the friction-velocity relationship depend qualitatively on
      dimensionality, commensurability, and details of the lubricant wall interaction.
      It is found that F(k) should be small between commensurate surfaces. F(k) is
      large for incommensurate surfaces, unless the lubricant's motion is confined to
      1D. The effects of thermal noise are discussed and computer simulations are
      employed to show the relevance of the predictions to less idealized models.

PMID- 12485072
TI  - Observation of broadband self-amplified spontaneous coherent terahertz
      synchrotron radiation in a storage ring.
AB  - Bursts of coherent synchrotron radiation at far-infrared and millimeter
      wavelengths have been observed at several storage rings. A microbunching
      instability has been proposed as the source for the bursts. However, the
      microbunching mechanism has yet to be elucidated. We provide the first evidence
      that the bursts are due to a microbunching instability driven by the emission of
      synchrotron radiation in the bunch. Observations made at the Advanced Light
      Source are consistent with the values predicted by the proposed microbunching
      model. These results demonstrate a new instability regime for high energy
      synchrotron radiation sources and could impact the design of future sources.

PMID- 12485073
TI  - Bursts of coherent synchrotron radiation in electron storage rings: a dynamical
      model.
AB  - Evidence of coherent synchrotron radiation has been reported recently at the
      electron storage rings of several light source facilities. The main features of
      the observations are (i) a radiation wavelength short compared to the nominal
      bunch length, and (ii) a coherent signal showing recurrent bursts of duration
      much shorter than the radiation damping time, but with spacing equal to a
      substantial fraction of the damping time. We present a model of beam longitudinal
      dynamics that reproduces these features.

PMID- 12485074
TI  - Prediction of significant tokamak turbulence at electron gyroradius scales.
AB  - The experimental conditions under which tokamak turbulence at hyperfine (electron
      gyroradius) scales is predicted to be significant and observable are described.
      The first quantitative predictions of fluctuation amplitudes, spectral features,
      and the associated electron energy transport are presented. A novel theoretical
      model which quantitatively describes the boundaries of the high-amplitude
      streamer transport regime is presented and shown to explain the gyrokinetic
      simulation results. This model uniquely includes consideration of two distinct
      secondary instabilities.

PMID- 12485075
TI  - Laser-generated ultrashort multimegagauss magnetic pulses in plasmas.
AB  - We demonstrate ultrashort (6 ps), multimegagauss (27 MG) magnetic pulses
      generated upon interaction of an intense laser pulse (10(16) W cm(-2), 100 fs)
      with a solid target. The temporal evolution of these giant fields generated near
      the critical layer is obtained with the highest resolution reported thus far.
      Particle-in-cell simulations and phenomenological modeling is used to explain the
      results. The first direct observations of anomalously rapid damping of plasma
      shielding currents produced in response to the hot electron currents penetrating
      the bulk plasma are presented.

PMID- 12485076
TI  - Effect of poloidal density variation of neutral atoms on the tokamak edge.
AB  - Neutral atoms in the tokamak edge affect the electric field and plasma flow
      through charge exchange. Here, it is shown that these effects depend sensitively
      on the poloidal location of the atoms. It is found that the radial electric field
      and toroidal flow velocity in a collisional edge plasma are largest if the atoms
      are concentrated on the inboard side. This feature may explain MAST and COMPASS-D
      observations indicating easier H-mode access for inboard gas puffing. The results
      suggest an external means of controlling the toroidal flow and radial electric
      field and their shear, and have motivated further MAST measurements appearing to
      support the predictions.

PMID- 12485077
TI  - Experimental and theoretical study of quasicoherent fluctuations in enhanced
      D(alpha) plasmas in the Alcator C-Mod tokamak.
AB  - A comparison of experimental measurements and theoretical studies of the
      quasicoherent (QC) mode, observed at high densities during enhanced D(alpha)
      (EDA) H mode in the Alcator C-Mod tokamak, are reported. The QC mode is a high
      frequency ( approximately 100 kHz) nearly sinusoidal fluctuation in density and
      magnetic field, localized in the steep density gradient ("pedestal") at the
      plasma edge, with typical wave numbers k(R) approximately 3-6 cm(-1), k(theta)
      approximately 1.3 cm(-1) (midplane). It is proposed here that the QC mode is a
      form of resistive ballooning mode known as the resistive X-point mode, in
      reasonable agreement with predictions by the BOUT (boundary-plasma turbulence)
      code.

PMID- 12485078
TI  - Effect of the symmetry of H2 molecules on their rotations around an OCS molecule
      in superfluid 4He droplets.
AB  - The infrared spectra of OCS-(H2)(n) clusters in cold (0.15 K) superfluid 4He
      droplets coated with 3He exhibit resolved rotational bands for each n up to n=8
      para-H2 (pH(2)) or ortho-D2 (oD(2)) molecules. An analysis of the different Q
      branch intensities based on the different spin symmetries of pH(2) and oD(2)
      indicates the formation of symmetric 5- or 6-membered rings around the linear
      carbonyl sulfide (OCS) chromophore. The rings of distinguishable oD(2) are found
      to undergo axial rotations, whereas for 6 pH(2) molecules the symmetry-allowed
      rotational levels lie too high to be excited at the 0.15 K droplet temperatures.

PMID- 12485079
TI  - Anchoring screening of defects interaction in a nematic liquid crystal.
AB  - The relaxation dynamic of a dipole of +1/2 and -1/2 parallel disclination lines
      in a confined geometry is measured. The confinement and the planar anchoring
      conditions force the disclinations to be normal to the glass plates. In a first
      asymptotic regime, the direct elastic interaction between disclination is
      completely screened out by the anchoring energy. In a second regime,
      corresponding to the final annihilation steps, the dynamic follows the square
      root law predicted by de Gennes for two isolated and parallel disclinations. The
      annihilation dynamic, in the asymptotic regime, is in good agreement with an
      elastic model based on an electrostatic analogy.

PMID- 12485080
TI  - Comprehensive ab initio thermodynamic treatment of impurities in ordered alloys:
      application to boron in B2 Fe-Al.
AB  - A rigorous description of impurities in nearly stoichiometric ordered systems,
      relying on independent-point-defect thermodynamics and density-functional-theory
      ab initio calculations, is presented and applied to the study of the equilibrium
      point defect structure of Fe-Al-B alloys in the B2 composition domain (x(Al)
      approximately 50 at. %, x(B) approximately 0), including the influences of (i)
      magnetism and (ii) the local density approximation (LDA) or generalized gradient
      approximation (GGA) exchange-correlation functionals. Whatever the alloy
      composition, B substitutes for Al, except in the nonmagnetic GGA scheme
      predicting a switch towards interstitial occupancy for sufficient Al contents.

PMID- 12485081
TI  - Molecular origin of auxetic behavior in tetrahedral framework silicates.
AB  - Recent analytical models for the Poisson's ratios (nu(ij)) of tetrahedral
      frameworks are applied to alpha-cristobalite and alpha-quartz for the first time.
      Rotation and dilation of the SiO4 tetrahedral subunits are considered. Each
      mechanism leads to negative nu(31) values, whereas negative and positive values
      are possible when they act concurrently. The concurrent model is in excellent
      agreement with experiment and explains the dichotomy between negative and
      positive nu(31) values in alpha-cristobalite and alpha-quartz, respectively. The
      predicted strain-dependent trends confirm those from molecular modeling.

PMID- 12485082
TI  - Isotropic-nematic transition in liquid-crystalline elastomers.
AB  - In liquid-crystalline elastomers, the nematic order parameter and the induced
      strain vary smoothly across the isotropic-nematic transition, without the
      expected first-order discontinuity. To investigate this smooth variation, we
      measure the strain as a function of temperature over a range of applied stress,
      for elastomers cross-linked in the nematic and isotropic phases, and analyze the
      results using a variation on Landau theory. This analysis shows that the smooth
      variation arises from quenched disorder in the elastomer, combined with the
      effects of applied stress and internal stress.

PMID- 12485083
TI  - Mechanism of interstitial oxygen diffusion in hafnia.
AB  - We have performed density functional calculations of oxygen incorporation and
      diffusion in monoclinic hafnia (HfO2) for a range of oxygen charge states. The
      calculations demonstrate that oxygen favors atomic incorporation and that O2- is
      the most stable species. We find that oxygen interstitials diffuse via exchange
      with lattice oxygen sites in hafnia, and that O- species have the smallest
      diffusion barrier.

PMID- 12485084
TI  - Atomic-scale spin-polarized scanning tunneling microscopy applied to Mn3N2(010).
AB  - Atomic-scale spin-polarized scanning tunneling microscopy is demonstrated in the
      case of the unique surface spin structure of Mn3N2(010) at 300 K. We find that
      the surface spin structure is manifested as a modulation of the normal atomic row
      height profile. The atomic-scale spin-polarized image is thus shown to contain
      two components, one the normal, nonpolarized part, and the other the magnetic,
      spin-polarized part. A method is presented for separating these two spatially
      correlated components, and the results are compared with simulations based on
      integrated local spin density of states calculated from first principles.

PMID- 12485085
TI  - Pressure-tuned collapse of the Mott-like state in Ca(n+1)Ru(n)O(3n+1) (n=1,2):
      Raman spectroscopic studies.
AB  - We report a Raman scattering study of the pressure-induced collapse of the Mott
      like phases of Ca3Ru2O7 (T(N)=56 K) and Ca2RuO4 (T(N)=110 K). The pressure
      dependence of the phonon and two-magnon excitations in these materials indicate
      (i) a T approximately 0 pressure-induced collapse of the antiferromagnetic (AF)
      insulating phase above P(*) approximately 55 kbar in Ca3Ru2O7 and P(*)
      approximately 5-10 kbar in Ca2RuO4, (ii) a remarkable insensitivity of the
      exchange interaction to pressure in both systems, and (iii) evidence for
      persistent AF correlations above the critical pressure of Ca2RuO4, suggestive of
      phase separation involving AF insulator and ferromagnetic metal phases.

PMID- 12485086
TI  - Geometrical-frustration-induced (Semi)metal-to-insulator transition.
AB  - We study the low-energy properties of the geometrically frustrated Hubbard model
      on a three-dimensional pyrochlore lattice and a two-dimensional checkerboard
      lattice on the basis of the renormalization group method and mean field analysis.
      It is found that, in the half-filling case, a (semi)metal to insulator transition
      (MIT) occurs. Also, in the insulating phase, which has a spin gap, the spin
      rotational symmetry is not broken, while charge ordering exists. The results are
      applied to the description of the MIT observed in the pyrochlore system Tl2Ru2O7.

PMID- 12485087
TI  - Criticality in the (2+1)-dimensional compact Higgs model and fractionalized
      insulators.
AB  - We use a novel method of computing the third moment M3 of the action of the (2+1)
      dimensional compact Higgs model in the adjoint representation with q=2 to extract
      correlation length and specific heat exponents nu and alpha without invoking
      hyperscaling. Finite-size scaling analysis of M3 yields the ratios (1+alpha)/nu
      and 1/nu separately. We find that alpha and nu vary along the critical line of
      the theory, which however exhibits a remarkable resilience of Z2 criticality. We
      propose this novel universality class to be that of the quantum phase transition
      from a Mott-Hubbard insulator to a charge-fractionalized insulator in two spatial
      dimensions.

PMID- 12485088
TI  - Landauer-type transport theory for interacting quantum wires: application to
      carbon nanotube y junctions.
AB  - We propose a Landauerlike theory for nonlinear transport in networks of one
      dimensional interacting quantum wires (Luttinger liquids). A concrete example of
      current experimental focus is given by carbon nanotube Y junctions. Our theory
      has three basic ingredients that allow one to explicitly solve this transport
      problem: (i) radiative boundary conditions to describe the coupling to external
      leads, (ii) the Kirchhoff node rule describing charge conservation, and (iii)
      density matching conditions at every node.

PMID- 12485089
TI  - Influence of impurities on short range electron transport in GaAs.
AB  - The influence of Cr impurities on muonium atom formation in GaAs has been studied
      using muon spin relaxation techniques with alternating electric fields. The
      results suggest that electron transport to and capture by the muon is suppressed
      by capture/scattering on intervening Cr centers. The length scale involved is
      estimated to be about 3x10(-6) cm. This offers an opportunity to study electron
      transport to positive centers in semiconductors on a microscopic scale.

PMID- 12485090
TI  - Surface-state depopulation on small Ag(111) terraces.
AB  - The dependence of the local density of states near the Fermi energy E(F) on the
      width of terraces T is investigated by tunneling scanning spectroscopy on Ag(111)
      at 7 K. With decreasing T, the electronic density in the occupied surface state
      shifts monotonically towards E(F), leading to a depopulation at T=3.2 nm in
      quantitative agreement with a Fabry-Perot model. Depopulation coincides with a
      switch from confinement by terrace modulation to step modulation.

PMID- 12485091
TI  - Quantitative study of magnetization reversal by spin-polarized current in
      magnetic multilayer nanopillars.
AB  - We have studied magnetic switching by spin-polarized currents and also the
      magnetoresistance in sub-100-nm-diam thin-film Co/Cu/Co nanostructures, with the
      current flowing perpendicular to the plane of the films. By independently varying
      the thickness of all three layers and measuring the change of the switching
      currents, we test the theoretical models for spin-transfer switching. In
      addition, the changes in the switching current and magnetoresistance as a
      function of the Cu layer thickness give two independent measurements of the room
      temperature spin-diffusion length in Cu.

PMID- 12485092
TI  - Kondo effect in a quantum antidot.
AB  - We report Kondo-like behavior in a quantum antidot (a submicron depleted region
      in a two-dimensional electron gas) in the quantum-Hall regime. When both spins of
      the lowest Landau level are present all around the antidot, the resonances
      between extended edge states via antidot bound states show an abnormal feature in
      alternate Coulomb-blockaded regions. The feature becomes suppressed when the
      temperature or source-drain bias is raised as for Kondo resonances in quantum
      dots. Although the exact mechanism is unknown, Kondo-like correlated tunneling
      may arise from a Skyrmion-type edge reconstruction. This observation demonstrates
      the generality of the Kondo phenomenon.

PMID- 12485093
TI  - Capacitive-coupling-enhanced switching gain in an electron y-branch switch.
AB  - We have fabricated electron Y-branch switches (YBS) on modulation doped
      GaAs/AlGaAs heterostructures. The Y branch consists of a one-dimensional source,
      which is split along the branching section into two one-dimensional drains. In
      addition to source drain voltages, external electric fields can be applied via
      gates along the branches. In the nonlinear transport regime sweeps of the side
      gate voltages lead to a voltage difference between the drain reservoirs with
      gain. This switching gain increases superlinearly with the bias voltage applied
      between the source and the drains of the YBS. We explain the bias voltage
      enhanced switching by a capacitive coupling of the branches.

PMID- 12485094
TI  - Valley splitting of AlAs two-dimensional electrons in a perpendicular magnetic
      field.
AB  - By measuring the angles at which the Landau levels overlap in tilted magnetic
      fields (the coincidence method), we determine the splitting of the conduction
      band valleys in high-mobility two-dimensional electrons confined to AlAs quantum
      wells. The data reveal that, while the valleys are nearly degenerate in the
      absence of magnetic field, they split as a function of perpendicular magnetic
      field. The splitting appears to depend primarily on the magnitude of the
      perpendicular component of the magnetic field, suggesting electron-electron
      interaction as its origin.

PMID- 12485095
TI  - Effective temperature in driven vortex lattices with random pinning.
AB  - We study numerically correlation and response functions in nonequilibrium driven
      vortex lattices with random pinning. From a generalized fluctuation-dissipation
      relation, we calculate an effective transverse temperature in the fluid moving
      phase. We find that the effective temperature decreases with increasing driving
      force and becomes equal to the equilibrium melting temperature when the dynamic
      transverse freezing occurs. We also discuss how the effective temperature can be
      measured experimentally from a generalized Kubo formula.

PMID- 12485096
TI  - Inhomogeneous stripe phase revisited for surface superconductivity.
AB  - We consider 2D surface superconductivity in high magnetic fields parallel to the
      surface. We demonstrate that the spin-orbit interaction at the surface changes
      the properties of the inhomogeneous superconducting Larkin-Ovchinnikov-Fulde
      Ferrell (LOFF) state that develops above fields given by the paramagnetic
      criterion. Strong spin-orbit interaction significantly broadens the range of
      existence of the LOFF phase, which takes the form of periodic superconducting
      stripes running along the field direction on the surface, leading to the
      anisotropy of its properties. Our results provide a tool for studying surface
      superconductivity as a function of doping.

PMID- 12485097
TI  - Shot noise and multiple Andreev reflections in d-wave superconductors.
AB  - We present a theoretical analysis of the shot noise in d-wave/d-wave contacts
      with arbitrary transparency, including the contribution of multiple Andreev
      reflections. The multiple charge quanta transferred in these processes are
      revealed as a huge enhancement of the noise-current ratio at low voltages, which
      survives for all crystal misorientations. We also show how different ingredients
      such as nonmagnetic impurities or a magnetic field produce very characteristic
      hallmarks in the shot noise, which can be used as a further test of the d-wave
      scenario in superconducting cuprates.

PMID- 12485098
TI  - Self-compensation in manganese-doped ferromagnetic semiconductors.
AB  - We present a theory of interstitial Mn in Mn-doped ferromagnetic semiconductors.
      Using density-functional theory, we show that under the nonequilibrium conditions
      of growth, interstitial Mn is easily formed near the surface by a simple low
      energy adsorption pathway. In GaAs, isolated interstitial Mn is an electron
      donor, each compensating two substitutional Mn acceptors. Within an impurity-band
      model, partial compensation promotes ferromagnetic order below the metal
      insulator transition, with the highest Curie temperature occurring for 0.5 holes
      per substitutional Mn.

PMID- 12485099
TI  - Tricritical point and the doping dependence of the order of the ferromagnetic
      phase transition of La1-xCaxMnO3.
AB  - We report on the doping dependence of the order of the ferromagnetic metal to
      paramagnetic insulator phase transition in La1-xCaxMnO3. At x=0.33, magnetization
      and specific heat data show a first order transition, with an entropy change (2.3
      J/mol K) accounted for by both volume expansion and the discontinuity of M
      approximately 1.7mu(B) via the Clausius-Clapeyron equation. At x=0.4, the data
      show a continuous transition with tricritical point exponents alpha=0.48+/-0.06,
      beta=0.25+/-0.03, gamma=1.03+/-0.05, and delta=5.0+/-0.8. This tricritical point
      separates first- (x<0.4) from second-order (x>0.4) transitions.

PMID- 12485100
TI  - Orbital ordering in frustrated Jahn-Teller systems with 90 degrees exchange.
AB  - We show that superexchange interactions in frustrated Jahn-Teller systems with
      transition metal ions connected by the 90 degrees metal-oxygen-metal bonds (e.g.,
      NaNiO2, LiNiO2, and ZnMn2O4) are much different from those in materials with the
      180 degrees bonds. In the 90 degrees -exchange systems spins and orbitals are
      decoupled: the spin exchange is much weaker than the orbital one and it is
      ferromagnetic for all orbital states. Though the mean-field orbital ground state
      is strongly degenerate, quantum orbital fluctuations select particular ferro
      orbital states. We explain the orbital and magnetic ordering observed in NaNiO2
      and show that LiNiO2 is not a spin-orbital liquid.

PMID- 12485101
TI  - Destruction of bulk ordering by surface randomness.
AB  - We demonstrate that the arbitrarily weak quenched disorder on the surface of a
      system of continuous symmetry destroys long-range order in the bulk, and,
      instead, quasi-long-range order emerges. Correlation functions are calculated
      exactly for the two- and three-dimensional XY models with surface randomness via
      the functional renormalization group. Even at strong quenched disorder the three
      dimensional XY model possesses topological order. We also determine roughness of
      a domain wall in the presence of surface disorder.

PMID- 12485102
TI  - Optically induced deexcitation of rare-Earth ions in a semiconductor matrix.
AB  - We report on verification of the proposed energy transfer mechanism responsible
      for photoluminescence of rare earth (RE) ions in semiconductors. Using two-color
      spectroscopy in the visible and the midinfrared regions (with a free-electron
      laser) we demonstrate reversal of the most important step in the excitation
      process. In that way, formation of the intermediate state bridging atomic states
      of the RE ion core and extended orbitals of a semiconducting host is explicitly
      confirmed and its characteristic energy spectroscopically determined. The study
      is performed for InP:Yb. It is argued, however, that the conclusions are valid
      for all semiconductor:RE systems, including the notorious Si:Er.

PMID- 12485103
TI  - Confinement of acoustical vibrations in a semiconductor planar phonon cavity.
AB  - Extending the idea of optical microcavities to sound waves, we propose a phonon
      cavity consisting of two semiconductor superlattices enclosing a spacer layer. We
      show that acoustical phonons can be confined in such layered structures when the
      spacer thickness is an integer multiple of the acoustic half-wavelength at the
      center of one of the superlattice folded minigaps. We report Raman scattering
      experiments that, taking profit of an optical microcavity geometry, demonstrate
      unambiguously the observation of a phonon-cavity confined acoustical vibration in
      a GaAs/AlAs based structure. The experimental results compare precisely with
      photoelastic model calculations of the Raman spectra.

PMID- 12485104
TI  - Picosecond transient photoconductivity in functionalized pentacene molecular
      crystals probed by terahertz pulse spectroscopy.
AB  - We have measured transient photoconductivity in functionalized pentacene
      molecular crystals using ultrafast optical pump-terahertz probe techniques. The
      single crystal samples were excited using 800 nm, 100 fs pulses, and the change
      in transmission of time-delayed, subpicosecond terahertz pulses was used to probe
      the photoconducting state over a temperature range from 10 to 300 K. A
      subpicosecond rise in photoconductivity is observed, suggesting that mobile
      carriers are a primary photoexcitation. At times longer than 4 ps, a power-law
      decay is observed consistent with dispersive transport.

PMID- 12485105
TI  - Quantum protocol for cheat-sensitive weak coin flipping.
AB  - We present a quantum protocol for the task of weak coin flipping. We find that,
      for one choice of parameters in the protocol, the maximum probability of a
      dishonest party winning the coin flip if the other party is honest is 1/sqrt[2].
      We also show that if parties restrict themselves to strategies wherein they
      cannot be caught cheating, their maximum probability of winning can be even
      smaller. As such, the protocol offers additional security in the form of cheat
      sensitivity.

PMID- 12485106
TI  - Correlated random networks.
AB  - We develop a statistical theory of networks. A network is a set of vertices and
      links given by its adjacency matrix c, and the relevant statistical ensembles are
      defined in terms of a partition function Z= summation operator exp([-betaH(c)].
      The simplest cases are uncorrelated random networks such as the well-known Erdos
      Renyi graphs. Here we study more general interactions H(c) which lead to
      correlations, for example, between the connectivities of adjacent vertices. In
      particular, such correlations occur in optimized networks described by partition
      functions in the limit beta--> infinity. They are argued to be a crucial
      signature of evolutionary design in biological networks.

PMID- 12485107
TI  - Comment on "Spontaneous branching of anode-directed streamers between planar
      electrodes".

PMID- 12485109
TI  - Comment on "Dependence of the dust-particle charge on its size in a glow
      discharge plasma".

PMID- 12485111
TI  - Comment on "Electronic correlation effects and the Coulomb gap at finite
      temperature".

PMID- 12485113
TI  - Two pseudogaps in the cuprates.

PMID- 12485115
TI  - beta-Glucosidase in cellulosome of the anaerobic fungus Piromyces sp. strain E2
      is a family 3 glycoside hydrolase.
AB  - The cellulosomes of anaerobic fungi convert crystalline cellulose solely into
      glucose, in contrast with bacterial cellulosomes which produce cellobiose.
      Previously, a beta-glucosidase was identified in the cellulosome of Piromyces sp.
      strain E2 by zymogram analysis, which represented approx. 25% of the
      extracellular beta-glucosidase activity. To identify the component in the fungal
      cellulosome responsible for the beta-glucosidase activity, immunoscreening with
      anti-cellulosome antibodies was used to isolate the corresponding gene. A 2737 bp
      immunoclone was isolated from a cDNA library. The clone encoded an extracellular
      protein containing a eukaryotic family 3 glycoside hydrolase domain homologue and
      was therefore named cel3A. The C-terminal end of the encoded Cel3A protein
      consisted of an auxiliary domain and three fungal dockerins, typical for
      cellulosome components. The Cel3A catalytic domain was expressed in Escherichia
      coli BL21 and purified. Biochemical analyses of the recombinant protein showed
      that the Cel3A catalytic domain was specific for beta-glucosidic bonds and
      functioned as an exoglucohydrolase on soluble substrates as well as cellulose.
      Comparison of the apparent K (m) and K (i) values of heterologous Cel3A and the
      fungal cellulosome for p -nitrophenyl-beta-D-glucopyranoside and D-glucono-1,5
      delta-lactone respectively indicated that cel3A encodes the beta-glucosidase
      activity of the Piromyces sp. strain E2 cellulosome.

PMID- 12485117
TI  - Chaperone-like activity of alpha-crystallin is enhanced by high-pressure
      treatment.
AB  - alpha-Crystallin, an oligomeric protein in vertebrate eye lens, is a member of
      the small heat-shock protein family. Several papers pointed out that its
      chaperone-like activity could be enhanced by increasing the temperature. We
      demonstrate in the present study that structural perturbations by high
      hydrostatic pressures up to 300 MPa also enhance this activity. In contrast with
      temperature-induced changes, the pressure-induced enhancement is reversible.
      After pressure release, the extra activity is lost with a relaxation time of
      2.0+/-0.5 h. Structural alterations contributing to the higher activity were
      studied with IR and fluorescence spectroscopy, and light-scattering measurements.
      The results suggest that while the secondary structure barely changes under
      pressure, the interactions between the subunits weaken, the oligomers dissociate,
      the area of accessible hydrophobic surfaces significantly increases and the
      environment of tryptophan residues becomes slightly more polar. It seems that
      structural flexibility and the total surface area of the oligomers are the key
      factors in the chaperone capacity, and that the increase in the chaperone
      activity does not require the increase in the oligomer size as was assumed
      previously [Burgio, Kim, Dow and Koretz (2000) Biochem. Biophys. Res. Commun.
      268, 426-432]. After pressure release, the structure of subunits are reorganized
      relatively quickly, whereas the oligomer size reaches its original value slowly
      with a relaxation time of 33+/-4 h. In our interpretation, both the fast and slow
      structural rearrangements have an impact on the functional relaxation.

PMID- 12485118
TI  - The effects of nocturnal acid breakthrough on Helicobacter pylori eradication.
AB  - BACKGROUND: The effects of nocturnal gastric acid breakthrough (NAB) on
      Helicobacter pylori eradication are still unknown in peptic ulcer patients. The
      purposes of this study were to compare the effect of lansoprazole 30 mg twice a
      day (bid) to lansoprazole 60 mg once a day (qd) on the prevalence of NAB, and to
      determine whether NAB affects the eradication of H. pylori in peptic ulcer
      patients. METHODS: Experiments were carried out in 67 patients with H. pylori
      positive peptic ulcers. They were randomized into two groups, one treated with a
      combination of lansoprazole 60 mg, clarithromycin 1.0 g, and amoxycillin 2.0 g
      once a day before breakfast (qd group), and the other, divided doses of the drugs
      were given before breakfast and dinner (bid group) for 2 weeks. RESULTS: NAB
      occurred in 31 patients, 55.2% in qd group, and 39.5% in bid group (p =.226). H.
      pylori eradication was achieved in 61.3% in NAB positive group and 83.3% in NAB
      negative group (p =.055). The mean duration of NAB for H. pylori eradication
      group was 99.3 +/- 22.7 min, and 293.2 +/- 49.8 min for H. pylori persistence
      group (p <.05). The median intragastric pH of the H. pylori eradication and
      persistence group was 5.7 +/- 0.2 and 4.2 +/- 0.4, respectively (p <.05).
      CONCLUSIONS: Neither the morning dose and the divided dose regimen of
      lansoprazole affected the intragastric acidity and occurrence of the NAB. NAB did
      not influence H. pylori eradication in peptic ulcer patients, but the duration of
      NAB and total intragastric median pH were found to influence the H. pylori
      eradication.

PMID- 12485116
TI  - Positive and negative regulation of T-cell activation through kinases and
      phosphatases.
AB  - The sequence of events in T-cell antigen receptor (TCR) signalling leading to T
      cell activation involves regulation of a number of protein tyrosine kinases
      (PTKs) and the phosphorylation status of many of their substrates. Proximal
      signalling pathways involve PTKs of the Src, Syk, Csk and Tec families, adapter
      proteins and effector enzymes in a highly organized tyrosine-phosphorylation
      cascade. In intact cells, tyrosine phosphorylation is rapidly reversible and
      generally of a very low stoichiometry even under induced conditions due to the
      fact that the enzymes removing phosphate from tyrosine-phosphorylated substrates,
      the protein tyrosine phosphatases (PTPases), have a capacity that is several
      orders of magnitude higher than that of the PTKs. It follows that a relatively
      minor change in the PTK/PTPase balance can have a major impact on net tyrosine
      phosphorylation and thereby on activation and proliferation of T-cells. This
      review focuses on the involvement of PTKs and PTPases in positive and negative
      regulation of T-cell activation, the emerging theme of reciprocal regulation of
      each type of enzyme by the other, as well as regulation of phosphotyrosine
      turnover by Ser/Thr phosphorylation and regulation of localization of signal
      components.

PMID- 12485119
TI  - Impact of Helicobacter pylori on the development of vitamin B12 deficiency in the
      absence of gastric atrophy.
AB  - BACKGROUND: Cobalamin (vitamin B12) deficiency is associated with Helicobacter
      pylori infection. This study examined how serum vitamin B12 levels relate to
      gastric mucosa H. pylori density and histology, and to hematological findings in
      patients with minimal or no gastric atrophy. A second aim was to confirm that H.
      pylori eradication therapy increases serum B12. MATERIALS AND METHODS: Biopsies
      of the gastric mucosa from a population of dyspeptic patients were graded for
      level of chronic inflammation, neutrophil activity, atrophy, and H. pylori
      density. A total of 145 H. pylori-infected patients with minimal or no atrophy
      were included in the study. Serum cobalamin level, hemoglobin level, and mean
      corpuscular volume were measured in the 145 patients before eradication therapy,
      and in 65 of the subjects after treatment. The hematologic findings before and
      after eradication therapy and correlations between serum vitamin B12 level and
      histologic parameters, hematologic findings, and patient age were statistically
      analyzed. RESULTS: There was no significant correlation between serum cobalamin
      level and patient age. Before treatment all the histopathological scores were
      inversely correlated with serum vitamin B12 level (p <.01) on univariate
      analysis. Only H. pylori density was significantly associated with B12 level on
      multivariate analysis. Serum hemoglobin and cobalamin levels were significantly
      increased after treatment, regardless of H. pylori eradication status (p <.001).
      CONCLUSION: The findings provide strong evidence that H. pylori infection is
      associated with cobalamin deficiency, and show that this is true even in patients
      with non-ulcer dyspepsia and minimal or no gastric atrophy.

PMID- 12485120
TI  - Oxidative stress in gastric mucosa of asymptomatic humans infected with
      Helicobacter pylori: effect of bacterial eradication.
AB  - BACKGROUND: Inducible nitric oxide synthase (iNOS) and interleukin 8 (IL-8) are
      positive in approximately 50% of Helicobacter pylori-related diseases but it is
      not clear whether oxidative stress is also present in H. pylori asymptomatic
      humans. Our aim was to study the expression of iNOS, superoxide dismutase,
      catalase and IL-8 production in H. pylori-infected asymptomatic humans, and to
      investigate the effect of eradication of H. pylori. MATERIALS AND METHODS:
      Biopsies of corpus and antrum of asymptomatic H. pylori positive and negative
      humans served for determination of the gastritis score and H. pylori status; iNOS
      was measured by reverse transcriptase polymerase chain reaction and
      immunohistochemistry and superoxide dismutase and catalase by
      immunohistochemistry. IL-8 in biopsies was assessed by enzyme-linked
      immunosorbent assay. RESULTS: Immunostaining of iNOS, catalase and superoxide
      dismutase was significantly associated with H. pylori infection and was localized
      to inflammatory cells. IL-8 concentrations were greater in the H. pylori positive
      than H. pylori negative group and decreased after bacterial eradication. A
      decrease in staining for iNOS and catalase was observed after H. pylori
      eradication. CONCLUSIONS: INOS and antioxidant enzymes are present in gastric
      biopsies of asymptomatic H. pylori positive humans. Eradication caused a
      significant decrease in staining for iNOS and catalase. These results indicate
      that oxidative stress occurs in asymptomatic patients and can be modulated by H.
      pylori eradication.

PMID- 12485121
TI  - Helicobacter pylori strain and the pattern of gastritis among first-degree
      relatives of patients with gastric carcinoma.
AB  - BACKGROUND: Relatives of gastric cancer patients have an increased risk of
      gastric cancer, possibly related to genetically-related strains of Helicobacter
      pylori or a common environment. METHODS: The pattern of gastritis and H. pylori
      from gastric cancer patients and their first-degree relatives were compared using
      detailed DNA fingerprints and vacA, cagA, and iceA genotyping. RESULTS: Sixteen
      index cases from Korea, the US, or Colombia and their 38 first-degree relatives
      (brothers, sisters, sons and daughters) were studied. No definite, or consistent,
      relationship between the pattern of gastritis and the relatedness of the H.
      pylori strain was observed (i.e. relatives could have an identical or a totally
      different pattern of gastritis regardless if they were infected with identical or
      highly similar organisms). For example, three elderly siblings of an index case
      with atrophic pangastritis had identical H. pylori isolates and environments in
      childhood and yet two had antral predominant nonatrophic gastritis, which is
      typically associated with duodenal ulcer instead of gastric cancer. CONCLUSIONS:
      The results of this study are not consistent with the hypothesis that specific
      virulence factors or similar H. pylori strains correlate with a specific
      histologic pattern or outcome even among those sharing the same environment in
      childhood.

PMID- 12485122
TI  - A population-based survey on gastrointestinal tract symptoms and Helicobacter
      pylori infection in children and adolescents.
AB  - BACKGROUND: Helicobacter pylori infection is a frequent infection mainly acquired
      in childhood. Even if the infection is almost invariably associated with mild to
      severe gastro-duodenal lesions, no specific clinical picture has been identified.
      The aim of this study was to evaluate the presence of dyspeptic symptoms and
      their relationship with the presence of H. pylori infection in the first two
      decades of life. MATERIALS AND METHODS: A school-population sample size of 808
      subjects from 6- to 19-year-olds was investigated for the presence of
      gastrointestinal tract symptoms and evaluated by a 13C-urea breath test for H.
      pylori infection. The relationship between clinical findings and H. pylori
      infection was evaluated by chi2 statistic or Fisher's exact test, as appropriate.
      RESULTS: Symptoms of dyspepsia were identified in 45% of subjects, while the
      picture of ulcer-like and dysmotility-like forms were present in 3-4%. H. pylori
      infection was demonstrated in 95 (11.8%) subjects, 49.5% of them without
      symptoms. Severe epigastric pain and ulcer-like dyspepsia were significantly
      associated with H. pylori infection, while recurrent abdominal pain or
      dysmotility-like dyspepsia were not. CONCLUSIONS: Dyspeptic symptoms are frequent
      in children, and its association with H. pylori infection is more evident than
      with recurrent abdominal pain. The age at which the infection is acquired seems
      to be under 6 years of age.

PMID- 12485123
TI  - No association between Helicobacter pylori genotypes and antibiotic resistance
      phenotypes within families.
AB  - BACKGROUND: Triple therapy combining a proton pump inhibitor with two
      antibiotics, e.g. clarythromycin (CLR), metronidazole (MTZ) or amoxicillin (AMX),
      represents the standard in Helicobacter pylori eradication regimens. Resistance
      to antimicrobial agents, particularly MTZ (up to 56% in Western countries) and
      CLR (up to 15% in southern Europe), is frequently observed and may be associated
      with treatment failure [1]. Recently, several studies indicated that individual
      H. pylori colonies from a single anatomic site may not always yield identical
      genotypes, or the identical patterns of susceptibility to antibiotics [2-5].
      Representative for every single patient we analyzed 27 H. pylori antrum isolates
      for susceptibility to antimicrobial agents in order to test whether identical H.
      pylori genotypes exhibit a similar pattern of susceptibility to antibiotics.
      METHODS: PCR, RELP, PFGE, antibiotic susceptibility testing. RESULTS: H. pylori
      genotype and antibiotic susceptibility pattern in families do not segregrate.
      CONCLUSION: Molecular typing of H. pylori from family members does not predict
      antibiotic susceptibility pattern.

PMID- 12485124
TI  - Significance of the caspase family in Helicobacter pylori induced gastric
      epithelial apoptosis.
AB  - BACKGROUND AND AIMS: H. pylori infection results in an increased epithelial
      apoptosis in gastritis and duodenal ulcer patients. We investigated the role and
      type of activation of caspases in H. pylori-induced apoptosis in gastric
      epithelial cells. METHODS: Differentiated human gastric cancer cells (AGS) and
      human gastric mucous cell primary cultures were incubated with H. pylori for 0.5
      24 hours in RPMI 1640 medium, and the effects on cell viability, epithelial
      apoptosis, and activity of caspases were monitored. Apoptosis was analyzed by
      detection of DNA-fragments by Hoechst stain(R), DNA-laddering, and Histone-ELISA.
      Activities of caspases were determined in fluorogenic assays and by Western
      blotting. Cleavage of BID and release of cytochrome c were analyzed by Western
      blot. Significance of caspase activation was investigated by preincubation of
      gastric epithelial cells with cell permeable specific caspase inhibitors.
      RESULTS: Incubation of gastric epithelial cells with H. pylori caused a time and
      concentration dependent induction of DNA fragmentation (3-fold increase),
      cleavage of BID, release of cytochrome c and a concomittant sequential activation
      of caspase-9 (4-fold), caspase-8 (2-fold), caspase-6 (2-fold), and caspase-3 (6
      fold). No effects on caspase-1 and -7 were observed. Activation of caspases
      preceded the induction of DNA fragmentation. Apoptosis could be inhibited by
      prior incubation with the inhibitors of caspase-3, -8, and -9, but not with that
      of caspase-1. CONCLUSIONS: Activation of certain caspases and activation of the
      mitochondrial apoptotic pathway are essential for H. pylori induced apoptosis in
      gastric epithelial cells.

PMID- 12485125
TI  - A group-specific PCR assay for the detection of Helicobacteraceae in human gut.
AB  - BACKGROUND: Enterohepatic Helicobacter species are emerging pathogens, which are
      increasingly isolated from humans with enteric diseases. Nevertheless, current
      methods to detect Helicobacteraceae in the human gut have significant
      limitations. METHODS: Based on 16S-rRNA gene alignments and computer aided primer
      analysis a set of group-specific PCR primers was designed. The evaluation of the
      PCR assay was performed using 36 ATCC reference strains and intestinal biopsies
      from 10 patients with defined gastric Helicobacter pylori status. The
      amplification products derived from clinical samples were cloned and subsequently
      analyzed by DNA sequencing. Sensitivity of the PCR-assay was determined by
      spiking previously negative tested samples with decreasing amounts of
      Helicobacter DNA. RESULTS: The analysis of the ATCC reference strains revealed
      amplification products in all 14 Helicobacter strains and Wolinella succinogenes,
      21 other microorganisms representing negative controls did not produce PCR
      fragments. Four out of the 10 patient-derived samples were positive. Three of
      them represented H. pylori-derived DNA confirming the gastric H. pylori infection
      in these patients. In the fourth patient, who was suffering from Crohn's disease,
      H. pullorum was identified. The sensitivity of the PCR assay was 0.1 pg of
      Helicobacter-derived DNA representing about 40 bacteria. CONCLUSION: The novel
      PCR assay described here is an important new tool in rapid and sensitive
      assessment for the presence of Helicobacteraceae in human gut.

PMID- 12485126
TI  - Polaprezinc attenuates Helicobacter pylori-associated gastritis in Mongolian
      gerbils.
AB  - BACKGROUND: The ammonia-monochloramine system plays an important role in
      Helicobacter pylori-associated gastric mucosal injury. Polaprezinc, a new
      antiulcer agent, has a scavenging action against monochloramine. The aim of the
      experiment was to investigate the inhibitory effects of polaprezinc on the H.
      pylori-induced gastritis in Mongolian gerbils. MATERIALS AND METHODS: Mongolian
      gerbils fasting for 24 hours were orally given culture broth containing 2-4 x
      10(8) colony-forming units of H. pylori ATCC 43054 per milliliter. From 4 hours
      after inoculation until the end of the experiment, gerbils were given chow
      pellets with or without 0.02% polaprezinc. All gerbils were killed 12 weeks
      later. The grades of H. pylori density and histologic features of gastritis were
      evaluated in accordance with the Updated Sydney System. The scavenging effect of
      polaprezinc on monochloramine was investigated spectrophotometrically. RESULTS:
      Polaprezinc had little or no influence on the H. pylori density in both pyloric
      and fundic mucosae. However, it significantly attenuated the development of
      polymorphonuclear neutrophil activity, mononuclear infiltration, and surface
      epithelial erosion in both pyloric and fundic mucosae compared with those of the
      control group. H. pylori inoculation significantly increased the heights of both
      pyloric and fundic mucosae (mainly due to the increased height of foveolar
      hyperplasia), but polaprezinc inhibited the increase of mucosal thickness in both
      pyloric and fundic mucasae. No intestinal metaplasia was detected in this study.
      Spectrophotometric examination revealed that polaprezinc scavenged
      monochloramine. CONCLUSIONS: Polaprezinc inhibited the development of H. pylori
      induced gastritis through its scavenging action against monochloramine.

PMID- 12485127
TI  - Enterocromaffin-like cell tumor induced by Helicobacter pylori infection in
      Mongolian gerbils.
AB  - BACKGROUND: Gastric carcinoids are strongly associated with chronic atrophic
      gastritis A, and it is suggested that hypergastrinemia plays a critical role in
      development of gastric carcinoids. Since Helicobacter pylori infection causes
      hypergastrinemia, it is held that H. pylori infection produces gastric
      carcinoids. We followed the histological changes of H. pylori-infected stomachs
      of Mongolian gerbils for a long time. MATERIALS AND METHODS: Five-week-old-male
      Mongolian gerbils were infected with H. pylori ATCC 43504 with cagA gene,
      expressing vacuolating cytotoxin. Determination of the serum gastrin and
      histopathological examination of the stomach at 6, 12, 18, and 24 months after H.
      pylori inoculation was studied and compared with uninfected animals. RESULTS: In
      infected animals, the gastric carcinomas appeared 18 and 24 months after
      infection. Endocrine cell dysplasias and carcinoids with marked atrophic
      gastritis of the oxyntic mucosa were observed in the infected animals 24 months
      after H. pylori inoculation. The serum gastrin level in the infected group
      increased from an average of 86.2 pg/ml at the beginning of the study to an
      average of 498 pg/ml and 989 pg/ml at 18 and 24 months after infection,
      respectively. These changes in the serum gastrin levels were significant compared
      with uninfected controls that showed no changes. CONCLUSIONS: H. pylori infection
      caused not only gastric carcinomas but also enterochromaffin-like cell tumors in
      Mongolian gerbils, due to hypergastrinemia. This model is thought to be useful to
      study the relationship between hypergastrinemia and gastric carcinoids.

PMID- 12485128
TI  - Evaluation of welfare rights advice in primary care: the general practice
      perspective.
AB  - Income maximisation may reduce enduring poverty-related health inequalities.
      Specialist welfare rights advice in primary care has been proposed and, in some
      areas, implemented, but evaluation data from the general practice perspective is
      needed. The present study aimed to evaluate the impact on general practice of
      specialist welfare rights advice, comparing practices with and without in-house
      provision of welfare advice using a cross-sectional postal questionnaire. This
      study was conducted in general practice surgeries in an inner-London health
      authority with high indicators of deprivation. Questionnaires were sent to
      practice managers. Comparative data (according to whether specialist advice was
      currently offered) addressed processes of identifying and meeting welfare needs
      and outcomes in terms of efficiency of provision. Seventy-nine surgeries
      participated. Those with welfare rights advisers (n = 42) were significantly more
      likely to report that current provision was adequate, that it was easier for
      staff to access advice on their patients' behalf (and by patients themselves) and
      that the process of advice provision ran smoothly. Lack of funding and space were
      the principal reasons for not having in-house advice. Surgeries wish provision to
      be expanded within practices. Welfare rights advice in surgeries improves ability
      to meet welfare needs via specialist advisers. Referral processes are simplified,
      enabling general practitioners to ensure that relevant advice is provided without
      the need for welfare knowledge themselves. General practices welcome the
      expansion of provision, with the proviso that adequate resources are identified.
      The current lack of basic information in surgeries must be addressed (e.g.
      information on local providers, printed information detailing range and
      eligibility criteria of welfare benefits).

PMID- 12485129
TI  - Community mental healthcare in England: associations between service organisation
      and quality of life.
AB  - The present authors set out to explore the relationship between different forms
      of service organisation and quality of life (QoL) for service users. Four mental
      health trusts and their corresponding social services departments were recruited
      to exemplify: (1). high and low levels of integration between health and social
      services; and (2). high and low levels of targeting at users with severe mental
      health problems. The authors used the Lancashire Quality of Life Profile, and
      chose their sample size to be able to detect a difference of 0.5 in subjective
      satisfaction scales. Analysis of covariance was used to investigate the
      simultaneous impact of variables representing user characteristics, objective and
      subjective QoL, and service organisation. Two hundred and sixty users selected at
      random from the active caseloads of mental health services in the four districts
      were interviewed at time 1 and 232 people were interviewed 6 months later (time
      2). No bias was detected in the non-respondents at time 2. The authors found few
      differences between districts. As in other similar studies, QoL seemed to be
      stable for the whole sample over time. In 6 months, general satisfaction with
      leisure increased and the number of people who had been in hospital fell.
      Negative affect score was the only variable found to be associated with
      subjective QoL, and no predictors of objective QoL were identified. There was
      some evidence of better objective outcomes for people in receipt of integrated
      mental health services. They socialised more, and seemed to have less difficulty
      accessing police and legal services. The results also suggest that interventions
      targeted at negative affect could have benefits for subjective QoL.

PMID- 12485130
TI  - Research and development at the health and social care interface in primary care:
      a scoping exercise in one National Health Service region.
AB  - The present project aimed to identify research activity at the health and social
      care interface in primary care within one National Health Service region, and to
      determine levels of research capacity and support within social services. The
      study was commissioned by a primary care research network (PCRN) in order to
      assess opportunities to increase research capacity within social services. Data
      were collected in two phases from 61 managers, team leaders and senior
      practitioners in social care, and six public health representatives in health
      authorities, using telephone interviews and focus groups. The findings
      highlighted a lack of infrastructure and support for research and development in
      social care. However, many social care respondents wanted opportunities to
      develop research skills with healthcare colleagues. Despite poor support, many
      small-scale projects were described, and many respondents showed an enthusiasm
      for engaging with research. Methods in use included surveys, action research,
      needs analysis and evaluation of service developments. Many examples of user
      involvement were given. Interface projects were usually instigated by interagency
      forums and funded from multiple sources. Most project work was motivated by
      service improvement or development, rather than aiming to produce generalisable
      knowledge. Barriers to conducting research included lack of confidence, research
      skills and time, as well as workload demands, lack of cover to release staff for
      research and lack of supervision. Research was not seen as legitimate work in
      some social care environments or as part of a career path. Existing joint working
      initiatives (such as the National Service Frameworks) were highlighted as
      flashpoints for potential research and evaluation activity. The findings suggest
      clear opportunities for PCRNs to develop research capacity at the interface with
      social care; for example, by signposting available resources, providing training
      grants and secondments for social care staff, and supporting interagency networks
      with a focus on evaluation. In turn, experience in promoting user involvement in
      social services could add value to research expertise at the primary care-social
      care interface.

PMID- 12485131
TI  - Objectivity in needs assessment practice: admission to a residential home.
AB  - In 1997, the Dutch government installed independent agencies to assess the long
      term care needs of individual clients and to give advice on the allocation of
      appropriate services. Needs assessors assess, among other things, the eligibility
      of clients requesting admission to a residential home. According to guidelines,
      needs assessors should do this objectively and independently from care providers
      and health care insurers. The present paper examines how needs assessors explore
      the clients' expressed needs, determine their normative needs and advise on
      allocation. Needs assessors perform these tasks in a situation where a clear
      professional framework is absent, and moreover, residential home capacity is
      limited. A qualitative study was undertaken, observing 13 house calls of clients
      requesting admission to a residential home. Furthermore, interviews were held
      with all needs assessors and a document analysis was made. It was found that
      needs assessors use comparable methods in exploring the clients' motivation and
      assessing their needs in the relevant areas, apparently using a professional
      framework. However, when transforming the needs of clients into an adequate
      allocation, needs assessors struggled with interpretation of criteria and
      included their personal ideas of services into the allocation decision. The paper
      concludes with the suggestion that further professionalisation may lead to a
      greater uniformity in needs assessment practice, and will assist needs assessors
      in the difficult task of transforming clients' needs into long-term care
      allocation advice.

PMID- 12485132
TI  - Specialist service use following psychiatric emergency presentation: an 18-month
      follow-up study.
AB  - The aim of the present study was to identify the subsequent use of specialist
      psychiatric services by a group of 170 individuals referred as psychiatric
      emergencies. Hospital and community mental health team (CMHT) records and
      databases were used to identify specialist contact in an 18-month follow-up
      period. Out of the total of 170 people, 169 were traced. The majority (60.9%) had
      had some specialist psychiatric contact in the follow-up period. Those with
      severe mental health problems formed a minority of presenters, but were heavy
      users of services. Coverage by CMHT services was insufficient to prevent crisis
      in many cases. Improved access to broader community services is needed for those
      with life crises. This study suggests some important gaps in coverage by wider
      mental health services, which the current mental health agenda goes some way
      towards addressing.

PMID- 12485133
TI  - Management of pain in older people within the nursing home: a preliminary study.
AB  - The provision of continuing care for older people has largely shifted from the
      hospital setting to the community, and nursing homes increasingly provide support
      for older people, many of whom exhibit multiple pathology and complex health and
      social care needs. However, the quality of pain management within this setting
      has been identified as an issue of concern. It has been estimated that
      approximately two-thirds of people aged 65 years and over experience chronic
      pain, and that the prevalence of chronic pain in nursing home residents is
      between 45% and 80%. However, there exist a number of barriers to the
      identification and management of chronic pain among older people resident in
      nursing homes, including sensory impairments in older people themselves and
      educational deficits among professionals. Such barriers need to be overcome if
      pain management is to be improved. The present study involved administering a pre
      piloted postal questionnaire to the managers of 121 nursing homes within a
      geographically defined area. Sixty-eight (56%) were completed and returned. The
      questionnaire broadly covered the following: prevalence of chronic pain and use
      of interventions; assessment and management strategies; education and training;
      and communication barriers. Overall, 37% of nursing home residents were
      identified as experiencing chronic non-malignant pain (pain lasting longer than 3
      months not caused by cancer) and 2% were reported as experiencing chronic
      malignant pain (pain lasting for more than 3 months caused by cancer).
      Paracetamol was identified as the most 'often' used analgesia for both pain
      modalities. Sixty-nine per cent of nursing homes did not have a written policy
      regarding pain management and 75% did not use a standardised pain assessment
      tool. Forty-four per cent of nursing homes provided education or training
      sessions for qualified staff and 34% provided this for care assistants. Forty per
      cent of qualified staff and 85% of care assistants had no specialist knowledge
      regarding the management of pain in older people. The present study confirms the
      need for the development of effective pain management strategies underpinned by
      appropriate training and education in order to meet the particular needs of older
      people.

PMID- 12485134
TI  - Coping and self-help group membership in Parkinson's disease: an exploratory
      qualitative study.
AB  - The present small-scale, exploratory, qualitative study was conducted to
      investigate how Parkinson's disease, a chronic progressive illness, had affected
      the lives of eight participants. It also explored whether self-help group
      membership was related to coping methods (four of the participants were members
      of the Parkinson's Disease Society and four were not). Semi-structured interviews
      were conducted and thematic analysis was used to identify and group themes which
      emerged from the participants' discourse. It was found that all participants had
      experienced losses of physical and mental functioning and independence, self
      identity and future, and were afraid of further losses. Although all participants
      used a range of coping methods, it was found that there were differences between
      members and non-members in the prominence of certain methods and overall coping
      style. For non-members, coping centred upon maintaining a normal life and denying
      the condition a central role, but for group members, the disease and its likely
      consequences were accepted and incorporated into everyday life. The discourse of
      non-members contained many references to a self-help group as a source of
      distress, while discourse of members identified it as a supportive resource. This
      exploratory study enhances our understanding of differences between people in
      their willingness to use a self-help group, and in turn, raises questions about
      the provision of psychological services in a chronic progressive illness.

PMID- 12485135
TI  - Satisfaction with respite care: a pilot study.
AB  - Satisfaction with respite care may be bound up with a variety of factors. The
      interaction of social support with ratings of a carer's satisfaction with respite
      care has not been explored in published work. The present authors postulated that
      social support, both during caring and during periods of relief from caring
      whilst in receipt of respite care, would be associated with greater satisfaction
      with respite care. They embarked upon a pilot study of carers who were looking
      after dependants with dementia, a particularly demanding form of care. Previously
      validated scales were used for determining levels of social support, and for
      assessing possible confounding factors such as carer depression or strain. One
      hundred and forty carers were contacted, but only 26 completed the
      questionnaires. In terms of perceived benefit to the carer, satisfaction was high
      (rating scale = 1-7, mean = 5.8, mode = 7) and correlated significantly with the
      numbers of people in the social support network (r = 0.57, P = 0.002), albeit not
      with any of the four measured types of support which they may have provided.
      Carer satisfaction was not significantly correlated with carer strain nor
      depression scores. Regression analysis demonstrated that 17% of the variance in
      this satisfaction score was accounted for by the numbers in the social support
      network. Other factors did not significantly explain the observed variation.

PMID- 12485136
TI  - Evaluating community capacity.
AB  - The aim of the present study was to examine the convergence of two approaches
      used to assess community capacity in health promotion interventions. One was used
      to examine women and men in rural communities in Fiji, and the other to study
      women only in rural communities in Nepal. Both approaches used a set of 'capacity
      domains', a ranking scale and a means of visually representing the findings. The
      experiences of using each approach, and the strengths and weaknesses of using
      rating scales and the 'capacity domains' to assess community capacity are
      discussed. The use of visual representations of community change, in particular
      the 'spider web' approach, are also discussed. The capacity building 'domains'
      presented in this study are robust and capture the essential qualities of a
      'capable community'. 'Parallel tracking' of the domains allows programmes
      themselves to be viewed as a means to the end of building community capacity.
      These approaches provide a useful new dimension to programme evaluation.

PMID- 12485137
TI  - Utilisation of postnatal care in Bangladesh: evidence from a longitudinal study.
AB  - Utilisation of health services is a complex behavioural phenomenon. Empirical
      studies of preventive and curative services in Bangladesh have often showed that
      the use of health services is related to the availability, quality and cost of
      services, as well as to social structure, health beliefs and personal
      characteristics of the users. The present paper attempts to examine factors
      associated with the utilisation of healthcare services during the postnatal
      period in Bangladesh by using prospective data from a survey on maternal
      morbidity in Bangladesh, conducted by the Bangladesh Institute of Research for
      Promotion of Essential and Reproductive Health and Technologies (BIRPERT). Both
      bivariate and multivariate analyses of the data confirmed that the mother's age
      at marriage had a significant and positive impact on the utilisation of quality
      healthcare services. The husband's occupation also showed a strong impact on
      healthcare utilisation, indicating higher use of quality care for postpartum
      morbidity by wives of business and service workers. The bivariate analysis showed
      that the number of pregnancies prior to the index pregnancy and desired
      pregnancies are significantly associated with the utilisation of postpartum
      healthcare. However, the results of this study were inconclusive on the influence
      of other predisposing and enabling factors, such as maternal education, the
      number of previous pregnancies, the occupation of the husband, antenatal care
      visits during pregnancy and access to health facilities. Multivariate logistic
      regression estimates did not show any significant impact of these factors on the
      use of maternal healthcare.

PMID- 12485138
TI  - Lay evaluation of services for childhood asthma.
AB  - Users' views on health services are increasingly valued, but insufficient
      attention has been given to evaluations of childhood services. Asthma, the most
      common chronic childhood disease, is an significant condition around which to
      explore views of childhood services, especially since most care is provided in
      the community rather than in hospital. The aim of the present study was to
      investigate the views of children, young people and their parents on primary care
      services for childhood asthma, to explain how they should be characterised as
      evaluators of health services, and to identify the dimensions of care which they
      see as important. The authors conducted semi-structured interviews with 20
      families recruited from responders to a respiratory symptoms questionnaire and
      from two general practices. Data were analysed using the constant comparative
      method. Children and young people identified outcomes of care, quality of care,
      communication and the professional-patient relationship, and organisation and
      access to healthcare as the key dimensions of their experiences of health
      services. They were active and critical, judging the performance and delivery of
      health services against standards which drew on lay knowledge and experience.
      Parents also emphasised outcomes, quality, organisation and access to healthcare
      as important, and drew attention to the complex and challenging nature of the
      professional-parent relationship. Parents had several roles, seeing themselves as
      carers and advocates as well as users of health services. They also drew on lay
      standards to evaluate care. Children and young people are willing and able to
      give active and critical views on health services. Parents' views should also be
      sought in their own right.

PMID- 12485139
TI  - Work satisfaction, stress, quality of care and morale of older people in a
      nursing home.
AB  - The aim in the present study, which was carried out in one nursing home for older
      people, was to determine the feasibility of working with care workers and very
      frail service users to investigate links between the levels of work satisfaction
      and stress of the staff, and the quality of care and morale of the residents.
      Most of the 44 care staff (70%) and 22 cognitively intact residents (82%)
      participated willingly in completing rating scales through self-completion
      questionnaire or by interview. Well-validated scales were used to measure job
      satisfaction, work stress, organisational commitment, perceived quality of care,
      and morale and mental health. The findings revealed a staff group with a fairly
      high level of job dissatisfaction and stress, who were, nevertheless, very
      committed to the nursing home. The morale of the residents was good although the
      residents rated the home atmosphere lower than the staff did. Significant
      correlations emerged, in the expected direction, between satisfaction,
      commitment, stress and quality of care perceived by staff. The correlations
      between home atmosphere perceived by residents, and their morale and mental
      health were low; further investigation is needed with a larger sample. This
      feasibility study supports the need for further research using a case-study
      approach in a small number of homes because of the labour-intensive nature of the
      data collection and the importance of triangulating data from many sources.

PMID- 12485148
TI  - HealthCyberMap: a semantic visual browser of medical Internet resources based on
      clinical codes and the human body metaphor.
AB  - OBJECTIVES: HealthCyberMap (HCM-http://healthcybermap.semanticweb.org) is a web
      based service for healthcare professionals and librarians, patients and the
      public in general that aims at mapping parts of the health information resources
      in cyberspace in novel ways to improve their retrieval and navigation. METHODS
      AND SERVICE DESCRIPTION: HCM adopts a clinical metadata framework built upon a
      clinical coding ontology for the semantic indexing, classification and browsing
      of Internet health information resources. A resource metadata base holds
      information about selected resources. HCM then uses GIS (Geographic Information
      Systems) spatialization methods to generate interactive navigational cybermaps
      from the metadata base. These visual cybermaps are based on familiar medical
      metaphors. CONCLUSIONS: HCM cybermaps can be considered as semantically
      spatialized, ontology-based browsing views of the underlying resource metadata
      base. Using a clinical coding scheme as a metric for spatialization ('semantic
      distance') is unique to HCM and is very much suited for the semantic
      categorization and navigation of Internet health information resources. Clinical
      codes ensure reliable and unambiguous topical indexing of these resources. HCM
      also introduces a useful form of cyberspatial analysis for the detection of
      topical coverage gaps in the resource metadata base using choropleth (shaded)
      maps of human body systems.

PMID- 12485149
TI  - A 5-star system for rating the quality of information based on DISCERN.
AB  - OBJECTIVE: To develop an explicit scheme for calculating a 5-star quality rating
      for consumer health information, and to test if there is good agreement be tween
      this and the final DISCERN quality question. DESIGN: A sample of 15 consumers and
      health professionals rated 26 health information leaflets covering a broad range
      of conditions and treatments using two new 5-star-rating schemes and the existing
      DISCERN final quality rating. Each scheme is based on the 15 DISCERN criteria,
      but the 5-star schemes provide more explicit methods for summarizing overall
      quality. The level of agreement between the three different rating systems was
      compared using Kappa scores with quadratic weights. Participants were also asked
      to complete a brief questionnaire that was designed to elicit their views on
      using a visual summary of the quality of health information. RESULTS: The level
      of agreement between each 5-star-rating system and the existing DISCERN quality
      rating question was high (kappa = 0.86, 95% CI 0.83-0.89 in both instances).
      Seventy-seven per cent of the sample preferred the second star-rating scheme, and
      80% reported they would use such a scheme. CONCLUSION: Assigning a single quality
      score using an explicit scoring scheme (represented by stars) based on answers to
      the DISCERN questionnaire is a reliable and valid way of rating consumer health
      information.

PMID- 12485152
TI  - Surfing for health: user evaluation of a health information website. Part two:
      fieldwork.

PMID- 12485150
TI  - Integrating medical communication skills with library skills curricula among
      first year medical students at the University of the West Indies, St. Augustine.
AB  - A two-year study designed to integrate the medical communication skills and
      library skills curricula at the University of the West Indies, St. Augustine is
      reported. Given that an integrated approach to curriculum development offers
      benefits to learners and staff. The objective of this study was to explore the
      feasibility of implementing this approach among Year 1 pre-clinical students in
      1997 and 1998. Student performance on an essay question that integrated the
      application of students' knowledge of written communication and library skills in
      a final examination performance was assessed. Pre- and post-test results of
      students' library skills were compared within each year. anova analysis indicated
      that there was a significant increase in mean scores from pre-test to post-test
      which suggests that students performed better on a test of their knowledge and
      application of library skills after instruction, but the unavailability of a
      control group made this finding inconclusive. The findings are discussed in
      relation to practical and intellectual issues in curriculum integration. It is
      concluded that this type of curriculum integration is feasible, creates linkages
      in the curriculum and does not increase demand on student time.

PMID- 12485153
TI  - Mapping medicine: collaborative collection management for biomedical resources.
      Review of the literature.

PMID- 12485154
TI  - Current Contents Connect and PubMed--a comparison of content and currency.

PMID- 12485155
TI  - Doctors' and patients' use of the Internet for healthcare: a study from one
      general practice.

PMID- 12485156
TI  - Information management in community health and primary care.

PMID- 12485157
TI  - On a cautious adoption of innovative projects.

PMID- 12485160
TI  - Two major Smad pathways in TGF-beta superfamily signalling.
AB  - Members of the transforming growth factor-beta (TGF-beta) superfamily bind to two
      different serine/threonine kinase receptors, i.e. type I and type II receptors.
      Upon ligand binding, type I receptors specifically activate intracellular Smad
      proteins. R-Smads are direct substrates of type I receptors; Smads 2 and 3 are
      specifically activated by activin/nodal and TGF-beta type I receptors, whereas
      Smads 1, 5 and 8 are activated by BMP type I receptors. Nearly 30 proteins have
      been identified as members of the TGF-beta superfamily in mammals, and can be
      classified based on whether they activate activin/TGF-beta-specific R-Smads (AR
      Smads) or BMP-specific R-Smads (BR-Smads). R-Smads form complexes with Co-Smads
      and translocate into the nucleus, where they regulate the transcription of target
      genes. AR-Smads bind to various proteins, including transcription factors and
      transcriptional co-activators or co-repressors, whereas BR-Smads interact with
      other proteins less efficiently than AR-Smads. Id proteins are induced by BR
      Smads, and play important roles in exhibiting some biological effects of BMPs.
      Understanding the mechanisms of TGF-beta superfamily signalling is thus important
      for the development of new ways to treat various clinical diseases in which TGF
      beta superfamily signalling is involved.

PMID- 12485161
TI  - Two conserved structural components, A-rich bulge and P4 XJ6/7 base-triples, in
      activating the group I ribozymes.
AB  - BACKGROUND: The A-rich bulge of the group I intron ribozyme, a highly conserved
      structural element in its P5 peripheral region, plays a significant role in
      activating the ribozyme. The bulge has been known to interact with the P4 stem
      forming P4 XJ6/7 base-triples in the conserved core. The base-triples by
      themselves have also been identified as a distinctive element responsible for
      enhancing the activity of the ribozyme. RESULTS: A weakly active variant of the
      Tetrahymena ribozyme lacking the P5 extension was dramatically activated by the
      addition of an A-rich bulge at the peripheral region, or by replacement of the
      original P4 XJ6/7 base-triples in the core structure with more stabilized
      isosteric ones. Biochemical analyses showed that the two methods of activation
      affect the ribozyme differently. CONCLUSIONS: The long-range interaction between
      the A-rich bulge and P4 or additionally stabilized P4 XJ6/7 base-triples can
      contribute dramatically to activation of the Tetrahymena ribozyme. Both improve
      the kcat value, which represents the rate of the limiting step of the ribozyme
      reaction when its binding site is saturated with GTP. However, the bulge or the
      modified base-triples gave a moderate reduction or considerable increase,
      respectively, to the Km(GTP) value.

PMID- 12485162
TI  - Signalling mechanisms in sphingosine 1-phosphate-promoted mesangial cell
      proliferation.
AB  - BACKGROUND: The bioactive sphingolipid sphingosine 1-phosphate (S1P) is formed by
      the activation of sphingosine kinase (SPHK) in diverse stimuli, such as platelet
      derived growth factor (PDGF). S1P acts not only as an extracellular mediator but
      also as an intracellular second messenger, resulting in the proliferation of
      various different types of cells. However, the signal transduction mechanism in
      S1P-induced proliferation of mesangial cells is poorly known. RESULTS: We
      examined the signalling mechanisms by which S1P and dihydro-S1P (DHS1P), another
      S1P receptor agonist, induce mesangial cell proliferation. We first observed that
      exogenous S1P/DHS1P had additive effects on the PDGF-promoted proliferation of
      mesangial cells. Treatment of mesangial cells with pertussis toxin almost
      completely inhibited S1P- and DHS1P-induced, and slightly inhibited PDGF-induced
      cell proliferation. Additionally, the ERK kinase inhibitor PD98059 partially
      blocked the proliferation of mesangial cells induced by all these ligands. N,N
      dimethylsphingosine, a competitive inhibitor of SPHK, reduced PDGF-induced
      mesangial cell proliferation, whereas over-expression of SPHK promoted it. We
      also revealed that PDGF induces SPHK mRNA expression and SPHK activity,
      suggesting that SPHK, which links the PDGF to the S1P signalling cascade, is, at
      least in part, involved in PDGF-induced mesangial cell proliferation. Moreover,
      we found that extracellular S1P stimulates two S1P receptors, EDG3 and EDG5,
      which leads to cell proliferation and survival. CONCLUSIONS: The data show that
      S1P-induced mesangial cell proliferation is mediated by EDG-dependent and 
      independent signalling pathways. S1P may cooperate with PDGF to increase the
      proliferation of mesangial cells during pathophysiological processes.

PMID- 12485163
TI  - Interaction of the chromatin compaction-inducing domain (LR domain) of Ki-67
      antigen with HP1 proteins.
AB  - BACKGROUND: The LR domain of marsupial chmadrin is defined by its C-terminal
      amino acid sequence, which contains several pairs of leucine (L) and arginine (R)
      residues. The LR domain of chmadrin causes a significant compaction of chromatin
      over the entire length of chromosomes when it is overproduced. The possible human
      homologue of chmadrin, Ki-67 antigen (pKi-67), also has a stretch of LR pairs,
      but with no obvious overall similarity, at its C-terminus. RESULTS: The LR domain
      of human pKi-67 also induced chromatin compaction, both in human and marsupial
      cells. A yeast two-hybrid assay and an in vitro binding assay demonstrated that
      the human LR domain binds to heterochromatin protein 1 (HP1), a well
      characterized molecule as a mediator of heterochromatin formation. In fixed cells
      stained with specific antibodies, the pKi-67 was found to be co-localized
      partially with HP1 at foci on chromosomes in an early G1 phase. Time-lapse
      observation in living cells co-expressing the fluorescently tagged proteins
      showed that the LR domain formed foci on chromosomes over a limited period of the
      cell cycle from the telophase to early G1 phase and that HP1 subsequently
      accumulated at these foci of the LR domain. CONCLUSIONS: Marsupial chmadrin and
      human pKi-67 induce chromatin compaction across species, possibly via the
      interaction of its LR domain with HP1.

PMID- 12485164
TI  - A minigene containing four discrete cis elements recapitulates GATA-1 gene
      expression in vivo.
AB  - BACKGROUND: The GATA-1haematopoietic enhancer (G1HE), located between 3.9 and 2.6
      kb 5' to the haematopoietic first exon, is essential for GATA-1 gene
      transcription in erythroid cells. However, G1HE is not sufficient to confer
      tissue specificity on the GATA-1 gene in vivo, indicating that additional
      regulatory sequences are necessary. RESULTS: We demonstrate here that two other
      upstream promoter elements containing a double GATA motif or two CACCC boxes are
      also indispensable for reporter gene expression in erythroid cells in the
      transgenic mouse. The combination of these three cis-acting regions was
      sufficient for reporter expression in primitive erythroid cells, as demonstrated
      by linking the elements together into a 659 bp artificial (GdC) minigene. The
      minigene activated the transcription of a reporter gene from either the
      endogenous or an exogenous thymidine kinase promoter, retaining cell type
      specificity. The addition of a 320 bp fragment in the first intron to the GdC
      minigene sustained reporter expression in the definitive stage. Moreover, a line
      of transgenic mouse that expressed GATA-1 cDNA under the control of the complete
      979 bp minigene rescued GATA-1 germ line mutant mice from embryonic lethality.
      CONCLUSIONS: A combination of four distinct sequence motifs co-operatively serve
      as a fundamental functional unit for GATA-1 erythroid transcription in vivo.

PMID- 12485165
TI  - Interaction between apterous and early expression of vestigial in formation of
      the dorso-ventral compartments in the Drosophila wing disc.
AB  - BACKGROUND: Compartment formation is a developmental process that requires the
      existence of barriers against intermixing between cell groups. In the Drosophila
      wing disc, the dorso-ventral (D/V) compartment boundary is defined by the
      expression of the apterous (ap) selector gene in the dorsal compartment. AP
      activity is under control of dLMO which destabilizes the formation of the AP-CHIP
      complex. RESULTS: We report that D/V boundary formation in the wing disc also
      depends on early expression of vestigial (vg). Our data suggest that vg is
      already required for wing cell proliferation before D/V compartmentalization. In
      addition, we show that over-expression of vg can, to some extent, rescue the
      effect of the absence of ap on D/V boundary formation. Early VG product regulates
      AP activity by inducing dLMO and thus indirectly regulating ap target genes such
      as fringe and the PSalpha1 and PSalpha2 integrins. CONCLUSION: Normal cell
      proliferation is necessary for ap expression at the level of the D/V boundary.
      This would be mediated by vg, which interacts in a dose-dependent way with ap.

PMID- 12485168
TI  - Good practice in head and neck fine needle aspiration cytology as assessed by
      CUSUM.
AB  - Providing data as evidence of good practice is becoming imperative to meet the
      demands of professional revalidation and clinical governance. Sensitivity and
      specificity are common performance measures in fine needle aspiration (FNA) but
      are vulnerable to discordant analytical methods. We introduce a CUSUM technique
      and show how it may be used to show attainment and maintenance of proficiency in
      head and neck (H&N) FNA. In addition, we show how it can be used to compare
      practices and demonstrate different performance for FNAs from different tissues;
      a fact that must be recognized by anyone devising minimum performance values.

PMID- 12485169
TI  - An audit of the accuracy of fine needle aspiration using a liquid-based cytology
      system in the setting of a rapid access breast clinic.
AB  - We have assessed the effectiveness and accuracy of reporting fine needle
      aspirates of the breast (FNAB) using a liquid-based cytology (LBC) system (the
      Cytospin) method) in the pressure situation of a rapid access clinic (RAC). We
      have reviewed every case from the RAC from June 1997 to February 2001 inclusive.
      There were 1322 cases, which accounted for 26% of the total FNAB received in our
      department over the period. There were 323 cancers and 999 benign cases in the
      group. The inadequate/nondiagnostic rate (C1) was 18%. The absolute sensitivity,
      including C1 cases, was 73% with the complete sensitivity being 90%. The groups
      of 'atypical, probably benign' (C3) and 'suspicious, probably malignant' (C4)
      accounted for a total of 6.2%. There were 28 false negative cases and 1 false
      positive case (a borderline phyllodes tumour). Comparing our results with the
      standards recommended by the NHSBSP has shown that the diagnosis of FNAB using
      this LBC method is feasible, accurate and reliable even in the pressure situation
      of a RAC.

PMID- 12485166
TI  - A comparative cDNA microarray analysis reveals a spectrum of genes regulated by
      Pax6 in mouse lens.
AB  - BACKGROUND: Pax6 is a transcription factor that is required for induction,
      growth, and maintenance of the lens; however, few direct target genes of Pax6 are
      known. RESULTS: In this report, we describe the results of a cDNA microarray
      analysis of lens transcripts from transgenic mice over-expressing Pax6 in lens
      fibre cells in order to narrow the field of potential direct Pax6 target genes.
      This study revealed that the transcript levels were significantly altered for 508
      of the 9700 genes analysed, including five genes encoding the cell adhesion
      molecules beta1-integrin, JAM1, L1 CAM, NCAM-140 and neogenin. Notably,
      comparisons between the genes differentially expressed in Pax6 heterozygous and
      Pax6 over-expressing lenses identified 13 common genes, including paralemmin,
      GDIbeta, ATF1, Hrp12 and Brg1. Immunohistochemistry and Western blotting
      demonstrated that Brg1 is expressed in the embryonic and neonatal (2-week-old)
      but not in 14-week adult lenses, and confirmed altered expression in transgenic
      lenses over-expressing Pax6. Furthermore, EMSA demonstrated that the BRG1
      promoter contains Pax6 binding sites, further supporting the proposition that it
      is directly regulated by Pax6. CONCLUSIONS: These results provide a list of genes
      with possible roles in lens biology and cataracts that are directly or indirectly
      regulated by Pax6.

PMID- 12485170
TI  - Efficacy and pattern of use of sputum cytology as a diagnostic test.
AB  - Sputum cytology is regarded by many clinicians as a noninvasive, cheap and simple
      test for the diagnosis of bronchogenic carcinoma. Since the introduction of fibre
      optic bronchoscopy and more easily obtained bronchial biopsies reliance on sputum
      cytology has diminished. However, in Edinburgh it was perceived that sputum
      samples were still being sent as well as, rather than instead of, bronchoscopic
      specimens. This retrospective study was undertaken to determine whether or not
      cytological examination of sputum is an efficient and sensitive test in the
      investigation of patients with suspected bronchogenic carcinoma. It demonstrated
      that the Lothian University Hospitals NHS Trust Pathology Directorate receives
      many sputa from departments not specializing in respiratory disease when there is
      no indication for the test. In addition, we have shown that the absolute
      sensitivity of the test is only 5% and that when there is a strong clinical
      suspicion of bronchogenic carcinoma the results of sputum cytology do not play a
      significant role in the management of the patient. We recommend that sputum
      cytology is restricted to those patients under the care of Respiratory Units in
      whom bronchoscopy is inappropriate or unsuccessful.

PMID- 12485171
TI  - Communicating mild and borderline abnormal cervical smear results: how and what
      are women told?
AB  - The way in which women are informed about borderline or mild smear results can
      have a significant psychological impact. By means of a questionnaire survey of
      general practices in Nottingham, England, this study audited the means by which
      abnormal smear results were normally communicated to subjects and analysed the
      content of these communications. Transmitting abnormal smear results, either by
      letter or by telephone call, was typically the responsibility of the practice
      nurse, and communications varied widely in informational content. We conclude
      that the method and content of communications imparting mild or borderline smear
      results differs between general practices, even within a small geographical area.

PMID- 12485172
TI  - Cytological features of chronic follicular cervicitis in liquid-based specimens:
      a potential diagnostic pitfall.
AB  - A review of negative split-sample cervical cytology cases revealed five cases
      reported as chronic follicular cervicitis. These cases showed characteristic
      morphological features in conventional smears with lymphoid cells, plasma cells
      and tingible body macrophages smeared across the slides. This contrasts with the
      presentation of ThinPrep samples (Cytic Corporation, Boxburgh, MA, USA), where
      cells were observed aggregated in clumps. The different presentation noted in
      liquid-based samples may require careful microscopic evaluation at high-power
      magnification.

PMID- 12485173
TI  - Gaucher's disease: morphological findings in a case studied with fine needle
      aspiration.
AB  - Fine needle aspiration (FNA) is a diagnostic tool whose inexpensiveness,
      simplicity and innocuousness have led it to be increasingly accepted in daily
      medical practice. This method, which is useful for the study of lesions that are
      accessible by radiological exploration or palpation, provides information about
      the cytological aspects of punctured lesions. Sometimes, such information can be
      extended to the histological area through study of cell blocks, true
      microbiopsies, which are of great diagnostic use. This was the technique used in
      the case described in the present report.

PMID- 12485174
TI  - Fine needle aspiration cytology in ameloblastoma of the mandible.

PMID- 12485175
TI  - BSCC terminology conference, koilocytosis and mild dyskaryosis.

PMID- 12485176
TI  - Sensitivity and specificity of urine cytology in the screening of transitional
      cell carcinomas.

PMID- 12485177
TI  - Liquid-based cytology.

PMID- 12485178
TI  - Filariasis in a tourist diagnosed by fine needle aspiration cytology.

PMID- 12485186
TI  - X-linked mental retardation: vanishing boundaries between non-specific (MRX) and
      syndromic (MRXS) forms.
AB  - This review covers the history and nosology of X-linked mental retardation (XLMR)
      in which the following, largely clinically based, subclassification was used:
      fragile X syndrome (FRAXA), syndromic forms (MRXS) and non-specific forms (MRX).
      After the discovery of the FMR2 gene at the FRAXE site, 10 MRX genes have been
      identified in the last 6 years. A short description is given of the strategies
      used to identify the genes that cause mental retardation (MR). Furthermore, their
      potential functions and the association with MR will be discussed. It is
      emphasized that mutations in several of these MR genes can result in non
      specific, as well as in syndromic forms of XLMR. Present findings stress the
      importance of accurate clinical evaluation. Most considerably, genotype-phenotype
      correlation studies of affected individuals in XLMR families with MRX gene
      mutations are necessary to define the criteria of MRX vs MRXS subclassification.

PMID- 12485190
TI  - Genetic landmarks through philately: Luis Morquio 1867-1935.
AB  - Morquio syndrome, also known as Mucopolysaccharidosis Type IV, is well known to
      pediatricians and geneticists, although it is rare. Many do not know much about
      the physician who first described this lysosomal disorder. In this brief review,
      the person and the disease are described, along with philatelic illustrations
      that have been issued to honor this famous Latin American medical hero.

PMID- 12485191
TI  - X-linked recessive Menkes disease: carrier detection in the case of a partial
      gene deletion.
AB  - X-linked recessive Menkes disease is a lethal disorder of copper metabolism,
      caused by defects in the ATP7A gene. About 15% of the mutations causing Menkes
      disease are partial gene deletions. We have previously demonstrated carrier
      diagnosis of deletions in heterozygotes by Southern blot analysis. As this
      technique is very time-consuming alternative methods are obviously of high value.
      Multiplex polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR) and
      spanning the deletion on genomic DNA can all be used for detection of partial
      gene deletions in male patients, but only spanning of the deletion can be applied
      for carrier detection. Simple multiplex PCR is not applicable for carrier
      detection because the normal allele of ATP7A will be PCR amplified thus masking
      the deletion. Here, we demonstrate, in addition to spanning of the deletion on
      genomic DNA, carrier detection based on the use of a previously unrecognized
      polymorphism in intron 13 of ATP7A in combination with previously identified
      intragenic polymorphic markers. We show that these intragenic markers can be used
      for carrier detection, not only indirectly by determining segregation of the
      disease related allele but also directly if located within the deleted region. We
      demonstrate determination of the carrier status of 21 at-risk carriers.

PMID- 12485192
TI  - X-linked recessive Menkes disease: identification of partial gene deletions in
      affected males.
AB  - Menkes disease is an X-linked recessive lethal disorder of copper metabolism,
      caused by defects in the ATP7A gene. Partial gene deletions comprise about 15% of
      the mutations causing Menkes disease. We have previously demonstrated
      identification of partial ATP7A deletions in patients by Southern blot analysis.
      In the present study, we report the use of three fast and reliable polymerase
      chain reaction (PCR)-based methods for the identification of partial ATP7A
      deletions in Menkes disease patients. First we demonstrate the use of multiplex
      PCR, a fast method for identification and rough localization of partial gene
      deletions, in which two exons of ATP7A are coamplified. Second, we present PCR
      amplification of genomic DNA across the deletion junctions, a method enabling
      identification of the deletion breakpoints and hence the exact size of the
      deletion. Finally, application of reverse transcription PCR (RT-PCR) for
      identification and localization of gene deletions at the cDNA level is
      demonstrated. By studying the mutation at the cDNA level the predicted effect of
      the mutation on the amino acid sequence and consequently the protein structure
      and function can be inferred. We demonstrate characterization of partial gene
      deletions in five patients, and in three of these we were able to determine the
      breakpoint sequences.

PMID- 12485193
TI  - Genetic origins in a South American clefting population.
AB  - It has been proposed that susceptibility to clefting in South America is related
      to Amerindian ancestry, where clefting is present at a higher frequency than in
      the other admixed populations (Caucasian and African) that make up the diverse
      racial mix of current South Americans. To clarify the genetic origins and
      establish a method for genetic mapping, mitochondrial DNA variation and Y
      chromosome markers were studied in a South American population affected with
      clefting. Two-hundred and seventeen subjects and matched controls were selected
      through the Latin-American Collaborative Study of Congenital Malformations
      (ECLAMC). The case group showed a higher frequency of Native American haplogroups
      and a lower frequency of African haplogroups (p < 0.00001). In addition, the case
      group showed a much higher frequency of the specific native American haplogroup D
      than the control group (p < 0.00001). For the Y-chromosome markers, the case
      group showed a lower frequency of the African-specific marker, YAP (p = 0.002),
      and a higher frequency of the Native American-specific marker, DYS199 (p <
      0.00001). Even though differences were found in the frequencies of the markers
      studied, the contribution of each founder population was similar for both groups.
      Results suggest a strong Native American maternal contribution and a strong
      Caucasian (Spanish and Portuguese) paternal contribution to the population
      studied. The implications of this finding include the possibility of using
      admixture mapping approaches to this population.

PMID- 12485194
TI  - Evaluation of the needs of spouses of female carriers of mutations in BRCA1 and
      BRCA2.
AB  - The process of genetic testing involves the entire family, including spouses. The
      objective of this study was to measure the specific needs and to describe the
      experiences of spouses of women who received genetic counseling for a positive
      BRCA1/2 result. We surveyed 59 spouses of female mutation carriers. The mean
      length of relationships was 26 years (range: 2.5-50 years). All were supportive
      of their spouses' decision to undergo genetic testing and counselling. Four
      respondents stated that they wished that they had received additional support at
      the time of test disclosure and 20% felt that their wives had received inadequate
      support. One-quarter of the spouses believed that their relationship had changed
      because of genetic testing; most felt that they had become closer to their wives.
      Husbands were most concerned about the risk of their wife dying of cancer (43%),
      followed by the risk of their spouse developing cancer (19%) and the risk that
      their children would test positive for the BRCA mutation (14%). Distress levels,
      measured by the Impact of Event scale, suggest that few spouses were experiencing
      clinical levels of distress.

PMID- 12485195
TI  - FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate.
AB  - We report a family showing autosomal-dominant segregation of upper- and lower
      eyelid distichiasis (double row of eyelashes) in seven affected relatives over
      three generations, in addition to below-knee lymphedema of pubertal onset
      (lymphoedema proecox) in three. Two children had cleft palate in addition to
      distichiasis, but without the previously reported association with the Pierre
      Robin sequence. Other ophthalmologic anomalies included divergent strabismus and
      early-onset myopia. This family was found to be completely linked to markers
      mapped to 16q24.3 and thereby proposed to be allelic to the distichiasis
      lymphedema syndrome (DL, MIM 153400), although pterygium colli, congenital heart
      disease, or facial dysmorphism were not features found here. As FOXC2/FKLH14
      mutations were found to underlie DL and diverse hereditary lymphedema conditions,
      this gene was examined by sequence analysis. An out-of-frame deletion (914
      921del) was identified and found to segregate with the disease, further
      highlighting the phenotypic heterogeneity of lymphedema conditions linked to
      FOXC2 truncating mutations. Whether such heterogeneity is related to genotype
      phenotype correlation, a hypothesis not primarily supported by the apparent loss
      of-function mechanism of the mutations, or governed by modifying genes, remains
      to be determined.

PMID- 12485196
TI  - Association between G-308A polymorphism of the tumor necrosis factor-alpha gene
      and 24-hour ambulatory blood pressure values in type 1 diabetic adolescents.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine, which also
      influences blood pressure (BP). The G-308A polymorphism of the TNF-alpha gene is
      associated with altered TNF-alpha production. The prevalence of the TNF-alpha
      308A allele is reportedly higher among patients with type 1 diabetes mellitus
      (T1DM) than in the healthy population. In this study we investigated whether this
      genetic polymorphism might correlate with BP values in diabetic adolescents.
      Ambulatory BP monitoring (ABPM) was performed in 126 adolescents with T1DM (mean
      age: 14 +/- 2.4 years). The TNF-alpha G-308A genotype was determined by using
      polymerase chain reaction (PCR) and restriction fragment length polymorphism
      (RFLP) methodologies. ABPM results were related to healthy reference values and
      are given as standard deviation score (SDS). The prevalence of the -308A allele
      was higher in diabetic adolescents than the Hungarian reference population (0.26
      vs 0.14, p < 0.01). TNF-alpha genotype was associated both with systolic and
      diastolic BP values (p < 0.01 and p < 0.01, respectively). In patients with TNF
      alpha-308GG and -308GA/AA genotypes, the 24-h systolic BP average values were
      0.37 +/- 1.33 and -0.38 +/- 1.28 SDS, while 24-h diastolic BP average values were
      0.09 +/- 1.30 and -0.67 +/- 1.31 SDS. Hence, the TNF-alpha-308A allele carrier
      state appears to be associated with lower systolic and diastolic BP values.

PMID- 12485197
TI  - Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in
      Singapore.
AB  - We report the prevalence and ethnic differences of autosomal-dominant cerebellar
      ataxia (ADCA) in Singapore. Amongst 204 patients with ataxia who underwent
      genetic testing for dentatorubral-pallidoluysian atrophy (DRPLA) and for
      spinocerebellar ataxias (SCA) 1, 2, 3, 6, 7, 8, 10 and 12, 58 (28.4%) patients
      from 36 families tested positive. SCA 3 was identified in 31 (53.4%) patients
      from 15 families, SCA 2 in 17 (29.3%) patients from 12 families and SCA 1 in four
      (6.9%) patients from four families. Other SCA subtypes were rare. SCA 2 was the
      only subtype identified amongst ethnic Malay and ethnic Indian families. The
      estimated prevalence of ADCA in Singaporean families was at least 1 : 27,000.
      Based on the history and ancestry of Singaporeans, our study supported a founder
      effect for specific SCA subtypes and the association of ethnicity-specific SCA
      subtypes. Our findings suggest that SCA 2 is relatively common amongst the Malay
      race and that priority testing for SCA 3 and SCA 2 for ethnic Chinese, and SCA 2
      for ethnic Malay, may be cost effective and relevant for the region.

PMID- 12485198
TI  - Characterization of partial trisomy 9p due to insertional translocation by
      chromosomal (micro)FISH.
AB  - We describe a family with an insertion 12;9 translocation occurring in a balanced
      form in a mother and two sons, but in an unbalanced form in the proband,
      resulting in trisomy of chromosome region 9p22-->9p24. The proband manifests
      typical features of trisomy 9p; the clinical signs were mental and growth
      retardation, microcephaly, epicanthus, low-set ears, micrognathia, clinodactyly
      and hypoplastic phalanges of the fifth fingers, hypoplasia or absence of
      toenails, and extremely small genitals. The GTG-banded findings were confirmed
      using (micro)FISH. Intriguingly, the mother and the two carrier sons exhibited
      major learning difficulties that were not present in the non-carrier sister of
      the mother: this may be due to a gene disruption or induction of abnormal
      expression. Dysmorphic features were not present in the three carriers. We
      compare our clinical and cytogenetic findings with other cases of partial trisomy
      9p reported in the literature.

PMID- 12485200
TI  - Hypovolaemic headache is complex.

PMID- 12485201
TI  - Benign cough headache.
AB  - Benign cough headache is an uncommon primary headache disorder marked by short
      lasting attacks of pain triggered by coughing. Magnetic resonance imaging of the
      brain is required to assure that the cough headache is truly benign. The
      aetiology of the pain is unclear, but is probably associated with the brief
      increased intracranial pressure that attends coughing. We have reviewed the
      clinical features, aetiology, differential diagnosis, management, and prognosis
      of benign cough headache.

PMID- 12485202
TI  - Spontaneous CSF leaks mimicking benign exertional headaches.
AB  - Spontaneous CSF leaks are increasingly recognized, and a broader clinical and
      imaging spectrum of the disorder is emerging. The headaches of CSF leaks are
      typically orthostatic, but sometimes especially with chronicity the orthostatic
      features are blurred into lingering chronic daily headaches. Additional types of
      headache are also increasingly recognized. Two patients with spontaneous CSF
      leaks presented with intermittent transient severe headaches provoked by Valsalva
      type manoeuvres. Orthostatic features were absent and the patients were
      asymptomatic if they avoided the provoking manoeuvres. One patient had been
      treated for 6 years for benign exertional headaches and had failed many medical
      treatments, including courses of indomethacin. He was found to have a leak from
      cribriform plate. The second patient had been symptomatic for several months, had
      diffuse pachymeningeal gadolinium enhancement on head magnetic resonance imaging,
      spinal meningeal diverticula, and CSF leak at the thoracic spine level. Headaches
      that mimic benign exertional headaches are yet another mode of the still
      broadening clinical presentation of spontaneous CSF leaks.

PMID- 12485203
TI  - Exertional headache. I. Vaga study of headache epidemiology.
AB  - The aim was to assess the prevalence ('life-time') and manifestations of
      exertional headache and to validate some of the clinical diagnostic criteria.
      This study is part of the Vaga headache epidemiology study, where 1838 18-65-year
      old dalesmen were personally examined in a 'semistructured' interview. With the
      criteria used, the prevalence was 12.3%. There was a slight but significant
      female preponderance (F/M ratio 1.38). There was a mixture of short- and more
      long-lasting attacks. Attacks followed long-lasting and strenuous
      effort/exhaustion. The precipitation mechanisms differed essentially from the
      cough/sneezing type of provocation. Blinded recheck of records (n = 100) as well
      as recheck of dalesmen (n = 41) showed high kappa values. The clinical
      manifestations differed essentially from Rooke's (1968) description (that mainly
      dealt with the 'cough headache'-type). The present findings were similar to those
      in Pascual's description of exertional headache from 1996.

PMID- 12485204
TI  - The sensitivity and specificity of the case definition criteria in diagnosis of
      headache: a school-based epidemiological study of 5562 children in Mersin.
AB  - The objectives of the present study were: (i) to estimate the prevalence of
      recurrent headaches in schoolchildren (ranging from 2nd to 5th degrees) in Mersin
      city of Turkey; (ii) to determine the sensitivity, specificity, positive
      predictive value and positive likelihood ratio of the diagnostic headache
      characteristics in children with migraine and tension-type headache (TTH) using
      neurologist's diagnosis as the gold standard. The stratified sample of study was
      composed of 5562 children. The prevalence of recurrent headache was 49.2% (2739
      of 5562) and the prevalence of current headache was 31.3% (859 of 2739). TTH was
      more common than migraine (24.7% vs. 10.4%). The most sensitive headache
      characteristic for migraine was 'severity of pain' and the most sensitive
      definitive symptom was 'duration of headache' in children with TTH. International
      Headache Society-based symptom definition criteria are highly beneficial in
      diagnosis of childhood headache, if used together with detailed clinical
      assessment.

PMID- 12485205
TI  - Preclinical studies characterizing the anti-migraine and cardiovascular effects
      of the selective 5-HT1D receptor agonist PNU-142633.
AB  - The present study describes the preclinical pharmacology of a highly selective 5
      HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human
      5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The
      intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to
      be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that
      of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log
      more potent than sumatriptan in preventing plasma protein extravasation induced
      by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU
      142633 reduced the increase in cat nucleus trigeminal caudalis blood flow
      elicited by electrical stimulation of the trigeminal ganglion compared with the
      vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated
      in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal
      and coronary arteries while PNU-142633 failed to alter resistance in these
      vascular beds. These data are discussed in relation to the clinical findings of
      PNU-142633 in a phase II acute migraine study.

PMID- 12485206
TI  - Ergot and triptan overuse in Austria--an evaluation of clinical data and cost.
AB  - Austria is one of the countries, in which ergots are still the most commonly used
      acute anti-migraine drugs. Overuse and chronification is a clinical problem for
      ergots, but also for the recently developed triptans. In a retrospective study
      for the year 1999 we evaluated clinical data from all Austrian neurological
      hospitals including cost of withdrawal as well as the estimated cost for ergots
      and triptans on the pharmaceutical retail market. We identified a total of 96
      patients that underwent withdrawal, all of whom because of ergot overuse, and
      some with considerable long-term side-effects. The cost of withdrawal (more than
      1300 000) together with direct cost of medication amounted to more than 11
      million. In contrast, cost of medication for triptans was 12.8 million for the
      same year, without any cost for withdrawal. If only cost aspects were to be
      considered in the prescription of acute anti-migraine drugs, our data would
      suggest to choose ergots rather than triptans. However, as scientific evidence is
      clearly in favour of triptans, decision making for the prescribing clinicians is
      more complex and will primarily focus on optimizing patient care, but also depend
      on the respective socio-economic situation.

PMID- 12485207
TI  - SUNCT syndrome: priming of symptomatic periods and worsening of symptoms by
      treatment with calcium channel blockers.
AB  - We report a SUNCT patient who showed both a precipitation and worsening of
      symptomatic periods after treatment with L-type calcium channel blockers. This
      pharmacological response may provide us with important clues for understanding
      the pathophysiology of SUNCT, and hopefully to find a remedy for the victims of
      this syndrome. This observation could also support a verapamil trial in SUNCT
      patients as a precipitating of attacks.

PMID- 12485208
TI  - Naratriptan in the preventive treatment of cluster headache.
AB  - We describe the preventive use of naratriptan, mostly as add-on to high-dose
      verapamil treatment, in nine patients with cluster headache. The addition of the
      naratriptan further improved the headaches in seven of the nine patients.

PMID- 12485209
TI  - Health-related quality of life in patients with cluster headache during active
      periods.
AB  - Cluster headache is characterized by excruciatingly painful headaches which occur
      one or several times during the day. Little is known about the functional
      consequences of this severe headache form. We assessed health-related quality of
      life in 56 consecutive patients, 34 of whom were episodic cluster headache
      patients during an active period, and 22 had chronic cluster headache. All
      patients completed the Short Form-36 (SF-36). We found lower scores in the
      studied patients than in those reported in the general population for all SF-36
      domains. For most scales the difference was significant (P < 0.0001, Student's t
      test, Bonferroni correction). Our findings suggest that cluster headache has
      marked functional consequences even when appropriate treatments are used.

PMID- 12485210
TI  - Spontaneous intracranial hypotension causing a partial third cranial nerve palsy:
      a novel observation.

PMID- 12485211
TI  - Hypnic headache syndrome: clinical aspects of eight patients in Brazil.

PMID- 12485213
TI  - Cervicogenic headache.

PMID- 12485215
TI  - Acute malignant colorectal obstruction and self-expandable metallic stents.

PMID- 12485216
TI  - Transanal endoscopic microsurgery comes to Australasia.

PMID- 12485217
TI  - Parathyroid autotransplantation: an essential technique for safe thyroid surgery.

PMID- 12485218
TI  - Transanal endoscopic microsurgery: the first 50 cases.
AB  - BACKGROUND: Transanal endoscopic microsurgery is a form of minimally invasive
      rectal surgery first used at Cabrini Hospital in April 1997. This paper presents
      a prospective analysis of the first 50 cases with a median follow up of 33 months
      (range 20-48 months). METHODS: Prospective data was obtained from all cases
      between April 1997 and June 2000. RESULTS: Forty-nine patients (30 men and 19
      women) underwent 50 procedures. Thirty-six had benign lesions and 14 malignant.
      The mean distance of the lower edge of the lesion from the anal verge was 8.7 cm.
      Three cases were converted to traditional transanal or transabdominal operations.
      Full-thickness excision was performed on 26 patients and the rectal wound was
      closed in 13 cases. The mean duration of transanal endoscopic microsurgery was 67
      min (range 20-175), with a mean blood loss of 24 mL (0-300). The mean diameter
      and area of the fixed specimen was 3.7 cm (1.5-9.8) and 11.4 cm2 (0.8-18.9),
      respectively. Complications included postoperative fever (3), urinary retention
      (1) and per rectum bleeding (1). There was one death. The mean length of stay was
      4 days. Histology confirmed complete excision in 39 (78%) cases and there have
      been two instances of local recurrence of adenoma (5%). CONCLUSIONS: Transanal
      endoscopic microsurgery is an effective, safe and cost-beneficial procedure for
      local excision of selected lesions in the middle and upper thirds of the rectum.

PMID- 12485219
TI  - Gall bladder cancer, extrahepatic bile duct cancer and ampullary carcinoma in New
      Zealand: Demographics, pathology and survival.
AB  - INTRODUCTION: The aim of present paper was to document the incidence of gall
      bladder cancer, cancer of the extrahepatic bile ducts and ampullary carcinoma in
      New Zealand. METHODS: Data were collected from the New Zealand Cancer Registry
      from 1980 to 1997 and combined with national census statistics to give crude and
      age standardized incidence rates. RESULTS: Over the 18-year study period, 226
      carcinomas of the ampulla of Vater, 608 gall bladder cancers, and 486
      extrahepatic cholangiocarcinomas were registered. The age standardized incidence
      rates for gall bladder carcinoma in all New Zealanders were 0.41/100 000 in men
      and 0.74/100 000 in women. The age standardized incidence rates for gall bladder
      cancer in Maori were 1.49/100 000 in Maori men and 1.59/100 000 in Maori women.
      The corresponding age standardized incidence rates for extrahepatic bile duct
      cancers were 0.67/100 000 in men and 0.45/100 000 in women. There were
      insufficient cases to calculate an age standardized incidence in Maori or Pacific
      Islanders. For carcinoma of the ampulla, the age standardized rates were 0.34/100
      000 in men and 0.25/100 000 in women. There were insufficient cases to calculate
      an age standardized incidence rate for Maori or Pacific Islanders. When histology
      was defined adenocarcinoma was the most common form of cancer occurring in 66% of
      gall bladder cancers, 91% of extrahepatic bile duct cancers and 70% of ampullary
      cancers. Most tumours were advanced at presentation with regional or distant
      metastases present in 72% of gall bladder cancers, 63% of extrahepatic bile duct
      cancers and 69% of ampullary tumours at diagnosis. Survival was poor with median
      survivals of 86 days, 151 days and 440 days recorded for gall bladder cancer,
      extrahepatic bile duct cancer and ampullary cancer, respectively. CONCLUSIONS:
      The demographic profile, pathology and survival of patients with gall bladder
      cancer, extrahepatic bile duct cancer and ampullary carcinoma are similar in New
      Zealand to that of other Western countries. However New Zealand Maori have a
      relatively high incidence of gall bladder cancer, and the incidence is equal in
      both Maori men and women, while cancers of the extra-hepatic bile duct and
      ampulla of Vater are rare in Maori. In comparison, cancers of the gall bladder,
      extrahepatic bile ducts and ampulla are rare in Pacific Islanders.

PMID- 12485221
TI  - Vascular closure staples reduce intimal hyperplasia in prosthesis implantation.
AB  - BACKGROUND: Vascular surgery, like the various other surgical specialities, has
      seen an increasing demand toward faster and more minimally invasive procedures.
      One such need is to create a reliable vascular anastomosis that is faster, easier
      and less damaging to the tissue. The vascular closure staples (VCS*) device
      provides such characteristics but, to date, no studies have investigated its
      effectiveness in reducing intimal hyperplasia when used for vascular prosthesis
      implantation. The present study evaluated its effectiveness compared with
      suturing of a graft in vascular prosthesis implantation. METHODS: Twelve female
      Merino sheep underwent gelatin sealed Dacron patch graft implantation into the
      left and right common carotid artery. Grafts were randomly allocated so that one
      carotid artery and graft was anastomosed using sutures and the other with VCS*.
      The two techniques were compared for operation time, clip/suture numbers and
      blood loss during the implantation procedure. After a 4-week period, the sheep
      were killed and the grafts were harvested for intimal hyperplasia (IH)
      assessment. RESULTS: There was a significant reduction in the amount of IH seen
      in the VCS* group (mean +/- SD: 0.278 +/- 0.079 mm2/mm) when compared with the
      sutured group (0.575 +/- 0.331 mm2/mm) (P < 0.05). There was also significant
      reduction in anastomosis time (mean +/- SD: 14 +/- 4.4 min) and fewer points of
      contact (23 +/- 1.4) using the VCS* compared with suturing (22 +/- 3.2 min, P <
      0.01; 27 +/- 3.3, P < 0.05, respectively). CONCLUSIONS: In this model, the VCS*
      shows several distinct advantages over suturing with significant time saving at
      operation and, most importantly, the reduction of IH seen at 1 month.

PMID- 12485222
TI  - Biliary tract injury in laparoscopic cholecystectomy: results of a single unit.
AB  - BACKGROUND: Laparoscopic cholecystectomy was introduced into Australia in early
      1990. Its rapid increase in acceptance was, however, tempered by reports of an
      increased incidence of bile duct injury. The aim of this study was to report on
      the incidence of biliary tract injuries in a single unit, comment on the way they
      were managed and look at strategies to prevent them. METHODS: A retrospective
      audit was conducted on laparoscopic cholecystectomies performed between January
      1992 and March 2001. The data was collated from patient medical record files and
      yielded a total of 1216 procedures. RESULTS: There were 899 women (74%) and 317
      men (26%), with an age range of 13-92 years. Most of the procedures were
      performed on an elective (94%) rather than emergent basis (6%). There was one
      bile duct injury (0.09%) and seven bile leaks (0.63%). The single injury involved
      common bile duct obstruction by a misplaced clip and was successfully managed by
      chol-angio-enteric bypass. Of the seven bile leaks, three were from the cystic
      duct stump, two from the gallbladder bed, and two were unidentified, settling
      conservatively. Of the five patients actively treated, two underwent therapeutic
      laparoscopy, two proceeded to laparotomy, and one was managed successfully by
      endoscopic stenting. CONCLUSIONS: Single-centre studies such as this are
      important in ensuring that standards of surgery are maintained in a community
      setting.

PMID- 12485223
TI  - Colonic epithelial atrophy induced by a fibre-free diet in rats is reversed by
      minimal amounts of luminal butyrate, but only in the short term.
AB  - BACKGROUND: Luminal butyrate may be trophic to the colonic epithelium, but this
      effect is poorly characterized. The aim of the present study was to define the
      dose-response, time-course, site-specificity and the dependence on background
      diet of the effects of butyrate on epithelial proliferation in normal distal
      colon, using an in vivo rat model of colonic substrate delivery. METHODS: Male
      Sprague-Dawley rats, maintained on a fibre-free diet, had butyrate infused twice
      daily into the colonic lumen via polyethylene tubes placed at laparotomy. Varying
      dose levels (0-80 micro mol/d; 4 d), site (caecal vs distal colonic), duration of
      infusions (1-5 weeks; 80 micro mol/d), or dietary fibre intake were investigated.
      Epithelial proliferative indices were assessed stathmokinetically. RESULTS: Four
      day infusions of butyrate led to a progressive trophic effect (cells/crypt column
      increased from 37.9 +/- 1.6 at 0 micro mol/d to 44.7 +/- 1.2 at 80 micro mol/d)
      on fibre-deprived colonic mucosa, related linearly to the daily butyrate dose (P
      < 0.001, linear regression). This effect was mediated by increases in the number
      and proportion of mitoses, related to the square of the butyrate dose (P < 0.001
      in each case, polynomial regression). Butyrate (80 micro mol/d) was associated
      with significantly higher cellularity (59.9 +/- 1.4) and mitotic activity (4.9 +/
      0.6) per crypt column compared to vehicle controls (50.3 +/- 1.6 and 0.9 +/-
      0.2, respectively; P < 0.05, t-tests), at 1 and 3 weeks, but not at 5 weeks.
      Butyrate had similar effects on distal colonic crypt cellularity (62.0 +/- 1.5)
      when delivered caecally, but in rats fed a fibre-containing diet, colonic crypt
      cellularity (55.3 +/- 3.2) was similar to baseline (59.6 +/- 1.9). CONCLUSIONS:
      Trophic effects of butyrate are concentration-dependent and occur at low doses in
      the short term, but are not sustained over longer periods. They are seen only in
      a fibre-deprived state and appear to be independent of the site of
      administration.

PMID- 12485224
TI  - Primary megaureter: results of surgical treatment.
AB  - BACKGROUND: The aim of this study was to assess the clinical and radiological
      outcome after surgical treatment for primary -megaureter. METHODS: A
      retrospective analysis of 16 patients who had reimplantation of 17 primary
      megaureters between January 1997 and April 2001 was performed. Patients who had
      additional urinary tract pathology were not included in this study. The intent of
      the study was to focus on the complex range of data points that were used to
      reach the decision to operate. RESULTS: Six of eight patients with febrile
      urinary tract infections prior to surgery have been without infections
      postoperatively. One patient who presented with daytime wetting has less wetting
      postoperatively, and one baby who presented with failure to thrive and postfeed
      vomiting, is feeding well postoperatively. On ultrasound investigation, the
      median diameter of the megaureter prior to operation was 11 mm (range 6-24 mm).
      One month after the operation, dilatation of the ureter could no longer be
      demonstrated in 10, was reduced in six, and increased in one of 17 ureters. Three
      months postoperatively, hydroureter was no longer detected in 14 and was reduced
      in three. In comparison, the hydronephrosis 1 month postoperatively was reduced
      in six, unchanged in seven and worse in four out of 17 kidneys, and 3 months
      after the operation, hydronephrosis was reduced in 13 and was unchanged in four
      compared with preoperative findings. Renograms at 3 months postoperatively showed
      free drainage in the 11 kidneys with impaired drainage preoperatively, and
      drainage continued to be normal in all six kidneys with normal drainage
      preoperatively. Median pre-operative renographic split function was 47% (range 39
      54%), and was not significantly changed 3 months after the operation.
      CONCLUSIONS: When the decision to surgically intervene was made on a
      multifactorial basis, reimplantation of a primary mega-ureter resulted in
      improved clinical status, reduced dilation of the ureter and renal pelvis, and
      free drainage of the upper urinary tract.

PMID- 12485225
TI  - Pancreatic abscess: 10 years experience.
AB  - BACKGROUND: Secondary infections of pancreatic and peripancreatic necrosis
      account for most of the deaths following acute pancreatitis. These infections
      occur in the form of 'infected pancreatic necrosis' and 'pancreatic abscess'. The
      latter is a rare complication of acute pancreatitis in comparison with the
      former. METHODS: Twenty-one patients with pancreatic abscess were managed over a
      10-year period at a tertiary care centre in Northern India. The present report
      details the clinical profile, investigations performed and management strategy
      (surgery and intervention radiology) of these patients. The role of surgery and
      percutaneous catheter drainage (PCD) in the management of pancreatic abscess is
      discussed, with emphasis on the successful outcome seen in a properly selected
      group of patients managed by PCD. RESULTS: Of the 21 patients, 12 were managed by
      percutaneous intervention, nine were managed surgically (of these, two had a
      prior PCD) and two patients were managed conservatively. The overall mortality
      was 9.5% (2/21). Thus, percutaneous management was suitable for 57% patients, was
      successful in 83.3%, with a mortality of 8.3%. Surgical therapy alone was offered
      to 33% of patients, was successful in 85.7%, with a mortality of 14.2%.
      Complications were seen in four of the nine patients managed by percutaneous
      drainage alone and eight of the nine patients managed surgically. CONCLUSIONS:
      Pancreatic abscess is a potentially lethal complication in patients recovering
      from acute pancreatitis. Early diagnosis and prompt intervention with careful
      selection of patients based on computed tomography imaging for surgical or
      percutaneous radio-logical management, is met with a successful outcome in a
      majority of patients. The roles of surgery and PCD are complementary.

PMID- 12485227
TI  - Recurrent laryngeal nerve in thyroid surgery: a critical appraisal.
AB  - BACKGROUND: Identification and preservation of the recurrent laryngeal nerve
      (RLN) is of major concern in surgery of the thyroid gland. The purpose of this
      study was to review the surgical anatomy of the nerve and to describe its
      relationship to other important structures. METHODS: A total of 325 patients were
      accrued in this prospective non-randomized study from January 1999 to December
      2000. All patients who had total, subtotal and hemithyroidectomies were included
      in this study. Each side of the thyroid gland was considered as a separate unit
      in the analysis of the results. RESULTS: Two hundred and seventy-six patients had
      thyroidectomies as their primary operation, while 49 patients had them as a
      reoperative procedure. There were 276 women and 46 men (6:1 female to male ratio)
      with a mean age of 43.1 years (range: 10-84 years). The total number of
      dissections was 502. The RLN was clearly identified in 491 (97.8%) dissections:
      single trunk in 323 dissections (65.8%), two extralaryngeal branches in 164
      dissections (33.4%), and three extralaryngeal branches in three dissections
      (0.6%). One non-recurrent laryngeal nerve was encountered (0.2%) in the series.
      The proximity of the RLN to the inferior thyroid artery (ITA) was noted in 444
      (90.4%) dissections: 372 (83.8%) nerves were described to be posterior and
      intertwined between the branches of the ITA, and in 72 (16.2%) RLNs, they were
      observed to be anterior to the ITA. The close association of RLN to an enlarged
      tubercle of Zuckerkandl was documented in 381 dissections (73.7%). A total of 231
      RLNs (60.8%) was seen in the tracheoesophageal groove, 18 (4.9%) nerves were
      observed to be lateral to the trachea, and in 109 (28.3%), they were posterior in
      location. Of concern in 23 (6.0%) dissections the RLN was on the anterior surface
      of the thyroid gland, which is at highest risk of injury before curving down to
      pass behind the tubercle of Zuckerkandl. It appears that the anterior course of
      the RLN was seen more often in the reoperative procedures to the thyroid gland
      (20%). CONCLUSIONS: Although various methods of localizing the RLN have been
      described, surgeons should be aware of the variations and have a thorough
      knowledge of normal anatomy in order to achieve a high standard of care. This
      will ensure the integrity and safety of the RLN in thyroid surgery. The
      anatomical variation may be minor in degree, but is of great importance as it may
      affect the outcome of the surgery and the patient's quality of life.

PMID- 12485228
TI  - Paediatric elective surgical conditions as seen at a referral hospital in Kumasi,
      Ghana.
AB  - BACKGROUND: Data on paediatric surgical conditions in sub-Saharan countries,
      including Ghana, are scanty and sketchy. Using hospital-based data, it is
      possible to assess the epidemiology of diseases among children, and the morbidity
      and mortality rates. METHODS: Between January 1997 and December 2000, records of
      1200 children treated consecutively with elective surgery at Komfo Anokye
      Teaching Hospital in Kumasi, Ghana, were analysed for name, age, sex,
      postoperative diagnosis, procedure carried out and outcome of treatment RESULTS:
      The ages of the children ranged from 0 to 14 years, with a mean age of 3.5 years
      (95% confidence interval: 3.3-3.7) with a boy/girl ratio of 3.1:1. Congenital
      anomalies were the most common problem (83%), followed by tumours (4%), cysts
      (3%), uncircumcised penis (2%), and lymphadenopathy of varying aetiologies (2%).
      The most common congenital anomaly was inguinal hernia, and the rarest, biliary
      atresia. Eighty-two percent of the children in this series were treated as day
      care cases. Overall mortality in the series was 0.8%. CONCLUSIONS: The data
      reviewed here demonstrate that there is a wide range of surgical conditions among
      children in the developing world. This poses a significant health-care problem
      and calls for improved management of such paediatric surgical problems to prevent
      high morbidity and mortality rates in African children.

PMID- 12485229
TI  - Initial experience with cultured epithelial autografts in massively burnt
      patients.
AB  - BACKGROUND: Prognosis in patients with severe burns is improved by early
      debridement and coverage with skin. The limiting factor in these patients is the
      lack of unburnt skin for harvesting. Cultured epithelial autograft (CEA) sheets
      provide an alternative means of covering debrided skin. This is a report on an
      initial experience with using CEA sheets. METHODS: The two patients in this study
      had their medical records examined retrospectively. RESULTS: The effective take
      of the CEA sheets was zero in both patients. One of the patients died
      approximately 6 weeks after admission. CONCLUSIONS: Because of the poor graft
      take seen in the patients in the present study, the use of CEA sheets only as a
      form of temporary biological dressing is recommended.

PMID- 12485230
TI  - How could management of rectoceles be optimized?
AB  - A posterior vaginal wall prolapse, also known as a rectocele, is a common
      condition and is an outpouching of the posterior vaginal wall and anterior rectal
      wall into the lumen of the vagina.1-5 Although more common in parous women,
      rectoceles of over 1 cm in size have been demonstrated in over 40% of nulliparous
      women. As rectoceles may be asymptomatic, their true prevalence is not clear.
      Many women with rectoceles present to their gynaecologist who may not ascertain
      any anorectal symptoms or perform a rectal examination. Conversely, colorectal
      surgeons often disregard a vaginal examination.6 Conventionally, gynaecologists
      have managed rectoceles, but increasingly colorectal surgeons are involved
      because of the prevalence of anorectal symptoms. There are many surgical
      techniques for the management of a symptomatic rectocele. There is, however,
      little data to suggest which is the most effective technique, or whether specific
      techniques are more appropriate in certain circumstances.7

PMID- 12485231
TI  - Parathyroid autotransplantation during thyroidectomy.
AB  - Permanent hypoparathyroidism is a debilitating morbidity following thyroidectomy,
      with a reported incidence of up to 43%. Apart from meticulous dissection to
      preserve parathyroid glands and their blood supply, parathyroid
      autotransplantation (PA) has been increasingly employed to preserve parathyroid
      function. The adoption of PA during thyroidectomy has been reported to be
      associated with a low incidence of permanent hypoparathyroidism. Biochemical
      function of parathyroid autografts can be demonstrated objectively by forearm
      reimplantation or during long-term follow up. The clearest indication for PA is
      for inadvertently removed or devascularized parathyroid glands during thyroid
      surgery. Other strategies, including routine autotransplantation of at least one
      parathyroid gland, can be considered, but is associated with a high incidence of
      transient hypocalcaemia. Apart from refinement in technique to facilitate graft
      success, a reliable way to assess overall parathyroid function or viability of
      individual parathyroid gland may assist in monitoring parathyroid function and
      selecting patients requiring this procedure to prevent permanent
      hypoparathyroidism.

PMID- 12485232
TI  - Endovascular repair of abdominal aortic aneurysm: an update.

PMID- 12485233
TI  - Anatomical dissection: why are we cutting it out? Dissection in undergraduate
      teaching.
AB  - Anatomy teaching and, more specifically, the use of dissection in undergraduate
      anatomy teaching is undergoing a sea change in Australian medical schools. Until
      as recently as the 1970s, all medical students in Australia underwent an
      extensive course in dissection, taking up as much as 700 hours of curriculum
      time. Today, dissection is compulsory in only a minority of anatomy departments.
      There has been much discussion about the use of dissection in anatomy teaching,
      and both sides of the argument have considerable merit. Less widely discussed
      have been the other benefits of anatomical dissection, such as the development of
      surgical skills, an appreciation of whole-body pathology, and the teaching of
      ethical and moral issues that are central to the development of the professional
      doctor. Dissection still has an important role to play in undergraduate medical
      education.

PMID- 12485234
TI  - Diplopia and headaches associated with cerebellopontine angle arachnoid cyst.

PMID- 12485235
TI  - Pseudomembranous colitis requiring surgical intervention following triple therapy
      for Helicobacter pylori eradication.

PMID- 12485237
TI  - Help granulating areas to heal: do not forget the experience of ages past!

PMID- 12485236
TI  - Septate gall bladder associated with cholecystitis and pancreatitis in children.

PMID- 12485238
TI  - Investigating chronic, bright red, rectal bleeding.

PMID- 12485240
TI  - Late laparoscopic nephrectomy for renal trauma.

PMID- 12485248
TI  - The transradial approach for selective carotid and vertebral angiography.
AB  - PURPOSE: The transradial approach is not so popular in cerebral angiography. The
      purpose of this study was therefore to present our experience of success rate and
      safety of this method. MATERIAL AND METHODS: From December 1998 to June 2001, 526
      carotid and vertebral angiographies with DSA were performed via the radial
      artery. A 1.4-mm catheter was used through a 1.4-mm introducer sheath. We
      evaluated the procedure as successful if sufficient images for diagnosis were
      obtained of the bilateral carotid arteries and unilateral vertebral artery. Each
      patient was reassessed for any complications, occurring until the next morning.
      The length of time needed for an examination was measured in the last 10 cases.
      RESULTS: In all but 5 cases, the procedures were evaluated as successful (99.0%).
      Unsuccessful cases manifested severe pain at the radial puncture, angiospasm at
      the radial artery, loop formation at the radial artery, occlusion at the
      subclavian artery, and an aberrant right subclavian artery. No severe
      complications including neurological ones were encountered. Minor complications
      were noted in 17 cases (3.2%): 4 cases of thrombus at the ulnar artery, 1
      angiospasm at the radial artery, and 12 cases of small hematoma at the puncture
      site. The radial approach took 14 min less in the common carotid study and 3 min
      30 s less in the internal carotid study than by the femoral approach. CONCLUSION:
      The transradial approach enabled selective studies for carotid and vertebral
      angiography with a high success rate and safety with few complications.

PMID- 12485249
TI  - Evaluation of pituitary adenomas by multidirectional multislice dynamic CT.
AB  - PURPOSE: Multidetector-row CT is a new technology with a short scanning time.
      Multislice dynamic CT (MSDCT) in various directions can be obtained using the
      multidetector-row CT with multiplanar reformatting (MPR) technique. MATERIAL AND
      METHODS: We evaluated the initial results of sagittal and coronal MSDCT images
      reconstructed by MPR (MSDCT-MPR) in 3 pituitary adenoma patients with a
      pacemaker. RESULTS: In a patient with microadenoma, the maximum contrast between
      the normal anterior pituitary gland and the adenoma occurred approximately 50 s
      after the start of the contrast medium injection. A microadenoma was depicted as
      a less enhanced area relative to normal pituitary tissue. The macroadenomas were
      depicted as a less enhanced mass with cavernous sinus invasion in 1 patient and
      as a non-uniformly enhanced mass in another patient. Bone destruction and
      incomplete opening of the sellar floor during previous surgery were clearly
      detected in 2 patients with macroadenomas. These pituitary adenomas were removed
      via the transnasal route based on information from the MSDCT-MPR images only. The
      findings were verified surgically. CONCLUSION: The MSDCT-MPR provided the
      information needed for surgery with good image quality in the 3 patients with
      pacemakers. MSDCT-MPR appears to be a useful technique for patients with a
      pituitary adenoma in whom MR imaging is not available. This is the first report,
      to our knowledge, of the MSDCT-MPR technique being used to demonstrate pituitary
      disorders.

PMID- 12485250
TI  - Conventional and diffusion-weighted MR imaging of intracranial tuberculomas. A
      case report.
AB  - Intracranial tuberculoma is a rare form of central nervous system tuberculosis.
      We here report on conventional and diffusion-weighted cranial MR images of a non
      immunocompromised patient with multiple intracranial tuberculomas, tuberculous
      lymphadenitis and pulmonary tuberculosis. Conventional MR imaging revealed
      multiple ring-enhancing mass lesions. At follow-up MR, appearances of both edema
      and number and size of nodules were decreased. Diffusion-weighted MR was normal
      and normal ADC values were found in this case of tuberculomas.

PMID- 12485251
TI  - Hemorrhagic brain metastases with high signal intensity on diffusion-weighted MR
      images. A case report.
AB  - Diffusion-weighted MR imaging has been applicable to the differential diagnosis
      of abscesses and necrotic or cystic brain tumors. However, restricted water
      diffusion is not necessarily specific for brain abscess. We describe ring
      enhancing metastases of lung carcinoma characterized by high signal intensity on
      diffusion-weighted MR images. The signal pattern probably reflected intralesional
      hemorrhage. The present report adds to the growing literature regarding the
      differential diagnosis of ring-enhancing brain lesions.

PMID- 12485252
TI  - CT appearances of unilateral cleft palate 20 years after bone graft surgery.
AB  - PURPOSE: To describe CT appearances in patients with unilateral cleft lip and
      palate (CLP) 20 years after bone graft surgery. MATERIAL AND METHODS: Eighteen
      consecutive patients with unilateral CLP were examined. All patients had been
      treated with primary closure, both in infancy and early childhood, supplemented
      with bone grafting at the age of around 10 years. The CT examination of the upper
      jaw included a dental CT program. The CT appearances of the cleft side were
      compared with those of the untreated non-cleft side. RESULTS: Abnormal CT
      appearances included skew nasal aperture (n=17), nasal septal deviation (n=17),
      low floor of nasal aperture (n=15) at or towards the cleft side, and deviation of
      anterior nasal spine towards the non-cleft side (n=18). The posterior part of the
      bone cleft was visible in all patients, and the dental arch was V-shaped in 8.
      CONCLUSION: Although adherence to the present treatment protocol is considered to
      give satisfactory functional and cosmetic results, certain abnormalities persist.
      A knowledge of these is a prerequisite for a complete and final evaluation of the
      surgical and orthodontic regimen.

PMID- 12485253
TI  - Volume of cervical lymph nodes using 3D ultrasonography. Differentiation of
      metastatic from reactive lymphadenopathy in primary head and neck malignancy.
AB  - PURPOSE: To assess the usefulness of volume measurement using 3D US for depicting
      metastatic cervical lymph nodes. MATERIAL AND METHODS: Thirty-five cervical lymph
      nodes in 13 patients with primary head and neck malignancy were included in this
      study. US with volume acquisition was prospectively performed with a 5-10 MHz
      linear mechanical volume probe. Volume measurement of the node was calculated
      using a 3D automatic volume calculation program. The excised nodes matched on US
      were examined histopathologically. RESULTS: The volume of malignant nodes ranged
      from 0.444 to 4.442 cm3, the volume of the benign nodes from 0.143 to 1.176 cm3.
      Combinations of high positive (>80%) and negative (>90%) predictive values were
      obtained at a cut-off value of 0.7 cm3. CONCLUSION: Volume measurement of
      cervical nodes using 3D US can be a useful tool for differentiating metastatic
      from benign nodes in patients with primary head and neck malignancy.

PMID- 12485254
TI  - Percutaneous vacuum-assisted core breast biopsy with upright stereotactic
      equipment. Indications, limitations and results.
AB  - PURPOSE: To assess the usefulness of stereotactic vacuum-assisted core breast
      biopsy (VCBB) performed using a stereotactic add-on device and film-screen
      technology with the patient in an upright seated position. MATERIAL AND METHODS:
      We reviewed a series of 129 women with non-palpable mammographic abnormalities
      who required stereotactic VCBB from December 1999 to November 2000. Twenty-seven
      (20.9%) cases were excluded due to difficulties in keeping the correct position
      during the procedure, while the other 102 (79.1%) underwent successful VCBB.
      Patients with lesions consisting of either atypical ductal hyperplasia or lobular
      carcinoma in situ were considered for excisional biopsy. Patients with either
      ductal carcinoma in situ or infiltrating breast cancer were referred for
      definitive surgery. The results of stereotactic VCBB were correlated to the
      subsequent surgical histology. RESULTS: Stereotactic VCBB was interrupted because
      of bleeding in 1 case and vasovagal reaction in 5 cases. Two haematomas occurred
      after the procedure. Overall underestimation rate was 10.5%. No new lesions were
      discovered after a mean follow-up of 18.7 months. CONCLUSION: Stereotactic VCBB
      performed using a standard add-on device with the patient in an upright seated
      position and analog technology is feasible in about 80% of cases, has a low
      complication rate, is not significantly time-consuming, and can offer the same
      accuracy as dedicated prone equipment.

PMID- 12485255
TI  - Evaluation of axillary status in breast cancer. CT-based determination of
      sentinel lymph node size.
AB  - PURPOSE: To determine whether the location and size of sentinel lymph nodes (SLN)
      on CT are predictive of the axillary lymph node status in patients with breast
      cancer. MATERIAL AND METHODS: Forty patients with confirmed breast cancer
      underwent 5-mm CT of both breasts and axillae and the most inferior lymph node in
      the affected axilla was designated the SLN. Based on CT assessment of the
      axillary lymph node status, 22 (55%) patients then underwent dye- and gamma probe
      (DGP)-guided SLN biopsy followed by axillary dissection; 18 (45%) underwent
      dissection without prior SLN biopsy. The localization and status of the SLN
      determined on CT and by DGP-guided biopsy were compared. Biopsied and excised
      nodes were subjected to histopathologic examinations. RESULTS: All SLN identified
      on CT were close to the lateral thoracic artery and their localization
      corresponded well with SLN identified by the DGP-guided method. The positive
      predictive value of CT diagnosis was 100%. Histopathologic examination of excised
      nodes confirmed that none of the SLN biopsies was false-negative. CONCLUSION: Our
      CT criteria were highly accurate for identification and diagnostic assessment of
      SLN and useful for evaluating the axillary status in patients with breast cancer.

PMID- 12485256
TI  - Evaluation of methods for MR imaging of human right ventricular heart volumes and
      mass.
AB  - PURPOSE: To assess the utility of two different imaging directions in the
      evaluation of human right ventricular (RV) heart volumes and mass with MR
      imaging; to compare breath-hold vs. non-breath-hold imaging in volume analysis;
      and to compare turbo inversion recovery imaging (TIR) with gradient echo imaging
      in RV mass measurement. MATERIAL AND METHODS: We examined 12 healthy volunteers
      (age 27-59 years). Breath-hold gradient echo MR imaging was performed in two
      imaging planes: 1) perpendicular to the RV inflow tract (RVIT view), and 2) in
      the transaxial view (TA view). The imaging was repeated in the TA view while the
      subjects were breathing freely. To analyze RV mass using TIR images, the RV was
      again imaged at end-diastole using the two views. The RV end-diastolic cavity
      (RVEDV) and muscle volume as well as end-systolic cavity volume (RVESV) were
      determined with the method of discs. All measurements were done blindly twice to
      assess repeatability of image analysis. To assess reproducibility of the
      measurements, 6 of the subjects were imaged twice at an interval of 5-9 weeks.
      RESULTS: RVEDV averaged 133.2 ml, RVESV 61.5 ml and the RVmass 46.2 g in the RVIT
      view and 119.9 ml, 56.9 ml and 38.3 g in the TA view, respectively. The volumes
      obtained with breath-holding were slightly but not significantly smaller than the
      volumes obtained during normal breathing. There were no marked differences in the
      RV muscle mass obtained with gradient echo imaging compared to TIR imaging in
      either views. Repeatability of volume analysis was better in TA than RVIT view:
      the mean differences were 0.7 +/- 4.0 ml and - 5.4 +/- 14.0 ml in end-diastole
      and 1.6 +/- 3.1 ml and - 1.5 +/- 13.9 ml in end-systole, respectively.
      Repeatability of mass analysis was good in both TIR and cine images in the RVIT
      view but slightly better in TIR images: - 0.5 +/ -2.4 g compared to 0.8 +/- 2.9 g
      in cine images. Reproducibility of imaging was good, mean differences for RVEDV
      and RVESV were -1.0 +/- 4.8 ml and -0.8 +/- 2.8 ml, respectively. Mean difference
      for RVmass was -0.9 +/- 2.6 g. CONCLUSION: The present study suggests that
      gradient echo MR imaging is well applicable to RV volume and mass measurements.
      The best imaging plane for volumetric analysis seems to be the TA plane and there
      was no significant difference between breath-hold and conventional imaging. To
      assess RV mass, we recommend RVIT view; the TIR sequence quickly produced images
      of better quality compared to gradient echo images but no significant difference
      between masses was found and repeatability of analysis was equally good with both
      methods.

PMID- 12485257
TI  - Detection of common bile duct stones before laparoscopic cholecystectomy.
      Evaluation with MR cholangiography.
AB  - PURPOSE: To assess the diagnostic value of MR cholangiography (MRC) for detecting
      common bile duct (CBD) stones in candidates for laparoscopic cholecystectomy
      (LC). MATERIAL AND METHODS: A series of 95 selected patients with gallstones and
      suspected CBD lithiasis (abnormal serum liver tests and/or CBD size > or = 6.5 mm
      at US) were referred to our institution for MRC, before LC. MRC was performed on
      a 0.5 T magnet through a non-breath-hold, respiratory-triggered, fat-suppressed,
      thin-slab, heavily T2-weighted fast spin-echo sequence and through a breath-hold,
      thick-slab, single-shot T2-weighted sequence in the coronal plane. Axial T1- and
      T2-weighted sequences were first obtained. Two observers in conference reviewed
      source images and maximum intensity projections to determine the presence or
      absence of choledocholithiasis. MR findings were compared with endoscopic
      retrograde cholangiography and intraoperative cholangiography (IOC); IOC was
      always performed during LC. RESULTS: CBD calculi (single or multiple) were
      identified in 41 out of 95 patients (43%). Two false-positive and 4 false
      negative cases were found on MRC. The sensitivity, specificity, accuracy,
      positive predictive value, and negative predictive value of MRC for
      choledocholithiasis were 90%, 96%, 94%, 95%, and 93%, respectively. CONCLUSION:
      MRC is a highly effective diagnostic modality for evaluation of patients with
      risk factors for CBD stones prior to LC.

PMID- 12485258
TI  - Reliability of endosonography in evaluation of anal fistulae and abscesses.
AB  - OBJECTIVE: To assess the reliability of anal endosonography (AES) in the
      diagnosis of anal fistulae and abscesses. MATERIAL AND METHODS: 86 patients with
      different types of anal fistulae and abscesses were prospectively examined with a
      7.0 MHz transducer. Type of anal fistulae, differentiation between simple and
      complex tracts, and location of their internal openings were defined. In 66 cases
      with permeable external opening, hydrogen peroxide solution was introduced into
      the fistula tract. Reliability of AES was defined after surgical treatment of all
      cases. RESULTS: 74 anal fistulae, including 43 transsphincteric, 11
      intersphincteric, 6 suprasphincteric, 3 superficial, and 11 ano-vaginal were
      found on AES. 27 fistulae were complex, and 47 simple fistulae. In 10 patients a
      coexisting abscess was found; the remaining 12 abscesses were without any
      fistula. Surgery confirmed the type of anal fistula in 64 patients (86.5%), and
      location of internal openings in 60 cases (81.1%). All abscesses were confirmed.
      CONCLUSION: AES showed high accuracy in diagnosing anal fistulae and abscesses.

PMID- 12485259
TI  - Herniographic findings in athletes with unclear groin pain.
AB  - BACKGROUND: Groin pain in athletes is a common symptom and may, among many other
      entities, be caused by skeletal changes in the symphysis and the pubic bone or
      hernia. MATERIAL AND METHODS: Herniographies in 51 athletes -- mainly soccer
      players -- with unclear groin pain were reviewed. The prevalence of various
      hernias and skeletal changes at the symphysis and os pubis was registered. A
      questionnaire was also sent to the patients 3-20 years after the herniography.
      RESULTS: A hernia was found in 13 patients. Four patients had an indirect
      inguinal hernia. Eight patients had a direct inguinal hernia and 1 had an
      obturator hernia. The prevalence of direct inguinal hernia was higher than
      expected in young men. This may be explained by strain at physical exercise. Bone
      changes at the pubic symphysis were found in 32 patients, 21 of whom had advanced
      changes. CONCLUSION: A hernia can be found with herniography in one-fourth of
      athletes with long-standing unclear groin pain. Therefore herniography should be
      included in the diagnostic procedure. Lesions of the symphysis may be the result
      of strain of tendons, ligaments and fascias. This may predispose for an inguinal
      hernia as well.

PMID- 12485260
TI  - Osteopenia and osteoporosis in postmenopausal women. Assessment by
      radiogrammetric measurement.
AB  - PURPOSE: To compare the ability of the medial cortical thickness ratio to the
      width of the second metacarpal bone at the midshaft (MCR) in discriminating
      patients as normal, osteopenic or osteoporotic. MATERIAL AND METHODS: MCR was
      calculated from radiographs of 120 postmenopausal women. By dual-energy X-ray
      absorptiometry, the mineral density was measured in the lumbar spine, the wrist
      and the femoral neck. Patients were grouped in accordance with the diagnostic
      criteria of WHO on the basis of t-scores. MCR values were compared with t-scores
      and the ability of the MCR technique in discriminating the patient groups was
      evaluated. RESULTS: Analysis of radiogrammetric data revealed significant
      differences in MCR value between the 3 groups. The MCR was lower in patients with
      osteoporosis and osteopenia compared with the normal group. The mean value of MCR
      was also slightly lower in patients with osteoporosis than in those with
      osteopenia. Accuracy assessment (ROC analysis) of MCR in the discrimination of
      patients with osteoporosis showed that test accuracy was acceptable, but less
      accurate than spinal, wrist and femoral neck t-scores. Compared with t-scores,
      this test was found to fairly discriminate those with and without osteopenia.
      CONCLUSION: The MCR method can discriminate patients as osteoporotic or normal.
      However, it seems that the MCR method should not be used for decisions concerning
      treatment of osteoporosis because of its low accuracy and thereby a risk for
      misclassification.

PMID- 12485261
TI  - Partial tear of pectoralis major muscle masquerading as a breast mass in an 87
      year-old woman. A case report.
AB  - We report on a case of a partial tear of the pectoralis major muscle mimicking a
      breast mass in an elderly patient. Breast MR was useful in identifying the
      traumatic muscular injury and in demonstrating the lack of any intraparenchymal
      breast lesion.

PMID- 12485262
TI  - Influence of two non-ionic radiographic contrast media with different
      osmolalities on coagulation in invasive cardiology. A prospective, randomised
      comparative study.
AB  - PURPOSE: To investigate the influence of two non-ionic radiographic contrast
      media with different osmolality on thrombocytic function and the plasmatic
      coagulation system. MATERIAL AND METHODS: The study was carried out as a
      randomised, prospective, comparative study with two contrast media in a heart
      catheter laboratory. RESULTS: Activating influences on platelet aggregation,
      procoagulatory or profibrinolytic functions or injury to the endothelium could be
      ruled out. Apparently, also differences in substance properties, such as the
      media's ionic character or osmolality had no demonstrable influence on the
      interaction with haemostatis and blood vessels. An adjuvant, antithrombotic
      therapy was carried out, which consisted of platelet aggregation inhibitors and
      heparins. CONCLUSION: Our findings agree with the results of recent clinical
      trials, which demonstrated no relevant disadvantage of non-ionic contrast media
      as regards thrombotic complications.

PMID- 12485263
TI  - Paediatric neurofibromatosis.

PMID- 12485264
TI  - Interpretation of ordinal agreement.

PMID- 12485265
TI  - An unusual case of diastematomyelia. Presence of one dural sheath associated with
      a bony spur.

PMID- 12485266
TI  - Neurofibromatosis type 1. Usefulness of MR imaging for diagnosis.

PMID- 12485267
TI  - Diagnostic criteria of colospasm at barium enema examination.

PMID- 12485273
TI  - Congenital cataract -- results of treatment.

PMID- 12485275
TI  - Corneal banking and grafting: the background to the Danish Eye Bank System, where
      corneas await their patients.

PMID- 12485276
TI  - Macular holes: classification, epidemiology, natural history and treatment.
AB  - BACKGROUND: Macular hole is a retinal disease primarily affecting elderly women.
      Its overall prevalence in the Danish population is estimated to be 0.14%. The
      majority of cases are unilateral. The fully developed macular hole evolves
      through a series of stages starting with an impending hole. About half of
      impending macular holes regress spontaneously. The remaining half progress to
      full thickness macular holes. In a patient with a macular hole in one eye, the
      risk of development of a macular hole in the fellow eye is less than 2% if
      posterior vitreous detachment is present. If the posterior vitreous is attached,
      the risk is approximately 15%. If an impending hole is found in the other eye,
      the risk rises to 50%. TREATMENT AND OUTCOMES: Macular hole surgery is able to
      close full thickness macular holes in approximately 90% of cases. Visual acuity
      of 20/50 or better can be obtained in approximately half of patients with recent
      onset of symptoms. Complications include retinal detachment, endophthalmitis,
      late reopening of an initially successfully closed hole and retinal pigment
      epithelial abnormalities. Retinal detachment should be expected in less than 5%
      of cases.

PMID- 12485277
TI  - Outcome after treatment of congenital unilateral cataract.
AB  - PURPOSE: To evaluate long-term functional outcome after treatment of congenital
      unilateral cataract. METHODS: The records of 30 consecutive children operated on
      before the age of 12 months at St. Erik's Eye Hospital over a 5-year period (1991
      96) were reviewed retrospectively. The patients were followed until 4-9.5 years
      of age. Linear Snellen visual acuity (VA), occlusion therapy compliance, and the
      presence of nystagmus, strabismus and other complications are reported. RESULTS:
      Six children achieved VA of 0.1 or better. They were all operated on before 3
      months of age. Of the 12 infants operated on before 6 weeks of age, four have VA
      between 0.3 and 0.4 and eight have VA of finger counting or less. Four developed
      severe secondary glaucoma within 6 months of cataract extraction. Two of these
      had persistent fetal vasculature. Three eyes developing glaucoma became
      amaurotic. Occlusion therapy was abandoned before the age of 2.5 years in 21
      children. CONCLUSION: Good levels of VA were achieved only in children who
      underwent cataract surgery before 3 months of age and who adhered to the
      occlusion therapy schedule. Severe secondary glaucoma developed in four out of 12
      children operated on within 6 weeks. Full compliance with the occlusion therapy
      programme was uncommon.

PMID- 12485278
TI  - Outcome after treatment of congenital bilateral cataract.
AB  - PURPOSE: To evaluate long-term functional outcome after treatment of dense
      congenital bilateral cataract. METHODS: The records of 22 consecutive children
      operated on before the age of 12 months at St. Erik's Eye Hospital over a 5-year
      period (1991-96) were reviewed retrospectively. Linear Snellen visual acuity (VA)
      at last check, presence of stereoacuity, nystagmus, strabismus and other
      complications are accounted for. Subject age at last check ranged from 4 to 9
      years. RESULTS: Visual acuity could be estimated in 19 children: the median VA of
      the better eye was 0.4 (range: counting fingers - 0.8) and of the fellow eye 0.15
      (range: amaurosis - 0.8). In nine otherwise healthy children who were operated on
      early (by 1 month of age), VA varied from 0.4 to 0.8 in the better eye. Four of
      these children achieved stereopsis. Pupillary block glaucoma developed in five
      eyes (in three children). Chronic glaucoma developed in eight eyes (in five
      children). Glaucoma occurred predominantly in children who underwent cataract
      extraction during the first week of life. Two of the latter had marked
      microphthalmos. CONCLUSION: Good postoperative VA was achieved in most healthy
      children with dense bilateral congenital cataract when surgery was performed
      early (before 6-8 weeks of age). Chronic glaucoma developed predominantly when
      cataract extraction was performed during the first week of life.

PMID- 12485279
TI  - A longitudinal study of visual acuity and visual rehabilitation needs in an urban
      Swedish population followed from the ages of 70 to 97 years of age.
AB  - PURPOSE: To investigate the longitudinal change in visual acuity (VA) in the
      oldest members of the elderly population, to estimate future numbers of people
      with visual impairments, and to estimate needs for and the effects of visual
      rehabilitation. METHODS: In the Gerontological and Geriatric Population Studies
      in Gothenburg, Sweden (H 70), subjects underwent repeated eye examinations at the
      ages of 70, 82, 88, 95 and 97 years. Logistic regression analysis was used to
      estimate the probability of independent living as a function of distance VA at
      different ages. RESULTS: Rates of normal VA (>or= 0.8) declined from 86% of the
      study group at age 70 to 7% of the study group at age 95 (0% at age 97). The
      incidence of VA <or= 0.1 increased from 1.4% at age 70 to 27% (all women) at age
      97. The deterioration was faster at higher ages. No statistically significant
      difference in best-corrected distance VA between genders was found. A substantial
      improvement was achieved by correcting refractive errors. There was a
      statistically significant correlation between distance VA and the probability of
      independent living at all ages except age 97. At ages 95 and 97, about 50% of the
      study group were able to read newspaper print with best-corrected glasses.
      CONCLUSIONS: The number of old people with impaired vision will increase. People
      aged 80 years and older should have regular eye-screening in order to preserve
      vision and present conditions of living. Cataract surgery and low vision
      rehabilitation should be offered when the subject can still benefit from it,
      preferably during their 80s at the latest.

PMID- 12485280
TI  - Preschool vision screening in a Swedish city region: results after alteration of
      criteria for referral to eye clinics.
AB  - PURPOSE: To investigate the results of preschool vision screening and to evaluate
      new referral criteria in a Swedish city region. Prior to 1992, all children with
      visual acuity (VA) of less than 0.8 at the age of 4 years were referred to an eye
      clinic. Since 1992, those with slightly reduced VA (0.65 in each eye or 0.65 in
      one eye and 0.8 in the other) have been retested at 5.5 years of age and referred
      if their VA is less than 0.8. METHODS: In a prospective study, the results of
      vision testing were collected for all children (n = 483) born in 1989-92
      inclusive and registered at one child health centre at 4 years of age. The study
      also involved 123 other children scheduled for retesting at the age of 5.5 years.
      The results of the examinations and treatments at the eye clinic are evaluated.
      RESULTS: Few of the children with slightly reduced VA who were retested at the
      age of 5.5 years had visual defects that required treatment. In those who were
      treated, the results of treatment were good. CONCLUSIONS: The new screening
      criteria appear to be appropriate and are recommended.

PMID- 12485281
TI  - Detection of herpes simplex virus in pseudoexfoliation syndrome and exfoliation
      glaucoma.
AB  - PURPOSE: The pathogenesis of pseudoexfoliation syndrome (PEX) remains unknown. An
      infection, possibly viral, is one of the proposed pathogenetic mechanisms. This
      study examines the presence of herpes simplex virus (HSV) and varicella-zoster
      virus (VZV) in iris and anterior capsule specimens of PEX and non-PEX patients.
      METHODS: Iris and anterior capsule specimens were obtained from 64 patients with
      PEX (study group, SG) and 61 patients without PEX (control group, CG). The
      presence of HSV and VZV DNA was evaluated with a polymerase chain reaction (PCR).
      RESULTS: Herpes simplex virus type I was detected significantly more often in
      iris specimens from the SG (13.79%), compared to those from the CG (1.75%).
      Varicella-zoster virus DNA was not detected in any of the examined specimens.
      CONCLUSION: Results imply a possible relationship between HSV type I and PEX,
      although no aetiological role of HSV infection in PEX pathogenesis can be
      established. Results also advocate against any association between VZV and PEX.

PMID- 12485282
TI  - Evaluation of the clinical association between exfoliation syndrome and abdominal
      aortic aneurysm.
AB  - PURPOSE: To assess the validity of the suggested association between intraocular
      exfoliation syndrome and aneurysm of the abdominal aorta. METHODS: A total of 77
      patients recently operated for abdominal aortic aneurysm underwent biomicroscopy
      under pupillary dilatation to detect the presence of manifest and suspect
      deposits of exfoliation material. RESULTS: The mean age of the 71 (92%) male and
      six female subjects was 73 years (range: 59-88 years). Manifest exfoliation was
      detected in 11 patients (14%; 95% CI 7-24), five of whom were aged 60-69 years
      and six of whom were aged 70-79 years. In addition, four patients (5%; 95% CI 1
      13) had suspect exfoliation. CONCLUSIONS: The prevalence of exfoliation syndrome
      in patients operated for abdominal aortic aneurysm was similar to that in the
      general population of the same age in Finland. This finding does not support the
      proposed connection between exfoliation syndrome and abdominal aortic aneurysm.

PMID- 12485283
TI  - Evaluation of VEP perimetry in normal subjects and glaucoma patients.
AB  - PURPOSE: To estimate sensitivity to glaucomatous visual field loss using
      multifocal visual evoked potential (VEP) perimetry, to compare these findings to
      those of conventional achromatic perimetry and to determine specificity of VEP
      perimetry in normal subjects. METHODS: A total of 33 glaucoma patients with known
      visual field defects in at least one eye on standard computerized perimetry and
      33 healthy subjects were tested with VEP perimetry. The glaucoma patients were
      also tested with standard computerized perimetry using the 30-2 SITA Fast program
      of the Humphrey Field Analyzer (HFA). Visual evoked potential perimetry
      classification and VEP probability maps were used to determine the sensitivity
      and specificity of the technique. RESULTS: Visual evoked potential perimetry
      classified 68% of all eyes in the glaucoma group (45/66) as pathological;
      sensitivity increased to 81% (38/47) when considering only those eyes with HFA
      field defects. It also identified more test locations with significant loss at
      the p < 5% level in both groups (48% and 37%, respectively) than did HFA, while
      HFA identified more loss at the higher significance levels p < 2%, and p < 1%.
      Visual evoked potential perimetry showed more significant loss in eyes with
      almost normal or slightly damaged standard fields, while HFA identified more
      significant field loss in eyes with severe conventional field damage. The mean
      VEP amplitude of the 66 glaucoma eyes was 1.46e(-7) V; it was 1.676e(-7) V for
      the 66 control eyes. This difference was significant (p = 0.0033), but the
      overlap between groups was large. Visual evoked potential perimetry classified
      42% of the control eyes as 'outside normal limits', and VEP probability maps
      showed 30.0% of test segments as significantly depressed at the p < 5% level,
      10.8% of sites at p < 2%, and 4.6% at the p < 1% level. CONCLUSION: Mean VEP
      amplitude differed significantly between normal and glaucoma eyes, but the
      overlap was considerable. Visual evoked potential perimetry falsely classified a
      large number of normal eyes as pathological and showed many more significantly
      depressed test locations than expected. Agreement between VEP and standard
      perimetry was relatively poor for the glaucoma group. Further refinements are
      needed before VEP perimetry can be regarded as a reliable clinical method of
      mapping glaucomatous visual fields.

PMID- 12485284
TI  - A comparison of glaucoma patients identified through mass screening and in
      routine clinical practice.
AB  - PURPOSE: To study differences between glaucoma patients identified through a
      population screening and glaucoma patients diagnosed in routine clinical practice
      (self-selected patients). METHODS: A total of 402 individuals with newly detected
      open-angle glaucoma were identified through a large population screening
      programme that ran from October 1992 to January 1997. The screening programme was
      attended by a total of 32918 citizens of Malmo, Sweden, aged between 57 and 79
      years. Citizens who had visited the Eye Department of Malmo University Hospital
      in the year before the screening of their birth cohort were not invited to
      participate (n = 4117). Among the latter, we identified 354 patients with open
      angle glaucoma through a retrospective examination of patient records. RESULTS:
      At detection, 52.9% of the glaucoma patients identified through screening had
      normal tension glaucoma (NTG), defined as intraocular pressure (IOP) < 21 mmHg in
      both eyes, compared to 13.5% of the self-selected patients (p < 0.0001). Mean IOP
      at the time of diagnosis was 22.9 mmHg in the screened group and 32.5 mmHg in the
      self-selected group. Pseudoexfoliation was present in 16.4% of the screened group
      and 44.0% of the self-selected group (p < 0.01). Bilateral disease was present in
      40.1% of the screened group and 34.6% of the self-selected group (p = 0.1160).
      Median MD (mean deviation from the age-corrected normal visual field) in the
      worse eye was -8.0 dB in the screened group and -16.2 dB in the self-selected
      group (p < 0.0001). Visual acuity was lower in the self-selected group, which was
      also on average slightly more myopic. Of the patients detected through screening,
      62% had seen an ophthalmologist previously, 17% within the preceding 2-year
      period. CONCLUSIONS: Normal tension glaucoma was four times as common in patients
      identified through population screening as in self-selected patients, suggesting
      that patients with NTG are easily overlooked in clinical practice. Even though
      the patients detected through population screening had lower mean IOP, lower
      prevalence of pseudoexfoliation, better visual fields and a lower incidence of
      bilateral disease than self-selected patients, many still had considerable
      damage. Special efforts, such as glaucoma screening, are needed if manifest
      glaucoma, and especially NTG, is to be detected at an earlier stage than it
      currently is.

PMID- 12485285
TI  - The short-term IOP-lowering effect of brimonidine 0.2% and dorzolomide 2%
      combination in primary open-angle glaucoma.
AB  - PURPOSE: To evaluate the ocular hypotensive effect of dorzolamide 2% in primary
      open-angle glaucoma (POAG) patients with intraocular pressure (IOP) of at least
      22 mmHg despite ongoing twice daily treatment with brimonidine 0.2%. PATIENTS AND
      METHODS: Nineteen eyes of 19 patients with POAG and IOP >or= 22 mmHg, on twice
      daily brimonidine therapy, were included in the study. Intraocular pressure and
      adverse effects were recorded on days 2, 7, 14 and 30 after adding dorzolamide
      three times daily to the treatment. RESULTS: Mean pretreatment IOP was 27.6 +/-
      2.2 mmHg. This decreased to 24.2 +/- 2.2 mmHg after a mean duration of 23.8 +/-
      12.1 days. After dorzolamide was added to the treatment, mean IOP was 20.8 +/-
      2.3 mmHg on day 2, 19.3 +/- 2.2 mmHg on day 7, 18.0 +/- 2.5 mmHg on day 14 and
      17.2 +/- 2.3 mmHg on day 30. The differences between pre- and post-treatment IOP
      values were statistically significant (p < 0.0001, anova test). CONCLUSION:
      Dorzolamide administered three times daily has significant additive ocular
      hypotensive effect in POAG patients whose IOP is elevated despite ongoing
      treatment with brimonidine.

PMID- 12485286
TI  - A comparison of the effects on intraocular pressure of latanoprost 0.005% and the
      fixed combination of dorzolamide 2% and timolol 0.5% in patients with open-angle
      glaucoma.
AB  - PURPOSE: To compare the effects on intraocular pressure (IOP) of latanoprost
      0.005% and the fixed combination of dorzolamide 2% and timolol 0.5%. METHODS:
      Overall, 226 patients whose IOP was insufficiently controlled by timolol alone
      were randomized to receive either latanoprost once daily or the fixed combination
      of dorzolamide plus timolol twice daily. Intraocular pressure was measured at
      10:00 am and 5:00 pm at baseline and after 3 months of treatment. RESULTS: Mean
      IOP was reduced from baseline in both groups (p < 0.001), with a mean +/- SEM
      reduction of - 4.3 +/- 0.3 mmHg (19%) for the latanoprost treatment group and -
      4.0 +/- 0.3 mmHg (17%) for the dorzolamide plus timolol treatment group. The two
      therapies were similarly effective in lowering IOP levels (mean difference in
      reduction: - 0.4 +/- 0.4; 95% confidence interval: - 1.1, 0.4). CONCLUSIONS:
      Monotherapy with latanoprost once daily was as effective in reducing mean IOP as
      the fixed combination of dorzolamide plus timolol twice daily in patients with
      IOP insufficiently controlled by timolol alone.

PMID- 12485287
TI  - Expression of 5'-nucleotidase and alkaline phosphatase in human aqueous drainage
      channels.
AB  - PURPOSE: Lymphatic vessels and blood vessels can be distinguished histochemically
      by their expression of 5'-nucleotidase and alkaline phosphatase. The aim of this
      study was to compare the expression of these enzymes in human aqueous drainage
      channels with that seen in lymphatics and blood vessels. METHODS: Histological
      sections from the angular regions of human eyes were prepared both by enzyme
      histochemical and immunohistochemical methods to analyse 5'-nucleotidase and
      alkaline phosphatase expression. In some of these eyes, Indian ink-stained
      gelatin was injected into Schlemm's canal and the suprachoroidal space to
      facilitate the identification of aqueous drainage routes. RESULTS: There was no
      expression of 5'-nucleotidase in the endothelium of aqueous drainage channels.
      Ocular blood vessels were characterized by strong expression of alkaline
      phosphatase, whereas the cellular lining of Schlemm's canal, the collector
      channels, the aqueous veins and a scleral channel from the suprachoroidal space
      showed significantly weaker expression or no expression at all. CONCLUSION: The
      study failed to show a histochemical similarity between lymphatics and human
      aqueous drainage channels, as no expression of 5'-nucleotidase could be found in
      any part of the aqueous outflow pathway. The endothelium of aqueous drainage
      channels also differed from normal blood vessels by a much weaker expression of
      alkaline phosphatase. This makes a histochemical distinction between aqueous
      veins and scleral veins possible.

PMID- 12485288
TI  - Analysis of mean retinal transit time from fluorescein angiography in human eyes:
      normal values and reproducibility.
AB  - OBJECTIVE: To evaluate three different techniques to quantify retinal blood flow
      transit times in normal human eyes from fluorescein angiograms. SUBJECTS AND
      METHODS: Fluorescein angiograms were recorded on two different occasions in 18
      normal individuals with a scanning laser ophthalmoscope. The angiograms were
      digitized (5 frames per second) and the images were aligned. Mean transit times
      (MTT) were analysed with a newly developed technique based on an impulse-response
      analysis (MTTIR) and again with the conventional technique (MTTSLOPE). Arterio
      venous passage times (AVP) were also calculated. RESULTS: At the first
      determination, mean values (SD) for MTTIR, MTTSLOPE, and AVP were 3.22 (0.78),
      4.88 (1.86), and 1.46 (0.57) seconds, respectively. Detection of an increase of
      25% with a power of 80% requires groups of 12, 86 and 17 individuals for the
      three techniques, respectively. CONCLUSIONS: Mean transit time is a well-defined
      physiological parameter. The technique based on impulse-response analysis allows
      for analysis of even badly defined dye curves. We found this technique to be
      superior to the conventional technique in terms of reproducibility.

PMID- 12485289
TI  - Chlamydia pneumoniae in central retinal artery occlusion.
AB  - PURPOSE: There is increasing evidence that the common respiratory human pathogen
      Chlamydia pneumoniae has a causative role in atherosclerosis. We investigated the
      association of this pathogen with acute central retinal artery occlusion (CRAO).
      PATIENTS AND METHODS: Sera of 14 consecutive patients with CRAO and of 14 age-
      and sex-matched control subjects were examined. Antibodies against chlamydial
      lipopolysaccharide (LPS) and outer membrane proteins of C. pneumoniae were
      determined by an enzyme-linked immunosorbent assay (ELISA). RESULTS: In the CRAO
      group, seven patients (50%) were found to be IgA positive, 12 (86%) were IgG
      positive and one (7%) was IgM positive for chlamydial LPS antibodies. In the
      control group 36%, 79% and 14% were IgA, IgG and IgM positive, respectively. The
      results showed no significant difference between the groups. In the CRAO group,
      IgA, IgG and IgM antibodies to C. pneumoniae were found in 43%, 79% and 0% of
      subjects, respectively. These findings did not differ significantly from those
      pertaining to matched controls. CONCLUSIONS: These data do not support an
      association between acute CRAO and current C. pneumoniae infection.

PMID- 12485290
TI  - Management of alveolar rhabdomyosarcoma of the orbit.

PMID- 12485291
TI  - Terson's syndrome presenting as an ophthalmic emergency.
AB  - PURPOSE: To report an unusual case of Terson's syndrome caused by a ruptured
      intracranial aneurysm presenting as an ophthalmic emergency with visual loss,
      without any neurological features at the time of presentation. METHODS: Case
      report. A 38-year-old man was referred to the eye emergency department with
      sudden loss of vision in both eyes. Vitreous haemorrhage was noted in both eyes.
      There was no history of loss of consciousness or headaches and no signs of
      meningeal irritation at presentation. The patient subsequently developed
      progressive neck stiffness and headache. RESULTS: Neuro-imaging studies revealed
      a subarachnoid haemorrhage resulting from a ruptured carotid-ophthalmic artery
      aneurysm. CONCLUSIONS: It is important to consider Terson's syndrome, a
      potentially life-threatening condition, in any patient presenting with bilateral
      vitreous haemorrhage. Some patients may not show any headache, neurological
      deficits or signs of meningeal irritation at presentation but may develop them
      later on.

PMID- 12485292
TI  - Retinal arteriolar obstruction with progestogen treatment of threatened abortion.
AB  - PURPOSE: To describe a case of a retinal arteriolar occlusion associated with
      progestogen treatment of threatened abortion. METHODS: Case report. RESULTS: A 30
      year-old woman who had received a 2-week course of high dose intramuscular
      progestogen for a threatened abortion presented with a paracentral scotoma in her
      right eye and occlusion of a small arteriole adjacent to the macula. There were
      no major subsequent variations in haemostasis and pre-existing systemic diseases
      were excluded. CONCLUSIONS: Retinal arteriolar occlusion may be associated with
      high dose progestogen-only therapy in pregnant women.

PMID- 12485293
TI  - Pseudomonas aeruginosa keratitis: resolution after debridement.

PMID- 12485294
TI  - Acute myelogenous leukaemia presenting as a conjunctival lesion and red eye.

PMID- 12485295
TI  - Secondary glaucoma associated with anterior uveitis, iris pigment epithelitis and
      herpetic eye infection.

PMID- 12485296
TI  - The role of interferon alpha 2b as an adjunctive treatment in the management of
      aggressive basal cell carcinoma of the eyelids.

PMID- 12485300
TI  - The neurotic versus delusional subtype of taijin-kyofu-sho: their DSM diagnoses.
AB  - The main purpose of the present study was to investigate the diagnostic concepts
      of taijin-kyofu-sho (TKS) and social phobia, by comparing the clinical diagnosis
      of TKS and the operational diagnosis of Diagnostic and Statistical Manual of
      Mental Disorders (3rd edition, revised; DSM-III-R). Three evaluators conducted
      semistructured interview for DSM-III-R (SCID axis I and II, the Japanese version)
      to 88 outpatients who visited Jikei University Daisan Hospital, Japan, over a
      period of 1 year, requesting Morita therapy. The patients were also independently
      diagnosed by three psychiatrists to identify TKS. A total of 65.8% of 38 cases of
      TKS were diagnosed as social phobia. Among the neurotic TKS cases, the percentage
      was high at 81.5%, while among the delusional TKS cases it was 27.3%. A total of
      42.1% of the TKS cases were diagnosed as mood disorder; 60.5% of the TKS cases
      presented some axis II disorders, among which avoidant personality disorder was
      the most prevalent (31.6%). There was no significant difference between the
      neurotic and delusional subtypes of TKS, regarding comorbidity with axis I
      diagnoses. As for axis II diagnoses, delusional TKS patients had a higher rate of
      comorbidity with paranoid personality disorder, although they demonstrated very
      similar trends in comorbidity with all other personality disorders. In the
      diagnostic system of DSM-III-R, it is highly likely that the neurotic and
      delusional subtypes of TKS will be seen to correspond to different diagnostic
      categories.

PMID- 12485301
TI  - Diagnostic consideration of Morita shinkeishitsu and DSM-III-R.
AB  - The purpose of the present study was to empirically and objectively clarify the
      diagnostic standing of Morita shinkeishitsu, the subject of Morita therapy, by
      comparing and contrasting it with the operational diagnosis of the Diagnostic and
      Statistical Manual of Mental Disorders (3rd edition, revised; DSM-III-R). Morita
      therapists' clinical diagnoses of 88 outpatients who requested Morita therapy
      were compared with the results of the independently conducted operational
      diagnoses (structured clinical interview for DSM (SCID) for DSM-III-R, the
      Japanese version). In view of the result of axis I diagnoses, Morita
      shinkeishitsu corresponds to anxiety disorders, although it is a complex that
      also embodies mood disorders, which were found in one-quarter of the cases, as
      well as personality disorders, which were found in half of the cases, especially
      cluster C (avoidant, obsessive-compulsive, and dependent personality disorders).
      Morita shinkeishitsu is almost equivalent to anxiety disorders (DSM-III-R, axis
      I), and is a complex, a part of which includes mood disorders and cluster C
      personality disorders.

PMID- 12485302
TI  - Factors of good outcome after discharge from support house (engoryou) for
      schizophrenia.
AB  - To restore mentally disabled persons to social activities, it is necessary to
      establish an appropriate facility and support system according to the severity of
      disorder. In the present study, in an attempt to obtain a guide to identifying
      conditions on which the use of the support house (engoryou) is effective,
      patients who had been discharged from the support house were divided into
      different groups by evaluation at discharge. The first group consisted of 30
      patients who underwent continued social rehabilitation (recovery group); the
      second group consisted of 25 patients with discontinued social rehabilitation
      (the re-hospitalization group), and their demographic factors were compared. The
      findings are summarized as follows: (i) the recovery group had a significantly
      shorter total hospitalization period and a smaller number of hospitalizations
      before entry into the facility, as compared to the re-hospitalization group; (ii)
      the recovery group was significantly better than the re-hospitalization group in
      terms of the score of 'thought disorder', although there was no difference in
      total Brief Psychiatric Rating Scale (BPRS) score, at the time of entry into the
      facility; (iii) the recovery group was better than the re-hospitalization group
      in terms of the Rehabilitation Evaluation Hall and Baker (REHAB) items 'speech
      skills' and 'self-care' at the time of entry into the facility; (iv) the re
      hospitalization group experienced relapse of symptoms, mainly positive ones, at
      the time of the discontinuation of the use of the facility or re-admission. These
      findings suggest that to make good use of the support house, the improvement of
      thought disturbance and self-care must be managed appropriately and the
      prolongation of hospital stay must be prevented before entry into the facility.

PMID- 12485303
TI  - Four cases of panic disorder successfully treated with Kampo (Japanese herbal)
      medicines: Kami-shoyo-san and Hange-koboku-to.
AB  - Kampo medicines have been used to treat patients with psychogenic disorders from
      ancient times. In the present report the cases are described of four patients
      with panic disorder successfully treated with Kampo medicines. These four
      patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders
      (DSM) criteria for panic disorder with agoraphobia. The Kampo medicine Kami-shoyo
      san (TJ-24) relieved panic attacks, anticipatory anxiety and agoraphobia in two
      patients, and Hange-koboku-to (TJ-16) relieved these symptoms in the other two
      patients. The patients in whom Kami-shoyo-san was effective were older and
      complained of more symptoms than those in whom Hange-koboku-to was effective.
      These Kampo medicines may be useful as additional or alternative treatments for
      panic disorder.

PMID- 12485304
TI  - Behavioral and developmental disorders among conduct disorder.
AB  - The purpose of the present study was to clarify the percentage of children with
      conduct disorder (CD) who also have behavioral and developmental disorders. A
      survey of comorbidity observed in children with CD, was carried out on 33
      subjects from a disciplinary facility for children. Female teachers as the mother
      were interviewed as regards the subjects' condition using the semistructured
      interview, and male teachers as the father were interviewed for their
      psychosocial problems. The subjects underwent the Wechsler Intelligence Scale for
      Children (WISC)-III and their conditions were diagnosed according to Diagnostic
      and Statistical Manual of Mental Disorders (4th edn; DSM-IV). Of the 33 children,
      27 were diagnosed as having CD. Of the 27 CD children, 18 (67%) were diagnosed as
      having attention deficit hyperactivity disorder (ADHD), and 19 (70%) had
      oppositional defiant feature (ODF). Eight children (30%) were diagnosed as having
      mental retardation and in seven children (26%), the verbal IQ was significantly
      lower than the performance IQ. Two (7%) were diagnosed as having pervasive
      developmental disorders (PDD). Of 27 children diagnosed with CD, 23 (85%) had
      some behavioral and developmental disorders. The classification of these
      behavioral and developmental disorders into the following three types appeared to
      be clinically useful: type 1, ADHD and ODF; type 2, low intelligence, especially
      low verbal intelligence; and type 3, PDD. To understand and treat children with
      CD, the accurate diagnosis of these underlying behavioral and developmental
      disorders is indispensable.

PMID- 12485305
TI  - Decreased serum albumin levels in Taiwanese patients with schizophrenia.
AB  - Previous papers have reported lower serum albumin levels in patients with
      schizophrenia. In the present study, the relationships between serum albumin
      levels and subtypes of schizophrenia, physical violence and suicide attempts were
      investigated. A review of medical charts over a 1-year period was carried out in
      a population of 213 Taiwanese psychiatric inpatients that included 106 patients
      with schizophrenia. The collected data included age, bodyweight, height, serum
      albumin levels and routine blood biochemistry examinations. These data were
      compared with data from a healthy control group (n = 32) composed of staff
      members using analysis of covariance after age adjustment. The statistical
      results showed significantly lower serum albumin levels in patients with
      schizophrenia in the acute phase than in the control group. However, no
      significant differences in serum albumin levels were found between paranoid and
      non-paranoid schizophrenic patients, between patients who had or had not
      exhibited physical violence, or between patients who had or had not made a
      suicide attempt.

PMID- 12485306
TI  - Electrophysiological correlates of personality dimensions measured by Temperament
      and Character Inventory.
AB  - The present exploratory study was attempted to investigate the relationship
      between components of event-related potential (ERP) and Cloninger's personality
      dimensions. The ERP was measured using the auditory oddball paradigm, and
      personality was evaluated by Temperament and Character Inventory (TCI) in 25
      healthy subjects. The results showed that P300 amplitude at Fz was significantly
      associated with reward dependence, and that P300 latency was positively
      correlated with persistence, and negatively correlated with novelty seeking. No
      correlations were found between N100, P200 and personality dimensions. These
      results indicate that personality dimension is related to information-processing
      in the brain. The neurobiological and psychological aspects of personality, which
      may relate to the P300 were considered.

PMID- 12485307
TI  - 19F-magnetic resonance spectroscopy and chemical shift imaging for schizophrenic
      patients using haloperidol decanoate.
AB  - Haloperidol decanoate is widely used in the maintenance treatment of
      schizophrenia and other psychotic disorders, but knowledge concerning its
      pharmacokinetics at the injected region is very limited. Because the chemical
      structure of haloperidol contains fluorine, in vivo 19F-magnetic resonance (MR)
      spectroscopy (repetition time (TR) = 1 s) and chemical shift imaging (CSI; TR = 1
      s, pixel size = 15 x 15 mm) were performed in schizophrenic patients who were
      treated with haloperidol decanoate (three men and one woman) to measure its
      diachronic change at the injection point and visualize its local distribution
      after intramuscular injection. 19F signals (T1 time = 365 ms) were obtained at
      the haloperidol decanoate-injected region. The decrease rate of the signal-to
      noise ratio (SNR) by 19F-MR spectroscopy seemed large in comparison with that of
      the plasma haloperidol concentration. The distribution was clearly visualized by
      19F-CSI for a few days after the injection, but after 1 week could no longer be
      seen. Although the slow-release characteristics of depot neuroleptics have been
      explained by the slow diffusion of esterified neuroleptics from the oil vehicle,
      this result may suggest that there are other mechanisms involved in maintaining
      the plasma haloperidol concentration. In vivo 19F-MR spectroscopy and CSI are
      potentially applicable for the pharmacokinetic analysis of haloperidol and other
      drugs containing fluorine in their structure.

PMID- 12485308
TI  - Mass family hysteria: a report from India.
AB  - The case of a 31-member family displaying mass hysteria in up to 10 members at
      one time is reported. The mass hysteria emerged in the context of the strong
      religious and cultural beliefs held by this closely knit family. The varied
      presentations included somatoform disorder, recurrent vomiting, conversion,
      dissociative and possession attacks. Two members had bipolar affective disorder
      that was recognized by the family as a 'medical' illness in contrast to other
      problems attributed to religiosity. The rarity of mass hysteria in a family and
      issues related to its medical and social management are highlighted.

PMID- 12485309
TI  - Case of mania induced by withdrawal of interferon-alpha in a patient affected by
      bipolar disorder.

PMID- 12485310
TI  - Wilson's disease in psychiatric patients.

PMID- 12485312
TI  - Post-marketing surveillance of novel foods.

PMID- 12485313
TI  - Relationships among specific viral pathogens, virus-induced interleukin-8, and
      respiratory symptoms in infancy.
AB  - Both virus-mediated damage to airway tissues and induction of pro-inflammatory
      cytokines such as interleukin-8 (IL-8) could contribute to symptom severity
      during viral respiratory infections in children. To test the hypothesis that IL-8
      contributes to the pathogenesis of respiratory symptoms during naturally acquired
      respiratory viral infections in children, nasal wash samples collected from
      infants with acute viral infections (n = 198) or from healthy uninfected infants
      (n = 31) were analysed for IL-8. Nasal wash IL-8 was positively related to age in
      uninfected children (rs = 0.36, p < 0.05). Respiratory syncytial virus (RSV)
      infection caused more severe respiratory symptoms compared to infections with
      influenza A, parainfluenza viruses, or rhinoviruses. In addition, RSV,
      parainfluenza and rhinovirus infections increased levels of IL-8 in nasal lavage
      fluid, and there were some differences in the ability of the viruses to induce IL
      8 production (RSV>influenza, p < 0.05). Finally, there were significant
      correlations between nasal wash IL-8 levels and symptom scores during infections
      with rhinovirus (rs = 0.56, p < 0.001) or influenza A (rs = 0.45, p < 0.05), but
      not with parainfluenza virus or RSV. These findings provide evidence of a close
      relationship between the generation of IL-8 and symptoms during acute community
      acquired infections with rhinovirus or influenza A. In contrast, for RSV and
      parainfluenza infections, factors in addition to IL-8 production appear to
      contribute to the generation of clinical symptoms.

PMID- 12485314
TI  - Exposure to pets and atopic dermatitis during the first two years of life. A
      cohort study.
AB  - The aim of this study was to assess the association between keeping pets in early
      childhood and the occurrence of atopic dermatitis in an ongoing birth cohort
      followed up to the age of 2 years. We analyzed data of 4578 children in the
      intervention and observation part of an ongoing cohort study. The children were
      recruited at birth in the two study regions Wesel and Munich between January 1996
      and June 1998. Information on atopic diseases and pet ownership was obtained by
      questionnaire at the child's first and second birthday. The logistic regression
      model showed a negative association between 'keeping any pet' and in particular
      'keeping dogs' in the 1st year of life and the development of atopic dermatitis
      in the 1st and the 2nd years of life. The protective effects remained
      statistically significant after adjusting for several possible confounding
      variables (1st year(any) pet OR 0.71, 95% CI [0.55;0.92], 1st year(dog) OR 0.62,
      95% CI [0.39;0.98], 2nd year(any) pet OR 0.74, 95% CI [0.57;0.97], 2nd year(dog)
      OR 0.63, 95% CI [0.40;0.98]). Ownership of small furred pets (hamster, rabbit and
      guinea pig) also showed a borderline protective effect for the 1st year. We
      assume an association between keeping pets and undefined environmental factor(s)
      that contribute protectively to the development of atopic dermatitis in early
      life, presumably by effects on the maturation of the immune system.

PMID- 12485315
TI  - An anthroposophic lifestyle and intestinal microflora in infancy.
AB  - The intestinal flora is considered to have an impact on the development of the
      immune system. In the anthroposophic lifestyle, a diet comprising vegetables
      spontaneously fermented by lactobacilli, and a restrictive use of antibiotics,
      anti-pyretics and vaccinations, is typical. The aim of this study was to assess
      the gut flora in infants in relation to certain lifestyle characteristics
      associated with anthroposophy. Sixty-nine children < 2 years of age with an
      anthroposophic lifestyle, and 59 infants of a similar age with a traditional
      lifestyle, were clinically examined and questionnaire replies assessed. Fecal
      samples were analyzed by bacterial enumeration, bacterial typing through
      biochemical fingerprinting and by measuring microflora-associated characteristics
      (MACs). The numbers of colony-forming units (CFU)/g of feces were significantly
      higher for enterococci and lactic acid bacteria in children who had never been
      exposed to antibiotics (5.5 x 107 vs. 2.1 x 107; p < 0.001 and 10 x 107 vs. 4.1 x
      107; p < 0.01, respectively). Furthermore, the number of enterococci was
      significantly higher in breastfed and vegetarian infants (p < 0.01). The
      diversity (Simpson's diversity index) of lactobacilli, as determined by
      biochemical fingerprinting, was higher in infants born at home than in those born
      in hospital (p < 0.01). Several MACs were related to specific lifestyle features,
      and infants with an anthroposophic lifestyle had a higher proportion of acetic
      acid and a lower proportion of propionic acid in their stool as compared to the
      control children. In conclusion, lifestyle factors related to the anthroposophic
      way of life influenced the composition of the gut flora in the infants. These
      differences may contribute to the lower prevalence of atopic disease previously
      observed in children in anthroposophic families.

PMID- 12485316
TI  - Domestic aeroallergen levels in Barcelona and Menorca (Spain).
AB  - Exposure to common indoor allergens is known to be associated with sensitization
      and triggers of asthma. Levels of allergens have been barely described in
      Mediterranean countries. This study reports domestic allergen levels among the
      general population of two regions of Spain. Dust samples were collected from
      living rooms and mattresses in homes of infants in Barcelona (n = 366) and
      Menorca (n = 475) and assayed for house dust mite (Der p 1) and cat allergen (Fel
      d 1) concentrations by enzyme-linked immunoabsorbent assay (ELISA). Geometric
      mean values (95% CI) of Der p 1 were 0.77 micro g/g (0.65, 0.92) in living rooms
      and 0.68 (0.56, 0.82) in children's mattresses in Barcelona, and 9.06 (7.93
      10.34) and 3.12 (2.71-3.59) in Menorca, respectively. Fel d 1 levels were 0.37
      micro g/g (0.31, 0.45) and 0.14 (0.12, 0.18) in Barcelona, and 0.42 (0.35, 0.50)
      and 0.20 (0.18, 0.24) in Menorca. Home characteristics were not consistently
      related to levels of aeroallergens in either location. Differences in Der p 1
      levels in the two locations indicate that levels cannot be extrapolated from one
      part of a country to another with any certainty. Additionally, allergen reduction
      measures related to indoor sources must be specific to each location.

PMID- 12485317
TI  - Wheezing requiring hospitalization in early childhood: predictive factors for
      asthma in a six-year follow-up.
AB  - Although asthma is common after wheezing in early childhood, the risk factors for
      and the prevention of later asthma are poorly understood. During the present
      follow-up study, a range of possible predictive factors for school-age asthma was
      evaluated. The study group consisted of 82 children hospitalized for wheezing at
      age < 2 years in 1992-93. The baseline data were collected on entry to the study.
      In 1999, the children were re-examined at the median age of 7.2 years. A
      structured questionnaire was applied to chart the symptoms suggestive of asthma,
      and the children were examined clinically. An exercise challenge test, as well as
      skin prick tests (SPT) to common inhalant allergens, was performed. Asthma was
      present in 33 (40%) children, 30 (91%) having continuous medication for asthma.
      The significant asthma-predictive factors, present on entry to the study, were
      blood eosinophilia (p = 0.0008), atopic dermatitis (p = 0.0089), elevated total
      serum immunoglobulin E (IgE) (p = 0.0452), and a history of earlier episodes of
      wheezing in infancy (p = 0.0468). SPT positivity in early childhood was also
      associated with school-age asthma (p = 0.002). In contrast, respiratory syncytial
      virus (RSV) identification during the index episode of wheezing played a minor
      role as a predictive factor for asthma. In conclusion, if hospitalization for
      wheezing occurs in infancy, more than every third child will suffer from asthma
      at early school age; the risk is significantly increased with recurrent wheezing
      in infancy and the development of allergic manifestations.

PMID- 12485318
TI  - Reduced expression of CD69 and adhesion molecules of T lymphocytes in asthmatic
      children receiving immunotherapy.
AB  - T lymphocytes play a fundamental role in the initiation and regulation of chronic
      inflammatory responses in patients with asthma. CD69 is an early marker of T-cell
      activation. The levels of intercellular adhesion molecule-1 (ICAM-1, CD54) and L
      selectin have been reported to increase in patients with allergic diseases and
      asthma. The present study was therefore undertaken to investigate the expression
      of CD69, CD54, and L-selectin by T lymphocytes of children with asthma, before
      and after immunotherapy. Eighteen children newly diagnosed with asthma, 11 good
      and nine poor responders to immunotherapy, and 16 normal subjects, were enrolled
      in this study. The percentages of CD69+, CD54+, and CD62L+ cells in T lymphocytes
      were measured by using flow cytometry. The levels of CD69, CD54, and CD62L in
      serum and culture supernatants were determined by using enzyme-linked
      immunosorbent assay (ELISA). The expression of CD69 and CD54 on CD3+ T
      lymphocytes was significantly higher in children with asthma than in control
      patients. All the patient groups expressed (spontaneously and following
      stimulation with phorbol myristate acetate and ionomycin together with mite
      extract proteins) greater amounts of CD69 and CD54 than did control subjects.
      With long-term immunotherapy, the percentages of CD69+ and CD54+ T lymphocytes
      were significantly lower in patients with a good response to immunotherapy. Our
      results also showed significantly lower serum L-selectin levels following
      immunotherapy. In conclusion, successful immunotherapy resulted in decreased
      expression and production of CD69 and CD54. These results may explain, in part,
      the clinical efficacy of immunotherapy.

PMID- 12485319
TI  - Time efficacy of a single dose of montelukast on exercise-induced asthma in
      children.
AB  - The aim of this study was to evaluate the timing of onset and the duration of
      action of a single oral-dose treatment with montelukast in comparison to placebo
      on exercise-induced asthma (EIA) in asthmatic children. Nineteen children (7-13
      years) with stable asthma were evaluated. Patients undertook three consecutive
      treadmill exercise tests, respectively, 2, 12 and 24 h after a single-dose
      administration. A double-blind randomized, single-dose, placebo-controlled,
      crossover design was used. To assess bronchoconstriction after the exercise
      challenge, the maximal percentage fall in FEV1 (DeltaFEV1) from the baseline
      value was considered. Two hours after dosing, DeltaFEV1 was -15.33 +/- 2.93 for
      placebo and -13.33 +/- 2.03 for montelukast. At 12 h, DeltaFEV1 was -18.69 +/-
      2.83 for placebo, -9.78 +/- 1.85 for montelukast (p < 0.005). No difference was
      observed between placebo (DeltaFEV1-10.21 +/- 2.07) and montelukast (DeltaFEV1
      9.10 +/- 2.02) at 24 h. Analysis of the degree of protection showed a significant
      efficacy of montelukast (p = 0.02) in comparison with placebo only at 12 h.
      Montelukast showed a significant protective effect 12 h after dosing, but no
      effect after 2 and 24 h. In mild asthmatics, the timing of administration of
      single dosage before exercise should be strictly considered in order to obtain
      the drug protective effects.

PMID- 12485320
TI  - Immunoglobulin G antibodies of children exposed to microorganisms in a water
      damaged school.
AB  - The aim of this study was to determine whether exposure to fungi (molds and
      yeasts) among children attending a water-damaged school was reflected by the
      children's immunoglobulin G (IgG) response to microorganisms typical of water
      damage and whether the presence of these IgG antibodies was associated with
      respiratory symptoms and morbidity. The relationships between positive IgG
      antibodies and atopy, described as elevated allergen-specific immunoglobulin E
      (IgE) antibodies, were also examined. The study population consisted of a
      randomly selected group of exposed children attending a water-damaged school and
      a group of unexposed children of the same age. Serum samples for analyses of IgG
      and IgE antibodies were drawn from the children. The respiratory morbidity, the
      number of positive IgG antibodies to nine microorganisms indicating water damage,
      and IgE sensitization to common environmental allergens (Phadiatop) were studied.
      The mean number of positive IgG findings was significantly higher among the
      exposed children. The number of positive IgG antibodies did not correlate with
      respiratory illnesses or symptoms at the individual level even though the exposed
      children who had positive IgG antibodies to four or more microorganisms in the
      total group comparison tended to have higher respiratory morbidity. In the
      exposed group, a negative correlation was found between the number of positive
      IgG antibodies and the total value of allergen-specific IgE antibodies. As among
      adults exposed to microorganisms at work, IgG antibodies in children seem to be a
      relevant indicator of exposure to microorganisms in a water-damaged school on the
      group level.

PMID- 12485321
TI  - Evaluation of the relevance of humoral immunodeficiencies in a pediatric
      population affected by recurrent infections.
AB  - Recurrent infections are a common cause of morbidity in childhood. Several
      reports have associated this condition to low levels of IgA and IgG subclasses
      and/or lack of specific antipolysaccharide antibody response, although the
      relevance of these defects in terms of prognosis and therapeutic approach is
      still unclear. The aim of our study was to determine the frequency and the
      clinical relevance of humoral immunodeficiency (HID) other than
      hypogammaglobulinemia in children affected by recurrent infections. We recruited
      67 pediatric patients affected by recurrent infections. Serum IgG, IgA, IgM,
      IgG2, IgG3, and specific anti-Haemophilus influenzae (anti-Hib) antibodies were
      determined. Thirty-seven out of 67 patients showed antibody defects (55%). IgA
      deficiency was observed in 21 out of 67 patients (31%), followed by IgG2 (18%),
      IgG3 (15%) and IgM (6%) defects. Anti-Hib deficiency was present in three out of
      44 patients (7%). A tendency for a higher occurrence of pneumonia and otitis,
      although not statistically significant (p > 0.05), was observed in HID patients
      compared to children with normal humoral function. No statistical difference as
      to the frequency of mild infections (URI) was found between HID and non-HID
      patients. We therefore suggest that the therapeutic program is based on the
      clinical status of the patients. Long-term follow-up with repeated determinations
      of antibody levels is crucial, however, to detect those defects that might evolve
      into more complex immunodeficiencies.

PMID- 12485323
TI  - Effects of tobacco smoke on the secretion of interleukin-1beta, tumor necrosis
      factor-alpha, and transforming growth factor-beta from peripheral blood
      mononuclear cells.
AB  - Alterations of the host response caused by short-term exposure to high levels of
      smoke during the act of smoking (acute smoke exposure) as well as long-term
      exposure to lower levels of tobacco substances in the bloodstream of smokers
      (chronic smoke exposure) may play a role in the pathogenesis of periodontal
      diseases in smokers. In this study, we examined the secretion of three cytokines
      [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and transforming
      growth factor (TGF)-beta] from mononuclear blood cells from current smokers and
      non-smokers exposed to in vitro tobacco smoke (which may be comparable to in vivo
      acute smoke exposure) and mononuclear blood cells from current smokers not
      exposed to further in vitro smoke (which may be comparable to chronic smoke
      exposure). Peripheral blood mononuclear cells were isolated from eight healthy
      current smokers and eight healthy non-smokers, plated in culture wells, exposed
      in vitro for 1-5 min to cigarette smoke in a smoke box system or not exposed
      (baseline controls), and then incubated without further smoke exposure for
      another 24 h. Supernatants from each well were then collected and assayed for the
      concentrations of the three cytokines by enzyme-linked immunosorbent assay
      (ELISA). At baseline, mean IL-1beta levels were higher in smokers than in non
      smokers (mean: 10.6 vs. 5.9 pg/ml, anova: P < 0.05). In both smokers and non
      smokers, secreted levels of IL-1beta increased from 0 to 5 min of in vitro smoke
      exposure (mean: 5.9-9.9 pg/ml, t-test: P < 0.05 for non-smokers only) with levels
      in smokers higher than in non-smokers (P > 0.05). Mean TNF-alpha levels increased
      from 0 to 2 min of smoke exposure and decreased from 2 to 5 min in smokers and
      non-smokers, with higher levels in non-smokers than smokers at all time-points (P
      > 0.05). Mean TGF-beta levels were higher in smokers than in non-smokers at all
      time-points (mean: 180.5 vs. 132.0 pg/ml, P < 0.05 at 5 min only) with no
      significant alteration of the pattern of secretion with cigarette smoke exposure.
      These observed alterations in the secretion of cytokines from mononuclear blood
      cells in smokers, relative to non-smokers, and with in vitro smoke exposure may
      play a role in the pathogenesis of periodontal diseases in smokers.

PMID- 12485324
TI  - Effects of apigenin and tt-farnesol on glucosyltransferase activity, biofilm
      viability and caries development in rats.
AB  - Propolis, a resinous hive product secreted by Apis mellifera bees, has been shown
      to reduce the incidence of dental caries in rats. Several compounds, mainly
      polyphenolics, have been identified in propolis. Apigenin and tt-farnesol
      demonstrated biological activity against mutans streptococci. We determined here
      their effects, alone or in combination, on glucosyltransferase activity, biofilm
      viability, and development of caries in rats. Sprague-Dawley rats were infected
      with Streptococcus sobrinus 6715 and treated topically twice daily as follows:
      (1) tt-farnesol, (2) apigenin, (3) vehicle control, (4) fluoride, (5) apigenin
      +tt-farnesol, and (6) chlorhexidine. Apigenin (1.33 mM) inhibited the activity of
      glucosyltransferases in solution (90-95%) and on the surface of saliva-coated
      hydroxyapatite beads (35-58%); it was devoid of antibacterial activity. tt
      Farnesol (1.33 mM) showed modest antibacterial activity against biofilms and its
      effects on glucosyltransferases were minimal. The incidence of smooth-surface
      caries was significantly reduced by apigenin +tt-farnesol (60%), fluoride (70%),
      and chlorhexidine (72%) treatments compared to control (P < 0.05).

PMID- 12485325
TI  - Cytokine production in response to endodontic infection in germ-free mice.
AB  - This study evaluated the cytokine profiles (type 1 or type 2) that are triggered
      by and modulate endodontic periapical infections in the root canal system of germ
      free mice. Microorganisms isolated from two patients with pulpal necrosis were
      inoculated into two groups of experimental animals: group I (Gemella morbillorum)
      and group II (Bifidobacterium adolescentis, Fusobacterium nucleatum and
      Clostridium butyricum). In vitro, G. morbillorum induced type 1 cytokine
      synthesis, while the modulation processed in vivo seemed to have the opposite
      effect, with a reduction in the basal levels of IL-12 and IFN-gamma, IL-4
      independent down-modulation. In vitro, microorganisms from group II, in poly
      infection, induced a reduction of type 1 cytokine levels from day 10 to day 20,
      which seemed to be modulated via IL-4. In vivo, however, a predominance of the
      immune response to one species over the others occurred.

PMID- 12485326
TI  - Sequence diversity in the major fimbrial subunit gene (flp-1) of Actinobacillus
      actinomycetemcomitans.
AB  - Cells of the periodontal pathogen Actinobacillus actinomycetemcomitans exhibit
      tight adherence to surfaces such as glass, plastic and hydroxyapatite, a property
      that probably plays an important role in the ability of this bacterium to
      colonize teeth and other surfaces. Tight adherence is mediated by long fibrils of
      bundled pili (fimbriae) that form on the surface of the cell. The flp-1 gene
      encodes the major pilin protein component of A. actinomycetemcomitans fimbriae.
      In this study we compared flp-1 DNA sequences from 43 strains of A.
      actinomycetemcomitans isolated in Europe, Japan and the United States and
      identified seven distinct flp-1 allelic classes. DNA and predicted protein
      sequences were almost completely conserved within each flp-1 class but were
      highly divergent between classes. Most amino acid substitutions occurred in the C
      terminus of the pilin protein, a region that has been shown to be important for
      the bundling and adhesive properties of the pili. flp-1 classes correlated with
      serotypes and 16S rRNA genotypes in most strains. At least five strains showed
      evidence of horizontal transfer of flp-1 between strains of different serotypes
      and 16S rRNA genotypes. Four of the seven flp-1 classes were present in
      geographically diverse isolates. Strains representing all seven flp-1 classes,
      but not a strain carrying a transposon insertion in flp-1, bound avidly to
      polystyrene in an in vitro adherence assay. Strains representing six of the seven
      flp-1 classes were isolated from localized juvenile periodontitis patients,
      suggesting that phylogenetically diverse strains carry pathogenic potential. Our
      findings provide a framework for future biochemical, immunological and genetic
      studies of A. actinomycetemcomitans fimbriae.

PMID- 12485327
TI  - Gender differences in HLA phenotype frequencies found in German patients with
      generalized aggressive periodontitis and chronic periodontitis.
AB  - HLA antigens have been considered as risk factors for periodontitis. Differences
      in prevalence and in the extent of attachment loss between males and females have
      suggested that gender-dependent HLA deviations could play a role in individual
      predisposition to periodontitis. The aim of the present study was therefore to
      investigate the incidence of gender-dependent HLA associations in 50 patients
      with generalized aggressive periodontitis (AP) and 102 patients with chronic
      periodontitis (CP) in comparison to 102 probands without any attachment loss
      caused by periodontitis. HLA typing was carried out using a microlymphocytotoxic
      test and a polymerase chain reaction with sequence-specific primers (PCR-SSP).
      Female AP patients showed an increase in the frequency of HLA-A*68/69 and a
      decrease in the frequency of DRBblank* (non-DRB3/4/5*) and DQB1*05-positive
      probands. Only in female CP patients was HLA-DQB1*0303 absent, whereas HLA
      DQB1*06 homozygosity increased significantly. With regard to the (AP + CP)
      periodontitis group as a whole, the increased frequency of HLA-DQB1*06
      homozygosity in females was similar to the findings obtained in the AP group.
      Evidently, gender is a confounding variable, which should be considered in
      further studies of HLA and periodontitis.

PMID- 12485328
TI  - Cytomegalovirus periodontal presence is associated with subgingival Dialister
      pneumosintes and alveolar bone loss.
AB  - Destructive periodontal disease is associated with human cytomegalovirus (HCMV),
      Epstein-Barr type 1 virus (EBV-1) and other members of the Herpesviridae family
      as well as with various gram-negative anaerobic bacteria, including the Dialister
      pneumosintes species. This study aimed to determine possible interrelationships
      between periodontal HCMV, EBV-1, herpes simplex virus and D. pneumosintes, and
      relate the microbiological findings to periodontitis clinical status. Sixteen
      subjects each contributed paper point samples from two progressing and two stable
      periodontitis lesions, as determined by ongoing loss of probing attachment.
      Polymerase chain reaction methodology was used to identify the study
      herpesviruses and D. pneumosintes. Chi-squared tests, Fisher exact tests and
      multivariate logistic regression were employed to identify statistical
      associations among herpesviruses, bacteria and clinical variables. HCMV, and no
      other virus or combination of viruses, was positively associated with the
      presence of D. pneumosintes, and the relationship was specific for individual
      periodontitis sites with no detectable subject effect. D. pneumosintes was in
      turn positively associated with periodontal pocket depth and disease-active
      periodontitis. When the average percentage of alveolar bone loss in all teeth was
      treated as a response, HCMV remained significant even after D. pneumosintes was
      included in the model, suggesting that both HCMV and D. pneumosintes affected
      bone loss or, alternatively, HCMV affected factors not studied that themselves
      can induce bone loss. We hypothesize that periodontal HCMV sets the stage for
      subgingival proliferation of D. pneumosintes and subsequent periodontal disease
      progression. Studies on herpesviral-bacterial interactions may hold great promise
      for delineating important etio-pathogenic aspects of destructive periodontal
      disease.

PMID- 12485329
TI  - Cytokines in the oral mucosa of mice infected with Candida albicans.
AB  - Oropharyngeal candidiasis is associated with defects in cell-mediated immunity,
      and is commonly seen in immunocompromised patients. We have previously shown that
      T-cell-deficient BALB/c nude (nu/nu) mice are extremely susceptible to
      oropharyngeal candidiasis, and that recovery from a chronic infection is
      dependent on CD4 T lymphocytes. In this study we describe the local tissue
      cytokine profile in lymphocyte-reconstituted immunodeficient mice and their
      euthymic counterparts. Mice were infected orally with 108 cells of the yeast
      Candida albicans, and oral tissues sampled on days 0, 4, 8, and 14. Nude mice
      were reconstituted with 3 x 107 naive lymphocytes following oral inoculation.
      Interleukin (IL)-6, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha
      were identified in the oral tissues of infected euthymic mice recovering from
      oral infection, as well as naive controls. TNF-alpha was identified in nude oral
      tissue on days 4 and 8, but only after lymphocyte reconstitution. No IL-2, IL-4
      or IL-10 was detected in either euthymic or athymic mice at any time-point
      throughout the experiment. This study confirms the functional activity of T
      lymphocytes in reconstituted nude mice, and suggests that TNF-alpha may be an
      important mediator in the recovery from oropharyngeal candidiasis.

PMID- 12485330
TI  - Similarity of the oral microbiota of pre-school children with that of their
      caregivers in a population-based study.
AB  - This study evaluated the similarity between the oral microbiota of young children
      and that of their adult caregivers. Oral samples from children (174 dentate and
      18 pre-dentate) aged 6-36 months and their caregivers in Saipan were assayed
      using a DNA probe assay. Many species including Streptococcus mutans,
      Streptococcus sobrinus, Actinomyces species, Campylobacter rectus, Fusobacterium
      nucleatum, Prevotella intermedia, and Porphyromonas gingivalis were detected in
      dentate and pre-dentate children, whereas Bacteroides forsythus was detected only
      in dentate children. A higher percentage of children were positive for the
      detection of an individual species if the caregiver was also positive. There were
      significant relative risks of species detection between dentate children and
      their caregivers. By logistic regression, there were significant positive
      associations between species detection in caregiver and in child, but not between
      species detection and child age or maternal education level. In conclusion,
      dental pathogens were detected in young, including pre-dentate, children. The
      microbial profiles of children were strongly associated with the microbiota of
      their caregivers.

PMID- 12485331
TI  - Antigen-presenting cells in human periodontal disease tissues.
AB  - T cells are present in the inflammatory infiltrates of periodontal disease
      lesions and require antigen presentation by antigen-presenting cells (APCs).
      While it is still not known whether Th1 or Th2 cells predominate in these
      lesions, it has been reported that different APCs may induce activation of
      different T-cell subsets. An immunoperoxidase technique was used to investigate
      the presence of CD1a+, CMRF-44+, CMRF-58+ and CD83+ dendritic cells, CD14+
      macrophages or dendritic cell precursors and CD19+ B cells in gingival biopsies
      from 21 healthy or gingivitis and 25 periodontitis subjects. The samples were
      divided into three groups according to the size of infiltrate (group 1, small
      infiltrates; group 2, medium infiltrates; group 3, extensive infiltrates). The
      presence of numerous CD1a+ Langerhans cells was noted in the epithelium with no
      differences between the healthy/gingivitis and periodontitis groups. The
      percentage of CD83+ dendritic cells in the infiltrates was higher than the
      percentage of CD1a+, CMRF-44+ or CMRF-58+ dendritic cells. Endothelial cells
      positive for CD83 were found predominantly in areas adjacent to infiltrating
      cells, CD83+ dendritic cells being noted in the region of CD83+ endothelium. The
      percentage of CD14+ cells in the inflammatory infiltrates was similar to that of
      CD83+ dendritic cells. B cells were the predominant APC in group 2 and 3 tissues.
      The percentage of B cells in group 3 periodontitis lesions was increased in
      comparison with group 1 periodontitis tissues and also in comparison with group 3
      healthy/gingivitis sections. Functional studies are required to determine the
      roles of different APC subpopulations in periodontal disease.

PMID- 12485332
TI  - Clonality of Fusobacterium nucleatum in root canal infections.
AB  - Fusobacterium nucleatum is a gram-negative non-spore-forming, non-motile,
      obligate anaerobic rod that is normally isolated from the oral cavity. Several
      studies have reported a significant heterogeneity within the F. nucleatum
      species. The aim of the present study was to analyze the clonal diversity of F.
      nucleatum strains isolated from intracanal infections and to evaluate the
      presence of Enterobacterial Repetitive Intergenic Consensus (ERIC)-like sequences
      in the genome of F. nucleatum. Samples were collected from 13 single-root teeth
      from adult patients, all having carious lesions, necrotic pulps and radiographic
      evidence of periradicular bone loss. F. nucleatum was isolated from two different
      patients (subjects 5 and 7) by culture. Amplification of 19 colonies from subject
      5 and 15 colonies from subject 7 using ERIC primers resulted in four clonal
      types, two per subject. An intense amplicon of approximately 700 bp was generated
      by ERIC-PCR for all F. nucleatum isolates and F. nucleatum ssp. polymorphum ATCC
      10953. The amplification reaction using primer 1254 confirmed the results
      obtained with the ERIC primer. Our findings indicate that DNA fingerprints
      provided by ERIC- and Arbitrarily Primed (AP)-PCR may constitute a powerful tool
      for investigating F. nucleatum clonal diversity.

PMID- 12485334
TI  - Role of Alicyclobacillus acidoterrestris in the development of a disinfectant
      taint in shelf-stable fruit juice.
AB  - AIMS: This study was undertaken to identify the bacterium and metabolic products
      contributing to a disinfectant taint in shelf-stable fruit juice and to determine
      some of the growth conditions for the organism. METHODS AND RESULTS:
      Microbiological examination of tainted and untainted fruit juice drinks detected
      low numbers of acid-dependent, thermotolerant, spore-forming bacteria in the
      tainted juices only. The presence of omega-cyclohexyl fatty acids was confirmed
      in two of the isolates by cell membrane fatty acid analysis. The isolates were
      subsequently identified as Alicyclobacillus acidoterrestris by partial 16S rDNA
      sequencing. Studies on the isolates showed growth at pH 2.5-6.0 and 19.5-58
      degrees C. Gas chromatography/mass spectrometry (GC/MS) was used to identify and
      quantify 2,6-dibromophenol (2,6-DBP) and 2,6-dichlorophenol (2,6-DCP) in the
      tainted juice. Challenge studies in a mixed fruit drink inoculated with the two
      isolates and the type strain of A. acidoterrestris, incubated at 44-46 degrees C
      for 4 d, showed the production of both metabolites, which were confirmed and
      quantified by GC/MS. CONCLUSIONS: The results show that A. acidoterrestris can
      produce 2,6-DBP and 2,6-DCP in shelf-stable juices. SIGNIFICANCE AND IMPACT OF
      THE STUDY: This is the first report detailing experimental methodology showing
      that A. acidoterrestris can produce 2,6-DCP in foods. Control of storage
      temperatures (to < 20 degrees C) immediately after processing may provide an
      effective control measure for the fruit juice industry to prevent spoilage by A.
      acidoterrestris.

PMID- 12485335
TI  - Inducible beta-glucosidase synthesis during germination and outgrowth of Bacillus
      subtilis ATCC 9372 spores.
AB  - AIMS: To investigate the role of germination processes in the expression of the
      beta-glucosidase enzyme in Bacillus subtilis ATCC 9372 spores. METHODS AND
      RESULTS: Enzyme activity was monitored in germinating and non-germinating spores
      of B. subtilis ATCC 9372. The expression of beta-glucosidase by spores of B.
      subtilis was further investigated in the presence of a germination inhibitor, d
      alanine, and a transcription inhibitor, novobiocin. Detection of enzyme activity
      required the presence of the germinant, l-alanine, as well as the inducer, 4
      methylumbelliferryl-beta-d-glucoside. Furthermore, beta-glucosidase synthesis was
      abolished in the presence of d-alanine or novobiocin. CONCLUSIONS: The data
      obtained in this study indicated that beta-glucosidase was not pre-existing, or
      merely attached to the spore, but was synthesized de novo during spore
      germination. SIGNIFICANCE AND IMPACT OF THE STUDY: The requirement of functional
      germination processes for the detection of beta-glucosidase activity makes this
      enzyme a good candidate for detection of spore viability.

PMID- 12485336
TI  - Preliminary investigations into possible resistance to oxytetracycline in
      Melissococcus plutonius, a pathogen of honeybee larvae.
AB  - AIMS: To investigate the occurrence of oxytetracycline (OTC) resistance in
      Melissococcus plutonius, which causes European foulbrood in honeybee colonies.
      METHODS AND RESULTS: Strains of M. plutonius were isolated from diseased colonies
      in England and Wales and tested for resistance to OTC. The minimum inhibitory
      concentration (MIC) of OTC was also determined for selected isolates. No
      resistance to the antibiotic was found in any isolate and the average MIC was
      found to be 3.9 microg ml-1. Melissococcus plutonius was found to be susceptible
      to both chlortetracycline and tetracycline. CONCLUSIONS: No resistance to OTC was
      found in M. plutonius. SIGNIFICANCE AND IMPACT OF THE STUDY: This study
      demonstrated that OTC can continue to be used to treat European foulbrood and
      that resistance may not explain why some treatments fail.

PMID- 12485337
TI  - Induced colistin resistance as an identifying marker for Aeromonas phenospecies
      groups.
AB  - AIMS: To investigate the taxonomic interest of colistin resistance as an
      identifying marker for Aeromonas phenospecies groups. METHODS AND RESULTS:
      Colistin resistance was investigated in 387 Aeromonas isolates identified at
      species level using a 14-test format protocol with miniaturized tests combined
      with determination of urocanic acid utilization whenever necessary. Colistin
      resistance, determined by the disc diffusion method, was unreliable when compared
      with minimum inhibitory concentration (MIC) determination. In some strains, the
      MIC values and resistance rates of colistin could be increased after overnight
      induction with a 50- microg colistin disc in 20 ml of Mueller-Hinton broth (2.5
      mg l(-1)). Colistin-induced resistance level was raised to 85.8% in the Aeromonas
      hydrophila complex, 2.1% in the A. caviae complex and 2.5% in the A. veronii
      complex except for A. jandaei (100% colistin resistant). This new marker allowed
      the identification of 96.2 and 93.6% of Aeromonas isolates to phenospecies and
      species level, respectively. CONCLUSIONS: Colistin-induced colistin resistance is
      a new phenotypic marker for Aeromonas isolates. SIGNIFICANCE AND IMPACT OF THE
      STUDY: With the present protocol, colistin resistance determination may improve
      the identification of Aeromonas isolates to phenogroup level, when results
      obtained by conventional biochemical methods are ambiguous.

PMID- 12485338
TI  - Development of a rapid polymerase chain reaction-ELISA assay using polystyrene
      beads for the detection of Toxoplasma gondii DNA.
AB  - AIMS: To develop a rapid colourimetric assay for the detection of Toxoplasma
      gondii DNA using polystyrene beads as solid support. METHODS AND RESULTS: A
      nested-polymerase chain reaction (PCR)-ELISA assay for the detection of T. gondii
      DNA was standardized by optimizing the hybridization time and probe
      concentration. Its detection threshold was then determined and compared with
      Southern blotting hybridization. These were found to be equivalent, but the PCR
      ELISA-beads test is easier to perform and the turnaround time is much shorter
      than with Southern blot. CONCLUSIONS: The PCR-ELISA-beads assay is a valuable
      tool for the detection of T. gondii DNA. SIGNIFICANCE AND THE IMPACT OF THE
      STUDY: Our results demonstrate that this PCR-ELISA assay, using polystyrene
      beads, can be used as a routine diagnostic test for the detection of T. gondii in
      clinical laboratories.

PMID- 12485339
TI  - Antimicrobial activity of essential oils isolated from Portuguese endemic species
      of Thymus.
AB  - AIMS: Thymus species are wild species mostly found in the arid lands of Portugal.
      Possible antimicrobial properties of Thymus essential oils have been
      investigated. The chemical composition of the essential oils and the
      antimicrobial activity of Thymus mastichina (L) L. subsp. mastichina, T.
      camphoratus and T. lotocephalus from different regions of Portugal were analysed.
      METHODS AND RESULTS: Hydrodistillation was used to isolate the essential oils and
      the chemical analyses were performed by gas chromatography (GC) and GC coupled to
      mass spectrometry. The antimicrobial activity was tested by the disc agar
      diffusion technique against Candida albicans, Escherichia coli, Listeria
      monocytogenes, Proteus mirabilis, Salmonella spp. and Staphylococcus aureus. Pure
      linalool, 1,8-cineole and a mixture (1 : 1) of these compounds were included.
      Linalool, 1,8-cineole or linalool/1,8-cineole and linalool/1,8-cineole/linalyl
      acetate were the major components of the essential oils, depending on the species
      or sampling place. The essential oils isolated from the Thymus species studied
      demonstrated antimicrobial activity but the micro-organisms tested had
      significantly different sensitivities. CONCLUSIONS: The antimicrobial activity of
      essential oils may be related to more than one component. SIGNIFICANCE AND IMPACT
      OF THE STUDY: Portuguese endemic species of Thymus can be used for essential oil
      production for food spoilage control, cosmetics and pharmaceutical use. Further
      studies will be required to elucidate the cell targets of the essential oil
      components.

PMID- 12485340
TI  - Variability in spore germination response by strains of proteolytic Clostridium
      botulinum types A, B and F.
AB  - AIMS: The objective of the study was to evaluate the variability of germination
      response of 10 strains of proteolytic Clostridium botulinum. METHODS AND RESULTS:
      An automated turbidometric method was used to follow the fall in optical density.
      Spores of proteolytic Cl. botulinum germinated in response to l-alanine alone,
      with rate and extent of germination increased by addition of l-lactate or
      bicarbonate ions. Other hydrophobic amino acids also triggered germination of
      spores of proteolytic Cl. botulinum but not AGFK and inosine, germinants for
      Bacillus subtilis or B. cereus. CONCLUSIONS: Unlike spores of nonproteolytic Cl.
      botulinum, all proteolytic Cl. botulinum germinate in hydrophobic l-amino acids
      without l-lactate. However, a great variability of response to germinant is
      evidenced between the species. SIGNIFICANCE AND IMPACT OF THE STUDY: The
      selection of a model strain to study germination of Cl. botulinum spores should
      consider the variability in sensitivity to germinants shown in this work. In
      particular, the sequenced strain ATCC 3502 may not be the most appropriate model
      for germination studies.

PMID- 12485341
TI  - Augmenting effect of acetic acid for acidification on bactericidal activity of
      hypochlorite solution.
AB  - AIMS: Bactericidal activity of chlorine solution is enhanced by weak
      acidification. We compared the effects of various acids on the bactericidal
      activity of hypochlorite solution to establish a method for safe and effective
      use of an acidic hypochlorite solution. METHODS AND RESULTS: The bactericidal
      activities of acidic hypochlorite solutions that had been adjusted to pH 5.0 with
      hydrochloric acid, acetic acid, citric acid, lactic acid, formic acid, phosphoric
      acid or sulphuric acid against Bacillus subtilis spores were compared. The acidic
      solutions prepared with hydrochloric acid and acetic acid showed the highest
      bactericidal activity, and all of the spores (5 x 106 cfu ml(-1)) were killed
      within 10 min. On the other hand, the solutions prepared with citric acid and
      lactic acid showed no bactericidal activity against any bacterial strains tested
      in this study despite the low pH. The amount of chlorine gas produced by the
      preparation using acetic acid was sixfold less than that produced from the
      preparation using hydrochloric acid. CONCLUSIONS: Acetic acid is the most
      suitable and safe acid for the preparation of an acidic hypochlorite solution.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study provide useful
      information for establishing a method for safe and effective use of an acidic
      hypochlorite solution.

PMID- 12485342
TI  - Bacteriophage isolation from human saliva.
AB  - AIMS: To detect bacteriophages for Gram-positive oral pathogens in human saliva.
      METHODS AND RESULTS: Saliva samples from 31 donors were screened for the presence
      of bacteriophages for Streptococcus sobrinus, Streptococcus mutans, Streptococcus
      salivarius, Actinomyces viscosus and Enterococcus faecalis. Bacteriophages for
      Enterococcus faecalis were found in seven samples. Enterococcus faecalis phages
      were still present in saliva re-collected from one donor one month, and one year
      after initial saliva collection. CONCLUSIONS: The presence and stability of the
      Enterococcus faecalis bacteriophages in human saliva suggests a possible role of
      these bacteriophages in the oral ecosystem. SIGNIFICANCE AND IMPACT OF THE STUDY:
      Phage therapy as a way to control oral bacteria might be considered.

PMID- 12485343
TI  - Saccharomyces cerevisiae biodiversity in spontaneous commercial fermentations of
      grape musts with 'adequate' and 'inadequate' assimilable-nitrogen content.
AB  - AIM: To evaluate whether intraspecific diversity of Saccharomyces cerevisiae in
      wine fermentations is affected by initial assimilable-nitrogen content. METHODS
      AND RESULTS: Saccharomyces cerevisiae isolates from two spontaneous commercial
      wine fermentations started with adequate and inadequate nitrogen amounts were
      characterized by mitochondrial DNA restriction analysis. Several strains occurred
      in each fermentation, two strains, but not the same ones, being predominant at
      frequencies of about 30%. No significant differences were detected by comparing
      the biodiversity indices of the two fermentations. Cluster analysis demonstrated
      that the strain distribution was independent of nitrogen content, the two pairs
      of closely related dominant strains grouping into clusters at low similarity.
      CONCLUSIONS: The genetic variability of S. cerevisiae in wine fermentations
      seemed not to depend on the nitrogen availability in must. SIGNIFICANCE AND
      IMPACT OF THE STUDY: Nitrogen content did not affect the genetic diversity but
      may have induced a 'selection effect' on S. cerevisiae strains dominating wine
      fermentations, with possible consequences on wine properties.

PMID- 12485344
TI  - Characterization of AnRP-mediated negative regulation of the xylanase gene, cgxA,
      from Chaetomium gracile in Aspergillus nidulans.
AB  - AIM: In vivo regulatory features of AnRP, a repressor for the cgxA gene, were
      characterized. METHODS AND RESULTS: Titration of AnRP by introducing multiple
      copies of its specific binding sequence 'TTGACAAAT' into an Aspergillus nidulans
      strain containing the Chaetomium gracile cgxA gene enhanced the cgxA gene
      expression. AnRP functions independently of and cooperatively with CreA to
      modulate the cgxA gene expression. CONCLUSIONS: AnRP is a CreA-independent
      negative regulatory factor controlling the cgxA expression. SIGNIFICANCE AND THE
      IMPACT OF THE STUDY: Xylanases of filamentous fungi have received increased
      interest because of their potential biotechnological applications. Elucidation of
      the factors involved in the regulation of the xylanolytic genes in fungi will
      help to increase levels of xylanase production.

PMID- 12485345
TI  - Ethidium bromide stimulated hyper laccase production from bird's nest fungus
      Cyathus bulleri.
AB  - AIMS: Effect of ethidium bromide, a DNA intercalating agent, on laccase
      production from Cyathus bulleri was studied. METHODS AND RESULTS: The bird's nest
      fungus, Cyathus bulleri was grown on 2% (w/v) malt extract agar (MEA)
      supplemented with 1.5 microg ml(-1) of the phenanthridine dye ethidium bromide
      (EtBr) for 7 d and when grown subsequently in malt extract broth (MEB), produced
      a 4.2-fold increase in laccase production as compared to the untreated fungus.
      The fungal cultures following a single EtBr treatment, when regrown on MEA devoid
      of EtBr, produced a sixfold increase in laccase in MEB. However, on subsequent
      culturing on MEA in the absence of EtBr, only a 2.5-fold increase in laccase
      production could be maintained. In another attempt, the initial EtBr-treated
      cultures, when subjected to a second EtBr treatment (1.5 microg ml(-1)) on MEA
      for 7 d, produced a 1.4-fold increase in laccase production in MEB. CONCLUSIONS:
      The white-rot fungus Cyathus bulleri, when treated with EtBr at a concentration
      of 1.5 microg ml(-1) and regrown on MEA devoid of EtBr, produced a sixfold
      increase in laccase production in MEB. SIGNIFICANCE AND THE IMPACT OF THE STUDY:
      The variable form of C. bulleri capable of hyper laccase production can improve
      the economic feasibility of environmentally benign processes involving use of
      fungal laccases in cosmetics (including hair dyes), food and beverages, clinical
      diagnostics, pulp and paper industry, industrial effluent treatment, animal
      biotechnology and biotransformations.

PMID- 12485346
TI  - In vitro and in vivo pharmacodynamic properties of the fluoroquinolone
      ibafloxacin.
AB  - The pharmacodynamic properties of a new veterinary fluoroquinolone antimicrobial
      agent, ibafloxacin, were evaluated. Minimal inhibitory concentrations (MIC), time
      kill kinetics, postantibiotic effect (PAE) and postantibiotic subminimal
      inhibitory concentration effects (PA-SME) were determined against pathogenic
      canine Gram-negative and Gram-positive bacterial isolates from dermal,
      respiratory and urinary tract infections. The synergistic interactions between
      ibafloxacin and its main metabolite, 8-hydroxy-ibafloxacin were investigated.
      Finally, the efficacy of ibafloxacin was tested in in vivo canine infection
      models. Ibafloxacin had good activity against Pasteurella spp., Escherichia coli,
      Klebsiella spp., Proteus spp. and Staphylococcus spp. (MIC90=0.5 microg/mL),
      moderate activity against Bordetella bronchiseptica, Enterobacter spp. and
      Enterococcus spp. (MIC50=4 microg/mL) and low activity against Pseudomonas spp.
      and Streptococcus spp. The time-killing analysis confirmed that ibafloxacin was
      bactericidal with a broad spectrum of activity. The PAE and PA-SME were between
      0.7-2.13 and 1-11.5 h, respectively. Finally, studies in dog models of wound
      infection and cystitis confirmed the efficacy of once daily oral ibafloxacin at a
      dosage of 15 mg/kg. Additional studies are needed to better define the importance
      of AUC/MIC (AUIC) and Cmax/MIC ratios on the outcome of fluoroquinolone therapy
      in dogs.

PMID- 12485347
TI  - Efficacy of trimethoprim-sulfadoxine against Escherichia coli in a tissue cage
      model in calves.
AB  - Tissue cages implanted subcutaneously in calves were infected with Escherichia
      coli. Twenty-four hours later, the calves were treated either with single doses
      of 2.5 + 12.5 or 5 + 25 mg/kg trimethoprim (TMP) + sulfadoxine (SDX) or with five
      doses of 7.5 + 37.5 mg/kg TMP + SDX at 12-h intervals. In addition, one cage in
      each of three calves in the highest dose group was infected 3 h after initiation
      of treatment. Untreated calves were kept as controls. Concentrations of TMP and
      SDX in plasma and tissue cage fluid (TCF) and counts of viable bacteria in TCF
      were determined. In the highest dose group, concentrations of TMP in TCF remained
      above the minimum inhibitory concentration of the test strain for 94-101 h and
      peak to minimum inhibitory concentration (MIC) ratio was close to 10. In spite of
      this, an effect of treatment was noted only in cages infected after initiation of
      treatment. In vitro studies and analysis of thymidine content in serum and TCF
      from calves suggest that levels of thymidine in TCF are high enough to antagonize
      the antibacterial effect of TMP. The results indicate that soft tissue infections
      in secluded infection sites of calves are refractory to treatment with TMP + SDX.

PMID- 12485348
TI  - Pharmacokinetics and toxicity of bromide following high-dose oral potassium
      bromide administration in healthy Beagles.
AB  - The pharmacokinetics of a multidose regimen of potassium bromide (KBr)
      administration in normal dogs was examined. KBr was administered at 30 mg/kg p.o.
      q 12 h for a period of 115 days. Serum, urine, and cerebrospinal fluid (CSF)
      bromide (BR) concentrations were measured at the onset of dosing, during the
      accumulation phase, at steady-state, and after a subsequent dose adjustment.
      Median elimination half-life and steady-state serum concentration were 15.2 days
      and 245 mg/dL, respectively. Apparent total body clearance was 16.4 mL/day/kg and
      volume of distribution was 0.40 L/kg. The CSF:serum BR ratio at steady-state was
      0.77. Dogs showed no neurologic deficits during maintenance dosing but
      significant latency shifts in waves I and V of the brainstem auditory evoked
      response were evident. Following a subsequent dose adjustment, serum BR
      concentrations of approximately 400 mg/dL were associated with caudal paresis in
      two dogs. Estimated half-life during the accumulation phase was shorter than
      elimination half-lives reported in other studies and was likely related to
      dietary chloride content. The range of steady-state concentrations achieved
      suggests individual differences in clearance and bioavailability between dogs.
      The described protocol reliably produced serum BR concentrations that are
      required by many epileptic patients for satisfactory seizure control.

PMID- 12485349
TI  - Pharmacodynamics and enantioselective pharmacokinetics of racemic carprofen in
      the horse.
AB  - Carprofen is a nonsteroidal anti-inflammatory drug of the 2-arylpropionate
      subclass. It contains a single chiral centre and exists in two enantiomeric
      forms. In this study rac-carprofen, at two dosages, 0.7 and 4.0 mg/kg, and
      placebo were administered i.v. to six New Forest horses in a three period cross
      over study. The concentration-time profiles were established for R(-) and S(+)
      carprofen for plasma and both inflamed (exudate) and noninflamed (transudate)
      tissue cage fluids. R(-)-carprofen was the predominant enantiomer in all three
      fluids, as indicated by plasma area under the curve (AUC) values for R(-) and
      S(+)-carprofen of 117.4 and 22.6 microg h/mL (low dose carprofen) and 557.5 and
      138.1 microg h/mL (high dose carprofen) respectively. Penetration of both
      enantiomers into exudate was slow and limited and passage into transudate was
      even lower. The pharmacodynamics of rac-carprofen was investigated at both the
      molecular level and in terms of the ability to suppress components of the tissue
      cage inflammatory response. Low dose carprofen produced only moderate and
      transient inhibition of serum thromboxane (Tx)B2 but failed to affect exudate
      prostaglandin (PG)E2 concentrations, whilst suppression of exudate leukotriene
      (LT)B4 and beta-glucuronidase was not significant. High dose carprofen produced
      greater and more persistent inhibition of serum TxB2 and virtually abolished
      exudate PGE2 synthesis. Some inhibition of LTB4 and beta-glucuronidase in exudate
      was also obtained. At both dosages rac-carprofen reduced the swelling produced by
      intradermal bradykinin injection but only high dose carprofen was anti
      inflammatory as indicated by suppression of temperature rise over exudate tissue
      cages and neither dose affected leucocyte numbers in exudate. When considered in
      conjunction with previous data on carprofen, the present findings indicate that
      carprofen is not a selective inhibitor of cyclooxygenase (COX) isoenzymes, COX-1
      and COX-2 in the horse, although it may show some preference for COX-2
      inhibition. Because low dose carprofen, which is the clinically recommended
      dosage, produces minimal inhibition of COX, it is likely to achieve its
      therapeutic effects at least partially through other pathways, possibly including
      weak to moderate inhibition of 5-lipoxygenase and of enzyme release. The good
      safety margin of carprofen in clinical use might also be explained by weak COX
      inhibition and by other actions at the molecular level.

PMID- 12485350
TI  - Disposition of sodium salicylate, flunixin and meloxicam after intravenous
      administration in broiler chickens.
AB  - Three nonsteroidal anti-inflammatory drugs (NSAIDs) [sodium salicylate, flunixin
      (FLU) and meloxicam (MEL)] were administered intravenously to broiler chickens.
      Plasma concentrations were determined by high-performance liquid chromatography
      methods and pharmacokinetic parameters were calculated. After intravenous
      administration of sodium salicylate (50 mg/kg), FLU (1.1 mg/kg) and MEL (0.5
      mg/kg), these drugs were eliminated from plasma with a mean half-life of 04.04,
      05.45 and 03.20 h, respectively. Apparent volumes of distribution (0.39, 0.08 and
      0.12 L/kg, respectively) indicated that tissue distribution was limited for the
      three drugs. Total body clearance was 70 mL/h.kg for sodium salicylate and 10 and
      25 mL/kg.h for FLU and MEL, respectively. Based on the pharmacokinetic parameters
      these NSAIDs may offer possibilities for treatment of various conditions in
      chickens.

PMID- 12485351
TI  - Pharmaco-epidemiology and -economics should be developed more extensively in
      veterinary medicine.
AB  - Pharmaco-epidemiology, which has emerged within the last 20 years as a new
      discipline in human medicine, deals with the quantities of drugs consumed and
      their effects on populations in terms of epidemiological concepts and tools. To a
      lesser extent, it is also practised in veterinary medicine. The applications
      presented in this review are illustrative of pharmaco-epidemiological and 
      economical concepts. Assessment of drug consumption, the study of adverse drug
      effects, and the economic implications of drug use are the three main fields
      considered. Developments can be expected in veterinary medicine within the next
      few years relative to novel areas of interest such as antimicrobial resistance
      and new therapeutic class uses. These applications will require methodological
      progress and the elimination of current gaps. Pharmaco-epidemiological methods
      need to be developed, which implies close co-operation between statisticians,
      pharmacologists, veterinary practitioners and epidemiologists. A greater use of
      the term 'pharmaco-epidemiology' as a keyword in literature would facilitate
      recognition of this domain which associates closely epidemiology and
      pharmacology.

PMID- 12485352
TI  - Free drug fraction vs free drug concentration: a matter of frequent confusion.

PMID- 12485353
TI  - Pharmacokinetics of thiamphenicol in pigs.

PMID- 12485354
TI  - Epidemiological and bacteriological aspects of mastitis associated with yellow
      jacket wasps (Vespula germanica) in a dairy cattle herd.
AB  - The German wasp, Vespula germanica has been observed to injure teats of dairy
      cows, causing lesions that are associated with clinical and subclinical mastitis.
      The presence of skin lesions on the teats, caused by the wasps, was recorded in a
      dairy cattle herd located in the Samaria foothills during July-October 1999. Wasp
      inflicted injuries were found in 43.6% (58 of 133) of the adult cows and 1.4%
      (one of 71) of the first-calving cows. They were located in 42.4% of cows (n =
      25) on all quarters, 18 cows (30.5%) had lesions on the front quarters and 27.1%
      (n = 16) of cows on the hind quarters only. Clinical and subclinical mastitis
      were diagnosed in 61% (36 of 59) and 28.8% (17 of 59), respectively, of the
      injured adult and first-calving cows. The most common bacterial isolates from the
      mastitic cows were Staphylococcus aureus 45.1% (n = 14), Streptococcus
      dysgalactiae 16.1% (n = 5), Streptococcus spp. 19.4% (n = 7) and others 13.9% (n
      = 5). The loss of milk production was estimated at 300 kg milk for each cow
      injured by wasps and exhibiting clinical mastitis. An increase in the bulk-milk
      somatic cell count, from 186 x 103 at 1 month prior to the outbreak to a peak of
      1200 x 10(3) in the post-outbreak month, was noted. The culling rate reached
      13.6% (eight of 59) of the affected cows. In summary, the considerable economic
      losses caused by the wasp infestation resulted from decreased milk production and
      a decline in milk quality, culling of affected cows, and increased demand for use
      of drugs and veterinary care.

PMID- 12485355
TI  - The effect of season and vaccination for Glasser's disease and post-weaning
      Colibacillosis in an outdoor pig unit endemically infected with virulent strain
      of Haemophilus Parasuis serotype 5 and pathogenic Escherichia coli.
AB  - The objective of this field trial was to determine if vaccination against
      Haemophilus parasuis serovar 5 (HPS 5) and pathogenic serotypes of Escherichia
      coli would improve nursery pig performance in an outdoor unit in different
      seasons. The unit was concurrently infected with HPS 5 and with different
      serotypes of E. coli. All piglets were born to HPS 5 vaccinated sows. The trial
      was carried out in four (two summer and two winter) groups. Group 1 (E. coli and
      HPS vaccinated, summer season) (n = 362): Piglets were vaccinated pre-weaning
      with inactivated E. coli-VT2e-toxin and post-weaning against HPS 5. Group 2 (non
      vaccinated, summer season) (n = 349): Piglets were not vaccinated. Group 3 (E.
      coli and HPS vaccinated, winter season) (n = 358): The animals were analogously
      treated as Group 1. Group 4 (non-vaccinated, winter season) (n = 353): Piglets
      were not vaccinated. The following parameters were evaluated: A: average daily
      nursery weight gain (ADG), B: nursery mortality, C: feed efficiency (FE). No
      significant weight differences were detected within the vaccinated and non
      vaccinated summer or winter raised groups of weaners. Summer raised weaners were
      significantly (P<0.05) heavier from day 35 on than winter raised animals. ADG and
      FE of summer raised pigs were significantly better (weeks 1-3 P<0.05; fourth week
      post-weaning P<0.01) during the nursery period than that of the winter raised
      groups. Winter raised vaccinated weaners showed during the last week of nursing
      significantly (P<0.05) better daily gain and feed efficiency compared with the
      non-vaccinated winter raised animals. Non-significant ADG and FE differences were
      detectable between the summer raised vaccinated or non-vaccinated groups of pig.
      Winter raised non-vaccinated animals suffered significantly (P<0.05) higher
      nursery mortality (10.63%) compared to the winter raised vaccinated animals.
      IMPLICATION: In cases of concurrent infections with HPS 5 and with different
      serotypes of E. coli, especially during winter season, vaccination against both
      diseases is suggested.

PMID- 12485356
TI  - Effects of thymomimetic drugs and zinc supplementation on the cellular immune
      response in hydrocortisone-suppressed mice.
AB  - The studies were carried out on Balb/c mice (5-6 weeks of age) exposed to
      immunosuppression by a single intraperitoneal dose (125 mg/kg) of hydrocortisone.
      Prior to hydrocortisone injection the mice were treated with
      diethyldithiocarbamate (DTC) intra-peritoneally at a dose of 20 mg/kg, five times
      at 48 h intervals or calf thymus extract (TFX) at a dose of 10 mg/kg, 10 times at
      24 h intervals. The two drugs were used per se or in zinc ions interactions, by
      adding zinc ions (as sulphate salt) to drinking water at a dose of 72
      microg/mouse per day. The results obtained in the study show that hydrocortisone
      injection drastically decreases the number of thymocytes and splenocytes, which
      is also accompanied by a decreasing weight ratio of the thymus and spleen. The
      decreasing number of thymic and spleen cells corresponds to a decreasing
      percentage of CD4+, CD8+ and CD19+ splenocytes and double positive CD4+CD8+
      thymocytes. Changes in the number of thymic cells affect their activity, which is
      expressed in a decreased proliferative response of thymocytes stimulated in vitro
      with concanavalin A (Con A) and phytohaemagglutinin (PHA). It has also been found
      that a single hydrocortisone dose decreases interleukin (IL)-1 production by
      murine intraperitoneal macrophages stimulated in vitro with lipopolysaccharide
      (LPS) from Escherichia coli. TFX or DTC counteract hydrocortisone-induced
      immunosuppression, which is expressed in partial normalization of the total
      number of thymic and spleen cells, accelerated regeneration of the two lymphatic
      organs, shorter suppressive action of hydrocortisone on the percentage of CD4+,
      CD8+ splenocytes and double positive (CD4+CD8+) and CD4+ thymocytes. Furthermore,
      total counteraction against the suppressive action of hydrocortisone to
      proliferative activity of thymocytes stimulated in vitro with Con A and PHA was
      observed. TFX administered prior to hydrocortisone injection partially prevented
      the suppressive action of the drug on IL-1 production by intraperitoneal
      macrophages, but such an effect was not observed with DTC. The immunorestorative
      effect of TFX and DTC was augmented by zinc supplementation. The results obtained
      in the study show that neither TFX nor DTC administration per se and in
      interaction with zinc supplementation were able to change the suppressive effect
      of hydrocortisone on the percentage of B splenocytes (CD19+ cells).

PMID- 12485357
TI  - Changes in distribution and numbers of CD4+ and CD8+ T-lymphocytes in lymphoid
      tissues and intestinal mucosa in the early phase of experimentally induced early
      onset mucosal disease in cattle.
AB  - Mucosal disease (MD), one sequelae of bovine virus diarrhoea virus (BVDV)
      infection, causes severe lesions in lymphoid tissues and mucosal surfaces.
      Lesions are associated with the presence of cytopathogenic (cp) BVDV and
      initially characterized by apoptotic cell death. The objective of this
      investigation was to determine if this cell death is mediated only by the cp
      BVDV, which is known to induce apoptosis in cell culture or if immune-mediated
      host reactions might also contribute. Early onset MD was experimentally induced
      in calves by inoculation of persistently viremic calves with a closely related cp
      BVDV. Calves were euthanized in the early phase of infection between days 5 and
      13 post-inoculation and tissues from tonsils, lymph nodes, Peyer's patches,
      jejunum and colon were collected. Presence of cp BVDV antigen was correlated with
      distribution of lymphocyte subpopulations in consecutive cryostat sections. In
      the lymphoid tissues, cp BVDV antigen was predominantly found in the lymphoid
      follicles. The increase of infected cells with time post-inoculation was
      paralleled by a decrease of B-lymphocytes and an increase of CD4+ T-lymphocytes.
      An increased number of CD8+ T-lymphocytes was seen in progressed lesions only. In
      the intestinal mucosa, initially multifocal, later diffuse infection with cp BVDV
      was accompanied by a multifocal or diffuse increase of CD4+ T-lymphocytes,
      respectively. Numbers of IgA+ plasma cells and CD8+ T-lymphocytes were decreased.
      The common change observed in lymphoid tissues and mucosa was the increase of
      CD4+ T-lymphocytes in sites with lesions. This might indicate a cell-mediated
      immune response to the cp BVDV. Besides their helper function to other cells of
      the immune system, activated CD4+ T-lymphocytes might also exert cytotoxic
      activity, induce apoptosis in target cells via Fas/Fas ligand binding and thus
      contribute to the severity of tissue lesions in MD.

PMID- 12485358
TI  - Transmission of Anaplasma phagocytophila (human granulocytic ehrlichiosis agent)
      in horses using experimentally infected ticks (Ixodes scapularis).
AB  - Most human granulocytic ehrlichiosis (HGE) studies carried out in horses use
      needle inoculation of infected leucocytes or cell cultures. This route of
      inoculation does not accurately reflect natural infection of the tick-borne
      agent. To investigate whether tick transmission influences the course of
      granulocytic ehrlichiosis in the horse model, experimental transmission through
      infected laboratory-reared Ixodes scapularis ticks was attempted into two healthy
      horses. One additional horse served as negative control and was exposed to
      uninfected ticks. Eleven days after exposure to nymphal or adult ticks infected
      with Anaplasma phagocytophila (HGE agent) the two horses developed severe
      clinical and laboratory signs consistent with granulocytic ehrlichiosis.
      Bacteraemia was determined at various time points in the two horses by
      observation of morulae within neutrophils and by detection of A. phagocytophila
      genomic DNA by PCR of peripheral blood leucocytes. Further, both horses
      seroconverted. In contrast the control horse stayed uninfected. The results
      demonstrate that A. phagocytophila can be experimentally transmitted by infected
      nymphal and adult ticks and that the agent is able to produce a severe disease,
      similar to naturally occurring cases. Therefore, tick transmission is highly
      reproducible and can be successfully used in the equine animal model in order to
      study HGE.

PMID- 12485359
TI  - Foetal protection against bovine virus diarrhoea virus after two-step
      vaccination.
AB  - In order to assess the efficacy of a two-step vaccination protocol with respect
      to foetal protection against transplacental infections with bovine virus
      diarrhoea virus (BVDV) with special attention to BVDV-2 seronegative heifers were
      vaccinated with an inactivated BVDV-1 vaccine and boostered with a modified live
      BVDV-1 vaccine after 4 weeks. A second group was left unvaccinated as control.
      Between days 30 and 120 of pregnancy the heifers of both groups were intranasally
      challenged with a mixture of BVDV-1 and -2. All heifers of the vaccinated group
      gave birth to nine clinically healthy, seronegative (precolostral) and BVDV-free
      calves. In contrast in the control group four BVDV viraemic underdeveloped calves
      were born. Additionally, one calf was stillborn and another viraemic calf was not
      viable and died 2 days after birth. All six calves of the control group were
      viraemic with BVDV-2. This study demonstrated for the first time that two-step
      vaccination of breeding cattle with a modified live BVDV vaccine 4 weeks after
      application of an inactivated BVDV vaccine was capable of providing a foetal
      protection against transplacental infection with BVDV-2.

PMID- 12485360
TI  - Pestivirus in cattle: experimentally induced persistent infection in calves.
AB  - Twenty-two heifers were infected intranasally with non-cytopathic bovine viral
      diarrhoea virus (BVDV) between days 74 and 82 of pregnancy. All animals had
      developed serum antibodies against BVDV 5 weeks later. No clinical effects were
      seen in the heifers, and they all delivered a live calf. The newborn calves were
      generally small, appeared unthrifty as typical 'poor doers', and some developed
      secondary infections with diarrhoea and signs of respiratory disease. Eighteen of
      the 22 calves were born without antibodies against BVDV and were persistently
      infected (PI) with the virus. One was weak at birth and died the following day.
      Four calves were born with serum antibodies against BVDV and with no detectable
      virus. Three of these showed signs and/or pathological changes indicating disease
      in the central nervous system. Otherwise, there were no obvious clinical
      differences between these calves and the PI calves, nor were there any apparent
      significant differences in blood parameters between these groups. In general, the
      calves showed low gamma-globulin values and thrombocytopaenia, but moderately
      increased fibrinogen values and relatively normal lymphocyte numbers.

PMID- 12485361
TI  - Optimization of a culture technique for the isolation of Listeria monocytogenes
      from faecal samples.
AB  - A culture technique employing cold enrichment at 4 degrees C followed by
      selective enrichment and plating at higher temperatures (30 degrees C) was used
      to isolate Listeria monocytogenes from faecal samples. The samples were held at 4
      degrees C for 15 weeks and cultured weekly to assess the sensitivity of the
      culture after cold storage for different lengths of time. No media, Listeria
      selective enrichment broth (LSEB), nutrient broth (NB) and saline were used as
      cold storage medium. Cold storage increased the frequency of Listeria positive
      samples. The sensitivity of the culture for Listeria spp. and L. monocytogenes
      was 72 and 94%, and 56 and 61% after third and seventh week of cold storage,
      respectively. When the results of third and seventh week of cold storage were
      combined, the sensitivity was 100% for Listeria spp. and 94% for L.
      monocytogenes. LSEB and NB as storage medium increased Listeria positive samples
      after the first week of cold storage but did not maintain the increase thereafter
      while saline had an adverse effect on the growth of the bacteria. However,
      samples held in no media in a pilot study involving monthly sampling of a herd
      revealed better results. Detection limit of the culture media was also
      investigated. The lowest concentration detected by culture media was 3.17
      organisms/ml. This was seven organisms/g for known Listeria positive sample. The
      faecal samples spiked with 10-fold dilutions of L. monocytogenes and held at 4
      degrees C revealed that the sample spiked with 3.17 x 10-1 cfu/ml organisms
      resulted in growth after the second week of cold storage. The results suggest
      that the culture technique employing cold enrichment followed by selective
      enrichment and plating is more sensitive, the storage of faecal samples in no
      media when compared with the samples in storage medium, LSEB, NB and saline,
      during cold enrichment is a better application and culture of faeces, immediately
      after collection, at third and seventh week of cold enrichment produce more
      satisfactory results.

PMID- 12485362
TI  - Comparative pharmacokinetics of enrofloxacin and tissue concentrations of parent
      drug and ciprofloxacin after intramuscular administrations of free and liposome
      encapsulated enrofloxacin in rabbits.
AB  - Pharmacokinetic properties and tissue concentrations of enrofloxacin and
      ciprofloxacin were compared after intramuscular (i.m.) administrations of free
      and liposome-encapsulated enrofloxacin at the dose of 5 mg/kg body weight (bw).
      Twelve healthy adult New Zealand white rabbits were used in the experiment. Blood
      samples were obtained at 10, 20, 40, 60 and 90 min and 2, 4, 6, 8 and 12 h and
      tissue samples were collected 24 h after injection. Concentrations of drugs in
      serum were determined by high-performance liquid chromatography. Pharmacokinetics
      were best described by a two-compartment open model. Results indicated that
      absorption rate was slow, peak concentration was higher (P < 0.05), and the time
      to peak concentration (tmax congruent with 1.5 h) was significantly longer (P <
      0.05) for liposome-encapsulated enrofloxacin (LEE) when compared with free
      enrofloxacin. Values of elimination half-life (t1/2beta = 12.9 h) and mean
      residence time (MRT = 17.6 h) of liposome-encapsulated enrofloxacin were longer
      (P < 0.05) and total clearance (Cl = 0.43 l/h/kg) was lower than those of free
      form. Moreover, the distribution volume at steady-state (Vd(ss) = 14.4 l/kg) of
      enrofloxacin administered encapsulated into liposomes was significantly higher (P
      < 0.05) than that of free enrofloxacin (FE). The tissue levels of enrofloxacin
      and ciprofloxacin after LEE injection were not different (P > 0.05) from FE. In
      conclusion, the result of present study suggest that LEE may be a beneficial and
      valuable formulation in the treatment of infectious diseases caused by sensitive
      pathogens in animals, providing sustained drug release from injection side and
      prolonged therapeutic serum concentrations after i.m. administration.

PMID- 12485363
TI  - Effects of subminimal inhibitory concentrations of amoxicillin against
      Actinobacillus pleuropneumoniae.
AB  - The bactericidal effects of amoxicillin at below minimum inhibitory concentration
      (MIC) against Actinobacillus pleuropneumoniae NB001 were studied in vitro and in
      vivo. In vivo, the efficacy of amoxicillin on experimentally induced A.
      pleuropneumoniae infection in disease-free pigs was evaluated. Nine pigs were
      divided into three groups and all three groups were housed in the same room.
      Group I pigs were given long-acting amoxicillin injection 22 h prior to A.
      pleuropneumoniae challenge. Group II pigs were also A. pleuropneumoniae
      challenged but not given long-acting amoxicillin. Group III pigs were not
      treated. In vitro, A. pleuropneumoniae growth was suppressed in porcine blood
      with amoxicillin at below MIC. In vivo, clinical signs of disease were absent or
      mild in group I during 50 h post-challenge, and serum amoxicillin concentration
      was already less than MIC from 15 h post-challenge. Infected group II controls
      were severely affected by the infection, and mortality reached 100% within 50 h
      post-challenge. All non-treated pigs in group III became infected with NB001 from
      infected control pigs, and they displayed severe clinical signs of disease within
      24 h post-challenge of groups I and II, and died within 50 h post-challenge of
      groups I and II.

PMID- 12485365
TI  - The chemistry of melatonin's interaction with reactive species.
AB  - Melatonin has been shown to be an effective antioxidant in a number of
      experimental models both in vitro and in vivo. Considering the data available, it
      is now clear that the indoleamine is involved in antioxidative mechanisms more
      complex than originally envisaged. These range from the direct radical scavenging
      of a variety of radicals and reactive species to the control and/or modulation of
      a number of processes which may trigger a redox imbalance between antioxidant and
      prooxidant species. This review focuses on the direct radical scavenging activity
      of melatonin and provides a summary of the mechanisms of the reactions between
      the indoleamine and reactive species in pure chemical solutions. These actions
      likely account for at least some of the protective actions of melatonin under
      conditions of high oxidative stress.

PMID- 12485366
TI  - Alterations in the circadian rhythm of salivary melatonin begin during middle
      age.
AB  - To investigate whether free melatonin may be better suited to reveal age-related
      changes, we studied the circadian rhythm alterations in saliva melatonin levels
      during aging. Special attention was paid to the question as to how the free
      melatonin rhythms change in aging and when such changes take place. A total of 52
      healthy volunteers participated in the study consisting of young, middle-aged,
      old and the oldest groups. In each subject, a total of 12 time-point salivary
      melatonin samples was taken over 24 hr. Of the 52 data sets, 51 exhibited
      significant circadian rhythm over 24 hr by using the base cosine function
      analysis to fit the data. A clear circadian rhythm of salivary melatonin was
      present in all age groups. The decline in nocturnal peak levels (amplitude) in
      salivary melatonin was found in old and the oldest subjects. Both the old and the
      oldest subjects showed an increased daytime (baseline) melatonin levels. The off
      set melatonin levels were more than two times higher in the oldest group than
      that in the other groups indicating a delayed phase of salivary melatonin. Most
      strikingly, we found that a step-wise decrease in the circadian rhythms of saliva
      melatonin occurred early in life, around 40 yr of ages. The middle-aged subjects
      had only 60% of the amplitude of the young subjects. In addition, the middle-aged
      subjects showed the longest peak levels duration and the lowest daytime melatonin
      levels. The present study showed that the alterations in the circadian rhythms of
      salivary melatonin begin during middle-age. Our results showed that salivary
      melatonin measurement is a reliable, sensitive and easy method to monitor changes
      in the circadian rhythms of melatonin during the course of aging.

PMID- 12485367
TI  - Oxidation of melatonin by carbonate radicals and chemiluminescence emitted during
      pyrrole ring cleavage.
AB  - Oxidation of melatonin was followed by measuring chemiluminescence emitted during
      pyrrole ring cleavage, a process leading to the main oxidation product of this
      indoleamine, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK). Radical reactions of
      melatonin were studied in two variants of a moderately alkaline (pH 8) H2O2
      system, one of which contained hemin as a catalyst. In both systems, light
      emission from melatonin oxidation lasted several hours. Time courses and turnover
      rates depended on the presence or absence of hemin; the catalyst enhanced light
      emission many-fold. In the two reaction systems, the presence of hydrogen
      carbonate (HCO)(3)(-) enhanced chemiluminescence by more than 10-fold, indicating
      scavenging of carbonate radicals. In the presence of 10% dimethylsulfoxide (DMSO)
      or 1 m mannitol, HCO(3)(-)-dependent as well as independent light emissions were
      only partially inhibited. With regard to the stimulatory effect of HCO(3)(-),
      this implies a formation of carbonate radicals (CO)(3)(-) independent of hydroxyl
      (OH) radicals, presumably involving superoxide anions abundantly present in the
      system. Tiron, a scavenger of superoxide anions, strongly and almost
      instantaneously inhibited chemiluminescence, in accordance to the requirement of
      this reactive oxygen species for AFMK formation and its involvement in -radical
      formation. Melatonin's capability of scavenging CO(3)(-) may contribute to its
      protective potency.

PMID- 12485368
TI  - Melatonin production during childhood and adolescence: a longitudinal study on
      the excretion of urinary 6-hydroxymelatonin sulfate.
AB  - Cross-sectional data on urinary 6-hydroxymelatonin sulfate (6-OHMS) excretion in
      children suggest a constant melatonin secretion during growth. The present
      longitudinal study concerned, accordingly, the intra-individual stability of
      melatonin production during childhood and adolescence. Urine samples collected
      during a longitudinal investigation of healthy white children and adolescents
      were analyzed. Forty-six boys and 38 girls were chosen for the present study.
      They had passed 3-15 annual examinations between their 3rd and 18th yr of age.
      Each examination included the collection of urine over 24 hr. The daily urinary
      output of 6-OHMS of the overall 621 samples was quantified by enzyme-linked
      immunosorbent assay. The analyses clearly revealed for the first time that,
      despite huge inter-individual differences, melatonin production remains constant
      in one and the same individual during childhood and adolescence. Additionally,
      neither a significant sex difference was observed nor was the 6-OHMS output
      affected by season. The dramatic decrease of plasma melatonin levels as described
      in the literature is mainly related to an increase in body size rather than to
      decreasing pineal secretion.

PMID- 12485369
TI  - Different responsiveness of central nervous system tissues to oxidative
      conditions and to the antioxidant effect of melatonin.
AB  - Melatonin, a product of the pineal gland, is an effective free-radical scavenger
      both in vitro and in vivo. Free-radical-mediated lipid peroxidation has been
      increasingly considered as an important factor in post-traumatic neuronal
      degeneration. The aim of the present study was (i). to examine the responses of
      different regions of central nervous system (CNS) to free-radical generation
      induced in vitro and (ii). to test the efficacy of melatonin in reducing
      oxidative damage in different regions of the CNS. Rat brain, total spinal cord,
      spinal cord white matter and optic nerves were dissected with the rats under
      general anesthesia and immediately frozen at -20 degrees C. Thiobarbituric acid
      reactive substances were measured as an index of lipid peroxidation. Peroxidation
      was induced with ferrous iron (0.02 mm), ascorbate (1 mm), and hydrogen peroxide
      (H2O2) (0.5 mm). All tissue samples showed increased lipid peroxidation levels
      after treatment with free-radical generating agents. The highest amount of damage
      was observed in the presence of ferrous iron, ascorbate, and H2O2. Melatonin
      showed antioxidant effects in the brain, total spinal cord, optic nerve, and
      spinal cord white matter. The results show that melatonin has differential
      protective effects on CNS tissues in vitro and the most potent effect is observed
      in the spinal cord white matter.

PMID- 12485370
TI  - Inhibitory effects of melatonin on neural lipid peroxidation induced by
      intracerebroventricularly administered homocysteine.
AB  - Melatonin, the main secretory product of the pineal gland, has been shown to be
      potentially effective in prevention of numerous types of neurodegenerative
      disorders in which free radical processes are involved. Homocysteine (Hcy), an
      independent risk factor for atherosclerosis, undergoes auto-oxidation and
      generates reactive oxygen species. The purpose of this study was to test whether
      intracerebroventricular (ICV) injection of Hcy leads to neural lipid peroxidation
      and also to investigate the protective effects of melatonin on the brain tissue
      from oxidative stress of Hcy. Adult male Wistar rats under anaesthesia were
      injected ICV with Hcy at a dose of 143 microg/kg. Melatonin was administered
      intraperitoneally to a group of rats for three consecutive days before Hcy
      injection. The rats were decapitated and brain tissues were removed and
      hippocampus, cortex and cerebellum were dissected. There was a significant
      development of oxidative stress as indicated by an increase in malondialdehyde in
      hippocampus, cortex and cerebellum of rats injected with Hcy, whereas melatonin
      prevented the elevation of lipid peroxidation. Furthermore, melatonin
      significantly increased glutathione levels and glutathione peroxidase activity in
      all brain regions. The present study demonstrates that Hcy, in high levels, may
      be a causal factor in generation of free radicals in the brain and it may be one
      of the mechanisms which cause neurodegeneration in elderly people. It also shows
      that melatonin could potentially be beneficial in prevention of neurodegeneration
      caused by hyperhomocysteinemia.

PMID- 12485371
TI  - Protective effect of melatonin and its precursor L-tryptophan on acute
      pancreatitis induced by caerulein overstimulation or ischemia/reperfusion.
AB  - Melatonin, a pineal secretory product, synthesized from l-tryptophan, has
      received increased attention because of its antioxidative and immunomodulatory
      properties. It has been detected in the gut and shown to protect the gastric
      mucosa, and liver from acute damage, but the role of melatonin in the protection
      of the pancreas against acute inflammation is not clear. The aim of this study
      was to investigate the effects of melatonin and its precursor, l-tryptophan, on
      caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked
      pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to
      the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic
      artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr)
      or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal
      (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were
      confirmed by histologic examination and manifested by typical pancreatic edema,
      by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and
      the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid
      peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE),
      were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood
      flow (PBF) was significantly reduced in these animals. Pretreatment of rats
      subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan
      (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of
      amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while
      enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory
      interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise
      of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an
      enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal
      rats and was significantly enhanced in the rats with CIP. We conclude that
      exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic
      damage induced by CIP or by I/R and this effect may be attributable to the
      reduction in lipid peroxidation and TNFalpha release combined with an increase of
      plasma anti-inflammatory IL-10 in rats with acute pancreatitis.

PMID- 12485372
TI  - Pineal melatonin synthesis and release are not altered throughout the estrous
      cycle in female rats.
AB  - Melatonin times reproduction with seasons in many photoperiodic mammalian
      species. Whether sexual hormones reflect on melatonin synthesis is still debated.
      The aim of this work was to study, using a large panel of technical approaches,
      whether the daily profile of pineal melatonin synthesis and release varies with
      the estrous cycle in the female rat. The mRNA levels and enzyme activities of the
      melatonin synthesizing enzymes, arylalkylamine N-acetyltransferase and
      hydroxyindole-O-methyltransferase were similar at the four stages of the rat
      estrous cycle. The endogenous release of melatonin, followed by transpineal
      microdialysis during six consecutive days in cycling female rats, displayed no
      significant variation during this interval. Taken together, the present results
      demonstrate that there is no regular fluctuation in the pineal metabolism leading
      to melatonin synthesis and release throughout the estrous cycle in female rats.

PMID- 12485373
TI  - Effects of continuous light exposure on antioxidant enzymes, porphyric enzymes
      and cellular damage in the Harderian gland of the Syrian hamster.
AB  - The Syrian hamster Harderian gland (HG), an organ present in the male two
      secretory cell types (type-I and type-II cells), is physiologically exposed to
      high oxidative stress because of high concentrations of porphyrins and their
      precursor, 5-aminolevulinic acid. Because of its juxtaorbital location, the HG is
      accessible to light, and subject to phototoxic effects of these substances. After
      having previously demonstrated circadian rhythms in antioxidant enzymes,
      porphyric enzymes and oxidative damage of proteins and lipids, as well as
      influences of melatonin on these parameters, we have now studied the effects of
      continuous light (LL), which suppresses melatonin secretion by the pineal gland.
      Measurements were performed in two different circadian phases, in order to detect
      the presence or absence of day/night differences. In LL, no differences between
      circadian phases of subjective day and subjective night were demonstrable for 5
      aminolevulinate synthase, 5-aminolevulinate dehydratase, porphobilinogen
      deaminase, or superoxide dismutase; temporal differences in glutathione reductase
      and catalase were markedly diminished, whereas all these parameters showed marked
      day/night differences in the rats exposed to a light/dark cycle of 14:10. In LL,
      oxidative damage to lipids was minimally effected, while protein damage was
      enhanced. LL also caused a reduction in the percentage of type-II cells.
      Therefore, cell differentiation in the HG does not seem to be controlled only by
      the androgen, but, unexpectedly, also by melatonin.

PMID- 12485374
TI  - Interferon-gamma independent oxidation of melatonin by macrophages.
AB  - Mononuclear phagocytes appear to synthesize kynurenine-like products from the
      oxidation of biologically active indole compounds including melatonin, catalyzed
      by interferon (IFN)-gamma-inducible enzyme indoleamine 2,3-dioxygenase (IDO).
      Concanavalin A (Con A) is a plant lectin that induces interferon-gamma (IFN
      gamma) production by T cells. In this study we investigated whether Con A-primed
      peritoneal macrophages are able to oxidize melatonin to N1-acetyl-N2-formyl-5
      methoxykynuramine (AFMK). The AFMK production was accompanied by
      chemiluminescence. It was found that Con A-primed but not resident macrophages
      produce AFMK. Surprisingly, Con A-primed macrophages from IFN-gamma-deficient
      mice were as effective as macrophages from IFN-gamma-sufficient mice in oxidizing
      melatonin. Moreover, addition of an inhibitor of IDO (1-methyltryptophan) did not
      affect melatonin oxidation. Con A-primed but not resident macrophages have a
      significant content of myeloperoxidase (MPO) and inhibition of MPO by azide
      completely blocked chemiluminescence and AFMK production. Thus, our findings
      provide evidence that melatonin oxidation by macrophages may occur through a
      mechanism dependent of MPO and independent of IFN-gamma and IDO activity.

PMID- 12485375
TI  - Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an
      antioxidant vitamin.
AB  - Melatonin, a derivative of an essential amino acid, tryptophan, was first
      identified in bovine pineal tissue and subsequently it has been portrayed
      exclusively as a hormone. Recently accumulated evidence has challenged this
      concept. Melatonin is present in the earliest life forms and is found in all
      organisms including bacteria, algae, fungi, plants, insects, and vertebrates
      including humans. Several characteristics of melatonin distinguish it from a
      classic hormone such as its direct, non-receptor-mediated free radical scavenging
      activity. As melatonin is also ingested in foodstuffs such as vegetables, fruits,
      rice, wheat and herbal medicines, from the nutritional point of view, melatonin
      can also be classified as a vitamin. It seems likely that melatonin initially
      evolved as an antioxidant, becoming a vitamin in the food chain, and in
      multicellular organisms, where it is produced, it has acquired autocoid, paracoid
      and hormonal properties.

PMID- 12485376
TI  - What constitutes a physiological concentration of melatonin?

PMID- 12485377
TI  - Physico-mechanical properties of a fast-set highly viscous GIC restorative.
AB  - The fast-setting reaction of 'fast-set' highly viscous glass-ionomer cements
      (GIC) may result in superior mechanical properties and good wear resistance as
      the material can theoretically achieve sufficient strength to resist masticatory
      loads within a shorter time. The aim of this study was to determine the hardness,
      strength (compressive and diametral tensile) and wear resistance of a 'fast-set'
      highly viscous GIC (Fuji IX GP Fast). Its regular set counterpart (Fuji IX GP)
      was used for comparison. The glass powders of the two cements were also
      characterized. Hardness testing [Vickers' hardness number (VHN)] was performed
      with a digital hardness tester (load=50 g; dwell time=30 s) and
      compressive/diametral tensile strength testing (MPa) was conducted based upon
      British Standards specification for GICs (BS6039, 1981). Wear testing was
      conducted using a reciprocal compression-sliding wear instrumentation at 20 MPa
      contact stress against SS304 counter-bodies with distilled water as lubricant.
      All specimens were immersed in distilled water at 37 degrees C and tested 24 h
      after start of mixing. Further mechanical tests (hardness and strength) were
      conducted with specimens stored for 1 week in distilled water at 37 degrees C.
      The glass powders were characterized using laser particle sizing, standard
      electron microscope (SEM) and energy dispressure X-ray (EDX) analysis. Results
      were analysed using multiple analysis of variance (manova) and independent
      samples t-test at significance level 0.05. No significant difference in hardness,
      compressive and diametral tensile strength was observed between Fuji IX GP and
      Fuji IX GP Fast at 1 day. There was also no significant difference in wear at all
      cyclic intervals. Although the difference in strength was not significant between
      the two cements at 1 week, Fuji IX GP Fast was significantly harder than Fuji IX
      GP. Particle size of both cements ranged from 0.3 to 200 microm. The mean
      particle sizes were, however, different and were 13.43 and 7.13 microm for Fuji
      IX GP and Fuji IX GP Fast, respectively. Fuji IX GP Fast offers no other
      advantage over Fuji IX GP with the exception of improved hardness. CLINICAL
      RELEVANCE: Besides being harder, the fast-set highly viscous GIC restorative
      offers no other physico-mechanical advantage over its regular set counterpart.

PMID- 12485378
TI  - Buccal and lingual activity during mastication and swallowing in typical adults.
AB  - A non-invasive protocol was developed to assess tongue and cheek movements during
      mastication and to evaluate the temporal relationship between mastication and the
      initiation of pharyngeal swallowing. Typical adults (three males and three
      females) were monitored during chewing. Miniature pressure transducers were
      bonded unilaterally to the buccal and lingual surfaces of the first mandibular
      molar and the buccal surface of the first maxillary molar on each subject's
      preferred chewing side. Surface electromyography of the ipsilateral masseter
      muscle was recorded as an indicator of jaw-closing activity. Pressure and
      electromyography (EMG) recordings were time-linked to simultaneous B-mode
      ultrasound imaging of the oral cavity using a submental, coronal view aligned
      with the first mandibular molar. The intervals between peak pressure recorded at
      each pressure transducer and peak jaw-closing activity for each masticatory cycle
      were not statistically different [analysis of variance (anova), P=0.9856] and
      displayed large statistical variation. These intervals were not different at the
      beginning of the trials (hard biscuit) than they were at the completion of
      mastication when the cookie had been broken down to a paste/puree consistency
      bolus. The interval between the last chewing stroke and the initiation of
      swallowing was 0.92 +/- 0.34 s). No significant difference existed among subjects
      for this time interval (anova, P=0.382).

PMID- 12485379
TI  - Is bruxism severity a predictor of oral splint efficacy in patients with
      myofascial face pain?
AB  - Both the efficacy and mechanism of any effect of oral splint therapy for patients
      with temporomandibular disorders (TMDs) are a matter of controversy. To address
      these issues, this study tested the hypothesis that oral splints produce the most
      marked pain relief for those TMD patients with myofascial face pain (MFP) who
      also brux (i.e. grind or clench) more than other MFP patients. In a 6-week
      randomized controlled clinical trial, 52 women with MFP were randomly assigned to
      receive either a full-coverage hard acrylic splint or a palatal-only splint.
      Bruxism was assessed both by self-report and by an objective assessment of molar
      microwear changes over a 2-week period prior to the start of the trial. Tested
      across multiple outcome measures, results indicated that those receiving the full
      coverage splint had marginally better improvement on some pain-related measures
      than those receiving the palatal splint, but severity of bruxism did not moderate
      the therapeutic effect of the full-coverage splint. These findings strongly argue
      against the belief that oral splints reduce MFP by reducing bruxism and raise
      questions about the importance of bruxism in the maintenance of MFP.

PMID- 12485380
TI  - Magnetic resonance imaging analysis on the relationship between anterior disc
      displacement and balancing-side occlusal contact.
AB  - The purpose of this study was to evaluate the relationship between balancing-side
      occlusal contact patterns and the prevalence of the internal derangement of the
      temporomandibular joint (TMJ). Forty-one patients were used for the magnetic
      resonance image (MRI) analysis of TMJ and occlusal examination. Balancing-side
      occlusal contact patterns observed during mandibular lateral excursive movements
      were classified into the three following categories: group A, simultaneous
      balancing-side contact, group B, balancing-side contact (with clenching only) and
      Group C, no balancing-side contact (with or without clenching). By the occlusal
      examination of 57 sides, 31.6% showed group A, 8.8% showed group B and 59.6%
      showed group C contact. Group A could not be observed in the patient group with
      normal disc position. In the disc displacement group, the prevalence of group A,
      group B and group C were 40.9, 6.8 and 52.3%, respectively. The higher prevalence
      of simultaneous balancing-side contact was revealed to be associated with
      articular disc dislocation.

PMID- 12485381
TI  - Evidence of an influence of asymmetrical occlusal interferences on the activity
      of the sternocleidomastoid muscle.
AB  - To investigate the hypothesis of a functional coupling between occlusion and neck
      muscles, the immediate effect of asymmetrical occlusal interferences on the
      pattern of contraction of the sternocleidomastoid muscles (SCM) during maximum
      voluntary clench (MVC) was analysed in 30 healthy subjects. All subjects had a
      complete and sound permanent dentition, without temporomandibular joint (TMJ) and
      craniocervical disorders. A 5-s surface electromyogram (EMG) examination of the
      SCM was performed during (1) MVC in intercuspal position and (2) MVC with a
      single 200-microm occlusal interference alternatively positioned on teeth 16, 13,
      23, 26. All subjects had a symmetrical EMG activity during MVC in intercuspal
      position. For each subject, SCM potentials were standardized as percentage of the
      mean potentials recorded during the MVC on natural dentition and the EMG waves of
      left- and right-side muscles were compared by computing the relevant percentage
      overlapping coefficient (POC). For each subject, the best and the worst POCs
      computed during the four MVC tests with occlusal interferences were found and the
      percentage difference between them was calculated. In the four MVC tests with
      occlusal interferences, SCM symmetry was very different from that recorded during
      MVC on natural dentition. The difference between the best and worst POCs computed
      within each subject was very variable, ranging from 1.52 to 41.57%. In
      conclusion, when young healthy subjects with a normal occlusion clench on an
      asymmetrical occlusal interference, they have an altered left-right side pattern
      of contraction of their SCM. In almost all subjects, a previously symmetrical
      pattern became asymmetrical.

PMID- 12485382
TI  - A mimic osseointegrated implant model for three-dimensional finite element
      analysis.
AB  - The purpose of this study was to develop a new three-dimensional (3D) mimic model
      of an osseointegrated implant for finite element analysis (FEA) and to evaluate
      stress distributions in comparison with a model commonly used in most studies as
      a control. Based on the 3D computer graphic data obtained by serial in vivo bucco
      lingual peri-implant bone structure at 75 microm interval in monkey, a mimic FEA
      model with trabecular structure and a control model with uniform cancellous bone
      were constructed. A vertical load of 143 N was applied at the top of the implant
      and induced stress was evaluated at the peri-implant bone. In the mimic model,
      stress was distributed at both cortical and cancellous bones (1-5 MPa) in bucco
      lingual central planes, but concentrated at the cortical crest (3-7 MPa) in the
      mesio-distal central plane. In contrast, the control model presented stress
      concentration at the cortical crest around the implant (5-14 MPa), with less
      stress (0-1 MPa) at the peri-implant cancellous bone in both planes. The
      findings, that stress distribution at the peri-implant bone were quite different
      between the mimic and control models, suggest the need to carefully interpret
      stress distribution in previous studies with models of uniform cancellous peri
      implant bone.

PMID- 12485383
TI  - The impact of oral disease among the institutionalized and non-institutionalized
      elderly in Hong Kong.
AB  - The study aimed to describe and compare the psychosocial and functional impact of
      oral disease on the quality of life of the institutionalized and non
      institutionalized elderly in Hong Kong. A total of 268 institutionalized and 318
      non-institutionalized elderly aged 60-80 years took part. The 49-statement Oral
      Health Impact Profile (OHIP) was administered in a structured interview format
      and sociodemographic information collected prior to a clinical, oral examination.
      A greater number of the institutionalized were edentulous (19%); they also had
      more untreated dental disease. The number of elderly reporting negative impacts
      was generally low. The percentage of institutionalized elderly reporting a
      negative impact was significantly lower in one of the OHIP subscales (handicap, P
      < 0.001) and similar in the other six. The main factors affecting the OHIP score
      were living location, socio-economic status, dental disease and treatment seeking
      behaviour. In conclusion, the psychosocial and functional impact of oral
      conditions was low and similar in the institutionalized and non-institutionalized
      elderly although the pattern of oral disease was different. Life events and
      socially and culturally derived values appeared to affect the elderly perception
      of the impact of oral disease.

PMID- 12485384
TI  - Removable dentures provided by dentists, denturists and laboratory technicians.
AB  - In several countries removable dentures can be supplied by either dentists or
      denturists. Dental laboratory technicians, on the other hand, are licensed only
      to construct dentures on the prescription of a dentist and do not supply dentures
      directly to patients. This study investigates provision of dentures by dentists,
      denturists and laboratory technicians to 264 elderly Finnish World War II
      veterans. The veterans were wearing 454 removable dentures, of which 272 were
      complete dentures (CD) and 177 were removable partial dentures (RPD). Dentists
      had supplied one-quarter of the CD and three-quarters of the RPD, denturists had
      supplied two-thirds of the CD and one-fifth of the RPD, whereas the dental
      laboratory technicians had supplied the remaining seven per cent of the CD and
      four per cent of the RPD. Denturists had provided mainly mandibular partial
      dentures. A high proportion of the RPD provided illegally by denturists were made
      to oppose CD. The subjects reported that maxillary CD were good or very good more
      often than mandibular CD and considered more often CD by dentists or denturists
      good or very good than CD by dental laboratory technicians.

PMID- 12485385
TI  - Finite element analysis of the possible mechanism of cervical lesion formation by
      occlusal force.
AB  - Recently, various authors have proposed the interesting idea that occlusal force
      may be a principal factor in cervical lesions of the tooth. It is speculated that
      the lateral force in non-ideal mastication causes the tooth to bend and that the
      resulting tensile stress damages the enamel surface. In this study, we carried
      out stress analysis on the upper central incisor and the lower first molar using
      the plastic-elastic deformation theory with two-dimensional finite element method
      (FEM). The essential feature that the tensile yield strength is much smaller than
      the compressive one was taken into account. Our results suggested that oblique
      loading on the tooth stretches the enamel surface near the cemento-enamel
      junction and causes plastic deformation which eventually leads to the cervical
      lesion.

PMID- 12485386
TI  - A new and simple method for evaluating masticatory function using newly developed
      artificial test food.
AB  - The aim of this study was to develop an objective evaluation system for the
      masticatory function. This system used paraffin wax cubes as a test food, which
      had six red- and green-coloured layers so that each of the six surfaces showed a
      pseudo-checkered pattern. A total of 100 paraffin cubes were chewed by 37
      subjects and the images of these samples were captured and analysed using a
      digital image analyzer. With regard to the colour and the shape of each sample,
      five parameters were obtained. Furthermore, an independent examiner graded the
      degree of colour mixing in the chewed samples into three groups (poor, medium and
      good) by visual inspection. A discriminant analysis was performed using the five
      variables as predictors of two groups (good and poor). Mixing Ability Index (MAI)
      was calculated from the discriminant function and using this index, 97% of the
      samples from these two groups were classified correctly. This system needed only
      a few minutes to complete and is easy to use. Therefore, it has high potentials
      for clinical use.

PMID- 12485387
TI  - Interfacial layer characterization in dental composite.
AB  - Nowadays, dental resins find increasing use by practitioners. However,
      photopolymerization of such resins is limited to a so-called 'depth of cure'. To
      face this problem, dentists superimpose resin layers of limited depth. This
      technique raises the problem of the quality of interlayer. This paper aims at
      screening different cases of adhesion at the interface. Shear strength of such
      interfacial layers is tested in shear mode in various conditions (with or without
      an oxygen-inhibited layer, or contaminated by saliva or water). Unexpectedly, the
      presence of an oxygen-inhibition on the first layer, as assessed using micro
      Raman spectroscopy, induces higher shear strength. In this case, a cohesive break
      occurs while an adhesive one is observed in all the other cases.

PMID- 12485388
TI  - Self-assessed bleeding as an indicator of gingival health among 12-14-year-old
      children.
AB  - The aim of this study was to evaluate the relationship between self-assessed
      gingival bleeding (GB) and clinically diagnosed gingival health among 12-14-year
      old school children. A study group (982) comprising of school children aged 12-14
      years was chosen by a simple random method from the five geographical areas in
      Irbid Governate, Jordan. All children completed a questionnaire related to self
      assessment of GB after brushing before they had a clinical examination for oral
      hygiene and gingival condition using the criteria of Silness & Loe plaque index
      (1964) and Loe and Silness gingival index (1963). The results showed that the
      proportions of children who had self-assessed or clinically assessed GB increased
      gradually from 12 to 14 years of age with no significant difference (P > 0.05).
      There were significantly higher proportions of boys than girls who had self
      assessed or were clinically assessed GB (P=0.02, 0.001). The mean plaque (1.83 +/
      0.54) and gingival scores (1.90 +/- 0.59) of children who reported GB were
      significantly higher than parallel scores of children without GB (1.27 +/- 0.62,
      1.23 +/- 0.59), respectively (P < 0.001). There was a moderate correlation
      (r=0.501) between self-assessed GB and gingival health. In conclusion, there was
      a positive correlation between self-assessed GB and gingival health of 12-14-year
      old children. Therefore, this may be beneficial for monitoring gingival health in
      children of, at least, developing countries.

PMID- 12485389
TI  - Shear bond strengths of tooth fragments reattached or restored.
AB  - This study investigated the shear bond strengths of sectioned human mandibular
      incisor edge fragments reattached using luting cements, bonding agents or
      restored with composite resins. Seventy teeth were randomly distributed among six
      experimental groups and a control group. Leaving half of the anatomic crowns
      exposed, the teeth were embedded in self-cure acrylic resins with the exposed
      part then sectioned. The fragments in groups 1-4 were bonded to their respective
      teeth using Clearfil Liner Bond 2V, Scotch Bond Multi Purpose Plus, Panavia-F and
      3M Opal Luting cement. The 5th and 6th groups were restored with composite resins
      (Silux 3M and Clearfil AP-X) using their bonding agents (Single Bond and Clearfil
      SE Bond). The results indicated that reattachment of fractured incisal fragments
      by using new generation bonding agents was effective against shear stresses,
      comparable with the intact teeth. Instead of restoration with composite resins
      therefore reattachment of a fractured fragment might be more preferable in cases
      of dental trauma.

PMID- 12485390
TI  - Dentoalveolar reconstruction of a missing premaxilla using bone graft and
      endosteal implants.
AB  - We report here on a patient with bilateral cleft lip and palate (BCLP) and a
      missing premaxilla, who underwent dentoalveolar reconstruction of the cleft and
      premaxillary alveolus using endosteal implants after bone grafting. The patient,
      whose maxillary incisors and premaxilla were missing, had corticocancellous bone
      grafting from the iliac crest, followed by excellent bone formation at the
      anterior alveolus. After the placement of the endosteal implants and the
      completion of the pre-surgical orthodontic alignment, orthognathic surgery was
      performed for the restoration of a Class III open bite. After post-operative
      orthodontic preparation, the final fixed prostheses were completed. This
      treatment procedure offers an option of dentoalveolar reconstruction for BCLP
      patients with an excised premaxilla.

PMID- 12485391
TI  - Surface texture and some properties of acrylic resins submitted to chemical
      polishing.
AB  - The effects of chemical polishing on dental acrylic resin properties are not well
      clarified. This study evaluated the effect of chemical and mechanical polishing
      on the residual monomer release (RM), Knoop hardness (KH), transverse strength
      (TS) and surface texture (ST) of a heat- and self-cured acrylic resin. Four
      groups were formed: GI-self-cured resin/mechanical polishing; GII-self-cured
      resin/chemical polishing; GIII-heat-cured resin/mechanical polishing; GIV-heat
      cured resin/chemical polishing. Following the polishing procedures, specimens
      were stored in distilled water at 37 degrees C. The KH and RM measurements were
      taken after 1, 2, 8 and 32 days of storage, and TS after 2, 8 and 32 days.
      Surface texture was observed under SEM evaluation. Results were compared
      statistically at a confidence level of 95%. The following conclusions were drawn:
      (1) regardless of the acrylic resin and the period of analysis, chemical
      polishing increased RM levels, reduced KH, and did not affect TS significantly;
      (2) water storage increased the surface hardness of GII and GIV; (3) GII and GIV
      showed a smooth and wavy surface under SEM evaluation.

PMID- 12485392
TI  - Temperature and thermal stress analysis of a crowned maxillary second premolar
      tooth using three-dimensional finite element method.
AB  - The purpose of this study was to calculate the temperature and thermal stress
      distribution as a result of hot/cold liquid in the mouth. This numerical study
      was carried out using three-dimensional finite element models and the tooth model
      was crowned with Au-Pd alloy, Ni-Cr alloy and porcelain. In the first part of the
      study, temperature changes as a result of hot/cold liquid in the mouth were
      calculated. In the second part, the thermal stresses caused by temperature
      changes were obtained. The tooth was assumed isotropic, homogenous, elastic and
      unsymmetrical. The authors using fortran 77 prepared all calculation programs.
      The distribution of temperature and thermal stress were plotted for some critical
      points.

PMID- 12485393
TI  - Cellular reactions to polylactide-based sponge and collagen gel in subcutaneous
      tissue.
AB  - Polylactide copolymer and collagen are now used as bio-absorbable scaffold
      materials for restoration of lost oral tissues. Polylactide caprolactone (PLCL)
      sponge and collagen gel were examined for their cellular reactions when implanted
      in 8-week-old Sprague-Dawley (SD) rats' subcutaneous tissues for up to 8 weeks.
      The PLCL sponges were slowly absorbed by a mild chronic inflammation process in
      which multinucleated giant cells covered and slowly captivated the sponge
      surfaces without thick encapsulation. On the other hand, collagen gel was
      surrounded by thick inflammatory reaction zones and infiltrated by acute
      inflammation cells including neutrophils, lymphocytes and macrophages, and
      disappeared more rapidly. Although the bio-absorption process differed, both
      materials, when combined, appear to be useful scaffold materials for tissue
      engineering therapy in future dental practice.

PMID- 12485394
TI  - Periodontal reasons for tooth extraction in an adult population in Jordan.
AB  - This survey studies the reasons for periodontal extraction of permanent teeth in
      an adult Jordanian population. A random sample of 30 general dental practitioners
      (GDPs) from a list of 300 GDPs (1:10) was contacted. Of these, the 26 dentists
      who participated in this study were asked to record teeth extracted and give
      reasons for extraction. Personal and demographic information and clinical details
      were obtained from 898 patients aged from 20 to 60 years. A total of 1,098 teeth
      were extracted during the 3-month study period. The results of this study
      revealed that dental caries (56.4% overall) was the main reason for tooth
      extraction, especially in 20-39 year olds. Periodontal disease (23.4% overall)
      was the next most frequent indication for extraction and became the commonest
      cause of tooth extraction in patients aged 40 years or more. Other reasons for
      tooth loss accounted for only 20.2% of the series. Advanced periodontal disease
      represented by pocketing were the dominant pathology when tooth loss occurred as
      the result of periodontal disease. As far as the type of tooth was concerned, the
      most frequently extracted teeth were molars followed by premolars, regardless of
      whether their loss was the result of the caries or the periodontal disease. This
      study suggests that caries and its consequences are responsible for more tooth
      loss in patients less than 40 years of age while extraction because of
      periodontal problems increases with age, and more commonly related to pocketing.

PMID- 12485396
TI  - The role of thrombin and thrombin receptors in ischemic, hemorrhagic and
      traumatic brain injury: deleterious or protective?
AB  - In the last two decades it has become apparent that thrombin has many
      extravascular effects that are mediated by a family of protease-activated
      receptors (PARs). PAR-1, -3 and -4 are activated via cleavage by thrombin. The
      importance of extravascular thrombin in modulating ischemic, hemorrhagic and
      traumatic injury in brain has recently become clear. Thus, in vitro, thrombin at
      low concentration protects neurons and astrocytes from cell death caused by a
      number of different insults. In vivo, pretreating the brain with a low dose of
      thrombin (thrombin preconditioning), attenuates the brain injury induced by a
      large dose of thrombin, an intracerebral hemorrhage or by focal cerebral
      ischemia. Thrombin may also be an important mediator of ischemic preconditioning.
      In contrast, high doses of thrombin kill neurons and astrocytes in vitro and
      cause disruption of the blood-brain barrier, brain edema and seizures in vivo.
      This review examines the role of thrombin in brain injury and the molecular
      mechanisms and signaling cascades involved.

PMID- 12485397
TI  - Mutant prion protein-mediated aggregation of normal prion protein in the
      endoplasmic reticulum: implications for prion propagation and neurotoxicity.
AB  - Familial prion disorders are believed to result from spontaneous conversion of
      mutant prion protein (PrPM) to the pathogenic isoform (PrPSc). While most
      familial cases are heterozygous and thus express the normal (PrPC) and mutant
      alleles of PrP, the role of PrPC in the pathogenic process is unclear. Plaques
      from affected cases reveal a heterogeneous picture; in some cases only PrPM is
      detected, whereas in others both PrPC and PrPM are transformed to PrPSc. To
      understand if the coaggregation of PrPC is governed by PrP mutations or is a
      consequence of the cellular compartment of PrPM aggregation, we coexpressed PrPM
      and PrPC in neuroblastoma cells, the latter tagged with green fluorescent protein
      (PrPC-GFP) for differentiation. Two PrPM forms (PrP231T, PrP217R/231T) that
      aggregate spontaneously in the endoplasmic reticulum (ER) were generated for this
      analysis. We report that PrPC-GFP aggregates when coexpressed with PrP231T or
      PrP217R/231T, regardless of sequence homology between the interacting forms.
      Furthermore, intracellular aggregates of PrP231T induce the accumulation of a C
      terminal fragment of PrP, most likely derived from a potentially neurotoxic
      transmembrane form of PrP (CtmPrP) in the ER. These findings have implications
      for prion pathogenesis in familial prion disorders, especially in cases where
      transport of PrPM from the ER is blocked by the cellular quality control.

PMID- 12485398
TI  - Constitutively and autonomously active protein kinase C associated with 14-3-3
      zeta in the rodent brain.
AB  - Persistent activation of protein kinase C (PKC) is required for the expression of
      synaptic plasticity in the brain. There are several mechanisms proposed that can
      lead to the prolonged activation of PKC. These include long lasting production of
      lipid activators (diacylglycerol and fatty acid) through mitogen-activated
      protein (MAP) kinase pathway, and a modification of PKC by reactive oxygen
      species. In nerve growth factor (NGF)-differentiated PC12 cells, we found that
      constitutive and autonomous Ca2+-independent PKC activity is associated with 14-3
      3 zeta. Because PKC and 14-3-3 zeta are both involved in synaptic plasticity and
      learning and memory, we examined whether PKC interacts with 14-3-3 zeta in the
      brain and whether the PKC/14-3-3 zeta complex has autonomous activity. Here we
      show that three subclasses of PKC, Ca2+-dependent classical PKC, Ca2+-independent
      novel PKC, and Ca2+-independent and diacylglycerol-insensitive atypical PKC, all
      interact with 14-3-3 zeta in the rodent brain. The pool size of 14-3-3 zeta bound
      form of PKC is small (1-4% of each PKC isoform), but they show constitutive and
      autonomous activity. Our study indicates that the binding of PKC with 14-3-3 zeta
      is at least in part independent of phosphorylation of PKC and that the C1 domain
      of PKC is involved in the binding. As both molecules are enriched in synaptic
      locus, the constitutive PKC activity and its interaction with 14-3-3 zeta could
      be a mechanism for the persistent PKC activation in the brain.

PMID- 12485400
TI  - Expression and functional characterization of the extraneuronal monoamine
      transporter in normal human astrocytes.
AB  - In this study we examined the functional expression of the extraneuronal
      monoamine transporter (EMT) in normal human astrocytes (NHA). RT-PCR with EMT
      specific primers demonstrated the presence of EMT mRNA in NHA. The RT-PCR
      products were subjected to restriction-site analysis using three different
      enzymes (HinfI, SacI and BclI). The restriction patterns with the three enzymes
      were identical and were exactly as expected from the known restriction map of
      human EMT cDNA. DNA sequencing was performed for the RT-PCR products from NHA.
      Sequence analysis demonstrated that the sequences of RT-PCR products were
      identical to that of EMT. The extract of NHA was immunoblotted with anti-EMT
      polyclonal antibody raised against EMT polypeptides. Western blotting indicated
      that anti-EMT polyclonal antibody recognized a band of 63 kDa. Immunocytochemical
      staining using anti-EMT polyclonal antibody in NHA revealed that the plasma
      membrane, as well as intracellular, perinuclear compartments, presumably
      endoplasmic reticulum or Golgi membranes, showed a considerable level of
      immunoreactivity. We examined the time course of temperature-dependent [3H]MPP+
      uptake in NHA for 60 min. Temperature-dependent [3H]MPP+ uptake increased in a
      time-dependent manner for the initial 45 min and almost reached a plateau level
      (8.70 +/- 0.59 pmol/mg protein) at 60 min. In the presence of 3 micro m
      decynium22 (D22) (the most potent EMT inhibitor), temperature-dependent [3H]MPP+
      uptake was strongly reduced by 61% (3.39 +/- 0.76 pmol/mg protein at 60 min). D22
      sensitive [3H]MPP+ uptake was saturable over a MPP+ concentration of 6.25-200
      micro m. Km for this process was 78.01 +/- 7.64 micro m and Vmax was 295.4 +/-
      12.8 pmol/mg protein/min. D22-sensitive [3H]MPP+ uptake was reduced when the
      astrocyte membrane potential was depolarized by increasing the concentration of
      K+ in the uptake buffer or by adding Ba2+ to the uptake buffer. These results
      provide evidence that the MPP+ transport activity in NHA is potential-sensitive.
      Moreover, D22-sensitive [3H]MPP+ uptake was independent of extracellular Na+. D22
      sensitive [3H]MPP+ uptake was inhibited by D22, various organic cations, steroids
      and monoamine neurotransmitters. Our results showed that the EMT is functionally
      expressed in NHA and may also play a key role in the disposition of cationic
      drugs, neurosteroids, the neurotoxin MPP+ and monoamine neurotransmitters in the
      brain.

PMID- 12485399
TI  - The synaptophysin/synaptobrevin interaction critically depends on the cholesterol
      content.
AB  - Synaptophysin interacts with synaptobrevin in membranes of adult small synaptic
      vesicles. The synaptophysin/synaptobrevin complex promotes synaptobrevin to built
      up functional SNARE complexes thereby modulating synaptic efficiency.
      Synaptophysin in addition is a cholesterol-binding protein. Depleting the
      membranous cholesterol content by filipin or beta-methylcyclodextrin (beta-MCD)
      decreased the solubility of synaptophysin in Triton X-100 with less effects on
      synaptobrevin. In small synaptic vesicles from rat brain the
      synaptophysin/synaptobrevin complex was diminished upon beta-MCD treatment as
      revealed by chemical cross-linking. Mice with a genetic mutation in the Niemann
      Pick C1 gene developing a defect in cholesterol sorting showed significantly
      reduced amounts of the synaptophysin/synaptobrevin complex compared to their homo
      or heterozygous littermates. Finally when using primary cultures of mouse
      hippocampus the synaptophysin/synaptobrevin complex was down-regulated after
      depleting the endogenous cholesterol content by the HMG-CoA-reductase inhibitor
      lovastatin. Alternatively, treatment with cholesterol up-regulated the
      synaptophysin/synaptobrevin interaction in these cultures. These data indicate
      that the synaptophysin/synaptobrevin interaction critically depends on a high
      cholesterol content in the membrane of synaptic vesicles. Variations in the
      availability of cholesterol may promote or impair synaptic efficiency by
      interfering with this complex.

PMID- 12485401
TI  - Region-specific and epileptogenic-dependent expression of six subtypes of
      alpha2,3-sialyltransferase in the adult mouse brain.
AB  - Sialylated glycoconjugates play important roles in various biological functions.
      The structures are also observed in brains and it has been proposed that
      sialylation may affect neural plasticity. To clarify the effects of sialylation
      in the brain, particular neurons that exhibit sialylation should first be
      determined. Using in situ hybridization, we performed systematic surveys of the
      localization of mRNAs encoding the six alpha2,3-sialyltransferases (ST3Gal I-VI)
      in the adult mouse brain with or without physiological stimulation. First,
      striking region-specific patterns of expression were observed: While ST3Gal II,
      III, and V mRNAs were in neuronal cells throughout the brain, ST3Gal I, IV, and
      VI mRNAs were in restricted brain regions. Next, to assess whether the expression
      of the six mRNAs can be regulated, we examined the effect of kindling
      epileptogenesis on the six mRNA levels. Of the six subtypes, upregulation in the
      ST3Gal IV level in the thalamus was most pronounced; the number of ST3Gal IV
      expressing neurons in the anterior thalamic nuclei increased from 2% to 21% in a
      time-dependent manner during epileptogenesis. Western blot analysis evaluated the
      increase of the end-products in the thalamus. These findings provide a molecular
      basis to clarify when and where sialylated glycoconjugates function accompanied
      by neural plasticity.

PMID- 12485402
TI  - Transient ischemia enhances tyrosine phosphorylation and binding of the NMDA
      receptor to the Src homology 2 domain of phosphatidylinositol 3-kinase in the rat
      hippocampus.
AB  - Tyrosine phosphorylation of the NMDA receptor has been implicated in the
      regulation of the receptor channel. We investigated the effects of transient (15
      min) global ischemia on tyrosine phosphorylation of NMDA receptor subunits NR2A
      and NR2B, and the interaction of NR2 subunits with the SH2 domain of
      phosphatidylinositol 3-kinase (PI3-kinase) in vulnerable CA1 and resistant
      CA3/dentate gyrus of the hippocampus. Transient ischemia induced a marked
      increase in the tyrosine phosphorylation of NR2A in both regions. The tyrosine
      phosphorylation of NR2B in CA3/dentate gyrus after transient ischemia was
      sustained and greater than that in CA1. PI3-kinase p85 was co-precipitated with
      NR2B after transient global ischemia. The SH2 domain of the p85 subunit of PI3
      kinase bound to NR2B, but not to NR2A. Binding to NR2B was increased following
      ischemia and the increase in binding in CA3/dentate gyrus (4.5-fold relative to
      sham) was greater than in CA1 (1.7-fold relative to sham) at 10 min of
      reperfusion. Prior incubation of proteins with an exogenous protein tyrosine
      phosphatase or with a phosphorylated peptide (pYAHM) prevented binding. The
      results suggest that sustained increases in tyrosine phosphorylation and
      increased interaction of NR2B with the SH2 domain of PI3-kinase may contribute to
      altered signal transduction in the CA3/dentate gyrus after transient ischemia.

PMID- 12485403
TI  - Altered levels and distribution of microtubule-associated proteins before disease
      onset in a mouse model of amyotrophic lateral sclerosis.
AB  - Alterations of the axonal transport and microtubule network are potential causes
      of motor neurodegeneration in mice expressing a mutant form of the superoxide
      dismutase 1 (SOD1G37R) linked to amyotrophic lateral sclerosis (ALS). In the
      present study, we investigated the biology of microtubule-associated proteins
      (MAPs), responsible for the formation and stabilization of microtubules, in
      SOD1G37R mice. Our results show that the protein levels of MAP2, MAP1A, tau 100
      kDa and tau 68 kDa species decrease significantly as early as 5 months before
      onset of symptoms in the spinal cord of SOD1G37R mice, whereas decrease in levels
      of tau 52-55 kDa species is most often noted with the manifestation of the
      clinical symptoms. Interestingly, there was no change in the protein levels of
      MAPs in the brain of SOD1G37R mice, a CNS organ spared by the mutant SOD1
      toxicity. Remarkably, as early as 5 months before disease onset, the binding
      affinities of MAP1A, MAP2 and tau isoforms to the cytoskeleton decreased in
      spinal cord of SOD1G37R mice. This change correlated with a hyperphosphorylation
      of the soluble tau 52-55 kDa species at epitopes recognized by the antibodies AT8
      and PHF-1. Finally, a shift in the distribution of MAP2 from the cytosol to the
      membrane is detected in SOD1G37R mice at the same stage. Thus, alterations in the
      integrity of microtubules are early events of the neurodegenerative processes in
      SOD1G37R mice.

PMID- 12485404
TI  - Distinct effects of methamphetamine and cocaine on preprodynorphin messenger RNA
      in rat striatal patch and matrix.
AB  - We and others previously reported that equimolar doses of methamphetamine and
      cocaine differentially increase preprodynorphin mRNA in striatum: methamphetamine
      causes a patchy increase, whereas cocaine produces a more homogenous one. The
      current study directly examined whether this effect reflects differential
      induction in the patch-matrix division of striatum, as identified by micro opioid
      receptor immunohistochemistry. In addition, we determined whether doses of
      cocaine (30 mg/kg) and methamphetamine (2 mg/kg) that produced equivalent
      increases in extracellular dopamine differentially affected preprodynorphin mRNA
      expression in striatum of male, Sprague-Dawley rats. In both experiments,
      methamphetamine and cocaine differentially affected preprodynorphin mRNA in
      striatum after 3 h. The high, equimolar dose of methamphetamine selectively
      increased preprodynorphin mRNA in the patch division of rostral striatum, whereas
      cocaine increased preprodynorphin mRNA throughout patch and matrix divisions of
      striatum. In contrast, a dose of methamphetamine (2.0 mg/kg) that caused an
      increase in extracellular dopamine similar to that produced by 30 mg/kg cocaine
      did not significantly affect preprodynorphin mRNA in any region of striatum.
      These data provide further evidence that cocaine and amphetamines exert distinct
      effects on the patch-matrix division of striatum and suggest further that the
      post-synaptic consequences of elevated extracellular dopamine produced by
      methamphetamine and cocaine are distinct.

PMID- 12485405
TI  - Transient modulation of cytoplasmic and nuclear retinoid receptors expression in
      differentiating human teratocarcinoma NT2 cells.
AB  - Human embryonal carcinoma Ntera2/D1 (NT2) cells treated with retinoic acid (RA)
      differentiate into several cell types including post-mitotic neurons. In this
      study we asked if RA-induced differentiation alters the expression of RA and
      retinol (ROL) binding proteins. The regulation of the intracellular carrier
      proteins for ROL and RA, cellular retinol binding protein I (CRBP-I), and
      cellular retinoic acid binding protein I and II (CRABP-I, CRABP-II) were studied
      along with the nuclear RA receptors RARalpha, RARbeta and RARgamma2. PCR analysis
      of total mRNA from RA-treated cells showed a biphasic early induction of CRBP-I,
      CRABP-II, and RARgamma2 genes. The immediate early gene Krox-24, a zinc finger
      transcription factor which is up-regulated during neuronal differentiation, was
      also induced, but after 1 week of treatment. The induction of CRBP-I protein
      synthesis in differentiating NT2 cells was confirmed by western blotting and
      immunofluorescence experiments. Conversely, the synthetic retinoid N-(4
      hydroxyphenyl)retinamide, which induces cell death, but not differentiation in
      different tumour cell types, did not produce the same modulation on gene
      expression in NT2 cells. These data suggest that the RA-specific induction of
      CRBP-I and CRABP-II could be an early event in the process leading to neuronal
      differentiation of NT2 cells.

PMID- 12485406
TI  - Long-lasting occupancy of central nicotinic acetylcholine receptors after
      smoking: a PET study in monkeys.
AB  - The aim of this study was to compare the degree of occupancy of central nicotinic
      acetylcholine receptors (nAChR) in isoflurane anaesthetized baboon brain
      following inhalation of tobacco smoke (one cigarette containing 0.9 mg nicotine)
      or i.v. nicotine (0.6 mg i.v.). [18F]Fluoro-A-85380 and positron emission
      tomography (PET) were used to assess the distribution volumes (DV) of the
      radiotracer in selected brain areas using a one-compartment model. Eighty minutes
      after nicotine i.v., DV was reduced by 50 and 66% in the thalamus and putamen,
      respectively. Six hours after nicotine, a reduction in DV (27% in the thalamus)
      was still observed. Eighty minutes after inhalation of tobacco smoke, DV was
      decreased by 52 and 65% in the thalamus and putamen, respectively. Previous PET
      experiments have demonstrated a short-lasting interaction of [11C]nicotine with
      nAChRs. Thus, we hypothesized that a metabolite of nicotine with high affinity
      and long half-live (several hours) could bind at nAChRs. Eighty minutes after a
      high dose of nornicotine (0.5 mg i.v.), DV was reduced by 53 and 31% in thalamus
      and putamen, respectively. No significant effect was observed following 0.15 mg
      nornicotine. Therefore, nornicotine could contribute to the long-lasting
      occupancy of central nAChRs after smoking.

PMID- 12485407
TI  - Quantitative relationship between inhibition of respiratory complexes and
      formation of reactive oxygen species in isolated nerve terminals.
AB  - In this study reactive oxygen species (ROS) generated in the respiratory chain
      were measured and the quantitative relationship between inhibition of the
      respiratory chain complexes and ROS formation was investigated in isolated nerve
      terminals. We addressed to what extent complex I, III and IV,respectively, should
      be inhibited to cause ROS generation. For inhibition of complex I, III and IV,
      rotenone, antimycin and cyanide were used, respectively, and ROS formation was
      followed by measuring the activity of aconitase enzyme. ROS formation was not
      detected until complex III was inhibited by up to 71 +/- 4%, above that threshold
      inhibition, decrease in aconitase activity indicated an enhanced ROS generation.
      Similarly, threshold inhibition of complex IV caused an accelerated ROS
      production. By contrast, inactivation of complex I to a small extent (16 +/- 2%)
      resulted in a significant increase in ROS formation, and no clear threshold
      inhibition could be determined. However, the magnitude of ROS generated at
      complex I when it is completely inhibited is smaller than that observed when
      complex III or complex IV was fully inactivated. Our findings may add a novel
      aspect to the pathology of Parkinson's disease, showing that a moderate level of
      complex I inhibition characteristic in Parkinson's disease leads to significant
      ROS formation. The amount of ROS generated by complex I inhibition is sufficient
      to inhibit in situ the activity of endogenous aconitase.

PMID- 12485408
TI  - Characterization and regulation of the 3beta-hydroxysteroid dehydrogenase
      isomerase enzyme in the rat sciatic nerve.
AB  - In the peripheral nervous system, progesterone (PROG) has a stimulatory effect on
      myelination. It could be derived from local synthesis, as Schwann cells in
      culture express the 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and convert
      pregnenolone (PREG) to PROG. Although 3beta-HSD mRNA can be detected by RT-PCR in
      peripheral nerves, the activity of the enzyme has so far not been demonstrated
      and characterized in nerve tissue. In this study, we show that homogenates
      prepared from rat sciatic nerves contain a functional 3beta-HSD enzyme and we
      have analysed its kinetic properties and its regulation by steroids. The activity
      of 3beta-HSD in homogenates was evaluated using 3H-labelled PREG as a substrate
      and NAD+ as a cofactor, the levels of steroids formed were calculated either by
      extrapolating the relationship between tritiated peaks obtained by TLC to the
      initial amount of PREG, or by gas chromatography/mass spectrometry determination.
      A rapid increase in PROG formation was found between 0 and 50 min of incubation
      and no further significant changes were observed between 1 and 4 h. The
      calculated Km value (1.06 +/- 0.19 microm) was close to the values described for
      the 3beta-HSD type-I and type-IV isoforms. Trilostane, a competitive inhibitor of
      the 3beta-HSD caused a potent inhibition of the rate of conversion of PREG to
      PROG (IC50 = 4.06 +/- 2.58 microm). When the effects of different steroids were
      tested, both oestradiol and PROG significantly inhibited the conversion of PREG
      to PROG.

PMID- 12485409
TI  - Identification of an amino acid sequence within GABA(A) receptor beta3 subunits
      that is important for receptor assembly.
AB  - GABA(A) receptors are chloride ion channels that can be opened by GABA, the most
      important inhibitory transmitter in the CNS. In the mammalian brain the majority
      of these pentameric receptors is composed of two alpha, two beta and one gamma
      subunit. To achieve the correct order of subunits around the pore, each subunit
      must form specific contacts via its plus (+) and minus (-) side. To identify a
      sequence on the beta3 subunit important for assembly, we generated various full
      length or truncated chimeric beta3 constructs and investigated their ability to
      assemble with alpha1 and gamma2 subunits. It was demonstrated that replacement of
      the sequence beta3(76-89) by the homologous alpha1 sequence impaired assembly
      with alpha1 but not with gamma2 subunits in alpha1beta3gamma2-GABA(A) receptors.
      Other experiments indicated that assembly was impaired via the beta3(-) side of
      the chimeric subunit. Within the sequence beta3(76-89) the sequence beta3(85-89)
      seemed to be of primary importance for assembly with alpha1 subunits. A
      comparison with the structure of the acetylcholine-binding protein supports the
      conclusion that the sequence beta3(85-89) is located at the beta3(-) side and
      indicates that it contains amino acid residues that might directly interact with
      the (+) side of the neighbouring alpha1 subunit.

PMID- 12485410
TI  - Functional expression of the norepinephrine transporter in cultured rat
      astrocytes.
AB  - We assessed the functional expression of the norepinephrine (NE) transporter
      (NET) in cultured rat cortical astrocytes. Specific [3H]NE uptake increased in a
      time-dependent manner, and this uptake involves temperature- and Na+-sensitive
      mechanisms. The Na+-dependent [3H]NE uptake was saturable, and the Km for the
      process was 539.3 +/- 55.4 nm and the Vmax was 1.41 +/- 0.03 pmol/mg protein/min.
      Ouabain, a Na+-K+ ATPase inhibitor, significantly inhibited Na+-dependent [3H]NE
      uptake. The selective NE uptake inhibitor nisoxetine, the tricyclic
      antidepressants desipramine and imipramine, and the serotonin and NE reuptake
      inhibitor (SNRI) milnacipran very potently inhibited Na+-dependent [3H]NE uptake.
      On the other hand, GBR-12935 (a selective dopamine uptake inhibitor), fluvoxamine
      (a selective serotonin reuptake inhibitor), venlafaxine (a SNRI) and cocaine had
      weaker inhibitory activities. RT-PCR demonstrated that astrocytes expressed mRNA
      for the cloned NET protein, which was characterized as neuronal NET. Western
      blots indicated that anti-NET polyclonal antibody recognized a major band of 80
      kDa in astrocytes. These data indicate that the neuronal NET is functionally
      expressed in cultured rat astrocytes. Glial cells may exert significant control
      of noradrenergic activity by inactivating NE that escapes neuronal re-uptake in
      sites distant from terminals, and are thus cellular targets for antidepressant
      drugs that inhibit NE uptake.

PMID- 12485411
TI  - Modulation of somatostatin receptors, somatostatin content and Gi proteins by
      substance P in the rat frontoparietal cortex and hippocampus.
AB  - Substance P (SP) and somatostatin (SRIF) are widely spread throughout the CNS
      where they play a role as neurotransmitters and/or neuromodulators. A
      colocalization of both neuropeptides has been demonstrated in several rat brain
      areas and SP receptors have been detected in rat cortical and hippocampal
      somatostatinergic cells. The present study was thus undertaken to determine
      whether SP could modulate SRIF signaling pathways in the rat frontoparietal
      cortex and hippocampus. A single intraperitoneal injection of SP (50, 250 or 500
      micro g/kg) induced an increase in the density of SRIF receptors in membranes
      from the rat frontoparietal cortex at 24 h of its administration, with no change
      in the hippocampus. The functionality of the SRIF receptors was next
      investigated. Western blot analysis of Gi proteins demonstrated a significant
      decrease in Gialpha1 levels in frontoparietal cortical membranes from rats
      treated acutely (24 h) with 250 micro g/kg of SP, which correlated with a
      decrease in functional Gi activity, as assessed by use of the non-hydrolyzable
      GTP analog 5'-guanylylimidodiphosphate. SRIF-mediated inhibition of basal or
      forskolin-stimulated adenylyl cyclase activity was also significantly lower in
      the frontoparietal cortex of the SP-treated group, with no alterations in the
      catalytic subunit of the enzyme. SRIF-like immunoreactivity content was increased
      in the frontoparietal cortex after acute (24 h) SP administration (250 or 500
      micro g/kg) as well as in the hippocampus in response to 7 days of SP (250 micro
      g/kg) administration. All these SP-mediated effects were prevented by
      pretreatment with the NK1 receptor antagonist RP-67580. Although the physiologic
      significance of these results are unknown, the increase in SRIF receptor density
      together with the desensitization of the SRIF inhibitory signaling pathway might
      be a mechanism to potentiate the stimulatory pathway of SRIF, inducing a
      preferential coupling of the receptors to PLC.

PMID- 12485412
TI  - Age-dependent myelin degeneration and proteolysis of oligodendrocyte proteins is
      associated with the activation of calpain-1 in the rhesus monkey.
AB  - Myelin provides important insulating properties to axons allowing for propagation
      of action potentials over large distances at high velocity. Disruption of the
      myelin sheath could therefore contribute to cognitive impairment, such as that
      observed during the normal aging process. In the present study, age-related
      changes in myelin, myelin proteins and oligodendrocyte proteins were assessed in
      relationship to calpain-1 expression and cognition in the rhesus monkey.
      Isolation of myelin fractions from brain white matter revealed that as the
      content of the intact myelin fraction decreased with age, there was a
      corresponding increase in the floating or degraded myelin fraction, suggesting an
      increased breakdown of intact myelin with age. Of the myelin proteins examined,
      only the myelin-associated glycoprotein decreased with age. Levels of the
      oligodendrocyte-specific proteins 2',3'-cyclic nucleotide 3'-phosphodiesterase
      (CNPase) and myelin/oligodendrocyte-specific protein (MOSP) increased
      dramatically in white matter homogenates and myelin with age. Age-related
      increases in degraded CNPase also were demonstrable in white matter in
      association with increases in activated calpain-1. Degraded CNPase was also
      detectable in myelin fractions, with only the floating fraction containing
      activated calpain-1. The increases in the activated enzyme in white matter were
      much greater than those found in myelin fractions suggesting a source other than
      the myelin membrane for the marked overexpression of activated calpain-1 with
      age. In addition, CNPase was demonstrated to be a substrate for calpain in vitro.
      In summary, changes in myelin and oligodendrocyte proteins occur with age, and
      they appear to have a significant relationship to cognitive impairment. The
      overexpression of CNPase and MOSP suggests new formation of myelin by
      oligodendrocytes, which may occur in response to myelin degradation and injury
      caused by proteolytic enzymes such as calpain.

PMID- 12485413
TI  - HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium.
AB  - Impaired function of the brain vasculature might contribute to the development of
      HIV-associated dementia. For example, injury or dysfunction of brain
      microvascular endothelial cells (BMEC) can lead to the breakdown of the blood
      brain barrier (BBB) and thus allow accelerated entry of the HIV-1 virus into the
      CNS. Mechanisms of injury to BMEC during HIV-1 infection are not fully
      understood, but the viral gene product Tat may be, at least in part, responsible
      for this effect. Tat can be released from infected perivascular macrophages in
      the CNS of patients with AIDS, and thus BMEC can be directly exposed to high
      concentrations of this protein. To study oxidative and inflammatory mechanisms
      associated with Tat-induced toxicity, BMEC were exposed to increasing doses of
      Tat1-72, and markers of oxidative stress, as well as redox-responsive
      transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator
      protein-1 (AP-1), were measured. Tat1-72 treatment markedly increased cellular
      oxidative stress, decreased levels of intracellular glutathione and activated DNA
      binding activity and transactivation of NF-kappaB and AP-1. To determine if Tat1
      72 can stimulate inflammatory responses in brain endothelium in vivo, expression
      of monocyte chemoattractant protein-1 (MCP-1), an NF-kappaB and AP-1-dependent
      chemokine, was studied in brain tissue in mice injected with Tat1-72 into the
      right hippocampus. Tat1-72 markedly elevated the MCP-1 mRNA levels in brain
      tissue. In addition, a double immunohistochemistry study revealed that MCP-1
      protein was markedly overexpressed on brain vascular endothelium. These data
      indicate that Tat1-72 can induce redox-related inflammatory responses both in in
      vitro and in vivo environments. These changes can directly lead to disruption of
      the BBB. Thus, Tat can play an important role in the development of detrimental
      vascular changes in the brains of HIV-infected patients.

PMID- 12485414
TI  - Transients in acetylcholine receptor site density and degradation during
      reinnervation of mouse sternomastoid muscle.
AB  - The degradation rates of acetylcholine receptors (AchRs) were evaluated at the
      neuromuscular junction during and just after reinnervation of denervated muscles.
      When mouse sternomastoid muscles are denervated by multiple nerve crush,
      reinnervation begins 2-4 days later and is complete by day 7-9 after the last
      crush. In fully innervated muscles, the AChR degradation rate is stable and slow
      (t1/2 approximately 10 days), whereas after denervation the newly inserted
      receptors degrade rapidly (t1/2 approximately 1.2 days). The composite profile of
      degradation, which a mixture of the stable and the rapid receptors would give, is
      not observed during reinnervation. Instead, the receptors inserted between 2.5
      and 7.5 days after the last crush all have an intermediate degradation rate of
      t1/2 approximately 3.7 days with standard error +/- 0.3 days. The total receptor
      site density at the endplate was evaluated during denervation and during
      reinnervation. As predicted theoretically, the site density increased
      substantially, but temporarily, after denervation. An analogous deleterious
      substantial decrease in density would be expected during reinnervation, without
      the intermediate receptor. This decrease is not observed, however, because of a
      large insertion rate at intermediate times (3000 +/- 700 receptor complexes per
      micro m2 per day). The endplate density of receptors thus remains relatively
      constant.

PMID- 12485415
TI  - Corticotropin-releasing hormone induces proliferation and TNF-alpha release in
      cultured rat microglia via MAP kinase signalling pathways.
AB  - We have previously demonstrated that corticotropin-releasing hormone (CRH)
      receptor 1 (CRH-R1) is functionally expressed in rat microglia. In the present
      study, we show that CRH, acting on CRH-R1, promoted cell proliferation and tumour
      necrosis factor-alpha (TNF-alpha) release in cultured rat microglia. Exogenous
      CRH resulted in an increase in BrdU incorporation compared with control cells,
      which was observed in a range of concentrations of CRH between 10 and 500 nm,
      with a maximal response at 50 nm. The effect of CRH on BrdU incorporation was
      inhibited by a CRH antagonist astressin but not by a cAMP-dependent protein
      kinase inhibitor H89. Exposure of microglial cells to CRH resulted in a transient
      and rapid increase in TNF-alpha release in a dose-dependent manner. In the
      presence of astressin, the effects of CRH on TNF-alpha release were attenuated.
      CRH effects on TNF-alpha release were also inhibited by specific inhibitors of
      MEK, the upstream kinase of the extracellular signal-regulated protein kinase
      (ERK) (PD98059) or p38 mitogen-activated protein kinase (SB203580), but not by
      H89. Furthermore, CRH induced rapid phosphorylation of ERK and p38 kinases.
      Astressin, PD98059, and SB230580 were able to inhibit CRH-induced kinase
      phosphorylation. These results suggest that CRH induces cell proliferation and
      TNF-alpha release in cultured microglia via MAP kinase signalling pathways,
      thereby providing insight into the interactions between CRH and inflammatory
      mediators.

PMID- 12485416
TI  - Two pathways for tBID-induced cytochrome c release from rat brain mitochondria:
      BAK- versus BAX-dependence.
AB  - The mechanisms of truncated BID (tBID)-induced Cyt c release from non
      synaptosomal brain mitochondria were examined. Addition of tBID to mitochondria
      induced partial Cyt c release which was inhibited by anti-BAK antibodies,
      implicating BAK. Immunoblotting showed the presence of BAK, but not BAX, in brain
      mitochondria. tBID did not release Cyt c from rat liver mitochondria, which
      lacked both BAX and BAK. This indicated that tBID did not act independently of
      BAX and BAK. tBID plus monomeric BAX produced twice as much Cyt c release as did
      tBID or oligomeric BAX alone. Neither tBID alone nor in combination with BAX
      induced mitochondrial swelling. In both cases Cyt c release was insensitive to
      cyclosporin A plus ADP, inhibitors of the mitochondrial permeability transition
      (mPT). Recombinant Bcl-xL inhibited Cyt c release induced by tBID alone or in
      combination with monomeric BAX. Koenig's polyanion, an inhibitor of VDAC,
      suppressed tBID-induced Cyt c release from brain mitochondria mediated by BAK but
      not by BAX. Thus, tBID can induce mPT-independent Cyt c release from brain
      mitochondria by interacting with exogenous BAX and/or with endogenous BAK that
      may involve VDAC. In contrast, neither adenylate kinase nor Smac/DIABLO was
      released from isolated rat brain mitochondria via BAK or BAX.

PMID- 12485419
TI  - More on MITF.

PMID- 12485420
TI  - Low-dose ultraviolet B rays alter the mRNA expression of the circadian clock
      genes in cultured human keratinocytes.
AB  - Current understanding of mammalian circadian rhythms suggests that they are
      regulated by light targeting signaling pathways in the hypothalamic
      suprachiasmatic nuclei. Recently, investigators have identified the existence of
      extraretinal photoreceptors and a potential role for the skin in this regulatory
      process has been implied. We demonstrated that mRNA of the circadian clock genes
      Per1, Clock, and bmal1/mop3 are expressed in normal human cultured keratinocytes.
      Low-dose ultraviolet B rays initially downregulate all circadian clock genes and
      then induce altered expression of the genes in keratinocyte cell cultures.
      Ultraviolet light targeting superficial layers of skin (keratinocytes) may
      therefore contribute to circadian rhythm modulation.

PMID- 12485421
TI  - Cystic fibrosis transport regulator and its mRNA are expressed in human
      epidermis.
AB  - Cystic fibrosis transport regulator is a cAMP-dependent chloride channel protein.
      Normal (non cystic fibrosis) human epidermis stained positive for cystic fibrosis
      transport regulator as densely as did the eccrine sweat gland when three
      monoclonal antibodies for R (regulatory) and C (C-terminus) domains of cystic
      fibrosis transport regulator were used. All the layers of the epidermis took up
      staining uniformly. A peptide for C-epitope completely blocked the staining with
      monoclonal antibodies for C. Nested reverse transcription polymerase chain
      reaction of freshly isolated human epidermal fragments and the eccrine sweat
      glands amplified the cystic fibrosis transport regulator mRNA sequence derived
      from exons 13 and 14 to comparable extents. The 526 base pair antisense, but not
      sense, RNA probe derived from exons 10-13 stained cystic fibrosis transport
      regulator mRNA in both the epidermis and the sweat gland to a similar extent. In
      the epidermis, the cytoplasm of basal cells, stratum spinosum cells, and granular
      layer cells were all stained uniformly, but not corneocytes in the stratum
      corneum. In the sweat secretory coils, both clear and dark cells were stained but
      not the myoepithelium, with the dark cells staining more densely than the clear
      cells as in a previous study. In the duct, both luminal and basal ductal cells
      took up cystic fibrosis transport regulator staining uniformly but luminal
      cytoplasm of luminal ductal cells was devoid of cystic fibrosis transport
      regulator mRNA. Although the function of cystic fibrosis transport regulator in
      the epidermis is totally unknown, its recently proposed role as a universal
      regulator of a variety of cellular and membrane functions necessitates further
      studies on its regulation and function in health and disease.

PMID- 12485422
TI  - Differential effects of desmoglein 1 and desmoglein 3 on desmosome formation.
AB  - The desmoglein plays an important part in the formation of desmosomes. We
      constructed recombinant adenoviruses containing desmoglein 1 and desmoglein 3
      derivatives partly lacking the extracellular domain (desmoglein 1DeltaEC and
      desmoglein 3DeltaEC, respectively), and full-length desmoglein 1 and desmoglein 3
      and studied the involvement of desmoglein 1 and desmoglein 3 in desmosome
      formation. During low-level expression of desmoglein 3DeltaEC in transduced HaCaT
      cells, keratin insertion at cell-cell contact sites was only partially inhibited
      and desmoplakin was partially stained at cell-cell contact sites. Low-level
      expression of desmoglein 1DeltaEC, however, resulted in complete inhibition of
      keratin insertion at the cell-cell contact sites, and desmoplakin was stained in
      perinuclear dots. These results indicate the dominant-negative effect of
      desmoglein 1DeltaEC on desmosome formation was stronger than that of desmoglein
      3DeltaEC. Desmoglein 1DeltaEC coprecipitated plakoglobin to approximately the
      same extent as desmoglein 3DeltaEC. Therefore, we conclude that the dominant
      negative effect of desmoglein 1DeltaEC is not simply due to plakoglobin
      sequestration. On the other hand, during low-level expression of full-length
      desmoglein 3 and desmoglein 1, they both colocalized with desmoplakin. During
      high-level expression, however, keratin insertion at cell-cell contact sites was
      inhibited in desmoglein 1 but not in desmoglein 3, and desmoplakin was stained at
      cell-cell contact sites in desmoglein 3 but not in desmoglein 1. These data
      suggest desmoglein 1 and desmoglein 3 expressed at low level were incorporated
      into desmosome but at high-level expression, desmoglein 1 disrupted desmosomes
      but desmoglein 3 did not. Our findings provide biologic evidence that desmoglein
      1 and desmoglein 3 play a different functional role in cell-cell adhesion of
      keratinocytes.

PMID- 12485423
TI  - Loss of cell adhesion in Dsg3bal-Pas mice with homozygous deletion mutation
      (2079del14) in the desmoglein 3 gene.
AB  - Pemphigus encompasses a group of autoimmune blistering diseases with circulating
      pathogenic autoantibodies recognizing several proteins, including the desmosomal
      cadherin, desmoglein 3. Targeted disruption of the Dsg3 gene by homologous
      recombination (Dsg3tm1stan) in mouse results in fragility of the skin and oral
      mucous membranes, analogous to the human disease. In addition, the Dsg3tm1stan
      mice develop phenotypic runting and hair loss, identical to that of the mouse
      mutant, Dsg3bal-2J. The Dsg3bal-2J mice are homozygous for a 1 bp insertion
      (2275insT) in the Dsg3 gene resulting in a nonfunctional Dsg3 mRNA. In this
      study, we characterized an allelic mutation, Dsg3bal-Pas, with clinical features
      similar to those in Dsg3bal-2J. We have identified a 14 bp deletion in exon 13 of
      the Dsg3 gene resulting in a frameshift and premature termination codon 7 bp
      downstream from the site of the deletion and causing a truncation of the
      desmoglein 3 polypeptide by 199 amino acids, eliminating virtually all of the
      intracellular domain. We demonstrate that, although a Dsg3 mRNA transcript was
      detectable in Dsg3bal-Pas skin, the corresponding protein for desmoglein 3 was
      completely absent in the oral mucosal epithelium of homozygous Dsg3bal-Pas
      compared with that of +/Dsg3bal-Pas mice. No significant changes in the
      expression of desmogleins 1 and 2 were detected. To elucidate a potential
      mechanism causing loss of cell adhesion in the Dsg3bal-Pas mice, we generated a
      myc-tagged truncated Dsg3bal-Pas desmoglein 3 protein and expressed it in
      keratinocytes. The myc-tagged truncated Dsg3bal-Pas desmoglein 3 protein was
      found predominantly in the cytoplasm possibly due to increased proteolytic
      degradation. Cell surface staining was also detected but was jagged, not linear
      along the cell-cell border like that observed for the full-length desmoglein 3.
      The expression of the myc-tagged truncated Dsg3bal-Pas desmoglein 3 protein
      resulted in a reduction in staining of other desmosomal proteins, including
      desmoglein 1 and 2, plakophilin 2, and plakoglobin. In addition, the cells
      expressing myc-tagged truncated Dsg3bal-Pas desmoglein 3 protein underwent
      dramatic changes in cell morphology and exhibited striking extensive filopodia.
      Collectively, these data showed that the perturbation of desmoglein 3 found in
      the Dsg3bal-Pas mice resulted in disadhesion of keratinocytes manifested with
      blistering phenotype.

PMID- 12485424
TI  - Inhibition of tumor necrosis factor-alpha stimulated NFkappaB/p65 in human
      keratinocytes by alpha-melanocyte stimulating hormone and adrenocorticotropic
      hormone peptides.
AB  - Alpha-melanocyte stimulating hormone (alpha-MSH) has pigmentary, anti
      inflammatory, antipyretic, and general immunomodulatory roles. It can oppose
      several cytokines including tumor necrosis factor-alpha in a number of tissues,
      including skin. We have previously shown that alpha-MSH can inhibit tumor
      necrosis factor-alpha stimulated intercellular adhesion molecule 1 upregulation
      and nuclear factor kappaB (NFkappaB) transcription factor activation in
      melanocyte and melanoma cells. It is thought, however, that this MSH biology may
      also extend to other cells of the skin and in this study we extend our work to
      keratinocytes. We have investigated in detail the ability of three alpha-MSH
      peptides to inhibit tumor necrosis factor alpha stimulated NFkappaB activation in
      nonpigmentary HaCaT keratinocytes (alpha-MSH, L-Lys-L-Pro-L-Val, and L-Lys-L-Pro
      D-Val) and two adrenocorticotropic hormone (ACTH) peptides (1-17 and 1-39),
      reported to be present in skin tissue. NFkappaB/p65 activation was analyzed by
      electrophoretic mobility shift assay and immunofluorescent microscopy. alpha-MSH,
      L-Lys-L-Pro-L-Val, and L-Lys-L-Pro-D-Val all significantly inhibited tumor
      necrosis factor alpha stimulated NFkappaB activation, whereas ACTH 1-17 and 1-39
      did not, in the HaCaT keratinocytes. MSH peptides and ACTH 1-39 were effective,
      however, at inhibiting NFkappaB activation in normal human keratinocytes.
      Immunolabeling of inhibitor kappaBalpha of NFkappaB (IkappaBalpha) revealed an
      abnormal localization to the nucleus of HaCaT cells, which was unaffected by
      MSH/ACTH peptides. In contrast, normal human keratinocytes showed a normal
      IkappaBalpha distribution that responded to MSH/ACTH with nuclear translocation.
      Our data support previous work on the role of MSH/ACTH peptides as
      immunomodulatory/anti-inflammatory regulators, and extend this work to
      keratinocytes identifying a novel IkappaBalpha mechanism and extends findings to
      ACTH peptides, identifying an abnormal IkappaBalpha mechanism in the immortal
      HaCaT versus normal keratinocyte.

PMID- 12485425
TI  - Interleukin-1-stimulated secretion of interleukin-8 and growth-related oncogene
      alpha demonstrates greatly enhanced keratinocyte growth in human raft cultured
      epidermis.
AB  - The CXC chemokines, interleukin-8 and growth-related oncogenealpha, are known to
      play a prominent part in wound healing as well as inflammatory skin disorders,
      including psoriasis. Both chemokines are potent neutrophil activators and were
      discussed as potential stimuli in keratinocyte growth. We examined the action of
      growth-related oncogene alpha and interleukin-8 in organotypic raft culture,
      which resembles in vivo skin in several respects. Addition of growth-related
      oncogene alpha and interleukin-8 resulted in a time- and concentration-dependent
      epidermal hyperproliferation in organotypic cultures. In cryostat sections an
      increased number of epidermal layers as well as significantly elevated number of
      Ki-67-stained keratinocytes indicate marked hyperproliferation with no evidence
      for the reduction of apoptotic cells. Terminal differentiation was shown to
      proceed in a regular fashion with formation of a cornified layer and the
      expression of suprabasal keratins in addition to the presence of differentiation
      markers. Interleukin-8-mediated hyperproliferation was inhibited by a blocking
      human monoclonal antibody. To demonstrate a specific receptor-mediated action of
      growth-related oncogene and interleukin-8, we used a CXC receptor 2 monoclonal
      antibody or a CXC receptor 2 selective nonpeptide antagonist, both of which lead
      to inhibition of interleukin-8-mediated hyperproliferation. Interleukin-1alpha
      caused induction of interleukin-8 and growth-related oncogene alpha mRNA as well
      as marked epidermal hyperproliferation. The interleukin-1alpha-mediated
      hyperproliferation was markedly reduced by both the interleukin-8-specific
      antibody and the CXC receptor 2 antagonist, indicating close correlation between
      the interleukin-8/CXC receptor 2 pathway and interleukin-1-induced keratinocyte
      growth stimulation. Our data indicate that interleukin-1 induces overexpression
      of interleukin-8 and growth-related oncogene alpha in human keratinocytes. These
      changes correlate with characteristic functional alterations of the epidermis as
      observed in psoriasis and wound healing.

PMID- 12485426
TI  - Beta-adrenergic receptor activation inhibits keratinocyte migration via a cyclic
      adenosine monophosphate-independent mechanism.
AB  - There is increasing evidence that G-protein-coupled receptors cross-talk with
      growth factor receptor-mediated signal transduction in a variety of cell types.
      We have investigated mechanisms by which the activation of beta-adrenergic
      receptors, classically GTP-binding proteins coupled receptors, influence the
      migration of cultured human keratinocytes. We found that iso-proterenol, a beta
      adrenergic receptor-selective agonist, inhibited cell migration stimulated by
      either epidermal growth factor, or extracellular Ca2+ in a concentration
      dependent manner. This was prevented by pretreatment of the cells with the beta
      adrenergic receptor-selective antagonist timolol. Interestingly, isoproterenol,
      at a concentration of 1 nm, did not measurably increase intracellular cyclic
      adenosine monophosphate concentrations yet inhibited cell migration by 50%. To
      test further if isoproterenol's actions were mediated via activation of adenylyl
      cyclase, two inhibitors of its activity, 2'5'-dideoxyadenosine and SQ22536, were
      used. Both compounds significantly diminished iso-proterenol-induced increases in
      intracellular cyclic adenosine monophosphate concentrations but did not attenuate
      isoproterenol-induced inhibition of cell migration. Also, forskolin (1 microm)
      markedly increased intracellular cyclic adenosine monophosphate concentrations
      but did not significantly inhibit cell migration. As mitogen-activated protein
      kinases are known to signal growth factor-stimulated cell migration, we examined
      whether beta-adrenergic receptor-mediated inhibition of keratinocyte migration
      might occur via inactivation of mitogen-activated protein kinases. We found that
      isoproterenol inhibited phosphorylation of extracellular signal-regulated kinase
      mitogen-activated protein kinase in a concentration-dependent manner but had no
      effect on the phosphorylation of the stress mitogen-activated protein kinases c
      jun N-terminal kinase and stress-activated protein kinase-2. Neither forskolin
      nor a membrane permeable cyclic adenosine monophosphate analog inhibited
      phosphorylation of any of these mitogen-activated protein kinases. These findings
      suggest that beta-adrenergic receptor-induced inhibition of keratinocyte
      migration is mediated through inhibition of the extracellular signal-regulated
      kinase mitogen-activated protein kinase signaling in a cyclic adenosine
      monophosphate-independent manner.

PMID- 12485427
TI  - Origin of the epidermal calcium gradient: regulation by barrier status and role
      of active vs passive mechanisms.
AB  - Mammalian epidermis displays a characteristic calcium gradient, with low calcium
      levels in the lower, basal, and spinous epidermal layers, whereas calcium levels
      increase progressively towards the outer stratum granulosum, and declining again
      in the stratum corneum. As the calcium gradient disappears after acute
      permeability barrier disruption, and returns after 6 h in parallel with barrier
      recovery, barrier function (through restriction of transcutaneous water movement)
      could regulate the formation of the epidermal calcium gradient. Two types of
      experiments confirmed the role of barrier status in regulating the calcium
      gradient: (i) either a vapor-permeable membrane (Gore-Tex) or an emollient
      (Vaseline), applied after acute barrier disruption, immediately restored barrier
      function, while accelerating the return of the calcium gradient, and (ii) in
      contrast, applications of lovastatin, a cholesterol synthesis inhibitor, which
      delayed barrier recovery and retarded the return of the calcium gradient. We next
      asked whether the calcium gradient is formed/maintained by passive and/or active
      mechanisms. Previous studies have demonstrated that cold exposure (4 degrees C)
      blocks permeability barrier recovery after acute disruption. Here, we abrogated
      the barrier with tape-stripping, and then compared barrier recovery and
      restoration of the calcium gradient in hairless mice exposed to 4 degrees C
      external temperatures, with and without occlusion with Gore-Tex. Although low
      levels of returned calcium throughout the epidermis, acutely disrupted,
      unoccluded, cold-exposed sites showed neither barrier recovery nor reappearance
      of the calcium gradient at 5 h. In contrast, acutely disrupted, cold-exposed
      sites, covered with Gore-Tex, likewise displayed little barrier recovery, but the
      calcium gradient largely returned by 3 h. These results show that (i) barrier
      status regulates formation of the calcium gradient, and (ii) passive processes
      alone can account for the formation/maintenance of the calcium gradient.

PMID- 12485428
TI  - Deletion of a cytoplasmic domain of integrin beta4 causes epidermolysis bullosa
      simplex.
AB  - Integrin alpha6beta4 is a hemidesmosomal transmembrane molecule involved in
      maintaining basal cell-matrix adhesion through interaction of the large
      intracytoplasmic tail of the beta4 subunit with the keratin intermediate filament
      network, at least in part through its binding with plectin and BP180/type XVII
      collagen. Here we report a patient with predominant features of epidermolysis
      bullosa simplex due to a mutation in the integrin beta4 gene. The patient, a 49-y
      old female, had mild blistering of hands and feet from birth on, dystrophy of the
      nails with onychogryposis, and enamel hypoplasia. She had no alopecia and no
      history of pyloric atresia. Electron microscopy and antigen mapping of a skin
      blister revealed that the level of separation was intraepidermal, low in the
      basal keratinocytes through the attachment plaque of the hemidesmosome. Immuno
      fluorescence microscopy revealed absent binding of monoclonal antibody 450-11 A
      against the third fibronectin III repeat on the intracellular domain of integrin
      beta4, whereas binding was reduced with monoclonal antibodies recognizing
      epitopes on amino-terminal and carboxy-terminal ends of the polypeptide. At the
      molecular level the phenotype was caused by a novel 2 bp deletion 4733delCT in
      ITGB4, resulting in in-frame skipping of exon 36 and a deduced 50 amino acid
      deletion (1450-1499) within the third fibronectin type III repeat in the
      cytoplasmic domain of the integrin beta4 polypeptide. Immunoblot analysis
      demonstrated a 5 kDa shorter beta4 polypeptide. The 4733delCT mutation was
      heterozygously present in the DNA. The patient is also expected to be
      heterozygous for a null allele, as no full-size protein was detected in vitro and
      the epitope 450-11 A was absent in vivo. These data show that deletion of the
      third fibronectin type III repeat in the cytoplasmic domain of integrin beta4,
      which is thought to interact with BP180/type XVII collagen, is clinically
      pathogenic and results in a mild phenotype with predominant features of
      epidermolysis bullosa simplex.

PMID- 12485429
TI  - Activation of protein kinase C triggers irreversible cell cycle withdrawal in
      human keratinocytes.
AB  - Irreversible cell cycle withdrawal occurs as normal keratinocytes detach from the
      basement membrane and initiate their terminal differentiation program. To
      investigate which signaling pathways regulate this permanent cell cycle
      withdrawal, we added inhibitors of kinases implicated in integrin signaling and
      keratinocyte differentiation to normal human keratinocytes induced to
      differentiate in suspension culture, and assayed the growth capacity of the
      recovered cells. Keratinocytes suspended in methylcellulose for 24 h underwent
      approximately 1000-fold loss of proliferative capacity. Of the kinase inhibitors
      tested, only the protein kinase C inhibitor Bisindolylmaleimide I (GF109203X)
      caused dramatic protection from loss of growth potential. Direct activation of
      protein kinase C by 12-O-tetradecanoyl-phorbol-13-acetate was also sufficient to
      trigger irreversible growth arrest. Protein kinase C inhibitors selective for
      protein kinase Calpha, the only Ca2+-dependent protein kinase C isoform in
      keratinocytes, protected keratinocytes from suspension-induced cell cycle
      withdrawal. Consistent with this finding, we measured a specific induction of
      Ca2+-dependent protein kinase C activity 2-3 h after keratinocytes were placed
      into suspension culture. Furthermore, protein kinase Calpha was strongly
      localized to cell membranes in the suprabasal keratinocytes of human epidermis,
      suggesting translocation and activation in vivo. Coordinated changes in cell
      cycle regulators (p21, p27, pRb, p107, p130) consistent with cells exiting the
      cell cycle were observed in suspended keratinocytes, and these changes were
      blocked by protein kinase C inhibition. These results indicate that the loss of
      cell matrix adhesion triggers protein kinase C activation, which is an early
      event required for cell cycle withdrawal of terminally differentiating normal
      human keratinocytes.

PMID- 12485430
TI  - Substance P enhances the production of interferon-induced protein of 10 kDa by
      human keratinocytes in synergy with interferon-gamma.
AB  - A neuropeptide substance P is related to skin inflammation. Interferon-induced
      protein of 10 kDa (IP-10) chemoattracts T helper 1 cells, and interferon-induced
      protein of 10 kDa production by keratinocytes is enhanced in inflammatory skin
      diseases such as psoriasis. We examined the in vitro effects of substance P on
      interferon-induced protein of 10 kDa production by human keratinocytes. Though
      substance P alone did not induce interferon-induced protein of 10 kDa production,
      it enhanced interferon-induced protein of 10 kDa secretion, mRNA expression, and
      promoter activity induced by suboptimal concentrations of interferon-gamma.
      Interferon-stimulated response element and two nuclear factor-kappaB sites on
      interferon-induced protein of 10 kDa promoter were responsible for the
      enhancement by substance P. Substance P alone enhanced transcriptional activity
      and transcription factor binding through the two nuclear factor-kappaB sites,
      whereas it did not alter interferon-gamma-induced transcriptional activity and
      transcription factor binding through interferon-stimulated response element. The
      effects of substance P on interferon-induced protein of 10 kDa production and
      nuclear factor-kappaB activation were inhibited by neurokinin-1 receptor
      antagonist, phospholipase C inhibitor, intracellular Ca2+ chelator, and anti
      oxidant. These results suggest that substance P may induce nuclear factor-kappaB
      activation and interferon-induced protein of 10 kDa production in synergy with
      interferon-gamma via neurokinin-1 receptor on keratinocytes. These effects of
      substance P may be mediated via phospholipase C activation, intra-cellular Ca2+
      signal, and reactive oxygen intermediates.

PMID- 12485432
TI  - Increased migration of murine keratinocytes under hypoxia is mediated by
      induction of urokinase plasminogen activator.
AB  - One of the key consequences of cutaneous wounding is the development of tissue
      hypoxia. Recent data have suggested that this is a potent stimulus for increased
      keratinocyte migration and hence re-epithelialization, although the mechanisms
      responsible for this remain unclear. In this study we have investigated the
      relationship between hypoxia, plasminogen activation, and in vitro wound healing.
      Exposure of keratinocyte cultures to hypoxia resulted in upregulation of
      urokinase plasminogen activator mRNA and a subsequent increase in urokinase
      plasminogen activator-mediated plasminogen activation, as determined by indirect
      chromogenic peptide assay and plasminogen-linked zymography. Analysis of
      keratinocyte wound healing in vitro confirmed enhanced wound closure in hypoxic
      cultures compared with normoxic cultures after 16 h. Pretreatment of normoxic and
      hypoxic cultures with mitomycin C and cytochalasin B indicated that in this
      system wound closure was due to keratinocyte migration rather than proliferation.
      Addition of the broad-spectrum serine proteinase inhibitor, p-aminobenzamidine,
      or the specific urokinase plasminogen activator inhibitors, amiloride and WX-293,
      significantly reduced wound closure in hypoxic cultures and abrogated the hypoxic
      enhancement of wound closure. These data indicate a central role for urokinase
      plasminogen activators in hypoxic keratinocyte migration and suggest a potential
      mechanism for enhanced re-epithelialization of wounds under low oxygen tensions.

PMID- 12485431
TI  - Role of peroxisome proliferator-activated receptor alpha in epidermal development
      in utero.
AB  - The protective function of the skin is mediated by the stratum corneum, the
      outermost layer of the skin, which is the end-product of epidermal
      differentiation. Previously, we showed that fetal rat skin explants complete the
      late-stage milestones of epidermal development when grown in a serum- and growth
      factor-free medium, suggesting that endogenous metabolites could regulate the
      late program that leads to barrier formation. Because a variety of endogenous
      free fatty acids are known activators, peroxisome proliferator-activated receptor
      alpha (PPAR-alpha) is a potential candidate for this key regulatory role. Indeed,
      whereas PPAR-alpha expression is first noted at gestational day 13.5 and peaks
      between days 14.5 and 15.5, fatty acid synthesis is very active in fetal rodent
      epidermis peaking at gestational day 17. Furthermore, we have reported that both
      epidermal differentiation and stratum corneum formation in utero are stimulated
      by pharmacologic activation of PPAR-alpha. This study was designed to test
      whether PPAR-alpha plays a physiologic role in epidermal differentiation and
      stratum corneum formation in utero. In PPAR-alpha-/- mice we observed delayed
      stratum corneum formation between day 18.5 of gestation and birth. Concurrently,
      there was diminished beta-glucocerebrosidase activity at the stratum granulosum
      stratum corneum junction and a modest decrease in both involucrin and loricrin
      protein expression, markers of keratinocyte differentiation. Both the number of
      stratum corneum cell layers was reduced and the processing of the lamellar
      bilayers was delayed in animals lacking PPAR-alpha, indicating a transient
      functional defect. In contrast, the lamellar body secretory system as well as
      rates of epidermal proliferation and cell death appeared normal in PPAR-alpha-/-
      mice. These results indicate that PPAR-alpha plays a physiologic role during
      fetal stratum corneum development. The transient and incomplete nature of the
      developmental delay, however, is consistent with regulation of the late stages of
      epidermal development by multiple factors.

PMID- 12485433
TI  - Label-retaining cells in the bulge region are directed to cell death after
      plucking, followed by healing from the surviving hair germ.
AB  - Hair plucking is the most frequently used method of anagen induction within hair
      follicles. In this study, we found that plucking leads to the entire renewal of
      the follicular stem cell region of the mouse pelage follicle. Comparative
      histochemical analysis revealed that S100A4 protein was specifically distributed
      in the outer layer of the epithelial sac, which has been identified as the stem
      cell region of the pelage follicle, whereas the slow cycling cells that retained
      5-bromo-2'-deoxyuridine label for 8 wk were located in the epithelial sac and
      also in the hair germ. Combined terminal deoxynucleotide transferase deoxyuridine
      triphosphate fluorescein nick end labeling method and immunohistochemistry
      revealed that positive cells were detected in the outer layer of the epithelial
      sac possessing both bromo-2'-deoxyuridine and S100A4 labels 4.5 h after plucking.
      No terminal deoxynucleotide transferase deoxyuridine triphosphate fluorescein
      nick end labeling signal, however, was observed in the hair germ. Serial
      inspection of the plucked follicle revealed that almost all regions of the
      epithelial sac became terminal deoxynucleotide transferase deoxyuridine
      triphosphate fluorescein nick end labeling positive 12 h after plucking. Terminal
      deoxynucleotide transferase deoxyuridine triphosphate fluorescein nick end
      labeling-positive cells ultimately degenerated without forming apoptotic bodies.
      Subsequently, the surviving label-retaining cells in the hair germ migrated
      upward to re-epithelialize the damaged portion. These results indicate that
      follicular stem cells in the epithelial sac underwent cell death after plucking.
      It is likely that the hair germ is responsible for the reconstruction of the stem
      cell region of the hair follicle.

PMID- 12485434
TI  - The influence of genetics and environmental factors in the pathogenesis of acne:
      a twin study of acne in women.
AB  - Acne is common and often leads to significant psychologic and physical morbidity.
      From clinical experience, acne appears to run in families; however, very few
      studies have investigated the genetic basis of this very common skin disease. A
      large twin study based on 458 pairs of monozygotic and 1099 pairs of dizygotic
      twins, all women with a mean age of 46 y was performed to investigate the
      relative contribution of genetic and environmental factors on the liability to
      acne. In addition, potential risk factors were assessed in twins with and without
      acne in a nested cross-sectional design. Fourteen percent of the twins reported a
      history of acne. Genetic modeling using acne scores showed that 81% (95%
      confidence interval 73-87%) of the variance of the disease was attributable to
      additive genetic effects. The remaining 19% was attributed to unique (i.e.,
      unshared) environmental factors. Of the potential risk factors tested in 400 acne
      twins and 2414 unaffected twins, only apolipoprotein A1 serum levels were
      significantly lower in acne twins even after adjusting for age and weight. Family
      history of acne was also significantly associated with an increased risk. No
      significant differences were found between acne twins and nonacne twins for
      weight, body mass index, height, birth weight, hair thinning, reproductive
      factors as well as cholesterol, triglycerides, high-density lipoprotein, and
      glucose levels. The lower serum levels of apolipoprotein A1 in acne twins were
      also confirmed when analyzing acne discordant twin pairs. The evidence of a major
      genetic influence on acne should stimulate the search for potential genes that
      may lead to new therapeutic approaches.

PMID- 12485435
TI  - Infrared-A radiation-induced matrix metalloproteinase 1 expression is mediated
      through extracellular signal-regulated kinase 1/2 activation in human dermal
      fibroblasts.
AB  - In addition to ultraviolet radiation, human skin is exposed to infrared radiation
      from natural sunlight as well as artificial ultraviolet and infrared irradiation
      devices used for therapeutic or cosmetic purposes. The molecular consequences
      resulting from infrared exposure are virtually unknown. In this study we have
      investigated whether infrared has the capacity to affect gene expression in human
      skin cells. Exposure of cultured human dermal fibroblasts to infrared in the
      range of 760-1400 nm (infrared-A) induced the expression of matrix
      metalloproteinase 1 at the mRNA and protein level in a time- and concentration
      dependent manner. Expression of tissue inhibitor of matrix metalloproteinase 1
      remained unaltered. These effects were not mediated by the generation of heat by
      infrared-A. Furthermore, infrared-A did not induce heat shock protein 70
      expression in human dermal fibroblasts under conditions that increased matrix
      metalloproteinase 1 expression. Here we provide evidence that infrared-A
      activated mitogen-activated protein kinase pathways. Extracellular signal
      regulated kinase 1/2 and p38-mitogen-activated protein kinase were rapidly
      activated after infrared-A exposure. The mitogen-activated protein
      kinase/extracellular signal-regulated kinase inhibitor PD 98059, which
      specifically blocked the extracellular signal-regulated kinase pathway, prevented
      infrared-A-induced matrix metalloproteinase 1 expression. Upregulation of matrix
      metalloproteinase 1 expression by infrared-A was thus shown to be dependent on
      extracellular signal-regulated kinase 1/2 activation. In conclusion, this study
      demonstrates that infrared-A is capable of inducing matrix metalloproteinase 1
      expression in human dermal fibroblasts via activation of the extracellular signal
      regulated kinase 1/2 signaling pathway. This previously unrecognized property of
      infrared-A points to its possible role in the photoaging of human skin.

PMID- 12485436
TI  - Modulation of microphthalmia-associated transcription factor gene expression
      alters skin pigmentation.
AB  - The microphthalmia-associated transcription factor is implicated in melanocyte
      development and in the regulation of melanogenesis. Microphthalmia-associated
      transcription factor is thought to bind to the M-box promoter elements of
      tyrosinase, tyrosinase-related protein-1 and dopachrome tautomerase/tyrosinase
      related protein-2 and transactivate these genes, resulting in increased
      pigmentation. Using a luciferase reporter construct driven by the microphthalmia
      associated transcription factor promoter, we identified agents that modulate
      microphthalmia-associated transcription factor promoter activity. Changes in
      endogenous microphthalmia-associated transcription factor expression levels upon
      treatment with these agents were confirmed using northern and western blots, and
      their pigmentary modulating activities were demonstrated. Ultraviolet B
      irradiation and traditional Chinese medicine-1, a natural extract used in
      traditional Chinese medicine, upregulated microphthalmia-associated transcription
      factor gene expression and enhanced tyrosinase activity in vitro. Dihydrolipoic
      acid, lipoic acid, and resveratrol reduced microphthalmia-associated
      transcription factor and tyrosinase promoter activities. These agents also
      inhibited the forskolin- and ultraviolet B-stimulated promoter activities of
      these genes and significantly reduced tyrosinase activity in melanocyte cultures,
      resulting in depigmentation. Overexpressed microphthalmia-associated
      transcription factor was capable of rescuing the repressive effects of these
      compounds on the cotransfected tyrosinase promoter. Dark-skinned Yucatan swine
      treated with these agents showed visible skin lightening, which was confirmed
      histologically, whereas ultraviolet B-induced tanning of light-skinned swine was
      inhibited using these agents. Our findings suggest that modulation of
      microphthalmia-associated transcription factor expression can alter skin
      pigmentation and further confirm the central role of microphthalmia-associated
      transcription factor in melanogenesis.

PMID- 12485437
TI  - Stimulation of melanoblast pigmentation by 8-methoxypsoralen:the involvement of
      microphthalmia-associated transcription factor, the protein kinase a signal
      pathway, and proteasome-mediated degradation.
AB  - In this study, we used melb-a melanoblasts as a model to study mechanisms
      involved in stimulating melanocyte function in vitiliginous skin following
      exposure to 8-methoxypsoralen (8MOP). Melanin content and tyrosinase activity
      increased 3- and 7-fold, respectively, in melanoblasts treated with 8MOP for 6 d
      compared with untreated controls. The intracellular signal pathways involved in
      8MOP-induced effects on melanoblasts were investigated, particularly the roles of
      protein kinase A and protein kinase C. Forskolin, a protein kinase A activator,
      mimicked and enhanced the 8MOP stimulation of melanoblast pigmentation whereas a
      protein kinase C activator, 1-oleoyl-2-acetylglycerol, had no effect, indicating
      that the protein kinase A pathway is involved rather than the protein kinase C
      pathway. Those observations were confirmed using inhibitors of the protein kinase
      A or protein kinase C pathways. Western blot and semiquantitative reverse
      transcriptase polymerase chain reaction were performed to assess the protein and
      mRNA expression levels of microphthalmia-associated transcription factor and
      tyrosinase in melanoblasts treated with 8MOP for 3 h, 6 h, 1 d, 3 d, or 6 d.
      Incubation with 8MOP stimulated microphthalmia-associated transcription factor
      protein and mRNA levels within 3 h, but, in contrast, tyrosinase mRNA and protein
      levels did not increase following 8MOP treatment until 1 d after treatment. The
      proteasome inhibitor lactacystin blocked the proteasome-mediated proteolysis of
      tyrosinase, and its effect on proteasomal function was enhanced by 8MOP. Taken
      together, these results show that 8MOP functions by initially stimulating levels
      of microphthalmia-associated transcription factor expression via activation of
      the protein kinase A pathway, which thereby stimulates tyrosinase expression and
      function and eventually leads to dramatic increases in melanin production by
      melanoblasts.

PMID- 12485438
TI  - Cell cycle deregulation and xeroderma pigmentosum group C cell transformation.
AB  - We previously described a genetically unstable human fibroblast cell strain
      (GM2995), isolated from normal appearing skin of a xeroderma pigmentosum group C
      patient that repeatedly underwent changes characteristic of the transformed
      phenotype upon serial cultivation in vitro. In order to gain information
      concerning genetic changes associated with the transformation of this xeroderma
      pigmentosum group C cell strain, we examined the expression/function of several
      cell cycle regulators during its serial cultivation. A mutation in exon 8 of the
      P53 gene was associated with loss of function of the p53 protein and appeared at
      about the same time that transformation occurred. Abnormal P53 function was
      confirmed by the lack of upregulation of p53 as well as activation of its
      downstream effectors p21Waf1 and HDM2 in high passage cells exposed to either
      gamma irradiation or ultraviolet C irradiation. Consistent with deregulation in
      cell cycle control, persistent hyper-phosphorylation of the retinoblastoma
      protein and lack of a decrease in p34cdc2 were observed in irradiated cells.
      Furthermore, retinoblastoma protein remained hyperphosphorylated in control high
      passage confluent cultures that were serum starved for 72 h. Compared with low
      passage cells, the expression levels of the cyclin-dependent kinase inhibitor
      p27Kip1 were significantly reduced and the pattern of expression of the von
      Hippel-Lindau protein was aberrant. These data indicate that the process of
      cellular transformation of this xeroderma pigmentosum group C cell strain
      involves the progressive acquisition of mutations and abnormalities in the
      expression/function of several cell cycle regulators.

PMID- 12485439
TI  - Germline and somatic mutations of the INK4a-ARF gene in a xeroderma pigmentosum
      group C patient.
AB  - Xeroderma pigmentosum is an inheritable autosomal recessive DNA repair deficient
      syndrome characterized by a high predisposition to skin cancers. An elevated
      proportion of tumors from xeroderma pigmentosum patients harbor ultraviolet
      induced mutations (CC:GG > TT:AA tandem transitions) of the p53 and/or the INK4a
      ARF genes. Here, we report the clinical and molecular features of a 12 y old
      xeroderma pigmentosum patient who, in addition to severe cutaneous clinical
      symptoms, also had three unusual tumors, a mediastinal lymphoblastic lymphoma, an
      atypical fibroxanthoma, and an epithelioid hemangioma. Single strand conformation
      polymorphism and sequencing analysis of the p53 and INK4a-ARF genes were carried
      out in DNA from normal skin and different tumors (four actinic keratosis, two
      microinvasive squamous cell carcinomas, one basal cell carcinoma, and one
      atypical fibroxanthoma) from the patient. After characterization of the xeroderma
      pigmentosum C complementation group, we found unexpectedly that this patient also
      carried a germline mutation of the INK4a-ARF locus affecting the p16INK4A reading
      frame. Three different somatic mutations that all harbor the signature of
      ultraviolet light (two of p16INK4A and one of p53) were also detected in the
      basal cell carcinoma. We hypothesize that the germline mutation of p16INK4A, in
      association with the nucleotide excision repair defect, could explain the
      patient's unusual phenotype. Furthermore, this study confirms that concomitant
      somatic mutations of INK4a-ARF and p53 occur in some xeroderma pigmentosum
      associated tumors, and seem to accumulate during tumor progression rather than
      the initiation step.

PMID- 12485440
TI  - Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel
      candidate region at 4q31 by genome-wide scan in Chinese hans.
AB  - Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility
      loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p,
      respectively. To investigate the psoriasis susceptibility loci in Chinese Hans, a
      genome-wide scan was performed with two-point and multipoint parametric and
      nonparametric linkage analyses in 61 multiplex families. These families were
      Chinese Hans residing in east and south-east China, comprising 189 affected and
      166 unaffected individuals. We detected evidence for linkage at 6p21 (PSORS1)
      with nonparametric linkage scores > 3 in the range of 39.9-62.3 cM and a maximum
      multipoint nonparametric linkage score of 4.58 (p=0.000032). Parametric analysis
      revealed a maximum two-point heterogeneity lod score of 4.30 with 58% as the
      proportion of linked families (alpha) and a maximum multipoint heterogeneity lod
      score of 4.25 (alpha=53%) under the assumption of a dominant model. We could not
      confirm a previous reported locus (PSORS3) on distal chromosome 4q; however, a
      region of highly suggestive linkage was identified proximal to this proposed
      locus. Multipoint nonparametric analysis demonstrated nonparametric linkage
      scores > 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a
      maximum peak of 3.69 (p=0.00033) at 157.9 cM, which locates D4S413. A maximum
      multipoint heterogeneity lod score of 2.31 (alpha=46%) was reached at 163.1 cM.
      With two-point parametric linkage analysis, we observed the highest lod score of
      2.43 and heterogeneity lod score of 3.94 (alpha=77%) at marker D4S1597. Our
      results showed that chromosomes 6p and 4q may contain genes involved in the
      susceptibility to psoriasis vulgaris in a Chinese Han population. Other regions
      with weaker evidence for linkage could also hide minor susceptibility genes.

PMID- 12485441
TI  - Keratoacanthomas frequently show chromosomal aberrations as assessed by
      comparative genomic hybridization.
AB  - Keratoacanthomas are commonly occurring benign skin lesions localized to sun
      exposed areas. They typically develop rapidly and may show cellular atypia and
      infiltration like cutaneous squamous cell carcinomas, but they finally regress
      spontaneously. This benign lesion shows a high degree of genetic instability as
      assessed by comparative genomic hybridization, with 35.7% (25 of 70) of the
      analyzed lesions harboring chromosomal aberrations. The same frequency of genetic
      imbalance was found in lesions from immunosuppressed organ transplant recipients
      (36.4%, 20 of 55) and in patients with keratoacanthomas without immunosuppression
      (33.3%, five of 15), indicating a common pathway in both situations. Recurrent
      aberrations, given as a fraction of lesions with aberrations, were gains on 8q
      (20.0%), 1p and 9q (each 16.0%), and deletions on 3p (20.0%), 9p (20.0%), 19p
      (20.0%), and 19q (16.0%). Many of the most frequently appearing aberrations in
      keratoacanthomas were not detected in any of the 10 squamous cell carcinomas
      analyzed, whereas some aberrations were shared by both types of lesions.
      Aberrations were found in early and late stages of keratoacanthoma development,
      indicating a role for genetic instability in the progression as well as
      involution of keratoacanthomas. There were no significant correlations between
      cytologic atypia and genetic imbalance, or between degree of infiltration and
      genetic aberrations, although there was a trend for keratoacanthomas with severe
      atypia to have aberrations. Thus malignant phenotypic development does not appear
      to be driven by the detected genetic aberrations. More detailed studies of
      chromosomal areas with recurrent aberrations are needed for the localization of
      putative genes that determine the biologic behavior of keratoacanthomas, and that
      may distinguish them from squamous cell carcinomas.

PMID- 12485442
TI  - The GSTM1 null genotype confers an increased risk for solar keratosis development
      in an Australian Caucasian population.
AB  - Solar keratoses affect approximately 50% of Australian Caucasians aged over 40 y.
      Solar keratoses can undergo malignant transformation into squamous cell carcinoma
      followed by possible metastasis and are risk factors for basal cell carcinoma,
      melanoma, and squamous cell carcinoma. The glutathione-S-transferase genes play a
      part in detoxification of carcinogens and mutagens, including some produced by
      ultraviolet radiation. This study examined the role of glutathione-S-transferase
      M1, T1, P1, and Z1 gene polymorphisms in susceptibility to solar keratoses
      development. Using DNA samples from volunteers involved in the Nambour Skin
      Cancer Prevention Trial, allele and genotype frequencies were determined using
      polymerase chain reaction and restriction enzyme digestion. No significant
      differences were detected in glutathione-S-transferase P1 and glutathione-S
      transferase Z1 allele or genotype frequencies; however, a significant association
      between glutathione-S-transferase M1 genotypes and solar keratoses development
      was detected (p=0.003) with null individuals having an approximate 2-fold
      increase in risk for solar keratoses development (odds ratio: 2.1; confidence
      interval: 1.3-3.5) and a significantly higher increase in risk in conjunction
      with high outdoor exposure (odds ratio: 3.4; confidence interval: 1.9-6.3). Also,
      a difference in glutathione-S-transferase T1 genotype frequencies was detected
      (p=0.039), although considering that multiple testing was undertaken, this was
      found not to be significant. Fair skin and inability to tan were found to be
      highly significant risk factors for solar keratoses development with odds ratios
      of 18.5 (confidence interval: 5.7-59.9) and 7.4 (confidence interval: 2.6-21.0),
      respectively. Overall, glutathione-S-transferase M1 conferred a significant
      increase in risk of solar keratoses development, particularly in the presence of
      high outdoor exposure and synergistically with known phenotypic risk factors of
      fair skin and inability to tan.

PMID- 12485443
TI  - Endothelial dysfunction in murine model of systemic sclerosis: tight-skin mice 1.
AB  - We conducted this study to analyze endothelial cell function within intact
      thoracic aorta of the systemic sclerosis murine model, the heterozygous tight
      skin mice 1: (i) assessing the distribution and activation intensity of
      endothelial cells, responsive to endothelium-dependent vasodilators
      (acetylcholine, adenosine triphosphate, bradykinin, and substance P) and
      Iloprost, using laser line confocal microscopy in combination with two Ca2+
      fluorescent dyes; (ii) evaluating en-dothelium-dependent vasodilator- and
      Iloprostinduced relaxation, using isometric tension measurement; and (iii)
      investigating the role of nitric oxide in mediating relaxation to acetylcholine
      and adenosine triphosphate. The number of activated endothelial cells was
      significantly lower in heterozygous tight-skin mice 1, compared with controls,
      for adenosine triphosphate and Iloprost. Maximal increase of Ca2+ fluorescence
      intensity ratio in activated endothelial cells was decreased for adenosine
      triphosphate, bradykinin, and Iloprost, in heterozygous tight-skin mice 1.
      Adenosine triphosphate- and Iloprost-mediated aortic relaxation was further
      impaired in heterozygous tight-skin mice 1. Finally, aortic relaxation to
      acetylcholine and adenosine triphosphate was markedly decreased by nitric oxide
      synthase inhibitor in heterozygous tight-skin mice 1. This study suggests that
      endothelial cell receptors for endothelium-dependent vasodilators and Iloprost
      may not be homogeneously distributed or continuously expressed in thoracic aorta
      of heterozygous tight-skin mice 1, resulting in endothelium-dependent
      vasodilatation dysfunction. Moreover, because endothelium-dependent relaxation
      was highly dependent on nitric oxide release in heterozygous tight-skin mice 1,
      endothelium-dependent relaxation may differ from that of controls by increased
      production of nitric oxide. In turn, in heterozygous tight-skin mice 1, the
      resulting elevated nitric oxide levels may contribute to nitric oxide-mediated
      free radical endothelial cytotoxicity, although endothelium impairment may be
      related to other factors, particularly: Fbn-1 gene mutation and transforming
      growth factor-beta.

PMID- 12485444
TI  - Expression of endomucin, a novel endothelial sialomucin, in normal and diseased
      human skin.
AB  - Endomucin is an endothelial sialomucin that was recently identified with the help
      of monoclonal antibodies raised against mouse endothelial cells. Cloning of human
      endomucin allowed us to generate monoclonal antibodies against soluble
      recombinant forms of human endomucin. In this study, we investigated the
      expression of this novel molecule in human skin under different conditions, using
      the monoclonal antibodies. In normal human skin, endomucin was detected for the
      monoclonal antibody L6H10 by immunoblotting, and immunohistologic analysis of wax
      embedded sections revealed that this glycoprotein is expressed on capillaries,
      venules, and lymphatic vessels. Interestingly, staining of arterial endothelium
      was either weak or focal using the monoclonal antibodies against endomucin. In
      situ hybridization of normal human skin confirmed the expression pattern on the
      messenger RNA level obtained above. We further analyzed the expression of
      endomucin in skin biopsy specimens from patients with inflammatory skin diseases,
      such as atopic dermatitis, psoriasis, lichen planus, cutaneous lupus
      erythematosus, and T cell lymphoma as well as with vascular skin tumors, such as
      hemangioma, pyogenic granuloma, angiolipoma, Kaposi's sarcoma, and angiosarcoma.
      We found endomucin expressed on the endothelium of each tissue, concluding that
      this novel molecule is a new endothelial-specific marker in the study of normal
      and diseased human skin.

PMID- 12485445
TI  - Mannose binding lectin (MBL) polymorphisms associated with low MBL production in
      patients with dermatomyositis.
AB  - One theory for the pathophysiology of photosensitive autoimmune skin diseases is
      that photoinduction of tumor necrosis factor alpha (TNFalpha) secretion leads to
      keratinocyte apoptosis and translocation of previously sequestered cellular
      antigens that then activate the immune system. We previously found an association
      of the overproducing TNFalpha-308 A variant with adult dermatomyositis and with
      subacute cutaneous lupus erythematosus. Here we focused on mannose binding lectin
      (MBL), which is one of several proteins involved in clearance of apoptotic cells
      and could thereby lessen photosensitive autoimmunity. We examined three variant
      MBL polymorphisms associated with decreased MBL protein (Asp54, Glu57, and the LX
      promoter polymorphism) in adult dermatomyositis, subacute cutaneous lupus
      erythematosus, and discoid lupus, and controls. The variant Asp54 allele was
      positively associated with adult dermatomyositis in a dose-responsive fashion
      (p=0.0004), as was the Glu57 allele (p=0.004). None of the three variant MBL
      alleles considered individually was significantly associated with either subacute
      cutaneous lupus erythematosus or discoid lupus. In adult dermatomyositis patients
      homozygous for the wild-type TNFalpha-308G allele (GG), i.e., presumably without
      elevated TNFalpha production, 69% had at least two of the MBL polymorphisms,
      versus 20% of healthy GG controls (p=0.0011). Combinations of low-producing MBL
      variants were over-represented in adult dermatomyositis in a dose-responsive
      fashion (p=0.0002). In adult dermatomyositis patients with one variant TNFalpha
      308 A allele (GA), 46% had at least two MBL polymorphisms, versus 7% of GA
      controls (p=0.0077). Thus, low-producing MBL genes are very strongly associated
      with adult dermatomyositis. Our model is that genetic polymorphisms leading to
      overproduction of apoptotic keratinocytes and then impaired clearance of these
      cells contribute to the pathogenesis of adult dermatomyositis, a photoinduced
      autoimmune skin disease.

PMID- 12485446
TI  - Neutral endopeptidase activity is increased in the skin of subjects with diabetic
      ulcers.
AB  - Cutaneous sensory nerves mediate inflammation and wound healing by releasing
      neuropeptides, such as substance P, which stimulates pro-inflammatory responses
      by keratinocytes, fibroblasts, and endothelial cells. The cell surface enzyme,
      neutral endopeptidase, degrades substance P, thereby regulating its biologic
      actions. We hypothesized that neutral endopeptidase enzymatic activity is
      increased in chronic wounds and skin from subjects with diabetes. We compared
      cutaneous neutral endopeptidase expression and enzymatic activity between normal
      controls and diabetic subjects with neuropathy and chronic wounds. Skin samples
      from subjects with diabetes were taken at the time of amputation for nonhealing
      ulcers. Skin taken from the ulcer margin, 1 cm from the ulcer (adjacent), and
      from the most proximal region of the amputated leg were studied. Skin biopsies
      from the leg of healthy control subjects were also studied. Neutral endopeptidase
      was localized by immunohistochemistry in all tissue sections. Neutral
      endopeptidase activity was measured using a fluorimetric assay. The median
      neutral endopeptidase activity of the ulcer margin was 1.21 x higher (p>0.2) than
      adjacent skin, 5.26 (p<0.001) than proximal skin, and 15.22 x higher (p<0.001)
      than control skin. Adjacent skin had a median neutral endopeptidase activity 4.34
      x higher (p<0.001) than proximal skin and 12.58 x higher (p<0.001) than control
      skin. The median neutral endopeptidase activity of proximal skin was 2.90 x
      higher (p<0.001) than control skin. This elevated neutral endopeptidase activity
      in the skin and chronic ulcers of subjects with diabetes combined with peripheral
      neuropathy may contribute to deficient neuroinflammatory signaling and may impair
      wound healing in subjects with diabetes.

PMID- 12485447
TI  - Increased CCR4 expression in cutaneous T cell lymphoma.
AB  - Chemokines are critical molecules in leukocyte trafficking, promoting site
      specific migration to various tissues. The chemokine receptor CCR4 has recently
      been associated with skin-homing T cells. In view of the potential importance of
      CCR4 in skin homing of T cells, we investigated the expression pattern of CCR4
      and its ligands TARC/CCL17 and MDC/CCL22 in the peripheral blood and skin of
      patients with cutaneous T cell lymphoma, a putative malignancy of the skin-homing
      T cells. In this study we analyzed the pattern of coexpression of the skin-homing
      molecules cutaneous lymphocyte antigen (CLA) and CCR4 in the blood and skin of
      patients with cutaneous T cell lymphoma. In the blood of cutaneous T cell
      lymphoma patients with peripheral blood involvement we found significantly
      increased percentages of T cells displaying the skin-homing phenotype (CLA+CCR4+)
      compared with healthy individuals. T cells expressing CLA and CCR4 were also
      found at high levels in cutaneous T cell lymphoma lesions along with abundant
      expression of the two CCR4 ligands TARC/CCL17 and MDC/CCL22. These data may
      explain, in part, why these T cells accumulate in the skin, a diagnostic feature
      of cutaneous T cell lymphomas.

PMID- 12485449
TI  - Surrogate endpoints for the treatment of venous leg ulcers.
AB  - Surrogate markers are endpoints that occur early in the course of treatment and
      are intended to predict the true, meaningful clinical endpoint. Surrogate markers
      have been used to study treatments for a wide range of diseases in which the true
      outcome is delayed. The evaluation of therapies for venous leg ulcers is
      challenged by the prolonged observation period necessary to reach the endpoint of
      healing. We have performed a large cohort study to examine wound healing
      characteristics as candidate surrogate markers of venous leg ulcer healing using
      the Curative Health Services population. A total of 58,038 wounds met our
      definition of venous leg ulcer; however, 1550 wounds were excluded based on size,
      depth, site, and/or involvement of tendon or bone, leaving 56,488 wounds in
      29,189 patients for analysis. The median wound size was 189 mm2, with a median
      wound duration of 3 mo. Using a large cohort of diverse venous leg ulcer
      patients, we demonstrate that after only 4 wk of treatment the wound parameters
      log healing rate, log wound area ratio, and percentage change in wound area can
      be valid surrogate markers of healing at 12 or 24 wk of care. Based on the area
      under the receiver operator characteristic curve log rate, log area ratio, and
      percentage change in area can discriminate which patients will heal at 12 or 24
      wk of care (receiver operator characteristic 0.72-0.80). These surrogates were
      further validated by demonstrating that established risk factors for not healing
      such as wound size and wound duration are also important risk factors for not
      achieving the surrogate endpoint. These surrogate markers for venous leg ulcer
      healing may allow for early clinical trials to be more efficient, and can allow
      clinicians to identify patients unlikely to heal early in the course of treatment
      in order to expedite referral to specialty centers or for the selection of
      stepped treatment algorithms.

PMID- 12485448
TI  - Histamine inhibits the production of interferon-induced protein of 10 kDa in
      human squamous cell carcinoma and melanoma.
AB  - Interferon-induced protein of (IP-10) inhibits tumor progression. Tumor cells can
      produce interferon-induced protein of IP-10 in response to interferon-g.
      Histamine in the vicinity of tumor cells may sustain the tumor progression. We
      examined the in vitro effects of histamine on interferon-induced protein of IP-10
      production in human squamous cell carcinoma and melanoma. Histamine suppressed
      interferon-g-mediated interferon-induced protein of IP-10 secretion and mRNA
      expression in SV40-transformed keratinocytes, SCC15, SCC4, and melanoma WM115,
      WM266-4, and C32. Histamine suppressed interferon-g-induced interferon-mediated
      protein of IP-10 promoter activation in these cells, and the interferon
      stimulated response element on the promoter was responsible for the suppression.
      Histamine suppressed interferon-g-mediated transcription through the interferon
      stimulated response element and signal transducer and activator of transcription
      1alpha binding to the interferon-stimulated response element. Histamine
      suppressed interferon-g-induced tyrosine phosphorylation of the signal transducer
      and activator of transcription 1alpha, Janus tyrosine kinase 1, and Janus
      tyrosine kinase 2. Histamine-mediated suppression on the interferon-g-induced
      interferon-mediated protein of IP-10 synthesis was counteracted by the H2
      receptor antagonist cimetidine, adenylate cyclase inhibitor SQ22536, and protein
      kinase A inhibitor H-89, but were not affected by H1 receptor antagonist
      mepyramine. Cimetidine, SQ22536, and H-89 also counteracted histamine-mediated
      suppression on the interferon-g-induced transcription through the interferon
      stimulated response element, signal transducer and activator of transcription
      1alpha binding to the interferon-stimulated response element, and tyrosine
      phosphorylation of the signal transducer and activator of transcription 1alpha,
      Janus tyrosine kinase 1, and Janus tyrosine kinase 2. Histamine increased
      intracellular 3',5'-adenosine cyclic monophosphate level and protein kinase A
      activity in squamous cell carcinoma and melanoma, and the effects of histamine
      were blocked by cimetidine. These results suggest that histamine may interact
      with H2 receptor on squamous cell carcinoma and melanoma and generate 3',5'
      adenosine cyclic monophosphate, which may activate protein kinase A. The cyclic
      3',5'-adenosine monophosphate/protein kinase A signaling pathway induced by
      histamine may inhibit interferon-g-induced signal transducer and activator of
      transcription 1alpha activation and suppress interferon-induced protein of IP-10
      synthesis.

PMID- 12485450
TI  - Resistance to alopecia areata in C3H/HeJ mice is associated with increased
      expression of regulatory cytokines and a failure to recruit CD4+ and CD8+ cells.
AB  - Grafting alopecia areata affected C3H/HeJ mouse skin to littermates induces
      alopecia areata, but high dietary soy oil reduces alopecia areata susceptibility.
      Alopecia areata affected and resistant mice were characterized to evaluate
      possible mechanisms involved in alopecia areata resistance. Of 44 mice that
      received alopecia areata affected skin grafts but failed to develop alopecia
      areata, only two of 22 receiving further alopecia areata affected skin grafts
      developed alopecia areata, whereas 39 of 44 controls developed alopecia areata.
      Alopecia areata affected skin contained increased numbers of CD4+ and CD8+ cells,
      increases in pro inflammatory T helper 1 and T helper 2 type cytokines, and
      upregulation of CD28, CD40L, and their ligands. In draining lymph nodes, a
      relatively high number of antigen-presenting cells was recovered, whereas several
      CD44v variants were downregulated. In contrast, alopecia areata resistant mouse
      skin did not display increased numbers of CD4+ and CD8+ cells, whereas counter
      regulatory cytokines interleukins 4 and 10 were upregulated. High expression of
      CD28, CD80, CD86, CD40, CTLA4, CD44v variants, and FasL occurred in alopecia
      areata resistant mouse spleens. In vitro, lymph node cells of susceptible and
      resistant mice responded equally to a mitogenic stimulus, but only lymph node
      cells from alopecia areata affected mice displayed an increased response with T
      cell receptor stimulation via anti-CD3 cross-linking. These results suggest
      alopecia areata is a cell-mediated autoimmune disease, but alopecia areata
      affected skin graft hosts may resist alopecia areata onset through active counter
      regulatory mechanisms. Because alopecia areata resistant mice showed unimpaired
      responsiveness and a transient inflammatory response towards the graft, it is
      suggested that alopecia areata develops as a consequence of an inappropriate
      immune response regulation.

PMID- 12485451
TI  - A novel immunosuppressive 1alpha,25-dihydroxyvitamin D3 analog with reduced
      hypercalcemic activity.
AB  - 1Alpha,25-dihydroxyvitamin D3, the biologically active form of vitamin D3, is a
      potent immunomodulatory molecule; however, its clinical use as an
      immunosuppressant is limited due to its strong effects on calcium homeostasis and
      the risk of associated side-effects. Here, we present a representative of a novel
      class of vitamin D analogs that exhibits potent immunosuppressive activity in a
      murine model of contact hypersensitivity when applied systemically and is
      efficacious also at nonhypercalcemic dosages. In vitro analysis revealed a
      binding affinity of ZK 191784 to the vitamin D receptor comparable with 1,25
      dihydroxyvitamin D3. This compound inhibits lymphocyte proliferation and
      secretion of tumor necrosis factor alpha and interleukin-12 in monocytes in a
      concentration-dependent manner, but with reduced potency and efficacy than 1,25
      dihydroxy-vitamin D3. Treatment of human monocytes with this analog significantly
      reduces expression of major histocompatibility complex class II, B7.1, and
      intercellular adhesion molecule-1 equipotent to 1,25-dihydroxyvitamin D3.
      Interestingly, the compound failed to induce vitamin D-induced differentiation of
      human promyelocytic leukemia cell line HL-60 to monocytes and was capable of
      antagonizing the action of 1,25-dihydroxyvitamin D3. In vivo, as analyzed in mice
      the compound potently inhibits the contact hypersensitivity when applied
      systemically. ZK 191784 has a clear therapeutic advantage over 1,25
      dihydroxyvitamin D3 by inducing immunosuppressive effects also at concentrations
      that do not cause hypercalcemia. ZK 191784 is the first representative of a novel
      class of vitamin D analogs that might have therapeutic potential in T cell
      mediated immune disorders.

PMID- 12485452
TI  - Aggregation of antigen-specific T cells at the inoculation site of mature
      dendritic cells.
AB  - Cellular immune responses are initiated by direct interaction of naive T cells
      with professional antigen-presenting cells, i.e., dendritic cells. In general,
      this interaction takes place in secondary lymphoid organs to which both naive T
      cells and mature dendritic cells preferentially home. This physiologic scenario
      differs substantially, however, from therapeutic dendritic-cell-based
      vaccinations used to treat human cancer. In fact, only a small fraction of
      intradermally injected dendritic cells migrate to the draining lymph node and the
      majority of cells remain at the site of inoculation. These sites are
      characterized by a distinct oligoclonal T cell infiltrate comprising both L
      Selectin+/CD45RA+ and L-Selectin+/CD45RA- cells. Blood vessels expressing
      peripheral lymph node addressin represent possible entry channels for such naive
      and central memory T cells, the former probably attracted by dendritic cell-CK1
      produced by the injected dendritic cells. In situ staining with multimeric
      peptide/major histocompatibility complex class I complexes revealed that
      infiltrating T cells specifically recognize peptide epitopes presented by the
      injected dendritic cells. Thus, the fraction of dendritic cells not migrating to
      secondary lymphatic tissue after therapeutic inoculation nevertheless seem to be
      involved in a specific immune modulation.

PMID- 12485454
TI  - Genotype-phenotype correlation in italian patients with dystrophic epidermolysis
      bullosa.
AB  - Dystrophic epidermolysis bullosa (DEB) is a rare skin disorder that is clinically
      heterogeneous and is transmitted either in dominant (DDEB) or recessive (RDEB)
      mode. Nevertheless, all variants of DEB are caused by mutations in type VII
      collagen gene (COL7A1). We report an analysis of COL7A1 mutations in 51 Italian
      DEB patients, 27 affected with Hallopeau-Siemens RDEB, 19 with non Hallopeau
      Siemens RDEB, two with DDEB, two with pretibial RDEB, and one with inversa RDEB.
      Forty-one mutations were identified, 18 of which are novel. Mutation consequences
      were analyzed at the mRNA and protein level and genotype-phenotype correlation
      was determined. Recessive inheritance of a new case of pretibial RDEB was also
      established. In RDEB patients, six recurrent mutations were identified: 7344G-
      >A, 425A-->G, 8441-14del21, 4783-1G-->A, 497insA, and G1664A, the last three
      being found only in Italian patients. Indeed, haplotype analysis supported
      propagation of ancestral mutated alleles within the Italian population for these
      particular mutations. Altogether recurrent mutations account for approximately
      43% of RDEB alleles in Italian patients and therefore new DEB patients should
      first be screened for the presence of these mutations.

PMID- 12485455
TI  - The chemokine receptor CCR6 identifies interferon-gamma expressing T cells and is
      decreased in atopic dermatitis as compared with psoriasis.

PMID- 12485453
TI  - Expression of hypothalamic-pituitary-thyroid axis related genes in the human
      skin.
AB  - The skin is commonly affected in thyroid diseases, but the mechanism for this
      association is still unclear. As the skin expresses numerous neuroendocrine
      elements, we tested the additional cutaneous expression of mediators operating in
      the hypothalamic-pituitary-thyroid axis. We found significant expression of the
      thyroid-stimulating hormone receptor mRNA in cultured keratinocytes, epidermal
      melanocytes, and melanoma cells. The presence of thyroid-stimulating hormone
      receptor was confirmed by northern analyses and the thyroid-stimulating hormone
      receptor was found to be functionally active in cyclic adenosine monophosphate
      signal assays. Thyroid-stimulating hormone receptor expressing cells also
      expressed the sodium iodide symporter and thyroglobulin genes. We also found
      expression of deiodinases 2 and 3 (mainly deiodinase 2) in whole skin biopsy
      specimens, and in the majority of epidermal and dermal cells by reverse
      transcription-polymerase chain reaction followed by sequencing of the amplified
      gene segments. There was selective expression of the gene for thyroid-stimulating
      hormone beta; detection of the thyroid-releasing hormone gene was minimal and
      thyroid-releasing hormone receptor mRNA was not detected in most of the samples.
      Expression of functional thyroid-stimulating hormone receptor in the skin may
      have significant physiologic and pathologic consequences, particularly in
      autoimmune conditions associated with production of stimulating antibodies
      against the thyroid-stimulating hormone receptor. We conclude that the expanding
      list of neuroendocrine elements expressed in the skin supports a strong role for
      this system in cutaneous biology.

PMID- 12485460
TI  - Angiogenesis in the female reproductive organs: pathological implications.
AB  - The female reproductive organs (ovary, uterus, and placenta) are some of the few
      adult tissues that exhibit regular intervals of rapid growth. They also are
      highly vascular and have high rates of blood flow. Angiogenesis, or vascular
      growth, is therefore an important component of the growth and function of these
      tissues. As with many other tissues, vascular endothelial growth factors (VEGFs)
      and fibroblast growth factors (FGFs) appear to be major angiogenic factors in the
      female reproductive organs. A variety of pathologies of the female reproductive
      organs are associated with disturbances of the angiogenic process, including
      dysfunctional uterine bleeding, endometrial hyperplasia and carcinoma,
      endometriosis, failed implantation and subnormal foetal growth, myometrial
      fibroids (uterine leiomyomas) and adenomyosis, ovarian hyperstimulation syndrome,
      ovarian carcinoma, and polycystic ovary syndrome. These pathologies are also
      associated with altered expression of VEGFs and/or FGFs. In the near future,
      angiogenic or antiangiogenic compounds may prove to be effective therapeutic
      agents for treating these pathologies. In addition, monitoring of angiogenesis or
      angiogenic factor expression may provide a means of assessing the efficacy of
      these therapies.

PMID- 12485461
TI  - Long-term evolution of the acute tubular necrosis (ATN) induced by glycerol: role
      of myofibroblasts and macrophages.
AB  - Late structural changes such as interstitial fibrosis in the renal cortex and
      tubular atrophy have been detected after severe acute tubular necrosis (ATN). The
      aim of this study was to investigate the expression of fibronectin, alpha-smooth
      muscle actin and macrophages during the evolution of the ATN induced by glycerol
      and their relationship with the late structural changes observed in the kidneys
      of these animals. Forty-nine male Wistar rats were injected with a 50% glycerol
      solution, 8 mL/kg (4 mL/kg applied i.m. to each hind leg) and 14 with 0.15 m NaCl
      solution. Before glycerol injection on day 1, water was removed for 17 h. Blood
      and urine samples were collected 1 day after the injection to quantify sodium and
      creatinine. The animals were killed 5, 30 and 60 days after the injections and
      the kidneys removed for histological and immunohistochemical studies. The results
      of the histological and immunohistochemical studies were scored according to the
      extent of lesion or staining in the cortical tubulointerstitium, respectively.
      The percentage of tubulointerstitial lesions was determined by morphometry.
      Glycerol-injected rats presented a transitory increase in plasma creatinine
      levels and in fractional sodium excretion. The immunohistochemical studies showed
      increased fibronectin, alpha-smooth muscle actin (alpha-SM-actin), TGF-beta and
      ED-1 (macrophages) staining in the renal cortex from rats killed 5, 30 and 60
      days after glycerol injection (P < 0.05) compared to control. The animals killed
      on day 30 and 60 also presented chronic lesions (fibrosis, tubular dilatation and
      atrophy) in the renal cortex, despite the recovery of renal function.
      Macrophages, TGF-beta and myofibroblasts may have contributed to the development
      of renal fibrosis in these rats.

PMID- 12485462
TI  - Chemopreventive effect of celecoxib and expression of cyclooxygenase-1 and
      cyclooxygenase-2 on chemically-induced rat mammary tumours.
AB  - We investigated the chemopreventive effect of celecoxib on 7,12
      dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumours and also the
      expression and immunolocalization of cyclooxygenase-1 (COX-1) and COX-2 in the
      various stages of rat mammary carcinogenesis. Rats were divided into normal
      control group, DMBA-control group, 500 p.p.m. celecoxib-treated group, and 1500
      p.p.m. celecoxib-treated group. Both incidence and multiplicity values of tumour
      for rats treated with celecoxib were less than those in rats of the DMBA-control
      group. The level of prostaglandin E2 was higher in tumours of the DMBA-control
      and both celecoxib-treated groups compared to normal mammary glands of each
      group. In Western blot analysis, all tumours of the DMBA-control group expressed
      COX-1, whereas normal mammary glands showed insignificant expression. COX-2
      expression was observed in 67% of the DMBA-control group and 20% of both
      celecoxib-treated groups and was absent in normal mammary glands. COX-1 protein
      was localized in the nuclear membrane and cytoplasm of epithelial tumour cells
      abutting on glandular lumen, stromal cells, and endothelial cells. COX-2 protein
      was detected in the perinuclear cytoplasm of tumour cells bordering on glandular
      lumen and surrounding stroma, stromal cells, and vascular smooth muscle. In the
      DMBA-control group, invasive carcinoma cells showed higher positive
      immunoreactivity of COX-2 than carcinomas in situ and atypical tumours. Tumours
      displayed an increased number of mast-like cells with COX-2 expression in
      comparison to carcinomas in situ. Our results suggest that COX-1 and COX-2
      expression in tumour cells and stromal cells play an important role in the
      various stages of DMBA-induced rat mammary carcinogenesis. In addition, we
      reconfirm that celecoxib reduces the growth of DMBA-induced rat mammary tumours.

PMID- 12485463
TI  - Titration of non-replicating adenovirus as a vector for transducing active TGF
      beta1 gene expression causing inflammation and fibrogenesis in the lungs of
      C57BL/6 mice.
AB  - Investigators have shown that interstitial pulmonary fibrosis (IPF) can be
      induced in rats by overexpressing transforming growth factor beta1 (TGF-beta1)
      through a replication-deficient recombinant adenovirus vector instilled into the
      lungs (Sime et al. 1997). We have shown that this vector induces IPF in
      fibrogenic-resistant tumour necrosis factor alpha-receptor knockout (TNF
      alphaRKO) mice (Liu et al. 2001). The object of our studies is to understand how
      peptide growth factors, such as TGF-beta1, mediate interstitial lung disease
      (ILD). To do so, we must be able to manipulate the dose of the factor and sort
      out its effects on multiple other mediators in the lung parenchyma. As a step in
      this complex process, in the studies reported here, we have determined the
      concentrations of the recombinant adenovirus vector carrying the gene for porcine
      active TGF-beta1 (AVTGFbeta1) that have little apparent effect, cause clear
      induction of disease, or severe disease. The disease largely resolves by 28 days
      in all cases, thus providing a valuable model to understand the mechanisms of the
      IPF that is mediated, at least in part, by TGF-beta1. The findings here show that
      10(6) plaque-forming units (pfu) of AVTGFbeta1, provide essentially a 'no-effect'
      dose, but even this amount of TGF-beta1 causes a significant increase in whole
      lung collagen by day 28 after treatment. In contrast, 10(8) and 10(9) pfu cause
      severe IPF in 4 days, whereas 10(7) and 5 x 10(7) are intermediate for all
      parameters studied, i.e. TGF-beta protein, inflammatory cells, cell
      proliferation, pro-alpha 1(I) collagen gene expression and whole-lung collagen
      accumulation, and expression of growth factors such as TGF-beta1, TNF-alpha and
      PDGF-A and -B. Interestingly enough, TGF-beta1, as a potent blocker of epithelial
      cell proliferation, appears to suppress airway epithelial cell growth that would
      be expected during the inflammatory phase of IPF. Thus, this model system helps
      us to understand some quantitative aspects of TGF-beta1 biological activity and
      allows us to manipulate this potent factor as a mediator of interstitial
      fibrogenesis.

PMID- 12485464
TI  - Dietary lectins can stimulate pancreatic growth in the rat.
AB  - Lectins are proteins or glycoproteins of nonimmune origin, which bind
      specifically to carbohydrate structures. They are widespread in the human diet,
      and many are resistant to digestion. High doses of lectins have been shown to
      stimulate intestinal and pancreatic growth. The aim of the present study was to
      investigate the long-term actions of low doses of lectins on the rat intestine
      and pancreas. A long-term carcinogenesis study was performed using low levels (40
      micro g/rat/day) of peanut (PNA) or mushroom lectin (ABA) which bind to O-linked
      (mucin-type) oligosaccharides in the gut. While this was primarily designed as a
      colon carcinogenesis study, the pancreas was also investigated. No significant
      changes in colon carcinogenesis were seen, however, the colons were slightly
      heavier in the lectin treated groups. The weight of the pancreas was
      significantly greater (by 18 and 23%) in both lectin treated groups (P <
      0.03/0.001). The weights of the acini and septal tissue were also increased by 39
      46% in PNA and ABA fed animals, respectively (P < 0.002); there was no
      significant change in the endocrine pancreas. In conclusion, long-term feeding of
      low doses of lectin can influence pancreatic growth, and this trophic action may
      have potential adverse implications for the development of pancreatic cancer in
      humans.

PMID- 12485466
TI  - The effect of Puerariae radix on lipoprotein metabolism in liver and intestinal
      cells.
AB  - BACKGROUND: Animal studies investigating the beneficial effects of Puerariae
      radix on cardiovascular disease have suggested this plant possesses anti-diabetic
      and lipid lowering properties. However, the exact mechanism by which Puerariae
      radix affects lipid metabolism is currently unknown. The aim of this study was to
      investigate the effect of the water extract of Puerariae radix on the secretion
      of VLDL and chylomicrons from HepG2 liver cells and CaCo2 cells, respectively, in
      humans. METHODS: The amount of apoB100 (a protein marker for VLDL) and apoB48 (a
      protein marker for chylomicrons) in cells and media were quantified by Western
      Blotting and enhanced chemiluminescence (ECL). Total, free and esterified
      cholesterol concentrations were measured by gas liquid chromatography. RESULTS:
      Treatment of cells with water extract of Puerariae radix significantly decreased
      apoB100 production and secretion from HepG2 cells up to 66% in a dose dependent
      manner. The intracellular total cholesterol and free cholesterol concentration in
      HepG2 cells also decreased with increasing concentration of the Puerariae radix.
      In contrast, water extract of Puerariae radix attenuated apoB48 concentrations in
      cells, but not apoB48 secretion from CaCo2 enterocytes. CONCLUSIONS:
      Collectively, our findings suggest that the water extract of Puerariae radix
      attenuates the hepatic lipoprotein production and secretion. Our present cell
      culture findings may explain why circulating VLDL and LDL levels were attenuated
      in animals supplemented with Puerariae radix. Since decreasing the production and
      secretion of atherogenic lipoproteins decreases the risk of development of
      cardiovascular disease, diets supplemented with radix may provide a safe and
      effective beneficial cardioprotective effects in humans.

PMID- 12485467
TI  - Multifunctional zinc finger proteins in development and disease.
AB  - Post-transcriptional processes contribute significantly towards the generation of
      proteomic diversity. An increasing number of mutations have been described that
      affect genes encoding components of the post-transcriptional machinery. In
      particular, multifunctional proteins that link transcription with post
      transcriptional processes have been implicated in several human diseases
      including cancer. A predominant feature of these proteins is the zinc finger, an
      ancient structural motif that mediates protein ratio protein interactions and is
      capable of interacting with both DNA and RNA. Zinc finger proteins are the most
      abundant class of proteins in the human proteome, yet the majority remain
      uncharacterised. Here we describe multifunctional zinc finger proteins linked to
      human development and disease. The examples discussed are WT1, ZNF74, EWS, TLS,
      TAFII68, YY1, CTCF and the GLI proteins. The study of these and other zinc finger
      proteins provides insights into the functional versatility of the zinc finger
      motif and suggests that both alternative splicing and sub-cellular
      compartmentalisation may modulate their multifunctionality.

PMID- 12485468
TI  - Interaction between smoking and the stromelysin-1 (MMP3) gene 5A/6A promoter
      polymorphism and risk of coronary heart disease in healthy men.
AB  - Smoking is a major risk factor for coronary heart disease (CHD), but this risk
      may be modified by an individual's genotype. A common functional 5A/6A
      polymorphism in the promoter of the stromelysin-1 (matrix metalloproteinase 3,
      MMP3) gene has been identified. The 6A allele has been consistently associated
      with faster progression of angiographically determined CHD, while the 5A allele
      has recently been associated with risk of acute myocardial infarction (MI) in
      patients with unstable angina. To date there has been no prospective study of the
      relationship of this genotype to CHD risk in smokers and non-smokers. DNA was
      available from 2,743 middle-aged men, free of CHD at baseline, recruited through
      nine general practices in the UK for prospective surveillance. To date there have
      been almost 24,000 person-years of follow-up with 125 CHD events (fatal and non
      fatal MI, sudden coronary death, need for coronary artery surgery or new major
      ECG Q-wave abnormality). Men with events were each matched for age, practice and
      cholesterol level with three healthy men. Smoking habit was determined by
      questionnaire. 5A/6A genotype was determined using a heteroduplex generator
      method. Associations between genotype and disease outcome, according to smoking
      status, were assessed using conditional logistic regression. Overall, current
      smoking was associated with a relative risk (RR) of 1.99 (95% CI 1.30-3.06) as
      compared with never-smokers and ex-smokers combined (p&0.002). In non-smoking
      men, and after adjustment for conventional risk factors, compared with the 5A5A
      group, the RR was 1.37 (0.64-2.94) in those with the genotype 5A6A and 3.02 (1.38
      6.61) in those with the genotype 6A6A. Smoking increased risk 1.4 fold in the
      5A6A group to 1.91 (1.84-4.36), by 1.3 fold in the 6A6A group to 4.01 (1.57
      10.24), but by 3.81 fold (1.54-9.40) in the 5A5A group (smoking-genotype
      interaction p = 0.01). The data indicate a key role for stromelysin in the
      atherosclerotic process. Men with the stromelysin genotype 5A5A represent 29% of
      the general population, and their high risk, if smokers, provides a further
      strong argument for smoking avoidance.

PMID- 12485469
TI  - Nijmegen breakage syndrome gene (NBS1) alterations and its protein (nibrin)
      expression in human ovarian tumours.
AB  - We looked for NBS1 gene (602667) alterations and changes in nibrin expression in
      162 human gynaecological tumours, mostly ovarian. Exons 6-8 and 10 of the NBS1
      gene were evaluated by the SSCP and direct sequencing method. Nibrin expression
      was detected immunohistochemically with the use of the p95NBS1 (Ab-1) antibody.
      The 657del5 mutation (Slavic mutation) was found in two of 117 carcinomas studied
      (1.7%) - in both cases it was present in the germline; one of these tumours
      showed loss of heterozygosity (LOH) for the 657del5 mutation and loss of nibrin
      expression. We have found three types of novel germline intron variants: (1) two
      concomitant transitions (G to A) at bases 14009 and 14256; (2) C to T transition
      at base 13998; (3) G to C transversion at base 20035. Among the carcinomas
      studied, the intron variants were associated with a clear cell histological type
      (p = 0.004). Our results may suggest that NBS1 gene alterations contribute to the
      development of rare ovarian carcinomas. LOH for 657del5 in tumour tissue may
      support the hypothesis that the NBS1 gene functions as a tumour suppressor.

PMID- 12485470
TI  - Bantu and European Y-lineages in Sub-Saharan Africa.
AB  - Ancient diversity in Sub-Saharan Africa is known to have been re-modulated to a
      large extent by Bantu migrations in the sub-Sahel region, in two southwards waves
      of advance through both the west and east coasts. Haplotype matching performed
      for Y-STR haplotypes in several sub-Saharan populations, both inside and outside
      the migration path, allowed the confirmation of a putative founder haplotype, and
      its one-step neighbours, of Bantu origin, and detected an increasing drift
      towards the south, with a stronger reduction of diversity along the western
      coast. A mixed frequency distribution for the Bantu haplotype core in South
      Africa, relative to the western and eastern pools, seems to provide evidence for
      the intermingling between both Bantu waves in that region. The proportion of male
      lineages considered as predating the Bantu expansion reached 8.8% in Mozambique.
      Further influence on sub-Saharan diversity may have occurred during the colonial
      period; in Mozambique, the European genetic impact in the male component was
      estimated to be around 5.9%, in significant contrast with the female counterpart
      where no European lineages were detected.

PMID- 12485471
TI  - Genetic dissection between coeliac disease and dermatitis herpetiformis in sib
      pairs.
AB  - Gluten sensitive enteropathy has various manifestations, of which the two major
      forms are classical coeliac disease (cCD) and dermatitis herpetiformis (DH). In
      cCD predominantly the small intestine is affected, whereas in DH also the skin is
      affected showing typical rash and IgA deposits. The symptoms in both forms are
      dependent on gluten intake. The factors diversifying these two clinical outcomes
      are unknown. In the present report we evaluated the role of the major genetic
      susceptibility locus, HLA DQ, in 25 families, in which both forms of the disease,
      cCD and DH, occurred in siblings. By using the family-based approach it can be
      assumed that within each family variation in environmental factors is
      substantially lower than in the standard case-control setting, and also the
      problems related to population stratification can be avoided. Results from the
      Finnish family material with 25 discordant and 85 concordant sib pairs, and from
      additional case-control material comprising 71 unrelated Hungarian DH and 68 cCD
      patients, together indicated that the HLA DQ locus did not differ between the two
      major outcomes of gluten sensitive enteropathy. The non-HLA DR;DQ factors are
      critical for the different clinical manifestations of gluten sensitivity.

PMID- 12485472
TI  - Identification of the sources of error in allele frequency estimations from
      pooled DNA indicates an optimal experimental design.
AB  - Genotyping costs still preclude analysis of a comprehensive SNP map in thousands
      of individual subjects in the search for disease susceptibility loci. Allele
      frequency estimation in DNA pools from cases and controls offers a partial
      solution, but variance in these estimates will result in some loss of statistical
      power. However, there has been no systematic attempt to quantify the several
      sources of error in previous studies. We report an analysis of the magnitude of
      variance components of each experimental stage in DNA pooling studies, and find
      that a design based on the formation of numerous small pools of approximately 50
      individuals is superior to the formation of fewer, larger pools and the
      replication of any of the experimental stages. We conclude that this approach may
      retain an effective sample size greater than 68% of the true sample size, whilst
      offering a 60-fold reduction in DNA usage and a greater than 30-fold saving in
      cost, compared to individual genotyping. The possibility of combining pooling
      with informed selection of haplotype tag SNPs is also considered. In this way
      further savings in efficiency may be possible by using pooled allele frequency
      estimates to infer haplotype frequencies and hence, allele frequencies at untyped
      markers.

PMID- 12485473
TI  - Power of a simplified multivariate test for genetic linkage.
AB  - In this paper we compare the power of the multivariate Haseman-Elston (MHE) test
      proposed earlier by Amos et al. (1990) and a computationally rapid new version of
      the multivariate Haseman-Elston test (NMHE) (Elston et al. 2000). We show that
      the power of NMHE was, for different simulation setups, identical or higher than
      that of MHE. In the bivariate case, the power of the NMHE method was somewhat
      less than that of the computationally intensive maximum likelihood variance
      components method (Amos et al. 2001). We present comparisons of the empirical
      distributions of the NMHE test to its limiting distributions for a range of
      numbers of traits. The distribution of the NMHE test appeared to conform
      satisfactorily to its limiting asymptotic distribution in large samples.
      Otherwise, empirical critical values for NMHE are somewhat higher than predicted,
      i.e. the test proposed by Elston et al. (2000) is non-conservative. The use of
      empirical critical values is therefore recommended for limited sample sizes (less
      than several hundred families). We also present the results of a linkage analysis
      performed by the NMHE method on a set of 4 body size-related traits. The method
      identified meaningful combinations of traits that showed significant linkage on
      chromosome 2 and suggestive linkage to regions on chromosomes 16 and 17.

PMID- 12485474
TI  - Association analysis for quantitative traits by data mining: QHPM.
AB  - Previously, we have presented a data mining-based algorithmic approach to genetic
      association analysis, Haplotype Pattern Mining. We have now extended the approach
      with the possibility of analysing quantitative traits and utilising covariates.
      This is accomplished by using a linear model for measuring association. We
      present results with the extended version, QHPM, with simulated quantitative
      trait data. One data set was simulated with the population simulator package
      Populus, and another was obtained from GAW12. In the former, there were 2-3
      underlying susceptibility genes for a trait, each with several ancestral disease
      mutations, and 1 or 2 environmental components. We show that QHPM is capable of
      finding the susceptibility loci, even when there is strong allelic heterogeneity
      and environmental effects in the disease models. The power of finding
      quantitative trait loci is dependent on the ascertainment scheme of the data:
      collecting the study subjects from both ends of the quantitative trait
      distribution is more effective than using unselected individuals or individuals
      ascertained based on disease status, but QHPM has good power to localize the
      genes even with unselected individuals. Comparison with quantitative trait TDT
      (QTDT) showed that QHPM has better localization accuracy when the gene effect is
      weak.

PMID- 12485475
TI  - Linkage mapping of quantitative trait loci in humans: an overview.
AB  - In this article, we provide an overview of the different statistical procedures
      that have been developed for linkage mapping of quantitative trait loci. We
      outline the model assumptions, the data requirements and the underlying tests for
      linkage for the different methods.

PMID- 12485477
TI  - [Expression of vascular endothelial growth factor and its receptors in
      endometrial carcinoma].
AB  - OBJECTIVE: To study the expression of vascular endothelial growth factor (VEGF)
      and its receptors, the fms-like tyrosine-1 (flt-1) and kinase insert domain
      containing receptor (KDR) in endometrial carcinoma and investigate the functions
      of VEGF and its receptors for endometrial carcinoma angiogenesis and its relation
      to the grade of tumor. METHODS: Immunocytochemistry and in situ hybridization
      technique were used to measure the level of VEGF, flt-1, KDR protein and mRNA in
      endometrial carcinoma tissue from 23 patients and endometrial samples from 6
      normal menopausal women. A few endometrial carcinoma samples were homogenized for
      Western blot analysis. The blood vessel density was estimated by counting blood
      vessels stained with endothelial marker VIII factor. RESULTS: The VEGF and its
      receptors were widely expressed in the cytoplasm of endothelial cells and tumor
      cells of endometrial carcinoma. The level of VEGF protein in endothelial cells
      and endometrial cancer cells of grade II and III tumor tissues was higher than
      that in grade I and normal menopausal endometrium (P < 0.05). VEGF mRNA did not
      show higher expression with the increase of tumor grade but its expression in
      normal tissue was lower than that in cancer (P < 0.05). The expression of flt-1
      protein and mRNA in endothelial cells got higher in III than in grade II and I (P
      < 0.05), but invariable in cancer cells (P > 0.05), flt-1 expression in cancer
      was higher than that in normal menopausal endometrium either in endothelial cells
      or in cancer cells (P < 0.05). The expression of KDR protein in endothelial and
      cancer cell was high but did not alter with the increase of tumor grade (P >
      0.05), the level of its mRNA was higher in cancer than that in normal tissue (P <
      0.05). The microvascular density in grade III (48 +/- 12) was higher than that in
      grade II (26 +/- 16), grade I (27 +/- 14) and normal menopausal tissue (26 +/-
      11, P < 0.05). CONCLUSIONS: The expression pattern of VEGF, flt-1 and KDR protein
      and mRNA increased with the increase of tumor grade in endometrial carcinoma
      indicates that VEGF and its receptors contribute to the neovascularization of
      tumors and is one of the factors that relate to rapid tumor growth of endometrial
      carcinoma.

PMID- 12485478
TI  - [Highly cellular leiomyoma of uterus: a comparative morphologic and
      immunohistochemical study of endometrial stromal tumors].
AB  - OBJECTIVE: To study the morphological characteristics and immunophenotype of
      highly cellular leiomyoma (HCL) of uterus, compared with that of uterine
      endometrial stromal tumors (EST). METHODS: HE and immuno-stained sections
      EnVision method from 20 cases of HCL, 21 cases of EST and 1 case of stromomyoma
      were reviewed. Monoclonal antibodies against h-caldesmon, calponin, CD10, desmin
      and smooth muscle actin (SMA) were used for immunohistochemistry studies.
      RESULTS: On microscopic examination, HCL were densely cellular and composed of
      cells that ranged from spindle-shaped to round with scanty cytoplasm. A focal
      fascicular pattern was present in all cases. Blood vessels with large, thick
      muscular walls were a conspicuous feature of the majority of tumors. Cleft-like
      spaces were present in 9 tumors and 15 cases exhibited irregular focal extensions
      into the adjacent myometrium. ESTs were composed of cells that resembled
      endometrial stromal cells of proliferative endometrium. These cases included a
      significant component of delicate blood vessels similar to spiral arterioles. All
      20 low grade endometrial stromal sarcoma cases had infiltrative growth to
      adjacent myometrium. Immunoreactivities of HCL for h-caldesmon, calponin, CD10,
      Desmin and SMA were 80.0% (16/20), 100% (20/20), 0 (0/20), 95.0% (19/20) and 100%
      (20/20), respectively, whereas the positive rates of EST were 4.7% (1/21), 23.8%
      (5/21), 66.7% (14/21), 23.8% (5/21) and 19.0% (4/21), respectively (P = 0.001).
      CONCLUSIONS: Highly cellular leiomyomas have distinct morphologic features. H
      caldesmon, calponin, CD10, desmin and SMA are helpful in the differential
      diagnosis of HCL and EST.

PMID- 12485479
TI  - [A clinicopathological study on minimal deviation adenocarcinoma of uterine
      cervix].
AB  - OBJECTIVE: Minimal deviation adenocarcinoma (MDA) is frequently underdiagnosed in
      pathology tests due to its benign histopathological features. Therefore, its
      clinical and pathological characters need to be further analyzed and to establish
      useful immunohistochemical markers to improve the accuracy of pathological
      diagnosis. METHODS: Clinical pathology data were of 13 MDA cases collected and
      analyzed in the First and Second Hospitals attached to the University, the
      pathological characters were compared with matched benign hyperplastic and
      atypical hyperplastic controls of the glandular epithelial cells to find
      histochemical and immunohistochemical indices valuable for the pathological
      diagnosis. 8 of these 13 cases were followed and their conditions were discussed.
      RESULTS: The main clinical symptoms were watery leucorrhagia, enlargement of the
      cervix with erosion and hardening. Thickened ligaments were also detected in some
      cases. The pathological findings included hyperplasia and mild abnormality of the
      glands, invasion effects into the stroma could be observed in some glands and
      abortive glands with desmoplastic changes, or edema and inflammatory infiltration
      around the glands were also observed. The invasion presented in the deep part of
      the cervix as well, some were found near larger blood vessels or in the small
      vessels. Compared with benign glands, the immunohistochemical indices of most MDA
      glands were demonstrated as cancer embryo antigen (CEA) + + +, Ki-67 +--+ + +,
      P53 +--+ + +, AB/PAS +/+ +, and focal defect on the basement membrane.
      CONCLUSIONS: Once any of the diagnostic characters summarized as above was
      determined, the probability of MDA should be seriously considered, at least
      atypical hyperplasia in cervical glands must be diagnosed, and follow-up on the
      patients and histological biopsy of deep tissues (> 5 mm) of the cervix will be
      necessary to determine the inclusion/exclusion of MDA. Obviously, a correct
      pathological diagnosis is extremely important for the patient to receive proper
      treatment in time and thereby improve her quality of life.

PMID- 12485480
TI  - [A clinicopathological study of bizarre leiomyoma].
AB  - OBJECTIVE: To investigate the feature of histomorphology and biology of uterine
      bizarre leiomyoma from the clinical, pathological features as well as the
      immunohistochemical expression. METHODS: Totally 25 cases of leiomyomas were
      studied. Among them, immuno-histochemical staining (SP and ABC methods) for
      smooth muscle actin (SMA), proliferative cell nucleus antigen (PCNA), estrogen
      receptors (ER), and progesterone receptors (PR) were performed in 20 cases. The
      clinical features and follow-up records were analyzed. RESULTS: The main clinical
      findings were irregular vaginal bleeding, pain and pelvic tumor. One case was
      with immense amount of ascitis and the other two were with pregnancy. All the
      cases had no history of taking pregestine. Light microscopy showed that part of
      all the cell nuclei were bizarre, accompanying with double or multiple nuclei in
      which rather big and reddish staining inclusion bodies were obtained (D = 7 - 26
      micro m), and the mitotic figures were 0 - 2/10 HPF. Among 20 cases with
      immunohistochemical staining, markers indicating muscle cells in origin were
      positive in the bizarre cells, 15 of which (75%) with negative or weak positive
      PCNA, and 18 of which (90%) with negative ER. There were significant difference
      between the studied and control groups (P = 0.027, P < 0.005 respectively) and in
      addition, PR was positive in both these two groups. A majority of the nucleus
      inclusion bodies was SMA positive. Follow-up records demonstrated so far no
      recurrence cases obtained. CONCLUSIONS: Uterine atypical leiomyoma belongs to
      benign tumor, although its shape is bizarre. In this group, the morphology
      changes are correlated with pregnancy, but not with pregestine. The expression of
      immunohistochemistry shows certain features, and is important to identify uterine
      bizarre leiomyoma with leiomyosarcoma and STUMP in pathological diagnosis.

PMID- 12485481
TI  - [A clinicopathological study of fifteen epithelioid angiosarcoma].
AB  - OBJECTIVE: To study the clinicopathological features of epithelioid angiosarcoma
      (EA) and to propose its differential diagnosis. METHODS: 15 EAs were observed by
      means of HE staining, immunohistochemical staining (ABC method) and in part by
      electron microscopy. RESULTS: Twelve cases occurred in men and three in women.
      Clinical symptoms included a focal mass with pain, weight loss and weakness. The
      tumors were located in the retroperitoneum (n = 3), extremities (n = 3), femur (n
      = 4), thyroid (n = 2), supraobit (n = 1), soft tissue of thorax (n = 1), soft
      tissue of neck (n = 1). Radiographic evaluation demonstrated solid to cystic
      neoplasms ranging from 3 to 20 cm in diameter. Histologically, the epithelioid
      cells were arranged diffusely or in nests with hemorrhage and focal necrosis.
      Atypical tumor cells lined the irregular spaces and single or small nests of
      cells grouped around a lumen containing red blood cells. FVIII, CD34, CD31,CK and
      EMA were positive in tumor cells and SMA was positive in pericytes.
      Ultrastructurally, intracytoplasmic vacuoles, Weibel-Palades, intermediate
      filaments and basal lamina could be seen. Surgical resection was the treatment of
      choice, occasionally with adjuvant chemotherapy. Follow-up. Two patients are
      presently alive 19 months and 7 years following diagnosis. Twelve died from 2
      weeks to 38 months with a median interval of 19 months after lumpectomy. One
      patient was lost to follow up. There were 8 cases which had metastases to lungs,
      bones, lymph nodes and abdominal cavity. CONCLUSIONS: EA is a high-grade sarcoma.
      Endothelial derivation can be confirmed by immunohistochemical staining and
      ultrastructural findings. The differential diagnosis of EA includes metastatic
      carcinoma, epithelioid hemangioendothelioma, melanoma, epithelioid sarcoma etc.

PMID- 12485482
TI  - [Sequence analysis of translocation t (X; 18) genomic breakpoints characterized
      in synovial sarcoma].
AB  - OBJECTIVE: To analyze the DNA sequence characteristics of translocation t (X; 18)
      genomic breakpoints and to study the mechanism underlying chromosomal
      translocation t (X; 18) in synovial sarcoma. METHODS: Two cases of synovial
      sarcoma were studied utilizing long-distance polymerase chain reaction (PCR) and
      sequence analysis to amplify the genomic DNA of translocation t (X; 18)
      breakpoints. RESULTS: Translocation t (X; 18) was detected in both cases, which
      generated SYT-SSX1 and SYT-SSX2 fusion gene respectively. Sequence analysis
      revealed that intron 10 of SYT was fused to the intron 4 of SSX1 or SSX2.
      Sequences highly homologous to consensus recognition motifs of translin were
      found adjacent to breakpoints in all three genes. Breakpoints in the three genes
      were close to or even at several palindromic oligomer sequences. The breaks in
      intron 4 of SSX1 and SSX2 were near an Alu sequence. No Alu or other repetitive
      sequences were found 500 bp upstream or downstream from the break in intron 10 of
      SYT. One topoisomerase II consensus site was found between the two breakpoints
      but with considerable distance from intron 10 of SYT. CONCLUSIONS: All three
      genes involved in synovial sarcomas contain characteristic sequence motifs in the
      breakpoint regions which may play an important role in the genesis of chromosomal
      translocation in synovial sarcoma.

PMID- 12485483
TI  - [Combined thymoma (AB + B)--pathological diagnosis and clinical significance].
AB  - OBJECTIVE: To discuss the pathological and biological characteristic and the
      clinic-pathological relevance of combined thymoma (AB + B). METHODS: According to
      the WHO Histological Typing of Thymic Tumors, the clinical features and
      pathological characteristics of AB + B thymomas were analyzed in a series of 141
      thymic epithelial tumors (TET) collected in Shanghai Chest Hospital and analyzed
      statistically with clinical therapy and follow-up data. RESULTS: Seven cases of
      type A (5.0%), 48 cases of type AB (34.0%), 14 cases of combined thymoma (AB + B)
      (9.9%), 9 cases of type B1 (6.4%), 22 cases of type B2 (15.6%), 21 cases of type
      B3 (14.9%) and 20 cases of type C (14.2%) were classified. The overall
      postoperative survival data showed highly significant differences amongst the
      histological subtypes. Combined thymoma (AB + B) showed distinctive
      histopathological characteristics, their prognostic properties were between A, AB
      and B1-B3, the differences between them being highly significant (log rank:
      chi(2) = 48.18, P < 0.001). Seventy-three patients (51.8%) were in stage I, 16
      (11.3%) were in stage II, 44 (31.2%) were in stage III, and 8 (5.7%) were in
      stage IV. The association between histological subtype and invasive stage was
      significant (chi(2) = 71.3, P < 0.001). Combined thymoma (AB + B) was grouped to
      grade II thymoma. Thymoma grading has a positive relationship with therapy and
      prognosis (log rank: chi(2) = 57.49, P < 0.001). CONCLUSIONS: It is proposed that
      combined thymoma (AB + B) may be named as the borderline thymoma. It has a
      distinctive histopathological definition and criteria and may be grouped as a
      subtype of thymoma. Its pathological and biological properties are between benign
      and malignant thymomas, and have significant differences.

PMID- 12485484
TI  - [Classification and grading of tumors of the central nervous system--pathological
      analysis of 4,373 cases].
AB  - OBJECTIVE: To research on the clinical application of the WHO 1979, 1993 and 2000
      classifications of tumours of the central nervous system. METHODS: With the
      analysis of 4 373 cases, problems were studied in applying the WHO
      classifications. RESULTS: (1) The 2000 classification used double criteria of WHO
      and ICD-O. The relationship between them was very confusing. (2) Opinions
      suggested for about 15 types of the tumours of meningothelial cells. (3) It was
      difficult to separate benign, atypical or anaplastic meningiomas. (4) The
      diagnostic criterion of anaplastic gliomas was not clear. (5) Practically,
      glioblastoma was a type of mixed gliomas. (6) More cases should be studied in
      order to recognize special types of the tumours of neuroepithelial tissue.
      CONCLUSIONS: Suggested to make out a criterion of classification and grading that
      is more applicable for clinical diagnosis.

PMID- 12485485
TI  - [Diagnostic accuracy of cell-block or tissue-fragment histology and cytology by
      fine needle lung aspiration].
AB  - OBJECTIVE: Study on the diagnostic accuracy and value of cell block and tissue
      fragment preparations collected from lung fine needle aspiration (FNA). METHODS:
      A total of 187 FNA (22G) samples from the lungs with matched histological
      diagnosis were studied. Among them, the diagnosis made by depending on 124 cell
      block and fragment preparations were analyzed in comparing retrospectively with
      the diagnosis of 187 cases by smear preparations. RESULTS: (1) Of the 124 cell
      blocks cases, 89 cases were true positives, 22 cases were true negatives, 13
      cases were false negatives and no false positives. Of the 187 smears cases, the
      figure were 136, 30, 19 and 2 cases respectively. The diagnostic accuracy of cell
      blocks was 87.3% in sensitivity, 100% in specificity, 89.5% in overall accuracy.
      The figures for smears were 87.7%, 93.8% and 88.8% respectively. (2) For
      malignant tumours, the histological typing accuracy of cell blocks was 93.3%
      (83/89), and to be 67.9% (91/134) by diagnosis depending on the smears (P <
      0.01). For the benign lesions, the figures were 86.4% (19/22) and 60% (18/30)
      respectively (P < 0.05). (3) It was possible to obtain many minisections for
      further studies from cell blocks. Immunoperoxidase staining on minisections was
      reliable and agreed with those on the surgical specimens. CONCLUSIONS: The
      diagnostic accuracy of cell block is high, particularly in histological typing
      which approaches to that of the diagnosis made depending on the postoperative
      specimens. A combined use of smears and cell block is recommended which may raise
      further the diagnostic accuracy.

PMID- 12485486
TI  - [The effect of diamide on the expression of macrophage inflammatory protein-1
      alpha in endothelial cells].
AB  - OBJECTIVE: To study the effect of diamide on the expression of macrophage
      inflammatory protein-1 alpha (MIP-1 alpha) in cultured human umbilical vein
      endothelial cells. METHODS: After exposure of the endothelial cells (ECs) to
      different concentrations of diamide for 4 hours, the MIP-1 alpha mRNA in the
      cells was detected by nuclease S1 protection assay and the MIP-1 alpha protein in
      those cells was determined by cell enzyme-linked immunosorbent assay. The
      chemotactic activity of MIP-1 alpha in the conditioned medium of ECs treated with
      diamide for peripheral blood monocytes was tested by microfilter method using
      modified Boyden chambers. RESULTS: Incubation of ECs with 5 micro mol/L diamide
      resulted in a 2.4-fold increase in the level of MIP-1 alpha mRNA expression as
      compared with the control group (t = 8.70, P < 0.05). Exposure of ECs to 1 micro
      mol/L, 5 micro mol/L and 10 micro mol/L diamide resulted in a 0.9-fold, 1.2-fold,
      and 0.7-fold increase in the level of MIP-1 alpha protein expression
      respectively, as compared with the control group (F = 35.65, P < 0.05).
      Chemotactic assay showed that the migration distance of monocytes towards the
      conditioned medium (CM) of ECs treated with 5 micromol/L diamide was 99.50 microm
      +/- 4.31 microm, which was significantly more than the 66.47 microm +/- 3.25
      microm towards the conditioned medium of ECs in the non-diamide group, the
      chemokinetic group (67.03 microm +/- 6.83 microm) and the random migration group
      (65.40 microm +/- 3.36 microm) (F = 404.31, P < 0.05). The results revealed that
      there might be chemotactic substances in the conditioned medium of 5 micro mol/L
      diamide treated ECs. The migration distance of monocytes towards the conditioned
      medium of the ECs exposed to 5 micromol/L diamide was significantly reduced to
      82.80 microm +/- 6.88 microm after the addition of goat anti-human MIP-1 alpha
      antibody (F = 192.25, P < 0.05), which indicates the chemotactic activity of MIP
      1 alpha in the conditioned medium of the ECs in the diamide group. CONCLUSIONS:
      Diamide, a lipid peroxidation inducer, could stimulate ECs to produce high levels
      of MIP-1 alpha with chemotactic activity, and may play an important role in
      atherogenesis through attraction of peripheral blood monocytes into arterial
      intima.

PMID- 12485487
TI  - [Aging changes of gelatinase activity in kidney tissue of autoimmune MRL/lpr
      mice].
AB  - OBJECTIVE: To determine whether increased expressions of gelatinases occur with
      aging in vivo in kidney tissue of autoimmune MRL/lpr mice by in situ zymography.
      METHODS: MRL/lpr mice at the age of 8 weeks, 16 weeks and 24 weeks were
      investigated. Kidney protein extracts were compared for activities of MMP-2/9 by
      gelatin zymography. Immunohistochemistry and SDS-PAGE gelatin zymography were
      used to determine the expressions and activities of gelatinase A (MMP-2) and
      gelatinase B (MMP-9). To determine the net gelatinase activities in murine lupus
      kidney, in situ zymography was used with autoradiographic emulsion as substrate.
      RESULTS: Both gelatinase A and B were seldom detected in the kidney tissue in 8
      week old mice, Increased expressions of both latent and activated form enzymes of
      MMP-2/9 were identified in kidney extraction by SDS-PAGE gelatin zymography and
      immunohistochemical staining showed both MMP-2 and MMP-9 were obviously up
      regulated within glomerulus as well as tubular-interstitium in mice at the age of
      16 and 24 weeks. In situ zymography showed markedly increased gelatinase
      activities in kidney tissue consistent with the results of immunohistochemical
      staining, it is mainly derived from MMPs and inhibited by EDTA but not by PMSF or
      aprotinin. CONCLUSIONS: These in vivo results suggested that MMP-2/-9 expressions
      were significantly up-regulated with aging in murine lupus nephritis, which may
      play an important role in promoting the remodeling formation of ECM and thus
      contribute to the progression of renal damage in this model.

PMID- 12485488
TI  - [The beneficial effect of phVEGF165 transfer on vascular remodelling after
      balloon injury and its possible mechanisms].
AB  - OBJECTIVE: To investigate the effect of phVEGF165 transfer on vascular
      remodelling after balloon injury and its possible mechanisms. METHODS: 90 New
      Zealand white rabbits were divided randomly into 3 groups: group I (balloon
      injury group), group II (pAdtrackCMV group) and group III (pAdtrackCMV-VEGF165
      group). All animals were given hypercholesterol diet for 7 days before experiment
      and continued to receive hypercholesterol diet until being killed. Each group was
      further divided into five subgroups according to the sacrifice time (3 days, 1,
      2, 4 and 8 weeks after transfection). Blood samples and arteries were harvested
      for further analysis. RESULTS: At the end of 2 weeks, areas of neointima plus
      media of group III were smaller than those of group I and II (P < 0.05). The
      areas under external elastic membrane were larger in group III at 4 weeks and
      lumen stenosis rates were significantly lower than group I and II (P < 0.05 or
      0.01). In group III, VEGF165, metalloproteinases (MMPs) -1, -2, -9 and their
      tissue inhibitors (TIMPs) 1, 2 could be detected from 3 days after gene transfer
      and reached the highest level at 2 weeks time and could not be detected by 8
      weeks time. In groups I and II, MMP-2 and TIMP-1, -2 could be detected during the
      whole procedure and the value of TIMP1/MMP1 was significantly higher than in
      group III (P < 0.01). CONCLUSION: Remodelling is the main reason for restenosis
      (RS) after vascular balloon injury. Local pAdtrackCMV-VEGF165 transfer can
      specifically change the expression of MMPs and facilitate the positive
      remodelling process, hence, inhibiting restenosis.

PMID- 12485489
TI  - [Hsp70-H22 tumor antigen peptide complex activated dendritic cell in the
      induction of antitumor immunity].
AB  - OBJECTIVE: To investigate the feasibility of reduction in tumor antigen peptide
      dose by dendritic cell (DC)-presenting so as to elucidate the characteristics of
      modifying DC by heat shock protein (Hsp70) and antigen peptide. METHODS: Antigen
      peptide bound to Hsp70 was used to modify DC in vitro. The metabolism of the
      modified DC and the cytokine secreted thereby was determined. Then the activation
      of lymphocytes by the modified DC and Hsp70-H22 peptide was tested. The
      cytotoxicity of the activated lymphocytes to H22 tumor cells and the inhibition
      of tumor in mice by DC injection and Hsp70-H22 peptide was tested. RESULTS: 0.15
      micro g of H22 peptide bound to Hsp70 could mature 2 x 10(5) DC. 4 x 10(3)
      matured DC could activate 2 x 10(6) lymphocytes. The same amount of lymphocyte
      could be activated to produce similar cytotoxicity to tumor cells by either DC
      modified by 0.003 micro g of peptides bound with Hsp70 or by direct stimulation
      with 0.15 micro g of peptides bound to Hsp70. The dose of peptide could be
      reduced to 1/50 if the modified DC injection was used instead of direct Hsp70
      peptide injection. Peptide from the normal hepatocytes, if bound to Hsp70, could
      not mature DC, nor could it activate lymphocytes through DC. CONCLUSION: The dose
      of Hsp70-H22 peptides can be reduced significantly by DC-presenting to activate
      lymphocytes. Peptides from normal cells, being unable to activate the lymphocytes
      by either Hsp70-presenting or DC-presenting, have little to offer in the
      induction of autoimmunity.

PMID- 12485490
TI  - [Effect of human calcyclin binding protein encoding gene on development of
      multiple drug resistance in gastric cancer].
AB  - OBJECTIVE: To study the effect of human calcyclin binding protein (CacyBP)
      encoding gene on the development of multiple drug resistance in gastric cancer.
      METHODS: hCacyBP sense nucleic acid eukaryotic expression vector
      (pcDNA3.1/hCacyBP +) was constructed and then transfected steadily into the
      gastric cancer drug sensitive cell (SGC7901) mediated by lipofectamine ( trade
      mark ) 2000. RT-PCR was used to measure the CacyBP mRNA expression level. MTT was
      used to measure the adriamycin (ADR) drug sensitivity of SGC7901 and SGC7901
      after transfection. FCM was used to measure the average ADR accumulation
      concentration and cell cycle of SGC7901 and SGC7901 after transfection. RESULTS:
      The hCacyBP mRNA expression level of SGC7901 transfected with pcDNA3.1/hCacyBP +
      was higher than SGC7901 transfected with pcDNA3.1 or SGC7901, with the higher
      survival rate in the former. The average ADR accumulation concentration in
      SGC7901 and SGC7901 transfected with pcDNA3.1 or pcDNA3.1/hCacyBP + was 5.64,
      5.49 and 5.17, respectively. The G(1) phase cell proportion of SGC7901
      transfected with pcDNA3.1/hCacyBP + or pcDNA3.1 was reduced slightly but G(2) and
      S phases increased slightly as compared with SGC7901. CONCLUSION: Calcyclin
      binding protein may play a certain role in gastric cancer drug resistance.

PMID- 12485491
TI  - [Differentially expressed gene in nasopharyngeal carcinoma cell lines with
      various metastatic potentialities].
AB  - OBJECTIVE: To investigate gene expression profile in nasopharyngeaL carcinoma
      (NPC) cell lines with different metastatic potentialities, in order to identify
      new candidate genes related to the development, progress and metastasis of NPC.
      METHODS: The mRNA expressions of high metastatic NPC cell line 5-8F, tumorigenic
      but nonmetastatic NPC cell line 6-10B and non-tumorigenic NPC cell line 13-9B (3
      sublines of SUNE-1) were investigated by cDNA microarray containing 14 000 cDNA
      clones. The alterations in gene expression levels were confirmed by reverse
      transcription PCR. RESULTS: There were 82 differentially expressed genes
      comparing 5-8F and 13-9B; 38 differentially expressed genes comparing 6-10B and
      13-9B; 54 comparing 5-8F and 6-10B. There were 12 common differentially expressed
      genes comparing 6-10B, 5-8F and 13-9B; 14 common differentially expressed genes
      comparing 5-8F and 13-9B, 6-10B. The expressions of the above genes were involved
      in metabolism, transcription, differentiation, apoptosis and signal transduction.
      CONCLUSION: The gene expression profile in nasopharyngeal carcinoma cell lines is
      an important index in the search of new candidate genes related to NPC.

PMID- 12485492
TI  - [The effect of multi-unit ribozymes on the growth inhibition and apoptosis
      induction of CML K562 cells].
AB  - OBJECTIVE: To investigate the possibility of multi-unit ribozymes to purge bone
      marrow of chronic myelocytic leukemia (CML), its in vitro cleavage ability and
      the reversal effect on CML cell's malignant phenotype. METHODS: As bcr-abl fusion
      gene plays an important role in CML pathology, three single-unit ribozymes were
      designed and synthesized in 44 base pairs near the fusion point, two enzyme
      cleavage sites on bcr gene and one on abl gene. Multi-unit ribozymes' in vitro
      transcription and retroviral vector through gene recombination were constructed.
      Then, its in vitro cleavage ability was tested and the retroviral vector was
      transfected into K562 cell. Through MTT assay, the incorporation rate of (3)H
      TdR, RT-PCR, Southern and Northern blot hybridization, flow cytometry,
      transmission and scanning electron microscopy were used to study the effect of
      multi-unit ribozymes on CML cell proliferation, cell structure, cell cycle and
      the induction of apoptosis. RESULTS: Multi-unit ribozymes had in vitro cleavage
      efficiency of 70.8%. After the transfection of multi-unit ribozymes retroviral
      vector into K562 cell, cell proliferation and DNA synthesis were greatly reduced
      with an inhibition rate of about 50% after 96 hours of transfection. Multi-unit
      ribozymes could cleave K562 cell's RNA with a reduction rate about one 1 000 th
      of the original. By flow cytometry (FCM), 18.4% cells underwent apoptosis after
      72 hours transfection with most of the cells blocked in the G phase. Here, the
      ratio in S phase was lowered by 41.9%. Under transmission and scanning electron
      microscope, compaction of nuclear chromation and apoptosis bodies were observed
      in the transfected cells. CONCLUSION: Multi-unit ribozymes possess high cleavage
      ability in vitro. The ribozymes, whose retroviral vector being transfected into
      CML cell, are able to express a lasting ability to cleave the fusion gene, induce
      apoptosis, reduce cell proliferation, revert the malignant phenotype. It is
      possible to make use of multi-unit ribozymes to purge CML bone marrow. Therefore,
      multi-unit ribozymes may very well be valuable in the gene therapy of CML.

PMID- 12485493
TI  - [Delayed rectifier K(+) channel regulated by cyclooxygenase-2 in human gastric
      cancer cell].
AB  - OBJECTIVE: To correlate delayed rectifier K(+) channel to cyclooxygenase-2 (COX
      2) in onco genesis of human gastric cancer cell. METHODS: Human COX-2 encoding
      gene was cloned with RT-PCR strategy and its antisense recombinant eukaryotic
      expression vector was constructed. COX-2 highly expressed human gastric cancer
      cell line SGC7901 was stably transfected with the antisense vector. The whole
      cell recording technique of perforated patch clamp was employed to observe the
      change of delayed rectifier K(+) current (I(k)) of SGC7901 after gene transfer or
      treatment with COX-2 inhibitor indomethacin. MTT was also performed to determine
      the effect of delayed rectifier K(+) channel inhibitors on cell growth. RESULTS:
      Stably transfected cell (7901-AS) was obtained and a down-regulated expression of
      COX-2 protein and mRNA in the cell was achieved. Patch clamp recording showed
      that both SGC7901 and 7901-AS cells had a typical delayed rectifier K(+) current.
      However, I(k) was significantly lower (P < 0.01) in transfected cell or cell
      treated with indomethacin at each test potential. The altered I(k) could be
      entirely recovered after drug removal from the cells. K(+) channel blockers
      tetraethylammonium (TEA) and 4-aminopyridine (4-AP) could retard the growth of
      SGC7901 and the transfected cell in a dose-dependent manner. CONCLUSION: Delayed
      rectifier K(+) channel, existing in human gastric cancer cell line SGC7901, is
      related to the growth of the cell. The highly expressed COX-2 may affect the
      biological behavior of gastric cancer cell by regulating this ion channel.

PMID- 12485494
TI  - [Demethylation in the promoter area by the antisense of human DNA MTase gene].
AB  - OBJECTIVE: To investigate the change in the expression of E-Cadherin of human
      hepatocarcinoma cell line SMMC-7721 after transfection by antisense human DNA
      MTase gene. METHODS: DNA MTase gene eukaryotic expression vectors, including
      sense and antisense fragments, were constructed with recombinant technology and
      transfected into the hepatocarcinoma cell line SMMC-7721 with liposome DOTAP. The
      expression of DNA MTase gene mRNA and E-Cadherin gene mRNA was examined with RT
      PCR and the expression of E-Cadherin with immunohistochemical and flow cytometry.
      The status of methylation in E-Cadherin gene promoter area was examined with
      methylation specific PCR (MSP). RESULTS: The sense and antisense eukaryotic
      expression vectors were successfully constructed and then the constructed
      recombinant plasmids were successfully transfected into SMMC-7721 cell with
      liposome DOTAP. The expression of endogenous DNA MTase mRNA was obviously
      decreased with E-Cadherin gene mRNA and its activity increased in the SMMC-7721
      cell, which was tranfected with antisense DNA MTase gene fragment. Moreover,
      demethylation in the promoter area of E-Cadherin gene was observed with MSP.
      CONCLUSION: Demethylation in the promoter area and increasing mRNA level of E
      Cadherin gene can be induced by expression inhibition of DNA MTase gene of SMMC
      7721 cell line.

PMID- 12485495
TI  - [Cloning, purification and biological activity of human vascular endothelial
      growth factor fragment in E. coli].
AB  - OBJECTIVE: To observe the effect of human vascular endothelial growth factor
      (VEGF) fragment (3 approximately 4 exon) in E. coli on anti-angiogenesis.
      METHODS: Through RT-PCR amplification, endonuclease cut and DNA sequence analysis
      identification, hVEGF fragment cDNA was inserted into E. coli expression vector
      pTrcHis2A. The prokaryotic expression plasmid pTrcHis2A/VEGF(3 approximately 4)
      was constructed and transformed into TOP10F. RESULTS: After 8hr isopropy-beta-D
      thiogalactoside (IPTG) induction, VEGF fragment was expressed in 15% of total
      proteins through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS
      PAGE). The expressed protein was highly antigenic and specific. The VEGF fragment
      was further purified by affinity, which could inhibit HUVEC proliferation and
      neovascularization of the chick chorioallantoic membrane. CONCLUSION: VEGF
      fragment is anti-angiogenetic, which may potentially be used in oncologico
      biological targeting therapy.

PMID- 12485496
TI  - [Anti-tumor effect through human endostatin gene transfer in mice bearing B16
      melanoma].
AB  - OBJECTIVE: To investigate the effects of direct intratumor injection of the
      packaged cells with retroviral vector carrying human endostatin (hEN) on the
      growth inhibition of B16 melanoma in C57/BL6 mice. METHODS: Retroviral vector,
      pLNC-hEN, was constructed with modified and identified hEN gene. The cell line,
      PA317, was used to establish ecotropic virus producing cells by transfecting and
      packing with pLNC-hEN. Then the cells were injected directly into the tumor in
      C57/BL6 mice bearing B16 melanoma, established by intra-cutaneous injection of
      B16 cell suspension. The tumor size was measured at different intervals to
      observe the antitumor effect. Micro-vessel density (MVD) in the tumor tissue was
      evaluated by immunohistological examination to count the apoptotic cells by TUMEL
      staining. RESULTS: Tumor with diameter of 2 - 3 mm was observed in all mice after
      7 - 9 days. The average tumor volume on D3, D5, D7 and D9 after gene transfection
      was 4.67 +/- 1.1, 22.25 +/- 13.06, 84.17 +/- 43.5 and 155.08 +/- 81.1 mm(3) in
      the gene therapy group but 136.17 +/- 30.61, 390.17 +/- 220.47, 1 021.67 +/-
      537.4 and 2 920.2 +/- 220.01 mm(3) in the control group, the difference of which
      was statistically significant. The average MVD in the gene therapy and control
      groups were 8 +/- 2.28 and 28.17 +/- 5.31 while the average apoptotic cell number
      in the two groups were 23.33 +/- 3.83 and 2.33 +/- 1.21, both of which were
      statistically significant. CONCLUSION: The direct injection of packaged cells
      carrying hEN gene is able to inhibit the growth of micro-blood vessels and
      promote tumor cell apoptosis, which ultimately inhibits the growth of B16
      melanoma.

PMID- 12485497
TI  - [Hypoxia augments the killing effect of herpes simplex virus thymidine kinase
      gene expression actuated by the promoter of the vascular endothelial growth
      factor gene on human hepatocellular tumor cells].
AB  - OBJECTIVE: To investigate the killing effect of herpes simplex virus thymidine
      kinase gene expression actuated by the promoter of the vascular endothelial
      growth factor gene on human hepatocellular tumor cells under hypoxic condition.
      METHODS: Recombinant adenoviral vectors, AdVEGF-tk and AdVEGF-GFP, were
      constructed with HSV-tk or GFP under the control of VEGF promoter through AdEasy
      system. Then GFP expression in hepatoma cell line HepG2 and normal liver cell
      line L02 transfected with AdVEGF-GFP were observed under fluorescence microscope,
      and the sensitivity to GCV of the AdVEGF-tk-transfected cells under normoxia or
      hypoxia condition were monitored by MTT method. RESULTS: GFP expression actuated
      by VEGF promoter was detected in sporadic L02 cells, but in almost all HepG2
      cells after transfected with AdVEGF-GFP. With GCV at 10 micro g/ml and MOI at
      100, L02 cells were insensitive to GCV under oxic condition, but more than 70%
      L02 cells were killed under hypoxic condition. Moreover, HepG2 cells infected
      with AdVEGF-tk showed the increased GCV sensitivity under hypoxia (over 80%
      killed) as compared with normoxia (over 60% killed) conditions. CONCLUSION:
      Hypoxia enhances the GCV sensitivity of human hepatocellular tumor cells infected
      with recombinant AdVEGF-tk under the control of VEGF promoter.

PMID- 12485498
TI  - [Allelic analysis on chromosome 5 in sporadic colorectal cancer patients].
AB  - OBJECTIVE: To evaluate and map the putative tumor suppressor loci on chromosome 5
      involved in tumor progress or metastasis. METHODS: Chromosome 5 of 83 patients
      with sporadic colorectal cancer was systemically screened. Fifteen microsatellite
      marker primers labeled with 3 different fluorescents were used to amplify the
      corresponding loci of the genome DNA. The PCR products were electrophoresed on a
      377 PRISM sequencer and the fluorescent signals were analyzed with Genotyper and
      Genescan software. RESULTS: The highest loss of heterozygosity (LOH) ratio was
      found at D5S416 (48.15%) on 5p and at D5S471 (38.71%) on 5q. The region (5q13.3 -
      31), where D5S471 and 3 neighboring loci (D5S428, D5S2027 and D5S2115) reside,
      presented high frequent LOH. CONCLUSION: The deletion of APC, MCC, CTNNA1 and IL
      cluster in the 5q 13.3 - 31.1 area play important role in the tumorogenesis of
      colorectal cancer, and the expected existence of another novel tumor suppressor
      gene on 5p is possible.

PMID- 12485499
TI  - [Expression and mutation of c-kit gene in gastrointestinal stromal tumor].
AB  - OBJECTIVE: To investigate the effect of the expression and mutation of c-kit gene
      and its relationship with clinical pathology and prognosis of gastrointestinal
      stromal tumor (GIST). METHODS: Immunohistochemical and PCR-SSCP techniques were
      used to detect c-kit protein expression and c-kit gene exon 11 mutation in 82
      patients with GIST. RESULTS: The positive c-kit protein expression and c-kit gene
      mutation rates were 97.6% (80/82) and 41.5% (34/82). Correlating the results of
      these two methods and clinicopathological factors, the c-kit expression and c-kit
      gene mutation rates were 95.0% (19/20) and 0 in benign GIST, and were 98.4%
      (61/62), 54.8% (34/62) in malignant GIST. Mutation positive GIST showed higher
      frequency of adjacent tissue invasion, metastasis and recurrence as compared with
      mutation negative ones. CONCLUSION: c-kit protein is an important diagnostic
      marker of gastrointestinal stromal tumor. c-kit gene mutation may play a
      significant role in the pathogenesis of GIST and also may be a prognostic marker.

PMID- 12485500
TI  - [Co-expression of immunoglobulin light chain kappa and lambda in gastric
      carcinoma cell].
AB  - OBJECTIVE: To study the expression of immunoglobulin light chain kappa and lambda
      (Igkappa and Iglambda) in gastric carcinoma cell and their co-expression.
      METHODS: Igkappa and Iglambda of 22 human gastric carcinoma specimens embedded in
      paraffin were monitored through immunohistochemical method-LSAB method. RESULTS:
      Among 22 gastric carcinoma specimens, both Igkappa and Iglambda were positive in
      17 (77.3%), only Igkappa was positive in 2 (9.1%), only Iglambda was positive in
      1 (4.5%), both Igkappa and Iglambda negative in 2 (9.1%). The expression of
      Igkappa and Iglambda in human gastric carcinoma cell showed significant close
      correlation (chi(2) = 5.49, P < 0.05). CONCLUSION: Co-expression of
      immunoglobulin light chain kappa and lambda in gastric carcinoma cell is common,
      which suggests that the activation mechanism of immunoglobulin gene in gastric
      carcinoma cell may be different from that in B-lymphocytes. Study on co
      expression of immunoglobulin light chain kappa and lambda in gastric carcinoma is
      promising.

PMID- 12485501
TI  - [Contamination with minimal residual disease in autologous peripheral stem cell
      collected from Non-Hodgkin's lymphoma patients treated with high-dose therapy].
AB  - OBJECTIVE: To detect the contaminating minimal residual disease (MRD) in
      autologous peripheral blood stem cells (APBSC) and evaluate its impact on the
      prognosis of non-Hodgkin's lymphoma NHL patients. METHODS: Minimal residual
      disease was detected in 72 APBSC samples from 33 NHL patients through PCR or PCR
      combined with DNA single-strand conformation polymorphism analysis (SSCP) with
      the BCL-2/IgH, clonal rearrangement of IgH and TCR gamma gene as markers. Minimal
      residual disease was also monitored in bone marrow samples collected pre-, post
      induction chemotherapy and post-transplantation. RESULTS: MRD was positive in
      17/72 (23.6%) APBSC samples. The incidence of positive MRD in bone marrow pre-,
      post-induction chemotherapy and post-transplantation was 44.0% (11/25), 28.1%
      (9/32) and 11.5% (3/26) respectively. Six (66.6%) of 9 patients with positive MRD
      in pre-mobilization bone marrow, compared with 2 (8.7%) of 23 patients with
      negative MRD in bone marrow, were positive in contamination (P < 0.01). The
      estimated overall 3-year post-transplantation survival rate for patients with
      positive and negative MRD in their APBSC would be 71.4% and 71.2% respectively,
      and the estimated 3-year disease free survival rates of 25.0% and 61.5%
      respectively (P = 0.53). CONCLUSION: APBSC collected from NHL patients after
      mobilization by chemotherapy combined with colony stimulating factor may be
      contaminated by lymphoma cells. The presence of minimal residual disease in bone
      marrow at mobilization may increase the incidence of APBSC contamination.

PMID- 12485502
TI  - [Radiation encephalopathy in nasopharyngeal carcinoma patients in mainland China:
      a systematic evaluation].
AB  - OBJECTIVE: To evaluate the clinical characteristics of radiation encephalopathy
      in nasopharyngeal carcinoma (NPC) patients of mainland China. METHODS: Based on
      the principle of systematic review, the search for literature in computerized
      Chinese Biology & Medicine database, 1979 to June 2001 (CBM) was performed, with
      the papers appraised according to conformation criteria, the methodological
      quality of the studies analyzed, and clinical data of patients processed using
      the statistical model. RESULTS: 553 cases accumulated from 18 identified articles
      submitted by 16 hospitals in China were analyzed. The mean incidence of
      encephalopathy diagnosed by CT or MRI was 1.9% (0.4% - 2.6%). The disease focus
      was located in the temporal lobe (80%) and in the brain stem (17%). The mean dose
      received in the first course of radiotherapy to the nasopharynx or skull base was
      72.9 Gy, and the latent period of this disease was 3.6 years. CONCLUSION: The
      probability of encephalopathy after radiation for nasopharyngeal carcinoma in
      mainland China is reported in this review. Multi-center case-control or Cohort
      studies are required in the future.

PMID- 12485503
TI  - [NOEY2 gene mRNA expression in breast cancer tissue and its relation to
      clinicopathological parameters].
AB  - OBJECTIVE: To investigate the expression of NOEY2 gene in breast cancer tissue
      and its relation to clinicopathological and other molecular parameters. METHODS:
      The mRNA expression of NOEY2 gene was monitored in benign and malignant breast
      lesions by RT-PCR and in situ hybridization (ISH) with transcripted antisense RNA
      probes. The protein expression of estrogen receptor (ER), Ki67, p27 and p21(WAF1)
      in the 60 breast cancer lesions was detected by immunohistochemical method.
      RESULTS: All 6 benign lesions, and 13 (72.2%) of the 18 breast cancers were NOEY2
      positive by RT-PCR. By ISH, positive NOEY2 was obtained in all 10 benign lesions
      but only in 31 (51.7%) of the 60 breast cancer lesions. The difference was
      statistically significant (P = 0.025). NOEY2 positive rate tended to decrease
      with the increase of histological grade. However, NOEY2 expression was negatively
      correlated with the status of axillary lymph nodes. The positive NOEY2 rate was
      75% in those without lymph node metastasis but only 26.7% in those with
      metastasis (P < 0.001). No correlation with other clinicopathological parameters
      including ER, Ki67, p27 or p21(WAF1) were found. CONCLUSION: NOEY2 gene may be
      related with the pathogenesis of breast cancer. A link between NOEY2 loss
      expression and the spreading mechanism of breast cancer may possibly exist.

PMID- 12485504
TI  - [Prognostic factors in patients with primary non-Hodgkin's lymphoma of the
      tonsil].
AB  - OBJECTIVE: To investigate the prognostic value of the size of primary tumor (T
      staging) and international prognostic index (IPI) for patients with non-Hodgkin's
      lymphoma (NHL) of the tonsil, and to recommend the treatment strategy for early
      stage patients. METHODS: 306 patients with untreated NHL of the tonsil were
      reviewed. According to Ann Arbor staging classification, 35 patients had stage I,
      178 stage II, 49 stage III and 44 stage IV disease. According to 1997' AJCC
      staging system, 29 patients had T1, 142 T2, 117 T3 and 18 T4 disease. Twelve
      stage I patients were given radiotherapy alone and 23 stage II patients were
      given combined modality therapy (CMT). For patients with stage II lesion, 57 were
      given radiotherapy alone, 2 chemotherapy alone and 119 CMT. Chemotherapy was the
      main treatment in patients with stage III or IV lesions. RESULTS: The 5-year
      cancer specific survival (CSS) was 74% for patients with T(1), 59% for T(2), 56%
      for T(3) and 26% for T(4), respectively (P = 0.000). The 5-year CSS was 70% for
      patients with 0 risk factor, 49% for 1 risk factor, 25% for 2 or 3 risk factor,
      respectively (P = 0.000). CMT significantly improved disease free survival (DFS)
      from 46% (radiotherapy alone) to 60% (CMT) for stage II patients (P = 0.046).
      Multivariate analysis showed that performance status, Ann Arbor staging, T
      staging, B symptom, and IPI were independent prognostic factors. CONCLUSION: The
      T staging of the primary tumor and IPI are the important prognostic factors of
      patients with NHL of the tonsil. Combined modality therapy significantly improves
      the disease free survival of stage II patients.

PMID- 12485505
TI  - [99mTc-Pingyangmycin imaging in the diagnosis of primary lung cancer].
AB  - OBJECTIVE: To evaluate the clinical value of (99m)Tc-Pingyangmycin (PYM) imaging
      for the diagnosis of primary lung cancer. METHODS: Radionuclide (99m)Tc
      Pingyangmycin (PYM) imaging was performed in 56 patients with pulmonary lesions.
      RESULTS: The uptake ratio and retention index (RI) were different in malignant
      and benign lesions. With the delayed ratio regarded as the threshold for lung
      cancer, the overall accuracy, sensitivity and specificity of (99m)Tc-PYM in the
      diagnosis of lung cancer were 82.1%, 82.7% and 80%, respectively. If RI was
      regarded as the threshold, the overall accuracy, sensitivity and specificity were
      94.6%, 93% and 100%, respectively. There was no significant difference among
      different histological types of the lung carcinoma. CONCLUSION: (99m)Tc-PYM, as a
      good imaging agent, is useful in differentiating malignant lung lesions from
      benign ones.

PMID- 12485506
TI  - [Sonographic diagnosis of carotid body tumor].
AB  - OBJECTIVE: To analyse the features of gray scale and colour Doppler sonography
      for carotid body tumor, to improve the sonographic diagnostic accuracy. METHODS:
      A retrospective review was performed of sonographic material of 18 carotid body
      tumors by gray scale sonography and 11 by colour Doppler sonography, with
      comparison with other diseases which are frequently misdiagnosed as carotid
      tumor. RESULTS: Well-defined, even weakly hypoechoic masses were noted on gray
      scale ultrasonogram at the carotid bifurcation, commonly broadening the carotid
      bifurcation and often encasing the common, external and internal carotid
      arteries. Disorderly non-echoic channel- like structures in the tumor were
      sometimes observed. Colour Doppler sonography showed abundant flow in the tumor.
      The non-echoic channel- like structures were vascularities. Seventeen masses
      diagnosed by ultrasound were proved to be carotid body tumors. The other was
      confirmed as a neurogenic tumor, giving an accuracy rate of 94.4% for sonographic
      diagnosis. CONCLUSION: Sonographic examination of the carotid body tumor is
      highly accurate. It is safe and reliable.

PMID- 12485507
TI  - [Clinico-pathological study of 98 patients with pulmonary solitary nodule].
AB  - OBJECTIVE: To arrive at correct diagnosis of pulmonary solitary nodule by
      clinical manifestation and chest CT scan. METHODS: Ninety-eight patients with
      pulmonary solitary nodule were treated from 1990 to 2000. Their CT findings with
      clinical manifestations were correlated with the pathology results. RESULTS: Of
      98 patients, there were 46 (46.9%) lung cancers, 14 (14.3%) benign tumors, 38
      (38.8%) tuberculosis. Fifty-six (57.1%) patients had been asymptomatic or only
      associated with cough and sputum. 50% of these patients had stage I lung cancer.
      Tuberculosis was diagnosed more frequently in young patients with protracted
      feverishness, night sweats, chest and back pain, whereas lung cancer was more
      common in older patients who were asymptomatic or associated only with cough,
      sputum and hemoptysis. Lesions with well-defined margin, smooth and in the middle
      lobe by chest CT was suggestive of benign tumor, while those with irregular
      margin, un-even density, spiculated margin, lobulated contour and pleural
      shrinkage were more commonly associated with lung cancer. Those with
      calcification and in the lower lobe implied tuberculosis. CONCLUSION: Screening
      of high risk population is useful in finding early lung cancer. Pulmonary
      solitary nodule can be correctly diagnosed chiefly by referring to the clinical
      manifestations and characteristics of chest CT scans. Nodules less than 1cm
      across are difficult to diagnose and, therefore, exploration is indicated.

PMID- 12485508
TI  - [Role of high resolution CT in diffuse pulmonary nodules].
AB  - OBJECTIVE: To evaluate high resolution CT (HRCT) in the diagnosis of diffuse
      pulmonary nodules. METHODS: Fifty normal chest radiographs, conventional CT and
      HRCT were used to evaluate the visualization of pulmonary lobule. The
      configuration, distribution and intrinsic structure of lesion in 38 patients with
      diffuse pulmonary nodules were analyzed by HRCT. RESULTS: The chest radiographs
      were not able to show the structure of pulmonary lobule. The visualization rates
      of pulmonary lobule were 20% by conventional CT and 50% by HRCT (P < 0.05). Of 38
      patients with diffuse pulmonary nodules, 19 had interstitial nodules which were
      located in the pulmonary intestities, the lobular septa and under the pleura.
      HRCT could clearly show their para-bronchial distribution with clear cut margin.
      Four had airspace nodules, chiefly shown as solidification of the air spaces.
      There was no nodule beneath the pleura or in the lobular septa. HRCT revealed
      even density and hazzy margins. Fifteen had randomly distributed nodules, with
      the nodules scattered at random. HRCT showed nodules with high density, sizes
      varying greatly but the margin was clear. CONCLUSION: High resolution CT is able
      to show the pattern of distribution, intranodular structures and background of
      the diffuse pulmonary nodules, which is valuable in the diagnosis and
      differential diagnosis of this disease.

PMID- 12485509
TI  - [Diagnosis and treatment of 178 patients with carcinoma of the head of pancreas].
AB  - OBJECTIVE: To improve the diagnosis and treatment of carcinoma of head of
      pancreas. METHODS: A retrospective study was carried out to evaluate 178 patients
      suffering from carcinoma of head of pancreas. RESULTS: Pain in the epigastrium
      and obstructive jaundice were observed in 70% and 74.2% of these 178 patients,
      both of which were of significance (P < 0.001) between stage I, II and stage III,
      IV disease. Only 18% of patients had pain in the back, 81.3% of whom belonged to
      the stage IV category. The detection rate of the tumor by B-ultrasound, CT and
      MRI were 74.2%, 87.3% and 85.5%, respectively. The success rate of
      pancreatoduodenectomy was 10.1%. The postoperative 1-, 3- and 5-year survival
      rates were 67.5%, 36% and 5.6%. Internal drainage was performed in 115 patients.
      The median survival time was 7 months in patients with unresectable tumor who
      received radiotherapy and/or chemotherapy. CONCLUSION: Pain in the epigastrium
      and obstructive jaundice are the most common symptoms. Hyperglycemia is the most
      common complication. Pain in the back implies an advanced lesion. CT is the most
      important way of diagnosis and the combination of B-ultrasound, CT and MRI may
      improve the rate of diagnosis up to 96.6%. By now, pancreaticoduodenectomy is
      still the only effective treatment for the carcinoma of head of pancreas and
      internal drainage is an important palliative measure.

PMID- 12485510
TI  - [Optimum mode of interventional treatment for hepatocellular carcinoma].
AB  - OBJECTIVE: To establish a reasonable protocol for interventional treatment of
      hepatocellular carcinoma (HCC). METHODS: The data of 1 000 HCC patients treated
      by different kinds of interventional treatment were reviewed with their results
      of biochemistry, imaging, pathology and survival rate evaluated. The value as
      well as the pros and cons of these various kinds of interventional treatment were
      compared in order to find an optimum protocol. RESULTS: Segmental-transcatheter
      oil chemoembolization (S-TOCE) was much effective eradicate the tumor yet
      inflicting less damage on the noncancerous hepatic tissue and giving much higher
      survival rate than the conventional transcatheter oil chemoembolization (C-TOCE).
      Percutaneous ethanol injection (PEI) played an important role in eradicating the
      residual tumor and improving the survival rate without damaging the noncancerous
      hepatic tissue. The survival quality or survival rate could be improved by
      choosing different ways of interventional treatments to cut down the
      complications. CONCLUSION: The selection of different interventional treatments
      should be done according to the size and type of HCC. Active management is
      indicated for different complications presenting along with HCC.

PMID- 12485512
TI  - [Combined treatment for locally advanced carcinoma of uterine cervix].
AB  - OBJECTIVE: To evaluate the feasibility of surgical management for patients with
      locally advanced carcinomas of uterine cervix after radical radiation therapy who
      were prone to develop central recurrence. METHODS: These 40 patients were treated
      by combined pre-operative radiotherapy with dose at point A of > 70 Gy in 30
      patients, 60 approximately 70 Gy in 7, 50 approximately 59 Gy in 2 and 44 Gy in
      1. The interval between radiation and surgery was 1 - 6 weeks. Extrafascial
      hysterectomy was performed in 15 patients, subradical hysterectomy in 23 and
      radical hysterectomy with pelvic lymphadenectomy in 2 cases. RESULTS: These
      patients have been followed up for 1 - 8 years with 2 died of other diseases and
      12 died of cancer. Eighteen of the 26 survivors have been followed up for more
      than 5 years. The 3- and 5-year survival rates were 74.9% and 66.8%. Half of the
      death occurred within the first year after treatment. The 2-year death rate was
      9/12 (75.0%). Three patients suffered from long term complications after the
      treatment, but all were cured by conservative management. CONCLUSION: The
      combination of hysterectomy performed shortly after radical radiotherapy, ie, for
      patients with locally poor prognostic cervical carcinoma is reasonable and
      feasible.

PMID- 12485511
TI  - [Nausea disintegrating buccal tablet in the prevention of gastrointestinal
      reaction induced by anticancer drugs].
AB  - OBJECTIVE: To evaluate the efficacy and safety of nausea oral, disintegrating
      buccal tablet (DBT) in the prevention of gastrointestinal reaction induced by
      anticancer drugs (cisplatin DDP 30 - 50 mg/m(2) or adramycin ADM >/= 40 mg/m(2)),
      as compared with those of kytril tablets. METHODS: A multicenter, open and
      randomized self-crossover control trial was carried out with all the eligible
      patients randomized into AB or BA group. Patients in AB group were given nausea
      0.1 mg as buccal tablet one hour before chemotherapy in the first cycle and
      kytril tablet 2 mg in the second cycle, those in BA group were given these drugs
      in the reverse order. RESULTS: Seventy-three patients were allotted to this
      study, including 44 patients in DDP-arm and 29 in ADM-arm. Sixty-two patients
      were evaluable for response and 70 patients for safety. Nausea DBT was as
      effective as kytril tablet in the control of anorexia, nausea and vomiting during
      the first 24 hours after chemotherapy, with response rates of 74.2%, 77.4%, 83.9%
      in nausea DBT and 74.2%, 71.0%, 88.7% DBT in kytril tablets. A high efficacy in
      the control of vommitting induced by cisplatin was observed in both nausea DBT
      and kytril tablets. The complete control rates and overall control rates were
      83.3%, 91.7% in nausea DBT and 86.1%, 97.2% in kytril tablets, respectively. The
      side effects of nausea DBT were head heaviness, dry mouth and somnolence, which
      were mild and comparable with kytril in their frequencies. CONCLUSION: Nausea
      disintegrating buccal tablet is able to effectively prevent gastrointestinal
      reaction induced by anticancer drugs, with efficacy and side effects similar to
      kytril tablets. Nausea DB tablet, an intraoral disintegrator, is very convenient
      for patients who can not swallow tablets for various reasons.

PMID- 12485513
TI  - [Clinical trial of lentaron for postmenopausal patients with advanced breast
      cancer].
AB  - OBJECTIVE: To evaluate the efficacy and adverse effects of lentaron for
      postmenopausal patients with recurrent and metastatic breast cancer. METHODS:
      Thirty-four patients with recurrent and metastatic breast cancer received 250 mg
      lentaron by intramuscular injection every 2 weeks for at least one month.
      RESULTS: In 34 patients who were evaluable for efficacy and toxicity, the
      complete response rate (CR), partial response rate (PR), disease stabilization
      rate (SD) and progressive disease rate (PD) were 0%, 14.7%, 58.8% and 26.5%. The
      clinical benefit rate (CR + PR + SD >/= 6 months) was 50.0%. (17/34) with 12
      patients (35.3%) having SD for at least 6 months. The response rates for bone,
      soft tissue and visceral metastasis were 28.6% (3/14), 13.6% (3/22) and 5.3%
      (1/19), respectively. There were no severe adverse effects in the treatment
      bylentaron. CONCLUSION: Lentaron is a well tolerated agent with reasonable
      efficacy but low toxicity for postmenopausal patients with recurrent and
      metastatic breast cancer.

PMID- 12485514
TI  - [The merits of comprehensive therapy for acute stroke].
AB  - OBJECTIVE: To evaluate the advantages of comprehensive therapy for acute stroke
      in a stroke unit. METHODS: The data of 207 acute stroke patients treated in a
      stroke unit in Australia (group A) were compared with those of 326 acute stroke
      patients treated in our neurological ward (group B). They were diagnosed by CT or
      MRI and found to have hemiplegia in 48 hours. RESULTS: There were significant
      differences between group A and group B in mortality within 14 days (5.3% vs
      10.4%), rate of non-cerebral causes of death (27.3% vs 64.7%) and rate of
      infection (17.9% vs 47.9%), P < 0.01. Moreover the scores of Europe Stroke Scale
      at 21 days and Modified Rankin Scale at 90 days were significantly different
      between the two groups (P < 0.01). CONCLUSION: Prognosis of acute stroke patients
      managed by comprehensive therapy in stroke unit was superior to that treated
      conventionally in neurological ward.

PMID- 12485515
TI  - [Evaluation of the factors leading to delay from stroke onset to arrival at
      hospital].
AB  - OBJECTIVE: To investigate the delay in time from stroke onset to arrival at the
      emergency department (ED) and to evaluate the factors associated with the delay.
      METHODS: In this prospective study, the factors influencing the delay in time
      from stroke onset to patients arrival at the ED and ED-CT and access to ED
      treatment were explored in 623 patients with acute stroke. The data recorded
      included patients' knowledge of stroke. RESULTS: The median time from onset to ED
      was 5.17 hours. Stepwise regression analysis showed that significant risk factors
      related to arrival delay included living alone at onset of the illness, no
      facility of ambulance transportation, presence of brain infarct, mild degree of
      neurological symptoms, long distance from home to hospital, not seeking seeking
      any help within the first hour, less attention to the stroke onset (P < 0.05 or P
      < 0.001). The median time from arrival at the ED to arrival at the CT scan was 10
      minutes. 75.8% patients finished CT scan within 30 minutes and 78.2% were treated
      within one hour. CONCLUSIONS: There is significant time delay from stroke onset
      to patients arrival at the ED. Further health education is necessary to increase
      the public awareness of seeking medical help after stroke onset and having
      ambulance transportation to an acute-care hospital.

PMID- 12485516
TI  - [A clinicopathological study of corticobasal degeneration].
AB  - OBJECTIVE: To elucidate clinical and pathological features of corticobasal
      degeneration. METHODS: Clinical and image materials of 2 the aged with movement
      disturbances and dementia were reviewed, their brain tissues were investigated by
      routine pathological methods, Gallyas-Braak staining and Tau immunohistochemical
      staining. RESULTS: Both cases early presented movement disturbance on unilateral
      extremity including akinesia, rest tremor, postural instability, and then
      gradually developed rigidity of axial and four extremities, myoclonus, impaired
      ocular movement, cognitive disturbance from moderate dementia to decorticate
      state. On SPECT, one case showed hypoperfusion of left frontal-temporal cortices,
      another presented asymmetric atrophy of frontal-parietal cortices on CT. Main
      findings on routine pathological examination were prominent atrophy of the
      frontal-parietal lobe, the basal ganglia, the midbrain and upper pons. The
      cortical layers of the frontal, parietal and insular lobe showed mild neuronal
      loss with gliosis and scattered ballooned neurons. Neuron losses and extensive
      gliosis of basal ganglia and substantia nigra were remarkable. Gallyas-Braak and
      tau staining showed globous inclusion in remaining neurons of basal ganglia,
      substantia nigra and locus ceruleus et at, substantive glial cytoskeletol
      degeneration including astrocyte plaques, tuft-shaped astrocyte were also found
      in cortex on frontal and parietal lobe and in basal ganglia. CONCLUSION: Based on
      the above-mentioned clinical and pathological features, it may be not difficult
      to diagnosis corticobasal degeneration.

PMID- 12485517
TI  - [The clinical and pathologic features of Charcot-Marie-Tooth disease].
AB  - OBJECTIVE: To study the clinical and pathological features of Charcot-Marie-Tooth
      disease (CMT). METHODS: The general clinical data, the changes of
      neuroelectrophysiology and the pathological features of neural and muscular
      biopsy of 20 CMT patients were comprehensively analyzed. RESULTS: The clinical
      manifestations in the two types of CMT were nearly the same, but the changes of
      neuroelectrophysiology and the pathological characteristics of the neural and
      muscular biopsy in the two types were obviously different. 16 cases of CMT type 1
      were characterized by decreased sensory nerve conduction velocity (SNCV < 30 m/s)
      and are associated with demyelinating hypertrophic neuropathy. 4 cases of CMT
      tylpe 2 were characterized by normal SNCV and associated with axonopathy.
      CONCLUSION: Neuroelectrophysiology and neural and muscular biopsy are important
      for the diagnosis of CMT.

PMID- 12485518
TI  - [The effect of age on the clinical outcomes of patients with acute myocardial
      infarction treated by direct percutaneous coronary intervention].
AB  - OBJECTIVE: To investigate the effect of old age on the clinical outcomes of
      patients with ST-segment elevation acute myocardial infarction (STEMI) treated by
      primary percutaneous coronary intervention (PCI). METHODS: 156 consecutive
      patients with STEMI treated by primary PCI were divided into two groups according
      to the age of patients: (1) >or= 75 years group (35 cases), with a mean (79.6 +/-
      4.1) years; (2) < 75 years group (121 cases), with a mean (60.5 +/- 8.7) years.
      The baseline clinical characteristics and coronary artery lesions were analyzed
      and major cardiovascular events (MACE) were followed-up during a period of 1 - 12
      months. RESULTS: There were higher proportion of stroke, longer duration of onset
      of symptom to balloon and lower left ventricular ejection fraction (LVEF) in
      patients >or= 75 years than in those < 75 years (all P < 0.05). Coronary
      angiogram indicated there was lower percentage of patients with single vessel
      disease, but higher percentage of patients with multivessel disease in >or= 75
      years group than in < 75 years group (all P < 0.05). One hundred and forty five
      patients (32 cases >or= 75 years and 113 cases < 75 years) were followed-up. No
      significant difference in rate of non-fatal reinfarction was found between the 2
      groups, but the hospital cardiac mortality was higher in patients >or= 75 years
      than in those < 75 years (9.4% vs 1.8%, P < 0.05). During a mean of (7.3 +/- 3.2)
      months follow-up, the total cardiac mortality rate increased significantly in
      >or= 75 years group than in < 75 years group (12.5% vs 1.8%, P < 0.05).
      Multivariate logistic regression analysis showed that age >or= 75 years and
      decrease in LVEF were associated with increased cardiac mortality in patients
      with STEMI referred to primary PCI. CONCLUSION: Age >or= 75 years was an
      independent predictor for increase in cardiac mortality in patients with STEMI
      treated by primary PCI.

PMID- 12485519
TI  - [Clinical analysis of 31 patients with gastric stromal tumors].
AB  - OBJECTIVE: To investigate the clinical manifestations, diagnosis and treatment of
      gastric stromal tumors. METHODS: 31 patients with gastric stromal tumors treated
      from 1993, 1 - 2001, 9 were analyzed retrospectively. All cases were diagnosed by
      pathological and immunohistochemistry examinations. According to Levin's standard
      combining with Hurliman's and Goldbum's methods, the patients were classified.
      RESULTS: There are no significant difference between male and female patients. 50
      - 60 years old patients have high incidence. The distribution of gastric tromal
      tumors is fundus > body > antrum. Diagnosis of this condition is sometimes
      difficult and treatment is often delayed because patients usually present with
      nonspecific abdominal symptoms. The main manifestations of gastric stromal tumors
      are upper gastrointestinal hemorrhage 61.3% (19/31), 7 patients with acute
      hemorrhage and 12 with chronic hemorrhage. Most of them were malignant. Abdominal
      malaises and/or distention 32.3% (10/31) and abdominal pain 22.6% (7/31).
      Gastroscopy, ultrasound gastroscopy, computed tomography, B type ultrasound and
      upper gastrointestinal X-ray series are helpful to diagnosis. But the final
      diagnosis is decided by pathological and immunohistochemistry examinations.
      Gastric stromal tumors exhibit consistent immunohistochemical expressions of
      CD(117) and/or CD(34). The operative treatment is thought of the first choice.
      Effect of the chemotherapy isn't satisfied. There is no standard chemotherapy for
      gastric stromal tumors. CONCLUSIONS: Gastric stromal tumor is a kind of separated
      submucosal tumor which is different from leiomyoma, leiomyosarcoma and neurogenic
      tumors. Pathological and immunohistochemistry inspectations are very important to
      make clear diagnosis. Early diagnosis and rational treatment are the keys to
      improve the prognosis.

PMID- 12485520
TI  - [The research the relationship between N-acetyltransferase 1 gene polymorphisms
      and genetic susceptibility to sporadic colorectal adenocarcinoma].
AB  - OBJECTIVE: In this study, we analyzed the association genetic polymorphisms of N
      acetyltransferase 1 (NAT1) with genetic susceptibility to sporadic colorectal
      adenocarcinoma (SCRAC). METHODS: All subjects are unrelated Han people in Hubei
      province of China. Using multiple PCR and PCR-RFLP, we studied the genotypes and
      genetic polymorphisms of the NAT1 gene of 101 healthy controls and 104 SCRAC
      patients. RESULTS: (1) The frequency of NAT1 * 10 was significantly higher among
      the SCRAC when compared with the controls (P < 0.05, OR = 1.91, 95% CI = 1.1 -
      3.4), and among the elder SCRAC when compared to the controls (P < 0.01, OR =
      2.91, 95% CI = 1.48 - 5.90), (2) The frequency of NAT1 * 10 relative to SCRAC
      tumor location as follow: proximal SCRAC (44.4%), distal SCRAC (41.6%), all the
      difference were not statistically significant relative to the controls; The
      frequency of NAT1 * 10 genotype was significantly higher in stage II cases (P <
      0.05, OR = 2.48, 95% CI = 1.18 - 5.20) and stage III and IV cases (P < 0.05, OR =
      3.04, 95% CI = 1.28 - 7.20) when compared with the controls. CONCLUSIONS: NAT1 *
      10 has increased risk of SCRAC and significantly related to the later stage
      tumors, is not significantly related to the tumor location, whether the elder
      individuals with NAT1 * 10 have increased risk of SCRAC needs further study.

PMID- 12485521
TI  - [Long-term outcome of acute massive pulmonary thromboembolism following
      thrombolysis].
AB  - OBJECTIVE: To evaluate in-hospital course and long-term outcome of acute massive
      pulmonary thromboembolism after thrombolysis and to determine its prognostic
      factors. METHODS: A total of 260 patients was retrospectively reviewed and
      followed up for 3.9 - 8.4 years. Close attention was paid to the clinical events,
      including death, recurrent thromboembolic events, chronic thromboembolic
      pulmonary hypertension, bleeding complications attributed to anticoagulant
      therapy, and requirement of oxygen therapy at home. Kaplan-Meier event-free
      survival curves were generated. RESULTS: The in hospital mortality rate was 8.5%,
      in which 68.2% were due to pulmonary thromboembolism itself, and the follow-up
      mortality rate was 31.7%, in which 29.2% were due to recurrent embolism.
      Univariate analysis showed that six variables were associated with the occurrence
      of clinical events: (1) Prior thromboembolic diseases; (2) Duration of
      anticoagulant therapy less than 6 months; (3) Inferior vena cava filter
      placement; (4) Remaining right ventricular dysfunction/dilatation after
      thrombolysis detected by echocardiography; (5) Systolic pulmonary pressure > 50
      mm Hg after thrombolysis by echocardiography; (6) Greater than 30% residual
      obstruction of pulmonary vasculature identified by lung ventilation/perfusion
      scintigraphy before hospital discharge. Multivariate analysis identified three
      independent risk factors for long-term mortality of acute massive pulmonary
      thromboembolism after thrombolysis: (1) Systolic pulmonary artery pressure > 50
      mm Hg (RR: 3.78, 95% CI = 2.70 - 4.86); (2) Right ventricular
      dysfunction/dilatation (RR: 2.18, 95% CI = 1.48 - 2.88); (3) Greater than 30%
      obstruction of pulmonary vasculature (RR: 1.99, 95% CI = 1.25 - 2.70).
      CONCLUSIONS: Doppler echocardiographic assessment after thrombolysis and
      ventilation/perfusion scintigraphy prior to hospital discharge are valuable to
      establish a new baseline condition, which is informative for risk stratification
      and prognostication of long-term outcome.

PMID- 12485522
TI  - [The relationship between serum leptin, proinsulin, true insulin levels and
      insulin resistance in non-diabetic subjects: a population-based study].
AB  - OBJECTIVE: Leptin is involved in the regulation of body weight and metabolism.
      Previous data have suggested that leptin levels are related to insulin resistance
      and in a few reports with impaired insulin secretion. Some even revealed the
      existence of adipoinsular axis. However, little is known of these relations in
      Chinese population. With the availability of measurements of true insulin (TI),
      proinsulin (PI) and leptin, we examined the possible correlation of leptin with
      TI, PI and with insulin resistance (the HOMA model) in non-diabetic subjects of
      north China. We also evaluated whether leptin levels were associated with
      impaired insulin secretion, as evaluated by the fasting PI/TI ratio. METHODS: 902
      non-diabetic subjects (670 with normal and 232 impaired glucose tolerance, aged
      30 - 80 y) from a population of Beijing residents who underwent a diabetes survey
      in 2000 were studied. Fasting serum leptin, PI and TI levels were detected by
      sensitive and specific enzyme-linked immunosorbent assays (ELISA) which were all
      developed in our laboratory. RESULTS: Serum leptin values were higher in women.
      Correlation analysis showed that leptin levels were significantly correlated with
      fasting TI, PI and insulin resistance (HOMA-IR) (in men, n = 794, r = 0.345,
      0.236 and 0.364 respectively; in women, n = 110, r = 0.574, 0.375 and 0.576
      respectively, P < 0.001), but not with PI/TI ratio (r = -0.09, P < 0.01) in both
      sex. After adjustment for age, body mass index (BMI) and waist-to-hip ratio
      (WHR), leptin levels remained significantly correlated with TI, PI and HOMA-IR,
      although the magnitude of the association was considerably attenuated.
      CONCLUSIONS: TI and PI levels were positively related to leptin levels
      independent of obesity and body fat distribution. Thus, subjects with increased
      insulin levels and/or insulin resistance may be relatively resistant to the
      effects of leptin, suggesting a dysfunction of leptin-insulin axis. However,
      leptin levels are not significantly associated with the fasting PI/TI ratio
      suggesting that leptin levels are not associated with an impairment in insulin
      secretion. The role of association between hyperinsulinemia/insulin resistance
      and hyperleptinemia/leptin resistance in the pathogenesis of insulin resistance
      related diseases needs further study.

PMID- 12485523
TI  - [Antigen transporter gene polymorphism and predisposition to Graves disease: a
      preliminary analysis].
AB  - OBJECTIVE: To examine the distribution of transporter associated with antigen
      processing (TAP) gene polymorphism in a southern Chinese population and the
      association between TAP gene polymorphism and predisposition to Graves disease.
      METHODS: We have performed TAP genotyping in 67 Graves disease patients and 69
      healthy controls by amplification refractory mutation system (ARMS). RESULTS:
      Distribution of TAP genes in our healthy controls shows similar but some
      different findings as compared with studies in other countries and other regions
      of our country, suggesting that the distribution of TAP genes might have ethnic
      or regional differences. The frequency of TAP1D haplotypes was significantly
      higher in the healthy controls than in the Graves disease patients (RR = 0.17, P
      < 0.01), and the frequency of TAP1C haplotypes was significantly lower in the
      healthy controls than in the Graves disease patients (RR = 2.05, P < 0.05). The
      frequency of TAP2A haplotypes was significantly higher in the healthy controls
      than in the Graves disease patients (RR = 0.46, P < 0.05), and the frequency of
      TAP2F haplotypes was significantly lower in the healthy controls than in the
      Graves disease patients (RR = 9.95, P < 0.05). CONCLUSION: TAP1D and TAP2A
      haplotypes might confer protection against Graves disease while TAP1C and TAP2F
      haplotypes might confer cause susceptibility to Graves disease.

PMID- 12485524
TI  - [The re-expression of p15(INK4B) gene in leukemia cells induced by in vitro DNA
      methyltransferase and histone deacetylase inhibition].
AB  - OBJECTIVE: To explore the possibility of re-expression of silenced p15(INK4B)
      gene in leukemia cells by 5-Aza-2'-deoxycytidine (CdR), a DNA methyltransferase
      inhibitor, and sodium butyrate (SB), a histone deacetylase inhibitor. METHODS: A
      myeloid leukemia cell line, KG1a and two primary cultured leukemia cells isolated
      from bone marrow of AML-M(2) and MDS-RAEB-T patients were chosen as the
      experimental target. The methylation pattern of p15(INK4B) gene was analyzed with
      restriction endonucleases combined with PCR technique. The expression level of
      mRNA and protein was detected by RT-PCR technique and Western blot. RESULTS: All
      detected leukemia cells showed a hypermethylated promoter region of p15(INK4B)
      gene with complete or partial loss of expression of mRNA and protein. Either CdR
      or SB induced weak expression of p15(INK4B) with a dose dependent effect.
      Combined low dose of CdR (0.5 micro mol/L) and SB (0.5 mmol/L) increased the
      expression level of p15(INK4B) significantly. The synergistic effect of the two
      drugs was significantly stronger than that of any drug of high dose alone.
      CONCLUSION: Hypermethylated and silenced p15(INK4B) gene could be re-expressed by
      synergy of CdR and SB.

PMID- 12485525
TI  - [Antigens of antineutrophil cytoplasmic autoantibodies in recognizing a novel
      neutrophil granule antigen in lupus nephritis and its association with
      photosensitivity and oral ulceration].
AB  - OBJECTIVE: To investigate whether there are some unknown target antigens of
      antineutrophil cytoplasmic autoantibodies (ANCA) in patients with lupus nephritis
      (LN) and the prevalence and the clinical significance of these unknown target
      antigens. METHODS: Serum was collected from 72 renal-biopsy-proven lupus
      nephritis (LN) patients. Mixed neutrophil granules were separated from normal
      human peripheral neutrophils and soluble acid extracts in non-reducing conditions
      were used as antigens in Western-blot analysis to detect ANCA in the serum sample
      of LN patients. RESULTS: Serum from seme LN patients could blot a few bands.
      Interestingly, serum from 14/72 (19.4%) of the patients recognized a novel 69,000
      protein band and that from 10/72 (13.9%) sera recognized a 55,000 protein band
      that might be the bactericidal/permeability-increasing protein (BPI). The 69,000
      target antigen was different from the known target ANCA antigens such as
      cathepsin G and lactoferrin. Further study revealed that the percentages of
      patients with photosensitivity and oral ulcer in anti-69,000 autoantibody
      positive group were significantly higher than those in the anti-69,000
      autoantibody negative group (57.1% vs 12.1%, P < 0.005, and 50.0% vs 17.2%, P <
      0.05, respectively). CONCLUSIONS: A novel 69,000 protein in human neutrophil
      granules is identified as a target antigen of ANCA in LN patients. The anti
      69,000 autoantibodies may be associated with photosensitivity and oral ulcer in
      LN patients.

PMID- 12485526
TI  - [Comparison of two score models in predicting prognosis and renal outcome in
      acute renal failure].
AB  - OBJECTIVE: To compare the value of ATN-ISI (acute tubular necrosis-individual
      severity index) and APACHE II (acute physiology and chronic health evaluation)
      score models in predicting mortality and renal outcome in patients with acute
      renal failure (ARF). METHODS: 422 in-hospital patients with ARF were
      retrospectively analysed, the value in predicting prognosis and renal outcome of
      these two score models was compared. Renal outcome was observed three times, i.e.
      >or= 30 days, >or= 45 days and >or= 60 days after the occurrence of ARF and
      discriminant analysis was used in the study. RESULTS: The scores of the two
      models both correlated significantly with the mortality of patients with ARF.
      When ATN-ISI scores were >or= 0.85, the mortality was 100% and it was the same
      with APACHE II when the scores were >or= 35. The areas under ROC curve of APACHE
      II and ATN-ISI were 0.817 +/- 0.021 and 0.880 +/- 0.018 respectively, suggesting
      good model discriminantion. For the correctly classificated rate of renal
      outcome, ATN-ISI was better than APACHE II at any time. When ATN-ISI scores were
      >or= 0.75, patients were dialysis dependent. When the scores were >or= 0.58 but
      less than 0.75, the patient's renal function did not recover but was not dialysis
      dependent; when the scores were < 0.58, the patients's renal function would
      recover. When APACHE II scores were >or= 26, patients were dialysis dependent.
      There was no cut-off score point to separate renal function recovery from renal
      dysfunction. However, when APACHE II scores were <or= 22, 19.6% of the patients
      had renal dysfunction and 80.4% of them had renal function recovered. CONCLUSION:
      Both the score models are of value in predicting mortality and renal outcome in
      patients with ARF. ATN-ISI score model was better than APACHE II.

PMID- 12485527
TI  - [The clinical significance of negative serological markers of hepatitis B
      infection in hepatitis B virus carriers with chronic hepatic disease].
AB  - OBJECTIVE: To assess the clinical significance of cases who were negative for
      hepatitis B serological markers but were found incidently to be HBV carriers with
      HBV replicative infection. METHODS: In 12 out of the 50 biopsy proved cases, the
      hepatitis B serological markers and anti-HCV were all negative and ALT level also
      normal in repeated assays. Serum HBV DNA and HCV RNA of all the cases were
      analysed by PCR. Liver specimens were examined by immunohistochemistory for HBsAg
      and HBcAg. The pathological changes were classified into 4 grades and 4 stages,
      and Knodell HAI was also recorded. RESULTS: Five cases initially diagnosed as HBV
      carriers showed high viral replication (4 cases had loads of 10(4) approximately
      10(5) copies/ml, the other 1 had < 10(4) copies/ml). The periportal and/or
      intralobular inflammation and fibrosis were G1 and S1. The virus load of the 4
      cases initially suspected of chronic hepatitis were even higher (2 case > 10(6)
      copies/ml, 2 case > 10(5) copies/ml). On the contrary, 3 cases initially
      suspected of liver cirrhosis showed low replication (all less than 10(4)
      copies/ml), but their histologic changes were more advanced, 2 cases of G4 and
      S4, 1 case of G3 and S4. Their HAI were 17, 17 and 11, respectively. CONCLUSIONS:
      HBV carriers with normal level of ALT and negative serological HBV markers are
      not very uncommon. They often have a high replicative infection. Some of the
      chronic hepatitis patients with normal ALT and negative serological HBV markers
      have more active viral replication. The clinical significance of this kind of
      patients should not be underestimated. It may be the cause of some cases of
      cryptogenic cirrhosis and hepatocellular carcinoma of unknown etiology.

PMID- 12485528
TI  - [The effects of hepatitis E virus superinfection on patients with chronic
      hepatitis B: a clinico-pathological study].
AB  - OBJECTIVE: To observe the effect of hepatitis E virus (HEV) superinfection on
      hepatic lesion and hepatitis B virus (HBV) replication in patients with chronic
      hepatitis B (CHB). METHODS: Totally 122 patients with CHB were enrolled in this
      study. They were tested for anti-HEV IgM and IgG in serum, amount of HBV DNA in
      serum and liver tissue obtained by liver biopsy and HBcAg expression in liver
      tissue. Other parameters such as ALT, total bilirubin (TBil), albumin (A) and
      globulin (G), gamma-electrophoretic protein (gamma-EP), prothrombin activity
      (PTA) were also measured. 21 of the 122 patients (17.2%) were found to have HEV
      superinfection and the remaining 101 were not. Repeat liver biopsy was performed
      after 1 year in 7 patients with HEV superinfection and 14 patients without.
      Moreover, HBV DNA amount in serum from 8 HBeAg negative patients with HEV
      superinfection were tested dynamically in acute and recovery stage of HEV
      infection. RESULTS: Comparison of the data from the 21 patients with HEV
      superinfection and 101 without showed that there was no significant difference in
      the level of A/G ratio (1.74 +/- 0.50 vs. 1.83 +/- 0.37) and gamma-EP [(24.18 +/-
      6.36)% vs. (22.27 +/- 4.59)%, P > 0.05]. However, the level of ALT [(244.61 +/-
      81.07) U/L vs. (143.87 +/- 47.69) U/L] and TBil [(88.24 +/- 28.54) micro mol/L
      vs. (46.16 +/- 17.13) micro mol/L] was significantly higher (P < 0.05), but that
      of PTA lower in the group with HEV superinfection than in the group without
      superinfection [(58.57 +/- 17.44)% vs. (72.52 +/- 12.25)%, P < 0.05]. So were the
      amount of HBV DNA in serum [(5.45 +/- 1.86) copies/ml vs. (6.59 +/- 1.28)
      copies/ml, P < 0.05] and liver tissue [(6.96 +/- 2.52) copies/g vs. (8.47 +/-
      1.79) copies/g, P < 0.05] as well as HBeAg and HBcAg positive rates (8/21 vs.
      64/101; 9/21 vs. 67/101, P < 0.05). Pathologically, the hepatic inflammatory
      activity was more severer in patients with HEV superinfection, but the severity
      of fibrosis was not significantly different. There was no difference in the
      severity of inflammatory activity and stage of fibrosis between the 7 patients
      with HEV superinfection and the 14 patients without as well as before and after 1
      year of treatment. The amount of HBV DNA and HBeAg positive rate in serum from
      recovery stage of HEV infection were higher than those of acute stage.
      CONCLUSIONS: HEV superinfection leads to activation of hepatic pathological
      changes and worsens the inflammatory activity. Moreover, HEV superinfection
      inhibits HBV replication, but it may not be long-lasting.

PMID- 12485529
TI  - [Effect of inhibitor RNA on intracellular inhibition of viral gene expression in
      5'-noncoding region of hepatitis C virus].
AB  - OBJECTIVE: To determine the effect of internal ribosome entry site (IRES)specific
      inhibitor RNA (IRNA) on viral gene expression mediated by HCV 5' noncoding region
      (NCR) in human hepatic carcinoma cell line. METHODS: Cotransfection of pCMVNCRluc
      containing 5'NCR-luc fusion genes and eukaryotic vectors of IRNA into human
      hepatic carcinoma cells (HHCC) was performed and the luciferase activity of
      reporter gene was measured by luminometer. RESULTS: pCMVNCRluc was efficiently
      expressed in HHCC. IRES specific IRNA significantly inhibited the expression of
      luc mediated by HCV IRES by 50% to 90%, but the mutant IRNA lost the activity of
      inhibition. CONCLUSION: IRNA can inhibit HCV IRES mediated gene expression in
      vivo.

PMID- 12485530
TI  - [Effect of metformin on gene expression of phosphoenolpyruvate carboxykinase].
AB  - OBJECTIVE: To investigate the effect and mechanism of antihyperglycemic agent
      metformin on the gene expression of phosphoenolpyruvate carboxykinase (PEPCK)-a
      key enzyme within the regulation of gluconeogenesis in hepatocytes and to
      determine whether the effects of metformin on hepatocytes are transmitted
      throughout the known insulin signaling pathways. METHODS: Confluent H4IIE rat
      heptoma cells were cultured with metformin 0.1 mmol/L for 16 h and then
      stimulated with various agents: insulin, cyclic adenosine monophosphate (cAMP),
      dexamethasone, signaling transduction inhibitor wortmannin and UO126. The gene
      expression of PEPCK was examined by Northern blot analysis. RESULTS: Metformin
      significantly decreased basal PEPCK mRNA levels by 75% (P < 0.01). Incubation
      with metformin alone had no significant effect on cAMP/dexamethasone stimulated
      PEPCK gene expression. In contrast, insulin 0.1 nmol/L significantly inhibited
      cAMP/dexamethasone stimulated PEPCK gene expression by 67% (P < 0.01), when
      insulin 0.1 nmol/L was present together with metformin, cAMP/dexamethasone
      induced PEPCK gene expression was decreased by 94% (P < 0.01). Both insulin
      signaling pathway inhibitors, phosphatidyl-inositol-3-kinase (PI3K) inhibitor
      wortmannin and mitogen-activated protein kinase (MAPK) inhibitor UO126, had no
      significant effect on inhibited PEPCK mRNA expression by metformin, but
      wortmannin blocked significantly inhibitory regulation of insulin on PEPCK gene
      expression (P < 0.01). CONCLUSION: Metformin can inhibit the PEPCK gene
      expression via either an insulin-independent or interaction with insulin manner.
      The inhibitory effects of insulin on PEPCK gene expression are mediated through
      PI3K pathway, not MAPK pathway.

PMID- 12485531
TI  - [Relationship between changes in activities of low density lipoprotein receptor
      and gene mutation in familial hypercholesterolemia].
AB  - OBJECTIVE: To analyse the LDL receptor (LDLR) function and gene mutation in a
      familial hypercholesterolemia (FH) patient and illustrate the effects of gene
      mutation type on LDL receptor function. METHODS: The pedigree of a FH proband was
      set up according to the serum lipid analysis and clinical presentations. The LDLR
      functions of cultured fibroblasts were investigated by radiolabelled ligand
      method. PCR-SSCP and DNA sequencing were performed on the genomic DNA isolated
      from whole blood RESULTS: 11 heterozygotes and 1 homozygote of FH were confirmed
      by pedigree analysis. The binding of LDL by LDLR of the proband was nearly normal
      while the uptake and degradation of LDL were only 3.6% and 1.7% as compared with
      controls. A frameshift mutation resulted from a G insert in codon 599 and a null
      mutation caused by CCA-->CCG base shift in codon 842 were found in exon 17.
      CONCLUSION: A novel mutation of LDLR gene was reported. This mutation may
      severely affect the function of LDLR.

PMID- 12485532
TI  - [The cognitive variations among non-dementia elders: from successful aging to
      mild cognitive impairment].
AB  - OBJECTIVE: To study the heterogeneity of cognitive function in the non-demented
      elderly population with complaint of memory decline. METHODS: Neuropsychological
      tests were carried out in 34 subjects by using clinical memory scales including
      17 variables and Q-type cluster analysis was performed. RESULTS: Fifteen subjects
      (44%) were diagnosed as mild cognitive impairment (MCI). Six new clusters were
      produced by cluster analysis. CONCLUSION: In the transitional period from normal
      aging to early Alzheimer's disease, the cognitive function of elders are
      heterogeneous, there may be cognition of successful aging, cognition of normal
      aging and even cognitive impairment with potential risk of dementia.

PMID- 12485533
TI  - [The systemic manifestations of ulcerative colitis].
AB  - OBJECTIVE: To probe the relationship between location and extent of ulcerative
      colitis (UC) by analyzing its extra-intestinal manifestations. METHODS: 392 UC
      cases in Peking Union Medical College Hospital from 1976 to 2000 were reviewed
      retrospectively. Chi-square test was used to test the difference between groups.
      RESULTS: 82 of 392 patients (20.9%) with UC had extra-intestinal manifestations,
      34 (8.7%) of these patients had more than one extra-colonic organ involvement; It
      shows that the extensive colitis has highest incidence of extra-intestinal
      manifestations with UC than that of the left-sided colitis did, while the
      proctitis had the lowest incidence. There were no significant difference (P >
      0.05) between the group of extensive colitis and that of left-side colitis; The
      incidence of extra-intestinal manifestations in severe cases was significantly
      greater than that in mild cases. There was a trend of increasing incidence from
      severe to moderate to mild type (P < 0.05); Most of the extra-intestinal
      manifestations were associated with active UC, except for AS, PSC, healed during
      SASP and/or steroid treatment. CONCLUSIONS: Extra-intestinal manifestations had a
      high incidence in UC. The most frequently involved organs were joints,
      hepatobiliary system, skin, mouth and eyes. The majority of them were associated
      with the active UC. The incidence of extra-intestinal manifestations with UC was
      closely related with the extent and severity of the lesions, and the most of the
      extra-intestinal manifestations occurred in the active phase of UC. But the
      incidence of extra-intestinal manifestations was not related to prognosis.

PMID- 12485534
TI  - [Correlation between exon5 polymorphism of glutathione S-transferase P1 gene and
      susceptibility to chronic obstructive pulmonary disease in northern Chinese
      population of Han nationality living in Beijing, China].
AB  - OBJECTIVE: This research aimed to investigate the correlation between glutathione
      S-transferase P1 (GSTP1) gene exon5 A/G polymorphism and chronic obstructive
      pulmonary disease (COPD) susceptibility in northern Chinese population of Han
      nationality living in Beijing. METHODS: The genotypes of 97 COPD patients and 67
      smoking control subjects without COPD were determined by polymerase chain
      reaction followed by restriction fragment length polymorphism for the GSTP1 gene
      exon5. RESULTS: No significant differences were observed in the frequencies of
      polymorphic genotypes in exon5 of GSTP1 gene between COPD patients and control
      smokers (genotype frequency: AA: 72% vs 61%; AG: 23% vs 36%; GG: 5% vs 3%; P >
      0.05). The allele frequencies were also not significantly different between two
      groups (A allele frequency: 84% vs 79%, P > 0.05; G allele frequency: 16% vs 21%;
      P > 0.05). There were no significant differences in the frequencies of
      polymorphic genotypes and allele of GSTP1 between the male COPD patients and male
      control smokers. CONCLUSION: The genetic polymorphism in GSTP1 gene exon5 was not
      associated with the susceptibility to COPD in northern Chinese population of Han
      nationality.

PMID- 12485535
TI  - [Regulation of alpha(1) type I collagen promoter by cytokines and losartan].
AB  - OBJECTIVE: To study the roles of transforming growth factor (TGF) beta(1), PDGF
      and losartan on regulation of collagen gene promoter. METHODS: To rat mesangial
      cells transfected by pCOLH 1.5 and pCOLH 2.5, which were composed of different
      length of alpha(1) type I collagen gene promoter segments and chloramphenicol
      acetyltransferase (CAT) were added different concentrations of TGF beta(1), PDGF,
      Ang II and losartan. The activity of CAT was measured by ELISA technique.
      RESULTS: TGF beta(1) enhanced the activity of pCOLH 1.5 and pCOLH 2.5 dose
      dependently, showing significant difference with the control (P < 0.01). CAT
      activities of pCOLH 1.5 and pCOLH 2.5 were not affected with 10 micro g/L and 25
      micro g/L of PDGF (P > 0.05). Ang II could increase the CAT activity of the two
      recombinants. Losartan inhibited the transcriptional activity of the promotor.
      Losartan + Ang II decreased the enhancement of the activity of promoter
      recombinant CAT (P < 0.01). CONCLUSION: In mesangial cells, TGF beta(1) enhanced
      the activity of alpha(1) type I collagen promoter. PDGF did not significantly
      regulate the activity of CAT. Losartan prevented the increase of the activity of
      promoter transcription induced by Ang II partly.

PMID- 12485536
TI  - [The morphological, immunophenotypical and cytogenetic characteristics study of
      blast crisis in chronic myeloid leukemia].
AB  - OBJECTIVE: To explore the morphological, immunophenotypical and cytogenetic (MIC)
      characteristics of chronic myeloid leukemia in blast crisis (CML-BC). METHODS:
      Marrow cells from 31 CML-BC patients were studied by bone marrow smears with
      morphological and cytochemical stain analysis. Immunophenotypic analysis was
      performed by micro blood method and flow cytometry. Cytogenetic analysis was
      performed using bone marrow cells prepared directly and or after 24 hours
      culture. RHG banding was used for karyotypic analysis. RESULTS: 23 patients
      (74.2%) were found to have myeloid blast crisis. 5 cases (16.1%) had a B-lymphoid
      immunophenotype and 4 of them expressed myeloid associated antigens at the same
      time. Another 3 cases were classified as acute undifferentiated leukemia (AUL 1
      patient) and acute myeloid -lymphoid leukemia (AMLL 2 patients) with B and
      myeloid markers expression. A significant proportion (67.7%) of blast crisis
      cases were CD(34) positive. CD(34) was expressed in 80.0% of lymphoid and 65.2%
      of myeloid BC. Analysis of the relationship between CD(7) and CD(34) expression
      in blasts of myeloid crisis showed their dual expression in 8/23 (34.8%) of the
      cases. Cytogenetic analysis indicated that 14/27 (51.9%) of the patients had
      developed secondary cytogenetic abnormalities in addition to the Ph chromosome.
      These newly emerging abnormalities included a trisomy 8 in 3 patients, a double
      Ph chromosome in 3 patients, an iso chromosome 17q in 2 patients, loss of Y
      chromosome in 1 patent and other complicated translocation in 5 patients.
      CONCLUSION: Blast crisis of CML is a kind of disease of stem cell. The
      differentiation of blast cell is blocked in the early stage. The prognosis of
      such patients is poor. MIC showed its important values in diagnosis, judgement of
      prognosis and determination of therapeutic protocol of CML-BC.

PMID- 12485537
TI  - Ginkgo is not a smart pill.

PMID- 12485538
TI  - Risperidone improves behavior in children with autism.

PMID- 12485539
TI  - Duplex ultrasound and magnetic resonance angiography are sensitive for severe
      carotid stenosis.

PMID- 12485540
TI  - How accurate is the D-dimer assay in diagnosing pulmonary embolism?

PMID- 12485541
TI  - Routine diagnostic hysteroscopy not necessary for premenopausal women with
      abnormal uterine bleeding.

PMID- 12485542
TI  - Beta-blockers no better than placebo in the treatment of vasovagal syncope.

PMID- 12485543
TI  - Vitamin E may worsen acute respiratory tract infections in the elderly.

PMID- 12485544
TI  - Maternal screening strategy more effective than risk-based approaches for
      preventing group B streptococcal disease in neonates.

PMID- 12485545
TI  - Classification of medical errors and preventable adverse events in primary care:
      a synthesis of the literature.
AB  - OBJECTIVE: To describe and classify process errors and preventable adverse events
      that occur from medical care in outpatient primary care settings. STUDY DESIGN:
      Systematic review and synthesis of the medical literature. DATA SOURCES: We
      searched MEDLINE and the Cochrane Library from 1965 through March 2001 with the
      MESH term medical errors, modified by adding family practice, primary health
      care, physicians/family, or ambulatory care and limited the search to English
      language publications. Published bibliographies and Web sites from patient safety
      and primary care organizations were also reviewed for unpublished reports,
      presentations, and leads to other sites, journals, or investigators with relevant
      work. Additional papers were identified from the references of the papers
      reviewed and from seminal papers in the field. OUTCOMES MEASURED: Process errors
      and preventable adverse events. RESULTS: Four original research studies directly
      studied and described medical errors and adverse events in primary care, and 3
      other studies peripherally addressed primary care medical errors. A variety of
      quantitative and qualitative methods were used in the studies. Extraction of
      results from the studies led to a classification of 3 main categories of
      preventable adverse events: diagnosis, treatment, and preventive services.
      Process errors were classified into 4 categories: clinician, communication,
      administration, and blunt end. CONCLUSIONS: Original research on medical errors
      in the primary care setting consists of a limited number of small studies that
      offer a rich description of medical errors and preventable adverse events
      primarily from the physician's viewpoint. We describe a classification derived
      from these studies that is based on the actual practice of primary care and
      provides a starting point for future epidemiologic and interventional research.
      Missing are studies that have patient, consumer, or other health care provider
      input.

PMID- 12485546
TI  - Is an elevated serum transferrin saturation associated with the development of
      diabetes?
AB  - OBJECTIVES: Diabetes mellitus is a common comorbid condition of hemochromatosis
      and is often identified as a complication of untreated hemochromatosis. However,
      there are few primary data examining the development of diabetes secondary to
      hemochromatosis. Our objective was to determine the likelihood of developing
      diabetes in a nationally representative cohort of patients who have an elevated
      serum transferrin saturation rate but no current diagnosis of diabetes. STUDY
      DESIGN: This is a retrospective cohort study based on merging the National Health
      and Nutrition Examination Survey I (1971-1974; NHANES I) with the NHANES I
      Epidemiologic Followup Study (1992). POPULATION: Individuals aged 25 to 74 years
      at the time of the NHANES I without diabetes (n = 9274). OUTCOMES MEASURED: The
      outcome was development of diabetes according to patient report, proxy report, or
      death certificate by the time of the follow-up interview. RESULTS: The incidence
      of diagnosed diabetes in the cohort was 10.2%. Among individuals with serum
      transferrin saturation levels above 55%, 7.5% developed diagnosed diabetes
      compared with 10.2% with a serum transferrin saturation of no more than 45% (P
      =.38). The relation remained nonsignificant in models adjusted for risk factors
      of diabetes and in analyses that assumed 10% of patients had received treatment
      for hemochromatosis. CONCLUSIONS: In this nationally representative cohort of
      adults, elevated serum transferrin saturation was not significantly associated
      with the development of diabetes.

PMID- 12485547
TI  - Validating an instrument for selecting interventions to change physician practice
      patterns: a Michigan Consortium for Family Practice Research study.
AB  - OBJECTIVES: The goal of this study was to develop a psychometric instrument that
      classified physiciansamprsquo response styles to new information as seekers,
      receptives, traditionalists, or pragmatists. This classification was based on
      specific combinations of 3 scales: (a) belief in evidence vs experience as the
      basis of knowledge, (b) willingness to diverge from common or previous practice,
      and (c) sensitivity to pragmatic concerns of practice. The instrument will help
      focus efforts to change practice more accurately. STUDY DESIGN: This was a cross
      sectional study of physician responses to a psychometric instrument. Paper-and
      pencil survey forms were distributed to 3 waves of physicians, with revision for
      improved internal consistency at each iteration. POPULATION: Participants were
      1393 primary care physicians at continuing education events in the Midwest or at
      primary care clinic sites in the Veteransamprsquo Health Administration system.
      OUTCOMES MEASURED: Internal consistency was measured by factor analysis with
      orthogonal rotation and Cronbachamprsquos alpha. RESULTS: A total of 1287 usable
      instruments were returned (106, 1120, and 61 in the 3 iterations, respectively),
      representing approximately three fourths of distributed forms. Final scale
      internal consistencies were a = 0.79, b = 0.74, and c = 0.68. The patterns of
      scores on the 3 scales were consistent with the predictions of the theoretical
      scheme of physician types. The "seeker" type was the rarest, at fewer than 3%.
      CONCLUSIONS: It is possible to reliably classify physicians into categories that
      a theoretical framework predicts will respond differently to different
      interventions for implementing guidelines and translating research findings into
      practice. The next step is to demonstrate that the classification predicts
      physician practice behavior.

PMID- 12485548
TI  - Does oral creatine supplementation improve strength? A meta-analysis.
AB  - OBJECTIVES: Oral creatine is the most widely used nutritional supplement among
      athletes. Our purpose was to investigate whether creatine supplementation
      increases maximal strength and power in healthy adults. STUDY DESIGN: Meta
      analysis of existing literature. DATA SOURCES: We searched MEDLINE (1966-2000)
      and the Cochrane Controlled Trials Register (through June 2001) to locate
      relevant articles. We reviewed conference proceedings and bibliographies of
      identified studies. An expert in the field was contacted for sources of
      unpublished data. Randomized or matched placebo controlled trials comparing
      creatine supplementation with placebo in healthy adults were considered. OUTCOMES
      MEASURED: Presupplementation and postsupplementation change in maximal weight
      lifted, cycle ergometry sprint peak power, and isokinetic dynamometer peak torque
      were measured. RESULTS: Sixteen studies were identified for inclusion. The
      summary difference in maximum weight lifted was 6.85 kg (95% confidence interval
      [CI], 5.24-8.47) greater after creatine than placebo for bench press and 9.76 kg
      (95% CI, 3.37-16.15) greater for squats; there was no difference for arm curls.
      In 7 of 10 studies evaluating maximal weight lifted, subjects were young men
      (younger than 36 years) engaged in resistance training. There was no difference
      in cycle ergometer or isokinetic dynamometer performance. CONCLUSIONS: Oral
      creatine supplementation combined with resistance training increases maximal
      weight lifted in young men. There is no evidence for improved performance in
      older individuals or women or for other types of strength and power exercises.
      Also, the safety of creatine remains unproven. Therefore, until these issues are
      addressed, its use cannot be universally recommended.

PMID- 12485549
TI  - Spirituality Index of Well-Being Scale: development and testing of a new measure.
AB  - OBJECTIVE: To evaluate the reliability and validity of the Spirituality Index of
      Well-Being (SIWB) Scale in a patient population. STUDY DESIGN: Cross-sectional
      survey. POPULATION: Community-dwelling elderly individuals (n = 277) recruited
      from primary care clinic sites in the Kansas City metropolitan area. OUTCOMES
      MEASURED: Internal consistency, concurrent construct validity, discriminant
      validity, and factor analysis with Varivax rotation. RESULTS: The initial version
      of the SIWB contained 40 items: 20 from a self-efficacy domain and 20 from a life
      scheme domain. Factor analysis yielded 6 items loaded most strongly on factor 1
      (intrapersonal self-efficacy) and 6 other items loaded strongly on factor 2 (life
      scheme). The Self-efficacy subscale had an alpha of.83 and the Life Scheme
      subscale had an alpha of.80; the total 12-item SIWB Scale had an alpha of.87. The
      SIWB had significant and expected correlations with other quality-of-life
      measures related to subjective well-being: EuroQol (r =.18), Geriatric Depression
      Scale (r = -35), the Physical Functioning Index from the Short Form 36 (r =.28),
      and the Years of Healthy Life Scale (r = -.35). Religiosity did not correlated
      significantly with the SIWB (r =.12, P =.056). CONCLUSIONS: The 12-item SIWB
      Scale is a valid and reliable measure of subjective well-being in an older
      patient population.

PMID- 12485550
TI  - Incontinence Quality of Life Instrument in a survey of primary care physicians.
AB  - OBJECTIVE: To assess the performance of the Incontinence Quality of Life (I-QOL)
      Instrument in measuring the impact of urinary incontinence on the quality of life
      of family medicine patients. STUDY DESIGN: Postal survey. Multiple imputations of
      missing answers. Linear regression analysis of I-QOL predictors. Comparison by
      receiver operating characteristic of the I-QOL and the Short Form 12 (SF-12).
      POPULATION: Women 45 years or older attending either of 2 family medicine
      clinics. Response rate was 605 (61%) of 992. OUTCOMES MEASURED: Prevalence of
      stress, urge, and mixed incontinence. Scores on the I-QOL and SF-12 instruments.
      RESULTS: Of the 605 respondents, 310 (51%) reported urinary incontinence in the
      month before the survey. One or more items were missing on 19% of the I-QOL
      scales and scores were imputed. The relation between I-QOL and the number of
      leakage episodes was nonlinear. I-QOL scores decreased with the number of
      episodes, the amount of leakage, and poorer general health. There was no
      association between the I-QOL and age, education, or type of incontinence. The I
      QOL was more sensitive than the SF-12 to the statement, "urinary incontinence is
      a problem." CONCLUSIONS: The I-QOL is a useful instrument for the investigation
      of incontinence-related quality of life in the community setting.

PMID- 12485551
TI  - Delayed antibiotic prescriptions: what are the experiences and attitudes of
      physicians and patients?
AB  - OBJECTIVE: To explore the experiences and opinions of family physicians and
      patients regarding the delay of antibiotic prescriptions, to be dispensed if
      symptoms persist or worsen over time, in treating upper respiratory tract
      infections. STUDY DESIGN: Qualitative study using semistructured interviews
      conducted in family practice in Auckland, New Zealand. POPULATION: Thirteen
      physicians recruited from a study of family physicians' reported antibiotic
      prescribing and 13 patients recruited from the intervention arm of a randomized
      controlled trial on delayed antibiotic prescribing. OUTCOMES MEASURED: Patients'
      and physicians' experiences of delayed antibiotic prescriptions for upper
      respiratory tract infections. RESULTS: The primary themes identified were value
      judgments of antibiotics, decreased antibiotic use, patient-centered factors,
      effects on the physician-patient relationship, patient convenience, adverse
      effects of delaying prescription, and selectivity for use of antibiotics. Many
      themes were common to both patients and physicians. Physicians valued empowering
      patients' decision making about their health care management more highly than did
      patients. Decreasing antibiotic use was not a key factor for most patients. Both
      groups acknowledged the value in saving patients time and money. Physicians
      viewed the strategy as giving patients reassurance and meeting their expectations
      for antibiotics. Negative implications included perception of physician
      incompetence and physician loss of management control. Opinions were mixed
      regarding which patients, under which conditions, were suitable for delayed
      antibiotic prescriptions. CONCLUSIONS: Although delayed antibiotic prescriptions
      are effective in decreasing antibiotic use for conditions not clinically
      warranting antibiotics, neither patients nor physicians universally endorsed this
      strategy. Research to establish formalized recommendations for patient
      suitability and instructions for use would be of value.

PMID- 12485552
TI  - The relation between methods and recommendations in clinical practice guidelines
      for hypertension and hyperlipidemia.
AB  - OBJECTIVE: To assess the association between methods used to develop clinical
      practice guidelines and the recommendations that are made. STUDY DESIGN:
      Systematic review of clinical practice guidelines for hypertension or
      hyperlipidemia. OUTCOMES MEASURED: Two people independently appraised guideline
      methods by using 8 criteria and the aggressiveness of recommendations for
      treatment thresholds, initial drug selection, and screening. RESULTS: We
      identified 33 guidelines. Only 6 fulfilled 5 or more of the 8 criteria. For 5 of
      the criteria, fewer than 50% of the guidelines fulfilled those criteria. There
      was wide variation in recommendations for treatment thresholds, drug selection,
      and cholesterol screening. Guidelines that did not fulfill the criteria tended to
      suggest more aggressive recommendations than did guidelines that met the
      criteria. For 6 of the 8 criteria, guidelines published by specialty societies
      were less likely to fulfill them compared with guidelines not published by
      specialty societies. CONCLUSIONS: Guideline developers who did not use rigorous
      methods tended to promote intervening more aggressively for hypertension and
      hyperlipidemia.

PMID- 12485553
TI  - Intention-to-treat analysis: who is in? Who is out?
AB  - To assess whether the term "intention to treat" (ITT) predicts inclusion of all
      randomized subjects in the analysis, we reviewed 100 randomly selected reports of
      randomized trials that mentioned analysis by ITT. Only 42 of 100 reports included
      all randomized subjects in the ITT analysis. We could not determine which
      categories of participants were excluded from the ITT analysis in 13 trials. The
      most common categories of excluded subjects were patients who, after
      randomization, received no follow-up (16/100), received no treatment (14/100), or
      were found not to meet study entry criteria (12/100). We could determine the
      number of participants in the ITT analysis for 92 studies. Nineteen of the 92
      studies excluded more than 5% of randomized participants, and 10 excluded more
      than 10%. There is considerable variation in how researchers define and apply the
      principle of intention to treat.

PMID- 12485554
TI  - How should low-density lipoprotein cholesterol concentration be determined?
AB  - The National Cholesterol Education Program Adult Treatment Panel III Report (NCEP
      ATP III) has identified low-density lipoprotein cholesterol (LDLC) as the primary
      target of therapy and has recommended using the Friedewald calculated LDL-C (CLDL
      C). The present study compared a direct LDLC (D-LDL-C) method with the C-LDL-C
      and determined the possible impact on treatment decisions. C-LDL-C and D-LDL-C
      were compared in 464 consecutive patients. The D-LDL-C was 18% higher than the C
      LDL-C at 100 mg/dL, an important level for medical decision making. This can
      result in inappropriate drug therapy (usually overtreatment) if the NCEP-ATP III
      treatment guidelines are followed with the D-LDL-C rather than the C-LDL-C. The C
      LDL-C is preferred because this assay has been used in clinical trials
      documenting the benefits of cholesterol-lowering therapy.

PMID- 12485555
TI  - Clinical inquiries. In patients with a previous CVA, do antioxidants protect
      against subsequent stroke?

PMID- 12485556
TI  - Clinical inquiries. Does postcoital voiding prevent urinary tract infections in
      young women?

PMID- 12485557
TI  - Clinical inquiries. Do antioxidants (vitamins C, E) improve outcomes in patients
      with coronary artery disease?

PMID- 12485558
TI  - On being a patient in the new millennium.

PMID- 12485559
TI  - Children's medical malapropisms.

PMID- 12485560
TI  - Are thiazolidinediones first-line agents?

PMID- 12485561
TI  - Homeopathy or isopathy?

PMID- 12485562
TI  - Influenza vaccine does not produce myopathy in patients taking statins.

PMID- 12485564
TI  - Management and leadership: a dual role in nursing education.
AB  - The purpose of this paper is to review the dual concepts of leadership and
      management in nursing education. It provides a consideration of caring as the end
      purpose of nursing education and argues that empowered caring makes use of
      professional academic credentials to form collaborative alliances that influence
      health care delivery. Inspiring and empowering leadership also transform
      educational services. In particular the key issues of investing in technology,
      supporting life long learning and creating a community workplace are addressed.
      It concludes with the suggestion that the nurse education ought to be led and
      managed differently.

PMID- 12485565
TI  - Reflection: a casualty of modularisation?
AB  - INTRODUCTION: The use of reflection in nursing and midwifery is well-established
      and reflective skills are taught on both pre- and post-registration courses as a
      way of integrating theory and practice, and of developing students' critical and
      analytical skills. Reflection is generally regarded positively with an assumption
      that reflective skills benefit both practitioners and patients. The aim of this
      study was to identify the educational strategies used to develop reflective
      skills in one pre-registration diploma in nursing curriculum. METHODS: The survey
      was cross-sectional in design. A questionnaire was designed for the study to
      explore perceptions of both students and lecturers in one educational
      establishment. Curriculum documentation was analysed to examine where in the
      curriculum the development of reflective skills was prominent. The sample
      consisted of two student cohorts from the adult branch and all senior lecturers
      within the Institute who taught on the pre-registration programme. RESULTS: The
      findings revealed a complex picture of students' and lecturers' views of the
      teaching and learning strategies used to develop reflective skills. Lectures and
      group work were the strategies cited most commonly by the students, whereas the
      lecturers felt the strategies used most often were personal tutorials, group work
      and case scenarios. The documentary analysis revealed that out of the 13 modules,
      there was explicit reference in only three modules to reflective practice.
      Furthermore, it was evident that the majority of lecturers were not clear where
      in the curriculum reflective skills were taught which suggested that an overview
      of the whole curriculum is not always evident. CONCLUSIONS: Modularisation may
      have contributed to a fragmentation in the way in which some key health
      practitioner skills are developed and built upon throughout a curriculum. There
      needs to be agreement on the nature of the skills which are central to the
      development of reflective practitioners and clear thinking on how these are
      developed and assessed within a curriculum.

PMID- 12485566
TI  - Student nurse-older person communication.
AB  - There is an increasing ageing population in western countries. Most nurses will
      be involved in caring for older people in the future. Over the last number of
      years much has been written about the benefits of effective nurse-patient
      communication. However, research findings indicate that the quality of nurse
      older person communication has been and continues to be poor. The purpose of this
      mini ethnography was to ascertain how student nurses communicate with older
      people. This is relevant as today's students are tomorrow's registered nurses and
      the manner in which they currently communicate with older person may indicate how
      they will interact with this population in the future. Data were collected using
      both participant observation and semi-structured interviews. Data were analysed
      using latent thematic analysis. Four major themes were identified from the
      findings. These were: Types of communication, modes of communication, factors
      that either hinder or enhance effective communication and student nurses'
      approach to communicating with older people. There are a number of
      recommendations from this study. These include, promoting a person-centred
      approach to care of the older person, ensuring appropriate clinical supervision
      of student nurse-older person communication by preceptors, increasing theoretical
      input in relation to interpersonal skills and communication theory, facilitating
      reflective practice whilst students are on clinical placement and regular
      auditing of clinical placements as suitable learning environments.

PMID- 12485567
TI  - An evaluation of nurses' clinical teaching role in Turkey.
AB  - A study of 91 nurses in Hacettepe University Adult Hospital in Turkey
      investigated how effective clinical nursing teaching was and analyzed the reasons
      for their teaching performance. Questionnaires about patient care, management,
      research, and teaching role were administered to the nurses in the study. The
      results of the questionnaires were expressed in numerical and percentage terms.
      Nurses were most effective in providing the patient care materials and equipment
      requested by students, helping students to adjust to a clinical environment and
      regarding students as team members. In contrast, nurses were least effective at
      discussing patients with students and at evaluating the patient care provided by
      students. The reasons that nurses gave for their clinical teaching performance
      were those of being overloaded with work, adhering to the view that teaching is
      not a nursing role, suffering from a lack of equipment, and the problem of
      students working slowly and hence wasting nurses' time. The nurses'
      recommendations for improving clinical teaching performance were those of
      increasing the co-operation between nursing schools and hospitals, the
      introduction of clinical nurse specialists, placing more emphasis on clinical
      teaching in nursing education and providing training courses on clinical
      teaching.

PMID- 12485568
TI  - Developing clinical leadership skills in student nurses.
AB  - A number of policy documents in recent years have identified the need for strong
      leadership within the NHS. The NHS Plan (2000) states that nurses need to take a
      lead role in the running of local health services. It also suggests that strong
      leadership is needed at a clinical level. The literature identifies a number of
      skills deemed to be essential for clinical leadership, some of these are
      difficult to achieve through pre-registration nurse education as they relate to
      an awareness of the structures and processes of the NHS and the ability to
      visualise or predict the future. Other skills relate to personal traits and
      qualities and it is these skills that are discussed. Four skills are identified
      for discussion; self-knowledge, communication skills, risk taking, and keeping
      informed. This paper analyses the way these skills are currently developed in one
      University's pre-registration nursing curriculum and concludes that although many
      opportunities are available to develop these skills in the classroom environment,
      there are many pressures that prevent use of these skills in a practice
      environment.

PMID- 12485569
TI  - What nurses say they do and need: implications for the educational preparation of
      nurses.
AB  - The scope of contemporary nursing is a critical factor in determining the
      appropriate educational preparation of nurses today and in the future. This
      qualitative study involved interviewing nurses throughout Australia in a variety
      of work and geographical settings to develop a snapshot of what nurses are doing,
      the skills needed and the challenges faced.The snapshot of contemporary practice
      that emerged is one of considerable diversity, which poses challenges for
      educators of nurses in terms of what constitutes appropriate or adequate
      educational preparation for nurses. Understandings of what constitutes clinical
      skills, and consequently clinical education, are explored as is what calls for
      'more' clinical education may actually mean. Caution is raised about educating
      for present needs that are based on limited conceptions of what constitutes a
      nursing workplace. It is argued that education for nurses, both initial and on
      going, must be cognizant of educating for what might be, not simply somewhat
      short-term imperatives.

PMID- 12485570
TI  - Peer supervision: an experimental scheme for nurse lecturers.
AB  - This paper reports on the implementation of a scheme of peer supervision in a
      team of mental health nursing lecturers working within a university setting. The
      rationale for the introduction of this scheme was the implementation of clinical
      supervision in nursing nationally and the role nurse education can play in this.
      Supervision is advocated as a way of providing education, support and quality
      checks for lecturers involved in supervising students. The peer supervision
      scheme is described and the experience of the lecturers involved discussed. The
      authors stress the value of this innovation to their professional lives and
      promote it as a good way of contributing to the implementation of clinical
      supervision in mental health nursing.

PMID- 12485571
TI  - An exploration of tutors' experiences of facilitating problem-based learning.
      Part 1--an educational research methodology combining innovation and
      philosophical tradition.
AB  - The use of problem-based learning (PBL) in Health Professional curricula is
      becoming more wide spread. Although the way in which the tutor facilitates PBL
      can have a major impact on students' learning (Andrews and Jones 1996), the
      literature provides little consistency as to how the tutor can effectively
      facilitate PBL (Haith-Cooper 2000). It is therefore important to examine the
      facilitation role to promote effective learning through the use of PBL. This
      article is the first of two parts exploring a study that was undertaken to
      investigate tutors' experiences of facilitating PBL. This part focuses on the
      methodology and the combining of innovative processes with traditional
      philosophical traditions to develop a systematic educational research
      methodology. The study was undertaken respecting the philosophy of hermeneutic
      phenomenology but utilised alternative data collection and analysis technique.
      Video conferencing and e-mail were used in conjunction with more traditional
      processes to access a worldwide sample. This paper explores some of the issues
      that arose when undertaking such a study. The second article then focuses on
      exploring the findings of the study and their implications for the facilitation
      of PBL.

PMID- 12485572
TI  - An exploration of tutors' experiences of facilitating problem-based learning.
      Part 2--implications for the facilitation of problem based learning.
AB  - This paper is the second of two parts exploring a study that was undertaken to
      investigate the role of the tutor in facilitating problem-based learning (PBL).
      The first part focussed on the methodological underpinnings of the study. This
      paper aims to focus on the findings of the study and their implications for the
      facilitation of PBL. Six essential themes emerged from the findings that
      described the facilitation role. The tutors believed that their facilitation role
      was essentially structured around the decision of when to intervene and how to
      intervene in the PBL process. Modelling and non-verbal communication were seen as
      essential strategies for the facilitator. Underpinning these decisions was the
      need to trust in the philosophy of PBL. However, within many of the themes, there
      was a divergence of opinion as to how the role should actually be undertaken.
      Despite this, these findings have implications for the future role of PBL
      facilitators in Health Professional Education.

PMID- 12485576
TI  - Biotransformation, genotoxic, and histopathological effects of environmental
      contaminants in European eel (Anguilla anguilla L.).
AB  - A prolonged toxicity study was carried out in young European eel (Anguilla
      anguilla L.) to evaluate the effects of environmental contaminants, namely, two
      individual standard compounds, benzo[a]pyrene (BaP) and dehydroabietic acid
      (DHAA), and a complex mixture, bleached kraft pulp mill effluent (BKPME). Fish
      were exposed to BaP (0.22, 0.45, and 0.9 microM) and BKPME (3.12%, 6.25%, and
      12.5% (v/v)) for 3, 7, and 30 days and to DHAA (0.07, 0.15, and 0.30 microM) for
      3, 7, 30, 90, and 180 days. The biomarkers include biotransformation and
      genotoxicity indicators, such as total ethoxyresorufin O-deethylase (EROD)
      activity and frequency of erythrocytic nuclear abnormalities (ENAs),
      respectively. Hematological dynamics was assessed as frequency of immature
      erythrocytes (IEs). Histopathological examinations were carried out for the
      highest concentrations and for 30 days and longer exposures. Total EROD increases
      significantly only after 180 days of DHAA exposure. However, significant ENA
      induction was generally observed during exposure to all contaminants tested.
      Nevertheless, some of the ENA results suggest an altered genotoxic response,
      which may arise either from short-term exposures to the highest contaminant
      levels or long-term exposures to the lowest contaminant levels. IE frequency
      decreased significantly after 30 days of exposure to 0.45 microM BaP and 180 days
      of exposure to the entire DHAA concentration range. Increased density of
      pigmented macrophage aggregates in 30-day BaP- and BKPME-exposed fish as well as
      in 90- and 180-day DHAA-exposed fish confirmed histopathological liver
      alterations. Bile accumulation in hepatocytes after BaP treatment, cytoplasmic
      vacuolization and cell atrophy following DHAA exposure, as well as liver loss of
      parenchymal cells in BKPME-exposed fish, were also detected. Dispersed necrosis
      and focal inflammation were observed in the livers of all treated groups. Fish
      exposed to DHAA and BKPME showed skin and gill disruption as well as kidney
      Malpighian corpuscle alterations. All 30-day-treated groups revealed intense
      spleen hemosiderosis, indicating increased erythrophagia. This splenic effect may
      be strongly correlated with the observed disappearance of ENAs. Neoplastic
      lesions were not found. A multibiomarker strategy, which includes EROD, ENA, and
      IE assays as well as histopathological studies, contributed to a better
      understanding of the global toxic process.

PMID- 12485577
TI  - A comparison of trace element concentrations in cultured and wild carp (Cyprinus
      carpio) of Lake Kasumigaura, Japan.
AB  - The concentrations of 13 elements were determined in the muscle, liver,
      intestine, kidney, and gonads of cultured and wild carp caught at two sites in
      Lake Kasumigaura, Japan, between September 1994 and September 1995. Despite
      having a reputation for being heavily polluted, the carp were not heavily
      burdened with metals. Our results suggest that despite their dietary differences,
      the wild and cultured fish were accumulating and distributing metals in the same
      manner and that aquaculture practices are not increasing metal concentrations in
      these fish. Metal concentrations were lowest in muscle, and did not exceed
      established quality standards for fish. The differences in metal concentrations
      between cultivated and wild carp are negligible and should pose no health
      problems for consumers of either type of fish.

PMID- 12485578
TI  - Long-term effects of a novel phosphorothionate (RPR-II) on detoxifying enzymes in
      brain, lung, and kidney rats.
AB  - The effects of a phosphorothionate, 2-butenoic acid-3-(diethoxyphosphinothioyl)
      methyl ester (RPR-II), on the activities of glutathione S-transferase (GST) and
      UDP-glucuronyltransferase (UDPGT) and the level of glutathione (GSH) were
      evaluated in rats after administration of RPR-II at 0.014 (low), 0.028 (medium),
      and 0.042 (high) mgkg(-1)day(-1) for 90 days and also at 28 days (withdrawal)
      after stopping treatment. Brain GST activity and GSH level decreased
      significantly at the high dose on the 45th and 90th days of treatment. Dose- and
      time-dependent decreases in GST activity and GSH was level were observed in lung
      at medium and high doses and in kidneys at all three doses on both the 45th and
      90th days. UDPGT activity increased significantly in kidneys at the medium and
      high doses at 45 and 90 days. Brain and lung did not display any significant
      variations in UDPGT activity when compared with the control. Interestingly, the
      withdrawal study revealed that the effect was reversible within 28 days of
      cessation of treatment, when enzyme activity reverted to levels close to those of
      controls. The study revealed that RPR-II affected the GSH- and GST-dependent
      detoxification system of the treated tissues of rat and its potential to modulate
      the enzymes is in the order kidneys>lung>>brain. The present subacute study
      suggests that RPR-II may bring about physiological upsets by altering GSH- and
      GST-dependent events in different tissues of exposed organisms.

PMID- 12485579
TI  - Relationship between biomarker activity and developmental endpoints in Chironomus
      riparius Meigen exposed to an organophosphate insecticide.
AB  - The biomarkers acetylcholinesterase (AChE) and glutathione S-transferase (GST)
      were measured in fourth-instar Chironomus riparius Meigen larvae exposed to the
      organophosphate insecticide pirimiphos methyl (0, 5, 10, and 50ng/g) for 48 or
      96h, and at high or low food ration. Larvae exposed to 50ng/g pirimiphos methyl
      died within 48h. The weight of larvae exposed to 10ng/g pirimiphos methyl was
      significantly lower than those exposed to 0 and 5ng/g. AChE activity was
      significantly reduced in larvae exposed to 10ng/g, but GST activity remained
      unaffected. Lower food ration reduced larval weights across all treatments but
      did not affect biomarker measurements. Insecticide exposure was associated with a
      longer time to adult emergence and oviposition, fewer egg masses, a greater
      proportion of deformed egg masses, and fewer eggs.

PMID- 12485580
TI  - Chemical and physical speciation of arsenic in a small pond receiving gold mine
      waste effluent.
AB  - The chemical and physical speciation of arsenic in a small pond that receives
      wastewater from a gold mine operation in western Victoria, Australia was studied
      using differential pulse polarography. By using different sample pretreatments,
      distinction between the physical states (dissolved or particulate As), between
      the oxidation states (As(III) or As(V)), and between the degrees of lability
      (labile or strongly bound) was achieved. The results are interpreted in terms of
      the physicochemical properties with reference to the use of the pond as a
      settlement dam for gold mining effluent. The speciation of arsenic was found to
      vary markedly with the physicochemical properties of the water. A model for the
      behavior of arsenic in the pond is proposed.

PMID- 12485581
TI  - Use of chronic tests with Daphnia magna for examination of diluted river water.
AB  - River water sampled in May and June 2000 was subjected to chronic tests with
      Daphnia magna to investigate the harmful effects of pesticides; then test animals
      were raised in reconstituted water (Elendt M-7) containing a solid-phase extract
      prepared from river water using polystyrene cartridges. The solid-phase extract
      was present in reconstituted water at a concentration equal to that in river
      water. Test animals died within 1-4 days in the reconstituted water containing
      the extract. On the other hand, these harmful effects were not realized if
      reconstituted water containing the extract was diluted several times. Assays were
      made using 53 kinds of pesticides as standards to investigate toxicity, and
      several pesticides were detected in the river water by GC-MS, GC, and HPLC. Two
      insecticides (fenitrothion and dichlorvos) affected D. magna significantly,
      because harmful effects were observed in chronic tests using reconstituted water
      to which the appropriate levels of pesticides had been added. Additionally, these
      results also indicate that factors other than the two insecticides may be
      involved in the harmful effects.

PMID- 12485582
TI  - Influence of oligomeric silicic and humic acids on aluminum accumulation in a
      freshwater grazing invertebrate.
AB  - This study examined the influence of oligomeric silicic acid and humic acid on
      aluminum in the water column and its accumulation in the freshwater snail Lymnaea
      stagnalis. Forty-eight hours after addition of Al (500 microg L(-1)), 83% of the
      metal was lost from the water column. This loss was reduced by oligomeric silica
      (20 mg L(-1)) and by humic acid (10 mg L(-1)). Aluminum accumulated in the
      digestive gland and, to a lesser extent, in the remaining soft tissues, and this
      accumulation was reduced by oligomeric silica. In the presence of humic acid, Al
      accumulation in the digestive gland was unaffected, though less was accumulated
      in the remaining tissues. Snails accumulated Si preferentially in the digestive
      gland and this accumulation was increased in the presence of added Al. Thus, both
      oligomeric silica and humic acid influence Al bioavailability and Si is
      upregulated in the digestive gland in the presence of Al.

PMID- 12485583
TI  - Lindane increases macrophage-activating factor production and intracellular
      calcium in rainbow trout (Oncorhynchus mykiss) leukocytes.
AB  - The authors studied the in vitro effects of lindane on macrophage-activating
      factor (MAF) production by peripheral blood leukocytes (PBLs) in rainbow trout.
      MAF production by PBLs induced normally by mitogens concanavalin A (ConA) and
      phorbol myristate acetate (PMA) was not modified by a pretreatment with lindane
      (from 2.5 to 50 microM). Only a concentration of 100 microM lindane decreased MAF
      production, associated with cellular death. Moreover, MAF activities were
      detected in supernatants of PBL cultures treated with lindane from 2.5 to 10
      microM in absence of ConA/PMA stimulation. Factors present in these supernatants
      remain to be identified. Lindane, at concentrations which did not induce MAF
      production (50 and 100 microM) led to an increase in PBL calcium levels by acting
      on the endoplasmic reticulum calcium stores. Although the intracytosolic calcium
      concentration ([Ca(2+)](i)) increase seems to be associated with cell death,
      lindane-induced MAF production may be linked with other intracellular mechanisms.

PMID- 12485584
TI  - Speciation of chromium in the presence of copper and zinc and their combined
      toxicity.
AB  - Speciation of chromium has attracted a great deal of interest in view of the
      toxic properties of Cr(6+) compared with the much less toxic Cr(3+). A freshwater
      plant, duckweed which is uniquely suitable for aquatic toxicity tests is utilized
      to study the growth responses and accumulation of chromium in the presence of
      copper and zinc. Speciation analysis was carried out by using differently
      activated alumina. Metal ion concentrations in the plant were determined by FAA
      spectrometry. Results of the present study revealed that the oxidation state of
      chromium as well as its concentration in media controlled the growth and the
      metal accumulation in duckweed. Regarding this, Lemna minor (common duckweed
      species) accumulated Cr(3+) in smaller quantities and it resulted in relatively
      larger growth responses, whereas Cr(6+) was accumulated in larger quantities and
      it yielded relatively smaller growth responses. Different types of metal
      interactions among chromium, copper, and zinc ions were evident. These
      interactions were classified as synergistic, antagonistic, and additive and they
      were strictly dependent on the oxidation state of the chromium ion.

PMID- 12485585
TI  - Evaluation of the joint-action toxicity of binary mixtures of heavy metals
      against the mangrove periwinkle Tympanotonus fuscatus var radula (L.).
AB  - The joint-action toxicity of binary mixtures of heavy metal compounds prepared in
      predefined ratios of 4:1, 3:2, 1:1, 2:3, and 1:4 (wt/wt) of Zn:Cu, Zn:Cd, and
      Cd:Cu, respectively, and tested against the mangrove periwinkle Tympanotonus
      fuscatus were carried out in laboratory bioassays. The interactions between
      binary mixtures showed significant departures from the action of the individual
      constituent metals when acting singly. On the basis of the models such as isobole
      representations, synergistic ratios (SRs), and concentration-addition models used
      for the joint-action evaluations, the interactions between the constituent metals
      in the various test proportions of the mixtures were largely in conformity with
      the models of antagonism. Furthermore, in most of the test combinations of the
      binary mixtures, the Zn compound was found to consistently reduce the toxic
      effect of Cu and Cd compounds when tested jointly against T. fuscatus. The
      possibility of utilizing the observed antagonistic interactions between Zn(2+)
      and Cd(2+) in the management of Cd-contaminated waterbodies was discussed and the
      synergistic ratio model was singled out as a better candidate model for joint
      action toxicity evaluations, which are aimed at establishing environmental safe
      limits of pollutants.

PMID- 12485586
TI  - INT-dehydrogenase activity test for assessing anaerobic biodegradability of
      organic compounds.
AB  - This study assessed anaerobic biodegradability of organic compounds from
      microorganism activity. Dehydrogenase activity can be a good parameter
      characterizing the microorganism activity. A modified method of 2-(p-iodophenyl-3
      (p-nitrophenyl)-5-pheny tetrazolium chloride-dehydrogenase activity determination
      was proposed in anaerobic biodegradability assessment. Cubic spline curves were
      adopted to link the data points. This curve was integrated twice to calculate
      areas. The microorganism activity index in anaerobic biodegradability assessment
      was calculated by standardizing the integral. According to the results of the
      activity index, 14 kinds of organic compounds were classified into readily,
      partially, and poorly biodegradable under anaerobic conditions, respectively. As
      a result, some conclusions for anaerobic biodegradability of organic compounds
      were reached, based on the activity index value.

PMID- 12485587
TI  - Long-term effects of chemical weapons on respiratory tract in Iraq-Iran war
      victims living in Babol (North of Iran).
AB  - In the Iraq-Iran war (1981-1989), extensive use of chemical weapons such as
      mustard gas caused high mortality, morbidity, injuries, and chronic side effects
      in vital organs, especially the respiratory tract. This study was performed to
      evaluate the long-term effects on respiratory tract of victims. Two hundred and
      twenty victims were referred from the Mostazafan and Janbazan Foundation of Babol
      from 1994 to 1998. Complete histories, physical examinations, chest X-rays, and
      PFTs were performed. Nearly all the victims complained of cough, dyspnea, and
      suffocation. Hemoptysis was found in 6 victims. In 4 patients, respiratory
      distress with use of accessory muscles was observed. Two-thirds of the subjects
      had wheezing and coarse rale. For the other third, physical examination revealed
      no abnormal finding. Radiographic findings were mostly normal. Spirometry
      revealed an obstructive pattern in all patients and PFT revealed mostly normal
      and restrictive patterns. The shortlist time from exposure to study was 7 years
      and the longest was 13 years. Most patients reported mustard gas exposure and a
      few of them did not know what type of gas exposure they had. The clinical
      evaluations, radiography, and PFTs revealed that the most prevalent effects of
      chemical weapons on respiratory tract were chronic obstructive lung disease,
      presenting as many types of obstructive involvement.

PMID- 12485588
TI  - Is the cadmium uptake from soil important in bioaccumulation and toxic effects
      for snails?
AB  - To evaluate the contribution of digestive and epithelial transfer of Cd from soil
      to snail, Helix aspersa was exposed to an artificial substrate contaminated with
      0,100,500, and 1000 microg Cd.g(-1) for 4 weeks under laboratory conditions. Two
      modes of exposure were used: (1) the snails were in direct contact with the
      substrate (DC) or (2) were separated from substrate with a perforated plate (no
      contact (NC)) which allowed ingestion of substrate but avoided epithelial
      contact. Cd concentrations in DC snails were twice as high as in NC snails. The
      bioaccumulation factors were 0.51+/-0.13 in DC snails and 0.26+/-0.04 in NC
      snails. Dose-dependent growth inhibition was noted in DC snails (500<EC(50)<1000
      microg.g(-1) and EC(10) around 100 microg.g(-1)) while only slight effects were
      noted in NC snails. Internal Cd concentrations in DC and NC snails were linearly
      correlated with growth effect whatever the contamination route.

PMID- 12485589
TI  - Aquatic toxicity evaluation of para-methylstyrene.
AB  - The aquatic toxicity of para-methylstyrene was evaluated in acute toxicity
      studies using fathead minnows (Pimephales promelas), daphnids (Daphnia magna),
      and freshwater green algae (Selenastrum capricornutum). Static tests were
      performed in sealed containers with no headspace to minimize loss of this
      volatile compound to the atmosphere. Concentrations of para-methylstyrene in test
      solutions were analyzed by gas chromatography equipped with a purge and trap
      module and flame ionization detection. Test results are based on mean, measured
      concentrations. para-Methylstyrene was moderately toxic to fathead minnows,
      daphnids, and green algae. The 96-h LC(50) and NOEC for fathead minnows were 5.2
      and 2.6 mg/L, respectively. The 48-h EC(50) and NOEC for daphnids were 1.3 and
      0.81 mg/L, respectively. The 72-h EC(50) and NOEC for green algae were 2.3 and
      0.53 mg/L, respectively; these effects were algistatic rather than algicidal.
      para-Methylstyrene's potential impact on aquatic ecosystems is significantly
      mitigated by its volatility, an important fate process.

PMID- 12485590
TI  - Photosynthetic responses of Lemna minor exposed to xenobiotics, copper, and their
      combinations.
AB  - The effects on the photosynthetic process of copper and pesticides, used in
      vineyards, and their combinations, were investigated by measuring different
      chlorophyll fluorescence parameters in Lemna minor. Cu and flumioxazin had a
      severe impact on duckweed since a decrease in their photosynthetic capacity was
      detected after 24h of exposure to 200 and 1 microg.L(-1), respectively. However,
      fungicides used to control Botrytis cinerea (procymidone, pyrimethanil, and
      fludioxonil) seem to have no marked effects on duckweed even at very high
      concentrations (50 mg.L(-1)). Analysis of the combinations between copper (200
      microg.L(-1)) and pesticides revealed different patterns of response: a
      synergistic effect was observed when Cu(2+) was added to flumioxazin (1 microg.L(
      1)). In contrast, an antagonism was detected when duckweed was exposed to a
      mixture of Cu(2+) and fludioxonil or procymidone. However, these interactions
      always tended toward additivity when pesticide concentrations increased.
      Additivity was also observed for the Cu(2+)-pyrimethanil mixture at each
      fungicide concentration.

PMID- 12485591
TI  - Antimicrobial and biological effects of N-diphenylphosphoryl-P
      triphenylmonophosphazene-II and di(o-tolyl) phosphoryl-P-tri(o
      tolyl)monophosphazene-III on bacterial and yeast cells.
AB  - The purpose of the study was to synthesize and evaluate the antimicrobial effects
      of two monophosphazenes, N-diphenylphosphoryl-P-triphenylmonophosphazene-II and N
      di(o-tolyl)phosphoryl-P-tri(o-tolyl)monophosphazene-III on bacterial and yeast
      strains. The biological effects of these molecules were compared with a potential
      antioxidant vitamin E. According to results, the triphenyl monophosphazene-II has
      antimicrobial effect on all the bacterial and yeast cells, but tri(o
      tolyl)monophosphazene-III has only antimicrobial effect on some bacterial cells.
      When the concentration of triphenyl monophosphazene-II was raised, it was
      observed that inhibition zone increased on the bacterial growth media. The
      biological effects of these molecules were compared to vitamin E in the
      Saccharomyces cerevisiae culture media. In 200 microg administered culture media,
      the cell density decreased in vitamin E, triphenyl monophosphazene-II and tri(o
      tolyl)monophosphazene-III groups at the end of 24 and 48 h incubation times
      (p<0.001,p<0.05). While the cell densities in vitamin E and tri(o
      tolyl)monophosphazene-II groups decreased partly at the end of 72 h incubation
      time (p<0.05), its level in triphenyl monophosphazene-II group increased (p<0.01)
      at the same incubation time. In 1,000 microg administered culture media, cell
      density was not found to differ between vitamin E and control groups at the end
      of 24h incubation time, but it was found that the cell densities in triphenyl
      monophosphazene and tri(o-tolyl)monophosphazene-III groups decreased at the same
      incubation time (p<0.001). The cell densities in tri(o-tolyl)monophosphazene-III
      group and triphenyl monophosphazene-II decreased at the end of 48 h incubation
      time (respectively, p<0.05,p<0.001). In 200 microg administered cell pellets,
      while the lipid level was not found to differ between control and vitamin E, the
      lipid level decreased in triphenyl monophosphazene-II and tri(o
      tolyl)monophospazene-III groups (respectively, p<0.001,p<0.01). In 1,000 microg
      administered cell pellets, it was found that the lipid level decreased in vitamin
      E, triphenyl monophosphazene-II and tri(o-tolyl)monophosphazene-III groups
      (p<0.001,p<0.01).

PMID- 12485592
TI  - Design, synthesis, and evaluation of 4-(4'-aminobenzyl)-2-oxazolidinones as novel
      inhibitors of the cytochrome P-450 enzyme aromatase.
AB  - The synthesis of a series of N-alkylated 4-(4(')aminobenzyl)-2-oxazolidinones is
      described using a synthetically useful scheme which avoids the use of phosgene
      since the derivatization is undertaken with the oxazolidin-2-one ring intact. The
      compounds were tested for human placental aromatase (AR) inhibition in vitro,
      using [1beta,2beta-3H]androstenedione as substrate for the AR enzyme. The
      compounds were found, in general, to be more potent than the standard compound,
      aminoglutethimide (AG), and as such proved to be good lead compounds in the
      search for more specific AR inhibitors.

PMID- 12485593
TI  - Making AppDNA using T4 DNA ligase.
AB  - 5('),5(')-Adenylyl pyrophosphoryl DNA (AppDNA) contains a high-energy
      pyrophosphate linkage and can be exploited as an activated DNA substrate to
      derive new DNA enzymes for carrying out various DNA modification reactions. For
      this reason, enzymatic synthesis of AppDNA is highly desirable. AppDNA is a known
      intermediate in DNA ligase mediated DNA ligation reactions, but rarely
      accumulates under normal reaction conditions. Here we report that T4 DNA ligase
      can quantitatively convert 5(')-phosphoryl DNA donor into AppDNA in the absence
      of acceptor DNA but in the presence of a template DNA that contains at least one
      unpaired nucleotide opposite the 5(')-phosphoryl DNA donor site. This
      adenylylation behavior of T4 DNA ligase is not observed with Thermus aquaticus
      (Taq) and Escherichia coli DNA ligases. We further found that a donor-template
      duplex of 11-bp in length is required by T4 DNA ligase for the formation of
      AppDNA.

PMID- 12485594
TI  - Effect of different strains of yeast on stereocontrolled reduction of 5
      acetylisoxazolines.
AB  - The stereocontrolled reduction of 3-aryl-5-acetylisoxazolines (1) to the
      corresponding alcohols (2 and 3) in the presence of four different yeast strains,
      recognized as Baker's yeast (commercial), Candida krusei (ATCC 14243), Pichia
      farinosa (NRRL Y110) and Sacchromyces sp. (soil isolate) have been attempted. The
      C. krusei was found to be diastereoselective for the (R)-1 while the Sacchromyces
      sp. led to complete reduction to yield the RS- and SS-alcohol in 1:1 ratio at 10
      g/L scale.

PMID- 12485595
TI  - N-Glycosylation pattern of the zymogenic form of human matrix metalloproteinase
      9.
AB  - Glycosylation of proteins has profound consequences on the activities of
      macromolecules and their interactions with inhibitors/substrates. Matrix
      metalloproteinase-9 (MMP-9, also known as gelatinase B) is a member of the MMP
      family of zinc-dependent endopeptidases, with critical functions in both
      physiological and pathological processes. MMP-9, a glycosylated MMP, is
      implicated in inflammation, angiogenesis and tumor metastasis. We have determined
      by the use of mass spectrometry that of the three possible N-glycosylation sites
      in human MMP-9 only two are glycosylated. The N-glycosylation sites are at
      asparagines in positions 38 and 120, the first site within the propeptide domain
      of the zymogenic form (pro-MMP-9) of the enzyme and the second in the catalytic
      domain. The chemical nature of the sugar attachments to both these sites was
      determined by mass spectrometry. Both N-glycosylation sites have NeuAcalpha(1,2)
      Galbeta(1,4)-GlcNAcbeta(1,2)-Manalpha(1,3)-[NeuAcalpha(1,2)-Galbeta(1,4)
      GlcNAcbeta(1,2)-Manalpha(1,6)-]Manbeta(1,4)-GlcNAcbeta(1,4)-[Fucalpha(1,6)
      ]GlcNAcbeta oligosaccharide chains. A computational model of glycosylated pro-MMP
      9 was generated and it was studied by dynamics simulations

PMID- 12485596
TI  - Further insights into the reaction of melatonin with hydroxyl radical.
AB  - Recent interest has focused on the use of exogenous melatonin as an antioxidant,
      particularly to scavenge the highly cytotoxic hydroxyl radical (HO(z.rad;)) which
      may be generated in many pathological conditions. However, in vitro and in vivo
      studies aimed at assessing the antioxidant properties of melatonin have produced
      conflicting results. While it is known that HO(z.rad;) reacts with melatonin at a
      diffusion limited rate, very little is known about the products of this reaction.
      In this investigation it is shown that incubation of melatonin with a Fenton-type
      HO(z.rad;)-generating system at pH 7.4 forms a complex mixture of primary
      products. These include 2-hydroxymelatonin, which was isolated as its more stable
      oxindole tautomer, 4- and 6-hydroxymelatonin, N-acetyl-N(2)-formyl-5
      methoxykynurenine and 7,7(')-bi-(5-methoxy-N-acetyltryptamine-4-one). Reaction
      pathways that might lead to these products are described. The differing
      biological effects of these products, while currently incompletely understood,
      might account for the controversy concerning the antioxidant properties of
      melatonin.

PMID- 12485597
TI  - Nitrosylation: the next phosphorylation?

PMID- 12485598
TI  - Interaction of phosphatidylinositolglycan(-peptides) with plasma membrane lipid
      rafts triggers insulin-mimetic signaling in rat adipocytes.
AB  - The phosphoinositolglycan(-peptide) (PIG-P) portion of
      glycosylphosphatidylinositol-anchored plasma membrane (GPI) proteins or synthetic
      PIG(-P) molecules interact with proteinaceous binding sites which are located in
      high-cholesterol-containing detergent/carbonate-insoluble glycolipid-enriched
      raft domains (hcDIGs) of the plasma membrane. In isolated rat adipocytes, PIG(-P)
      induce the redistribution of GPI proteins from hcDIGs to low-cholesterol
      containing DIGs (lcDIGs) and concomitantly provoke insulin-mimetic signaling and
      metabolic action. Using a set of synthetic PIG(-P) derivatives we demonstrate
      here that their specific binding to hcDIGs and their insulin-mimetic
      signaling/metabolic activity strictly correlate with respect to (i) translocation
      of the GPI proteins, Gce1 and 5(')-nucleotidase, from hcDIGs to lcDIGs, (ii)
      dissociation of the nonreceptor tyrosine kinase, pp59(Lyn), from caveolin
      residing at hcDIGs, (iii) translocation of pp59(Lyn) from hcDIGs to lcDIGs, (iv)
      activation of pp59(Lyn), (v) tyrosine phosphorylation of insulin receptor
      substrate proteins-1/2, and finally (vi) stimulation of glucose transport. The
      natural PIG(-P) derived from the carboxy-terminal tripeptide of Gce1, YCN-PIG,
      exhibits the highest potency followed by a combination of the separate
      peptidylethanolamidyl and PIG constituents. We conclude that efficient positive
      cross-talk of PIG(-P) to the insulin signaling cascade requires their interaction
      with hcDIGs. We suggest that PIG(-P) thereby displace GPI proteins from binding
      to hcDIGs leading to their release from hcDIGs for lateral movement to lcDIGs
      which initiates signal transduction from DIGs via caveolin and pp59(Lyn) to the
      insulin receptor substrate proteins of the insulin signaling pathway.

PMID- 12485599
TI  - Interaction of phosphoinositolglycan(-peptides) with plasma membrane lipid rafts
      of rat adipocytes.
AB  - Insulin receptor-independent activation of the insulin signal transduction
      cascade in insulin-responsive target cells by phosphoinositolglycans (PIG) and
      PIG-peptides (PIG-P) is accompanied by redistribution of
      glycosylphosphatidylinositol (GPI)-anchored plasma membrane proteins (GPI
      proteins) and dually acylated nonreceptor tyrosine kinases from
      detergent/carbonate-resistant glycolipid-enriched plasma membrane raft domains of
      high-cholesterol content (hcDIGs) to rafts of lower cholesterol content (lcDIGs).
      Here we studied the nature and localization of the primary target of PIG(-P) in
      isolated rat adipocytes. Radiolabeled PIG-P (Tyr-Cys-Asn-NH-(CH(2))(2)-O-PO(OH)O
      6Manalpha1(Manalpha1-2)-2Manalpha1-6Manalpha1-4GluN1-6Ino-1,2-(cyclic)-phosphate)
      prepared by chemical synthesis or a radiolabeled lipolytically cleaved GPI
      protein from Saccharomyces cerevisiae, which harbors the PIG-P moiety, bind to
      isolated hcDIGs but not to lcDIGs. Binding is saturable and abolished by
      pretreatment of intact adipocytes with trypsin followed by NaCl or with N
      ethylmaleimide, indicating specific interaction of PIG-P with a cell surface
      protein. A 115-kDa polypeptide released from the cell surface by the trypsin/NaCl
      treatment is labeled by [(14)C]N-ethylmaleimide. The labeling is diminished upon
      incubation of adipocytes with PIG-P which can be explained by direct binding of
      PIG-P to the 115-kDa protein and concomitant loss of its accessibility to N
      ethylmaleimide. Binding of PIG-P to hcDIGs is considerably increased after
      pretreatment of adipocytes with (glycosyl)phosphatidylinositol-specific
      phospholipases compatible with lipolytic removal of endogenous ligands, such as
      GPI proteins/lipids. These data demonstrate that in rat adipocytes synthetic PIG(
      P) as well as lipolytically cleaved GPI proteins interact specifically with
      hcDIGs. The interaction depends on the presence of a trypsin/NaCl/NEM-sensitive
      115-kDa protein located at hcDIGs which thus represents a candidate for a binding
      protein for exogenous insulin-mimetic PIG(-P) and possibly endogenous GPI
      proteins/lipids.

PMID- 12485600
TI  - Rat liver glucose-6-phosphatase system: light scattering and chemical
      characterization.
AB  - Glucose-6-phosphatase is a multicomponent system located in the endoplasmic
      reticulum, involving both a catalytic subunit (G6PC) and several substrate and
      product carriers. The glucose-6-phosphate carrier is called G6PT1. Using light
      scattering, we determined K(D) values for phosphate and glucose transport in rat
      liver microsomes (45 and 33mM, respectively), G6PT1 K(D) being too low to be
      estimated by this technique. We provide evidence that phosphate transport may be
      carried out by an allosteric multisubunit translocase or by two distinct
      proteins. Using chemical modifications by sulfhydryl reagents with different
      solubility properties, we conclude that in G6PT1, one thiol group important for
      activity is facing the cytosol and could be Cys(121) or Cys(362). Moreover, a
      different glucose-6-phosphate translocase, representing 20% of total glucose-6
      phosphate transport and insensitive to N-ethylmaleimide modification, could
      coexist with liver G6PT1. In the G6PC protein, an accessible thiol group is
      facing the cytosol and, according to structural predictions, could be Cys(284).

PMID- 12485601
TI  - Purification and characterization of a glycoprotein inhibitor of toxic
      phospholipase from Withania somnifera.
AB  - A phospholipase inhibitor (WSG) has been purified from Withania somnifera using
      gel-filtration and ion-exchange chromatographies. The WSG is an acidic
      glycoprotein. Its molecular mass as determined by SDS-PAGE was 27kDa. It
      neutralized the enzyme activity and pharmacological properties such as
      cytotoxicity, edema, and myotoxicity of a multi-toxic Indian cobra venom
      phospholipase (NNXIa-PLA) but failed to neutralize the neurotoxicity. The glycan
      part of the molecule does not appear to be involved in any of the pharmacological
      properties studied. The results suggest that the neutralization of the
      pharmacological effects of the toxic phospholipase is brought about by inhibition
      of the enzyme activity by formation of a complex between the WSG and the toxic
      phospholipase. We report the purification and characterization of a glycoprotein
      phospholipase A inhibitor from Withania somnifera, medicinal plant.

PMID- 12485602
TI  - Identification and analysis of a conserved immunoglobulin E-binding epitope in
      soybean G1a and G2a and peanut Ara h 3 glycinins.
AB  - To identify conserved immunoglobulin E (IgE)-binding epitopes among legume
      glycinins, we utilized recombinant soybean G2a and G2a-derived polypeptide
      fragments. All of these fusion polypeptides bound IgE, and the C-terminal 94
      residue fragment appeared to bind more IgE. Using synthetic peptides we
      identified S219-N233 (S(219)GFAPEFLKEAFGVN(233)) as the dominant IgE-binding
      epitope. Alanine scanning of this epitope indicated that six amino acids (E224,
      F225, L226, F230, G231, and V232) contributed most to IgE binding. Among these
      amino acids, only G231 of soybean G2a is not conserved in soybean G1a (S234) and
      peanut Ara h 3 (Q256). Synthetic peptides corresponding to the equivalent regions
      in G1a and Ara h 3 bound IgE in the order Ara h 3>/=soybean G2a>soybean G1a. This
      sequence represents a new IgE-binding epitope that occurs in a highly conserved
      region present in legume glycinins. Such IgE-binding sites could provide a
      molecular explanation for the IgE cross-reactivity observed between soybean and
      peanut proteins.

PMID- 12485603
TI  - Hemin-mediated restoration of allylisopropylacetamide-inactivated CYP2B1: a role
      for glutathione and GRP94 in the heme-protein assembly.
AB  - Administration of the cytochrome P450 (P450) suicide inactivator
      allylisopropylacetamide (AIA) to phenobarbital (PB)-pretreated rats results in
      rapid and marked inactivation of several liver endoplasmic reticulum (ER)-bound
      P450s. A few of these such as CYP2B1, inactivated due to AIA-mediated prosthetic
      heme N-alkylation, can be structurally and functionally restored nearly
      completely by exogenous hemin in vivo or in vitro. Such in vitro hemin-mediated
      reassembly is unsuccessful with purified AIA-inactivated CYP2B1 and, as shown
      herein, is not very effective even when heme is incubated with just the
      corresponding liver microsomes that contain the reconstitutable CYP2B1 protein,
      thereby implicating a requirement for additional factors provided by the intact
      liver cell homogenates, ER, and/or cytosol. Using various approaches that include
      high-performance liquid chromatographic fractionation of the liver cytosolic
      subfraction as well as chemical and immunological probes such as the Hsp90/GRP94
      specific inhibitor geldanamycin (GA) and polyclonal anti-GRP94 antibodies,
      respectively, we now demonstrate that the in vitro hemin-mediated reassembly of
      heme-stripped microsomal CYP2B1 requires GSH as well as the ER chaperone GRP94,
      but not the cytosolic chaperone heat shock protein 90. It remains to be
      determined whether GSH acts directly or indirectly, via a putative ER thiol
      reductase, to maintain the conserved active site cysteine-thiol (Cys436 in
      CYP2B1) in a reduced state, competent for heme binding and repair.

PMID- 12485604
TI  - Chronic liver and renal diseases differently affect structure of human serum
      albumin.
AB  - Human serum albumin (HSA) binding with endogenous metabolites and drugs is
      substantially decreased in chronic renal and liver diseases. To test the
      hypothesis that the decreased binding ability is caused by conformational changes
      of the protein, we analyzed infrared and Raman spectra of HSA isolated from
      healthy donors and patients with chronic uremia and liver cirrhosis. Uremia did
      not affect the secondary structure of HSA but modified the environment of its
      Asp/Glu residues. Liver cirrhosis increased the amount of extended and beta
      structures, modified the environment of Asp/Glu and Tyr side chains, and changed
      the configuration of disulfide bridges in albumin molecules. The conformational
      changes of "cirrhotic" albumin were not caused by reversibly bound ligands and
      resembled a partial unfolding of the protein induced by adsorption on the
      charcoal surface. The dramatic structural alterations of HSA in liver cirrhosis
      may be caused by its oxidative modification and might underlie the decreased
      binding ability and changed body distribution of albumin.

PMID- 12485605
TI  - Regulatory role of sphingomyelin metabolites in hypoxia-induced vascular smooth
      muscle cell proliferation.
AB  - Vascular cell adaptive response to hypoxic stress includes enhanced production of
      sphingomyelin metabolites that regulate cell growth. Here, we examined the
      vascular smooth muscle (VSM) cell adaptive response to hypoxia (2 and 5% O(2))
      and demonstrated that acute (</=16h) hypoxic stress significantly stimulated VSM
      cell growth compared to cells grown under normoxic (21% O(2)) conditions. This
      stimulatory effect of hypoxia on VSM cell growth was significantly inhibited by
      pretreatment of cells with D-erythro-N,N-dimethylsphingosine, an inhibitor of
      sphingosine kinase. These results suggest a mechanism by which sphingosine 1
      phosphate (S-1-P), a promitogenic sphingolipid-derived second messenger, may play
      a key role in hypoxia-induced VSM cell growth. Supporting this, S-1-P formation
      was significantly increased in VSM cells subjected to hypoxia. The hypoxia
      induced increase in S-1-P level correlated with the decrease in total cellular
      ceramide content, a sphingolipid metabolite associated with inhibition of cell
      growth. The activity of sphingomyelinase was also significantly inhibited in
      hypoxia-treated VSM cells, likely further contributing to a decrease in total
      intracellular content of ceramide. As a decrease in ceramide content may play a
      role in hypoxia-induced VSM growth, we next examined the effects of ceramide in
      VSM cell growth. Elevating intracellular ceramide content through exogenous (C(6)
      ceramide) or endogenous (ceramidase inhibition) manipulations led to a decrease
      in hypoxia-induced VSM cell growth. In contrast, hypoxia-induced VSM cell growth
      was further enhanced by S-1-P treatment. Together, our study indicates that
      hypoxia-induced VSM cell growth may be modulated by sphingomyelin metabolism that
      results in reduction of total intracellular ceramide level with concomitant
      increase in S-1-P formation.

PMID- 12485606
TI  - A novel prothrombin activator from the venom of Micropechis ikaheka: isolation
      and characterization.
AB  - A novel prothrombin activator, Mikarin, has been isolated from Micropechis
      ikaheka venom. It is a single polypeptide chain metalloproteinase with the
      apparent molecular weight of 47kDa. Mikarin exhibits Ca(2+)-independent
      prothrombin activation, but no effects on other blood coagulation factors, such
      as factor X and fibrinogen. Mikarin is the first member of group I prothrombin
      activators from elapid venom. Like other high-molecular-weight snake venom
      proteinases, it has three structural domains, metalloproteinase and disintegrin
      like and Cys-rich domains, and belongs to the P-III class of snake venom
      metalloproteinases. The N-terminal of Mikarin exhibits 76% sequence identity with
      Cobrin, a metalloproteinase identified from Naja naja venom, but very lower
      identities were found when compared with those from viperid and crotalid venom.
      In addition, the presence of disintegrin-like and Cys-rich domains in snake venom
      metalloproteinases with diverse biological activities suggests that these domains
      may be important for their function.

PMID- 12485607
TI  - The subdomains of the transactivation domain of the aryl hydrocarbon receptor
      (AhR) inhibit AhR and estrogen receptor transcriptional activity.
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) activates the aryl hydrocarbon
      receptor (AhR) to mediate transcriptional activity of dioxin-responsive genes.
      The transactivation domain (TAD) of human AhR (hAhR) has potentially distinct
      acidic, glutamine-rich, and proline/serine/threonine-rich subdomains.
      Cotransfection of exogenous hAhR into BP8 cells with isolated subdomains of hAhR
      TAD fused to glutathione S-transferase exhibited squelching of TCDD-dependent
      dioxin-response element (DRE)-driven luciferase reporter-gene activity with each
      subdomain. To study the potential cross talk between AhR- and estrogen receptor
      (ER)-mediated activities, BP8 cells were cotransfected with hAhR TAD subdomain
      constructs and ERalpha. The three hAhR TAD subdomains inhibited the 17beta
      estradiol-induced estrogen-response element-mediated reporter-gene
      transactivation. Cotransfection of hAhR with the ligand-binding domain (LBD) of
      ERalpha also squelched TCDD-dependent DRE-driven reporter-gene activity in the
      presence of 17beta-estradiol. Similar results were observed in T47D cells that
      express functional AhR and ERalpha. These results indicate that the isolated
      subdomains of hAhR's TAD and LBD of ERalpha are capable of squelching ligand
      dependent transactivation of either the AhR or the ER, by titrating crucial
      proteins from an existing common pool of cofactors.

PMID- 12485608
TI  - Proteasome-mediated degradation of tau proteins occurs independently of the
      chymotrypsin-like activity by a nonprocessive pathway.
AB  - 20S proteasomes form the proteolytic core of the 26S proteasome responsible for
      degradation of substrates of the ubiquitin-proteasome pathway. In addition, 20S
      proteasomes have themselves been linked to degradation of intracellular proteins.
      This multienzyme complex expresses three distinct catalytic sites, each with
      unique substrate specificity. The contribution of these sites to overall
      proteolysis remains unclear. Also unclear is the kinetic mechanism of
      degradation. Studies with denatured or covalently modified proteins suggest that
      degradation is nonprocessive in some cases and processive in others. We sought
      greater insight into these questions by analyzing degradation of tau proteins and
      beta-casein. Tau proteins were readily degraded by bovine pituitary proteasomes.
      Degradation yielded large quantities of intermediates, which were more abundant
      as tau concentration was increased, indicating that degradation occurred by a
      nonprocessive pathway. Similar findings were observed for degradation of beta
      casein. Experiments with inhibitors demonstrated that degradation of both full
      length tau and the intermediates derived from it was largely dependent on the
      trypsin-like activity. A combination of inhibitors against the trypsin-like and
      glutamyl activities almost completely blocked tau degradation, while inhibitors
      active toward the chymotrypsin-like activity had minimal effects on degradation
      of tau and intermediates derived from it. These findings are discussed with
      respect to the contribution of the three catalytic sites to overall intracellular
      proteolysis, the factors contributing to nonprocessive degradation, and the
      implications of this type of pathway for intracellular proteolysis.

PMID- 12485609
TI  - Comparison between D-[3-3H]- and D-[5-3H]glucose and fructose utilization in
      pancreatic islets from control and hereditarily diabetic rats.
AB  - The metabolism of D-glucose and/or D-fructose was investigated in pancreatic
      islets from control rats and hereditarily diabetic GK rats. In the case of both D
      glucose and D-fructose metabolism, a preferential alteration of oxidative events
      was observed in islets from GK rats. The generation of 3HOH from D-[5-3H]glucose
      (or D-[5-3H]fructose) exceeded that from D-[3-3H]glucose (or D-[3-3H]fructose) in
      both control and GK rats. This difference, which is possibly attributable to a
      partial escape from glycolysis of tritiated dihydroxyacetone phosphate, was
      accentuated whenever the rate of glycolysis was decreased, e.g., in the absence
      of extracellular Ca(2+) or presence of exogenous D-glyceraldehyde. D
      Mannoheptulose, which inhibited D-glucose metabolism, exerted only limited
      effects upon D-fructose metabolism. In the presence of both hexoses, the paired
      ratio between D-[U-14C]fructose oxidation and D-[3-3H]fructose or D-[5
      3H]fructose utilization was considerably increased, this being probably
      attributable, in part at least, to a preferential stimulation by the aldohexose
      of mitochondrial oxidative events. Moreover, this coincided with the fact that D
      mannoheptulose now severely inhibited the catabolism of D-[5-3H]fructose and D-[U
      14C]fructose. The latter situation is consistent with both the knowledge that D
      glucose augments D-fructose phosphorylation by glucokinase and the findings that
      D-mannoheptulose, which fails to affect D-fructose phosphorylation by
      fructokinase, inhibits the phosphorylation of D-fructose by glucokinase.

PMID- 12485610
TI  - Identification of beta-type phospholipase A(2) inhibitor in a nonvenomous snake,
      Elaphe quadrivirgata.
AB  - A novel serum protein inhibiting specifically the enzymatic activity of the basic
      phospholipase A(2) (PLA(2)) from the venom of the Chinese mamushi snake
      (Agkistrodon blomhoffii siniticus) was purified from a nonvenomous Colubridae
      snake, Elaphe quadrivirgata. The purified inhibitor was a 150-kDa glycoprotein
      having a trimeric structure, composed of two homologous 50-kDa subunits. Their
      amino acid sequences, containing leucine-rich repeats, were typical of the beta
      type PLA(2) inhibitor (PLIbeta), previously identified from the serum of A.
      blomhoffii siniticus. The inhibitor inhibited exclusively group II basic PLA(2)s
      and did not inhibit other kinds of PLA(2)s. This is the first paper reporting the
      existence of PLIbeta in a nonvenomous snake. The existence of PLIbeta in the
      nonvenomous snake reflects that PLIbetas are widely distributed over the snake
      species and participate commonly in regulating the physiological activities of
      the unidentified target PLA(2)s.

PMID- 12485611
TI  - Effects of proline analog binding on the spectroscopic and redox properties of
      PutA.
AB  - The PutA flavoprotein regulates proline metabolism in Escherichia coli by
      performing two distinct functions. First, in the cytoplasm, PutA represses
      transcription of the put (proline utilization) regulon. Second, PutA associates
      with the membrane to oxidize proline to glutamate using discrete proline
      dehydrogenase and Delta(1)-pyrroline-5-carboxylate dehydrogenase domains. Here,
      we identify a proline analog that will be useful for testing the role substrate
      binding has in regulating PutA functions. L-Tetrahydro-2-furoic acid (L-THFA) was
      found to display simple competitive inhibition of proline dehydrogenase activity
      in PutA (apparent K(i)=0.2mM) and to perturb the flavin adenine dinucleotide
      (FAD) absorbance spectrum upon complexation to PutA. At pH 7.5, a reduction
      potential (E(m)) of -0.089V for the FAD/FADH(2) couple in L-THFA-complexed PutA
      was determined by potentiometric titrations. The E(m) value for L-THFA-complexed
      PutA is 12mV more negative than the E(m) for uncomplexed PutA (E(m)=-0.077V, pH
      7.5) and corresponds to just a twofold increase in the dissociation constant of L
      THFA with PutA upon reduction of FAD.

PMID- 12485612
TI  - Site-directed mutagenesis of a potential catalytic and formyl phosphate binding
      site and substrate inhibition of N10-formyltetrahydrofolate synthetase.
AB  - Structural studies of N(10)-formyltetrahydrofolate synthetase (FTHFS) have
      indicated the involvement of Arg 97 in the binding of the formyl phosphate
      intermediate. Two site-directed mutants were constructed to test this hypothesis:
      R97S (Ser substitution) and R97E (Glu substitution). The k(cat) of R97S was
      approximately 60% that of the wild-type enzyme and had K(m) for ATP and formate
      twofold higher than those of wild type. R97E was completely inactive and had a
      K(m) for ATP nearly six times that of wild type. Substrate inhibition by
      tetrahydrofolate was shown to occur in wild-type and R97S enzymes using both
      steady-state and transient-state kinetic approaches. These results lend greater
      insight into the mechanistic function of FTHFS by confirming the interaction of
      both ATP and formate with Arg 97 and introducing the aspect of substrate
      inhibition by tetrahydrofolate with regard to substrate binding and dissociation.

PMID- 12485613
TI  - Conserved proline residues near the N-terminus are important for enzymatic
      activity of class A bacterial acid phosphatases.

PMID- 12485614
TI  - Tempting fate: BMP signals for cardiac morphogenesis.
AB  - Heart muscle cell specification (cardiac myogenesis) and creating the four
      chambered heart (cardiac morphogenesis) are subject to regulation, in certain
      model organisms, by bone morphogenetic proteins and their receptors.
      Extrapolation to mammals from organisms that develop outside the mother (flies,
      fish, frogs, and avians) has been confounded by very early lethality-at
      gastrulation-of many null alleles needed to prove cause-effect relations in this
      pathway. Here, we describe the use of lineage- or compartment-restricted null
      alleles as well as hypomorphic alleles, which circumvent these limitations and
      pinpoint novel essential functions for the bone morphogenetic protein cascade in
      mammalian cardiac development.

PMID- 12485615
TI  - New perspectives on growth factor-sex steroid interaction in the prostate.
AB  - Many organs respond to both sex steroids and growth factors. Regulation of these
      pathways is integral to cell-cell communications during development and aberrant
      changes cause disease pathogenesis. Traditionally, paracrine and endocrine
      actions of growth factors and steroid hormones are considered independently.
      Recently, new data indicated that activin/TGFbeta and sex steroid signalling are
      linked; explicitly, that the pathways cross-talk intracellularly. Here we present
      new perspectives on these interactions, using examples predominantly from the
      prostate, as it is a well-characterised organ in this context. While this
      information provides insight to the potential mechanisms behind these
      interactions, it also presents a new challenge; the action of any of these
      factors cannot be considered exclusively without considering the impact on the
      other biological pathways.

PMID- 12485616
TI  - CD100/Sema4D, a lymphocyte semaphorin involved in the regulation of humoral and
      cellular immune responses.
AB  - The semaphorin family consists of soluble and membrane-bound proteins that act as
      chemorepulsive factors in neuronal development, thereby playing a crucial role in
      axon guidance. Although they are expressed in a broad range of embryonic and
      adult tissues, their physiological role outside the nervous system remains to be
      determined. Recently, emerging evidence has suggested that several semaphorins
      function as part of the immune system. CD100/Sema4D is the first semaphorin
      family member for which a critical role in the immune response has been
      identified. CD100 is involved in several arms of the immune response, including
      humoral and cell-based immunity. This review will focus on our current
      understanding of the role of this immunoregulatory semaphorin.

PMID- 12485617
TI  - Alpha(1)-acid glycoprotein: an acute phase protein with inflammatory and
      immunomodulating properties.
AB  - alpha(1)-Acid glycoprotein (AGP) is a protein with a molecular weight of 41-43
      kDa and is heavily glycosylated (45%). Due to the presence of sialic acids, it is
      negatively charged (pI=2.7-3.2). AGP is an acute phase protein in all mammals
      investigated to date. The serum concentration of AGP rises several fold during an
      acute phase response, the systemic answer to a local inflammatory stimulus. Also,
      its glycosylation pattern can change depending on the type of inflammation. The
      biological function of this protein is not clear. A number of activities on
      different type of blood cells have been described. In vivo, AGP clearly has
      protective effects in several models of inflammation. Here we review the data
      supporting an anti-inflammatory and immunomodulating role of AGP.

PMID- 12485618
TI  - MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine.
AB  - The melanoma differentiation-associated gene-7 (mda-7) was cloned by subtraction
      hybridization as a molecule whose expression is elevated in terminally
      differentiated human melanoma cells. Current information based on structural and
      sequence homology, has led to the recognition of MDA-7 as an IL-10 family
      cytokine member and its renaming as IL-24. Northern blot analysis revealed mda
      7/IL-24 expression in human tissues associated with the immune system such as
      spleen, thymus, peripheral blood leukocytes and normal melanocytes. The MDA-7/IL
      24 mouse counterpart, FISP, appears to be a Th2-specific protein and the rat
      counterpart, C49A/MOB-5, is associated with wound healing and is also induced as
      a consequence of ras-transformation. A notable property of MDA-7/IL-24 is its
      ability to induce apoptosis in a large spectrum of human cancer derived cell
      lines, in mouse xenografts and upon intratumoral injection in human tumors (phase
      I clinical trials). Various aspects of this intriguing molecule including its
      cytokine and anti-tumoral effects are described and discussed.

PMID- 12485619
TI  - Non-apoptotic Fas signaling.
AB  - Fas (Apo-1, CD95) and Fas-Ligand (FasL, CD95L) are typical members of the TNF
      receptor and TNF ligand family, respectively, with a pivotal role in the
      regulation of apoptotic processes, including activation-induced cell death, T
      cell-induced cytotoxicity, immune privilege and tumor surveillance. Impairment of
      the FasL/Fas system has been implicated in liver failure, autoimmune diseases and
      immune deficiency. Thus, the FasL/Fas system was mainly appreciated with respect
      to its death-inducing capabilities. However, there is increasing evidence that
      activation of Fas can also result in non-apoptotic responses like cell
      proliferation or NF-kappaB activation. While the apoptotic features of the
      FasL/Fas system and the pathways involved are comparably well investigated, the
      pathways that are utilized by Fas to transduce proliferative and activating
      signals are poorly understood. This review is focused on the non-apoptotic
      functions of the FasL/Fas system. In particular, the similarities and differences
      of the molecular mechanisms of apoptotic and non-apoptotic Fas signaling are
      addressed.

PMID- 12485620
TI  - Infection and cancer: the common vein.
AB  - The role of infectious agents in the development of cancer is well documented.
      The pathogenesis of various human neoplasms ranging from non-Hodgkin lymphoma
      (NHL) to cervical carcinoma frequently involves a chronic, most often viral,
      infection. At the same time, there is compelling evidence that certain acute
      infections result in the inhibition of neoplastic growth. The basis for this
      phenomenon is often thought to be concomitant anti-tumor immunity. Yet,
      experimental data supporting this hypothesis are scarce, and other non-immune
      anti-tumor factors could be involved. For instance, since virtually all
      aggressive tumors outstrip their blood supply, development of new vessels, or
      angiogenesis, is a limiting factor during neoplastic growth. In this review, we
      will discuss recent studies that implicate anti-angiogenesis in infection
      mediated tumor suppression and suggest that this mechanism could also complement
      cytotoxic immunity arising from the use of cancer vaccines.

PMID- 12485621
TI  - A peptide agonist of the neural cell adhesion molecule (NCAM), C3, protects
      against developmental defects induced by a teratogen pyrimethamine.
AB  - The neural cell adhesion molecule, NCAM, not only plays an important role in
      neuronal migration, differentiation and formation of connections in the
      developing nervous system, but also in the condensation of the mesodermal
      mesenchyme of the limb bud. Therefore, NCAM may be regarded as a target molecule
      for preventive strategies aimed at minimizing the effects of teratogens affecting
      the prenatal development of the nervous system and the skeleton. Treatment of
      fetuses with the teratogen pyrimethamine results in a reduced body weight,
      microcephaly and malformations of the hind limbs and forelimbs, e.g. micromelia,
      brachydactyly and adactyly. We here show that a peptide agonist of NCAM, C3,
      partly prevented the defects induced by this treatment. Although intra-amniotic
      administration of C3 at gestational day 14 had no effect on the pyrimethamine
      induced reduction in body weight, it rescued the deficit in brain weight
      (microcephaly), partly reversed a decrease in thickness of the cortical plate,
      and significantly reduced the number of malformed fetuses. In vitro, C3 promoted
      survival of PC12-E2 cells treated with pyrimethamine. Since C3 is a peptide
      mimetic of NCAM, our data strongly suggest that stimulating of NCAM results in
      neuroprotection in vivo and in vitro.

PMID- 12485622
TI  - Influence of neurotrophins on the synaptogenesis of inner hair cells in the deaf
      Bronx waltzer (bv) mouse organ of Corti in culture.
AB  - The Bronx waltzer (bv) deaf mouse is characterized by massive degeneration of the
      primary auditory receptors, the inner hair cells, which occurs during the time of
      expected afferent synaptogenesis. The process is associated with degeneration and
      protracted division of the normally postmitotic afferent spiral ganglion neurons.
      To investigate the potential role of neurotrophins in the afferent synaptogenesis
      of inner hair cells, we exposed bv newborn cochleas in organotypic culture to
      brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth
      factor (NGF), and also to gamma aminobutyric acid (GABA), for up to 8 days. The
      study was done using light and electron microscopy. Only about 20% of the inner
      hair cells survived in culture, regardless of the treatment, similar to the
      number in the intact mutant in our colony. Depending on the exogenous treatment,
      this population consisted of either innervated ultrastructurally normal cells or
      denervated dedifferentiated cells wrapped-in lieu of nerve endings-by the
      supporting inner phalangeal and border cells. In the control and GABA cultures,
      inner hair cells were mostly denervated. BDNF and NT-3 alone or combined
      increased synaptogenesis and hair cell survival only during the first 3 days (by
      about 10%); however, the cells became denervated by 8 postnatal (PN). Only NGF
      induced stable innervation and differentiation of neurosensory relationships,
      including supernumerary innervation characteristic of the intact bv. Denervation
      among the remaining 20% of inner hair cells induced a reactive wrapping by inner
      phalangeal and border cells which evidently extended inner hair cell survival.
      Immunocytochemical studies of these reactive supporting cells were done in the
      intact (8 PN) mutant cochlea. The supporting cells that provide sustenance to the
      denervated inner hair cells displayed strong BDNF (and possibly NT-3)
      immunoreactivity. Subsequently, we revealed the presence of all three
      neurotrophins in the inner hair cell region of the developing (1-8 PN) cochlea of
      the normal ICR mouse. The inner hair cells expressed all three neurotrophins;
      BDNF prevailed in the inner phalangeal cells, NT-3 in the pillar cells and inner
      phalangeal cells, and NGF in the pillar cells. IN CONCLUSION: initially, the 80%
      loss of inner hair cells is apparently caused by their failed afferent
      synaptogenesis. Exogenous neurotrophins influence synaptogenesis in the bv in
      culture, but NGF alone is successful in promoting stable neurosensory
      relationships. The presence of neurotrophins in supporting cells in the normal
      and degenerating cochlea indicates their role in the sustenance of inner hair
      cells.

PMID- 12485623
TI  - Bimodal upregulation of glial cell line-derived neurotrophic factor (GDNF) in the
      neonatal rat brain following ischemic/hypoxic injury.
AB  - In order to delineate the spatial and temporal patterns of glial cell line
      derived neurotrophic factor (GDNF) expression following ischemic/hypoxic injury
      in immature and neonatal brain, GDNF protein levels and immunocytochemistry were
      studied in rats subjected to a modified Levine procedure. Significant
      upregulation of GDNF protein occurred in a bimodal fashion in the damaged left
      cerebral cortex and hippocampus, while the levels in the right cerebral
      hemisphere of both control and ischemic groups remained relatively unchanged.
      Immunocytochemical studies indicated that the early rise in GDNF levels was most
      likely to be related to enhanced neuronal release of GDNF. The second rise was
      probably related to progressive astrogliosis that occurred in response to injury.
      In contrast to the lack of GDNF expression among astrocytes in normal mature
      brains, reactive astrocytes in the neonate appear to possess a ready capacity to
      express GDNF. Spatial and temporal changes in the pattern of GDNF expression
      following injury, as determined in this study may provide insight into the
      functions of GDNF in vivo and into possible therapeutic approaches toward
      prevention of damage or rescue of neurons following brain injury.

PMID- 12485624
TI  - Undersulfation of proteoglycans and proteins alter C6 glioma cells proliferation,
      adhesion and extracellular matrix organization.
AB  - Proteoglycans are considered to be important molecule in cell-microenvironment
      interactions. They are overexpressed in neoplastic cells modifying their growth
      and migration in hosts. In this work we verified that undersulfation of
      proteoglycans and other sulfated molecules, induced by sodium chlorate treatment,
      inhibited C6 glioma cells proliferation in a dose-dependent way. This effect was
      restored by the addition of exogenous heparin. We could not detect significant
      cell mortality in our culture condition. The treatment also impaired in a dose
      dependent manner, C6 cell adhesion to extracellular matrix (ECM) proteins
      (collagen IV, laminin and fibronectin). In addition, sodium chlorate treatment
      altered C6 glioma cell morphology, from the fibroblast-like to a more rounded
      one. This effect was accompanied by increased synthesis of fibronectin and
      alterations in its extracellular network organization. However, we could not
      observe modifications on laminin organization and synthesis. The results suggest
      an important connection between sulfation degree with important tumor functions,
      such as proliferation and adhesion. We suggest that proteoglycans may modulate
      the glioma microenvironment network during tumor cell progression and invasion.

PMID- 12485625
TI  - Information provided by the skeletal muscle and associated neurons is necessary
      for proper brain development.
AB  - Previously, motor cortex of term Myf5(-/-):MyoD(-/-) fetuses (e.g. have ablated
      skeletal myogenesis and consequent early loss of lower motor and proprioceptive
      neurons) was found to lack giant pyramidal cells. We further investigated how the
      absence of the extrinsic stimuli from the lacking structures influences brain
      development. Apparently normal motor cortex of mutant fetuses was found to have
      dramatically reduced presence of nestin-expressing processes of neural
      precursors, calretinin-expressing pyramidal neurons and calbindin-expressing
      neurons. Consistently, some areas of the extrapyramidal tract had significantly
      decreased number of differentiated neurons in mutant brains. Surprisingly, we
      were unable to detect any change in proliferation or cell death in the mutant
      neuroepithelium. Together, it appears that the information provided by the
      lacking structures influences the ratios of the differentiated neuronal types and
      their progenitor cells.

PMID- 12485626
TI  - A neural network-based similarity index for clustering DNA microarray data.
AB  - A common approach to the analysis of gene expression data is to define clusters
      of genes that have similar expression. A critical step in cluster analysis is the
      determination of similarity between the expression levels of two genes. We
      introduce a neural network-based similarity index as a non-linear similarity
      index and compare the results with other proximity measures for Saccharomyces
      cerevisiae gene expression data. We show that the clusters obtained using
      Euclidean distance, correlation coefficients, and mutual information were not
      significantly different. The clusters formed with the neural network-based index
      were more in agreement with those defined by functional categories and common
      regulatory motifs.

PMID- 12485627
TI  - Identifying splicing sites in eukaryotic RNA: support vector machine approach.
AB  - We introduce a new method for splicing sites prediction based on the theory of
      support vector machines (SVM). The SVM represents a new approach to supervised
      pattern classification and has been successfully applied to a wide range of
      pattern recognition problems. In the process of splicing sites prediction, the
      statistical information of RNA secondary structure in the vicinity of splice
      sites, e.g. donor and acceptor sites, is introduced in order to compare
      recognition ratio of true positive and true negative. From the results of
      comparison, addition of structural information has brought no significant benefit
      for the recognition of splice sites and had even lowered the rate of recognition.
      Our results suggest that, through three cross validation, the SVM method can
      achieve a good performance for splice sites identification.

PMID- 12485628
TI  - Human vs machine: evaluation of fluorescence micrographs.
AB  - To enable high-throughput screening of molecular phenotypes, multi-parameter
      fluorescence microscopy is applied. Object of our study is lymphocytes which
      invade human tissue. One important basis for our collaborative project is the
      development of methods for automatic and accurate evaluation of fluorescence
      micrographs. As a part of this, we focus on the question of how to measure the
      accuracy of microscope image interpretation, by human experts or a computer
      system. Following standard practice we use methods motivated by receiver operator
      characteristics to discuss the accuracies of human experts and of neural network
      based algorithms. For images of good quality the algorithms achieve the accuracy
      of the medium-skilled experts. In images with increased noise, the classifiers
      are outperformed by some of the experts. Furthermore, the neural network-based
      cell detection is much faster than the human experts.

PMID- 12485629
TI  - A dynamic nonlinear time domain model for reconstruction and compression of
      cardiovascular signals with application to telemedicine.
AB  - A new nonlinear time domain model is proposed in this paper for signals of
      cardiovascular origin. An equation of the dynamic nonlinear model has been
      obtained by considering a masking function, which is modulated by a harmonic
      series with the baseline drift incorporated into the model. Signal reconstruction
      using model parameters has established the effectiveness of the model for signal
      compression. Improvement has been effected by using neural networks for reducing
      the time for optimizing the initial parameters. An improved adaptive optimization
      step size algorithm has also been implemented. Results show that the technique is
      able to provide reasonable compression with low error between the original and
      reconstructed signals. One of the main advantages of the model is its potential
      of being used for compression of many different types of biosignals transmitted
      in parallel. Incorporation of the compression model into a telemedicine system
      has led to considerable saving in transmission time for patient data.

PMID- 12485630
TI  - Mechanical analysis of a prototype of small diameter vascular prosthesis:
      numerical simulations.
AB  - This paper concerns a mechanical analysis of a prototype of a small diameter
      vascular prosthesis made of a fibre reinforcement silicone material. The
      theoretical approach is carried out for a neoHookean strain energy function
      augmented with unidirectional reinforcing that is characterized by a single
      additional constitutive parameter for strength of reinforcement. Numerical
      simulations based on a finite element model compare the compliance of different
      grafts and predict the degree of the compliance mismatch in an anastomosis
      between native artery and vascular prosthesis. Furthermore, specific applied
      strains on the prototype, viewed as arising surgical manipulation and implying
      telescopic shear have been simulated. Thus, for different fibre reinforcements,
      the stress gradient through the wall of the tubular structure is evaluated.

PMID- 12485631
TI  - Hepatic tumor enhancement in computed tomography: combined models of liver
      perfusion and dynamic imaging.
AB  - The objective of this study is to show how computational modeling can be used to
      increase our understanding of liver enhancement in dynamic computer tomography.
      It relies on two models: (1). a vascular model, based on physiological rules, is
      used to generate the 3D hepatic vascular network; (2). the physical process of CT
      acquisition allows to synthesize timed-stamped series of images, aimed at
      tracking the propagation of a contrast material through the vessel network and
      the parenchyma. The coupled models are used to simulate the enhancement of a
      hyper-vascular tumor at different acquisition times, showing a maximum
      conspicuity during the arterial phase.

PMID- 12485632
TI  - Smoothness-based forces for deformable models: a long-range force and a corner
      fitting force.
AB  - Deformable models, originally proposed by Terzopoulos et al. (Artif. Intell. 36
      (1988) 91) and Kass et al. (Int. J. Comput. Vision 1 (1988) 321) in 1988, have
      been widely used in medical image segmentation. However, they manifest two well
      known limitations: the lack of an appropriate long-range force to drive the model
      surface towards the object boundary and poor performance at high curvature
      boundaries (such as corners) due to the models' intrinsic smoothness constraint.
      In this paper, a new smoothness force with local control is proposed. The local
      control is used to devise a long-range force, referred to as the self-zoom force,
      and a corner fitting force. The self-zoom force enables the model surface to
      expand and shrink without a limit in range. The corner fitting force propels the
      model surface to fit high-curvature boundaries. Experiments demonstrate that the
      model surface is driven to the object boundary by the new forces even if the
      initial estimate is not close and the object is nonconvex or has a high local
      curvature.

PMID- 12485633
TI  - The development of contact force construction in the dynamic-contact task of
      cycling [corrected].
AB  - Purposeful movement requires that an individual produce appropriate joint torques
      to accelerate segments, and when environmental contact is involved, to develop
      task-appropriate contact forces. Developmental research has been confined largely
      to the mastery of unconstrained movement skills (pointing, kicking). The purpose
      of this study was to study the developmental progression that characterizes the
      interaction of muscular and non-muscular forces in tasks constrained by contact
      with the environment. Seven younger children (YC, 6-8 years), 7 older children
      (OC, 9-11 years) and 7 adults (AD) pedaled an ergometer (80 rpm) at an
      anthropometrically scaled cycling power. Resultant forces measured at the pedal's
      surface were decomposed into muscle, inertia and gravity components. Muscle pedal
      forces were further examined in terms of the underlying lower extremity joint
      torques and kinematic weights that constitute the muscular component of the pedal
      force. Data showed children applied muscle forces to the pedal in a significantly
      different manner compared to adults, and that this was due to the children's
      lower segmental mass and inertia. The children adjusted the contribution of the
      proximal joint muscle torques to compensate for reduced contributions to the
      resultant pedal force by gravitational and inertial components. These data show
      that smaller segmental mass and inertia limit younger children's ability to
      construct the dynamic-contact task of cycling in an adult-like form. On the basis
      of these results, however, the children's response was not "immature". Rather,
      the results show a task-appropriate adaptation to lower segmental mass and
      inertia.

PMID- 12485634
TI  - Model-guided derivation of lumbar vertebral kinematics in vivo reveals the
      difference between external marker-defined and internal segmental rotations.
AB  - This study investigated whether the external marker-defined spine inter-segmental
      rotation is different from the internal vertebral rotation, and explored how to
      estimate the latter from limited surface measurement. A kinematic model was first
      created to elucidate analytically the relation between the external and internal
      rotations. A novel approach guided by the model was proposed for deriving
      vertebral centers of rotation (CORs) from measured planar trajectories of skin
      surface markers. The approach involved a recursive procedure for establishing
      local (anatomical) coordinate systems, and an optimization routine that
      identified the maximum-likelihood circles best fitting the marker trajectories in
      local coordinate systems. An experiment with 10 subjects (5 males and 5 females)
      was conducted to test the approach along with the model. Skin-surface markers
      were strategically placed over individual spinous processes and other body
      landmarks, and recorded by an opto-electronic system while sagittally symmetric
      load-lifting movements were being performed. For the majority (89%) of measured
      motions, the COR locations for lumbar vertebrae (L2-L5) were derived
      successfully: solutions resulting from the optimization routine met a convergence
      criterion governed by the model, and were in agreement with existing data from
      radiographic or cadaveric studies. Empirical results confirmed the differences
      between the external marker-defined inter-segmental motions and corresponding
      internal vertebral rotations (1.1-5.8 degrees on average, all statistically
      significant). The study demonstrated the necessity and viability of quantifying
      internal vertebral kinematics when utilizing non-invasive marker-based
      measurement for spine-related clinical diagnosis and biomechanical modeling.

PMID- 12485635
TI  - How the stiffness of meniscal attachments and meniscal material properties affect
      tibio-femoral contact pressure computed using a validated finite element model of
      the human knee joint.
AB  - In an effort to prevent degeneration of articular cartilage associated with
      meniscectomies, both meniscal allografts and synthetic replacements are subjects
      of current interest and investigation. The objectives of the current study were
      to (1) determine whether a transversely isotropic, linearly elastic, homogeneous
      material model of the meniscal tissue is necessary to achieve a normal contact
      pressure distribution on the tibial plateau, (2) determine which material and
      boundary condition (attachments) parameters affect the contact pressure
      distribution most strongly, and (3) set tolerances on these parameters to restore
      the contact pressure distribution to within a specified error. To satisfy these
      objectives, a finite element model of the tibio-femoral joint of a human
      cadaveric knee (including both menisci) was used to study the contact pressure
      distribution on the tibial plateau. To validate the model, the contact pressure
      distribution on the tibial plateau was measured experimentally in the same knee
      used to create the model. Within physiologically reasonable bounds on five
      material parameters and four attachment parameters associated with a meniscal
      replacement, an optimization was performed under 1200 N of compressive load on
      the set of nine parameters to minimize the difference between the experimental
      and model results. The error between the experimental and model contact variables
      was minimized to 5.4%. The contact pressure distribution of the tibial plateau
      was sensitive to the circumferential modulus, axial/radial modulus, and horn
      stiffness, but relatively insensitive to the remaining six parameters.
      Consequently, both the circumferential and axial/radial moduli are important
      determinants of the contact pressure distribution, and hence should be matched in
      the design and/or selection of meniscal replacements. In addition, during
      surgical implantation of a meniscal replacement, the horns should be attached
      with high stiffness bone plugs, and the attachments of the transverse ligament
      and deep medial collateral ligament should be restored to minimize changes in the
      contact pressure distribution, and thereby possibly prevent the degradation of
      articular cartilage.

PMID- 12485636
TI  - Osteoblastic cells have refractory periods for fluid-flow-induced intracellular
      calcium oscillations for short bouts of flow and display multiple low-magnitude
      oscillations during long-term flow.
AB  - Partitioning a daily mechanical stimulus into discrete loading bouts enhances
      bone formation in rat tibiae (J. Bone Mineral Res. 15(8) (2000) 1596). We
      hypothesized that a refractory period exists in primary rat osteoblastic cells,
      during which fluid-flow-induced [Ca(2+)](i) oscillations are insensitive to
      additional short bouts (2 min) of fluid flow. Because the frequency of
      [Ca(2+)](i) oscillations is believed to be important for regulating cellular
      activity and long-term fluid flow alters gene expression in bone cells, we also
      hypothesized that long-term (15 min) oscillating fluid flow produces multiple
      [Ca(2+)](i) oscillations in osteoblastic cells. Primary osteoblastic cells from
      rat long bones were exposed to 2 min of oscillating fluid flow that produced
      shear stresses of 2 Pa at 2 Hz. After a rest period of 5, 30, 60, 300, 600, 900,
      1800, or 2700 s, the cells were exposed to a second 2-min bout of flow. A 600 s
      rest period was required to recover the percentage of cells responding to fluid
      flow and a 900 s rest period was required to recover the [Ca(2+)](i) oscillation
      magnitude. The magnitude and shape of the two [Ca(2+)](i) oscillations were
      strikingly similar for individual cells after a 900 s rest period. During 15 min
      of continuous oscillating flow, some individual cells displayed between 1 and 9
      oscillations subsequent to the initial [Ca(2+)](i) oscillation. However, only 54%
      of the cells that responded initially displayed subsequent [Ca(2+)](i)
      oscillations during long-term flow and the magnitude of the subsequent
      oscillations was only 28% of the initial response.

PMID- 12485637
TI  - Concentration polarization of macromolecules in canine carotid arteries and its
      implication for the localization of atherogenesis.
AB  - To test the hypothesis that concentration polarization of atherogenic lipids may
      occur in the arterial system and play an important role in the localization of
      atherogenesis, we measured in vitro the luminal surface concentration of bovine
      serum albumin (as a tracer macromolecule) in the canine carotid artery by
      directly taking liquid samples from the luminal surface of the artery. The
      experimental results show that the luminal surface albumin concentration, c(w),
      was higher than the bulk concentration, c(0) as predicted by our theory. The
      relative luminal surface albumin concentration, c(w)/c(0), decreased very sharply
      at low wall shear rate, G, but gradually approached the value of 1.0
      asymptotically as G was increased. The experiment shows that water flux rate
      across the vessel wall, v(w), has a profound impact on concentration
      polarization. For instance, at G = 0 and 185 s(-1), when v(w) = 8.9 +/- 1.7 x 10(
      6) cm/s, c(w) was 65% and 15% higher than c(0), respectively, meanwhile when v(w)
      = 4.8 +/- 0.6 x 10(-6)cm/s, c(w) was only 42% and 5% higher than c(0),
      respectively. The experiment also revealed that concentration polarization
      occurred in a thin layer close to the luminal surface of the artery. The
      thickness of this layer was water flux rate-dependent. The higher the water flux
      rate, the thicker was the layer. The present study therefore confirms that
      concentration polarization can indeed occur in the arterial system and our
      theoretical analysis is accurate in predicting this mass transfer phenomenon.

PMID- 12485638
TI  - Stroke frequency in front crawl: its mechanical link to the fluid forces required
      in non-propulsive directions.
AB  - Two hypotheses were tested: (a) stroke frequency is predictable from the
      amplitudes of bodyroll and the turning effect around the body's long-axis
      generated by the non-propulsive fluid forces (that is, the torque driving
      bodyroll), and (b) swimmers exhibit at least one alteration in the factors
      influencing the bodyroll cycle as they increase the stroke frequency for faster
      swimming, so that they can reduce the fluid forces "wasted" in non-propulsive
      directions. The mechanical formula that links stroke frequency and the kinetics
      of bodyroll was derived on the basis of Euler's equation of motion. Experimental
      data were collected from competitive swimmers to validate the derived mechanical
      relations and to examine the strategy that skilled swimmers would use to change
      the stroke frequency as they swam faster. A strong correlation (slow: r = 0.70
      and fast: r = 0.85) and a non-significant difference between the observed stroke
      frequency and the formula-based estimates supported the first hypothesis. As the
      subjects increased stroke frequency (38%) for faster swimming, bodyroll decreased
      (19%) and the trunk twist increased (40%). The combined alterations resulted in a
      small reduction in the shoulder roll (12%), enabling the swimmers to gain the
      benefits associated with a large rolling action of the upper trunk, while
      limiting the amount of increase in the turning effect of fluid forces in non
      propulsive directions (40%). The second hypothesis was, therefore, supported. The
      derived mechanical formula provides a theoretical basis to explore mechanisms
      underlying the interrelations among stroke frequency, stroke length and swimming
      speed, and sheds light on a possible reason that swimmers generally adopt six
      beat kicks.

PMID- 12485639
TI  - Friction between human finger flexor tendons and pulleys at high loads.
AB  - A method was developed to indirectly measure friction between the flexor tendons
      and pulleys of the middle and ring finger in vivo. An isokinetic movement device
      to determine maximum force of wrist flexion, interphalangeal joint flexion
      (rolling in and out) and isolated proximal interphalangeal (PIP) joint flexion
      was built. Eccentric and concentric maximum force of these three different
      movements where gliding of the flexor tendon sheath was involved differently
      (least in wrist flexion) was measured and compared. Fifty-one hands in 26 male
      subjects were evaluated. The greatest difference between eccentric and concentric
      maximum force (29.9%) was found in flexion of the PIP joint. Differences in the
      rolling in and out movement (26.8%) and in wrist flexion (14.5%) were
      significantly smaller. The force of friction between flexor tendons and pulleys
      can be determined by the greater difference between eccentric and concentric
      maximum force provided by the same muscles in overcoming an external force during
      flexion of the interphalangeal joints and suggests the presence of a non-muscular
      force, such as friction. It constitutes of 9% of the eccentric flexion force in
      the PIP joint and therefore questions the low friction hypothesis at high loads.

PMID- 12485640
TI  - Effects of broad frequency vibration on cultured osteoblasts.
AB  - Bone is subjected in vivo to both high amplitude, low frequency strain, incurred
      by locomotion, and to low amplitude, broad frequency strain. The biological
      effects of low amplitude, broad frequency strain are poorly understood. To
      evaluate the effects of low amplitude strains ranging in frequency from 0 to 50
      Hz on osteoblastic function, we seeded MC3T3-E1 cells into collagen gels and
      applied the following loading protocols for 3 min per day for either 3 or 7 days:
      (1) sinusoidal strain at 3 Hz, with 0-3000 microstrain peak-to-peak followed by
      0.33 s resting time, (2) "broad frequency vibration" of low amplitude strain
      (standard deviation of 300 microstrain) including frequency components from 0 to
      50 Hz, and (3) sinusoidal strain combined with broad frequency vibration (S + V).
      The cells were harvested on day 4 or 8. We found that the S + V stimulation
      significantly repressed cell proliferation by day 8. Osteocalcin mRNA was up
      regulated 2.6-fold after 7 days of S + V stimulation, and MMP-9 mRNA was elevated
      1.3-fold after 3 days of vibration alone. Sinusoidal stimulation alone did not
      affect the cell responses. No differences due to loading were observed in
      alkaline phosphatase activity and in mRNA levels of type I collagen, osteopontin,
      connexin 43, MMPs-1A, -3, -13. These results suggest that osteoblasts are more
      sensitive to low amplitude, broad frequency strain, and this kind of strain could
      sensitize osteoblasts to high amplitude, low frequency strain. This suggestion
      implies a potential contribution of stochastic resonance to the mechanical
      sensitivity of osteoblasts.

PMID- 12485641
TI  - Changes in talocrural joint contact stress characteristics after simulated
      rotationplasty.
AB  - In order to assess the changes in talocrural joint contact stress after
      rotationplasty, 10 lower-leg cadaver specimens were axially loaded with 600 N and
      investigated in two loading situations: (1) Normal loading with a plantigrade
      foot; (2) in an equinus position of a simulated rotationplasty. Joint contact
      stress in the talar facet of the talocrural joint was determined with Fuji
      Prescale film cut to size and analyzed with digital image analysis for joint
      contact area, mean and peak pressure, contact force, and location of the load
      application on the trochlea tali. The results demonstrate a significant transfer
      on the loading zone to the posterior part of the talus (p = 0.005), a significant
      reduction of the contact area (p = 0.005) and force (p = 0.005), and a
      significant increase of the mean (p = 0.022) and maximum pressures (p = 0.013).
      These results indicate that the rotationplasty causes pronounced changes in joint
      loading characteristics.

PMID- 12485642
TI  - How do load carriage and walking speed influence trunk coordination and stride
      parameters?
AB  - To determine the effects of load carriage and walking speed on stride parameters
      and the coordination of trunk movements, 12 subjects walked on a treadmill at a
      range of walking speeds (0.6-1.6 m s(-1)) with and without a backpack containing
      40% of their body mass. It was hypothesized that compared to unloaded walking,
      load carriage decreases transverse pelvic and thoracic rotation, the mean
      relative phase between pelvic and thoracic rotations, and increases hip
      excursion. In addition, it was hypothesized that these changes would coincide
      with a decreased stride length and increased stride frequency. The findings
      supported the hypotheses. Dimensionless analyses indicated that there was a
      significantly larger contribution of hip excursion and smaller contribution of
      transverse plane pelvic rotation to increases in stride length during load
      carriage. In addition, there was a significant effect of load carriage on the
      amplitudes of transverse pelvic and thoracic rotation and the relative phase of
      pelvic and thoracic rotation. It was concluded that the shorter stride length and
      higher stride frequency observed when carrying a backpack is the result of
      decreased pelvic rotation. During unloaded walking, increases in pelvic rotation
      contribute to increases in stride length with increasing walking speed. The
      decreased pelvic rotation during load carriage requires an increased hip
      excursion to compensate. However, the increase in hip excursion is insufficient
      to fully compensate for the observed decrease in pelvis rotation, requiring an
      increase in stride frequency during load carriage to maintain a constant walking
      speed.

PMID- 12485643
TI  - Cell orientation determines the alignment of cell-produced collagenous matrix.
AB  - In healing ligaments and tendons, the cells are not aligned and collagen matrix
      is not organized as in normal tissues. In addition, the mechanical properties of
      the tissues are abnormal. We hypothesized that the lack of alignment of the
      collagen matrix results from random orientation of the cells seen in the healing
      area. To test this hypothesis, a novel in vitro model was used in which the
      orientation of cells could be controlled via microgrooves, and alignment of the
      collagen matrix formed by these cells could be easily observed. It is known that
      cells align uniformly along the direction of microgrooves; therefore MC3T3-E1
      cells, which produce large amounts of collagen, were grown on silicone membranes
      with parallel microgrooves (10 microm wide x 3 microm deep) in the surface. As a
      control, the same cells were also grown on smooth silicone membranes. Cells on
      both the microgrooved and smooth silicone surfaces produced a layer of readily
      visible collagen matrix. Immunohistochemical staining showed that the matrix
      consisted of abundant type I collagen. Polarized light microscopy of the collagen
      matrix revealed the collagen fibers to be parallel to the direction of the
      microgrooves, whereas the collagen matrix produced by the randomly oriented cells
      on the smooth membranes was disorganized. Thus, the results of this study suggest
      that the orientation of cells affects the organization of the collagenous matrix
      produced by the cells. The results also suggest that orienting cells along the
      longitudinal direction of healing ligaments and tendons may lead to the
      production of aligned collagenous matrix that more closely represents the
      uninjured state. This may enhance the mechanical properties of healing ligaments
      and tendons.

PMID- 12485644
TI  - A three-dimensional computational analysis of fluid-structure interaction in the
      aortic valve.
AB  - Numerical analysis of the aortic valve has mainly been focused on the closing
      behaviour during the diastolic phase rather than the kinematic opening and
      closing behaviour during the systolic phase of the cardiac cycle. Moreover, the
      fluid-structure interaction in the aortic valve system is most frequently ignored
      in numerical modelling. The effect of this interaction on the valve's behaviour
      during systolic functioning is investigated. The large differences in material
      properties of fluid and structure and the finite motion of the leaflets
      complicate blood-valve interaction modelling. This has impeded numerical analyses
      of valves operating under physiological conditions. A numerical method, known as
      the Lagrange multiplier based fictitious domain method, is used to describe the
      large leaflet motion within the computational fluid domain. This method is
      applied to a three-dimensional finite element model of a stented aortic valve.
      The model provides both the mechanical behaviour of the valve and the blood flow
      through it. Results show that during systole the leaflets of the stented valve
      appear to be moving with the fluid in an essentially kinematical process governed
      by the fluid motion.

PMID- 12485645
TI  - A new parametric approach for modeling hip forces during gait.
AB  - An analytical parametric model was developed to estimate the natural biological
      variations in muscle forces and their effect on the hip forces subject only to
      physiological constraints and not predefined optimization criterion. Force
      predictions are based on the joint kinematics and kinetics of each subject, a
      previously published muscle model, and physiological constraints on the muscle
      force distributions. The model was used to determine the hip contact forces
      throughout the stance phase of gait of a subject with a total hip replacement
      (THR). The parametrically modeled peak hip force without antagonistic muscle
      activity varied from 2.7 to 3.2 Body Weights (mean 2.9 Body Weights), which
      agreed well with published in vivo measurements from instrumented THRs in other
      subjects. For every 10% increase in antagonistic activity, the mean peak hip
      force increased by 0.2 Body Weights. The parametric model allows one to examine
      the effect of specific muscle weaknesses or increased antagonistic muscle
      activity on the hip forces. The model also provides a tool for studying the
      effect of gait adaptations on hip forces, as predictions are based on each
      individual's gait data. Differences in peak forces between subjects can then be
      evaluated relative to the uncertainty in not knowing the precise muscle force
      distributions.

PMID- 12485646
TI  - Experimental validation of a microcracking-based toughening mechanism for
      cortical bone.
AB  - It has been proposed that cortical bone derives its toughness by forming
      microcracks during the process of crack propagation (J. Biomech. 30 (1997) 763;
      J. Biomech. 33 (2000) 1169). The purpose of this study was to experimentally
      validate the previously proposed microcrack-based toughening mechanism in
      cortical bone. Crack initiation and propagation tests were conducted on cortical
      bone compact tension specimens obtained from the antlers of red deer. For these
      tests, the main fracture crack was either propagated to a predetermined crack
      length or was stopped immediately after initiating from the notch. The
      microcracks produced in both groups of specimens were counted in the same surface
      area of interest around and below the notch, and crack growth resistance and
      crack propagation velocity were analyzed. There were more microcracks in the
      surface area of interest in the propagation than in initiation specimens showing
      that the formation of microcracks continued after the initiation of a fracture
      crack. Crack growth resistance increased with crack extension, and crack
      propagation velocity vs. crack extension curves demonstrated the characteristic
      jump increase and decrease pattern associated with the formation of microcracks.
      The scanning electron micrographs of crack initiation and propagation displayed
      the formation of a frontal process zone and a wake, respectively. These results
      support the microcrack-based toughening mechanism in cortical bone. Bone
      toughness is, therefore, determined by its ability to form microcracks during
      fracture.

PMID- 12485647
TI  - A constraint-based approach to modelling the mobility of the human knee joint.
AB  - A model of knee mobility able to predict the range and pattern of movement in the
      unloaded joint was proposed by Wilson et al. (J. Biomech. 31 (1998) 1127-1136).
      The articular surfaces in the lateral and medial compartments and isometric
      fascicles in three of the knee ligaments were represented as five constraints on
      motion between the femur and tibia in a single degree-of-freedom parallel spatial
      mechanism. The path of movement of the bones during passive flexion was found by
      solving the forward kinematics of the mechanism using an iterative method. The
      present paper shows that such a mechanism-based solution approach can lead to an
      underestimation of the flexion range. This is due to the mechanism reaching a
      'stationary configuration' and 'locking'. A new, constraint-based approach to the
      solution of the model joint displacement is proposed. It avoids the
      representation of ligaments and articular surfaces by kinematically equivalent
      chains of one degree-of-freedom pairs which are prone to singularities. It relies
      instead on a numerical solution of five non-linear constraint equations to find
      the relative positions of the bones at a series of flexion angles. The method is
      successful both in its ability to predict motion through a physiological range
      and in its efficiency with a solution rate forty times faster than the original
      algorithm. The new approach may be extended to include more complex joint surface
      geometry, allowing a study of the effects of articular surface shape and ligament
      arrangement on joint kinematics.

PMID- 12485648
TI  - Effect of micromechanical stimulations on osteoblasts: development of a device
      simulating the mechanical situation at the bone-implant interface.
AB  - Many experimental models have been developed to investigate the effects of
      mechanical stimulation of cells, but none of the existing devices can simulate
      micromotions at the cellular-mechanical interface with varying amplitudes and
      loads. Osteoblasts are sensitive to mechanical stimuli, so to study the bone
      implant interface it would be important to quantify their reaction in a situation
      mimicking the mechanical situation arising at that interface. In this study, we
      present the development of a new device allowing the application of micromotions
      and load on cells in vitro. The new device allowed the cells to be stimulated
      with sinusoidal motions of amplitudes comprised between +/- 5 and +/- 50 microm,
      frequencies between 0.5 and 2 Hz, and loads between 50 and 1000 Pa. The device,
      with a total length of 20 cm, was designed to work in an incubator at 37 degrees
      C and 100% humidity. Expression of various bone important genes was monitored by
      real-time RT-PCR. Micromotions and load were shown to affect the behavior of
      osteoblasts by down-regulating the expression of genes necessary for the creation
      of organic extracellular matrix (collagen type I) as well as for genes involved
      in the mineralization process (osteocalcin, osteonectin). The developed device
      could then be used to simulate different mechanical situations at the bone
      implant interface.

PMID- 12485649
TI  - A multi-station culture force monitor system to study cellular contractility.
AB  - Cellular contraction contributes to the formation of scar tissue, which is
      characterized by an over-produced, disorganized collagen matrix. To study the
      contractility of cells in vitro and its potential contribution to scar tissue
      formation, we have developed a multi-station culture force monitor (CFM) system.
      This system consists of four vertical cantilever beams with semiconductor strain
      gages and a computerized data acquisition unit to monitor contractile forces of
      the cells in a collagen gel. Calibration showed that this system has a highly
      linear voltage-force relationship (R(2) > 0.99). Further, to demonstrate the
      applicability of this system, contractile forces of human skin fibroblasts in a
      collagen gel were measured. These fibroblasts were found to produce an average
      force of 0.2 nN/cell, which is consistent with the data in literature. The
      significant advantage of this CFM system is its ability to test multiple samples
      simultaneously. Therefore, the system can facilitate statistical design and
      analysis of experiments to study the effects of growth factors (e.g., TGF-betas)
      on cellular contraction and their potential role in scar tissue formation.

PMID- 12485650
TI  - Effect of metal and sampling rate on accuracy of Flock of Birds electromagnetic
      tracking system.
AB  - Electromagnetic tracking devices are used in many biomechanics applications.
      Previous studies have shown that metal located within the working field of direct
      current electromagnetic tracking devices produces significant errors. However,
      the effect of sampling rate on the errors produced in a metallic environment has
      never been studied. In this study, the accuracy of Ascension Technologies' Flock
      of Birds was evaluated at sampling rates of 20, 60, 100, and 140 Hz, in the
      presence of both aluminum and steel. Aluminum interference caused an increase in
      measurement error as the sampling rate increased. Conversely, steel interference
      caused a decrease in measurement error as the sampling rate increased. We
      concluded that the accuracy of the Flock of Birds tracking system can be
      optimized in the presence of metal by careful choice in sampling rate.

PMID- 12485651
TI  - The muscle standardised femur.

PMID- 12485655
TI  - Study of the 111In-DTPA complex by the electromigration method.
AB  - The electrophoretic behavior of the 111In-DTPA radiopharmaceutical has been
      investigated. The stability constant, diffusion coefficient and effective charge
      of the complex as well as the temperature dependence of the electrophoretic
      mobility were determined. No-carrier-added 111In with high specific activity was
      used in the electrophoretic experiments in ultramicroconcentrations (10(-9)M).

PMID- 12485656
TI  - Gold analysis by the gamma absorption technique.
AB  - Gold (Au) analyses are generally performed using destructive techniques. In this
      study, the Gamma Absorption Technique has been employed for gold analysis. A
      series of different gold alloys of known gold content were analysed and a
      calibration curve was obtained. This curve was then used for the analysis of
      unknown samples. Gold analyses can be made non-destructively, easily and quickly
      by the gamma absorption technique. The mass attenuation coefficients of the
      alloys were measured around the K-shell absorption edge of Au. Theoretical mass
      attenuation coefficient values were obtained using the WinXCom program and
      comparison of the experimental results with the theoretical values showed
      generally good and acceptable agreement.

PMID- 12485657
TI  - A new 68Ge/68Ga generator system using an organic polymer containing N
      methylglucamine groups as adsorbent for 68Ge.
AB  - A macroporous styrene-divinylbenzene copolymer containing N-methylglucamine
      groups was selected for a new 68Ge/68Ga generator system. This resin packed into
      a column effectively adsorbed the parent nuclide 68Ge. The daughter 68Ga was
      eluted from the resin with a solution of a low-affinity gallium chelating ligand
      such as citric or phosphoric acid. The 68Ge leakage was less than 0.0004% of the
      68Ge adsorbed on the resin. By simple mixing of transferrin and desferoxamine
      conjugated HSA and IgG with the eluate from the column, 68Ga-labeling was
      completed in high yield.

PMID- 12485658
TI  - Seed-less iodine-125 ophthalmic applicator.
AB  - A method of preparation a seed-less active insert of iodine-125 ophthalmic
      applicator is described. Internal electrolysis was applied for fixing iodine-125
      on the concave surface of the silver shell which is afterwards hermetically
      sealed inside a spherically shaped acrylic insert. The current-voltage
      characteristics of the galvanic cell used for deposition of silver iodide were
      determined. The results of the measurements of the energy spectra of the
      radiation emitted by a seed-less and seed-containing applicator are presented.
      The iodine-125 surface distribution uniformity on a silver shell was measured.
      The depth dose rate measurements indicate that the total activity incorporated in
      a seed-less applicator can be lower than that in seed-containing, while
      simultaneously assuring the desired dose rate.

PMID- 12485659
TI  - Water-cooled grid support for high-power irradiation with thin target windows.
AB  - A new thin window support system for the accelerator production of positron
      emitters (e.g. 17F, 18F 11C, 15O) has been developed. The integrated support grid
      and cooling design has been optimized for 6-13 MeV protons or deuterons. The
      water-cooled support grid regularly operated at > 100 microA of 6 MeV deuterons
      and protons. The grid performed without failure at > or = 50 microA of 13 MeV
      protons on a 3.1 MPa gas target using 25.4 microm aluminum target foil.
      Transmission for the smallest hole grid of 72% based on uniform parallel beam
      agreed with the measured yield of 71 +/- 1% compared to the theoretical maximum
      yield.

PMID- 12485660
TI  - Performance tests of external moderators of a PGNAA setup.
AB  - Performance tests of external cylindrical moderators of an accelerator-based
      prompt gamma ray neutron activation analysis (PGNAA) setup have been carried out
      through thermal neutrons and prompt gamma-ray yield measurements. The PGNAA setup
      is to be used for analysis of cement samples. This study was conducted to
      investigate the effects of geometry of cylindrical moderator on yield of thermal
      neutrons and prompt gamma-rays for two different types of moderator assemblies.
      One of the moderators was to be used with a small sample and the other to be used
      with a large sample. Fast and thermal neutron yield was measured inside the
      sample volume as a function of the front moderator thickness as well as sample
      length. Neutron yield measurement was carried out at the King Fahd University of
      Petroleum and Minerals 350 keV pulsed beam accelerator using nuclear track
      detectors. The pulsed 200 keV deuteron beam with 5 ns pulse width and 31.25 kHz
      frequency was used to produce 2.8 MeV neutrons via D(d,n) reaction. Neutron yield
      measurements showed that the large sample moderator has a smaller yield of
      thermal neutrons as compared to the small sample moderator, which is in complete
      agreement with the results of Monte Carlo yield calculations of the thermal and
      fast neutrons from both the moderators. Finally, the prompt gamma-ray yield from
      a Portland cement sample was measured using the two moderators and was compared
      with each other. As predicted by Monte Carlo simulations, in spite of a smaller
      yield of thermal neutrons, the large sample moderator has a higher yield of
      prompt gamma-rays.

PMID- 12485662
TI  - Corrections to "How to calculate lead concentration and concentration uncertainty
      in XRF in vivo bone lead analysis" by Kondrashov and Rothenberg.
AB  - Kondrashov and Rothenberg (Appl. Radiat. Isot. 55 (2001) 799) have published "a
      substantial correction for calculating estimates of lead concentration and
      uncertainty for in vivo X-ray fluorescent bone analysis with Cd-109 source"
      (sic). Our paper shows that their correction fails to consider two important
      points that render it (i) a correction to a superseded method and (ii) of limited
      effect. Also, their approach to a "crude" estimate produces measurement
      uncertainties that are implausibly small. In order that they not be propagated in
      the literature, our paper also corrects several misstatements and errors in
      Kondrashov and Rothenberg.

PMID- 12485664
TI  - Iodine-124 labelled annexin-V as a potential radiotracer to study apoptosis using
      positron emission tomography.
AB  - Annexin-V is a calcium-dependent protein that binds with high affinity to
      phosphaditylserine exposed during apoptosis. The aim of this study was to
      radiolabel annexin-V with iodine-124 for use as a potential probe of apoptosis by
      positron emission tomography. Annexin-V was radioiodinated directly using the
      cyclotron-produced positron emitter iodine-124 by the chloramine-T (CAT) method
      and indirectly by the pre-labelled reagent N-succinimidyl 3-[124I]iodobenzoate
      ([124I]m-SIB). Some reaction parameters of the CAT method such as reaction time
      and pH were optimised to give radiochemical yields of 22.3 +/- 2.6%(n = 3, gel
      filtration). After incubation with [124I]m-SIB, radiolabelled annexin-V was
      obtained in 14% and 25% yield by FPLC and gel-filtration, respectively. The
      radiochemical purities from direct and indirect labelling were 97.7 +/- 1.0%(n =
      3) and 96.7 +/- 2.1%(n = 3), respectively. The new radiotracers could be stored
      for up to four days without significant de-iodination. The biological activity of
      radiolabelled annexin-V was tested in control and camptothecin-treated (i.e.
      apoptotic) human leukaemic HL60 cells. A significantly higher (21%) binding in
      treated cells was observed with [125I]m-SIB-annexin-V. The binding of [125I]m-SIB
      labelled annexin-V to camptothecin treated cells was blocked (68%) by a 100-fold
      excess of unlabelled annexin-V.

PMID- 12485665
TI  - Electron paramagnetic resonance of some gamma-irradiated drugs.
AB  - Some drugs, used mainly in treatment of some neurological diseases and
      hypertension were exposed to gamma-irradiation, and the samples were investigated
      by electron paramagnetic resonance (EPR). The observed spectra were interpreted
      in terms of some type of alkyl and amine radical fragments. The spectra were
      computer simulated and the g values of the radicals and the hyperfine structure
      constants of the free electron with nearby protons were determined. The species
      were found to be stable at room temperature for more than a year. The samples
      were found to display no EPR signal without irradiation.

PMID- 12485666
TI  - Some optimisation studies relevant to the production of high-purity 124I and
      120gI at a small-sized cyclotron.
AB  - Optimisation experiments on the production of the positron emitting radionuclides
      124I(T(1/2) = 4.18d) and (120g)I (T(1/2) = 1.35 h) were carried out. The TeO(2)
      target technology and dry distillation method of radioiodine separation were
      used. The removal of radioiodine was studied as a function of time and the loss
      of TeO(2) from the target as a function of oven temperature and time of
      distillation. A distillation time of 15 min at 750 degrees C was found to be
      ideal. Using a very pure source and comparing the intensities of the annihilation
      and X-ray radiation, a value of 22.0 +/- 0.5% for the beta(+) branching in 124I
      was obtained. Production of 124I was done using 200 mg/cm(2) targets of 99.8%
      enriched 124TeO(2) on Pt-backing, 16 MeV proton beam intensities of 10 microA,
      and irradiation times of about 8 h. The average yield of 124I at EOB was 470
      MBq(12.7 mCi). At the time of application (about 70 h after EOB) the
      radionuclidic impurity 123I (T(1/2) = 13.2 h) was <1%. The levels of other
      impurities were negligible (126I < 0.0001%;125I = 0.01%). Special care was taken
      to determine the 125I impurity. For the production of (120g)I only a thin 30 mg
      target (on 0.5 cm(2) area) of 99.9% enriched 120TeO(2) was available.
      Irradiations were done with 16 MeV protons for 80 min at beam currents of 7
      microA. The 120gI yield achieved at EOB was 700 MBq(19 mCi), and the only
      impurity detected was the isomeric state 120 mI(T(1/2) = 53 min) at a level of
      4.0%. The radiochemical purity of both 124I and 120gI was checked via HPLC and
      TLC. The radioiodine collected in 0.02 M NaOH solution existed >98% as iodide.
      The amount of inactive Te found in radioiodine was <1 microg. High purity 124I
      and 120gI can thus be advantageously produced on a medium scale using the low
      energy (p,n) reaction at a small-sized cyclotron.

PMID- 12485667
TI  - Chemical dosimetry using an iodide/iodate aqueous solution: application to the
      gamma irradiation of blood.
AB  - A method is presented for measuring and verifying the radiation dose in gamma
      irradiators used for treating blood prior to transfusion. This method employs the
      iodide/iodate dosimeter (0.6M iodide, 0.1M iodate, and 0.01 borate at pH 9.25)
      which forms triiodide upon exposure to ionizing radiation; for Cs-137 radiation
      the G value is 14.1. Samples were placed in a canister and irradiated in a
      conventional blood bank irradiator containing several Cs-137 sources. The
      following were exposed: (a) nine 1.5 ml plastic tubes containing dosimetry
      solution taped inside a 250 ml blood bag, which, in turn, was filled with either
      water or blood, (b) 50 ml plastic syringes containing varying amounts of
      dosimetry solution, (c) a whole blood bag containing 250 ml of the dosimetry
      solution. A water phantom was not used during exposure. The absorbance changes at
      352 nm due to triiodide formation were used to determine a dose rate, which was
      on the order of 10 Gy/min (+/-5%) for all samples measured. This value is
      consistent with an average time-decayed dose rate for the irradiation volume as
      determined from the manufacturers calibration of the unit taking into account the
      heterogeneous nature of the radiation field inside the irradiator and the absence
      of a water phantom. Because of its sensitivity, ease of operation, and
      reproducibility, it is suggested that the iodide/iodate dosimetry system be
      considered for on-site periodic conformation/verification of the radiation dose
      as part of a quality assurance requirement for blood irradiators.

PMID- 12485668
TI  - Properties of sintered amethyst pellets as thermoluminescent dosimeters.
AB  - The main dosimetric characteristics of amethyst, Brazilian natural semi-precious
      stone, were investigated in this work, in order to verify the possibility of its
      use for gamma-radiation detection using the thermoluminescent (TL) technique. The
      samples were tested in X- and gamma-radiation beams, and their TL glow curves,
      dependences of the response on the absorbed dose and radiation energy, and the
      response reproducibility were investigated. The preliminary results show the
      usefulness of this material in dosimetry for radiation processing.

PMID- 12485669
TI  - Indoor light on thermoluminescence of CVD diamond film used as a high-energy
      photon dosimeter.
AB  - The effect of light on polycrystalline diamond film that was produced by chemical
      vapor deposition and is used as a thermoluminescent dosimeter should be
      considered, although some researchers have indicated that such an effect was
      theoretically unlikely to happen. A 15 min exposure to a normal desk light bulb
      induces significant thermoluminescence (TL) comparable to a 0.5 Gy exposure to
      high-energy photons. This light-induced TL will be saturated within 2 h. The
      saturated TL intensity depends on the frequency of the light and the blue light
      dominates. The TL peak area at a temperature of 605 K is insensitive to light but
      is sensitive to high-energy photons. Another peak at about 410 K is caused by
      light only, because the TL from the ionization radiation at the same location is
      bleached. The effect of light could be easily distinguished by a numerical or an
      experimental method. Lamps with a green lampshade or pure red lights are
      suggested for use as indoor light sources. To reduce the effect of light, pre
      heating treatment before readout is also suggested.

PMID- 12485670
TI  - Autoradiographical methods for the assessment of radionuclides in hot particles
      on filter samples.
AB  - Three different autoradiographical methods were tested for detection,
      localisation and quantification of radionuclides in hot particles deposited on
      air filters. With all methods, hot particles could successfully be localised on
      air filters. Two methods, a X-ray film technique and a digital autoradiography
      technique using a microchannel array detector, have been examined with particles
      of known activity and with particles on air filter samples of the Chernobyl area
      to be able to quantify the 90Sr activity in the hot particles consistently. The
      results obtained in this study suggest that the digital autoradiography system is
      a very useful tool having a high efficiency with a low measurement uncertainty
      and allowing short exposure times for extensive measurement tasks.

PMID- 12485671
TI  - Search for lost or orphan radioactive sources based on NaI gamma spectrometry.
AB  - Within recent decades many radioactive sources have been lost, stolen, or
      abandoned, and some have caused contamination or irradiation of people. Therefore
      reliable methods for source recovery are needed. The use of car borne NaI(Tl)
      detectors is discussed. Standard processing of spectra in general can disclose
      strong and medium level signals from manmade nuclides. But methods for detecting
      low level signals from weak, distant or shielded sources can be improved. New
      methods for source detection and identification based on noise adjusted singular
      value decomposition and on area specific stripping of spectra are presented.

PMID- 12485672
TI  - Some microdosmetric data on Astatine-211.
AB  - Radionuclides which emit short range, high LET radiations such as alpha and Auger
      electrons have very promising applications in cancer therapy. Such radionuclides
      should eventually be incorporated into cell nuclei to achieve high radiotoxic
      effectiveness. This means that the dose distribution within the cell nucleus at
      microscopic levels is very important for comparison of the real differences
      between the radiotoxic effectiveness of different radionuclides. An experimental
      setup to determine real dose absorption on the microscopic scale is extremely
      difficult to design. For this reason, calculation procedures for microscopic dose
      absorption are of special interest for the diagnostic and therapeutic
      applications of radionuclides which emit short-range and high LET radiations. A
      specific calculation method for microscopic energy absorptions within the cell
      nucleus from Auger electrons of 125I was described earlier. In this study, the
      radiotoxic effectiveness of 211At and 125I has been compared using the data
      obtained by this calculation method. The data obtained show clearly that the
      radiotoxicity of the alpha and Auger emitter radionuclide 211At is comparable to
      that of 125I.

PMID- 12485673
TI  - A method for the rapid radiochemical analysis of uranium and thorium isotopes in
      impure carbonates.
AB  - A simple method combining solvent extraction and electrodeposition procedures is
      described for the determination of the isotopic composition and content of
      uranium and thorium in travertine samples. The actinide elements are extracted
      with diethyl ether from a calcium nitrate solution. The isolation of the elements
      and the alpha source preparation are performed in two steps after the sample
      digestion. The acid leaching of samples is performed using both partial and total
      dissolution methods. High recoveries of both uranium and thorium and good alpha
      spectra are obtained with both partial and total dissolution methods.

PMID- 12485674
TI  - Radon concentrations in Algerian oil and gas industry.
AB  - Concentrations of 222Rn in produced water, crude oil, natural gas (NG) and
      natural gas liquids (NGL) in on-shore Algeria were measured using scintillation
      cell techniques (Lucas cells) and electret ion chamber (EIC). The first method,
      active, is based on the use of a Lucas-type scintillation chamber in conjunction
      with a portable monitor (model Pylon AB-5); the second method, passive, using an
      EIC with a 4 l glass analysis bottle. The activities of 222Rn were in the range
      of 0.98-18.50 Bq/l for produced water, 0.02-0.3 Bq/g for crude oil, 40-1000
      Bq/m(3) for NG and 300-2500 Bq/m(3) for NGL, respectively. These values are
      compared with concentrations reported for other countries.

PMID- 12485675
TI  - Are geological media homogeneous or heterogeneous for neutron investigations?
AB  - The thermal neutron absorption cross section of a heterogeneous material is lower
      than that of the corresponding homogeneous one which contains the same
      components. When rock materials are investigated the sample usually contains
      grains which create heterogeneity. The heterogeneity effect depends on the mass
      contribution of highly and low-absorbing centers, on the ratio of their
      absorption cross sections, and on their sizes. An influence of the granulation of
      silicon and diabase samples on the absorption cross section measured with
      Czubek's method has been experimentally investigated. A 20% underestimation of
      the absorption cross section has been observed for diabase grains of sizes from
      6.3 to 12.8 mm.

PMID- 12485676
TI  - The optimisation of the fast neutron and gamma-ray transmission set-up for
      moisture measurement of coke.
AB  - In the present paper, modelling calculations with the Monte Carlo (MCNP4C) code
      were performed for the optimisation of the fast neutron and gamma-ray
      transmission, set-up, used for the humidity measurement of coke. The optimisation
      focused on maximising the sensitivity of the neutron flux to humidity changes and
      on lowering neutron-counting error, both leading to higher accuracy of coke
      moisture determination. Different materials used for the source shielding and
      neutron collimation, together with different dimensions of the neutron
      collimators were studied. The results obtained from the Monte Carlo modelling
      correlate with the real instrument performance.

PMID- 12485677
TI  - Radioactivity levels of salt for natural sediments in the northwestern desert and
      local markets in Egypt.
AB  - Thirteen samples of salt collected from different locations of old sediments in
      the western desert at El-Harra and Ain Giffara, Sitra lake and local markets in
      Egypt have been investigated. Natural radionuclide contents have been measured by
      gamma-ray spectrometry employing a shielded HPGe detector. The activities of
      238U, 232Th and 40K have been determined in Bq/kg dry weight. The absorbed dose
      rate of gamma radiation was estimated to be 1.46-16.13 nGy/h. The thorium-to
      uranium concentration ratios were also estimated for the samples.

PMID- 12485679
TI  - Synthesis of 32P-labelled protein probes using a modified thioredoxin fusion
      protein expression system in Escherichia coli.
AB  - The thioredoxin fusion protein expression system from invitrogen was modified so
      that 32P-labelled recombinant proteins can be easily obtained in large quantities
      for functional studies. Proteins that are prone to form the inclusion bodies can
      be functionally expressed as thioredoxin fusion proteins in Escherichia coli.
      After expression, the recombinant proteins can be easily phosphorylated with 32P
      gamma ATP and the 32P-labelled protein can be obtained functionally via a mild
      proteolytic digestion to cleave off the thioredoxin moiety. A deletion construct
      of the Ah receptor nuclear translocator protein was used as an example to
      illustrate how this protein expression system works.

PMID- 12485680
TI  - Nucleotide replacement at two sites can be directed by modified single-stranded
      oligonucleotides in vitro and in vivo.
AB  - Studies involving the alteration of DNA sequences by modified single-stranded
      oligonucleotides in vitro and in vivo have revealed potential applications for
      functional genomics. Repair of a replacement, deletion, or insertion mutation has
      already been achieved with molecules having lengths between 25 and 74 bases. But,
      other vector parameters still remain to be explored. Here, the position of the
      single base in the vector directing the alteration was examined and the optimal
      site was found to be at or near the center of the vector. If that position is
      staggered 3' or 5', the frequencies of gene repair in vitro decreases. The
      potential of a single vector to direct two nucleotide changes at a specific site
      in a target sequence was also examined. Both targeted bases are corrected
      together at the same frequency if the sites are separated by three bases, but
      conversion linkage decreases precipitously when the distance is expanded to 15
      and 27 nucleotides, respectively. These results suggest that single
      oligonucleotides can be used to direct nucleotide exchange at two independent
      sites, a reaction characteristic that may be useful for many genomics
      applications.

PMID- 12485681
TI  - A two-component modular approach for enhancing T-cell activation utilizing a
      unique anti-FcgammaRI-streptavidin construct and microspheres coated with
      biotinylated-antigen.
AB  - The professional antigen presenting cell (APC) plays an essential role in the
      initiation and propagation of the acquired immune response. Thus, much work has
      been done in designing strategies that target vaccine antigen (Ag) to APC.
      Utilizing recombinant DNA technology, we have created a unique two-component
      system that delivers biotinylated Ag to the Fc gamma receptor type I (FcgammaRI)
      on APC. Our studies demonstrate that we can successfully engineer FcgammaRI
      specific targeting element proteins that simultaneously bind both biotin and
      recognize FcgammaRI. Additionally, we are able to engineer biotinylated Ag, which
      form functional elements when adsorbed onto latex microspheres. Furthermore, the
      targeting and functional element components bind to each other and successfully
      form two-component immunogens. T-cell activation in response to targeted Ag-laden
      microspheres is 10- to 100-fold greater than the response to the non-targeted Ag
      laden microspheres. This enhancement is 100- to 1000-fold greater than the
      responses generated to soluble Ag. Thus, our results suggest that specific
      targeting of Ag-laden microspheres to FcgammaRI may significantly enhance the
      adjuvant properties of microparticulate delivery systems. Further development of
      this system may help to elucidate the mechanisms involved in generating enhanced
      responses to APC-targeted vaccines and significantly advance vaccine technology.

PMID- 12485682
TI  - Tendon--bridging the gap.

PMID- 12485683
TI  - Force transmission via axial tendons in undulating fish: a dynamic analysis.
AB  - Sonomicrometrics of in vivo axial strain of muscle has shown that the swimming
      fish body bends like a homogenous, continuous beam in all species except tuna.
      This simple beam-like behavior is surprising because the underlying tendon
      structure, muscle structure and behavior are complex. Given this incongruence,
      our goal was to understand the mechanical role of various myoseptal tendons. We
      modeled a pumpkinseed sunfish, Lepomis gibbosus, using experimentally-derived
      physical and mechanical attributes, swimming from rest with steady muscle
      activity. Axially oriented muscle-tendons, transverse and axial myoseptal
      tendons, as suggested by current morphological knowledge, interacted to replicate
      the force and moment distribution. Dynamic stiffness and damping associated with
      muscle activation, realistic muscle force generation, and force distribution
      following tendon geometry were incorporated. The vertebral column consisted of 11
      rigid vertebrae connected by joints that restricted bending to the lateral plane
      and endowed the body with its passive viscoelasticity. In reaction to the
      acceleration of the body in an inviscid fluid and its internal transmission of
      moment via the vertebral column, the model predicted the kinematic response.
      Varying only tendon geometry and stiffness, four different simulations were run.
      Simulations with only intrasegmental tendons produced unstable axial and lateral
      tail forces and body motions. Only the simulation that included both intra- and
      intersegmental tendons, muscle-enhanced segment stiffness, and a stiffened caudal
      joint produced stable and large lateral and axial forces at the tail. Thus this
      model predicts that axial tendons function within a myomere to (1) convert axial
      force to moment (moment transduction), (2) transmit axial forces between adjacent
      myosepta (segment coupling), and, intersegmentally, to (3) distribute axial
      forces (force entrainment), and (4) stiffen joints in bending (flexural
      stiffening). The fact that all four functions are needed to produce the most
      realistic swimming motions suggests that axial tendons are essential to the
      simple beam-like behavior of fish.

PMID- 12485684
TI  - The skeletal attachment of tendons--tendon "entheses".
AB  - Tendon entheses can be classed as fibrous or fibrocartilaginous according to the
      tissue present at the skeletal attachment site. The former can be "bony" or
      "periosteal", depending on whether the tendon is directly attached to bone or
      indirectly to it via the periosteum. At fibrocartilaginous entheses, the
      uncalcified fibrocartilage dissipates collagen fibre bending and tendon narrowing
      away from the tidemark; calcified fibrocartilage anchors the tendon to the bone
      and creates a diffusion barrier between the two. Where there are additional
      fibrocartilaginous specialisations in the tendon and/or bone next to the
      enthesis, an "enthesis organ" is created that reduces wear and tear. Little
      attention has been paid to bone at entheses, despite the obvious bearing this has
      on the mechanical properties of the interface and the clinical importance of
      avulsion fractures. Disorders at entheses (enthesopathies) are common and occur
      in conditions such as diffuse idiopathic skeletal hyperostosis and the
      seronegative spondyloarthropathies. They are also commonly seen as sporting
      injuries such as tennis elbow and jumper's knee.

PMID- 12485685
TI  - The structure and functional significance of variations in the connective tissue
      within muscle.
AB  - The amount of intramuscular connective tissue (IMCT) and its morphological
      distribution is highly variable between muscles of differing function. The
      functional roles of this component of muscle have been poorly understood, but a
      picture is gradually emerging of the central role this component has in growth,
      transmission of mechanical signals to muscle cells and co-ordination of forces
      between fibres within a muscle. The aim of this review is to highlight recent
      advances that begin to show the functional significance of some of the
      variability in IMCT. IMCT has a number of clearly defined roles. It patterns
      muscle development and innervation, and mechanically integrates the tissue. In
      developing muscles, proliferation and growth of muscle cells is stimulated and
      guided by cell-matrix interactions. Recent work has shown that the topography of
      collagen fibres is an important signal. The timing and rates of expression of
      connective tissue proteins also show differences between muscles. Discussion of
      mechanical roles for IMCT has traditionally been limited to the passive elastic
      response of muscle. However, it is now clear that IMCT provides a matrix to
      integrate the contractile function of the whole tissue. Mechanical forces are co
      ordinated and passed between adjacent muscle cells via cell-matrix interactions
      and the endomysial connective tissue that links the cells together. An emerging
      concept is that division of a muscle into fascicles by the perimysial connective
      tissue is related to the need to accommodate shear strains as muscles change
      shape during contraction and extension.

PMID- 12485686
TI  - Morphology and mechanics of myosepta in a swimming salamander (Siren lacertina).
AB  - In contrast to the complex, three-dimensional shape of myomeres in teleost
      fishes, the lateral hypaxial muscles of salamanders are nearly planar and their
      myosepta run in a roughly straight line from mid-lateral to mid-ventral. We used
      this relatively simple system as the basis for a mathematical model of segmented
      musculature. Model results highlight the importance of the mechanics of myosepta
      in determining the shortening characteristics of a muscle segment. We used
      sonomicrometry to measure the longitudinal deformation of myomeres and the
      dorsoventral deformation of myosepta in a swimming salamander (Siren lacertina).
      Sonomicrometry results show that the myosepta allow some dorsoventral
      lengthening, indicating an amplification of myomere shortening that is greater
      than that produced by muscle fiber angle alone (10% muscle fiber shortening
      produces 28.7% myomere shortening). Polarized light and DIC microscopy of
      isolated hypaxial myosepta revealed that the collagen fiber orientation in
      hypaxial myomeres is primarily mediolateral. The mediolateral collagen fiber
      orientation, combined with our finding that the hypaxial myosepta lengthen
      dorsoventrally during swimming, suggests that one possible function of hypaxial
      myosepta in S. lacertina is to increase the strain amplification of the muscle
      fibers by reducing the mediolateral bulging of the myomeres and redirecting the
      bulging toward the dorsoventral direction.

PMID- 12485687
TI  - Collagen fibril biosynthesis in tendon: a review and recent insights.
AB  - The development and evolution of multicellular animals relies on the ability of
      certain cell types to synthesise an extracellular matrix (ECM) comprising very
      long collagen fibrils that are arranged in very ordered 3-dimensional scaffolds.
      Tendon is a good example of a highly ordered ECM, in which tens of millions of
      collagen fibrils, each hundreds of microns long, are synthesised parallel to the
      tendon long axis. This review highlights recent discoveries showing that the
      assembly of collagen fibrils in tendon is hierarchical, and involves the
      formation of fairly short "collagen early fibrils" that are the fusion precursors
      of the very long fibrils that occur in mature tendon.

PMID- 12485688
TI  - The implications of the adaptable fatigue quality of tendons for their
      construction, repair and function.
AB  - Different tendons are (i) subject to very different stresses from their muscles
      and (ii) differ in their susceptibility to fatigue damage. The fatigue quality of
      each tendon is matched to the stress it experiences, so that, in life, all
      tendons are similarly prone to damage. On-going damage must be routinely repaired
      to maintain homeostasis and prevent damage from becoming symptomatic. The
      discovery of major differences in fatigue quality among tendons, which had
      previously seemed fairly similar in their mechanical properties, raises a wide
      range of new questions. (A) What structural and chemical differences underlie the
      variations in fatigue quality? (B) What molecular structure in the tendon is
      damaged and how is repair organised? (C) Is fatigue quality adaptable and if so
      what is the trigger for adaptation? Putting these questions into context leads to
      an integrated review of tendon, including structure and chemistry, the turnover
      of proteins, the cross-linking of collagen and the response of tenocytes to load
      on the tendon.

PMID- 12485689
TI  - Tendon elasticity and muscle function.
AB  - Vertebrate animals exploit the elastic properties of their tendons in several
      different ways. Firstly, metabolic energy can be saved in locomotion if tendons
      stretch and then recoil, storing and returning elastic strain energy, as the
      animal loses and regains kinetic energy. Leg tendons save energy in this way when
      birds and mammals run, and an aponeurosis in the back is also important in
      galloping mammals. Tendons may have similar energy-saving roles in other modes of
      locomotion, for example in cetacean swimming. Secondly, tendons can recoil
      elastically much faster than muscles can shorten, enabling animals to jump
      further than they otherwise could. Thirdly, tendon elasticity affects the control
      of muscles, enhancing force control at the expense of position control.

PMID- 12485690
TI  - Spatial arrangement of white muscle fibers and myoseptal tendons in fishes.
AB  - We describe the arrangement of white muscle fibers and tendinous myoseptal
      structures and the relation of these structures to each other in order to provide
      an anatomical framework for discussions and experimental research on fish
      swimming mechanics. For the three major craniate groups, the petromyzontids,
      myxinids and gnathostomes, we identify three conditions that differ remarkably.
      Myxinids are characterized by asymmetrical myosepta with long cones. Within a
      single myoseptum these are connected by collagenous fibers that are almost
      oriented longitudinally. Distinct tendons are absent in myxinid myosepta.
      Petromyzontid myosepta lack cones and distinct myoseptal tendons, whereas
      gnathostomes bear cones and distinct tendinous structures: the lateral band,
      epineural (epipleural) tendon and myhabdoid tendon. Myoseptal fibers of
      petromyzontids and myoseptal tendons of gnathostome myosepta are firmly anchored
      in the skin. Myxinids lack firm myoseptal-skin-connections. Their muscular
      arrangement is neither comparable to that of petromyzontids nor to that of
      gnathostomes. The latter two bear archlike arrangements of muscle fibers spanning
      several segments that are hypothesized to play a role during bending. In
      gnathostomes, archlike helical muscle fiber arrangements (HMFAs) are present that
      span the length of several body segments and are multiply intersected by
      myosepta. Hence, a series of tendinous lateral bands of myosepta is embedded in
      HMFAs. The posterodorsally oriented HMFAs are underlain by posteroventrally
      oriented crossing muscle fibers (CMFs). Bending may be generated by contraction
      of the muscle fibers belonging to an HMFA and the simultaneous counteraction of
      CMFs. Moving caudally, this anterior muscle fiber arrangement gradually changes,
      eventually becoming the posterior muscle fiber arrangement. This pattern suggests
      that the function of the myomeres will also change. Three additional putative
      roles of myoseptal tendons can be deduced from their relations to white muscle
      fibers in gnathostomes (and in part in petromyzontids): (1) Posterior
      transmission of anteriorly generated muscular forces via lateral bands and/or
      myorhabdoid tendons. These tendons are more robust posteriorly. Anterior and
      posterior cones appear to play an important role in force transmission. (2)
      Pulling on collagen fibers of the skin via lateral bands and myorhabdoid tendons,
      suggesting a transmission of muscular forces that puts the skin into tension. (3)
      Resisting radial expansion of contracting muscle fibers by epineural (epipleural)
      tendons. By the latter two mechanisms modulation of body stiffness is likely to
      be achieved.

PMID- 12485692
TI  - The evolution of hindlimb tendons and muscles on the line to crown-group birds.
AB  - The anatomy and functions of muscle-tendon complexes and their bony attachments
      in birds and their outgroups show how the major pelvic limb muscle groups
      evolved. Fossils reveal that most changes evolved after the divergence of
      archosaurs in the Triassic, particularly in the dinosaurian precursors to birds.
      Three-dimensional limb control became concentrated at the hip joint; more distal
      joints and muscles were restricted to flexion or extension early in dinosaur
      evolution. Hip extensors expanded even though the primary femoral retractor M.
      caudofemoralis longus was reduced. Hip flexors and two-joint "hamstring" muscles
      were simplified to a few large heads. Knee extensors increased their sizes and
      moment arms early in bipedal dinosaurs, but the patella and cranial cnemial crest
      evolved later in birds. Lower limb muscles expanded as ossifications such as the
      hypotarsus increased their moment arms. The ossification of lower limb tendons,
      particularly in extensors, is a recent novelty of birds. Muscles and tendons that
      develop large forces, stresses, and moments to stabilize or move the limbs became
      increasingly prominent on the line to birds. Locomotion evolved in a stepwise
      pattern that only recently produced the derived limb control mechanisms of crown
      group birds, such as the strongly flexed hip and knee joints.

PMID- 12485691
TI  - The influence of ageing and exercise on tendon growth and degeneration-
      hypotheses for the initiation and prevention of strain-induced tendinopathies.
AB  - Strain-induced tendinopathy is a common injury in both human and equine athletes,
      with increasing incidence associated with greater involvement in sport and an
      increasingly aged population. This paper reviews our studies on the abundant non
      collagenous protein, cartilage oligomeric matrix protein (COMP), in equine
      tendons. Its variation between tendon type and site, age and exercise has
      provided an insight into how age and exercise influence tendon growth and
      maturation. Tendons can be broadly divided into two types, reflecting their
      different matrix composition and function: the energy-storing tendons used for
      weight-bearing and locomotion, which suffer a high incidence of strain-induced
      tendinopathy, and positional tendons involved in limb placement or manipulative
      skills. It would appear that while energy-storing tendon can respond to the
      mechanical forces applied to it during growth, there is no evidence that it can
      do so after skeletal maturity. Instead, cumulative fatigue damage causes
      degeneration at the molecular level, potentially weakening it and increasing the
      risk of clinical injury. Appropriate exercise regimes early in life may help to
      improve the quality of growing tendon, thereby reducing the incidence of injury
      during ageing or subsequent athletic career.

PMID- 12485693
TI  - The integrated function of muscles and tendons during locomotion.
AB  - The mechanical roles of tendon and muscle contractile elements during locomotion
      are often considered independently, but functionally they are tightly integrated.
      Tendons can enhance muscle performance for a wide range of locomotor activities
      because muscle-tendon units shorten and lengthen at velocities that would be
      mechanically unfavorable for muscle fibers functioning alone. During activities
      that require little net mechanical power output, such as steady-speed running,
      tendons reduce muscular work by storing and recovering cyclic changes in the
      mechanical energy of the body. Tendon stretch and recoil not only reduces
      muscular work, but also allows muscle fibers to operate nearly isometrically,
      where, due to the force-velocity relation, skeletal muscle fibers develop high
      forces. Elastic energy storage and recovery in tendons may also provide a key
      mechanism to enable individual muscles to alter their mechanical function, from
      isometric force-producers during steady speed running to actively shortening
      power-producers during high-power activities like acceleration or uphill running.
      Evidence from studies of muscle contraction and limb dynamics in turkeys suggests
      that during running accelerations work is transferred directly from muscle to
      tendon as tendon stretch early in the step is powered by muscle shortening. The
      energy stored in the tendon is later released to help power the increase in
      energy of the body. These tendon length changes redistribute muscle power,
      enabling contractile elements to shorten at relatively constant velocities and
      power outputs, independent of the pattern of flexion/extension at a joint. Tendon
      elastic energy storage and recovery extends the functional range of muscles by
      uncoupling the pattern of muscle fiber shortening from the pattern of movement of
      the body.

PMID- 12485694
TI  - Effects of exercise on the biomechanical, biochemical and structural properties
      of tendons.
AB  - Tendon has been shown to undergo remodeling in response to strength or endurance
      training, however, compared to muscle, studies of the effects of exercise on
      tendon are limited and the information is inconsistent. Exercise may influence
      the structure, chemical composition and/or mechanical properties of tendon.
      Studies that have examined mechanical changes of tendon in response to endurance
      training suggest that ultimate failure strength and stiffness increase with
      training. Available reports indicate that increases in tensile strength and
      stiffness are probably not associated with increases in collagen concentration or
      with tendon hypertrophy. The paucity of data renders it impossible to evaluate
      the response of other structural, chemical and mechanical parameters to training.
      Furthermore, few investigators have included discrete measures of structural,
      biomechanical and biochemical variables within a single study. The lack of
      integrative studies makes it difficult to definitively associate changes in the
      mechanical properties of tendon with chemical composition and structure.

PMID- 12485695
TI  - Structure and function of tuna tail tendons.
AB  - The caudal tendons in tunas and other scombrid fish link myotomal muscle directly
      to the caudal fin rays, and thus serve to transfer muscle power to the hydrofoil
      like tail during swimming. These robust collagenous tendons have structural and
      mechanical similarity to tendons found in other vertebrates, notably the leg
      tendons of terrestrial mammals. Biochemical studies indicate that tuna tendon
      collagen is composed of the (alpha1)(2),alpha2 heterotrimer that is typical of
      vertebrate Type I collagen, while tuna skin collagen has the unusual
      alpha1,alpha2,alpha3 trimer previously described in the skin of some other
      teleost species. Tuna collagen, like that of other fish, has high solubility due
      to the presence of an acid-labile intermolecular cross-link. Unlike collagen in
      mammalian tendons, no differences related to cross-link maturation were detected
      among tendons in tuna ranging from 0.05 to 72 kg (approx. 0.25-6 years). Tendons
      excised post-mortem were subjected to load cycling to determine the modulus of
      elasticity and resilience (mean of 1.3 GPa and 90%, respectively). These material
      properties compare closely to those of leg tendons from adult mammals that can
      function as effective biological springs in terrestrial locomotion, but the
      breaking strength is substantially lower. Peak tendon forces recorded during
      steady swimming appear to impose strains of much less than 1% of tendon length,
      and no more than 1.5% during bursts. Thus, the caudal tendons in tunas do not
      appear to function as elastic storage elements, even at maximal swimming effort.

PMID- 12485696
TI  - Structure-function considerations of muscle-tendon junctions.
AB  - Skeletal muscle cells transmit force across the cell membrane to the
      extracellular matrix and ultimately to tendons. Force transmission may occur both
      along the lateral surfaces of muscle fibers and at their ends. Forces within
      muscles may follow the path of greatest resistance. Sites of force transmission
      are morphologically and compositionally specialized for this function. They are
      also specialized to provide stress-information that feeds into the synthetic
      programs of the muscle cell. A detailed analysis of the structures and functions
      of muscle-tendon junctions is essential to a comprehensive understanding of the
      way in which muscles and their connective tissues are controlled to move joints
      and to respond to mechanical stresses.

PMID- 12485697
TI  - The structure and function of normally mineralizing avian tendons.
AB  - The leg tendons of certain avian species normally calcify. The gastrocnemius, or
      Achilles, tendon of the domestic turkey, Meleagris gallopavo, is one such
      example. Its structure and biomechanical properties have been studied to model
      the adaptive nature of this tendon to external forces, including the means by
      which mineral deposition occurs and the functional role mineralization may play
      in this tissue. Structurally, the distal rounded, thick gastrocnemius bifurcates
      into two smaller proximal segments that mineralize with time. Mineral deposition
      occurs at or near the bifurcation, proceeding in a distal-to-proximal direction
      along the segments toward caudal and medial muscle insertions of the bird hip.
      Mineral formation appears mediated first by extracellular matrix vesicles and
      later by type I collagen fibrils. Biomechanical analyses indicate lower tensile
      strength and moduli for the thick distal gastrocnemius compared to narrow, fan
      shaped proximal segments. Tendon mineralization here appears to be strain
      induced, the muscle forces causing matrix deformation leading conceptually to
      calcium binding through the exposure of charged groups on collagen, release of
      sequestered calcium by proteoglycans, and increased diffusion. Functionally, the
      mineralized tendons limit further tendon deformation, reduce tendon strain at a
      given stress, and provide greater load-bearing capacity to the tissue. They also
      serve as important and efficient elastic energy storage reservoirs, increasing
      the amount of stored elastic energy by preventing flexible type I collagen
      regions from stretching and preserving muscle energy during locomotion of the
      animals.

PMID- 12485698
TI  - The evolution of tendon--morphology and material properties.
AB  - Phylogenetically, tendinous tissue first appears in the invertebrate chordate
      Branchiostoma as myosepta. This two-dimensional array of collagen fibers is
      highly organized, with fibers running along two primary axes. In hagfish the
      first linear tendons appear and the myosepta have developed specialized regions
      with unidirectional fiber orientation-a linear tendon within the flat sheet of
      myoseptum. Tendons react to compressive load by first forming a
      fibrocartilaginous pad, and under severe stress, sesamoid bones. Evidence for
      this ability to react to load first arises in the cartilaginous fish, here
      documented in a tendon from the jaw of a hard-prey crushing stingray. Sesamoid
      bones are common in bony fish and also in tetrapods. Tendons will also calcify
      under tensile loads in some groups of birds, and this reaction to load is seen in
      no other vertebrates. We conclude that the evolutionary history of tendon gives
      us insight into the use of model systems for investigating tendon biology. Using
      mammal and fish models may be more appropriate than avian models because of the
      apparent evolution of a novel reaction to tensile loads in birds.

PMID- 12485699
TI  - Biomimetic approaches to tendon repair.
AB  - The linear organization of collagen fibers in tendons results in optimal
      stiffness and strength at low strains under tensile load. However, this
      organization makes repairing ruptured or lacerated tendons extremely difficult.
      Current suturing techniques to join split ends of tendons, while providing
      sufficient mechanical strength to prevent gapping, are inadequate to carry normal
      loads. Immobilization protocols necessary to restore tendon congruity result in
      scar formation at the repair site and peripheral adhesions that limit excursion.
      These problems are reviewed to emphasize the need for novel approaches to tendon
      repair, one of which is the development of biomimetic tendons. The objective of
      the empirical work described here was to produce biologically-based,
      biocompatible tendon replacements with appropriate mechanical properties to
      enable immediate mobilization following surgical repair. Nor-dihydroguaiaretic
      acid (NDGA), a di-catechol from creosote bush, caused a dose dependent increase
      in the material properties of reconstituted collagen fibers, achieving a 100-fold
      increase in strength and stiffness over untreated fibers. The maximum tensile
      strength of the optimized NDGA treated fibers averaged 90 MPa; the elastic
      modulus of these fibers averaged 580 MPa. These properties were independent of
      strain rates ranging from 0.60 to 600 mm/min. Fatigue tests established that
      neither strength nor stiffness were affected after 80 k cycles at 5% strain.
      Treated fibers were not cytotoxic to tendon fibroblasts. Fibroblasts attached and
      proliferated on NDGA treated collagen normally. NDGA-fibers did not elicit a
      foreign body response nor did they stimulate an immune reaction during six weeks
      in vivo. The fibers survived 6 weeks with little evidence of fragmentation or
      degradation. The polymerization scheme described here produces a fiber-reinforced
      NDGA-polymer with mechanical properties approaching an elastic solid. The
      strength, stiffness and fatigue properties of the NDGA-treated fibers are
      comparable to those of tendon. These fibers are biocompatible with tendon
      fibroblasts and elicit little rejection or antigenic response in vivo. These
      results indicate that NDGA polymerization may provide a viable approach for
      producing collagenous materials that can be used to bridge gaps in ruptured or
      lacerated tendons. The tendon-like properties of the NDGA-fiber would allow early
      mobilization after surgical repair. We predict that timely loading of parted
      tendons joined by this novel biomaterial will enhance mechanically driven
      production of neo-tendon by the colonizing fibroblasts and result in superior
      repair and rapid return to normal properties.

PMID- 12485700
TI  - Variation in the use of online clinical evidence: a qualitative analysis.
AB  - OBJECTIVE: To investigate factors influencing variations in clinicians' use of an
      online evidence retrieval system. SETTING: Public hospitals in New South Wales,
      Australia. METHOD: Web log analysis demonstrated considerable variation in rates
      of evidence use by clinicians at different hospitals. Focus groups and interviews
      were held with 61 staff from three hospitals, two with high rates of use and one
      with a low rate of use, to explore variation in evidence use. RESULTS:
      Differences between hospitals' and professional groups' (doctors, nurses and
      allied health) use of online evidence could be explained by organizational,
      professional and cultural factors. These included the presence of champions,
      organizational cultures which supported evidence-based practice (EBP), and
      database searching skills of individual clinicians. Staff shortages, ease of
      access and time taken to use the online evidence system were cited as barriers to
      use at the low use site, but no objective differences in these measures were
      found between the high and low use sites. CONCLUSION: Social and cultural factors
      were found to be better discriminators of high and low evidence use than
      technical factors.

PMID- 12485701
TI  - Tissue counter analysis of benign common nevi and malignant melanoma.
AB  - OBJECTIVE: The aim of this study was to evaluate the applicability of tissue
      counter analysis to the interpretation of skin images. METHOD: Digital images
      from microscopic views of benign common nevi and malignant melanoma were
      classified by the use of features extracted from histogram and co-occurrence
      matrix. Eighty cases were sampled and split into a training set and a test set.
      The images were dissected in square elements and the different features were
      calculated for each element. The classification was done by classification and
      regression trees (CART) analysis. In the CART procedure, the square elements were
      split into disjunctive nodes, which were characterized by a relevant subset of
      the features. The classification results were indicated in the original image in
      order to evaluate the performance of the procedure. RESULTS: For the learning set
      and the test set there is a significant difference between benign nevi and
      malignant melanoma without overlap. Discriminant analysis based on the percentage
      of 'malignant elements' facilitated a correct classification of all cases.
      DISCUSSION: Since no image segmentation was needed, problems related to this task
      were avoided. Though wrong classification of individual elements is unavoidable
      to some degree, tissue counter analysis shows a good discrimination between
      benign common nevi and malignant melanoma. CONCLUSION: In conclusion, tissue
      counter analysis may be a useful method for the interpretation of melanocytic
      skin tumors.

PMID- 12485702
TI  - Enabling technologies promise to revitalize the role of nursing in an era of
      patient safety.
AB  - The application of information technology (IT) in health care has the potential
      to transform the delivery of care, as well as the health care work environment,
      by streamlining processes, making procedures more accurate and efficient, and
      reducing the risk of human error. For nurses, a major aspect of this
      transformation is the refocusing of their work on direct patient care and away
      from being a conduit of information and communication among departments. Several
      of the technologies discussed, such as physician order entry and bar code
      technology, have existed for years as standalone systems. Many others are just
      being developed and are being integrated into complex clinical information
      systems (CISs) with clinical decision support at their core. While early
      evaluation of these systems shows positive outcome measurements, financial,
      technical, and organizational hurdles to widespread implementation still remain.
      One major issue is defining the role nurses, themselves, will play in the
      selection and implementation of these systems as they become more steeped in the
      knowledge of nursing informatics. Other challenges revolve around issues of job
      satisfaction and the attraction and retention of nursing staff in the midst of a
      serious nursing shortage. Despite these concerns, it is expected that, in the
      long run, the creation of an electronic work environment with systems that
      integrate all functions of the health care team will positively impact cost
      effectiveness, productivity, and patient safety while helping to revitalize
      nursing practice.

PMID- 12485703
TI  - Evaluation of a segmentation procedure to delineate organs for use in
      construction of a radiation therapy planning atlas.
AB  - OBJECTIVES: This paper evaluates a semi-automatic segmentation procedure to
      enhance utilizing atlas based treatment plans. For this application, it is
      crucial to provide a collection of 'reference' organs, restorable from the atlas
      so that they closely match those of the current patient. To enable assembling
      representative organs, we developed a semi-automatic procedure using an active
      contour method. METHOD: The 3D organ volume was identified by defining contours
      on individual slices. The initial organ contours were matched to patient volume
      data sets and then superimposed on them. These starting contours were then
      adjusted and refined to rapidly find the organ outline of the given patient.
      Performance was evaluated by contouring organs of different size, shape
      complexity, and proximity to surrounding structures. We used representative
      organs defined on CT volumes obtained from 12 patients and compared the resulting
      outlines to those drawn by a radiologist. RESULTS: A strong correlation was found
      between the area measures of the delineated liver (r = 0.992), lung (r = 0.996)
      and spinal cord (r = 0.81), obtained by both segmentation techniques. A paired
      Student's t-test showed no statistical difference between the two techniques
      regarding the liver and spinal cord (p > 0.05). CONCLUSION: This method could be
      used to form 'standard' organs, which would form part of a whole body atlas (WBA)
      database for radiation treatment plans as well as to match atlas organs to new
      patient data.

PMID- 12485704
TI  - International distance-learning outreach: the APEC EINet experience.
AB  - BACKGROUND: The Emerging Infections Network is a mature electronic network that
      links Public Health professionals in the Asia Pacific through regular e-mail
      bulletins and an extensive Web site (http://www.apec.org/infectious). Emerging
      infections is a new area of study; learning materials help foster education. Our
      objective is to quantify the response of the network to the introduction of
      distance-learning materials on the Web site. METHODS: Distance-learning
      materials, developed by the University of Washington School of Public Health,
      were field tested and launched on the site. Publicity was carried out prior to
      the launch of the materials. Access was tracked prospectively using server counts
      of page downloads. RESULTS: Web access increased substantially during the month
      after the materials were launched, especially among Asia based computers. The
      effect was isolated to the distance-learning pages, and not general to the site.
      CONCLUSIONS: This Web site appears to be responsive to the advertisement and to
      the materials. Prospective Web-site monitoring proved useful.

PMID- 12485705
TI  - Usage of a diabetes simulation system for education via the internet.

PMID- 12485708
TI  - On-line sample preconcentration techniques in micellar electrokinetic
      chromatography.
AB  - This review provides an overview as well as a practical understanding of on-line
      sample concentration techniques in micellar electrokinetic chromatography (MEKC).
      MEKC as well as other capillary electrophoretic modes suffer from low
      concentration sensitivity due to minute sample volume and limited optical
      pathlength for on-capillary photometric detection. Two on-line sample
      preconcentration techniques, sample stacking and sweeping are known to be
      effective techniques for enhancement of the concentration sensitivity in MEKC.
      Sample stacking occurs as ions cross a boundary that separates regions of the
      high electric field sample zone and the low electric field background solution
      zone. The difference in migration velocity of pseudostationary phases within the
      two zones is the key to achieving the focusing effect. Sweeping is defined as the
      picking and accumulating of analytes by the pseudostationary phase that
      penetrates the sample zone devoid of pseudostationary phase. In this review,
      several examples of the sample stacking and sweeping under different experimental
      conditions are given, besides many references to applications.

PMID- 12485709
TI  - Microchip electrophoresis-based separation of DNA.
AB  - Miniaturized instruments have developed very quickly in the last decade. This
      review is focused on the microchip electrophoresis-based separation of DNA.
      Fundamentals, including the chip format, substrates and fabrication technologies,
      fluid control, as well as various detection methods, are summarized. Array
      electrophoresis microchip and the on-chip integration of electrophoresis with
      other systems are introduced as well. In addition, the application of microchip
      electrophoresis in DNA sizing, genetic analysis and DNA sequencing are also
      presented in this paper.

PMID- 12485710
TI  - Recent progress in derivatization methods for LC and CE analysis.
AB  - The derivatization procedure with a suitable fluorescence or chemiluminescence
      reagent is performed for the purpose of increasing the detection sensitivity and
      selectivity, in high-performance liquid chromatography (HPLC) and/or capillary
      electrophoresis (CE). In this article, recent derivatization methods and their
      applications to biosamples are described. In HPLC, femto mol order of mass
      detection limits are obtained by derivatization. Regarding the fluorescence
      reagents, the use of water-soluble reagents has been effective to avoid an
      undesired adsorption in the process of determination of peptides. In CE, the
      advantages of having extremely low mass detection limits (ranging from atto to
      yocto mol level) and requiring only a very short analysis time (less than a few
      minutes) are made possible by using laser-induced fluorescence or near infra-red
      detections.

PMID- 12485711
TI  - Analysis of carbohydrates as 1-phenyl-3-methyl-5-pyrazolone derivatives by
      capillary/microchip electrophoresis and capillary electrochromatography.
AB  - The 1-phenyl-3-methyl-5-pyrazolone (PMP) method has many advantages over hitherto
      reported methods based on reductive amination and hydrazone formation. This short
      review summarizes the various aspects of the PMP method, including the principle
      of derivatization, the simplicity of derivatization procedure, the high
      sensitivities to UV monitoring and ESI-MS, and the diversity of separation modes
      in capillary electrophoresis, and presents a number of application data for
      carbohydrate analysis in biological samples by this method. It also describes
      successful automation of carbohydrate analysis by in-capillary derivatization
      with PMP and miniaturization to microchip electrophoresis with whole channel UV
      detection allowing rapid (within 1 min) analysis of small amounts of PMP
      derivatives of carbohydrates. Furthermore, it discusses the possibility of
      capillary electrochromatography in carbohydrate analysis as PMP derivatives, and
      proposes an in-capillary modification strategy for improving column efficiency
      and elution time reproducibility.

PMID- 12485712
TI  - Immobilized nicotinic receptor stationary phases: going with the flow in high
      throughput screening and pharmacological studies.
AB  - The nicotinic acetylcholine receptor (nAChR) subtypes alpha3beta4-nAChR and
      alpha4beta2-nAChR have been immobilized and the resulting stationary phases used
      to determine binding affinities. The alpha3beta4-nAChR column was coupled to a
      C(18) column and a mixture of 18 compounds was sorted into ligands and non
      ligands for the alpha3beta4-nAChR. The results demonstrate that the nAChR
      stationary phases can be used for on-line high-throughput screening (HTS).

PMID- 12485713
TI  - New label enzymes for bioluminescent enzyme immunoassay.
AB  - Firefly luciferase catalyzes the oxidation of luciferin in the presence of ATP,
      magnesium ion and molecular oxygen with a high quantum yield. Due to its high
      sensitivity and specificity for ATP, luciferase has been used for bioluminescent
      detection of ATP in various biological samples. But it is not known well to apply
      the detection of immunoassay. In this article, the use of various enzymes as
      labels in the design and development of immunoassays for biomolecules has been
      reviewed.

PMID- 12485714
TI  - Analysis of an anti-inflammatory steroidal drug, difluprednate, in aqueous humor
      by combination of semi-micro HPLC and column switching method.
AB  - A specific and sensitive method for the determination for difluprednate (DFBA)
      and its metabolite (deacetylated DFBA, DFB) in aqueous humor was developed. DFBA
      and DFB were initially absorbed on a Pinkerton-type column, then analyzed by high
      performance liquid chromatography using a semi-micro column after column
      switching. Under the optimized conditions, calibration curves for DFBA and DFB
      showed good linearity over the range of 1.0-50 and 0.5-50 ng/ml, respectively. We
      applied the method to the analysis of DFBA and DFB in rabbit aqueous humor, and
      found that DFBA in rabbit aqueous humor 1 h after instillation of 0.002% DFBA
      ophthalmic emulsion was not detected, but DFB was present at the concentration of
      4.3+/-3.1 ng/ml.

PMID- 12485715
TI  - Measurement of bisphenol A levels in human blood serum and ascitic fluid by HPLC
      using a fluorescent labeling reagent.
AB  - A sensitive column-switching HPLC method with fluorescence detection was
      developed for the determination of bisphenol A (BPA) in human blood serum and
      ascitic fluid samples. 4-(4,5-Diphenyl-1H-imidazol-2-yl)benzoyl chloride (DIB-Cl)
      was used as the fluorescent label, and the excess reagent was removed by a column
      switching technique. Liquid-liquid extraction with chloroform was used for the
      pretreatment of serum and ascitic fluid samples. BPA in both the samples could be
      determined in the concentration range of 0.1-7.0 ppb with the detection limit of
      0.04 ppb at a signal-to-noise ratio of 3. The recoveries of BPA spiked to serum
      and ascitic fluid were 78.6 and 77.7%, respectively. The mean concentrations of
      BPA (n=9) in maternal and umbilical cord blood sera obtained from healthy
      pregnant women were 0.46+/-0.20 and 0.62+/-0.13 ppb, respectively. BPA levels
      (n=21) in blood sera and ascitic fluid obtained from the patients with sterility
      were also determined to be 0.46+/-0.20 and 0.56+/-0.19 ppb, respectively.
      Relationships of BPA concentrations were observed between maternal and umbilical
      cord blood serum samples (r=0.626), as well as blood serum and ascitic fluid
      samples (r=0.785).

PMID- 12485716
TI  - Determination of inorganic anions via postcolumn reaction with iodide in ion
      chromatography.
AB  - Inorganic anions were determined as triiodide by postcolumn reaction with iodide
      under an acidic condition with help of alpha-cyclodextrin in ion chromatography.
      Analytes reacting with iodide to produce iodine could be determined by the
      present method. The analytes were indirectly detected at 287 or 355 nm. The
      presence of alpha-cyclodextrin caused an increase in the concentration of
      triiodide, leading to improvement of the sensitivity. The present system achieved
      good selectivity to iodate, bromate and nitrite as well as good repeatability
      under the optimum conditions. The determination of nitrite in river water was
      possible.

PMID- 12485717
TI  - Analysis of acetaminophen glucuronide conjugate accompanied by adduct ion
      production by liquid chromatography-atmospheric pressure chemical ionization-mass
      spectrometry.
AB  - Liquid chromatography-mass spectrometry (LC-MS) is an effective method for the
      analysis of polar compounds. A coupling of LC-MS, which is used under
      conventional conditions, and atmospheric-pressure chemical ionization (APCI),
      which applies mild ionization for the analysis of water-soluble drug conjugates,
      would offer a very convenient method. The APCI method is effective for ionizing
      low- and medium-polarized compounds, but not for highly polarized compounds. In
      this study, we have tried derivatization of carboxyl group of glucuronic acid, to
      which direct ionization is difficult to apply under the APCI method, was
      conducted using glucuronides. Methyl ester derivatives were found to be
      effectively ionized. Furthermore, acetaminophen glucuronide conjugate was
      investigated in detail. Methyl ester derivatives of acetaminophen glucuronide
      conjugate (ACEG) were detected at m/z 373 as O(2) adduct ion [M+O(2)](-) in the
      negative mode, and p-nitrophenyl beta-D-glucuronide (PNPG) demonstrated
      ionization behaviors very similar to ACEG. Quantitation of ACEG was examined
      using PNPG as an internal standard, and satisfactory results were obtained for
      the recovery test and quantification.

PMID- 12485718
TI  - Sensitive determination of a beta-lactam antibiotic, cefaclor by liquid
      chromatography with chemiluminescence detection.
AB  - We present a sensitive method for the determination of cefaclor (CCL), a beta
      lactam antibiotic. It was based on the chemical derivatization of the drug with 4
      (2'-cyanoisoindolyl)phenylisothiocynate (CIPIC) under the reaction conditions
      with heating at 80 degrees C for 7 min in the presence of pyridine. The CIPIC
      reagent could react with the primary amino group of the drug to form the CIPIC
      conjugated CCL. The derivatives emitted not only fluorescence (FL) at maximum
      emission wavelength of 410 nm with irradiation at 310 nm, but also
      chemiluminescence (CL) in the presence of H(2)O(2), borate buffer (pH 9.6) and
      acetonitrile. After separation of the CIPIC derivatives of CCL and cephradine as
      internal standard in human serum by reversed-phase liquid chromatography, the
      derivatives could be monitored with both FL and CL detections. The detection
      limit (S/N=3) in the chromatograph was 1 pmol by the CL detection and 10 pmol by
      the FL detection. The proposed CL method permitted the most sensitive
      determination of CCL in the human serum after its oral administration.

PMID- 12485719
TI  - Determination of hypnotic benzodiazepines (alprazolam, estazolam, and midazolam)
      and their metabolites in rat hair and plasma by reversed-phase liquid
      chromatography with electrospray ionization mass spectrometry.
AB  - Sensitive determination of benzodiazepines i.e., alprazolam (ALP), estazolam
      (EST), and midazolam (MDZ), and their metabolites, was carried out by reversed
      phase liquid chromatography coupled with electrospray ionization mass
      spectrometry (HPLC-ESI-MS). The chromatography separations were achieved using a
      semi-micro HPLC column (3 microm particle size; 100 x 2.0 mm, i.d.) with
      acetonitrile-water containing 1% acetic acid as eluent. The mass spectrometer was
      operated in selected-ion monitoring mode at protonated-molecular ions [M+H](+) of
      parent drugs and the metabolites. The proposed procedure was applied to the
      determination in hair shaft of Dark Agouti rats after intraperitoneal (i.p.)
      administration of benzodiazepines twice a day for 5 days. Various metabolites
      together with parent drugs were identified in the hair shaft, 1-hydroxyalprazolam
      (1-HA) and 4-hydroxyalprazolam (4-HA) from ALP administration; 8-chloro-6-phenyl
      4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-one (K-EST) from EST
      administration; 1-hydroxymidazolam (1-HM) and 4-hydroxymidazolam (4-HM) from MDZ
      administration. A few unknown metabolites were also detected in the hair samples.
      These structures were elucidated with acetylation using acetic anhydride and
      pyridine. The time course studies of parent drugs and the metabolites in both
      hair root and plasma were also carried out after single i.p. administration of
      benzodiazepines. The results suggested that the concentrations of parent drugs
      and the metabolites in the hair samples were mainly dependent upon those in the
      plasma.

PMID- 12485720
TI  - Micro-HPLC and standard-size HPLC for the separation of peptide stereoisomers
      employing an ion-exchange principle.
AB  - Standard-size (4 mm ID) and micro-HPLC columns (0.5 mm ID) packed with a quinine
      based ion-exchange type chiral stationary phase are comparatively evaluated for
      the separation of peptide enantiomers with up to six amino acid residues. The
      results show that downscaling the separation system in order to gain the
      advantages of miniaturized HPLC is possible without sacrificing separation power.
      Further, five different N-terminal protections (3,5-dinitrobenzoyl, 2,4
      dinitrophenyl, 3,5-dinitrobenzyloxycarbonyl, carbazole-9-carbonyl, and 9
      fluorenylmethoxycarbonyl) of the analytes are investigated regarding their effect
      on enantioselectivity. A comparison between a hydro-organic and a polar-organic
      mobile phase is also reported. The enantiomers of the peptides containing one to
      four amino acid residues were baseline resolved, while for the penta- and
      hexamers only partial separations were possible. In addition, all four
      stereoisomers of alanylalanine could be baseline separated.

PMID- 12485721
TI  - Polymer-coated fibrous extraction medium for sample preparation coupled to
      microcolumn liquid-phase separations.
AB  - Polymer-coated fibrous material has been introduced as the extraction medium for
      a miniaturized sample preparation method being coupled with microcolumn liquid
      chromatography. The preconcentration and the subsequent liquid chromatographic
      separation of tricyclic antidepressants (TCAs) drugs, amitriptyline, imipramine,
      nortriptyline and desipramine, was carried out with the hyphenated system.
      Several basic experimental parameters, such as extraction and separation
      conditions, were investigated along with the applicability of the method for the
      analysis of biological fluids. The results clearly showed that the on-line
      coupled system could be a powerful tool for the analysis of complex mixtures in
      biological matrix without a large solvent consumption and specially designed
      instruments. The lowest limit of quantification was quite acceptable for the
      analysis of TCAs in clinical and forensic situations.

PMID- 12485722
TI  - Semi-micro column HPLC of triazolam in rat plasma and brain microdialysate and
      its application to drug interaction study with itraconazole.
AB  - Semi-micro column high-performance liquid chromatographic method with ultraviolet
      detection for the determination of triazolam (TZ) in rat plasma and brain
      microdialysate is described. The separation was achieved on a 250 x 1.5 mm, i.d.
      C(18) column and the column effluent was monitored at 222 nm. The detection
      limits at a signal-to-noise ratio of 3 obtained using spiked plasma and
      artificial cerebrospinal fluid were 2.1 and 0.7 ng/ml, respectively. The method
      was applied to drug-drug interaction study of TZ with itraconazole (ITZ). The
      peak concentration (C(max)) and the area under the curve (AUC) of TZ in brain
      microdialysate after simultaneous administration of TZ (2.5 mg/kg, intravenously
      (i.v.)) and ITZ (25 mg/kg, p.o.) to rats increased 3.4-folds (P<0.001) and 2.9
      folds (P<0.001), respectively, compared to those of TZ alone. Also, the AUC of TZ
      in plasma increased 2.6-folds and remarkable delay in its elimination half-life
      (t(1/2)) was observed. The concentrations of TZ in brain microdialysate and
      plasma were also measured after single administration of TZ (2.5 mg/kg, i.v.) to
      rats pretreated with daily administration of ITZ (25 mg/kg, p.o.) once a day for
      a week. There was no significant difference in TZ's C(max) in both ITZ treatments
      (P>0.2) however its t(1/2) after the daily pretreatment with ITZ was
      significantly increased (P<0.05). In plasma, the AUC of TZ after daily
      pretreatment of ITZ was lower than the single combined treatment, but
      significantly different from TZ's AUC in the absence of ITZ (P<0.05). As a
      result, single simultaneous administration of TZ with ITZ and single
      administration of TZ after daily pretreatment with ITZ to rats, ITZ seriously
      interfered with the pharmacokinetic parameters of TZ in plasma and brain
      micodialysate.

PMID- 12485723
TI  - Stereospecific analysis of omeprazole in human plasma as a probe for CYP2C19
      phenotype.
AB  - Omeprazole is a class referred to as proton pump inhibitor; it acts to regulate
      acid production in the stomach and is used to treat various acid-related
      gastrointestinal disorders. In the liver, it is metabolized to varying degrees by
      several cytochrome P-450 (CYP) isoenzymes which are further categorized into
      subfamilies of related polymorphic gene products. The metabolism of omeprazole is
      to a large extent dependent on CYP3A4 and CYP2C19. Omeprazole is metabolized to
      two major metabolites, 5-hydroxyomeprazole (CYP2C19) and omeprazole sulfone
      (CYP3A4). Minor mutations in CYP2C19 affect its activity in the liver and, in
      turn, the metabolic and pharmacokinetic profiles of omeprazole. The frequency of
      CYP2C19 poor metabolizers in population of Asian descent has been reported to
      range from 10 to 20%. Accordingly, results from population studies indicate that
      omeprazole can be used as a probe drug for phenotyping CYP2C19. The optical
      isomers of omeprazole show a clear difference in their metabolism by human liver
      microsomes. This study demonstrates the stereospecific analysis of omeprazole in
      human plasma as a probe drug of CYP2C19 phenotyping. The chiral separation of
      omeprazole was achieved on a chiral column with circular dichroism (CD) detection
      and LC/MS. A good resolution of enantiomers was obtained. The column used for
      chiral separation was CHIRALPAK AD-RH column (4.6 x 150 mm) using phosphate
      buffer and (or ammonium acetate) acetonitrile as an eluent. After a single oral
      dose of omeprazole (20 mg), the plasma concentrations of the separate enantiomers
      of omeprazole were determined for 3.5 h after drug intake. The present study is
      useful because of the part polymorphism plays in the therapeutic effectiveness of
      proton pump inhibitors during the treatment of acid-related diseases.

PMID- 12485724
TI  - Quantification of the isomerization of Asp residue in recombinant human alpha A
      crystallin by reversed-phase HPLC.
AB  - A method for determining the isomerization of Asp residues in proteins is
      described and demonstrated by quantifying the isomerization of Asp(151) in
      recombinant human alphaA-crystallin. First, four types of dodecapeptide fragment
      ((146)IQTGLD(151)ATHAER(157)) in which the Asp residue was either L-Asp, D-Asp, L
      isoAsp or D-isoAsp were synthesized, and RP-HPLC conditions were established for
      their separation. Next, the Asp(151)-containing peptide fragments isolated from
      the tryptic hydrolysate of recombinant alphaA-crystallin were analyzed under
      these conditions. New peaks, the retention times of which were the same as those
      of peptides containing D-Asp, L-isoAsp and D-isoAsp, were generated when alphaA
      crystallin was incubated for 140 days at 37 degrees C. An amino acid composition,
      amino acid sequence, and enantiomeric analysis revealed that two peaks with
      retention times identical to those of peptides containing L-isoAsp and D-isoAsp
      represented dodecapeptide fragments containing L-isoAsp(151) and D-isoAsp(151),
      respectively. RP-HPLC analysis under other condition suggested that the peak with
      retention time identical to that of peptide containing D-Asp represented
      dodecapeptide fragments containing D-Asp(151). The present method does not
      require acid hydrolysis, which generates further isomerization products as
      artifacts, and thus make possible the sensitive quantification of each type of
      Asp isomer individually at a specific site in a protein. In our analysis of the
      Asp(151) residue in human alphaA-crystallin, the degree of isomerization from L
      Asp to D-Asp can be determined to a level as low as 0.3%.

PMID- 12485725
TI  - Uniformly sized molecularly imprinted polymers for bisphenol A and beta
      estradiol: retention and molecular recognition properties in hydro-organic mobile
      phases.
AB  - Uniformly sized molecularly imprinted polymers (MIPs) for bisphenol A (BPA) have
      been prepared using ethylene glycol dimethacrylate (EDMA) as a cross-linker and
      methacrylic acid, 2-diethylaminoethyl methacrylate or 4-vinylpyridine (4-VPY) as
      a functional monomer or without use of a functional monomer. The MIPs obtained
      for BPA were evaluated using a mixture of phosphate buffer (or water) and
      acetonitrile or only acetonitrile as the mobile phase. Among the MIPs prepared,
      that using 4-VPY showed the highest retentivity and selectivity for BPA. The
      highest selectivity factor, which is defined as the ratio of the retention
      factors (k) on the molecularly imprinted and non-imprinted polymers,
      k(imprinted)/k(non-imprinted), was 9.4 for BPA on the BPA-imprinted 4-VPY-co-EDMA
      polymers, while that for beta-estradiol on the beta-estradiol-imprinted 4-VPY-co
      EDMA polymers was 2.4. The differences in the selectivity factors between BPA and
      beta-estradiol on the respective MIPs could be ascribable to differences in the
      number of interaction sites. It is plausible that the phenol groups of BPA could
      interact with two pyridyl groups of the MIP by hydrogen bonding interactions,
      while there is only one such site for beta-estradiol. Furthermore, the results
      suggest that hydrophobic and hydrogen bonding interactions can play an important
      role in the retention and recognition of BPA and beta-estradiol in the hydro
      organic mobile phase, while hydrogen bonding interactions seem to be useful for
      the retention and recognition when acetonitrile is used as the mobile phase.

PMID- 12485726
TI  - Investigation of chromatographic performances and binding characteristics of BSA
      encapsulated capillary column prepared by the sol-gel method.
AB  - We have developed a novel protein-encapsulation technique using the sol-gel
      method for the preparation of monolithic capillary columns for capillary
      electrochromatography. Bovine serum albumin (BSA) was encapsulated in
      tetramethoxysilane-based hydrogel and the enantioselectivity was evaluated. The
      present work examined the effect of various factors such as running buffer pH and
      concentration or organic modifier on the chromatographic performances as well as
      binding characteristics of BSA for D,L-tryptophan (Trp). The retention and
      enantioseparation dramatically changed depending on the buffer pH and
      concentrations. These factors influenced EOF and especially binding
      characteristics of BSA for L-Trp. Under the optimized conditions, the BSA
      encapsulated columns revealed the adequate repeatability concerning column-to
      column and run-to-run.

PMID- 12485727
TI  - Amino acid and peptide analysis using derivatization with p-nitrophenol-2,5
      dihydroxyphenylacetate bis-tetrahydropyranyl ether and capillary electrophoresis
      with electrochemical detection.
AB  - The amine derivatization reagent p-nitrophenol-2,5-dihydroxyphenylacetate bis
      tetrahydropyranyl ether (NDTE) was used in conjunction with capillary
      electrophoresis (CE) and electrochemical detection (EC) for the pre-separation
      derivatization of primary amine analytes present in aqueous solution. Glycine,
      several dipeptides and angiotensin II were used as model analytes. A miniaturized
      EC detection cell was designed and fabricated, which featured a fractured-joint
      field decoupler with a fixed end-column carbon fiber electrode. When a series of
      glycine and angiotensin II calibration solutions were derivatized with NDTE
      followed by CE-EC determination, linear calibration plots resulted with pre
      derivatization concentration limits of detection of 500 nM (106 attomoles on
      column) and 6 microM (1.275 femtomoles on-column), respectively.

PMID- 12485728
TI  - On-line preconcentration and enantioselective separation of triadimenol by
      electrokinetic chromatography using cyclodextrins as chiral selectors.
AB  - Enantioselective separation of triadimenol, a component of systemic agricultural
      fungicide, by electrokinetic chromatography (EKC) using cyclodextrins (CDs) as
      chiral selectors was investigated. Both a neutral CD derivative, hydroxypropyl
      gamma-CD (HP-gamma-CD), and an ionic one, heptakis-6-sulfato-beta-CD (HS-beta
      CD), were employed as an additive in cyclodextrin-modified micellar
      electrokinetic chromatography (CD-MEKC) and as a chiral pseudostationary phase in
      CDEKC, respectively. In each system, four stereoisomeric peaks were completely or
      partially separated from each other. To enhance the detectability or the
      concentration sensitivity, on-line preconcentration techniques were applied to
      both EKC systems. Sweeping was used in the CD-MEKC system under an acidic
      condition, whereas stacking with a reverse migrating pseudostationary phase
      (SRMP) in the CDEKC system. Around 10-fold increase in the detection sensitivity
      for each peak was attained with both sweeping and SRMP systems. Good
      repeatabilities in the migration time, corrected peak area, and peak height were
      recognized in terms of the relative standard deviation. The limit of detection
      for each peak in the SRMP-CDEKC system, calculated from the calibration curve,
      was found to be 0.8-3.8 ppm.

PMID- 12485729
TI  - Role of phospholipids in drug-LDL bindings as studied by high-performance frontal
      analysis/capillary electrophoresis.
AB  - The binding study between basic drugs ((S)-verapamil (VER) and (S)-propranolol
      (PRO)) and phospholipid liposomes was performed by using high-performance frontal
      analysis/capillary electrophoresis (HPFA/CE) in order to investigate the effect
      of oxidative modification of low-density lipoprotein (LDL) upon drug-binding
      affinity from molecule-based viewpoint. 1-Palmitoyl-2-oleoyl-phosphatidylcholine
      (POPC, 16:0, 18:1), 1-palmitoyl-2-linoleoyl-phosphatidylcholine (PLPC, 16:0,
      18:2), dilauloyl-phosphatidylcholine (DLaPC, 12:0, 12:0), 1-palmitoyl-2-oleoyl
      phosphatidyl-glycerol (POPG, 16:0, 18:1), and 1-palmitoyl-sn-glycero-3
      phosphocholine (monoPPC, 16:0) were used to prepare the model liposomes. At
      physiological pH (pH 7.4), the model liposome prepared from POPG+POPC had
      negative net charges, while the total net charge of the other model liposomes
      (POPC liposome, PLPC liposome, DLaPC liposome, and monoPPC+POPC liposome) was
      zero. The drug and the model liposome mixed solutions were subjected to HPFA/CE,
      and the total binding affinities (nK) were calculated. The nK values of VER and
      PRO to POPG+POPC liposome were more than six and 10 times higher than those of
      other liposomes, respectively. On the other hand, the nK values of the model
      drugs to POPC liposome, PLPC liposome, DLaPC liposome and monoPPC+POPC liposome
      showed small differences less than twice. These results indicate that the
      electrostatic interaction plays an important effect on drug-liposome binding, and
      suggest that the increase in the negative charge of LDL phospholipids gives more
      significant effect on the drug-binding affinity of the basic drugs than the acyl
      chain structure.

PMID- 12485730
TI  - Determination of clotrimazole in mice plasma by capillary electrophoresis.
AB  - In addition to its antifungal activity, clotrimazole attracts interest as an anti
      inflammatory drug. In order to correlate this effect with plasma concentrations
      in mice, a capillary electrophoretic method was developed. Sample preparation was
      carried out by protein precipitation using methanol. Quantification of
      clotrimazole was achieved by means of capillary electrophoresis using
      ketoconazole as an internal standard (IS). The background electrolyte (BGE)
      composed of a Tris buffer solution (100 mM, pH 3.0, adjusted with acetic acid)
      and methanol (8:2, v/v). Injection was carried out electrokinetically with 10 kV
      over a time period of 20 s. A special rinsing procedure utilizing a sequence of a
      SDS/methanol solution, a sodium hydroxide solution, water and BGE, was applied to
      enhance the reproducibility. With this procedure, an intermediate precision (day
      to-day precision) of the area ratios of clotrimazole and IS of 5.0% for 0.5
      microg ml(-1) and 2.6% for 10 microg ml(-1) was obtained. In summary, with the
      described capillary zone electrophoresis (CZE) method it is possible to handle
      small sample volumes of 60 microl, to detect clotrimazole concentrations of 0.3
      microg ml(-1) (limit of detection), and to quantify clotrimazole down to
      concentrations of 0.5 microg ml(-1) (limit of quantification).

PMID- 12485731
TI  - Evaluation of an atmospheric pressure chemical ionization interface for capillary
      electrophoresis-mass spectrometry.
AB  - A simple and inexpensive approach to modify a commercial atmospheric pressure
      chemical ionization (APCI) interface was proposed for capillary electrophoresis
      mass spectrometry (CE-MS). In order to accommodate lower flow rates in the range
      1-10 microl/min, both sheath liquid and nebulizing gas were coaxially supplied to
      the nebulizer as an arrangement of pneumatically assisted electrospray interface.
      Since this paper focused on the primary study of the modified APCI interface, the
      performance of the interface was first evaluated by the direct infusion of a
      reserpine solution. Optimization of several APCI parameters, such as temperature
      of APCI vaporizer, nebulizing gas flow and APCI corona discharge current, were
      accomplished. The orifice dimension for the nebulizing gas flow was largely
      independent of the MS sensitivity when the nebulizing gas flow rate was ca. 0.4
      l/min. A successful CE-APCI-MS separation is obtained using the modified APCI
      interface.

PMID- 12485732
TI  - Comparative study on the application of capillary liquid chromatography and
      capillary electrochromatography for investigation of enantiomeric purity of the
      contraceptive drug levonorgestrel.
AB  - In the last few years, it has been shown that capillary electrochromatography
      (CEC) is a promising technique for enantioseparations. However, to date almost no
      studies are published on a critical comparison of CEC and its pressure-driven
      counterpart, capillary liquid chromatography (CLC) for real samples. In this
      study, the goal was to compare CLC and CEC for the determination of the
      enantiomeric purity of the contraceptive drug levonorgestrel and its
      pharmaceutical formulation. The study prevailed that not all potential advantages
      of CEC over CLC can easily be transformed in a real gain of detection limit of
      the enantiomeric impurity. However, certain advantages of CEC over CLC have been
      unambiguously shown.

PMID- 12485733
TI  - Studies on neurosteroids XV. Development of enzyme-linked immunosorbent assay for
      examining whether pregnenolone sulfate is a veritable neurosteroid.
AB  - An enzyme-linked immunosorbent assay (ELISA) of pregnenolone sulfate (PREGS) has
      been developed for examining whether it is a veritable neurosteroid. 11alpha
      Hemiglutaryloxy-PREGS was newly synthesized and conjugated with bovine serum
      albumin (BSA), which was injected to rabbits for the production of anti-PREGS
      antibodies. A bridge-heterologous ELISA system employing the sequential
      saturation method exhibited a high sensitivity with a midpoint of 30 pg. Although
      the antibody showed some cross-reactivity with PREG (4.4%), it easily
      discriminated other related steroids reported to exist in the mammalian brain.
      The rat brain homogenate was treated with hexane and subjected to an OASIS HLB
      cartridge, which was washed with AcOEt to remove the unconjugated steroids, and
      then the desired sulfate was eluted with EtOH. The recovery rate of PREGS through
      the pretreatment was satisfactory, but its brain levels in the preliminary
      experiments were much lower than those previously measured by gas chromatography
      (GC)-mass spectrometry (MS) after solvolysis. These results practically agreed
      with our previous results by liquid chromatography (LC)-electrospray ionization
      (ESI)-MS without deconjugation.

PMID- 12485734
TI  - A possible purification method of DNAs' fragments from humic matters in soil
      extracts using novel stimulus responsive polymer adsorbent.
AB  - Novel stimulus responsive, uniformly sized polymer-based adsorbent was prepared
      for a possible purification method of DNAs from humic matters in soil extracts.
      The prepared polymer adsorbent has a pair of anion exchangeable and cation
      exchangeable polymeric selectors, which are reversibly responded by the changes
      of column temperature as well as pH of mobile phase. At pH 5, DNAs and humic
      matters were completely adsorbed on the polymer adsorbent at room temperature,
      while up to 90% of the adsorbed DNAs were released and recovered at 70 degrees C
      with no release of adsorbed humic matters. Cleaning up of the polymer adsorbent
      could be performed by washing the adsorbed humic matters with alkaline mobile
      phase (pH 9) to recover those and realize repeatable use of the adsorbent.

PMID- 12485735
TI  - Flow injection analysis of ascorbic acid using carriers modified with metal
      porphine as oxidative solid catalyses.
AB  - To investigate one of practical applications of the supports modified with metal
      porphines as artificial solid-catalysts, columns into which the supports were
      packed were supplied to catalytic columns for a flow injection analysis (FIA)
      system for determination of ascorbic acid (AsA) by the following reactions:
      AsA+O(2)-->dehydoroAsA+H(2)O(2),H(2)O(2)+chromogen-->2H(2)O+Dye. Among the
      columns tested, the column containing silica gels modified with Co
      tetrakis(carboxyphenyl)porphine catalyzed most rapidly the oxidation reaction of
      AsA that is accompanied by the formation of hydrogen peroxide. The resulting
      hydrogen peroxide was determined by FIA system equipped with the column
      containing glass beads modified with Mn-tetrakis(carboxyphenyl)porphine, which
      gave a linear calibration curve and large peak-areas of the range corresponding
      to AsA concentration between 0.2 and 10 micromol/ml. The results indicated that
      some supports modified with metal-porphine would be applicable to the FIA for AsA
      as the solid catalyses which function as if the immobilized enzymes.

PMID- 12485736
TI  - Nuclear magnetic resonance studies for the chiral recognition of (+)-(R)-18-crown
      6-tetracarboxylic acid to amino compounds.
AB  - Chiral recognition capability of (+)-(R)-18-crown-6-tetracarboxylic acid
      (18C6H(4)) to various amino compounds containing 16 amino acids, five alkyl
      amines, seven aminoalcohols and other amino compounds in nuclear magnetic
      resonance (1H-NMR) analysis was investigated. In general, amino compounds having
      an aromatic ring were well chiral recognized with 18C6H(4) compared with those
      having no aromatic ring. Effects of 18C6H(4) concentration and the kind of
      deuterated solvents (D(2)O, CD(3)OD and CD(3)CN) for measurement on the chiral
      recognition was investigated in detail. Concentration of 5 equivalent 18C6H(4) to
      the amino compounds was found to be sufficient for the chiral recognition. On the
      other hand, an effective deuterated solvent (D(2)O, CD(3)OD or CD(3)CN) for
      measurement was different in each compound. Distinguishment of 1.0% of the minor
      enantiomer (D-form) in L-alanine-beta-naphthylamide was found to be possible by
      1H-NMR employing 18C6H(4) as a chiral shift reagent.

PMID- 12485737
TI  - Novel strategy for molecular imprinting of phenolic compounds utilizing disulfide
      templates.
AB  - A molecularly imprinted polymer was synthesized by using allyl phenyl disulfide
      as a template. The mixture of allyl phenyl disulfide, divinylbenzene, and 2,2'
      azobis(isobutyronitrile) in chloroform was polymerized by UV irradiation for 24 h
      at 5 degrees C and further 3 h at 80 degrees C. The disulfide bonds of the
      resulting polymer were reductively cleaved by NaBH(4) in methanol to give thiol
      groups in the binding sites. The polymer selectively recognized phenol rather
      than thiophenol. In chromatographic study using polymer-packed columns, the
      retention factor of the IP for phenol was 5.60 and that of a reference polymer
      was 4.20. The higher retention for phenol was supported by ab initio calculation.

PMID- 12485738
TI  - The construction of large number representations in adults.
AB  - What is the nature of our mental representation of quantity? We find that human
      adults show no performance cost of comparing numerosities across vs. within
      visual and auditory stimulus sets, or across vs. within simultaneous and
      sequential sets. In addition, reaction time and performance in such tasks are
      determined by the ratio of the numerosities to be compared; absolute set size has
      no effect. These findings suggest that modality-specific stimulus properties
      undergo a non-iterative transformation into representations of quantity that are
      independent of the modality or format of the stimulus.

PMID- 12485739
TI  - Reasoning with quantifiers.
AB  - In the semantics of natural language, quantification may have received more
      attention than any other subject, and one of the main topics in psychological
      studies on deductive reasoning is syllogistic inference, which is just a
      restricted form of reasoning with quantifiers. But thus far the semantical and
      psychological enterprises have remained disconnected. This paper aims to show how
      our understanding of syllogistic reasoning may benefit from semantical research
      on quantification. I present a very simple logic that pivots on the monotonicity
      properties of quantified statements--properties that are known to be crucial not
      only to quantification but to a much wider range of semantical phenomena. This
      logic is shown to account for the experimental evidence available in the
      literature as well as for the data from a new experiment with cardinal
      quantifiers ("at least n" and "at most n"), which cannot be explained by any
      other theory of syllogistic reasoning.

PMID- 12485740
TI  - Scalar implicatures: experiments at the semantics-pragmatics interface.
AB  - In this article we present two sets of experiments designed to investigate the
      acquisition of scalar implicatures. Scalar implicatures arise in examples like
      Some professors are famous where the speaker's use of some typically indicates
      that s/he had reasons not to use a more informative term, e.g. all. Some
      professors are famous therefore gives rise to the implicature that not all
      professors are famous. Recent studies on the development of pragmatics suggest
      that preschool children are often insensitive to such implicatures when they
      interpret scalar terms (Cognition 78 (2001) 165; Chierchia, G., Crain, S.,
      Guasti, M.T., Gualmini, A., & Meroni, L. (2001). The acquisition of disjunction:
      evidence for a grammatical view of scalar implicatures. In A.H.-J. Do, L.
      Dominguez, & A. Johansen (Eds.), Proceedings of the 25th Boston University
      Conference on Language Development (pp. 157-168). Somerville, MA: Cascadilla
      Press; Musolino, J., & Lidz, J. (2002). Preschool logic: truth and felicity in
      the acquisition of quantification. In B. Skarabela, S. Fish, & A.H.-J. Do,
      Proceedings of the 26th Boston University Conference on Language Development (pp.
      406-416). Somerville, MA: Cascadilla Press). This conclusion raises two important
      questions: (a) are all scalar terms treated in the same way by young children?,
      and (b) does the child's difficulty reflect a genuine inability to derive scalar
      implicatures or is it due to demands imposed by the experimental task on an
      otherwise pragmatically savvy child? Experiment 1 addresses the first question by
      testing a group of 30 5-year-olds and 30 adults (all native speakers of Greek) on
      three different scales, <oli, meriki> (<all, some>), <tris, dio> (<three, two>)
      and <teliono, arxizo> (<finish, start>). In each case, subjects were presented
      with contexts which satisfied the semantic content of the stronger (i.e. more
      informative) terms on each scale (i.e. all, three and finish) but were described
      using the weaker terms of the scales (i.e. some, two, start). We found that,
      while adults overwhelmingly rejected these infelicitous descriptions, children
      almost never did so. Children also differed from adults in that their rejection
      rate on the numerical scale was reliably higher than on the two other scales. In
      order to address question (b), we trained a group of 30 5-year-olds to detect
      infelicitous statements. We then presented them with modified versions of the
      stories of Experiment 1, which now more readily invited scalar inferences. These
      manipulations gave rise to significantly higher rejection rates than those
      observed in Experiment 1. Overall, these findings indicate that children do not
      treat all scalar terms alike and, more importantly, that children's ability to
      derive scalar implicatures is affected by their awareness of the goal of the
      task. Developmental and methodological implications as well as theoretical
      implications for the semantics of numeral terms are discussed.

PMID- 12485741
TI  - Constraining the comprehension of pronominal expressions in Chinese.
AB  - This paper reports a series of self-paced reading time experiments designed to
      probe how the reference of pronominal expressions is resolved on-line in
      (Mandarin) Chinese. It is assumed that pronoun resolution is achieved by
      narrowing the candidate set of potential antecedents for a pronoun. The
      experimental evidence reported here indicates that two factors--syntactic
      prominence and the matching of lexical features (e.g. gender)--play a significant
      role in filtering this candidate set. It is shown that syntactic prominence and
      feature matching work in conjunction with each other rather than in a
      competitive, winner-take-all manner. Furthermore, the evidence suggests that
      syntactic prominence is sensitive to structural relations rather than exclusively
      to grammatical functions (such as subject and direct object) or semantic roles
      (such as agent and patient) as has been assumed in the psycholinguistic
      literature.

PMID- 12485742
TI  - Holding on to childhood language memory.
AB  - While early language experience seems crucial for mastering phonology, it remains
      unclear whether there are lasting benefits of speaking a language regularly
      during childhood if the quantity and quality of speaking drop dramatically after
      childhood. This study explored the accessibility of early childhood language
      memory. Specifically, it compared perception and production of Korean speech
      sounds by childhood speakers who had spoken Korean regularly for a few years
      during childhood to those of two other groups: (1) childhood hearers who had
      heard Korean regularly during childhood but had spoken Korean minimally, if at
      all; and (2) novice learners. All three groups were enrolled in first-year
      college Korean language classes. Childhood speakers were also compared to native
      speakers of Korean to see how native-like they were. The results revealed
      measurable long-term benefits of childhood speaking experience, underscoring the
      importance of early language experience, even if such experience diminishes
      dramatically beyond childhood.

PMID- 12485743
TI  - Effects of environmental factors on leucine catabolism by Carnobacterium
      piscicola.
AB  - The metabolites from leucine degradation are involved in dry fermented sausage
      aroma. The catabolism of leucine by a strain of Carnobacterium piscicola was
      studied directly in the growth medium with 3H-labelled leucine to investigate the
      effect of five parameters: phase of growth, pH, oxygen, glucose and alpha
      ketoisocaproic acid. Resting cells (RC) were also incubated with 3H-labelled
      leucine. The radioactive metabolites from leucine catabolism were analysed by
      high performance liquid chromatography (HPLC). At pH 5.4 and 7.2, the main
      metabolites detected were 3-methyl butanal, 3-methyl butanol and alpha
      ketoisocaproic acid. At pH 6.5, the leucine catabolism was maximum and was
      characterised by a high production of 3-methyl butanoic acid. Leucine catabolism
      was most important during the exponential phase of growth. The addition of alpha
      ketoisocaproic acid at 1%, glucose at levels of 0.5% to 2% and shaking of the
      growth medium increased leucine catabolism.

PMID- 12485744
TI  - SEM study of water activity and temperature effects on the initial growth of
      Aspergillus ochraceus, Alternaria alternata and Fusarium verticillioides on maize
      grain. Scanning electron microscopy.
AB  - A scanning electron microscopy (SEM) study of the effect of water activity
      (a(w)), temperature and fungal interactions on the very early phases of
      Aspergillus ochraceus, Alternaria alternata and Fusarium verticillioides
      development on maize grains was carried out. Germination and growth of individual
      fungal strains were assayed at 0.92, 0.95 and 0.98 a(w), and 20 and 30 degrees C.
      Hyphal lengths were measured on micrographs taken by SEM at different periods of
      incubation. A. alternata had the highest linear growth at 0.98 a(w), and was the
      only species able to grow under all conditions tested, whereas A. ochraceus was
      not able to germinate at 0.92 a(w) at any temperature assayed. F. verticillioides
      demonstrated a different behaviour depending on growth temperature. Fungal
      interactions were studied at 0.95a(w) and 30 degrees C. A. ochraceus germination
      was inhibited when it was co-inoculated with one or two of the other species. A.
      alternata showed an increased growth rate when growing together with the other
      fungi, whereas growth of F. verticillioides was significantly inhibited when
      paired with A. ochraceus.

PMID- 12485745
TI  - Rapid detection of Paenibacillus larvae from honey and hive samples with a novel
      nested PCR protocol.
AB  - The bacterial pathogen Paenibacillus larvae is the causative agent of American
      foulbrood disease in honeybees (Apis mellifera). A touchdown nested PCR protocol
      was developed to detect the presence of P. larvae spores directly in honey and
      hive samples. This approach allows early discovery of the bacteria even at
      concentrations below pathogenic levels, opening the door to new prophylactic
      approaches against American foulbrood and real-time epidemiological studies.

PMID- 12485746
TI  - PCR detection of Bifidobacterium strains and Streptococcus thermophilus in feces
      of human subjects after oral bacteriotherapy and yogurt consumption.
AB  - Streptococcus thermophilus, Bifidobacterium infantis Y1 and Bifidobacterium breve
      Y8 strains were identified and enumerated by PCR assay in human fecal samples
      after intake of the pharmaceutical preparation VSL-3 or yogurt. ThI/ThII primer
      set, specific for S. thermophilus, was selected testing its specificity against
      several strains of enterococci, streptococci and other genera colonizing the
      human intestine. A culture-independent PCR protocol, developed in this study,
      allowed to directly detect and enumerate S. thermophilus in human feces,
      excluding culture-based techniques or time consuming DNA isolation and
      purification procedures. Intestinal persistence of S. thermophilus was studied in
      feces of 10 healthy subjects given VSL-3 or yogurt. Streptococcal population was
      detected after 3 days of administration and persisted for 6 days after the
      treatment suspension. In the same trial, the colonization kinetics of B. infantis
      Y1 and B. breve Y8 were studied by amplification of colonies with the strain
      specific primer sets InfY-BV.L/R and BreY-BV.R/L, showing a host-dependent
      transient colonization behaviour. PCR analysis of feces from 10 patients affected
      by inflammatory bowel diseases (IBD) and treated with VSL-3 for 2 months showed a
      colonization pattern of S. thermophilus, B. infantis Y1 and B. breve Y8 similar
      to that observed with the healthy subjects.

PMID- 12485747
TI  - The lactoperoxidase system increases efficacy of high-pressure inactivation of
      foodborne bacteria.
AB  - The inactivation of eight different bacteria comprising Escherichia coli LMM1010
      and MG1655, respectively a pressure-resistant strain and the corresponding wild
      type, Salmonella Typhimurium, Pseudomonas fluorescens, Staphylococcus aureus,
      Enterococcus faecalis, Listeria innocua and Lactobacillus plantarum, by high
      hydrostatic pressure in skim milk supplemented with the lactoperoxidase-hydrogen
      peroxide-thiocyanate (LP) system at naturally occurring concentration was
      studied. In the absence of pressure treatment, the LP system had either no
      effect, i.e. on S. Typhimurium and E. coli LMM1010, a growth inhibiting effect,
      i.e. on E. coli MG1655, L. innocua, S. aureus, L. plantarum and E. faecalis, or a
      bactericidal effect, i.e. on P. fluorescens. The presence of the LP system
      affected inactivation by high pressure in a cell density-dependent manner. At low
      cell concentration (10(6) cfu/ml), the LP system strongly increased high-pressure
      inactivation as measured immediately after pressure treatment of all bacteria
      except the pressure-resistant E. coli. At high cell density (10(9) cfu/ml), only
      inactivation of L. innocua, E. faecalis and L. plantarum were enhanced. For both
      E. coli strains, the fate of the bacteria during 24 h following pressure
      treatment was also studied. It was found that in the presence of the LP system,
      considerable further inactivation occurred in the first hours after pressure
      treatment. The potential of the LP system to improve the bactericidal efficiency
      of high-pressure treatment for food preservation is discussed.

PMID- 12485748
TI  - Kinetic model for the inactivation of Lactobacillus plantarum by pulsed electric
      fields.
AB  - The kinetics of Lactobacillus plantarum inactivation by pulsed electric fields
      (PEF) was studied in two different growth stages (exponential and stationary),
      but in the same reference medium (0.6% peptone water). Electric field intensity
      and treatment time varied from 20 to 28 kV/cm and 30 to 240 micros, respectively.
      The experimental data showed that cells in the exponential growth stage were more
      sensitive to PEF treatment than those in the stationary stage. The inactivation
      data were adjusted to the Bigelow and Hulsheger models and the Weibull frequency
      distribution function, and constants were calculated for both growth stages in
      each model. The models were tested and their accuracy was assessed by using the
      Accuracy Factor. According to this parameter, the Weibull frequency distribution
      function gave better fittings for the inactivation by PEF than Bigelow or
      Hulsheger models. On the other hand, the Bigelow model gave a good accuracy
      factor and is simpler.

PMID- 12485749
TI  - Rapid detection and identification of Streptococcus macedonicus by species
      specific PCR and DNA hybridisation.
AB  - The aim of this study was to develop a simple and specific method for the rapid
      detection and identification of Streptococcus macedonicus. The method was based
      on polymerase chain reaction (PCR) using species-specific primers derived from
      the 16S rRNA gene. Specific identification was proven on seven S. macedonicus
      strains, while 16 strains belonging to different lactic acid bacteria species
      were tested negative. The PCR assay was capable of detecting 100 pg of S.
      macedonicus DNA, and it was also efficient on single colonies of the bacterium.
      Furthermore, the same bacterial strains were used for the specificity evaluation
      of a S. macedonicus species-specific probe. Neither species-specific PCR nor DNA
      hybridisation experiments could differentiate Streptococcus waius from S.
      macedonicus, due to the identity of the 16S rRNA gene of the two species,
      indicating high phylogenetical relatedness. This was further confirmed by the
      comparative sequence analysis of the 16S-23S rRNA intergenic regions. It was thus
      clearly demonstrated that S. waius, recently described as a novel Streptococcus
      species, is phylogenetically identical to S. macedonicus.

PMID- 12485750
TI  - Occurrence of Listeria spp. in critical control points and the environment of
      Minas Frescal cheese processing.
AB  - Critical control points (CCPs) associated with Minas Frescal cheese (a Brazilian
      soft white cheese, eaten fresh) processing in two dairy factories were determined
      using flow diagrams and microbiological tests for detection of Listeria
      monocytogenes and other species of Listeria. A total of 218 samples were
      collected along the production line and environment. The CCPs identified were
      reception of raw milk, pasteurization, coagulation and storage. Thirteen samples
      were positive for Listeria; 9 samples were Listeria innocua, 2 were Listeria
      grayi and 2 were L. monocytogenes. In factory A, Listeria was found in 50% of raw
      milk samples, 33.3% of curd samples, 16.7% of pasteurized milk samples, 16.7% of
      cheese samples and 25% of rubber pipes used to transport the whey. The
      microorganism was not obtained from environmental samples in this plant. In
      factory B, Listeria was found in one sample of raw milk (16.7%) and in three
      samples of environment (17.6%) and L. monocytogenes was obtained from raw milk
      (16.7%) and the floor of the cheese refrigeration room (14.3%). Two serotypes, 4b
      and 1/2a, were observed among the strains of L. monocytogenes isolated, both
      which are frequently involved in outbreaks of food-borne listeriosis and sporadic
      cases of the disease all over the world.

PMID- 12485751
TI  - Bacillus cereus, Bacillus thuringiensis and Bacillus mycoides differentiation
      using a PCR-RE technique.
AB  - A method was developed to differentiate between Bacillus cereus, Bacillus
      mycoides and Bacillus thuringiensis using the polymerase chain reaction combined
      with a restriction endonuclease (PCR-RE) technique. This fast and simple
      protocol, applied to pure culture strains, was developed using the gyrB DNA
      sequence, as previously proposed by other authors. Strains from international
      collections were used to optimize the method which was then applied to the
      identification of strains isolated from food samples. Amplifications were
      specific for the B. cereus group. Only Staphylococcus aureus gave the same size
      PCR product, but it was easily differentiated from strains in the B. cereus group
      by using restriction analysis, based on digestion with the RsaI, Sau3AI and EcoRI
      endonucleases. Specific amplifications and good differentiations were obtained
      using pure strains, suggesting the possibility of using the method described to
      identify the B. cereus group directly in food samples.

PMID- 12485752
TI  - Microbial contamination on beef and sheep carcases in South Australia.
AB  - A total of 523 chilled beef and lamb carcases were sampled from four abattoirs
      and 13 very small plants (VSPs) in South Australia during March 2002 in order to
      develop a microbiological profile of meat produced for domestic consumption
      within the State. Aerobic viable counts (AVCs) and Escherichia coli counts were
      obtained from samples taken by sponge-sampling the muscle-adipose tissue at sites
      designated for each species in the Microbiological Guidelines to the Australian
      Standard for Hygienic Production of Meat for Human Consumption (identical with
      those of the USA Pathogen Reduction: hazard analysis and critical control point
      (HACCP) systems: final rule). On beef carcases (n=159) mean log AVC/cm(2) was
      1.82 and E. coli was detected on 18.8% of carcases (area sampled 200 cm(2)) for
      which the mean log of the positives was -0.34; for lamb carcases, on which 75
      cm(2) was sampled (n=364), corresponding values were 2.59, 36.2% and log(10)
      0.27, respectively. There was little difference in mean log AVC/cm(2) of carcases
      produced at abattoirs and VSPs, 1.72 versus 1.81, respectively, for beef, and
      2.80 versus 2.44, respectively, for sheep. Prevalence of E. coli was lower at
      VSPs, however, with abattoirs having 28.4% for beef and 61.5% for sheep, compared
      with corresponding values of 4.7% and 18.5% at VSPs. In VSPs, the range of mean
      log AVC/cm(2) was 0.47-3.16 for beef and 1.63-3.65 for sheep carcases, data which
      will allow the Controlling Authority to assist plants to improve performance of
      slaughter and dressing techniques. The present survey is part of an assessment by
      the State meat authority of the effectiveness of co-regulation of meat hygiene
      between government and industry.

PMID- 12485753
TI  - Prevalence and resistance to antibiotics for Aeromonas species from retail fish
      in Malaysia.
AB  - A total of 87 market fish samples representing five types of fish were evaluated
      for the presence of Aeromonas spp. Of the samples examined, 69%, 55%, 11.5% and
      2.3% harbored Aeromonas spp., A. veronii biovar sobria, A. hydrophila and A.
      caviae, respectively. The 60 isolated Aeromonas spp. strains were further
      examined for hemolytic activity, resistance to antimicrobial agents and presence
      of plasmids. Hemolytic activity varied widely among the isolated strains. Though
      all the isolates demonstrated resistance to three or more of the antibiotics
      tested, all were susceptible to ceptazidime. Thirty-four (56.7%) of the sixty
      isolates harbored plasmids, with sizes ranging from 2.3 to 15.7 kb. These results
      indicate that hemolytic, multiple antibiotic resistant and genetically diverse
      aeromonads are easily recovered from fish in this region.

PMID- 12485757
TI  - Optical biosensor for urea with improved response time.
AB  - An optical biosensor for urea measurements was developed. The operation of the
      sensor is based on the well-known urease enzyme-catalyzed hydrolysis of urea. The
      ammonium ions liberated in the reaction are detected with an ion selective optode
      membrane containing nonactin as ion selective ionophore and ETH 5294
      chromoionophore in a thin (1 microm) plasticized poly(vinylchloride) film. The
      basic sensing element was home made of a microscope glass slide, a HeNe laser
      light source, photodiode light detector and light in coupling, de-coupling
      elements. The transducer membrane and the enzyme containing reaction layer were
      sandwich-cast with spin coating onto the surface of the sensing slide. The
      attenuation of the laser light propagating inside the glass wave-guide was used
      as signal for urea measurements. With this arrangement membranes provided good
      sensitivity (0.05 absorption unit when going from 0.1 to 1 mM urea) and short (16
      20 s) response time. Taking advantage on the improved response time, flow
      injection urea measurements were made in the 0.01-2 mM concentration range.
      Thirty sample/hour analysis-rate, good peak-to-peak reproducibility (RSD=0.02)
      and recovery (95-104%) was achieved with buffer diluted urea solutions.
      Applications for the analysis of real samples are planned to do in the future.

PMID- 12485758
TI  - MIP-based solid phase extraction cartridges combined with MIP-based sensors for
      the detection of microcystin-LR.
AB  - Microsystin-LR is one of the most widespread and dangerous toxins produced by the
      freshwater Cyanobacteria. The contamination of water supplies with microcystin-LR
      has been reported in several areas around the world and the development of an
      easy-to-use, rapid, robust and inexpensive sensor for this toxin is urgently
      required. In this work an artificial receptor for microcystin-LR was synthesised
      using the technique of molecular imprinting. The composition of the molecularly
      imprinted polymer (MIP) was optimised using computer modelling. The synthesised
      polymer was used both as a material for solid-phase extraction (SPE) and as a
      sensing element in a piezoelectric sensor. Using the combination of SPE followed
      by detection with a piezoelectric sensor the minimum detectable amount of toxin
      was 0.35 nM. The use of MIP-SPE provided up to 1000 fold pre-concentration, which
      was more than sufficient for achieving the required detection limit for
      microcystin-LR in drinking water (1 nM). This work is the first example where the
      same MIP receptor has been used successfully for both SPE and the corresponding
      sensor.

PMID- 12485759
TI  - Quartz crystal microbalance (QCM) affinity biosensor for genetically modified
      organisms (GMOs) detection.
AB  - A DNA piezoelectric sensor has been developed for the detection of genetically
      modified organisms (GMOs). Single stranded DNA (ssDNA) probes were immobilised on
      the sensor surface of a quartz crystal microbalance (QCM) device and the
      hybridisation between the immobilised probe and the target complementary sequence
      in solution was monitored. The probe sequences were internal to the sequence of
      the 35S promoter (P) and Nos terminator (T), which are inserted sequences in the
      genome of GMOs regulating the transgene expression. Two different probe
      immobilisation procedures were applied: (a) a thiol-dextran procedure and (b) a
      thiol-derivatised probe and blocking thiol procedure. The system has been
      optimised using synthetic oligonucleotides, which were then applied to samples of
      plasmidic and genomic DNA isolated from the pBI121 plasmid, certified reference
      materials (CRM), and real samples amplified by the polymerase chain reaction
      (PCR). The analytical parameters of the sensor have been investigated
      (sensitivity, reproducibility, lifetime etc.). The results obtained showed that
      both immobilisation procedures enabled sensitive and specific detection of GMOs,
      providing a useful tool for screening analysis in food samples.

PMID- 12485760
TI  - Investigation of concentration profiles inside operating biocatalytic sensors
      with scanning electrochemical microscopy (SECM).
AB  - Scanning electrochemical microscopy (SECM) with amperometric or potentiometric
      measuring tips was used to investigate biocatalytic reactions inside the enzyme
      layer of a biosensor during its operation. The well known glucose oxidase
      catalyzed oxidation of glucose has been selected for the studies. Local,
      instantaneous concentration of dissolved oxygen and hydrogen peroxide was studied
      observing the amperometric current while miniaturized potentiometric tip served
      for local pH measurements. Liquid enzyme layer immobilized with Cellophane
      membrane or cross linked polyacrilamide gel membrane containing entrapped enzyme
      served for biocatalytic media in the SECM imaging. Local maximum of H(2)O(2) and
      minimum of O(2) profiles were found at approximately 200 microm far from the
      substrate/enzyme layer boundary. From the experimental findings guidelines to
      design well functioning biocatalytic sensors could be concluded. The
      concentration profiles obtained with SECM techniques were compared with the
      results of simple model calculations carried out with the method of finite
      changes. Most of earlier made SECM studies dealing with enzyme reactions imaged
      the electrolyte being in contact with the immobilized enzyme. The data in our
      investigation, however, were collected inside the working catalytic layer.

PMID- 12485761
TI  - Short peptide receptor mimics for atherosclerosis risk assessment of LDL.
AB  - Short peptides sequences were selected that showed binding selectivity towards
      healthy or oxidised (unhealthy) low density lipoprotein (LDL), respectively.
      These were investigated for application in atherosclerosis risk monitoring.
      Comparison was also made with the LDL receptor ligand repeat peptide (LR5). The
      peptides were immobilised on a gold surface plasmon resonance surface and LDL
      binding detected as a shift in the resonance. 3.7x10(7) (+/-5.6x10(6))
      LDL/mm(2)/microg/ml solution LDL were bound on GlySerAspGlu-OH and 6.8x10(7) (+/
      9.2x10(6)) LDL/mm(2)/microg/ml on GlyCystineSerAspGlu, compared with
      approximately 10(8) LDL/mm(2)/microg/ml on LR5. In this first group, binding of
      LDL decreased with oxidation level and a good correlation was found between LDL
      binding and residual amino groups on the apoprotein of the LDL following
      oxidation, or the change in relative electrophoretic mobility (REM) of LDL. The
      decrease in binding was 1.1x10(7) LDL particles/mm(2) per% oxidation for
      GlySerAspGlu-OH, 1.8x10(7) LDL particles/mm(2) per% oxidation for
      GlyCystineSerAspGlu and 2.4x10(7) LDL particles/mm(2) per% oxidation for LR5. A
      second group of three peptides were also selected showing increased binding with
      LDL oxidation: GlyCystineCysCys (1.5x10(7) LDL/mm(2) per microg/ml), GlyLysLysCys
      SH (10(7) LDL/mm(2) per microg/ml) and GlyLysLys-OH (5.6x10(7) LDL/mm(2) per
      microg/ml). The latter gave a linear increase in LDL binding with oxidation level
      (1.2x10(7) LDL particles/mm(2) per% oxidation). LDL concentration is around 2-3
      mg/ml in plasma compared with the low detection levels with this method (1-10
      microg/ml), allowing a strategy to be developed requiring the minimum sample
      volume and diluting with physiological buffer prior to assay. By using a
      comparative reading between LDL adsorption on surfaces from the first and second
      group of peptides (e.g. GlyCystineSerAspGlu and GlyLysLys-OH, respectively), LDL
      oxidation could be determined without knowledge of LDL concentration. Higher
      binding was seen on GlyCystineSerAspGlu than GlyLysLys-OH below 30% LDL
      oxidation, whereas above 30% oxidation the binding on the latter surface was
      greater. Simple correlation of this form could provide good tests for
      atherosclerosis risk.

PMID- 12485762
TI  - Prussian Blue based screen printed biosensors with improved characteristics of
      long-term lifetime and pH stability.
AB  - The promising advantages of Prussian Blue (PB) as catalyst and of the thick film
      screen printing technology have been combined to assemble sensors with improved
      characteristics for the amperometric determination of H(2)O(2). PB-modified
      screen printed electrodes were applied to detect H(2)O(2) at an applied potential
      of -0.05 V versus the internal screen printed Ag pseudoreference electrode,
      showing a detection limit of 10(-7) mol l(-1), a linearity range from 10(-7) to
      5x10(-5) mol l(-1), a sensitivity of 234 microA mmol l(-1) cm(-2), and a high
      selectivity. Improved stability at alkaline pH values was also observed, which
      made possible their use with enzymes having an optimum basic pH. Then, the
      immobilisation of a single enzyme (glucose oxidase (GOD) or choline oxidase
      (ChOX)) or of two enzymes, acetylcholinesterase (AchE) coimmobilised with ChOX,
      has been performed on the surface of PB modified screen-printed electrodes (SPEs)
      using glutaraldehyde and Nafion. ChOX has been selected as an example of enzyme
      working at alkaline pH. The choline biosensors showed a detection limit of 5x10(
      7) mol l(-1), a wide linearity range (5x10(-7)-10(-4) mol l(-1)), a high
      selectivity and a remarkable long term stability of 9 months at 4 degrees C, and
      at least 4 weeks at room temperature. Similar analytical characteristics and
      stability were observed with the acetylcholine biosensors.

PMID- 12485763
TI  - Design and fabrication of a silica on silicon integrated optical biochip as a
      fluorescence microarray platform.
AB  - Previous research into the use of Flame Hydrolysis Deposition (FHD) of glasses in
      integrated optics has focused on the successful commercial exploitation of low
      cost optical devices within the field of telecommunications and optoelectronics.
      Recently we have sought to apply these fabrication technologies to the
      development of optical biochips, utilising their ability to be integrated with
      microfluidics as a 'Lab-on-a-chip' platform. In this paper, we carry this
      development forward by seeking to create a microarray of integrated optical
      sensing elements, addressed using a glass-polymer hybrid technology in which
      poly(dimethylsiloxane), PDMS, is used as an elastomeric packaging over-layer. In
      particular, we describe the wide range of modelling and microfabrication
      processes required for the successful manufacture, integration and packaging of
      such arrays. The integration of both optical and fluidic circuits in this device
      avoids precise alignment requirements and results in a compact, robust and
      reliable device. Finally, in this paper, we describe the implementation of a
      pumping system for delivering small amounts of fluid across the array together
      with an optical signal treatment.

PMID- 12485764
TI  - Amperometric determination of choline released from rat submandibular gland
      acinar cells using a choline oxidase biosensor.
AB  - A choline (CHO) biosensor based on the determination of H(2)O(2) generated at the
      electrode surface by the enzyme choline oxidase (CHOx) was developed. The
      biosensor consisted of CHOx retained onto a horseradish peroxidase (HRP)
      immobilized solid carbon paste electrode (sCPE). The HRPsCPE contained the
      molecule phenothiazine as redox mediator and CHOx was physically retained on the
      electrode surface using a dialysis membrane. Several parameters have been studied
      such as, mediator amount, influence of applied potential, etc. The CHO
      measurements were performed in 0.1 M phosphate buffer, pH 7.4. Amperometric
      detection of CHO was realized at an applied potential of 0.0 mV vs Ag/AgCl. The
      response is linear over the concentration range 5.0x10(-7)-7.0x10(-5) M, with a
      detection limit of 1.0x10(-7) M. This biosensor was used to detect choline
      released from phosphatidylcholine (PC) by phospholipase D (PLD) in isolated rat
      salivary gland cells stimulated by a purinergic agonist (ATP).

PMID- 12485765
TI  - Sensor and biosensor based on Prussian Blue modified gold and platinum screen
      printed electrodes.
AB  - Gold (Au) and platinum (Pt) screen-printed electrodes were modified with Prussian
      Blue (PB) for the development of amperometric sensors selective for hydrogen
      peroxide detection. The sensors exhibited sensitivities towards H(2)O(2) equal to
      2 A M(-1) cm(-2) for Au and 1 A M(-1) cm(-2) for Pt electrodes. The sensors were
      also employed as the basis for construction of glucose biosensors through further
      modification with crystallised glucose oxidase immobilised in a Nafion membrane.
      In order to improve the operational stability of the modified electrodes a buffer
      solution containing tetrabutylammonium toluene-4-sulfonate was used. The long
      term performance of the sensors and biosensors were evaluated by continuous
      monitoring of hydrogen peroxide and glucose solutions (50 microM and 1 mM,
      respectively) in the flow-injection mode for 10 h.

PMID- 12485766
TI  - Design of acetylcholinesterases for biosensor applications.
AB  - In recent years, the use of acetylcholinesterases (AChEs) in biosensor technology
      has gained enormous attention, in particular with respect to insecticide
      detection. The principle of biosensors using AChE as a biological recognition
      element is based on the inhibition of the enzyme's natural catalytic activity by
      the agent that is to be detected. The advanced understanding of the structure
      function-relationship of AChEs serves as the basis for developing enzyme
      variants, which, compared to the wild type, show an increased inhibition
      efficiency at low insecticide concentrations and thus a higher sensitivity. This
      review describes different expression systems that have been used for the
      production of recombinant AChE. In addition, approaches to purify recombinant
      AChEs to a degree that is suitable for analytical applications will be elucidated
      as well as the various attempts that have been undertaken to increase the
      sensitivity of AChE to specified organophosphates and carbamates using side
      directed mutagenesis and employing the enzyme in different assay formats.

PMID- 12485767
TI  - Novel carbon materials in biosensor systems.
AB  - In this work, novel carbon materials are evaluated as transducers, stabilizers
      and mediators for the construction of amperometric biosensors. It is shown that
      materials such as fullerenes and carbon nanotubes are promising materials as
      electrochemical mediators and enzyme stabilizers. Additionally porous carbon and
      porous glassy carbon are excellent transducers for amperometric measurements,
      while they provide cavities adequate for enzyme immobilization. At the same time,
      the sensitivity to peroxide is shown to depend on the activation procedures.
      Treatment that introduces oxygen groups increases the sensitivity of the carbon
      based sensor to hydrogen peroxide considerably. These materials are used for the
      construction, mediation and stabilization of glucose biosensor.

PMID- 12485768
TI  - Immunoassay for the determination of morphine-3-glucuronide using a surface
      plasmon resonance-based biosensor.
AB  - Polyclonal antibodies were produced for the development of competitive ELISA's
      and surface plasmon resonance (SPR)-based BIAcore inhibition assays for the
      detection of morphine-3-glucuronide (M3G, the main metabolite of heroin and
      morphine). A conjugate consisting of M3G and ovalbumin was produced and used for
      the generation of antibodies, for the coating of immunoplates and for
      immobilisation onto BIAcore chips. Competition ELISA's were developed in PBS and
      urine to characterise the antibodies ability to recognise free M3G. SPR-based
      inhibition immunoassays on BIAcore were developed. The regeneration of the
      surface of a chip immobilised with conjugate following antibody binding,
      essential for the development of inhibition assays was investigated. Regeneration
      of the conjugate-coated surface was optimised for both polyclonal antibodies
      resulting in binding-regeneration capacities of approximately 60 cycles for one
      antibody and 50 cycles for the second antibody. The inhibition assays developed
      in urine had ranges of detection of 762-24,400 (antibody 1) and 976-62,500 pg ml(
      1) (antibody 2). The inter-day coefficients of variation for the assays ranged
      from 1.48 to 11.24%.

PMID- 12485769
TI  - Electrochemical assay of protease activities based on polycation/polyanion
      complex as substrate and polyion sensitive membrane electrode detection.
AB  - A novel electrochemical method to detect protease activities is demonstrated. The
      assay is based on the use of a macromolecular polycation/polyanion substrate;
      specifically, a complex of the arginine-rich peptide protamine and pentosan
      polysulfate (PPS), a highly sulfated polysaccharide. As the protease of interest
      cleaves the protamine within the complex into smaller fragments, free PPS is
      generated and detected potentiometrically via a polyanion sensitive membrane
      electrode. Thus, the rate of free PPS generation is proportional to the activity
      of the protease in the assay solution. The effect of the substrate concentration
      is examined, as is the influence of the protamine/PPS stoichiometry on the assay
      performance. Using the optimized composition and concentration of the complex,
      the determination of trypsin at levels down to 5 U/ml and plasmin at levels
      approaching 0.002 U/ml can be achieved in a 10 min period. The prospects of
      further adapting this scheme to determine clot-busting plasminogen activators
      (e.g. streptokinase, tissue plasminogen activator, etc.) in samples as complex in
      whole blood are discussed.

PMID- 12485770
TI  - Reactivities of organic phase biosensors: 6. Square-wave and differential pulse
      studies of genetically engineered cytochrome P450(cam) (CYP101) bioelectrodes in
      selected solvents.
AB  - Cytochrome P450(cam) (CYP101) bioelectrodes suitable for application in organic
      phases were prepared from genetically engineered CYP101 and vesicular dispersions
      of didodecyldimethylammonium bromide. The amperometric biosensor system was
      characterised under anaerobic conditions by cyclic and square-wave voltammetric
      methods. Cyclic- and square-wave-voltammetry studies showed that the biosensors
      exhibited direct reversible electron transfer between the haem iron atom and the
      glassy carbon electrode surface. The formal redox potential estimated for the
      electrode in acetonitrile was -380 mV/Ag-AgCl. The formal potential shifted
      anodically as the organic phase biosensor responded irreversibly to substrate
      (camphor) under anaerobic and aerobic conditions in acetonitrile. Differential
      pulse analysis of the reactivities of the CYP101 enzyme electrode confirmed the
      square-wave voltammetry result, which showed that the binding of substrate
      decreased the redox potential necessary for initiating the monooxygenation
      reaction of cytochrome P450(cam).

PMID- 12485771
TI  - Carbonate ion-selective electrode with reduced interference from salicylate.
AB  - A carbonate ion-selective electrode for determination of total carbon dioxide
      species such as carbon dioxide, bicarbonate and carbonate with reduced
      interference from salicylate is described. Derivatives of trifluoroacetophenone
      were used as neutral carriers for carbonate. A polymer-free liquid carbonate
      selective membrane with a cellophane outer membrane was found to give a carbonate
      selective electrode with a negligible response to salicylate. The electrical
      contact was obtained by insertion of a silver/silver chloride electrode directly
      into the liquid membrane. The electrode does not require any aqueous filling
      solution and is therefore maintenance-free. The response to carbon dioxide
      species was found to be highly reproducible with a response time of 1-2 min at
      total carbon dioxide concentrations in the range from 5 to 50 mM. The lifetime of
      the electrode was at least 3 months. The electrode is regarded as very promising
      for clinical analysis of carbon dioxide species in body fluids such as plasma and
      serum.

PMID- 12485772
TI  - Flow injection amperometric detection of OP nerve agents based on an
      organophosphorus-hydrolase biosensor detector.
AB  - A flow-injection system with an organophosphorus-hydrolase (OPH)-biosensor
      detector has been developed and characterized for the rapid detection of
      organophosphorus (OP) nerve agents. The enzyme was immobilized onto a thin-film
      gold detector through a cystamine-glutaraldehyde coupling. Factors influencing
      the performance were optimized. The resulting flow system offered a fast,
      sensitive, selective, and stable response. The peak current increased linearly
      with the concentration of paraoxon and methyl parathion over the 1-10 microM
      range (sensitivity, 2.29 and 1.04 nA/microM, respectively). The OPH-biosensor
      flow injection systems offered low detection limits (e.g. 0.1 microM paraoxon),
      along with a good precision (R.S.D. of 3.6% for 20 successive injections of a 1.0
      microM paraoxon solution). The OPH-biosensor flow detector offers great promise
      for rapid field screening of OP pesticides and nerve agents.

PMID- 12485773
TI  - Voltammetric detection of inorganic phosphate using ion-channel sensing with self
      assembled monolayers of a hydrogen bond-forming receptor.
AB  - A voltammetric ion-channel sensing for phosphate based on gold electrodes
      modified with the self-assembled monolayers of a bis-thiourea receptor was
      developed to detect phosphate. The working principle of this voltammetric sensor
      conceptually mimics that of ligand gated ion-channel proteins, as to chemically
      stimulated changes in membrane permeability. The response to analytes is based on
      the change in electron transfer rate constant of the redox reaction of
      [Fe(CN)(6)](4-/3-) marker, before and after binding of phosphate to the receptor
      on the electrode surface; where the electrostatic repulsion between a phosphate
      receptor complex and the marker induced the decrease in the rate constant. In a
      solution of pH 7.0, a high selectivity was observed for phosphate and the sensor
      was virtually insensitive at all to many of other anions, such as SO(4)(2-), AcO(
      ), NO(3)(-), and Cl(-). The sensor response was obtained with phosphate
      concentrations above 5.0 x 10(-4) M using cyclic voltammetry and differential
      pulse voltammetry.

PMID- 12485774
TI  - Immobilization of DNA on glassy carbon electrodes for the development of affinity
      biosensors.
AB  - The adsorption and electrooxidation of nucleic acids on glassy carbon electrodes
      are evaluated by using chronopotentiometric stripping analysis. The influence of
      electrochemical pretreatments, supporting electrolyte, halides and monovalent
      cations levels as well as the role of the oligonucleotide length and composition,
      accumulation potential and time on the adsorption and further electrooxidation of
      oligo(dG)(11) and oligo(dG)(21) are discussed. The adsorption behavior of single
      and double stranded calf thymus DNA on untreated glassy carbon electrodes is also
      evaluated. Trace (microg/l) levels of the oligonucleotides and polynucleotides
      can be readily detected following short accumulation periods with detection
      limits of 25, 60, 126 and 219 microg/l for oligo(dG)(21), oligo(dG)(11), ss and
      ds calf thymus DNA, respectively. The confined DNA layers demonstrated to be
      stable in air, in 0.200 M acetate buffer pH 5.00 and in 0.020 M phosphate buffer
      pH 7.40+0.50 M NaCl.

PMID- 12485775
TI  - Enzyme inhibition-based biosensors and biosensing systems: questionable
      analytical devices.
AB  - An overview of methods based on enzyme inhibition is presented. Both biosensors
      and biosensing systems (implemented in continuous and discontinuous approaches)
      are considered. The aim of the overview is to alert users on the use of these
      devices which, despite they can involve selective biocatalysts, the inhibition
      effect is not selective. Tables and examples illustrate this assertion.

PMID- 12485776
TI  - Electrochemistry of immobilized CuZnSOD and FeSOD and their interaction with
      superoxide radicals.
AB  - Copper, zinc superoxide dismutase (CuZnSOD) from bovine erythrocytes and iron
      superoxide dismutase from Escherichia coli (FeSOD) were immobilized on 3
      mercaptopropionic acid (MPA)-modified gold electrodes, respectively. The
      characterization of the SOD electrodes showed a quasi-reversible, electrochemical
      redox behavior with a formal potential of 47+/-4 mV and -154+/-5 mV (vs. Ag/AgCl,
      1 M KCl) for surface adsorbed CuZnSOD and FeSOD, respectively. The heterogeneous
      electron transfer rate constants were determined to be about 65 and 35/s,
      respectively. Covalent fixation of both SODs was also feasible with only slight
      changes in the formal potential. The interaction of superoxide radicals (O(2)(-))
      with the SOD electrode was investigated. No catalytic current could be observed.
      However, due to the fast cyclic redox reaction of SOD with superoxide, the
      communication of the protein with the electrode was strongly influenced. The
      amperometric detection of superoxide radicals is discussed.

PMID- 12485777
TI  - Detection of pesticides using an amperometric biosensor based on
      ferophthalocyanine chemically modified carbon paste electrode and immobilized
      bienzymatic system.
AB  - A new highly sensitive amperometric method for the detection of organophosphorus
      compounds has been developed. The method is based on a ferophthalocyanine
      chemically modified carbon paste electrode coupled with acetylcholinesterase and
      choline oxidase co-immobilized onto the surface of a dialysis membrane. The
      activity of cholinesterase is non-competitively inhibited in the presence of
      pesticides. The highest sensitivity to inhibitors was found for a membrane
      containing low enzyme loading and this was subsequently used for the construction
      of an amperometric biosensor for pesticides. Analyses were done using
      acetylcholine as substrate; choline produced by hydrolysis in the enzymatic layer
      was oxidized by choline-oxidase and subsequently H(2)O(2) produced was
      electrochemically detected at +0.35 V vs. Ag/AgCl. The decrease of substrate
      steady-state current caused by the addition of pesticide was used for evaluation.
      With this approach, up to 10(-10) M of paraoxon and carbofuran can be detected.

PMID- 12485778
TI  - Stabilization and re-activation of trapped enzyme by immobilized heat shock
      protein and molecular chaperones.
AB  - The potential of using immobilized Heat Shock Protein 70 (HSP 70) in combination
      with other molecular chaperones to ameliorate problems of enzyme denaturation was
      investigated. Firefly luciferase was used as a model enzyme due to its
      sensitivity to thermal denaturation, and the availability of a sensitive
      chemiluminescent assay method for determination of relative activity of this
      enzyme. Control experiments and development of effective combinations of HSP with
      other chaperones involved re-activation of enzyme in bulk solution. A combination
      of HSP 70, alpha-crystallin and reticulocyte lysate (RL) in bulk solution were
      found to re-activate soluble firefly luciferase to about 60% of the initial
      activity after the enzyme activity had been reduced to less than 2% by thermal
      denaturation. HSP 70 that was covalently immobilized onto glass surfaces was also
      able to re-activate denatured enzyme that was in bulk solution. Over 30% of the
      initial activity could be regained from heat denatured enzyme when using
      immobilized HSP in the presence of other chaperones. The activity of soluble
      enzyme decayed to negligible values in a period of days when stored at room
      temperature. In the presence of immobilized HSP and chaperones, activity
      stabilized at about 10% of the initial activity even after many weeks. The
      results suggest that immobilized molecular chaperones such as HSP 70 may provide
      some potential for stabilization and re-activation of enzymes that are trapped in
      thin aqueous films for applications in biosensors and reactors.

PMID- 12485779
TI  - Amperometric biosensors based on recombinant laccases for phenols determination.
AB  - Graphite (GE) or printed graphite electrode (PGE) based biosensors containing
      recombinant fungal laccase Polyporus pinsitus (rPpL), and Myceliophthora
      thermophila (rMtL) were developed. The enzymes were immobilized using bovine
      serum albumin and glutaraldehyde. At pH 5.5 and -0.1 V, the calibration graphs of
      GE based biosensors were hyperbolic if pyrocatechol was used. The concentration
      of substrate that results in 50% of steady-state response (EC(50)) was 0.7 mM and
      sensitivity (S) was 3.8 mA/M. The sensitivity increased up to 4 A/M if larger
      amount of rPpL was used. The sensitivity of biosensors changed little during 9
      days of exploitation, but decreased at longer time. The PGE based biosensors were
      mounted into the flow-through cell and calibrated under kinetic regime. EC(50) of
      the biosensors containing rPpL varied from 0.6 to 4.0 mM and sensitivity varied
      from 0.11 to 1.9 mA/M. The response of biosensor containing thermostable laccase
      rMtL was less, but response saturated at larger pyrocatechol concentration. The
      sensitivity changed little during 6 days. Both type of biosensors responded also
      to 1-naphthol, o-phenylenediamine, guaiacol, o-anizidine, benzidine. The
      experiments demonstrate recombinant laccases application to biosensor engineering
      and their use to phenol and related compound determination under steady-state and
      flow-through regimes.

PMID- 12485780
TI  - Control of current and future neural prostheses.

PMID- 12485781
TI  - Advanced modeling environment for developing and testing FES control systems.
AB  - Realistic models of neuromusculoskeletal systems can provide a safe and
      convenient environment for the design and evaluation of controllers for
      functional electrical stimulation (FES) prior to clinical trials. We have
      developed a set of integrated musculoskeletal modeling tools to facilitate the
      model building process. Simulink models of musculoskeletal systems are created
      using two software packages developed in our laboratory, Musculoskeletal Modeling
      in Simulink (MMS) and virtual muscle, in addition to one software package
      available commercially, SIMM (Musculographics Inc., USA). MMS converts
      anatomically accurate musculoskeletal models generated by SIMM into Simulink(R)
      blocks. It also removes run-time constraints on kinetic simulations in SIMM, and
      allows the development of complex musculoskeletal models without writing a line
      of code. Virtual muscle builds realistic Simulink models of muscles responding to
      either natural recruitment or FES. Models of sensorimotor control systems can be
      developed using various Matlab (Mathworks Inc., USA) toolboxes and integrated
      easily with these musculoskeletal blocks in the graphical environment of
      Simulink.

PMID- 12485782
TI  - A wheelchair modified for leg propulsion using voluntary activity or electrical
      stimulation.
AB  - A commercially available wheelchair has been modified for propulsion by movements
      of the lower legs. The feet are attached securely to a foot rest that can rotate
      around the knee joint. Movement is generated either with residual voluntary
      activation of the quadriceps (knee extensor) and hamstring (knee flexor) muscles,
      or with electrical stimulation of these muscles, if voluntary control is absent.
      Either a chain or a lever can couple the movements through a gearbox to the wheel
      to propel the wheelchair forward. Control of a wheelchair with the legs is more
      efficient than using the arms and has the potential to increase the mobility and
      whole-body fitness of many wheelchair users, but there is considerable
      variability between subjects. To address this variability, we measured for
      individual subjects the passive properties of the legs and foot at rest
      (effective stiffness and viscosity), the length-tension (torque-angle) properties
      of the active muscle groups, as well as their force-velocity curve and their
      activation and fatigue rates. The measured values were then inserted into a model
      of the leg-propelled wheelchair. The purpose of this paper is to test whether the
      model could predict the performance of individual subjects accurately and could
      be used, for example, to optimize the speed of the wheelchair for a given
      subject.

PMID- 12485783
TI  - Three dimensional inertial sensing of foot movements for automatic tuning of a
      two-channel implantable drop-foot stimulator.
AB  - A three dimensional inertial sensing system for measuring foot movements during
      gait is proposed and tested. It can form the basis for an automated tuning system
      for a two-channel implantable drop-foot stimulator. The foot orientation and
      position during the swing phase of gait can be reconstructed on the basis of
      three-dimensional measurement of acceleration and angular velocity, using initial
      and final conditions during mid-stance. The foot movements during gait of one
      stroke person using the implanted two-channel stimulator were evaluated for
      several combinations of stimulation parameters for both channels. The
      reconstructed foot movements during gait in this person indicated that the
      channel stimulating the deep peroneal nerve contributes mainly to dorsiflexion
      and provides some reduction of inversion seen without stimulation, while the
      channel activating the superficial peroneal nerve mainly provides additional
      reduction of inversion. This agrees with anatomical knowledge about the function
      of the muscles activated by both branches of the peroneal nerve. The inertial
      sensor method is expected to be useful for the clinical evaluation of foot
      movements during gait supported by the two-channel drop-foot stimulator.
      Furthermore, it is expected to be applicable for the automated balancing of the
      two stimulation channels to ensure optimal support of gait.

PMID- 12485784
TI  - Biopotentials as command and feedback signals in functional electrical
      stimulation systems.
AB  - Today Functional Electrical Stimulation (FES) is available as a clinical tool in
      muscle activation used for picking up objects, for standing and walking, for
      controlling bladder emptying, and for breathing. Despite substantial progress in
      development and new knowledge, many challenges remain to be resolved to provide a
      more efficient functionality of FES systems. The most important task of these
      challenges is to improve control of the activated muscles through open loop or
      feedback systems. Command and feedback signals can be extracted from
      biopotentials recorded from muscles (Electromyogram, EMG), nerves
      (Electroneurogram, ENG), and the brain (Electroencephalogram (EEG) or individual
      cells). This paper reviews work in which EMG, ENG, and EEG signals in humans have
      been used as command and feedback signals in systems using electrical stimulation
      of motor nerves to restore movements after an injury to the Central Nervous
      System (CNS). It is concluded that the technology is ready to push for more
      substantial clinical FES investigations in applying muscle and nerve signals.
      Brain-computer interface systems hold great prospects, but require further
      development of faster and clinically more acceptable technologies.

PMID- 12485785
TI  - Control of neural prostheses for grasping and reaching.
AB  - In recent years several neural prostheses have been developed and tested as
      orthoses or as therapeutic systems for hemiplegic and tetraplegic subjects aiming
      to improve the upper extremities function. The use of neural prostheses
      demonstrated that the targeted group of subjects could significantly benefit from
      functional electrical stimulation that is integrated in goal directed movements.
      In this paper the control for neural prostheses is explained using available
      systems that apply either surface or implantable interfaces to sensory-motor
      systems. Further more, a new strategy that has been tested for control of
      reaching and grasping within a neural prosthesis especially designed for
      neurorehabilitation is described. This, so-called, coordination strategy was
      based on mimicking the output space model of natural control determined in
      reach/grasp/release movements of healthy humans.

PMID- 12485786
TI  - Control of posture with FES systems.
AB  - One of the major obstacles in restoration of functional FES supported standing in
      paraplegia is the lack of knowledge of a suitable control strategy. The main
      issue is how to integrate the purposeful actions of the non-paralysed upper body
      when interacting with the environment while standing, and the actions of the
      artificial FES control system supporting the paralyzed lower extremities. In this
      paper we provide a review of our approach to solving this question, which focuses
      on three inter-related areas: investigations of the basic mechanisms of
      functional postural responses in neurologically intact subjects; re-training of
      the residual sensory-motor activities of the upper body in paralyzed individuals;
      and development of closed-loop FES control systems for support of the paralyzed
      joints.

PMID- 12485787
TI  - Automatic vs hand-controlled walking of paraplegics.
AB  - A rule-based control and its application in functional electrical stimulation
      (FES) assisted walking of subjects with paraplegia are described in this paper.
      The design of rules for control comprises the following two steps: (1)
      determination of muscle activation patterns by using a fully customized spatial
      (3D) model of paraplegic walking, and (2) learning of rules, that is, correlation
      between the muscle activation patterns and kinematics of walking by means of an
      artificial neural network. The adopted FES system activated eight muscle groups
      with surface electrodes. The only joints allowing movement in the coronal plane
      were the hips, and externally controlled joints in sagittal plane were ankles,
      knees and hips. The simulation minimized the tracking error of the joint angles
      and the total activation of all eight muscles being stimulated. A radial-basis
      function artificial neural network was applied for learning of rules. Three
      automatically controlled modes (slow, near-normal, and near-ballistic) and hand
      controlled walking were evaluated in six subjects with a complete spinal cord
      lesion (T8-T10). The performance of walking was assessed by the following: (1)
      energy consumption based on oxygen uptake, (2) physiological cost index, (3)
      maximum speed of walking, and (4) a questionnaire. The results showed that all
      modes of walking are achievable and that automatic control leads to more
      efficient and faster walking. The speed of walking achieved by automatic control
      was almost three times bigger compared with the speed of hand-controlled walking.
      The energy cost and rate decreased significantly when automatic control was
      applied; yet, they were still much bigger than the values measured in able-bodied
      subjects. The objective outcome measures suggest that the near-ballistic walking
      was the most effective, yet a questionnaire shows that most subjects preferred
      slow walking. The most likely reason for the preference of lower efficiency
      walking over the faster end energy efficient near-ballistic walking was that
      paraplegic patients had difficulties in synchronizing the voluntary movement of
      the trunk and arms to the artificially controlled movements of legs.

PMID- 12485788
TI  - Functional electrical stimulation and rehabilitation--an hypothesis.
AB  - Functional Electrical Stimulation (FES), used to mimic a weak or paralysed
      movement, sometimes is followed by a specific recovery of voluntary power in that
      movement. The mechanism by which this occurs is unclear, and the presumption has
      often been that FES may somehow promote adaptive changes in cortical
      connectivity. However, the unique feature of electrical stimulation is that it
      activates nerve fibres both orthodromically and antidromically. The antidromic
      impulse in motor nerve fibres will reach the anterior horn cell, but it can go no
      further up the neuraxis. If the corticospinal-anterior horn cell synapse is a
      Hebb-type modifiable synapse (i.e. one that is strengthened by the coincidence of
      presynaptic and postsynaptic activity), then FES, combined with coincident
      voluntary effort through a damaged pyramidal motor system, could help to promote
      restorative synaptic modifications at anterior horn cell level, by this unique
      adaptive mechanism.

PMID- 12485789
TI  - An in vivo study of bone response to implants topographically modified by laser
      micromachining.
AB  - Dental implants topographically modified by laser ablation of periodic arrays of
      micron-sized craters, were studied in a two-part laboratory investigation. The
      patterned and control (turned) implants were inserted in rabbit femur and tibia.
      After 12 weeks the fixation in the bone was evaluated mechanically or by
      histomorphometry (all threads along the implant and the three best consecutive
      threads were analysed). In the pilot study no difference was found with respect
      to bone-to-implant contact and peak removal torque. Significantly more bone was
      found for the control implants when measuring the bone area inside the threads in
      the tibia. In the second part of the study, the pattern was improved and
      significantly more bone-to-implant contact was found for the laser-machined
      implants. The second part of the study also demonstrated significantly greater
      peak removal torque values in the tibia with the test implants than the control
      implants.

PMID- 12485790
TI  - Biocompatibility and healing process of polyester meshes in the brain: in vivo
      examination in rats.
AB  - OBJECTIVES: To analyze the biocompatibility of multifilament polyester (PET)
      meshes used for the implantation of auditory brainstem implants in a standardized
      Wistar rat model (n=29). METHODS: The physical properties of the meshes were
      examined during surgery. Using a modified plastic embedding, the local tissue
      reaction and the stability of mesh position in the region of the fourth ventricle
      were evaluated in section series from day 3 to 64. The cellular reaction was
      further differentiated using transmission and scanning electron microscopy.
      RESULTS: PET meshes were stable for handling. However, sharp edges inevitably led
      to brainstem and cerebellar penetration in some cases. The meshes were preserved
      in situ in all section series. Positioning was stable with one exception. A
      sufficient fibroblast and collagen fiber encasement was reached after 14 days. In
      all cases, no further change was observed through day 64. The host-defense
      reaction was persistent and characterized by numerous macrophages and foreign
      body giant cells. Bacterial infection occurred in three cases. CONCLUSIONS: PET
      meshes proved to have an acceptable biocompatibility regarding local-tissue
      reaction in the brain. Modified polymer structures should be developed to reduce
      risk of injury. Anti-inflammatory surface treatments and monofilament meshes
      could reduce the infection rate.

PMID- 12485791
TI  - In vitro behavior of HVOF sprayed calcium phosphate splats and coatings.
AB  - Hydroxyapatite (HA) coatings and splats deposited by high velocity oxy-fuel
      (HVOF) spray technique was investigated in vitro. HA coatings prepared from two
      different HA powder size range (30+/-5 and 50 +/-5 microm) were immersed in a
      simulated body fluid with various incubation periods of maximum 6 weeks. The
      dissolution/precipitation behavior was studied and the degradation of HA coatings
      caused by in vitro ageing was demonstrated by measuring the changes in flexural
      modulus through a 3-point bend test. It was found that the dissolution and
      precipitation behavior of the coatings was significantly dependent upon the
      incipient coating phase composition and the precipitation of bone-like
      hydroxyapatite on the coating's surface was found to be directly related to the
      dissolution process. Higher dissolution rates of tricalcium phosphate,
      tetracalcium phosphate and amorphous calcium phosphate relative to HA, resulted
      in accelerated precipitation. Furthermore, analysis of coatings' surface
      morphology demonstrated that advanced precipitation invariably occurred at
      regions where dissolution took place. Results showed that the changes in flexural
      modulus of investigated HA coatings accompanying different incubation duration
      was not systematic but was found to be dependent upon changes of coating
      structure and other factors brought about by in vitro ageing. In vitro
      investigation of individual HA splats collected from different HA particle sizes
      revealed, after 3 days ageing, that the rate ratio of precipitation to
      dissolution was directly determined by the local phase composition, and this
      phenomenon could be effectively used to explain the behavior of thermally sprayed
      HA coatings in vitro. It implied that the precipitation was strongly dependent on
      the first molecule attachment. To achieve rapid precipitation in vitro, partial
      molten state of HA particles during HVOF coating deposition was recommended.

PMID- 12485792
TI  - Comparison of the response of human peripheral blood mononuclear cells to
      challenge with particles of three bone cements in vitro.
AB  - This study compared the effects of different sizes of three clinically relevant
      endotoxin free bone cement particles on primary human macrophage TNF-alpha
      production in vitro. The bone cements used were CMW original, CMW1RO and Palacos
      R. The cement wear debris was generated aseptically and then sequentially
      filtered to produce the size ranges 0.1-1 microm, 0.1-10 microm, 1-10 microm and
      >10 microm. The debris was cultured with human peripheral blood mononuclear cells
      at particle volume (microm(3)) per cell ratios of 100:1, 10:1 and 1:1. TNF-alpha
      production was determined by ELISA and cell viability by MTT conversion. CMW1RO
      particles induced increased TNF-alpha production by PBMNCs when tested in the
      size range 0.1-1 microm, and also to a lesser degree in the sizes 0.1-10 microm
      and 1-10 microm at the particle volume (microm(3)) to cell number ratios of 100:1
      and 10:1. The increase in TNF-alpha production induced by Palacos R debris was
      only observed with the particle size ranges less than 10 microm at the ratio of
      100:1. This study demonstrated that bone cement particles are capable of inducing
      raised TNF-alpha production in vitro. This is dependent upon cement particle
      size, volume and cement particle type, with cement particles containing radio
      opaque additives being the most active.

PMID- 12485793
TI  - Soft-tissue response to injectable calcium phosphate cements.
AB  - In this study, the soft tissue reaction to two newly developed injectable calcium
      phosphate bone cements (cement D and W) was evaluated after implantation in the
      back of goats. For one of the cements (cement D) the tissue reaction was also
      investigated after varying the concentration of accelerator Na(2)HPO(4) in the
      cement liquid (resulting in cement D1 and D2). Eight healthy mature female Saanen
      goats were used. The cement was applied 10min after mixing while it was still
      moldable and plastic. The material was given a standardized cylindrical shape.
      Thirty-two implants of each cement formulation were inserted and left in place
      for 1, 2, 4, and 8weeks. At the end of the study, eight specimens of each
      material and healing period were available for further analysis. Two specimens
      were used for X-ray diffraction (XRD) and Fourier Transform Infrared Spectroscopy
      (FTIR) and six specimens were used for light microscopical evaluation. XRD and
      FTIR showed that the cements did set as microcrystalline carbonate apatite with
      the disappearance of monetite from the cements during implantation. Histological
      analysis showed that after 8weeks of implantation around all materials a thin
      soft-tissue capsule was formed (thickness ranging from 5 to 15 cell layers) with
      almost complete absence of inflammatory cells. Only in some specimens a slightly
      higher inflammatory reaction was observed. This was due to cement surface defects
      and a zone of dispersed particles near the cement-soft tissue interface. There
      was almost no resorption of the material after 8 weeks of implantation. In a few
      4 and 8weeks samples, small areas of calcification were found in the fibrous
      capsule surrounding the implants. On the basis of our observations, we conclude
      that the tested cements were biocompatible and can be used next to soft tissue.

PMID- 12485794
TI  - Influence of different crosslinking treatments on the physical properties of
      collagen membranes.
AB  - The physical properties of collagen-based biomaterials are profoundly influenced
      by the method and extent of crosslinking. In this study, the influence of various
      crosslinking treatments on the physical properties of reconstituted collagen
      membranes was assessed. Five crosslinking agents viz., GTA, DMS, DTBP, a
      combination of DMS and GTA and acyl azide method were used to stabilize collagen
      matrices. Crosslinking density, swelling ratio, thermo-mechanical properties,
      stress-strain characteristics and resistance to collagenase digestion were
      determined to evaluate the physical properties of crosslinked matrices. GTA
      treatment induced the maximum number of crosslinks (13) while DMS treatment
      induced the minimum (7). Of the two diimidoesters (DMS and DTBP), DTBP was a more
      effective crosslinking agent due to the presence of disulphide bonds in the DTBP
      crosslinks. T(s) for DTBP and DMS crosslinked collagen were 80 degrees C and 70
      degrees C, and their HIT values were 5.4 and 2.85MN/m(2), respectively. Low
      concentration of GTA (0.01%) increased the crosslinking density of an already
      crosslinked matrix (DMS treated matrix) from 7 to 12. Lowest fracture energy was
      observed for the acyl azide treated matrix (0.61MJ/m(3)) while the highest was
      observed for the GTA treated matrix (1.97MJ/m(3)). The tensile strength of GTA
      treated matrix was maximum (12.4MPa) and that of acyl azide treated matrix was
      minimum (7.2MPa). GTA, DTBP and acyl azide treated matrices were equally
      resistant to collagenase degradation with approximately 6% solubilization after
      5h while the DMS treated was least stable with 52.4% solubilization after the
      same time period. The spatial orientation of amino acid side chain residues on
      collagen plays an important role in determining the crosslinking density and
      consequent physical properties of the collagen matrix.

PMID- 12485795
TI  - Characterization of the bone-like apatite precipitated on high velocity oxy-fuel
      (HVOF) sprayed calcium phosphate deposits.
AB  - Bone-like apatite was precipitated on the surface of thermal sprayed calcium
      phosphate coatings following in vitro incubation in a simulated body fluid. The
      coatings were initially deposited on titanium alloy substrates by the high
      velocity oxy-fuel (HVOF) spray technique. Structural characterization and
      mechanical evaluation of the precipitated apatite layer were conducted. Results
      showed that the precipitation rate was directly influenced by the local Ca(2+)
      concentration in the vicinity of the coating's surface and that preferential
      dissolution of certain phases was found to accelerate the precipitation of the
      bone-like apatite. The dense precipitates exhibited a competitive Young's modulus
      value of approximately 120GPa, which was obtained through nanoindentation. This
      compared favorably to the calcium phosphate matrix. Differences in microstructure
      at various locations within the layer resulted in altered Young's modulus and
      microhardness values. Precipitation mechanism investigation was carried out
      through a comparative experiment. Chemical analysis showed that the precipitation
      of bone-like apatite on the calcium phosphate coating was quite conceivably a
      partial diffusion-controlled process.

PMID- 12485796
TI  - In vivo studies of polypyrrole/peptide coated neural probes.
AB  - Neural probes are micromachined multichannel electrode arrays that facilitate the
      functional stimulation and recording of neurons in the peripheral and central
      nervous system. For long-term implantations, surface modification is necessary
      for maintaining the stable connection between electrodes and neurons. The
      conductive polymer polypyrrole (PPy) and synthetic peptide DCDPGYIGSR were co
      deposited on the electrode surface by electrochemical polymerization. The
      stability of PPy/DCDPGYIGSR coatings was tested in soaking experiments. It was
      found that the peptide was entrapped in the PPy film and did not diffuse away
      within 7 weeks of soaking in DI water. Coated probes were implanted in guinea pig
      brain for periods of 1, 2 and 3 weeks. Recording tests were performed and the
      impedance was monitored. The explanted probes and tissue were examined by
      immunocytochemical studies. Significantly more neurofilament positive staining
      was found on the coated electrode which indicated that the coatings had
      established strong connections with the neuronal structure in vivo. Good
      recordings were obtained from the coated sites that had neurons attached. First
      week tissue sections had no significant gliosis. In week 2, a layer of non
      neuronal tissue consisting of mostly meningeal fibroblasts and ECM protein
      including at least fibronectin was formed around the probe tracks of both coated
      and uncoated probes. Astrocytes started to form a loosely organized layer by the
      end of the third week.

PMID- 12485797
TI  - Silk fibroin/poly(carbonate)-urethane as a substrate for cell growth: in vitro
      interactions with human cells.
AB  - Silk fibroin (SF)-based or -coated biomaterials are likely to be endowed with
      structural and surface properties that render them particularly apt for
      biomedical applications. In this work we investigated the behavior of four
      different strains of normal human adult fibroblasts that had been seeded onto
      membranes made up of poly(carbonate) urethane (PCU), the surfaces of which had or
      had not been homogeneously coated with SF. Cell adhesion within 3h to the SF
      coated PCU films was 2.2-fold that to their uncoated homologues. After 30 days of
      incubation in vitro, 2.5-fold more cells had grown on the SF-coated specimens
      than on the uncoated ones. This enhanced cell adherence and hence growth on the
      SF-coated surfaces was coupled with higher cumulative rates of D-glucose (but not
      L-glutamine) uptake and of both lactate and interleukin-6 (IL-6) cumulative
      secretion. Conversely, human fibroblasts cultured on either type of PCU scaffolds
      never secreted any ELISA-assayable amount of three main proinflammatory
      cytokines, namely interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF
      alpha), and transforming growth factor-beta1 (TGF-beta1). Finally, when the
      metabolic activities were compared on a per 10(5) cells basis, it became clear
      that the adhesion to SF favored an initially higher consumption of D-glucose, a
      late higher release of IL-6, and an at-first more intense, but declining,
      extracellular assembly of type I collagen fibers. Overall, these results show
      that SF-coated PCU membranes represent a novel type of biomaterial that favors
      the adhesion, the growth and performance of specific metabolic tasks by normal
      human adult fibroblasts without eliciting any concurrent secretion of some of the
      chief proinflammatory cytokines.

PMID- 12485798
TI  - A novel degradable polycaprolactone networks for tissue engineering.
AB  - Polycaprolactone (PCL) macromer was obtained by the reaction of PCL diol with
      acryloyl chloride and confirmed using Fourier transform infrared and nuclear
      magnetic resonance spectrometer. Novel degradable PCL networks were prepared
      through photopolymerization of the PCL macromer. Thermal, mechanical, and
      morphological characteristics as well as degradability and biocompatibility of
      the PCL networks were investigated. Differential scanning calorimetry showed that
      the melting temperature and the calculated weight average crystallinity of PCL
      networks were decreased with a decrease of molecular weight of PCL diols due to
      the increased crosslinking density. Thermal stability of PCL networks was higher
      than that of PCL diols. PCL networks showed faster degradation, and higher
      compressive modulus and compressive recovery ratios than those of PCL itself
      because of their low crystallinity and the modification of terminal groups. The
      porosity of the PCL networks can be controlled by the amounts and size of porogen
      used. MG-63 osteoblast cell was attached and proliferated on PCL networks. PCL
      networks therefore may have considerable potential as scaffold for tissue
      engineering.

PMID- 12485799
TI  - Hydroxyapatite cement scaffolds with controlled macroporosity: fabrication
      protocol and mechanical properties.
AB  - Precipitated hydroxyapatite cement scaffolds with macroporosity of controlled
      size and shape were successfully built using a solid freeform fabrication
      process. The negative macroporosity was designed using CAD software and built
      with an inkjet machine. A slip casting process using a plaster mold was used to
      precipitate the cement and manufacture samples for mechanical testing. The
      negative macroporosity was then extracted from the samples using a thermal
      process. Compression, tension and torsion tests were completed successfully on
      the precipitated hydroxyapatite cement samples in moist condition. Elastic and
      strength properties were measured for these three loading cases and compared to
      the plain hydroxyapatite cement properties reported in a previous study.
      Homogenization theory was applied to estimate the elastic properties of the
      manufactured scaffolds. A good correlation was obtained between the experimental
      data and the theory.

PMID- 12485800
TI  - Manufacture of porous polymer nerve conduits by a novel low-pressure injection
      molding process.
AB  - A method to fabricate porous, biodegradable conduits using a combined injection
      molding, thermally induced phase transition technique was developed which
      produced conduits with dimensionally toleranced, longitudinally aligned channels.
      The geometry of the channels was designed to approximate the architecture of
      peripheral nerves and to support the monolayer adherence of physiologically
      relevant numbers of Schwann cells. The channel configuration could be varied from
      a single 1.35 mm diameter channel up to 100 0.08 mm diameter channels. A conduit
      with 100 channels has approximately 12.5 times the lumenal surface area of a
      single channel conduit and supports the adherence of five times the number of
      Schwann cells in the native peripheral nerve. In this study, poly(DL-lactide-co
      glycolide) (DL-PLGA) was dissolved in acetic acid and injected into a cold mold
      which induced solid-liquid phase separation and, ultimately, solidification of
      the polymer solution. The acetic acid was removed by sublimation and the
      resulting foam had a macrostructure of high anisotropy. Semi-permeable skins
      formed on the outer and lumen diameters of the conduit as a consequence of rapid
      quenching. Macropores were organized into bundles of channels, up to 20 microm
      wide, in the DL-PLGA matrix and represented remnants of acetic acid that
      crystallized during solidification.

PMID- 12485801
TI  - Effects of alpha-TCP and TetCP on MC3T3-E1 proliferation, differentiation and
      mineralization.
AB  - Calcium phosphates with high solubility in water such as alpha-tricalcium
      phosphate (alpha-TCP) and tetracalcium phosphate (TetCP) have received
      considerable attention as components of bone-substitution materials. However, the
      osteoblast response to these materials has not yet been clearly understood. This
      study examined the effects of alpha-TCP and TetCP on osteoblast proliferation,
      differentiation and mineralization in the culture system of MC3T3-E1 cells. Cells
      were cultured in a differentiation medium with or without alpha-TCP or TetCP at 1
      or 10 microM, and the number of cells attached to the culture plates was
      determined. To examine osteoblast differentiation, the alkaline phosphatase (ALP)
      activity was measured and the expression of osteoblastic markers analyzed by RT
      PCR. In addition, mineralization was evaluated by staining the calcium deposit
      with Alizalin red. Culture in the presence of alpha-TCP or TetCP showed no
      significant influence on cell proliferation. ALP activities of the cells were
      enhanced by both calcium phosphates for 3d and the expression of type I collagen
      was promoted at 12h and 1d after incubation. Enhancement of bone-like tissue
      formation by the addition of alpha-TCP or TetCP at 10 microM was observed after
      7d incubation and thereafter. The results of the present study indicate that
      alpha-TCP and TetCP promote osteogenesis by increasing collagen synthesis and
      calcification of the extra-cellular matrix.

PMID- 12485802
TI  - Adhesion contact dynamics of HepG2 cells on galactose-immobilized substrates.
AB  - The specific recognition between asialoglycoprotein receptor and galactose ligand
      at cell-substrate interfaces has been shown to mediate hepatocyte adhesion and
      maintain liver specific functions of hepatocytes. Conventionally, the success of
      hepatocyte attachment on engineered tissue scaffold is inferred from the degree
      of two-dimensional cell spreading that is measured by transmitted light
      microscopy. However, the actual contact mechanics and adhesion strength of
      hepatocytes during two-dimensional cell spreading has not been elucidated due to
      lack of biophysical probe. In this study, a novel biophysical technique known as
      confocal reflectance interference contrast microscopy (C-RICM) in conjunction
      with phase contrast microscopy is utilized to probe the adhesion dynamics,
      contact mechanics and two-dimensional spreading kinetics of HepG2 cells on
      galactose immobilized and collagen gel coated substrates. C-RICM demonstrates
      that HepG2 cells form strong adhesion contacts with both galactose-immobilized
      surfaces and collagen gel coated substrates. Moreover, HepG2 cells maintain their
      compact shapes in the presence of asialoglycoprotein receptor-mediated
      recognition while they become exceedingly spread under integrin-mediated adhesion
      on collagen gel coated substrate. The initial rate of adhesion contact formation
      and the steady-state adhesion energy of HepG2 cell population are highest on
      substrate conjugated with galactose ligand via a longer spacer. The adhesion
      dynamics and final adhesion energy of HepG2 cells depends both on the type of
      ligand-receptor interaction and the length of spacer between the ligand and
      substrate. Most importantly, new biophysical insights into the initial hepatocyte
      attachment that are critical for hepatocyte culture are provided through the
      decomposition of two-dimensional spreading and adhesion contact formation on bio
      functional substrates.

PMID- 12485803
TI  - Ascorbate modulation of bovine chondrocyte growth, matrix protein gene expression
      and synthesis in three-dimensional collagen sponges.
AB  - This report completes a previous study on the growth and metabolism of fetal
      bovine epiphyseal chondrocytes cultured, within native or cross-linked collagen
      sponges carried out without the addition of fresh ascorbate. At low initial cell
      density (2.3 x 10(6)cells/cm(3)) cell proliferation and a low matrix deposition
      were observed, whereas at high initial cell density (2.3 x 10(7)cells/cm(3))
      there was an absence of cell proliferation, but the deposition of a cartilage
      like matrix was measured. In both cases, only traces of type I collagen (marker
      of chondrocyte dedifferentiation) were detected. In this report, we observed,
      after 1 month in culture with ascorbate, in both type of scaffolds and initial
      cell densities, an increase in cell proliferation (2-fold) and in expression of
      genes encoding for collagen types I, II, X and MMP-2 and -13, but no change in
      the level of matrix deposition (collagen and GAG). With regard to the proteins
      present, the main differences with or without ascorbate concerned the increase of
      neosynthesised type I collagen (up to 35% of the total collagen deposited in the
      sponge) and of the MMP-2 active form. In conclusion, these results show that
      ascorbate is an important factor to consider when preparing cartilage constructs
      for its action on chondrocyte phenotype modulation and proliferation.

PMID- 12485804
TI  - Mannosides as crucial part of bioactive supports for cultivation of human
      epidermal keratinocytes without feeder cells.
AB  - Large-scale production of keratinocytes by cell culture is of interest for
      medical applications. Long-term cultivation of epidermal cells is presently
      possible with feeder cells, i.e. 3T3 fibroblasts with arrested mitosis, or with
      specially formulated culture medium. To define refinements for in vitro
      conditions, the analysis of the natural environment with growth
      maintaining/stimulating factors can provide important clues. Cells with
      proliferative activity are located in the basal layer of the epidermis in close
      contact with a basement membrane. Employing lectin and reverse lectin
      histochemistry of skin, muscle fibers and feeder cells, we assumed that the
      interplay of mannose-binding sites of epidermal cells, detected by a labeled
      neoglycoprotein, with glycoligands in the feeder cell layer or basement membrane
      could trigger signaling with relevance for adhesion and growth regulation.
      Indeed, coating of polystyrene with mannose-containing neoglycoprotein mimicking
      a mannose-rich cell matrix enabled the cultivation of keratinocytes without
      feeder cells in a Ca(2+)-dependent manner in serum-containing culture medium.
      Following this experimental demonstration of specific binding of mannose residues
      as part of a neoglycoprotein controlled by testing sugar-free carrier protein and
      other substances, we next synthesized and tested biocompatible polymers.
      Attachment and proliferation of keratinocytes on the surface of these polymers
      compared favorably to control experiments using feeder cells. In conclusion, we
      suggest that these polymers are bioactive offering a perspective for keratinocyte
      cultivation without feeder cells.

PMID- 12485806
TI  - Scanning electron microscopic examination of bacterial immobilisation in a
      carboxymethyl cellulose (AQUACEL) and alginate dressings.
AB  - Dressings have been applied to open wounds for centuries. Traditionally they have
      been absorbent, permeable materials, i.e. gauze that could adhere to desiccated
      wound surfaces, inducing trauma on removal. With the advent of modern wound care
      products many dressings are now capable of absorbing large volumes of exudate
      whilst still continuing to provide a moist wound healing environment. Equally
      important is their ability to lock exudate in the dressing (i.e. bacterial
      retention within the dressing matrix) such that upon removal from a wound surface
      bacterial dispersion is minimised. In these studies detailed scanning electron
      microscopy techniques have demonstrated the fluid controlling properties of
      alginate wound dressings and a carboxymethylated cellulose wound dressing
      (AQUACEL) Hydrofiber) dressing (CMCH)). It was demonstrated that following
      hydration of the latter wound dressing, the subsequent formation of a cohesive
      gel was effective in encapsulating large populations of potentially pathogenic
      bacteria such as Psuedomonas aeruginosa and Staphylococcus aureus under the
      gelled surface, as well as being immobilised within the swollen fibres. In
      contrast, hydrated alginate wound dressings did not form a uniform, cohesive gel
      structure, with the result that fewer bacteria were immobilised within the gel
      matrix. Many bacteria were trapped on individual, non-hydrated fibres. The unique
      absorbent gelling properties of the CMCH dressing appears to provide an ideal
      environment for immobilising bacteria.

PMID- 12485805
TI  - The effect of Gu-Sui-Bu (Drynaria fortunei J. Sm) immobilized modified calcium
      hydrogenphosphate on bone cell activities.
AB  - In our previous study, we have validated the efficacy and the safety of Gu-Sui-Bu
      [Drynaria fortunei (Kunze) J. Sm.] by the bone cells culture. However, a
      satisfactory delivery system for Gu-Sui-Bu must be developed before it can be
      used in clinical medicine. In this study, we try to use modified calcium
      hydrogenphosphate (MCHP) bioceramic as a carrier to transport Gu-Sui-Bu into the
      bone cell culture system. Toward this goal, we evaluated the effect of a Gu-Sui
      Bu-immobilized modified calcium hydrogenphosphate (GI-MCHP) on the bone cells
      activities. THE CHINESE MEDICINE: Gu-Sui-Bu [Drynaria fortunei (kunze) J. Sm] was
      extracted and then immobilized on the surface of MCHP. The rat osteoblasts
      osteoclasts co-culture system was used as the experimental model. After the cells
      grew to 80% confluence, different sizes of GI-MCHP particles were tested. The
      mitochondria activity of the bone cells after exposure was determined by
      colorimetric assay. Biochemical markers such as lactate dehydrogenase (LDH),
      alkaline phosphatase (ALP), acid phosphatase (ACP) and prostaglandin E(2) titer
      were analyzed to evaluate the bone cells activities. Histomorphometric study of
      osteoclasts activities and the phenotype expression of osteoblasts were also
      evaluated. There is no detectable titer of LDH secretion into the medium and no
      significant change in the intracellular ALP content. The ALP titer in the culture
      medium did increase significantly at 3 days' culture, while there is a
      significant decrease in the intracellular ACP content and significant increase in
      the ACP titer in the medium. The concentrations of PGE(2) in tested medium are
      always significantly higher than that of control medium during the 7 days'
      culture. At the end of 7 days' culture, the PGE(2) concentrations in the tested
      medium were still 4.74 times that of the control medium. After GI-MCHP treatment
      on bone cells, the size of the osteoclasts seems decreased and their cell
      integrity seems lost, while the osteoblasts phenotype expression was relatively
      preserved. From this study, we demonstrated that Gu-Sui-Bu [Drynaria fortunei
      (Kunze) J. Sm.] immobilized MCHP has well preserved the potential beneficial
      effects of Gu-Sui-Bu on the bone cells culture.

PMID- 12485807
TI  - Aging and insulin secretion.
AB  - Glucose tolerance progressively declines with age, and there is a high prevalence
      of type 2 diabetes and postchallenge hyperglycemia in the older population. Age
      related glucose intolerance in humans is often accompanied by insulin resistance,
      but circulating insulin levels are similar to those of younger people. Under some
      conditions of hyperglycemic challenge, insulin levels are lower in older people,
      suggesting beta-cell dysfunction. When insulin sensitivity is controlled for,
      insulin secretory defects have been consistently demonstrated in aging humans. In
      addition, beta-cell sensitivity to incretin hormones may be decreased with
      advancing age. Impaired beta-cell compensation to age-related insulin resistance
      may predispose older people to develop postchallenge hyperglycemia and type 2
      diabetes. An improved understanding of the metabolic alterations associated with
      aging is essential for the development of preventive and therapeutic
      interventions in this population at high risk for glucose intolerance.

PMID- 12485808
TI  - The other side of the orexins: endocrine and metabolic actions.
AB  - Although it is clear that the orexin/hypocretin peptides have a significant,
      physiologically relevant role in sleep/wakefulness, a broader picture has emerged
      indicating metabolic actions that may depend upon both neural and endocrine
      mechanisms for their manifestation. The ability of exogenous peptide to activate
      sympathetic tone, increase locomotor activity, and alter feeding behavior,
      together with the observed alterations in those functions in knockout animals,
      strongly suggests important neural actions of the endogenous orexins/hypocretins.
      Likewise, the action of exogenously administered peptides to alter endocrine
      function, in particular corticotropin release, has now been mirrored by potential
      endocrinopathies in knockout animals. Thus these pluripotent peptides hold great
      potential not only for the treatment of human narcolepsy but also to provide
      insight into the coordinated regulation of multiple physiological systems.

PMID- 12485809
TI  - Use of a novel triple-tracer approach to assess postprandial glucose metabolism.
AB  - Numerous studies have used the dual-tracer method to assess postprandial glucose
      metabolism. The present experiments were undertaken to determine whether the
      marked tracer nonsteady state that occurs with the dual-tracer approach after
      food ingestion introduces error when it is used to simultaneously measure both
      meal glucose appearance (R(a meal)) and endogenous glucose production (EGP). To
      do so, a novel triple-tracer approach was designed: 12 subjects ingested a mixed
      meal containing [1-(13)C]glucose while [6-(3)H]glucose and [6,6-(2)H(2)]glucose
      were infused intravenously in patterns that minimized the change in the plasma
      ratios of [6-(3)H]glucose to [1-(13)C]glucose and of [6,6-(2)H(2)]glucose to
      endogenous glucose, respectively. R(a meal) and EGP measured with this approach
      were essentially model independent, since non-steady-state error was minimized by
      the protocol. Initial splanchnic glucose extraction (ISE) was 12.9% +/- 3.4%, and
      suppression of EGP (EGPS) was 40.3% +/- 4.1%. In contrast, when calculated with
      the dual-tracer one-compartment model, ISE was higher (P < 0.05) and EGPS was
      lower (P < 0.005) than observed with the triple-tracer approach. These errors
      could only be prevented by using time-varying volumes different for R(a meal) and
      EGP. Analysis of the dual-tracer data with a two-compartment model reduced but
      did not totally avoid the problems associated with marked postprandial changes in
      the tracer-to-tracee ratios. We conclude that results from previous studies that
      have used the dual-tracer one-compartment model to measure postprandial
      carbohydrate metabolism need to be reevaluated and that the triple-tracer
      technique may provide a useful approach for doing so.

PMID- 12485810
TI  - Acute lowering of circulating fatty acids improves insulin secretion in a subset
      of type 2 diabetes subjects.
AB  - We tested the effects of acute perturbations of elevated fatty acids (FA) on
      insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with
      hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic
      subjects participated. Glucose-stimulated insulin secretion was monitored during
      hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added
      during minutes 60-120. In one of two tests, the subjects ingested 250 mg of
      Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox)
      was performed in 17 of the diabetic subjects after 3 days of a low-fat diet.
      Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and
      diabetic subjects alike. Acipimox administration failed to affect insulin
      secretion rates in nondiabetic subjects and in the group of diabetic subjects as
      a whole. However, in the diabetic subjects, Acipimox increased integrated insulin
      secretion rates during minutes 60-120 in the 50% having the lowest levels of
      hemoglobin A(1c) (379 +/- 34 vs. 326 +/- 30 pmol x kg(-1) x min(-1) without
      Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from
      39 to 23% without affecting FA levels and without improving the insulin response
      during clamps. Elevated FA levels may tonically inhibit stimulated insulin
      secretion in a subset of type 2 diabetic subjects.

PMID- 12485811
TI  - Differential expression of VEGF receptors in adrenal atrophy induced by
      dexamethasone: a protective role of ACTH.
AB  - Although ACTH is important to adrenal growth and steroidogenesis, its role in
      vascular development and function has not been established in vivo. In the
      present study, we demonstrate the expression of mRNA for all four VEGF isoforms
      (mVEGF(120,144,164,188)) and for Flk-1/KDR and Flt-1 receptors in the mouse
      adrenal in vivo. Suppression of the pituitary adrenocortical axis by
      dexamethasone (0.5 mg x 100 g body wt(-1) x day(-1) during 6 days) induced a
      decrease in corticosterone levels, adrenal weights by 50% (P < 0.001), VEGF(188)
      mRNA, and Flk-1/KDR mRNA, whereas Flt-1 remained consistent during steroid
      treatment. A daily injection of ACTH-(1-39) restored the transcript for Flk-1/KDR
      and both VEGF(188) and plasma corticosterone to control levels. To gain further
      insights into the effects of ACTH, cultured endothelial cells (ECs) were treated
      with forskolin, which increases cAMP, the second messenger in ACTH action. We
      demonstrate that Flk-1/KDR protein expression was markedly increased by forskolin
      within 24-48 h of treatment in a dose-dependent manner (0.1-10 microM). The
      biological effect of ACTH on ECs was then tested by use of coincubations of
      fasciculata cells and ECs in 3D-collagen assay. Within 5-7 days of culture, ECs
      organized into multicellular structures that resemble networks of
      microvasculature, which characterize angiogenesis in vitro.

PMID- 12485812
TI  - IGF-I and IGFBP-3 transport in the rat heart.
AB  - Specific binding of IGF-binding protein (IGFBP)-3 was shown to be present in the
      isolated, beating rat heart. The uptake of perfused (125)I-labeled IGF-I in the
      beating heart was decreased to 9% by blocking IGF-I binding sites with the IGF-I
      analog Long R(3) (LR(3)) IGF-I. When LR(3) was perfused with complexes of (125)I
      IGF-I. IGFBP-3, uptake of (125)I-IGF-I was decreased to 41%, which was
      significantly greater than LR(3) and (125)I-IGF-I (41 vs. 9%). These data suggest
      that both microvessel IGF-I and IGFBP-3 binding sites contribute to the transport
      of IGF-I in the perfused rat heart. This also suggests a novel and plausible
      mechanism whereby circulating IGFs reach sites of IGF bioactivity.

PMID- 12485813
TI  - Defective mitochondrial DNA replication and NRTIs: pathophysiological
      implications in AIDS cardiomyopathy.

PMID- 12485814
TI  - Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human
      dilated cardiomyopathy.
AB  - The purpose of the study was to investigate interactions between myocardial
      nitric oxide synthase (NOS) and myocardial fibrosis, both of which determine left
      ventricular (LV) preload reserve in patients with nonischemic dilated
      cardiomyopathy (DCM). In previous animal experiments, chronic inhibition of NOS
      induced myocardial fibrosis and limited LV preload reserve. Twenty-eight DCM
      patients underwent LV catheterization, balloon caval occlusions (BCO; n = 8),
      intracoronary substance P infusion (n = 8), and procurement of LV endomyocardial
      biopsies for determinations of collagen volume fraction (CVF), of gene expression
      of NOS2, NOS3, heme oxygenase (HO)-1, and TNF-alpha, and of NOS2 protein. CVF was
      unrelated to the intensity of NOS2, NOS3, HO-1, or TNF-alpha gene expression or
      of NOS2 protein expression. Preload recruitable LV stroke work (PR-LVSW)
      correlated directly with NOS2 gene expression (P = 0.001) and inversely with CVF
      (P = 0.04). High CVF (>10%) reduced baseline LVSW and PR-LVSW at each level of
      NOS2 gene expression. In DCM, myocardial fibrosis is unrelated to the intensity
      of myocardial gene expression of NOS, antioxidative enzymes (HO-1), or cytokines
      (TNF-alpha) and blunts NOS2-related recruitment of LV preload reserve.

PMID- 12485815
TI  - In vivo measurement of coronary circulation angiotensin-converting enzyme
      activity in humans.
AB  - Angiotensin-converting enzyme (ACE) is present on the luminal surface of the
      coronary vessels, mostly on capillary endothelium. ACE is also expressed on
      coronary smooth muscle cells and on plaque lipid-laden macrophages. Excessive
      coronary circulation (CC)-ACE activity might be linked to plaque progression.
      Here we used the biologically inactive ACE substrate (3)H-labeled benzoyl-Phe-Ala
      Pro ([(3)H]BPAP) to quantify CC-ACE activity in 10 patients by means of the
      indicator-dilution technique. The results were compared with atherosclerotic
      burden determined by coronary angiography. There was a wide range of CC-ACE
      activity as revealed by percent [(3)H]BPAP hydrolysis (30-74%). The
      atherosclerotic extent scores ranged from 0.0 to 66.97, and the plaque area
      scores ranged from 0 to 80 mm(2). CC-ACE activity per unit extracellular space
      (V(max)/K(m)V(i)), an index of metabolically active vascular surface area, was
      correlated with myocardial blood flow (r = 0.738; P = 0.03) but not with measures
      of the atherosclerotic burden. These results show that CC-ACE activity can be
      safely measured in humans and that it is a good marker of the vascular area of
      the perfused myocardium. It does not, however, reflect epicardial atherosclerotic
      burden, suggesting that local tissue ACE may be more important in plaque
      development.

PMID- 12485816
TI  - Parathyroid hormone-related peptide improves contractile function of stunned
      myocardium in rats and pigs.
AB  - The effect of synthetic parathyroid hormone (PTH)-related peptide [PTHrP(1-34)]
      on regional myocardial function was studied in 11 anesthetized pigs.
      Intracoronary infusion of PTHrP (cumulative dose: 14 +/- 1 microg) decreased
      coronary resistance to 33 +/- 2% of baseline (P < 0.05) and regional myocardial
      function to 90 +/- 3% of baseline (not significant). Ischemia-reperfusion alters
      the activity of several kinases and therefore possibly the myocardial effects of
      PTHrP. In stunned myocardium, induced by 20-min ischemia and 30-min reperfusion,
      the dose of PTHrP reducing coronary resistance to a minimum of 29 +/- 2% was
      decreased to 8 +/- 2 microg (P < 0.05). Regional myocardial function was no
      longer decreased but increased to 132 +/- 9% (P < 0.05). The increase in regional
      myocardial function during PTHrP was inversely related to baseline function at 30
      min reperfusion in vivo (r = 0.9) as well as in myocytes isolated from stunned
      pig hearts (r = 0.7). In isolated rat hearts subjected to 30-min global ischemia
      followed by 30-min reperfusion, blockade of endogenous PTHrP by d-Trp(12)-Tyr(34)
      PTH(7-34) attenuated the recovery of left ventricular developed pressure by 30 +/
      14% (P < 0.05). Thus endogenous and exogenous PTHrP impact on the function of
      stunned myocardium.

PMID- 12485817
TI  - PTK, MAPK, and NOC/oFQ impair hypercapnic cerebrovasodilation after
      hypoxia/ischemia.
AB  - This study characterized the contributions of protein tyrosine kinase (PTK) and
      mitogen-activated protein kinase (MAPK) in nociceptin/orphanin FQ (NOC/oFQ)
      induced impairment of hypercapnic pial artery dilation (PAD) after
      hypoxia/ischemia (H/I) in piglets equipped with a closed cranial window. NOC/oFQ
      (10(-10) M cerebrospinal fluid H/I concentration) impaired hypercapnic PAD (21 +/
      2% vs. 13 +/- 1%). Coadministration of either of the PTK inhibitors genistein or
      tyrphostin A23 or the MAPK inhibitors U-0126 or PD-98059 with NOC/oFQ (10(-10) M)
      partially prevented the inhibition of hypercapnic PAD compared with that observed
      in their absence (21 +/- 2% vs. 17 +/- 1% for genistein). After exposure to H/I,
      PAD in response to hypercapnia was impaired, but pretreatment with either
      genistein, tyrphostin A23, U-0126, or PD-98059 partially protected such
      impairment (17 +/- 1% vs. 4 +/- 1% vs. 9 +/- 1% for sham control, H/I, and H/I +
      genistein pretreatment, respectively). These data show that PTK and MAPK
      activation contribute to NOC/oFQ-induced impairment of hypercapnic PAD. These
      data suggest that activation of PTK and MAPK is also involved in the mechanism by
      which NOC/oFQ impairs hypercapnic PAD after H/I.

PMID- 12485818
TI  - Changes in extracellular collagen matrix alter myocardial systolic performance.
AB  - The purpose of this study was to test the hypothesis that acute disruption of
      fibrillar collagen will decrease myocardial systolic performance without changing
      cardiomyocyte contractility. Isolated papillary muscles were treated either with
      plasmin (0.64 U/ml, 240 min) or untreated and served as same animal control.
      Plasmin treatment caused matrix metalloproteinase activation and collagen
      degradation as measured by gelatin zymography, hydroxyproline assays, and
      scanning electron microscopy. Plasmin caused a significant decrease in myocardial
      systolic performance. Isotonic shortening extent and isometric developed tension
      decreased from 0.17 +/- 0.01 muscle length (ML) and 45 +/- 4 mN/mm(2) in
      untreated muscles to 0.09 +/- 0.01 ML and 36 +/- 3 mN/mm(2) in treated muscles (P
      < 0.05). However, plasmin treatment (0.64 U/ml, 240 min) did not alter shortening
      extent or velocity in isolated cardiomyocytes. Acute disruption of the fibrillar
      collagen network caused a decrease in myocardial systolic performance without
      changing cardiomyocyte contractility. These data support the hypothesis that
      fibrillar collagen facilitates transduction of cardiomyocyte contraction into
      myocardial force development and helps to maintain normal myocardial systolic
      performance.

PMID- 12485819
TI  - Effect of nitric oxide on excitatory amino acid-evoked discharge of neurons in
      NTS.
AB  - N-methyl-d-aspartate (NMDA) and non-NMDA excitatory amino acid (EAA) receptor
      subtypes are involved in the integration of visceral afferent inputs within the
      nucleus of the solitary tract (NTS). Microinjection studies indicate interactions
      between nitric oxide (NO) and EAA receptors within the NTS. To examine these
      interactions at the single cell level, this study characterized the effects of
      the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the NO
      donor 3-[2-hydroxy-2-nitroso-1-propylhydrazino]-1-propanamine (PAPA-NONOate) on
      the excitatory responses of vagus nerve (VN)-evoked NTS neurons to the activation
      of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA
      receptors in rats. Iontophoresis of l-NAME did not alter spontaneous or VN-evoked
      discharges, but significantly decreased the number of action potentials (APs)
      evoked by iontophoretic application of AMPA. The effects of l-NAME on NMDA-evoked
      discharge were variable; for the population, l-NAME did not change the number of
      APs evoked by NMDA. PAPA-NONOate enhanced the spontaneous discharge and the
      number of APs elicited by AMPA but not NMDA. Iontophoresis of the inactive
      enantiomers N(G)-nitro-d-arginine methyl ester and hydroxydiazenesulfonic acid 1
      oxide disodium salt had no effect on AMPA-evoked discharge. Our data suggest that
      NO facilitates AMPA-mediated neuronal transmission within the NTS.

PMID- 12485820
TI  - Role of intracellular antioxidant enzymes after in vivo myocardial ischemia and
      reperfusion.
AB  - Reactive oxygen species induce myocardial damage after ischemia and reperfusion
      in experimental animal models. Numerous studies have investigated the deleterious
      effects of ischemia-reperfusion (I/R)-induced oxidant production using various
      pharmacological interventions. More recently, in vitro studies have incorporated
      gene-targeted mice to decipher the role of antioxidant enzymes in myocardial
      reperfusion injury. We examined the role of cellular antioxidant enzymes in the
      pathogenesis of myocardial I/R (MI/R) injury in vivo in gene-targeted mice.
      Neither deficiency nor overexpression of Cu-Zn superoxide dismutase (SOD) altered
      the extent of myocardial necrosis. Overexpression of glutathione peroxidase did
      not affect the degree of myocardial injury. Conversely, overexpression of
      manganese (Mn)SOD significantly attenuated myocardial necrosis after MI/R.
      Transthoracic echocardiography was performed on MnSOD-overexpressing and wild
      type mice that were subjected to a more prolonged period of reperfusion. Cardiac
      output was significantly depressed in the nontransgenic but not the transgenic
      MnSOD-treated mice. Anterior wall motion was significantly impaired in the
      nontransgenic mice. These findings demonstrate an important role for MnSOD but
      not Cu/ZnSOD or glutathione peroxidase in mice after in vivo MI/R.

PMID- 12485821
TI  - Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an
      endotoxin model.
AB  - This study addressed the possible role of cyclooxygenase (COX) and its products
      in the rebound response to inhaled nitric oxide (INO). Anesthetized, mechanically
      ventilated piglets were exposed to endotoxin alone, endotoxin combined with INO,
      or endotoxin with INO plus the COX inhibitor diclofenac (3 mg/kg iv) (n = 8
      piglets/group). A control group of healthy pigs (n = 6) was also studied.
      Measurements were made of blood gases, hemodynamic parameters, lung tissue COX
      expression, and plasma concentrations of thromboxane B(2) (TxB(2)), PGF(2alpha),
      and 6-keto-PGF(1alpha). Endotoxin increased lung inducible COX (COX-2) expression
      and circulating prostanoids concentrations. Inhalation of NO during endotoxemia
      increased the constitutive COX (COX-1) expression, and the circulating TxB(2) and
      PGF(2alpha) increased further after INO withdrawal. The combination of COX
      inhibitor with INO blocked all these changes and eliminated the rebound reaction
      to INO withdrawal, which otherwise was seen in endotoxemic piglets given INO
      only. We conclude that the rebound response to INO discontinuation is related to
      COX products.

PMID- 12485823
TI  - Representing the architecture of signal transduction networks in an algebraic
      form: protein target finding.

PMID- 12485824
TI  - Molecular chaperones in the regulation of signal transduction.

PMID- 12485826
TI  - Inducible hsp70 expression analysis after heat and physical exercise:
      transcriptional, protein expression, and subcellular localization.

PMID- 12485825
TI  - mUBPy and MSJ-1, a deubiquitinating enzyme and a molecular chaperone specifically
      expressed in testis, associate with the acrosome and centrosome in mouse germ
      cells.

PMID- 12485827
TI  - Suppression of adaptive immune responses: a novel mechanism by which peroxisome
      proliferators exert antiinflammatory effects?

PMID- 12485828
TI  - The effects of peroxisome proliferators on global lipid homeostasis and the
      possible significance of these effects to other responses to these xenobiotics:
      an hypothesis.
AB  - Peroxisome proliferators (PPs) have been shown to regulate hepatic lipid
      metabolism via activation of the peroxisome proliferator-activated receptor alpha
      (PPAR-alpha). Recent studies have revealed that PPs also exert considerable
      influence on certain extrahepatic tissues, including adipose tissue and lymphoid
      organs, in an indirect fashion. Inhibition of the proliferation of thymocytes and
      splenocytes and alteration of fatty acid uptake into and release from adipose
      tissue might be consequences of the hypolipidemic effect of PPs involving both
      PPARalpha-dependent and -independent pathways. Exposure to PPs reduces the
      cholesterol content of circulating low-density lipoprotein (LDL), which is the
      major supply of this steroid to most peripheral tissues. In addition, PPs
      increase serum levels of high-density lipoprotein (HDL), which extracts
      cholesterol from peripheral tissues and returns it to the liver, thereby further
      decreasing the cholesterol content of peripheral tissues. This net flux of
      cholesterol from extrahepatic tissues to the liver represents a change in global
      lipid homeostasis. In normal healthy young mice, this hypolipidemic effect could
      result in loss of cholesterol and other lipids from peripheral tissues (e.g.,
      adipose tissue, thymus, and spleen), especially from plasma membrane caveolae,
      which might perturb normal cellular signaling and result in tissue atrophy. On
      the other hand, the increased hepatic cholesterol content in the hepatocyte
      plasma membrane might actually enhance signaling, playing a role in the liver
      hypertrophy and hepatocarcinogenecally associated with long-term PP treatment. In
      conclusion, it is important to consider the systemic effects of PPs, rather than
      to focus on the liver alone.

PMID- 12485829
TI  - The role of PPAR-gamma/RXR-alpha heterodimers in the regulation of human
      trophoblast invasion.
AB  - PPAR-gamma/RXR heterodimers play a key regulatory role in murine placental
      development. We report here that PPAR-gamma and RXR-alpha are highly expressed in
      cultured primary extravillous cytotrophoblasts (EVCT) isolated from human first
      trimester placenta. Using this cell culture model, we showed that PPAR-gamma
      agonists inhibit EVCT invasion, whereas PPAR-gamma or pan-RXR antagonists
      promoted EVCT invasion by themselves and abolished PPAR-gamma agonist-mediated
      effect. Together these data underscore an important function of PPAR/RXR
      heterodimers in the modulation of trophoblast invasion.

PMID- 12485830
TI  - Ultraviolet-B irradiation and matrix metalloproteinases: from induction via
      signaling to initial events.
AB  - Effects of sunlight have fascinated researchers for decades because nearly every
      living thing on earth is likely to be exposed to sunlight and the ultraviolet
      (UV) fraction of it. In addition to detrimental long-term effects such as
      immunosuppression and skin cancer, premature aging of the skin (photoaging) is a
      well-documented consequence of exposure to UVA and UVB. Photoaged skin is
      biochemically characterized by an overgrowth of abnormal elastic fibers in the
      dermis and by a dramatic decrease of distinct collagen types. Ultraviolet
      irradiation induces delayed UV-responsive genes, among them matrix
      metalloproteinases, which degrade macromolecules of the extracellular matrix, a
      hallmark in carcinogenesis and aging. We are interested in UVB-triggered initial
      events and in subsequent signaling resulting in enhanced expression of two major
      members of the matrix metalloproteinase family, the interstitial collagenase (MMP
      1) and stromelysin-1 (MMP-3), in human dermal fibroblasts. Especially, these skin
      cells play a central role in connective tissue breakdown in photoaging and as
      stromal cells in tumor invasion and metastasis by means of their capability to
      produce matrix metalloproteinases. In this review, we will focus on UVB-triggered
      induction of matrix metalloproteinases, the so far identified components of the
      UVB-modulated signal transduction pathway(s), and the UVB irradiation-associated
      generation of reactive oxygen species (ROS). Finally, a potentially novel aspect
      in UVB irradiation-mediated expression of interstitial collagenase and
      stromelysin-1-namely, the involvement of reactive nitrogen species (RNS)-is
      discussed.

PMID- 12485831
TI  - Exposure of human skin diploid fibroblasts to repeated subcytotoxic doses of
      ultraviolet-B induces the overexpression of transforming growth factor-beta1
      mRNA.
AB  - In this work we show that the steady state mRNA level of TGF-beta1 is
      significantly increased in UVB-induced premature senescence.

PMID- 12485832
TI  - Doxorubicin increases intracellular diacylglycerol by the mobilization of choline
      enriched phospholipids in rat hepatocytes.

PMID- 12485833
TI  - Intracellular diacylglycerol accumulation induced by doxorubicin in rat
      hepatocytes: potential involvement of phospholipases C and D.

PMID- 12485834
TI  - Dual role of cytochalasin D in the regulation of connective tissue growth factor.

PMID- 12485835
TI  - Expression of the chemokine receptor CXCR4 and its ligand stromal cell-derived
      factor 1 in human brain tumors and their involvement in glial proliferation in
      vitro.
AB  - Chemokines are a family of proteins that chemoattract and activate cells by
      interacting with specific receptors on the surface of their targets. They are
      grouped into four classes based on the position of key cysteine residues: C, CC,
      CXC, and CX3C. Stromal cell-derived factor 1 (SDF1), the ligand of the CXCR4
      receptor, is a CXC chemokine involved in chemotaxis and brain development that
      also acts as coreceptor for HIV-1 infection. It has been proposed that CXCR4 is
      overexpressed and required for proliferation in human brain tumor cells. We
      previously demonstrated that CXCR4 and SDF1 are expressed in culture of cortical
      type I rat astrocytes, cortical neurons, and cerebellar granule cells. In this
      study, we analyzed the expression of CXCR4 and SDF1 in four human brain tumor
      tissues, showing that CXCR4 is expressed in all tumors analyzed, whereas SDF1 is
      expressed only in two tumor tissues. We also investigated the possible functions
      of CXCR4 expressed in rat type I cortical astrocytes, demonstrating that
      SDF1alpha stimulates the proliferation of these cells in vitro. Moreover, we
      studied by western blot the intracellular pathway involved in cell proliferation,
      demonstrating that SDF1alpha induces the ERK1/2 phosphorylation that is reduced
      by the PD98059 compound, an MEK inhibitor.

PMID- 12485836
TI  - Signaling pathways mediate the neuroprotective effects of GDNF.
AB  - We show that the glial cell line-derived neurotrophic factor (GDNF) activates the
      PI3K/Akt-signaling pathway in human neuroblastoma cells that express functional
      Ret-receptor complexes. Consistent with this finding we show PI3K-dependent Bad
      inactivation by binding to 14-3-3 proteins in response to GDNF. Using
      differential display techniques we detected several cDNA clones differentially
      expressed after treatment with GDNF or 6-OHDA.

PMID- 12485837
TI  - Space flight and insulin-like growth factor-I signaling in rat osteoblasts.
AB  - The primary culture of rat osteoblasts was treated with 1alpha,25
      dihydroxyvitamin D(3) and fixed with guanidine isothiocyanate solution during a
      space shuttle flight. The mRNA levels were analyzed by quantitative reverse
      transcription-polymerase chain reaction. Microgravity decreased the mRNA levels
      of insulin-like growth factor-I (IGF-I) and increased reciprocally the IGF-I
      receptor mRNA levels, as compared to the ground (1 x g) control. Microgravity
      completely suppressed the mRNA expression of the insulin receptor substrate-1,
      the postreceptor signaling molecule of IGF-I. Microgravity might deteriorate the
      action and signaling of IGF-I in rat osteoblasts.

PMID- 12485838
TI  - Suppressor of cytokine signaling-1 inhibits interferon-gamma-induced activation
      of human keratinocytes.

PMID- 12485840
TI  - Hepatic insulin-like growth factor-I binding protein 3 gene expression in rats
      with endotoxic shock: the role of glucocorticoids.
AB  - The aim of this work was to study the role of glucocorticoids in the insulin-like
      growth factor binding protein (IGFBP)-3 response to endotoxin. Lipopolysaccharide
      (LPS) administration decreased IGFBP-3 serum levels as well as hepatic IGFBP-3
      gene expression in both adrenalectomized and sham-operated rats. These data
      suggest that the decrease in hepatic IGFBP-3 gene expression induced by LPS is
      not mediated by glucocorticoids.

PMID- 12485839
TI  - Expression of steroidogenic acute regulatory protein in cultured Schwann cells
      and its regulation by cAMP.
AB  - In steroidogenic cells the steroidogenic acute regulatory (StAR) protein plays a
      key role in the transport of cholesterol to the inner mitochondrial membrane,
      where the first step of steroidogenesis, the conversion of cholesterol to
      pregnenolone, takes place. cAMP is a known positive regulator of StAR gene
      expression and steroid biosynthesis in steroidogenic cells. As some steroids,
      such as progesterone, can also be synthesized de novo in the central and
      peripheral nervous systems and display neuroprotective and neurotrophic effects,
      we decided to verify the effect of cAMP on StAR gene expression in cultured
      Schwann cells. We observed that (1) in the presence of serum, forskolin, an agent
      known to elevate intracellular cAMP, induced both a morphological change and
      proliferation of cultured Schwann cells; (2) StAR mRNA and protein were expressed
      in Schwann cells; (3) unexpectedly, forskolin and 8 Br-cAMP, a cell-permeant
      analogue of cAMP, extinguishcd StAR gene expression; and (4) this response was
      similar in the presence or absence of serum.

PMID- 12485841
TI  - Further immunohistochemical evidence for impaired NO signaling in the
      hypothalamus of depressed patients.
AB  - The cellular expression of nitric oxide synthase (NOS) was studied in neurons of
      the Nuc. suprachiasmaticus (SCN) of depressed patients and matched controls. The
      number of NOS-immunoreactive SCN neurons was significantly reduced in depression.
      We conclude that affective disorders are accompanied by impaired hypothalamic NO
      signaling.

PMID- 12485842
TI  - Nitric oxide production stimulated by the basic fibroblast growth factor requires
      the synthesis of ceramide.
AB  - Nitric oxide (NO) is an intracellular and intercellular mediator involved in the
      modulation of many physiologic and pathologic processes including the regulation
      of neoangiogenesis. We analyzed the effects of basic fibroblast growth factor
      (bFGF) on NO production in CHO-K1 cells and the intracellular mechanisms
      involved. bFGF induces NO production through activation of the endothelial NO
      synthase (eNOS), causing a subsequent increase in cGMP levels. In most systems,
      eNOS activation is a Ca(2+)-calmodulin-dependent process. In CHO-K1 cells, NO
      production by bFGF is Ca(2+) and MAP kinase independent, because it was not
      reverted by pretreatment with intracellular Ca(2+) chelators or MEK inhibitors.
      Translocation of the eNOS from the plasma membrane, where it is bound to caveolin
      1, to the cytosol is the crucial step in the synthesis of NO. We demonstrate that
      the cytosolic translocation of eNOS is caused by increased synthesis of ceramide
      dependent by the bFGF activation of sphingomyelinase. Indeed, in the presence of
      the sphingomyelinase inhibitors D609 or desipramine, bFGF-dependent NO production
      is abrogated. To support this evidence we evaluated ceramide concentration using
      HPLC-electrospray ionization-mass spectrometry in controls and in bFGF-treated
      cells: after bFGF stimulation, a substantial increase in ceramide levels was
      observed. These data were further confirmed by the lack of NO production in
      response to fibroblast growth factor in fibroblasts derived from Niemann Pick
      patients who genetically lack the enzyme sphingomyelinase. In conclusion,
      ceramide in CHO-K1 cells is responsible for a novel Ca(2+)/calmodulin-independent
      mechanism for eNOS activation after fibroblast growth factor stimulation.

PMID- 12485843
TI  - Involvement of RAS-ERK signaling in multiple biological responses to HGF/SF.

PMID- 12485844
TI  - Structure of the amino-terminal nuclear export domain of the APC tumor suppressor
      protein.

PMID- 12485845
TI  - Antagonistic signaling pathways regulate alternative splicing of CD44 in T cells.

PMID- 12485846
TI  - Denervation is not a primary cause of prion protein down-regulation occurring in
      the spinal cord of a transgenic model of amyotrophic lateral sclerosis.

PMID- 12485847
TI  - The activity of the insulin receptor assessed by bioluminescence resonance energy
      transfer.
AB  - This work describes a new assay, based on the bioluminescence resonance energy
      transfer (BRET) methodology, to monitor the activation state of the insulin
      receptor.

PMID- 12485848
TI  - The F-actin content of multiple myeloma cells as a measure of their migration.
AB  - One of the main characteristics of multiple myeloma (MM) cells is their specific
      homing and growth in the bone marrow (BM). For their homing, MM cells need
      chemotactic signals to be attracted towards the BM and to be activated. Profound
      knowledge of the different chemokines for MM cells and their signal transduction
      pathways is necessary to interfere in this process. We studied here an extra
      possible tool for the investigation of the different chemokines and their
      pathways. The 5T experimental mouse model was used to investigate the migration
      of MM cells towards BM stromal cells. We studied the changes of the F-actin
      content in the 5TMM cells in the presence of BM stromal cell conditioned medium
      and we correlated this with their migratory capacity. F-actin became polarized
      when the cells were migrating, in contrast to nonmigrating cells. This
      polarization could not only be seen by fluorescence and confocal laser scanning
      microscopy, but also could be quantified by fluorometry and flow cytometry. The
      correlation between the F-actin content of the MM cells and their migration
      capacity thus makes its quantification a useful tool in studying their migratory
      behavior.

PMID- 12485849
TI  - Cloning and characterization of a new Ral-GEF expressed in mouse testis.

PMID- 12485850
TI  - beta-Arrestin 1 couples thrombin to the rapid activation of the Akt pathway.
AB  - In a variety of cell types including chinese hamster embryonic fibroblasts (IIC9
      cells), alpha-thrombin is a potent mitogen. Thrombin irreversibly activates Par
      1, a member of the seven membrane-spanning superfamily of G protein-coupled
      receptors (GPCRs). This, in turn, activates several heterotrimeric G proteins and
      induces signaling pathways that are critical for cell cycle reentry and
      proliferation. In IIC9 cells, alpha-thrombin activates the phosphatidylinositol-3
      OH kinase (PI 3-Kinase)/Akt pathway, which is essential for G1 cell cycle
      progression. At present the mechanism for activation and regulation of the PI 3
      kinase/Akt pathway is not fully understood. My preliminary data demonstrates a
      role for beta-arrestin 1 in the regulation of alpha-thrombin-induced Akt
      activity. In addition to their importance in receptor down-regulation, beta
      arrestins are now known to scaffold proteins involved in stimulating specific
      signaling pathways. My preliminary data show that equal to or precedes -thrombin
      activates a rapid Akt activity in a beta-arrestin 1-dependent manner in IIC9
      cells.

PMID- 12485851
TI  - alpha-Thrombin activates Akt via a nonreceptor tyrosine kinase in IIC9 cells.
AB  - Previous data from our laboratory show that PI 3-kinase is required for alpha
      thrombin-stimulated G(1) progression in IIC9 cells. In IIC9 cells, PI 3-kinase
      acts downstream of Ras to activate Akt, in a pathway parallel to ERK1. Here we
      show that alpha-thrombin does not transactivate either the EGF receptor or the
      PDGF receptor as measured by tyrosine phosphorylation, suggesting that activation
      of PI 3-kinase by alpha-thrombin is not the result of an RTK. Interestingly, both
      genistein and PP1 block alpha-thrombin-stimulated Akt phosphorylation, suggesting
      the involvement of a member of the Src family of nonreceptor tyrosine kinases.

PMID- 12485852
TI  - Activation of ERK, controlled by Rac1 and Cdc42 via Akt, is required for anoikis.
AB  - We have recently reported that two Rho family GTPases, Rac1 and Cdc42, are
      intimately involved in the control of cell survival of murine fibroblasts linked
      to adherence to the extracellular matrix. Inhibition of either Rac1 or Cdc42
      signaling in adherent cells mimics the loss of anchorage and efficiently induces
      apoptosis in both immortalized and primary cells. In both cases cell death is
      dependent on the wild-type p53 tumor suppressor and is accompanied by activation
      of endogenous p53. Here, we describe that the inhibition of Rac1 or Cdc42
      signaling leads to MAPK ERK activation via a pathway involving PI(3)K, Akt, Raf,
      and MEK, but not Ras. The moderate level of ERK activation that accompanies
      anoikis is an essential component of proapoptotic signaling; whereas sustained,
      high-intensity ERK signaling promotes survival in the same experimental system.

PMID- 12485853
TI  - Decorin affects endothelial cells by Akt-dependent and -independent pathways.
AB  - Decorin, a small multifunctional proteoglycan, has been shown to be causally
      involved in the formation of capillary-like structures and a decrease in
      apoptosis. Here we investigated signal transduction pathways mediating effects of
      decorin on endothelial cells (ECs). Addition of decorin led to a fourfold
      increase in phosphorylation of Akt/protein kinase B on Thr307 and a l.4-fold
      increase on Ser473 after 10 min, but this phosphorylation could not be blocked by
      preincubation with Ly29400 (10 micro M). Six hours after the addition of decorin,
      the synthesis of p21 and p27, two inhibitors of cyclin-dependent kinases, started
      and increased up to 18 h, while synthesis of cyclin A peaked at 12 h and
      decreased after 24 h below base level. Induction of dominan-negative Akt by a
      replication-deficient adenovirus blocked p21 and cyclin A synthesis, but had no
      effect on p27. Dominant-negative Akt also blocked the antiapoptotic effect of
      decorin on ECs, but induction of dominant-positive Akt could not rescue the cells
      from apoptosis. Thus, the matrix proteoglycan decorin is a signaling molecule in
      ECs that affects cell survival by Akt-dependent and -independent pathways.

PMID- 12485854
TI  - Induction of cyclooxygenase-2 in Ras-transformed human mammary epithelial cells
      undergoing apoptosis.
AB  - COX-2 expression has been reported to be elevated in several forms of human
      cancer. The presence of oncogenic ras has been associated with constitutive
      induction of COX-2, which confers resistance to apoptosis. Contrary to the above
      notion, we have found that H-ras-transformed human breast epithelial (MCF10A-ras)
      cells treated with the anticancer drug ET-18-O-CH(3) exhibit an increased
      expression of COX-2, while they still undergo apoptosis. To determine whether the
      induction of COX-2 by ET-18-O-CH(3) could contribute to apoptosis in MCF10A-ras
      cells, the selective COX-2 inhibitor celecoxib (SC-58635) was used. Celecoxib
      treatment attenuated ET-18-O-CH(3)-induced cell death. Taken together, the above
      findings suggest that COX-2 up-regulation does not necessarily confer the
      resistance to apoptosis in ras-transformed cells, but rather may sensitize these
      cells to apoptotic death.

PMID- 12485855
TI  - Activation of the p38 MAPK and ERK1/2 pathways is required for Fas-induced IL-8
      production in colonic epithelial cells.
AB  - This paper aims to examine the contribution of all three of the MAP kinase
      signaling pathways to Fas-induced IL-8 up-regulation in HT29 colon epithelial
      cells.

PMID- 12485856
TI  - Treating Crohn's disease by inducing T lymphocyte apoptosis.
AB  - Apoptosis is one of the most important regulatory mechanisms in immunological
      homeostasis. Disturbances in the apoptotic pathways lead to autoimmune disease.
      Crohn's disease is a chronic inflammatory bowel disease of unknown origin, which
      seems to be mediated by excessive T cell-mediated immunity. Recently,
      disturbances in apoptotic pathways of lamina propria T lymphocytes of patients
      with Crohn's disease have been identified. In the uninflamed, normal intestinal
      mucosa, lamina propria (LP) T cells are susceptible to activation-induced cell
      death, but these cells show a resistance to apoptosis based on several
      disturbances compared to controls. Recently, intriguing data were published using
      cytokine-targeted therapy (anti-IL12, anti-IL6 receptor, anti-TNF). Actually,
      these medications restored mucosal immunological imbalance by inducing apoptosis
      of the LP T cells and seemed to be beneficial in models of Crohn's disease. In
      this review, mechanisms of immunological homeostasis will be discussed. We will
      also discuss the fascinating new results of cytokine-targeted therapy in animal
      models of Crohn's disease and the effects of these drugs in patients with Crohn's
      disease.

PMID- 12485857
TI  - Signaling pathways leading to apoptosis or survival in immature and mature B
      cells.
AB  - In the absence of phosphorylated Gab2, immature B cells are unable to maintain a
      prolonged signal transduction, which is necessary for the transcriptional
      regulation and activation of the cells. Thus, the lack of Gab2 phosphorylation
      may drive immature B cells to apoptosis.

PMID- 12485858
TI  - Extracellular ATP induces phosphatidylserine externalization earlier than nuclear
      apoptotic events in thymocytes.
AB  - The present study shows for the first time that ATP(ec) induces a very early PS
      exposure in thymocytes and that this process can be induced in the absence of
      Ca(2+) influx and caspase activation.

PMID- 12485859
TI  - Involvement of sphingosine in dexamethasone-induced thymocyte apoptosis.
AB  - It is generally accepted that ceramide plays an essential role in apoptosis. In
      this study we suggest that in thymocytes, dexamethasone-induced apoptosis is
      mediated by sphingosine rather than ceramide, through the activation of an aSMase
      and a cerase in a caspase-dependent manner.

PMID- 12485860
TI  - Increased in vitro cytotoxicity of TNF-alpha analog LK-805 is based on the
      interaction with cell surface heparan sulfate proteoglycan.
AB  - Our tumor necrosis factor-alpha (TNF-alpha) analog LK-805 (E107K) exhibited
      twofold higher specific cytotoxicity on the mouse fibroblast L-929 cell line than
      its native counterpart. In addition, significantly lowered systemic toxicity was
      observed in tumor-bearing mouse models treated with this analog. Due to a charge
      reversal and clustering of three lysines in the exposed tip region of LK-805, we
      assumed that additional ionic interactions between the positively charged TNF
      analog and the negatively charged components of the cell surface were created,
      which might contribute to improved properties of LK-805. To prove this
      hypothesis, we designed truncated forms of TNF-alpha and analog LK-805 and
      performed three independent sets of experiments: measurement of cytotoxic
      activity in the presence of excess heparan sulfate, determination of cytotoxic
      activity on heparinase-treated L-929 cells, and binding of various TNF-alpha
      proteins onto the heparin-sepharose affinity column. Cytotoxicity studies of both
      kinds confirmed the pivotal role of the E107K mutation for interaction with
      heparan sulfate proteoglycans on the cell surface of L-929 cells. However,
      heparin-binding studies revealed that intact, full-length N-termini of TNF-alpha
      or its analogs were necessary for high retention on the heparin affinity column,
      whereas the three-lysine containing tip of LK-805 by itself was not enough for
      binding. Obviously, immobilized heparin does not represent an adequate model for
      membrane-bound heparan sulfate proteoglycans of L-929 cells.

PMID- 12485861
TI  - TNF-alpha potentiates IL-4/IL-13-induced IL-13Ralpha2 expression.

PMID- 12485862
TI  - Epidermal growth factor receptor ligands and tumor necrosis factor-alpha
      coregulate chemokine expression in human keratinocytes.

PMID- 12485863
TI  - Hepatocytes transgenic for the full hepatitis C virus open reading frame are
      resistant to fas-induced cell death.

PMID- 12485864
TI  - Involvement of protein kinase C in fluoride-induced apoptosis in different types
      of lung cells.

PMID- 12485865
TI  - Selenite inhibits apoptosis via activation of the PI3-K/Akt pathway.

PMID- 12485866
TI  - Activation of the phosphatidylinositol-3'-kinase/protein kinase B-dependent
      antiapoptotic pathway plays an important role in the development of
      radioresistance of human glioma cells.

PMID- 12485867
TI  - beta-Amyloid induces oxidative DNA damage and cell death through activation of c
      Jun N terminal kinase.
AB  - Oxidative stress induced by reactive oxygen species has been implicated in the
      pathophysiology of many neurodegenerative disorders including Alzheimer's disease
      (AD). In this study, we have investigated the molecular mechanisms underlying
      oxidative cell death induced by beta-amyloid, a neurotoxic peptide associated
      with senile plaques found in the brains of patients with AD. PC12 cells treated
      with beta-amyloid underwent apoptotic cell death as determined by characteristic
      morphological features, cleavage of poly(ADP-ribose)polymerase, and positive in
      situ terminal-end labeling (TUNEL). Furthermore, beta-amyloid treatment led to
      activation of c-Jun N terminal kinase (JNK) and intracellular accumulation of
      ROS. In another experiment, beta-amyloid caused strand scission in phiX174 DNA in
      the presence of ferrous iron. These findings suggest that production of ROS and
      subsequent activation of JNK play an important role in beta-amyloid-induced
      apoptotic cell death.

PMID- 12485868
TI  - Activation of the c-Jun N terminal kinase pathway in an animal model of
      Parkinson's disease.
AB  - In neuronal stress and degeneration, mitogen-activated protein (MAP) kinase
      signaling pathways play an important role. We studied the pattern of activation
      of the c-Jun N terminal kinase (JNK) signal transduction pathway during the
      course of a subacute MPTP mouse model of Parkinson's disease. In this model,
      there was no significant neuronal loss, but the function of the dopaminergic
      neurons was significantly decreased. During MPTP administration, phosphorylation
      of p-Jun was increased in the substantia nigra, and MKK4 was increased both in
      the striatum and substantia nigra. We conclude that after MPTP intoxication in
      the mouse, activation of the JNK pathway occurs both in the striatum and in the
      substantia nigra. This activation does not seem to corrrelate with loss of
      neuronal cell bodies but might represent a response to damage/loss of axonal
      terminals.

PMID- 12485869
TI  - The role of mitogen-activated protein kinases and their relationship with NF
      kappaB and PPARgamma in indomethacin-Induced apoptosis of colon cancer cells.
AB  - We have evaluated the role of mitogen-activated protein kinases (MAPKs) and their
      relationship with nuclear factor kappaB (NF-kappaB) and peroxisome proliferator
      activated receptor gamma (PPARgamma) in indomethacin-induced apoptosis of colon
      cancer cells. We demonstrated that indomethacin can induce the prolonged
      activation of MAPKs in colon cancer cells; and that of these MAPKs, p38 MAPK may
      play a partial but significant role in indomethacin-induced apoptosis.
      Furthermore, indomethacin-induced p38 MAPK-mediated apoptosis of colon cancer
      cell lines is independent of caspase activation and not associated with
      indomethacin-induced NF-kappaB suppression and PPARgamma activation.

PMID- 12485870
TI  - Prodigiosin induces caspase-9 and caspase-8 activation and cytochrome C release
      in Jurkat T cells.
AB  - Prodigiosin (PG) is an active component of bacterial origin, with reported
      apoptotic effects. We examined the activation of caspases-9, -8, and -3 in PG
      treated Jurkat cells in a dose-response study. These caspases were activated in
      apoptotic cells, as judged by the appearance of cleavage products from
      procaspases, and cytochrome c (cyt c) was released to the cytosol. In addition,
      PG induced the cleavage of poly (ADP-ribose) polymerase (PARP). This study
      demonstrates that the activation of caspases-9, -8, and -3 mediates PG-induced
      apoptosis.

PMID- 12485872
TI  - Low-dose radiation-induced adaptive response in the murine system.

PMID- 12485871
TI  - Curcumin induces caspase-3-independent apoptosis in human multidrug-resistant
      cells.
AB  - Curcumin, the major component of the spice turmeric, used in 50- micro M
      concentration, induced cell death in multidrug-resistant CEM(P-gp4) and LoVo(P
      gp4) cells as well as in their sensitive counterparts as assessed by TUNEL method
      and morphological observation. In all cells induced to undergo cell death with
      curcumin, there was no caspase-3 activation because only the unprocessed form of
      caspase-3 was observed using immunoblotting.

PMID- 12485873
TI  - Nucleolus and apoptosis.
AB  - The nucleolus represents a highly dynamic nuclear compartment of the interphase
      nucleus. It plays a key role in ribosome biogenesis. The number of nucleoli,
      their size, and their activity increase in exponentially growing cells; therefore
      these parameters reflect the proliferating activity of the cells. A variety of
      staining techniques have been employed to vizualize nucleolar changes in
      malignant cells. Staining of so-called nucleolar organizer regions (NORs), based
      upon a strong avidity of nucleolar proteins to bind silver ions, represents the
      technique most frequently used by pathologists. Nucleolar changes and
      pleomorphism associated with overt proliferation of tumor cells have also been
      documented by immunohistochemical and ultrastructural studies. Contrary to cell
      proliferation, cytostatics-induced changes of nucleolar phenotype in malignant
      cells point to a potential role of nucleolar components in the execution of
      active cell death. Recent studies have provided direct clues that so-called death
      domains and other apoptosis-related proteins are accumulated in nucleoli upon
      induction of active cell death. It can be concluded that the plurifunctionality
      of nucleoli regarding cell proliferation and apoptosis could open new vistas
      toward understanding dysregulation in malignant cells.

PMID- 12485874
TI  - Activation and phosphorylation on Thr-160 of nuclear-targeted CDK2 Is ERK
      dependent.

PMID- 12485875
TI  - Association of Bcl-2 with cyclin a/Cdk-2 complex and its effects on Cdk-2
      activity.
AB  - In the human endometrial carcinoma cell line HEC1B, the overexpression of Bcl-2
      leads to a G2/M cell cycle arrest. The experiments presented in this work suggest
      a direct interaction between the antiapoptotic protein Bcl-2 and the cyclin
      dependent kinase Cdk-2 and suggest that such interaction is cell cycle dependent.
      While further experiments are currently under way in our laboratory to elucidate
      the significance of Cdk-2/Bcl-2 complexes in PCD and cell cycle regulation, we
      demonstrate also a specific inhibitory function of Bcl-2 on the activity of the
      coprecipitated kinase.

PMID- 12485876
TI  - Dynamic localization/association of protein kinase CK2 subunits in living cells:
      a role in its cellular regulation?
AB  - Accumulating evidence indicates that in addition to the classical complex, the
      catalytic and regulatory subunits of CK2 can also exist as free populations in
      living cells. The association of recombinant CK2 subunits in vitro has been
      characterized, providing evidence for the first time for their targeted
      interactions in living cells. The data also suggest that the regulation by
      phosphorylation of many CK2 substrates may strongly depend on the dynamic
      localization/association of its subunits.

PMID- 12485877
TI  - Cigarette smoke-induced oxidative stress and TGF-beta1 increase p21waf1/cip1
      expression in alveolar epithelial cells.
AB  - Sustained oxidative stress caused by cigarette smoking induces a chronic
      inflammatory response, resulting in the destruction of the alveolar cell wall
      characteristic of emphysema. The loss of tissue may involve the progressive
      depletion of epithelial cells through inhibition of proliferation leading to cell
      death. The cell cycle regulator p21(waf1/cip1) acts as a G(1)/S and G(2)/M phase
      checkpoint regulator. We hypothesize that cigarette smoke-induced oxidative
      stress and transforming growth factor beta 1 (TGF-beta(1)) may inhibit cellular
      proliferation by p21(waf1/cip1) in type II alveolar epithelial cells (A549). A
      significant increase was observed in p21(waf1/cip1) mRNA expression in A549 cells
      by cigarette smoke condensate, H(2)O(2), and TGF-beta(1). In conclusion,
      cigarette smoke-induced oxidative stress and TGF-beta(1) modulate expression of
      the cell cycle inhibitor p21(waf1/cip1). This may be important in the growth
      arrest and cell survival of alveolar type II cells in the G(1) phase.

PMID- 12485879
TI  - Metamorphosis of the selenoprotein PHGPx during spermatogenesis.

PMID- 12485878
TI  - Assessment of p16, p21, and p27 in granulocytic differentiation of human
      promyelocytic HL-60 cell line.

PMID- 12485880
TI  - Detection and characterization of membrane-bound selenoproteins in the kidney of
      the rat.
AB  - The essential trace element selenium is of fundamental importance to human
      biology. Information on the membrane-bound selenoproteins was obtained by
      labeling of rats in vivo with (75)Se-selenite, subcellular fractionation of the
      tissue homogenates, separation of the proteins by SDS-PAGE, two-dimensional
      electrophoresis, and selenium detection by autoradiography. In this way, in
      addition to already known membrane-bound selenoproteins three novel
      selenoproteins in the molecular mass range of 38-40, 18, and 12-13 kDa were
      detected in the microsomal membranes.

PMID- 12485881
TI  - Decreased expression of glucose transport protein (Glut3) in aging and vitamin E
      deficiency.

PMID- 12485882
TI  - Implication of copper zinc superoxide dismutase (SOD-1) in human placenta
      development.

PMID- 12485883
TI  - The role of lipid rafts in T lymphocyte signal transduction with aging.

PMID- 12485884
TI  - The role of Mcl-1 and Bax expression alteration in the decreased rescue of human
      neutrophils from apoptosis by GM-CSF with aging.

PMID- 12485885
TI  - Proteasome inhibition enhances lipofuscin formation.
AB  - Lipofuscin, a hallmark of aged nondividing cells, is an undegradable
      autofluorescent intralysosomal substance composed essentially of oxidized, cross
      linked proteins. To test whether impaired activity of proteasomes-which, along
      with lysosomes, belong to major cellular proteolytic systems-may contribute to
      lipofuscinogenesis, we exposed growth-arrested human fibroblasts to subapoptotic
      doses (2 and 5 nM) of a highly specific proteasome inhibitor, MG-262. This
      resulted in accelerated lipofuscin accumulation (especially when MG-262 exposure
      was combined with mild hyperoxia-i.e., cultivation at 40% ambient oxygen versus
      8% for controls); and enhanced immunostaining for ubiquitin, reflecting
      accumulation of modified cytosolic proteins subjected for degradation, and
      cathepsin L, reflecting enlargement of the lysosomal compartment. These data
      suggest that insufficient proteasomal function may contribute to
      lipofuscinogenesis by a compensatory increase in the amount of proteins that are
      difrected for lysosomal degradation. The findings may be helpful for the
      understanding of cellular aging as well as diseases associated with
      intralysosomal accumulation of undegradable material.

PMID- 12485886
TI  - Effects of ethanol on GAP-43 levels in hippocampus and cerebellum of aged rats.

PMID- 12485887
TI  - Potential intervention by vaccinia virus complement control protein of the
      signals contributing to the progression of central nervous system injury to
      Alzheimer's disease.
AB  - Traumatic brain injury (TBI) is one of the few known risk factors for Alzheimers
      disease (AD) and for depression. The mechanisms by which trauma causes delayed
      cognitive deficits are largely unknown. In recent studies, it was demonstrated
      that the complement system (an important component of the immune system and a
      mediator of inflammation) is activated both in human AD and following
      experimental TBI in rats. Amyloid proteins are also present in AD and following
      TBI, and are known to activate complement in vitro. Based on these and other
      previous studies, it was hypothesized that regulation of the complement system
      will attenuate the long-term consequences of TBI. Vaccinia virus complement
      control protein (VCP) is a protein encoded by vaccinia virus. It blocks both the
      classic and alternative pathways of complement activation in vitro, and by doings
      so prevents the generation of proinflammatory chemotactic factors. Based on in
      vitro studies VCP can block the complement activation by the amyloid beta
      peptide. Using a fluid percussion rat model that causes traumatic brain injury
      (TBI), it was found that VCP significantly enhances functional recovery as
      determined by the Morris Water Maze test. Taken togther these studies indicate
      that potentially VCP could block molecular signals such as the formation of
      amyloid beta or the activation of complement to inhibit formation of AD following
      TBI.

PMID- 12485888
TI  - Signal transduction through tyrosine-phosphorylated carboxy-terminal fragments of
      APP via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive
      astrocytes of Alzheimer's disease brain.
AB  - The processing of the amyloid precursor protein (APP) through the formation of C
      terminal fragments (CTFs) and the production of beta-amyloid, are events likely
      to influence the development and the progression of Alzheimer's disease (AD). APP
      is a transmembrane protein similar to a cell-surface receptor with the
      intraluminal NPTY motif in the cytosolic C terminus. Although APP holoprotein can
      be bound to intracellular proteins like Fe65, X11, and mDab, the ultimate
      function and the mechanisms through which this putative receptor transfers its
      message are unclear. Here it is shown that in human brain, a subset of tyrosine
      phosphorylated CTFs represent docking sites for the adaptor protein ShcA. ShcA
      immunoreactivity is greatly enhanced in Alzheimer's patients; it is mainly
      localized to glial cells and occurs at reactive astrocytes surrounding cerebral
      vessels and amyloid plaques. Grb2 also is involved in complexes with ShcA and
      tyrosine-phosphorylated CTFs, and in AD brain the interaction between Grb2-ShcA
      and CTFs is enhanced. Also, a higher amount of phospho-ERK1,2 is present in AD
      brain in comparison with control cases, likely as a result of the ShcA
      activation. In vitro experiments show that the ShcA-CTFs interaction is strictly
      confined to glial cells when treated with thrombin, which is a well-known ShcA
      and ERK1,2 activator, mitogen, and regulator of APP cleavage. In untreated cells
      ShcA does not interact with either APP or CTFs, although they are normally
      produced. Altogether these data suggest that CTFs are implicated in cell
      signaling via Shc transduction machinery, likely influencing MAPK activity and
      glial reaction in AD patients.

PMID- 12485889
TI  - The role of the carboxyl-terminal fragments of amyloid precursor protein in
      Alzheimer's disease.
AB  - Two major pathological hallmarks of Alzheimer's disease (AD) are the senile
      plaques that are primarily composed of amyloid beta-peptide (Abeta) and
      neurofibrillary tangles consisting of tau aggregates. Abeta is generated
      proteolytically from a family of Abeta-containing precursor proteins (APP; 695
      770 amino acid) by secretase enzymes to different specific carboxyl-terminal
      fragments (CTFs). Herein we examined APP and its products in autopsied brain
      sections from 10 AD and 10 non-AD control subjects immunochemically using an
      antibody that was raised against APP751-770 residue (O443). The O443 antibody was
      initially characterized by Western blot analysis and immunoprecipitation. In this
      study, we used this antibody for immunohistochemical analysis to determine the
      distribution of APP and its CTF species. In 10 brain regions showing different
      levels of plaques and tangles, antibody O443 stained the perinuclear region of
      the nucleus, plaques, and neurites. Tangle-bearing neurons also appeared to stain
      with the antibody, suggesting that these dysfunctional neurons continue to
      synthesize APP/CTF. Alternatively, the normally short-lived APP/CTF can be
      stabilized and persist in these neurons. Taken together, these results suggest
      that, in addition to the widely believed role of Abeta, CTFs may play a key role
      in the pathogenesis of AD. Studying their localization and biogenesis may reveal
      the biological activities of CTFs of APP. The present study may pave the way for
      possible antiamyloidogenic therapy in the treatment of AD.

PMID- 12485890
TI  - Functional characterization of the 5'-regulatory region of the murine
      apolipoprotein gene.
AB  - The apolipoprotein E (APOE) gene causes a major risk factor for the development
      of Alzheimer's disease (AD). To study the transcription control of the mouse (m)
      APOE gene, we first tested the promoter activity of a 721-base-pair (bp) 5'
      flanking region, which is located 771 bp upstream from the translation initiation
      codon. We cloned the 721-bp region upstream of the reporter chloramphenicol
      acetyl transferase (CAT) gene into a promoterless vector (pBLCAT3). The mAPOE
      promoter and vector DNA were separately transfected in rat glial C6 and neuronal
      PC12 cell lines. The 721-bp APOE region (from position 329 to 1050) is
      functionally active in different cell lines tested. The serial deletion analysis
      indicates that the 266-bp promoter region (from 784 to 1050) has the highest and
      the 67-bp region (from 983 to 1050) the lowest activity on the reporter gene in
      neuronal and astrocytic cell lines. These studies suggest that the 147-bp region
      (from 637 to 784) has a negative regulatory effect on the reporter gene. In the
      gel shift assay, the 67-bp region binds to a specific transcription factor(s) in
      PC12 nuclear extracts. Our results suggest that mAPOE can also be expressed in
      neuronal cells in addition to the astrocytic cells. Characterization of mAPOE
      promoter is important for the AD drug development discovery and APOE transgenic
      mice studies.

PMID- 12485891
TI  - Vanadate inhibition of protein tyrosine phosphatases mimics hydrogen peroxide in
      the activation of the ERK pathway in alveolar macrophages.

PMID- 12485893
TI  - Inhibition of p38 MAP kinase corrects biochemical and neurological deficits in
      experimental diabetic neuropathy.
AB  - Diabetes is known to activate MAP kinase p38 in sensory neurons in both rats and
      patients. In vitro, activation of p38 in sensory neurons by combined glucose and
      oxidant stress causes cell damage or death. Consequently we tested the hypothesis
      that inhibition of MAP kinase p38 might prevent neuronal dysfunction in rats with
      experimental diabetes, such as the classical defect of slowed nerve conduction.
      Thus, treatment of streptozotocin-diabetic rats with the p38 inhibitor SB239063
      for the second half of a 12-week diabetes protocol selectively prevented the
      nerve conduction deficit in sensory neurons. This implicates activation of MAP
      kinase p38 as an early step in the signal pathway to dysfunction in experimental
      diabetic neuropathy.

PMID- 12485892
TI  - From extracellular to intracellular targets, inhibiting MAP kinases in treatment
      of Crohn's disease.
AB  - In recent years the emphasis in finding new therapeutic options for chronic
      inflammatory diseases has been on targeting extracellular mediators of
      inflammation. A range of tools has become available to interfere with signaling
      by cytokines and their receptors. As our understanding of the intracellular
      pathways that mediate inflammatory signals expands, new therapeutic targets
      within the inflammatory cells come into sight. In this review we will discuss
      possible intracellular targets for treatment in Crohn's disease, a chronic
      relapsing inflammatory disease of the gut. Despite the encouraging results with
      anti-TNF antibodies in patients with Crohn's disease, our current treatment
      options are still insufficient and warrant novel treatment strategies. The
      mitogen-activated protein kinase (MAPK) family of signal transduction proteins is
      an important intracellular mediator of inflammation, and recently a MAPK
      inhibitor was successfully used in patients with Crohn's disease. We will discuss
      our current understanding of the molecular pathophysiology of Crohn's disease and
      also novel therapies that specifically target members of the MAPK pathway.

PMID- 12485894
TI  - Elucidation of transcriptional elements and the genomic structure of DAP-like
      kinase.

PMID- 12485895
TI  - Modulation of kinase activity by polyphenols.

PMID- 12485896
TI  - Enhancement of radioresponse of murine tumors by ERK inhibitor.

PMID- 12485897
TI  - Regulation of p53: intricate loops and delicate balances.
AB  - The p53 tumor suppressor protein provides a major anti-cancer defense mechanism,
      as underscored by the fact that the p53 gene is the most frequent target for
      genetic alterations in human cancer. Recent work has led to the realization that
      p53 lies at the hub of a very complex network of signaling pathways that
      integrate a variety of intracellular and extracellular inputs. Part of this
      network consists of an array of autoregulatory feedback loops, where p53 exhibits
      very intricate interactions with other proteins known to play important roles in
      the determination of cell fate. We discuss two such loops, one involving the beta
      catenin protein and the other centering on the Akt/PKB protein kinase. In both
      cases, the central module is the interplay between p53 and the Mdm2 protein,
      which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated
      beta-catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can
      promote the degradation and down-regulation of beta-catenin. Similarly, Akt can
      block p53 activation by potentiating Mdm2, whereas activated p53 can tune down
      Akt in several different ways. In each case, the actual output of the loop is
      determined by the delicate balance between the opposing effects of its different
      components. Often, this balance is dictated by additional signaling processes
      that occur simultaneously within the same cell. Genetic alterations
      characteristic of cancer are capable of severely distorting this balance, thereby
      overriding the tumor suppressor effects of p53 in a manner that facilitates
      neoplastic conversion.

PMID- 12485898
TI  - The roles of p53, DNA repair, and oxidative stress in ultraviolet C induction of
      proliferating cell nuclear antigen expression.
AB  - The expression of proliferating cell nuclear antigen (PCNA) promoter was
      moderately induced in UV-irradiated, quiescent human and rodent cells. The
      induction was independent of tumor suppressor gene p53, because the PCNA
      expression was UV-inducible in the subclones of human fibroblasts in which the
      activity of p53 was abrogated by human papilloma virus E6. Furthermore, the
      induction did not depend on DNA repair, since PCNA was UV inducible in UVL-10 and
      xrs-6 cells, in which nucleotide excision repair and double-stranded repair,
      respectively, are largely compromised. However, the induction was inhibited by
      antioxidant N-acetylcysteine. The role of oxidative stress observed here is
      consistent with the previous finding that the proximal AP-1 site is critical to
      the UV inducibility of PCNA promoter.

PMID- 12485899
TI  - Chemopreventive agents induce suppression of nuclear factor-kappaB leading to
      chemosensitization.
AB  - Nuclear factor-kappaB (NF-kappaB), a transcription factor, is present normally in
      the cytoplasm as an inactive heterotrimer consisting of p50, p65, and
      IkappaBalpha subunits. When activated, NF-kappaB translocates to the nucleus as a
      p50-p65 heterodimer. This factor regulates the expression of various genes that
      control apoptosis, viral replication, tumorigenesis, various autoimmune diseases,
      and inflammation. NF-kappaB has been linked to the development of carcinogenesis
      for several reasons. First, various carcinogens and tumor promoters have been
      shown to activate NF-kappaB. Second, activation of NF-kappaB has been shown to
      block apoptosis and promote proliferation. Third, the tumor microenvironment can
      induce NF-kappaB activation. Fourth, constitutive expression of NF-kappaB is
      frequently found in tumor cells. Fifth, NF-kappaB activation induces resistance
      to chemotherapeutic agents. Sixth, several genes involved in tumor initiation,
      promotion, and metastasis are regulated by NF-kappaB. Seventh, various
      chemopreventive agents have been found to down-regulate the NF-kappaB activation.
      All these observation suggest that NF-kappaB could mediate tumorigenesis and thus
      can be used as a target for chemoprevention and for the treatment of cancer.
      Agents that suppress NF-kappaB activation can suppress the expression of genes
      involved in carcinogenesis and tumorigenesis in vivo.

PMID- 12485900
TI  - Effects of selected ginsenosides on phorbol ester-induced expression of
      cyclooxygenase-2 and activation of NF-kappaB and ERK1/2 in mouse skin.
AB  - Our previous studies have demonstrated that the methanol extract of heat
      processed Panax ginseng C.A. Meyer exerts antioxidative, antiinflammatory, and
      anti-tumor-promoting effects. In the present study, we examined the
      antiinflammatory effects of several ginsenosides (Rb(1), Rc, Re, Rg(1), Rg(3))
      derived from P. ginseng. Topical application of each of these ginsenosides
      significantly attenuated ear edema induced by 12-O-tetradecanoylphorbol-13
      acetate (TPA). These ginsenosides also suppressed expression of cyclooxygenase-2
      (COX-2) and activation of NF-kappaB in the TPA-treated dorsal skin of mice. Of
      the ginsenosides tested, Rg(3) was found to be most effective in terms of
      inhibiting TPA-induced ear edema, COX-2 expression, and NF-kappaB activation.

PMID- 12485901
TI  - Proteasome inhibitors induce cerebellar granule cell death: inhibition of nuclear
      factor-kB activation.
AB  - Many activities of neuronal cells, such as synaptic transmission, inflammation,
      neuroprotection, and neurotoxicity, are regulated by the activity of the
      transcription factor nuclear factor-kappaB (NF-kappaB). In resting cells, NF
      kappaB activity is present both in the cytoplasm, as an inducible-inactive
      complex, and in the nucleus as a constitutive form. The activation of its
      inducible form is related to processing of IkappaB(s), which occurs through the
      proteasome. To understand whether NF-kappaB is involved in the survival of
      cerebellar granule cells (CGCs) maintained under conditions of mild
      depolarization (25 mM KCl), these cells were treated with different proteasome
      inhibitors. The results presented show that these pharmacological tools reduce
      CGC survival with changes in nuclear morphology and induction of apoptosis.
      Furthermore, we demonstrate that PSI-induced apoptosis is reverted by inhibitors
      of transcription and translation, as well as by specific caspase inhibitors.
      These issues are also associated with a redistribution of NF-kappaB, in that a
      reduced amount of nuclear NF-kappaB and an increased p65 cytoplasmic level have
      been observed. Finally, we propose that, at least in part, p65 metabolism could
      also be regulated by the ubiquitin-proteasome complex. Altogether, the results
      presented define an important role for NF-kappaB in maintainig CGC survival.

PMID- 12485902
TI  - Thalidomide suppresses the interleukin 1beta-induced NFkappaB signaling pathway
      in colon cancer cells.
AB  - Thalidomide has been shown to have both antiinflammatory and antiangiogenic
      effects in several diseases. However, its cellular target and mechanism of action
      are poorly understood. We investigated the action mechanism of thalidomide
      through the NFkappaB pathway. Thalidomide inhibited interleukin (IL) 1beta
      induced NFkappaB transcriptional activation and IL-8 production in Caco-2 colon
      cancer cells. In addition, thalidomide suppressed NFkappaB nuclear translocation,
      IkappaB degradation, and NFkappaB-inducing kinase (NIK)-induced NFkappaB
      transcriptional activation. These results suggest that the molecular target of
      the effects of thalidomide may be IkappaB phosphorylation by IkappaB kinase
      (IKK), whose activation follows NIK activation and precedes IkappaB degradation
      in the NFkappaB pathway.

PMID- 12485903
TI  - Multiple redox regulation of the cellular signaling system linked to AP-1 and
      NFkappaB: effects of N-acetylcysteine and H2O2 on the receptor tyrosine kinases,
      the MAP kinase cascade, and IkappaB kinases.

PMID- 12485904
TI  - Rapid estradiol activation of AP-1 and CREB in rat white adipocytes.

PMID- 12485906
TI  - Antiinflammatory action of EGCG, the main component of green tea, through STAT-1
      inhibition.

PMID- 12485905
TI  - Multiple degradation pathways for Fos family proteins.
AB  - c-Fos protooncoprotein is a short-lived transcription factor with oncogenic
      potential. It is massively degraded by the proteasome in vivo under various
      experimental conditions. Those include consititutive expression in exponentially
      growing cells and transient induction in cells undergoing the G0/G1 phase
      transition upon stimulation by serum. Though there is evidence that c-Fos can be
      ubiquitinylated in vitro, the unambigous demonstration that prior
      ubiquitinylation is necessary for degradation by the proteasome in vivo is still
      lacking. c-Jun, one of the main dimerization partners of c-Fos within the AP-1
      transcription complex, is also an unstable protein. Its degradation is clearly
      proteasome dependent. However, several lines of evidence indicate that the
      mechanisms by which it addresses the proteasome are different from those
      operating on c-Fos. Moreover, genetic analysis has indicated that c-Fos is
      addressed to the proteasome via pathways that differ depending on the conditions
      of expression. c-Fos has been transduced by two murine osteosarcomatogenic
      retroviruses in mutated forms, which are more stable and more oncogenic. The
      stabilization is not simply accounted for by simple deletion of one of the main c
      Fos destabilizers but, rather, by a complex balance between opposing
      destabilizing and stabilizing mutations. However, although viral Fos proteins
      have acquired full resistance to proteasomal degradation, stabilization is
      limited because the mutations they have accumulated, during or after c-fos gene
      transduction, confer sensitivity to an unidentified proteolytic system(s). This
      observation is consistent with the idea that fos-expressing viruses have evolved
      expression machineries to ensure controlled protein levels in order to maintain
      an optimal balance between prooncogenic and proapoptotic activities of v-Fos
      proteins.

PMID- 12485907
TI  - Constitutive repression of E2F1 transcriptional activity through HDAC proteins is
      essential for neuronal survival.

PMID- 12485908
TI  - CoCl2, a chemical inducer of hypoxia-inducible factor-1, and hypoxia reduce
      apoptotic cell death in hepatoma cell line HepG2.
AB  - HIF-1 (hypoxia-inducible factor-1) is the major transcription factor that is
      specifically activated during hypoxia. This transcription factor is composed of
      two subunits: HIF-1alpha and ARNT (aryl hydrocarbon receptor nuclear
      translocator). ARNT is constitutively expressed, whereas HIF-1alpha is targeted
      to proteasome degradation by ubiquitination during normoxia. In hypoxia, HIF
      1alpha is stabilized and translocates to the nucleus, where it binds to ARNT. The
      active HIF-1 induces expression of various genes whose products play an adaptive
      role to the new conditions induced by hypoxia. Besides the role played by HIF-1
      in the adaptation to hypoxia, recent data describe a possible role for HIF-1 in
      the modulation of apoptosis. According to some authors, hypoxia induces
      apoptosis. However, it has also been reported that hypoxia could protect cells
      against apoptotic cell death induced by various agents such as serum deprivation
      and incubation in the presence of chemotherapy agents. These contradictory data
      suggest that HIF-1 could display either a proapoptotic or an antiapoptotic role
      according to the conditions. In order to study how HIF-1 can modulate apoptosis,
      we studied whether hypoxia or cobalt chloride, a chemical inducer of HIF-1, could
      influence apoptosis induced by tert-butyl hydroperoxide (t-BHP), serum
      deprivation, or both in hepatoma cell line HepG2. HepG2 cells were incubated 8
      hours under normoxia or hypoxia in the presence of t-BHP with or without CoCl2.
      CoCl2 reduced the apoptotic death of HepG2 cells induced by t-BHP and serum
      deprivation, as measured by DNA fragmentation. This effect was confirmed by
      measurement of the caspase activity. Moreover, hypoxia also prevented t-BHP- or
      serum deprivation-induced DNA fragmentation and caspase activation-however, to a
      lower extent than CoCl2. These different data suggest a possible antiapoptotic
      role of HIF-1. More experiments are needed to define if HIF-1 actually plays an
      active role in cell death protection and to determine the exact mechanism
      underlying this effect.

PMID- 12485909
TI  - ERK and calcium in activation of HIF-1.
AB  - HIF-1 (hypoxia-inducible factor-1) is the main transcription factor responsible
      for increased gene expression in hypoxia. The oxygen-dependent regulation of HIF
      1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF
      1alpha protein expression have been most extensively analyzed, but the ones
      modulating HIF-1 transcriptional activity remain unclear. Changes in the
      phosphorylation and/or redox status of HIF-1alpha certainly play a role. Here, we
      show that ionomycin could activate HIF-1 transcriptional activity in a way that
      is additive to the effect of hypoxia without affecting HIF-1alpha protein level
      and HIF-1 DNA binding capacity. In addition, a calmodulin dominant-negative
      mutant as well as BAPTA, an intracellular calcium chelator, inhibited the hypoxia
      induced HIF-1 activation. These results indicate that elevated calcium in hypoxia
      could participate in HIF-1 activation. PD98059, an inhibitor of the ERK pathway,
      but not KN-93, an inhibitor of calmodulin kinases II and IV, also blocked HIF-1
      activation by hypoxia and by ionomycin. Altogether, these results suggest that
      calcium and calmodulin would act upstream of ERK in the hypoxia signal
      transduction pathway leading to enhanced HIF-1 transcriptional activity.

PMID- 12485910
TI  - Transcription of the human prolactin gene in mammary cells.
AB  - Expression of human prolactin in the mammary gland, one of the main target organs
      of this hormone, leads to the formation of an autocrine-paracrine proliferative
      loop in this tissue. Involvement of prolactin in normal and neoplastic mammary
      development triggered the interest in transcriptional regulation of the human
      prolactin gene in mammary cells. Analysis of this regulation, and comparison to
      that in the pituitary, will contribute to a better understanding of mammary gland
      development and tumor formation. Here we present the first extensive analysis of
      the transcriptional regulation of the human prolactin gene in human mammary tumor
      cells.

PMID- 12485911
TI  - Transcriptional inhibition of CYP24 by genistein.
AB  - 1,25 Dihydroxyvitamin D3 (1,25-D3) can be considered an antitumorigenic agent,
      which can be used in the therapy of malignant diseases such as prostate cancer.
      In this respect, it is important to note that some prostatic cancer cells express
      high levels of CYP24, a cytochrome enzyme involved in degradation of 1,25-D3.
      Genistein, a widely occurring isoflavonoid, inhibits cytochrome enzymes and also
      exerts antitumorigenic effects. Here, we therefore investigated the effect of
      genistein on cytochrome enzymes involved in vitamin D metabolism. Treatment of DU
      145 prostatic cancer cells with genistein led to a time- and dose-dependent
      inhibition of CYP24. Additionally CYP27B1 was also inhibited. CYP27B1 is the
      cytochrome enzyme that synthesizes 1,25-D3. RT-PCR showed that the effect of
      genistein was mainly due to inhibition of transcription. This often involves the
      activity of histone deacetylases (HDAC). Thus we tested if the HDAC inhibitor
      trichostatin A (TSA) reversed the effect of genistein on vitamin D hydroxylases.
      TSA per se reduced expression of CYP24 mRNA and synergized with genistein to
      abolish expression after an incubation of 24 h. Importantly, TSA, which itself
      did not affect CYP27B1 expression, rescued CYP27B1 from transcriptional
      inhibition by genistein. In conclusion, our data argue for the use of genistein
      to resensitize prostate cancer cells to 1,25-D3; the addition of TSA may preserve
      the ability of these cells to synthesize 1,25-D3.

PMID- 12485912
TI  - Regulation of promoter activity of the APP gene by cytokines and growth factors:
      implications in Alzheimer's disease.
AB  - One of the major pathological hallmarks of Alzheimer's disease (AD) is the
      presence of brain depositions of senile plaques that are primarily composed of
      potentially toxic amyloid beta-peptide (Abeta), which is generated from a family
      of Abeta-containing precursor proteins (APP; 695-770 amino acids). The role of
      inflammatory cytokines and growth factors has been implicated in the pathogenesis
      of AD. Our goal is to study the effects of these factors on the regulation of APP
      gene expression. Here we compared APP promoter activity in the presence of
      different growth factors and cytokines such as brain-derived neurotrophic factor
      (BDNF), interleukin (IL-1), nerve growth factor (NGF), neurotrofin-3 (NT-3),
      transforming growth factor (TGF-beta1), and tumor necrosis factor (TNF-alpha1).
      PC12 neuronal cells, which were treated separately with these agents, were
      transfected with the construct containing either 190 bp APP proximal promoter
      region (-46 to 144 bp with respect to the transcription start site [+1]), 94 bp
      APP 5'-untranslated region (UTR, +50 to 144) or other 5'-UTR-deleted regions.
      Each construct was cloned upstream of a reporter chloramphenicol acetyl
      transferase gene (CAT). The treatment of PC12 cells with NGF stimulated reporter
      activity in all constructs tested. The treatment of cells with BDNF, NT3, TGF
      beta1, or TNF-alpha stimulated reporter activity in a promoter/UTR-specific
      manner. Transfection with the complete -46 to 144 region retained the maximum
      stimulatory activity for any treatment tested in PC12 cells. These results
      suggest that the regulatory elements of the APP gene respond to the stimulation
      of different growth factors, cytokines, and interleukins. This is consistent with
      the effects of the different growth factors, cytokines, and interleukins on APP
      message and protein levels.

PMID- 12485913
TI  - Transcriptional regulation of the human MDR1 gene at the level of the inverted
      MED-1 promoter region.
AB  - The typical multidrug resistance phenotype (MDR), the major cause of failure of
      cancer chemotherapy, is the result of the overexpression of the human MDR1 gene,
      the regulation of which is still incompletely understood. Using several EMSA
      experiments, we have identified a new regulatory sequence located from -103 to 
      98 bp relative to the +1 start site in the MDR1 promoter region. This sequence,
      which we called inverted MED-1, acts as a cis-activator for this gene. In
      transient transfection experiments of highly resistant human lymphoblastic
      CEM/VLB5 cells, its deletion from the promoter region is responsible for 60%
      inhibition of the MDR1 transcriptional activity. This sequence specifically binds
      a nuclear protein of about 150-160 kDa. We showed that its binding capacity is
      related to the chemoresistance level of the studied cell lines and may reflect
      the increased transcriptional activity of the MDR1 gene in multidrug-resistant
      cells.

PMID- 12485914
TI  - Diminished transcription factor survival signals in dorsal root ganglia in rats
      with streptozotocin-induced diabetes.
AB  - Rats with experimental diabetes show changes in prenuclear signals that might
      impact on neuronal transcription factors; these in turn may be responsible for
      the phenotype switches characteristic of diabetic neuropathies. This study was
      designed to examine the effect of streptozotocin-diabetes of 12 weeks' duration
      on the activation of three transcription factors known to affect neuronal
      phenotype in dorsal root ganglia (DRG). Pooled L4 and L5 were subject to gel
      shift analysis to measure binding to consensus oligonucleotides. This revealed
      significant reduction in activation of CREB and NFkappaB in DRG from diabetic
      rats, but no effect on AP-1. The CREB change may be secondary to target tissue
      NGF depletion, and the reduced NFkappaB indicates impaired capacity to withstand
      neurotrophic defects. Thus, these changes my underlie consequences of impaired
      neurotrophic regulation of phenotype reported in other studies in diabetic rats.

PMID- 12485915
TI  - Cyclooxygenase-2 expression by transcription factors in Helicobacter pylori
      infected gastric epithelial cells: comparison between HP 99 and NCTC 11637.
AB  - Helicobacter pylori, a gram-negative spiral bacterium, has been associated with
      chronic gastritis and gastric cancer. HP 99, isolated from the Korean patients,
      and NCTC 11637, obtained from ATCC, have different genotypes. The present study
      aims to investigate whether these H. pylori strains show the discrepancy for
      activating transcription factors (NF-kappaB, AP-1, C/EBP) and induction of
      cyclooxygenase-2 (COX-2) gene in gastric epithelial AGS cells. After treatment of
      H. pylori to AGS cells at the ratio of 300:1, the activation of transcription
      factors was assessed by electrophoretic mobility shift assay. COX-2 protein was
      determined by Western blot analysis. The level of 6-keto-prostaglandin F(1alpha)
      (6-keto-PGF(1alpha)), a COX-2 product, was measured in the medium by enzyme
      linked immunosorbent assay. As a result, both H. pylori strains similarly induced
      COX-2 expression via activation of NF-kappaB, not C/EBP, and increased the level
      of 6-keto-PGF(1alpha). HP 99 showed much higher activation of AP-1 compared to
      NCTC 11637. NF-kappaB might play an important role in COX-2 expression in H.
      pylori-induced gastric inflammation as compared to other transcription factors.

PMID- 12485916
TI  - Triamcinolone acetonide and dexamethasome suppress TNF-alpha-induced histone H4
      acetylation on lysine residues 8 and 12 in mononuclear cells.

PMID- 12485917
TI  - Steroid receptors in various glial cell lines expression and functional studies.
AB  - In glial cell lines from the central (CG4, C6) and peripheral (MSC80, CR3a1, and
      CR1b4) nervous systems, glucocorticoid receptor (GR) messenger RNA was clearly
      detected and was consistent with significant GR binding and transcriptional
      activity. Mineralocorticosteroid receptor mRNA was less abundant, with no
      corresponding binding and lack of transcriptional activity. Other steroid
      receptors were not significantly detected.

PMID- 12485918
TI  - Glutathione in defense and signaling: lessons from a small thiol.
AB  - The mechanisms of thiol metabolism and chemistry have particular relevance to
      both cellular defenses against toxicant exposure and to redox signaling. Here, we
      will focus on glutathione (GSH), the major endogenous low- molecular-weight
      nonprotein thiol synthesized de novo in mammalian cells. The major pathways for
      GSH metabolism in defense of the cell are reduction of hydroperoxides by
      glutathione peroxidases (GSHPx) and some peroxiredoxins, which yield glutathione
      disulfide (GSSG), and conjugation reactions catalyzed by glutathione-S
      transferases. GSSG can be reduced to GSH by glutathione reductase, but
      glutathione conjugates are excreted from cells. The exoenzyme gamma
      glutamyltranspeptidase (GGT) removes the glutamate from extracellular GSH,
      producing cysteinyl-glycine from which a dipeptidase then generates cysteine, an
      amino acid often limiting for de novo GSH synthesis. Synthesis of GSH from the
      constituent amino acids occurs in two regulated, enzymatically catalyzed steps.
      The signaling pathways leading to activation of the transcription factors that
      regulate these genes are a current area of intense investigation. The elucidation
      of the signaling for GSH biosynthesis in human bronchial epithelial cells in
      response to 4-hydroxynonenal (4HNE), an end product of lipid peroxidation, will
      be used as an example. GSH also participates in redox signaling through the
      removal of H(2)O(2), which has the properties of a second messenger, and by
      reversing the formation of sulfenic acid, a moiety formed by reaction of critical
      cysteine residues in signaling proteins with H(2)O(2). Disruption of GSH
      metabolism will therefore have major a impact upon function of cells in terms of
      both defense and normal physiology.

PMID- 12485919
TI  - Redox signaling through NADPH oxidases: involvement in vascular proliferation and
      coagulation.
AB  - Reactive oxygen species (ROS) have been shown to play important functions as
      signaling molecules in the vasculature. Several NADPH oxidase isoforms have been
      identified in endothelial and smooth muscle cells, which are largely responsible
      for basal and stimulated ROS production in these cells. Moreover, evidence
      increases that activation of these enzymes contributes to stimulation of
      signaling cascades modulating essential functions in the vasculature such as
      endothelial and smooth muscle cell proliferation as well as thrombosis.

PMID- 12485920
TI  - Redox control by dithiol-disulfide exchange in plants: I. The chloroplastic
      systems.
AB  - In plants, the photons of light are absorbed at the level of the photosystems in
      the chloroplasts. The functioning of the photosynthetic electron transfer chain
      linked to this process is required to generate NADPH and ATP. In addition, the
      light signal promotes a regulatory cascade, situated in the stroma, that involves
      ferredoxin, ferredoxin-thioredoxin reductase, and thioredoxins. This redox-based
      signal transduction chain allows fine regulation of stromal enzymes and tight
      control of the photosynthetic process. The molecular properties and the
      functioning of this redox regulatory chain will be described in this review.

PMID- 12485921
TI  - Redox control by dithiol-disulfide exchange in plants: II. The cytosolic and
      mitochondrial systems.
AB  - This paper describes the existence of two pathways efficient in the reduction of
      disulfide bridges on selected proteins and mitochondria of photosynthetic
      organisms. The first is constituted by NADPH, the flavoenzyme NADPH thioredoxin
      reductase, and thioredoxin; and the second by NADPH, glutathione reductase,
      glutathione, and glutaredoxin. Molecular details concerning the proteins
      participating in these redox regulatory cascades are provided, and their
      molecular targets and functions are described.

PMID- 12485922
TI  - Purification of proteins susceptible to oxidation at cysteine residues:
      identification of malate dehydrogenase as a target for S-glutathiolation.
AB  - The cysteine residues of proteins are susceptible to a range of oxidative
      modifications, including S-glutathiolation. Here we present a study in which we
      used glutathione-agarose to purify cardiac proteins that undergo S
      glutathiolation during oxidative stress. We then identified one of the oxidized
      proteins as malate dehydrogenase.

PMID- 12485923
TI  - Contribution of covalent protein modification to the antiinflammatory effects of
      cyclopentenone prostaglandins.
AB  - Cyclopentenone prostaglandins, which are produced during inflammatory processes,
      may exert a negative feedback on inflammation. These reactive compounds may form
      covalent adducts with thiol groups in glutathione or in proteins. The
      transcription factor NF-kappaB is key for the expression of numerous
      proinflammatory genes. We have observed that treatment of mesangial cells with 15
      deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) inhibits the cytokine-elicited
      DNA binding activity of NF-kappaB, both in intact cells and in isolated nuclear
      extracts, thus suggesting a direct effect on DNA binding. By using a biotinylated
      15d-PGJ(2) derivative, we have observed that 15d-PGJ(2) forms an adduct with the
      p50 subunit of NF-kappaB, as shown by Western blot and detection with horseradish
      peroxidase-conjugated streptavidin. In contrast, a p50 construct that bears a
      mutation in the cysteine residue involved in DNA binding (Cys62Ser) and is not
      susceptible to inhibition by 15d-PGJ(2) does not incorporate biotinylated 15d
      PGJ(2). The labeling of several polypeptides after incubation of cells with
      biotinylated 15d-PGJ(2) suggests that there may be multiple targets for
      modification by 15d-PGJ(2). We propose that the covalent modification of NF
      kappaB (and potentially other proteins) by 15d-PGJ(2) may contribute to the
      antiinflammatory effects of this prostaglandin.

PMID- 12485924
TI  - Possible signaling by glutathione and its novel analogue through potent
      stimulation of fontocortical G proteins in normal aging and in Alzheimer's
      disease.
AB  - In the frontal cortex (FC) of the normally aging human brain, glutathione (GSH)
      and its novel analogue, UPF1, stimulate G proteins more than in Alzheimer's
      disease (AD) FC. In normal aging and in AD, UPF1 is a more efficient stimulator
      of G proteins than GSH. In normal FC, both GSH and UPF1 stimulate G proteins,
      which mediate inhibitory signals to the cAMP system; while in AD, only UPF1
      exhibits the same action. Stimulation of G proteins and coupled signaling by GSH
      antioxidant analogues, as potential signaling molecules, may ameliorate the
      oxidative impairments of neuronal signaling in AD.

PMID- 12485925
TI  - Transcriptional regulation by thiol compounds in Helicobacter pylori-induced
      interleukin-8 production in human gastric epithelial cells.
AB  - Reactive oxygen species (ROS) have been counted among the potential toxic factors
      involving Helicobacter pylori (H. pylori)-induced gastric injury. Transcription
      nuclear factor-kappaB (NF-kappaB) is activated by ROS and regulates inflammatory
      gene expression. Thiol compounds, such as glutathione and N-acetylcysteine,
      scavenge hydrogen peroxide and are reported to prevent oxidative damage in
      various cells. The present study aims to investigate whether thiol compounds
      could affect H. pylori-induced IL-8 production by regulating transcription factor
      NF-kappaB in human gastric epithelial AGS cells. AGS cells were incubated with H.
      pylori (NCTC 11637) at a ratio of 1:100 in the presence or absence of thiol
      compounds. ROS generation was determined by confocal microscopy using ROS
      sensitive dichlorofluorescein diacetate dye. Levels of hydrogen peroxide and IL-8
      in the medium and DNA binding activity of NF-kappaB were determined by enzyme
      linked immunosorbent assay, colorimetric assay, and electrophoretic mobility
      shift assay. Results indicated both thiol compounds inhibited H. pylori-induced
      hydrogen peroxide production, in accordance with their inhibition on NF-kappaB
      activation and IL-8 production induced by H. pylori in AGS cells. In conclusion,
      ROS may be a signaling molecule triggering NF-kappaB activation and the
      expression of inflammatory genes such as IL-8.

PMID- 12485926
TI  - Reactive oxygen species accumulation induced by homocysteine in human platelets.

PMID- 12485927
TI  - Effects of homocysteine on the cellular responses of murine endothelial cells
      cultured in vitro.
AB  - Homocysteine, derived from the metabolism of methionine, is claimed as a
      proatherogenic factor that leads to vascular dysfunction. To gain better insight
      into the molecular mechanisms involved, homocysteine was tested on a model of
      murine endothelial cells cultured in vitro, using a prototype DNA chip. The DNA
      chip was designed to follow the expression at the mRNA level of some major
      proinflammatory genes; TNF-alpha was used as a positive control.

PMID- 12485928
TI  - Type I insulin-like growth factor receptor expression on colorectal
      adenocarcinoma cell lines is decreased in response to the chemopreventive agent N
      acetyl-l-cysteine.
AB  - Increased expression of the type I insulin-like growth factor receptor (IGF-1R)
      is associated with colon cancer, while the antioxidant N-acetyl-l-cysteine (NAC)
      is known to suppress colonic proliferation. We demonstrate that NAC down
      regulates the expression of IGF-1R on three colorectal adenocarcinoma cell lines
      (HT29, SW480, and LoVo). NAC also abrogates the proliferative effect of IGF-I on
      HT29 cells. This indicates a novel mechanism for the therapeutic effects of NAC.

PMID- 12485929
TI  - HERG K+ channels and beta1 integrins interact through the assembly of a
      macromolecular complex.

PMID- 12485930
TI  - Regulation of the metastatic process by E-selectin and stress-activated protein
      kinase-2/p38.
AB  - The formation of metastasis is a dreadful complication of cancer that is
      associated with a poor prognosis. Several clinical observations and experimental
      findings indicate that the metastatic process is nonrandom and involves a
      sequence of multistep events that may all be targeted for therapy. This includes
      angiogenesis of the primary neoplasm, release of malignant cells from this
      neoplasm, entry of cancer cells into the blood circulation, interaction of cancer
      cells with vascular endothelial cells in distant organs, and growth of blood
      borne cancer cells locally in the vessels or distally following extravasation.
      Our working hypothesis is that metastatic cancer cells exploit the mechanisms of
      the inflammation process to successfully migrate into distant organs. This
      implies a pivotal role for specific adhesive interactions between cancer cells
      and vascular endothelial cells and activation of migratory pathways in the cancer
      cells. We review here the roles played by the endothelial adhesive molecule E
      selectin and by the motogenic stress-activated protein kinase-2 (SAPK2/p38)
      pathway of cancer cells in modulating transendothelial migration of cancer cells.

PMID- 12485931
TI  - Intercellular adhesion molecule-1 in the heart.
AB  - Intercellular adhesion molecule-1 (ICAM-1) belongs to the superfamily of
      immunoglobulin-like adhesion molecules. Up-regulation of ICAM-1 occurs in many
      different pathophysiological processes. Also, cardiomyocytes can express ICAM-1
      for example, in acute myocardial infarction. Moreover, inhibition of ICAM-1
      expression in the heart dramatically reduces infarct size. Hence, inhibitors of
      ICAM-1 may provide a novel therapeutic option for acute myocardial infarction.

PMID- 12485933
TI  - Adhesion molecules as costimulators: ICAM-3 signaling potentiates CD3-mediated
      HIV-1 stimulation.

PMID- 12485932
TI  - Analysis of in vivo endothelial cell activation applying RT-PCR following
      endothelial cell isolation by laser dissection microscopy.
AB  - Laser dissection microscopy was applied to isolate endothelial cells from tumors
      obtained from mice treated with TNF-alpha. RNA integrity was demonstrated from
      whole sections and dissected cells after acetone fixation and hematoxylin
      staining. RT-PCR for GAPDH, CD31, VCAM-1, ICAM-1, and E-selectin was successfully
      performed on these samples. These data demonstrate the feasibility of analyzing
      local endothelial cell responses in diseased tissues at the level of gene
      expression.

PMID- 12485934
TI  - The signaling pathway for beta1-integrin/ERKs is involved in the adaptation of
      adipocyte functions to cell size.

PMID- 12485936
TI  - Mac-1 (CD11b/CD18) is crucial for effective Fc receptor-mediated immunity to
      melanoma.
AB  - Antibody-reliant destruction of tumor cells by immune effector cells is mediated
      by antibody-dependent cellular cytotoxicity, in which Fc receptor (FcR)
      engagement is crucial. This study documents an important role for the beta(2)
      integrin Mac-1 (CD11b/CD18) in FcR-mediated protection against melanoma. CD11b
      deficient mice, those that lack Mac-1, were less protected by melanoma-specific
      monoclonal antibody TA99 than wild-type (WT) mice. Significantly more lung
      metastases and higher tumor loads were observed in Mac-1(-/-) mice. Histologic
      analyses revealed no differences in neutrophil infiltration of lung tumors
      between Mac-1(-/-) and WT mice. Importantly, Mac-1(-/-) phagocytes retained the
      capacity to bind tumor cells, implying that Mac-1 is essential during actual FcR
      mediated cytotoxicity. In summary, this study documents Mac-1 to be required for
      FcR-mediated antimelanoma immunity in vivo and, furthermore, supports a role for
      neutrophils in melanoma rejection.

PMID- 12485938
TI  - Leukocyte reduction and HTLV-I: is the glass half empty or half full?

PMID- 12485937
TI  - GA-binding protein (GABP) and Sp1 are required, along with retinoid receptors, to
      mediate retinoic acid responsiveness of CD18 (beta 2 leukocyte integrin): a novel
      mechanism of transcriptional regulation in myeloid cells.
AB  - CD18 (beta(2) leukocyte integrin) is transcriptionally regulated in myeloid
      cells, but the mechanisms that increase its expression in response to retinoic
      acid (RA) have not been defined. The CD18 promoter was activated by RA treatment
      in stably transfected U937 myeloid cells. We identified a retinoic acid response
      element (RARE) that lies nearly 900 nucleotides upstream of the CD18
      transcriptional start site that was bound by the RA receptors, retinoic acid
      receptor (RAR) and retinoic X receptor (RXR). This RARE accounted for one half of
      the RA responsiveness of CD18. However, unexpectedly, one half of the dynamic
      response to RA was mediated by the 96-nucleotide CD18 minimal promoter, which
      lacks a recognizable RARE. Binding sites for the ets transcription factor, GA
      binding protein (GABP), and Sp1 were required for full RA responsiveness of both
      the CD18 minimal promoter and the full-length promoter. The ets sites conferred
      RA responsiveness on an otherwise unresponsive heterologous promoter, and RA
      responsiveness was directly related to the number of ets sites. The
      transcriptional coactivator p300/CBP physically interacted with GABP in vivo, and
      p300 increased the responsiveness of the CD18 promoter to RA. These studies
      demonstrate a novel role for non-RAR transcription factors in mediating RA
      activation in myeloid cells. They support the concept that transcription factors
      other than RARs are required for RA-activated gene expression. We hypothesize
      that a multiprotein complex--an enhanceosome--that includes GABP, other
      transcription factors, and coactivators, dynamically regulates CD18 expression in
      myeloid cells.

PMID- 12485939
TI  - Factor XIII activation by thrombin depends on FXIIIVal34Leu genotype.

PMID- 12485940
TI  - Iron status indicators: hello new, goodbye old?

PMID- 12485941
TI  - Donor lymphocyte infusions as primary therapy for neoplasms.

PMID- 12485942
TI  - p14ARF, p15INK4b, and p16INK4a methylation status in chronic myelogenous
      leukemia.

PMID- 12485943
TI  - Telomere length in peripheral blood granulocytes reflects response to treatment
      with imatinib in patients with chronic myeloid leukemia.

PMID- 12485944
TI  - The role of interleukin-3 and stem cell factor in classical Hodgkin disease.

PMID- 12485945
TI  - Expression and cyclic variability of CYP3A4 and CYP3A7 isoforms in human
      endometrium and cervix during the menstrual cycle.
AB  - CYP3A4, a cytochrome p450 (p450) isoform metabolizes estrogens, whereas CYP3A7, a
      fetal liver p450 isoform, is involved in estriol biosynthesis. The goal of this
      study was to evaluate expression of these enzymes in human uterine tissue during
      the proliferative and secretory phases of the menstrual cycle. Endometrium and
      cervix specimens were collected from women undergoing hysterectomy (n = 36).
      Total mRNA was extracted, quantified, and reverse-transcription polymerase chain
      reaction (RT-PCR) was carried out using consensus primers for CYP3A. The 453 base
      pairs PCR product was hybridized with specific internal oligonucleotide probes
      for CYP3A4 or CYP3A7 end labeled with (32)P gamma-ATP. The relative intensity of
      hybridization was determined by autoradiography. Expression of CYP3A7 in
      endometrium was significantly greater (approximately 10-fold) in the
      proliferative phase compared with the secretory phase (p < 0.05). CYP3A4
      expression was comparable between the two phases. Expression of both enzymes was
      minimal in the cervix. Fluorescence in situ hybridization of paraffinized
      sections indicated localized expression of CYP3A enzymes in the glandular
      epithelium as well as the stroma. Comparison of relative fluorescence intensity
      indicated differential expression of CYP3A7 in various phases of the menstrual
      cycle. These results suggest that CYP3A expression in the endometrium of
      premenopausal women may vary depending on the menstrual cycle phase.

PMID- 12485946
TI  - Constitutive androstane receptor and pregnane X receptor gene expression in human
      liver: interindividual variability and correlation with CYP2B6 mRNA levels.
AB  - The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) mediate
      the expression of mammalian cytochrome p450 (p450) 2B genes, including CYP2B6 in
      humans. Large interindividual differences exist in hepatic CYP2B6 expression, but
      the molecular basis for this variability is not well understood. In the present
      study, we developed real-time polymerase chain reaction methods to measure
      CYP2B6, CAR, and PXR mRNA expression and compared the levels in a panel of 12
      individual human liver samples. The transcripts of CAR and CYP2B6 were present in
      all the samples analyzed, whereas those of PXR were detectable in all but one
      sample. A striking finding was the 240-fold interindividual variability in
      hepatic CAR mRNA levels, which was similar to the variability (278-fold) in
      CYP2B6 mRNA levels but greater than the 27-fold variability in PXR mRNA
      expression. Additional analysis revealed positive and statistically significant
      correlations between the mRNA levels of CAR and CYP2B6 (r(2) = 0.63, p = 0.002),
      PXR and CYP2B6 (r(2) = 0.75. p < 0.001), and CAR and PXR (r(2) = 0.86, p <
      0.001). In summary, substantial interindividual differences exist in hepatic CAR
      and, to a lesser extent, PXR gene expression. The variability in the abundance of
      these transcription factors may contribute to the large interindividual
      differences in CYP2B6 gene expression in human liver.

PMID- 12485947
TI  - Bioflavonoid stimulation of glutathione transport by the 190-kDa multidrug
      resistance protein 1 (MRP1).
AB  - In tumor cells, the human multidrug resistance protein 1 (MRP1), confers
      resistance to a broad spectrum of anticancer agents. MRP1 is also expressed in
      many normal tissues where it acts as an ATP-dependent transporter of organic
      anions. Reduced glutathione (GSH) is transported by MRP1 with very low affinity,
      and certain MRP1 substrates are transported in association with this tripeptide.
      Previous studies have shown that various dietary flavonoids stimulate the ATPase
      activity of MRP1 and inhibit transport of its conjugated organic anion substrates
      but are poor reversers of MRP1-mediated drug resistance. In contrast, many of the
      same flavonoids markedly stimulate GSH transport by MRP1. In the present study,
      we found that stimulation of GSH transport in inside-out MRP1-enriched membrane
      vesicles by apigenin, naringenin, genistein, and quercetin was maximum at a
      concentration of 30 microM. Apigenin was the most efficacious of the four
      bioflavonoids, showing a maximal 6-fold increase over basal levels of GSH
      transport. The apparent K(m) and V(max) for GSH uptake in the presence of 30
      microM apigenin were 116 microM and 666 pmol mg(-1) min(-1), respectively.
      Chemosensitivity assays with control-transfected and MRP1-transfected HeLa cell
      lines showed that the IC(50) values for apigenin, naringenin, genistein, and
      quercetin were similar, demonstrating that overexpression of MRP1 does not confer
      resistance to these bioflavonoids. Our results suggest that flavonoids stimulate
      MRP1-mediated GSH transport by increasing the apparent affinity of the
      transporter for GSH but provide no evidence that a cotransport mechanism is
      involved.

PMID- 12485948
TI  - Cocaethylene metabolism and interaction with cocaine and ethanol: role of
      carboxylesterases.
AB  - Carboxylesterases are important in the metabolism of cocaine, catalyzing the
      hydrolysis of cocaine to its two major metabolites, benzoylecgonine and ecgonine
      methyl ester. In the presence of ethanol, some cocaine undergoes
      transesterification with ethanol instead of hydrolysis with water producing the
      active metabolite, cocaethylene. The metabolic fate of cocaethylene is unknown,
      but given its structural similarity to cocaine, it was hypothesized that
      cocaethylene would also be metabolized by carboxylesterases and its elimination
      decreased in the presence of ethanol, as is cocaine's. Dogs were given cocaine
      alone, cocaethylene alone, cocaine and ethanol, cocaethylene and ethanol, and
      cocaine and cocaethylene on separate study days and sequential blood samples
      drawn. Plasma concentrations of cocaine, benzoylecgonine, and cocaethylene were
      determined by high-performance liquid chromatography. The pharmacokinetic
      dispositions of cocaine and cocaethylene were similar with clearance values of
      0.91 +/- 0.22 and 0.79 +/- 0.16 l/min, and volumes of distribution of 2.6 +/-
      0.82 and 2.7 +/- 0.47 l/kg, respectively. Both cocaine and cocaethylene
      clearances were decreased about 20% when given with ethanol. Following
      administration of cocaethylene alone, benzoylecgonine achieved similar plasma
      concentrations as those attained following cocaine alone, which indicates that
      benzoylecgonine is a major metabolite of cocaethylene. Carboxylesterases play an
      important role in the elimination of both cocaine and cocaethylene.

PMID- 12485949
TI  - Mouse liver and kidney carboxylesterase (M-LK) rapidly hydrolyzes antitumor
      prodrug irinotecan and the N-terminal three quarter sequence determines substrate
      selectivity.
AB  - Antitumor prodrug irinotecan is used for a variety of malignancies such as
      colorectal cancer. It is hydrolyzed to the metabolite, 7-ethyl-10
      hydroxycamptothecin (SN-38), which exerts its antineoplastic effect. Several
      human and rodent carboxylesterases are shown to hydrolyze irinotecan, but the
      overall activity varies from enzyme to enzyme. This report describes a novel
      mouse liver and kidney carboxylesterase (M-LK) that is highly active toward this
      prodrug. Northern analyses demonstrated that M-LK was abundantly expressed in the
      liver and kidney and slightly in the intestine and lung. Lysates from M-LK
      transfected cells exhibited a markedly higher activity on irinotecan hydrolysis
      than lysates from the cells transfected with mouse triacylglycerol hydrolase
      (TGH) (6.9 versus 1.3 pmol/mg/min). Based on the immunostaining intensity with
      purified rat hydrolase A, M-LK had a specific activity of 173 pmol/mg/min, which
      ranked it as one of the most efficient esterases known to hydrolyze irinotecan. A
      chimeric carboxylesterase and its wild-type enzyme (e.g., M-LKn and M-LK),
      sharing three quarters of the entire sequence from the N-terminus, exhibited the
      same substrate preference toward irinotecan and two other substrates, suggesting
      that the N-terminal sequence determines substrate selectivity. M-LK transfected
      cells manifested more severe cytotoxicity than TGH transfected cells upon being
      exposed to irinotecan. Topoisomerase I inhibitors such as irinotecan represent a
      promising class of anticancer drugs. Identification of M-LK as an efficient
      carboxylesterase to activate irinotecan provides additional sequence information
      to locate residues involved in irinotecan hydrolysis and thus facilitates the
      design of new analogs.

PMID- 12485950
TI  - Mechanism-based inactivation of cytochrome P450 2B6 by a novel terminal acetylene
      inhibitor.
AB  - N-(3,5-Dichloro-4-pyridyl)-3-(cyclopentyloxy)-4-methoxybenzamide (DCMB) is a
      known marker substrate for cytochrome p450 2B6. Based on the chemical template of
      DCMB, a novel terminal acetylene compound, N-(3,5-dichloro-4-pyridyl)-4-methoxy-3
      (prop-2-ynyloxy)benzamide (TA) was synthesized and evaluated as a mechanism-based
      inactivator of p450 2B6. The pseudo first-order inactivation of expressed p450
      2B6 by TA was both substrate and time-dependent. The kinetics of inhibition
      resulted in a maximal rate constant (k(inactivation)) of 0.09 min(-1) and an
      apparent K(I) of 5.1 microM. Incubation of expressed p450 2B6 with TA and NADPH
      resulted in a 68% loss in enzyme activity and a concurrent 62% loss in the
      formation of a reduced carbon monoxide complex, suggesting that heme destruction
      is the primary mode of enzyme inactivation. Enzyme inactivation of p450 2B6 was
      not reduced by the presence of 10 mM glutathione and was protected by incubation
      of excess DCMB with TA. The production of the carboxylic acid metabolite, N-(3,5
      Dichloro-4-pyridyl)-3-(2-carboxyethoxy)-4-methoxybenzamide (TA-COOH), during the
      incubation of TA with 2B6 suggests that inactivation proceeds through a ketene
      intermediate. For 2B6 inactivation, the partition ratio was approximately 1.5
      nmol TA-COOH formed/nmol P450 inactivated. Finally, TA was evaluated for
      mechanism-based inactivation of p450 3A4, 2C9, 2C19, 2D6, and 2E1 using human
      liver microsomes. In addition to 2B6, p450 2C forms were also found to be
      sensitive to TA-mediated inactivation, suggesting that subtle changes in the O
      alkyl chain of the parent may be critical for the selectivity of enzyme
      inactivation.

PMID- 12485951
TI  - Acyl glucuronidation and glucosidation of a new and selective endothelin ET(A)
      receptor antagonist in human liver microsomes.
AB  - Compound A [(+)-(5S,6R,7R)-2-isopropylamino-7-[4-methoxy-2-((2R)-3-methoxy-2
      methylpropyl)-5-(3,4-methylenedioxyphenyl) cyclopenteno [1,2-b] pyridine 6
      carboxylic acid] is a new and selective endothelin ET(A) receptor antagonist. It
      underwent significant acyl glucuronidation and acyl glucosidation in human liver
      microsomes supplemented with UDP-glucuronic acid (UDPGA) and UDP-glucose (UDPG).
      These two conjugations were observed in a panel of human liver microsomal samples
      (n = 16) that gave rise to varying activities but with no significant correlation
      with each other in the native and activator-treated microsomal preparations (r(2)
      <or= 0.4, p > 0.05). The lack of correlation may be explained by the involvement
      of multiple UDP-glucuronosyltransferases (UGTs; UGT1A1, 1A3, 1A9, 2B7 and 2B15)
      in the glucuronidation but essentially solely UGT2B7 in the glucosidation. Both
      reactions conformed to monophasic Michaelis-Menten kinetics in human liver
      microsomes. The glucuronidation reaction exhibited apparent K(m) values (mean +/-
      S.E.) for compound A and UDPGA of 8.4 +/- 0.6 and 605 +/- 35 microM,
      respectively, whereas the values for the glucosidation reaction were 10.2 +/- 1.5
      and 670 +/- 120 microM, respectively. In both pooled human liver microsomes and
      expressed UGT2B7, UDPG and UDPGA competitively inhibited their counterpart
      conjugations with K(i) values close to their K(m) values, indicating a comparable
      affinity of the enzyme toward these two nucleotide sugars. We herein report a
      drug acyl glucoside formed in human liver microsomes at a considerable turnover
      rate and provide the evidence for a UGT isoform (UGT2B7) capable of transferring
      both glucuronic acid and glucose from UDPGA and UDPG to an aglycone.

PMID- 12485952
TI  - The mechanism-based inactivation of human cytochrome P450 2B6 by phencyclidine.
AB  - Phencyclidine (PCP) was analyzed for its ability to inactivate human cytochrome
      p450 (p450) 2B6. PCP inactivated the 7-ethoxy-4-(trifluoromethyl)coumarin O
      deethylation activity of p450 2B6 in a concentration-, time-, and NADPH-dependent
      manner and exhibited pseudo-first order kinetics. The K(I) was 10 microM,
      k(inact) was 0.01 min(-1), which corresponds to a t(1/2) of 31 min. The partition
      ratio was approximately 45. Spectral analysis of the heme moiety demonstrated
      that the heme was not modified during inactivation. Extensive dialysis of the PCP
      inactivated p450 2B6 did not cause a return in catalytic activity demonstrating
      PCP inactivation was irreversible. Including 7-ethoxycoumarin, an alternate
      substrate, protected 2B6 from inactivation by PCP indicating competition of the
      two substrates for the active site. Exogenous nucleophiles such as glutathione
      (GSH) and cyanide could not protect p450 2B6 from PCP inactivation demonstrating
      that the reactive intermediate remained within the p450 active site. High
      performance liquid chromatography analysis of p450 2B6 inactivated in the
      presence of (3)H-labeled PCP showed that PCP binding was specific for the p450
      and not to other proteins in the reaction mixture. The stoichiometry of binding
      of PCP to p450 2B6 was demonstrated using (3)H-labeled PCP. In the absence of
      GSH, the stoichiometry was 5.5:1 (PCP/p450). In the presence of GSH, the
      stoichiometry was 1:1. This stoichiometry was further supported using
      electrospray ionization-liquid chromatography-mass spectrometry to analyze PCP
      inactivated p450 2B1, 2B4, and 2B6.

PMID- 12485953
TI  - The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is
      inhibited by atorvastatin.
AB  - The prodrug clopidogrel (Plavix) is activated by cytochrome p450 (p450) to a
      metabolite that inhibits ADP-induced platelet aggregation. Clopidogrel is
      frequently administered to patients in conjunction with the CYP3A4 substrate
      atorvastatin (Lipitor). Since clinical studies indicate that atorvastatin
      inhibits the antiplatelet activity of clopidogrel, we investigated whether CYP3A4
      metabolized clopidogrel in vitro. Microsomes prepared from dexamethasone
      pretreated rats metabolized clopidogrel at a rate of 3.8 nmol min(-1) nmol of
      p450(-1), which is 65 and 1270% faster than the rate of metabolism by microsomes
      from control and beta-napthoflavone-treated rats, respectively. To identify the
      human p450s responsible for clopidogrel oxidation, genetically engineered
      microsomes containing a single human p450 isozyme were tested for their ability
      to oxidize clopidogrel. CYP3A4 and 3A5 metabolized clopidogrel at a significantly
      higher rate than eight other p450 isozymes, suggesting that CYP3A4 and 3A5 are
      primarily responsible for in vivo clopidogrel metabolism. Clopidogrel interacts
      with human CYP3A4 with a spectral dissociation constant (K(s)), K(m), and V(max)
      of 12 microM, 14 +/- 1 microM and 6.7 +/- 1 nmol min(-1) nmol p450(-1),
      respectively. Atorvastatin lactone, the physiologically relevant substrate,
      inhibits clopidogrel with a K(i) of 6 microM. When clopidogrel and atorvastatin
      are present at equimolar concentrations, clopidogrel metabolism is inhibited by
      greater than 90%. Since CYP3A4 and 3A5 metabolize clopidogrel faster than other
      human p450 isozymes and are the most abundant p450s in human liver, they are
      predicted to be predominantly responsible for the activation of clopidogrel in
      vivo.

PMID- 12485954
TI  - Differences in cytochrome P450 forms involved in the metabolism of N,N-dipropyl-2
      [4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a
      novel sigma ligand, in human liver and intestine.
AB  - N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride
      (NE-100) has been developed to treat subjects with schizophrenia. This drug is
      mainly excreted in the form of oxidative metabolites. In the present study,
      identification of p450 forms involved in the metabolism was carried out using
      human livers and intestinal microsomes (HLM and HIM). Eadie-Hofstee plots for NE
      100 disappearance in HLM were biphasic, thus indicating the involvement of at
      least two p450 forms. The metabolism of NE-100 was mediated with recombinant
      CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A significant correlation
      was observed between activities of NE-100 metabolism and dextromethorphan O
      demethylation (a specific activity for CYP2D6) or testosterone 6beta
      hydroxylation (a specific activity for CYP3A4) in HLM. The activity of NE-100
      metabolism was inhibited by approximately 80% by an anti-CYP2D6 antibody and only
      by quinidine among the p450-selective inhibitors at a low substrate concentration
      (0.1 microM). In contrast, with a high substrate concentration (10 microM), the
      activity was inhibited by an anti-CYP3A4 antibody and by ketoconazole. On the
      other hand, in HIM, the Eadie-Hofstee plots for NE-100 disappearance were
      monophasic, and the metabolism was strongly inhibited by an anti-CYP3A4 antibody
      and by ketoconazole but not by other inhibitors used. These results strongly
      suggest that NE-100 has different profiles regarding metabolism between liver and
      intestine. During absorption, NE-100 is mainly metabolized by CYP3A4 in the
      intestine and thereafter by CYP2D6 in the liver in the presence of therapeutic
      doses.

PMID- 12485955
TI  - Comparative biotransformation of radiolabeled [(14)C]omapatrilat and stable
      labeled [(13)C(2)]omapatrilat after oral administration to rats, dogs, and
      humans.
AB  - Omapatrilat, a novel vasopeptidase inhibitor, is under development for the
      treatment of hypertension and congestive heart failure. This study describes the
      comparative biotransformation of radiolabeled [(14)C]- and stable-labeled
      [(13)C(2)]omapatrilat after administration of single oral doses to rats, dogs,
      and humans. The metabolites were identified by a combination of methods including
      reduction, hydrolysis, and comparison of high performance liquid chromatography
      retention times with those of the synthetic standards. Urinary metabolites were
      further characterized by liquid chromatography tandem mass spectrometry analysis.
      Prominent metabolites identified in human plasma, which were also present in rat
      and dog plasma, were S-methyl omapatrilat and S-2-thiomethyl-3-phenylpropionic
      acid. Omapatrilat accounted for only a small portion of the extractable
      radioactivity in plasma in all three species. A portion of the plasma
      radioactivity was unextractable in all three species (27-53%). The majority of
      unextractable radioactivity in plasma was characterized after dithiothreitol
      reduction to be omapatrilat and (S)-2-thio-3-phenylpropionic acid, both
      apparently bound to plasma proteins by reversible disulfide bonds. The major
      human urinary metabolites were the amine hydrolysis product, diasteromeric
      sulfoxide of (S)-2-thiomethyl-3-phenylpropionic acid, acyl glucuronide of S
      methyl omapatrilat, and S-methyl omapatrilat. The minor metabolites were acyl
      glucuronide of (S)-2-thiomethyl-3-phenylpropionic acid, L-cysteine mixed
      disulfide of omapatrilat, diastereomers of S-methyl sulfoxide of omapatrilat, and
      S-methyl omapatrilat ring sulfoxide. The metabolic profiles of dog and human
      urine were qualitatively similar whereas rat urine showed only metabolites
      arising from hydrolysis of omapatrilat. Unchanged omapatrilat was not found in
      rat, dog, or human urine samples indicating extensive metabolism in vivo.

PMID- 12485957
TI  - Disposition and metabolic fate of atomoxetine hydrochloride: pharmacokinetics,
      metabolism, and excretion in the Fischer 344 rat and beagle dog.
AB  - These studies were designed to characterize the disposition and metabolism of
      atomoxetine hydrochloride [(-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine
      hydrochloride; formerly know as tomoxetine hydrochloride] in Fischer 344 rats and
      beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and
      cleared primarily by metabolism with the majority of its metabolites being
      excreted into the urine, 66% of the total dose in the rat and 48% in the dog.
      Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to
      be due to biliary elimination and not due to unabsorbed dose. Nearly the entire
      dose was excreted within 24 h in both species. In the rat, low oral
      bioavailability was observed (F = 4%) compared with the high oral bioavailability
      in dog (F = 74%). These differences appear to be almost purely mediated by the
      efficient first-pass hepatic clearance of atomoxetine in rat. The
      biotransformation of atomoxetine was similar in the rat and dog, undergoing
      aromatic ring hydroxylation, benzylic oxidation (rat only), and N-demethylation.
      The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which
      was subsequently conjugated forming O-glucuronide and O-sulfate (dog only)
      metabolites. Although subtle differences were observed in the excretion and
      biotransformation of atomoxetine in rats and dogs, the primary difference
      observed between these species was the extent of first-pass metabolism and the
      degree of systemic exposure to atomoxetine and its metabolites.

PMID- 12485956
TI  - Metabolism, pharmacokinetics, and excretion of a highly selective N-methyl-D
      aspartate receptor antagonist, traxoprodil, in human cytochrome P450 2D6
      extensive and poor metabolizers.
AB  - The excretion, biotransformation, and pharmacokinetics of a selective N-methyl-D
      aspartate receptor antagonist, traxoprodil, were investigated in six healthy male
      volunteers, phenotyped either as CYP2D6 extensive or poor metabolizers of
      dextromethorphan. Each subject received an i.v. infusion of a single 50-mg (100
      microCi) dose of [(14)C]traxoprodil. Approximately 89% of the administered dose
      was recovered in poor metabolizers (PMs) and 61% in extensive metabolizers (EMs),
      with the majority of the dose being excreted in the urine (86% in PMs and 52% in
      EMs). The elimination of traxoprodil was more rapid in EMs than in PMs with
      terminal elimination half-lives of 2.8 and 26.9 h, respectively, for EMs and PMs.
      Area under the plasma concentration-time curve from time 0 to T (AUC((0-Tlast)))
      values for unchanged traxoprodil were 1.2 and 32.7% of the corresponding AUC
      values for total radioactivity in EMs and PMs, respectively. Traxoprodil was
      metabolized in both EMs and PMs, with approximately 7 and 50% of the administered
      radioactivity excreted as unchanged drug in the excreta of EMs and PMs,
      respectively. Hydroxylation at the 3-position of the hydroxyphenyl ring and
      methylation of the resulting catechol followed by conjugation were identified as
      the main metabolic pathways in EMs. In contrast, direct conjugation of
      traxoprodil with glucuronic or sulfuric acid was the major pathway in PMs. In
      vitro studies using CYP2D6-selective inhibitor and recombinant enzyme also
      support that the metabolism of traxoprodil is mainly mediated by CYP2D6. Taken
      together, these studies suggest that traxoprodil is eliminated mainly by Phase I
      oxidative metabolism mediated by CYP2D6 isozyme in EMs and by Phase II
      conjugation and renal clearance of parent in PMs.

PMID- 12485958
TI  - Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6
      in human disposition and metabolism.
AB  - The role of the polymorphic cytochrome p450 2D6 (CYP2D6) in the pharmacokinetics
      of atomoxetine hydrochloride [(-)-N-methyl-gamma-(2
      methylphenoxy)benzenepropanamine hydrochloride; LY139603] has been documented
      following both single and multiple doses of the drug. In this study, the
      influence of the CYP2D6 polymorphism on the overall disposition and metabolism of
      a 20-mg dose of (14)C-atomoxetine was evaluated in CYP2D6 extensive metabolizer
      (EM; n = 4) and poor metabolizer (PM; n = 3) subjects under steady-state
      conditions. Atomoxetine was well absorbed from the gastrointestinal tract and
      cleared primarily by metabolism with the preponderance of radioactivity being
      excreted into the urine. In EM subjects, the majority of the radioactive dose was
      excreted within 24 h, whereas in PM subjects the majority of the dose was
      excreted by 72 h. The biotransformation of atomoxetine was similar in all
      subjects undergoing aromatic ring hydroxylation, benzylic oxidation, and N
      demethylation with no CYP2D6 phenotype-specific metabolites. The primary
      oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was
      subsequently conjugated forming 4-hydroxyatomoxetine-O-glucuronide. Due to the
      absence of CYP2D6 activity, the systemic exposure to radioactivity was prolonged
      in PM subjects (t(1/2) = 62 h) compared with EM subjects (t(1/2) = 18 h). In EM
      subjects, atomoxetine (t(1/2) = 5 h) and 4-hydroxyatomoxetine-O-glucuronide
      (t(1/2) = 7 h) were the principle circulating species, whereas atomoxetine
      (t(1/2) = 20 h) and N-desmethylatomoxetine (t(1/2) = 33 h) were the principle
      circulating species in PM subjects. Although differences were observed in the
      excretion and relative amounts of metabolites formed, the primary difference
      observed between EM and PM subjects was the rate at which atomoxetine was
      biotransformed to 4-hydroxyatomoxetine.

PMID- 12485959
TI  - Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite
      of irinotecan (CPT-11), by human UGT1A1 variants, G71R, P229Q, and Y486D.
AB  - 7-Ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of antitumor agent
      irinotecan (CPT-11), is conjugated and detoxified to SN-38-glucuronide by UDP
      glucuronosyltransferase (UGT) 1A1. Genetic polymorphisms in UGT1A1 are thought to
      contribute to severe diarrhea and/or leukopenia caused by CPT-11. In this regard,
      it has been reported that polymorphisms in the promoter region could affect the
      CPT-11 pharmacokinetics and interindividual variation of toxicity. However,
      little information is available on the influence of UGT1A1 polymorphisms in the
      coding region on the SN-38 glucuronidation activity. In the present study, wild
      type (WT) and three variant (G71R, P229Q, and Y486D) cDNAs of human UGT1A1s were
      transiently expressed in COS-1 cells, and the kinetic parameters of these UGT1A1s
      were determined for SN-38 glucuronidation. A partially reduced UGT1A1 protein
      expression was observed in COS-1 cells for G71R and Y486D. WT UGT1A1 catalyzed SN
      38 glucuronidation with an apparent K(m) value of 11.5 microM, whereas those of
      G71R, P229Q, and Y486D were 14.0, 18.0, and 63.5 microM, respectively. The SN-38
      glucuronidation efficiency ratio (V(max)/K(m)) normalized for the level of
      expression was 1.4, 0.66 (47% of WT), 0.73 (52%), and 0.07 (5%) microl/min/mg of
      protein for WT, G71R, P229Q, and Y486D, respectively. Thus, the SN-38
      glucuronidation activity of Y486D was drastically reduced, whereas the reduction
      in the G71R and P229Q activities was fractional. The decreased SN-38
      glucuronidation efficiency ratio of G71R and P229Q could be critical in
      combination with other polymorphisms in the UGT1A1 gene.

PMID- 12485960
TI  - Amino acid conjugates: metabolites of 2-propylpentanoic acid (valproic acid) in
      epileptic patients.
AB  - In this study, spectroscopic and chromatographic evidence is presented for the
      identification and characterization of the metabolites, valproyl glutamate (2
      propylpentanoyl glutamate, VPA-GLU) and valproyl glutamine (2-propylpentanoyl
      glutamine, VPA-GLN) in the urine, serum, and cerebrospinal fluid (CSF) of
      patients on valproic acid (VPA) therapy. Moreover, the identification of valproyl
      glycine (2-propylpentanoyl glycine, VPA-GLY) in the serum and urine of patients
      on VPA, albeit in trace concentrations, is also reported here. The three amino
      acid conjugates excreted in urine accounted for about 1% of the VPA dose in four
      patients who were on VPA therapy chronically and had reached steady state. VPA
      GLU was quantitatively the most prominent metabolite (0.66-13.1 microg/mg
      creatinine) compared with VPA-GLN (0.78-9.93 microg/mg creatinine) and VPA-GLY
      (trace-1.0 microg/mg creatinine) in overnight urine samples of all patients
      studied (n = 29). The relatively low serum concentrations of the three amino acid
      conjugates of VPA in six patients suggest that the metabolites are readily
      excreted once formed. In contrast, whereas VPA GLY was absent in the CSF of one
      patient on VPA, the concentrations of VPA-GLU and VPA-GLN in this CSF sample were
      9 and 5 times, respectively, their corresponding serum concentrations.

PMID- 12485961
TI  - Metabolism of (S)-5,6-difluoro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4
      dihydro-2(1H)-quinazolinone, a non-nucleoside reverse transcriptase inhibitor, in
      human liver microsomes. Metabolic activation and enzyme kinetics.
AB  - (S)-5, 6-Difluoro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4-dihydro- 2-(1H)
      quinazolinone (DPC 963), a specific non-nucleoside inhibitor of human
      immunodeficiency virus-1 reverse transcriptase, is primarily metabolized in
      humans to the glucuronide conjugate of 8-OH DPC 963 (M8). Electrospray ionization
      liquid chromatography/mass spectrometry analyses of urine from subjects dosed
      with DPC 963 also revealed the presence of other minor metabolites including
      glucuronide conjugate of 6-OH DPC 963 (M7). An oxidative defluorination pathway
      involving a putative p-benzoquinone imine capable of being reduced to the
      hydroquinone (M7) is postulated. The formation of the benzoquinone imine
      [detected as a glutathione (GSH) adduct, M5] was primarily carried out by CYP3A4,
      whereas M8 was formed mainly by the polymorphic CYP2B6. The kinetic studies with
      human liver microsomes showed that the apparent K(m) and V(max) values for the
      formation of M5 were 65.8 microM and 25.6 pmol/min/mg of protein, respectively.
      The formation of M8 showed K(m) and V(max) values of 15.1 microM and 22.9
      pmol/min/mg of protein, respectively. The microsomal studies also revealed the
      occurrence of a possible oxirene intermediate that was trapped as GSH adducts M3
      and M4. It was demonstrated, for the first time, that CYP3A4 was capable of
      directly oxidizing the triple bond of the cyclopropyl ethynyl group to an
      unstable oxirene. The apparent K(m) and V(max) values for the formation of an
      oxirene (detected as the GSH adduct M3) were 1.9 mM and 10.2 pmol/min/mg of
      protein, respectively. These results suggest that CYP2B6 has a higher affinity
      than CYP3A4 toward DPC 963. This consequently leads to greater levels of CYP2B6
      catalyzed product, M8, than CYP3A4-mediated bioactivation of DPC 963 to
      benzoquinone imine or oxirene intermediates.

PMID- 12485962
TI  - Validation of serotonin (5-hydroxtryptamine) as an in vitro substrate probe for
      human UDP-glucuronosyltransferase (UGT) 1A6.
AB  - Investigation of human UDP-glucuronosyltransferase (UGT) isoforms has been
      limited by a lack of specific substrate probes. In this study serotonin was
      evaluated for use as a probe substrate for human UGT1A6 using recombinant human
      UGTs and tissue microsomes. Of the 10 commercially available recombinant UGT
      isoforms, only UGT1A6 catalyzed serotonin glucuronidation. Serotonin-UGT activity
      at 40 mM serotonin concentration varied more than 40-fold among human livers (n =
      54), ranging from 0.77 to 32.9 nmol/min/mg of protein with a median activity of
      7.1 nmol/min/mg of protein. Serotonin-UGT activity kinetics of representative
      human liver microsomes (n = 7) and pooled human kidney, intestinal and lung
      microsomes and recombinant human UGT1A6 typically followed one enzyme Michaelis
      Menten kinetics. Serotonin glucuronidation activity in these human liver
      microsomes had widely varying V(max) values ranging from 0.62 to 51.3 nmol/min/mg
      of protein but very similar apparent K(m) values ranging from 5.2 to 8.8 mM.
      Pooled human kidney, intestine, and lung microsomes had V(max) values (mean +/-
      standard error of the estimates) of 8.8 +/- 0.4, 0.22 +/- 0.00, and 0.03 +/- 0.00
      nmol/min/mg of protein (respectively) and apparent K(m) values of 6.5 +/- 0.9,
      12.4 +/- 2.0, and 4.9 +/- 3.3 mM (respectively). In comparison, recombinant
      UGT1A6 had a V(max) of 4.5 +/- 0.1 nmol/min/mg of protein and an apparent K(m) of
      5.0 +/- 0.4 mM. A highly significant correlation was found between immunoreactive
      UGT1A6 protein content and serotonin-UGT activity measured at 4 mM serotonin
      concentration in human liver microsomes (R(s) = 0.769; P < 0.001) (n = 52). In
      conclusion, these results indicate that serotonin is a highly selective in vitro
      probe substrate for human UGT1A6.

PMID- 12485963
TI  - Bisphenol A glucuronidation and absorption in rat intestine.
AB  - Bisphenol A, an environmental estrogen, can be leached from plastic tableware and
      from the coating of food and drink cans, orally exposing human beings to the
      compound. The present study focuses on the absorption and metabolism of bisphenol
      A in the rat intestine, as elucidated experimentally by segmented everted
      intestine. One hour after the application of 2 micromol of bisphenol A to the
      mucosal fluid, the absorption of bisphenol A was slightly greater in the colon
      (48.6%) than in the proximal jejunum (37.5%). In the serosal side, unconjugated
      bisphenol A appeared in small amounts, increasing distally (maximal 1.6 nmol,
      colon). Large amounts of the bisphenol A glucuronide were then transported into
      the serosal side, also increasing distally (proximal, 80.4 nmol; distal, 478.4
      nmol). The greatest amount of the glucuronide (approximately 573 nmol) was
      excreted into the mucosal side of the small intestine, whereas in the colon,
      mucosal excretion was minimal (67.2 nmol). On high-dose application of bisphenol
      A to the mucosal fluid, the transported unconjugated bisphenol A increased
      markedly throughout the intestine and colon. These results suggest that bisphenol
      A in the intestinal lumen is glucuronidated almost exclusively during its passage
      through the intestinal wall.

PMID- 12485965
TI  - Primary prevention of cardiovascular disease: a call to action.

PMID- 12485966
TI  - Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on
      Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
      Treatment Panel III) final report.

PMID- 12485967
TI  - Cardiology patient page. Catheter ablation of arrhythmias.

PMID- 12485968
TI  - Cardiology patient pages. Supraventricular tachycardia.

PMID- 12485969
TI  - Images in cardiovascular medicine. Bronchogenic cyst: acute presentation.

PMID- 12485971
TI  - Therapeutic angiogenesis: hope or hype.

PMID- 12485973
TI  - Criss-cross heart with d-ventricular loop.

PMID- 12485972
TI  - Plasma catecholamines and chronic congestive heart failure.

PMID- 12485974
TI  - Predicting death in patients with acute type a aortic dissection.

PMID- 12485975
TI  - Acronyms Must always bE defiNed (AMEN).

PMID- 12485976
TI  - Effect of roxithromycin treatment on the endothelial function of Chlamydia
      pneumoniae seropositive men suffering from peripheral arterial occlusive disease.

PMID- 12485977
TI  - ATP III calls for more intensive low-density lipoprotein lowering in target
      groups.

PMID- 12485978
TI  - Implications of long-term outcome research for the management of patients with
      borderline personality disorder.
AB  - Fifteen- and 27-year follow-up studies of patients with borderline personality
      disorder show that most of them no longer meet full criteria for the disorder by
      age 40, and that even more show improvement by age 50. The mechanisms behind
      remission could include maturation, social learning, and the avoidance of
      conflictual intimacy. Affective instability is slower to change than impulsivity.
      Suicide rates in patients with this disorder are close to 10%, with most
      completions occurring late in the course of illness; early mortality from all
      causes exceeds 18%. All of these findings have clinical implications. Although
      treatment effects must be assessed in the context of naturalistic improvement,
      therapy can hasten remission.

PMID- 12485980
TI  - The overlap of depressive personality disorder and dysthymia: a categorical
      problem with a dimensional solution.
AB  - In this paper we review the research literature on depressive personality. We
      begin with a brief discussion of the historical antecedents of the current
      debate, noting the long-standing uncertainty about the relation of this construct
      to both major mood disorders and normal temperament. Then we examine the DSM-IV
      Appendix B construct of depressive personality disorder, in particular its
      controversial overlap with dysthymic disorder. This overlap is discussed within
      the construct validation criteria proposed by Robins and Guze (1970),
      highlighting recent developments and responding to criticisms of our previous
      theoretical review. Finally, we examine dimensional alternatives to the current
      proposed depressive personality disorder construct using the framework of the
      five-factor model. We conclude that, despite persuasive evidence for the
      existence of depressive personality traits, support is insufficient for the
      inclusion of depressive personality disorder as currently defined. Instead, we
      propose that depressive traits are best conceptualized dimensionally, and as part
      of an overarching model of personality structure, rather than as a discrete
      diagnostic entity. Since this conclusion could also be drawn for many existing
      personality disorders, the issues raised here are relevant to the construction of
      DSM-V.

PMID- 12485981
TI  - Recurrent suicide attempts, self-mutilation, and binge/purge behavior: a case
      report.

PMID- 12485979
TI  - Diffusion tensor imaging and its application to neuropsychiatric disorders.
AB  - Magnetic resonance diffusion tensor imaging (DTI) is a new technique that can be
      used to visualize and measure the diffusion of water in brain tissue; it is
      particularly useful for evaluating white matter abnormalities. In this paper, we
      review research studies that have applied DTI for the purpose of understanding
      neuropsychiatric disorders. We begin with a discussion of the principles involved
      in DTI, followed by a historical overview of magnetic resonance diffusion
      weighted imaging and DTI and a brief description of several different methods of
      image acquisition and quantitative analysis. We then review the application of
      this technique to clinical populations. We include all studies published in
      English from January 1996 through March 2002 on this topic, located by searching
      PubMed and Medline on the key words "diffusion tensor imaging" and "MRI."
      Finally, we consider potential future uses of DTI, including fiber tracking and
      surgical planning and follow-up.

PMID- 12485982
TI  - Was there a communist psychiatry? Politics and East German psychiatric care, 1945
      1989.

PMID- 12485983
TI  - Implications of developments in cognitive neuroscience for psychoanalytic
      psychotherapy.

PMID- 12485985
TI  - Matrix metalloproteinases in the adult brain physiology: a link between c-Fos, AP
      1 and remodeling of neuronal connections?
AB  - Matrix metalloproteinases (MMPs), together with their endogenous inhibitors
      (TIMPs) form an enzymatic system that plays an important role in a variety of
      physiological and pathological conditions. These proteins are also expressed in
      the brain, especially under pathological conditions, in which glia as well as
      invading inflammatory cells provide the major source of the MMP activity.
      Surprisingly little is known about the MMP function(s) in adult neuronal
      physiology. This review describes available data on this topic, which is
      presented in a context of knowledge about the MMP/TIMP system in other organs as
      well as in brain disorders. An analysis of the MMP and TIMP expression patterns
      in the brain, along with a consideration of their regulatory mechanisms and
      substrates, leads to the proposal of possible roles of the MMP system in the
      brain. This analysis suggests that MMPs may play an important role in the
      neuronal physiology, especially in neuronal plasticity, including their direct
      participation in the remodeling of synaptic connections-a mechanism pivotal for
      learning and memory.

PMID- 12485984
TI  - A fly's eye view of EGF receptor signalling.

PMID- 12485986
TI  - Structural and functional characterization of the Pseudomonas hydroperoxide
      resistance protein Ohr.
AB  - Bacteria have developed complex strategies to detoxify and repair damage caused
      by reactive oxygen species. These compounds, produced during bacterial aerobic
      respiration as well as by the host immune system cells as a defense mechanism
      against the pathogenic microorganisms, have the ability to damage nucleic acids,
      proteins and phospholipid membranes. Here we describe the crystal structure of
      Pseudomonas aeruginosa Ohr, a member of a recently discovered family of organic
      hydroperoxide resistance proteins. Ohr is a tightly folded homodimer, with a
      novel alpha/beta fold, and contains two active sites located at the monomer
      interface on opposite sides of the molecule. Using in vitro assays, we
      demonstrate that Ohr functions directly as a hydroperoxide reductase, converting
      both inorganic and organic hydroperoxides to less toxic metabolites. Site
      directed mutagenesis confirms that the two conserved cysteines in each active
      site are essential for catalytic activity. We propose that the Ohr catalytic
      mechanism is similar to that of the structurally unrelated peroxiredoxins,
      directly utilizing highly reactive cysteine thiol groups to elicit hydroperoxide
      reduction.

PMID- 12485987
TI  - A novel variant of the immunoglobulin fold in surface adhesins of Staphylococcus
      aureus: crystal structure of the fibrinogen-binding MSCRAMM, clumping factor A.
AB  - We report here the crystal structure of the minimal ligand-binding segment of the
      Staphylococcus aureus MSCRAMM, clumping factor A. This fibrinogen-binding segment
      contains two similarly folded domains. The fold observed is a new variant of the
      immunoglobulin motif that we have called DE-variant or the DEv-IgG fold. This
      subgroup includes the ligand-binding domain of the collagen-binding S.aureus
      MSCRAMM CNA, and many other structures previously classified as jelly rolls.
      Structure predictions suggest that the four fibrinogen-binding S.aureus MSCRAMMs
      identified so far would also contain the same DEv-IgG fold. A systematic docking
      search using the C-terminal region of the fibrinogen gamma-chain as a probe
      suggested that a hydrophobic pocket formed between the two DEv-IgG domains of the
      clumping factor as the ligand-binding site. Mutagenic substitution of residues
      Tyr256, Pro336, Tyr338 and Lys389 in the clumping factor, which are proposed to
      contact the terminal residues (408)AGDV(411) of the gamma-chain, resulted in
      proteins with no or markedly reduced affinity for fibrinogen.

PMID- 12485988
TI  - Immune response of Anopheles gambiae to the early sporogonic stages of the human
      malaria parasite Plasmodium falciparum.
AB  - Deciphering molecular interactions between the malaria parasite and its mosquito
      vector is an emerging area of research that will be greatly facilitated by the
      recent sequencing of the genomes of Anopheles gambiae mosquito and of various
      Plasmodium species. So far, most such studies have focused on Plasmodium berghei,
      a parasite species that infects rodents and is more amenable to studies. Here, we
      analysed the expression pattern of nine An.gambiae genes involved in immune
      surveillance during development of the human malaria parasite P.falciparum in
      mosquitoes fed on parasite-containing blood from patients in Cameroon. We found
      that P.falciparum ingestion triggers a midgut-associated, as well as a systemic,
      response in the mosquito, with three genes, NOS, defensin and GNBP, being
      regulated by ingestion of gametocytes, the infectious stage of the parasite.
      Surprisingly, we found a different pattern of expression of these genes in the
      An.gambiae-P.berghei model. Therefore, differences in mosquito reaction against
      various Plasmodium species may exist, which stresses the need to validate the
      main conclusions suggested by the P.berghei-An.gambiae model in the P.falciparum
      An.gambiae system.

PMID- 12485989
TI  - Pep-13, a plant defense-inducing pathogen-associated pattern from Phytophthora
      transglutaminases.
AB  - Innate immunity, an ancient form of defense against microbial infection, is well
      described for animals and is also suggested to be important for plants.
      Discrimination from self is achieved through receptors that recognize pathogen
      associated molecular patterns (PAMPs) not found in the host. PAMPs are
      evolutionarily conserved structures which are functionally important and, thus,
      not subject to frequent mutation. Here we report that the previously described
      peptide elicitor of defense responses in parsley, Pep-13, constitutes a surface
      exposed fragment within a novel calcium-dependent cell wall transglutaminase
      (TGase) from Phytophthora sojae. TGase transcripts and TGase activity are
      detectable in all Phytophthora species analyzed, among which are some of the most
      destructive plant pathogens. Mutational analysis within Pep-13 identified the
      same amino acids indispensable for both TGase and defense-eliciting activity. Pep
      13, conserved among Phytophthora TGases, activates defense in parsley and potato,
      suggesting its function as a genus-specific recognition determinant for the
      activation of plant defense in host and non-host plants. In summary, plants may
      recognize PAMPs with characteristics resembling those known to trigger innate
      immune responses in animals.

PMID- 12485990
TI  - Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate
      to shape the sensory hair cell bundle.
AB  - Deaf-blindness in three distinct genetic forms of Usher type I syndrome (USH1) is
      caused by defects in myosin VIIa, harmonin and cadherin 23. Despite being
      critical for hearing, the functions of these proteins in the inner ear remain
      elusive. Here we show that harmonin, a PDZ domain-containing protein, and
      cadherin 23 are both present in the growing stereocilia and that they bind to
      each other. Moreover, we demonstrate that harmonin b is an F-actin-bundling
      protein, which is thus likely to anchor cadherin 23 to the stereocilia
      microfilaments, thereby identifying a novel anchorage mode of the cadherins to
      the actin cytoskeleton. Moreover, harmonin b interacts directly with myosin VIIa,
      and is absent from the disorganized hair bundles of myosin VIIa mutant mice,
      suggesting that myosin VIIa conveys harmonin b along the actin core of the
      developing stereocilia. We propose that the shaping of the hair bundle relies on
      a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is
      essential to ensure the cohesion of the stereocilia.

PMID- 12485991
TI  - SCL/tal-1-dependent process determines a competence to select the definitive
      hematopoietic lineage prior to endothelial differentiation.
AB  - Hematopoiesis in most vertebrate species occurs in two distinct phases, primitive
      and definitive, which diverge from FLK1(+)VE-cadherin(-) mesoderm and FLK1(+)VE
      cadherin(+) endothelial cells (EC), respectively. This study aimed at determining
      the stage at which hematopoietic lineage fate is determined by manipulating the
      SCL/tal-1 expression that is known to be essential for the early development of
      the primitive and definitive hematopoietic systems. We established SCL-null ES
      cell lines in which SCL expression is rescued by tamoxifen-inducible Cre
      recombinase-loxP site-mediated recombination. While no hematopoietic cells (HPC)
      were detected in SCL-null ES cell differentiation cultures, SCL gene reactivation
      from day 2 to day 4 after initiation of differentiation could rescue both
      primitive and definitive hematopoiesis. SCL reactivation at later phases was
      ineffective. Moreover, generation of VE-cadherin(+) EC that can give rise to
      definitive HPC required SCL reactivation prior to VE-cadherin expression. These
      results indicated that the competence to become HPC is acquired at the mesodermal
      stage by a SCL-dependent process that takes place independently of determination
      of endothelial fate.

PMID- 12485992
TI  - Adaptation to Fe-deficiency requires remodeling of the photosynthetic apparatus.
AB  - The molecular mechanisms underlying the onset of Fe-deficiency chlorosis and the
      maintenance of photosynthetic function in chlorotic chloroplasts are relevant to
      global photosynthetic productivity. We describe a series of graded responses of
      the photosynthetic apparatus to Fe-deficiency, including a novel response that
      occurs prior to the onset of chlorosis, namely the disconnection of the LHCI
      antenna from photosystem I (PSI). We propose that disconnection is mediated by a
      change in the physical properties of PSI-K in PSI in response to a change in
      plastid Fe content, which is sensed through the occupancy, and hence activity, of
      the Fe-containing active site in Crd1. We show further that progression of the
      response involves remodeling of the antenna complexes-specific degradation of
      existing proteins coupled to the synthesis of new ones, and establishment of a
      new steady state with decreased stoichiometry of electron transfer complexes. We
      suggest that these responses are typical of a dynamic photosynthetic apparatus
      where photosynthetic function is optimized and photooxidative damage is minimized
      in graduated responses to a combination of nutrients, light quantity and quality.

PMID- 12485993
TI  - Physiological calcium concentrations regulate calmodulin binding and catalysis of
      adenylyl cyclase exotoxins.
AB  - Edema factor (EF) and CyaA are calmodulin (CaM)-activated adenylyl cyclase
      exotoxins involved in the pathogenesis of anthrax and whooping cough,
      respectively. Using spectroscopic, enzyme kinetic and surface plasmon resonance
      spectroscopy analyses, we show that low Ca(2+) concentrations increase the
      affinity of CaM for EF and CyaA causing their activation, but higher Ca(2+)
      concentrations directly inhibit catalysis. Both events occur in a physiologically
      relevant range of Ca(2+) concentrations. Despite the similarity in Ca(2+)
      sensitivity, EF and CyaA have substantial differences in CaM binding and
      activation. CyaA has 100-fold higher affinity for CaM than EF. CaM has N- and C
      terminal globular domains, each binding two Ca(2+) ions. CyaA can be fully
      activated by CaM mutants with one defective C-terminal Ca(2+)-binding site or by
      either terminal domain of CaM while EF cannot. EF consists of a catalytic core
      and a helical domain, and both are required for CaM activation of EF. Mutations
      that decrease the interaction of the helical domain with the catalytic core
      create an enzyme with higher sensitivity to Ca(2+)-CaM activation. However, CyaA
      is fully activated by CaM without the domain corresponding to the helical domain
      of EF.

PMID- 12485994
TI  - Glycerotoxin from Glycera convoluta stimulates neurosecretion by up-regulating N
      type Ca2+ channel activity.
AB  - We report here the purification of glycerotoxin from the venom of Glycera
      convoluta, a novel 320 kDa protein capable of reversibly stimulating spontaneous
      and evoked neurotransmitter release at the frog neuromuscular junction. However,
      glycerotoxin is ineffective at the murine neuromuscular junction, which displays
      a different subtype of voltage- dependent Ca(2+) channels. By sequential and
      selective inhibition of various types of Ca(2+) channels, we found that
      glycerotoxin was acting via Ca(v)2.2 (N-type). In neuroendocrine cells, it
      elicits a robust, albeit transient, influx of Ca(2+) sensitive to the Ca(v)2.2
      blockers omega-conotoxin GVIA and MVIIA. Moreover, glycerotoxin triggers a Ca(2+)
      transient in human embryonic kidney (HEK) cells over-expressing Ca(v)2.2 but not
      Ca(v)2.1 (P/Q-type). Whole-cell patch-clamp analysis of Ca(v)2.2 expressing HEK
      cells revealed an up-regulation of Ca(2+) currents due to a leftward shift of the
      activation peak upon glycerotoxin addition. A direct interaction between Ca(v)2.2
      and this neurotoxin was revealed by co-immunoprecipitation experiments.
      Therefore, glycerotoxin is a unique addition to the arsenal of tools available to
      unravel the mechanism controlling Ca(2+)-regulated exocytosis via the specific
      activation of Ca(v)2.2.

PMID- 12485995
TI  - Store-operated Ca2+ entry depends on mitochondrial Ca2+ uptake.
AB  - Store-operated Ca(2+) channels, which are activated by the emptying of
      intracellular Ca(2+) stores, provide one major route for Ca(2+) influx. Under
      physiological conditions of weak intracellular Ca(2+) buffering, the ubiquitous
      Ca(2+) releasing messenger InsP(3) usually fails to activate any store-operated
      Ca(2+) entry unless mitochondria are maintained in an energized state.
      Mitochondria rapidly take up Ca(2+) that has been released by InsP(3), enabling
      stores to empty sufficiently for store-operated channels to activate. Here, we
      report a novel role for mitochondria in regulating store-operated channels under
      physiological conditions. Mitochondrial depolarization suppresses store-operated
      Ca(2+) influx independently of how stores are depleted. This role for
      mitochondria is unrelated to their actions on promoting InsP(3)-sensitive store
      depletion, can be distinguished from Ca(2+)-dependent inactivation of the store
      operated channels and does not involve changes in intracellular ATP, oxidants,
      cytosolic acidification, nitric oxide or the permeability transition pore, but is
      suppressed when mitochondrial Ca(2+) uptake is impaired. Our results suggest that
      mitochondria may have a more fundamental role in regulating store-operated influx
      and raise the possibility of bidirectional Ca(2+)-dependent crosstalk between
      mitochondria and store-operated Ca(2+) channels.

PMID- 12485996
TI  - Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin
      chains.
AB  - Loss of the tumour suppressor BRCA1 results in profound chromosomal instability.
      The fundamental defect underlying this catastrophic phenotype is not yet known.
      In vivo, BRCA1 forms a heterodimeric complex with BARD1. Both proteins contain an
      N-terminal zinc RING-finger domain which confers E3 ubiquitin ligase activity. We
      have isolated full-length human BRCA1/BARD1 complex and have shown that it has a
      dual E3 ubiquitin ligase activity. First, it mediates the monoubiquitylation of
      nucleosome core histones in vitro, including the variant histone H2AX that co
      localizes with BRCA1 at sites of DNA damage. Secondly, BRCA1/BARD1 catalyses the
      formation of multiple polyubiquitin chains on itself. Remarkably, this auto
      polyubiquitylation potentiates the E3 ubiquitin ligase activity of the
      BRCA1/BARD1 complex >20-fold. Even though BRCA1 has been reported to associate
      with a C-terminal ubiquitin hydrolase, BAP1, this enzyme does not appear to
      function in the deubiquitylation of the BRCA1/BARD1 complex.

PMID- 12485997
TI  - Is protein disulfide isomerase a redox-dependent molecular chaperone?
AB  - Protein disulfide isomerase (PDI) is a multifunctional protein catalysing the
      formation of disulfide bonds, acting as a molecular chaperone and being a
      component of the enzymes prolyl 4-hydroxylase (P4H) and microsomal triglyceride
      transfer protein. The role of PDI as a molecular chaperone or polypeptide-binding
      protein is mediated primarily through an interaction of substrates with its b'
      domain. It has been suggested that this binding is regulated by the redox state
      of PDI, with association requiring the presence of glutathione, and dissociation
      the presence of glutathione disulfide. To determine whether this is the case, we
      investigated the ability of PDI to bind to a folding polypeptide chain within a
      functionally intact endoplasmic reticulum and to be dissociated from the alpha
      subunit of P4H in vitro in the presence of reducing or oxidizing agents. Our
      results clearly demonstrate that binding of PDI to these polypeptides is not
      regulated by its redox state. We also demonstrate that the dissociation of PDI
      from substrates observed in the presence of glutathione disulfide can be
      explained by competition for the peptide-binding site on PDI.

PMID- 12485998
TI  - PDK1-dependent activation of atypical PKC leads to degradation of the p21 tumour
      modifier protein.
AB  - p21(WAF1/CIP1) Contributes to positive and negative growth control on multiple
      levels. We previously mapped phosphorylation sites within the C-terminal domain
      of p21 that regulate proliferating cell nuclear antigen binding. In the current
      study, a kinase has been fractionated from mammalian cells that
      stoichiometrically phosphorylates p21 at the Ser146 site, and the enzyme has been
      identified as an insulin-responsive atypical protein kinase C (aPKC). Expression
      of PKCzeta or activation of the endogenous kinase by 3-phosphoinositide dependent
      protein kinase-1 (PDK1) decreased the half-life of p21. Conversely, dnPKCzeta or
      dnPDK1 increased p21 protein half-life, and a PDK1-dependent increase in the rate
      of p21 degradation was mediated by aPKC. Insulin stimulation gave a biphasic
      response with a rapid transient decrease in p21 protein levels during the initial
      signalling phase that was dependent on phosphatidylinositol 3- kinase, PKC and
      proteasome activity. Thus, aPKC provides a physiological signal for the
      degradation of p21. The rapid degradation of p21 protein during the signalling
      phase of insulin stimulation identifies a novel link between energy metabolism
      and a key modulator of cell cycle progression.

PMID- 12485999
TI  - Gelsolin-induced epithelial cell invasion is dependent on Ras-Rac signaling.
AB  - Gelsolin is a widely distributed actin binding protein involved in controlling
      cell morphology, motility, signaling and apoptosis. The role of gelsolin in tumor
      progression, however, remains poorly understood. Here we show that expression of
      green fluorescent protein (GFP)-tagged gelsolin in MDCK-AZ, MDCKtsSrc or HEK293T
      cells promotes invasion into collagen type I. In organ culture assays, MDCK cells
      expressing gelsolin-GFP invaded pre-cultured chick heart fragments. Gelsolin
      expression inhibited E-cadherin-mediated cell aggregation but did not disrupt the
      E-cadherin-catenin complex. Co-expression of dominant-negative Rac1N17, but not
      RhoAN19 or Cdc42N17, counteracted gelsolin-induced invasion, suggesting a
      requirement for Rac1 activity. Increased ARF6, PLD or PIP5K 1alpha activity
      canceled out gelsolin-induced invasion. Furthermore, we found that invasion
      induced by gelsolin is dependent on Ras activity, acting through the PI3K-Rac
      pathway via the Ras guanine nucleotide exchange factor Sos-1. These findings
      establish a connection between gelsolin and the Ras oncogenic signaling pathway.

PMID- 12486000
TI  - Activation of Rac1 by shear stress in endothelial cells mediates both
      cytoskeletal reorganization and effects on gene expression.
AB  - Hemodynamic shear stress is a fundamental determinant of vascular remodeling and
      atherogenesis. Changes in focal adhesions, cytoskeletal organization and gene
      expression are major responses of endothelial cells to shear stress. Here, we
      show that activation of the small GTPase Rac is essential for gene expression and
      for providing spatial information for shear stress-induced cell alignment.
      Fluorescence resonance energy transfer (FRET) localizes activated Rac1 in the
      direction of flow. This directional Rac1 activation is downstream of shear
      induced new integrin binding to extracellular matrix. Additionally, Rac1 mediates
      flow-induced stimulation of nuclear factor kappaB (NF-kappaB) and the subsequent
      expression of intercellular cell adhesion molecule 1 (ICAM-1), an adhesion
      receptor involved in the recruitment of leukocytes to atherosclerotic plaque.
      These studies provide a unifying model linking three of the main responses to
      shear stress that mediate both normal adaptation to hemodynamic forces and
      inflammatory dysfunction of endothelial cells in atherosclerosis.

PMID- 12486001
TI  - HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro
      apoptotic Bcl-2 relative Bim.
AB  - Depletion of CD4(+) T cells is the hallmark of HIV infection and AIDS
      progression. In addition to the direct killing of the viral-infected cells, HIV
      infection also leads to increased apoptosis of predominantly uninfected bystander
      cells. This is mediated in part through the HIV-1 Tat protein, which is secreted
      by the infected cells and taken up by uninfected cells. Using an affinity
      purification approach, a specific and direct interaction of Tat with tubulin and
      polymerized microtubules has been detected. This interaction does not affect the
      secretion and uptake of Tat, but is critical for Tat to induce apoptosis. Tat
      binds tubulin/microtubules through a four-amino-acid subdomain of its conserved
      core region, leading to the alteration of microtubule dynamics and activation of
      a mitochondria-dependent apoptotic pathway. Bim, a pro-apoptotic Bcl-2 relative
      and a transducer of death signals initiated by perturbation of microtubule
      dynamics, facilitates the Tat-induced apoptosis. Our findings reveal a strategy
      by which Tat induces apoptosis by targeting the microtubule network. Thus HIV-1
      Tat joins a growing list of pathogen-derived proteins that target the
      cytoskeleton of host cells.

PMID- 12486002
TI  - Differential acetylation of Tat coordinates its interaction with the co
      activators cyclin T1 and PCAF.
AB  - The HIV-1 transactivator protein, Tat, is an atypical transcriptional activator
      that functions through binding, not to DNA, but to a short leader RNA, TAR.
      Although details of its functional mechanism are still unknown, emerging findings
      suggest that Tat serves primarily to adapt co-activator complexes such as p300,
      PCAF and P-TEFb to the HIV-1 long terminal repeat. Hence, an understanding of how
      Tat interacts with these cofactors is crucial. It has recently been shown that
      acetylation at a single lysine, residue 50, regulated the association of Tat with
      PCAF. Here, we report that in the absence of Tat acetylation, PCAF binds to amino
      acids 20-40 within Tat. Interestingly, acetylation of Tat at Lys28 abrogates Tat
      PCAF interaction. Acetylation at Lys50 creates a new site for binding to PCAF and
      dictates the formation of a ternary complex of Tat-PCAF-P-TEFb. Thus,
      differential lysine acetylation of Tat coordinates the interactions with its co
      activators, cyclin T1 and PCAF. Our results may help in understanding the ordered
      recruitment of Tat co-activators to the HIV-1 promoter.

PMID- 12486003
TI  - In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation.
AB  - Trichostatin A (TSA) inhibits all histone deacetylases (HDACs) of both class I
      and II, whereas trapoxin (TPX) cannot inhibit HDAC6, a cytoplasmic member of
      class II HDACs. We took advantage of this differential sensitivity of HDAC6 to
      TSA and TPX to identify its substrates. Using this approach, alpha-tubulin was
      identified as an HDAC6 substrate. HDAC6 deacetylated alpha-tubulin both in vivo
      and in vitro. Our investigations suggest that HDAC6 controls the stability of a
      dynamic pool of microtubules. Indeed, we found that highly acetylated
      microtubules observed after TSA treatment exhibited delayed drug-induced
      depolymerization and that HDAC6 overexpression prompted their induced
      depolymerization. Depolymerized tubulin was rapidly deacetylated in vivo, whereas
      tubulin acetylation occurred only after polymerization. We therefore suggest that
      acetylation and deacetylation are coupled to the microtubule turnover and that
      HDAC6 plays a key regulatory role in the stability of the dynamic microtubules.

PMID- 12486004
TI  - HDA6, a putative histone deacetylase needed to enhance DNA methylation induced by
      double-stranded RNA.
AB  - To analyze relationships between RNA signals, DNA methylation and chromatin
      modifications, we performed a genetic screen to recover Arabidopsis mutants
      defective in RNA-directed transcriptional silencing and methylation of a nopaline
      synthase promoter-neomycinphosphotransferase II (NOSpro- NPTII) target gene.
      Mutants were identified by screening for recovery of kanamycin resistance in the
      presence of an unlinked silencing complex encoding NOSpro double-stranded RNA.
      One mutant, rts1 (RNA-mediated transcriptional silencing), displayed moderate
      recovery of NPTII gene expression and partial loss of methylation in the target
      NOSpro, predominantly at symmetrical C(N)Gs. The RTS1 gene was isolated by
      positional cloning and found to encode a putative histone deacetylase, HDA6. The
      more substantial decrease in methylation of symmetrical compared with
      asymmetrical cytosines in rts1 mutants suggests that HDA6 is dispensable for RNA
      directed de novo methylation, which results in intermediate methylation of
      cytosines in all sequence contexts, but is necessary for reinforcing primarily
      C(N)G methylation induced by RNA. Because CG methylation in centromeric and rDNA
      repeats was not reduced in rts1 mutants, HDA6 might be specialized for the RNA-
      directed pathway of genome modification.

PMID- 12486005
TI  - An Arabidopsis SET domain protein required for maintenance but not establishment
      of DNA methylation.
AB  - Cytosine methylation is critical for correct development and genome stability in
      mammals and plants. In order to elucidate the factors that control genomic DNA
      methylation patterning, a genetic screen for mutations that disrupt methylation
      correlated silencing of the endogenous gene PAI2 was conducted in Arabidopsis:
      This screen yielded seven loss-of-function alleles in a SET domain protein with
      histone H3 Lys9 methyltransferase activity, SUVH4. The mutations conferred
      reduced cytosine methylation on PAI2, especially in non-CG sequence contexts, but
      did not affect methylation on another PAI locus carrying two genes arranged as an
      inverted repeat. Moreover, an unmethylated PAI2 gene could be methylated de novo
      in the suvh4 mutant background. These results suggest that SUVH4 is involved in
      maintenance but not establishment of methylation at particular genomic regions.
      In contrast, a heterochromatin protein 1 homolog, LHP1, had no effect on PAI
      methylation.

PMID- 12486006
TI  - R2 retrotransposition on assembled nucleosomes depends on the translational
      position of the target site.
AB  - R2 retrotransposons insert into the 28S rRNA genes of insects. Integration occurs
      by specific cleavage of the target site and utilization of the released DNA end
      to prime reverse transcription of the RNA transcript. Specificity of the protein
      to the target site is dependent upon nucleotide sequence recognition extending
      from 35 bp upstream to 15 bp downstream of the cleavage site. In this report, we
      show that sequence recognition and cleavage by the R2 protein can occur while the
      target site is assembled into nucleosomes. Reconstitution of DNA fragments
      containing the 28S gene sequence into a set of nucleosomes with different
      translational frames revealed that the R2 site adopted the same rotational
      orientation with respect to the histone octamer. Binding and cleavage by the R2
      protein were most efficient when the upstream binding site for the R2 protein was
      near a nucleosome end. Interaction of the R2 protein with the nucleosome
      disrupted the histone:DNA contacts in the 50 bp region directly bound by R2, but
      did not modify the remainder of the nucleosome structure.

PMID- 12486007
TI  - The DNA chaperone HMGB1 facilitates ACF/CHRAC-dependent nucleosome sliding.
AB  - Nucleosome remodelling complexes CHRAC and ACF contribute to chromatin dynamics
      by converting chemical energy into sliding of histone octamers on DNA. Their
      shared ATPase subunit ISWI binds DNA at the sites of entry into the nucleosome. A
      prevalent model assumes that DNA distortions catalysed by ISWI are converted into
      relocation of DNA relative to a histone octamer. HMGB1, one of the most abundant
      nuclear non-histone proteins, binds with preference to distorted DNA. We have now
      found that transient interaction of HMGB1 with nucleosomal linker DNA overlapping
      ISWI-binding sites enhances the ability of ACF to bind nucleosomal DNA and
      accelerates the sliding activity of limiting concentrations of remodelling
      factor. By contrast, an HMGB1 mutant with increased binding affinity was
      inhibitory. These observations are consistent with a role for HMGB1 as a DNA
      chaperone facilitating the rate-limiting DNA distortion during nucleosome
      remodelling.

PMID- 12486008
TI  - An inserted region of leucyl-tRNA synthetase plays a critical role in group I
      intron splicing.
AB  - Yeast mitochondrial leucyl-tRNA synthetase (LeuRS) binds to the bI4 intron and
      collaborates with the bI4 maturase to aid excision of the group I intron.
      Deletion analysis isolated the inserted LeuRS CP1 domain as a critical factor in
      the protein's splicing activity. Protein fragments comprised of just the LeuRS
      CP1 region rescued complementation of a yeast strain that expressed a splicing
      defective LeuRS. Three-hybrid analysis determined that these CP1-containing LeuRS
      fragments, ranging from 214 to 375 amino acids, bound to the bI4 intron. In each
      case, interactions with only the LeuRS protein fragment specifically stimulated
      bI4 intron splicing activity. Substitution of a homologous CP1 domain from
      isoleucyl-tRNA synthetase or mutation within the LeuRS CP1 region of the smallest
      protein fragment abolished RNA binding and splicing activity. The CP1 domain is
      best known for its amino acid editing activity. However, these results suggest
      that elements within the LeuRS CP1 domain also play a novel role, independent of
      the full-length tRNA synthetase, in binding the bI4 group I intron and
      facilitating its self-splicing activity.

PMID- 12486009
TI  - The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment
      to 5' splice sites.
AB  - The U1 small nuclear ribonucleoprotein (U1 snRNP) binds to the pre-mRNA 5' splice
      site (ss) at early stages of spliceosome assembly. Recruitment of U1 to a class
      of weak 5' ss is promoted by binding of the protein TIA-1 to uridine-rich
      sequences immediately downstream from the 5' ss. Here we describe a molecular
      dissection of the activities of TIA-1. RNA recognition motifs (RRMs) 2 and 3 are
      necessary and sufficient for binding to the pre-mRNA. The non- consensus RRM1 and
      the C-terminal glutamine-rich (Q) domain are required for association with U1
      snRNP and to facilitate its recruitment to 5' ss. Co-precipitation experiments
      revealed a specific and direct interaction involving the N-terminal region of the
      U1 protein U1-C and the Q-rich domain of TIA-1, an interaction enhanced by RRM1.
      The results argue that binding of TIA-1 in the vicinity of a 5' ss helps to
      stabilize U1 snRNP recruitment, at least in part, via a direct interaction with
      U1-C, thus providing one molecular mechanism for the function of this splicing
      regulator.

PMID- 12486010
TI  - In Saccharomyces cerevisiae, ATP2 mRNA sorting to the vicinity of mitochondria is
      essential for respiratory function.
AB  - We recently demonstrated that polysome-associated mRNAs that co-isolate with
      mitochondria encode a subset of mitochondrial proteins, and that the 3' UTRs of
      these transcripts are essential for their localization to the vicinity of the
      organelle. To address the question of the involvement of the mRNA targeting
      process in mitochondrial biogenesis, we studied the role of ATP2 3' UTR. An
      altered ATP2 allele in which the 3' UTR was replaced by the ADH1 3' UTR exhibits
      properties supporting the importance of mRNA localization to the vicinity of
      mitochondria: (i) the mutated strain presents a respiratory dysfunction; (ii)
      mitochondrial import of the protein translated from the altered gene is strongly
      reduced, even though the precursor is addressed to the organelle surface; (iii)
      systematic deletions of ATP2 3' UTR revealed a 100 nucleotide element presenting
      RNA targeting properties. Additionally, when the ATM1 3' UTR was replaced by the
      ADH1 3' UTR, we obtained cells in which ATM1 mRNA is also delocalized, and
      presenting a respiratory dysfunction. This demonstrates that mRNA localization to
      the vicinity of mitochondria plays a critical role in organelle biogenesis.

PMID- 12486011
TI  - PNPase activity determines the efficiency of mRNA 3'-end processing, the
      degradation of tRNA and the extent of polyadenylation in chloroplasts.
AB  - The exoribonuclease polynucleotide phosphorylase (PNPase) has been implicated in
      mRNA processing and degradation in bacteria as well as in chloroplasts of higher
      plants. Here, we report the first comprehensive in vivo study of chloroplast
      PNPase function. Modulation of PNPase activity in Arabidopsis chloroplasts by a
      reverse genetic approach revealed that, although this enzyme is essential for
      efficient 3'-end processing of mRNAs, it is insufficient to mediate transcript
      degradation. Surprisingly, we identified PNPase as also being indispensable for
      3'-end maturation of 23S rRNA transcripts. Analysis of tRNA amounts in transgenic
      Arabidopsis plants suggests a direct correlation of PNPase activity and tRNA
      levels, indicating an additional function of this exoribo nuclease in tRNA decay.
      Moreover, the extent of polyadenylated mRNAs in chloroplasts is negatively
      correlated with PNPase activity. Together, our results attribute novel functions
      to PNPase in the metabolism of all major classes of plastid RNAs and suggest an
      unexpectedly complex role for PNPase in RNA processing and decay.

PMID- 12486012
TI  - Human Dcp2: a catalytically active mRNA decapping enzyme located in specific
      cytoplasmic structures.
AB  - We have cloned cDNAs for the human homologues of the yeast Dcp1 and Dcp2 factors
      involved in the major (5'-3') and NMD mRNA decay pathways. While yeast Dcp1 has
      been reported to be the decapping enzyme, we show that recombinant human Dcp2
      (hDcp2) is enzymatically active. Dcp2 activity appears evolutionarily conserved.
      Mutational and biochemical analyses indicate that the hDcp2 MutT/Nudix domain
      mediates this activity. hDcp2 generates m7GDP and 5'-phosphorylated mRNAs that
      are 5'-3' exonuclease substrates. Corresponding decay intermediates are present
      in human cells showing the relevance of this activity. hDcp1 and hDcp2 co
      localize in cell cytoplasm, consistent with a role in mRNA decay. Interestingly,
      these two proteins show a non-uniform distribution, accumulating in specific
      foci.

PMID- 12486013
TI  - The function of SECIS RNA in translational control of gene expression in
      Escherichia coli.
AB  - The incorporation of selenocysteine into proteins is directed by specific UGA
      codons and mRNA secondary structures, designated SECIS elements. In bacteria,
      these elements are positioned within the reading frame of selenoprotein mRNAs
      immediately downstream of the triplet coding for selenocysteine, and they tether
      a complex of the selenocysteine-specific elongation factor SelB, GTP and
      selenocysteyl-tRNA(Sec) to the site of UGA decoding. A SECIS-like structure was
      identified in the 5' non-translated region of the selAB transcript, encoding
      selenocysteine synthase and SelB. It specifically binds to SelB and the formation
      of a SelB.GTP.selenocysteyl-tRNA(Sec) complex on the SECIS-like element represses
      expression of the downstream gene. This effect is abolished by mutations
      preventing formation of the complex. The regulatory pattern observed correlated
      with the levels of sel gene products. As quaternary complex formation on the
      SECIS-like element did not influence the transcription rate and only slightly
      reduced the level of selAB mRNA, it was concluded that the structure is involved
      in regulating translation initiation efficiency, thereby coupling selenocysteine
      biosynthesis to the availability of the trace element selenium.

PMID- 12486014
TI  - F-actin-like filaments formed by plasmid segregation protein ParM.
AB  - It was the general belief that DNA partitioning in prokaryotes is independent of
      a cytoskeletal structure, which in eukaryotic cells is indispensable for DNA
      segregation. Recently, however, immunofluorescence microscopy revealed highly
      dynamic, filamentous structures along the longitudinal axis of Escherichia coli
      formed by ParM, a plasmid-encoded protein required for accurate segregation of
      low-copy-number plasmid R1. We show here that ParM polymerizes into double
      helical protofilaments with a longitudinal repeat similar to filamentous actin (F
      actin) and MreB filaments that maintain the cell shape of non-spherical bacteria.
      The crystal structure of ParM with and without ADP demonstrates that it is a
      member of the actin family of proteins and shows a domain movement of 25 degrees
      upon nucleotide binding. Furthermore, the crystal structure of ParM reveals major
      differences in the protofilament interface compared with F-actin, despite the
      similar arrangement of the subunits within the filaments. Thus, there is now
      evidence for cytoskeletal structures, formed by actin-like filaments that are
      involved in plasmid partitioning in E.coli.

PMID- 12486015
TI  - Modulation of DNA repair by mutations flanking the DNA channel through RNA
      polymerase.
AB  - The RuvABC and RecBCD proteins promote rescue of stalled or broken DNA
      replication forks in Escherichia coli. Strains lacking these proteins cope poorly
      with DNA damage and have problems with chromosome segregation and cell division.
      We show how these difficulties are overcome to varying degrees by a sub-class of
      RNA polymerase mutations selected for their stringent phenotype. Thirty-five
      mutations were sequenced. All but one change single amino acids in RpoB or RpoC
      that lie on or near the path taken by DNA through the enzyme, indicating they may
      affect the stability of transcription complexes. Four mutant enzymes are shown to
      form unstable open complexes at the lambdacro promoter. At least one may also
      release stalled complexes or limit their formation, as it reduces the need for
      reactivation of transcription by GreA or GreB, and for transcription-coupled DNA
      repair of UV damage by Mfd. The results shed light on the interplay between DNA
      replication and transcription and suggest ways in which conflicts between these
      two vital cellular processes are avoided or resolved.

PMID- 12486017
TI  - Closer to the edge? Contractions, pressures, waterfalls and blood flow to
      contracting skeletal muscle.

PMID- 12486018
TI  - Medullary raphe neuron activity is altered during fictive cough in the
      decerebrate cat.
AB  - Chemical lesions in the medullary raphe nuclei region influence cough. This study
      examined whether firing patterns of caudal medullary midline neurons were altered
      during cough. Extracellular neuron activity was recorded with microelectrode
      arrays in decerebrated, neuromuscular-blocked, ventilated cats. Cough-like motor
      patterns (fictive cough) in phrenic and lumbar nerves were elicited by mechanical
      stimulation of the intrathoracic trachea. Discharge patterns of respiratory and
      nonrespiratory-modulated neurons were altered during cough cycles (58/133); 45
      increased and 13 decreased activity. Fourteen cells changed firing rate during
      the inspiratory and/or expiratory phases of cough. Altered patterns in 43 cells
      were associated with the duration of, or extended beyond, the cough episodes. The
      different response categories suggest that multiple factors influence the
      discharge patterns during coughing: e.g., respiratory-modulated and tonic inputs
      and intrinsic connections. These results suggest involvement of midline neurons
      (i.e., raphe nuclei) in the cough reflex.

PMID- 12486019
TI  - Laryngeal elevation achieved by neuromuscular stimulation at rest.
AB  - During swallowing, airway protection is achieved in part by laryngeal elevation.
      Although multiple muscles are normally active during laryngeal elevation,
      neuromuscular stimulation of select muscles was evaluated to determine which
      single muscle or muscle pair best elevates the larynx and should be considered
      during future studies of neuromuscular stimulation in dysphagic patients. Hooked
      wire monopolar electrodes were inserted into mylohyoid, thyrohyoid, and
      geniohyoid muscle regions in 15 healthy men selected for having a highly visible
      thyroid prominence for videotaping. During trials of single, bilateral, and
      combined muscle stimulations, thyroid prominence movements were video recorded,
      digitized, and normalized relative to elevation during a 2-ml water swallow.
      Individual muscle stimulation induced approximately 30% of the elevation observed
      during a swallow and approximately 50% of swallow velocity, whereas paired muscle
      stimulation resulted in approximately 50% of the elevation and approximately 80%
      of the velocity produced during a swallow. Paired muscle stimulation produced
      significantly greater elevation than single muscle stimulation and could assist
      with laryngeal elevation in dysphagic patients with reduced or delayed laryngeal
      elevation.

PMID- 12486020
TI  - Effect of hyperthyroidism on spontaneous physical activity and energy expenditure
      in rats.
AB  - Thyroid hormone excess is associated with increased energy expenditure. The
      contributions of increases in spontaneous physical activity and nonexercise
      activity thermogenesis (NEAT) to this effect have not been defined. To address
      the hypothesis that hyperthyroidism is associated with increased spontaneous
      physical activity and NEAT, we rendered rats hyperthyroid by using continuous
      infusion of high-dose triiodothyronine for 14 days and measured the effects on
      physical activity and NEAT. On day 14, in the hyperthyroid group the mean +/- SD
      triiodothyronine concentration was 755 +/- 137 (range 574-919) ng/dl and in the
      control group 59 +/- 0.5 (58-59) ng/dl. Over the 14-day treatment period, mean
      spontaneous physical activity increased in the hyperthyroid rats from 24 +/- 7 to
      36 +/- 6 activity units (AU)/min; P < 0.001 but did not increase in the controls
      (23 +/- 7 vs. 22 +/- 4 AU/min). Also, over the 14-day period, daily NEAT
      increased in the hyperthyroid rats from 8.1 +/- 2.8 to 19.7 +/- 5.0 kcal/day (P <
      0.001) but did not increase in the controls (8.7 +/- 3.5 cf 9.4 +/- 1.7 kcal/day;
      not significant). In conclusion, hyperthyroidism is associated with increased
      spontaneous physical activity and NEAT.

PMID- 12486021
TI  - Middle ear pressure change during controlled breathing with gas mixtures
      containing nitrous oxide.
AB  - The change in middle ear pressure while breathing gas mixtures containing N(2)O
      was studied in four monkeys. At each of three experimental sessions, monkeys were
      anesthetized, acclimated for 60 min, breathed with room air for 60 min, and then
      breathed with 5, 10, or 20% N(2)O for 60 min. Middle ear pressure, rectal
      temperature, and vital signs were recorded throughout. The time constant for
      blood-middle ear N(2)O exchange was calculated from these data. Middle ear
      pressure decreased during acclimation, was stable during air breathing, and
      increased during N(2)O breathing. The rate of pressure change was similar for
      both ears of each animal and was directly related to N(2)O percent. The
      calculated time constant ranged from 0.003 to 0.008 min(-1) across animals but
      was not different for a given ear across sessions. These results show that
      breathing gas mixtures containing N(2)O causes predictable and quantifiable
      increases in middle ear pressure.

PMID- 12486022
TI  - Frequency dependence of respiratory system mechanics during induced constriction
      in a murine model of asthma.
AB  - Airway dysfunction in asthma is characterized by hyperresponsiveness,
      heterogeneously narrowed airways, and closure of airways. To test the hypothesis
      that airway constriction in ovalbumin (OVA)-sensitized OVA-intranasally
      challenged (OVA/OVA) mice produces mechanical responses that are similar to those
      reported in asthmatic subjects, respiratory system resistance (Rrs) and elastance
      (Edyn,rs) spectra were obtained in OVA/OVA and control mice during intravenous
      methacholine (MCh) infusions. In control mice, MCh at 1,700 microg x kg(-1) x
      min(-1) produced 1) a 495 and 928% increase of Rrs at 0.5 Hz and 19.75 Hz,
      respectively, 2) a 33% rise in Edyn,rs at 0.5 Hz, and 3) a mild frequency (f)
      dependent increase of Edyn,rs. The same MCh dose in OVA/OVA mice produced 1)
      elevations of Rrs at 0.5 Hz and 19.75 Hz of 1,792 and 774%, respectively, 2) a
      390% rise in Edyn,rs at 0.5 Hz, and 3) marked f-dependent increases of Edyn,rs.
      During constriction, the f dependence of mechanics in control mice was consistent
      with homogeneous airway narrowing; however, in OVA/OVA mice, f dependence was
      characteristic of heterogeneously narrowed airways, closure of airways, and
      airway shunting. These mechanisms amplify the pulmonary mechanical responses to
      constrictor stimuli at physiological breathing rates and have important roles in
      the pathophysiology of human asthma.

PMID- 12486023
TI  - Combined intervention of exercise and genistein prevented androgen deficiency
      induced bone loss in mice.
AB  - There is evidence that estrogen plays an important role in skeletal tissue in
      males as well as females. We have reported that phytoestrogens, such as
      genistein, selectively act on bone and exhibit cooperative effects on bone mass
      when combined with exercise in ovariectomized mice. In this study, we examined
      whether both interventions exhibit cooperative effects on bone loss in androgen
      deficient mice similar to those in estrogen-deficient mice. Male mice aged 7 wk
      were either sham operated or orchidectomized (ORX) and divided into six groups:
      1) sham; 2) ORX; 3) ORX and treated with genistein (0.4 mg/day) subcutaneously;
      4) ORX, exercised on a treadmill daily for 30 min/day at 12 m/min; 5) ORX, given
      genistein, and exercised (ORX+ExG); and 6) ORX and treated with 17beta-estradiol
      (E(2)). Four weeks after the intervention, seminal vesicle weight strikingly
      decreased in ORX mice, and it was not affected by administration of genistein or
      E(2). Bone mineral density of whole femur was significantly reduced by ORX, and
      bone loss was prevented by the combined intervention. Histomorphometric analysis
      showed that bone volume and trabecular thickness in the distal femoral cancellous
      bone were significantly lower in the ORX group than in the Sham group, and they
      were completely restored in the ORX+ExG group, as in the ORX with E(2) group.
      These results indicate that the combined intervention of moderate exercise and a
      low dose of genistein administration shows an additive effect in preventing bone
      loss in ORX mice similar to that in ovariectomized mice.

PMID- 12486024
TI  - Neuroplasticity in respiratory motor control.
AB  - Although recent evidence demonstrates considerable neuroplasticity in the
      respiratory control system, a comprehensive conceptual framework is lacking. Our
      goals in this review are to define plasticity (and related neural properties) as
      it pertains to respiratory control and to discuss potential sites, mechanisms,
      and known categories of respiratory plasticity. Respiratory plasticity is defined
      as a persistent change in the neural control system based on prior experience.
      Plasticity may involve structural and/or functional alterations (most commonly
      both) and can arise from multiple cellular/synaptic mechanisms at different sites
      in the respiratory control system. Respiratory neuroplasticity is critically
      dependent on the establishment of necessary preconditions, the stimulus paradigm,
      the balance between opposing modulatory systems, age, gender, and genetics.
      Respiratory plasticity can be induced by hypoxia, hypercapnia, exercise, injury,
      stress, and pharmacological interventions or conditioning and occurs during
      development as well as in adults. Developmental plasticity is induced by
      experiences (e.g., altered respiratory gases) during sensitive developmental
      periods, thereby altering mature respiratory control. The same experience later
      in life has little or no effect. In adults, neuromodulation plays a prominent
      role in several forms of respiratory plasticity. For example, serotonergic
      modulation is thought to initiate and/or maintain respiratory plasticity
      following intermittent hypoxia, repeated hypercapnic exercise, spinal sensory
      denervation, spinal cord injury, and at least some conditioned reflexes.
      Considerable work is necessary before we fully appreciate the biological
      significance of respiratory plasticity, its underlying cellular/molecular and
      network mechanisms, and the potential to harness respiratory plasticity as a
      therapeutic tool.

PMID- 12486025
TI  - Developmental plasticity in respiratory control.
AB  - Development of the mammalian respiratory control system begins early in gestation
      and does not achieve mature form until weeks or months after birth. A relatively
      long gestation and period of postnatal maturation allows for prolonged pre- and
      postnatal interactions with the environment, including experiences such as
      episodic or chronic hypoxia, hyperoxia, and drug or toxin exposures.
      Developmental plasticity occurs when such experiences, during critical periods of
      maturation, result in long-term alterations in the structure or function of the
      respiratory control neural network. A critical period is a time window during
      development devoted to structural and/or functional shaping of the neural systems
      subserving respiratory control. Experience during the critical period can disrupt
      and alter developmental trajectory, whereas the same experience before or after
      has little or no effect. One of the clearest examples to date is blunting of the
      adult ventilatory response to acute hypoxia challenge by early postnatal
      hyperoxia exposure in the newborn. Developmental plasticity in neural respiratory
      control development can occur at multiple sites during formation of brain stem
      neuronal networks and chemoafferent pathways, at multiple times during
      development, by multiple mechanisms. Past concepts of respiratory control system
      maturation as rigidly predetermined by a genetic blueprint have now yielded to a
      different view in which extremely complex interactions between genes,
      transcriptional factors, growth factors, and other gene products shape the
      respiratory control system, and experience plays a key role in guiding normal
      respiratory control development. Early-life experiences may also lead to
      maladaptive changes in respiratory control. Pathological conditions as well as
      normal phenotypic diversity in mature respiratory control may have their roots,
      at least in part, in developmental plasticity.

PMID- 12486026
TI  - Plasticity can be defined as the ability to retain a shape when deformed.

PMID- 12486027
TI  - A novel hematopoietic adaptor protein, Chat-H, positively regulates T cell
      receptor-mediated interleukin-2 production by Jurkat cells.
AB  - Chat (Cas/HEF1-associated signal transducer) is a novel adaptor protein with an N
      terminal Src homology-2 domain and C-terminal Cas/HEF1 association domain. We
      report here the molecular cloning of Chat-H, the hematopoietic isoform of Chat.
      Chat-H has an extended N-terminal domain besides the known Chat domain
      structures, suggesting a unique function of Chat-H in hematopoietic cells. Jurkat
      transfectants overexpressing Chat-H show a marked increase in interleukin-2
      production after costimulation of T cell receptor and CD28. The degree of JNK
      activation is enhanced substantially in the Chat-H transfectants upon
      costimulation. The Src homology-2 domain mutant of Chat-H loses this signal
      modulating activity. Expression of the Cas/HEF1 association domain mutant
      exhibits a dominant negative effect on both JNK activation and interleukin-2
      production. We further found that Chat-H forms a complex with Pyk2H and enhances
      its tyrosine 402 phosphorylation, an up-regulator of the JNK pathway. These
      results suggest that Chat-H positively controls T cell function via integrating
      the costimulatory signals.

PMID- 12486028
TI  - Functional and biochemical consequences of abrogating the activation of multiple
      diverse early signaling pathways in Kit. Role for Src kinase pathway in Kit
      induced cooperation with erythropoietin receptor.
AB  - Kit receptor tyrosine kinase and erythropoietin receptor (Epo-R) cooperate in
      regulating blood cell development. Mice that lack the expression of Kit or Epo-R
      die in utero of severe anemia. Stimulation of Kit by its ligand, stem cell factor
      activates several distinct early signaling pathways, including phospholipase C
      gamma, phosphatidylinositol 3-kinase, Src kinase, Grb2, and Grb7. The role of
      these pathways in Kit-induced growth, proliferation, or cooperation with Epo-R is
      not known. We demonstrate that inactivation of any one of these early signaling
      pathways in Kit significantly impairs growth and proliferation. However,
      inactivation of the Src pathway demonstrated the most profound defect. Combined
      stimulation with Epo also resulted in impaired cooperation between Src-defective
      Kit mutant and Epo-R and, to a lesser extent, with Kit mutants defective in the
      activation of phosphatidylinositol 3-kinase or Grb2. The impaired cooperation
      between the Src-defective Kit mutant and Epo-R was associated with reduced
      transphosphorylation of Epo-R and expression of c-Myc. Remarkably, restoration of
      only the Src pathway in a Kit receptor defective in the activation of all early
      signaling pathways demonstrated a 50% correction in proliferation in response to
      Kit stimulation and completely restored the cooperation with Epo-R. These data
      demonstrate an essential role for Src pathway in regulating growth,
      proliferation, and cooperation with Epo-R downstream from Kit.

PMID- 12486029
TI  - An interferon-gamma-binding protein of novel structure encoded by the fowlpox
      virus.
AB  - Poxviruses have evolved various strategies to counteract the host immune
      response, one of which is based on the expression of soluble cytokine receptors.
      Using various biological assays, we detected a chicken interferon-gamma (chIFN
      gamma)-neutralizing activity in supernatants of fowlpox virus (FPV)-infected
      cells that could be destroyed by trypsin treatment. Secreted viral proteins were
      purified by affinity chromatography using matrix-immobilized chIFN-gamma,
      followed by two-dimensional gel electrophoresis. Matrix-assisted laser
      desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) analysis
      indicated that the viral IFN-gamma-binding protein in question was encoded by the
      FPV gene 016. The chicken IFN-gamma binding and neutralizing activity of the
      recombinant FPV016 protein was confirmed using supernatants of cells infected
      with a recombinant vaccinia virus that lacked its own IFN-gamma-binding protein
      but instead expressed the FPV016 gene. The FPV016 gene product also neutralized
      the activity of duck and human IFN-gamma but failed to neutralize the activity of
      mouse and rat IFN-gamma. Unlike previously known cellular and poxviral IFN-gamma
      receptors, which all contain fibronectin type III domains, the IFN-gamma-binding
      protein of FPV contains an immunoglobulin domain. Remarkably, it exhibits no
      significant homology to any known viral or cellular protein. Because IFN-gamma
      receptors of birds have not yet been characterized at the molecular level, the
      possibility remains that FPV016 represents a hijacked chicken gene and that avian
      and mammalian IFN-gamma receptors have fundamentally different primary
      structures.

PMID- 12486030
TI  - Biochemical analysis of the damage recognition process in nucleotide excision
      repair.
AB  - XPA, XPC-hHR23B, RPA, and TFIIH all are the damage recognition proteins essential
      for the early stage of nucleotide excision repair. Nonetheless, it is not clear
      how these proteins work together at the damaged DNA site. To get insight into the
      molecular mechanism of damage recognition, we carried out a comprehensive
      analysis on the interaction between damage recognition proteins and their
      assembly on damaged DNA. XPC physically interacted with XPA, but failed to
      stabilize the XPA-damaged DNA complex. Instead, XPC-hHR23B was effectively
      displaced from the damaged DNA by the combined action of RPA and XPA. A mutant
      RPA lacking the XPA interaction domain failed to displace XPC-hHR23B from damaged
      DNA, suggesting that XPA and RPA cooperate with each other to destabilize the XPC
      hHR23B-damaged DNA complex. Interestingly, the presence of hHR23B significantly
      increased RPA/XPA-mediated displacement of XPC from damaged DNA, suggesting that
      hHR23B may modulate the binding of XPC to damaged DNA. Together, our results
      suggest that damage recognition occurs in a multistep process such that XPC
      hHR23B initiates damage recognition, which was replaced by combined action of XPA
      and RPA. XPA and RPA, once forming a complex at the damage site, would likely
      work with TFIIH, XPG, and ERCC1-XPF for dual incision.

PMID- 12486031
TI  - Yeast tRNA(Asp) charging accuracy is threatened by the N-terminal extension of
      aspartyl-tRNA synthetase.
AB  - This study evaluates the role of the N-terminal extension from yeast aspartyl
      tRNA synthetase in tRNA aspartylation. The presence of an RNA-binding motif in
      this extension, conserved in eukaryotic class IIb aminoacyl-tRNA synthetases,
      provides nonspecific tRNA binding properties to this enzyme. Here, it is assumed
      that the additional contacts the 70 amino acid-long appendix of aspartyl-tRNA
      synthetase makes with tRNA could be important in expression of aspartate identity
      in yeast. Using in vitro transcripts mutated at identity positions, it is
      demonstrated that the extension grants better aminoacylation efficiency but
      reduced specificity to the synthetase, increasing considerably the risk of
      noncognate tRNA mischarging. Yeast tRNA(Glu(UUC)) and tRNA(Asn(GUU)) were
      identified as the most easily mischarged tRNA species. Both have a G at the
      discriminator position, and their anticodon differs only by one change from the
      GUC aspartate anticodon.

PMID- 12486032
TI  - The prefusogenic intermediate of HIV-1 gp41 contains exposed C-peptide regions.
AB  - The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein is composed
      of a complex between the surface subunit gp120, which binds to cellular
      receptors, and the transmembrane subunit gp41. Upon activation of the envelope
      glycoprotein by cellular receptors, gp41 undergoes conformational changes that
      mediate fusion of the viral and cellular membranes. Prior to formation of a
      fusogenic "trimer-of-hairpins" structure, gp41 transiently adopts a prefusogenic
      conformation whose structural features are poorly understood. An important
      approach toward understanding structural conformations of gp41 during HIV-1 entry
      has been to analyze the structural targets of gp41 inhibitors. We have
      constructed epitope-tagged versions of 5-Helix, a designed protein that binds to
      the C-peptide region of gp41 and inhibits HIV-1 membrane fusion. Using these 5
      Helix variants, we examined which conformation of gp41 is the target of 5-Helix.
      We find that although 5-Helix binds poorly to native gp41, it binds strongly to
      gp41 activated by interaction of the envelope protein with either soluble CD4 or
      membrane-bound cellular receptors. This preferential interaction with activated
      gp41 results in the accumulation of 5-Helix on the surface of activated cells.
      These results strongly suggest that the gp41 prefusogenic intermediate is the
      target of 5-Helix and that this intermediate has a remarkably "open" structure,
      with exposed C-peptide regions. These results provide important structural
      information about this intermediate that should facilitate the development of HIV
      1 entry inhibitors and may lead to new vaccine strategies.

PMID- 12486034
TI  - Wind River Conference on Prokaryotic Biology--2002.

PMID- 12486033
TI  - Rambling and scrambling in bacterial transformation--a historical and personal
      memoir.

PMID- 12486035
TI  - Cadaverine inhibition of porin plays a role in cell survival at acidic pH.
AB  - When grown at acidic pH, Escherichia coli cells secrete cadaverine, a polyamine
      known to inhibit porin-mediated outer membrane permeability. In order to
      understand the physiological significance of cadaverine excretion and the
      inhibition of porins, we isolated an OmpC mutant that showed resistance to
      spermine during growth and polyamine-resistant porin-mediated fluxes. Here, we
      show that the addition of exogenous cadaverine allows wild-type cells to survive
      a 30-min exposure to pH 3.6 better than cells expressing the cadaverine
      insensitive OmpC porin. Competition experiments between strains expressing either
      wild-type or mutant OmpC showed that the lack of sensitivity of the porin to
      cadaverine confers a survival disadvantage to the mutant cells at reduced pH. On
      the basis of these results, we propose that the inhibition of porins by excreted
      cadaverine represents a novel mechanism that provides bacterial cells with the
      ability to survive acid stress.

PMID- 12486036
TI  - Cinnamate:coenzyme A ligase from the filamentous bacterium streptomyces
      coelicolor A3(2).
AB  - 4-Coumarate:coenzyme A ligase (4CL) plays a key role in phenylpropanoid
      metabolism, providing precursors for a large variety of important plant secondary
      metabolites, such as lignin, flavonoids, and phytoalexins. Although 4CLs have
      been believed to be specific to plants, a gene encoding a 4CL-like enzyme which
      shows more than 40% identity in amino acid sequence to plant 4CLs was found in
      the genome of the gram-positive, filamentous bacterium Streptomyces coelicolor
      A3(2). The recombinant enzyme, produced in Escherichia coli with a histidine tag
      at its N-terminal end, showed distinct 4CL activity. The optimum pH and
      temperature of the reaction were pH 8.0 and 30 degrees C, respectively. The K(m)
      value for 4-coumarate and k(cat) were determined as 131 +/- 4 micro M and 0.202
      +/- 0.007 s(-1), respectively. The K(m) value was comparable to those of plant
      4CLs. The substrate specificity of this enzyme was, however, distinctly different
      from those of plant 4CLs. The enzyme efficiently converted cinnamate (K(m), 190
      +/- 2 micro M; k(cat), 0.475 +/- 0.012 s(-1)), which is a very poor substrate for
      plant 4CLs. Furthermore, the enzyme showed only low activity toward caffeate and
      no activity toward ferulate, both of which are generally good substrates for
      plant 4CLs. The enzyme was therefore named ScCCL for S. coelicolor A3(2)
      cinnamate CoA ligase. To determine the amino acid residues providing the unique
      substrate specificity of ScCCL, eight ScCCL mutant enzymes having a mutation(s)
      at amino acid residues that probably line up along the substrate-binding pocket
      were generated. Mutant A294G used caffeate as a substrate more efficiently than
      ScCCL, and mutant A294G/A318G used ferulate, which ScCCL could not use as a
      substrate, suggesting that Ala(294) and Ala(318) are involved in substrate
      recognition. Furthermore, the catalytic activities of A294G and A294G/A318G
      toward cinnamate and 4-coumarate were greatly enhanced compared with those of the
      wild-type enzyme.

PMID- 12486037
TI  - Regulation of the Escherichia coli rrnB P2 promoter.
AB  - The seven rRNA operons in Escherichia coli each contain two promoters, rrn P1 and
      rrn P2. Most previous studies have focused on the rrn P1 promoters. Here we
      report a systematic analysis of the activity and regulation of the rrnB P2
      promoter in order to define the intrinsic properties of rrn P2 promoters and to
      understand better their contributions to rRNA synthesis when they are in their
      natural setting downstream of rrn P1 promoters. In contrast to the conclusions
      reached in some previous studies, we find that rrnB P2 is regulated: it displays
      clear responses to amino acid availability (stringent control), rRNA gene dose
      (feedback control), and changes in growth rate (growth rate-dependent control).
      Stringent control of rrnB P2 requires the alarmone ppGpp, but growth rate
      dependent control of rrnB P2 does not require ppGpp. The rrnB P2 core promoter
      sequence (-37 to +7) is sufficient to serve as the target for growth rate
      dependent regulation.

PMID- 12486038
TI  - Binding of sigma(A) and sigma(B) to core RNA polymerase after environmental
      stress in Bacillus subtilis.
AB  - In Bacillus subtilis, the alternative sigma factor sigma(B) is activated in
      response to environmental stress or energy depletion. The general stress regulon
      under the control of sigma(B) provides the cell with multiple stress resistance.
      Experiments were designed to determine how activated sigma(B) replaces sigma(A)
      as a constituent of the RNA polymerase holoenzyme. Studies of the transcription
      of the sigma(A)-dependent stress gene clpE under sigma(B)-inducing conditions
      showed that expression was higher in a sigB mutant background than in the wild
      type. The relative affinities of sigma(A) and sigma(B) for binding to the core
      RNA polymerase (E) were determined by means of indirect surface plasmon
      resonance. The results showed that the affinity of sigma(B) for E was 60-fold
      lower than that of sigma(A). Western blot analyses with antibodies against
      sigma(A), sigma(B), and E showed that, after exposure to ethanol stress, the
      concentration of sigma(B) was only twofold higher than those of sigma(A) and E.
      Thus, the concentration of sigma(B) after stress is not high enough to compensate
      for its relatively low affinity for E, and it seems that additional mechanisms
      must be invoked to account for the binding of sigma(B) to E after stress.

PMID- 12486039
TI  - Characterization of the 4-carboxy-4-hydroxy-2-oxoadipate aldolase gene and operon
      structure of the protocatechuate 4,5-cleavage pathway genes in Sphingomonas
      paucimobilis SYK-6.
AB  - The protocatechuate (PCA) 4,5-cleavage pathway is the essential metabolic route
      for degradation of low-molecular-weight products derived from lignin by
      Sphingomonas paucimobilis SYK-6. In the 10.5-kb EcoRI fragment carrying the genes
      for PCA 4,5-dioxygenase (ligAB), 2-pyrone-4,6-dicarboxylate hydrolase (ligI), 4
      oxalomesaconate hydratase (ligJ), and a part of 4-carboxy-2-hydroxymuconate-6
      semialdehyde dehydrogenase (ligC), we found the ligK gene, which encodes 4
      carboxy-4-hydroxy-2-oxoadipate (CHA) aldolase. The ligK gene was located 1,183 bp
      upstream of ligI and transcribed in the same direction as ligI. We also found the
      ligR gene encoding a LysR-type transcriptional activator, which was located 174
      bp upstream of ligK. The ligK gene consists of a 684-bp open reading frame
      encoding a polypeptide with a molecular mass of 24,131 Da. The deduced amino acid
      sequence of ligK showed 57 to 88% identity with those of the corresponding genes
      recently reported in Sphingomonas sp. strain LB126, Comamonas testosteroni
      BR6020, Arthrobacter keyseri 12B, and Pseudomonas ochraceae NGJ1. The ligK gene
      was expressed in Escherichia coli, and the gene product (LigK) was purified to
      near homogeneity. Electrospray-ionization mass spectrometry indicated that LigK
      catalyzes not only the conversion of CHA to pyruvate and oxaloacetate but also
      that of oxaloacetate to pyruvate and CO(2). LigK is a hexamer, and its
      isoelectric point is 5.1. The K(m) for CHA and oxaloacetate are 11.2 and 136
      micro M, respectively. Inactivation of ligK in S. paucimobilis SYK-6 resulted in
      the growth deficiency of vanillate and syringate, indicating that ligK encodes
      the essential CHA aldolase for catabolism of these compounds. Reverse
      transcription-PCR analysis revealed that the PCA 4,5-cleavage pathway genes of S.
      paucimobilis SYK-6 consisted of four transcriptional units, including the ligK
      orf1-ligI-lsdA cluster, the ligJAB cluster, and the monocistronic ligR and ligC
      genes.

PMID- 12486040
TI  - A bacitracin-resistant Bacillus subtilis gene encodes a homologue of the membrane
      spanning subunit of the Bacillus licheniformis ABC transporter.
AB  - Bacitracin is a peptide antibiotic nonribosomally produced by Bacillus
      licheniformis. The bcrABC genes which confer bacitracin resistance to the
      bacitracin producer encode ATP binding cassette (ABC) transporter proteins, which
      are hypothesized to pump out bacitracin from the cells. Bacillus subtilis 168,
      which has no bacitracin synthesizing operon, has several genes homologous to
      bcrABC. It was found that the disruption of ywoA, a gene homologous to bcrC,
      resulted in hypersensitivity to bacitracin. Resistance to other drugs such as
      surfactin, iturin A, vancomycin, tunicamycin, gramicidin D, valinomycin and
      several cationic dyes were not changed in the ywoA disruptant. Spontaneous
      bacitracin-resistant mutants (Bcr-1 and -2) isolated in the presence of
      bacitracin have a single base substitution from A to G in the ribosome binding
      region. Northern hybridization analysis and determination of the expression of
      ywoA-LacZ transcriptional fusion gene revealed that the transcription of the ywoA
      gene was dependent on extracytoplasmic function (ECF) sigma factors sigma(M) and
      sigma(X). Preincubation of wild-type cells in the presence of a low concentration
      of bacitracin induced increased resistance to bacitracin about two- to threefold,
      although the mechanism of this induction has not yet been elucidated. It has been
      reported that a commercially available bacitracin is a mixture of several
      components and also contains impurity. Bacitracin A was purified by reverse phase
      high-performance liquid chromatography (HPLC). Similar results were obtained with
      bacitracin A as those with crude bacitracin, indicating that contaminating
      substances were not responsible for the results obtained in this study.

PMID- 12486041
TI  - The Streptococcus pneumoniae cia regulon: CiaR target sites and transcription
      profile analysis.
AB  - The ciaR-ciaH system is one of 13 two-component signal-transducing systems of the
      human pathogen Streptococcus pneumoniae. Mutations in the histidine protein
      kinase CiaH confer increased resistance to beta-lactam antibiotics and interfere
      with the development of genetic competence. In order to identify the genes
      controlled by the cia system, the cia regulon, DNA fragments targeted by the
      response regulator CiaR were isolated from restricted chromosomal DNA using the
      solid-phase DNA binding assay and analyzed by hybridization to an oligonucleotide
      microarray representing the S. pneumoniae genome. A set of 18 chromosomal regions
      containing 26 CiaR target sites were detected and proposed to represent the
      minimal cia regulon. The putative CiaR target loci included genes important for
      the synthesis and modification of cell wall polymers, peptide pheromone and
      bacteriocin production, and the htrA-spo0J region. In addition, the transcription
      profile of cia loss-of-function mutants and those with an apparent activated cia
      system representing the off and on states of the regulatory system were analyzed.
      The transcript analysis confirmed the cia-dependent expression of seven putative
      target loci and revealed three additional cia-regulated loci. Five putative
      target regions were silent under all conditions, and for the remaining three
      regions, no cia-dependent expression could be detected. Furthermore, the
      competence regulon, including the comCDE operon required for induction of
      competence, was completely repressed by the cia system.

PMID- 12486042
TI  - Function of oxygen resistance proteins in the anaerobic, sulfate-reducing
      bacterium Desulfovibrio vulgaris hildenborough.
AB  - Two mutant strains of Desulfovibrio vulgaris Hildenborough lacking either the sod
      gene for periplasmic superoxide dismutase or the rbr gene for rubrerythrin, a
      cytoplasmic hydrogen peroxide (H(2)O(2)) reductase, were constructed. Their
      resistance to oxidative stress was compared to that of the wild-type and of a sor
      mutant lacking the gene for the cytoplasmic superoxide reductase. The sor mutant
      was more sensitive to exposure to air or to internally or externally generated
      superoxide than was the sod mutant, which was in turn more sensitive than the
      wild-type strain. No obvious oxidative stress phenotype was found for the rbr
      mutant, indicating that H(2)O(2) resistance may also be conferred by two other
      rbr genes in the D. vulgaris genome. Inhibition of Sod activity by azide and
      H(2)O(2), but not by cyanide, indicated it to be an iron-containing Sod. The
      positions of Fe-Sod and Sor were mapped by two-dimensional gel electrophoresis
      (2DE). A strong decrease of Sor in continuously aerated cells, indicated by 2DE,
      may be a critical factor in causing cell death of D. vulgaris. Thus, Sor plays a
      key role in oxygen defense of D. vulgaris under fully aerobic conditions, when
      superoxide is generated mostly in the cytoplasm. Fe-Sod may be more important
      under microaerophilic conditions, when the periplasm contains oxygen-sensitive,
      superoxide-producing targets.

PMID- 12486043
TI  - The SecB chaperone is bifunctional in Serratia marcescens: SecB is involved in
      the Sec pathway and required for HasA secretion by the ABC transporter.
AB  - HasA is the secreted hemophore of the heme acquisition system (Has) of Serratia
      marcescens. It is secreted by a specific ABC transporter apparatus composed of
      three proteins: HasD, an inner membrane ABC protein; HasE, another inner membrane
      protein; and HasF, a TolC homolog. Except for HasF, the structural genes of the
      Has system are encoded by an iron-regulated operon. In previous studies, this
      secretion system has been reconstituted in Escherichia coli, where it requires
      the presence of the SecB chaperone, the Sec pathway-dedicated chaperone. We
      cloned and inactivated the secB gene from S. marcescens. We show that S.
      marcescens SecB is 93% identical to E. coli SecB and complements the secretion
      defects of a secB mutant of E. coli for both the Sec and ABC pathways of HasA
      secretion. In S. marcescens, SecB inactivation affects translocation by the Sec
      pathway and abolishes HasA secretion. This demonstrates that S. marcescens SecB
      is the genuine chaperone for HasA secretion in S. marcescens. These results also
      demonstrate that S. marcescens SecB is bifunctional, as it is involved in two
      separate secretion pathways. We investigated the effects of secB point mutations
      in the reconstituted HasA secretion pathway by comparing the translocation of a
      Sec substrate in various mutants. Two different patterns of SecB residue effects
      were observed, suggesting that SecB functions may differ for the Sec and ABC
      pathways.

PMID- 12486044
TI  - Mutational analysis of a conserved signal-transducing element: the HAMP linker of
      the Escherichia coli nitrate sensor NarX.
AB  - The HAMP linker, a predicted structural element observed in sensor proteins from
      all domains of life, is proposed to transmit signals between extracellular
      sensory input domains and cytoplasmic output domains. HAMP (histidine kinase,
      adenylyl cyclase, methyl-accepting chemotaxis protein, and phosphatase) linkers
      are located just inside the cytoplasmic membrane and are projected to form two
      short amphipathic alpha-helices (AS-1 and AS-2) joined by an unstructured
      connector. The presumed helices are comprised of hydrophobic residues in heptad
      repeats, with only three positions exhibiting strong conservation. We generated
      missense mutations at these three positions and throughout the HAMP linker in the
      Escherichia coli nitrate sensor kinase NarX and screened the resulting mutants
      for defective responses to nitrate. Most missense mutations in this region
      resulted in a constitutive phenotype mimicking the ligand-bound state, and only
      one residue (a conserved Glu before AS-2) was essential for HAMP linker function.
      We also scanned the narX HAMP linker with an overlapping set of seven-residue
      deletions. Deletions in AS-1 and the connector resulted in constitutive
      phenotypes. Two deletions in AS-2 resulted in a novel reversed response phenotype
      in which the response to ligand was the opposite of that seen for the narX(+)
      strain. These observations are consistent with the proposed HAMP linker
      structure, show that the HAMP linker plays an active role in transmembrane signal
      transduction, and indicate that the two amphipathic alpha-helices have different
      roles in signal transduction.

PMID- 12486045
TI  - Lack of the ApbC or ApbE protein results in a defect in Fe-S cluster metabolism
      in Salmonella enterica serovar Typhimurium.
AB  - The isc genes function in the assembly of Fe-S clusters and are conserved in many
      prokaryotic and eukaryotic organisms. In most bacteria studied, the isc operon
      can be deleted without loss of cell viability, indicating that additional systems
      for Fe-S cluster assembly must exist. Several laboratories have described
      nutritional and biochemical defects resulting from mutations in the isc operon.
      Here we demonstrate that null mutations in two genes of unknown function, apbC
      and apbE, result in similar cellular deficiencies. Exogenous ferric chloride
      suppressed these deficiencies in the apbC and apbE mutants, distinguishing them
      from previously described isc mutants. The deficiencies caused by the apbC and
      isc mutations were additive, which is consistent with Isc and ApbC's having
      redundant functions or with Isc and ApbC's functioning in different areas of Fe-S
      cluster metabolism (e.g., Fe-S cluster assembly and Fe-S cluster repair). Both
      the ApbC and ApbE proteins are similar in sequence to proteins that function in
      metal cofactor assembly. Like the enzymes with sequence similarity to ApbC,
      purified ApbC protein was able to hydrolyze ATP. The data herein are consistent
      with the hypothesis that the ApbC and ApbE proteins function in Fe-S cluster
      metabolism in vivo.

PMID- 12486046
TI  - Inactivation of the selB gene in Methanococcus maripaludis: effect on synthesis
      of selenoproteins and their sulfur-containing homologs.
AB  - The genome of Methanococcus maripaludis harbors genes for at least six
      selenocysteine-containing proteins and also for homologs that contain a cysteine
      codon in the position of the UGA selenocysteine codon. To investigate the
      synthesis and function of both the Se and the S forms, a mutant with an
      inactivated selB gene was constructed and analyzed. The mutant was unable to
      synthesize any of the selenoproteins, thus proving that the gene product is the
      archaeal translation factor (aSelB) specialized for selenocysteine insertion. The
      wild-type form of M. maripaludis repressed the synthesis of the S forms of
      selenoproteins, i.e., the selenium-independent alternative system, in selenium
      enriched medium, but the mutant did not. We concluded that free selenium is not
      involved in regulation but rather a successional compound such as selenocysteyl
      tRNA or some selenoprotein. Apart from the S forms, several enzymes from the
      general methanogenic route were affected by selenium supplementation of the wild
      type or by the selB mutation. Although the growth of M. maripaludis on H(2)/CO(2)
      is only marginally affected by the selB lesion, the gene is indispensable for
      growth on formate because M. maripaludis possesses only a selenocysteine
      containing formate dehydrogenase.

PMID- 12486047
TI  - Global role for ClpP-containing proteases in stationary-phase adaptation of
      Escherichia coli.
AB  - To elucidate the involvement of proteolysis in the regulation of stationary-phase
      adaptation, the clpA, clpX, and clpP protease mutants of Escherichia coli were
      subjected to proteome analysis during growth and during carbon starvation. For
      most of the growth-phase-regulated proteins detected on our gels, the clpA, clpX,
      or clpP mutant failed to mount the growth-phase regulation found in the wild
      type. For example, in the clpP and clpA mutant cultures, the Dps protein, the
      WrbA protein, and the periplasmic lysine-arginine-ornithine binding protein ArgT
      did not display the induction typical for late-stationary-phase wild-type cells.
      On the other hand, in the protease mutants, a number of proteins accumulated to a
      higher degree than in the wild type, especially in late stationary phase. The
      proteins affected in this manner include the LeuA, TrxB, GdhA, GlnA, and MetK
      proteins and alkyl hydroperoxide reductase (AhpC). These proteins may be directly
      degraded by ClpAP or ClpXP, respectively, or their expression could be modulated
      by a protease-dependent mechanism. From our data we conclude that the levels of
      most major growth-phase-regulated proteins in E. coli are at some point
      controlled by the activity of at least one of the ClpP, ClpA, and ClpX proteins.
      Cultures of the strains lacking functional ClpP or ClpX also displayed a more
      rapid loss of viability during extended stationary phase than the wild type.
      Therefore, regulation by proteolysis seems to be more important, especially in
      resting cells, than previously suspected.

PMID- 12486048
TI  - Metal ion dependence of recombinant Escherichia coli allantoinase.
AB  - Allantoinase is a suspected dinuclear metalloenzyme that catalyzes the hydrolytic
      cleavage of the five-member ring of allantoin (5-ureidohydantoin) to form
      allantoic acid. Recombinant Escherichia coli allantoinase purified from
      overproducing cultures amended with 2.5 mM zinc, 1 mM cobalt, or 1 mM nickel ions
      was found to possess approximately 1.4 Zn, 0.0 Co, 0.0 Ni, and 0.4 Fe; 0.1 Zn,
      1.0 Co, 0.0 Ni, and 0.2 Fe; and 0.0 Zn, 0.0 Co, 0.6 Ni, and 0.1 Fe per subunit,
      respectively, whereas protein obtained from nonamended cultures contains near
      stoichiometric levels of iron. We conclude that allantoinase is incompletely
      activated in the recombinant cells, perhaps due to an insufficiency of a needed
      accessory protein. Enzyme isolated from nonsupplemented cultures possesses very
      low activity (k(cat) = 34.7 min(-1)) compared to the zinc-, cobalt-, and nickel
      containing forms of allantoinase (k(cat) values of 5,000 and 28,200 min(-1) and
      200 min(-1), respectively). These rates and corresponding K(m) values (17.0,
      19.5, and 80 mM, respectively) are significantly greater than those that have
      been reported previously. Absorbance spectroscopy of the cobalt species reveals a
      band centered at 570 nm consistent with five-coordinate geometry. Dithiothreitol
      is a competitive inhibitor of the enzyme, with significant K(i) differences for
      the zinc and cobalt species (237 and 795 micro M, respectively). Circular
      dichroism spectroscopy revealed that the zinc enzyme utilizes only the S isomer
      of allantoin, whereas the cobalt allantoinase prefers the S isomer, but also
      hydrolyzes the R isomer at about 1/10 the rate. This is the first report for
      metal content of allantoinase from any source.

PMID- 12486049
TI  - Arsenite oxidase aox genes from a metal-resistant beta-proteobacterium.
AB  - The beta-proteobacterial strain ULPAs1, isolated from an arsenic-contaminated
      environment, is able to efficiently oxidize arsenite [As(III)] to arsenate
      [As(V)]. Mutagenesis with a lacZ-based reporter transposon yielded two knockout
      derivatives deficient in arsenite oxidation. Sequence analysis of the DNA
      flanking the transposon insertions in the two mutants identified two adjacent
      open reading frames, named aoxA and aoxB, as well as a putative promoter upstream
      of the aoxA gene. Reverse transcription-PCR data indicated that these genes are
      organized in an operonic structure. The proteins encoded by aoxA and aoxB share
      64 and 72% identity with the small Rieske subunit and the large subunit of the
      purified and crystallized arsenite oxidase of Alcaligenes faecalis, respectively
      (P. J. Ellis, T. Conrads, R. Hille, and P. Kuhn, Structure [Cambridge] 9:125-132,
      2001). Importantly, almost all amino acids involved in cofactor interactions in
      both subunits of the A. faecalis enzyme were conserved in the corresponding
      sequences of strain ULPAs1. An additional Tat (twin-arginine translocation)
      signal peptide sequence was detected at the N terminus of the protein encoded by
      aoxA, strongly suggesting that the Tat pathway is involved in the translocation
      of the arsenite oxidase to its known periplasmic location.

PMID- 12486050
TI  - Growth of mycobacteria on carbon monoxide and methanol.
AB  - Several mycobacterial strains, such as Mycobacterium flavescens, Mycobacterium
      gastri, Mycobacterium neoaurum, Mycobacterium parafortuitum, Mycobacterium
      peregrinum, Mycobacterium phlei, Mycobacterium smegmatis, Mycobacterium
      tuberculosis, and Mycobacterium vaccae, were found to grow on carbon monoxide
      (CO) as the sole source of carbon and energy. These bacteria, except for M.
      tuberculosis, also utilized methanol as the sole carbon and energy source. A CO
      dehydrogenase (CO-DH) assay, staining by activity of CO-DH, and Western blot
      analysis using an antibody raised against CO-DH of Mycobacterium sp. strain JC1
      (formerly Acinetobacter sp. strain JC1 [J. W. Cho, H. S. Yim, and Y. M. Kim, Kor.
      J. Microbiol. 23:1-8, 1985]) revealed that CO-DH is present in extracts of the
      bacteria prepared from cells grown on CO. Ribulose bisphosphate
      carboxylase/oxygenase (RubisCO) activity was also detected in extracts prepared
      from all cells, except M. tuberculosis, grown on CO. The mycobacteria grown on
      methanol, except for M. gastri, which showed hexulose phosphate synthase
      activity, did not exhibit activities of classic methanol dehydrogenase,
      hydroxypyruvate reductase, or hexulose phosphate synthase but exhibited N,N
      dimethyl-4-nitrosoaniline-dependent methanol dehydrogenase and RuBisCO
      activities. Cells grown on methanol were also found to have dihydroxyacetone
      synthase. Double immunodiffusion revealed that the antigenic sites of CO-DHs,
      RuBisCOs, and dihydroxyacetone synthases in all mycobacteria tested are identical
      with those of the Mycobacterium sp. strain JC1 enzymes.

PMID- 12486051
TI  - Protease-deficient DegP suppresses lethal effects of a mutant OmpC protein by its
      capture.
AB  - The expression of assembly-defective outer membrane proteins can confer lethality
      if they are not degraded by envelope proteases. We report here that the
      expression of a mutant OmpC protein, OmpC(2Cys), which forms disulfide bonds in
      the periplasm due to the presence of two non-native cysteine residues, is lethal
      in cells lacking the major periplasmic protease, DegP. This lethality is not
      observed in dsbA strains that have diminished ability to form periplasmic
      disulfide bonds. Our data show that this OmpC(2Cys)-mediated lethality in a
      degP::Km(r) dsbA(+) background can be reversed by a DegP variant, DegP(S210A),
      that is devoid of its proteolytic activity but retains its reported chaperone
      activity. However, DegP(S210A) does not reverse the lethal effect of OmpC(2Cys)
      by correcting its assembly but rather by capturing misfolded mutant OmpC
      polypeptides and thus removing them from the assembly pathway. Displacement of
      OmpC(2Cys) by DegP(S210A) also alleviates the negative effect that the mutant
      OmpC protein has on wild-type OmpF.

PMID- 12486052
TI  - Transcriptome analysis of Neisseria meningitidis during infection.
AB  - Neisseria meningitidis is the cause of septicemia and meningococcal meningitis.
      During the course of infection, N. meningitidis encounters multiple environments
      within its host, which makes rapid adaptation to environmental changes a crucial
      factor for neisserial pathogenicity. Employing oligonucleotide-based DNA
      microarrays, we analyzed the transcriptome of N. meningitidis during two key
      steps of meningococcal infection, i.e., the interaction with epithelial cells
      (HeLa cells) and endothelial cells (human brain microvascular endothelial cells).
      Seventy-two genes were differentially regulated after contact with epithelial
      cells, and 48 genes were differentially regulated after contact with endothelial
      cells, including a considerable proportion of well-known virulence genes. While a
      considerable number of genes were in concordance between bacteria adherent to
      both cell types, we identified several open reading frames that were
      differentially regulated in only one system. The data obtained with this novel
      approach may provide insight into the pathogenicity mechanisms of N. meningitidis
      and could demonstrate the importance of gene regulation on the transcriptional
      level during different stages of meningococcal infection.

PMID- 12486053
TI  - Subunit topology of two 20S proteasomes from Haloferax volcanii.
AB  - Haloferax volcanii, a halophilic archaeon, synthesizes three different proteins
      (alpha1, alpha2, and beta) which are classified in the 20S proteasome
      superfamily. The alpha1 and beta proteins alone form active 20S proteasomes; the
      role of alpha2, however, is not clear. To address this, alpha2 was synthesized
      with an epitope tag and purified by affinity chromatography from recombinant H.
      volcanii. The alpha2 protein copurified with alpha1 and beta in a complex with an
      overall structure and peptide-hydrolyzing activity comparable to those of the
      previously described alpha1-beta proteasome. Supplementing buffers with 10 mM
      CaCl(2) stabilized the halophilic proteasomes in the absence of salt and enabled
      them to be separated by native gel electrophoresis. This facilitated the
      discovery that wild-type H. volcanii synthesizes more than one type of 20S
      proteasome. Two 20S proteasomes, the alpha1-beta and alpha1-alpha2-beta
      proteasomes, were identified during stationary phase. Cross-linking of these
      enzymes, coupled with available structural information, suggested that the alpha1
      beta proteasome was a symmetrical cylinder with alpha1 rings on each end. In
      contrast, the alpha1-alpha2-beta proteasome appeared to be asymmetrical with homo
      oligomeric alpha1 and alpha2 rings positioned on separate ends. Inter-alpha
      subunit contacts were only detected when the ratio of alpha1 to alpha2 was
      perturbed in the cell using recombinant technology. These results support a model
      that the ratio of alpha proteins may modulate the composition and subunit
      topology of 20S proteasomes in the cell.

PMID- 12486054
TI  - Biochemical and mutational characterization of the heme chaperone CcmE reveals a
      heme binding site.
AB  - CcmE is a heme chaperone that binds heme transiently in the periplasm of
      Escherichia coli and delivers it to newly synthesized and exported c-type
      cytochromes. The chemical nature of the covalent bond between heme and H130 is
      not known. We have purified soluble histidine-tagged CcmE and present its
      spectroscopic characteristics in the visible range. Alanine scanning mutagenesis
      of conserved amino acids revealed that H130 is the only residue found to be
      strictly required for heme binding and delivery. Mutation of the hydrophobic
      amino acids F37, F103, L127, and Y134 to alanine affected CcmE more than mutation
      of charged and polar residues. Our data are in agreement with the recently solved
      nuclear magnetic resonance structure of apo-CcmE (PDB code 1LIZ) and suggest that
      heme is bound to a hydrophobic platform at the surface of the protein and then
      attached to H130 by a covalent bond. Replacement of H130 with cysteine led to the
      formation of a covalent bond between heme and C130 at a low level. However, the
      H130C mutant CcmE was not active in cytochrome c maturation. Isolation and
      characterization of the heme-binding peptides obtained after a tryptic digest of
      wild-type and H130C CcmE support the hypothesis that heme is bound covalently at
      a vinyl group.

PMID- 12486055
TI  - Transcriptional organization of the Pseudomonas putida tol-oprL genes.
AB  - Proteins of the Tol system play a key role in the maintenance of outer membrane
      integrity and cell morphology in gram-negative bacteria. In Pseudomonas putida,
      the seven genes, orf1, tolQ, tolR, tolA, tolB, oprL, and orf2, which encode the
      proteins of this complex, are clustered in a 5.8-kb region of chromosomal DNA.
      Analysis of polar mutations, reverse transcriptase PCR assays, and
      transcriptional fusion constructs with a promoterless lacZ gene revealed that the
      genes are arranged in two operons: orf1 tolQ tolR tolA tolB and oprL orf2. We
      were also able to find a transcript that was initiated at the orf1 promoter and
      covered the two operons in a single mRNA. On the basis of the OprL protein level,
      we surmised that this transcript contributed only about 10 to 15% of the total
      OprL protein. Primer extension analysis identified the oprL orf2 operon promoter
      within the tolB gene, and the -10 and -35 regions exhibited some similarity to
      those of sigma(70)-recognized promoters. The transcription start point of orf1
      was located 91 bp upstream of the orf1 start codon, and the -10/-35 region also
      exhibited sigma(70) -10/-35 recognition sequences. The expression from both
      promoters in rich and minimal media was constitutive and was very little
      influenced by the growth phase or iron-deficient conditions. In addition,
      analyses of the beta-galactosidase activities of different translational fusion
      constructs revealed that translation of tolA and orf2 genes was dependent on the
      translation of their corresponding upstream genes (tolR and oprL, respectively).

PMID- 12486056
TI  - Recruitment of MinC, an inhibitor of Z-ring formation, to the membrane in
      Escherichia coli: role of MinD and MinE.
AB  - In Escherichia coli, the min system prevents division away from midcell through
      topological regulation of MinC, an inhibitor of Z-ring formation. The topological
      regulation involves oscillation of MinC between the poles of the cell under the
      direction of the MinDE oscillator. Since the mechanism of MinC involvement in the
      oscillation is unknown, we investigated the interaction of MinC with the other
      Min proteins. We observed that MinD dimerized in the presence of ATP and
      interacted with MinC. In the presence of a phospholipid bilayer, MinD bound to
      the bilayer and recruited MinC in an ATP-dependent manner. Addition of MinE to
      the MinCD-bilayer complex resulted in release of both MinC and MinD. The release
      of MinC did not require ATP hydrolysis, indicating that MinE could displace MinC
      from the MinD-bilayer complex. In contrast, MinC was unable to displace MinE
      bound to the MinD-bilayer complex. These results suggest that MinE induces a
      conformational change in MinD bound to the bilayer that results in the release of
      MinC. Also, it is argued that binding of MinD to the membrane activates MinC.

PMID- 12486057
TI  - Requirement of ArcA for redox regulation in Escherichia coli under microaerobic
      but not anaerobic or aerobic conditions.
AB  - In Escherichia coli, the two-component regulatory ArcAB system functions as a
      major control system for the regulation of expression of genes encoding enzymes
      involved in both aerobic and anaerobic catabolic pathways. Previously, we have
      described the physiological response of wild-type E. coli to changes in oxygen
      availability through the complete range from anaerobiosis to full aerobiosis (S.
      Alexeeva, B. de Kort, G. Sawers, K. J. Hellingwerf, and M. J. Teixeira de Mattos,
      J. Bacteriol. 182:4934-4940, 2000, and S. Alexeeva, K. J. Hellingwerf, and M. J.
      Teixeira de Mattos, J. Bacteriol. 184:1402-1406, 2002). Here, we address the
      question of the contribution of the ArcAB-dependent transcriptional regulation to
      this response. Wild-type E. coli and a mutant lacking the ArcA regulator were
      grown in glucose-limited chemostat cultures at controlled levels of oxygen
      availability ranging from full aerobiosis to complete anaerobiosis. A flux
      analysis of the distribution of catabolic fluxes over parallel pathways was
      carried out, and the intracellular redox state (as reflected by the NADH/NAD
      ratio) was monitored for all steady states. Deletion of ArcA neither
      significantly altered the in vivo activity of the pyruvate dehydrogenase complex
      and pyruvate formate lyase nor significantly affected catabolism under fully
      aerobic and fully anaerobic conditions. In contrast, profound effects of the
      absence of ArcA were seen under conditions of oxygen-restricted growth: increased
      respiration, an altered electron flux distribution over the cytochrome o- and d
      terminal oxidases, and a significant change in the intracellular redox state were
      observed. Thus, the ArcA regulator was found to exert major control on flux
      distribution, and it is concluded that the ArcAB system should be considered a
      microaerobic redox regulator.

PMID- 12486058
TI  - Targeted gene disruption by homologous recombination in the hyperthermophilic
      archaeon Thermococcus kodakaraensis KOD1.
AB  - In contrast to the high accumulation in sequence data for hyperthermophilic
      archaea, methodology for genetically manipulating these strains is still at an
      early stage. This study aimed to develop a gene disruption system for the
      hyperthermophilic euryarchaeon Thermococcus kodakaraensis KOD1. Uracil
      auxotrophic mutants with mutations in the orotidine-5'-monophosphate
      decarboxylase gene (pyrF) were isolated by positive selection using 5
      fluoroorotic acid (5-FOA) and used as hosts for further transformation
      experiments. We then attempted targeted disruption of the trpE locus in the host
      strain by homologous recombination, as disruption of trpE was expected to result
      in tryptophan auxotrophy, an easily detectable phenotype. A disruption vector
      harboring the pyrF marker within trpE was constructed for double-crossover
      recombination. The host cells were transformed with the exogenous DNA using the
      CaCl(2) method, and several transformants could be selected based on genetic
      complementation. Genotypic and phenotypic analyses of a transformant revealed the
      unique occurrence of targeted disruption, as well as a phenotypic change of
      auxotrophy from uracil to tryptophan caused by integration of the wild-type pyrF
      into the host chromosome at trpE. As with the circular plasmid, gene disruption
      with linear DNA was also possible when the homologous regions were relatively
      long. Shortening these regions led to predominant recombination between the pyrF
      marker in the exogenous DNA and the mutated allele on the host chromosome. In
      contrast, we could not obtain trpE disruptants by insertional inactivation using
      a vector designed for single-crossover recombination. The gene targeting system
      developed in this study provides a long-needed tool in the research on
      hyperthermophilic archaea and will open the way to a systematic, genetic approach
      for the elucidation of unknown gene function in these organisms.

PMID- 12486059
TI  - Contrasting sensitivities of Escherichia coli aconitases A and B to oxidation and
      iron depletion.
AB  - Superoxide damages dehydratases that contain catalytic [4Fe-4S](2+) clusters.
      Aconitases are members of that enzyme family, and previous work showed that most
      aconitase activity is lost when Escherichia coli is exposed to superoxide stress.
      More recently it was determined that E. coli synthesizes at least two isozymes of
      aconitase, AcnA and AcnB. Synthesis of AcnA, the less-abundant enzyme, is
      positively controlled by SoxS, a protein that is activated in the presence of
      superoxide-generating chemicals. We have determined that this arrangement exists
      because AcnA is resistant to superoxide in vivo. Surprisingly, purified AcnA is
      extremely sensitive to superoxide and other chemical oxidants unless it is
      combined with an uncharacterized factor that is present in cell extracts. In
      contrast, AcnB is highly sensitive to a variety of chemical oxidants in vivo, in
      extracts, and in its purified form. Thus, the induction of AcnA during oxidative
      stress provides a mechanism to circumvent a block in the tricarboxylic acid
      cycle. AcnA appears to be as catalytically competent as AcnB, so the retention of
      the latter as the primary housekeeping enzyme must provide some other advantage.
      We observed that the [4Fe-4S] cluster of AcnB is in dynamic equilibrium with the
      surrounding iron pool, so that AcnB is rapidly demetallated when intracellular
      iron pools drop. AcnA and other dehydratases do not show this trait. Demetallated
      AcnB is known to bind its cognate mRNA. The absence of AcnB activity also causes
      the accumulation and excretion of citrate, an iron chelator for which E. coli
      synthesizes a transport system. Thus, AcnB may be retained as the primary
      aconitase because the lability of its exposed cluster allows E. coli to sense and
      respond to iron depletion.

PMID- 12486060
TI  - Multiple promoter inversions generate surface antigenic variation in Mycoplasma
      penetrans.
AB  - Mycoplasma penetrans is a newly identified species of the genus MYCOPLASMA: It
      was first isolated from a urine sample from a human immunodeficiency virus (HIV)
      infected patient. M. penetrans changes its surface antigen profile with high
      frequency. The changes originate from ON<==>OFF phase variations of the P35
      family of surface membrane lipoproteins. The P35 family lipoproteins are major
      antigens recognized by the human immune system during M. penetrans infection and
      are encoded by the mpl genes. Phase variations of P35 family lipoproteins occur
      at the transcriptional level of mpl genes; however, the precise genetic
      mechanisms are unknown. In this study, the molecular mechanisms of surface
      antigen profile change in M. penetrans were investigated. The focus was on the 46
      kDa protein that is present in M. penetrans strain HF-2 but not in the type
      strain, GTU. The 46-kDa protein was the product of a previously reported mpl
      gene, pepIMP13, with an amino-terminal sequence identical to that of the P35
      family lipoproteins. Nucleotide sequencing analysis of the pepIMP13 gene region
      revealed that the promoter-containing 135-bp DNA of this gene had the structure
      of an invertible element that functioned as a switch for gene expression. In
      addition, all of the mpl genes of M. penetrans HF-2 were identified using the
      whole-genome sequence data that has recently become available for this bacterium.
      There are at least 38 mpl genes in the M. penetrans HF-2 genome. Interestingly,
      most of these mpl genes possess invertible promoter-like sequences, similar to
      those of the pepIMP13 gene promoter. A model for the generation of surface
      antigenic variation by multiple promoter inversions is proposed.

PMID- 12486061
TI  - The global transcriptional response of Bacillus subtilis to peroxide stress is
      coordinated by three transcription factors.
AB  - Bacillus subtilis exhibits a complex adaptive response to low levels of
      peroxides. We used global transcriptional profiling to monitor the magnitude and
      kinetics of changes in the mRNA population after exposure to either hydrogen
      peroxide (H(2)O(2)) or tert-butyl peroxide (t-buOOH). The peroxide stimulons
      could be largely accounted for by three regulons controlled by the PerR,
      sigma(B), and OhrR transcription factors. Three members of the PerR regulon
      (katA, mrgA, and zosA) were strongly induced by H(2)O(2) and weakly induced by t
      buOOH. The remaining members of the PerR regulon were only modestly up-regulated
      by peroxide treatment. Overall, the magnitude of peroxide induction of PerR
      regulon genes corresponded well with the extent of derepression in a perR mutant
      strain. The sigma(B) regulon was activated by 58 micro M H(2)O(2) but not by 8
      micro M H(2)O(2) and was strongly activated by either t-buOOH or, in a control
      experiment, tert-butyl alcohol. Apart from the sigma(B) regulon there was a
      single gene, ohrA, that was strongly and rapidly induced by t-buOOH exposure.
      This gene, controlled by the peroxide-sensing repressor OhrR, was not induced by
      any of the other conditions tested.

PMID- 12486062
TI  - The crystal structure of the phosphorylation domain in PhoP reveals a functional
      tandem association mediated by an asymmetric interface.
AB  - PhoP from Bacillus subtilis belongs to the OmpR subfamily of response regulators.
      It regulates the transcription of several operons and participates in a signal
      transduction network that controls adaptation of the bacteria to phosphate
      deficiency. The receiver domains of two members of this subfamily, PhoB from
      Escherichia coli and DrrD from Thermotoga maritima, have been structurally
      characterized. These modules have similar overall folds but display remarkable
      differences in the conformation of the beta4-alpha4 and alpha4 regions. The
      crystal structure of the receiver domain of PhoP (PhoPN) described in this paper
      illustrates yet another geometry in this region. Another major issue of the
      structure determination is the dimeric state of the protein and the novel mode of
      association between receiver domains. The protein-protein interface is provided
      by two different surfaces from each protomer, and the tandem unit formed through
      this asymmetric interface leaves free interaction surfaces. This design is well
      suited for further association of PhoP dimers to form oligomeric structures. The
      interprotein interface buries 970 A(2) from solvent and mostly involves
      interactions between charged residues. As described in the accompanying paper,
      mutations of a single residue in one salt bridge shielded from solvent prevented
      dimerization of the unphosphorylated and phosphorylated response regulator and
      had drastic functional consequences. The three structurally documented members of
      the OmpR family (PhoB, DrrD, and PhoP) provide a framework to consider possible
      relationships between structural features and sequence signatures in critical
      regions of the receiver domains.

PMID- 12486063
TI  - Residue R113 is essential for PhoP dimerization and function: a residue buried in
      the asymmetric PhoP dimer interface determined in the PhoPN three-dimensional
      crystal structure.
AB  - Bacillus subtilis PhoP is a member of the OmpR/PhoB family of response regulators
      that is directly required for transcriptional activation or repression of Pho
      regulon genes in conditions under which P(i) is growth limiting. Characterization
      of the PhoP protein has established that phosphorylation of the protein is not
      essential for PhoP dimerization or DNA binding but is essential for
      transcriptional regulation of Pho regulon genes. DNA footprinting studies of PhoP
      regulated promoters showed that there was cooperative binding between PhoP dimers
      at PhoP-activated promoters and/or extensive PhoP oligomerization 3' of PhoP
      binding consensus repeats in PhoP-repressed promoters. The crystal structure of
      PhoPN described in the accompanying paper revealed that the dimer interface
      between two PhoP monomers involves nonidentical surfaces such that each monomer
      in a dimer retains a second surface that is available for further
      oligomerization. A salt bridge between R113 on one monomer and D60 on another
      monomer was judged to be of major importance in the protein-protein interaction.
      We describe the consequences of mutation of the PhoP R113 codon to a glutamate or
      alanine codon and mutation of the PhoP D60 codon to a lysine codon. In vivo
      expression of either PhoP(R113E), PhoP(R113A), or PhoP(D60K) resulted in a Pho
      negative phenotype. In vitro analysis showed that PhoP(R113E) was phosphorylated
      by PhoR (the cognate histidine kinase) but was unable to dimerize. Monomeric
      PhoP(R113E) approximately P was deficient in DNA binding, contributing to the
      PhoP(R113E) in vivo Pho-negative phenotype. While previous studies emphasized
      that phosphorylation was essential for PhoP function, data reported here indicate
      that phosphorylation is not sufficient as PhoP dimerization or oligomerization is
      also essential. Our data support the physiological relevance of the residues of
      the asymmetric dimer interface in PhoP dimerization and function.

PMID- 12486064
TI  - LuxS-based signaling in Streptococcus gordonii: autoinducer 2 controls
      carbohydrate metabolism and biofilm formation with Porphyromonas gingivalis.
AB  - Communication based on autoinducer 2 (AI-2) is widespread among gram-negative and
      gram-positive bacteria, and the AI-2 pathway can control the expression of genes
      involved in a variety of metabolic pathways and pathogenic mechanisms. In the
      present study, we identified luxS, a gene responsible for the synthesis of AI-2,
      in Streptococcus gordonii, a major component of the dental plaque biofilm. S.
      gordonii conditioned medium induced bioluminescence in an AI-2 reporter strain of
      Vibrio harveyi. An isogenic mutant of S. gordonii, generated by insertional
      inactivation of the luxS gene, was unaffected in growth and in its ability to
      form biofilms on polystyrene surfaces. In contrast, the mutant strain failed to
      induce bioluminescence in V. harveyi and was unable to form a mixed species
      biofilm with a LuxS-null strain of the periodontal pathogen Porphyromonas
      gingivalis. Complementation of the luxS mutation in S. gordonii restored normal
      biofilm formation with the luxS-deficient P. gingivalis. Differential display PCR
      demonstrated that the inactivation of S. gordonii luxS downregulated the
      expression of a number of genes, including gtfG, encoding glucosyltransferase;
      fruA, encoding extracellular exo-beta-D-fructosidase; and lacD encoding tagatose
      1,6-diphosphate aldolase. However, S. gordonii cell surface expression of SspA
      and SspB proteins, previously implicated in mediating adhesion between S.
      gordonii and P. gingivalis, was unaffected by inactivation of luxS. The results
      suggest that S. gordonii produces an AI-2-like signaling molecule that regulates
      aspects of carbohydrate metabolism in the organism. Furthermore, LuxS-dependent
      intercellular communication is essential for biofilm formation between nongrowing
      cells of P. gingivalis and S. gordonii.

PMID- 12486065
TI  - Common extracellular sensory domains in transmembrane receptors for diverse
      signal transduction pathways in bacteria and archaea.
AB  - Transmembrane receptors in microorganisms, such as sensory histidine kinases and
      methyl-accepting chemotaxis proteins, are molecular devices for monitoring
      environmental changes. We report here that sensory domain sharing is widespread
      among different classes of transmembrane receptors. We have identified two novel
      conserved extracellular sensory domains, named CHASE2 and CHASE3, that are found
      in at least four classes of transmembrane receptors: histidine kinases, adenylate
      cyclases, predicted diguanylate cyclases, and either serine/threonine protein
      kinases (CHASE2) or methyl-accepting chemotaxis proteins (CHASE3). Three other
      extracellular sensory domains were shared by at least two different classes of
      transmembrane receptors: histidine kinases and either diguanylate cyclases,
      adenylate cyclases, or phosphodiesterases. These observations suggest that
      microorganisms use similar conserved domains to sense similar environmental
      signals and transmit this information via different signal transduction pathways
      to different regulatory circuits: transcriptional regulation (histidine kinases),
      chemotaxis (methyl-accepting proteins), catabolite repression (adenylate
      cyclases), and modulation of enzyme activity (diguanylate cyclases and
      phosphodiesterases). The variety of signaling pathways using the CHASE-type
      domains indicates that these domains sense some critically important
      extracellular signals.

PMID- 12486066
TI  - Evolutionary history of hrgA, which replaces the restriction gene hpyIIIR in the
      hpyIII locus of Helicobacter pylori.
AB  - A recently identified Helicobacter pylori gene, hrgA, was previously reported to
      be present in 70 (33%) of 208 strains examined (T. Ando, T. M. Wassenaar, R. M.
      Peek, R. A. Aras, A. I. Tschumi, L.-J. Van Doorn, K. Kusugami, and M. J. Blaser,
      Cancer Res. 62:2385-2389, 2002). Sequence analysis of nine such strains indicated
      that in each strain hrgA replaced hpyIIIR, which encodes a restriction
      endonuclease and which, together with the gene for its cognate methyltransferase,
      constitutes the hpyIII locus. As a consequence of either the hrgA insertion or
      independent mutations, hpyIIIM function was lost in 11 (5%) of the 208 strains
      examined, rendering chromosomal DNA sensitive to MboI digestion. The evolutionary
      history of the locus containing either hpyIII or hrgA was reconstructed. By
      homologous recombination involving flanking sequences, hrgA and hpyIIIR can
      replace one another in the hpyIII locus, and there is simultaneous replacement of
      several flanking genes. These findings, combined with the hpyIM/iceA2 locus
      discovered previously, suggest that the two most strongly conserved methylase
      genes of H. pylori, hpyIIIM and hpyIM, are both preceded by alternative genes
      that compete for presence at their loci.

PMID- 12486067
TI  - A previously unrecognized step in pentachlorophenol degradation in Sphingobium
      chlorophenolicum is catalyzed by tetrachlorobenzoquinone reductase (PcpD).
AB  - The first step in the pentachlorophenol (PCP) degradation pathway in Sphingobium
      chlorophenolicum has been believed for more than a decade to be conversion of PCP
      to tetrachlorohydroquinone. We show here that PCP is actually converted to
      tetrachlorobenzoquinone, which is subsequently reduced to tetrachlorohydroquinone
      by PcpD, a protein that had previously been suggested to be a PCP hydroxylase
      reductase. pcpD is immediately downstream of pcpB, the gene encoding PCP
      hydroxylase (PCP monooxygenase). Expression of PcpD is induced in the presence of
      PCP. A mutant strain lacking functional PcpD has an impaired ability to remove
      PCP from the medium. In contrast, the mutant strain removes tetrachlorophenol
      from the medium at the same rate as does the wild-type strain. These data suggest
      that PcpD catalyzes a step necessary for degradation of PCP, but not for
      degradation of tetrachlorophenol. Based upon the known mechanisms of flavin
      monooxygenases such as PCP hydroxylase, hydroxylation of PCP should produce
      tetrachlorobenzoquinone, while hydroxylation of tetrachlorophenol should produce
      tetrachlorohydroquinone. Thus, we proposed and verified experimentally that PcpD
      is a tetrachlorobenzoquinone reductase that catalyzes the NADPH-dependent
      reduction of tetrachlorobenzoquinone to tetrachlorohydroquinone.

PMID- 12486068
TI  - The cobY gene of the archaeon Halobacterium sp. strain NRC-1 is required for de
      novo cobamide synthesis.
AB  - Genetic and nutritional analyses of mutants of the extremely halophilic archaeon
      Halobacterium sp. strain NRC-1 showed that open reading frame (ORF) Vng1581C
      encodes a protein with nucleoside triphosphate:adenosylcobinamide-phosphate
      nucleotidyltransferase enzyme activity. This activity was previously associated
      with the cobY gene of the methanogenic archaeon Methanobacterium
      thermoautotrophicum strain DeltaH, but no evidence was obtained to demonstrate
      the direct involvement of this protein in cobamide biosynthesis in archaea.
      Computer analysis of the Halobacterium sp. strain NRC-1 ORF Vng1581C gene and the
      cobY gene of M. thermoautotrophicum strain DeltaH showed the primary amino acid
      sequence of the proteins encoded by these two genes to be 35% identical and 48%
      similar. A strain of Halobacterium sp. strain NRC-1 carrying a null allele of the
      cobY gene was auxotrophic for cobinamide-GDP, a known intermediate of the late
      steps of cobamide biosynthesis. The auxotrophic requirement for cobinamide-GDP
      was corrected when a wild-type allele of cobY was introduced into the mutant
      strain, demonstrating that the lack of cobY function was solely responsible for
      the observed block in cobamide biosynthesis in this archaeon. The data also show
      that Halobacterium sp. strain NRC-1 possesses a high-affinity transport system
      for corrinoids and that this archaeon can synthesize cobamides de novo under
      aerobic growth conditions. To the best of our knowledge this is the first genetic
      and nutritional analysis of cobalamin biosynthetic mutants in archaea.

PMID- 12486069
TI  - Interdomain linkers of homologous response regulators determine their mechanism
      of action.
AB  - OmpR and PhoB are response regulators that contain an N-terminal phosphorylation
      domain and a C-terminal DNA binding effector domain connected by a flexible
      interdomain linker. Phosphorylation of the N terminus results in an increase in
      affinity for specific DNA and the subsequent regulation of gene expression.
      Despite their sequence and structural similarity, OmpR and PhoB employ different
      mechanisms to regulate their effector domains. Phosphorylation of OmpR in the N
      terminus stimulates the DNA binding affinity of the C terminus, whereas
      phosphorylation of the PhoB N terminus relieves inhibition of the C terminus,
      enabling it to bind to DNA. Chimeras between OmpR and PhoB containing either
      interdomain linker were constructed to explore the basis of the differences in
      their activation mechanisms. Our results indicate that effector domain regulation
      by either N terminus requires its cognate interdomain linker. In addition, our
      findings suggest that the isolated C terminus of OmpR is not sufficient for a
      productive interaction with RNA polymerase.

PMID- 12486070
TI  - Quorum sensing controls exopolysaccharide production in Sinorhizobium meliloti.
AB  - Sinorhizobium meliloti is a soil bacterium capable of invading and establishing a
      symbiotic relationship with alfalfa plants. This invasion process requires the
      synthesis, by S. meliloti, of at least one of the two symbiotically important
      exopolysaccharides, succinoglycan and EPS II. We have previously shown that the
      sinRI locus of S. meliloti encodes a quorum-sensing system that plays a role in
      the symbiotic process. Here we show that the sinRI locus exerts one level of
      control through regulation of EPS II synthesis. Disruption of the autoinducer
      synthase gene, sinI, abolished EPS II production as well as the expression of
      several genes in the exp operon that are responsible for EPS II synthesis. This
      phenotype was complemented by the addition of acyl homoserine lactone (AHL)
      extracts from the wild-type strain but not from a sinI mutant, indicating that
      the sinRI-specified AHLs are required for exp gene expression. This was further
      confirmed by the observation that synthetic palmitoleyl homoserine lactone
      (C(16:1)-HL), one of the previously identified sinRI-specified AHLs, specifically
      restored exp gene expression. Most importantly, the absence of symbiotically
      active EPS II in a sinI mutant was confirmed in plant nodulation assays,
      emphasizing the role of quorum sensing in symbiosis.

PMID- 12486071
TI  - The stm4066 gene product of Salmonella enterica serovar Typhimurium has
      aminoimidazole riboside (AIRs) kinase activity and allows AIRs to satisfy the
      thiamine requirement of pur mutant strains.
AB  - In bacteria the biosynthetic pathways for purine mononucleotides and the
      hydroxymethyl pyrimidine moiety of thiamine share five reactions that result in
      the formation of aminoimidazole ribotide, the last metabolite common to both
      pathways. Here we describe the characterization of a Salmonella enterica mutant
      strain that has gained the ability to efficiently use exogenous aminoimidazole
      riboside (AIRs) as a source of thiamine. The lesion responsible for this
      phenotype is a null mutation in a transcriptional regulator of the GntR family
      (encoded by stm4068). Lack of this protein derepressed transcription of an
      associated operon (stm4065-4067) that encoded a predicted kinase. The stm4066
      gene product was purified and shown to have AIRs kinase activity in vitro. This
      activity was consistent with the model presented to explain the phenotype caused
      by the original mutation. This mutation provides a genetic means to isolate the
      synthesis of the hydroxymethyl pyrimidine moiety of thiamine from the pathway for
      purine mononucleotide biosynthesis and thus facilitate in vivo analyses.

PMID- 12486072
TI  - Forespore-specific expression of Bacillus subtilis yqfS, which encodes type IV
      apurinic/apyrimidinic endonuclease, a component of the base excision repair
      pathway.
AB  - The temporal and spatial expression of the yqfS gene of Bacillus subtilis, which
      encodes a type IV apurinic/apyrimidinic endonuclease, was studied. A reporter
      gene fusion to the yqfS opening reading frame revealed that this gene is not
      transcribed during vegetative growth but is transcribed during the last steps of
      the sporulation process and is localized to the developing forespore compartment.
      In agreement with these results, yqfS mRNAs were mainly detected by both Northern
      blotting and reverse transcription-PCR, during the last steps of sporulation. The
      expression pattern of the yqfS-lacZ fusion suggested that yqfS may be an
      additional member of the Esigma(G) regulon. A primer extension product mapped the
      transcriptional start site of yqfS, 54 to 55 bp upstream of translation start
      codon of yqfS. Such an extension product was obtained from RNA samples of
      sporulating cells but not from those of vegetatively growing cells. Inspection of
      the nucleotide sequence lying upstream of the in vivo-mapped transcriptional yqfS
      start site revealed the presence of a sequence with good homology to promoters
      preceding genes of the sigma(G) regulon. Although yqfS expression was temporally
      regulated, neither oxidative damage (after either treatment with paraquat or
      hydrogen peroxide) nor mitomycin C treatment induced the transcription of this
      gene.

PMID- 12486073
TI  - Transient association of an alternative sigma factor, ComX, with RNA polymerase
      during the period of competence for genetic transformation in Streptococcus
      pneumoniae.
AB  - Natural transformation in Streptococcus pneumoniae is regulated by a quorum
      sensing system that acts through accumulation and sensing of a peptide pheromone
      (competence-stimulating peptide [CSP]) to control many competence-specific genes
      acting in DNA uptake, processing, and integration. The period of competence
      induced by CSP lasts only 15 min (quarter-height peak width). The recently
      identified regulator ComX is required for the CSP-dependent expression of many
      competence-specific genes that share an unusual consensus sequence (TACGAATA) at
      their promoter regions. To test the hypothesis that this regulator acts as a
      transient alternative sigma factor, ComX was purified from an Escherichia coli
      overexpression strain and core RNA polymerase was purified from a comX-deficient
      S. pneumoniae strain. The reconstituted ComX-polymerase holoenzyme produced
      transcripts for the competence-specific genes ssbB, cinA, cglA, celA, and dalA
      and was inhibited by anti-ComX antibody, but not by anti-sigma(70) antibody.
      Western blotting using antibodies specific for ComX, sigma(70), and poly-His
      revealed a transient presence of ComX for a period of 15 to 20 min after CSP
      treatment, while RNA polymerase remained at a constant level and sigma(A)
      remained between 60 and 125% of its normal level. ComX reached a molar ratio to
      RNA polymerase of at least 1.5. We conclude that ComX is unstable and acts as a
      competence-specific sigma factor.

PMID- 12486074
TI  - Transcriptional regulation and signature patterns revealed by microarray analyses
      of Streptococcus pneumoniae R6 challenged with sublethal concentrations of
      translation inhibitors.
AB  - The effects of sublethal concentrations of four different classes of translation
      inhibitors (puromycin, tetracycline, chloramphenicol, and erythromycin) on global
      transcription patterns of Streptococcus pneumoniae R6 were determined by
      microarray analyses. Consistent with the general mode of action of these
      inhibitors, relative transcript levels of genes that encode ribosomal proteins
      and translation factors or that mediate tRNA charging and amino acid biosynthesis
      increased or decreased, respectively. Transcription of the heat shock regulon was
      induced only by puromycin or streptomycin treatment, which lead to truncation or
      mistranslation, respectively, but not by other antibiotics that block
      translation, transcription, or amino acid charging of tRNA. In contrast, relative
      transcript amounts of certain genes involved in transport, cellular processes,
      energy metabolism, and purine nucleotide (pur) biosynthesis were changed by
      different translation inhibitors. In particular, transcript amounts from a pur
      gene cluster and from purine uptake and salvage genes were significantly elevated
      by several translation inhibitors, but not by antibiotics that target other
      cellular processes. Northern blotting confirmed increased transcript amounts from
      part of the pur gene cluster in cells challenged by translation inhibitors and
      revealed the presence of a 10-kb transcript. Purine metabolism genes were
      negatively regulated by a homologue of the PurR regulatory protein, and full
      derepression in a DeltapurR mutant depended on optimal translation. Unexpectedly,
      hierarchical clustering of the microarray data distinguished among the global
      transcription patterns caused by antibiotics that inhibit different steps in the
      translation cycle. Together, these results show that there is extensive control
      of transcript amounts by translation in S. pneumoniae, especially for de novo
      purine nucleotide biosynthesis. In addition, these global transcription patterns
      form a signature that can be used to classify the mode of action and potential
      mechanism of new translation inhibitors.

PMID- 12486075
TI  - Choline starvation induces the gene licD2 in Streptococcus pneumoniae.
AB  - Mutant strains of Streptococcus pneumoniae were constructed to monitor the
      regulation of three dispersed genes known or predicted to act in choline
      metabolism. One gene (licD2) was regulated in response to choline deprivation
      over a 30-fold range. The other two (SP1860 and licC) responded little if at all
      to the same challenge.

PMID- 12486076
TI  - Membrane topology of the ZntB efflux system of Salmonella enterica serovar
      Typhimurium.
AB  - The membrane topology of the ZntB Zn(2+) transport protein of Salmonella enterica
      serovar Typhimurium was determined by constructing deletion derivatives of the
      protein and genetically fusing them to blaM or lacZ cassettes. The enzymatic
      activities of the hybrid proteins indicate that ZntB is a bitopic integral
      membrane protein consisting largely of two independent domains. The first 266
      amino acids form a large, highly charged domain within the cytoplasm, while the
      remaining 61 residues form a small membrane domain containing two membrane
      spanning segments. The overall orientation towards the cytoplasm is consistent
      with the ability of ZntB to facilitate zinc efflux.

PMID- 12486077
TI  - The Pseudomonas aeruginosa rhlAB operon is not expressed during the logarithmic
      phase of growth even in the presence of its activator RhlR and the autoinducer N
      butyryl-homoserine lactone.
AB  - The Pseudomonas aeruginosa rhlAB operon encodes the enzyme rhamnosyltransferase
      1, which produces the biosurfactant mono-rhamnolipid; rhlAB induction is
      dependent on the quorum-sensing transcription activator RhlR complexed with the
      autoinducer N-butyryl-homoserine lactone (C(4)-HSL). In this work we studied
      rhlAB induction in a P. aeruginosa and Escherichia coli background. We found
      that, in both bacteria, its expression is not induced during the logarithmic
      phase of growth even in the presence of RhlR and C(4)-HSL. Additionally, we found
      that rhlAB expression is partially sigma(s) dependent.

PMID- 12486078
TI  - Identification of a helix-turn-helix motif of Bacillus thermoglucosidasius HrcA
      essential for binding to the CIRCE element and thermostability of the HrcA-CIRCE
      complex, indicating a role as a thermosensor.
AB  - In the heat shock response of bacillary cells, HrcA repressor proteins negatively
      control the expression of the major heat shock genes, the groE and dnaK operons,
      by binding the CIRCE (controlling inverted repeat of chaperone expression)
      element. Studies on two critical but yet unresolved issues related to the
      structure and function of HrcA were performed using mainly the HrcA from the
      obligate thermophile Bacillus thermoglucosidasius KP1006. These two critical
      issues are (i) identifying the region at which HrcA binds to the CIRCE element
      and (ii) determining whether HrcA can play the role of a thermosensor. We
      identified the position of a helix-turn-helix (HTH) motif in B.
      thermoglucosidasius HrcA, which is typical of DNA-binding proteins, and indicated
      that two residues in the HTH motif are crucial for the binding of HrcA to the
      CIRCE element. Furthermore, we compared the thermostabilities of the HrcA-CIRCE
      complexes derived from Bacillus subtilis and B. thermoglucosidasius, which grow
      at vastly different ranges of temperature. The thermostability profiles of their
      HrcA-CIRCE complexes were quite consistent with the difference in the growth
      temperatures of B. thermoglucosidasius and B. subtilis and, thus, suggested that
      HrcA can function as a thermosensor to detect temperature changes in cells.

PMID- 12486079
TI  - Neuronal developmental marker FORSE-1 identifies a putative progenitor of the
      pulmonary neuroendocrine cell lineage during lung development.
AB  - The FORSE-1 (forebrain-surface-embryonic) monoclonal antibody (MAb) recognizes a
      carbohydrate cell surface epitope related to the Lewis-X (LeX) and stage-specific
      embryonic antigens (SSEAs). In the developing CNS, the FORSE-1 epitope is
      believed to serve as a marker of progenitor cells. We studied the expression of
      the FORSE-1 epitope in pulmonary neuroendocrine cells (PNECs) and related
      neuroepithelial bodies (NEBs), cell types implicated in paracrine regulation of
      lung development. We used dual immunolabeling to identify PNECs/NEBs in tissue
      sections from developing rabbit fetal lungs and corresponding primary lung cell
      cultures. During the early stage (E16), the FORSE-1 MAb labeled primitive airway
      epithelium, whereas serotonin (5HT) immunoreactivity, a marker of PNEC/NEB
      differentiation, was negative. After E18, FORSE-1 labeling became restricted to
      PNECs and NEBs, identified by co-expression with 5HT, then decreased coincident
      with an increase in 5HT. Expression of the FORSE-1 epitope correlated inversely
      with 5HT expression in PNEC/NEB cells. FORSE-1 immunoreactivity correlated with
      cell proliferation assessed by BrdU labeling. Downregulation of the FORSE-1
      epitope correlated with maturation of PNECs/NEBs. The presence of few FORSE-1/5HT
      positive cells in postnatal lung suggests retention of progenitors. The FORSE-1
      epitope was associated with a high molecular weight (286 kD) glycoprotein that
      decreased with increasing gestational age, as demonstrated by immunoblotting.
      Overall expression of SSEA-1, -3, and -4 antigens was similar to FORSE-1/5HT,
      although the former was preferentially localized to neurite-like processes.
      Because the role of the FORSE-1 epitope in the CNS probably involves cell
      adhesion and differentiation, we propose a similar function in developing lung.
      The demonstration of LeX/SSEA antigen expression in the PNEC/NEB cell lineage
      underscores the importance of these cells in developing lung. Furthermore, the
      FORSE-1 antigen may identify committed progenitors of the PNEC/NEB cell system.

PMID- 12486080
TI  - In vivo activation of STAT3 signaling in satellite cells and myofibers in
      regenerating rat skeletal muscles.
AB  - Although growth factors and cytokines play critical roles in skeletal muscle
      regeneration, intracellular signaling molecules that are activated by these
      factors in regenerating muscles have been not elucidated. Several lines of
      evidence suggest that leukemia inhibitory factor (LIF) is an important cytokine
      for the proliferation and survival of myoblasts in vitro and acceleration of
      skeletal muscle regeneration. To elucidate the role of LIF signaling in
      regenerative responses of skeletal muscles, we examined the spatial and temporal
      activation patterns of an LIF-associated signaling molecule, the signal
      transducer and activator transcription 3 (STAT3) proteins in regenerating rat
      skeletal muscles induced by crush injury. At the early stage of regeneration,
      activated STAT3 proteins were first detected in the nuclei of activated satellite
      cells and then continued to be activated in proliferating myoblasts expressing
      both PCNA and MyoD proteins. When muscle regeneration progressed, STAT3 signaling
      was no longer activated in differentiated myoblasts and myotubes. In addition,
      activation of STAT3 was also detected in myonuclei within intact sarcolemmas of
      surviving myofibers that did not show signs of necrosis. These findings suggest
      that activation of STAT3 signaling is an important molecular event that induces
      the successful regeneration of injured skeletal muscles.

PMID- 12486081
TI  - Neuroglobin, a novel member of the globin family, is expressed in focal regions
      of the brain.
AB  - Hemoproteins are widely distributed among unicellular eukaryotes, plants, and
      animals. In addition to myoglobin and hemoglobin, a third hemoprotein,
      neuroglobin, has recently been isolated from vertebrate brain. Although the
      functional role of this novel member of the globin family remains unclear,
      neuroglobin contains a heme-binding domain and may participate in diverse
      processes such as oxygen transport, oxygen storage, nitric oxide detoxification,
      or modulation of terminal oxidase activity. In this study we utilized in situ
      hybridization (ISH) and RT-PCR analyses to examine the expression of neuroglobin
      in the normoxic and hypoxic murine brain. In the normoxic adult mouse,
      neuroglobin expression was observed in focal regions of the brain, including the
      lateral tegmental nuclei, the preoptic nucleus, amygdala, locus coeruleus, and
      nucleus of the solitary tract. Using ISH and RT-PCR techniques, no significant
      changes in neuroglobin expression in the adult murine brain was observed in
      response to chronic 10% oxygen. These results support the hypothesis that
      neuroglobin is a hemoprotein that is expressed in the brain and may have diverse
      functional roles.

PMID- 12486082
TI  - NFkappaB and caspase-3 activity in apoptotic hepatocytes of galactosamine
      sensitized mice treated with TNFalpha.
AB  - Tumor necrosis factor-alpha (TNFalpha) induces apoptosis in hepatocytes only
      under transcriptional arrest induced by galactosamine (GalN). In this study we
      demonstrated the shuttle of the transcription factor NFkappaB (nuclear factor
      kappa B) in the liver tissue of mice within 30 min-4.5 hr hours after
      GalN/TNFalpha treatment. NFkappaB translocation from cytoplasm to the nucleus is
      initiated by its separation from the inhibitory IkappaB proteins which include
      IkappaBalpha, IkappaBbeta, and IkappaB. Thirty minutes after GalN/TNFalpha
      administration, NFkappaBp65 in hepatocellular nuclei becomes increasingly
      detectable and reaches its highest level after 2.5 hr. Then export back into
      cytoplasm begins but, surprisingly, approximately 30% of NFkappaB remains in the
      nuclear fraction and appears as an immunoprecipitate in the nuclei of apoptotic
      hepatocytes. Non-apoptotic hepatocytes do not show any reaction product in the
      nuclei 4.5 hr after treatment. Correspondingly, the amount of dissociated
      IkappaBbeta decreases in the cytoplasm up to 2.5 hr and increases again
      afterwards, although it does not reach the level of the control samples. No
      evidence of IkappaBbeta in the nuclei was found either immunocytochemically or
      biochemically. Caspase-3 activity, which is responsible for apoptosis, increases
      significantly after 3.5 hr. At that time, apoptotic hepatocytes can occasionally
      be observed and, 4.5 hr after GalN/TNFalpha treatment, constitute approximately
      30% of the hepatocytes.

PMID- 12486083
TI  - Structural integrity of the Golgi stack is essential for normal secretory
      functions of rat parotid acinar cells: effects of brefeldin A and okadaic acid.
AB  - We examined the effects of specific inhibitors, brefeldin A (BFA) and okadaic
      acid (OA), on the ultrastructural organization of the Golgi apparatus and
      distributions of amylase, Golgi-associated proteins, and cathepsin D in the rat
      parotid acinar cells. BFA induced a rapid regression of the Golgi stack into
      rudimentary Golgi clusters composed of tubulovesicules, in parallel with a
      redistribution of the Golgi-resident proteins and a coat protein (beta-COP) into
      the region of the rough endoplasmic reticulum (rER) or cytosol. The rapid
      disruption of the Golgi stack could also be induced by the effect of OA. However,
      redistribution of the Golgi proteins in rER or cytosol could not be observed and
      beta-COP was not dispersed but was retained on the rudimentary Golgi apparatus.
      These findings suggested that the mechanism of OA in inducing degeneration of the
      Golgi stack was markedly different from that of BFA. In addition, missorting of
      amylase, a Golgi protein, and cathepsin D into incorrect transport pathways is
      apparent in the course of the disruption of the Golgi stack by OA. These Golgi
      disrupting effects are reversible and the reconstruction of the stacked structure
      of the Golgi apparatus started immediately after the removal of inhibitors. In
      the recovery processes, missorting was also observed until the integrated
      structure of the Golgi apparatus was completely reconstructed. This suggested
      that the integrated structure of the Golgi apparatus was quite necessary for the
      occurrence of normal secretory events, including proper sorting of molecules.

PMID- 12486084
TI  - Distinct distribution of laminin and its integrin receptors in the pancreas.
AB  - Tissue function is regulated by the extracellular microenvironment including cell
      basement membranes, in which laminins are a major component. Previously, we found
      that laminin-1 promotes differentiation and survival of pancreatic islet cells.
      Here we characterize the expression pattern of laminins and their integrin
      receptors in adult pancreas. Although they are expressed in the basement membrane
      of acinar cells and duct epithelium, no laminin chains examined were detected
      extracellularly in the pancreatic islets. In contrast to laminin beta(1)- and
      gamma(1)-chains, the alpha(1)-chain, unique to laminin-1, was not detected.
      Laminin-10 (alpha(5)beta(1)gamma(1)) was expressed in acinar tissue, whereas
      laminins-2 (alpha(2)beta(1)gamma(1)) and -10 were expressed in the blood vessels.
      The laminin connector molecule, nidogen-1, had a distribution similar to that of
      laminin beta(1) and gamma(1), whereas fibulin-1 and -2, which compete with
      nidogen-1, were mostly confined to blood vessels. Integrin subunits alpha(6) and
      alpha(3) were detected in acinar cells and duct epithelial cells, but alpha(6)
      was absent in islet cells. Integrin alpha(6)beta(4) was detected only in duct
      cells, alpha(6)beta(1) in both acinar and ductal cells, and alpha(3)beta(1) in
      acinar, duct, and islet cells. These findings are a basis for further
      investigation of the role of extracellular matrix molecules and their receptors
      in pancreas function.

PMID- 12486085
TI  - Evaluation of thymidylate synthase protein expression by Western blotting and
      immunohistochemistry on human colon carcinoma xenografts in nude mice.
AB  - In this study we investigated the relationship between thymidylate synthase (TS)
      protein expression, evaluated by Western blotting analysis and by
      immunohistochemistry (IHC), and growth rate in human colon xenograft tumors in
      nude mice. Human colon cancer cell lines were used to induce xenograft tumors and
      the tumor mass growth rate was calculated by measuring tumor size variations over
      time. TS 106 monoclonal antibody was used for both Western blotting and IHC TS
      detection. Tumor cell growth fraction was measured by Ki67/MIB1 immunolabeling
      and tumor cell growth rate by evaluating the mean nucleolar size in silver
      stained sections. TS Western blotting values were related to tumor mass growth
      rate (p<0.001) and cell growth rate (p=0.002) but not to cell growth fraction
      (p=0.676). The degree of the IHC staining showed only a trend to be associated
      with TS protein expression measured on Western blotting, and was not related
      either to tumor mass growth or cell proliferation rate. Tumor xenografts were
      also characterized for TS promoter tandem repeat and p53 status. No relationship
      was observed between these variables and TS expression evaluated by both Western
      blotting and IHC analysis. Our results demonstrate that TS expression evaluated
      by Western blotting analysis is directly related to the tumor mass growth rate
      and question the use of the IHC approach to obtain precise quantitative
      information on TS expression in tumor samples.

PMID- 12486086
TI  - Lac z Histochemistry and immunohistochemistry reveal ephrin-B ligand expression
      in the inner ear.
AB  - Immunostaining in transgenic mice carrying the lac z gene can be used to map gene
      and protein distribution in a single tissue. In this study, we examined inner
      ears from ephrin-B3 homozygous and ephrin-B2 heterozygous mice. Ephrin-B3 lac z
      expression was limited in these mice. However, immunostaining revealed ephrin-B3
      throughout cochlear and vestibular regions. Immunoreactivity was absent in ephrin
      B3-homozygous null mutants, demonstrating the specificity of the antibody. Ephrin
      B2 lac z reactivity was detected in a limited number of cells in cochlear and
      vestibular regions. Different immunostaining patterns were found with different
      antibodies. Comparison with lac z expression indicated which antibody was
      specific for the transmembrane-bound ephrin-B2 ligand.

PMID- 12486087
TI  - The mt1 melatonin receptor and RORbeta receptor are co-localized in specific TSH
      immunoreactive cells in the pars tuberalis of the rat pituitary.
AB  - The pars tuberalis (PT) of the pituitary represents an important target site for
      the time-pacing pineal hormone melatonin because it expresses a large number of
      mt1 receptors. Functional studies suggest that the PT mediates the seasonal
      effects of melatonin on prolactin (PRL) secretion. The aim of this study was the
      characterization of the phenotype of melatonin-responsive cells. Furthermore, we
      determined whether RORbeta, a retinoid orphan receptor present in the PT, was co
      expressed in the same cells. We combined nonradioactive in situ hybridization
      (ISH) with hapten-labeled riboprobes for detection of the receptors and
      immunocytochemistry (ICC) for detection of alphaGSU (alpha-glycoprotein subunit),
      betaTSH, betaFSH, betaLH, GH, PRL, and ACTH. Expression of mt1 mRNA was found in
      small round cells, co-localized with alphaGSU and betaTSH. However, not all
      betaTSH-containing cells expressed mt1 mRNA. The distribution of mt1- and RORbeta
      positive cells appeared to overlap, although more cells were labeled for RORbeta
      than for mt1. Gonadotrophs, as well as other pars distalis cell types, were never
      labeled for mt1 melatonin receptor. Therefore, this study identifies the
      "specific" cells of the PT as the mt1 melatonin receptor-expressing cells.

PMID- 12486088
TI  - Depletion of intracellular zinc from neurons by use of an extracellular chelator
      in vivo and in vitro.
AB  - The membrane-impermeable chelator CaEDTA was introduced extracellularly among
      neurons in vivo and in vitro for the purpose of chelating extracellular Zn(2+).
      Unexpectedly, this treatment caused histochemically reactive Zn(2+) in
      intracellular compartments to drop rapidly. The same general result was seen with
      intravesicular Zn(2+), which fell after CaEDTA infusion into the lateral
      ventricle of the brain, with perikaryal Zn(2+) in Purkinje neurons (in vivo) and
      with cortical neurons (in vitro). These findings suggest either that the volume
      of zinc ion efflux and reuptake is higher than previously suspected or that EDTA
      can enter cells and vesicles. Caution is therefore warranted in attempting to
      manipulate extracellular or intracellular Zn(2+) selectively.

PMID- 12486089
TI  - Gender- and age-dependent changes in kidney androgen protein mRNA expression in a
      knockout mouse model for nephrolithiasis.
AB  - Kidney androgen-regulated protein (Kap) is the most abundant protein in the mouse
      kidney, but its function is unknown. We previously observed a significant
      decrease in Kap mRNA expression in whole kidney tissue from male mice with
      adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadenine
      (DHA) nephrolithiasis. The disease phenotype is more severe in male mice and is
      age-dependent. To identify the cellular basis for differential Kap expression, we
      used in situ hybridization (ISH) and reverse transcription-polymerase chain
      reaction ISH (RT-PCR ISH) to identify the cell types expressing this mRNA in
      paraffin-embedded kidney sections. In 1-month-old wild-type male mice, Kap was
      detected primarily in S3 proximal tubule segments, but expression was very low in
      female mice. In 1-month-old APRT-deficient male mice, Kap expression was
      decreased significantly and was undetectable in female mice. Kap mRNA was not
      detected in 3- or 6-month-old mice using our standard ISH protocol, but we
      observed intense cytoplasmic staining in S3 proximal tubules in wild-type male
      mice of these age groups using an improved RT-PCR ISH procedure. Our studies
      demonstrate age-, gender-, and APRT genotype-dependent changes in Kap mRNA
      expression in mouse kidney. Kap expression is under multihormonal control, and
      hormonal changes in DHA-induced nephrolithiasis may account for the decreased Kap
      expression in APRT-deficient mice.

PMID- 12486090
TI  - Expression of P-glycoprotein in human cerebral cortex microvessels.
AB  - P-Glycoprotein (P-gp) is an ATP-dependent efflux transporter that extrudes non
      polar molecules, including cytotoxic substances and drugs, from the cells. It was
      initially found in cancer cells and then was shown to be a normal component of
      complex transport systems working at the blood-brain barrier (BBB). Previous
      studies have demonstrated that, in the brain, P-gp is localized on the luminal
      plasmalemma of BBB endothelial cells and that it may interact with the caveolar
      compartment of these cells. The aim of this study was to identify the site of
      cellular expression of P-gp in human brain in situ and to morphologically
      determine whether an association may exist between P-gp and caveolin-1, a
      structural and functional protein of the caveolar frame. The study was carried
      out on human cerebral cortex by immunoconfocal microscopy with antibodies to both
      P-gp and caveolin-1. The results show that P-gp marks the microvessels of the
      cortex and that the transporter is localized in the luminal endothelial
      compartment, where it co-localizes with caveolin-1. The demonstration of this co
      localization of P-gp with caveolin-1 contributes a morphological backing to
      biochemical studies on P-gp/caveolin-1 relationships and leads us to suggest that
      interactions between these molecules may occur at the BBB endothelia.

PMID- 12486091
TI  - Strong expression of interleukin-1 receptor type I in the rat carotid body.
AB  - One of the unsolved key questions in neuroimmunomodulation is how peripheral
      immune signals are transmitted to the brain. It has been reported that the vagus
      might play a role in this regard. The underlying mechanism for this immune system
      to-brain communication route is related to the binding of cytokines, such as
      interleukin (IL)-1beta originating from activated immune cells, to their
      receptors in glomus cells of the vagal paraganglia. The existence of IL-1
      receptor type I (IL-1RI) in vagal paraganglia has been proved. On the basis of
      these studies, a hypothesis is raised that the carotid body, as the largest
      paraganglion, might play a similar role to that of its abdominal partner. In this
      study we examined the distribution of IL-1RI in the carotid body by
      immunohistochemistry (IHC) and Western blotting techniques. The IHC results
      showed that almost all glomus cells in the carotid body displayed strong IL-1RI
      immunoreactivity. The IL-1RI-immunoreactive products were localized in the
      cytoplasm, nucleus, and cell membrane of the glomus cells. The Western blotting
      results also confirmed the existence of IL-1RI in both membranous and cytoplasmic
      elements of the carotid body. These results imply that the carotid body not only
      serves as a chemoreceptor for modulation of cardiorespiratory performance, as
      traditionally recognized, but also acts as a cytokine chemorereceptor for sensing
      immune signals.

PMID- 12486092
TI  - Fiber composition and oxidative capacity of hamster skeletal muscle.
AB  - The hamster is a valuable biological model for physiological investigation.
      Despite the obvious importance of the integration of cardiorespiratory and
      muscular system function, little information is available regarding hamster
      muscle fiber type and oxidative capacity, both of which are key determinants of
      muscle function. The purpose of this investigation was to measure
      immunohistochemically the relative composition and size of muscle fibers composed
      of types I, IIA, IIX, and IIB fibers in hamster skeletal muscle. The oxidative
      capacity of each muscle was also assessed by measuring citrate synthase activity.
      Twenty-eight hindlimb, respiratory, and facial muscles or muscle parts from adult
      (144-147 g bw) male Syrian golden hamsters (n=3) were dissected bilaterally,
      weighed, and frozen for immunohistochemical and biochemical analysis. Combining
      data from all 28 muscles analyzed, type I fibers made up 5% of the muscle mass,
      type IIA fibers 16%, type IIX fibers 39%, and type IIB fibers 40%. Mean fiber
      cross-sectional area across muscles was 1665 +/- 328 microm(2) for type I fibers,
      1900 +/- 417 microm(2) for type IIA fibers, 3230 +/- 784 microm(2) for type IIX
      fibers, and 4171 +/- 864 microm(2) for type IIB fibers. Citrate synthase activity
      was most closely related to the population of type IIA fibers (r=0.68, p<0.0001)
      and was in the rank order of type IIA > I > IIX > IIB. These data demonstrate
      that hamster skeletal muscle is predominantly composed of type IIB and IIX
      fibers.

PMID- 12486093
TI  - Effect of fixation period on HER2/neu gene amplification detected by fluorescence
      in situ hybridization in invasive breast carcinoma.
AB  - This study investigated if formalin fixation duration affects HER2/neu gene
      amplification detection by fluorescence in situ hybridization (FISH) in breast
      cancer. Tumor tissues from 35 cases were divided into three groups and subjected
      to two formalin fixation protocols per group (12 hr, 27 hr in the first; 2 hr,
      17.5 hr in the second; 28.5 hr, 541 hr in the third) before FISH analysis. There
      was no significant difference in FISH signal detection between the two different
      fixation protocols in the first two groups. In the third, no signal was detected
      in 4/6 cases fixed for an extended duration.

PMID- 12486094
TI  - Suspension (S)-FISH, a new technique for interphase nuclei.
AB  - We describe a versatile method for performing fluorescence in situ hybridization
      (FISH) in suspension instead of on a slide as usually done. This so-called
      suspension-FISH (S-FISH) opens new possibilities for the analysis of shape and
      functions of the human interphase nucleus. The procedure is described and the
      first results using this approach are presented.

PMID- 12486095
TI  - O-acetylation of GD3: an enigmatic modification regulating apoptosis?

PMID- 12486096
TI  - Acetylation suppresses the proapoptotic activity of GD3 ganglioside.
AB  - GD3 synthase is rapidly activated in different cell types after specific
      apoptotic stimuli. De novo synthesized GD3 accumulates and contributes to the
      apoptotic program by relocating to mitochondrial membranes and inducing the
      release of apoptogenic factors. We found that sialic acid acetylation suppresses
      the proapoptotic activity of GD3. In fact, unlike GD3, 9-O-acetyl-GD3 is
      completely ineffective in inducing cytochrome c release and caspase-9 activation
      on isolated mitochondria and fails to induce the collapse of mitochondrial
      transmembrane potential and cellular apoptosis. Moreover, cells which are
      resistant to the overexpression of the GD3 synthase, actively convert de novo
      synthesized GD3 to 9-O-acetyl-GD3. The coexpression of GD3 synthase with a viral
      9-O-acetyl esterase, which prevents 9-O-acetyl-GD3 accumulation, reconstitutes
      GD3 responsiveness and apoptosis. Finally, the expression of the 9-O-acetyl
      esterase is sufficient to induce apoptosis of glioblastomas which express high
      levels of 9-O-acetyl-GD3. Thus, sialic acid acetylation critically controls the
      proapoptotic activity of GD3.

PMID- 12486097
TI  - Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing
      pattern.
AB  - We have studied the regulation of anti-DNA B cells in transgenic mice with a
      heavy chain transgene (3H9H/56R). This transgene codes for a heavy chain that
      forms anti-double-stranded DNA (dsDNA) antibody when paired with most members of
      the endogenous Vkappa repertoire, but certain L chains, referred to as Vkappa
      editors, do not sustain dsDNA binding in combination with 3H9H/56R. In the
      nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the
      transgene itself is edited or is associated with a Vkappa editor. A minor
      population of B cells (30%) bind dsDNA and express the lambda1 light chain (known
      to sustain 3H9H/56R DNA binding). These 3H9/56R/lambda1 B cells coexpress a kappa
      editor, and we propose that the down-regulation of the anti-DNA BCR caused by the
      dual L chain expression may prevent activation of this kappa/lambda population.
      These kappa/lambda B cells are sequestered in the marginal zone. Here, we studied
      the influence of autoimmunity on expression and regulation of 3H9H/56R. In
      3H9H/56R MRL/lpr mice, the expression of anti-dsDNA is vastly accelerated. Anti
      dsDNA B cells use noneditor kappas but, in addition, most anti-dsDNA B cells have
      edited the heavy chain transgene. lambda1 B cells (without the coexpression of a
      kappa editor) are found and the kappa/lambda1 MZ population is absent. Our
      results suggest that improper editing and failure to sequester autoreactive B
      cells may contribute to the breakdown of tolerance in MRL/lpr mice.

PMID- 12486098
TI  - Opsonization of apoptotic cells by autologous iC3b facilitates clearance by
      immature dendritic cells, down-regulates DR and CD86, and up-regulates CC
      chemokine receptor 7.
AB  - Immature dendritic cells (iDCs) do not mature after uptake of apoptotic cells and
      may play a role in the induction of peripheral tolerance to self antigens derived
      from apoptotic material. The integrins, alphavbeta3, alphavbeta5, and the
      scavenger receptor, CD36, have been shown to mediate uptake of apoptotic cells by
      iDCs. However, it is not known whether the complement system, also takes part in
      this process. In this study we investigated the ability of iDCs to bind to
      apoptotic cells opsonized by iC3b. Monocyte-derived dendritic cells were offered
      apoptotic Jurkat cells opsonized by autologous iC3b and labeled with 1,1'
      dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanineperchlorate. A significant
      increase (P < 0.001) in the amount of cleared apoptotic cells was seen at low
      ratios. Despite increased efficiency of uptake, interaction between iC3b
      opsonized apoptotic cells and iDCs down-regulated the expression of major
      histocompatibility complex class II, CD86, CC chemokine receptor (CCR)2, CCR5,
      and beta2-integrins (P < 0.001), and up-regulated expression of CCR7 (P < 0.001).
      In addition, iDC maturation responses to CD40L and lipopolysaccharide were
      significantly inhibited. We conclude that opsonization of apoptotic cells by iC3b
      induces tolerant iDCs that are able to migrate to lymph nodes.

PMID- 12486099
TI  - Genetic dissection of the cellular pathways and signaling mechanisms in modeled
      tumor necrosis factor-induced Crohn's-like inflammatory bowel disease.
AB  - Recent clinical evidence demonstrated the importance of tumor necrosis factor
      (TNF) in the development of Crohn's disease. A mouse model for this pathology has
      previously been established by engineering defects in the translational control
      of TNF mRNA (Tnf(Delta)(ARE) mouse). Here, we show that development of intestinal
      pathology in this model depends on Th1-like cytokines such as interleukin 12 and
      interferon gamma and requires the function of CD8(+) T lymphocytes. Tissue
      specific activation of the mutant TNF allele by Cre/loxP-mediated recombination
      indicated that either myeloid- or T cell-derived TNF can exhibit full pathogenic
      capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF
      receptor-deficient mice revealed that TNF signals are equally pathogenic when
      directed independently to either bone marrow-derived or tissue stroma cell
      targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the
      absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase
      deficient genetic background. Our data establish the existence of redundant
      cellular pathways operating downstream of TNF in inflammatory bowel disease, and
      demonstrate the therapeutic potential of selective kinase blockade in TNF
      mediated intestinal pathology.

PMID- 12486100
TI  - CD1-mediated gamma/delta T cell maturation of dendritic cells.
AB  - Immature myeloid dendritic cells (DCs) express only low levels of major
      histocompatibility complex (MHC) class II but express high levels of CD1 a, b,
      and c antigen-presenting molecules at the cell surface. As Vdelta1+ gamma/delta T
      cells are the main tissue subset of gamma/delta T cells and they are known to
      recognize CD1c in the absence of specific foreign antigen recognition, we
      examined the possible interaction of these T cells with immature DCs. We show
      that CD1-restricted gamma/delta T cells can mediate the maturation of DCs. DC
      maturation required cell-cell contact and could be blocked by antibodies against
      CD1c. The maturation process was partially mediated by tumor necrosis factor
      alpha. Importantly, immature DCs matured in the presence of lipopolysaccharide
      and CD1-restricted gamma/delta T cells produced bioactive interleukin-12p70. In
      addition, these DCs were able to efficiently present peptide antigens to naive
      CD4+ T cells. CD1-restricted gamma/delta T cell recognition of immature DCs
      provides the human immune system with the capacity to rapidly generate a pool of
      mature DCs early during microbial invasion. This may be an important source of
      critical host signals for T helper type 1 polarization of antigen-specific naive
      T cells and the subsequent adaptive immune response.

PMID- 12486101
TI  - Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses.
AB  - CD4+ T cell help is important for the generation of CD8+ T cell responses. We
      used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T
      cell responses after secondary infection of mice with the intracellular bacterium
      Listeria monocytogenes, or after boost immunization by specific peptide or DNA
      vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell
      responses markedly enlarged the population size of antigen-specific CD8+ T cells.
      After boost immunization with peptide or DNA, this effect was particularly
      profound, and antigen-specific CD8+ T cell populations were enlarged at least 10
      fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell
      population consisted of functional effector T cells. In depletion and transfer
      experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our
      results demonstrate that CD4+ T cells control the CD8+ T cell response in two
      directions. Initially, they promote the generation of a CD8+ T cell responses and
      later they restrain the strength of the CD8+ T cell memory response. Down
      modulation of CD8+ T cell responses during infection could prevent harmful
      consequences after eradication of the pathogen.

PMID- 12486102
TI  - Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity.
AB  - Genetic ablation of the Lyn tyrosine kinase has revealed unique inhibitory roles
      in B lymphocyte signaling. We now report the consequences of sustained activation
      of Lyn in vivo using a targeted gain-of-function mutation (Lyn(up/up) mice).
      Lyn(up/up) mice have reduced numbers of conventional B lymphocytes, down
      regulated surface immunoglobulin M and costimulatory molecules, and elevated
      numbers of B1a B cells. Lyn(up/up) B cells are characterized by the constitutive
      phosphorylation of negative regulators of B cell antigen receptor (BCR) signaling
      including CD22, SHP-1, and SHIP-1, and display attributes of lymphocytes rendered
      tolerant by constitutive engagement of the antigen receptor. However, exaggerated
      positive signaling is also apparent as evidenced by the constitutive
      phosphorylation of Syk and phospholipase Cgamma2 in resting Lyn(up/up) B cells.
      Similarly, Lyn(up/up) B cells show a heightened calcium flux in response to BCR
      stimulation. Surprisingly, Lyn(up/up) mice develop circulating autoreactive
      antibodies and lethal autoimmune glomerulonephritis, suggesting that enhanced
      positive signaling eventually overrides constitutive negative signaling. These
      studies highlight the difficulty in maintaining tolerance in the face of chronic
      stimulation and emphasize the pivotal role of Lyn in B cell signaling.

PMID- 12486103
TI  - The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in
      nuclear factor kappaB activation pathways.
AB  - Apoptosis-associated speck-like protein containing a Caspase recruitment domain
      (ASC) belongs to a large family of proteins that contain a Pyrin, AIM, ASC, and
      death domain-like (PAAD) domain (also known as PYRIN, DAPIN, Pyk). Recent data
      have suggested that ASC functions as an adaptor protein linking various PAAD
      family proteins to pathways involved in nuclear factor (NF)-kappaB and pro
      Caspase-1 activation. We present evidence here that the role of ASC in modulating
      NF-kappaB activation pathways is much broader than previously suspected, as it
      can either inhibit or activate NF-kappaB, depending on cellular context. While
      coexpression of ASC with certain PAAD-family proteins such as Pyrin and Cryopyrin
      increases NF-kappaB activity, ASC has an inhibitory influence on NF-kappaB
      activation by various proinflammatory stimuli, including tumor necrosis factor
      (TNF)alpha, interleukin 1beta, and lipopolysaccharide (LPS). Elevations in ASC
      protein levels or of the PAAD domain of ASC suppressed activation of IkappaB
      kinases in cells exposed to pro-inflammatory stimuli. Conversely, reducing
      endogenous levels of ASC using siRNA enhanced TNF- and LPS-induced degradation of
      the IKK substrate, IkappaBalpha. Our findings suggest that ASC modulates diverse
      NF-kappaB induction pathways by acting upon the IKK complex, implying a broad
      role for this and similar proteins containing PAAD domains in regulation of
      inflammatory responses.

PMID- 12486104
TI  - Non-T cell activation linker (NTAL): a transmembrane adaptor protein involved in
      immunoreceptor signaling.
AB  - A key molecule necessary for activation of T lymphocytes through their antigen
      specific T cell receptor (TCR) is the transmembrane adaptor protein LAT (linker
      for activation of T cells). Upon TCR engagement, LAT becomes rapidly tyrosine
      phosphorylated and then serves as a scaffold organizing a multicomponent complex
      that is indispensable for induction of further downstream steps of the signaling
      cascade. Here we describe the identification and preliminary characterization of
      a novel transmembrane adaptor protein that is structurally and evolutionarily
      related to LAT and is expressed in B lymphocytes, natural killer (NK) cells,
      monocytes, and mast cells but not in resting T lymphocytes. This novel
      transmembrane adaptor protein, termed NTAL (non-T cell activation linker) is the
      product of a previously identified WBSCR5 gene of so far unknown function. NTAL
      becomes rapidly tyrosine-phosphorylated upon cross-linking of the B cell receptor
      (BCR) or of high-affinity Fcgamma- and Fc epsilon -receptors of myeloid cells and
      then associates with the cytoplasmic signaling molecules Grb2, Sos1, Gab1, and c
      Cbl. NTAL expressed in the LAT-deficient T cell line J.CaM2.5 becomes tyrosine
      phosphorylated and rescues activation of Erk1/2 and minimal transient elevation
      of cytoplasmic calcium level upon TCR/CD3 cross-linking. Thus, NTAL appears to be
      a structural and possibly also functional homologue of LAT in non-T cells.

PMID- 12486105
TI  - Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in
      the steady state leads to antigen presentation on major histocompatibility
      complex class I products and peripheral CD8+ T cell tolerance.
AB  - To identify endocytic receptors that allow dendritic cells (DCs) to capture and
      present antigens on major histocompatibility complex (MHC) class I products in
      vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues.
      Ovalbumin (OVA) protein, when chemically coupled to monoclonal alphaDEC-205
      antibody, was presented by CD11c+ lymph node DCs, but not by CD11c- cells, to OVA
      specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400
      times more efficient than unconjugated OVA and, for MHC class I, the DCs had to
      express transporter of antigenic peptides (TAP) transporters. When alphaDEC
      205:OVA was injected subcutaneously, OVA protein was identified over a 4-48 h
      period in DCs, primarily in the lymph nodes draining the injection site. In vivo,
      the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells,
      again at least 400 times more effectively than soluble OVA and in a TAP-dependent
      fashion. Targeting of alphaDEC-205:OVA to DCs in the steady state initially
      induced 4-7 cycles of T cell division, but the T cells were then deleted and the
      mice became specifically unresponsive to rechallenge with OVA in complete
      Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus
      via CD40, together with alphaDEC-205:OVA, induced strong immunity. The CD8+ T
      cells responding in the presence of agonistic alphaCD40 antibody produced large
      amounts of interleukin 2 and interferon gamma, acquired cytolytic function in
      vivo, emigrated in large numbers to the lung, and responded vigorously to OVA
      rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism
      for DCs to process proteins for MHC class I presentation in vivo, leading to
      tolerance in the steady state and immunity after DC maturation.

PMID- 12486106
TI  - Chlamydia pneumoniae infection of the central nervous system worsens experimental
      allergic encephalitis.
AB  - Experimental allergic encephalitis (EAE) is considered by many to be a model for
      human multiple sclerosis. Intraperitoneal inoculation of mice with Chlamydia
      pneumoniae, after immunization with neural antigens, increased the severity of
      EAE. Accentuation of EAE required live infectious C. pneumoniae, and the severity
      of the disease was attenuated with antiinfective therapy. After immunization with
      neural antigens, systemic infection with C. pneumoniae led to the dissemination
      of the organism into the central nervous system (CNS) in mice with accentuated
      EAE. Inoculation with Chlamydia trachomatis did not worsen EAE and infectious
      organisms were not seen in the CNS. These observations suggest that dissemination
      of C. pneumoniae results in localized infection in CNS tissues in animals with
      EAE. We propose that infection of the CNS by C. pneumoniae can amplify the
      autoreactive pool of lymphocytes and regulate the expression of an autoimmune
      disease.

PMID- 12486107
TI  - Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2
      responses to inhaled antigen.
AB  - Allergic asthma is an inflammatory lung disease initiated and directed by T
      helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses
      to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests
      that exposure to lipopolysaccharide (LPS) or other microbial products can
      influence the development and severity of asthma. However, the mechanism by which
      LPS influences asthma pathogenesis remains undefined. Although it is known that
      signaling through Toll-like receptors (TLR) is required for adaptive T helper
      cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming.
      Here, we report that low level inhaled LPS signaling through TLR4 is necessary to
      induce Th2 responses to inhaled antigens in a mouse model of allergic
      sensitization. The mechanism by which LPS signaling results in Th2 sensitization
      involves the activation of antigen-containing dendritic cells. In contrast to low
      levels, inhalation of high levels of LPS with antigen results in Th1 responses.
      These studies suggest that the level of LPS exposure can determine the type of
      inflammatory response generated and provide a potential mechanistic explanation
      of epidemiological data on endotoxin exposure and asthma prevalence.

PMID- 12486108
TI  - The fibronectin-binding integrins alpha5beta1 and alphavbeta3 differentially
      modulate RhoA-GTP loading, organization of cell matrix adhesions, and fibronectin
      fibrillogenesis.
AB  - We have studied the formation of different types of cell matrix adhesions in
      cells that bind to fibronectin via either alpha5beta1 or alphavbeta3. In both
      cases, cell adhesion to fibronectin leads to a rapid decrease in RhoA activity.
      However, alpha5beta1 but not alphavbeta3 supports high levels of RhoA activity at
      later stages of cell spreading, which are associated with a translocation of
      focal contacts to peripheral cell protrusions, recruitment of tensin into
      fibrillar adhesions, and fibronectin fibrillogenesis. Expression of an activated
      mutant of RhoA stimulates alphavbeta3-mediated fibrillogenesis. Despite the fact
      that alpha5beta1-mediated adhesion to the central cell-binding domain of
      fibronectin supports activation of RhoA, other regions of fibronectin are
      required for the development of alpha5beta1-mediated but not alphavbeta3-mediated
      focal contacts. Using chimeras of beta1 and beta3 subunits, we find that the
      extracellular domain of beta1 controls RhoA activity. By expressing both beta1
      and beta3 at high levels, we show that beta1-mediated control of the levels of
      beta3 is important for the distribution of focal contacts. Our findings
      demonstrate that the pattern of fibronectin receptors expressed on a cell
      dictates the ability of fibronectin to stimulate RhoA-mediated organization of
      cell matrix adhesions.

PMID- 12486109
TI  - Dual role for phosphoinositides in regulation of yeast and mammalian
      phospholipase D enzymes.
AB  - Phospholipase D (PLD) generates lipid signals that coordinate membrane
      trafficking with cellular signaling. PLD activity in vitro and in vivo is
      dependent on phosphoinositides with a vicinal 4,5-phosphate pair. Yeast and
      mammalian PLDs contain an NH2-terminal pleckstrin homology (PH) domain that has
      been speculated to specify both subcellular localization and regulation of PLD
      activity through interaction with phosphatidylinositol 4,5-bisphosphate
      (PI[4,5]P2). We report that mutation of the PH domains of yeast and mammalian PLD
      enzymes generates catalytically active PI(4,5)P2-regulated enzymes with impaired
      biological functions. Disruption of the PH domain of mammalian PLD2 results in
      relocalization of the protein from the PI(4,5)P2-containing plasma membrane to
      endosomes. As a result of this mislocalization, mutations within the PH domain
      render the protein unresponsive to activation in vivo. Furthermore, the integrity
      of the PH domain is vital for yeast PLD function in both meiosis and secretion.
      Binding of PLD2 to model membranes is enhanced by acidic phospholipids. Studies
      with PLD2-derived peptides suggest that this binding involves a previously
      identified polybasic motif that mediates activation of the enzyme by PI(4,5)P2.
      By comparison, the PLD2 PH domain binds PI(4,5)P2 with lower affinity but
      sufficient selectivity to function in concert with the polybasic motif to target
      the protein to PI(4,5)P2-rich membranes. Phosphoinositides therefore have a dual
      role in PLD regulation: membrane targeting mediated by the PH domain and
      stimulation of catalysis mediated by the polybasic motif.

PMID- 12486110
TI  - Symmetrical dimethylarginine methylation is required for the localization of SMN
      in Cajal bodies and pre-mRNA splicing.
AB  - The nuclear structures that contain symmetrical dimethylated arginine (sDMA)
      modified proteins and the role of this posttranslational modification is unknown.
      Here we report that the Cajal body is a major epitope in HeLa cells for an sDMA
      specific antibody and that coilin is an sDMA-containing protein as analyzed by
      using the sDMA-specific antibody and matrix-assisted laser desorption ionization
      time of flight mass spectrometry. The methylation inhibitor 5'-deoxy-5'
      methylthioadenosine reduces the levels of coilin methylation and causes the
      appearance of SMN-positive gems. In cells devoid of Cajal bodies, such as primary
      fibroblasts, sDMA-containing proteins concentrated in speckles. Cells from a
      patient with spinal muscular atrophy, containing low levels of the methyl-binding
      protein SMN, localized sDMA-containing proteins in the nucleoplasm as a discrete
      granular pattern. Splicing reactions are efficiently inhibited by using the sDMA
      specific antibody or by using hypomethylated nuclear extracts, showing that
      active spliceosomes contain sDMA polypeptides and suggesting that arginine
      methylation is important for efficient pre-mRNA splicing. Our findings support a
      model in which arginine methylation is important for the localization of coilin
      and SMN in Cajal bodies.

PMID- 12486111
TI  - Mitochondrial release of apoptosis-inducing factor occurs downstream of
      cytochrome c release in response to several proapoptotic stimuli.
AB  - Mitochondrial outer membrane permeabilization by proapoptotic Bcl-2 family
      proteins, such as Bax, plays a crucial role in apoptosis induction. However,
      whether this only causes the intracytosolic release of inducers of caspase
      dependent death, such as cytochrome c, or also of caspase-independent death, such
      as apoptosis-inducing factor (AIF) remains unknown. Here, we show that on
      isolated mitochondria, Bax causes the release of cytochrome c, but not of AIF,
      and the association of AIF with the mitochondrial inner membrane provides a
      simple explanation for its lack of release upon Bax-mediated outer membrane
      permeabilization. In cells overexpressing Bax or treated either with the Bax- or
      Bak-dependent proapoptotic drugs staurosporine or actinomycin D, or with hydrogen
      peroxide, caspase inhibitors did not affect the intracytosolic translocation of
      cytochrome c, but prevented that of AIF. These results provide a paradigm for
      mitochondria-dependent death pathways in which AIF cannot substitute for caspase
      executioners because its intracytosolic release occurs downstream of that of
      cytochrome c.

PMID- 12486112
TI  - Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac
      hypertrophy.
AB  - The transcription factor nuclear factor-kappaB (NF-kappaB) regulates expression
      of a variety of genes involved in immune responses, inflammation, proliferation,
      and programmed cell death (apoptosis). Here, we show that in rat neonatal
      ventricular cardiomyocytes, activation of NF-kappaB is involved in the
      hypertrophic response induced by myotrophin, a hypertrophic activator identified
      from spontaneously hypertensive rat heart and cardiomyopathic human hearts.
      Myotrophin treatment stimulated NF-kappaB nuclear translocation and
      transcriptional activity, accompanied by IkappaB-alpha phosphorylation and
      degradation. Consistently, myotrophin-induced NF-kappaB activation was enhanced
      by wild-type IkappaB kinase (IKK) beta and abolished by the dominant-negative
      IKKbeta or a general PKC inhibitor, calphostin C. Importantly, myotrophin-induced
      expression of two hypertrophic genes (atrial natriuretic factor [ANF] and c-myc)
      and also enhanced protein synthesis were partially inhibited by a potent NF
      kappaB inhibitor, pyrrolidine dithio-carbamate (PDTC), and calphostin C.
      Expression of the dominant-negative form of IkappaB-alpha or IKKbeta also
      partially inhibited the transcriptional activity of ANF induced by myotrophin.
      These findings suggest that the PKC-IKK-NF-kappaB pathway may play a critical
      role in mediating the myotrophin-induced hypertrophic response in cardiomyocytes.

PMID- 12486113
TI  - Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial
      cells through ERK1/2 and PI 3-kinase/AKT.
AB  - Ghrelin is an acyl-peptide gastric hormone acting on the pituitary and
      hypothalamus to stimulate growth hormone (GH) release, adiposity, and appetite.
      Ghrelin endocrine activities are entirely dependent on its acylation and are
      mediated by GH secretagogue (GHS) receptor (GHSR)-1a, a G protein-coupled
      receptor mostly expressed in the pituitary and hypothalamus, previously
      identified as the receptor for a group of synthetic molecules featuring GH
      secretagogue (GHS) activity. Des-acyl ghrelin, which is far more abundant than
      ghrelin, does not bind GHSR-1a, is devoid of any endocrine activity, and its
      function is currently unknown. Ghrelin, which is expressed in heart, albeit at a
      much lower level than in the stomach, also exerts a cardio protective effect
      through an unknown mechanism, independent of GH release. Here we show that both
      ghrelin and des-acyl ghrelin inhibit apoptosis of primary adult and H9c2
      cardiomyocytes and endothelial cells in vitro through activation of extracellular
      signal-regulated kinase-1/2 and Akt serine kinases. In addition, ghrelin and des
      acyl ghrelin recognize common high affinity binding sites on H9c2 cardiomyocytes,
      which do not express GHSR-1a. Finally, both MK-0677 and hexarelin, a nonpeptidyl
      and a peptidyl synthetic GHS, respectively, recognize the common ghrelin and des
      acyl ghrelin binding sites, inhibit cell death, and activate MAPK and Akt.These
      findings provide the first evidence that, independent of its acylation, ghrelin
      gene product may act as a survival factor directly on the cardiovascular system
      through binding to a novel, yet to be identified receptor, which is distinct from
      GHSR-1a.

PMID- 12486114
TI  - Cell migration requires both ion translocation and cytoskeletal anchoring by the
      Na-H exchanger NHE1.
AB  - Directed cell movement is a multi-step process requiring an initial spatial
      polarization that is established by asymmetric stimulation of Rho GTPases,
      phosphoinositides (PIs), and actin polymerization. We report that the Na-H
      exchanger isoform 1 (NHE1), a ubiquitously expressed plasma membrane ion
      exchanger, is necessary for establishing polarity in migrating fibroblasts. In
      fibroblasts, NHE1 is predominantly localized in lamellipodia, where it functions
      as a plasma membrane anchor for actin filaments by its direct binding of
      ezrin/radixin/moesin (ERM) proteins. Migration in a wounding assay was impaired
      in fibroblasts expressing NHE1 with mutations that independently disrupt ERM
      binding and cytoskeletal anchoring or ion transport. Disrupting either function
      of NHE1 impaired polarity, as indicated by loss of directionality,
      mislocalization of the Golgi apparatus away from the orientation of the wound
      edge, and inhibition of PI signaling. Both functions of NHE1 were also required
      for remodeling of focal adhesions. Most notably, lack of ion transport inhibited
      de-adhesion, resulting in trailing edges that failed to retract. These findings
      indicate that by regulating asymmetric signals that establish polarity and by
      coordinating focal adhesion remodeling at the cell front and rear, cytoskeletal
      anchoring by NHE1 and its localized activity in lamellipodia act cooperatively to
      integrate cues for directed migration.

PMID- 12486116
TI  - Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats
      within the ligand-binding site and the Abruptex region.
AB  - Fringe plays a key role in the specification of boundaries during development by
      modulating the ability of Notch ligands to activate Notch receptors. Fringe is a
      fucose-specific beta1,3-N-acetylglucosaminyltransferase that modifies O-fucose
      moieties on the epidermal growth factor-like (EGF) repeats of Notch. To
      investigate how the change in sugar structure caused by Fringe modulates Notch
      activity, we have analyzed the sites of O-fucose and Fringe modification on mouse
      Notch1. The extracellular domain of Notch1 has 36 tandem EGF repeats, many of
      which are predicted to be modified with O-fucose. We recently proposed a
      broadened consensus sequence for O-fucose, C(2)X(3-5)(S/T)C(3) (where C(2) and
      C(3) represent the second and third conserved cysteines), significantly expanding
      the potential number of modification sites on Notch. Here we demonstrate that
      sites predicted using this broader consensus sequence are modified with O-fucose
      on mouse Notch1, and we present evidence suggesting that the consensus can be
      further refined to C(2)X(4-5)(S/T)C(3). In particular, we demonstrate that EGF
      12, a portion of the ligand-binding site, is modified with O-fucose and that this
      site is evolutionarily conserved. We also show that endogenous Fringe proteins in
      Chinese hamster ovary cells (Lunatic fringe and Radical fringe) as well as
      exogenous Manic fringe modify O-fucose on many but not all EGF repeats of mouse
      Notch1. These findings suggest that the Fringes show a preference for O-fucose on
      some EGF repeats relative to others. This specificity appears to be encoded
      within the amino acid sequence of the individual EGF repeats. Interestingly, our
      results reveal that Manic fringe modifies O-fucose both at the ligand-binding
      site (EGF 12) and in the Abruptex region. These findings provide insight into
      potential mechanisms by which Fringe action on Notch receptors may influence both
      the affinity of Notch-ligand binding and cell-autonomous inhibition of Notch
      signaling by ligand.

PMID- 12486115
TI  - Mps3p is a novel component of the yeast spindle pole body that interacts with the
      yeast centrin homologue Cdc31p.
AB  - Accurate duplication of the Saccharomyces cerevisiae spindle pole body (SPB) is
      required for formation of a bipolar mitotic spindle. We identified mutants in SPB
      assembly by screening a temperature-sensitive collection of yeast for defects in
      SPB incorporation of a fluorescently marked integral SPB component, Spc42p. One
      SPB assembly mutant contained a mutation in a previously uncharacterized open
      reading frame that we call MPS3 (for monopolar spindle). mps3-1 mutants arrest in
      mitosis with monopolar spindles at the nonpermissive temperature, suggesting a
      defect in SPB duplication. Execution point experiments revealed that MPS3
      function is required for the first step of SPB duplication in G1. Like cells
      containing mutations in two other genes required for this step of SPB duplication
      (CDC31 and KAR1), mps3-1 mutants arrest with a single unduplicated SPB that lacks
      an associated half-bridge. MPS3 encodes an essential integral membrane protein
      that localizes to the SPB half-bridge. Genetic interactions between MPS3 and
      CDC31 and binding of Cdc31p to Mps3p in vitro, as well as the fact that Cdc31p
      localization to the SPB is partially dependent on Mps3p function, suggest that
      one function for Mps3p during SPB duplication is to recruit Cdc31p, the yeast
      centrin homologue, to the half-bridge.

PMID- 12486117
TI  - Phosphorylation of 69-kDa choline acetyltransferase at threonine 456 in response
      to amyloid-beta peptide 1-42.
AB  - Choline acetyltransferase synthesizes acetylcholine in cholinergic neurons. In
      the brain, these neurons are especially vulnerable to effects of beta-amyloid (A
      beta) peptides. Choline acetyltransferase is a substrate for several protein
      kinases. In the present study, we demonstrate that short term exposure of IMR32
      neuroblastoma cells expressing human choline acetyltransferase to A beta-(1-42)
      changes phosphorylation of the enzyme, resulting in increased activity and
      alterations in its interaction with other cellular proteins. Using mass
      spectrometry, we identified threonine 456 as a new phosphorylation site in
      choline acetyltransferase from A beta-(1-42)-treated cells and in purified
      recombinant ChAT phosphorylated in vitro by calcium/calmodulin-dependent protein
      kinase II (CaM kinase II). Whereas phosphorylation of choline acetyltransferase
      by protein kinase C alone caused a 2-fold increase in enzyme activity,
      phosphorylation by CaM kinase II alone did not alter enzyme activity. A 3-fold
      increase in choline acetyltransferase activity was found with coordinate
      phosphorylation of threonine 456 by CaM kinase II and phosphorylation of serine
      440 by protein kinase C. This phosphorylation combination was observed in choline
      acetyltransferase from A beta-(1-42)-treated cells. Treatment of cells with A
      beta-(1-42) resulted in two phases of activation of choline acetyltransferase,
      the first within 30 min and associated with phosphorylation by protein kinase C
      and the second by 10 h and associated with phosphorylation by both CaM kinase II
      and protein kinase C. We also show that choline acetyltransferase from A beta-(1
      42)-treated cells co-immunoprecipitates with valosin-containing protein, and
      mutation of threonine 456 to alanine abolished the A beta-(1-42)-induced effects.
      These studies demonstrate that A beta-(1-42) can acutely regulate the function of
      choline acetyltransferase, thus potentially altering cholinergic
      neurotransmission.

PMID- 12486118
TI  - Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus
      functionally interacts with heterochromatin protein 1.
AB  - Latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated
      herpesvirus plays an important role in maintenance of the viral genome during
      latent infection. LANA additionally participates in the transcriptional
      regulation of several viral and cellular promoters. When tethered to
      constitutively active promoters, the protein exhibits transcriptional repressor
      activity. In this report, we further characterized cell type-, promoter-, and
      domain-specific transcriptional repression by LANA. We additionally speculated on
      the mechanism underlying transcriptional repression by the C terminus of the
      protein. Subnuclear localization patterns and association with heterochromatin
      suggested a possible link between LANA and heterochromatin protein 1, a
      representative heterochromatin-associated protein. In vivo and in vitro binding
      and immunofluorescence assays revealed that LANA associates with heterochromatin
      protein 1 in an isotype-specific manner. Furthermore, biochemical fractionation
      and transient replication assays supported the possibility that this interaction
      contributes to transcriptional repression, targeting to subnuclear structures,
      and latent DNA replication activity of LANA.

PMID- 12486119
TI  - Identification of residues in glutathione transferase capable of driving
      functional diversification in evolution. A novel approach to protein redesign.
AB  - Evolution of protein function can be driven by positive selection of advantageous
      nonsynonymous codon mutations that arise following gene duplication. By observing
      the presence and degree of site-specific positive selection for change between
      divergent paralogs, residue positions responsible for functional changes can be
      identified. We applied this analysis to genes encoding Mu class glutathione
      transferases, which differ widely in substrate specificities. Approximately 3% of
      the amino acid residue positions, both near to and distant from the active site,
      are under statistically significant positive selection for change. Relevant human
      glutathione transferase (GST) M1-1 and GST M2-2 codons were mutated. A chemically
      conservative threonine to serine mutation in GST M2-2 elicited a 1,000-fold
      increase in specific activity with the GST M1-1-specific substrate trans-stilbene
      oxide and a 30-fold increase with the alternative epoxide substrates styrene
      oxide and nitrophenyl glycidol. The reverse mutation in GST M1-1 resulted in
      reciprocal decreases in activity. Thus, identification of hypervariable codon
      positions can be a powerful aid in the redesign of protein function, lessening
      the requirement for extensive mutagenesis or structural knowledge and sometimes
      suggesting mutations that would otherwise be considered functionally
      conservative.

PMID- 12486120
TI  - The auto-inhibitory function of importin alpha is essential in vivo.
AB  - Proteins that contain a classical nuclear localization signal (NLS) are
      recognized in the cytoplasm by a heterodimeric import receptor composed of
      importin/karyopherin alpha and beta. The importin alpha subunit recognizes
      classical NLS sequences, and the importin beta subunit directs the complex to the
      nuclear pore. Recent work shows that the N-terminal importin beta binding (IBB)
      domain of importin alpha regulates NLS-cargo binding in the absence of importin
      beta in vitro. To analyze the in vivo functions of the IBB domain, we created a
      series of mutants in the Saccharomyces cerevisiae importin alpha protein. These
      mutants dissect the two functions of the N-terminal IBB domain, importin beta
      binding and auto-inhibition. One of these importin alpha mutations, A3, decreases
      auto-inhibitory function without impacting binding to importin beta or the
      importin alpha export receptor, Cse1p. We used this mutant to show that the auto
      inhibitory function is essential in vivo and to provide evidence that this auto
      inhibitory-defective importin alpha remains bound to NLS-cargo within the
      nucleus. We propose a model where the auto-inhibitory activity of importin alpha
      is required for NLS-cargo release and the subsequent Cse1p-dependent recycling of
      importin alpha to the cytoplasm.

PMID- 12486121
TI  - Agrin regulates rapsyn interaction with surface acetylcholine receptors, and this
      underlies cytoskeletal anchoring and clustering.
AB  - The acetylcholine receptor (AChR)-associated protein rapsyn is essential for
      neuromuscular synapse formation and clustering of AChRs, but its mode of action
      remains unclear. We have investigated whether agrin, a key nerve-derived
      synaptogenic factor, influences rapsyn-AChR interactions and how this affects
      clustering and cytoskeletal linkage of AChRs. By precipitating AChRs and probing
      for associated rapsyn, we found that in denervated diaphragm rapsyn associates
      with synaptic as well as with extrasynaptic AChRs showing that rapsyn interacts
      with unclustered AChRs in vivo. Interestingly, synaptic AChRs are associated with
      more rapsyn suggesting that clustering of AChRs may require increased interaction
      with rapsyn. In similar experiments in cultured myotubes, rapsyn interacted with
      intracellular AChRs and with unclustered AChRs at the cell surface, although
      surface interactions are much more prominent. Remarkably, agrin induces
      recruitment of additional rapsyn to surface AChRs and clustering of AChRs
      independently of the secretory pathway. This agrin-induced increase in rapsyn
      AChR interaction strongly correlates with clustering, because staurosporine and
      herbimycin blocked both the increase and clustering. Conversely, laminin and
      calcium induced both increased rapsyn-AChR interaction and AChR clustering.
      Finally, time course experiments revealed that the agrin-induced increase occurs
      with AChRs that become cytoskeletally linked, and that this precedes receptor
      clustering. Thus, we propose that neural agrin controls postsynaptic aggregation
      of the AChR by enhancing rapsyn interaction with surface AChRs and inducing
      cytoskeletal anchoring and that this is an important precursor step for AChR
      clustering.

PMID- 12486122
TI  - Activation of heterotrimeric G proteins by a high energy phosphate transfer via
      nucleoside diphosphate kinase (NDPK) B and Gbeta subunits. Specific activation of
      Gsalpha by an NDPK B.Gbetagamma complex in H10 cells.
AB  - Formation of GTP by nucleoside diphosphate kinase (NDPK) can contribute to G
      protein activation in vitro. To study the effect of NDPK on G protein activity in
      living cells, the NDPK isoforms A and B were stably expressed in H10 cells, a
      cell line derived from neonatal rat cardiomyocytes. Overexpression of either NDPK
      isoform had no effect on cellular GTP and ATP levels, basal cAMP levels, basal
      adenylyl cyclase activity, and the expression of G(s)alpha and G(i)alpha
      proteins. However, co-expression of G(s)alpha led to an increase in cAMP
      synthesis that was largely enhanced by the expression of NDPK B, but not NDPK A,
      and that was confirmed by direct measurement of adenylyl cyclase activity. Cells
      expressing an inactive NDPK B mutant (H118N) exhibited a decreased cAMP formation
      in response to G(s)alpha. Co-immunoprecipitation studies demonstrated a complex
      formation of the NDPK with Gbetagamma dimers. The overexpression of NDPK B, but
      not its inactive mutant or NDPK A, increased the phosphorylation of Gbeta
      subunits. In summary, our data demonstrate a specific NDPK B-mediated activation
      of a G protein in intact cells, which is apparently caused by formation of NDPK
      B.Gbetagamma complexes and which appears to contribute to the receptor
      independent activation of heterotrimeric G proteins.

PMID- 12486123
TI  - Activation of heterotrimeric G proteins by a high energy phosphate transfer via
      nucleoside diphosphate kinase (NDPK) B and Gbeta subunits. Complex formation of
      NDPK B with Gbeta gamma dimers and phosphorylation of His-266 IN Gbeta.
AB  - G protein betagamma dimers can be phosphorylated in membranes from various
      tissues by GTP at a histidine residue in the beta subunit. The phosphate is high
      energetic and can be transferred onto GDP leading to formation of GTP. Purified
      Gbetagamma dimers do not display autophosphorylation, indicating the involvement
      of a separate protein kinase. We therefore enriched the Gbeta-phosphorylating
      activity present in preparations of the retinal G protein transducin and in
      partially purified G(i/o) proteins from bovine brain. Immunoblots,
      autophosphorylation, and enzymatic activity measurements demonstrated enriched
      nucleoside diphosphate kinase (NDPK) B in both preparations, together with
      residual Gbetagamma dimers. In the retinal NDPK B-enriched fractions, a Gbeta
      specific antiserum co-precipitated phosphorylated NDPK B, and an antiserum
      against the human NDPK co-precipitated phosphorylated Gbetagamma. In addition,
      the NDPK-containing fractions from bovine brain reconstituted the phosphorylation
      of purified Gbetagamma. For identification of the phosphorylated histidine
      residue, bovine brain Gbetagamma and G(t)betagamma were thiophosphorylated with
      guanosine 5'-O-(3-[(35)S]thio)triphosphate, followed by digestion with
      endoproteinase Glu-C and trypsin, separation of the resulting peptides by gel
      electrophoresis and high pressure liquid chromatography, respectively, and
      sequencing of the radioactive peptides. The sequence information produced by both
      methods identified specific labeled fragments of bovine Gbeta(1) that overlapped
      in the heptapeptide, Leu-Met-Thr-Tyr-Ser-His-Asp (amino acids 261-267). We
      conclude that NDPK B forms complexes with Gbetagamma dimers and contributes to G
      protein activation by increasing the high energetic phosphate transfer onto GDP
      via intermediately phosphorylated His-266 in Gbeta(1) subunits.

PMID- 12486124
TI  - Crystal structure of AlgQ2, a macromolecule (alginate)-binding protein of
      Sphingomonas sp. A1, complexed with an alginate tetrasaccharide at 1.6-A
      resolution.
AB  - Sphingomonas sp. A1 possesses a high molecular weight (HMW) alginate uptake
      system composed of a novel pit formed on the cell surface and a pit-dependent ATP
      binding cassette (ABC) transporter in the inner membrane. The transportation of
      HMW alginate from the pit to the ABC transporter is mediated by the periplasmic
      HMW alginate-binding proteins AlgQ1 and AlgQ2. We determined the crystal
      structure of AlgQ2 complexed with an alginate tetrasaccharide using an alginate
      free (apo) form as a search model and refined it at 1.6-A resolution. One
      tetrasaccharide was found between the N and C-terminal domains, which are
      connected by three extended hinge loops. The tetrasaccharide complex took on a
      closed domain form, in contrast to the open domain form of the apo form. The
      tetrasaccharide was bound in the cleft between the domains through van der Waals
      interactions and the formation of hydrogen bonds. Among the four sugar residues,
      the nonreducing end residue was located at the bottom of the cleft and exhibited
      the largest number of interactions with the surrounding amino acid residues,
      suggesting that AlgQ2 mainly recognizes and binds to the nonreducing part of a
      HMW alginate and delivers the polymer to the ABC transporter through
      conformational changes (open and closed forms) of the two domains.

PMID- 12486125
TI  - A short regulatory domain restricts glycerol transport through yeast Fps1p.
AB  - The controlled export of solutes is crucial for cellular adaptation to hypotonic
      conditions. In the yeast Saccharomyces cerevisiae glycerol export is mediated by
      Fps1p, a member of the major intrinsic protein (MIP) family of channel proteins.
      Here we describe a short regulatory domain that restricts glycerol transport
      through Fps1p. This domain is required for retention of cellular glycerol under
      hypertonic stress and hence acquisition of osmotolerance. It is located in the N
      terminal cytoplasmic extension close to the first transmembrane domain. Several
      residues within that domain and its precise position are critical for channel
      control while the proximal residues 13-215 of the N-terminal extension are not
      required. The sequence of the regulatory domain and its position are perfectly
      conserved in orthologs from other yeast species. The regulatory domain has an
      amphiphilic character, and structural predictions indicate that it could fold
      back into the membrane bilayer. Remarkably, this domain has structural similarity
      to the channel forming loops B and E of Fps1p and other glycerol facilitators.
      Intragenic second-site suppressor mutations of the sensitivity to high osmolarity
      conferred by truncation of the regulatory domain caused diminished glycerol
      transport, confirming that elevated channel activity is the cause of the
      osmosensitive phenotype.

PMID- 12486126
TI  - Loss of multidrug resistance protein 1 expression and folate efflux activity
      results in a highly concentrative folate transport in human leukemia cells.
AB  - We studied the molecular basis of the up to 46-fold increased accumulation of
      folates and methotrexate (MTX) in human leukemia CEM-7A cells established by
      gradual deprivation of leucovorin (LCV). CEM-7A cells consequently exhibited 10-
      and 68-fold decreased LCV and folic acid growth requirements and 23-25-fold
      hypersensitivity to MTX and edatrexate. Although CEM-7A cells displayed a 74-86
      fold increase in the reduced folate carrier (RFC)-mediated influx of LCV and MTX,
      RFC overexpression per se cannot induce a prominently increased folate/MTX
      accumulation because RFC functions as a nonconcentrative anion exchanger. We
      therefore explored the possibility that folate efflux activity mediated by
      members of the multidrug resistance protein (MRP) family was impaired in CEM-7A
      cells. Parental CEM cells expressed substantial levels of MRP1, MRP4, poor MRP5
      levels, whereas MRP2, MRP3 and breast cancer resistance protein were
      undetectable. In contrast, CEM-7A cells lost 95% of MRP1 levels while retaining
      parental expression of MRP4 and MRP5. Consequently, CEM-7A cells displayed a 5
      fold decrease in the [(3)H]folic acid efflux rate constant, which was identical
      to that obtained with parental CEM cells, when their folic acid efflux was
      blocked (78%) with probenecid. Furthermore, when compared with parental CEM, CEM
      7A cells accumulated 2-fold more calcein fluorescence. Treatment of parental
      cells with the MRP1 efflux inhibitors MK571 and probenecid resulted in a 60-100%
      increase in calcein fluorescence. In contrast, these inhibitors failed to alter
      the calcein fluorescence in CEM-7A cells, which markedly lost MRP1 expression.
      Replenishment of LCV in the growth medium of CEM-7A cells resulted in resumption
      of normal MRP1 expression. These results establish for the first time that MRP1
      is the primary folate efflux route in CEM leukemia cells and that the loss of
      folate efflux activity is an efficient means of markedly augmenting cellular
      folate pools. These findings suggest a functional role for MRP1 in the
      maintenance of cellular folate homeostasis.

PMID- 12486127
TI  - Manipulation of EphB2 regulatory motifs and SH2 binding sites switches MAPK
      signaling and biological activity.
AB  - Signaling by the Eph family of receptor tyrosine kinases (RTKs) is complex,
      because they can interact with a variety of intracellular targets, and can
      potentially induce distinct responses in different cell types. In NG108 neuronal
      cells, activated EphB2 recruits p120RasGAP, in a fashion that is associated with
      down-regulation of the Ras-Erk mitogen-activated kinase (MAPK) pathway and
      neurite retraction. To pursue the role of the Ras-MAPK pathway in EphB2-mediated
      growth cone collapse, and to explore the biochemical and biological functions of
      Eph receptors, we sought to re-engineer the signaling properties of EphB2 by
      manipulating its regulatory motifs and SH2 binding sites. An EphB2 mutant that
      retained juxtamembrane (JM) RasGAP binding sites but incorporated a Grb2 binding
      motif at an alternate RasGAP binding site within the kinase domain had little
      effect on basal Erk MAPK activation. In contrast, elimination of all RasGAP
      binding sites, accompanied by the addition of a Grb2 binding site within the
      kinase domain, led to an increase in phospho-Erk levels in NG108 cells following
      ephrin-B1 stimulation. Functional assays indicated a correlation between neurite
      retraction and the ability of the EphB2 mutants to down-regulate Ras-Erk MAPK
      signaling. These data suggest that EphB2 can be designed to repress, stabilize,
      or activate the Ras-Erk MAPK pathway by the manipulation of RasGAP and Grb2 SH2
      domain binding sites and support the notion that Erk MAPK regulation plays a
      significant role in axon guidance. The behavior of EphB2 variants with mutations
      in the JM region and kinase domains suggests an intricate pattern of regulation
      and target recognition by Eph receptors.

PMID- 12486128
TI  - Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists
      increase glucose metabolism in astrocytes.
AB  - Activation of peroxisome proliferator-activated receptors (PPARs) can regulate
      brain physiology and provide protection in models of neurological disease;
      however, neither their exact targets nor mechanisms of action in brain are known.
      In many cells, PPAR gamma agonists increase glucose uptake and metabolism.
      Because astrocytes store glucose and provide lactate to neurons on demand, we
      tested effects of PPAR gamma agonists on astroglial glucose metabolism.
      Incubation of cortical astrocytes with the PPAR gamma thiazolidinedione (TZD)
      agonist pioglitazone (Pio) significantly increased glucose consumption in a time-
      and dose-dependent manner, with maximal increase of 36% observed after 4 h in 30
      microm Pio. Pio increased 2-deoxy-glucose uptake because of increased flux
      through the type 1 glucose transporter. However, at this time point Pio did not
      increase type 1 glucose transporter expression, nor were its effects blocked by
      transcriptional or translational inhibitors. Pio also increased astrocyte lactate
      production as soon as 3 h after incubation. These effects were replicated by
      other TZDs; however, the order of efficacy (troglitazone > pioglitazone >
      rosiglitazone) suggests that effects were not mediated via PPAR gamma activation.
      TZDs increased astrocyte cAMP levels, and their glucose modifying effects were
      reduced by protein kinase A inhibitors. TZDs inhibited state III respiration in
      isolated brain mitochondria, whereas in astrocytes they caused mitochondrial
      membrane hyperpolarization. Pio protected astrocytes against hypoglycemia-induced
      cell death. Finally, glucose uptake was modified in brain sections prepared from
      Pio-fed rats. These results demonstrate that TZDs modify astrocyte metabolism and
      mitochondrial function, which could be beneficial in neurological conditions
      where glucose availability is reduced.

PMID- 12486129
TI  - The homeodomain protein Barx2 promotes myogenic differentiation and is regulated
      by myogenic regulatory factors.
AB  - The homeobox protein Barx2 is expressed in both smooth and skeletal muscle and is
      up-regulated during differentiation of skeletal myotubes. Here we use antisense
      oligonucleotide inhibition of Barx2 expression in limb bud cell culture to show
      that Barx2 is required for myotube formation. Moreover, overexpression of Barx2
      accelerates the fusion of MyoD-positive limb bud cells and C2C12 myoblasts.
      However, overexpression of Barx2 does not induce ectopic MyoD expression in
      either limb bud cultures or in multipotent C3H10T1/2 mesenchymal cells, and does
      not induce fusion of C3H10T1/2 cells. These results suggest that Barx2 acts
      downstream of MyoD. To test this hypothesis, we isolated the Barx2 gene promoter
      and identified DNA regulatory elements that might control Barx2 expression during
      myogenesis. The proximal promoter of the Barx2 gene contained binding sites for
      several factors involved in myoblast differentiation including MyoD, myogenin,
      serum response factor, and myocyte enhancer factor 2. Co-transfection experiments
      showed that binding sites for both MyoD and serum response factor are necessary
      for activation of the promoter by MyoD and myogenin. Taken together, these
      studies indicate that Barx2 is a key regulator of myogenic differentiation that
      acts downstream of muscle regulatory factors.

PMID- 12486130
TI  - Co-translational targeting and translocation of the amino terminus of opsin
      across the endoplasmic membrane requires GTP but not ATP.
AB  - The tight coupling between ongoing translation and translocation across the
      mammalian endoplasmic reticulum has made it difficult to determine the
      requirements that are specific for translocation. We have developed an in vitro
      assay that faithfully mimics the co-translational targeting and translocation of
      the amino terminus of opsin without ongoing translation. Using this system we
      demonstrate that this post-translational targeting and translocation requires
      nucleotide triphosphates but not cytosolic proteins. The addition of GTP alone
      was sufficient to fully restore targeting. The addition of ATP was not
      specifically required, and non-hydrolyzable analogs of ATP that blocked 90% of
      the ATPase activity also had no inhibitory effect on translocation.

PMID- 12486131
TI  - Identification of a novel testicular orphan receptor-4 (TR4)-associated protein
      as repressor for the selective suppression of TR4-mediated transactivation.
AB  - Although many co-activators have been identified for various nuclear receptors,
      relatively fewer co-repressors have been isolated and characterized. Here we
      report the identification of a novel testicular orphan nuclear receptor-4 (TR4)
      associated protein (TRA16) that is mainly localized in the nucleus of cells as a
      repressor to suppress TR4-mediated transactivation. The suppression of TR4
      mediated transactivation is selective because TRA16 shows only a slight influence
      on the transactivation of androgen receptor, glucocorticoid receptor, and
      progesterone receptor. Sequence analysis shows that TRA16 is a novel gene with
      139 amino acids in an open reading frame with a molecular mass of 16 kDa, which
      did not match any published gene sequences. Mammalian two-hybrid system and co
      immunoprecipitation assays both demonstrate that TRA16 can interact strongly with
      TR4. The electrophoretic mobility shift assay suggests that TRA16 may suppress
      TR4-mediated transactivation via decreased binding between the TR4 protein and
      the TR4 response element on the target gene(s). Furthermore, TRA16 can also block
      the interaction between TR4 and TR4 ligand-binding domain through interacting
      with TR4-DNA-binding and ligand-binding domains. These unique suppression
      mechanisms suggest that TRA16 may function as a novel repressor to selectively
      suppress the TR4-mediated transactivation.

PMID- 12486132
TI  - Vasodilation by the calcium-mobilizing messenger cyclic ADP-ribose.
AB  - In artery smooth muscle, adenylyl cyclase-coupled receptors such as beta
      adrenoceptors evoke Ca(2+) signals, which open Ca(2+)-activated potassium
      (BK(Ca)) channels in the plasma membrane. Thus, blood pressure may be lowered, in
      part, through vasodilation due to membrane hyperpolarization. The Ca(2+) signal
      is evoked via ryanodine receptors (RyRs) in sarcoplasmic reticulum proximal to
      the plasma membrane. We show here that cyclic adenosine diphosphate-ribose
      (cADPR), by activating RyRs, mediates, in part, hyperpolarization and
      vasodilation by beta-adrenoceptors. Thus, intracellular dialysis of cADPR
      increased the cytoplasmic Ca(2+) concentration proximal to the plasma membrane in
      isolated arterial smooth muscle cells and induced a concomitant membrane
      hyperpolarization. Smooth muscle hyperpolarization mediated by cADPR, by beta
      adrenoceptors, and by cAMP, respectively, was abolished by chelating
      intracellular Ca(2+) and by blocking RyRs, cADPR, and BK(Ca) channels with
      ryanodine, 8-amino-cADPR, and iberiotoxin, respectively. The cAMP-dependent
      protein kinase A antagonist N-(2-[p-bromocinnamylamino]ethyl)-5
      isoquinolinesulfonamide hydrochloride (H89) blocked hyperpolarization by
      isoprenaline and cAMP, respectively, but not hyperpolarization by cADPR. Thus,
      cADPR acts as a downstream element in this signaling cascade. Importantly,
      antagonists of cADPR and BK(Ca) channels, respectively, inhibited beta
      adrenoreceptor-induced artery dilation. We conclude, therefore, that relaxation
      of arterial smooth muscle by adenylyl cyclase-coupled receptors results, in part,
      from a cAMP-dependent and protein kinase A-dependent increase in cADPR synthesis,
      and subsequent activation of sarcoplasmic reticulum Ca(2+) release via RyRs,
      which leads to activation of BK(Ca) channels and membrane hyperpolarization.

PMID- 12486133
TI  - The amino-terminal domain of G-protein-coupled receptor kinase 2 is a regulatory
      Gbeta gamma binding site.
AB  - G-protein-coupled receptor kinase 2 (GRK2) is activated by free Gbetagamma
      subunits. A Gbetagamma binding site of GRK2 is localized in the carboxyl-terminal
      pleckstrin homology domain. This Gbetagamma binding site of GRK2 also regulates
      Gbetagamma-stimulated signaling by sequestering free Gbetagamma subunits. We
      report here that truncation of the carboxyl-terminal Gbetagamma binding site of
      GRK2 did not abolish the Gbetagamma regulatory activity of GRK2 as determined by
      the inhibition of a Gbetagamma-stimulated increase in inositol phosphates in
      cells. This finding suggested the presence of a second Gbetagamma binding site in
      GRK2. And indeed, the amino terminus of GRK2 (GRK2(1-185)) inhibited a Gbetagamma
      stimulated inositol phosphate signal in cells, purified GRK2(1-185) suppressed
      the Gbetagamma-stimulated phosphorylation of rhodopsin, and GRK2(1-185) bound
      directly to purified Gbetagamma subunits. The amino-terminal Gbetagamma
      regulatory site does not overlap with the RGS domain of GRK-2 because GRK2(1-53)
      with truncated RGS domain inhibited Gbetagamma-mediated signaling with similar
      potency and efficacy as did GRK2(1-185). In addition to the Gbetagamma regulatory
      activity, the amino-terminal Gbetagamma binding site of GRK2 affects the kinase
      activity of GRK2 because antibodies specifically cross-reacting with the amino
      terminus of GRK2 suppressed the GRK2-dependent phosphorylation of rhodopsin. The
      antibody-mediated inhibition was released by purified Gbetagamma subunits,
      strongly suggesting that Gbetagamma binding to the amino terminus of GRK2
      enhances the kinase activity toward rhodopsin. Thus, the amino-terminal domain of
      GRK2 is a previously unrecognized Gbetagamma binding site that regulates GRK2
      mediated receptor phosphorylation and inhibits Gbetagamma-stimulated signaling.

PMID- 12486134
TI  - Altered sphingolipid metabolism in N-(4-hydroxyphenyl)-retinamide-resistant A2780
      human ovarian carcinoma cells.
AB  - In the present work, we studied the effects of fenretinide (N-(4
      hydroxyphenyl)retinamide (HPR)), a hydroxyphenyl derivative of all-trans-retinoic
      acid, on sphingolipid metabolism and expression in human ovarian carcinoma A2780
      cells. A2780 cells, which are sensitive to a pharmacologically achievable HPR
      concentration, become 10-fold more resistant after exposure to increasing HPR
      concentrations. Our results showed that HPR was able to induce a dose- and time
      dependent increase in cellular ceramide levels in sensitive but not in resistant
      cells. This form of resistance in A2780 cells was not accompanied by the
      overexpression of multidrug resistance-specific proteins MDR1 P-glycoprotein and
      multidrug resistance-associated protein, whose mRNA levels did not differ in
      sensitive and resistant A2780 cells. HPR-resistant cells were characterized by an
      overall altered sphingolipid metabolism. The overall content in
      glycosphingolipids was similar in both cell types, but the expression of specific
      glycosphingolipids was different. Specifically, our findings indicated that
      glucosylceramide levels were similar in sensitive and resistant cells, but
      resistant cells were characterized by a 6-fold lower expression of
      lactosylceramide levels and by a 6-fold higher expression of ganglioside levels
      than sensitive cells. The main gangliosides from resistant A2780 cells were
      identified as GM3 and GM2. The possible metabolic mechanisms leading to this
      difference were investigated. Interestingly, the mRNA levels of glucosylceramide
      and lactosylceramide synthases were similar in sensitive and resistant cells,
      whereas GM3 synthase mRNA level and GM3 synthase activity were remarkably higher
      in resistant cells.

PMID- 12486135
TI  - Rpn6p, a proteasome subunit from Saccharomyces cerevisiae, is essential for the
      assembly and activity of the 26 S proteasome.
AB  - We report the functional characterization of RPN6, an essential gene from
      Saccharomyces cerevisiae encoding the proteasomal subunit Rpn6p. For this
      purpose, conditional mutants that are able to grow on galactose but not on
      glucose were obtained. When these mutants are shifted to glucose, Rpn6p depletion
      induces several specific phenotypes. First, multiubiquitinated proteins
      accumulate, indicating a defect in proteasome-mediated proteolysis. Second,
      mutant yeasts are arrested as large budded cells with a single nucleus and a 2C
      DNA content; in addition, the spindle pole body is duplicated, indicating a
      general cell cycle defect related to the turnover of G(2)-cyclins after DNA
      synthesis. Clb2p and Pds1p, but not Sic1p, accumulate in the arrested cells.
      Depletion of Rpn6p affects both the structure and the peptidase activity of
      proteasomes in the cell. These results implicate Rpn6p function in the specific
      recognition of a subset of substrates and point to a role in maintaining the
      correct quaternary structure of the 26 S proteasome.

PMID- 12486136
TI  - HIV-1 Nef stabilizes the association of adaptor protein complexes with membranes.
AB  - The maximal virulence of HIV-1 requires Nef, a virally encoded peripheral
      membrane protein. Nef binds to the adaptor protein (AP) complexes of coated
      vesicles, inducing an expansion of the endosomal compartment and altering the
      surface expression of cellular proteins including CD4 and class I major
      histocompatibility complex. Here, we show that Nef stabilizes the association of
      AP-1 and AP-3 with membranes. These complexes remained with Nef on juxtanuclear
      membranes despite the treatment of cells with brefeldin A, which induced the
      release of ADP-ribosylation factor 1 (ARF1) from these membranes to the cytosol.
      Nef also induced a persistent association of AP-1 and AP-3 with membranes despite
      the expression of dominant-negative ARF1 or the overexpression of an ARF1-GTPase
      activating protein. Mutational analysis indicated that the direct binding of Nef
      to the AP complexes is essential for this stabilization. The leucine residues of
      the EXXXLL motif found in Nef were required for binding to AP-1 and AP-3 in vitro
      and for the stabilization of these complexes on membranes in vivo, whereas the
      glutamic acid residue of this motif was required specifically for the binding and
      stabilization of AP-3. These data indicate that Nef mediates the persistent
      attachment of AP-1 and AP-3 to membranes by an ARF1-independent mechanism. The
      stabilization of these complexes on membranes may underlie the pleiotropic
      effects of Nef on protein trafficking within the endosomal system.

PMID- 12486137
TI  - Peptide ligands for the fibronectin type II modules of matrix metalloproteinase 2
      (MMP-2).
AB  - The interaction of matrix metalloproteinase 2 (MMP-2) with gelatin is mediated by
      three repeats homologous to fibronectin type II (FN2) modules, which are inserted
      in the catalytic domain in proximity of the active site. We screened a random 15
      mer phage display library to identify peptides that interact with the FN2 modules
      of MMP-2. Interestingly, the selected peptides are not gelatin-like and do not
      share a common, obvious sequence motif. However, they contain a high proportion
      of aromatic residues. The interactions of two peptides, WHWRH0RIPLQLAAGR and
      THSHQWRHHQFPAPT, with constructs comprising the in-tandem first and second and
      second and third FN2 modules of MMP-2 (Col-12 and Col-23, respectively) were
      characterized by NMR. Both peptides interact with Col-12 and Col-23 with apparent
      association constants in the mm(-1) range. Peptide binding results in
      perturbation of signals from residues located in the gelatin-binding pocket and
      flexible parts of the molecule. Although the former finding suggests that the
      gelatin-binding site is involved in the contact, the interpretation of the latter
      is less straightforward and may well reflect both the direct and indirect effects
      of the interaction.

PMID- 12486138
TI  - Low resolution structure determination shows procollagen C-proteinase enhancer to
      be an elongated multidomain glycoprotein.
AB  - Procollagen C-proteinase enhancer (PCPE) is an extracellular matrix glycoprotein
      that can stimulate the action of tolloid metalloproteinases, such as bone
      morphogenetic protein-1, on a procollagen substrate, by up to 20-fold. The PCPE
      molecule consists of two CUB domains followed by a C-terminal NTR (netrin-like)
      domain. In order to obtain structural insights into the function of PCPE, the
      recombinant protein was characterized by a range of biophysical techniques,
      including analytical ultracentrifugation, transmission electron microscopy, and
      small angle x-ray scattering. All three approaches showed PCPE to be a rod-like
      molecule, with a length of approximately 150 A. Homology modeling of both CUB
      domains and the NTR domain was consistent with the low-resolution structure of
      PCPE deduced from the small angle x-ray scattering data. Comparison with the low
      resolution structure of the procollagen C-terminal region supports a recently
      proposed model (Ricard-Blum, S., Bernocco, S., Font, B., Moali, C., Eichenberger,
      D., Farjanel, J., Burchardt, E. R., van der Rest, M., Kessler, E., and Hulmes, D.
      J. S. (2002) J. Biol. Chem. 277, 33864-33869) for the mechanism of action of
      PCPE.

PMID- 12486139
TI  - Reduction-reoxidation cycles contribute to catalysis of disulfide isomerization
      by protein-disulfide isomerase.
AB  - Protein-disulfide isomerase (PDI) catalyzes the formation and isomerization of
      disulfides during oxidative protein folding. This process can be error-prone in
      its early stages, and any incorrect disulfides that form must be rearranged to
      their native configuration. When the second cysteine (CGHC) in the PDI active
      site is mutated to Ser, the isomerase activity drops by 7-8-fold, and a covalent
      intermediate with the substrate accumulates. This led to the proposal that the
      second active site cysteine provides an escape mechanism, preventing PDI from
      becoming trapped with substrates that isomerize slowly (Walker, K. W., and
      Gilbert, H. F. (1997) J. Biol. Chem. 272, 8845-8848). Escape also reduces the
      substrate, and if it is invoked frequently, disulfide isomerization will involve
      cycles of reduction and reoxidation in preference to intramolecular isomerization
      of the PDI-bound substrate. Using a gel-shift assay that adds a polyethylene
      glycol-conjugated maleimide of 5 kDa for each sulfhydryl group, we find that PDI
      reduction and oxidation are kinetically competent and essential for
      isomerization. Oxidants inhibit isomerization and oxidize PDI when a redox buffer
      is not present to maintain the PDI redox state. Reductants also inhibit
      isomerization as they deplete oxidized PDI. These rapid cycles of PDI oxidation
      and reduction suggest that PDI catalyzes isomerization by trial and error,
      reducing disulfides and oxidizing them in a different configuration. Disulfide
      reduction-reoxidation may set up critical folding intermediates for
      intramolecular isomerization, or it may serve as the only isomerization
      mechanism. In the absence of a redox buffer, these steady-state reduction
      oxidation cycles can balance the redox state of PDI and support effective
      catalysis of disulfide isomerization.

PMID- 12486140
TI  - Starburst cells nondirectionally facilitate the responses of direction-selective
      retinal ganglion cells.
AB  - The mechanism of direction selectivity in retinal ganglion cells remains
      controversial. An important issue is how the starburst amacrine cells, which are
      known to provide a major synaptic input to the direction-selective ganglion
      cells, participate in the directional discrimination. Here, we present evidence
      that the cholinergic outputs of the starburst cells affect the responses of the
      ganglion cells symmetrically; they provide a feedforward excitation that
      facilitates the response of the ganglion cells to movement in both the preferred
      and null directions. This seems to place a constraint on models of the
      directional discrimination in which the starburst cells participate, namely, that
      their cholinergic synapses be nondirectional in their effects on the ganglion
      cells.

PMID- 12486141
TI  - One-trial in vitro conditioning regulates a cytoskeletal-related protein (CSP24)
      in the conditioned stimulus pathway of Hermissenda.
AB  - Hermissenda CSP24 (cytoskeletal-related protein 24) is a 24 kDa beta-thymosin
      like protein that is associated with intermediate memory. We showed previously
      that one-trial conditioning resulted in a significant increase in the
      phosphorylation of CSP24 detected in lysates of the pathway supporting the
      conditioned stimulus (CS). Here we report the association of the protein with the
      actin cytoskeleton and the distribution of CSP24-immunoreactive neurons in two
      sensory structures and the circumesophageal nervous system. Identified
      photoreceptors, hair cells, and neurons in the cerebropleural and pedal ganglia
      were immunoreactive for CSP24. Immunoprecipitation experiments with 32PO4-labeled
      lysates of the circumesophageal nervous system identified a 44 kDa protein band
      (consistent with actin) that coprecipitates with CSP24. An analysis of
      immunoprecipitates on Western blots probed with anti-actin antibody also showed
      that actin coprecipitates with CSP24. Laser confocal microscopy of photoreceptors
      costained with fluorescently labeled anti-actin antibody and anti-CSP24 antibody,
      or fluorescent phalloidin and anti-CSP24 antibody showed that CSP24 is localized
      with actin in the cytosol of photoreceptor cell bodies and colocalized with
      presumed G-actin, but not F-actin, in regions adjacent to the plasma membrane.
      Although CSP24 is widely distributed in the Hermissenda nervous system, its
      regulation by one-trial conditioning was observed only in the CS pathway. Our
      findings suggest that CSP24 may interact with components of the actin
      cytoskeleton that contribute to structural changes underlying the formation and
      maintenance of enduring forms of memory.

PMID- 12486142
TI  - A reciprocal relationship between reliability and responsiveness in developing
      visual cortical neurons.
AB  - As the visual cortex matures, developmental modifications change the visually
      evoked firing patterns of single neurons. To explore the relationship between
      these developmental changes and the fidelity with which neurons transmit
      information, we measured the reliability of neuronal responses during postnatal
      development. Infant neurons have lower variability and higher dependence of
      transmitted information on firing rate than adult cells. Fewer spikes are needed
      by the infant cortex to convey the same amount of information. The increase in
      firing rates that occurs during development is largely offset, therefore, by a
      decrease in the reliability of responses. We propose that these changes are a
      consequence of the increasing ability of cortical cells to encode rapid changes
      in the visual environment.

PMID- 12486143
TI  - Presynaptic Ca2+ entry is unchanged during hippocampal mossy fiber long-term
      potentiation.
AB  - The hippocampal mossy fiber (MF)-CA3 synapse exhibits NMDA receptor-independent
      long-term potentiation (LTP), which is expressed by presynaptic mechanisms
      leading to persistent enhancement of transmitter release. Recent studies have
      identified several molecules that may play an important role in MF-LTP. These
      include Rab3A, RIM1alpha, kainate autoreceptor, and hyperpolarization-activated
      cation channel (I(h)). However, the precise cellular expression mechanism remains
      to be determined because some studies noticed essential roles of release
      machinery molecules, whereas others suggested modulation of the ionotropic
      processes affecting Ca2+ entry into the presynaptic terminals. Using fluorescence
      recordings of presynaptic Ca2+ in hippocampal slices, here we demonstrated that
      MF-LTP is not accompanied by an increase in presynaptic Ca2+ influx during an
      action potential. Whole-cell recordings from CA3 neurons revealed long-lasting
      increases in mean frequency, but not mean amplitude, of miniature EPSCs after the
      high-frequency stimulation of MFs. These data indicate that the presynaptic
      expression mechanisms responsible for enhanced transmitter release during MF-LTP
      involve persistent modification of presynaptic molecular targets residing
      downstream of Ca2+ entry.

PMID- 12486144
TI  - Modulation of serotonin 2C receptor editing by sustained changes in serotonergic
      neurotransmission.
AB  - Serotonin 2C (5-HT2C) receptor pre-mRNA is a substrate for RNA editing enzymes
      that convert five adenosines (named A, B, C', C, and D editing sites) to
      inosines. Editing of two of these sites (C' and C) is crucial for decreasing the
      efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of
      mouse forebrain neocortical 5-HT2C mRNA isoforms revealed that editing at these
      two sites is regulated in a serotonin-dependent manner. In serotonin-depleted
      mice, C'- and C-site editing is significantly decreased. This results in an
      increased expression of 5-HT2C mRNA isoforms encoding receptors with higher
      sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT2A/2C agonist
      (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the
      editing frequency at the C' site and leads to increased expression of 5-HT2C mRNA
      isoforms encoding receptors that activate G-protein least efficiently. None of
      the drug treatments led to alterations in cytoplasmic 5-HT2C mRNA levels. These
      data indicate that editing of 5-HT2C pre-mRNA is a mechanism that retains basic
      response properties of 5-HT2C receptors in the face of changing synaptic input to
      keep receptor activation within an optimal range for information processing. Key
      words: serotonin; 5.

PMID- 12486145
TI  - Elementary properties of axonal calcium currents in type B photoreceptors in
      Hermissenda crassicornis.
AB  - Axons of the type B photoreceptors form synapses with hair cells and interneurons
      that are involved in classical conditioning in Hermissenda. We examined the
      differences in the Ca2+ channels expressed in the soma and axons of the B
      photoreceptors by direct functional recordings of single-channel currents.
      Although the soma of the B cells express two Ca2+ current subtypes, a transient
      BayK 8644-insensitive (approximately 17 pS) current and a sustained BayK 8644
      sensitive (approximately 10 pS) current, the axons expressed only the latter. The
      axonal Ca2+ current activated at potentials positive to -20 mV. Moreover, the
      Ca2+ channels are distributed heterogeneously along the length of the axon, with
      the higher channel density (approximately 10-15 channel microm(-2)) occurring at
      the distal one-third of the isolated axons, with respect to the soma. The regions
      of Ca2+ channel clusters may represent the presynaptic site of the photoreceptor
      interneuron synapses. Furthermore, the high-density clusters of Ca2+ channels may
      augment postsynaptic responses. The results of the present study represent the
      first direct recordings of Ca2+ currents at presumed synaptic sites. Expression
      of different Ca2+ channel subtypes at distinct compartments of the type B
      photoreceptors may generate diverse Ca2+ domains that may be required for
      neuronal plasticity in Hermissenda.

PMID- 12486146
TI  - Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice
      by human apolipoprotein E depends on isoform, aging, and overexpression of
      amyloid beta peptides but not on plaque formation.
AB  - The most frequent human apolipoprotein (apo) E isoforms, E3 and E4,
      differentially affect Alzheimer's disease (AD) risk (E4 > E3) and age of onset
      (E4 < E3). Compared with apoE3, apoE4 promotes the cerebral deposition of amyloid
      beta (Abeta) peptides, which are derived from the amyloid precursor protein (APP)
      and play a central role in AD. However, it is uncertain whether Abeta deposition
      into plaques is the main mechanism by which apoE isoforms affect AD. We analyzed
      murine apoE-deficient transgenic mice expressing in their brains human APP (hAPP)
      and Abeta together with apoE3 or apoE4. Because cognitive decline in AD
      correlates better with decreases in synaptophysin-immunoreactive presynaptic
      terminals, choline acetyltransferase (ChAT) activity, and ChAT-positive fibers
      than with plaque load, we compared these parameters in hAPP/apoE3 and hAPP/apoE4
      mice and singly transgenic controls at 6-7, 12-15, and 19-24 months of age. Brain
      aging in the context of high levels of nondeposited human Abeta resulted in
      progressive synaptic/cholinergic deficits. ApoE3 delayed the synaptic deficits
      until old age, whereas apoE4 was not protective at any of the ages analyzed. Old
      hAPP/apoE4 mice had more plaques than old hAPP/apoE3 mice, but
      synaptic/cholinergic deficits preceded plaque formation in hAPP/apoE4 mice.
      Moreover, despite their different plaque loads, old hAPP/apoE4 and hAPP/apoE3
      mice had comparable synaptic/cholinergic deficits, and these deficits were found
      not only in the hippocampus but also in the neocortex, which in most mice
      contained no plaques. Thus, apoE3, but not apoE4, delays age- and Abeta-dependent
      synaptic deficits through a plaque-independent mechanism. This difference could
      contribute to the differential effects of apoE isoforms on the risk and onset of
      AD.

PMID- 12486147
TI  - tan and ebony genes regulate a novel pathway for transmitter metabolism at fly
      photoreceptor terminals.
AB  - In Drosophila melanogaster, ebony and tan, two cuticle melanizing mutants,
      regulate the conjugation (ebony) of beta-alanine to dopamine or hydrolysis (tan)
      of the beta-alanyl conjugate to liberate dopamine. beta-alanine biosynthesis is
      regulated by black. ebony and tan also exert unexplained reciprocal defects in
      the electroretinogram, at ON and OFF transients attributable to impaired
      transmission at photoreceptor synapses, which liberate histamine. Compatible with
      this impairment, we show that both mutants have reduced histamine contents in the
      head, as measured by HPLC, and have correspondingly reduced numbers of synaptic
      vesicles in their photoreceptor terminals. Thus, the histamine phenotype is
      associated with sites of synaptic transmission at photoreceptors. We demonstrate
      that when they receive microinjections into the head, wild-type Sarcophaga
      bullata (in whose larger head such injections are routinely possible) rapidly (<5
      sec) convert exogenous [3H]histamine into its beta-alanine conjugate, carcinine,
      a novel metabolite. Drosophila tan has an increased quantity of [3H]carcinine,
      the hydrolysis of which is blocked; ebony lacks [3H]carcinine, which it cannot
      synthesize. Confirming these actions, carcinine rescues the histamine phenotype
      of ebony, whereas beta-alanine rescues the carcinine phenotype of black;tan
      double mutants. The equilibrium ratio between [3H]carcinine and [3H]histamine
      after microinjecting wild-type Sarcophaga favors carcinine hydrolysis, increasing
      to only 0.5 after 30 min. Our findings help resolve a longstanding conundrum of
      the involvement of tan and ebony in photoreceptor function. We suggest that
      reversible synthesis of carcinine occurs in surrounding glia, serving to trap
      histamine after its release at photoreceptor synapses; subsequent hydrolysis
      liberates histamine for reuptake.

PMID- 12486148
TI  - Electrical synapses mediate signal transmission in the rod pathway of the
      mammalian retina.
AB  - In the retina, AII (rod) amacrine cells are essential for integrating rod signals
      into the cone pathway. In addition to being interconnected via homologous gap
      junctions, these cells make extensive heterologous gap junctions with ON-cone
      bipolar cells (BCs). These gap junctions are the pathway for transfer of rod
      signals to the ON-system. To investigate the functional properties of these gap
      junctions, we performed simultaneous whole-cell recordings from pairs of AII
      amacrine cells and ON-cone bipolar cells in the in vitro slice preparation of the
      rat retina. We demonstrate strong electrical coupling with symmetrical junction
      conductance (approximately 1.2 nS) and very low steady-state voltage sensitivity.
      However, signal transmission is more effective in the direction from AII amacrine
      cells to ON-cone bipolar cells than in the other direction. This functional
      rectification can be explained by a corresponding difference in membrane input
      resistance between the two cell types. Signal transmission has low-pass filter
      characteristics with increasing attenuation and phase shift for increasing
      stimulus frequency. Action potentials in AII amacrine cells evoke distinct
      electrical postsynaptic potentials in ON-cone bipolar cells. Strong and
      temporally precise synchronization of subthreshold membrane potential
      fluctuations are commonly observed.

PMID- 12486149
TI  - Three-dimensional reconstruction of a calyx of Held and its postsynaptic
      principal neuron in the medial nucleus of the trapezoid body.
AB  - The three-dimensional morphology of the axosomatic synaptic structures between a
      calyx of Held and a principal neuron in the medial nucleus of the trapezoid body
      (MNTB) in the brainstem of young postnatal day 9 rats was reconstructed from
      serial ultrathin sections. In the apposition zone between the calyx and the
      principal neuron two types of membrane specializations were identified: synaptic
      contacts (SCs) with active zones (AZs) and their associated postsynaptic
      densities (PSDs) constituted approximately 35% (n = 554) of the specializations;
      the remaining 65% (n = 1010) were puncta adherentia (PA). Synaptic contacts
      comprised approximately 5% of the apposition area of presynaptic and postsynaptic
      membranes. A SC had an average area of 0.100 microm(2), and the nearest neighbors
      were separated, on average, by 0.59 microm. Approximately one-half of the
      synaptic vesicles in the calyx were clustered within a distance of 200 nm of the
      AZ membrane area, a cluster consisting of approximately 60 synaptic vesicles (n =
      52 SCs). Approximately two synaptic vesicles per SC were "anatomically docked."
      Comparing the geometry of the synaptic structure with its previously studied
      functional properties, we find that during a single presynaptic action potential
      (AP) (1) approximately 35% of the AZs release a transmitter quantum, (2) the
      number of SCs and anatomically docked vesicles is comparable with the low
      estimates of the readily releasable pool (RRP) of quanta, and (3) the broad
      distribution of PSD areas [coefficient of variation (CV) = 0.9] is likely to
      contribute to the large variability of miniature EPSC peaks. The geometry of the
      reconstructed synapse suggests that each of the hundreds of SCs is likely to
      contribute independently to the size and rising phase of the EPSC during a single
      AP.

PMID- 12486150
TI  - Bursting in leech heart interneurons: cell-autonomous and network-based
      mechanisms.
AB  - Rhythmic activity within the heartbeat pattern generator of the medicinal leech
      is based on the alternating bursting of mutually inhibitory pairs of oscillator
      heart interneurons (half-center oscillators). Bicuculline methiodide has been
      shown to block mutual inhibition between these interneurons and to cause them to
      spike tonically while recorded intracellularly (Schmidt and Calabrese, 1992).
      Using extracellular recording techniques, we show here that oscillator and
      premotor heart interneurons continue to burst when pharmacologically isolated
      with bicuculline, although the bursting is not robust in some preparations. We
      propose that a nonspecific leak current introduced by the intracellular
      microelectrode suppresses endogenous bursting activity to account for the
      discrepancy with results using intracellular recording. A two-parameter
      bifurcation diagram (E(leak) vs g(leak)) of a mathematical model of a single
      heart interneuron shows a narrow stripe of parameter values where bursting
      occurs, separating large zones of tonic spiking and silence. A similar analysis
      performed for a half-center oscillator model outlined a much larger area of
      bursting. Bursting in the half-center oscillator model is also less sensitive to
      variation in the maximal conductances of voltage-gated currents than in the
      single-neuron model. Thus, in addition to ensuring appropriate bursting
      characteristics such as period, phase, and duty cycles, the half-center
      configuration enhances oscillation robustness, making them less susceptible to
      random or imposed changes in membrane parameters. Endogenous bursting, in turn,
      ensures appropriate bursting if the strength of mutual inhibition is weakened and
      limits the minimum period of the half-center oscillator to a period near that of
      the single neuron.

PMID- 12486151
TI  - Timing and efficacy of Ca2+ channel activation in hippocampal mossy fiber
      boutons.
AB  - The presynaptic Ca2+ signal is a key determinant of transmitter release at
      chemical synapses. In cortical synaptic terminals, however, little is known about
      the kinetic properties of the presynaptic Ca2+ channels. To investigate the
      timing and magnitude of the presynaptic Ca2+ inflow, we performed whole-cell
      patch-clamp recordings from mossy fiber boutons (MFBs) in rat hippocampus. MFBs
      showed large high-voltage-activated Ca(2+) currents, with a maximal amplitude of
      approximately 100 pA at a membrane potential of 0 mV. Both activation and
      deactivation were fast, with time constants in the submillisecond range at a
      temperature of approximately 23 degrees C. An MFB action potential (AP) applied
      as a voltage-clamp command evoked a transient Ca2+ current with an average
      amplitude of approximately 170 pA and a half-duration of 580 microsec. A prepulse
      to +40 mV had only minimal effects on the AP-evoked Ca2+ current, indicating that
      presynaptic APs open the voltage-gated Ca2+ channels very effectively. On the
      basis of the experimental data, we developed a kinetic model with four closed
      states and one open state, linked by voltage-dependent rate constants.
      Simulations of the Ca2+ current could reproduce the experimental data, including
      the large amplitude and rapid time course of the current evoked by MFB APs.
      Furthermore, the simulations indicate that the shape of the presynaptic AP and
      the gating kinetics of the Ca2+ channels are tuned to produce a maximal Ca2+
      influx during a minimal period of time. The precise timing and high efficacy of
      Ca2+ channel activation at this cortical glutamatergic synapse may be important
      for synchronous transmitter release and temporal information processing.

PMID- 12486152
TI  - Active contribution of dendrites to the tonic and trimodal patterns of activity
      in cerebellar Purkinje neurons.
AB  - The cerebellum is responsible for coordination of movement and maintenance of
      balance. Cerebellar architecture is based on repeats of an anatomically well
      defined circuit. At the center of these functional circuits are Purkinje neurons,
      which form the sole output of the cerebellar cortex. It is proposed that
      coordination of movement is achieved by encoding timing signals in the rate of
      firing and pattern of activity of Purkinje cells. An understanding of cerebellar
      timing requires an appreciation of the intrinsic firing behavior of Purkinje
      cells and the extent to which their activity is regulated within the functional
      circuits. We have examined the spontaneous firing of Purkinje neurons in
      isolation from the rest of the cerebellar circuitry by blocking fast synaptic
      transmission in acutely prepared cerebellar slices. We find that, intrinsically,
      mature Purkinje cells show a complex pattern of activity in which they
      continuously cycle among tonically firing, bursting, and silent modes. This
      trimodal pattern of activity emerges as the cerebellum matures anatomically and
      functionally. Concurrent with the transformation of the immature tonically firing
      cells to those with the trimodal pattern of activity, the dendrites assume a
      prominent role in regulating the excitability of Purkinje cells. Thus,
      alterations in the rate and pattern of activity of Purkinje neurons are not
      solely the result of synaptic input but also arise as a consequence of the
      intrinsic properties of the cells.

PMID- 12486153
TI  - An essential component in steroid synthesis, the steroidogenic acute regulatory
      protein, is expressed in discrete regions of the brain.
AB  - Recent data implicate locally produced steroids, termed neurosteroids, as
      regulators of neuronal function. Adrenal and gonadal steroidogenesis is
      controlled by changes in the steroidogenic acute regulatory protein (StAR);
      however, little is known about the regulation of neurosteroid production. We now
      demonstrate unequivocally that StAR mRNA and protein are expressed within glia
      and neurons in discrete regions of the mouse brain, and that glial StAR
      expression is inducible. Consistent with a role in de novo neurosteroidogenesis,
      StAR colocalizes with the cholesterol side-chain cleavage enzyme P450(scc) in
      both mouse and human brains. These data support a role for StAR in the production
      of neurosteroids and identify potential sites of active de novo steroid synthesis
      in the brain.

PMID- 12486154
TI  - Aberrant neuronal and paracellular deposition of endostatin in brains of patients
      with Alzheimer's disease.
AB  - Cerebrovascular pathology is common in Alzheimer's disease (AD) and is considered
      to contribute to cerebral malfunction. However, distinct antiangiogenic proteins
      that accumulate in AD brains have not yet been identified. Endostatin is a 20 kDa
      C-terminal fragment of collagen XVIII that, when added exogenously, inhibits
      endothelial proliferation and migration in vitro and angiogenesis and tumor
      growth in vivo by inducing apoptosis in endothelial cells. We produced a
      monoclonal antibody directed against endostatin and observed significantly more
      (p < 0.0001) immunoreactive cortical neurons in AD brains compared with age
      matched neuropathologically unaltered controls. High numbers of extracellular and
      frequently perivascular endostatin deposits were detected in the cerebral
      hemispheres. Double-labeling experiments revealed colocalization of endostatin in
      amyloid-beta(1-40) (Abeta(1-40)), tau protein, and periodic acid-Schiff stain
      positive plaques that were surrounded by focal gliosis. Western blotting revealed
      more 20 kDa endostatin in an AD patient compared with a control. In unstimulated
      SKNSH supernatants, endostatin was detected that increased predominantly after
      hypoxia in supernatants and cellular lysates. Abeta(1-40) (80 microg/ml)
      supplementation to SKNSH neurons for 24 hr completely abolished the release of
      endostatin. These data show that endostatin is released by neurons to accumulate
      in amyloid plaques in Alzheimer's disease. Induction by hypoxia and complete
      abrogation of endostatin release after Abeta(1-40) challenge reveals intricate
      interactions between the two proteins and opens new avenues for the development
      of novel treatment strategies of AD patients.

PMID- 12486155
TI  - Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of
      cholinergic smooth muscle contractions but still viable.
AB  - Cholinergic agents elicit prominent smooth muscle contractions via stimulation of
      muscarinic receptors that comprise five distinct subtypes (M1-M5). Although such
      contractions are important for autonomic organs, the role of each subtype has not
      been characterized precisely because of the poor selectivity of the currently
      available muscarinic ligands. Here, we generated a mutant mouse line (M2-/-M3-/-
      mice) lacking M2 and M3 receptors that are implicated in such cholinergic
      contractions. The relative contributions of M2 and M3 receptors in vitro was
      approximately 5 and 95% for the detrusor muscle contraction and approximately 25
      and 75% for the ileal longitudinal muscle contraction, respectively. Thus, M1,
      M4, or M5 receptors do not seem to play a role in such contractions. Despite the
      complete lack of cholinergic contractions in vitro, M2-/-M3-/- mice were viable,
      fertile, and free of apparent intestinal complications. The urinary bladder was
      distended only in males, which excludes a major contribution by cholinergic
      mechanisms to the urination in females. Thus, cholinergic mechanisms are
      dispensable in gastrointestinal motility and female urination. After 10 Hz
      electrical field stimulation, noncholinergic inputs were found to be increased in
      the ileum of M2-/-M3-/- females, which may account for the lack of apparent
      functional deficits. Interestingly, the M2-/-M3-/- mice had smaller ocular pupils
      than M3-deficient mice. The results suggest a novel role of M2 in the pupillary
      dilation, contrary to the well known cholinergic constriction. These results
      collectively suggest that an additional mechanism operates in the control of
      pupillary constriction-dilatation.

PMID- 12486156
TI  - Pertussis toxin-induced reversible encephalopathy dependent on monocyte
      chemoattractant protein-1 overexpression in mice.
AB  - In this report we describe pertussis toxin-induced reversible encephalopathy
      dependent on monocyte chemoattractant protein-1 (MCP-1) overexpression (PREMO), a
      novel animal model that exhibits features of human encephalopathic complications
      of inflammatory disorders such as viral meningoencephalitis and Lyme
      neuroborreliosis as well as the mild toxic encephalopathy that commonly precedes
      relapses of multiple sclerosis (MS). Overexpression of the mouse MCP-1 gene
      product (classically termed JE) in astrocytes, the major physiological CNS
      cellular source of MCP-1, failed to induce neurological impairment. Unexpectedly,
      transgenic (tg) mice overexpressing MCP-1 at a high level (MCP-1(hi)) manifested
      transient, severe encephalopathy with high mortality after injections of
      pertussis toxin (PTx) plus complete Freund's adjuvant (CFA). Surviving mice
      showed markedly improved function and did not relapse during a prolonged period
      of observation. Tg mice that expressed lower levels of MCP-1 were affected
      minimally after CFA/PTx injections, and tg expression of other chemokines failed
      to elicit this disorder. The disorder was significantly milder in mice lacking T
      cells, which therefore play a deleterious role in this encephalopathic process.
      Disruption of CC chemokine receptor 2 (CCR2) abolished both CNS inflammation and
      encephalopathy, identifying CCR2 as a relevant receptor for this disorder.
      Proinflammatory and type 1 cytokines including TNF-alpha, IL-1beta, IFN-gamma, IL
      2, RANTES, and IP-10 were elevated in CNS tissues from mice with PREMO. These
      studies characterize a novel model of reversible inflammatory encephalopathy that
      is dependent on both genetic and environmental factors.

PMID- 12486157
TI  - A novel sorting motif in the glutamate transporter excitatory amino acid
      transporter 3 directs its targeting in Madin-Darby canine kidney cells and
      hippocampal neurons.
AB  - The glutamate transporter excitatory amino acid transporter 3 (EAAT3) is
      polarized to the apical surface in epithelial cells and localized to the
      dendritic compartment in hippocampal neurons, where it is clustered adjacent to
      postsynaptic sites. In this study, we analyzed the sequences in EAAT3 that are
      responsible for its polarized localization in Madin-Darby canine kidney (MDCK)
      cells and neurons. Confocal microscopy and cell surface biotinylation assays
      demonstrated that deletion of the EAAT3 C terminus or replacement of the C
      terminus of EAAT3 with the analogous region in EAAT1 eliminated apical
      localization in MDCK cells. The C terminus of EAAT3 was sufficient to redirect
      the basolateral-preferring EAAT1 and the nonpolarized EAAT2 to the apical
      surface. Using alanine substitution mutants, we identified a short peptide motif
      in the cytoplasmic C-terminal region of EAAT3 that directs its apical
      localization in MDCK cells. Mutation of this sequence also impairs dendritic
      targeting of EAAT3 in hippocampal neurons but does not interfere with the
      clustering of EAAT3 on dendritic spines and filopodia. These data provide the
      first evidence that an identical cytoplasmic motif can direct apical targeting in
      epithelia and somatodendritic targeting in neurons. Moreover, our results
      demonstrate that the two fundamental features of the localization of EAAT3 in
      neurons, its restriction to the somatodendritic domain and its clustering near
      postsynaptic sites, are mediated by distinct molecular mechanisms.

PMID- 12486158
TI  - Correlated calcium uptake and release by mitochondria and endoplasmic reticulum
      of CA3 hippocampal dendrites after afferent synaptic stimulation.
AB  - Mitochondria and endoplasmic reticulum (ER) are important modulators of
      intracellular calcium signaling pathways, but the role of these organelles in
      shaping synaptic calcium transients in dendrites of pyramidal neurons remains
      speculative. We have measured directly the concentrations of total Ca (bound plus
      free) within intracellular compartments of proximal dendrites of CA3 hippocampal
      neurons at times after synaptic stimulation corresponding to the peak of the
      cytoplasmic free Ca2+ transient (1 sec), to just after its decay (30 sec), and to
      well after its return to prestimulus levels (180 sec). Electron probe
      microanalysis of cryosections from rapidly frozen slice cultures has revealed
      that afferent mossy fiber stimulation evokes large, rapid elevations in the
      concentration of total mitochondrial Ca ([Ca](mito)) in depolarized dendrites. A
      single tetanus (50 Hz/1 sec) elevated [Ca](mito) more than fivefold above
      characteristically low basal levels within 1 sec of stimulation and >10-fold by
      30 sec after stimulation. This strong Ca accumulation was reversible, because
      [Ca](mito) had recovered by 180 sec after the tetanus. Ca sequestered within
      mitochondria was localized to small inclusions that were distributed
      heterogeneously within, and probably among, individual mitochondria. By 30 sec
      after stimulation an active subpopulation of ER cisterns had accumulated more Ca
      than had mitochondria despite a approximately 1 sec delay before the onset of
      accumulation. Active ER cisterns retained their Ca load much longer (>3 min) than
      mitochondria. The complementary time courses of mitochondrial versus ER Ca2+
      uptake and release suggest that these organelles participate in a choreographed
      interplay, each shaping dendritic Ca2+ signals within characteristic regimes of
      cytosolic Ca2+ concentration and time.

PMID- 12486159
TI  - Proinflammatory mediators, stimulators of sensory neuron excitability via the
      expression of acid-sensing ion channels.
AB  - Tissue acidosis is an important feature of inflammation. It is a direct cause of
      pain and hyperalgesia. Protons activate sensory neurons mainly through acid
      sensing ion channels (ASICs) and the subsequent membrane depolarization that
      leads to action potential generation. We had previously shown that ASIC
      transcript levels were increased in inflammatory conditions in vivo. We have now
      found that this increase is caused by the proinflammatory mediators NGF,
      serotonin, interleukin-1, and bradykinin. A mixture of these mediators increases
      ASIC-like current amplitude on sensory neurons as well as the number of ASIC
      expressing neurons and leads to a higher sensory neuron excitability. An analysis
      of the promoter region of the ASIC3 encoding gene, an ASIC specifically expressed
      in sensory neurons and associated with chest pain that accompanies cardiac
      ischemia, reveals that gene transcription is controlled by NGF and serotonin.

PMID- 12486160
TI  - Modulation of the readily releasable pool of transmitter and of excitation
      secretion coupling by activity and by serotonin at Aplysia sensorimotor synapses
      in culture.
AB  - Short-term homosynaptic depression and heterosynaptic facilitation of transmitter
      release from mechanoreceptor sensory neurons of Aplysia are involved in
      habituation and sensitization, respectively, of defensive withdrawal reflexes. We
      investigated whether synaptic transmission is regulated in these forms of
      plasticity by means of changes in the size of the pool of transmitter available
      for immediate release [the readily releasable pool (RRP)] or in the efficacy of
      release from an unchanging pool. Using sensorimotor synapses formed in cell
      culture, we estimated the number of transmitter quanta in the RRP from the
      asynchronous release of neurotransmitter caused by application of a hypertonic
      bathing solution. Our experiments indicate that the transmitter released by
      action potentials and by hypertonic solution comes from the same pool. The RRP
      was reduced after homosynaptic depression of the EPSP by low-frequency
      stimulation and increased after facilitation of the EPSP by application of the
      endogenous facilitatory transmitter serotonin (5-HT) after homosynaptic
      depression. However, although the fractional changes in the RRP and in the EPSP
      were similar for both synaptic depression and facilitation when depression was
      induced by repeated hypertonic stimulation, the changes in the EPSP were
      significantly greater than the changes in the RRP when depression was induced by
      repeated electrical stimulation. These observations indicate that homosynaptic
      depression and restoration of depressed transmission by 5-HT are caused by
      changes in both the amount of transmitter available for immediate release and in
      processes involved in the coupling of the action potential to transmitter
      release.

PMID- 12486161
TI  - Effects of 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one on synaptic vesicle
      cycling at the frog neuromuscular junction.
AB  - Inositol phospholipids are thought to play an important regulatory role in
      synaptic membrane traffic. We investigated the effects of perturbing 3
      phosphoinositide metabolism on neurotransmission at the frog neuromuscular
      junction. We used the reversible phosphoinositide-3 kinase (PI3K) inhibitor 2-(4
      morpholinyl)-8-phenyl-4H-1-benzopyran-4-one [LY294002 (LY)] and we examined its
      effects by intracellular recording, fluorescence imaging with styryl dyes (FM 1
      43 and FM 2-10), calcium imaging, and electron microscopy. LY treatment
      reversibly inhibited vesicle cycling; electron micrographs indicated a dramatic
      reduction in the number of vesicles, balanced by the appearance of numerous
      cisternas. LY wash-off reverted the phenotype; terminals were refilled with
      vesicles, and they resumed normal FM 1-43 uptake and release. Surprisingly, LY
      treatment also enhanced the frequency of spontaneous release up to 100-fold in a
      calcium-independent manner. LY evoked similar effects in normal frog Ringer's
      solution, Ca-free Ringer's solution, and BAPTA AM-pretreated preparations;
      imaging of nerve terminals loaded with the calcium-sensitive fluorescent dye fluo
      3 showed no significant change in fluorescence intensity during LY treatment. FM
      1-43 imaging data suggested that LY evoked the cycling of 70-90% of all vesicles.
      The LY-induced effect on spontaneous release was reproduced by the casein kinase
      2 inhibitor 5,6-dichlorobenzimidazole riboside but not, however, by the PI3K
      inhibitor wortmannin. Because LY has been shown recently to potently inhibit
      casein kinase 2 as well as PI3K, we hypothesize that casein kinase 2 inhibition
      is responsible for the enhancement of spontaneous release, whereas PI3K
      inhibition induces the block of vesicle cycling.

PMID- 12486162
TI  - Endoplasmic reticulum stress and the unfolded protein response in cellular models
      of Parkinson's disease.
AB  - 6-hydroxydopamine, 1-methyl-4-phenyl-pyridinium (MPP+), and rotenone cause the
      death of dopaminergic neurons in vitro and in vivo and are widely used to model
      Parkinson's disease. To identify regulated genes in such models, we performed
      serial analysis of gene expression on neuronal PC12 cells exposed to 6
      hydroxydopamine. This revealed a striking increase in transcripts associated with
      the unfolded protein response. Immunoblotting confirmed phosphorylation of the
      key endoplasmic reticulum stress kinases IRE1alpha and PERK (PKR-like ER kinase)
      and induction of their downstream targets. There was a similar response to MPP+
      and rotenone, but not to other apoptotic initiators. As evidence that endoplasmic
      reticulum stress contributes to neuronal death, sympathetic neurons from PERK
      null mice in which the capacity to respond to endoplasmic reticulum stress is
      compromised were more sensitive to 6-hydroxydopamine. Our findings, coupled with
      evidence from familial forms of Parkinson's disease, raise the possibility of
      widespread involvement of endoplasmic reticulum stress and the unfolded protein
      response in the pathophysiology of this disease.

PMID- 12486163
TI  - Functional and biochemical analysis of a sodium channel beta1 subunit mutation
      responsible for generalized epilepsy with febrile seizures plus type 1.
AB  - Generalized epilepsy with febrile seizures plus type 1 is an inherited human
      epileptic syndrome, associated with a cysteine-to-tryptophan (C121W) mutation in
      the extracellular immunoglobin domain of the auxiliary beta1 subunit of the
      voltage-gated sodium channel. The mutation disrupts beta1 function, but how this
      leads to epilepsy is not understood. In this study, we make several observations
      that may be relevant for understanding why this beta1 mutation results in
      seizures. First, using electrophysiological recordings from mammalian cell lines,
      coexpressing sodium channel alpha subunits and either wild-type beta1 or
      C121Wbeta1, we show that loss of beta1 functional modulation, caused by the C121W
      mutation, leads to increased sodium channel availability at hyperpolarized
      membrane potentials and reduced sodium channel rundown during high-frequency
      channel activity, compared with channels coexpressed with wild-type beta1. In
      contrast, neither wild-type beta1 nor C121Wbeta1 significantly affected sodium
      current time course or the voltage dependence of channel activation. We also
      show, using a Drosophila S2 cell adhesion assay, that the C121W mutation disrupts
      beta1-beta1 homophilic cell adhesion, suggesting that the mutation may alter the
      ability of beta1 to mediate protein-protein interactions critical for sodium
      channel localization. Finally, we demonstrate that neither functional modulation
      nor cell adhesion mediated by wild-type beta1 is occluded by coexpression of
      C121Wbeta1, arguing against the idea that the mutant beta1 acts as a dominant
      negative subunit. Together, these data suggest that C121Wbeta1 causes subtle
      effects on channel function and subcellular distribution that bias neurons toward
      hyperexcitabity and epileptogenesis.

PMID- 12486164
TI  - Telomerase mediates the cell survival-promoting actions of brain-derived
      neurotrophic factor and secreted amyloid precursor protein in developing
      hippocampal neurons.
AB  - Telomerase, a reverse transcriptase that maintains chromosome ends (telomeres)
      during successive cell divisions in mitotic cells is present in neuroblasts and
      early postmitotic embryonic neurons but is absent from adult neurons. The signals
      that control telomerase levels during development are unknown, as are the
      functions of telomerase in developing neurons. We now report that telomerase
      activity and levels of its catalytic subunit telomerase reverse transcriptase
      (TERT) are increased in embryonic hippocampal neurons by brain-derived
      neurotrophic factor (BDNF) and a secreted form of beta-amyloid precursor protein
      (sAPP). BDNF and sAPP promote the survival of the embryonic neurons, and these
      trophic effects are blocked when TERT production is suppressed using antisense
      technology. Telomerase is required for the long-term survival of early
      postmitotic neurons during a time window of approximately 1 week in culture;
      telomerase is then downregulated and is not required for BDNF and sAPP survival
      signaling in mature neurons. The increase in telomerase activity and trophic
      effects of BDNF and sAPP are mediated by phosphatidylinositol-3 kinase and
      p42/p44 MAP kinases. Our findings demonstrate a requirement for telomerase in the
      cell survival-promoting actions of BDNF and sAPP in early postmitotic hippocampal
      neurons, suggesting a previously unknown role for telomerase in mediating the
      biological actions of neurotrophic factors during brain development.

PMID- 12486165
TI  - Bergmann glia GABA(A) receptors concentrate on the glial processes that wrap
      inhibitory synapses.
AB  - We studied the cellular and subcellular distribution of GABA(A) receptors in the
      Bergmann glia and Purkinje cells in the molecular layer of the cerebellum by
      using electron microscopy postembedding immunogold techniques. Gold particles
      corresponding to alpha2 and gamma1 immunoreactivity were localized in Bergmann
      glia processes that wrapped Purkinje cell somata, dendritic shafts, and some
      dendritic spines. The gold particles were mainly located on the glial plasma
      membrane or intracellularly but near the plasma membrane. The density of gold
      particles corresponding to alpha2 and gamma1 GABA(A) receptor subunits was 4.3
      fold higher in the glial processes wrapping Purkinje cell somata than in the
      glial processes wrapping Purkinje cell dendritic spines. Moreover, the Bergmann
      glia GABA(A) receptors were often located in close proximity to the type II
      GABAergic synapses made by the basket cell axons on Purkinje cell somata. These
      GABAergic synapses were enriched in neuronal GABA(A) receptors containing alpha1
      and beta2/3 subunits. Unexpectedly, 2.8% of the Purkinje cell dendritic spines
      also showed immunoreactivity for the neuronal alpha1 or beta2/3 subunits, which
      were located on the spine in type I synapses or extrasynaptically. Double
      labeling immunogold experiments showed that approximately 50% of the dendritic
      spines that were immunolabeled with the neuronal GABA(A) receptors were wrapped
      by Bergmann glia processes containing glial GABA(A) receptors. These results are
      consistent with a role of the Bergmann glial GABA(A) receptors in sensing
      GABAergic synaptic function.

PMID- 12486166
TI  - Nicotinic receptors mediate changes in spinal motoneuron development and axonal
      pathfinding in embryonic zebrafish exposed to nicotine.
AB  - We show that transient exposure of embryonic zebrafish to nicotine delays the
      development of secondary spinal motoneurons. Furthermore, there is a long-lasting
      alteration in axonal pathfinding in secondary motoneurons that is not ameliorated
      by drug withdrawal. These effects of nicotine were reversed by mammalian
      nicotinic receptor antagonists. Coupled with these changes is a long-term
      alteration in swimming behavior. Our results show that transient embryonic
      exposure to nicotine leads to long-lasting effects on the vertebrate nervous
      system. These results also demonstrate that the zebrafish is a useful model to
      examine the effects of nicotine specifically, and drugs of abuse in general, on
      the development of the CNS in vertebrates.

PMID- 12486167
TI  - Arcuate plan of chick midbrain development.
AB  - In spinal cord and hindbrain development, neurons are generated as longitudinal
      cell columns aligned with the ventral and dorsal midlines. For rostral brain,
      however, the fundamental structure of early neuronal patterning remains poorly
      understood. We report here that, in the chick embryo, the ventral midbrain is
      remarkably regular in its cellular and molecular organization; it is arranged as
      a reiterative series of arcuate territories arrayed bilateral to the ventral
      midline. In the mantle layer of the ventral midbrain, an arcuate series of
      neuronal cell columns (midbrain arcs) is demonstrated by acetylcholinesterase
      histochemistry and gene expression for class III beta-tubulin, homeodomain
      transcription factors, and neurotransmitter synthetic enzymes. In the ventricular
      layer of midbrain progenitor cells, WNT and NOTCH ligand gene expression displays
      arcuate periodicities that form a tight three-dimensional registration with the
      arcs of the underlying mantle layer. Ventral midbrain arcuate patterning is even
      macroscopically visible, forming ridges along the ventricular surface. These
      observations establish that a single plan of arcuate organization governs the
      morphogenesis and cell-type specification of the ventral midbrain. Arcs are not
      restricted to the midbrain tegmentum but extend through the subthalamic tegmentum
      of the forebrain. Thus, the chick rostral brain, which is classically divided
      into midbrain and forebrain, can also be partitioned into the following: (1) a
      neuraxial region of arcs and (2) an anterodorsal cap that includes midbrain
      tectum and nonsubthalamic forebrain. We show that this partition of brain tissue
      is supported by the expression patterns of homologs of Drosophila gap genes.

PMID- 12486168
TI  - Identification of an axotomy-induced glycosylated protein, AIGP1, possibly
      involved in cell death triggered by endoplasmic reticulum-Golgi stress.
AB  - We developed a new method, designated N-linked glycosylation signal (NGS)
      differential display (DD)-PCR, that enables the identification of genes encoding
      N-linked glycosylated molecules that exhibit varying patterns of expression.
      Using this innovative technique, we identified an N-linked glycosylated 11
      transmembrane domain protein that is upregulated in response to axotomy.
      Expression levels increased 3 d after axotomy, reached maximal levels at
      approximately postoperative days 5-7, and then gradually decreased through day
      20. The protein was termed axotomy-induced glycosylated/Golgi-complex protein 1
      (AIGP1). AIGP1 immunoreactivity is specifically localized in neurons, with
      subcellular localization within the Golgi, indicating that AIGP1 is a resident
      Golgi protein. Moreover, AIGP1 gene expression in cultured neurons is
      specifically induced by the endoplasmic reticulum (ER)-Golgi stressors
      tunicamycin and brefeldin A. We observed that the frequency of cell death is
      increased by AIGP1 overexpression and that the corresponding region of the
      protein implicated in the activity involves the large eighth and ninth
      transmembrane loops. Our results suggest that AIGP1 gene activation and protein
      accumulation in the Golgi complex in response to axotomy-induced ER-Golgi stress
      may contribute to signaling during programmed cell death in damaged neurons.

PMID- 12486169
TI  - Changes in mitochondrial status associated with altered Ca2+ homeostasis in aged
      cerebellar granule neurons in brain slices.
AB  - In the present work, we investigated the relationship between mitochondrial
      function and Ca2+ homeostasis in brain slices obtained from mice that aged
      normally. In acute preparations, the cerebellar neurons had similar values for
      intracellular free Ca2+ ([Ca2+]i) regardless of their age (range, 6 weeks to 24
      months). However, compared with the young slices, the aged neurons (20-24 months)
      showed an enhanced rate of [Ca2+]i increases as a function of the time the slices
      were maintained in vitro. When slices were stimulated (KCl depolarization), there
      were significant differences in the patterns of [Ca2+]i signal displayed by the
      young and old cerebellar granule neurons. More importantly, the aged neurons
      showed a significant delay in their capacity to recover the resting [Ca2+]i. The
      relationship between [Ca2+]i and mitochondrial membrane potential was assessed by
      recording both parameters simultaneously, using fura-2 and rhodamine-123. In both
      young and aged neurons, the cytosolic [Ca2+]i signal was associated with a
      mitochondrial depolarization response. In the aged neurons, the mitochondria had
      a significantly longer repolarization response, and quantitative analysis showed
      a direct correlation between the delays in mitochondrial repolarization and
      [Ca2+]i recovery, indicating the causal relationship between the two parameters.
      Thus, the present results show that the reported changes in Ca2+ homeostasis
      associated with aging, which manifest principally in a decreased capacity of
      maintaining a stable resting [Ca2+]i or recovering the resting [Ca2+]i values
      after stimulation, are primarily attributable to a metabolic dysfunction in which
      the mitochondrial impairment plays an important role.

PMID- 12486170
TI  - Alpha 4 integrins and vascular cell adhesion molecule-1 play a role in
      sympathetic innervation of the heart.
AB  - Sympathetic neurons innervate the heart early in postnatal development, an event
      that is crucial for proper modulation of blood pressure and cardiac function.
      However, the axon guidance cues that direct sympathetic neurons to the heart, and
      the neuronal receptors that recognize those cues, are poorly understood. Here we
      present evidence that interactions between the alpha4beta1 integrin on
      sympathetic neurons and vascular cell adhesion molecule-1 (VCAM-1) in the heart
      plays a role in cardiac innervation. The alpha4 subunit was detected on postnatal
      rat superior cervical ganglion (SCG) neurons in culture and in cryosections of
      SCG and heart. VCAM-1 immunoreactivity was detected on cardiac myocytes that
      associate with invading sympathetic neurons. Purified recombinant soluble VCAM-1
      (rsVCAM-1) stimulated SCG neurite outgrowth at levels comparable with laminin 2/4
      and fibronectin (Fn), and outgrowth on rs-VCAM-1 and Fn was blocked by antibodies
      specific for the alpha4 and beta1 integrin subunits. Intrathoracic injection of
      function-blocking antibodies to alpha4 and VCAM-1, as well as a small molecule
      inhibitor of alpha4 integrins, significantly reduced sympathetic innervation of
      the heart. These results indicate that the interaction between alpha4 integrin
      and VCAM-1 is important for sympathetic innervation of the heart.

PMID- 12486172
TI  - Highly variable spike trains underlie reproducible sensorimotor responses in the
      medicinal leech.
AB  - The nervous system of the leech is a particularly suitable model to investigate
      neural coding of sensorimotor responses because it allows both observation of
      behavior and the simultaneous measurement of a large fraction of its underlying
      neuronal activity. In this study, we used a combination of multielectrode
      recordings, videomicroscopy, and computation of the optical flow to investigate
      the reproducibility of the motor response caused by local mechanical stimulation
      of the leech skin. We analyzed variability at different levels of processing:
      mechanosensory neurons, motoneurons, muscle activation, and behavior. Spike
      trains in mechanosensory neurons were very reproducible, unlike those in
      motoneurons. The motor response, however, was reproducible because of two
      distinct biophysical mechanisms. First, leech muscles contract slowly and
      therefore are poorly sensitive to the jitter of motoneuron spikes. Second, the
      motor response results from the coactivation of a population of motoneurons
      firing in a statistically independent way, which reduces the variability of the
      population firing. These data show that reproducible spike trains are not
      required to sustain reproducible behaviors and illustrate how the nervous system
      can cope with unreliable components to produce reliable action.

PMID- 12486171
TI  - Involvement of tissue plasminogen activator in onset and effector phases of
      experimental allergic encephalomyelitis.
AB  - Inflammation, demyelination, and neurodegeneration are pathological features of
      multiple sclerosis (MS). In the brains of MS patients, tissue plasminogen
      activator (tPA) mRNA and protein are upregulated, and changes in the levels of
      tPA correlate with progression of the disease. However, the role of tPA in MS is
      as yet unknown. tPA functions in the CNS in neuronal plasticity and cell death.
      tPA also mediates the activation of microglia, the CNS "immune cells." In this
      study, we establish that tPA activity increases during major oligodendrocyte
      glycoprotein-induced experimental allergic encephalomyelitis (EAE) in normal
      mice. To explore the role of tPA in this disease as a model for MS, we have
      examined the EAE course and expression of histopathological markers in mice
      lacking tPA (tPA(-/-)). We find that tPA(-/-) mice have a delayed onset of EAE
      but then exhibit increased severity and delayed recovery from the neurological
      dysfunction. Demyelination and axon degeneration are delayed, microglial
      activation is attenuated, and the production of chemokines is decreased. Our
      results suggest that tPA and activated microglia have complex roles in MS/EAE,
      and that these roles are harmful during the onset of the disease but beneficial
      in the recovery phase. A temporally restricted attenuation of tPA activity could
      have therapeutic potential in the management of MS.

PMID- 12486174
TI  - Isolation of relevant visual features from random stimuli for cortical complex
      cells.
AB  - A crucial step in understanding the function of a neural circuit in visual
      processing is to know what stimulus features are represented in the spiking
      activity of the neurons. For neurons with complex, nonlinear response properties,
      characterization of feature representation requires measurement of their
      responses to a large ensemble of visual stimuli and an analysis technique that
      allows identification of relevant features in the stimuli. In the present study,
      we recorded the responses of complex cells in the primary visual cortex of the
      cat to spatiotemporal random-bar stimuli and applied spike-triggered correlation
      analysis of the stimulus ensemble. For each complex cell, we were able to isolate
      a small number of relevant features from a large number of null features in the
      random-bar stimuli. Using these features as visual stimuli, we found that each
      relevant feature excited the neuron effectively in isolation and contributed to
      the response additively when combined with other features. In contrast, the null
      features evoked little or no response in isolation and divisively suppressed the
      responses to relevant features. Thus, for each cortical complex cell, visual
      inputs can be decomposed into two distinct types of features (relevant and null),
      and additive and divisive interactions between these features may constitute the
      basic operations in visual cortical processing.

PMID- 12486173
TI  - Mice lacking D5 dopamine receptors have increased sympathetic tone and are
      hypertensive.
AB  - Dopamine is an important transmitter in the CNS and PNS, critically regulating
      numerous neuropsychiatric and physiological functions. These actions of dopamine
      are mediated by five distinct receptor subtypes. Of these receptors, probably the
      least understood in terms of physiological functions is the D5 receptor subtype.
      To better understand the role of the D5 dopamine receptor (DAR) in normal
      physiology and behavior, we have now used gene-targeting technology to create
      mice that lack this receptor subtype. We find that the D5 receptor-deficient mice
      are viable and fertile and appear to develop normally. No compensatory
      alterations in other dopamine receptor subtypes were observed. We find, however,
      that the mutant mice develop hypertension and exhibit significantly elevated
      blood pressure (BP) by 3 months of age. This hypertension appears to be caused by
      increased sympathetic tone, primarily attributable to a CNS defect. Our data
      further suggest that this defect involves an oxytocin-dependent sensitization of
      V1 vasopressin and non-NMDA glutamatergic receptor-mediated pathways, potentially
      within the medulla, leading to increased sympathetic outflow. These results
      indicate that D5 dopamine receptors modulate neuronal pathways regulating blood
      pressure responses and may provide new insights into mechanisms for some forms of
      essential hypertension in humans, a disease that afflicts up to 25% of the aged
      adult population in industrialized societies.

PMID- 12486175
TI  - Functional heterogeneity in human olfactory cortex: an event-related functional
      magnetic resonance imaging study.
AB  - Studies of patients with focal brain injury indicate that smell perception
      involves caudal orbitofrontal and medial temporal cortices, but a more precise
      functional organization has not been characterized. In addition, although it is
      believed that odors are potent triggers of emotion, support for an anatomical
      association is scant. We sought to define the neural substrates of human
      olfactory information processing and determine how these are modulated by
      affective properties of odors. We used event-related functional magnetic
      resonance imaging (fMRI) in an olfactory version of a classical conditioning
      paradigm, whereby neutral faces were paired with pleasant, neutral, or unpleasant
      odors, under 50% reinforcement. By comparing paired (odor/face) and unpaired
      (face only) conditions, odor-evoked neural activations could be isolated
      specifically. In primary olfactory (piriform) cortex, spatially and temporally
      dissociable responses were identified along a rostrocaudal axis. A nonhabituating
      response in posterior piriform cortex was tuned to all odors, whereas activity in
      anterior piriform cortex reflected sensitivity to odor affect. Bilateral amygdala
      activation was elicited by all odors, regardless of valence. In posterior
      orbitofrontal cortex, neural responses evoked by pleasant and unpleasant odors
      were segregated within medial and lateral segments, respectively. The results
      indicate functional heterogeneity in areas critical to human olfaction. They also
      show that brain regions mediating emotional processing are differentially
      activated by odor valence, providing evidence for a close anatomical coupling
      between olfactory and emotional processes.

PMID- 12486176
TI  - Appetitive and aversive olfactory learning in humans studied using event-related
      functional magnetic resonance imaging.
AB  - We combined event-related functional magnetic resonance imaging (fMRI) with
      olfactory classical conditioning to differentiate the neural responses evoked
      during appetitive and aversive olfactory learning. Three neutral faces [the
      conditioned stimuli (CS+)] were repetitively paired with pleasant, neutral, or
      unpleasant odors [the unconditioned stimuli (UCS)] in a partial reinforcement
      schedule. A fourth face was never paired to odor [the nonconditioned stimulus (CS
      )]. Learning-related neural activity, comparing unpaired (face only) CS+ stimuli
      with CS-, showed valence-independent activations in rostral and caudal
      orbitofrontal cortex (OFC). Medial OFC responded to the appetitive (app) CS+,
      whereas lateral OFC responded to the aversive (av) CS+. Within nucleus accumbens,
      neural responses showed divergent activation profiles that increased with time in
      response to the appCS+ but decreased in response to the avCS+. In posterior
      amygdala, responses were elicited by the appCS+, which habituated over time. In
      temporal piriform cortex, neural responses were evoked by the avCS+, which
      progressively increased with time. These results highlight regional and temporal
      dissociations during olfactory learning and imply that emotionally salient odors
      can engender cross-modal associative learning. Moreover, the findings suggest
      that the role of human primary (piriform) and secondary olfactory cortices
      transcends their function as mere intermediaries of chemosensory information
      processing.

PMID- 12486177
TI  - Efferent protection from acoustic injury is mediated via alpha9 nicotinic
      acetylcholine receptors on outer hair cells.
AB  - Exposure to intense sound can damage the mechanosensors of the inner ear and
      their afferent innervation. These neurosensory elements are innervated by a sound
      activated feedback pathway, the olivocochlear efferent system. One major
      component of this system is cholinergic, and known cholinergic effects are
      mediated by the alpha9/alpha10 nicotinic acetylcholine receptor (nAChR) complex.
      Here, we show that overexpression of alpha9 nAChR in the outer hair cells of
      bacterial artificial chromosome transgenic mice significantly reduces acoustic
      injury from exposures causing either temporary or permanent damage, without
      changing pre-exposure cochlear sensitivity to low- or moderate-level sound. These
      data demonstrate that efferent protection is mediated via the alpha9 nAChR in the
      outer hair cells and provide direct evidence for a protective role, in vivo, of a
      member of the nAChR family.

PMID- 12486178
TI  - Rostral ventromedial medulla neurons that project to the spinal cord express
      multiple opioid receptor phenotypes.
AB  - The rostral ventromedial medulla (RVM) forms part of a descending pathway that
      modulates nociceptive neurotransmission at the level of the spinal cord dorsal
      horn. However, the involvement of descending RVM systems in opioid analgesia are
      a matter of some debate. In the present study, patch-clamp recordings of RVM
      neurons were made from rats that had received retrograde tracer injections into
      the spinal cord. More than 90% of identified spinally projecting RVM neurons
      responded to opioid agonists. Of these neurons, 53% responded only to the mu
      opioid agonist D-Ala2, N-Me-Phe4, Gly-ol5 enkephalin, 14% responded only to the
      kappa-opioid agonist U-69593, and another group responded to both mu and kappa
      opioids (23%). In unidentified RVM neurons, a larger proportion of neurons
      responded only to mu opioids (75%), with smaller proportions of kappa- (4%) and
      mu/kappa-opioid (13%) responders. These RVM slices were then immunostained for
      tryptophan hydroxylase (TPH), a marker of serotonergic neurons. Forty-percent of
      spinally projecting neurons and 11% of unidentified neurons were TPH positive. Of
      the TPH-positive spinally projecting neurons, there were similar proportions of
      mu- (33%), kappa- (25%), and mu/kappa-opioid (33%) responders. Most of the TPH
      negative spinally projecting neurons were mu-opioid responders (67%). These
      findings indicate that functional opioid receptor subtypes exist on spinally
      projecting serotonergic and nonserotonergic RVM neurons. The proportions of mu-
      and kappa-opioid receptors expressed differ between serotonergic and
      nonserotonergic neurons and between retrogradely labeled and unlabeled RVM
      neurons. We conclude that important roles exist for both serotonergic and
      nonserotonergic RVM neurons in the mediation of opioid effects.

PMID- 12486179
TI  - Elevated expression of 5-HT1B receptors in nucleus accumbens efferents sensitizes
      animals to cocaine.
AB  - Although the effects of psychostimulants on brain dopamine systems are well
      recognized, the direct actions of cocaine on serotonin systems also appear to be
      important to its addictive properties. For example, serotonin actions at 5-HT1B
      receptors in the ventral tegmental area (VTA) modulate cocaine-induced dopamine
      release in the nucleus accumbens (NAcc) and alter the rewarding and stimulant
      properties of cocaine. However, the mechanisms of these effects have been
      unclear, because several neuron types in VTA express 5-HT1B receptors. One
      possibility is that 5-HT1B receptors on the terminals of GABAergic projections
      from NAcc to VTA inhibit local GABA release, thereby disinhibiting VTA neurons.
      We tested this hypothesis directly by using viral-mediated gene transfer to
      overexpress 5-HT1B receptors in NAcc projections to VTA. A viral vector
      containing either epitope hemagglutinin-tagged 5-HT1B and green fluorescent
      protein (HA1B-GFP) cassettes or green fluorescent protein cassette alone (GFP
      only) was injected into the NAcc shell, which sends projections to the VTA. HA1B
      GFP injection induced elevated expression of 5-HT1B receptors in neuronal fibers
      in VTA and increased cocaine-induced locomotor hyperactivity without affecting
      baseline locomotion. Overexpression of 5-HT1B receptors also shifted the dose
      response curve for cocaine-conditioned place preference to the left, indicating
      alterations in the rewarding effects of cocaine. Thus, increased expression of 5
      HT1B receptors in NAcc efferents, probably in the terminals of medium spiny
      neurons projecting to the VTA, may contribute to psychomotor sensitization and
      offer an important target for regulating the addictive effects of cocaine.

PMID- 12486180
TI  - Vocal control neuron incorporation decreases with age in the adult zebra finch.
AB  - In adult male zebra finches, high vocal center (HVC) neurons continuously die and
      are replaced. Many of these cells are projection neurons that form part of the
      efferent pathway controlling learned song production. Although it is known that
      HVC receives new neurons well into adulthood, it is unknown whether this occurs
      at a constant rate or declines with adult age. We used [3H]thymidine to label new
      HVC neurons in male zebra finches that were 3-36 months of age. Birds were killed
      4 months after 3H injections to measure the long-term incorporation of new HVC
      neurons. HVC neurons projecting to the robust nucleus of the archistriatum (HVC
      RA) were retrogradely labeled with Fluoro-Gold 4 d before death. We found a
      dramatic age-related decline in the number of 3H-labeled HVC-RA neurons present 4
      months after cell birth dating. A similar decline in new HVC neurons was found as
      soon as 1 month after their formation. These results indicate that the production
      or early survival of adult-formed neurons decreases with age. HVC volume and
      total neuron number did not change with bird age, suggesting that the age-related
      decrease in new neuron addition was balanced by increased survivorship of neurons
      incorporated previously. Reliance of song structure on auditory feedback also
      wanes with age. We propose that with aging, fewer new cells are added as the
      numbers of functionally appropriate cells increase, a process that may be linked
      to age-related increases in motor program stability.

PMID- 12486181
TI  - Confocal analysis of reciprocal feedback at rod bipolar terminals in the rabbit
      retina.
AB  - Amacrine cells in the mammalian retina are famously diverse in shape and
      function. Here, we show that two wide-field GABA amacrine cells, S1 and S2, have
      stereotyped synaptic contacts with the appropriate morphology and distribution to
      perform specific functions. S1 and S2 both supply negative feedback to rod
      bipolar terminals and thus provide a substrate for lateral inhibition in the rod
      pathway. Synapses are specialized structures, and the presynaptic compartment is
      normally characterized by a swelling or varicosity. Each S1 amacrine cell has
      approximately 280 varicosities, whereas an S2 cell has even more, approximately
      500 per cell. Confocal analysis shows that essentially all varicosities aggregate
      around rod bipolar terminals where they are apposed by postsynaptic GABA
      receptors. Each rod bipolar terminal is contacted by varicosities from
      approximately 25 different S1 and 50 different S2 amacrine cells. In fact, rod
      bipolar cells are the only synaptic target for S1 and S2 amacrine cells: all of
      the output from these two wide-field GABA amacrine cells goes to rod bipolar
      terminals. It has long been a puzzle why two amacrine cells, apparently with the
      same connections, are required. However, an analysis of the distribution of
      varicosities suggests that S1 and S2 amacrine cells provide different signals. S2
      amacrine cells dominate within 200 mu from a rod bipolar terminal and can provide
      an inhibitory input with spatial characteristics that match the size of the
      surround signal recorded from AII amacrine cells in the rod pathway. In contrast,
      the larger, better-coupled S1 amacrine cells may provide a more distant network
      signal.

PMID- 12486182
TI  - Inhibition of cAMP response element-binding protein or dynorphin in the nucleus
      accumbens produces an antidepressant-like effect.
AB  - The cAMP response element-binding protein (CREB) is a critical integrator of
      neural plasticity that is responsive in a brain region-specific manner to a
      variety of environmental and pharmacological stimuli, including widely prescribed
      antidepressant medications. We developed inducible transgenic lines of mice that
      express either CREB or a dominant-negative mutant of CREB (mCREB) in forebrain
      regions and used these mice to determine the functional significance of this
      transcription factor in the learned helplessness paradigm, a behavioral model of
      depression. We also use a complementary viral-mediated gene transfer approach to
      directly test the effect of mCREB in the nucleus accumbens, a brain region
      important for motivation and reward. The results demonstrate that blockade of
      CREB by overexpression of mCREB in transgenic mice or by viral expression of
      mCREB in the nucleus accumbens produces an antidepressant-like effect, whereas
      overexpression of CREB in transgenic mice results in the opposite phenotype. In
      addition, mCREB expression was colocalized with and decreased the expression of
      prodynorphin in nucleus accumbens medium spiny neurons, and antagonism of
      dynorphin in the nucleus accumbens was sufficient to produce an antidepressant
      like effect similar to that observed after blockade of CREB. Together, the
      results demonstrate that nucleus accumbens CREB-dynorphin influence behavior in
      the learned helplessness model and suggest that this signaling cascade may
      contribute to symptoms of depression.

PMID- 12486183
TI  - Direct projections from cochlear nuclear complex to auditory thalamus in the rat.
AB  - It is known that the dorsal cochlear nucleus and medial geniculate body in the
      auditory system receive significant inputs from somatosensory and visual-motor
      sources, but the purpose of such inputs is not totally understood. Moreover, a
      direct connection of these structures has not been demonstrated, because it is
      generally accepted that the inferior colliculus is an obligatory relay for all
      ascending input. In the present study, we have used auditory neurophysiology,
      double labeling with anterograde tracers, and retrograde tracers to investigate
      the ascending projections of the cochlear nuclear complex. We demonstrate that
      the dorsal cochlear nucleus and the small cell cap of the ventral cochlear
      nucleus have a direct projection to the medial division of the medial geniculate
      body. These direct projections from the cochlear nucleus complex bypass the
      inferior colliculus and are widely distributed within the medial division of the
      medial geniculate, suggesting that the projection is not topographic. As a
      nonlemniscal auditory pathway that parallels the conventional auditory lemniscal
      pathway, its functions may be distinct from the perception of sound. Because this
      pathway links the parts of the auditory system with prominent nonauditory,
      multimodal inputs, it may form a neural network through which nonauditory sensory
      and visual-motor systems may modulate auditory information processing.

PMID- 12486184
TI  - Rhythmicity without synchrony in the electrically uncoupled inferior olive.
AB  - Neurons of the inferior olivary nucleus (IO) form the climbing fibers that excite
      Purkinje cells of the cerebellar cortex. IO neurons are electrically coupled
      through gap junctions, and they generate synchronous, subthreshold oscillations
      of membrane potential at approximately 5-10 Hz. Experimental and theoretical
      studies have suggested that both the rhythmicity and synchrony of IO neurons
      require electrical coupling. We recorded from pairs of IO neurons in slices of
      mouse brainstem in vitro. Most pairs of neurons from wild-type (WT) mice were
      electrically coupled, but coupling was rare and weak between neurons of knock-out
      (KO) mice for connexin36, a neuronal gap junction protein. IO cells in both WT
      and KO mice generated rhythmic membrane fluctuations of similar frequency and
      amplitude. Oscillations in neighboring pairs of WT neurons were strongly
      synchronized, whereas the oscillations of KO pairs were uncorrelated. Spontaneous
      oscillations in KO neurons were not blocked by tetrodotoxin. Spontaneously
      oscillating neurons of both WT and KO mice generated occasional action potentials
      in phase with their membrane rhythms, but only the action potentials of WT neuron
      pairs were synchronous. Harmaline, a beta-carboline derivative thought to induce
      tremor by facilitating rhythmogenesis in the IO, was injected systemically into
      WT and KO mice. Harmaline-induced tremors were robust and indistinguishable in
      the two genotypes, suggesting that gap junction-mediated synchrony does not play
      a role in harmaline-induced tremor. We conclude that electrical coupling is not
      necessary for the generation of spontaneous subthreshold oscillations in single
      IO neurons, but that coupling can serve to synchronize rhythmic activity among IO
      neurons.

PMID- 12486185
TI  - Genetic dissociation of opiate tolerance and physical dependence in delta-opioid
      receptor-1 and preproenkephalin knock-out mice.
AB  - Previous experiments have shown that mice lacking a functional delta-opioid
      receptor (DOR-1) gene do not develop analgesic tolerance to morphine. Here we
      report that mice lacking a functional gene for the endogenous ligand
      preproenkephalin (ppENK) show a similar tolerance deficit. In addition, we found
      that the DOR-1 and ppENK knock-outs as well as the NMDA receptor-deficient 129S6
      inbred mouse strain, which also lacks tolerance, exhibit antagonist-induced
      opioid withdrawal. These data demonstrate that although signaling pathways
      involving ppENK, DOR, and NMDA receptor are necessary for the expression of
      morphine tolerance, other pathways independent of these factors can mediate
      physical dependence. Moreover, these studies illustrate that morphine tolerance
      can be genetically dissociated from physical dependence, and thus provide a
      genetic framework to assess more precisely the contribution of various cellular
      and molecular changes that accompany morphine administration to these processes.

PMID- 12486186
TI  - Induction of hippocampal long-term potentiation during waking leads to increased
      extrahippocampal zif-268 expression during ensuing rapid-eye-movement sleep.
AB  - Rapid-eye-movement (REM) sleep plays a key role in the consolidation of memories
      acquired during waking (WK). The search for mechanisms underlying that role has
      revealed significant correlations in the patterns of neuronal firing, regional
      blood flow, and expression of the activity-dependent gene zif-268 between WK and
      subsequent REM sleep. Zif-268 integrates a major calcium signal transduction
      pathway and is implicated by several lines of evidence in activity-dependent
      synaptic plasticity. Here we report that the induction of hippocampal long-term
      potentiation (LTP) during WK in rats leads to an upregulation of zif-268 gene
      expression in extrahippocampal regions during subsequent REM sleep episodes. This
      upregulation occurs predominantly in the amygdala, entorhinal, and auditory
      cerebral cortices during the first REM sleep episodes after LTP induction and
      reaches somatosensory and motor cerebral cortices as REM sleep recurs. We also
      show that hippocampal inactivation during REM sleep blocks extrahippocampal zif
      268 upregulation, indicating that cortical and amygdalar zif-268 expression
      during REM sleep is under hippocampal control. Thus, expression of an activity
      dependent gene involved in synaptic plasticity propagates gradually from the
      hippocampus to extrahippocampal regions as REM sleep recurs. These findings
      suggest that a progressive disengagement of the hippocampus and engagement of the
      cerebral cortex and amygdala occurs during REM sleep. They are also consistent
      with the view that REM sleep constitutes a privileged window for hippocampus
      driven cortical activation, which may play an instructive role in the
      communication of memory traces from the hippocampus to the cerebral cortex.

PMID- 12486187
TI  - Spinal inhibitory neurons that modulate cutaneous sensory pathways during
      locomotion in a simple vertebrate.
AB  - During locomotion, reflex responses to sensory stimulation are usually modulated
      and may even be reversed. This is thought to be the result of phased inhibition,
      but the neurons responsible are usually not known. When the hatchling Xenopus
      tadpole swims, responses to cutaneous stimulation are modulated. This occurs
      because sensory pathway interneurons receive rhythmic glycinergic inhibition
      broadly in phase with the motor discharge on the same side of the trunk. We now
      describe a new whole-cell recording preparation of the Xenopus tadpole CNS. This
      has been used with neurobiotin injection to define the passive and firing
      properties of spinal ascending interneurons and their detailed anatomy. Paired
      recordings show that they make direct, glycinergic synapses onto spinal sensory
      pathway interneurons, and the site of contact can be seen anatomically. During
      swimming, ascending interneurons fire rhythmically. Analysis shows that their
      firing is more variable and not as reliable as other interneurons, but the
      temporal pattern of their impulse activity is suitable to produce the main peak
      of gating inhibition in sensory pathway interneurons. Ascending interneurons are
      not excited at short latency after skin stimulation but are strongly active after
      repetitive skin stimulation, which evokes vigorous and slower struggling
      movements. We conclude that ascending interneurons are a major class of
      modulatory neurons producing inhibitory gating of cutaneous sensory pathways
      during swimming and struggling.

PMID- 12486188
TI  - Attenuation of nicotine-induced antinociception, rewarding effects, and
      dependence in mu-opioid receptor knock-out mice.
AB  - The involvement of mu-opioid receptors in different behavioral responses elicited
      by nicotine was explored by using mu-opioid receptor knock-out mice. The acute
      antinociceptive responses induced by nicotine in the tail-immersion and hot-plate
      tests were reduced in the mutant mice, whereas no difference between genotypes
      was observed in the locomotor responses. The rewarding effects induced by
      nicotine were then investigated using the conditioning place-preference paradigm.
      Nicotine produced rewarding responses in wild-type mice but failed to produce
      place preference in knock-out mice, indicating the inability of this drug to
      induce rewarding effects in the absence of mu-opioid receptors. Finally, the
      somatic expression of the nicotine withdrawal syndrome, precipitated in dependent
      mice by the injection of mecamylamine, was evaluated. Nicotine withdrawal was
      significantly attenuated in knock-out mutants when compared with wild-type mice.
      In summary, the present results show that mu-opioid receptors are involved in the
      rewarding responses induced by nicotine and participate in its antinociceptive
      responses and the expression of nicotine physical dependence.

PMID- 12486189
TI  - Grouping of spindle activity during slow oscillations in human non-rapid eye
      movement sleep.
AB  - Based on findings primarily in cats, the grouping of spindle activity and fast
      brain oscillations by slow oscillations during slow-wave sleep (SWS) has been
      proposed to represent an essential feature in the processing of memories during
      sleep. We examined whether a comparable grouping of spindle and fast activity
      coinciding with slow oscillations can be found in human SWS. For negative and
      positive half-waves of slow oscillations (dominant frequency, 0.7-0.8 Hz)
      identified during SWS in humans (n = 13), wave-triggered averages of root mean
      square (rms) activity in the theta (4-8 Hz), alpha (8-12 Hz), spindle (12-15 Hz),
      and beta (15-25 Hz) range were formed. Slow positive half-waves were linked to a
      pronounced and microV (23.4%; p < 0.001, with reference to baseline) at the
      midline central electrode (Cz). In contrast, spindle activity was suppressed
      during slow negative half-waves, on average by -0.65 +/- 0.06 microV at Cz (-22%;
      p < 0.001). An increase in spindle activity 400-500 msec after negative half
      waves was more than twofold the increase during slow positive half-waves (p <
      0.001). A similar although less pronounced dynamic was observed for beta
      activity, but not for alpha and theta frequencies. Discrete spindles identified
      during stages 2 and 3 of non-rapid eye movement (REM) sleep coincided with a
      discrete slow positive half-wave-like potential preceded by a pronounced negative
      half-wave (p < 0.01). These results provide the first evidence in humans of
      grouping of spindle and beta activity during slow oscillations. They support the
      concept that phases of cortical depolarization during slow oscillations,
      reflected by surface-positive (depth-negative) field potentials, drive the
      thalamocortical spindle activity. The drive is particularly strong during
      cortical depolarization, expressed as surface-positive field potentials.

PMID- 12486190
TI  - Depression of fast excitatory synaptic transmission in large aspiny neurons of
      the neostriatum after transient forebrain ischemia.
AB  - Spiny neurons in the neostriatum die within 24 hr after transient global
      ischemia, whereas large aspiny (LA) neurons remain intact. To reveal the
      mechanisms of such selective cell death after ischemia, excitatory
      neurotransmission was studied in LA neurons before and after ischemia. The
      intrastriatally evoked fast EPSCs in LA neurons were depressed < or =24 hr after
      ischemia. The concentration-response curves generated by application of exogenous
      glutamate in these neurons were approximately the same before and after ischemia.
      A train of five stimuli (100 Hz) induced progressively smaller EPSCs, but the
      proportion of decrease in EPSC amplitude at 4 hr after ischemia was significantly
      smaller compared with control and at 24 hr after ischemia. Parallel depression of
      NMDA receptor and AMPA receptor-mediated EPSCs was also observed after ischemia,
      supporting the involvement of presynaptic mechanisms. The adenosine A1 receptor
      antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the inhibition of evoked
      EPSCs at 4 hr after ischemia but not at 24 hr after ischemia. Electron
      microscopic studies demonstrated that the most presynaptic terminals in the
      striatum had a normal appearance at 4 hr after ischemia but showed degenerating
      signs at 24 hr after ischemia. These results indicated that the excitatory
      neurotransmission in LA neurons was depressed after ischemia via presynaptic
      mechanisms. The depression of EPSCs shortly after ischemia might be attributable
      to the enhanced adenosine A1 receptor function on synaptic transmission, and the
      depression at late time points might result from the degeneration of presynaptic
      terminals.

PMID- 12486191
TI  - Modulation by central and basolateral amygdalar nuclei of dopaminergic correlates
      of feeding to satiety in the rat nucleus accumbens and medial prefrontal cortex.
AB  - Current studies raise the possibility that subregions within the amygdala may
      interact with the mesocorticolimbic dopamine (DA) system to subserve specific
      psychological processes underlying food reward. The present study compared the
      effect of reversible inactivation of the central nucleus (CeN) versus the
      basolateral amygdala (BLA) on DA efflux in the nucleus accumbens (NAc) and medial
      prefrontal cortex (mPFC) in hungry rats that were tested in a food-devaluation
      procedure. During DA microdialysis experiments, lidocaine, a sodium channel
      blocker, was delivered via reverse dialysis into the CeN or BLA while rats were
      given two consecutive meals of Froot Loops. Loss of CeN function impaired the
      development of satiety during an initial meal and, consequently, diminished the
      effect of devaluation by satiety on intake of the same food during a second meal.
      Inactivation of the CeN was also associated with decreased basal levels of DA
      efflux in the NAc before food intake and attenuated increases in DA efflux
      related to anticipatory and consummatory aspects of feeding in both the NAc and
      mPFC. In contrast, inactivation of the BLA did not affect feeding behavior or DA
      efflux. Overall, these findings indicate that the CeN and BLA independently
      modulate DA transmission in both terminal regions. It is proposed that
      interaction between the CeN and mesocorticolimbic DA activity may be a mechanism
      by which hunger and satiety signals influence the value of food reward, or
      alternatively, a mechanism by which memory for a recently consumed food regulates
      food intake.

PMID- 12486192
TI  - Feedforward mechanisms of excitatory and inhibitory cortical receptive fields.
AB  - Excitatory and inhibitory cortical layer IV neurons have distinctive response
      properties. Thalamocortical connectivity that may underlie differences was
      examined using cross-correlation analyses of pairs of thalamic and cortical
      neurons in the rat whisker/barrel system. Cortical layer IV cells discharging
      fast spikes, presumed inhibitory neurons, were distinguished from regular-spike
      units, presumed excitatory neurons, by the extracellular waveform shape. Regular
      spike neurons fired less robustly and had smaller receptive fields (RFs) and
      greater directional tuning than fast-spike cells. Presumed excitatory neurons
      were less likely to receive thalamocortical connections, and their connections
      were, on average, weaker. RF properties of thalamic inputs to both cell types
      were equivalent, except that the most highly responsive thalamic cells contacted
      only fast-spike neurons. In contrast, the size and directional tuning of cortical
      RFs were related to the number of detectable thalamocortical inputs. Connected
      thalamocortical pairs were likely to have matching RF characteristics. The
      smaller, more directionally selective RFs of excitatory neurons may be a
      consequence of their weaker net thalamic drive, their more nonlinear firing
      characteristics and pervasive feedforward inhibition provided by strongly driven,
      broadly tuned inhibitory neurons.

PMID- 12486193
TI  - Sensitivity to instrumental contingency degradation is mediated by the entorhinal
      cortex and its efferents via the dorsal hippocampus.
AB  - Previous studies have shown that electrolytic lesions of the dorsal hippocampus
      render the instrumental performance of rats insensitive to selective degradation
      of the action-outcome contingency (Corbit and Balleine, 2000). In the present
      experiments, we sought to replicate this finding and to examine the effects of
      excitotoxic lesions. In the first three experiments, rats with either
      electrolytic or NMDA lesions of the dorsal hippocampus and sham-lesioned controls
      were trained to press two levers, each of which delivered a unique food outcome,
      before their sensitivity to outcome devaluation and degradation of the
      instrumental contingency was assessed. Although we were able to replicate our
      original finding that electrolytic lesions of the dorsal hippocampus render rats
      insensitive to selective degradation of the instrumental contingency, NMDA
      lesions of the dorsal hippocampus had no effect. Neither lesion had any
      detectable effect on sensitivity to outcome devaluation. In experiment 4, we
      assessed the possibility that the effect of the electrolytic lesion resulted from
      damage to fibers originating in the retrohippocampal region (including both
      entorhinal cortex and subiculum) by examining the impact of bilateral NMDA
      induced lesions of the retrohippocampus on the same tasks. Importantly, this
      lesion produced a deficit similar to that observed after electrolytic hippocampal
      lesions. The final experiment used a disconnection procedure to assess more
      directly whether damage to efferents from the retrohippocampal region, rather
      than the dorsal hippocampus itself, can account for the observed deficit. The
      data from these tests suggest that the deficits observed previously after
      electrolytic hippocampal lesions were the result of damage to entorhinal
      efferents.

PMID- 12486194
TI  - Effectiveness of estrogen replacement in restoration of cognitive function after
      long-term estrogen withdrawal in aging rats.
AB  - Recent studies suggest that some aspects of learning and memory may be altered by
      a midlife loss of estrogen, indicating a potential causal relationship between
      the deficiency of ovarian hormones and cognitive aging. In this study, the
      effects of estrogen withdrawal and replacement were tested in middle-aged Fischer
      344 rats using different memory tasks. Estrogen withdrawal accelerated the rate
      of cognitive aging. A deficit first occurred 4 months after ovariectomy in
      working memory, which was tested in a delayed-nonmatching-to-position task, and
      progressed from long-delay to short-delay trials. Reference memory, which was
      tested in a place discrimination task and a split-stem T-maze, was not affected
      by aging or ovariectomy. The efficacy of estrogen in ameliorating the cognitive
      deficit in old rats depended on the type of treatment (acute vs chronic) and
      whether the aging-related decline in a particular cognitive process was
      aggravated by estrogen withdrawal. Chronic estrogen treatment (implants) was
      effective in improving working memory only when primed with repeated injections
      of estrogen, indicating that simulating the estrogen fluctuations of the estrous
      cycle may be more effective than the widely used mode of chronic pharmacological
      treatment. A challenge with scopolamine revealed that ovariectomy-induced
      cognitive deterioration coincided with a compromised cholinergic system.
      Importantly, the estrogen treatment that had restored effectively the cognitive
      abilities of old ovariectomized rats did not reduce their sensitivity to
      scopolamine. Taking into consideration that estrogen was highly effective against
      the amnestic action of scopolamine when tested in young-adult rats, these data
      emphasize that mechanisms of the protective effect of estrogen differ in young
      and old rats.

PMID- 12486195
TI  - The role of rat medial frontal cortex in effort-based decision making.
AB  - We conducted a series of experiments to elucidate the role of rat medial frontal
      cortex (MFC) (including prelimbic, infralimbic, and cingulate cortices) in effort
      based decision making. Rats were trained on a cost-benefit T-maze task in which
      they could either choose to climb a barrier to obtain a high reward in one arm
      (HR arm) or could obtain a small reward in the other with no barrier present (LR
      arm). Before surgery, all animals were selecting the HR arm on almost every
      trial. However, after excitotoxic lesions to MFC, the rats shifted to selecting
      the LR arm on almost every trial. This was not caused by a spatial memory or
      motor deficit because the same rats returned to selecting the HR arm when the
      amount of effort needed to be expended to obtain reward in either arm was
      equalized by putting an identical barrier in the LR arm. Additional experiments
      demonstrated that the change in effort-based decisions observed in the rats was
      not caused by a complete insensitivity to reward and effort because they returned
      to choosing the HR arm if either the cost was reduced (by making the barrier
      smaller) or the benefit was increased (increasing the food ratio differential).
      Instead, the MFC lesion shifted the animals' decision criterion, making them more
      likely to choose the LR arm than the sham-lesioned animals. These results imply
      that medial frontal cortex is important for allowing the animal to put in more
      work to obtain greater rewards.

PMID- 12486196
TI  - Interaction of excitation and inhibition in anteroventral cochlear nucleus
      neurons that receive large endbulb synaptic endings.
AB  - Spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive
      their main excitatory input from auditory nerve fibers (ANFs) through large
      synapses, endbulbs of Held. These cells are also the target of inhibitory inputs
      whose function is not well understood. The present study examines the role of
      inhibition in the encoding of low-frequency sounds in the gerbil's AVCN. The
      presynaptic action potentials of endbulb terminals and postsynaptic action
      potentials of SBCs were monitored simultaneously in extracellular single-unit
      recordings in vivo. An input-output analysis of presynaptic and postsynaptic
      activity was performed for both spontaneous and acoustically driven activity. Two
      tone stimulation and neuropharmacological experiments allowed the effects of
      neuronal inhibition and cochlear suppression on SBC activity to be distinguished.
      Ninety-one percent of SBCs showed significant neuronal inhibition. Inhibitory
      sidebands enclosed the high- or low-frequency, or both, sides of the excitatory
      areas of these units; this was reflected as a presynaptic to postsynaptic
      increase in frequency selectivity of up to one octave. Inhibition also affected
      the level-dependent responses at the characteristic frequency. Although in all
      units the presynaptic recordings showed monotonic rate-level functions, this was
      the case in only half of the postsynaptic recordings. In the other half of SBCs,
      postsynaptic inhibitory areas overlapped the excitatory areas, resulting in
      nonmonotonic rate-level functions. The results demonstrate that the sound-evoked
      spike activity of SBCs reflects the integration of acoustically driven excitatory
      and inhibitory input. The inhibition specifically affects the processing of the
      spectral, temporal, and intensity cues of acoustic signals.

PMID- 12486198
TI  - The contribution of the amygdala to conditioned thalamic arousal.
AB  - Previous research has demonstrated that thalamocortical neurons within the dorsal
      lateral geniculate nucleus (dLGN) are affected by an acoustic, fear-arousing,
      conditioned stimulus (Cain et al., 2000). This effect is reflected in an increase
      in activity and a tonic firing pattern, a pattern that assures the most accurate
      relay of information from the retina to the visual neocortex. Such an effect is
      considered to be indicative of a heightened state of arousal. The present
      research was designed to determine the extent to which the central nucleus of the
      amygdala (ACe) contributes to this effect. To this end, in experiment 1
      extracellular recordings were made from single dLGN neurons in the awake rabbit
      during electrical stimulation of the ACe. Increased neuronal activity was
      observed in response to stimulation in the majority of neurons. Neurons that were
      in a burst firing pattern immediately before stimulation assumed a tonic firing
      pattern in response to stimulation. Experiment 2 was designed to determine
      whether inactivation of the ACe with muscimol would attenuate the response of
      dLGN neurons in the awake rabbit to the presentation of acoustic, fear-arousing,
      conditioned stimuli. Compared with vehicle injections, infusions of muscimol
      attenuated both the spontaneous activity and the response of dLGN neurons to the
      presentations of these stimuli. The results provide support for the hypothesis
      that the amygdala, and in particular the ACe, contributes to a heightened state
      of arousal during conditioned fear.

PMID- 12486197
TI  - Enhancement of signal-to-noise ratio and phase locking for small inputs by a low
      threshold outward current in auditory neurons.
AB  - Neurons possess multiple voltage-dependent conductances specific for their
      function. To investigate how low-threshold outward currents improve the detection
      of small signals in a noisy background, we recorded from gerbil medial superior
      olivary (MSO) neurons in vitro. MSO neurons responded phasically, with a single
      spike to a step current injection. When bathed in dendrotoxin (DTX), most cells
      switched to tonic firing, suggesting that low-threshold potassium currents
      (I(KLT)) participated in shaping these phasic responses. Neurons were stimulated
      with a computer-generated steady barrage of random inputs, mimicking weak
      synaptic conductance transients (the "noise"), together with a larger but still
      subthreshold postsynaptic conductance, EPSG (the "signal"). DTX reduced the
      signal-to-noise ratio (SNR), defined as the ratio of probability to fire in
      response to the EPSG and the probability to fire spontaneously in response to
      noise. The reduction was mainly attributable to the increase of spontaneous
      firing in DTX. The spike-triggered reverse correlation indicated that, for spike
      generation, the neuron with I(KLT) required faster inward current transients.
      This narrow temporal integration window contributed to superior phase locking of
      firing to periodic stimuli before application of DTX. A computer model including
      Hodgkin-Huxley type conductances for spike generation and for I(KLT) (Rathouz and
      Trussell, 1998) showed similar response statistics. The dynamic low-threshold
      outward current increased SNR and the temporal precision of integration of weak
      subthreshold signals in auditory neurons by suppressing false positives.

PMID- 12486199
TI  - High-resolution analysis of ethanol-induced locomotor stimulation in Drosophila.
AB  - Understanding how ethanol influences behavior is key to deciphering the
      mechanisms of ethanol action and alcoholism. In mammals, low doses of ethanol
      stimulate locomotion, whereas high doses depress it. The acute stimulant effect
      of ethanol has been proposed to be a manifestation of its rewarding effects. In
      Drosophila, ethanol exposure transiently potentiates locomotor activity in a
      biphasic dose- and time-dependent manner. An initial short-lived peak of activity
      corresponds to an olfactory response to ethanol. A second, longer-lasting period
      of increased activity coincides with rising internal ethanol concentrations;
      these closely parallel concentrations that stimulate locomotion in mammals. High
      resolution analysis of the walking pattern of individual flies revealed that
      locomotion consists of bouts of activity; bout structure can be quantified by
      bout frequency, bout length, and the time spent walking at high speeds. Ethanol
      exposure induces both dramatic and dynamic changes in bout structure. Mutants
      with increased ethanol sensitivity show distinct changes in ethanol-induced
      locomotor behavior, as well as genotype-specific changes in activity bout
      structure. Thus, the overall effect of ethanol on locomotor behavior in
      Drosophila is caused by changes in discrete quantifiable parameters of walking
      pattern. The effects of ethanol on locomotion are comparable in flies and
      mammals, suggesting that Drosophila is a suitable model system to study the
      underlying mechanisms.

PMID- 12486200
TI  - Evidence for sequential decision making in the medicinal leech.
AB  - Decision making can be a complex task involving a sequence of subdecisions. For
      example, we decide to pursue a goal (e.g., get something to eat), then decide how
      to accomplish that goal (e.g., go to a restaurant), and then make a sequence of
      more specific plans (e.g., which restaurant to go to, how to get there, what to
      order, etc.). In characterizing the effects of stimulating individual brain
      neurons in the isolated nervous system of the leech Hirudo medicinalis, we have
      found evidence that leeches also make decisions sequentially. In this study, we
      describe a pair of interneurons that elicited locomotory motor programs, either
      swimming or crawling, in isolated nerve cords. In semi-intact animals,
      stimulating the same neurons also produced either swimming or crawling, and which
      behavior was produced could be controlled experimentally by manipulating the
      depth of saline around the intact part of the leech. These same neurons were
      excited and fired strongly when swimming or crawling occurred spontaneously or in
      response to mechanosensory stimulation. We conclude that these brain interneurons
      help to decide on locomotion (i.e., they are "locomotory command-like neurons")
      and that the ultimate behavior is determined downstream, in a part of the
      decision-making hierarchy that monitors stimuli related to the depth of fluid
      surrounding the leech.

PMID- 12486201
TI  - Endogenous activation of serotonin-2A receptors is required for respiratory
      rhythm generation in vitro.
AB  - Endogenous amines and peptides continuously modulate the activity of neuronal
      networks and are required even for their normal operation. The respiratory rhythm
      generator, localized in the pre-Botzinger complex, is not an exception. This
      network is modulated by various neurotransmitters, including serotonin (5-HT). In
      this study, we isolated the respiratory network in brainstem slices and
      demonstrate that the endogenous activation of 5-HT(2A) is required for the
      generation of the respiratory rhythm in vitro. At the network level, activation
      of 5-HT(2A) receptors with 4-iodo-2,5-dimethoxyamphetamine or the 5-HT uptake
      blocker alaproclate increased the frequency of respiratory activity. Blockade of
      endogenously activated 5-HT(2A) receptors with three different antagonists
      decreased the frequency, amplitude, and regularity of respiratory population
      activity, an effect that was blocked by protein kinase C (PKC) activators. At the
      cellular level, blockade of 5-HT(2A) receptors reduced the action potential
      discharge in all examined respiratory neurons, which was associated with a
      reduction in the fast and the persistent sodium current. Continuous application
      of 5-HT(2A)-receptor antagonists differentially affected pacemaker neurons.
      Pacemaker activity was eliminated in cadmium-insensitive pacemaker neurons. In
      cadmium-sensitive pacemaker neurons, the frequency of pacemaker activity was
      unaffected and the amplitude of pacemaker bursts was enhanced. It is assumed that
      cadmium-insensitive pacemakers rely on the persistent sodium current, whereas
      cadmium-sensitive pacemakers depend on the activation of calcium currents. We
      conclude that endogenously activated 5-HT(2A) receptors are required for
      maintaining fictive respiratory activity in the brainstem slice by modulating
      sodium conductances via a PKC pathway.

PMID- 12486203
TI  - Aging: predictions of a new perspective on old data.

PMID- 12486202
TI  - Electroconvulsive seizure behavior in Drosophila: analysis of the physiological
      repertoire underlying a stereotyped action pattern in bang-sensitive mutants.
AB  - Drosophila bang-sensitive mutants display a remarkable stereotyped behavioral
      sequence during mechanical disturbances. This seizure repertoire consists of
      initial and delayed bouts of spasm interposed with paralysis and followed by
      recovery of activity and a period of refractoriness to further stimulation.
      Electroconvulsive stimuli across the brain induced a similar seizure behavior in
      tethered flies, in which corresponding electrophysiological events could be
      readily recorded in indirect flight muscles [dorsal longitudinal muscles (DLMs)]
      of the giant fiber (GF) pathway. The DLM physiological repertoire consisted of
      initial and delayed discharges (IDs and DDs), a response failure and recovery,
      followed by a refractory period. Interestingly, wild-type flies also displayed
      the same electroconvulsive repertoire, albeit inducible only at higher stimulus
      intensities and with briefer expression. The DLM repertoire presumably originated
      from activities of distinct neural circuits subserving normal function and
      reflected the general sequence of excitation and depression of the nervous system
      as a whole, as shown by simultaneous recordings along the different body axes.
      The well characterized GF pathway facilitated localization of circuits
      responsible for response failure and ID and DD motor patterns by surgical
      manipulations, recording-stimulating site analysis, and genetic mosaic studies. A
      flight pattern generator is most likely the major contributor to shaping the DD
      pattern, with modifications by active integration of individual motor neurons and
      associated interneurons. The robust electroconvulsive repertoire of DLMs provides
      a convenient window for further genetic analysis of the interacting neural
      mechanisms underlying a stereotyped action pattern in Drosophila, which shows
      striking parallels with aspects of seizure in mammalian species.

PMID- 12486204
TI  - Transforming growth factor-beta signal transduction and progressive renal
      disease.
AB  - Transforming growth factor-beta (TGF-beta) superfamily members are
      multifunctional growth factors that play pivotal roles in development and tissue
      homeostasis. Recent studies have underscored the importance of TGF-beta in
      regulation of cell proliferation and extracellular matrix synthesis and
      deposition. TGF-beta signaling is initiated by ligand binding to a membrane
      associated receptor complex that has serine/threonine kinase activity. This
      receptor complex phosphorylates specific Smad proteins, which then transduce the
      ligand-activated signal to the nucleus. Smad complexes regulate target gene
      transcription either by directly binding DNA sequences, or by complexing with
      other transcription factors or co-activators. There is extensive crosstalk
      between the TGF-beta signaling pathway and other signaling systems, including the
      mitogen-activated protein kinase pathways. The importance of TGF-beta in
      regulation of cell growth has been emphasized by recent observations that
      mutations of critical elements of the TGF-beta signaling system are associated
      with tumor progression in patients with many different types of epithelial
      neoplasms. TGF-beta has emerged as a predominant mediator of extracellular matrix
      production and deposition in progressive renal disease and in other forms of
      chronic tissue injury. In this overview, recent advances in our understanding of
      TGF-beta signaling, cell cycle regulation by TGF-beta, and the role of TGF-beta
      in progressive renal injury are highlighted.

PMID- 12486205
TI  - Role of Nociceptin/Orphanin FQ in the physiologic and pathologic control of the
      cerebral circulation.
AB  - Nociceptin/orphanin FQ is a newly described member of the opioid family. Previous
      minireviews in this series have described the contribution of important factors,
      including opioids, in the regulation of the cerebral circulation during
      physiologic and pathologic conditions. The present review extends these initial
      comments to an opioid whose vascular actions have only very recently been
      appreciated. In particular, this review discusses the contribution of
      nociceptin/orphanin FQ to impaired cerebral hemodynamics after cerebral
      hypoxia/ischemia and traumatic brain injury.

PMID- 12486206
TI  - Mechanism of action of progesterone antagonists.
AB  - The effects of progesterone on target tissues are mediated by progesterone
      receptors (PRs), which belong to a family of nuclear receptors and function as
      ligand-activated transcription factors to regulate the expression of specific
      sets of target genes. Progesterone antagonists repress the biological actions of
      progesterone by "actively" inhibiting PR activation. This work discusses the
      first clinically used progesterone antagonist RU486 and closely related compounds
      in terms of how these compounds inhibit progesterone action through
      heterodimerization and competition for DNA binding and by the recruitment of
      corepressors to promoters of target genes to repress transcription. We discuss
      cellular factors that may influence the activity of these compounds, such as the
      availability of coactivators and corepressors and the context of specific target
      promoters in any given cell type. We also discuss steroidal and nonsteroidal
      antagonist selectivity for PR versus other steroid hormone receptors and suggest
      that it may be possible to develop tissue/cell specific modulators of PR.

PMID- 12486207
TI  - Ingested type I interferon: state of the art as treatment for autoimmunity.
AB  - We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity
      that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome.
      We have examined toxicity and potential efficacy in three phase I (type 1
      diabetes, rheumatoid arthritis, multiple sclerosis) and one phase II clinical
      trials in multiple sclerosis. In a phase I open-label trial in type 1 diabetes,
      ingested IFN-alpha preserved residual beta-cell function in recent onset
      patients. In a second phase I trial, treatment of rheumatoid arthritis with
      ingested IFN-alpha reduced the secretion of interleukin (IL)-1, a pro
      inflammatory cytokine. In a third phase I trial in multiple sclerosis, there was
      a significant decrease in peripheral blood mononuclear cell IL-2 and IFN-gamma
      production after ingesting IFN-alpha. In a phase II randomized, placebo
      controlled, double-blind trial in multiple sclerosis, 10,000 IU ingested IFN
      alpha significantly decreased gadolinium enhancements compared with the placebo
      group at month 5. Tumor necrosis factor-alpha and IFN-gamma cytokine secretion in
      the 10,000 IU group at month 5 showed a significant decrease that corresponded
      with the effect of ingested IFN-alpha on decreasing gadolinium enhancements.
      Ingested IFN-alpha was not toxic in any of these clinical trials. These studies
      suggest that ingested IFN-alpha may have a potential role in the treatment of
      autoimmunity.

PMID- 12486208
TI  - Is metabolic syndrome X an inflammatory condition?
AB  - It is suggested that metabolic syndrome X is a low-grade systemic inflammatory
      condition.

PMID- 12486209
TI  - The role of histidine in the anemia of folate deficiency.
AB  - The amino acid histidine is metabolized to glutamic acid in mammalian tissue.
      Formiminoglutamic acid (FIGLU) is an intermediary in this reaction, and
      tetrahydrofolic acid is the coenzyme that converts it to glutamic acid. A test
      for folate deficiency concerns the measurement of urinary FIGLU excretion after a
      histidine load. It was observed that folate-deficient individuals receiving the
      histidine for the FIGLU test made hematological response that alleviated the
      anemia associated with this deficiency. This was unusual in that a biochemical
      test to determine the deficiency results in a beneficial effect for one aspect of
      the deficiency. The studies reported in this paper give a metabolic explanation
      for this phenomenon. Urine was collected for 24 hr from 25 folate-deficient
      subjects, 10 vitamin B(12)-deficient subjects, and 15 normal controls. Urinary
      excretion of histidine was a mean of 203 mg with a range of 130-360 mg for the
      folate-deficient subjects; 51.5 mg with a range of 30-76.6 mg for normal
      subjects; and 60.0 mg with a range of 32.3-93.0 mg for the vitamin B(12)
      deficient subjects. All the folate-deficient subjects subsequently made a
      hematological response to the histidine administered for the FIGLU test. No
      hematological response was observed in the vitamin B(12)-deficient individuals.
      When folic acid was given to folate-deficient subjects who received no histidine,
      urinary histidine levels returned to normal levels rapidly and this was followed
      by a hematological response. Others have shown that volunteers fed a histidine
      free diet developed anemia. In normal subjects, histidine is excreted much more
      in the urine than other essential amino acids are. Hemoglobin protein contains
      10% histidine. Under normal conditions, dietary histidine can supply sufficient
      histidine to prevent anemia. When the dietary intake is diminished or the urinary
      excretion is greatly increased, anemia results. It is concluded that folate
      deficiency causes histidine depletion through increased urinary excretion of this
      amino acid. Feeding histidine replenishes tissue levels of histidine, resulting
      in hemoglobin regeneration. Folic acid administration results in return of
      histidine to normal urinary levels. Thus, a combination of folic acid histidine
      would be beneficial for folate deficient individuals.

PMID- 12486210
TI  - Apolipoprotein A-I expression in rats is not altered by troglitazone.
AB  - Insulin is known to upregulate apolipoprotein A-I (apoA-I) promoter activity and
      to increase apoA1 gene expression in vivo. To determine if enhancement of insulin
      action with insulin sensitizers can also increase the apoA-I expression, we
      studied the in vivo effect of troglitazone, a potent insulin sensitizer, on the
      expression of rat hepatic and intestinal apoA-I mRNA using Northern blot
      analysis. The plasma, hepatic, and intestinal apoA-I content was also measured
      with immunoblot analysis using a specific anti-rat apoA-I antiserum.
      Troglitazone, given mixed with rat chow (0.2%) for 18 days, did not increase
      either plasma or tissue apoA-I mRNA or protein content. Intestinal apoA-I mRNA
      content relative to glyceraldehyde-3 phosphate dehydrogenase (G(3)PDH) mRNA was
      significantly lower compared with hepatic tissue content in both control and
      troglitazone-treated rats. The effect of troglitazone on the rat apoA-I promoter
      was examined using transient transfection analysis in HepG2 cells transfected
      with the apoA-I-chloramphenicol acetyl transferase (CAT) reporter plasmid
      (pAI.474.CAT). CAT activity (percentage acetylation of chloramphenicol as means
      +/- SEM) was not significantly different in ethanol (vehicle)-treated cells
      compared with cells treated with troglitazone (50.5% +/- 2.5% in control cells vs
      57.7% +/- 8.2% and 53.5% +/- 4.2% in cells treated with 10 and 100 mM
      troglitazone, respectively). It is concluded that troglitazone doses known to
      achieve insulin sensitization did not enhance rat apoA-I promoter activity
      sufficiently to result in an increased apoA-I mRNA or protein expression in the
      intact rat. However, peroxisome proliferator activator receptor (PPAR) agonists
      that have significant PPAR alpha activity in addition to their PPAR gamma
      effects, may well be able to induce apoA-I expression.

PMID- 12486211
TI  - Wound closure in sheared endothelial cells is enhanced by modulation of vascular
      endothelial-cadherin expression and localization.
AB  - We previously demonstrated that laminar shear stress enhances human coronary
      artery endothelial cell (HCAEC) wound closure via the mechanisms of cell
      spreading and migration. Because cell-cell junctional proteins such as vascular
      endothelial cell cadherin (VE-cadherin) are critical to cell-cell adhesion and
      motility, we tested the hypothesis that modulation of VE-cadherin expression
      under shear stress may be linked to this enhancement in wound closure. HCAEC
      monolayers were preconditioned to attain cellular alignment by shearing at 12
      dynes/cm(2) for 18 hr in a parallel-plate flow chamber. Subsequently, they were
      divided into the following three groups: (i) control; (ii) treated with anti
      cadherin-5 antibody; or (iii) treated with the calcium chelating agent EGTA.
      Next, the monolayers were wounded with a metal spatula and resheared at 20
      dynes/cm(2) or left static. Time-lapse imaging was performed during the first 3
      hr after imposition of these conditions. Immunocytochemistry or Western blot
      analyses for VE-cadherin expression were performed on all wounded monolayers.
      Deconvolution microscopy, three-dimensional cell-cell junctional reconstruction
      images, and histogram analyses of interendothelial junction signal intensities
      were performed on cells at the wound edge of a monolayer. Under shear, HCAEC
      demonstrated increased VE-cadherin immunofluorescence and protein expression
      despite an enhancement in wound closure compared with static conditions. In
      separate experiments, application with anti-cadherin-5 antibody or treatment with
      EGTA attenuated VE-cadherin expression and further enhanced wound closure
      compared with control shear and all static conditions. In addition, the pattern
      of VE-cadherin localization with these treatments became more intracellular and
      nuclear in appearance. These findings of changes in this junctional adhesion
      protein expression and localization may further our understanding of laminar
      shear stress-induced endothelial repair in the coronary circulation.

PMID- 12486212
TI  - Modulation of CD8+ intraepithelial lymphocyte distribution by dietary fiber in
      the rat large intestine.
AB  - We studied whether ingestion of dietary fiber modifies the distribution of
      intraepithelial lymphocytes (IEL) in a physiological condition. Male WKAH rats
      were fed diets either with fiber (sugar beet fiber or crystalline cellulose, 100
      g/kg diet each) or without fiber for 3 weeks. The number of CD8(+), CD4(+), and
      NKR-P1(+) IEL per epithelial layer in the crypt section of the cecum, proximal
      colon, and distal colon were scored by immunohistochemical staining. We found
      that the proportion of CD8(+) IEL was greater in the cecal mucosa and was
      gradually reduced toward the distal large intestine in general. In contrast,
      there was no difference in the proportion of CD4(+) and NKR-P1(+) IEL in the
      large intestine. Dietary sugar beet fiber, but not crystalline cellulose,
      increased the proportion of CD8(+) IEL, especially in the cecal mucosa, but not
      the CD4(+) and NKR-P1(+) IEL. Analysis of cecal organic acid concentration
      confirmed higher concentrations of acetate and butyrate, and lower concentration
      of succinate and isovalerate, in the cecum of the rats fed sugar beet fiber than
      other diets. These results indicate that ingestion of some dietary fiber
      modulates local cell proliferation of a progenitor of CD8(+) IEL or promotes
      homing of CD8(+) T cells into the large intestinal epithelium, most likely via
      the fermentation in the luminal contents.

PMID- 12486213
TI  - Nitric oxide-cyclic GMP signaling pathway in the regulation of rabbit clitoral
      cavernosum tone.
AB  - We investigated the role of nitric oxide (NO)-guanosine 3',5'-cyclic
      monophosphate (cGMP) signaling in the regulation of rabbit clitoral cavernosum
      (CC) tone. Tension measurements, reverse transcriptase-polymerase chain reaction
      (RT-PCR), Western blotting, and NADPH-diaphorase staining were performed in CC.
      In the precontracted CC strips with phenylephrine (10(-5) M), acetylcholine (ACh)
      relaxed, dependent on dosage. Pretreatment with atropine, N(omega) nitro-L
      arginine-methyl ester (NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
      (ODQ), guanylate cyclase inhibitor abolished the ACh-induced relaxations, but
      tetrodotoxin (TTX) did not. Sodium nitroprusside relaxed the strips in the
      presence of atropine and NAME, but not in the presence of ODQ. Electrical field
      stimulation (EFS) relaxed the strips dependent on stimulus strength. Pretreatment
      with TTX, NAME, or ODQ abolished the EFS-induced relaxation, but atropine did
      not. L-Arginine partially restored the inhibited response to ACh and EFS. The
      inducible NO synthase (iNOS) and neuronal NOS (nNOS) mRNAs and iNOS and
      endothelial NOS (eNOS) proteins were identified in the CC. NADPH-diaphorase
      staining revealed the positivity on the nerve trunks and fine nerve fibers in the
      CC. Finally, results demonstrate that the nNOS, ENOS, and the NO-cGMP signaling
      pathway are involved in the regulation of clitoral tumescence.

PMID- 12486214
TI  - Acetaminophen in the post-ischemia reperfused myocardium.
AB  - Acetaminophen was administered acutely at the onset of reperfusion after 20 min
      of low-flow, global myocardial ischemia in isolated, perfused guinea pig hearts
      (Langendorff) to evaluate its influence in the postischemia, reperfused
      myocardium. Similarly prepared hearts were treated with vehicle or with uric acid
      (another phenol for comparison). Functionally, acetaminophen-treated hearts (0.35
      mM) achieved significantly greater recovery during reperfusion. For example, left
      ventricular developed pressures at 40 min reperfusion were 38 +/- 3, 27 +/- 3,
      and 20 +/- 2 in the presence of acetaminophen (P < 0.05, relative to the other
      two groups), vehicle, and uric acid, respectively. Coronary perfusion pressures
      and calculated coronary vascular resistances, in the acetaminophen-treated
      hearts, were significantly lower at the same time (e.g., coronary perfusion
      pressures in the three groups, respectively, were 40 +/- 2 [P < 0.05], 51 +/- 3,
      and 65 +/- 12 mm Hg). Under baseline, control conditions, creatine kinase ranged
      from 12-15 units/liter in the three groups. It increased to 35-40 units/liter (P
      < 0.05) during ischemia but was significantly reduced by acetaminophen during
      reperfusion (e.g., 5.3 +/- 0.8 units/liter at 40 min). Oxidant-mediated
      chemiluminescence in all three treatment groups during baseline conditions and
      ischemia was similar (i.e., approximately 1.5-2.0 min for peak luminescence to
      reach its half maximal value). It took significantly more time during reperfusion
      for the oxidation of luminol in the presence of acetaminophen (>20 min, P < 0.05)
      than in its absence (3-8 min in uric acid- and vehicle-treated hearts). These
      results suggest that administration of acetaminophen (0.35 mM), at the onset of
      reperfusion, provides anti-oxidant-mediated cardioprotection in the postischemia,
      reperfused myocardium.

PMID- 12486215
TI  - Protein kinase C-mediated desmin phosphorylation is related to myofibril disarray
      in cardiomyopathic hamster heart.
AB  - The cardiomyopathic (CM) Syrian golden hamster (strain UM-X7.1) exhibits a
      hereditary cardiomyopathy, which causes premature death resulting from congestive
      heart failure. The CM animals show extensive cardiac myofibril disarray and
      myocardial calcium overload. The present study has been undertaken to examine the
      role of desmin phosphorylation in myofibril disarray observed in CM hearts. The
      data from skinned myofibril protein phosphorylation assays have shown that desmin
      can be phosphorylated by protein kinase C (PKC). There is no significant
      difference in the content of desmin between CM and control hamster hearts.
      However, the desmin from CM hearts has a higher phosphorylation level than that
      of the normal hearts. Furthermore, we have examined the distribution of desmin
      and myofibril organization with immunofluorescent microscopy and immunogold
      electron microscopy in cultured cardiac myocytes after treatment with the PKC
      activating phorbol ester, 12-O-tetradecanylphorbol-13-acetate (TPA). When the
      cultured normal hamster cardiac cells are treated with TPA, desmin filaments are
      disassembled and the myofibrils become disarrayed. The myofibril disarray closely
      mimics that observed in untreated CM cultures. These results suggest that
      disassembly of desmin filaments, which could be caused by PKC-mediated
      phosphorylation, may be a factor in myofibril disarray in cardiomyopathic cells
      and that the intermediate filament protein, desmin, plays an important role in
      maintaining myofibril alignment in cardiac cells.

PMID- 12486216
TI  - Relaxin stimulates bronchial epithelial cell PKA activation, migration, and
      ciliary beating.
AB  - Relaxin is an insulin-like serum protein secreted during pregnancy and found in
      many tissues, including the lung. Relaxin is reported to stimulate epithelial
      cell proliferation, but the effects of relaxin on airway epithelium are unknown.
      We tested the hypothesis that relaxin would stimulate the increased migration of
      bronchial epithelial cells (BEC) in response to wounding. Using monolayers of BEC
      in a wound-healing model, relaxin augmented wound closure with maximal closure
      occurring at 12 hr (1 micro M). Unlike cytokines, relaxin did not stimulate
      increased BEC interleukin-8 (IL-8) release. Relaxin caused a significant
      stimulation of ciliary beat frequency (CBF) in BEC. Because protein kinase (PKA)
      activation increases CBF and relaxin can elevate intracellular cAMP levels, we
      measured PKA activity in BEC treated with relaxin. Relaxin increased PKA activity
      3-4 fold by approximately 4 hr, with a return to baseline levels by 8-10 hr.
      Relaxin-stimulated PKA activity differs temporally from the rapid (1 hr) beta
      adrenergic activation of PKA in BEC. These data suggest that relaxin augments
      epithelial repair by increasing airway cell migration and CBF via PKA-dependent
      mechanisms.

PMID- 12486217
TI  - Mechanism of regulation of phosphate dissociation from actomyosin-ADP-Pi by thin
      filament proteins.
AB  - Regulation by calcium and myosin-S1 of the acceleration of the rate of phosphate
      release from myosin-ADP-inorganic phosphate (M-ADP-Pi) by the thin filament actin
      tropomyosin (Tm)-troponin (Tn), was measured directly by using double mixing
      stopped-flow experiments with fluorescent phosphate binding protein. At low
      calcium and without rigor myosin-S1, saturating concentrations of thin filaments
      accelerate the rate of phosphate dissociation from M-ADP-Pi 8-fold, from 0.08 to
      0.64 s(-1). If either myosin-S1 or calcium is bound to the thin filaments,
      phosphate release is a biphasic process in which the fast phase is the
      dissociation of Pi from actoTmTnM-ADP-Pi and the slow phase is limited by the
      hydrolysis of actoTmTnM-ATP to actoTmTnM-ADP-Pi. The maximum accelerations of the
      fast components by saturating thin filaments (relative to M-ADP-Pi alone) are:
      approximately equal 200-fold, 16 s(-1) (calcium only); approximately equal 400
      fold, 30 s(-1) (EGTA and rigor S1); and approximately equal1,000-fold, 75 s(-1)
      (calcium and rigor S1). The maximum rate of phosphate dissociation attained with
      S1 and calcium bound to the thin filament is the same as for unregulated actin.
      Regulation of the rate of phosphate dissociation by calcium and myosin-S1 is
      partially explained by the model of Geeves [McKillop, D. F. and Geeves, M. A.
      (1993) Biophys. J. 65, 693-701], in which calcium and rigor S1 perturb the
      equilibria among three states of the thin filament (blocked, closed, and open).
      However, a quantitative description of the regulatory mechanism requires
      acceleration by calcium of an additional step of the mechanism, either phosphate
      dissociation or a preceding conformational change.

PMID- 12486218
TI  - Dynamics of microtubule asters in microfabricated chambers: the role of
      catastrophes.
AB  - Recent in vivo as well as in vitro experiments have indicated that microtubule
      pushing alone is sufficient to position a microtubule-organizing center within a
      cell. Here, we investigate the effect of catastrophes on the dynamics of
      microtubule asters within microfabricated chambers that mimic the confining
      geometry of living cells. The use of a glass bead as the microtubule-organizing
      center allows us to manipulate the aster by using optical tweezers. In the case
      in which microtubules preexist, we show that because of microtubule buckling,
      repositioning almost never occurs after relocation with the optical tweezers,
      although initial microtubule growth always leads the aster to the geometrical
      center of the chamber. When a catastrophe promoter is added, we find instead that
      the aster is able to efficiently explore the chamber geometry even after being
      relocated with the optical tweezers. As predicted by theoretical calculations,
      the results of our in vitro experiments clearly demonstrate the need for
      catastrophes for proper positioning in a confining geometry. These findings
      correlate with recent observations of nuclear positioning in fission yeast cells.

PMID- 12486219
TI  - Genome-wide coexpression dynamics: theory and application.
AB  - High-throughput expression profiling enables the global study of gene activities.
      Genes with positively correlated expression profiles are likely to encode
      functionally related proteins. However, all biological processes are interlocked,
      and each protein may play multiple cellular roles. Thus the coexpression of any
      two functionally related genes may depend on the constantly varying, yet often
      unknown cellular state. To initiate a systematic study on this issue, a theory of
      coexpression dynamics is presented. This theory is used to rationalize a strategy
      of conducting a genome-wide search for the most critical cellular players that
      may affect the coexpression pattern of any two genes. In one example, using a
      yeast data set, our method reveals how the enzymes associated with the urea cycle
      are expressed to ensure proper mass flow of the involved metabolites. The
      correlation between ARG2 and CAR2 is found to change from positive to negative as
      the expression level of CPA2 increases. This delicate interplay in correlation
      signifies a remarkable control on the influx and efflux of ornithine and reflects
      well the intrinsic cellular demand for arginine. In addition to the urea cycle,
      our examples include SCH9 and CYR1 (both implicated in a recent longevity study),
      cytochrome c1 (mitochondrial electron transport), calmodulin (main calcium
      binding protein), PFK1 and PFK2 (glycolysis), and two genes, ECM1 and YNL101W,
      the functions of which are newly revealed. The complexity in computation is eased
      by a new result from mathematical statistics.

PMID- 12486221
TI  - Crop pollination from native bees at risk from agricultural intensification.
AB  - Ecosystem services are critical to human survival; in selected cases, maintaining
      these services provides a powerful argument for conserving biodiversity. Yet, the
      ecological and economic underpinnings of most services are poorly understood,
      impeding their conservation and management. For centuries, farmers have imported
      colonies of European honey bees (Apis mellifera) to fields and orchards for
      pollination services. These colonies are becoming increasingly scarce, however,
      because of diseases, pesticides, and other impacts. Native bee communities also
      provide pollination services, but the amount they provide and how this varies
      with land management practices are unknown. Here, we document the individual
      species and aggregate community contributions of native bees to crop pollination,
      on farms that varied both in their proximity to natural habitat and management
      type (organic versus conventional). On organic farms near natural habitat, we
      found that native bee communities could provide full pollination services even
      for a crop with heavy pollination requirements (e.g., watermelon, Citrullus
      lanatus), without the intervention of managed honey bees. All other farms,
      however, experienced greatly reduced diversity and abundance of native bees,
      resulting in insufficient pollination services from native bees alone. We found
      that diversity was essential for sustaining the service, because of year-to-year
      variation in community composition. Continued degradation of the agro-natural
      landscape will destroy this "free" service, but conservation and restoration of
      bee habitat are potentially viable economic alternatives for reducing dependence
      on managed honey bees.

PMID- 12486220
TI  - Engineered calmodulins reveal the unexpected eminence of Ca2+ channel
      inactivation in controlling heart excitation.
AB  - Engineered calmodulins (CaMs), rendered Ca2+-insensitive by mutations, function
      as dominant negatives in heterologous systems, and have revealed mechanisms of
      ion channel modulation by Ca2+/CaM. The use of these CaMs in native mammalian
      cells now emerges as a strategy to unmask the biology of such Ca2+ feedback.
      Here, we developed recombinant adenoviruses bearing engineered CaMs to facilitate
      their expression in adult heart cells, where Ca2+ regulation may be essential for
      moment-to-moment control of the heartbeat. Engineered CaMs not only eliminated
      the Ca2+-dependent inactivation of native calcium channels, but exposed an
      unexpectedly large impact of removing such feedback: the unprecedented (4- to 5
      fold) prolongation of action potentials. This striking result recasts the basic
      paradigm for action-potential control and illustrates the promise of virally
      delivered engineered CaM to investigate the biology of numerous other CaM
      signaling pathways.

PMID- 12486222
TI  - Photoresponsive polymer-enzyme switches.
AB  - The ability to photoregulate enzyme activities could provide important new
      opportunities for development of diagnostic assays, sequential bioprocessing, and
      lab assays in both traditional and microfluidic formats. We show here that the
      photoinduced changes in the size and hydration of a "smart" polymer chain coil
      can be used to regulate substrate access and enzyme activity when conjugated to
      the enzyme at a specific point just outside the active site. The photoresponsive
      polymers thus serve jointly as antennae and actuators that reversibly respond to
      distinct optical signals to switch the polymer-enzyme conjugates on and off, and
      work when the conjugate is free in solution or when immobilized on magnetic
      beads.

PMID- 12486223
TI  - A robust and scalable microfluidic metering method that allows protein crystal
      growth by free interface diffusion.
AB  - Producing robust and scalable fluid metering in a microfluidic device is a
      challenging problem. We developed a scheme for metering fluids on the picoliter
      scale that is scalable to highly integrated parallel architectures and is
      independent of the properties of the working fluid. We demonstrated the power of
      this method by fabricating and testing a microfluidic chip for rapid screening of
      protein crystallization conditions, a major hurdle in structural biology efforts.
      The chip has 480 active valves and performs 144 parallel reactions, each of which
      uses only 10 nl of protein sample. The properties of microfluidic mixing allow an
      efficient kinetic trajectory for crystallization, and the microfluidic device
      outperforms conventional techniques by detecting more crystallization conditions
      while using 2 orders of magnitude less protein sample. We demonstrate that
      diffraction-quality crystals may be grown and harvested from such nanoliter
      volume reactions.

PMID- 12486224
TI  - ARF mutation accelerates pituitary tumor development in Rb+/- mice.
AB  - Mice heterozygous for the retinoblastoma (Rb) tumor suppressor gene develop
      pituitary and thyroid tumors with high penetrance. We demonstrate here that loss
      of the ARF tumor suppressor strongly accelerates intermediate lobe pituitary
      tumorigenesis in Rb heterozygous mice. These effects in the pituitary are greater
      than those conferred by p53 loss in that Rb+-;ARF-- mice display significantly
      more early atypical lesions than Rb+-; p53-- mice. Also, Rb+-;ARF-- compound
      mutants do not develop many of the novel tumors or precancerous lesions seen in
      Rb+-;p53-- compound mutants. Although complete loss of ARF expression is not
      obligatory for pituitary tumorigenesis in Rb+- mice, alterations of the ARF locus
      are observed in tumors from Rb+-;ARF+- mice, consistent with a selective
      advantage of ARF inactivation in this context. We conclude that inactivation of
      ARF acts more broadly than that of p53 in connecting abrogation of the Rb pathway
      to tumorigenesis.

PMID- 12486225
TI  - Anaerobic enzyme.substrate structures provide insight into the reaction mechanism
      of the copper-dependent quercetin 2,3-dioxygenase.
AB  - Quercetin 2,3-dioxygenase (2,3QD) is the only firmly established copper
      dioxygenase known so far. Depending solely on a mononuclear Cu center, it
      catalyzes the breakage of the O-heterocycle of flavonols, producing more easily
      degradable phenolic carboxylic acid ester derivatives. In the enzymatic process,
      two CC bonds are broken and concomitantly carbon monoxide is released. The x-ray
      structures of Aspergillus japonicus 2,3QD anaerobically complexed with the
      substrate kaempferol and the natural substrate quercetin have been determined at
      1.90- and 1.75-A resolution, respectively. Flavonols coordinate to the copper ion
      as monodentate ligands through their 3OH group. They occupy a shallow and overall
      hydrophobic cavity proximal to the metal center. As a result of a van der Waals
      contact between the most outward flavonol A-ring and Pro(164), a flexible loop in
      front of the active site becomes partly ordered. Interestingly, flavonols bound
      to 2,3QD are bent at the C2 atom, which is pyramidalized. The increased local
      sp(3) character at this atom may stabilize a carbon-centered radical activated
      for dioxygen attack. Glu(73) coordinates the copper through its O epsilon 1 atom.
      The short distance of about 2.55 A between its O epsilon 2 atom and the flavonol
      O3 atom suggests that a hydrogen bond exists between the two atoms, indicating
      that Glu(73) can act as a base in flavonol deprotonation and that it retains the
      proton. Structure-based geometric considerations indicate O(2) binding to the
      flavonol C2 atom as the preferred route for flavonol dioxygenation.

PMID- 12486226
TI  - Binding and release of iron by gel-encapsulated human transferrin: evidence for a
      conformational search.
AB  - Human transferrin is a single-chain bilobal protein with each of the two similar
      but not identical lobes in turn composed of two domains. Each lobe may assume one
      of two stable structural conformations, open or closed, determined by a rigid
      rotation of the domains with respect to each other. In solution, the
      transformation of a lobe between open and closed conformations is associated with
      the release or binding of an Fe(III) ion. The results of the present study
      indicate that encapsulation of transferrin within a porous sol-gel matrix allows
      for a dramatic expansion, to days or weeks, of this interconversion time period,
      thus providing an opportunity to probe heretofore inaccessible transient
      intermediates. Sol-gel-encapsulated iron-free transferrin samples are prepared by
      using two protocols. In the first protocol, the equilibrium form of
      apotransferrin is encapsulated in the sol-gel matrix, whereas in the second
      protocol holotransferrin is first encapsulated and then iron is removed from the
      protein. Results of kinetic and spectroscopic studies allow for distinguishing
      between two models for iron binding. In the first, iron is assumed to bind to
      amino acid ligands of one domain, inducing a rigid rotation of the second domain
      to effect closure of the interdomain cleft. In the second, iron undertakes a
      conformational search among the thermally accessible states of the lobe,
      "choosing" the state which most nearly approximates the stable closed state when
      iron is bound. Our experimental results support the second mechanism.

PMID- 12486228
TI  - Carotenoid to chlorophyll energy transfer in the peridinin-chlorophyll-a-protein
      complex involves an intramolecular charge transfer state.
AB  - Carotenoids are, along with chlorophylls, crucial pigments involved in light
      harvesting processes in photosynthetic organisms. Details of carotenoid to
      chlorophyll energy transfer mechanisms and their dependence on structural
      variability of carotenoids are as yet poorly understood. Here, we employ
      femtosecond transient absorption spectroscopy to reveal energy transfer pathways
      in the peridinin-chlorophyll-a-protein (PCP) complex containing the highly
      substituted carotenoid peridinin, which includes an intramolecular charge
      transfer (ICT) state in its excited state manifold. Extending the transient
      absorption spectra toward near-infrared region (600-1800 nm) allowed us to
      separate contributions from different low-lying excited states of peridinin. The
      results demonstrate a special light-harvesting strategy in the PCP complex that
      uses the ICT state of peridinin to enhance energy transfer efficiency.

PMID- 12486227
TI  - Differential lipid biosynthesis underlies a tradeoff between reproduction and
      flight capability in a wing-polymorphic cricket.
AB  - The biochemical basis of life-history tradeoffs is a poorly studied aspect of
      life-history evolution. We used radiotracer and endocrine approaches to
      investigate the extent to which morphs of a wing-polymorphic insect differ in the
      biosynthesis of lipid classes important for dispersal capability vs. reproduction
      (ovarian growth). The flight-capable genotype of Gryllus firmus biosynthesized a
      greater amount of total lipid and triglyceride (main flight fuel), which was
      preferentially allocated to somatic tissue during early adulthood. By contrast,
      the flightless genotype biosynthesized a significantly greater amount of
      phospholipid (important in egg development), which was preferentially allocated
      to ovaries. Topical application of a juvenile-hormone mimic to the flight-capable
      morph caused it to express all aspects of lipid metabolism seen in the flightless
      morph. Differences in biosynthesis between morphs (i) occur coincident with 100
      400% greater ovarian growth in the flightless morph, (ii) result from alterations
      of both de novo biosynthesis of fatty acid and downstream partitioning of fatty
      acids into triglyceride vs. phospholipid, and (iii) possibly result from
      genetically polymorphic hormonal regulators with negative pleiotropic effects on
      lipid biosynthesis and ovarian growth. The present study provides direct
      documentation of genetically based alterations of in vivo flux through pathways
      of intermediary metabolism leading to the differential production of end products
      central to the specialization of phenotypes for alternate life histories.

PMID- 12486229
TI  - Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from
      huntingtin polyglutamine neurotoxicity.
AB  - Huntington's disease is a progressive neurodegenerative disease caused by a
      polyglutamine (polyQ) repeat expansion in the huntingtin protein [Huntington's
      Disease Collaborative Research Group (1993) Cell 72, 971-983]. To understand the
      mechanism by which polyQ repeats cause neurodegeneration and cell death, we
      modeled polyQ neurotoxicity in Caenorhabditis elegans. In our model, expression
      of N-terminal fragments of human huntingtin causes polyQ-dependent degeneration
      of neurons. We conducted a genetic screen to identify proteins that protect
      neurons from the toxic effects of expanded polyQ tracts. Loss of polyQ enhancer-1
      (pqe-1) gene function strongly and specifically exacerbates neurodegeneration and
      cell death, whereas overexpression of a pqe-1 cDNA protects C. elegans neurons
      from the toxic effects of expanded huntingtin fragments. A glutamineproline-rich
      domain, along with a charged domain, is critical for PQE-1 protein function.
      Analysis of pqe-1 suggests that proteins exist that specifically protect neurons
      from the toxic effects of expanded polyQ disease proteins.

PMID- 12486230
TI  - Reversal of DNA alkylation damage by two human dioxygenases.
AB  - The Escherichia coli AlkB protein protects against the cytotoxicity of
      methylating agents by repair of the DNA lesions 1-methyladenine and 3
      methylcytosine, which are generated in single-stranded stretches of DNA. AlkB is
      an alpha-ketoglutarate- and Fe(II)-dependent dioxygenase that oxidizes the
      relevant methyl groups and releases them as formaldehyde. Here, we identify two
      human AlkB homologs, ABH2 and ABH3, by sequence and fold similarity, functional
      assays, and complementation of the E. coli alkB mutant phenotype. The levels of
      their mRNAs do not appear to correlate with cell proliferation but tissue
      distributions are different. Both enzymes remove 1-methyladenine and 3
      methylcytosine from methylated polynucleotides in an alpha-ketoglutarate
      dependent reaction, and act by direct damage reversal with the regeneration of
      the unsubstituted bases. AlkB, ABH2, and ABH3 can also repair 1-ethyladenine
      residues in DNA with the release of acetaldehyde.

PMID- 12486231
TI  - RNA polymerase II-dependent transcription in trypanosomes is associated with a
      SNAP complex-like transcription factor.
AB  - Spliced leader RNA transcription is essential for cell viability in trypanosomes.
      The SL RNA genes are expressed from the only defined RNA polymerase II-dependent
      promoter identified to date in the trypanosome genome. The SL RNA gene promoter
      has been shown by in vitro and in vivo analyses to have a tripartite
      architecture. The upstream most cis-acting element, called PBP-1E, is located
      between 70 and 60 bp upstream from the transcription start site. This essential
      element functions along with two downstream elements to direct efficient and
      proper initiation of transcription. Electrophoretic mobility-shift studies
      detected a 122-kDa protein, called PBP-1, which interacts with PBP-1E. This
      protein is the first sequence-specific, double-stranded DNA-binding protein
      isolated in trypanosomes. Three polypeptides copurify with PBP-1 activity,
      suggesting that PBP-1 is composed of 57-, 46-, and 36-kDa subunits. We have
      cloned the genes that encode the 57- and 46-kDa subunits. The 46-kDa protein is a
      previously uncharacterized protein and may be unique to trypanosomes. Its
      predicted tertiary structure suggests it binds DNA as part of a complex. The 57
      kDa subunit is orthologous to the human small nuclear RNA-activating protein
      (SNAP)50, which is an essential subunit of the SNAP complex (SNAPc). In human
      cells, SNAPc binds to the proximal sequence element in both RNA polymerase II-
      and III-dependent small nuclear RNA gene promoters. These findings identify a
      surprising link in the transcriptional machinery across a large evolutionary
      distance in the regulation of small nuclear RNA genes in eukaryotes.

PMID- 12486232
TI  - A polyphosphate kinase (PPK2) widely conserved in bacteria.
AB  - Synthesis of inorganic polyphosphate (poly P) from the terminal phosphate of ATP
      is catalyzed reversibly by poly P kinase (PPK, now designated PPK1) initially
      isolated from Escherichia coli. PPK1 is highly conserved in many bacteria,
      including some of the major pathogens such as Pseudomonas aeruginosa. In a null
      mutant of P. aeruginosa lacking ppk1, we have discovered a previously
      uncharacterized PPK activity (designated PPK2) distinguished from PPK1 by the
      following: synthesis of poly P from GTP or ATP, a preference for Mn2+ over Mg2+,
      and a stimulation by poly P. The reverse reaction, a poly P-driven nucleoside
      diphosphate kinase synthesis of GTP from GDP, is 75-fold greater than the forward
      reaction, poly P synthesis from GTP. The gene encoding PPK2 (ppk2) was identified
      from the amino acid sequence of the protein purified near 1,000-fold, to
      homogeneity. The 5'-end is 177 bp upstream of the annotated genome sequence of a
      "conserved hypothetical protein"; ppk2 (1,074 bp) encodes a protein of 357 aa
      with a molecular mass of 40.8 kDa. Sequences homologous to PPK2 are present in
      two other proteins in P. aeruginosa, in two Archaea, and in 32 other bacteria
      (almost all with PPK1 as well); these include rhizobia, cyanobacteria,
      Streptomyces, and several pathogenic species. Distinctive features of the poly P
      driven nucleoside diphosphate kinase activity and structural aspects of PPK2 are
      among the subjects of an accompanying report.

PMID- 12486233
TI  - Z-DNA-binding proteins can act as potent effectors of gene expression in vivo.
AB  - The role of Z-DNA-binding proteins in vivo is explored in yeast. A conformation
      specific yeast one-hybrid system is made in which formation of Z-DNA is studied
      near a minimal promoter site where it can be stabilized by negative supercoiling
      in addition to protein binding. Experiments were carried out with a Z-DNA-binding
      protein domain from the editing enzyme, double-stranded RNA adenosine deaminase
      1. In the one-hybrid system, the reporter gene is activated when a Z-DNA-specific
      binding domain is fused with an activation domain and expressed in vivo.
      Significantly, it was found that even in the absence of the activation domain
      there is substantial transcription of the reporter gene if the Z-DNA-binding
      protein is expressed in the cell. This result suggests that Z-DNA formation in
      the promoter region induced or stabilized by a Z-DNA-binding protein can act as a
      cis-element in gene regulation. Related results have been found recently when the
      human chromatin-remodeling system converts a segment of DNA in the promoter
      region of the human colony-stimulating factor 1 gene into the left-handed Z
      conformation.

PMID- 12486234
TI  - There's NO binding like NOS binding: protein-protein interactions in NO/cGMP
      signaling.

PMID- 12486235
TI  - Can the Ca2+ hypothesis and the Ca2+-voltage hypothesis for neurotransmitter
      release be reconciled?
AB  - It is well established that Ca2+ plays a key role in promoting the physiological
      depolarization-induced release (DIR) of neurotransmitters from nerve terminals
      (Ca2+ hypothesis). Yet, evidence has accumulated for the Ca2+-voltage hypothesis,
      which states that not only is Ca2+ required, but membrane potential as such also
      plays a pivotal role in promoting DIR. An essential aspect of the Ca2+-voltage
      hypothesis is that it is depolarization that is responsible for the initiation of
      release. This assertion seems to be contradicted by recent experiments wherein
      release was triggered by high concentrations of intracellular Ca2+ in the absence
      of depolarization [calcium-induced release (CIR)]. Here we show that there is no
      contradiction between CIR and the Ca2+-voltage hypothesis. Rather, CIR can be
      looked at as a manifestation of spontaneous release under conditions of high
      intracellular Ca2+ concentration. Spontaneous release in turn is governed by a
      subset of the molecular scheme for DIR, under conditions of no depolarization.
      Prevailing estimates for the intracellular calcium concentration, [Ca2+]i, in
      physiological DIR rely on experiments under conditions of CIR. Our theory
      suggests that these estimates are too high, because depolarization is absent in
      these experiments and [Ca2+]i is held at high levels for an extended period.

PMID- 12486236
TI  - Hyperinsulinism induced by targeted suppression of beta cell KATP channels.
AB  - ATP-sensitive K+ (K(ATP)) channels couple cell metabolism to electrical activity.
      To probe the role of K(ATP) in glucose-induced insulin secretion, we have
      generated transgenic mice expressing a dominant-negative, GFP-tagged K(ATP)
      channel subunit in which residues 132-134 (Gly-Tyr-Gly) in the selectivity filter
      were replaced by Ala-Ala-Ala, under control of the insulin promoter. Transgene
      expression was confirmed by both beta cell-specific green fluorescence and
      complete suppression of channel activity in those cells ( approximately 70%) that
      did fluoresce. Transgenic mice developed normally with no increased mortality and
      displayed normal body weight, blood glucose levels, and islet architecture.
      However, hyperinsulinism was evident in adult mice as (i) a disproportionately
      high level of circulating serum insulin for a given glucose concentration (
      approximately 2-fold increase in blood insulin), (ii) enhanced glucose-induced
      insulin release from isolated islets, and (iii) mild yet significant enhancement
      in glucose tolerance. Enhanced glucose-induced insulin secretion results from
      both increased glucose sensitivity and increased release at saturating glucose
      concentration. The results suggest that incomplete suppression of K(ATP) channel
      activity can give rise to a maintained hyperinsulinism.

PMID- 12486237
TI  - Genes for the cytoskeletal protein tubulin in the bacterial genus
      Prosthecobacter.
AB  - Tubulins, the protein constituents of the microtubule cytoskeleton, are present
      in all known eukaryotes but have never been found in the Bacteria or Archaea.
      Here we report the presence of two tubulin-like genes [bacterial tubulin a
      (btuba) and bacterial tubulin b (btubb)] in bacteria of the genus Prosthecobacter
      (Division Verrucomicrobia). In this study, we investigated the organization and
      expression of these genes and conducted a comparative analysis of the bacterial
      and eukaryotic protein sequences, focusing on their phylogeny and 3D structures.
      The btuba and btubb genes are arranged as adjacent loci within the genome along
      with a kinesin light chain gene homolog. RT-PCR experiments indicate that these
      three genes are cotranscribed, and a probable promoter was identified upstream of
      btuba. On the basis of comparative modeling data, we predict that the
      Prosthecobacter tubulins are monomeric, unlike eukaryotic alpha and beta
      tubulins, which form dimers and are therefore unlikely to form microtubule-like
      structures. Phylogenetic analyses indicate that the Prosthecobacter tubulins are
      quite divergent and do not support recent horizontal transfer of the genes from a
      eukaryote. The discovery of genes for tubulin in a bacterial genus may offer new
      insights into the evolution of the cytoskeleton.

PMID- 12486238
TI  - Effects of strand and directional asymmetry on base-base coupling and charge
      transfer in double-helical DNA.
AB  - Mechanistic models of charge transfer (CT) in macromolecules often focus on CT
      energetics and distance as the chief parameters governing CT rates and
      efficiencies. However, in DNA, features unique to the DNA molecule, in
      particular, the structure and dynamics of the DNA base stack, also have a
      dramatic impact on CT. Here we probe the influence of subtle structural
      variations on base-base CT within a DNA duplex by examining photoinduced
      quenching of 2-aminopurine (Ap) as a result of hole transfer (HT) to guanine (G).
      Photoexcited Ap is used as a dual reporter of variations in base stacking and CT
      efficiency. Significantly, the unique features of DNA, including the strandedness
      and directional asymmetry of the double helix, play a defining role in CT
      efficiency. For an (AT)n bridge, the orientation of the base pairs is critical;
      the yield of intrastrand HT is markedly higher through (A)n compared with (T)n
      bridges, whereas HT via intrastrand pathways is more efficient than through
      interstrand pathways. Remarkably, for reactions through the same DNA bridge, over
      the same distance, and with the same driving force, HT from photoexcited Ap to G
      in the 5' to 3' direction is more efficient and less dependent on distance than
      HT from 3' to 5'. We attribute these differences in HT efficiency to variations
      in base-base coupling within the DNA assemblies. Thus base-base coupling is a
      critical parameter in DNA CT and strongly depends on subtle structural nuances of
      duplex DNA.

PMID- 12486239
TI  - Properties of linkage disequilibrium (LD) maps.
AB  - A linkage disequilibrium map is expressed in linkage disequilibrium (LD) units
      (LDU) discriminating blocks of conserved LD that have additive distances and
      locations monotonic with physical (kb) and genetic (cM) maps. There is remarkable
      agreement between LDU steps and sites of meiotic recombination in the one body of
      data informative for crossing over, and good agreement with another method that
      defines blocks without assigning an LD location to each marker. The map may be
      constructed from haplotypes or diplotypes, and efficiency estimated from the
      empirical variance of LD is substantially greater for the rho metric based on
      evolutionary theory than for the absolute correlation r, and for the LD map
      compared with its physical counterpart. The empirical variance is nearly three
      times as great for the worst alternative (r and kb map) as for the most efficient
      approach (rho and LD map). According to the empirical variances, blocks are best
      defined by zero distance between included markers. Because block size is
      algorithm-dependent and highly variable, the number of markers required for
      positional cloning is minimized by uniform spacing on the LD map, which is
      estimated to have approximately equal 1 LDU per locus, but with much variation
      among regions. No alternative representation of linkage disequilibrium (some of
      which are loosely called maps) has these properties, suggesting that LD maps are
      optimal for positional cloning of genes determining disease susceptibility.

PMID- 12486240
TI  - Analysis of chromosomal instability in human colorectal adenomas with two
      mutational hits at APC.
AB  - In vitro data show that the adenomatous polyposis coli (APC) protein associates
      with the mitotic spindle and that mouse embryonic stem cells with biallelic Apc
      mutations are karyotypically unstable. These findings led to suggestions that APC
      acts in chromosomal segregation and that APC inactivation leads to chromosomal
      instability (CIN). An alternative hypothesis based on allelic loss studies in
      colorectal adenomas proposes that CIN precedes and contributes to genetic changes
      at APC. We determined whether colorectal adenomas with two mutations at APC show
      features consistent with these models by studying 55 lesions (average size 5 mm;
      range 1-13 mm) from patients with familial adenomatous polyposis. A variety of
      methods was used depending on available material, including flow cytometry,
      comparative genomic hybridization, and loss of heterozygosity (LOH) analysis.
      Selected adenomas were assessed for proliferative activity by Ki-67
      immunocytochemistry. Seventeen of 20 (85%) tumors were diploid, two were near
      diploid, and one was hypotetraploid. Just one (near-diploid) tumor showed
      increased proliferative activity. LOH was found occasionally on chromosome 15q (2
      of 49 tumors), but not on chromosome 18q (0 of 48). In 20 adenomas, LOH at APC
      was associated with loss at 5q but not 5p markers, with the former encompassing a
      minimum of 20 Mb. However, three of these lesions analyzed by comparative genomic
      hybridization displayed normal profiles, suggesting, together with other data,
      that the mechanism of LOH at APC is probably somatic recombination. Our results
      therefore do not support the hypothesis that CIN precedes APC mutations in
      tumorigenesis. Regarding the model in which APC mutations lead directly to CIN,
      if APC mutations do have this effect in vivo, it must be subtle. Alternatively,
      CIN associated with APC mutations might be essentially an in vitro phenomenon.

PMID- 12486241
TI  - Engagement of CD160 receptor by HLA-C is a triggering mechanism used by
      circulating natural killer (NK) cells to mediate cytotoxicity.
AB  - Circulating human natural killer (NK) lymphocytes have been functionally defined
      by their ability to exert cytotoxic activity against MHC class I-negative target
      cell lines, including K562. Therefore, it was proposed that NK cells recognized
      the "missing self." We show here that the Ig-like CD160 receptor expressed by
      circulating CD56(dim+) NK cells or IL-2-deprived NK cell lines is mainly involved
      in their cytotoxic activity against K562 target cells. Further, we report that
      HLA-C molecules that are constitutively expressed by K562 trigger NK cell lysis
      through CD160 receptor engagement. In addition, we demonstrate, with recombinant
      soluble HLA-Cw3 and CD160 proteins, direct interaction of these molecules. We
      also find that CD158b inhibitory receptors partially interfere with CD160
      mediated cytotoxicity, whereas CD94CD159a and CD85j have no effect on engagement
      with their respective ligands. Thus, CD160HLA-C interaction constitutes a unique
      pathway to trigger NK cell cytotoxic activity.

PMID- 12486242
TI  - Topology of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum
      (RyR1).
AB  - To define the topology of the skeletal muscle ryanodine receptor (RyR1), enhanced
      GFP (EGFP) was fused in-frame to the C terminus of RyR1, replacing a series of C
      terminal deletions that started near the beginning or the end of predicted
      transmembrane helices M1-M10. The constructs were expressed in HEK-293 (human
      embryonic kidney cell line 293) or mouse embryonic fibroblast (MEF) cells, and
      confocal microscopy of intact and saponin-permeabilized cells was used to
      determine the subcellular location of the truncated fusion proteins. The fusion
      protein truncated after M3 exhibited uniform cytoplasmic fluorescence, which was
      lost after permeabilization, indicating that proposed M', M", M1, M2, and M3
      sequences are not membrane-associated. The fusion protein truncated at the end of
      the M4-M5 loop and containing M4 was membrane-associated. All longer truncated
      fusion proteins were also associated with intracellular membranes. Mapping by
      protease digestion and extraction of isolated microsomes demonstrated that EGFP
      positioned after either M5, the N-terminal half of M7 (M7a), or M8 was located in
      the lumen, and that EGFP positioned after either M4, M6, the C-terminal half of
      M7 (M7b), or M10 was located in the cytoplasm. These results indicate that RyR1
      contains eight transmembrane helices, organized as four hairpin loops. The first
      hairpin is likely to be made up of M4a-M4b. However, it could be made up from M3
      M4, which might form a hairpin loop even though M3 alone is not membrane
      associated. The other three hairpin loops are formed from M5-M6, M7a-M7b, and M8
      M10. M9 is not a transmembrane helix, but it might form a selectivity filter
      between M8 and M10.

PMID- 12486244
TI  - Design then mutate.

PMID- 12486243
TI  - Gene function: getting specific, generally speaking.

PMID- 12486245
TI  - Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal
      cochlear nucleus.
AB  - The dorsal cochlear nucleus integrates acoustic with multimodal sensory inputs
      from widespread areas of the brain. Multimodal inputs are brought to spiny
      dendrites of fusiform and cartwheel cells in the molecular layer by parallel
      fibers through synapses that are subject to long-term potentiation and long-term
      depression. Acoustic cues are brought to smooth dendrites of fusiform cells in
      the deep layer by auditory nerve fibers through synapses that do not show
      plasticity. Plasticity requires Ca(2+)-induced Ca(2+) release; its sensitivity to
      antagonists of N-methyl-d-aspartate and metabotropic glutamate receptors differs
      in fusiform and cartwheel cells.

PMID- 12486246
TI  - Specificity emerges in the dissection of diacylglycerol- and protein kinase C
      mediated signalling pathways.

PMID- 12486247
TI  - Revealingly odd couples.

PMID- 12486248
TI  - Increased level of hemoglobin 1 enhances survival of hypoxic stress and promotes
      early growth in Arabidopsis thaliana.
AB  - Overexpression of a class 1 Hb (GLB1) protects Arabidopsis thaliana plants from
      the effects of severe hypoxia. Overexpression of the bifunctional symbiotic Hb
      (GLB1S) from Parasponia andersonii in A. thaliana also increases survival after
      hypoxia. Plants overexpressing the Hb 1 protein, mutated to have a low oxygen
      affinity, are as susceptible to hypoxia as WT plants, suggesting that the
      protection against hypoxia depends on the ability of the Hb to bind ligands, such
      as oxygen, with high affinity. A mild hypoxia pretreatment (5%) induces the Hb
      gene and increases the survival of plants after severe hypoxic treatment (0.1%).
      These results with Hb 1 show that plant Hbs have a role other than in nitrogen
      fixing root nodules. Plants overexpressing the GLB1 protein show early vigorous
      growth in nonhypoxic conditions and are 50% larger in weight than the controls at
      14 days. The constitutive expression of GLB1 also resulted in a reduced number of
      root hairs and increased number of laterals in the root system.

PMID- 12486249
TI  - Intrinsic susceptibility of mouse trophoblasts to natural killer cell-mediated
      attack in vivo.
AB  - Protecting the fetus and placenta from the maternal immune system has long been
      considered a function of placental trophoblasts. Here, we present two related
      lines of evidence that contradict this assumption. First, we show that
      transformed mouse trophoblast cell lines akin to human choriocarcinomas form
      tumors in syngeneic and immunodeficient mice, yet are rejected in immunocompetent
      allogeneic mice. Second, we show that wild-type trophoblasts are rapidly killed
      after i.v. injection into allogeneic mice. In both cases, the pattern of
      trophoblast killing in different strains of immunodeficient mice indicated that
      rejection involved host natural killer cells, and this was corroborated by in
      vitro killing assays. The apparent intrinsic susceptibility of mouse trophoblasts
      to immune attack strongly suggests that it is instead some property of the
      pregnant uterus that is of primary importance in preventing rejection of the
      fetus.

PMID- 12486250
TI  - Autoantibodies against alpha -MSH, ACTH, and LHRH in anorexia and bulimia nervosa
      patients.
AB  - The hypothalamic arcuate nucleus is involved in the control of energy intake and
      expenditure and may participate in the pathogenesis of eating disorders such as
      anorexia nervosa (AN) and bulimia nervosa (BN). Two systems are of particular
      interest in this respect, synthesizing alpha-melanocyte-stimulating hormone
      (alpha-MSH) and synthesizing neuropeptide Y, respectively. We report here that 42
      of 57 (74%) AN andor BN patients studied had in their plasma Abs that bind to
      melanotropes andor corticotropes in the rat pituitary. Among these sera, 8 were
      found to bind selectively to alpha-MSH-positive neurons and their hypothalamic
      and extrahypothalamic projections as revealed with immunostaining on rat brain
      sections. Adsorption of these sera with alpha-MSH peptide abolished this
      immunostaining. In the pituitary, the immunostaining was blocked by adsorption
      with alpha-MSH or adrenocorticotropic hormone. Additionally, 3 ANBN sera bound to
      luteinizing hormone-releasing hormone (LHRH)-positive terminals in the rat median
      eminence, but only 2 of them were adsorbed with LHRH. In the control subjects, 2
      of 13 sera (16%) displayed similar to ANBN staining. These data provide evidence
      that a significant subpopulation of ANBN patients have autoantibodies that bind
      to alpha-MSH or adrenocorticotropic hormone, a finding pointing also to
      involvement of the stress axis. It remains to be established whether these Abs
      interfere with normal signal transduction in the brain melanocortin circuitryLHRH
      system andor in other central and peripheral sites relevant to food intake
      regulation, to what extent such effects are related to andor could be involved in
      the pathophysiology or clinical presentation of ANBN, and to what extent
      increased stress is an important factor for production of these autoantibodies.

PMID- 12486251
TI  - Imaging direct, dynamin-dependent recapture of fusing secretory granules on
      plasma membrane lawns from PC12 cells.
AB  - During exocytosis, secretory granules fuse with the plasma membrane and discharge
      their content into the extracellular space. The exocytosed membrane is then
      reinternalized in a coordinated fashion. A role of clathrin-coated vesicles in
      this process is well established, whereas the involvement of a direct retrieval
      mechanism (often called kiss and run) is still debated. Here we report that a
      significant population of docked secretory granules in the neuroendocrine cell
      line PC12 fuses with the plasma membrane, takes up fluid-phase markers, and is
      retrieved at the same position. Fusion allows for complete discharge of small
      molecules, whereas GFP-labeled neuropeptide Y (molecular mass approximately equal
      35 kDa) is only partially released. Retrieved granules were preferentially
      associated with dynamin. Furthermore, recapture is inhibited by guanosine 5'
      [gamma-thio]triphosphate and peptides known to block dynamin function. We
      conclude that secretory granules can be recaptured immediately after formation of
      an exocytotic opening by an endocytic reaction that is spatially and temporally
      coupled to soluble N-ethylmaleimide-sensitive factor attachment protein receptor
      (SNARE)-dependent fusion, but is not a reversal of the fusion reaction.

PMID- 12486253
TI  - Drug treatments for eye movement disorders.

PMID- 12486252
TI  - Sensitization of regulated exocytosis by protein kinase C.
AB  - Activation of protein kinase C (PKC) increases vesicular secretion in many cell
      types. We determined the calcium dependence of secretion and the size of the
      readily releasable pool of secretory granules in pituitary gonadotropes by
      photorelease of caged-calcium. The calcium affinity for exocytosis was roughly
      doubled by activation of PKC by a phorbol ester, whereas the size of the readily
      releasable pool was not greatly increased. The effect was due to activation of
      PKC, because it was blocked by a PKC inhibitor and was not mimicked by an
      inactive phorbol ester analogue. A similar increase in calcium sensitivity was
      induced by preincubation with gonadotropin-releasing hormone, the physiological
      releasing hormone. These findings provide direct evidence for physiological
      regulation of secretion by enhancement of Ca2+-sensing steps. Because exocytosis
      depends on the third- to fourth-power of intracellular free Ca2+ concentration,
      this mechanism ensures a powerful up-regulation of hormone release and may
      explain how PKC can stimulate exocytosis without an increase of Ca2+ above the
      resting level.

PMID- 12486254
TI  - Assessment of health needs in multidisciplinary care.

PMID- 12486255
TI  - Blood-brain barrier permeability in type II diabetes.

PMID- 12486256
TI  - Spontaneous retinal venous pulsation: aetiology and significance.
AB  - Spontaneous retinal venous pulsation is seen as a subtle variation in the calibre
      of the retinal vein(s) as they cross the optic disc. The physical principles
      behind the venous pulsations has been the point of much debate. Initial theories
      suggested that the pulsation occurred because of the rise in intraocular pressure
      in the eye with the pulse pressure. This article presents an argument that this
      is not the case. The pulsations are in fact caused by variation in the pressure
      gradient along the retinal vein as it traverses the lamina cribrosa. The pressure
      gradient varies because of the difference in the pulse pressure between the
      intraocular space and the cerebrospinal fluid. The importance of this is that as
      the intracranial pressure rises the intracranial pulse pressure rises to equal
      the intraocular pulse pressure and the spontaneous venous pulsations cease. Thus
      it is shown that cessation of the spontaneous venous pulsation is a sensitive
      marker of raised intracranial pressure. The article discusses the specificity of
      the absence of spontaneous venous pulsation and describes how the patient should
      be examined to best elicit this important sign.

PMID- 12486257
TI  - Hans Berger (1873-1941), Richard Caton (1842-1926), and electroencephalography.

PMID- 12486258
TI  - Internet resources for psychiatry and neuropsychiatry.

PMID- 12486259
TI  - Constipation in neurological diseases.

PMID- 12486260
TI  - The INTERMED: a screening instrument to identify multiple sclerosis patients in
      need of multidisciplinary treatment.
AB  - OBJECTIVE: To analyse the value of the INTERMED, a screening instrument to assess
      case complexity, compared with the Expanded Disability Status Scale (EDSS) and
      the Guy's Neurological Disability Scale (GNDS) to identify multiple sclerosis
      (MS) patients in need of multidisciplinary treatment. METHODS: One hundred MS
      patients underwent INTERMED, EDSS, and GNDS examinations. Patient care needs were
      assessed by a multidisciplinary team and a goal oriented treatment plan was
      defined. Correlations between INTERMED, individual INTERMED domains, EDSS, GNDS
      sum score, and total number of proposed disciplines involved in the treatment
      plan were studied. RESULTS: Mean (SD) age was 40.6 (10.1) years. Median scores
      were 14.0 for the INTERMED, 4.0 for the EDSS, and 13.5 for the GNDS sum score.
      Moderate correlations were found between the INTERMED sum score and EDSS (r=0.59)
      and GNDS sum score (r=0.60). The number of disciplines as proposed by the
      multidisciplinary team showed the highest statistically significant correlation
      with the INTERMED sum score (r=0.41) compared with EDSS (r=0.32) and GNDS sum
      score (r=0.34). No significant or only weak correlations were found between the
      psychological domain of the INTERMED and EDSS or GNDS. CONCLUSION: The findings
      in this study show that there is an additional value of the INTERMED compared
      with the EDSS and GNDS in identifying MS patients in need of multidisciplinary
      treatment. The INTERMED domains show the area of the patient's vulnerability and
      care needs: especially the INTERMED's psychological and social domains may guide
      the clinician to deal with specific problems that complicate healthcare delivery.

PMID- 12486261
TI  - Multiple sclerosis in Finland: incidence trends and differences in relapsing
      remitting and primary progressive disease courses.
AB  - OBJECTIVE: To compare the secular trends and geographical differences in the
      incidence of relapsing-remitting (RRMS) and primary progressive multiple
      sclerosis (PPMS) in Finland, and to draw inferences about aetiological
      differences between the two forms of the disease. METHODS: New multiple sclerosis
      cases in southern Uusimaa and the western districts Vaasa and Seinajoki of
      Finland in 1979-1993 were verified from hospital records and classified into RRMS
      and PPMS. Patients met the Poser criteria for definite multiple sclerosis or
      otherwise satisfied the criteria for PPMS. Disease course was categorised by the
      same neurologist. Crude and age adjusted incidence in 1979-1993 was estimated.
      RESULTS: During 1979-1993 the age adjusted incidence was 5.1 per 100 000 person
      years in Uusimaa, 5.2 in Vaasa, and 11.6 in Seinajoki. The rates in Uusimaa
      remained stable, while a decrease occurred in Vaasa and an increase in Seinajoki.
      Between 1979-86 and 1987-93 the incidence of PPMS increased in Seinajoki from 2.6
      to 3.7 per 10(5) and decreased in Vaasa from 1.9 to 0.2 per 10(5); the trends
      were similar for RRMS. CONCLUSIONS: There are significant differences in secular
      trends for multiple sclerosis incidence in Finland by geographical area, but
      these are similar for PPMS and RRMS. The recent changes point to locally acting
      environmental factors. The parallel incidence trends for RRMS and PPMS suggest
      similar environmental triggers for the two clinical presentations of multiple
      sclerosis.

PMID- 12486262
TI  - Incidence (1988-97) and prevalence (1997) of multiple sclerosis in Vasterbotten
      County in northern Sweden.
AB  - OBJECTIVE: To investigate the incidence and prevalence of multiple sclerosis in
      Vasterbotten County in northern Sweden. METHODS: Multiple sources were used in
      the case identification process. Follow up interviews with clinical examinations
      were undertaken and, when indicated, additional paraclinical investigations were
      done. In this way case ascertainment was assured and supplemental clinical data
      were collected. The incidence rate was based on symptom onset. Onset adjusted
      prevalence was applied. RESULTS: The crude incidence rate of multiple sclerosis
      in 1988-97 in Vasterbotten County was 5.2/10(5) (95% confidence interval, 4.4 to
      6.2): 6.7/10(5) (6.0 to 8.3) in women and 3.7/10(5) (2.7 to 4.9) in men. The
      onset adjusted prevalence for 31 December 1997 was 154/10(5) (139 to 170):
      202/10(5) (179 to 228) in women and 105/10(5) (89 to 125) in men. When compared
      with a previous estimate of prevalence, a yearly 2.6% increase in prevalence
      between 1990 and 1997 was found, mainly attributable to a higher incidence than
      mortality. CONCLUSIONS: The present incidence rate and prevalence confirms
      earlier findings that Vasterbotten is a high risk area for multiple sclerosis.
      The adjusted incidence was twice as high as the incidence from 1974-88 in the
      only previous Swedish population based study from Goteborg, but comparable with
      other recent Fennoscandian multiple sclerosis incidence rates.

PMID- 12486263
TI  - Thalamic proton magnetic resonance spectroscopy in vegetative state induced by
      traumatic brain injury.
AB  - OBJECTIVES: To determine whether proton magnetic resonance spectroscopy (MRS), a
      newer radiographic technology, would be useful in the evaluation of the thalamus
      of patients in vegetative states resulting from traumatic brain injury. METHODS:
      14 victims of severe traumatic brain injury who were in the vegetative state and
      whose magnetic resonance images of the thalamus were normal underwent bilateral
      thalamic proton (MRS) studies. The N-acetyl aspartate to creatine (NAA:Cr) and
      choline to creatine (Cho:Cr) ratios were obtained for each patient. The proton
      thalamic MRS findings of patients who were in a persistent vegetative state (n =
      8) and in patients who had regained awareness after being in the vegetative state
      (n = 6) were compared with proton thalamic MRS findings in five healthy
      volunteers. RESULTS: While conventional magnetic resonance imaging suggested that
      each patient had a normal thalamus, proton MRS indicated that the thalamus of
      each patient in the series was damaged. The NAA:Cr ratio was significantly lower
      in the thalami of both the patients who remained in a persistent vegetative state
      for the duration of the study and in those who regained awareness after being in
      the vegetative state (p < 0.001). In addition, NAA:Cr ratios were lower in the
      group of patients who remained in a persistent vegetative state than in the group
      of patients who regained awareness after being in the vegetative state (p <
      0.001). CONCLUSIONS: Results suggest that the NAA:Cr ratio within the thalamus is
      significant and that thalamic MRS may be helpful when attempting to determine the
      degree of severity of neuronal and axonal injury in patients in the vegetative
      state.

PMID- 12486264
TI  - Outcome after mild traumatic brain injury: an examination of recruitment bias.
AB  - OBJECTIVES: Research concerning the natural history after mild traumatic brain
      injury (TBI) faces a number of methodological challenges, including those related
      to subject recruitment. The aim of this study was to determine whether subjects
      who agree to participate in longitudinal research differ from those who do not.
      The presence of identifiable, selective factors operating during recruitment may
      be an important source of systematic bias. In Canada, given the presence of
      universal healthcare coverage, this issue can be examined using population based,
      administrative databases to obtain information about a cohort that was approached
      for study enrollment, regardless of whether they ultimately agreed to
      participate. METHODS: A sample of 626 consecutive patients with mild TBI was
      invited to enroll in TBI outcome research. Those who agreed to participate
      (n=272) were compared with those who refused (n=354) on demographic, past health,
      and injury related variables. Thereafter, using encrypted health card data, the
      two groups were contrasted with respect to pre-injury and post-injury healthcare
      utilisation. RESULTS: No premorbid differences between the groups emerged.
      However, all early indices of TBI severity were significantly worse for the
      participants group (p<0.001). Consistent with these findings, healthcare
      utilisation rates were no different before injury, but were significantly
      increased after injury for the participants (p<0.001), even beyond the period of
      study enrollment (p<0.001). Differences remained even after controlling for those
      with significant non-TBI injuries. CONCLUSIONS: Premorbid factors did not predict
      whether patients comply with, or refuse study participation. However, the
      participants group was biased toward those with more significant injuries, which
      translated into higher rates of healthcare utilisation after injury. These
      results strike a cautionary note, given the apparent systematic bias influencing
      enrollment in longitudinal studies of mild TBI.

PMID- 12486265
TI  - fMRI studies of associative encoding in young and elderly controls and mild
      Alzheimer's disease.
AB  - OBJECTIVE: To examine alterations in patterns of brain activation seen in normal
      aging and in mild Alzheimer's disease by functional magnetic resonance imaging
      (fMRI) during an associative encoding task. METHODS: 10 young controls, 10
      elderly controls, and seven patients with mild Alzheimer's disease were studied
      using fMRI during a face-name association encoding task. The fMRI paradigm used a
      block design with three conditions: novel face-name pairs, repeated face-name
      pairs, and visual fixation. RESULTS: The young and elderly controls differed
      primarily in the pattern of activation seen in prefrontal and parietal cortices:
      elderly controls showed significantly less activation in both superior and
      inferior prefrontal cortices but greater activation in parietal regions than
      younger controls during the encoding of novel face-name pairs. Compared with
      elderly controls, the Alzheimer patients showed significantly less activation in
      the hippocampal formation but greater activation in the medial parietal and
      posterior cingulate regions. CONCLUSIONS: The pattern of fMRI activation during
      the encoding of novel associations is differentially altered in the early stages
      of Alzheimer's disease compared with normal aging.

PMID- 12486266
TI  - Persistent abnormality detected in the non-ictal electroencephalogram in primary
      generalised epilepsy.
AB  - OBJECTIVES: Gamma oscillations (30-100 Hz gamma electroencephalographic (EEG)
      activity) correlate with high frequency synchronous rhythmic bursting in
      assemblies of cerebral neurons participating in aspects of consciousness.
      Previous studies in a kainic acid animal model of epilepsy revealed increased
      intensity of gamma rhythms in background EEG preceding epileptiform discharges,
      leading the authors to test for intensified gamma EEG in humans with epilepsy.
      METHODS: 64 channel cortical EEG were recorded from 10 people with primary
      generalised epilepsy, 11 with partial epilepsy, and 20 controls during a
      quiescent mental state. Using standard methods of EEG analysis the strength of
      EEG rhythms (fast Fourier transformation) was quantified and the strengths of
      rhythms in the patient groups compared with with controls by unpaired t test at 1
      Hz intervals from 1 Hz to 100 Hz. RESULTS: In patients with generalised epilepsy,
      there was a threefold to sevenfold increase in power of gamma EEG between 30 Hz
      and 100 Hz (p<0.01). Analysis of three unmedicated patients with primary
      generalised epilepsies revealed an additional 10-fold narrow band increase of
      power around 35 Hz-40 Hz (p<0.0001). There were no corresponding changes in
      patients with partial epilepsy. CONCLUSIONS: Increased gamma EEG is probably a
      marker of the underlying ion channel or neurotransmitter receptor dysfunction in
      primary generalised epilepsies and may also be a pathophysiological prerequisite
      for the development of seizures. The finding provides a new diagnostic approach
      and also links the pathophysiology of generalised epilepsies to emerging concepts
      of neuronal correlates of consciousness.

PMID- 12486267
TI  - Autonomic nervous system testing may not distinguish multiple system atrophy from
      Parkinson's disease.
AB  - BACKGROUND: Formal laboratory testing of autonomic function is reported to
      distinguish between patients with Parkinson's disease and those with multiple
      system atrophy (MSA), but such studies segregate patients according to clinical
      criteria that select those with autonomic dysfunction for the MSA category.
      OBJECTIVE: To characterise the profiles of autonomic disturbances in patients in
      whom the diagnosis of Parkinson's disease or MSA used criteria other than
      autonomic dysfunction. METHODS: 47 patients with parkinsonism and autonomic
      symptoms who had undergone autonomic laboratory testing were identified and their
      case records reviewed for non-autonomic features. They were classified clinically
      into three diagnostic groups: Parkinson's disease (19), MSA (14), and uncertain
      (14). The performance of the patients with Parkinson's disease was compared with
      that of the MSA patients on five autonomic tests: RR variation on deep breathing,
      heart rate changes with the Valsalva manoeuvre, tilt table testing, the sudomotor
      axon reflex test, and thermoregulatory sweat testing. RESULTS: None of the tests
      distinguished one group from the other with any statistical significance, alone
      or in combination. Parkinson's disease and MSA patients showed similar patterns
      of autonomic dysfunction on formal testing of cardiac sympathetic and
      parasympathetic, vasomotor, and central and peripheral sudomotor functions.
      CONCLUSIONS: This study supports the clinical observation that Parkinson's
      disease is often indistinguishable from MSA when it involves the autonomic
      nervous system. The clinical combination of parkinsonism and dysautonomia is as
      likely to be caused by Parkinson's disease as by MSA. Current clinical criteria
      for Parkinson's disease and MSA that direct patients with dysautonomia into the
      MSA group may be inappropriate.

PMID- 12486268
TI  - Loss of spatial learning in a patient with topographical disorientation in new
      environments.
AB  - The case is described of a patient who, following cerebral hypoxia, developed
      severe difficulty in orienting himself in new environments in the context of a
      mild global amnesic syndrome. Some episodes he related suggested that his main
      difficulty was remembering the spatial/directional value of landmarks he
      recognised. A neuroradiological examination documented severe bilateral atrophy
      of the hippocampi associated with atrophic changes in the cerebral hemispheres,
      most marked in the dorsal regions. Neuropsychological and experimental evaluation
      showed a severe deficit of spatial learning with substantially preserved ability
      to learn verbal and visual-object information. He was also virtually unable to
      learn a route in a maze task based exclusively on spatial data, but the
      availability of visual cues substantially improved his learning. Finally, he
      performed within normal limits on various tests investigating knowledge acquired
      premorbidly regarding famous buildings, routes in the town he had been living in
      since childhood, and geography. Topographical disorientation may be subtended by
      a specific difficulty in storing the spatial/directional value of visual
      landmarks in novel environments. The hippocampus appears to be involved in the
      acquisition of new topographical spatial knowledge.

PMID- 12486269
TI  - Increased blood-brain barrier permeability in type II diabetes demonstrated by
      gadolinium magnetic resonance imaging.
AB  - OBJECTIVES: Patients with type II diabetes are at increased risk of cognitive
      impairment. The retinal and renal complications of diabetes follow microvascular
      damage permitting small arterioles to leak, hence the cerebral damage might also
      follow loss of blood-brain barrier (BBB) integrity. Magnetic resonance (MR) brain
      imaging with intravenous gadolinium (Gd) diethylenetriamine pentaacetic acid (Gd
      DTPA) was used to identify increased BBB permeability. METHODS: Ten well
      controlled type II diabetic patients aged 65-70 years and 10 controls underwent
      MR brain imaging with fluid attenuated inversion recovery (FLAIR); T1 weighted
      (T1W) volumetric imaging before; and T1W volumetric imaging at 5, 15, 30, 45, 60,
      and 90 minutes after intravenous Gd-DTPA. The T1W image before Gd-DTPA was
      subtracted from the images at each time point after Gd-DTPA. Net signal intensity
      was plotted against time for different brain regions. White matter
      hyperintensities were scored from the FLAIR image. RESULTS: The signal
      intensity/time curves showed that brain signal intensity increased more in the
      diabetic group than controls during the first 15 minutes after Gd-DTPA,
      particularly in the basal ganglia (p=0.018). Signal intensity in controls peaked
      at five minutes and diabetics at 15 minutes. Subjects with more white matter
      hyperintensities had greater signal increase after Gd-DTPA, whether diabetic or
      not (p=0.001). CONCLUSIONS: Increased BBB permeability with MR imaging was
      detected in patients with type II diabetes or white matter hyperintensities.
      Increased permeability of the BBB might account for some of the cerebral effects
      of type II diabetes, and so possibly also for the effect of other conditions that
      affect the microvasculature (like hypertension), on the brain.

PMID- 12486270
TI  - Willis on narcolepsy.

PMID- 12486271
TI  - The impact of delays in computed tomography of the brain on the accuracy of
      diagnosis and subsequent management in patients with minor stroke.
AB  - OBJECTIVES: To determine the proportion of haemorrhagic strokes misdiagnosed as
      infarcts on computed tomography (CT) in patients with mild stroke, and the
      implications for health care. METHODS: Patients with mild stroke presenting as
      inpatients or outpatients four or more days after stroke to our stroke service
      (catchment population 500 000) were recruited prospectively. They underwent
      detailed clinical examination and brain imaging with CT and magnetic resonance
      imaging (MRI) on the day of presentation. CT and MR images were examined
      independently to identify infarct, primary intracerebral haemorrhage,
      haemorrhagic transformation, or non-vascular lesion. RESULTS: In 228 patients
      with mild stroke (median time from stroke to scan 20 days), primary intracerebral
      haemorrhage was identified by CT in two patients (0.9%; 95% confidence interval
      (CI), 0.1% to 3.1%) and MRI in eight (3.5%; 1.5% to 6.8%). Haemorrhagic
      transformation was identified by CT in three patients (1.3%; 0.1% to 5.6%) and
      MRI in 15 (6.6%; 3.7% to 10.6%). The earliest time primary intracerebral
      haemorrhage was not identified on CT was 11 days. CONCLUSIONS: CT failed to
      identify 75% of primary intracerebral haemorrhages, equivalent to 24 patients per
      1000 (95% CI, 14 to 37) with mild strokes. To detect haemorrhages reliably, CT
      would need to have been performed within about eight days. Rapid access to
      neurovascular clinics with same day CT brain imaging is required to avoid
      inappropriate secondary prevention. Increased public awareness of the need to
      seek urgent medical attention after stroke should be encouraged. MRI should be
      considered in late presenting patients.

PMID- 12486272
TI  - Application of time-frequency analysis to somatosensory evoked potential for
      intraoperative spinal cord monitoring.
AB  - OBJECTIVE: To investigate the improvement in the reliability of intraoperative
      spinal cord monitoring by applying time-frequency analysis to somatosensory
      evoked potentials (SEP). METHODS: 34 patients undergoing scoliosis surgery were
      studied. SEP were recorded during different stages of scoliosis surgery. Averaged
      SEP signals were analysed intraoperatively by short time Fourier transform
      (STFT). The time-frequency characteristics of SEP were observed during surgery.
      The main peak in the time-frequency interpretation of SEP was measured in peak
      time, peak frequency, and peak power. The changes in these variables were
      compared with the changes in latency and amplitude during different surgical
      stages. RESULTS: During different surgical stages, changes in peak times and peak
      powers were found to correlate with the changes in latency and amplitude,
      respectively. Peak time showed more variability than latency (p < 0.01), while
      peak power showed less variability than amplitude (p < 0.01). The peak frequency
      of SEP appeared to be unchanged during surgery. SEP signals were found to have
      specific time-frequency characteristics, with the time-frequency distribution of
      the signals being located in a particular time-frequency space. CONCLUSIONS: Time
      frequency analysis of SEP waveforms reveals stable and easily identifiable
      characteristics. Peak power is recommended as a more reliable monitoring
      parameter than amplitude, while peak time monitoring was not superior to latency
      measurement. Applying time-frequency analysis to SEP can improve the reliability
      of intraoperative spinal cord monitoring.

PMID- 12486273
TI  - Radiofrequency neurotomy for the treatment of third occipital headache.
AB  - OBJECTIVE: To evaluate the efficacy of a revised technique of percutaneous
      radiofrequency neurotomy for third occipital headache. METHODS: The revisions
      included using a large gauge electrode, ensuring minimum separation between the
      three electrode placements, and holding the electrode in place by hand. The
      revised technique was used to treat 51 nerves in 49 patients diagnosed as
      suffering from third occipital headache on the basis of controlled diagnostic
      blocks of the third occipital nerve. The criteria for successful outcome were
      complete relief of pain for at least 90 days associated with restoration of
      normal activities of daily living, and no use of drug treatment for the headache.
      RESULTS: Of the 49 patients, 43 (88%) achieved a successful outcome. The median
      duration of relief in these patients was 297 days, with eight patients continuing
      to have ongoing relief. Fourteen patients underwent a repeat neurotomy to
      reinstate relief, with 12 (86%) achieving a successful outcome. The median
      duration of relief in these patients was 217 days, with six patients having
      ongoing relief. Side effects of the procedure were consistent with coagulation of
      the third occipital nerve and consisted of slight ataxia, numbness, and temporary
      dysaesthesia. No side effects required intervention, and they were tolerated by
      the patients in exchange for the relief of headache. CONCLUSIONS: Use of the
      revised procedure greatly improved the rather low success rate previously
      encountered with third occipital neurotomy. Although the relief of headache is
      limited in duration, it is profound and can be reinstated by repeat neurotomy. No
      other form of treatment has been validated for this common form of headache.

PMID- 12486275
TI  - Brain white matter lesions detected by magnetic resonance [correction of
      resosnance] imaging are associated with balance and gait speed.
AB  - OBJECTIVE: To investigate the relations between premorbid and current mental
      ability, mood, and white matter signal abnormalities detected by T2 weighted
      brain magnetic resonance imaging (MRI) and impairment of balance and mobility in
      older adults. METHODS: 97 subjects from the Aberdeen 1921 birth cohort underwent
      brain MRI, evaluation of balance, and measurement of gait speed. White matter
      hyperintensities detected on T2 weighted MRI scans were rated by three
      independent raters on three variables: white matter lesions; periventricular
      lesions; and brain stem lesions. RESULTS: Decreased gait speed was correlated
      with impaired visual acuity (p = 0.020), shorter stature (p = 0.008), a lower
      childhood IQ (p = 0.030), a lower current Raven's progressive matrices score
      (Raven score) (p < 0.001), a higher hospital anxiety and depression scale (HADS)
      score (p = 0.004), and an increased grade of brain stem lesions on MRI. Inability
      to balance was correlated with Raven score (p = 0.042), brain stem lesions (p =
      0.003), white matter lesions (p = 0.003), and periventricular lesions (p =
      0.038). Binary logistic regression identified brain stem lesions (odds ratio (OR)
      0.22; 95% confidence interval 0.09 to 0.54) and HADS depression score (OR 0.75;
      0.58 to 0.97) as the only significant associations with balance. Structural
      equation modelling detected an association between two latent traits representing
      white matter disease and an integrating function, respectively. CONCLUSIONS: In
      this cohort, white matter lesions, periventricular lesions, and brain stem
      lesions were associated with impaired balance. Current mental ability was
      strongly related to gait speed. There appears to be a concordance between motor
      skills and intellect in old age, which is degraded by white matter disease.

PMID- 12486277
TI  - Coexistent cerebral metastasis and cavernous malformation.

PMID- 12486276
TI  - Connecting impairment, disability, and handicap in immune mediated
      polyneuropathies.
AB  - BACKGROUND: In the World Health Organisation (WHO) International Classification
      of Impairments, Disabilities, and Handicaps (ICIDH), it is suggested that various
      levels of outcome are associated with one another. However, the ICIDH has been
      criticised on the grounds that it only represents a general, non-specific
      relation between its entities. OBJECTIVE: To examine the significance of the
      ICIDH in immune mediated polyneuropathies. METHODS: Four impairment measures
      (fatigue severity scale, MRC sum score, "INCAT" sensory sum score, grip strength
      with the Vigorimeter), five disability scales (nine hole peg test, 10 metres
      walking test, an overall disability sum score (ODSS), Hughes functional grading
      scale, Rankin scale), and a handicap scale (Rotterdam nine items handicap scale
      (RIHS9)) were assessed in 113 clinically stable patients (83 with Guillain-Barre
      syndrome, 22 with chronic inflammatory demyelinating polyneuropathy, eight with a
      gammopathy related polyneuropathy). Regression analyses with backward and forward
      stepwise strategies were undertaken to determine the correlation between the
      various levels of outcome (impairment on disability, impairment on handicap,
      disability leading to handicap, and impairment plus disability on handicap).
      RESULTS: Impairment measures explained a substantial part of disability (R(2) =
      0.64) and about half of the variance in handicap (R(2) = 0.52). Disability
      measures showed a stronger association with handicap (R(2) = 0.76). Combining
      impairment and disability scales accounted for 77% of the variance in handicap
      (RIHS9) scores. CONCLUSIONS: In contrast to some suggestions, support for the
      ICIDH model is found in the current study because significant associations were
      shown between its various levels in patients with immune mediated
      polyneuropathies. Further studies are required to examine other possible
      contributors to deficits in daily life and social functioning in these
      conditions.

PMID- 12486278
TI  - A case of frontal network amnesia.
AB  - A 63 year old man developed an amnesic syndrome coupled with an array of "frontal
      lobe" signs after bilateral small subcortical infarcts. His amnesia was
      characterised by severe difficulty in voluntary recall of recently memorised
      verbal and non-verbal materials, while his recognition for the same materials was
      less affected. The symptoms remained unimproved at a follow up evaluation eight
      months after onset. Magnetic resonance imaging showed two small circumscribed
      lesions, one in the dorsomedial nucleus of the left thalamus and the other in a
      region of the right globus pallidus and anterior limb of the right internal
      capsule. The mammillothalamic tracts and anterior nuclei of the thalami were
      clearly spared bilaterally. The left dorsomedial nucleus lesion disrupted the
      thalamofrontal circuit, while the anterior limb lesion of the right internal
      capsule disconnected the same circuit by damaging part of the anterior thalamic
      radiation. Thus the amnesia in this patient may have been caused by disruption of
      the bilateral thalamofrontal circuits. This type of amnesic pathology should be
      separated from more conventional types of amnesia that are produced by disruption
      of the so called Papez circuit or the Delay-Brion memory system.

PMID- 12486279
TI  - Limbic encephalitis presenting with topographical disorientation and amnesia.
AB  - A case of paraneoplastic limbic encephalitis presenting with topographical
      disorientation is reported. A 70 year old woman became unable to identify
      familiar buildings and landscapes and could not recall the way to destinations
      she had known very well for years. She also showed attentional disturbance and
      severe anterograde amnesia. Her retrograde amnesia extended for one year at most.
      No other neuropsychological deficits were noted. Thus her topographical
      disorientation was of the primary form. Specific tests related to topographical
      disorientation showed that her two main symptoms seem to fall into the categories
      of landscape agnosia and heading disorientation. T2 weighted magnetic resonance
      imaging revealed high intensity signals in the anteromedial temporal lobes
      bilaterally, in the right posterior parahippocampal gyrus, in the right
      retrosplenial region, and in the right inferior precuneus. Anti-Hu antibody was
      found in the serum. This case shows that topographical disorientation can be a
      primary symptom of limbic encephalitis.

PMID- 12486280
TI  - Brain acetylcholinesterase activity in mild cognitive impairment and early
      Alzheimer's disease.
AB  - OBJECTIVE: Brain acetylcholinesterase activity was determined in healthy controls
      and in patients with mild cognitive impairment and early Alzheimer's disease.
      METHODS: A specific acetylcholinesterase tracer, [methyl-(11)C]N-methyl-piperidyl
      4-acetate ([(11)C]MP4A), and a three dimensional PET system with magnetic
      resonance coregistration were used for imaging. RESULTS: There was a significant
      difference in the acetylcholinesterase activity in the hippocampus between the
      groups (p = 0.03), the mean (SD) acetylcholinesterase activity (k(3) values, min(
      1)) being 0.114 (0.036) in controls, 0.098 (0.023) in mild cognitive impairment,
      and 0.085 (0.022) in Alzheimer's disease. The mini-mental state examination score
      showed no significant relation with acetylcholinesterase activity in any brain
      area in the combined mild cognitive impairment/Alzheimer group. CONCLUSIONS:
      Hippocampal acetylcholinesterase activity is only slightly reduced in mild
      cognitive impairment and early Alzheimer's disease and so the value of in vivo
      acetylcholinesterase measurements in detecting the early Alzheimer process is
      limited.

PMID- 12486281
TI  - Retinotopic modulation of space misrepresentation in unilateral neglect: evidence
      from quadrantanopia.
AB  - A patient with right sided brain damage suffered contralesional neglect, inferior
      quadrantanopia (with 0 degrees sparing in the left eye and 13 degrees sparing in
      the right), and a visual field restriction (to 15 degrees ) in the upper
      contralesional quadrant of the left eye. In binocular vision, the patient showed
      underestimation of the horizontal size of contralesional line segments unless
      cued to localise their end points. When asked to reproduce, in monocular vision,
      10 degrees and 20 degrees distances between two attentionally cued end points
      lying on the frontal vertical plane, the patient showed relative contralesional
      overextension and ipselesional underextension along the directions falling within
      the blind sectors of the neglected space. No asymmetry was present along the
      directions falling within the seeing sectors of the same space. These findings
      suggest precise retinotopic modulation of space misrepresentation in unilateral
      neglect.

PMID- 12486282
TI  - Behavioural abnormalities contribute to functional decline in Huntington's
      disease.
AB  - The independent and relative contributions of motor, cognitive, and behavioural
      deficits to functional decline in patients with Huntington's disease are
      examined. Twenty two patients with Huntington's disease were assessed with rating
      scales for motor dysfunction, cognitive measures of executive functions, and
      behavioural measures of apathy, executive dysfunction, and disinhibition. Their
      functional status was assessed with informant based and clinician based ratings
      of activities of daily living (ADL). A composite apathy/executive dysfunction
      behavioural index was strongly related to decline in ADL independently and after
      controlling for motor and cognitive deficits. These results suggest that
      behavioural dysfunction contributes to functional decline in patients with
      Huntington's disease and may impede their ability to utilise motor or cognitive
      skills that remain available in the early stages of the disease.

PMID- 12486283
TI  - Interferon gamma and interleukin 4 producing T cells in peripheral blood of
      multiple sclerosis patients undergoing immunomodulatory treatment.
AB  - Intracellular cytokine flow cytometry was used to analyse the percentages of
      interferon (IFN) gamma and interleukin (IL)-4 producing T cells in the peripheral
      blood of multiple sclerosis patients, before and after immunomodulatory
      treatment, and of healthy controls. After six months of treatment, different
      doses of IFN beta1a (Avonex or Rebif) decreased CD4+ (Th1, Th2) and CD8+ (Tc1)
      cells to a similar extent, without affecting the Th1/Th2 ratio. These T cell
      subsets were unmodified after nine months of glatiramer acetate (Copaxone)
      treatment, and after six day courses of high dose 6-methylprednisolone. The data
      suggest that IFN beta1a produces sustained downmodulation of IFN gamma and IL-4
      producing T cells in vivo, which may contribute to its therapeutic efficacy; that
      glatiramer acetate possibly acts without altering non-specific cellular immunity;
      and that glucocorticoid induced lymphocytopenia does not affect the percentages
      of Th1, Th2, and Tc1 cells; at least in the periphery, none of the treatments
      caused a Th1 to Th2 shift that could account for their respective therapeutic
      effects.

PMID- 12486284
TI  - Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia.
AB  - The discovery that hypocretins are involved in narcolepsy, a disorder associated
      with excessive daytime sleepiness, cataplexy, and unusually rapid transitions to
      rapid eye movement sleep, opens a new field of investigation in the area of
      disorders of sleep and activation. Hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt
      2) (also called orexin-A and orexin-B) are newly discovered neuropeptides
      processed from a common precursor. Hypocretin containing cells are located
      exclusively in the lateral hypothalamus, with widespread projections within the
      central nervous system. The role of the hypocretin system in other disorders
      causing excessive daytime sleepiness is more uncertain. This study reports the
      findings of a prospective study measuring cerebrospinal fluid concentrations of
      hypocretin-1 and hypocretin-2 in HLA DQB1*0602 positive narcolepsy with
      cataplexy, monosymptomatic narcolepsy, and primary hypersomnia. The results
      confirmed the previous observations, that hcrt-1 is deficient in narcolepsy and
      for the first time report very low levels of hcrt-1 in primary hypersomnia. It is
      also reported for the first time that there is a generalised defect in hcrt-2
      transmission in all three of these clinical entities compared with controls.

PMID- 12486285
TI  - Late clinical and magnetic resonance imaging follow up of Nipah virus infection.
AB  - The Nipah virus is a newly identified paramyxovirus responsible for an outbreak
      of fatal encephalitis in Malaysia and Singapore. This paper reports the follow up
      clinical and magnetic resonance imaging findings in 22 affected subjects. Of 13
      patients with encephalitis, one died, one was lost to follow up, and seven
      recovered. Among the four remaining patients, one had residual sixth nerve palsy,
      another suffered from severe clinical depression, and a third patient had
      evidence of retinal artery occlusion. One patient with delayed onset Horner
      syndrome had a single lesion in the cervical spinal cord. The brain magnetic
      resonance findings were stable or improved in nine patients over 18 months of
      follow up. Among a second group of nine asymptomatic seropositive abattoir
      workers, magnetic resonance examination in seven subjects revealed discrete small
      lesions in the brain; similar to those detected in encephalitis patients. These
      findings suggest that in addition to encephalitis, the newly discovered Nipah
      virus affects the spinal cord and the retina. Late clinical and radiological
      findings can occur in Nipah virus infections as with other paramyxoviruses.

PMID- 12486287
TI  - Focal hand dystonia after cervical whiplash injury.

PMID- 12486286
TI  - Encephalomyeloradiculopathy associated with wasp sting.

PMID- 12486288
TI  - Debrisoquine hydroxylase gene polymorphism (CYP2D6*4) in dementia with Lewy
      bodies.

PMID- 12486289
TI  - Meningioma presenting as stroke: report of two cases and estimation of incidence.

PMID- 12486290
TI  - Parkinsonism associated with a serotonin and noradrenaline reuptake inhibitor,
      milnacipran.

PMID- 12486291
TI  - The relation between daytime sleepiness, fatigue, and reduced motivation in
      patients with adult onset myotonic dystrophy.

PMID- 12486292
TI  - Measuring carotid stenosis.

PMID- 12486296
TI  - Stewardship of the seas.
AB  - Our seas offer food, beauty and fascination, and are fundamental in regulating
      our climate - but are we doing enough to protect them?

PMID- 12486293
TI  - Cerebral metastasis after primary renal cell carcinoma.

PMID- 12486297
TI  - Bio-diversity.

PMID- 12486299
TI  - Carnivorous plants--classic perspectives and new research.
AB  - The ranks of known carnivorous plants have grown to approximately 600 species. We
      are learning that the relationships between these feeders and their prey are more
      complex, and perhaps gentler, than previously suspected. Unfortunately, these
      extraordinary life forms are becoming extinct before we can even document them

PMID- 12486300
TI  - How to move with no rigid skeleton? The octopus has the answers.
AB  - The octopus is amazingly flexible and shows exceptional control and coordination
      in all its movements. It seems remarkable to us skeletal creatures that the
      octopus achieves all this without a single bone.

PMID- 12486301
TI  - Talking genes - the molecular basis of language impairment.
AB  - Many children acquire language so smoothly that it appears to be an innate
      ability. If this is true, then it should be possible to identify genes that
      underlie variations in linguistic abilities.

PMID- 12486302
TI  - Another road to making embryonic pattern.
AB  - The body plan of a n animal is formed during embryonic development. One mechanism
      employs gradients of morphogens to direct cells in different parts of the embryo
      to become different adult structures. But is this the only way of producing
      tissue patterns? An alternative patterning is suggested by work on social
      amoebae.

PMID- 12486303
TI  - Ligula intestinalis--a tapeworm contraceptive.
AB  - Human contraceptives are 'big business', but might the real breakthrough come out
      from the pharmaceutical industry but from a tapeworm? Ligula intestinalis can
      induce infertility in infected fish of the carp family - both males and females.
      If the mechanism for this can be discovered, this humble flatworm could
      drastically change contraceptive practices with one pill for all.

PMID- 12486304
TI  - Hermit crabs, humans and crowded house markets.
AB  - There is a complex and dynamic interrelationhip between hermit crabs, humans and
      the coastal environment. Hermit crab homes (shells) are often hard to come by,
      but humans are helping out by piling middens of shells and rubbish on beachers.
      Hermit crabs are useful to humans as fishing bait, pets and living wasted
      disposal systems, and so useful to other animals that they may even be hijacked.

PMID- 12486305
TI  - The heart as an endocrine organ.
AB  - The discovery of atrial natruietic peptide firmly established that the heart was
      not just a pump and provided the long-sought-after link between the heart and the
      kidney in the control of soduim balance. Pharmacological targeting of the
      natruiretic peptide system is now leading to novel advances in the treatment of
      hypertension and of heart failure - two of the most common causes of human
      disability and death.

PMID- 12486306
TI  - Who was... Almroth Wright?
AB  - Sir Almroth Edward Wright CB MD FRS (1861-1947) was Britains first academic
      immunologist. He was qualified in both Arts and Medicine and commenced his
      professional life as a Physiologist, became Professor of Pathology and led the
      study of immunity to infectious diseases. He was often a controversial scientist
      and not always right in his views, hence his nickname 'Sir Almost Right'!

PMID- 12486307
TI  - A multi-factor Rasch scale for artistic judgment.
AB  - Measurement properties are reported for a combined scale of abstract and
      figurative artistic judgment aptitude items. Abstract items are synthetic, rule
      based images from Visual Designs Test which implements a statistical algorithm to
      control design complexity and redundancy, and figurative items are canvas
      paintings in five styles, Fauvism, Post-Impressionism, Surrealism, Renaissance,
      and Baroque especially created for this research. The paintings integrate
      syntactic structure from VDT Abstract designs with thematic content for each
      style at four levels of complexity while controlling redundancy. Trained test
      administrators collected preference for synthetic abstract designs and authentic
      figurative art from 462 examinees in Johnson O'Connor Research Foundation testing
      offices in Boston, New York, Chicago, and Dallas. The Rasch model replicated
      measurement properties for VDT Abstract items and identified an item hierarchy
      that was statistically invariant between genders and generally stable across age
      for new, authentic figurative items. Further examination of the figurative item
      hierarchy revealed that complexity interacts with style and meaning. Sound
      measurement properties for a combined VDT Abstract and Figurative scale shows
      promise for a comprehensive artistic judgment construct.

PMID- 12486308
TI  - Establishing longitudinal factorial construct validity of the quality of school
      life scale for secondary students.
AB  - The purpose of this study was to establish the longitudinal factorial construct
      validity of the Quality of School Life (QSL) scale, which was initially designed
      to measure the well-being of students in Australian high schools. The items
      comprising the scale were based on theoretical models and existing measurement
      instruments concerning the domains of schooling and the quality of life
      experienced by adults. Three latent structure models, two reported earlier in the
      literature and one new in this context, were reviewed and their merits compared
      on the basis of two sets of empirical data comprising, respectively, 5932
      secondary students in the 1993 cohort and 8269 secondary students in the 1999
      cohort using confirmatory factor analysis procedures. Results indicate that there
      is strong evidence in support of the factorial construct validity of the Quality
      of School Life scale.

PMID- 12486309
TI  - Rasch-transformed raw scores and Two-way ANOVA: a simulation analysis.
AB  - This article demonstrates, through the exposition of underestimated variable
      effects or spurious interaction effects, the inherent inadequacy of untransformed
      0-1 raw scores for analysis via Two-Way analysis of variance (ANOVA). The
      pioneering work in this field, conducted in the 1990's by Dr. Susan Embretson of
      the University of Kansas, USA, is highlighted, and the eminent suitability of
      Rasch transformations of 0-1 raw scores for analysis via Two-Way ANOVA is also
      demonstrated. In this study Monte Carlo techniques or simulations are utilized to
      determine the precise psychometric conditions under which differences between raw
      scores and Rasch transformations of those raw scores are detectable via Two-Way
      ANOVA. This study partially replicates Dr. Embretson's studies, and also defines
      the extent of underestimation and spuriousness which ensue when uniform or skewed
      distributions of item difficulties are used instead of normal distributions, and
      misfitting raw data are utilized instead of fitting data.

PMID- 12486310
TI  - Development of measurability and importance scales for the NATA athletic training
      educational competencies.
AB  - A recent mandate issued by the National Athletic Trainers' Association Board of
      Certification (NATABOC) stated that beginning in 2004 a student must graduate
      from an accredited Commission on Accreditation of Allied Health Education
      Programs (CAAHEP) in order to qualify for the NATABOC exam. The content of this
      exam is based on the National Athletic Trainers' Association (NATA) Athletic
      Training Educational Competencies. These 542 competencies in 12 different domains
      were developed through role delineation studies with the most recent edition
      published in 1999. Therefore, these competencies must be included in each
      athletic training curriculum program across the country in order to prepare their
      students for certification and to achieve program accreditation. Concern over the
      large number of competencies to be attained within the educational time frame
      created the need to develop an instrument to examine this issue. In response,
      instruments were developed to examine one domain of the NATA Educational
      Competencies. Specifically, the General Medical Conditions and Disabilities
      competencies were assessed for their perceived importance and measurability by
      certified athletic trainers and sports medicine physicians. This article reports
      the results of a validation study of an instrument designed to measure the
      perceived measurability and importance of the NATA Athletic Training Educational
      Competencies. Generally, the results are encouraging. The data supports six
      constructs, and each of these constructs exhibits high reliabilities. Relative
      competency calibrations within and between scales were consistent with theory.
      And, ratings assigned by different groups of trainers were comparable.

PMID- 12486311
TI  - Measuring leader perceptions of school readiness for reforms: use of an iterative
      model combining classical and Rasch methods.
AB  - This study examines validity of data generated by the School Readiness for
      Reforms: Leader Questionnaire (SRR-LQ) using an iterative procedure that combines
      classical and Rasch rating scale analysis. Following content-validation and pilot
      testing, principal axis factor extraction and promax rotation of factors yielded
      a five factor structure consistent with the content-validated subscales of the
      original instrument. Factors were identified based on inspection of pattern and
      structure coefficients. The rotated factor pattern, inter-factor correlations,
      convergent validity coefficients, and Cronbach's alpha reliability estimates
      supported the hypothesized construct properties. To further examine
      unidimensionality and efficacy of the rating scale structures, item-level data
      from each factor-defined subscale were subjected to analysis with the Rasch
      rating scale model. Data-to-model fit statistics and separation reliability for
      items and persons met acceptable criteria. Rating scale results suggested
      consistency of expected and observed step difficulties in rating categories, and
      correspondence of step calibrations with increases in the underlying variables.
      The combined approach yielded more comprehensive diagnostic information on the
      quality of the five SRR-LQ subscales; further research is continuing.

PMID- 12486312
TI  - Construction of measures from many-facet data.
AB  - An extension to the Rasch model for fundamental measurement is described in which
      there is parameterization not only for examinee ability and item difficulty but
      also for judge severity. Variants of this model are discussed and judging plans
      reviewed. Its use and characteristics are explained by an application of the
      model to an empirical testing situation. A comparison with Generalizability
      Theory using a common data set is presented as a contrast in approaches to
      resolving judge indeterminacy.

PMID- 12486313
TI  - On vowel height and consonantal voicing effects: data from Italian.
AB  - This paper reports an acoustic study of CV sequences in Italian (where C is /b,
      d, g, p, t, k/ and V is one of the seven Italian vowels in stressed position). It
      explores the effects of vowel height, consonantal voicing, and place of
      articulation on a number of acoustic attributes of vowels (duration, f(0), F(1)),
      and on the duration of the preceding stop closure, VOT and RVOT (defined as the
      interval from C release to the acoustic vowel onset). The aim is to provide, for
      Italian, a comprehensive account of all the various interactions between
      consonantal voicing, vowel height and consonant place on the above acoustic
      attributes in order to propose an explanation for such effects, and to compare
      the present results and interpretations with previous explanations and with
      previous data on Italian and other languages.

PMID- 12486314
TI  - Effects of speaking rate on temporal patterns of English.
AB  - Individual subjects have been found to show considerable variation in the extent
      to which they manifest certain temporal patterns of English in their speech.
      Because at least some differences across speakers appear to be related to the
      fact that some subjects typically talk faster/slower than others, the present
      investigation examined variability in temporal patterns by having subjects
      produce target stimuli in sentences spoken at normal and fast rates. The results
      from these manipulations of speaking rate generally supported previous findings
      related to temporal patterns as a function of 'natural' variations in rate of
      speech. That is, there was considerable variability among the 15 subjects in the
      normal speaking rate condition in the extent to which temporal parameters such as
      final-syllable vowel lengthening occurred. In addition, there was substantial
      variation in these parameters in the fast speaking rate condition, and some
      systematic changes in certain patterns also occurred as a function of the rate
      change. For example, vowel lengthening preceding voiced obstruents tended to
      decrease when subjects spoke at a fast versus a normal rate, whereas phrase-final
      vowel lengthening was typically greater when they spoke at a faster rate.

PMID- 12486315
TI  - The trough effect: implications for speech motor programming.
AB  - While the existence of the trough effect is unquestioned, its theoretical
      significance is unknown. A multifaceted instrumental approach - spectrographic,
      cineradiographic, and vocal tract modeling - was used to document the trough
      effect in open (V.CV) and closed (VC.V) syllable forms using a symmetrical vowel
      context surrounding labial stops. Collectively, the results document the trough
      phenomenon as a momentary deactivation of tongue and/or lip movement after V1 and
      continuing into the stop closure. This empirical event suggests a segment-by
      segment activation pattern as opposed to a diphthongal vowel-to-vowel trajectory
      with an independent and superimposed consonantal gesture. Quantitative models of
      VCV coarticulation must incorporate the trough effect in order to more
      effectively capture the kinematic properties of speech.

PMID- 12486316
TI  - Substance p-fibronectin-cytokine interactions in myeloproliferative disorders
      with bone marrow fibrosis.
AB  - Bone marrow (BM) fibrosis could occur secondarily to several clinical disorders:
      hematological and nonhematological. Clinical presentation of fibrosis could occur
      in myeloproliferative diseases, lymphoma, myelodysplastic syndrome and myeloma.
      The pathophysiology underlying BM fibrosis remains unclear despite intensive
      study, with a corresponding lack of specific therapy. This review discusses new
      insights in the role of substance P, cytokines and fibronectin in the development
      of BM fibrosis. Substance P is a neuropeptide that possesses pleiotropic
      properties, e.g. neurotransmission and immune/hematopoietic modulation and is
      linked to BM fibrosis. Cytokines and growth factors, in particular those
      associated with fibrogenic properties, e.g. TGF-beta, IL-1 and platelet-derived
      growth factor, are linked to BM fibrosis. Extracellular matrix proteins are
      increased in patients with BM fibrosis. Fibronectin in the sera of patients with
      BM fibrosis is complexed to substance P. Fibronectin appears to protect substance
      P from degradation by endogenous peptidases. This review describes the
      preliminary findings on the colocalization of substance P and fibronectin in the
      BM of patients with fibrosis. These data are reviewed in the context of published
      reports with particular focus on the relevant cytokines. A more detailed
      understanding of intra- and intercellular mechanisms in BM fibrosis may lead to
      effective therapy.

PMID- 12486317
TI  - Hypothyroidism and thyroiditis after therapy for Hodgkin's disease.
AB  - During the follow-up of thyroid function of 151 patients with Hodgkin's disease
      in complete remission for at least 1 year, 26 cases of subclinical, 12 cases of
      manifest clinical hypothyroidism and 2 cases of hyperthyroidism (Graves-Basedow
      disease) were confirmed. Thyroid dysfunction was more frequent in patients who
      had undergone mantle or neck radiotherapy. Hypothyroidism was most often revealed
      from the 6th year on following radiotherapy. Thyroid autoantibody positivity was
      found to be more frequent in patients with thyroid dysfunction, and conversely,
      thyroid dysfunction was more frequent among the 28 patients with autoantibody
      positivity. Ultrasound examination and fine needle aspiration cytology of the
      thyroid confirmed thyroiditis in 96% of the patients with antibody positivity. No
      relationship was found between thyroiditis and the form of treatment for
      Hodgkin's disease. We have found that both neck irradiation and thyroiditis may
      play a role in the increased number of thyroid dysfunction in patients treated
      for Hodgkin's disease. Thyroiditis is not caused by neck radiotherapy but may be
      the result of immune regulation disorders in Hodgkin's disease. For substitution
      or isohormone therapy, levothyroxine is suggested for use. We suggest that
      examination of the thyroid should be performed at least once a year during the
      follow-up of Hodgkin's disease patients.

PMID- 12486318
TI  - An ELISA assay for the detection of factor VIII antibodies - comparison with the
      conventional Bethesda assay in a large cohort of haemophilia samples.
AB  - An enzyme-linked immunosorbent assay (ELISA) has been developed to measure factor
      VIII antibodies in haemophilia patients. The assay utilizes binding of the
      antibodies in the plasma to solid phase antigen, i.e. recombinant factor VIII
      which was subsequently detected by a human polyclonal IgG labelled with the
      alkaline phosphatase-p-nitrophenyl phosphate substrate system. Comparisons were
      made with the Bethesda assay for the quantitation of factor VIIII inhibitors.
      Dose response curves for the reference standards were consistently linear and
      reproducible. The assay was specific for factor VIII antibodies, showing a
      negative reaction for antibodies to other coagulation factors, antinuclear
      factors and antiphospholipid antibodies. Using this method, 312 samples from
      haemophilia A patients and 31 samples from healthy controls were screened for the
      presence of inhibitors and compared with the conventional Bethesda assay. Twenty
      four cases were found to be positive for inhibitors in both the ELISA and
      Bethesda assay. Five additional cases were also found to be positive in the ELISA
      assay, which, however, were negative in Bethesda assay. One patient who was
      initially positive for factor VIII inhibitors both by the Bethesda assay and
      ELISA eventually became negative for the Bethesda assay (<0.5 BU/ml) but was
      still positive for the ELISA assay. The ELISA thus described had a specificity of
      97.8% and a sensitivity of 100% when tested against a large cohort of haemophilia
      A samples.

PMID- 12486319
TI  - Serum soluble interleukin-2 receptor in eosinophilia.
AB  - The relationship between soluble interleukin-2 receptor (sIL-2R) levels and
      clinical characteristics was evaluated in patients with eosinophilia. Thirty
      eight out of 60 patients showed sIL-2R levels of more than 800 U/ml. In these
      patients, sIL-2R was closely related to the eosinophil count, but not the IgE
      level. Their underlying diseases were heterogeneous, including neoplasms and
      collagen diseases. In patients with lower sIL-2R levels, there was no
      relationship to the eosinophil count, but sIL-2R was correlated with the IgE
      level. These findings indicate that patients with eosinophilia and higher sIL-2R
      levels tend to have underlying diseases other than allergy, and might be more
      severely ill than patients with lower sIL-2R levels. sIL-2R may be a good marker
      for evaluating patients with eosinophilia, as an indicator of the probable
      etiology and severity of their diseases.

PMID- 12486320
TI  - Apoptosis in relation to CD34 antigen expression in normal and myelodysplastic
      bone marrow.
AB  - An increased bone marrow (BM) apoptosis is one of the mechanisms responsible for
      the ineffective hematopoiesis of myelodysplastic syndromes (MDS). It is
      controversial whether the excessive apoptosis in myelodysplasia predominantly
      involves the subset of progenitor cells or of maturing cells. We investigated the
      degree of apoptosis in MDS BM and its differences from normal marrow in relation
      to CD34 antigen expression. A double-labelling technique that combined the Tdt
      mediated dUTP nick end labelling (TUNEL) method with immunocytochemistry for CD34
      antigen was used on BM slides of 18 MDS patients and 11 controls. The apoptotic
      rate (AR) appeared significantly higher in CD34-negative than in CD34-positive
      cell subsets both in myelodysplastic and in normal BM. When MDS and normal CD34
      negative cell populations were compared, a greater AR in MDS CD34-negative cells
      was found, while no statistical difference in AR resulted from the comparison
      between MDS and normal CD34-positive cell populations. Our results suggest that
      in myelodysplastic as well as in normal BM the apoptotic phenomenon predominantly
      involves the maturing cells. The increase in apoptotic levels which can be
      observed in myelodysplastic compared to normal BM seems to be mainly due to an
      increase in apoptosis in the differentiated cell population.

PMID- 12486321
TI  - Antihistone and other autoantibodies in beta-thalassemia major patients receiving
      iron chelators.
AB  - This study was designed to find out the incidence of various autoantibodies in
      patients receiving iron chelators. Two groups were studied for comparison. One
      group consisted of thalassemia major cases on deferiprone (L1) and the second
      group were those receiving desferrioxamine therapy. Various autoantibodies such
      as antihistone antibodies and its subfractions H1, H2A-H4B, H2B, H3, ANF, anti
      dsDNA, anti-nRNP, anti-Sm, ANCA and rheumatoid factor were tested. Out of 180
      patients 50 patients (27.8%) were on desferrioxamine therapy, and 60 patients
      (33.3%) were taking deferiprone, whereas 70 patients (38.9%) were untreated.
      Antihistone antibodies were found in 30% of patients receiving deferiprone and
      48% in the desferrioxamine group, respectively, as compared to control
      thalassemics (14.3%). Also, the levels of antihistone antibody were significantly
      elevated in the chelator groups as compared to controls. When antibodies to
      subfractions of the histone molecule were studied, it was observed that
      antibodies to H1 were most commonly seen and IgG was the major immunoglobulin
      subclass. Anti-dsDNA and anti-Sm antibodies, which are the diagnostic markers of
      idiopathic SLE, were absent in these patients. beta-Thalassemia major patients on
      iron chelators such as desferrioxamine and deferiprone show changes in their
      autoimmune profile suggestive of some humoral immune alterations.

PMID- 12486322
TI  - Thrombotic thrombocytopenic purpura associated with ticlopidine.
AB  - Thrombotic thrombocytopenic purpura is a syndrome characterized by hemolytic
      anemia, thrombocytopenia, neurological symptoms, fever and renal dysfunction.
      Although the syndrome is usually associated with various infections, vasculitis
      and pregnancy, rarely can it be associated with certain neoplasms and drugs such
      as ticlopidine. A 63-year-old woman, who had undergone coronary angioplasty and
      had been started on ticlopidine, was admitted to our clinic with a history of
      vomiting, fatigue, hematuria and deterioration in her cognitive abilities.
      Thrombotic thrombocytopenic purpura was diagnosed on the basis of neurological
      changes, an increase in LDH, urea, creatinine, indirect bilirubin levels, anemia
      and peripheral smear findings. Treatment was initiated with daily plasmapheresis
      and complete clinical and laboratory recovery developed. The patient was
      discharged after 14 days.

PMID- 12486323
TI  - Rituximab for immune hemolytic anemia following T- and B-Cell-depleted
      hematopoietic stem cell transplantation.
AB  - The treatment of immune-mediated hemolytic anemia (IHA) complicating
      hematopoietic stem cell transplantation (HSCT) is often unsatisfactory. We report
      a case of IHA which occurred after T- and B-cell depleted unrelated donor HSCT
      carried out for mucopolysaccharidosis type I-H (Hurler syndrome) which was
      successfully treated with anti-CD20+ monoclonal antibody

PMID- 12486324
TI  - Interaction of sickle cell trait with hereditary spherocytosis: splenic infarcts
      and sequestration.
AB  - The association of sickle cell trait (SCT) and hereditary spherocytosis (HS) has
      been reported in only 18 patients. Three of these 18 patients experienced splenic
      infarct or acute splenic sequestration. We report here a 46-year-old African
      American male, the oldest reported case to date, who experienced episodes of
      hemolysis and severe left upper quadrant pain for the past 26 years. The patient
      had compensated hemolysis with splenomegaly. A CT scan of the abdomen revealed a
      large infarct in the spleen. The diagnosis of SCT was confirmed with isoelectric
      focusing, cation exchange and reverse-phase HPLC. The presence of a silent,
      interacting globin variant as the cause of hemolysis and sickling in the spleen
      was ruled out by sequencing of the alpha1-, alpha2- and beta-globin genes. The
      diagnosis of HS was established by an osmotic fragility test. The interaction of
      HS and SCT leads to RBC dehydration with increased MCHC and intracellular Hb S
      concentration presumably favoring intrasplenic sickling and resultant splenic
      infarcts and sequestration as seen in this case.

PMID- 12486325
TI  - No significant correlation exists between nitric oxide production and apoptosis
      in myelodysplastic syndromes.

PMID- 12486326
TI  - Impact of bone marrow morphology on multivariate risk classification in chronic
      myelogenous leukemia.

PMID- 12486327
TI  - Comparing qualitative and quantitative spectroscopic techniques for the detection
      of the effect of direct iron loading of mammalian cell cultures.
AB  - Iron overload augments diseases of the liver and microorganism infection as well
      as deregulates the immune system. In vitro analysis of the effects of iron
      loading and its chelation involves determining the amount of iron constituting
      overload, which metal sources and cell lines to use and reliable assay methods.
      The uptake of 500 microM FeSO4 or FeEDTA by CEMss, U937 or leukocytes was
      confirmed by inductively coupled plasma-atomic emission spectroscopy (ICP-AES).
      Excess iron increased CEMss viability (assessed by MTT, XTT, Trypan- and Alamar
      Blue) by an average of 18% (P = 0.034). Flow cytometry indicated dye-viable cells
      to be undergoing apotosis/necrosis while still confirming an increase (9%, P <
      0.001) in excess iron-induced viability. The iron chelator desferioxamine (DFO)
      when added in addition to Fe, reversed the effects of excess iron (and vice
      versa) and had detrimental effects when used on its own (33% inhibition of
      viability as measured by dyes and 10.85%; P = 0.0427 assessed by flow cytometry).
      The 4 dyes demonstrated different levels of sensitivity in detecting the
      influence of iron or DFO but gave a related, qualitative picture while flow
      cytometry and ICP-AES data was more quantitative.

PMID- 12486328
TI  - Isolation of vascular smooth muscle cells from a single murine aorta.
AB  - The vascular smooth muscle cell plays a significant role in many important
      cardiovascular disorders, and smooth muscle biology is therefore important to
      cardiovascular research. The mouse is critical to basic cardiovascular research,
      largely because techniques for genetic manipulation are more fully developed in
      the mouse than in any other mammalian species. We describe here a technique for
      isolating smooth muscle cells from a single mouse aorta. This technique is
      particularly useful when material is limiting, as is frequently the case when
      genetically modified animals are being characterized.

PMID- 12486329
TI  - An improved method for culture of epidermal keratinocytes from newborn mouse
      skin.
AB  - Reproducible isolation and long term culture of epidermal keratinocytes from
      transgenic mouse lines is critically needed but most techniques have been
      unsuccessful. In this report we describe in detail a simplified method to isolate
      putative keratinocyte stem cells from newborn mouse skin and to maintain them for
      long term in culture. The cell cultures were established by enzymatically
      separating keratinocytes from newborn mouse skin. For selecting the putative
      keratinocyte stem cells for culture, the cells are allowed to attach for 10
      minutes on a composite matrix made of type I collagen and fibronectin. Unattached
      cells were discarded and the attached cells were cultured in a defined culture
      medium containing low Ca2+ concentration, 9% FBS, conditioned medium from newborn
      mouse skin fibroblasts, and EGF. For subculturing, the cells were seeded on
      tissue culture plastic. The isolated cells showed the typical basal keratinocyte
      morphology and expressed the epithelial cell specific integrin alpha v beta 6.
      The expression level of alpha v beta 6 integrin was comparable to human skin
      keratinocytes. The keratinocytes were also able to differentiate to form an
      epidermis in an organotypic culture model. By using the described protocol, the
      keratinocytes from frozen stocks have been subcultured up to 26 times without
      change in cell viability, proliferation rate or morphology.

PMID- 12486330
TI  - Modification of cell perifusion for extended study of hormone release in the rat
      pituitary.
AB  - We use a flow-through cell perifusion system allowing continuous sampling of
      Luteinizing Hormone (LH) release from excised pituitary tissue. With this system,
      we are able to sample from viable tissue in primary culture for three days as
      opposed to a more typical of primary culture of 6-12 hours. Rat pituitary tissue
      was perifused and challenged with a physiological dose of LHRH. Samples were
      collected for 3.5 hours on each of 3 consecutive days in a refrigerated fraction
      collector and assayed for LH concentration by radioimmunoassay. In these
      experiments we tested two types of media, each with or without fetal calf serum
      supplementation, for their ability to support pituitary tissue for extended
      lengths of perifusion. In addition, we broadened the use of aseptic technique,
      sterile media and equipment to limit microbial contamination. Our results
      indicate that perifusion of pituitary tissue can be done successfully for 3 or
      more days at a modest cost, greatly increasing the amount of information that can
      be collected from each piece of tissue harvested.

PMID- 12486331
TI  - Preparation of dissociated zebrafish spinal neuron cultures.
AB  - The method described here explains a simple protocol for how to prepare
      dissociated Zebrafish spinal neuron cultures. The neurons grow fast in a simple
      culture medium and at room temperature. Considering the advantages afforded by
      the optical transparency of the Zebrafish embryo combined with the powerful
      molecular perturbation techniques available, this technique has potential to
      further advance molecular analysis of axon growth and guidance.

PMID- 12486332
TI  - Induction of reduced endothelial permeability to horseradish peroxidase by
      factor(s) of human astrocytes and bladder carcinoma cells: detection in multi
      well plate culture.
AB  - Endothelial permeability to horseradish peroxidase (HRP) was assayed in multi
      well plate culture. Confluent cobblestone-monolayers of endothelial cells were
      incubated with HRP, and the amounts of HRP that permeated the monolayer and
      reached the bottom substrate were estimated by extraction of HRP with
      deoxycholate and following addition of chromogenic substrate of HRP into the
      extracts. Using this in situ assay method, we detected the reduced permeability
      to HRP in aortic and brain microvascular endothelial cells after 4-5 days culture
      with conditioned media of human astrocytes or bladder carcinoma cells.
      Preliminary characterization of the active factors(s) released from these cells
      was performed. This method will be useful for monitoring impermeable endothelial
      cell monolayers and identifying the active factor(s).

PMID- 12486333
TI  - Effects of temperature on the susceptibility of insect cells to infection by
      baculoviruses.
AB  - Three insect cell lines were tested for susceptibility to baculovirus infection
      by use of a typical endpoint assay procedure. Cell lines from Spodoptera
      frugiperda (IPLB-Sf21AE), Lymantria dispar (IPLB-LdEIta), and Heliothis virescens
      (IPLB-HvE6s) in 96-well tissue culture plates were each infected with dilutions
      of extra cellular virus suspensions of the Autographa californica
      nucleopolyhedrovirus (AcMNPV). In addition, the L. dispar and H. virescens cells
      were also infected with L. dispar nucleopolyhedrovirus, and Helicoverpa zea
      nucleopolyhedrovirus, respectively. Each cell/virus combination was incubated at
      three temperatures: 22, 27 and 32 degrees C and wells were scored for positive
      infection (presence of occlusion bodies in cell nuclei) at 2 to 4 day intervals
      for up to 4 weeks. The resulting data were analyzed by the Spearman-Karber
      method, providing virus titers for each combination of virus, cell line, and
      temperature. The results were categorized by accuracy (assuming the highest titer
      achieved was the most accurate) and by rapidity of maximum titer. AcMNPV reached
      the highest titer in each line at 22 degrees C although equivalent titers were
      reached with both AcMNPV and HzSNPV in the HvE6a line at all three temperatures.
      This line actually reported about 100-fold less AcMNPV than the other two lines
      with the same virus sample. Alternatively, the Sf21AE and LdEIta lines reached 10
      fold higher titers at the lowest temperature as compared with the higher
      temperatures, although also at a slower rate.

PMID- 12486334
TI  - [Pathophysiology of allergic rhinitis].

PMID- 12486335
TI  - [Expression of heme oxygenase-1 and its effects in allergic airway inflammation
      and hyperresponsiveness].
AB  - We investigated whether an expression of hemeoxygenase-1 (HO-1) within the lung
      tissue is related to allergic airway inflammation and HO-1 expression could
      influence airway hyperreactivity (AHR) and eosinophilia in C57BL/6 mice actively
      sensitized to ovalbumin. The number of HO-1 positive cells was increased in the
      subepithelium of the bronchi after OVA challenge and HO-1 was localized to
      alveolar macrophage.Zinc-protoporphyrin (Zn-PP), a competitive inhibitor of
      hemeoxygenase, by intraperitoneal injection clearly inhibited AHR, pulmonary
      eosinophilia and IL-5 and IL-13 in the lung tissue. These data indicate that the
      expression of HO-1 is increased within the lung tissue in allergic airway
      inflammation and the overexpression of HO-1 could enhanced allergic airway
      inflammation.

PMID- 12486336
TI  - [A study on the nasal and eye symptoms of pollinosis in hakodate].
AB  - We have investigated the nasal and eye symptoms of pollinosis in Hakodate. There
      were elevated levels of dispersion of Cryptomeria japonica pollen in Hakodate in
      1995 and 1998. In 1995 and 2001, there were also elevated levels of dispersion of
      Betula platyphylia var. japonica pollen. From March to June and September from
      July 1999 to May 2002, there was an increased incidence of pollinosis in
      Hakodate. In 641 patients with allergic rhinitis, the specific IgE positive rates
      for house dust and mite, Artemisia (Art), Gramineae (Gra), Betulaplatyphylia var.
      japonica (BJ), and Cryptomeria Japonica (CJ) were 73.5, 28.5, 25.7, 14.2 and
      21.2%, respectively. The subjects with pollinosis in 2001 and 2002 (n=95) were
      divided into four groups as follows: Cryptomeria japonica (n=49), Betula
      platyphylia var. japonica (n=11), Gramineae (n=18) and Artemisia (n=17)
      pollinosis. The general severity of rhinitis and conjunctivitis were divided into
      four grades ( (-), (+), (++) and (+++) ), respectively. The combined (++) and
      (+++) rates observed for the general severity of rhinitis for all these subjects
      (n=95) was 86.4% and there was no significant difference in the general severity
      of rhinitis between any of the four groups. The combined (++) and (+++) rates for
      the general severity of conjunctivitis for all subjects (n=95) was 56.9% and the
      general severity of conjunctivitis for BJ and Gra pollinosis were significantly
      (P<0.01) higher than those observed for CJ pollinosis. In conclusion, the present
      data shows that the general severity of rhinitis in subjects with pollinosis in
      Hakodate was more severe than that of conjunctivitis and also that the general
      severity of conjunctivitis was dependent on the specific pollen (s) responsible
      for the pollinosis.

PMID- 12486337
TI  - [Effects of sedative odorant inhalation on patients with atopic dermatitis].
AB  - Atopic dermatitis (AD) has been clinically well-known to be frequently
      exacerbated by psychological and physiological stress. In this study, we examined
      effects of sedative odorant (modified valerian oil) inhalation on patients with
      AD. We investigated clinical scores, skin physiological parameters and
      psychological questionnaire (POMS) every 2 weeks. For first 2 weeks, we arranged
      non-inhalation period. Results for non-inhalation period were compared with these
      of 2- or 4-week inhalation. As results, sum of skin clinical scores significantly
      improved after odorant inhalation. Some patients improved for non-inhalation
      period, too. However, patients that had not improved for non-inhalation period
      significantly improved after odorant inhalation. Skin conductance and skin
      dryness/scaling score also improved after odorant inhalation without improving
      for non-inhalation period. Psychological parameter (POMS) also tended to improve
      after odorant inhalation. These results suggest that sedative odorants may be
      useful as a complementary therapy for AD through psychosomatic stress care.

PMID- 12486338
TI  - [A case of Sjogren's syndrome with hypereosinophilia and increase of serum IgE].

PMID- 12486339
TI  - [A case of Churg-Strauss syndrome with heart failure developed by use of
      fluticasone propionate].

PMID- 12486340
TI  - [The utility of the interrupter technique in pediatric asthma].
AB  - Interrupter respiratory resistance (Rint) is a new lung function test for
      measuring airway resistance. We investigated the utility of the Rint lung
      function test in pediatric patients with asthma. Thirty seven asthmatic patients
      with mild or moderate asthma attack (asthma group) and 9 healthy children
      (control group) were enrolled in the study, and the utility of the Ring test was
      compared with that of the PEF lung function test. Rint and PEF were measured
      after the inhalation of saline or beta(2) stimulant, and the values for the
      asthma and control groups were compared. The rint and PEF values did not change
      after the inhalation of saline, but both values improved after the inhalation of
      beta(2) stimulant in the asthma group. In the control group, the PEF and Rint
      values measured after saline or beta(2) stimulant were not significantly
      different. Rint measurements may be more useful than PEF tests for evaluating
      therapeutic responses to mild asthma attacks in children. These findings suggest
      that Rint is a useful respiratory function test for evaluating children with
      asthma.

PMID- 12486341
TI  - Can passive prone extensions of the back prevent back problems? A randomized,
      controlled intervention trial of 314 military conscripts.
AB  - SUMMARY OF BACKGROUND DATA: Back schools may be effective in treating back
      problems, but there is conflicting evidence of the effect on prevention.
      OBJECTIVES: To investigate if passive prone extensions of the back can prevent
      back problems. STUDY DESIGN: Prospective, randomized controlled intervention
      trial. METHODS: In total, 314 male conscripts were randomized into two groups.
      After randomization, 65 conscripts dropped out for administrative reasons,
      leaving 249 conscripts to participate fully in the study. Data were collected
      through questionnaires at the start of military duty and after 10 months. All
      conscripts in the intervention group had one 40-minute theoretical lesson on back
      problems and ergonomics and had to perform passive prone extensions of the back
      daily during the rest of their military duty. The control group had no
      intervention. Outcome variables were as follows: 1) number of persons with self
      reported back problems during the last 3 weeks; 2) number of persons with self
      reported back problems during the last year; and 3) number of persons who
      reported having consulted the regiment medical physician with back problems
      during their military service. RESULTS: In an intention-to-treat analysis,
      significantly fewer persons in the intervention group versus those in the control
      group reported back problems during the last year (33% versus 51%), and the
      number needed to prevent was 6. Significantly fewer persons in the intervention
      group versus those in the control group consulted the regiment infirmary (9%
      versus 25%), and the number needed to prevent was 6. CONCLUSION: It may be
      possible to reduce the prevalence rate of back problems and the use of health
      care services during military service, at a low cost, using passive prone
      extensions of the back motivated by a back school approach, including the theory
      of the disc as a pain generator and ergonomic instructions.

PMID- 12486342
TI  - One versus two BAK fusion cages in posterior lumbar interbody fusion to L4-L5
      degenerative spondylolisthesis: a randomized, controlled prospective study in 25
      patients with minimum two-year follow-up.
AB  - STUDY DESIGN: We accomplish posterior lumbar interbody fusion using
      posterolateral insertion of a single BAK fusion cage (Sulzer Spine-Tech,
      Minneapolis, MN) with unilateral facetectomy and hemilaminectomy. OBJECTIVE: To
      subject a single BAK fusion cage inserted posterolaterally in posterior lumbar
      interbody fusion to a randomized, controlled trial to assess its clinical safety
      and efficacy. SUMMARY OF BACKGROUND DATA: Routinely, two threaded cages in
      posterior lumbar interbody fusion have been recommended, which need bilateral
      facetectomy, extensive exposure, and retraction of cauda equina. Our
      biomechanical study showed that it is feasible to accomplish posterior lumbar
      interbody fusion using posterolateral insertion of a single threaded cage with
      unilateral facetectomy and hemilaminectomy. MATERIALS AND METHODS: Patients with
      a primary diagnosis of L4-L5 degenerative spondylolisthesis accompanied by low
      back pain and unilateral leg pain, having failed conservative treatment, were
      considered for the procedure. Twenty-five patients were randomized into two
      groups of 13 and 12, respectively, using a random number table. Group 1 had a
      single BAK fusion cage inserted posterolaterally and oriented counter
      anterolaterally on the symptomatic side with unilateral facetectomy and
      hemilaminectomy. Group 2 had two BAK fusion cages inserted posteriorly with
      bilateral facetectomy and laminectomy. RESULTS: A total of 12 of 13 patients in
      Group 1 and 11 of 12 patients in Group 2 achieved successful radiographic
      arthrodesis. Clinical results at 2 years for 7 of 13 patients in Group 1 were
      excellent, 4 of 13 were good, 2 of 13 fair, and no poor clinical results; 4 of 12
      patients in Group 2 were excellent, 5 of 12 good, 1 of 12 fair, and 2 of 12 poor.
      Regarding complications, 2 of 12 in Group 2 had a postoperative motor and sensory
      deficit of the opposite adjacent (upper) nerve root. CONCLUSION: Posterior lumbar
      interbody fusion using diagonal insertion of a single threaded cage by a
      posterior approach with unilateral facetectomy enables sufficient decompression
      and solid interbody arthrodesis to be achieved while maintaining a majority of
      the posterior elements. It is a clinically safe, easy, and economic technique to
      treat lumbar degenerative spondylolisthesis.

PMID- 12486343
TI  - The impact of self-retaining retractors on the paraspinal muscles during
      posterior spinal surgery.
AB  - STUDY DESIGN: This was a prospective pilot study examining pre-, intra- and
      postoperative measures. OBJECTIVES: The aim of the study was to investigate the
      effect of muscle retractors on the posterior spinal muscles during posterior
      spinal surgery. SUMMARY OF BACKGROUND DATA: Previous studies have identified
      changes in the structure and function of the back extensor mechanism as a result
      of low back pain. However, the effect of surgery on the functioning of these
      muscles, particularly surgical retraction, has received less attention. METHODS:
      Twenty patients undergoing posterior spinal surgery were recruited into this
      study, and recordings of intramuscular pressure during surgery were performed
      using a pressure-monitoring system before insertion of retractors, 5, 30, and 60
      minutes into surgery, and on removal of retractors. Before and following use of
      the retractors, muscle biopsies were taken from the multifidus muscle for
      analysis using birefringence techniques. RESULTS: A significant increase in
      intramuscular pressure (P < 0.001) was observed during surgery. On removal of
      retractors, this pressure returned to or near to the original value. Analysis of
      muscle biopsies using calcium activated adenosine triphosphatase birefringence
      revealed a reduction in muscle function following prolonged use of self-retaining
      retractors. CONCLUSIONS: A substantial rise in pressure in the erector spinae
      muscle during posterior spinal surgery was observed, and this appeared to be
      associated with marked changes in the function of the muscles. This could be an
      important factor in the generation of operative scar tissue and postoperative
      dysfunction of the spinal muscles.

PMID- 12486344
TI  - Posterior stabilization at the cervicothoracic junction: a biomechanical study.
AB  - STUDY DESIGN: This study biomechanically evaluated three fixation devices for
      stability with posterior two- and three-column injuries. OBJECTIVES: To find an
      effective means of posteriorly stabilizing injuries at the cervicothoracic
      junction. SUMMARY OF BACKGROUND DATA: The cervicothoracic spine is complex
      anatomically and has been a difficult challenge in approach and stabilization of
      traumatic and degenerative disorders. METHODS: Twenty-one human cadaveric spines
      (C3-T3) were loaded in flexion, extension, lateral bending, and axial torsion. A
      posterior two-column injury was created at C7-T1. One of three posterior fixation
      systems was applied (two rod-screw systems, one plate-screw system, all with
      screws at C5, C6 and T1, T2). The spines were tested again. A three-column injury
      was created by transecting the remaining anterior structures; the spines were
      tested a final time. RESULTS: In flexion-extension, there were no significant
      differences in stiffness between intact and instrumented two-column injury
      specimens for all systems; the instrumented three-column injury was significantly
      (P < 0.05) less stiff than intact specimens in extension. Ranges of motion and
      neutral zones decreased from intact to instrumented two-column injuries and
      increased from intact to three-column constructs. In lateral bending and axial
      rotation, all systems were stiffer than intact spines for both injuries; ranges
      of motion and neutral zones were reduced for both injuries compared with intact
      specimens. CONCLUSION: All three systems stabilize the cervicothoracic junction
      with a posterior two-column injury in flexion-extension, lateral bending, and
      axial rotation; none was adequate for a three-column injury, particularly in
      extension. A three-column injury at this level would warrant supplemental
      anterior fixation.

PMID- 12486345
TI  - Atlantoaxial rotatory fixation-subluxation revisited: a computed tomographic
      analysis of acute torticollis in pediatric patients.
AB  - STUDY DESIGN: Cross-sectional clinical and radiologic study with a normal control
      group. OBJECTIVES: To compare the range of motion of the atlantoaxial joint in
      patients with acute torticollis with those of normals as measured from computed
      tomography scans, to look for the existence of atlantoaxial rotatory fixation in
      any position (subluxation or normal range of motion) in this group of patients,
      and to clarify the definition of atlantoaxial rotatory subluxation by measuring
      the atlantodental interval and analyzing the location of the center of rotation
      in patients as well as normal controls. SUMMARY OF BACKGROUND DATA: Although
      acute acquired torticollis is usually termed atlantoaxial rotatory subluxation or
      atlantoaxial rotatory fixation, the radiologic definition of these conditions is
      not clear. PATIENTS AND METHODS: Thirty-three consecutive pediatric patients
      (average age 8.5 years, range 2-18 years) with acute acquired torticollis were
      analyzed. All were neurologically intact. Anteroposterior and lateral radiographs
      were obtained in all atlantoaxial computed tomography scans in 31 patients
      (dynamic in 23 and static in 8). Twelve age-matched patients with normal cervical
      spines were also analyzed with dynamic computed tomography as normal controls.
      Atlantoaxial rotatory subluxation, atlantoaxial angle, center of rotation, and
      presence of atlantoaxial rotatory fixation were analyzed in each computed
      tomography. All patients were treated conservatively. Eight had control dynamic
      computed tomography scans at the end of the treatment. RESULTS: All patients had
      atlantoaxial rotatory subluxation <or=3 mm. On dynamic computed tomography, the
      range of atlantoaxial rotation was 30.4 degrees (range 11-54 degrees) toward
      deformity and 28.3 degrees (range 18-54 degrees) away from deformity (P = 0.333).
      Atlantoaxial rotatory fixation was not noted in any of the patients. The same
      measurement for the normal control group was 28 degrees (range 5-41 degrees) (P =
      0.770). Of the eight patients with repeat control computed tomography, the
      atlantoaxial rotatory subluxation was 26 degrees before and 29 degrees after
      treatment (P = 0.691 to right and P= 0.199 to left). The center of rotation was
      within dens in 15 of 19 patients, outside dens in 2 of 19, and undetectable in 2
      of 19. In the control group, it was within dens in 8 of 11, outside dens in 2 of
      11, and undetectable in 1 of 11. All patients were symptom free at the end of the
      conservative treatment. CONCLUSION: We could not demonstrate the presence of
      atlantoaxial rotatory subluxation or atlantoaxial rotatory fixation in our series
      of 33 consecutive pediatric patients with acute torticollis. Our findings suggest
      that the existence of these phenomena are doubtful, although not associated with
      acute acquired torticollis. Acute acquired torticollis is not necessarily the
      sign of a pathologic condition of the atlantoaxial joint. Finally, it is probably
      not necessary to obtain computed tomography scans (static or dynamic) in this
      group of patients at the time of presentation.

PMID- 12486346
TI  - Disc stimulation and patterns of referred pain.
AB  - STUDY DESIGN: Prospective, within-subjects, observational experimental design.
      OBJECTIVES: To determine the pattern of pain response to noxious stimulation of
      the intervertebral disc. SUMMARY OF BACKGROUND DATA: Experimental studies have
      demonstrated that noxious stimulation of interspinous ligaments, facet joints,
      and paravertebral muscles causes referred pain into the extremity, with the
      distal extent of radiation dependent on the intensity of stimulation. Analogous
      studies have not been performed on the lumbar intervertebral disc. METHODS: A
      total of 25 consecutive patients meeting inclusion criteria completed a pain
      diagram before undergoing the intradiscal electrothermal annuloplasty procedure.
      The location, intensity, and familiarity of any pain provoked during disc heating
      were correlated with presenting symptoms and duration of heating. RESULTS: During
      disc heating, 68% of patients reported exact reproduction of their presenting
      pain, in both pain quality and location. None of the patients experienced
      unfamiliar pain during the procedure. The pattern of pain reproduction was
      consistent; pain originated proximally and progressed distally as stimulus
      intensity increased. CONCLUSION: Noxious stimulation of the intervertebral disc
      may result in low back and referred extremity in patients presenting with these
      symptoms. The distal extent of pain produced depends on the intensity of
      stimulation. Disc stimulation may reproduce pain that extends to below the knee.

PMID- 12486347
TI  - The treatment of unstable thoracic spine fractures with transpedicular screw
      instrumentation: a 3-year consecutive series.
AB  - STUDY DESIGN: The treatment of unstable thoracic spine fractures remains
      controversial. Theoretical biomechanical advantages of transpedicular screw
      fixation include three-column control of vertebral segments and fixation of a
      vertebral segment in the absence of intact posterior elements. Additionally,
      pedicle screw constructs may obviate the need for neural canal dissection and
      potential neural element impingement by intracanal instrumentation. A 3-year
      consecutive series was performed to evaluate the use of transpedicular screw
      fixation in the treatment of unstable thoracic spine injuries. OBJECTIVE: This
      study was performed to evaluate the efficacy of transpedicular screw fixation in
      the upper, middle, and lower thoracic spine. SUMMARY OF BACKGROUND DATA: The use
      of rod/hook and rod/wiring techniques has been evaluated in the treatment of
      thoracic spine injuries. To date, a study evaluating the safety and efficacy of
      pedicle screw instrumentation in the upper, middle, and lower thoracic spine has
      not been reported. METHODS: Thirty-two patients with 79 individual vertebral
      injury levels (T2-L1) treated with transpedicular spinal stabilization and bone
      fusion were evaluated during a 3-year consecutive series from 1998 to 2001.
      Patient charts, operative reports, preoperative and postoperative radiographs,
      computed tomography scans, and postoperative follow-up examinations and
      radiographs were reviewed from the time of surgery to final follow-up assessment.
      Radiographic measurements included: sagittal index, Gardner segmental kyphotic
      deformity, and compression percentage. RESULTS: A total of 252 pedicle screws
      were placed, of which 222 were placed in segments T2-L1. Clinical examination and
      plain radiographs were used to determine the presence of a solid fusion. Fracture
      healing and radiographic stabilization occurred at an average of 4.8 months after
      the initial operation. There were no reported cases of hardware failure, loss of
      reduction, or painful hardware removal. Two hundred fifty-two transpedicular
      screws were successfully placed without intraoperative complications. The mean
      preoperative sagittal index was 13.9 degrees, whereas the mean follow-up was 5.25
      degrees (P < 0.001). The mean final correction of sagittal index achieved was
      8.65 degrees, or a 62.2% improvement. The mean Gardner segmental kyphotic angle
      was 15.9 degrees, whereas the mean follow-up angle was 10.6 degrees (P < 0.0005).
      The mean compression percentage was 35.4, and at follow-up was 27.4 (P < 0.07).
      CONCLUSIONS: In carefully selected instances, pedicle screw fixation of upper,
      middle, and lower thoracic and upper thoracolumbar spinal injuries is a reliable
      and safe method of posterior spinal stabilization. Transpedicular screw fixation
      may offer superior three-column control in the absence of posterior element
      integrity and obviates the need for intracanal placement of hardware.
      Transpedicular instrumentation provides rigid fixation for upper, middle, and
      lower unstable thoracic spine injuries and produces early pain-free fusion
      results. These results provide evidence that with appropriate preoperative
      radiographic evaluation of pedicular size and orientation using computed
      tomography as well as radiograph assessment, transpedicular instrumentation is a
      safe and effective alternative in the treatment of unstable thoracic (T2-L1)
      spinal injuries.

PMID- 12486348
TI  - Pediatric spinal cord injury without radiographic abnormality (SCIWORA): the
      absence of occult instability and lack of indication for bracing.
AB  - STUDY DESIGN: A retrospective review of medical records and imaging studies of
      children diagnosed with spinal cord injury without radiographic abnormality
      (SCIWORA) or SCIWORA-like symptoms at Children's Hospital of Pittsburgh between
      1965 and 1999 was undertaken. OBJECTIVES: To evaluate the existence of occult
      segmental spinal instability and a role for bracing as treatment for SCIWORA, we
      contrasted the Children's Hospital of Pittsburgh experience with literature
      reports on SCIWORA. SUMMARY OF BACKGROUND DATA: There is a great deal of
      confusion and conflicting evidence regarding pediatric SCIWORA in the literature.
      Previous reports from our institution reported unique findings, including the
      only description of serious, recurrent SCIWORA in the literature. These findings
      have frequently been cited as the justification for long-term immobilization in
      all cases of SCIWORA. METHODS: All records on patients coded as spinal cord
      injury without fracture or dislocation (ICD-9 code 952.xx) were reviewed.
      Children 17 years of age or younger with traumatic spinal cord injury and normal
      plain radiographic findings were included. Penetrating trauma, infection, or
      metabolic diseases were excluded. RESULTS: A total of 189 patients were diagnosed
      with SCIWORA at our institution over the 35-year review period. These patients
      differed from those reported in the literature with respect to a higher
      incidence, older age, less involved neurologic injury, and more low-energy
      mechanisms, such as sports and falls. There were no cases of a patient with
      SCIWORA who deteriorated and developed a permanent neurologic deficit after
      having either recovered or plateaued from an initial SCIWORA. All recurrent
      SCIWORA recovered to normal neurologic function. Bracing did not demonstrate any
      benefit in preventing these minor recurrent SCIWORAs. CONCLUSION: We identified
      no cases of serious, recurrent SCIWORA at our institution from 1965 to 1999. A
      case-by-case evaluation is required for the treatment of spinal cord injury
      without apparent spinal column injury, and bracing is not uniformly indicated.

PMID- 12486350
TI  - Identifying sources of variability in scoliosis classification using a rule-based
      automated algorithm.
AB  - STUDY DESIGN: Use of a rule-based automated algorithm to determine sources of
      variability in radiographic classification. OBJECTIVES: To determine whether
      unambiguous rules encoded in a computer program would ensure reliable
      classification. SUMMARY OF BACKGROUND DATA: Reliability problems have been
      identified in classifications used in surgical planning for patients with
      thoracic idiopathic scoliosis, but the sources of unreliability are not
      understood. METHODS: Objective classification methodology was tested on the King
      et al (1983) scheme. There were two novel components: 1) positions of the corners
      of vertebrae in radiographs were digitized relative to a defined axis system and
      used in automated evaluation of spinal shape parameters required for
      classification; and 2) the assignment of a classification was done with a rule
      based algorithm. The algorithm was implemented after some ambiguities and absence
      of precise definitions in the King et al classification scheme had been resolved.
      The algorithm was tested with radiographs of patients having adolescent
      idiopathic scoliosis. RESULTS: The automated procedure could encounter
      reliability problems in cases in which a lumbar curve was very close to crossing
      the midline, thoracic and lumbar curves were of approximately equal value, when
      the apex level in the thoracolumbar region was ambiguous, when a Cobb angle was
      close to 10 degrees, or when the flexibility index was close to unity.
      CONCLUSION: Objective measurements and rule-based algorithms can eliminate some
      sources of interobserver and intraobserver errors in classification of spinal
      deformity. When classification parameters fall close to the boundaries for
      classification, reliability problems will persist.

PMID- 12486351
TI  - The diagnostic value of contrast-enhanced magnetic resonance imaging in the
      detection of experimentally induced anular tears in sheep.
AB  - STUDY DESIGN: An investigation of the visualization of experimental anular tears
      using contrast-enhanced magnetic resonance imaging. OBJECTIVES: To investigate
      how different kinds of experimentally induced anular tears can be visualized on
      contrast-enhanced magnetic resonance imaging. SUMMARY OF BACKGROUND DATA: Because
      the outer part of the anulus is innervated, tears of this part of disc are
      considered one cause for lumbar back pain. Moreover, clinical and experimental
      studies suggest that anular injuries may lead to a progressive degeneration of
      the entire disc. In the human disc, vascularized anular tears associated with
      disc degeneration can be visualized with contrast-enhanced magnetic resonance
      imaging, but acute peripheral anular injuries, probably caused by sudden trauma,
      have not been studied with this method. METHODS: Two adjacent lumbar discs in
      adult sheep (n = 11) were injured with a scalpel blade. The L2-L3 discs were
      injured superficially, whereas in the L3-L4 discs, the incision reached the
      nucleus pulposus (full-thickness injury). In seven animals, only a stab incision
      was made to the disc, and in four animals, a small fragment (5 x 2 x 3 mm) of
      anulus was cut and removed. The animals were killed 3 weeks (acute injury, n = 5)
      and 3 months (subacute injury, n = 6) after surgery. Five minutes before death,
      gadolinium-diethylenetriaminepentaacetic acid was injected intravenously. After
      death, the whole lumbar spines were excised and 1.5-T high-field magnetic
      resonance imaging was immediately performed. Thereafter, the disc samples were
      examined histologically to determine the existence of blood capillaries. RESULTS:
      In all injured discs, the injured area was macroscopically visible.
      Histologically, blood capillaries, lamellar destruction, and granulation tissue
      were clearly seen in every injured anulus. Contrast-enhanced magnetic resonance
      imaging showed that the superficial injuries were only occasionally visible in
      magnetic resonance imaging (3 of 11), whereas the full-thickness injuries were
      visible in a majority of the discs (8 of 11). In magnetic resonance imaging, the
      size of the injury did not relate to the enhancement intensity. The subacute
      injuries, particularly the full-thickness injuries, were more often visualized
      than the acute ones. CONCLUSION: Even though macroscopically visible and
      histologically evident, it was not always possible to demonstrate experimental
      anulus injuries by contrast-enhanced magnetic resonance imaging. This
      experimental study shows that further research work is needed to develop more
      sensitive methods to detect peripheral, relatively small, but probably clinically
      important disc injuries.

PMID- 12486352
TI  - Detection of lumbosacral nerve root compression with a novel composite nerve
      conduction measurement.
AB  - STUDY DESIGN: Multivariate logistic regression techniques were used to develop a
      composite nerve conduction measurement that detects lumbosacral (L5, S1, or both)
      nerve root compression. OBJECTIVES: To evaluate the diagnostic efficacy of a
      composite nerve conduction measurement for detection of lumbosacral nerve root
      compression. SUMMARY OF BACKGROUND DATA: Nerve root involvement is characterized
      by clinical abnormalities and confirmed by radiologic and electrodiagnostic
      studies. Imaging studies visualize structural abnormalities; however, they are
      associated with high false-positive rates. Electrodiagnostic methods assess the
      physiologic integrity of the nerve roots. One form of electrodiagnostic testing,
      nerve conduction studies, is widely used for evaluation of musculoskeletal and
      neuromuscular complaints. Although similar clinical value is expected for the
      evaluation of nerve root compromise, prior applications of nerve conduction
      studies have yielded widely varying results. METHODS: Two groups of subjects were
      compared. The L5-S1 compression group was composed of 25 patients with magnetic
      resonance imaging-confirmed lumbosacral (L5, S1, or both) nerve root compression
      and symptoms in the appropriate segmental distribution. The majority of subjects
      (22) had at least one of the following findings on physical examination: positive
      straight-leg raise test, diminished ankle reflexes, sensory loss, or weakness.
      The control group consisted of 35 asymptomatic individuals with no history of
      radiculopathy or potentially confounding neuropathology. The posterior tibial and
      deep peroneal nerves were evaluated bilaterally in all study subjects using
      standard nerve conduction procedures, which consisted of the measurement of
      distal motor latencies and F-wave latencies that assess nerve root
      pathophysiology. A composite nerve conduction measurement was determined using
      multivariate logistic regression analysis. The efficacy of the composite
      measurement was assessed by receiver operating characteristic curve analysis and
      by the diagnostic sensitivity and specificity. RESULTS: Five F-wave latency
      parameters (peroneal mean F-wave latency, odds ratio = 0.42; peroneal seventh F
      wave latency decile, odds ratio = 2.71; tibial mean F-wave latency, odds ratio =
      8.90; tibial first F-wave latency decile, odds ratio = 0.47; tibial maximum F
      wave latency, odds ratio = 0.44) were found to be predictive of nerve root
      compression. A composite nerve conduction measurement, NC composite, constructed
      from these five parameters (NC composite = exp(phi)/(1 + exp(phi)), phi = -31.2 +
      1.0 * Per7 Decile - 0.88 * PerMean + 2.2 * TibMean - 0.88 * Tib1 Decile - 0.83 *
      TibMax) yielded an area under the receiver operating characteristic curve of
      0.91. At a threshold of 0.20, NC composite had a diagnostic specificity of 84.3%
      and a sensitivity of 83.3%. CONCLUSION: This preliminary study suggests that a
      novel composite nerve conduction measurement, based on F-wave latency parameters,
      may be highly effective at detecting magnetic resonance imaging-confirmed
      lumbosacral nerve root compression. Because these measurements provide objective
      evidence of functional nerve root compromise and are noninvasive, they may be of
      diagnostic value to clinicians evaluating patients presenting with low back and
      leg pain.

PMID- 12486354
TI  - The prognostic value of asymmetric laxity of the sacroiliac joints in pregnancy
      related pelvic pain.
AB  - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To determine the prognostic
      value of asymmetric laxity of the sacroiliac joints during pregnancy on pregnancy
      related pelvic pain postpartum. SUMMARY OF BACKGROUND DATA: In a previous study,
      we observed a significant relation between asymmetric laxity of the sacroiliac
      joints and moderate to severe pregnancy-related pelvic pain during pregnancy.
      METHODS: A group of 123 women were prospectively questioned and examined, and
      sacroiliac joint laxity was measured by means of Doppler imaging of vibrations at
      36 weeks' gestation and at 8 weeks' postpartum. A left to right difference in
      sacroiliac joint laxity >or=3 threshold units was considered to indicate
      asymmetric laxity of the sacroiliac joints. RESULTS: In subjects with moderate to
      severe pregnancy-related pelvic pain during pregnancy, sacroiliac joint
      asymmetric laxity was predictive of moderate to severe pregnancy-related pelvic
      pain persisting into the postpartum period in 77% of the subjects. The
      sensitivity, specificity, and positive predictive value of sacroiliac joint
      asymmetric laxity during pregnancy for pregnancy-related pelvic pain persisting
      postpartum were 65%, 83%, and 77%, respectively. Subjects with moderate to severe
      pregnancy-related pelvic pain and asymmetric laxity of the sacroiliac joints
      during pregnancy have a threefold higher risk of moderate to severe pregnancy
      related pelvic pain postpartum than subjects with symmetric laxity. CONCLUSION:
      These data indicate that in women with moderate to severe complaints of pelvic
      pain during pregnancy, sacroiliac joint asymmetric laxity measured during
      pregnancy is predictive of the persistence of moderate to severe pregnancy
      related pelvic pain into the postpartum period.

PMID- 12486355
TI  - Spinal injury patterns resulting from car and motorcycle accidents.
AB  - STUDY DESIGN: Retrospective data analysis. OBJECTIVES: To determine spinal injury
      patterns and clinical outcomes in patients involved in automotive accidents.
      SUMMARY OF BACKGROUND DATA: The records of 22,858 patients collected
      prospectively as part of the Trauma Audit Research Network (UK) Database (1993
      2000). METHODS: Analysis of the records of 1121 motorcyclists and 2718 car
      occupants involved in automotive trauma. RESULTS: Spinal injury occurred in 126
      (11.2%) motorcyclists and 383 (14.1%) car occupants. Victims were predominantly
      young (mean ages: motorcycle 30.2 years, car 37.8 years) and male (motorcycle
      88.9%, car 60.6%). The mean Injury Severity Scores were 18.8 and 15.1,
      respectively. Isolated spinal injuries occurred in 30 (23.8%) motorcyclists and
      130 (33.9%) car occupants. The thoracic spine was most commonly injured in
      motorcyclists (54.8%), and the cervical spine was most commonly injured in car
      occupants (50.7%). Multiple regions were injured in 14 (10.3%) motorcyclists and
      33 (8.5%) car occupants. Nine motorcyclists and 43 car occupants required spinal
      surgery. Median hospital stays were 11.5 days (range 0-235 days) and 10 days
      (range 0-252 days) in the motorcyclists and car occupants, respectively. There
      were 13 (10.3%) motorcycle- and 26 (6.8%) car-related deaths. CONCLUSION: Spinal
      injury patterns may reflect differing mechanisms of injury between the restrained
      car occupant and unrestrained motorcyclist. The motorcyclists were more severely
      injured, had more extremity trauma, a higher mortality rate, and a spinal injury
      pattern consistent with forced hyperflexion of the thoracic spine. The
      predominance of cervical injuries and higher incidence of neck and facial
      injuries in car occupants may reflect abdominothoracic seat belt restraint. The
      high frequency of multilevel injuries reaffirms the need for vigilance in patient
      assessment.

PMID- 12486356
TI  - Incidence of four syndromes of pregnancy-related pelvic joint pain.
AB  - STUDY DESIGN: A prospective epidemiologic cohort study. OBJECTIVE: To determine
      the incidence of clearly defined pelvic joint pain in pregnancy based on both
      history and objective confirmation and to classify pelvic joint pain into four
      groups and determine their incidence. SUMMARY AND BACKGROUND DATA: Pelvic and low
      back pain in pregnancy is a substantial problem, and the correct treatment is
      hampered by several factors, such as the lack of clearly defined clinical
      conditions, variety of nomenclature, and great variance in reported incidence
      (range 4-76.4%). This variation in incidence is a problem that calls for a
      clearly defined criteria and a study design aimed at resolving such varying
      incidence rates. METHODS: All pregnant women booked for delivery at two Danish
      hospitals over a 1-year period were offered to participate in the study in week
      33 of gestation. Women who reported daily pain from pelvic joints, which could be
      objectively confirmed, were divided, according to symptoms, into five subgroups:
      four classification groups (pelvic girdle syndrome, symphysiolysis, one-sided
      sacroiliac syndrome, and double-sided sacroiliac syndrome) and one miscellaneous.
      A total of 1460 women formed the incidence cohort based on geographic criteria.
      RESULTS: A total of 293 women (20.1%) were found to have pelvic joint pain
      divided in one of the four classification groups: pelvic girdle syndrome 6.0%,
      symphysiolysis 2.3%, one-sided sacroiliac syndrome 5.5%, and double-sided
      sacroiliac syndrome 6.3%. CONCLUSION: This study proposes new, more precise
      procedures for the identification and classification of pregnancy-related pelvic
      joint pain based on both reports from the women and a physical examination.
      Presumably, the 20.1% incidence rate, identified in the present study, represents
      the most precise and reliable information available hitherto, regarding the
      incidence of pregnancy-related pelvic joint pain.

PMID- 12486357
TI  - A clinical prediction rule for classifying patients with low back pain who
      demonstrate short-term improvement with spinal manipulation.
AB  - STUDY DESIGN: A prospective, cohort study of patients with nonradicular low back
      pain referred to physical therapy. OBJECTIVE: Develop a clinical prediction rule
      for identifying patients with low back pain who improve with spinal manipulation.
      SUMMARY OF BACKGROUND DATA: Development of clinical prediction rules for
      classifying patients with low back pain who are likely to respond to a particular
      intervention, such as manipulation, would improve clinical decision-making and
      research. METHODS: Patients with nonradicular low back pain underwent a
      standardized examination and then underwent a standardized spinal manipulation
      treatment program. Success with treatment was determined using percent change in
      disability scores over three sessions and served as the reference standard for
      determining the accuracy of examination variables. Examination variables were
      first analyzed for univariate accuracy in predicting success and then combined
      into a multivariate clinical prediction rule. RESULTS: Seventy-one patients
      participated. Thirty-two had success with the manipulation intervention. A
      clinical prediction rule with five variables (symptom duration, fear-avoidance
      beliefs, lumbar hypomobility, hip internal rotation range of motion, and no
      symptoms distal to the knee) was identified. The presence of four of five of
      these variables (positive likelihood ratio = 24.38) increased the probability of
      success with manipulation from 45% to 95%. CONCLUSION: It appears that patients
      with low back pain likely to respond to manipulation can be accurately identified
      before treatment.

PMID- 12486358
TI  - Changes in the microhemodynamics of nerve root retraction in patients with lumbar
      spinal canal stenosis.
AB  - STUDY DESIGN: Assessment of qualitative and quantitative changes in the
      microcirculation of nerve roots, such as the diameter of blood vessels and the
      low rate of erythrocytes, was observed during lumbar interbody fusion. OBJECTIVE:
      To ascertain changes in the microcirculation of nerve roots before and after
      retraction during lumbar interbody fusion surgery. SUMMARY OF BACKGROUND DATA:
      The changes in microhemodynamics caused by nerve root retraction have not yet
      been elucidated. METHODS: Subjects were patients with lumbar spinal canal
      stenosis who underwent lumbar interbody fusion. Changes in the microcirculation
      of nerve roots were examined in the L5 nerve root in 26 patients and the S1 nerve
      root in 3 patients. Through the use of video images captured by contact endoscope
      and stored in a computer, erythrocytes were automatically followed to measure
      flow rate and the diameter of blood vessels. RESULTS: Plasma skimming, where
      blood cells and plasma flow separately, was seen in 3 of the 29 patients (10.3%)
      before retraction of the nerve root and in 8 of the 29 patients (27.6%) following
      retraction. Intravascular erythrocyte agglutination, when erythrocytes flow in
      clumps due to changes in the charge state of erythrocytes, was seen in blood
      vessels larger than 100 microm in 3 patients (10.3%) after retraction. Following
      nerve root retraction, the flow rate of erythrocytes through blood vessels
      decreased an average of 23.9% (P< 0.005). CONCLUSIONS: A contact endoscope was
      used to observe the microhemodynamics of nerve roots before and after retraction
      of the nerve root during lumbar interbody fusion surgery, and a decrease in the
      flow rate of erythrocytes was observed.

PMID- 12486359
TI  - Intraoperative monitoring with near-infrared spectroscopy (NIRS).

PMID- 12486360
TI  - Anterior lumbar interbody fusion with processed sea coral (coralline
      hydroxyapatite) as part of a circumferential fusion.
AB  - STUDY DESIGN: A retrospective review of 20 patients undergoing circumferential
      lumbar fusion with coralline hydroxyapatite blocks anteriorly and autograft with
      transpedicular or translaminar facet screw fixation posteriorly. OBJECTIVES: To
      examine the efficacy of coralline hydroxyapatite as a bone graft substitute for
      anterior lumbar interbody fusion. SUMMARY OF BACKGROUND DATA: Autograft is the
      gold standard for bone grafting in the anterior lumbar spine. Harvesting bone
      from the iliac crest leads to significant postoperative pain and morbidity.
      Femoral ring allograft is a widely used alternative to autograft but has some
      inherent problems. Coralline hydroxyapatite was shown to be 100% successful for
      anterior cervical fusion when combined with rigid plating. METHODS: A
      retrospective review of 20 patients with low back pain and indicated for surgical
      intervention. A circumferential instrumented fusion was performed with coralline
      hydroxyapatite blocks anteriorly and transpedicular or translaminar facet
      fixation and autograft posteriorly. All patients reached a minimum 3-year
      clinical and radiologic follow-up. RESULTS: Radiographic follow-up yielded a
      solid arthrodesis rate of 93.8% by level (30 of 32 disc spaces) and 90% by
      patient (18 of 20). Clinical follow-up generated a mean pain reduction of 61.8%
      with clinical success demonstrated in 80% (16 of 20) of all patients who reported
      good or excellent pain relief. Eight of 12 (66.7%) patients employed before
      surgery returned to work in some capacity. CONCLUSIONS: Coralline hydroxyapatite
      is a practicable anterior lumbar interbody fusion alternative to autograft and
      allograft as part of a circumferential fusion with rigid posterior fixation. It
      is not recommended for stand-alone anterior lumbar interbody fusion without
      further study.

PMID- 12486363
TI  - Superior mesenteric artery syndrome following surgery for scoliosis.
AB  - STUDY DESIGN: A retrospective report of three cases outlining upper intestinal
      obstruction as a rare complication following surgery for scoliosis. OBJECTIVE: To
      present the clinical features, progression, and management of duodenal
      obstruction due to superior mesenteric artery compression after surgical
      treatment of scoliosis. SUMMARY OF BACKGROUND DATA: Superior mesenteric artery or
      cast syndrome has been reported historically in the literature. Many causes are
      described, among which is the complication of the surgical and nonoperative
      treatment of scoliosis. METHODS: Three adolescent patients were investigated for
      nausea and vomiting following surgical correction of scoliosis. RESULTS: Contrast
      radiography confirmed extrinsic obstruction of the third part of the duodenum by
      the superior mesenteric artery in all three patients. They were jointly managed
      with the gastrointestinal surgeons. Two patients recovered with conservative
      treatments, but the third required operative intervention with a laparotomy.
      CONCLUSIONS: Vomiting following surgery for scoliosis should be investigated
      thoroughly, as superior mesenteric artery syndrome carries significant morbidity,
      protracted hospital stay, and potential mortality.

PMID- 12486364
TI  - Traumatic spinal subdural hematoma with spontaneous resolution.
AB  - STUDY DESIGN: A case report with a literature review is presented. OBJECTIVE: To
      describe and review the clinical presentations, characteristic findings from
      imaging studies, and treatment of traumatic spinal subdural hematoma. SUMMARY OF
      BACKGROUND DATA: Traumatic spinal subdural hematoma is uncommon, and only eight
      cases have been reported in the literature. Concomitant intracranial and spinal
      subdural hematoma in the same patient has not been well studied. METHODS: A case
      of concomitant spinal and intracranial subdural hematoma is reported as well as a
      review of the literature. RESULTS: Including our patient, we found that five of
      the nine patients with traumatic spinal subdural hematoma also had intracranial
      hematoma. We hypothesize that the mechanism of traumatic spinal subdural hematoma
      may be associated with intracranial events. Recognition of blood products in
      magnetic resonance imaging scans is important to distinguish spinal subdural
      hematoma from other spinal lesions. It is generally agreed that prompt
      laminectomy with evacuation of hematoma should be performed before irreversible
      damage to the spinal cord occurs. However, including our patient, three of the
      nine reported cases with thoracic or lumbar subdural hematoma resolved
      spontaneously with conservative treatment. CONCLUSIONS: This 12-year-old boy
      illustrated the rapid spontaneous resolution of traumatic subdural hematoma in
      both left hemisphere and lumbar spine with conservative treatment. This report
      suggests a possible role of conservative management for traumatic lumbar subdural
      hematoma, especially when the patients already have neurologic recovery.

PMID- 12486365
TI  - Hemimetameric segmental shift: a case series and review.
AB  - STUDY DESIGN: A case series of patients with hemimetameric shift. OBJECTIVES: To
      describe the radiographic and physical findings as well as treatment provided to
      a subset of patients with congenital scoliosis. SUMMARY OF BACKGROUND DATA:
      Hemimetameric segmental displacement, or hemimetameric shift, is a clinical
      entity defined by two contralateral hemivertebrae separated by at least one
      normal vertebra. Although the entity is briefly described in textbooks, there are
      no published series to date. METHODS: From 1974 to 2000, 186 cases of congenital
      scoliosis were identified from two referral centers. Of these, 27 cases (15%) of
      hemimetameric shift were identified. Medical records and radiographs were
      reviewed, as well as magnetic resonance imaging when available. RESULTS: There
      were an average of 2.9 hemivertebrae per patient (range 2-6) with the following
      distribution: T1-T6 (29), T7-T11 (28), T12-L1 (10), L2-L4 (11), and L5 (1). The
      average curve magnitude at presentation was 28 degrees (range 9 degrees -55
      degrees). Nine patients required surgery-most commonly with involvement of the
      thoracolumbar or lumbosacral junction. Eleven patients also had associated
      anomalies to include Klippel-Feil syndrome (3), Goldenhar syndrome (2),
      imperforate anus (2), tracheoesophageal fistula (2), and a single kidney (2).
      There was only one patient who had an abnormal magnetic resonance imaging (1 out
      of 17; 6%). CONCLUSIONS: Hemimetameric shift is a common finding in congenital
      scoliosis. Hemivertebrae are most commonly found in the thoracic spine; however,
      surgical intervention is most commonly observed when the caudal hemivertebrae is
      located from the thoracolumbar to lumbosacral junction. The incidence of abnormal
      magnetic resonance imaging findings is low (6%).

PMID- 12486366
TI  - Primary leptomeningeal melanoma.
AB  - STUDY DESIGN: A retrospective review of a case of primary leptomeningeal
      melanoma. OBJECTIVES: To present a previously undescribed tumor of the lumbar
      meninges. BACKGROUND: The case described the first report of lumbar localization
      and of bony metastasis of this tumor. METHODS: The authors present a case of a 65
      year-old man with a destruction of the fifth lumbar vertebra and an exacerbation
      of lumbar pain and acute sensorimotor radiculopathy. RESULTS: The histologic
      examination of the resected tissue after the transpedicular stabilization
      suggested the presence of metastatic melanoma. After the development of
      progressive paraplegia and a second operation, subsequent histologic examination
      of the resected tissue showed the lesion to be a primary leptomeningeal melanoma.
      The patient's condition deteriorated progressively, and 31 days after
      confirmation of the diagnosis, he died of meningeal melanomatosis. CONCLUSION: By
      indicating the possibility of hitherto unreported sites of occurrence, routes of
      metastatic spread, and manifestations of this malignant tumor, this case report
      may contribute to the further elucidation of this disease.

PMID- 12486367
TI  - Depression and health-related quality of life.
AB  - Chronic medical conditions drastically affect the lives of those afflicted,
      leading to pain, disability, and disruption. Comorbid depression can exacerbate
      the effects of medical illness and may be an independent source of suffering and
      disability. Data from the Epidemiological Follow-Up Study (NHEFS) of the first
      National Health and Nutrition Examination Survey (NHANES I) are used to examine
      the manner in which depression and comorbid medical conditions interact to affect
      health-related quality of life (HRQOL). The findings suggest a) that the effects
      of depression are comparable with those of arthritis, diabetes, and hypertension;
      and b) that depression and chronic medical illnesses interact to amplify the
      effects of the medical illness. The data also support the merit of adopting a
      multidimensional approach to HRQOL rather than treating it unidimensionally.

PMID- 12486368
TI  - Posttraumatic stress disorder symptoms influence health status of deployed
      peacekeepers and nondeployed military personnel.
AB  - Posttraumatic stress disorder (PTSD) is associated with depression and alcohol
      abuse. PTSD symptoms also contribute to poor health among military veterans. The
      aim of the present study was to test models pertaining to the direct and indirect
      influences of PTSD symptoms on the health status of deployed and
      sociodemographically comparable nondeployed military personnel. Participants were
      1,187 deployed male peacekeepers and 669 nondeployed male military personnel who
      completed a battery of questionnaires, including measures of PTSD symptoms,
      depression, alcohol use, and general health status. Structural equation modeling
      was used to test predictions regarding the direct and indirect influences of PTSD
      symptoms on health status. Results indicate that PTSD symptoms have a direct
      influence on health, regardless of deployment status. PTSD symptoms also
      indirectly promote poorer health through influence on depression, but not alcohol
      use, in deployed and nondeployed peacekeepers. Increased alcohol use did not
      contribute to poorer health beyond the contribution of PTSD symptoms alone.
      Future research directions are discussed.

PMID- 12486369
TI  - Traumatic stress responses in treatment-seeking earthquake survivors in Turkey.
AB  - This study examined the incidence of posttraumatic stress disorder (PTSD) and
      depression in 1,027 earthquake survivors who were consecutively referred to a
      community center at a mean of 14 months after the August 1999 earthquake in
      Turkey. Seventy-seven percent of referrals were women. The estimated rates of
      PTSD and major depression were 63% and 42%, respectively. More severe PTSD
      symptoms related to greater fear during the earthquake, female gender, lower
      education, loss of friends, shorter time since the earthquake, and material loss.
      More severe depression symptoms related to female gender, longer time since the
      earthquake, lower educational level, loss of a family member, and past
      psychiatric illness. In conclusion, long-term public mental health policies are
      needed for postearthquake psychological problems. These policies need to take
      into account the risk factors for traumatic stress and the gender differences in
      referral patterns. The differential stressor-response relationship may have
      important implications for treatment.

PMID- 12486370
TI  - Posttraumatic, dissociative and grief symptoms in Turkish children exposed to the
      1999 earthquakes.
AB  - Grief and dissociation after traumatic exposures are among the most important
      predictors of posttraumatic stress disorder (PTSD). This article introduces the
      Traumatic Dissociation and Grief Scale (TDGS), a 23-item measure easily
      administered. The TDGS, the Child PTSD-Reaction Index (CPTSD-RI), and a
      questionnaire concerning risk factors related to the event (losses, injury, and
      witnessing death and injuries) were administered to school-aged children who had
      been directly exposed to the 1999 earthquakes in Turkey and to a nonexposed
      control group. Factor analysis of the TDGS yielded four factors: perceptual
      distortions, body-self distortions, irritability, and guilt and anhedonia. A
      moderate positive correlation was noted between the TDGS and the CPTSD-RI.
      Different sets of risk factors were associated with the different scale factors.
      The results suggest that the assessment of psychopathology in children following
      a disaster requires the complementary evaluation of symptoms of posttrauma,
      dissociation, and grief.

PMID- 12486371
TI  - Psychiatric patients' vulnerability in the wake of the September 11th terrorist
      attacks.
AB  - The September 11, 2001 (9/11) terrorist attacks led to speculation about the
      vulnerability of psychiatric patients to psychological distress following such
      events. This study examined the impact of national terrorist attacks on
      psychiatric and medical outpatients living approximately 150 to 200 miles from
      the attack sites (N = 308). Two to 3 weeks following 9/11, patients were given
      questionnaires assessing background information, healthcare service utilization,
      and posttraumatic stress disorder (PTSD) symptoms. Psychiatric patients (33%)
      were significantly more likely than medical patients (13%) to report distressing
      symptoms meeting criteria for PTSD (except for the duration criterion) despite no
      differences in learning about the attacks or personal involvement with the
      victims. Patients meeting PTSD criteria were more likely to schedule an
      appointment to speak with their physician about their reactions. Psychiatric
      patients not directly impacted by the 9/11 terrorist attacks are at increased
      risk for experiencing distressing symptoms following national terrorist attacks.

PMID- 12486372
TI  - Exposure to trauma: the long-term effects of suppressing emotional reactions.
AB  - A cross-sectional study of 437 ambulance officers in a large state of Australia
      examined the long-term effects of suppressing emotion reactions to exposure to
      trauma. Results indicate that the use of emotion-suppressing defenses (e.g.,
      withdrawal or acting out) have a highly significant positive relationship with
      physical and psychological stress symptoms. Alexithymia scores were also
      positively associated with stress symptoms. In addition, there was a positive
      association between years of ambulance service and stress symptoms. Implications
      of the findings are discussed for recovery from exposure to trauma of emergency
      services personnel and more generally to the experience of survivors of trauma.

PMID- 12486373
TI  - Comparison of insight in patients with schizophrenia and bipolar disorder in
      remission.

PMID- 12486374
TI  - [Airborne particles: where are they taking us?].

PMID- 12486375
TI  - [Critical analysis of a parallel group randomized trial].
AB  - Reading a clinical trial must not be limited to examining the result. It is
      essential to analyze the study methodology, the only guarantee of valid results.
      Among the standard methodological elements required for clinical trials, the
      notions of a controlled, randomized, double-blind study are of utmost importance.
      The results should also be interpreted in light of the main outcome, as well as
      the selection criteria used to establish the study groups. Finally, the results
      should be interpreted in terms of their clinical relevance, which is not
      necessarily implied by statistical significance.

PMID- 12486376
TI  - [Contribution of DNA chips in lung cancer: an update].
AB  - Progress in techniques and computer processing over the last few years have led
      to the development of new methods of molecular biology. These new methods allow
      rapid data processing, often allowing data to be shared via networks. An example
      of this new technology is the transcriptome analysis via a microarray chip. This
      chip allows analysis of a very large number of RNA messenger transcripts that can
      be used for diagnostic or prognostic purposes. The first applications in lung
      cancer have been aimed to distinguish pulmonary adenocarcinoma from other
      adenocarcinomas. Another approach is to use these chips as a diagnostic tool to
      identify genes with expressions specific for non-small-cell lung cancer. The
      early results have been promising and encouraging for future developments,
      particularly in the domain of applied therapeutics.

PMID- 12486377
TI  - [Bronchial endoscopy for the diagnosis of tuberculous mediastinal adenopathies].
AB  - The aim of this retrospective study was to evaluate the yield of bronchial
      endoscopy for the diagnosis of tuberculous mediastinal adenopathies. We analyzed
      the results in 200 procedures in patients with tuberculous mediastinal
      adenopathies. Mediastinal tuberculous adenopathies were found in 6% of the
      patients with tuberculosis diagnosed during the same period. Mean age of the
      patients was 30.5 years, and the sex ratio was 1.5. Bronchial endoscopy improved
      the diagnostic yield of the bronchial aspiration fluid (22% versus 11% without
      endoscopy). This method allowed positive diagnosis of tuberculosis in 164
      patients (82%) by visualizing specific lesions such as compressions,
      granulations, and gangliobronchial fistulae. Histological confirmation was
      obtained in 72 (79%) patients among 91 biopsy specimens. Bronchial endoscopy
      remains a crucial exploration for the diagnosis of mediastinal tuberculous
      adenopathy, even in HIV-infected patients, because in our series, among 101
      treated patients, 99 were HIV positive (98%).

PMID- 12486378
TI  - [Asthma from tropical abachi wood].
AB  - We report the case of a 28-year old man suffering from rhinitis and asthma which
      appeared 8 years after exposure to different woods, especially abachi wood.
      Serial PEFR monitoring at work and away from work were consistent with
      occupational asthma. Spirometry showed an airway obstruction, and metacholine
      inhalation test was positive. Skin prick-tests performed with different woods
      were only positive to abachi wood extract. The search for specific IgE was
      positive to abachi wood (4, 98 KU/l, class 3). The diagnosis of occupational
      asthma caused by exposure to abachi wood was established, the mechanism
      underlying this asthma was IgE mediated. Despite respiratory protection measures,
      the patient had persisting symptoms and was laid off. The German service for
      social cover asked for an expert evaluation: specific nasal and inhalation
      provocation tests performed by exposure to fine abachi wood dust were positive.
      This is an observation with a double significance: first, although the mechanisms
      underlying wood occupational asthma remain largely unknown, an IgE mechanism for
      abachi wood was demonstrated; second, legislation is different in France and
      Germany where occupational asthma will only be acknowledged if inhalation tests
      are positive.

PMID- 12486379
TI  - [Endobronchial pulmonary rhabdomyosarcoma. A case report].
AB  - We report a case of pleiomorphous pulmonary rhabdomyosarcoma observed in a 64
      year-old patient with no history of soft tissue tumor. The tumor was found
      extending into the right lower and middle lobes. The intra-parenchymatous
      extension protruded into the middle lobular bronchus and was prolonged by a 4 cm
      polyp. The polyp extended up to the carina and reached the contralateral common
      bronchus. Outcome was fatal after surgery performed in an emergency setting due
      to asphyxia. Explorations could not be continued to determine the primary or
      secondary nature of the tumor. An intraparenchymatous endobronchial localization
      is uncommon. Primary rhabdomyosarcoma is generally a purely intra-parenchymatous
      tumor. The endobronchial localization has been described before but is very
      exceptional. This localization would also be exceptional for secondary
      rhabdomyosarcoma mimicking a primary malignant tumor. The histology study
      revealed an undifferentiated pleiomorphous tumor. Immunohistochemistry provided
      the final diagnosis.

PMID- 12486380
TI  - [Bronchectasia and microscopic polyangeitis].
AB  - Microscopic polyangeitis is a necrosing vascularitis with pulmonary and renal
      tropism. Localized in the lung, microscopic polyangeitis leads to intra-alveolar
      hemorrhage. We report our observations in two patients who presented with
      concomitant bronchectasia. The parallel course of these two conditions suggests a
      possible relationship. We propose a pathophysiological approach involving a
      direct role of polymorphonuclear neutrophils and neutrophilic proteases secreted
      in response to activation of anti-polymorphonuclear cytoplasm anti-bodies (ANCA)
      during microscopic polyangeitis aggravating bronchectasia.

PMID- 12486381
TI  - [Mature teratoma of the posterior mediastinum].
AB  - Mature teratoma is the most frequent primary germ-cell occurring in the anterior
      mediastinum. We report a case of a 67-year-old man with mature teratoma of the
      posterior mediastinum. Computed tomography was helpful in suggesting a diagnosis
      of mature teratoma by demonstrating the presence of fat and calcification.

PMID- 12486382
TI  - [Diagnostic difficulty of a pulmonary mass in an infant].

PMID- 12486383
TI  - [Contraception and neurology].
AB  - The purpose of this article is to clarify interactions between oral contraception
      (using low- and high-dose oral contraceptives) and the main neurological diseases
      occurring in genitally active women. Vascular disorders predominate, since
      contraception is in itself a well-recognized a risk factor, especially in case of
      other intercurrent risk factors (high blood pressure, smoking, diabetes, history
      of vascular event) contradicting contraception. Low-dose oral contraception can
      be proposed for women free of these risk factors. There is however a formal
      contraindication for oral contraception, even with mini-dose contraceptives, for
      women with a history of cerebral venous thrombosis. In case of migraine headache,
      which is also a risk factor of vascular disease (especially in case of aura),
      oral contraceptives should be discussed on an individual basis, depending on the
      presence of other risk factors. Contraception has no effect on epilepsy but oral
      contraceptives may be inhibited by inducing anti-seizure drugs. Non-inducing
      drugs are preferable. The course of certain brain tumors known to express
      estrogen or progesterone receptors (particularly meningiomas and
      hemangioblastomas) may worsen with oral contraception, which is formally
      contradicted except when search for hormone receptors is negative. Oral
      contraception has no influence in other disease such as multiple sclerosis

PMID- 12486384
TI  - [Families of patients with anorexia or bulimia. Review of the literature and
      therapeutic implications].
AB  - This review of literature summarizes current knowledge concerning family
      functioning and comorbidity in families of adolescents with eating disorders. We
      discuss involvement of the family in the treatment of eating disorders.

PMID- 12486385
TI  - [Giant cell arteritis after the age of 75].
AB  - Despite its increasing incidence giant cell arteritis is not well detected in the
      elderly. Response to corticosteroid treatment is the same before and after the
      age of 75, but there are many steroid-induced side effects, particularly bone
      fractures, in the elderly. Therefore, it is important to reduce the
      corticosteroid load in elderly and frail people. In this cases, 0.3 to 0.5mg/kg,
      or 15 to 25mg daily prednisone-equivalent dose at start seems to be enough to
      prevent blindness in simple forms. This dose has to be rapidly reduced whenever
      the C-reactive protein remains moderately elevated. Moreover, an anti-agregant or
      anticoagulant treatment must be associated at the beginning of steroid treatment
      to prevent ischemic complications, as well as biphosphonates, which could prevent
      corticosteroid-induced osteoporosis.

PMID- 12486386
TI  - [Sjogren's syndrome in the elderly].
AB  - Sjogren's syndrome is an immune exocrinopathy. This paper will deal with the
      primary Sjogren's syndrome non associated with another rheumatologic disease
      (polyarthritis or systemic lupus erythematosus). Its prevalence is claimed to
      increase with age. The main clinical manifestation is salivary and/or ocular
      dryness due to a lymphocytic infiltration of the salivary or lacrimal glands or
      both. However, sicca symptoms are very frequent in the elderly, most often
      iatrogenic. The problem, particularly in this population, is the diagnosis of
      Sjogren's syndrome. There are yet no consensual criteria, the most used in the
      literature are the European criteria, published in 1993 and revised in 1996. Some
      tests, such as the Schirmer's test and non stimulated salivary flow, are not
      specific over 60 years. The results of other tests are discussed as the focus
      score on the lip salivary glands biopsy. The diagnosis of Sjogren's syndrome
      should be envisaged in the elderly, when systemic manifestations are associated
      with sicca symptoms.

PMID- 12486387
TI  - [Amyloidosis and aging].
AB  - Amyloidosis is a heterogeneous group of extracellular protein deposition
      diseases. Age-related amyloidosis may be systemic or localized. The systemic
      forms include associated-myeloma AL amyloidosis and senile systemic amyloidosis
      which is the only clear-cut systemic form related to age and derived from normal
      transthyretin. In localized amyloidosis, the fibril protein precursors are
      synthesized in the tissue involved by the amyloid. In most cases, localized age
      related amyloidosis does not appear to cause clinical disease with the exception
      of amyloid associated with Alzeihmer's disease and type 2 diabetes mellitus. The
      significance of aortic amyloidosis, amyloidosis of seminal vesicles, amyloid of
      the endocrine glands, and articular amyloidosis remains unknown.

PMID- 12486388
TI  - [Other systemic diseases in the elderly].
AB  - The prevalence of systemic diseases depends on patient age. One third to one half
      of the patients with Wegener's granulomatosis are over 60 years at the diagnosis.
      In the elderly, renal insufficiency, lymphopenia and central nervous system
      involvement are more frequent, and upper airways involvement and hemoptysis less
      frequent. Signs suggestive of temporal arteritis may initiate the disease.
      Mortality is increased in the elderly, and aging is an independent predictor of
      poor prognosis. Henoch-Schonlein purpura is uncommon in adulthood; one quarter of
      adult cases involves an elderly patient. End-stage renal failure and association
      with neoplasia are common. In some cases, synchronous course of purpura and
      neoplasia leads to consider it as a true paraneoplastic syndrome. Periarteritis
      nodosa in the elderly is characterized by an increased frequency of the
      association with viral B hepatitis and skin vasculitis. Histological location of
      necrotizing arteritis involving the temporal artery is possible. It should be
      considered as a borderline disease, and treated as the more severe disease. Aging
      is predictive of poor prognosis. Cholesterol emboli are a classic complication of
      atheroembolic disease and may mimic an inflammatory and multisystemic disease
      with renal, cardiac, pulmonary, digestive, neuropsychiatric, skin and muscle
      involvements due to ischemic phenomena leading to necrosis. One-year mortality is
      over 60% in the symptomatic forms.

PMID- 12486389
TI  - [Comprehensive geriatric assessment: a useful tool for prevention of acute
      situations in the elderly].
AB  - Comprehensive geriatric assessment is a useful complement to the standard
      clinical examination of elderly people. It focuses on a systematic evaluation of
      functional status, dependency, cognitive functions, psychological status,
      continence, nutritional status and social way of life, administered by a
      multidisciplinary team. Standardized test, well-validated in the elderly, are
      used. Most studies have demonstrated the efficacy of geriatric assessment
      programs in outpatients, hospitalized patients or in emergency unit patients.
      Mostly useful in frail elderly patients, geriatric assessment results in a
      decrease in morbidity and dependency, shorter hospital stays and fewer referrals
      to nursing homes. By introducing adequate medical and social interventions,
      comprehensive geriatric assessment, even in very old people, is useful in
      preventing acute situations leading to emergency referrals.

PMID- 12486390
TI  - [Headache due to idiopathic intracranial hypotension. Three case reports].
AB  - Headaches were classified in 1988 by the International Headache Society (IHS).
      Postural headache is related to intracranial hypotension, most often secondary to
      lumbar puncture. We report three observations where headache of unknown cause led
      to the diagnosis of spontaneous intracranial hypotension.

PMID- 12486391
TI  - [Sarcoidosis and ankylosing spondylitis. A case report and review of the
      literature].
AB  - Ankylosing spondylitis is a very uncommon finding in patients with sarcoidosis.
      Thirteen cases have been reported in the literature. We report a new case.
      Observation. - A 40-year-old man had inflammatory low back pain since 1983 which
      formerly responded to nonsteroidal inflammatory drugs (NSAIDs). He developed
      dyspnea and skin rash in 1993. Physical exam found cervical and lumbar spine
      stiffness and violaceous and circular lesions on the forehead, nose and right
      cheek. Laboratory tests showed: ESR at 50 mm, increased serum angiotensin-1
      converting enzyme, and negative HLA B27. X-rays showed sacroiliac ankylosis,
      cervical and lumbar syndesmophytes and cervical facet joint ankylosis. The plain
      chest x-ray showed an interstitial syndrome. Chest CT scan showed mediastinal
      adenopathies. Skin biopsy disclosed non-caseating epitheliod and giant-cell
      granuloma. Outcome was good with steroid therapy but back pain was only improved
      by NSAIDs. DISCUSSION: - This association raises a diagnostical problem because
      spine involvement in sarcoidosis can mimic ankylosing spondylitis. It also
      suggests the hypothesis of a pathophysiological link between the two diseases.

PMID- 12486392
TI  - [Acetaminophen-induced hypothermia, an AIDS related side-effect? About 4 cases].
AB  - Hypothermia is an uncommon side effect of acetaminophen. We report 4 cases of HIV
      infected patients who developed hypothermia after intravenous injection of
      propacetamol (the parenteral formulation of acetaminophen). The mechanism of this
      hypothermia is unknown. AIDS-induced changes in the metabolism of acetaminophen,
      could be an explanation. AIDS-associated opportunistic diseases may account for
      part of the mechanism. These hypothermias occur within 6 hours after the
      injection, are well tolerated and regress spontaneously.

PMID- 12486393
TI  - [Treatment of severe Behcet's disease with anti-TNF-alpha: infliximab. A case
      report].

PMID- 12486394
TI  - [Plasma exchanges and replacement fluids for adult thrombotic microangiopathy.
      Synopsis of the Round table held on May 3, 2001].

PMID- 12486395
TI  - Mouse cone arrestin expression pattern: light induced translocation in cone
      photoreceptors.
AB  - PURPOSE: Arrestins are a superfamily of regulatory proteins that down-regulate
      activated and phosphorylated G-protein coupled receptors (GPCRs). Cone arrestin
      (CAR) is expressed in cone photoreceptors and pinealocytes and may contribute to
      the shutoff mechanisms associtated with high acuity color vision. To initiate a
      study of CAR's function in cone phototransduction, the mouse CAR (mCAR)
      transcript and protein expression patterns are examined and in vitro binding
      assays are also presented. METHODS: Tissue distribution of mCAR was determined by
      Northern and immunoblot analyses and its cellular localization identified by In
      situ hybridization and immunohistochemistry. The protein expression pattern of
      mCAR in the postnatal developmental and adult mouse retina was analyzed by
      immunoblotting in normal C57 and rd/rd mouse retinas. In vitro binding assays
      with in vitro translated arrestins were used to study the interaction of mCAR and
      mouse S-antigen (mSAG) with embryonic chicken outer segment (OS) membranes
      containing both rod and cone opsins. RESULTS: MCAR has a high level of amino acid
      sequence identity with orthologous sequences reported for other species except
      the C-terminal region, which is highly conserved between mouse and rat but
      divergent in other species. MCAR is expressed exclusively in the retina and the
      pineal gland, and unique isoforms are expressed during postnatal development of
      the retina and the pineal gland. The postnatal developmental expression pattern
      of mCAR and mSAG in the rd/rd mouse retina parallels the generation and
      degeneration of the cone and rod photoreceptors in these mice. In situ and
      immunohistochemistry both reveal cone-specific expression of mCAR in the retina.
      Immunofluorescent staining of retinal sections from dark-adapted or light-exposed
      mice suggests a light-dependent translocation of mCAR immunoreactivity from the
      cone inner segments (CIS) and other parts of the cell body to the cone outer
      segments (COS), similar to but not as dramatic as rod arrestin. In vitro binding
      assays show a small yet significant increase in binding of the full-length mCAR
      (mCARFL) to embryonic chicken OS membranes following light activation and
      phosphorylation of the opsins in the membranes. CONCLUSIONS: MCAR is expressed in
      retinal cone photoreceptors and the pineal gland. The light-dependent
      translocation of mCAR immunoreactivity and the increase of mCAR binding to light
      activated, phosphorylated embryonic chicken OS membranes, compared to its binding
      to dark, unphosphorylated membranes, suggest the possibility that mCAR is
      involved in shutting off the phototransduction cascade in cone photoreceptors as
      rod arrestin does in rod photoreceptors. However, prominent differences exist
      between rod arrestin and CAR, suggesting other functions for CAR.

PMID- 12486396
TI  - Localisation of aphidicolin-induced break points in Holstein-Friesian cattle (Bos
      taurus) using RBG-banding.
AB  - Fragile sites (FS) seem to play a role in genome instability and may be involved
      in karyotype evolution and chromosome aberrations. The majority of common fragile
      sites are induced by aphidicolin. Aphidicolin was used at two different
      concentrations (0.15 and 0.30 microM) to study the occurrence of FS in the cattle
      karyotype. In this paper, a map of aphidicolin induced break points and fragile
      sites in cattle chromosomes was constructed. The statistical analysis indicated
      that any band with three or more breaks was significantly damaged (P<0.05).
      According to this result, 30 of the 72 different break points observed were
      scored as fragile sites. The Pearson correlation test showed a positive
      association between chromosome length and the number of fragile sites (r=0.54).
      On the contrary, 21 FS were identified on negative R bands while 9 FS were
      located on positive R bands.

PMID- 12486397
TI  - The covariance between relatives conditional on genetic markers.
AB  - The development of molecular genotyping techniques makes it possible to analyze
      quantitative traits on the basis of individual loci. With marker information, the
      classical theory of estimating the genetic covariance between relatives can be
      reformulated to improve the accuracy of estimation. In this study, an algorithm
      was derived for computing the conditional covariance between relatives given
      genetic markers. Procedures for calculating the conditional relationship
      coefficients for additive, dominance, additive by additive, additive by
      dominance, dominance by additive and dominance by dominance effects were
      developed. The relationship coefficients were computed based on conditional QTL
      allelic transmission probabilities, which were inferred from the marker allelic
      transmission probabilities. An example data set with pedigree and linked markers
      was used to demonstrate the methods developed. Although this study dealt with two
      QTLs coupled with linked markers, the same principle can be readily extended to
      the situation of multiple QTL. The treatment of missing marker information and
      unknown linkage phase between markers for calculating the covariance between
      relatives was discussed.

PMID- 12486398
TI  - Marker assisted selection with optimised contributions of the candidates to
      selection.
AB  - The benefits of marker assisted selection (MAS) are evaluated under realistic
      assumptions in schemes where the genetic contributions of the candidates to
      selection are optimised for maximising the rate of genetic progress while
      restricting the accumulation of inbreeding. MAS schemes were compared with
      schemes where selection is directly on the QTL (GAS or gene assisted selection)
      and with schemes where genotype information is not considered (PHE or phenotypic
      selection). A methodology for including prior information on the QTL effect in
      the genetic evaluation is presented and the benefits from MAS were investigated
      when prior information was used. The optimisation of the genetic contributions
      has a great impact on genetic response but the use of markers leads to only
      moderate extra short-term gains. Optimised PHE did as well as standard truncation
      GAS (i.e. with fixed contributions) in the short-term and better in the long
      term. The maximum accumulated benefit from MAS over PHE was, at the most, half of
      the maximum benefit achieved from GAS, even with very low recombination rates
      between the markers and the QTL. However, the use of prior information about the
      QTL effects can substantially increase genetic gain, and, when the accuracy of
      the priors is high enough, the responses from MAS are practically as high as
      those obtained with direct selection on the QTL.

PMID- 12486399
TI  - Detection of quantitative trait loci for carcass composition traits in pigs.
AB  - A quantitative trait locus (QTL) analysis of carcass composition data from a
      three-generation experimental cross between Meishan (MS) and Large White (LW) pig
      breeds is presented. A total of 488 F2 males issued from six F1 boars and 23 F1
      sows, the progeny of six LW boars and six MS sows, were slaughtered at
      approximately 80 kg live weight and were submitted to a standardised cutting of
      the carcass. Fifteen traits, i.e. dressing percentage, loin, ham, shoulder,
      belly, backfat, leaf fat, feet and head weights, two backfat thickness and one
      muscle depth measurements, ham + loin and back + leaf fat percentages and
      estimated carcass lean content were analysed. Animals were typed for a total of
      137 markers covering the entire porcine genome. Analyses were performed using a
      line-cross (LC) regression method where founder lines were assumed to be fixed
      for different QTL alleles and a half/full sib (HFS) maximum likelihood method
      where allele substitution effects were estimated within each half-/full-sib
      family. Additional analyses were performed to search for multiple linked QTL and
      imprinting effects. Significant gene effects were evidenced for both leanness and
      fatness traits in the telomeric regions of SSC 1q and SSC 2p, on SSC 4, SSC 7 and
      SSC X. Additional significant QTL were identified for ham weight on SSC 5, for
      head weight on SSC 1 and SSC 7, for feet weight on SSC 7 and for dressing
      percentage on SSC X. LW alleles were associated with a higher lean content and a
      lower fat content of the carcass, except for the fatness trait on SSC 7.
      Suggestive evidence of linked QTL on SSC 7 and of imprinting effects on SSC 6,
      SSC 7, SSC 9 and SSC 17 were also obtained.

PMID- 12486400
TI  - Epitope masking of rhabdomeric rhodopsin during endocytosis-induced retinal
      degeneration.
AB  - PURPOSE: To determine the fate of rhodopsin during endocytosis-mediated retinal
      degeneration. METHODS: Drosophila stocks were raised in complete darkness and
      shifted to light for 24 h prior to dissection and fixation of retinas. 1 microm
      frozen sections were cut on an ultracryomicrotome, then stained with antibodies
      specific for rhodopsin or arrestin. Localization of photoreceptor cell-specific
      proteins was determined by confocal microscopy. RESULTS: Flies that are in the
      process of undergoing endocytosis-mediated retinal degeneration exhibit an
      apparent loss of rhabdomeric rhodopsin at early times during the degenerative
      process. Using different immunological agents, genetic backgrounds, and light
      treatments, we have found that the binding of arrestin to rhodopsin masked the C
      terminal monoclonal antibody epitope and resulted in the loss of rhodopsin
      immunoreactivity. The loss of immunoreactive rhabdomeric rhodopsin only occurred
      when rhodopsin was depleted from the plasma membrane such that it was found
      within the rhabdomere at stoichiometric levels with arrestin. CONCLUSIONS: When
      rhodopsin and arrestin are found at equal levels, binding of arrestin to
      rhodopsin results in the masking of the antibody epitope on the C-terminus of
      rhodopsin. Since masking can only occur after most of the rhodopsin has been
      depleted from the rhabdomere, it can be concluded that during endocytosis-induced
      retinal degeneration, much of the rhodopsin is localized to the cell body in
      small puncta. These data suggest that rhodopsin is at extremely high local
      concentrations in the cytoplasm. The data are discussed in the context of a model
      for photoreceptor cell apoptosis in retinal degenerative disorders.

PMID- 12486401
TI  - Complementary medicine in pediatrics: a review of acupuncture, homeopathy,
      massage, and chiropractic therapies.

PMID- 12486403
TI  - Glutathione: a marker and antioxidant for aging.

PMID- 12486404
TI  - Doxycycline induces apoptosis by way of caspase-3 activation with inhibition of
      matrix metalloproteinase in human T-lymphoblastic leukemia CCRF-CEM cells.
AB  - Evidence for nonantibiotic activity displayed by tetracycline has been
      extensively reported in the field of antiinflammation. Here, we report a growth
      inhibitory effect of doxycycline on CCRF-CEM, a T-lymphoblastic human leukemic
      cell line. Cells were incubated with doxycycline at concentrations ranging from
      zero to 50 micromol/L. We examined the hypothesis that induction of apoptosis is
      one of the mechanisms by which doxycycline inhibits CCRF-CEM proliferation.
      Caspase-3 activity of cells grown in the presence of 10 micromol/L and 50
      micromol/L doxycycline increased dose-dependently after 24 hours in culture. The
      demonstration that doxycycline induces APO 2.7 expression in CCRF-CEM cells in
      vitro also supports its capacity for induction of apoptosis. The level of matrix
      metalloproteinase-2 was significantly lower in the medium cultured with 50
      micromol/L doxycycline than the control. These phenomena suggest that this well
      tolerated oral agent has the potential to be of value in antileukemic therapy.

PMID- 12486405
TI  - Structural analysis of gallstones with thin-section petrographic microscopy: a
      study of 100 gallstones from Taiwanese patients.
AB  - Cholecystolithiasis is a common disease, making cholecystectomy a commonly
      performed surgical procedure. The gross appearance of gallstones differs from
      case to case. To classify gallstones on the basis of their structure, we randomly
      collected gallstones from 100 (64 of them women) of 3,289 patients who underwent
      cholecystectomy at our hospital. The stones were grossly classified into five
      major types: pure-cholesterol stones, combination stones, mixed stones, black
      stones, and calcium bilirubinate stones. We then used thin-section petrographic
      microscopic study (TSPMS) to inspect each stone under a polarizing microscope.
      Final classification of the stone depended on TSPMS findings. Of the 100
      patients, 35 had pure-cholesterol stones, 12 had combination stones, 17 had mixed
      stones, 25 had black stones, and 8 had calcium bilirubinate stones; the stones
      from 3 patients could not be classified on TSPMS. Accurate structural
      classification of gallstones could be made by gross inspection with confirmation
      by TSPMS, a useful method of classifying gallstones.

PMID- 12486406
TI  - Ethanol enhances the inhibitory effect of an oral GPIIb/IIIa antagonist on human
      platelet function.
AB  - Ethanol is a commonly used substance that can significantly influence platelet
      responses when combined with therapeutic drugs. In in vitro studies, we combined
      ethanol with LY309562, a novel 2,6-disubstituted isoquinolone RGD mimic that
      competes for fibrinogen binding to GPIIb/IIIa. Ethanol inhibits aggregation and
      secretion, partly by inhibiting thromboxane A(2) formation. We measured
      aggregation and secretion of dense granule contents by platelets labeled with
      [(14)C] serotonin in plasma from blood anticoagulated with FPRCH(2)Cl (PPACK).
      Alone, LY309562 dose-dependently inhibited aggregation induced by 10 micromol/L
      adenosine diphosphate, 1 microg/mL collagen, 2 micromol/L U46619 (a thromboxane
      A(2) mimetic), or 15 micromol/L SFLLRN (protease-activated receptor-1-activating
      peptide); inhibition was complete at 1 micromol/L LY309562 and partial at 0.1
      micromol/L (50% inhibitory concentration [IC(50)] 0.19-0.33 micromol/L).
      Secretion induced by collagen, U46619, and SFLLRN was also inhibited by LY309562
      (IC(50) 0.08-0.31 micromol/L). At inhibitory concentrations of LY309562, ethanol
      (2 or 4 mg/mL) further inhibited responses to collagen, U46619, and SFLLRN
      (IC(50) for aggregation 0.12-0.16 micromol/L; for secretion 0.04-0.12
      micromol/L). Responses of aspirin-treated platelets to U46619 were also
      inhibited, indicating that ethanol was not acting solely by inhibiting
      thromboxane A(2) formation. Because it is likely that our results with LY309562
      are representative of results with other GPIIb/IIIa antagonists, our in vitro
      data suggest that the concomitant use of GPIIb/IIIa antagonists and consumption
      of alcoholic beverages may result in further impairment of platelet participation
      in hemostasis and thrombosis.

PMID- 12486407
TI  - Size-dependent binding of IgA to HepG2, U937, and human mesangial cells.
AB  - IgA nephropathy (IgAN) is characterized by increased circulating IgA and
      mesangial IgA deposition. The mechanism of mesangial IgA deposition remains
      poorly understood in IgAN. In this report, we studied the binding characteristics
      of serum IgA from patients with IgAN and healthy controls to different cell
      types, including a liver-cell line (HepG2), a monocytic cell line (U937), and
      human mesangial cells (HMCs). Jacalin-bound proteins (JBPs) were purified from
      serum IgA by means of jacalin affinity chromatography. Total IgA concentrations
      were significantly higher in patients with IgAN than in controls (P <.001). JBPs
      were further separated by means of size exclusion chromatography, and six pooled
      fractions with molecular weight ranging from 50 to 1,000 kD were obtained. The
      concentration of low-molecular-weight (LMW) IgA complexes (150-300 kD) and high
      molecular-weight (HMW) IgA complexes (300-1,000 kD) were significantly higher in
      patients than in healthy controls (P <.001 and.05, respectively). Cultured human
      mesangial cells bound more IgA of 300 to 610 kD in IgA isolated from patients
      with IgAN (P <.01). The binding of IgA (LMW and HMW) from patients with IgAN to
      HepG2 was significantly higher than that of IgA preparations from controls. U937
      significantly bound more IgA of 150 to 825 kD in IgA isolated from patients with
      IgAN (P <.01). Different and distinct binding patterns were observed in the three
      cell types for IgA with different molecular weights. HMCs bound more HMW than LMW
      IgA. We noted preferential binding of LMW (150 to 300 kDa) and intermediate (350
      710 kDa) IgA to HepG2 than of IgA complexes of more than 710 kDa. U937 mainly
      bound LMW and intermediate size IgA (150 to 710 kDa) with no binding of IgA with
      size greater than 710 kD. Our findings suggest that monocytes, hepatocytes, and
      mesangial cells have unique properties with regard to their binding to different
      forms of IgA. These characteristic properties may alter the catabolism of
      circulating IgA and, hence, predispose their deposition in the kidney mesangium
      in IgAN.

PMID- 12486408
TI  - Nucleated red blood cells indicate high risk of in-hospital mortality.
AB  - The presence of nucleated red blood cells (NRBCs) in the blood of patients with a
      variety of severe diseases is known to be highly associated with increased
      mortality. Blood analyzers to routinely measure NRBC concentrations are now
      available. However, the prognostic significance of such measurements has not been
      evaluated. Using a Sysmex XE-2100 (Sysmex; Norderstedt, Germany), we measured
      NRBC concentrations in 15,541 blood samples from 4,173 patients at a university
      clinic over the course of 12 weeks. NRBCs were found at least once in 7.5% of all
      patients. The highest incidence (20.0%) was found in patients from the intensive
      care unit of the general and accident surgery. The incidence of NRBC increased
      with age. The mortality of NRBC-positive patients (n = 313) was 21.1% (n = 66);
      this was significantly higher (P <.001) than the mortality of NRBC-negative
      patients (1.2%, n = 3,860). Mortality increased with increasing NRBC
      concentration. With regard to in-hospital mortality, NRBCs in blood showed
      sensitivity and specificity of 57.9% and 93.9%, respectively. NRBCs were detected
      for the first time, on average, 21 days (median 13 days) before death. The
      routine analysis of NRBCs in blood is of high prognostic power with regard to in
      hospital mortality. This parameter may serve as an early indicator of patients at
      increased risk.

PMID- 12486409
TI  - High blood glutathione levels accompany excellent physical and mental health in
      women ages 60 to 103 years.
AB  - Earlier we found a high percentage of subnormal total glutathione (G(T)) levels
      in blood from elderly subjects and patients with chronic diseases. These findings
      suggested a hypothesis that high levels of G(T) in the blood occur in old persons
      who are in excellent physical and mental health. To this end, we recruited 87
      white women who ranged in age from 60 to 103 years and reported that they felt
      healthy. Their health was verified with physical examinations, clinical chemistry
      profiles, psychosocial assessments, and blood G(T) determinations. This
      evaluation was performed in three waves over a 5-year period. The values were
      compared with those from representative individuals in this region and with
      normal national data. The results verified that these healthy subjects were in
      top physical and mental health. We also found that subjects of all ages had very
      high blood G(T) levels in waves I and II but only normal levels in wave III.
      These findings confirm that high blood G(T) concentrations and excellent physical
      and mental health are characteristics of long-lived women.

PMID- 12486410
TI  - Reference citation is important.

PMID- 12486411
TI  - New options in lipid management--can we extend the benefits of current therapy?
      Introduction.

PMID- 12486412
TI  - What do the statins tell us?
AB  - Until the recent introduction of the 3-hydroxy-3-methylglutaryl coenzyme A
      reductase inhibitors (statins), the potential effect of cholesterol lowering on
      the prevention of clinical manifestations of coronary disease was a matter of
      debate. In trials conducted before the introduction of statins, cholesterol
      levels were lowered, on average, by only approximately 10%, resulting in
      prevention of coronary events but with no effect on total mortality rates.
      However, statins have been able to reduce low-density lipoprotein cholesterol
      levels by a mean of roughly 28%, significantly decreasing both relative and
      absolute risk levels of coronary events and total mortality. These benefits have
      been demonstrated not only in middle-aged men but also in women and patients aged
      >65 years. Aggressive cholesterol lowering has also been shown to yield larger
      decreases in the incidence of subsequent coronary events than angioplasty, and to
      reduce the occurrence of such events in patients who have undergone coronary
      artery bypass graft surgery, which raises the question of whether these
      procedures should be relegated to symptom relief, with cholesterol lowering as
      the primary means of coronary heart disease event prevention. Statins, therefore,
      have unequivocally shown the importance of cholesterol lowering in the prevention
      of morbidity and mortality due to coronary disease. Ongoing research will
      elucidate the role of statin therapy in the prevention of strokes and in the
      treatment of patients aged >75 years, and future trials will be needed to
      evaluate the potential role of statins in primary prevention for younger
      populations who cannot control cholesterol with lifestyle changes.

PMID- 12486413
TI  - Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme
      A reductase.
AB  - 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) catalyzes the
      committed step in cholesterol biosynthesis. HMGR is the target of compounds (HMGR
      inhibitors, commonly referred to as statins) that are very effective in lowering
      serum cholesterol levels. These inhibitors have K(i) values in the nanomolar
      range and are widely prescribed in the treatment of hypercholesterolemia. We have
      determined structures of this enzyme in complexes with 6 different statins
      (compactin, simvastatin, fluvastatin, cerivastatin, atorvastatin, and
      rosuvastatin). The statins occupy a portion of the binding site of HMG-CoA, thus
      blocking access of this substrate to the active site. The nicotinamide binding
      pocket of NADP(H) (the second substrate of the enzyme) is unoccupied by the
      inhibitor molecules. Near the C-terminus of HMGR, several catalytically relevant
      residues are disordered in the enzyme-statin complexes. The flexibility of these
      residues is critical for binding with statins; if ordered, they would sterically
      hinder such binding.

PMID- 12486414
TI  - High-density lipoprotein cholesterol and triglycerides as therapeutic targets for
      preventing and treating coronary artery disease.
AB  - Epidemiologic and clinical trials show that elevated triglycerides and low levels
      of high-density lipoprotein cholesterol (HDL-C) are independent risk factors for
      coronary heart disease (CHD). However, adjustment for covariates frequently
      weakens or abolishes the predictive significance of triglycerides, whereas the
      evidence for HDL-C is more consistently strong. Data indicate that there is a 2%
      to 3% decrease in coronary risk for each 1 mg/dL increase in HDL-C, whereas the
      benefit of triglyceride lowering appears to occur largely in patients with the
      highest baseline levels. The 2001 National Cholesterol Education Program Adult
      Treatment Panel III (ATP III) guidelines for detecting and treating high blood
      cholesterol reflect our improved understanding of triglycerides and HDL as CHD
      risk factors. However, the guidelines place more emphasis on lowering
      triglycerides than on raising HDL-C by identifying non-HDL-C (ie, low-density
      lipoprotein cholesterol [LDL-C] + very-low-density lipoprotein cholesterol [VLDL
      C]) as a secondary target of therapy. In clinical practice, VLDL-C is the most
      readily available measure of atherogenic triglyceride-rich remnant lipoproteins.
      On the basis of the available epidemiologic and clinical evidence, refinement of
      the NCEP guidelines to include more emphasis on raising HDL-C levels should be
      considered. Novel drugs are being developed that have the potential to increase
      HDL-C concentrations and/or improve the functionality of HDL.

PMID- 12486415
TI  - Management of dyslipidemia in the high-risk patient.
AB  - Lipid-lowering agents have been shown to reduce morbidity and mortality
      associated with coronary heart disease (CHD), particularly in high-risk patients.
      The identification and treatment of these patients should therefore be a high
      priority for clinicians. Guidelines from medical organizations, such as the
      National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) and the
      American Diabetes Association (ADA), suggest that patients with low-density
      lipoprotein cholesterol (LDL-C) levels > or =130 mg/dL, and perhaps even those
      with levels > or =100 mg/dL, should receive drug therapy. Optimal LDL-C levels
      have been set at <100 mg/dL and <115 mg/dL for high-risk patients by US and
      European guidelines, respectively. However, a recent survey shows that only about
      20% of high-risk patients currently meet these goals. In order to achieve
      therapeutic targets for LDL-C, the statins are the foundation of treatment, as
      they are the most effective and best-tolerated form of lipid-lowering therapy.
      Other therapeutic options include bile acid sequestrants, niacin, and plant
      stanols, although seldom as monotherapy. Combination therapy with a statin and
      one of these other lipid-lowering agents can be useful in patients who are unable
      to achieve target lipid levels through monotherapy. There remains, however, a
      need for additional agents. Some of the new options for reducing LDL-C levels
      that may be available in the near future include 2 new statins, pitavastatin and
      rosuvastatin. In patients with heterozygous familial hypercholesterolemia,
      rosuvastatin, which is currently under review by the Food and Drug Administration
      (FDA), has been shown to produce significantly greater reductions in LDL-C than
      atorvastatin over its full dose range. In comparative clinical trials, it has
      also enabled more patients with primary hypercholesterolemia to meet lipid goals
      than atorvastatin, simvastatin, and pravastatin. Inhibitors of bile acid
      transport or cholesterol absorption may also have therapeutic value. The first
      cholesterol absorption inhibitor, ezetimibe, which has just been approved by the
      FDA, appears to be most effective when combined with a statin. It is anticipated
      that such new options will allow clinicians to optimize the management of
      dyslipidemia in high-risk patients, thereby reducing the morbidity and mortality
      of CHD.

PMID- 12486416
TI  - Things ain't what they used to be: impact of a new definition of myocardial
      infarction.

PMID- 12486417
TI  - Genetics in heart failure: practical incorporation of this new biologic
      dimension.

PMID- 12486418
TI  - The relevance of subgroup-specific treatment effects: the Studies Of Left
      Ventricular Dysfunction (SOLVD) revisited.
AB  - BACKGROUND: The overall effect sizes estimated from randomized clinical trials
      may not apply similarly to all patients. Univariate subgroup analyses are often
      used to help determine the generalizability of a trial's results, but may
      themselves be misleading. We reanalyzed the Studies of Left Ventricular
      Dysfunction (SOLVD) to determine whether the treatment effect depended on the
      patients' baseline prognosis, defined on the basis of multiple clinical
      variables. METHODS: The SOLVD prevention (4228 patients) and the SOLVD treatment
      (2569 patients) trials were randomized, double-blind trials that studied the
      effect of enalapril in patients with reduced left-ventricular function or
      congestive heart failure. We combined both SOLVD populations and compared the
      results of a univariate analysis to a multivariate approach in which 3 patient
      subgroups were defined according to baseline risks for the combined end point of
      death or hospitalization for heart failure. RESULTS: Enalapril treatment resulted
      in 24% fewer events. The strongest predictors of an event were ejection fraction,
      New York Heart Association classification and age, antiplatelet agents, history
      of diabetes mellitus, treatment with digoxin or diuretics, and race. Only
      ejection fraction produced a significant treatment interaction (P =.004).
      Consistent with the original SOLVD reports, this interaction was also
      demonstrable when ejection fraction was scaled into tertiles and examined on its
      own (P =.012). However, there was no interaction present when patients were
      divided into tertiles of multifactorial baseline risk. CONCLUSIONS: We confirmed
      the treatment effect of enalapril, the impact of left-ventricular systolic
      function, and the negative prognostic importance of diabetes mellitus in this
      population. Although ejection fraction led to a subgroup-treatment interaction in
      the main SOLVD publications, a multifactorial approach to prognostic grouping
      abolished the interaction. These findings highlight the limitations of univariate
      subgroup analyses and illustrate that multivariate risk group analysis may be a
      complementary method for assessing the generalizability of the overall treatment
      effects observed in randomized trials.

PMID- 12486419
TI  - In search of left septal fascicular block.
AB  - BACKGROUND: In most humans, the left bundle branch divides into 3 fascicles.
      Electrocardiographic changes resulting from conduction abnormalities of the left
      anterior and left posterior fascicles are well described and commonly diagnosed.
      Existence of conduction defects of the left septal fascicle is controversial,
      without generally accepted criteria for diagnosis. METHODS: Approximately 26,000
      electrocardiograms were reviewed to find examples consistent with left septal
      fascicle block according to criteria derived from review of the literature.
      RESULTS: Electrocardiograms meeting proposed criteria were found in about 0.5% of
      tracings. Illustrative examples are shown with discussion of reasons for their
      selection. CONCLUSIONS: Left septal fascicle block seems to exist, is
      polymorphic, and may explain some previously inadequately understood
      electrocardiographic abnormalities.

PMID- 12486420
TI  - Changing the diagnosis of acute myocardial infarction: implications for practice
      and clinical investigations.

PMID- 12486421
TI  - European Society of Cardiology and American College of Cardiology guidelines for
      redefinition of myocardial infarction: how to use existing assays clinically and
      for clinical trials.
AB  - BACKGROUND: The European Society of Cardiology and American College of Cardiology
      guidelines for redefinition of myocardial infarction suggest that the cutoff
      value for diagnosis of acute myocardial infarction (AMI) be the 99th percentile
      of the reference population at a level measured with imprecision (coefficient of
      variation) > or =10%. No current commercially available troponin assay meets this
      requirement. Accordingly, questions have been raised about how to implement
      cutoff values from the guidelines. The Clinical Outcomes Utilizing
      Revascularization and Aggressive druG Evaluation (COURAGE) trial asked for
      recommendations concerning the use of troponin assays for the trial. METHODS:
      Cutoff values for the various assays were obtained from package inserts or from
      direct communication with manufacturers. RESULTS: The cutoff value with > or =10%
      imprecision was above the 99th percentile of the reference range for all assays.
      For the present, we suggest that this value be used for clinical and clinical
      trial purposes. It will account for analytic variability and individual
      biological changes. We provide recommendations for clinical practice and clinical
      trials concerning how to make the diagnosis of AMI in patients with ischemic
      symptoms and patients who undergo percutaneous coronary intervention and coronary
      artery bypass surgery. CONCLUSIONS: This is a first attempt to define cutoff
      values on the basis of the European Society of Cardiology and American College of
      Cardiology guidelines. These criteria will provide increased consistency until
      assays improve to allow full implementation of the guidelines.

PMID- 12486422
TI  - Does chronic Chlamydia pneumoniae infection increase the risk of myocardial
      injury? Insights from patients with non-ST-elevation acute coronary syndromes.
AB  - BACKGROUND: Cumulative evidence suggests a positive association between Chlamydia
      pneumoniae (Cpn) infection and risk of future coronary events among patients with
      stable coronary artery disease. However, its prognostic role in unstable coronary
      syndromes is less well defined. Because Cpn immunoglobulin A (IgA) may be a more
      reliable indicator of chronic infection than immunoglobulin G (IgG), we
      speculated that in patients with non-ST-elevation acute coronary syndromes (ACS),
      this marker might serve as a more useful prognostic tool. Accordingly, we
      evaluated plasma samples acquired at presentation in 178 patients with ACS for a
      possible association between Cpn IgA titer and biochemical evidence of myocardial
      injury. METHODS: Cpn IgG (positive if > or =1:32), and IgA titers (positive if >
      or =1:16) were measured by use of the microimmunofluorescence technique in 70
      patients with ACS in whom myocardial injury developed associated with their
      presenting events (elevated CK-MB and/or troponin I); and in 108 patients with
      ACS without such injury. The odds ratios (ORs) for myocardial injury associated
      with consecutive antibody titers were determined for each of Cpn IgG and IgA.
      Multiple logistic regression was applied to adjust for key baseline
      characteristics. RESULTS: Median age of subjects was 64 years; 63% were male and
      33% were smokers. The median antibody titers among those with and without
      myocardial injury respectively were as follows: IgG (1:128 vs 1:128), IgA (1:32
      vs <1:16, P =.2). The adjusted ORs for myocardial injury associated with
      consecutive IgA titers were as follows: IgA > or =1:16, adjusted OR 1.49 (P
      =.22); > or =1:32, OR 1.95 (P =.04); > or =1:64, OR 1.37 (P =.38); > or =1:128,
      OR 0.77 (P =.55). No significant trend was found for any IgG titer. CONCLUSIONS:
      Among patients with non-ST-elevation ACS, a Cpn IgA > or =1:32 at presentation
      was associated with a significantly higher risk of myocardial injury complicating
      the presenting event.

PMID- 12486423
TI  - Promise of combined low-molecular-weight heparin and platelet glycoprotein
      IIb/IIIa inhibition: results from Platelet IIb/IIIa Antagonist for the Reduction
      of Acute coronary syndrome events in a Global Organization Network B (PARAGON B).
AB  - BACKGROUND: Low-molecular-weight heparin (LMWH) has a more predictable
      anticoagulant effect than unfractionated heparin (UFH), is easier to administer,
      and does not require monitoring. Minimal data are available on LMWH combined with
      platelet glycoprotein (GP) IIb/IIIa inhibitors. METHODS: In the Platelet IIb/IIIa
      Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global
      Organization Network B (PARAGON B) trial, patients with an acute coronary
      syndrome were randomized to receive the IIb/IIIa inhibitor lamifiban or a
      placebo. To rigorously explore the potential benefits of LWMH and GP IIb/IIIa
      inhibition, we analyzed the rates of ischemic complications and safety outcomes
      in PARAGON B. RESULTS: Approximately one fifth of the patients received LMWH (805
      vs 4395 UFH). For the overall cohort, the incidence of death/myocardial
      infarction (MI)/severe recurrent ischemia (SRI) was 12.2%, and this composite end
      point was numerically lowest in the lamifiban with LMWH group (10.2%). Similarly,
      the incidence of death/MI was 11.0% for the entire cohort and lowest in the
      lamifiban and LMWH group (9.0%). The lower event rate for patients taking LMWH in
      the lamifiban group was sustained at 6 months, with a lower revascularization
      rate (51.5% vs 42.8%) and a lower composite of death/MI (13.8% vs 11.9%).
      Bleeding was comparable in the 2 heparin groups (1.4% with UFH vs 0.9% with
      LMWH). The propensity adjusted odds ratio for 30-day revascularization was
      significantly lower with LMWH (odds ratio 0.67, 95% CI 0.57-0.79, P <.001). There
      were no significant differences in death/MI/SRI at 30 days (P =.465), death/MI at
      30 days (P =.264), and stroke at 30 days with the type of heparin use (P =.201)
      after propensity risk adjustment. CONCLUSIONS: In the PARAGON B trial, use of
      LMWH in conjunction with a GP IIb/IIIa inhibitor was safe and associated with a
      lower revascularization rate. These findings support the rationale and promise
      for combining GP IIb/IIIa blockers and LMWH for future management of acute
      coronary syndrome.

PMID- 12486424
TI  - Elevated serum creatinine is associated with 1-year mortality after acute
      myocardial infarction.
AB  - BACKGROUND: Cardiovascular mortality is high in individuals with end-stage renal
      disease. However, less is known about the prognostic importance of moderate renal
      insufficiency in patients with acute myocardial infarction. METHODS: We studied
      all patients with acute myocardial infarction admitted through the emergency
      department to an urban, academic hospital over 1 year. Patients were classified
      as having elevated (>133 micromol/L [1.5 mg/dL]) or normal (< or =133 micromol/L)
      serum creatinine at presentation. RESULTS: Of 483 patients, 22% had elevated
      creatinine and 78% had normal creatinine. By 1 year, 46% of patients with
      elevated creatinine and 15% of patients with normal creatinine had died (P
      <.001). The unadjusted hazard ratio for 1-year mortality was increased in
      patients with elevated creatinine compared with those with normal creatinine
      (hazard ratio 3.85, 95% CI 2.61-5.67). After adjustment for baseline
      characteristics and treatment, the multivariable-adjusted hazard ratio for 1-year
      mortality remained increased in patients with elevated creatinine compared with
      those with normal creatinine (hazard ratio 2.40, 95% CI 1.55-3.72). There was an
      important modification of the prognostic value of creatinine by the presence of
      congestive heart failure at presentation (P value for interaction =.04). The
      adjusted hazard ratio for 1-year death associated with elevated creatinine
      compared with normal creatinine was 3.89 (95% CI 1.87-8.07) in patients without
      congestive heart failure and 1.92 (95% CI 1.10-3.36) in patients with congestive
      heart failure. CONCLUSIONS: Elevated serum creatinine at presentation is
      associated with 1-year mortality after acute myocardial infarction. Further study
      is needed to optimize treatment after myocardial infarction in this high-risk
      group.

PMID- 12486425
TI  - Symptom presentation of acute myocardial infarction: influence of sex, age, and
      risk factors.
AB  - OBJECTIVES: The purpose of this study was to examine the symptomatology of onset
      of acute myocardial infarction (AMI) in patients according to sex, age, and
      existence of conventional risk factors. BACKGROUND: Some studies have suggested
      that sex and other patient characteristics may influence symptoms in AMI, but
      data were limited and conflicting. METHODS: This was a prospective, observational
      study of a large number of symptoms in 1996 patients admitted to Clinical
      Hospital Split between January 1990 and July 1995 as the result of a first AMI.
      For each patient, the structured data form covering experience of pain at 10 body
      locations and 11 other symptoms, baseline characteristics, risk factors, and peak
      cardiac enzyme levels was completed a median of 3 days after AMI. RESULTS: Any
      pain, and specifically chest pain, was more often reported by male patients,
      smokers, hypertensive patients, nondiabetic patients, and hypercholesterolemic
      patients. Women were more likely to report nonchest pain other than epigastric
      and right shoulder pain, as well as various nonpain symptoms. The independent
      predictors of atypical AMI presentation (ie, absence of pain) in both men and
      women were lower levels of creatine kinase-MB fraction (P <.0001 and P =.0003,
      respectively), diabetes mellitus (P =.0002 and P =.002, respectively), older age
      (P =.001 and P =.01, respectively), and absence of smoking in men (P =.005). The
      independent predictors of presence of nonpain symptoms in both men and women were
      higher levels of creatine kinase-MB fraction (P =.01 and P =.049, respectively)
      and diabetes mellitus (P =.048 and P =.005, respectively); in men, it was
      hypercholesterolemia (P =.01). CONCLUSIONS: Our results suggest that sex, age,
      smoking, hypertension, diabetes, and hypercholesterolemia may affect the symptoms
      in AMI. Women with diabetes represent a high-risk subgroup for painless onset
      followed by various other symptoms.

PMID- 12486426
TI  - Risks and benefits of early treatment of acute myocardial infarction with an
      angiotensin-converting enzyme inhibitor in patients with a history of arterial
      hypertension: analysis of the GISSI-3 database.
AB  - BACKGROUND: Many trials have proved the benefits of early systematic treatment
      with angiotensin-converting enzyme inhibitors in patients with acute myocardial
      infarction (AMI). Pathophysiological studies, however, suggest potential harm in
      excessive reduction of blood pressure (BP) in hypertensive patients with ischemic
      heart disease. METHODS: We analyzed data from the GISSI-3 (Gruppo Italiano per lo
      Studio della Sopravvivenza nell'Infarto miocardico) trial to assess the effects
      of early treatment with angiotensin-converting enzyme inhibitors during AMI in
      patients with a history of hypertension compared with normotensive patients. The
      trial randomly assigned 19,394 patients to 6 weeks of lisinopril treatment or
      control, starting treatment within 24 hours of AMI onset. RESULTS: In the 10,661
      normotensive patients, lisinopril significantly reduced lethal events, but in the
      7362 hypertensive patients, a higher rate of lethal events was reported the first
      day of treatment, and the benefits only appeared subsequently. These results may
      be attributable to the subgroup of 1165 hypertensive patients with low baseline
      systolic BP (lower quintile, BP <120 mm Hg), in whom critical hypotension was
      more prone to develop after lisinopril treatment. In fact, these patients showed
      a higher mortality rate as the result of an excess of cardiogenic shock during
      the first day of lisinopril treatment (odds ratio 3.07, 95% CI 1.39-6.77) and a
      persistent, unfavorable death trend after 6 weeks. CONCLUSIONS: These data
      suggest that caution should be exercised when using lisinopril in the acute phase
      of a myocardial infarction in patients with a history of hypertension but low
      systolic BP at presentation.

PMID- 12486427
TI  - Significance of small dense low-density lipoproteins and other risk factors in
      patients with various types of coronary heart disease.
AB  - BACKGROUND: It remains unclear how closely the small dense low-density
      lipoprotein (LDL) (diameter < or =25.5 nm) is associated with various types of
      coronary heart disease (CHD) in Japanese patients, an ethnic group with lower
      serum cholesterol levels and less massive obesity compared with Western
      populations. METHODS AND RESULTS: We measured mean LDL particle diameter by
      gradient gel electrophoresis in 571 patients with CHD and in 263 healthy subjects
      who served as control patients. Patients with CHD were classified into acute
      coronary syndrome (ACS), stable CHD and vasospastic angina. High-density
      lipoprotein cholesterol and apolipoprotein-A1 and -B were significantly different
      between patients with CHD and controls. LDL size in patients with CHD was
      markedly smaller than that in controls in both men and women (25.5 +/- 0.7 vs
      25.9 +/- 0.4 and 25.7 +/- 0.7 vs 26.0 +/- 0.5 nm, respectively). LDL cholesterol
      was significantly higher in patients with ACS than in other groups. Plasma levels
      of high-density lipoprotein cholesterol decreased as the number of diseased
      vessels or angiographic coronary severity evaluated by Gensini score increased,
      but the LDL size was comparable irrespective of the type of CHD and the extent
      and severity of the lesions. Multiple logistic regression analysis revealed that
      small dense LDL was independently associated with the incidence of CHD in both
      sexes (odds ratio [OR] 3.5, 95% CI 2.1-5.7, and OR 2.9, 95% CI 1.5-5.6, P <.005).
      CONCLUSION: Our study suggests that the small dense LDL is strongly associated
      with various types of CHD, independent of traditional and nontraditional coronary
      risk factors, but is not related to the severity and extent of the coronary
      lesions.

PMID- 12486428
TI  - Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in
      patients with hypercholesterolemia: a randomized, double-blind, 52-week trial.
AB  - OBJECTIVE: The primary objective of this trial was to compare the efficacy of
      rosuvastatin with that of pravastatin and simvastatin for lowering low-density
      lipoprotein cholesterol (LDL-C) levels. METHODS: In this randomized, double
      blind, multicenter trial, lipid levels were measured in 477 patients (baseline
      LDL-C > or =160 and <250 mg/dL) who received fixed doses of 5 mg of rosuvastatin,
      10 mg of rosuvastatin, 20 mg of pravastatin, or 20 mg of simvastatin for 12
      weeks. For an additional 40 weeks, individual daily doses were sequentially
      doubled to a maximum of 80 mg of rosuvastatin, 40 mg of pravastatin, and 80 mg of
      simvastatin, according to investigator discretion and if National Cholesterol
      Education Program Adult Treatment Panel II (ATP II) LDL-C goals were not
      achieved. RESULTS: At 12 weeks, percent LDL-C reductions after both 5-mg and 10
      mg rosuvastatin treatment, which were 39.1% and 47.4%, respectively, were
      significantly different (P <.05) from LDL-C reductions after 20-mg pravastatin
      (26.5%) and 20-mg simvastatin (34.6%) treatment. After 52 weeks, more
      rosuvastatin-treated patients remained at their starting dose than did
      simvastatin or pravastatin patients. After dose titration, 88% and 87.5% of the
      rosuvastatin 5-mg and 10-mg groups, respectively, achieved their ATP II LDL-C
      goals, compared with 60% for pravastatin and 72.5% for simvastatin. All study
      treatments were well tolerated. CONCLUSION: Rosuvastatin reduced LDL-C levels
      more than pravastatin or simvastatin in patients with hypercholesterolemia in a
      52-week dose-titration study.

PMID- 12486430
TI  - Race and sex differences in the refusal of cardiac catheterization among elderly
      patients hospitalized with acute myocardial infarction.
AB  - BACKGROUND: Prior studies have reported race and sex differences in cardiac
      catheterization use after acute myocardial infarction (AMI). It is unclear
      whether race or sex differences in procedure refusal may contribute to this
      difference. We sought to determine whether cardiac catheterization refusal rates
      differ by patient race or sex. METHODS: We evaluated medical records of 74,745
      Medicare beneficiaries hospitalized for AMI between January 1994 and February
      1996 to ascertain refusal of cardiac catheterization during hospitalization.
      Patient race and sex were evaluated for their association with cardiac
      catheterization refusal adjusting for patient, physician, and hospital
      characteristics. RESULTS: The cardiac catheterization refusal rate in the overall
      cohort was 2.92% (95% CI 2.80%-3.04%). Race and sex differences in cardiac
      catheterization were observed after multivariate adjustment, with white women
      (odds ratio [OR] 1.28), black men (OR 1.34), and black women (OR 1.37) more
      likely to refuse cardiac catheterization than white men (OR 1.00). Relative
      differences in refusal were associated with only modest absolute differences in
      risk-standardized rates of cardiac catheterization refusal; rates were lowest for
      white men (2.55%), and higher for white women (3.21%), black men (3.36%), and
      black women (3.38%, P <.001 for global comparison). CONCLUSIONS: Patient race and
      sex were associated with cardiac catheterization refusal among elderly patients
      hospitalized with AMI. However, absolute race and sex differences in rates of
      procedure refusal were small, suggesting that race and sex differences in cardiac
      catheterization refusal provide only a partial explanation of observed
      differences in cardiac procedure use.

PMID- 12486429
TI  - Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in
      patients with hypercholesterolemia.
AB  - BACKGROUND: Despite the demonstrated benefits of low-density lipoprotein
      cholesterol (LDL-C) reduction in reducing the risk of coronary heart disease,
      many patients receiving lipid-lowering therapy fail to achieve LDL-C goals. We
      compared the effects of rosuvastatin and atorvastatin in reducing LDL-C and
      achieving LDL-C goals in patients with primary hypercholesterolemia. METHODS AND
      RESULTS: In this 52-week, randomized, double-blind, multicenter trial
      (4522IL/0026), 412 patients with LDL-C 160 to <250 mg/dL received a 5-mg dose of
      rosuvastatin (n = 138), a 10-mg dose of rosuvastatin (n = 134), or a 10-mg dose
      of atorvastatin (n = 140) for 12 weeks; during the following 40 weeks, dosages
      could be sequentially doubled up to 80 mg if National Cholesterol Education
      Program Adult Treatment Panel II (ATP-II) LDL-C goals were not achieved. At 12
      weeks, 5- and 10-mg doses of rosuvastatin were associated with significantly
      greater LDL-C reductions than 10-mg doses of atorvastatin (46% and 50% vs 39%,
      both P <.001). At 12 weeks, both rosuvastatin dosages brought more patients to
      within ATP-II and European LDL-C goals than atorvastatin (86% and 89% vs 73% and
      75%, and 86% vs 55%, respectively). At 52 weeks, compared with atorvastatin, both
      initial rosuvastatin treatment groups significantly reduced LDL-C (47% and 53% vs
      44%, P <.05 and P <.001). Overall, more patients in the initial rosuvastatin 10
      mg group achieved their ATP-II LDL-C goal than those in the initial atorvastatin
      10-mg group (98% vs 87%), with 82% of patients treated with rosuvastatin
      achieving their goal at the 10-mg starting dosage without the need for titration,
      compared with 59% of patients treated with atorvastatin. Both treatments were
      well tolerated over 52 weeks. CONCLUSION: Compared with atorvastatin,
      rosuvastatin produced greater reductions in LDL-C, which may offer advantages in
      LDL-C goal attainment over existing lipid-lowering therapies.

PMID- 12486431
TI  - Change of left ventricular geometric pattern after 1 year of antihypertensive
      treatment: the Losartan Intervention For Endpoint reduction in hypertension
      (LIFE) study.
AB  - BACKGROUND: Patients with hypertension have different types of left ventricular
      (LV) geometry, but the impact of blood pressure (BP) reduction on LV geometry
      change during antihypertensive treatment remains unclear. METHODS: Two
      dimensional and M-mode echocardiograms were recorded at baseline in 853
      unmedicated patients with stage II to III hypertension and LV hypertrophy
      determined by electrocardiography (Cornell voltage duration > or =2440 mV x ms or
      modified Sokolow-Lyon criteria: SV1 + RV5/RV6 >38 mV) after 14 days of placebo
      treatment. Follow-up echocardiography was done after 1 year of blinded treatment
      with either losartan or atenolol, in some cases supplemented with thiazide and
      calcium antagonist to reach target a BP of 140/90 mm Hg. RESULTS: Baseline
      systolic/diastolic BP were reduced from 174 +/- 20/95 +/- 11 to 151 +/- 19/84 +/-
      11 mm Hg. LV mass was reduced from 234 +/- 56 to 207 +/- 51 g and relative wall
      thickness from 0.41 +/- 0.07 to 0.38 +/- 0.06 (all P <.001). Prevalence of
      concentric LV hypertrophy decreased from 24% to 6%, eccentric LV hypertrophy from
      46% to 37%, and concentric LV remodeling from 10% to 6%; normal geometry
      increased from 20% to 51%. A shift toward lower LV mass and relative wall
      thickness was found, as approximately 73% of those with concentric LV remodeling
      at baseline shifted to normal geometric pattern, whereas only 7% of those with
      normal pattern at baseline shifted to concentric LV remodeling. Of patients with
      concentric LV hypertrophy at baseline, 34% shifted to eccentric LV hypertrophy,
      whereas only 3% with eccentric LV hypertrophy at baseline had concentric LV
      hypertrophy. Furthermore, multiple regression analysis showed that Doppler stroke
      volume reduction was a significant correlate of LV mass reduction (beta = 0.108,
      P <.001) independent of BP, heart rate change, and assigned drug treatment.
      CONCLUSIONS: Antihypertensive treatment reduces LV mass and decreases the
      prevalence of LV hypertrophy and concentric LV remodeling. Additional control of
      Doppler stroke volume potentiates the effect of BP reduction on LV mass
      regression independent of the BP reduction per se.

PMID- 12486432
TI  - Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis
      of observational studies.
AB  - BACKGROUND: Fenfluramine-derivative diet pills were withdrawn from the market in
      1997 because of an association with valvular regurgitation, but subsequent
      estimates of the prevalence of this condition have varied widely. We
      systematically reviewed evidence regarding the prevalence of valvular disease
      after fenfluramine exposure. METHODS: We searched multiple databases with
      multiple search terms. Conference proceedings from 1997 onward were searched by
      index. Authors of eligible studies were contacted to identify unpublished works.
      Selection criteria were liberally determined. Ten of the identified 11 articles
      met these criteria. Reviewers assessed the studies' methodologic quality by use
      of a standard form to evaluate selection, attrition, performance, and detection
      bias. The studies were analyzed in 2 groups on the basis of length of exposure
      (<90 days or >90 days). The Mantel-Haenszel method was used to summarize data.
      Quantitative and qualitative tests for heterogeneity were performed. Tests for
      publication bias were also done. RESULTS: Tests for heterogeneity were
      nonsignificant after removing 1 outlier trial. The pooled prevalence of valvular
      regurgitation meeting Food and Drug Administration criteria (at least mild aortic
      regurgitation or at least moderate mitral regurgitation) among patients treated
      for >90 days was 12.0% compared with 5.9% for the unexposed group (prevalence
      odds ratio 2.2, 95% CI 1.7-2.7). The combined analyses also identified a small
      but statistically significant increase in mitral regurgitation not previously
      identified by individual studies (exposed 3.5%, unexposed 1.8%, prevalence odds
      ratio 1.6, 95% CI 1.05-2.3). Among patients exposed for <90 days, a trend toward
      more regurgitation was not statistically significant by either combined Food and
      Drug Administration criteria (exposed 6.8%, unexposed 5.8%, prevalence odds ratio
      1.4, 95% CI 0.8-2.4) or by individual valve. CONCLUSIONS: These data indicate
      that fenfluramine-associated valvular regurgitation is less common than initially
      reported, but still present in 1 of 8 patients treated for >90 days.

PMID- 12486433
TI  - Comparison of percutaneous transmitral commissurotomy with Inoue balloon
      technique and metallic commissurotomy: immediate and short-term follow-up results
      of a randomized study.
AB  - BACKGROUND: The Inoue balloon technique for mitral commissurotomy is well
      established and carried out worldwide. Metallic commissurotomy is reported to be
      a cheaper and effective alternative to balloon mitral commissurotomy. METHODS:
      One hundred patients were randomized into 2 groups to undergo percutaneous
      transmitral commissurotomy (PTMC) by means of the Inoue balloon technique (IBMC,
      n = 49) or metallic commissurotomy (PMMC, n = 51). Patients were crossed over to
      the other technique when the initial technique was a failure. Success of
      valvotomy, procedure-related complications, and follow-up events of the 2
      techniques were compared. RESULTS: Basal echocardiographic and hemodynamic data
      were similar in both groups. Procedural success was similar in both groups: 45 of
      49 procedures (91.8%) in the IBMC group, compared with 46 of 51 procedures
      (90.18%) in the PMMC group (P = 1.0). Crossover was also comparable, with 1
      occurring in the IBMC group, compared with 3 in the PMMC group. Complications
      such as cardiac tamponade and mitral regurgitation (requiring or not requiring
      mitral valve replacement) were similar in both groups, with 3 complications in
      the IBMC group, compared with 4 complications in the PMMC group (P =.29). After a
      follow-up period of approximately 4 months, both groups had similar event rates
      and comparable hemodynamic parameters (P = not significant). CONCLUSIONS: Both
      IBMC and PMMC are successful means of providing relief from severe mitral
      stenosis with a gain in valve area and reduction in transmitral gradient. Both
      techniques have similar procedural success, complication rates, and follow-up
      events.

PMID- 12486434
TI  - A novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent
      conduction system disease, and need for permanent pacemaker implantation.
AB  - BACKGROUND: The LMNA gene, which encodes the nuclear envelope protein lamin A/C,
      is thought to be the most common of 8 autosomal disease genes implicated in
      familial dilated cardiomyopathy (FDC). Each family reported to date has a unique
      mutation and variable degrees of cardiac conduction system, dilated
      cardiomyopathy, or skeletal muscle disease. METHODS AND RESULTS: Coding regions
      of the LMNA gene were screened in 12 biological members of a family with dilated
      cardiomyopathy and conduction system disease. A novel missense mutation
      (Leu215Pro) in exon 4 was identified in 8 subjects. Disease was manifested as
      brady- and tachyarrhythmias, often necessitating permanent pacemaker
      implantation, and later onset of dilated cardiomyopathy and heart failure. No
      features of skeletal muscle disease were noted. The high percentage of affected
      individuals who needed pacemaker therapy (88%) was a unique characteristic of
      this family compared with other FDC families with LMNA mutations. CONCLUSIONS:
      Careful examination of clinical data in families with FDC and LMNA mutations may
      reveal subtle genotype-phenotype correlations. Knowledge of such correlations may
      help to further define the mechanisms of disease in LMNA-associated FDC and can
      assist in the monitoring of disease for at-risk family members.

PMID- 12486435
TI  - Noninvasive estimation of both systolic and diastolic pulmonary artery pressure
      from Doppler analysis of tricuspid regurgitant velocity spectrum in patients with
      chronic heart failure.
AB  - BACKGROUND: Noninvasive estimation of pulmonary artery systolic and diastolic
      pressures usually requires the investigation of both tricuspid and pulmonary
      regurgitant jets and an estimate of right atrial pressure. A new, noninvasive
      method to obtain pulmonary diastolic pressure (based on the hemodynamic
      demonstration that right ventricular systolic pressure and pulmonary artery
      diastolic pressure are equal at the time of pulmonary valve opening) from the
      analysis of tricuspid regurgitation alone has been described in a small cohort of
      patients. We sought to verify the accuracy of this method in a large population
      of patients with heart failure. METHODS: An estimate of pulmonary artery
      diastolic pressure was obtained by transposing the pulmonary opening time (from
      the onset of the R wave on the electrocardiographic tracing to the beginning of
      pulmonic forward flow on Doppler examination) onto the tricuspid regurgitant
      velocity curve and calculating the pulmonary artery diastolic pressure value as
      the pressure gradient between the right ventricle and right atrium at this time.
      The study group included 86 consecutive patients (64 men, aged 52 +/- 11 years)
      with heart failure (New York Heart Association class > or =II, 94%) who were in
      stable clinical condition with a chiefly idiopathic (57%), ischemic (24%), or
      other form (13%) of dilated cardiomyopathy. Noninvasive, right-sided pressures
      were compared with invasive measurements obtained during right heart
      catheterization performed within 24 hours. The Bland and Altman graphic method
      was used together with the calculation of the Lin concordance correlation
      coefficient and its 95% CI to assess the agreement between hemodynamic and
      echocardiographic measurements. RESULTS: Catheter-derived pulmonary artery
      systolic pressure ranged from 8 to 119 mm Hg (mean 42 +/- 21 mm Hg), pulmonary
      artery diastolic pressure from 1 to 59 mm Hg (mean 20 +/- 11 mm Hg), and right
      atrial pressure from -5 to 20 mm Hg (mean 6 +/- 5 mm Hg). Tricuspid regurgitation
      was detected in 75 of 86 patients (87%). Pulmonary artery systolic pressure
      ranged from 13 to 110 mm Hg (mean 44 +/- 21 mm Hg); the pressure gradient between
      the right ventricle and right atrium at time t of the pulmonary valve opening on
      the tricuspid regurgitation velocity curve was measurable in 70 of 75 (93%) cases
      and ranged from 3.5 to 64 mm Hg (mean 22 +/- 11 mm Hg). Good agreement was
      observed not only for pulmonary artery systolic pressure but also for pulmonary
      artery diastolic pressure, based on the analysis of the tricuspid regurgitation
      velocity jet, with a slight difference between measurements (-1.8 and 0.1,
      respectively), no evident pattern of point scattering, and a high concordance
      correlation coefficient that was elicited by the virtually total overlapping of
      lines on the graph. Overall results were not significantly different whether
      patients with depressed right ventricular function (right ventricular ejection
      fraction < or =35%), with a tricuspid regurgitation grade > or =2 and atrial
      fibrillation were included in the analysis. CONCLUSIONS: The narrow paired
      difference for the estimate of pulmonary artery systolic pressure and the even
      better difference for pulmonary artery diastolic pressure using the tricuspid
      regurgitation velocity curve analysis indicates that this new method reliably
      estimates invasive right-sided pressures over a wide range of pressure values in
      patients with heart failure. The overall good correlation with invasive values
      indicates that Doppler examination of tricuspid regurgitation alone may provide a
      simple and comprehensive new method for the noninvasive evaluation of right
      ventricular and pulmonary hemodynamics in patients with heart failure.

PMID- 12486436
TI  - Amiodarone and mortality among elderly patients with acute myocardial infarction
      with atrial fibrillation.
AB  - BACKGROUND: Amiodarone has been shown to be safe in patients with acute
      myocardial infarction (AMI) who are at risk for sudden cardiac death. However,
      there is limited data concerning the safety of amiodarone in patients who
      experience AMI complicated by atrial fibrillation. METHODS: To determine the
      safety of amiodarone therapy, we conducted a retrospective analysis of elderly
      patients hospitalized with AMI who experienced atrial fibrillation and had
      survived to hospital discharge (n = 17,597). Amiodarone prescribed at discharge
      was evaluated for its association with short-term and long-term mortality in
      crude and adjusted analyses employing propensity score methods. RESULTS: Of the
      17,597 patients, 550 patients (3.1%) were prescribed amiodarone, 2317 patients
      (13.2%) were prescribed other antiarrhythmic agents (excluded from analysis), and
      14,730 (83.7%) were prescribed no antiarrhythmic medication at discharge. Thirty
      day mortality rates were similar for patients prescribed amiodarone and those not
      prescribed amiodarone (6.8% amiodarone vs 5.4% no amiodarone, P =.21), but
      mortality at 1 year was higher among patients prescribed amiodarone (35.6% vs
      31.6%, P =.001). However, amiodarone was not associated with mortality at 30 days
      (odds ratio 0.80, 95% CI 0.53-1.20) or at long-term follow-up (mean duration 612
      days, hazard ratio 1.04, 95% CI 0.92-1.18) after multivariable modeling.
      CONCLUSIONS: Amiodarone was not independently associated with short-term or long
      term mortality in elderly patients discharged after a hospitalization for AMI
      complicated by atrial fibrillation. Although our data suggest that amiodarone may
      be safe to use in this population, randomized controlled trial data are needed to
      confirm this finding.

PMID- 12486437
TI  - Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular
      arrhythmias in the treatment of patients with acutely decompensated congestive
      heart failure: the PRECEDENT study.
AB  - BACKGROUND: Dobutamine is commonly used as a means of treating decompensated
      congestive heart failure (CHF). Although typically effective at improving short
      term hemodynamics and symptomatology, the frequent occurrence of arrhythmias and
      tachycardia is undesirable. In this randomized, multicenter trial, we compared
      the safety and clinical effectiveness of the cardiac hormone nesiritide (human B
      type natriuretic peptide) with dobutamine in hospitalized patients with
      decompensated CHF. METHODS: The study population consisted of 255 patients who
      were randomized to 1 of 2 doses of intravenous nesiritide (0.015 or 0.03
      microg/kg/min) or dobutamine (> or =5 microg/kg/min) and stratified by means of
      an earlier history of ventricular tachycardia. Patients were also assessed with
      24 hour Holter recordings immediately before and during study drug therapy and by
      means of signs and symptoms of CHF. RESULTS: Dobutamine significantly increased
      the mean (1) number of ventricular tachycardia events per 24 hours by 48 +/- 205
      (P =.001), (2) repetitive ventricular beats per hour by 15 +/- 53 (P =.001), (3)
      premature ventricular beats per hour by 69 +/- 214 (P =.006), and (4) heart rate
      by 5.1 +/- 7.7 beats per minute (P <.001). These end points were significantly
      decreased or unchanged in the nesiritide groups. Nesiritide did not increase
      heart rate, despite a greater reduction of blood pressure. Both drugs were
      similarly effective means of improving signs and symptoms of CHF. CONCLUSIONS:
      Dobutamine is associated with substantial proarrhythmic and chronotropic effects
      in patients with decompensated CHF, whereas nesiritide actually reduces
      ventricular ectopy or has a neutral effect. Compared with dobutamine, nesiritide
      may be a safer, short-term treatment for patients with decompensated CHF.

PMID- 12486438
TI  - Autonomic alterations in cocaine-exposed infants.
AB  - BACKGROUND: Heart rate variability (HRV) reflects autonomic control of the heart.
      After intrauterine cocaine exposure, asymptomatic newborn infants within 72 hours
      of life have decreased HRV. It is unknown whether these alterations are transient
      (acute effect) or persist in older infants and possibly reflect a teratogenic
      effect of cocaine. METHODS: This study prospectively evaluated HRV in 2- to 6
      month-old infants who were exposed to cocaine in-utero (Group 1, n = 71). Their
      data were compared to normal controls (Group 3, n = 77) and to newborns exposed
      to drugs other than cocaine (Group 2, n = 89). Based on our previous study, heavy
      and light cocaine exposure was also defined a priori as the amount of cocaine
      used during the pregnancy that was more than or less than the 70th percentile,
      respectively. RESULTS: At the age of 2 to 6 months, infants with in-utero cocaine
      exposure had higher vagal tone and higher HRV (total power) than normal controls
      (no exposure to drugs). Most of this increase in vagal tone occurred in the light
      cocaine-exposure group. HRV and vagal tone in the heavy-cocaine-exposure group
      were similar to the noncocaine-exposed group. CONCLUSIONS: At 2 to 6 months of
      age, asymptomatic infants exposed to cocaine in-utero have recovered from lower
      HRV seen within 72 hours of age. Infants exposed to light cocaine recovered by a
      rebound by increasing their vagal tone to above-normal levels. A similar response
      was blunted in heavily-cocaine-exposed infants. These alterations noted at follow
      up suggest a possible teratogenic effect of cocaine on the developing autonomic
      system.

PMID- 12486439
TI  - Effect of atenolol on symptomatic ventricular arrhythmia without structural heart
      disease: a randomized placebo-controlled study.
AB  - BACKGROUND: Ventricular arrhythmia (VA) from the right ventricular outflow tract
      (RVOT) is a common problem. Symptomatic patients are usually treated with beta
      blockers. There is little data on the systematic evaluation of the efficacy of
      beta-blocker. We determine the efficacy of atenolol in the treatment of
      symtomatic VA from RVOT compared with placebo. METHODS AND RESULTS: This was a
      randomized, double-blinded, placebo-controlled study. We prospectively studied 52
      consecutive patients with symptomatic VA. Severity of symptoms, 24-hour
      ambulatory monitoring (AECG) and quality of life (QOL) were assessed at baseline
      and 1 month after atenolol. Exercise testing was performed at baseline. Average
      premature ventricular complex (PVC) count at baseline was 21,407 +/- 1740 beats
      per 24 hours, and 19% had ventricular tachycardia as measured by AECG. Results of
      this study showed that atenolol significantly decreased symptom frequency (P
      =.03), PVC count (P =.001) and average heart rate (P <.001) measured by AECG,
      whereas placebo significantly decreased symptom frequency (P =.002) but had no
      effect on PVC count (P =.78) or average heart rate (P =.44). Neither atenolol nor
      placebo had an effect on QOL. CONCLUSIONS: Atenolol improves symptoms and
      decreases PVC count from ambulatory monitoring. Placebo improved symptoms to the
      same extent as atenolol but had no effect on severity of VA. This might be the so
      called placebo effect, which is a concern when treating patients or doing
      research on the effects of a drug.

PMID- 12486440
TI  - Polyunsaturated fatty acids and cardiovascular risk: interference at the level of
      gene expression.
AB  - Long-chain polyunsaturated fatty acids (PUFA) are important structural components
      of the cell membrane as well as precursors of highly active lipid mediators, the
      eicosanoids. In addition, they have been identified as novel intracellular
      signaling molecules which either directly or indirectly through the modulation of
      other signaling pathways activate transcription factors and gene expression. With
      regard to cardiovascular risk and diseases, effects of PUFA have been observed on
      genes whose products regulate either metabolic processes, especially fatty acid
      metabolism, or are involved in inflammatory and mitogenic processes of vascular
      cells. Often, the effects of n-3 and n-6 PUFA on the expression of both types of
      genes are antagonistic indicating a balancing role of n-3 and n-6 PUFA in cell
      metabolism and function already at the level of gene expression.

PMID- 12486441
TI  - Dietary intake analysis in institutionalized elderly: a focus on nutrient
      density.
AB  - BACKGROUND: Inadequate food intake in old age can lead to marginal or suboptimal
      nutrient intakes causing the deterioration of physiological and health states.
      OBJECTIVE: To describe, by intake assessment, nutritional status of
      institutionalized elderly and to compare the data to other studies findings.
      DESIGN: Dietary intake was assessed in 50 (18 males, 32 females, average age 84 6
      years) institutionalized elderly according to data collected by using structured
      food frequency questionnaires based on the institutional kitchen recipes, weekly
      menu and portion size. RESULTS: Daily energy intake was 1.91 0.48 Mcal and energy
      density was 4.97 kcal/g dry matter. Energy derived from protein and fat was 15.1%
      and 35.4%, respectively. Dietary fiber consumption was very low, 3.92 g/Mcal.
      Calcium intake of all of the subjects, and magnesium, zinc and copper intakes of
      most of them, were low. Iron intake of almost all of the subjects was sufficient
      or above RDA. Intake of vitamins D, E, B6, thiamin (vitamin B1) and folic acid in
      all or most of the subjects was low. In almost all of the 39 studies and reviews,
      including ours, densities of at least two nutrients did not meet the calculated
      RDA density. Particularly low were the nutrient densities of vitamins C and E,
      thiamin, vitamin B6, folic acid and vitamin D, as well as of calcium, magnesium,
      zinc and copper. CONCLUSION: Supplementation with half the RDA of micronutrients
      (except for vitamin A and iron) may result in micronutrient intakes that are
      higher than two-thirds of the RDA.

PMID- 12486442
TI  - Zinc deficiency is of limited clinical importance in the elderly (>69 y) of Oslo.
AB  - BACKGROUND: Zinc is an important trace element, and deficiency can cause disease
      and impairment of several physiological functions. OBJECTIVE: To examine s-zinc
      concentration in a large elderly population (347 subjects), and correlate it to
      standard biochemical markers, nutritional core indicators, and anamnestic data.
      DESIGN: A randomized population survey, studying two groups of elderly; one
      living at home and the other recently admitted to hospital. RESULTS: Serum zinc
      concentration was (Mean SD) in the home group (11.6 1.8 micromoles /L), and in
      the hospital group (11,5 2.5 micromoles /L). S-zinc was below 8 micromol/L in the
      hospital group in 22 of 250 patients and in 4 out of 97 of the home group. There
      was no significant difference in prevalence of zinc deficiency in hospital versus
      the home living group. Low s-zinc was significantly correlated to diarrhea, but
      to no other marker used in this study. CONCLUSION: Zinc deficiency is most
      probably of limited clinical importance in the elderly of Oslo, and there is no
      biochemical or nutritional marker that in addition to s-zinc can aid in the
      diagnosis.

PMID- 12486443
TI  - Research and practice in Alzheimer's disease 2002.

PMID- 12486444
TI  - Energy balance in Alzheimer's disease.
AB  - Alzheimer s disease is the most frequent cause of dementia in elderly people and
      it is one of the leading causes of death among older individuals. Weight loss is
      a frequent clinical finding in Alzheimer s disease patients, and it is actually
      listed as a symptom consistent with the diagnosis of Alzheimer s disease, but its
      significance has not been clearly understood until now. This review examines the
      role of the components of energy balance in determining weight loss in AD
      patients, on the basis of data collected from the literature. We also considered
      the possible causes of anorexia in AD patients. In the last years many
      researchers investigated the possible role of abnormally high energy expenditure,
      or low energy intakes, or both, to explain weight loss in these patients. Studies
      on energy intake, energy expenditure and body composition in AD patients have
      been reviewed. The results of published studies do not seem to support the
      hypothesis of an hypermetabolic state or inadequate energy intake in AD patients,
      but further studies, with greater samples are necessary in the future to
      investigate weight loss in AD patients. A better understanding of this finding
      could be important to obtain the maximal lifespan of demented patients.

PMID- 12486445
TI  - Prevalence of vitamin B12 deficiency among demented patients and cognitive
      recovery with cobalamin replacement.
AB  - OBJECTIVE: To find out the prevalence of vitamin B12 deficiency among demented
      patients and to look at the effects of cobalamin repletion on cognition in
      elderly, subjects with low serum cobalamin and evidence of cognitive dysfunction.
      DESIGN: Time series data collected in a single-blinded trial of parenteral
      cobalamin therapy. SETTINGS: Nursing home facility and Outpatient geriatric
      assessment center. PARTICIPANTS: Sixty-two subjects with low serum cobalamin
      (<300 pg/ml) and evidence of cognitive dysfunction were entered consecutively
      over a two years period of time. Fifty-six subjects completed the study.
      INTERVENTIONS: Subjects received 1000 micrograms of cyanocobalamin
      intramuscularly daily for 1 week, then weekly for 1 month, then monthly
      thereafter for a minimum of six months. OUTPATIENT MEASURE: The Folstein
      Minimental Status Examination(MMSE), clock drawing tests, and caregiver
      interviews were administered both before and at 3 months after full cobalamin
      replacement therapy. Assessment was repeated thereafter every three months. The
      hypothesis that cognitive improvement was dependent on the duration of cognitive
      symptoms. RESULTS: After a minimum of 12 months of cobalamin therapy, 40 of 56
      patients revealed cognitive improvement. There was a prominent correlation
      between duration of cognitive symptoms and response to therapy. Patients
      symptomatic for <12 months gained an average of six points on the MMSE (paired t
      test P = 0.0065), whereas patients symptomatic >12 months gained an average of
      four points (paired t test P = 0.25). Six patients symptomatic for only 3 to six
      months normalized their MMSE scores, gaining 1,2,3, 6, and 9 points,
      respectively. CONCLUSION: It seems that there may be a time-limited window of
      opportunity for effective intervention in patients with cognitive dysfunction and
      low serum cobalamin.

PMID- 12486446
TI  - Oxidative stress and cognitive impairment in the elderly.
AB  - Cognitive impairment is a major component of age-related dementing diseases and
      it has been suggested that it could share the same pathological pathways with
      neurodegenerative processes and cerebrovascular lesions. The free radical theory
      of aging could be one of these pathways. Observational studies of relationships
      between cognitive impairment and antioxidant status are based on the evaluation
      of dietary intake or on the levels of carotenoids, selenium and vitamins A, C and
      E in plasma. More convincing results were obtained on vitamin C and carotenoids.
      Despite some limitations, the comparison between results obtained in various
      populations is becoming increasingly informative and these studies argue for a
      protective effect of antioxidants on cognitive performance.

PMID- 12486447
TI  - Gender, cohort and geographical differences in 10-year mortality in elderly
      people living in 12 European towns.
AB  - BACKGROUND: In 1988/89, 2586 randomly selected elderly of both sexes born between
      1913 and 1918 and living in 19 centres of 12 European countries participated in
      the SENECA Study on Nutrition and the Elderly in Europe. Differences in
      nutritional and health status as well in lifestyle factors, namely dietary
      habits, between the elderly living in the several centres were observed.
      OBJECTIVE: To study gender, cohort and geographical differences in 10-year
      mortality in elderly people from the SENECA Study. DESIGN: Longitudinal study.
      Information on vital status of the elderly people who participated in the
      baseline study performed in 1988/89 was obtained by standardized procedures in
      1999, until 30 April. RESULTS: In all centres, men had higher mortality rates
      than women. A cohort effect in mortality is observed, particularly in men. A
      geographical pattern in mortality also more evident in men is shown. In fact,
      elderly men living in Eastern Europe, represented by the Polish centre, had the
      highest average hazard rate, 108, while those living in Southern Europe,
      including the French, the Swiss, the Italian, the Spanish and the Portuguese
      centres, had the lowest average hazard rates, ranging from 52 in Betanzos/Spain
      to 67 in the two French towns. Finally, those living in Northern Europe,
      represented by the Danish, the Dutch and the Belgian centres had intermediate
      values, from 68 in Roskilde/ Denmark to 85 in Culemborg/the Netherlands. Kaplan
      Meier survival curves confirmed the gender, cohort and geographical differences
      in survival (log-rank test P  0.0001). CONCLUSION: The gender and geographical
      differences in mortality observed in elderly people living in different regions
      of Europe put in evidence the potential for increasing the life expectancy in
      Europe through intervention programs tackling the lifestyle and socio-economic
      factors behind those differences.

PMID- 12486448
TI  - The GAIN (Geriatric Anorexia Nutrition) registry: the impact of appetite and
      weight on mortality in a long-term care population.
AB  - PURPOSE: To investigate nursing home residents at high nutritional risk to
      determine: 1) which baseline nutrition or health status indicators correlated
      with subsequent weight gain or appetite improvement; and, 2) whether a continued
      weight loss correlated with higher mortality. METHODS: At study entry,
      nutritional, health status, and demographic data were extracted from the nursing
      home chart or the MDS. Each subject was tracked for 6 months with survival,
      weight gain of   5%, and appetite improvement the primary outcome measures.
      RESULTS: During the 6-month study, younger age was the strongest correlate of
      appetite improvement. The odds of gaining weight were negatively correlated with
      BMI, age, and feeding dependency. Subjects who were receiving appetite stimulants
      (orexigenics) at study entry had a 70% greater probability of gaining weight than
      those who were not. A weight loss during the 6-month period was associated with a
      nearly two-fold increase in the likelihood of dying (adjusted RR: 1.95, 95% CI
      1.43 to 2.66). CONCLUSION: The course of nutritional problems within nursing
      homes is highly variable. Continued weight loss, however, appears to have ominous
      implications for mortality. Younger residents who are not dependent on others for
      feeding assistance, and who receive orexigenics tend to experience weight gain.

PMID- 12486449
TI  - Nutrition and health of the elderly: osteoporosis.
AB  - Osteoporosis is a debilitating disease that affects many older people. Its
      aetiology is complex and nutrition is only one of many factors which influence
      bone mass and the risk of fragility fractures. This review briefly describes the
      biology and epidemiology of osteoporosis and focuses on role of nutrition in the
      bone health of older people. An overview of the current evidence relating calcium
      intake and vitamin D status in the elderly to bone mass and fractures is
      presented and set in context of recent population-based surveys that have
      identified important nutritional inadequacies among sub-groups of the elderly
      population in Europe.

PMID- 12486451
TI  - Presence of two novel cardiolipins in the halophilic archaeal community in the
      crystallizer brines from the salterns of Margherita di Savoia (Italy) and Eilat
      (Israel).
AB  - Two novel cardiolipin derivatives were recently detected in Halobacterium
      salinarum, namely an archaeal analog of bisphosphatidylglycerol (BPG) and a
      glycocardiolipin (GlyC). GlyC was found to be tightly bound to bacteriorhodopsin.
      To obtain information on the presence and distribution of these archaeal
      cardiolipins, we have analyzed the lipids extracted from the crystallizer ponds
      of the salterns of Margherita di Savoia (Italy) and Eilat (Israel) and from
      cultures of representative species of the Halobacteriaceae by electrospray
      ionization mass spectrometry. BPG was present as a minor lipid component in the
      lipids extracted from the biomass of the Margherita di Savoia and the Eilat
      salterns, while GlyC was detected only in the extract of the biomass of
      Margherita di Savoia. Both compounds were enriched in the membrane fraction
      obtained by dialysis of the cells against distilled water. We detected BPG in all
      members of the Halobacteriaceae tested, but GlyC has so far been found only in
      the genera Halobacterium and Haloarcula. A sulfated diglycosyl diether was the
      major glycolipid detected in the biomass of both salterns.

PMID- 12486452
TI  - Halosimplex carlsbadense gen. nov., sp. nov., a unique halophilic archaeon, with
      three 16S rRNA genes, that grows only in defined medium with glycerol and acetate
      or pyruvate.
AB  - A halophilic archaeon has been isolated from unsterilized salt crystals taken
      from the 250-million-year-old Salado formation in southeastern New Mexico. This
      microorganism grows only on defined media supplemented with either a combination
      of acetate and glycerol, glycerol and pyruvate, or pyruvate alone. The archaeon
      is unable to grow on complex media or to use carbohydrates, amino acids, fats,
      proteins, or nucleic acids for growth. Unlike other halophilic microbes, this
      organism possesses four glycolipids, two of which may be novel. The microbe is
      unique in that it has three dissimilar 16S rRNA genes. Two of the three genes
      show only 97% similarity to one another, while the third gene possesses only 92%
      93% similarity to the other two. Inferred phylogenies indicate that the organism
      belongs to a deep branch in the line of Haloarcula and Halorhabdus. All three
      lines of taxonomic evidence: phenotype, lipid patterns, and phylogeny, support
      creation of a new genus and species within the halophilic Archaea. The name
      suggested for this new genus and species is Halosimplex carlsbadense. The type
      strain is 2-9-1(T) (= ATCC BAA-75 and JCM 11222) as written in the formal
      description.

PMID- 12486453
TI  - Novel insights into the role of potassium for osmoregulation in Halomonas
      elongata.
AB  - The role of K(+) in osmoregulation of the halophilic bacterium Halomonas elongata
      was investigated. At lower salinities (0.51 M NaCl), K(+) was the predominant
      cytoplasmic solute (1.25 micro mol mg protein(-1)). At higher salinities (1.03 M
      NaCl) ectoine became the main cytoplasmic solute (1.57 micro mol mg protein(-1)),
      while the K(+) content remained unchanged. In response to osmotic upshock, cells
      of H. elongata simultaneously accumulated ectoine and K(+) glutamate. The ectoine
      and K(+) glutamate levels in osmotically stressed cells exceeded the level of
      cells adapted to high salinities. The increase in K(+) glutamate was long lasting
      (>120 min) and not transient, as described for non-halophiles. Regulation of the
      synthesis of ectoine and glutamate was proven to occur mainly at the level of
      enzyme activity. Limitation of K(+) inhibited the growth of salt-adapted H.
      elongata cells, especially at high salinities, and caused a decrease of the
      intracellular organic solute content, inhibition of respiration, and an abolition
      of the cell's ability to respond to osmotic stress. The saturation constant K(S)
      for K(+) was estimated to be 105 micro M at a salinity of 0.51 M NaCl, indicating
      that an uptake system of medium affinity is responsible for K(+) accumulation in
      H. elongata.

PMID- 12486454
TI  - A novel thermophilic fusion enzyme for trehalose production.
AB  - In recent years a number of hyperthermophilic micro-organisms of Sulfolobales
      have been found to produce trehalose from starch and dextrins. In our laboratory
      genes encoding the trehalosyl dextrin forming enzyme (TDFE) and the trehalose
      forming enzyme (TFE) of S. solfataricus MT4 have been cloned and expressed in E.
      coli (Rb791). Here we report the construction of a new protein obtained by fusion
      of TFE and TDFE coding sequences which is able to produce trehalose from dextrins
      at high temperature by sequential enzymatic steps. We demonstrate that the
      bifunctional fusion enzyme is able to produce trehalose starting from malto
      oligosaccharides at 75 degrees C. Furthermore we partially purified the
      recombinant fusion protein from bacterial cell free extracts and from insoluble
      fractions in which the fusion protein was also found as aggregate in inclusion
      bodies.

PMID- 12486455
TI  - Biochemical characterization of an ATP-dependent DNA ligase from the
      hyperthermophilic crenarchaeon Sulfolobus shibatae.
AB  - A gene encoding a putative ATP-dependent DNA ligase was identified in the genome
      of the hyperthermophilic archaeon Sulfolobus shibatae and expressed in
      Escherichia coli. The 601 amino acid recombinant polypeptide was a monomeric
      protein capable of strand joining on a singly nicked DNA substrate in the
      presence of ATP ( K(m)=34 micro mu) and a divalent cation (Mn(2+), Mg(2+), or
      Ca(2+)). dATP was partially active in supporting ligation catalyzed by the
      protein, but GTP, CTP, UTP, dGTP, dCTP, dTTP, and NAD(+) were inactive. The
      cloned Ssh ligase showed an unusual metal cofactor requirement; it was
      significantly more active in the presence of Mn(2+) than in the presence of
      Mg(2+) or Ca(2+). Unexpectedly, the native Ssh ligase preferred Mg(2+) and Ca(2+)
      rather than Mn(2+). Both native and recombinant enzymes displayed optimal nick
      joining activity at 60-80 degrees C. Ssh ligase discriminated against substrates
      containing mismatches on the 3'-side of nick junction and was more tolerant of
      mismatches at the 5'-end than of those at the penultimate 5'-end. The enzyme
      showed little activity on a 1-nucleotide gapped substrate. This is the first
      biochemical study of a DNA ligase from the crenarchaeotal branch of the archaea
      domain.

PMID- 12486456
TI  - Taxonomic characterization of Haloferax sp. (" H. alicantei") strain Aa 2.2:
      description of Haloferax lucentensis sp. nov.
AB  - An extremely halophilic archaeon, previously named as Haloferax sp. strain Aa 2.2
      or "Haloferax alicantei" that has been extensively used for genetic studies with
      halobacteria, was taxonomically characterized by using phenotypic tests
      (including morphological, physiological, biochemical and nutritional features),
      DNA-DNA hybridization and 16S rRNA sequence phylogenetic analysis. This organism
      was isolated in 1986 by Torreblanca et al. from a pond of a Spanish saltern
      located in Alicante. The cells were pleomorphic, Gram negative and grew optimally
      at 25% NaCl. The polar lipid composition was similar to that of species of the
      genus Haloferax. The DNA G+C content of this strain was 64.5 mol%. Phylogenetic
      analysis based on 16S rRNA sequence comparison confirmed that this archaeon is a
      member of the genus Haloferax and was most closely related to Haloferax volcanii.
      DNA-DNA hybridization between strain Aa 2.2 and the type strain of all named
      species of the genus Haloferax revealed low levels of relatedness (25-2%),
      supporting the placement of this organism in a new species. On the basis of the
      phenotypic characteristics, molecular data and phylogenetic analysis we propose
      to name strain Aa 2.2 as a new species, Haloferax lucentensis sp. nov. The type
      strain is Aa 2.2 (=JCM 9276=NCIMB 13854=CIP 107410=DSM 14919=CECT 5871=CCM 7023).

PMID- 12486457
TI  - Thermal stability of aminoacyl-tRNAs in aqueous solutions.
AB  - Life in hot environments poses certain constraints on the metabolism of
      thermophilic organisms. Many universal metabolic intermediates are quite labile
      compounds, and without protection will rapidly decompose at elevated
      temperatures. Among these are aminoacyl-tRNAs that are necessarily formed upon
      functioning of the translation apparatus. Aminoacyl-tRNAs are known to be
      hydrolyzed rapidly even at moderate temperatures under mild alkaline conditions.
      We studied the thermal stability of phenylalanyl- and alanyl-tRNA in aqueous
      solutions in order to evaluate a potential threat posed by high temperatures to
      these components of the translation machinery of thermophiles. Specific second
      order rate constants of the aminoacyl-tRNA hydrolysis reaction were determined in
      the range 20 degrees -80 degrees C. The activation energy of phenylalanyl- and
      alanyl-tRNA hydrolysis was found to be about 42 and 23 kJ/mol, respectively. The
      calculated half-lives of aminoacyl-tRNAs at sub-80 degrees C temperatures vary
      from several seconds to several dozens of seconds at near-neutral pH. The
      possible mechanisms counteracting the observed thermolability of aminoacyl-tRNAs
      in vivo are discussed.

PMID- 12486458
TI  - Intracellular ion and organic solute concentrations of the extremely halophilic
      bacterium Salinibacter ruber.
AB  - Salinibacter ruber is a red obligatory aerobic chemoorganotrophic extremely
      halophilic Bacterium, related to the order Cytophagales. It was isolated from
      saltern crystallizer ponds, and requires at least 150 g l(-1) salt for growth.
      The cells have an extremely high potassium content, the ratio K(+)/protein being
      in the same range as in halophilic Archaea of the order Halobacteriales. X-ray
      microanalysis in the electron microscope of cells grown in medium of 250 g l(-1)
      salt confirmed the high intracellular K(+)concentrations, and showed
      intracellular chloride to be about as high as the cation concentrations within
      the cells. A search for intracellular organic osmotic solutes, using (13)C-NMR
      and HPLC techniques, showed glutamate, glycine betaine, and N-alpha-acetyllysine
      to be present in low concentrations only, contributing very little to the overall
      osmotic balance. The results presented suggest that the extremely halophilic
      Bacterium Salinibacteruses a similar mode of haloadaptation to that of the
      Archaea of the order Halobacteriales, and does not accumulate organic osmotic
      solutes such as are used by all other known halophilic and halotolerant aerobic
      Bacteria.

PMID- 12486460
TI  - Solute accumulation in the deep-sea bacterium Photobacterium profundum.
AB  - The identity and amounts of intracellular solutes in the deep-sea bacterium
      Photobacterium profundum strain SS9 were studied using nuclear magnetic resonance
      techniques. P. profundum strain SS9, a moderate piezophile which grows optimally
      at 20-30 MPa primarily accumulated glutamate and betaine, with lesser amounts of
      alanine, beta-hydroxybutyrate (beta-HB) and oligomers composed of the beta-HB
      units when grown at 0.1 MPa to early stationary phase. When grown at the optimal
      pressure, the cells preferentially increased intracellular concentrations of beta
      HB and beta-HB oligomers, while the amino acid pools remained relatively
      constant. Since the organic solutes increased with increasing external NaCl in
      the medium, they are functioning as osmolytes. The beta-HB molecules represent a
      novel class of osmolytes, termed 'piezolytes,' whose cellular levels responded to
      hydrostatic pressure as well as osmotic pressure. Factors such as cell growth
      stage and temperature were also examined for their effect on the solute
      distribution in these cells.

PMID- 12486461
TI  - Japan's share of articles in orthopedics.
AB  - We investigated Japan's contribution to research in orthopedics during the last
      decade. Articles published during 1991-2000 in highly reputed orthopedics
      journals were accessed through the MEDLINE database. Articles with an affiliation
      with a Japanese institution were recorded along with the publication year. The
      proportions of randomized controlled trials (RCTs), cohort studies, and case
      reports among the articles from Japan were also generated and compared with the
      overall number for all articles published in these journals. The shares of the
      top-ranking countries are presented along with the trend over time. Of the total
      articles (10 551), Japan's share for the selected journals in orthopedics was
      8.3% (878 articles), ranking third in the world, after the United States (50.3%)
      and the United Kingdom (11.2%). The recent increase in the share was not
      statistically significant for Japan. Proportions of the level of evidence were
      lower for Japan-originated articles than for the total articles. Japan's
      contribution to orthopedics research is higher than that in other biomedical
      fields, but the number of high-quality clinical research studies conducted in
      Japan in this field was meager, similar to that in other fields.

PMID- 12486459
TI  - Isolation and characterization of a halotolerant Bacillus subtilis BBK-1 which
      produces three kinds of lipopeptides: bacillomycin L, plipastatin, and surfactin.
AB  - Twenty-three halotolerant and biosurfactant producing strains were collected from
      salty conditions in central Thailand. One of the strains designated BBK-1
      produced the biosurfactants with the highest activity. BBK-1 was isolated from
      fermented foods and was identified as B. subtilis based on its physiological
      characteristics and 16S rRNA gene sequence. We show that the strain grows in
      media containing NaCl up to 16% (w/v) and produces biosurfactants in NaCl up to
      8%. We found that B. subtilis BBK-1 produces three kinds of surface-active
      lipopeptides simultaneously. By their respective molecular weights and amino acid
      compositions, it is indicated that these lipopeptides are bacillomycin L,
      plipastatin, and surfactin. In order to analyze the production mechanism of
      lipopeptides further in the strain, a generally important biosynthetic gene
      encoding 4'-phosphopantetheinyl transferase was cloned and sequenced. The gene
      existed in a single copy in the genome and the deduced amino acid sequence was
      almost identical to that of Lpa-14 from B. subtilis strain RB14, which co
      produces iturin A and surfactin.

PMID- 12486462
TI  - Epidemiology and demographics of slipped capital femoral epiphysis in Japan: a
      multicenter study by the Japanese Paediatric Orthopaedic Association.
AB  - Anationwide survey of the epidemiology and demographics of slipped capital
      femoral epiphysis (SCFE) was carried out using questionnaires to investigate the
      incidence, clinical characteristics, and frequently used treatment procedures in
      Japan. Inquiries were sent to 2040 of the leading hospitals nationwide. Data were
      collected for the period between January 1997 and December 1999. Inquiries
      included onset age, sex, past medical history, type of slip, height, weight, and
      treatment procedure. Altogether, 314 cases were reported (237 boys, 77 girls)
      from 131 hospitals. The average annual incidence was estimated to be at least
      2.22 for boys and 0.76 for girls for every 100 000 in the age group of 10- to 14
      year-olds. These estimations are five times higher than the 1976 statistics from
      the eastern half of Japan. The average onset age was 11 years 10 months in boys
      and 11 years 5 months in girls. The most common treatment was surgery including
      in situ fixation (61.4%), osteotomies (25.9%), fixation after manual reduction
      (11.9%), and skeletal traction (0.9%). All patients except two were treated
      surgically. We concluded that SCFE has markedly increased during the last 25
      years in Japan, and therefore further study of SCFE is needed to understand this
      disorder.

PMID- 12486463
TI  - Changes in lumbar lordosis in young patients with low back pain during a 10-year
      period.
AB  - Height and muscle strength have reportedly changed among Japanese youth during
      the past 10 years. Height has increased, and the back muscles have become weaker
      than 10 years ago. We compared the lumbar lordosis of youth today (113 men and 76
      women) and of 10 years ago (85 men and 62 women). Lumbar lordosis and sacral
      inclination were measured on lateral standing radiographs of the lumbar spine. We
      also measured the same parameters among adults today (63 men and 63 women) and 10
      years ago (56 men and 73 women) to study postural changes in another generation.
      In both men and women, the lumbar lordosis and the sacral inclination of youth
      today were approximately 10 degrees larger than they were 10 years ago ( P <
      0.0001). However, there was no significant difference between the values among
      adults today and those of the same generation 10 years ago.

PMID- 12486464
TI  - Ultrasound velocity in the tibia in Japanese patients with hip fracture.
AB  - The speed of sound in the tibia (tibial SOS) was measured in elderly women to
      determine whether the tibial SOS declined with age, similarly to bone mineral
      density (BMD), as determined by dual-energy X-ray absorptiometry (DXA), and
      whether the tibial SOS in elderly hip fracture patients was lower than that in a
      control group. The subjects in this study included 38 female patients with hip
      fracture aged 65 years or more and 38 age-matched women living in a nursing home
      as the control group. There was a significant decline in the tibial SOS with age
      in women in the control group, but not in those with hip fracture. In all
      subjects aged under 80 years, the tibial SOS in women with hip fracture was
      significantly lower than that in women in the control group. In all subjects who
      were 80 years or older, the tibial SOS was not significantly different between
      women with hip fracture and the control group; thus, the tibial SOS in both
      groups was low, and they were considered to have progressive osteoporosis. The
      tibial ultrasound velocity can be expected to be useful as an indicator of the
      risk of limb fracture in the elderly.

PMID- 12486465
TI  - Surgical treatment of cervical spondylotic myelopathy associated with athetoid
      cerebral palsy.
AB  - After a mean follow-up period of 7 years (range 4-17 years), we reviewed the
      cases of 14 patients who underwent surgical treatment for cervical spondylotic
      myelopathy associated with athetoid cerebral palsy. All of the patients who
      underwent anterior decompression and arthrodesis showed degeneration and
      increased range of motion of the adjacent disc despite halo-vest immobilization
      postoperatively. Laminoplasty is useful in cases in which physiological lordosis
      is present preoperatively, whereas a case with preoperative kyphotic deformity
      showed increased neurological symptoms and deterioration of activities of daily
      living postoperatively due to increased kyphotic deformity and canal stenosis.
      Anterior decompression and arthrodesis following posterior fusion with lateral
      mass plating and posterior wiring is a favorable option for patients with highly
      kyphotic deformity and canal stenosis, as it preserves neurological status and
      cervical alignment postoperatively.

PMID- 12486467
TI  - Impact of waist/hip ratio on the therapeutic efficacy of lumbosacral corsets for
      chronic muscular low back pain.
AB  - Aseries of 143 new outpatients who had had chronic low back pain for longer than
      3 months, with neither a positive straight leg raise test nor radiographic
      abnormality including lumbar spondylosis, were treated for 4 weeks with a
      traditional lumbosacral corset or one with a front-to-back tensile band
      (extensile corset). Randomization was performed according to birth date.
      Radiographs were used to analyze the change in sacral inclination angle with and
      without the respective corset. Central obesity subgroups consisted of men with a
      waist/hip ratio (W/H) of > or =90% and women with a W/H ratio of > or = 80%.
      Quebec Back Pain Disability Scale scores were measured at baseline and at 4
      weeks. The mean changes in sacral inclination were +3.8 degrees +/- 5.4 degrees
      in the extensile corset group ( n = 72) and -2.6 degrees +/- 4.6 degrees in the
      traditional corset group ( n = 71). Thus, the extensile corset had a mechanical
      effect opposite to that of the traditional corset. Participants without central
      obesity who were treated with the extensile corset ( n = 30) demonstrated
      significant improvement compared to participants with the traditional corset ( n
      = 33) ( P = 0.034). Central obesity should be considered when recommending
      corsets for patients with chronic muscular low back pain.

PMID- 12486466
TI  - Effects of 5-year treatment with elcatonin and alfacalcidol on lumbar bone
      mineral density and the incidence of vertebral fractures in postmenopausal women
      with osteoporosis: a retrospective study.
AB  - The purpose of this retrospective study was to compare the effects of long-term
      treatment (5 years) with elcatonin and alfacalcidol on bone mineral density (BMD)
      and the incidence of vertebral fractures in postmenopausal women with
      osteoporosis. Fifty-six osteoporotic women, more than 5 years after menopause and
      58-79 years of age, were enrolled in the study and allocated to an elcatonin
      treatment group (20 units IM, weekly; n = 30) or an alfacalcidol treatment group
      (1 micro g/day, daily; n = 26). BMD of the lumbar spine (L2-L4) was measured by
      dual energy X-ray absorptiometry at baseline and every year for 5 years. There
      were no significant differences in age, body mass index, years since menopause,
      BMD, or number of prevalent vertebral fractures at baseline between the two
      groups. One-way analysis of variance with repeated measurements showed no
      significant longitudinal changes in BMD in either group, suggesting that both
      treatments sustained the BMD over 5 years. Two-way analysis of variance with
      repeated measurements also showed no significant differences in longitudinal
      changes in BMD between the two groups, suggesting that the effects of the two
      treatments on BMD were similar. However, the number of incident vertebral
      fractures per patient was significantly lower in the alfacalcidol treatment group
      than in the elcatonin treatment group (0.80 +/- 1.19 and 2.08 +/- 2.73,
      respectively; P < 0.05). These findings indicate that both treatments appeared to
      sustain lumbar BMD similarly over a 5-year period in postmenopausal women with
      osteoporosis, but alfacalcidol treatment may be superior to elcatonin treatment
      regarding the incidence of vertebral fractures. Further study with prospective
      observations are needed to confirm the results of the present study.

PMID- 12486468
TI  - Analysis of stress distribution in the humeroradial joint.
AB  - Stress distribution in the humeroradial joint was analyzed with pressure
      sensitive film, a tactile sensor, and by the three-dimensional finite element
      method. Fifteen cadaveric elbows with minimal osteoarthritic changes were loaded
      perpendicular to the articular surface of the radial head in the full pronation,
      supination, and neutral positions from 0 degrees to 90 degrees. Finite element
      analysis of stress distribution in the joint was based on a model of the same
      conditions. The patterns of stress distribution were similar with all three
      analysis methods. High stress was concentrated laterally in supination, and
      medially in the neutral and pronation positions. The results of the analyses
      closely resembled those found in some studies of the pathophysiology of
      degenerative changes in the humeroradial joint.

PMID- 12486469
TI  - Biomechanical evaluation of reconstructed lumbosacral spine after total
      sacrectomy.
AB  - When a sacral tumor involves the first sacral vertebra, total sacrectomy is
      necessary. It is mandatory to reconstruct the continuity between the spine and
      the pelvis after total sacrectomy. In this study, strain and stress on the
      instruments and the bones were evaluated for two reconstruction methods: a
      modified Galveston reconstruction (MGR) and a triangular frame reconstruction
      (TFR). Compressive loading tests were performed using polyurethane vertebral
      models, and a finite element model of a lumbar spine and pelvis was constructed.
      Then three-dimensional MGR and TFR models were reconstructed, and finite element
      analysis was performed to account for the stress on the bones and instruments.
      With MGR, excessive stress was concentrated at the spinal rod, and there was a
      strong possibility that the rod between the spine and the pelvis might fail.
      Although there was no stress concentration on the instruments with TFR, excessive
      stress on the iliac bone around the sacral rod was more than the yielding stress
      of the iliac bone. Such stress may cause loosening of the sacral rod from the
      iliac bone. If the patient were to stand or sit immediately after MGR or TFR,
      instrumentation failure or loosening might occur.

PMID- 12486470
TI  - Biochemical analysis of collagen in adhesive tissues formed after digital flexor
      tendon injuries.
AB  - Restrictive adhesion is a major problem following flexor tendon surgery. We
      investigated crosslinks and types of collagen in two adhesive tissue models in
      chickens, characterized by loose adhesion and dense adhesion. The flexor
      digitorum profundus tendon was cut and sutured in two ways: (1) the severed
      tendon was sutured outside the tendon sheath (loose adhesion model), and (2) the
      tendon sheath was excised and the severed tendon was sutured on the damaged bony
      floor (dense adhesion model). Biochemical analysis of collagen was done for each
      group after tenorrhaphy. In the outside-sheath group, the ratio of the collagen
      crosslinks, dihydroxylysinonorleucine/hydroxylysinonorleucine, was lower than
      that in the sheath-excised group at 12 weeks, while the collagen crosslinks ratio
      remained considerably high in the sheath-excised group. The ratio of type III
      collagen to type I collagen in the outside-sheath group was higher than that in
      the sheath-excised group at 12 weeks and approached an almost normal value at 24
      weeks. The collagen type III/I ratio remained low in the sheath-excised group.
      The current study shows that biochemical properties are different between loose
      and dense adhesions. In dense adhesive scars, pathological collagen turnover
      occurs even at 24 weeks after tenorrhaphy.

PMID- 12486471
TI  - Effect of femoral nerve resection on progression of cartilage degeneration
      induced by anterior cruciate ligament transection in rabbits.
AB  - The purpose of this study was to evaluate the effect of femoral nerve resection
      on the progression of cartilage degeneration in an anterior cruciate ligament
      transection (ACLT) and partial meniscectomy (PM) model in rabbits. To induce
      degeneration of articular cartilage, PM and ACLT were performed on the bilateral
      knees of 24 rabbits, and femoral sensory nerve selective resection (FNR) was
      additionally performed on the left knee. Six rabbits each were killed 6 and 10
      weeks after surgery to observe early cartilage degeneration and 17 and 24 weeks
      after surgery to evaluate the late phase. Mankin's histological score at 10 weeks
      (7.5 +/- 2.7 points; mean +/- SD) after surgery in the FNR group was higher than
      that at 6 weeks (3.0 +/- 0.6 points) ( P < 0.05). In the control group the score
      at 17 weeks (7.8 +/- 2.0 points) was higher than that at 6 weeks (2.7 +/- 0.5
      points) ( P < 0.05). The concentration of chondroitin sulfate in the joint fluid
      was quantified by high-performance liquid chromatography. The concentration of
      chondroitin 6-sulfate in the FNR group at 10 weeks (11.6 +/- 4.1 nmol/ml) was
      higher than that at the other times and that of the control group at 10 weeks
      (5.4 +/- 3.2 nmol/ml) after surgery ( P < 0.05). These results indicate that FNR
      may promote the progression of cartilage degeneration in knees with PM and ACLT.

PMID- 12486472
TI  - Hydroxyapatite ceramics as a carrier of gene-transduced bone marrow cells.
AB  - The aim of this study was to develop an efficient exogenous gene delivery system
      using cultured marrow cells and porous hydroxyapatite ceramics. Bone marrow cells
      were obtained from the femoral shaft of a Fischer 344 rat and cultured in a
      medium containing 15% fetal bovine serum until confluent. After trypsinization,
      cells were subcultured at a cell density of 1 x 10(4) cells/cm2 in the presence
      of fetal bovine serum. The subcultured bone marrow cells were infected with
      recombinant retroviruses carrying the lacZ gene. The retrovirus infection was
      performed seven times from day 1 to day 7 during the culturing procedure. Cells
      expressing the lacZ gene were stained blue with the X-gal staining and
      represented approximately 80%. Composites of virus-infected bone marrow cells and
      hydroxyapatite ceramics were implanted at the subcutaneous site of recipient
      Fischer 344 rats. Four weeks after the implantation the ceramics were harvested.
      The histological sections of the ceramics showed abundant bone formation in the
      pores of the ceramics and obviously blue-stained osteoblasts and osteocytes.
      Other cell types that were stained blue were some fibroblastic cells and
      endothelial cells in the newly formed capillaries. These findings indicate that
      osteoblasts and osteocytes in the newly formed bone were derived from the
      cultured bone marrow cells, and therefore gene transfection by retroviruses did
      not disturb the bone formation process. Because of the durability of the newly
      formed bone tissue, creating composites of cultured bone marrow cells and
      hydroxyapatite ceramics might be an ideal method for exogenous gene transfection.

PMID- 12486473
TI  - Primary stability of various implants in tibial opening wedge osteotomy: a
      biomechanical study.
AB  - High tibial osteotomy (HTO) is an established method for treating varus
      gonarthrosis. The opening wedge HTO has some advantages over the lateral closed
      wedge technique. In this biomechanical study various systems of internal fixation
      of medial HTO were compared using an animal cadaver model (lower leg specimens
      from 1-year-old female domestic pigs). The first osteotomy (10 degrees ) was
      carried out and stabilized with a C-plate, an Arthrex spacer plate, or an AO
      tibial plate with or without bone graft. The resistance to axial stress was
      tested in a mechanical testing machine. Under lower axial stress (25, 50, 75, 100
      N) the axial displacement between the various specimens did not show any
      significant differences. Under maximal axial force, the specimen fixed with the C
      plate ( Fmax 2042 N) showed significantly better stability than the Arthrex plate
      ( Fmax 1687 N); P < 0.05. The AO plate ( Fmax 1612 N without bone graft and Fmax
      1583 N with bone graft) showed the lowest axial exposure to stress. Moreover, the
      influence of the osteotomy angle (7.5 degrees, 10 degrees, 12.5 degrees, 15
      degrees ) on axial stress resistance ( Fmax 2548, 2090, 1975, and 1740,
      respectively) was evaluated, and a direct correlation was found ( R = 0.794, P <
      0.05).

PMID- 12486474
TI  - Malignant lymphoma in skeletal muscle with rhabdomyolysis: a report of two cases.
AB  - Malignant lymphoma is rarely found in skeletal muscle. In this article, we
      present two cases of malignant lymphomas that were located in skeletal muscle and
      caused rhabdomyolysis. One case was a primary skeletal muscle lymphoma (which is
      quite rare), and the other was a skeletal muscle metastasis of lymphoma. The
      patient with primary skeletal muscle lymphoma was diagnosed with a diffuse type
      of non-Hodgkin's lymphoma of T-cell origin, which may be linked to a history of
      injury. Both patients exhibited diffuse, homogeneous lesions of the affected
      muscles on computed tomography (CT) and magnetic resonance imaging (MRI). The
      blood levels of some enzymes and potassium, indicative of rhabdomyolysis, were
      elevated. Bone scintigraphy depicted widespread, diffuse accumulation of the
      radioisotope in the affected muscles of both patients, typical of rhabdomyolysis.
      Rhabdomyolysis may be a sequela of lymphoma, as a result of the tendency of
      malignant lymphoma to infiltrate diffusely into muscles, to affect multiple
      neighboring muscle compartments, and to metastasize into other soft tissues, as
      well as being a sequela of possible cytotoxic or humoral actions, all of which
      may increase the amount of muscle damage. When a patient presents with diffuse
      muscle swelling, one should consider a diagnosis of a hematogenous disease, which
      may cause rhabdomyolysis complicated by renal dysfunction.

PMID- 12486475
TI  - Charcot joint-like changes following ankle fracture in a patient with no
      underlying disease: report of a rare case.
AB  - Charcot joint is a disease that often occurs in patients with diabetes mellitus,
      tabes dorsalis, syringomyelia, chronic alcoholism, leprosy, trauma, or infection
      after fractures and dislocations. The treatment for Charcot joint has various
      complications, such as skin lesions, infections, and delayed union. We present
      our experience with a male patient who developed Charcot joint-like changes
      without diabetes mellitus or any other disease after an ankle fracture due to
      minor trauma.

PMID- 12486476
TI  - Undifferentiated leiomyosarcoma showing various sarcomatous components with
      incidental B-cell lymphoma after tumor recurrence.
AB  - We report a rare case of undifferentiated leiomyosarcoma (LMS) with incidental B
      cell lymphoma in a 70-year-old woman. T2-weighted magnetic resonance images
      revealed a high signal intensity mass measuring 9 x 8 cm in the gluteus muscle.
      The pathological diagnosis of repeated surgery was undifferentiated LMS that
      included various sarcomatous components, such as fibrosarcomatous,
      rhabdomyosarcomatous, and malignant fibrous histiocytoma-like elements. A
      specimen from a supraclavicular lymph node showed the characteristics of
      malignant B-cell lymphoma (follicle type). Adjuvant chemotherapy or radiation
      therapy was not performed because of the patient's advanced age. The patient died
      from liver metastasis and dysfunction 5 years 8 months after the initial therapy.
      This is a rare case of LMS with malignant lymphoma. Considerable debate remains
      whether the B-cell lymphoma developed incidentally.

PMID- 12486477
TI  - Periodontoid pannus migration into the spinal canal with reduction of rheumatoid
      atlantoaxial subluxation: a case report.
AB  - We report a patient with rheumatoid arthritis in whom periodontoid pannus
      migrated into the spinal canal with reduction of atlantoaxial subluxation. In
      this case, magnetic resonance imaging in the extension position was valuable for
      determining the therapeutic strategy.

PMID- 12486478
TI  - Insufficiency fracture of the femoral neck during osteoporosis treatment: a case
      report.
AB  - Acase of insufficiency fracture of the femoral neck that occurred during
      treatment for osteoporosis is reported. A 77-year-old woman (height 150 cm, body
      weight 43 kg) with osteoporosis associated with high bone turnover was treated
      with oral cyclical etidronate (400 mg/day for 2 weeks every 3 months). Three
      months after the treatment was started the patient experienced pain in the right
      hip joint while walking despite no evidence of trauma. Although radiographs were
      normal, weight-bearing was not possible because of pain. T2-weighted magnetic
      resonance (MR) imaging was used to detect a fracture line localized on the
      inferior aspect of the femoral neck. Because on bone marker measurement bone
      resorption was increased and bone formation was decreased from baseline,
      treatment was switched to oral alendronate (5 mg/day, daily). Pain resolved 3
      weeks after the fracture was evident, and free gait was possible during the
      following 3 weeks. Follow-up radiographs, obtained 3 and 6 months after the
      fracture was evident, showed bony sclerosis on the aspect in which the fracture
      line was observed on the T2-weighted MR image. The dissociation (imbalance) of
      bone formation and resorption was also alleviated. A possibility of increased
      bone fragility should be kept in mind when oral cyclical etidronate is applied to
      elderly Japanese, small-physique women with osteoporosis at a daily dose of 400
      mg (higher dose).

PMID- 12486479
TI  - Complete paralysis of the quadriceps muscle caused by traumatic iliacus hematoma:
      a case report.
AB  - A15-year-old girl who developed traumatic iliacus hematoma and complete paralysis
      of the quadriceps muscle is reported. The current case and literature review
      revealed that incomplete quadriceps paralysis associated with traumatic iliacus
      hematoma is likely to progress to complete paralysis in days or weeks as a result
      of increased intracompartmental pressure. However, surgical decompression of the
      femoral nerve could produce good results even in patients who have complete
      quadriceps paralysis preoperatively.

PMID- 12486480
TI  - Combination of lumbar kyphosis, epidural lipomatosis, and perineural cyst as a
      cause of neurological deficit: a case report.
AB  - We describe the rare simultaneous occurrence of epidural lipomatosis and a
      perineural cyst at the same level, lumbar kyphosis, osteoporotic vertebral
      fractures, and neurological deficits. A 75-year-old corticosteroid-dependent
      female farmer presented with severe low back pain, progressive lumbar kyphosis,
      and inability to stand because of numbness and muscle weakness of both legs.
      Plain radiographs displayed markedly decreased bone density, significant lumbar
      kyphosis, and vertebral compression fractures of L2, L3, and L4. Magnetic
      resonance imaging of the lumbar spine revealed a perineural cyst at the L2-3
      level, extensive epidural lipomatosis, and spinal canal stenosis. Laminectomy
      from L3 to L5 with resection of epidural fatty tissue restored her walking
      ability. We postulate that the osteoporotic fractures and epidural lipomatosis
      were induced by corticosteroid therapy. Preexisting degenerative lumbar kyphosis
      of the type commonly seen in elderly farmers could have promoted osteoporotic
      lumbar vertebral fractures at points where bending stress had been strongly
      exerted. The combination of a perineural cyst and epidural lipomatosis at the
      same level has not been reported previously.

PMID- 12486481
TI  - Juxtacortical osteoma of the ulna.
AB  - Acase of juxtacortical osteoma of the ulna in a 47-year-old woman is presented.
      She had a dense bony mass on the ulna. Radiological examinations (plain
      radiography, computed tomography, magnetic resonance imaging) strongly suggested
      a rare case of juxtacortical osteoma of a long tubular bone. The differential
      diagnosis included parosteal osteosarcoma, melorheostosis, osteochondroma, end
      stage juxtacortical myositis ossificans, and fibrous dysplasia protuberans. The
      tumor was excised totally for thorough pathological examination, which revealed
      it to be composed of lamellar bone, suggesting that the origin was periosteal.

PMID- 12486482
TI  - Evolution of the Koch model of the biomechanics of the hip: clinical perspective.
AB  - Over the past several decades numerous researchers have revisited the model of
      the biomechanics of the hip first predicated by John Koch in 1917. The
      contributions of Blount (1956), Frankel (1960), Pauwels (1976), Toridis (1969),
      Rybicki (1972), Fetto (1994, 1995), Ling (1996), and Lu (1997, 1998) among others
      created a more complete picture. The present article briefly reviews the previous
      biomechanical concept and its clinical inconsistencies and offers a model that
      includes the dynamic and static input of the soft tissues. The action of the
      iliotibial band (ITB) and the vastus lateralis-gluteus medius complex (as static
      and dynamic tension bands lateral to the femur) counterbalance the varus bending
      torque of the loads acting on the hip, transforming the tensile stresses in the
      lateral femur (as hypothesized by Koch) into compressive stresses. The inclusion
      of the soft tissues, extending the previous model, widens our understanding of
      the forces acting on the hip. Thus, a variety of clinical observations can be
      better explained in a comprehensive theoretical framework.

PMID- 12486483
TI  - Evidence-based medicine for orthopedic practice.
AB  - Evidence-based medicine (EBM) is regarded as a new paradigm in medical practice,
      equal in enormity to the human genome project. However, there is still much
      confusion and misunderstanding about the concept and content of EBM. It is often
      limited to searching the literature and reading papers, serving cost cutters, and
      suppressing clinical freedom. Some believe that the use of clinical guidelines or
      the managed care system intimidates doctors' discretion during clinical practice
      and that EBM is a fashionable tendency of a group of medical academics armed with
      epidemiological and statistical jargon. Medical practice is a lifelong,
      continuous process of self-learning, and it requires clinicians to keep up to
      date on various developments. EBM is our practice for integrating individual
      clinical expertise with the best available evidence when making decisions about
      our care for each patient. EBM is one answer for making it possible to cover most
      of our activities as orthopedic surgeons, from the daily practice of patient care
      to writing and reading scientific papers.

PMID- 12486484
TI  - A comparison of the progression of early Parkinson's disease in patients started
      on ropinirole or L-dopa: an 18F-dopa PET study.
AB  - OBJECTIVE: To study the relative rates of progression of early Parkinson's
      disease (PD) in patients started on a dopamine agonist, ropinirole, or L-dopa.
      METHODS: A double-blind study of 45 early PD patients [mean age 61 +/- 9.8 SD and
      mean symptom duration, 26 +/- 16 SD months] randomized 2 : 1 (ropinirole : L
      dopa). Supplementary L-dopa was allowed if, during the trial, there was lack of a
      therapeutic effect. (18)F-dopa PET scans were performed at baseline (n = 45) and
      2 years (n = 37). RESULTS: At two years, the mean percentage reduction in putamen
      (18)F-dopa uptake (Ki(o)) was not significantly different between the two groups
      (13% ropinirole, n = 28 versus 18% L-dopa, n = 9). CONCLUSIONS: We found no
      significant overall difference in underlying PD progression, after two years
      treatment, between patients groups. In summary, (18)F-dopa PET can be employed to
      objectively evaluate the effect of potential neuroprotective agents on
      dopaminergic function.

PMID- 12486485
TI  - Moderate hyperhomocysteinaemia and immune activation in Parkinson's disease.
AB  - Moderate hyperhomocysteinaemia has been linked to an increased risk for
      cardiovascular diseases. Increased homocysteine concentrations may follow folate
      depletion due to insufficient dietary intake of the vitamin, but there is also
      some indication that immune activation could play a role. In this preliminary
      study, homocysteine, folate, and vitamin B(12) concentrations were measured in 19
      patients with Parkinson's disease, 61-90 years of age, and compared to a healthy
      control group of similar age and to neopterin concentrations as an indicator of
      immune activation. A subgroup of patients presented with increased homocysteine
      and low folate concentrations. Homocysteine levels correlated inversely with
      vitamins folate and B(12) and positively with neopterin concentrations. Disturbed
      homocysteine metabolism in Parkinson's disease may be associated with vitamin
      deficiency and with immune system activation which may underlie folate depletion.

PMID- 12486486
TI  - Catatonia and neuroleptic malignant syndrome: psychopathology and
      pathophysiology.
AB  - Catatonia was originally described as a psychomotor syndrome in the 19th century
      by Kahlbaum including motor, affective and behavioral symptoms. Later, at the
      beginning of the 20th century, catatonia was rather considered as the motoric
      manifestation of schizophrenia. Accordingly, neuropathological research focused
      predominantly on those neuroanatomical substrates, i.e. the basal ganglia being
      primarily involved in the generation of movements. Even though some authors
      observed minor alterations in the basal ganglia, consistent findings in these
      subcortical structures could not be obtained. Since neuroleptics can induce
      catatonic-like symptoms i.e. neuroleptic malignant syndrome (NMS), there has been
      a recent re-emergence in clinical and scientific interest in catatonia. However,
      exact psychopathological and pathophysiological characterization of both NMS and
      catatonia remains unclear.Clinically, catatonia and NMS show more or less similar
      motor symptoms i.e. akinesia. These may be accounted for by dysregulation in
      cortical-subcortical circuits between motor/premotor cortex and basal ganglia
      i.e. the so-called "motor loop". While in NMS the "motor loop" may be
      dysregulated by neuroleptic blockade of subcortical striatal D-2 receptors one
      may rather assume cortical gaba-ergic alteration in catatonia. The premotor/motor
      cortex and consecutively the "motor loop" may be dysregulated by gaba-ergic
      abnormalities in orbitofrontal cortex. Gaba-ergic cortical dysfunction may
      account for affective and behavioural abnormalities in catatonia which cannot be
      observed as such in NMS. Consequently, one may characterize catatonia as a
      cortical "psychomotor syndrome" while NMS may rather be regarded as subcortical
      "motor syndrome".

PMID- 12486487
TI  - Mini-review: multiple developmental forms of parkinsonism. The basis for further
      research as to the pathogenesis of parkinsonism.
AB  - A range of extrapyramidal disturbances have been reported in children following
      early brain damage. In adults, damage to the basal ganglia can elicit abnormal
      motor activity in either direction; it would seem reasonable that the same would
      apply to damage occurring at an earlier developmental stage. The Viennese
      paediatrician Widhalm described a hypokinetic/parkinsonoid syndrome ("infantile
      hypokinetic-hypertonic syndrome with Parkinson symptomatic") presented by a
      significant minority of the children with extrapyramidal movement disturbances,
      corresponding to the mild rigid-akinetic type of Parkinson's disease. In contrast
      to classical parkinsonism, but consistent with some forms of post-encephalitic
      parkinsonism, the syndrome was reversible, although only after L-DOPA therapy.
      Widhalm's observation that at least one form of childhood parkinsonism can be
      cured with L-DOPA also suggests that the amino acid plays a more active role than
      mere replacement therapy in children, perhaps also acting as a neurotrophic
      agent. It is proposed that environmental factors, including viral and risk
      factors associated with pregnancy and birth, together with genetically determined
      lability, may increase the incidence of early hypokinesia/parkinsonism in
      particular and of Parkinson's disease in later life by disturbing the immature
      basal ganglia at critical developmental stages. The spectrum disorder of
      Parkinson's disease thereby occurs as a number of various etiopathologically
      distinct syndrome subtypes, including early onset developmental forms caused by
      in utero or early post partum trauma.

PMID- 12486488
TI  - Melatonin in concentrated ethanol and ethanol alone attenuate methamphetamine
      induced dopamine depletions in C57BL/6J mice.
AB  - The present study aimed to investigate the protective effects of melatonin,
      ethanol and temperature changes on methamphetamine-induced neurotoxicity in both
      sexes of mice. Mice exhibited a similar degree of striatal dopamine depletion
      when methamphetamine was administered during the light and dark cycles. Moreover,
      10 mg/kg, but not 5 mg/kg, of methamphetamine, significantly increased body
      temperature even though dopamine depletions were observed following both doses.
      Melatonin (80 mg/kg) dissolved in 30% (v/v) ethanol and 30% ethanol alone exerted
      a moderate to full protection against methamphetamine-induced dopamine depletions
      in both sexes of mice, whereas the same dose of melatonin in 3% ethanol exerted
      no protective effect. Furthermore, ethanol attenuated methamphetamine-induced
      dopamine depletions in a dose-dependent manner with the exception of high
      efficacy of ethanol at low doses. Finally, the protective effects of ethanol were
      not blocked by bicuculline. Together, we conclude that ethanol may protect mice
      against methamphetamine-induced dopamine depletion probably via non-GABAA
      receptor activation.

PMID- 12486489
TI  - CSF markers related to pathogenetic mechanisms in Alzheimer's disease.
AB  - Serum amyloid P component (SAP) and complement C1q are found highly co-localized
      with extracellular fibrillar amyloidbeta (Abeta) deposits in Alzheimer's disease
      (AD) brain. Conflicting data were reported earlier about the cerebrospinal fluid
      (CSF) levels of SAP and C1q in AD compared to controls. The objective of the
      present study was to compare the levels of Abeta(1-42), tau, C1q and SAP in CSF
      of a well characterized group of AD patients and controls, and to assess the
      association with dementia severity. Significantly decreased CSF levels of Abeta(1
      42) were observed in the AD group (480 +/- 104 ng/L) as compared to controls
      (1,040 +/- 213 ng/L), whereas tau levels were significantly higher in patients
      with AD (618 +/- 292 ng/L) than in controls (277 +/- 136 ng/L). Combining the
      results of Abeta(1-42) and tau measurements resulted in a clear separation
      between the AD group and the controls. No significant differences in CSF levels
      of SAP and C1q were observed between the well characterized AD patients and non
      demented control group. Furthermore, we could not demonstrate a correlation
      between SAP and C1q CSF levels and the severity of the disease, expressed in Mini
      Mental State Examination (MMSE) scores. Therefore, in our opinion these factors
      can be excluded from the list of potentially interesting biomarkers for AD
      diagnosis and progression.

PMID- 12486490
TI  - Homocysteine and risk of open-angle glaucoma.
AB  - Homocysteine levels and the frequency of heterozygous methylenetetrahydrofolate
      reductase (MTHFR) C677T mutation are increased in open-angle glaucoma. Since
      homocysteine can induce vascular injury, alterations in extracellular matrix
      remodelling, and neuronal cell death, these findings may have important
      implications for understanding glaucomatous optic neuropathy.

PMID- 12486491
TI  - Pharmacodynamic studies on the central mode of action of S-adenosyl-L-methionine
      (SAMe) infusions in elderly subjects, utilizing EEG mapping and psychometry.
AB  - In a double-blind, placebo-controlled cross-over study, the acute and subacute
      effects of S-adenosyl-L-methionine (SAMe), or ademetionine, on brain function and
      behavior of 10 elderly normal healthy volunteers (5 males and 5 females, aged 56
      71 years, mean: 59.3 years) were investigated by means of EEG mapping and
      psychometry. In random order they received infusions of 800 mg SAMe and placebo,
      administered over 30 minutes for 7 days, with a wash-out period of 3 weeks in
      between. EEG recordings and psychometric tests were carried out 0, 1, 3 and 6
      hours after drug administration on days 1 and 7. Multivariate analysis based on
      MANOVA/Hotelling T(2) tests demonstrated significant central effects of SAMe as
      compared with placebo after acute, subacute and superimposed drug administration.
      Acute SAMe-induced changes were characterized by a decrease in total power, an
      increase in absolute delta and a decrease in absolute alpha power, further by an
      increase in relative delta and a decrease in relative alpha power, a slowing of
      the delta/theta centroid as well as a slowing of the centroid of the total power
      spectrum. These changes are typical of classical antidepressants of the
      thymoleptic type such as imipramine and amitriptyline. After one week of daily
      infusions there was a marked increase in total power, reminiscent of nootropic
      drug effects. One additional superimposed dosage mitigated these effects in the
      direction of an antidepressant profile, with the inter-drug differences waning in
      the 6(th) hour. Our pharmaco-EEG findings suggest both inhibitory and excitatory
      drug effects underlying the antidepressant properties of SAMe well-documented in
      clinical trials. Psychometric tests concerning noopsychic and thymopsychic
      measures as well as critical flicker frequency generally demonstrated a lack of
      differences between SAMe and placebo, which again reflects a good tolerability of
      the drug in elderly subjects.

PMID- 12486492
TI  - Associations of plasma homocysteine concentration in subjects with type 2
      diabetes mellitus.
AB  - We investigated the potential relationship between hyperhomocysteinemia and the
      presence of coronary heart disease (CHD) and chronic complications in a
      consecutive series of 358 (156 men) Kuwaiti type 2 diabetic subjects. The median
      (2.5(th), 97.5(th) percentiles) fasting plasma concentration of total
      homocysteine (tHcy) in the patients was 10.2 (5.4, 19.1) micromol/l. Fasting tHcy
      concentration was significantly (p<0.001) higher among men [11.3 (7.1, 24.6)
      micromol/l] compared to women [8.8 (5.3, 16.3) micromol/l]. Of the 57 patients
      with a history of CHD and/or electrocardiographic (ECG) evidence of CHD, 9 (16%)
      had hyperhomocysteinemia (tHcy > or =15 micromol/l) compared to 8.3% (25 of 301)
      of patients without evidence of CHD. In univariate analysis, plasma tHcy
      concentration was significantly (p<0.01) higher in those diabetic subjects with
      history of CHD and/or abnormal ECG. Although hyperhomocysteinemia was more common
      in patients with microalbuminuria (15%) compared to patients with
      normoalbuminuria (12%), there was no significant association between
      hyperhomocysteinemia and the degree of albuminuria. After controlling for age and
      sex, multiple regression analyses showed significant associations of plasma tHcy
      concentration with glycated hemoglobin (p<0.05), plasma concentrations of
      creatinine (p<0.001) and apolipoprotein-B (p<0.05), but not with smoking,
      neuropathy or retinopathy. It seems that the association of hyperhomocysteinemia
      with diabetic microvascular complications is mediated by the confounding effect
      of other factors like age, sex and plasma creatinine concentration. In
      conclusion, we have found a univariate association between hyperhomocysteinemia
      and CHD but not with microalbuminuria, neuropathy and retinopathy. Although
      routine estimation of plasma homocysteine may be useful, the association with
      cardiovascular disease or microvascular complications in patients with type 2 DM
      deserves prospective studies.

PMID- 12486493
TI  - Hypocalcemia reduces insulin turnover but not insulin-mediated glucose metabolism
      in piglets.
AB  - Disturbances of glucose metabolism similar to type II diabetes are often
      accompanied by low extra cellular calcium concentrations, as shown in
      periparturient ruminants. Hypocalcemia reduces insulin secretion and possibly
      endogenous glucose production, but whether hypocalcemia also affects peripheral
      actions of insulin is not clear. The problem was investigated with piglets in
      this study. Insulin-mediated turnover of glucose and the clearance of insulin
      were measured in 7 control piglets (+D) and in 10 piglets with inherited
      calcitriol deficiency (-D). The measurements involved continuous intravenous
      infusions of insulin (1, 2, 5, 7.5 and 10 mU x kg(-1) x min(-1)) and glucose to
      maintain a glucose concentration of 7 mmol x l(-1) (combined insulin and glucose
      clamps). Both groups of piglets were studied under normo- and hypocalcemic
      conditions. During hypocalcemia and with equal insulin infusion rates, -D and +D
      piglets attained significantly higher (28%-133%) steady state insulin
      concentrations in plasma than during normocalcemia. This showed that the
      clearance rates of insulin during hypocalcemia were 48% lower in +D and 20% lower
      in -D piglets than during normocalcemia. With equivalent insulin infusion rates
      +D piglets developed significantly higher (15%-48%) steady state insulin
      concentrations in plasma than -D piglets, indicating that the clearance rate of
      insulin was higher in the calcitriol-deficient state. The relationship between
      insulin concentration in plasma and glucose turnover (measured with [3
      (3)H]glucose) was not influenced by the calcemic and vitamin D status of the
      piglets. This indicated that the peripheral action of insulin on glucose
      metabolism was not influenced by the extracellular calcium concentration and
      vitamin D status.

PMID- 12486494
TI  - Post-absorptive and insulin-mediated muscle protein metabolism in liver
      transplanted patients.
AB  - Cirrhotic patients after liver transplantation show a near-normal glucose
      homeostasis when in stable condition. In contrast, the basal and insulin-mediated
      whole-body protein metabolism remain altered several years after the graft. To
      examine whether the persisting defect of protein metabolism was due to the
      muscle, 7 non-diabetic liver-transplanted patients in stable condition were
      studied by means of the catheterization of the brachial artery and the deep
      forearm vein (to measure the balance across the forearm) and the infusion of
      labelled leucine and phenylalanine associated with indirect calorimetry. Whole
      body proteolysis (as determined by endogenous leucine flux, ELF), protein
      synthesis (from non-oxidative leucine disposal, NOLD) and leucine oxidation (LO)
      were reduced in comparison to previously obtained values in a normal population.
      Insulin infusion (while maintaining euglycemia) induced a not significant
      variation of forearm phenylalanine Ra (24.4-->16.5 micromol/100 ml forearm min(
      1); proteolysis) and Rd (18.5-->19.7; protein synthesis). In contrast, the whole
      body insulin-dependent inhibitions of ELF (31.5-->21.8 micromol/m(2) min) and
      NOLD (27.3-->18.4) were impaired with respect to a normal population. On the
      basis of the present results, we conclude that skeletal muscle is not responsible
      for the alterations of leucine metabolism persisting after liver transplantation.
      By exclusion, this points to the liver as the major determinant of the leucine
      metabolism defect.

PMID- 12486495
TI  - Low serum magnesium levels and metabolic syndrome.
AB  - Low serum magnesium levels are related to diabetes mellitus (DM) and high blood
      pressure (HBP), but as far as we know, there are no previous reports that
      analyzed the serum magnesium concentration in individuals with metabolic syndrome
      (MS). We performed a cross-sectional population-based study to compare 192
      individuals with MS and 384 disorder-free control subjects, matched by age and
      gender. Magnesium supplementation treatment and conditions likely to provoke
      hypomagnesemia, including previous diagnosis of diabetes mellitus (DM) and/or
      high blood pressure (HBP), were exclusion criteria. In this regard, only incident
      cases of DM and HBP were included. MS was defined by the presence at least of two
      of the following features: hyperglycemia (> or =7.0 mmol/l); HBP (> or =160/90
      mmHg); dyslipidemia (fasting triglycerides > or =1.7 mmol/l and/or HDL
      cholesterol <1.0 mmol/l); and obesity (body mass index > or =30 kg/m(2) and/or
      waist-to-hip ratio > or =0.85 in women or > or =0.9 in men). Low serum magnesium
      levels were identified in 126 (65.6%) and 19 (4.9%) individuals with and without
      MS, p<0.00001. The mean serum magnesium level among subjects with MS was 1.8+/
      0.3 mg/dl, and among control subjects 2.2+/-0.2 mg/dl, p<0.00001. There was a
      strong independent relationship between low serum magnesium levels and MS (odds
      ratio (OR)=6.8, CI(95%) 4.2-10.9). Among the components of MS, dyslipidemia (OR
      2.8, CI(95%) 1.3-2.9) and HBP (OR 1.9, CI(95%) 1.4-2.8) were strongly related to
      low serum magnesium levels. This study reveals a strong relationship between
      decreased serum magnesium and MS.

PMID- 12486496
TI  - LDL-cholesterol/apolipoprotein B ratio is a good predictor of LDL phenotype B in
      type 2 diabetes.
AB  - LDL phenotype B is a component of diabetic dyslipidaemia, but its diagnosis is
      cumbersome. Our aim was to find easily available markers of phenotype B in a
      group of type 2 diabetic subjects. We studied 123 type 2 diabetic patients (67.5%
      male, aged 59.3+/-10.1 years, mean HbA1c 7.4%). Clinical features and fasting
      total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol (LDLc, using
      Friedewald's equation and an alternative formula), apolipoprotein B (apoB),
      lipoprotein (a) and LDL particle size (on gradient polyacrylamide gel
      electrophoresis) were assessed. Patients with phenotypes A (predominant LDL size
      > or =25.5 nm) and B (<25.5 nm) were compared, and regression analysis was
      performed to find the best markers of LDL particle. Cut-off points were obtained
      and evaluated as predictors of phenotype B (kappa index). Patients with phenotype
      B (36%) showed higher total cholesterol, triglyceride and apolipoprotein B, and
      lower HDL cholesterol and LDLc/apoB ratio. Triglyceride was the best predictor of
      LDL particle size (r=-0.632, p<0.01), but an LDLc/apoB ratio below 1.297 mmol/g
      detected phenotype B best (sensitivity 65.9%, specificity 92.4%, kappa=0.611).
      Although triglyceride concentration is the best predictor of LDL size in type 2
      diabetes, LDLcholesterol/apolipoproteinB ratio is the best tool to detect
      phenotype B.

PMID- 12486497
TI  - Decrease in the insulin receptor protein level by anti-insulin receptor
      antibodies: roles of tyrosine kinase activity and receptor internalization.
AB  - To investigate the mechanism of severe impairment of insulin action in type B
      insulin resistance, we extracted IgG from the serum of a patient with type B
      insulin resistance (B-IgG) and analyzed the inhibiting effect of B-IgG not only
      on insulin signaling but also on IGF-I signaling in Chinese hamster ovary (CHO)
      cells expressing human insulin receptor or human IGF-I receptor. Preincubation
      with 1 mg/ml B-IgG prevented insulin-induced phosphorylation of insulin receptor
      and insulin receptor substrate-1 (IRS-1) but did not alter the IGF-I-induced
      phosphorylation of the IGF-I receptor and IRS-1. (125)I-insulin binding was
      inhibited by 93% after preincubation with B-IgG at 37 degrees C and was recovered
      up to 50% of the control value by acid washing. However, when cells were
      preincubated with B-IgG at 4 degrees C, the insulin binding completely recovered
      the control value by acid washing. (125)I-IGF-I binding was not altered by B-IgG
      preincubation. Immunoblot study revealed that the protein level of the insulin
      receptor was strongly decreased by preincubation with 1 mg/ml B-IgG at 37 degrees
      C, but never at 4 degrees C. The IRS-1 protein level did not change by B-IgG
      preincubation. In order to know the role of the insulin receptor internalization
      in the inhibiting effect of B-IgG, we employed CHO cells expressing mutant
      insulin receptors which do not undergo internalization (CHO-K1018R). B-IgG
      incubation of CHO-K1018R at 37 degrees C failed to decrease the protein level of
      the insulin receptor. The present data indicate that IgG from the diabetic
      patient with type B insulin resistance decreased insulin receptor protein level,
      probably due to the enhanced degradation rate of the insulin receptor, in which
      insulin receptor tyrosine kinase activity and internalization are required for
      this process. This effect of B-IgG was specific for the insulin receptor with no
      effect on either IGF-I receptor or IRS-1, as reflected by the IGF-I effectiveness
      on glycemic control in this patient.

PMID- 12486498
TI  - Secretory defects induced by immunosuppressive agents on human pancreatic beta
      cells.
AB  - Despite the considerable interest for islet and pancreas transplantation,
      remarkably little is known about the direct effects of immunosuppressive drugs on
      human beta-cell function. We measured different insulin secretory parameters and
      insulin gene expression of human islets cultured for 5 days in the presence of
      mycophenolate mofetil (MMF), cyclosporin A (CsA), tacrolimus (FK506) or a mixture
      of 3 cytokines. Basal insulin release after exposure to cytokines and FK506 was
      significantly higher than in control islets. Responsiveness to an acute glucose
      stimulus did not differ significantly between control and treated islets.
      However, absolute incremental insulin responses (delta-AUCs) of islets exposed to
      cytokines or FK506 were significantly higher compared to islets exposed to CsA or
      MMF, mainly because of the higher basal release. Indeed, maximal over basal
      release (stimulation index, SI) tended to be lower in islets exposed to FK506
      than in control islets. Insulin gene expression was significantly reduced only in
      islets exposed to CsA. FK506 was, among those tested, the immunosuppressive drug
      that most profoundly altered the normal insulin secretory pattern of human beta
      cells, whereas CsA was the only inhibiting insulin gene expression. Although the
      abnormalities induced by the immunosoppressive drugs utilized in this study were
      modest, these in vitro data are consistent with the reported in vivo
      diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive
      agent from a pancreatic beta-cell point of view.

PMID- 12486499
TI  - Association between diabetic ketoacidosis and thyrotoxicosis.
AB  - Three cases of diabetic ketoacidosis precipitated by thyrotoxicosis are
      presented. Two of them are young women with type 1 diabetes mellitus; the third
      case is a middle-aged woman with type 2 diabetes mellitus. All of them were
      diagnosed with Graves' disease. They typically showed tachycardia at rest in
      spite of correction of the metabolic disorder. Hyperthyroidism worsens glycemic
      control in diabetic patients and may precipitate diabetic ketoacidosis. On the
      other hand, women with diabetes have a higher prevalence of Graves' disease.
      Thus, in diabetic ketoacidosis without an obvious triggering factor, the presence
      of hyperthyroidism should be investigated, particularly in women.

PMID- 12486501
TI  - Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked
      adrenoleukodystrophy.
AB  - In an attempt to elucidate prognostic factors, the data on 12 boys who underwent
      haematopoietic stem cell transplantation (HSCT) for cerebral X-linked
      adrenoleukodystrophy were evaluated. Two further patients received HSCT but died
      from transplantation-related complications. The data included neurological
      examination, neuropsychological testing and magnetic resonance imaging (MRI).
      Follow-up after HSCT was up to 5.5 years. Six patients showed a moderate to
      severe clinical deterioration after HSCT including two who died within 6 months.
      In this group, a MRI severity score of 10 or higher before HSCT was associated
      with severe impairment and a score of more than 12 was followed by rapid
      deterioration and death after HSCT. The presence of neurological symptoms before
      HSCT also affected prognosis. Six patients showed no deterioration in
      neurological or neuropsychological assessment after HSCT. CONCLUSION: our data
      confirm that haematopoietic stem cell transplantation can stop the progress of
      demyelination when performed at a critical early stage of the disease. The
      prognosis in an individual patient for the clinical course after stem cell
      transplantation can in general be given based on the status before
      transplantation, although individual patients may show an unexpected course.

PMID- 12486500
TI  - Frequency of coeliac disease in Hungarian children with type 1 diabetes mellitus.
AB  - Coeliac disease and type 1 diabetes mellitus can frequently coexist, presumably
      due to a common genetic predisposition. The present study was designed to
      evaluate the frequency of coeliac disease among Hungarian diabetic children and
      to study the effect of gluten-free diet on glycaemic control. A total of 205
      diabetic children (age range 2.0-17.0 years, median 11.6 years) were screened for
      coeliac disease by determination of IgA-endomysium (EMA) antibodies. In the
      positive cases, a jejunal biopsy was performed and, in addition to routine
      histology, the number of intraepithelial gamma/delta T-cells was also determined.
      Insulin requirement, glycosylated haemoglobin level and body mass index of
      diabetic children with coeliac disease were determined before and 3 months after
      the introduction of gluten-free diet. IgA-EMA was positive in 24 cases, 17 of
      them (8.3% of all diabetic children) had a subtotal villous atrophy and thus
      coeliac disease was diagnosed. In all but two of these children, the mean number
      of gamma/delta T-cells was elevated (above 7 cells/mm). Of the remaining seven
      patients with positive EMA but normal villous structure, five (2.4%) had elevated
      number of epithelial gamma/delta T-cells, indicating probable latent coeliac
      disease. The insulin requirement of the children had significantly increased 3
      months after the introduction of gluten-free diet (median values 0.64 versus 0.48
      U/kg per day, P<0.05). Median body mass indices also showed significant elevation
      after this period (16.8 versus 14.2 kg/m(2), P<0.05) CONCLUSION: the frequency of
      coeliac disease was high in the studied group. Introduction of a gluten-free diet
      improved the somatic development of these children. A latent form of coeliac
      disease is also frequent in children with type 1 diabetes mellitus.

PMID- 12486502
TI  - Changes in lymphocyte subsets after cardiac surgery in children.
AB  - Children undergoing cardiopulmonary bypass (CPB) operations have an increased
      risk of developing severe infections. Impairment of the immune system may
      contribute to the development of sequelae such as capillary leaks, pulmonary
      dysfunction and auto-immune reactions. The objective of this study was to
      investigate the impact of cardiac surgery with CPB on the immune system of
      infants and young children. We conducted a prospective study to investigate the
      changes in circulating lymphocyte subpopulations in a sample of 21 consecutive
      infants and young children undergoing cardiac surgery for congenital heart
      disease. The following statistically significant ( P<0.05) results were obtained:
      leucocyte counts rose 6 h after surgery due to the increase in neutrophils.
      Absolute T-cell number and absolute T-helper cell number decreased within 24 h
      after CPB. The proportion of T-cells expressing the T-cell receptor gammadelta as
      well as natural killer cells increased during CPB. In contrast, the proportion of
      T-cells expressing activation markers (CD25, CD45R0) decreased within 24 h after
      CPB, as did the number of cells expressing adhesion molecules (CD11b and ICAM).
      CONCLUSION: during cardiac surgery with cardiopulmonary bypass, absolute natural
      killer cell counts increase while T-cells decrease, presumably due to an
      extravasation or adhesion of activated T-cells. The relevance of this finding
      regarding the risk of infection is discussed.

PMID- 12486503
TI  - Insulin injection regimens and metabolic control in an international survey of
      adolescents with type 1 diabetes over 3 years: results from the Hvidore study
      group.
AB  - The optimal insulin regimen for paediatric patients with type 1 diabetes remains
      controversial. Therefore this multicentre study was performed in adolescents over
      a 3-year period to assess metabolic control, severe hypoglycaemia, and weight
      gain in relation to insulin injection regimens. Out of 2873 children and
      adolescents in an international survey in 1995, 872 adolescents (433 boys, 439
      girls, mean age in 1995 11.3+/-2.2 years) were restudied in 1998, relating
      insulin regimens to HbA(1c) measured in a central laboratory. In addition, the
      daily dose of insulin, changes in body mass index (BMI), and events of severe
      hypoglycaemia were evaluated. Over 3 years, the use of multiple injection
      regimens increased from 42% to 71%: 251 patients remained on twice daily insulin,
      365 remained on multiple injections and 256 shifted from twice daily insulin to
      multiple injections. In all three subgroups an increase in insulin dose, a
      deterioration of metabolic control, and an increase in BMI were observed.
      Metabolic control deteriorated less than expected over 3 years during adolescence
      (HbA(1c) 1995: 8.7+/-1.6%; 1998 observed: 8.9+/-1.6%, HbA(1c) expected for 1998:
      9.0%). BMI increased more than expected, the increase was greatest in patients
      switching from twice daily to multiple injections, and higher in females compared
      to males. CONCLUSION: in this international study, metabolic control was
      unsatisfactory in many adolescents with type 1 diabetes irrespective of the
      insulin regimen. No improvement in metabolic control was observed in this cross
      sectional survey, over 3 years in any of the subgroups. Even the group switching
      from twice to multiple injections did not improve blood glucose control and the
      increase in body mass index was most pronounced in this group. Conclusive
      evidence, however, should be based on prospectively planned, randomised
      therapeutic trials in paediatric patients.

PMID- 12486504
TI  - Familial factors and hearing impairment modulate the neuromotor phenotype in
      Turner syndrome.
AB  - In Turner syndrome (TS), an X-chromosomal anomaly characterised by total or
      partial loss of the second X-chromosome, muscle hypotonia, and lower proficiency
      in fine and gross motor skills have been described. It is assumed that the
      neuromotor phenotype in TS is linked with X-chromosomal factors (individual
      mosaicism) and with the oestrogen deficiency due to streak gonads. From studies
      in normal populations, a further risk factor may be recurrent otitis media (OM),
      which occurs frequently in TS, often in combination with hearing impairment (HI).
      It is also likely that familial factors are involved. The aim of our study was to
      specify the respective impact of the interindividual varying status of mosaicism
      and of hypergonadotropic hypogonadism as well as of the risk factors recurrent OM
      and HI in comparison to familial coinfluences on the neuromotor proficiency (MOP)
      in TS. We used the Bruininks-Oseretsky Test of Motor Proficiency to examine 105
      subjects with TS (mean age 9.4 years; SD 3.3 years) and 52 sisters (mean age 9.8
      years; SD 3.7 years). Significant correlations were found for familial covariance
      regarding the relation between TS subjects and their sisters ( r=0.42, P<0.01)
      and HI and MOP ( r=-0.39, P<0.01) CONCLUSION: we conclude that the familial
      influences and risk factors such as recurrent otitis media in combination with
      hearing impairment serve primarily as important predictors of the individual
      neuromotor phenotype in Turner syndrome.

PMID- 12486505
TI  - Alopecia universalis congenita, XY gonadal dysgenesis and laryngomalacia: a novel
      malformation syndrome.
AB  - We report on five individuals with the following consistent findings: alopecia
      universalis congenita, XY gonadal dysgenesis and laryngomalacia persisting beyond
      infancy. The clinical presentation of the XY gonadal dysgenesis was ambiguous
      genitalia, appearing as male or, more commonly, female. In one affected
      individual mullerian structures were present. The affected individuals come from
      two unrelated families. While in the first family the two affected individuals
      come from two related sibships, three affected individuals come from one sibship
      in the second family. Parents of affected individuals in the three sibships are
      first cousins. To our knowledge, this association has not been reported before.
      We speculate that the mode of inheritance of this disorder is autosomal recessive
      with probable sex limitation.

PMID- 12486506
TI  - Method of endotracheal tube fixation and iatrogenic ear deformities.
AB  - There is no consensus regarding which type of endotracheal tube or method of
      fixation should be employed in neonates. We use oral endotracheal tubes held in
      place by a flange tied to a bonnet. In three very preterm infants the ligatures
      holding the bonnet to the flange caused pressure necrosis to the ear while the
      infants suffered poor perfusion due to profound hypotension. Permanent ear
      deformities have resulted. CONCLUSION: extra vigilance and precautions are
      required to prevent iatrogenic problems in sick, very prematurely born infants.

PMID- 12486507
TI  - A 7-year-old boy with mycoplasmal infection requiring extracorporeal membrane
      oxygenation.
AB  - A 7-year-old boy with Down syndrome developed severe acute respiratory distress
      syndrome after a respiratory infection with Mycoplasma pneumoniae with an
      unusually high agglutination titre (1:10240). Initially, mechanical ventilation
      and nitric oxide inhalation were used, but these did not improve the alveolar
      arterial oxygen gradient. Extracorporeal membrane oxygenation for 152 h improved
      the lung condition. CONCLUSION: our case suggests that Mycoplasma pneumoniae
      should be considered as an aetiological agent in acute respiratory distress
      syndrome. Extracorporeal membrane oxygenation might have a valuable role in the
      management.

PMID- 12486508
TI  - Painful hand and foot swelling in a 6-month-old girl.

PMID- 12486509
TI  - Effect of smoking on tear proteins.
AB  - PURPOSE: Cigarette smoking is a serious risk factor for many diseases, e.g.,
      cardiovascular and pulmonary diseases. It is also a risk factor in several eye
      diseases, including macula degeneration, glaucoma, and cataract. Ischemic, toxic,
      and oxidative effects of cigarettes are thought to play an important role in
      damaging ocular tissue. Furthermore, smoking can cause symptoms of dry-eye
      disease. The aim of this study was to analyze and compare electrophoretic
      patterns in tears of smokers (SP), severs smokers (SSP), and nonsmokers (CTRL).
      METHODS: We examined 105 eyes (SP: n=29, SSP: n=26, CTRL: n=50). Each patient was
      asked for subjective symptoms such as burning, itching, and foreign-body
      sensation. Tear proteins were separated by Sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis (SDS-PAGE). Digital image analysis was performed by
      BioDocAnalyze (Biometra, Gottingen, Germany), with densitometric data files being
      created for each electrophoretic lane. Data was analyzed by multivariate
      statistical techniques. RESULTS: Tear protein patterns in SP ( P<0.05) and SSP (
      P<0.05) were different from those of CTRL. There were significantly more protein
      peaks in the SSP group ( P<0.005) than in CTRL. CONCLUSION: Electrophoretic
      analysis of tear protein patterns could detect changes in tear proteins of
      smokers in comparison to nonsmokers. These changes were correlated with an
      increase of dry-eye-related subjective symptoms in smokers. Thus, electrophoretic
      analysis of tear proteins provided greater insight into the pathogenesis of
      smoking-induced ocular surface diseases.

PMID- 12486511
TI  - The effect of sample treatment on separation profiles of tear fluid proteins:
      qualitative and semi-quantitative protein determination by an automated analysis
      system.
AB  - PURPOSE: Qualitative and quantitative determination of tear fluid components is
      of increasing interest in ophthalmology. Until now, for diagnosis and course
      control of some diseases of the anterior parts of the eye, different methods for
      tear fluid protein analysis are available. Results can be obtained by
      polyacrylamide gel electrophoresis (PAGE), immunochemistry, and high-performance
      liquid chromatography (HPLC). A new method for protein separation, identification
      and semi-quantitative determination on a chip-based micro-fluidic technique is
      used for the first time to investigate tear fluids. METHODS: Normal human reflex
      tears were obtained by stimulation with China mint oil and collected using glass
      capillary tubes. A lab-on-a-chip technology (developed by Agilent Technologies,
      Waldbronn, Germany, in co-operation with Caliper Technologies, Mountain View,
      California, USA) was used for separation and semi-quantitative determination of
      tear proteins. Tear fluid was separated on the Agilent 2100 Bioanalyzer in
      combination with the Protein 200 LabChip kit and the dedicated protein assay
      software. Time and temperature of the incubation with sample buffer were varied,
      and the influence of these parameters on protein separation profiles was studied.
      Tear proteins were also analysed by PAGE, and the results obtained by both
      methods were compared. RESULTS: The different proteins of tear fluid can be
      separated by the Agilent 2100 Bioanalyzer method in very short time. By this
      method, the molecular weight as well as the concentration of proteins can be
      determined. Data are automatically stored in digital format and can be retrieved
      and shared. Results of this technology were comparable with the protein pattern
      obtained by PAGE. It was confirmed by both methods that, depending on incubation
      time of tear fluid with sample buffer and on temperature, different protein
      pattern can be obtained from the tears of one specimen. CONCLUSION: Tear proteins
      - in contrast to serum or aqueous humour proteins - are very sensitive to changes
      in sample buffer temperature as well as incubation time with buffer. To obtain
      comparable results for tear fluid proteins, the sample buffer applied and the
      incubation time and temperature must be observed carefully. This can be
      demonstrated by both the new Agilent 2100 Bioanalyzer method and PAGE. These
      results are of importance when comparing tear fluid protein pattern for the
      diagnosis and course control of dry-eye syndrome and of other diseases of the
      anterior part of the eye.

PMID- 12486510
TI  - A comparison of the fixed combination of latanoprost and timolol with its
      individual components.
AB  - PURPOSE: To evaluate the intraocular pressure (IOP)-reducing effect of the fixed
      combination of 0.005% latanoprost and 0.5% timolol compared with the individual
      monotherapies. METHODS: A 6-month, randomised, double-masked, controlled
      multicentre study followed by 6 months of open-label treatment was carried out in
      patients with glaucoma or ocular hypertension with pre-enrolment IOP >/=25 mmHg
      on glaucoma medication or >/=30 mmHg if untreated. Following a 2- to 4-week run
      in period on timolol twice daily, 436 patients were randomised: 140 to fixed
      combination therapy once daily in the morning, 147 to latanoprost once daily in
      the morning and 149 to timolol twice daily. During the open-label extension,
      patients received fixed combination drug once daily in the morning. RESULTS: The
      difference in mean change from baseline in diurnal IOP from week 2 to week 26 was
      -1.2 mmHg between fixed combination and latanoprost (95% confidence interval. CI:
      -1.8 to -0.5; P<0.001; repeated-measures analysis of covariance). The
      corresponding difference between fixed combination and timolol was -1.9 mmHg (95%
      CI -2.5 to -1.2; P<0.001). No long-term drift in IOP was detected in patients
      treated for 12 months with fixed combination. All treatments were well tolerated
      with no major differences among groups in the incidence of clinically relevant
      adverse events. CONCLUSION: The fixed combination of 0.005% latanoprost and 0.5%
      timolol administered once daily in the morning for 6 months was more effective in
      reducing IOP than the individual components alone and was effective over 12
      months.

PMID- 12486512
TI  - Monitoring accommodative ciliary muscle function using three-dimensional
      ultrasound.
AB  - BACKGROUND: Our objective was to develop a three-dimensional high-resolution
      ultrasonic imaging technique to be utilized for in-vivo characterization of the
      ciliary body and the posterior iris. The benefit of this imaging in enhancing the
      quantification of the configurational changes in the ciliary body during
      accommodation is demonstrated. METHODS: Sequential ultrasound biomicroscopic
      images of the ciliary body region were obtained with a computer-controlled
      scanning device designed for use with a standard ultrasound biomicroscope for 3D
      imaging. Custom-made software allows online data collection, data analysis and 3D
      reconstruction in conjunction with commercially available VoxelView software.
      RESULTS: The three-dimensional presentation allows a close approximation of the
      ciliary muscle inside the ciliary body in vivo. We are able to distinguish and to
      analyze the changes in the muscle contour in different accommodation states.
      During accommodation a shift in the ciliary muscle center of gravity in a range
      of 0.04-0.26 mm (mean 0.13+/-0.06 mm) in the direction of the lens equator, with
      an interindividual variation and a small decrease with age, was observed.
      CONCLUSIONS: High-resolution ultrasound is a well established technique for in
      vivo investigation of the anterior segment. Three-dimensional ultrasound
      biomicroscopy allows an assessment of the individual ciliary muscle activity in
      consideration of the ciliary processes. In combination with a contour analysis
      tool we improved the muscle contour determination during different accommodation
      states. The investigation showed an activity of the ciliary muscle in young
      volunteers as well as those of presbyopic age.

PMID- 12486513
TI  - Indocyanine-green-assisted internal limiting membrane peeling in macular hole
      surgery--a follow-up study.
AB  - BACKGROUND: Macular hole surgery including vitrectomy and peeling of epiretinal
      membranes and the internal limiting membrane (ILM) has become a standard
      procedure in retinal surgery. Poor visualization of the ILM is an obstacle for
      successful surgery. Recently, indocyanine green (ICG) has been reported to be a
      helpful intraocular substance in identifying these membranes. PATIENTS AND
      METHODS: Eighteen eyes with macular holes stages 2-4 were included.
      Intraoperatively, the ILM was stained with three drops of 1:9-diluted ICG. After
      1 min incubation, the vitreous cavity was rinsed with Ringer's lactate solution,
      and the ILM was peeled. Autologous thrombocytes were applied to the macular hole
      and the eye was endotamponaded with 20% SF-6 gas. Preoperatively, 6 weeks
      postoperatively, and in 3-month intervals thereafter, visual acuity, fundus
      photographs, scanning laser ophthalmoscope imaging, and Humphrey 24-2 static
      perimetry was performed. RESULTS: Intraoperatively, the ILM could be nicely
      visualized by ICG, which allowed easier and less traumatic peeling. At 6 weeks
      follow-up, visual acuity had improved in 14 of 18 patients, and the macular hole
      was closed 6 weeks after surgery. Scanning laser imaging revealed a strong
      signal. During prolonged follow-up, visual acuity declined due to cataract
      formation. CONCLUSION: ICG as an intraocular tool for staining of the ILM is
      helpful in macular hole surgery. We observed no negative effects on retinal
      function, but patients should be followed.

PMID- 12486514
TI  - Ultrasound biomicroscopy images: long-term results after deep sclerectomy with
      collagen implant.
AB  - PURPOSE: The aim of this study was to understand the long-term outflow pathway
      mechanisms after deep sclerectomy - when collagen implant is resorbed - using
      ultrasound biomicroscopy (UBM). METHODS: Forty-three eyes of 32 patients with
      medically uncontrolled open-angle glaucoma at least 1 year after deep sclerectomy
      were studied in an observational, non-randomised, consecutive case series.
      Postoperatively 15 eyes (35.7%) had goniopuncture with the Nd:YAG laser. Four
      eyes (9.5%) had postoperative subconjunctival injections of mitomycin C and two
      eyes (4.7%) had an injection of 5-fluorouracil, because of intraocular pressure
      (IOP) increase. Complete examination and UBM of the filtering site were performed
      1-6 years after surgery. The following parameters were assessed: (1) Presence of
      a subconjunctival filtering bleb; (2) presence and volume of an intrascleral
      cavity; (3) presence of a suprachoroidal hypoechoic area. RESULTS: Intraocular
      pressure decreased significantly from 28.1+/-2.5 mmHg preoperatively to 12.4+/
      3.8 (range 7-25) mmHg at the time of UBM (at least 1 year after surgery). Forty
      eyes showed clinically a diffuse filtering bleb. UBM demonstrated a
      subconjunctival space in all eyes. In 39 eyes (92.8%) an intrascleral cavity was
      observed. The mean volume of this cavity was 1.8 (range 0.11-6.53) mm(3). In 19
      eyes (45.2%) we observed a hypoechoic area in the suprachoroidal space.
      CONCLUSION: UBM examination demonstrated several aqueous humour drainage
      pathways. A low-reflective diffuse subconjunctival space meant persistent
      filtration in all eyes. More than 1 year after surgery 92.8% of eyes had a
      remaining intrascleral cavity. In almost half of the patients an additional
      suprachoroidal outflow was observed, significantly correlated with a lower IOP.

PMID- 12486515
TI  - Tear osteopontin levels in patients with allergic conjunctival diseases.
AB  - BACKGROUND: Recent reports have revealed the importance of several cytokines in
      chronic conjunctival allergic diseases (ACD) such as vernal keratoconjunctivitis
      (VKC) and atopic keratoconjunctivitis (AKC). Osteopontin (OPN) is a
      noncollagenous adhesive matrix protein that is expressed by activated
      macrophages. There has been considerable interest in the potential role of OPN in
      monocyte infiltration at sites of inflammation. We measured OPN level in tears
      using ELISA, to determine whether the level of this cytokine is elevated in ACD.
      METHODS: The level of OPN in tears was measured by ELISA using samples from
      patients with VKC, AKC or allergic conjunctivitis (AC) and from normal subjects.
      The level of OPN in tears was compared with the clinical severity of ACD and
      serum level of total IgE. RESULTS: The level of OPN in tears in AKC patients was
      significantly higher than that in AC and normal controls. Tear level of OPN in
      patients with VKC was also significantly elevated compared to those with AC and
      to normal controls. The clinical severity of ACD correlated significantly with
      the level of OPN. However, no correlation was observed between tear OPN level and
      serum level of total IgE. CONCLUSIONS: These results indicate that OPN plays an
      important pathophysiological role in severe ocular allergic conditions and that
      an elevated level of OPN in tear fluid reflects the local clinical status of
      ocular allergy, which may be an example of tissue remodeling.

PMID- 12486516
TI  - Efficacy of indomethacin 0.1% and fluorometholone 0.1% on conjunctival
      inflammation following chronic application of antiglaucomatous drugs.
AB  - BACKGROUND: Subclinical conjunctival inflammation has been shown to have a
      deleterious effect on the outcome of filtering surgery. The study was designed to
      assess the efficacy and safety of a non-steroidal anti-inflammatory ophthalmic
      solution (preservative-free indomethacin 0.1%) on conjunctival inflammation
      following chronic application of antiglaucomatous drugs, in comparison with a
      steroidal ophthalmic solution (preserved fluorometholone). METHODS: Eighty-nine
      glaucomatous patients were included in a randomised, multicentre study comparing
      two parallel groups of treatment given on the basis of 1 drop 4 times daily for 1
      month before filtering surgery. Patients had been treated with one or more
      antiglaucomatous drugs for at least 3 years. The routine antiglaucomatous
      treatment was continued during the study. Evaluations were carried out at
      baseline and after 30 days of treatment. Conjunctival inflammation was assessed
      under masked conditions by means of conjunctival impression analysis which
      determined the percentage of cells expressing HLA-DR. The ocular surface was also
      examined using the fluorescein test and lissamine green staining. RESULTS: Paired
      conjunctival impression specimens available both on day 0 (D0) and day 30 (D30)
      involved 49 patients. Among them, 34 eyes had a positive expression of HLA-DR at
      inclusion. On D30, in patients positive to HLA-DR on D0, the percentage of cells
      expressing HLA-DR had significantly decreased in both treatment groups: the mean
      reduction was 29.7% from a baseline value of 51.4% in the indomethacin group (
      P=0.019) and 32.5% from a baseline value of 48.7% in the fluorometholone group (
      P<0.001). There was no significant difference between groups. Seven cases of drug
      related superficial punctate keratitis were observed on D30 by means of a
      fluorescein test: one in the indomethacin group and six in the fluorometholone
      group. CONCLUSION: Both anti-inflammatory eyedrops were effective in reducing
      subclinical conjunctival inflammation before filtering surgery. Regarding
      superficial punctate keratitis, the corneal tolerance of preservative-free
      indomethacin 0.1% eyedrops seemed to be better than that of preserved
      fluorometholone eyedrops.

PMID- 12486517
TI  - Nitric oxide/guanylate cyclase pathways and flow in anterior segment perfusion.
AB  - BACKGROUND: The nitric oxide/guanylate cyclase pathway has been suggested to
      participate in the regulation of intraocular pressure. In the present study, the
      involvement of nitric oxide pathways on the outflow through the trabecular
      meshwork was assessed using pharmacological manipulation of the nitric oxide
      pathway. METHODS: Anterior segments of human donor eyes were maintained in an
      organ culture perfusion system, and the effects of L-NAME, an inhibitor of nitric
      oxide synthase, on the flow rate was determined. In a second series, the effects
      of consecutive application of L-arginine as substrate for nitric oxide synthase,
      L-NAME, and sodium nitroprusside, a nitric oxide-donor, were studied. The cyclic
      GMP levels in the perfusate were assessed with an ELISA immunoassay kit. RESULTS:
      In the first series of experiments, L-NAME caused a statistically significant
      decrease in flow rate of 10%, accompanied by a decrease in cGMP levels. In the
      second series, L-arginine did not alter flow, and the effect of L-NAME seen in
      the first series was prevented by the high preload of L-arginine. Nitroprusside
      caused a significant 10% increase of flow rate. In the perfusate, cGMP levels
      were not altered by L-arginine and L-NAME, but were increased after
      nitroprusside. CONCLUSION: Under organ culture perfusion conditions, modulation
      of the nitric oxide/guanylate cyclase system alters the flow rate through the
      trabecular meshwork within a total range of 20%; i.e. the difference between
      inhibition of NO synthesis and the presence of a NO-donor. These results indicate
      that the nitric oxide/guanylate cyclase system plays a role in aqueous humour
      dynamics and, therefore, in the regulation of intraocular pressure.

PMID- 12486518
TI  - Non-invasive determination of intraocular pressure in the rat eye. Comparison of
      an electronic tonometer (TonoPen), and a rebound (impact probe) tonometer.
AB  - BACKGROUND: The reproducibility and accuracy of the induction/impact (I/I) probe
      device (rebound tonometer) and the TonoPen XL electronic tonometer were compared
      through the measurement of intraocular pressure (IOP) differences between
      contralateral rat eyes. METHODS: IOP was measured in 18 female Wistar rats with
      variable, modest elevations of IOP in one eye. Mean IOP from five measurements on
      each of the 36 eyes was determined using the rebound tonometer, followed by the
      TonoPen XL. Following cannulation, true (manometrically determined) IOP was
      recorded with a calibrated pressure transducer. Differences between the operated
      and normal eye of each animal for each tonometric method of measurement were
      correlated with the true difference in IOP. RESULTS: IOP differences between the
      operated and contralateral normal eye ranged from +5.9 to -1.7 mmHg (mean +1.7
      mmHg) when measured by cannulation and from +7.2 to -1.4 mmHg (mean +2.4 mmHg)
      and +9.8 to -3.2 mmHg (mean +3.6 mmHg) when measured with the rebound tonometer
      and TonoPen XL respectively. Differences between eyes recorded by rebound
      tonometer ( y) correlated with those determined by cannulation ( x) in a linear
      fashion ( y=0.8243 x+1.0721; R(2)=0.6603). Correlation for the TonoPen XL was
      much weaker ( y=0.8675 x+2.1672; R(2)=0.2077). IOP measurements using the rebound
      tonometer did not differ significantly from true IOP, whereas TonoPen XL
      increasingly underestimated IOP with increasing IOP (9-20 mmHg). CONCLUSION: The
      rebound tonometer displayed greater accuracy and less variability than TonoPen XL
      in measuring the IOP of the rat eye (range 9-20 mmHg).

PMID- 12486519
TI  - Activation zones in cat visual cortex evoked by electrical retina stimulation.
AB  - BACKGROUND: A retina implant for restoring simple basic visual perception in
      patients who are blind due to photoreceptor loss requires optimisation of
      stimulation parameters for obtaining high spatio-temporal resolution. We
      developed effective low-power epi-retinal stimulation and intracortical recording
      in semichronically prepared cats. METHODS: Individually driveable fibre
      electrodes were inserted through a small scleral incision and positioned at the
      area centralis. Polyimide-platinum film electrodes were inserted via a corneal
      incision and fixed by instillation of perfluorocarbon liquid on the internal
      limiting membrane. For electrical stimulation we used short charge-balanced
      current impulses of 100-400 micro s duration and amplitudes ranging from 1 to 100
      micro A. During stimulation we recorded multiple single-cell and population
      activities from areas 17 and 18. Recordings were stored digitally. Stimulus
      response relations including response strength, cortical activation zones,
      information transmission, and electrical receptive fields were analysed off-line.
      RESULTS: We found low-threshold activations with fibre electrodes and polyimide
      platinum film electrodes in close mechanical contact to the retina. Retinal
      stimulation with bipolar charge-balanced impulses resulted in cortical activation
      zones corresponding to 1-5 degrees visual angle at paracentral locations
      dependent on the eccentricity of the retinal stimulation point. Retino-cortical
      transinformation analysis revealed 20-30 bits/s per electrode, corresponding to
      10-15 four-level pictures/s. Electrical receptive fields had sizes of 1-3 degrees
      visual angle. CONCLUSIONS: Coarse visuomotor coordination and navigation seems
      possible with retina implants.

PMID- 12486520
TI  - Improving the analysis of arteriovenous passage times.
AB  - PURPOSE: This study evaluated the effect of two techniques, time-based correction
      (TBC) and de-interlacing, on the quality of an image sequence from a scanning
      laser ophthalmoscope (SLO), and their impact on subsequent analysis for the
      determination of arteriovenous passage (AVP) times. METHODS: Fluorescein
      angiograms obtained from one patient participating in a concurrent study approved
      by an institutional review board (IRB) were analyzed before and after the serial
      connection of a TBC, and before and after de-interlacing of the images. Informed
      consent was obtained, and all tenets of the Declaration of Helsinki were
      followed. AVP times were determined and the variance in time per 100 frames was
      calculated. RESULTS: The average error in the determination of AVP times was
      significantly less after the application of these techniques ( p<0.05). Also, the
      coefficient of variance in the time elapsed per 100 frames was reduced after TBC
      and de-interlacing of the video sequence. CONCLUSION: The study showed that in
      addition to the subjective improvement in image quality after de-interlacing and
      TBC, quantitative parameters are improved. This leads to a more accurate analysis
      of the angiogram.

PMID- 12486521
TI  - Verification of a novel NADH-binding motif: combinatorial mutagenesis of three
      amino acids in the cofactor-binding pocket of Corynebacterium 2,5-diketo-D
      gluconic acid reductase.
AB  - A screening method has been developed to support randomized mutagenesis of amino
      acids in the cofactor-binding pocket of the NADPH-dependent 2,5-diketo-D-gluconic
      acid (2,5-DKG) reductase. Such an approach could enable the isolation of an
      enzyme that can better catalyze the reduction of 2,5-DKG to 2-keto-L-gulonic acid
      (2-KLG) using NADH as a cofactor. 2-KLG is a valuable precursor to ascorbic acid,
      or vitamin C, and an enzyme with increased activity with NADH may be able to
      improve two potential vitamin C production processes. Previously we have
      identified three amino acid residues that can be mutated to improve activity with
      NADH as a cofactor. As a pilot study to show feasibility, a library was made with
      these three amino acids randomized, and 300 random colonies were screened for
      increased NADH activity. The activities of seven mutants with apparent
      improvements were verified using activity-stained native gels, and sequencing
      showed that the amino acids obtained were similar to some of those already
      discovered using rational design. The four most active mutants were purified and
      kinetically characterized. All of the new mutations resulted in apparent kcat
      values that were equal to or higher than that of the best mutant obtained through
      rational design. At saturating levels of cofactor, the best mutant obtained was
      almost twice as active with NADH as a cofactor as the wild-type enzyme is with
      NADPH. This screen is a valuable tool for improving 2,5-DKG reductase, and it
      could easily be modified for improving other aspects of this protein or similar
      enzymes.

PMID- 12486522
TI  - Simultaneous horizontal gene transfer of a gene coding for ribosomal protein l27
      and operational genes in Arthrobacter sp.
AB  - Phylogenetic analysis of bacterial L27 ribosomal proteins showed that, against
      taxonomy, the L27 protein from the Actinobacteria Arthrobacter sp. clusters with
      protein sequences from the Bacillus group. The L27 gene clusters in the
      Arthrobacter sp. genome with six genes responsible for creatinine and sarcosine
      degradation. Phylogenetic analyses of orthologue proteins encoded by three of
      these genes also showed a phylogenetic relationship with Bacillus species.
      Comparisons between the synonymous codon usage of the Arthrobacter sp. genes and
      those from complete genomes showed that Arthrobacter genes encoding the L27
      ribosomal protein and the proteins responsible for the degradation of creatinine
      and sarcosine have a codon usage that is more similar to that of Bacillus species
      than that of Arthrobacter. We suggest that the Arthrobacter sp. genes encoding
      the L27 ribosomal protein and the proteins responsible for the degradation of
      creatinine and sarcosine were acquired simultaneously through horizontal gene
      transfer from an unknown Bacillus species.

PMID- 12486523
TI  - Molecular classification of coxsackie A viruses on the basis of the 5'-UTR:
      structural and evolutionary aspects.
AB  - The sequences from a large part of the 5'-UTR of 21 coxsackie A virus (CAV)
      reference strains for which such data did not exist in the past were obtained.
      Those sequences, along with the respective available sequences from the rest of
      the CAV reference strains and many other enteroviruses, were compared. According
      to the results of this comparison, enteroviruses are classified into two genetic
      clusters on the basis of 5'-UTR, and CAVs are divided into these two clusters.
      Specifically, it was found that CAV1, -11, -13, -15, -17 to -22, and -24 are
      classified together with polioviruses and enterovirus 70, whereas the rest of the
      CAVs are classified along with coxsackie B viruses, echoviruses, and the rest of
      the other enteroviruses. No correlation between overall 5'-UTR identity and the
      currently recognized human enterovirus species was found. The phenomenon of
      "covariance" in the 5'-UTR was followed for the prediction of the possible
      secondary structure of the 5'-UTR of the CAVs sequenced in the present study.

PMID- 12486524
TI  - Geographic genetic variation in populations of the dengue virus vector Aedes
      aegypti.
AB  - Isoenzyme variation was assessed in 79 mosquito samples of Aedes aegypti, and
      susceptibility to a dengue 2 virus strain was evaluated in 83 samples. Analysis
      of FST values, differentiation indexes, and geographic distances separating
      populations revealed that genetic differences between populations depended on the
      species' history of migration and colonization. Three major clusters were
      identified: (1). the sylvan form, Ae. ae. formosus, from West Africa and some
      islands in the Indian Ocean; (2). the domestic form, Ae. ae. aegypti, from
      Southeast Asia and South America; and (3). Ae. ae. aegypti populations from the
      South Pacific islands. Two groups were identified on the basis of susceptibility
      to the dengue virus: (1). populations with high infection rates, mostly the Ae.
      ae. aegypti form, and (2). mosquitoes with lower infection rates, specifically
      Ae. ae. formosus. Other evolutionary and epidemiological implications of the
      genetic variability of Ae. aegypti are also discussed.

PMID- 12486525
TI  - Pokey, a new DNA transposon in Daphnia (cladocera: crustacea).
AB  - We report the complete sequence of two representatives of the transposable
      element, Pokey, isolated from the ribosomal DNA of the cladoceran, Daphnia
      pulicaria. We describe the general features of this element, which confirms its
      classification as a DNA transposon. We show that Pokey is similar to piggyBac
      and, as such, is a member of the TTAA-specific family of elements. Pokey is
      putatively autonomous, possessing an open reading frame that encodes a putative
      protein with similarity to piggyBac's transposase, in addition to putative
      proteins from Drosophila and human LOOPER elements, and several human proteins of
      unknown function. We show that these proteins all contain amino acid motifs that
      are perhaps conserved for similar functions. We demonstrate that Pokey is
      carrying several regions of similarity to Daphnia pulex IGS sequences, likely the
      result of some sort of recombination event with the host genome. Pokey inserts
      into a conserved region of the large subunit ribosomal RNA gene known to contain
      other arthropod elements, suggesting that this location is a hot spot for
      insertional activity. However, Pokey is unique in that it is the only DNA
      transposon yet known to insert into this region, as other such insertions are non
      LTR retrotransposons. It is now clear that this "ecological niche" has been
      effectively exploited by both retrotransposons and DNA transposons.

PMID- 12486526
TI  - Negative charge correlates with neural expression in vertebrate aldolase
      isozymes.
AB  - Electrophoretic studies suggest that negatively charged neural proteins are a
      general feature of jawed vertebrates. In an apparent example of this, teleost
      fish express three aldolase isozymes, one of which is expressed predominantly in
      neural tissues and is more negatively charged than its more generally expressed
      paralogues. We characterized three aldolase isozymes from a single species of
      teleost fish, zebrafish (Danio rerio). These sequences indicated that the
      correlation of net negative charge and neural expression suggested in other
      species by gel electrophoresis was supported by sequence analysis. When aldolase
      sequences from the databases were included in phylogenetic analyses, the negative
      charge/neural expression phenomenon was observed across the gnathostome
      vertebrate sequences examined. We found no evidence for a period of positive
      Darwinian selection resulting in an accumulation of negatively charged amino
      acids during the evolution of the neural aldolase isozymes. This is likely
      attributable, however, to limitations associated with the age of the duplication
      responsible for the neural isozyme and the reconstruction of ancestral sequences.

PMID- 12486527
TI  - Estimation of evolutionary parameters with phylogenetic trees.
AB  - An important issue in the phylogenetic analysis of nucleotide sequence data using
      the maximum likelihood (ML) method is the underlying evolutionary model employed.
      We consider the problem of simultaneously estimating the tree topology and the
      parameters in the underlying substitution model and of obtaining estimates of the
      standard errors of these parameter estimates. Given a fixed tree topology and
      corresponding set of branch lengths, the ML estimates of standard evolutionary
      model parameters are asymptotically efficient, in the sense that their joint
      distribution is asymptotically normal with the variance-covariance matrix given
      by the inverse of the Fisher information matrix. We propose a new estimate of
      this conditional variance based on estimation of the expected information using a
      Monte Carlo sampling (MCS) method. Simulations are used to compare this
      conditional variance estimate to the standard technique of using the observed
      information under a variety of experimental conditions. In the case in which one
      wishes to estimate simultaneously the tree and parameters, we provide a
      bootstrapping approach that can be used in conjunction with the MCS method to
      estimate the unconditional standard error. The methods developed are applied to a
      real data set consisting of 30 papillomavirus sequences. This overall method is
      easily incorporated into standard bootstrapping procedures to allow for proper
      variance estimation.

PMID- 12486528
TI  - Identification of immunoreactive material in mammoth fossils.
AB  - The fossil record represents a history of life on this planet. Attempts to obtain
      molecular information from this record by analysis of nucleic acids found within
      fossils of extreme age have been unsuccessful or called into question. However,
      previous studies have demonstrated the long-term persistence of peptides within
      fossils and have used antibodies to extant proteins to demonstrate antigenic
      material. In this study we address two questions: Do immunogenic/antigenic
      materials persist in fossils? and; Can fossil material be used to raise
      antibodies that will cross-react with extant proteins? We have used material
      extracted from a well-preserved 100000-300000-year-old mammoth skull to produce
      antisera. The specificity of the antisera was tested by ELISA, western blotting,
      and immunohistochemistry. It was demonstrated that antisera reacted specifically
      with the fossils and not the surrounding sediments. Reactivity of antisera with
      modern proteins and tissues was also demonstrated, as was the ability to detect
      evolutionary relationships via antibody-antigen interactions. Mass spectrometry
      demonstrated the presence of amino acids and specific peptides within the fossil.
      Peptides were purified by anion-exchange chromatography and sequenced by tandem
      mass spectrometry. The collagen-derived peptides may have been the source of at
      least some of the immunologic reactivity, but the antisera identified molecules
      that were not observed by mass spectrometry, indicating that immunologic methods
      may have greater sensitivity. Although the presence of peptides and amino acids
      was demonstrated, the exact nature of the antigenic material was not fully
      clarified. This report demonstrates that antibodies may be used to obtain
      information from the fossil record.

PMID- 12486529
TI  - A DNA sequence evolution analysis generalized by simulation and the markov chain
      monte carlo method implicates strand slippage in a majority of insertions and
      deletions.
AB  - To study the mechanisms for local evolutionary changes in DNA sequences involving
      slippage-type insertions and deletions, an alignment approach is explored that
      can consider the posterior probabilities of alignment models. Various patterns of
      insertion and deletion that can link the ancestor and descendant sequences are
      proposed and evaluated by simulation and compared by the Markov chain Monte Carlo
      (MCMC) method. Analyses of pseudogenes reveal that the introduction of the
      parameters that control the probability of slippage-type events markedly augments
      the probability of the observed sequence evolution, arguing that a cryptic
      involvement of slippage occurrences is manifested as insertions and deletions of
      short nucleotide segments. Strikingly, approximately 80% of insertions in human
      pseudogenes and approximately 50% of insertions in murids pseudogenes are likely
      to be caused by the slippage-mediated process, as represented by BC in ABCD -->
      ABCBCD. We suggest that, in both human and murids, even very short repetitive
      motifs, such as CAGCAG, CACACA, and CCCC, have approximately 10- to 15-fold
      susceptibility to insertions and deletions, compared to nonrepetitive sequences.
      Our protocol, namely, indel-MCMC, thus seems to be a reasonable approach for
      statistical analyses of the early phase of microsatellite evolution.

PMID- 12486530
TI  - The association between HLA-A alleles and young Alu dimorphisms near the HLA-J, 
      H, and -F genes in workshop cell lines and Japanese and Australian populations.
AB  - At least two polymorphic Alu insertions have been previously identified and
      characterized within the class I region of the major histocompatibility complex
      (MHC). We have identified another two new polymorphic Alu insertions, AluyHJ and
      AluyHF, located near HLA-J and HLA-F, respectively, within the a block of the
      MHC. Here we report on (1). the haplotypic relationships between the Alu
      dimorphisms and the HLA-A locus within a panel of 51 IHW homozygous cell lines
      representing at least 36 HLA class I haplotypes, (2). the Alu genotype, allele,
      and haplotype frequencies present in the Australian Caucasians and Japanese
      populations, and (3). the frequency of association between the different Alu
      dimorphisms and the HLA-A alleles in 109 Australian Caucasians and 99 Japanese.
      PCR was used to detect the presence or absence of insertion for AluyHJ, AluyHG,
      and AluyHF within the DNA samples prepared from the cell lines and the two
      population groups that had been previously typed for HLA-A. In the homozygous
      cell lines, all three Alu insertions were found in only one HLA class I haplotype
      (HLA-A1, -B57, -Cw6), no Alu insertions were detected in six HLA class I
      haplotypes and one or more of the Alu insertions were found in 29 HLA class I
      haplotypes. At least one of the Alu insertions was found in about 86% of the
      Japanese and Australian individuals, with the AluyHJ generally related inversely
      to AluyHG and/or AluyHF. The gene frequency of the AluyHJ and AluyHF insertions
      was significantly different (p <0.05) between Japanese and Australians, whereas
      there was no difference (P > 0.05) between the frequencies of AluyHG in the two
      populations. The Alu haplotype frequencies were also significantly different
      between the Japanese and the Australians. In the cell lines and the population
      groups, the AluyHJ insertion was most frequently found associated with HLA-A1 or
      A24, AluyHG with HLA-A2, and AluyHF with HLA-A2, -A10, or -A26. This study
      suggests that the three polymorphic Alu elements have been inserted into the a
      block of the MHC in different progenitor groups and therefore will be useful
      lineage and linkage markers in human population studies and for elucidating the
      evolution of HLA class I haplotypes.

PMID- 12486531
TI  - Intron positions delineate the evolutionary path of a pervasively appended
      peptide in five human aminoacyl-tRNA synthetases.
AB  - Recent progress in genome sequencing has revealed a correspondence between the
      evolution of multicellularity and the appending of new peptides onto age-old
      enzyme bodies. Indicative of the pervasive nature of these appended peptides, in
      some cases the same sequences have been appended to a number of different
      enzymes. By analyzing the positions of introns within one such roaming peptide,
      an approximately 50-amino acid motif appended to five human aminoacyl-tRNA
      synthetases, I have delineated its path in eukaryote evolution. The motif was
      first acquired as an N-terminal extension by histidyl- and glycyl-tRNA
      synthetases at a very early stage of eukaryote evolution. Later, but not less
      than 1200 million years ago, the motif spread from histidyl-tRNA synthetase to
      the C and N terminals of glutamyl- and prolyl-tRNA synthetase, respectively, and
      then spread further during the evolution of the Chordate lineage to the N
      terminal of tryptophanyl-tRNA synthetase. In similar fashion, the motif in glycyl
      tRNA synthetase spread to the C terminal of methionyl-tRNA synthetase not later
      than 1000 million years ago.

PMID- 12486532
TI  - Gene Import or Deletion: A Study of the Different Genes in Escherichia coli
      Strains K12 and O157:H7.
AB  - By comparing two strains of Escherichia coli (K12 and O157:H7) with an outgroup
      of Salmonella and Klebsiella species and analyzing the sets of genes which are
      present or absent in either of the three groups, we study the gene history of
      K12, in particular, since the respective divergences of these bacteria.
      Furthermore, by using a compositional method based on context bias, we evaluate
      not only recently imported genes but also deleted genes. In addition, we examine
      recent gene duplications in the two E. coli strains. It is found that turnover of
      DNA is high in E. coli and, more importantly, that turnover is highest for genes
      of low GC content. Although levels of import are high, most of the imported genes
      seem to be "junk" or have poorly understood functions. Nevertheless, selected
      genes do persist, and may even define some E. coli strains as pathogenic. Our
      results support the conclusion that some of the pathogenic islands in O157:H7 are
      likely to have been imported in recent time.

PMID- 12486533
TI  - Functional constraints of the Cu,Zn superoxide dismutase in species of the
      Drosophila melanogaster subgroup and phylogenetic analysis.
AB  - The phylogenetic relationships among the Drosophila melanogaster subgroup species
      were analyzed using approximately 1550-nucleotide-long sequences of the Cu,Zn SOD
      gene. Phylogenetic analysis was performed using separately the whole region and
      the intron sequences of the gene. The resulting phylogenetic trees reveal
      virtually the same topology, separating the species into distinct clusters. The
      inferred topology generally agrees with previously proposed classifications based
      on morphological and molecular data. The amino acid sequences of the Cu,Zn SOD of
      the D. melanogaster subgroup species reveal a high-conservation pattern. Only
      3.9% of the total amino acid sites are variable, and none affects the major
      structural elements. Comparison of the Drosophila Cu,Zn SOD amino acid sequences
      with the Cu,Zn SOD of Bos taurus and Xenopus laevis (whose three-dimensional
      structure has been elucidated) reveals conservation of all the protein's
      functionally important amino acids and no substitutions that dramatically change
      the charge or the polarity of the amino acids.

PMID- 12486534
TI  - Unusually expanded SSU ribosomal DNA of primary osmotrophic euglenids: molecular
      evolution and phylogenetic inference.
AB  - Expansion segments within eukaryotic nuclear SSU ribosomal RNA have been
      characterized in many diverse organisms. So far, only a few studies have examined
      the evolutionary history of SSU rDNA variable regions for monophyletic groups. A
      euglenozoan SSU rDNA data set was analyzed combining phylogenetic inference and
      examination of expansion segment evolution. Although SSU rDNA length expansion
      could be ascribed to all Euglenozoa, most unusual length variation occurs within
      primary osmotrophic euglenids, particularly within the genus Distigma. The
      longest SSU rRNA gene reported to date can be found in D. sennii, comprising more
      than 4500 bases. RT-PCR analyses revealed that the complete gene is transcribed
      into RNA without posttranscriptional modifications. Further investigations
      uncovered that most of the length extension is due to elongated variable regions
      V2 and V4, but virtually all variable regions except for V3 are extended within
      primary osmotrophic euglenids. Analyses of secondary structure revealed several
      insertion points within variable regions, some of which are of phylogenetic
      importance. Varying GC content has been detected among species and between
      expansion segments and core regions. Nevertheless, individual expansion segments
      of one species as well as variable sequence positions within core regions tend to
      evolve in parallel concerning nucleotide frequencies. The presence of a large
      internal repeat within V2 of Distigma sennii hints at a possible mechanism for
      large-scale sequence length expansion.

PMID- 12486535
TI  - Characterization and phylogenetic relationship of prosimian MHC class I genes.
AB  - MHC class I cDNA sequences from the most divergent primate group of extant
      primates compared to human, the suborder Strepsirrhini (prosimians), are
      described. The sequences are derived from the gray mouse lemur (Microcebus
      murinus) and the ring-tailed lemur (Lemur catta), which are members of the
      malagasy Lemuriformes, as well as from the pygmy slow loris (Nycticebus
      pygmaeus), a prosimian from East Asia. The M. murinus sequences have been
      analyzed in detail. Analysis of the expression level, G/C content, and synonymous
      vs. nonsynonymous substitution rates in the peptide-binding region codons
      suggests that these cDNA clones represent classical class I (class Ia) genes.
      According to Southern blot analysis, the genome of the gray mouse lemur might
      contain about 10 class I genes. In gene tree analysis, the strepsirrhine class Ia
      genes described here cluster significantly separately from the known class I
      genes of Catarrhini (humans, apes, Old World monkeys) and Platyrrhini (New World
      monkeys) species, suggesting that the class I loci of Simiiformes arose by gene
      duplications which occurred after the divergence of prosimians.

PMID- 12486536
TI  - Phylogenetic relationships, evolution of broodcare behavior, and geographic
      speciation in the wrasse tribe Labrini.
AB  - The family Labridae is a large assemblage of marine fish composed of about 580
      species in 82 genera distributed in tropical and temperate marine waters around
      the world. Several subgroups, currently classified as tribes, have been
      identified in this large family, yet only a few phylogenetic analyses have been
      performed on labrid clades. We confirm monophyly of the labrid tribe Labrini and
      propose a phylogeny of the 23 species of the genera Acantholabrus, Centrolabras,
      Ctenolabrus, Labrus, Lappanella, Symphodus, Tautoga, and Tautogolabrus occurring
      in the eastern and western Atlantic and the Mediterranean. We analyzed a 577-bp
      segment of the mitochondrial 16S rDNA and a 506-bp segment of the mitochondrial
      control region in 22 species, for a total of up to 1069 bp per species. We used
      both parsimony and likelihood approaches under a variety of assumptions and
      models to generate phylogenetic hypotheses. The main features of the molecular
      phylogeny for the Labrini turned out to be the same for the two algorithms
      applied. The tree structure is similar to a previous, unpublished morphological
      phylogeny for a subset of labrine species. Estimated divergence times of the
      Labrini based on fossils and a molecular clock range from about 15 mya for the
      deepest splits to less than 1 mya for younger clades. Biogeographic patterns of
      the Symphodus species group and the genus Labrus are dominated by speciation
      events driven by the closing and opening of the Mediterranean Sea and periodic
      glaciation events during the past 1 million years. The Labrini are the only clade
      in the entire Labridae that exhibit nest-building and broodcare behavior. We use
      the phylogeny to show that similar broodcare behavior has evolved twice in the
      labrine fish and discuss scenarios for the evolution of broodcare from the
      diandric protogynous hermaphroditism found in ancestral labrines and many other
      wrasses.

PMID- 12486537
TI  - [Rheumatoid arthritis of the cervical spine. Current concepts for diagnosis and
      therapy].
AB  - The involvement of the cervical spine in patients with rheumatoid arthritis (RA)
      is common,and has recently received growing attention. In the early stage of the
      disease, there is an isolated atlantoaxial subluxation (AAS). With further
      progression, osseous destruction of the joints can lead to vertical instability.
      While the involvement of the middle and lower cervical spine can cause a subaxial
      instability, neurological deficits can occur at any time. The onset of cervical
      myelopathy in patients with RA is often missed because of additional problems
      related to the hands and feet. If patients show clear symptoms of cervical
      myelopathy, the progression of the disease cannot be stopped by conservative
      treatment. Other indications for operative treatment are severe pain and
      radiological evidence of progressive instability. In the case of an isolated AAS,
      fusion can be restricted to the C1/C2 segment. If there is evidence for vertical
      or subaxial instability, an occipitocervical fusion has to be performed. To avoid
      instability adjacent to the fusion, the surgeon must check for signs of potential
      subaxial instability. If this is the case, fusion should include the entire
      cervical spine. Additional transoral decompression may be necessary when there is
      persistent retrodental pannus or osseous compression by an irreducible transverse
      dislocation or cranial migration of the dens. Non-ambulatory myelopathic patients
      are more likely to present severe surgical complications with limited prospects
      of functional recovery. Therefore, it is important to avoid the development of
      severe cervical myelopathy by early surgical intervention.

PMID- 12486538
TI  - [The influence of rheumatoid and degenerative disease on hospital resources in
      the operative treatment of cervical spine instability].
AB  - The aim of this study was to compare perioperative diagnostic and therapeutic
      measures in the treatment of cervical spine instability in patients with
      rheumatoid arthritis or degenerative disease. Twenty patients (ten in each group)
      were evaluated and compared with regard to age, sex, surgery time, total
      operating room time, intensive care time, extent of physical therapy, nursing
      requirements, costs of medication and radiography. Rheumatoid arthritis patients
      required more resources with regard to surgery, nursing and rehabilitation than
      the patients with degenerative disease. Significant differences existed with
      regard to patient age (P=0.0005), surgery time (P=0.0021), total operating room
      time (P=0.0001), duration of intensive care (P=0.0005), nursing requirements
      (P=0.0000), costs of medication (P=0.0000), costs of radiography (P=0.0015) and
      the duration of hospitalisation (P=0.0115). The data suggest that it is necessary
      to distinguish patients with rheumatoid or degenerative cervical spine
      instability from an economic point of view, as the treatment of the rheumatoid
      cervical spine requires more resources.

PMID- 12486539
TI  - [Differential therapy for the rheumatoid shoulder].
AB  - Despite frequent involvement, the rheumatoid shoulder is neglected in operative
      treatment of the upper extremities. The slow course of omarthritis, the
      compensation mechanism of scapulothoracic motion and neighbouring joints as well
      as dominating disabilities of the lower extremities and the rheumatoid hand are
      possible explanations. The pattern of destruction of the rheumatoid shoulder is
      characterized by progressive joint and soft tissue deterioration. Soft tissue
      involvement determines the course of the shoulder joint. The subacromial space is
      a common and early site for rheumatoid involvement, often leading to bursitis,
      tenosynovitis of the biceps tendon and rotator cuff rupture. Sonography and MRI
      enable the early detection of subacromial and glenohumeral pathology before
      deterioration is visible radiologically. Surgical intervention in patients with
      rheumatoid arthritis of the shoulder is based on the degree of radiological
      destruction according to Larsen, the natural course of the shoulder joint and the
      soft-tissue condition. The goals of surgery are to relieve pain, increase motion
      and restore shoulder function. Surgery should be carried out early in the course
      of the disease, thus determining the long-term prognosis and the remaining
      surgical options. Depending on the pattern of destruction of the rheumatoid
      shoulder, the options for treatment can be divided into early and late
      procedures.Joint-preserving surgery is indicated in the early stages of
      radiological destruction according to Larsen classification O-III, whereas the
      late stages of destruction (Larsen IV-V) require reconstructive surgery. The
      introduction of arthroscopic and semiarthroscopic techniques has improved the
      acceptance of early synovectomy for the rheumatoid shoulder, but there is still a
      place for open synovectomy in patients with extensive soft-tissue repair and bone
      remodelling procedures. Arthroscopic and open synovectomy are supplementary and
      noncompetitive surgical procedures for the rheumatoid shoulder. With proceeding
      bone and soft-tissue destruction corresponding to Larsen stage IV and V,
      synovectomy is not successful and reconstructive surgery is necessary. Resection
      interposition-arthroplasty (RAIP) remains a controversial alternative to
      arthroplasty in young patients with sufficient bone stock and a reconstructable
      rotator cuff. The success of cup-replacement will additionally restrict the
      indications for RAIP. RIAP remains a possible salvage procedure after aseptic and
      septic loosening of shoulder arthroplasty. Glenohumeral replacement arthroplasty
      has become the procedure of choice in reconstructive surgery of the shoulder. The
      severity of soft-tissue and bone destruction determines the choice of shoulder
      prosthesis. Current modular shoulder systems with increased numbers of humeral
      head stem combinations are calculated to achieve a better adjustment of the soft
      tissue tension and to optimize the adaptation between head geometry and the
      natural shape of the glenoid.The surrounding soft-tissue structure, especially
      the condition of the rotator cuff, is very important for the functional recovery
      after shoulder arthroplasty. We prefer a hemiarthroplasty of the rheumatoid
      shoulder joint to avoid critical glenoid fixation. Patients with irreparable
      rotator cuff tears and severe glenohumeral arthritis remain a difficult challenge
      in shoulder surgery and the ideal procedure has not yet been found.Pain relief
      and a modest increase in active motion are the main goals in operative treatment.
      Bipolar shoulder arthroplasty represents an adequate alternative to currently
      favoured hemiarthroplasty in patients with cuff-deficient shoulders.

PMID- 12486540
TI  - [Therapy of rheumatoid cubarthritis].
AB  - With the progression of rheumatoid arthritis (RA),more than half of the patients
      develop an affliction of the elbow.Cub arthritis has to be regarded as a part of
      systemic rheumatoid disease. Thus, the indication for operative treatment depends
      not only on local changes but is determined by the pattern of all affected
      joints, the activity of the basic rheumatic disease as well as the effect of
      physical therapy and medication. The complexity of the rheumatic disease, which
      typically affects many joints, demands an individual therapeutic plan that can
      only be developed and accomplished successfully when rheumatologists, rheumatoid
      surgeons and other specialists cooperate. In cases of recurrent cub arthritis,in
      spite of adequate medication, synoviorthesis or synovectomy should be performed.
      This may relieve pain and swelling,however if lesions of the cartilage already
      exist,progressive joint destruction cannot be prevented. Arthroscopic surgery of
      the elbow provides all of the known advantages of minimal traumatisation. In
      RA,it is used mainly when there is ligament laxity in late synovectomies
      eventually combined with arthroscopically assisted resection of caput radii. In
      contrast to monoarticular diseases in RA,the adjoining bursa olecrani,
      neighbouring joints and nerve entrapment syndromes also require treatment. The
      treatment for advanced cub arthritis is arthroplasty. Due to progress in the
      development of elbow endoprotheses, the range of indications for resection
      (interposition) arthroplasty has increased. It is now preferred mainly in younger
      patients with ankylosing arthritis. Rheumatoid changes in the bone and soft
      tissue impede the implantation of artificial joints and require time consuming
      and precise preparation techniques. When choosing either an unconstrained or semi
      constrained prosthesis,one has to bear in mind the actual ligament stability and
      its often unpredictable changes during the course of the disease.Perioperative
      measures, postoperative care and therapy is made even more difficult due to the
      involvement of several joints, often extensive permanent medication, secondary
      lesions such as ldquo;corticoid skin" and in most cases the multimorbidity of
      patients after many years of chronic disease. When comparing elbow surgery in
      osteoarthritis and RA,we found that patients with RA clearly required more
      elaborate surgery and more extensive perioperative and postoperative care.

PMID- 12486541
TI  - [The rheumatoid wrist. Pathobiomechanics and therapy].
AB  - A stable and pain-free wrist is a prerequisite for normal hand function. Since
      the wrist joint is involved early in rheumatoid disease and progress is rapid,
      operative treatment is of major importance. It is indicated not only for
      treatment of established osseous changes with instability, deformation, and
      extensor tendon ruptures but for early treatment of drug-resistant synovitis and
      monarthritis of the wrist.A considerable number of operative procedures is
      available: arthroscopic or open synovectomy of the radio- and midcarpal as well
      as the distal radioulnar joint, possibly with resection of the ulna head, partial
      arthrodeses, complete arthrodeses,and arthroplasty. When choosing the procedure,
      type and stage of wrist changes as well as the pathobiomechanic situation have to
      be considered. The individual course of the disease and patient requirements have
      to be taken into account.Thus, for long periods of time a pain-free stable wrist
      can be preserved, albeit sometimes with only limited but functional mobility.

PMID- 12486542
TI  - [Differences between rheumatoid and degenerative disease in total hip
      replacement].
AB  - The aim of this study was to compare total hip replacement (THR) in rheumatoid
      and osteoarthritic patients. Ten rheumatoid and ten osteoarthritic patients
      undergoing THR were compared with respect to preoperative diagnostics, operative
      therapy, nursing and rehabilitation. Statistically significant differences
      existed between the groups: In rheumatoid patients, radiographic diagnostics were
      more extensive ( P=0.0021), surgery time was extended ( P=0.0355), referrals to
      non-orthopedic subspecialties were more frequent ( P=0.0524) and rehabilitation
      was more extensive ( P=0.0000). The groups were not significantly different with
      respect to the duration of hospitalisation, preoperative hemoglobin,
      perioperative blood loss, transfusion requirements, duration of intensive care
      and nursing requirements. THR in the rheumatoid population required additional
      resources during inpatient therapy in comparison to THR in osteoarthritic
      patients.

PMID- 12486543
TI  - [Intra-articular steroid therapy for inflammatory rheumatic diseases in children
      and adolescents].
AB  - In addition to systemic medication,physiotherapy, and operative measures,
      intraarticular therapy with corticosteroids (iaST) is a well established
      treatment for juvenile idiopathic arthritis (JIA). IaST is indicated in children
      whose inflamed joints do not respond sufficiently to systemic antiarthritic drugs
      and is normally carried out under in-patient conditions. Triamcinolone
      hexacetonide (TH) is the drug of choice for iaST because of its well documented,
      long-lasting effects. In younger children or those who require simultaneous
      injections into multiple joints, a short general anesthesia is useful, while
      single injections in older children can be administered after topical application
      of a local anesthetic. Intensive physiotherapy after iaST is important for
      regaining mobility lost due to the arthritis, and 2 or 3 days of post-injection
      rest should be adhered to after iaST of joints of the lower extremities. Several
      studies demonstrate long-lasting remission in the majority of the injected joints
      in JIA patients, with good pain-relief, improved mobility, and a significant
      delay in further joint destruction in comparison with joints in which the
      synovitis could not be adequately controlled. Various sub-types of JIA have been
      shown to respond differently to iaST. Intraarticular steroids can also be used to
      treat coxitis, since recent data failed to show a subsequent increase in the rate
      of femoral head necrosis. Septic arthritis, the most feared complication after
      iaTH, seems to be extremely rare in children. Other complications, like
      periarticular calcifications or subcutaneous atrophy, also occur only rarely,
      provided the steroid is injected correctly. The present data indicate that iaST
      is an effective and safe treatment for JIA. The therapeutic approach to children
      with JIA is multidisciplinary, and these young patients should be treated in
      specialised centres.

PMID- 12486544
TI  - [A comparison of total knee replacement in patients with rheumatoid arthritis and
      those with degenerative arthritis].
AB  - This article aims at determining the differences in resources needed for the
      treatment of patients with rheumatoid arthritis as opposed to osteoarthritis.
      Data on ten patients for each of these diagnoses, all of whom had been subject to
      the implantation of a knee arthroplasty,were compared. We looked at parameters
      such as the duration of surgery, further diagnoses, costs of radiological
      measures and medical treatment, simultaneous operations, need of nursing
      care,physical and occupational therapy and complications. Patients presenting
      with rheumatoid arthritis in many respects required substantially more clinical
      and/or financial resources than osteoarthritis patients. This statement holds
      true at least for the period of hospital care during which the knee-prosthesis
      was implanted.

PMID- 12486545
TI  - [The treatment of rheumatoid foot deformities].
AB  - Rheumatoid hindfoot deformity presents with hindfoot eversion, flattening of the
      longitudinal arch and abduction of the forefoot. Splayfoot, as the typical
      rheumatoid forefoot deformity, is mostly associated with various toe
      malformations, i.e. hallux valgus,hammer toe and claw toe,which may either be
      attributed to hindfoot malalignment or develop as a separate entity. The
      algorithm of treatment, comprising clinical assessment of both lower limbs,
      includes both orthotic shoe devices and surgical treatment. In rheumatoid
      flatfoot, arthrodesis of the hindfoot with lengthening of the lateral column and
      reorientation of joint congruency represent the gold standard of treatment.
      Despite this principle, the ankle joint should be kept mobile to facilitate
      standing and walking. Therefore, total ankle prosthesis is thought to be
      superior. Methods involving the preservation of the lesser metatarsophalangeal
      joints may be of benefit in providing sufficient ground contact with the toes.
      Nevertheless, resection arthroplasties are frequently required in cases of
      arthritic joint destruction. Arthrodesis of the first metatarsophalangeal joint
      may provide an adequate push-off for the big toe which can not be expected from
      resectional arthroplasties.

PMID- 12486546
TI  - [Development of the leg axis in childhood and treatment options for deformities
      near the knee joint].

PMID- 12486547
TI  - [WHO-classification of malignant lymphomas].
AB  - Because of the multiple developmental stages of lymphocytes and the complexity of
      the immune system,the corresponding neoplasms, the malignant lymphomas, represent
      a complex group of diseases. The clinical grouping of the KIEL-classification,
      distinguishing high grade from low grade lymphomas, has been abandoned in the WHO
      classification as it is partly misleading. Especially,mantle cell lymphoma which,
      according to its morphology, represents a low grade lymphoma, is characterized by
      an extremely aggressive clinical course. The therapy of malignant non-Hodgkin
      lymphomas has become more and more diverse. The great advances in survival and
      quality of life of patients with malignant lymphomas have been reached in
      multiple clinical studies to optimize therapy and simultaneously set up standards
      of quality for the diagnosis and therapy of malignant lymphoma (see
      http://www.lymphome.de). Especially in the group of so-called low grade lymphomas
      according to the KIEL-classification, clinical studies in Germany follow
      different therapy concepts for each of the diseases. Therefore,patients should be
      treated within such a study.

PMID- 12486548
TI  - [Medicinal therapy of malignant lymphomas].
AB  - Chemotherapy represents the most important therapeutic option in malignant
      lymphomas. Low to intermediate risk Hodgkin's disease is treated by a combination
      of chemotherapy and radiation. The new chemotherapy protocol BEACOPP has improved
      the outcome of advanced stages in comparison with the internationally accepted
      standard protocol COPP/ABVD. Dependent on the initial staging, cure rates between
      50 and 95% can be achieved.Indolent non-Hodgkin's lymphomas usually present in
      advanced stages of disease. Chemotherapy in these cases has palliative character
      and aims at improving patients'quality of life and at avoiding complications due
      to the disease. In aggressive and very aggressive non-Hodgkin's lymphoma
      chemotherapy is curative and must be initiated immediately irrespective of the
      staging results. The efficacy of the standard protocol CHOP
      (cyclophosphamide,doxorubicin, vincristine and prednisone), that was established
      in the 1970s, has recently been improved by shortening of the therapy interval
      (CHOP-14 vs.CHOP-21),addition of etoposide (CHOEP) and combination with the
      monoclonal antibody rituximab (R-CHOP). The value of high dose chemotherapy with
      stem cell transplantation has been shown unequivocally only for aggressive non
      Hodgkin lymphoma and relapsed Hodgkin's disease responsive to chemotherapy. The
      therapeutic strategy of malignant lymphomas is likely to be improved within the
      next years due to the introduction of novel cytostatic agents, the broadening
      application of monoclonal antibodies,upcoming new transplantation procedures and
      the development of substances with molecular targets. To rapidly increase our
      current knowledge on the topic it is mandatory to include patients into the large
      national and international multicenter studies.

PMID- 12486549
TI  - [CT staging of malignant lymphoma. How to avoid misinterpretations].
AB  - Therapeutic strategy and prognosis of malignant lymphoma are influenced by
      staging. Therefore, evaluation of pattern of lymphatic involvement is highly
      relevant. There are numerous pitfalls possible in detection and description when
      malignant lymphomas are visualized by computed tomography (CT). Normal anatomic
      structures may be interpreted as pathologic lymph nodes by inexperienced
      radiologists. Assessment and detection of lymphomas require precise knowledge of
      normal anatomic structures as well as roentgenological criteria and adequate
      methods of imaging. This report provides an overview of the relevant pitfalls and
      often overlooked areas in staging of malignant lymphomas.

PMID- 12486550
TI  - [Imaging of supradiaphragmatic manifestations of extranodal non-Hodgkin's
      lymphoma].
AB  - Malignant lymphomas are differentiated into Hodgkin's and non-Hodgkin's-lymphoma
      (NHL). The following article discusses the imaging of extranodal NHL in
      supradiaphragmatic localizations. Lymphoma can affect nearly all tissues, and
      represent a rare entity as primary extranodal NHL. A secondary involvement of non
      nodal tissue as consequence of a generalized lymphoproliferative disease is more
      common,and may be seen as well in HIV-positive patients defining AIDS. As
      extranodal lymphoma mimic the radiologic appearance of other malignant tumors,
      direct diagnosis without histologic analysis is often impossible. The article
      describes typical manifestations of lymphoma of the lungs, the head and neck area
      including the large glands, and rare localizations as the heart or the breast.

PMID- 12486551
TI  - [Extranodale lymphomas infradiaphragmal].
AB  - Non-Hodgkin's lymphoma occurs in up to 30% primarily out of lymph nodes
      (extranodal). In the abdomen, beside spleen and liver the gastrointestinal tract
      is often and the kidneys are not rarely affected. However, each abdominal organ
      and peritoneal space, muscles and skin can be affected at various frequencies.
      While an exclusive manifestation within an organ without lymphadenopathy is
      rather unusual, often a concomitant lymphadenopathy is present. A secondary
      infiltration of an organ due to widespread lymphoma,hematogenous spread or
      relapse occurs more frequently. On the other hand, in Hodgkin's lymphoma, except
      spleen and liver other organs are only rarely affected. Mostly it occurs by
      direct invasion from adjacent pathological lymph nodes.Frequency, morphology at
      and problems of imaging of extranodal lymphoma are presented.

PMID- 12486552
TI  - [Musculoskeletal lymphomas].
AB  - Primary lymphomas of bone or skeletal muscle are rare entities. The most frequent
      among these diseases are primary non-Hodgkin's lymphomas of bone. They account
      for 3-5% of all bone tumors and 5% of all primary extranodal non-Hodgkin's
      lymphomas. Primary manifestations of Hodgkin's disease in bone or skeletal muscle
      are rarities. Primary non-Hodgkin's lymphomas of skeletal muscle are rarities as
      well. Primary non-Hodgkin's lymphomas of bone can be found in any patient age. A
      preference exists for the 3.-6. decade of life. The radiographic appearance of
      these entities resembles other aggressive bone tumors. Their differential
      diagnosis includes -- depending on the patient's age -- Ewing's sarcoma,malignant
      fibrous histiocytoma,metastases of small cell tumors and osteomyelitis.Further
      differential diagnoses are the peripheral primitive neuroectodermal tumor (PNET),
      osteosarcoma, eosinophilic granuloma and fibrosarcoma. Treatment of primary non
      Hodgkin's lymphomas uses combinations of chemotherapy and radiation therapy.
      Operative treatment is reserved for the treatment of complications. The prognosis
      of primary non-Hodgkin's lymphomas is reflected by 10-year-survival-rates without
      recurrence of more than 80% in unifocal manifestations.

PMID- 12486553
TI  - [Relevance of magnetic resonance imaging for the staging and follow up of lymph
      node pathologies in adults with primary malignant lymphomas].
AB  - Lymph node histology and staging with cross sectional imaging remains basis for
      the treatment planning in primary malignant lymphoma. Contrast enhanced computed
      tomography is considered to be gold standard. However, MRI is equally able to
      provide staging and follow up in the same quality as helical CT, as several
      studies and clinical experience show. MRI is considered as the superior imaging
      modality for extranodal lymphoma. Advantages of MRI are that it works without
      ionizing radiation and contrast media;however, MRI is more expensive and time
      consuming. However, both imaging modalities are limited by the fact that the
      differentiation of affected and non affected lymph nodes is based on size only.
      Also the results of recent clinical studies with USPIOs (SINEREM((R):)) for
      intravenous MR lymphography in primary malignant lymphoma do not look promising.
      Despite these disadvantages of MRI, for young patients with malignant lymphoma
      radiation protection should be taken into account because of frequent imaging in
      staging and follow up.

PMID- 12486554
TI  - [Valence of F-18-FDG-PET in the diagnosis of malignant lymphoma].
AB  - PET enables tomographic imaging and quantification of molecular metabolism with
      high temporal and spatial resolution. For routine clinical questions in oncology
      F-18-labeled fluorodeoxyglucose is the tracer of choice. In malignant lymphoma
      staging, response control and follow-up studies are valid indications. The
      initial glucose-uptake and especially the response of metabolism to therapy are
      in correlation with the outcome of the disease. Complementary to conventional
      staging PET is able to detect further lymphnode manifestation or extranodal
      involvement that can result in up-staging. Down-staging is less frequent. In
      follow-up studies PET is valuable, to assess therapy response, to differentiate
      viability of lymphoma from fibrous remnants at end of therapy and to detect
      relapse at an early stadium. In this context it proves to be superior to
      conventional tomographic imaging. In individual cases relevant therapeutic
      consequences arise from the metabolic PET-informations. Whether in future PET
      will be able to partially replace conventional imaging and whether it withstands
      to cost/effectiveness analysis requires additional prospective studies.

PMID- 12486555
TI  - [Value of CT-guided biopsy in malignant lymphoma].
AB  - Management of diagnosing malignant lymphomas has changed with development of CT
      guided techniques and reliable biopsy tools. Pathologists can use representative
      tissue samples for sub classification in more than 90%. Evaluation of residual
      lymphoma or relapse can be nearly as effective. Therefore percutaneous biopsy can
      be considered as primary diagnostic tool in the absence of peripheral
      lymphadenopathy. CT-guided biopsies can be performed on an outpatient basis under
      conscious sedation considering contraindications as well as regional
      complications. Acceptance of percutaneous biopsy by the pathologist and
      oncologist is based on diagnostic effectiveness that is significantly improved if
      more than 3 dagger solid tissue samples are taken. This article reviews the value
      of CT-guided biopsy in comparison to surgical procedures in patients with
      malignant lymphoma. Essential aspects that lead to a diagnostic percutaneous
      biopsy are discussed on grounds of the current literature.

PMID- 12486562
TI  - [Vascular vertigo syndromes].
AB  - Ischemia,hemorrhages, and other vascular disorders can result in various central
      or peripheral vestibular syndromes with vertigo, oculomotor/balance disturbances,
      and nausea. The vascular vertigo syndromes listed in Table 1 can however be
      brought about by other causes such as demyelitizing focuses in multiple sclerosis
      or space-occupying lesions, so that not only localization of the damaged
      structure but also the various etiologies are decisive for the choice of therapy.
      Occasionally, combined functional disturbances of the peripheral and central
      vestibular system appear, such as an infarction of the inferior anterior
      cerebellar artery, which supplies the labyrinth and parts of the brainstem and
      cerebellum. In rare cases, a central lesion can have the same signs as a
      peripheral-vertibular disturbance: a lacunar infarct at the root entry zone of
      the eighth nerve can mimic a unilateral partial loss of labyrinth function as it
      occurs in vestibular neuritis, thus named "pseudoneuritis". Differential
      diagnosis between vestibular migraine, vestibular paroxysmia, transient ischemic
      brainstem attacks, and Meniere's disease is sometimes so difficult that only
      trial therapies such as prophylaxis with beta blockers, carbamazepine,
      thrombocyte aggregation inhibitors, antiplatelet drugs, or betahistin can clarify
      the issue.

PMID- 12486563
TI  - [Neuropsychological disorders in amyotrophic lateral sclerosis].
AB  - Amyotrophic lateral sclerosis (ALS) has traditionally been assumed to be a purely
      motor disturbance. It is now recognized that 2-5% of patients with ALS develop
      frontotemporal dementia. Additionally, neuropsychological analysis and functional
      imaging suggest that a proportion of patients with classical ALS also have
      neuropsychological impairment. On postmortem examination, ALS patients classified
      as not demented showed atrophy of the frontotemporal cortex. Conversely, in
      patients with frontotemporal dementia without known motor impairment, atrophy of
      spinal and bulbar neurons were found on postmortem examination. It is still not
      known whether patients with ALS and neuropsychological impairment form a distinct
      subgroup or if they are part of a continuous spectrum that runs from pure motor
      impairment to pure neuropsychological impairment.

PMID- 12486564
TI  - [Multifocal motor neuropathy: diagnosis and differential diagnosis].
AB  - Multifocal motor neuropathy (MMN) is an acquired immune mediated motor neuropathy
      with characteristic clinical and neurographic features.Clinically, MMN is
      characterized by progressive, predominantly distal and asymmetrical limb
      weakness. Neurographic recordings demonstrate features of multifocal
      demyelination with or without conduction block. Sensory nerves are not affected.
      Due to strict diagnostic criteria,MMN may be underdiagnosed in patients with
      motor neuropathies. Since intravenous immunglobulins are an efficient therapy for
      MMN,clinical and electrophysiological differentiation from other neuromuscular
      disorders is mandatory to prevent progressive impairment of motor function. We
      present a patient with MMN and review the clinical, electrophysiological, and
      histological features. In addition,pathogenesis, differential diagnosis and
      treatment of MMN are discussed.

PMID- 12486565
TI  - [Cerebrotendinous xanthomatosis, a treatable metabolic disorder].
AB  - Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of
      bile acid synthesis which can be clinically diagnosed and specifically treated.
      It is an underdiagnosed disorder worldwide.Here,we describe two women who were
      diagnosed with CTX during their forties after symptoms had already developed 15
      years earlier. Both patients showed gait ataxia, spastic paraparesis,
      polyneuropathy, bilateral premature cataracts, tendon xanthomas, and cognitive
      deficits. One of the patients had also chronic diarrhea. The deficiency of the
      mitochondrial enzyme sterol 27-hydroxylase results in a virtual absence of
      chenodeoxycholic acid. This leads to excessive production of cholestanol and
      cholesterol and accumulation of these sterols in many tissues, especially the eye
      lens, central nervous system,and tendons. The determination of a high cholestanol
      serum level allows the diagnosis,which can be confirmed through genetic analysis.
      Early diagnosis of CTX is important, since an effective therapy is available.
      Long-term therapy with chenodeoxycholic acid is effective for CTX, mainly in
      prevention of further deterioration.

PMID- 12486566
TI  - [Pattern of paralysis and reconstructive operations after traumatic brachial
      plexus lesions].
AB  - The aim of this study was to evaluate persistent patterns of paralysis after
      traumatic brachial plexus lesions. As a result, consecutive reconstructive
      operations according to our differential therapy concept are presented. Between
      04/1994 and 12/2000 in 104 patients with brachial plexus palsy, the grade of
      muscle power of the affected upper extremities was evaluated prospectively. The
      neuromuscular patterns of defect showed, in most cases, insufficient muscle power
      grades of 0-2 for the deltoid muscle (90%), supraspinatus muscle (82%),
      infraspinatus muscle (93%), elbow flexors (67% to 77%), hand and finger extensors
      (69% to 71%), and the abductor and extensors of the thumb (67% to 70%). In
      corresponding frequency, the following operations were performed between 04/1994
      and 06/2002: shoulder arthrodesis (n 26), trapezius transfer (n 80), rotation
      osteotomy of humerus (n 10), triceps to biceps transposition (n 11),
      transposition of forearm flexors or extensors/Steindler operation (n 12),
      latissimus transfer (n 7), pectoralis transfer (n 1), teres major transfer (n 1),
      transposition of forearm flexors to the tendons of extensor digitorum (n 19) and
      of the extensor pollicis longus (n 9), and wrist arthrodesis (n 5). On
      malfunction of muscles following brachial plexus lesions, taking into account the
      individual neuromuscular defect, passive joint function, and bony deformities,
      different procedures such as muscle transposition, arthrodesis, and corrective
      osteotomy can be performed to improve function of the upper extremity.

PMID- 12486567
TI  - [HIV-associated cerebral toxoplasmosis -- review and retrospective analysis of 36
      patients].
AB  - Highly active antiretroviral therapy (HAART) has resulted in a reduction of
      morbidity and mortality in HIV-associated cerebral opportunistic infection.
      Before HAART, up to 50% of all HIV-infected patients in Europe developed cerebral
      toxoplasmosis, an encephalitis caused by reactivation of Toxoplasma gondii
      infection. Although potent therapeutical options exist, the prognosis is still
      poor. We describe the course of 36 AIDS patients with cerebral toxoplasmosis and
      present a review of clinical signs, diagnosis, therapy, and survival times. The
      main criteria for differential diagnosis from other secondary neuromanifestations
      such as primary CNS lymphoma, progressive multifocal leukencephalopathy,
      abscesses, and ischemic infarctions are described. Indications and problems of
      stereotactic biopsy are discussed.

PMID- 12486568
TI  - [Treatment of hip adductor spasticity with botulinum toxin type B].
AB  - For the treatment of focal spasticity using botulinum toxin, only studies using
      type A have been published. Botulinum toxin type B (Neurobloc) is registered for
      cervical dystonia, but there is increasing interest in ist effectiveness for
      treating other diseases. Four patients, each with seriously disabling hip
      adductor spasticity of different origins, were treated with botulinum toxin type
      B following the failure of other therapeutic options. Total doses of 10,000 IU to
      22,000 IU were injected bilaterally into the hip adductor muscles. A reduction in
      muscle tone or painful spasms was observed in all patients within 2 weeks,
      leading to an improvement in gait and increased ease of nursing care. Therefore,
      botulinum toxin type B may be a more cost-effective treatment for hip adductor
      spasticity than botulinum toxin type A.

PMID- 12486569
TI  - [Myxedema coma as a rare differential diagnosis of severe consciousness
      disturbance].
AB  - Myxedema coma is a rare and life-threatening complication of untreated
      hypothyroidism. Therefore, it must be part of the differential diagnosis in
      comatose patients. We report one patient who presented with CO(2)
      narcosis,hypothermia, bradycardia,hyporeflexia, tetraparesis, ascitis, pleural
      effusions, and heart insufficiency. Examination of the CSF, cranial CT, MRI, and
      MR angiography were normal. In suspicion of myxedema coma,the patient was treated
      with high dose L-thyroxine and hydrocortisone for preventing secondary adrenal
      insufficiency. A fast clinical recovery, decreased T4 (7.2 ng/l) and T3 (0.93
      ng/l), and increased TSH (20.19 mU/l) together with the following anamnesis of
      radio iodine therapy and insufficient thyroxine intake confirmed the diagnosis.
      In conclusion, treatment of the myxedema coma must be started as soon as the
      laboratory results are confirmatory, since its course depends on the time of
      initiation of treatment.

PMID- 12486570
TI  - [Localized invasive intracranial aspergillosis with multiple cranial nerve
      failure -- case report and review of the literature].
AB  - Contrary to the more frequent hematogenously spread cerebral aspergillosis,
      localized invasive intracranial aspergillosis is a fungal infection that can also
      occur in patients who are not severely immunosuppressed. This illness can be
      effectively treated in some of these patients by early and rigorous therapy.
      Localized invasion of the fungus, generally from one of the nasal sinuses, causes
      intracranial growth mainly along the base of the skull and larger vessels,where
      fibrous, granulomatous tissue develops. This generally leads to damage of the
      cranial nerves (primarily I-VI) as well as localized pain syndromes. We report on
      the clinical course documented by MRI of a patient with localized invasive
      intracranial aspergillosis who had multiple failure of cranial nerves following
      surgery for an aspergilloma of the maxillary sinus. Clinical course, imaging
      findings, and treatment of the illness are discussed with a review of the
      relevant literature.

PMID- 12486571
TI  - [Problems of differential diagnosis in tick-borne encephalitis-induced
      polyradiculitis].
AB  - In about 10% of cases, tick-borne encephalitis (TBE) presents with additional
      myeloradiculitic features mimicking acute poliomyelitis, which can rarely appear
      as the sole symptom. We report on a 59-year-old man infected with TBE in
      Thuringia,Germany, who developed polyradiculitis with rapidly progressive,
      predominantly proximal tetraparesis and respiratory failure. We discuss the
      differential diagnosis and the epidemiological relevance in conjunction with a
      second typical case of TBE acquired in the same region and time period.

PMID- 12486572
TI  - [Von Hippel-Lindau syndrome with spinal, cerebellar, and retinal hemangioblastoma
      in identical twins].
AB  - We report about a case of a 22-year-old women who was admitted because of sudden
      and painless proximal paraparesis, sensory loss at distal L 1, and bladder
      dysfunction. In MRI, cystic lesions in the spinal cord were identified at C 1,C
      6,T 1,T 6,and T 11 as well as in the cerebellum.A tentative diagnosis of spinal
      hemangioblastomas was confirmed by spinal angiography and postoperative histology
      of the symptomatic tumor at T11.Furthermore, retinal hemangioblastomas were
      detected by fluorescence angiography and treated with laser surgery. Based on the
      clinical findings,we assumed the diagnosis of von Hippel-Lindau syndrome
      (vHL).Postoperatively, the paraparesis and sensory deficit improved, but the
      bladder dysfunction persisted. The patient's identical twin was screened for
      hemangioblastomas, too, and spinal, retinal, and one cerebellar tumor with a
      nearly identical location pattern were found. There was no evidence for
      pancreatic, adrenal, or renal involvement in both twins. The twins were
      investigated for inactivating mechanisms of the vHL germline mutations using
      single-strand conformational polymorphism (SSCP) and Southern blotting, but none
      of the known germline mutations were identified. Because the family history is
      devoid of vHL disease, spontaneous mutation might be causal for the syndrome in
      our patients.

PMID- 12486573
TI  - [Intervention project on cerebrovascular diseases and dementia in the Ebersberg
      district (INVADE): rationale and design].
AB  - The aim of INVADE (Intervention project on cerebrovascular diseases and dementia
      in the district of Ebersberg) is to analyse the effect of risk factor evaluation
      and modification (arterial hypertension, dyslipoproteinaemia, diabetes
      mellitus,hyperhomocysteinaemie, smoking, adipositas, alcohol abuse, lack of
      movement and depression) on the incidence of stroke and dementia in a population
      based sample. Stroke represents the third-common cause of death in the
      industrialized countries and is together with dementia one of the main causes for
      dependency in the activities of daily living. The project was performed in an
      area near to Munich, the district of Ebersberg. Risk factors were evaluated and
      if necessary modified by means of the primary care concept. INVADE was performed
      in cooperation with the health insurance company AOK and most of the general
      practitioners (n=65) of the district. All inhabitants of the district born 1946
      and earlier who were also member of the AOK (10548 persons) are able to
      participate.

PMID- 12486574
TI  - [Injury prevention in the elderly population].
AB  - Injuries in the elderly population have more considerable consequences (more
      difficult treatment, higher costs,worse outcome) than in the younger population.
      Therefore, the prevention is especially important. The majority of the injuries
      are caused by traffic accidents and falls. TRAFFIC ACCIDENTS: An analysis of the
      current injury situation in elderly road users (65 years and older) involved in
      road traffic accidents was intended to allow conclusions regarding future
      prophylaxis. FALLS: Falls are mostly caused by numerous factors. The most
      important predictors for falls are dementia,Parkinson-Syndrome and neurologic
      deficits after cerebrovascular insults. The most important symptoms, that
      indicate an increased risk for fall are gait abnormalities, balance lack and
      underweight. The most important anamnestic indications are more than one falls in
      the recent 90 days, need for assistance in daily living and prevailing
      medication. Another important factor is the residential setting (lighting,
      stairs, floor conditions,bath installations). The most affective protective
      interventions involve multiple factors. The incidence of falls could be reduced
      by 30%. The hip protector is an effective protection against proximal femur
      fractures. which is the most frequent fracture in the elderly population that
      requires treatment as an inpatient. Injury prevention in the elderly population
      is an interdisciplinary task as for example shown by the successful fall clinics
      in the anglo-american area.

PMID- 12486575
TI  - [The sublabral foramen. Congenital or an acquired variance?].
AB  - The sublabral foramen is considered to be a clinically asymptomatic, isolated
      variant of the anterior-superior capsulo-labral-complex. It may be observed
      during shoulder arthroscopy and may implicate problems in differential diagnosis
      of traumatic lesions. In an anatomic study on 89 macroscopically healthy shoulder
      specimens the age distribution and the incidence in relation to the varying shape
      of the glenoid as feasible factors of influence for a sublabral foramen (SF) were
      analyzed in order to elucidate the unknown pathogenesis of SF. In addition
      histologic sections of three SF samples were obtained. Mean age of the specimens
      with a sublabral foramen [n=20; 69 (37-84) years] was significantly higher
      (p=0.04) compared to samples without a sublabral foramen [n=69; 59 (18-94)
      years]. An increased incidence of a sublabral foramen in relation to a distinct
      shape of the glenoid could not be established although a prevalence of a glenoid
      with anterior notch was observed. The results indicate an age-related development
      of the sublabral foramen,thus in younger patients with an anterior-superior
      capsulolabral displacement local signs of trauma and involvement of the biceps
      anchor should be controlled before definitive diagnosis.

PMID- 12486576
TI  - [Mobility of unstable fractures of the odontoid during helmet removal. A
      biomechanical study].
AB  - In severe motorcyclist accidents unstable injuries of the cervical spine can
      usually not be excluded before an X-ray has been taken in the hospital. Despite
      this the helmet has to be taken off at the place of the accident in order to
      provide adequate treatment and airway management of the injured driver. There are
      no data in the current literature showing what happens to unstable lesions of the
      cervical spine during helmet removal. An experimental unstable lesion of the
      cervical spine was created by an osteotomy of the odontoid in 10 fresh frozen
      cadavers with intact soft tissues. All motions occurring in the segments C1-2 and
      C2-3 during helmet removal were recorded by fluoroscopy. The average motion in
      the unstable segment C1-2 was 23.7 degrees during a full range of extension
      flexion movement of the cervical spine without any signs of dislocation of the
      segment. After application of the helmet there was one case of dislocation of C1
      2 in neutral supine position already, and two further cases of dislocations
      during helmet removal. The average motion of C1-2 recorded during helmet removal
      was 19.0 degrees (2-25 degrees ), median 18.0 degrees. In order to avoid fracture
      dislocations and motion in the unstable upper cervical spine the helmet should
      better be cut in pieces at the place of the accident. There is a need for
      discussions with helmet producers to develop a new generation of helmets that can
      be removed easily without manipulating the head.

PMID- 12486577
TI  - [Technical defects of tourniquet manometers].
AB  - The use of a tourniquet causes in 0.013% to 1.15% complications (e.g. delayed
      wound healing, increased rate of infections, thrombosis, pulmonary
      embolisms,rhabdomyolysis, and compartment syndromes). The rate of these
      complications depends on the applied pressure, the duration and the cuff design.
      Also a technical defect of the pressure gauge can lead to complications. A
      patient with a peroneal palsy after the use of a tourniquet was referred to the
      Department for Trauma Surgery of the Medical School of the University of Vienna
      for medical evidence. As there were no reports in the literature about the
      occurrence rate of technical defects of tourniquet manometers, we checked all
      tourniquet pressure gauges used at our clinic. Six from eleven gauges were defect
      and had to be replaced. To minimize the risk for our patients we recommend to
      check the calibration of the pressure gauges periodically. With regard to the
      used pressure rate and duration only different recommendations can be found in
      literature.

PMID- 12486578
TI  - [Retrograde intramedullary nailing of femoral shaft fractures. A prospective
      study].
AB  - PURPOSE OF THE STUDY: Antegrade intramedullary nailing is seen as a most
      effective method in the management of femoral fractures. However, complications
      may arise due to the surgical approach.Can these disadvantages be avoided by
      using a retrograde approach? MATERIAL AND METHODS: In a prospective study 70
      femoral fractures in 62 patients were stabilised using a long intramedullary nail
      by a retrograde approach. RESULTS: We were able to re-examine 50 patients (57
      fractures) 13,3 (3-36) months after the operation. Apart from one non-union by
      infection, all fractures healed in time. Flexion of the knee joint was within a
      normal ROM in 81% of shaft fractures 12 months or more after the operation, as
      was the case in 44% of distal fractures. A inhibition of extension was not found
      in any patient. Two patients had a femoral shortening of up to one centimeter. We
      observed no rotational malalignment of more than 5 degrees. The clinical results
      were excellent in 89% of shaft fractures, and in 50% of supra-/diacondylar
      fractures. In 18 cases a nail removal was already performed, thereby allowing an
      arthroscopic follow-up inspection of the knee joint. No knee pathology due to
      nailing was found in either case. CONCLUSION: Our results show the advantages of
      retrograde intramedullary nailing in comparison to the antegrade method.

PMID- 12486579
TI  - [Functional bracing after operative treatment of metacarpal fractures].
AB  - Metacarpal fractures are frequently immobilized for several weeks in forearm
      plaster cast, even after operative stabilisation. The purpose of this study was
      to assess the results after early functional treatment using metacarpal braces.
      87 patients with 105 metacarpal fractures were included in a prospective study
      from February 1997 until November 2000. The AO-classification of the fractures
      was assessed for all patients: n=33 A1,n=9 A2,n=3 A3, n=27 B1,n=6 B2,n=7 B3,n=10
      C1,n=7 C2, n=3 C3.Exclusion criteria were tendon or nerve injuries,pathological
      fractures (tumor or metabolic),additional digital fractures of the same ray,and a
      patients age of less then 18 years. All fractures were treated operatively. 73
      patients (84%) were recruited for follow up after an average period of nine
      months. Average grip strength reached 96% (Jamar II) for the power grip, 97% for
      the three finger and 98% for the pinch grip compared to the contra-lateral side
      in the group where the dominant hand was affected. It was 88% for the power grip,
      91% for the three finger grip and 94% for the pinch grip after injury of the non
      dominant hand. The mean postoperative pain score on the visual analog scale was
      0.2 for resting conditions, 0.8 for motion and 2.2 under stress.A decreased total
      range of motion was observed in 15 of 73 patients (21%). The average DASH score
      reached 6.5 points. Physical therapy was required for an average of 6.7 weeks.
      Only 41% of the patients with early functional treatment required further
      physical therapy after removal of the brace. The metacarpal brace used in this
      series protects from direct trauma,and provides a high patients comfort.It has no
      disadvantages considering fracture retention compared to conventional plaster
      casts or splints. The need for physical therapy is reduced after functional
      fracture bracing.Thus, the metacarpal brace has proven to be a suitable tool for
      early functional treatment after operative stabilisation of metacarpal fractures.

PMID- 12486580
TI  - [Pilon tibial fractures].

PMID- 12486581
TI  - [Palmar lunate dislocation].
AB  - Palmar lunate dislocation as the end stage of a perilunate dislocation is a very
      uncommon injury. Having treated 19,534 hospitalized patients between 1 January
      1986 and 1 October 2001 the diagnosis was recorded in four male trauma patients
      (33, 36, 37 and 62 years old). Among the operatively treated carpal dislocations
      and carpal fracture dislocations those of the lunate were seen in five per cent.
      The dislocation was caused in by an acute hyperextension injury resulting of
      falls from heights in three cases, and of a motorcycle accident in a further
      case. In two of these cases a complete palmar lunate dislocation was analysed
      that were produced by fall from seven meters heights of a young craftsman and by
      accident of a motorcyclist. First using a longitudinal palmar approach in both
      cases a revision of the hemorrhagic carpal canal was performed urgently, the
      largely denuded lunate was reduced and the repair of identified ligamentous
      structures was performed by means of sutures respectively suture anchors.
      Reduction was stabilized with Kirschner wires. Afterwards performed computed
      tomography identified the result of reduction and associated defects (subluxation
      distal radioulnar joint). In one patient a soft tissue infection prevented the
      dorsal ligamentous repair. In spite of a consequent after-treatment and a good
      functional result a scapho-lunate dissociation was proved. An avascular defect of
      the lunate could be excluded by magnetic resonance imaging. In case of a
      secondary performed dorsal repair a persisting carpal stabilization with a
      satisfactory functional result could achieved. At second hand an advanced carpal
      collapse was proved. CONCLUSIONS: If reduction cannot be achieved by closed
      manipulation or a loss of reduction is shown, open reduction is indicated first
      by a palmar approach. An additional dorsal ligamentous repair seems to be
      necessary. Transfixation by Kirschner wires and suture anchors stabilize the
      restored anatomic relationships. Wrist immobilization in a cast for at least
      eight weeks is recommended. Although ligamentous insufficiency, osteoarthrosis
      and avascular necrosis are often proved, functional results are satisfactory.

PMID- 12486582
TI  - [Multiple enchondromatosis: Ollier's disease].
AB  - In contrast to solitary enchondroma,patients with multiple enchondromatosis of
      bone (Ollier's disease) get affected in childhood by bone swelling and growth
      retardation. In adults, the main problem is the risk of malign transformation up
      to 40%.Pain, increasing local tumor and thinning of the corticalis are the
      typical clinical and radiological signs of transformation to a low grade
      chondrosarcoma. There is no need for a regular radiological screening. If a
      malign transformation occurs,marginal or wide resection of the lesion should be
      performed.

PMID- 12486583
TI  - [Skin burns under application of electro-surgical devices: aspects of liability
      and medicine].
AB  - Under established jurisdiction,burn damage to the skin in connection with the use
      of coagulating current is not regarded as unavoidable. On the contrary, a breach
      of duty by the surgeon will be assumed.He is responsible for acquainting himself
      with the techniques and the risks of the high-frequency surgical devices he is
      using.He has to prevent injuries on the basis of controllable risks, even those
      which only appear as a result of cooperation with other specialist. The
      evaluation of judicial decisions, the literature, damage reports and expert
      opinions confirms that most injuries could have been avoided by compliance with
      the recommended precautions.

PMID- 12486584
TI  - [Analgesia during labour: from taboo to evidence-based medicine].
AB  - Peripartum care of parturients has contributed a great deal to the development of
      modern anaesthesia during the past 150 years. The introduction of general and
      regional anaesthesia provided new options of relieving pain during delivery and
      preventing suffering. However,provision of effective labor analgesia gave and
      still gives rise to controversy as to whether interfering with natural events
      such as delivery was justifiable on a religious,moral or ideological level. A new
      era of obstetric pain relief was initiated when a study design was devised to
      define the Minimum Local Analgesic Concentration (MLAC) needed for epidural
      analgesia. Using the MLAC model as a scientifically based pharmacodynamic measure
      of analgesia, empirically developed "recipes" can be compared and validated. The
      importance of this clinical model will be put into a pharmacological context
      including issues such as the up-down sequential allocation technique, dose
      response curves and differential nerve blockade.

PMID- 12486585
TI  - [Recovery from anaesthesia and incidence and intensity of postoperative nausea
      and vomiting following a total intravenous anaesthesia (TIVA) with S-(+)
      ketamine/propofol compared to alfentanil/propofol].
AB  - BACKGROUND: Opioids contribute to postoperative nausea and vomiting (PONV). An
      intraoperative analgesia with S-(+)-ketamine will make opioid administration
      dispensable and may reduce postoperative analgesic requirements. The aim of the
      study was to record the incidence and intensity of PONV following a total
      intravenous anesthesia (TIVA) with S-(+)-ketamine/propofol (K/P) or
      alfentanil/propofol (A/P) as well as recovery from anaesthesia. PATIENTS AND
      METHODS: A total of 145 patients received a TIVA with K/P or A/P. Recovery
      time,PONV, intensity of pain and overall acceptance of the delivered anaesthesia
      were recorded. RESULTS: Recovery times were prolonged in the K/P group. Both
      groups had a comparable incidence of PONV (26% and 22% for K/P vs A/P,
      respectively), the intensity was low in both groups with a VAS of <6/100 mm at
      all times. The intensity of postoperative pain and analgesic requirement did not
      differ. Overall acceptance of the delivered anaesthesia was lower in the K/P
      group. Unpleasant dreams were not more common in the K/P group. CONCLUSIONS: A
      TIVA with K/P did not reduce PONV when compared to A/P, but prolonged recovery.

PMID- 12486586
TI  - [Narcotrend EEG monitoring during total intravenous anaesthesia in 4.630
      patients].
AB  - INTRODUCTION: The Narcotrend is a new EEG monitor designed to measure the
      hypnotic component of anaesthesia; however, a major clinical evaluation is still
      missing. This prospective multicentre study was designed to investigate the
      feasibility of Narcotrend monitoring in a large number of patients under
      different clinical conditions and to define its impact on recovery times after
      propofol-based total intravenous anaesthesia. METHODS: After legal authority
      approval and patients'informed consent had been obtained, total intravenous
      anaesthesia was induced and maintained with propofol and an opioid analgesic at
      the discretion of the attending anaesthesiologist. In the first 10-15 patients of
      each centre the anaesthesiologist was blinded to the Narcotrend recordings and
      propofol was dosed according to clinical needs. In the following patients
      propofol was infused at a rate sufficient to achieve a target Narcotrend stage of
      D or E. With termination of propofol infusion,recovery times were recorded and
      analysed for the patients with or without Narcotrend monitoring; in addition,
      recovery times were analysed depending on the Narcotrend stage at the moment of
      termination of propofol infusion. RESULTS: In total, 4,630 adult patients were
      studied at 46 institutions, 521 without and 4,109 with Narcotrend monitoring.
      Demographic data and duration of anaesthesia were comparable. Emergence from
      anaesthesia was significantly shorter in Narcotrend monitored patients,
      e.g.opening eyes after 9.8+/-5.9 (mean+/-SD) vs.11.8+/-7.1 min. In
      addition,awakening was significantly more rapid when the propofol infusion was
      stopped at a lower level of hypnosis as indicated by Narcotrend monitoring,
      e.g.opening eyes after 7.1+/-4.5 min with stage C instead of 17.0+/-7.4 min with
      stage F. CONCLUSIONS: The EEG monitor Narcotrend can be used for adult patients
      of different ages and during various surgical procedures.Narcotrend monitoring
      facilitates a reduction of recovery times after propofol-based total intravenous
      anaesthesia,presumably by allowing for an individual titration of the propofol
      dosage. Moreover, it appears that the profile of recovery can be optimised when
      at the end of surgery,the propofol infusion is controlled to Narcotrend stage C
      instead of D, E, or F.

PMID- 12486587
TI  - [Transient neurologic symptoms after spinal anesthesia with 4% hyperbaric
      mepivacaine].
AB  - This is a case report of transient neurologic symptoms (TNS) after spinal
      anesthesia with 4% hyperbaric mepivacaine,which have not been reported before.
      The patient was a 44-year-old man with a meniscus lesion who received spinal
      anesthesia with 80 mg 4% mepivacaine while undergoing knee arthroscopy. A L3-L4
      mid-line approach was used with a 26-gauge Quincke needle and a 21-gauge
      introducer. The local anaesthetic was injected over approximately 30 s with the
      aperture of the Quincke needle in a cephalad direction. A transient pain syndrome
      was observed 4 h after spinal anesthesia, which included symmetric pain and/or
      dysesthesia in the buttocks and posterior thighs appearing 4 h after recovery
      from the spinal anesthesia and had a duration of 2 days. The patient stated that
      the pain radiated through the hips, buttocks, and posterior thighs and extended
      past the buttocks and lower legs. The pain was described as strong and
      aching,occasionally decreasing when walking around. It responded well to NSAID
      and resolved spontaneously within 3 days. No other neurologic symptoms or signs
      were noted.

PMID- 12486588
TI  - [Cesarian section and local anaesthesia: insufficient spread of spinal
      anaesthesia with hyperbaric bupivacaine 0.5%/5% glucose compared to hyperbaric
      bupivacaine 0.5%/8% glucose?].
AB  - In our hospital hyperbaric Carbostesin 0.5% (AstraZeneca) had been substituted by
      hyperbaric Bucain 0.5% (Curasan) and both drugs were believed to be identical in
      their actions.However, both local anaesthetics differ in the amount of glucose
      they contain. We report about three patients who underwent cesarian section under
      spinal anaesthesia. In two patients we observed an insufficient spread of spinal
      anaesthesia after administration of hyperbaric Bucain 0.5%. The third patient
      received the normally used combination of hyperbaric Carbostesin 0.5% and
      fentanyl and the subarachnoid block proceeded completely uneventfully. According
      to the literature the clinical efficacy of hyperbaric Carbostesin 0.5% and
      hyperbaric Bucain 0.5% should be identical and therefore a critical dilution of
      the Bucain should not have occurred because of the addition of fentanyl.

PMID- 12486589
TI  - [Nociceptin and the ORL1 receptor: pharmacology of a new opioid receptor].
AB  - Molecular biological investigations led to the discovery of the ORL1 receptor (
      opioid receptor like-1 receptor) and its endogenous ligand nociceptin. Although
      its sequence and structure are closely related to traditional opioid receptors,
      the ORL1 receptor shows low binding affinities for selective opioid agonists and
      antagonists. On the other hand, the ORL1 ligand nociceptin does not bind to the
      three traditional opioid receptors. The activation of the G protein-coupled ORL1
      receptor inhibits adenlylate cyclase activity, reduces the intracellular
      concentration of the second messenger cAMP and regulates ion channels. The
      supraspinal administration of nociceptin produces hyperalgesia. unlike opioids.
      Spinal intrathecal and peripheral administration of nociceptin causes
      hyperalgesia in low doses and analgesia in high doses. The physiological role and
      detailed mechanisms of these dose-dependent nociceptin effects in opposite
      directions are not yet known. In addition, nociceptin modulates other biological
      phenomena such as feeding, locomotion, gastrointestinal function,memory,
      cardiovascular function,immunity, renal function, anxiety,dependence and
      tolerance.Future research on the physiological and pathophysiological importance
      of the nociceptin/ORL1 receptor systems may provide a target for novel
      therapeutics.

PMID- 12486590
TI  - [Ultrasound in local anaesthesia. Part II: ultrasound-guided blockade of
      peripheral nerve channels].
AB  - Recent developments in blockade techniques are based on the possibilities offered
      by modern sonography. With high frequency linear probes, the smallest tissue
      structures, such as peripheral nerves, in areas close to the surface can be
      visualised. This is the prerequisite for ultrasound-guided blockade techniques
      which has now been established for available peripheral blockades. These
      techniques are basically far superior to all other assist methods of peripheral
      blockades, because they allow a success rate close to 100%, a short preparation
      time and a reduction in the use of local anaesthetic agents. Apart from these,
      one particularly important aspect is that they reduce the risks of local
      anaesthesia procedures by direct imaging of neighbouring anatomical structures.
      In this article the theoretical basis of ultrasound techniques and their
      practical use in local anaesthesia will be presented.

PMID- 12486591
TI  - [50th anniversary of the Swiss Society for Anesthesiology and Resuscitation].

PMID- 12486592
TI  - [The Nobel Prize 2002. Organ development and programmed cell death].

PMID- 12486593
TI  - [Spinal anesthesia: articaine, prilocaine, lidocaine?].

PMID- 12486595
TI  - Responses of chinchilla inferior colliculus neurons to amplitude-modulated tones
      with different envelopes.
AB  - Responses of single neurons in the inferior colliculus of the chinchilla to
      amplitude-modulated tones were obtained. In one condition, the modulating
      waveform was a low-frequency sinusoid (SAM tone). In the other, the modulator was
      a trapezoid with fixed parameters, used to create trains of brief tone bursts
      presented at various repetition rates (TRAM tone). Modulation frequency (or
      repetition rate) was varied over the range from 10 to 200 Hz. Many individual
      neurons exhibited strong selectivity for modulator type. Neurons with pauser
      discharge patterns to steady-state tones usually exhibited greater responsiveness
      to SAM tones than to TRAM. In contrast, neurons that responded transiently to
      steady-state tones usually exhibited greater responsiveness to TRAM tones than to
      SAM. Neurons with sustained responses to steady-state tones responded strongly to
      both types of modulated tones. The selectivity for modulator type suggests that
      transient neurons may play a different functional role in the representation of
      envelopes than do other types of neurons.

PMID- 12486594
TI  - Myosin-I isozymes in neonatal rodent auditory and vestibular epithelia.
AB  - Myosin isozymes are essential for hair cells, the sensory cells of the inner ear.
      Because a myosin-I subfamily member may mediate adaptation of mechanoelectrical
      transduction, we examined expression of all eight myosin-I isozymes in rodent
      auditory and vestibular epithelia. Using RT-PCR, we found prominent expression of
      three isozymes, Myo1b (also known as myosin-Ia or myr 1). Myo1c (myosin-Ib or myr
      2). and Myo1e (myr 3). By contrast, Myo1a (brush-border myosin-I), Myo1d (myosin
      lg or myr 4). Myo1f, Myo1g, and Myo1h were less readily amplified. Because
      sequence analysis demonstrated that the RT-PCR products encoded the appropriate
      isozymes, this represents the first demonstration of expression of all eight
      mouse myosin-I genes. Using immunocytochemistry with isozyme-selective
      antibodies, we found that Myo1b was located at apical surfaces of supporting
      cells that surround hair cells in auditory epithelia of postnatal rats. In
      vestibular epithelia, Myo1b was present in a ring within the apical pole of the
      hair cell. In both cases, expression was prominent only immediately after birth.
      Myo1e was found in hair cells of the auditory and vestibular epithelia; this
      isozyme was enriched in the cuticular plate, the actin meshwork that anchors the
      stereocilia. Myo1c was found in hair-cell stereocilia, concentrated towards their
      tips; we confirmed this localization by using adenovirus vectors to direct
      expression of a GFP-Myo1c tail fusion protein; this fusion protein localized to
      plasma membranes, often concentrating at stereociliary tips. Myo1c therefore
      remains the myosin isozyme best localized to carry out transducer adaptation.

PMID- 12486596
TI  - The effects of congenital deafness on auditory nerve synapses: Type I and Type II
      multipolar cells in the anteroventral cochlear nucleus of cats.
AB  - Sensory deprivation has been shown to exert detrimental effects on the structure
      and function of central sensory systems. Congenital deafness represents an
      extreme form of auditory deprivation, and in the adult white cat, synapses
      between auditory nerve endings and resident cells of the anteroventral cochlear
      nucleus exhibited abnormal structure. Endbulbs of Held were reduced in branching
      and displayed striking hypertrophy of their postsynaptic densities. So-called
      modified endbulbs showed no change in branching complexity but did exhibit
      hypertrophy of their postsynaptic densities. These differential pre- and
      postsynaptic effects prompted the question of how deafness might affect other
      primary endings and synapses. Thus, we studied type I and type II multipolar
      cells that receive bouton endings from auditory nerve fibers. Type I multipolar
      cells project to the contralateral inferior colliculus and have relatively few
      axosomatic endings; type II multipolar cells project to the contralateral
      cochlear nucleus and have many axosomatic endings. Compared with normal-hearing
      cats, bouton endings of congenitally deaf cats were smaller but there was no
      difference in synaptic vesicle density or size of postsynaptic densities. These
      data reveal that different classes of primary endings and second-order neurons
      exhibit different degrees of synaptic anomalies to deafness.

PMID- 12486597
TI  - Embryonic inner ear cells reaggregate into specific patterns in vitro.
AB  - The sensory epithelia of the mammalian inner ear consist of a highly precise
      pattern of sensory hair cells and supporting cells. The mechanisms regulating
      this patterning are only beginning to be determined. The present study describes
      a method for culturing dissociated embryonic inner ear cells and the resulting
      patterning that occurs in these cultures. The results indicate that developing
      inner ear cells aggregate into precise patterns on a two-dimensional substrate,
      suggesting that intrinsic patterning mechanisms remain active in vitro. Using
      antibodies and scanning electron microscopy to detect hair cells and nonsensory
      cells, it was determined that only a subset of aggregates contained sensory hair
      cells. The hair cells were organized into specific patterns and surrounded by
      supporting cells, similar to the in vivo pattern. Additionally, hair cells
      increased their immunoreactivity and number of stereocilia over time, suggesting
      that hair cells continue to mature in vitro. Thus, the study reveals that the
      cells of the developing inner ear provide the necessary signals that direct
      sensory hair cells and supporting cells to reassociate into very precise patterns
      in vitro and that these patterns are reminiscent of the patterning that occurs in
      vivo.

PMID- 12486599
TI  - Reduction in sharpness of frequency tuning but not endocochlear potential in
      aging and noise-exposed BALB/cJ mice.
AB  - Schuknecht proposed categories for human age-related hearing loss (ARHL) based
      upon whether the primary degeneration involves the organ of Corti (sensory ARHL),
      spiral ganglion cells (neural), stria vascularis (strial), or a combination of
      these (mixed). Genetically standardized mouse ARHL models can help validate
      Schuknecht's framework and clarify the underlying cellular processes. Much recent
      work has focused on the mouse Ahl locus, which promotes both ARHL and noise
      induced hearing loss. On the C57BL/6 inbred background, Ahl has been associated
      with degeneration of organ of Corti, afferent neurons, and stria
      vascularis/spiral ligament, suggesting that it promotes mixed
      (sensory/neural/strial) ARHL. Some cochlear degeneration in C57BL/6 mice could be
      caused by genes other than Ahl, however. The question of what constitutes Ahl
      related pathology can be addressed by comparing C57BL/6 mice with other strains
      that carry the same allele, including BALB/c substrains. We examined the effects
      of aging and broadband noise exposure in inbred BALB/cJ mice (1.5-13.0 mos) using
      measures of frequency tuning (compound action potential tuning curves) (CAPTCs),
      strial function (endocochlear potential recording, EP), and light microscopy.
      Aging and noise led to generally similar physiological and anatomical changes.
      Reductions in sensitivity and sharpness of frequency tuning were not consistently
      linked to hair cell loss, reduction in the EP, or changes in the lateral wall.
      Instead they appeared best explained by alterations in supporting cells in the
      basal half of the cochlear and in the spiral limbus in the apex. These results
      emphasize the importance of cell types other than hair cells in cochlear
      pathology. They also indicate that Ahl does not necessarily promote a strial form
      of ARHL.

PMID- 12486598
TI  - Changes in the three-dimensional angular vestibulo-ocular reflex following
      intratympanic gentamicin for Meniere's disease.
AB  - The 3-dimensional angular vestibulo-ocular reflexes (AVOR) elicited by rapid
      rotary head thrusts were studied in 17 subjects with unilateral Meniere's disease
      before and 2-10 weeks after treatment with intratympanic gentamicin and in 13
      subjects after surgical unilateral vestibular destruction (SUVD). Each head
      thrust was in the horizontal plane or in either diagonal plane of the vertical
      semicircular canals, so that each head thrust effectively stimulated only one
      pair of canals. The AVOR gains (eye velocity/head velocity during the 30 ms
      before peak head velocity) for the head thrusts exciting each individual canal
      were averaged and taken as a measure of the function of that canal. Prior to
      intratympanic gentamicin, gains for head thrusts that excited canals on the
      affected side were 0.91 +/- 0.20 (horizontal canal, HC), 0.78 +/- 0.20 (anterior
      canal, AC), and 0.83 +/- 0.10 (posterior canal, PC). The asymmetries between
      these gain values and those for head thrusts that excited the contralateral
      canals were <2%. In contrast, caloric asymmetries averaged 40% +/- 32%.
      Intratympanic gentamicin resulted in decreased gains attributable to each canal
      on the treated side: 0.40 +/- 0.12 (HC), 0.35 +/- 0.14 (AC), 0.31 +/- 0.14 (PC)
      (p <0.01). However, the gains attributable to contralateral canals dropped only
      slightly, resulting in marked asymmetries between gains for excitation of
      ipsilateral canals versus their contralateral mates: HC: 34% +/- 12%, AC: 24% +/-
      25%, and PC: 42% +/- 13%. There was no difference in the AVOR gain for excitation
      of the ipsilateral HC after gentamicin in patients who received a single
      intratympanic injection (0.39 +/- 0.11, n = 12) in comparison to those who
      received 2-3 injections (0.42 +/- 0.15, n = 5, p = 0.7). Gain decreases
      attributed to the gentamicin-treated HC and AC were not as severe as those
      observed after SUVD. This finding suggests that intratympanic gentamicin causes a
      partial vestibular lesion that may involve preservation of spontaneous discharge
      and/or rotational sensitivity of afferents.

PMID- 12486600
TI  - Organization of olivocochlear neurons in the cat studied with the retrograde
      tracer cholera toxin-B.
AB  - We employed cholera toxin-B (CTB), an efficient retrograde tracer, to examine
      olivocochlear (OC) neurons in the cat. Our primary goals were (1). to determine
      whether the cat has two types of lateral OC (LOC) neurons as is found in certain
      rodents and (2). to document the morphology, number, and caudorostral
      distribution of OC neurons, bilaterally. Adult cats received injections of CTB
      through the round window of the left cochlea, and, after 3-6 days, the brains
      were sectioned transversely and CTB was revealed immunocytochemically in every
      section. In three cats, OC neurons were mapped, counted differentially according
      to cell group, and the numbers of each plotted bilaterally from caudal to
      rostral. In one cat, measurements were made on labeled LOC and medial OC (MOC)
      neurons. The results indicate that LOC neurons can be divided into two groups
      based on their proximity to the lateral superior olive (LSO): a more populous
      group of small neurons that have intimate contact with the LSO, designated
      marginal-LOC neurons, and a less populous, morphologically heterogeneous group,
      lying more distantly from the LSO, designated para-LOC neurons. Para-LOC neurons
      lying dorsal and rostral to LSO were significantly larger than marginal-LOC. We
      hypothesize that the cat marginal-LOC neurons and most probably the larger para
      LOC neurons correspond to rodent intrinsic and shell LOC neurons, respectively,
      which have focal versus diffuse projections beneath the inner hair cells.
      Concerning MOC neurons, we confirm and extend previous observations on the
      clustering of these neurons near the rostral tip of the medial superior olivary
      nucleus and also show that MOC neurons differ in size according to cell group.
      Finally, we compare the present counts of OC neurons (mean total 1607, consisting
      of 1058 LOC neurons and 549 MOC neurons innervating one cochlea) and their
      proportional distribution ipsilaterally and contralaterally with those reported
      previously. Our estimate of the number of LOC neurons is somewhat higher than
      those previously obtained either by retrograde labeling with horseradish
      peroxidase or by counting unmyelinated axons in the olivocochlear bundle. In
      contrast, our estimate of the number of MOC neurons is very similar to those
      previously reported.

PMID- 12486601
TI  - Postnatal development of NR2A and NR2B mRNA expression in rat auditory cortex and
      thalamus.
AB  - Sensory cortex in the rat undergoes rapid postnatal development, especially
      following the onset of sensory function during so-called "critical periods." To
      investigate potential mechanisms in the auditory forebrain involving different
      NMDA receptor subunits, we have used in situ hybridization to determine
      expression patterns of NR2A and NR2B mRNA at postnatal days 4, 10, 13, 18, 25,
      and adult. In auditory cortex, NR2A mRNA expression is initially weak but
      increases rapidly over approximately 2 weeks. NR2B mRNA levels are initially high
      and remain high. For both subunits, expression tends to be highest in superficial
      layers of the cortex (except layer 1). Expression is weaker in the auditory
      thalamus (medial geniculate). Initially, NR2A mRNA expression is very low,
      whereas NR2B mRNA expression is moderate; both levels increase over approximately
      2 weeks. Among medial geniculate subdivisions, NR2A mRNA expression occurs
      preferentially in the medial division, whereas NR2B mRNA expression is strongest
      in the ventral division. For auditory cortex and thalamus, NR2A and NR2B mRNA
      expression peaks about 1 week after the onset of hearing before declining
      slightly into adulthood. The heterogeneous distribution of NMDAR subunit mRNA
      throughout development may play a role in auditory forebrain development and
      function.

PMID- 12486602
TI  - Genetics of susceptibility to leprosy.
AB  - The ancient disease of leprosy can cause severe disability and disfigurement and
      is still a major health concern in many parts of the world. Only a subset of
      those individuals exposed to the pathogen will go on to develop clinical disease
      and there is a broad clinical spectrum amongst leprosy sufferers. The outcome of
      infection is in part due to host genes that influence control of the initial
      infection and the host's immune response to that infection. Identification of the
      host genes that influence host susceptibility/resistance will enable a greater
      understanding of disease pathogenesis. In turn, this should facilitate
      development of more effective therapeutics and vaccines. So far at least a dozen
      genes have been implicated in leprosy susceptibility and a genome-wide linkage
      study has lead to the identification of at least one positional candidate. These
      findings are reviewed here.

PMID- 12486603
TI  - Association tests with systemic lupus erythematosus (SLE) of IL10 markers
      indicate a direct involvement of a CA repeat in the 5' regulatory region.
AB  - Many lines of evidence suggest that IL10 is a strong candidate gene for systemic
      lupus erythematosus (SLE) susceptibility. In our previously reported study an
      allele (IL10.G-140bp) of the microsatellite IL10.G located at position -1100 was
      significantly increased in Italian SLE patients in comparison with controls.
      Starting from this observation, we tested if sequence variations in the vicinity
      of IL10.G were more strongly associated with SLE. We performed a comprehensive
      association study including 26 SNPs (of which four were newly identified in the
      present study by DHPLC analysis) spanning 8.5 Kb of the 5' flanking and the
      transcribed region of the IL10 gene. The association study was performed by the
      DNA pool method on an extended panel of Italian patients (205) and controls
      (631). Haplotypic associations were studied by individual typing of seven
      selected markers surrounding IL10.G. Gene, genotype and haplotype frequencies
      were not significantly different in patients and controls. Thus the IL10.G
      microsatellite remains to date the only IL10 marker associated with SLE in our
      population. A meta-analysis of all published results indicates a possible direct
      role of the IL10.G repeat number in SLE susceptibility.

PMID- 12486604
TI  - A genome screen for linkage in Australian sibling-pairs with multiple sclerosis.
AB  - The role of genetic factors in determining susceptibility to multiple sclerosis
      is well established but, despite the global distribution of the disease,
      systematic efforts to locate susceptibility genes have concentrated exclusively
      on populations from the Northern Hemisphere. We performed a genome wide screen of
      linkage in the Australian population using a panel of 397 microsatellite markers
      in 54 affected sibling-pairs. Multipoint linkage analysis revealed four regions
      of suggestive linkage (on chromosomes 2p13, 4q26-28, 6q26 and Xp11) and 18
      additional regions of potential linkage (at 1q43-44, 3q13-24, 4q24, 4q31-34, 5q11
      13, 6q27, 7q33-35, 8p23-21, 9q21, 13q31-32, 16p13, 16p11, 16q23-24, 17p13, 18p11,
      20p12-11, Xp21-11 and Xq23-28). Our results contribute to the available data
      adding new provisional regions of linkage as well as increasing support for areas
      previously implicated in genetic susceptibility to multiple sclerosis.

PMID- 12486605
TI  - Linkage disequilibrium analysis of chromosome 12q14-15 in multiple sclerosis:
      delineation of a 118-kb interval around interferon-gamma (IFNG) that is involved
      in male versus female differential susceptibility.
AB  - We have recently reported the association of a polymorphic intronic CA-repeat in
      the interferon-gamma gene (IFNG) with gender bias in susceptibility to multiple
      sclerosis (MS) in a Sardinian population. This association could refer to a
      functional polymorphism within IFNG or could be due to linkage disequilibrium
      between the IFNG marker and a neighbouring susceptibility locus. Within the
      average reach of linkage disequilibrium, various other candidate genes are
      located. Among these the most striking ones are the genes coding for the
      cytokines interleukin-22 (IL-22) and interleukin-26 (IL-26) that constitute
      together with IFNG a cytokine cluster on chromosome 12q14. To determine more
      precisely the location of this gender-associated susceptibility locus, we have
      now performed a more extensive linkage disequilibrium screen of this region using
      nine additional microsatellite markers. This locus appeared to be confined to a
      118-kb interval that is bordered by the markers D12S313 and D12S2511, in which
      IFNG itself remains the main candidate gene. Haplotype analysis confirmed that
      this MS-associated locus protects males from developing MS according to a
      recessive or allele-dosage model. Our results indicate that the well-documented
      gender differences in susceptibility to MS are at least partially caused by
      genetic factors in the region surrounding IFNG.

PMID- 12486606
TI  - Association of HLA-A*3303-B*4403-DRB1*1302 haplotype, but not of TNFA promoter
      and NKp30 polymorphism, with postherpetic neuralgia (PHN) in the Japanese
      population.
AB  - Herpes zoster is a common disease caused by reactivation of the varicella zoster
      virus (VZV). In a small number of herpes zoster patients, pain persists beyond 4
      weeks or more after healing of vesicular eruptions; this condition is termed
      postherpetic neuralgia (PHN). Positive associations of human histocompatibility
      leukocyte antigens (HLA) class I antigens, A33 and B44, with PHN in the Japanese
      population have been reported. Our hypothesis is that susceptibility genes to PHN
      might exist in the HLA region and the study objective is to further examine
      possible associations of genes in HLA class I, II and III regions, HLA-A, -B, 
      DRB1, tumor necrosis factor alpha (TNFA) promoter, and a natural killer cell
      activating receptor, NKp30 polymorphisms with PHN. Although TNFA or NKp30 in the
      class III region had been considered as a candidate locus, we found no
      associations of TNFA promoter or NKp30 polymorphisms with PHN in this study. We
      demonstrated that HLA-A*3303, -B*4403 and -DRB1*1302 alleles were significantly
      associated with PHN (P = 0.0007 for A*3303, P = 0.001 for B*4403 and P = 0.001
      for DRB1*1302). The frequency of the HLA-A*3303-B*4403-DRB1*1302 haplotype was
      also significantly higher in the PHN patients than in the healthy controls (P =
      0.0039). Our results suggest that this haplotype might be related to the
      pathogenesis of PHN.

PMID- 12486607
TI  - TNF-alpha promoter single nucleotide polymorphisms are markers of human ancestry.
AB  - We present a map of single nucleotide polymorphisms (SNPs) in the human tumor
      necrosis factor (TNF)-alpha promoter based upon exploratory sequencing of 333
      human TNF-alpha gene promoters from individuals of distinct ancestral
      backgrounds. We detect 10 TNF-alpha promoter SNPs that occur with distinct
      frequencies in populations of different ancestry. Consistent with these findings,
      we show that two TNF-alpha SNPs, the -243 SNP and the -856 SNP, are the first SNP
      markers of a sub-Saharan African-derived extended haplotype and an Amerindian HLA
      haplotype, respectively. Comparisons of TNF-alpha promoter SNP allele frequencies
      can thus help elucidate variation of HLA haplotypes and their distribution among
      existing ethnic groups and shed light into the history of human populations.

PMID- 12486608
TI  - Studies on the association of Fc gamma receptor IIA, IIB, IIIA and IIIB
      polymorphisms with rheumatoid arthritis in the Japanese: evidence for a genetic
      interaction between HLA-DRB1 and FCGR3A.
AB  - We recently detected a new single nucleotide polymorphism of FcgammaRIIB gene,
      which alters an amino acid within the transmembrane domain from Ile to Thr
      (I232T), and its association with SLE in the Japanese. This study was performed
      to examine whether FCGR2B-I232T was associated with susceptibility to rheumatoid
      arthritis in the Japanese. At the same time, FCGR2A, 3A and 3B polymorphisms were
      also examined. Genotyping of FCGR2B-I232T, FCGR2A-H131R, FCGR3A-F176V and FCGR3B
      NA1/2 polymorphisms were performed using genomic DNA. Association with RA was
      analyzed in 382 Japanese patients with RA and 303 healthy individuals using a
      case-control approach. In addition, the same groups of patients and controls were
      genotyped for HLA-DRB1 to examine possible interaction with FCGR genes.
      Significantly different distribution of genotype, allele carrier and allele
      frequencies was not observed between patients with RA and healthy individuals in
      any of the four polymorphisms. When the subjects were stratified according to the
      carriage of HLA-DRB1 shared epitope (SE), significant increase of FCGR3A-176F/F
      genotype was observed in SE positive patients compared with SE positive healthy
      individuals (P=0.009, P(corr)=0.07). In conclusion, FCGR3A-176F/F genotype was
      considered to confer risk through genetic interaction with HLA-DRB1 SE.

PMID- 12486609
TI  - A polymorphism in the IL11 gene is associated with ulcerative colitis.
AB  - Inflammatory bowel diseases (IBD) are multifactorial disorders characterised by
      the host's inability to limit the inflammatory response to luminal antigens. The
      association of polymorphisms in the CARD15 gene with Crohn's disease (CD)
      demonstrates the relevance of activated transcription factor NF(kappa)B in
      mononuclear cells. Interleukin 11 (IL11) mediates anti-inflammatory effects and
      is able to downregulate LPS-induced NF(kappa)B activation. The IL11 gene is
      therefore a good candidate involved in genetic predisposition to IBD. To evaluate
      the role of the IL11 gene in IBD, two polymorphisms, including a dinucleotide
      repeat in the promoter region, have been genotyped in 222 patients with CD, 152
      patients with ulcerative colitis (UC) and 400 healthy controls. PCR-SSCP analysis
      of the coding region revealed a single polymorphism in exon 4 leading to an amino
      acid exchange (G335A; R112H), not significantly associated with either disease.
      Dinucleotide repeat frequencies of the IL11.A1 allele and of IL11.A1 homozygous
      individuals were significantly increased among the patients with UC (P < 0.002
      and (P < 0.003, respectively) but not with CD. Altered expression of IL11 appears
      to be involved in the genetic predisposition of UC.

PMID- 12486610
TI  - Erythrocyte CR1 expression level does not correlate with a HindIII restriction
      fragment length polymorphism in Africans; implications for studies on malaria
      susceptibility.
AB  - Complement receptor 1 (CR1) expression level on erythrocytes is genetically
      determined, and in Caucasian populations is linked to high (H) and low (L)
      expression alleles identified by a HindIII restriction fragment length
      polymorphism (RFLP). Erythrocyte CR1 may be an important factor in determining
      malaria susceptibility, as low expression of CR1 reduces the rosetting of
      uninfected erythrocytes with Plasmodium falciparum-infected cells, a process that
      contributes to malaria pathogenesis. Prior to studying CR1 expression and malaria
      susceptibility, we have investigated whether the quantity of erythrocyte CR1
      correlates with the H and L alleles in an African population. Mean erythrocyte
      CR1 in 149 Malian adults was 415 molecules per cell, which is comparable to
      Caucasian populations; however, there was no relationship between erythrocyte CR1
      level and genotype for the HindIII RFLP (mean CR1 per erythrocyte HH = 414, HL =
      419 and LL = 403, P > 0.1, Student's t-test). The conclusions of a previous study
      of erythrocyte CR1 expression level and malaria susceptibility in West Africa
      that was based on HindIII RFLP genotyping may therefore need to be re-evaluated.

PMID- 12486611
TI  - Genetic control of innate immune responses against cytomegalovirus: MCMV meets
      its match.

PMID- 12486612
TI  - ["Time of awakening" or "What is the significance of the competing risks in small
      cell bronchogenic carcinoma for our interdisciplinary therapy concepts"?].

PMID- 12486613
TI  - [Treating acute exacerbations of chronic bronchitis with N-acetylcysteine?].

PMID- 12486614
TI  - [Non-invasive ventilation as long-term treatment for respiratory insufficiency in
      severe COPD. Nothing is really proven].

PMID- 12486615
TI  - [Significance of pulmonary lymph node metastases in locally advanced non-small
      cell lung cancer].
AB  - BACKGROUND: The locally advanced (T3 - 4) non-small cell lung cancer with
      pulmonary lymph node metastases (N1) is a mixture of different subgroups of
      disease with varying pattern of tumor extension and long-term survival rates.
      PATIENTS AND METHODS: We retrospectively reviewed hospital records and follow-up
      data of 181 patients operated on between 1990 and 1995 with pathological stage
      IIIA-pT3N1 and IIIB-pT4N1. Median age was 62 years (range 34 - 80). RESULTS: The
      operative mortality was 3.7 %. The analysis was carried out on the 181 hospital
      survivors. The operative procedure was a pneumonectomy in 110 cases (60.8 %) and
      a lobectomy/bilobectomy in 71 (39.26 %). The pathological stage according to the
      UICC TNM-Classification of 1997 was T3N1 in 128 (70.7 %) and T4N1 in 53 (29.3 %).
      We observed a metastatic involvement of the hilar, interlobar and lobar lymph
      nodes in 44 (24.3 %), 17 (9.4 %), and 27 (14.9 %) patients, respectively, whereas
      a direct infiltration in 93 patients (51.4 %). The actuarial overall 3-, 5- and
      10-year survival rates for N1 hilar was 23 %, 13 % and 8 %, for N1 interlobar was
      18 %, 6 % and 0 %, for N1 lobar was 48 %, 37 % and 22 %, and for N1 direct was 32
      %, 27 % and 21 %, respectively. The involvement of hilar lymph nodes correlates
      with a worse prognosis (p =.0366). CONCLUSIONS: Metastases to the hilar lymph
      nodes in locally advanced NSCLC can be considered an initial N2-disease and
      should be treated correspondingly. Lymph node involvement by direct invasion is
      associated with a relatively more favourable prognosis for the patients.

PMID- 12486616
TI  - [Risk factors for pneumonia in patients with cardiovascular diseases].
AB  - A case-control-study was performed to identify patients at particularly high risk
      of community-acquired pneumonia and nosocomial pneumonia with a special focus on
      cardiovascular diseases as potential risk factors. Thirty-six consecutive
      hospitalized patients with cardiovascular diseases and pneumonia were matched
      with 36 controls also suffering from cardiovascular diseases but without
      pneumonia. From all cardiovascular diseases only heart failure proved to be an
      independent risk factor for pneumonia (OR 5.69, 95 % KI 1.69 - 19.04, p =
      0.0048). Both chronic (p = 0.009) and acute heart failure (p = 0.028) were
      associated with an increased risk of pneumonia. The risk of pneumonia was closely
      related to the degree of ventricular function impairment. Coronary heart disease,
      valvular disease, arrythmia, myocarditis, endocarditis and cardiomyopathy did not
      increase the risk for pneumonia unless accompanied by heart failure. Pulmonary
      (OR 9.24, 95 % KI 1.48 - 57.74, p = 0.00174) and renal diseases (OR 7.49, 95 % KI
      1.38 - 40.76, p = 0.0197) were validated as additional independent risk factors.
      A history of smoking was also associated with an increased risk of pneumonia (p =
      0,023). This study supports the hypothesis that heart failure resulting from
      cardiovascular disease and not cardiovascular disease itself mounts the risk for
      pneumonia.

PMID- 12486617
TI  - [Choristoma of the diaphragm. Case report of a rare tumor and approach through
      lateral thoracotomy].
AB  - Tumors of the diaphragm are rare and caused by there special localisation
      difficult to diagnose. We describe the case of a 31 year old man with a
      choristoma of the left diaphragmal crux where the localisation and genesis could
      only be cleared through lateral thoracotomy. Nor the CT guided puncture or the
      laparoscopy-although sufficient samples for the pathology could be gained-allowed
      the right diagnose. The importance of good diagnostic approach to select the
      right operative procedure-in this case the anterolateral thoracotomy-is
      described.

PMID- 12486618
TI  - [N-acetylcystein in the therapy of chronic bronchitis].
AB  - Chronic bronchitis (CB) shows an increasing global morbidity and mortality with
      major impact on socioeconomics. N-Acetylcysteine (NAC), previously used as a
      mucolytic compound in CB, has also antioxidative effects. Furthermore it
      influences intrabronchial bacterial colonisation. In a randomised pilot study of
      24 patients (16-male, 8 female, mean age 66 +/- 10 years) with acute exacerbation
      of CB and positive bacterial culture in the sputum, the addition of twice daily
      600 mg NAC to standard antibiotic therapy lead to a significantly higher
      bacterial eradication rate (70 % versus 36 %, p < 0.03). Clinical studies suggest
      that treatment with NAC has different effects in CB including a reduction of the
      number and duration of acute exacerbation episodes and possibly influences lung
      function. The improvement of symptoms and quality of life also has an impact on
      socio-economic costs. The use of NAC in CB as an antioxidative rather than a
      mucolytic compound should be considered. However, further placebo controlled
      studies are undergoing to definitively establish the role of NAC for the
      treatment of CB and COPD.

PMID- 12486619
TI  - [Bronchiolitis obliterans organizing pneumonia (BOOP)].

PMID- 12486620
TI  - [Recommendations for the diagnosis, therapy and prevention of pneumonia in the
      immunocompromised host].

PMID- 12486621
TI  - [Rescue of auditory hair cells from ototoxicity by CEP-11 004, an inhibitor of
      the JNK signaling pathway].
AB  - The hair cells (HCs) are the most vulnerable elements in the cochlea and damage
      to them is the most common cause of sensorineural hearing loss (SNHL).
      Understanding the intracellular events that lead to the death of HCs is a key to
      developing protective strategies. Recently, it has been shown that the c-Jun-N
      terminal kinase (JNK) pathway is activated in HCs in response to aminoglycosides
      and CEP-1347, an inhibitor of the JNK signaling pathway protected HCs from
      ototoxicity. We have studied another inhibitor (CEP-11 004) of this signaling
      pathway in its ability to protect HCs from aminoglycoside ototoxicity in vitro.
      Organ of Corti explants from p5 rat basal turns were maintained in tissue culture
      and treated with CEP-11 004 for 12 hours. They were then treated with CEP-11 004
      plus gentamicin for 72 hours. Significantly less HC death was observed compared
      to gentamicin alone. CEP-11 004 alone had no effect on HCs. We conclude that the
      JNK signaling pathway plays a role in aminoglycoside ototoxicity signaling.

PMID- 12486622
TI  - [Therapy of acute mastoiditis].
AB  - BACKGROUND: Acute otitis media is a common disease, mostly contracted at
      childhood. The development of acute mastoiditis has been decreased since the
      introduction of antibiotics. Currently it is only developed in 0.004 % cases of
      acute otitis media. But despite of this fact, even today one should not neglect
      this condition as the complications such as intracranial spread and lateral sinus
      thrombosis are still life threatening. METHODS AND PATIENTS: In a retrospective
      study from 01/96 - 09/00 we reviewed the cases of acute mastoiditis as a result
      of acute otitis media at our department. Additionally we compared study results
      out of 1972 until 1989 with our current results. RESULTS: Altogether
      mastoidectomy has been carried out at 157 patients. The cases have steadily
      increased since 1996. This is confirmed by comparison with study results of
      previous years. The majority of the patients were between 8 months and 3 years
      old (60 %). When the patients first presented at our department, the first signs
      of otitis media were 19.5 days ago in average. 38 % of the patients received no
      antibiotic treatment before admission. A thickened mucous membrane was seen by
      the mastoidectomy mostly (58 %). A subperiostal abscess we noted in 8.5 %. The
      most common isolated bacteria were Streptococcus pneumoniae (33 %) and
      Streptococcus pyogenes (11 %). The patients stayed at the department about 10
      days. In comparison to recent study results the "typical" mastoiditis has
      decreased. The causative pathogens have not changed. CONCLUSIONS: In the last
      years we realised an increasing number of mastoiditis at our department. The
      isolated bacteria are the same as presented in the literature. Early surgery
      combined with an effective antibiotic treatment can avoid the known complications
      of mastoiditis.

PMID- 12486623
TI  - [Immunoelectron microscopic findings in patients with allergic rhinitis].
AB  - BACKGROUND: In middle Europe the prevalence of allergic rhinitis is up to 15 % to
      25 %. Allergic rhinitis is characterised by an inflammation of the nasal mucosa
      induced by different allergens. The patients suffer from symptoms like sneezing,
      rhinorrhea and nasal airway obstruction caused by morphological changes of the
      nasal mucosa. This symptomatology is considered to be a result of accumulation
      and activation of inflammatory cells. Further some neuropeptides like Calcitonin
      Gene Related Peptide (CGRP) and Substance P (SP) play an additional role in
      pathophysiology of allergic rhinitis. PATIENTS AND METHODS: Tissue samples from
      28 human turbinates of patients with perennial rhinitis were taken during nasal
      surgery and preserved in phosphate-buffered glutaraldehyde or paraformaldehyde.
      Ultrathin sections were cut. The samples were dehydrated and embedded in Araldit.
      After polymerization an immunocytochemical staining-technique using a gold
      labeled antibody was carried out. Immunostained structures were photodocumented
      by using a transmission electron microscope. RESULTS: In the lamina propria
      mucosae an extensive edema and several inflammatory cells like lymphocytes,
      plasma cells, eosinophiles and macrophages was found. The capillaries showed an
      activated endothelium. Immunoreactive nerve fibers were found in the
      periglandular tissue around the acini, ducts and in the glandular connective
      tissue. Neuroglandular synapses with dense core vesicles and positive
      immunoreactions to CGRP and SP could be detected. Neuropeptidergic axons were
      often observed near to plasma cells. CONCLUSIONS: In the edematous nasal mucosa
      an infiltration with different inflammatory cells was found. Using electron
      microscopical techniques nerve structures near the submucosal glands could be
      demonstrated. Immunoreactions to the neuropeptides CGRP and SP were detected in
      the periglandular nerves and in neuroglandular synapses. These findings
      demonstrate the direct nerve control of glandular functions in allergic rhinitis.
      CGRP is generally known to have a vasodilatatory effect and to stimulate the
      secretion of nasal seromucous glands. In addition, SP as a short-acting
      vasodilatator may induce vascular permeability and glandular secretion. These
      immunoelectron microscopical findings further elucidate pathomorphological
      mechanisms in allergic rhinitis.

PMID- 12486624
TI  - [Relevance of colour-duplex echography for detection and therapy of recurrences
      in the follow-up of head and neck cancer].
AB  - BACKGROUND: Head and neck malignancies have a high rate of recurrences. Since the
      prognosis is often limited an early detection and therapy onset is essential for
      survival. This study surveys the relevance of regular colour-duplex echography
      examinations in the follow-up for detection and therapy of recurrent head and
      neck carcinomas. PATIENTS AND METHODS: In a prospective non-randomized study 43
      patients were surveyed over a mean observation period of 28 (8-44) months. In
      addition to clinical and colour-duplex echography (CDS) examinations, computed
      tomography (CT) and positron-emission-tomography using 18fluorodeoxyglucose (PET)
      were performed. RESULTS: A recurrence was detected in 17/43 (39.5 %) patients.
      The median survival was 42 months. CDS was the most reliable procedure for the
      diagnosis of regional recurrences with an accuracy of 94.2 %. Sensitivity and
      specificity of CDS for the diagnosis of all recurrences was found to be 80 % and
      78,6 % respectively. CT yielded identical results. In PET sensitivity was 82.4 %
      and specificity was found to be 88.4 %. In clinical examinations including
      panendoscopy sensitivity was 64.7 % only. In 7/17 recurrences a therapy was
      performed with curative intention. In 4 cases an early diagnosis by CDS
      contributed to a successful therapy. CONCLUSION: CDS is the imaging procedure of
      choice for the routine follow-up of head and neck cancer patients. In order to
      perform a comprehensive assessment of the head and neck region, for re-staging
      and to exclude second primary tumours additional (pan)endoscopy is necessary. CDS
      supports due to a high resolution and reliability an early therapy onset and a
      minimal invasive therapy. Thus, this procedure can significantly contribute to
      the successful treatment of recurrences in head and neck cancer.

PMID- 12486625
TI  - [Presentation of an oncological database adapted for head and neck cancer].
AB  - BACKGROUND: By law, oncological databases are required in Germany since 1999.
      These databases can be used for epidemiological or other scientific studies and
      quality control. METHODS: Based on ACCESS software a newly developed database is
      introduced, which is optimized for head and neck tumor patients. The database
      acquires epidemiological data, surgical and medical treatment protocols,
      histological and tumorbiological data, clinical data of speech, swallowing,
      breathing and general health, and examinations used for tumor staging and
      clinical outcome. RESULTS: Per patient less than 20 minutes are required to fill
      the data sheets and the data for the national cancer registry can be extracted as
      a table sheet. This database can also be used for scientific protocols and for
      multicenter studies.

PMID- 12486626
TI  - [Perforation of hypopharynx -- a uncommon complication of transesophageal
      endosonography].
AB  - BACKGROUND: Today the endoscopical sonography of the oesophagus and heart is a
      useful diagnostic procedure. Perforations of the oesophagus or hypopharynx after
      this procedure are grave and life-threatening complications of this invasive
      diagnostic procedure. MATERIAL AND METHODS: In the past 8 years we observed 3
      cases of hypopharyngeal perforation as complication of endosonographic procedure.
      These cases were evaluated retrospectively. RESULTS: In all 3 cases an increased
      resistance against insertion of the probe had been observed. In two cases the
      perforation was found in the right sinus piriformis. The third patient had a
      perforation of the posterior hypopharyngeal wall adjacent to the upper
      oesophageal sphincter. The former patients underwent an open transcervical
      revision, in the latter patient the perforation was clipped endoluminally to his
      impaired general condition. CONCLUSIONS: Perforations of the hypopharynx
      represent a rare but potentially life threatening complication of
      transoesophageal sonography. The endoscopically working physician should know and
      recognize the clinical signs for surgical treatment before further complications
      (e. g. mediastinitis) may occur.

PMID- 12486627
TI  - [Fibrolipoma of the larynx].
AB  - Benign mesenchymal tumors of the upper aerodigestive tract are very rare. In this
      localisation some tumors cause life-threatening upper airway obstruction. We
      report on a 42-year old man who complained dysphagia and globus sensation. The
      physical examination revealed a smooth tumor of the left aryepiglottic fold. A
      magnet resonance imaging (MRI) leaded to the suspicion of a laryngocele with
      extension in the left aryepiglottic fold. The therapeutical procedure included
      the microlaryngoscopical extirpation of the tumor with laser surgery. The
      histology showed a fibrolipoma of the larynx. Because of frequent recurrences
      even after an extended period of time long term follow-up is necessary.

PMID- 12486628
TI  - [Mechanical ileus caused by a Provox voice prosthesis -- an "iatrogenic" enteral
      complication in voice prosthesis rehabilitation of laryngectomees].
AB  - BACKGROUND: During the exchange of a defect Provox-I voice prosthesis followed by
      an insertion of a Provox-II voice prosthesis the esophageal part of the
      prosthesis often is pushed into the esophagus, as the enteral passage of the
      prosthesis was thought to be less traumatic for the voice shunt in comparison to
      a complete extraction of the stiff esophageal flange through the tracheostoma.
      This procedure is also recommended in the users video of the ATOS company. CASE:
      A laryngectomized patient, in whom the change of the voice prosthesis was carried
      out pushing the esophageal flange of the prosthesis into the esophagus, developed
      a mechanical ileus, as the voice prosthesis got stuck in Bauhin's valve. This
      resulted in the necessity of a laparatomy for removal of the voice prosthesis.
      CONCLUSION: During the replacement of the Provox voice prosthesis it is necessary
      in all cases that the esophageal remnant of the voice prosthesis either is pulled
      out of the tracheoesophageal shunt via the tracheostoma or removed with a guide
      wire transorally.

PMID- 12486629
TI  - [Results of videostroboscopic examinations of vocally healthy candidates for
      voice intensive professions].
AB  - BACKGROUND: Questions regarding the vocal aptitude for voice professions are
      common in the daily phoniatrical and otorhinolaryngological practice. According
      to the classification by Koufman, Isaccson and Stemple professions can be
      classified into four groups. While it is common to perform laryngeal
      investigations and analyses of the vocal efficacy for candidates of elite vocal
      performers (level 1), i. e. singers and actors, those examinations are usually
      not executed for voice and speaking intensive professions (level 2) like
      teachers, as there is no legal base. This group is, however, predisposed with
      regard to professional voice disorders. METHODS: Aim of the study was therefore
      to determine the frequency of laryngeal findings in a group of previously
      asymptomatic subjects using videostroboscopic examinations and to assess the risk
      concerning the emergence of professional voice disorders. 545 candidates for
      voice intensive professions have been examined with regard to the existence of
      any organic or secondary organic alterations on the vocal folds. RESULTS: One
      third of the subjects showed benign laryngeal alterations, which were not
      consequentially associated with auditive alterations of the voice sound and/or a
      consciousness of a voice disorder. Apart from 33 organic laryngeal alterations
      129 phonation associated alterations of the vocal fold were determined.
      CONCLUSIONS: These subjects should especially in cases of excessive vocal demand
      and additional the efficacy reducing factors be regarded as a high risk group
      with regard to the emergence of professional voice disorders. The results
      underline the necessity to require vocal examinations and vocal assessment
      analyses for candidates of voice intensive professions in order to avoid
      professional voice disorders.

PMID- 12486631
TI  - [Mechanisms of hoarseness -- visualization and interpretation by means of
      nonlinear dynamics].

PMID- 12486630
TI  - [The history of head and neck sonography].
AB  - Although today ultrasound is well accepted in the diagnosis of head and neck
      diseases, often little is known about the young history of this technique. Many
      pioneers, physicians and engineers were involved in the development of the
      technique. In this article the history of ultrasound in general and of ultrasound
      of the head and neck is reflected.

PMID- 12486632
TI  - [Diagnosis of apoplectiform deafness with loss of hearing].

PMID- 12486633
TI  - Are we ready for the future?

PMID- 12486634
TI  - Preparation of independent researchers.

PMID- 12486635
TI  - From expert to novice.

PMID- 12486636
TI  - Telehealth technologies enhance children's health care.

PMID- 12486637
TI  - The nursing faculty shortage: Is there hope?
AB  - The present nursing faculty shortage is linked to the general nursing shortage.
      Without enough nurse educators to teach the increasing number of nurses that are
      needed, the health of U.S. residents is at stake. This article examines progress
      made on solutions proposed over the past decade such as increasing graduate and
      certificate programs for nurse educators, more aggressive recruitment of graduate
      students into faculty roles, and delayed retirement of current faculty. Potential
      new solutions are proposed. These include: fast-track bachelor's of science in
      nursing to doctor of philosophy curricula; recruiting advanced practice nurses
      (APNs) into faculty roles with arrangements made for clinical practice time;
      raising the image of nursing education as a prestigious career; developing
      national certification for nurse educators; and partnering with health care
      agencies. Linking the general nursing shortage with the faculty shortage may
      provide a stronger case for public policy and funding initiatives. There are
      signs that some initiatives are working. Present faculty need to maintain a
      culture of hope while potential solutions are being implemented.

PMID- 12486638
TI  - Bridging culture on-line: Strategies for teaching cultural sensitivity.
AB  - The demand for on-line learning experiences is greatly increasing, especially for
      place-bound students living in rural areas. Faculty at the University of
      Wisconsin-Eau Claire School of Nursing responded to the need for coursework
      focusing on cultural competence by offering an elective course at both the
      undergraduate and graduate level through asynchronous delivery systems. To
      accomplish this, specific strategies were used in the course on cross-cultural
      health. These approaches were thoughtfully developed to bridge cultures in an on
      line environment for students who do not have cross-cultural experiences easily
      accessible within their home communities. Strategies included: (1) culturally
      congruent use of a minority visiting scholar who is a leader in professional
      nursing and a traditional woman healer within her Native American community to
      provide wisdom, information, and support to students and faculty, in the novel
      role of guest listener; (2) requiring participation in cultural enrichment
      activities, designed to assist the student in discovering the similarities and
      differences among diverse peoples in their lives; and (3) developing course and
      faculty evaluations that are congruent with the asynchronous learning
      environment.

PMID- 12486639
TI  - Do nurses feel empowered? Nurses' assessments of their own qualities and
      performance with regard to nurse empowerment.
AB  - Empowerment ideology has been adopted increasingly as one conceptual framework
      for the development of nursing care, training, and management. The present
      article examines a quantitative study (n = 416) on critical care, long-term care,
      and public health nurses' views over their personal qualities and performance in
      relation to an ideal model of nurse empowerment. The results obtained provide
      strong evidence that nurses do have a positive image of their own empowerment.
      There was only slight variation between different groups of nurses. Length of
      working history and employment status (permanent/temporary) correlated highly
      with empowerment. The ideal model seems to depict nurse empowerment relatively
      well. It might be feasible to develop these concepts further so as to obtain a
      tool for the enhancement of professional competence, nursing education, and
      personnel management.

PMID- 12486640
TI  - Respiratory intensive care unit resource use and outcomes in Taiwan.
AB  - Based on a revision of Donabedian's classic structure, process, and outcome
      conceptual framework, this study examined the relationship between resource use
      (length of stay) and outcome (transfer status) in two respiratory intensive care
      units (ICUs). Medical records of respiratory ICU patients (N = 194) from a
      medical center in northern Taiwan were reviewed. Data collection focused on
      patient demographic profile (age, gender, and medical diagnosis), Acute
      Physiology and Chronic Health Evaluation (APACHE) score, nursing diagnoses, ICU
      length of stay, and transfer status. The results indicate that patients with
      lower APACHE scores and more nursing diagnoses had a longer ICU length of stay.
      In addition, both the number of nursing diagnoses and APACHE scores significantly
      explained the variance in the length of stay. Nonetheless, a higher APACHE score
      was correlated with a poor transfer status. These findings indicate that, in
      addition to the traditional indicators, nursing diagnoses may be a vital variable
      in predicting ICU length of stay. The results also imply that patients with lower
      APACHE scores are in better physical condition and are therefore
      institutionalized longer in ICUs.

PMID- 12486641
TI  - Commentary: Problematic issues in cultural comparisons.
AB  - This commentary offers a critique of cross-cultural comparisons of health care
      systems between the United States and less economically developed nations. Two
      main issues are discussed: the abuse of power in such comparisons and the
      reluctance of nurses from the United States to address conditions of suffering in
      their own country. Recommendations are given to increase sensitivity of nurses.

PMID- 12486642
TI  - Experiencing cultural differences: reflections on cultural diversity.
AB  - Achieving cultural diversity is one of the priorities in many nursing schools.
      Although being culturally aware takes a lot of effort, this awareness does not
      necessarily translate into behavior until one experiences day-to-day life with
      someone from another culture. My experience as a nurse coming from another
      country and working in the United States illustrates this difficulty.

PMID- 12486643
TI  - Teaching portfolios are one way to document educators' effectiveness.

PMID- 12486644
TI  - Beta-adrenergic-receptor blockade and myocardial ischemia: something old,
      something new.

PMID- 12486645
TI  - Beta-adrenergic blockade during severe ischemia.
AB  - OBJECTIVE: To examine the effect of acebutolol, a beta-adrenergic-receptor
      blocker, on severe regional myocardial ischemia, specifically the effects on
      regional myocardial function and metabolism. DESIGN: Randomized study. SETTING:
      Animal laboratory of the Department of Anesthesiology and Critical Care,
      University of Stellenbosch Medical School. PARTICIPANTS: Anesthetized open-chest
      pig model (n = 18). INTERVENTIONS: Regional left ventricular function and
      metabolism were evaluated. Severe stenosis was applied to the left anterior
      descending coronary artery. After establishing regional myocardial ischemia,
      acebutolol was administered intravenously, and results were compared with
      controls who did not receive acebutolol. Animals were prospectively randomized to
      1 of the groups. MEASUREMENTS AND MAIN RESULTS: Regional myocardial function and
      metabolism were assessed by end-systolic pressure relationship, regional systolic
      shortening, postsystolic shortening, regional myocardial oxygen consumption, and
      lactate dynamics. Coronary blood flow was determined with a Doppler flow probe.
      Results indicated that acebutolol increased regional myocardial blood flow, and
      this resulted in less severe regional myocardial ischemia, improved function, and
      an increase in regional myocardial oxygen consumption. CONCLUSION: The beta
      Adrenergic-receptor antagonist was successful in reducing regional myocardial
      ischemia in this model. This reduction was achieved by an increase in coronary
      blood flow, which resulted in an improvement in regional mechanical function and
      an increase in oxygen consumption.

PMID- 12486647
TI  - Hemodynamic changes during displacement of the beating heart using epicardial
      stabilization for off-pump coronary artery bypass graft surgery.
AB  - OBJECTIVE: To evaluate the hemodynamic alterations during off-pump coronary
      artery bypass graft surgery to determine the degree of impairment caused and the
      techniques to rectify them. DESIGN: Prospective, observational cohort study
      performed from January 2000 through September 2000. PARTICIPANTS: Patients (n =
      500) with coronary artery disease undergoing multivessel off-pump coronary artery
      bypass graft surgery using the Octopus tissue stabilizer (Medtronic, Inc,
      Minneapolis, MN). Unstable patients with ongoing ischemia were excluded from the
      study. INTERVENTIONS: All patients were monitored with radial artery and
      pulmonary artery catheters and continuous transesophageal echocardiography
      monitoring with a multiplane transducer. The perioperative requirement of an
      intracoronary shunt, inotropes, or an intra-aortic balloon pump was noted. The
      effect of the Trendelenburg position and fluids on hemodynamics was observed. The
      need for defibrillation and institution of emergency cardiopulmonary bypass were
      major endpoints to determine the inability of the patient to tolerate
      displacement of the heart. MEASUREMENTS AND MAIN RESULTS: Mean patient age was
      59.3 +/- 11.6 years. There were 204 (40%) patients in the high-risk category; 54
      (10.8%) patients had left ventricular ejection fraction <25%. The mean number of
      grafts was 2.7 +/- 0.8. Vertical displacement of the heart to access the lateral
      and inferior walls decreased the mean arterial pressure by 18 +/- 4% (p < 0.01),
      with a concomitant increase in central venous pressure of 66 +/- 18% (p < 0.001).
      The stroke volume and the cardiac index were reduced by 35.7 +/- 11% (p < 0.001)
      and 45 +/- 13% (p < 0.001). On transesophageal echocardiography, there was
      development of new regional wall motion abnormalities in 59.2% and a decrease in
      global left ventricular functions in 61.2%. The use of inotropes was highest
      during anastomosis on the posterior wall-78.4% compared with 21.9% for the
      anterior wall. An intra-aortic balloon pump was used in 55 (11.2%) patients, and
      7 (0.71 %) patients had to be put on emergency CPB. The in-hospital mortality was
      1.2%. CONCLUSION: Most patients had hemodynamic changes easily correctable by
      fluids and inotropes. Monitoring of left ventricular and right ventricular
      function by transesophageal echocardiography enhances safety of the procedure and
      is recommended. The use of the Octopus II tissue stabilizer proved to be a safe
      and versatile means to stabilize the heart during off-pump coronary artery bypass
      procedures, especially in high-risk patients.

PMID- 12486646
TI  - Effect of thoracic epidural analgesia on refractory angina pectoris: long-term
      home self-treatment.
AB  - OBJECTIVES: To evaluate the effects of long-term home self-treatment with
      thoracic epidural analgesia (TEA) on angina, quality of life, and safety. DESIGN:
      Prospective consecutive pilot study. SETTING: Department of Cardiology, Heart
      Center, Linkoping University Hospital. PARTICIPANTS: Between January 1998 and
      January 2000, 37 consecutive patients with refractory angina began treatment with
      TEA, using a subcutaneously tunnelled epidural catheter. INTERVENTIONS: The
      patients were trained to provide self-treatment at home with intermittent
      injections of bupivacaine. Data were collected until January 2001, and the follow
      up for each patient was 1 to 3 years. MEASUREMENTS AND MAIN RESULTS: All but 1 of
      the patients improved symptomatically. The improvement was maintained throughout
      the treatment period (4 days to 3 years). The Canadian Cardiovascular Society
      angina class decreased from 3.6 to 1.7, frequency of anginal attacks decreased
      from 46 to 7 a week, nitroglycerin intake decreased from 32 to 5 a week, and the
      overall self-rated quality of life assessed by visual analog scale increased from
      24 to 76 (all p < 0.001). No serious catheter-related complications occurred;
      however, 51% of the catheters became displaced and a new one had to be inserted
      during the study. CONCLUSION: Long-term self-administered home treatment with TEA
      seems to be an effective and safe adjuvant treatment for patients with refractory
      angina. It produces symptomatic relief of angina and improves the quality of
      life.

PMID- 12486648
TI  - Beating-heart coronary artery bypass graft surgery at San Raffaele Hospital: four
      years of experience.
AB  - OBJECTIVE: To review the database of 1,902 consecutive patients who underwent
      coronary artery bypass graft (CABG) surgery in the period 1998 through 2001 at
      this institution, and to compare the preoperative status, anesthetic management,
      and postoperative outcome of 364 patients with the beating-heart technique with
      1,538 patients who underwent the operation on cardiopulmonary bypass. DESIGN:
      Observational study. SETTING: University hospital. PARTICIPANTS: Consecutive
      patients (n = 1,902) who underwent CABG surgery in the period 1998 through 2001.
      MEASUREMENTS AND MAIN RESULTS: Comparison (chi-square test) of the preoperative
      status shows that surgeons' choice for the beating-heart technique was based on
      the presence of severe preoperative comorbidities: renal impairment (p < 0.0001),
      chronic obstructive pulmonary disease (p < 0.04), and low ejection fraction (p <
      0.0001). On a multivariate analysis, the beating-heart technique was associated
      with reduced transfusion needs and duration of mechanical ventilation.
      CONCLUSION: Beating-heart surgery is gaining popularity as a safe method for
      myocardial revascularization. Excellent results have been achieved with this
      technique in this center.

PMID- 12486649
TI  - Safety and preliminary efficacy of hemoglobin raffimer for patients undergoing
      coronary artery bypass surgery.
AB  - OBJECTIVE: To evaluate the safety and preliminary efficacy of escalating doses of
      hemoglobin raffimer (Hemolink) with intraoperative autologous blood donation for
      coronary artery bypass graft (CABG) surgery. DESIGN: Randomized, controlled,
      single-blind phase II dose escalation trial. SETTING: Multi-institutional
      university setting. PARTICIPANTS: Adult patients (n = 60) undergoing elective
      CABG surgery. INTERVENTIONS: After induction of anesthesia, autologous whole
      blood was collected to achieve a hemoglobin of 7 g/dL on cardiopulmonary bypass.
      Patients were randomized to receive either hemoglobin raffimer (treatment) or 6%
      hetastarch (control) in sequential escalating dose blocks of 250 mL, 500 mL, or
      750 mL. After return of autologous blood, allogeneic red blood cells were
      transfused according to predetermined hemoglobin triggers. MEASUREMENTS AND MAIN
      RESULTS: Safety parameters (vital signs, hematology, blood chemistry,
      coagulation, and adverse events) were monitored from randomization through week 4
      postdischarge. Serious adverse events were distributed evenly between the 2
      groups of patients. Elevated blood pressure was more frequent in the treatment
      group (16/28 mmHg v 9/32 mmHg, p = 0.036). In the group of 40 patients in the 750
      mL dose block, 8 of the 18 treatment patients and 4 of the 22 control patients
      avoided allogeneic red blood cell transfusion (p = 0.093). Median volume of
      allogeneic red blood cells transfused was lower in treated subjects compared with
      controls (p = 0.042). CONCLUSION: Hemoglobin raffimer is well tolerated and may
      be effective in reducing transfusion for patients undergoing CABG surgery.
      Although perioperative hypertension was more frequent in the treated patients,
      blood pressure management prevented serious adverse sequelae. Definitive
      evaluation of efficacy in a larger phase III trial is warranted.

PMID- 12486651
TI  - A combination of intrathecal morphine and remifentanil anesthesia for fast-track
      cardiac anesthesia and surgery.
AB  - OBJECTIVE: To determine if the combined remifentanil and intrathecal morphine
      (RITM) anesthetic technique facilitates early extubation in patients undergoing
      coronary artery bypass graft (CABG) surgery. DESIGN: Prospective, randomized,
      controlled clinical trial. SETTING: Referral center for cardiothoracic surgery at
      a university hospital. PARTICIPANTS: Patients (n = 24) undergoing first-time
      elective CABG surgery. INTERVENTIONS: Two groups represented RITM (n = 12) and
      fentanyl-based (controls, n = 12) anesthesia. Premedication was standardized to
      temazepam, 0.4 mg/kg, and anesthesia was induced with etomidate, 0.3 mg/kg, in
      both groups. The RITM group received remifentanil, 1 microg/kg bolus followed by
      0.25 to 1 microg/kg/min infusion, and intrathecal morphine, 2 mg. The control
      group received fentanyl, 12 microg/kg in 3 divided doses. Anesthesia was
      maintained with isoflurane and pancuronium in both groups. After completion of
      surgery, the remifentanil infusion was stopped. Complete reversal of muscle
      relaxation was ensured with a nerve stimulator, and a propofol infusion, 0.5 to 3
      mg/kg/h, was started in both groups. All patients were transferred to the
      intensive care unit (ICU) to receive standardized postoperative care.
      Intensivists and ICU nurses were blinded to the group assignment. Propofol
      infusion was stopped, and the tracheal extubation was accomplished when
      extubation criteria were fulfilled. MEASUREMENTS AND MAIN RESULTS: Both groups
      were similar with respect to demographic data and surgical characteristics.
      Extubation times were 156 +/- 82 minutes and 258 +/- 91 minutes in the RITM and
      control groups (p = 0.012). Patients in the RITM group exhibited lower visual
      analog scale pain scores during the first 2 hours after extubation (p < 0.04).
      Morphine requirements during the 24 hours after extubation were 2.5 +/- 3 mg in
      the RITM group and 16 +/- 11 mg in the control group (p = 0.0018). Sedation
      scores were lower in the RITM group during the first 3 hours after extubation (p
      < 0.03). Pulmonary function tests as assessed by spirometry were better in the
      RITM group at 6 and 12 hours after extubation (p < 0.04). There were no
      significant differences in PaO(2) and PaCO(2) after extubation between the 2
      groups. None of the patients had episodes of apnea during the immediate 24-hour
      postextubation period. Two patients from the RITM group required reintubation on
      the second and sixth postoperative days. There were no differences in ICU and
      hospital length of stay between the 2 groups. CONCLUSION: Implementation of the
      RITM technique provided earlier tracheal extubation, decreased level of sedation,
      excellent analgesia, and improved spirometry in the early postoperative period.
      The impact of RITM on ICU and hospital length of stay and potential cost benefits
      require further evaluation.

PMID- 12486650
TI  - Remifentanil-clonidine-propofol versus sufentanil-propofol anesthesia for
      coronary artery bypass surgery.
AB  - OBJECTIVE: To compare a remifentanil-clonidine-propofol regimen with conventional
      sufentanil-propofol anesthesia. DESIGN: Randomized, nonblinded trial. SETTING: A
      single university hospital. PARTICIPANTS: Male patients scheduled for coronary
      artery bypass graft (CABG) surgery. INTERVENTIONS: In the control group,
      anesthesia was induced with 0.5 microg/kg of sufentanil and 0.2 to 0.3 mg/kg of
      etomidate after preoxygenation. Propofol (50 to 100 microg/kg/min) and sufentanil
      (0.5 to 1.0 microg/kg/h) were started after endotracheal intubation. Sufentanil
      was stopped after aortic decannulation. In the remifentanil-clonidine group,
      anesthesia was started with remifentanil (0.15 to 0.3 microg/kg/min), followed by
      etomidate (0.2 to 0.3 mg/kg). Propofol was started at 50 to 100 microg/kg/min,
      and after endotracheal intubation, clonidine infusion was started (6 to 20
      microg/h). Patients received piritramide (0.15 mg/kg) and metamizole (20 mg/kg)
      for transitional analgesia. In both groups, propofol infusion was reduced to 30
      to 60 microg/kg/min at skin closure and stopped when assisted spontaneous
      breathing led to adequate gas exchange. MEASUREMENTS AND MAIN RESULTS: The main
      outcomes were recovery times; somatic variables; plasma catecholamine levels; and
      self-recorded pain, nausea, and vomiting. Patients in the remifentanil-clonidine
      group were extubated earlier and had lower plasma epinephrine and norepinephrine
      levels. After transitional analgesia, the remifentanil-clonidine patients had
      similar postoperative analgesic use and self-reported pain and side-effect
      scores. CONCLUSION: Compared with a sufentanil-propofol regimen, an anesthetic
      regimen for CABG surgery that combines remifentanil, clonidine, and propofol
      provides similar hemodynamics. The remifentanil-clonidine regimen reduces
      catecholamine levels and hastens recovery from anesthesia.

PMID- 12486652
TI  - Centrifugal versus roller head pumps for cardiopulmonary bypass: effect on early
      neuropsychologic outcomes after coronary artery surgery.
AB  - OBJECTIVE: To test the hypothesis that routine use of a centrifugal pump in the
      cardiopulmonary bypass circuit would result in a lower incidence of early
      neuropsychologic deficit when compared with conventional roller pumps. DESIGN:
      Prospective, randomized, double-blind. SETTING: University teaching hospital.
      PARTICIPANTS: Patients (n = 103) scheduled for elective coronary artery surgery.
      INTERVENTIONS: Patients were randomized into group C (centrifugal pump for
      cardiopulmonary bypass; n = 54) and group R (roller pump for cardiopulmonary
      bypass; n = 49). MEASUREMENTS AND MAIN RESULTS: A neuropsychologic test battery
      of 6 standard tests was administered before surgery and 5 days after surgery. An
      abnormal test result was defined as deterioration by >1 group SD from an
      individual's preoperative test performance. There were no significant differences
      between groups in preoperative or surgical parameters, intensive care unit stay,
      or hospital stay. There were no significant differences in the incidence of
      neuropsychologic deficit for patients with a deficit in at least 1 test (group C,
      33%; group R, 51%; odds ratio, 0.48; 95% confidence interval, 0.22 to 1.06) or
      patients with a deficit in >/=2 tests (group C, 6%; group R, 18%; odds ratio,
      0.26; 95% confidence interval, 0.07 to 1.03). In group R, there were more
      individual test deficits per patient than in group C (p = 0.04). CONCLUSION:
      There was no significant difference in the incidence of neuropsychologic deficit
      postoperatively with routine use of centrifugal pumps. The larger number of
      individual test deficits in the roller pump group suggest that further studies to
      assess the potential neuropsychologic benefits of the use of centrifugal pumps
      are warranted.

PMID- 12486653
TI  - Thoracic epidurals in heart valve surgery: neurologic risk evaluation.
AB  - OBJECTIVE: To evaluate the risk of neurologic complications resulting from
      epidural hematoma in a series of patients who had surgery for repair or
      replacement of heart valves under combined general and thoracic epidural
      anesthesia (TEA). DESIGN: Prospective observational study. SETTING: General
      reference hospital associated with a university. PARTICIPANTS: Patients (n = 305)
      who had surgery for replacement or repair of heart valves. INTERVENTIONS: An
      epidural catheter was inserted at T1-3 as soon as the patient was in the
      operating room, and local anesthetic was administered as a bolus, then as a
      continuous infusion throughout the operation and postoperatively. A protocol for
      postoperative neurologic evaluation was used to rule out clinical signs of spinal
      lesions. A set of safety guidelines was routinely followed. MEASUREMENTS AND MAIN
      RESULTS: Preoperatively a battery of coagulation tests was systematically carried
      out: activated partial thromboplastin time, platelet count, and prothrombin time.
      Oral anticoagulants (warfarin) were stopped >60 hours before surgery, and
      antiplatelet drugs (aspirin) were stopped 7 days before. No patient required
      parenteral opiates postoperatively. Of the patients, 65% were extubated in the
      operating room. There were no neurologic complications resulting from epidural
      hematoma. CONCLUSION: TEA can provide effective postoperative analgesia and
      assist in early tracheal extubation in cardiac valve surgery. In this series,
      there were no neurologic deficits detected. When certain safety measures are
      taken, routine TEA is feasible and helpful in cardiac valve surgery.

PMID- 12486654
TI  - Validation of continuous thermodilution cardiac output in patients implanted with
      a left ventricular assist device.
AB  - OBJECTIVE: To assess the accuracy of a continuous cardiac output (CCO) monitor
      against an independent, intravascular measurement of flow as can be performed in
      patients fitted with a left ventricular assist device (LVAD). DESIGN: A
      prospective cohort study. SETTING: Academic tertiary-care center. PARTICIPANTS:
      Adult patients (n = 15) presenting for LVAD placement. INTERVENTIONS: Consenting
      patients presenting for LVAD placement for end-stage cardiac failure were
      anesthetized, and a CCO pulmonary artery catheter was placed (OptiQ, CCO/SvO(2);
      Abbott Critical Care, North Chicago, IL). Patients were monitored with
      transesophageal echocardiography and excluded from analysis if aortic
      regurgitation was found. Cardiac output was determined using a Q-Vue, CCO/SvO(2)
      computer with digital readout (Abbott Critical Care, North Chicago, IL). The LVAD
      was placed in standard fashion during cardiopulmonary bypass. The Thoratec vented
      electric Heartmate (Thoratec Co, Pleasanton, CA) incorporates an LVAD flow
      console, which computes LVAD flow within +/- 5% (range, 1.8 to 10 L/min).
      MEASUREMENTS AND MAIN RESULTS: Cardiac output flow measurements were made from
      both systems at the following time points: 5 minutes and 30 minutes after
      protamine administration, at chest closure, and after skin closure. Mean cardiac
      output for each device did not differ at any time point. Regression analysis
      (Pearson's) showed acceptable correlation (r(2) = 0.79, p < 0.0001), whereas a
      bias of 529 mL with limits of agreement of 1,208 mL were shown for CCO
      measurement compared with LVAD flow. CONCLUSION: The data indicate that the CCO
      system tends to overestimate cardiac output by approximately 500 mL/min when
      compared with LVAD flow. Nevertheless, this bias is within the range found by
      other less-invasive studies done to assess the accuracy of this system and
      further serves to confirm its relative accuracy.

PMID- 12486655
TI  - Anesthetic and perioperative outcome of teenagers and adults with congenital
      heart disease.
AB  - OBJECTIVE: To compare the perioperative outcome of patients >or=13 years old
      undergoing surgery for congenital heart disease in a children's hospital by a
      dedicated congenital heart surgery and anesthesia team with procedure-matched
      younger control patients. DESIGN: Retrospective medical record review study. From
      October 1997 to July 2000, medical records of all patients >12 years old
      requiring cardiopulmonary bypass were reviewed. A control group of patients <or=5
      years old was reviewed, and 2 patients were matched to each older patient by
      diagnosis and surgical procedure. Data are reported as mean +/- SD. Older (study)
      patients were compared with younger (control) patients using t-test or chi
      square, with p <or= 0.05 significant. SETTING: Medical school-affiliated tertiary
      care children's hospital. PARTICIPANTS: Patients undergoing congenital heart
      surgery. MEASUREMENTS AND MAIN RESULTS: The study group (older patients)
      comprised 85 patients, and the control group (younger patients) comprised 170
      patients. There were no intraoperative deaths. All major complications
      cardiopulmonary resuscitation, neurologic injury, massive hemorrhage with
      sternotomy, femoral cannulation for emergent bypass, and severe episodes of
      hypotension on induction of anesthesia-occurred in older patients undergoing
      repeat sternotomy. CONCLUSION: Mortality and major morbidity were low in both
      groups; however, all major intraoperative incidents occurred in older repeat
      sternotomy patients, suggesting increased perioperative risk for adverse outcomes
      in these patients.

PMID- 12486656
TI  - Time course of neuromuscular blockade with rocuronium in children with
      intracardiac shunts.
AB  - OBJECTIVE: To evaluate the time course of neuromuscular blockade after rocuronium
      in children with intracardiac shunts. DESIGN: Prospective study. SETTING:
      University hospital. PARTICIPANTS: Consecutive children (n = 52) with
      intracardiac shunts scheduled for elective cardiac surgery. Participants were
      allocated to 2 groups according to the direction of the shunt. INTERVENTIONS:
      Rocuronium, 0.6 mg/kg, was administered for muscle relaxation. The ulnar nerve
      was stimulated at 20-second intervals with a supramaximal 2-Hz train-of-4
      stimulation (TOF-Guard nerve stimulator; Biomet International, Odense, Denmark).
      The onset time to maximal twitch depression and the time to clinical recovery
      were compared between the 2 groups. MEASUREMENTS AND MAIN RESULTS: The time to
      maximal block was significantly faster in children with a right-to-left shunt:
      56.8 +/- 5.3 seconds versus 77.1 +/- 6.6 seconds (p = 0.01). There was a tendency
      to shorter recovery in children with a right-to-left shunt: 42.3 +/- 6.1 minutes
      versus 55.4 +/- 4.9 minutes (p = NS). CONCLUSION: This study shows a more rapid
      onset of rocuronium in children with cyanotic congenital heart disease. In these
      patients, rocuronium is indicated, particularly for rapid airway control.

PMID- 12486657
TI  - Coronary artery disease and anesthesia-related death in children with Williams
      syndrome.

PMID- 12486658
TI  - Dicrotic pulse in pericardial tamponade.

PMID- 12486659
TI  - Inhaled nitric oxide for perioperative management of an adult patient with atrial
      septal defect and severe pulmonary hypertension.

PMID- 12486660
TI  - Dynamic left ventricular outflow tract obstruction caused by afterload reduction
      induced by intra-aortic balloon counterpulsation.

PMID- 12486661
TI  - Coagulation abnormalities in patients with cyanotic congenital heart disease.

PMID- 12486662
TI  - Transesophageal echocardiography-guided transventricular balloon dilation of
      congenital critical aortic stenosis in the neonate and young infant.

PMID- 12486663
TI  - Pro: Vasopressin is the vasoconstrictor of choice after cardiopulmonary bypass.

PMID- 12486664
TI  - Con: Vasopressin is not the vasoconstrictor of choice after cardiopulmonary
      bypass.

PMID- 12486665
TI  - High cardiac output by a continuous cardiac output pulmonary artery catheter.

PMID- 12486666
TI  - An interesting transesophageal echocardiography sequence. Inadvertent
      dislodgement of a left atrial appendage thombus.

PMID- 12486667
TI  - Detection of oxygen delivery failure during cardiopulmonary bypass: an even
      earlier warning technique.

PMID- 12486668
TI  - Response to "Safe internal jugular cannulation".

PMID- 12486669
TI  - Double-lumen tube audit.

PMID- 12486670
TI  - Resolution of fibrinolysis.

PMID- 12486671
TI  - Thoracic epidural anesthesia and analgesia for coronary artery bypass graft
      surgery.

PMID- 12486675
TI  - Unexpected lack of effect of the rifampin-induced P-glycoprotein on the oral
      bioavailability of its substrate, talinolol, in humans: implication in
      phenotyping.

PMID- 12486677
TI  - Determination of l-alpha-acetylmethadol (LAAM), norLAAM, and dinorLAAM in
      clinical and in vitro samples using liquid chromatography with electrospray
      ionization and tandem mass spectrometry.
AB  - l-Alpha-acetylmethadol (LAAM) is an alternative to methadone for the maintenance
      treatment of opioid dependence. LAAM has a longer therapeutic half-life than
      methadone, primarily because it is metabolized to more active metabolites,
      norLAAM and dinorLAAM. We have developed a liquid chromatography-tandem mass
      spectrometry method capable of measuring LAAM and its metabolites, norLAAM and
      dinorLAAM, at lower concentrations with 1.0-mL aliquots of plasma (range of 0.25
      to 100 ng/mL) or higher concentration with 0.2-mL aliquots of plasma (range 1.25
      to 500 ng/mL). It has acceptable precision and accuracy across both linear
      ranges, as well as in the urine matrix. Results from this assay correlate well
      with our previously validated gas chromatograghy-mass spectrometry method. All
      analytes had acceptable stability after three freeze-thaw cycles, room
      temperature storage for 20 h, or storage of extracts either at -20 degrees C for
      6 days or on the autosampler (10 degrees C) for 4 days. The pharmacokinetics of
      LAAM, norLAAM, and dinorLAAM were determined for the first time in three male
      opioid-naive individuals receiving a single oral dose of 5 mg LAAM/70 kg. Using
      this method, we could monitor the in vitro N-demethylation of LAAM and norLAAM at
      substrate concentrations in the therapeutic range of 0.5 and 1.0 microM by cDNA
      expressed cytochrome P450s. This confirmed the involvement of cytochrome P450s
      3A4, 2B6, 2C8, and 2C18 at therapeutic concentrations of LAAM. An accurate and
      precise method for determination of LAAM and its metabolites, norLAAM and
      dinorLAAM, that is suitable for both in vivo and in vitro metabolism studies has
      been developed and validated.

PMID- 12486678
TI  - Automated analysis of polyethylene glycol-induced inhibition of P-glycoprotein
      activity in vitro.
AB  - Previous studies in our laboratories have shown that commonly used
      polyethoxylated pharmaceutical excipients inhibit P-glycoprotein activity in cell
      culture models of the intestinal mucosa. The results presented in this technical
      note show that the TECAN Genesis robotic workstation can be utilized to automate
      cellular transport studies for evaluating excipient effects on P-glycoprotein
      activity in vitro and for estimating the permeation of drug-like molecules across
      cell monolayers.

PMID- 12486679
TI  - An application of nonlinear mixed-effects modeling to pharmacokinetic data
      exhibiting nonlinear and time-dependent behavior.
AB  - A population pharmacokinetic (PK) analysis was performed on plasma concentrations
      of GW468816 observed in dogs after 10, 25, and 50 mg/kg/day repeated intravenous
      administration. A two-compartment model was fitted to the concentration-time data
      using the NONMEM program. Dose and time dependency of PK parameters was
      investigated. Selection of the best model was performed using a stepwise
      approach. A Michaelis-Menten elimination process was used to describe the PK dose
      dependency, whereas an interoccasion variability on V(m) (the maximum elimination
      rate of the Michaelis-Menten elimination process) was initially used to describe
      the time dependency of the PKs, and the final model included an exponential
      function to account for time variance on V(m). The K(m) value of the final model
      was 29.6 microg/mL, whereas V(m) was estimated to vary with time from 4.97
      microg/h/kg at day 1 to a maximum mean value of 9.64 microg/h/kg at day 14. This
      approach can be applied to either rich or sparse data leading to estimates of
      individual parameters by using Bayesian feedback. The overall information
      obtained can be used to interpret toxicological and pharmacological endpoints and
      integrated with further in vitro-in vivo studies to supply a comprehensive PK
      behavior before the first time in human studies.

PMID- 12486680
TI  - Micronization of anti-inflammatory drugs for pulmonary delivery by a controlled
      crystallization process.
AB  - Jet-milling as the common way for micronization of drugs shows several
      disadvantages. Drug powder properties are decisive for pulmonary use because,
      besides a small particle size, a good deagglomeration behavior is required. In
      this study, several anti-inflammatory drugs [beclomethasone-17,21-dipropionate
      (BDP), betamethasone-17-valerate (BV), triamcinolone acetonide, ECU-R2,
      budesonide, and prednisolone] were micronized by controlled crystallization
      without any milling processes. First the drug is dissolved in an organic solvent
      (BDP/BV: 4%; ECU-R2: 1% in acetone) and precipitated by a solvent change method
      in the presence of a cellulose ether (hydroxypropylmethylcellulose) as
      stabilizing hydrocolloid. By rapid pouring the solution of
      hydroxypropylmethylcellulose in water (BDP/BV: 0.005%; ECU-R2: 0.025%) into the
      drug solution under stirring in a relationship (v/v) of 1:16 (BDP/BV), 1:4 (ECU
      R2), the previously molecularly dispersed drug was associated to small particles
      and stabilized against crystal growth simultaneously. This dispersion was spray
      dried, resulting in a drug powder with a uniform particle-size distribution and a
      drug load of up to 98% (BDP, BV). The mean particle size of the drug was lower
      than 5 microm in most cases and consequently in the respirable range. Whereas the
      fine particle fraction (<5 microm, measured without excipients and without an
      inhalation device) of jet-milled drugs is 9.5 (BDP) or 13.1 (ECU-R2), fine
      particle fractions of 25.6% (BDP) resp. 78.2% (ECU-R2) are obtained with the
      spray-dried powders. As the formation of the small crystals requires a rapid
      solvent change process, the affinity of the hydrocolloid, and a high difference
      between the solubility in the solvent and nonsolvent, the drug's partition
      coefficient limits the method as drugs which are more hydrophilic form larger
      particles.

PMID- 12486681
TI  - Interaction of quinine with model lipid membranes of different compositions.
AB  - The binding of a drug such as Quinine with neutral and negatively charged small
      unilamellar lipid vesicles at pH 7 and 37 degrees C was investigated. Changes in
      the fluorescence properties of the drug after association with the liposomes were
      used to obtain binding isotherms over a range of phospholipid compositions at
      different ionic strengths. Under such conditions, the association was strongly
      enhanced by the negative net charge of the bilayer but diminished by the
      increasing presence of electrolytes in the aqueous media. Binding data were
      analyzed in terms of a surface partition equilibrium without and after correcting
      for electrostatic effects by means of the Gouy-Chapman theory. The intrinsic
      (hydrophobic) constant, obtained after charge correction, was smaller than the
      apparent binding constant determined without taking into account such an effect.
      A new analysis considering the two components not fully dissociated and affected
      by an identical screening factor has been introduced. It yielded rather similar
      hydrophobic partition coefficients for all conditions, independent of both the
      surface charge density of the lipid vesicles and the ionic strength, with an
      average value estimated to be (3 +/- 1) x 10(3) M(-1). All the findings suggested
      that the association of Quinine to liposomes is controlled primarily through
      electrostatic attractions, and, in a lesser extent, by hydrophobic forces.
      Because electrostatic and hydrophobic interactions play a crucial role in both
      the drug-membrane affinity and the location of the drug, their quantitative
      evaluation can shed light on the mechanism for a next therapeutic "action."

PMID- 12486682
TI  - The effect of lipophilicity of spin-labeled compounds on their distribution in
      solid lipid nanoparticle dispersions studied by electron paramagnetic resonance.
AB  - Solid lipid nanoparticles (SLN) constitute an attractive drug carrier system. The
      aim of this study was to investigate the influence of lipophilicity and structure
      of different model molecules on their distribution in SLN dispersions. SLN
      composed of glyceryl tripalmitate as lipid and soybean lecithin and poloxamer 188
      as stabilizers were prepared by a melt-emulsification process. PC(10,3),
      MeFASL(10,3), C(14)-Tempo, and Tempol were incorporated into SLN as spin-labeled
      compounds. The partition of SP between triglyceride and water was determined
      experimentally by electron paramagnetic resonance (EPR) and compared with
      calculated partition coefficients. The distribution of molecules in SLN
      dispersions was determined from the parameters of EPR spectra, from the reduction
      kinetics of the spin-labeled compounds with sodium ascorbate, and by computer
      simulation of EPR spectral line shapes. The experimentally obtained partition
      coefficients increase in the order Tempol < MeFASL(10,3) < C(14)-Tempo, showing
      the same trend as the partition coefficients calculated according to Rekker. In
      SLN dispersions, it was estimated that the ratio of SP between solid lipid core,
      phospholipid layers (deeper in SLN layer or in liposomes and closer to the
      surface of SLN), and water is for Tempol 0:0:100, for C(14)-Tempo 46:54(20:34):0,
      for MeFASL(10,3) 34:65(38:27):1, and for PC(10,3) 10:89(26:3:60):1.

PMID- 12486683
TI  - Mechanism of hepatobiliary transport of a novel thromboxane A2 receptor
      antagonist, [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335), and
      its xenobiotic taurine conjugate (Z-335-Tau) in rats.
AB  - We investigated the mechanism of hepatobiliary transport of a novel thromboxane
      A(2) receptor antagonist, [2-(4-chlorophenylsulfonylaminomethyl)indan-5
      yl]acetate (Z-335), and its taurine conjugate (Z-335-Tau) in normal Sprague
      Dawley rats (SDRs) and Eisai hyperbilirubinemic rats (EHBRs). The biliary
      excretion rate/unbound concentration in the cytosol (nu(bile)/C(u,cyt)) of Z-335
      was markedly decreased in EHBRs, whereas nu(bile)/C(u,cyt) values for Z-335-Tau
      did not differ significantly between EHBRs and SDRs. These results suggest that
      biliary excretion of Z-335 involves mrp2, whereas Z-335-Tau is excreted by other
      transporters. The effects of inhibitors on the biliary excretion of Z-335 and Z
      335-Tau were also examined in SDRs. After infusion of bromosulfophthalein (BSP),
      the nu(bile)/C(u,cyt) of Z-335 was significantly decreased, whereas that of Z-335
      Tau decreased to 50% of control values by infusion of indocyanine green (ICG) or
      taurocholate. However, biliary excretion of Z-335-Tau was maintained at a highly
      concentrative. In conclusion, the biliary excretion of Z-335 involves mrp2,
      whereas Z-335-Tau is excreted into the bile by active transport systems that
      remain intact in EHBRs. The mdr2 and/or BSEP/spgp might contribute to a part of
      total biliary excretion of Z-335-Tau, however, these transporters have not played
      a major role in the biliary excretion of Z-335-Tau.

PMID- 12486684
TI  - Self-assembly of drug-polymer complexes: a spontaneous nanoencapsulation process
      monitored by atomic force microscopy.
AB  - Since hydrophilic matrices were proposed for controlled drug delivery, many
      polymeric excipients have been studied to make drug release fit the desired
      profiles. It has been pointed out that lambda-carrageenan, a sulfated polymer
      from algae, can suitably control the release rate of basic drugs from hydrophilic
      matrices. Furthermore, the relevance of hydrophobic interactions in drug-polymer
      aqueous systems has already been demonstrated, although no references to
      morphological features as well as to the kinetics of the interaction complexes
      formation have been published to date. In this work, we propose a method to
      monitor the topographical evolution of the interaction between lambda-carrageenan
      and dexchlorpheniramine maleate, in order to determine how the release profiles
      can be so easily controlled. For this purpose, solutions of both polymer and drug
      were prepared at very low concentration. Solutions were mixed and small volumes
      were taken every hour for over a period of 24 h and subsequently analyzed. The
      characterization technique used, atomic force microscopy, provides a high
      resolution, allowing plotting of three-dimensional images of the sample
      morphology within the nanometric scale. The results demonstrate that lambda
      carrageenan is able to nanoencapsulate spontaneously dexchlorpheniramine maleate
      molecules, which offers the possibility of controlling the release rate of the
      drug with no need of complex technological processes. Moreover, this work
      demonstrates the suitability of atomic force microscopy for the specific case of
      the on-time monitoring of interaction processes that occur in pharmaceutical
      systems.

PMID- 12486685
TI  - In vitro transdermal iontophoretic delivery of leuprolide-mechanisms under
      constant voltage application.
AB  - The transdermal iontophoretic delivery of Leuprolide, a nonapeptide LHRH agonist
      was studied with the aim of understanding the mechanisms of iontophoresis.
      Permeation studies were carried out at pH 4.5 and 7.2, at which the average ionic
      valence of the drug molecule was roughly 2 and 1, respectively. Heat-separated
      human epidermal membrane was subjected to constant voltage within the range of
      250 to 1000 mV during the iontophoretic phase. Iontophoretic enhancement at pH
      7.2 was greater than at 4.5. A model for iontophoretic enhancement was developed
      that takes into consideration the membrane alterations caused by iontophoresis
      depicted as increased porosity and the permeation through lipid pathways of the
      stratum corneum. Model-based evaluation yielded that first, the porosity
      increased with the applied voltage to as much as three times the original at 1000
      mV. Second, the lipid pathways contributed approx. 20% to the total permeation
      during the passive phase. Third, the electro-osmotic flow contributed
      significantly to the enhancement and its direction was from anode to cathode at
      pH 7.2 and the opposite at pH 4.5. The magnitude of the electro-osmotic flow was
      at pH 4.5 somewhat lower than at pH 7.2. Addition of a negatively charged water
      soluble peptide, Acetyl leucine leucinolyl phosphate as an adjuvant led to
      twofold increase in the enhancement factor at pH 4.5 and a decrease in the
      magnitude of the electro-osmotic flow from cathode to anode. Repeated
      iontophoretic applications of 250 mV on the same skin specimen resulted in same
      enhancement every time and did not cause any barrier alterations when applied for
      1 h every 24 h, which was not the case if the duration between the two
      iontophoretic applications was only 3 h.

PMID- 12486686
TI  - A novel method for identifying PEGylation sites of protein using biotinylated PEG
      derivatives.
AB  - The identification of PEGylation sites is essential in the characterization of
      PEGylated therapeutic proteins. This report describes a simple and novel method
      of finding poly(ethylene glycol) (PEG) conjugation sites in PEGylated proteins by
      using a hetero-functional biotin-PEG-N-hydroxyl succinimide derivative. PEGylated
      lysozyme species having a biotin moiety at each PEG chain end were separated and
      digested by trypsin. Among the digested lysozyme fragments, biotin-terminated
      PEGylated peptide fragments were purified by a monomeric avidin immobilized
      column. Their mass was analyzed by matrix-assisted laser desorption ionization
      time of flight mass spectrometry, directly indicating that PEG was conjugated to
      lysine 33, 97, 116 residues. Reversed-phase high-pressure liquid chromatography
      results for the PEGylated peptide fragments exhibited that PEGylation occurred
      preferentially at lysine 33> lysine 97> lysine 116.

PMID- 12486687
TI  - The influence of endotoxemia on the pharmacokinetics and the
      electroencephalographic effect of propofol in the rat.
AB  - Endotoxemia decreases the dose requirement for anesthetics but no data are
      available for propofol. A rat model was used in which the influence of endotoxin
      administration on the pharmacokinetics and pharmacodynamics of propofol was
      investigated. Chronically instrumented rats were randomly allocated to either a
      control (n = 9) or an endotoxin (n = 9) group. Six hours after pretreatment with
      either endotoxin or its solvent, propofol was infused (150 mg x kg(-1) x h(-1))
      until isoelectric periods of 5 s or longer were observed in the
      electroencephalogram. The changes observed in the electroencephalogram were
      quantified using aperiodic analysis and used as a surrogate measure of hypnosis.
      The righting reflex served as a clinical measure of hypnosis. The propofol dose
      needed to reach the electroencephalographic end point in the endotoxin-treated
      rats was reduced by almost 50% (p < 0.01). This could be attributed to a decrease
      in propofol clearance and in distribution volume related to the degree of
      physiologic and metabolic disturbances induced by endotoxin. To investigate
      changes in end organ sensitivity, the biphasic electroencephalographic effect
      versus effect-site concentration relationship was studied. This relationship was
      characterized by descriptors that showed an increased intrinsic efficacy of
      propofol in the endotoxin group. The effect-site concentration at the return of
      righting reflex was lower in the endotoxin group. Our study demonstrates that
      endotoxin-treated animals need a lower dose of propofol to reach the same degree
      of anesthetic effect which can mainly be attributed to changes in
      pharmacokinetics.

PMID- 12486688
TI  - An infrared spectroscopic study of the effect of hydration on cationic lipid/DNA
      complexes.
AB  - Infrared spectroscopy was used to examine the effect of dehydration on the
      structure of DNA and cationic lipid/DNA complexes (CLDCs). Information regarding
      the effect of hydration on the interface between the cationic lipids and DNA was
      obtained by following subtle but reproducible changes in vibrational bands
      arising from the DNA bases and phosphate backbone as well as bands from the lipid
      ester groups within the interfacial region of the bilayer. Dehydration of
      supercoiled plasmid DNA induces a transition from a B-conformation in solution to
      a mixed conformation in the dried state. Changes in vibrations of the bases upon
      drying suggest a change to an A-conformation whereas vibrations from the
      phosphate moieties suggest A- or C-forms. Vibrational changes in the ribose ring
      suggest adoption of a C-conformation. When CLDCs composed of either DOTAP (1,2
      dioleoyl-3-trimethylammonium-propane) or DDAB (dioctadecyldimethylammonium
      bromide) cationic lipids with or without equimolar amounts of the helper lipids
      cholesterol or DOPE (1,2-dioleoylphosphatidylethanolamin) are dried, the DNA is
      still able to undergo these structural transitions suggesting a nonrigid CLDC
      structure. The effect of dehydration on these interfacial interactions was found
      to be dependent on the type of cationic lipid used as well as the type of helper
      lipid. In addition, this work provides a simple spectroscopic analytical approach
      that can be used for the characterization of nonviral vectors that has potential
      pharmaceutical utility.

PMID- 12486689
TI  - Chemical and physical stability of hydroxypropylmethylcellulose matrices
      containing diltiazem hydrochloride after gamma irradiation.
AB  - In recent years, the exposure to gamma-radiation is an increasingly used method
      to sterilize or to reduce bacterial charge in drug-delivery devices. The aim of
      this study was to investigate whether the ionizing radiation may be responsible
      for drug inactivation or for the alteration of the functional excipient used to
      modulate drug release from a controlled-release delivery system. In this work, we
      investigated the physical and dissolution stability of prolonged release matrix
      tablets containing diltiazem hydrochloride, as a model drug, and
      hydroxypropylmethylcellulose (HPMC) of two different viscosity grades, as the
      retarding polymer, before and after exposure to increasing doses of gamma-rays.
      The results show that gamma-irradiation induces chemical modifications in the
      structure of the active agent, and also of the hydrophilic polymer. The
      electronic paramagnetic resonance analysis of gamma-irradiated diltiazem has
      afforded evidence of carbon radicals stemming from C-H bond ruptures and sulphur
      radicals, the latter being formed mainly after admission of air at room
      temperature. The major radical products in the HPMC polymer radiolysis have been
      reckoned with chain scission events in agreement with the results of viscosity
      measurements that show a progressive decrease of the average molecular weight
      with increasing the radiation dose. The elaboration of the viscosity data has led
      to linear relationships between the eta(o)/eta ratio and the radiation dose D
      which were rationalized with the following equation under the assumption of a
      Mark-Houwink Sakurada coefficient a approximately equal 1: eta(o)/eta = (1 +
      uy(o) D)(a). In this equation, D is gamma-radiation dose, eta(o) and eta are the
      reduced viscosities before and after the irradiation respectively, u is the
      number average degree of polymerization, and y(o) is the chain scission
      radiolytic yield. From the linear relationships G(chain scissions) = 1.2 x 10(-6)
      and 1.4 x 10(-6) moles/J have been obtained for the two HPMC polymer samples M100
      and M4 of different molecular weight used in the experiments. These changes could
      be responsible for the alteration of the drug-release mechanism and reduced
      polymer efficacy in controlling drug release.

PMID- 12486690
TI  - Enhanced econazole penetration into human nail by 2-n-nonyl-1,3-dioxolane.
AB  - This study determines the enhancing effects of 2-n-nonyl-1,3-dioxolane on the
      penetration of econazole, an antifungal drug, into the deeper layers of the human
      nail where fungal infection resides. Aliquots (10 microL) of Econail lacquer
      formulation containing 0.45 mg of [(14)C]-econazole with 18% 2-n-nonyl-1,3
      dioxolane (test group) or without 2-n-nonyl-1,3-dioxolane (control group) were
      applied twice daily for 14 days to human nails that had been washed with ethanol
      before each morning's application. The hydration of the nail sample was well
      controlled to simulate normal physiological conditions. After 14 days of dosing,
      the inner ventral section of the nail plate was assayed for absorbed drug
      content, using a micrometer-controlled drilling and nail powder removal system.
      The mass balance values of [(14)C]-econazole in this study were 90.8 and 96.4%
      for the test and control groups, respectively. The weight-normalized econazole
      content in the ventral/intermediate nail plate center in the test group was 6
      fold greater than that in the control (p = 0.008). The total econazole absorbed
      into the supporting bed cotton ball in the test group was nearly 200-fold greater
      than that in the control group (p = 0.008) over the 14-day period. The amount of
      econazole after dosing in the inner part of the human nail (potential diseased
      area) was 11.1 +/- 2.6 (SD) microg/mg of nail powder with 2-n-nonyl-1,3-dioxolane
      in the lacquer and 1.78 +/- 0.32 microg/mg without 2-n-nonyl-1,3-dioxolane (p =
      0.008). The surface nail contained more econazole (p = 0.004), that is,
      nonabsorbed drug, where 2-n-nonyl-1,3-dioxolane was not part of the dosing
      solution. Econazole in the support bed under the nail (the total absorbed dose)
      was 47.5 +/- 22.0 mg in the lacquer with 2-n-nonyl-1,3-dioxolane and 0.2 +/- 0.1
      mg in the lacquer without 2-n-nonyl-1,3-dioxolane (p = 0.008). Moreover the
      concentration in the deep nail layer in the test group is 14,000 times higher
      than minimum inhibitory concentration (MIC) believed necessary to inhibit the
      growth of infecting fungi (Dermatophytes species). In a subsequent study, [(14)C]
      dioxolane did not penetrate the nail well. Therefore, the mechanism of
      enhancement of econazole penetration is at the formulation/nail interface.

PMID- 12486691
TI  - Laser Raman spectroscopic analysis of polymorphic forms in microliter fluid
      volumes.
AB  - Knowledge and control of the polymorphic phase of chemical compounds are
      important aspects of drug development in the pharmaceutical industry. We report
      herein in situ and real-time Raman spectroscopic polymorphic analysis of
      optically trapped microcrystals in a microliter volume format. The system studied
      in particular was the recrystallization of carbamazepine (CBZ) in methanol. Raman
      spectrometry enabled noninvasive measurement of the amount of dissolved CBZ in a
      sample as well as polymorphic characterization, whereas exclusive
      recrystallization of either CBZ form I or CBZ form III from saturated solutions
      was achieved by specific selection of sample cell cooling profiles. Additionally,
      using a microcell versus a macroscopic volume gives the advantage of reaching
      equilibrium much faster while using little compound quantity. We demonstrate that
      laser Raman spectral polymorphic analysis in a microliter cell is a potentially
      viable screening platform for polymorphic analysis and could lead to a new high
      throughput method for polymorph screening.

PMID- 12486692
TI  - Carbendazim: disposition, cellular permeability, metabolite identification, and
      pharmacokinetic comparison with its nanoparticle.
AB  - The purpose of this study was to systematically evaluate the pharmacokinetic
      profiles of carbendazim, a novel anticancer drug. Carbendazim reached the highest
      concentrations in stomach and small intestine by 1 h after oral administration
      (500 mg/kg) to tumor-bearing nude mice. Four hours later, carbendazim in the
      large intestine reached maximum concentrations, probably because of pH-induced
      precipitation of the drug in the large intestine. The highest concentrations of
      carbendazim in well-perfused tissues, solid tumor, and blood ranged from 63 to
      164 microg/g by 4 h. The percentage of carbendazim distributed to solid tumor by
      4 h was higher than most well-perfused tissues. Carbendazim concentrations in
      blood were similar to, or somewhat lower than, those in tumor and other tissues.
      By 24 h post-dosing, carbendazim concentrations in tissues and blood declined to
      almost basal levels. The total percentage of administered carbendazim eliminated
      in urine was 25.7%, and in feces 16.6% within 24 h. Carbendazim exhibited fast
      permeation across Caco-2 and HT-29 carcinoma cell lines with corresponding
      permeability coefficients 7.74-8.06 x 10(-5) and 6.8-8.42 x 10(-5) (cm/s). The
      overall plasma protein binding of carbendazim (0.2-125 microg/mL) assessed by
      ultrafiltration ranged from 60 to 74%. Comparative pharmacokinetics was conducted
      in rats by high-pressure liquid chromatography to evaluate the relative
      bioavailability of carbendazim versus its nanoparticle formulation. Carbendazim
      and its nanoparticle reached T(max) at 2.01 and 1.57 h, respectively. The
      relative bioavailability of nanoparticle carbendazim versus regular carbendazim
      was 166%. High-pressure liquid chromatography analysis of the rat serum obtained
      at 20 h after oral dosing revealed a carbendazim metabolite, which was identified
      by mass spectroscopy analysis as 2-aminobenzimidazole, a hydrolyzed product of
      carbendazim. Incubation of carbendazim with human and rat liver microsomes
      produced a metabolite identified by mass spectrometry as 5(6)- or 4(7)-hydroxyl
      carbendazim. The comprehensive pharmacokinetic information is important to the
      current clinical investigation of carbendazim.

PMID- 12486693
TI  - pH-induced modifications to stratum corneum lipids investigated using thermal,
      spectroscopic, and chromatographic techniques.
AB  - The effects of nonphysiological pH on stratum corneum lipid content and structure
      have been studied. Human stratum corneum samples were soaked in solutions at pH
      1, 2, 6, 11, or 12 for up to 24 h. After removal of the stratum corneum, the
      buffer solutions were analyzed for lipid composition using thin-layer
      chromatography analysis and the stratum corneum sheets were examined using
      differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR)
      spectroscopy. The results demonstrate that only buffers of pH 11 or higher affect
      the stratum corneum lipids. No large difference in the contents of ceramides and
      cholesterol extracted by buffers of varying pH was observed. In contrast, free
      fatty acid extraction was pH dependent; amounts removed by 24-h treatment with pH
      11 or 12 buffers were comparable, and were similar to amounts extracted with a
      methanol-chloroform mixture for 15 min. No appreciable changes in DSC and FTIR
      spectra were detected between untreated stratum corneum and stratum corneum
      samples treated with buffers at pHs in the range 1-6. For tissue treated with pH
      11 and 12, the position of the endothermal melting peak T2 shifted from 72 to 74
      degrees C on the DSC thermograms. Small changes in the broadness of spectral
      peaks at 2855 cm(-1) [attributable to upsilon(CH(2)) stretching of stratum
      corneum lipids and 1655 cm(-1) upsilon(C=O) stretching amide I band] can be seen
      in the FTIR spectra from the treated stratum corneum samples, although no shifts
      in peak positions were observed. Intensity changes in peaks from extraneous
      lipids [upsilon(C=O) stretching mode at 1735 cm(-1)] were observed after buffer
      treatments. The changes provoked by the alkaline buffers are not dramatic and it
      may be concluded that the stratum corneum appears remarkably resilient to
      extended exposure in both highly acidic (pH 1) and highly alkaline (pH 12)
      environments.

PMID- 12486694
TI  - The effect of hypoxic hypoxia on the systemic and myocardial pharmacokinetics and
      dynamics of lidocaine in sheep.
AB  - It was hypothesized that the increased myocardial blood flow known to occur
      during some types of hypoxia may alter the kinetics and dynamics of cardio-active
      drugs such as lidocaine that act directly on the myocardium. In a randomized
      cross-over design, iv lidocaine (100 mg over 2 min) was administered to conscious
      instrumented sheep in a control state (C) or when the sheep were rendered hypoxic
      (H) by the addition of nitrogen to their inspired air (average Pa(O2) = 26 mmHg).
      Hypoxia caused a significant increase in myocardial blood flow (193% of control,
      SD = 37%, p < 0.05), a nonsignificant increase in cardiac output, and unchanged
      heart rate and blood pressure. Peak arterial lidocaine concentrations were
      unchanged, but peak concentrations in coronary sinus blood (effluent from the
      myocardium) were increased (maximum 201% of control, SD = 63%, p < or = 0.05),
      suggesting more rapid uptake of lidocaine into the myocardium in hypoxia. There
      was a linear relationship between coronary sinus lidocaine concentrations and
      reductions in myocardial contractility. However, the higher myocardial
      concentrations associated with H were not associated with overall greater
      reductions in contractility, as baseline contractility was elevated by H. Thus,
      hypoxia was not detrimental with respect to this adverse effect of lidocaine on
      the myocardium.

PMID- 12486695
TI  - Dose-independent pharmacokinetics of a new neuroprotective agent for ischemia
      reperfusion damage, KR-31543, after intravenous and oral administration to rats:
      hepatic and intestinal first-pass effects.
AB  - The purpose of this study was to report dose-independent pharmacokinetics of KR
      31543, a new neuroprotective agent for ischemia-reperfusion damage, after
      intravenous (iv) and oral (po) administration and first-pass effects after iv,
      intraportal, intragastric, and intraduodenal administration in rats. After iv
      (10, 20, and 50 mg/kg) and oral (10, 20, and 50 mg/kg) administration, the
      pharmacokinetic parameters of KR-31543 were dose independent. The extent of
      absolute oral bioavailability (F) was 27.4% at 20 mg/kg. Considering the amount
      of unabsorbed KR-31543 from the gastrointestinal tract at 24 h (4.11%), the low F
      value could be due to the hepatic, gastric, and/or intestinal first-pass effects.
      After iv administration of three doses, the total body clearances were
      considerably slower than the reported cardiac output in rats, suggesting almost
      negligible first-pass effect in the heart and lung in rats. The areas under the
      plasma concentration-time curves from time zero to time infinity (AUCs) were not
      significantly different between intragastric and intraduodenal administration of
      KR-31543 (20 mg/kg), suggesting that the gastric first-pass effect of KR-31543
      was almost negligible in rats. However, the values were significantly smaller
      (305 and 318 microg x min/mL) than that after intraportal administration (494
      microg x min/mL), indicating a considerable intestinal first-pass effect of KR
      31543 in rats; that is, approximately 40% of the oral dose. Approximately 50% of
      KR-31543 absorbed into the portal vein was eliminated by the liver (hepatic first
      pass effect) based on iv and intraportal administration (the value, 50%, was
      equivalent to approximately 30% of the oral dose). The low F value of KR-31543
      after oral administration of 20 mg/kg to rats was mainly due to considerable
      intestinal (approximately 40%) and hepatic (approximately 30%) first-pass
      effects.

PMID- 12486696
TI  - Introduction: behavioral genetics--the third century.

PMID- 12486697
TI  - Genetic and environmental influences on human psychological differences.
AB  - Psychological researchers typically distinguish five major domains of individual
      differences in human behavior: cognitive abilities, personality, social
      attitudes, psychological interests, and psychopathology (Lubinski, 2000). In this
      article we: discuss a number of methodological errors commonly found in research
      on human individual differences; introduce a broad framework for interpreting
      findings from contemporary behavioral genetic studies; briefly outline the basic
      quantitative methods used in human behavioral genetic research; review the major
      criticisms of behavior genetic designs, with particular emphasis on the twin and
      adoption methods; describe the major or dominant theoretical scheme in each
      domain; and review behavioral genetic findings in all five domains. We conclude
      that there is now strong evidence that virtually all individual psychological
      differences, when reliably measured, are moderately to substantially heritable.

PMID- 12486699
TI  - Molecular approaches to aggregation behavior and social attachment.
AB  - In many animal species individuals aggregate to live in groups. A range of
      experimental approaches in different animals, including studies of social feeding
      in nematodes, maternal behavior in rats and sheep, and pair-bonding in voles, are
      providing insights into the neural bases for these behaviors. These studies are
      delineating multiple neural circuits and gene networks in the brain that interact
      in ways that are as yet poorly understood to coordinate social behavior.

PMID- 12486698
TI  - Analysis of quantitative trait loci that influence animal behavior.
AB  - Behavioral differences between inbred strains of mice and rats have a genetic
      basis that can now be dissected using quantitative trait locus (QTL) analysis.
      Over the last 10 years, a large number of genetic loci that influence behavior
      have been mapped. In this article I review what that information has revealed
      about the genetic architecture of behavior. I show that most behaviors are
      influenced by QTL of small effect, each contributing to less than 10% of the
      variance of a behavioral trait. The small effect of each QTL on behavioral
      variation suggests that the mutational spectrum is different from that which
      results in Mendelian disorders. Regions of DNA should be appropriately
      prioritized to find the molecular variants, for instance by looking at sequences
      that control the level of gene expression rather than variants in coding regions.
      While the number of allelic loci that can contribute to a trait is large, this is
      not necessarily the case: the analysis of selected strains shows that a
      remarkably small number of QTL can explain the bulk of the genetic variation in
      behavior. I conclude by arguing that genetic mapping has more to offer than a
      starting point for positional cloning projects. With advances in multivariate
      analyses, mapping can also test hypotheses about the psychological processes that
      give rise to behavioral variation.

PMID- 12486700
TI  - Genetic basis of male sexual behavior.
AB  - Male sexual behavior is increasingly the focus of genetic study in a variety of
      animals. Genetic analysis in the soil roundworm Caenorhabditis elegans and the
      fruit fly Drosophila melanogaster has lead to identification of genes and
      circuits that govern behaviors ranging from motivation and mate-searching to
      courtship and copulation. Some worm and fly genes have counterparts with related
      functions in higher animals and many more such correspondences can be expected.
      Analysis of mutations in mammals can potentially lead to insights into such
      issues as monogamous versus promiscuous sexual behavior and sexual orientation.
      Genetic analysis of sexual behavior has implications for understanding how the
      nervous system generates and controls a complex behavior. It can also help us to
      gain an appreciation of how behavior is encoded by genes and their regulatory
      sequences.

PMID- 12486701
TI  - Genetic analysis of the circadian system in Drosophila melanogaster and mammals.
AB  - The fruit fly, Drosophila melanogaster, has been a grateful object for circadian
      rhythm researchers over several decades. Behavioral, genetic, and molecular
      studies helped to reveal the genetic bases of circadian time keeping and rhythmic
      behaviors. Contrary, mammalian rhythm research until recently was mainly
      restricted to descriptive and physiologic approaches. As in many other areas of
      research, the surprising similarity of basic biologic principles between the
      little fly and our own species, boosted the progress of unraveling the genetic
      foundation of mammalian clock mechanisms. Once more, not only the basic
      mechanisms, but also the molecules involved in establishing our circadian system
      are taken or adapted from the fly. This review will try to give a comparative
      overview about the two systems, highlighting similarities as well as specifics of
      both insect and murine clocks.

PMID- 12486702
TI  - Behavioral genetic approaches to visual system development and function in
      zebrafish.
AB  - The zebrafish is a recent vertebrate model system that shows great potential for
      a genetic analysis of behavior. Early development is extraordinarily rapid, so
      that larvae already display a range of behaviors 5 days after fertilization. In
      particular the visual system develops precociously, supporting a number of
      visually mediated behaviors in the larva. This provides the opportunity to use
      these visually mediated behaviors to screen chemically mutagenized strains for
      defects in vision. Larval optokinetic and optomotor responses have already been
      successfully employed to screen for mutant strains with defects in the visual
      system. In the adult zebrafish a visually mediated escape response has proved
      useful for screening for dominant mutations of the visual system. Here, I
      summarize visually mediated behaviors of both larval and adult zebrafish and
      their applicability for genetic screens, and present, the approaches and results
      of visual behavior carried out to date.

PMID- 12486703
TI  - Invertebrate models of drug abuse.
AB  - Susceptibility to drug addiction depends on genetic and environmental factors and
      their complex interactions. Studies with mammalian models have identified
      molecular targets, neurochemical systems, and brain regions that mediate some of
      the addictive properties of abused drugs. Yet, our understanding of how the
      primary effects of drugs lead to addiction remains incomplete. Recently,
      researchers have turned to the invertebrate model systems Drosophila melanogaster
      and Caenorhabditis elegans to dissect the mechanisms by which abused drugs
      modulate behavior. Due to their sophisticated genetics, relatively simple
      anatomy, and their remarkable molecular similarity to mammals, these invertebrate
      models should provide useful insights into the mechanisms of drug action. Here we
      review recent behavioral and genetic studies in flies and worms on the effects of
      ethanol, cocaine, and nicotine, three of the most widely abused drugs in the
      world.

PMID- 12486704
TI  - Perchance to dream: solving the mystery of sleep through genetic analysis.
AB  - Sleep has been identified in all mammals and nonmammalian vertebrates that have
      been critically evaluated. In addition, sleep-like states have also been
      identified and described in several invertebrates. Despite this prevalence
      throughout the animal kingdom, the function of sleep remains a mystery. The
      completion of several genome sequencing projects has led to the expectation that
      fundamental aspects of sleep can be elucidated through genetic dissection.
      Indeed, studies in both the mouse and fly have begun to reveal tantalizing
      suggestions about the underlying principles that regulate sleep homeostasis. In
      this article we will review recent studies that have used genetic techniques to
      evaluate sleep in the fruit fly and the mouse.

PMID- 12486705
TI  - Behavioral plasticity in C. elegans: paradigms, circuits, genes.
AB  - Life in the soil is an intellectual and practical challenge that the nematode
      Caenorhabditis elegans masters by utilizing 302 neurons. The nervous system
      assembled by these 302 neurons is capable of executing a variety of behaviors,
      some of respectable complexity. The simplicity of the nervous system, its
      thoroughly characterized structure, several sets of well-defined behaviors, and
      its genetic amenability combined with its isogenic background make C. elegans an
      attractive model organism to study the genetics of behavior. This review
      describes several behavioral plasticity paradigms in C. elegans and their
      underlying neuronal circuits and then goes on to review the forward genetic
      analysis that has been undertaken to identify genes involved in the execution of
      these behaviors. Lastly, the review outlines how reverse genetics and genomic
      approaches can guide the analysis of the role of genes in behavior and why and
      how they will complement the forward genetic analysis of behavior.

PMID- 12486706
TI  - Molecular and cellular cognitive studies of the role of synaptic plasticity in
      memory.
AB  - Synaptic plasticity has a central role in nearly all models of learning and
      memory. Besides experiments documenting changes in synaptic function during
      learning, most of the evidence supporting a role for synaptic plasticity in
      memory comes from manipulations that either enhance or lesion synaptic processes.
      In the last decade, mouse transgenetics (knock outs and transgenics) have
      provided compelling evidence that the molecular mechanisms responsible for the
      induction and stability of synaptic changes have a critical role in the
      acquisition and storage of information. Here, I will review this literature, with
      a special focus on studies of hippocampal-dependent learning and memory.

PMID- 12486707
TI  - Neural substrates of memory: from synapse to system.
AB  - One of the fundamental challenges of modern neuroscience is to understand how
      memories are acquired, stored, and retrieved by the brain. In the broadest terms,
      attempts to dissect memory can be broken down into four experimental disciplines:
      (1) identification of molecular components, (2) ex vivo and in vivo cellular
      analysis of neuronal function, (3) theoretical modeling approaches of neural
      systems, and (4) organismal-level behavioral analyses. Our objective here is to
      offer a conceptually unifying perspective and to discuss this perspective in
      relation to an experiment analysis of memory in Drosophila.

PMID- 12486708
TI  - Cellular bases of behavioral plasticity: establishing and modifying synaptic
      circuits in the Drosophila genetic system.
AB  - Genetic malleability and amenability to behavioral assays make Drosophila an
      attractive model for dissecting the molecular mechanisms of complex behaviors,
      such as learning and memory. At a cellular level, Drosophila has contributed a
      wealth of information on the mechanisms regulating membrane excitability and
      synapse formation, function, and plasticity. Until recently, however, these
      studies have relied almost exclusively on analyses of the peripheral
      neuromuscular junction, with a smaller body of work on neurons grown in primary
      culture. These experimental systems are, by themselves, clearly inadequate for
      assessing neuronal function at the many levels necessary for an understanding of
      behavioral regulation. The pressing need is for access to physiologically
      relevant neuronal circuits as they develop and are modified throughout life. In
      the past few years, progress has been made in developing experimental approaches
      to examine functional properties of identified populations of Drosophila central
      neurons, both in cell culture and in vivo. This review focuses on these exciting
      developments, which promise to rapidly expand the frontiers of functional
      cellular neurobiology studies in Drosophila. We discuss here the technical
      advances that have begun to reveal the excitability and synaptic transmission
      properties of central neurons in flies, and discuss how these studies promise to
      substantially increase our understanding of neuronal mechanisms underlying
      behavioral plasticity.

PMID- 12486709
TI  - Functional genomics of neural and behavioral plasticity.
AB  - How does the environment, particularly the social environment, influence brain
      and behavior and what are the underlying physiologic, molecular, and genetic
      mechanisms? Adaptations of brain and behavior to changes in the social or
      physical environment are common in the animal world, either as short-term (i.e.,
      modulatory) or as long-term modifications (e.g., via gene expression changes) in
      behavioral or physiologic properties. The study of the mechanisms and constraints
      underlying these dynamic changes requires model systems that offer plastic
      phenotypes as well as a sufficient level of quantifiable behavioral complexity
      while being accessible at the physiological and molecular level. In this article,
      I explore how the new field of functional genomics can contribute to an
      understanding of the complex relationship between genome and environment that
      results in highly plastic phenotypes. This approach will lead to the discovery of
      genes under environmental control and provide the basis for the study of the
      interrelationship between an individual's gene expression profile and its social
      phenotype in a given environmental context.

PMID- 12486710
TI  - Different data from different labs: lessons from studies of gene-environment
      interaction.
AB  - It is sometimes supposed that standardizing tests of mouse behavior will ensure
      similar results in different laboratories. We evaluated this supposition by
      conducting behavioral tests with identical apparatus and test protocols in
      independent laboratories. Eight genetic groups of mice, including equal numbers
      of males and females, were either bred locally or shipped from the supplier and
      then tested on six behaviors simultaneously in three laboratories (Albany, NY;
      Edmonton, AB; Portland, OR). The behaviors included locomotor activity in a small
      box, the elevated plus maze, accelerating rotarod, visible platform water escape,
      cocaine activation of locomotor activity, and ethanol preference in a two-bottle
      test. A preliminary report of this study presented a conventional analysis of
      conventional measures that revealed strong effects of both genotype and
      laboratory as well as noteworthy interactions between genotype and laboratory. We
      now report a more detailed analysis of additional measures and view the data for
      each test in different ways. Whether mice were shipped from a supplier or bred
      locally had negligible effects for almost every measure in the six tests, and sex
      differences were also absent or very small for most behaviors, whereas genetic
      effects were almost always large. For locomotor activity, cocaine activation, and
      elevated plus maze, the analysis demonstrated the strong dependence of genetic
      differences in behavior on the laboratory giving the tests. For ethanol
      preference and water escape learning, on the other hand, the three labs obtained
      essentially the same results for key indicators of behavior. Thus, it is clear
      that the strong dependence of results on the specific laboratory is itself
      dependent on the task in question. Our results suggest that there may be
      advantages of test standardization, but laboratory environments probably can
      never be made sufficiently similar to guarantee identical results on a wide range
      of tests in a wide range of labs. Interpretations of our results by colleagues in
      neuroscience as well as the mass media are reviewed. Pessimistic views, prevalent
      in the media but relatively uncommon among neuroscientists, of mouse behavioral
      tests as being highly unreliable are contradicted by our data. Despite the
      presence of noteworthy interactions between genotype and lab environment, most of
      the larger differences between inbred strains were replicated across the three
      labs. Strain differences of moderate effects size, on the other hand, often
      differed markedly among labs, especially those involving three 129-derived
      strains. Implications for behavioral screening of targeted and induced mutations
      in mice are discussed.

PMID- 12486711
TI  - Deep trefoil knot implicated in RNA binding found in an archaebacterial protein.

PMID- 12486712
TI  - Backbone dynamics of the CC-chemokine eotaxin-2 and comparison among the eotaxin
      group chemokines.
AB  - The eotaxin group chemokines (eotaxin, eotaxin-2, and eotaxin-3) share only 35
      41% sequence identity but are all agonists for the receptor CCR3. Here we present
      a detailed comparison between the backbone dynamics of these three chemokines.
      The dynamics of eotaxin-2 were determined from 15N NMR relaxation data and
      compared to those obtained previously for eotaxin and eotaxin-3. For all three
      chemokines, the majority of residues in the first two beta-strands and the alpha
      helix show highly restricted motions on the subnanosecond time scale but there is
      dramatically higher flexibility in the N- and C-terminal regions and also
      substantial mobility for residues in the N-loop region and the third beta-strand.
      The latter two regions form a groove on the chemokine surface that is the likely
      binding site for the N-terminal region of the receptor. Taken together, the
      available data suggest a model in which conformational rearrangements of both the
      chemokine and the receptor are likely to occur during binding and receptor
      activation.

PMID- 12486713
TI  - Phage-display and correlated mutations identify an essential region of subdomain
      1C involved in homodimerization of Escherichia coli FtsA.
AB  - FtsA plays an essential role in Escherichia coli cell division and is nearly
      ubiquitous in eubacteria. Several evidences postulated the ability of FtsA to
      interact with other septation proteins and with itself. To investigate these
      binding properties, we screened a phage-display library with FtsA. The isolated
      peptides defined a degenerate consensus sequence, which in turn displayed a
      striking similarity with residues 126-133 of FtsA itself. This result suggested
      that residues 126-133 were involved in homodimerization of FtsA. The hypothesis
      was supported by the analysis of correlated mutations, which identified a mutual
      relationship between a group of amino acids encompassing the ATP-binding site and
      a set of residues immediately downstream to amino acids 126-133. This information
      was used to assemble a model of a FtsA homodimer, whose accuracy was confirmed by
      probing multiple alternative docking solutions. Moreover, a prediction of
      residues responsible for protein-protein interaction validated the proposed model
      and confirmed once more the importance of residues 126-133 for homodimerization.
      To functionally characterize this region, we introduced a deletion in ftsA, where
      residues 126-133 were skipped. This mutant failed to complement conditional
      lethal alleles of ftsA, demonstrating that amino acids 126-133 play an essential
      role in E. coli.

PMID- 12486714
TI  - Modeling alpha-helical coiled-coil interactions: the axial and azimuthal
      alignment of 1B segments from vimentin intermediate filaments.
AB  - Attempts at predicting the relative axial alignments of fibrous protein molecules
      in filamentous structures have relied upon representing the (multichain)
      molecular structure by a one-dimensional sequence of amino acids. Potential
      intermolecular ionic and apolar interactions were counted and determined as a
      function of the relative axial stagger between the molecules. No attempts were
      made to consider the azimuthal aspect of the interacting molecules and neither
      were apolar or ionic energy terms used. Surprisingly, this simple approach proved
      remarkably informative and yielded accurate predictions of the axial periods
      present. However, a more comprehensive analysis involving the energetics of
      aggregation taking due regard for the relative azimuths of the molecules as well
      as their separation should decrease the noise level in the calculations and
      reveal other pertinent information. Toward that end, we have modeled the
      interaction between two alpha-helical coiled-coil segments in intermediate
      filament molecules (1B segments from human vimentin). The relative axial
      alignment and polarity of the molecules is already known from detailed
      crosslinking studies and this provides a criterion against which the success (or
      otherwise) of the modeling can be judged. The results confirm that an
      antiparallel alignment of two 1B segments is preferred over any of the parallel
      options (as observed experimentally). The calculated axial alignment, however, is
      not identical to that observed from detailed crosslinking studies indicating that
      other parts of the molecule (probably the head and tail domains as well as other
      coiled-coil segments) have a crucial role in determining the precise mode of
      axial aggregation. The results also show that the apolar interactions seem to be
      significantly less important in the alignment process than the ionic ones. This
      is consistent with the observation of a well-defined period in the linear
      disposition of the charged (but not apolar) residues along the length of the
      outer surface of the vimentin molecule.

PMID- 12486715
TI  - Interaction of E. coli outer-membrane protein A with sugars on the receptors of
      the brain microvascular endothelial cells.
AB  - Esherichia coli, the most common gram-negative bacteria, can penetrate the brain
      microvascular endothelial cells (BMECs) during the neonatal period to cause
      meningitis with significant morbidity and mortality. Experimental studies have
      shown that outer-membrane protein A (OmpA) of E. coli plays a key role in the
      initial steps of the invasion process by binding to specific sugar moieties
      present on the glycoproteins of BMEC. These experiments also show that polymers
      of chitobiose (GlcNAcbeta1-4GlcNAc) block the invasion, while epitopes
      substituted with the L-fucosyl group do not. We used HierDock computational
      technique that consists of a hierarchy of coarse grain docking method with
      molecular dynamics (MD) to predict the binding sites and energies of interactions
      of GlcNAcbeta1-4GlcNAc and other sugars with OmpA. The results suggest two
      important binding sites for the interaction of carbohydrate epitopes of BMEC
      glycoproteins to OmpA. We identify one site as the binding pocket for chitobiose
      (GlcNAcbeta1-4GlcNAc) in OmpA, while the second region (including loops 1 and 2)
      may be important for recognition of specific sugars. We find that the site
      involving loops 1 and 2 has relative binding energies that correlate well with
      experimental observations. This theoretical study elucidates the interaction
      sites of chitobiose with OmpA and the binding site predictions made in this
      article are testable either by mutation studies or invasion assays. These results
      can be further extended in suggesting possible peptide antagonists and drug
      design for therapeutic strategies.

PMID- 12486716
TI  - Dynamic effects of mutations within two loops of cytochrome c551 from Pseudomonas
      aeruginosa.
AB  - In this work, we investigated the structural and dynamic consequences of two
      substitutions, P58A and G36P, located in two different solvent-exposed loops of
      cytochrome c551. The results show that both mutations affect regions that are
      distant from the site of mutation. Here, the two loops appear to be dynamically
      coupled to each other, because the substitution at one site affects the structure
      and the dynamics of the other site. However, the substitutions at Gly-36 and Pro
      58 presented substantial differences, which were related to the mechanical
      (rigidity and deformability) properties of the site surrounding the mutation.
      Although the P58A mutant conserved a significant dynamic similarity to the wild
      type protein as the immediate surroundings of position 58 became more rigid, the
      G36P mutant, which had deformed its flexible surroundings, presented a dynamic
      behavior that was markedly different from that of the wild-type protein. These
      results suggest that perturbation of sterically isolated and flexible regions,
      such as solvent-exposed loops, can have strong dynamic consequences on the
      protein as a whole, raising the possibility that these effects could in turn
      affect the stability or the function of the protein.

PMID- 12486717
TI  - Structure of human aldose reductase holoenzyme in complex with statil: an
      approach to structure-based inhibitor design of the enzyme.
AB  - Aldose reductase, a monomeric NADPH-dependent oxidoreductase, catalyzes the
      reduction of a wide variety of aldehydes and ketones to their corresponding
      alcohols. The X-ray structure of human aldose reductase holoenzyme in complex
      with statil was determined at a resolution of 2.1 A. The carboxylate group of
      statil interacted with the conserved anion binding site located between the
      nicotinamide ring of the coenzyme and active site residues Tyr48, His110, and
      Trp111. Statil's hydrophobic phthalazinyl ring was bound in an adjacent pocket
      lined by residues Trp20, Phe122, and Trp219, with the bromo-fluorobenzyl group
      penetrating the "specificity" pocket. The interactions between the inhibitor's
      bromo-fluorobenzyl group and the enzyme include the stacking against the side
      chain of Trp111 as well as hydrogen bonding to residues Leu300 and Thr113. Based
      on the model of the ternary complex, the program GRID was used in an attempt to
      design novel potential inhibitors of human aldose reductase with enhanced binding
      energies of the complex. Molecular modeling calculations suggested that the
      replacement of the fluorine atom of statil with a carboxylate functional group
      may enhance the binding energies of the complex by 33%.

PMID- 12486718
TI  - Distal heme pocket regulation of ligand binding and stability in soybean
      leghemoglobin.
AB  - Leghemoglobins facilitate diffusion of oxygen through root tissue to a bacterial
      terminal oxidase in much the same way that myoglobin transports oxygen from blood
      to muscle cell mitochondria. Leghemoglobin serves an additional role as an oxygen
      scavenger to prevent inhibition of nitrogen fixation. For this purpose, the
      oxygen affinity of soybean leghemoglobin is 20-fold greater than myoglobin,
      resulting from an 8-fold faster association rate constant combined with a 3-fold
      slower dissociation rate constant. Although the biochemical mechanism used by
      myoglobin to bind oxygen has been described in elegant detail, an explanation for
      the difference in affinity between these two structurally similar proteins is not
      obvious. The present work demonstrates that, despite their similar structures,
      leghemoglobin uses methods different from myoglobin to regulate ligand affinity.
      Oxygen and carbon monoxide binding to a comprehensive set of leghemoglobin distal
      heme pocket mutant proteins in comparison to their myoglobin counterparts has
      revealed some of these mechanisms. The "distal histidine" provides a crucial
      hydrogen bond to stabilize oxygen in myoglobin but has little effect on bound
      oxygen in leghemoglobin and is retained mainly for reasons of protein stability
      and prevention of heme loss. Furthermore, soybean leghemoglobin uses an unusual
      combination of HisE7 and TyrB10 to sustain a weak stabilizing interaction with
      bound oxygen. Thus, the leghemoglobin distal heme pocket provides a much lower
      barrier to oxygen association than occurs in myoglobin and oxygen dissociation is
      regulated from the proximal heme pocket.

PMID- 12486719
TI  - The HI0073/HI0074 protein pair from Haemophilus influenzae is a member of a new
      nucleotidyltransferase family: structure, sequence analyses, and solution
      studies.
AB  - The crystal structure of HI0074 from Haemophilus influenzae, a protein of unknown
      function, has been determined at a resolution of 2.4 A. The molecules form an up
      down, four-helix bundle, and associate into homodimers. The fold is most closely
      related to the substrate-binding domain of KNTase, yet the amino acid sequences
      of the two proteins exhibit no significant homology. Sequence analyses of
      completely and incompletely sequenced genomes reveal that the two adjacent genes,
      HI0074 and HI0073, and their close relatives comprise a new family of
      nucleotidyltransferases, with 15 members at the time of writing. The analyses
      also indicate that this is one of eight families of a large
      nucleotidyltransferase superfamily, whose members were identified based on the
      proximity of the nucleotide- and substrate-binding domains on the respective
      genomes. Both HI0073 and HI0074 were annotated "hypothetical" in the original
      genome sequencing publication. HI0073 was cloned, expressed, and purified, and
      was shown to form a complex with HI0074 by polyacrylamide gel electrophoresis
      under nondenaturing conditions, analytic size exclusion chromatography, and
      dynamic light scattering. Double- and single-stranded DNA binding assays showed
      no evidence of DNA binding to HI0074 or to HI0073/HI0074 complex despite the
      suggestive shape of the putative binding cleft formed by the HI0074 dimer.

PMID- 12486720
TI  - High-resolution structure and biochemical properties of a recombinant Proteus
      mirabilis catalase depleted in iron.
AB  - Heme catalases are homotetrameric enzymes with a highly conserved complex
      quaternary structure, and their functional role is still not well understood.
      Proteus mirabilis catalase (PMC), a heme enzyme belonging to the family of NADPH
      binding catalases, was efficiently overexpressed in E. coli. The recombinant
      catalase (rec PMC) was deficient in heme with one-third heme and two-thirds
      protoporphyrin IX as determined by mass spectrometry and chemical methods. This
      ratio was influenced by the expression conditions, but the enzyme-specific
      activity calculated relative to the heme content remained unchanged. The crystal
      structure of rec PMC was solved to a resolution of 2.0 A, the highest resolution
      obtained to date with PMC. The overall structure was quite similar to that of
      wild-type PMC, and it is surprising that the absence of iron had no effect on the
      structure of the active site. Met 53 close to the essential His 54 was found less
      oxidized in rec PMC than in the wild-type enzyme. An acetate anion was modeled in
      an anionic pocket, away from the heme group but important for the enzymatic
      reaction. An alternate conformation observed for Arg 99 could play a role in the
      formation of the H-bond network connecting two symmetrical subunits of the
      tetramer.

PMID- 12486721
TI  - Protein side-chain rearrangement in regions of point mutations.
AB  - A major problem in predicting amino acid side-chain rearrangements following
      point mutations is the potentially large search space. We analyzed a nonredundant
      data set of 393 Protein Data Bank protein pairs, each consisting of structures
      differing in one amino acid, to determine the number of residues changing
      conformation in the region of mutation. In 91-95% of cases, two or fewer residues
      underwent side-chain conformational change. If mutation sites with backbone
      displacements were excluded, the number increased to 97%. The majority of
      rearrangements (over 60%) were due to the inherent flexibility of side-chains, as
      derived from analysis of a control set of protein subunits whose crystal
      structures were determined more than once. Different amino acids demonstrated
      different degrees of flexibility near mutation sites. Large polar or charged
      residues, and serine, are more flexible, while the aromatic amino acids, and
      cysteine, are less so. This pattern is common to the inherent side-chain
      flexibility, as well as the increased flexibility at ligand binding sites and
      mutation sites. The probability for conformational change was correlated with B
      factor, frequency of the side-chain conformation in proteins and solvent
      accessibility. The last trend was stronger for aromatic and hydrophilic residues
      than for hydrophobic ones. We conclude that the search space for predicting side
      chain conformations in the region of mutation can be effectively restricted.
      However, the overall ability to predict a particular side-chain conformation, or
      to check predictions according to individual existing structures, is limited.
      These findings may be useful in deriving empirical rules for modeling side-chain
      conformations.

PMID- 12486722
TI  - BisANS binding to tubulin: isothermal titration calorimetry and the site-specific
      proteolysis reveal the GTP-induced structural stability of tubulin.
AB  - Interactions of bisANS and ANS to tubulin in the presence and absence of GTP were
      investigated, and the binding and thermodynamic parameters were determined using
      isothermal titration calorimetry. Like bisANS binding to tubulin, we observed a
      large number of lower affinity ANS binding sites (N1 = 1.3, K1 = 3.7 x 10(5) M(
      1), N2 = 10.5, K2 = 7 x 10(4)/M(-1)) in addition to 1-2 higher affinity sites.
      Although the presence of GTP lowers the bisANS binding to both higher and lower
      affinity sites (N1 = 4.3, N2 = 11.7 in absence and N1 = 1.8, N2 = 3.6 in presence
      of GTP), the stoichiometries of both higher and lower affinity sites of ANS
      remain unaffected in the presence of GTP. BisANS-induced structural changes on
      tubulin were studied using site-specific proteolysis with trypsin and
      chymotrypsin. Digestion of both alpha and beta tubulin with trypsin and
      chymotrypsin, respectively, has been found to be very specific in presence of
      GTP. GTP has dramatic effects on lowering the extent of nonspecific digestion of
      beta tubulin with trypsin and stabilizing the intermediate bands produced from
      both alpha and beta. BisANS-treated tubulin is more susceptible to both trypsin
      and chymotrypsin digestion. At higher bisANS concentration (>20 microM) both
      alpha and beta tubulins are almost totally digested with enzymes, indicating
      bisANS-induced unfolding or destabilization of tubulin structure. Again, the
      addition of GTP has remarkable effect on lowering the bisANS-induced enhanced
      digestion of tubulin as well as stabilizing effect on intermediate bands. These
      results of isothermal titration calorimetry, proteolysis and the DTNB-kinetics
      data clearly established that the addition of GTP makes tubulin compact and rigid
      and hence the GTP-induced stabilization of tubulin structure. No such
      destabilization of tubulin structure has been noticed with ANS, although, like
      bisANS, ANS possesses a large number of lower affinity binding sites. On the
      basis of these results, we propose that the unique structure of bisANS, which in
      absence of GTP can bind tubulin as a bifunctional ligand (through its two ANS
      moieties), is responsible for the structural changes of tubulin.

PMID- 12486723
TI  - A novel approach to the recognition of protein architecture from sequence using
      Fourier analysis and neural networks.
AB  - A novel method is presented for the prediction of protein architecture from
      sequence using neural networks. The method involves the preprocessing of protein
      sequence data by numerically encoding it and then applying a Fourier transform.
      The encoded and transformed data are then used to train a neural network to
      recognize a number of different protein architectures. The method proved
      significantly better than comparable alternative strategies such as percentage
      dipeptide frequency, but is still limited by the size of the data set and the
      input demands of a neural network. Its main potential is as a complement to
      existing fold recognition techniques, with its ability to identify global
      symmetries within protein structures its greatest strength.

PMID- 12486724
TI  - Predictive crystallization of ribonuclease A via rapid screening of osmotic
      second virial coefficients.
AB  - Important progress has been made in recent years toward developing a molecular
      level understanding of protein phase behavior in terms of the osmotic second
      virial coefficient, a thermodynamic parameter that characterizes pairwise protein
      interactions. Yet there has been little practical application of this knowledge
      to the field of protein crystallization, largely because of the difficult and
      time-consuming nature of traditional techniques for characterizing protein
      interactions. Self-interaction chromatography has recently been proposed as a
      highly efficient method for measuring the osmotic second virial coefficient. The
      utility of the technique is examined in this work by characterizing virial
      coefficients for ribonuclease A under 59 solution conditions using several
      crystallization additives, including PEG, sodium chloride, ammonium sulfate, and
      propanol. The virial coefficient measurements show some counterintuitive trends
      and shed light on the previous difficulties in crystallizing ribonuclease A.
      Crystallization experiments at the corresponding solution conditions were
      conducted by using ultracentrifugal crystallization. Using this methodology,
      ribonuclease A crystals were obtained under conditions for which the virial
      coefficients fell within the "crystallization slot." Crystallographic
      characterization showed that the crystals diffract to high resolution. Metastable
      crystals were also obtained for conditions outside, but near, the
      "crystallization slot," and they could also be frozen and used to collect
      structural information.

PMID- 12486725
TI  - Insights into the bile acid transportation system: the human ileal lipid-binding
      protein-cholyltaurine complex and its comparison with homologous structures.
AB  - Bile acids are generated in vivo from cholesterol in the liver, and they undergo
      an enterohepatic circulation involving the small intestine, liver, and kidney. To
      understand the molecular mechanism of this transportation, it is essential to
      gain insight into the three-dimensional (3D) structures of proteins involved in
      the bile acid recycling in free and complexed form and to compare them with
      homologous members of this protein family. Here we report the solution structure
      of the human ileal lipid-binding protein (ILBP) in free form and in complex with
      cholyltaurine. Both structures are compared with a previously published structure
      of the porcine ILBP-cholylglycine complex and with related lipid-binding
      proteins. Protein structures were determined in solution by using two-dimensional
      (2D)- and 3D-homo and heteronuclear NMR techniques, leading to an almost complete
      resonance assignment and a significant number of distance constraints for
      distance geometry and restrained molecular dynamics simulations. The
      identification of several intermolecular distance constraints unambiguously
      determines the cholyltaurine-binding site. The bile acid is deeply buried within
      ILBP with its flexible side-chain situated close to the fatty acid portal as
      entry region into the inner ILBP core. This binding mode differs significantly
      from the orientation of cholylglycine in porcine ILBP. A detailed analysis using
      the GRID/CPCA strategy reveals differences in favorable interactions between
      protein-binding sites and potential ligands. This characterization will allow for
      the rational design of potential inhibitors for this relevant system.

PMID- 12486726
TI  - Structure of deoxyhemoglobin: ionizable groups and polyethylene glycol.
AB  - X-ray studies on deoxy-hemoglobin have been reported on crystals grown under
      conditions of high (about 2.5 M) and low salt (about 0.1 M). The high-salt
      crystals were grown in water, whereas the low-salt crystals were prepared in
      polyethylene glycol solutions (m.w. 6000-8000 Da, 10-30% w/v). Oxygen-binding
      characteristics of hemoglobin in these two environments differ radically. In salt
      solutions, hemoglobin binds oxygen with a p50 value of about 5 torr of oxygen and
      in a cooperative manner characterized with an n value of Hill varying from two to
      three. In polyethylene glycol solutions, hemoglobin crystals are oxygenated with
      a p50 value of about 270 torr of oxygen, without exhibiting a cooperative effect.
      I report on a detailed study of the X-ray data defining the dimer interface
      (alpha1beta2) of these two forms of hemoglobin. The study reveals that the main
      difference between the two structures lies in the number and arrangement of the
      water molecules and in distances between ionizable side chains in the dimer
      interface. I propose that these differences lead to significant shifts in the pK
      values of the ionizable groups in the dimer interface.

PMID- 12486727
TI  - Differential scanning calorimetric, circular dichroism, and Fourier transform
      infrared spectroscopic characterization of the thermal unfolding of xylanase A
      from Streptomyces lividans.
AB  - The thermal unfolding of xylanase A from Streptomyces lividans, and of its
      isolated substrate binding and catalytic domains, was studied by differential
      scanning calorimetry and Fourier transform infrared and circular dichroism
      spectroscopy. Our calorimetric studies show that the thermal denaturation of the
      intact enzyme is a complex process consisting of two endothermic events centered
      near 57 and 64 degrees C and an exothermic event centered near 75 degrees C, all
      of which overlap slightly on the temperature scale. A comparison of the data
      obtained with the intact enzyme and isolated substrate binding and catalytic
      domains indicate that the lower- and higher-temperature endothermic events are
      attributable to the thermal unfolding of the xylan binding and catalytic domains,
      respectively, whereas the higher-temperature exothermic event arises from the
      aggregation and precipitation of the denatured catalytic domain. Moreover, the
      thermal unfolding of the two domains of the native enzyme are thermodynamically
      independent and differentially sensitive to pH. The unfolding of the substrate
      binding domain is a reversible two-state process and, under appropriate
      conditions, the refolding of this domain to its native conformation can occur. In
      contrast, the unfolding of the catalytic domain is a more complex process in
      which two subdomains unfold independently over a similar temperature range. Also,
      the unfolding of the catalytic domain leads to aggregation and precipitation,
      which effectively precludes the refolding of the protein to its native
      conformation. These observations are compatible with the results of our
      spectroscopic studies, which show that the catalytic and substrate binding
      domains of the enzyme are structurally dissimilar and that their native
      conformations are unaffected by their association in the intact enzyme. Thus, the
      calorimetric and spectroscopic data demonstrate that the S. lividans xylanase A
      consists of structurally dissimilar catalytic and substrate binding domains that,
      although covalently linked, undergo essentially independent thermal denaturation.
      These observations provide valuable new insights into the structure and thermal
      stability of this enzyme and should assist our efforts at engineering xylanases
      that are more thermally robust and otherwise better suited for industrial
      applications.

PMID- 12486728
TI  - Structural modeling of ataxin-3 reveals distant homology to adaptins.
AB  - Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG
      repeat expansion in the coding region of a gene encoding ataxin-3, a protein of
      yet unknown function. Based on a comprehensive computational analysis, we propose
      a structural model and structure-based functions for ataxin-3. Our predictive
      strategy comprises the compilation of multiple sequence and structure alignments
      of carefully selected proteins related to ataxin-3. These alignments are
      consistent with additional information on sequence motifs, secondary structure,
      and domain architectures. The application of complementary methods revealed the
      homology of ataxin-3 to ENTH and VHS domain proteins involved in membrane
      trafficking and regulatory adaptor functions. We modeled the structure of ataxin
      3 using the adaptin AP180 as a template and assessed the reliability of the model
      by comparison with known sequence and structural features. We could further infer
      potential functions of ataxin-3 in agreement with known experimental data. Our
      database searches also identified an as yet uncharacterized family of proteins,
      which we named josephins because of their pronounced homology to the Josephin
      domain of ataxin-3.

PMID- 12486729
TI  - Crystal structure of a zinc-containing glycerol dehydrogenase (TM0423) from
      Thermotoga maritima at 1.5 A resolution.

PMID- 12486730
TI  - Crystal structure of YbaB from Haemophilus influenzae (HI0442), a protein of
      unknown function coexpressed with the recombinational DNA repair protein RecR.

PMID- 12486731
TI  - Anatomy and physiology of the perionychium.
AB  - The nail is a unique structure in the human. Its anatomy and physiology are not
      well understood by many physicians caring for nail problems. The perionychial
      anatomy is described along with the physiology pertinent to care of the nail and
      its surroundings.

PMID- 12486732
TI  - Anatomical variations of the ten triangles around the cavernous sinus.
AB  - The dimensions of the 10 triangles around the cavernous sinus were measured to
      define the anatomical characteristics of the triangles and to compare their
      consistency in shape and area. Twelve tissue blocks containing the bilateral
      cavernous sinuses and medial two-thirds of the middle cranial fossae were
      obtained from Japanese adults at autopsy, fixed to a stereotactic frame, and
      examined with an operative microscope. The dimensions of each triangle were
      measured with calipers and compared, based on the same point and border. The
      anteromedial triangle and the superolateral (Parkinson's) triangle were more
      consistent in shape than the paramedial and oculomotor triangles, but the
      oculomotor triangle was larger in area than these other triangles. The
      posteromedial (Kawase's) triangle was more consistent in shape and larger than
      the anterolateral, lateral, and the posterolateral (Glasscock's) triangles. The
      anteromedial and superolateral (Parkinson's) triangles are important for the
      combined epi- and subdural approach to cavernous sinus lesions. The posteromedial
      (Kawase's) triangle is important for gaining access to the posterior cranial
      fossa from the middle cranial fossa.

PMID- 12486733
TI  - Finding an ideal site for intraosseous infusion of the tibia: an anatomical
      study.
AB  - Intraosseous infusion is a technique used for the administration of fluids to a
      hemodynamically shocked child in whom attempts to access the vascular system have
      been unsuccessful. Although few complications are seen, injury to the epiphyseal
      growth plate during the performance of this technique remains a serious problem.
      This study investigates the relationship between the site of insertion of the
      intraosseous needle and the epiphyseal growth plate, and the ease of needle
      insertion into various locations of the tibia in newborn infants. Fourteen
      newborn infant cadavers (28 tibias in total) were dissected after placement of
      four needles: 1). through the tibial tuberosity (Site A); 2). 10 mm distal to the
      tibial tuberosity (Site B); 3). 20 mm distal to the tibial tuberosity (Site C)
      and; 4). 10 mm proximal to the tibial tuberosity (Site D). Distances from the
      distal end of the epiphyseal growth plate were measured. A high number of needle
      placements at Site A were inserted into the epiphyseal growth plate. Most
      placements at Site B were between 10 and 16 mm from the epiphyseal growth plate
      on the right side and between 10 and 15 mm on the left side, and all were
      inserted without difficulty. Although far from the epiphyseal growth plate, most
      placements at Site C were very difficult to insert because of the thick cortical
      bone. All placements at Site D entered the epiphysis or the epiphysis and joint
      space of the knee. An insertion site of at least 10 mm distal to the tibial
      tuberosity is therefore recommended to avoid epiphyseal growth plate injury and
      ensure ease of insertion.

PMID- 12486734
TI  - Vascularity and neuroreceptors of the pes anserinus: anatomic study.
AB  - The primary aim of this work was to evaluate the neurovascular network of the pes
      anserinus (PA) at its tibial insertion because the PA is often used for anterior
      cruciate ligament (ACL) reconstruction. Four fresh cadaver knees were injected
      with India ink gelatin solution and the arteries that supply blood to the PA were
      identified; microscopic studies of vessels and nerve fibers were also performed.
      Superficial and deep branches of the inferior medial genicular artery contribute
      to an arterial arch that courses deep to the PA insertion. A widespread array of
      small vessels and nerve fibers penetrate the PA insertion and course along the
      length of the gracilis and semitendinosus tendons. Computer analysis revealed
      that the mean diameter of the vessels decreased from 2201 microm at the insertion
      to 661 microm midway along the length of the tendon (mean tendon length = 17 cm;
      range = 13-21 cm); the cross-sectional area of the vessels per histologic section
      decreased from 336.37-137.05 microm(2). This study demonstrates that the PA
      insertion is well vascularized and richly innervated and that these morphological
      features continue along the length of the tendons.

PMID- 12486735
TI  - Extensive somatosensory innervation in infants with obstetric brachial palsy.
AB  - In the pre-operative screening of infants with obstetric brachial palsy (OBP),
      the results of routine electromyography are often overly optimistic when compared
      to the peri-operative findings. This prompted us to include investigation of the
      sensory innervation of these infants using the N20 (the first cortical response
      to a peripheral stimulation) of the somatosensory evoked potentials (SSEP). Three
      to seven months after birth, SSEP were recorded at the skull after stimulation of
      the thumb and middle finger in infants with obstetric rupture of the upper trunk
      or avulsion of roots C5, C6, or C7, and in whom no clinical improvement of motor
      function was observed in the biceps brachii and deltoid muscles. In most infants,
      a normal N20 could be evoked, indicating the existence of peripheral sensory
      pathways. From the thumb, these sensory pathways would necessarily bypass the
      upper trunk and dorsal roots of spinal nerves C5 and C6, and from the middle
      finger bypass the middle trunk and dorsal root C7, before extending into the
      dorsal column and projecting toward the thalamus and cerebral cortex. These data
      suggest that in infancy the segmental sensory innervation of the hand is more
      diverse than is described in most textbooks.

PMID- 12486736
TI  - Coexistence of multiple anomalies in the celiac-mesenteric arterial system.
AB  - The origins and distribution of arteries of the celiac-mesenteric system were
      examined by dissection of 52 formalin-fixed human cadavers. Seventy-five percent
      of the cadavers exhibited the classic Michels' Type I hepatolienogastric pattern;
      25% had different branching patterns. Multiple anomalies of the celiac-mesenteric
      arterial system were observed in one Caucasian female cadaver: a short
      lienogastric trunk; a common hepatic artery arising directly from the abdominal
      aorta; an anomalous course of the hepatic arteries; an accessory left hepatic
      artery arising from the left and right gastric arterial anastomosis along the
      lesser curvature of the stomach; a double cystic artery; a common inferior
      phrenic trunk arising from the celiac trunk; and an aberrant arterial channel
      connecting the proximal segments of the splenic and gastroduodenal arteries. A
      patent ductus venosus and an anomalous formation of the portal vein by the
      confluence of the splenic and superior and inferior mesenteric veins was also
      observed. Although single anomalies of the celiac-mesenteric arterial system are
      common, complex combinations, such as were observed in the present case,
      represent a significant deviation from the normal developmental pattern. There
      seems to be no report in the literature of such a combination of anomalies
      coexisting in one individual. The developmental and clinical significance of
      these anomalous vessels is discussed.

PMID- 12486737
TI  - Multiple variations of abdominal vessels in a single cadaver.
AB  - Variations of abdominal vessels are common and there are many reports about this
      subject. We report numerous variations of the superior part of the abdominal
      aorta and renal vessels which were determined in a single cadaver.

PMID- 12486738
TI  - Anomalous flexor of the little finger.
AB  - We report an anomalous palmar muscle belly of the flexor digitorum superficialis
      muscle (FDS) in the right hand of an 80-year-old female cadaver. The muscle
      originated from the center of the volar surface of the flexor retinaculum and
      inserted onto the palmar aspect of the base of the middle phalanx of the little
      finger. Its tendon of insertion divided into two bands, a pattern typical of the
      FDS tendon, between which the tendon of flexor digitorum profundus muscle to the
      little finger passed. The tendon of the usual antebrachial FDS to the little
      finger was absent. The anomalous muscle belly was innervated by a branch from the
      median nerve.

PMID- 12486739
TI  - Teaching and learning gross anatomy using modern electronic media based on the
      visible human project.
AB  - This article reviews online (Internet) anatomy projects and multimedia
      productions (books and CD-ROMs) based on the Visible Human Project (VHP) of the
      United States National Library of Medicine. The focus of these projects and
      productions is on the teaching of 3D anatomy using the digitized sections of the
      visible human male and female. The article also provides information about the
      VHP, its goals and what it has achieved thus far.

PMID- 12486740
TI  - Profile of on-line anatomy information resources: design and instructional
      implications.
AB  - This study is based on a review of 40 on-line anatomy web resources compiled from
      sites selected from our own searches as well as sites reviewed and published by
      an external group (Voiglio et al., 1999, Surg. Radiol. Anat. 21:65-68; Frasca et
      al., 2000, Surg. Radiol. Anat. 22:107-110). The purpose of our survey was to
      propose criteria by which anatomy educators could judge the characteristics of
      the currently available web-based resources for incorporation into the courses
      they teach. Each site was reviewed and scored based on a survey matrix that
      included four main categories: 1). site background information, 2). content
      components, 3). interactivity features, and 4). user interface design components.
      The average score of the reviewed sites was 3.3 of the total possible score of
      10, indicating the limited use of computer-based design features by the majority
      of sites. We found, however, a number of programs in each of the survey
      categories that could serve as prototypes for designing future on-line anatomy
      resources. From the survey we conclude that various design features are less
      important than the comprehensiveness, depth, and logical organization of content.
      We suggest that the content should be sufficient for supporting explicitly
      defined educational objectives, which should target specific end-user
      populations. The majority of anatomy programs currently accessible on-line fall
      short of these requirements. There is a need for a coordinated and synergistic
      effort to generate a comprehensive anatomical information resource that is of
      sufficient quality and depth to support higher levels of learning beyond the
      memorization of structure names. Such a resource is a prerequisite for meaningful
      on-line anatomy education.

PMID- 12486741
TI  - Clinical conundrum.

PMID- 12486743
TI  - Terminological desiderata.

PMID- 12486744
TI  - Terminological desiderata.

PMID- 12486746
TI  - Terminogical desiderata.

PMID- 12486747
TI  - ICH E9 guideline 'Statistical principles for clinical trials': a case study.
AB  - The International Conference on Harmonization (ICH) E9 guideline 'Statistical
      principles for clinical trials' was adopted by the Committee for Proprietary
      Medicinal Products in March 1998, and consequently is operational in Europe. It
      has also been adopted in the U.S.A. and Japan. The aim of this paper is to relate
      the problems encountered during a recent regulatory submission to those discussed
      in the ICH E9 guideline. Statistical principles discussed in the guideline, but
      not comprehensively addressed when the clinical development programme was
      initiated in the mid-1990s, will be reviewed. The impact of each issue on the
      approvability of the dossier will be discussed, together with recommendations on
      how to avoid such problems with other ongoing clinical development programmes.

PMID- 12486749
TI  - Selective exclusion of treatment arms in multi-arm randomized clinical trials.
AB  - In this paper we discuss a design for multi-arm randomized clinical trials (RCTs)
      in which clinicians and their patients can selectively exclude one of the
      randomized treatment arms. This approach has the advantage that it should
      expedite protocol development, and allow easier and faster recruitment of
      patients into the trial. However, to preserve the randomized nature of treatment
      comparisons, not all recruited patients can be included in all treatment
      comparisons. This dictates that treatment arms are compared in a pairwise
      fashion, and that the numbers of patients included in different treatment
      comparisons may not be equal. The total trial size of a multi-arm RCT that
      allowed selective exclusion of arms would be greater than the size of an
      equivalent standard multi-arm RCT. However, the duration of time taken to recruit
      the study would be reduced. The implications for the design, monitoring and
      analysis of such RCTs are discussed.

PMID- 12486750
TI  - Tests for individual and population bioequivalence based on generalized p-values.
AB  - The U.S. Food and Drug Administration (FDA) has proposed new regulations that
      address the 'prescribability' and 'switchability' of new formulations of already
      approved drugs. These new criteria are known, respectively, as population and
      individual bioequivalence. Two methods have been proposed in the bioequivalence
      literature for assessing population and individual bioequivalence that calculate
      an upper 95 per cent confidence bound for the bioequivalence criterion in
      question, and then test bio-equivalence by comparing this bound to the limit
      established by the FDA. In this paper we propose applying the generalized test
      function (GTF) methodology of Tsui and Weerahandi (Journal of the American
      Statistical Association 1989; 602-607) to this problem to produce tests based on
      a generalized p-value (GPV). This methodology allows us to construct hypothesis
      tests in the presence of nuisance parameters. Using simulation we show that these
      tests perform well in comparison to the confidence interval methods and have
      superior power for assessing population bioequivalence.

PMID- 12486751
TI  - In vitro bioequivalence testing.
AB  - A statistical test is proposed for in vitro bioequivalence testing between drug
      products such as nasal aerosols and nasal sprays. The proposed test generalizes
      the one recommended in the FDA 1999 guidance to the situation where replicated
      observations obtained from each sampled canister or bottle of the drug product
      are available. The technique developed by Hyslop, Hsuan and Holder is used so
      that the proposed test is asymptotically accurate. The type I error probability
      and power of the proposed test are investigated through a simulation study. A
      method for determining the required sample size to achieve a desired power is
      also proposed. A numerical example is given for illustration.

PMID- 12486752
TI  - Improved up-and-down designs for phase I trials.
AB  - We consider several designs from the family of up-and-down rules for the
      sequential allocation of dose levels to subjects in a dose-response study. We
      show that an up-and-down design can be improved by using more information than
      the most recent response. For example, the k-in-a-row rule uses up to the k most
      recent responses. We introduce a new design, the Narayana rule, which uses a
      local estimate of the probability of toxicity calculated from all previous
      responses. For the Narayana rule, as the sample size gets large, the probability
      of assignment goes to zero for dose levels not among the two (or three) closest
      to the target. Different estimators of the target dose are compared. We find that
      the isotonic regression estimator is superior to other estimators for small to
      moderate sample sizes.

PMID- 12486753
TI  - Alternative definitions of comparable case groups and estimates of lead time and
      benefit time in randomized cancer screening trials.
AB  - Randomized screening trials provide the optimal means of assessing the benefit of
      screening for cancer and other chronic diseases. Unlike therapy trials, however,
      where strict eligibility criteria assure the comparability of cases of disease in
      the arms of the trial, the cancer cases identified during follow-up are a subset
      of all randomized participants. Furthermore, those cases detected by screening
      tend to arise from length biased sampling which also can bias estimates of the
      screening benefit and of average lead time. To reduce or eliminate this bias, we
      propose several methods for defining comparable groups of cases from the trial
      arms. We examine, via simulation, these methods with respect to their effects on
      (i). point and interval estimates of average lead time and average benefit time
      and (ii). the logrank test statistic for a mortality effect of screening. The
      most successful new method for defining comparable case groups uses an estimate
      of the mean sojourn time (mean preclinical duration), and results in nearly
      unbiased estimates of average lead time and average benefit time as well as an
      unbiased logrank test statistic.

PMID- 12486754
TI  - Late detection of breast and colorectal cancer in Minnesota counties: an
      application of spatial smoothing and clustering.
AB  - Cancers detected at a later disease stage are associated with significantly
      higher mortality risk. Lack of uniformity in county-level cancer detection rates
      is thus of substantial interest to state health departments and other public
      health professionals. In this paper, we perform several spatial analyses of
      breast and colorectal cancer detection data for Minnesota counties for 1995-1997.
      We look for outliers and clusters in the late detection rates using a number of
      techniques: (i). applying various mapping schemes, (ii). smoothing the data using
      Bayesian methods implemented via Markov chain Monte Carlo, and (iii). applying
      maximum likelihood techniques to test for the presence of clusters and to
      identify the most likely clustersOur results suggest a fairly uniform spatial
      pattern in both sets of detection rates. Spatially smoothed rates did not reveal
      clusters of counties with significantly higher late detection risk, nor were
      county-level covariates (such as income, education, and race) particularly
      helpful in explaining the rates. However, our spatial clustering approach (using
      the scan statistic) did produce statistically significant clusters of counties
      which may indicate differences of practical importance for public health.

PMID- 12486755
TI  - Case-control studies of genotypic relative risks using children of cases as
      controls.
AB  - The use of a child as a case's control in a case-control study of genetic factors
      may be advantageous in some situations. We describe three methods of analysing
      such data. A method based upon the unconditional likelihood using case/child
      pairings apparently is the most efficient method. However, a conditional
      likelihood method using case/child pairs is more robust in that it allows for
      heterogeneity of the genetic trait among subpopulations as long as matings occur
      only within the same subpopulation. We argue that the child can be considered a
      genetic surrogate for the missing spouse and hence such designs are as valid as
      are those using spouses.

PMID- 12486756
TI  - Tumour grading from magnetic resonance spectroscopy: a comparison of feature
      extraction with variable selection.
AB  - Magnetic resonance spectroscopy (MRS) provides a non-invasive measurement of the
      biochemistry of living tissue. However, signal variation due to tissue
      heterogeneity causes considerable mixing between different disease categories,
      making accurate class assignments difficult. This paper compares a systematic
      methodology for classifier design using multivariate bayesian variable selection
      (MBVS), with one based on feature extraction using independent component analysis
      (ICA). We illustrate the methodology and assess the classification performance
      using a data set comprising 41 magnetic resonance spectra acquired in vivo from
      two grades of brain tumour, namely low- and medium-grade astrocytic tumours,
      labelled astrocytomas (AST), and high-grade gliomas and glioblastomas labelled
      glioblastomas (GL). The aim of this study is threefold. First, to describe the
      application of the alternative methodologies to MRS, then to benchmark their
      classification performance, and finally to interpret the classification models in
      terms of biologically relevant signals derived from the spectra. The
      classification performance is assessed using the bootstrap method and by
      application to a test sample in a retrospective study.

PMID- 12486757
TI  - Comment on antiepileptics and antipsychotics.

PMID- 12486759
TI  - Annual commentary on human teratogens.

PMID- 12486760
TI  - Conjoined twins in a monozygotic triplet pregnancy: prenatal diagnosis and X
      inactivation.
AB  - BACKGROUND: The etiology of monozygotic twinning is not known. Some investigators
      have implicated abnormal X-inactivation, which could also be related to the
      increased female:male ratio in higher order multiple gestations in general, and
      in monozygotic and conjoined twins (CTS) in particular. CTS are rare, and even
      more unusual when part of a triplet pregnancy. METHODS: DNA polymorphism analysis
      using 13 markers in the buccal cells of the triplets and the lymphocytes of the
      parents were used to evaluate zygosity. We investigated the X-inactivation
      pattern of the triplets by analyzing methylation at the androgen receptor gene.
      RESULTS: We found a female triplet gestation consisting of CTS and a normal
      singleton. The thoracopagus CTS were joined from the clavicles to the umbilicus.
      Congenital heart disease was suspected antenatally, but the precise delineation
      of the heart defects required extensive postnatal evaluation. There was a single
      placental mass with a thin dividing membrane. Cesarean section was carried out at
      32 weeks after the onset of labor. Histologically, the placenta was diamniotic
      monochorionic. The normal singleton did well after delivery; the CTS died at 35
      days from cardiopulmonary collapse. The babies were monozygotic (>99.99%
      probability). Each baby in this triplet set exhibited a random and symmetric X
      inactivation pattern. The degree of X-inactivation skewing fell in the range of
      50-65%. CONCLUSION: Genetic or environmental factors other than abnormal X
      inactivation must be involved in causing monozygous multiple gestation or CTS.
      Despite prenatal diagnosis, shared myocardium or cardiac anomalies in CTS often
      determine the prognosis.

PMID- 12486761
TI  - Diprosopus: a unique case and review of the literature.
AB  - BACKGROUND: We present a case of partial facial duplication in a male infant.
      METHODS: The clinical, radiological, and laboratory findings for this patient are
      described, followed by a review of the literature. RESULTS: Craniofacial
      duplication is a rare form of conjoined twinning and presents in a wide spectrum,
      from dicephalus to diprosopus to partial facial duplication. Many of these cases
      can be diagnosed prenatally. Prenatal assessment of our patient revealed only
      agenesis of the corpus callosum. CONCLUSIONS: The pathogenesis is believed to
      involve duplication of the notochord. Where there are more severe associated
      anomalies, the prognosis is poor. Partial facial duplication, as in our case, is
      associated with fewer anomalies, and the prognosis is better. Symmetry and an
      excess of tissue, rather than deficiency, favor a positive result.

PMID- 12486762
TI  - Role of caspases in murine limb bud cell death induced by 4
      hydroperoxycyclophosphamide, an activated analog of cyclophosphamide.
AB  - BACKGROUND: Caspases play a pivotal role in the regulation and execution of
      apoptosis, an essential process during limb development. Caspase 8 activation is
      usually downstream of the Fas/FasL death receptors, whereas caspase 9 mediates
      the mitochondrial signaling pathway of apoptosis. Caspase 3 is an effector
      caspase. Previous studies have shown that the exposure of embryonic murine limbs
      in vitro to 4-hydroperoxycyclophosphamide (4-OOHCPA), an activated analog of the
      anticancer alkylating agent, cyclophosphamide, induced limb malformations and
      apoptosis. The goal of this study was to determine the role of caspases in
      mediating apoptosis in this model system. METHODS: Limb buds from gestational day
      12 CD-1 mice were excised and cultured in roller bottles in a chemically defined
      medium for up to 6 days in the absence or presence of 4-OOHCPA. Apoptosis was
      indicated by internucleosomal DNA fragmentation, as detected by TUNEL staining.
      The profile of caspase activation was characterized by Western blot analysis and
      immunohistochemistry of control and treated limbs. To determine the consequences
      to limb morphology of inhibiting caspase activation, DEVD-CHO, a caspase-3
      inhibitor, was added to the cultures. RESULTS: Limbs cultured in the presence of
      4-OOHCPA were growth retarded and malformed; apoptosis was increased in the
      apical ectodermal ridge and interdigital areas. Western blot analysis showed that
      4-OOHCPA exposure did not activate procaspases 8 or 9 in limbs. In contrast,
      procaspase-3 cleavage was increased in a concentration and time-dependent manner
      after exposure of limbs to 4-OOHCPA. Immunoreactive activated caspase-3 was
      localized in the interdigital areas and the apical ectodermal ridge region in
      control limbs; staining in these areas and in the interdigital areas was
      increased dramatically in limbs exposed to 4-OOHCPA. Inhibition of caspase 3
      activation with DEVD-CHO partially protected limbs from insult with 4-OOHCPA.
      CONCLUSION: Caspase-dependent and caspase-independent pathways of cell death are
      both important is mediating the abnormal limb development triggered by insult
      with 4-OOHCPA.

PMID- 12486763
TI  - Effect of sera from women with systemic lupus erythematosus or antiphospholipid
      syndrome and recurrent abortions on human placental explants in culture.
AB  - BACKGROUND: Systemic lupus erythematosus (SLE) with or without evidence of
      antiphospholipid antibodies (aPA) and antiphospholipid syndrome (APS) is
      associated with a high rate of spontaneous abortions. The placenta is thought to
      be the site of pathological damage in many of these abortions. To test this
      hypothesis, we studied the effects of sera obtained from women with SLE with or
      without treatment on human placental explants in culture. METHODS: We cultured
      5.5- to 7.5-week-old human placental explants in a culture medium containing F-12
      DMEM and 10% FCS or in 90% human serum obtained from nonpregnant women with SLE
      prior to or after treatment. Culture was carried out for 96 hr. At the end of the
      culture period, we studied the secretion of the placental hormones estrogen (E2),
      progesterone (PGN), and human chorionic gonadotropin (hCG). In addition, we
      studied the proliferation rate (using PCNA staining) and the rate of apoptosis
      (using ApoTag) of the trophoblastic cells. RESULTS: Placentae grew better in
      normal human serum than in a chemically defined medium of F-12 DMEM and 10% FCS.
      Enhanced growth and higher secretion rates for hCG and estradiol (E2) were
      manifested in placentae cultured in control sera with no change in PGN secretion.
      Secretion rates of hCG and PGN (but not of E2 in the treated group) by placental
      explants were similar to that of controls. However, the serum levels prior to
      culture were not measured. Further, explants in serum from untreated women with
      SLE produced a significant decrease in the proliferation rate of the
      trophoblastic cells and an increase of apoptosis. Treatment significantly reduced
      the apoptotic rate and increased cell proliferation, but the cell proliferation
      rate was still lower than that noted in controls. CONCLUSIONS: We conclude that
      sera from women with SLE may directly damage the developing placenta reducing
      proliferation and enhancing apoptosis. Successful treatment of the women reduces
      that damage.

PMID- 12486764
TI  - Dose and litter allocations in the design of teratological studies for detecting
      hormesis.
AB  - BACKGROUND: Hormesis is being recognized in the field of toxicology due to the
      stimulating effects of some toxic compounds at low exposure levels. Therefore, it
      is desirable that experimental designs for toxicological studies be flexible
      enough to aid in the detection of hormetic effects. Current designs may still not
      have enough power to do this. METHODS: A simulation study was conducted to
      determine teratological study designs that would yield more power over standard
      designs in detecting hormesis. Developmental toxicity endpoints of interest are
      the number of dead/resorbed or malformed fetuses in a litter. The simulation
      designs mimic teratological experiments in terms of sample size and number of
      dose levels. Modified designs with even dose spacing at low levels and
      reallocated litters are investigated to determine the power of hormetic
      detection. RESULTS: Designs with reallocated litters (with more litters at low
      exposure levels than at high levels) and even dose spacing have more power than
      those with equal litters per group and uneven dose spacing. CONCLUSIONS: Through
      appropriate modifications of current experimental designs, such as reallocation
      of litters and even dose spacing, we can better detect hormetic effects.

PMID- 12486765
TI  - A new rapid radiological procedure for routine teratological use in bone
      ossification assessment: a supplement for staining methods.
AB  - BACKGROUND: Presently, bone ossification is assessed by the study of single
      stained fetal bones (alizarin red-S) or double-stained bones and cartilaginous
      structures (alcian blue followed by alizarin red-S). Both methods, especially
      double-staining, are labor-intensive, time-consuming, and provide qualitative
      information regarding skeleton ossification. Quantitative evaluation of
      ossification is more difficult and is usually based on determination of calcium
      and other minerals in the bone by means of atomic absorption spectrometry. Here
      we introduce a simple new method that allows quantitative determination of
      skeleton ossification before routine staining examination. METHODS: Fetuses
      delivered by laparotomy on the 16th and 21st day of gestation as well as 1-day
      old rat pups were examined. The fetuses and pups were prenatally subcutaneously
      exposed to sodium valproate or to physiological saline. Lateral, prone, and
      supine digital radiograms of each fetus were taken using the Digora-Soredex
      digital radiography system and the Planmeca Intra intraoral X-ray machine.
      According to the best visualization, the data concerning vertebra were analyzed.
      All the fetuses were then routinely double-stained using alcian blue and alizarin
      red-S. RESULTS: Malformations of axial skeleton (rib, sternum, and thoracic and
      sacral vertebra) were found in valproate-treated groups. Unlike cartilage
      malformations, the bone changes were detected in similar frequency in
      radiological and staining methods. Differences in densities according to the
      degree of ossification in the vertebral arches and bodies at different levels of
      the vertebral column, between drug-treated and negative control groups were
      noted. CONCLUSIONS: The preliminary results suggest that digital radiography
      examination is a useful method in determining delaying of skeleton ossification
      not detectable by other methods. It balances qualitative and quantitative aspects
      of the presently used methods and is also simple, objective, fast, and relatively
      inexpensive.

PMID- 12486766
TI  - Timing of prenatal care initiation and risk of congenital malformations.
AB  - BACKGROUND: Although previous studies provide some evidence that timing of
      prenatal care initiation is associated with risks of congenital malformation, the
      issue has not previously been examined in depth. This study uses data from a
      large population-based registry to explore the association of timing of prenatal
      care initiation with risks of selected congenital malformation phenotypes.
      METHODS: Data on cases were grouped according to four-digit malformation codes of
      the International Classification of Diseases, Ninth Revision (ICD-9). A randomly
      selected group of 10,000 nonmalformed deliveries served as the comparison group.
      Information on month of initiation of prenatal care (categorized as during months
      1-3 of gestation, months 4-7, or after month 7) and other maternal
      characteristics were derived from vital statistics data. RESULTS: Among the 176
      four-digit ICD groupings, 67 had an adjusted odds ratio for at least one of the
      two prenatal care categories that was either < or = 0.67 or > or = 1.50. Later
      prenatal care initiation was associated with risk > or = 1.50 for most groups.
      Later care was associated with risk < or = 0.67 for only two groups, and the
      effects were imprecise. Statistical interaction between parity and prenatal care
      was indicated for 13 groups (P < 0.10). Risks among women with no previous
      pregnancy tended to increase with later prenatal care initiation; risks among
      parous women tended to be somewhat weaker. In general, associations applied to a
      wide range of malformation groups. CONCLUSIONS: This is the first large-scale
      study of the association of timing of prenatal care initiation and congenital
      malformation risks. Further defining the phenomena that surround prenatal care as
      a marker may help clarify the etiologies of a variety of malformations.

PMID- 12486767
TI  - Quantification and localization of expression of the retinoic acid receptor-beta
      and -gamma mRNA isoforms during neurulation in mouse embryos with or without
      spina bifida.
AB  - BACKGROUND: Previous studies observed that retinoic acid receptor-gamma
      (RARgamma) is expressed in the open caudal neuroepithelium but that RARbeta is
      expressed in the closed neural tube. Furthermore, retinoic acid (RA) induces
      RARbeta expression, a molecular event associated with neural tube closure, but
      treatment with RA at the appropriate gestation time causes failure of neural tube
      closure. Since there are four isoforms of RARbeta, perhaps the isoforms expressed
      in the closed neural tube and induced by RA are different. To investigate the
      hypothesis that the switch from RARgamma to RARbeta is mechanistically linked to
      neural tube closure, this study determined the concentrations and distributions
      of RARbeta and RARgamma isoforms in mouse embryos with RA-induced neural tube
      defects and in splotch (Sp) mutant embryos with spina bifida. METHODS: Absolute
      concentrations of RARbeta and RARgamma isoforms were determined throughout
      primary neurulation (gestational day 8.5-10.0) in treated or untreated C57BL/6J
      mouse whole embryos by ribonuclease protection analysis. Treatment consisted of
      an oral dose of 100 mg/kg of all-trans-RA on gestational day 8.5. Spatial
      distributions of RARbeta and RARgamma were examined in RA-treated and Sp mutant
      embryos by in situ hybridization. RESULTS: RARbeta2, gamma1, and gamma2 were
      expressed in untreated embryos and were induced 4.5-, 1.6-, and 4.0-fold,
      respectively, 4 hr after treatment with RA. In embryos with RA-induced spina
      bifida, RARbeta2 was expressed in the closed neural tube while RARgamma1 and
      RARgamma2 were expressed in the open caudal neuroepithelium. In splotch mice with
      spina bifida, the boundary between RARbeta and RARgamma did not correspond to the
      site of neural tube closure. CONCLUSIONS: In RA-treated embryos, the relationship
      between RARbeta expression in the closed and RARgamma in the open caudal
      neuroepithelium was not altered. However, in splotch embryos with spina bifida,
      the juncture between RARbeta and RARgamma expression remained in the same
      anatomical position in the neuroepithelium irrespective of the neural tube
      closure status and suggests that the switch from RARgamma to RARbeta expression
      in the closing caudal neuroepithelium may not be causally linked to neural tube
      closure in the splotch mutant.

PMID- 12486768
TI  - Statement of the Public Affairs Committee of the Teratology Society on the fetal
      alcohol syndrome.

PMID- 12486770
TI  - Follow-up on Trinity.

PMID- 12486771
TI  - Exposure assessment in epidemiology and practice: mind the gap!

PMID- 12486772
TI  - Assessment of variability in biomonitoring data using a large database of
      biological measures of exposure.
AB  - Although intra- and interindividual sources of variation in airborne exposures
      have been extensively studied, similar investigations examining variability in
      biological measures of exposure have been limited. Following a review of the
      world's published literature, biological monitoring data were abstracted from 53
      studies that examined workers' exposures to metals, solvents, polycyclic aromatic
      hydrocarbons, and pesticides. Approximately 40% of the studies also reported
      personal sampling results, which were compiled as well. In this study, the
      authors evaluated the intra- and interindividual sources of variation in
      biological measures of exposure collected on workers employed at the same plant.
      In 60% of the data sets, there was more variation among workers than variation
      from day to day. Approximately one-fourth of the data were homogeneous with small
      differences among workers' mean exposure levels. However, an almost equal number
      of data sets exhibited moderate to extreme levels of heterogeneity in exposures
      among workers at the same facility. In addition, the relative magnitude of the
      intra- to interindividual source of variation was larger for biomarkers with
      short compared to long half-lives, which suggests that biomarkers with half-lives
      of 7 days or longer exhibit physiologic dampening of fluctuations in external
      levels of the workplace contaminant and thereby may offer advantages when
      compared to short-lived biomarkers or exposures assessed by air monitoring. The
      use of biological indices of exposure, however, places an additional burden on
      the strategy used to evaluate exposures, because data may be serially correlated
      as evidenced in this study, which could result in biased estimates of the
      variance components if autocorrelation is undetected or ignored in the
      statistical analyses.

PMID- 12486773
TI  - Performance of deterministic workplace exposure assessment models for various
      contaminant source, air inlet, and exhaust locations.
AB  - Contaminant concentration estimates from simple models were compared with
      concentration fields obtained by computational fluid dynamic (CFD) simulations
      for various room and source configurations under steady-state conditions. Airflow
      and contaminant distributions in a 10 x 3 x 7-m room with a single contaminant
      source on a 1-m high table were simulated using CFD for steady, isothermal
      conditions. For a high wall jet inlet, simulations were performed for nine room
      air exhaust locations and eight source locations. For a ceiling diffuser inlet
      the impact of two exhaust locations and eight source locations were investigated.
      Because CFD treats determinants of contaminant transport explicitly and agreed
      well with experimental results, it was used as the standard for comparison.
      Parameters of the one- and two-zone completely mixed models (CM-1 and CM-2) and
      the uniform turbulent diffusivity model (UD) were determined from CFD simulation
      results. Concentration estimates from these were compared with CFD results in the
      breathing zone (BZ) plane (1.5 m above the floor) for the entire BZ, the source
      "near field," and the source "far field." In the near field the mean percentage
      difference between the model concentration estimates and the CFD results for all
      room configurations were -21.9, 32.3, and 126% for the CM-1, CM-2, and UD models,
      respectively, with standard deviations of 26.8, 111, and 103%. In the far field
      the mean percentage difference between the model estimates and CFD results were 
      4.8, -2.3, and -36.3%. The CM-1 model had generally the best performance for
      applications such as occupational epidemiology for the conditions and
      configurations studied. However, CM-1 tended to underestimate the near field
      concentration; thus, CM-2 was judged to be better in the near field when
      underestimation is undesirable, such as when determining compliance with
      occupational exposure limits. The agreement of CM-2 estimates with CFD results in
      the near field was more variable than that of the CM-1. The UD model performed
      poorly on average in both near and far fields, and the difficulty in accurately
      estimating the turbulent diffusivity presents a significant impediment to UD
      model use for exposure estimation.

PMID- 12486774
TI  - Characterization of particulate matter in carbon-graphite/epoxy advanced
      composite material smoke.
AB  - The physical and chemical properties of the particulate fraction of carbon
      graphite/epoxy advanced composite material (cgeACM) smoke were measured to
      address concerns regarding potential health hazards posed by the release of
      fibers during pyrolysis of this material. Filter, low-pressure cascade impactor,
      and electrostatic precipitator samples were collected from cgeACM smoke in which
      the aerosol concentration ranged from 0.20 to 5.39 g/m3. Fibers were found in the
      smoke among individual, spherical, or nearly spherical particles and chain
      aggregates. The fibers had a mean count diameter of 0.54 micron and an average
      length of 2.84 microns. However, fibers accounted for approximately 0.3% of the
      particles counted. The smoke aerosols (including fibers) had mass median
      aerodynamic diameters (MMAD) ranging from 1.4 to 1.9 microns with standard
      geometric deviations ranging from 1.6 to 1.8, and hence more than 88% of the
      particles were in the thoracic size range (MMAD < or = 4.0 microns). All
      particles were composed primarily of carbon, silicon, sulfur, and oxygen with
      traces of other metals. By comparison fibers were composed almost exclusively of
      silicon.

PMID- 12486775
TI  - Variation in exposure levels for high hazard frequently monitored agents.
AB  - Assumptions about the underlying distribution of occupational exposures are
      important to the practice of industrial hygiene. They affect decisions on
      exposure monitoring strategies, the interpretation of monitoring results, and the
      degree of protection provided by occupational exposure limits and action levels.
      However, there is little published data validating these assumptions. Strict
      exposure limits for three highly hazardous agents, asbestos, beryllium, and
      ionizing radiation, led to frequent monitoring of occupational exposure levels.
      Consequently, sets of hundreds to thousands of exposure measurements are
      available for analysis. Statistical analysis of these data sets indicates that
      within-worker variation, as measured by geometric standard deviation (GSD), tend
      to be higher than is generally assumed for occupational exposures. The success of
      health protection programs in identifying and controlling predictable sources of
      exposure through frequent monitoring is offered as a possible explanation for the
      relatively high variation observed in these data sets. Despite the high exposure
      variation, arithmetic mean levels and the percentage of measurements exceeding
      exposure limits were low, indicating that a large GSD does not imply that working
      conditions are unacceptable. However, more frequent monitoring is required to
      assure exposures are acceptable. This article also presents an adaptation of
      graphical methods, using probability plotting and linear regression, to estimate
      the distribution parameters of a data set that contains a high percentage of
      nondetected results.

PMID- 12486776
TI  - Comparison of endotoxin assays using agricultural dusts.
AB  - Endotoxins from gram-negative bacteria pose a significant respiratory hazard.
      Establishing dose-response relationships is problematic because there are no
      standard procedures for sampling and analysis. The goal of this study was to
      compare endotoxin analyses in six laboratories using Limulus-based assays for
      analysis of organic dusts from three agricultural environments: chicken barns,
      swine barns, and corn processing facilities. For each dust generation experiment
      14 side-by-side air samples were collected on 37-mm glass fiber filters at flows
      of 1.8 L/min. Each laboratory was randomly allocated two filters from each of
      seven experiments per dust type. Three laboratories used the QCL-1000 endpoint
      assay, and three used the kinetic-QCL method. To eliminate variability among
      different lots, a single lot of Limulus amebocyte lysate for endpoint assays and
      one similar lot for kinetic assays was provided. Precision of assays performed
      within labs was very good, with pooled coefficients of variation for replicate
      samples ranging from 1 to 11% over all labs and all dust types. There were
      significant differences between laboratories for all three dust types (p < 0.01).
      The pattern of differences between labs varied by dust type. For chicken dust,
      labs using the endpoint method reported higher results than those using kinetic
      methods. For swine and corn dusts, labs using the kinetic method reported the
      highest endotoxin values. For chicken dust, results from all labs except A and B
      were highly correlated (r = 0.86-1.00). For swine dust, only labs B and E, and C
      and D were correlated. For corn, A, B, and D were significantly correlated with
      most other labs. In conclusion, statistical differences in performance between
      laboratories were apparent and may be related to the extraction and analytical
      methods. The results of this study will be useful for standardization of sampling
      and analysis of airborne endotoxin in agriculture.

PMID- 12486777
TI  - Whole-body vibration exposure study in U.S. railroad locomotives--an ergonomic
      risk assessment.
AB  - Whole-body vibration exposure of locomotive engineers and the vibration
      attenuation of seats in 22 U.S. locomotives (built between 1959 and 2000) was
      studied during normal revenue service and following international measurement
      guidelines. Triaxial vibration measurements (duration mean 155 min, range 84-383
      min) on the seat and on the floor were compared. In addition to the basic
      vibration evaluation (aw rms), the vector sum (av), the maximum transient
      vibration value (MTVV/aw), the vibration dose value (VDV/(aw T1/4)), and the
      vibration seat effective transmissibility factor (SEAT) were calculated. The
      power spectral densities are also reported. The mean basic vibration level (aw
      rms) was for the fore-aft axis x = 0.18 m/sec2, the lateral axis y = 0.28 m/sec2,
      and the vertical axis z = 0.32 m/sec2. The mean vector sum was 0.59 m/sec2 (range
      0.27 to 1.44). The crest factors were generally at or above 9 in the horizontal
      and vertical axis. The mean MTVV/aw was 5.3 (x), 5.1 (y), and 4.8 (z), and the
      VDV/(aw T1/4) values ranged from 1.32 to 2.3 (x-axis), 1.33 to 1.7 (y-axis), and
      1.38 to 1.86 (z-axis), generally indicating high levels of shocks. The mean seat
      transmissibility factor (SEAT) was 1.4 (x) and 1.2 (y) and 1 (z), demonstrating a
      general ineffectiveness of any of the seat suspension systems. In conclusion,
      these data indicate that locomotive rides are characterized by relatively high
      shock content (acceleration peaks) of the vibration signal in all directions.
      Locomotive vertical and lateral vibrations are similar, which appears to be
      characteristic for rail vehicles compared with many road/off-road vehicles.
      Tested locomotive cab seats currently in use (new or old) appear inadequate to
      reduce potentially harmful vibration and shocks transmitted to the seated
      operator, and older seats particularly lack basic ergonomic features regarding
      adjustability and postural support.

PMID- 12486778
TI  - Exposures to quartz, diesel, dust, and welding fumes during heavy and highway
      construction.
AB  - Personal samples for exposure to dust, diesel exhaust, quartz, and welding fume
      were collected on heavy and highway construction workers. The respirable,
      thoracic, and inhalable fractions of dust and quartz exposures were estimated
      from 260 personal impactor samples. Respirable quartz exposures exceeded the
      National Institute for Occupational Safety and Health (NIOSH) recommended
      exposure limit (REL) in 7-31% of cases for the trades sampled. More than 50% of
      the samples in the installation of drop ceilings and wall tiles and concrete
      finish operations exceeded the NIOSH REL for quartz. Thoracic exposures to quartz
      and dust exceeded respirable exposures by a factor of 4.5 and 2.8, respectively.
      Inhalable exposures to quartz and dust exceeded respirable exposures by a factor
      of 25.6 and 9.3, respectively. These findings are important due to the
      identification of quartz as a carcinogen by the National Toxicology Program and
      the International Agency for Research on Cancer. Fourteen percent of the personal
      samples for EC (n = 261), collected as a marker for diesel exhaust, exceeded the
      American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit
      value (TLV) for diesel exhaust. Seventeen of the 22 (77%) samples taken during a
      partially enclosed welding operation reached or exceeded the ACGIH TLV of 5 mg/m3
      for welding fume.

PMID- 12486779
TI  - The effect of local exhaust ventilation controls on dust exposures during
      concrete cutting and grinding activities.
AB  - This study assessed the effectiveness of commercially available local exhaust
      ventilation (LEV) systems for controlling respirable dust and crystalline silica
      exposures during concrete cutting and grinding activities. Work activities were
      performed by union-sponsored apprentices and included tuck-point grinding,
      surface grinding, paver block and brick cutting (masonry saw), and concrete block
      cutting (hand-held saw). In a randomized block design, implemented under
      controlled field conditions, three ventilation rates (0, 30, and 75 cfm) were
      tested for each tool. Each ventilation treatment was replicated three times in
      random order for a total of nine 15-min work sessions per study subject. With the
      exception of the hand-held saw, the use of LEV resulted in a significant (p <
      0.05) reduction in respirable dust exposure. Mean exposure levels for the 75 cfm
      treatments were less than that of the 30 cfm treatments; however, differences
      between these two treatments were only significant for paver block cutting (p <
      0.01). Although exposure reduction was significant (70-90% at the low ventilation
      rate and 80-95% reduction at the high ventilation rate), personal respirable dust
      [corrected] exposures remained very high: 1.4-2.8 x PEL (permissible exposure
      limit) at the low ventilation rate and 0.9-1.7 x PEL at the high ventilation
      rate. Exposure levels found under actual field conditions would likely be lower
      due to the intermittent nature of most job tasks. Despite incomplete control LEV
      has merit, as it would reduce the risk of workers developing disease, allow
      workers to use a lower level of respiratory protection, protect workers during
      short duration work episodes reduce exposure to nearby workers, and reduce clean
      up associated dust exposures.

PMID- 12486780
TI  - Inhalation exposures to acrylamide in biomedical laboratories.
AB  - This study evaluated airborne acrylamide exposures experienced by laboratory
      personnel using either crystalline or commercially available solutions of
      acrylamide to make polyacrylamide gels. Exposures were monitored for a short-term
      (15-min) sampling period, during the weighing of the crystalline acrylamide or
      the removal of the acrylamide solution from its original container, and a long
      term period, during which a sample was collected for as long as the subject was
      potentially exposed to acrylamide. Mean air concentrations for the 15-min
      exposures were 7.20 +/- 5.64 micrograms/m3 and 5.81 +/- 4.53 micrograms/m3 for
      the users of crystalline and solution acrylamide, respectively, although this
      difference was not statistically significant (p > 0.05). Mean concentrations for
      the long-term exposures were 12.77 +/- 24.20 micrograms/m3 for workers employing
      crystalline acrylamide and 4.22 +/- 7.05 micrograms/m3 for personnel using
      acrylamide solutions. This difference was also not statistically significant.
      Although the results indicate that the research laboratory personnel were
      generally exposed to measurable concentrations of acrylamide, with several
      subjects exposed to elevated levels, the calculated 8-hour time-weighted average
      exposures were below current occupational exposure limits. However, because the
      neurotoxic effects of acrylamide are cumulative and it is a suspected carcinogen,
      all exposures should be kept as low as reasonably achievable.

PMID- 12486781
TI  - The effect of spraying and rolling process factors on styrene emission during the
      application of unsaturated polyester resins.
AB  - In recent years the awareness of the problems caused by styrene emission during
      the processing of unsaturated polyester resins has enlarged. The spray-up
      application of gel coats is especially problematic, and it produces high styrene
      emission rates. The emission of styrene has been reduced through material
      changes, work practice controls, and add-on controls. However, the influence of
      the spray-up process factors on styrene emission has not been studied before. The
      aim of this study was to examine possibilities to reduce styrene emission by
      optimization of spray-up process factors. The following factors were studied
      under controlled laboratory conditions: orifice size and angle of the spray gun
      tip, spraying pressure, distance between spray gun and mold, and shape of the
      mold. The influence of the rolling pattern during lamination was also studied.
      Several significant factors were found. High pressure and long spraying distance
      increased both the unit styrene emission and the emission rate. The orifice size
      had two effects; a large orifice decreased the amount of styrene emitted per
      sprayed amount of resin but increased the emission rate of styrene. The shape of
      the mold did not affect the styrene emission. Styrene emission is greater if the
      entire mold area is rolled. To achieve lower emission is it necessary to roll an
      area as small as possible; this is especially important if a large mold is
      laminated. The results showed that emission of styrene can be reduced
      significantly by an optimal selection of the spray gun settings and the way of
      working. Optimal settings also increased the transfer efficiency resulting in
      decreased material loss.

PMID- 12486782
TI  - Changes over time in audiometric thresholds in a group of automobile stamping and
      assembly workers with a hearing conservation program.
AB  - Noise induced hearing loss (NIHL) is among the 10 leading occupational diseases,
      afflicting between 7.4 and 10.2 million people who work in noise above 85 dBA.
      Although mandatory hearing conservation programs (HCPs) have been in effect since
      1972, this problem persists, as hearing protectors are not consistently used by
      workers, or may not attenuate to manufacturer's estimates in real world
      conditions. In this study, information from noise and hearing protection use
      measurements taken at an automobile assembly plant were used to construct average
      lifetime noise exposure and hearing protection compliance estimates for use in
      modeling to predict both total hearing loss and onset of two accepted definitions
      of hearing loss. There were 301 males and females in this cohort; their mean age
      was 42.6 (7.2) years, and mean tenure was 14.3 (3.5) years. Average length of
      follow-up was 14.0 years. There were 16 members of this cohort who had hearing
      loss at the speech frequencies (defined as an average hearing level > or = 25 dB
      at 500, 1000, and 2000 Hz). In cross-sectional multivariate analyses, years of
      employment, male gender, and proportion of time wearing hearing protection were
      the factors most associated with hearing loss at the average of 2000, 3000, and
      4000 Hz (p < 0.0001) controlling for age, transfer status (as a surrogate for
      previous noise exposure), race, and lifetime average noise exposure. The most
      consistent predictor of hearing loss in both univariate and multivariate analyses
      was percentage of time having used hearing protection during the workers' tenure.

PMID- 12486783
TI  - Extracting metalworking fluid aerosol samples in cassettes by provisional ASTM
      and NIOSH methods.
AB  - Recent provisional methods for the determination of metalworking fluid aerosol in
      workplace air involve a solvent extraction procedure to separate the nonvolatile
      fraction of the fluid from insoluble material such as metal turnings and dirt.
      The procedure calls for preweighing a filter (W1) and assembling it into a
      cassette and taking a sample. In the laboratory the filter is removed from the
      cassette, desiccated to remove any collected water or other volatile substances,
      and weighed again (W2). The filter is then extracted in an organic solvent blend,
      allowed to dry, and weighed a final time (W3). The total weight collected by the
      filter is given by (W2-W1), and the weight of (nonvolatile) metalworking fluid
      collected is given by (W2-W3). The extraction step can take place within a
      cassette housing if it is relatively inert to the solvent blend used. The
      extraction of four metalworking fluids (straight oil, soluble oil, synthetic and
      semisynthetic) within disposable polypropylene cassettes was investigated using
      the same protocol used to evaluate the original method. For all fluids the
      extraction efficiency was greater than 95% with a precision better than 5%. The
      mean blank contribution to the extraction step was 16 micrograms. Blanks were
      also evaluated after storage, and after transport and storage. A small additional
      blank contribution could be removed by desiccation. The limits of detection and
      quantitation of the extraction step were calculated to be 28 and 94 micrograms,
      respectively.

PMID- 12486784
TI  - Liberation of hydrogen cyanide and hydrogen chloride during high-temperature
      dispersion of CS riot control agent.
AB  - High temperature dispersion (greater than 700 degrees C) of the riot control
      agent orthochlorobenzylidenemalononitrile (CS) has previously been shown to
      produce a number of organic thermal degradation products through rearrangements
      and loss of cyano and chlorine substituents present on the parent CS compound.
      Until now the possibility that HCN and HCl might also be air contaminants
      produced during high temperature CS dispersion has not been examined. Air samples
      were collected to detect HCN and HCl as air contaminants released during high
      temperature CS dispersion indoors. Sampling and analysis based on National
      Institute of Occupational Safety and Health methods 7904 and 6010 for HCN, and
      7903 for HCl, showed evidence that both compounds were present in air samples
      collected. A reassessment of human health risks associated with exposure to CS
      riot control agent dispersed at high temperature should be conducted, and should
      consider the full range of contaminants produced during the dispersion process.

PMID- 12486785
TI  - AIHA. Consultants listing. American Industrial Hygiene Association.

PMID- 12486786
TI  - Overview: fungal infections in the transplant patient.
AB  - Fungal infection remains a major hurdle in solid organ transplantation. A variety
      of new antifungal agents have become available and new diagnostic tools are in
      development. This conference was convened to review current approaches to the
      prevention and treatment of fungal infection in transplantation. Among the keys
      to successful management of fungal infection are identification of patients at
      risk for infection (stratification), eradication or control of established
      infection in advance of transplantation, the demonstration of cure by radiologic
      and histopathologic means, and the use of surgical debridement, reduction in
      immune suppression, and fungicidal therapies whenever possible. The absence of
      sensitive diagnostic tools and standardization of antifungal susceptibility
      testing for the filamentous fungi are identified as major impediments to care in
      this area.

PMID- 12486787
TI  - Overview: pathogenesis of fungal infections in the organ transplant recipient.

PMID- 12486788
TI  - Fungal infection in liver transplantation.
AB  - Infection is the common cause of death following transplantation. Fungal
      infections are associated with high morbidity and mortality, and make up a
      significant proportion of infectious complications. Unfortunately, the diagnosis
      is usually made late--symptoms may be mild and non-specific, even with
      dissemination. Mortality associated with disseminated fungal infections is high,
      while those associated with limited fungal infections is low. Although the risk
      factors for invasive fungal infections in liver transplant patients are well
      identified, early diagnosis is challenging, and commonly used diagnostic methods
      lack sensitivity and specificity. Although the incidence of fungal infections
      following liver transplantation appears to be falling, mortality and morbidity
      associated with fungal infections suggests that future developments should focus
      on enhancing earlier diagnosis, implementing more effective and less toxic anti
      fungal therapies.

PMID- 12486789
TI  - Fungal infection in lung transplantation.
AB  - Fungal infection remains a significant cause of postoperative morbidity and
      mortality in lung transplant recipients. The lung recipient remains the only
      solid-organ allograft continuously open to the environment and to the myriad of
      fungal spores and pathogens. Many factors may predispose to fungal infection in
      these patients, including: preoperative chronic lung diseases and inherent
      palliative immunosuppression, intraoperative complications such as abnormalities
      in the bronchial anastomosis or lung injury, and postoperative complications such
      as enhanced immunosuppression for early rejection, graft dysfunction, concurrent
      viral and bacterial infections, and bronchiolitis obliterans syndrome. The risk
      factors and time course for fungal infection in lung transplant recipients
      parallel the observations in other solid-organ transplant recipients. Early
      fungal infections are related to surgical complications, while the period of 1-6
      months reflect opportunistic, relapsed, or residual infections; fungal infections
      greater than 6 months and thereafter are usually associated with treatments for
      chronic rejection or bronchial airway mechanical abnormalities. The majority of
      fungal infections in lung transplant recipients involve Aspergillus species,
      followed by Candida, Pneumocystis, Cryptococcus, geographically-restricted
      agents, and newly emerging fungal pathogens. The identification of at-risk
      patients (preoperatively and postoperatively) is essential in implementing
      prophylaxis or preemptive management. Some anti-fungal strategies and future
      options for clinical research are discussed.

PMID- 12486790
TI  - Diagnosis of fungal infection: new technologies for the mycology laboratory.
AB  - The dramatic increase in nosocomial invasive mycoses over the past two decades
      has led to increased interest in the area of antifungal development.
      Unfortunately, the infusion of new diagnostic technology into the clinical
      mycology laboratory has lagged behind. Although newer, automated, continuous
      monitoring blood culture systems are as sensitive as the older, manual "gold
      standard" system, the recovery of fungi from blood, as well as other clinical
      specimens, remains an insensitive marker for invasive fungal infection. Antigen
      assays for the rapid diagnosis of invasive fungal infections are in development,
      and galactomannan and glucan are two such promising antigens. Glucan may be
      present in the blood of patients with infection secondary to a wide variety of
      fungal pathogens, including Candida, Aspergillus, Fusarium, Saccharomyces,
      Trichosporon and Acremonium species. Early data suggest galactomannan may be
      present in the blood in detectable levels very early in the course of invasive
      aspergillosis. The galactomannan assay currently undergoing evaluations may
      actually be positive prior to the clinical suspicion for infection and may be
      useful in monitoring therapeutic response as well; however, the etiology of false
      positive results following cytotoxic chemotherapy still has to be elucidated. PCR
      assays are also being developed in the research laboratory, however, the PCR
      assays will require a significant amount of adaptation and validation before they
      are ready for clinical care. Well-planned studies to evaluate the performance
      characteristics as well as appropriate clinical and cost-effective application of
      these new tests are needed.

PMID- 12486791
TI  - Fungal susceptibility testing: where are we now?
AB  - Invasive fungal infections have been noted in increasing frequency in
      immunosuppressed patients and may be due to organisms that are less susceptible
      or frankly resistant to antifungal agents. Recently, standards have been
      established for testing both yeasts and moulds for susceptibility to antifungal
      agents. While these tests are increasingly available for clinical use, clinicians
      are faced with the challenge of whether these tests offer benefit in terms of
      management and when they should be obtained. In this review, the relevance of
      these tests is discussed, as are the clinical data, especially for yeasts, that
      support their use. In addition, the strategy of identifying yeasts to the species
      level as a means for predicting susceptibility is also discussed. While
      susceptibility testing of all fungal isolates is not necessary and not
      recommended, the judicious use of these tests and the role of the mycology
      laboratory in assisting in management of invasive fungal infection is also
      evaluated.

PMID- 12486792
TI  - Prevention of fungal infection in transplantation.
AB  - Despite significant advances in the diagnosis, prevention, and treatment of
      fungal infection in transplant recipients, this infection complication remains a
      major cause of morbidity and mortality. Our understanding of the pathogenesis of
      the different fungal microorganisms has enabled us to identify patients at risk
      for such infections. While Candida infection remains a major complication in
      patients with intra-abdominal solid organ transplantations in which the bowel is
      surgically manipulated, Aspergillus infection remains the main fungal
      complication in lung transplantation recipients. The incidence of all types of
      fungal infection remains around 5-10%, while mortality following Aspergillus
      infection remains around 70%. Suppression of Candida growth at the time of
      surgical manipulation of the bowel should be the mainstay of prevention of this
      infection in intra-abdominal organ transplantation. Fluconazole is effective and
      relatively safe at 100-400 mg daily for the first 1-3 months post-liver
      transplantation. Prevention strategies toward Aspergillus infections remain
      elusive, but a number of manipulations, such as inhaled liposomal preparations
      post-organ transplantation or the preemptive use or universal prophylaxis of
      itraconazole are being validated. The next step is to determine the clinical
      value of molecular diagnostic techniques for the identification and preemptive
      therapy of patients at risk for the variety fungal infections.

PMID- 12486793
TI  - New antifungal agents.

PMID- 12486794
TI  - Clinical cases in transplantation.
AB  - A series of cases are presented to illustrate the complexity of the care of
      immunocompromised patients with established invasive fungal infections. These
      discussions by an expert panel serve to identify areas of controversy and for
      future research in the care of transplant recipients.

PMID- 12486795
TI  - Summary: future directions in antifungal therapy.
AB  - The development of strategies for the prevention and treatment of invasive fungal
      infection is reviewed. The optimal deployment of antifungal agents is impeded by
      delays in diagnosis, which reflect the need for tissue samples for histopathology
      and/or the slow growth of organisms in culture for identification. Further, the
      lack of rapid and standardized methods for antimicrobial susceptibility testing
      has been identified as a major hurdle to optimal management. It is likely that
      combinations of antifungal agents will be needed to accelerate the clinical
      response to therapy (i.e., killing of fungus in tissues more rapidly). Such
      combinations may have the capacity to reduce toxicity while providing either true
      additive or synergistic activities or improved pharmacokinetics to "target"
      infection in multiple sites. Preclinical studies and clinical trials will begin
      to identify candidate therapies for invasive fungal infections in
      transplantation.

PMID- 12486796
TI  - [Anti-Pseudomonas aerosol therapy in cystic fibrosis: improvement with
      tobramycin].
AB  - Aerosol delivery of antibiotics offers the potential to achieve high antibiotic
      concentrations at the site of infection while reducing the risk of systemic
      untoward effects because of minimal resorption into the bloodstream. We reviewed
      knowledge acquired in this field over the two latter decades. While the earliest
      data were obtained with gentamycin, the most conclusive evidence presently
      regards aminoglycosides and colistin. Aerosol delivery of tobramycin was recently
      improved with the development of a new formulation for inhalation. Coupled with
      an adequate nebulization system, intermittent treatment with tobramycin for
      inhalation has been evaluated in randomized placebo-controlled studies. These
      studies have demonstrated a significant improvement of respiratory function.

PMID- 12486797
TI  - [Domiciliary assisted ventilation in children].
AB  - The concept of assisted ventilation in the home setting has greatly progressed as
      a routine practice. This technique was used from 1990 to 2000 in 16 children
      cared for at our center. Ten children had neuromuscular disease (infantile spinal
      amyotrophy 6, Duchenne myopathy 3, and mitochondrial myopathy 1) or other
      conditions including central hypoventilation (n = 2), traumatic tetraplegia (n =
      2), encephalopathy with chronic bronchitis (n = 1) and bronchopulmonary dysplasia
      (n = 1). Only 5 children had a tracheotomy, the others were treated successfully
      with non-invasive ventilatory assistance. Initialization of non-invasive
      ventilatory assistance had been planned before development of respiratory failure
      in 4 of the 11 children, but generally was indicated after an episode of acute
      respiratory distress. Home ventilation, particularly with non-invasive assistance
      is a reliable method for long-term treatment of chronic alveolar hypoventilation
      in children. The appropriate time for initiating this therapy should be better
      defined.

PMID- 12486798
TI  - [Pyothorax in pneumonectomy cavity. Apropos of 24 cases].
AB  - AIM OF THE STUDY: Describe as series of post-pneumonectomy empyema episodes, with
      or without bronchial fistula treated at the department of Thoracic Surgery,
      University of Ibn Sina, Rabat, Morocco. PATIENTS, METHOD AND RESULTS: Twenty-four
      patients with post-pneumonectomy pyothorax cared for between 1991 and 2000 were
      reviewed retrospectively. There were 15 men and 9 women, mean age 34 years.
      Pneumonectomy was indicated for tuberculous pyothorax and destroyed lung (n = 8),
      8 destroyed lung (n = 8), pulmonary aspergilloma (n = 2), pulmonary hydatidosis
      (n = 2), bronchial dilatation (n = 2), lung cancer (n = 1), and bullet wound (n =
      1). The patients were divided into two groups according to presence or absence of
      bronchial fistula: group 1, 19 patients with without bronchial fistula, and group
      2 5 with bronchial fistula. Fourteen patients in group 1 (73.7%) achieved
      definitive cure, 12 after drainage and washout (63%) at mean delay of 45 days and
      2 after drainage and washout with thoracoplasty. Five patients did not respond to
      hospital drainage and washout and remained under definitive ambulatory drainage
      as they declined further surgical treatment. One death occurred in this group.
      Two patients in group 2 (40%) achieved definitive cure, one after daily
      aspiration, and the other after thoracoplasty. Two fistulae in one patient were
      treated with nitratage. For this patient, we also attempted revision of the
      bronchial stube via posterior throacotomy, the closure of the bronchial fistula
      using an intercostal muscle flap associated with thoracoplasty. All these methods
      failed. There were two deaths in this group. CONCLUSION: Sixteen patients were
      definitively cured (66.6%). Eight patients (33.3%) remain in a chronic condition.
      Patients with pyothorax on a pneumonectomy cavity should be managed in
      specialized centers before reaching the chronic stage. Thoracomyoplasty with
      preparation of the cavity by thoracostomy should be proposed.

PMID- 12486799
TI  - [Isolated pleurisy revealing ovarian hyperstimulation syndrome].
AB  - Ovarian hyperstimulation is a rare but serious iatrogenic complication following
      induction of ovulation cycles. Release of vasoactive substances by the stimulated
      ovaries leads to leakage of intravascular fluid into the extracellular and serous
      spaces due to enhanced capillary permeability. Pleural effusion is a classical
      finding in the most severe forms, often associated with ascitis and signs of
      hemoconcentration. We report the case of a women who presented pleural effusion
      as the sole inaugural sign of ovarian hyperstimulation.

PMID- 12486800
TI  - [Myxoid liposarcoma of the mediastinum: a case report].
AB  - We describe a mediastinal myxoid liposarcoma in a 47-year-old man who developed
      recurrent lung infection, treated by surgery associated with radiotherapy. The
      report of this case and a review of literature bring the authors to outline the
      epidemiological, clinical and therapeutic profile of this rare tumor.

PMID- 12486801
TI  - [Hydatid cyst of thoracic soft tissues].
AB  - Hydatid cysts are uncommon in thoracic soft tissue. We report a case of hydatid
      cyst which had developed within the lattissimus dorsi presenting as a left
      parietal scapular mass diagnosed by ultrasound and CT scan, which remains the
      preferred primary examination for the investigation of masses of this type. We
      discuss the various possible clinical and paraclinical contexts and recommend
      total pericystectomy of a closed cyst as the best treatment for this kind of
      cyst.

PMID- 12486802
TI  - [Bronchopulmonary Kaposi's disease in 2 AIDS patients living in a zone of high
      tuberculosis/HIV prevalence].
AB  - The epidemic form of Kaposi's disease, called Kaposi-AIDS, was first described in
      1981 by Hymmes in two young AIDS patients. Lung lesions are observed in 10 to 45%
      of patients with cutaneous Kaposi and are the second leading localization of
      visceral involvement after the digestive tract. Diagnosis and management of these
      visceral forms remains difficult. We report two cases of broncho-pulmonary Kaposi
      AIDS in two patients treated for cutaneous Kaposi's disease. The diagnosis was
      made on the basis of epidemiological, clinical, biological, radiological,
      endoscopic, and histological evidence. The diagnosis was achieved by elimination
      after ruling out all other opportunistic diseases with pulmonary tropism. The
      fear of miliary tuberculosis remains strong in zones with a high prevalence of
      tuberculosis. Despite considerable improvement with antiretroviral drugs,
      especially antiproteases, outcome remains unpredictable with or without specific
      treatment.

PMID- 12486803
TI  - [Clinical Practice Guidelines. Therapeutic education of the adult and adolescent
      asthmatic patient. June 2001].

PMID- 12486804
TI  - Role of serotonin, gamma-aminobutyric acid, and glutamate in the behavioral
      thermoregulation of female tilapia during the prespawning phase.
AB  - The role of hypothalamic neurotransmitter systems in behavioral thermoregulation
      was investigated in the prespawning female tilapia, Oreochromis mossambicus.
      Intrahypothalamic microinjection with serotonin (5-HT, 3 microliters of 1.0 x 10(
      6) M) resulted in a significant increase in the selected temperature. This effect
      was mimicked by the agonist of 5-HT1A, 1B, and 2C receptors, N-3
      trifluoromethylphenyl piperazine. Intrahypothalamic microinjection of tilapia
      with gamma-aminobutyric acid (GABA) resulted in a biphasic effect of the
      temperature selection, whereas microinjection with muscimol, an agonist of GABAA
      receptor, had no effect on temperature selection. Both agonist and antagonist of
      glutamate (Glu), N-methyl-D-aspartate (NMDA), and MK-801 (1.0 x 10(-6) M), a
      noncompetitive blocker of NMDA receptor, significantly decreased the preferred
      temperature. These results indicate that the hypothalamic 5-HT, GABA, and Glu
      systems play a role in the temperature selection of prespawning female tilapia.

PMID- 12486805
TI  - Effects of posture on the respiratory mechanics of the chick embryo.
AB  - In the chicken embryo, pulmonary ventilation and pulmonary gas exchange begin
      approximately one day before the completion of hatching. We asked to what extent
      the posture inside the egg, and the presence of the eggshell and membranes, may
      alter the mechanical behaviour of the respiratory system. The passive mechanical
      properties of the respiratory system were studied in chicken embryos during the
      internal pipping phase (rupture of the air cell) or the external pipping phase
      (hole in the eggshell). Tracheal pressure and changes in lung volume were
      recorded during mechanical ventilation, first, with the embryo curled up inside
      the egg, then again after exteriorization from the eggshell. In the internal
      pippers, respiratory system compliance increased and expiratory resistance
      decreased after exteriorization, whereas the mean inspiratory impedance did not
      change. In the external pippers, exteriorization had no significant effects on
      respiratory compliance, resistance, or impedance, and the values were similar to
      those of newly hatched chicks. We conclude that, in the chicken embryo, at a time
      when pulmonary ventilation becomes an important mechanism for gas exchange, the
      curled up posture inside the egg does not provide any significant mechanical
      constraint to breathing.

PMID- 12486806
TI  - Influence of cortisol on developmental rhythms during embryogenesis in a tropical
      damselfish.
AB  - Newly-spawned teleost eggs can vary widely in their maternal endowment of a
      variety of hormones, including cortisol. Field and laboratory experiments have
      shown that initial egg cortisol concentrations directly influence the size at
      hatching of the benthic spawning damselfish, Pomacentrus amboinensis. The present
      study examines the mechanism by which cortisol influences larval size at hatching
      by investigating the growth and developmental rhythms throughout embryogenesis.
      Newly spawned eggs of P. amboinensis were collected from natural benthic nests,
      and half of each clutch was incubated in a moderate level of cortisol (2.7 x 10(
      6) M, equivalent to a concentration of 0.79 pg/egg). Cortisol was found to have
      no affect on the rate of cell-pulsations up to epiboly (18 hr post
      fertilization), with cells pulsing at a mean rate of 56-60 pulses/min. Cortisol
      had an affect on the relative growth rate from the start of gastrulation to knot
      formation. Growth in the cortisol-supplemented embryos was pulsed, with periods
      of fast growth punctuated by long periods of stasis. Overall growth rates during
      this period were lower in the cortisol-supplemented embryos despite their higher
      growth during active periods. Pulse rates of somite cells and contraction rhythms
      of myotomes and the heart were twice as high in cortisol-supplemented embryos
      than controls. Despite this, cortisol-supplemented eggs developed at the same
      rate as controls and hatched at the same time. This study suggests that the
      maternal endowment of cortisol to eggs plays a vital role in determining the
      embryonic rhythms by which embryos grow and may be directly influencing
      metabolism.

PMID- 12486807
TI  - Skin flaps inhibit both the current of injury at the amputation surface and
      regeneration of that limb in newts.
AB  - For over two decades, we have been investigating a strong (ca. 20-100
      microA/cm2), outwardly directed electric current driven through the limb stump
      for the first few days following amputation in regenerating salamanders. This
      current is driven through the stump in a proximal/distal direction by the
      amiloride-sensitive transcutaneous voltage of the intact skin of the stump. Limb
      regeneration can be manipulated by several technique that manipulate this
      physiology, demonstrating that the ionic current is necessary, but not
      sufficient, for normal regeneration of the amphibian limb. Here, we demonstrate
      that a full thickness graft of skin covering the forelimb stump of newts
      strikingly inhibits the regeneration of the limb, and that this procedure is also
      highly correlated to a suppression of peak outwardly directed stump currents in
      those animals that fail to regenerate.

PMID- 12486808
TI  - Mollusc larval shell formation: amorphous calcium carbonate is a precursor phase
      for aragonite.
AB  - The larval shells of the marine bivalves Mercenaria mercenaria and Crassostrea
      gigas are investigated by polarized light microscopy, infrared spectroscopy,
      Raman imaging spectroscopy, and scanning electron microscopy. Both species
      contain similar shell ultrastructures. We show that larval shells contain
      amorphous calcium carbonate (ACC), in addition to aragonite. The aragonite is
      much less crystalline than non-biogenic aragonite. We further show that the
      initially deposited mineral phase is predominantly ACC that subsequently
      partially transforms into aragonite. The postset juvenile shell, as well as the
      adult shell of Mercenaria also contains aragonite that is less crystalline than
      non-biogenic aragonite. We conclude that ACC fulfills an important function in
      mollusc larval shell formation. It is conceivable that ACC may also be involved
      in adult shell formation.

PMID- 12486809
TI  - Relation between the reproductive status and somatolactin cell activity in the
      pituitary of pejerrey, Odontesthes bonariensis (Atheriniformes).
AB  - The aim of this study was to analyze the relationship between somatolactin (SL)
      expressing cells and the reproductive status in a multiple spawning fish, the
      pejerrey Odontesthes bonariensis. Somatolactin cells were identified in adults of
      both sexes by immunocytochemistry using a heterologous piscine antiserum. The
      area of the cells that showed immunoreactivity to SL (ir-SL) was compared in
      specimens with different degrees of reproductive activity as inferred from
      histological examination of the gonads and calculation of the gonadosomatic index
      (GSI %). The results showed a significant difference between the area of ir-SL
      cells of resting/regressing (62.9 +/- 2.1 micron 2) and sexually
      active/vitellogenic (76.8 +/- 2.3 micron 2) females and a significant positive
      correlation between the ir-SL cellular area and the GSI % (P < 0.01 in both
      cases). In males, the correlation between the area of ir-SL cells and the GSI %
      was not statistically significant. However, in those animals with the highest GSI
      % values, the ir-SL cells appeared more numerous and showed an increase in the
      immunostained area when compared to individuals with lower GSI % values. The
      present in morphological observations are in accordance with biochemical data
      obtained from other species and support the assumption that SL might be involved
      in the regulation of reproduction in fish.

PMID- 12486810
TI  - Characterization of aromatase activity in the sea bass: effects of temperature
      and different catalytic properties of brain and ovarian homogenates and
      microsomes.
AB  - Two aromatase genes have been discovered in the brain and ovary of some teleosts.
      However, data on native aromatase enzyme kinetics and thus actual catalytic
      activity are scarce in fish, impeding comparison of aromatase activity (AA) from
      different organs within and between species. In the present study, the tritiated
      water assay was optimized and validated to measure AA in the sea bass using 1
      beta-[3H]-androstenedione as a substrate in crude homogenates and microsomes.
      Optimized assay variables included pH, temperature, buffer strength, incubation
      time, amount of fresh tissue, substrate, and cofactor concentration. Specificity
      of the assay was verified by using known inhibitors, inappropriate substrates,
      and heat-inactivation. Subcellular fractionation revealed ten-fold more activity
      in the microsomal over the cytosolic fraction. The assay was also validated by
      comparing results from the direct product isolation method. The validated assay
      described allows measurement of AA to levels as low as < 10 fmol/mg protein/hr.
      Sex differentiation is temperature-dependent in the sea bass. It was found that
      in the physiological range of temperatures where the sea bass can live, 10-30
      degrees C, AA is highly dependent on temperature in a linear fashion (brain: r2 =
      0.92; P < 0.001; ovary: r2 = 0.94; P < 0.001). When AA levels from brain and
      ovarian homogenates obtained from the same fish during the spawning season were
      compared, the respective Michaelis-Menten constant (Km) values were 7.3 nM vs.
      4.6 nM, with no significant differences detected between the two tissues. Thus,
      sea bass aromatase has a very high affinity for androstenedione, similar to what
      has been found in goldfish, but much higher than other piscine or mammalian
      aromatases (30-435 nM). In contrast, the brain maximum reaction rate (Vmax 7.8
      pmol/mg protein/hr) was four-fold higher (P < 0.001) than the ovarian Vmax (2.1
      pmol/mg protein/hr). Consistent results were found using purified microsomes.
      Although this is the first time that the kinetic parameters are reported for a
      native piscine aromatase in two different tissues within the same fish, it
      remains to be determined whether this is a reflection of two distinct isoforms in
      this particular species.

PMID- 12486811
TI  - Isolation increases milt production in goldfish.
AB  - Milt volume in goldfish is increased by female steroid and prostaglandin
      pheromones, by exposure to males with elevated gonadotropin levels, and by
      isolation from conspecifies. This study examined various aspects of the isolation
      effect on milt volume and serum gonadotropin II (GTH II). The latency of
      isolation-induced milt increase in this study (12-24 hr) was longer than the
      latencies to pheromone-induced milt increase in previous work (0.5-6.0 hr), was
      not affected by the time of day at which males were isolated, persisted for at
      least 72 hr in isolated males, and was terminated within 24 hr in males that were
      returned to groups. Isolated males maintained high milt production when separated
      from tank mates by a perforated barrier or when exposed to visual and odor cues
      from males in other tanks, suggesting that the unknown conspecific cues that
      maintain low milt production in groups operate at close range. Isolation appears
      to increase milt through a mechanism different from that mediating response to
      female pheromones because: (1) unlike female pheromones, which consistently
      increase serum GTH II, no isolation or regrouping treatment in this study
      affected male GTH II concentration; and (2) the effects of isolation and of
      exposure to the female pheromone 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one
      (17,20 beta-P) are additive. Finally, males that were previously isolated or
      exposed to 17,20 beta-P increased milt (but not GTH II) in grouped males,
      suggesting that the effects of isolation and pheromone exposure can indirectly
      stimulate male conspecifics. Although the biological function of the isolation
      effect is not clear, we propose that it illustrates the effect of removal from
      inhibitory cues normally received from male conspecifies.

PMID- 12486812
TI  - Induction of parturition in snow skinks: can low temperatures inhibit the actions
      of AVT?
AB  - The influence of environmental factors on the timing of parturition has not been
      investigated in viviparous squamates. We investigated the interaction between
      temperature and parturition in two viviparous skink species, the southern snow
      skink (Niveoscincus microlepidotus) and the metallic skink (N. metallicus). In
      these species, the timing of parturition is separated from the completion of
      embryonic development; the delay is attributed to their cool and variable
      habitats. We examined whether the neurohypophyseal hormone arginine vasotocin
      (AVT) stimulated parturition in southern snow skinks with late stage embryos in
      autumn (approximately 6-7 months prior to parturition) and in metallic skinks
      with late stage embryos in summer (approximately 2-3 weeks prior to parturition).
      The experiments were conducted at a range of environmentally relevant
      temperatures (6 degrees C, 15 degrees C, 22 degrees C, and 28 degrees C). AVT
      induced parturition in both species at all temperatures; time until birth,
      however, occurred more quickly at warmer temperatures (22 degrees and 28 degrees
      C), whereas cooler temperatures delayed parturition. We hypothesize that if cool
      temperatures are preventing parturition, then temperature must act at some level
      within the brain to prevent or slow the secretion of AVT. Future experiments will
      need to determine how temperature influences AVT production. Further research is
      also required to determine how the timing of parturition is influenced by
      interactions between temperature, photoperiod, and seasonal hormone patterns.

PMID- 12486813
TI  - In vivo transfection of the mouse vas deferens.
AB  - To explore the possibility that specific characteristics of the epithelium of the
      male tract can be modified, transfections of the mouse vas deferens have been
      performed using in vivo injections of cationic DNA/liposome complexes. Gene
      transfer was done employing the reporter genes pEGFP-C1 encoding Green
      Fluorescent Protein (GFP) and pCMV-nls-beta encoding the nuclear beta
      Galactosidase (beta-Gal). Foreign gene expression reached a maximum of 6.8% in
      the epithelial cells of the vas after treatment with the nuclear beta-Gal gene
      construction and of 13.3% after employing the GFP gene construction. Expression
      of the GFP gene appeared from one week up to three months following injection,
      and it appeared as patches of modified cells along the epithelium. Results from
      immunocytochemistry and Western Blotting support the conclusion that transfection
      of epithelial cells was achieved. We have also transfected the vas using gene
      constructions that express secretory proteins--specifically, the reporter system
      pSEAP-control that expresses a secretory form of human placental alkaline
      phosphatase, and the pGFP-Ctk-37 that expresses a secretion form of GFP. In both
      cases, the fluids expressed from the transfected vas showed a significant
      increase of alkaline phosphatase activity after pSEAP transfection and the
      presence of GFP protein when pGFP-Ctk-37 gene construction was employed. Our
      results indicate that the vas can be transfected in vivo using liposomes as
      vectors of foreign genes and that the vas fluid contents can be modified.

PMID- 12486814
TI  - The case for a 0.05% criminal law blood alcohol concentration limit for driving.

PMID- 12486815
TI  - Immune responses to viruses, bacteria, parasites and fungi in humans.

PMID- 12486816
TI  - Recent advances in the molecular basis of pathogen recognition and host responses
      in the urinary tract.

PMID- 12486817
TI  - Viruses and the type I interferon antiviral system: induction and evasion.
AB  - The type I interferon (IFN) system responds to viral infection and induces an
      "antiviral state" in cells, providing an important first line of defense against
      virus infection. Interaction of type I IFNs (IFN alpha and IFN beta) with their
      receptor induces hundreds of cellular genes. Of the proteins induced by IFN, the
      antiviral function of only a few is known, and their mechanisms of action are
      only partly understood. Additionally, although viral-encoded mechanisms that
      counteract specific components of the type I IFN response have been known for
      some time, it has recently become clear that many (if not most) viruses encode
      some form of IFN-antagonist. Understanding the interplay between viral-encoded
      IFN antagonists and the interferon response will be essential if the therapeutic
      potential of IFNs is to be fully exploited.

PMID- 12486818
TI  - Antiviral immunity and the role of dendritic cells.
AB  - Using our experimental model we demonstrate the need for Th1 immune responses for
      recovery from influenza virus infection. Inoculation of IL-4 concurrent with
      infection significantly delays virus clearance and converts the immune response
      to a Th2 response. Immunization using live virus in the presence of IL-4 leads to
      generation of Th2 memory cells that fail to facilitate recovery upon subsequent
      virus infection. Inactivated virus expands Th2 cells, leading to responses
      similar to those observed following IL-4 infusion. Immunization using cultured
      dendritic cells incubated with live or inactivated virus mimics the results
      observed with direct virus injection. We demonstrate that in contrast to live
      virus-infected dendritic cells, inactivated virus fails to elicit Th1 immunity.
      This failure correlates with the inactivated viruses' inability to induce
      dendritic cell maturation. Thus, our data suggest that the polarity of the immune
      response is dictated by the nature of the antigen, and the trigger for influenza
      virus-induced DC maturation leading to Th1 immunity is dependent on virus
      replication.

PMID- 12486819
TI  - Cytokines in experimental herpes simplex virus infection.
AB  - Herpes simplex virus (HSV) causes productive and latent forms of infection in
      humans and experimental animals. The primary infection and reactivation of the
      latent infection evoke an immune response in the host organism, involving
      activities of macrophages, CD4+ and CD8+ lymphocytes, and B lymphocytes. Strong
      cytokine responses are associated with the acute and recurrent phases of HSV
      infection. Also, during the latent phase of HSV infection in the sensory ganglia,
      expression of certain cytokines can be detected. The cytokine response to HSV
      infection is dominated by proinflammatory and Th1 type cytokines; however, Th2
      type cytokines such as interleukin-4 also are expressed in the infected tissue.
      The use of novel HSV-derived, cytokine-expressing gene therapy vectors
      necessitates studies on the possible modulation of the host responses by the
      virus-encoded cytokine transgenes. This review focuses on the roles of certain
      Th1 and Th2 type cytokines in different phases of the experimental HSV
      infections.

PMID- 12486820
TI  - The role of cytokines and their signaling pathways in the regulation of immunity
      to Toxoplasma gondii.
AB  - The development of a strong cellular immune response is critical for the control
      of the intracellular pathogen Toxoplasma gondii. This occurs by activation of a
      complex, integrated immune response, which utilizes cells of the innate and
      adaptive immune systems. In the last two decades there have been major advances
      in our understanding of the role of cytokines in the initiation and maintenance
      of protective immunity to T. gondii, and IFN-gamma has been identified as the
      major mediator of resistance to this pathogen. This article provides an overview
      of the biology of toxoplasmosis and focuses on the pivotal role of cytokines and
      their signaling pathways during infection. It also addresses the role of
      cytokines in modulating other immune functions that are critical in determining
      the balance between a protective and a pathological immune response.

PMID- 12486821
TI  - Roles of IFN-gamma on stage conversion of an obligate intracellular protozoan
      parasite, Toxoplasma gondii.
AB  - IFN-gamma downregulates the stage conversion of Toxoplasma gondii (T. gondii),
      from bradyzoites to tachyzoites, and the expression of heat shock protein 70
      (HSP70) of T. gondii (T.g.HSP70) by tachyzoites. T.g.HSP70 has been shown to
      downregulate NO release from macrophages and also to induce auto-HSP70 antibody
      formation and IL-10 secretion by VH11-JH1 B-1 cells, resulting in the suppression
      of host defense responses to T. gondii infection. A novel category of virulent
      tachyzoite stage of T. gondii expressing T.g.HSP70 (virulent tachyzoite), which
      indirectly manifests its pathogenicity by downregulating host defense responses,
      has been proposed.

PMID- 12486822
TI  - Cryptococcal infection and Th1-Th2 cytokine balance.
AB  - Cytokines have been recognized as key factors in determining host resistance to
      infectious pathogens. In particular, Th1-Th2 cytokine balance in hosts is
      profoundly associated with the outcome of infection caused by intracellular
      microbes. In a murine model of pulmonary and disseminated infection with
      Cryptococcus neoformans, an opportunistic fungal pathogen that frequently leads
      to fatal meningoencephalitis in severely immunocompromised hosts, expression of
      cytokine mRNA in the lungs from infected animals revealed Th2-dominant profiles,
      while administration of IL-12, which rescued mice from fatal infection, converted
      such balance toward Th1-dominant states in a drastic fashion. Thus, commitment of
      Th phenotypes critically determines host sensitivity to cryptococcal infection.
      In this review, we described how Th1-Th2 cytokine balance influences host
      protective responses to C. neoformans, and we identify the host and pathogen
      factors that regulate such balance.

PMID- 12486823
TI  - Cytokine and chemokine responses underlying acute and chronic Trichuris muris
      infection.
AB  - Intestinal nematode parasites are some of the most prevalent infections of man.
      Infections tend to be chronic and, after drug treatment, have high reinfection
      rates. Control programs relying solely on drugs are thus at best short-term
      solutions; immunization programs are our long-term goal. A prerequisite to
      effective disease control by immunotherapy is the need to understand the immune
      responses that underlie resistance and susceptibility to infection. Most of our
      current understanding of immunity to Trichuris trichiura infection in man has
      come from the laboratory model, Trichuris muris in the mouse. Over the last
      decade we have learned that the type of T helper cell response (Th1 or Th2)
      mounted by the host is critical to the outcome of infection, and we have
      identified key Th2- and Th1-associated cytokines that contribute to resistance or
      susceptibility, respectively. Notably, the number of these key cytokines is still
      growing. Our model of immunity to Trichuris has developed from one resolving
      round IL-4 and IFN-gamma to one that also has to accommodate IL-9, IL-10, IL-13,
      TNF-alpha, IL-12, and IL-18. Importantly, resistance to infection is not just
      about making an appropriate type 2 response. Effector cells have to be recruited
      locally to the site of infection in order to culminate in worm expulsion, which
      brings new key players into our model, including chemokines.

PMID- 12486824
TI  - Atherothrombotic plaques and the need for imaging.
AB  - The assessment of atherothrombotic plaques by imaging techniques is essential for
      the in vivo identification of vulnerable plaques. Several invasive and
      noninvasive imaging techniques are available to assess atherothrombotic disease.
      The use of some of the available imaging modalities for the study of regression
      and progression of atherothrombosis are described in more detail in the
      subsequent articles.

PMID- 12486825
TI  - Embolization in atherosclerosis.
AB  - Much has been learned about microembolization in the last two decades. The
      promising blood markers for brain injury will further enhance our future
      understanding of microembolic events. New surgical techniques, drugs, and devices
      have substantially reduced microembolization during carotid angioplasty, CEA, and
      CABG.

PMID- 12486826
TI  - Noninvasive imaging of atherosclerotic plaque in the arch of the aorta with
      transcutaneous B-mode ultrasonography.
AB  - Atherosclerotic plaque at the arch of the aorta has been identified as a
      potential source for atheroembolic stroke. Imaging of aortic arch plaque can be
      performed with transesophageal echocardiography (TEE), but TEE is an invasive
      procedure. A new noninvasive method has been developed to image aortic arch
      plaque employing transcutaneous real time B-mode ultrasonography with color flow
      duplex Doppler. B-mode imaging has an 86% accuracy for identifying complex aortic
      arch plaques as compared with TEE. Noninvasive imaging of the aortic arch can be
      employed in diagnosing the etiology of cerebrovascular disease in patients with
      stroke or transient ischemic attack in conjunction with duplex B-mode sonography
      of the extracranial carotid arteries. It also provides a noninvasive method for
      studying atherosclerotic plaque in the aortic arch which is applicable for
      investigational studies of the mechanisms of atherosclerosis and evaluation of
      pharmacological agents designed to treat atherosclerotic disease.

PMID- 12486827
TI  - Diffusion and perfusion MRI for the assessment of carotid atherosclerosis.
AB  - Atherosclerotic disease of the extracranial vessels is a frequent cause of
      cerebral ischemia and stroke. Many natural history studies and prospective
      treatment trials with large patient samples have focused on optimal patient
      assessment in regard to medical or interventional measures. Clinical decision
      making nowadays is largely based on the identification, visualization, and
      grading of the local stenosis, and the identification of neurologic symptoms
      related to carotid artery stenosis. MRI already has contributed considerably as
      many surgeons no longer require preoperative conventional contrast angiography
      but may use the combination of duplex ultrasound studies and MRA for
      visualization of the pathology. Besides MRA improvements, DWI and PWI are
      increasingly used in addition to conventional MR contrasts (PD, T2-, T1-weighted
      MRI) in attempts to gather information on tissue status and the pathophysiology
      of hemodynamic compromise and cerebral ischemia in patients with carotid artery
      stenosis. Obtaining background information using this array of MR data may
      eventually become a basis for optimal risk-benefit assessment in patients with
      carotid artery stenosis.

PMID- 12486828
TI  - Carotid atherosclerotic wall imaging by MRI.
AB  - High spatial resolution magnetic resonance imaging (MRI) is one of the most
      promising modalities for visualizing the carotid atherosclerotic plaque. MR
      allows direct visualization of the diseased vessel wall, is capable of
      characterizing plaque morphology, and can potentially monitor progression of the
      disease. Though ultrasound and angiography have been the principal methods for
      determining the severity of carotid atherosclerosis and the need for
      endarterectomy, these methods only measure percentage of vessel stenosis. There
      is strong evidence that this is not the best indicator for assessing clinical
      risk. Improved imaging techniques are therefore needed to reliably identify the
      high-risk plaques that lead to cerebrovascular events. This article focuses on
      the current state-of-the-art in MR carotid atherosclerotic plaque imaging to
      evaluate plaque morphology and composition.

PMID- 12486829
TI  - Clinical carotid atherosclerosis.
AB  - Atherogenesis is an inflammatory process that begins in childhood. Early
      detection of atherosclerosis might allow for selection of subjects at risk for
      future cerebrovascular events at a time when dietary and lifestyle modification
      may have its greatest impact, and medical intervention may be useful for those
      who are refractory to such treatment or who are at greater risk for an event.
      Early detection relies on a knowledge of the distribution of atheroma formation,
      which can be predicted by understanding the hemodynamic patterns of blood flow.
      Early formation is accompanied by a vascular remodeling that normalizes the area
      of the vessel lumen, making early detection impossible by angiography. Elevated
      serologic markers of inflammation may be used as evidence of formation of
      atherosclerosis, but inflammatory markers lack sensitivity and specificity.
      Preliminary evidence supports the ability of MRI to detect early atheroma
      formation, possibly even before substantial wall thickening occurs. Once atheroma
      has formed with measurable stenosis, the goal of imaging studies is to predict
      stroke risk and determine the need for surgical intervention. Subjects with
      symptomatic high-grade carotid stenosis have been shown to benefit from surgery
      with a reduced stroke risk when compared with medical management alone, although
      controversy exists regarding the management of moderate symptomatic carotid
      stenosis or asymptomatic carotid disease. In these individuals, understanding
      atheroma morphology may prove to be of greater utility for assessing stroke risk
      and determining the appropriate management. Morphologic characterization may also
      be helpful in monitoring the effect of medical intervention. MRI has proven
      capable of characterizing the morphologic composition of carotid atheroma,
      although the clinical implications continue to be investigated.

PMID- 12486830
TI  - B-mode ultrasound and spiral CT for the assessment of carotid atherosclerosis.
AB  - More studies on the natural history of carotid artery plaques are needed to
      predict more reliably which plaque types or features are the most dangerous (see
      Table 2). Studies on carotid and coronary endarterectomy specimens indicate a
      dynamic process of rupture, thrombus formation, healing, and remodeling of the
      plaque. A plaque from a symptomatic patient may not show any signs of plaque
      rupture if the plaque has healed or evolved since the debut of symptoms.
      Selection of high-risk symptomatic patients with carotid atherosclerosis for
      medical or surgical treatment requires reliable, noninvasive, and cost-effective
      imaging methods. B-mode ultrasonography can be used for detection of early (IMT)
      as well as late (plaque morphology) atherosclerotic disease. Plaque morphology
      evaluation on spiral CT imaging is only for research and not yet for clinical
      use. Asymptomatic patients with carotid atherosclerosis hardly benefit from
      surgical treatment, as the minimal decrease in ischemic stroke risk is almost
      equal to the risk of perioperative stroke or death. A high degree of carotid
      stenosis measured using conventional angiography is an accepted risk factor for
      stroke but does not identify all vulnerable plaques. Echolucency on ultrasound B
      mode imaging can be included as an important parameter in this risk
      stratification, as it appears to predict rupture-prone, lipid-rich plaques in the
      mild to severely stenotic carotid artery of a symptomatic patient. The subjective
      evaluation of plaque morphology on B-mode ultrasound should be complemented or
      substituted with objective evaluation such as videodensitometric analysis. This
      method is commercially available and is a relatively cheap and investigator
      independent solution, but more studies are required to determine the exact
      contribution of echolucency to stroke risk. Furthermore, the evaluation of plaque
      morphology using ultrasound B-mode is still subject to large variations and
      observer-dependence, limiting its clinical use. In contrast, carotid IMT
      measurements are reliable to monitor progression and regression of early carotid
      disease as well as the impact of interventions. This method, however, suffers
      when used in severely diseased vessels where the boundaries of the IMT complex
      are hard to distinguish in all segments of the artery. Spiral CT imaging is a
      preliminary test for plaque characterization, as it primarily identifies
      calcification but not the more relevant lipid component. Moreover, it is time and
      resource demanding and involves use of both contrast and radiation, increasing
      the risk of allergic events and cancer. Standardization and continuous quality
      control are important, as are consensus agreements on how to quantify lesions
      (especially IMT), calibrate and standardize B-mode images and outline the plaque,
      and analyze data. The development of imaging methods for atherosclerotic research
      is currently fast and promising. This progress is most necessary, considering the
      very high demands for surrogate endpoints and risk markers in clinical
      intervention studies. Whether ultrasonic plaque characterization can be
      implemented in broad general clinical practice, for example, in screening of
      individuals at high risk of developing atherosclerosis and ischemic events, has
      to be based upon data from large prospective studies with long-term follow-up.
      IMT is already used in population screening, as in the ARIC study [9,101].

PMID- 12486831
TI  - Diagnostic imaging of aortic atherosclerosis and its complications.
AB  - Thoracic aortic atherosclerosis has been shown to be an important cause of severe
      morbidity and mortality. At the present time, the case of performance, detailed
      information obtainable, and availability make TEE the procedure of choice for the
      imaging of thoracic aortic atherosclerosis; however, further technical advances
      in MR and CT, particularly in MR plaque characterization and the use of plaque
      specific contrast agents, may allow for a less invasive and more complete
      evaluation of thoracic aortic atherosclerosis in the near future. Gadolinium
      enhanced 3DMRA is the procedure of choice for the noninvasive detection of plaque
      in the proximal aortic arch vessels. Furthermore, both CT and MRI are better
      suited to evaluate penetrating atherosclerotic ulcers and their complications
      such as intramural hematoma, pseudoaneurysm formation, and aortic rupture.

PMID- 12486832
TI  - Transesophageal echocardiography aortic plaque imaging.
AB  - Despite some limitations, TEE is a sensitive and specific diagnostic technique
      for the diagnosis and evaluation of aortic plaque. TEE provides a semi-invasive,
      portable, and widely available means for assessing aortic plaque and associated
      embolic risk in patients with embolic events, thus guiding rational therapeutic
      choices. Improvement in tissue characterization and three-dimensional
      capabilities may further improve the diagnostic accuracy of TEE for aortic plaque
      detection and evaluation.

PMID- 12486833
TI  - Noncoronary and coronary atherothrombotic plaque imaging and monitoring of
      therapy by MRI.
AB  - In the future, the use of imaging methods to quantify the progression and
      regression of atherosclerosis could play a strong role in the management of
      patients. High-resolution, noninvasive MRI may provide exhaustive 3-D anatomic
      information about the lumen and the vessel wall. Furthermore, MRI has the ability
      to characterize plaque composition and microanatomy and therefore to identify
      lesions vulnerable to rupture or erosion. The high resolution of MRI and the
      development of sophisticated contrast agents offer the promise of molecular in
      vivo molecular imaging of the plaque. This may aid early intervention (e.g.,
      lipid lowering drug regiments) in both primary and secondary treatment of
      vascular disease in all arterial beds.

PMID- 12486834
TI  - Pathogenesis of Meniere's disease: treatment considerations. Preface.

PMID- 12486835
TI  - Meniere's disease: overview, epidemiology, and natural history.
AB  - Meniere's disease is a disease of the inner ear characterized by a triad of
      symptoms: vestibular symptoms, auditory symptoms, and pressure. The pathologic
      correlate of Meniere's disease is endolymphatic hydrops and the etiopathogenesis
      involves a deficiency in the absorption of endolymph. The pathophysiology of the
      symptoms is still disputed: membranous ruptures, pressure and mechanical
      displacement of the end organs, or obstruction followed by an abrupt clearance of
      the endolymphatic duct. The course of the disease may be progressive or
      nonprogressive and, in addition to the typical presentation of Meniere's disease,
      two variations of the disorder have been identified: cochlear Meniere's disease,
      and vestibular Meniere's disease. It can be further broken into two subsets:
      Meniere's syndrome, with a known and well-established cause, and Meniere's
      disease, in which the cause seems to be idiopathic. It is likely that there are
      racial (genetic) as well as environmental factors that influence differences in
      incidence among countries and among various sections of countries. The disease is
      much more common in adults, with an average age of onset in the fourth decade,
      the symptoms beginning usually between ages 20 and 60 years. Meniere's disease is
      (grossly) equally common in each sex, and right and left ears are affected with
      fairly equal frequency. The diagnosis of Meniere's disease is by exclusion, and a
      careful history is the most important guide to a correct diagnosis. Its medical
      treatment is largely empiric. Surgery can be considered when, even after medical
      therapy, the disease progresses and the symptoms become intractable. Surgery may
      be either conservative or destructive. Bilaterality must be considered when
      deciding the best surgical option for a patient with Meniere's disease. It is the
      authors' opinion that endolymphatic sac surgery is an extension of conservative
      treatment.

PMID- 12486836
TI  - Genetics (molecular biology) and Meniere's disease.
AB  - COCH is not the FMD gene detected in our linkage study; furthermore, COCH and FMD
      are not allelic. The indications are that FMD is heterogenetic. The linkage
      analysis points to the possibility of one FMD mutation in one of the neighboring
      candidate genes on chromosome 14, and, with anticipation, possibly a triple
      repeat amplification. Recently, the myotonic dystrophy type 2 locus has been
      shown to contain an expanded tetranucleotide repeat [46], so the search for a
      similar repeat on 14q is indicated.

PMID- 12486837
TI  - Pathology and pathophysiology of Meniere's disease.
AB  - Histopathologic study of the human temporal bone entails microscopic examination
      and analysis of a series of histologic sections. This is currently the most
      effective method for observing the pathologic conditions of MD by examining the
      entire inner ear. Complete temporal bone histopathology cannot be replaced by
      either clinical pathologic study of small biopsy specimens obtained during
      surgery, or experimental animal studies that can create endolymphatic hydrops but
      not create MD. We believe that the histopathologic findings together with
      clinical information on MD is valuable in enhancing our understanding of the
      pathophysiology of the inner ear in MD. For example, a hypoplastic VA and ES in
      MD seem to indicate that there may be congenital predisposing factors in the
      development of MD. The exact pathologic findings characteristic of MD remains
      unclear, however. Many of the temporal bone specimens were obtained years after
      patients were diagnosed with MD and those specimens were involved with moderate
      postmortem changes. For these reasons, further collection of temporal bone
      specimens with fewer postmortem changes, obtained within a shorter premortem time
      period between occurrence of the disease and the time of the patients' death, and
      from patients with a well-characterized clinical history of MD, is imperative.
      Contemporary temporal bone studies now include in situ hybridization
      histochemistry or polymerase chain reaction (PCR) analysis for protein, enzymes,
      or viral antigens that can be directed at specimens from patients with MD
      [54,55]. It is hoped that in the near future such advanced research studies with
      human temporal bone histology sections will support and enhance the significant
      contribution of temporal bone histopathology to clinical otology.

PMID- 12486838
TI  - Etiology, pathophysiology of symptoms, and pathogenesis of Meniere's disease.
AB  - Endolymphatic hydrops is the pathologic feature associated with Meniere's
      disease. The development of endolymphatic hydrops appears to arise from
      multifactorial inheritance with alteration of endolymphatic homeostasis. Various
      factors associated with the phenomenon of hydrops include functional or anatomic
      obstruction of endolymphatic flow, malabsorption of endolymph, genetic anomalies,
      vasodilation, allergy, viral infection, and autoimmunity.

PMID- 12486839
TI  - Diagnosis of Meniere's disease: routine and extended tests.
AB  - Meniere's disease can compromise the quality of life of some patients in a manner
      so seriously that it can cause social segregation, even from family. Hearing
      loss, tinnitus, aural pressure, and disturbances in equilibrium added to an
      emotional instability frequently present in these patients may take them to a
      progressive state of solitude and depression, marking their lives by personal
      tragedy and making life a living hell. The clinical picture of Meniere's disease
      fluctuates, however. Individually, subsidiary examinations become impotent in
      diagnosing Meniere's disease. To be called Meniere's disease, the cause must be
      unknown; otherwise it would constitute Meniere's syndrome. Taking all of this
      into consideration, one would call this an unusual situation, or at least
      confusing. The lack of an etiologic diagnosis in medicine always creates anxiety
      for doctors and patients. What is considered to be either a routine or an
      extended test may change from service to service. The physician does not need to
      order all tests. What the physician needs is a protocol he or she trusts. Test
      results can vary, even depending on the moment when they are performed. More
      important than the number of tests ordered is the strategy by which the tests
      should be put together at that certain moment. The authors believe that one
      should have his or her own protocol for diagnosis, always beginning with a
      detailed history taking being guided by them most of the time. It is the authors'
      understanding that patients with Meniere's disease should be followed closely by
      their ear, nose, and throat doctor in episodes of vertigo or fluctuation of their
      hearing, tinnitus, or aural pressure. Should the patient be experiencing a stable
      period, a clinical visit along with an audiovestibular workup should be performed
      at least once a year. By monitoring the course of the disease, clinicians would
      be able to detect early changes in symptoms and/or test results, giving them the
      possibility to intervene clinically as early as possible in acute episodes of
      vestibulocochlear disorganization, protecting the inner ear, and minimizing
      sequelae from spells of hydrops. The authors believe that only the association of
      clinical sense and as many subsidiary tests as are useful will lead to a
      desirable level of certainty in the diagnosis of Meniere's disease, and will
      allow clinicians to presume bilateral involvement, monitor the development of the
      disease, intervene in its natural course, and idealize appropriate treatment.

PMID- 12486840
TI  - History of Meniere's disease and its clinical presentation.
AB  - The term Meniere's disease is used to define either the classic triad of
      vestibular and cochlear symptoms and aural pressure from known or unknown causes
      or its clinical variants, vestibular and cochlear Meniere's disease. Some
      variants evolve after years into typical forms, whereas others do not. Some
      symptoms (positional vertigo) have been long underestimated in previous reports.
      The more we study our patients and correlate clinical findings and the natural
      history with pathologic studies on temporal bones and laboratory research, the
      more we will understand Meniere's disease and its causes. Some causes have
      already been identified as most probable. Extrinsic factors (inflammation,
      trauma, otosclerosis, autoimmunity, endocrine disorders, and such) interact with
      congenital (genetic) and developmental intrinsic factors (primary or secondary,
      acquired) into a multifactorial inheritance that is, to date, the best
      explanation for the basis of Meniere's disease. Endolymphatic hydrops is widely
      accepted as the pathologic substrate, but not all hydrops seems to be progressive
      or becomes clinically manifest. Endolymphatic hydrops is the result of a
      dysfunction in the mechanism of production/absorption of endolymph, which is
      mainly due to defective absorptive activity of the endolymphatic duct and sac.
      Hyperproduction of endolymph cannot be excluded in some cases. Ruptures of the
      labyrinthine membranes do not satisfactorily substantiate the multiform duration,
      recurrence, and repetitiveness of attacks of Meniere's disease, nor do they
      explain the entire complex of symptoms. It seems reasonable to explain symptoms
      of Meniere's disease on the basis of mechanical factors (as observed in temporal
      bone studies) associated with biologic and biochemical factors.

PMID- 12486841
TI  - Medical management of Meniere's disease.
AB  - Medical therapy of Meniere's disease is geared not only toward the differential
      diagnosis that has led to Meniere's disease and the supportive therapy for the
      physical manifestations of the disease but also for the psychologic sequelae of
      the disease such as mild-to-moderate situational depression and even chronic
      depression. Overall, with adequate medical therapy, allergy workup, and
      immunotherapy for patients with known diagnoses of allergies, the author's clinic
      has been able to help more than 85% of its patients who present with symptoms of
      Meniere's disease. For intractable cases where autoimmune phenomena can be
      suspected with a strong degree of suspicion, the author's clinic has also treated
      patients with immunosuppressive medications such as azathioprine and/or
      methotrexate in a low dose.

PMID- 12486842
TI  - Endolymphatic sac surgery for Meniere's disease: experience with over 3000 cases.
AB  - The foregoing discussion has attempted to substantiate and clarify the six
      propositions outlined at the outset in light of the author's personal experience.
      In sum, the following points are emphasized: Employment of ESS for treatment of
      intractable Meniere's disease in cases where the sac is definitively delineated,
      the real sac lumen entered, the sac's integrity preserved, and sac enlargement
      technique is employed has an approximate 90% chance of achieving complete or
      substantial control of vertigo in the short run (2-3 years). Although there seems
      to be little likelihood of pushing the short-term rate of vertigo control
      obtainable with ESS significantly beyond the 90% mark, there is still room for
      improvement of longer-term control of Meniere's disease symptoms, either through
      modification of surgical procedure or, as the author recommends, through
      treatment at an early stage of the disease. The efficacy of ESS almost certainly
      has a definite, although presently ill-understood, pathophysiologic basis and
      cannot be purely attributable to a placebo effect. Regardless of limitations and
      uncertainties surrounding Meniere's disease and treatment of it, ESS is
      indisputably both safe and highly effective and, in the author's opinion,
      continues to be the preferred treatment for medically refractory Meniere's
      symptom-complex.

PMID- 12486843
TI  - Revision of endolymphatic sac surgery for recurrent Meniere's disease.
AB  - Understanding the pathogenesis of Meniere's disease can result from studying its
      natural history; however, a marvelous opportunity for this understanding exists
      in surgical revisions of endolymphatic sac enhancement. In addition to avoiding
      destructive procedures, revision of endolymphatic sac enhancement has restored
      health to many patients. The procedures and findings from such revisions, which
      are briefly described in this article, have provided the best opportunity for the
      author to understand and observe the pathogenesis of Meniere's disease.

PMID- 12486844
TI  - Endolymphatic sac enhancement: reversal of pathogenesis.
AB  - As this article and many other publications have indicated, many thousands of
      patients with incapacitating intractable progressive Meniere's disease have had
      their lives restored through endolymphatic sac enhancement surgery. This is the
      only nondestructive procedure for Meniere's disease that has stood the test of
      time. Destructive procedures such as labyrinthectomy (chemical or physical) and
      vestibular nerve section are reserved for rare cases of failure or recurrence
      after sac enhancement, despite revision of the enhancement. There is much
      evidence to support the concept that endolymphatic sac enhancement reverses or
      enhances the pathogenesis of Meniere's disease. With additional clinical and
      molecular biologic research, endolymphatic sac enhancement will continue to
      improve and become more efficacious in the new millennium.

PMID- 12486846
TI  - Vestibular nerve section.
AB  - When the vertigo of Meniere's disease becomes refractory to medical management, a
      variety of surgical options are available. If intratympanic gentamicin has failed
      or is not recommended and serviceable hearing is present, sectioning the
      vestibular nerve is an excellent option in terms of vertigo control, hearing
      preservation, and postoperative quality of life. Transection of the vestibular
      nerve has gone through a metamorphosis since attempted by Krause over a century
      ago. The microsurgical posterior fossa vestibular neurectomy has undergone an
      evolution, resulting in the combined RRVN. This is essentially a retrosigmoid
      approach with exposure of the lateral venous sinus to allow forward retraction of
      the sinus and better exposure. This technique has the advantages of minimization
      of required mastoid and suboccipital bone work, elimination of the need for
      cerebellar retraction, improved exposure, ability to achieve watertight dural
      closure to minimize incidence of CSF leakage, low incidence of postoperative
      headache, and low overall complication rate. If a cleavage plain cannot be
      readily identified, then the superior half of the eighth nerve is sectioned near
      the brainstem. The results are essentially the same whether the vestibular nerve
      is cut in the IAC or the posterior fossa. Vertigo has been completely controlled
      in 85% and hearing has been preserved at the preoperative level in 80% of
      patients. Combined RRVN is a direct and safe technique, with high success in
      properly selected patients.

PMID- 12486845
TI  - Chemical perfusion of the inner ear.
AB  - In general, chemical perfusion therapy of inner ear disease is safe, inexpensive,
      and easy to perform. High inner ear medication concentrations can be achieved
      while minimizing systemic side effects. Most delivery methods are minimally
      invasive and can be performed in the office. The treatment is usually well
      accepted by patients. Vertigo control rates for Meniere's disease have been
      excellent--rivaling other prominent surgical treatments--allowing intratympanic
      therapy to become the most prominent first-line treatment for Meniere's disease.
      Side effects of ototoxicity occurring in approximately 30% of patients remain as
      one of the primary hurdles to overcome. Most patients who experience hearing
      loss, however, do not complain of the loss and are simply happy to be free of
      their vertigo attacks. The use of oral steroids to rescue and preserve hearing
      during gentamicin perfusion remain promising, and complete recovery and even
      hearing improvement have been observed [30]. Steroid perfusion of the inner ear
      also is variably effective for the treatment of SSHL, and is particularly
      indicated when oral steroids fail or are contraindicated due to other health
      reasons. Many inner ear perfusion methods and philosophies of treatment exist.
      Each technique has its associated advantages and disadvantages, and the
      individual surgeon must decide which technique to use in concordance with the
      patient's disease and expectations. In the future, new medications likely will be
      developed to treat certain types of inner ear disease, including SSHL, tinnitus,
      and various forms of vertigo. These medications can be administered by direct
      chemical perfusion of the inner ear.

PMID- 12486847
TI  - Chemical and physical labyrinthectomy for Meniere's disease.
AB  - The use of intratympanic gentamicin is currently a popular and easily performed
      office procedure for the conservative treatment of the Meniere's disease patient
      who has failed medical therapy or who is not a candidate for surgical therapy.
      The procedure provides excellent control for the symptom of vertigo. Despite this
      success, there remains a significant risk of hearing loss irrespective of
      administered dose. In the future, antioxidant [42,43] or salicylate therapy may
      prevent aminoglycoside toxicity [44]. These prophylaxis methods have shown
      promise in the laboratory. Current methods do not allow for accurate drug
      delivery to the inner ear. Middle ear mucosal status, round window thickness or
      adhesion, patency of eustachian tube, and the effect of endolymphatic hydrops on
      ototoxicity are factors simply out of the control of the operator's hands.
      Judging by the number of recent articles, intratympanic gentamicin instillation
      will continue to be an area of interest for the otologist. Users should be
      encouraged to be consistent and conservative in gentamicin dosing. It is clear
      that vestibular ablation is not necessary for adequate control of vestibular
      symptoms and that larger doses may increase the risk of hearing loss. American
      Academy of Otolaryngology-Head and Neck Surgery guidelines [45] should be used
      and adhered to for reporting on the treatment of Meniere's disease, so that the
      literature may be more comparable. In the same light, a prospective standardized
      trial would be helpful in determining ultimate efficacy and risk to the patient.
      Transmastoid labyrinthectomy remains the surgical standard for extirpating the
      offending labyrinth when hearing preservation is not an issue. In appropriate
      patients, the procedure is a safe and effective method for relieving patients of
      vertiginous attacks. Most patients tolerate the procedure very well and are able
      to compensate fairly well over the course of several weeks to months.

PMID- 12486848
TI  - Early vestibular rehabilitation in patients with Meniere's disease.
AB  - This article proposes a broadened definition of vestibular rehabilitation to
      include patients with active, fluctuating Meniere's disease. Pedagogy in the
      program shifts from amelioration of symptoms by vestibular adaptation or
      habituation to education, prevention, and self-empowerment. Recommendations are
      given for patient education, prevention, and examination.

PMID- 12486849
TI  - High-risk polypectomy: how to prevent major complications.

PMID- 12486850
TI  - Clips for the prevention and treatment of postpolypectomy bleeding (hemoclips in
      polypectomy).
AB  - INTRODUCTION: The most accurate method for the prevention and treatment of
      complications after polypectomy has not been well defined. The prophylactic use
      of hemoclips may reduce the risk of bleeding, mainly in pedunculated big polyps.
      OBJECTIVE: To evaluate the accuracy of hemoclips in the prophylaxis and treatment
      of bleeding after endoscopic polypectomy. MATERIAL AND METHODS: Retrospective
      study of 223 consecutive endoscopic polypectomies performed in our Endoscopy Unit
      between january and october 2001. Hemoclips were routinely used only for large
      polyps (15 to 40 mm); all of them were located in the colon except one, a gastric
      polyp. RESULTS: From a total of 223 polypectomies (215 patients), hemoclips were
      used for 34 (15.2%), in 30 of them just before and in 4 just after polypectomy.
      When used prophylactically no complication was observed, except one mild bleeding
      episode (3.3%) that stopped with the placing of a second hemoclip. The
      therapeutic clipping (4 polypectomies) induced immediate haemostasis in all
      cases. CONCLUSIONS: The prophylactic use of hemoclips is associated with a very
      low risk of bleeding after endoscopic resection of big polyps. Therapeutic
      clipping is an effective measure for polypectomy-related bleeding.

PMID- 12486851
TI  - Digestive anisakiasis: clinical manifestations and diagnosis according to
      localization.
AB  - OBJECTIVES: Digestive anisakiasis is a parasitic disease whose clinical
      manifestations depend on the effect of Anisakis simplex on the digestive tract
      wall. Larvae are acquired by eating raw or poorly cooked fish. It is estimated
      that this entity is currently under-diagnosed, although publications are becoming
      increasingly common. We analyse our series of digestive anisakiasis checking
      localization and studying its relationship with symptoms and method of diagnosis.
      PATIENTS AND METHOD: We review 23 cases of digestive anisakiasis registered
      between 1989 and 2001, and confirmed by the measurement of specific serum Ig E
      antibodies. We analyse clinical symptoms and method of diagnosis according to
      whether localization was gastro-duodenal or intestinal, evaluating whether
      surgical intervention was needed for a correct diagnosis. The statistical
      analysis is made using Fisher's test. RESULTS: 23 patients were included between
      1989 and 2001, 8 with gastro-duodenal localization and 15 with intestinal
      localization. All patients with intestinal localization had abdominal pain.
      Symptoms were less severe for gastro-duodenal cases, and diagnosis was made by
      clinical suspicion and subsequent gastroscopy, whereas more than a half of
      intestinal cases required histological examination of a surgical specimen for
      correct diagnosis. In the remaining half, diagnosis was made by abdominal
      ultrasonography. We also observed that the need for surgery has decreased with
      time from 6/6 cases in the 1989-1996 period of time to 2/9 in the 1997-2001
      period of time. CONCLUSIONS: Clinical manifestations of anisakiasis vary
      depending on localization, symptoms being more severe in intestinal forms. The
      diagnosis of gastro-duodenal anisakiasis did not need surgery and was based
      mainly on gastroscopy findings, whereas intestinal forms frequently required
      histological examination of the surgical specimen. In our hospital, a higher
      index of clinical suspicion allowed us to diagnose intestinal anisakiasis without
      examination of surgical specimens in the last years.

PMID- 12486852
TI  - Spontaneous bacterial peritonitis in patients with hepatic cirrhosis: evaluation
      of a treatment protocol at specialized units.
AB  - INTRODUCTION: Spontaneous bacterial peritonitis is a common and severe
      complication in patients with cirrhosis and ascitis. Its prognosis clearly
      depends on its precocious clinical recognition and efficacious therapy. AIM: To
      optimize a treatment protocol, after auditing clinical efficacy and describe
      microorganisms implicated at our institution. MATERIAL AND METHODS: Retrospective
      study of clinical files of patients with hepatic cirrhosis with positive culture
      of ascitic fluid (AF) and/or an AF polymorphonuclear (PMN) count of more than
      250/mm3, treated at our units between 1st January, 2000 and 31st December, 2001
      (n = 38). Patients showed a median age of 49 years (30-76), 63% of which were
      male. Forty-eight percent were classified as belonging to Child-Pugh B class, and
      52% to C. RESULTS: First, considering cases with PMN > 250/mm3 (n = 29),
      antibiotics were given to all patients (cefotaxime and ampiciline). Fifty-two
      percent had hepatic encephalopathy, 42% had fever, 66% abdominal pain. In 42% a
      microorganism was isolated. Although 24% of fatal cases (only two related to
      infection), we noted a 73% clinical and laboratorial response. Five patients
      (72%) that died, showed renal failure by the time of death. Second, in all cases
      with positive culture of ascitic fluid (n = 21), 42% of which with PMN > 250/mm3
      and 9 monobacterial nonneutrocytic bacterascites' cases, one only agent was
      found: E. coli in 36%, Streptococci (37%), Staphylococci (14%), and other (14%):
      Klebsiella oxytoca, n = 1; Salmonella enteritidis, n = 1; Enterococcus faecium, n
      = 1, Acinectobacter anitratus, n = 1. Only one of the agents, E. faecium (3%)
      showed in vitro sensitivity exclusively to ampiciline; all other were cefotaxime
      sensitivite. CONCLUSIONS: Our protocol will be modified, to treat patients with
      spontaneous bacterial peritonitis with cefotaxime, as monotherapy. Albumin
      infusion will also be added to the protocol, as, we found renal failure to be an
      important negative prognosis factor.

PMID- 12486853
TI  - Role of capsule endoscopy in the management of patients with obscure
      gastrointestinal bleeding.
AB  - The recent emergence of capsule endoscopy has entailed a relevant diagnostic
      imaging advance for gastrointestinal conditions, especially those involving the
      small bowel. Gastrointestinal haemorrhage of obscure origin is probably the most
      widely accepted indication for this new technique, and promising results have
      been reported from series extant to date. In view of data available on this new
      modality, and looking forward to having wide, well designed studies fr
      corroboration, this paper suggests a tentative algorithm for the management of
      this patient group.

PMID- 12486854
TI  - Hepatoma in a 40-year old male with hereditary hemochromatosis in the absence of
      cirrhosis. Implications of molecular diagnosis.
AB  - Hepatocarcinoma is a poor-prognosis complication of hereditary hemochromatosis
      (HH). It occurs with a frequency rate of 10-20%. It is usually diagnosed during
      the 6th or 7th decade of life, and it appears almost exclusively in association
      with liver cirrhosis or in the presence of other known risk factors such as HBV
      or HCV. We present a case of hepatocarcinoma in a 40-year-old male with a long
      history of ethanol abuse of more than 100 g/day. The patient was studied through
      familial HH screening, and firstly diagnosed of HH on the base of biochemical
      blood tests. Subsequently, a C282Y mutation--homozygous--was identified. Studies
      performed on the patient did not suggest liver cirrhosis. Serology for HBV and
      HCV was negative. Concurrently, the patient presented an isolated liver lesion of
      4 cm in segment 6 of the right lobe. Imaging techniques suggested an hepatoma. A
      surgical resection of the tumor by right hepatectomy was performed. The diagnosis
      of HH, complicated by hepatoma, on a non-cirrhotic liver was confirmed. After 2
      years of post-surgery follow-up, a period during which the patient underwent
      treatment including periodic phlebotomies, he remains asymptomatic and with no
      signs of tumor recurrence.

PMID- 12486855
TI  - [Splenorenal shunt in a hemophiliac patient].

PMID- 12486856
TI  - [Triple pylorus or double antroduodenal fistula].

PMID- 12486857
TI  - [Late presentation of Wilson's disease].

PMID- 12486858
TI  - [Candida esophagitis in a non-immunosuppressed patient].

PMID- 12486859
TI  - [Segmental Caroli's disease].

PMID- 12486860
TI  - Atherothrombotic disease and factor XIII: lucky for some?

PMID- 12486861
TI  - Elastic tissue abnormalities in inherited haemolytic syndromes.

PMID- 12486862
TI  - Polymorphisms of genes affecting thrombosis and risk of myocardial infarction.
AB  - BACKGROUND: As thrombosis is an essential factor in the pathogenesis of acute
      myocardial infarction (AMI), the genes of proteins affecting haemostasis are good
      candidate genes for AMI. DESIGN: Associations of the known polymorphisms of the
      coagulation factor VII (FVII) gene (R353Q), the coagulation factor XIII (FXIII)
      gene (V34L) and the glycoprotein Ia (Gp1a) gene (C807T) with the occurrence of
      AMI were studied in 142 AMI survivors and 142 age- and sex-matched control
      subjects. RESULTS: Among those who smoked, the L34 allele of the amino acid FXIII
      polymorphism was less common in the AMI patients (16%) than in the controls (27%)
      (P = 0.06), suggesting a possible interaction of AMI risk between the FXIII
      genotype and smoking status. No differences in the allele or genotype frequencies
      of the studied polymorphisms were seen between the whole study groups. Logistic
      regression analysis showed the carriers of the L34 allele of the FXIII amino acid
      polymorphism to have a significantly (P = 0.03) lower AMI risk compared with
      those homozygous for the V34 allele (odds ratio = 0.54, 95% confidence interval
      0.31-0.93). CONCLUSION: The L34 allele of the amino acid polymorphism of the
      FXIII gene is associated with a decreased risk of AMI, and this protecting
      association seems to be more pronounced in smokers.

PMID- 12486863
TI  - Ca2+ mobilization in saphenous vein smooth muscle cells derived from patients
      with primary varicosity.
AB  - BACKGROUND: Human primary varicosity is associated with 'weakness' of the vein
      wall. We investigated whether the reduced responsiveness of varicose veins to
      physiological vasoconstrictors might result from impaired Ca2+ mobilization in
      venous smooth muscle. MATERIALS AND METHODS: The hypothesis was tested in cells
      derived from phenotypically different vein segments that were obtained from the
      inguinal saphenous vein (tissue with incompetent valves), the distal portion of
      the long saphenous vein just above the medial ankle (clinically healthy tissue),
      and from a tributary to the long saphenous vein just below the knee (incompetent
      and overtly varicose tissue). Saphenous vein from patients undergoing cardiac
      surgery served as control. Cytosolic free Ca2+ levels ([Ca2+]i) were determined
      with the fura-2 method in cultured medial smooth muscle cells of third to sixth
      passage (21-23 measurements per tissue derived from five controls and seven
      patients). RESULTS: Angiotensin II (10 nmol L-1 to 10 mumol L-1) induced a
      significantly (P < 0.05) smaller rise in [Ca(2+)1i response in cells derived from
      incompetent or varicose segments (approximatley 70 nmol L-1) than in cells
      derived from clinically healthy vein (approximately 130 nmol L-1) or controls
      (approximately 170 nmol L-1). Likewise, the effect of endothelin-1 (100 nmol L-1)
      on [Ca2+]i was considerably less in cells derived from segments with incompetent
      valves or from varicose vessel segments than in cells derived from control
      patients (P < 0.05). In organ baths, endothelium-denuded strips of varicose
      vessels contracted significantly less in response to these agonists than
      clinically healthy segments from the same patient. CONCLUSIONS: The reduced
      contractility of diseased human varicose veins in response to angiotensin II and
      endothelin-1 involves impaired Ca2+ mobilization.

PMID- 12486864
TI  - Selectin-P and interleukin-8 plasma levels in coronary heart disease patients.
AB  - BACKGROUND: Alterations of the immune system are now believed to play crucial
      role in the pathogenesis of atherosclerosis. The aim of this study was analysis
      of soluble forms of selectin-P and interleukin-8 levels in patients with
      different form of coronary heart disease. MATERIALS AND METHODS: In the study
      took part 18 patients with stable coronary heart disease, 20 patients with
      unstable coronary heart disease and 15 healthy persons from control group.
      Soluble selectin-P and interleukin-8 levels were measured in EDTA plasma with the
      use of enzyme immunoassay ELISA. RESULTS: The level of soluble selectin-P was
      significantly higher in unstable coronary heart disease patients in comparison to
      the stable coronary heart disease patients (P < or = 0.01) and nonsignificantly
      higher in comparison to the control group. The level of interleukin-8 were
      significantly higher in unstable coronary heart disease patients in comparison to
      the stable coronary heart disease patients (P < or = 0.01) and in comparison to
      the control group (P < or = 0.02). CONCLUSION: Our findings suggest that soluble
      form of selectin-P and interleukin-8 may be useful clinical predictors of
      unstable coronary heart disease. The assessment of the risk for the development
      of coronary heart disease requires further serial investigation.

PMID- 12486865
TI  - Effect of low doses of 5-methyltetrahydrofolate and folic acid on plasma
      homocysteine in healthy subjects with or without the 677C-->T polymorphism of
      methylenetetrahydrofolate reductase.
AB  - BACKGROUND: The 677C-->T polymorphism of methylenetetrahydrofolate reductase can
      lead to increased homocysteine. Moderate increases of homocysteine can be lowered
      by folic acid (0.4-10 mg day-1). This study compared the effect of folic acid
      with 5-methyltetrahydrofolate, the active form of folate generated by this
      reductase, on homocysteine levels in healthy subjects and whether this is
      influenced by the 677C-->T polymorphism. MATERIALS AND METHODS: Either 400
      micrograms day-1 of [6RS] 5-methyltetrahydrofolate or 400 micrograms day-1 of
      folic acid were administered orally to 10 wild-type and 10 homozygous subjects.
      Total homocysteine and folate were determined before and after 3 and 7 weeks of
      treatment, and 24 weeks after stopping treatment. RESULTS: After 3 and 7 weeks of
      treatment with 5-methyltetrahydrofolate, homocysteine levels fell from 11.6 +/-
      1.5 to 9.0 +/- 2.3 and 8.7 +/- 1.8 (P < 0.005) in wild-type subjects and from
      16.9 +/- 6.8 to 12.3 +/- 4.3 and 11.6 +/- 4.4 mumol/L, mean +/- SD (P < 0.005) in
      homozygous subjects, proving biological availability of 5-methyltetrahydrofolate
      irrespective of the 677C-->T genotype. After folic acid for 3 and 7 weeks, values
      fell from 12.6 +/- 3.3 to 9.2 +/- 2.9 and 9.2 +/- 2.7 (P < 0.005) and from 15.6
      +/- 4.9 to 11.7 +/- 3.9 and 9.1 +/- 2.4 mumol L-1, mean +/- SD (P < 0.005) in
      wild-type and homozygous subjects, respectively. Six months after stopping
      treatment, homocysteine levels remained lower than pretreatment levels, with
      statistical significance, only in homozygous subjects treated with 5
      methyltetrahydrofolate (12.1 +/- 2.5 vs. 16.9 +/- 6.8, P < 0.01). CONCLUSIONS: 5
      methyltetrahydrofolate showed comparable efficacy in reducing homocysteine as
      folic acid. A prolonged effect 6 months after ceasing treatment with 5
      methyltetrahydrofolate in homozygous subjects represents a further phenotypic
      effect of the 677TT methylenetetrahydrofolate reductase genotype.

PMID- 12486866
TI  - Rate-dependency of calcitonin secretion in response to increased plasma Ca2+.
AB  - BACKGROUND: Calcitonin (CT) is a polypeptide hormone secreted from C-cells of the
      thyroid gland in response to hypercalcemia. The physiological contribution of CT
      to calcium homeostasis has not been completely clarified. The present study
      therefore further characterized the sigmoidal relationship between plasma ionized
      calcium (P-Ca2+) and CT in normal rats, and examined the possibility of rate
      dependency of CT secretion in response to changes in P-Ca2+. DESIGN:
      Hypercalcaemia was induced by an infusion of calcium gluconate at rate of 4.5 x
      10(-2) mmol h-1 rat-1 i.v. (n = 8) and hypocalcaemia was induced by an EGTA
      infusion at a rate of 4.5 x 10(-2) mmol h-1 rat-1 (n = 7) in one protocol: the
      'slow' protocol. In another protocol an increased rate of infusion of calcium
      gluconate or EGTA was used to induce a more rapid change in P-Ca2+. Calcium
      gluconate was infused at a rate of 6.0 x 10(-2) mmol h-1 rat-1 (n = 6) and EGTA
      infused at a rate of 7.5 x 10(-2) mmol h-1 rat-1 (n = 7): the 'rapid' protocol.
      RESULTS: The infusions of both the 'slow' and 'rapid' protocols resulted in
      linear changes in P-Ca2+, but with significantly different slopes (P < 0.01). The
      Ca2+/CT curves of both protocols were represented by sigmoidal curves. The
      'rapid' increase of P-Ca2+ resulted in a higher maximal CT secretion (2032 +/-
      215 pg mL-1) than the 'slow' increase of P-Ca2+ (1213 +/- 85 pg mL-1; P < 0.001),
      despite similar minimal and maximal levels being obtained in P-Ca2+ in the two
      protocols. Thus, a significantly greater CT response was obtained with a more
      rapid increment in P-Ca2+. CONCLUSION: The relationship between P-Ca2+ and CT is
      represented by a sigmoidal curve, as previously shown. The CT response depended,
      however, not only upon the concentration of P-Ca2+ obtained but also upon the
      rate of increase in P-Ca2+, demonstrating rate-dependency as another significant
      physiological relation between Ca2+ and CT.

PMID- 12486867
TI  - Role of calcitonin in the rapid minute-to-minute regulation of plasma Ca2+
      homeostasis in the rat.
AB  - BACKGROUND: Plasma ionized calcium (Ca2+) is maintained at a very stable
      concentration in mammals. The hormones or factors involved in the very rapid
      regulation of calcium homeostasis are still debated. Thus, previous results from
      our laboratory have clearly shown that parathyroid hormone (PTH) and 1,25(OH)2D3
      are not responsible for the rapid up-regulation of plasma Ca2+ after a brief
      induction of hypocalcaemia. The present investigation therefore examined in vivo
      the possible role of calcitonin (CT) in the very rapid, minute-to-minute
      regulation of plasma Ca2+ in rats. STUDY DESIGN: The rapid calcaemic response to
      acute thyroparathyroidectomy (TPTX) and to acute selective thyroidectomy (TX) (n
      = 10), as well as the possible effect of CT on the very rapid recovery of plasma
      Ca2+ after termination of a brief induction of hypocalcaemia were studied.
      Hypocalcaemia was induced by a 30-min EGTA infusion in ras in three different
      protocols: 1 h after TPTX (n = 9) compared with control TPTX rats not given EGTA
      (n = 13); 1 h after TX (n = 7); and 1 h after TPTX, but during supplementation
      with exogenous CT (n = 8) and compared with the response in TPTX rats infused
      with vehicle (n = 8). RESULTS: An immediate and significant increase of plasma
      Ca2+ was found after TPTX (P < 0.01) as well as after selective TX (P < 0.01) in
      the nonfasting rats. Significant hypercalcaemia (P < 0.05) was still present in
      rats fasting for 2 days before these procedures, but the increase in plasma Ca2+
      was considerably less (P < 0.01). After induction of a brief period of
      hypocalcaemia by infusion of EGTA a significant (P < 0.01) and rapid recovery of
      plasma Ca2+ took place within 10 min and a further increase within the next 60
      min (P < 0.01), whether or not the rats were normal, TPTX, TX or were
      supplemented by CT during the experiments. The plasma Ca2+ recovery curves after
      termination of a brief induction of hypocalcaemia all had similar appearances,
      indicating that presence or absence of CT had no influence on this very rapid
      Ca2+ recovery after induction of hypocalcaemia. CONCLUSIONS: Acute removal of the
      tonus of CT results in an acute increase in plasma Ca2+ for up to 3 h. This
      effect of CT is probably mainly related to the postprandial maintenance of
      normocalcaemia, but is also seen in fasting rats, although to a lesser degree.
      The very rapid calcaemic recovery after discontinuation of a brief induction of
      hypocalcaemia is, however, not a result of suppressed plasma calcitonin levels.

PMID- 12486868
TI  - Effect of Sildenafil on hypertensive lower oesophageal sphincter.
AB  - BACKGROUND: Sildenafil relaxes the muscle cells of the penis arterioles by
      inhibiting phosphodiesterase-type 5 (PD-5), inactivating the nitric oxide
      stimulated cyclic guanosine monophosphate. We investigated whether this effect of
      Sildenafil is also displayed on the muscles of the hypertensive lower oesophageal
      sphincter (LES). METHODS: In 14 patients with symptomatic hypertensive LES,
      oesophageal motility was recorded by means of a low-compliance manometric system
      with five manometric ports for the oesophageal body and a sleeve for the
      sphincter. After a basal period of 60 min a tablet of Sildenafil 50 mg (group A;
      seven patients) or one of placebo (group B; seven patients) ground and dissolved
      in 20 cc of water was infused in the stomach, randomly and in double-blind
      manner. Recording continued for a further 60 min. Sphincter tone and pressure
      wave amplitude were measured each minute and the values averaged for each 5-min
      period for the post-infusion period of 60 min. The values of the whole post
      infusion period, the lowest values among the 5-min periods (nadir values) and the
      values of the last 5-min periods were compared with the basal values in each
      group, and those of group A were compared with the corresponding values of group
      B. RESULTS: Sphincter tone and wave amplitude showed after Sildenafil a
      significant decrease comparable that of the basal period and the placebo. The
      inhibitory effect reached its maximum 10 min after the infusion and lasted
      approximately 1 h. CONCLUSIONS: Sildenafil inhibits the lower oesophageal
      sphincter tone and pressure wave amplitude of patients with symptomatic
      hypertensive LES. These findings suggest a clinical application of PD-5
      inhibitors in the treatment of spastic oesophageal motor disorders.

PMID- 12486869
TI  - Lipid peroxidation and antioxidant status in professional American football
      players during competition.
AB  - BACKGROUND: Oxidative stress occurs during strenuous physical exercise, perhaps
      as a result of increased consumption of oxygen. MATERIALS AND METHODS: In this
      study, different markers of oxidative stress were determined in eight national
      league American football players. Before (March) and at three time-points during
      the competition season (May, June, July) serum total peroxide concentrations,
      auto-antibody titres against oxidized low-density lipoprotein (oLab), and lag
      time of reactive oxygen species-induced degradation of the fluorophore 1
      palmitoyl-2-((2-(4-(6-phenyl-trans-1,3,5-hexatrienyl)phenyl)ethyl)- carbonyl)-sn
      glycero-3-phosphocholine (DPHPC) were measured along with serum ascorbate, alpha-
      and gamma-tocopherol, and beta-carotene concentrations. RESULTS: Before the
      competition season, serum antioxidant concentrations were within the lower normal
      range; ascorbate concentrations increased significantly during the competition
      period (P < 0.05). Serum peroxide concentrations were within the normal range and
      increased significantly during the competition period (P < 0.05); in four of the
      eight subjects the increase was several times the baseline values, while four
      athletes did not show any increase. The oLab titres increased significantly at
      the mid-competition period time-point (P < 0.01), but levelled off thereafter.
      DISCUSSION: Given that it could not be predicted from the baseline oxidative
      stress and antioxidant status which subject would respond to strenuous exercise
      with an increase in oxidative stress status, it is concluded that oxidative
      stress should be monitored in all athletes.

PMID- 12486870
TI  - Calcium affects biomarkers of colon carcinogenesis after right hemicolectomy.
AB  - BACKGROUND: In Western societies colonic cancer most frequently develops in the
      distal colon, largely as a result of the composition of the diet. Modulation of
      dietary factors is therefore an attractive modality to reduce colorectal cancer
      risk. This study aims to evaluate the potentially protective effects of calcium
      in right hemicolectomy patients. MATERIALS AND METHODS: A randomized controlled
      cross-over intervention trial was performed with 1000 mg of elemental calcium per
      day for 2 months in 15 right hemicolectomy patients. Primary endpoints were
      proliferative activity, determined by immunohistochemical detection of BrdU
      labeled cells (LI) in rectal biopsies, and cytotoxicity and alkaline phosphatase
      activity of faecal water. Secondary endpoints were bile acid composition in
      faeces. RESULTS: Calcium-reduced LI in the superficial one-third of the crypt
      (from 0.84 +/- 0.27% to 0.37 +/- 0.08%, P = 0.04) and a trend towards a lower
      total LI and LI in the mid one-third of the crypt was observed. Alkaline
      phosphatase activity was reduced from 6.2 +/- 2.6 U mL-1 in the placebo period to
      4.6 +/- 2.2 in the calcium period (P = 0.02), and a trend toward a lower
      cytotoxicity of faecal water was observed. No effect on total bile acids in
      faeces was observed, but calcium increased the percentage of deoxycholic acid
      (from 49.6 +/- 7.0% to 56.5 +/- 6.2%, P = 0.03) and decreased the percentages of
      cholic acid (from 10.3 +/- 4.7% to 5.8 +/- 2.7%, P = 0.05) and lithocholic acid
      (from 26.7 +/- 3.4% to 23.9 +/- 2.9%, P = 0.04). CONCLUSION: Calcium may have a
      protective effect against colorectal cancer risk in right hemicolectomy patients.

PMID- 12486871
TI  - Cardiovascular involvement in thalassaemic patients with pseudoxanthoma elasticum
      like skin lesions: a long-term follow-up study.
AB  - BACKGROUND: Congenital haemolytic anaemia may be associated with pseudoxanthoma
      elasticum (PXE)-like clinical manifestations. METHODS: The cardiovascular system
      of 14 homozygous and double heterozygous beta-thalassaemia patients with skin and
      retinal vessel alterations similar to those in genetic PXE was analysed over a
      period of 12 years and compared with that of 13 relatives (five sets of parents,
      one single parent, two thalassaemic brothers), and that of the control group
      composed of 16, age- and sex-matched, thalassaemic patients. RESULTS: All
      patients with clinical PXE-like skin lesions exhibited, by light and electron
      microscopy, dermal alterations and mineralization of elastic fibres identical to
      those typical of inherited PXE. None of the relatives and none of the control
      group showed clinical or structural findings of PXE. The follow-up started in
      1988. After 12 years of clinical observation, six patients showed dramatic
      progression of skin involvement, angioid streaks had progressed in two subjects.
      One patient had recurrent gastrointestinal bleeding and underwent partial stomach
      removal for gastric artery aneurysm, one underwent colon resection for intestinal
      infarct, one patient had a transitory ischaemic attack, one died after an
      intracranial haemorrhage, two patients died from cardiovascular disease and one
      from neoplasia. CONCLUSIONS: Thalassaemic patients with PXE-like skin lesions
      also manifest PXE-like vessel alterations that progress with time. Considering
      the severe outcome of these lesions, accurate monitoring should be routinely
      performed on the cardiovascular system of thalassaemic patients with PXE-like
      skin manifestations.

PMID- 12486872
TI  - Molecular study of electron transfer flavoprotein alpha-subunit deficiency in two
      Japanese children with different phenotypes of glutaric acidemia type II.
AB  - BACKGROUND: Electron transfer flavoprotein is a mitochondrial matrix protein
      composed of alpha- and beta-subunits (ETF alpha and ETF beta, respectively). This
      protein transfers electrons between several mitochondrial dehydrogenases and the
      main respiratory chain via ETF dehydrogenase (ETF-DH). Defects in ETF or ETF-DH
      cause glutaric acidemias type II (GAII). MATERIALS AND METHODS: We investigated
      the molecular basis of ETF alpha deficiency in two Japanese children with
      different clinical phenotypes using expression study. RESULTS: Patient 1 had the
      severe form of GAII, a compound heterozygote of two mutations: 799G to A (alpha
      G267R) and nonsense 7C to T (alpha R3X). Patient 2 had the mild form and carried
      two heterozygous mutations: 764G to T (alpha G255V) and 478delG (frameshift).
      Both patients had one each of missense mutations in one allele; the others were
      either nonsense or truncated. Restriction enzyme digestion assay using genomic
      DNAs from 100 healthy Japanese revealed that these mutations were all novel. No
      signal for ETF alpha was detected by immunoblotting in cases of missense mutants,
      while wild-type cDNA resulted in expression of ETF alpha protein. Transfection
      with wild-type ETF alpha cDNA into cultured cells from both patients elevated
      incorporation of radioisotope-labelled fatty acids. CONCLUSION: These four
      mutations were pathogenic for GAII and missense mutations, alpha G255V and alpha
      G267R were considered anecdotal for mild and severe forms, respectively.

PMID- 12486873
TI  - Effect of fluticasone on the elastase:antielastase profile of the normal lung.
AB  - BACKGROUND: Excessive elastolytic activity contributes to the pathogenesis of
      several inflammatory respiratory diseases. The effect of glucocorticoids, which
      are potent anti-inflammatory agents, on the elastase:antielastase balance of the
      human respiratory tract is unclear, as studies on patients and in vitro have
      yielded inconsistent results. DESIGN: To clarify this, bronchoalveolar lavage and
      lavage fluids from the upper and central airways were collected from 10 healthy,
      nonsmoking volunteers before and after a 2-week course of inhaled fluticasone
      propionate (2 x 500 micrograms day-1). Concentrations of two neutrophil elastase
      inhibitors, alpha-1-proteinase inhibitor (PI) and secretory leukoproteinase
      inhibitor (SLPI), as well as neutrophil elastase (NE) activity and NE inhibitory
      capacity (NEIC) were quantified in all lavage fluids. RESULTS: Concentrations of
      SLPI were highest in the proximal airways and decreased distally. Neutrophil
      elastase inhibitory capacity activity followed the same gradient and correlated
      positively and consistently with SLPI, suggesting that this inhibitor makes an
      important contribution to the regulation of elastolytic activity in the healthy
      human respiratory tract. Inhaled fluticasone propionate had no effect on any
      component of the elastase:antielastase balance at any level of the respiratory
      tract, even though circulating cortisol levels were reduced in all subjects,
      confirming subject compliance and adequate pulmonary delivery of the drug.
      CONCLUSION: This lack of action in the respiratory tract may contribute to the
      ineffectiveness of inhaled glucocorticoids in respiratory conditions
      characterised by excessive elastolytic activity.

PMID- 12486874
TI  - On the TRAIL to apoptosis.
AB  - Apoptosis in mammalian cells can be initiated through two major interrelated
      pathways, one involving engagement of the TNF family of death receptors, the
      other involving the release of cytochrome c from mitochondria. Unlike other
      members of the TNF ligand family, TNF-related apoptosis-inducing ligand (TRAIL)
      preferentially induces apoptosis in tumor cell lines, but not in normal cells,
      suggesting that TRAIL could potentially represent a powerful cancer therapeutic.
      Recent experiments have revealed that one of the key regulators of TRAIL
      expression in lymphocytes is the NF-kappa B transcription factors. Several TRAIL
      receptors have been identified: two of these receptors TRAIL-R1/DR4 and TRAIL
      R2/DR5 contain cytoplasmic death domains and signal apoptosis, while two other
      decoy receptors, TRAIL-R3/DcR1 and TRAIL-R4/DcR2 lack a functional death domain
      and do not mediate apoptosis. Many cancer cell lines preferentially express TRAIL
      R1 and TRAIL-R2, suggesting differential regulation of the death and decoy
      receptors. Further knowledge of the regulation and physiological role of TRAIL
      and TRAIL receptors may aid in the rational design of regimens that utilize the
      TRAIL signaling pathway to eliminate tumor cells.

PMID- 12486875
TI  - Interactions between opioid and chemokine receptors: heterologous
      desensitization.
AB  - The opioid and chemokine receptors are both members of the seven transmembrane G
      protein-coupled receptor (GPCR) superfamily. Desensitization is believed to be a
      major element of the regulation of the function of these receptors, and recent
      findings suggest that both agonist-dependent (homologous) desensitization and
      heterologous desensitization can control receptor activity. The cross
      desensitization between opioid and chemokine receptors has significant
      implications for our understanding of both the regulation of leukocyte
      trafficking, as well as the regulation of chemokine receptor function in
      inflammatory disease states. We also review findings which suggest that pro
      inflammatory chemokine receptor-induced heterologous desensitization of opioid
      receptors has important implications for the regulation of opioid receptor
      function in the nervous system.

PMID- 12486876
TI  - The family of IL-10-related cytokines and their receptors: related, but to what
      extent?
AB  - Five novel cytokines (IL-19, IL-20, IL-22 (IL-TIF), IL-24 (human MDA-7, mouse
      FISP, rat C49A/Mob-5), and IL-26 (AK155)) demonstrating limited primary sequence
      identity and probable structural homology to IL-10 have been identified. These
      cellular cytokines, as well as several cytokines encoded in viral genomes (viral
      cytokines), form a family of IL-10-related cytokines or the IL-10 family. These
      cytokines share not only homology but also receptor subunits and perhaps
      activities. Receptors for these cytokines belong to the class II cytokine
      receptor family. The receptors are IL-10R2 (CRF2-4), IL-22R1 (CRF2-9), IL-22BP
      (CRF2-10), IL-20R1 (CRF2-8) and IL-20R2 (CRF2-11). Biological activities of these
      cytokines, receptor utilization and signaling, as well as expression patterns for
      cytokines and their receptors are summarized. Although data indicate that these
      cytokines are involved in regulation of inflammatory and immune responses, their
      major functions remain to be discovered.

PMID- 12486877
TI  - Recent advances in TGF-beta effects on chondrocyte metabolism. Potential
      therapeutic roles of TGF-beta in cartilage disorders.
AB  - Novel approaches to treat osteoarthritis are required and progress in
      understanding the biology of cartilage disorders has led to the use of genes
      whose products stimulate cartilage repair or inhibit breakdown of the
      cartilaginous matrix. Among them, transforming growth factor-beta (TGF-beta)
      plays a significant role in promoting chondrocyte anabolism in vitro (enhancing
      matrix production, cell proliferation, osteochondrogenic differentiation) and in
      vivo (short-term intra-articular injections lead to increased bone formation and
      subsequent cartilage formation, beneficial effects on osteochondrogenesis). In
      vivo induction of the expression of TGF-beta and the use of gene transfer may
      provide a new approach for treatment of osteoarthritic lesions.

PMID- 12486878
TI  - Acetylation in hormone signaling and the cell cycle.
AB  - The last decade has seen a substantial change in thinking about the role of
      acetylation in regulating diverse cellular processes. The correlation between
      histone acetylation and gene transcription has been known for many years. The
      cloning and biochemical characterization of the enzymes that regulate this post
      translational modification has led to an understanding of the diverse role
      histone acetyltransferases (HATs) play in cellular function. Histone acetylases
      modify histones, transcription factors, co-activators, nuclear transport
      proteins, structural proteins and components of the cell cycle. This review
      focuses on the role of histone acetylases in coordinating hormone signaling and
      the cell cycle. Transition through the cell cycle is regulated by a family of
      protein kinase holoenzymes, the cyclin-dependent kinases (Cdks) and their
      heterodimeric cyclin partners. Recent studies have identified important cross
      talk between the cell cycle regulatory apparatus and proteins regulating histone
      acetylation. The evidence for a dynamic interplay between components regulating
      the cell cycle and acetylation of target substrates provides an important new
      level of complexity in the mechanisms governing hormone signaling.

PMID- 12486879
TI  - Exploring the interface between metallo-proteinase activity and growth factor and
      cytokine bioavailability.
AB  - Metallo-proteinases are implicated in many processes involved in tissue
      remodeling, cell motility, morphogenesis, and cell and organ growth and
      differentiation. Recent data suggest that several members of the metzincin family
      including the matrix metallo-proteinases (MMPs), adamalysin-related proteinases,
      and the newly described pappalysins, are intimately involved in the activation
      and/or release of cytokines and growth factors. We review how metzincins, working
      through unique mechanisms, influence the extracellular milieu of several
      important cytokines and growth factors including transforming growth factor-beta
      (TGF-beta), TNF-alpha, IGFs and HB-epidermal growth factor (EGF). Because
      metzincins can modulate the bioavailability of these peptides, they may serve as
      unique target molecules to control cytokine and growth factor action in the
      extracellular environment.

PMID- 12486880
TI  - [Research of saccadic and anti-saccadic abnormalities].

PMID- 12486881
TI  - [Problems of subjective experience and behavior in schizophrenia].

PMID- 12486882
TI  - [Schizo-affective disorders: a valid phenotype?].

PMID- 12486883
TI  - [Sensitivity to psychotropic drugs in schizophrenia].

PMID- 12486884
TI  - [Research of minor neurological signs].

PMID- 12486885
TI  - [Which phenotype for the psychiatric research?].

PMID- 12486886
TI  - [Maximal isometric bite force and sports. Preliminary study].
AB  - INTRODUCTION: The evaluation of the bite forces coupled with EMG activity of
      masseter muscles allows to point out temporo-mandibular joint disorders. The
      intense practice of sports induces stress which may affect the mandibular
      statics, due to an hyperfunction of the elevator masticatory muscles, especially
      the masseter muscles. This concept has led us to compare the maximum isometric
      bite forces of sedentary and physically trained subjects. MATERIAL AND METHODS:
      The aim of this experimentation is to study the maximum isometric bite forces of
      the premolars, with a force transducer, for two groups of physically trained and
      sedentary volunteers (25 subjects), with distinction between male and female
      subjects. Subjects with normal denture and no temporo-mandibular joint disorder
      were retained. EMG and force recording were synchronized and recorded during 10
      seconds of maximal contraction. RESULTS: The male subjects developed a maximal
      bite-force significantly higher (p < 0.05) compared to the female subjects. There
      is no significant difference between subjects practising a sport (at least 6
      hours a week) and sedentary ones. The evolution of force during the contraction
      is different between sexes. EMG activity allowed to control that subjects
      developed a maximal force and an increase in muscular fatigability of physically
      active females compared to sedentary ones was noticed. DISCUSSION: The difference
      of maximal force between men and women is similar to the one found for the
      locomotor muscles. The analysis of the evolution of the force according to the
      contraction duration, might be linked to a different distribution of muscular
      fibers according to the sex. The practice of a sport might increase the
      fatigability of the masseter muscles and might be a factor inducing a muscular
      imbalance of the mandibular posture. But the relatively low number of subjects
      and the absence of well defined distinctions between different kinds of sport
      limit our conclusions.

PMID- 12486887
TI  - [Retrospective study of two years of surgery for temporomandibular joint pain
      dysfunction syndrome].
AB  - BACKGROUND: Assessment of temporomandibular joint (TMJ) surgery is a
      controversial topic. We analyzed our long-term surgical results in a set of
      patients who underwent TMJ surgery in our unit from January 1995 through December
      1996. We used a simple methodology based on 4 criteria: pain, mouth opening, type
      of feeding and patient satisfaction. MATERIAL AND METHODS: We reviewed 21
      operated patients who had been managed by an orthodontist after surgery. The post
      surgical follow-up was 4 years. Patient age at surgery ranged from 14 to 51
      years; the sex ratio was 1/9 M/F. Seventeen patients suffered a closed-lock, 2
      had fibrous ankylosis of the disc. Fifteen patients underwent bilateral TMJ
      arthrotomy with joint fixation and, very often, mandibulo-condylar-plasty to
      counteract the bony compression inside the joint. We rated outcome as "very good"
      if four factors were found: resolution or improvement of pain, more than 40 mm
      post-surgery mouth opening or at least 10 mm improvement for patients with less
      than 40 mm post-surgical mouth opening, normal feeding, subjective satisfaction
      rated as very or quite good. Outcome was thus rated as very good (4 factors),
      quite good (3 factors), good (2 factors), poor (1 factor), failure (0 factors).
      RESULTS: Resolution of pain was achieved in 55% of the patients with an
      improvement in the others. All patients recovered normal feeding. Mouth opening
      remained limited for two patients. Subjective patient satisfaction was very or
      quite good in 80% of the cases. Outcome was rated very good in 9 patients, quite
      good in 7, and good in 5. There were no patients with poor outcome or failure.
      Analysis of the good outcome group showed that 3 had experience a post-surgery
      trauma, one had not complied with rehabilitation therapy, and one suffered from
      undiagnosed rheumatoid polyarthritis. CONCLUSION: According to the literature,
      TMJ surgery is an effective means of treating pain and reducing dysfunction. We
      obtained good and stable outcome in patients who participated in our
      postoperative follow-up. The TMJ is a fragile joint particularly susceptible to
      trauma.

PMID- 12486888
TI  - [Tools available for the diagnosis of obstructive sleep apnea syndrome.
      Measurements for the evaluation of therapeutic efficacy].
AB  - Obstructive sleep apnea syndrome (OSAS) is characterized by the development of
      repeated episodes of pharyngeal collapse. Respiratory movements attempt to reopen
      the closed pharynx leading to resumption of ventilation associated with micro
      arousals. Three kinds of measurements are needed to establish the diagnosis of
      OSAS: airflow (reduction or complete interruption), respiratory effort in
      response to increased airway resistance, micro-arousals associated with the end
      of the respiratory event. Classically, polysomnography was used to establish
      sleep architecture using electroencephalography, electromyography and electro
      oculography. Air flow was measured by thermistors, chest and abdominal movements
      and oximetry were monitored. Other more accessible methods can also be used to
      establish reliable diagnosis. Measuring pulse transit time using ECG and oximeter
      sensors provide a semi-quantitative measurement of respiratory effort. Likewise,
      cardiovascular markers (heart rate, blood pressure, pulse time) can be used
      instead of electroencephalography to establish the arousal pattern.
      Cardiovascular markers are as sensitive and probably as specific as EEG for
      identifying micro-arousals. Measuring nasal pressure provides a much less
      invasive quantitative assessment of airflow than pneumotachography. The shape of
      the inspiratory signal is also an indirect marker of respiratory effort. These
      new tools can be used to characterize the three elementary abnormalities observed
      in OSAS: variations in airflow, increased respiratory effort, fragmented sleep,
      using a very simplified setting compared with classical techniques. Therapeutic
      monitoring of OSAS patients, particularly after surgery, should not be limited to
      physical examination known to lack sufficient sensitivity. It should also include
      simplified methods or complete polysomnography to obtain a precise measurement of
      residual respiratory events and sleep pattern after treatment.

PMID- 12486889
TI  - [Cephalometric assessment in obstructive sleep apnea and hypopnea syndrome].
AB  - Several cephalometric studies have been published to study sleep apnea and
      hypopnea. The purpose of this review is to provide a clear analysis of the
      different and apparently contradictory cephalometric results and to describe
      certain pitfalls of the method. In general, an excessive development of the
      tongue and soft palate are observed in these subjects, limiting the pharyngeal
      airway. Bony anomalies include mandibular retrognathism and an excessive anterior
      ventral development of the skull associated with insufficient anterior growth of
      the base of the skull. The head is held in extension. These different factors
      contribute to blocking the upper airway and favor pharyngeal collapse.
      Cephalometry can be used to identify patients at risk and to propose an
      apnea/hypopnea index for precise etiological diagnosis and therapeutic decision
      making.

PMID- 12486890
TI  - [Obstructive sleep apnea syndrome: medical treatment].
AB  - Medical management of patients with obstructive sleep apnea syndrome (OSAS)
      implies a multidisciplinary organization. Dietary advice is always needed because
      the great majority of these patients are significantly overweight. Drinking
      alcoholic beverages before bedtime and smoking must be advised against. Re
      learning good sleeping habits is also necessary for certain patients with a
      chronic disorder. In patients with a mild to moderate OSAS, or whose diagnostic
      tracing demonstrates position-related respiratory events, it may be useful to
      avoid dorsal decubitus when sleeping. Sedatives should of course be totally
      avoided. Drug treatment for OSAS has generally been disappointing, but new
      serotoninergic receptor antagonists offer new possibilities. Medical management
      of associated conditions such as hypothyroidism must also be an integral part of
      the long term treatment of OSAS. The gold standard treatment remains continuous
      nocturnal positive pressure ventilation with proven efficacy largely demonstrated
      in several controlled trials showing often spectacular response within days.
      Prescription is guided by the intensity of the clinical diurnal and nocturnal
      symptoms, better results being obtained in patients with a high index of
      respiratory events. For patients with mild to moderate disease (index < 30) or
      for patients with severe disease who do not tolerate positive pressure
      ventilation, surgery or a mandibular advancement device should be considered.

PMID- 12486891
TI  - [Treatment of obstructive sleep apnea syndrome with mandibular advancement
      appliances].
AB  - Mandibular advancement device provide a therapeutic option for obstructive sleep
      apnea syndrome (OSAS). Clinical improvement has been proven in the different
      available studies, mainly on nocturnal respiratory events and quality of sleep.
      Less snoring have been noted by bed partners and objective studies have
      demonstrated a decrease in snoring frequency and intensity. The effects of these
      appliances on upper airways resistance syndrome is not yet well documented. The
      significant clinical improvement is secondary to the decrease in the occurrence
      of apneas and hypopneas. Polysomnographic improvement criteria with an apnea
      hypopnea index less than 10 per hour has been noted in certain cases, although no
      improvement or even worsening was noted in other cases. Sleep architecture has
      also changed in these patients, with a decrease in the time spent in stages 1 and
      2, and an increase in the time spent in stages 3, 4 and rapid eye movement sleep.
      Micro-arousals are also reduced in number. Somnolence and loss of attention are
      improved; these have been evaluated subjectively or by a well known and approved
      somnolence scale. In some cases a test for vigilance was done. Our results are
      identical to those published in the different studies concerning respiratory
      events and sleep architecture.

PMID- 12486892
TI  - [Surgery and obstructive sleep apnea syndrome: indications and precautions].
AB  - Surgery has long been a therapeutic option for obstructive sleep apnea syndrome
      (OSAS). The first procedures targeted the soft palate but results of isolated
      uvulo-palatopharyngoplasty (UPPP) were inconstant. A better understanding of the
      mechanisms involved in pharyngeal collapse incited interest in the role of the
      tongue and the retropharyngeal space. Surgical procedures were then developed for
      this level of the upper airways. There are a large number of possibilities.
      Excepting tracheostomy which court-circuits the collapsed zone, all the other
      procedures are designed to widen more or less one or more of the upper airway
      levels. The target can be the nose, the soft palate or the tongue, alone or in
      combinations. In all cases, the surgical alternative should be balanced against a
      non-invasive option: continuous positive pressure ventilation. The objective is
      to minimize the operative risks and sequelae while assuring success equivalent to
      positive pressure ventilation. It is important to note that sufficiently
      effective and permanent results have not been proven for any surgical technique,
      excepting tracheostomy and to a lesser degree bimaxillary advancement osteotomy,
      due to the lack of objective long-term rigorous evaluation. A considerable effort
      must be made in this domain.

PMID- 12486893
TI  - [Clinical protocols for therapy of obstructive sleep apnea syndrome: the role of
      the stomatologist].

PMID- 12486894
TI  - [Traumatic loss of substance of the upper lip].

PMID- 12486895
TI  - [Ectopic parotid gland in the mandible and masseter muscle].
AB  - An unusual case of double salivary ectopy of parotid gland is described into the
      masseter muscle and the mandibular ramus in a 45 year-old patient. He first was
      seen for a slow course tumefaction of the cheek. Imaging demonstrated the
      intramasseteric localization of the tumefaction and revealed a bone defect in the
      upper medial part of the mandibular ramus. The intramasseteric salivary ectopy
      has been confirmed by histologic examination.

PMID- 12486896
TI  - [Epileptic psychosis].
AB  - A relationship between serious psychiatric disorders and epilepsy has been
      observed since antiquity. An association between schizophrenia and epilepsy has
      been noted since the turn of century, but this relationship appeared to be
      uncertain. From the 1950s on, a number of studies were devoted to this subject.
      Epileptic patients are more risk for psychosis than the general population.
      Others psychiatric syndromes, some of which have been individualized recently,
      can occur in patients with epilepsy: alternative psychosis, affective states,
      postictal psychoses, postoperative psychoses. In this article we present the
      different aspects of the psychoses of epilepsy. Their knowledge allows in most
      cases a precise diagnosis and an appropriate treatment.

PMID- 12486897
TI  - [Inflammatory optic neuropathy and multiple sclerosis].
AB  - The diagnosis of inflammatory optic neuritis remains essentially clinical, and
      may be improved by complementary investigations. The prognosis is related to the
      evolution of visual acuity and the risk of development of multiple sclerosis. The
      treatment of acute episodes is better precised but remains a matter of debate.
      Long term treatment has benefited from the results of recent MRI studies.

PMID- 12486898
TI  - [Perturbations of activities of daily living in Alzheimer's disease. A study of
      172 patients with the using a questionnaire completed by caregivers].
AB  - Functional decline was studied retrospectively in 172 patients with Alzheimer's
      disease, AD, using a questionnaire completed by the caregiver. Ninety-nine of
      these patients had a second assessment after a follow-up of 22.1 +/- 13.8 months.
      The questionnaire included French versions of the Physical Self-Maintenance
      Activities, ADL, and of the Instrumental Activities of Daily Living, IADL (Lawton
      and Brody, 1969). A third part assessing social activities, SADL, was derived
      from Katz and Lyerly (1963). The earliest and most frequent perturbations in
      early AD involved SADL, mainly a reduction in social and leisure activities,
      appearing in subjects with a MMSE score > 26. The earliest decline in IADL
      involved the ability for handling finances, odd jobs-sewing, and shopping, which
      were more frequently perturbed than ability to use telephone, traveling or
      handling medication. The most interesting results of our study were as follows.
      Functional decline did not allow to distinguish patients with early AD (MMSE
      score > or = 24) from those with mild dementia (MMSE score 20-23). Mild
      perturbations of ADL, mainly dressing and walking, were observed in early AD.
      There was a good correlation, but no parallelism, between functional decline and
      cognitive decline. Disturbances in ADL and SADL significantly differed only
      between patients with severe dementia (MMSE < 10) and those of the three other
      groups. Apathy appeared to be a stronger predictor of functional decline than the
      score on the MMSE in the early stages of AD. There was a great variability among
      the patients regarding the type of functional decline as well as the rate of
      decline. Functional decline is very useful for detecting early AD. However, its
      specificity seems to be low and the diagnosis should be supported by cognitive
      assessment.

PMID- 12486899
TI  - [The effects of normal aging on face naming and recognition of famous people:
      battery 75].
AB  - The difficulty to recall proper nouns is often something elderly people complain
      about. Thus, we tried to build and standardize a tool that could allow a
      quantified estimation of the naming and recognition abilities about famous people
      faces, specifying the part of gender, age and cultural level for each kind of
      test. The performances of 542 subjects divided in 3 age brackets and 3 academic
      knowledge levels were analysed. To carry out the test material, the artistic team
      of the Grevin Museum (Paris) was called upon. Their work offers a homogeneous way
      to shape famous people faces. One same person thus photographed 75 characters
      from different social categories with the same conditions of light, during only
      one day. The results of the study show that men perform better than women as
      concerns naming task, but that there's no difference between genders as concerns
      recognition task. Recognition performances are significantly better whatever the
      age, the gender and the cultural level may be. Generally, performances are all
      the more better since subjects are younger and have a higher cultural level. Our
      study then confirms the fact that normal aging goes hand in hand with rising
      difficulties to name faces. Moreover, results tend to show that recognition of
      faces remains better preserved and that the greater disability to recall a name
      is linked to difficulties in lexical accessing.

PMID- 12486900
TI  - [Encephalopathy associated with severe bacterial infections: "presuppurative
      encephalitis" or "toxi-infectious disorder"?].
AB  - Three children are reported, exhibiting encephalopathic symptoms in the course of
      a severe bacterial infection, though they had no sign of intracranial purulent
      collection nor metabolic disturbances: the first was associated with a
      appendicular peritonitis, the second with a purulent knee arthritis, the third
      with a pneumoccus septicemia. The elements are reviewed that favor either a true
      septic encephalitis, i.e. microscopic presuppurative foci, versus a
      toxiinfectious process, either by direct action of toxins or through
      intracerebral activation of pre-inflammatory cytokines. Whatever the mechanism
      involved in individual cases, the treatment is mainly based on prompt
      administration of the convenient antibiotics.

PMID- 12486901
TI  - [Chronic inflammatory polyradiculoneuritis and the axonal cytoskeleton:
      morphometric and immunocytochemical data].
AB  - We report morphometric and immunocytochemical data obtained from nervous biopsy
      in 7 patients with chronic inflammatory demyelinating neuropathy (CIDP), compared
      to 5 controls (without neurological involvement). Fiber loss was present in all
      cases and reached 50 p. 100 or more in 4 cases. The g myelination ratio was
      elevated in 3 cases only, indicating demyelination. The number of fibers labelled
      for the L subunit of neurofilaments was normal in cases with moderate fiber loss
      and dropped down for densities < 3900/mm2 (4 cases). Labelling with anti-GAP43
      antibody was considerably increased in 3 cases, but did not correlate with fiber
      density or disease duration. These data confirm the importance of axonal lesions
      in CIDP and offer the opportunity to discuss their pathophysiological mechanisms.

PMID- 12486902
TI  - [Validation of the combined SF36/MSQOL test of evaluation of quality of life in
      migraine patients in France].
AB  - The impact of migraine on patients quality of life is great, even between
      attacks. The aim of this study was to assess the properties of a French language
      quality of life questionnaire, which associates the Medical Outcome Study Short
      Form (MOS SF 36) with the Migraine-Specific Quality of Life (MSQOL). Data were
      obtained from 110 consultant patients of neurology units located in three
      University hospitals in the center of France. The results indicated a good
      acceptability of the association of the two questionnaires with a 84p.cent
      response rate. The Principal Component Analysis showed no change in both SF-36
      and MSQOL structures. It also suggested that the two questionnaires were
      complementary. The high values of the Cronbach alpha coefficients for each scale
      indicated a high level of internal consistency. The quality of life scores were
      correlated with external parameters such as frequency, intensity and length of
      migraine attacks, and social activity reduction due to these attacks. In
      conclusion, the association of the SF-36 with the MSQOL has the interest of
      associating generic and specific questionnaire, in a complementary way. This
      association has good psychometric properties, and can be used to evaluate
      migraineurs quality of life in French speaking countries.

PMID- 12486903
TI  - [Sudden bilateral hearing loss disclosing meningeal carcinomatosis].
AB  - We report the case of a patient presenting a sudden bilateral hearing loss. Four
      years before, a bladder carcinoma was resected and a chemotherapy was started.
      Gadolinium-enhanced magnetic resonance images revealed enhancement of both
      acoustic nerves. Cerebrospinal fluid analysis showed malignant cells consistent
      with the initial bladder cancer. Meningeal metastases from bladder carcinoma are
      extremely rare. Systemic chemotherapy and its low meningeal diffusion may enhance
      the incidence of this complication. Bilateral hearing loss is a rare initial
      manifestation of meningeal carcinomatosis.

PMID- 12486904
TI  - [Giant arteriovenous malformation of the vein of Galen in a 50 year old man].
AB  - True malformations of the vein of Galen are usually diagnosed within the first
      weeks of life. They represent less than 1 p. 100 of the cerebral arteriovenous
      malformations. These true malformations are exceptional in adults but should be
      known as an endovascular treatment could be performed. The most frequent clinical
      presentation is a severe cardiac failure leading to death. We report a giant
      arteriovenous malformation of the vein of Galen in a right-handed, 50 year-old
      man. During childhood, he suffered from a compensated cardiac failure which
      remained of unknown cause. Neurological examination showed kinetic and static
      cerebellar syndrome and a Parinaud syndrome. A cerebral MRI scan revealed a giant
      vascular malformation of the vein of Galen with a normal posterior fossa. The
      angiography enabled the diagnosis of a true malformation of the vein of Galen in
      its choroidian form. Its high blood flow entails cardiac failure because of a
      steal phenomenon. An endovascular treatment was declined because of numerous
      arterial afferences and the potential risks of peroperative haemorrhage.

PMID- 12486905
TI  - [Necrosis of a hypophyseal adenoma and ischemic cerebral vascular accident ].
AB  - A 78-year old man developed an acute intracranial hypertension followed by
      central left facial palsy. CT Scan and MRI revealed an ischemia within the right
      lenticulostriate arteries territory and a hemorrhagic infarction of a pituitary
      adenoma without extrinsic carotid artery compression. Neuroophthalmologic
      examination and hormonal screening were normal. Though pituitary apoplexy and
      stroke might represent a fortuitous association, several mechanisms underlying
      such clinical picture are advanced.

PMID- 12486906
TI  - [Bilateral phrenic nerve paralysis, dysautonomia and restrictive cardiomyopathy
      in a case of POEMS syndrome].
AB  - We report a case of POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy,
      M protein and Skin changes) with unusual clinical features. A 62-year-old woman
      presented a severe polyneuropathy with dysphonia and vegetative symptoms,
      including bradycardia and sphincterial disorders. The clinical examination showed
      facial hyperpigmentation, cachexia, anasarca and splenomegaly. She also presented
      restrictive cardiomyopathy and endocrine disturbances. Nerve conduction studies
      revealed a severe demyelinating sensorimotor neuropathy. Cerebrospinal fluid
      analysis showed an elevated protein level. We detected a biclonal gammapathy (Ig
      G and Ig A with lambda light chain) and lytic pelvic bone lesions. Later, she
      developed a severe ventilatory failure due to a bilateral phrenic nerve paralysis
      leading to a mechanical ventilation. Steroids followed by localized radiotherapy
      partially improved the respiratory status and stabilized the neuropathy. Phrenic
      nerve paralysis, restrictive cardiomyopathy, vegetative symptoms and cranial
      nerve palsy are exceptional in POEMS syndrome. Moreover, this case emphasizes the
      importance of radiological investigations since the discover of plasmocytoma may
      improve the prognosis of POEMS syndrome.

PMID- 12486907
TI  - [Ptosis and mastication disorders revealing concurrent myasthenia gravis and
      chronic polyradiculoneuritis].
AB  - Although myasthenia gravis (MG) has frequently been associated with other
      autoimmune disorders, it has only rarely been reported in conjunction with
      diseases of the nervous system. A 74-year-old patient with hypertension suddenly
      presented left unilateral ptosis and mastication disorders. Clinical examination
      showed a concomitant loss of strength distally and reduced deep tendon reflex.
      Electrophysiologic data indicated a diagnosis of MG and chronic inflammatory
      demyelinating polyneuropathy; acetylcholine receptor antibody was elevated at 4.1
      nmol/L (normal < 2 nmol/L). Improvement was rapid after initiation of
      pyridostigmine in association with corticosteroid (1 mg/kg/day). One month later,
      the cranial nerve deficit disappeared and strength was normal. It is likely that
      a basic abnormality of immune regulation was responsible for the emergence of
      diseases with different clinical presentations, but similar immunopathogenesis.
      Corticosteroid seemed to be the most effective treatment.

PMID- 12486908
TI  - [Pergolide: a useful agonist for the treatment of Parkinson disease].
AB  - The efficiency of pergolide has been confirmed by the study of a group 29
      parkinsonian patients. They were relatively young, and the duration of evolution
      of their Parkinson's disease was more then ten years, with levodopa-induced
      dyskinesia and fluctuations. In this group of patients with most serious motor
      disability, it has been possible to improve dyskinesia and fluctuations with a
      relatively important dosage of pergolide and without increase of levodopa dosage.

PMID- 12486909
TI  - Traumatic brain injury and inhibitory processes.

PMID- 12486910
TI  - [Post-prandial hypotension: a cause of unconsciousness in the elderly].

PMID- 12486911
TI  - [Injury of the external branch of the accessory nerve].

PMID- 12486912
TI  - [Current data on the genetic of Parkinson disease].

PMID- 12486913
TI  - The enslaved healers of eighteenth-century Saint Domingue.
AB  - Enslaved healers including herbalists, kaperlatas, hospitalieres, infirmieres,
      and accoucheuses existed and flourished in the medical world of Saint Domingue.
      They were responsible for the creation of an indigenous form of medicine on the
      island. Using Western, African, and Caribbean remedies, they treated their fellow
      slaves and white residents of the island. Slaves were more comfortable and more
      familiar with the care and techniques employed by the popular healers, especially
      the kaperlatas and the herbalists. Plantation managers took advantage of the
      labor of female medical workers in order to reap economic profits for their
      planter employers and for themselves. Lower-class whites, unable to afford and
      unwilling to consult mainstream medical care, sought the assistance of healers
      known as kaperlatas. Lastly, orthodox medical practitioners turned to slave
      healers, especially herbalists, to exploit the therapeutic knowledge that the
      slaves possessed and, in the case of enslaved midwives, to bring them more
      closely under the authority of European medical men.

PMID- 12486914
TI  - The chapel and the operating room: the struggle of Roman Catholic clergy,
      physicians, and believers with the dilemmas of obstetric surgery, 1800-1900.
AB  - By 1800, the Roman Catholic Church and organized medicine faced the dilemma of
      how to resolve cases of obstructed births. American physicians usually practiced
      destructive operations, like craniotomy, in an attempt to save the lives of
      mothers. The church allowed such operations after the death of the infant. A new
      technique of surgery, the cesarean operation, offered hope that both patients
      would survive childbirth. Medical progress, and an emerging Catholic belief that
      the fetus was human, prompted Catholic physicians to advocate the new operation,
      and stirred a renewed debate among European theologians on the propriety of
      craniotomy. In America, the broad Christian tradition promoted by the Catholic
      Church began to inform medicine on the moral and ethical parameters of surgery.
      American physicians, for their part, engaged in their own debate on the propriety
      of the cesarean operation. This article, focusing on the cesarean debate, reveals
      the intersections of Catholicism and medical progress amid the growth of
      obstetric surgery from 1800 to 1900.

PMID- 12486915
TI  - Chorea and community in a nineteenth-century town.
AB  - The dominant historical narrative of Huntington's disease (Huntington's chorea)
      has portrayed the early American sufferers from this disorder as marginalized and
      vilified. This article argues, however, that afflicted families in East Hampton,
      New York--the site of George Huntington's mid-nineteenth-century observations-
      were mostly accepted and integrated within the community, some of them as members
      of the gentry and active participants in local governance. As descendants of
      early English settlers in this multiracial town, these white Presbyterian
      families, some of whose members were afflicted with what was locally called "St.
      Vitus's dance" or "that disorder," were always defined as "one of ours." While
      this fatal inherited neurological illness became more secret and hidden toward
      the end of the nineteenth century, this article suggests that it was larger
      cultural and social changes, rather than factors intrinsic to the disease, that
      led to the shift. The East Hampton story suggests the ways in which specific
      historical circumstances in a community may shape the-social meanings of even so
      severe a disease as Huntington's, and that social integration of the afflicted
      families may have helped mitigate the suffering of the disease.

PMID- 12486916
TI  - Early conjectures that Down syndrome is caused by chromosomal nondisjunction.
AB  - In 1959, cytologic studies demonstrated that Down syndrome was associated with a
      nondisjunction now known as trisomy 21. Twenty years earlier (1932-39), at least
      three writers conjectured, independently of one another, that Down syndrome might
      be a form of nondisjunction: Petrus J. Waardenburg (1932), Adrien Bleyer (1934),
      and G. Fanconi (1938). In separate papers, Raymond Turpin (1937), Walter E.
      Southwick (1939), and Lionel S. Penrose (1939) also proposed that Down syndrome
      could be a chromosomal anomaly, but without specifying nondisjuction. However,
      these conjectures were largely ignored by contemporary medical writers. This
      essay (1) explores the background and context of early conjectures that Down
      syndrome is a form of nondisjunction, (2) provides some possible reasons why
      these conjectures were not given greater credence, and (3) traces early efforts
      to assimilate Down syndrome and other genetic disorders to what Robert Koch
      called the etiologic standpoint.

PMID- 12486917
TI  - Spontaneous intracerebral hemorrhage: epidemiology and clinical presentation.
AB  - The advent of widespread CT availability has dramatically changed our
      understanding of the incidence and risk factors regarding intracerebral
      hemorrhage (ICH). In the pre-CT era, many patients with a small ICH were
      misclassified having had ischemic strokes and patients with massive ICH or
      subarachnoid hemorrhage (SAH) were often difficult to classify correctly. The
      fact that the precise mechanism of spontaneous ICH is often difficult to
      ascertain without pathologic evidence continues to hamper epidemiologic studies.
      This article reviews the incidence rates, natural history, epidemiology, and
      clinical presentations of nontraumatic ICH.

PMID- 12486918
TI  - Spontaneous intracerebral hemorrhage: epidemiology, pathophysiology, and medical
      management.
AB  - This article introduces the basic epidemiology of intracerebral hemorrhage (ICH)
      and discusses the current available literature on the pathophysiology of primary
      ICH, hematoma enlargement, and cerebral edema. The article also includes a brief
      presentation of the basic steps regarding initial ICH management is presented as
      a framework for patient care.

PMID- 12486919
TI  - Intracerebral hemorrhage secondary to vascular lesions.
AB  - The article reviews intracerebral hemorrhage caused by vascular malformations.
      The article also reviews incidence, prevalence, and distribution of parenchymal
      hemorrhage caused by aneurysms, arteriovenous malformations, and cavernous
      malformations are defined, and less common vascular lesions. There is a
      discussion of the role of cerebral vascular malformations in producing cerebral
      hemorrhage in young adults abusing illicit drugs.

PMID- 12486920
TI  - Drug-induced iatrogenic intraparenchymal hemorrhage.
AB  - Intracerebral hemorrhage is bleeding into the brain parenchyma with possible
      extension into the ventricles and subarachnoid space. Each year, approximately
      37,000 to 52,400 people suffer from intraparenchymal hemorrhage (IPH) in the
      United States. This rate is expected to rise dramatically in the next few decades
      as a result of the increasing age of the population and a change in racial
      demographics. IPH accounts for 8% to 13% of all stroke cases and is associated
      with the highest mortality rate.

PMID- 12486921
TI  - Diagnostic imaging for intracerebral hemorrhage.
AB  - Magnetic resonance imaging (MRI) is an excellent tool for the diagnosis and
      evaluation of intracerebral hemorrhage with its unique specificity to hemoglobin
      degradation products in different stages. Computed tomography (CT) remains the
      diagnostic test of choice in the setting of acute intracerebral hemorrhage
      because of its exquisite sensitivity and specificity for small amounts of
      intracerebral hemorrhage (although there is emerging evidence that MRI may be as
      sensitive as CT). The effects of the biochemical evolution of intracerebral
      hemorrhage on the temporal MRI signal changes are described. This article
      discusses imaging features of the common causes of intracerebral hemorrhage.

PMID- 12486922
TI  - Medical management of increased intracranial pressure after spontaneous
      intracerebral hemorrhage.
AB  - There are several medical therapies available to lower unacceptable ICP. We
      advocate the stepwise institution of these therapies to maintain adequate CPP. At
      every step in the process, consideration of definitive surgical intervention
      (e.g., hemicraniectomy, clot evacuation) should be entertained. At this time, we
      cannot recommend hypothermia as a routine last step of therapy given the
      complications and lack of clinical effect described previously. Research into
      this therapy continues, however. The next several years may show us when, how,
      and in what situations this strategy can be applied.

PMID- 12486923
TI  - Medical versus surgical therapy for spontaneous intracranial hemorrhage.
AB  - Based on currently available literature, there is no definitive evidence to
      support decisions about which ICH patients should be managed surgically and which
      should be managed by medical therapy alone. Furthermore, when surgical ICH
      management is undertaken, there is no definitive evidence to suggest which
      procedure is indicated under different circumstances. Additional randomized
      controlled trials are needed to provide this evidence. Currently underway, the
      International Surgical Trial in Intracerebral Hemorrhage is a randomized
      controlled trial designed to determine if early surgical removal of ICH is
      superior to initial conservative management [30-32]. As of July 2001, 668
      patients from 65 centers had been randomized to this trial. The investigators
      plan to enroll 1000 patients so as to achieve adequate statistical power.
      Preliminary results revealed that the median patient age was 65 years and that
      most patients were randomized within the first 24 hours of ictus. The presenting
      GCS scores ranged between 5 and 15, with the scores of half of the patients being
      greater than 10. Fewer than 15% of all patients had a favorable outcome based on
      the Glasgow Outcome Scale. No data are available on mortality rates or other
      outcome measures. Comparisons between the two treatment groups await the trial's
      conclusion. Future randomized controlled trials are clearly needed. A sufficient
      number of patients should be enrolled to assess the affects of patients age,
      comorbidities, hematoma volume, hematoma site (including dominant versus
      nondominant hemisphere), presenting neurologic examination, timing of surgery,
      and different surgical procedures (e.g., craniotomy, craniectomy, stereotactic
      needle aspiration, stereotactically guided endoscopic evacuation). Trials
      designed specifically to compare different surgical methods would be helpful.

PMID- 12486924
TI  - Minimally invasive therapy for intracerebral hematomas.
AB  - The efficacy of surgical treatment of ICH remains unproven and controversial
      [40]. Although open surgery does not appear to improve the patient's outcome [2],
      less invasive methods of hematoma evacuation seem to show promising results in
      improving patient outcome and survival. To date, the only two clinical trials
      that have demonstrated benefit from surgical treatment over medical therapy for
      ICH have used minimally invasive techniques [27,38]. Randomized controlled
      clinical trials comparing minimally invasive surgical techniques versus best
      medical treatment are needed to determine the best management of ICH.

PMID- 12486925
TI  - Cerebral blood flow changes associated with intracerebral hemorrhage.
AB  - Recent advances have furthered our understanding of changes in CBF after ICH.
      Recent evidence from experimental and clinical studies has not supported the role
      of CBF changes in the pathogenesis of neuronal injury. A better understanding of
      these changes in ICH has modified the basis for formulating treatment strategies
      and developing innovative therapies.

PMID- 12486926
TI  - Pathophysiology of brain edema formation.
AB  - A number of mechanisms seem to be involved in edema formation after an ICH. At
      least three phases of edema are involved in ICH. These include a very early phase
      (first several hours) involving hydrostatic pressure and clot retraction, a
      second phase (first 2 days) involving the activation of the coagulation cascade
      and thrombin production, and a third phase (after 3 days) involving RBC lysis and
      hemoglobin-induced neuronal toxicity. Activation of the complement system in
      brain parenchyma also plays an important role in the second and third phases.
      There are potential therapeutic strategies to address each of these mechanisms.
      Because the adverse effect of an ICH seems to result from a toxic effect of blood
      components on brain tissue, early clot removal may be the best strategy, because
      it results in the removal of all the toxic components [93]. Hematoma aspiration
      after tissue plasminogen activator (tPA) infusion has also been shown to be
      relatively safe and effective in animal models. Kaufman et al [94] reported that
      tPA lysed the hematoma in minutes and did not cause inflammation or bleeding in
      rabbits. Because clots lysed with tPA can be aspirated through a needle or
      catheter, mechanical brain injury by this method is minimized. In a rat model,
      aspiration of clot with tPA reduced clot volume and brain injury [95,96].
      Recently, Wagner et al [97] infused tPA into hematomas in a porcine model at 3
      hours after induction and aspirated the liquified clots 1 hour later. Clot
      removal after tPA treatment resulted in a 72% reduction in hematoma volume
      compared with untreated controls. Clot removal also reduced brain edema volume
      and BBB disruption and improved cerebral tissue pressure [93]. Six randomized
      trials have been accomplished, but surgical evacuation of the clot remains
      controversial [98-103]. Recently, thrombolysis and aspiration under CT guidance
      reduced the hematoma volume effectively [104]. Infusion of tPA directly into the
      hematoma before clot aspiration has also been used in human beings. Up to 90% of
      the original hematoma volume can be removed [105, 106]. Schaller et al [107]
      injected tPA directly into a hematoma 72 hours after the ictus in patients. The
      hematomas were lysed, and the liquified clots were drained in 14 patients. Two
      patients died, but none had recurrent hemorrhage. In conclusion, much has been
      learned about the basic mechanisms involved in edema formation after ICH. Animal
      models indicate that a number of components of blood are capable of inducing
      brain injury and brain edema. Now, it is time to translate that basic information
      into clinical trials.

PMID- 12486927
TI  - Experimental animal models of intracerebral hemorrhage.
AB  - Experimental animal ICH models are able to reproduce the overall important
      pathophysiologic events documented in human ICH, including edema development,
      markedly reduced metabolism, and tissue pathologic responses. Thus, ICH models
      serve as an important tool for new understanding of the mechanisms underlying
      brain injury after an intracerebral bleed. Currently, ongoing studies in several
      laboratories using these models investigating secondary inflammatory responses as
      well as intracellular signaling and molecular events are expected to provide
      therapeutic targets for treating ICH. Future studies should also be directed at
      one aspect of ICH modeling that has received little attention--potential
      differences in the hemostatic systems and physical and biochemical properties of
      clots in animals that might make their susceptibility to aspiration and/or
      fibrinolytic drugs and rates of rehemorrhage different than in human beings.
      Also, future efforts should be directed toward the development of a model that
      mimics the pathophysiologic processes that lead to spontaneous ICH, progression
      of hemorrhage, and the recurrence of bleeding in human beings. This model would
      not only provide better understanding of the dynamic events leading to ICH and
      tissue injury but should also lead to the development of highly effective
      pharmacologic and surgical treatments.

PMID- 12486928
TI  - [Dynamics in neuronal migration and axonal expansion].

PMID- 12486929
TI  - [Development and migration of lot cell, the guidepost neuron of the lateral
      olfactory tract].

PMID- 12486930
TI  - [Migration modes of cortical neurons].

PMID- 12486931
TI  - [Neuronal migratory behavior revealed in organotypic culture].

PMID- 12486932
TI  - [Mechanisms for the formation of thalamocortical projection].

PMID- 12486933
TI  - [Wave and somite segmentation: a view from zebrafish genetic analyses].

PMID- 12486934
TI  - [Structure and function of nitric oxide synthases].

PMID- 12486935
TI  - [Cyclopentenone prostaglandin derivatives as neuroprotective compounds].

PMID- 12486936
TI  - [Computational power of DNA molecules and its possible biological relevance].

PMID- 12486937
TI  - Diagnosis and misdiagnosis of inflammatory bowel disease.
AB  - Several diseases can mimic IBD clinically, but careful and repeated evaluations,
      if necessary, will dramatically decrease the likelihood of misdiagnosis. A
      careful consideration of patient's clinical, radiographic, endoscopic, and
      histopathologic features will establish the correct diagnosis in the majority of
      cases.

PMID- 12486938
TI  - Upper gastrointestinal tract endoscopy in inflammatory bowel disease.
AB  - Upper gastrointestinal endoscopy is used to evaluate upper gastrointestinal
      symptoms in patients with inflammatory bowel disease. This article discusses the
      procedure, which may allow for the diagnosis of Crohn's disease of the esophagus,
      stomach, and/or duodenum. Biopsies of normal gastric mucosa in patients with
      indeterminate colitis may be helpful in making a diagnosis of Crohn's colitis.
      Upper gastrointestinal endoscopy may allow for therapeutic intervention in terms
      of bleeding and stricturing disease.

PMID- 12486939
TI  - Colonoscopy in inflammatory bowel disease.
AB  - This article discusses the important role endoscopy plays in the diagnosis and
      management of inflammatory bowel disease and how the procedure adds crucial
      information to the constellation of history, physical examination, radiographic
      findings, and laboratory values. Differentiation between Crohn's disease and
      ulcerative colitis has important ramifications for medical therapy, surgical
      options, and prognosis. This distinction can be accurately made in at least 85%
      of patients.

PMID- 12486940
TI  - Endoscopy of the small bowel in inflammatory bowel disease.
AB  - With the heterogeneous clinical presentation of IBD, endoscopy plays an integral
      role in the initial diagnosis of Crohn's disease. Although radiographic tests are
      often supplemental in the evaluation of Crohn's disease, they previously had been
      the only modality available allowing for visualization of much of the small
      bowel. The advent of small bowel endoscopy allows for direct visualization, and
      often biopsy, of the small bowel, allowing for confirmation of diagnosing and
      extent of involvement. Currently, the only mode for obtaining biopsies from
      beyond the ligament of Treitz is via push enteroscopy or intraoperative
      enteroscopy. Knowing the extent of disease can also help explain recalcitrant
      symptoms or lack of response to certain therapies. With the advent of capsule
      endoscopy, endoscopic visualization of the entire small intestine is now possible
      with a relatively noninvasive test. Further advancements in capsule endoscopy may
      relegate push enteroscopy and intraoperative enteroscopy to those cases in which
      biopsies or therapy are required. In the future, total enteroscopy with new
      enteroscopes may become more widely available, allowing biopsies and therapy in
      all segments of the small intestine, without the need for operative intervention.

PMID- 12486941
TI  - Colonic dysplasia and cancer in inflammatory bowel disease.
AB  - Extracolonic malignancies are a relatively rare complication of inflammatory
      bowel disease. In contrast, colorectal cancer remains a major concern for
      patients with long-standing UC. The best available evidence suggests that
      patients with long-standing Crohn's colitis are at similar risk for colorectal
      cancer as those patients with long-standing UC. In patients with UC, the
      magnitude of this increased risk appears to be greater in patients with more
      extensive colonic involvement. It appears that the magnitude of this risk
      increases with increasing duration of disease, at least in UC. Whether this
      reflects the increased risk of cancer that occurs with the aging process or a
      separate phenomena distinct to UC is unclear. To date, the methods available to
      reduce the risk of cancer are less than optimal. Although surgical procedures
      eliminate the risk, the mental and physical sequelae of these procedures can be
      substantial. Surveillance with colonoscopic biopsies is likely effective in
      reducing although not eliminating the risk of colorectal cancer. Efforts to
      develop chemopreventative agents and improved surveillance methods remain areas
      of active investigation.

PMID- 12486942
TI  - Evaluation of polypoid lesions in inflammatory bowel disease.
AB  - This article discusses patients with inflammatory bowel disease (IBD), a group
      which is at increased risk for colorectal carcinoma based on extent and duration
      of their disease. Patients with chronic IBD (at least 8-10 years duration) should
      be screened with colonoscopy every 1 to 2 years with multiple jumbo biopsies
      every 10 cm through the entire colon. Patients with sporadic adenomas can be
      followed after complete polypectomy, whereas patients with adenoma-like dysplasia
      associated lesion or mass (DALMs) need increased surveillance. Patients with flat
      dysplasia or non adenoma-like DALMs are at high risk for progression and should
      undergo colectomy. The patients who have indeterminate lesions can be
      differentiated based on the endoscopic, histologic, and molecular features of the
      lesion. Long-term follow-up is necessary to determine the natural history of
      these lesions.

PMID- 12486943
TI  - Pancreatic and biliary tract disorders in inflammatory bowel disease.
AB  - Hepatobiliary disorders occur frequently in patients with IBD, with PSC and
      cholangiocarcinoma being the most clinically significant for endoscopists.
      Endoscopic therapy for PSC is effective in improving symptoms, biochemical
      parameters, and radiographic abnormalities. Endoscopic therapy may also confer
      survival benefit, but this has yet to be confirmed in randomized, controlled
      trials. Treatment should be restricted to those individuals with a rapid decline
      in liver function testing or those with recurrent cholangitis. Cholangiocarcinoma
      is a serious complication of PSC and carries an extremely poor prognosis. ERCP
      with brush cytology has a relatively low sensitivity and the diagnosis is usually
      made after the disease has become metastatic. Malignant biliary obstruction can
      be palliated by endoscopic stenting. Photodynamic therapy is a promising
      experimental technique that may confer symptomatic and survival benefit in
      patients with nonresectable, advanced cholangiocarcinoma. IBD patients also have
      an elevated risk for developing acute and chronic pancreatitis as well as
      pancreatic insufficiency. The majority of cases of acute pancreatitis are likely
      due to medication side effects and local structural complications of IBD. The
      remainder may possibly represent true extraintestinal manifestations of IBD.
      Chronic pancreatitis is frequently subclinical, but may be accompanied by
      clinically relevant exocrine insufficiency. ERCP is the test of choice for the
      diagnosis of chronic pancreatitis, but the role of endoscopy in the therapeutic
      management of IBD-associated chronic pancreatitis remains to be defined.

PMID- 12486944
TI  - The role of endoscopic ultrasound in inflammatory bowel disease.
AB  - Ultrasonography has been applied to the diagnosis and management of inflammatory
      bowel disease for over 20 years. The combination of endoscopy with ultrasound has
      resulted in the application of intraluminal sonographic imaging to multiple
      diseases, including inflammatory bowel disease. Initial efforts were focused on
      the sonographic assessment of disease severity as based on bowel wall thickness,
      but this has been inconsistently demonstrated. Furthermore, disease severity is a
      clinical assessment that is based on both clinical and imaging studies.
      Recognizing that Crohn's disease tends to be transmural and ulcerative colitis a
      superficial mucosal inflammatory process, hopes were raised that endosonography
      would be effective in discriminating cases of otherwise indeterminate colitis.
      Efforts to demonstrate this, however, have been largely disappointing, and EUS
      plays a limited role in discriminating ulcerative colitis from Crohn's disease.
      On a more positive note, EUS evaluation of perirectal and perianal complications
      of Crohn's disease has been demonstrated to be superior to fistulography, CT, and
      equal to or superior to MRI. Because accurate anatomic information is required to
      guide surgical therapy of these lesions, EUS has the potential to emerge as a
      powerful imaging tool in the management of perianorectal Crohn's disease.

PMID- 12486945
TI  - Enhanced endoscopy in inflammatory bowel disease.
AB  - Spectroscopy and OCT are two new methods for imaging the gastrointestinal mucosa.
      They both rely on the interaction of light within a tissue and have been adapted
      for use with endoscopes. It is unlikely that any one type of imaging modality
      will be able to reliably diagnose the presence of microscopic dysplasia. However,
      combining different methods may prove to be extremely accurate for detecting
      dysplasia and may therefore obviate a need for taking tissue biopsies. For
      instance, LSS may be most helpful in detecting early dysplasia because it is
      sensitive to changes in nuclear size and crowding. As more cells become
      dysplastic, fluorescence may play a role in defining changes in content of
      collagen or markers of metabolism (i.e. NADH). Finally, reflectance spectroscopy
      becomes useful in detecting characteristic changes in the tissue architecture as
      dysplasia progresses to invasive cancer. Using all three types of spectroscopy at
      once ("tri-modal spectroscopy") has proven to be extremely accurate for
      classifying Barrett's mucosa as either dysplastic or nondysplastic [9]. Our
      current method for detecting microscopic dysplasia relies upon random biopsies
      and interpretation of histology by pathologists. Interobserver agreement among
      even experienced pathologists regarding the presence or absence and degree of
      dysplasia in histologic specimens is not consistent [50]. Spectroscopy and OCT
      may ultimately provide new methods for accurately diagnosing dysplasia in real
      time, without the need for tissue processing, and without the interobserver
      variations of histologic interpretation.

PMID- 12486946
TI  - Therapeutic options in the management of strictures in Crohn's disease.
AB  - Intestinal strictures are a commonly encountered problem in patients with Crohn's
      disease. Endoscopic management with hydrostatic balloon dilation is an effective
      alternative to surgery in patients with endoscopically accessible lesions that
      are shorter than 7-8 cm. Endoscopic balloon dilation is the preferred initial
      modality in anastomotic strictures. The presence of inflammation near the
      stricture should not be considered a contraindication to dilation, and
      intralesional steroid injection should be considered in these patients with
      inflammation present in the area of the stricture. Further technological
      developments in endoscopes and balloon dilators may allow for broader application
      of these techniques.

PMID- 12486947
TI  - The role of endoscopy in the evaluation of pouches and ostomies.
AB  - Patients with ileal pouches and ostomies present with management issues that are
      challenging to the clinician. Endoscopy plays a significant role in diagnosing
      and guiding therapy in such patients. Unfortunately, there are very few
      prospective studies that evaluates endoscopy in these situations. Nevertheless,
      it is clear that endoscopy remains a powerful tool that is important for
      diagnosis and therapy of complications unique to these surgical procedures. It
      seems prudent to advocate endoscopic cancer surveillance for patients with
      pouches and ostomies; however, it remains to be seen whether these efforts will
      ultimately have an impact on long-term patient morbidity and mortality.

PMID- 12486948
TI  - The role of endoscopy in the evaluation of fistulizing Crohn's disease.
AB  - Fistulas in Crohn's disease are classified as internal fistulas, for example,
      enteroenteric, enterovesical, rectovaginal, and external fistulas, for example,
      enterocutaneous, perianal, and parastomal. Although radiographic contrast studies
      are superior to endoscopy for diagnosing fistulas, endoscopic procedures have a
      definite role in the evaluation and management of fistulizing Crohn's disease.
      Endoscopy allows for tissue sampling, and provides information regarding the
      extent and severity of gastrointestinal inflammation, and the presence of such
      complications as strictures and cancer. Preoperative colonoscopy has particular
      value in assessing an enterocolonic fistula, and has important implications
      regarding the type of surgery performed. Endoscopic therapy for Crohn's fistula
      is less certain, but may allow for dilation of associated strictures, and may
      someday serve as a better delivery system for targeted anticytokine and
      immunologically based therapy.

PMID- 12486949
TI  - Endoscopy in the pregnant patient with inflammatory bowel disease.
AB  - Although little data exist directly evaluating the utility and safety of
      endoscopy in the pregnant woman with IBD, it appears to be well tolerated by both
      mother and fetus, and provides useful clinical information. When performed to
      evaluate gastrointestinal bleeding, EGD has a high diagnostic yield, while EGD
      for nausea and vomiting is less informative. In the patient without IBD
      presenting with hematochezia, unexplained diarrhea, severe abdominal pain, or
      severe rectal pain, careful sigmoidoscopic examination is indicated, often
      leading to a diagnosis of new-onset or unsuspected IBD. Likewise, the pregnant
      IBD patient with worsening symptoms, despite appropriate medical therapy, may
      also benefit from sigmoidoscopy. Colonoscopy is less often indicated, but can be
      safely performed in the carefully selected pregnant patient. In all cases
      obstetrical consultation should be obtained prior to endoscopy, and the risks and
      benefits of endoscopy to both mother and child should be considered. Close
      attention should be paid to appropriate drug selection for conscious sedation,
      and sedation should be administered to provide patient comfort, while avoiding
      oversedation. Extrapolating from data obtained during endoscopic examination of
      the pregnant non-IBD patient, fetal monitoring is generally not indicated,
      although it should be considered for the high-risk or late third-trimester
      patient. Following these principles assures that endoscopy can be safely
      performed in the pregnant IBD patient with the best possible outcome for both
      mother and baby.

PMID- 12486950
TI  - [Is a full-term childbirth a natural event or a medical problem?].

PMID- 12486951
TI  - [HPV vaccination--a possibility for prevention of cervical cancer].

PMID- 12486952
TI  - [Year 2002 Anders Jahre Young Scientist Award to Kalle Saksela].

PMID- 12486953
TI  - [Right and wrong in medicine].

PMID- 12486954
TI  - [Examination of a patient with ureter calculi and the possibilities of diet and
      drug therapy].

PMID- 12486955
TI  - [RNA interference in the prevention of viral diseases?].

PMID- 12486956
TI  - [Dissociative disorders and their therapy].

PMID- 12486957
TI  - [Changed diagnostic imaging in rheumatoid arthritis].

PMID- 12486958
TI  - [Verification of coronary artery stenosis by Doppler echocardiography].

PMID- 12486959
TI  - [Sudden ventilation difficulty of an infant during anesthesia induction].

PMID- 12486960
TI  - [Prevention of infections in cancer patients with the help of antimicrobial
      agents].

PMID- 12486961
TI  - [Empirical antimicrobial therapy in a patient with neutropenia].

PMID- 12486962
TI  - [Granulocyte colony-stimulating factors as a support therapy in malignant
      diseases].

PMID- 12486963
TI  - [Research is necessary within all health care--also outside the universities].

PMID- 12486964
TI  - [The voice of SBU only is not enough to influence the clinical practice].

PMID- 12486965
TI  - [To diagnose Cushing syndrome in adults is difficult. Current diagnostic methods
      can improve prognosis].

PMID- 12486966
TI  - [Clinical research and continuing education on county hospital level. Experiences
      with cooperation between health care and academies].

PMID- 12486967
TI  - [How the SBU influenced clinical practice. Consequences of seven reports
      scrutinized].

PMID- 12486968
TI  - [Follow-up of Cushing syndrome in western Sweden. More than one treatment method
      needed for cure, hormonal deficiencies common].
AB  - Results from a follow-up of all patients with Cushing's syndrome who visited the
      Division of Endocrinology at Sahlgrenska University Hospital, Goteborg, Sweden,
      during 1997-1998 revealed 28 patients with ACTH-dependent disease and 3 with ACTH
      independent disease. Female/male ratio was 4:1 with mean age at diagnosis 30
      years. Mean time from first symptoms to diagnosis was three years (range 0-8).
      The most frequent signs were hypertrichosis, easy bruising, hypertension,
      osteoporosis and diabetes mellitus. Out of the 28 patients with ACTH-dependent
      disease, 16 underwent more than one treatment method
      (transcranial/transsphenoidal pituitary surgery, pituitary irradiation,
      adrenalectomy), 26 were cured and 25 developed hormonal deficiencies after
      treatment. Five of the 11 patients who underwent adrenalectomy developed Nelson
      tumors. All patients in the ACTH-independent group were cured after unilateral
      adrenalectomy.

PMID- 12486969
TI  - [Catheter ablation--new cure for paroxysmal atrial fibrillation. Case reports
      show how the trigger mechanism can be abolished].
AB  - The trigger mechanism of paroxysmal atrial fibrillation is usually an atrial
      ectopic beat originating in the muscular sleeves of the pulmonary veins. These
      and other origins of the trigger mechanisms can be explored with
      electroanatomical mapping technique. Once identified, the trigger mechanism may
      be abolished by using the catheter ablation technique to cure the arrhythmia. We
      present the results for two patients with trigger mechanisms of different origin
      whose arrhythmia has been cured using the focal ablation technique.

PMID- 12486970
TI  - [Medication a complement to other forms of pain management in osteoarthritis].
AB  - Osteoarthritis of the peripheral joints is a common cause of joint pain and joint
      stiffness. There is still no treatment that effectively can inhibit the
      structural changes of osteoarthritis, i.e. osteophytes, cartilage thinning and
      subchondral sclerosis. The main goal of treating patients with osteoarthritis is
      thus to relieve symptoms and to restore function. Pharmacological treatment with
      NSAIDs is often, used. However, there is good evidence for the effectiveness of
      both other pharmacological treatments (i.e. paracetamol) and non-pharmacological
      treatments like training, patient education and sometimes local treatment of
      affected joints. When using pharmacological treatment, a standardised evaluation
      is recommended. There are studies suggesting a "disease modifying effect" of some
      compounds, but their role in modern osteoarthritis therapy remains to be
      established.

PMID- 12486971
TI  - [Excellent results of surgical management of osteoarthritis. Arthroplasty and
      osteotomy provide pain relief and restore joint function].
AB  - The treatment of osteoarthrosis is through the insertion of an artificial joint,
      arthroplasty. Quantitatively, operations of the hip and the knee are the most
      important and the results are extremely well documented and good both in terms of
      functional results as well as in terms of longevity. In recent years,
      arthroplasty of other joints such as the elbow and the shoulder has been
      developed to a satisfactory degree of perfection. Even the ankle joint, hitherto
      resistant to arthroplasty, has yielded promising results. In the knee joint,
      osteotomy is a viable alternative.

PMID- 12486972
TI  - [Emergency medicine in the USA--a well-functioning specialty].

PMID- 12486973
TI  - [The scientific committee's task is to identify the best research].

PMID- 12486974
TI  - [Reply on the issue of specialist examination: The aim is not first of all to
      measure, but to assure the quality of internship!].

PMID- 12486975
TI  - [What is evidence-based psychiatric care?].

PMID- 12486976
TI  - Medical applications of industrial safety science.

PMID- 12486977
TI  - Breaking bad news.

PMID- 12486978
TI  - Guideline adherence rates and interprofessional variation.

PMID- 12486979
TI  - Length of in-hospital stay and its relationship to quality of care.

PMID- 12486980
TI  - Pediatric Peri-Operative Cardiac Arrest (POCA) Registry.

PMID- 12486981
TI  - National Service Frameworks as tools for quality improvement.

PMID- 12486982
TI  - Can the sum of projects end up in a program? The strategies that shape quality of
      care research.

PMID- 12486983
TI  - Guideline adherence rates and interprofessional variation in a vignette study of
      depression.
AB  - OBJECTIVE: To assess the appropriateness of and variation in intention-to-treat
      decisions in the management of depression in the Netherlands. DESIGN: Mailed
      survey with 22 paper cases (vignettes) based on a population study. SETTING: A
      random sample from four professional groups in the Dutch mental healthcare
      system. SUBJECTS: 264 general practitioners, psychiatrists, psychotherapists, and
      clinical psychologists. MAIN OUTCOME MEASURES: Each vignette contained
      information on a number of patient characteristics taken from three national
      depression guidelines. The distribution of patient characteristics was based on
      data from a population study. Respondents were asked to choose the best treatment
      option and the best treatment setting. For each vignette we examined which of the
      selected treatments was appropriate according to the recommendations of the three
      published Dutch clinical guidelines and a panel of experts. RESULTS: 31% of all
      intention-to-treat decisions were not consistent with the guidelines. Overall,
      less severe depression, alcohol abuse, psychotic features, and lack of social
      resources were related to more inappropriate judgements. There was considerable
      variation between the professional groups: psychiatrists made more appropriate
      choices than the other professions although they had the highest rate of
      overtreatment. CONCLUSIONS: There is sufficient variation in the intentions to
      treat depression to give it priority in quality assessment and guideline
      development. Efforts to achieve appropriate care should focus on treatment
      indications, referral patterns, and overtreatment.

PMID- 12486984
TI  - Relationship between hospital length of stay and quality of care in patients with
      congestive heart failure.
AB  - OBJECTIVE: To determine the relationship between hospital length of stay (LOS)
      and quality of care in patients admitted for congestive heart failure (CHF).
      METHODS: This observational study was conducted in the medical wards of the
      Geneva University Hospitals, Geneva, Switzerland. A random sample of 371 patients
      was drawn from the 1084 patients discharged alive with a principal diagnosis of
      CHF between January 1997 and December 1998. Explicit criteria grouped into three
      scores were used to assess the quality of processes of care: admission work-up
      (admission score); evaluation and treatment during the stay (treatment score);
      and readiness for discharge (discharge score). The association between LOS and
      quality of care was analysed using linear regression with adjustment for clinical
      characteristics. RESULTS: The mean proportion of criteria met were 80% for the
      admission score, 66% for the treatment score, and 76% for the discharge score.
      Mean (SD) LOS was 13.2 (8.8) days. The admission score was not associated with
      LOS, but the treatment score increased by 0.5% (95% CI 0.3 to 0.7; p < 0.001)
      with each additional day in hospital and the discharge score increased by 2.5%
      (95% CI 1.6 to 3.3; p < 0.001) per day from admission to day 10 but remained
      unchanged thereafter. Adjustment for potential confounders did not substantially
      modify these relationships. CONCLUSIONS: In patients with CHF there is a
      significant association between LOS and the quality of the treatment provided, as
      well as with readiness for discharge. Appropriate reorganisation of processes of
      care should accompany attempts at reducing LOS to avoid detrimental effects on
      quality of care.

PMID- 12486985
TI  - Setting priorities for patient safety.
AB  - BACKGROUND: Current "flags" for adverse events (AEs) are biased towards those
      with serious outcomes, potentially leading to failure to address mundane common
      problems. AIM: To provide a basis for setting priorities to improve patient
      safety by ranking adverse events by resource consumption as well as by outcome.
      This was done by classifying a set of AEs, according to how they may be
      prevented, into "Principal Natural Categories" (PNCs). SETTING: AEs associated
      with a representative sample of admissions to Australian acute care hospitals.
      DESIGN: AEs were classified into PNCs which were ranked by overall frequency, an
      index of resource consumption (a function of mean extended hospital stay and the
      number of cases in each PNC), and severity of outcome. RESULTS: The 1712 AEs
      analysed fell into 581 PNCs; only 28% had more than two cases. Most resource use
      (60%) was by AEs which led to minor disabilities, 36% was by those which led to
      major disabilities, and 4% by those associated with death. Most of the events
      with serious outcomes fell into fewer than 50 PNCs; only seven of these PNCs had
      more than six cases resulting in serious outcomes. CONCLUSIONS: If interventions
      for AEs are triggered only by serious outcomes by, for example, using recommended
      risk scoring methods, most problems would not be addressed, particularly the
      large number of mundane problems which consume the majority of resources. Both
      serious and mundane problems should be addressed. Most types of events occur too
      infrequently to be characterised at a hospital level and require large scale
      (preferably national) collections of incidents and events.

PMID- 12486986
TI  - Secondary prevention following myocardial infarction: evidence from an audit in
      South Wales that the National Service Framework for coronary heart disease does
      not address all the issues.
AB  - OBJECTIVES: To assess local uptake of treatments for secondary prevention of
      myocardial infarction and compare with targets in the National Service Framework
      (NSF) for coronary heart disease. DESIGN: Retrospective audit of case notes with
      follow up questionnaire at 1 year. SETTING: Teaching hospital and community.
      PARTICIPANTS: 100 patients alive in December 1998 who had been admitted with an
      acute myocardial infarction between October 1997 and October 1998. MAIN OUTCOME
      MEASURES: Local use of aspirin, beta blockers, ACE inhibitors, and statins.
      RESULTS: Unless contraindicated, discharge aspirin use was 100%, beta blocker use
      84%, statin prescription and/or provision of dietetic advice 66% and ACE
      inhibitors where any heart failure was found was 97%. 1-2 years later total
      cholesterol remained greater than 5.0 mmol/l in 25% of patients, 24% had stopped
      beta blockers, and ACE inhibitors remained at a low dose in half of those
      surveyed. CONCLUSIONS: The NSF for coronary heart disease states that by April
      2002 80-90% of patients should be prescribed appropriate secondary prevention.
      This had nearly been achieved at hospital discharge in 1999. However, follow up
      indicated problems in ongoing care with cholesterol targets not always being
      achieved, beta blockers often being stopped, and ACE inhibitors frequently
      remaining at low doses. Gaining maximum benefit from treatment depends on these
      secondary targets also being achieved. In these aspects of secondary prevention
      the NSF represents only an initial step towards effective prevention of coronary
      heart disease; perhaps the most difficult and expensive steps are yet to be fully
      realised.

PMID- 12486987
TI  - A preliminary taxonomy of medical errors in family practice.
AB  - OBJECTIVE: To develop a preliminary taxonomy of primary care medical errors.
      DESIGN: Qualitative analysis to identify categories of error reported during a
      randomized controlled trial of computer and paper reporting methods. SETTING: The
      National Network for Family Practice and Primary Care Research. PARTICIPANTS:
      Family physicians. MAIN OUTCOME MEASURES: Medical error category, context, and
      consequence. RESULTS: Forty two physicians made 344 reports: 284 (82.6%) arose
      from healthcare systems dysfunction; 46 (13.4%) were errors due to gaps in
      knowledge or skills; and 14 (4.1%) were reports of adverse events, not errors.
      The main subcategories were: administrative failure (102; 30.9% of errors),
      investigation failures (82; 24.8%), treatment delivery lapses (76; 23.0%),
      miscommunication (19; 5.8%), payment systems problems (4; 1.2%), error in the
      execution of a clinical task (19; 5.8%), wrong treatment decision (14; 4.2%), and
      wrong diagnosis (13; 3.9%). Most reports were of errors that were recognized and
      occurred in reporters' practices. Affected patients ranged in age from 8 months
      to 100 years, were of both sexes, and represented all major US ethnic groups.
      Almost half the reports were of events which had adverse consequences. Ten errors
      resulted in patients being admitted to hospital and one patient died.
      CONCLUSIONS: This medical error taxonomy, developed from self-reports of errors
      observed by family physicians during their routine clinical practice, emphasizes
      problems in healthcare processes and acknowledges medical errors arising from
      shortfalls in clinical knowledge and skills. Patient safety strategies with most
      effect in primary care settings need to be broader than the current focus on
      medication errors.

PMID- 12486988
TI  - Quality improvement for patients with hip fracture: experience from a multi-site
      audit.
AB  - PROBLEM: The first East Anglian audit of hip fracture was conducted in eight
      hospitals during 1992. There were significant differences between hospitals in 90
      day mortality, development of pressure sores, median lengths of hospital stay,
      and in most other process measures. Only about half the survivors recovered their
      pre-fracture physical function. A marked decrease in physical function (for 31%)
      was associated with postoperative complications. DESIGN: A re-audit was conducted
      in 1997 as part of a process of continuing quality improvement. This was an
      interview and record based prospective audit of process and outcome of care with
      3 month follow up. Seven hospitals with trauma orthopaedic departments took part
      in both audits. Results from the 1992 audit and indicator standards for re-audit
      were circulated to all orthopaedic consultants, care of the elderly consultants,
      and lead audit facilitators at each hospital. KEY MEASURES FOR IMPROVEMENT:
      Processes likely to reduce postoperative complications and improve patient
      outcomes at 90 days. STRATEGY FOR CHANGE: As this was a multi-site audit, the
      project group had no direct power to bring about changes within individual NHS
      hospital trusts. RESULTS: Significant increases were seen in pharmaceutical
      thromboembolic prophylaxis (from 45% to 81%) and early mobilisation (from 56% to
      70%) between 1992 and 1997. There were reduced levels of pneumonia, wound
      infection, pressure sores, and fatal pulmonary embolism, but no change was
      recorded in 3 month functional outcomes or mortality. LESSONS LEARNT: While some
      hospitals had made improvements in care by 1997, others were failing to maintain
      their level of good practice. This highlights the need for continuous quality
      improvement by repeating the audit cycle in order to reach and then improve
      standards. Rehabilitation and long term support to improve functional outcomes
      are key areas for future audit and research.

PMID- 12486989
TI  - Lessons from the Australian Patient Safety Foundation: setting up a national
      patient safety surveillance system--is this the right model?
AB  - The evolution of the concepts and processes underpinning the Australian Patient
      Safety Foundation's systems over the last 15 years are traced. An ideal system
      should have the following attributes: an independent organisation to coordinate
      patient safety surveillance; agreed frameworks for patient safety and
      surveillance systems; common, agreed standards and terminology; a single,
      clinically useful classification for things that go wrong in health care; a
      national repository for information covering all of health care from all
      available sources; mechanisms for setting priorities at local, national and
      international levels; a just system which caters for the rights of patients,
      society, and healthcare practitioners and facilities; separate processes for
      accountability and "systems learnings"; the right to anonymity and legal
      privilege for reporters; systems for rapid feedback and evidence of action;
      mechanisms for involving and informing all stakeholders. There are powerful
      reasons for establishing national systems, for aligning terminology, tools and
      classification systems internationally, and for rapid dissemination of successful
      strategies.

PMID- 12486990
TI  - Unexpected cardiac arrest among children during surgery, a North American
      registry to elucidate the incidence and causes of anesthesia related cardiac
      arrest.
AB  - Relatively rare adverse events, such as unexpected cardiac arrest, are difficult
      to study in the clinical setting. These events are often unpredictable in their
      occurrence (prompting interest in their investigation) and do not occur with
      sufficient frequency in any single institution to provide an adequate sample for
      analysis. A disease-specific registry is an epidemiological technique that can be
      used to collect data on a set of relatively rare unpredictable events. This
      approach was adopted for investigation of cardiac arrest in children when it
      became apparent from analysis of malpractice claims that a significant clinical
      problem existed. This report provides a brief historical account of the
      development of the Pediatric Peri-Operative Cardiac Arrest (POCA) Registry and
      elaborates on the methodology including strengths, weaknesses, and practical
      implementation issues.

PMID- 12486991
TI  - Learning from prescribing errors.
AB  - The importance of learning from medical error has recently received increasing
      emphasis. This paper focuses on prescribing errors and argues that, while
      learning from prescribing errors is a laudable goal, there are currently barriers
      that can prevent this occurring. Learning from errors can take place on an
      individual level, at a team level, and across an organisation. Barriers to
      learning from prescribing errors include the non-discovery of many prescribing
      errors, lack of feedback to the prescriber when errors are discovered by other
      healthcare professionals, and a culture that does not encourage reflection on
      errors together with why they occurred and how they can be prevented. Changes are
      needed in both systems and culture to provide an environment in which lessons can
      be learnt from errors and put into practice.

PMID- 12486992
TI  - Information technology and medication safety: what is the benefit?
AB  - Medication errors occur frequently and have significant clinical and financial
      consequences. Several types of information technologies can be used to decrease
      rates of medication errors. Computerized physician order entry with decision
      support significantly reduces serious inpatient medication error rates in adults.
      Other available information technologies that may prove effective for inpatients
      include computerized medication administration records, robots, automated
      pharmacy systems, bar coding, "smart" intravenous devices, and computerized
      discharge prescriptions and instructions. In outpatients, computerization of
      prescribing and patient oriented approaches such as personalized web pages and
      delivery of web based information may be important. Public and private mandates
      for information technology interventions are growing, but further development,
      application, evaluation, and dissemination are required.

PMID- 12486993
TI  - Lessons learned from non-medical industries: root cause analysis as culture
      change at a chemical plant.
AB  - Root cause analysis was introduced to a chemical plant as a way of enhancing
      performance and safety, exemplified by the investigation of an explosion. The
      cultural legacy of the root cause learning intervention was embodied in managers'
      increased openness to new ideas, individuals' questioning attitude and
      disciplined thinking, and a root cause analysis process that provided continual
      opportunities to learn and improve. Lessons for health care are discussed, taking
      account of differences between the chemical and healthcare industries.

PMID- 12486994
TI  - Evaluation of quality improvement programmes.
AB  - In response to increasing concerns about quality, many countries are carrying out
      large scale programmes which include national quality strategies, hospital
      programmes, and quality accreditation, assessment and review processes.
      Increasing amounts of resources are being devoted to these interventions, but do
      they ensure or improve quality of care? There is little research evidence as to
      their effectiveness or the conditions for maximum effectiveness. Reasons for the
      lack of evaluation research include the methodological challenges of measuring
      outcomes and attributing causality to these complex, changing, long term social
      interventions to organisations or health systems, which themselves are complex
      and changing. However, methods are available which can be used to evaluate these
      programmes and which can provide decision makers with research based guidance on
      how to plan and implement them. This paper describes the research challenges, the
      methods which can be used, and gives examples and guidance for future research.
      It emphasises the important contribution which such research can make to
      improving the effectiveness of these programmes and to developing the science of
      quality improvement.

PMID- 12486995
TI  - Preventable anesthesia mishaps: a study of human factors. 1978.

PMID- 12486996
TI  - Looking back on the anesthesia critical incident studies and their role in
      catalysing patient safety.

PMID- 12486997
TI  - Interventions for the treatment and management of chronic fatigue
      syndrome/myalgic encephalomyelitis.

PMID- 12486998
TI  - Bruce Psaty and the risks of calcium channel blockers.

PMID- 12486999
TI  - External research service with critical appraisal of the medical literature at a
      university medical centre.

PMID- 12487000
TI  - A lesson for our times.

PMID- 12487001
TI  - Cardiac baroreflex control in humans during and immediately after brief exposure
      to simulated high altitude.
AB  - To examine the baroreflex response in humans during and immediately after acute
      hypoxia exposure, the cardiac baroreflex sensitivity (BRS) was studied using
      adaptation of RR intervals in response to spontaneous systolic blood pressure
      fluctuations (sequences methodology) in 11 unacclimatized subjects. All
      measurements were made under fixed breathing rate, and realized consecutively at
      baseline level (20 min), at an inspired oxygen concentration of 11% (15 min) and
      again under normoxic conditions (20 min; recovery period). The spontaneous
      baroreflex response decreases progressively during hypoxic exposure, causing a
      tachycardic response at this FiO2 without any significant alteration of the
      systolic or diastolic blood pressure. The magnitude of decrease for this variable
      at the end of exposure averaged 42.9 +/- 15.6%. The simultaneous spectral
      analysis of heart rate (HR) variability in hypoxic condition confirmed an
      alteration in the parasympathetic activity (HFnu: -17.8 +/- 30.9% versus basal
      conditions, P < 0.01) counterbalanced by an exaggerated sympathetic activity
      (LFnu: +33 +/- 42.4%, P < 0.05) at the sinus node. Interestingly, we could
      observe an enhanced cardiac baroreflex response during the period following the
      inhalation of the hypoxic mixture (+130.6 +/- 15.6% of basal conditions, P <
      0.001). There is a relationship with a significant and abrupt increase in the
      parasympathetic control of HR (mean HR reached 111 +/- 8.1% of the mean basal HR,
      P < 0.01). These results suggest that brief exposure to hypoxia under rate
      controlled ventilation is associated with a significant alteration in the
      spontaneous cardiac baroreflex. This important cardiac autonomic imbalance is
      followed by a significant increase in the cardiac parasympathetic drive even
      after the disappearance of the hypoxic stimulus.

PMID- 12487002
TI  - The effect of equicaloric medium-chain and long-chain triglycerides on pancreas
      enzyme secretion.
AB  - It has been shown previously that medium chain triglycerides (MCT) do not affect
      gallbladder emptying and cholecystokinin (CCK) release. The effect of MCT on
      exocrine pancreas secretion in humans is unknown. We have compared the effect of
      enteral administration of MCT versus long chain triglycerides (LCT) on exocrine
      pancreatic secretion. Eight healthy subjects (three female, five male; mean age
      22 +/- 1.9 years) participated in two experiments, performed in random order.
      Duodenal contents, obtained by aspiration, were used to calculated the output of
      pancreatic enzymes and bilirubin. An equicaloric amount of either MCT or LCT (2
      kcal min-1) oil was continuously administered in the proximal jejunum for 2 h.
      Gallbladder volume was measured by ultrasonography and blood samples were drawn
      for determination of CCK. The experiments consisted of 1 h basal secretion, 2 h
      of continuous oil administration and 1 h poststimulation. During the LCT feeding
      the pancreatic enzyme secretion, bilirubin output, gallbladder emptying and CCK
      release increased significantly (P < 0.05) over basal levels. MCT had no effect
      on pancreatic enzyme secretion nor gallbladder emptying or CCK release. We
      conclude that enteral administration of MCT in the proximal jejunum does not
      stimulate exocrine pancreatic secretion nor gallbladder contraction or CCK
      release, in contrast to an equicaloric amount of LCT.

PMID- 12487003
TI  - Decreased actin solubility observed during ATP-depletion is mimicked by severing
      agents but not depolymerizing agents in isolated and cultured proximal tubular
      cells.
AB  - The microvilli of the apical membrane of proximal tubule (PT) cells are supported
      by the underlying actin cytoskeleton. Ischaemic or anoxic ATP-depletion leads to
      the disruption of the actin cytoskeleton, resulting in microvillar retraction and
      loss of membrane polarity. Using isolated PT cells, we have previously
      demonstrated that actin filaments (F-actin) are likely severed during ATP
      depletion. A sequential extraction protocol revealed a decrease in actin
      solubility, resulting in the sequestration of a distinct F-actin pool with the
      insoluble cellular complex in ATP-depleted PT cells. We demonstrate here that
      decreased actin solubility is not only a reliable end-marker of ATP-depletion
      induced injury in freshly isolated PT cells, but also serves as a biochemical
      marker in the cultured proximal tubular cell line LLC-PK1. In the present
      studies, we also investigated specific actin-binding drugs to determine if they
      mimic the effects observed during energy depletion. Jasplakinolide (JP), a
      compound which binds F-actin and prevents depolymerization, did not effect actin
      solubility during ATP-depletion. Furthermore, swinholide A (SA), an F-actin
      severing agent, resulted in decreased actin solubility, mimicking the effects of
      ATP-depletion. Interestingly, latrunculin A (LA), an agent which depolymerizes F
      actin, did not reduce actin solubility, but rather resulted in an increase in
      digitonin-soluble actin. Taken collectively, our results support previous work
      and suggest that disruption of the actin cytoskeleton during ATP-depletion is
      mediated by F-actin severing/fragmentation and not depolymerization. The
      differential effects of F-actin disrupting agents and the consistencies observed
      in both models of ischaemic injury will provide a basis for a more detailed
      understanding of the pathological events of PT-cell dysfunction.

PMID- 12487004
TI  - Non-linear behaviour of respiratory movement in obstructive sleep apnoea
      syndrome.
AB  - In this study we investigated the non-linear properties of respiratory movement
      in patients with obstructive sleep apnoea syndrome (OSAS) during sleep without
      and with nasal continuous positive airway pressure (nCPAP). To calculate the
      correlation dimension (D2) in respiratory movement we applied an algorithm
      proposed by Grassberger and Procaccia. Non-linearity in respiratory movement was
      tested by comparing D2 for the original data with that for surrogate data.
      Respiratory movement was recorded from 10 patients with OSAS. D2 during both
      wakefulness with eyes closed and during sleep with nCPAP at 8 cm H2O could be
      computed in all subjects (2.50 +/- 0.69 and 1.68 +/- 0.17, respectively). On the
      other hand, D2 during sleep with apnoea could not be computed in patients with
      severe OSAS. These results indicate the abnormal properties of respiratory
      movement during apnoeic sleep in severe OSAS. Moreover, respiratory movement with
      nCPAP was shown to be non-linear deterministic behaviour in respiratory movement
      during sleep. Analysis of D2 for respiratory movement may be useful in adjusting
      (titrating) nCPAP and classifying severity in OSAS.

PMID- 12487005
TI  - PET imaging using a triple-head gamma camera.
AB  - Interest in clinical fluorodeoxyglucose (FDG) imaging with multiple-head gamma
      cameras is growing. To improve sensitivity, triple-head coincidence imaging has
      been proposed. We report our initial experiences with a triple-head coincidence
      gamma camera with 19 mm sodium iodide crystal thickness. Several positron
      emission tomography-image quality parameters were evaluated using a Carlson and
      line source phantom. The system sensitivity with two-dimensional axial shields
      was 830 cps kBq-1 ml-1 and maximum noise equivalent count rate 1900 cps for an
      18F-activity of 50 MBq. The imaging resolution was in central axial 7.0 mm and in
      central transaxial 7.6 mm, respectively. The average scatter fraction in
      scattered media was 29%. Clinical brain, heart and whole body images studies with
      [18F]FDG were acquired and they show good correlation with the phantom image
      quality. As a conclusion, triple-head coincidence gamma camera provides
      relatively high-count rate imaging with good contrast and resolution.

PMID- 12487006
TI  - Lower reference limit for maximal oxygen uptake in men and women.
AB  - Maximal oxygen uptake (VO2max) is an important measure of exercise tolerance and
      low values may have clinical significance. Our purpose was to develop the
      necessary statistics--prediction equations and standard errors of estimate (SEE)-
      so that the lower reference limit for VO2max can be predicted for men and women.
      The subjects were healthy, non-smoking, sedentary men (n = 115) and women (n =
      115) aged 20-70 years who performed 15 W min-1 cycle ergometer exercise tests.
      Three equations were developed for each gender using multiple linear regression
      with the non-exercise predictor variables of age and height, age and mass, and
      age and fat-free mass (FFM). The assumptions of regression analysis were examined
      and the predicted residual sum of squares (PRESS) method was used to cross
      validate each equation. Healthy and diseased individual subject data from the
      literature were used to externally validate our lower reference limit statistics.
      The equations developed meet the assumptions of regression analysis and have an
      accuracy similar to the non-exercise prediction equations in the literature with
      R2 values of approximately 0.581. The PRESS method revealed that the equations
      are generalizable, i.e. may be used in future studies without a significant loss
      of accuracy. The lower reference limit predictions for the healthy and diseased
      individual subject data from the literature produced few miscategorizations
      unless the subjects were obese and mass was used as a predictor variable. In
      conclusion, the equations and SEE generated in this study can be used to predict
      an accurate and valid VO2max lower reference limit for a given subject.

PMID- 12487008
TI  - Physiological and symptomatic responses to cycling and walking in intermittent
      claudication.
AB  - To shed light on the potential efficacy of cycling as a testing modality in the
      treatment of intermittent claudication (IC), this study compared physiological
      and symptomatic responses to graded walking and cycling tests in claudicants.
      Sixteen subjects with peripheral arterial disease (resting ankle: brachial index
      (ABI) < 0.9) and IC completed a maximal graded treadmill walking (T) and cycle
      (C) test after three familiarization tests on each mode. During each test,
      symptoms, oxygen uptake (VO2), minute ventilation (VE), respiratory exchange
      ratio (RER) and heart rate (HR) were measured, and for 10 min after each test the
      brachial and ankle systolic pressures were recorded. All but one subject
      experienced calf pain as the primary limiting symptom during T; whereas the
      symptoms were more varied during C and included thigh pain, calf pain and
      dyspnoea. Although maximal exercise time was significantly longer on C than T
      (690 +/- 67 vs. 495 +/- 57 s), peak VO2, peak VE and peak heart rate during C and
      T were not different; whereas peak RER was higher during C. These responses
      during C and T were also positively correlated (P < 0.05) with each other, with
      the exception of RER. The postexercise systolic pressures were also not different
      between C and T. However, the peak decline in ankle pressures from resting values
      after C and T were not correlated with each other. These data demonstrate that
      cycling and walking induce a similar level of metabolic and cardiovascular
      strain, but that the primary limiting symptoms and haemodynamic response in an
      individual's extremity, measured after exercise, can differ substantially between
      these two modes.

PMID- 12487007
TI  - Interferential therapy: lack of effect upon experimentally induced delayed onset
      muscle soreness.
AB  - This study was designed to assess the analgesic effects of interferential therapy
      (IFT) on experimentally induced muscular pain under randomized, double-blind,
      placebo-controlled conditions. After ethical approval and written consent were
      obtained, 40 healthy human volunteers (20 males: 20 females) aged 18-25 years
      were recruited and randomly assigned to one of four experimental groups (n = 10
      per group: male = female): IFT 1, IFT 2, control or placebo. Delayed onset muscle
      soreness (DOMS) was induced in the elbow flexors of the non-dominant arm of each
      subject using a single bout of eccentric exercises to exhaustion. Measurements of
      isometric peak torque, resting angle, mechanical pain threshold and visual
      analogue scales were performed at set time points. Treatment was applied for 30
      min daily over the biceps brachii muscle, for five consecutive days, according to
      group allocation. IFT 1 received 10-20 Hz, whilst subjects in IFT 2 were treated
      with 80-100 Hz (bi-pole; carrier frequency: 4 kHz; pulse duration: 125
      microseconds). For the placebo group, the procedure was identical to that in the
      active treatment groups; however, no interferential current was delivered. The
      control group received no treatment. No significant between group difference was
      identified at any time point (P > or = 0.14). However, some inconsistent, yet
      significant differences in daily treatment effects, interactive effects and
      effects over time were detected. Based on the results of this study it can be
      concluded that application of IFT at the parameters used here, had no overall
      beneficial effect on DOMS.

PMID- 12487009
TI  - Reference values for 99mTc-MAG3 renography determined in healthy, potential renal
      donors.
AB  - BACKGROUND: Reference values for 99mTc-MAG3 renography were determined and the
      influence of sex and age (< 50/ > or = 50 years) was elucidated. METHODS: Sixty
      eight potential renal donors were evaluated by renography among other tests.
      Through examination of their records 41 healthy subjects with a normal renal
      arteriography were included in this study and the reference values of the
      functional distribution (the split function, SF), the time to peak renal
      parenchymal activity (Tmax) and the residual activity (RA) were calculated.
      RESULTS: For Tmax there was no significant influence of sex or age. Mean RA
      increased significantly with age (20.5 vs. 23.2%, P = 0.03), but no difference
      was found between sexes. Mean SF (right kidney) was significantly higher among
      males. CONCLUSIONS: When a diuresis of at least 2 ml min-1 is demanded we found
      the following normal ranges: SF > 41%, Tmax < 4.3 min and RA < 33.7%.

PMID- 12487010
TI  - Oxygen transport and organ dysfunction in the older trauma patient.
AB  - OBJECTIVES: To determine baseline values of cardiac index (CI) and oxygen
      transport variables in patients with multiple trauma within 24 hours of admission
      to a level I trauma center. METHOD: This project was part of a larger study
      comparing methods of measuring oxygen consumption (VO2) in 38 severely injured
      patients. Measurements of CI, oxygen delivery (DO2), and VO2 were performed every
      6 hours for 24 hours. Patients were monitored for multiple organ dysfunction
      syndrome. RESULTS: The mean age was 59 (+/- 17) years, with 74% (n = 28) of
      patients 50 years or older. Patients 65 years or older had significantly lower
      levels of CI, DO2, and VO2. Initial age-related differences in CI (P < .001)
      persisted at each time period (P < .0136). Younger patients generated a higher
      DO2 at each time period (P < .0005). Even though there were persistent age
      related differences in VO2 over time (P < .0001), no interaction between age and
      time was found. Survivors had lower scores for multiple organ dysfunction
      syndrome than did nonsurvivors (P < .0001), all of whom were 50 years or older.
      Mortality was 21%. CONCLUSIONS: All patients were hypermetabolic, but older
      patients were much less so. Younger patients progressively had increased CI and
      DO2 levels, whereas older patients started with low levels that remained so.
      Patients in each age group appeared to lock into a level of VO2 that did not
      change over time. These findings underscore the vulnerability of older patients
      to poor outcomes. As the magnitude of the postinjury response is partly age
      dependent, future research should differentiate patient characteristics
      associated with positive outcomes among elderly trauma patients.

PMID- 12487011
TI  - Acute myocardial infarction in the elderly with diabetes.
AB  - OBJECTIVE: Diabetes mellitus (DM) has been associated with an elevated, short
      term risk of death after myocardial infarction (MI). Among the studies of DM,
      however, few studies have included elderly subjects. The purpose of the present
      investigation was to determine if non-insulin-treated DM (NIRxDM) and insulin
      treated DM (IRxDM) were associated with specific comorbid conditions, clinical
      findings on arrival, and MI characteristics, as well as a higher 30-day mortality
      rate in elderly patients with acute MI. DESIGN: The study design was a
      retrospective medical record review and secondary data analysis of previously
      collected data from the Cooperative Cardiovascular Project. SETTING: Study
      setting was Connecticut from June 1, 1992, through February 28, 1993. PATIENTS:
      Subjects included the entire Medicare population (n = 2050), aged 65 years or
      older who were hospitalized for acute MI. OUTCOME MEASURES: Mortality rate at 30
      days after MI was measured. RESULTS: A history of DM was observed in 29% of the
      study population. DM status was associated with previous comorbid conditions,
      poorer functional status, higher body mass index, heart failure on arrival, non-Q
      wave MI, and development of atrial fibrillation and oliguria during
      hospitalization. Patients with DM were less likely to have chest pain on arrival
      to the hospital. Diabetic status was not a significant predictor of short-term
      mortality; at 30 days after MI, 17% (n = 242) of the subjects without DM, 19% (n
      = 71) of those with NIRxDM, and 18% (n = 39) of the subjects with IRxDM died (P =
      .460). After adjustment for other prognostic factors, it was noted that MI
      characteristics present on hospital arrival predicted mortality at 30 days in
      both patients with NIRxDM and patients with IRxDM. CONCLUSIONS: The slightly, but
      not significantly, increased mortality risk in patients with DM should not
      minimize the importance of monitoring DM in the acute MI setting. Hospitalization
      for MI provides an opportunity to provide aggressive lipid and blood pressure
      management, optimize blood glucose, control heart failure, and institute other
      secondary preventive interventions in the elderly population with DM.

PMID- 12487012
TI  - Telemanagement of heart failure: a diuretic treatment algorithm for advanced
      practice nurses.
AB  - Thirty-three percent of patients with heart failure (HF) are readmitted to the
      hospital with worsening disease within 90 days of discharge. Acute decompensation
      accounts for nearly 50% of these admissions because of nonadherence with diet
      guidelines, medication regimens, or both. One way to promote adherence is through
      a disease management approach that can prevent HF decompensation by providing
      aggressive follow-up care. Within such an approach, advanced practice nurses can
      use a decision algorithm to implement pharmacologic and nonpharmacologic
      interventions. This article presents a diuretic treatment algorithm for advanced
      practice nurses as part of a telemanagement program. Preliminary data from the
      implementation of such an algorithm within an established HF program shows a
      decrease in hospitalizations rates and cost of care. In addition, the algorithm
      helps define the scope of advanced practice nursing and promotes consistency
      across health care sites.

PMID- 12487013
TI  - A videotape intervention for sexual counseling after myocardial infarction.
AB  - OBJECTIVE: The purpose of this study was to describe the development and testing
      of a videotape intervention for sexual counseling after myocardial infarction
      (MI). INTERVENTION: A videotape was developed as a research intervention for
      sexual counseling after MI. The concepts of sexual integrity, quality of life,
      and stress and coping were key concepts underpinning the intervention. This
      article describes the development of the videotape and its content, including
      considerations for planning, testing, and producing a videotape for research. The
      videotape intervention is currently being used in a study of patients with MI who
      are pretested while hospitalized and posttested at 1, 3, and 5 months after MI.
      Subjects in the treatment group receive the videotape to view in the privacy of
      their home. Control subjects receive the videotape after the 5-month follow-up
      period. All subjects receive the usual written and verbal instructions while
      hospitalized. OUTCOME MEASURES: The 5 outcome variables tested in the study with
      the videotape are quality of life, knowledge, anxiety, sexual satisfaction, and
      return to sexual activity. CONCLUSION: The use of a videotape intervention in the
      home setting provides an additional method of patient education. This approach
      appears ideal for this sensitive topic.

PMID- 12487014
TI  - The recovery mosaic: older women's lived experiences after a myocardial
      infarction.
AB  - OBJECTIVE: The purpose of this study was to examine the experience of recovery in
      women 65 years of age and older during initial recovery from acute myocardial
      infarction. DESIGN: The study was designed with Heideggerian phenomenology,
      purposive sampling, and unstructured interactive interviews. Data were analyzed
      with interpretive processes of hermeneutics. SETTING: The study was set in a
      Canadian metropolitan teaching hospital and in patient homes. PARTICIPANTS: Seven
      women who had had a first time myocardial infarction were recruited. Age ranged
      from 67 to 86 years (mean, 74 years). RESULTS: Analysis revealed that recovery
      for these women was highly contextual and consisted of life experience resembling
      a mosaic, in which the women described how they "created a new picture for
      themselves." The data were clustered into 4 substantive themes that included:
      life is scattered; trying to make sense of it; learning to live with it; and
      getting settled. CONCLUSION: The older women in this study underestimated their
      susceptibility to acute myocardial infarction, were avid planners and
      coordinators of their recovery, equated the loss of the homemaker role to job
      loss, used their ability to socialize as an indicator of the recovery progress,
      and lacked support to perform household duties, such as laundry, and those women
      with fewer symptoms "cheated" in relation to activity and diet. These findings
      may serve as a basis for the development of healthcare strategies reflective of
      older women's recovery.

PMID- 12487015
TI  - Women's Initiative for Nonsmoking (WINS V): under-use of nicotine replacement
      therapy.
AB  - OBJECTIVE: The purpose of this study was to assess the use of nicotine
      replacement therapy (NRT) in a nurse-managed smoking cessation program. DESIGN: A
      cohort design nested within the WINS randomized clinical trial was used with
      follow-up at 2, 7, 21, 28, and 90 days. SETTING: The study took place in 10
      hospitals in the San Francisco Bay Area. SUBJECTS: Participants included 142
      women hospitalized with cardiovascular disease (CVD). OUTCOME MEASURE: The
      outcome measure was the use of NRT after having been assessed as eligible for its
      use. INTERVENTION: NRT was used as an adjunct in the behavioral intervention
      protocol. NRT was recommended during the hospital intervention and during the 90
      day outpatient phase. RESULTS: Of 142 women in the intervention group, 127 met
      the criteria for NRT use. During the 5 follow-up assessments, the reported NRT
      use ranged from 9% to 22%. CONCLUSION: A low NRT use rate among women with CVD is
      evident. The results suggest that future research about NRT myths pertaining to
      women is needed. Nurses can help patients dispel these myths and prevent smoking
      relapse in women with CVD.

PMID- 12487016
TI  - Relationship between different indices of exercise capacity and clinical measures
      in patients with chronic obstructive pulmonary disease.
AB  - PURPOSE: The purpose of this study was to make comparisons between different
      types of exercise tests used in chronic obstructive pulmonary disease (COPD) to
      better interpret the results and to select the most suitable testing procedure.
      Therefore, we evaluated the relationship between exercise capacity and other
      clinical measures and their relative contributions to exercise capacity in
      patients with COPD. METHOD: We studied 36 patients with stable COPD. All patients
      underwent baseline pulmonary function testing. Dyspnea during activities of daily
      living was assessed with the Oxygen Cost Diagram (OCD). The Hospital Anxiety and
      Depression Scale and the St George's Respiratory Questionnaire were used to
      assess psychologic status and health-related quality of life, respectively. All
      patients performed the 6-minute walking test, progressive cycle ergometry, and
      the cycle endurance test. RESULTS: Each exercise capacity result correlated
      significantly with pulmonary function, the OCD, and the Activity and Total scores
      of the St George's Respiratory Questionnaire. Multiple regression analyses
      revealed that the OCD was an important predictor of exercise capacity, especially
      for the walking test. Diffusing capacity was also a significant predictor on
      progressive cycle ergometry. Body mass index was the most significant predictor
      of the endurance time. CONCLUSION: The 3 different exercise tests had similar
      characteristics in relation to pulmonary function, dyspnea, and health-related
      quality of life in patients with COPD. However, some differences were found in
      the aspects they evaluated.

PMID- 12487017
TI  - Prevalence and antimicrobial patterns of Acinetobacter baumannii on hands and
      nares of hospital personnel and patients: the iceberg phenomenon again.
AB  - OBJECTIVE: To determine the prevalence and antimicrobial susceptibility patterns
      of Acinetobacter baumannii on the hands and nares of health care workers and
      patients from intensive care and rehabilitation units at two hospitals in
      northern Manhattan, New York. DESIGN: Prevalence survey of Acinetobacter on the
      hands and anterior nares of staff (n = 184) and patients (n = 98) in
      rehabilitation and intensive care units of two hospitals. RESULTS: Twenty
      subjects (7.1%) had positive test results for A baumannii (6 staff [3.3%] and 14
      patients [14.3%]). Five patients had positive test results at both sites, four in
      the nares only, and 11 on hands only. Among patients, four significant predictors
      of A baumannii were days on unit (P = .003), location (hospital A or B) (P =
      .01), surgery (P = .04), and receiving an antifungal agent (P = .02; OR, 5.6; 95%
      CI, 1.25-24.52). Among staff, predictors were skin damage (P = .02) and
      employment in hospital B (P = .03). Nine of the 20 subjects (45%) had positive
      test results for multiresistant strains, one from a staff member and eight from
      patients. CONCLUSION: Patients whose conditions are not clinically symptomatic
      for A baumannii, as well as staff, are often colonized. Staff with damaged skin
      are more likely to be colonized. Control of this organism will only be possible
      when the principle of the iceberg phenomenon--all patients (and staff) treated
      with standard, Universal Precautions--is strictly followed. Further, the endemic
      prevalence of multiresistant strains may be higher than previously appreciated.

PMID- 12487018
TI  - The complex that wasn't there.

PMID- 12487019
TI  - Genomic organization of the murine aminomethyltransferase gene (Amt).
AB  - Aminomethyltransferase (Amt), also called glycine cleavage system T-protein is an
      important enzyme in glycine metabolism (EC 2.1.2.10). Mutations in this gene in
      humans lead to nonketotic hyperglycinemia, a fatal Mendelian disease. Here, we
      report the cloning and sequencing of the murine Amt gene. The murine Amt gene
      consists of nine closely spaced exons that are contained within approximately 5
      kb of genomic DNA. It encodes a protein of 403 amino acids that is highly
      homologous to other mammalian aminomethyltransferases. The cis-acting promoter of
      the Amt gene is likely to be very short as immediately upstream of the murine Amt
      gene another gene termed Nicolin 1 gene (Nicn1) is located.

PMID- 12487020
TI  - cDNA hox sequences 3' of the homeobox isolated from the sea urchin Holopneustes
      purpurescens are definitive for sea urchin Hox orthologues.
AB  - In an investigation into Hox genes in sea urchin development, cDNA nucleotide
      sequences were isolated from seven Hox genes of Holopneustes purpurescens by 3'
      RACE. Each sequence extended from the homeobox through the coding region 3' of
      the homeobox to the 3'untranslated region and, in the majority of sequences, to a
      poly(A) signal and a poly(A) tail. The cDNA sequences 3' of the homeoboxes were
      very different between the seven Hox genes. In contrast, the sequences within
      each Hox gene 3' of the homeobox were very similar, especially at the amino acid
      level, between the sea urchin species for which sequences are available. The
      coding regions 3' of the homeodomains are thus a means of unambiguously
      identifying homologies between sea urchin Hox genes. A phylogenetic analysis
      where amino acid motifs in these 3' coding regions were aligned with similar
      motifs in chordate species led us to classify two posterior sea urchin Hox genes,
      of uncertain affinity, as orthologues of Hox9 and Hox10 genes. Putative
      cytoplasmic polyadenylation elements were mapped in the 3' untranslated region of
      sea urchin Hox genes.

PMID- 12487021
TI  - Cloning and prokaryotic expression of a salt-induced cDNA encoding a
      chloroplastic fructose-1,6-diphosphate aldolase in Dunaliella salina
      (Chlorophyta).
AB  - A salt-induced fructose-1,6-diphosphate (FDP) aldolase cDNA (DsALDP) in
      Dunaliella salina was cloned by suppression subtractive hybridization (SSH) and
      rapid amplification of cDNA ends (RACE) techniques. Sequence analysis of DsALDP
      revealed that the 1520 bp cDNA had an open reading frame (ORF) of 327 amino acid
      residues. BLAST Search showed that DsALDP shared an amino acid identity (73-66%)
      with AldP in other plants. Alignment with homologues in other plants indicated
      that all the conserved substrate-specific binding sites could also be found in
      DsALDP. Phylogenetic analysis further confirmed the deduced amino acid sequence
      of the D. salina DsALDP gene belonged to the same subfamily to AldP of other
      green algae. Southern blot analysis suggested possible presence of the D. salina
      DsALDP gene as a few copies and Northern blot analysis confirmed salt-induced
      expression pattern at the transcriptional level. A 62 kDa fusion protein
      generated by adding a Trx-His.tag at the N-terminal of DsALDP was induced by IPTG
      in Escherichia coli BL21. An improvement of salt tolerance in E. coli expressing
      DsALDP fusion protein was observed.

PMID- 12487022
TI  - Sequence analysis of a Hoxa4-Hoxa5 intergenic region including shared regulatory
      elements.
AB  - The dynamic patterns of Hox gene expression are generated by a combination of
      regulatory elements differentially controlling Hox gene transcription in a spatio
      temporal and tissue-specific fashion. Regulatory elements can either be exclusive
      for a particular gene, shared by neighboring Hox genes, or be competed for by
      different promoters. Our interest in Hoxa5 gene function and regulation have led
      us to localize Hoxa5 cis-acting regulatory elements in the intergenic region
      between the Hoxa4 and Hoxa5 genes and involved in Hoxa5 organ expression. Mapping
      of the region and sequence analysis revealed some discrepancies with a previously
      published sequence. Here, we report an additional DNA fragment of 282 base pairs
      that possesses high homology with the human HOX sequence, and contains potential
      binding sites for trans-acting factors.

PMID- 12487023
TI  - cDNA cloning of the human polybromo-1 gene on chromosome 3p21.
AB  - The bromodomain is suggested as a chromatin-targeting domain involved in
      regulation of gene expression and chromatin structure. We here report the cDNA
      cloning of the human polybromo-1 (hPB1) gene that encodes a 1634-amino acid
      polypeptide containing six bromodomains. The hPB1 polypeptide shows 91% identity
      to the previously identified chicken polybromo-1 with conservation of the
      bromodomains and other characteristic features. Northern blot analysis detected
      the ubiquitous expression of hPB1 mRNA in a variety of human tissues. Four
      alternative splicings were found within the hPB1 coding region: three making in
      frame deletions and one resulting in a C-terminal truncation. The hPB1 gene is
      located on chromosome 3p21, where the tumor suppressor genes for breast, lung and
      kidney cancers have been mapped.

PMID- 12487024
TI  - Molecular cloning, mRNA expression and chromosomal localization of mouse
      angiotensin-converting enzyme-related carboxypeptidase (mACE2).
AB  - We isolated two mouse cDNA clones which show significant similarities with human
      angiotensin-converting enzyme-related carboxypeptidase (ACE2). The cDNAs were
      2746 and 1995 bp in length and seemed to arise from the same gene by alternative
      splicing. The longer cDNA encoded a 798-amino acid protein containing the
      sequence motif conserved among zinc metallopeptidases. Mouse ACE2 showed 83%
      identity with human ACE2. Northern blot analysis revealed that 2.8- and 2.0-kb
      transcripts were expressed mainly in the kidney and the lungs. The mouse ACE2
      gene was mapped to chromosome X 70.5 cM.

PMID- 12487025
TI  - Cloning and sequencing of the canine neutrophil elastase cDNA.
AB  - Human cyclic neutropenia, also referred to as cyclic hematopoiesis, is a rare
      disease characterized by periodic fluctuations in blood cell production by the
      bone marrow and a corresponding recurrent severe neutropenia every 19-21 days.
      This results in bacterial infections and shortened life expectancy. Platelets,
      monocytes, lymphocytes, and reticulocytes cycle with the same periodicity. It has
      been determined that the neutrophil elastase (NE) gene is mutated in all cases of
      human cyclic hematopoiesis. Currently, the only animal model for this disease is
      the grey collie dog, in which there is a strikingly similar periodic neutropenia
      every 12-14 days. Towards the validation of this animal model, we have cloned and
      sequenced the canine NE cDNA from a normal dog.

PMID- 12487026
TI  - Characterization of Xenopus EED pseudogene, a Polycomb group gene.
AB  - A EED pseudogene transcript (psXEED) has been isolated from the cDNA pool of
      Xenopus laevis. The open reading frame of psXEED was interrupted with a 40 bp
      insertion. Its untranslated region was identical with that of the functional
      XEED. Furthermore, the EED pseudogene was organized as a processed pseudogene in
      the genomic level. Interestingly, the EED pseudogene was transcribed both
      maternally and zygotically throughout embryogenesis.

PMID- 12487027
TI  - Genomic structure of two ras family genes in the slime mold Physarum
      polycephalum.
AB  - Genomic structure of two Physarum polycephalum ras family genes, Ppras2 and
      Pprap1, has been determined, including the upstream region of the latter. The
      genes are interrupted by three and four introns, respectively. The first intron
      of Ppras2 has the same location within the coding sequence as the first intron in
      another ras homolog from this organism, Ppras1 [Trzcinska-Danielewicz, J.,
      Kozlowski, P., and Toczko, K. (1996). "Cloning and genomic sequence of the
      Physarum polycephalum Ppras1 gene, a homologue of the ras protooncogene", Gene
      169, pp. 143-144]. All introns, ranging from 53 to ca. 460 base pairs, have the
      canonical 5' and 3' ends, are greatly enriched in pyrimidines in the coding
      strand and have frequent pyrimidines-only tracts. These latter features seem to
      be responsible for the difficulties in cloning and sequencing of parts of these
      genes. Short sequences shared with P. polycephalum transposon-like repeats are
      common in the introns, indicating a possible role of transposition in intron
      evolution. In all three ras family genes phase zero introns are located mostly
      between sequences coding for regular protein secondary structure elements.

PMID- 12487028
TI  - Complete cDNA sequence encoding 20S proteasome alpha 5 subunit PAE from soybean.
AB  - The 20S proteasome is the proteolytic complex that is responsible for degrading
      short-lived and abnormal proteins, especially those targeted by ubiquitin
      conjugation. The complex exists, as a hollow cylinder shaped structure comprised
      of four stacked rings. The outer rings contain 7 alpha subunits and the inner
      rings contain 7 beta subunits. In this study, we report the amino acid sequence
      of the alpha 5 subunit (PAE) in soybean (Gylcine max) based on the cDNA sequence.
      The amino acid sequence identity is 96% with the Arabidops alpha 5 subunit and
      95% with the rice alpha 5 subunit. The highly conserved sequence homology
      suggests there is an important biological role for this proteasome.

PMID- 12487029
TI  - Endothelial dysfunction in atherosclerosis.

PMID- 12487030
TI  - Vasoactive substances: nitric oxide and endothelial dysfunction in
      atherosclerosis.
AB  - The endothelium synthesizes and releases nitric oxide (NO) to maintain
      homeostatic function. Under basal conditions, endothelium-derived NO maintains a
      nonthrombogenic surface, prohibits leukocyte attachment, and promotes vascular
      relaxation. In the setting of clinical syndromes associated with the development
      of atherothrombosis, there is decreased bioavailable NO owing to diminished
      synthesis and release in addition to increased generation of reactive oxygen
      species. These biochemical changes perturb significantly vascular homeostatic
      mechanisms and promote platelet aggregation, inflammatory cell diapedesis, and
      vasoconstriction. Endothelial dysfunction may be evaluated using invasive and/or
      noninvasive techniques, including coronary artery reactivity to acetylcholine and
      brachial artery ultrasonography, respectively. NO replacement therapies may be
      initiated to restore deficits associated with dysfunctional endothelium.
      Strategies to replenish bioavailable NO include the administration of organic
      nitrosovasodilators or NO donor compounds, therapies to improve NO synthase
      function, and gene therapy.

PMID- 12487031
TI  - The role of MAP kinases in endothelial activation.
AB  - Activation of endothelial cells by proinflammatory stimuli results in increased
      migration of leukocytes across the endothelium, which contributes to the
      progression of atherosclerosis. Thus, control of the inflammatory status of
      endothelial cells, which is achieved by a balance of pro- and antiinflammatory
      signals, is crucial to limiting the disease. The mitogen-activated protein
      kinases (MAPKs) are a family of central signaling molecules that respond to
      numerous stimuli by phosphorylating a variety of substrates including
      transcription factors, enzymes, and other kinases. While the extracellular signal
      related kinases (ERK1/2) and big MAPK-1 (BMK1) are primarily involved in growth
      and cytoprotective functions, Jun amino-terminal kinases (JNK) and p38 proteins
      play an important role in inflammatory and stress responses. Because they have
      contradictory roles, the relative activation of these proteins is important to
      the inflammatory status of the cell. Additionally, there is known to be a
      crosstalk between MAPK cascades whereby the activity of one MAPK can be
      influenced by another. Thus, these proteins collectively integrate the pro- and
      antiinflammatory stimuli acting on the cell to produce the appropriate downstream
      effects. Here we review the roles of the MAPKs and the implications of MAPK
      crosstalk on endothelial activation.

PMID- 12487032
TI  - Endothelial cell response to hyperlipemia. Activation-dysfunction-injury, the
      protective role of simvastatin.
AB  - Experiments on hypercholesterolemic rabbits and hamsters (HH) showed that
      hyperlipemia induces initial activation of endothelial cells (EC) expressed by
      modulation of constitutive functions: increased transcytosis of low-density
      lipoproteins (LDL) and enhanced synthesis of basal lamina. Accumulated LDL
      appears in the meshes of basal lamina as modified and reassembled lipoproteins
      (MRL) that, together with hyperlipemia, triggers EC dysfunction. This induces
      monocyte recruitment, adhesion, diapedesis and residence within the
      subendothelium where upon activation become macrophages, take up MRL and turn
      into foam cells. With time, EC overlaying atheroma alter their nonthrombogenic
      surface and become loaded with lipid droplets, resulting as marks of EC injury.
      Simvastatin administration to HH increased the antioxidant potential of the
      serum, diminished transcytosis of lipoproteins (Lp) and restored the endothelium
      dependent relaxation.

PMID- 12487033
TI  - Regulation of chemokine expression in atherosclerosis.
AB  - (1) Chemokines play a central role in the pathogenesis of atherosclerosis,
      contributing to leukocyte recruitment, angiogenesis and also proliferation and
      migration of smooth muscle cells into atherosclerotic plaques. (2) Leukocytes and
      endothelial cells are an important source of chemokines, and many of the risk
      factors associated with atherosclerosis increase chemokine expression. There is
      now a body of evidence to suggest that interactions between cells such as
      leukocytes and endothelial cells amplify chemokine release, and this may
      contribute to sustained chemokine generation in inflammatory conditions. (3) This
      article summarises, briefly, what is currently known about chemokines release. A
      number of important pharmacological strategies used in the treatment of
      atherosclerosis inhibit chemokine release and the extent to which this may
      contribute to their therapeutic effect will be discussed. Understanding the
      mechanisms controlling chemokine expression is essential for the design of
      specific therapeutic interventions in atherosclerosis.

PMID- 12487034
TI  - Homocysteine and arterial disease. Experimental mechanisms.
AB  - Hyperhomocysteinemia (hH(e)) in the general population is associated with
      incidence and progression of arterial occlusive disease, although the underlying
      mechanisms are not well defined. Current research supports a role for
      homocysteine (H(e))-mediated endothelial damage and endothelial dysfunction. This
      mechanism appears to be a key factor in subsequent impaired endothelial-dependent
      vasoreactivity and decreased endothelium thromboresistance. These consequences
      may predispose hyperhomocysteinemic vessels to the development of increased
      atherogenesis. Additional mechanisms of H(e)-mediated vascular pathology,
      including protein homocysteinylation and vascular smooth muscle cell
      proliferation may also play a role. Continued investigation into the mechanisms
      contributing to H(e) toxicity will provide further insight into the processes by
      which hH(e) may increase atherosclerosis.

PMID- 12487035
TI  - Whither the sanctity and sanctuary of medical information?

PMID- 12487036
TI  - Learning the lessons of September 11: terrorism and beyond.

PMID- 12487037
TI  - 'ED phone home?'.

PMID- 12487038
TI  - The global threat of terrorism and its impact on Australia.

PMID- 12487039
TI  - Medical response to a terrorist attack and weapons of mass destruction.

PMID- 12487040
TI  - The tools of the trade: weapons of mass destruction.

PMID- 12487041
TI  - Nurse-initiated intravenous morphine in the emergency department: efficacy, rate
      of adverse events and impact on time to analgesia.
AB  - OBJECTIVES: The objectives of this study were: (i) to measure the analgesic
      efficacy and frequency of adverse events following autonomous nurse-initiated
      intravenous morphine in patients presenting with acute pain, awaiting medical
      assessment; and (ii) to determine whether such a process would improve the time
      to analgesia. METHODS: A prospective convenience sample of patients presenting in
      acute pain received titrated intravenous morphine by experienced emergency
      nurses. Pain scores on a 10.0 cm visual analogue scale and predetermined adverse
      events defined by physiological parameters were measured at regular intervals
      over the following 60 min. Demographic, diagnostic and waiting time data were
      also recorded. RESULTS: Three hundred and forty nine patients were enrolled over
      a 12-month period. The median initial pain score was 8.5 cm, with a reduction to
      4.0 cm at 1 h. Respiratory rate, oxygen saturation, heart rate and blood pressure
      all showed small but statistically significant reductions over 60 min. There were
      15 predefined adverse events, 10 episodes of hypotension and five episodes of
      oxygen desaturation. No intervention other than supplemental oxygen was required.
      There were no episodes of bradycardia, bradypnoea or reduced level of
      consciousness. The median time to narcotic was 18 min and the median time to be
      seen by a doctor was 52 min. CONCLUSION: Experienced emergency nurses can
      initiate effective intravenous narcotic analgesia for patients in acute pain
      awaiting medical assessment, with minimal change in physiological parameters.
      This process can improve the time to analgesia for patients in acute pain.

PMID- 12487042
TI  - Knowledge of heart attack symptoms in a community survey of Victoria.
AB  - OBJECTIVE: To ascertain the level of knowledge of heart attack symptoms in the
      Victorian public. METHODS: This was a cross sectional telephone survey conducted
      during 2000-01. The questionnaire contained sections regarding participant
      demographics and knowledge of heart attack symptoms. RESULTS: A total of 1489
      people completed the questionnaire (79% of eligible participants). The mean
      number of correct heart attack symptoms was 2.5 (95% CI 2.45, 2.60) (median three
      out of 10). Only 4.2% of participants reported at least five correct symptoms and
      4.1% could not report any symptoms. A total of 84.6% of respondents reported
      chest pain as a symptom of heart attack. CONCLUSIONS: The Victorian public
      appears to lack the knowledge of the varied range of heart attack symptoms.
      Methods of disseminating information regarding symptoms and ways to reduce
      prehospital delay need to be devised, particularly methods which target the older
      'at risk' population.

PMID- 12487043
TI  - Factors influencing prehospital and emergency department analgesia administration
      to patients with femoral neck fractures.
AB  - OBJECTIVES: To assess the analgesia practices of ambulance personnel and
      emergency department staff treating patients with fractured neck of femur.
      METHODS: This is a retrospective analysis of 176 patients with an admission
      diagnosis of fractured neck of femur, who presented to a major western Sydney
      teaching hospital, between January and November 1999. RESULTS: One hundred and
      twenty-eight patients met the inclusion criteria. The median age was 82, there
      were more female than male subjects. Ambulance officers made a clinical diagnosis
      of fractured neck of femur in 68% of cases. In 49% of cases no analgesia was
      given. Patients were given a higher triage category and pain relief faster if
      they had been given analgesia by ambulance officers, P = 0.0018 and P = 0.002,
      respectively. The median time to analgesia was 2 h 48 min. CONCLUSIONS: Only a
      modest proportion of patients with fractured neck of femur received prehospital
      analgesia and delays to analgesia in the emergency department are considerable.
      Strategies to address the delivery of appropriate analgesia to this group of
      patients should be developed.

PMID- 12487044
TI  - Thrombolysis for acute myocardial infarction in Australasia 1999.
AB  - OBJECTIVE: To describe revascularization practice for acute myocardial infarction
      in a sample of Australasian hospitals during 1999. DESIGN: Survey for the 1999
      calendar year. SETTING: Hospitals with Australasian College for Emergency
      Medicine-accredited emergency departments in Australia and New Zealand.
      PARTICIPANTS: Forty-eight hospitals of 80 surveyed (60%), comprising 15 tertiary
      and 33 non-tertiary hospitals. MAIN OUTCOME MEASURES: Time from arrival in
      emergency department to initiation of thrombolytic therapy, site of therapy,
      agent used, mortality and intracranial haemorrhage rates. RESULTS: Approximately
      30% of patients with acute myocardial infarction had revascularization therapy.
      Sixty-two per cent of patients receiving thrombolytics were given this treatment
      in the emergency department, the remainder in the coronary care unit. Overall
      median door-to-needle times were 35.0 min emergency department versus 48.3 min
      coronary care unit. Streptokinase was used for 58.3% of thrombolysis. In-hospital
      mortality of thrombolysed patients was 6.7% in the emergency department versus
      4.3% in the coronary care unit with intracranial haemorrhage rates of 0.8%
      emergency department and 0.7% coronary care unit. CONCLUSIONS: Overall times to
      thrombolysis and outcome rates in this sample were within internationally
      reported figures. Emergency department times were shorter than in coronary care
      unit.

PMID- 12487045
TI  - Intranasal fentanyl reduces acute pain in children in the emergency department: a
      safety and efficacy study.
AB  - INTRODUCTION: Provision of rapid, painless and effective analgesia to children
      remains problematic in the prehospital and emergency setting. Intranasal fentanyl
      has the potential to eliminate many of the problems of narcotic administration in
      children. The aim of this study, conducted in a tertiary paediatric emergency
      department was to evaluate the safety and efficacy of intranasal fentanyl in
      children. METHODS: Children in acute pain aged between three and 12 years
      inclusive were enrolled on presentation to the emergency department. Routine
      observations and pain scoring by the child and caregiver was undertaken prior to
      the child receiving fentanyl (20 micrograms for 3-7 year olds and 40 micrograms
      for 8-12 year olds) and at intervals of 5 min for 30 min Additional fentanyl at
      the dose of 20 micrograms was given 5 minutely as required. Caregivers and older
      children used a visual analogue scale (VAS) and the younger children used the
      Wong-Baker faces scale (WBS). RESULTS: Forty five children were enrolled with a
      mean age of 8.0 years. The median dose of fentanyl administered was 1.5
      micrograms/kg. Mean pain score in 32 children using the VAS was 62.3 mm (95%
      confidence interval 53.2-69.4 mm) at presentation and reduced at 10 min to 44.6
      mm (95% confidence interval 36.2-53.1 mm). In 16 children using WBS the initial
      mean reading was 4.0 (95% confidence interval 3.3-4.7) and reduced to 2.2 (95%
      confidence interval 1.3-3.1) at 10 min. Caregiver pain scores showed a mean
      preintervention pain score of 64.9 mm (95% confidence interval 57.7-72.2 mm) with
      a significant reduction at 10 min to 41.7 mm (95% confidence interval 34.7-48.6
      mm). There was no significant alteration in pulse rate, respiratory rate, and
      blood pressure or oxygen saturations. There were no negative side-effects.
      CONCLUSIONS: Early and significant reduction in pain (compared to baseline
      assessments) was achieved in children using intranasal fentanyl by 10 min and
      sustained throughout the 30 min of observations. This raises the possibility of
      using intranasal fentanyl in children in the prehospital setting as well as a
      role for this form of analgesia as triage nurse-initiated administration in the
      emergency department.

PMID- 12487046
TI  - Non-invasive positive pressure ventilation in patients with acute respiratory
      failure.
AB  - Non-invasive positive pressure ventilation is an emerging modality in
      contemporary critical care practice. Perhaps the most widely utilized and
      familiar form of non-invasive positive pressure ventilation is mask continuous
      positive airway pressure. Other common modes include mask Bi-level positive
      airway pressure and mask pressure support ventilation. All feature the delivery
      of positive airway pressure via a mask (full-face, naso-oral or nasal), and a
      patient-controlled respiratory cycle. The physiological benefits of non-invasive
      positive pressure ventilation suggested by a number of studies include improved
      oxygenation, decreased work of breathing, improved ventilation and perfusion
      matching, decreased fatigue, and increased minute ventilation. The utilization of
      non-invasive positive pressure ventilation has now been reported for a variety of
      clinical indications. In most, randomized trials are lacking, and the benefits
      and preferred mode of non-invasive positive pressure ventilation are still to be
      elucidated. In general, in patients that are candidates for endotracheal
      intubation, non-invasive positive pressure ventilation should be used as a way to
      possibly avoid endotracheal intubation rather than as an alternative to
      endotracheal intubation. Whilst the benefit of non-invasive positive pressure
      ventilation appears to be established in patients with chronic obstructive
      airways disease with hypercapnic acute respiratory failure, one of the major
      unresolved issues is whether one modality is significantly better than the
      others. Unfortunately, the question of whether Bi-level positive airway pressure
      is better than continuous positive airway pressure in this clinical scenario has
      not been satisfactorily addressed in any large randomized and controlled clinical
      trial. Further, there is no 'gold standard' for predicting success with non
      invasive positive pressure ventilation, although several studies have looked at
      this aspect.

PMID- 12487047
TI  - Cannabis and driving: a new perspective.
AB  - Cannabis and driving is an emerging injury-prevention concern. The incidence of
      driving while affected by cannabis is rising in parallel with increased cannabis
      use in the community. Younger drivers are at particular risk. Improvements in
      research methodology, technology and laboratory testing methods have occurred in
      the last 10 years. These cast doubt on earlier results and conclusions. Studies
      now show that cannabis has a significant impairing effect on driving when used
      alone and that this effect is exaggerated when combined with alcohol. Of
      particular concern is the presence of cannabis as the sole psychoactive drug in
      an increasing number of road fatalities and the lack of any structural response
      to this problem. A review of testing methods, laboratory and real driving
      studies, and recent epidemiological studies is presented. Suggestions for methods
      of further data collection and future public policy are made.

PMID- 12487048
TI  - Vasopressin.

PMID- 12487049
TI  - A follow-up study of electromagnetic interference of cellular phones on
      electronic medical equipment in the emergency department.
AB  - OBJECTIVE: Considering the growing use of cellular phones and the fast appearance
      of new phone models, the electromagnetic interference of currently popular
      cellular phones on electronic medical equipment was tested. METHODS: Three
      Personal Communication System cellular phones were put at different distances
      from multiple electronic medical devices, the interference effect was observed
      and the electromagnetic field strength measured with a spectrum analyser.
      RESULTS: Only two small pieces of equipment, the CO2 airway adapter and the
      haemoglucostix meter were affected and then only when the phone was in very close
      proximity. CONCLUSION: Compared to the results of our study in 1997 testing
      Global System for Mobile Communication phones, the Personal Communication System
      phones generated less electromagnetic interference. However a much larger scaled
      study and an accurate international electromagnetic interference standard are
      recommended before any change in the current restrictive hospital policy on
      mobile phone usage could be recommended.

PMID- 12487050
TI  - Optic neuropathy resulting from indirect trauma.
AB  - Minor blunt injury to the head and face may result in optic nerve contusion with
      secondary optic atrophy. The resulting visual loss is devastating for the
      individual. We report an uncommon but important complication that may result from
      an apparently trivial injury. Early identification and initiation of appropriate
      management may restore the individual's vision. Emergency physicians are often
      the first to see patients at risk of this complication yet there is little
      discussion of this injury in the emergency medicine literature.

PMID- 12487051
TI  - High-pressure water injection injury: emergency presentation and management.
AB  - Presentations of high-pressure water blaster injuries to the emergency department
      are varied. Though these injuries are sometimes described as a 'benign variant'
      of high-pressure injection injuries, external appearances can be deceptive. These
      injuries can produce an unexpected pattern of severe internal injury and
      infectious complications. Such injuries are surgical emergencies and must be
      evaluated quickly and thoroughly in the emergency department. We review the
      current literature of these injuries and present the first reported case
      involving a forearm injury.

PMID- 12487053
TI  - Use of length-based and age-based calculations of weight in paediatric emergency
      care.

PMID- 12487052
TI  - Intensive care unit survival: different populations studied.

PMID- 12487054
TI  - Introduction to cancer gene therapy.
AB  - Over the past decade, the unprecedented growth in science and technology has
      fueled the development of novel treatment strategies to combat disease. The
      creative and innovative efforts of scientists and clinicians to overcome the
      multitude of unforeseen obstacles to success is no better exemplified than in the
      field of cancer gene therapy. Since its inception, developers of cancer gene
      therapy have been charged with the challenge of altering basic tumor biology or,
      alternatively, the host responses for the purpose of tumor eradication and
      prevention. Several major therapeutic strategies have emerged from preclinical
      studies, and results from these early studies hold promise for altering the
      clinical outcome in a variety of malignancies. These strategies may be broadly
      subcategorized and range in intent from alteration of the tumor cell phenotype by
      replacement of defective cellular response genes (e.g., mutated or deleted tumor
      suppressor genes) to the enhancement of the immunological response to cancer
      (e.g., amplification of the cell surface antigen signature or modulation of the
      host response). Not surprisingly, the increasingly intricate nature of tumor
      biology revealed over the past several years has effectively raised the bar of
      success for those involved in the development of effective molecular and cancer
      gene therapy strategies. This, in turn, has led to the development of more
      complex therapies that frequently draw upon multiple disciplines in an effort to
      optimize treatment response.

PMID- 12487055
TI  - Clinical update of Ad-p53 gene therapy for lung cancer.
AB  - These preliminary Phase I and II gene therapy trials in NSCLC have demonstrated
      that Ad-p53 gene transfer is associated with low toxicity and evidence of
      antitumoral activity at the locoregional site. Effort to enhance antitumoral
      efficacy with chemotherapy and radiation therapy have not increased Ad-p53
      toxicity and appear to be feasible. Randomized Phase III studies are now needed
      to determine the potential of Ad-p53 to improve overall survival in selected
      subsets of NSCLC patients. Future gene therapy research is required to develop
      systemic delivery systems and to overcome p53 tumor resistance. It is hoped that
      these efforts will ultimately lead to a novel mode of therapy to complement
      conventional chemotherapy, radiation therapy, and surgical treatment strategies.

PMID- 12487056
TI  - Gene therapy for pancreatic cancer.
AB  - Gene transfer technology has the potential to revolutionize cancer treatment.
      Developments in molecular biology, genetics, genomics, stem cell technology,
      virology, bioengineering, and immunology are accelerating the pace of innovation
      and movement from the laboratory bench to the clinical arena. Pancreatic
      adenocarcinoma, with its particularly poor prognosis and lack of effective
      traditional therapy for most patients, is an area where gene transfer and
      immunotherapy have a maximal opportunity to demonstrate efficacy. In this review,
      we have discussed current preclinical and clinical investigation of gene transfer
      technology for pancreatic cancer. We have emphasized that the many strategies
      under investigation for cancer gene therapy can be classified into two major
      categories. The first category of therapies rely on the transduction of cells
      other than tumor cells, or the limited transduction of tumor tissue. These
      therapies, which do not require efficient gene transfer, generally lead to
      systemic biological effects (e.g., systemic antitumor immunity, inhibition of
      tumor angiogenesis, etc) and therefore the effects of limited gene transfer are
      biologically "amplified." The second category of gene transfer strategies
      requires the delivery of therapeutic genetic material to all or most tumor cells.
      While these elegant approaches are based on state-of-the-art advances in our
      understanding of the molecular biology of cancer, they suffer from the current
      inadequacies of gene transfer technology. At least in the short term, it is very
      likely that success in pancreatic cancer gene therapy will involve therapies that
      require only the limited transduction of cells. The time-worn surgical maxim, "Do
      what's easy first," certainly applies here.

PMID- 12487057
TI  - Liver-directed viral therapy for cancer p53-targeted adenoviruses and beyond.
AB  - Loss of p53 function is one of the most frequent genetic alterations in human
      cancers. Both replication-incompetent (rAd.p53, or SCH58500) and replication
      selective (dl1520, or Onyx-015) adenoviruses are being developed for the
      treatment of p53-deficient cancers. Hepatic arterial infusion (HAI) has
      historically been used to selectively target colorectal tumors within the liver;
      consequently, regional therapy with adenovirus in this setting is an attractive
      approach. This article reviews Phase I and I/II HAI trial results with these
      adenovirus constructs.

PMID- 12487058
TI  - Prostate cancer gene therapy.
AB  - Numerous gene therapy trials in the United States and throughout the world using
      various strategies are in progress for the treatment of locally advanced and
      metastatic prostate cancer. Although vector technology advances at a rapid pace,
      progress in elucidating the molecular pathways critical for the development and
      progression of prostate cancer has been slower and more deliberate. Thus far,
      prostate gene therapy appears to be safe and well tolerated. Through these early
      clinical trials, the safety and efficacy of gene therapy alone or in combination
      with more conventional therapy as a basis for the treatment of prostate cancer
      will ultimately be determined.

PMID- 12487059
TI  - Applications of gene transfer to cellular immunotherapy.
AB  - Adoptive cellular therapy remains a potentially powerful method of eradicating
      established tumors. T-cells have been particularly potent effector cells, as
      demonstrated in animal models and clinical studies, and it is apparent that the
      stimulation of certain subpopulations of T-cells that are reactive to tumor
      antigens can lead to more therapeutic T-cells. The use of gene transfer
      techniques has resulted in more effective and specific methods to generate these
      tumor-specific T-cells. Another area of tremendous interest is in the adoptive
      transfer of DCs manipulated to present tumor antigen to resting, naive T-cells.
      Gene transfer techniques may offer more optimal ways to generate therapeutic DCs.
      Adoptive immunotherapy may ultimately [figure: see text] have its greatest use in
      patients undergoing cellular rescue after ablative chemotherapy; the infusion of
      immunocompetent T-cells, genetically modified stem cells, or programmed DCs may
      offer the opportunity to direct a patient's immune response to eliminate residual
      microscopic disease.

PMID- 12487060
TI  - Dendritic cell gene therapy.
AB  - All of these studies taken together highlight key areas that must be addressed in
      the future in order for the field to continue to move forward. These issues are
      many, including but not limited to method of delivery of dendritic cells to
      patients, maturation status of the dendritic cells, and methods of monitoring
      responses to these vaccines. Each of these requires some comment. Different
      strategies of immunization were used in these studies. DCs were injected at
      various times and in various locations, including intradermally/subcutaneously,
      intranodally, and intravenously. Investigation of the pattern of spread of
      subcutaneously injected fluorescently labeled DCs in the chimpanzee was studied
      at the University of Pittsburgh. Although rodent DCs had previously been shown to
      remain at the site of injection, these immature primate DCs migrated to draining
      lymph nodes and interact appropriately with T cells for as long as 5 days after
      administration. Data not shown in the same study reveal that intravenously
      administered DCs were undetectable in draining lymph nodes. Two groups have
      undertaken evaluation of route of administration of DCs in humans. The first of
      these examined migration of immature, indium-111-labeled dendritic cells after
      RNA-loading in metastatic cancer patients [44]. The DCs were injected either
      intravenously, subcutaneously, and intradermally. Only DCs injected intradermally
      were cleared from the injection site with migration to regional lymph nodes. The
      immunologic significance of these findings is unclear, however. Another study
      examined this issue by studying prostatic acid phosphatase (PAP) protein-loaded
      mature DCs injected intravenously, intradermally, and intralymphatically in
      prostate cancer patients [45]. Regardless of route of administration, T cell
      responses were induced as measured by proliferation when PBMCs in vitro were
      stimulated with the PAP protein. Cytokine analysis of the patients revealed that
      the majority of patients undergoing either intralymphatic or intradermal
      injection had increases in measurable interferon-gamma but that none of the
      intravenously-injected patients did. The intralymphatic and intradermal routes
      thus seem to lead to stronger Th1 responses. But no data was presented regarding
      the numbers of PAP precursors induced by vaccination nor their
      specificity/cytotoxicity. Another issue in DC administration that should also
      affect route of administration is maturation status of the dendritic cells. Many
      of the studies used immature dendritic cells to immunize patients whereas others
      used mature cells. A number of studies have demonstrated that maturation signals
      such as inflammatory cytokines and CD40 ligation lead to down-regulation of
      antigen processing and up-regulation of the chemokine receptor CCR7, which leads
      to homing to lymph nodes [46] as well as the MHC molecules, costimulatory
      molecules, and maturation markers [8,47,48]. In addition, different maturation
      agents and sequences of addition of these maturation agents may lead to
      differences in functions of dendritic cells [48-51]. Others have found that
      injection of immature DCs pulsed with influenza matrix peptide and KLH, and lead
      to greater numbers of influenza-specific T cells, but these cells had reduced
      interferon-gamma production and lacked killer activity [52]. Perhaps the most
      impressive results in a clinical trial, however, were gained by injecting similar
      cells loaded with melanoma peptides [21]. In addition, sequence of loading and
      maturation may be important in creating vaccines. One study using CEA peptides
      and CEA RNA found that optimal T cell presentation occurs when peptides are
      loaded after maturation with CD40 ligand and when RNA is transfected before
      maturation with CD40 ligand [53]. As all of these studies reveal, more
      investigation into the role of DC maturation as well as its timing and sequence
      is needed. Finally, a multitude of methods to detect response to vaccination have
      been attempted in all of the above studies. Many use DTH responses, but these may
      measure CD4 T cells instead of CD8 T cells. The availability of tetramers allows
      easier quantification of CTL precursors, but they provide no assessment of the
      function of these T cells. Enzyme-linked immunospot assays allow identification
      and quantification of numbers of cells producing cytokines such as interferon
      gamma when encountering target antigens, but cytokine production may not
      correlate with tumor cell killing. Chromium release assays or flow cytometric
      assays for molecules such as perforin may be used to validate killing, but
      inability of many tumors to grow in vitro precludes direct assessment of tumor
      cell killing via this method. Other responses in human subjects may also be
      measured. Some of the cited studies yielded clinical responses that could be
      measured via physical examination or radiologic study. This is the exception
      rather than the rule, however. Others have monitored the decrease in serum tumor
      markers such as PSA or CEA. But these may not correlate directly with tumor
      burden. Indirect calculation of tumor burden by using quantitative PCR to
      estimate the number of circulating tumor cells in peripheral blood may be
      promising in this regard. Despite the lack of consensus as to what constitutes an
      effective response, most would agree that monitoring of these patients should
      include measures of both immunologic response and clinical tumor effect. All of
      this leads to the conclusion that DC-based cancer vaccines have progressed a
      great deal but that much work still needs to be done. Only rigorous bench top
      experimentation followed by careful patient selection and vaccine administration,
      and then by meticulous patient monitoring, will lead to advances in the field.

PMID- 12487061
TI  - Viral oncolysis.
AB  - Although the concept of using viruses as antineoplastic agents dates back nearly
      a century, recent advances in the fields of molecular biology, genetics, and
      virology have enabled investigators to engineer viruses with greater potency and
      tumor specificity. Further enhancements involve arming these viruses with
      therapeutic transgenes, and combining the traditional modalities of chemotherapy
      and radiation therapy with oncolytic viral therapy in hopes of reducing the
      chance of developing resistant tumor cell clones. Another means of augmenting the
      antineoplastic effect of these viruses involves modulating the immune response to
      minimize antiviral immunity, while at the same time maximizing antitumor
      immunity. A better understanding of mechanisms that viruses use to overcome
      cellular defenses to achieve robust replication within the cell will lead to
      development of oncolytic viruses with better tumor specificity and reduced
      toxicity. Initial clinical studies have shown that oncolytic viral therapy for
      metastatic disease is safe and well tolerated. In addition, using similar genetic
      modification strategies, these viruses have demonstrated antineoplastic effects
      in humans similar to those seen in preclinical animal models.

PMID- 12487062
TI  - Cytokine modified tumor vaccines.
AB  - The immune system can recognize tumors, but may be actively tolerized to tumors
      during the tumorigenesis process. The identity of most tumor antigens remains
      unknown, but the number is growing due to new techniques. Most clinical trials
      using genetically modified tumor vaccines have shown immunological responses
      (DTH), but few clinical responses. Certain chemotherapeutic agents may enhance
      the immune effects of genetically modified tumor vaccines.

PMID- 12487063
TI  - Protein/DNA polyplexes for gene therapy.
AB  - The development of molecular conjugates as components of Protein/DNA polyplexes
      has resulted in the creation of a simple, non-virus vector for the targeted
      delivery of nucleic acids into specific cell types. This vector has many of the
      positive attributes of viruses, on without the limitations that continue to
      plague recombinant viruses. The simplicity of this vector allows for quick
      analysis of nucleic acids, expression vectors, and therapeutic genes in vitro and
      potentially in vivo, because the time that would be involved in the generation of
      recombinant viral vectors is not present. Essentially, the development of this
      delivery vector has resulted in the creation of a "synthetic virus" that has the
      capability of targeted delivery without the negative attributes of viruses.

PMID- 12487064
TI  - Clinical trials for cancer gene therapy.

PMID- 12487065
TI  - [Indications for the prescription of hearing aids by the otorhinolaryngologist].

PMID- 12487066
TI  - [Antitumoral effect of HSV-tk suicide gene associated with ganciclovir in an
      experimental model of head and neck epidermoid carcinoma].
AB  - INTRODUCTION: We studied the transfection by adenoviral vectors and the
      antitumoral effect of HSV-tk gene associated with ganciclovir (AdCMVtk/GCV) in KB
      human oral cavity squamous cell carcinoma, in vitro and in vivo. MATERIALS AND
      METHODS: Transfection was assessed by the X-gal stain. It was used in cell
      cultures and tumoral sections previously exposed to adenoviral vector AdCMVlacZ.
      In vitro, in order to study the antitumoral effect of AdCMVtk/GCV, survival of
      cell cultures exposed to AdCMVtk/GCV and to AdCMVlacZ/GCV was compared. In vivo,
      necrotic volume as a percentage of total tumoral volume, was compared between
      AdCMVtk/GCV treated group and AdCMVlacZ/GCV exposed group. Hepatic and renal
      toxicities were assessed. RESULTS: In vitro, survival of cell cultures treated
      with AdCMVtk/GCV was less than AdCMVlacZ/GCV exposed cells. In vivo, necrotic
      volume was larger in AdCMVtk/GCV treated group than in AdCMVlacZ/GCV exposed
      group. No toxicity was found (hepatic, renal). CONCLUSIONS: KB cells are
      transfected by adenoviral vectors and are killed by AdCMVtk/GCV, both in vitro
      and in vivo (no toxicity was found in the animal model).

PMID- 12487067
TI  - [Myringoplasty: our results].
AB  - Tympanoplasty is the surgical technique used to restore the anatomy and function
      of the middle ear. The tympanoplasty type I or myringoplasty is performed when
      the ear only has a perforation of the tympanic membrane without any ossicular
      damage. We present a retrospective study started in 1997 and finished in 2000
      with a total of 118 cases who had undergone a myringoplasty along this period of
      time. The percentage of closure was 85.59% (n = 101). The techniques used were
      underlay in a 60.16% of the patients (n = 71), overlay in 34.74% (n = 41) and
      sandwich in 5.08% (n = 6). In the paediatric patients (under 14 years of age) the
      percentage of a successful graft following surgery was 88% and in the adults
      83.87%. More than fifty years have passed. Since Zollner and Wullstein described
      for the first time this type of surgery important because of its good results.

PMID- 12487068
TI  - [Endoscopic dacryocystorhinostomy: a modified technique].
AB  - Dacryocystorhinostomy (DCR) is a surgical technique which has been adopted by
      otolaryngologists in the last years, because of the improvement in the endonasal
      approach by means of endoscopes. Although the results with the different
      techniques regarding permeability of the lacrimal duct are similar, we present
      some modifications in the surgical technique which contribute to a better
      postoperatory mucosal recovery, due to its more functional and less aggressive
      nature, improving the cost-benefit ratio. Two groups are compared, the first one
      (96 DCR) performing osteotomies with a chisel, without doing lacrimal duct and
      mucosa flaps, the second one (40 DCR) applying the modified technique using Smith
      Kerrison forceps to perform osteotomies and creating lacrimal duct and mucosa
      flaps. Final results referred to permeability are similar (92.7% vs 87.5%). No
      major complications were found, and the most common minor complication was
      postoperative eyelid hematoma in cases of orbital fat exposure (5 cases vs 7
      cases).

PMID- 12487070
TI  - [Parapharyngeal space tumors. Our experience. I.P.O. Francisco Gentil, Lisbon].
AB  - Primary parapharyngeal space tumours are rare, representing only a 0.5% of head
      and neck neoplasms. The authors report a case series review of 38 patients with
      parapharyngeal tumours who underwent surgical excision between 1975 and 1998.
      Twenty-six of them were female (68%) and twelve male (32%). Thirty-three tumours
      (87%) were benign and five (13%) were malignant being the Pleomorphic adenoma the
      most common neoplasm (39%). All patients were treated surgically: the trans
      cervical approach was used in 19 cases, cervical-parotid in 5, the trans-parotid
      approach in 7 patients, transoral in 5, the cervical-parotid approach with
      mandibulectomy in 2 and the combined transoral-cervical approach in 1 case. Out
      of the 33 patients with benign neoplasms, 1 (a pleomorphic adenoma treated
      through a transoral approach) had a recurrence. Amongst the 5 with malignant
      disease, recurrence or persistent local tumour was seen in 4 cases; and of these,
      3 with persistent local tumour after incomplete excision died.

PMID- 12487069
TI  - [Clinical descriptive study of 40 patients with carcinoma of the nasopharynx in
      advanced stage in an area of low epidemiological risk].
AB  - The nasopharyngeal carcinoma in Spain, low risk geographical area, is a rare
      tumor. This is the cause why there few papers about it in our country. We have
      carried out a muestral descriptive statistical study. We have selected among all
      the patients diagnosed of nasopharyngeal carcinoma a big group who, have been
      treated with induction chemotherapy followed by radiotherapy with or without
      surgery, they presented very complete clinical histories in the Departments of
      E.N.T., Oncology and Radiotherapy that allowed us to compare all the picked up
      data and this increased, without doubt, the reliability of them. The results
      obtained in the different examined variables of our patients are the same that
      those we found in literature. The nasopharyngeal carcinoma is a tumor that
      usually affects young patients, of both sexes, without previous consumption of
      alcohol and tobacco and they are diagnosed in advanced stages. The rhinologic
      symptoms are the most frequent ones but the cervical nodes are the usual cause
      for consulting a doctor with a long diagnostic interval. There is a prevalence in
      the undifferentiated tumors showed by histology.

PMID- 12487071
TI  - [Is there a place for otorhinolaryngology in primary care? Analysis of different
      areas].
AB  - Otolaryngological disorders do have a high incidence, and prevalence and require
      specific physical examinations amongst general population. As a result, it is
      believed that it would be efficient to have otorhinolaryngologists within the
      primary care system. The main aim of this study was to assess the differences in
      hospital referrals comparing primary care units with and without ENT specialists.
      The study was carried out in Osona County (Catalonia, Spain). We studied the
      referrals to the hospital from two different primary care units, one with
      otorhinolaryngology services and the other without them. We analysed the
      morbidity, follow up and demographic variables of first visits in the hospital
      ENT department referred by these two primary care units. The primary care
      organisation without ENT specialist tends to refer more patients (3.96 first
      visits more per 1000 inhabitants a year, CI 95% 2.84-5.09) with ENT problems than
      the primary care one with ENT specialist. The difference is mainly due to an
      higher number of referrals that do not require hospital treatment (i.e. acute
      otitis, patients without an ENT clear diagnosis). In the area with ENT
      specialist, GP's also tend to refer patients directly to the hospital, hampering
      the organisation efficiency. The referrral pattern of GPs from the two
      organisations is quite similar, and they refer a high percentage of patients that
      do not need ENT hospital care. The study shows that ENT specialists in primary
      care units refer less patients with ENT disorders that can be successfully
      diagnosed and treated outside the hospital.

PMID- 12487072
TI  - [Video fiber endoscopy during induced sleep].
AB  - Video-fiberoscopy is the exploration of upper respiratory airways used in our
      diagnostic protocol in patients with chronic snoring and obstructive sleep apnea
      syndrome (OSAS). We perform a fibroscopy during propofol induced sleep without
      tracheal intubation; video recording and monitoring of level of sleep, pulse
      oximetry, blood pressure, ECG, etc. is used. This exploration allows us to asses
      upper respiratory airways when the patient is asleep as well as the areas of
      collepse and vibration both from a functional and anatomical points of view.

PMID- 12487073
TI  - [Spontaneous middle ear meningoencephalic herniation. 2 case reports].
AB  - Two cases of idiopathic brain herniation into the middle ear without previous
      surgery are reported. Brain herniation is an unusual pathology, usually related
      to middle ear surgery. The idiopathic appearance of this disease is the secondly
      most frequent cause. Its origin is believed to be related to a congenital defect
      of tegmen timpani. Two elements, both rare, are emphazised: the spontaneous
      bilateral presentation in one of the cases, and the CSF leak as an initial
      symptom. We present a review of the literature, describing epidemiology results
      and the main accepted etiology theories. We discuss the diagnosis and treatment
      methods: magnetic resonance imaging and surgery.

PMID- 12487074
TI  - [Endolymphatic sac tumor and von Hippel-Lindau disease. Review of the
      literature].
AB  - This report describes a patient with Von Hippel-Lindau disease revealed by an
      endolymphatic sac tumor. Endolymphatic sac tumor (EST) was only recently
      recognized as a manifestation of Von Hippel-Lindau (VHL) disease. EST are
      vascular lesions that destroy and expand bone. We report a recently treated case
      of an EST. A 30-year-old woman presented with otalgia and hearing loss. Computed
      tomography and magnetic resonance imaging showed typical features of an EST. We
      checked for VHL and found this disease in the patient. VHL disease is a
      hereditary cancer syndrome caused by germline mutations of the VHL tumor
      suppressor gene. A molecular diagnosis of VHL is nowadays available, and this has
      change the clinical management of patients and their families. Diagnosis of VHL
      has to be suspected in patients with a VHL-related tumor without familial history
      and especially in those cases of hemangioblastoma or endolymphatic sac tumors.
      Such patients should be systematically investigated for clinical and molecular
      evidence of VHL disease.

PMID- 12487075
TI  - [Cervical recurrence in the pathologically negative neck (pNO): finding a needle
      in a haystack].
AB  - Recurrence in the pathologically negative neck (pN0) is one of the most striking
      events occurring in head and neck tumors. It is not even mentioned in many neck
      dissection studies. The presence of micrometastases has been suggested as an
      explanation for this event. In accordance to a recent study performed in our
      institution, we bring up this controversial issue. A definitive explanation for
      recurrence in the pN0 has not yet been proposed.

PMID- 12487076
TI  - The expanding role of the otolaryngologist in managing infants and children with
      hearing loss.
AB  - Universal newborn hearing screening will increase the number of very young
      children requiring care from an otolaryngologist. Although the otolaryngologist
      is the perceived expert in managing hearing loss, he or she must collaborate with
      a team of specialists to provide comprehensive treatment for the newly diagnosed
      child and its family. Working within a team that includes a pediatrician,
      audiologist, otolaryngologist, speech pathologist, teachers, and care
      coordinators allows each professional to contribute significantly to the well
      being of the child and parents. Group cooperation and parental support can
      increase the chances of normal speech and language development in an infant with
      hearing loss. By identifying related or syndromal associations, the
      otolaryngologist can prevent complications related to other organ systems such as
      the heart and eyes. Most importantly, parents and patients look up to the
      validation of the care plan by the ear physician.

PMID- 12487077
TI  - Audiologic assessment of children with suspected hearing loss.
AB  - In assessing children with suspected hearing loss, audiologists are faced with
      the challenge of attempting to describe auditory function in a population that
      presents with a wide range developmental levels and abilities. Fortunately, there
      are a number of behavioral and physiologic tools available for the evaluation of
      auditory sensitivity and system integrity in children of all ages and
      developmental abilities. As powerful as many of these tools may be, however, it
      is important that the diagnosis of hearing loss be based on the outcome of
      independent measures of auditory function, which serve to cross-check and
      complement one another. Failure to do so is likely to result in inaccurate or
      incomplete delineation of auditory function.

PMID- 12487078
TI  - Deciphering auditory processing disorders in children.
AB  - APD is not a label for a unitary disease entity but rather a description of
      functional deficits [3]. It is a complex and heterogeneous group of auditory
      specific disorders usually associated with a range of listening and learning
      deficits [3,4]. Underlying APD is a deficit observed in one or more of the
      auditory processes responsible for generating the auditory evoked potentials and
      the following behaviors: around localization and lateralization; auditory
      discrimination; auditory pattern recognition; temporal aspects of audition,
      including temporal resolution, masking, integration, and ordering; auditory
      performance with competing acoustic signals; and auditory performance with
      degraded acoustic signals [2]. Comprehensive assessment is necessary for the
      accurate differential diagnosis of APD from other "look-alike" disorders, most
      notably ADHD and language processing disorders. Speech-language pathologists,
      psychologists, educators, and physicians contribute to this more comprehensive
      assessment. The primary role of otolaryngologists is to evaluate and treat
      peripheral hearing disorders, such as otitis media. Children with APDs may
      present to an otolaryngologist, thus requiring the physician to make appropriate
      referral for assessment and intervention. Currently, diagnosis of APD is based on
      the outcomes of behavioral tests, supplemented by electroacoustic measures and,
      to a lesser extent, by electrophysiologic measures [1]. Intervention for APD
      focuses on improving the quality of the acoustic signal and the listening
      environment, improving auditory skills, and enhancing utilization of
      metacognitive and language resources [2]. Additional controlled case studies and
      single-subject and group research designs are needed to ascertain systematically
      the relative efficacy of various treatment and management approaches.

PMID- 12487079
TI  - Medical evaluation of pediatric hearing loss. Laboratory, radiographic, and
      genetic testing.
AB  - Specific investigations of pediatric hearing loss are based on the history,
      physical examination, and age of the patient. The radiographic investigation of
      choice is high-resolution CT of the temporal bone. Patients with a dilated
      vestibular aqueduct need to be investigated further for Pendred syndrome.
      Screening for mutations in connexin 26 has become increasingly available in many
      centers and should be performed in all cases of nonsyndromic hearing loss. It is
      important to understand the implications and pitfalls of genetic testing. Genetic
      counseling is necessary.

PMID- 12487080
TI  - Evaluation of vestibular function in young children.
AB  - Together, these tests provide a full evaluation of vestibular function in infants
      and small children. If attention is paid to creating the appropriate testing
      environment, and interpretation of the tests takes into account the unique
      properties of the responses of infants and young children, this testing can
      provide a useful adjunct to audiometric evaluation in young children.

PMID- 12487081
TI  - Fitting hearing aids on infants and children: a primer for otolaryngologists.
AB  - Fitting hearing aids on young infants presents a unique set of problems, and to
      some extent, requires a unique set of skills. First, a complete, frequency
      specific evoked potential assessment is needed to define the loss and establish
      hearing aid fitting targets. The selected hearing aids must be flexible and must
      be adjusted to account for the acoustic characteristics of a small ear canal.
      Automatic volume control, wide dynamic range compression, directional
      microphones, and direct audio input are among the optional features to consider.
      In general, advanced technology, such as digital, programmable hearing aids offer
      the greatest flexibility in meeting the instrument-related challenges of the
      infant hearing-aid fitting. Finally, hearing aids are only one component of the
      management sequence. An early interventionist must be involved from the start to
      coordinate rehabilitation and ensure that the needs of the entire family are
      being met in the process.

PMID- 12487082
TI  - The eustachian tube. Update on anatomy, development, and function.
AB  - Central to many pathologic conditions affecting the middle ear is the failure of
      the ET to perform its functions of regulation of middle ear pressure, clearance
      of middle ear secretions, and protection of the middle ear space. Recent advances
      in radiologic imaging and fiberoptic endoscopes have allowed a more detailed
      description of the structure and function of this area. Hopefully, with the
      knowledge gained from advances in this area, more effective medical treatment
      options for common otologic problems, such as otitis media, will become
      available.

PMID- 12487083
TI  - Medical and surgical management of otitis media in children.
AB  - OM, though frequent and seemingly simple to evaluate and manage, remains a
      treatment challenge. Increasingly sophisticated clinical trials assessing OM
      medical treatment efficacy and outcome have demonstrated that many treatment
      regimens that were commonly used a decade ago are no longer recommended. Surgical
      therapy for OM, though remaining the same, has come under intense scrutiny from
      several angles but still plays a central role for this disease. Given the
      multiple facets of OM, its frequency, and its potential to cause short- and long
      term morbidity in children, the next decade is sure to bring further treatment
      innovations.

PMID- 12487084
TI  - Surgical management of chronic otitis media: beyond tympanotomy tubes.
AB  - Chronic ear disease encompasses a wide range of clinical entities amenable to
      medical and surgical intervention. The otolaryngologist must always consider the
      goals of surgery--first and foremost to achieve a safe ear. The least invasive
      procedure capable of eradicating disease is generally chosen. During surgery, a
      delicate balance has to exist between the careful preservation of function and
      the aggressive prevention of potentially recurrent disease. Postoperatively,
      thorough follow-up and good judgment are paramount in avoiding complications and
      preventing unnecessary additional surgical procedures.

PMID- 12487085
TI  - The management of pediatric cholesteatoma.
AB  - Pediatric cholesteatoma can be congenital or acquired. The two types appear to be
      separate and distinct entities based on molecular studies and clinical course.
      Pediatric cholesteatoma behaves differently from cholesteatomas in the adult.
      This may have more to do with anatomic and physiologic differences than with the
      molecular structure of the cholesteatoma. Treatment requires an individualized
      approach taking into account the experience of the operative surgeon and the high
      risk of recidivism of this disease.

PMID- 12487086
TI  - Surgical management of conductive hearing loss in children.
AB  - Patients with congenital conductive hearing loss present a surgical challenge.
      Surgeons must be aware of the potential altered anatomy, in particular the
      potential risks to the facial nerve and inner ear structures; however, meticulous
      attention to detail in the preoperative evaluation and in the operating room can
      minimize these risks. If surgery poses too high a risk to these structures, the
      chances of success are low, or there is a contraindication to surgery,
      traditional air-conduction hearing aids or bone-anchored hearing aids should be
      considered.

PMID- 12487087
TI  - Congenital auricular atresia: update on options for intervention and timing of
      repair.
AB  - Although the surgical correction of congenital atresia is difficult, it has the
      potential to achieve a level of patient and physician satisfaction unparalleled
      in other types of ear surgery.

PMID- 12487088
TI  - Etiology of syndromic and nonsyndromic sensorineural hearing loss.
AB  - The past 10 years have seen an explosive gain in our understanding of molecular
      mechanisms of hearing and deafness. This has already resulted in improved
      diagnosis for the population with hereditary hearing loss. For syndromic hearing
      loss, we will see a shift from the historical terminology to a more precise
      genetic definition based on specific genetic abnormality. Functional studies of
      nonsyndromic deafness genes will elucidate the complex functional and hemostatic
      mechanisms in the inner ear. Ultimately, availability of gene therapy for the
      affected patients will bring to closure the circle of detection, identification,
      and correction of the disease.

PMID- 12487089
TI  - Fluctuating sensorineural hearing loss in children.
AB  - Childhood sensorineural hearing loss (SNHL) that fluctuates or is progressive
      enhances parental concern and complicates medical management, hearing aid
      selection, and individualized educational planning for the affected child.
      Despite intensive multidisciplinary evaluation and intervention, continued
      threshold fluctuation or a gradual decline in auditory acuity may proceed
      unabated in a significant percentage of these youngsters. With the adoption of
      universal newborn hearing screening mandates by an increasing number of states,
      any challenges to the accurate determination of auditory thresholds must be
      addressed within the first few months of life.

PMID- 12487090
TI  - Cochlear implants in young children.
AB  - The past 20 years have seen the cochlear implant evolve from an innovative but
      radical concept to the standard of care in the management of children with severe
      to profound hearing loss. All children receiving the cochlear implant achieve
      substantial benefit; however, performance gains are optimized by a team approach
      to the evaluation and management of these children. The critical elements of this
      team include audiologists, speech pathologists, and surgeons with specific
      interest, expertise, and dedication to the management of children with cochlear
      implants. Children are not well served by practitioners who delegate follow-up to
      educational programs not experienced in children with implants. Long-term
      involvement and dedication on the part of teachers, speech pathologists,
      audiologists, surgeons, and family are critical to maximizing the benefit the
      child receives.

PMID- 12487091
TI  - A correction procedure for the volume conductor effect in the compound action
      potential recorded from isolated nerve trunk.
AB  - The shape and magnitude of the compound action potential (CAP), which is the
      linear summation of the single fiber action potentials, depend strongly on the
      recording conditions. Volume conductor effect should be eliminated or corrected
      in order to get reliable information about the functional state of the nerve
      trunk. In the case of monophasic extracellular recordings, the integral of CAP
      recorded extracellularly tends to decrease with the distance, because the
      extracellular resistance between the stimulating and recording electrodes
      changes. To compensate for this effect, we took into account the spatial
      deviation of the integral of CAP versus distance and defined a spatial correcting
      factor, g(x). By applying g(x) to all CAPs, we get corrected CAP (cCAP) data for
      further evaluations. It is well known that the slope of the maximum derivative of
      CAP versus distance curve would be a measure of conduction velocity distribution
      for the fast conducting nerves in a nerve trunk. The slopes of these curves for
      extracellular and suction techniques on the same nerves are compared; we
      concluded that the difference between the two techniques was not important for
      the correction procedure on extracellular records.

PMID- 12487092
TI  - The effect of pergolide on cognitive performance of young and middle-aged rats.
AB  - In this study, we investigated the effect of pergolide, a dopaminergic agonist,
      on cognitive ability in young and middle-aged rats using the Morris Water Maze
      (MWM). Pergolide 0.5/mg/day i.p. was administered to young and middle-aged rats,
      whereas only vehicle was given to their age-matched controls. During the
      acquisition period of 6 days, young rats showed normal escape latency pattern,
      which was not affected by pergolide. Middle-aged rats, however, showed poor
      escape latency pattern, and this poor pattern was also not affected by pergolide.
      On the 7th day, pergolide decreased retention time of young rats compared to
      control values. Middle-aged rats also showed reduced retention time. In contrast
      to the findings of young rats, retention time was not affected by pergolide in
      middle-aged rats. We concluded that pergolide does not alter escape latency at
      any age. It has a negative effect on retention time of young rats, whereas it has
      no effect on middle-aged ones.

PMID- 12487093
TI  - Blood brain barrier in right- and left-pawed female rats assessed by a new
      staining method.
AB  - The asymmetrical breakdown of the blood-brain barrier (BBB) was studied in female
      rats. Paw preference was assessed by a food reaching test. Adrenaline-induced
      hypertension was used to destroy the BBB, which was evaluated using
      triphenyltetrazolium (TTC) staining of the brain slices just after giving
      adrenaline for 30 s. In normal rats, the whole brain sections exhibited complete
      staining with TTC. After adrenaline infusion for 30 s, there were large unstained
      areas in the left brain in right-pawed animals, and vice versa in left-pawed
      animals. Similar results were obtained in seizure-induced breakdown of BBB. These
      results were explained by an asymmetric cerebral blood flow depending upon the
      paw preference in rats. It was suggested that this new method and the results are
      consistent with contralateral motor control that may be important in determining
      the dominant cerebral hemisphere in animals.

PMID- 12487095
TI  - Approach to the study of neurophysiological mechanism of food motivation.
AB  - The present article estimates depolarization-polarization processes in the nerve
      tissue of afferent systems, including visceral ones, according to the changes of
      the direct current (DC) potential level. Food motivation is formed and satisfied
      concurrently with changes in the neocortex direct current potential level and a
      number of cerebral brain limbic structures in rats. Lateral hypothalamic nucleus,
      basolateral amygdala area, and auditory cortex in hungry rats have a more
      negative DC potential shift than in satisfied animals, while a reverse relation
      is observed in the ventromedial hypothalamic nucleus. The results obtained are
      considered an indication of polarization shifts in the mechanism of motivated and
      emotional behavior. An idea of the determining role of polarization processes in
      the mechanism of motivated and emotional behavior is developed.

PMID- 12487094
TI  - Covariation of spectral and nonlinear EEG measures with alpha biofeedback.
AB  - This study investigated how different spectral and nonlinear EEG measures
      covaried with alpha power during auditory alpha biofeedback training, performed
      by 13 healthy subjects. We found a significant positive correlation of alpha
      power with the largest Lyapunov-exponent, pointing to an increased dynamical
      instability of the EEG accompanying alpha enhancement. Alpha power amplification,
      moreover, was significantly correlated with a decrease of spectral entropy within
      the alpha range. This outcome reflects a sharpening of the alpha peak during
      biofeedback training. The fact that the sharpening effect clearly preceded the
      increase of alpha amplitude could be exploited in future biofeedback settings.

PMID- 12487096
TI  - Derived trail making test indices in a sample of narcotic/other opiate abusers:
      demographic effects.
AB  - Derived indices on the Trail Making Test (TMT), a test often used to screen for
      cognitive impairment, were examined in a sample of 191 narcotic/other opiate
      abusers in drug abuse treatment programs. A mixed race sample was drawn from
      electronic files of data from the Drug Abuse Treatment Outcome Study (DATOS). The
      DATOS was a naturalistic, prospective cohort study that collected data from 1991
      1993 in 96 programs in 11 cities in the United States. Data were analyzed to
      determine the effects of demographic variables on derived indices created by
      adding, subtracting, multiplying, and dividing parts A and B of the TMT in this
      large treatment sample of substance abusers. The variables of age, ethnicity, and
      education were statistically significant for the total score (A + B) and
      interaction score (A x B/100) derived indices of the TMT. In addition, the
      difference score (B - A) was statistically significant for education. The ratio
      score (B/A) was not significant for any demographic variable.

PMID- 12487097
TI  - Perinatal complications as predictors of infantile autism.
AB  - This study investigated the relationship between reported perinatal complications
      and autism. The biological mothers of 183 autistic children and 209 normals
      completed the Maternal Perinatal Scale (MPS), a maternal self-report that surveys
      complications of pregnancies and medical conditions of the mother. Previous
      research in this area has been limited, with no definitive conclusions. A
      discriminant analysis was performed to consider perinatal complications as
      predictors between the autistic and normal subjects. Using the MPS, 65% of the
      autistic cases were correctly grouped. The results further indicated significant
      differences on 3 of the 10 factors of the MPS, in particular, Gestational Age,
      Maternal Morphology, and Intrauterine Stress. When considered in an item by item
      fashion, 5 items were found to significantly predict group membership
      (prescriptions taken during pregnancy, length of labor, viral infection, abnormal
      presentation at delivery, and low birth weight). Finally, 3 maternal medical
      conditions were found to be highly significant and contribute to the separation
      between groups, including urinary infection, high temperatures, and depression.

PMID- 12487098
TI  - Predicting scores of the Halstead Category Test with the WAIS-III.
AB  - The Halstead Category Test (HCT) and the Wechsler Adult Intelligence Scale (WAIS)
      are two of the most widely used neuropsychological tests. Often assessment
      conclusions are dependent upon the comparison of these measures. Therefore, it is
      crucial for clinicians to know how they relate to one another. This study
      examined the relationship between the HCT and the WAIS-III with undergraduate
      psychology students. Correlational analyses were conducted between HCT scores and
      WAIS-III subtests, Verbal and Performance IQ, and Full Scale IQ scores.
      Additionally, the new WAIS-III scales (Letter-Number Sequencing, Matrix
      Reasoning, and Symbol Search) were further examined. Regression analyses were run
      to develop predictor equations for the HCT using VIQ, PIQ, and FSIQ. Finally,
      predictor tables were generated between the HCT and VIQ, PIQ, and FSIQ to provide
      assessment of brain dysfunction for clinical use.

PMID- 12487099
TI  - Generalizability of sensory and motor tests.
AB  - Differences between practitioners in the selection of tests of specific
      pathognomonic sensory and motor signs, administration procedures, and scoring
      criteria have resulted in inconsistencies that have confounded attempts to study
      the incidence and patterns of deficits. Tests of sensory-motor functioning have
      been standardized in the Dean-Woodcock Sensory-Motor Battery (D-WSMB; Dean and
      Woodcock, in preparation). This study used the D-WSMB to: (a) estimate the point
      prevalence of pathognomonic signs in a normal adult; (b) identify items with
      difficulty levels likely to result in overidentification of abnormality; (c)
      estimate the interrater agreement and reliability for items; and (d) identify
      tests most vulnerable to subjective interpretation. Results suggested adequate to
      excellent rater agreement and reliability. Specific minor modifications are
      recommended to improve the reliability of these tests.

PMID- 12487100
TI  - [Nutrition, bone disease and alcoholic cirrhosis].
AB  - OBJECTIVES: To know the prevalence of osteopenia and osteoporosis in alcoholic
      cirrhotic males from 45 to 65 years old. To prove if the nutritional state is
      involved in the loss of bone mass in the hepatic disease. MATERIAL AND METHODS: 
      STUDY POPULATION: 52 alcoholic cirrhotic males from 45 to 65 years old, with
      normal kidney function, non-sedentary and with no treatment that could alterate
      the study. Design and variables: transversal descriptive study finished in 2
      years. The nutritional state was evaluated by means of classic anthropometric
      parameters (weight, height, perimeter of the arm and skin folds) and total body
      densitometry (DPX plus LUNAR-DEXA with dual energy X-ray absorptiometry.
      STATISTICAL ANALYSIS: Mc Intosh computer (Filemaker PRO program). T Student was
      used to compare groups and p was significant if alpha alpha < or = 0.05. Clinical
      severity of cirrhosis: Child-Turcotte classification. RESULTS: Osteopenia was
      diagnosed if bone mineral density (BMD) was higher than 1 standard deviation (SD)
      but lower than 3 SD below T score (mean values for adult women) and osteoporosis
      (OP) if BMD was higher than 3 SD or vertebral compression fractures appeared in
      simple radiographies. The prevalence of bone disease was 58%. The percentages of
      fat obtained by means of anthropometric and densitometric measures were higher in
      non-osteopenic patients. DISCUSSION: The prevalence of bone disease was higher
      than another studies. The total body densitometry is a more exact method to
      measure the percentage of body fat. The percentages of fat obtained with both
      methods were not related to the loss of bone mass. The nutritional state as an
      isolated factor does not lead to bone disease in these patients.

PMID- 12487101
TI  - [Editorial: atypical neuroleptics].

PMID- 12487102
TI  - [Airway fire, a serious complication during laryngeal laser surgery].

PMID- 12487103
TI  - Higher-level relationships of snakes inferred from four nuclear and mitochondrial
      genes.
AB  - Higher-level snake relationships are inferred from sequence analyses of one
      nuclear gene (C-mos) and three mitochondrial genes (12S rRNA, 16S rRNA and
      cytochrome b). Extant snakes belong to two lineages: the fossorial Scolecophidia,
      which feed on small prey on a frequent basis, and the ecologically diverse
      Alethinophidia ('typical' snakes), which feed on large prey on an infrequent
      basis. The vast majority of Alethinophidia, if not all of them, belong to two
      clades, corresponding to two distinct prey neutralization modes: unimodal
      constriction for the Henophidia (locomotor and feeding systems coupled) and
      injection of toxic saliva, in addition (or not) to diverse alternate modes of
      constriction, for the Caenophidia (locomotor and feeding systems uncoupled).
      Within Alethinophidia, non-macrostomatan (small gape) Aniliidae (genus Anilius)
      and macrostomatan (large gape) Tropidophiidae (genera Trachyboa and Tropidophis),
      both from the Neotropics, are closest relatives. Although our data are
      insufficient to robustly infer the ancestral mode of life of snakes, we find
      evidence of plasticity in the basic ecological and trophic modes of snakes.
      Consequently, the macrostomatan condition should not be treated a priori as a
      derived character state devoid of homoplasy.

PMID- 12487104
TI  - Model studies of cyclophosphamide resistance in human myeloid leukemia.

PMID- 12487105
TI  - [Hantaviruses--"exotic" viruses in Germany].

PMID- 12487106
TI  - Questions over GA.

PMID- 12487107
TI  - Disability discrimination.

PMID- 12487108
TI  - Blood pressure monitoring.

PMID- 12487109
TI  - Rubber dam.

PMID- 12487110
TI  - Rubber dam.

PMID- 12487111
TI  - The student and junior doctor in distress - "our duty of care". Proceedings of a
      Conference of the Confederation of Postgraduate Medical Education Councils. July
      19-20, 2001.

PMID- 12487112
TI  - Slick footwork by the UK government restores the legality of therapeutic cloning.

PMID- 12487113
TI  - Designer babies are acceptable to the UK HFEA.

PMID- 12487114
TI  - Pre-ovulatory events in the rhesus monkey follicle during ovulation induction.
AB  - Pituitary gonadotrophins, notably LH, and ovarian steroids, such as progesterone,
      play essential roles in the events leading to ovulation of the mature follicle
      and development of the subsequent corpus luteum. Rhesus monkeys (Macaca mulatta)
      undergoing controlled ovarian stimulation cycles comparable to those in clinical
      IVF/assisted reproduction treatment protocols provide a non-human primate model
      for studying peri-ovulatory events. The ability to manipulate the intrafollicular
      steroid milieu, via oral administration of a steroid synthesis inhibitor, with or
      without steroid replacement, allows one to distinguish between gonadotrophin
      initiated, steroid-dependent versus steroid-independent processes. The length of
      the peri-ovulatory interval (onset of the LH surge to follicle rupture) is long
      (36-40 h) in primates and can be considered in terms of early (< or = 12 h)
      versus later (> or = 24 h) events. Granulosa cells lose their proliferative
      activity and differentiate into progesterone-secreting cells during the early
      peri-ovulatory interval. The rapid increase in progesterone synthetic capacity
      and expression of progesterone receptors suggests that this steroid has early
      actions, e.g. in controlling cell cycle machinery or differentiation. However, it
      is not until later that morphological luteinization is evident. By this stage,
      progesterone may serve as a potent anti-apoptotic factor and regulator of tissue
      remodelling through control of protease expression and activity, angiogenesis, or
      other events. Application of modern techniques to study LH- and progesterone
      responsive gene expression will further unravel ovulatory and luteinization
      processes in specific compartments of the primate follicle.

PMID- 12487115
TI  - Getting ahead in the field.

PMID- 12487116
TI  - A short-term sink for atmospheric CO2 in subtropical mode water of the North
      Atlantic Ocean.
AB  - Large-scale features of ocean circulation, such as deep water formation in the
      northern North Atlantic Ocean, are known to regulate the long-term physical
      uptake of CO2 from the atmosphere by moving CO2-laden surface waters into the
      deep ocean. But the importance of CO2 uptake into water masses that ventilate
      shallower ocean depths, such as subtropical mode waters of the subtropical gyres,
      are poorly quantified. Here we report that, between 1988 and 2001, dissolved CO2
      concentrations in subtropical mode waters of the North Atlantic have increased at
      a rate twice that expected from these waters keeping in equilibrium with
      increasing atmospheric CO2. This accounts for an extra 0.4-2.8 Pg C (1 Pg =
      10(15) g) over this period (that is, about 0.03-0.24 Pg C yr(-1)), equivalent to
      3-10% of the current net annual ocean uptake of CO2 (ref. 3). We suggest that the
      lack of strong winter mixing events, to greater than 300 m in depth, in recent
      decades is responsible for this accumulation, which would otherwise disturb the
      mode water layer and liberate accumulated CO2 back to the atmosphere. However,
      future climate variability (which influences subtropical mode water formation)
      and changes in the North Atlantic Oscillation (leading to a return of deep winter
      mixing events) may reduce CO2 accumulation in subtropical mode waters. We
      therefore conclude that, although CO2 uptake by subtropical mode waters in the
      North Atlantic--and possibly elsewhere--does not always represent a long-term CO2
      sink, the phenomenon is likely to contribute substantially to interannual
      variability in oceanic CO2 uptake.

PMID- 12487117
TI  - Save our skin.

PMID- 12487118
TI  - [Are the women physicians responsible for postulated decline of the university
      teachers' new generation?].

PMID- 12487119
TI  - John P. Peters and Nephrology.

PMID- 12487120
TI  - Learning more about eosinophilic esophagitis.

PMID- 12487121
TI  - Zebrafish melanopsin: isolation, tissue localisation and phylogenetic position.
AB  - Photoreception is best understood in retinal rods and cones, but it is not
      confined to these cells. In non-mammals, intrinsically photosensitive cells have
      been identified within several structures including the pineal, hypothalamus and
      skin. More recently novel light sensitive cells have been identified in the
      inner/basal retina of both teleosts and rodents. Melanopsin has been proposed as
      the photopigment mediating many of these non-rod, non-cone responses to light.
      However, much about the melanopsin gene family remains to be clarified including
      their potential role as photopigments, and taxonomic distribution. We have
      isolated the first orthologue of melanopsin from a teleost fish and show
      expression of this gene in a sub-set of retinal horizontal cells (type B).
      Zebrafish melanopsin, and orthologues of this gene, differ markedly from the
      vertebrate photopigment opsins. The putative counterion is not a glutamate but a
      tyrosine, the putative G-protein binding domain in the third cytoplasmic loop is
      not conserved, and they show low levels of amino acid identity (approximately
      27%) to both the known photopigment opsins and to other members of the melanopsin
      family. Mouse melanopsin is only 58% identical to Xenopus, and 68% identical to
      zebrafish. By contrast, the photosensory opsin families show approximately 75%
      conservation. On the basis of their structure, genomic organisation, discrete
      evolutionary lineage, and their co-expression with other opsins, the melanopins
      are not obvious photosensory opsins. They might represent a separate branch of
      photopigment evolution in the vertebrates or they may have a non-direct
      photosensory function, perhaps as a photoisomerase, in non-rod, non-cone light
      detection.

PMID- 12487123
TI  - Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS:
      therapeutic implications for Canavan disease.
AB  - Canavan disease is a devastating neurodegenerative childhood disease caused by
      mutations in aspartoacylase, an enzyme that deacetylates N-acetylaspartate to
      generate free acetate in the brain. Localization of aspartoacylase in different
      cell types in the rat brain was examined in an attempt to understand the
      pathogenesis of Canavan disease. In situ hybridization histochemistry with a
      riboprobe based on murine aspartoacylase cDNA was used in this study. The
      hybridization signal was detectable primarily in the myelin-synthesizing cells,
      namely oligodendroglia. These findings provide strong additional support for
      insufficient myelin synthesis as the pathogenic basis of Canavan disease and make
      a compelling case for acetate supplementation as a simple and noninvasive therapy
      for this fatal disease with no treatment.

PMID- 12487122
TI  - Summary of the scientific literature for pain and anxiety control in dentistry.

PMID- 12487125
TI  - Critical role for GALR1 galanin receptor in galanin regulation of neuroendocrine
      function and seizure activity.
AB  - The GALR1 galanin receptor is expressed at high levels within the central nervous
      system. To determine which specific actions of galanin are mediated by GALR1, we
      have developed mice with an insertional inactivating mutation within the gene
      encoding GALR1 (Galr1). Homozygous Galr1-/- mice are viable and capable of
      breeding. They exhibit no significant difference in growth rate relative to
      Galr1+/+ controls but have reduced circulating levels of insulin-like growth
      factor-I (IGF-I) and exhibit spontaneous tonic-clonic seizures. The phenotype of
      these mice identifies a critical role for GALR1 in neuroendocrine regulation and
      in mediating the anti-seizure activity of galanin.

PMID- 12487124
TI  - Summary of the scientific literature for pain and anxiety control in dentistry.

PMID- 12487127
TI  - Summary of the 1982 scientific literature for pain and anxiety control in
      dentistry.

PMID- 12487128
TI  - Hepatitis A: a preventable threat.

PMID- 12487129
TI  - Clinical quiz. Esophageal stricture caused by reflux esophagitis.

PMID- 12487130
TI  - A coupled dummy head rotation using four different methods.

PMID- 12487131
TI  - Effect of conformational preorganization of a three-armed host on anion binding
      and selectivity.
AB  - A set of three-armed urea-containing anion receptors was prepared. The receptors
      all have the same binding topology but differ in the level of conformational
      preorganization with respect to the arrangement of the side-arms relative to the
      platform and within the side arms themselves. This is mirrored in a specific
      increase (x 2.5) in the binding constant for chloride and in a 12-fold increase
      in the chloride/nitrate-selectivity.

PMID- 12487132
TI  - Helical (isotactic) and syndiotactic silver(I) metallo-supramolecular
      coordination polymers assembled from a readily prepared bis-pyridylimine ligand
      containing a 1,5-naphthalene spacer.
AB  - A ligand in which two pyridylimine binding units are linked by a 1,5-naphthalene
      spacer is prepared and its silver(I) coordination chemistry investigated. In the
      solid state, a pair of C-H triplebond N interactions between pyridylimine units
      link the free ligands into chain structures, with further C-H triplebond N and
      some -stacking interactions linking these chains into a three-dimensional
      structure. The spacer constrains the ligand to dinucleate, and with silver(I) the
      metal coordinates to two pyridylimine units from two separate ligands and this
      leads to the formation of coordination polymers with a range of different anions.
      Different twisting motifs within the ligand control the tacticity of these
      coordination polymers and both isotactic, helical polymers and syndiotactic
      (achiral) polymers result. The core of the isotactic polymer strands contains two
      metallo-vectors and results in long-range ordering of the metal centres into a 2
      x n grid arrangement. The solution behaviour indicates that exchange between the
      diastereomeric forms occurs. Since this must involve inversion at the metal
      centres, atactic species may also form a component of the solution library.

PMID- 12487133
TI  - Light-emitting molecular machines: pH-induced intramolecular motions in a
      fluorescent nickel(II) scorpionate complex.
AB  - A cyclam-like macrocycle has been synthesized with a pendant arm containing a
      dansylamide group. In the corresponding nickel(II) complex, binding of the
      pendant arm to the metal is pH controlled. In particular, at pH 4.3, the
      sulfonamide group deprotonates and coordinates the NiII center, giving rise to a
      complex of trigonal bipyramidal stereochemistry, as shown by X-ray diffraction
      studies performed on the crystalline complex salt. At pH 7.5, an OH- ion binds
      the metal and a six-coordinate species forms. The binding-detachment of the
      pendant arm to/from the NiII center is signaled by changes in the emission
      properties of the dansyl subunit in the side chain; the fluorescence of this side
      chain is high when the pendant arm is not coordinated and low when the
      sulfonamide group is bound to the metal. The system investigated represents the
      prototype of a light-emitting molecular machine, driven by a pH change.

PMID- 12487134
TI  - Strategies to stabilize new members of the (A3A'BO6)alpha (A3B3O0)beta homologous
      series in the Sr-Rh-O system: structure of the one-dimensional (alpha = 3, beta =
      2) [Sr10(Sr0.5Rh1.5)TP(Rh6)Oh])24 oxide.
AB  - The (alpha =3, beta =2) member of the (A3ABO6) (A3B3O9) homologous series has
      been stabilised in the Sr-Rh-O system for a [Sr10(Sr0.5Rh1.5)TP(Rh6)Oh]O24
      composition. The structural characterisation has been performed by powder X-ray
      and electron diffraction measurements and high-resolution electron microscopy. In
      this structure, three face-sharing [RhO6] octahedra linked by one [Rh/SrO6]
      trigonal prism comprise the infinite one-dimensional chain that runs parallel to
      the c axis of a trigonal unit cell (Pc1), with parameters a=9.6411(1) and
      c=21.2440(4) A.

PMID- 12487136
TI  - Society for Oral Physiology Store Kro Group. Twenty-Second Biennial Meeting.
      Lugano, Switzerland, 7-10 June 2001. Abstracts of Selected Presentations.

PMID- 12487135
TI  - Structural effects on the formation of proton and alkali metal ion adducts of
      apolar, neutral peptides: electrospray ionization mass spectrometry and Ab initio
      theoretical studies.
AB  - Apolar, neutral peptides have been shown to ionize extremely well under the
      conditions used for electrospray ionization mass spectrometry (ESIMS). Peptides
      for which the conformations have been independently determined in solution and in
      crystals have been examined by ESIMS. Studies of peptide helices ranging from 7
      to 18 residues reveal that shorter helices yield exclusively singly charged ions,
      while in larger helices multiply charged species are detectable. Multiple sites
      for protonation/metallation are introduced in the helix by proline insertion or
      by changing the chirality in the residue. The preferred site of cation binding to
      helices may be the C-terminus end, where three free CO groups are available for
      chelation. Ab initio and DFT calculations at several levels have been carried out
      for the binding of H+, Li+, Na+, and K+ to CHO-(Gly)3)-OMe. The results reveal
      that metallation in helices is favoured by chelation to carbonyl groups at the C
      terminus, while protonation involved two carbonyl groups and thus favour a 10
      membered cyclic hydrogen-bonded structure. In -strands, metallation/protonation
      occurs at isolated carbonyl groups. Collision induced fragmentation of
      hydrophobic peptides under ESI conditions reveals that helix fragmentation occurs
      predominantly from the C-terminus, while in -hairpins cleavage occurs
      simultaneously at multiple sites.

PMID- 12487137
TI  - Environmental, policy, and cultural factors related to physical activity in a
      diverse sample of women: the Women's Cardiovascular Health Network Project-
      introduction and methodology.
AB  - Ethnic minority and low-income populations have some of the highest rates of
      cardiovascular disease (CVD) and the highest rates of physical inactivity, an
      independent risk factor for CVD. Ethnic minority and low-income women are
      especially at risk. Because programs designed to increase physical activity have
      the potential to reduce CVD rates in specific populations, research in this area
      is expanding. As part of the Women's Cardiovascular Health Network funded by the
      Centers for Disease Control and Prevention, the goal of this multi-site project
      is to identify factors, particularly environmental, policy, and cultural factors,
      that may influence physical activity among ethnic minority and low-income women
      ages 20-50 years. To achieve this goal, 42 focus groups were conducted in various
      locations throughout the United States with African American, American Indian,
      Latina and White women. Groups represented both urban and rural living
      environments. This article explains the basis for this project and the
      methodology used. Other articles in this series explain the results from the
      focus groups in detail.

PMID- 12487126
TI  - Summary of the scientific literature for pain and anxiety control in dentistry
      journal literature, January 1986-December 1987.
AB  - This bibliography contains both foreign (in brackets) and English language
      citations obtained from Index to Dental Literature, Index Medicus, and
      Psychological Abstracts for the period January 1986 to December 1987. Although a
      careful search of these indexes was performed, every relevant citation may not be
      included. Comments or suggestions regarding this bibliography are welcomed by the
      author.

PMID- 12487138
TI  - Environmental, policy, and cultural factors related to physical activity in
      urban, African American women.
AB  - This study was part of a multi-site project carried out with seven universities
      throughout the United States to identify cultural, environmental, and policy
      determinants of physical activity in ethnic minority women aged 20 to 50 years.
      Following an extensive literature review, nine core research questions were
      created to examine potential barriers to physical activity as well as enabling
      factors. Methods and findings presented are from six focus groups of low-income,
      urban African American women. These focus groups were held at each of two health
      centers serving communities in Chicago, Illinois, that are predominantly African
      American and low income and have households usually headed by women. Forty-eight
      women participated, with 5 to 11 in each group. Most (85%) were unmarried, 40%
      had less than a high school education, and 33% were neither employed nor
      attending school. Findings reflected the influence of a culture of poverty and
      the importance of environmental safety and community support. The findings will
      be used to inform the development of community-based exercise interventions and
      policies that are culturally and socially sensitive to the needs of low-income,
      urban African American women.

PMID- 12487139
TI  - Environmental, policy, and cultural factors related to physical activity in well
      educated urban African American women.
AB  - The purpose of this qualitative study was to identify environmental, policy, and
      cultural predictors of physical activity in urban African American women living
      in Baltimore, MD. Thirty-nine mostly well-educated women participated in eight
      focus group discussions, five for women aged 36 to 50 years and three for women
      20 to 35 years of age. Transcripts were analyzed using QSR NUD*IST qualitative
      software, and themes were identified. The discussions identified numerous
      opportunities and barriers for physical activity. The women reported being aware
      of physical activity resources and facilities available to them, but they lacked
      time and motivation to participate. Family responsibilities and duties unique to
      African American women were cited often. The results suggest that providing more
      environmental facilities may not be sufficient to increase physical activity in
      well-educated urban African American women. Intervention strategies that place
      value on family and cultural responsibilities should be considered.

PMID- 12487140
TI  - Environmental, policy, and cultural factors related to physical activity among
      Latina immigrants.
AB  - According to national surveillance studies, participation in leisure-time
      physical activity remains low among minority women. Furthermore, the correlates
      of such activity in this group are not well understood. To better understand the
      environmental, policy, and sociocultural correlates of physical activity among
      Latina immigrants, six focus groups were conducted in rural North Carolina. Among
      the 49 participants, median age was 32 years and median education 11 years.
      Participants were first generation immigrants from Mexico (n = 43), El Salvador
      (n = 3), Colombia (n = 1), the Dominican Republic (n = 1), and Honduras (n = 1).
      Environmental and policy barriers to activity were identified, including
      transportation, lack of facilities, cost, and safety. Sociocultural correlates of
      activity included gender roles for activity, importance of support from the
      family and husband, child care issues tied to having few relatives who lived
      close by, language, and isolation in the community. The women suggested changes
      and programs that could promote physical activity through multiple channels,
      especially involving the family. This information can be used to develop
      culturally appropriate interventions to increase physical activity among Latinas.

PMID- 12487141
TI  - Environmental, policy, and cultural factors related to physical activity in
      sedentary American Indian women.
AB  - Focus group interviews were conducted to explore sociocultural, environmental,
      and policy-related determinants of physical activity among sedentary American
      Indian women. Thirty women aged 20 to 50 years (mean = 37.4 +/- 10.6 years)
      participated. Three sessions were conducted with women aged 20 to 34 years and
      three with women aged 35 to 50 to evaluate response differences by age. Because
      no obvious age differences were observed, data were pooled. Barriers to physical
      activity included inadequate support for household and child care
      responsibilities and difficulties balancing home-related and societal
      expectations with physical activity. In addition, women reported little support
      from their communities and work sites to be physically active. Environmental
      barriers included lack of safe outdoor areas and accessible walking trails.
      Weather and stray dogs were also commonly mentioned. Sociocultural barriers
      included giving family obligations priority above all other things, being
      expected to eat large portions of high-fat foods, and failing to follow a
      traditionally active lifestyle. Enablers of physical activity included support
      from family and coworkers and participation in traditional community events.
      Suggested intervention approaches included accessible and affordable programs and
      facilities, community emphasis on physical activity, and programs that
      incorporated the needs of larger women and of families. Participants emphasized a
      preference for programs that were compatible with the role expectations of their
      families and communities, and they expressed the desire for acceptance and
      encouragement to be physically active from the family, the community, the
      worksite, and their tribal leaders.

PMID- 12487142
TI  - Environmental, policy, and cultural factors related to physical activity among
      rural, African American women.
AB  - Sixty-one African American women (ages 20-50 years) from a rural community in
      Alabama participated in six focus groups. Barriers to and enablers of physical
      activity were identified and grouped into personal, environmental (social and
      physical), policy, and cultural themes for qualitative analyses. Personal factors
      included motivation, perceived health, feeling tired, and lack of time; social
      environmental factors included support from friends, family, and issues related
      to child care; physical environmental factors included weather, access to
      facilities, availability of sidewalks or other places to walk; policy factors
      included personal safety concerns (loose dogs, traffic, etc.) and inflexible work
      environments. Some, but not all, women perceived cultural differences as a factor
      affecting physical activity levels. Differences in socioeconomic levels and time
      demands among women of different cultures were identified as factors that may
      influence physical activity. Participants provided suggestions for community
      based physical activity interventions using an environmental approach.

PMID- 12487143
TI  - Environmental, policy, and cultural factors related to physical activity in
      African American women.
AB  - Six focus groups were conducted in South Carolina with African American women (n
      = 42) aged 19-51 years to identify factors that influence physical activity.
      Transcripts were analyzed using NUD*IST. Cultural influences were seen as more
      important in determining the type of physical activity than its level. Barriers
      to and enablers of physical activity were identified in the social and physical
      environments, as were policy issues affecting physical activity in the community
      and at the work site. Potential community and work site interventions were
      suggested. Child care and monetary costs were frequently cited as barriers to
      physical activity.

PMID- 12487144
TI  - Environmental and policy factors related to physical activity in rural white
      women.
AB  - Physical activity is an important aspect of health promotion and disease
      prevention. However, women often have lower rates of physical activity than men.
      The purpose of this study was to identify environmental and policy determinants
      to physical activity among rural white women. Six focus groups were conducted
      with women aged 20-50 years who were not currently regular exercisers. Women
      reported that the social environment had a strong impact on physical activity
      level. Factors of the social environment included guilt, family responsibility,
      and social support. Environmental and policy barriers such as lack of access to
      places to exercise and safety concerns were also discussed. Intervention
      suggestions included family exercise and work-site programs. Information gained
      from this study can be used to fuel further research and inform future physical
      activity interventions.

PMID- 12487146
TI  - In vitro studies in drug discovery and development: an analysis of study
      objectives and application of good laboratory practices (GLP).
AB  - In vitro drug metabolism studies play a dual role along the path from drug
      discovery to preclinical development. By analyzing the objectives of each type of
      study the question of whether to apply good laboratory practices (GLP)
      requirements is clarified. This review outlines the various in vitro techniques
      available and categorizes the goals for which they are applied as either
      supporting drug discovery or influencing decisions of clinical safety. Based on
      this categorization it is proposed that studies performed to explore the utility
      of a potential drug candidate be conducted non-GLP, while studies used to support
      IND and post-IND submissions be considered for GLP.

PMID- 12487145
TI  - Environmental, policy, and cultural factors related to physical activity in a
      diverse sample of women: The Women's Cardiovascular Health Network Project-
      summary and discussion.
AB  - Ethnic minority and low-income populations have the highest rates of
      cardiovascular disease and the lowest rates of leisure-time physical activity.
      Because physical activity reduces the risk of premature death and disability from
      cardiovascular disease, researching correlates to such activity in these
      populations is an important aspect of health promotion in the US. To identify
      environmental, policy, and cultural barriers to physical activity in women, The
      Women's Cardiovascular Health Network Project conducted focus groups with White,
      African American, Latina, and American Indian women aged 20-50 years. The focus
      groups were audiotaped, transcribed, and analyzed with QSR NUD*IST qualitative
      software using a set of codes developed a priori by the research team. Family
      priorities were a main barrier to physical activity in all the groups. Having
      multiple roles as wife, mother, daughter, and as an active community member was
      mentioned as time-consuming and difficult, leaving little time or energy for
      exercise. Cultural barriers, which varied among the groups, included
      acculturation issues, lack of community support, and lack of past experience with
      exercise. Physical activity interventions suggested involved work programs,
      family-friendly programs, increased social support, and the availability of safer
      places to exercise such as parks, well-lit walking trails, and recreation
      centers. Many of the barriers were common to all groups (e.g., family priority)
      while some were unique (e.g., lack of community support). Assessing and
      addressing the issues raised should be considered when planning physical activity
      interventions for these populations.

PMID- 12487147
TI  - Mechanistic enzymology of oxygen activation by the cytochromes P450.
AB  - The P450 cytochromes represent a universal class of heme-monooxygenases. The
      detailed mechanistic understanding of their oxidative prowess is a critical theme
      in the studies of metabolism of a wide range of organic compounds including
      xenobiotics. Integral to the O2 bond cleavage mechanism by P450 is the enzyme's
      concerted use of protein and solvent-mediated proton transfer events to transform
      reduced dioxygen to a species capable of oxidative chemistry. To this end, a wide
      range of kinetic, structural, and mutagenesis data has been accrued. A critical
      role of conserved acid-alcohol residues in the P450 distal pocket, as well as
      stabilized waters, enables the enzyme to catalyze effective monooxygenation
      chemistry. In this review, we discuss the detailed mechanism of P450 dioxygen
      scission utilizing the CYP101 hydroxylation of camphor as a model system. The
      application of low-temperature radiolytic techniques has enabled a structural and
      spectroscopic analysis of the nature of critical intermediate states in the
      reaction.

PMID- 12487148
TI  - Structural biology and function of solute transporters: implications for
      identifying and designing substrates.
AB  - Solute carrier (SLC) proteins have critical physiological roles in nutrient
      transport and may be utilized as a mechanism to increase drug absorption.
      However, we have little understanding of these proteins at the molecular level
      due to the absence of high-resolution crystal structures. Numerous efforts have
      been made in characterizing the peptide transporter (PepT1) and the apical sodium
      dependent bile acid transporter (ASBT) that are important for both their native
      transporter function as well as targets to increase absorption and act as
      therapeutic targets. In vitro and computational approaches have been applied to
      gain some insight into these transporters with some success. This represents an
      opportunity for optimizing molecules as substrates for the solute transporters
      and providing a further screening system for drug discovery. Clearly the future
      growth in knowledge of SLC function will be led by integrated in vitro and in
      silico approaches.

PMID- 12487149
TI  - Predicting pharmacokinetics and drug interactions in patients from in vitro and
      in vivo models: the experience with 5,6-dimethylxanthenone-4-acetic acid (DMXAA),
      an anti-cancer drug eliminated mainly by conjugation.
AB  - The novel anti-tumor agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was
      developed in the Auckland Cancer Society Research Center. Its pharmacokinetic
      properties have been investigated using both in vitro and in vivo models, and the
      resulting data extrapolated to patients. The metabolism of DMXAA has been
      extensively studied mainly using hepatic microsomes, which indicated that UGT1A9
      and UGT2B7-catalyzed glucuronidation on its acetic acid side chain and to a
      lesser extent CYP1A2-catalyzed hydroxylation of the 6-methyl group are the major
      metabolic pathways, resulting in DMXAA acyl glucuronide (DMXAA-G) and 6
      hydroxymethyl-5-methylxanthenone-4-acetic acid. The predominant metabolite in
      human urine (up to 60% of total dose) was identified as DMXAA-G, which was
      chemically reactive, undergoing hydrolysis, intramolecular rearrangement, and
      covalent binding to plasma proteins. In vivo formation of DMXAA-protein adducts
      were also observed in cancer patients receiving DMXAA treatment. The comparison
      of the in vitro human hepatic microsomal metabolism and inhibition of DMXA by UGT
      and/or CYP substrates with animal species indicated species differences. Renal
      microsomes from all animal species examined had glucuronidation activity for
      DMXAA, but lower than the liver. In vitro-in vivo extrapolations based on human
      microsomal data indicated a 7-fold underestimation of plasma clearance in
      patients. In contrast, allometric scaling using in vivo data from the mouse, rat,
      and rabbit predicted a plasma clearance of 3.5 mL/min/kg, similar to that
      observed in patients (3.7 mL/min/kg). Based on in vitro metabolic inhibition
      studies, it appears possible to predict the effects on the plasma kinetic profile
      of DMXAA of drugs such as diclofenac, which are mainly metabolized by UGT2B7.
      However, it did not appear possible to predict the effect of thalidomide on the
      pharmacokinetics of DMXAA in patients based on in vitro inhibition and animal
      studies. These data indicate that preclincial pharmacokinetic studies using both
      in vitro and in vivo models play an important but different role in predicting
      pharmacokinetics and drug interactions in patients.

PMID- 12487151
TI  - Glutathione conjugates and their synthetic derivatives as inhibitors of
      glutathione-dependent enzymes involved in cancer and drug resistance.
AB  - Alterations in levels of glutathione (GSH) and glutathione-dependent enzymes have
      been implicated in cancer and multidrug resistance of tumor cells. The activity
      of a number of these, the multidrug resistance-associated protein 1, glutathione
      S-transferase, DNA-dependent protein kinase, glyoxalase I, and gamma-glutamyl
      transpeptidase, can be inhibited by GSH-conjugates and synthetic analogs thereof.
      In this review we focus on the function of these enzymes and carriers in cancer
      and anti-cancer drug resistance, in relation to their inhibition by GSH-conjugate
      analogs.

PMID- 12487150
TI  - Naphthalene-induced respiratory tract toxicity: metabolic mechanisms of toxicity.
AB  - The lung, which is in intimate contact with the external environment, is exposed
      to a number of toxicants both by virtue of its large surface area and because it
      receives 100% of the cardiac output. Lung diseases are a major disease entity in
      the U.S. population ranking third in terms of morbidity and mortality. Despite
      the importance of these diseases, key issues remain to be resolved regarding the
      interactions of chemicals with lung tissue and the factors that are critical
      determinants of chemical-induced lung injury. The importance of cytochrome P450
      monooxygenase dependent metabolism in chemical-induced lung injury in animal
      models was established over 25 years ago with the furan, 4-ipomeanol. Since then,
      the significance of biotransformation and the reasons for the high degree of
      pulmonary selectivity for a myriad of different chemicals has been well
      documented, mainly in rodent models. However, with many of these chemicals there
      are substantial differences in the susceptibility of rats vs. mice. Even within
      the same species, varied levels of the respiratory tract respond differently.
      Thus, key pieces of data are still missing when evaluating the applicability of
      data generated in rodents to primates, and as a result of this, there are
      substantial uncertainties within the regulatory community with regards to
      assessing the risks to humans for exposure to some of these chemicals. For
      example, all of the available data suggest that the levels of cytochrome P450
      monooxygenases in rodent lungs are 10-100 times greater than those measured in
      the lungs of nonhuman primates or in man. At first glance, this suggests that a
      significant margin of safety exists when evaluating the applicability of rodent
      studies in the human, but the issues are more complex. The intent of this review
      is to outline some of the work conducted on the site and species selective
      toxicity and metabolism of the volatile lung toxic aromatic hydrocarbon,
      naphthalene. We argue that a complete understanding of the cellular and
      biochemical mechanisms by which this and other lung toxic compounds generate
      their effects in rodent models with subsequent measurement of these cellular and
      biochemical events in primate and human tissues in vitro will provide a far
      better basis for judging whether the results of studies done in rodent models are
      applicable to humans.

PMID- 12487152
TI  - Interindividual differences in nicotine metabolism and genetic polymorphisms of
      human CYP2A6.
AB  - Nicotine is widely consumed throughout the world, and exerts a number of
      physiological effects. After nicotine is absorbed through the lungs by cigarette
      smoking, it undergoes extensive metabolism in humans. Nicotine is mainly
      metabolized to cotinine by cytochrome P450 (CYP) 2A6. CYP2A6 can metabolize some
      pharmaceutical agents such as halothane, valproic acid, and fadrozole, and
      activate tobacco-specific nitrosamines. There are large interindividual
      differences in nicotine metabolism, and it has been found that the
      interindividual differences are attributed to the genetic polymorphisms of CYP2A6
      gene. This review describes the techniques for determination of in vivo nicotine
      metabolism, characteristics of each human CYP2A6 alleles, and ethnic differences.
      The relationship between CYP2A6 genetic polymorphism and potency of nicotine
      metabolism, smoking behavior, and cancer risk are extensively reviewed. Finally,
      the usefulness of nicotine metabolism for phenotyping of CYP2A6 in individuals
      and implication of the significance of CYP2A6 genetic polymorphism in a clinical
      perspective are discussed.

PMID- 12487153
TI  - Systemic capillary leak syndrome.

PMID- 12487154
TI  - Is it rare to have two adrenal diseases combined?

PMID- 12487155
TI  - Possible involvement of hypersecretion of progesterone from an adrenal adenoma
      without androgen excess in primary amenorrhea.

PMID- 12487156
TI  - New therapeutic approaches for patients with Fabry disease.

PMID- 12487157
TI  - Diagnosis of nocardial infection by microscopic analysis of infected specimens.

PMID- 12487158
TI  - Acute eosinophilic pneumonia: possible role of hyperreactivity of airway
      epithelial cells.

PMID- 12487159
TI  - Primary HIV infection.

PMID- 12487160
TI  - Clinical implication of persistent ischemic chest pain on admission in patients
      with late reperfused acute myocardial infarction.
AB  - OBJECT: Although previous studies reported that late reperfusion might prevent
      left ventricular dilation after acute myocardial infarction (AMI), implication of
      persistent ischemic chest pain on admission remains to be investigated. This
      study was undertaken to assess the implication of persistent ischemic chest pain
      on in-hospital outcome and left ventricular function after late reperfused AMI.
      METHODS AND PATIENTS: We studied 63 patients with a first anterior AMI who
      underwent percutaneous coronary intervention 6 to 24 hours (11.2+/-4.5 hours)
      after the onset. Of 63 patients, 48 (76%) had persistent ischemic chest pain on
      admission. RESULTS: Incidence of in-hospital death, reinfarction or congestive
      heart failure was similar between the 2 groups. Pretreatment left ventricular
      ejection fraction and end-diastolic volume were similar between the 2 groups.
      Predischarge angiography was performed at 17+/-5 days after the onset. Late
      reperfusion prevented the dilation of left ventricular end-diastolic volume in
      patients with chest pain (78+/-12 to 75+/-17 ml/m2, p=0.15), but did not in those
      without (75+/-20 to 93+/-28 ml/m2, p=0.03). A multivariate analysis revealed that
      absence of persistent ischemic chest pain was an independent predictor of
      predischarge left ventricular end-diastolic volume >100 ml/m2 (odds ratio 0.10,
      p=0.04). CONCLUSIONS: Our data demonstrated that absence of persistent ischemic
      chest pain appears to be a simple and reliable marker which predicts left
      ventricular dilation after late reperfused AMI.

PMID- 12487161
TI  - Left ventricular hypertrophy was infrequent in patients starting dialysis after
      undergoing a strict blood pressure control in the pre-dialytic period.
AB  - OBJECTIVE: We retrospectively investigated the factors influencing the left
      ventricular hypertrophy (LVH) occurrence in patients with chronic renal failure
      (CRF). METHODS AND PATIENTS: Blood pressure and echocardiographyically determined
      LVH were assessed in 110 patients on the basis of availability of monthly follow
      up data obtained during the period of 2 years before the start of dialysis. When
      the patients showed the left ventricular mass index of not less than 125 g/m2,
      they were diagnosed as having LVH. Mean casual blood pressure distribution was
      classified into 5 groups: Group 1; <93 mmHg, Group 2; 93-100 mmHg, Group 3; 100
      106 mmHg, Group 4; 106-114 mmHg and Group 5; >114 mmHg. RESULTS: LVH frequencies
      were 31.8, 72.7, 72.7, 81.8 and 95.5 (%) in Groups 1-5, respectively. Logistic
      regression showed that the factors influencing the progression of LVH were the
      duration of hypertension (per 1 year relative risk) (RR) 1.13, 95% confidential
      interval (CI) (1.01-1.26), treatment with angiotensin-converting enzyme
      inhibitors (ACE-1) (RR: 0.20, 95%CI: 0.04-0.99), pulse pressure (RR: 1.06, 95%CI:
      1.00-1.11) and mean blood pressure (MBP). The RR of developing LVH increased
      progressively as MBP increased: Compared with LVH frequency in Group 1, RR of
      Group 2 was 4.38 (95%CI: 1.05-18.19), that of Group 3 was 5.50 (95%CI: 1.08
      28.02), that of Group 4 was 5.66 (95%CI: 1.22-26.15), and that of Group 5 was
      19.13 (95%CI: 1.75-209.4). CONCLUSION: Strict blood pressure control and ACE-I
      treatment could prevent LVH in patients with CRF.

PMID- 12487162
TI  - Serum cystatin C concentration as a marker of glomerular filtration rate in
      patients with various renal diseases.
AB  - OBJECTIVE: The present study was undertaken to evaluate clinical application of
      serum cystatin C as a new marker of glomerular filtration rate (GFR) in patients
      with various renal diseases. PATIENTS AND METHODS: A total of 140 patients were
      enrolled in the study. We measured the serum cystatin C levels and compared them
      with creatinine clearance (Ccr) and inulin clearance (Cin) as an indicator of
      GFR. RESULTS: There was a significant positive correlation between serum cystatin
      C and creatinine levels (r=0.928). Serum cystatin C was inversely correlated with
      creatinine clearance. Moreover, the reciprocal serum cystatin C level was
      positively correlated with Cin (r=0.882). The receiver-operating characteristic
      curve of serum cystatin C and creatinine demonstrated that the diagnostic
      accuracy of the serum cystatin C level is superior to that of creatinine in
      identifying individuals with reduced GFR. CONCLUSION: These results indicated
      that measurement of serum cystatin C is useful to estimate GFR, and in
      particular, to detect a mild reduction of GFR in patients with renal diseases.

PMID- 12487163
TI  - Glomerular and serum IgG subclasses in diffuse proliferative lupus nephritis,
      membranous lupus nephritis, and idiopathic membranous nephropathy.
AB  - OBJECTIVE: To determine whether a different renal histopathology is associated
      with the characteristic IgG subclass distribution, and whether a distinct IgG
      subclass distribution is involved in a unique immunopathological expression, we
      compared the distributions of glomerular and serum IgG subclasses in diffuse
      proliferative lupus nephritis (DPLN), membranous LN (MLN), and idiopathic
      membranous nephropathy (MN). PATIENTS AND METHODS: The glomerular IgG subclass
      distributions in patients with DPLN (n=7), MLN (n=10) or MN (n=16) were assessed
      by direct immunofluorescence microscopy. Serum levels of each IgG subclass were
      quantitated by ELISA in DPLN, MLN, and MN patients, and in normal human sera
      (NHS) (n=14). RESULTS: IgG1, IgG2, IgG3, and, to a lesser degree, IgG4 were
      similarly present in glomerular deposits in both DPLN and MLN. In contrast, IgG4
      was the predominant glomerular IgG subclass in MN. Regarding the serum IgG
      subclasses, the mean IgG subclass concentrations and the mean proportion of each
      IgG subclass to the total IgG (%IgG subclass) in DPLN and MLN were not
      significantly different from those in NHS, except for the increased %IgG1 in MLN.
      In MN, the mean %IgG4 was selectively increased (p<0.01 vs NHS) in association
      with a slightly elevated IgG4 concentration; however, the mean concentrations of
      other IgG subclasses were significantly decreased (p<0.01 vs NHS), and the %IgG
      subclasses were not significantly different from those in NHS. CONCLUSIONS: The
      results indicate that the IgG subclass distribution is not associated with the
      different renal histopathologies of DPLN and MLN. This study also shows the
      selective significance of IgG4 in MN, but not in MLN, another form of membranous
      glomerulopathy.

PMID- 12487164
TI  - Community-acquired Chlamydia pneumoniae pneumonia in Japan: a prospective
      multicenter community-acquired pneumonia study.
AB  - OBJECTIVE: To investigate the clinical features of Chlamydia pneumoniae pneumonia
      in Japan and to evaluate the newly created Japanese community-acquired pneumonia
      (CAP) guidelines. PATIENTS AND METHODS: A multicenter CAP surveillance study was
      carried out in 20 hospitals between December 1999 and March 2000. The diagnosis
      of C. pneumoniae infection was based on isolation in cell culture, the polymerase
      chain reaction and serologic testing of antibodies by the microimmunofluorescence
      test. RESULTS: Among 232 CAP cases, C. pneumoniae was identified as the etiologic
      agent in 15 cases (6.5%). C. pneumoniae was the only pathogen identified in nine
      of these cases, while one or more additional etiological agents were found in the
      other six cases. Of the present and previously reported single agent C.
      pneumoniae pneumonia cases, about 50% were more than 60 years old and had
      underlying diseases. A relatively slow pulse rate in relation to fever was not
      seen in these patients. The mean WBC count of all patients was normal. No patient
      required respiratory support or admission to an intensive care unit and no deaths
      occurred among these patients. CONCLUSION: The clinical pictures of C. pneumoniae
      pneumonia as a single agent were mild to moderate and were remarkably different
      from those of cases of C. pneumoniae pneumonia concomitant with other bacteria.
      If the patient is less than 60 years old and some guideline headings are
      excluded, we think it would be possible to distinguish between C. pneumoniae and
      bacterial pneumonia.

PMID- 12487165
TI  - Hepatic portal venous gas disappearing within 24 hours.
AB  - Hepatic portal venous gas (HPVG) was detected by CT in a 64-year-old woman who
      suddenly complained of lower abdominal pain. However, the abdominal symptoms
      disappeared rapidly, and lower gastrointestinal endoscopy indicated only terminal
      ileitis. Conservative treatment alone was performed, and HPVG completely
      disappeared approximately 18 hours later. The use of CT proved to be useful for
      following the course of HPVG.

PMID- 12487166
TI  - Systemic capillary leak syndrome.
AB  - Systemic capillary leak syndrome (SCLS) is characterized by recurrent hypovolemic
      shock attributable to increased systemic capillary leakage. A 46-year-old man was
      admitted to our hospital because of recurrent episodes of generalized edema with
      hypovolemic shock. Blood laboratory data revealed severe hypoproteinemia with a
      small monoclonal IgG-kappa protein. These findings suggested strongly the
      diagnosis of SCLS. A regimen with steroid pulse therapy was tried; however,
      intravascular overloading accompanied by the recruitment of the initially
      extravasated fluids resulted in acute pulmonary edema. Intensive care and careful
      monitoring of fluid volume are required in SCLS.

PMID- 12487167
TI  - Infected left atrial myxoma.
AB  - A 47-year-old Japanese woman with a continuing high fever was promptly diagnosed
      as having infected atrial myxoma one day after admission based on transthoracic
      echocardiographic findings and positivity for bacteria in blood culture. The mass
      was removed by an urgent open heart surgery. Histopathological examination
      confirmed that this mass was a myxoma with gram-positive bacterial colonies.
      Generally, antemortem diagnosis is difficult and there is a high mortality of
      patients with infected myxoma; however, this patient completely recovered from
      the illness because of the prompt diagnosis. This is the 37th case of definite
      infected myxoma reported in the literature. The cause of infection of this
      patient might have been the acupuncture therapy she underwent for weight
      reduction.

PMID- 12487168
TI  - Successful treatment of chronic pulmonary thromboembolism by long-term
      intermittent administration of milrinone, a phosphodiesterase-ill inhibitor.
AB  - We report a 71-year-old man with right heart failure due to chronic pulmonary
      thromboembolism. Oral medications failed to control the condition but he was
      later successfully treated with intermittent administration of a PDE-III
      inhibitor for 2 years. Such therapy did not result in exacerbation of right heart
      failure but improvement of ANP/BNP levels to 32/104 pg/ml from a pretreatment
      value of 61/158 pg/ml, although no improvement was noted in pulmonary artery
      pressure or cardiac index. Intermittent administration of PDE-III inhibitors is a
      useful treatment for patients with right heart failure resistant to oral agents.

PMID- 12487169
TI  - Combined primary aldosteronism and Cushing's syndrome due to a single
      adrenocortical adenoma complicated by Hashimoto's thyroiditis.
AB  - A 43-year-old Japanese woman presented hypertension, hypokalemia and typical
      Cushingoid signs. Autonomous secretion of both aldosterone and cortisol was
      shown. Abdominal computed tomography demonstrated a single tumor in the right
      adrenal gland, which established the diagnosis of combined primary aldosteronism
      and Cushing's syndrome. The resected tumor was a golden yellow-colored adenoma
      (diameter 4.3 cm) which expressed P450(aldo) and P450(11beta), causing
      oversecretion of both hormones from this adenoma. After tumor resection,
      overproduction of both hormones disappeared and she developed adrenal
      insufficiency, suggesting the strong suppression of normal adrenal function. This
      case was complicated by Hashimoto's thyroiditis.

PMID- 12487170
TI  - Primary amenorrhea accompanied by adrenal adenoma: start of menarche soon after
      tumor resection.
AB  - We report a patient with primary amenorrhea accompanied by adrenal adenoma. A 21
      year-old woman was admitted to our hospital because of primary amenorrhea and
      hyperprogesteronemia without virilization. Venous sampling showed progesterone
      overproduction at the left adrenal gland. Computed tomography revealed a 7 cm
      mass in left adrenal gland. Serum pregnenorone, 17-hydroxypregnenorone,
      dehydroepiandrosterone, 17-hydroxyprogesterone, deoxycorticosterone, and 11
      deoxycortisol were elevated. The diagnosis of steroid hormone producing tumor was
      made. Following tumor resection, serum progesterone normalized 4 days later, and
      menarche occurred 51 days after operation. The present case indicated that
      adrenal functioning tumor should not be overlooked in patients with primary
      amenorrhea.

PMID- 12487171
TI  - Graves' disease development during sizofiran treatment.
AB  - It has been reported that various types of immunoactivators can induce Graves'
      disease. We describe here a case of Graves' disease during treatment with
      sizofiran, an immunoactivator. A 42-year-old woman who had previously been in an
      euthyroid state with Hashimoto's thyroiditis, experienced thyrotoxicosis during
      continuous administration of sizofiran as immunotherapy for endometrial
      carcinoma. Since the TSH receptor-antibody was positive, and a thyroid scintigram
      showed diffuse goiter and high uptake, she was diagnosed as having Graves'
      disease. It is suggested that the administration of sizofiran may be one of the
      triggers of Graves' disease.

PMID- 12487172
TI  - KL-6-producing invasive thymoma.
AB  - We report a patient with KL-6-producing invasive thymoma. A 58-year-old man was
      admitted complaining of dyspnea and fatigability. Computed tomography of the
      chest revealed interstitial pneumonia and an anterior mediastinal tumor. The
      tumor was surgically extirpated and diagnosed as invasive thymoma. Serum KL-6
      levels later increased further and another tumor was found in the liver. That
      liver tumor was resected and histologically diagnosed as a metastasis of thymoma.
      Following resection, the serum KL-6 level decreased. Tumor cells of both primary
      and metastatic lesions exhibited positive reactivity to immunohistochemical
      staining for KL-6. A review of this case is presented.

PMID- 12487173
TI  - Fabry disease with few clinical signs and symptoms.
AB  - We describe a 25-year-old man with Fabry disease who remained undiagnosed until
      progressive renal involvement had begun, because of few clinical signs or
      symptoms except intermittent acroparesthesia. He had non-nephrotic proteinuria
      and normal renal function. Renal biopsy revealed focal and segmental glomerular
      sclerosis with vacuolated podocytes. Electron microscopy demonstrated
      characteristic lamellated bodies. Alpha-galactosidase A (alpha-galA) activity was
      markedly decreased. Early diagnosis of Fabry disease is becoming important
      because of the prospect of recombinant alpha-galA replacement therapy. Careful
      history taking, physical examinations, and renal histology with electron
      microscopy are essential for the diagnosis in the course of the disease.

PMID- 12487174
TI  - Pulmonary nocardiosis with bilateral diffuse granular lung shadows in a patient
      with subcutaneous panniculitic T-cell lymphoma.
AB  - A 40-year-old woman undergoing prednisolone and cyclosporine therapy for
      subcutaneous panniculitic T-cell lymphoma complained of a cough for a few weeks.
      A chest X-ray revealed bilateral diffuse granular shadows. Additionally, the
      patient was discovered to have multiple subcutaneous abscesses. Gram-stained
      smears of sputum and pus from the abscess showing branched gram-positive rods led
      to a diagnosis of pulmonary nocardiosis with dissemination to the lungs and
      subcutaneous tissues. Combination therapy consisting of
      sulfamethoxazole/trimethoprim and panipenem/betamipron produced rapid improvement
      of radiographic abnormalities. It is suggested that pulmonary nocardiosis should
      be considered in the differential diagnosis of diffuse granular shadows on chest
      X-rays, especially in immunocompromised patients.

PMID- 12487175
TI  - Pulmonary sequestration associated by Mycobacterium intracellulare infection.
AB  - A case of a 29-year-old woman with intralobar pulmonary sequestration infected
      with Mycobacterium intracellulare is presented. A chest CT scan revealed a
      density in the posterior segment of the left lower lobe, and an acid-fast
      bacillus sputum culture yielded Mycobacterium intracellulare. After 3 months of
      treatment with clarithromycin, streptomycin, rifampicin and ethambutol, the
      patient underwent partial resection of the left lower lobe. At the 6-month follow
      up the patient's clinical status is excellent. A review of the literature
      revealed only three case reports of pulmonary sequestration associated with
      Mycobacterium avium-intracellulare complex infection.

PMID- 12487176
TI  - Cigarette smoke-induced acute eosinophilic pneumonia accompanied with
      neutrophilia in the blood.
AB  - Smoking causes various changes in the lung. This report describes a case of
      cigarette smoke-induced acute eosinophilic pneumonia (CS-AEP) with neutrophilia
      in the blood. However, the precise mechanism is unknown, so we examined the
      effect of exposure to cigarette smoke extracts on the production of interleukin
      (IL)-4, IL-5, IL-8, IL-18, granulocyte macrophage-colony stimulating factor (GM
      CSF), and vascular endothelial growth factor (VEGF) by human bronchial epithelial
      cells (HBECs) obtained from the patient. We found that IL-8 released from HBECs
      was involved in neutrophilia in the blood, and is a new factor in the development
      of AEP, especially in the early phase.

PMID- 12487177
TI  - Lung cancer with focal lymphocytic interstitial pneumonia.
AB  - A 65-year-old man was found to have a mass lesion surrounded by ground-glass
      attenuation in the left upper lobe on chest radiography. He was diagnosed with
      stage IA adenocarcinoma of the lung. The resected lung specimen revealed
      papillary adenocarcinoma associated with infiltralion of numerous lymphocytes in
      the alveolar septa, which was consistent with focal lymphocytic interstitial
      pneumonia (LIP). However, it was not associated with Sjogren's syndrome or any
      other immunologic abnormalities. Immunohistochemical study disclosed that CD8
      positive T-cells constituted the major element of the infiltrated lymphocytes in
      the tumor, and were also found in the enlarged alveolar septa, suggesting an
      association between lung cancer and LIP. To our knowledge, this is the first
      description of an association between LIP and lung cancer. In addition, the focal
      LIP in this case probably reflected local immune response to an antigenic
      stimulus caused by lung cancer.

PMID- 12487178
TI  - Occurrence of bronchioloalveolar cell carcinoma in two brothers: comparison of
      clinical features and immunohistochemical findings.
AB  - It has been suggested that lung cancer sometimes aggregates in families. However,
      the familial occurrence of bronchioloalveolar carcinoma (BAC) is extremely rare.
      We present a family in which two brothers had BAC. The clinical features and
      immunohistochemical findings of BAC in the two brothers were compared.
      Immunohistochemical findings revealed that both cases of BAC had very similar
      immunopathological features in epithelial marker expression. A review of the
      literature revealed that this is the third case of BACs in a single family.

PMID- 12487179
TI  - Giant cell interstitial pneumonia in a 15-year-old boy.
AB  - Giant cell interstitial pneumonia (GIP) is a very uncommon respiratory disease.
      We report a juvenile patient with GIP aged 15 years. Although he has a negative
      past history of direct exposure to hard metals, we could not exclude possible
      exposure in very small amounts through his parents. Microscopic examination of
      lung biopsy specimen obtained by video-assisted thoracoscopy revealed marked
      cellular interstitial infiltrates and prominent intraalveolar macrophages as well
      as giant cells showing cellular cannibalism. Analysis of the biopsied lung tissue
      for cobalt and tungsten was negative. Clinical symptoms, laboratory, and
      radiological findings improved markedly after treatment with corticosteroids. To
      our knowledge, only eleven cases of GIP have been reported in Japan. Although
      possible exposure to hard metals was identified in 9 of the 11 reported cases,
      there is no clear dose-dependent relationship with onset and prognosis. The
      average age at onset was 46.2+/-15.0 years. Our patient is the youngest case of
      GIP reported in the world.

PMID- 12487180
TI  - A limited form of Wegener's granulomatosis with bronchiolitis obliterans
      organizing pneumonitis-like variant in an ulcerative colitis patient.
AB  - A case of a 19-year-old man with ulcerative colitis (UC) developed multiple
      pulmonary nodular shadows with cavity formation, elevated perinuclear antinuclear
      cytoplasmic antibody (pANCA) and positive lymphocyte stimulation test by drug
      (DLST) for mesalazine suggesting mesalazine induced Wegener's granulomatosis
      (WG). Transbronchial biopsy specimens were consistent with WG and thoracoscopic
      biopsy specimens were consistent with bronchiolitis obliterans organizing
      pneumonitis (BOOP). We diagnosed WG with BOOP-like variant, which was induced by
      mesalazine. To our knowledge, this is the first report of a limited form of WG
      associated with orally administered mesalazine.

PMID- 12487181
TI  - Acute eosinophilic pneumonia following cigarette smoking: a case report including
      cigarette-smoking challenge test.
AB  - A 21-year-old woman presented with acute progressive dyspnea. Chest computed
      tomography (CT) revealed diffuse bilateral infiltrates. Based on the results of
      transbronchial lung biopsy (TBLB) and bronchoalveolar lavage fluid (BALF) and her
      clinical course, she was diagnosed as having acute eosinophilic pneumonia. We
      suspected that the disease was related to smoking because she had started smoking
      ten days before the onset of symptoms. Therefore, a cigarette-smoking challenge
      test was done with the patient's informed consent. After the challenge,
      eosinophilic pneumonia was documented by BALF and TBLB findings, which were
      similar to those detected on admission, without significant radiographic
      findings.

PMID- 12487182
TI  - Pulmonary sarcoidosis with associated bloody pleurisy.
AB  - A 64-year-old man was admitted to our hospital complaining of non-productive
      cough and right chest pain. Chest radiographs showed bilateral hilar
      lymphadenopathy, diffuse granular nodules and right pleural effusion. Serum
      angiotensin-II-converting enzyme and lysozyme levels were elevated. Since
      thoracentesis indicated bloody pleurisy, video-assisted thoracoscopy was
      performed and revealed multiple white nodules on both the visceral and parietal
      pleura. Resected pleural biopsy specimens showed non-caseous granulomas.
      Furthermore, some nodules were observed to compress and involve small vessels and
      capillaries. The bloody pleurisy was assumed to have been derived from the
      rupture of small vessels that had been compressed and affected by the granuloma
      with sarcoidosis.

PMID- 12487183
TI  - Legionella pneumophila pneumonia successfully treated with intravenous
      ciprofloxacin.
AB  - A 69-year-old man developed a cough and fever during treatment with
      corticosteroid (p.o. and external use) for erythroderma. Chest X-ray films
      revealed a consolidation shadow in the right upper lung field. Initial treatment
      with sulbactam sodium/ampicillin followed by imipenem/cilastatin was not
      effective. A urinary antigen test for Legionella was positive, making for a
      diagnosis of Legionella pneumonia. Intravenous treatment with ciprofloxacin
      (CPFX) was remarkably effective. His symptoms, chest X-ray and laboratory data
      rapidly improved after its initiation. Our findings strongly suggest that
      intravenous treatment with fluoroquinolones including CPFX should also be a first
      choice for Legionella pneumonia in Japan.

PMID- 12487184
TI  - Bilateral pleural effusion and pulmonary edema caused by a fistulous aneurysm of
      the ductus arteriosus.
AB  - We report an unusual case of pulmonary edema and rapid collection of bilateral
      pleural effusion caused by a fistulous large aneurysm of the ductus arteriosus
      (DAA). The diagnosis was performed by contrast CT and aortography. The cause of
      pulmonary edema and effusion was thought to be both elevated capillary pressure
      due to overload of the pulmonary circulation and decreased water clearance due to
      compression of the lymphatic system by the large DAA itself. Therefore, fistulous
      DAA should be considered when a continuous heart murmur and swelling in the
      aortic window are recognized. Once DAA is diagnosed, surgery should be performed
      without delay.

PMID- 12487185
TI  - Inflammatory abdominal aortic aneurysm followed by disseminated intravascular
      coagulation and immune thrombocytopenia.
AB  - A 71-year-old man was diagnosed as having an abdominal aortic aneurysm when he
      was treated for idiopathic interstitial pneumonia (IIP). Three years later, he
      developed severe thrombocytopenia and had disseminated intravascular coagulation
      (DIC) that was associated with the inflammatory abdominal aortic aneurysm (IAAA).
      The coagulation abnormalities were corrected by low-molecular weight heparin,
      however the platelet count remained low. Bone marrow showed normocellularity with
      an increase of immature and mature forms of megakaryocytes. Platelet-associated
      IgG level was high. These findings suggested that the patient had severe
      thrombocytopenia caused by unusual complications of immune thrombocytopenic
      purpura and IAAA-associated DIC.

PMID- 12487186
TI  - Polycystic kidney disease associated with cervical arteriovenous shunt and
      bilateral jugular vein occlusion.
AB  - A 59-year-old man with abnormal vascular features (intracranial aneurysm, a
      cervical arteriovenous shunt, bilateral internal jugular vein occlusions, and
      left transverse sinus hypoplasia), as well as left optic atrophy was suspected to
      have familial polycystic kidney disease. The possibility of autosomal dominant
      polycystic kidney disease complicated by Ehlers-Danlos syndrome type IV due to
      the coexistence of vasculopathy and polycystic kidneys was considered. However,
      the negative results of a skin fibroblast culture rendered the diagnosis of
      Ehlers-Danlos syndrome type IV unlikely. The cause of left optic atrophy in our
      patient remains unclear although it was suspected to be a secondary consequence
      of papilledema, which was caused by intracranial hypertension.

PMID- 12487187
TI  - von Recklinghausen disease in a patient with X-linked agammaglobulinemia.
AB  - A 33-year-old man was referred to our hospital because of intractable cellulitis
      in his left lower leg. He was diagnosed with agammaglobulinemia at the age of 6
      years and had been receiving gamma-globulin supplementation since then.
      Laboratory examination revealed a markedly reduced number of B cells, decreased
      protein amount of Bruton's tyrosine kinase (BTK) in monocytes, and a single base
      substitution of C994-->T(missense mutation of Arg288-->Trp) in BTK gene,
      confirming the diagnosis of X-linked agammaglobulinemia (XLA). The patient also
      had characteristic features of von Recklinghausen disease, such as numerous
      subcutaneous nodules, cafe-au-lait spots, Lisch nodules in the iris and spinal
      scoliosis. Biopsy of a subcutaneous nodule confirmed a neurofibroma. Although the
      influence of XLA on the development of von Recklinghausen disease is unknown for
      the moment, this is, to our knowledge, the first report of a patient with XLA who
      also developed von Recklinghausen disease.

PMID- 12487188
TI  - Concomitant Cushing's syndrome due to adrenal adenoma in a patient with systemic
      lupus erythematosus.
AB  - A 51-year-old woman had been administered 5 mg/day of prednisolone due to
      systemic lupus erythematosus (SLE). She developed hypertension, hypokalemia and a
      pathologic pubic fracture during two years before admission. Although iatrogenic
      Cushing's syndrome was initially suspected, we diagnosed her as concomitant
      Cushing's syndrome due to a left adrenal tumor. The elevated endogeneous
      glucocorticoids were evaluated from urinary excretions of 17
      hydroxycorticosteroids, which was 2-fold higher than normal and equivalent to 10
      mg of prednisolone. After laparoscopic left adrenalectomy, SLE was favorably
      controlled with 15 mg of prednisolone, the dosage of which was equivalent to the
      estimated amount of preoperative glucocorticoids.

PMID- 12487189
TI  - An anti-nuclear antibody-negative patient with systemic lupus erythematosus (SLE)
      accompanied with anti-ribosomal P antibody (anti-P).
AB  - We report a case of an anti-nuclear antibody (ANA)-negative patient with systemic
      lupus erythematosus (SLE) accompanied with anti-phospholipid antibody syndrome
      (APS) and lupus nephritis (LN). Histological examination of placenta obtained by
      an artificially-induced abortion revealed multiple thromboses in the placental
      villi. Histology of biopsied kidney tissue revealed minimal change with deposits
      of immunoglobulin and complement. Anti-ribosomal P antibodies (anti-P) and lupus
      anticoagulant (LAC) were positive and anti-double stranded DNA antibody (anti
      DNA) showed only a slightly positive titer in her serum. The intensity of
      proteinuria of the patient was correlated with the anti-P, but not anti-DNA
      titers.

PMID- 12487190
TI  - A long-survival case of systemic AL amyloidosis with nephrotic syndrome.
AB  - A 49-year-old Japanese female was initially diagnosed as having monoclonal
      gammopathy of undetermined significance in June 1993 (IgG lambda: 3,120 mg/dl).
      Four years later, she developed AL amyloidosis complicated by nephrotic syndrome
      and renal failure. Before receiving 5 courses of MP therapy (melphalan plus
      prednisolone), her serum IgG level had decreased in accordance with the
      appearance of nephrotic syndrome, which led to the leakage of serum
      immunoglobulin into the urine. After the discontinuation of the MP therapy,
      hypogammaglobulinemia has been kept over 24 months, though she still shows a
      leakage of 4-5 g/day of serum protein, including IgG into the urine. There were
      no signs of the progression of amyloidosis or renal failure, resulting in a good
      clinical performance status. Hypogammaglobulinemia due to nephrotic syndrome may
      have prevented the progression of AL amyloidosis in this case.

PMID- 12487191
TI  - Chronic lupus peritonitis with massive ascites at elderly onset: case report and
      review of the literature.
AB  - A 77-year-old Japanese woman with massive painless ascites caused by chronic
      lupus peritonitis is reported. Peritoneal effusion had been resistant to the
      administration of steroids during the whole treatment period. It was
      characteristic that the titers of anti-DNA antibodies and the level of immune
      complex were elevated in the peritoneal fluid with suppressed levels of
      complements in ascites, although serum immunological markers reflecting the
      activity of SLE presented improvement after initiation of the treatment. Fifteen
      patients with chronic lupus peritonitis were reported previously. We reviewed the
      literature and suggest that chronic lupus peritonitis at elderly onset may
      demonstrate a poor response to the glucocorticoid therapy because of persistent
      inflammation in the peritoneum and the presence of impaired vascular circulation
      in addition to immunological mechanisms.

PMID- 12487192
TI  - Good's syndrome and pernicious anemia.
AB  - In a rare case of Good's syndrome with pernicious anemia, one year after
      thymectomy, recurrent respiratory infections developed. Both panhypoglobulinemia
      and pernicious anemia were disclosed. An immunological analysis revealed the
      absence of circulating B cells, but T cell numbers and mitogenic responses were
      normal. Regular gammaglobulin and vitamin B12 injections were successful in
      keeping the patient symptom free.

PMID- 12487193
TI  - Focal tuberculous lymphadenitis in an HIV-1 infected patient.
AB  - A 41-year-old man was admitted to the hospital because of focal swelling of the
      left supraclavicular lymph nodes. Eighteen months prior to admission, he had been
      diagnosed with human immunodeficiency virus type 1 (HIV-1) infection and was
      started on highly active antiretroviral therapy (HAART). He responded well to
      HAART with an increase in CD4+ cell count and improvement in symptoms. However,
      one year after the initiation of HAART, he developed progressive enlargement of
      left supraclavicular lymph nodes. An excisional lymph node biopsy was performed
      for diagnosis, which revealed tuberculous lymphadenitis. Rifabutin, isoniazid,
      and ethambutol were initiated for treatment.

PMID- 12487194
TI  - Hepatic encephalopathy in primary human immunodeficiency virus type 1 (HIV-1)
      infection.
AB  - Primary infection of human immunodeficiency virus type 1 (HIV-1) is occasionally
      associated with common cold-like symptoms, and rarely with a self-limited illness
      resembling infectious mononucleosis. We report a 32-year-old man who presented
      with infectious mononucleosis-like blood picture on admission. Five days after
      admission he developed hepatic encephalopathy, which was ameliorated by
      administration of bolus corticosteroid. Based on the results of serologic
      studies, we diagnosed that he had primary HIV-1 infection. To our knowledge, this
      is the first published report of hepatic encephalopathy as a clinical
      manifestation of primary HIV-1 infection.

PMID- 12487195
TI  - Successful treatment of listerial brain abscess: a case report and literature
      review.
AB  - Listerial brain abscess is extremely rare; only two cases have been reported in
      Japan. We encountered a female patient with immunoblastic lymphadenopathy, who
      developed listerial brain abscess after 8 years of treatment with antineoplastic
      agents and corticosteroids. Brain MRI revealed multiple space occupying lesions,
      suggesting abscesses which were possibly caused by hematogenous spread of the
      bacteria. Immediate blood culture enabled early diagnosis, and she entered into
      complete remission with high-dose ampicillin. Blood culture and brain imaging
      seem to play a crucial role in making an early diagnosis, and the administration
      of high dose of antibiotics is recommended for improvement of this disease.

PMID- 12487196
TI  - Adverse reactions to bovine proteins--then and now.

PMID- 12487197
TI  - Cow's milk proteins/allergens.
AB  - OBJECTIVE: The primary objective of this review is to provide updated data on the
      structure and function of the main cow's milk proteins (CMPs) identified as
      allergens and on the characterization of their epitopes. DATA SOURCES: The review
      represents a synthesis of basic literature and most relevant original recent
      publications on both topics of clinical and epidemiologic aspects of milk allergy
      and of milk protein's bio- and immunochemistry. STUDY SELECTION: The expert
      opinion of the author was used to select the relevant data for the review.
      RESULTS: Most CMPs are potential allergens, even the proteins present at very low
      concentration. There are both conformational and linear epitopes, widely spread
      all along the protein molecules. They may be short fragments, located in
      hydrophobic parts of the molecule which comprise highly conserved sequences
      responsible for immunoglobulin E cross-reactivity with corresponding milk
      proteins of other mammals, including human beings. Those sequential epitopes have
      also been proposed as good markers of persistent allergy to CMPs. CONCLUSIONS: No
      specific structure nor function is associated with allergenicity of CMPs.
      Variability and heterogeneity of the human immunoglobulin E response preclude
      anticipating the allergenic potential of any CMP or fragment thereof, as well as
      justify the need for being careful before using peptides for desensitization or
      proposing any milk protein hydrolysate in a diet for highly allergenic children.

PMID- 12487198
TI  - Cross-reactivity between mammalian proteins.
AB  - BACKGROUND: Cross-reactivity between food allergens occurs when they share part
      of their amino acid sequence, or when their three-dimensional molecular structure
      causes them to have a similar capacity to bind specific antibodies. OBJECTIVES:
      To review data from our laboratory on cross-reactivity between mammalian proteins
      (milk and meat allergens). METHODS: Studies used immunoelectrophoresis (sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis/polyacrylamide gel
      electrophoresis and immunoblotting), and animal monoclonal antibodies. RESULTS:
      The findings suggest that animal monoclonal antibodies specific for cow's milk
      proteins are able to recognize the major part of milk proteins from mammals bred
      in Mediterranean countries (sheep, goat, and buffalo); weak cross-reactivity was
      observed with milk proteins from mares and donkeys. None of the antibodies used
      in our studies reacted with proteins from an exotic mammalian species: the camel.
      Similar cross-reactions were found with human circulating immunoglobulin E from
      children allergic to milk. With regard to beef allergy, monoclonal antibodies
      specific for bovine serum albumin cross-reacted only with ovine serum albumin,
      whereas the number of sera from allergic children able to recognize other
      mammalian serum albumins depended directly on the closeness of phylogenetic
      relationship between animal species and inversely on the percent identity with
      human serum albumin in the main epitopic sequence. CONCLUSION: An area of
      heterogeneity between animal and human species in a critical amino acid sequence
      (epitope) of an allergen can determine the degree of immunogenic activity.

PMID- 12487199
TI  - Stability of bovine allergens during food processing.
AB  - OBJECTIVE: The primary objective of this review was to summarize reported
      findings about the influence of various food manufacturing processes on the
      potential alteration of bovine allergens in cow's milk, beef, and related food
      products. DATA SOURCES: This review was based on literature research in two
      German databases. STUDY SELECTION: The expert opinion of the authors was used to
      select the relevant data for the review. RESULTS: Changes in allergenic activity
      during food processing are attributable to inactivation or destruction of epitope
      structures, formation of new epitopes, or improved access of previously hidden
      epitopes. The allergenic potency of food could be altered by several food
      manufacturing procedures--such as mechanical, purification, thermal, biochemical,
      and chemical processes. The main processing steps studied by investigators were
      heating (dry heating, boiling, or cooking) and enzymatic digestion. A review of
      the available literature on the alteration of bovine allergens in cow's milk,
      meat, and related food products revealed reduction (but not elimination) of
      allergenicity by heating of cow's milk for 10 minutes. Although homogenization
      did not change the allergenic potency of cow's milk, it decreased the
      allergenicity of beef, as did freeze-drying. Digestion studies showed varied
      results. CONCLUSIONS: The allergenicity of some food products decreased during
      certain processing steps, but the results of other investigations differed.
      Therefore, more systematic research on the influence of food processing on
      allergenicity should be undertaken.

PMID- 12487200
TI  - Accuracy of specific IgE antibody assays for diagnosis of cow's milk allergy.
AB  - OBJECTIVE: The primary objective of this report was to discuss the accuracy of
      specific immunoglobulin (Ig)E antibody determinations in the diagnosis and
      prognosis of reactions to allergens, especially cow's milk, in the context of
      other relevant clinical information. DATA SOURCES: A review was undertaken of the
      relevant literature on IgE antibody assays in conjunction with some unpublished
      information from the authors' investigations. STUDY SELECTION: The pertinent data
      for this article were selected on the basis of the expert opinion of the authors.
      RESULTS: IgE antibody formation and allergy commence early in life, which can be
      reflected by specific IgE antibody determinations in serum samples with use of
      particular systems developed for commercial use. After the first such system was
      introduced in 1974, development of the technology has ensued. Some systems using
      excess of allergen extracts of good quality have proven to yield highly accurate
      results over time. Assays that detect all antibodies present in the serum sample
      and that demonstrate parallelism between dilutions of specific IgE antibodies and
      total IgE concentration also allow quantitative determinations of specific IgE
      antibodies. Such specific IgE antibody data can be used not only for a
      dichotomized evaluation of the presence or absence of sensitization in an
      individual patient, but also for an evaluation of the relative risk for a
      clinical reaction to an allergen such as cow's milk. Thus, the specific IgE
      antibody information can be used in the diagnosis, prediction of the course, and
      followup management of allergic disease, particularly when sensitization to
      multiple allergens is present. CONCLUSIONS: Specific IgE antibodies can be
      accurately determined with certain technologic systems. Such determinations
      provide information, not available by other means, for the diagnosis, prognosis,
      and followup of patients with allergy-like symptoms.

PMID- 12487201
TI  - Accuracy of skin prick tests in IgE-mediated adverse reactions to bovine
      proteins.
AB  - OBJECTIVES: To review the recent literature on the diagnostic accuracy of skin
      prick tests (SPTs) in pediatric food allergy, focusing on adverse reactions to
      milk and beef. To present data about the test performance characteristics of beef
      extracts used in SPTs among children with atopic dermatitis (AD) reporting
      immediate hypersensitivity to beef. DATA SOURCES: MEDLINE search using the
      following algorithm ["skin prick test" AND "food allergy" OR allergen; 1997-2002;
      English; all children]. Prospective sensitivity study of SPTs in 34 patients.
      STUDY SELECTION: Thirty-four children with AD (median age 2.29 years) were
      consecutively recruited between 1992 and 2000 because of immediate reactions to
      beef. On double-blind, placebo-controlled food challenges (entry criterion), 20
      of the patients reacted to beef and 14 did not. Cut-off points for skin prick
      test wheal positivity was selected by receiving-operator characteristic analysis
      for fresh and commercial beef allergens. Sensitivity and specificity of skin
      tests and indices of reproducibility were calculated. RESULTS: In the literature,
      the positive predictive accuracies of skin prick tests vary between 69 and 100%
      and the negative predictive accuracies between 20 to 86% for cow's milk. In our
      series, SPTs with commercial beef extracts were highly diagnostic (100%
      sensitivity; 10% false positive rate) and SPTs with fresh beef were highly
      specific (100%), albeit with a false-positive rate of 21.42%. CONCLUSIONS: From
      the literature, we conclude that the diagnostic accuracy of SPTs with milk should
      be reappraised in the workup of cow's milk allergy. Carrying out commercial and
      fresh food SPTs at the same time substantially reduces costs and diagnostic work.
      Oral provocation is necessary in 20.68% of children with AD who have immediate
      symptoms to beef. Greater allergen standardization and streamlining of the workup
      of cow's milk allergy are desirable future goals.

PMID- 12487202
TI  - Frequency of cow's milk allergy in childhood.
AB  - OBJECTIVE: The primary objective of this review is to discuss the clinical
      features, diagnosis, natural history, and prognosis of cow's milk allergy in
      early childhood and its relationship to development of inhalant allergies. DATA
      SOURCES: A review of 229 PubMed (National Library of Medicine) articles on cow's
      milk allergy (CMPA) for the years 1967 through 2001 was performed. In addition,
      references from other review articles have been included. This review represents
      a synthesis of these sources and the expert opinion of the author. STUDY
      SELECTION: The expert opinion of the author was used to select the relevant data
      for this review. RESULTS: The diagnosis of reproducible adverse reactions to
      cow's milk protein (CMP), ie, CMPA, has to be confirmed by controlled elimination
      and challenge procedures. The incidence of CMPA in infancy seems to be
      approximately 2 to 3% in developed countries. Symptoms suggestive of CMPA may be
      encountered in approximately 5 to 15% of infants emphasizing the importance of
      controlled elimination/milk challenge procedures. Reproducible clinical reactions
      to CMP in human milk have been reported in approximately 0.5% of breastfed
      infants. Most infants with CMPA develop symptoms before 1 month of age, often
      within 1 week after introduction of CMP-based formula. The majority has two or
      more symptoms from two or more organ systems. Approximately 50 to 60% have
      cutaneous symptoms, 50 to 60% have gastrointestinal symptoms, and approximately
      20 to 30% respiratory symptoms. Symptoms may occur within 1 hour after milk
      intake (immediate reactions) or after 1 hour (late reactions). The prognosis of
      CMPA is good with a remission rate of approximately 45 to 50% at 1 year, 60 to
      75% at 2 years, and 85 to 90% at 3 years. Associated adverse reactions to other
      foods develop in up to 50% and allergy against inhalants in 50 to 80% before
      puberty. CONCLUSIONS: CMPA is the most common food allergy in early childhood
      with an incidence of 2 to 3% in the first year of life. The overall prognosis of
      CMPA in infancy is good with a remission rate of approximately 85 to 90%. In
      particular, gastrointestinal symptoms show a good prognosis. An early increased
      immunoglobulin E-response to CMP is associated with an increased risk of
      persistent allergy to CMP, development of adverse reactions to other foods, and
      development of asthma and rhinoconjunctivitis later in childhood.

PMID- 12487203
TI  - Beef allergy in children with cow's milk allergy; cow's milk allergy in children
      with beef allergy.
AB  - OBJECTIVE: To review the literature on the prevalence of beef allergy in children
      allergic to cow's milk and to report a series of patients with beef allergy
      evaluated for cow's milk allergy. DATA SOURCES: A MEDLINE search for cow's milk
      allergy and beef allergy was conducted. Also included in this report is a
      clinical evaluation of both these entities in a population of children with
      atopic dermatitis. STUDY SELECTION: Data from the literature were summarized.
      Recruited patients with beef allergy were evaluated on the basis of history,
      serology, skin prick tests, and double-blind, placebo-controlled food challenge
      (entry criterion), and presented between 1992 and 2000. RESULTS: In the
      literature, between 13 and 20% of children with cow's milk allergy also have beef
      allergy. In our personal series of patients, 28 children (18 boys and 10 girls)
      diagnosed with beef allergy underwent skin prick tests and double-blind, placebo
      controlled food challenge, which showed that 26 (92.9%) were allergic to cow's
      milk. Two children nonallergic to cow's milk were the only ones who were not
      sensitized to bovine serum albumin. CONCLUSIONS: Most children with beef allergy
      are also allergic to cow's milk and should avoid the consumption of dairy
      products. Sensitization to bovine serum albumin is a marker of cow's milk allergy
      in children with beef allergy. Elimination of beef from the diet of children with
      cow's milk allergy should be evaluated on an individual basis after diagnostic
      workup.

PMID- 12487204
TI  - Food allergy: what can be done to prevent progression to asthma?
AB  - OBJECTIVES: The primary objective of this review is to discuss risk factors for
      asthma development in food allergen-sensitized children. In the paper we discuss
      the possible measures to prevent progression to asthma by allergen and other
      adjuvant factor avoidance. DATA SOURCES: A review from literature of articles on
      these topics was performed. STUDY SELECTION: Relevant publications on asthma risk
      factors and implementation of protective factors were critically evaluated.
      RESULTS: Children with familiar history of atopy and sensitization to food
      proteins in early infancy are at high risk of subsequent respiratory allergic
      diseases and require specific prevention. Because early allergic sensitization is
      a significant risk factor for later development of asthma, prevention of asthma
      by early allergen avoidance is mandatory in high-risk children. Adjuvant factors
      such as tobacco smoke and mold exposure may act as nonspecific triggers for the
      development of atopy. The role of protective factors such as infections in early
      life, breast-feeding, a "healthy" diet needs to be evaluated in prospective
      studies. Pharmacologic intervention with antihistamines led to significant
      reduction in incidence of asthma in high-risk children, but confirmatory
      longitudinal studies in large populations are necessary. CONCLUSIONS: There is
      now accumulating evidence that preventing exposure to house-dust mite may
      significantly reduce the prevalence of childhood asthma. However, allergen
      avoidance can not be recommended as the only strategy. Avoidance of adjuvant
      factors and implementation of potential protective factors aimed to reduce the
      risk to progression to asthma need to be evaluated in prospective studies.

PMID- 12487205
TI  - Natural course of cow's milk allergy in childhood atopic eczema/dermatitis
      syndrome.
AB  - OBJECTIVE: This review was undertaken to determine the role of adverse reactions
      to bovine proteins in atopic dermatitis, recently called atopic eczema/dermatitis
      syndrome (AEDS). DATA SOURCES: A PubMed literature search was conducted with use
      of the following phrases: atopic dermatitis and food allergy, atopic dermatitis
      and cow's milk, and cow's milk and eczema. STUDY SELECTION: The authors' judgment
      and personal interest guided the literature selection. RESULTS: Food allergy has
      a role in at least 20% of the cases of AEDS in children younger than 4 years.
      Cow's milk is usually the first food given to an infant, and cow's milk
      hypersensitivity is often the first symptom of an atopic condition. Adverse
      reactions to cow's milk proteins are usually categorized as immunoglobulin (Ig)E
      mediated or non-IgE-mediated cow's milk allergy and nonallergic hypersensitivity
      (intolerance); the symptoms do not allow differentiation of these entities. In
      patients with cow's milk allergy and AEDS, resolution occurs in 90% by the age of
      4 years. Non-IgE-mediated cow's milk allergy often disappears before the age of 1
      year. Associated reactions to other foods develop in approximately 45% of
      patients. Allergy to potential environmental inhalant allergens has been reported
      in up to 28% of patients by 3 years of age and up to 80% before puberty. After
      consumption of large amounts of cow's milk, 45% of 10-year-old children who had
      become tolerant of cow's milk, but also 15% of control subjects, still had
      gastrointestinal complaints. The presence of cow's milk allergy during infancy
      increases the risks for development of other food allergies, respiratory atopy,
      and persistence of AEDS. CONCLUSION: Adverse reactions to bovine proteins have an
      important role in AEDS.

PMID- 12487206
TI  - Cow's milk allergy versus cow milk intolerance.
AB  - BACKGROUND: Although cow's milk allergy (CMA) and cow's milk intolerance (CMI)
      are two different terms, they are often used interchangeably, resulting in
      confusion both in clinical practice and in research reports. OBJECTIVE: To
      promote the appropriate differential use of the terms CMA and CMI. METHODS:
      Highlighting the differences in clinical and laboratory findings between CMA and
      CMI. Information was derived from reviewing the literature on these two topics,
      supplemented by the clinical experience of the author. RESULTS: CMA is an
      immunologically mediated reaction to cow's milk proteins that may involve the
      gastro-intestinal tract, skin, respiratory tract, or multiple systems, ie,
      systemic anaphylaxis. Its prevalence in the general population is probably 1 to
      3%, being highest in infants and lowest in adults. Even though it can cause
      severe morbidity and even fatality, dietary elimination is associated with good
      prognosis. However, CMI should refer to nonimmunologic reactions to cow's milk
      (CM), such as disorders of digestion, absorption, or metabolism of certain CM
      components. The most common cause of CMI is lactase deficiency, which is mostly
      acquired during late childhood or adulthood. It has high racial predilection,
      being highest in dark-skinned populations and lowest in northern Europeans.
      Lactose intolerance is generally a benign condition, with symptoms limited to the
      gastro-intestinal tract, yet the primary acquired type lasts for a lifetime.
      Symptoms can be well ameliorated by reducing the intake of CM or using lactose
      hydrolyzing agents. CONCLUSIONS: Adverse reactions to CM should be differentiated
      into immunologic (CMA) and nonimmunologic (CMI). The latter is still a general
      term that comprises several conditions and requires further differentiation.

PMID- 12487207
TI  - Anaphylaxis to cow's milk and beef meat proteins.
AB  - OBJECTIVE: This report summarizes a review of anaphylactic reactions to cow's
      milk and beef presented at a recent conference on adverse reactions to bovine
      proteins. DATA SOURCES: A review of pertinent PubMed (National Library of
      Medicine) articles was performed. Relevant publications were critically analyzed.
      STUDY SELECTION: The expert opinion of the author was used to select the relevant
      data for the review. RESULTS: Although cow's milk has been recognized for many
      years as one of the leading causes of food allergy, beef has only recently been
      identified as a cause of immunoglobulin (Ig)E-mediated reactions. Epidemiologic
      data indicate that the prevalence of cow's milk allergy is approximately 1 to 2%,
      but no definite data are available for beef allergy. Anaphylaxis to both foods
      has been well characterized in childhood; however, a subset of adult patients may
      become reactive to cow's milk and have the characteristic features of
      anaphylaxis. The diagnosis is primarily based on skin prick tests and measurement
      of cow's milk- or beef-specific IgE antibodies. In selected patients, a
      standardized food challenge might be necessary to determine the diagnosis.
      CONCLUSIONS: In the absence of a proactive treatment of food allergy, patients
      with anaphylaxis to cow's milk or beef must be instructed to avoid these foods in
      their diet. Although cow's milk allergy generally is associated with a good
      prognosis, with most young children spontaneously "outgrowing" the disease,
      current research is focusing on the prevention and the treatment of this
      condition.

PMID- 12487208
TI  - Gastrointestinal manifestations of cow's milk allergy.
AB  - OBJECTIVE: To review and discuss the relationship between cow's milk allergy
      (CMA) and some gastrointestinal manifestations, such as gastroesophageal reflux,
      constipation, food protein-induced enterocolitis, and food-induced eosinophilic
      proctocolitis, with respect to diagnostic strategies that might eliminate the
      need for a double-blind, placebo-controlled oral food challenge (DBPCFC). DATA
      SOURCES: A review of pertinent PubMed articles, published during the past 10
      years, was performed. STUDY SELECTION: To obtain positive and negative predictive
      values known as posterior probabilities and to calculate the likelihood ratio,
      only those studies including both patients and control subjects were selected for
      analysis. RESULTS: With respect to gastroesophageal reflux, a typical 24-hour
      esophageal pH monitoring pattern might obviate the performance of a DBPCFC in
      patients with symptoms of reflux suspected of having CMA, provided this pH
      pattern is confirmed in other studies. A relationship between CMA and
      constipation has been reported in only one prospective controlled study; the
      clinical and laboratory variables of perianal lesions, histologic abnormalities,
      and signs of hypersensitivity had likelihood ratios of 2.2, 2.4, and 3.7,
      respectively, and posttest probabilities of 83, 84, and 88%, respectively.
      Therefore, a DBPCFC is warranted. In reference to food protein-induced
      enterocolitis, clinical and laboratory criteria suggested in the literature for
      defining a food challenge as positive have not been prospectively evaluated in
      the untreated state. Some simple stool tests, such as fecal tumor necrosis factor
      alpha and alpha1-antitrypsin determination, might be candidates for diagnostic
      studies in patients with food protein-induced enterocolitis, if prospectively
      evaluated. In infants with food-induced eosinophilic proctocolitis, rectal biopsy
      invariably shows eosinophilic infiltration and thus makes performance of a DBPCFC
      unnecessary. CONCLUSION: Although the current diagnosis of gastrointestinal
      manifestations of CMA usually depends on a DBPCFC, investigators continue to
      study other options for confirming the diagnosis.

PMID- 12487209
TI  - Inner-city asthma and the hygiene hypothesis.
AB  - OBJECTIVE: Our goals were to analyze some of the similarities and differences in
      the increase in asthma, hay fever, and atopic sensitization between Europe and
      the United States and attempt to explain "inner-city asthma" within the framework
      of the hygiene hypothesis. DATA SOURCES: We reviewed historical descriptions of
      hay fever and asthma as well as the currently available related literature. STUDY
      SELECTION: The authors' judgment was used in the selection of historical and
      epidemiologic evidence. RESULTS: Analyses of patterns of risk factors for
      allergic rhinoconjunctivitis and asthma in Europe led to a causal theory of the
      epidemic: the hygiene hypothesis. This theory claims that hygiene removed a
      protective influence against atopy and asthma that was once provided by exposure
      to infections in early life. This hypothesis has been questioned in the United
      States, where allergic asthma since the 1970s has increased among minorities
      living in poverty and with suboptimal hygienic conditions (inner-city asthma).
      When seen from a historical perspective, the recent increasing trend in
      respiratory allergies among the less advantaged in the United States may be
      explained as the consequence of several epiphenomena linked to westernization
      (including declining exposure to foodborne and orofecal infections) that first
      affected the richest socioeconomic strata during the 19th century, expanded among
      the middle classes during the first half of the 20th century, and eventually
      cascaded down to affect the least-advantaged Americans. CONCLUSION: Inner-city
      asthma may be the final stage of a class-driven urbanization and westernization
      that began 2 centuries ago in the United States and that is now coming full
      circle.

PMID- 12487210
TI  - Inventing probiotic functional foods for patients with allergic disease.
AB  - OBJECTIVE: The primary objective of this review is to discuss the rationale for
      and applicability of probiotics as part of the nutritional approach to the
      prevention and management of allergic disease. DATA SOURCES: This review
      represents a synthesis of recent literature published in the fields of
      probiotics, nutrition, and allergic disease. STUDY SELECTION: The expert opinions
      of the authors were used to select the relevant data for the review. RESULTS: The
      hygiene hypothesis suggests that allergic disease may arise from a lack of
      counterbalancing microbial exposure at an early age. Thus, the initial
      compositional development of gut microbiota is considered a key determinant in
      the development of both the immune responder phenotype and the normal gut barrier
      functions. A wide range of data documents the specific actions of selected
      probiotics. The regulatory role of probiotics in allergic disease has been
      demonstrated as improving the clinical course or preventing the development of
      atopic eczema in infants given a probiotic-supplemented diet. In addition,
      certain types of fatty acids and antioxidants have been proposed for protective
      effects against the development of allergy and to diminish the inflammatory
      response in allergic disease. CONCLUSIONS: The increase in the prevalence of
      allergic disease during the past decades is likely to be explained by changes in
      the environment, including reduced microbial exposure and altered food
      consumption. Scientifically composed functional foods containing probiotics and
      other functional components offer a nutritional strategy for both the prevention
      and the management of allergic disease. Further research is needed to
      characterize the gut microbiota and to clarify the mechanisms of action that
      control specific physiologic processes not only in the evolution of allergic
      disease in at-risk populations but also in the management of allergic diseases.

PMID- 12487211
TI  - The implications of nomenclature.
AB  - BACKGROUND: To be able to draw the right conclusions from clinical research, it
      is essential that words have the same meaning to all researcher and clinicians.
      OBJECTIVE: To present the new nomenclature for allergy and discuss its influence
      on conclusions drawn from clinical studies with one example illustrating that
      conclusions change with the use of definitions and nomenclature. METHODS: To
      review one recent study at odds with the new allergy nomenclature. Atopy is
      defined as a personal or familial tendency to produce immunoglobulin (Ig)E
      antibodies in response to low doses of allergens, usually proteins, and to
      develop typical symptoms such as asthma, rhinoconjunctivitis, or
      eczema/dermatitis. Allergy is defined as a hypersensitivity reaction initiated by
      immunologic mechanisms and divided into IgE-mediated and non-IgE-mediated
      allergy. What has been called atopic diseases, eg, infantile eczema, can be
      caused by both IgE-mediated allergy (atopy) and non-Ig-mediated mechanisms. In
      the study, two groups of mothers/infants were given either Lactobacillus GG or
      placebo with the incidence of infantile eczema as primary outcome parameter.
      RESULTS: The study analyzed concludes that probiotic bacteria supplied to mother
      and child prevents infantile eczema development caused by both IgE-mediated
      (atopy) and non-IgE-mediated allergic mechanisms. The study also shows that IgE
      sensitization was similar in the two groups. Thus, "atopic disease" was prevented
      (subjective evaluation), whereas atopy, ie, IgE induction was not prevented.
      CONCLUSIONS: Nomenclature is of utmost importance to interpret results in allergy
      research. If preventive measures, such as oral treatment with Lactobacilli, have
      an effect, this should be tested against a single mechanism of disease rather
      than against a disease caused by several mechanisms. However, in the study
      Lactobacilli are said to prevent atopic disease, and also that Lactobacilli do
      not hinder development of IgE sensitization, one of the mechanisms causing this
      disease.

PMID- 12487212
TI  - Use of hydrolysates in the treatment of cow's milk allergy.
AB  - BACKGROUND: Hydrolyzed formulas (HFs) are in general well tolerated by children
      with cow's milk allergy (CMA), although cases of allergic reactions have been
      reported and residual allergenicity of HF has been demonstrated OBJECTIVE: To
      review the most relevant studies of the HFs for residual allergenicity,
      tolerance, and safety in the past 20 years. DATA SOURCES AND METHODS: MEDLINE
      searches for the years 1970 to 2001 using the following algorithm (hydrolysate
      and allergy; food intolerance/allergy; protein hydrolysate). RESULTS: The
      literature confirmed that although some antigenicity remains, HFs are well
      tolerated by children with CMA. Rice HF has proven safe when tested by double
      blind, placebo-controlled food challenge in a study population of 18 children
      allergic both to cow's milk (CM) and soy protein. CONCLUSIONS: Absolute avoidance
      of CM proteins means substitution by soy-, rice-, or amino acid-based formulas.
      As 8 to 14% of infants allergic to CM react to soy and amino acid-based formulas
      are expensive, scientific societies recommend the use of formulas based on
      extensively hydrolyzed CM proteins as first alternatives in children with CMA.
      Although both soy- and rice-based HFs have now been shown to be safe for these
      children, further nutritional and clinical studies are needed.

PMID- 12487213
TI  - Management of bovine protein allergy: new perspectives and nutritional aspects.
AB  - OBJECTIVES: Awareness of the considerable incidence of bovine protein allergy in
      infancy makes it necessary to eliminate cow's milk antigens from the diet in
      special cases. The primary objective of this review is to discuss the nutritional
      aspects and appropriate use of hypoallergenic formulas as a substitute for cow's
      milk formulas and to present new alternative feeding modalities in this field.
      DATA SOURCES: Related articles in PubMed (National Library of Medicine) were
      reviewed. This review is a synthesis of these sources along with the discussions
      with experts in this field and the expert opinion of the authors. RESULTS: Soy
      protein-based and hydrolyzed milk protein formulas are the most commonly used
      alternative protein sources in the case of bovine protein allergy. Despite the
      adequacy of their nutritional values, there are still some problems to be solved
      regarding these formulas. In addition, a considerable percentage of the infants
      with bovine protein allergy may also present allergenic reactions to soy proteins
      as well as to hydrolyzed milk proteins. Thus, there still exists chaos in the
      selection of the most appropriate formula for infants sensitized to cow's milk
      protein. Rice protein-based formulas, probiotics, and prebiotics are expected to
      be new effective alternatives. CONCLUSIONS: Bovine protein allergy constitutes an
      important place in childhood food allergies. Soy protein-based and hydrolyzed
      protein formulas have some disadvantages and risk of allergenic activity that is
      not to be underestimated. So, substitution of cow's milk protein with an
      alternative protein source in sensitized infants has become an art rather than a
      science. Rice protein, prebiotics, and probiotics appear to be valuable
      alternatives giving hope for the future.

PMID- 12487214
TI  - Soy formulas and nonbovine milk.
AB  - BACKGROUND: Cow's milk allergy is frequently observed during the first year of
      life when nutritional requirements are critical. In those cases where breast
      feeding is not available, a safe and adequate substitute to cow's milk should be
      offered. OBJECTIVE: The primary aim of this review is to evaluate the clinical
      use of milk derived from vegetable proteins, such as soy, or from animals such as
      goat, mare, or donkey, or elemental diet in children with cow's milk allergy.
      METHODS: MEDLINE searches were conducted with key words such as soy, goat's milk,
      donkey's milk, mare's milk, and elemental diet. Additional articles were
      identified from references in books or articles. Original research papers and
      review articles from peer-reviewed journals were chosen. RESULTS: Soy formulas
      are nutritionally adequate and can be used in children with immunoglobulin E
      mediated nongastrointestinal manifestations of cow's milk allergy. Goat's milk is
      as allergenic as cow's milk. Mare's milk and donkey's milk may be used in
      selected cases of cow's milk allergy after appropriate modification to make them
      suitable for human infants. Elemental diets are usually restricted to the most
      severe cases of cow's milk allergy (ie, sensitivity to extensively hydrolyzed
      protein formulas). CONCLUSIONS: Vegetable formulas obtained from soy and milk
      derived from other mammals, such as mare or donkey, homemade preparations, and
      elemental diet may represent valid alternatives for children with cow's milk
      allergy. Extensive clinical trials are needed on the safety profile of any
      alternative mammal-derived milk. The choice of alternative milk should take into
      account the clinical profile of the child allergic to cow's milk, particularly as
      concerns age, severity of symptoms, degree of sensitivity to cow's milk proteins,
      and any multiple food allergies.

PMID- 12487215
TI  - Species of Cladosporium.

PMID- 12487216
TI  - Sense and sensitivity: assessing inhaled corticosteroid effects on the
      hypothalamic-pituitary-adrenal axis.

PMID- 12487217
TI  - The ongoing evaluation of the impact of depression on asthma.

PMID- 12487218
TI  - Sensitivity to nonsteroidal anti-inflammatory drugs.
AB  - BACKGROUND: Aspirin can provoke reactions ranging from respiratory to cutaneous
      in susceptible individuals. There has been particular attention looking at the
      role of cyclo-oxygenase enzymes 1 and 2 and their role in aspirin-exacerbated
      respiratory disease. OBJECTIVE: Patients who present with a spectrum of allergic
      and pseudoallergic reactions to aspirin pose a special challenge for the
      physician. This article discusses proposed classification system, clinical
      manifestations, pathogenesis of disease, and current treatment options of aspirin
      related disease. DATA SOURCES: Relevant articles in the medical literature were
      derived from searching the MEDLINE database with key terms aspirin-sensitive
      asthma, cyclo-oxygenase enzymes 1 and 2. Sources also include review articles,
      randomized control trials, and standard textbooks of allergy and immunology.
      RESULTS: Aspirin-exacerbated respiratory disease remains a complex, heterogenous
      disease with varied clinical presentations. There have been many advances in
      trying to elucidate the pathogenesis of this disease. The classification system
      presented will provide greater ease when reading the literature and communicating
      with one another. Oral aspirin challenge remains the diagnostic test of choice
      for both respiratory and cutaneous reactions. Aspirin desensitization is an
      option for those with refractory respiratory disease or who require aspirin for
      other medical conditions. CONCLUSIONS: This review discusses the challenges in
      classification, diagnosis, and treatment of those patients with a sensitivity to
      aspirin. Special attention is made to the possible mechanisms mediating disease
      progression and how specific therapies, such as leukotriene modifiers, may be
      helpful.

PMID- 12487219
TI  - Viral respiratory infections in association with asthma and sinusitis: a review.
AB  - OBJECTIVE: Viral respiratory infections (VRIs) commonly precede asthma
      exacerbations in both children and adults. Likewise, VRIs may affect the
      paranasal sinuses, predisposing infected individuals to the development of
      subsequent acute bacterial sinusitis. This article discusses the role that
      viruses play in both the development of asthma and in acute asthma exacerbations.
      Mechanisms by which viral infections provoke asthma exacerbations are reviewed,
      and treatment of such episodes is discussed. The pathogenesis of sinusitis and
      association with VRIs is reviewed along with treatment recommendations. DATA
      SOURCES: Relevant articles in the medical literature were reviewed with sources
      including randomized, controlled clinical trials, review articles, epidemiologic
      studies, and standard textbooks in allergy and immunology. CONCLUSIONS: This
      review highlights the prominent role that viral pathogens (especially rhinovirus)
      play in exacerbation of asthma and in the development of sinus disease. The
      specific mechanisms whereby viral infection leads to an acute asthma exacerbation
      or to subsequent bacterial sinusitis are described. Treatment options are
      outlined including the potential future application of antiviral compounds.

PMID- 12487220
TI  - Facial swelling and eosinophilia in a 44-year-old woman.

PMID- 12487221
TI  - Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide:
      comparison between dry powder inhaler and pressurized metered-dose inhaler
      attached to a spacer.
AB  - BACKGROUND: Dry powder inhalers (DPI) have in recent years become a common mode
      for administration of inhaled corticosteroids for preventive therapy of asthma.
      Inhaled steroids delivered by DPI achieve increased lung deposition compared with
      pressurized metered-dose inhalers (pMDI), which is associated with increased
      therapeutic effect. This may be associated with increased systemic absorption.
      OBJECTIVE: The purpose of this study was to evaluate the prevalence of adrenal
      suppression in children using low-dose budesonide given by DPI, as compared with
      pMDI attached to a large-volume spacer device (pMDI + spacer). METHODS: In an
      open-labeled crossover study, 15 asthmatic children aged 5 to 15 years received
      200 microg of inhaled budesonide twice daily by DPI (Turbuhaler, Astra, Draco AB,
      Lund, Sweden) and by pMDI + spacer, 1 month each, in a randomized order. Twenty
      four-hour urine collections were performed at baseline and at the end of each of
      the 2 months of the study period, and urinary cortisol and creatinine were
      measured. RESULTS: Baseline urinary cortisol:creatinine was 0.038 +/- 0.012
      microg/mg, similar in both groups. After 1 month of DPI therapy, urinary
      cortisol:creatinine was reduced by 27 +/- 16% to 0.028 +/- 0.012 microg/mg (P =
      0.018). Urinary cortisol:creatinine after 1 month of pMDI + spacer therapy was
      similar to baseline 0.037 +/- 0.019 microg/mg (P = 0.78). CONCLUSIONS: Treatment
      of asthmatic children with budesonide 400 microg daily given via a DPI for 1
      month was associated with hypothalamic-pituitary-adrenal axis suppression. This
      effect was not observed with the same dose of budesonide administered via pMDI +
      spacer. This indicates that systemic absorption might be reduced with pMDI +
      spacer therapy.

PMID- 12487222
TI  - Caregiver negative affect is a primary determinant of caregiver report of
      pediatric asthma quality of life.
AB  - BACKGROUND: Quality of life has increased in popularity as an outcome measure in
      health research. However, the measurement of quality of life has been questioned
      on methodologic grounds, as it often shows little association with objective
      measures of disease status. OBJECTIVE: For this report we studied the
      determinants of pediatric asthma caregiver report of quality of life and its
      relationship to disease burden. METHOD: Ninety-eight children who were admitted
      to a Pediatric Day Program for an asthma evaluation were enrolled in an outcome
      study. A complete set of medical records for the 2-year period before and after
      the admission was collected and systematically coded for health care utilization.
      Using the Pediatric Asthma Caregiver's Quality of Life Questionnaire, data were
      collected at baseline, discharge, and year after the admission. Caregiver
      negative affect (anxiety and depression), measured with the Brief Symptom
      Inventory, was also collected at baseline and discharge. RESULTS: Caregiver
      report of quality of life was unrelated to health care utilization at baseline
      but instead was significantly related to baseline caregiver negative affect. A
      significant relationship between health care utilization and quality of life was
      present at followup. The Emotional Function scale from the quality of life
      measure can account for most of the relationship between quality of life and
      negative affect. CONCLUSIONS: Caregiver affect may have a considerable influence
      on report of quality of life. Understanding the individual characteristics of the
      respondent is important when using a quality of life instrument as an outcome
      measure.

PMID- 12487224
TI  - Lactic acidosis and status asthmaticus: how common in pediatrics?
AB  - BACKGROUND: Lactic acidosis is a well described phenomenon in adult patients with
      severe asthma. However, this entity is rarely reported in children with status
      asthmaticus. OBJECTIVE: To report our experience in a 13-year-old girl who
      developed lactic acidosis as a complication of status asthmaticus and to
      investigate the prevalence of this complication of severe asthma. We sought to
      determine the frequency of lactic acidosis in such patients and to review
      etiologies of lactic acidosis. METHODS: 1) Observations on the clinical and
      laboratory findings in an adolescent girl with status asthmaticus who developed
      lactic acidosis were recorded. 2) The medical records of 100 children and
      adolescents with status asthmaticus admitted to an intensive care unit were
      reviewed for laboratory evidence of lactic acidosis. 3) We also reviewed our own
      previous experience of status asthmaticus with respiratory failure. RESULTS:
      Among 100 patients admitted to a pediatric intensive care unit for status
      asthmaticus, a single case of isolated metabolic acidosis was identified. This
      proved to be attributable to lactic acidosis. When records of patients with
      severe respiratory failure were examined, no cases of metabolic acidosis were
      found. CONCLUSIONS: Although rare, lactic acidosis does occur in pediatric-aged
      patients during status asthmaticus. It is important that this complication be
      recognized and treated because acidosis may inhibit the effectiveness of
      bronchodilator therapy, produce electrolyte disturbances, and cause serious
      adverse effects on the patient's cardiovascular system.

PMID- 12487223
TI  - Effects of fexofenadine on the early response to nasal allergen challenge.
AB  - BACKGROUND: Previous studies using nasal allergen challenge models have shown
      that terfenadine, an H1 antihistamine, inhibits histamine release during the
      early response to allergen provocation. Fexofenadine, the active metabolite of
      terfenadine, has strong H1-antihistaminic activity and no cardiac effects.
      Clinical studies have documented the efficacy of fexofenadine in the treatment of
      allergic rhinitis. OBJECTIVE: To determine whether fexofenadine, like
      terfenadine, inhibits histamine and tryptase release during the early allergic
      response. METHODS: Randomized, double blind, placebo-controlled, two-way
      crossover study in 20 subjects with seasonal allergic rhinitis, out of their
      allergy season (median age 27.5 years, 13 males and 7 females). Subjects were
      medicated with either placebo or fexofenadine 180 mg orally daily for 1 week
      followed by nasal challenge with allergen. After each challenge, sneezes and
      nasal symptoms were recorded, and a nasal lavage was obtained for the assay of
      albumin, an indicator of vascular permeability, and histamine and tryptase,
      indicators of mast cell degranulation. RESULTS: When patients were on placebo,
      allergen challenges led to significant increases in all measured parameters
      compared with the sham challenges with diluent. Treatment with fexofenadine
      resulted in inhibition of allergen-induced symptoms and increased vascular
      permeability, but not the release of histamine and tryptase. CONCLUSION:
      Fexofenadine is an effective H1 antihistamine, but in contrast to its parent
      compound, terfenadine, it does not affect the release of the mast cell mediators
      histamine and tryptase.

PMID- 12487225
TI  - The comparison of the efficacy and safety of cetirizine, oxatomide, ketotifen,
      and a placebo for the treatment of childhood perennial allergic rhinitis.
AB  - BACKGROUND: There has been no study comparing the long-term effects of ketotifen,
      oxatomide, and cetirizine for the treatment of perennial allergic rhinitis among
      children. OBJECTIVE: We conducted a study to compare the efficacy of the three
      agents for the treatment of perennial allergic rhinitis among children. METHODS:
      The study consisted of a double-blind, placebo-controlled, randomized design,
      comprising 69 perennial allergic rhinitis patients with mite allergy, aged 6 to
      12 years, randomly assigned to 1 of 4 test treatment groups for 3 months: 19 in
      the cetirizine group (10 mg daily), 18 in the ketotifen group (1 mg, twice
      daily), 16 in the oxatomide group (1 mg/kg, twice daily), and 16 in the placebo
      group. We used the nasal symptom score of diary card and the Pediatric
      Rhinoconjunctivitis Quality of Life Questionnaire and eosinophil cation protein
      peripheral blood total eosinophil count and immunoglobulin E level, eosinophil
      proportion from a nasal smear, and nasal peak expiratory flow rate to evaluate
      the effect of the four agents. RESULTS: Cetirizine was significantly more
      effective at reducing the mean rhinorrhea score compared with oxatomide for both
      weeks 8 and 12 (P < 0.01). Before the end of week 12, cetirizine was
      significantly more effective than ketotifen (P < 0.01). Cetirizine and oxatomide
      significantly decreased the mean Pediatric Rhinoconjunctivitis Quality of Life
      Questionnaire score compared with the placebo for week 12 (P < 0.05).
      CONCLUSIONS: Cetirizine was more effective than oxatomide and ketotifen for the
      relief of nasal congestion and rhinorrhea, and was responsible for significantly
      decreasing the eosinophil representation of a posttreatment nasal smear.

PMID- 12487226
TI  - Anti-inflammatory effects of montelukast in mild cystic fibrosis.
AB  - BACKGROUND: Immune-mediated inflammation contributes to progressive pulmonary
      damage in cystic fibrosis (CF). Sputum cysteinyl leukotriene levels, eosinophil
      cationic protein (ECP), and interleukin-8 (IL-8) are significantly related to
      disease severity. OBJECTIVE: The aim of this study was to evaluate the anti
      inflammatory and clinical effects of the cysteinyl leukotriene receptor
      antagonist montelukast in children with CF. METHODS: A double-blind, randomized,
      crossover design was used. Patients received montelukast (6 to < or = 14 years, 5
      mg; > 14 years, 10 mg) or placebo as a once-daily tablet for 21 days and then,
      after a washout period of at least 4 weeks, crossed over to receive the
      alternative treatment. Blood and native nasal fluid were taken on days 1 and 21
      of each treatment block, and WBC count, ECP, and IL-8 were analyzed using a
      chemiluminescent immunometric assay. RESULTS: Sixteen CF patients (10 boys, 6
      girls; age, 5 to 18 years, median 9.5 years) completed the trial. There was a
      significant (P < or = 0.02) reduction of serum ECP (median reduction: montelukast
      7.7 microg/L vs placebo 0.15 microg/L) and eosinophils (P < or = 0.027; median
      reduction: montelukast 85/microL vs placebo 0/microL). There was no significant
      change in nasal ECP, IL-8, or serum IL-8 after a 21-day course of montelukast.
      Clinical symptom scores did not change significantly. CONCLUSIONS: Montelukast
      reduces eosinophilic inflammation in CF patients. Multicenter trials providing
      more patients to create more data to prove the hypothesis that montelukast is an
      effective tool to cut down disease severity in CF patients are needed.

PMID- 12487227
TI  - Lack of correlation between bronchial late allergic reaction to Dermatophagoides
      pteronyssinus and in vitro immunoglobulin E reactivity to histamine-releasing
      factor derived from mononuclear cells.
AB  - BACKGROUND: Activity of immunoglobulin (Ig)E-dependent histamine-releasing factor
      (HRF) is dependent on the IgE molecules bound to the surface of basophils. Sera
      capable of passively sensitizing basophils to release histamine to HRF were
      designated IgE+ sera. IgE+ and HRF have been suggested to play a role in late
      allergic reaction (LAR). OBJECTIVE: The working hypothesis was tested that IgE+
      induces a LAR. Further, activity of HRF produced by mononuclear cells (HRF(mn))
      was compared with that of recombinant HRF p23. METHODS: Atopic patients (n = 82)
      were bronchially provoked with Dermatophagoides pteronyssinus extract and the
      change in forced expiratory volume in 1 second was monitored. A LAR was defined
      as forced expiratory volume in 1 second as percentage of baseline < 80% 4 to 10
      hours after allergen challenge. The presence of HRF-responsive IgE in serum was
      determined using basophils sensitized in vitro by serum. RESULTS: The presence of
      HRF(mn)-responsive IgE (IgE(mn+)) in serum was shown not be essential for a LAR:
      63% of the patients with a LAR had no IgE(mn+) in their serum. Further, 71% of
      patients with IgE(mn+) did not have a LAR. HRF(mn) and recombinant HRF p23 were
      not equivalent in the bioassay: serum of 38 of 82 atopic patients sensitized
      basophils to release histamine to HRF(mn), whereas this was found with serum of 1
      of 82 patients to HRF p23. CONCLUSIONS: The results do not support the hypothesis
      that IgE(mn+) induces a LAR, but do not exclude the alternative hypothesis that
      HRFs are released during a LAR and contribute to asthma severity.

PMID- 12487228
TI  - Evaluation of patatin as a major cross-reactive allergen in latex-induced potato
      allergy.
AB  - BACKGROUND: Potential cross-reactions between natural rubber latex and
      fruit/vegetable specific immunoglobulin (Ig)E antibodies have been reported for
      many years. This study was designed to investigate the molecular basis of
      acquired food sensitization focusing on the storage protein patatin and the
      patatin-like latex protein Hev b 7. OBJECTIVE: The amount of potato-specific IgE
      in the serum of latex-allergic health care workers and children with atopic
      dermatitis was determined to evaluate cross-reactivity between Hev b 7 and
      patatin. Additionally, the stability of potato patatin to digestion was
      investigated. METHODS: Human serum was tested on its reactivity to latex and
      potato proteins by IgE immunoblotting after one-dimensional (1-D) and 2-D
      electrophoresis. Latex- and potato-specific IgE concentrations were measured in
      fluorescence enzyme immunoassays (CAP, Pharmacia, Uppsala, Sweden). Further,
      potato patatin was chromatographically isolated to perform auto-inhibition tests.
      Stability of patatin to degradation was determined by digestion in vitro.
      RESULTS: Patatin was identified as major cross-reactive potato allergen by N
      terminal sequencing. Seventy-five percent of the potato-sensitized people reacted
      with patatin in 1-D immunoblots, and 25% of the positive reactions to Hev b 7
      could be blocked by preincubation of the patients' sera with purified potato
      patatin. Examination of children with atopic dermatitis showed that most sera
      contained patatin-specific IgE, whereas no Hev b 7-specific IgE was detected.
      Finally, patatin has been found partially stable to digestion in vitro.
      CONCLUSIONS: Patatin was identified as a major cross-reactive protein in latex
      associated potato allergy and appears to be relevant for atopic dermatitis.
      Therefore, patatin could be a suitable marker for the determination of potato
      sensitization, and it may also constitute an important food allergen. Cross
      reactivity between Hev b 7 and patatin was restricted to primarily latex
      sensitized adults, suggesting a different mechanism of sensitization in children
      with atopic dermatitis.

PMID- 12487229
TI  - Longitudinal changes in airflow limitation and airway hyperresponsiveness in
      patients with stable asthma.
AB  - BACKGROUND: There are few long-term studies of the effects of treatment on the
      natural course of asthma. OBJECTIVE: To investigate the longitudinal changes in
      airflow limitation and airway hyperresponsiveness (AHR) in asthma. METHODS: We
      recruited 81 outpatients (never smokers) with stable asthma from the Kyoto
      University Hospital. They were evaluated for pulmonary function and AHR,
      expressed by forced expiratory volume in 1 second (FEV1) and the provocation dose
      that caused a 20% fall in FEV1 (PD20-FEV1), respectively, at entry and every 6
      months over 3 years. We used random effects models to estimate the slopes of
      these changes, and then evaluated the relationship between these changes and
      their predictive factors. RESULTS: Using random effects models, the percentage of
      the predicted FEV1 (%FEV1) declined significantly but slightly at a mean rate of
      0.5%/year (P = 0.002; 95% confidence interval, 0.3 to 0.8). The mean decline rate
      of FEV1 was 34 mL/year. However, Log(PD20-FEV1) showed significant improvement at
      a mean rate of 0.088 cumulative units/year (P < 0.001; 95% confidence interval,
      0.053 to 0.122). Multiple regression analysis showed that the baseline values of
      %FEV1 and Log(PD20-FEV1) were the most significant predictive factors for their
      subsequent changes, respectively. CONCLUSIONS: In stable asthmatic patients
      treated according to international guidelines, airflow limitation progressed at a
      nearly normal rate over 3 years. However, AHR continued to improve despite its
      ceiling effects. Multiple regression analysis revealed a significant negative
      relationship between the initial values and the subsequent changes in airflow
      limitation and AHR, respectively.

PMID- 12487230
TI  - Introduction: Progress and issues in drug treatment courts.
AB  - The first drug treatment court began in Miami, Florida in 1989, in direct
      response to the backlog of court cases for drug possession and trafficking. By
      mid-2001, there were 700 operational drug treatment courts and 400 more in the
      planning stages in the United States. In addition to providing an overview of the
      growth and development of drug treatment courts in the United States, this
      special issue examines their development in Australia, Canada, and the United
      Kingdom. The primary focus is the evaluation research conducted to date, which
      identifies some of the critical unresolved issues facing drug treatment courts.

PMID- 12487231
TI  - A dozen years of drug treatment courts: uncovering our theoretical foundation and
      the construction of a mainstream paradigm.
AB  - The creation of the first drug treatment courts were in response to the revolving
      door of drug use and recidivism. There was no theoretical basis for these courts
      and no universal support for them. Twelve years have brought incredible changes.
      Therapeutic jurisprudence says, in essence, whether intended or not, that legal
      rules and procedures have therapeutic effects. Drug treatment courts have adopted
      principles of TJ to enhance their functioning. The Conference of Chief Justices
      recently issued a resolution supporting "problem-solving" courts. New trial court
      standards legitimize drug courts' procedures. Drug treatment courts are now
      mainstream and can no longer be seen as "boutique" courts staffed by renegade
      judges. Working therapeutically is an appropriate, effective, and productive way
      for the justice system to function.

PMID- 12487232
TI  - A decade of drug treatment court research.
AB  - As drug treatment courts have multiplied over the past decade, so too have
      research evaluations conducted on their implementation and effectiveness. This
      article explores the decade of drug treatment court research conducted at RAND,
      starting with the experimental field evaluation of Maricopa's drug testing and
      treatment options to the most current 14-site national evaluation of courts
      funded in 1995-96 by the Drug Court Program Office. The article presents
      summaries of findings, a brief description of a drug treatment court typology,
      and suggestion of where future research might focus.

PMID- 12487233
TI  - Drug treatment courts--a viable option for Canada? Sentencing issues and
      preliminary findings from the Toronto court.
AB  - The first drug treatment court in Canada began operation in Toronto in December
      of 1998. This paper describes some aspects of the evolution, structure, and
      operation of this court. In addition, the federally-funded evaluation of the new
      program has produced data from the first 18 months of its full operation when 198
      drug-dependent individuals were admitted. These preliminary results are described
      and compared to the findings of an Australian study and to select American
      studies. Important differences in sentencing practices and options for drug
      offenses between Canada and the United States are highlighted. Even at this early
      stage of development, it is suggested that the types of clients retained and more
      successful in this Canadian experiment may be quite different from the more
      typical American drug treatment court clientele. The need for careful monitoring
      and more complete, long-term information is emphasized before the viability of
      this approach is established for Canada.

PMID- 12487234
TI  - The emergence of drug treatment courts in Australia.
AB  - The paper begins by placing the emergence of drug treatment courts within the
      context of rising property crime rates, the development of open-air illicit drug
      markets, and the rise in opiate overdoses in Australia. The paper then highlights
      the way in which the U.S. concept of drug treatment courts was adopted and
      adapted by state politicians in attempts to deal with drug-use-related offenders.
      This response has been specifically targeted at repeat property offenders "at
      risk" of imprisonment, and comes within the broad brush of harm minimization
      strategies for diverting offenders with a drug-use-related problem away from the
      traditional criminal justice response of imprisonment. The prospects for the
      future of drug treatment courts in a Federalist system are also discussed.

PMID- 12487235
TI  - Drug treatment courts, British style: the drug treatment court movement in
      Britain.
AB  - There has been an uneven pattern of development of drug treatment courts
      throughout Britain. The Republic of Ireland has a drug treatment court and
      Scotland will have one by the end of 2001, but there are no drug treatment courts
      in England and Wales, or Northern Ireland, although in the latter there is a
      growing interest. It is suggested the Drug Treatment and Testing Order (DTTO) in
      England and Wales has acted as an impediment as this is a very weak version of
      drug treatment court and was proposed by the Prime Minister when Shadow Home
      Secretary. Drug treatment courts in Eire and Scotland have adapted their program
      to fit local conditions, although neither have opted for a fully fledged drug
      user treatment court on the Miami model.

PMID- 12487236
TI  - Factors associated with completion of a drug treatment court diversion program.
AB  - Factors related to successful completion of a first offender diversion program
      were examined from initial data of a longitudinal study of drug treatment court
      outcomes in Delaware. The strongest predictors of success were factors associated
      with social stakeholder values, especially those involving employment. Other
      factors associated with program completion included race, education, and
      frequency of drug use. While the overall success of drug treatment courts
      continues to be documented, these data suggest success varies with individual
      characteristics. The continuing study will explore whether these characteristics
      are also related to subsequent outcomes, especially drug use relapse and criminal
      recidivism, over a 24-month post-treatment period.

PMID- 12487237
TI  - The challenges of conducting research in drug treatment court settings.
AB  - National and local interest in drug treatment courts has grown substantially
      since the first program was established in Miami (FL) in 1989. Through May 2001,
      there were 688 operational drug treatment courts and 432 in various stages of
      planning. The U.S. Department of Justice provides about $50 million annually to
      fund the planning and implementation of drug treatment courts. Despite this
      support and widespread popularity, there has been relatively little rigorous
      empirical research on the operations, impacts, and economic impacts of drug
      treatment courts. This article explores the development of drug treatment court
      research over the past ten years, the current state of research on drug treatment
      courts, and the organizational and scientific challenges to conducting research
      in these settings. Recommendations are presented for improving the scope and
      rigor of drug treatment court research.

PMID- 12487238
TI  - Treatment inside the drug treatment court: the who, what, where, and how of
      treatment services.
AB  - Drug treatment courts provide a new strategy for providing treatment services to
      offenders within the criminal justice system. With over 400 drug treatment courts
      in the United States, the courts have evolved to provide treatment services under
      different models. This article will review the different typologies for delivery
      of treatment services to drug user offenders in the drug treatment court setting,
      and it will raise questions about some of the difficult issues underscoring an
      integrated service delivery model. The paper then identifies some research
      questions for the future.

PMID- 12487239
TI  - Juvenile drug treatment courts in the United States: initial lessons learned and
      issues being addressed.
AB  - This paper provides an overview of the development of juvenile drug treatment
      court programs in the United States; the goals of these programs; a comparison of
      the traditional juvenile justice process and services with that of the juvenile
      drug treatment court; and principal areas in which the juvenile drug treatment
      court experience has differed from that of the adult drug treatment court. The
      paper also provides a description of early models and the modifications and
      enhancements that have subsequently been instituted to enhance program
      effectiveness; a summary description of the range of juvenile drug treatment
      court activity currently underway in the United States; the nature of substance
      use and other issues presented by participating youth; and the major challenges
      juvenile drug treatment courts are currently addressing.

PMID- 12487240
TI  - Drug treatment courts and the disease paradigm.
AB  - A defining feature of the drug treatment court movement is the judicial adoption
      of the disease model for explaining drug using behavior; an interpretive paradigm
      that historically has not played a defining role in the adjudication of drug
      offenders. In drug treatment courts, however, the disease model finds a very
      central place in the adjudicative process, and profoundly shapes the way judges
      view and treat defendants. This article examines the application of the disease
      model to drug and non-drug-related crimes in the context of drug treatment
      courts, and considers the significance of these developments as it concerns the
      meaning of criminal justice.

PMID- 12487241
TI  - Parathyroid introduction.

PMID- 12487242
TI  - Sestamibi scintigraphy for the application of minimally invasive surgery of
      hyperfunctioning parathyroid lesions.
AB  - Complete surgical resection of hyperfunctioning parathyroid tissue is essential
      for the curative treatment of hyperparathyroidism. It is very important to
      identify the accurate location of the affected parathyroid glands by imaging
      tests to successfully achieve this surgical treatment. Tc-99m labeled sestamibi
      is a radiopharmaceutical with high affinity for endocrinologically active
      parathyroid tissue, and scintigraphic evaluation using this radioactive agent is
      very useful in confirming the location of the affected parathyroid glands. The
      recent remarkable development of hand-held gamma-ray detectors makes it easy to
      perform radio-guided surgery, which is a combination of a preoperative
      intravenous injection of sestamibi and intraoperative navigation by the gamma
      rays radiating from the pathological sites. This strategy can be easily applied
      to the resection of the ectopically located gland and is also useful to confirm
      the absence of endocrinologically active tissue after the operation. Additional
      chest SPECT imaging might be effective in the risk assessment of cardiac
      incidence in the perioperative period, as sestamibi was originally developed for
      the evaluation of myocardial perfusion. In conclusion, Tc-99m sestamibi will be
      more popularly applied to the treatment of hyperparathyroidism as minimally
      invasive surgery increases in favor.

PMID- 12487243
TI  - Direct mini-incision parathyroidectomy.
AB  - We describe our technique for performing a mini-incision parathyroidectomy in
      patients with hyperparathyroidism. Since our procedure differs from conventional
      parathyroidectomy in requiring a 2- or 3-cm skin incision and no raising of skin
      flap, this technique resulted in a good cosmetic status and less invasiveness.
      Hypesthesia or paresthesia in the neck and discomfort while swallowing related to
      a large skin incision and raising of skin flap are minimized. Although the
      cosmetic results of endoscopic techniques are better than those of our
      procedures, endoscopic instruments remain traumatic, can easily inflict
      iatrogenic lesions to parathyroid adenomas and enhance the risk of tumor cell
      exfoliation, especially if the parathyroid adenoma is manipulated by the
      instruments. Our surgical procedure can be less technically demanding and time
      consuming. Although the number of patients whom we have treated in this manner is
      still small, we believe that our new procedure constitutes a useful surgical
      treatment for hyperparathyroidism.

PMID- 12487244
TI  - Video-assisted parathyroidectomy.
AB  - A parathyroid tumor is not larger than other tumors, so minimally invasive
      surgery has long been a major focus of parathyroid surgeons. Improving endoscopic
      instruments has facilitated the recent changes in approaches to parathyroid
      surgery. Endoscopic parathyroidectomy is developed in a totally closed space with
      CO2 gas insufflation. This method has a risk of complications, such as extensive
      emphysema or hypercarbia. Minimally invasive video-assisted parathyroidectomy
      (MIVAP) has greater safety, low cost, easy procedure and flexibility in changing
      the working space including conversion to open method when compared with
      endoscopic parathyroidectomy. MIVAP can be performed with only a 1-1.5-cm small
      incision on the neck. MIVAP is indicated in the patient with parathyroid adenoma
      or renal hyperplasia that is defined preoperatively using ultrasonography and
      99mTc-methoxyisobutylisonitrile (MIBI) scan. Furthermore, the radio-guided
      technique using nuclear navigation after preoperative administered MIBI is being
      developed. This method is so useful during MIVAP that we combined MIVAP and radio
      guided surgery to develop minimally invasive radio-guided and video-assisted
      parathyroidectomy (MIRVAP). After injection of 600 MBq of MIBI, intraoperative
      nuclear mapping was performed using a hand-held gamma probe. Then we expected to
      find swollen parathyroid tumor at surgery when radioactivity at a level
      relatively higher than background was found. Following this mapping result, MIVAP
      was started and succeeded. The radio-guided technique is also indicated for open
      parathyroidectomy (radio-guided open parathyroidectomy, RGOP) in multiglandular
      disease (MGD) when it was not possible to identify those lesions completely, for
      instance in asymmetric hyperplasia, such as multiple endocrine neoplasia (MEN) 1.
      In conclusion, MIVAP is beneficial for minimal invasiveness and cosmesis.
      Furthermore, radio-guided parathyroidectomy (MIRVAP and RGOP) is more useful and
      feasible. Improvement of endoscopic instruments and modification of the dose of
      MIBI administered might facilitate treating more cases by MIRVAP instead of RGOP.

PMID- 12487245
TI  - Total endoscopic parathyroidectomy.
AB  - During the last five years, minimally invasive procedures have been adopted for
      the surgical treatment of hyperparathyroidism, because preoperative localization
      studies such as high-resolution ultrasonography and sestamibi scintigraphy,
      guidance by intraoperative scans, and the use of quick, intraoperative
      parathyroid hormone assay have improved. Endoscopic parathyroidectomy was
      performed by Gagner in 1996, and surgical procedures using endoscopy have been
      devised. The endoscopic procedures range from the "pure" endoscopic approach
      characterized by constant gas insufflation to video-assisted gasless techniques.
      We adopted the "pure" endoscopic approach, because a small incision can be made
      far from the neck and the cosmetic result is excellent. We report our technique
      with no scars in the neck region for endoscopic unilateral neck exploration with
      primary hyperparathyroidism and for endoscopic bilateral neck exploration with
      renal hyperparathyroidism.

PMID- 12487246
TI  - Intraoperative quick parathyroid hormone assay in the surgical management of
      hyperparathyroidism.
AB  - Intraoperative quick parathyroid hormone (QPTH) assay is claimed to prevent
      failure during parathyroidectomy for hyperparathyroidism. The causes of operative
      failure have included multiglandular disease, ectopic parathyroid glands,
      supernumerary parathyroid glands, errors in frozen section evaluations, and
      missed diagnosis. A QPTH assay has been recognized as a useful method of
      determining whether hyperfunctioning tissues have been completely excised.
      However, an intraoperative QPTH assay may fail to detect the presence of double
      parathyroid adenomas. Use of this assay in conjunction with preoperative and
      intraoperative localization studies has led to the advocacy of more directed
      cervical procedures, such as limited, video-assisted, and endoscopic
      parathyroidectomy.

PMID- 12487247
TI  - Minimally invasive parathyroidectomy under local anesthesia.
AB  - Primary hyperparathyroidism is commonly associated with uniglandular swelling,
      and thus the lesion has been localized before surgical reduction. Since March
      1997, we have performed uniglandular parathyroidectomy under local anesthesia
      with combined scintigram and ultrasound tomography in patients with primary
      hyperparathyroidism preoperatively identified for uniglandular swelling. We had
      seen consecutive 18 patients with primary hyperparathyroidism until April 2001;
      15 of those underwent surgical reduction. Postoperative intact PTH value was
      normalized in 14 patients. The remaining patient, diagnosed with thyroid adenoma,
      required re-surgery due to proved intake on scintigram a year later. Mean follow
      up period is 33 months, and the disease does not relapse. In addition, we removed
      the swollen gland in two patients with renal hyperparathyroidism under local
      anesthesia; the disease involved two glands in a patient and one gland in another
      patient. After surgery, their subjective symptoms including itching and
      arthralgia were eliminated, and did not relapse at 30 and 14 months,
      respectively. Minimally invasive parathyroidectomy under local anesthesia might
      be performed as a same-day surgery, and improve QOL of patients.

PMID- 12487248
TI  - Thoracoscopic excision for ectopic mediastinal parathyroid tumor.
AB  - Ectopic parathyroid adenoma or hyperplasia in the mediastinum are seen in a
      percentage of patients with hyperparathyroidism and have generally been treated
      by conventional open surgery. However, due to recent improvements in the ability
      of diagnostic imaging such as 99mTc-methoxyisobutylisonitrile (MIBI) scintigraphy
      to identify these lesions, we have been obtaining favorable results from
      thoracoscopic excision of mediastinal parathyroid tumors. In thoracoscopic
      surgery, three to four trocars were inserted between the fourth and seventh ribs
      from a lateral approach. Based on diagnostic imaging, tumors were identified and
      excised by the shortest possible route. Surgery time for four consecutive
      patients ranged from 50 to 140 min, and hemorrhage volumes were small. No intra-
      or postoperative complications were observed, and the postoperative course for
      these patients has been uneventful. Analgesia was required only a few times for
      each patient. In the most recent patient, radioisotope-navigated thoracoscopic
      excision was performed using 99mTc-MIBI. When thoracoscopic excision was combined
      with radioisotope navigation, tumor identification took less time, cutting the
      surgery time in half and ultimately placing less stress on the patient.

PMID- 12487249
TI  - Minimally invasive radioguided parathyroidectomy.
AB  - The recent development of radioguided parathyroidectomy has allowed
      parathyroidectomy to be quickly performed by a significantly less invasive
      procedure. Radioguided parathyroidectomy is also likely to decrease operation
      time, risk of complications, hospital stay, and the overall cost of patient care,
      result in a smaller scar and rapid, nearly pain-free recovery, and allow local
      anesthesia. Despite these apparent benefits, a case-control study showed no
      distinct advantages of employing intraoperative sestamibi identification during
      parathyroidectomy.

PMID- 12487250
TI  - Prognosis of parathyroid function after minimally invasive radioguided
      parathyroidectomy (MIRP) and percutaneous ethanol injection therapy (PEIT) for
      primary hyperparathyroidism.
AB  - During parathyroidectomy (PTx) for primary hyperparathyroidism (PHP), we
      surgically explored the contralateral parathyroid glands as well as those whose
      localization was clarified by ultrasonography and parathyroid scintigraphy.
      Although it is important to explore the contralateral side and other glands, we
      frequently treat only the gland whose localization is confirmed. Recently, we
      have performed minimally invasive radioguided parathyroidectomy (MIRP) that
      resects only one gland observed on the imaging under technetium 99m-labeled
      sestamibi (MIBI) scanning guidance after obtaining prior informed consent. In
      this surgery, even if recurrence is observed contralaterally, it is possible to
      apply a similar procedure to the contralateral side again. We examined six PHP
      patients who underwent MIRP and two PHP patients treated with percutaneous
      ethanol injection therapy (PEIT). The follow-up period was 2 years. PEIT was
      selected as a treatment method for two patients based on the patients'
      characteristics. When only one gland is treated, the efficacy of PEIT was
      considered to be similar to that of MIRP.

PMID- 12487251
TI  - Endoscopic neck surgery: current status for thyroid and parathyroid diseases.
AB  - During the last 3 years, 59 patients underwent endoscopic neck surgery. We
      started the video-assisted neck surgery with the gasless skin-lifting method for
      benign thyroid and parathyroid diseases to avoid complications of carbon dioxide
      (CO2) insufflation. Hemithyroidectomy was performed for benign thyroid tumors and
      subtotal thyroidectomy was selected for Graves' disease. Parathyroid adenomas
      were extirpated for primary hyperparathyroidism with precise preoperative
      localization by imaging modalities. In order to obtain a better visual field and
      to improve the cosmetic results, we have adopted the complete endoscopic method
      via breast approach with low CO2 insufflation pressure since August 2001. An
      intraoperative parathormone assay was introduced recently to confirm the complete
      removal of parathyroid adenomas. Both gasless and insufflation methods are
      feasible for endoscopic neck surgery with excellent cosmetic results.

PMID- 12487252
TI  - Thyroid introduction.

PMID- 12487253
TI  - Thyroid ultrasonography B-mode and color-Doppler.
AB  - Recently, ultrasonography of the thyroid gland has proved to be a useful clinical
      diagnostic method. The newly developed high-resolution ultrasonography with color
      Doppler flow mapping function can reveal fine details of the thyroid gland and
      the hemodynamic features of thyroid neoplasmas. Ultrasonography can deliver a
      diagnostic accuracy of over 90% in thyroid carcinoma, especially papillary
      carcinoma. However, in the case of follicular carcinoma, neither conventional B
      mode ultrasound imaging nor aspiration biopsy cytology can deliver satisfactory
      results. Color-Doppler imaging examination of 212 follicular tumors has been
      carried out, resulting in the characteristic finding that a high-velocity
      pulsative blood flow penetrates the tumor in the case of follicular carcinoma,
      which led to new diagnostic criteria with color-Doppler examination. The
      differential diagnostic grading score using color-Doppler examination and FFT
      analysis can show a dramatic diagnostic accuracy of 81.0%, a sensitivity of 88.9%
      and a specificity of 74.2%. Ultrasound with the color-Doppler function can play a
      more important role in the differential diagnosis of thyroid tumors.

PMID- 12487254
TI  - Direct mini-incision thyroidectomy.
AB  - We recently developed a new surgical technique for carrying out thyroidectomy, to
      minimize surgical invasiveness and improve the cosmetic result. Our procedure
      differs from conventional thyroidectomy in requiring a 3-cm skin incision and no
      raising of the skin flap. Since this technique decreased tissue trauma by
      obviating unnecessary neck exploration, hypesthesia or paresthesia in the neck
      and discomfort while swallowing, related to a large skin incision and raising of
      the skin flap, are minimized. Since thyroidectomy is performed after delivering
      the thyroid gland through the small skin incision, sufficient exposure for
      dissection of the pretracheal and paratracheal space can be obtained. Therefore,
      injuring the recurrent laryngeal nerve and the parathyroid gland can be avoided.
      Although the number of patients that we have treated in this manner is still
      small, we believe that our new procedure constitutes a useful surgical treatment
      for patients with thyroid disease.

PMID- 12487255
TI  - Total endoscopic and video-assisted thyroidectomy: cervical approach.
AB  - Several procedures have been proposed for surgical treatment of the thyroid
      nodule; they have not gained wide acceptance, however, because of the expertise
      required, the relatively long operation times, the wide dissection needed to
      create a working space, and the extra cost of specialized instruments, especially
      when port sites are created in the remote area. These barriers have led some
      surgeons to perform video-assisted thyroidectomy via the neck. We describe the
      indications for, procedures related to, and results of both total endoscopic
      thyroidectomy and video-assisted thyroidectomy via the neck. Excellent cosmetic
      results were obtained by both procedures; however, video-assisted procedures
      required less time and a smaller dissection area.

PMID- 12487256
TI  - Total video endoscopic thyroidectomy via the anterior chest approach using the
      cervical region-lifting method.
AB  - Endoscopic surgery offers superior cosmetic results compared to open procedures
      and is strongly preferred by many patients, especially women. We performed total
      endoscopic thyroidectomy via the anterior chest approach using a neck skin
      lifting technique in which the skin is lifted by a large number of hooks to
      create the working space. This method is quite flexible and can be modified based
      on the size of the space needed. The fine hooks leave no scar on the anterior
      neck, the skin incisions are small, and the scars are completely covered by
      patients' undergarments. Endoscopic thyroidectomy is suitable for benign thyroid
      nodules, but some malignant foci diagnosed by frozen section usually can be
      managed without conversion to an open procedure. Women under 45 years of age with
      nodules <2 cm who have no evidence of lymphatic spread or local invasion are
      ideal candidates for this procedure.

PMID- 12487257
TI  - Total endoscopic thyroidectomy: axillary or anterior chest approach.
AB  - We have developed endoscopic thyroidectomy by an anterior chest approach and an
      axillary approach. In this study, we evaluate the efficacy of these two types of
      endoscopic procedures and conventional open surgery. The degree of surgical
      invasiveness and the nature of patients' complaints after surgery were compared
      using the results of the operation and a questionnaire. The mean operating time
      for the endoscopic procedure was significantly longer than that for open surgery;
      however, there was no difference in postoperative pain in the three groups. Three
      months after surgery, the incidence of discomfort while swallowing in open
      surgery was higher than that in endoscopic surgery. All the patients who were
      treated using the axillary approach were satisfied with the cosmetic results.
      However, five patients (25%) who were treated using the anterior chest approach
      and 15 patients (75%; P < 0.01) who underwent open surgery complained abut the
      cosmetic results. The incidence of postoperative complaints after endoscopic
      surgery is significantly lower than that after open surgery. Patients who were
      treated using the axillary approach can obtain superior cosmetic results,
      compared with those who received other procedures.

PMID- 12487258
TI  - PEI therapy for thyroid lesions.
AB  - PEI therapy has been applied clinically as a new treatment strategy for cystic
      lesions and autonomous functioning nodules of the thyroid. Some additional
      indications currently under consideration include cold benign tumors and
      inoperable advanced cancer of the thyroid, and postoperative recurrence of
      Graves' disease. At our institution, we have treated 2323 patients with thyroid
      disease by PEI therapy from 1999 to 2001. PEI is usually administered under
      ultrasound guidance in cases of cystic lesions, and under color-Doppler guidance
      in cases of solid lesions of the thyroid, with the goal of attenuating tumor
      blood flow. In consequence, of the total 2323 cases who received PEI therapy at
      our hospital, 1989 (85.6%) were classified as showing an effective response (ER)
      or partial response (PR). There were no major complications, such as recurrent
      laryngeal nerve palsy, uncontrollable pain, bleeding, or thyrotoxicosis. Our
      results also emphasize the importance of the use of color-Doppler guidance for
      control of the injection volume of ethanol to the minimum required for completely
      attenuating the tumor vascularity.

PMID- 12487259
TI  - Sentinel lymph node biopsy in patients with thyroid carcinoma.
AB  - The subject of performing prophylactic or elective modified dissections of the
      neck in patients with clinically occult lymph nodal metastases from thyroid
      cancers is controversial since metastases to lymph nodes are associated with high
      rates of recurrences. Biopsies of sentinel lymph nodes can be performed
      successfully in patients with thyroid cancers since they can be identified with
      dyes or 99mTc. Our preliminary findings indicate that biopsies of sentinel lymph
      nodes can be useful in the treatment of thyroid cancers; however, the clinical
      significance of identifying metastases in regional lymph nodes by this technique
      remains to be determined.

PMID- 12487260
TI  - Video-assisted minimally invasive endoscopic thyroid surgery using a gasless neck
      skin lifting method--153 cases of benign thyroid tumors and applicability for
      large tumors.
AB  - Endoscopic surgery is often considered to be 'minimally invasive surgery' in the
      light of recent developments. In particular, endoscopic endocrine neck surgery is
      desirable from a cosmetic viewpoint. Here we compared the usefulness of our
      original endoscopic method of video-assisted neck surgery (the VANS method) with
      conventional surgery when challenged with the removal of thyroid tumors measuring
      more than 5 cm in diameter, based on our experience with 167 cases (162 thyroid
      tumors, five parathyroid tumors). The percentage of patients who underwent the
      VANS method of the total number of patients who underwent neck surgery was
      determined and the operative procedures used in the different surgeries were
      analyzed. The operating time and blood loss for 153 benign thyroid tumors were
      statistically compared between the small-tumor group (n = 130, < 5 cm) and the
      large-tumor group (n = 23, > or = 5 cm). More than 60% of the benign and 5.3% of
      the malignant thyroid tumors were operated on by the VANS method. Near- or
      subtotal lobectomy was the most common procedure (64.1%) for benign tumors.
      Malignancy was defined as papillary carcinoma less than 1 cm in diameter. Total
      lobectomy with lymph node clearance was performed for all malignant tumors.
      Although the operating time and the 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 support the idea
      that the VANS method is feasible, practical, and safe, and has great cosmetic
      benefits, even for the removal of large benign tumors.

PMID- 12487261
TI  - Video-assisted neck surgery for thyroid and parathyroid diseases.
AB  - BACKGROUND: Endoscopic surgery has now become a well-established modality for the
      treatment of various organ diseases. In the present study, we analyzed the
      surgical results achieved by video-assisted neck surgery (VANS) in thyroid and
      parathyroid diseases. METHODS: From January 2000 to April 2002, 87 patients
      (eight males and 79 females) with a mean age of 49 years underwent VANS. The
      preoperative diagnoses of these patients included 37 benign thyroid tumors, 30
      Graves' diseases, 17 parathyroid adenomas and three thyroid cancers. RESULTS: The
      mean operative time of VANS was 165 min for a hemithyroidectomy, 287 min for a
      subtotal thyroidectomy, and 157 min for a parathyroidectomy. The mean
      intraoperative blood loss was 60, 183 and 23 g for a hemithyroidectomy, subtotal
      thyroidectomy and parathyroidectomy, respectively. No conversion from VANS to
      conventional surgery was experienced. Three patients (3.4%) had temporary palsy
      of the recurrent laryngeal nerve. Otherwise, the postoperative courses were
      uneventful. CONCLUSIONS: VANS for thyroid and parathyroid diseases was found to
      be safe and effective. From a cosmetic point of view, a high degree of patient
      satisfaction was obtained. VANS is thus considered to be an excellent option for
      selected patients with thyroid and parathyroid diseases.

PMID- 12487262
TI  - Anterior chest wall approach for video-assisted thyroidectomy using a modified
      neck skin lifting method.
AB  - Neck endoscopic surgery is likely to prove less invasive and more cosmetically
      advantageous than conventional methods. The surgical procedure used for 42
      consecutive patients undergoing video-assisted thyroidectomy by the anterior
      chest wall approach is described herein. A 3-4 cm incision was made at the
      anterior chest wall 2 cm below the clavicle on the tumor side. Two Kirshner wires
      connected to a winching device were horizontally inserted beneath the skin in
      order to lift the neck skin. Specially made retractors were passed through the
      chest wall wound to the lateral neck bilaterally. Strap muscle on the tumor side
      was retracted laterally and the thyroid tumor was retracted medially. A suitable
      working space was thus created using this modified neck lifting method without
      gas insufflation. All patients underwent video-assisted thyroidectomy utilizing
      an anterior chest wall approach without conversion to open thyroidectomy. Mean
      operative time from incision to removal of the tumor was 145 min. Mean tumor size
      was 4.1 cm (range: 2.0-7.5 cm). The advantage of our approach is that the scar
      below the clavicle is invisible under normal clothing. In addition, conventional
      instruments for open thyroidectomy can be used. In our method, the thyroid tumor
      and trachea are palpable and some parts of the operation can be conducted under
      direct visualization if the assistant retracts the anterior chest wall wound
      upward. Video-assisted thyroidectomy utilizing an anterior chest wall approach is
      cosmetically less invasive, particularly for women who are frequently nervous
      about operative scars on the neck.

PMID- 12487263
TI  - Intraoperative lymphatic mapping and sentinel lymph node biopsy in patients with
      papillary carcinoma of the thyroid gland.
AB  - We examined the feasibility of sentinel lymph node biopsy for thyroid cancer.
      Thirty-eight patients with papillary thyroid carcinoma underwent intraoperative
      lymphatic mapping and sentinel lymph node biopsy. At surgery, we exposed the
      thyroid gland and used a tuberculin syringe to inject 0.2 ml of 1% patent blue
      dye directly into the thyroid mass. The lymphatics and the lymph node dyed with
      blue dyes, was excised as a sentinel lymph node. Modified radical neck dissection
      was performed following sentinel lymph node biopsy and the diagnostic ability of
      sentinel lymph node biopsy was examined. A sentinel lymph node was identified
      successfully in 27 (71%) of 38 patients. Sentinel lymph node biopsy removed one
      to three lymph nodes (median, two nodes). Eighteen patients had paratracheal
      sentinel lymph nodes, five patients had jugular sentinel lymph nodes, and four
      patients had both. Histological nodal metastasis was recognized in 16 of 27
      cases. The positive rate of cancer metastases in sentinel lymph nodes was 58%,
      which was significantly higher than 11% in non-sentinel lymph nodes. Diagnostic
      ability of sentinel lymph node biopsy showed that accuracy was 89%, sensitivity
      was 84%, and specificity was 100%. Our preliminary study indicated that sentinel
      lymph node biopsy was available on detection of non-palpable nodal metastasis in
      the patients with thyroid cancer; however, further experience and refinement are
      needed.

PMID- 12487264
TI  - Adrenal overview.
AB  - Adrenalectomy is ideally suited to minimally invasive surgery. The adrenal glands
      can be approached endoscopically using either transperitoneal or retroperitoneal
      access. The transabdominal lateral approach is more direct, allows the gravity
      facilitated exposure of the adrenals and results in less dissection than does the
      anterior approach. The transabdominal lateral approach is currently the most
      widely practiced approach since it provides a wide operative field and direct
      access to the blood vessels.

PMID- 12487265
TI  - Laparoscopic adrenalectomy: current status with a review of Japanese literature.
AB  - A decade has elapsed since laparoscopic adrenalectomy was first performed in
      1992. Accumulated experiences of laparoscopic adrenalectomy have shown superior
      results to treat small functional benign tumors and make the indication expand to
      large tumors, pheochromocytomas and localized malignant tumors. Following the
      initially established transperitoneal approach, which includes anterior and
      lateral approaches, the retroperitoneal lateral flank and posterior lumber
      approaches have been performed. Each approach has advantages and disadvantages.
      The transperitoneal approach supplies a large operative field, many anatomical
      landmarks and easy handling. But it causes post-operative irritability and it is
      very difficult to perform after previous upper abdominal surgery. The
      retroperitoneal approach can be performed even after previous abdominal surgery
      and patients may be more comfortable after the operation. However, the narrow
      working space and the lack of anatomical landmarks may increase the rate of intra
      operative complications and the rate of conversion to open surgery. Although
      there is no clear preference between transperitoneal and retroperitoneal
      approaches, the transperitoneal approach is commonly employed and the
      transperitoneal anterior approach seems to be the easiest one for right adrenal
      tumors and the transperitoneal lateral approach for left adrenal tumors. The
      shorter convalescence with laparoscopic adrenalectomy as compared with open
      adrenalectomy has been accepted and lower morbidity from laparoscopic
      adrenalectomy has been achieved. The operative time has been shortened to the
      level of open adrenalectomy. Less blood loss, less pain and better cosmesis are
      absolute advantages for the patients. Laparoscopic adrenalectomy is now the gold
      standard for the treatment of adrenal tumors.

PMID- 12487266
TI  - Retroperitoneal laparoscopic adrenalectomy.
AB  - Retroperitoneoscopic adrenalectomy is currently performed either by lateral flank
      approach or posterior lumbar approach. The retroperitoneal laparoscopic
      adrenalectomy avoids invading the intraperitoneal cavity and possible injury to
      the abdominal organs. The posterior lumbar approach allows direct access to the
      main adrenal vascular supply before the gland is manipulated. Retroperitoneal
      laparoscopic adrenalectomy by the posterior approach is technically feasible and
      most effective as regards the simplicity of vascular control. The lateral flank
      approach allows a more spacious working cavity, but a large tumor obscures the
      surgical plane to the adrenal vessels. The transection of the adrenal vein is
      performed at the end of the procedure. The operating time, perioperative
      morbidity and cost have been reduced with these retroperitoneal approaches. The
      retroperitoneal approach to the adrenal gland is technically simple and can be
      performed quickly, with a low postoperative morbidity and should be regarded as
      the routine approach for relatively small adrenal benign tumors that are less
      than 5 cm in diameter.

PMID- 12487267
TI  - Laparoscopic bilateral adrenalectomy for Cushing's syndrome due to ACTH
      independent macronodular adrenocortical hyperplasia.
AB  - We performed simultaneous bilateral laparoscopic total adrenalectomy in two
      patients with Cushing's syndrome due to ACTH-independent macronodular
      adrenocortical hyperplasia (AIMAH). Preoperative serum cortisol in the patients
      was 29.5 and 53.2 microg/dl, respectively. The clinical symptoms of the latter
      patient were advanced, and respiration was labored with orthopnea. Laparoscopic
      adrenalectomies were performed transabdominally in the sequential lateral
      decubitus positions with extension of the lateral abdominal wall of the affected
      side. Three 12-mm and three 5-mm trocars were positioned, and two trocar sites in
      the midline were used on both sides. The flexible fiberscope was inserted through
      the umbilical port. The adrenal glands were large, fragile, and multinodular. The
      maximal diameters of the removed glands were 7.8 and 8.7 cm, respectively. In
      both patients, the adrenal glands were successfully removed without
      fragmentation. The operation times were 505 and 320 min, and the estimated blood
      loss was 150 and 5 ml, respectively. Neither intraoperative nor postoperative
      complications occurred, although the latter patient required muscle training
      before ambulation on postoperative day 42. The procedures resulted in marked
      clinical improvements. Compliance with the substitutive therapy remained
      excellent, and the patients expressed a very high degree of satisfaction with the
      laparoscopic adrenal surgery. The procedures of bilateral laparoscopic
      adrenalectomy were successful, and provided increased experience with the
      laparoscopic techniques.

PMID- 12487268
TI  - Laparoscopic partial adrenalectomy.
AB  - Since corticosteroids are indispensable hormones, partial or cortical-sparing
      adrenalectomies may be adopted for the surgical treatment of adrenal diseases. In
      this article, we describe the technique and results of these procedures.
      Laparoscopic partial or cortical-sparing adrenalectomy has been performed in 10
      patients. Seven cases had an aldosterone-producing adenoma (APA) and three had a
      pheochromocytoma. Three cases with an APA and a case with a pheochromocytoma had
      tumors located far from the adrenal central vein, and the vein could be
      preserved. Four cases with an APA and two with a pheochromocytoma had tumors
      located close to the adrenal central vein, and it was necessary to section the
      central vein to resect them. All endoscopic procedures were performed
      successfully. There were no postoperative complications. At follow-up, adrenal
      131I-adosterol scintigrams showed the preservation of remnant adrenal function in
      all patients. Laparoscopic partial or cortical-sparing adrenal surgery was safely
      performed, and adrenal function was preserved irrespective of whether the adrenal
      central vein could be preserved or not. We consider this to be a useful operative
      technique for selected cases.

PMID- 12487269
TI  - Laparoscopic adrenalectomy for pheochromocytoma: a literature review.
AB  - Laparoscopic adrenalectomy has become the standard treatment for benign adrenal
      tumors, providing minimal invasiveness and early recovery. In the case of
      pheochromocytomas, special attention should be paid perioperatively to prevent
      excessive hypertension or hypotension. The protocol should include sufficient
      preoperative medication with alpha 1 blockers, early ligation of the adrenal
      vein, and minimal handling of the tumor itself. A literature review of 227
      laparoscopic adrenalectomies for pheochromocytomas revealed that the
      perioperative data, including the operative time, blood loss, and hemodynamic
      status, were similar or slightly better in the laparoscopic procedures as
      compared to the open procedures, although the convalescence period was
      significantly shorter in the laparoscopic surgery. The majority of surgeons
      prefer the transperitoneal approach for pheochromocytomas, although some authors
      use the retroperitoneal approach successfully. A comparison of the perioperative
      data from laparoscopic surgeries for pheochromocytomas versus those for other
      adrenal tumors showed that the former had slightly higher demands to complete the
      procedure safely. In the treatment of familial pheochromocytoma due to multiple
      endocrine neoplasia type 2 or von Hippel-Lindau disease, a cortical-sparing
      adrenalectomy can be safely performed laparoscopically. In conclusion,
      laparoscopic adrenalectomy is the standard for small pheochromocytomas, with a
      high success rate when the procedure is performed by experienced surgeons.

PMID- 12487270
TI  - Laparoscopic surgery for malignant adrenal tumors.
AB  - This paper outlines the indications and techniques of laparoscopic surgery for
      malignant adrenal tumors. Laparoscopic surgery is not indicated for adrenal
      tumors of any size when invasion of the surrounding tissues is clearly detected
      by preoperative imaging. When laparoscopic surgery is performed for a tumor
      without invasion that has a maximum diameter of more than 6 cm or a tumor that is
      considered potentially malignant from preoperative imaging or endocrine studies,
      it is important to inform the patient and family that the tumor may be malignant
      and that conversion to open surgery may be necessary. The transperitoneal
      approach is appropriate for primary adrenal malignancies. For metastatic cancer,
      the transperitoneal approach is suitable for radical surgery and the
      extraperitoneal approach for histological diagnosis by partial resection or tumor
      biopsy. In either case, it is important for the surgeon to have a sufficiently
      wide working space, to remove the tumor and surrounding fat en bloc, to never
      grasp the tumor or adrenal tissue, and to carefully handle the ultrasonically
      activated scalpel or ultrasonic aspirator so that it does not touch the tumor
      surface due to the risk of tumor cell dissemination. It is also essential not to
      unreasonably persist with laparoscopic procedures, but to immediately switch to
      open surgery when laparoscopic surgery becomes difficult.

PMID- 12487271
TI  - Mini review: surgical indications for adrenal incidentaloma.
AB  - The detection of an adrenal mass as an incidental finding has become so frequent
      that this trend is considered to be an endocrine epidemic. In these adrenal
      incidentalomas, a difficult problem is to distinguish between benign and
      malignant primary or secondary tumors. Another major problem in the management of
      patients with incidentally discovered adrenal mass is whether and when the mass
      puts the patient at increased risk of an adverse outcome. A Japanese government
      supported study conducted by Professor Miyachi's research committee reviewed the
      records of all university hospitals and hospitals possessing more than 200 beds
      in Japan and found 2106 Japanese patients with adrenal incidentaloma during the
      year 1999. They comprised 1095 males (52%) and 1011 females (48%), mostly
      distributed between 50 and 59 years of age. The tumor size ranged mostly from 1.1
      to 2.0 cm. Almost half (50.3%) of all the incidentalomas were diagnosed as non
      functional adenomas, and 5.6% were primary or secondary malignant tumors. In
      conclusion, accurate assessment of tumor size is an important consideration
      during preoperative evaluation of adrenal tumors in order to rule out malignancy.
      Careful evaluation of endocrine functions of the hypothalamic-pituitary-adrenal
      axis is necessary before surgical treatment in patients with adrenal
      incidentaloma. Patients with adrenal incidentaloma should be carefully followed,
      especially regarding size and hormonal conditions.

PMID- 12487272
TI  - Laparoscopic adrenalectomy for pheochromocytoma.
AB  - We reviewed 10 cases of laparoscopic adrenalectomy for pheochromocytoma and
      compared the results with those of a recent series of 11 patients who underwent
      open adrenalectomy. Of the 10 cases, the tumor was removed successfully in all
      cases except in one case with laparoscopy that required open laparotomy. A pair
      of laparoscopic coagulating scissors was utilized in all except the initial two
      cases. In the laparoscopy group (excluding the initial two cases and the case
      that required conversion to open surgery), mean operative time and blood loss
      were 145 min and 55 ml, respectively. No significant difference was observed in
      mean operative time between the laparoscopy group and the open surgery group (165
      min for open surgery). Mean blood loss of the laparoscopy group was significantly
      less than that of the open surgery group (330 ml for open surgery, P = 0.01).
      Mean intervals to first ambulation and oral intake, and postoperative hospital
      stay of the laparoscopy group, tended to be less than those of the open surgery
      group, although no statistical significance was observed (2.3 versus 3.2 d, 2.9
      versus 3.6 d, and 12 versus 14 d, respectively). We conclude that laparoscopic
      adrenalectomy for pheochromocytoma is equally effective and less invasive than
      open adrenalectomy and should be considered the therapy of choice even for
      pheochromocytoma.

PMID- 12487273
TI  - Contemporary transsphenoidal surgery for pituitary adenomas with emphasis on
      complications.
AB  - The indication and complications of transsphenoidal surgery (TSS) were reported
      with an emphasis on our experiences. Although new therapies have been developed
      one after another, TSS is still main stream in the treatment of most pituitary
      adenomas. One century after the birth of TSS, it has evolved into a more
      sophisticated and less invasive procedure. The present microscopic TSS will be
      replaced by endoscopic TSS in the near future. Complications can occur with any
      surgery, but we can reduce their possibility and degree by enriching experience.
      In our series, the morbidity rate was 2.7%, but operative death was absent. A
      better understanding of the reported complications and a careful preoperative
      design will contribute to a better outcome of TSS.

PMID- 12487274
TI  - Endoscopic approach to the pituitary lesions: contemporary method and review of
      the literature.
AB  - The present status of endoscopic transsphenoidal surgery is introduced and
      reviewed. The difference between endoscopic and microscopic transsphenoidal
      surgery is explained and also the characteristics of the transnostril approach is
      mentioned. The advantages of endoscopic surgery are (1) good anatomical
      orientation with wider view, (2) tumors at the dead angle can be removed under
      the direct visualization, and (3) the patients can drink, eat and even brush
      their teeth just after surgery. Short hospital stay and even day-surgery could be
      possible when a patient is carefully selected. The disadvantages and the
      limitation of endoscopic surgery have been solved and improved with several new
      instruments and ideas. Moreover, we have made use of the surgical simulation with
      the three-dimensional (3-D) CT virtual navigation endoscopic image and the
      navigation system with the ENT application and the SureTrak of the Stealth
      Station. There is no need for head fixation with a Mayfield clamp or a C-arm
      intraoperative fluoroscopic image. This image guidance enabled a correct and
      smooth approach even in those patients with complicated and abnormal anatomical
      structures by prior surgery such as for sinusitis. The sellar floor can be safely
      and correctly opened even in patients with conchal type sphenoid sinus using a
      navigation system that helps to understand the locations of the cavernous sinus
      and the internal carotid arteries. The overall result by endoscopic
      transsphenoidal surgery is as good as or better than that by the traditional
      microscopic transsphenoidal surgery.

PMID- 12487275
TI  - Sublabial transsphenoidal pituitary surgery: a new modified technique for a less
      invasive sublabial approach.
AB  - The history of the transsphenoidal approach for pituitary surgery is reviewed in
      this mini review. There are several approaches to the sphenoid sinus, and the
      sublabial transseptal and transnasal transseptal approaches are presently the
      most widely accepted standard techniques. Although the transnasal approach has
      several advantages in comparison with the sublabial approach, it is difficult to
      accomplish in the small nostril without an alotomy incision or external
      rhinoplasty incision, which may lead to noticeable scarring or nasal deformity.
      Therefore, the sublabial approach still remains the workhorse method, especially
      for patients with small nostrils like Asian people including the Japanese. We
      have developed a less-invasive sublabial approach to overcome the disadvantages
      associated with the conventional sublabial approach. The basic differences
      between this modified sublabial approach and the conventional approach are: a
      smaller incision (1-1.5 cm long) and almost midline vertical skin incision
      underneath the upper lip, minimal development of an inferior tunnel, no widening
      of the maxillary rim of the piriform aperture, and a strictly unilateral
      approach. This less-invasive approach uses a slim and small nasal speculum
      originally designed for the transnasal approach. This modified sublabial approach
      was applied to 41 patients and was confirmed to be a simple, rapid, and less
      invasive technique with significantly fewer mucosal complications compared with
      the conventional approach. We conclude that this modified sublabial approach
      offers a good alternative to the conventional standard sublabial approach.

PMID- 12487276
TI  - New devices for direct transnasal surgery on pituitary adenomas.
AB  - A micro-pressure-suction-irrigation system (MPSIS) is a surgical device that
      cleans the operative field of blood and tumor tissues with one-hand manipulation,
      dissects tumor tissue with its rapid flow, and removes debris by suction without
      injury to the normal tissue structures. Since 1997, good transnasal surgical
      results for pituitary adenomas have been achieved in Japan using this system.
      However, the surgical results for large, fibrous pituitary adenomas were
      unfavorable. Ultrasonic surgical aspirators with needle-type probes and an
      electromagnetic field system, all recently developed in Japan, are improving the
      results of direct transnasal surgery on pituitary adenomas. The MPSIS effectively
      dissects typical adenoma tissue with rapid irrigation and removes it by suction.
      A tumor in the cavernous sinus was removed by this system under direct vision in
      combination with pituitary mirrors. Fibrous adenomas were resected using
      ultrasonic surgical aspirators with needle-type probes. Thick mucosa and a firm
      tumor were vaporized with an electromagnetic field system. The sellar floor was
      reconstructed with combined ceramics, used in cases requiring additional surgery
      or drainage of cerebrospinal fluid leakage during surgery. Direct transnasal
      surgery with these devices was performed to remove 143 pituitary adenomas. Most
      of these pituitary adenomas could be selectively removed except for those lesions
      with extensive cavernous sinus invasion. There was no surgical morbidity or
      mortality. With the advancement of surgical technique and the development of
      surgical devices, most pituitary adenomas, even those that are fibrous or firm,
      can be removed via the transnasal route.

PMID- 12487277
TI  - Gamma knife radiosurgery for pituitary adenoma.
AB  - For the treatment of pituitary adenomas, transsphenoidal surgery is established
      as a first choice of treatment. However, pituitary adenomas are often not curable
      with surgery alone, and further treatment including radiation therapy is required
      to control the disease. In this report, we review the literature of gamma knife
      radiosurgery for pituitary adenomas and discuss the efficacy of this modern
      technology. Radiosurgery achieved 85-100% of growth control rates with only mild
      and transient neurological complications in most cases. Endocrinological
      normalization was obtained in more than 65% of GH producing tumors. These
      hormonal control rates seemed to be slightly better in GH producing tumors
      compared to ACTH producing tumors. To normalize the excessive GH or ACTH levels,
      radiosurgery for functioning adenomas requires a relatively higher dose, ideally
      more than 35 Gy at tumor margin. However, the adjacent optic apparatus is less
      tolerable for irradiation, and the tumors have to be sufficiently separated from
      it to prevent the radiation-induced visual deficits. Therefore, the role of
      surgery should not be underevaluated, and even if radiosurgery alone may be able
      to achieve an excellent outcome in some cases, surgical resection will remain the
      primary treatment for pituitary adenomas. For high-risk patients or patients with
      residual tumors after transsphenoidal surgery, gamma knife radiosurgery can be a
      first choice of treatment, achieving both growth control and hormonal remission
      with minimum neurological complications, which is equivalent to conventional
      radiation therapy but with much less risk of radiation injury to the surrounding
      structures.

PMID- 12487278
TI  - Overview: current status of breast conserving therapy in Japan.
AB  - Breast conserving operations have become the standard operation for early breast
      cancer. They were performed in about 40% of all breast cancer patients in Japan
      in 2000, and the percentage is still increasing. Ductal carcinoma in situ (DCIS)
      accounts for about 7% of all breast cancers and breast conserving operations for
      DCIS have been followed by a low in-breast recurrence rate, leading to wider
      indications for breast conserving operations as screening mammography has come to
      be used in Japan. In-breast recurrence is correlated to surgical margin status.
      It is important to evaluate the surgical margin for volume of cancer cell nests
      as well as for positivity. Neoadjuvant chemotherapy has become popular as an in
      vivo sensitivity test and as a means of down-staging to increase the possibility
      of performing a breast conserving operation. There are two patterns of shrinkage
      when neoadjuvant chemotherapy is effective: cocentric and honeycomb, and the
      pattern of residual cancer cell nests must be determined before surgery. MRI is
      an effective method of evaluating residual cancer cell nests. The in-breast
      recurrence rate after down-staging to perform breast conserving operations is
      reported to be higher than among candidates for breast conserving operation at
      the start. Sentinel node biopsy techniques and endoscopic operations are now
      being assessed in conjunction with breast conserving operations. The current
      status of breast conserving operations in Japan is reviewed in comparison with
      their status in Western countries.

PMID- 12487279
TI  - Overview: video-assisted breast surgery.
AB  - Since 1992, video-assisted surgery for the breast has been developed mainly in
      the field of plastic surgery, notably in breast augmentation surgery. Today,
      video-assisted surgery, indicating partial or total endoscopic surgery, can be
      performed for the treatment of both benign and malignant breast tumors to improve
      the cosmetic outcome. Although, in some respects, this kind of surgery for
      malignant tumors is still experimental, it is feasible enough for clinical use,
      and is expected to become one of the standard operations for breast cancer.

PMID- 12487280
TI  - Sentinel node biopsy for breast cancer patients in Japan.
AB  - Sentinel node biopsy may become a standard procedure to detect lymph node
      metastases in early breast cancer. Numerous studies have confirmed and
      demonstrated the reliability of the hypothesis of sentinel node biopsy, with a
      high identification rate and overall accuracy connected with dye-guided and radio
      guided sentinel node biopsy. To assess the benefit of sentinel node biopsy,
      randomized clinical trials are underway in Western countries comparing sentinel
      node biopsy with conventional axillary lymph node dissection. In Japan,
      feasibility studies on sentinel node biopsy started in the mid-1990s. The dye and
      radiopharmaceuticals associated with sentinel node biopsy commonly used in
      Western countries are not available in Japan. Japanese investigators have
      attempted to perform sentinel node biopsy using other dyes and
      radiopharmaceuticals. The results from feasibility studies have been similar to
      those reported previously. In conclusion, sentinel node biopsy for breast cancer
      patients is successful in Japan. The current status and the problems are
      discussed.

PMID- 12487281
TI  - Breast-conserving therapy consisting of wide excision, axillary dissection, and
      radiotherapy for early-stage breast cancer: the experience of the National
      Shikoku Cancer Center.
AB  - Four hundred and forty-eight breasts of 443 female patients were treated with
      breast-conserving therapy (BCT) consisting of wide excision, axillary dissection,
      and radiotherapy for early-stage breast cancer at the National Shikoku Cancer
      Center between July 1989 and December 1999. The average age at operation was 48.7
      years, and the mean tumor size by palpation was 1.9 cm. Three hundred and twenty
      cases (71.4%) were pathologically node-negative. During a median follow-up period
      of 53 months, 13 patients developed local recurrence. The 5-year overall survival
      and local recurrence rate registered 94.5% and 3.0%, respectively. Age at
      operation (35 years or younger vs. 36 years or older; P = 0.0184), pathological
      lymph node status (P = 0.0261), adjuvant chemotherapy (P = 0.0198), and the
      combination of estrogen receptor (ER) status and adjuvant tamoxifen (TAM) (ER+
      and TAM+ vs. ER- or TAM-; P = 0.0136) were statistically significantly associated
      with local recurrence. Histological margin status associated with local
      recurrence was marginally significantly (P = 0.0751). The results of multivariate
      analysis revealed that age at operation, pathological lymph node status, the
      combination of ER status and adjuvant TAM, and histological margin status were
      statistically independent predictors for local recurrence. In conclusion, BCT
      consisting of wide excision, axillary dissection and radiotherapy is useful and
      effective for patients with early-stage breast cancer.

PMID- 12487282
TI  - Breast conserving treatment without radiotherapy.
AB  - Radiotherapy (RT) is not always necessary for the prevention of ipsilateral
      breast recurrence in cases where cancer is not detected in the remaining breast
      tissue after breast conserving surgery. In addition, under these circumstances,
      the rate of a second primary cancer of the remaining breast is theoretically
      equal to the rate of contralateral breast cancer. In performing breast conserving
      treatment (BCT) at our institution we do not treat with RT if a strict serial
      pathological examination of the specimen (every 5 mm) reveals that the case has
      been safely resected (negative surgical margins). From 1986 to 1998, 827 patients
      (157 were ductal carcinoma in situ, and 670 were invasive) underwent BCT without
      RT at the Cancer Institute Hospital. Ipsilateral breast cancer was observed in 46
      cases or 5.6% (0.85% annually) during a median observation period of 67 months.
      Of these 46 cases, 19 (2.3%) were diagnosed as a recurrence and 27 cases (3.3%)
      were second primary cancers. This recurrence rate is equivalent to the rate
      observed in 406 cases of BCT (1.7%) that were treated with RT. Most of these
      cases had shown positive surgical margins. Furthermore, the rate of occurrence of
      second cancers is not significantly different from the rate of occurrence of
      contralateral breast cancers. These results suggest that, by selecting
      irradiation cases based on careful pathological examinations, BCT can be safely
      performed.

PMID- 12487283
TI  - Video-assisted total glandectomy and immediate reconstruction for breast cancer.
AB  - This paper describes a new surgical technique and our clinical experience with
      video-assisted endoscopic total glandectomy via a middle axillary incision
      followed by immediate reconstruction with latissimus dorsi muscle flap (LDMF)
      performed in 17 patients with bigger, multiple tumors or extensive ductal spread
      of breast cancer. The novel techniques in this procedure are as follows: (1) By
      securing patients in a semi-lateral position and suspending the upper extremity,
      either supine or semi-lateral position can be easily achieved by simply rotating
      the operating table, resulting in a wider working space from the axillary to hip
      area. (2) By applying a retractor for skin flap traction, endoscopic glandectomy
      and reconstruction become safe and reliable. As a result, the mean number and
      size of tumors were 1.2 and 4.12 cm, respectively. Surgical margins of all the
      cases were pathologically negative and there were no recurrences observed during
      14 months follow-up to date. Esthetic results have been satisfactory and the
      surgical wounds were not visible from the front in any case. Compared to
      mastectomy, this procedure shows the same therapeutic results, but offers a
      greater esthetic and psychological advantage to all the patients.

PMID- 12487284
TI  - Patient age affects identification rate of sentinel nodes in breast cancer.
AB  - BACKGROUND: The aim of this study was to investigate whether clinicopathological
      features affect the success rate of identifying sentinel nodes using a
      combination method of dye and radioisotope in breast cancer patients. METHODS:
      Sentinel node biopsy was performed in patients (n = 154) with stage I and II
      breast cancer using a combination method. The association between the
      clinicopathological features of breast cancer and the success rate in the
      identification of sentinel nodes was investigated. RESULTS: Sentinel nodes were
      successfully identified in 147 (95.5%) of the 154 patients. There was a
      concordance between the sentinel-node and axillary-node status in 146 (99.3%) of
      147 cases. The false negative rate of the sentinel node biopsy was 2.4% (1/42).
      The identification rate of sentinel nodes was significantly (P = 0.005) lower in
      patients > or = 60 years (84.4%) than in those < 60 years (98.4%). The tumor
      size, histological node status, lympo-vascular invasion, history of previous
      surgical biopsy, operative procedure, tumor location, and histological type were
      not related with the identification rate of sentinel nodes. The mean count ratio
      of all hot nodes was 14.0 (range 2.0-73.6) in patients > or = 60 years and 73.4
      (2.0-1700.6) in patients < 60 years, and this difference was statistically
      significant (P < 0.0001). In addition, the mean number of sentinel nodes was
      significantly (P = 0.0006) lower in patients > or = 60 years (1.3; range one to
      four) than in patients < 60 years (2.1; range one to 12). CONCLUSIONS: Patient
      age affects the identification rate of sentinel nodes using a combination method
      in breast cancer.

PMID- 12487285
TI  - Sentinel lymph node biopsy in breast cancer using technetium-99m tin colloids of
      different sizes.
AB  - Axillary lymph node dissection (ALND) in the treatment of breast cancer is
      essential for predicting the prognosis and regional control of the tumor. At the
      same time ALND is associated with pain, numbness and sometimes lymphedema.
      Sentinel lymph node biopsy (SLNB) is a potential alternative procedure to
      conventional ALND in clinically node-negative breast cancer. In this study, we
      prepared the technetium-99m-labeled tin colloids with different sizes and
      compared their efficacy in SLNB. From September 1998 to February 2002, 184
      clinically node-negative breast cancer patients were enrolled in the study at
      Keio University Hospital. Sentinel lymph nodes (SLNs) were identified by both
      blue dye and radioisotope. We prepared small-sized technetium-99m-labeled tin
      colloid (particle size: 200-400 nm in diameter). Regular-sized technetium-99m
      labeled tin colloid is 400-1000 nm in diameter. In 74 patients, a SLNB was
      performed using regular-sized tin colloid; small-sized tin colloid was used in
      110 patients. Subsequently, all of the patients were immediately followed by
      ALND. All dissected lymph nodes were evaluated by routine histopathological
      examination. The clinicopathological characteristics of the two groups were
      comparable. The lymphoscintigram detected SLN more frequently in the small-sized
      colloid group than in the regular-sized colloid group (P < 0.01). Small-sized tin
      colloid was also superior to regular-sized tin colloid in the SLN identification
      rate (97.3% versus 86.5%; P = 0.01). The mean value for ex vivo counts of the
      hottest sentinel lymph nodes of the small-sized colloid group was significantly
      higher than the counts of the regular-sized colloid group (P < 0.01). There was
      no significant difference in the accuracy between the two groups. It was
      concluded that SLNB using the small-sized tin colloid was technically feasible
      and provided higher detection and identification rates than the regular-sized tin
      colloid.

PMID- 12487286
TI  - Minimally invasive surgery for gastric carcinoid tumor.
AB  - Minimally invasive laparoscopic wedge resection for gastric mucosal carcinoma and
      submucosal tumor was first performed in Keio University hospital in 1992. Since
      then, 172 gastric tumor patients, including four cases of carcinoid tumor, have
      been successfully treated at the Keio University hospital using this procedure.
      No local disease recurrence or distant metastases have been observed in follow
      ups over as long as 10 years. Chronic atrophic gastritis patients with carcinoid
      tumors occurring secondary to hypergastrinemia are candidates for the minimally
      invasive surgery. With careful patient selection according to tumor size, depth
      of invasion, and histopathological findings of malignancy grade, endoscopic and
      laparoscopic therapy for these patients can be a safe, curative, and minimally
      invasive procedure.

PMID- 12487287
TI  - Minimally invasive surgery for carcinoid tumors in the rectum.
AB  - Most carcinoid tumors of the rectum are confined to the submucosa with a size
      less than 1-2 cm and are usually suitable for local excision, as metastasis to
      the regional nodes is limited. Endoscopic excision of carcinoid tumors has been
      performed for this entity as a least invasive method but incomplete resection
      and/or unclear surgical margin and curability have been reported to occur in 24
      42% of cases because of a limited resection up to the submucosal layer and burn
      effect. Transanal local excision has often been applied for rectal carcinoid
      tumor as a least invasive method among local excision procedures to accomplish
      full thickness excision for determining the curability. However, it is often
      difficult to obtain free access with a sufficient surgical field by the
      conventional method. Transanal endoscopic microsurgery (TEM) has appeared as a
      useful option to access a high tumor with fine visibility but special caution has
      to be taken for tumors sited above the peritoneal reflection. To facilitate full
      thickness excision even for high tumors, novel local excisional technique called
      minimally invasive transanal surgery (MITAS) has been developed and used for
      local removal of carcinoid tumors in the rectum. A specially designed anal
      retractor connected to the Octopus retractor holder with several novel techniques
      facilitated excisional procedures around the anus with a sufficient fixed
      surgical field and an ENDO-stapler allowed the simultaneous excision and
      anastomosis to be performed. The technique facilitated total excisional biopsy
      with less operative time and blood loss, and no mobility or mortality in 12
      patients with rectal carcinoid tumors.

PMID- 12487288
TI  - Minimally invasive endocrine surgery: laparoscopic resection of insulinomas.
AB  - Pancreatic insulinomas are mostly benign and solitary tumors. Successful
      management of patients with insulinoma relies on accurate localization of the
      tumors and the use of appropriate surgical techniques. However, preoperative
      radiological imaging studies often fail to localize the insulinomas because of
      the small tumor sizes. Conventional intraoperative ultrasonography combined with
      palpation has been widely used as the best localization tool. Since contact
      ultrasonography, a new technique for localizing pancreatic lesions, became
      available as a laparoscopic study, several surgeons have utilized laparoscopy for
      not only localization but also resection of insulinomas. Previous reports of
      laparoscopic ultrasonography for intraoperative identification of insulinomas
      showed a 100% success rate in cases with insulinoma localized by preoperative
      imaging studies, but a less satisfactory rate in cases with occult insulinoma.
      Laparoscopic resection of insulinomas located in the head of the pancreas is
      often difficult because of its anatomical relationship with important adjacent
      structures such as pancreatic duct and mesenteric vessels. In contrast,
      insulinomas located in the body or tail of the pancreas are laparoscopically
      resectable even when they are in close proximity to the major pancreatic duct.
      Laparoscopic procedure is a feasible technique with low morbidity for surgical
      management of insulinomas. Accurate preoperative localization is essential for
      safe performance of this minimally invasive procedure.

PMID- 12487289
TI  - Changing trends in sulfur emissions in Asia: implications for acid deposition,
      air pollution, and climate.
AB  - In the early 1990s, it was projected that annual SO2 emissions in Asia might grow
      to 80-110 Tg yr(-1) by 2020. Based on new high-resolution estimates from 1975 to
      2000, we calculate that SO2 emissions in Asia might grow only to 40-45 Tg yr(-1)
      by 2020. The main reason for this lower estimate is a decline of SO2 emissions
      from 1995 to 2000 in China, which emits about two-thirds of Asian SO2. The
      decline was due to a reduction in industrial coal use, a slowdown of the Chinese
      economy, and the closure of small and inefficient plants, among other reasons.
      One effect of the reduction in SO2 emissions in China has been a reduction in
      acid deposition not only in China but also in Japan. Reductions should also
      improve visibility and reduce health problems. SO2 emission reductions may
      increase global warming, but this warming effect could be partially offset by
      reductions in the emissions of black carbon. How SO2 emissions in the region
      change in the coming decades will depend on many competing factors (economic
      growth, pollution control laws, etc.). However a continuation of current trends
      would result in sulfur emissions lower than any IPCC forecasts.

PMID- 12487290
TI  - Retrospective analysis of the response of soil and stream chemistry of a northern
      forest ecosystem to atmospheric emission controls from the 1970 and 1990
      Amendments of the Clean Air Act.
AB  - The 1970 and 1990 Amendments of the Clean Air Act (CAAA) have resulted in a
      decline in acidic deposition in the northeastern United States. Results from the
      application of a biogeochemical model (PnET-BGC) at the Hubbard Brook
      Experimental Forest in New Hampshire suggest that, without the implementation of
      the CAAAs, soil base saturation and soil solution molar Ca/Al ratio would
      decrease to values below 6% and 1.0, respectively, while S would continue to
      accumulate in organic matter and adsorbed pools at rates of 2 and 3 kg of S ha(
      1) yr(-1), respectively. This scenario of conditions without the CAAAs was
      projected to result in higher stream concentrations of SO4(2-), NO3-, and Ca2+;
      monomeric Al; pH below 4.8; and acid-neutralizing capacity (ANC) less than -15
      microequiv L(-1). The implementation of the CAAAs has led to a slight improvement
      in the soil base saturation, while recovery of soil solution Ca/Al cannot be
      fully assessed because of variability in observed values. Our evaluation of the
      relative benefits of the 1970 and 1990 CAAAs indicate that although the magnitude
      of the cumulative decrease in strong acid deposition was greater following the
      1970 CAAA as compared to the 1990 CAAA, the extent of ecosystem recovery relative
      to the changes in acidic deposition suggests that the 1990 CAAA was also
      beneficial. The slow recovery rates might be the result of a legacy of chemical
      effects of acidic deposition for the last 150 years and suggests that additional
      controls in emissions might be required to show significant changes.

PMID- 12487291
TI  - Comparative risk analysis of six volatile organic compounds in California
      drinking water.
AB  - The widespread use and storage of volatile organic compounds (VOCs) in the United
      States has led to releases of these chemicals into the environment, including
      groundwater sources of drinking water. Many of these VOCs are commonly found in
      public drinking water supplies across the nation and are considered by state or
      federal agencies to be potentially carcinogenic to humans. In this paper, we
      evaluate the detection frequencies, detected concentrations, and relative cancer
      risks of six VOCs in drinking water sources in California from 1995 to 2001. We
      find that during this 7-year period, the most frequently detected VOCs in sampled
      drinking water sources were chloroform (12-14%), PCE (11-13%), and TCE (10-12%).
      Detection frequencies in water were lower for 1,1-DCE (3-6%), MTBE (1-3%), and
      benzene (<1%). Mean detected concentrations were also consistently above
      California's primary maximum contaminant level for some VOCs, including benzene,
      PCE, and TCE. Although none of the six VOCs necessarily poses a significant
      public health threat from drinking water exposures, 1,1-DCE and benzene werefound
      to pose the greatest cancer risk relative to the other VOCs. However, after
      adjusting for the occurrence of each VOC in drinking water, chloroform and PCE
      were found to pose the greatest relative cancer risk. Despite media reports about
      significant MTBE contamination of drinking watersupplies in California, MTBE
      detections were infrequent and this chemical was found to pose the least cancer
      risk relative to the other VOCs.

PMID- 12487292
TI  - Short-term changes in bacterial community fingerprints and potential activities
      in an alfisol supplemented with solid waste leachates.
AB  - We investigated the effect on soil functioning of adding leachates from municipal
      solid waste incinerator (MSWI) ashes to laboratory columns (bare soil) and to
      field experimental plots (bare soil or grass cover). Leachate of MSWI-solidified
      air pollution control residues (SAPCr) contained more salts but less heavy metals
      than did MSWI-bottom ash (BA) leachate. Leachate-supplemented soils (BA soil,
      SAPCr soil) and control (water added) soil (W) were analyzed after 30 days.
      Potential denitrifying activity (PDA) and potential N2 fixation (acetylene
      reduction assay, ARA) were measured in controlled conditions. PDA was
      significantly lower in SAPCr soil than in W soil, both in the laboratory (-45%)
      and in bare soil in the field (-31%). ARA values were lower in bare SAPCr soil (
      54%) and in bare BA (-25%) soil. Both activities remained unaffected by leachate
      supplementation in soil under permanent grass cover. Automated ribosomal
      intergenic spacer analysis (A-RISA) fingerprints and RFLP of nifH gene pools were
      used to assess changes in the structure of bacterial community. Multivariate
      analysis of these fingerprints revealed that SAPCr leachate had a stronger effect
      than BA leachate on the total and N2-fixing bacterial communities. Similar
      results were obtained for laboratory and bare soil field plots, but leachates did
      not affect nifH gene pools from soil under permanent grass cover. The stronger
      impact of SAPCr leachate on both structure of bacterial communities and
      activities supports the conclusion that observed effects would result from the
      abundance of salts rather than from heavy metal toxicity.

PMID- 12487293
TI  - Coplanar polychlorinated biphenyls (PCB) in indoor air.
AB  - Indoor air levels of coplanar polychlorinated biphenyls (mono- and non-ortho
      substituted PCB) of various buildings were determined. As a consequence of the
      presence of joint sealings containing PCB, total PCB concentrations in indoor air
      up to 4,200 ng/m3 were detected (data based on a survey including 29 sampling
      sites). In a PCB contaminated industrial building, total indoor air PCB levels up
      to 13,000 ng/m3 were measured. Typical PCB congeners in indoor air include PCB
      28, PCB 52, and PCB 101. Concentrations of coplanar (dioxin-like) PCB have been
      determined for six different sites. The most abundant coplanar PCB congener in
      indoor air is PCB 118, followed by PCB 105, PCB 123, and PCB 77 in various order.
      Levels of coplanar PCB, expressed as toxicity equivalents (TEG), do correlate
      well with the total indoor air PCB concentration: a total PCB level of 1,000
      ng/m3 corresponds to a concentration of coplanar PCB of 1.2 pg TEQ/m3. Based on
      this correlation and on an indoor air PCB level of 6,000 ng/m3 (tentative
      guideline value for PCB in indoor air in Switzerland based on a daily exposure of
      8 h), the maximum daily intake of coplanar PCB via indoor air was estimated to be
      0.6 pg TEQ/kg body weight.

PMID- 12487294
TI  - Atmospheric concentrations and fluxes of organic compounds in the northern San
      Francisco Estuary.
AB  - A study was conducted to measure atmospheric concentrations of PAHs and PCBs and
      estimate their fluxes between air and water in the northern San Francisco
      Estuary. Ambient air samples were collected once every 12 days at a single
      sampling site in Concord, CA, from June to November 2000, using a modified high
      volume air-sampling device equipped with glass fiber filters and polyurethane
      foam. Concentrations of total PAHs and PCBs ranged from 5.7 to 56 and 0.17 to
      0.32 ng/m3, respectively. PAHs and PCBs in the ambient air were predominantly in
      the vapor phase (83-99%). Gaseous fluxes of PAHs in the estuary showed high
      seasonal variation, ranging from 110 ng x m(-2) x day(-1) efflux in August to
      1,050 ng x m(-2) x day(-1) influx in November. Gaseous PCBs showed consistent net
      volatilization 12.2-24 ng x m(-1) x day(-1)) for this period. Particle settling
      contributed estimated net deposition fluxes of 45-960 ng x m(-2) day(-1) for PAHs
      and 0.39-2.1 ng x m(m(-2) x day(-1) for PCBs. Combining these fluxes, PAHs were
      either deposited to or lost from the estuary via the atmosphere, depending on the
      month. In contrast, there consistently was net emission of PCBs from the estuary
      to the atmosphere.

PMID- 12487295
TI  - Assessing the contents of polycyclic aromatic hydrocarbons in the tollbooths of a
      highway toll station via direct and indirect approaches.
AB  - The present study was set out to assess the contents of polycyclic aromatic
      hydrocarbons (PAHs) in three types of tollbooths at a highway toll station via
      direct and indirect approaches. Direct sampling results show that no significant
      difference could be found in the PAH homologue distributions for samples
      collected from the car lane/ticket-payment and car lane/cash-payment tollbooths,
      but both were significantly different from that for the bus/ truck lane
      tollbooth. The above results could be due to the former two types of tollbooths
      that were designed for the same type of traffic (i.e., cars and vans), but the
      latter was designed for a different type of traffic (i.e., buses and trucks). For
      any given type of tollbooth, the total-PAH content (C(Total-PAHs)) found during
      the day shift (= 9,370-15,500 ng/m3) were not significantly different from that
      found during the night shift (= 9,550-14,900 ng/m3), but both were significantly
      higher than that found during the late-night shift (= 5,560-11,100 ng/m3). During
      any given work shift we found C(Total-PAH5) for the three types of tollbooths as
      the following: bus/truck lane (= 11,100-15,500 ng/m3) > car lane/ticket-payment
      (= 7,260-13,500 ng/m3) > car lane/ cash-payment (= 5,560-9,550 ng/m3). After
      conducting multivariate regression analyses, we found that none of the three
      environmental factors (i.e., wind speed,temperature, and relative humidity),
      except for the vehicle flow rate (Q(Vehicle)) had a significant effect on C(Total
      PAHs) for any given type of tollbooth. Considering directly measuring PAH
      contents was labor-consuming and costly, and the above results suggest the
      possibility of using Q(Vehicle) to predict C(Total-PAHs) for any given type of
      tollbooth. After conducting simple linear regression analyses, we found that (1)
      all resultant regression coefficients were found with positive values indicating
      that an increase in the Q(Vehicle) would lead to an increase in the C(Total
      PHHs). (2) from the magnitude of the resultant regression coefficients indicating
      that an increase in C(Total-PAHs) caused by per unit Q(Vehicle) for the three
      types of tollbooths were the following: bus/truck lane > car lane/cash-payment >
      car lane/ticket-payment, and (3) the resultant R2 values fell to the 0.54-0.75
      range indicating that the variations in C(Total-PAHs) could be explained well by
      Q(Vehicle) for the three types of tollbooths. It is concluded that measuring
      Q(Vehicle) can be regarded as an effective indirect method for estimating PAH
      contents in various types of tollbooths.

PMID- 12487296
TI  - The West Falmouth oil spill after thirty years: the persistence of petroleum
      hydrocarbons in marsh sediments.
AB  - The long-term fate of petroleum hydrocarbons in marsh sediments (West Falmouth,
      MA) contaminated in 1969 by the spill of the barge Florida was investigated. A 36
      cm-long sediment core was collected in August 2000, and sediment extracts were
      analyzed by gas chromatography (GC) and comprehensive two-dimensional gas
      chromatography (GC x GC). The latter technique is capable of separating 1 order
      of magnitude more compounds than the former and was used to observe whether any
      compositional changes in the unresolved complex mixture (UCM) occurred. No
      evidence of petroleum residues was detected in the top 6 cm (0-6 cm) and the
      lower 8 cm (28-36 cm) of the core. However, the central sections 16-28 cm) were
      dominated by a UCM in the boiling range of n-C13-n-C25 alkanes, consistent with a
      No. 2 fuel oil source. The 12-14- and 14-16-cm sections had the highest
      concentrations of UCM approximately 8 mg g(-1)). These values are similar to
      concentrations observed shortly after the spill. Initial GC x GC analysis
      revealed that only the n-alkanes were completely degraded, and contrary to
      previous studies, pristane and phytane as well as numerous other branched alkanes
      are still present in the sediments. These results suggestthatatthis site
      hydrocarbon contamination will persist indefinitely in the sedimentary record.

PMID- 12487297
TI  - Predicted distribution and ecological risk assessment of a "segregated"
      hydrofluorrother in the Japanese environment.
AB  - An assessment of HFE-7500, a 'segregated' hydrofluoroether, was conducted to
      evaluate the potential for exposure to and subsequent effects on humans and
      wildlife in Japan. The segregated hydrofluoroethers belong to a class of
      fluorochemicals currently being proposed as replacements for traditional
      fluorochemicals (CFCs and PFCs) that are currently being used in several
      industries, in particular, the semiconductor industry. These traditional
      compounds have been implicated as ozone-depleting or potent "greenhouse gases".
      The segregated hydrofluoroethers have useful physical and chemical properties,
      but do not contribute to ozone depletion and have lower "global warming
      potential" (GWP) indices. Although the physical properties of these materials
      (low H2O solubility and high vapor pressure) suggest there would be a very low
      level of risk to aquatic systems, a thorough analysis had not been previously
      performed. Predicted environmental concentrations (PECs) of HFE-7500 in Japan
      were determined with the Higashino model, a Gausian puff and plume model that
      used an approximation of environmental releases to the atmosphere as input to the
      model. Allowable concentrations to protect aquatic life, wildlife, and humans
      from noncancer effects were determined as detailed in USEPA's final Water Quality
      Guidance for the Great Lakes Systems. Potential risk to ecological receptors and
      humans was determined by calculating hazard quotients and margins of safety. The
      results of the risk assessment indicate that HFE-7500 poses no significant risk
      to either aquatic or terrestrial wildlife species or humans living in the
      Japanese environment. The least margin of safety for any ecological receptor was
      100,000, and a margin of safety greater than 100,000,000 for most receptors
      indicated that HFE-7500 poses no threat to human health. Because of a scarcity of
      toxicity and exposure data, the risk assessment was based on very conservative
      assumptions. Therefore, the actual margins of safety for both humans and wildlife
      could have been 100- to 1,000-fold greater if additional data were available such
      that less stringent uncertainty factors could be applied. These results suggest
      that the environmental impact of HFE-7500 should be inconsequential based on the
      marked improvement in its atmospheric properties relative to the traditional
      compounds currently in use. Given the short atmospheric lifetime and low global
      warming potential of this material, its replacement of CFCs and PFCs would result
      in a net improvement of environmental health and safety.

PMID- 12487298
TI  - Single-particle characterization of urban aerosol particles collected in three
      Korean cites using low-Z electron probe X-ray microanalysis.
AB  - A recently developed single-particle analytical technique, called low-Z electron
      probe X-ray microanalysis (low-Z EPMA), was applied to characterize urban aerosol
      particles collected in three cities of Korea (Seoul, CheongJu, and ChunCheon) on
      single days in the winter of 1999. In this study, it is clearly demonstrated that
      the low-Z EPMA technique can provide detailed and quantitative information on the
      chemical composition of particles in the urban atmosphere. The collected aerosol
      particles were analyzed and classified on the basis of their chemical species.
      Various types of particles were identified, such as soil-derived, carbonaceous,
      marine-originated, and anthropogenic particles. In the sample collected in Seoul,
      carbonaceous, aluminosilicates, silicon dioxide, and calcium carbonate aerosol
      particles were abundantly encountered. In the CheongJu and ChunCheon samples,
      carbonaceous, aluminosilicates, reacted sea salts, and ammonium sulfate aerosol
      particles were often seen. However, in the CheongJu sample, ammonium sulfate
      particles were the most abundant in the fine fraction. Also, calcium sulfate and
      nitrate particles were significantly observed. In the ChunCheon sample, organic
      particles were the most abundant in the fine fraction. Also, sodium nitrate
      particles were seen at high levels. The ChunCheon sample seemed to be strongly
      influenced by sea-salt aerosols originating from the Yellow Sea, which is located
      about 115 km away from the city.

PMID- 12487299
TI  - Organic matter in central California radiation fogs.
AB  - Organic matter was studied in radiation fogs in the San Joaquin Valley of
      California during the California Regional Particulate Air Quality Study (CRPAQS).
      Total organic carbon (TOC) concentrations ranged from 2 to 40 ppm of C. While
      most organic carbon was found in solution as dissolved organic carbon (DOC), 23%
      on average was not dissolved inside the fog drops. We observe a clear variation
      of organic matter concentration with droplet size. TOC concentrations in small
      fog drops (<17 microm) were a factor of 3, on average, higher than TOC
      concentrations in larger drops. As much as half of the dissolved organic matter
      was determined to have a molecular weight higher than 500 Da. Deposition fluxes
      of organic matter in fog drops were high (0.5-4.3 microg of C m(-2) min(-1)),
      indicating the importance of fog processing as a vector for removal of organic
      matter from the atmosphere. Deposition velocities of organic matter, however,
      were usually found to be lower than deposition velocities for fogwater,
      consistent with the enrichment of the organic matter in smaller fog drops with
      lower terminal settling velocities.

PMID- 12487300
TI  - Geographical distribution (2000) and temporal trends (1981-2000) of brominated
      diphenyl ethers in Great Lakes hewing gull eggs.
AB  - Geographical distribution of brominated diphenyl ether (BDE) flame retardants in
      the North American Great Lakes ecosystem in 2000 was determined by analysis of
      herring gull eggs (13 egg pools) from a network of 15 monitoring colonies
      scattered throughout the lakes and connecting channels. sigmaBDEs were found at
      concentrations ranging from 192 to 1,400 microg/kg, mean of 662 +/- 368 microg/kg
      (wet weight of egg contents). Highest concentrations were found in northern Lake
      Michigan and Toronto harbor (1,000-1,400 microg/kg) and lowest in Lake Huron and
      Lake Erie (192-340 microg/kg). The distribution suggested that input from large
      urban/ industrial areas through air or water emissions contributes local
      contamination to the herring gull food web in addition to background levels from
      regional/global transport. The congener composition was similar among sampling
      sites. Major congeners were BDE-47 (43%), BDE-99 (26%), BDE-100 (13%) BDE-153
      (11%), BDE-154 (4%), BDE-183 (2%) and BDE-28 (1%). Temporal trends of BDE
      contamination, 1981-2000, were established by analysis of archived herring gull
      eggs (10 egg pools) from colonies in northern Lake Michigan, Saginaw Bay, Lake
      Huron and eastern Lake Ontario. BDE-47, -99 and -100, and BDE-153, -154 and -183
      concentrations were grouped separately for analysis because these two groups had
      different trends and are primarily associated with the Penta BDE and Octa BDE
      flame retardant formulations, respectively. SigmaBDE47,99,100 concentrations were
      5-12 microg/kg (wet weight) in 1981-1983 and then increased exponentially (p <
      0.00001) at all three sites to 400-1,100 microg/kg over the next 17 years.
      Doubling times were 2.6 years in Lake Michigan, 3.1 years in Lake Huron and 2.8
      years in Lake Ontario. SigmaBDE154,153,183 concentrations generally increased but
      varied in an erratic fashion among sites and decreased as a fraction of sigmaBDE
      over time. Concentrations of sigmaBDE154,153,183 were 100-200 microg/kg in eggs
      from all three colonies in 2000. Therefore, most of the dramatic increases in
      sigmaBDE concentrations observed over the past 20 years in the Great Lakes
      aquatic ecosystem seem to be connected with the Penta BDE formulation, which is
      mainly used as a flame retardant in polyurethane foam in North America. If
      present rates of change continue, concentrations of sigmaBDEs will equal or
      surpass those of sigmaPCBs in Great Lakes herring gull eggs in 10-15 years.

PMID- 12487301
TI  - Hydrolysis of VX on concrete: rate of degradation by direct surface interrogation
      using an ion trap secondary ion mass spectrometer.
AB  - The nerve agent VX (O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate) is
      lethal at very low levels of exposure, which can occur by dermal contact with
      contaminated surfaces. Hence, behavior of VX in contact with common urban or
      industrial surfaces is a subject of acute interest. In the present study, VX was
      found to undergo complete degradation when in contact with concrete surfaces. The
      degradation was directly interrogated at submonolayer concentrations by
      periodically performing secondary ion mass spectrometry (SIMS) analyses after
      exposure of the concrete to VX. The abundance of the [VX + H]+ ion in the SIMS
      spectra was observed to decrease in an exponential fashion, consistent with first
      order or pseudo-first-order behavior. This phenomenon enabled the rate constant
      to be determined at 0.005 min(-1) at 25 degrees C, which corresponds to a half
      life of about 3 h on the concrete surface. The decrease in [VX + H]+ was
      accompanied by an increase in the abundance of the principal degradation product
      diisopropylaminoethanethiol (DESH), which arises by cleavage of the P-S bond.
      Degradation to form DESH is accompanied by the formation of ethyl
      methylphosphonic acid, which is observable only in the negative ion spectrum. A
      second degradation product was also implicated, which corresponded to a
      diisopropylvinylamine isomer (perhaps N,N-diisopropyl aziridinium) that arose via
      cleavage of the S-C bond. No evidence was observed for the formation of the toxic
      S-2-diisopropylaminoethyl methylphosphonothioic acid. The degradation rate
      constants were measured at four different temperatures (24-50 degrees C), which
      resulted in a linear Arrhenius relationship and an activation energy of 52 kJ
      mol(-1). This value agrees with previous values observed for VX hydrolysis in
      alkaline solutions, which suggests that the degradation of submonolayer VX is
      dominated by alkaline hydrolysis within the adventitious water film on the
      concrete surface.

PMID- 12487302
TI  - Comparing PAH availability from manufactured gas plant soils and sediments with
      chemical and biological tests. 1. PAH release during water desorption and
      supercritical carbon dioxide extraction.
AB  - Soil and sediment samples from oil gas (OG) and coal gas (CG) manufactured gas
      plant (MGP) sites were selected to represent a range of PAH concentrations (150
      40,000 mg/kg) and sample matrix compositions. Samples varied from vegetated soils
      to lampblack soot and had carbon contents from 3 to 87 wt %. SFE desorption (120
      min) and water/XAD2 desorption (120 days) curves were determined and fit with a
      simple two-site model to determine the rapid-released fraction (F) for PAHs
      ranging from naphthalene to benzo[ghi]perylene. F values varied greatly among the
      samples, from ca. 10% to >90% for the two- and three-ring PAHs and from <1% to
      ca. 50% for the five- and six-ring PAHs. Release rates did not correlate with
      sample matrix characteristics including PAH concentrations, elemental composition
      (C, H, N, S), or "hard" and "softs" organic carbon, indicating that PAH release
      cannot easily be estimated on the basis of sample matrix composition. Fvalues for
      CG site samples obtained with SFE and water desorption agreed well (linear
      correlation coefficient, r2 = 0.87, slope = 0.93), but SFE yielded higher F
      values for the OG samples. These behaviors were attributed to the stronger
      ability of carbon dioxide than water to desorb PAHs from the highly aromatic
      (hard) carbon of the OG matrixes, while carbon dioxide and water showed similar
      abilities to desorb PAHs from the more polar (soft) carbon of the CG samples. The
      combined SFE and water desorption approaches should improve the understanding of
      PAH sequestration and release from contaminated soils and sediments and provide
      the basis for subsequent studies using the same samples to compare PAH release
      with PAH availability to earthworms.

PMID- 12487303
TI  - Complexation with dissolved organic matter and solubility control of heavy metals
      in a sandy soil.
AB  - The complexation of heavy metals with dissolved organic matter (DOM) in the
      environment influences the solubility and mobility of these metals. In this
      paper, we measured the complexation of Cu, Cd, Zn, Ni, and Pb with DOM in the
      soil solution at pH 3.7-6.1 using a Donnan membrane technique. The results show
      that the DOM-complexed species is generally more significant for Cu and Pb than
      for Cd, Zn, and Ni. The ability of two advanced models for ion binding to humic
      substances, e.g., model VI and NICA-Donnan, in the simulation of metal binding to
      natural DOM was assessed by comparing the model predictions with the
      measurements. Using the default parameters of fulvic and humic acid, the
      predicted concentrations of free metal ions from the solution speciation
      calculation using the two models are mostly within 1 order of magnitude
      difference from the measured concentrations, except for Ni and Pb in a few
      samples. Furthermore, the solid-solution partitioning of the metals was simulated
      using a multisurface model, in which metal binding to soil organic matter,
      dissolved organic matter, clay, and iron hydroxides was accounted for using
      adsorption and cation exchange models (NICA-Donnan, Donnan, DDL, CD-MUSIC). The
      model estimation of the dissolved concentration of the metals is mostly within 1
      order of magnitude difference from those measured except for Ni in some samples
      and Pb. The solubility of the metals depends mainly on the metal loading over
      soil sorbents, pH, and the concentration of inorganic ligands and DOM in the soil
      solution.

PMID- 12487304
TI  - Anaerobic, sulfate-dependent degradation of polycyclic aromatic hydrocarbons in
      petroleum-contaminated harbor sediment.
AB  - It has previously been demonstrated that [14C]-labeled polycyclic aromatic
      hydrocarbons (PAHs) can be oxidized to 14CO2 in anoxic, PAH-contaminated, marine
      harbor sediments in which sulfate reduction is the terminal electron-accepting
      process. However, it has not previously been determined whether this degradation
      of [14C]-PAHs accurately reflects the degradation of the in situ pools of
      contaminant PAHs. In coal tar-contaminated sediments from Boston Harbor, [14C]
      naphthalene was readily oxidized to 14CO2, but, after 95 d of incubation under
      anaerobic conditions, there was no significant decrease in the detectable pool of
      in situ naphthalene in these sediments. Therefore, to better evaluate the
      anaerobic biodegradation of the in situ PAH pools, the concentrations of these
      contaminants were monitored for ca. 1 year during which the sediments were
      incubated under conditions that mimicked those found in situ. There was loss of
      all of the PAHs that were monitored (2-5 ring congeners), including high
      molecular weight PAHs, such as benzo[a]pyrene, that have not previously been
      shown to be degraded under anaerobic conditions. There was no significant change
      in the PAH levels in the sediments amended with molybdate to inhibit sulfate
      reducing bacteria or in sediments in which all microorganisms had been killed
      with glutaraldehyde. In some instances, over half of the detectable pools of in
      situ 2-3 ring PAHs were degraded. In general, the smaller PAHs were degraded more
      rapidly than the larger PAHs. A distinct exception in the Boston Harbor sediment
      was naphthalene which was degraded very slowly at a rate comparable to the larger
      PAHs. In a similar in situ-like study of fuel-contaminated sediments from Liepaja
      Harbor, Latvia, there was no decline in PAH levels in samples that were sulfate
      depleted. However, when the Latvia sediments were supplemented with sufficient
      sodium sulfate or gypsum to elevate pore water levels of sulfate to approximately
      14-25 mM there was a 90% decline in the naphthalene and a 60% decline in the 2
      methylnaphthalene pool within 90 days. These studies demonstrate for the first
      time that degradation by anaerobic microorganisms can significantly impact the in
      situ pools of PAHs in petroleum-contaminated, anoxic, sulfate-reducing harbor
      sediments and suggest that the self-purification capacity of contaminated harbor
      sediments is greater than previously considered.

PMID- 12487305
TI  - 241Am migration in a sandy aquifer studied by long-term column experiments.
AB  - The migration behavior of 241Am(III) in a sandy aquifer was studied under near
      natural conditions by long-term column experiments of more than 1 year duration.
      Columns with 50 cm length and 5 cm in diameter were packed with aeolian quartz
      sand and equilibrated with two different groundwaters having an original
      dissolved organic carbon concentration (DOC) of 1.1 and 7.2 mg x dm(-3),
      respectively,from the Gorleben site (Lower Saxony, Germany). In each experiment,
      1 cm3 of Am-spiked groundwater ([Am] = 0.2 to 2 micromol x dm(-3)) was injected
      into the column. The flow rate of the groundwater was adjusted to 0.28 m x d(-1).
      A small colloid-borne Am fraction was found to elute together with tritiated
      water. After 414 and 559 days, respectively, the experiments were terminated.
      Whereas the nonsorbing tracer of tritiated water would have covered a distance of
      about 350 m in that time period, the maximum of the Am activity was detected
      between 32 and 40 mm column length. Applying selective dissolution analysis to
      the sand surface, Am was found to be preferentially bound to iron hydroxide/oxide
      sites. From this Am distribution, a retardation factor R of about 10(4) was
      determined and compared to static batch experiments. The Am breakthrough was
      calculated forthe conditions of the column experiment

PMID- 12487306
TI  - Speciation of Cu and Zn in drainage water from agricultural soils.
AB  - Inputs of copper and zinc from agricultural soils into the aquatic system were
      investigated in this study, because of their heavy agricultural usage as feed
      additives and components of fertilizers and fungicides. As the mobility and
      bioavailability of these metals are affected by their speciation, the lipophilic,
      colloidal and organic fractions were determined in drainage water from a loamy
      and a humic soil treated with fungicides or manure. This study therefore
      investigates the impact of agricultural activity on a natural environment and
      furthers our understanding of the mobility of metals in agricultural soils and
      aquatic pollution in rural areas. Marked increases in the total dissolved metal
      concentrations were observed in the drainage water during rain events with up to
      0.3 microM Cu and 0.26 microM Zn depending on the intensity of the rainfall and
      soil type. The mobile metal fractions were of a small molecular size (<10 kD) and
      mainly hydrophilic. Lipophilic complexes originating from a dithiocarbamate (DTC)
      fungicide could not be observed in the drainage water; however, small amounts of
      lipophilic metal complexes may be of natural origin. Cu was organically complexed
      to > 99.9% by abundant organic ligands (log K 10.5-11.0). About 50% of dissolved
      Zn were electrochemically labile, and the other 50% were complexed by strong
      organic ligands (log K 8.2-8.6). Therefore very little free metal species were
      found suggesting a low bioavailability of these metals in the drainage water even
      at elevated metal concentrations.

PMID- 12487307
TI  - Modeling the atmospheric transport and deposition of PCDD/F to the Great Lakes.
AB  - Atmospheric deposition is a significant loading pathway for polychlorinated
      dibenzo-p-dioxins and dibenzofurans (dioxin) to the Great Lakes. An innovative
      approach using NOAA's HYSPLIT atmospheric fate and transport model was developed
      to estimate the 1996 dioxin contribution to each lake from each of 5,700 point
      sources and 42,600 area sources in a U.S./Canadian air emissions inventory. These
      unusually detailed source-receptor modeling results show that deposition to each
      lake arises from a broad geographical region, with significant contributions from
      up to 2,000 km away. The source categories contributing most significantly to
      1996 dioxin deposition appear to be municipal waste incineration, iron sintering,
      medical waste incineration, and cement kilns burning hazardous waste. Model
      predicted air concentrations and deposition fluxes were consistent with ambient
      measurement data, within the uncertainties in each, but there may be a moderate
      tendency toward underestimation using midrange emissions estimates. The most
      likely reason for this tendency appears to be missing or underestimated emissions
      sources, but in-situ atmospheric formation of octachlorinated dibenzo-p-dioxin
      (OCDD) and heptachlorinated dibenzo-p-dioxin (HpCDD) may have also contributed.
      Despite uncertainties, the findings regarding the relative importance of
      different sources types and source regions appear to be relatively robust and may
      be useful in prioritizing pollution prevention efforts.

PMID- 12487308
TI  - Surface-catalyzed transformations of aqueous endosulfan.
AB  - We report the effect of suspended solids on the oxidation and hydrolysis of the
      insecticide endosulfan (alpha and beta isomers) and its degradation products:
      endosulfan diol, endosulfan sulfate, endosulfan ether, and endosulfan lactone in
      0.001 M NaHCO3 buffer (pH 8.15). Suspensions of sea sand, TiO2, alpha-Fe2O3,
      alpha-FeOOH, Laponite, and SiO2 all catalyzed the hydrolysis of endosulfan to the
      less toxic endosulfan diol. Suspended creek sediment (Bread and Butter Creek SC,
      4% OC) inhibited endosulfan hydrolysis. Heterogeneous and homogeneous rate
      constants of endosulfan hydrolysis were measured and indicate that beta
      endosulfan hydrolyzes faster than alpha-endosulfan. This observation was
      explained by a more stable transition state for beta-endosulfan that was
      confirmed with ab initio molecular orbital calculations (STO-6G) on the anionic
      intermediates of endosulfan hydrolysis. Rates of endosulfan hydrolysis over the
      different surfaces corresponded to their tritium-exchange site-density and
      suggest a mechanism involving surface coordination prior to nucleophilic attack.
      The oxidation of alpha-endosulfan and beta-endosulfan to the persistent pollutant
      endosulfan sulfate was not observed in this study.

PMID- 12487309
TI  - Low nitrogen losses with a new source of nitrogen for cultivation of conifer
      seedlings.
AB  - Losses of nitrogen (N) when cultivating plants may cause a number of adverse
      environmental effects. N losses from conifer nurseries, for instance, may have a
      considerable impact on the local environment, and studies indicate that the bulk
      of added N is not recovered in the cultivated plants. This study was conducted to
      obtain insight into the causes of the low recovery and to test an alternative N
      fertilizer. Hence, growth of the economically important Scots pine (Pinus
      sylvestris (L).) seedlings and the recovery of different forms of added nitrogen
      (N) were investigated in a greenhouse experiment. Containerized seedlings were
      grown in peat for one summer, with two different N fertilizers, one organic
      (arginine) and one inorganic (a commercial fertilizer (CF) containing a mixture
      of ammonium and nitrate) each at an N concentration of 3 mM. At the end of the
      growth period, some seedlings were labeled with solutions containing either U
      [13C6], [15N4]-arginine, (15NH4)2SO4, or K15NO3 supplied to the growth substrate.
      Labeled seedlings were harvested 1 h, 5 days, and 19 days after tracer addition,
      and the recovery of each added nitrogen source in both the seedlings and the
      growth substrate was measured. The retention of the three N forms during
      discharge of solutions from the growth substrate, peat, was tested in a separate
      experiment. Arginine-fed seedlings grew better and had higher needle N
      concentrations than the CF-fed seedlings. Isotopic data showed that the arginine
      treatment gave significantly higher N recoveries (80%) compared to the CF
      treatment (50%). The low recovery of N in the CF treatment was largely due to
      very low recovery (30%) of NO3- -N. The retention of the different N forms during
      discharge of solutions from the growth substrate was highest for arginine,
      somewhat lower for NH44+, and very low for NO3-. The high rate of seedling growth
      and the small nitrogen losses observed when using arginine suggest that this
      amino acid may be an efficient and environmentally favorable N source for
      cultivating conifer seedlings.

PMID- 12487310
TI  - The influence of vertical sorbed phase transport on the fate of organic chemicals
      in surface soils.
AB  - Gaseous exchange between surface soil and the atmosphere is an important process
      in the environmental fate of many chemicals. It was hypothesized that this
      process is influenced by vertical transport of chemicals sorbed to soil
      particles. Vertical sorbed phase transport in surface soils occurs by many
      processes such as bioturbation, cryoturbation, and erosion into cracks formed by
      soil drying. The solution of the advection/diffusion equation proposed by Jury et
      al. to describe organic chemical fate in a uniformly contaminated surface soil
      was modified to include vertical sorbed phase transport This process was modeled
      using a sorbed phase diffusion coefficient, the value of which was derived from
      soil carbon mass balances in the literature. The effective diffusivity of the
      chemical in a typical soil was greater in the modified model than in the model
      without sorbed phase transport for compounds with log K(OW) > 2 and log K(OA) >
      6. Within this chemical partitioning space, the rate of volatilization from the
      surface soil was larger in the modified model than in the original model by up to
      a factor of 65. The volatilization rate was insensitive to the value of the
      sorbed phase diffusion coefficient throughout much of this chemical partitioning
      space, indicating that the surface soil layer was essentially well-mixed and that
      the mass transfer coefficient was determined by diffusion through the atmospheric
      boundary layer only. When this process was included in a non-steady-state
      regional multimedia chemical fate model running with a generic emissions scenario
      to air, the predicted soil concentrations increased by upto a factor of
      25,whilethe air concentrations decreased by as much as a factor of approximately
      3. Vertical sorbed phase transport in the soil thus has a major impact on
      predicted air and soil concentrations, the state of equilibrium, and the
      direction and magnitude of the chemical flux between air and soil. It is a key
      process influencing the environmental fate of persistent organic pollutants
      (POPs).

PMID- 12487311
TI  - A field-based approach for deterimining ATOFMS instrument sensitities to ammonium
      and nitrate.
AB  - Aerosol time-of-flight mass spectrometry (ATOFMS) instruments measure the size
      and chemical composition of individual particles in real-time. ATOFMS chemical
      composition measurements are difficult to quantify, largely because the
      instrument sensitivities to different chemical species in mixed ambient aerosols
      are unknown. In this paper, we develop a field-based approach for determining
      ATOFMS instrument sensitivities to ammonium and nitrate in size-segregated
      atmospheric aerosols, using tandem ATOFMS-impactor sampling. ATOFMS measurements
      are compared with collocated impactor measurements taken at Riverside, CA, in
      September 1996, August 1997, and October 1997. This is the first comparison of
      ion signal intensities from a single-particle instrument with quantitative
      measurements of atmospheric aerosol chemical composition. The comparison reveals
      that ATOFMS instrument sensitvities to both NH4+ and NO3- decline with increasing
      particle aerodynamic diameter over a 0.32-1.8 microm calibration range. The
      stability of this particle size dependence is tested overthe broad range of fine
      particle concentrations (PM1.8) = 17.6 +/- 2.0-127.8 +/- 1.8 microg m(-3)),
      ambient temperatures (23-35 degrees C), and relative humidity conditions (21
      69%), encountered during the field experiments. This paper describes a
      potentially generalizable methodology for increasing the temporal and size
      resolution of atmospheric aerosol chemical composition measurements, using tandem
      ATOFMS-impactor sampling.

PMID- 12487312
TI  - Flow-through sequential extraction approach developed from a batch extraction
      method.
AB  - Sequential extractions of contaminants from a soil or sediment have been shown to
      be cost-effective contaminated site assessment tools that provide information on
      contaminant partitioning within an environmental matrix. Such information is
      necessary for defining remediation alternatives and mitigation strategies. The
      typical sequential extraction approach involves a batch method, and known
      limitations include the possibility of contaminant readsorption to the remaining
      soil or sediment In this work, a flow-through reactor was constructed and tested
      for application in a sequential extraction scheme. The sequential extraction
      scheme used was one developed for actinide-contaminated materials. The flow
      through approach gave partitioning results that were similar to the batch method
      for uranium. We also monitored the extraction of stable Ca, K, Fe, Al, Zr, and Sc
      and obtained partitioning results generally similar to those observed with the
      batch extraction, except for Ca. Our results indicate readsorption of Ca when
      using a batch approach is small but significant and is eliminated with our new
      flow-through method. A limitation of the flow-through method is the possibility
      of underextraction of certain phases and higher analytical uncertainties. These
      uncertainties are more difficult to minimize, as compared to the uncertainty
      obtained with a batch approach.

PMID- 12487314
TI  - Evolutionary affinity and selectivity optimization of a pesticide-selective
      antibody utlizing a hapten-selective immunoglobulin repertoire.
AB  - Selectivity and sensitivity are considered as pivotal criteria for the quality of
      immunochemical assay designs in environmental analysis. They are essentially
      determined by the variable domains of the implemented antibody. The variable
      domains of a triazine-selective single-chain Fv (scFv) were genetically
      engineered by stringent molecular evolution in order to optimize analytical
      characteristics of the corresponding atrazine immunoassay. Gene variation of the
      template antibody by sequential shuffling against the variable heavy and light
      chain repertoire of a triazine-selective immunoglobulin library was enhanced by
      introducing additional point mutatons. Improved scFv variants were selected by
      phage display employing an atrazine derivative. By this means the paramounting
      affinity of the initial scFv to sebuthylazine was shifted for the mutant
      antibodies toward a preferential recognition of the envisaged target analyte
      atrazine. In addition, the detection limit of the atrazine assaywas significantly
      improved by factor 25 from 5.1 microg/L for the initial template antibody to 0.2
      microg/L for the mutant antibodies. The contribution of the engineered antibody
      variants to the assay improvement is also reflected by a shift of the equilibrium
      dissociation constant KD from 1.27 x 10(-8) M of the template antibody to 7.46 x
      10(-10) M of the optimized variant. Sequence analysis revealed a bias of amino
      acid substitutions in the first two complementarity-determining regions (CDR) and
      the flanking framework regions of both variable chains for the shuffled clones as
      well as a deletion in the CDR3 of the light chain. Particularly the mutations of
      the VL domain turned out to have a decisive impact on the alterations in the
      analytical performance of the engineered scFv mutants. The application of the
      mutant antibodies for the atrazine determination of soil samples revealed
      consistency with HPLC data within the experimental error.

PMID- 12487315
TI  - Use of ICP/MS with ultrasonic nebulizer for routine determination of uranium
      activity ratios in natural water.
AB  - A method is described that allows precise determination of 234U/238U activity
      ratios (UAR) in most natural waters using commonly available inductively coupled
      plasma/mass spectrometry (ICP/MS) instrumentation and accessories. The precision
      achieved by this technique (+/- 0.5% RSD, 1 sigma) is intermediate between
      thermal ionization mass spectrometry (+/- 0.25% RSD, 1 sigma) and alpha particle
      spectrometry (+/- 5% RSD, 1 sigma). It is precise and rapid enough to allow
      analysis of a large number of samples in a short period of time at low cost using
      standard, commercially available quadrupole instrumentation with ultrasonic
      nebulizer and desolvator accessories. UARs have been analyzed successfully in
      fresh to moderately saline waters with U concentrations of from less than 1
      microg/L to nearly 100 microg/L. An example of the uses of these data is shown
      for a study of surface-water mixing in the North Platte River in western
      Nebraska. This rapid and easy technique should encourage the wider use of uranium
      isotopes in surface-water and groundwater investigations, both for qualitative
      (e.g. identifying sources of water) and quantitative (e.g. determining end-member
      mixing ratios purposes.

PMID- 12487313
TI  - Determination of trace mercury in environmental and foods samples by online
      coupling of flow injection displacement sorption preconcentration to
      electrothermal atomic absorption spectrometry.
AB  - The toxic effects of mercury are well-known. To establish sources of mercury
      contamination and to evaluate levels of mercury pollution, sensitive, selective,
      and accurate analytical methods with excellent reproducibility are required. We
      have developed a novel methodology for the determination of trace mercury in
      environmental and foods samples by online coupling of flow injection (FI)
      displacement sorption preconcentration in a knotted reactor (KR) to
      electrothermal atomic absorption spectrometry (ETAAS). The developed methodology
      involved the online formation of copper pyrrolidine dithiocarbamate (Cu-PDC),
      presorption of the resulting Cu-PDC onto the inner walls of the KR, and selective
      retention of the analyte Hg(ll) onto the inner walls of the KR through online
      displacement reaction between Hg(ll) and the presorbed Cu-PDC. The retained
      analyte was subsequently eluted by 50 microL of ethanol and online detected by
      ETAAS. Interferences from coexisting heavy metal ions with lower stability of
      their APDC complexes relative to Cu- PDC were minimized without the need of any
      masking reagents. The tolerable concentrations of Cu(II), Cd(II), Fe(III),
      Ni(III), and Zn(II) were up to 12, 20, 16, 20, and 60 mg L(-1), respectively. No
      additional chemical modifiers for the stabilization of mercury were required in
      the present system owing to the stability of Hg-PDC at the drying stage, and no
      pyrolysis stage was necessary due to the effective removal of the matrices. With
      consumption of 2.5 mL of sample solution, an enhancement factor of 91 was
      obtained in comparison with direct injection of 50 microL of aqueous solution.
      The relative detection limit (3s) was 6.2 ng L(-1), corresponding to an absolute
      detection limit of 15.5 pg. The precision (RSD, n = 13) was 1.1% at the 2 microg
      L(-1) level. The method was successfully applied to the determination of mercury
      in several certified environmental and foods reference materials and locally
      collected water samples.

PMID- 12487316
TI  - Oral bioaccessibility of dioxins/furans at low concentrations (50-350 ppt
      toxicity equivalent) in soil.
AB  - Animal studies have indicated that the oral bioavailability of 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) in environmentally contaminated soil could
      range from 0.5 to 60%. To estimate the oral bioavailability of TCDD, and the 16
      other 2,3,7,8-substituted dioxin/furan congeners, this study used a
      physiologically based extraction test, designed around the anatomic and
      physiologic characteristics of the human digestive tract. This test measures the
      fraction of dioxins/furans in soil that would be solubilized in the
      gastrointestinal tract (i.e., that would be bioaccessible) and therefore
      available for absorption. Eight soils from Midland, MI, were evaluated in this
      study and exhibited TCDD concentrations of 1.7-139 pg/g (ppt) and total TEQ
      concentrations of 6-340 ppt. Bioaccessibility of dioxins/furans from these soils
      ranged from 19 to 34% averaged across the 17 2,3,7,8-substituted dioxin/furan
      congeners), with an average of 25%. The total organic carbon in these soils was
      low--ranging from 1 to 4%--particularly for the soil series from which they were
      collected. Bioaccessibility of individual congeners did not appear to be
      correlated with degree of chlorination. Even though these dioxin/furan
      concentrations are much less than studied previously, these results are
      consistent with those from animal studies at other sites, which have generally
      yielded values of 20-60% relative bioavailability for TCDD in soil.

PMID- 12487317
TI  - Development of a flow controller for long-term sampling of gases and vapors using
      evacuated canisters.
AB  - Anthropogenic activities contribute to the release of a wide variety of volatile
      organic compounds (VOC) into microenvironments. Developing and implementing new
      air sampling technologies that allow for the characterization of exposures to VOC
      can be useful for evaluating environmental and health concerns arising from such
      occurrences. A novel air sampler based on the use of a capillary flow controller
      connected to evacuated canisters (300 mL, 1 and 6 L) was designed and tested. The
      capillary tube, used to control the flow of air, is a variation on a sharp-edge
      orifice flow controller. It essentially controls the velocity of the fluid (air)
      as a function of the properties of the fluid, tube diameter and length. A model
      to predict flow rate in this dynamic system was developed. The mathematical model
      presented here was developed using the Hagen-Poiseuille equation and the ideal
      gas law to predict flow into the canisters used to sample for long periods of
      time. The Hagen-Poiseuille equation shows the relationship between flow rate,
      pressure gradient, capillary resistance, fluid viscosity, capillary length and
      diameter. The flow rates evaluated were extremely low, ranging from 0.05 to 1 mL
      min(-1). The model was compared with experimental results and was shown to
      overestimate the flow rate. Empirical equations were developed to more accurately
      predict flow for the 300 mL, 1 and 6 L canisters used for sampling periods
      ranging from several hours to one month. The theoretical and observed flow rates
      for different capillary geometries were evaluated. Each capillary flow controller
      geometry that was tested was found to generate very reproducible results, RSD <
      2%. Also, the empirical formulas developed to predict flow rate given a specified
      diameter and capillary length were found to predict flow rate within 6% of the
      experimental data. The samplers were exposed to a variety of airborne vapors that
      allowed for comparison of the effectiveness of capillary flow controllers to
      sorbent samplers and to an online gas chromatograph. The capillary flow
      controller was found to exceed the performance of the sorbent samplers in this
      comparison.

PMID- 12487318
TI  - Use of hydrochloric acid for determinining solid-phase arsenic partitioning in
      sulfidic sediments.
AB  - We examined the use of room-temperature hydrochloric acid (1-6 M) and salt
      solutions of magnesium chloride, sodium carbonate, and sodium sulfide for the
      removal of arsenic from synthetic iron monosulfides and contaminated sediments
      containing acid-volatile sulfides (AVS). Results indicate that acid-soluble
      arsenic reacts with H2S released from AVS phases and precipitates at low pH as
      disordered orpiment or alacranite. Arsenic sulfide precipitation is consistent
      with geochemical modeling in that conditions during acid extraction are predicted
      to be oversaturated with respect to orpiment, realgar, or both. Binding of
      arsenic with sulfide at low pH is sufficiently strong that 6 M HCl will not keep
      spiked arsenic in the dissolved fraction. Over a wide range of AVS concentrations
      and molar [As]/[AVS] ratios, acid extraction of arsenic from sulfide-bearing
      sediments will give biased results that overestimate the stability or
      underestimate the bioavailability of sediment-bound arsenic. Alkaline solutions
      of sodium sulfide and sodium carbonate are efficient in removing arsenic from
      arsenic sulfides and mixed iron-arsenic sulfides because of the high solubility
      of arsenic at alkaline pH, the formation of stable arsenic complexes with sulfide
      or carbonate, or both.

PMID- 12487319
TI  - Studies on the surface chemistry based on competive adsorption of NOx-SO2 onto a
      KOH impregnated activated carbon in excess O2.
AB  - This study identifies surface chemistry characteristics based on competitive
      behavior in the simultaneous adsorption behavior of NOx (NO rich) and SO2 using
      KOH impregnated activated carbon (K-IAC) in excess O2. The NOx and SO2 adsorption
      on K-IAC occurred mainly through the acid-base reaction. The high surface area
      with many pores of activated carbon acted as storage places of oxide crystal
      produced from NOx and SO2 adsorption. KOH, an impregnant, provided the selective
      adsorption sites to NOx and SO2, enabling simultaneous adsorption. However,
      larger amounts of SO2, with higher adsorption affinity to K-IAC compared to NOx,
      were adsorbed in a NOx/SO2 coexistent atmosphere. Oxygen was chemisorbed to K
      IAC, which enhanced the selective adsorptivity for NO. In binary-component
      adsorption of NOx and SO2 on K-IAC, oxide crystals such as KNO, (x = 2,3) and
      K2SOx (x = 3,4) were dominantly formed through two different adsorption
      mechanisms by chemical reacton. Depending on the extent that oxide crystals
      blocked pores, compositions of oxide crystals were distributed differently
      according to depth.

PMID- 12487320
TI  - Urban residential refuse composition and generation rates for the 20th century.
AB  - Examination of historical data shows that 3.5 x 10(8) tonnes (t) of residential
      refuse was discarded in New York City (NYC) during the 20th century. Maximum and
      minimum rates of per capita mass discard of residential refuse during this time
      are reported in 1940 (940 kg per capita yr(-1)) and 1961, 1963 (320 kg per capita
      yr(-1)), respectively. Since 1980, per capita residential refuse discard rates
      have been steady and comparatively low (430 kg per capita yr(-1) +/- 2.5%). Fuel
      ash accounted for approximately 34% of residential refuse in NYC during the
      century. A decline of refuse bulk density (as collected) from approximately 500
      to 200 kg m(-3) and an increase in refuse organic matter content from 20% to 80%
      (by mass) is reported between 1920 and 1990 and is due largely to mass fraction
      reductions forfuel ash and increases for paper and plastic. Approximately 4.9 x
      10(8) t of refuse was disposed in NYC during the 20th century (including
      commercial and residential refuse), representing a total pool of about 8.0 x
      10(7) t of organic carbon (as C) that has entered city landfills and
      incinerators.

PMID- 12487321
TI  - Camphor-Crataegus berry extract combination dose-dependently reduces tilt induced
      fall in blood pressure in orthostatic hypotension.
AB  - In order to test the efficacy of a combination of natural D-camphor and an
      extract of fresh crataegus berries (Korodin Herz-Kreislauf-Tropfen) on
      orthostatic hypotension, two similar, controlled, randomized studies were carried
      out in a balanced crossover design in 24 patients each with orthostatic
      dysregulation. The camphor-crataegus berry combination (CCC) was orally
      administered as a single regimen in 3 different dosages of 5 drops, 20 drops and
      80 drops; a placebo with 20 drops of a 60% alcoholic solution served as control.
      Orthostatic hypotension was assessed with the tilt table test before and after
      medication. Source data of both studies were pooled and meta-analytically
      evaluated for all 48 patients. CCC drops decreased the orthostatic fall in blood
      pressure versus placebo, as almost uniformly established at all times by mean
      arterial pressure and diastolic blood pressure. Mean arterial pressure
      demonstrated the very fast onset of action by a clearly dose-dependent
      statistically significant effect even after 1-minute orthostasis. Increase of
      mean arterial pressure as compared to the orthostasis test before medication was
      on average 4.5 mmHg. CCC affected diastolic blood pressure after 1 minute of
      orthostasis in all dosages as compared to placebo. A statistically significant
      effect of the highest dose of 80 drops on diastolic blood pressure could be
      demonstrated after 1-, 3-, and 5-minute orthostasis. The hemodynamic findings of
      a stabilizing effect on arterial pressure in orthostasis corroborate the long
      term medical experience with CCC and justify the indication orthostatic
      hypotension.

PMID- 12487322
TI  - A double blind, placebo-controlled study of Andrographis paniculata fixed
      combination Kan Jang in the treatment of acute upper respiratory tract infections
      including sinusitis.
AB  - A double blind, placebo-controlled, parallel-group clinical study was carried out
      to evaluate the effect of an Andrographis paniculata (N.) extract SHA-10 fixed
      combination, Kan Jang, in the treatment of acute upper respiratory tract
      infections, including sinusitis. Ninety-five individuals in the treatment group
      and 90 individuals in the placebo group completed the study according to the
      protocol. The medication was taken for 5 days. Temperature, headache, muscle
      aches, throat symptoms, cough, nasal symptoms, general malaise and eye symptoms
      were taken as outcome measures with given scores. The total score analysis showed
      a highly significant improvement in the verum group versus the placebo. This
      result applied to the group as a whole and to the sinusitis subgroups. The
      individual symptoms of headache and nasal and throat symptoms together with
      general malaise showed the most significant improvement while cough and eye
      symptoms did not differ significantly between the groups. Temperature was
      moderately reduced in the verum group. It can be concluded that Kan Jang has a
      positive effect in the treatment of acute upper respiratory tract infections and
      also relieves the inflammatory symptoms of sinusitis. The study drug was well
      tolerated.

PMID- 12487323
TI  - Effect of andrographolide and Kan Jang--fixed combination of extract SHA-10 and
      extract SHE-3--on proliferation of human lymphocytes, production of cytokines and
      immune activation markers in the whole blood cells culture.
AB  - The immunomodulatory properties of a diterpene lactone andrographolide and Kan
      Jang--a standardized fixed combination of Andrographis paniculata extract SHA-10
      and Eleutherococcus senticosus extract SHE-3 were investigated. Their role on
      spontaneous and phytohemagglutinin (PHA)-induced proliferation of human
      peripheral blood lymphocytes (PBL) and on production of interferon-gamma (INF
      gamma) and tumor necrosis factor-alpha (TNF-alpha) were determined in vitro.
      Proliferation of PBL induced by PHA was enhanced by co stimulation with
      andrographolide and Kan Jang. At the same time andrographolide and Kan Jang
      inhibit spontaneous proliferation of PBL in vitro. These preparations also have
      effect on the formation of INF-gamma, TNF-alpha and some immune activation
      markers such as neopterin (Neo), beta-2-microglobulin (beta2MG), and soluble
      receptor for interleukin-2 (sIL-2R or sCD25) in blood cells culture.
      Andrographolide and Kan Jang stimulate the INF-gamma, Neopterin and beta2MG
      formation, but do not have any significant effect on the production of INF-gamma
      and Neopterin in PHA stimulated blood cells. An opposite effect on these immune
      makers was observed in the PHA-stimulated blood cells: both andrographolide and
      Kan Jang increase the formation of TNF-alpha and beta2MG in cultivated whole
      blood cells. Thus, andrographolide and Kan Jang can have an in vitro effect on
      the activation and proliferation of immunocompetent cells as well on the
      production of key cytokines and immune activation markers. The results show an
      overall higher effect of the fixed combination as compared with the equivalent
      amount of the pure substance andrographolide. The data are consistent with
      results from clinical studies of Kan Jang and contributed to a better
      understanding of these results.

PMID- 12487324
TI  - Effect of an orally applied herbal immunomodulator on cytokine induction and
      antibody response in normal and immunosuppressed mice.
AB  - The influence of the oral administration of a herbal immunomodulator, consisting
      of an aqueous-ethanolic extract of the mixed herbal drugs Thujae summitates,
      Baptisiae tinctoriae radix, Echinaceae purpureae radix and Echinaceae pallidae
      radix, on cytokine induction and antibody response against sheep red blood cells
      was investigated in mice. The treatment of the animals with the extract caused no
      enhancement of the cytokine titers in the serum. Spleen cells isolated from the
      treated mice, however, produced higher amounts of IL-2, IFNgamma and GM-CSF ex
      vivo in comparison to spleen cells isolated from control animals, especially
      after additional stimulation by lipopolysaccharides or concanavalin A. The
      application of the extract also triggered the production of IL-1 and TNFalpha by
      peritoneal macrophages ex vivo. The influence of the herbal extract on the
      antibody response was examined by the plaque forming cell assay. The
      administration of the extract caused a significant enhancement of the antibody
      response against sheep red blood cells, inducing an increase in the numbers of
      splenic plaque forming cells and the titers of specific antibodies in the sera of
      the treated animals. In mice, immunosuppressed by old age or additional treatment
      with hydrocortisone, the therapy with the extract resulted in a normalization of
      the antibody response against sheep red blood cells.

PMID- 12487325
TI  - Intestinal immune system modulating polysaccharides in a Japanese herbal (Kampo)
      medicine, Juzen-Taiho-To.
AB  - A commercially available dried extract (TJ-48) of Japanese herbal (Kampo)
      prescription, Juzen-Taiho-To has been found to enhance functions of Peyer's patch
      cells (intestinal immune system modulating activity) in vitro and in vivo. When
      TJ-48 was fractionated, the dialyzable fraction (F-3) and the polysaccharide
      fraction (F-5) expressed the in vitro activity. Oral administration of F-5 (150
      mg/kg/day) to mice showed the intestinal immune system modulating activity. When
      the galacturonan moiety of pectic polysaccharides in F-5 was degraded
      enzymatically by endo-polygalacturonase, the digestion products significantly
      increased the activity of F-5. Purification the polygalacturonase-digested F-5
      indicated that the active substances were composed mainly of the enzyme-resistant
      or undigestable polysaccharide molecules. Gel filtrations and anion-exchange
      chromatographies of F-5 gave 12 kinds of polysaccharides, and among them, 7
      polysaccharides had significant intestinal immune system modulating activity.
      Component sugar analysis suggests that some active polysaccharides are grouped
      into pectic polysaccharides containing arabinogalactan or heteroglycan chains.
      Single radial gel diffusion analysis using beta-D-glucosyl-Yariv antigen
      indicated that some of the active polysaccharides comprised arabino-3,6-galactan
      moiety, and this moiety was suggested to play an important role partly for
      expression of the activity by single linear regression analysis between degree of
      the activity and reactivity with beta-D-glyucosyl-Yariv antigen.

PMID- 12487326
TI  - Quercetin glucuronides inhibited 2-aminofluorene acetylation in human acute
      myeloid HL-60 leukemia cells.
AB  - Our earlier study has demonstrated that following the exposure of rat to the
      arylamine carcinogen 2-aminofluorene, DNA-2-aminofluorene adducts were found in
      the target tissues liver, bladder, colon, lung and also in circulating leukocytes
      (lymphocytes and monocytes). The result also demonstrated that orally treated
      antioxidants decreased N-acetylation of 2-aminofluorene in target tissues and
      leukocytes. Therefore, this study investigated whether quercetin glucuronides
      could affect N-acetylation of 2-aminofluorene in human acute myeloid leukemia HL
      60 cells. Evidence is presented here that human leukemia cells are capable of
      acetylating 2-aminofluorene. Quercetin glucuronides did inhibit 2-aminofluorene
      acetylation in intact cells. The results also indicated that quercetin
      glucuronides induced cytotoxicity in dose-dependent manner in the examined human
      acute myeloid leukemia HL-60 cells.

PMID- 12487327
TI  - Evaluation of anti-inflammatory activity of Alstonia macrophylla Wall ex A. DC.
      leaf extract.
AB  - Methanolic extract of dried leaves of Alstonia macrophylla Wall ex A. DC. and its
      fractions were investigated for its anti-inflammatory activity. The extract at a
      concentration of 200 mg kg(-1) and 400 mg kg(-1), p.o. and its fractions at 25 mg
      kg(-1) and 50 mg kg(-1), p.o. showed the significant dose dependent
      antiinflammatory activity in carrageenan and dextran-induced rats hind paw edema
      (acute models) as well as in cotton pellet-induced granuloma (chronic model) in
      rats. Anti-inflammatory activity of the tested extract and its fractions was
      comparable with that of the standard drug Indomethacin (10 mg kg(-1)).

PMID- 12487328
TI  - Inhibitory effects of Choto-san (Diao-teng-san), and hooks and stems of Uncaria
      sinensis on free radical-induced lysis of rat red blood cells.
AB  - The present study is designed to test our hypothesis that the ingestion of
      Uncaria sinensis (US), the main medicinal plant of Choto-san (Diao-teng-san, CS),
      would protect red blood cell (RBC) membrane from free radical-induced oxidation
      if polyphenolics in US could be absorbed and circulated in blood. When incubated
      with RBC suspension, Choto-san extract (CSE) and Uncaria sinensis extract (USE)
      exhibited strong protection for RBC membrane against hemolysis induced by 2,2-azo
      bis (2-amidinopropane) dihydrochloride (AAPH), an azo free-radical initiator. The
      inhibitory effect was dose-dependent at concentrations of 50 to 1000 microg/mL.
      Ingestion of 200 mg of USE was associated with a significant decrease in
      susceptibility of RBC to hemolysis in rats. Furthermore, caffeic acid, an
      antioxidative hydroxycinnamic acid, was identified in rat plasma after
      administration of URE.

PMID- 12487329
TI  - Anti-herpes simplex virus effect of a seed extract from the tropical plant
      Licania tomentosa (Benth.) Fritsch (Chrysobalanaceae).
AB  - Incubation of acyclovir-resistant herpes simplex virus type 1 (ACVr-HSV1), during
      infection of the HEp-2 cell culture, with an extract prepared from the seeds of
      Licania tomentosa (Benth.) Fritsch (Chrysobalanaceae) species impaired the
      productive replication of this virus in a concentration-dependent manner. The
      extract was able to inhibit extracellular virus (virucidal effect) and also
      interfered with a very early event of cell infection, at a non-cytotoxic
      concentration.

PMID- 12487330
TI  - Topical anti-inflammatory activity of Bauhinia tarapotensis leaves.
AB  - The topical anti-inflammatory properties of Bauhinia tarapotensis Benth.
      (Leguminosae) leaves have been studied by the inhibition of the croton oil
      induced ear edema in mice. A bioassay-guided fractionation showed an interesting
      anti-inflammatory activity of the chloroform extract, that justifies the activity
      of the whole herbal drug. The main anti-inflammatory principles of B.
      tarapotensis leaves are triterpenic acids of ursane and oleanane series. The
      antiphlogistic activity of mixtures constituted of two ursane and oleanane
      isomers with different hydroxylation pattern, in the ratio 2:1, is comparable to
      that of indomethacin (ID50 ranging from 95 to 147 microg/cm2 and 93 microg/cm2,
      respectively).

PMID- 12487331
TI  - Effects of tenuiorin and methyl orsellinate from the lichen Peltigera
      leucophlebia on 5-/15-lipoxygenases and proliferation of malignant cell lines in
      vitro.
AB  - The orcinol derivatives tenuiorin (1) and methyl orsellinate (2) were identified
      as active components of an extract from the lichen Peltigera leucophlebia (Nyl.)
      Gyeln. showing in vitro inhibitory activity against 15-lipoxygenase from
      soybeans. The compounds were subsequently tested for in vitro activity against 5
      lipoxygenase from porcine leucocytes and proved to be moderately active, with
      IC50 values of 41.6 microM and 59.6 microM respectively. Tenuiorin is a known
      constituent of several Peltigera species but has not previously been isolated
      from P. leucophlebia. As correlation between 5-lipoxygenase inhibition and
      antiproliferative effects has earlier been witnessed for related lichen
      metabolites, tenuiorin and methyl orsellinate were further tested for
      antiproliferative activity on cultured human breast (T-47D)-, pancreatic (PANC-1)
      and colon (WIDR) cancer cell lines. The monomeric methyl orsellinate exhibited
      no detectable antiproliferative activity whereas the trimeric tenuiorin caused
      moderate/weak reduction in [3H]-thymidine uptake of the pancreatic- and colon
      cancer cells, with ED50 values of 87.9 and 98.3 microM respectively.

PMID- 12487332
TI  - Isolation of biologically active fractions from the water soluble components of
      fulvic and ulmic acids from peat.
AB  - With a view to clarifying the excitatory action of aqueous peat extract (APE) on
      the spontaneous contractile activity (SCA) of the smooth muscles, in vitro
      studies were made of the influences of the water-soluble HPLC-fractions of fulvic
      and ulmic acids separated from peat on smooth-muscle preparations of guinea-pig
      stomach. The results obtained show that peat contains a large number of water
      soluble components, which possess agonistic or partial agonistic actions on the
      alpha2-adreno- and D2-dopamine receptors. These are chemically stable substances,
      which retain for months their biological activity unchanged in aqueous solution.
      The excitatory effect of APE on the SCA of the smooth-muscle preparations was
      found to be more pronounced than the reactivity of alpha2-adrenoreceptors.

PMID- 12487333
TI  - Effects of Annona squamosa extract on early pregnancy in rats.
AB  - Annona squamosa Linn., family Annonaceae, is said to show varied medicinal
      effects, including insecticide, antiovulatory and abortifacient. The purpose of
      present study was to investigate if A. squamosa seed aqueous extract, in doses
      higher than that popularly used to provoke abortion, interferes with reproductive
      performance, and to correlate the ingestion of this extract with possible
      alterations in rat embryonic implantation. Doses of 300 mg/kg (Treated Group I, n
      = 17) and 600 mg/kg (Treated Group II, n = 12) body wt. were administered by
      gavage, during days 1 to 5 of pregnancy (preimplantation period). The control
      group (n = 13) received water in the same manner, during the same period for
      comparison with experimental groups. The animals were euthanized on day 10 of
      pregnancy. Treatment of dams during the preimplantation period showed no signs of
      toxicity, and no alteration in the corpora lutea, implantations and embryo in
      terms of development numbers. The percentage of preimplantation and
      postimplantation losses in treated groups I and II did not differ from those of
      control. Treatment with aqueous extract of A. squamosa seeds caused no
      morphological change in the endometrium. The absence of morphological alterations
      in uterine epithelial cells in treated groups I and II permitted a viable
      embryonic implantation, as verified by the number of embryos in development at
      day 10 of pregnancy. Thus, A. squamosa seed aqueous extract did not interfere
      with the reproductive performance of pregnant rats.

PMID- 12487334
TI  - Top management's contribution to quality management.

PMID- 12487335
TI  - The autopsy: a professional responsibility in assuring quality of care.

PMID- 12487336
TI  - Making "me-too" drugs benefit the public.
AB  - The Food and Drug Administration (FDA), in its review of pharmaceuticals for
      safety and effectiveness, has relied heavily on placebo-controlled studies. In
      their prescribing practice, physicians often face clinical decisions between
      several FDA-approved drugs for the same indication, with little guidance from the
      FDA on the similarities or differences of the drugs. The public could benefit if
      the FDA were more proactive in declaring, when applicable, that the best
      available evidence does not indicate any significant clinical advantage for a
      particular FDA-approved drug compared with others.

PMID- 12487337
TI  - Chemotherapy dose intensity determination as a quality of care measure for
      managed care organizations in the treatment of early-stage breast cancer.
AB  - The objective of this study was to demonstrate how a clinical practice database
      can be used to illustrate the variations in adjunctive chemotherapy for breast
      cancer, to describe a measure of dose intensity (DI) to monitor that variation,
      and to design interventions to maximize a full-planned dose. An arbitrary sample
      of oncology practices across the United States was selected, each providing data
      on 10-20 patients treated with adjuvant chemotherapy for early-stage breast
      cancer. Data on 17,566 patients from 1,438 sites were collected, consisting of
      patient characteristics including age, number of positive nodes, planned and
      delivered chemotherapy agents, and a sample of absolute neutrophil or white blood
      cell counts by cycle. Mean age of the patient cohort was 48.5 years, and 54% of
      patients were below the age of 49. Treatment for the disease has changed during
      the 2 periods studied, 1983-1994 and 1995-1999. Use of Adriamycin/Cytoxan (AC)
      increased, whereas use of Cytoxan/Adriamycin/Fluorouracil (CAF) and full-dose
      Cytoxan/Methotrexate/Fluorouracil (CMF1) decreased. However, the less intense
      Cytoxan/Methotrexate/Fluorouracil combination (CMF2) has seen an actual increase
      in use during the 2 periods. Within the context of oncology care, including
      chemotherapy, full-dose intensive therapy and cure has always been the ultimate
      goal. In this study only 10% of the patients given AC received less than 85% of
      the full referenced dose, whereas about 20% of those receiving the other
      combinations fell into this category. Also, the summation dose intensity (SDI), a
      measure tying level of dose to survival, was highest in the AC group and lowest
      in the CMF2 group. Dose delays and dose reductions appear to account for the
      decrease in DI in the CMF1, CMF2, and CAF groups. DI, particularly SDI of
      adjuvant chemotherapy, which ties level of dose to survival in breast cancer
      patients, appears to be a reliable measure with which to assess the quality of
      care in community oncology practices. The 2 measures presented in this paper may
      be useful to managed care organizations for monitoring quality outcomes in this
      serious disease. Because one of the major reasons for reduction in chemotherapy
      dose appears to be neutropenia and its complications, these organizations can
      establish programs using DI as a basis for developing guidelines to optimize the
      clinical benefits of growth factors.

PMID- 12487338
TI  - The effect of external feedback on the management of medicare inpatients with
      congestive heart failure.
AB  - The purpose of this study was to compare the effect of 2 feedback strategies on
      the adherence to congestive heart failure (CHF) guidelines. Thirty-two hospitals
      in 4 states were randomized to receive either a written feedback intervention
      (low-intensity intervention [LII]) or an intervention involving feedback, a
      physician liaison, and quality improvement tools (high-intensity intervention
      [HII]). CHF quality indicators were assessed, and quality managers were
      interviewed at baseline and remeasurement. No significant changes in quality
      indicators were found as a result of either intervention. Seventy-eight percent
      of quality managers indicated that hospital project implementation had not begun
      until shortly before remeasurement. HII quality managers perceived the CHF
      project as significantly more successful compared with LII quality managers (63%
      versus 13%, P < .01). Evaluation of the effects of external feedback on practice
      behavior requires sufficient time for organizational and individual clinician
      change to occur. Physician liaisons may play a role in facilitating this change.

PMID- 12487339
TI  - Hospital organizational change and financial status: costs and outcomes of care
      in Philadelphia.
AB  - Two recent changes in Philadelphia-area hospital organizations are consolidation
      into systems and acquisition of 2 medical school hospitals by a for-profit chain.
      This study explored whether such consolidation and conversion affected costs and
      outcomes of care. The analysis included 1,617,581 discharges from 49 acute-care
      hospitals from 1997 to 1999. Analyses within and between medical school hospitals
      examined trends in discharges, case mix, length of stay, and mortality. The study
      addressed 2 questions: whether, as hospitals consolidate into medical school
      hospital-based systems, volume, severity, length of stay, and mortality increase
      in those hospitals; and whether for-profit conversion redistributes complex, high
      cost admissions to nonprofit hospitals. The 2 medical school hospitals that
      became for-profit experienced decreases in volume and resource intensity, coupled
      at one with an increase in severity. However, these patterns were produced more
      by the system's financial instability than by consolidation or conversion.

PMID- 12487340
TI  - A different perspective on quality.
AB  - Evaluation of physicians in the credentialing processes of hospitals has
      generally been viewed as focused upon whether the physicians will provide
      services to patients at the appropriate level of professional performance and
      will not engage in disruptive behavior at the institution. Three measures-
      exclusive contracting, medical staff planning, and exclusive credentialing--have
      been employed, singly or in combination, at many hospitals to restrict or to deny
      medical staff appointments and clinical privileges to professionally qualified
      and competent physicians. Because the hospitals have articulated links, when
      employing these restrictive measures in making credentialing decisions, to the
      public's interest in their being able to provide good quality services to the
      communities they serve, the hospitals have usually been successful in litigation
      brought by physicians who have been denied staff appointment or specific clinical
      privileges.

PMID- 12487341
TI  - Breaking through barriers to recovery from a stroke: both sides of the
      experience.

PMID- 12487342
TI  - Speciation despite gene flow when developmental pathways evolve.
AB  - Evolutionary biologists assume that species formation requires a drastic
      reduction in gene exchange between populations, but the rate sufficient to
      prevent speciation is unknown. To study speciation, we use a new class of
      population genetic models that incorporate simple developmental genetic rules,
      likely present in all organisms, to construct the phenotype. When we allow
      replicate populations to evolve in parallel to a new, shared optimal phenotype,
      often their hybrids acquire poorly regulated phenotypes: Dobzhansky-Muller
      incompatibilities arise and postzygotic reproductive isolation evolves. Here we
      show that, although gene exchange does inhibit this process, it is the proportion
      of migrants exchanged (m) rather than the number of migrants (Nm) that is
      critical, and rates as high as 16 individuals exchanged per generation still
      permit the evolution of postzygotic isolation. Stronger directional selection
      counters the inhibitory effect of gene flow, increasing the speciation
      probability. We see similar results when populations in a standard two-locus, two
      allele Dobzhansky-Muller model are subject to simultaneous directional selection
      and gene flow. However, in developmental pathway models with more than two loci,
      gene flow is more able to impede speciation. Genetic incompatibilities arise as
      frequent by-products of adaptive evolution of traits determined by regulatory
      pathways, something that does not occur when phenotypes are modeled using the
      standard, additive genetic framework. Development therefore not only constrains
      the microevolutionary process, it also facilitates the interactions among genes
      and gene products that make speciation more likely-even in the face of strong
      gene flow.

PMID- 12487343
TI  - The evolution of embryo size in angiosperms and other seed plants: implications
      for the evolution of seed dormancy.
AB  - Seed dormancy plays an important role in germination ecology and seed plant
      evolution. Morphological seed dormancy is caused by an underdeveloped embryo that
      must mature prior to germination. It has been suggested that the presence of an
      underdeveloped embryo is plesiomorphic among seed plants and that parallel
      directional change in embryo morphology has occurred separately in gymnosperms
      and in angiosperms. We test these hypotheses using original data on embryo
      morphology of key basal taxa, a published dataset, and the generalized least
      squares (GLS) method of ancestral character state reconstruction. Reconstructions
      for embryo to seed ratio (E:S) using family means for 179 families showed that
      E:S has increased between the ancestral angiosperm and almost all extant
      angiosperm taxa. Species in the rosid clade have particularly large embryos
      relative to the angiosperm ancestor. Results for the gymnosperms show a similar
      but smaller increase. There were no statistically significant differences in E:S
      between basal taxa and any derived group due to extremely large standard errors
      produced by GLS models. However, differences between reconstructed values for the
      angiosperm ancestor and more highly nested nodes are large and these results are
      robust to topological and branch-length manipulations. Our analysis supports the
      idea that the underdeveloped embryo is primitive among seed plants and that there
      has been a directional change in E:S within both angiosperms and gymnosperms. Our
      analysis suggests that dormancy enforced by an underdeveloped embryo is
      plesiomorphic among angiosperms and that nondormancy and other dormancy types
      probably evolved within the angiosperms. The shift in E:S was likely a
      heterochronic change, and has important implications for the life history of seed
      plants.

PMID- 12487344
TI  - Patterns of genetic variation suggest a single, ancient origin for the diploid
      hybrid species Helianthus paradoxus.
AB  - Experimental and comparative evidence implies that homoploid hybrid speciation is
      a reproducible process, mediated in part by ecological selection. Here, molecular
      data from the chloroplast genome and 17 nuclear microsatellite loci were employed
      to determine whether a well-documented homoploid hybrid species, Helianthus
      paradoxus, has arisen multiple times. Helianthus paradoxus is ecologically
      divergent from its parental species, and has a disjunct geographic distribution
      consistent with multiple origins. The molecular data, however, strongly support a
      single hybrid origin. First, all sampled populations of H. paradoxus are fixed
      for a single chloroplast DNA (cpDNA) haplotype, whereas local populations of both
      parental species, H. annuus and H. petiolaris, have multiple cpDNA haplotypes.
      Second, H. paradoxus populations form a single, well-supported clade (99.8%
      bootstrap support) in a neighbor-joining tree based on microsatellite allele
      frequencies. The microsatellite data also tentatively place the origin of H.
      paradoxus between 75,000 years and 208,000 years before present, indicating that
      anthropogenic disturbance likely did not play a role in the formation of this
      species. Finally, the genetic structure of this species is not consistent with
      passive riparian dispersal, which has been suggested for other wetland plant
      species, but may be explained by dispersal mechanisms implicated for H. annuus,
      such as large migratory mammals.

PMID- 12487345
TI  - Minor quantitative trait loci underlie floral traits associated with mating
      system divergence in Mimulus.
AB  - The genetic basis of species differences provides insight into the mode and tempo
      of phenotypic divergence. We investigate the genetic basis of floral differences
      between two closely related plant taxa with highly divergent mating systems,
      Mimulus guttatus (large-flowered outcrosser) and M. nasutus (small-flowered
      selfer). We had previously constructed a framework genetic linkage map of the
      hybrid genome containing 174 markers spanning approximately 1800 cM on 14 linkage
      groups. In this study, we analyze the genetics of 16 floral, reproductive, and
      vegetative characters measured in a large segregating M. nasutus x M. guttatus F2
      population (N = 526) and in replicates of the parental lines and F1 hybrids.
      Phenotypic analyses reveal strong genetic correlations among floral traits and
      epistatic breakdown of male and female fertility traits in the F2 hybrids. We use
      multitrait composite interval mapping to jointly locate and characterize
      quantitative trait loci (QTLs) underlying interspecific differences in seven
      floral traits. We identified 24 floral QTLs, most of which affected multiple
      traits. The large number of QTLs affecting each trait (mean = 13, range = 11-15)
      indicates a strikingly polygenic basis for floral divergence in this system. In
      general, QTL effects are small relative to both interspecific differences and
      environmental variation within genotypes, ruling out QTLs of major effect as
      contributors to floral divergence between M. guttatus and M. nasutus. QTLs show
      no pattern of directional dominance. Floral characters associated with pollinator
      attraction (corolla width) and self-pollen deposition (stigma-anther distance)
      share several pleiotropic or linked QTLs, but unshared QTLs may have allowed
      selfing to evolve independently from flower size. We discuss the polygenic nature
      of divergence between M. nasutus and M. guttatus in light of theoretical work on
      the evolution of selfing, genetics of adaptation, and maintenance of variation
      within populations.

PMID- 12487346
TI  - Reducing environmental bias when measuring natural selection.
AB  - Crucial to understanding the process of natural selection is characterizing
      phenotypic selection. Measures of phenotypic selection can be biased by
      environmental variation among individuals that causes a spurious correlation
      between a trait and fitness. One solution is analyzing genotypic data, rather
      than phenotypic data. Genotypic data, however, are difficult to gather, can be
      gathered from few species, and typically have low statistical power.
      Environmental correlations may act through traits other than through fitness
      itself. A path analytic framework, which includes measures of such traits, may
      reduce environmental bias in estimates of selection coefficients. We tested the
      efficacy of path analysis to reduce bias by re-analyzing three experiments where
      both phenotypic and genotypic data were available. All three consisted of plant
      species (Impatiens capensis, Arabidopsis thaliana, and Raphanus sativus) grown in
      experimental plots or the greenhouse. We found that selection coefficients
      estimated by path analysis using phenotypic data were highly correlated with
      those based on genotypic data with little systematic bias in estimating the
      strength of selection. Although not a panacea, using path analysis can
      substantially reduce environmental biases in estimates of selection coefficients.
      Such confidence in phenotypic selection estimates is critical for progress in the
      study of natural selection.

PMID- 12487347
TI  - Experimental life-history evolution: selection on the allocation to sexual
      reproduction and its plasticity in a clonal plant.
AB  - Allocation to sexual reproduction is an important life-history trait in clonal
      plants. Different selection pressures between competitive and competition-free
      environments are likely to result in the evolution of specialized genotypes and
      to maintain genetic variation in reproductive allocation. Moreover, selection may
      also result in the evolution of plastic allocation strategies. The necessary
      prerequisite for evolution, heritable genetic variation, can best be studied with
      selection experiments. Starting from a base population of 102 replicated
      genotypes of the clonal herb Ranunculus reptans, we imposed selection on the
      proportion of flowering rosettes in the absence of competition (base population:
      mean = 0.391, broad-sense heritability = 0.307). We also selected on the
      plasticity in this trait in response to competition with a naturally coexisting
      grass in a parallel experiment (base population: 14% lower mean in the presence
      of competition, broad-sense heritability = 0.072). After two generations of
      bidirectional selection, the proportion of flowering rosettes was 26% higher in
      the high line than in the low line (realized heritability +/- SE = 0.205 +/-
      0.017). Moreover, genotypes of the high line had 11% fewer carpels per flower, a
      22% lower proportion of rooted rosettes, and a 39% smaller average distance
      between rosettes within a clone. In the second experiment, we found no
      significant responses to selection for high and low plasticity in the proportion
      of flowering rosettes (realized heritability +/- SE = -0.002 +/- 0.013). Our
      study indicates a high heritability and potential for further evolution of the
      proportion of flowering rosettes in R. reptans, but not for its plasticity, which
      may have been fixed by past evolution at its current level. Moreover, our results
      demonstrate strong genetic correlations between allocation to sexual reproduction
      and other clonal life-history characteristics.

PMID- 12487348
TI  - A cost of restoration of male fertility in a gynodioecious species, Lobelia
      siphilitica.
AB  - Models allowing the coexistence of females and hermaphrodites in gynodioecious
      populations assume a simple genetic system of sex determination, a seed fitness
      advantage of females (compensation), and a negative pleiotropic effect of nuclear
      sex-determining genes on fitness (cost of restoration). In Lobelia siphilitica,
      sex is determined by both mitochondrial genes causing cytoplasmic male sterility
      (CMS) and nuclear genes that restore fertility when present with specific CMS
      haplotypes (nuclear restorers). I tested for a cost of restoration in L.
      siphilitica by measuring restored hermaphrodites for five fitness components and
      estimating the number of nuclear restorers by crosses with females carrying CMS1
      and CMS2. A cost of restoration appears as a significant negative coefficient (B)
      in the regression model explaining fitness. I found that hermaphrodites carrying
      more nuclear restorer genes for CMS2 (or restorer genes of greater effect) have
      lower pollen viability (B = -1.08, P = 0.001). This pollen viability cost of
      restoration in L. siphilitica supports the theoretical prediction that negative
      pleiotropic effects of restorers will exist in populations of gynodioecious
      species containing females. The existence of such a cost supports the view that
      gynodioecy can be a stable breeding system in nature.

PMID- 12487349
TI  - Anther-stigma separation is associated with inbreeding depression in Datura
      stramonium, a predominantly self-fertilizing annual.
AB  - Genetically based variation in outcrossing rate generates lineages within
      populations that differ in their history of inbreeding. According to some models,
      mating-system modifiers in such populations will demonstrate both linkage and
      identity disequilibrium with fitness loci, resulting in lineage-specific
      inbreeding depression. Other models assert that differences among families in
      levels of inbreeding depression are mainly attributable to random accumulation of
      genetic load, unrelated to variation at mating-system loci. We measured female
      reproductive success of selfed and outcrossed progeny from naturally occurring
      lineages of Datura stramonium, a predominantly self-fertilizing annual weed that
      has heritable variation in stigma-anther separation, a trait that influences
      selfing rates. Progeny from inbred lineages (as identified by high degree of
      anther-stigma overlap) showed equal levels of seed production, regardless of
      cross type. Progeny from mixed lineages (as identified by relatively high
      separation between anthers and stigma) showed moderate levels of inbreeding
      depression. We found a significant correlation between anther-stigma separation
      and relative fitness of selfed and outcrossed progeny, suggesting that family
      level inbreeding depression may be related to differences among lineages in
      inbreeding history in this population. Negative inbreeding depression in
      putatively inbred lineages may be due in part to additive effects or to epistatic
      interactions among loci.

PMID- 12487350
TI  - Is induction response negatively correlated with constitutive resistance in black
      mustard?
AB  - Black mustard, Brassica nigra, is highly variable in both constitutive resistance
      and induction response following damage by herbivores. A focal population from
      Ithaca, New York, was used to test the following two predictions of optimal
      defense theory: (1) that allocation to resistance will reduce plant performance
      in the absence of herbivores; and (2) that induction response will be negatively
      correlated with constitutive resistance. The experiment consisted of a half-sib
      mating design with 47 paternal families and four dams per sire, fully crossed
      with a damage treatment consisting of 25% leaf removal by the cabbage white
      butterfly, Pieris rapae, when plants had four leaves. Leaf trichome density,
      sinigrin concentration, and glucobrassicin concentration were 38%, 19%, and 16%
      higher, respectively, for the seventh leaf of damaged plants. Paternal families
      did not vary significantly in their induction response. Narrow-sense
      heritabilities were h(S)(2) = 0.51, 0.76, and 0.50 for constitutive leaf trichome
      density, sinigrin concentration, and glucobrassicin concentration, respectively.
      Positive genetic correlations were found between glucobrassicin concentration and
      days to first flower, suggesting a genetic cost of resistance. Induction
      responses were negatively correlated with constitutive allocation for leaf
      trichome density and sinigrin concentration. The results were therefore
      consistent with optimal defense theory, offering modest evidence for both
      predictions.

PMID- 12487351
TI  - Ecological genetics of an induced plant defense against herbivores: additive
      genetic variance and costs of phenotypic plasticity.
AB  - Adaptive phenotypic plasticity in chemical defense is thought to play a major
      role in plant-herbivore interactions. We investigated genetic variation for
      inducibility of defensive traits in wild radish plants and asked if the evolution
      of induction is constrained by costs of phenotypic plasticity. In a greenhouse
      experiment using paternal half-sibling families, we show additive genetic
      variation for plasticity in glucosinolate concentration. Genetic variation for
      glucosinolates was not detected in undamaged plants, but was significant
      following herbivory by a specialist herbivore, Pieris rapae. On average, damaged
      plants had 55% higher concentrations of glucosinolates compared to controls. In
      addition, we found significant narrow-sense heritabilities for leaf size,
      trichome number, flowering phenology, and lifetime fruit production. In a second
      experiment, we found evidence of genetic variation in induced plant resistance to
      P. rapae. Although overall there was little evidence for genetic correlations
      between the defensive and life-history traits we measured, we show that more
      plastic families had lower fitness than less plastic families in the absence of
      herbivory (i.e., evidence for genetic costs of plasticity). Thus, there is
      genetic variation for induction of defense in wild radish, and the evolution of
      inducibility may be constrained by costs of plasticity.

PMID- 12487352
TI  - Historical vicariance and postglacial colonization effects on the evolution of
      genetic structure in Lophocereus, a Sonoran Desert columnar cactus.
AB  - Distinguishing the historical effects of gene migration and vicariance on
      contemporary genetic structure is problematic without testable biogeographic
      hypotheses based on preexisting geological and environmental evidence. The
      availability of such hypotheses for North America's Sonoran Desert has
      contributed to our understanding of the effect of historical vicariance and
      dispersal events on the diversification of this region's vertebrate biota but
      have not yet been applied to its flora. In this paper we describe a detailed
      allozyme analysis of the population genetic structure and phylogeography of the
      Sonoran Desert columnar cactus, Lophocereus schottii (senita). Inferred
      phylogroup distributions reflect two historical vicariance events: (1) a middle
      Pliocene northward transgression of the Sea of Cortez that is reflected in well
      supported Baja California peninsular and continental phylogroups but not in
      current taxonomic treatments of the species; and (2) a late Pliocene
      transpeninsular seaway across southern Baja that is reflected in tentative
      support for peninsular and southern Cape Region phylogroups corresponding to
      taxonomic varieties L. schottii var. schottii and L. schottii var. australis,
      respectively. A middle Pleistocene midpeninsular seaway hypothesized to explain
      congruent phylogroup distributions in several vertebrate taxa is not reflected in
      L. s. var. schottii, nor is the distinction of a third variety, L. s. var.
      tenuis, from continental populations of L. s. var. schottii. Linear regression of
      pairwise estimates of interpopulation differentiation (M and F(ST)/[1 - F(ST)])
      on interpopulation geographic distance revealed significant evidence of isolation
      by distance within peninsular and continental phylogroups but not between them,
      consistent with historical vicariance between but not within these regions. We
      also found significant evidence of isolation by distance between putative L. s.
      var. schottii and L. s. var. australis phylogroups, suggesting that reproductive
      isolation between peninsular and Cape Region forms is incomplete. Within
      peninsular, but not continental, phylogroups, northward range expansion from
      southern Pleistocene refugia is reflected in significant declines in genetic
      variation with increasing latitude and in an area phenogram in which populations
      are progressively nested from south (ancestral) to north (descendant) along the
      Baja peninsula. Although the geographic concordance of phylogenetic topologies
      suggests that ancient vicariance events, and not dispersal, have primarily
      influenced the biogeographic distributions of Baja's vertebrate biota, the
      phylogeographic structure of L. schottii suggests that Sonoran Desert plant
      species may exhibit genetic signatures of postglacial range expansion and gene
      flow as well as vicariance.

PMID- 12487353
TI  - Incipient speciation across a depth gradient in a scleractinian coral?
AB  - A few marine cases have demonstrated morphological and genetic divergence in the
      absence of spatial barriers to gene flow, suggesting that the initial phase of
      speciation is possible without geographic isolation. In the Bocas del Toro
      Archipelago of the Atlantic Coast of Panama, we found two morphotypes of the
      scleractinian coral Favia fragum with opposing depth distributions. One
      morphotype fit the classical description of F. fragum and was most abundant at 3
      m depth. A second morphotype was distinguished by raised corallites and was
      restricted to < or = 1 m depth. The two morphotypes overlapped in distribution at
      1 m depth. Multivariate analysis of polyp-level characters (shape and
      distribution of septa within corallites) divided samples into two groups
      corresponding to initial qualitative observations of colony shape and corallite
      relief. To determine whether reduced gene flow maintains morphological variation,
      we measured the frequencies of alleles at five allozyme loci in both morphotypes
      at three sites 1-2 km distant. While there were significant differences in allele
      frequencies between morphotypes within sites, there were also frequency
      differences among sites at most loci, with the exception of nearly fixed alleles
      at the PGM locus. Extremely low heterozygosity permitted us to use haplotypes to
      compare genetic distance between morphotypes and among sites. Comparisons between
      haplotype data and a null model assuming gene flow between morphotypes showed
      that the two morphotypes shared significantly fewer haplotypes than expected, and
      average genetic distance between morphotypes was significantly greater than
      expected. Partitioning haplotype variation with analysis of molecular variance
      demonstrated that 35% of the variation was explained by morphotype, whereas 28%
      of the variation was explained by site. Two PGM heterozygotes and several
      individuals homozygous for rare PGM alleles are consistent with hybridization,
      and perhaps introgression by selfing within morphotypes. We consider three
      hypotheses for this morphological and genetic divergence in F. fragum: (1)
      intraspecific polymorphism, (2) incipient species, (3) biological species; and
      discuss the role of reproductive characters in a divergence-with-gene flow
      mechanism of speciation.

PMID- 12487354
TI  - Outcrossing increases infection success and competitive ability: experimental
      evidence from a hermaphrodite parasite.
AB  - The maintenance of two genetically distinct reproductive modes such as
      outcrossing and selfing within a population of animals or plants is still a
      matter of considerable debate. Hermaphroditic parasites often reproduce either
      alone by selfing or in pairs by outcrossing. They can be used as a model to study
      potential benefits of outcrossing. Any advantage from outcrossing may be
      important, especially in host-parasite coevolution, but has not, to our
      knowledge, been studied yet in any parasite species. We studied the potential
      effect of outcrossing in a tapeworm, Schistocephalus solidus, on both infection
      success and growth in its first intermediate host, the copepod Macrocyclops
      albidus. Tapeworms that had been obtained from natural populations of three
      spined sticklebacks (Gasterosteus aculeatus) were allowed to reproduce either
      alone or in pairs, in an in vitro system that replaced the final host's gut. This
      resulted in either selfed or outcrossed offspring, respectively. In one part of
      the experiment, copepods were exposed to either selfed or outcrossed parasites,
      in a second part to both types simultaneously, in order to study the effect of
      competition between them. To discriminate parasites of either origin within the
      same host, a novel method for fluorescent vital labeling was used. We show here
      for the first time that outcrossed parasites had a higher infection success and
      faster development in the host. This advantage of outcrossing became apparent
      only in the competitive situation, in which superior abilities of parasites to
      extract limiting resources from the host become crucial.

PMID- 12487355
TI  - High fidelity of mitochondrial genome transmission under the doubly uniparental
      mode of inheritance in freshwater mussels (Bivalvia: Unionoidea).
AB  - Doubly uniparental inheritance (DUI) of mitochondrial DNA (mtDNA) has been
      demonstrated in both mytilid and unionid bivalves. Under DUI, females pass on
      their mtDNA to both sons and daughters, whereas males pass on their mtDNA to only
      sons. In mytilids, the loss of an original male (or M) mitotype, with its
      subsequent replacement by that lineage's female (or F) mitotype, has been called
      a role-reversal or, more specifically, a masculinization event. Multiple
      masculinization events have been inferred during the evolutionary history of
      mytilids but not unionids. The perceived lack of role-reversal events in unionids
      may represent a significant difference in the evolutionary dynamics of DUI
      between the two bivalve taxa or simply a lack of sufficient taxon sampling in
      unionids. To evaluate these alternative hypotheses, six additional unionoidean
      bivalve genera were sampled for DUI including one genus from the sister taxon of
      the Unionidae, the Hyriidae. Phylogenetic analyses of 619 base pairs of
      cytochrome c oxidase I (COI) from eight genera (nine species) of unionoidean
      bivalves, plus the sister taxon to the Unionoida, Neotrigonia, revealed that the
      M and F unionoidean mitotypes were contained in gender-specific, topologically
      congruent clades. This supports the hypothesis that either role-reversal events
      do not occur in unionoideans or, if they do occur, their products are ephemeral
      in an evolutionary sense. Furthermore, the fact that the mantle-tissue-derived
      Neotrigonia mitotype is the sister mitotype to the unionoidean F mitotype clade
      suggests that DUI has been operating with high fidelity in unionoids for at least
      200 million years. A relatively low incidence of interspecific hybridization in
      unionoideans and a possibly obligate role for the M mitotype in unionoidean
      gender determination are offered as potential explanations for the disparate
      evolutionary dynamics of DUI observed between mytilid and unionoidean bivalves.

PMID- 12487356
TI  - Genetics of a difference in pigmentation between Drosophila yakuba and Drosophila
      santomea.
AB  - Drosophila yakuba is a species widespread in Africa, whereas D. santomea, its
      newly discovered sister species, is endemic to the volcanic island of Sao Tome in
      the Gulf of Guinea. Drosophila santomea probably formed after colonization of the
      island by its common ancestor with D. yakuba. The two species differ strikingly
      in pigmentation: D. santomea, unlike the other eight species in the D.
      melanogaster subgroup, almost completely lacks dark abdominal pigmentation. D.
      yakuba shows the sexually dimorphic pigmentation typical of the group: both sexes
      have melanic patterns on the abdomen, but males are much darker than females. A
      genetic analysis of this species difference using morphological markers shows
      that the X chromosome accounts for nearly 90% of the species difference in the
      area of abdomen that is pigmented and that at least three genes (one on each
      major chromosome) are involved in each sex. The order of chromosome effects on
      pigmentation area are the same in males and females, suggesting that loss of
      pigmentation in D. santomea may have involved the same genes in both sexes.
      Further genetic analysis of the interspecific difference between males in
      pigmentation area and intensity using molecular markers shows that at least five
      genes are responsible, with no single locus having an overwhelming effect on the
      trait. The species difference is thus oligogenic or polygenic. Different
      chromosomal regions from each of the two species influenced pigmentation in the
      same direction, suggesting that the species difference (at least in males) is due
      to natural or sexual selection and not genetic drift. Measurements of sexual
      isolation between the species in both light and dark conditions show no
      difference, suggesting that the pigmentation difference is not an important cue
      for interspecific mate discrimination. Using DNA sequence differences in nine
      noncoding regions, we estimate that D. santomea and D. yakuba diverged about
      400,000 years ago, a time similar to the divergences between two other well
      studied pair of species in the subgroup, both of which also involved island
      colonization.

PMID- 12487357
TI  - Allele frequency shifts in response to climate change and physiological
      consequences of allozyme variation in a montane insect.
AB  - Rapid changes in climate may impose strong selective pressures on organisms.
      Evolutionary responses to climate change have been observed in natural
      populations, yet no example has been documented for a metabolic enzyme locus.
      Furthermore, few studies have linked physiological responses to stress with
      allozyme genotypic variation. We quantified changes in allele frequency between
      1988 and 1996 at three allozyme loci (isocitrate dehydrogenase, Idh;
      phosphoglucose isomerase, Pgi; and phosphoglucomutase, Pgm) for the leaf beetle
      Chrysomela aeneicollis in the Bishop Creek region of the Sierra Nevada of
      California (2900-3300 m). Beetles often experience high daytime (> 32 degrees C)
      and extremely low nighttime (< -5 degrees C) temperatures during summer. Bishop
      Creek weather station data indicated that conditions were unusually dry before
      1988, and that conditions were cool and wet during the years preceding the 1996
      collection. We found directional changes in allele frequency at Pgi (11% increase
      in the Pgi-1 allele), but not at Idh or Pgm. We also found that physiological
      response to thermal extremes depended on Pgi genotype. Pgi 1-1 individuals
      induced expression of a 70-kD heat shock protein (HSP) at lower temperatures than
      1-4 or 4-4 individuals, and 1-1 individuals expressed higher levels of HSP70
      after laboratory exposure to temperatures routinely experienced in nature.
      Survival after nighttime laboratory exposure to subzero temperatures depended on
      gender, previous exposure to cold, and Pgi genotype. Females expressed higher
      levels of HSP70 than males after exposure to heat, and recovery by female Pgi 1-1
      homozygotes after exposure to cold (-5 degrees C) was significantly better than 1
      4 or 4-4 genotypes. These data suggest that the cooler climate of the mid-1990s
      may have caused an increase in frequency of the Pgi-1 allele, due to a more
      robust physiological response to cold by Pgi 1-1 and 1-4 genotypes.

PMID- 12487358
TI  - How can sex ratio distorters reach extreme prevalences? Male-killing Wolbachia
      are not suppressed and have near-perfect vertical transmission efficiency in
      Acraea encedon.
AB  - Maternally transmitted bacteria that kill male hosts early in their development
      are found in many insects. These parasites typically infect 1-30% of wild
      females, but in a few species of insects, prevalences exceed 95%. We investigated
      one such case in the butterfly Acraea encedon, which is infected with a male
      killing Wolbachia bacterium. We measured three key parameters that affect the
      prevalence of the parasite: transmission efficiency, rate of survival of infected
      males, and the direct cost of infection. We observed that all wild females
      transmit the bacterium to all their offspring and that all infected males die in
      wild populations. We were unable to detect any physiological cost to infection in
      lab culture. These observations explain the high prevalence of the A. encedon
      male killer, as theory predicts that under these conditions the parasite will
      spread to fixation. This will occur provided the death of males provides some
      benefit to the surviving infected females. The problem therefore becomes why the
      bacterium has not reached fixation and driven the butterfly extinct due to the
      shortage of males. We therefore investigated whether males choose to mate with
      uninfected rather than infected females, as this would prevent the bacterium from
      reaching fixation. We tested this hypothesis in the "lekking swarms" of virgin
      females found in the most female-biased populations, and were unable to detect
      any evidence of mate choice. In conclusion, this male killer has spread to high
      prevalence because it has a high transmission efficiency and low cost, but the
      factors maintaining uninfected females in the population remain unknown.

PMID- 12487359
TI  - A fine-scale spatial analysis of the mosaic hybrid zone between Gryllus firmus
      and Gryllus pennsylvanicus.
AB  - The pattern of character variation within a hybrid zone, the hybrid zone
      structure, has been used to infer the processes that maintain hybrid zones.
      Unfortunately it is difficult to infer process from structure alone because many
      different processes can produce the same pattern of character variation. Mosaic
      hybrid zones may be maintained by exogenous selection in a heterogeneous
      environment and/or endogenous selection against hybrid individuals; habitat
      preference, premating isolating barriers and/or fertility selection can also
      contribute. The spatial scale at which a hybrid zone is sampled affects its
      apparent structure; a hybrid zone may appear clinal at one scale and mosaic at
      another. Here, we sample the mosaic hybrid zone between two field crickets,
      Gryllus firmus and G. pennsylvanicus, at a scale that spans the boundaries
      between individual soil-habitat patches. From our analysis, we find that at fine
      scales, the mosaic hybrid zone resolves into a set of steep clines across patch
      boundaries. Both morphological and molecular traits exhibit sharp and generally
      concordant clines. However, clines for mitochondrial DNA and one anonymous
      nuclear marker are clearly displaced as a result of current hybridization or past
      introgression (the "ghost of hybridization past"). Thus, scale is important for
      the structure of this and probably other hybrid zones. The extremely sharp,
      concordant clines across patch boundaries indicate that the cricket hybrid zone
      is undoubtedly structured by selection. However, the detailed mechanisms
      responsible for the maintenance of the hybrid zone--whether endogenous selection
      against hybrids, exogenous selection by the environment, and/or behavioral
      preferences for mates or habitats--remain to be elucidated. Determining these
      mechanisms will depend on closer inspection of the organisms themselves and their
      interactions, as is the case for all hybrid zones.

PMID- 12487360
TI  - Direct benefits and the evolution of female-biased cooperative breeding in
      Seychelles warblers.
AB  - Inclusive fitness benefits have been suggested to be a major selective force
      behind the evolution of cooperative breeding. We investigated the fitness
      benefits selecting for cooperative breeding in the Seychelles warbler,
      Acrocephalus sechellensis. A microsatellite-based genotyping method was used to
      determine the relatedness of subordinates to group offspring in an isolated
      population of Seychelles warblers. The indirect and direct breeding benefits
      accruing to individual subordinates were then calculated for every successful
      breeding event over a three-year period. We show that female subordinates
      frequently gained parentage and that this, combined with high levels of
      extragroup paternity, resulted in low levels of relatedness between subordinates
      and nondescendent offspring within a territory. Direct breeding benefits were
      found to be significantly higher than indirect kin benefits for both female and
      male subordinates. As predicted, female subordinates gained significantly more
      direct breeding opportunities and therefore higher inclusive fitness benefits by
      being a subordinate within a group than did males. This may explain why most
      subordinates in the Seychelles warbler are female.

PMID- 12487361
TI  - Genetically based phenotype-environment association for swimming behavior in lake
      whitefish ecotypes (Coregonus clupeaformis Mitchill).
AB  - Studies of phenotype-environment associations in adaptive radiation have focused
      largely on morphological traits related to resource-based phenotypic differences.
      The genetic basis of adaptive behaviors implicated in population divergence
      remains poorly understood, as few studies have tested the hypothesis of
      behavioral phenotype-environment associations. We provide evidence of a phenotype
      environment association for differential adaptive swimming behaviors through
      experiments conducted on dwarf, normal, and hybrid lake whitefish (Coregonus
      clupeaformis). Highly significant differences were observed for depth selection,
      directional changes, and burst swimming, implicating a genetic basis for these
      behaviors. Hybrid crosses revealed that depth selection is under additive genetic
      control, while dominance effects were suggested for directional changes and burst
      swimming. Estimates for the genetic basis of behavioral differentiation from an
      animal model were consistent with these observations. Comparative estimates of
      behavioral differentiation (Q(ST)) against neutral expectations (F(ST)) revealed
      pronounced departures from neutral expectations in all three behavioral
      phenotypes, consistent with the hypothesis that directional selection has driven
      the divergence of behavior in dwarf and normal lake whitefish ecotypes.

PMID- 12487362
TI  - Phylogeny affects estimation of metabolic scaling in mammals.
AB  - The relationship between body size and metabolic rate is a crucial issue in
      organismal biology and evolution. There has been considerable debate over whether
      the scaling exponent of the relationship is 0.75 (Kleiber's Law) or 0.67. Here we
      show that determination of this exponent for mammals depends on both the
      evolutionary tree and the regression model used in the comparative analysis. For
      example, more recent molecular-based phylogenies tend to support a 0.67 exponent,
      whereas older phylogenies, mostly based on morphological data, suggest a 0.75
      exponent. However, molecular phylogenies yield more variable results than
      morphological phylogenies and thus are not currently helping to resolve the
      issue.

PMID- 12487363
TI  - Critical review and evaluation of the uterotrophic bioassay for the
      identification of possible estrogen agonists and antagonists: in support of the
      validation of the OECD uterotrophic protocols for the laboratory rodent.
      Organisation for Economic Co-operation and Development.
AB  - A current issue for regulatory agencies is endocrine-related modes of action such
      as those mediated by the estrogen, androgen, and thyroid nuclear receptors. At
      the national and international levels, the consensus recommendation for the
      assessment of such modes of action is a tiered series of in vitro and in vivo
      protocols. The tiered framework begins with screens for structural alerts and
      then moves to rapid, mechanistic in vitro screening assays, and then to in vivo
      screening bioassays. The objective of these screens is to identify substances
      that may warrant testing for endocrine-mediated adverse effects. The final
      framework tier as needed is to test these substances in long-term bioassays for
      adverse endocrine-mediated reproductive and/or developmental effects. The subject
      of this review, the rodent uterotrophic bioassay, is intended to be a rapid in
      vivo screening bioassay for possible estrogen agonists and based on the response
      of the estrogen-sensitive uterus. The central metric of bioassay is a
      statistically significant increase in the weight of the uterus after 3
      consecutive days of test substance administration. The extensive background
      literature is summarized in this review on the mode of action underlying the
      bioassay and the uterine response to estrogens. The review includes the
      bioassay's history of development and how its employment has changed and evolved
      over time. The review describes two major uterotrophic bioassay versions, the
      intact, immature female and the mature, ovariectomized female, and the protocol
      factors likely to influence relevance, reproducibility, and reliability of
      bioassay. The emphasis of the review is the ability of the uterotrophic bioassay
      to identify the substances of current interest: weak estrogen agonists with
      binding affinities relative to the natural 17beta-estradiol in the log 0 to log 
      3 range. Using selected model substances having RBAs in this target range, the
      bioassay's performance in a hierarchical, tiered approach is evaluated, including
      the predictive capability of the uterotrophic bioassay based on available
      reproductive and developmental testing data. The review concludes that the
      uterotrophic bioassay is reliable and can identify substances that may act via an
      estrogen-mode of action, supporting the validity of the uterotrophic bioassay and
      its regulatory use as an in vivo mechanistic screening bioassay for estrogen
      agonists and antagonists.

PMID- 12487364
TI  - Evaluation of Tier I screening approaches for detecting endocrine-active
      compounds (EACs).
AB  - In 1996, Congress passed legislation requiring the U.S. Environmental Protection
      Agency (EPA) to implement screening/testing strategies for endocrine-active
      compounds (EACs). In response, EPA convened the Endocrine Disruptor Screening and
      Testing Advisory Committee (EDSTAC) to advise the agency on a strategy to screen
      and test xenobiotics for endocrine disruption. EDSTAC completed their charter in
      1998 by recommending a tiered screening and testing scheme to evaluate compounds
      for their potential to act as agonists or antagonists to the estrogen or androgen
      receptors, steroid biosynthesis inhibitors, or their ability to alter thyroid
      function. For Tier I, the EDSTAC-recommended screening battery comprised eight
      different assays, but EDSTAC also proposed two alternative batteries that were
      deemed worthy of further evaluation. The challenge currently confronting EPA is
      to choose among the Tier I screening options and then to standardize protocols,
      validate the assays, and determine the criteria for judging a compound as
      positive or negative in the battery. The purpose of the current review is to: (1)
      provide an overview of the three EDSTAC options, (2) evaluate the data currently
      available for the individual assays of the three EDSTAC options and discuss the
      strengths and limitations of each, and (3) provide a final recommendation for a
      Tier I screen based on the experiences of the authors who have used all of the
      individual assays under consideration by EDSTAC. The goal of this report is not
      to provide an exhaustive historical review of each assay, but rather to summarize
      some of the more relevant data from available published reports as it relates to
      current proposed study designs for those particular assays. Based on the current
      data, a Tier I screening battery consisting of in vitro receptor binding assays,
      a 3-day uterotrophic assay, and a 15-day intact male assay are recommended as the
      preferred approach on which future validation efforts should be focused. This
      screening approach is a mode-of-action screen that will identify specific types
      of endocrine activity. Because it utilizes many endpoints from the same test
      animals (i.e., it integrates), it is the most cost-effective and efficient option
      in terms of animal usage. The mode-of-action screening approach advances
      scientific understanding and is preferred over other options based on apical
      tests, as these essentially are reproductive effects screens that are not
      necessarily specific for endocrine activity. Because Tier II tests include the
      critical apical endpoints used in the pubertal models, a mode-of-action approach
      provides complementary rather than redundant data. By identifying the potential
      mode of action, critical endpoints can be included in Tier II studies that will
      be used to define dose-response curves and no observed adverse effect levels
      (NOAELs)/no observed effect levels (NOELs) for the compound.

PMID- 12487365
TI  - O-phenylphenol and its sodium and potassium salts: a toxicological assessment.
AB  - Ortho-phenylphenol (OPP) and its sodium (SOPP) and potassium (POPP) salts are
      used as fungicides and disinfectants. Due to the widespread use of especially OPP
      and SOPP, the potential for consumer exposure and some "critical" findings the
      toxicological database is quite extensive and complex. In experimental animals
      toxicity after single oral and dermal administration of these compounds is low.
      For the skin and mucous membranes, OPP has to be considered as irritating, and
      SOPP and POPP as corrosive. A large number of chronic toxicity and reproduction
      studies did not show any indication of oestrogen-like or other endocrine effects
      of OPP in the mammalian organism. No teratogenic effects were observed after the
      administration of OPP or SOPP in rats, mice, and rabbits. In two-generation
      studies in rats, OPP did not affect reproduction. The available data do not
      suggest a relevant potential for immunotoxic properties. The administration of
      high dietary concentrations of OPP to mice up to 2 years induced hepatocellular
      changes indicative of adaptations to metabolic demands, zonal degeneration, focal
      hepatocellular necrosis, and/or pigmentation of the liver. Only in male mice of
      one study, using a strain prone to develop hepatocellular tumors at high
      spontaneous incidences, the incidence of hepatocellular adenomas was increased.
      The incidence of hepatocellular carcinomas was not affected by treatment. The
      urothel of the urinary bladder (at very high doses also of the renal pelvis and
      the papilla) is the main target tissue after the repeated oral exposure of rats.
      The changes initially consist of increased mitosis, followed by simple epithelial
      hyperplasia, developing to a papillary and/or nodular form, later on to
      papillomas and transitional carcinomas. Crystals or stones in the bladder do not
      play a decisive role in this cascade. SOPP is more effective than OPP in this
      respect. Male rats are much more sensitive than females. In mice, hamsters,
      guinea pigs, and dogs, urothelial lesions do not develop even at very high oral
      dose levels. The findings in rats explain why there is a large
      genotoxicity/mutagenicity data base not only for OPP and SOPP but also for their
      metabolites on nearly all kinds of endpoints/targets. The weight of evidence
      suggests that genotoxicity of OPP/SOPP or their metabolites does not play a
      decisive role for the carcinogenicity at the urothel. Among them are lack of DNA
      binding of OPP to the rat bladder epithelium, the differences between OPP and
      SOPP, between male and female rats, between rats and mice (despite roughly
      comparable toxicokinetics), as well as the fact that tumors develop only at dose
      levels inducing hyperplasias. In addition, the strong dependence of the incidence
      and severity of the nonneoplastic and neoplastic bladder changes on urinary pH
      values (modified by feeding of ammonium chloride or sodium hydrogen carbonate) is
      consistent with the hypothesis of a nongenotoxic mode of action. Finally, there
      is no correlation between the urinary concentration of OPP or its metabolites and
      the incidence of hyperplasias/tumors in the urinary bladder. Both tumorigenic
      effects in rats and male mice are considered to represent high-dose, sex- and/or
      species-specific phenomena, based on nongenotoxic mechanisms of action and
      therefore allow the conclusion that the conventional margin of safety approaches
      are appropriate when assessing the risk of applications of OPP and its salts.

PMID- 12487366
TI  - The physiological scavenger receptor function of hepatic sinusoidal endothelial
      and Kupffer cells is independent of scavenger receptor class A type I and II.
AB  - This study was undertaken to determine the role of scavenger receptor class A
      type I and II (SR-Al/II) in the physiological scavenger function of hepatic
      sinusoidal endothelial cells (SEC) and Kupffer cells (KC). Following intravenous
      administration of radiolabelled SR-ligands, [advanced glycation end (AGE)
      products, N-terminal propeptide of type III procollagen (PIIINP) and formaldehyde
      treated serum albumin (FSA)] in SR-AI/II-deficient and wild-type mice,
      radioactivity was removed equally rapidly from the circulation of both types of
      mice. The major site of uptake was the liver. Separation of liver cells showed
      that the population of SEC and KC were responsible for approximately 55 and
      approximately 25% of the uptake. There was no difference in plasma clearance,
      organ distribution or cell distribution in SR-Al/Il-deficient and wild-type mice.
      Experiments performed to determine the specificity of endocytosis in cultured SEC
      showed that uptake of radiolabelled SR-ligands (AGE-protein, PIIINP or FSA) was
      inhibited equally well by unlabelled FSA and AGE-protein in SEC from receptor
      deficient and wild-type mice. We conclude from these findings that SR-Al/lI is of
      minor importance in the plasma clearance of physiological as well as foreign SR
      ligands.

PMID- 12487367
TI  - Combination therapy of N-acetylcysteine, sodium nitroprusside and phosphoramidon
      attenuates ischemia-reperfusion injury in rat kidney.
AB  - Renal ischemia is of clinical interest because of its role in renal failure and
      also renal graft rejection. To evaluate the effect of the combination of N
      acetylcysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric
      oxide donor, and phosphoramidon (P), an endothelin converting enzyme inhibitor,
      on tissue protection against ischemia-reperfusion injury, we studied the
      biochemical and morphological changes due to 90 min of renal ischemia-reperfusion
      in the rat model. Ninety min of ischemia caused very severe injury and the
      animals could not survive after 4 days without any treatment. Whereas, animals in
      the treated groups survived i.e. the NAC group (25%), NAC + SNP group (43%) and
      in the NAC + SNP + P group (100%), 2 weeks after 90 min of ischemia. A
      significant increase in the serum levels of creatinine and urea nitrogen was
      shown in the untreated group and to a much lesser extent in the treated group,
      especially in the NAC + SNP + P group. The protective effect was also supported
      by light microscopic studies on renal tissue sections. We also measured the
      activities of antioxidant enzymes in tissue homogenates. With the exception of Mn
      superoxide dismutase, the activities of antioxidant enzymes (catalase,
      glutathione peroxidase, CuZn-superoxide dismutase) were decreased in the
      untreated kidney. The administration of NAC alone and NAC + SNP protected against
      the loss of activities. Treatment with a combination of NAC, SNP and P showed a
      synergistic effect as evidenced by the best protection. These results suggest
      that pre-administration of a combination of antioxidant (NAC) with endothelin
      derived vasodilators (sodium nitroprusside and Phosphoramidon) attenuates renal
      ischemia-reperfusion injury, e.g. in donor kidney for transplantation, by
      protecting cells against free radical damage.

PMID- 12487368
TI  - Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine,
      sodium nitroprusside and phosphoramidon.
AB  - Ischemia followed by reperfusion has a number of clinically significant
      consequences. A number of pathophysiological processes appear to be involved in
      ischemia/reperfusion (I/R) injury. The mitogen activated protein kinases (MAPK)
      are integral components of the parallel MAP kinase cascades activated in response
      to a variety of cellular stress inducing ischemia/ATP depletion and inflammatory
      cytokines. Many studies suggest that members of the MAP kinase family in
      particular Jun N-terminal kinase (JNK) are activated in kidney following
      ischemia/reperfusion of this tissue. The present study underlines the therapeutic
      potential of the combination of N-acetyl cysteine (NAC), a potent antioxidant,
      sodium nitroprusside (SNP), a nitric oxide donor and phosphoramidon (P), an
      endothelin-1 converting enzyme inhibitor in ameliorating the MAPK induced damage
      during renal ischemia/reperfusion injury. Our previous results showed that 90 min
      of ischemia followed by reperfusion caused very severe injury and that the
      untreated animals had 100% mortality after the 3rd day whereas there was improved
      renal function and 100% survival of animals in the three drug combination
      treatment group. The present study, mainly on tissue sections, further supports
      the protection provided by the triple drug therapy. A higher degree of expression
      of all the three classes of MAPK, i.e. JNK, P38 MAP kinases and P-extracellular
      signal regulated kinases (ERKs) can be seen in kidneys subjected to
      ischemia/reperfusion insult. Pretreatment with a combination of N-acetyl
      cysteine, sodium nitroprusside, and phosphoramidon completely inhibits all three
      classes of MAPK and ameliorates AP-1 whereas individual or a combination of any
      two drugs is not as effective.

PMID- 12487369
TI  - A selective somatostatin type-2 receptor agonist inhibits neointimal thickening
      and enhances endothelial cell growth and morphology following aortic balloon
      injury in the rabbit.
AB  - Somatostatin analogs have been shown to inhibit vascular smooth muscle cell
      (VSMC) proliferation and attenuate neointimal thickening following experimental
      balloon catheter injury. In this study, the effects of a selective agonist for
      the somatostatin receptor subtype 2, PRL-2486, on neointimal thickening and
      endothelial cell regrowth 2 weeks following balloon catheterization of male New
      Zealand White rabbits were determined. Rabbits treated 2 days prior to and 2
      weeks after catheter injury with 10 microg/kg/day PRL-2486 (PRL-tx) had decreased
      I/M ratios (intimal area/medial area x 100; p < 0.05) but had no effect at lower
      (5 microg/kg/day) or higher (20 microg/kg/day) doses. PRL-tx had significantly
      decreased VSMC proliferation compared to untreated animals. PRL-tx increased
      endothelial regrowth by over 2-fold (p < 0.002) and improved endothelial cell
      morphology. Endothelial-dependent relaxation responses to acetylcholine were
      attenuated by catheter injury, and were not improved with PRL-tx. These data
      suggest that the PRL-2486-mediated inhibition of neointimal thickening exhibits a
      bell-shaped dose-response curve. This inhibition may be due in part to decreased
      VSMC proliferation, which may be a function of enhanced endothelial regrowth, but
      not the return of endothelium-dependent vascular function.

PMID- 12487370
TI  - Cytokine G-protein signaling crosstalk in cardiomyocytes: attenuation of Jak-STAT
      activation by endothelin-1.
AB  - The IL-6-related cytokines, LIF and cardiotrophin-1, are important growth
      promoting and cardioprotective agents for cardiomyocytes. However, factors that
      regulate their actions in the heart are poorly understood. In this study, we
      tested the hypothesis that endothelin-1, a peptide hormone that produces a
      pattern of cardiac hypertrophy distinct from LIF and cardiotrophin-1, modulates
      LIF-induced signaling in cardiomyocytes. Upon binding LIF or cardiotrophin-1, the
      LIF receptor alpha subunit (LIFRalpha) dimerizes with gp130, leading to
      activation of constitutively associated Jak1 proteins and LIFRalpha-gp130
      tyrosine phosphorylation. We found that pretreatment of neonatal rat ventricular
      myocytes with endothelin-1 rapidly inhibited LIF-induced LIFRalpha tyrosine
      phosphorylation and Jak1 activation. This effect of endothelin-1 on LIFalpha and
      Jak1 was attenuated by the MEK1 inhibitor, PD98059, implicating involvement of
      the ERK kinases. Radioligand binding studies showed that inhibition of LIF
      signaling resulted from a reduction in cell surface LlFRalpha levels.
      Additionally, endothelin-1 was found to reduce LIF-induced STAT3 activation, as
      indexed by STAT3 Y705 phosphorylation. Finally, endothelin-1 and LIF were shown
      to induce opposite patterns of STAT3 activation in cardiomyocytes. LIF induced
      rapid, robust STAT3 Y705 phosphorylation; endothelin-1 produced a delayed, modest
      increase, and initially decreased STAT3 Y705 phosphorylation. Overall our
      findings indicate that endothelin-1 acts to temper IL-6-related cytokine
      signaling in cardiomyocytes, in particular STAT3 activation.

PMID- 12487371
TI  - The transcriptional activation of the human copper/zinc superoxide dismutase gene
      by 2,3,7,8-tetrachlorodibenzo-p-dioxin through two different regulator sites, the
      antioxidant responsive element and xenobiotic responsive element.
AB  - Cu/Zn superoxide dismutase (SOD1) catalyzes the dismutation of superoxide
      radicals produced during biological oxidations and environmental stress. The most
      toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces SOD1 in human
      liver cells. Deletion analyses showed that the promoter region between -400 and 
      239 was responsible for the induction, in which two different characteristic
      regulatory elements, the antioxidant responsive element (ARE) and xenobiotic
      responsive element (XRE), are located. When the cells transfected with the
      plasmid containing those two cis-elements, the transactivation of SOD1 promoter
      was about 4-fold by TCDD, whereas mutation either on the ARE or XRE elevated the
      promoter activity by about 2-fold. Functional analyses of these two elements by
      deletion, mutation in the natural context, heterologous promoter assay, and gel
      mobility shift assay supported the notion that the activation of the SOD1
      promoter was induced by TCDD through these two regulatory elements ARE and XRE.
      These results alongside our previous data indicate that the induction of SOD1 in
      response to TCDD is mediated by either Nrf2 protein or Ah receptor protein
      through ARE and XRE, respectively. These results also imply that the SOD1 can be
      induced by dioxin either in combination with or independently of these two
      regulatory elements to effectively defend cells from oxidative stress.

PMID- 12487373
TI  - Estrogen-induced regulation of the ATP-binding cassette transporter A1 (ABCA1) in
      mice: a possible mechanism of atheroprotection by estrogen.
AB  - Estrogens are suggested to be antiatherogenic by affecting the vessel wall
      components. Since ABCA1 was recently shown to be atheroprotective, it was
      examined if estrogen-induced atheroprotection occurs partly via the regulation of
      the ABCA1. Since hepatic ABCA1 expression was also suggested to contribute to the
      bulk HDL levels, regulation of the ABCA1 under conditions of high or low levels
      of HDL were investigated in mice expressing normal or elevated levels of apoAI.
      To delineate whether estrogen's effect occurs via estrogen receptor-alpha
      mediated pathway, the estrogen receptor-alpha-deficient (ER-alpha)-/- mice were
      also administered either placebo or beta-estradiol for 5 consecutive days.
      Estrogen treatments decreased circulating HDL levels by 30%, but increased
      hepatic and intestinal ABCA1 mRNA by 2- and 1.5-fold, respectively. Hepatic ABCA1
      mRNA also increased in the ER-alpha-/- mice by 3-fold. These results suggest that
      estrogen, despite lowering the levels of HDL, it up-regulated the hepatic ABCA1
      mRNA, and in the absence of ER-alpha, ER-beta could compensate for ER-alpha. To
      study whether HDL levels correlate with the ABCA1 expression, wild-type (WT) and
      the apoAI transgenic (A1-Tg) mice were fed high fat (HF) diet with or without
      cholic acid (CA) for 3 weeks. One group of mice was treated with fenofibrate,
      known to elevate HDL levels. CA without HF decreased HDL levels, while
      fenofibrate increased HDL levels. However, neither CA nor fenofibrate altered
      hepatic ABCA1 mRNA levels. HF diet increased the hepatic ABCA1 mRNA 1.8-fold in
      WT, but lowered ABCA1 mRNA by 2-fold in A1-Tg mice, suggesting that ABCA1 levels
      did not correlate with circulating HDL levels, while basal levels of HDL
      influenced ABCA1 expression. These data show for the first time that estrogen's
      antiatherogenic effects may occur via ABCA1-mediated pathway, and circulating HDL
      levels may influence expression of ABCA1.

PMID- 12487372
TI  - Streptozotocin-induced diabetes impairs G-protein linked signal transduction in
      vascular smooth muscle.
AB  - The present studies were undertaken to examine if the impaired vascular function
      observed in diabetes is attributed to the altered levels of G-protein. Diabetes
      was induced in Sprague Dawley rats by a single intraperitoneal injection of
      streptozotocin (STZ) (60 mg/kg body wt) and after a period of 5 days, the aorta
      were used for adenylyl cyclase activity determination and protein quantification.
      A temporal relationship between the expression of Gialpha proteins and
      development of diabetes was also examined on day 1, 2, 3, 4 and 5 of injection of
      STZ. Blood glucose levels were significantly increased from day 1 in STZ-rats as
      compared to their counterpart control rats and reached to about 20 mM on 3rd day
      and 30 mM on 5th day. The expression of Gialpha-2 and Gialpha-3 proteins as
      determined by immunoblotting techniques was decreased by about 70 and 50%
      respectively in aorta from STZ rats compared to the control rats after 5 days of
      treatment, whereas 40% decrease in Gialpha-2 and Gialpha-3 was observed after 3rd
      day of STZ injection. On the other hand, the expression of Gsalpha was unaltered
      in STZ rats. In addition, the stimulatory effect of cholera toxin (CT) on GTP
      mediated stimulation of adenylyl cyclase was not different in STZ as compared to
      the control group. However, the stimulatory effects of isoproterenol, glucagon,
      NaF and FSK on adenylyl cyclase activity were significantly enhanced in STZ rats
      as compared to control rats, whereas basal adenylyl cyclase activity was
      significantly lower in STZ-rats as compared to control rats. In addition,
      GTPgammaS inhibited FSK-stimulated adenylyl cyclase activity in concentration
      dependent manner (receptor-independent functions of Gialpha) in control rats
      which was completely attenuated in STZ-rats. In addition, receptor-mediated
      inhibitions of adenylyl cyclase by angiotensin II, oxotremorine, atrial
      natriuretic peptide (ANP99-126) and C-ANP4-23 were also attenuated (receptor
      dependent functions of Gialpha) in STZ-rats. These results indicate that aorta
      from diabetic rats exhibit decreased levels of cAMP and decreased expression of
      Gialpha. The decreased expression of Gialpha may be responsible for the altered
      responsiveness of adenylyl cyclase to hormonal stimulation and inhibition in STZ
      rats. It may thus be suggested that the impaired adenylyl cyclase-Gialpha protein
      signaling may be one of the possible mechanisms responsible for the impaired
      vascular functions in diabetes.

PMID- 12487374
TI  - Low enzyme content in the pancreas does not reduce the severity of acute
      pancreatitis induced by bile-pancreatic duct obstruction.
AB  - Enzyme load in pancreas has been considered a risk factor in the development of
      acute pancreatitis. In order to confirm this hypothesis our aim was to analyze
      the development and evolution of acute pancreatitis (AP) induced by bile
      pancreatic duct obstruction (BPDO) after reducing the pancreatic enzyme content.
      L-364,718 - a potent CCK-receptor antagonist - was administered (0.1 mg/kg/day)
      for 7 days before inducing AP by BPDO. The course of AP was evaluated at
      different times from 1.5-48 h after BPDO. Amylase and trypsinogen contents and
      cytosolic calcium levels were measured by flow cytometry using specific antisera
      against pancreatic enzymes labelled with isothiocyanate of fluorescein and Fluo
      3, respectively. The severity of the disease at the different stages was
      evaluated by measurements of amylase activity in ascites and plasma, percentage
      of pancreatic fluid and haematocrit. Electron microscopy study of the pancreas
      showed an increased number of zymogen granules spread through the acinar cells of
      control rats treated with L-364,718 for 7 days, however, total enzyme content in
      individual acinar cells was significantly (p < 0.01) diminished. AP significantly
      increased intracellular amylase and trypsinogen load from 3-12 h after BPDO, and
      prior L-364,718 treatment enhanced the blockade of enzyme secretion. As a result,
      acinar enzyme content was significantly increased from earlier stages (1.5 h
      after BPDO). In parallel, increased cytosolic calcium levels observed up to 24 h
      after BPDO appeared earlier in L-364,718-treated rats than in those not treated.
      The severity of AP seems to have been higher in rats previously treated with the
      CCK-receptor antagonist as indicated by the significantly higher pancreatic fluid
      and amylase activity in ascites and plasma observed at different times after
      BPDO. Our results indicate that there is no correlation between the severity of
      pancreatitis and the amount of enzymes accumulated in the pancreas before the
      disease is induced.

PMID- 12487375
TI  - Acrolein activates mitogen-activated protein kinase signal transduction pathways
      in rat vascular smooth muscle cells.
AB  - Acrolein, a major component of cigarette smoke, an environmental pollutant and an
      endogenous lipid peroxidation product, has been implicated in the development of
      atherosclerosis. Although a link between vascular injury and acrolein has been
      indicated, the exact molecular mechanism of acrolein-induced toxicity to
      vasculature is unknown. In an effort to elucidate the molecular basis of acrolein
      induced vascular toxicity, the possibility of the intracellular signaling system
      as one of the targets of acrolein-induced toxicity is investigated in the present
      study. Exposure of cultured rat vascular smooth muscle cells (VSMCs) to different
      doses of acrolein not only causes cytotoxicity but also alters cellular
      morphology in a concentration and time-dependent manner. VSMCs exhibit
      cytotoxicity to a narrow concentration range of 5-10 microg/ml and display no
      toxicity to 2 microg/ml acrolein even after 24 h of exposure. Furthermore,
      exposure to acrolein results in activation of members of the mitogen-activated
      protein kinase (MAPK) family and protein tyrosine kinases. The extracellular
      signal-regulated kinases 1 and 2 (ERK1/2), stress-activated protein kinases/c-jun
      NH2-terminal kinases (SAPK/JNK) and p38MAPK are effectively and transiently
      activated by acrolein in a concentration and time-dependent fashion. While all
      three MAPKs exhibit significant activation within 5 min of exposure to acrolein,
      maximum activation (ERK1/2 and p38MAPK) or close to maximum activation (SAPK/JNK)
      occurs on exposure to 5 microg/ml acrolein for 2 h. Acrolein-induced activation
      of MAPKs is further substantiated by the activation of transcription factors, c
      jun and activator transcription factor-2 (ATF-2), by acrolein-activated SAPK/JNK
      and p38MAPK, respectively. Additionally several cellular proteins exhibit
      spectacular protein tyrosine phosphorylation, particularly in response to 2 and 5
      microg/ml of acrolein. Interestingly, the acrolein-induced activation of MAPKs
      precedes acrolein-stimulated protein tyrosine phosphorylation, which occurs after
      2 h of exposure to acrolein. However, the time course of maximum protein tyrosine
      phosphorylation profile corresponds to the peak activation profile of MAPKs. The
      activation of MAPKs and protein tyrosine phosphorylation by acrolein appears to
      be independent of acrolein-induced toxicity. VSMCs exposed to 2 microg/ml
      acrolein exhibit no toxicity but stimulates significant activation of MAPKs and
      protein tyrosine phosphorylation. Although acrolein-induced VSMC toxicity is not
      blocked by MAPK inhibitors, PD98059, an inhibitor of MAPK kinase and SB203580, an
      inhibitor of p38MAPK, eitheralone or in combination, each MAPK responds
      differently to the inhibitors. Most prominently, although SB203580, an inhibitor
      of both SAPK/JNK and p38MAPK, significantly inhibited acrolein-induced activation
      of p38MAPK, it also stimulated SAPK/JNK activation by acrolein alone and in
      combination with PD98059. These results provide the first evidence that the
      activation of both growth-regulated (ERK1/2) and stress-regulated (SAPK/JNK and
      p38MAPK) MAPKs as well as tyrosine kinases are involved in the mediation of
      acrolein-induced effects on VSMC, which may play a crucial role in vascular
      pathogenesis due to environmentally and endogenously produced acrolein.

PMID- 12487377
TI  - Snake venom hyaluronidase: an evidence for isoforms and extracellular matrix
      degradation.
AB  - The present study attempts to establish the isoforms of hyaluronidase enzyme and
      their possible role in the spreading of toxins during envenomation. Screening of
      venoms of 15 snakes belonging to three different families revealed varied
      hyaluronidase activity in ELISA-like assay, but with relatively similar pH and
      temperature optima. The zymograms of individual venoms showed varied activity
      banding patterns and indicated the presence of at least two molecular forms of
      the enzyme. During envenomation, activity of hyaluronidase is considered crucial
      for the spreading of toxins and is presumed to distort the integrity of
      extracellular matrix through the degradation of hyaluronic acid in it. This
      property has been addressed through localization of hyaluronic acid in human skin
      and muscle tissue sections using the probe, biotinylated hyaluronic acid binding
      protein. Faint and discontinuous staining pattern of hyaluronidase treated tissue
      sections over intense staining of untreated tissue sections confirm the selective
      degradation of hyaluronic acid in extracellular matrix and thus provide an
      evidence for the spreading property of the enzyme.

PMID- 12487376
TI  - Beneficial effects of a novel IH636 grape seed proanthocyanidin extract and a
      niacin-bound chromium in a hamster atherosclerosis model.
AB  - Atherosclerosis is a disease of the arteries in which fatty plaques develop on
      the inner arterial wall, which eventually obstructs blood flow. Identified risk
      factors for atherosclerosis include genetics, diet, lifestyle, smoking,
      circulating lipid and cholesterol levels, and molecular and circulating signals
      of chronic vascular inflammation. The link between flavonoids and atherosclerosis
      is based partly on the evidence that some flavonoids possess antioxidant
      properties and have been shown to be potent inhibitors of LDL oxidation in vitro.
      Hypercholesterolemia, a significant cardiovascular risk factor is prevalent in
      the American population. Grape seed proanthocyanidin extracts are known to
      exhibit a broad spectrum of chemopreventive and cardioprotective properties
      against oxidative stress. A recent study has shown that a combination of IH636
      grape seed proanthocyanidin extract (GSPE) and a niacin-bound chromium (NBC) can
      decrease total cholesterol, LDL and oxidized LDL levels in hypercholesterolemic
      human subjects. In this study, we assessed the efficacy of GSPE supplementation
      in hamsters, singly and in combination with NBC, since these animals have a
      similar lipid profile to hypercholesterolemic humans when fed a
      hypercholesterolemic diet of 0.2% cholesterol and 10% coconut oil (HCD). After 10
      weeks of feeding HCD, these animals developed foam cells, which is a biomarker of
      early stages of atherosclerosis. Atherosclerosis (% of aorta covered with foam
      cells) was reduced by approximately 50% and 63% following supplementation of
      these animals with 50 mg/kg and 100 mg/kg of GSPE, respectively, in conjunction
      with a HCD, while approximately 32% reduction was observed following
      supplementation of GSPE plus NBC. A range of 7-9 animals was used in each study
      group. GSPE alone and in combination with NBC exerted a pronounced effect on the
      cholesterol, and triglyceride levels, as well as oxidative lipid damage as
      demonstrated by the formation of thiobarbituric acid reactive substances (TBARS).
      This data demonstrates that GSPE and NBC may provide significant health benefits
      by dramatically ameliorating the incidence of atherosclerosis as demonstrated by
      reducing the formation of foam cells.

PMID- 12487378
TI  - Implication of guanosine 3',5'-cyclic monophosphate, adenosine 3',5'-cyclic
      monophosphate, adenosine 5'-mono-, di- and triphosphate and fructose-2,6
      bisphosphate in the regulation of the glycolytic pathway in hypoxic/anoxic
      mussel, Mytilus galloprovincialis.
AB  - The change in the content of cyclic GMP, cyclic AMP, ATP, ADP, AMP and fructose
      2,6-bisphosphate that occurred in the mantle of the mussel Mytilus
      galloprovincialis Lmk when specimens of this mollusk were subjected to a
      hypoxia/anoxia situation were assessed. After the early 24 h in anaerobiosis, a
      clear decrease was observed in the ATP content, which remained close to that
      value for the rest of the time. AMP content doubled during the early 24 h in
      anaerobiosis and, from that time on, it remained close to that value. Fructose
      2,6-bisphoshate and cyclic GMP showed a similar behavior. The levels of these
      compounds rose significantly during the early hours in anaerobiosis, and then
      fell to values similar to those of aerobiosis, remaining constant for the rest of
      the time. Neither ADP nor cAMP showed significant variations.

PMID- 12487380
TI  - The tyrosine kinase inhibitor genistein increases basal cAMP and potentiates
      forskolin-induced cAMP accumulation in A549 human airway epithelial cells.
AB  - Genistein is often used as an inhibitor of tyrosine kinases. A less studied side
      effect of genistein is an inhibition of cyclic AMP-phosphodiesterase (cAMP-PDE)
      activity resulting in increased cAMP accumulation. The effect of genistein on
      intracellular cAMP-levels, basal and forskolin-induced, was studied in A549 human
      airway epithelial cells and compared with the unspecific PDE inhibitor,
      isobutylmethylxanthine (IBMX). It was shown that genistein (50 microM) increased
      basal cAMP and potentiated forskolin-induced cAMP accumulation to the same extent
      as IBMX (100 microM). Thus, the use of genistein in studies on signaling
      transductions may result in erroneous conclusions since increased cAMP may cause
      or contribute to the observed effects.

PMID- 12487379
TI  - Regulation of catalase enzyme activity by cell signaling molecules.
AB  - Mitogenic cell proliferation requires a rapid and transient H2O2 generation,
      which is blocked by catalase or PKA activators. Previously, we observed that
      anemic HIV(+) individuals expressed acidic pIs of catalase in RBC with
      significantly high activities [Mol Cell Biochem 165: 77-81, 1996]. These findings
      led us to hypothesize that cell signaling molecules regulate catalase to control
      cell mitogenesis. To test the hypothesis, we determined (i) whether RBC counts
      correlate with their catalase activities, (ii) whether protein kinases and
      phosphatases alter catalase activity in vitro, and (iii) whether protein kinase
      activators increase catalase activity to suppress proliferation of cultured
      cells. The results indicated that RBC counts inversely correlated with RBC
      catalase activities in both HIV(+) (r: -0.6769, r2: 0.4582, n: 69 male, p <
      0.0001) and HIV(-) (r: -0.3827, r2: 0.1464, n: 177 male, p < 0.0001) populations.
      Catalytic PKA, PKC and Casein Kinase II, but none of PKG, Ca2+/calmodulin kinase
      II and p34cdc/cyclinB, rapidly elevated catalase activity in vitro by up to 2
      fold. Whereas a major CAT subunit (60 kDa) showed immunoreactive phosphoserine
      and phosphothreonine, the kinases- and gamma-32P-ATP-dependent phosphorylation
      occurred with a minor component (110 kDa). Among PKC isozymes examined, PKCzeta
      was the most effective modulator followed by PKCgamma, and protein phosphatase
      1gamma and 2A decreased the catalase activity. PKA and PKCzeta activators of
      forskolin and okadaic acid increased catalase activity and 110 kDa expression in
      NIH3T3 cells up to 2.4-fold and suppressed the cell growth, showing an inverse
      correlation of the indices (r: -0.9286, r2: 0.8622, n: 18, p < 0.0001). Taken
      together, these results suggest for the first time that catalase is under the
      regulation of cell signaling molecules and capable of modulating mitogenic cell
      proliferation.

PMID- 12487381
TI  - Association of antiretroviral resistance genotypes with response to therapy-
      comparison of three models.
AB  - Genotype-based resistance assays are commonly used to aid treatment in HIV
      infected individuals failing antiretroviral therapy. The relationship between
      genotype and antiretroviral therapy comes mostly from in vitro assays of the
      response to a single drugs although there is a need for a prediction of clinical
      response to combination therapy. We have compared three different methods of
      analysing genotype data as a predictor of clinical response in a small clinical
      cohort of highly antiretroviral-experienced individuals failing therapy. No
      method performed well beyond 8 weeks into a new therapeutic regimen. A model
      based on the number of 'primary' mutations was statistically significant, but a
      multiple regression model, which identified specific mutations explained
      threefold more variation in response. Optimal prediction in this dataset was
      given by a model obtained from a classification tree analysis, in which genotype
      at amino acid sites 135 and 202 were combined with amino acid site 184, which
      explained over 50% of the deviance in the data and had a classification success
      of 86%.

PMID- 12487382
TI  - Baseline thymic volume is a predictor for CD4 T cell repopulation in adult HIV
      infected patients under highly active antiretroviral therapy.
AB  - The objective of the present study was to assess the impact of baseline thymic
      volume on the CD4 cell repopulation induced by highly active antiretroviral
      therapy (HAART) in HIV-infected adults. Therefore, 37 previously untreated HIV-1
      infected adults were prospectively followed from August 1998 to September 2001.
      All patients underwent a thorax CT scan at starting HAART to measure thymic
      volume. The median follow-up time was 189 [87.5-498.5] days. CD4 cell
      repopulation was considered as an increase > or = 200 cells/mm3 above baseline
      count. Twenty-one (57%) patients achieved this CD4 repopulation. Baseline thymic
      volume was the main independent factor associated with CD4 repopulation (P =
      0.016); this factor was a positive predictor (adjusted hazard ratio: 1.25 [95%
      confidence interval 1.1-1.4]). Although, CD4 cell count and non-AIDS diagnosis at
      baseline were associated with CD4 cell repopulation on the univariate analysis (P
      = 0.03 and P = 0.02, respectively), no statistical signification was found on the
      multivariate test. In summary, baseline thymic volume is a predictor of early CD4
      cell repopulation in adult HIV-1-infected patients taking HAART.

PMID- 12487383
TI  - Analysis of the virological response with respect to baseline viral phenotype and
      genotype in protease inhibitor-experienced HIV-1-infected patients receiving
      lopinavir/ritonavir therapy.
AB  - The virological response of multiple protease inhibitor-experienced, non
      nucleoside reverse transcriptase inhibitor-naive, HIV-1-infected subjects was
      examined with respect to baseline viral phenotype and genotype through 72 weeks
      of therapy with lopinavir/ritonavir plus efavirenz and nucleoside reverse
      transcriptase inhibitors (Study M98-957). Using a 'dropouts as censored'
      analysis, plasma HIV RNA < or = 400 copies/ml was observed in 93% (25/27), 73%
      (11/15) and 25% (2/8) of subjects with <10-fold, 10- to 40-fold, and >40-fold
      reduced susceptibility to lopinavir at baseline, respectively. In addition,
      virological response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) of
      subjects with baseline lopinavir mutation score of 0-5, 6-7 and > or = 8,
      respectively. Through 72 weeks, all subjects experiencing virological failure
      whose baseline isolates contained six or more protease inhibitor mutations had a
      common genotypic pattern, with mutations at positions 82, 54 and 10, along with a
      median of four additional mutations in protease. However, an equal number of
      subjects with a similar genotypic pattern experienced virological response.
      Further analysis revealed the baseline phenotypic susceptibility to lopinavir to
      be an additional covariate predicting response in this subset of subjects. In
      multivariate analyses, baseline susceptibility to lopinavir was associated with
      response at each time point examined (weeks 24, 48 and 72). These results provide
      guidance for clinically relevant interpretation of phenotypic and genotypic
      resistance tests when applied to lopinavir/ritonavir.

PMID- 12487384
TI  - Evaluation of the risk factors associated with lipodystrophy development in a
      cohort of HIV-positive patients.
AB  - The prevalence of lipodystrophy in an HIV-infected population and the risk
      factors associated with body shape changes were analysed in this study. Five
      hundred and four subjects were included. Among these, 201 (39.9%) had features of
      lipodystrophy syndrome (cases); 303 (60.1%) constituted the control group.
      Compared with the control group, the lipodystrophy subjects were different in age
      (P = 0.01); duration of antiretroviral therapy (P < 0.001); length of exposure to
      nucleoside reverse transcriptase inhibitors (NRTIs) (P < 0.001) and to protease
      inhibitors (P < 0.001); nadir of CD4 cell count (P < 0.001); and value of plasma
      HIV-RNA before antiretroviral therapy (P = 0.008). In a multivariate analysis,
      length of therapy and a nadir CD4 cell count below 250 cell/microl were
      associated with an increased risk of lipodystrophy. Among patients with
      lipodystrophy, isolated fat loss was observed in 46 (23%); isolated fat
      accumulation in 40 (20%); mixed (loss and accumulation) syndrome in 50 (25%); and
      isolated metabolic changes in 65 (32%). Subjects with morphological alterations
      displayed a greater cumulative time of exposure to NRTIs and to protease
      inhibitors than patients with isolated metabolic alterations. Patients with
      lipoatrophy had had a greater exposure to stavudine.

PMID- 12487385
TI  - Trimethoprim-sulfamethoxazole (TMP/SMX) potentiates indinavir nephrotoxicity.
AB  - OBJECTIVES: Indinavir is a widely prescribed protease inhibitor in the treatment
      of HIV infection. It has been associated with nephrolithiasis, crystalluria and
      tubulointerstitial nephritis. Nelfinavir is another protease inhibitor used
      successfully in AIDS treatment. The objective of this study was to evaluate the
      effect of both indinavir and nelfinavir individually, and in association with
      trimethoprim-sulfamethoxazole (TMP/SMX), on renal function in Wistar rats.
      METHODS: Doses of indinavir (80 mg/kg body weight [BW] daily), nelfinavir (75
      mg/kg BW daily) and TMP/SMX (100 mg TMP/kg BW daily) were given by gavage for 15
      days. Seven groups were studied: control, vehicle, TMP/SMX, indinavir,
      indinavir+TMP/SMX, nelfinavir, and nelfinavir+TMP/SMX. RESULTS: No changes were
      observed in body weight, urine volume and blood pressure. The vehicle group did
      not differ from the control group. TMP/SMX induced a small decrease in inulin
      clearance with no tubular alterations. Indinavir decreased inulin clearance
      (indinavir: 0.48 +0.03 vs control: 0.93 +/- 0.08, P < 0.001) and renal blood flow
      (indinavir: 6.2 +/- 0.2 vs control: 8.0 +/- 0.3, P < 0.05). These effects were
      potentiated by TMP/SMX, which produced high vasoconstriction associated with
      alterations in tubular functions, characterised by increased fractional excretion
      of sodium (indinavir+TMP/SMX: 1.14 +/- 0.16 vs control: 0.39 +/- 0.07, P < 0.01).
      Nelfinavir either alone or in combination with TMP/SMX did not change the renal
      function of the rats. CONCLUSION: These results suggest that indinavir
      nephrotoxicity in rats is potentiated by TMP/SMX and that nelfinavir alone or in
      combination with TMP/SMX is not nephrotoxic.

PMID- 12487386
TI  - Consequences and determinants of adherence to antiretroviral medication: results
      from Adult AIDS Clinical Trials Group protocol 370.
AB  - OBJECTIVES: (1) To document rates and patterns of adherence from enrollment until
      week 24 of an AIDS clinical trial; (2) to examine the association of adherence to
      clinical end-points including plasma HIV-1 RNA level and CD4 cell count; and (3)
      to identify predictors of adherence from clinical, behavioural, psychosocial and
      demographic factors. DESIGN: Sub-study of a multicentre, randomised, open-label,
      comparison-controlled trial; 21 collaborating units of the Adult AIDS Clinical
      Trials Group. Observational, prospective analysis. METHODS: Ninety-three subjects
      with baseline plasma HIV-1 RNA levels >500 copies/ml, who completed clinical
      assessment, plasma HIV-1 RNA titres and CD4 cell counts at study entry, weeks 2,
      4 and every 4 weeks thereafter until week 24. All patients were antiretroviral
      experienced but were naive to non-nucleoside reverse transcriptase inhibitors and
      protease inhibitors. Self-reported adherence to antiretroviral therapies
      prescribed as part of the trial was assessed every 4 weeks from trial, week 4
      until week 24. RESULTS: Average adherence was high, with 63% of subjects
      reporting >95% adherence across the trial. However, there was a significant
      decline in adherence over time on trial. After controlling for potential
      confounding variables, patients who were less than 95% adherent to medications
      were 3.5-times more likely to have treatment failure (HIV-1 RNA >50 copies/ml)
      than subjects with adherence rates of 95-100%. The strongest predictor of
      adherence was adverse clinical events (for example, dermatological,
      gastrointestinal symptoms): patients with adverse events were 12.8-times less
      likely to have 95-100% adherence. Other clinical, demographic, psychosocial and
      behavioural factors were also significant predictors of adherence. CONCLUSIONS:
      Adherence influences virological outcome even in AIDS clinical trials where
      overall adherence rates are high and should therefore be monitored in future
      trials. Intervention may be warranted to enhance adherence for subjects who have
      early toxicities, express concern about taking medications as directed, and for
      women and minorities.

PMID- 12487387
TI  - Metabolic and immunological effects of antiretroviral agents in healthy
      individuals receiving post-exposure prophylaxis.
AB  - We have assessed metabolic and immunological effects of a nelfinavir-containing
      regimen in healthy HIV-1-uninfected individuals receiving post-exposure
      prophylaxis. Our data suggest that this regimen is well tolerated and did not
      modify the lipid or hepatic profiles. This antiretroviral regimen seems to have
      no effect on lymphocyte T cell subsets, however, it could have an immune
      modulator role, inducing an increase in the proliferative responses to mitogens.

PMID- 12487388
TI  - Efficacy and safety of twice-daily versus three-times daily saquinavir soft
      gelatin capsules as part of triple combination therapy for HIV-1 infection.
AB  - OBJECTIVE: The objective of this study was to determine whether a triple therapy
      regimen incorporating twice-daily saquinavir is as effective as a three-times
      daily regimen. METHODS: This was an open-label, Phase III, multicentre, 48-week
      study involving 837 HIV-1-infected patients randomised to one of the following:
      saquinavir soft gel capsule (SGC) 1200 mg three-times daily, plus two nucleoside
      reverse transcriptase inhibitors (NRTIs) (arm A); saquinavir SGC 1,600 mg twice
      daily, plus two NRTIs (arm B); saquinavir SGC 1,200 mg twice-daily and nelfinavir
      1,250 mg twice-daily, plus a single NRTI (arm C). The primary outcome measure was
      the virological response in arm A versus B and in arm A versus C with respect to
      the percentage of patients whose plasma HIV-1 RNA levels fell below the level of
      quantification for the Amplicor assay (<400 copies/ml) at weeks 24 and 48.
      RESULTS: At 48 weeks, the percentage of patients with plasma HIV-1 RNA levels
      <400 copies/ml was 47.1% (arm A), 45.3% (arm B) and 42.7% (arm C) in the
      intention-to-treat analysis. The treatment difference between arm B-arm A was 
      1.8% (95% confidence intervals -10.1, 6.5) and for arm C-arm A was -4.5% (95%
      confidence intervals -12.7, 3.7) in the intention-to-treat analysis. These
      differences fell within the maximum allowable difference (+/- 12%) for arm B
      compared with arm A. At week 24, the percentage of patients with HIV-1 RNA levels
      <400 copies/ml was 59.6% (arm A), 57.6% (arm B) and 51.3% (arm C). CONCLUSIONS: A
      twice-daily triple therapy regimen incorporating saquinavir SGC plus two NRTIs
      was of equivalent efficacy to the three-times daily regimen studied. All regimens
      were generally well tolerated.

PMID- 12487389
TI  - Impact of stavudine phenotype and thymidine analogues mutations on viral response
      to stavudine plus lamivudine in ALTIS 2 ANRS trial.
AB  - OBJECTIVE: Stavudine-based antiretroviral combinations are less effective in
      zidovudine-experienced patients than in naive subjects and recently, mutations
      have been described to be associated to the use of both stavudine and zidovudine.
      In the ALTIS 2 trial, it was shown that a combination of stavudine and lamivudine
      is less effective in zidovudine-experienced patients than in naive patients. We
      conducted a retrospective genotypic and phenotypic resistance study (expressed as
      stavudine phenotypic index, calculated by dividing the inhibitory concentrations
      50% [IC50] by the mean value of the sensitive viruses) to evaluate the factors
      associated with decrease in plasma HIV-1 RNA. DESIGN: Associations with
      continuous variables were studied using non-parametric Spearman correlation
      coefficients. Associations with categorical variables were studied using non
      parametric Mann-Whitney tests. Multivariate stepwise regression analyses were
      used to determine independent prognostic factors of the virological response.
      RESULTS: At baseline, most of the subjects harboured zidovudine-associated
      mutations in plasma and peripheral blood mononuclear cells. Zidovudine and
      stavudine IC50 and IC50 were strongly associated with response. It appears that a
      cut-off of stavudine phenotypic index of 1.8-fold of IC50, much lower than the
      usually used value, could be clinically significant for response to stavudine. In
      the multivariate analysis, the stepwise model with the higher multiple
      correlation coefficient (R2 = 0.742) included the presence of a 215 Y/F mutation,
      the number of previously used nucleoside analogues and a resistant stavudine
      phenotype. CONCLUSION: These results argue for a phenotypic and genotypic cross
      resistance between stavudine and zidovudine. Modest increases of IC50 and IC50
      for stavudine had an important impact on the virological response during the
      trial and plead for a new definition of the threshold value for stavudine
      phenotypic index.

PMID- 12487390
TI  - Daily dialysis in the intensive care unit.

PMID- 12487391
TI  - Genetic variability of hepatitis C virus in dialysis: the implications.

PMID- 12487392
TI  - Results from EuCliD (European Clinical Dialysis Database): impact of shifting
      treatment modality.
AB  - BACKGROUND: The use of biocompatible high-flux membranes is more efficient than
      low-flux membranes in controlling a number of hemodialysis-related diseases. The
      aim of this cooperative study was to evaluate the 6-month effect of a switch from
      low- to high-flux dialysers on patients treated in 39 Spanish dialysis centres.
      METHODS: The clinical data used in this analysis were prospectively collected by
      the EuCliD database, developed to monitor the quality of treatment delivered in a
      large network of European Dialysis Centres. Inclusion criteria for the study were
      the condition of end-stage renal disease (ESRD) on chronic hemodialysis and low
      flux dialysis for at least six months before the switch to high-flux dialysis. Of
      1,543 patients enrolled in the study between 2000 and 2001, 1,046 patients were
      considered for the analysis. 497 patients were excluded because they did not
      complete the follow-up. Outcome measures were the reduction of pre-dialysis beta
      2 microglobulin, the improvement of anemia or reduction in rHu-EPO dose required
      to maintain best correction of anemia, reduction of inflammatory parameters
      (CRP), improvement in lipid profile (Total and HDL cholesterol, tryglycerides),
      maintenance of nutritional status. Albumin and "dry" (post-hemodialysis) body
      weight were both evaluated as nutritional indexes. RESULTS: During the six months
      of high-flux hemodialysis, there was a significant increase in hemoglobin (from
      11.55 +/- 1.41 to 11.88 +/- 1.43 g/L; p < 0.001). Considering the temporarily
      untreated patients on a 0 U/week dose, erythropoietin remained stable (from 5,670
      +/- 4,199 to 5,657 +/- 4,411 U/week). During the second part of the follow-up,
      the lipid profile significantly improved (Fig. 3). Total cholesterol and
      triglycerides decreased significantly (p < 0.001), while HDL cholesterol
      increased (p = 0.006). Calculated levels of LDL cholesterol also significantly
      decreased (p = 0.001). Dry body weight remained stable (64.7 +/- 11.9 vs. 64.7 +/
      12.0 kg) as well as in albumin levels (3.93 +/- 0.43 vs. 3.94 +/- 0.43 g/dL)
      between the two modalities of treatment. The level of beta2-microglobulin
      significantly decreased during high-flux dialysis (33.5 +/- 14.4 vs. 26.3 +/- 8.6
      mg/dL, p < 0.001). CONCLUSION: All above mentioned results may have as a common
      denominator an improved blood purification from uremic toxins and a reduced level
      of chronic sub-clinical inflammation. All together, these results seem to confirm
      the superiority of high-flux dialysis in terms of clinical and physiological
      outcomes.

PMID- 12487393
TI  - Strategy for the treatment of noncompliant hypertensive hemodialysis patients.
AB  - Hypertensive hemodialysis patients noncompliant for their medications do not
      benefit from pharmacologic advances in the treatment of high blood pressure, and
      increase their already high risk of cardiovascular complications. The medical
      staff often becomes frustrated by severe hypertension in those who refuse to take
      medicines at home, drink excessive fluids, miss multiple dialysis sessions and
      sign-off dialysis early. In addition to addressing the psychosocial, financial,
      educational and substance abuse problems which contribute to noncompliance, we
      have developed a medication strategy to serve as an at least interim means of
      lowering blood pressure. Antihypertensive agents which have long half-lives in
      renal failure (lisinopril) and/or are intrinsically long acting (transdermal
      clonidine and amlodipine) were administered on dialysis days by the unit
      personnel to those patients who did not or would not take that or any dose on
      their own. The lisinopril and amlodipine were assured to have been taken on at
      least the dialysis days (thrice weekly), and the clonidine patch replaced weekly.
      Sixteen patients were thus treated when they failed to reliably self-administer
      medications. They had a significant decline in the predialysis systolic pressure
      of 15 mm Hg (175 +/- 6 to 160 +/- 5 mm Hg), diastolic of 12 mm Hg (103 +/- 3 to
      91 +/- 3 mm Hg), and mean pressure of 13 mm Hg (127 +/- 4 to 114 +/- 4 mm Hg).
      There was an improvement in post-dialysis bood pressures, with the mean pressure
      declining 13 mm Hg from 110 +/- 4 to 97 +/- 4 mm Hg. Many individuals had erratic
      blood pressure control, having intermittently missed dialysis and hence unit
      administered medicine, as well as continued fluid or drug abuse. The patients had
      uniformly excellent acceptance of this regimen, even spontaneously requesting it,
      and had no appreciable adverse effects. In summary while noncompliance is being
      addressed by the entire medical team, dialysis unit administration of long-acting
      medicines helps many hypertensive dialysis patients who would otherwise be at
      increased risk for severe cardiovascular complications.

PMID- 12487394
TI  - Continuous venovenous hemofiltration: effects on monocyte and lymphocyte
      immunophenotype in critically ill patients.
AB  - The aim of this study was to test the hypothesis that continuous venovenous
      hemofiltration (CVVH) increases HLA-DR expression on monocytes and T lymphocytes
      in critically ill patients. 24 septic (SP) and 10 non-septic (NSP) medical ICU
      patients with acute renal failure were studied prospectively. The ultrafiltration
      rate was 20-30 ml.kg(-1).h(-1). The total and differential white cell counts were
      measured and CD3+ lymphocyte count, HLA-DR expression on CD14+ monocytes and CD3+
      lymphocytes were analysed by two-colour flow cytometry before, 4 and 24 h after
      CVVH initiation, respectively. CVVH did not influence leukocyte, granulocyte,
      total lymphocyte and CD3+ lymphocyte counts in both groups of patients. The
      percentage of HLA-DR+/CD14+ monocytes in SP revealed no changes, whereas it
      decreased after 4 h of CWH in NSP (p < 0.05). The percentage of HLA-DR+/CD3+
      lymphocytes in SP decreased after 24 h (p < 0.05), whereas it remained unchanged
      in NSP. We conclude that CWH initiation is not associated with the increase of
      HLA-DR expression on CD14+ monocytes and T lymphocytes in critically ill patients
      with acute renal failure.

PMID- 12487395
TI  - Influence of transmyocardial laser revascularization (TMLR) on regional cardiac
      function and metabolism in an isolated hemoperfused working pig heart.
AB  - The mechanism of an indirect revascularization in ischemic myocardium by
      transmyocardial laser revascularization (TMLR) is not yet fully understood. An
      improvement of clinical symptoms caused by TMLR is reported in many clinical
      trials with patients in which a direct revascularization is not possible. An
      increase of myocardial perfusion through laser channels is doubtful, because the
      myocardial pressure in the wall is higher than in the cavum. Therefore we
      measured the local cardiac function (intramyocardial pressure, wall thickness,
      pressure-length curves) and acute metabolic changes (tissue lactate content,
      tissue pO2) in ischemic and nonischemic regions before and after TMLR in isolated
      hemoperfused pig hearts. An isolated heart was chosen because it enabled us to
      separate coronary flow from flow through ventricular channels. The ischemia was
      induced by coronary occlusion or microembolization (eight hearts each). It should
      be noted that microembolization leads to conditions which are more comparable
      with those found in patients selected for TMLR. In the isolated working heart,
      the coronary perfusion can be controlled independently from perfusion through the
      ventricular cavum. Under the ischemic conditions mentioned above, we observed
      that the intramyocardial pressure in the ischemic region decreased below the left
      ventricular pressure, so one premise for indirect perfusion was met. TMLR after
      microembolization led to a significant improvement of regional cardiac work and
      the tissue oxygen pressure. These acute effects demonstrate the possibility of
      functional and metabolic amelioration by TMLR after ischemia induced by
      microembolization in an isolated hemoperfused pig heart.

PMID- 12487396
TI  - The heart-pump interaction: effects of a microaxial blood pump.
AB  - BACKGROUND: When we use rotary blood pumps as an assist device, an interaction
      takes place between the pump performance and the native heart function (native
      heart influences pump performance and vice versa). The interaction between native
      heart and rotary blood pump can be useful to predict recovery of the failing
      heart. METHODS: The rotary blood pumps used were microaxial catheter-mounted
      pumps with an external diameter of 6.4 mm (Impella, Aachen, Germany). The pump
      heart interaction was studied in five juvenile sheep with a mean body weight of
      68.5 +/- 8.7 kg. The pumps were introduced via the left carotid artery and placed
      in transvalvular aortic position. Recorded parameters were pump speed (rpm),
      generated flow (L/min) and differential pressure (mm Hg) obtained at high
      frequency rate of data recordings (25 sets of data per second). This allowed
      continuous analysis of the pump performance during cardiac cycle. Under clinical
      conditions the interaction was studied in a 60-year-old male, in whom the device
      was applied due to postcardiotomy heart failure after myocardial infarction.
      RESULTS: Heart-pump interaction was analyzed based on pump flow differential
      pressure. This relationship, analyzed continuously during cardiac cycle, presents
      as a loop. The dynamic contribution of the heart to the flow generated by the
      pump leads to continuous fluctuation in the pressure head and the creation of
      hysteresis. The improved function of the failing heart under clinical conditions
      after seven days of mechanical support was expressed by: increased hysteresis of
      the loop caused by increased gradient of flow generated during cardiac cycle, a
      more pronounced venticular ejection phase that indicates more dynamic heart
      contribution to the generated flow, and finally increased gradient of the
      differential pressure during cardiac cycle, caused predominantly by increased
      aortic pressure and decreased left ventricle pressure during diastolic phase.
      CONCLUSIONS: The heart-pump interaction based on the pump flow-differential
      pressure relationship can be useful in predicting the possibility to wean the
      patient from the device.

PMID- 12487397
TI  - In vitro hydrodynamics of a decellularized pulmonary porcine valve, compared with
      a glutaraldehyde and polyurethane heart valve.
AB  - BACKGROUND: Hydrodynamic performance of a decellularized pulmonary porcine valve
      was evaluated with a computer versatile pulse duplicator and compared to
      glutaraldehyde fixated stentless porcine bioprosthesis and a polyurethane heart
      valve. METHODS: Decellularized pulmonary porcine matrices (Group I, n = 5) were
      treated chemically to become cell-free collagen matrices. The findings of this
      heart valve were compared with aortic glutaraldehyde treated porcine prostheses
      (Group II, n = 5) and polyurethane three leaflet valve prostheses (Group III, n =
      1). Measurements were performed in 0.9% saline test fluid at room temperature.
      Measurements compared were closing time, closing volume, systemic pressure
      difference and energy losses. Each valve was measured 6 times with 70
      beats/minute, a stroke volume of 70 ml corresponds to a cardiac output of 4.9
      L/minute. RESULTS: Group I and group III showed no significant differences
      between parameters. The measured closing time was significantly different (p <
      0.001) between group I and II, respectively 24.333 and 53.600 ms and group II and
      III respectively 53.600 and 24.000. Difference in closing volume was significant
      (p < 0.05) between groups II and I respectively 3.67 and 0.68 ms and group II and
      III respectively 3.67 and 0.71. Systolic mean pressure gradient was 18.25 +/-
      1.04 mm Hg in group II which was significantly different (p < 0.001) from groups
      I and III, respectively 10.65 +/- 0.29 mm Hg and 7.70 +/- 0.30 mm Hg.
      CONCLUSIONS: Decellularized pulmonary porcine valves showed the same excellent
      performance as polyurethane valve prosthesis, which are superior to the
      investigated glutaraldehyde fixed xenograft.

PMID- 12487398
TI  - Regenerative repair of the mandible using a collagen sponge containing TGF-beta1.
AB  - INTRODUCTION: Alveolar bone resorption and atrophy of the mandible are a major
      challenge for regeneration medicine. In the present investigation, a collagen
      sponge that contained TGF-beta1 was placed at a mandibular defect and the
      osteogenic effects of collagen-TGF-beta1, complex were evaluated. MATERIAL AND
      METHODS: The Pm2, Pm3, and Pm4 teeth on both sides of the mandibles of 12 adult
      beagle dogs (9.0-12.0 kg) were extracted. After the extraction-site wounds
      healed, a bone defect (10.0 x 15.0 mm-wide, 10.0 mm-deep or 10.0 x 10.0 mm-wide,
      10.0 mm-deep) was created on the mandible. A collagen sponge (10.0 x 10.0 x 10.0
      mm) that contained TGF-beta1 (1.0 microg, 5.0 microg, or 10.0 microg, in
      physiological saline) was placed at the bottom of the defect and the overlying
      mucous membrane was sutured with 4-0 prolene. As a control, a collagen sponge
      that contained physiological saline only was placed in a defect on the opposite
      side. Two weeks after the surgery the wounds above the bone defects on both the
      control and TGF-beta1-treated sides had healed completely. RESULTS: At four, six,
      or eight weeks post-operatively animals were killed. Soft X-ray and bone-salt
      measurement analyses confirmed clearly that there was greater calcified bone
      formation in the defects into which TGF-beta1 had been incorporated than with the
      control defects. The implanted collagen sponges were fully resorbed and the bone
      tissue had regenerated from the bottom of the defects on the TGF-beta1, side by
      four weeks. On the control side, no such regeneration was observed. CONCLUSIONS:
      These results indicate that TGF-beta1, released slowly from a collagen sponge was
      effective in promoting bone remodeling when applied to mandibular defects in
      adult dogs.

PMID- 12487399
TI  - Ginsenoside Rb1 enhances peripheral nerve regeneration across wide gaps in
      silicone rubber chambers.
AB  - Silicone rubber chambers filled with collagen containing ginsenoside Rb1 (GRb1)
      were used to repair lesioned rat sciatic nerves with 15-mm gaps between stumps.
      Six weeks after implantation, histology of the nerve regenerated in the chambers
      filled with GRb1 and collagen contained larger axons than those in the chambers
      with collagen only. This study showed that the GRb1 could exert a positive
      influence on nerve regeneration when using silicone rubber tubes.

PMID- 12487400
TI  - Mechanical resistance of biological repair cartilage: comparative in vivo tests
      of different surgical repair procedures.
AB  - The former common knowledge that cartilage lesions do not heal has been modified
      over the last few years due to new technologies. For repair of deeper
      circumscribed lesions osteochondral press-fit grafting and tissue engineering are
      used in clinical application. The histological data of the hyaline-like tissue
      obtained by engineering are just as satisfactory as the surviving grafted hyaline
      cartilage on top of osteochondral cylinders. But comparative studies are still
      lacking. To fill the gap and with a view to repairing larger osteoarthritic
      defects we have performed an in vivo study on 16 goats. Three months after the
      creation of a full thickness wide cartilage defect on the femoral condyle with
      harvesting of cartilage samples for tissue cultures we performed secondary
      cartilage repair procedures on the installed osteoarthritis areas: 1) grafting
      with autogenic osteochondral press-fit cylinders from the opposite knee, 2)
      autologous engineered chondrocyte grafting under periosteal flaps, 3) both in
      combination. The harvesting defects were either left as controls or filled with a
      hyaluronate fleece. After eight months the repaired areas and the harvesting
      defects were examined for cartilage stiffness as a novel comparative parameter.
      Compared to normal the cartilage on top of osteochondral grafts is considerably
      stiffer. Engineered cartilage is weaker than normal. Spontaneously ingrown
      fibrous cartilage is much weaker even with a carrier fleece. A combination of
      osteochondral press-fit grafts with engineered autologous cells restores
      biomechanical qualities to repaired larger degenerative cartilage defects.

PMID- 12487401
TI  - Imaging of the larynx--extending the use of stroboscopy-related techniques.
AB  - Three methods (I-III) are presented to demonstrate how technical modifications in
      the use of stroboscopy-related techniques can be applied to further analyze vocal
      fold vibrations. (I) With double exposure videostroboscopy, dynamic properties of
      vocal folds can be visualized within one single image. This allows for
      estimations of horizontal vibratory velocity of the vocal fold margins. (II)
      Stroboscopic transillumination of the larynx makes it possible to localize
      initial vocal fold opening in the horizontal glottal plane and to visualize
      different vibratory opening patterns. Bidirectional color-coded endoscopic
      imaging of the larynx facilitates a semi-automated, digital measurement of the
      glottal area. (III) Stroboscopic illumination using four light emitting diodes
      (LEDs) clipped on a rigid endoscope and triggered by a portable 'pocket-sized',
      battery-powered electronic control device offers new prospects for performing
      stroboscopy outside of specialized clinical facilities.

PMID- 12487402
TI  - Clinical pilot study assessment of a portable real-time voice analyser.
AB  - The use of computer-based real-time visual displays is now well established in
      voice clinics. A number of situations exist, however, where a computer-based
      system is inconvenient and a battery-powered hand-held version would be
      preferred. This would, for example, enable voice monitoring to be carried out at
      any time and place, including during home visits. This paper describes a purpose
      built device that provides real-time displays of fundamental frequency and larynx
      closed quotient (CQ) derived from the electrolaryngograph output. The fundamental
      frequency data can in addition, be acquired from a microphone. The system has
      been in use recently in a speech and language therapy clinic in Sheffield, UK and
      the advantages and disadvantages noted during that trial are discussed.

PMID- 12487403
TI  - The use of electroglottography in the treatment of deaf adolescents with
      puberphonia.
AB  - Electroglottography (EGG) was used as a visual feedback tool in the treatment of
      four male profoundly deaf adolescents of 15 years of age with puberphonia. A
      laryngograph, oscilloscope, computer, and laryngostroboscope were used for this
      research. The EGG was used during phonopedic exercises, which consisted of the
      patient producing voiced coughing in modal register and extended these into
      prolonged vowels. The investigation showed that EGG facilitated the production of
      vocal fold vibration in the modal register. It was concluded that EGG was highly
      effective in changing the production of vocal register and could be recommended
      in the treatment of puberphonia in the deaf.

PMID- 12487404
TI  - Voice source changes of child and adolescent subjects undergoing singing training
      -a preliminary study.
AB  - Many vocal practitioners have strong beliefs regarding the age at which singing
      training of a child should begin, and the different ways in which male and female
      children should be treated. These beliefs are not substantiated by any scientific
      research, leading to considerable dispute between vocal coaches and choral
      directors. The singing voices of over 127 child singers and non-singers aged 8-18
      were analysed using electrolaryngographic measures. Analysis particularly
      concentrated on the laryngographically derived vocal fold closed quotient (CQ).
      Results indicated that the voice source characteristics of subjects could be
      divided into groups according to age, gender and the level of vocal training
      received. Female subjects in particular exhibited a marked development of voice
      source production according to the length of training received, while male
      subjects exhibited patterning according to both age (and related pubertal
      development), and training received. It was concluded that the process of
      training a young voice has a quantifiable effect upon the singing voice
      production of the child, and in particular on the female voice, while pubertal
      development also creates measurable effects on the voice source production of the
      male child.

PMID- 12487405
TI  - Hidden respiratory allergies in voice users: treatment strategies.
AB  - The treatment of the allergic voice patient may be somewhat different than other
      voice patients. Antihistamines are generally avoided, though decongestants with
      Guaifenesin may be useful. Steroids are more useful in perennial allergic
      systems. Steroids may be inhaled nasally, inhaled orally, or given systemically.
      Systemic steroids are especially useful for a performer who needs quick relief.
      We strongly feel that vocalists with chronic laryngitis and dysphonia should be
      allergy tested. A hidden dust mite or cat dander allergy is often found. A clean
      indoor environment can then be established. Immunotherapy injections can also be
      initiated. Both of these treatments, desensitization injections and environmental
      control, are especially useful in vocalists. These treatments are helpful in
      keeping a vocalist's trachea, larynx, and nasal cavity healthy. A careful search
      for mild asthma should be considered. Establishing good vocal hygiene and voice
      training may also be necessary.

PMID- 12487406
TI  - A case study of successful voice imitation.
AB  - Our voices and speech behaviour give cues to the listener as to our identity.
      These cues make it possible for the listener to recognise a voice without seeing
      the speaker. A professional impersonator has to identify the salient and
      characteristic features of the target voice in order to succeed. The present
      phonetic study of a Swedish professional impersonator and one of his voice
      imitations compares the target voice, the voice imitation and the impersonator's
      own voice. The findings indicate that a successful impersonation is the result of
      the impersonator's ability to alter his voice in numerous ways.

PMID- 12487407
TI  - Psychogenic voice disorders--heroes or hysterics? A brief overview with questions
      and discussion.
AB  - A brief overview of the field in relation to psychogenic voice disorders is given
      with reference to past and present terminology used, the common presentations
      seen, followed by the more subtle or ambiguous examples which may challenge our
      notions of psychogenic or clear-cut functional versus organic dichotomies. Issues
      related to aetiology, personality and psychological correlates are discussed, and
      a number of questions regarding the phenomenology of psychogenic dysphonia and
      its therapeutic resolution are raised. Since prevalence continues to be
      significantly in favour of women, it is suggested psychogenic voice disorder as a
      feminist issue might be worthy of our further consideration.

PMID- 12487408
TI  - Integrin-dependent interaction of human vascular endothelial cells on biomimetic
      peptide surfactant polymers.
AB  - Biomimetic surfactant polymers designed by molecular grafting of pendant RGD
      peptides (Pep) and dextran oligosaccharides (Dex) in different ratios onto the
      backbone of poly(vinyl amine) (PVAm) were examined for their ability to promote
      endothelial cell (EC) growth. Adhesion, formation of focal contacts, and
      expression of integrin receptors were examined in EC seeded onto a series of
      novel surfactants containing 100% dextran (PVAm[Pep (0%)]) to 100% peptide
      (PVAm[Pep (100%)]) compared to fibronectin control. Interaction of EC on polymer
      was specific, as soluble GRGDSP, but not GRGESP, was able to inhibit both
      adhesion and spreading of EC. At three hours, EC attachment and spreading were
      rapid and comparable on fibronectin and PVAm[Pep (100%)], rounded on PVAm[Pep
      (0%)], and intermediate on PVAm[Pep (25%)], (PVAm[Pep (50%)], and PVAm[Pep
      (75%)], with increasing peptide ratio favoring more spreading, although all the
      substrates had similar hydrophilicity. Cells that spread well on fibronectin and
      PVAm[Pep (100%)] had sharp spikes of vinculin localized at the termination point
      of actin stress fibers. Formation of stress fibers and focal adhesions on other
      substrates were correlated with spreading pattern of EC and the peptide content.
      EC seeded on fibronectin expressed alpha5beta1 integrins all along the stress
      fibers and throughout the entire cytoskeleton, but this distribution pattern was
      less prominent on PVAm[Pep (100%)]. However, expression and distribution of
      vitronectin receptors (alpha(v)beta3) were similar on both fibronectin and
      PVAm[Pep (100%)], suggesting a strong cell adhesion on PVAm[Pep (100%)].
      Viability of EC was also comparable on both fibronectin and PVAm[Pep (100%)] at
      24 h. Substrates with high proportion of dextran limited cell adhesion, probably
      by decreasing protein adsorption. These results suggest that it may be possible
      to engineer substrates that promote cell adhesion in a receptor-dependent manner
      while blocking nonspecific protein adsorption, which may have potential as
      interface materials for prostheses used in cardiovascular system.

PMID- 12487409
TI  - The highly conserved Gln49 and Ser50 of mammalian connexin43 are present in chick
      connexin43 and essential for functional gap junction channels.
AB  - In an attempt to compare the regulation of chick connexin43 channels to those of
      mammalian connexin43, we found that the nucleotide sequence reported for chick
      connexin43 differs from that of the chick connexin gene by two codons that had
      been entered as histidine49 (H49) and valine50 (V50) (accession no. M29003), but
      are in fact glutamine49 (Q49) and serine50 (S50). Neuro2A cells were transfected
      with corrected wild-type (Q49/S50) chick connexin43 (accession no. AF233738), the
      double-replacement Q49H/S50V connexin43, or the single replacement of Q49H or
      S50V. All clones had gap junctions in membrane based on immunocytochemistry and
      immunoblots of the triton-resistant membrane fraction. Wild-type transfectants
      had three conductance states with a predominant channel conductance of 85 +/- 5
      pS. Cells producing the Q49H-Cx43 or the double-replacement Q49H/S50V-Cx43
      protein had no detectable connexin43 channels. In contrast, cells expressing S50V
      Cx43 gap junctions had channels with reduced conductances (75 +/- 8 pS) compared
      to wild-type controls. Low or high pH of the bathing solution had no effect on
      the Q49H-Cx43 channels. We conclude that glutamine49 is important for channel
      function, and replacement of this residue with histidine most likely distorts
      secondary structure of the first extracellular loop, possibly by changing the
      orientation of conserved cysteines, and this inhibits channel function. The S50V
      substitution may also cause similar but less severe structural changes.

PMID- 12487410
TI  - The invasive phenotype in HMT-3522 cells requires increased EGF receptor
      signaling through both PI 3-kinase and ERK 1,2 pathways.
AB  - We studied the invasion of HMT-3522 breast epithelial cells in response to
      epidermal growth factor (EGF), and the associated signaling pathways. HMT-3522 T4
      2 cells were shown to invade Matrigel-coated Transwell membranes in response to
      EGF while HMT-3522 S-1 cells failed to invade when treated with EGF. Studies
      utilizing specific molecular inhibitors showed the importance of beta1 integrin,
      phosphatidylinositol 3 kinase (PI 3-kinase), p38, extracellular regulated kinase
      1, 2 (Erk 1,2) MAP kinases, and metalloproteinases in invasion and motility. T4-2
      cell invasion was shown to be time-dependent and also gene transcription
      dependent as shown by inhibition with Actinomycin D. T4-2 cells exhibited an
      increased activation of MAP kinases Erk 1,2 (2-fold), EGF receptor (3-fold), and
      PI 3-kinase (3- to 4-fold) when compared to the S-1 cells. In response to EGF, T4
      2 cells showed a 5-fold greater secretion of matrix metalloproteinase-9 (MMP-9)
      as compared to S-1 cells, and this increase was largely dependent on the activity
      of PI 3-kinase. These findings indicate that expression of the invasive phenotype
      in these breast epithelial cells requires increased EGF receptor signaling,
      involving both PI 3-kinase and Erk 1,2 activities, which leads to multiple
      downstream effects, including enhanced secretion of MMP-9 and transcription of
      invasion-related genes.

PMID- 12487411
TI  - Differential displacement of classical cadherins by VE-cadherin.
AB  - VE-cadherin is an endothelial cell-specific, type II classical cadherin that
      plays an important role in permeability, vasculogenesis, and vascular remodeling.
      Endothelial cells express equal levels of VE- and N-cadherin; VE-cadherin is
      present injunctions while N-cadherin is diffusely expressed over the surface of
      the cell. The present study was designed first to determine if the ability of VE
      cadherin to displace N-cadherin from junctions was endothelial-cell specific, and
      second to determine if VE-cadherin could displace other classical cadherins from
      cell junctions. Our data suggest that VE-cadherin specifically influences the
      cellular localization of N-cadherin, independent of cell type, and does not
      effect the localization of other classical cadherins.

PMID- 12487412
TI  - Natural remobilization of multicomponent DNAPL pools due to dissolution.
AB  - Mixtures of dense nonaqueous phase liquids (DNAPLs) trapped in the subsurface can
      act as long-term sources of contamination by dissolving into flowing groundwater.
      If the components have different solubilities then dissolution will alter the
      composition of the remaining DNAPL. We theorized that a multicomponent DNAPL pool
      may become mobile due to the natural dissolution process. In this study, we
      focused on two scenarios: (1) a DNAPL losing light component(s), with the
      potential for downward migration; and (2) a DNAPL losing dense component(s), with
      the potential for upward migration following transformation into a less dense
      than water nonaqueous phase liquid (LNAPL). We considered three binary mixtures
      of common groundwater contaminants: benzene and tetrachloroethylene (PCE), PCE
      and dichloromethane (DCM), and DCM and toluene. A number of physical properties
      that control the retention and transport of DNAPL in porous media were measured
      for the mixtures, namely: density, interfacial tension, effective solubility, and
      viscosity. All properties except density exhibited nonlinear relationships with
      changing molar ratio of the DNAPL. To illustrate the potential for natural
      remobilization, we modelled the following two primary mechanisms: the reduction
      in pool height as mass is lost by dissolution, and the changes in fluid
      properties with changing molar ratio of the DNAPL. The first mechanism always
      reduces the capillary pressure in the pool, while the second mechanism may
      increase the capillary pressure or alter the direction of the driving force. The
      difference between the rate of change of each determines whether the potential
      for remobilization increases or decreases. Static conditions and horizontal
      layering were assumed along with a one-dimensional, compositional modelling
      approach. Our results indicated that for initial benzene/PCE ratios greater than
      25:75, the change in density was sufficiently faster than the decline in pool
      height to promote DNAPL breakthrough into the adjacent porous medium. In
      contrast, there was no potential for natural remobilization of a PCE-DCM mixture,
      primarily because the densities of the components are not sufficiently different.
      Dissolution of a DCM-toluene mixture decreased the density, reducing the tendency
      for downward displacement. However, the ultimate transformation from a DNAPL to
      an LNAPL may induce upward displacement. These results suggest that at sites with
      DNAPL pools containing a mix of components of sufficiently different densities
      and relative solubilities, natural remobilization may be an active mechanism,
      with implications for site evaluation and remediation.

PMID- 12487413
TI  - Controlled release, blind tests of DNAPL characterization using partitioning
      tracers.
AB  - The partitioning tracer technique for dense nonaqueous phase liquid (DNAPL)
      characterization was evaluated in an isolated test cell, in which controlled
      releases of perchloroethylene (PCE) had occurred. Four partitioning tracer tests
      were conducted, two using an inverted, double five-spot pumping pattern, and two
      using vertical circulation wells. Two of the four tests were conducted prior to
      remedial activities, and two were conducted after. Each test was conducted as a
      "blind test" where researchers conducting the partitioning tracer tests had no
      knowledge of the volume, method of release, nor resulting spatial distribution of
      DNAPL. Multiple partitioning tracers were used in each test, and the DNAPL volume
      estimates varied significantly within each test based on the different
      partitioning tracers. The tracers with large partitioning coefficients generally
      predicted a smaller volume of PCE than that expected based on the actual release
      volume. However, these predictions were made for low DNAPL saturations (average
      saturation was approximately 0.003), under conditions near the limits of the
      method's application. Furthermore, there were several factors that may have
      hindered prediction accuracy, including tracer degradation and remedial fluid
      interference.

PMID- 12487414
TI  - Mobilization and entry of DNAPL pools into finer sand media by cosolvents: two
      dimensional chamber studies.
AB  - Two-dimensional chamber studies were conducted to determine qualitative and
      quantitative performance of cosolvents targeted at pooled dense non-aqueous phase
      liquid (DNAPL) (perchlorethylene, PCE) residing above a fine-grain capillary
      barrier. Downward mobilization of DNAPL, up gradient along an overriding
      cosolvent front, was observed. This produced significant pooling above a fine
      grain layer that in some cases lead to entry into the capillary barrier beneath.
      Entry pressure calculations using physical and hydrogeologic parameters provided
      an excellent prediction of breakthrough of DNAPL into the capillary barrier.
      Calculations predict approximately 0.5 m of DNAPL would be necessary to enter a
      Beit Netofa clay, under extreme cosolvent flooding conditions (100% ethanol).
      Gradient injection of cosolvent did not appear to provide any benefit suggesting
      a rapid decrease in interfacial tension (IFT) compared to the rate of DNAPL
      solubilization. Use of a partitioning alcohol (tertiary butyl alcohol, TBA)
      resulted in DNAPL swelling and reduced entry into the capillary barrier. However,
      the trapping of flushing solution, containing PCE, could potentially lead to
      longer remediation times.

PMID- 12487415
TI  - Engineered and subsequent intrinsic in situ bioremediation of a diesel fuel
      contaminated aquifer.
AB  - A diesel fuel contaminated aquifer in Menziken, Switzerland was treated for 4.5
      years by injecting aerated groundwater, supplemented with KNO3 and NH4H2PO4 to
      stimulate indigenous populations of petroleum hydrocarbon (PHC) degrading
      microorganisms. After dissolved PHC concentrations had stabilized at a low level,
      engineered in situ bioremediation was terminated. The main objective of this
      study was to evaluate the efficacy of intrinsic in situ bioremediation as a
      follow-up measure to remove PHC remaining in the aquifer after terminating
      engineered in situ bioremediation. In the first 7 months of intrinsic in situ
      bioremediation, redox conditions in the source area became more reducing as
      indicated by lower concentrations of SO4(2-) and higher concentrations of Fe(II)
      and CH4. In the core of the source area, strongly reducing conditions prevailed
      during the remaining study period (3 years) and dissolved PHC concentrations were
      higher than during engineered in situ bioremediation. This suggests that
      biodegradation in the core zone was limited by the availability of oxidants. In
      lateral zones of the source area, however, gradually more oxidized conditions
      were reestablished again, suggesting that PHC availability increasingly limited
      biodegradation. The total DIC production rate in the aquifer decreased within 2
      years to about 25% of that during engineered in situ bioremediation and remained
      at that level. Stable carbon isotope analysis confirmed that the produced DIC
      mainly originated from PHC mineralization. The total rate of DIC and CH4
      production in the source area was more than 300 times larger than the rate of PHC
      elution. This indicates that biodegradation coupled to consumption of naturally
      occurring oxidants was an important process for removal of PHC which remained in
      the aquifer after terminating engineered measures.

PMID- 12487416
TI  - Towards a better understanding of tetrachloroethene entry pressure in the matrix
      of Permo-Triassic sandstones.
AB  - The pressure required for a chlorinated solvent to enter a geological medium can
      be calculated given knowledge of the characteristic pore size of the medium and
      the interfacial tension (IFT) and contact angle of the solvent-water-rock system.
      Using a centrifuge-based method, capillary pressure-saturation curves have been
      determined for 30 water-saturated samples of Permo-Triassic sandstones for the
      solvent tetrachloroethene (PCE). These curves have been successfully fitted using
      the van Genuchten function to determine PCE entry pressure for each of the
      sandstone samples. A plot of PCE entry pressures against average pore diameter
      shows a linear relationship in log-log space; however, observed values for PCE
      entry pressure are significantly lower than would be expected theoretically for a
      sandstone-PCE-water system. This may be explained either by a decrease in the IFT
      or an increase in the contact angle. The IFT may decrease during contact with
      sandstones due to hysteresis effects during imbibition and drainage of fluids,
      but this is unlikely to be sufficient to account for the low entry pressures
      observed. Therefore, it is inferred that the low observed PCE entry pressures are
      due to higher than expected PCE contact angles, and that the average pore-throat
      surface of the sandstones is more solvent wetting than would be expected. A weak
      acid extraction indicates the presence of calcite and dolomite in the sandstone
      cores, and a correlation is observed between carbonate content per unit porosity
      and a reduction in PCE entry pressure. It is suggested that these mineral phases
      are responsible for observed wettability changes and a conceptual model is
      proposed. One consequence of the lower observed entry pressures is that solvents
      are likely to penetrate deeper into the matrix of water-saturated sandstones than
      previously expected.

PMID- 12487417
TI  - Contaminant transport in dual-porosity media with dissolved organic matter and
      bacteria present as mobile colloids.
AB  - In riverbank filtration, contaminant transport is affected by colloidal particles
      such as dissolved organic matter (DOM) and bacterial particles. In addition, the
      subsurface heterogeneity influences the behavior of contaminant transport in
      riverbank filtration. A mathematical model is developed to describe the
      contaminant transport in dual-porosity media in the presence of DOM and bacteria
      as mobile colloids. In the model development, a porous medium is divided into the
      mobile and immobile regions to consider the presence of ineffective micropores in
      physically heterogeneous riverbanks. We assume that the contaminant transport in
      the mobile region is controlled by the advection and dispersion while the
      contaminant transport in the immobile region occurs due to the molecular
      diffusion. The contaminant transfer between the mobile and immobile regions takes
      place by diffusive mass transfer. The mobile region is conceptualized as a four
      phase system: two mobile colloidal phases, an aqueous phase, and a solid matrix.
      The complete set of governing equations is solved numerically with a fully
      implicit finite difference method. The model results show that in riverbank
      filtration, the contaminant can migrate further than expected due to the presence
      of DOM and bacteria. In addition, the contaminant mobility increases further in
      the presence of the immobile region in aquifers. A sensitivity analysis shows
      that in dual-porosity media, earlier breakthrough of the contaminant takes place
      as the volumetric fraction of the mobile region decreases. It is also
      demonstrated that as the contaminant mass transfer rate coefficient between the
      mobile and immobile regions increases, the contaminant concentration gradient
      between the two regions reverses at earlier pore volumes. The contaminant mass
      transfer coefficient between the mobile and immobile regions mainly controls the
      tailing effect of the contaminant breakthrough. The contaminant breakthrough
      curves are sensitive to changes in contaminant adsorption and desorption rate
      coefficients on DOM and bacteria. In situations where the contaminant is released
      in the presence of DOM and bacteria in dual-porosity media, the early
      breakthrough and tailing occur due to the colloidal facilitation and presence of
      immobile regions.

PMID- 12487418
TI  - Theory for reactive solute transport through clay membrane barriers.
AB  - The theoretical development for one-dimensional, coupled migration of solutes
      with different ionic mobilities through clay soils that behave as ion-restrictive
      membranes, referred to as clay membrane barriers (CMBs), is presented. The
      transport formulation is based on principles of irreversible thermodynamics and
      accounts explicitly for coupling effects of hyperfiltration (ultrafiltration) and
      chemico-osmotic counter-advection associated with clay membrane behavior in the
      absence of electrical current. Since, by definition, no solute can enter a
      "perfect" or "ideal" membrane, the concept of an implicit coupling effect, such
      that the effective salt-diffusion coefficient, Ds* approaches zero as the chemico
      osmotic efficiency coefficient, omega approaches unity is introduced. The
      theoretical development also illustrates that, even in the absence of membrane
      behavior, traditional advective-dispersive transport theory based on a constant
      value of Ds* for the solutes may not be appropriate for simulating transient
      transport in reactive (ion exchanging) systems. This potential limitation is
      illustrated through simulations for solute mass flux involving the migration of a
      binary salt solution (KCl) through a clay barrier with exchange sites saturated
      with a single exchangeable cation (e.g., Na+) that enters the pore solution upon
      ion exchange with the salt cation (K+).

PMID- 12487419
TI  - Magnesium and exercise.
AB  - Magnesium is an essential element that regulates membrane stability and
      neuromuscular, cardiovascular, immune, and hormonal functions and is a critical
      cofactor in many metabolic reactions. The Dietary Reference Intake for magnesium
      for adults is 310 to 420 mg/day. However, the intake of magnesium in humans is
      often suboptimal. Magnesium deficiency may lead to changes in gastrointestinal,
      cardiovascular, and neuromuscular function. Physical exercise may deplete
      magnesium, which, together with a marginal dietary magnesium intake, may impair
      energy metabolism efficiency and the capacity for physical work. Magnesium
      assessment has been a challenge because of the absence of an accurate and
      convenient assessment method. Recently, magnesium has been touted as an agent for
      increasing athletic performance. This article reviews the various studies that
      have been conducted to investigate the relationship of magnesium and exercise.

PMID- 12487420
TI  - Variables influencing food perception reviewed for consumer-oriented product
      development.
AB  - Consumer wishes have to be translated into product characteristics to implement
      consumer-oriented product development. Before this step can be made, insight in
      food-related behavior and perception of consumers is necessary to make the right,
      useful, and successful translation. Food choice behavior and consumers'
      perception are studied in many disciplines. Models of food behavior and
      preferences therefore were studied from a multidisciplinary perspective. Nearly
      all models structure the determinants related to the person, the food, and the
      environment. Consequently, the overview of models was used as a basis to
      structure the variables influencing food perception into a model for consumer
      oriented product development. To this new model, referred to as food perception
      model, other variables like time and place as part of consumption moment were
      added. These are important variables influencing consumers' perception, and
      therefore of increasing importance to consumer-oriented product development
      nowadays. In further research, the presented food perception model is used as a
      tool to implement successful consumer-oriented product development.

PMID- 12487421
TI  - Fat, moisture, and ethanol migration through chocolates and confectionary
      coatings.
AB  - The migration of fat, moisture, and ethanol is a common problem with chocolate
      coated confectionery products. Migration of one of these components into the
      coating leads to visual and sensory defects such as sugar or fat bloom, making
      the product unacceptable to the consumer. The migration rate depends on the
      structure and composition of the coating. The migration of each of these species
      can be slowed to a certain extent by proper tempering of the coating, because
      proper tempering will give a structure that resists migration. In the continuous
      lipid phase, these chemical species migrate mainly through the liquid portion.
      Thus, the migration rate depends on the amount of liquid oil present in the
      product. Migration can be delayed either by reducing the liquid fat content or by
      immobilizing the liquid phase. The actual mechanisms for the migration processes
      are speculative, and a more thorough understanding is necessary to better abate
      quality deterioration. Armed with this understanding, a manufacturer would know a
      priori the effect of changing the ingredient or process. A few methods for
      control have been suggested, but have found limited application. Mathematical
      models have been proposed to predict the migration behavior, but their
      application is hindered because of the simplified assumptions employed. There is
      a need for developing better models that combine mass transfer with the phase
      behavior to be able to accurately predict the migration process. This review
      discusses the current understanding of fat, moisture, and ethanol migration
      through chocolate coatings and also includes a brief description of the
      theoretical aspects governing migration.

PMID- 12487422
TI  - Food processing by high hydrostatic pressure.
AB  - The use of high hydrostatic pressures (HHP) for food processing is finding
      increased application within the food industry. One of the advantages of this
      technology is that because it does not use heat, sensory, and nutritional
      attributes of the product remain virtually unaffected, thus yielding products
      with better quality than those processed traditional methods. HHP have the
      ability to inactivate microorganisms as well as enzymes responsible for
      shortening the life of a product. In addition to lengthening the shelf-life of
      food products, HHP can modify functional properties of components such as
      proteins, which in turn can lead to the development of new products. Equipment
      for large-scale production of HHP processed products are commercially available
      nowadays. Guacamole, sliced ham, oysters, and fruit juices are some of the
      products currently available on the market. HHP technology is one of the most
      promising nonthermal processes.

PMID- 12487423
TI  - Rainforest endophytes and bioactive products.
AB  - An increase in the number of people in the world having health problems caused by
      certain cancers, drug-resistant bacteria, parasitic protozoans, and fungi has
      caused alarm. An intensive search for newer and more effective agents to deal
      with these problems is now underway. Endophytes are a potential source of novel
      chemistry and biology to assist in helping solve not only human health, but plant
      and animal health problems also. Endophytes reside in the tissues between living
      plant cells. The relationship that they establish with the plant varies from
      symbiotic to bordering on pathogenic. Of all of the world's plants, it seems that
      only a few grass species have had their complete complement of endophytes
      studied. As a result, the opportunity to find new and interesting endophytes
      among the myriad of plants is great. Sometimes extremely unusual and valuable
      organic substances are produced by these endophytes. These compounds may
      contribute to the host-microbe relationship. The initial step in dealing with
      endophytic microorganisms is their successful isolation from plant materials.
      Then, the isolation and characterization of bioactive substances from culture
      filtrates is done using bioassay guided fractionation and spectroscopic methods.
      Some of the more interesting compounds produced by endophytic microbes with which
      we have dealt are taxol, cryptocin, cryptocandin, jesterone, oocydin,
      isopestacin, the pseudomycins and ambuic acid. This review discusses an approach
      for bio-prospecting the rainforests, not only to harvest their endophytic
      microorganisms, but to eventually build a better understanding of the importance
      and value they have to humankind.

PMID- 12487424
TI  - A retrospective look at the cationic peanut peroxidase structure.
AB  - The cationic peanut peroxidase has been studied in detail, not only with regard
      to its peptide structure, but also to the sites and role of the three moieties
      linked to it. Peanut peroxidase lends itself well to a close examination as a
      potential example for other plant peroxidase studies. It was the first plant
      peroxidase for which a 3-D structure was derived from crystals, with the glycans
      intact. Subsequent analysis of peroxidases structures from other plants have not
      shown great differences to that of the peanut peroxidase. As the period of
      proteomics follows on the era of genomics, the study of glycans has been brought
      back into focus. With the potential use of peroxidase as a polymerization agent
      for industry, there are some aspects of the overall structure that should be kept
      in mind for successful use of this enzyme. A variety of techniques are now
      available to assay for these structures/moieties and their roles. Peanut
      peroxidase data are reviewed in that light, as well as defining some true terms
      for isozymes. Because a high return of the enzyme in a pure form has been
      obtained from cultured cells in suspension culture, a brief review of this is
      also offered.

PMID- 12487425
TI  - Production and mass transfer characteristics of non-Newtonian biopolymers for
      biomedical applications.
AB  - The market for microbial biopolymers is currently expanding to include several
      emerging biomedical applications. Specifically, these applications are drug
      delivery and wound healing. A fundamental understanding of the key fermentation
      parameters is necessary in order to optimize the production of these biopolymers.
      Considering that most microbial biopolymer systems exhibit non-Newtonian
      rheology, oxygen mass transfer can be an important parameter to optimize and
      control. In this article, we present a critical review of recent advances in
      rheological and mass transfer characteristics of selected biopolymers of
      commercial interest in biomedical applications.

PMID- 12487426
TI  - Microbial beta-glucosidases: cloning, properties, and applications.
AB  - Beta-glucosidases constitute a major group among glycosylhydrolase enzymes. Out
      of the 82 families classified under glycosylhydrolase category, these belong to
      family 1 and family 3 and catalyze the selective cleavage of glucosidic bonds.
      This function is pivotal in many crucial biological pathways, such as degradation
      of structural and storage polysaccharides, cellular signaling, oncogenesis, host
      pathogen interactions, as well as in a number of biotechnological applications.
      In recent years, interest in these enzymes has gained momentum owing to their
      biosynthetic abilities. The enzymes exhibit utility in syntheses of diverse
      oligosaccharides, glycoconjugates, alkyl- and aminoglucosides. Attempts are being
      made to understand the structure-function relationship of these versatile
      biocatalysts. Earlier reviews described the sources and properties of microbial
      beta-glucosidases, yeast beta-glucosidases, thermostable fungal beta-glucosidase,
      and the physiological functions, characteristics, and catalytic action of native
      beta-glucosidases from various plant, animal, and microbial sources. Recent
      efforts have been directed towards molecular cloning, sequencing, mutagenesis,
      and crystallography of the enzymes. The aim of the present article is to describe
      the sources and properties of recombinant beta-glucosidases, their classification
      schemes based on similarity at the structural and molecular levels, elucidation
      of structure-function relationships, directed evolution of existing enzymes
      toward enhanced thermostability, substrate range, biosynthetic properties, and
      applications.

PMID- 12487427
TI  - Investigation of bradykinin metabolism in human and rat plasma in the presence of
      the dual ACE/NEP inhibitors GW660511X and omapatrilat.
AB  - Several studies have suggested that the accumulation of bradykinin, or that of
      one its metabolites BK1-8, is involved in the occurrence of side effects such as
      AE associated with the use of various ACEi. In this work a novel approach
      combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in
      human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the
      presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently
      under clinical trial. In human plasma the BrBK half-life values in the absence or
      in the presence of GW660511X (3.8 microM) or omapatrilat (32 nM) were 38.7 +/-
      2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into
      BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the
      levels of these resultant metabolites were different. Unlike GW660511X,
      omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better
      ACE inhibition effect over GW660511X as no NEP activity was found. In addition
      the production of BrBK1-8 was enhanced in the presence of these inhibitors with a
      greater accumulation being observed with omapatrilat. The production of Br-Phe5
      was reduced with GW660511X while no significant change was observed with
      omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in
      the absence or in the presence of GW660511X (530 nM) or omapatrilat (50 nM) were
      9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was
      degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and
      BrBK2-8 metabolites not found in human plasma. GW660511X and omapatrilat reduced
      the production of BrBK1-5 and BrBK1-7 with more effect being observed with
      omapatrilat. GW660511X and omapatrilat increased the production of both BrBK1-8
      and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the
      potency of GW660511X in comparison with omapatrilat is more than 100-fold lower
      in human, but less than 10-fold lower in rat plasma, suggesting that rat may not
      be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation
      to effects in humans.

PMID- 12487428
TI  - Post-synthesis incorporation of a lipidic side chain into a peptide on solid
      support.
AB  - A new strategy for the synthesis of lipopeptides has been developed. Using
      Weinreb (N-methoxy, N-methyl) amide as an aldehyde function precursor on the side
      chains of Asp or Glu residues, this new strategy avoids the synthesis of a
      lipidic amino acid residue before its incorporation in the peptide sequence. The
      aldehyde generated on the solid support can react with ylides leading to
      unsaturated or saturated side chains or with various nucleophiles to yield non
      coded amino acid residues incorporated into the sequence.

PMID- 12487429
TI  - SPPS of protected peptidyl aminoalkyl amides.
AB  - Monophthaloyl diamines derived from naturally occurring amino acids were attached
      through their free amino functions to resins of the trityl type. The phthaloyl
      groups were removed by hydrazinolysis, and peptide chains were assembled using
      Fmoc/tBu-amino acids on the liberated amino functions. The peptidyl aminoalkyl
      amides obtained were cleaved from the resins by mild acidolysis, with the tBu
      side chain protection remaining intact.

PMID- 12487430
TI  - Synthesis of complex phosphopeptides as mimics of p53 functional domains.
AB  - A complete set of mono-, di- and triphosphorylated peptides comprising amino
      acids 10-27, the Mdm2 and p300 binding site(s) of p53, with and without a
      fluorescein label at the N-terminus, was synthesized by step-by-step solid phase
      synthesis. Fluorescence polarization analysis revealed that phosphorylation at
      Thr18 decreased binding to recombinant Mdm2 protein compared with the
      unphosphorylated and the two other single phosphorylated analogues. Unlabelled
      multiply phosphorylated peptides corresponding to this amino-terminal
      transactivation domain proved to be powerful tools in analysing the phosphate
      specificity of existing anti-p53 monoclonal and polyclonal antibodies using
      direct ELISA. The tetramerization domain of human p53 protein was modelled with a
      53 residue-long unlabelled unphosphorylated and Ser315-phosphorylated peptide
      pair. CD analysis showed similar alpha-helical structures for both peptides and
      no major difference in the secondary structure could be observed upon
      phosphorylation. Size-exclusion HPLC indicated that these synthetic
      oligomerization domain mimics underwent a pH-dependent tetramerization process,
      but the presence of a phosphate group at Ser315 did not modify the oligomeric
      state of the 308-360 p53 fragments. Nevertheless, the fluorescein-labelled Ser315
      phosphorylated peptide bound to the downstream signalling ligand DNA
      topoisomerase I protein with slightly higher affinity than did the
      unphosphorylated analogue.

PMID- 12487431
TI  - NMR studies on Ni(II) induced cyclization of a histidine-tagged peptide.
AB  - A linear decapeptide, HGASYQDLGH, was synthesized and used as a model to evaluate
      the effect of nickel addition upon non-covalent backbone cyclization. The NMR
      data, obtained for the peptide in the presence of the metal ion, support the
      existence of predominant folded structures in solution, where the two His
      residues are maintained close to each other. These results suggest that insertion
      of even a single His residue at each peptide terminus can be used efficiently to
      reduce peptide flexibility without any backbone modification.

PMID- 12487432
TI  - Critical care outreach services--do they make a difference?

PMID- 12487433
TI  - Nurse led weaning from ventilatory and respiratory support.
AB  - Weaning from mechanical ventilation is challenging and requires expert knowledge
      and skill. Weaning can be defined as the process of assisting patients to breathe
      spontaneously without mechanical ventilatory support [Am. J. Crit. Care 7 (1998)
      1491. Weaning from mechanical ventilation is not about the method used but more
      about how that method is employed [Crit. Care Med. 27 (1999) 2331]. A review of
      the literature revealed that there was no one method of weaning that was
      superior, furthermore evidence suggests that the use of a protocol was more
      effective in reducing the duration of weaning [Dimensions Crit. Care Nurs. 2
      (1991) 398; Respir. Care Clin. North Am. 2 (1996) 105; AACN Clin. Issues Crit.
      Care 7 (1996) 550; Crit. Care Med. 25 (1997) 567; Arch. Surg. 133 (1998) 483;
      Chest 118 (2000) 459]. A retrospective audit of all patients who were ventilated
      for 7 or more days in one intensive care over a 1-year period, revealed 94 (of
      500) patients were ventilated for an average of 16.8 days. There were no weaning
      guidelines or protocols in place at this time and weaning from mechanical
      ventilation was inconsistent and uncoordinated. A process mapping exercise
      revealed there was a delay in initiating the decision to wean of 96 h. Weaning
      protocols were put in place and nurse led weaning was initiated and supported by
      the nurse consultant. Monthly statistics were collated and this revealed the
      average ventilator time had reduced. Protocol led weaning has been effective in
      reducing the duration of ventilation. Problems still occur in initiating the
      decision to wean early. An audit of patient notes has revealed many reasons for
      this. These reasons include, over sedation, the use of morphine and midazolam,
      particularly in the elderly and those with renal impairment, is delaying weaning.
      Other reasons include, delay in tracheostomy placement. Staff are not initiating
      weaning guidelines early this may be due to lack of knowledge, lack of support or
      failure of the guidelines. Mechanisms are in place to support nurses at the
      bedside.

PMID- 12487434
TI  - From ward-based critical care to educational curriculum 2: a focussed
      ethnographic case study.
AB  - The earlier published literature review (Part 1) identified the limits of our
      current understanding of the context of ward-based critical care nursing.
      Critical care curriculum for acute ward nurses, which will have to develop as
      part of meeting the mandates for 'training' outlined in Comprehensive Critical
      Care [Comprehensive Critical Care: a Review of Adult Critical Care Services
      (2000) Department of Health], will benefit from greater understanding of the
      culture and context of ward-based critical care nursing. In this, Part 2, the
      methods and findings of a focussed ethnographic case study are presented. The
      study explored, in depth, the culture and context of ward-based critical care in
      one acute surgical ward. Seven nurses were interviewed about their experiences of
      caring for critically ill ward patients. The data were analysed with a view to
      exploring what knowledge and skills were 'compatible' with the nurses' perceived
      role and the 'practical applicability' and 'relative advantage' of such knowledge
      for these practitioners. The context of ward care was found to be busy and
      contradictory for the nurses. The concepts central to this study;
      'compatibility', 'practical applicability' and 'relative advantage'
      [Communication of Innovations (1971) The Free Press] were found to be complex
      concepts when studied in relation to real life clinical practice.

PMID- 12487435
TI  - Evaluation of a sedation protocol for intubated critically ill children.
AB  - The aim of this study was to conduct an evaluation of a sedation protocol that
      transfers some decision-making authority for analgesia and sedation, within
      clearly defined parameters, to nurses in a pediatric intensive care unit (PICU).
      The sedation protocol used in this study was appropriate for any age group. The
      clinical course of 10 patients admitted to the PICU during a 5-month interval who
      were on the sedation protocol during their stay was examined using retrospective
      chart review. Time intervals when patients were on the protocol were compared
      with clinically comparable time intervals, in terms of acuity, when the same
      patient received conventional management. Data were collected on the number of
      days a child was ventilated, the number of days in the PICU, the number of days
      hospitalized and severity of illness. Additionally, data were collected on the
      amounts of sedation and analgesia required and the incidence of under-sedation.
      Physician and nurse satisfaction with the sedation protocol was examined using a
      self-report survey. The findings of this study indicate that the delegation of
      decision-making authority for analgesia and sedation to PICU nurses can provide
      effective and timely management of patient comfort, without an increase in
      morbidity, in a manner that is more satisfying for physicians and nurses.

PMID- 12487436
TI  - Management of severe tongue trauma with custom made oral appliance.

PMID- 12487437
TI  - Binding of free bile acids by cells of yogurt starter culture bacteria.
AB  - Several strains of Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus
      thermophilus, which produced exocellular polysaccharides (EPS), varied in the
      amount produced. The streptococci tended to produce the most EPS per milliliter
      of culture; however, when compared on the basis of amounts per 10(7) cfu, the
      lactobacilli produced the most. Lactobacillus delbrueckii ssp. bulgaricus strains
      Lb-18 and Lb-10442 and S. thermophilus St-143 produced significantly larger
      amounts per 107 cfu than did other strains tested. These three cultures plus two
      strains of the streptococci that produced the greatest amounts of EPS per ml of
      culture were tested for the ability to bind bile acids from laboratory media. The
      two cultures of L. delbrueckii ssp. bulgaricus (Lb-18 and Lb-10442) bound
      significantly higher amounts of cholic acid than did the three strains of
      streptococci. These two cultures of lactobacilli bound up to 15.3% of the cholic
      acid present in laboratory media, up to 452 microg/mg of EPS and 2.9 microg/10(7)
      cfu. None of the cultures tested in this study were able to bind the conjugated
      bile acid, glycocholic acid.

PMID- 12487438
TI  - Casein interactions studied by the surface plasmon resonance technique.
AB  - Surface plasmon resonance technique was investigated for the first time to study
      the apparent hydrophobicity and association properties of the major bovine
      caseins: alpha(s)-(alpha(s1)- and alpha(s2)-caseins in a 4:1 proportion), beta-,
      and kappa-caseins. The apparent hydrophobicities of the caseins were evaluated by
      a new method based on the binding level of casein on a hydrophobic sensor chip,
      and kinetic and equilibrium affinity constants were determined for the following
      casein interactions: alpha(s)/alpha(s), alpha(s)/beta, alpha(s)/kappa, beta/beta,
      and beta/kappa, using a sensor chip modified with covalent immobilized caseins.
      The study by surface plasmon resonance technology of these casein interactions
      under different conditions (pH, ionic strength, calcium concentration, chemical
      modification) demonstrated that, at neutral pH, electrostatic repulsive forces
      play an important role since an increase in ionic strength of the medium resulted
      in a stronger interaction. When charge repulsions were reduced by either
      acidification, increase in ionic strength, or dephosphorylation, casein
      interactions were reinforced, presumably due to weak attractive forces. Moreover,
      in this molecular model, we showed that addition of calcium greatly increased the
      binding response between the most phosphorylated caseins and that the added
      calcium (2 mM) participated directly in the formation of bridges between the
      phosphate groups of the casein molecules.

PMID- 12487439
TI  - Effect of biopolymers on structure and ice recrystallization in dynamically
      frozen ice cream model systems.
AB  - Ice crystal growth and microstructure of sugarsolutions prepared with stabilizers
      (carboxymethyl cellulose [CMC], xanthan gum, locust bean gum [LBG], and gelatin)
      with or without milk solids-nonfat (MSNF) after freezing in a scraped surface
      heat exchanger and temperature cycling (5 cycles from -6 degrees C to -20 degrees
      C) were studied. Ice crystal growth was calculated from brightfield microscopic
      images acquired from samples before and after cycling. Freeze-substitution and
      low-temperature embedding (LR-Gold resin) were sample preparation techniques
      utilized for structure analyses by light microscopy and transmission electron
      microscopy. Differential staining for carbohydrates and proteins allowed the
      identification of stabilizer gel-like structures in LBG, gelatin, and
      gelatin/MSNF solutions. In the absence of milk proteins, xanthan and LBG were the
      most effective at retarding recrystallization, while in their presence, only
      xanthan had an effect. Cryo-gelation of the LBG was observed but is not the only
      mechanism of stabilizer action. Thermodynamic incompatibility between biopolymers
      was observed to promote localized high concentrations of milk proteins located at
      the ice crystal interface, probably exerting a water-holding action that
      significantly enhanced the stabilizer effect. Qualitatively, solution
      heterogeneity (phase separation) was directly proportional to ice crystal growth
      inhibition. It is suggested that water-holding by stabilizer and proteins, and in
      some cases steric hindrance induced by a stabilizer gel-like network, caused a
      reduction in the kinetics of the ice recrystallization phenomena and promoted
      mechanisms of melt-regrow instead of melt-diffuse-grow recrystallization, thus
      resulting in the preservation of the ice crystal size and in a small span of the
      ice crystal size distribution.

PMID- 12487440
TI  - Immunomodulating effects of peptidic fractions issued from milk fermented with
      Lactobacillus helveticus.
AB  - The effect of peptides released during the fermentation of milk on the humoral
      immune system and on fibrosarcoma growth was studied. Lactobacillus helveticus
      was able to release peptidic compounds during milk fermentation due to its high
      proteolytic activity, as was shown by the degree of proteolysis and size
      exclusion HPLC elution profiles. Three fractions of these compounds were
      separated and fed to mice during different periods (2, 5, and 7 d). The humoral
      immune response was assessed by following the number of IgA-secreting cells, and
      the antitumor activity was monitored by studying the regression of subcutaneously
      implanted fibrosarcomas. Feeding during 2 and 7 d with the medium-sized fraction
      (Fraction II) significantly increased the IgA-producing cells in the intestines,
      whereas feeding with the large compound fraction (Fraction I) during 5 d and the
      small compound fraction (Fraction III) during all three feeding periods provided
      similar increases. A double dose of Fraction II showed the highest IgA-producing
      cell count. The increase by Fraction III was shown to be caused by the presence
      of L-Tryptophan. Fraction II significantly decreased the size of fibrosarcoma
      when previously fed during 7 d, and feeding with Fraction I during 5 d decreased
      significantly its size after 35 d of growth. Although the mechanisms by which
      lactic acid bacteria enhance the immune system are not clear, this study clearly
      shows that bioactive compounds released in fermented milks contribute to the
      immunoenhancing and antitumor properties of these products. The release of
      bioactive peptides by lactic acid bacteria can have important implications on the
      modulation of the cellular immune response.

PMID- 12487441
TI  - Torsion gelometry of cheese.
AB  - Torsion gelometry, a fundamental rheological test in which specimens are twisted
      until they fracture, was applied to several different cheese varieties to
      determine its suitability for measuring their textural properties. Fresh and aged
      Brick, Cheddar, Colby, Gouda, Havarti, Mozzarella, and Romano cheeses were
      subjected to torsion analysis, and the results were compared with those from
      small amplitude oscillatory shear (SAOS) tests and texture profile analysis
      (TPA). Strong relationships (correlation coefficients > 0.8) were found between
      torsion shear stress and TPA hardness, and between torsion shear strain and TPA
      cohesiveness. SAOS, which measures rheological properties of intact samples, did
      not correlate well with torsion or TPA. A map showing trends during aging toward
      brittle, mushy, rubbery, and tough texture was drawn using the torsion data. The
      findings show that torsion gelometry provides fundamental rheological data on
      cheese at the fracture point. The information can be used to compare textural
      qualities of cheese samples as they are being cut.

PMID- 12487442
TI  - Proteolytic specificity of Lactobacillus delbrueckli subsp. bulgaricus influences
      functional properties of mozzarella cheese.
AB  - Low-moisture part-skim Mozzarella cheeses were manufactured from 2% fat milk and
      aged for 21 d. Treatments included cheeses made with one of three different
      strains of Lactobacillus delbrueckii ssp. bulgaricus in combination with a single
      strain of Streptococcus thermophilus. A fourth, control treatment consisted of
      cheeses made with only S. thermophilus. Although total proteolytic ability of
      these strains, as indicated by the o-phthaldialdehyde analysis, was similar in
      each of the three strains of L. bulgaricus, these strains exhibited different
      proteolytic specificities toward the peptide, alpha(s1)-CN (f 1-23). On the basis
      of their alpha(s1)-CN (f 1-23) cleavage patterns and a previously described
      classification, these strains were assigned to the groups I, III, and V. The
      objective of this study was to investigate the influence of lactobacilli
      proteolytic systems, based on specificity toward alpha(s1)-CN (f 1-23), on
      functionality of part-skim Mozzarella cheese. Moisture, fat, protein, salt-in
      moisture, and moisture in nonfat substances content of cheeses made with groups
      I, III, and V strain were similar. Control cheese had a lower moisture content
      than did other treatments. Significant differences were observed in functional
      properties between cheeses manufactured using groups III and V strains. Cheeses
      made with groups I and III strains were similar in their meltability, hardness,
      cohesiveness, melt strength, and stretch quality. Meltability and cohesiveness
      increased with age, while melt strength and stretch quality decreased with age
      for all cheeses. Additionally, HPLC showed that total peak areas of water-soluble
      peptides derived from cleavage of alpha(s1)-CN (f 1-23) by different strains of
      lactobacilli could be highly correlated to meltability and stretch
      characteristics of cheeses made with those strains.

PMID- 12487443
TI  - Improvement of sensory quality of lowfat kefalograviera-type cheese by using
      commercial special starter cultures.
AB  - Two commercially available special starter culture systems, Alp DIP and a mixture
      of Alp DIP D and Joghurt V1, were compared with one commercial regular starter
      culture, CH-1, for their effects on the compositional, sensory and textural
      characteristics of lowfat (9.5%) high moisture (49.6%) Kefalograviera-type cheese
      during aging. A full-fat control Kefalograviera cheese (30.8% fat, 37.8%
      moisture) was also made with the regular starter culture. The results indicated
      that the type of starter did not affect the composition (moisture, fat, protein,
      salt and pH) of the lowfat cheese. Sensory analysis showed that the lowfat
      cheeses made with the special cultures received greater body and texture scores
      and significantly higher flavor scores than the lowfat control cheese after aging
      for 90 and 180 d. Moreover, the former cheeses received body and texture and
      flavor scores not significantly different from those of the full-fat cheese.
      Texture profile analysis by Instron showed that there were no significant
      differences in the textural characteristics (force and compression to fracture,
      cohesiveness, springiness, gumminess and chewiness) between lowfat cheeses made
      with the special cultures and that made with the regular starter, except for
      hardness which was significantly lower in the former cheeses.

PMID- 12487444
TI  - A nonlinear programming optimization model to maximize net revenue in cheese
      manufacture.
AB  - A nonlinear programming optimization model was developed to maximize net revenue
      in cheese manufacture and is described in this paper. The model identifies the
      optimal mix of milk resources together with the types of cheeses and co-products
      that maximize net revenue. It works in Excel while it takes the data specified by
      the user from a user-friendly interface created in Access. The user can specify
      any number of resources, cheese types, and co-products. To demonstrate the
      capabilities of the model, we determined the impact of variation in milk price
      and composition in the period 1998 to 2000 on the optimal mix of resources and
      optimal type of co-product for Cheddar and low-moisture, part-skim Mozzarella. It
      was also desired to determine the impact of variation in protein content of
      nonfat dry milk (NDM) on net revenue, and examine the effect of reconstitution of
      NDM with water versus milk on net revenue. The optimal mix of resources and the
      net revenue markedly varied as milk resource prices and composition varied. The
      net revenue for Mozzarella was much higher than for Cheddar when the price of
      cream was high. Cheese plants that did not optimize the use of resources in
      response to variations in prices and composition missed a significant profit
      opportunity. Whey powder was more profitable than 34% whey protein concentrate
      and lactose in most months. The use of high-protein NDM led to an appreciable
      increase in net revenue. When the value of the nonfat portion of raw milk was
      high, reconstitution of NDM with water rather than milk markedly raised net
      revenue.

PMID- 12487445
TI  - Factors affecting growth and pigmentation of Penicillium caseifulvum.
AB  - Color formation, metabolite production and growth of Penicillium caseifulvum were
      studied in order to elucidate factors contributing to yellow discoloration of
      Blue Cheese caused by the mold. A screening experiment was set up to study the
      effect of pH, concentration of salt (NaCl), P, K, N, S, Mg and the trace metals
      Fe, Cu, Zn, Mn on yellow color formation, metabolite production and mold growth.
      Multivariate statistical analysis showed that the most important factor affecting
      yellow color formation was pH. The most pronounced formation of yellow color,
      supported by highest amount of colored metabolites, appeared at low pH (pH 4).
      Mold growth was not correlated to the yellow color formation. Salt concentration
      was the most important factor affecting mold growth and length of lag phase.
      Production of secondary metabolites was strongly influenced by both pH and salt
      concentration. The screening results were used to divide the metabolites into the
      following three groups: 1) correlated to growth, 2) correlated to color
      formation, and 3) formed at high pH. Subsequently, a full factorial experiment
      with factors P, Mg and Cu, showed that low P concentrations (2,000 mg/kg) induced
      yellow color formation. Among the factors contributing to yellow color formation,
      pH and salt concentration are easy to control for the cheesemaker, while the
      third factor, P-concentration, is not. Naturally occurring variations in the P
      concentration in milk delivered to Blue Cheese plants, could be responsible for
      the yellow discoloration phenomenon observed in the dairy industry.

PMID- 12487446
TI  - Variation of the milk antibody response to paratuberculosis in naturally infected
      dairy cows.
AB  - A longitudinal study was performed to determine the course of the milk antibody
      response in cows presumably infected with Mycobacterium avium subsp.
      paratuberculosis. Milk samples were collected repeatedly (1 to 10 times) from all
      lactating cows in seven Danish dairy herds. A total of 4,289 observations from
      812 cows was analyzed after exclusion of samples collected after 280 days in milk
      (DIM). The level of antibodies in the milk samples was assessed using an indirect
      ELISA. A piece-wise linear random coefficient regression model was specified. The
      model controlled for the effect of herd, breed, laboratory effects, and age at
      first calving to estimate parity-specific antibody responses in relation to DIM.
      Separate antibody profiles were estimated for fecal culture-positive and fecal
      culture-negative cows. The resulting population average models showed higher
      antibody levels for fecal culture-positive cows and higher antibody levels with
      increasing parity. On average, the antibody response was high at the beginning
      and end of lactation. However, evaluating the cows individually indicated that
      most cows actually had quite stable ELISA levels throughout lactation, with some
      cows having higher levels than others. Thus, two criteria seem applicable to
      assess whether a cow is infected: stability and ELISA level. The random
      coefficients for each cow were highly significant. Thus, the study suggests that
      all cows can be classified into one of the four categories by combining the cow
      level ELISA characteristics "stability" and "level" as an aid in the diagnosis
      ofparatuberculosis and thereby substantially increasing the sensitivity of the
      ELISA.

PMID- 12487447
TI  - Fertilization and early embryonic development in heifers and lactating cows in
      summer and lactating and dry cows in winter.
AB  - Two experiments in two seasons evaluated fertilization rate and embryonic
      development in dairy cattle. Experiment 1 (summer) compared lactating Holstein
      cows (n = 27; 97.3 +/- 4.1 d postpartum [dppl; 40.0 +/- 1.5 kg milk/d) to
      nulliparous heifers (n = 28; 11 to 17 mo old). Experiment 2 (winter) compared
      lactating cows (n = 27; 46.4 +/- 1.6 dpp; 45.9 +/- 1.4 kg milk/d) to dry cows (n
      = 26). Inseminations based on estrus included combined semen from four high
      fertility bulls. Embryos and oocytes recovered 5 d after ovulation were evaluated
      for fertilization, embryo quality (1 = excellent to 5 = degenerate),
      nuclei/embryo, and accessory sperm. In experiment 1, 21 embryos and 17
      unfertilized oocytes (UFO) were recovered from lactating cows versus 32 embryos
      and no UFO from heifers (55% vs. 100% fertilization). Embryos from lactating cows
      had inferior quality scores (3.8 +/- 0.4 vs. 2.2 +/- 0.3), fewer nuclei/embryo
      (19.3 +/- 3.7 vs. 36.8 +/- 3.0) but more accessory sperm (37.3 +/- 5.8 vs. 22.4
      +/- 5.5/embryo) than embryos from heifers. Sperm were attached to 80% of UFO
      (17.8 +/- 12.1 sperm/UFO). In experiment 2, lactating cows yielded 36 embryos and
      5 UFO versus 34 embryos and 4 UFO from dry cows (87.8 vs. 89.5% fertilization).
      Embryo quality from lactating cows was inferior to dry cows (3.1 +/- 0.3 vs. 2.2
      +/- 0.3), but embryos had similar numbers of nuclei (27.2 +/- 2.7 vs. 30.6 +/-
      2.1) and accessory sperm (42.0 +/- 9.4 vs. 36.5 +/- 6.3). From 53% of the
      flushings from lactating cows and 28% from dry cows, only nonviable embryos were
      collected. Thus, embryos of lactating dairy cows were detectably inferior to
      embryos from nonlactating females as early as 5 d after ovulation, with a
      surprisingly high percentage of nonviable embryos. In addition, fertilization
      rate was reduced only in summer, apparently due to an effect of heat stress on
      the oocyte.

PMID- 12487448
TI  - Ovarian structures and circulating steroids in heifers and lactating cows in
      summer and lactating and dry cows in winter.
AB  - Two experiments compared follicular and luteal development and circulating
      steroid concentrations from induced luteolysis to ovulation in lactating Holstein
      cows (n = 27; 40.0 +/- 1.5 kg milk/day) vs. nulliparous heifers (n = 28; 11 to 17
      mo-old) during summer (Experiment 1), and in lactating (n = 27; 45.9 +/- 1.4 kg
      milk/d) vs. dry cows (n = 26) during winter (experiment 2). All females received
      PGF2,, 6 d after ovulation and were monitored until next ovulation by daily
      ultrasound and assay of serum progesterone (P4) and estradiol (E2). Every female
      was used two or three times. In Experiment 1, lactating cows had high incidence
      of multiple ovulation (63.5%) compared with heifers (1.3%). Among single
      ovulators, there was no difference in maximal size of ovulatory follicles between
      lactating cows and heifers (15.8 vs. 16.5 mm, respectively). However, lactating
      cows had lower peak serum E2 (8.6 vs. 12.1 pg/ml), took longer to ovulate after
      luteolysis (4.6 vs. 3.8 d), developed more luteal tissue volume (7,293.6 vs.
      5,515.2 mm3), and had lower serum P4 on d 6 after ovulation (2.0 vs. 3.0 ng/ml)
      than heifers (data included multiple ovulators). In experiment 2, multiple
      ovulations were similar between lactating and dry cows (17.9 vs. 17.2%,
      respectively). Peak serum E2 was also similar between lactating and dry cows (7.6
      vs. 8.5 pg/ml) although lactating cows had larger ovulatory follicles (18.6 vs.
      16.2 +/- 0.4 mm). Lactating cows took longer to ovulate (4.8 vs. 4.2 d),
      developed more luteal tissue (7,599 vs. 5,139 +/- 468 mm3), but had similar serum
      P4 (2.2 vs. 1.9 ng/ ml) compared with dry cows. Therefore, lactating cows had
      similar or lower circulating steroid concentrations than dry cows or heifers,
      respectively, despite having larger ovarian structures.

PMID- 12487449
TI  - Effects of whole cottonseed diet and recombinant bovine somatotropin on ovarian
      follicles in lactating dairy cows.
AB  - The effects of whole cottonseed (WCS) in the diet and the administration of
      bovine somatotropin (bST) on ovarian follicular dynamics and plasma progesterone
      (P4) concentrations were examined in cows during a period of synchronized
      follicular growth. Lactating Holstein cows (n = 28) were randomly assigned to
      treatments in a 2 x 2 factorial arrangement. Diets consisted of WCS (15% of dry
      matter) or no WCS, and bST at a dose of 0 or 208 mg/14 d. Dietary treatments
      began within 24 h of calving and bST treatments began within 7 d postpartum. Cows
      received GnRH at 65 +/- 3 d postpartum (d 0), PGF2alpha, (d 7), a second dose of
      GnRH (d 9), and were inseminated 16 h later (d 10). Ovarian changes were
      monitored daily by ultrasonography from d 0 to 9. On d 9,93% of cows had a
      preovulatory follicle and 86% ovulated. For Class 2 (6 to 9 mm) follicles, a diet
      x bST interaction was detected, with bST stimulating Class 2 follicles in cows
      fed WCS, but not in cows on the control diet. Neither diet nor bST affected
      numbers of Class 1 (2 to 5 mm) or Class 3 (> or = 10 mm) follicles or sizes of
      the subordinate and dominant follicles. During the luteal phase of the cycle,
      lactating cows fed WCS tended to have elevated concentrations of plasma P4,
      whereas bST was without effect. Plasma concentrations of high-density lipoprotein
      cholesterol were increased in cows fed WCS. Number and diameter of corpora lutea
      did not differ among treatments.

PMID- 12487450
TI  - High feed intake increases liver blood flow and metabolism of progesterone and
      estradiol-17beta in dairy cattle.
AB  - Increased liver blood flow (LBF) resulting from elevated feed intake in lactating
      dairy cows may increase steroid metabolism. Continuous infusion of
      bromosulphthalein (BSP; specifically metabolized in liver) was used to measure
      LBF. Similarly, progesterone (P4) and estradiol-17beta (E2) were administered by
      continuous infusion. Circulating concentrations at steady state were used to
      calculate the metabolic clearance rate (MCR) of BSP, P4, and E2. Experiment 1:
      Variation in LBF was determined in thee nonlactating and four lactating cows over
      3 d at 3 to 5 h after feeding. Coefficients of variation ranged from 14 to 31%
      among cows within day and from 4 to 8% within cows across days. Experiment 2: Six
      nonlactating cows were used in a 3 x 3 Latin-square design with three feed
      regimens: no feed, 0.5 maintenance diet (M), and 1.5 M. Experiment 3: Eight
      lactating cows were used in a 4 x 4 Latin-square design with four feed regimens:
      no feed, 0.5 M, 1.5 M, and 2.2 M. In experiments 2 and 3, LBF and MCR of P4
      increased immediately after feed consumption and increases persisted longer at
      higher intakes. The LBF reached a maximum at 2 h after feeding and MCR of P4
      reached maximum at 3 h after feeding with a positive correlation (r = 0.92)
      between LBF and MCR for P4. Experiment 4: A crossover design was used to
      determine MCR of E2 in unfed or full-fed lactating dairy cows. The MCR of E2
      increased immediately after feeding and stayed elevated throughout the 4.5-h
      infusion period. Thus, LBF and steroid metabolism were acutely elevated by feed
      consumption in lactating and nonlactating cows. Higher rates of LBF and steroid
      metabolism in lactating than in nonlactating cows may indicate chronic effects of
      higher feed intakes as well.

PMID- 12487451
TI  - Effect of electric and magnetic fields (60 Hz) on production, and levels of
      growth hormone and insulin-like growth factor 1, in lactating, pregnant cows
      subjected to short days.
AB  - Electric and magnetic fields (EMF) are generated by the transmission of
      electricity through high tension lines traversing rural areas. Previous studies
      showed increased dry matter intake (DMI) and fat corrected milk in dairy cows
      exposed to EMF. Because EMF exposure has been shown to suppress pineal release of
      melatonin in some species, it was hypothesized that EMF effects resemble those of
      exposure to long days. Previous studies have shown that DMI and milk production
      increase in dairy cattle in response to long day photoperiods, and this has been
      observed in association with increased circulating insulin-like growth factor 1
      (IGF-1), but not growth hormone (GH). The hypothesis that EMF act by modifying
      the response to photoperiod was tested by subjecting dairy cows to controlled EMF
      exposure while keeping them under short-day conditions. Sixteen lactating,
      pregnant Holstein cows were exposed to a vertical electric field of 10 kV/m and a
      horizontal magnetic field of 30 microT in a crossover design with treatment
      switchback. Two groups of eight cows each were exposed to EMF for 16 h/d in
      either oftwo sequences. Each sequence consisted of three consecutive 28-d
      periods. All animals were maintained under short day conditions (8 h light, 16 h
      dark) during the trial. DMI and plasma IGF-1 were increased (P < 0.01) during EMF
      exposure (17.03 vs.16.04 kg/d, SE = 0.4; 137 +/- 6 ng/ml vs 126 +/- 6,
      respectively). The mean GH concentration was not affected, but a treatment x hour
      interaction was detected, with GH lower for the EMF exposed animals during the
      first 16 h of the sampling period, and higher for the last 8 h. Overall, the
      yield of milk or its components was not affected by EMF exposure, but milk yield
      was significantly higher for the exposed animals during wk 4 of treatment.

PMID- 12487452
TI  - Indicators of acute pain and fly avoidance behaviors in Holstein calves following
      tail-docking.
AB  - Previous work showed that the banding process of docking minimally affected
      mature cows' behavior and physiology, but cutting off the necrotic tail increased
      haptoglobin. Additionally the docked cows had more flies on the rear legs and
      exhibited more fly avoidance behaviors. Because many producers dock young calves
      while they are in hutches where fly problems are more pronounced, we investigated
      changes in behavior and physiology of young calves following docking by banding.
      Twenty calves (3 to 5 wk of age) were assigned to a docked or control group, at
      each of two locations (Indiana and Wisconsin). After applying a band to dock the
      tail, calves were tested every 15 min for sensitivity to heat below the band at
      the Indiana location. Calf behavior was recorded for 2 h postbanding and analyzed
      continuously for that period. After 3 wk, tails were removed and then 1 wk later,
      fly counts and fly avoidance behaviors were observed at both locations. Tails
      were sensitive to heat below the banding site, for 60 to 120 min postbanding
      (mean 87 min). Banded calves were more active than control calves during the 2 h
      following banding. Percentage of time spent lying was greater for control calves,
      and the percentage of time spent walking was greater for docked than control
      calves. More importantly, movements of the head to touch the tail were increased
      for banded calves (eight-fold more movements). Fly avoidance behaviors directed
      toward the rear of the calf were evident at noon or in the afternoon. Ear
      twitches were more frequent for the docked calves and less frequent in the
      morning for all calves. Licking was more frequent for the docked calves at 1200
      and 1600 h. Tail swings were most frequent at 1200 and more frequent for control
      calves. Two acute phase proteins, haptoglobin and alpha1 acid-glycoprotein, were
      not different at any time. In this study, calves that were banded at 3-wk-of-age
      showed behaviors indicative of discomfort for 2 h, were attacked by more flies,
      and showed increased fly avoidance behaviors when docked.

PMID- 12487453
TI  - Functional maturation during bovine granulopoiesis.
AB  - Granulocytic precursor cells undergo morphologic changes in the nucleus and the
      cytoplasm during the process of granulopoiesis, which takes place in the bone
      marrow. These changes are associated with the development of stage-specific
      proteins necessary for the highly specialized roles of polymorphonuclear
      leukocytes in phagocytosis, bacterial killing, and in mediating the inflammatory
      process. The objective of the current study was to sequence the various events
      that occur upon functional development of granulocytic bone marrow cells in the
      bovine species. Cells were obtained from the bone marrow of clinically healthy
      cows and separated into different stages of maturation using density gradient
      centrifugation. Three cellular fractions were obtained that were enriched for
      either early immature, late immature or mature granulocytic cells. Functions and
      receptor expressions assessed in the three maturation stages were:Fc-IgG2
      receptor and CD11b expression, phagocytosis of Escherichia coli, respiratory
      burst activity, and cellular myeloperoxidase activity. Immature cells expressed
      already Fc-IgG2 receptor and CD11b on their cytoplasma membrane. Phagocytic
      ability was acquired in the myelocytic stage, but only the more mature forms were
      readily capable of phagocytosis. Promyelocytes, myelocytes and metamyelocytes
      showed no respiratory burst activity. Only band and segmented cells produced
      reactive oxygen species. Myeloperoxidase was present at all stages of maturity.
      Thus, each of the maturation stages was characterized by a selective expression
      of one or more functions and receptors. Therefore, sequential biochemical
      maturation is postulated during bovine granulopoiesis.

PMID- 12487454
TI  - Milk quality on Danish farms with automatic milking systems.
AB  - The bulk-milk quality of 98 Danish farms with automatic milking systems was
      analyzed from 1 yr before introduction of automatic milking until 1 yr after.
      Bulk-milk total bacterial count, spores of anaerobes, somatic cell count (SCC),
      and freezing point increased when automatic milking was introduced and the
      frequency of milk-quality failures almost doubled. Milk-quality failures were
      most frequent in the first 3 mo after the start of automatic milking. The
      increase in spores of anaerobes indicated that the increase in total bacterial
      count originated partly from contamination of milk from the teat surface and
      partly from lack of cleaning of the milking equipment or cooling of the milk. The
      increase in bulk-milk SCC indicated that milk from clinically infected cows and
      cows with high cell counts was not diverted to the same degree, milking
      automatically rather than milking conventionally. A self-monitoring program
      including survey of the bulk-milk quality was established to help farmers in the
      transition period going from conventional to automatic milking. The program was
      introduced on 84 farms. Farms on the self-monitoring program reduced bulk-milk
      cell count. Application of the program did not reduce the frequency of high total
      bacterial counts and freezing points of the bulk milk to the level of
      conventional milking. However, the program reduced the overall frequency of milk
      quality failures.

PMID- 12487455
TI  - The yield and composition of milk in Sarda, Awassi, and Merino sheep milked
      unilaterally at different frequencies.
AB  - Sarda (n = 8), Awassi (n = 8), and Merino (n = 8) ewes were subjected
      unilaterally to once-daily milking (ODM) or twice daily milking (TDM) to test the
      hypothesis that the two breeds highly selected for milk production (Sarda and
      Awassi) would not respond as much to a change in the frequency of milking as the
      Merino, a wool sheep that has not been selected for dairy production. Milk
      composition and somatic cell count (SCC) were also assessed to determine if the
      changes in milking frequency affected milk quality. Milk yield was 24% and 18%
      lower in ODM udder halves than TDM udder halves in Sarda and Awassi breeds,
      respectively. The yield loss due to ODM was similar to that observed in Merino
      ewes (23%) and did not support our hypothesis. Fat content did not differ
      significantly in any breeds between ODM and TDM udder halves. Protein content was
      higher in the milk of ODM than TDM udder halves in Sarda and Merino ewes. The SCC
      was influenced by milking treatment only in the Sarda ewes, with high values
      observed in the milk of ODM udder halves. The same trend was observed in the
      Awassi and Merino breeds, but the differences were not significant. The effects
      on milk yield, composition, and SCC caused by ODM were completely reversed when
      TDM was resumed. This suggests that in sheep flocks the milk yield losses due to
      short-time suppression of one daily milking, for example, on festive days, are
      low and temporary.

PMID- 12487456
TI  - Factors affecting somatic cell counts and their relations with milk and milk
      constituent yield in buffaloes.
AB  - Data concerning daily milk yield (MY), percentage of milk fat (%F), protein (%P),
      lactose (%LT), and total solids (%TS), and somatic cell counts (SCC) for a herd
      of 222 Murrah buffalo reared in the state of Sao Paulo, Brazil, were collected
      monthly from 1997 to 2000 in order to study the factors affecting SCC and their
      relation to milk production and constituents during lactation. SCC decreased in
      the second month of lactation and increased thereafter, up to the ninth month of
      lactation. The interaction of month of lactation x order of calving was
      significant. Mean MY observed during the first month of lactation was 6.87 kg,
      which increased to 7.65 kg during the second month, and then decreased until the
      ninth month of lactation (3.83 kg). During the different months of lactation, %F,
      %P, %LT, and %TS ranged from 6.28 to 8.38%, 4.05 to 4.59%, 4.96 to 5.34%, and
      16.94 to 18.55%, respectively. Calving year, calving order, and order of month of
      lactation significantly affected MY, %F, %P, %LT, and %TS. The regression
      coefficients of transformed SCC on MY and %LT were negative and significant
      during all months of lactation, showing that milk and lactose yield decreased
      with increased transformed SCC, causing losses to buffalo milk producers.

PMID- 12487457
TI  - Ruminal fermentation and nutrient digestion by dairy cows fed varying amounts of
      soyhulls as a replacement for corn grain.
AB  - Five multiparous Holstein cows cannulated in the rumen and duodenum that averaged
      63 d in milk were used in a 5 x 5 Latin square design with 14-d periods to
      evaluate the incremental substitution of soyhulls for corn in the diet. Diets
      contained 23% alfalfa silage, 23% corn silage, and 54% concentrate on a dry
      matter (DM) basis. Pelleted soyhulls replaced corn in the concentrate to supply
      0, 10, 20, 30, or 40% of the dietary DM. The intakes of DM and organic matter
      were unaffected by treatments. Intakes of acid detergent fiber and neutral
      detergent fiber increased linearly, but the intake of nonstructural carbohydrates
      decreased linearly as soyhulls increased from 0 to 40% of dietary DM. The amount
      of acid detergent fiber and neutral detergent fiber digested was increased
      whereas the amount of nonstructural carbohydrate digested was decreased in the
      rumen, in the lower digestive tract, and in the total digestive tract as soyhulls
      replaced corn in the diet. Passage to the duodenum of nonammonia N, microbial N,
      nonammonia nonmicrobial N, total essential amino acids, total nonessential amino
      acids, and total amino acids were not affected by treatments. Yield of milk (29.5
      kg/d) was not affected by treatments in this experiment. In a companion
      experiment, cows fed the 40% SH diet produced 1.2 kg/day per cow less (P < 0.07)
      milk than cows fed the control diet which is similar to the 1.3 kg/day per cow
      less milk produced by cows fed the same 40% SH diet in this experiment.
      Differences in the source of energy (fiber vs. nonstructural carbohydrates), in
      the amount of fiber and nonstructural carbohydrates digested, and in the site of
      digestion in the gastrointestinal tract may cause a shortage of the source and/or
      amount of energy that is required for maximum milk production in high producing
      cows when more than 30% of the dietary DM that is supplied as corn is replaced
      with soyhullss.

PMID- 12487458
TI  - Performance of lactating dairy cows fed varying amounts of soyhulls as a
      replacement for corn grain.
AB  - Fifteen multiparous Holstein cows averaging 112 d in milk were used in a
      replicated 5 x 5 Latin square to evaluate the incremental substitution of
      soyhulls for corn in the diet. Diets contained 23% alfalfa silage, 23% corn
      silage, and 54% concentrate on a dry matter basis. Pelleted soyhulls replaced
      corn in the concentrate to supply 0, 10, 20, 30, or 40% of the dietary dry
      matter. Dry matter intake decreased linearly as soyhulls replaced corn in the
      diet, but the major decrease in dry matter intake occurred when soyhulls provided
      30 and 40% of the dietary dry matter. Intakes of both acid and neutral detergent
      fiber increased linearly as soyhulls increased from 0 to 40% of dietary dry
      matter. Production of milk tended to decrease when soyhulls supplied 40% of the
      dietary dry matter. Production of 3.5% fat-corrected milk, milk crude protein
      percentage and yield, milk urea N, and total solids yield were not affected by
      treatments. Production of true protein, but not percentage, tended to decrease by
      about 5% when soyhulls supplied 40% of the dietary dry matter. Increasing the
      percentage of soyhulls in the dietary dry matter increased linearly milk fat
      content and yield, and total solids content in milk. These data suggest that
      soyhulls can successfully supply up to about 30% of the dry matter intake of
      midlactation cows without depressing animal performance. Furthermore, replacing
      part of the corn with soyhulls in high grain diets may be viable when milk fat
      has a high monetary value or when soyhulls can be purchased at a more competitive
      price than grains on a nutrient content basis.

PMID- 12487459
TI  - Corn silage management II: effects of hybrid, maturity, and mechanical processing
      on digestion and energy content.
AB  - Two experiments were conducted to evaluate the effects of maturity and mechanical
      processing of two hybrids of whole plant corn on starch, fiber, and ether extract
      digestibilities and energy content of the total mixed ration fed to lactating
      Holstein cows. In the first experiment, Pioneer hybrid 3845 whole plant corn was
      harvested at hard dough, one-third milkline, and two-thirds milkline with a
      theoretical length of cut of 6.4 mm. At each stage of maturity, corn was
      harvested with and without mechanical processing. In the second experiment,
      Pioneer hybrids 3845 and Quanta were harvested at one-third milkline, two-thirds
      milkline, and blackline stages of maturity with and without mechanical
      processing. The theoretical length of cut was 12.7 mm. The measured TDN and NEL
      concentrations were lower for diets containing processed corn silage in
      experiment 1 and greater for diets containing processed corn silage in experiment
      2, compared with diets containing unprocessed corn silage. The lower energy
      content for diets containing processed corn silage in experiment 1 can be
      explained by the lower total tract NDF, ether extract, and CP digestibilities.
      The greater energy content for diets containing processed corn silage in
      experiment 2 can be attributed to greater total tract starch and NDF
      digestibilities for cows fed processed corn silage diets. In experiment 2, diets
      containing processed corn silage (1.59 Mcal/kg) had approximately 2.6% more
      energy available per kilogram of DM consumed compared with diets containing
      unprocessed corn silage (1.55 Mcal/kg). For hybrid Quanta in experiment 2, the
      TDN and NEL concentrations of diets containing corn silage harvested at two
      thirds ML were greater than at other maturities.

PMID- 12487460
TI  - Corn silage management III: effects of hybrid, maturity, and processing on
      nitrogen metabolism and ruminal fermentation.
AB  - Two experiments were conducted to evaluate the effects of maturity and mechanical
      processing of two hybrids of whole plant corn silage on DM and OM digestibility,
      nitrogen metabolism, ruminal fermentation, and milk production and composition in
      lactating Holstein cows. In the first experiment, Pioneer hybrid 3845 whole plant
      corn was harvested at hard dough, one-third milkline, and two-thirds milkline
      with a theoretical length-of-cut of 6.4 mm. At each stage of maturity, corn was
      harvested with (1-mm roll clearance) and without (15.9-mm roll clearance)
      mechanical processing using a John Deere 5830 harvester with an on-board kernel
      processor. In the second experiment, Pioneer hybrids 3845 and Quanta were
      harvested at one-third milkline, two-thirds milkline, and blackline stages of
      maturity with and without mechanical processing. The theoretical length-of-cut
      was 12.7 mm. Total tract DM and OM digestibilities were lower for cows fed diets
      containing processed corn silage in experiment 1, and tended to be lower for cows
      fed diets containing unprocessed corn silage in experiment 2. Ruminal acetate
      concentrations were greater and ruminal propionate concentrations were lower 2
      and 6 h after feeding for cows fed diets containing corn silage harvested at
      physiological maturity in experiment 2. This was due to decreased digestion of
      starch at advanced maturities in experiment 2. Ruminal pH tended to decline
      rapidly after feeding for cows fed hybrid Quanta (2 h) compared to hybrid 3845 (5
      h) corn silage based diets. Ruminal acetate concentrations decreased and ruminal
      propionate concentrations increased 2 and 6 h after feeding for cows fed diets
      containing hybrid Quanta corn silage compared to hybrid 3845 corn silage. This
      was related to a greater starch concentration in the corn silage, greater starch
      intake, and increased rate of starch digestion for cows fed hybrid Quanta corn
      silage-based diets. Microbial nitrogen flow was lower and feed nitrogen flow was
      greater for cows fed diets containing hybrid Quanta corn silage. The lower
      microbial nitrogen flow was due to lower microbial nitrogen concentration and
      nonammonia nitrogen flow to the duodenum. Milk fat and protein concentrations had
      a strong quadratic relationship with forage NDF intake as a percentage of body
      weight. When forage NDF intake as a percentage of body weight dropped below
      0.70%, there was a rapid decline in milk fat and protein concentrations.

PMID- 12487461
TI  - Performance of high producing dairy cows with three different feeding systems
      combining pasture and total mixed rations.
AB  - Forty-five Holsteins cows in early to mid lactation were used to compare three
      feeding systems combining pasture and total mixed rations (TMR) on animal
      performance in a 21-wk repeated-measures experiment. The three treatments were:
      1) pasture plus concentrate (PC), 2) pasture plus partial TMR (pTMR), and 3) TMR
      (non-pasture). Total dry matter intake, using chromic oxide as a marker, was
      21.6, 25.2, and 26.7 kg/d for PC, pTMR, and TMR, respectively. Milk production
      was highest for TMR (38.1 kg/d), lowest on PC (28.5 kg/d), and intermediate for
      pTMR (32.0 kg/d). Cows on pTMR and TMR had higher milk fat and true protein
      percentages than cows on PC. Cows on PC gained less body weight and lost more
      body condition compared with cows on pTMR and TMR. Initial concentrations of
      plasma nonesterified fatty acids were higher on PC (302 microeq/L) than on pTMR
      (130 microeq/L) and TMR (225 microeq/L). Plasma and milk urea nitrogen were lower
      on both pTMR and TMR than on PC. Combining pasture and TMR resulted in higher
      milk production, milk fat and protein percentage, and maintenance in body
      condition score compared to pasture plus concentrate. The TMR feeding system
      resulted in the highest total dry matter intake and milk production.

PMID- 12487462
TI  - Ruminal digestion and fermentation of high-producing dairy cows with three
      different feeding systems combining pasture and total mixed rations.
AB  - Six multiparous Holstein cows fitted with rumen cannulas were used to study the
      effect of three feeding systems combining pasture and total mixed rations (TMR)
      on ruminal digestion in a 21-wk repeated measures experiment. The three
      treatments were: 1) pasture plus concentrate (PC), 2) pasture plus partial TMR
      (pTMR), and 3) TMR (nonpasture). Ruminal NH3-N concentration was lower on both
      the pTMR and TMR treatments (10.2 +/- 0.5 mg/dL) than on the PC treatment (19.9
      +/- 0.5 mg/dL). Ruminal pH was not affected by treatments and averaged 5.87.
      Neither total volatile fatty acid concentration (137.5 mmol/L) nor individual
      volatile fatty acid proportions (63.1,20.6, and 12.0 mol/ 100 mol for acetate,
      propionate, and butyrate, respectively) differed among treatments. The pTMR
      treatment reduced the total potentially degradable fraction of dry matter (85.5
      vs. 82.3%) and the potentially digestible fraction of neutral detergent fiber
      (82.1 vs. 74.9%) of pasture compared to the PC treatment. Ruminal NH3-N losses
      were reduced when combining pasture and TMR; however this combination decreased
      the ruminal digestion of pasture, indicating the presence of associative effects
      in the rumen.

PMID- 12487463
TI  - Variations in mammary protein metabolism during the natural filling of the udder
      with milk over a 12-h period between two milkings: leucine kinetics.
AB  - To define the temporal variations of whole body and mammary leucine kinetics over
      a 12-h period between two milkings, we used two groups of four Holstein cows, one
      in their second and the other in their third or fourth lactation. Cows were
      infused with L-[1-13C]leucine during the 12-h interval between two milkings.
      Blood was sampled every 30 min during that period from arterial and mammary
      sources. Timeafter milking did not affect whole body irreversible loss rate of
      leucine but affected whole body leucine oxidation, which broadly followed
      variations in arterial plasma leucine concentration. Similarly, mammary leucine
      irreversible loss rate and leucine used for protein synthesis were not affected
      by time after milking. Leucine oxidation by the mammary gland was, however,
      affected by time after milking. It increased by 15% from the first 2-h period to
      the following 4-h period and then decreased by 13% over the following 2-h period.
      A 21% increase in leucine oxidation was observed from 8 to 10 h after milking,
      and then it decreased by 26% over the last 2-h period. Protein degradation
      expressed as percentage of mammary leucine flux followed a similar temporal
      pattern. Leucine used for protein synthesis by the mammary gland was unaltered
      over time after milking, suggesting that the increased availability of leucine
      resulting from mammary protein breakdown would increase intracellular
      concentrations of leucine, which would have favored its catabolism. Overall,
      these results confirm the high metabolic activity of the mammary gland, as
      protein synthesis by the mammary gland averaged 43% of whole body protein
      synthesis.

PMID- 12487464
TI  - The effect of a ruminal nitrogen (N) deficiency in dairy cows: evaluation of the
      cornell net carbohydrate and protein system ruminal N deficiency adjustment.
AB  - Twenty-four multiparous and fifteen first lactation Holstein cows averaging 263
      days in milk and weighing 614 kg were fed diets adequate or deficient in ruminal
      nitrogen (N), based on predictions of the Cornell Net Carbohydrate and Protein
      System (CNCPS). After adjustment to a low crude protein (CP) total mixed rations
      (TMR; 12.6% CP), the cows were allocated to 13 blocks based on lactation number,
      milk production, body condition score, and body weight. Within each block, cows
      were randomly assigned to one of the 3 treatment (TRT) diets (9.4, 11.1 and 14.1%
      CP for TRT 1, 2, and 3, respectively). All diets contained the same proportion of
      high moisture corn, chopped grass hay, and minerals, with urea substituted for
      corn silage as needed to reach the three CP levels. The TRT diets were then fed
      to the cows for 4 wk. Milk production was significantly affected by TRT: 15.5,
      18.8, and 21.7 kg/d for TRT diets 1, 2, and 3, respectively. DMI was increased
      significantly as the percentage of CP increased from 9.4 to 14.1% CP: 17.6, 20.0,
      and 21.2 kg/d for TRT diets 1,2, and 3, respectively. CNCPS predictions for
      production (with and without the N adjustment for ruminal N deficiency) of
      metabolizable protein (MP) allowable milk were compared with observed milk
      production. Using the average individual weekly cow data from all 3 TRT, we found
      that the CNCPS accounted for 72 and 68% of the variation in MP allowable milk
      without and with the N deficiency adjustment, respectively. The overall mean bias
      without the N adjustment was 3.3 kg of milk (over prediction model bias of 14.6%,
      P < 0.001), and the N adjustment reduced the model over-prediction bias to 0.01
      kg of milk (P = 0.96).

PMID- 12487465
TI  - Influence of particle size on the effectiveness of the fiber in alfalfa silage.
AB  - The objective was to determine the influence of alfalfa silage particle length on
      milk yield, milk composition, and chewing activity. Sixteen multiparous lactating
      Holsteins were used in each of two separate feeding trials over a 2-yr period
      providing two repetitions. Each trial was based on 4 x 4 Latin squares with 21-d
      periods. All four diets (2-yr average, dry basis) contained a basal level of
      10.7% neutral detergent fiber from corn silage and 2.3% neutral detergent fiber
      from chopped alfalfagrass hay. One of the diets served as a low forage, low fiber
      control and contained only the basal forages. The other three diets contained an
      additional 8.6% neutral detergent fiber from coarser alfalfa silage, finely
      rechopped alfalfa silage or an equal mixture ofthe two. An increase in the forage
      content above the basal amount using alfalfa silage increased 4% fat-corrected
      milk yield, milk fat yield and concentration, eating time, and total chewing
      time. Dry matter intake was not influenced by diet. Linear increases in
      rumination and total chewing times were observed as the mean particle size of the
      alfalfa silage increased from finer to coarser. There was no linear effect of
      alfalfa silage particle size on milk yield, 4% fat-corrected milk yield, dry
      matter intake, or milk composition.

PMID- 12487466
TI  - Relationship between corn vitreousness and ruminal in situ starch degradability.
AB  - The objective of this experiment was to determine the relationship between corn
      kernel vitreousness and ruminal in situ starch degradation. Fourteen U.S. and
      five Brazilian corn hybrids cultivated in their respective countries were
      evaluated. The U.S. dent hybrids were harvested at one-half milk line, black
      layer, and 21 d after black layer stages of maturity. Brazilian flint hybrids
      were harvested only at the latest stage of maturity. Vitreousness was determined
      by manual dissection of the kernels. Ruminal in situ degradation of starch was
      determined in three lactating Holstein cows fitted with ruminal cannulae.
      Vitreousness of the five mature Brazilian hybrids averaged 73.1% (range of 64.2%
      to 80.0%), while vitreousness of the 14 mature U.S. hybrids averaged 48.2% (range
      of 34.9% to 62.3%). Within the 14 U.S. hybrids, average vitreousness increased
      from 42.8% to 48.2% as stage of maturity progressed from one-half milk line to 21
      d after black layer. The correlation between kernel density and vitreousness was
      0.87. The correlations between kernel vitreousness or density and ruminal starch
      availability were -0.93 and -0.87, respectively. With advancing maturity, kernel
      vitreousness and density increased while ruminal starch availability decreased.
      Kernel vitreousness and density may be useful parameters for which to select corn
      hybrids for high ruminal starch availability. Density may be a more practical
      measurement than vitreousness for screening large corn data sets.

PMID- 12487467
TI  - Effect of dietary fiber on endogenous nitrogen flows in lactating dairy cows.
AB  - The effect of dietary fiber on endogenous N secretion was studied using a 15N
      isotope dilution technique in four fistulated Holstein cows. Two isonitrogenous
      diets differing only in fiber (NDF and ADF) content were used in a crossover
      design. One diet (HF) contained 37.4% NDF, while the other (LF) contained 23.3%.
      A new model was developed to estimate endogenous N secretions and losses for the
      preintestinal, intestinal, and the total sections of the gastrointestinal tract.
      Three precursor pools: TCA-soluble fraction of plasma, intestinal mucosa, and
      milk were compared. Although endogenous losses estimated with the model were
      numerically different for each precursor pool selected (TCA-soluble fraction >
      mucosa > milk), treatment effects were similar. As intestinal mucosa is probably
      closest to the precursor pool, these data are discussed. Non-urea N endogenous
      secretions contributed 13% of the duodenal N flow but were not affected by the
      fiber content of the diet. The nonurea N endogenous flow at the duodenum was
      comprised of approximately equal inputs from endogenous N direct, and that
      incorporated into the microbial biomass. Total endogenous N flows at the duodenum
      exceeded, by nearly twofold, estimated inputs of urea-N to microbial biomass.
      Metabolic fecal output averaged 17% of fecal N and was not affected by level of
      dietary fiber, but net losses from secretions occurring in the small intestine
      were higher with the low fiber diet. Overall, endogenous N secretions represented
      30% of total digestive tract protein synthesis.

PMID- 12487468
TI  - Fatty acid metabolism in liver of dairy cows fed supplemental fat and nicotinic
      acid during an entire lactation.
AB  - Liver biopsies from 38 multiparous Holstein cows were used to determine rates of
      peroxisomal beta-oxidation and total beta-oxidation of palmitate in liver
      homogenates and contents of total lipid, triglyceride, and glycogen during the
      lactation cycle. Cows were assigned to one of four diets from wk 4 through wk 42
      of lactation: control, control plus nicotinic acid (12 g/d), supplemental fat, or
      supplemental fat plus nicotinic acid. Liver biopsies were obtained at wk 3
      (covariate), 6, 12, 24, and 42 of lactation. Neither supplemental fat nor
      nicotinic acid affected palmitate oxidation in liver homogenates or liver
      composition. Peroxisomal beta-oxidation capacity and the ratio of peroxisomal to
      total beta-oxidation decreased from wk 3 to 12 and then increased at wk 42.
      Contents of total lipid and triglyceride decreased, and content of glycogen
      increased, from wk 3 to 12. Total oxidation capacity in liver homogenates was
      correlated negatively with total lipid and triglyceride in liver, yields of milk
      and solids-corrected milk (SCM), and plasma nonesterified fatty acids (NEFA), and
      was correlated positively with liver glycogen, dry matter intake (DMI), energy
      balance, and plasma glucose. Peroxisomal beta-oxidation was correlated negatively
      with yields of milk and SCM. The ratio of peroxisomal to total beta-oxidation was
      correlated positively with liver total lipid, liver TG, and plasma NEFA and
      negatively with DMI and energy balance. When only data from wk 3 postpartum were
      considered, both total and peroxisomal beta-oxidation were correlated negatively
      with hepatic concentrations of total lipid and TG. Peroxisomal beta-oxidation in
      liver of dairy cows is not affected by feeding supplemental fat or nicotinic acid
      during wk 4 to 42 of lactation but may be a part of the hepatic adaptations to
      negative energy balance.

PMID- 12487469
TI  - Forage intake, meal patterns, and milk production of lactating dairy cows fed
      grass silage or pea-wheat bi-crop silages.
AB  - This study investigated the feed intake, milk production, and plasma nutrient
      status in dairy cows fed inter-cropped pea-wheat (bi-crop) silages comprised of
      contrasting ratios of pea to wheat. Spring peas (cv. Magnus) and wheat (cv.
      Axona) sown at either high (75:25) or low (25:75) pea inclusion rates were
      harvested after 13 (Cut 1) or 15 (Cut 2) wk. Eighteen Holstein-Friesian cows
      between wk 9 and 10 of lactation were used in a cyclical changeover design with
      three 28-d periods. Cows were fed the bi-crop silages and 6 kg of concentrates or
      second-cut grass silage supplemented with 6 (GS6) or 9 (GS9) kg/d of
      concentrates. Forage intakes were higher when bi-crops were fed (10.3 to 11.4 kg
      dry matter [DM]/d) than when grass silage was fed (8.6 kg DM/d). Total DM intake
      was similar among cows fed the bi-crop silages and GS9 diets, but intakes for GS6
      were at least 1.7 kg DM/d lower. Increasing the pea inclusion rate increased the
      crude protein (CP) content of the ration, but it did not enhance forage quality
      or animal performance. The rate of intake of the different forages was similar,
      so that the higher intakes of bi-crop silages were associated with more time
      spent at the feedbunk and an increased number of meals. Diet digestibility ranged
      from 531 to 650 g/kg, and the highest value was given by the Cut 1 bi-crop silage
      diet. Milk yield tended to be similar for cows fed the Cut 2 bi-crop and GS9
      diets, and these values were at least 1.7 kg higher than those for cows fed on
      other treatments. Generally, the bi-crop diets resulted in higher milk fat
      contents and lower polyunsaturated fatty acid contents. Milk protein content was
      highest for cows fed the GS9 diet. Blood metabolite content was unaffected by
      treatment except for blood urea nitrogen content, which was higher in cows fed
      the bi-crop silages, reflecting reduced N-use efficiency with these diets. The
      study showed that pea-wheat bi-crop silages can be used to replace moderate
      quality grass silage in dairy cow rations, but their role as alternatives to high
      quality forages requires additional investigation.

PMID- 12487470
TI  - The detection and avoidance of lead-contaminated herbage by dairy cows.
AB  - Lead from industry, and vehicles in some countries, can contaminate cattle
      pastures. We determined the concentrations of lead on herbage that cows can
      detect. Four cows were trained in a four-lane maze to detect an herbage sample
      that was superficially contaminated with 240 mg Pb/kg from three uncontaminated
      samples, and four were trained to detect an uncontaminated sample from three
      contaminated samples. Pb concentrations were reduced until the cows could not
      discriminate between samples, which occurred at 30 to 60 mg/kg. In a second
      experiment, 12 cows were allocated to two groups that grazed either pasture with
      added Pb (86 mg/kg) or pasture with no added Pb for 4 wk. Lead reduced grazing
      time and pasture biting rates, leading to an increase in herbage height.
      Immediately afterwards, these cows were grazed for 4 wk on a mosaic of 18 plots
      with no added lead, a low Pb level (67 mg/kg), or a high Pb level (102 mg/kg)
      (Experiment 3). Lead reduced grazing time and pasture biting rate, particularly
      at the high level. Plots without added Pb were grazed to the shortest height, and
      plots treated with Pb at 102 mg/kg were tallest. Prior exposure to Pb increased
      grazing time, especially on the high Pb level, and it increased the rate of
      biting pasture without Pb. To understand these phenomena, herbage samples from
      Experiments 2 and 3 were incubated in rumen liquor and artificial saliva, and gas
      production was measured over 48 h. In both experiments, the application of Pb
      reduced the rate of gas production or total gas production. It is concluded that
      cows can detect Pb on herbage, that it reduces their grazing time and pasture
      biting rate, and that they prefer to graze pasture without Pb. The aversion to Pb
      on pasture, which may be due to adverse effects on ruminal digestion, diminishes
      over time.

PMID- 12487471
TI  - Effects of ad libitum milk intake on dairy calves.
AB  - Conventional milk feeding for calves (by bucket twice daily at a total of 10% of
      body weight) was compared with feeding milk for ad libitum consumption from a
      nipple. Calves were weaned gradually between d 37 and 42 by diluting the milk
      with water, and body weight and feed consumption were followed until d 63. Calves
      fed ad libitum drank 89% more milk than calves fed conventionally during the
      preweaning period, but the ad libitum-fed calves ate only 16% as much calf
      starter and 17% as much hay. Consumption of starter and hay increased rapidly
      after weaning, and treatment differences disappeared. Probably as a result of the
      much higher intake of milk, the ad libitum-fed calves gained 63% more weight than
      the conventionally fed calves before weaning, resulting in a 10.5-kg weight
      advantage on d 35. During and immediately after weaning, the rate of weight gain
      slowed for both treatment groups, but recovered by approximaely d 49. There were
      no treatment differences in weight gains over the weaning or postweaning periods,
      and at the end of the experiment on d 63, the calves fed ad libitum maintained an
      advantage in mean (+/- SEM) body weight (89.07 +/- 2.47 kg vs 81.07 +/- 2.47 kg
      for the conventionally fed calves). Incidence of diarrhea was low and did not
      differ between treatment groups. We conclude that ad libitum nipple feeding of
      milk to dairy calves can allow for increased milk intake and weight gain with no
      detrimental effects on intake of solid food after weaning.

PMID- 12487472
TI  - Technical note: effect of removal of microbial cells by centrifugation on peptide
      and alpha-amino nitrogen concentrations in ruminal fluid.
AB  - We evaluated the effect of centrifuging rumen fluid prior to analysis on
      concentrations of alpha-amino N (AAN) and peptides. Rumen fluid was collected
      from steers fed grain-based diets at either various times after feeding or after
      dosing the rumens with solubilized casein. Fluid was either directly processed
      for peptide analysis by acidifying 10 ml of rumen fluid with 0.5 ml of 70%
      (wt/wt) perchloric acid, or first centrifuged at 500 x g for 20 min to remove
      protozoa and then at 30,000 x g for 15 min to remove bacterial cells prior to
      further processing. By removing microbial cells, intracellular AAN and peptides
      were not included in subsequent analyses. Concentrations of AAN were
      determinedusing an automated trinitrobenzene sulfonic acid assay, and peptides
      were determined as the increase in AAN following acid hydrolysis of the samples.
      When casein was not dosed, removal of microbial cells prior to analysis decreased
      concentrations of both AAN andpeptides, and the decrease was greater for AAN (2.2
      mM)than for peptides (1.2 mM). Dosing with casein led to much higher
      concentrations of ruminal peptides and AAN. After casein dosing, decreases in AAN
      and peptidecon-centrations due to prior centrifugation (2.1 mM and 1.0 mM for AAN
      a nd pept ides, respectively) were similar to the decreases observed before the
      casein dosing. Results suggest that the contribution of intracellular AAN and
      peptides to the concentrations in ruminal fluid are relatively constant across
      broad ranges of dietary protein supply for cattle fed corn-based diets.

PMID- 12487473
TI  - Heritability and correlations among body condition score loss, body condition
      score, production and reproductive performance.
AB  - The objectives of this study were to estimate the heritability of body condition
      score loss (BCSL) in early lactation and estimate genetic and phenotypic
      correlations among BCSL, body condition score (BCS), production, and reproductive
      performance. Body condition scores at calving and postpartum, mature equivalents
      for milk, fat and protein yield, days to first service, and services per
      conception were obtained from Dairy Records Management Systems in Raleigh, NC.
      Body condition score loss was defined as BCS at calving minus postpartum BCS.
      Heritabilities and correlations were estimated with a series of bivariate animal
      models with average-information REML. Herd-year-season effects and age at calving
      were included in all models. The length of the prior calving interval was
      included for all second lactation traits, and all nonproduction traits were
      analyzed with and without mature equivalent milk as a covariable. Initial
      correlations between BCS and BCSL were obtained using BCSL and BCS observations
      from the same cows. Additional genetic correlation estimates were generated
      through relationships between a group of cows with BCSL observations and a
      separate group of cows with BCS observations. Heritability estimates for BCSL
      ranged from 0.01 to 0.07. Genetic correlation estimates between BCSL and BCS at
      calving ranged from -0.15 to -0.26 in first lactation and from -0.11 to -0.48 in
      second lactation. Genetic correlation estimates between BCSL and postpartum BCS
      ranged from -0.70 to -0.99 in first lactation and from -0.56 to -0.91 in second
      lactation. Phenotypic correlation estimates between BCSL and BCS at calving were
      near 0.54, whereas phenotypic correlation estimates between BCSL and postpartum
      BCS were near -0.65. Genetic correlations between BCSL and yield traits ranged
      from 0.17 to 0.50. Genetic correlations between BCSL and days to first service
      ranged from 0.29 to 0.68. Selection for yield appears to increase BCSL by
      lowering postpartum BCS. More loss in BCS was associated with an increase in days
      to first service.

PMID- 12487474
TI  - The genetic relationship between commencement of luteal activity and calving
      interval, body condition score, production, and linear type traits in Holstein
      Friesian dairy cattle.
AB  - The decline of fertility in the UK dairy herd and the unfavorable genetic
      correlation (r(a)) between fertility and milk yield has necessitated the
      broadening of breeding goals to include fertility. The coefficient of genetic
      variation present in fertility is of similar magnitude to that present in
      production traits; however, traditional measurements of fertility (such as
      calving interval, days open, nonreturn rate) have low heritability (h2 < 0.05),
      and recording is often poor, hindering identification of genetically superior
      animals. An alternative approach is to use endocrine measurements of fertility
      such as interval to commencement of luteal activity postpartum (CLA), which has a
      higher h2 (0.16 to 0.23) and is free from management bias. Although CLA has
      favorable phenotypic correlations with traditional measures of fertility, if it
      is to be used in a selection index, the genetic correlation (ra) of this trait
      with fertility and other components of the index must be estimated. The aim of
      the analyses reported here was to obtain information on the ra between lnCLA and
      calving interval (CI), average body condition score (BCS; one to nine, an
      indicator of energy balance estimated from records taken at different months of
      lactation), production and a number of linear type traits. Genetic models were
      fitted using ASREML, and r(a) were inferred from genetic regression of lnCLA on
      sire-predicted transmitting abilities (PTA) for the trait concerned by
      multiplying the regression coefficient (b) by the ratio of the genetic standard
      deviations. The inferred r(a) between lnCLA and CI and average BCS were 0.36 and 
      0.84, respectively. Genetic correlations between InCLA and milk fat and protein
      yields were all positive and ranged between 0.33 and 0.69. Genetic correlations
      between InCLA and linear type traits reflecting body structure ranged from -0.25
      to 0.15, and between udder characteristics they ranged from -0.16 to 0.05. Thus,
      incorporation of endocrine parameters of fertility, such as CIA, into a fertility
      index may offer the potential to improve the accuracy of breeding value
      prediction for fertility, thus allowing producers to make more informed selection
      decisions.

PMID- 12487475
TI  - Interval and composite interval mapping of somatic cell score, yield, and
      components of milk in dairy cattle.
AB  - Single-marker, interval-mapping (IM) and composite interval mapping (CIM) were
      used to detect quantitative trait loci (QTL) controlling milk, fat and protein
      yields, and somatic cell score (SCS). A granddaughter design was used to combine
      molecular genetic information with predicted transmitting abilities (PTA) and
      estimated daughter yield deviations (DYD) from eight Dairy Bull DNA Repository
      Holstein families. Models that included and excluded weights accounting for the
      uncertainty of the response variable were evaluated in each trait, family and
      phenotype (DYD and PTA) combination. The genotypic information consisted of 174
      microsatellite markers along 29 Bos taurus autosomes. The average number of
      informative markers per autosome was three and the number of informative sons per
      family and marker varied between 21 and 173. Within-family results from the least
      squares single-marker analyses were used in expectation-maximization likelihood
      IM and CIM implemented with QTL Cartographer. Different CIM model specifications,
      offering complementary control on the background QTL outside the interval under
      study, were evaluated. Permutation techniques were used to calculate the genome
      wide threshold test statistic values based on 1,000 samples. Results from the DYD
      and PTA analyses were highly consistent across traits and families. The minor
      differences in the estimates from the models that accounted for or ignored the
      uncertainty of the DYD (variance) and PTA (inverse of reliability) may be
      associated to the elevated and consistent precision of the DYD and PTA among
      sons. The CIM model best supported by the data had 10 markers controlling for
      background effects. On autosome (BTA) three, a QTL at 32 cM influencing protein
      yield was located in family five and a QTL at 74 cM for fat yield was located in
      family eight. Two map positions associated with SCS were detected on BTA 21, one
      at 33 cM in family one and the other at 84 cM in family three. A QTL for protein
      yield was detected between 26 and 36 cM on BTA six, family six, and a QTL for
      milk yield was detected at 116 cM on BTA seven in family three. The IM and CIM
      approaches detected a QTL at 3 cM on BTA 14 influencing fat yield in family four.
      Two map positions on BTA 29 were associated with significant variation of milk (0
      cM) and fat yield (14 cM) in family seven. These results suggest the presence of
      one QTL with pleiotropic effects on multiple traits or multiple QTL within the
      marker interval. Findings from this study could be used in subsequent fine
      mapping work and applied to marker-assisted selection of dairy production and
      health traits.

PMID- 12487476
TI  - Effect of heat stress on nonreturn rate in Holstein cows: genetic analyses.
AB  - The genetic component in heat tolerance for nonreturn rate in Holsteins was
      estimated using an animal linear model augmented by a random regression on a
      temperature-humidity index (THI). Data consisted of 18,059 nonreturn rates at
      45,60, and 90 d after insemination and 81,674 first-parity test-day milk yields
      from 78 herds in Florida. The THI on the day of insemination or test day was
      added to each record. Only first-insemination records were used. The model for
      nonreturn rate included the effects of herd-year-season, age, days in milk, milk
      yield, THI as a covariable, regular additive effect, and random regression on THI
      for heat-tolerance additive effect. With a single-trait model, heritability
      estimates for NR45, NR60, and NR90 at THI = 70 for first-lactation cows were
      0.006, 0.014, and 0.053, respectively. Genetic correlation between regular NR90
      and heat tolerance was -0.95. A bivariate analysis for NR90 and test-day milk
      production yielded a correlation between regular merit and heat tolerance for
      NR90 of -0.35, substantially lower than by the univariate model, indicating a
      bias in the univariate estimates caused by ignored selection. The regular genetic
      correlation between NR90 and milk yield was -0.41. Genetic correlation between
      heat tolerance for NR90 and heat tolerance for milk yield was -0.04, indicating
      the need to separate selection.

PMID- 12487477
TI  - Effect of heat stress on nonreturn rate in Holsteins: fixed-model analyses.
AB  - The objective of this study was to examine the relationship between reproductive
      traits and heat stress. Nonreturn rate at 45 d (NR45) was analyzed in a fixed
      effect model that included the temperature-humidity index (THI) from a nearby
      weather station as a measurement of heat stress. Data consisted of 150,200 first
      inseminations at first and later parities of 110,860 Holstein cows from 550 herds
      in Georgia, Tennessee, and Florida with weather information from 16 weather
      stations. THI on the day of the insemination, 2 d prior, 5 d prior, 5, 10, 20,
      and 30 d after insemination were studied as independent variables. The THI on the
      day of insemination showed the highest effect on NR45, followed by 2 d prior, 5 d
      prior, and 5 d after insemination, but no relationship was found with THI at 10,
      20, and 30 d after insemination. NR45 showed a decrease of 0.005 per unit
      increase in THI on the day of insemination for THI >68. First and later parities
      presented similar thresholds but responded differently to an increase in THI,
      with NR45 being significantly lower and more susceptible to increases of THI in
      cows in their first parity than in later parities (0.008 vs. 0.005 decrease).
      Threshold for sensitivity to heat stress changed with the states, with Florida,
      Georgia, and Tennessee having thresholds of 70, 70, and 66, respectively. The
      decrease in NR45 per unit increase of THI was 0.007, 0.005, and 0.006 for
      Florida, Georgia, and Tennessee, respectively. With respect to only the Florida
      data, the final fixed-effect model used was NR45 = herd(year) + month(year) +
      month(year) + age(parity) + days in milk + 100d milk + THI + error. Animals with
      more than 150 d in milk (DIM) had a 0.16 lower NR45 than animals with less than
      60 DIM at insemination. Lower milk-producing animals showed 0.08 higher NR45 than
      higher-producing animals. A difference of 0.10 in NR45 was observed between THI
      lower than 70 and THI 84. This variation in NR45 caused by THI changes is
      sufficient to merit further studies to examine genetic components of heat
      tolerance for this trait.

PMID- 12487478
TI  - Test day and lactation yield predictions in Italian simmental cows by ARMA
      methods.
AB  - Autoregressive Moving Average (ARMA) models, originally developed in the contest
      of time series analysis, were used to predict Test Day (TD) yields of milk
      production traits in dairy cows. ARMA models areable to take into account both
      the average lactation curve of homogeneous groups of animals and the residual
      individual variability that may be explained in terms of probability models, such
      as Autoregressive (AR) and Moving Average (MA) processes. Milk, fat, and protein
      yields of 6000 Italian Simmental cows with 8 TD records per lactation were
      analyzed. Data were grouped according to parity (1st, 2nd, and 3rd calving) and
      fitted to a Box-Jenkins ARMA model in order to predict TD yields in five
      situations of incomplete lactations. Reasonable accuracies have been obtained for
      a limited horizon of prediction: average correlations among actual and predicted
      data were 0.85, 0.72, and 0.80 for milk, fat and protein yields when the first
      predicted TD was one step ahead (on average 42d) of the last actual record
      available. Cumulative 305-d yields were calculated using all actual (actual
      yields) or actual plus forecasted (estimated yields) daily yields. Accuracy of
      lactation predictions was remarkable even when only a few actual TD records were
      available, with values of 0.88 for milk and protein and 0.84 for fat for the
      correlations between actual and estimated yields when 6 out of 8 TD records were
      predicted. Accuracy rapidly increases with the number of actual TD available:
      correlations were about 0.96 for milk and protein and 0.93 for fat when 4 out of
      8 TD records were predicted. In comparison with other prediction methods, ARMA
      modelsare very simple and can be easily implemented in data recording software,
      even at the farm level.

PMID- 12487479
TI  - Genotype x environment interaction for protein yield in Dutch dairy cattle as
      quantified by different models.
AB  - Variance components and breeding values for protein yield were estimated with
      REML without and with correction for heterogeneity of variances. Three different
      sire models were applied, which all accounted for genotype x environment (G x E)
      interaction. The first model included a sire x herd-year-season subclass (HYS)
      interaction. The second model divided all records in four different types of
      management groups, based on estimated HYS subclass effect. The third model, the
      reaction norm model, performed a random linear regression on the estimated HYS
      effect. For comparison, a standard model that did not take G x E interaction into
      account was also applied. Data consisted of 102,899 305-d first-lactation protein
      records of Holstein Friesians of 1,000 ofthe largest Dutch dairy herds. All
      animals calved in 1997, 1998, or 1999. Estimated breeding values (EBV) for 2,150
      bulls with at least five daughters were calculated. The interaction model
      detected an interaction variance of 2.5% of the phenotypic variance. The EBV
      showed a correlation of 1.00 with those of the standard model without
      interaction. The model with the division in groups showed correlations between
      groups ranging from 0.73 to 0.86. The EBV showed correlations from 0.84 to 0.91
      with the EBV of the standard model. The reaction norm model calculated EBV that
      had a correlation of 1.00 with the EBV of the standard model. The reaction norm
      model was not able to detect significant variance of the slope for the protein
      data corrected for heterogeneity of variances.

PMID- 12487480
TI  - A genome scan for quantitative trait loci affecting milk production in Norwegian
      dairy cattle.
AB  - An autosomal genome scan for quantitative trait loci (QTL) affecting milk
      production traits was carried out on the Norwegian Dairy Cattle population. Six
      half-sibling families with a total of 285 sons organized according to a
      granddaughter design were analyzed by a multiple marker regression method.
      Suggestive QTL for one or several of the five milk traits (milk yield, protein
      percentage, protein yield, fat percentage and fat yield) were detected on
      chromosomes 3, 5, 6, 11, 13, 18 and 20. Among these results, the findings on
      chromosomes 3, 6, and 20 are highly supported by literature. The most convincing
      result was found close to marker FBN9 on chromosome 6, where a QTL was detected
      with alleles that cause a marked reduction in both protein and fat percentages
      and an increase in milk yield. The results for fat and protein percentage were
      highly significant even after accounting for multiple testing across the genome.
      Using bootstrapping, a 95% confidence interval for the position of the QTL for
      the percentage traits on chromosome 6 was estimated to 16 cM.

PMID- 12487481
TI  - Estimates of genetic parameters for single- and multiple-country test-day models.
AB  - Single- and multiple-country random regression models were applied to estimate
      genetic parameters for first-lactation test-day milk yield of cows from four
      countries: Australia, Canada, Italy, and New Zealand. Selected countries
      represented a wide range of production systems and environments. Milk production
      in Canada and Italy is based mainly on intensive management systems, while
      Australia and New Zealand are largely based on rotational grazing. Legendre
      polynomials with five coefficients were used to model genetic and environmental
      lactation curves. Covariance components of lactation curve coefficients within
      and across countries, and selected functions of those, were estimated by Bayesian
      methods with Gibbs sampling, on selected subsets of data. Countries differed in
      both phenotypic and genetic parameters of lactation curves between d 5 and 305 of
      lactation. Principal component analysis of single-trait genetic and environmental
      covariance matrices showed, however, that the pattern of variability in test-day
      milk yield was very similar between countries. General level of milk production
      in lactation and persistency components accounted for more than 90% of the total
      variance. Estimated genetic correlations between countries for total yield in
      lactation ranged from 0.65 (Italy and New Zealand) to 0.83 (Australia and New
      Zealand), indicating a possibility of genotype by environment interaction for
      some pairs of countries.

PMID- 12487482
TI  - Production and feeding strategies for phosphorus management on dairy farms.
AB  - Long-term accumulation of soil phosphorus (P) is becoming a concern on some
      watersheds heavily populated with animal feeding facilities, including dairy
      farms. Management changes in crop production and feeding may help reduce the
      accumulation of excess P, but farm profitability must be maintained or improved
      to assure adoption of such changes. Whole-farm simulation was used to evaluate
      the long-term effects of changes in feeding, cropping, and other production
      strategies on P loading and the economics of 100-cow and 800-cow dairy farms in
      southeastern New York. Simulated farms maintained a long-term P balance if the
      following occurred: 1) animals were fed to meet recommended minimum amounts of
      dietary P, 2) the cropping strategy and land base supplied all of the forage
      needed, 3) all animals were fed a high forage diet, and 4) replacement heifers
      were produced on the farm to utilize more forage. The most easily implemented
      change was to reduce the supplemental mineral P fed to that required to meet
      current NRC recommended amounts, and this provided an annual increase in farm
      profit of about $22/cow. Intensifying the use of grassland and improving grazing
      practices increased profit along with a small reduction in excess P. Conversion
      from dairy production to heifer raising or expansion from 100 cows to a 250-cow
      "state-of-the-art" confinement facility (with a 70% increase in land area) were
      also profitable options. These options provided a long-term P balance for the
      farm as long as the production and use of forage was maximized and minimum
      dietary P amounts were those recommended by the NRC. Thus, management changes can
      be made to prevent the long-term accumulation of soil P on dairy farms while
      improving farm profitability.

PMID- 12487483
TI  - Attention and memory for faces and actions in infancy: the salience of actions
      over faces in dynamic events.
AB  - Discrimination and memory for video films of women performing different
      activities was investigated in 5.5 month-old infants. In Experiment 1, infants (N
      = 24) were familiarized to the faces of one of three women performing one of
      three repetitive activities (blowing bubbles, brushing hair, and brushing teeth).
      Overall, results indicated discrimination and memory for the actions but not the
      faces after both a 1-min and a 7-week delay. Memory was demonstrated by a visual
      preference for the novel actions after the 1-min delay and for the familiar
      actions after the 7-week delay, replicating prior findings that preferences shift
      as a function of retention time. Experiment 2 (N = 12) demonstrated
      discrimination and memory for the faces when infants were presented in static
      poses at the 1-min delay, but not the 7-week delay. In Experiment 3 (N = 18),
      discrimination of the actions was replicated, but no discrimination among the
      objects embedded in the actions (hairbrush, bubble wand, toothbrush) was found.
      These findings demonstrate the attentional salience of actions over faces in
      dynamic events to 5.5 month-olds. They highlight the disparity between results
      generated from moving versus static displays in infancy research and emphasize
      the importance of using dynamic events as a basis for generalizing about
      perception and memory for events in the real world.

PMID- 12487484
TI  - Developmental changes in endogenous control of attention: the role of target
      familiarity on infants' distraction latency.
AB  - This study evaluated the interactive effects of endogenous and exogenous
      influences on infants' attention allocation by assessing the role of target
      familiarity on distraction latency during object exploration. In Experiment 1 (N
      = 54), infants' distraction latencies as they investigated both familiar toys
      (ones they previously had seen in a familiarization procedure) and novel toys
      (ones they had not seen in the familiarization procedure) were assessed
      longitudinally at 6.5 and 9 months of age. In Experiment 2 (N = 32), infants'
      distraction latencies were assessed at either 6.5 or 10 months as they
      investigated either familiar or novel targets. In both experiments, older
      infants, but not younger infants, exhibited longer latencies as they investigated
      novel toys as compared with their latencies as they investigated familiar toys.
      These results are discussed in terms of developmental changes in the interactive
      effects of endogenous and exogenous factors controlling attention allocation.

PMID- 12487485
TI  - Perceptual causality in children.
AB  - Three experiments considered the development of perceptual causality in children
      from 3 to 9 years of age (N = 176 in total). Adults tend to see cause and effect
      even in schematic, two-dimensional motion events: Thus, if square A moves toward
      B, which moves upon contact, they report that A launches B--physical causality.
      If B moves before contact, adults report that B tries to escape from A--social or
      psychological causality. A brief pause between movements eliminates such
      impressions. Even infants in the first year of life are sensitive to causal
      structure in both contact and no-contact events, but previous research with
      talking-age children found poor verbal reports. The present experiments used a
      picture-based forced-choice task to reduce linguistic demands. Observers saw
      eight different animations involving squares A and B. Events varied in whether or
      not these agents made contact; whether or not there was a delay at the closest
      point; and whether they moved rigidly or with a rhythmic, nonrigid "caterpillar"
      motion. Participants of all ages assigned events with contact to the physical
      domain and events without contact to the psychological domain. In addition,
      participants of all ages chose causality more often for events without delay than
      with delay, but these events became more distinct over the preschool range. The
      manipulation of agent motion had only minor and inconsistent effects across
      studies, even though children of all ages considered only the nonrigid motion to
      be animal-like. These results agree with the view that perceptual causality is
      available early in development.

PMID- 12487486
TI  - Testosterone during pregnancy and gender role behavior of preschool children: a
      longitudinal, population study.
AB  - Levels of testosterone (T) and sex hormone-binding globulin (SHBG) were measured
      in blood samples from pregnant women and related to gender role behavior in 342
      male and 337 female offspring at the age of 3.5 years. Gender role behavior was
      assessed using the Pre-School Activities Inventory, a standardized measure on
      which a parent indicates the child's involvement with sex-typical toys, games,
      and activities. Levels of T, but not SHBG, related linearly to gender role
      behavior in preschool girls. Neither hormone related to gender role behavior in
      boys. Other factors, including the presence of older brothers or sisters in the
      home, parental adherence to traditional sex roles, the presence of a male partner
      in the home, and maternal education, did not relate to gender role behavior in
      this sample and did not account for the relation observed between T and behavior.
      Although other, unmeasured factors may explain the relation, the results suggest
      that normal variability in T levels prenatally may contribute to the development
      of individual differences in the gender role behavior of preschool girls.

PMID- 12487487
TI  - Phantoms and fabrications:young children's detection of implausible lies.
AB  - The present study investigated whether young children are gullible and readily
      deceived by another's lies. Specifically, this study examined whether young
      children believe a lie teller's statement when the statement violates their
      developing knowledge of a distinction between reality and fantasy. In the first
      three experiments 3- to 6-year-olds (N = 293) were presented with either a story
      or a live staged event in which an individual made an implausible statement about
      a misdeed (claiming that a ghost jumped out of a book and broke a glass). A
      significant age effect was obtained: 5- and 6-year-olds tended to report that the
      individual who made the implausible statement had actually committed the misdeed,
      whereas 3- and 4-year-olds tended to accept the claim of the protagonist.
      Experiment 4 revealed that 5- and 6-year-olds (N = 43) not only disbelieved an
      individual's implausible statement but also inferred that the individual was
      lying and had a deceptive intent. In contrast, Experiment 5 revealed that 3- and
      4-year-olds (N = 41) had difficulty disbelieving an individual's implausible
      claim about an inanimate object (i.e., the claim that a chair came alive and
      broke the glass). The findings suggest that 5- and 6-year-olds are not so
      gullible as previously thought, and that they use their well-developed real-world
      knowledge to detect scapegoating lies. In contrast, many younger children tend to
      believe another's implausible lies, perhaps due to the fact that the knowledge
      needed to detect such lies has not yet been consolidated.

PMID- 12487488
TI  - Developmental change in proactive interference.
AB  - The aim of the present research was to examine age-related change in proactive
      interference, which refers to impaired recall due to interference from material
      presented previously. Study 1 was a meta-analysis based on 26 studies that
      included 82 data sets. The results indicated that proactive interference
      decreased between 4 and 13 years of age. In Study 2, children from grades 3
      through 6 and college students (N = 125) were administered a short-term memory
      task in which they briefly remembered sets of three words. For all ages, recall
      was accurate on Trial 1. However, recall became less accurate over Trials 2
      through 4, particularly for the younger children in the sample. In addition,
      structural equation modeling revealed that age-related change in interference was
      linked to age-related change in speed of information processing. Results are
      discussed in terms of the nature of age-related change in interference.

PMID- 12487489
TI  - Maternal mind-mindedness and attachment security as predictors of theory of mind
      understanding.
AB  - This study investigated relations between social interaction during infancy and
      children's subsequent theory of mind (ToM). Infant-mother pairs (N = 57) were
      observed in a free-play context at 6 months. Interactions were coded for (a)
      mothers' use of mental state language that commented appropriately on the
      infants' mental states, and (b) mothers' use of mental state language that did
      not appropriately reflect their infants' minds. A third variable was (c) security
      of attachment, which was assessed using the Strange Situation procedure at 12
      months. Performance on a battery of ToM tasks at 45 and 48 months was positively
      correlated with (a), but was not related to (b) or (c). A regression analysis
      showed that mothers' use of appropriate mental state comments independently
      predicted overall ToM performance, accounting for 11% of the variance. Children's
      verbal ability was the only other independent predictor of ToM performance,
      accounting for 16% of the variance. These findings represent the earliest known
      social predictor of individual differences in ToM.

PMID- 12487490
TI  - Children's understanding of the distinction between intentions and desires.
AB  - Much of the previous research on children's understanding of intentions
      confounded intentions with desires. Intentions and desires are different, in that
      a desire can be satisfied in a number of ways, but an intention must be satisfied
      by carrying out the intended action. Children 3 through 7 years of age and adults
      were presented with situations in which intentions were satisfied but desires
      were not, or vice versa, in a story-comprehension task (N = 71) and a target
      hitting game (N = 45). Although 3- and 4-year-olds were unable to differentiate
      desires and intentions consistently, 5- and 7-year-olds often matched the adult
      pattern. Younger children's difficulties in understanding intentions are
      discussed in terms of their use of a desire-outcome matching strategy and the
      representational complexities of intentions.

PMID- 12487491
TI  - Teenage childbearing, marital status, and depressive symptoms in later life.
AB  - This study examined the role of prechildbearing characteristics in later-life
      depressive symptomatology among 990 married and unmarried teenage childbearers.
      Data from teenagers in the National Longitudinal Survey of Youth (NLSY79) were
      used to test the relative contribution of age and marital status at first birth
      to depressive symptomatology measured during young adulthood (ages 27-29).
      Unmarried teenage childbearers displayed higher levels of depressive symptoms in
      young adulthood than did women who first give birth as married adults. However,
      the psychological health of married teenage mothers in later life was as good as
      that of married adult mothers, whereas unmarried adult mothers and unmarried
      teenage mothers had similarly poor outcomes. The findings of this study suggest
      that marital status, rather than age at first birth, may be more relevant for
      later-life psychological health.

PMID- 12487492
TI  - Adolescent twins and emotional distress: the interrelated influence of nonshared
      environment and social structure.
AB  - This study examined the power of nonshared environment to differentiate the
      development of adolescent monozygotic twins, and the extent to which this power
      varied across social structural contexts (e.g., ethnicity, socioeconomic status).
      Estimation of difference score models on 289 same-sex monozygotic twin pairs from
      the National Longitudinal Study of Adolescent Health revealed that differences in
      maternal closeness, teacher bonding, and religious participation differentiated
      monozygotic twins on emotional distress, with the more distressed twin typically
      lower on all three. Family income was the strongest structural moderator of these
      relations, with parental autonomy granting more important in higher income
      families and religious participation more important in lower income families.
      Finally, in some groups, one monozygotic twin's emotional distress was also
      associated with the other twin's familial and extrafamilial relationships. The
      results of this study demonstrate that interpersonal contexts can shape
      monozygotic twins' individual experiences within the structure of the larger
      society.

PMID- 12487493
TI  - Modeling emotional, cognitive, and behavioral predictors of peer acceptance.
AB  - Integrating principles of differential emotions theory and social information
      processing theory, this study examined a model of emotional, cognitive, and
      behavioral predictors of peer acceptance in a sample of 201 early elementary
      school-age children (mean age = 7 years, 5 months). A path analytic model showed
      that social skills mediated the effect of emotion knowledge on both same- and
      opposite-sex social preference, but social skills and verbal ability were more
      strongly related to opposite-sex peer acceptance. These findings suggest that
      adaptive social skills constitute a mechanism through which children express
      their emotion knowledge and achieve peer acceptance. Results also supported
      findings of previous studies that showed that emotion knowledge mediated the
      effect of verbal ability on social skills. Findings from the present study have
      specific implications for emotion-centered prevention programs that aim to
      improve children's socioemotional competence and enhance the likelihood of peer
      acceptance.

PMID- 12487494
TI  - Japanese and American children's evaluations of peer exclusion, tolerance of
      differences, and prescriptions for conformity.
AB  - Children and adolescents (N = 1,057), divided by gender, at fourth, seventh, and
      tenth grades, from two mid-sized cities in the United States and in Japan, were
      surveyed regarding their evaluations of peer group exclusion of atypical peers.
      Six reasons for atypicality were being aggressive, having an unconventional
      appearance, acting like a clown, demonstrating cross-gender behavior, being a
      slow runner, and having a sad personality. Analyses revealed significant effects
      for age, gender, country membership, and the context of exclusion. With age,
      children demonstrated context sensitivity, and believed that the excluded child
      should not change him- or herself to be accepted by the group. Across contexts,
      girls were less willing to exclude than were boys, and were more tolerant of
      differences. The context of exclusion had an effect on all forms of judgments
      about exclusion, and there were very few overall effects for culture. Most
      children disagreed with the decision to exclude, believed that they were
      different from the atypical child, and believed that the excluded child should
      change him- or herself to be accepted by the group. The results support a theory
      of developmental social cognition in which multiple sources of influence have a
      significant effect on social decision making involving the exclusion of others.

PMID- 12487495
TI  - Self in context: autonomy and relatedness in Japanese and U.S. mother-preschooler
      dyads.
AB  - Cultural differences and similarities in socialization during two contrasting
      laboratory tasks were examined in 30 Japanese mothers and their preschoolers,
      both temporarily residing in the United States, and 30 U.S. mothers and their
      preschoolers (age: M = 55.8 months, SD = 4.9). Mother and child actions, speech,
      emotion, and attention were coded from videotaped observations during a free play
      task and waiting task. Cross-cultural comparisons showed that U.S. mothers had
      more conversations that emphasized individual experiences, more often acted as
      playmates and used joint attention, maintained more physical distance, showed
      more positive emotions, and made more positive responses to child accomplishment.
      In contrast, Japanese mothers had more conversations that emphasized shared
      experiences, showed more divided attention, and maintained social role
      distinctions. Similar, but fewer cultural differences emerged for children.
      However, maternal and child characteristics also varied by task context. The
      results suggested an emphasis on autonomy in U.S. dyads and an emphasis on
      relatedness in Japanese dyads, but the interactions with task context revealed
      the coexistence of autonomy and relatedness.

PMID- 12487496
TI  - Group size regulates self-assertive versus self-deprecating responses to
      interpersonal competition.
AB  - The current study examined the hypothesis that group size can influence whether
      children display self-assertive versus self-deprecating responses to
      interpersonal competition, especially under stress. Twenty same-sex play-groups
      (N = 120) of 9- to 10-year-old children played a competitive game in groups and
      in dyads. Stress was induced by causing some of the children to lose the game and
      watch as their opponents received psychological and material rewards. Results
      demonstrated that both the dynamics of the game and individual reactions to
      stress varied consistently as a function of the social context. Individuals
      displayed more assertive behaviors in groups than in dyads. In contrast,
      individuals exhibited more self-deprecating behaviors in dyads than in groups.
      Given that under naturalistic conditions males are more likely than are females
      to interact in groups and females are more likely than are males to interact in
      dyads, group size provides one possible mechanism for the development of sex
      differences in self-assertive versus self-deprecating behaviors.

PMID- 12487497
TI  - Co-rumination in the friendships of girls and boys.
AB  - This research addresses a new construct, co-rumination. Co-rumination refers to
      extensively discussing and revisiting problems, speculating about problems, and
      focusing on negative feelings. Friendship research indicates that self-disclosure
      leads to close relationships; however, coping research indicates that dwelling on
      negative topics leads to emotional difficulties. Co-rumination is a single
      construct that integrates both perspectives and is proposed to be related both to
      positive friendship adjustment and problematic emotional adjustment. Third-,
      fifth-, seventh-, and ninth-grade participants (N = 608) responded to
      questionnaires, including a new measure of co-rumination. Co-rumination was
      related to high-quality, close friendships and aspects of depression and anxiety.
      Girls reported co-ruminating more than did boys, which helped to account for
      girls' more positive friendship adjustment and greater internalizing symptoms.
      Other analyses addressed whether co-rumination and the related constructs of self
      disclosure and rumination had different relations with friendship and emotional
      adjustment.

PMID- 12487498
TI  - Neighborhood income and physical and social disorder in Canada: associations with
      young children's competencies.
AB  - This study examined the association of census level, observational, and parent
      reported neighborhood characteristics on the verbal and behavioral competencies
      of a national sample of Canadian preschoolers (N = 3,350). Children's verbal
      ability scores were positively associated with residing in neighborhoods with
      affluent residents and negatively associated with residing in neighborhoods with
      poor residents and in neighborhoods with low cohesion, even after controlling for
      family socioeconomic factors. Behavior problem scores were higher when children
      lived in neighborhoods that had fewer affluent residents, high unemployment
      rates, and neighborhoods with low cohesion, after controlling for family
      socioeconomic factors. These findings are discussed in light of neighborhood
      studies of children in the United States in the mid-1990s.

PMID- 12487499
TI  - How money matters for young children's development: parental investment and
      family processes.
AB  - This study used data from the Panel Study of Income Dynamics and its 1997 Child
      Development Supplement to examine how family income matters for young children's
      development. The sample included 753 children who were between ages 3 and 5 years
      in 1997. Two sets of mediating factors were examined that reflect two dominating
      views in the literature: (1) the investment perspective, and (2) the family
      process perspective. The study examined how two measures of income (stability and
      level) were associated with preschool children's developmental outcomes (Woodcock
      Johnson [W-J] Achievement Test scores and the Behavior Problem Index [BPI])
      through investment and family process pathways. Results supported the hypothesis
      that distinct mediating mechanisms operate on the association between income and
      different child outcomes. Much of the association between income and children's W
      J scores was mediated by the family's ability to invest in providing a
      stimulating learning environment. In contrast, family income was associated with
      children's BPI scores primarily through maternal emotional distress and parenting
      practices. Level of income was associated with W-J letter-word scores and income
      stability was associated with W-J applied problem scores and BPI, even after all
      controls were included in the models.

PMID- 12487500
TI  - Children's patterns of preserving emotional security in the interparental
      subsystem.
AB  - Guided by the emotional security hypothesis, this research identified (1)
      individual differences in children's strategies for preserving their emotional
      security in the interparental relationship, and (2) the psychosocial and family
      correlates of these individual differences. Study 1 assessed reactivity to
      parental conflict simulations among 56 school-age children, whereas Study 2
      solicited child and mother reports of 170 young adolescents' reactions to actual
      marital conflict. Cluster analyses in both studies indicated that children fit
      three profiles: (1) secure children, who showed well-regulated concern and
      positive representations of interparental relationships; (2) insecure-preoccupied
      children, who evidenced heightened distress, involvement or avoidance, and
      negative representations of interparental relationships; and (3) insecure
      dismissing children, who displayed overt signs of elevated distress, avoidance,
      and involvement and low levels of subjective distress, avoidance and intervention
      impulses, and negative internal representations. Results in both studies
      indicated that preoccupied and dismissing children experienced more interparental
      conflict than did secure children, and preoccupied children evidenced the highest
      levels of internalizing symptoms. Study 2 results indicated that dismissing
      children had the highest levels of externalizing symptoms and preoccupied and
      dismissing children reported more coping, family, and personality difficulties
      than did secure children.

PMID- 12487501
TI  - How economists think about family resources and child development.
AB  - Research in child development reveals that the sources, level, stability, and
      uses of family resources have a profound effect on children's well-being and long
      term outcomes. Although that research has incorporated economic constructs and
      measures, developmentalists generally ignore the formal economic framework for
      thinking about family resources and child outcomes. Building on the premise that
      children are an investment, that framework explains how families allocate
      resources and links that decision to other family choices and to key child
      outcomes, such as schooling, morbidity, and mortality among others. This article
      explains economists' general approach to family behavior (the so-called theory of
      household production) and then describes how that framework is useful for
      thinking about families and children. The article then outlines how economists
      model parental investment in children and examines the implications of that
      approach for developmental science. This discussion is illustrated using an
      example of interest to developmentalists--the involvement of children and
      adolescents in after-school activities. A concluding section discusses the
      benefits of and potential barriers to collaboration between economists and
      developmentalists.

PMID- 12487502
TI  - A postmarketing clinical experience study of Metadate CD.
AB  - OBJECTIVE: The objective of the study was to investigate the effectiveness and
      safety of Metadate CD (methylphenidate HCl, USP) Extended Release Capsules in the
      treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), in actual clinical
      practice. METHOD: This was a multicenter, open-label, postmarketing study.
      Eligible patients were aged 6-17 with a diagnosis of ADHD and receiving either no
      treatment or maintenance treatment with another approved methylphenidate (MPH)
      product. Metadate CD was administered once daily for 3 weeks, titrated against
      reported and observed symptoms. Clinical Global Impression (CGI) scores at Week 3
      were used for the primary efficacy evaluation. Patient treatment satisfaction was
      determined by questionnaire at the final evaluation visit. Safety was assessed
      through adverse event reporting, laboratory tests and vital sign measurements.
      RESULTS: Overall, of the 308 patients in the Intent-To-Treat population, the
      majority (65%) demonstrated a positive response to Metadate CD (defined as CGI
      Global Improvement rating of very much or much improved). In addition, patients
      previously treated with immediate-release or extended-release tablet formulations
      of MPH were successfully converted to Metadate CD at a comparable dose. Most
      patients (87%) were very satisfied or moderately satisfied with study treatment,
      and among previously treated patients, 71% rated Metadate CD as much better or
      better than their previous MPH treatment. Adverse events were consistent with
      current FDA-approved product labeling for Metadate CD. CONCLUSIONS: Metadate CD
      is effective and well-tolerated in actual clinical use for ADHD.

PMID- 12487503
TI  - Therapeutic efficacy and clinical acceptability of fusafungine in follicular
      pharyngitis.
AB  - Eighty-one patients suffering from follicular pharyngitis were treated for 7 days
      in a double-blind, multicentre controlled study of fusafungine versus placebo.
      Evaluations were performed at inclusion, after 7 days of treatment, and 3 weeks
      after the end of the treatment. The effects of the pharyngitis on day-to-day
      life, changes in symptoms, morphological changes of lesions, and general changes
      observed by the investigator and expressed by the patient were the parameters
      evaluated at each visit. Results confirmed the efficacy of fusafungine in the
      treatment of local and symptomatic manifestations of follicular pharyngitis.
      Effects of follicular pharyngitis on day-to-day life decreased after 7 days of
      treatment and the differences between the treatment group and the placebo group
      was close to significance in favour of fusafungine. For the majority of symptoms,
      the percentage of patients who did not display the symptoms at D7 was greater in
      the fusafungine group. Postnasal drip decreased significantly in the fusafungine
      group. The investigators' and patients' judgement was also in favour of the
      fusafungine treatment. These improvements were confirmed at least 3 weeks after
      the end of the treatment.

PMID- 12487504
TI  - Trimetazidine limits the effects of myocardial ischaemia during percutaneous
      coronary angioplasty.
AB  - This open-label, randomised, controlled study is aimed at assessing the effect of
      pre-treatment with the metabolic agent trimetazidine on the degree of ischaemia
      during percutaneous transluminal coronary angioplasty (PTCA). Overall 44 patients
      with one-vessel coronary artery stenosis (> 70%) in the medial part of the left
      anterior descending artery were included. One group (n = 22) was pre-treated with
      oral trimetazidine. The other group (n = 22) was the control. All patients (n =
      44) were administered aspirin and conventional treatment. All patients underwent
      PTCA; stents were implanted in 11 trimetazidine patients and in seven control
      patients. The mean ST-segment elevation during all balloon inflations was
      significantly lower in the trimetazidine group than in the control group (-1.66
      +/- 1.50 mm vs. 3.29 +/- 1.59 mm, p = 0.001). Maximal ST-segment elevations and
      mean ST elevation values during sequential balloon inflations were also
      significantly lower with trimetazidine (p = 0.018). The mean amplitude of the T
      wave alterations during all balloon inflations was significantly lower with
      trimetazidine (3.09 +/- 2.39 mm vs. 6.83 +/- 4.31 mm; p = 0.001). Similarly, the
      maximal amplitude of the T-wave alterations was 4.50 +/- 2.90 mm with
      trimetazidine vs. 9.25 +/- 4.97 mm in control patients (p = 0.0005). Angina and
      rhythm disturbances were more frequent in the control group. Time from balloon
      inflation to onset of angina was 50 +/- 26.2 s with trimetazidine vs. 32 +/- 15.0
      s, for control group (p = 0.03). The time to pain relief after deflation was 19.3
      +/- 11.4 s with trimetazidine vs. 28.2 +/- 16.8 s (p = 0.001). Trimetazidine
      administered a few days before PTCA appears to be a cardioprotective agent for
      the prevention of myocardial ischaemia.

PMID- 12487505
TI  - Efficacy and safety of telithromycin in community-acquired pneumonia.
AB  - Telithromycin, the first ketolide antibacterial, was developed for the treatment
      of community-acquired respiratory tract infections. This multicenter, open-label,
      uncontrolled study assessed the efficacy and safety of 800 mg, once-daily
      telithromycin in adults with community-acquired pneumonia (CAP). Based on
      bacteriologic eradication rates, telithromycin was shown to be effective for the
      treatment of CAP. Telithromycin was generally well tolerated, with gastro
      intestinal adverse events observed most frequently (diarrhea 4/218 [1.8%], nausea
      4/218 [1.8%], vomiting 5/218 [2.3%]). These results were consistent with those
      observed in randomized, active-controlled studies.

PMID- 12487506
TI  - Advances in breast oncology: the 2002 ASCO meeting.
AB  - At this year's American Society of Clinical Oncology (ASCO) meeting, a number of
      important advances in breast cancer diagnosis, treatment and prevention were
      reported. In this article, we review these current developments, focusing
      particularly on the ASCO technology assessment report--which discussed the
      adjuvant use of aromatase inhibitors in breast cancer--and other significant
      studies which were presented or updated: the role of taxanes in neoadjuvant and
      adjuvant therapy; current concepts regarding the timing of hormonal therapy
      during adjuvant chemotherapy; and cyclooxygenase-2 (COX-2) as a target for
      disruption in breast cancer treatment and prevention. With regards to advances in
      surgery, we review studies which were presented concerning the evolving role of
      sentinel lymph node biopsy in the management of the axilla in breast cancer, and
      review the latest meta-analysis on this subject presented at the meeting.

PMID- 12487507
TI  - Denopamine, a selective beta1-receptor agonist and a new coronary vasodilator.
AB  - Up until now, it has been suggested that nitrate and/or calcium channel blockers
      were effective against variant angina pectoris. On the other hand, it is known
      that about 20% of variant angina pectoris was refractory to both nitrate and
      calcium channel blockers. In Japan, it has been reported that denopamine, which
      is an oral beta1-adrenoceptor selective agonist developed by the Japanese
      pharmaceutical industry (Tanabe Seiyaku), is effective in those refractory cases.
      To date, in Japan nine cases have been recognized of patients with vasospastic
      angina pectoris whose symptoms were relieved by taking denopamine, including one
      case in which the author has had personal experience. Eight of these nine cases
      were refractory, and were not relieved by combined therapy using both nitrate and
      a calcium channel blocker. It was also documented that denopamine was effective
      in cases where attacks were not relieved by prazosin or magnesium, which have
      been documented as effective in other refractory cases. In a study of canine
      coronary arteries, localization of beta-adrenoceptor subtypes was documented,
      with the beta1-adrenoceptor predominantly found in the conduit coronary artery.
      In recent years it has been emphasized that the principal role of sympathetic
      nerves was not associated with the constrictive action of alpha-adrenoceptors,
      but with the coronary dilative action of beta-adrenoceptors. It would therefore
      be worthwhile to determine whether denopamine is able to relieve vasospastic
      angina pectoris in many more cases.

PMID- 12487508
TI  - New guidelines for the management of migraine in primary care.
AB  - Despite repeated initiatives over the past decade, migraine remains under
      recognised, under-diagnosed and under-treated in everyday clinical practice. The
      Migraine in Primary Care Advisors (MIPCA) group has produced new guidelines for
      migraine management to attempt to rectify this situation. MIPCA is a group of
      physicians, nurses, pharmacists and other healthcare professionals dedicated to
      the improvement of headache management in primary care, who have also worked
      closely with the Migraine Action Association (the UK patients' group) in the
      development of these guidelines. The principles of the new MIPCA guidelines are:
      To arrange specific consultations for headache. To institute a system of detailed
      history taking, patient education and buy-in at the outset of the consultation.
      To utilise a new screening algorithm for the differential diagnosis of headache,
      which can be confirmed by further questioning, if necessary. To institute a
      process of management that is individualised for each patient, using a new
      algorithm. Assessing the impact on the patient's daily life is a key aspect of
      diagnosis and management. To prescribe only treatments that have objective
      evidence of favourable efficacy and tolerability. To utilise prospective follow
      up procedures to monitor the success of treatment. To organise a team approach to
      headache management in primary care.

PMID- 12487509
TI  - Improved haemoglobin concentrations with IV darbepoetin alfa--case studies of
      haemodialysis patients.
AB  - This paper presents two case histories of patients receiving intravenous (IV)
      darbepoetin alfa for the treatment of anaemia in chronic renal failure. The paper
      sets these cases against the general clinical picture of patients receiving
      intravenous darbepoetin alfa in our renal unit.

PMID- 12487510
TI  - Comments on effect of food on early drug exposure from extended-release
      stimulants: results from the Concerta, Adderall XR food evaluation study.

PMID- 12487512
TI  - Auld--the criminal Woolf?

PMID- 12487511
TI  - The conjoined twins. Transcript of the speeches given at the BAFS annual dinner
      on 28 February 2002. British Academy of Forensic Sciences.

PMID- 12487513
TI  - The eye of the beholder: ratings of risk using a reliable instrument and
      identical clinical material.
AB  - Risk management is increasingly seen as a task for health professionals. However
      little is known about how different professionals perceive and rate risk. The
      purpose of this study was to see if professional background and experience
      influence how an assessor rates risk. Psychiatric staff were presented with
      identical clinical information about one case. They were then asked to score the
      HCR-20. This is a structured clinical assessment and gives a score of between 0
      and 40. Higher scores indicate increased risk of future violence. There was a
      twofold variation in the score from 15 to 30. There was no difference between
      medical and non-medical staff. However there was a significant difference between
      different grades of psychiatrists. Senior psychiatrists scored the clinical and
      risk items significantly lower when compared with junior psychiatrists. There was
      no significant difference in the scoring of historical items. The twofold
      variation in the score on the HCR-20 emphasises that risk assessment is a two-way
      process. Individual differences of assessors may be very important. Our findings
      suggest that senior psychiatrists score risks as lower. Possible explanations are
      discussed.

PMID- 12487514
TI  - Assessing the therapeutic impact of a community group on a secure hospital ward.
AB  - The constructs of ward staff and patients in a medium secure rehabilitation ward
      were assessed before and after an eight-month trial of a twice weekly community
      group. One of the aims of this group was to address day-to-day interpersonal
      issues and to encourage patients to take social responsibility for their actions
      and to learn to support one another. Another aim was to encourage staff and
      patients to consider the possibility of applying some therapeutic community
      principles on the ward. These aims were assessed using repertory grid techniques.
      The results were that over the eight-month pilot both staff and patient groups
      shifted towards viewing their ideal ward as a therapeutic community (TC). However
      qualitative information suggested that considerable difficulties arose in
      bringing about the necessary cultural changes. As a result both staff and
      patients felt confused and disempowered. Future attempts are highly recommended,
      however better resourcing, particularly in the form of employing a trained full
      time individual to co-ordinate activities, is essential.

PMID- 12487515
TI  - Massive hepatocellular [correction of hepatocullular] necrosis: was it caused by
      Orlistat?
AB  - Orlistat (tetrahydrolipostatin) is a lipase inhibitor which is used, in
      conjunction with appropriate dietary control, for the treatment of obesity. It is
      generally deemed to be a safe drug, which mainly exerts a topical action on the
      stomach and small bowel, with negligible systemic absorption and oral
      bioavailability. Consequently, its adverse effects have largely been limited to
      relatively mild gastrointestinal disorders. However, there have been recent,
      published reports of non-fatal acute hepatitis and systemic hypertension
      associated with its use. The present case concerns a 62-year-old male who died
      from massive hepatocellular necrosis, consistent with drug-induced, fulminant
      hepatitis, associated with the use of oral orlistat, presumably administered at
      the recommended daily dose of 360 mg. It is postulated that this may represent a
      rare idiosyncratic reaction to the drug.

PMID- 12487516
TI  - Left side right ventricular cardiomyopathy.
AB  - Arrhythmogenic right ventricular cardiomyopathy or dysplasia, a heart muscle
      disease of unknown cause, is anatomically characterized by variable replacement
      of myocardial muscle with adipose or fibroadipose tissue. It is usually
      considered a selective disorder whereas concomitant left ventricular involvement
      has been noted in a few cases. Two cases of the disease with evidence of
      extensive left ventricular involvement at pathologic examination are described.
      Hearts from two patients who died suddenly showed extensive biventricular
      infiltration by fibrofatty tissue in the first case and exclusively in the wall
      of the left ventricle the localization of the fatty and fibrotic lesions. These
      findings might suggest that the various localizations of the fibroadipose tissue
      are rather different expressions of the same disease and it is preferable to be
      termed 'arrhythmogenic cardiomyopathy' as other studies also indicate.

PMID- 12487517
TI  - Prospective study of coroner's autopsies in Benin City, Nigeria.
AB  - A prospective study of 726 cases of coroner's autopsies carried out over a period
      of two years (1st January, 1996 - 31st December, 1997) was reviewed. The causes
      and circumstances of death are defined and classified into natural and unnatural
      deaths. Fifty cases (6.3%) were children while the remaining 676 cases (93.1%)
      were adults in a male to female ratio of 2.6 to 1. The most common indications
      for coroner's autopsies were sudden unnatural deaths (SUDs) accounting for 485
      cases (66.8%) and also sudden unexpected natural deaths (SUNDs) (241 cases)
      accounting for 33.2%. In the first category, road traffic accidents accounted for
      86.7% of cases with deaths involving motor vehicle drivers and their passengers
      (41.8%); pedestrians (37.1%); and motorcyclists and their passengers (18.6%). The
      commonest causes of death in all road traffic accidents were craniocerebral
      injuries and haemorrhagic shock. In the second category the most common causes of
      sudden unexpected natural death were cardiovascular diseases resulting from
      complications of hypertension (54.7%) occurring in apparently healthy
      individuals. Other causes of death were pneumonia, pulmonary tuberculosis,
      typhoid fever and neoplastic diseases. This study showed that in Nigeria, with an
      increasing acquisition of dietary and life style habits of the developed western
      world, there is becoming a concomitant risk of deaths from road traffic accidents
      and sudden unexpected natural deaths from hypertensive cardiovascular disease.

PMID- 12487518
TI  - Mental impairment in the West Midlands: 10 years on.
AB  - In 1989, a survey was undertaken to describe the learning disabled population,
      originating from the West Midlands, classified as mentally impaired or severely
      mentally impaired under the Mental Health Act 1983. The results obtained were
      then used to help guide future service development within the region. Given the
      marked changes in service provision over the subsequent decade, the study was
      repeated in 1998-1999, looking at the same population on 1st December 1997 (prior
      to the Bournewood Ruling). Attempts were made to identify all people residing
      within the West Midlands region, or originating from it, and classified as
      mentally impaired or severely mentally impaired under the Mental Health Act
      (1983). This was achieved by contacting medical records departments, learning
      disability consultants and Health Authorities. The same data set as the original
      study was then collected from case notes to allow comparison. The current study
      however, collected extra information, relating to diagnosis, treatment and
      outcome. Ninety-three people were identified for the study. Over the 10 years,
      there has been approximately a 100% increase in the numbers of people detained
      under these categories of the Mental Health Act (1983). There has been a marked
      increase in the use of the private sector, as well as out-of-region placements.
      Sexual offending seemed a common reason for detention. The authors attempt to
      explain this phenomenon. They also highlight the need for future developments and
      greater systematic data collection.

PMID- 12487519
TI  - Their last words: a review of suicide notes in the elderly.
AB  - Suicide notes are considered as markers of the severity of a suicide attempt and
      are said to provide valuable insight into the thinking of suicide victims before
      the fatal act. However, very few studies have described elderly suicide note
      writers and their final thoughts. In this retrospective review of suicide notes
      obtained from coroners' records in North Cheshire over a period of 13 years from
      1989-2001 we examined the content of suicide notes and their clinical
      significance. Suicide note-writers may not be typical of the average suicide and
      information elicited from the study of suicide notes may only apply to note
      writers and not to suicide in general. However, the absence of a suicide note
      must not be considered an indicator of a less serious attempt. Future studies of
      suicide notes need to provide insight into the unique nature of these documents
      and to allow better understanding of the suicidal mind.

PMID- 12487520
TI  - Conditionally discharged restricted patients and the need for long-term medium
      security.
AB  - In the context of a larger investigation of follow-up of a specific group of
      mentally disordered individuals, the study described here examined the
      characteristics of all 55 people conditionally discharged for the first time from
      a medium secure unit in the West Midlands over a 13-year period. A retrospective
      case note analysis was undertaken. The findings illustrate that these patients
      are a distinct group. They were mainly single men who had committed a grave
      offence. The majority had an extensive criminological history with early onset of
      offending and chronic mental illness. Fifty percent of those with a criminal
      record had received at least one custodial sentence prior to the index offence.
      Co-morbid substance misuse was common, as was a history of self-harm. There were
      high levels of previous contact with psychiatric services and compulsory in
      patient treatment. Most were detained under the Mental Health Act category of
      mental illness. A quarter had been transferred from a special hospital prior to
      conditional discharge into the community. The characteristics of this sample
      demonstrate clearly the need for the provision of long-term medium secure
      facilities and allied services.

PMID- 12487521
TI  - Sexual assaults in Singapore: a comparative study of rapists and molesters.
AB  - Sexual assaults vary in terms of severity from molestation, which involves
      touching, stroking, fondling or grabbing of any part of the victim's body, to
      rape, where victims have been known to suffer severe emotional trauma. The aim of
      the study is to compare molesters with rapists using hypotheses that molesters
      and rapists commit their offences at different times of the day, at differing
      locations and with differing relationships with their victims. The influence of
      alcohol on both groups was also studied. Convicted molesters and rapists were
      given a semi-structured interview in prison. Demographic information and details
      of each offence were obtained from prison records. Comparisons were made of the
      demography, time, place, reasons for assault, relationship of offender to victims
      and the role of alcohol and drugs consumed by the perpetrators. Molesters and
      rapists were of similar age and ethnicity, but differed in that rapists had
      attained a lower educational level and were more likely to be single. Rapists
      were more likely to report having drunk alcohol, committing rape after midnight
      and in secluded places. Molesters struck in the afternoon hours and usually in
      crowded places. Victims of molesters tended to be relatives whereas victims of
      rapists were more likely to be ex-spouses or ex-lovers. Molesters tended to give
      other reasons for their offences. Differences between molesters and rapists could
      lead to intervention strategies chiefly targeting the issues of poor
      socialisation skills in molesters and alcohol counseling for rapists.

PMID- 12487522
TI  - An antique pistol fatality: consideration of the legal and pathological aspects:
      a case report.
AB  - This article presents a case report of a shooting using an antique pistol. The
      unusual pathological findings are presented, together with a review of the law in
      this area. It seems that there is currently a loophole in the 1997 Firearms Act
      by means of which 'enthusiasts' or 'collectors' may legally possess weapons and
      then subsequently acquire ammunition illegally.

PMID- 12487523
TI  - An autopsy case of a stunt man who jumped into seawater riding a motorcycle: a
      case report.
AB  - We report a rare case of the death of a stunt man who jumped into the sea driving
      a motorcycle on location for a TV drama. A special ramp had been constructed for
      the jump. The stunt man and a passenger drove up the ramp at a speed of 60-70
      km/h and jumped into the sea from a height of about five metres. Both men swam
      up, but the driver fell unconscious at the surface. He was sent to hospital, but
      did not recover. The autopsy revealed a deep laceration of the right axilla with
      complete rupture of the axillary artery, bone fractures of the right ribs and the
      right pelvis, and a small laceration of the upper lobe of the right lung. Other
      visceral organs were not injured. We finally judged that his cause of death was
      exsanguination due to rupture of the right axillary artery on the basis of the
      presence of a small amount of blood inside the heart and ischemic organs. All
      injuries were probably inflicted by a collision with the motorcycle upon reaching
      the water surface; the axillary injury might be due to the left handlebar
      piercing into the part.

PMID- 12487524
TI  - Head injury with traumatic and postural asphyxia: a case report.
AB  - An autopsy was performed on a 22-year-old tractor driver who was found on a
      cliff, 20 feet down from the highway, trapped between the wheel of a tractor
      trolley and some stones in an inverted position, after sustaining a head injury.
      Post mortem lividity was present above the knee joints except where the left arm
      was firmly adducted on the chest and where the cloth folds were compressing on
      the chest and abdomen all round. Sub-mucosal ecchymoses and petechial hemorrhages
      were present in the pharyngeal walls, and on both surfaces of the epiglottis and
      larynx above the vestibular folds. Such hemorrhages were first noticed along with
      other findings of traumatic and postural asphyxia.

PMID- 12487525
TI  - Increases in fluoroquinolone-resistant Neisseria gonorrhoeae--Hawaii and
      California, 2001.
AB  - Neisseria gonorrhoeae is a major cause of pelvic inflammatory disease, ectopic
      pregnancy, and infertility, and it can facilitate human immunodeficiency virus
      (HIV) transmission. Gonorrhea is the second most frequently reported communicable
      disease in the United States, with 361,705 reported cases in 2001. During the
      1980s, gonococcal resistance to penicillin and tetracycline became widespread; as
      a result, CDC recommended using cephalosporins as first-line treatment for
      gonorrhea. Since 1993, CDC also has recommended using fluoroquinolones (i.e.,
      ciprofloxacin, ofloxacin, or levofloxacin) for gonorrhea treatment.
      Fluoroquinolone therapy is used widely because it is a relatively inexpensive,
      oral, and single-dose therapy. However, fluoroquinolone-resistant N. gonorrhoeae
      (QRNG) is being identified more frequently. This report summarizes investigations
      of increases in QRNG in Hawaii and California in 2001 and provides data to
      support the recommendation that cephalosporins (i.e., ceftriaxone or cefixime) be
      used instead of fluoroquinolones as first-line treatment for gonorrhea acquired
      in these two states. The increases in QRNG highlight the importance of monitoring
      gonococcal resistance throughout the United States to guide local treatment
      decisions.

PMID- 12487526
TI  - Multistate outbreaks of Salmonella serotype Poona infections associated with
      eating cantaloupe from Mexico--United States and Canada, 2000-2002.
AB  - Three multistate outbreaks of Salmonella serotype Poona infections associated
      with eating cantaloupe imported from Mexico occurred in the spring of consecutive
      years during 2000-2002. In each outbreak, the isolates had indistinguishable
      pulsed-field gel electrophoresis (PFGE) patterns; the PFGE patterns observed in
      the 2000 and 2002 outbreaks were indistinguishable, but the pattern from 2001 was
      unique among them. Outbreaks were identified first by the California Department
      of Health Services (2000 and 2001) and the Washington State Department of Health
      (2002) and involved residents of 12 states and Canada. This report describes the
      investigations, which led ultimately to an import alert on cantaloupes from
      Mexico. To limit the potential for cantaloupe contamination, the Food and Drug
      Administration (FDA) continues to work with the Mexican government on a food
      safety program for the production, packing, and shipping of fresh cantaloupes.

PMID- 12487527
TI  - Enterovirus surveillance--United States, 2000-2001.
AB  - Enteroviruses are common viruses associated with diverse clinical manifestations
      ranging from mild febrile illness to severe and potentially fatal syndromes
      including aseptic meningitis, encephalitis, neonatal systemic enteroviral
      disease, and paralytic poliomyelitis. A total of 64 enterovirus serotypes are
      recognized, including 61 nonpolio enteroviruses. Individual serotypes have
      different temporal patterns of circulation and often are associated with
      different clinical manifestations. This report describes temporal trends in
      reported enterovirus infections in the United States during 2000-2001, including
      widespread activity of two serotypes (echoviruses 13 and 18) that previously were
      detected rarely. Monitoring of circulating enterovirus serotypes helped identify
      these two agents as the primary causes of aseptic meningitis outbreaks in the
      United States in 2001. Further improvements in timeliness of reporting and
      geographic representation of the system are needed to allow more complete
      surveillance for enteroviruses.

PMID- 12487528
TI  - West Nile virus activity--United States, November 14-20, 2002, and Missouri,
      January 1-November 9, 2002.
AB  - This report summarizes West Nile virus (WNV) surveillance data reported to CDC
      through ArboNET and by states and other jurisdictions as of 9 a.m. Mountain
      Standard Time, November 20, 2002.

PMID- 12487529
TI  - Approval of a new rapid test for HIV antibody.
AB  - On November 7, 2002, the Food and Drug Administration announced approval of the
      OraQuick Rapid HIV-1 Antibody Test (OraSure Technologies, Inc., Bethlehem,
      Pennsylvania) for use by trained personnel as a point-of-care test to aid in the
      diagnosis of infection with human immunodeficiency virus type 1 (HIV-1). OraQuick
      is a simple, rapid test that can detect antibodies to HIV in fingerstick whole
      blood specimens and provide results in as little as 20 minutes [corrected]. The
      test has been categorized as moderate complexity under the Clinical Laboratory
      Improvement Amendments of 1988 (CLIA). A second FDA-approved moderate-complexity
      rapid HIV test, Single Use Diagnostic System for HIV-1 (Abbott-Murex Inc.,
      Norcross, Georgia), remains available in the United States for use with serum or
      plasma specimens.

PMID- 12487530
TI  - Dietetics education today: dynamic, diverse and essential.

PMID- 12487531
TI  - Online diet analysis tools: a functional comparison.

PMID- 12487532
TI  - Food safety and home delivery.

PMID- 12487533
TI  - Assist the next generation of dietitians.

PMID- 12487534
TI  - Computer-assisted nutrition education.

PMID- 12487535
TI  - Refocusing on public policy--in step with member value.

PMID- 12487536
TI  - Tailoring advice on dietary supplements: an opportunity for dietetics
      professionals.

PMID- 12487537
TI  - Communication between family physicians and registered dietitians in the
      outpatient setting.
AB  - OBJECTIVE: To elicit how registered dietitians and family physicians communicate
      in the outpatient setting. DESIGN: A descriptive pilot study using two mailed
      surveys was conducted to elicit aspects of outpatient communication between
      registered dietitians and family physicians. A sample of nutrition correspondence
      from registered dietitians to family physicians was also requested. SUBJECTS:
      Surveys were distributed to 504 licensed dietitians and 626 family physicians.
      STATISTICAL ANALYSES: Descriptive statistics were used to analyze survey results.
      RESULTS: Responses were received from 389 registered dietitians (77% return rate)
      and 235 family physicians (37.5% return rate). We received 104 sample notes of
      correspondence with physicians from dietitians. Among dietitians, 80% reported
      that they always assess a patient's lifestyle and educational level before
      choosing an educational approach, and 69% send the nutrition treatment plan to
      the referring family physician. Among family physicians, 49% often or always find
      the communications they receive from registered dietitians to be helpful.
      However, 41% of family physicians reported that they rarely receive detailed
      nutrition assessments or recommendations about the referred patient from the
      dietitian, and 54% of all family physicians surveyed often think that this lack
      of feedback compromises patient care. APPLICATIONS/CONCLUSION: Dietitians can
      improve communications with family physicians by standardizing the format and
      focus of nutrition correspondence and assuring that the referring family
      physician receives the patient's nutrition care plan. These simple changes would
      close a very important communication loop, forge stronger partnerships between
      dietitians and family physicians, and potentially improve patient outcomes.

PMID- 12487538
TI  - Fruit and vegetable assessment: performance of 2 new short instruments and a food
      frequency questionnaire.
AB  - OBJECTIVE: To evaluate the ability of 2 new short assessment instruments and a
      food frequency questionnaire (FFQ) to measure intake of fruit and vegetables. The
      "All-Day" screener asks frequency and portion size questions about 9 food items.
      The "By-Meal" screener is similar, except that it asks about 2 of those 9 food
      items in terms of mealtime. DESIGN: Survey participants completed 4 telephone
      administered 24-hour dietary recalls over 1 year, a self-administered FFQ 1 to 2
      months later, and 1 of 2 self-administered screeners after an additional 7
      months. SUBJECTS/SETTING: Participating were 202 men and 260 women aged 20 to 70
      years living throughout the United States. STATISTICAL ANALYSES: Fruit and
      vegetable intakes measured by each screener and the FFQ were compared with true
      usual intake based on a measurement error model with 24-hour dietary recalls as
      the reference instrument. RESULTS: Estimates of median daily servings of fruit
      and vegetables were as follows: For men: True intake (5.8) vs All-Day screener
      (5.0), By-Meal screener (5.5), and FFQ (6.6); for women: true intake (4.2) vs All
      Day screener (5.0), By-Meal screener (5.4), and FFQ (6.2). Estimated correlations
      between the test instruments and true intake were as follows: For men: All-Day
      screener (0.66), By-Meal screener (0.67), FFQ (0.68); for women: All-Day screener
      (0.51), By-Meal screener (0.53), and FFQ (0.54). APPLICATIONS/CONCLUSIONS: Both
      screeners might be useful to estimate median intakes of fruit and vegetable
      servings in US populations, but they might be less useful in accurately ranking
      individuals. More research is needed before using the screeners in ethnic or low
      literacy populations.

PMID- 12487539
TI  - Children's dietary fat intake and fat practices vary by meal and day.
AB  - OBJECTIVE: This research examined the relationship between the dietary fat intake
      and fat practices of children by meal, day of week, and weekend day vs weekday.
      DESIGN: Cross-sectional study. SUBJECTS/SETTING: Fourth- to sixth-grade students
      (n = 520; 25% African-American, 32% white, 33% Mexican-American, 10% Asian/other,
      58% girls) attending 8 parochial schools in Houston, Texas. MAIN MEASURES:
      Students completed daily food records in the classroom for 7 days. Food records
      were hand-coded for high-fat (eg, frying foods, adding fat) and low-fat (eg,
      removing meat fat, drinking low-fat milk) practices, and percent energy from fat.
      STATISTICAL ANALYSES: Descriptive statistics, Spearman correlation coefficients,
      and analysis of variance on fat intake and fat practices by demographic variables
      and weekend vs weekday. RESULTS: Students consumed 36% of total energy from fat,
      reported 0.59 low-fat practices, and 6.3 high-fat practices per day. Only 13%
      consumed 30% or less energy from fat. Significant correlations were found between
      percent energy from fat and high-fat practices and low-fat practices (r = 0.27, P
      < .001 and r = -0.15, P < .01, respectively). APPLICATIONS/CONCLUSIONS:
      Intervention programs targeting children's dietary fat behaviors should include
      teaching skills that enable children to ask for low-fat foods like fruit,
      vegetables, low-fat snacks and dairy foods. These foods should be made available
      in the home to encourage children to practice low-fat dietary behaviors, which
      may differ depending on meal, day, and meal source.

PMID- 12487540
TI  - Anthropometric measurements and body silhouette of women: validity and
      perception.
AB  - OBJECTIVE: To examine the validity of self-reported values for current
      anthropometric measurements and factors related to misreporting. DESIGN: E3N, a
      prospective cohort study of cancer risk factors, conducted in France and part of
      the European Prospective Investigation on Cancer. E3N comprises 100,000 women,
      born between 1925 and 1950, followed with self-administered questionnaires sent
      every 18 to 24 months starting in 1990. SUBJECTS: 152 women for the validation
      study of self-reported anthropometric measurements, and 91,815 women selected to
      evaluate factors affecting misreporting of body silhouette. STATISTICAL ANALYSIS:
      Paired t tests, Pearson and Spearman correlations were applied to evaluate the
      validity of self-reported measures, and analysis of variance and logistic
      regression were used to assess the factors influencing misreporting of
      silhouette. RESULTS: The correlation coefficients between self- and external
      measurements were high. All but sitting height (r = 0.56) were more than 0.80,
      with weight and bust (nipples) measurement correlation coefficients attaining
      0.94. The correlation between body mass index (BMI), measured by the technician
      and the self-reported silhouette, was 0.78. Small height was always associated
      with misclassification. Specific factors related to a more favorable perception
      of body silhouette were: being overweight, small height, younger age, and a lower
      level of education. These women were also more frequently unmarried, more
      physically active, and had had a slender body shape during adolescence. Results
      denoting a less favorable perception of body shape were reversed.
      CONCLUSION/APPLICATIONS: Self-reported measurements (made with or without help)
      are valid measures in epidemiological studies. Body silhouettes are simple and
      useful indicators of body mass index. However they should be interpreted with
      caution in certain instances, especially for overweight subjects.

PMID- 12487541
TI  - School food policies and practices: a state-wide survey of secondary school
      principals.
AB  - OBJECTIVE: To describe food-related policies and practices in secondary schools
      in Minnesota. DESIGN: Mailed anonymous survey including questions about the
      secondary school food environment and food-related practices and policies.
      SUBJECTS/SETTING: Members of a statewide professional organization for secondary
      school principals (n = 610; response rate: 463/610 = 75%). Of the 463 surveys
      returned, 336 met the eligibility criteria (current position was either principal
      or assistant principal and school included at least one of the grades of 9
      through 12). STATISTICAL ANALYSIS: Descriptive statistics examined the prevalence
      of specific policies and practices. Chi2 analysis examined associations between
      policies and practices and school variables. RESULTS: Among principals, 65%
      believed it was important to have a nutrition policy for the high school;
      however, only 32% reported a policy at their school. Principals reported positive
      attitudes about providing a healthful school food environment, but 98% of the
      schools had soft drink vending machines and 77% had contracts with soft drink
      companies. Food sold at school fundraisers was most often candy, fruit, and
      cookies. APPLICATIONS: Dietetics professionals who work in secondary school
      settings should collaborate with other key school staff members and parents to
      develop and implement a comprehensive school nutrition policy. Such a policy
      could foster a school food environment that is supportive of healthful food
      choices among youth.

PMID- 12487542
TI  - Demonstrating the impact of nutrition intervention in a heart failure program.
AB  - Outpatient heart failure centers using a multidisciplinary approach to management
      of heart failure are recognized as essential to decreasing costs of treating
      heart failure. These centers do not typically employ registered dietitians. With
      hospital foundation funding, our objective was to develop the role of the
      dietitian and to evaluate the impact of nutrition intervention in a
      multidisciplinary heart failure program. Based on a needs assessment, the
      dietitian developed and tested a medical nutrition therapy protocol, education
      materials, and special education projects. Unannounced 24-hour recalls at 3
      points in time were used to determine changes in sodium and fluid intakes. An
      outcome tracking system was implemented. Intake data were analyzed for patients
      who were in the program 9 or more months (n = 79). Patients' sodium and fluid
      intakes at 2 to 3 months and 6 to 9 months were compared with their baseline
      intakes using paired t test. The sodium decrease of 0.5 g at 2 to 3 months and 6
      to 9 months and the fluid decrease of 15 oz at 2 to 3 months and 12 oz at 6 to 9
      months were all highly significant (P < .001). Patients active in year 3 (n = 82)
      completed the Minnesota Quality of Life Questionnaire. Compared with baseline,
      quality of life scores improved by 6.7 points (P < .003) at 3 months and by 5.9
      points (P < .04) at 6 months. Of 83 patients hospitalized over 3 years, 6
      hospitalizations were the result of an excessive sodium intake. At the completion
      of the project, the center provided funding for the dietitian to become a
      permanent team member. These positive findings indicate dietitians should seek
      involvement in heart failure centers.

PMID- 12487543
TI  - Food management practices used by people with limited resources to maintain food
      sufficiency as reported by nutrition educators.
AB  - The food management practices used by people with limited resources to ensure
      food sufficiency have not been fully characterized. Semistructured interviews
      were conducted with 51 nutrition educators from the New Jersey Expanded Food and
      Nutrition Education Program and Food Stamp Nutrition Education Program, regarding
      the food management practices of program participants. Practices were grouped
      into two categories using the constant comparative method: manage food supply (n
      = 14) and regulate eating patterns (n = 15). Well-documented stratagems, such as
      overeating when food is available and cycling monthly eating patterns, were
      confirmed. Novel practices were identified. Practices causing food safety or
      nutritional risks included removing spoiled sections, slime, mold, and insects
      from food; eating other people's leftovers; and, eating meat found as road kill.
      A foundation was formed for a grounded theory concerning food management
      practices by people with limited resources. Verification of these results with
      audiences with limited resources and determination of prevalence and relative
      risk of these practices is necessary. This research is important for nutrition
      professionals who work with people with limited resources because it elucidated a
      spectrum of safe and risky food management practices, proposed methods to
      ameliorate monthly eating pattern cycles, and exposed the possibility of food
      insecurity in unsuspected cases.

PMID- 12487544
TI  - Management of fatty acid oxidation disorders: a survey of current treatment
      strategies.
AB  - Standardization of the nutritional care for patients with fatty-acid oxidation
      disorders is lacking. A literature review and national survey of metabolic
      dietitians describes the range of therapeutic strategies currently employed in
      the U.S. to treat patients with fatty-acid oxidation disorders. Questionnaire
      responses provided by dietitians specializing in metabolic disorders evaluated
      practices used for treatment of fatty acid oxidation disorders, medium-chain acyl
      CoA dehydrogenase deficiency (MCAD), very-long-chain acyl-CoA dehydrogenase
      deficiency (VLCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
      (LCHAD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), and Trifunctional
      Protein deficiency (TFP). This survey reveals a significant lack of evidence
      supporting the protocols in use. Recent advances in tandem mass spectrometry
      technology promises an increase in the number of identified patients with fatty
      acid oxidation disorders, which reinforces the need for comprehensive, clinical
      research studies to determine optimal care for patients with these genetic
      disorders.

PMID- 12487545
TI  - Dietary intakes and serum concentrations of vitamin E and total carotenoids of
      healthy adults with severe physical disabilities are lower than matched controls.
AB  - Millions of people worldwide have severe chronic physical disabilities (e.g.,
      polio, spinal cord injury). We hypothesized that these people are at risk for
      poor antioxidant nutrient intakes and status, because of their typically low
      energy expenditures and low socioeconomic status. We surveyed antioxidant
      nutrient intakes and concentrations in subjects with physical disabilities and
      age matched non-disabled controls. Only one subject with physical disabilities
      ate five or more servings of vegetables per day. The group had low intakes of
      vegetables (minus potatoes) and citrus fruits, and trends for low intakes of all
      antioxidant nutrients. Serum a-tocopherol and total carotenoid concentrations
      were lower in subjects with physical disabilities, while retinol and individual
      carotenoids showed non-significant lower trends. Since adequate antioxidant
      nutrients are associated with decreased chronic disease risk, nutrition
      professionals might improve the health of patients with physical disabilities by
      periodically monitoring their intakes and status of antioxidant nutrients.

PMID- 12487546
TI  - Effects of a new soy/beta-sitosterol supplement on plasma lipids in moderately
      hypercholesterolemic subjects.
AB  - Our aim was to test the hypocholesterolemic effect of a low-dose formulation of
      soy proteins supplemented with isolated b-sitosterol in a ratio of 4:1 in 20
      moderately hypercholesterolemic subjects. The study has been divided in three
      different periods of forty days each: a stabilization diet period, then a
      treatment period during which all subjects assumed 10 g one time a day of the
      tested product and, finally, a wash out period. From the end of the stabilization
      diet period to the end of the soy protein added in b-sitosterol supplementation
      we observed a 0.45 +/- 0.30 mmol/L, 0.09 +/- 0.31 mmol/L and 0.17 +/- 0.22 mmol/L
      mean +/- SE decrease in respectively LDL-C, TG and apoB levels, associated with a
      0.12 +/- 0.25 and 0.03 +/- 0.51 mg/dL mean increase respectively in HDL-C and
      apoA plasma concentrations. According to this recommends, low doses of soy
      protein added in b-sitosterol seems to be a practical and safe alternative for
      patients seeking modest reductions in LDL-C (< 15%).

PMID- 12487547
TI  - Nutritional assesment and management of malabsorption in the hematopoietic stem
      cell transplant patient.

PMID- 12487548
TI  - Key trends affecting the dietetics profession and the American Dietetic
      Association.
AB  - When an association faces its future, the information its board and leadership
      have about the world in which it must operate will shape their perceptions and
      influence their strategic thinking. One of the primary purposes of an
      environmental scan is to elucidate emerging issues and trends so that strategic
      attention can be focused on them. An environmental scan can also suggest emerging
      opportunities and challenges.

PMID- 12487549
TI  - Position of the American Dietetic Association: domestic food and nutrition
      security.
AB  - In 2000, over 10% of United States (US) households, including more than 33
      million people, experienced food insecurity. Food insecurity negatively affects
      the dietary intake and nutritional status of adults leading to poor health and
      increased risk for the development of chronic diseases. Food insecurity also
      negatively affects children's health, psychological and cognitive functioning,
      and their academic achievement. It is the position of the American Dietetic
      Association that systematic and sustained action is needed to bring an end to
      domestic food insecurity and hunger and to achieve food and nutrition security
      for all in the US. Immediate and long-range interventions, including adequate
      funding for and increased utilization of food and nutrition assistance programs,
      the inclusion of food and nutrition education in all programs providing food and
      nutrition assistance, and innovative programs to promote and support the economic
      self-sufficiency of individuals and families, are key to ending domestic food
      insecurity. Dietetics professionals can play a key role in ending food insecurity
      not only through competent and collaborative practice, but also through advocacy
      efforts at the local, state, regional, and national levels.

PMID- 12487550
TI  - Guidelines for the delineation of nodal regions of the head and neck on axial
      computed tomography images.
AB  - Delineation of target volumes is increasingly recognized as the most crucial step
      within the process of modern conformal radiotherapy. In the field of head and
      neck radiation oncology, the need for a standardized methodology in the
      delineation of nodal regions of the neck on computed tomography (CT) images has
      recently emerged. To address this issue, a consensus document has been prepared
      by the Head and Neck Working Party of the AIRO-Lombardia Cooperative Group, based
      on the proceedings of multidisciplinary meetings and on literature findings. The
      document contains detailed guidelines for the delineation on CT images of the
      nodal regions of the neck, including for each nodal region (1 to 7) the
      description of anatomical limits as seen on CT images.

PMID- 12487552
TI  - An estimate of prostate cancer prevalence in Italy.
AB  - Estimates of the total number of men with a previous diagnosis of prostate cancer
      in Italy range from 55,000 to 135,000. This wide range of variation is largely
      due to uncertainties on the number of protein-specific antigen-detected,
      asymptomatic cases. The number of clinically detected cases, including cases with
      advanced disease, is less subject to uncertainty, with reasonable estimates
      ranging from 45,000 to 60,000.

PMID- 12487551
TI  - CD40 activation as potential tool in malignant neoplasms.
AB  - BACKGROUND: CD40, a cell surface molecule, is expressed on B-cell malignancies
      and many different solid tumors. It is capable of mediating diverse biological
      phenomena such as the induction of apoptosis in tumors and stimulation of the
      immune response. It has thus been studied as a possible target for antitumor
      therapy. The general aim of this review is to focus the attention of clinical
      oncologists on the involvement of CD40 in tumors and the rationale of CD40
      activation-based therapies in new, biologically oriented antitumor protocols.
      METHODS: A Medline review of published papers about the role of CD40 activation
      in cancer therapy. RESULTS: Many authors have shown that CD40 activation promotes
      apoptotic death of tumor cells and that the presence of the molecule on the
      surface of carcinoma lines is an important factor in the generation of tumor
      specific T-cell responses that contribute to tumor cell elimination. The CD40
      ligand (CD40L) is the natural ligand for CD40; it is expressed primarily on the
      surface of activated T lymphocytes. Preclinical studies suggest that CD40-CD40L
      interaction could be useful for cytotoxicity against CD40-expressing tumors and
      for immune stimulation. Tumor inhibition was observed when tumor cells were
      treated with agonistic anti-CD40 monoclonal antibodies or with the soluble form
      of CD40L. The results of the first phase I clinical trial to treat cancer
      patients with subcutaneous injection of recombinant human CD40L have been
      recently reported. Immunohistochemical studies have revealed that detection of
      CD40 in primary cutaneous malignant melanoma and lung cancer may have a negative
      prognostic value. Interestingly, up-regulation of CD40 was observed in the tumor
      vessels of renal carcinomas and Kaposi's sarcoma, suggesting possible involvement
      of CD40 in tumor angiogenesis. Recently, it has also been shown that CD40
      engagement on endothelial cells induces in vitro tubule formation and expression
      of matrix metalloproteinases, two processes involved in the neovascularization
      and progression of tumors. CONCLUSIONS: CD40 activation represents an exciting
      target for hematological malignancies and solid tumors expressing the molecule,
      but its functional role in cancer development still remains unclear and
      controversial.

PMID- 12487553
TI  - Feasibility of peritonectomy associated with intraperitoneal hyperthermic
      perfusion in patients with Pseudomyxoma peritonei.
AB  - AIMS AND BACKGROUND: Pseudomyxoma peritonei is a rare disease characterized by a
      complete redistribution of mucin within the peritoneal cavity. It can be
      classified into three histologic groups: disseminated peritoneal adenomucinosis,
      peritoneal mucinous carcinomatosis, and an intermediate group. The aim of the
      present study was to evaluate the feasibility of cytoreductive surgery requiring
      peritonectomy procedures associated with intraperitoneal hyperthermic perfusion,
      a technique that combines hyperthermia and high drug doses administered locally.
      METHODS: Twenty-seven patients with pseudomyxoma peritonei (19 males and 8
      females) were enrolled in a phase II clinical trial. Twenty-two cases underwent
      cytoreductive surgery plus intraperitoneal hyperthermic perfusion, and 6 received
      debulking surgery only. One patient was operated on twice for disease recurrence.
      All patients with peritoneal mucinous carcinomatosis presented serous ascites,
      whereas all but one patient with disseminated peritoneal adenomucinosis or in the
      intermediate group presented mucinous ascites. Cytoreductive surgery was
      performed with peritonectomy procedures. The closed abdomen technique was adopted
      for intraperitoneal hyperthermic perfusion using a preheated polysaline perfusate
      containing cisplatin (25 mg/m2/L) plus mitomycin-C (3.3 mg/m2/L) through a heart
      lung pump at a mean flow of 600 mL/min for 60 mins from the hyperthermic phase
      (42.5 degrees C). RESULTS: All but one of the patients with disseminated
      peritoneal adenomucinosis and 2 of the 3 patients in the intermediate group were
      optimally cytoreduced. Patients with serous ascites (all patients with peritoneal
      mucinous carcinomatosis and 1 patient with disseminated peritoneal
      adenomucinosis) were considered ineligible for treatment because of tumor
      diffusion. The morbidity rate was 22%. There was one case of treatment-related
      mortality 30 days after treatment. CONCLUSIONS: The following conclusions can be
      drawn from this phase II clinical trial: 1) patients with pseudomyxoma peritonei
      originating from undifferentiated mucinous adenocarcinoma (peritoneal mucinous
      carcinomatosis), with complete distribution into the peritoneal cavity, are not
      eligible for the cytoreductive surgery plus intraperitoneal hyperthermic
      perfusion technique; 2) the presence of serous ascites would seem to exclude
      patients from the treatment; 3) cytoreductive surgery associated with
      intraperitoneal hyperthermic perfusion is the most suitable approach for patients
      with disseminated peritoneal adenomucinosis and in the intermediate group.

PMID- 12487554
TI  - Prognostic effects of local recurrence after conservative treatment for early
      infiltrating breast carcinoma.
AB  - AIM: A study was carried out to determine whether local recurrence after
      quadrantectomy, axillary dissection and radiotherapy (QUART) affects the
      oncologic prognosis of patients with early infiltrating breast carcinoma.
      METHODS: A total of 149 patients were submitted to QUART between 1981 and 1990
      and followed by an average period of 120.9 months (range, 16-213). Local
      recurrence was not observed in 132 cases (group 1) but was detected in 17
      patients (group 2). RESULTS: In group 1, 39 cases (29.5%) presented distant
      metastases and 34 (25.8%) evolved to death. In group 2, 10 (51.8%) distant
      metastases and 9 deaths (52.9%) were verified. The survival curves estimated by
      the Kaplan-Meier method and analyzed by the logrank test were statistically
      different for distant metastases-free survival (P = 0.03) and for overall
      survival (P = 0.01). The relative risk in patients with post-QUART local
      recurrence for distant metastases was 2.09 and for death 2.34. CONCLUSIONS: It
      was concluded that post-QUART local recurrences are a poor prognostic factor in
      patients with early infiltrating breast carcinoma.

PMID- 12487555
TI  - Comparison of radiation-induced oral mucositis scoring systems.
AB  - BACKGROUND: A number of oral toxicity scoring systems have been described, but
      their direct comparison has rarely been undertaken and little data exists. An
      impediment to mucositis research has been the lack of an accepted, validated
      scoring system. The objective of this study was to design a test and validation
      of scoring systems. MATERIALS AND METHODS: Forty-three patients with head and
      neck malignancies who had been irradiated were evaluated. Five different
      mucositis scoring systems (World Health Organization, Radiation Therapy Oncology
      Group, "Hickey", "Van der Schueren" and "Makkonen") were compared with each
      other. RESULTS: Daily mucositis scores demonstrated a high correlation among
      scoring systems (P < 0.05 and coefficient of correlation kappa and r = 0.5-0.95).
      Objective mucositis scores demonstrated a strong correlation with symptoms.
      CONCLUSIONS: All scoring systems were equally valid. The exact grading of
      mucositis is achieved by combining clinical information about pain and
      nutritional status with oral mucosal reactions.

PMID- 12487556
TI  - The efficacy of orgotein in the treatment of acute toxicity due to radiotherapy
      on head and neck tumors.
AB  - AIMS AND BACKGROUND: To assess the efficacy of orgotein in the treatment of acute
      secondary effects of radiotherapy on head and neck tumors. MATERIAL AND METHODS:
      Data were collected on 41 patients who received radiotherapy for tumors of the
      head and neck. Radiotherapy was the exclusive treatment in 19.5% of cases, with
      surgery in 24.4%, chemotherapy in 48.8%, and with both in 7.3%. The toxicity
      requiring use of orgotein was: oropharynx mucositis (26.8%), dysphagia (34.2%),
      or both (39%), in grade 2 or more according to the RTOG scale. Orgotein (8 mg
      i.m.) was administered every 48 hrs until radiotherapy was finished. RESULTS: The
      overall response rate was 92.5%; a complete response was obtained in 12 patients
      (30%) and partial in 25 (62.5%). The reduction in toxicity at the end of
      radiotherapy was one grade in 18 patients (45%), 2 grades in 16 (40%), 3 in 2
      patients (5%), and 4 grades in the only patient with grade 4 acute toxicity. A
      statistically significant influence was shown in obtaining complete response:
      laryngeal tumor location (P = 0.037), duration of radiotherapy of more than 53
      days (P = 0.002), discontinuation for non-toxic reasons (P = 0.008). CONCLUSIONS:
      We consider that orgotein is highly effective in dealing with acute secondary
      effects of radiotherapy on the head and neck area.

PMID- 12487557
TI  - Muscle-invasive bladder cancer in elderly-unfit patients with concomitant
      illness: can a curative radiation therapy be delivered?
AB  - AIMS AND BACKGROUND: There is no standard treatment for elderly-unfit patients
      with muscle-invasive bladder cancer. Pelvic irradiation alone is an usual
      approach in this instance, and some reports have demonstrated that curative
      radiotherapy is feasible in elderly patients. To our knowledge, no data exist
      about the feasibility of a curative treatment in elderly patients with
      concomitant illness and a Charlson Comorbidity Index (an index of comorbidity
      that includes age) greater than 2. The main purpose of the present study was to
      establish the feasibility of irradiation in a cohort of elderly patients in poor
      general condition. METHODS: The records of 45 elderly-unfit patients (median age,
      75 years; range, 70-85), with a comorbid Charlson score >2, treated with curative
      dose, planned continuous-course, external beam radiotherapy for muscle-invasive
      bladder cancer were reviewed. The patients were treated to a median total dose of
      60 Gy (range, 56-64), with an average fractional dose of 190 +/- 10 cGy using
      megavoltage (6-15 MV). All patients were treated with radiation fields
      encompassing the bladder and grossly involved lymph nodes with a radiographic
      margin of at least 1.5 cm. RESULTS: No treatment-related mortality and clinically
      insignificant acute morbidity was recorded. No patient was hospitalized during or
      after the irradiation because of gastrointestinal or urogenital side effects. In
      one patient a week rest from therapy was necessary due a febrile status. Median
      survival was 21.5 months; overall 3- and 5-year survival was 36% and 19.5%,
      respectively. CONCLUSIONS: Elderly-unfit patients with comorbidities and >70
      years of age can be submitted to radical pelvic irradiation. The results observed
      in this retrospective analysis have encouraged us to use non-palliative
      radiotherapy doses in these patients with muscle-invasive bladder cancer.

PMID- 12487558
TI  - Prognostic significance of blood group antigen expression of tumor tissue in lung
      cancer patients.
AB  - AIMS AND BACKGROUND: Many prognostic factors have been evaluated both for SCLC
      and NSCLC. The prognostic significance of blood group antigen expression of tumor
      tissues has been studied particularly in NSCLC, yielding divergent results. The
      aim of the present study was to investigate the prognostic value of the tumoral
      expression of blood group antigens ABH in lung cancer. METHODS: The presence of
      blood group antigens was assessed immunohistochemically in paraffin-embedded
      tumor samples from 92 patients diagnosed between 1996 and 1997. Monoclonal
      antibodies were used to detect blood group antigens. RESULTS: The median survival
      was longer in NSCLC patients whose tumors were positive for blood group antigen A
      (P = 0.009). Since the expression of blood group antigen A in tumor cells was
      limited to patients with type A or AB blood, survival analysis of these patients
      showed survival to be longer in non-small cell lung cancer patients with blood
      group antigen A-positive tumors (P= 0.0019). CONCLUSIONS: Expression of blood
      group antigen A in tumor cells is an important, favorable prognostic factor in
      patients with non-small cell lung cancer, which could be useful to stratify
      patients with blood group A or AB according to possible outcome, and to guide
      therapeutic decision-making. The expression of blood group antigens ABH should be
      evaluated in larger series of lung cancer patients (including small and non-small
      cell lung cancer) with all blood types.

PMID- 12487560
TI  - Radiation therapy combined with photofrin or 5-ALA: effect on Lewis sarcoma tumor
      lines implanted in mice. Preliminary results.
AB  - AIMS AND BACKGROUND: Ionizing irradiation is a well-established therapeutic
      modality for cancer. Photodynamic therapy (PDT), especially with 5-ALA and
      Photofrin, is highly effective in some tumor types. Chemical modifiers, so-called
      radiosensitizers, are used in order to increase the efficacy of radiotherapy.
      Most of the known and routinely used radiosensitizers are not tumor selective, so
      that the normal tissue reaction toxicity is also increased. In the present study
      we investigated whether a porphyrin derivative that is currently used as a tumor
      photosensitizing agent in photodynamic therapy (PDT) may also act as a tumor
      specific radiosensitizer. MATERIALS AND METHODS: For our investigation we used
      Balb/c mice implanted with Lewis sarcoma and irradiated with 3 Gy combined with
      injection of 5-ALA or Photofrin at various concentrations before irradiation.
      RESULTS: 5-ALA had no effect as a radiosensitizer at any of the concentrations
      examined. Photofrin at a concentration of 5 mg/kg proved to be a chemical
      modifier of ionizing radiation, delaying tumor growth and reducing the overall
      tumor volume by about 50% after six days. CONCLUSION: Photofrin has marked
      efficacy as a radiosensitizer and can be used in the future as a selective tumor
      radiosensitizer.

PMID- 12487559
TI  - Lack of HCV infection in malignant cells refutes the hypothesis of a direct
      transforming action of the virus in the pathogenesis of HCV-associated B-cell
      NHLs.
AB  - AIMS AND BACKGROUND: Preliminary evidence suggests that hepatitis C virus (HCV)
      might play a pathogenetic role in autoimmune-related, non-malignant B-cell
      lymphoproliferation, as well as in a subset of B-cell non-Hodgkin's lymphomas
      (NHLs). With regard to the mechanism(s) by which HCV might favor B-cell expansion
      and malignant transformation, most data support an indirect pathogenetic role of
      the virus as an exogenous trigger. A direct oncogenetic role of HCV by direct
      cell infection and deregulation has only been hypothesized on the basis of the
      lymphotropism of the virus. METHODS: In this study we investigated the possible
      HCV infection of NHL B cells by means of sensitive and quantitative polymerase
      chain reaction (PCR) on affinity-purified neoplastic cells, and by HCV-specific
      immunohistochemistry and in situ hybridization. RESULTS: HCV infection of
      neoplastic B cells was documented in only three cases, namely the low-grade B
      cell NHLs that arose in the course of mixed cryoglobulinemia syndrome (MC). HCV
      infection, below one viral genome per cell, was detectable only by PCR. All the
      remaining low-grade (one case) and high-grade B-cell NHLs (two cases) were HCV
      uninfected. Previous immunoglobulin gene analyses were consistent with an antigen
      driven B-cell lymphoproliferation in the studied cases. CONCLUSIONS: Overall, our
      data are consistent with an indirect oncogenetic role of HCV in B-cell
      lymphomagenesis as an exogenous trigger. Infection of B cells by HCV appears
      possible in some NHL subsets, but the implications remain unknown.

PMID- 12487561
TI  - An alternative method for preventing extravasation complications in vascular
      access catheters with reservoirs for subcutaneous infusion: the double injection
      technique.
AB  - Long-term intravascular access catheters with reservoirs are a common requirement
      for cancer patients. Complications resulting from the use of these devices have
      been studied in several single-institution investigations, the consensus being
      that they are safe and have a low complication rate. However, extravasation may
      occur especially in obese patients due to accidental infusion of the subcutaneous
      tissue. To prevent this problem we describe an easy method that could be an
      alternative to the widely used ultrasonography-guided injection method.

PMID- 12487562
TI  - Bleomycin-induced upper lobe fibrosis: a case report.
AB  - We report a case of late-onset pulmonary fibrosis involving the upper lobes that
      occurred in a young man treated with bleomycin for mediastinal germ-cell
      carcinoma. The parenchymal lesions became clinically apparent about two years
      after chemotherapy had been completed, with a slowly progressive course and
      sparing the lower lung fields during follow-up. Other possible diagnoses could be
      excluded on the basis of the patient's clinical history, laboratory tests and
      pathological findings.

PMID- 12487563
TI  - Acute occlusion of abdominal aorta: unusual embolization site for a cardiac tumor
      mass.
AB  - We report a rare case of complete embolization of a left atrial myxoma resulting
      in total occlusion of the suprarenal abdominal aorta. A 54-year-old man was
      admitted to hospital because of acute thoracic pain with paraplegia and acute
      renal failure. Abdominal computed tomography and angiography showed evidence of
      total occlusion of the suprarenal aorta. Intraoperatively, the aorta was found to
      be occluded by a hard neoformation, histologically defined as atrial myxoma. A
      diagnosis of atrial myxoma should be suspected in young patients suffering from
      acute thoracic pain and affected by paraplegia and acute renal failure. Early
      diagnosis may significantly abate the morbidity and mortality rates associated
      with this condition.

PMID- 12487564
TI  - Solitary plasmacytoma of the jaw occurring in an elderly woman affected by
      hepatitis C virus infection: a case report.
AB  - Solitary plasmacytoma accounts for a small percentage of plasma cell neoplasms.
      The disease often affects older people and is potentially curable. Only a few
      cases of solitary jaw plasmacytoma have been described in the literature. Here we
      report the case of a 76-year-old woman affected by chronic hepatitis C infection
      and isolated plasmacytoma of the left jaw. Plasmacytoma was diagnosed in January
      2001, but the swelling of the mandible had been present since 1993. Two different
      pathologists made the diagnosis on the basis of biopsy material from the
      mandibular swelling.

PMID- 12487565
TI  - Lymph nodal Merkel cell carcinoma: primary or metastatic disease? a clinical
      case.
AB  - We report a case of Merkel cell carcinoma (MCC) presenting in the lymph nodes in
      the absence of a primary cutaneous site. The MCC was treated by palliative
      radiotherapy, which controlled the disease locally. Eight months after diagnosis
      a mass appeared on the ipsilateral knee; histopathological examination of this
      lesion confirmed the diagnosis of MCC. The patient died two months later due to
      the development of pulmonary metastases. Interestingly, the neoplastic tissue was
      confined to the regional lymph nodes for several months before the primary site
      appeared. Primary lymph nodal MCC is rare and the diagnosis is difficult. In our
      opinion the only way to make a diagnosis of primary lymph nodal MCC is by
      appropriate clinical follow-up.

PMID- 12487566
TI  - Duodenal obstruction from isolated breast cancer metastasis: a case report.
AB  - Metastatic involvement of the upper gastrointestinal tract from breast cancer has
      been reported in autopsy series as occurring in more than 15% of patients,
      usually associated with extensive systemic spread; clinical manifestations from
      such metastases have been described in less than 1% of cases. Lobular
      infiltrating carcinoma seems to have a different metastatic pattern than the
      ductal type, with an apparent predilection for the gastrointestinal tract.
      Metastatic presentation as an isolated intestinal obstruction without other signs
      of metastatic spread is extremely rare. We present a case of isolated duodenal
      metastasis from breast cancer, associated with intestinal obstruction, as the
      first sign of metastatic spread.

PMID- 12487568
TI  - Synchronous tumors: a proposal for standardization.

PMID- 12487567
TI  - Parathyroid cancer in a hemodialysis patient: a case report.
AB  - An extremely rare case of parathyroid cancer in a hemodialysis patient is
      presented here. A 69-year-old man was operated on for secondary
      hyperparathyroidism due to chronic renal failure. A locally invasive tumor of the
      right inferior parathyroid gland and enlargement of the other three parathyroid
      glands were found during bilateral neck exploration. Surgical management
      consisted of en bloc resection of the right inferior parathyroid gland with the
      right thyroid lobe and part of a sternothyroid muscle along with subtotal
      parathyroidectomy of the three enlarged parathyroid glands. Histological
      examination of the resected tumor provided evidence of a parathyroid cancer in
      the right inferior parathyroid gland. Nodular hyperplasia was confirmed
      histologically in the other three glands. With less than 20 previous cases
      described in the literature, parathyroid cancer is a very rare condition in
      hemodialysis patients.

PMID- 12487569
TI  - Controlled interparticle spacing through self-assembly of Au nanoparticles and
      poly(amidoamine) dendrimers.
AB  - Control of particle-particle spacing is a key determinant of optical, electronic,
      and magnetic properties of nanocomposite materials. We have used poly(amidoamine)
      (PAMAM) dendrimers to assemble carboxylic acid-functionalized mixed monolayer
      protected clusters (MMPCs) through acid/base chemistry between the particle and
      dendrimer. Small angle X-ray scattering was then used to establish average inter
      MMPC distances. Five generations of PAMAM dendrimer (0, 1, 2, 4, 6) were
      investigated, with a monotonic increase in interparticle spacing from 4.1 to 6.1
      nm observed with increasing generation.

PMID- 12487570
TI  - Spontaneous formation of hexameric resorcinarene capsule in chloroform solution
      as detected by diffusion NMR.
AB  - NMR diffusion measurements provide unequivocal proof that the resorcinarene 1b
      self-assembles spontaneously into a stable hexamer capsule in chloroform solution
      by encapsulating several chloroform molecules, which occupy different chemical
      positions. Although the affinity of tetrahexylammonium bromide (2a) toward the
      cavity of the hexamer is much higher than that of the chloroform molecules, it
      was found that the same amount of DMSO is needed to disrupt the two hexamers,
      thus suggesting similar stabilities for these two supramolecular capsules.

PMID- 12487571
TI  - Dynamics and fluidity of amyloid fibrils: a model of fibrous protein aggregates.
AB  - A previous experimentally defined model for the fibril formed from the core
      residues of the beta-amyloid (Abeta) peptides of Alzheimer's disease,
      10YEVHHQKLVFFAEDVGSNKGAIIGLM, Abeta(10-35) using spectroscopic and scattering
      analyses reports on the average structure, benefiting immensely from the
      homogeneous assembly of Abeta(10-35). However, the energetic constraints that
      contribute to fibril dynamics and stability remain poorly understood. Here we
      perform molecular dynamics simulations to extend the structural assignment by
      providing evidence for a dynamic average ensemble with transient backbone H-bonds
      and internal solvation contributing to the inherent stability of amyloid fibrils.

PMID- 12487572
TI  - Cobalt-carbene complex with single-bond character: intermediate for the cobalt
      complex-catalyzed cyclopropanation.
AB  - It is generally considered that metal-carbene carbon bonds in carbene complexes
      for cyclopropanation should be double-bonded; however, the theoretical and FT-IR
      analyses revealed that the cobalt-carbene carbon bond of the 3
      oxobutylideneaminato or the salen-cobalt-carbene complexes was characterized as a
      single bond.

PMID- 12487573
TI  - Transition metal-catalyzed hetero-[5 + 2] cycloadditions of cyclopropyl imines
      and alkynes: dihydroazepines from simple, readily available starting materials.
AB  - The first example of a transition metal-catalyzed hetero-[5 + 2] cycloaddition
      reaction is described. Use of cyclopropyl imines as five-atom components, an
      alkyne as a two-carbon component, and a Rh(I) catalyst enables a new route to
      dihydroazepines. This new hetero-[5 + 2] cycloaddition works well with aldimines,
      ketimines, and with substituted cyclopropanes and affords the desired
      dihydroazepines in excellent yields as single regioisomers. Use of serial imine
      formation/aza-[5 + 2] cycloaddition generates the desired dihydroazepines in one
      operation from three commercially available starting materials. The reaction has
      been scaled to give gram quantities of dihydroazepine.

PMID- 12487574
TI  - Reductive generation of enolates from enones using elemental hydrogen: catalytic
      C-C bond formation under hydrogenative conditions.
AB  - Exposure of enones to elemental hydrogen in the presence of a Rh(I) catalyst
      enables reductive enolate generation, as evidenced by electrophilic trapping of
      the enolate by appendant and exogenous aldehyde partners. The significance of
      these findings resides in the ability to regioselectivity generate and transform
      transition metal enolates under catalytic conditions that circumvent formation of
      stoichiometric byproducts.

PMID- 12487575
TI  - Chain-growth polycondensation for well-defined aramide. Synthesis of
      unprecedented block copolymer containing aramide with low polydispersity.
AB  - Poly(p-benzamide) with a defined molecular weight and a low polydispersity and a
      block copolymer containing this well-defined aramide was synthesized. Phenyl 4
      aminobenzoate, which would yield poly(p-benzamide), did not polymerize under the
      conditions of chain-growth polycondensation. However, phenyl 4-(4
      octyloxybenzylamino)benzoate (1b) polymerized at room temperature in the presence
      of base and phenyl 4-nitrobenzoate (2) as an initiator in a chain-growth
      polycondensation manner to give well-defined aromatic polyamides having the 4
      octyloxybenzyl groups as a protecting group on nitrogen in an amide. It was
      confirmed by a model reaction that deprotection of this protecting group
      proceeded completely with trifluoroacetic acid (TFA) without breaking the amide
      linkage. The utility of this approach to poly(p-benzamide) with a low
      polydispersity was demonstrated by the synthesis of block copolymers. Thus,
      phenyl 4-(octylamino)benzoate (1a) polymerized in the presence of 2 and base,
      followed by addition of 1b and base to the reaction mixture of the prepolymer to
      yield the block copolymer of 1a and 1b with a controlled molecular weight and a
      low polydispersity. The block copolymer was treated with TFA, resulting in a
      soluble block copolymer of poly(N-octyl-p-benzamide) and poly(p-benzamide). The
      SEM images of the supramolecular assemblies of the block copolymer showed mum
      sized bundles and aggregates of flake structures.

PMID- 12487576
TI  - Nearly planar nonsolvated monomeric silyl- and germyllithiums as a result of an
      intramolecular CH-Li agostic interaction.
AB  - Pale-yellow crystals of the nonsolvated monomeric silyl- and germyllithiums,
      tris[di-tert-butyl(methyl)silyl]silyllithium 2a and tris[di-tert
      butyl(methyl)silyl]germyllithium 2b, were obtained by one-electron reduction of
      the corresponding silyl and germyl radicals with lithium in hexane. The crystal
      structure analysis of both 2a and 2b showed almost planar geometry around the
      anionic centers, due to both intramolecular CH-Li agostic interactions and steric
      reasons. However, the free anions [(tBu2MeSi)3Si-][Li+(THF)4] 3a and
      [(tBu2MeSi)3Ge-][Li+(THF)n] (n = 3, 4) 3b no longer showed a planar geometry,
      because of the absence of the intramolecular CH-Li agostic interaction. A
      temperature-dependent 1H NMR study of 2a showed that the CH-Li interaction is
      weak.

PMID- 12487577
TI  - Collagen mimetic dendrimers.
AB  - The synthesis of single-chain, scaffold (TRIS)- and dendrimer-assembled collagen
      mimetics (both Gly-Pro-Nleu and Gly-Nleu-Pro sequences) is reported. From the CD
      spectra and the thermal denaturation studies it can be readily seen that mimetics
      prepared from the Gly-Nleu-Pro sequence form more thermally stable triple helices
      than the Gly-Pro-Nleu sequence. Furthermore, the 162-residue collagen mimetic
      dendrimers exhibit enhanced triple helical stability compared to equivalent
      scaffold-terminated structures by a substantial increase in the melting
      temperature in H2O and 2:1 EG/H2O. The concentration dependence for the melting
      transition was measured which determined that the stabilization effect arises
      from the intramolecular clustering of the triple helical arrays about the core
      structure. This ensemble excludes solvent from the interior portion of the array
      which stabilizes the triple helical bundle.

PMID- 12487578
TI  - Regio- and enantioselective allylic amination of achiral allylic esters catalyzed
      by an iridium-phosphoramidite complex.
AB  - A new catalytic asymmetric process, the iridium-catalyzed enantioselective
      allylic amination of (E)-cinnamyl and terminal aliphatic allylic carbonates, was
      developed by exploring complexes of chiral phosphoramidites. The reaction
      provided branched secondary and tertiary allylic amines in high yields with
      excellent regio- and enantioselectivity (13 examples over 94% ee). Although the
      reactions in polar solvent such as DMF, EtOH, and MeOH were fast, they gave low
      enantiomeric excesses. In contrast, reactions in THF displayed the most suitable
      balance of rate and enantioselectivity. Both the binaphthol unit and the
      disubstituted amine in the phosphoramidite affected reactivity and selectivity,
      and complexes of O,O'-(R)-(1,1'-dinaphthyl-2,2'-diyl)-N,N'-di-(R,R)-1
      phenylethylphosphoramidite provided the highest reactivity and selectivity.
      Primary and cyclic secondary amines reacted at room temperature, and acyclic
      diethylamine reacted at 50 degrees C. p-Methoxy-substituted cinnamyl carbonate
      reacted similarly to the unsubstituted cinnamyl carbonate, but the o-methoxy
      substituted substrate gave lower enantiomeric excess. High ee's were also
      observed for the products from the reaction of furanyl- and alkyl-substituted (E)
      allylic carbonates.

PMID- 12487579
TI  - What is the mechanism of oriented crystal growth on rubbed polymer substrates?
      Topography vs epitaxy.
AB  - From the oriented growth of p-nitroaniline crystals on various rubbed polymer
      substrates, the orientation mechanism was found to basically rely upon the
      formation of intermolecular interactions at the crystal/polymer interface. The
      observations also show that the surface topography only plays a minor role in the
      oriented nucleation.

PMID- 12487580
TI  - An annulative approach to highly substituted indoles: unusual effect of phenolic
      additives on the success of the arylation of ketone enolates.
AB  - A novel palladium-catalyzed arylation of ketone enolates with o-nitrohaloarenes
      was achieved through the addition of phenol additives. The mild reaction
      conditions employed allowed for the inclusion of a wide variety of functional
      groups in both substrates to be tolerated. The products of this reaction were
      then readily reductively cyclized to give highly substituted indoles in moderate
      to excellent overall yields.

PMID- 12487581
TI  - A stable manganese(V)-oxo corrolazine complex.
AB  - The synthesis and characterization of an oxomanganese(V) corrolazine,
      (TBP)8(Cz)Mn(V)O (2), are reported. This remarkably stable high-valent complex is
      obtained from the stoichiometric reaction of (TBP)8(Cz)Mn(III) (1) with m-CPBA
      and is easily purified by standard chromatographic methods on silica gel at room
      temperature. Complex 2 exhibits a diamagnetic 1H NMR spectrum indicative of a low
      spin d2 Mn(V)O species. LDI-TOFMS of 2 shows the predicted isotopic envelope at
      m/z 1426.8. This envelope shifts to higher mass as expected after the facile
      exchange of the terminal oxo group with H218O. The resonance Raman spectrum of 2
      either in solution or in the solid state shows a strongly enhanced Raman band for
      the stretching mode of the Mn-oxo bond, which also shifts as expected upon 18O
      substitution: 2(16O), 979 cm-1; 2(18O), 938 cm-1 (in CH2Cl2). Initial reactivity
      studies show that 2 rapidly transfers the terminal oxo ligand to PPh3, resulting
      in the quantitative formation of OPPh3 and concomitant reduction of 2 back to 1.
      Complex 2 is the first example of an oxomanganese(V)-porphyrinoid complex that
      can be isolated at room temperature.

PMID- 12487582
TI  - Ruthenium-catalyzed propargylic substitution reaction of propargylic alcohols
      with thiols: a general synthetic route to propargylic sulfides.
AB  - A novel cationic methanethiolate-bridged diruthenium complex [Cp*RuCl(mu2
      SMe)2RuCp*(OH2)]OTf (1e) has been disclosed to promote the catalytic propargylic
      substitution reaction of propargylic alcohols bearing not only terminal alkyne
      group but also internal alkyne group with thiols. It is noteworthy that neutral
      thiolate-bridged diruthenium complexes (1a-1c), which were known to promote the
      propargylic substitution reactions of propargylic alcohols bearing a terminal
      alkyne group with various heteroatom- and carbon-centered nucleophiles, did not
      work at all. The catalytic reaction described here provides a general and
      environmentally friendly preparative method for propargylic sulfides, which are
      quite useful intermediates in organic synthesis, directly from the corresponding
      propargylic alcohols and thiols.

PMID- 12487583
TI  - Aromatic oligomers that form hetero duplexes in aqueous solution.
AB  - The electron-deficient 1,4,5,8-naphthalenetetracarboxylic diimide (Ndi) and
      electron-rich 1,5-dialkoxynaphthalene (Dan) have been shown to complex strongly
      with each other in water due to the hydrophobic effect as modulated through the
      electrostatic complementarity of the stacked dimer. Previously, oligomers of
      alternating Ndi and Dan units, termed aedamers, were the first foldamers to
      employ intramolecular aromatic stacking to effect the formation of secondary
      structure of nonnatural chains in aqueous solution. Described here is the use of
      this aromatic-aromatic (or pi-pi) interaction, this time in an intermolecular
      format, to demonstrate the self-assembly of stable hetero duplexes from a set of
      molecular strands (1a-4a) and (1b-4b) incorporating Ndi and Dan units,
      respectively. A 1-to-1 binding stoichiometry was determined from NMR and
      isothermal titration calorimetry (ITC) investigations, and these experiments
      indicated that association is enthalpically favored with the tetra-Ndi (4a) and
      tetra-Dan (4b) strands forming hetero duplexes (4a:4b) with a stability constant
      of 350 000 M-1 at T = 318 K. Polyacrylamide gel electrophoresis (PAGE) also
      illustrated the strong interaction between 4a and 4b and support a 1-to-1 binding
      mode even when one component is in slight excess. Overall, this system is the
      first to utilize complementary aromatic units to drive discrete self-assembly in
      aqueous solution. This new approach for designing assemblies is encouraging for
      future development of duplex systems with highly programmable modes of binding in
      solution or on surfaces.

PMID- 12487584
TI  - Self-assembly of biphenylene-bridged hybrid mesoporous solid with molecular-scale
      periodicity in the pore walls.
AB  - A synthesis of ordered biphenylene-bridged mesoporous material with a crystal
      like periodic pore wall structure is reported.

PMID- 12487585
TI  - Acyclic tautomers in crystalline carbohydrates: the keto forms of 1-deoxy-1
      carboxymethylamino-D-2-pentuloses (pentulose-glycines).
AB  - NMR and X-ray diffraction studies on acyclic carbohydrate keto tautomers of N-(1
      deoxy-d-erythro-2-pentulos-1-yl)- and N-(1-deoxy-d-threo-2-pentulos-1-yl)glycines
      (ribulose-glycine, 1 and xylulose-glycine, 2), are reported. In aqueous
      solutions, both 1 and 2 exist as a tautomeric mixture, with the beta-furanose as
      a major form, followed by the alpha-furanose and the acyclic keto tautomer. Both
      1 and 2 crystallize as zwitterions in the acyclic keto form. Solid-state 13C NMR
      spectra reveal the existence of two crystallographically independent molecules in
      2 but only one in crystalline 1. The structure of 2 was solved by X-ray
      diffraction; in the crystal, two conformational isomers, 2a and 2b in a 1:1
      ratio, were identified. The conformers are packed in stacks of similar molecules,
      with a system of intermolecular hydrogen bonds involving all hydroxyl, ammonium,
      and carboxyl groups. The structural data indicate that the sugar portion of
      acyclic 2 adopts conformations similar to those proposed for the parent d
      xylulose.

PMID- 12487586
TI  - Rational growth of Bi2S3 nanotubes from quasi-two-dimensional precursors.
AB  - Synthesis of Bi2S3 nanotubes from rolling of the quasi-two-dimensional (2-D)
      layered precursor represents new progress in the synthetic approach and adds new
      members to the present inorganic fullerene family. These nanotubes display
      multiwalled structures that resemble that of a multiwalled carbon nanotube. The
      successful synthesis of Bi2S3 nanotubes highlights the feasibility of inorganic
      fullerene-like structures from other chemicals that possess layered crystalline
      structures, not only the well-known 2-D family, but possibly also those quasi-2-D
      members.

PMID- 12487587
TI  - Synthesis of silver nanodisks using polystyrene mesospheres as templates.
AB  - We report the synthesis of Ag nanodisk using polystyrene mesospheres as
      templates. TEM measurements show that the average disk thickness is 9.0 +/- 1.0
      nm and the diameter is 36 +/- 8 nm. The particles exhibit an intense electronic
      spectrum that differs markedly from that for spheres (purple vs yellow
      solutions). We present electromagnetic theory calculations which exhibit a
      qualitative match with the observed spectrum, enabling us to assign several of
      the plasmon resonance features.

PMID- 12487588
TI  - [Li(CH(Me)P(Ph)2(NCO2Me))2(THF)2]: crystal, solution, and calculated structure of
      a N-delocalized lithium phosphazene.
AB  - The first crystal structure of the lithium complex of a P-alkyl-P,P-diphenyl(N
      methoxycarbonyl)phosphazene has been characterized. It is dimeric, with the anion
      chelating the lithium in an unusual six-membered ring. A monomer-dimer
      equilibrium has been identified in THF solution. Ab initio calculations indicated
      that the six-membered ring is electronically favored over an alternative Li-C-P-N
      four-membered ring.

PMID- 12487589
TI  - A rhodium(I)-catalyzed formal allenic Alder ene reaction for the rapid and
      stereoselective assembly of cross-conjugated trienes.
AB  - A rhodium(I)-catalyzed allenic Alder ene reaction to prepare cross-conjugated
      trienes has been discovered. The scope and limitations are currently being
      investigated, and the results obtained to date are reported on. This method shows
      enticing functional group compatibility by tolerating terminal and internal
      alkynes, hydroxyl, sulfonamide, ether, and diester groups. Progress has been made
      to increase the stereoselectivity of the olefinic side chain via an
      unprecendented iridium(I) catalyzed Alder-ene reaction.

PMID- 12487590
TI  - Efficient nickel-catalyzed [2 + 2 + 2] cycloaddition of CO2 and diynes.
AB  - A mild and general route for preparing 2-pyrones from CO2 and diynes is
      described. Under only 1 atm of CO2, excellent yields of pyrone are obtained using
      catalytic amounts of Ni(COD)2 and imidazolylidene ligand, IPr. In addition,
      stoichiometric reactions between the isolated complex Ni(IPr)2, diynes, and CO2
      suggest that the pathway involves initial reaction with CO2 as the key step.

PMID- 12487591
TI  - [(CH3)4N][(C5H5NH)0.8((CH3)3NH)0.2]U2Si9O23F4 (USH-8): an organically templated
      open-framework uranium silicate.
AB  - The open-framework uranium fluorosilicate
      [(CH3)4N][(C5H5NH)0.8((CH3)3NH)0.2]U2Si9O23F4 (USH-8) has been synthesized
      hydrothermally by using tetramethylammonium hydroxide and pyridine-HF. The
      compound has a framework composition U2Si9O23F4 based on silicate double layers
      that are linked by chains of UO3F4 pentagonal bipyramids. The framework has 12
      ring channels along [010] and 7-ring channels along [100]. The [010] 12-ring
      channels have a calabash-shape with the middle part partially blocked by the
      uranyl oxygen atoms. The narrow side of the 12-ring channels is occupied by well
      ordered TMA cations while the wide side is occupied by disordered pyridinium and
      trimethylammonium cations.

PMID- 12487592
TI  - Colloidal transition-metal-doped ZnO quantum dots.
AB  - Methods for introducing new magnetic, optical, electronic, photophysical, or
      photochemical properties to semiconductor nanocrystals are attracting intense
      applications-oriented interest. In this communication, we report the preparation
      and electronic absorption spectroscopy of colloidal ZnO DMS-QDs. Our synthetic
      procedure involves modification of literature methods known to yield highly
      crystalline and relatively monodisperse nanocrystals of pure ZnO to allow
      introduction of transition-metal dopants. We use ligand-field electronic
      absorption spectroscopy as a dopant-specific optical probe to monitor dopant
      incorporation during nanocrystal growth and to verify internal substitutional
      doping in Co2+:ZnO and Ni2+:ZnO DMS-QDs. To the best of our knowledge, these are
      the first free-standing oxide DMS-QDs reported. The synthesis of colloidal oxide
      DMS-QDs introduces a new category of magnetic semiconductor materials available
      for detailed physical study and application in nanotechnology.

PMID- 12487593
TI  - Polyhedral oligomeric silsesquioxanes: a new class of amphiphiles at the
      air/water interface.
AB  - Insoluble films of trisilanolisobutyl-POSS and octaisobutyl-POSS at the air/water
      interface are investigated by means of surface pressure - area per molecule
      isotherm (Pi - A) and Brewster angle microscopy (BAM). Analysis of the
      experimental results shows the partial cage molecule, trisilanolisobutyl-POSS, is
      a surface-active molecule that self-assembles into uniform monolayer upon
      compression; but the fully condensed cage molecule, octaisobutyl-POSS, is
      nonamphiphilic.

PMID- 12487594
TI  - Intramolecular silicon-assisted cross-coupling: total synthesis of (+)
      brasilenyne.
AB  - The first, total synthesis of (+)-brasilenyne (1) has been achieved in 19 steps
      from l-(S)-malic acid. The key elements of this approach are a highly
      diastereoselective ring-opening of a 1,3-dioxolanone with
      bis(trimethylsilyl)acetylene) promoted by TiCl4 to set a propargylic stereocenter
      and the successful application of the sequential ring closing metathesis/silicon
      assisted intramolecular cross-coupling reaction for construction of the oxonin
      core structure of 1.

PMID- 12487595
TI  - Polymeric nanogels produced via inverse microemulsion polymerization as potential
      gene and antisense delivery agents.
AB  - Polymeric nanogel vectors were developed for cellular gene and antisense
      delivery. Inverse microemulsion polymerization was utilized to synthesize
      biocompatible nanogels with controlled size, morphology, and composition. The
      chemical composition, size, polydispersity, stability, and swelling behavior of
      the nanogels were investigated by NMR, light scattering, transmission electron
      microscopy, and atomic force microscopy. The cell viability, uptake, and physical
      stability of nanogel-DNA complexes were evaluated under physiological conditions.
      Monodisperse nonionic and cationic nanogels were produced with controllable sizes
      ranging from 40 to 200 nm in diameter. The nanogels demonstrated extended
      stability in aqueous media and exhibited low toxicity in cell culture. Cationic
      nanogels formed monodisperse complexes with oligonucleotides and showed enhanced
      oligonucleotide uptake in cell culture. The nanogels synthesized in this study
      demonstrate potential utility as carriers of oligonucleotides and DNA for
      antisense and gene delivery.

PMID- 12487596
TI  - FRET study of a trifluorophore-labeled DNAzyme.
AB  - A fluorescence resonance energy transfer (FRET) study of biomolecules typically
      employs two fluorophores. The increasing number of branches and complexity of
      biomolecules call for simultaneously monitoring structures and dynamics of
      several branches in a single system. Furthermore, despite recent studies that
      show DNAzymes can be a stable and cost-effective alternative to protein and
      ribozymes for pharmaceutical and biotechnological applications, no FRET study of
      DNAzymes has been reported. Here, we describe the FRET study of a trifluorophore
      labeled "8-17" DNAzyme, in which each of the three branches is labeled with a
      different fluorophore. From the study, we found that the (ratio)(A) method that
      has been commonly used in dual-fluorophore-labeled systems is also applicable to
      trifluorophore-labeled systems. However, while both FRET efficiency and
      fluorophore-to-fluorophore distance can be used to measure FRET in dual
      fluorophore-labeled systems, only the average distance should be used in
      trifluorophore-labeled systems. The ability to monitor all three branches in a
      single system allowed us to reveal new metal-ion-dependent conformational changes
      in the DNAzyme. The trifluorophore-labeled "8-17" DNAzyme has been found to adopt
      a two-step folding process in the presence of Zn(2+). Each step is induced by one
      Zn(2+) binding, with apparent dissociation constants of 19 microM and 260 microM
      for binding the first and second Zn(2+), respectively. The trifluorophore FRET
      results are verified by a dual-labeled control experiment. The results
      demonstrated that the trifluorophore-labeled system is simple and yet powerful in
      studying complicated biomolecular structure and dynamics and is capable of
      revealing new sophisticated structural changes that may have functional
      implications.

PMID- 12487597
TI  - Synthesis and application of a fluorescent substrate analogue to study ligand
      interactions for undecaprenyl pyrophosphate synthase.
AB  - Farnesyl pyrophosphate (FPP) serves as a common substrate for many
      prenyltransferases involved in the biosynthesis of isoprenoid compounds.
      Undecaprenyl pyrophosphate synthase (UPPs) catalyzes the chain elongation of FPP
      to C(55) undecaprenyl pyrophosphate (UPP) which acts as a lipid carrier in
      bacterial peptidoglycan synthesis. In this study, 7-(2,6-dimethyl-8-diphospho-2,6
      octadienyloxy)-8-methyl-4-trifluoromethyl-chromen-2-one geranyl pyrophosphate, a
      fluorescent analogue of FPP, was prepared and utilized to study ligand
      interactions with E. coli UPPs. This compound displays an absorbance maximum at
      336 nm and emission maximum at 460 nm without interference from protein
      autofluorescence. It is a competitive inhibitor with respect to FPP (K(i) = 0.57
      microM) and also serves as an alternative substrate (K(m) = 0.69 microM and
      k(cat) = 0.02 s(-)(1)), but mainly reacts with one isopentenyl pyrophosphate
      (IPP) probably due to unfavorable product translocation. Fluorescence intensity
      of this compound is reduced when bound to the enzyme (1:1 stoichiometry), and is
      recovered by FPP replacement. Using stopped-flow apparatus, the interaction of
      enzyme with the compound was measured (k(on) = 55.3 microM(-)(1) s(-)(1) and
      k(off) = 31.6 s(-)(1)). The product dissociation rate constant (0.5 s(-)(1))
      determined from the competition experiments is consistent with our previous
      prediction from kinetic simulation. Unlike several other prenyltransferase
      reactions in which FPP dissociates slowly, UPPs binds FPP in a rapid equilibrium
      manner with a fast release rate constant of 30 s(-)(1). The fluorescent analogue
      of FPP presented here may provide a tool to investigate the ligand interactions
      for a broad class of FPP-binding proteins.

PMID- 12487598
TI  - Kinetics of reductive N-O bond fragmentation: the role of a conical intersection.
AB  - N-alkoxyheterocycles can act as powerful one-electron acceptors in photochemical
      electron-transfer reactions. One-electron reduction of these species results in
      formation of a radical that undergoes N-O bond fragmentation to form an alkoxy
      radical and a neutral heterocycle. The kinetics of this N-O bond fragmentation
      reaction have been determined for a series of radicals with varying substituents
      and extents of delocalization. Rate constants varying over 7 orders of magnitude
      are obtained. A reaction potential energy surface is described that involves
      avoidance of a conical intersection. A molecular basis for the variation of the
      reaction rate constant with radical structure is given in terms of the
      relationship between the energies of the important molecular orbitals and the
      reaction potential energy surface. Ab initio and density functional electronic
      structure calculations provide support for the proposed reaction energy surface.

PMID- 12487599
TI  - Single-site beta-diiminate zinc catalysts for the ring-opening polymerization of
      beta-butyrolactone and beta-valerolactone to poly(3-hydroxyalkanoates).
AB  - Polymerization of beta-butyrolactone (BBL) and beta-valerolactone (BVL) using the
      zinc alkoxide initiator (BDI-1)ZnO(i)()Pr [(BDI-1) = 2-((2,6
      diisopropylphenyl)amido)-4-((2,6-diisopropylphenyl)imino)-2-pentene] proceeds
      very rapidly under mild conditions to produce poly(3-hydroxybutyrate) (PHB) and
      poly(3-hydroxyvalerate) (PHV), respectively. For the monomer-to-initiator ratio
      200:1, PHB number-average molecular weights (M(n)) are proportional to conversion
      throughout the reaction and polydispersity indices (PDIs) are narrow, consistent
      with a living polymerization. Higher monomer-to-initiator ratios can be used to
      achieve high molecular weight PHB (M(n) > 100 000). End-group analysis verifies
      that the polymerization of BBL follows a coordination-insertion mechanism, where
      complexes of the form (BDI-1)ZnOCH(Me)CH(2)CO(2)R are the active species.
      Variable temperature NMR experiments show that (BDI-1)ZnO(i)()Pr is monomeric in
      benzene-d(6) solution. In contrast, (BDI-2)ZnO(i)()Pr [(BDI-2) = 2-((2,6
      diethylphenyl)amido)-4-((2,6-diethylphenyl)imino)-2-pentene] is a poor initiator
      at room temperature because it prefers to form a bis-mu-isopropoxide dimer in
      solution. According to kinetic studies, propagation by (BDI-1)ZnO(i)()Pr is first
      order in both monomer as well as (BDI-1)ZnO(i)()Pr concentration. These results
      lead us to propose a monometallic active species. Several results suggest that
      elimination side reactions are slowly catalyzed by zinc alkoxides, leading to
      degradation of the polymer.

PMID- 12487600
TI  - Specific interactions of complementary mono- and multivalent guests with
      recognition-induced polymersomes.
AB  - We have explored the interactions of mono- and multivalent guests with
      Recognition-Induced Polymersomes (RIPs) formed from complementary random
      copolymers featuring diamidopyridine and thymine functionality. Addition of
      monovalent guests featuring imide functionality to these RIPs induced a temporary
      swelling of the vesicles, followed by dissociation of the vesicles due to
      competitive binding of the guest. Conversely, multivalent thymine-functionalized
      nanoparticle guests were rapidly incorporated into the RIPs, inducing a
      contraction of RIP diameter over time. These mono- and multivalent interactions
      were extremely specific: highly analogous control systems showed no interaction
      with the RIP structures. Taken together, these studies demonstrate highly
      selective molecular "lock and key" control over higher-order assembly and
      recognition processes.

PMID- 12487601
TI  - A highly cis-selective synthesis of 2-ethynylaziridines by intramolecular
      amination of chiral bromoallenes: improvement of stereoselectivity based on the
      computational investigation.
AB  - The base-mediated intramolecular amination of bromoallenes having an axial
      chirality is described. The treatment of (4S,aR)-4-alkyl-4-[N
      (arylsulfonyl)amino]-1-bromobuta-1,2-dienes with NaH in DMF affords 2,3-cis-2
      ethynylaziridines in good to excellent selectivity (2,3-cis:trans = 92:8-99:1).
      The reaction of (4S,aS)-bromoallenes with NaH/DMF also gives 2,3-cis-2
      ethynylaziridines selectively (79:21-91:9). These experimental results have been
      rationalized by B3LYP density functional calculations together with the 6-31+G(d)
      basis set and the Onsager solvation model. The transition structures for cis
      aziridine formation of both (4S,aR)- and (4S,aS)-bromoallenes in DMF are favored
      over the corresponding trans transition structures by 4.35 and 1.41 kcal/mol,
      respectively. Furthermore, the calculations predicted that a less polar solvent
      gives higher cis selectivity for (4S,aS)-bromoallenes. In fact, improvement of
      the cis selectivity to 99:1 has been realized by using a less polar solvent such
      as THF. The cyclization of bromoallenes bearing a beta- or gamma-amino group also
      affords four- and five-membered azacycles in a highly cis-selective manner.

PMID- 12487602
TI  - A NMR and theoretical study of the aggregates between alkyllithium and chiral
      lithium amides: control of the topology through a single asymmetric center.
AB  - The complexes between methyllithium and chiral 3-aminopyrrolidine (3-AP) lithium
      amides bearing a second asymmetric center on their lateral amino group were
      studied using multinuclear ((1)H, (6)Li, (13)C, (15)N) low-temperature NMR
      spectroscopies in tetrahydrofuran-d(8). The results indicate that lithium
      chelation forces the pyrrolidine ring of the 3-AP to adopt a norbornyl-like
      conformation and that robust 1:1 noncovalent complexes between methyllithium and
      3-AP lithium amides form in the medium. A set of (1)H-(1)H and (1)H-(6)Li NMR
      cross-coupling correlations shows that the binding of methyllithium can take
      place along the "exo" or the "endo" face of this puckered structure, depending on
      the relative configuration of the lateral chiral group. This aggregation step
      renders the nitrogen of the 3-amino group chiral, the "exo" and "endo" topologies
      corresponding to the (S) and (R) configurations, respectively, of this atom.
      Density functional theory calculations show that the "exo" and "endo"
      arrangements are, for both diastereomers, almost isoenergetic even when solvent
      is taken into account. This result suggests that the formation of the mixed
      aggregates is under strict kinetic control. A relationship between the topology
      of these complexes and the sense of induction in the enantioselective alkylation
      of aromatic aldehydes by alkyllithiums is proposed.

PMID- 12487603
TI  - Triple tandem catalyst mixtures for the synthesis of polyethylenes with varying
      structures.
AB  - Tandem catalysis in a single medium presents challenges and opportunities for
      creating novel synthetic protocols. Thus far, only two homogeneous catalysts have
      been used in tandem. Herein, we report that it is possible to coordinate the
      action of three well-defined homogeneous catalysts to produce a wide range of
      branched polyethylenes from a single monomer. Thus, ([(eta(5)
      C(5)Me(4))SiMe(2)(eta(1)-NCMe(3))]TiMe)(MeB(C(6)F(5))(3)) (1),
      [(C(6)H(5))(2)PC(6)H(4)C(OB(C(6)F(5))(3))O-kappa(2)P,O]Ni(eta(3)-CH(2)C(6)H(5))
      (2), and ((H(3)C)C[N(C(6)H(5))]C[O-B(C(6)F(5))(3)][N(C(6)H(5))]
      kappa(2)N,N)Ni(eta(3)-CH(2)C(6)H(5)) (3) react with ethylene to produce branched
      polyethylene with structures that cannot be obtained using a single- or a two
      component catalyst combination. The properties of the polyethylene depend on the
      ratio of the three catalysts. High-throughput screening techniques proved
      essential for optimizing reaction conditions and for probing how the catalyst
      composition influences the polymer properties.

PMID- 12487604
TI  - Mesomorphism, isomerization, and dynamics in a new series of pyramidic liquid
      crystals.
AB  - Nona-alkanoyloxy tribenzocyclononene (CTV-n, where n is the number of carbons in
      the side chains) were prepared for n = 2 to 14. The homologues of this series
      appear in two stable isomeric forms, rigid crown and flexible saddle. We report
      on their isomerization equilibria and dynamics in solution and on their
      mesomorphic properties in the neat state. The crown-saddle equilibrium and
      interconversion kinetics of the CTV-8 isomers were studied in dimethyl formamide
      solutions using high-resolution (1)H NMR in the temperature range from 50 to 130
      degrees C. At lower temperatures, the isomerization is too slow to measure. In
      this range the equilibrium saddle fraction increases from approximately 0.40 to
      approximately 0.65, whereas the isomerization rate increases from approximately
      10(-)(4) to approximately 1 s(-)(1). The saddle isomer undergoes fast
      pseudorotation at room temperature, but below about -50 degrees C, it becomes
      slow enough to affect the NMR line width. The rate parameters for this process
      were estimated from the carbon-13 spectra in methylene chloride solutions to be,
      k(p)(-100 degrees C) approximately 1.7 x 10(3) s(-)(1) and E(a) approximately 9.6
      kJ/mol. The slow crown-saddle isomerization at room temperature (half-life of
      about one year) allows quantitative separation (by chromatography) of the two
      isomers and their separate investigation. When the alkanoyloxy side chains are
      sufficiently long both isomers are mesogenic (n >or= 4 for the saddle and n >or=
      5 for the crown), exhibiting hexagonal columnar mesophases. The structure,
      dynamics, and mesomorphic properties of these mesophase were investigated by X
      ray diffraction, optical polarizing microscopy, differential scanning
      calorimetry, and NMR. The lattice parameters of the crown and saddle mesophases
      of corresponding homologues are almost identical and increase monotonically with
      increasing length of the side chains. The clearing temperatures of the saddle
      isomers are consistently lower than those of the corresponding crowns. Within
      each series, the clearing temperatures are almost independent of the length of
      the side chains (156 to 170 degrees C for the crown and 115 to 148 degrees C for
      the saddle). The thermal and kinetic properties of the neat compounds lead to
      peculiar phase sequences, as observed in the polarizing microscope and in the DSC
      thermogram, involving repeated, back and forth, interconversion between the two
      isomers. Carbon-13 MAS NMR measurements of the crown and saddle mesophases of
      several homologues were carried out. The spectra of the crown mesophase exhibit
      dynamic features consistent with planar 3-fold molecular jumps about the column
      axes. A quantitative analysis for the CTV-8 crown homologue yielded the following
      Arrhenius parameters, A = 3.1 x 10(22)s(-)(1) and E(a) = 130.1kJ/mol. These
      unusually high values suggest that the barrier to the jump process is temperature
      dependent, decreasing with increasing temperature. The rate of this 3-fold jump
      process is slower for the lower homologues and faster for the higher ones. In
      contrast, the saddle isomers in the mesophase do not show dynamic effects in
      their carbon-13 MAS spectra. They do not undergo pseudorotation, and it appears
      that the molecules remain locked within the columns in a saddle conformation, up
      to the clearing temperature. However, on (super-)cooling to room temperature and
      below, selective line broadening is observed in their carbon-13 MAS spectra. This
      suggests that the saddle conformation is twisted in the mesophase and undergoes
      fast high-amplitude jumps between the twisted forms. On cooling, these high
      amplitude librations freeze out to give an orientationally disordered state. On a
      very long time scale (of the order of days at 100 degrees C), the saddle
      mesophase transforms into that of the crown, apparently by sublimation.

PMID- 12487605
TI  - Octachloroazulene.
AB  - The title compound, the first perhaloazulene, has been synthesized from
      hexachlorobutadiene and cyclopentadiene. Further chlorination of 1,3,4,5,6,7
      hexachloroazulene results in addition, not substitution, under electrophilic as
      well as free radical conditions. Radical chlorination of the hexachloroazulene
      affords in good yield a single decachlorotetrahydroazulene. Treatment of this
      Cl(10) compound with one equiv of a phosphazene base gives a
      nonachlorodihydroazulene, but the addition of a second equiv results in
      dechlorination to 1,2,3,4,5,6,7-heptachloroazulene as well as dehydrochlorination
      to octachloroazulene. The former azulene is obtained cleanly from the Cl(9)
      compound with acid catalysis or by reduction with mercury. In the presence of
      calcium carbonate, however, the Cl(9) intermediate yields the dark green
      octachloroazulene. Although octachloronaphthalene is readily converted into its
      octafluoro counterpart, the isomeric octachloroazulene is far too sensitive to
      undergo the analogous transformation.

PMID- 12487606
TI  - First determination of absolute rate constants for the reaction of aroyl
      substituted benzyl carbanions in water and DMSO.
AB  - The prompt generation of carbanions II and III within the duration of the
      nanosecond laser pulse provides a way of evaluating absolute rate constants for
      their two decay pathways, protonation and cyclization, the latter resulting from
      an intramolecular nucleophilic carbanion displacement of iodide tethered at the
      end of the lateral alkyl chain. Absolute rate constants are given for both
      carbanions (II and III) and show that the intra-S(N)2 reaction is favored in
      aprotic media, such as dimethyl sulfoxide (DMSO), while protonation is the
      dominant reaction in basic aqueous media.

PMID- 12487607
TI  - First comprehensive bakkane approach: stereoselective and efficient
      dichloroketene-based total syntheses of (+/-)- and (-)-9-acetoxyfukinanolide, (+/
      )- and (+)-bakkenolide A, (-)-bakkenolides III, B, C, H, L, V, and X, (+/-)- and
      (-)-homogynolide A, (+/-)-homogynolide B, and (+/-)-palmosalide C.
AB  - Cycloaddition of dichloroketene with dimethylcyclohexenes has been used as the
      key reaction in an efficient, general approach to the bakkanes. New methods and
      methodologies that have been developed in this work include spiro beta-methylene
      gamma-butyrolactonizations, a vicinal dicarboxylation, an angelic ester
      preparation, a transesterification, an epoxy ketone double reduction, and a retro
      aldol-aldol approach to low-energy aldol isomers.

PMID- 12487608
TI  - Novel inorganic frameworks constructed from double-four-ring (D4R) units:
      computational design, structures, and lattice energies of silicate,
      aluminophosphate, and gallophosphate candidates.
AB  - The design of new and interesting inorganic frameworks is an ongoing challenge in
      materials sciences. New structures containing double-four-ring (D4R) units have
      recently received particular attention. The present work focuses on the
      computational design of new three-dimensional frameworks made of D4R units
      exclusively. In a first step, our simulations explore the possible ways to
      assemble predefined D4R units in 3D space using a sophisticated cascade of
      simulated annealing/minimizations steps (autoassembly of secondary building units
      method). While the existing zeotype topologies were successfully generated, new
      topologies were predicted including very open frameworks containing new types of
      cages. In a second step, lattice energy minimizations were performed to estimate
      the viability of these hypothetical frameworks as silicate, aluminophosphaste,
      and gallophosphate candidates. When comparing the hypothetical structures to
      existing compounds, our results raise the challenging question of the appropriate
      chemical composition that should be aimed at for a given framework topology of
      interest.

PMID- 12487609
TI  - Elucidation of a low spin cobalt(II) system in a distorted tetrahedral geometry.
AB  - We have prepared a series of divalent cobalt(II) complexes supported by the
      [PhBP(3)] ligand ([PhBP(3)] = [PhB(CH(2)PPh(2))(3)](-)) to probe certain
      structural and electronic phenomena that arise from this strong field, anionic
      tris(phosphine) donor ligand. The solid-state structure of the complex
      [PhBP(3)]CoI (1), accompanied by SQUID, EPR, and optical data, indicates that it
      is a pseudotetrahedral cobalt(II) species with a doublet ground state-the first
      of its type. To our knowledge, all previous examples of 4-coordinate cobalt(II)
      complexes with doublet ground states have adopted square planar structure types.
      Complex 1 provided a useful precursor to the corresponding bromide and chloride
      complexes, ([PhBP(3)]Co(mu-Br))(2), (2), and ([PhBP(3)]Co(mu-Cl))(2), (3). These
      complexes were similarly characterized and shown to be dimeric in the solid
      state. In solution, however, the monomeric low spin form of 2 and 3 dominates at
      25 degrees C. There is spectroscopic evidence for a temperature-dependent
      monomer/dimer equilibrium in solution for complex 3. Furthermore, the dimers 2
      and 3 did not display appreciable antiferromagnetic coupling that is typical of
      halide and oxo-bridged copper(II) and cobalt(II) dimers. Rather, the EPR and
      SQUID data for solid samples of 2 and 3 suggest that they have triplet ground
      states. Complexes 1, 2, and 3 are extremely oxygen sensitive. Thus,
      stoichiometric oxidation of 1 by dioxygen produced the 4-coordinate, high spin
      complex [PhB(CH(2)P(O)Ph(2))(2)(CH(2)PPh(2))]CoI, (4), in which the [PhBP(3)]
      ligand had undergone a 4-electron oxidation. Reaction of 1 with TlOAr (Ar = 2,6
      Me(2)Ph) afforded an example of a 4-coordinate, high spin complex, [PhBP(3)]Co(O
      2,6-Me(2)Ph) (5), with an intact [PhBP(3)] ligand. The latter two complexes were
      spectroscopically and structurally characterized for comparison to complexes 1,
      2, and 3. Our data for these complexes collectively suggest that the [PhBP(3)]
      ligand provides an unusually strong ligand-field to these divalent cobalt
      complexes that is chemically distinct from typical tris(phosphine) donor ligand
      sets, and distinct from tridentate borato ligands that have been previously
      studied. Coupling this strong ligand-field with a pronounced axial distortion
      away from tetrahedral symmetry, a geometric consequence that is enforced by the
      [PhBP(3)] ligand, provides access to monomeric [PhBP(3)]CoX complexes with
      doublet rather than quartet ground states.

PMID- 12487610
TI  - Insights into the metathesis reaction involving M-M, C-C, and M-C triple bonds
      from computations employing density functional theory on model compounds M2(OH)6
      and M2(SH)6, where M = Mo and W.
AB  - Calculations employing density functional theory (Gaussian 98, B3LYP, LANL2DZ, 6
      31G) have been undertaken to interrogate the factors influencing the metathesis
      reaction involving M-M, C-C, and M-C triple bonds for the model compounds
      M(2)(EH)(6), M(2)(EH)(6)(mu-C(2)H(2)), and [(HE)(3)M(tbd1;CH)](2), where M = Mo,
      W and E = O, S. Whereas in all cases the ethyne adducts are predicted to be
      enthalpically favored in the reactions between M(2)(EH)(6) compounds and ethyne,
      only when M = W and E = O is the alkylidyne product [(HO)(3)W(tbd1;CH)](2)
      predicted to be more stable than the alkyne adduct. For the reaction
      M(2)(EH)(6)(mu-C(2)H(2)) --> [(HE)(3)M(tbd1;CH)](2), the deltaG degrees values
      (kcal mol(-)(1)) are -6 (M = W, E = O), +5 (M = Mo, E = O), +18 (M = W, E = S),
      and +21 (M = Mo, E = S) and the free energies of activation are calculated to be
      deltaG() = +19 kcal mol(-)(1) (M = W, E = O) and +34 kcal mol(-)(1) (M = Mo, E =
      O), where the transition state involves an asymmetric bridged structure
      M(2)(OH)(4)(mu-OH)(2)(CH)(mu-CH) in which the C-C bond has broken; C.C = 1.89 and
      1.98 A for W and Mo, respectively. These results are discussed in terms of the
      experimental observations of the reactions involving ethyne and the symmetrically
      substituted alkynes (RCCR, where R = Me, Et) with M(2)(O(t)()Bu)(6) and
      M(2)(O(t)()Bu)(2)(S(t)()Bu)(4) compounds, where M = Mo, W.

PMID- 12487611
TI  - Comparative study of the high-pressure behavior of As, Sb, and Bi.
AB  - The high-pressure behavior of the heavier group 15 elements As, Sb, and Bi was
      investigated by means of ab initio density functional calculations employing
      pseudopotentials and a plane wave basis set. The high-pressure structural
      sequence of these elements is distinguished by the occurrence of the Bi-III
      structure, which is a complex, incommensurately modulated, host-guest structure.
      We approximated this structure by a supercell which reproduced the experimentally
      established pressure stability ranges of the host-guest structure for the
      different elements extremely well. With pressure we find an increasing admixture
      of d states (s-d hybridization) in the occupied levels of the electronic
      structure of As, Sb, and Bi. However, the s-d mixing remains at a low level.
      Thus, the emergence of a complex intermediate pressure structure cannot be
      explained by a pressure-induced altered valence state for these elements.
      Instead, it is argued that the Bi-III structure is a consequence of a delicate
      interplay between the electrostatic and the band energy contribution to the total
      energy. In the intermediate pressure range of heavier group 15 elements, both
      important parts of the total energy account equally for structural stability.

PMID- 12487612
TI  - Saturation transfer difference 1D-TOCSY experiments to map the topography of
      oligosaccharides recognized by a monoclonal antibody directed against the cell
      wall polysaccharide of group A streptococcus.
AB  - A new saturation transfer difference 1D-TOCSY NMR experiment that allows the
      investigation of complex ligands interacting with proteins and its application in
      the mapping of which portions of oligosaccharide ligands (epitope) interact with
      a complementary antibody are described. The interaction between trisaccharide and
      hexasaccharide ligands, corresponding to fragments of the cell-wall
      polysaccharide of Streptococcus Group A, and a monoclonal antibody directed
      against the polysaccharide is investigated at the molecular level. The
      polysaccharide consists of alternating alpha-(1-->2) and alpha-(1-->3) linked L
      rhamnopyranose (Rha) residues with branching N-acetyl-D-glucopyranosylamine
      (GlcNAc) residues linked beta-(1-->3) to alternate rhamnopyranose rings. The
      epitope is proven to consist not only of the immunodominant GlcNAc sugar but also
      of an entire branched trisaccharide repeating unit. The experimental NMR data
      serve to check and validate the computed models of the oligosaccharide-antibody
      complexes.

PMID- 12487613
TI  - Thermal and photochemical rearrangement of bicyclo[3.1.0]hex-3-en-2-one to the
      ketonic tautomer of phenol. Computational evidence for the formation of a
      diradical rather than a zwitterionic intermediate.
AB  - The ground state (S(0)) and lowest-energy triplet state (T(1)) potential energy
      surfaces (PESs) concerning the thermal and photochemical rearrangement of
      bicyclo[3.1.0]hex-3-en-2-one (8) to the ketonic tautomer of phenol (11) have been
      extensively explored using ab initio CASSCF and CASPT2 calculations with several
      basis sets. State T(1) is predicted to be a triplet pipi lying 66.5 kcal/mol
      above the energy of the S(0) state. On the S(0) PES, the rearrangement of 8 to 11
      is predicted to occur via a two-step mechanism where the internal cyclopropane C
      C bond is broken first through a high energy transition structure (TS1-S(0)()),
      leading to a singlet intermediate (10-S(0)()) lying 25.0 kcal/mol above the
      ground state of 8. Subsequently, this intermediate undergoes a 1,2-hydrogen shift
      to yield 11 by surmounting an energy barrier of only 2.7 kcal/mol at 0 K. The
      rate-determining step of the global rearrangement is the opening of the three
      membered ring in 8, which involves an energy barrier of 41.2 kcal/mol at 0 K.
      This high energy barrier is consistent with the fact that the thermal
      rearrangement of umbellulone to thymol is carried out by heating at 280 degrees
      C. Regarding the photochemical rearangement, our results suggest that the most
      efficient route from the T(1) state of 8 to ground state 11 is the essentially
      barrierless cleavage of the internal cyclopropane C-C bond followed by
      radiationless decay to the S(0) state PES via intersystem crossing (ISC) at a
      crossing point (S(0)()/T(1)()-1) located at almost the same geometry as TS1
      S(0)(), leading to the formation of 10-S(0)() and the subsequent low-barrier 1,2
      hydrogen shift. The computed small spin-orbit coupling between the T(1) and S(0)
      PESs at S(0)()/T(1)()-1 (1.2 cm(-)(1)) suggests that the ISC between these PESs
      is the rate-determining step of the photochemical rearrangement 8 --> 11.
      Finally, computational evidence indicates that singlet intermediate 10-S(0)()
      should not be drawn as a zwitterion, but rather as a diradical having a polarized
      C=O bond.

PMID- 12487614
TI  - Tris(trifluoromethyl)borane carbonyl, (CF3)3BCO-synthesis, physical, chemical and
      spectroscopic properties, gas phase, and solid state structure.
AB  - Tris(trifluoromethyl)borane carbonyl, (CF(3))(3)BCO, is obtained in high yield by
      the solvolysis of K[B(CF(3))(4)] in concentrated sulfuric acid. The in situ
      hydrolysis of a single bonded CF(3) group is found to be a simple, unprecedented
      route to a new borane carbonyl. The related, thermally unstable borane carbonyl,
      (C(6)F(5))(3)BCO, is synthesized for comparison purposes by the isolation of
      (C(6)F(5))(3)B in a matrix of solid CO at 16 K and subsequent evaporation of
      excess CO at 40 K. The colorless liquid and vapor of (CF(3))(3)BCO decomposes
      slowly at room temperature. In the gas phase t(1/2) is found to be 45 min. In the
      presence of a large excess of (13)CO, the carbonyl substituent at boron undergoes
      exchange, which follows a first-order rate law. Its temperature dependence yields
      an activation energy (E(A)) of 112 kJ mol(-)(1). Low-pressure flash thermolysis
      of (CF(3))(3)BCO with subsequent isolation of the products in low-temperature
      matrixes, indicates a lower thermal stability of the (CF(3))(3)B fragment, than
      is found for (CF(3))(3)BCO. Toward nucleophiles (CF(3))(3)BCO reacts in two
      different ways: Depending on the nucleophilicity of the reagent and the stability
      of the adducts formed, nucleophilic substitution of CO or nucleophilic addition
      to the C atom of the carbonyl group are observed. A number of examples for both
      reaction types are presented in an overview. The molecular structure of
      (CF(3))(3)BCO in the gas phase is obtained by a combined microwave-electron
      diffraction analysis and in the solid state by single-crystal X-ray diffraction.
      The molecule possesses C(3) symmetry, since the three CF(3) groups are rotated
      off the two possible positions required for C(3)(v)() symmetry. All bond
      parameters, determined in the gas phase or in the solid state, are within their
      standard deviations in fair agreement, except for internuclear distances most
      noticeably the B-CO bond lengths, which is 1.69(2) A in the solid state and
      1.617(12) A in the gas phase. A corresponding shift of nu(CO) from 2267 cm(-)(1)
      in the solid state to 2251 cm(-)(1) in the gas phase is noted in the vibrational
      spectra. The structural and vibrational study is supported by DFT calculations,
      which provide, in addition to the equilibrium structure, confirmation of
      experimental vibrational wavenumbers, IR-band intensities, atomic charge
      distribution, the dipole moment, the B-CO bond energy, and energies for the
      elimination of CF(2) from (CF(3))(x)()BF(3)(-)(x)(), x = 1-3. In the vibrational
      analysis 21 of the expected 26 fundamentals are observed experimentally. The
      (11)B-, (13)C-, and (19)F-NMR data, as well as the structural parameters of
      (CF(3))(3)BCO, are compared with those of related compounds.

PMID- 12487620
TI  - Responsible prescribing of opioids for the management of chronic pain.
AB  - The management of patients with chronic pain is a common clinical challenge.
      Indeed, chronic pain is often inadequately controlled in patients with cancer and
      in those with non-cancer chronic pain. Because of the complex nature of chronic
      pain, successful long-term treatment is more difficult than for acute pain. Most
      often acute pain is nociceptive, whereas chronic pain can be nociceptive (i.e.,
      in response to noxious stimuli), neuropathic (i.e., initiated by a primary lesion
      or dysfunction in the nervous system) or mixed in origin. Opioids are the current
      standard of care for the treatment of moderate or severe nociceptive pain.
      Opioids mediate their actions by binding and activating receptors both in the
      peripheral nervous system and those that are found in inhibitory pain circuits
      that descend from the midbrain to the spinal cord dorsal horn. Opioid agonists
      exert a number of physiological responses including analgesia, which increases
      with increasing doses. The use of opioids to manage pain in patients with cancer
      is well accepted. The WHO step-wise algorithm for analgesic therapy based on pain
      severity reserves the use of opioid therapy for moderate and severe pain. The WHO
      algorithm has proven to be highly effective for the management of cancer pain.
      However, the use of opioids to treat patients with chronic non-cancer pain is
      controversial because of concerns about efficacy and safety, and the possibility
      of addiction or abuse. The results of clinical surveys and retrospective case
      series involving patients with non-cancer chronic pain have been inconsistent in
      regard to resolving these controversial issues. The oral route of drug
      administration is most appropriate for patients receiving opioids; although
      rectal, transdermal and parenteral routes of administration are used in specific
      situations. For continuous chronic pain, opioids should be administered around
      the-clock and several long-acting formulations are available that require
      administration only once or twice daily. Opioid doses should be titrated
      according to agent-specific schedules to maximise pain relief and maintain
      tolerability. Adverse effects include constipation, nausea and vomiting,
      sedation, cognitive impairment and respiratory depression. Tolerance to the
      analgesic and adverse effects as well as physical dependence, which causes
      withdrawal symptoms upon discontinuance, may occur with opioid use. Estimates of
      addiction rates among patients with chronic non-cancer pain range from 3.2 to
      18.9%. Successful pain treatment and symptom management is an attainable goal for
      the majority of patients with chronic pain. Further controlled clinical trials
      are needed to define the role of opioid therapy in chronic non-cancer pain, and
      to establish criteria for patient selection and specific treatment algorithms.

PMID- 12487619
TI  - Intestinal graft-versus-host disease: mechanisms and management.
AB  - Allogeneic haematopoietic stem cell transplantation remains the treatment of
      choice for a number of malignancies. However, graft-versus-host disease (GVHD)
      has long been regarded as a serious complication of this procedure. Although GVHD
      may affect any organ, intestinal GVHD is particularly important because of its
      frequency, severity and impact on the general condition of the patient. Recent
      studies have led to progressive elucidation of the mechanism of GVHD. Donor T
      cells are critical for the induction of GVHD, because depletion of T cells from
      bone marrow grafts effectively prevents GVHD but also results in an increase of
      leukaemia relapse. It has been shown that the gastrointestinal tract plays a
      major role in the amplification of systemic disease because gastrointestinal
      damage increases the translocation of endotoxins, which promotes further
      inflammation and additional gastrointestinal damage. Consequently, the management
      of intestinal GVHD (and the intestine itself) is a subject that should be
      highlighted. In this article, approaches to the prevention of intestinal GVHD are
      discussed after being classified into three categories: regimens in common
      clinical use, regimens under investigation and original regimens used at our
      hospital. The standard regimen that is used most widely for prevention of GVHD is
      cyclosporin plus short-term methotrexate. Corticosteroids can be added to this
      regimen but careful consideration of the adverse effects of these hormones should
      be considered. Tacrolimus is a newer, more potent alternative to cyclosporin. T
      cell depletion (TCD) after transplantation has been shown to prevent acute GVHD,
      however, the survival benefit of TCD has not been as great as expected.
      Mycophenolate mofetil can be useful for the treatment of acute GVHD as part of
      combination therapy. Regimens currently under investigation in animal experiments
      include suppression of inflammatory cytokines and inhibition of T-cell
      activation, and, specifically at our institution, hepatocyte growth factor gene
      therapy. The evidence-based therapy used at our institution includes systemic
      antibacterial therapy (including eradication of intestinal bacteria) to prevent
      the intestinal translocation of lipopolysaccharide and avoid the subsequent
      increase of various inflammatory cytokines. In addition, because of the
      similarities between intestinal GVHD and ulcerative colitis, sulfasalazine,
      betamethasone enemas and eicosapentaenoic acid have been used to treat intestinal
      GVHD in some patients.

PMID- 12487621
TI  - The second generation of COX-2 inhibitors: what advantages do the newest offer?
AB  - The discovery of two cyclooxygenase (COX)-isoenzymes, a constitutive COX-1,
      serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for
      proinflammatory prostanoid production, led to the development of new non
      steroidal anti-inflammatory drugs (NSAIDs), the selective COX-2 inhibitors,
      promising minimal NSAID-typical toxicity with full anti-inflammatory efficacy. So
      far, the strategy of selective COX-2 inhibition has been successful. Selective
      COX-2 inhibitors have significantly less gastrotoxicity and no effects on
      platelet aggregation. However, with regard to renal adverse events, selective COX
      2 inhibitors do not offer a clinically relevant advantage over non-selective
      inhibitors. Moreover, concerns over the cardiovascular risk of selective COX-2
      inhibitors have recently been raised. The second generation of COX-2 inhibitors
      with higher COX-2 selectivity was developed with the promise of further reduction
      of NSAID-typical adverse effects. The leading compounds are valdecoxib,
      parecoxib, etoricoxib and lumaricoxib. At the present time they have proven
      efficacy for the treatment of pain and inflammation. Parecoxib as a parenteral,
      highly selective COX-2 inhibitor has the potential to become the NSAID of choice
      for treatment of postoperative pain. In clinical trials, valdecoxib, parecoxib,
      etoricoxib and lumaricoxib have caused no more endoscopic ulcers than placebo.
      However, to date, no data on the clinically relevant endpoints perforation,
      symptomatic ulcer and bleeding are available. Furthermore, no definite
      conclusions on renal and cardiovascular safety are possible. Current evidence
      points to a marginal, if any, gain of safety compared with the first generation
      of COX-2 inhibitors. However, trials with the new COX-2 inhibitors offer the
      chance to address these open questions of highly selective COX-2 inhibition; that
      is, thrombogenic risk, sodium and water retention, and interference with tissue
      repair, in particular, healing of mucosal damage.

PMID- 12487622
TI  - Nesiritide: a review of its use in acute decompensated heart failure.
AB  - Nesiritide (Natrecor) is a recombinant form of human B-type (brain) natriuretic
      peptide that has beneficial vasodilatory, natriuretic, diuretic and neurohormonal
      effects. The drug is administered intravenously for the management of patients
      with decompensated congestive heart failure (CHF). In the Vasodilation in the
      Management of Acute Congestive Heart Failure (VMAC) study, patients hospitalised
      with acute decompensated CHF who received nesiritide had significantly greater
      mean reductions from baseline in pulmonary capillary wedge pressure 3 hours after
      starting treatment than nitroglycerin or placebo recipients (-5.8 vs -3.8 and -2
      mm Hg, respectively); all patients also received standard therapy (e.g.
      intravenous diuretics). Improvements in other haemodynamic parameters were also
      seen in nesiritide recipients. In addition, significantly more nesiritide than
      placebo recipients reported an improvement in dyspnoea after 3 hours' treatment
      in VMAC, whereas there was no significant difference between nitroglycerin and
      placebo recipients. Improvements in global clinical status, dyspnoea and fatigue
      were also seen with nesiritide in another active-comparator study and in a
      placebo-controlled study. In VMAC, there was no significant difference between
      nesiritide and nitroglycerin recipients in 6-month mortality. In the other active
      comparator trial, 6-month mortality was significantly lower in recipients of
      nesiritide 0.015 micro g/kg/min than in dobutamine recipients (although mortality
      was not a prespecified endpoint and this result should be interpreted with
      caution). In this same study, the 21-day all-cause hospital readmission rate was
      significantly lower with nesiritide 0.015 micro g/kg/min than with dobutamine and
      the duration of active drug treatment was significantly shorter with nesiritide
      than with dobutamine. Nesiritide is generally well tolerated. In VMAC,
      significantly more adverse events occurred with nitroglycerin than with
      nesiritide. The most common adverse events reported during the first 24 hours of
      therapy in nesiritide and nitroglycerin recipients included general pain,
      abdominal pain, catheter-related pain, headache, nausea, asymptomatic and
      symptomatic hypotension, nonsustained ventricular tachycardia and angina
      pectoris. Most episodes of symptomatic hypotension resolved spontaneously or
      after an intravenous volume challenge of </=250 ml. In addition, nesiritide does
      not appear to be proarrhythmic. CONCLUSION: Short-term intravenous infusion of
      nesiritide is associated with haemodynamic and symptomatic improvements in
      patients with acutely decompensated CHF. Nesiritide may offer tolerability and
      practical advantages over currently used vasodilators, inodilators and inotropes
      in this condition; in particular, nesiritide does not appear to have
      proarrhythmic effects. Nesiritide also appears to be effective and well tolerated
      in patients receiving concomitant beta-blocker therapy and in patients with renal
      insufficiency. Thus, nesiritide is a suitable first-line option for the treatment
      of patients with acutely decompensated CHF and is a welcome addition in an area
      where intravenous agents are few.

PMID- 12487623
TI  - Micronised purified flavonoid fraction: a review of its use in chronic venous
      insufficiency, venous ulcers and haemorrhoids.
AB  - Micronised purified flavonoid fraction (MPFF) [Daflon 500 mg], an oral
      phlebotropic drug consisting of 90% micronised diosmin and 10% flavonoids
      expressed as hesperidin, improves venous tone and lymphatic drainage, and reduces
      capillary hyperpermeability by protecting the microcirculation from inflammatory
      processes. The absorption of diosmin is improved by its micronisation to
      particles with a diameter <2 microm. Compared with placebo, MPFF 500 mg twice
      daily significantly decreased ankle or calf circumference, and improved many
      symptoms of chronic venous insufficiency (CVI) and plethysmographic parameters in
      two randomised, double-blind, 2-month studies. Improvement in symptoms was
      parallelled by an improvement in health-related quality of life in a nonblind, 6
      month trial. Significantly more venous leg ulcers </=10 cm in diameter completely
      healed with MPFF 500 mg twice daily plus standard management (compression and
      local treatment) for 2-6 months than with standard management alone or with
      placebo in a nonblind and a double-blind trial. The addition of MPFF to standard
      management was cost effective in a retrospective pharmacoeconomic analysis of the
      6-month trial. Compared with placebo, the duration and/or intensity of individual
      symptoms of grade 1 or 2 acute internal haemorrhoids improved significantly with
      3 tablets of MPFF 500 mg twice daily for 4 days then 2 tablets of MPFF 500 mg
      twice daily for 3 days. Two tablets of MPFF 500 mg daily for 60 or 83 days
      reduced the frequency, duration and/or severity of acute haemorrhoidal symptoms
      and improved the overall signs and symptoms of chronic (recurrent) haemorrhoids
      compared with placebo. Compared with a control group, MPFF significantly reduced
      the risk of secondary bleeding after elective haemorrhoidectomy. In clinical
      trials, MPFF had a tolerability profile similar to that of placebo; the most
      frequently reported adverse events were gastrointestinal and autonomic in nature.
      In conclusion, MPFF is a well established and well tolerated treatment option in
      patients with CVI, venous ulcers, or acute or chronic internal haemorrhoids. MPFF
      is indicated as a first-line treatment of oedema and the symptoms of CVI in
      patients in any stage of the disease. In more advanced disease stages, MPFF may
      be used in conjunction with sclerotherapy, surgery and/or compression therapy, or
      as an alternative treatment when surgery is not indicated or is unfeasible. The
      healing of venous ulcers </=10 cm in diameter is accelerated by the addition of
      MPFF to standard venous ulcer management. MPFF may reduce the frequency, duration
      and/or intensity of symptoms of grade 1 or 2 acute internal haemorrhoids, and
      also the severity of the signs and symptoms of chronic haemorrhoids.

PMID- 12487624
TI  - Pantoprazole: an update of its pharmacological properties and therapeutic use in
      the management of acid-related disorders.
AB  - Pantoprazole (Protonix) is an irreversible proton pump inhibitor (PPI) that
      reduces gastric acid secretion. In combination with two antimicrobial agents
      (most commonly metronidazole, clarithromycin or amoxicillin) for 6-14 days,
      pantoprazole 40 mg twice daily produced Helicobacter pylori eradication rates of
      71-93.8% (intent-to-treat [ITT] or modified ITT analysis) in patients without
      known antibacterial resistance. Pantoprazole-containing triple therapy was at
      least as effective as omeprazole- and similar in efficacy to lansoprazole
      containing triple therapy in large trials. In the treatment of moderate to severe
      gastro-oesophageal reflux disease (GORD), oral pantoprazole 40 mg/day was as
      effective as other PPIs (omeprazole, omeprazole multiple unit pellet system,
      lansoprazole and esomeprazole) and significantly more effective than histamine
      H(2)-antagonists. Pantoprazole 20 mg/day provided effective mucosal healing in
      patients with GORD and mild oesophagitis. Intravenous pantoprazole 40 mg/day can
      be used in patients who are unable to take oral medication. Oral pantoprazole 20
      40 mg/day for up to 24 months prevented relapse in most patients with healed
      GORD. According to preliminary data, oral pantoprazole 20 or 40 mg/day was
      effective at healing and preventing non-steroidal anti-inflammatory drug (NSAID)
      related ulcers, and intravenous pantoprazole was at least as effective as
      intravenous ranitidine in preventing ulcer rebleeding after endoscopic
      haemostasis. Oral or intravenous pantoprazole up to 240 mg/day maintained target
      acid output levels in most patients with hypersecretory conditions, including
      Zollinger-Ellison syndrome. Oral and intravenous pantoprazole appear to be well
      tolerated in patients with acid-related disorders in short- and long-term trials.
      Tolerability with oral pantoprazole was similar to that with other PPIs or
      histamine H(2)-antagonists in short-term trials. Formal drug interaction studies
      have not revealed any clinically significant interactions between pantoprazole
      and other agents. In conclusion, pantoprazole is an effective agent in the
      management of acid-related disorders. As a component of triple therapy for H.
      pylori eradication and as monotherapy for the healing of oesophagitis and
      maintenance of GORD, pantoprazole has shown similar efficacy to other PPIs and
      greater efficacy than histamine H(2)-antagonists. Limited data suggest that it is
      also effective in Zollinger-Ellison syndrome and in preventing ulcer rebleeding.
      Pantoprazole is well tolerated with minimal potential for drug interactions. The
      availability of pantoprazole as both oral and intravenous formulations provides
      flexibility when the oral route of administration is not appropriate. Thus,
      pantoprazole is a valuable alternative to other PPIs in the treatment of acid
      related disorders.

PMID- 12487625
TI  - Active-site-mutagenesis study of rat liver betaine-homocysteine S
      methyltransferase.
AB  - A site-directed-mutagenesis study of putative active-site residues in rat liver
      betaine-homocysteine S-methyltransferase has been carried out. Identification of
      these amino acids was based on data derived from a structural model of the
      enzyme. No alterations in the CD spectra or the gel-filtration chromatography
      elution pattern were observed with the mutants, thus suggesting no modification
      in the secondary structure content or in the association state of the proteins.
      All the mutants obtained showed a reduction of the enzyme activity, the most
      dramatic effect being that of Glu(159), followed by Tyr(77) and Asp(26). Changes
      in affinity for either of the substrates, homocysteine or betaine, were detected
      when substitutions were performed of Glu(21), Asp(26), Phe(74) and Cys(186).
      Interestingly, Asp(26), postulated to be involved in homocysteine binding, has a
      strong effect on affinity for betaine. The relevance of these results is
      discussed in the light of very recent structural data obtained for the human
      enzyme.

PMID- 12487626
TI  - Cross-talk between glucocorticoid and retinoic acid signals involving
      glucocorticoid receptor interaction with the homoeodomain protein Pbx1.
AB  - Glucocorticoid (GC) signalling influences the response of the cell to a number of
      other signals via a mechanism referred to as 'cross-talk'. This cross-talk may
      act at several levels, including an interaction between the transcription factors
      involved in the signalling pathways. In the present paper, we demonstrate a novel
      functional interaction between GC and all- trans -retinoic acid (RA) signalling.
      We show that, in P19 embryonal carcinoma cells, GCs potentiate RA-induced
      expression of the murine Hoxb -1 gene through an autoregulatory element, b1-ARE,
      recognized by the Pbx1 and HOXB1 homoeodomain proteins. The synergistic effect of
      GC did not involve GC receptor (GR) binding to the b1-ARE, and the GC-GR complex
      alone was unable to activate transcription via the element. Furthermore, the
      ability of the GR to transactivate was not required, excluding expression of a GC
      induced protein as the mechanism for the GC/RA synergy. Additional transfection
      experiments showed that the Pbx1/HOXB1 heterodimer was the target for the GC
      effect. Furthermore, functional dissection of the GR demonstrated that the DNA
      binding domain (DBD) of the GR was required for the synergy. A physical
      interaction between the GR and Pbx1 proteins was demonstrated in vivo by co
      immunoprecipitation experiments. These results are compatible with a model in
      which the GC/RA synergy is mediated by a direct interaction between the GR and
      Pbx1. On the basis of the ubiquitous expression of both GR and Pbx1, a number of
      genes regulated by Pbx are likely to be important targets for GC-mediated 'cross
      talk'.

PMID- 12487627
TI  - Characterization of Streptococcus pneumoniae enoyl-(acyl-carrier protein)
      reductase (FabK).
AB  - The enoyl-(acyl-carrier protein) (ACP) reductase catalyses the last step in each
      cycle of fatty acid elongation in the type II fatty acid synthase systems. An
      extensively characterized NADH-dependent reductase, FabI, is widely distributed
      in bacteria and plants, whereas the enoyl-ACP reductase, FabK, is a distinctly
      different member of this enzyme group discovered in Streptococcus pneumoniae. We
      were unable to delete the fabK gene from Strep. pneumoniae, suggesting that this
      is the only enoyl-ACP reductase in this organism. The FabK enzyme was purified
      and the biochemical properties of the reductase were examined. The visible
      absorption spectrum of the purified protein indicated the presence of a flavin
      cofactor that was identified as FMN by MS, and was present in a 1:1 molar ratio
      with protein. FabK specifically required NADH and the protein activity was
      stimulated by ammonium ions. FabK also exhibited NADH oxidase activity in the
      absence of substrate. Strep. pneumoniae belongs to the Bacillus / Lactobacillus /
      Streptococcus group that includes Staphylococcus aureus and Bacillus subtilis.
      These two organisms also contain FabK-related genes, suggesting that they may
      also express a FabK-like enoyl-ACP reductase. However, the genes did not
      complement a fabI (Ts) mutant and the purified flavoproteins were unable to
      reduce enoyl-ACP in vitro and did not exhibit NAD(P)H oxidase activity,
      indicating they were not enoyl-ACP reductases. The restricted occurrence of the
      FabK enoyl-ACP reductase may be related to the role of substrate-independent NADH
      oxidation in oxygen-dependent anaerobic energy metabolism.

PMID- 12487628
TI  - Characterization of the Aspergillus nidulans transporters for the siderophores
      enterobactin and triacetylfusarinine C.
AB  - The filamentous ascomycete Aspergillus nidulans produces three major
      siderophores: fusigen, triacetylfusarinine C, and ferricrocin. Biosynthesis and
      uptake of iron from these siderophores, as well as from various heterologous
      siderophores, is repressed by iron and this regulation is mediated in part by the
      transcriptional repressor SREA. Recently we have characterized a putative
      siderophore-transporter-encoding gene ( mirA ). Here we present the
      characterization of two further SREA- and iron-regulated paralogues (mirB and
      mirC ), including the chromosomal localization and the complete exon/intron
      structure. Expression of mirA and mirB in a Saccharomyces cerevisiae strain,
      which lacks high affinity iron transport systems, showed that MIRA transports
      specifically the heterologous siderophore enterobactin and that MIRB transports
      exclusively the native siderophore triacetylfusarinine C. Construction and
      analysis of an A. nidulans mirA deletion mutant confirmed the substrate
      specificity of MIRA. Phylogenetic analysis of the available sequences suggests
      that the split of the species A. nidulans and S. cerevisiae predates the
      divergence of the paralogous Aspergillus siderophore transporters.

PMID- 12487629
TI  - The metabolism of S-nitrosothiols in the trypanosomatids: the role of ovothiol A
      and trypanothione.
AB  - It has recently been established that nitrosoglutathione is the preferred
      substrate of the glutathione-dependent formaldehyde dehydrogenase from divergent
      organisms. Trypanosomatids produce not only glutathione, but also
      glutathionylspermidine, trypanothione and ovothiol A. The formaldehyde
      dehydrogenase activity of Crithidia fasciculata was independent of these thiols
      and extracts possessed very low levels of nitrosothiol reductase activity with
      glutathione or its spermidine conjugates as the thiol component. Although
      ovothiol A did not form a stable nitrosothiol, it decomposed the S -nitroso
      groups of nitrosoglutathione (GSNO) and dinitrotrypanothione [T(SNO)(2)] with
      second-order rate constants of 19.12 M(-1) x s(-1) and 8.67 M(-1) x s(-1)
      respectively. The reaction of T(SNO)(2) with ovothiol A, however, accelerated to
      a rate similar to that seen with GSNO. Ovothiol A can act catalytically to
      decompose these nitrosothiols, although non-productive mechanisms exist. The
      catalytic phase of the reaction was dependent on the production of thiyl
      radicals, since it was abolished in the presence of 5,5-dimethyl-1-pyrroline- N 
      oxide and the formation of nitric oxide could be detected by means of the
      conversion of oxyhaemoglobin into methaemoglobin. The rate-limiting step in the
      catalytic process was the reduction of oxidized ovothiol species and, in this
      respect, T(SNO)(2) is a more efficient substrate than GSNO. Trypanothione
      decomposed GSNO with a second-order rate constant of 0.786 M(-1) x s(-1) and the
      major nitrogenous end product changed from nitrite to ammonia as the ratio of
      thiol to nitrosothiol increased. The results indicate that ovothiol A acts in
      synergy with trypanothione in the decomposition of T(SNO)(2).

PMID- 12487630
TI  - Identification, functional expression and enzymic analysis of two distinct CaaX
      proteases from Caenorhabditis elegans.
AB  - Post-translational processing of proteins such as the Ras GTPases, which contain
      a C-terminal CaaX motif (where C stands for cysteine, a for aliphatic and X is
      one of several amino acids), includes prenylation, proteolytic removal of the C
      terminal tripeptide and carboxy-methylation of the isoprenyl-cysteine residue. In
      the present study, we report the presence of two distinct CaaX-proteolytic
      activities in membrane extracts from Caenorhabditis elegans, which are sensitive
      to EDTA and Tos-Phe-CH(2)Cl (tosylphenylalanylchloromethane; 'TPCK')
      respectively. A protein similar to the mammalian and yeast farnesylated-proteins
      converting enzyme-1 (FACE-1)/Ste24p CaaX metalloprotease, encoded by a
      hypothetical gene (CeFACE-1/C04F12.10) found in C. elegans chromosome I, probably
      accounts for the EDTA-sensitive activity. An orthologue of FACE-2/Rce1p, the
      enzyme responsible for the proteolytic maturation of Ras oncoproteins and other
      prenylated substrates, probably accounts for the Tos-Phe-CH(2)Cl-sensitive
      activity, even though the gene for FACE-2/Rce1 has not been previously identified
      in this model organism. We have identified a previously overlooked gene in C.
      elegans chromosome V, which codes for a 266-amino-acid protein (CeFACE-2) with
      30% sequence identity to human FACE-2/Rce1. We show that both CeFACE-1 and CeFACE
      2 have the ability to promote production of the farnesylated yeast pheromone a 
      factor in vivo and to cleave a farnesylated peptide in vitro. These results
      indicate that CeFACE-1 and CeFACE-2 are bona fide CaaX proteases and support the
      evolutionary conservation of this proteolytic system in eukaryotes.

PMID- 12487632
TI  - The relationship between left ventricular shape and QT interval dispersion.
AB  - Left ventricular geometry is suspected to affect heterogeneity of myocardial
      repolarization; therefore, it is plausible but unproven that increased sphericity
      of the left ventricle is associated with greater QT interval dispersion. In 60
      patients with dilated cardiomyopathy with left ventricular ejection fraction < or
      = 30%, we found that spherical distortion of the left ventricle was associated
      with increased QT dispersion, implying increased heterogeneity of myocardial
      repolarization.

PMID- 12487631
TI  - Species-specific protein sequence and fold optimizations.
AB  - BACKGROUND: An organism's ability to adapt to its particular environmental niche
      is of fundamental importance to its survival and proliferation. In the largest
      study of its kind, we sought to identify and exploit the amino-acid signatures
      that make species-specific protein adaptation possible across 100 complete
      genomes. RESULTS: Environmental niche was determined to be a significant factor
      in variability from correspondence analysis using the amino acid composition of
      over 360,000 predicted open reading frames (ORFs) from 17 archaea, 76 bacteria
      and 7 eukaryote complete genomes. Additionally, we found clusters of
      phylogenetically unrelated archaea and bacteria that share similar environments
      by amino acid composition clustering. Composition analyses of conservative,
      domain-based homology modeling suggested an enrichment of small hydrophobic
      residues Ala, Gly, Val and charged residues Asp, Glu, His and Arg across all
      genomes. However, larger aromatic residues Phe, Trp and Tyr are reduced in folds,
      and these results were not affected by low complexity biases. We derived two
      simple log-odds scoring functions from ORFs (CG) and folds (CF) for each of the
      complete genomes. CF achieved an average cross-validation success rate of 85 +/-
      8% whereas the CG detected 73 +/- 9% species-specific sequences when competing
      against all other non-redundant CG. Continuously updated results are available at
      http://genome.mshri.on.ca. CONCLUSION: Our analysis of amino acid compositions
      from the complete genomes provides stronger evidence for species-specific and
      environmental residue preferences in genomic sequences as well as in folds.
      Scoring functions derived from this work will be useful in future protein
      engineering experiments and possibly in identifying horizontal transfer events.

PMID- 12487633
TI  - Validation of six noninvasive Doppler methods for the assessment of left
      ventricular filling pressure.
AB  - OBJECTIVES: The aim of this study was to determine the accuracy of six
      noninvasive Doppler methods for assessing invasively derived left ventricular
      diastolic pressure (LVDP). BACKGROUND: To date, no studies have evaluated which
      of the various available Doppler methods are most reliable in determining LVDP in
      a consecutive patient population with different cardiac diseases. METHODS: LVDP
      was estimated by the following Doppler methods (M): (1) M1-the peak mitral
      regurgitant flow velocity (peak MR), (2) M2-the mitral regurgitant velocity at
      the time of aortic valve opening (MRAVO), (3) M3-the aortic regurgitant end
      diastolic flow velocity (ARED), (4) M4-the ratio of the transmitral to mitral
      annular early diastolic velocity (ETM/EDTI), (5) M5-a transmitral flow velocity
      regression equation (RegrTM), and (6) M6-the difference of pulmonary venous and
      transmitral A wave duration (APV - ATM duration). For M1-M3, sphygmomanometric
      blood pressure was used to calculate LVDP. RESULTS: In 101 patients, the
      regression coefficient, standard error of estimate, and mean difference with
      confidence limits between Doppler and catheter-derived measurements were as
      follows: M1 (n = 46): r = 0.81 (P < 0.0001), 4.3 mmHg and 3.7 +/- 12.0 mmHg; M2
      (n = 47): r = 0.79 (P < 0.0001), 5.4 mmHg and 1.1 +/- 11.2 mmHg; M3 (n = 20): r =
      0.64 (P = 0.002), 7.8 mmHg and 4.6 +/- 17.6 mmHg; M4 (n = 50): r = 0.62 (P <
      0.0001), 5.6 mmHg and 0 +/- 11.2 mmHg; M5 (n = 79): r = 0.24 (P = 0.03), 7.1 mmHg
      and - 0.1 +/- 16.8 mmHg; and M6 (n = 79): r = 0.22 (P = 0.05), 7.3 mmHg and 0 +/-
      14.4 mmHg, respectively. CONCLUSIONS: The Doppler measurement of mitral
      regurgitant jets is most accurate method to estimate left ventricular filling
      pressure noninvasively.

PMID- 12487634
TI  - How can coronary flow reserve be altered by severe aortic stenosis?
AB  - The coronary flow reserve, a well-known characteristic of the distensibility of
      the coronary arteries, can be measured by means of dipyridamole stress
      transesophageal echocardiography. This study compared the coronary flow reserve
      in patients with normal coronary arteries with aortic stenosis (Group 1), in
      patients with normal coronary arteries without aortic stenosis (Group 2), and in
      patients with significant left anterior descending coronary artery disease (Group
      3). PATIENTS AND METHODS: Groups 1 and 2 were comprised of 21 patients each,
      while Group 3 was comprised of 37 patients. Transesophageal stress
      echocardiography was carried out according to a standard protocol, with a
      vasodilator stimulus of dipyridamole in a dose of 0.56 mg/kg over 4 minutes. The
      coronary flow reserve was calculated as the ratio of posthyperemic to basal peak
      (CFR) and mean (mean CFR) diastolic flow velocities. RESULTS: The left
      ventricular mass and left ventricular mass index were significantly higher in
      Group 1 than in Groups 2 and 3. The coronary flow reserve and the posthyperemic
      mean diastolic flow velocities were significantly lower, while the resting mean
      diastolic flow velocities were significantly higher in Groups 1 and 3 than in
      Group 2. CONCLUSIONS: In patients with aortic stenosis and a normal coronary
      angiogram, the coronary flow reserve is significantly lower, similarly as in the
      case of significant left anterior descending coronary artery disease. In severe
      aortic stenosis with left ventricular hypertrophy, stress transesophageal
      echocardiography is unable to distinguish between the drop in coronary flow
      reserve caused by a vascular or a myocardial component, and therefore, not
      suitable for the selection of patients with significant coronary artery disease,
      even in cases of left anterior descending coronary artery disease.

PMID- 12487635
TI  - Relation of vasodilator response of the brachial artery to inflammatory markers
      in patients with coronary artery disease.
AB  - Endothelial dysfunction of the coronary artery is closely related to elevated
      levels of systemic inflammatory markers and cardiovascular events in patients
      with coronary artery disease (CAD). We hypothesized that patients with CAD may
      have a higher risk of endothelial dysfunction of the peripheral artery than
      patients without evidence of CAD, and that endothelial dysfunction of the
      peripheral artery also may be related to elevated levels of inflammatory markers.
      Using high resolution ultrasound, we assessed the brachial vasodilator response
      to reactive hyperemia (endothelium-dependent) and sublingual nitroglycerin
      (endothelium-independent). As inflammatory markers, serum C-reactive protein
      (CRP), erythrocyte sedimentation rate (ESR) levels, and lipid profiles were
      measured in patients with CAD (n = 30, 16 male and 14 female) and normal subjects
      without evidence of CAD (n = 45, 23 male and 22 female). Patients with CAD (Group
      II) showed a significantly reduced endothelium-dependent vasodilation as compared
      with normal subjects (Group I) (4.4 +/- 3.6 vs 7.4 +/- 6.1%, P < 0.05). However,
      endothelium-independent vasodilation was not significantly different between the
      two groups (7.7 +/- 7.1 vs 9.7 +/- 8.0%, P > 0.05). In Group II, CRP level was
      inversely related to endothelium-dependent vasodilation (r = -0.398, P = 0.029).
      In contrast, ESR level was not significantly associated to endothelium-dependent
      vasodilation (r = -0.113, P = 0.552). On multivariate analysis, CRP and low
      density lipoprotein cholesterol levels were significant independent predictors of
      a blunted endothelium-dependent vasodilation in Group II. Our study showed that
      elevated CRP level was associated with blunted endothelium-dependent vasodilation
      of the brachial artery in patients with CAD. Thus, identification of elevated CRP
      levels combined with demonstration of endothelial dysfunction of the brachial
      artery may have a possible clinical application for the detection of high risk
      CAD patients.

PMID- 12487636
TI  - Strain rate imaging: an in vitro "validation" study using a physiologic balloon
      model mimicking the left ventricle.
AB  - BACKGROUND: Strain rate imaging (SRI) can be implemented from digital ultrasound
      loops of tissue Doppler imaging (TDI) data and is performed as an autocorrelation
      solution of the distance between intramyocardial targets. As such, it should have
      better resolution along longer distances of wall segments that are imaged at the
      length of individual ultrasound scan lines. METHODS: We used a new left
      ventricular double-balloon phantom with a tissue-mimicking gel between the walls.
      Mounted in a water bath and connected to a pulsatile flow pump at four-stroke
      volume (30-50 ml/beat), the high frame rate, digital, multiple two
      dimensional/tissue/TDI loops of balloon wall motion were recorded using a GE
      VingMed system FiVe (3.5 MHz phased array transducer), with the model scanned
      longitudinally from the apex. The strain rate (SR) values were measured at the
      apex and the lateral wall using an offline measurement program, and mean SR
      values for every 100 msec were calculated by averaging three determinations at
      each point. The excursions of the apex and lateral wall also were measured
      directly by high speed digital video imaging, and consecutive velocity profiles
      were calculated every 100 msec. A total of 40 data points for four-stroke volumes
      were analyzed. RESULTS: While our balloon model had enough gel targets between
      the walls to produce a good mimic of myocardial speckle with walls that thickened
      and thinned, samples immediately across the apex and apex SR values (Hz) varied
      substantially. In contrast, systematic signals could be obtained from lines
      imaged >15 degrees from the true apex and crossing a longer length of myocardium.
      At the lateral wall, there was a close correlation between the video velocities
      and SR values, as well as a close overlap of the phasic patterns. CONCLUSIONS:
      SRI produces more reliable data from wall segments parallel to scan lines.

PMID- 12487637
TI  - Hypovolemia-induced reversible severe mitral regurgitation due to left
      ventricular outflow tract obstruction.
AB  - We describe a hypertensive patient who developed profound cardiogenic shock after
      treatment with nitrates and diuretics. Echocardiography revealed a marked left
      ventricular outflow tract obstruction with severe mitral regurgitation that were
      reversible after aggressive fluid therapy.

PMID- 12487638
TI  - Paroxysmal ventricular tachycardia due to interventricular hydatid cyst.
AB  - A 35-year-old male patient with palpitations and mild lightheadedness was
      admitted to our clinic. Short-lasting paroxysmal ventricular tachycardia was
      diagnosed following 12-lead electrocardiography (ECG). A mass that included two
      thirds of the interventricular septum and the left ventricular cavity was seen by
      two-dimensional echocardiography and magnetic resonance imaging (MRI). Specific
      hemagglutination tests for hydatid cyst were positive. The mass was excised, and
      the patient had a septoplasty operation to repair the remaining septal defect. He
      is currently being followed and reports no complaints. No evidence of arrhythmia
      was noted in 24-hour ambulatory ECG monitoring.

PMID- 12487639
TI  - Anomalous right coronary artery from the main pulmonary artery in a patient with
      double-chambered right ventricle.
AB  - We describe a rare case of double-chambered right ventricle (DCRV) in a 32-year
      old female presenting to the echocardiography lab for evaluation of congenital
      heart disease. We identified a unique constellation of findings, including the
      DCRV, a perimembranous ventricular septal defect, aortic valve prolapse, patent
      foramen ovale, and an anomalous right coronary artery coming off the main
      pulmonary artery. To the best of our knowledge, this is the first reported case
      describing the association of an anomalous right coronary artery coming off the
      main pulmonary artery in a patient with DCRV.

PMID- 12487640
TI  - Giant left atrium, giant thrombus, and left atrial prolapse in a patient with
      mitral valve replacement.

PMID- 12487641
TI  - A case of coronary artery ectasia with thrombus detected by transthoracic two
      dimensional echocardiography.

PMID- 12487642
TI  - Transesophageal echocardiographic detection of left vertebral artery origin
      stenosis.
AB  - We discuss the case of a patient with stroke in whom severe stenosis at the
      origin of the left vertebral artery was identified by transesophageal
      echocardiography and subsequently confirmed with conventional angiography.

PMID- 12487643
TI  - Update on intraoperative echocardiography, part II.

PMID- 12487644
TI  - Intraoperative transesophageal echocardiography in valve replacement surgery.
AB  - Transesophageal echocardiography (TEE) is applied widely during heart valve
      replacement surgery. Intraoperative TEE (IOTEE) is used to formulate the surgical
      plan, assess cardiac function, and evaluate surgical outcome. This review
      describes the methodology of IOTEE, focusing on its role in valve replacement
      surgery. Specific aspects, such as its role in surgical decision making,
      selection of the prosthetic model and size, detection and quantification of
      paravalvular leaks, outflow tract obstruction, and acute prosthetic valve
      obstruction, are discussed. Furthermore, a description of the value of IOTEE in
      newer procedures, such as port access surgery, is presented.

PMID- 12487645
TI  - Intraoperative transesophageal echocardiography in congenital heart disease.
AB  - Intraoperative transesophageal echocardiography has become an integral component
      of the repair of congenital heart defects. It currently has a direct impact on
      reducing morbidity and mortality in the pediatric cardiac population. To
      establish a successful program, it is important to follow guidelines for training
      as well as having a systematic approach to the evaluation of this patient
      population. This article addresses the specific indications in a patient
      population as practiced at the Hospital For Sick Children, Toronto. While there
      may be subtle differences between programs, the objectives are to provide
      excellent service to the pediatric cardiac patient in the operating room.

PMID- 12487646
TI  - New technology and methodologies for intraoperative, perioperative, and
      intraprocedural monitoring of surgical and catheter interventions for congenital
      heart disease.
AB  - We review the new technology and methods available for support of intraoperative
      and intraprocedural imaging in the catheterization laboratory for surgical and
      interventional catheterization procedures in the treatment of congenital heart
      disease. The methods reviewed include miniaturized probes and new ways of using
      them perioperatively for cardiac imaging from transesophageal, substernal, and
      intracardiac imaging locations. The smaller and more versatile the probes, the
      better adapted they will be in providing methods to improve the outcomes in
      babies born with serious forms of congenital heart disease.

PMID- 12487647
TI  - Intraoperative epicardial coronary artery imaging: rationale, methods, and
      applications.
AB  - Epicardial coronary imaging using high frequency (7-12 MHz) ultrasound probes
      could aid the surgeon performing coronary artery bypass procedures by localizing
      the coronary artery segments underneath epicardial fat, identifying the site of
      coronary stenosis to be bypassed, evaluating the integrity of distal coronary
      artery, assessing the efficacy of anastomosis, and detecting anastomotic
      complications. While an ideal coronary imaging probe is yet to be developed,
      early clinical experience with vascular imaging probes applied on the coronary
      vessels suggests that epicardial coronary artery imaging could enhance the
      optimum performance of coronary interventions. Fabrication of a flexible high
      frequency probe that could be applied not only on the arteries on the anterior
      surface of the heart but also on the lateral and posterior surfaces could
      facilitate development of newer surgical procedures as well.

PMID- 12487663
TI  - The ultrastructure of cholesterol granuloma of the middle ear: an electron
      microscope study. The Journal of Laryngology and Otology, 1979; Vol. 93, pp. 433
      442.

PMID- 12487664
TI  - McBride and the midfacial granuloma syndrome. The Journal of Laryngology and
      Otology, 1982; Vol. 96, pp. 1-23.

PMID- 12487665
TI  - Five-year results of curettage-cryosurgery for 100 consecutive auricular non
      melanoma skin cancers.
AB  - Large excisions or Mohs' micrographic surgery (MMS) are often the suggested
      treatments for non-melanoma skin cancers (NMSCs) of the external ear. This five
      year follow-up attempts to evaluate whether curettage-cryosurgery could be an
      alternative therapy for selected auricular NMSCs. One hundred auricular NMSCs,
      selected at a skin tumour clinic, were treated by a thorough curettage, with
      different-sized curettes, followed by cryosurgery in a double freeze-thaw cycle.
      Seventy-seven basal cell carcinomas (BCCs), 13 squamous cell carcinomas (SCCs),
      six SCCs in situ, and four basosquamous carcinomas were included. The mean
      diameter of the tumours was 18 mm (range 5-70). Morphoeiform BCCs, recurrent BCCs
      with fibrotic component, and most of the SCCs were selected for MMS. Seventy-one
      patients with 81 tumours were followed-up for at least five years with only one
      recurrence. Nineteen patients with 19 tumours, followed-up for two to four years,
      died from other causes with no sign of recurrence at their last visit. Patients
      followed-up for less than two years were excluded. No major problems were
      registered after treatment. The cosmetic result was good or acceptable in most
      patients. In carefully selected patients a thorough curettage followed by
      freezing with liquid nitrogen in a double freeze-thaw cycle could be a safe and
      inexpensive therapy even for large NMSCs of the external ear.

PMID- 12487666
TI  - Paediatric day-stay myringoplasty: a review of 74 consecutive cases.
AB  - Day-case surgery is particularly attractive for children, allowing post-operative
      recovery in the safe environment of the family home. Myringoplasty using the
      traditional method of underlay temporalis fasia is usually performed as an in
      patient. From 1995 to 2000, 74 myringoplasties were performed in a dedicated
      paediatric day surgery unit at the Mayday University Hospital. We have
      retrospectively reviewed the outcome results of these procedures and reported
      them here. Only three patients required admission overnight (four per cent) and
      six grafts failed (8.5 per cent) complying with accepted standards. This series
      suggests that day-case surgery is a safe and desirable practice for children
      undergoing myringoplasty. However, there should be the facility for admission if
      required.

PMID- 12487667
TI  - Paediatric epistaxis: Alder Hey experience.
AB  - Referrals for epistaxis management constitute a significant proportion of
      paediatric ENT consultations. A prospective audit of all new referrals to our
      paediatric ENT department for epistaxis management yielded 88 patients over four
      months. Parents completed a questionnaire with particular reference to the
      duration of history and frequency of epistaxis. After assessment some patients
      were given topical chlorhexidine and neomycin cream (Naseptin), in addition some
      children also underwent chemical cautery (silver nitrate). Of the 64 children in
      whom out-patient nasal cautery was attempted it was tolerated by 63 (98 per
      cent). In response to a follow-up postal questionnaire returned by 65 per cent,
      most parents (74 per cent) felt that Naseptin was useful. A telephone survey of
      the patients' general practitioners found that 91 per cent of the children did
      not consult their general practitioner regarding epistaxis again. We conclude
      that paediatric epistaxis can be effectively managed with a single out-patient
      consultation.

PMID- 12487668
TI  - Current aetiology of unilateral vocal fold paralysis in a teaching hospital in
      the West of Scotland.
AB  - Between May 1997 and May 2001 all patients presenting with a unilateral vocal
      fold palsy at Gartnavel General hospital were entered into a prospective
      observational study. The sex, age, side of palsy and aetiology were documented.
      The aim of the study was to assess the current aetiology of vocal fold palsy in a
      large teaching hospital in the West of Scotland, and to compare this with the
      established aetiology in other parts of the world. Seventy-seven patients were
      studied. Eighty-three per cent were found to have a left and 17 per cent a right
      vocal fold palsy. The male to female ratio was 2:1, with an age range of 23-85,
      mean 61. Forty-three per cent of all vocal fold palsies were secondary to an
      underlying bronchogenic carcinoma and a further nine per cent due to other
      malignancies. This contrasted with figures quoted in other studies, that gave
      lung cancer causes of vocal fold palsies ranging from four to 22 per cent.
      Surgical trauma accounted for 24 per cent and in 11 per cent no cause was found.
      In conclusion, in our hospital population there is a high rate of vocal fold
      palsy secondary to bronchogenic carcinoma. This is likely to be associated with
      the high levels of smoking found in Scotland. Lung cancer rates in Scotland are
      1.6 times greater for men, and two times greater for women than the world
      standard. Malignancies overall cause over 50 per cent of our vocal fold palsies.
      Vigilance is required in any patient presenting with a vocal fold palsy to ensure
      a malignancy is not overlooked.

PMID- 12487669
TI  - Histological features in routine tonsillectomy specimens: the presence and the
      proportion of mesenchymal tissues and seromucinous glands.
AB  - Tonsillectomy is a frequently performed operation but there is little information
      about the histological features of a tonsillectomy specimen. In this study, we re
      evaluated archival materials of 1220 cases who underwent tonsillectomy because of
      hyperplastic tonsils. Haematoxylin and eosin sections of the cases were re
      examined and the presence and the proportion of mesenchymal tissues (skeletal
      muscle, cartilage, fat, bone) and seromucinous glands were noted as focal,
      multifocal or abundant. The incidence of skeletal muscle was 89 per cent (1085
      cases; 206 focal, 465 multifocal, 414 abundant), seromucinous glands 35 per cent
      (429 cases; 236 focal, 134 multifocal, 59 abundant), fat 21 per cent (251 cases;
      208 focal, 43 multifocal), cartilage three per cent (31 cases), and bone one per
      cent (seven cases). Also in 165 cases (14 per cent) skeletal muscle, in 12 cases
      (one per cent) was seromucinous glands, in eight cases (one per cent) was
      cartilage, in seven cases (one per cent) fat, and in four cases (less than one
      per cent) bone were found between hyperplastic lymphoid tissue. It can be
      concluded that mesenchymal tissues (skeletal muscle, cartilage, fat, bone) and
      seromucinous glands may be seen in different proportions in routine tonsillectomy
      specimens.

PMID- 12487670
TI  - Dangerous Doughty--a quantitative study of disproportion between the size of
      endotracheal tubes and splits in tonsillectomy gag blades.
AB  - The Doughty split tongue blade is used routinely with the Boyle Davis mouth gag
      during tonsillectomy. If the width of the slot in the blade is excessive, then
      the endotracheal tube may herniate through the slot in the blade and become fixed
      and inseparable from the blade. We report two cases of paediatric tonsillectomy
      where this potentially serious complication occurred. The slot widths of
      disposable and reusable Doughty blades were measured and specifications were
      obtained from several manufacturers. All disposable paediatric Doughty blades and
      some of the reusable blades were found to have excessively and potentially
      dangerously wide slots. Compression testing of endotracheal tubes by the
      manufacturer demonstrated marked increases in deformability on warming to body
      temperature. Ensuring that the slot width of the Doughty blade is not excessive
      for the endotracheal tube used is essential and we give recommendations.

PMID- 12487671
TI  - Effectiveness of treatment of tonsillopharyngitis: comparative study.
AB  - This study was performed to find out the effectiveness of three different
      treatments of patients having acute tonsillopharyngitis. Three groups of patients
      were selected (50 patients in each group). Group I received one antibiotic
      according to the result of culture and sensitivity test, while groups II and III
      received two antibiotics or one antibiotic respectively without a culture and
      sensitivity test. Diagnosis was based on the acutely subjective symptoms of sore
      throat and positive clinical examination findings. The effectiveness of treatment
      in group I (96 per cent) was statistically significant (p<0.05) and higher than
      group II (82 per cent) and group III (74 per cent), while the difference between
      group II and III was not statistically significant (p>0.05). Our findings
      demonstrate that a culture and sensitivity test of the throat swab is necessary
      before treating acute tonsillopharyngitis. It was suggested that there should be
      appropriate selection of antibiotics to preserve normal flora, avoidance
      antibiotics for viral infections, patient compliance with prescription and
      educational programmes directed at patients and physicians. All of these measures
      would assist in reducing the volume of antibiotic use, bacterial resistance and
      the overall cost of treatment of tonsillopharyngitis.

PMID- 12487672
TI  - Post-operative radiation therapy for advanced-stage oropharyngeal cancer.
AB  - Between 1985 and 1999, 43 patients with locally-advanced, resectable
      oropharyngeal cancer were treated with combined surgery and post-operative
      radiation therapy (RT) at Oregon Health and Science University. Five patients (12
      per cent) had Stage III disease and 38 patients (88 per cent) had Stage IV
      disease. All patients had gross total resections of the primary tumour. Thirty
      seven patients had neck dissections for regional disease. RT consisted of a mean
      tumour-bed dose of 63.0 Gy delivered in 1.8-2.0 Gy fractions over a mean of 49
      days. At three- and five-years, the actuarial local control was 96 per cent and
      the actuarial local/regional control was 80 per cent. The three- and five-year
      actuarial rates of distant metastases were 41 per cent and 46 per cent,
      respectively. The actuarial overall survival at three- and five-years was 41 per
      cent and 34 per cent, respectively. The actuarial rates of progression-free
      survival were 49 per cent at three-years and 45 per cent at five years. Combined
      surgery and post-operative RT for advanced-stage oropharyngeal cancer results in
      excellent local/regional control. This particular group of patients experienced a
      high-rate of developing distant metastases.

PMID- 12487673
TI  - Cervical node metastases in oropharyngeal squamous cell carcinoma: prospective
      analysis of prevalence and distribution.
AB  - The treatment of cervical lymph node metastases is an important part of the
      management of oropharyngeal squamous cell cancer. Metastases are already
      clinically present in 61 per cent (+ or -2.6 per cent) of patients at
      presentation. Previous studies concerning the prevalence and distribution of neck
      node metastases in oropharyngeal carcinoma have been retrospective, and little or
      no information is available about the histopathological methods used. This study
      has prospectively analysed 85 neck dissection specimens in 72 consecutive
      patients with squamous cell carcinoma of the oropharynx, both with clinically
      N(0) and N+ve necks, to identify the prevalence and distribution of cervical
      metastases. We have used a technique to separate the neck dissection into nodal
      levels per-operatively, and then embedded the entire specimen for histological
      examination to avoid missing metastatic disease in small lymph nodes (<3mm
      diameter).

PMID- 12487674
TI  - Microvascular free tissue reconstruction following extirpation of head and neck
      tumour: experience towards an optimal outcome.
AB  - Familiarity with four types of free tissues transfers allows appropriate
      reconstruction of most defects in the head and neck region functionally and
      aesthetically. These include jejunal graft, radial forearm, rectus abdominus
      myocutaneous and fibula osteocutaneous flaps. Free colonic and gastric patches
      were used occasionally. We report our experience of 215 free tissue transfers for
      reconstruction of defects in the head and neck region after tumour extirpation.
      The overall success rate was 94 per cent. The commonest cause of failure was
      related to arterial inflow (70 per cent). Three patients died in hospital, but
      their mortality was not related to the tissue transfers. Complications due to
      free tissue transfer at both the donor and recipient sites were few and
      manageable. The co-operation between the two surgical teams, together with the
      timely application of suitable salvage procedures, contribute to an optimal
      outcome.

PMID- 12487675
TI  - Conductive hearing loss: investigation of possible inner ear origin in three
      cases studies.
AB  - This is a report of three cases of mixed hearing loss that resulted from inner
      ear disorders. Two cases were unilateral and the third was bilateral. The
      diagnosis was based on the findings of normal middle and external ears in
      association with the absence of round window reflexes. The contralateral
      stapedial reflex was present in the two unilateral cases. This is the first
      documentation of conductive deafness due to inner ear abnormality. This diagnosis
      should be considered in cases of conductive hearing loss if the middle and
      external ears are normal. More studies are needed to establish the
      pathophysiology of this entity.

PMID- 12487676
TI  - Scala vestibuli cochlear implantation in patients with partially ossified
      cochleas.
AB  - Partial cochlear obstruction is a relatively common finding in candidates for
      cochlear implants and frequently involves the inferior segment of the scala
      tympani in the basal turn of the cochlea. In such patients, the scala vestibuli
      is often patent and offers an alternative site for implantation. The current
      report describes two patients with such partial obstruction of the inferior
      segment of the basal cochlear turn, caused in one case by systemic vasculitis
      (Takayasu's disease) and in the other by obliterative otosclerosis. A scala
      vestibuli implantation allowed for complete insertion of the electrode array. No
      problems were encountered during the surgical procedures and the good post
      operative hearing and communicative outcomes achieved were similar to those
      reported in patients without cochlear ossification. The importance of accurate
      pre-operative radiological study of the inner ear is underscored, to disclose the
      presence and define the features of the cochlear ossification and ultimately to
      properly plan the surgical approach.

PMID- 12487677
TI  - Endoscopic sinus surgery for sinonasal haemangiopericytomas.
AB  - Haemangiopericytomas are rare peri-vascular tumours with variable malignant
      potential. The nasal cavity and the paranasal sinuses are most often involved in
      the head and neck. Five cases of haemangiopericytomas treated by a strict
      endonasal endoscopic approach are presented. Bleeding and nasal obstruction are
      the most frequent symptoms. Computed tomography (CT) scan and magnetic resonance
      imaging (MRI) allowed pre-operative assessment. Angiography with embolization was
      needed in two of the five cases. None of our patients presented with malignant
      histology. Our five cases were operated on, and a total tumour excision was
      performed through the endoscopic endonasal approach. We had one recurrence with a
      mean follow-up of 4.5 years. We suggest that when the tumour is purely intranasal
      or strictly located in the ethmoid or sphenoid sinus, it can be removed via an
      endonasal approach under endoscopic guidance in experienced hands.

PMID- 12487678
TI  - Osteochondroma of the posterior nasal septum managed by endoscopic transnasal
      transseptal approach.
AB  - A case of osteochondroma of the posterior nasal septum is presented. A 57-year
      old female patient presented with a history of bilateral nasal obstruction for 20
      years. To the best of our knowledge, this is the second reported case of an
      osteochondroma of the nasal septum. It was treated by endoscopic transnasal
      transseptal surgery.

PMID- 12487679
TI  - Intractable paroxysmal sneezing.
AB  - Intractable paroxysmal sneezing is a rare disease primarily affecting teenage
      girls. We present the case of a 12-year-old girl who demonstrated the classical
      features of intractable paroxysmal sneezing of psychogenic origin. Most of the
      reported cases are psychogenic in origin, but a number of other conditions may
      cause intractable paraoxysmal sneeze. Apart from a detailed history, clinical
      examination and relevant investigations, topical nasal anaesthesia should be
      tried for control of symptoms--that will help to differentiate psychogenic
      sneezing from organic sneezing. A timely diagnosis can avoid unnecessary medical
      trials, parental anxiety and poor school performance, as most of the patients are
      very young.

PMID- 12487680
TI  - Spontaneous orbital haematoma.
AB  - Spontaneous orbital haematoma is uncommon in ENT practice. The sudden
      presentation of proptosis and diplopia may guide the differential diagnosis
      towards more common pathologies such as an intraorbital complication of acute
      sinusitis or neoplasm of the orbit. The diagnosis by computed tomography (CT)
      scan, the management of this orbital disease and the literature in this field are
      discussed.

PMID- 12487681
TI  - Solitary plasmacytoma and extramedullary plasmacytoma of the paranasal sinuses
      and soft palate.
AB  - Solitary plasmacytoma of the paranasal sinuses are uncommon neoplasms of B
      lymphocyte origin. They comprise one per cent of all head and neck tumours of the
      upper respiratory tract. They can be solitary plasmacytomas of the bone (SPB), an
      extramedullary plasmacytoma or a local manifestation of multiple myeloma.
      Conversion to multiple myeloma happens more frequently in SPB. Radiotherapy is
      the common modality of treatment with, or without, adjuvant chemotherapy.
      Extramedullary plasmacytoma carries a better prognosis than a solitary
      plasmacytoma of the bone. We report four cases of solitary plasmacytoma of the
      bone and an extramedullary plasmacytoma of the paranasal sinuses and soft palate.

PMID- 12487682
TI  - Limited form of Churg-Strauss syndrome presenting as a mass in the neck.
AB  - A 53-year-old man was referred to the ENT department with a large mass in the
      left supraclavicular fossa. The histological diagnosis showed the mass to have
      arisen due to a granulomatous vasculitis consistent with Churg-Strauss syndrome
      (CSS). CSS usually comprises asthma, eosinophilia and systemic vasculitis
      although limited forms of the disease exist where one of these diagnostic
      criteria is missing. This is one such case as the patient was non-asthmatic.

PMID- 12487683
TI  - Haemangiopericytoma of the submental region.
AB  - Haemangiopericytoma refers to an uncommon vascular/perivascular neoplasm of which
      a minority of cases arise in the head and neck. It comprises a group of lesions
      with marked clinical and pathological heterogeneity and a lack of positive
      criteria by which to make a definitive diagnosis. We describe an unusual case of
      such a tumour in the submental region, review its pathological features and
      discuss issues in management and prognosis.

PMID- 12487684
TI  - Usability of the revised NIOSH lifting equation.
AB  - Following the revision of the 1981 National Institute for Occupational Safety and
      Health (NIOSH) lifting equation, research needs related to the new equation were
      outlined. Aside from epidemiological studies, the need to evaluate the usability
      of the 1991 NIOSH equation in realistic work environments was expressed. This
      paper reports on extensive experiences with training users and application of the
      equation in varied work settings. Qualitative results from training sessions
      indicated that frequency, asymmetry and duration were the parameters that
      required relatively longer instruction periods and resulted in the most
      questions. Field applications indicated that the variable nature of
      lifting/lowering demands found in many jobs resulted in difficulty applying the
      equation. Approximately 35% of 1103 lifting and lowering tasks had at least one
      parameter outside of acceptable ranges, while a majority of workers (62.8%)
      reported other manual handling tasks that are counter to assumptions made in the
      development of the equation. The practical implications of the findings are
      discussed.

PMID- 12487685
TI  - Hyperoxia improves maximal exercise with the self-contained breathing apparatus
      (SCBA).
AB  - The effects of hyperoxia on maximal exercise while breathing from a self
      contained breathing apparatus (SCBA) were studied in 25 males. Each participant
      completed three graded exercise tests (GXT) for the assessment of maximal oxygen
      uptake (VO(2max)): two with 20.95 +/- 0.28% O(2) and the third (GXT(40)) while
      breathing hyperoxia (40.64 +/- 1.29% O(2)). No significant differences were found
      between the two normoxic tests, except for a 16W increase in maximal power output
      (PO(max)) in the second trial (GXT(21)). Compared to GXT(21), hyperoxia
      significantly increased VO(2max) and PO(max) by 10.0 +/- 3.8% and 10.2 +/- 7.1%,
      respectively. This was likely due to an increase in O(2) delivery as suggested by
      the significantly higher oxyhemoglobin saturation. The increase in VO (2max) with
      hyperoxia was similar to the increase in carbon dioxide production (9.3 +/-
      6.5%). No other significant di.fferences were found at maximal exercise. However,
      at the intensity that elicited VO(2max) in GXT(21), pulmonary ventilation and
      SCBA mask pressure were significantly lower during GXT(40), suggesting a decrease
      in the work of breathing. These findings could have significant implications for
      occupations that involve heavy work with SCBA.

PMID- 12487686
TI  - The effect of hyperoxia on submaximal exercise with the self-contained breathing
      apparatus.
AB  - The effects of hyperoxia on submaximal exercise with the self-contained breathing
      apparatus (SCBA) were studied in 25 males. Each participant completed a graded
      exercise test for the determination of ventilatory threshold (VT) and then a
      submaximal practice trial with a normoxic gas mixture. The normoxic (20.93 +/-
      0.22% O(2); SUB(21)) and hyperoxic (40.18 +/- 0.73% O(2); SUB(40)) submaximal
      trials were then administered in a random order. All exercise tests were
      completed on separate days while wearing firefighting gear and the SCBA. Compared
      with SUB(21), hyperoxia significantly reduced minute ventilation (V(E)), mask
      pressure (P(mask)), heart rate, blood lactate concentration, perceived exertion,
      and perceived breathing distress. As expected, hemoglobin saturation remained
      higher (p < 0.05) during SUB(40). The reductions in both V(E) and P(mask) with
      hyperoxia imply a reduction in the work of breathing during exercise. Total gas
      consumption was 10.3 +/- 8.1% lower during SUB(40) when compared to SUB(21),
      another finding that has significant practical implications for occupational
      safety.

PMID- 12487687
TI  - Evaluation of training in patient handling and moving skills among hospital and
      home care personnel.
AB  - The aim of the study was to evaluate the training programme in patient handling
      and moving skills according to the Stockholm Training Concept. The evaluation
      focused on work technique, musculoskeletal problems, job strain and the
      experience of the person being transferred. The training programme consisted of
      two models of learning: traditional groups and quality circles. Fifty-one people
      employed at geriatric hospitals and in primary care, participated in the training
      programme. For the evaluation, the participants were video-recorded in one
      standardized transfer situation: moving the patient from bed to wheelchair,
      before and after the training. The participants' work technique during the
      patient transfer was assessed using seven items. A questionnaire covering
      individual factors, physical exertion, job strain, and musculoskeletal problems,
      was filled in by the participants before training and also six months after. The
      results showed improvements in six of the seven work technique items, directly
      after training. A decrease in the participants' physical exertion during
      transfers of patients from 'bed to chair' was shown six months after completion
      of the training programme. There was no significant decrease in the participants'
      musculoskeletal problems and job strain after training. Ninety-eight per cent of
      the participants were positive about having participated in the training.
      Training in patient handling and moving skills led to improved work technique.
      The participants improved their transfer technique and experienced less
      discomfort during the transfer, and patients experienced greater comfort and
      safety when being transferred.

PMID- 12487688
TI  - Unsafe acts and unsafe outcomes in aircraft maintenance.
AB  - Road safety studies using the Driver Behaviour Questionnaire (DBQ) have provided
      support for a three-way distinction between violations, skill-based errors and
      mistakes, and have indicated that a tendency to commit driving violations is
      associated with an increased risk of accident involvement. The aims of this study
      were to examine whether the three-way distinction of unsafe acts is applicable in
      the context of aircraft maintenance, and whether involvement in maintenance
      safety occurrences can be predicted on the basis of self-reported unsafe acts. A
      Maintenance Behaviour Questionnaire (MBQ) was developed to explore patterns of
      unsafe acts committed by aircraft maintenance mechanics. The MBQ was completed
      anonymously by over 1300 Australian aviation mechanics, who also provided
      information on their involvement in workplace accidents and incidents. Four
      factors were identified: routine violations, skill-based errors, mistakes and
      exceptional violations. Violations and mistakes were related significantly to the
      occurrence of incidents that jeopardized the quality of aircraft maintenance, but
      were not related to workplace injuries. Skill-based errors, while not related to
      work quality incidents, were related to workplace injuries. The results are
      consistent with the three-way typology of unsafe acts described by Reason et al.
      (1990) and with the DBQ research indicating an association between self-reported
      violations and accidents. The current findings suggest that interventions
      addressed at maintenance quality incidents should take into account the role of
      violations and mistakes, and the factors that promote them. In contrast,
      interventions directed at reducing workplace injury are likely to require a focus
      on skill-based errors.

PMID- 12487689
TI  - Using a circadian rhythms model to evaluate shift schedules.
AB  - As long as the need for shiftwork exists, so will the demand for an optimal
      scheduling strategy that balances the needs of both industry and the shiftworker.
      One aim is for schedules that require workers to be on duty during the times that
      they are most naturally alert and awake. Czeisler et al. (1982) developed a set
      of circadian rhythm based guidelines intended to aid in designing such shiftwork
      schedules. This paper takes research one step further by testing such empirical
      criteria in a mathematical setting. The two-oscillator model of free-run human
      circadian rhythms developed by Kronauer et al. (1982) was modified to represent
      the circadian rhythms of a shiftworker on a pre-selected shiftwork schedule.
      Numerical simulations were used to compare the circadian rhythms produced from a
      variety of shiftwork schedules to the free-run rhythms. Shift schedules that
      resulted in circadian rhythms closest to the free-run rhythms were identified as
      preferred schedules. The numerical results supported Czeisler's findings (1982),
      indicating the best shift schedules adopt a slow, forward-shifting rotation
      pattern, rotate shifts after 2-week periods and allow an average of 2 days off
      per week.

PMID- 12487690
TI  - A statistical human resources costing and accounting model for analysing the
      economic effects of an intervention at a workplace.
AB  - The study had two primary aims. The first aim was to combine a human resources
      costing and accounting approach (HRCA) with a quantitative statistical approach
      in order to get an integrated model. The second aim was to apply this integrated
      model in a quasi-experimental study in order to investigate whether preventive
      intervention affected sickness absence costs at the company level. The
      intervention studied contained occupational organizational measures, competence
      development, physical and psychosocial working environmental measures and
      individual and rehabilitation measures on both an individual and a group basis.
      The study is a quasi-experimental design with a non-randomized control group.
      Both groups involved cleaning jobs at predominantly female workplaces. The study
      plan involved carrying out before and after studies on both groups. The study
      included only those who were at the same workplace during the whole of the study
      period. In the HRCA model used here, the cost of sickness absence is the net
      difference between the costs, in the form of the value of the loss of production
      and the administrative cost, and the benefits in the form of lower labour costs.
      According to the HRCA model, the intervention used counteracted a rise in
      sickness absence costs at the company level, giving an average net effect of
      266.5 Euros per person (full-time working) during an 8-month period. Using an
      analogue statistical analysis on the whole of the material, the contribution of
      the intervention counteracted a rise in sickness absence costs at the company
      level giving an average net effect of 283.2 Euros. Using a statistical method it
      was possible to study the regression coefficients in sub-groups and calculate the
      p-values for these coefficients; in the younger group the intervention gave a
      calculated net contribution of 605.6 Euros with a p-value of 0.073, while the
      intervention net contribution in the older group had a very high p-value. Using
      the statistical model it was also possible to study contributions of other
      variables and interactions. This study established that the HRCA model and the
      integrated model produced approximately the same monetary outcomes. The
      integrated model, however, allowed a deeper understanding of the various possible
      relationships and quantified the results with confidence intervals.

PMID- 12487691
TI  - Inter- and intra-observer reliability of calculating cumulative lumbar spine
      loads.
AB  - The aim of this study was to quantify the precision of manual video digitization
      of three typical industrial tasks, as evaluated by the comparison of four
      cumulative kinetic parameters at the L4/L5 intervertebral joint: compression,
      joint shear, reaction shear and moment. Ten observers were recruited (five male
      and five female), with an undergraduate background in human anatomy. On each of
      three test days, each observer digitized five repeats of each of three typical
      industrial lifting tasks of 5 to 6 s in duration. A rigid link segment model that
      incorporated a single muscle equivalent model was used to calculate the
      cumulative loading based on the digitized coordinates. Inter-observer reliability
      was assessed using a mixed model ANOVA, and no significant differences were found
      to result from observer, gender, day or trial. Intraclass correlation
      coefficients (ICC) were calculated within each task to quantify intra-observer
      reliability. Overall, the ICCs were excellent (>0.75), with the exception of
      moderate values for reaction shear for Tasks 2 and 3. Compression and moment
      demonstrated the highest reliability of the four parameters studied, which is
      beneficial from an ergonomic standpoint, as compression is the most commonly used
      parameter for job assessments. This study demonstrated manual video digitization
      to be a reliable tool for the quantification of cumulative spinal loading, both
      within a given observer, and across days, trials and observers.

PMID- 12487692
TI  - Physiologic responses during rest on a sleep system at varied degrees of firmness
      in a normal population.
AB  - This study explores the hypothesis that a high degree of sustained muscle
      activity associated with a sub-optimal spinal orientation may compromise an
      individual's ability to relax or initiate sleep. Data from 22 participants who
      were considered to be part of a normal, back-pain-free population were used in
      these studies. Participants laid down on a mattress in a foetal position (i.e. on
      their sides) at three varying bed pressures while EMG activities, heart rates,
      blood pressures, subjective comfort levels and spinal alignment data were
      recorded. Minor effects of mattress inflation pressures were associated with
      changes in EMG activity, heart rate, blood pressure and/or subjective comfort. In
      contrast, spinal alignment assessment revealed significant differences between
      the three different inflation pressures studied (827.4, 2413.2 and 3999.0 Pa). It
      was concluded that in a population of normal participants, although mattress
      inflation pressure induced significant changes in spinal alignment, these changes
      were of little physiological consequence. Nevertheless, this data provides
      baseline information needed to assess similar correlations in a symptomatic
      population (e.g. those with either acute or chronic neck or back pain).

PMID- 12487694
TI  - Grounded theory and gender relevance.

PMID- 12487695
TI  - Illuminating social determinants of women's health using grounded theory.
AB  - Emphasis in health policy has shifted from curative intervention to prevention
      and health promotion through personal responsibility for lifestyle choices and,
      most recently, to the social determination of health. These shifts draw attention
      to and legitimize women's health research that moves beyond biomedical,
      epidemiological, and subjective knowledge to question previously unquestioned
      societal norms and structures that influence women's health. The challenge is to
      avoid relying solely on population-based studies that support relationships
      between social determinants and indicators of women's health and to find ways to
      illuminate the processes by which social determinants interact with the health of
      specific groups of women. Without such research, our knowledge of how social
      factors that underpin women's health interact will be faceless and will not
      address the interplay of health and social policy within women's lives. One
      research method that may be useful for exploring the interplay between such
      policies and women's health is grounded theory. Grounded theory is a widely used
      approach in women's health research. The goal of grounded theory is the discovery
      of dominant social and structural processes that account for most of the
      variation in behavior in a particular situation. Despite the usefulness of this
      method for capturing the interaction between social conditions and women's health
      experiences, many grounded theory researchers restrict themselves to women's
      subjective experiences as a source of data for theory development. Consequently,
      the resultant theory's capacity to illuminate the effects of the social
      determinants of health is limited. The purpose of this article is to discuss how
      the grounded theory method can be used in a participatory way to theoretically
      sample structural conditions at many levels. Using examples from completed and
      ongoing women's health research where data have and have not been collected
      primarily from women themselves, we outline the benefits and process for using
      grounded theory to influence health and public policy in women's health.

PMID- 12487696
TI  - Informed consent and the history of inclusion of women in clinical research.
AB  - The purposes of this paper are to (a) discuss the troubled history of informed
      consent for research on women and its ramifications for women's participation in
      clinical trials; (b) interrogate current informed consent practices as to their
      accountability and justice in the treatment of women; and (c) recommend to nurse
      researchers and clinical nurses ways of improving the practice of informed
      consent in research with women.

PMID- 12487697
TI  - Application of feminist theory in nursing research: the case of women and
      cardiovascular disease.
AB  - Researchers have provided evidence that women recover from and live with heart
      disease in very distinct ways from men. The challenge for researchers has been to
      discuss women in a manner that allows their differences to emerge but does not
      depict them as inferior to men. Our goal is to review current cardiovascular
      research on women from a feminist theoretical perspective. We believe that a
      feminist perspective in cardiovascular research will advance the knowledge and
      recognition of women's health. We examined nine qualitative research articles in
      depth and applied a model of feminist research critique to them (Bunting, 1997).
      Historical androcentric notions in women's health and cardiovascular research are
      discussed. Also included are recommendations for future research to influence
      social change in women's cardiac health.

PMID- 12487698
TI  - Concepts of health: women's struggle for wholeness in the midst of poverty.
AB  - This article describes the findings of a modest qualitative study that deals with
      the concept of health and involves the women-centered interviewing of six women
      who live in poverty. The themes uncovered in this study identify the struggle for
      wholeness in the midst of poverty. The findings validate many of the nursing
      theorists' definitions of health as wholeness, and challenge care providers to
      bring an appreciation of this view to their understanding of women's health.

PMID- 12487699
TI  - Examining the standardized application of rape kits: an exploratory study of post
      sexual assault professional practices.
AB  - In this exploratory study we examine the practices surrounding with respect to
      standardization the administration and processing of the Sexual Assault Evidence
      Kit (SAEK). Despite the presumed scientific objectivity of this protocol, our
      survey of sexual assault nurses, physicians, police, and forensic scientists
      found that discretionary practices pervaded the evidentiary process. We argue
      that there must be greater awareness of the shaping of medicolegal evidence.
      Given the diverse characteristics of sexual assaults and of the health care needs
      of sexually assaulted women, we also suggest that it may be unreasonable to apply
      a single standard model of a rape kit.

PMID- 12487700
TI  - Unresolved issues in contraceptive health policy.
AB  - The year 2000 marked the fortieth anniversary of the oral contraceptive known as
      the "pill." Despite the availability of the pill, and other contraceptives, many
      unresolved issues remain. Concerns with contraceptive side effects, high use
      failure rates, and high rates of both unintended pregnancies and abortions
      indicate a need for improved contraceptive choices. Experts have called for a
      second contraceptive revolution that would bring radically new contraceptive
      products to the market. Unfortunately, this second revolution has not occurred,
      and contraceptive research has been virtually abandoned by most major
      pharmaceutical firms. We suggest that inclusion of contraceptives within the 1983
      Orphan Drug Act and U.S. federal legislation known as the Food and Drug
      Administration (FDA) defense could provide the economic incentives needed to
      spark the second contraceptive revolution.

PMID- 12487701
TI  - Multinational corporations, the politics of the world economy, and their effects
      on women's health in the developing world: a review.
AB  - Presently, globalization and the world economy maintain power relations that
      hamper the economic integrity and the political autonomy of the developing world.
      My paper addresses specific economic conditions that perpetuate poverty and poor
      health. I examine multinational corporations and their effects on women's health,
      particularly in Mexico and parts of Asia. The advent of multinational corporate
      business in Mexico, Malaysia, Philippines, India, and Indonesia has led to
      increased poverty and human rights abuses. Women bear the brunt of this because
      of specific international economic arrangements and their low social status, both
      locally and globally. As a result, their physical, mental, and emotional health
      is suffering. Solutions to these health problems have been proposed on multiple
      levels: international top-down approaches (i.e., employing international
      protectionist regulatory standards, exposing multinationals who infringe on their
      workers' human rights), as well as local grassroots organizational campaigns
      (i.e., conducting informational human rights workshops for factory workers).
      Ultimately, the answers lie in holding corporations accountable to their laborers
      while developing countries maintain their comparative advantage; this is the only
      way women's health will improve and the developing world can entice corporate
      investment.

PMID- 12487702
TI  - Establishing reliability and validity of an instrument measuring Jordanian Muslim
      women's contraceptive beliefs.
AB  - We tested the psychometric properties of an instrument entitled intention to use
      oral contraceptive tool (IUOCT). This instrument was developed to evaluate
      Jordanian Muslim women's intention to use oral contraceptives (OCs). We used the
      theory of planned behavior (TPB) as a conceptual framework for developing the
      IUOCT. The internal consistency of the IUOCT ranged from .70 to .94. The
      stability of IUOCT ranged from.79 to.85. Factor analysis identified four factors
      that represented the three constructs of the TPB. The known-group technique
      showed significant difference between past users and nonpast users of OCs. The
      predictive validity analysis showed that each scale contributed to the
      variability in the intention.

PMID- 12487703
TI  - Stroll your way to well-being: a survey of the perceived benefits, barriers,
      community support, and stigma associated with pram walking groups designed for
      new mothers, Sydney, Australia.
AB  - In our survey of 500 mothers with children 0-5 years involving telephone
      interviews (n = 450) and focus groups (n = 50), we showed that 87% of mothers
      telephone surveyed used a pram for incidental activities, whilst 47% used the
      pram specifically for exercise. Factors preventing mothers exercising more
      included poor weather, lack of time, and poor quality paths. Ninety-two percent
      of mothers believed that pram walking would increase mental well-being, and 87%
      felt that it would help to reduce postnatal depression (PND). However, feedback
      from focus groups expressed less confidence in the program's ability to
      potentially benefit mothers with PND. Programs will have to be marketed carefully
      to avoid the stigma associated with PND and successfully target mothers at risk.

PMID- 12487704
TI  - Physical activity: perspectives of Mexican American and Anglo American midlife
      women.
AB  - Despite the well-known health benefits of physical activity (PA), most midlife
      and older adults lead sedentary lifestyles. Anglo American women and Mexican
      Americans of both genders are two of the least physically active groups. We
      conducted three focus groups to identify attitudes and beliefs about PA among
      Mexican American and Anglo American midlife women. Our long-term goal was to
      identify culture-specific interventions that promote long-term PA continuation.
      Significant differences were found between the two groups. While Anglo American
      women valued individual outcomes, and spoke of personal factors promoting or
      preventing exercise, Mexican American women viewed PA as prescriptive, important
      for restoring health, and cited family responsibilities and family attitudes as
      factors that promoted or prevented them from exercising. We found that in order
      for PA interventions to be successful in each group, they must be tailored to the
      values of each cultural group.

PMID- 12487705
TI  - Physical activity in young African American women.
AB  - African American women are reported to be less physically active than other
      population groups. This study examined personal behavioral and psychosocial and
      environmental factors associated with physical activity in African American women
      living at or below poverty. Most participants engaged in some moderate physical
      activity through housework and child care; 71% engaged in activity such as
      walking from one to seven times per week; but only 5% were vigorously active.
      Seventy-seven percent were active in the past, but 80% dropped out within 6
      months, citing "lack of time and feeling bad" as the main reasons. Exercise self
      efficacy was positively correlated with beliefs about physical and social
      outcomes of activity, with more active than inactive women believing that
      physical activity had more physical health outcomes. One-third of the women
      reported that family or friends disapproved of their spending time being
      physically active, and 45% had never been encouraged to be active by a health
      professional. However, health professionals' influence was positively correlated
      with weight reduction but not physical activity participation.

PMID- 12487706
TI  - The role of physical activity in preparing women for pregnancy and delivery in
      Poland.
AB  - Our aim in conducting this study is to document different forms of recreational
      activities chosen by women before and during pregnancy and to answer the question
      of how women prepared themselves physically to deliver their babies. We included
      266 women who were in the third trimester of their pregnancies in this study.
      (The women were randomized.) Methods of recreation were divided into two groups:
      active (involving physical exercise) and passive (physical exercise not
      involved). From our findings we suggest that pregnancy dramatically changes the
      behavior of women with regard to physical recreation. There was a lack of
      professional preparation for delivery; only 12% of women in this study took part
      in so-called delivery classes.

PMID- 12487707
TI  - Effects of exercise on stress in Thai postmenopausal women.
AB  - Several researchers have investigated the impact of menopause on American and
      European women. Yet there is little research that has focused on the meaning of
      this experience in other cultural and ethnic groups. In Thailand, although there
      is research concerning the physical symptomotology associated with the
      postmenopausal period, scant data exists on psychological stress among this
      cohort. Exercise is important for both stress reduction and health promotion.
      However, no clear consensus has been reached, suggesting the need for exploration
      of the relationship between exercise and psychological stress. Our purpose of
      this study was to examine the effects of exercise on stress in Thai
      postmenopausal women. A one-group pretest posttest design was utilized. Data were
      collected on 102 Thai postmenopausal women. The findings suggest that an exercise
      program may be a safe, simple, and cost beneficial intervention.

PMID- 12487708
TI  - The credibility of the Breast Cancer Risk Assessment (BCRA) tool for Asians.
AB  - This paper presents an overview of the Breast Cancer Risk Assessment (BCRA) Tool,
      assessing the credibility of the BCRA tool in estimating the risk of developing
      breast cancer for Asians and the carrying out of tests to identify the changes in
      the risks that follow with changes in one or more risk factors of the tool. It is
      essential to increase the awareness of women of their risk of developing breast
      cancer, as it is not surprising that some women may not even be conscious of the
      individual factors that might contribute to the increase of their risk of
      developing breast cancer. On the other hand, relatively accurate means of
      determining increases in relative risks of developing breast cancer due to
      changes in some of the risk factors are also important. This is done so that
      unnecessary worry due to an overestimation of an individual's risk of developing
      breast cancer can be avoided. Due to the origin of the BCRA tool which is used in
      this study, it is important to verify the validity of the tool on Asians and to
      identify, as far as possible, the effect that each risk factor has on
      individuals. The effect that a specific risk factor has on a white woman may not
      be exactly the same for that of an Asian woman. As the above-mentioned tool has
      been arrived at using the statistics and databases of white women, in this work,
      tests have been carried out to determine the suitability of the tool on Asian
      women. On top of that, various tests are also carried out to determine the
      effects of the change of certain risk factors on a woman's risk of developing
      breast cancer. These factors include age, number of breast biopsies and number of
      first-degree relatives with breast cancer. Five-year risks and lifetime risks are
      also looked into separately with the change of each of these factors.

PMID- 12487709
TI  - On modelling the kinestatic charge detector for digital radiographic diagnostic
      and portal imaging.
AB  - The kinestatic charge detection (KCD) principle has been a digital radiography
      technique for more than a decade. The advances of the KCD technique have gone
      from diagnostic imaging to portal imaging. However, little work has been done on
      understanding the selection of key KCD parameters and relationships between them.
      In the present study, an engineering model was established that could be used to
      optimize the placements of key parameters in terms of KCD system mechanical
      design. In the proposed KCD engineering model, the basic energy conservation law
      was applied to the process of ion transmission. It allows for the computation of
      the KCD design parameters such as the optimum grid placement, high voltage board
      tilt angle and grid wire space, as well as to provide recommendations on high
      voltage board and electric potentials and their ratio.

PMID- 12487710
TI  - Experimental method to reveal the effect of rotor magnet size and air gap on
      artificial heart driving motor torque and efficiency.
AB  - To investigate experimentally the effect of rotor magnet design on artificial
      heart driving motor performance, seven rotors with different magnet lengths or
      thicknesses, as well as different peripheral angles, were manufactured and tested
      in the same motor stator with different rotating speeds. The input power (voltage
      and current) and output torque were measured and the motor efficiency was
      computed. The results demonstrated that the reduction of rotor magnet size and
      the enlargement of the air gap between the rotor magnets and the stator coil core
      have no significant effect on motor efficiency, but will reduce the torque value
      on which the motor achieves the highest efficiency; it could be remedied however
      by increasing the rotating speed, because the torque at the high efficiency point
      will increase along with the rotating speed. These results may provide a basis
      for developing small rotor magnets, large air gap and high efficiency motors for
      driving an artificial heart pump.

PMID- 12487711
TI  - Morse code recognition system with fuzzy algorithm for disabled persons.
AB  - It is generally known that Morse code is an efficient input method for one or two
      switches and it is made from long and short sounds separated by silence between
      the sounds. The long-to-short ratio in the definition is always 3 to 1, but the
      long-to-short ratio variation for a disabled person is so large that it is
      difficult to recognize. In the last few years, several Morse code recognition
      methods have been successfully built on the LMS adaptive algorithms and neural
      network algorithm. But LMS-related adaptive algorithms need mass computation to
      infer the characteristic of the controller; also the neural network must learn
      first, by inputting some data before it is used to recognize the Morse code
      sequence. In this study, two fuzzy algorithms are used to recognize the unstable
      Morse code sequences and the result demonstrates a significant improvement of
      recognition for real time signal processing in a single-chip microprocessor.

PMID- 12487712
TI  - An accurate amperometric glucose sensor based glucometer with eliminated cross
      sensitivity.
AB  - This paper represents an experimental analysis of cross-sensitivity, which is the
      main problem that usually faces amperometric glucose sensors. The elimination of
      cross-sensitivity is based on experimental determination and verification of new
      correction factors. The correction factors obtained were then used to design a
      new glucometer with cross-sensitivity of the amperomtric glucose sensor to urea
      concentration in human blood eliminated. The accuracy of this glucometer
      satisfies the clinical requirements and the results of glucose measurements
      obtained using this glucometer are highly correlated with the glucose
      measurements for the same blood samples obtained using the well-known Yellow
      Springs Instrument glucose analyser.

PMID- 12487713
TI  - A novel impeller TAH using magnetic bearings for load reduction.
AB  - A novel impeller TAH (total artificial heart), i.e. bi-ventricular assist
      impeller pumps, has been developed. The device consists of a rotor with motor
      magnets and two impellers, a stator with motor coil and iron core, and two pump
      housings. In both sides of the rotor magnets, as well as the stator coil core, a
      pair of magnetic bearings was devised to partly counteract the attractive forces
      between the rotor magnets and the stator coil core. This means the magnetic
      bearings are used for load reduction. On hydrodynamic testing, the two pumps both
      produced a flow rate as high as 6 l min(-1) and the left pump had a pressure head
      of 150 mm Hg, and that of the right pump was 50 mm Hg. The highest efficiency of
      the device, including the motor, the two pumps and the controller, reached 14.7%.
      The device, weighing 250 g, had a length of 80 mm and a diameter of 40 mm at its
      largest point. Currently in the world, this is a unique TAH, which is
      electrically powered and driven by a single motor and has only one moving part,
      can produce either pulsatile or non-pulsatile flow, both pumps eject flow
      synchronistically by pulsatile mode, and the volume equilibrium of the two pumps
      can be achieved automatically without the need for control.

PMID- 12487714
TI  - Motorized head impulse stimulator to determine angular horizontal vestibulo
      ocular reflex.
AB  - The objective of the current study was to develop a computer-controlled
      mechanical system for the generation of impulsive head rotations to measure eye
      movements induced by angular horizontal vestibulo-ocular reflex. This is a
      clinical eye movement test recently introduced for the usage of otoneurological
      balance laboratories. We built the system and modified our prior computer
      software developed for other types of eye movement tests. Motor controlled
      stimulation has fulfilled the requirement of more uniform and constant
      acceleration stimulation than obtained with manually administrated impulses.
      After having executed preliminary experiments at our balance laboratory we found
      the system to be efficient, reliable and secure.

PMID- 12487715
TI  - A methodological approach for the characterization of cardiac pacemaker immunity
      to low frequency interferences: case of 50 Hz, 60 Hz, 10 kHz and 25 kHz led
      disruptions.
AB  - The goal of this work is the implementation of a metrological set up dedicated to
      the characterization of cardiac pacemakers' immunity at low frequency
      electromagnetic disruptions. The studied frequencies are 50 Hz, 60 Hz, 10 kHz and
      25 kHz. The assessment methodology that is applied is in accord with the
      electromagnetic compatibility. The tests are carried out on single-chamber
      pacemakers. The first approach, consisting of the application of the interfering
      signal directly between the housing and the electrode, enabled us to point out
      the influence of a preset detection sensitivity on the signal levels induced
      between the terminal and the pacemaker's housing. These attempts are completed by
      in vitro tests using an electromagnetic model which allows one to take into
      account the interface which constitutes the human body, and thus to get closer to
      a real life situation. The visualization of the pacemaker generated signal
      illustrates the performance of the pacemaker according to different test
      configurations. It is an initial approach meant to create a base for the creation
      of a metrological protocol.

PMID- 12487717
TI  - Family caregivers' reactions and coping for persons with brain injury.
AB  - BACKGROUND: This study was a follow-up of a previous study on the empowerment of
      families caring for Chinese persons with brain injury. OBJECTIVE: The present
      study examined, in a qualitative way, the impact of brain injury on the family
      and the complex array of factors that appears to be related to effective family
      coping and their independence. The reactions of families under stress and their
      coping strategies are summarized. Individual families' differences in terms of an
      empowerment framework are discussed for possible guidance in family intervention.
      METHOD: Individual families were interviewed using open-ended questions, their
      responses and the verbatim transcripts of long interviews performed with selected
      families were examined. RESULTS: A total of 50 family members were successfully
      recruited for interview. They were found to show typical coping strategies,
      including shock and uncertainty, which are suggested to be relating closely to
      the nature of brain injury and the difficulties in managing it. The physical and
      psychological burdens involved in caring for members with brain injury were also
      reflected. Content analysis of the long interviews of four selected families
      showed that it was not every family that coped well. Possible factors leading to
      better adjustment, such as clear personal expectations, a desire to master the
      situation, strong motivation, flexibility to adjust life goals and awareness of
      one's own powerless state are proposed. CONCLUSION: The results indicated that
      family coping varies with individual families and should be explored further for
      the development of intervention guidelines.

PMID- 12487718
TI  - Predictors of caregiver burden following traumatic brain injury.
AB  - PRIMARY OBJECTIVE: To investigate the relationship of demographic characteristics
      of the caregiver (i.e. race, age, household income, education) to caregiver
      burden, family needs, family functioning and social support to assess the
      predictors of caregiver burden. RESEARCH DESIGN: Information was obtained through
      mailed surveys and follow-up phone interviews. METHODS AND PROCEDURES:
      Participants were 24 African American and 21 White caregivers of individuals with
      traumatic brain injury who were at least 1-year post-injury. Measures
      administered included the Head Injury Family Interview, Family Needs
      Questionnaire, Family Assessment Device and the NON, a measure of social support.
      MAIN OUTCOMES AND RESULTS: Regression analyses revealed that importance of needs
      and percentage of needs met accounted for a significant amount of the variance in
      predicting affective/behavioural, cognitive and physical/dependency burden.
      CONCLUSIONS: Rehabilitation professionals need to provide support that includes
      ongoing assessment of needs and provides a resource for steering caregivers to
      potential sources for meeting those needs.

PMID- 12487719
TI  - Applicability of the 15-item versions of the Judgement of Line Orientation Test
      for individuals with traumatic brain injury.
AB  - PRIMARY OBJECTIVE: To determine if short forms (i.e. 15 item) of the Judgment of
      Line Orientation (JOLO) test are equivalent to the full JOLO (i.e. 30 item).
      RESEARCH DESIGN: Retrospective analysis of JOLO test performance. METHODS AND
      PROCEDURES: Seventy-two persons with TBI evaluated at a Midwestern University
      neuropsychology laboratory were administered the JOLO test, Form V, as part of a
      larger battery of neuropsychological tests. Short forms (i.e. odd and even number
      short forms) were correlated with the 30 item to determine equivalency of forms.
      The Statistical Package for the Social Sciences (version 10) was used for the
      data analyses (SPSS). MAIN OUTCOMES AND RESULTS: Pearson's correlations indicate
      that the JOLO odd and even short forms are significantly correlated with the full
      JOLO score (r = 0.90 and 0.93, respectively), and that 100% of the participants'
      estimated JOLO full score fell within 2 points of the actual full JOLO score.
      CONCLUSIONS: The results confirm the validity of the short forms of the JOLO for
      persons with TBI and that gender effects were not significant.

PMID- 12487720
TI  - Identification of rehabilitation problems after head injury.
AB  - We have reported a large study of patients admitted to hospital following head
      injury in the city of Glasgow over one calendar year. This showed 1000 patients
      still to be disabled one year after their injury. In order to see whether the
      difficulties reported by these patients represented needs for rehabilitation
      services, we undertook a parallel study in which a separate group of 26 patients
      were assessed by the same methods as in the main group, but also had a clinical
      review by an experienced rehabilitation medicine physician, to determine the
      patient's rehabilitation needs. The physician was unaware of the results of the
      first assessment. Both the extent and the nature of the services as needed were
      reported remarkably similarly by each form of assessment. In addition, the
      Glasgow Outcome Scale categories were closely related to the need for services.
      We conclude that the data reported by Thornhill et al. can be used to estimate
      the volume and type of rehabilitation services required by head injured patients
      in the early months after injury.

PMID- 12487721
TI  - Treatment of story grammar following traumatic brain injury: a pilot study.
AB  - Recent investigations have documented a variety of discourse deficits following
      traumatic brain injuries (TBI). However, there is a paucity of information
      relating to the treatment of such deficits. The present study investigated the
      treatment of discourse production deficits, specifically story grammar ability,
      in an individual with TBI. Treatment emphasized meta-linguistic comprehension of
      story grammar structure and the identification and generation of episode
      components within stories. Over the course of treatment, a marked increase in the
      number of complete episodes generated by the individual with TBI was noted in
      story grammar probes. Follow-up probes at 1 and 3 months post-treatment, however,
      indicated limited carryover and poor generalization of the treatment effects.
      Findings are interpreted in terms of the individual's chronic cognitive deficits,
      disruptions in managerial knowledge, and the limitations of treating discourse
      acontextually.

PMID- 12487722
TI  - Prediction of employment status following traumatic brain injury using a
      behavioural measure of frontal lobe functioning.
AB  - OBJECTIVE: To examine whether a behavioural measure of frontal lobe functioning,
      the Brock Adaptive Functioning Questionnaire (BAFQ), could predict employment
      status following traumatic brain injury (TBI). DESIGN: A discriminant function
      analysis was conducted to determine the ability of the BAFQ, along with other
      factors, to predict occupational status post-injury. METHODS: Sixty-one TBI
      survivors completed a background information questionnaire, the BAFQ, and an
      employment status rating scale. RESULTS: A factor analysis of the BAFQ sub-scales
      revealed two factors, one related to functioning in the orbitofrontal area, and
      one related to dorsolateral frontal lobe functioning. These two factors, along
      with background information, were entered into a discriminant function analysis,
      revealing a 77.4% accuracy rate in predicting occupational status post-injury.
      CONCLUSIONS: Demographic variables were found to differentiate employed from
      unemployed survivors. The BAFQ appeared useful in differentiating survivors who
      may return to their pre-injury employment level from those who may require
      modified employment.

PMID- 12487723
TI  - Exploring a repetitive training regime for upper limb hemiparesis in an in
      patient setting: a report on three case studies.
AB  - PRIMARY OBJECTIVE: To explore the efficacy of a task-oriented repetitive training
      protocol (RTx) in chronic hemiparetic patients in an in-patient rehabilitation
      unit. RESEARCH DESIGN: Three case studies; ABAB design (A=RTx; B=regular
      rehabilitation programme; 1 week per phase, respectively) in case P1, pre-post
      intervention comparison in case P2; repeated measure design in case P3. METHODS
      AND PROCEDURES: Daily training of task-oriented affected hand movements using
      shaping procedures developed in Constraint-Induced (CI) Movement Therapy.
      Patients 1 and 2 were trained daily for 90 minutes over 2 weeks. Patient 3
      received 60 minutes of daily training for a period of 4 weeks. Outcome measures
      were Wolf Motor Function Test (WMFT), Frenchay Arm Test, nine-hole peg test,
      upper extremity MRC, and grip force. MAIN OUTCOMES AND RESULTS: Substantial
      clinical benefits were achieved in all patients. The subjective observations
      mirrored significant improvements in the outcome parameters. CONCLUSION: The
      affected hand training improves upper limb motor functions in chronic patients.
      It is a 'practicable' approach for in-patient rehabilitation units.

PMID- 12487724
TI  - Comparative study of the metabolism of drug substrates by human cytochrome P450
      3A4 expressed in bacterial, yeast and human lymphoblastoid cells.
AB  - 1. The aim was to compare the metabolic activity of human CYP3A4 expressed in
      bacteria (E. coli), yeast (S. cerevisiae) and human lymphoblastoid cells (hBl),
      with the native CYP3A4 activity observed in a panel of human livers. 2. Three
      CYP3A4 substrates were selected for study: dextromethorphan (DEM), midazolam
      (MDZ) and diazepam (DZ). The substrate metabolism in each of the four systems was
      characterized by deriving the kinetic parameters K(m) or S(50), V(max) and
      intrinsic clearance (CL(int)) or maximum clearance (CL(max)) from the kinetic
      profiles; the latter differing by 100-fold across the three substrates. 3. The
      K(m) or S(50) for the formation of metabolites 3-methoxymorphinan (MEM), 1'
      hydroxymidazolam (1'-OH MDZ) and 3-hydroxydiazepam (3HDZ) compared well in all
      systems. For CYP3A4-mediated metabolism of DEM, MDZ and DZ, the V(max) for hBl
      microsomes were generally 2-9-fold higher than the respective yeast and human
      liver microsomes and E. coli membrane preparations, resulting in greater CL(int)
      or CL(max). In the case of 3HDZ formation, non-linear kinetics were observed for
      E. coli, hBl microsomes and human liver microsomes, whereas the kinetics observed
      for S. cerevisiae were linear. 4. The use of native human liver microsomes for
      drug metabolic studies will always be preferable. However, owing to the limited
      availability of human tissues, we find it is reasonable to use any of the
      recombinant systems described herein, since all three recombinant systems gave
      good predictions of the native human liver enzyme activities.

PMID- 12487725
TI  - In vitro identification of metabolic pathways and cytochrome P450 enzymes
      involved in the metabolism of etoperidone.
AB  - 1. In vitro studies have been carried out to investigate the metabolic pathways
      and identify the hepatic cytochrome P450 (CYP) enzymes involved in etoperidone
      (Et) metabolism. 2. Ten in vitro metabolites were profiled, quantified and
      tentatively identified after incubation with human hepatic S9 fractions. Et was
      metabolized via three metabolic pathways: (A) alkyl hydroxylation to form OH
      ethyl-Et (M1); (B) phenyl hydroxylation to form OH-phenyl-Et (M2); and (C) N
      dealkylation to form 1-m-chlorophenylpiperazine (mCPP, M8) and triazole propyl
      aldehyde (M6). Six additional metabolites were formed by further metabolism of
      M1, M2, M6 and M8. 3. Kinetic studies revealed that all metabolic pathways were
      monophasic, and the pathway leading to the formation of OH-ethyl-Et was the most
      efficient at eliminating the drug. On incubation with microsomes expressing
      individual recombinant CYPs, formation rates of M1-3 and M8 were 10-100-fold
      greater for CYP3A4 than that for other CYP forms. The formation of these
      metabolites was markedly inhibited by the CYP3A4-specific inhibitor ketoconazole,
      whereas other CYP-specific inhibitors did not show significant effects. In
      addition, the production of M1-3 and M8 was strongly correlated with CYP3A4
      mediated testosterone 6beta-hydroxylase activities in 13 different human liver
      microsome samples. 4. Dealkylation of the major metabolite M1 to form mCPP (M8)
      was also investigated using microsomes containing recombinant CYP enzymes. The
      rate of conversion of M1 to mCPP by CYP3A4 was 503.0 +/- 3.1 pmole nmole(-1) min(
      1). Metabolism of M1 to M8 by other CYP enzymes was insignificant. In addition,
      this metabolism in human liver microsomes was extensively inhibited by the CYP3A4
      inhibitor ketoconazole, but not by other CYP-specific inhibitors. In addition,
      conversion of M1 to M8 was highly correlated with CYP3A4-mediated testosterone
      6beta-hydroxylase activity. 5. The results strongly suggest that CYP3A4 is the
      predominant enzyme-metabolizing Et in humans.

PMID- 12487726
TI  - Decreased activity of hepatic P-glycoprotein in the isolated perfused liver of
      the adjuvant arthritis rat.
AB  - 1. We investigated the hepatobiliary transport of doxorubicin in the isolated
      perfused liver prepared from the adjuvant arthritis rat, an animal model for
      rheumatoid arthritis, to examine the hepatic P-glycoprotein activity in the
      adjuvant arthritis rat. 2. Liver was isolated from the normal and the adjuvant
      arthritis rat and perfused for 60 min with recirculating buffer and the perfusate
      and bile samples were collected at timed interval. 3. The elimination of
      doxorubicin in the adjuvant arthritis rat tended to be reduced, but it was not
      significantly different from the normal rat. Biliary clearance (CL(bile)) in the
      normal rat was 1.93 +/- 0.48 ml min(-1), whereas, CL(bile) in the adjuvant
      arthritis rat was significantly decreased to 0.40 +/- 0.13 ml min(-1). 4.
      CL(bile) was markedly decreased to about 0.15 ml min(-1) in the presence of 100
      microM verapamil in both types of rat. Methotrexate treatment had no effect on
      CL(bile) in both the normal and adjuvant arthritis rat (2.18 +/- 0.22 and 0.47 +/
      0.22 ml min(-1), respectively). 5. The results suggest that the hepatic P
      glycoprotein activity was markedly decreased in the adjuvant arthritis rat and
      the effect of methotrexate on the hepatic P-glycoprotein activity did not
      corresponded to its anti-inflammatory effect.

PMID- 12487727
TI  - Differential induction of midazolam metabolism in the small intestine and liver
      by oral and intravenous dexamethasone pretreatment in rat.
AB  - 1. Midazolam is metabolized in the rat by CYP3A enzymes to 4-OH-midazolam (4-OH
      MDZ) and 1'-OH-midazolam (1'-OH-MDZ). The induction of midazolam metabolism was
      studied in male Wistar rats treated with dexamethasone (50 mg kg(-1) day(-1))
      during 4 days via the oral or intravenous routes. Microsomes were prepared from
      the liver and the proximal small intestine and in vitro metabolism of midazolam
      was determined. In addition, CYP3A1- and CYP3A2-like protein levels were measured
      by gel electrophoresis and immunoblotting. 2. The V(max)'s (mean SEM) for 4-OH
      MDZ and 1'-OH-MDZ formation were much lower in intestinal (0.078 +/- 0.002 and
      0.074 +/- 0.002 microM min(-1) mg(-1) protein, respectively) compared with
      hepatic microsomes prepared from the uninduced rat (0.870 +/- 0.007 and 0.310 +/-
      0.020 microM min(-1) mg(-1) protein, respectively). Induction by oral or
      intravenous dexamethasone pretreatment led to significant increases in V(max) for
      4-OH-MDZ and 1'-OH-MDZ by both intestinal and hepatic microsomes. Oral
      dexamethasone pretreatment via the oral route resulted in a more pronounced
      increase in V(max) compared with intravenous administration of the inducer. 3.
      CYP3A1 and CYP3A2 protein levels in liver microsomes were significantly increased
      following oral (3.7- and 3.2-fold, respectively) or intravenous (2.6- and 2.1
      fold, respectively) pretreatment with dexamethasone. On the contrary, only oral
      dexamethasone pretreatment resulted in a significant change in intestinal CYP3A2
      like protein (7.3-fold). A slight difference in the migration distance of the
      immunoreactive band for CYP3A2 was also observed for intestinal microsomes. 4.
      These results suggest that intestinal CYP3A enzymes in the rat differ from
      hepatic CYP3A1 and CYP3A2. They also demonstrate that systemic dexamethasone
      administration can induce intestinal microsome activity.

PMID- 12487728
TI  - Characterization of testosterone metabolism and 7-hydroxycoumarin conjugation by
      rat and human liver slices after storage in liquid nitrogen for 1 h up to 6
      months.
AB  - 1. Slices of human and rat liver were cryopreserved in 18% dimethyl sulphoxide
      (DMSO) and subsequently stored in liquid nitrogen for periods up to as long as 6
      months. After thawing, the metabolism of testosterone to hydroxylated products
      and conjugation of 7-hydroxycoumarin were investigated. 2. Rat liver slices
      stored in liquid nitrogen for 6 months exhibited rates of formation of 7alpha-,
      6beta- 16alpha- and 2alpha-hydroxytestosterone, and of androstenedione that did
      not differ significantly from those observed with fresh slices. 3. No formation
      of 2alpha-hydroxytestosterone was detected with slices of human liver. However,
      in contrast with the rat, human slices produced 2beta-hydroxytestosterone. The
      rates of formation of 7alpha-, 6beta-, 16alpha- and 2beta-hydroxytestosterone and
      of androstenedione by human liver slices after 6 months of storage in liquid
      nitrogen were 82, 71, 236, 66 and 92%, respectively, of the corresponding rates
      by fresh slices. 4. The rates of sulphation and glucuronidation of 7
      hydroxycoumarin by slices from rat liver were 97 and 119%, respectively, of the
      corresponding fresh values after 6 months of storage in liquid nitrogen. 5. 7
      Hydroxycoumarin glucuronidation by human liver slices was 53% of the
      corresponding fresh values after 6 months of storage. However, human slices
      showed little or no capacity to conjugate 7-hydroxycoumarin with sulphate. 6. It
      was demonstrated that slices of both human and rat liver can be cryopreserved and
      stored in liquid nitrogen for at least 6 months without major changes in their
      rates of metabolism of testosterone to its hydroxylated products and of 7
      hydroxycoumarin conjugation. These findings further emphasize that
      cryopreservation of liver slices can be an effective tool in the use of
      biological material of limited availability.

PMID- 12487729
TI  - Comparison of rat and human cytochrome P450 (CYP) sources of N
      alkylprotoporphyrin IX. Formation after interaction with porphyrinogenic
      xenobiotics: studies with cDNA-expressed single CYP enzymes.
AB  - 1. The porphyrinogenicity of certain xenobiotics is due to mechanism-based
      inactivation of selected cytochrome P450 (CYP) enzymes, with concurrent formation
      of N-alkylprotoporphyrins (N-alkylPPs), which disrupt control of haem
      biosynthesis. An ambiguity arises when extrapolating results obtained with such
      porphyrinogenic xenobiotics in animals to humans owing to species' differences in
      CYP enzymes. The objective was to use cDNA-expressed individual rat CYP enzyme
      preparations in microsomes prepared from baculovirus-infected insect cells to
      determine which rat CYP enzymes were the source of N-alkylPPs after interaction
      with three porphyrinogenic xenobiotics and to compare the results with formation
      of N-alkylPPs in individual human CYP enzyme orthologues. 2. A sensitive
      fluorometric technique was employed to quantitate N-alkylPP formation after
      interaction of individual CYP enzymes with a porphyrinogenic xenobiotic. 3. N
      alkylPP formation was found following the interaction of three porphyrinogenic
      xenobiotics with CYP1A2, 2B1, 2C6, 2C11 and 3A2, in amounts ranging from 0.45 to
      0.07 nmol N-alkylPP nmol(-1) CYP. The results obtained with rat CYP1A2, 2C6, 2C11
      and 3A2 were compared with those previously obtained with the human CYP
      orthologues 1A2, 2C9 and 3A4. 4. Some results corresponded while others did not,
      reinforcing a previous recommendation that when dealing with xenobiotics whose
      porphyrinogenicity depends upon interaction with CYP enzymes resulting in N
      alkylPP formation, animal experiments should be augmented with studies using
      human CYP preparations.

PMID- 12487730
TI  - Changes in glutathione-redox balance induced by hexachlorocyclohexane and lindane
      in CHO-K1 cells.
AB  - 1. The basal cytotoxic effect of the organochlorine pesticides
      hexachlorocyclohexane and lindane on CHO-K1 cultures was assessed at fractions of
      their lethal doses as determined by the neutral red incorporation (NRI) assay
      (NRI(6.25), NRI(12.5) and NRI(25)). The sulphur-redox cycle enzymes glutathione
      peroxidase, glutathione reductase and glutathione S-transferase, and total and
      oxidized glutathione were evaluated at several points during the standard growth
      curve of the cultures. 2. After incubation with each compound for 24 h, both
      glutathione peroxidase and reductase showed a substantial increase at the lowest
      exposure doses (NRI(6.25))--more significantly for lindane than for 1,2,3,4,5,6
      hexachlorocyclohexane (HCH)--and dropped at higher doses of both compounds. The
      reduced and oxidized glutathione content was greatly diminished at the lower
      exposures, whereas the total glutathione content was higher at NRI(12.5) values.
      3. Changes in cell membrane integrity were assessed for a wide range of pesticide
      concentrations with the lactate dehydrogenase release assay and lipid
      peroxidation. Membrane leakage and peroxide production were significantly
      enhanced at concentrations of HCH 50 microg ml(-1), although this effect was not
      significant at lindane concentrations < 200 microg ml(-1). 4. Lipid peroxidation
      increased with exposure to HCH at concentrations as low as NRI(6.25), whereas in
      the case of lindane, this increase was only significant at doses of NRI(25) and
      above.

PMID- 12487731
TI  - In vitro biotransformation of 2,6,9-trisubstituted purine-derived cyclin
      dependent kinase inhibitor bohemine by mouse liver microsomes.
AB  - 1. Biotransformation pathways of the cyclin-dependent kinase inhibitor 6
      benzylamino-2-(3-hydroxypropylamino)-9-isopropylpurine (bohemine) by mouse liver
      microsomes in vitro were investigated. 2. Metabolite profiles of [8-(3)H]
      labelled bohemine were established by TLC/(3)H-autoradiography and enzymatic and
      MS analyses were used to elucidate the chemical structures of the metabolites.
      The structures of the main primary metabolites were confirmed by synthesis of
      authentic compounds. 3. A schema of the primary NADPH-dependent pathways has been
      proposed involving N(2)- and N9-dealkylation, N(6)-debenzylation, aromatic
      hydroxylation, and C2 side chain oxidation of bohemine. Three of the primary
      metabolites detected, 6-(benzylamino)-2-(3-hydroxypropylamino)purine (M4), 6
      amino-2-(3-hydroxypropylamino)-9-isopropylpurine (M5) and 6-(4
      hydroxybenzylamino)-2-(3-hydroxypropylamino)-9-isopropylpurine (M6), all
      retaining their parent primary hydroxyl group, were subsequently shown to be
      converted, by a liver cytosolic NAD(+)-dependent system, into their corresponding
      carboxylic acids. M6 was subject to microsomal glycosidations requiring UDP-sugar
      donors. NADPH-dependent conversion of M6 into M5 by microsomes was also
      demonstrated. 4. Cytochrome P450 (CYP) enzymes-selective inhibitors were used to
      identify CYPs involved in bohemine biotransformation. The findings suggested that
      CYP2a and CYP3a substantially contributed to the NADPH-dependent bohemine
      transformation in vitro. 5. The findings will facilitate experiments designed to
      dissect enzymatic systems catalysing clearance of C2,C6,N9-trisubstituted purine
      compounds from mammalian tissues.

PMID- 12487732
TI  - Induction of cytochrome P4501A1 by autoclavable culture medium change in HepG2
      cells.
AB  - 1. Without the addition of xenobiotics, only by changing the culture medium can
      one induce extensively and transiently cytochrome P4501A1 (CYP1A1) protein and
      mRNA in human hepatoma HepG2 cells. The induction was aryl hydrocarbon receptor
      (AhR)-dependent, and was proven by: (1) the medium change activated the AhR, as
      judged by a electrophoretic mobility shift assay; and (2) the AhR inhibitor alpha
      naphthoflavone inhibited the medium change-mediated induction. 2. Induction of
      CYP1A1 was related to medium prepared by autoclaving. By screening the
      ingredients in the medium, the serum had no effect on CYP1A1 induction, whereas
      both photo-oxidized and autoclaved tryptophan were shown to induce CYP1A1, as
      indicated by CYP1A1 protein or ethoxyresorufin-O-deethylase activity. The
      autoclaved tryptophan contained in an autoclavable medium was a more potent
      inducer of CYP1A1 than photo-oxidized tryptophan. 3. The results provide some
      practical suggestions with experiments related to CYP1A1.

PMID- 12487733
TI  - Disposition of LY333531, a selective protein kinase C beta inhibitor, in the
      Fischer 344 rat and beagle dog.
AB  - 1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the
      disposition of LY333531 and its equipotent active des-methyl metabolite,
      LY338522, both potent and selective inhibitors of the beta-isozyme of protein
      kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mg
      kg(-1) oral dose of (14)C-LY333531. Urine, faeces, bile and plasma were collected
      and analysed for (14)C, LY333531 and LY338522. 3. LY333531 was eliminated
      primarily in the faeces (91% by 120 h in rat, 90% by 96 h in dog). Bile
      contributed the majority of the radioactivity excreted in the faeces in rat (66%
      in the cannulated bile duct study) and a variable but significant proportion in
      dog. 4. Pharmacokinetics following a single 5 mg kg(-1) oral dose of (14)C
      LY333531 to the male rat produced C(max) and AUC(0-infinity ) for LY333531 of
      14.7 ng ml(-1) and 60.8 ng h ml(-1), respectively, with a half-life of 2.5 h.
      LY338522 and total radioactivity showed similar profiles. 5. In the female dog at
      the same dose, C(max) and AUC(0-infinity ) of LY333531 were higher, producing 245
      +/- 94 ng ml(-1) and 1419 +/- 463 ng h ml(-1), respectively, with a half-life of
      5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat
      and dog.

PMID- 12487734
TI  - Phenotype distribution and gender-related differences of CYP2E1 activity in a
      Chinese population.
AB  - 1. The aim was to investigate the phenotype distribution characteristic and
      gender-related differences of CYP2E1 activity in a healthy Chinese population. 2.
      Two hundred and three healthy Chinese subjects (105 men, 98 women) were enrolled
      in this study. 3. CYP2E1 activity was determined by plasma 6-hydroxychlorzoxazone
      to-chlorzoxazone concentration ratio (CHZ-MR) 4h after chlorzoxazone dosing. The
      concentrations of 6-hydroxychlorzoxazone and chlorzoxazone in plasma were
      detected by reversed-phase HPLC. 4. The results showed an almost 9-fold variation
      of CYP2E1 activity at a range of from 0.23 to 1.99. The coefficient of variation
      CY % was demonstrated with skewness and kurtosis of the ratios in the studied
      population were 44%, 0.96 and 1.10, respectively. 5. CYP2E1 activity was normally
      distributed in logarithmic form of 6-OH-CHZ/CHZ as evaluated by Kolmogorov
      Smirnov test of normality (p = 0.20). Probit plots of the CYP2E1 activity index
      of men shifted to the right as compared with that of women. The mean CHZ-MR in
      men was significantly higher than that in women (0.76 +/- 0.30 versus 0.60 +/-
      0.28, p < 0.001), and this difference still existed when normalized by weight
      (0.73 +/- 0.28 versus 0.66 +/- 0.32, p = 0.016). Body weight correlated
      positively with CYP2E1 activity in the total group(r < 0.212, p < 0.01).

PMID- 12487735
TI  - Production of serum-free and total prostate-specific antigen due to prostatic
      intraepithelial neoplasia.
AB  - OBJECTIVE: High serum total prostate-specific antigen (PSA) levels have proven to
      be predictive of concurrent cancer but the role of prostatic intraepithelial
      neoplasia (PIN) in the production of total (t) and free (f) PSA is still the
      subject of research. In this study we wanted to discover whether variations in
      serum fPSA and tPSA levels are caused by PIN. MATERIAL AND METHODS: We reviewed
      the medical records of 87 patients: in 32 of them the diagnosis of isolated PIN
      was made from surgical samples (simple prostatectomy, n = 19; radical cystectomy,
      n = 13); in 30 patients a diagnosis of benign prostatic hyperplasia (BPH) without
      PIN or prostatic carcinoma was made after simple prostatectomy (n = 20) or
      radical cystectomy (n = 10); and in 25 patients a clinically significant
      prostatic cancer was diagnosed and these patients underwent radical
      prostatectomy. All patients underwent a standard preoperative evaluation,
      including serum fPSA and tPSA determinations and PSA density. RESULTS: The
      frequency of isolated PIN in simple prostatectomy specimens was 6.3%. The mean
      f/t PSA ratios were 17.66% in the 32 patients with PIN, 19.2% in the 8 patients
      with low-grade PIN, 17.6% in the 24 patients with high-grade PIN, 24.2% in
      patients with BPH and 13% in patients who underwent radical prostatectomy.
      CONCLUSIONS: We believe that to make a definitive diagnosis of isolated PIN
      without carcinoma, study of the whole prostate gland is necessary, in order to
      definitively exclude the presence of concurrent neoplastic foci. Our data show
      that PIN does not contribute to tPSA levels and density; however, it may be
      responsible for a slight reduction in the f/t PSA ratio, with a significant
      reduction in cases with high-grade PIN (17.6%) compared to those with BPH
      (24.2%).

PMID- 12487736
TI  - Calculated fast-growing benign prostatic hyperplasia--a risk factor for
      developing clinical prostate cancer.
AB  - OBJECTIVE: Whether there is an association between the development of benign
      prostatic hyperplasia (BPH) and clinical prostate cancer is controversial. The
      present report tests the hypothesis of an association between BPH growth and the
      development of clinical prostate cancer by examining stage, grade and PSA-level
      in men with recently discovered clinical prostate cancer with slow or fast
      growing BPH. If the hypothesis is true, men with fast-growing BPH would have a
      more advanced clinical prostate cancer. MATERIAL AND METHODS: Two hundred and
      twenty patients in whom a clinical prostate cancer was diagnosed were
      consecutively included. The prevalence of atherosclerotic disease, non-insulin
      dependent diabetes mellitus (NIDDM) or treated hypertension was provided by the
      respective patient's medical history. Tallness, body weight, waist measurement,
      hip measurement and blood pressure were determined. The body mass index (BMI) and
      waist/hip ratio (WHR) were calculated. Blood samples were drawn to determine
      triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol, uric acid,
      ALAT and the fasting plasma insulin level. The prostate gland volume was measured
      using transrectal ultrasound. The annual BPH growth rate was calculated, assuming
      that the total prostate gland volume was 20 mL at the patient age of forty. The
      prostate cancer diagnosis was established using the technique of transrectal
      ultrasound-guided automatic needle biopsy of the prostate. RESULTS: Men with
      clinical prostate cancer, PSA <50 ng/mL, and with fast-growing BPH had a higher
      systolic (p = 0.009) and diastolic (p = 0.020) blood pressure, were taller (p <
      0.001) and more obese, as determined by body weight (p < 0.001), BMI (p = 0.005),
      waist measurement (p < 0.001) and hip measurement (p = 0.003). They also had a
      higher fasting plasma insulin level (p = 0.014) and a lower HDL-cholesterol level
      (p = 0.067) than men with slow-growing BPH. Moreover, men with clinical prostate
      cancer, PSA <50 ng/mL, and fast-growing BPH had more pronounced clinical prostate
      cancer, as measured by grade (p = 0.029) and PSA-level (p = 0.016), than men with
      slow-growing BPH. In the total material, including men with clinical prostate
      cancer, PSA >/=50 ng/mL, men with fast-growing BPH also had a higher prevalence
      of NIDDM (p = 0.039) and a borderline statistical significance for higher stage
      (p = 0.09) than men with slow-growing BPH. The BPH growth rate was significantly
      associated with the clinical prostate cancer grade (p = 0.018) and PSA-level (p =
      0.002) but not with the clinical cancer stage in a multivariate statistical
      analysis. CONCLUSIONS: This report confirms findings in previous studies that
      fast-growing BPH is a risk factor for NIDDM, hypertension, tallness, obesity,
      dyslipidaemia and hyperinsulinaemia. The present report extends this list of risk
      factors to include atherosclerotic disease manifestations, hyperuricaemia and
      higher ALAT levels. The study suggests that fast-growing BPH is a risk factor for
      developing clinical prostate cancer and, thus, supports the hypothesis of an
      association between the development of BPH and clinical prostate cancer. The
      study generates the hypothesis that clinical prostate cancer is a component of
      the metabolic syndrome and that insulin is a promoter of clinical prostate
      cancer.

PMID- 12487738
TI  - The cost of bladder tumour treatment and follow-up.
AB  - OBJECTIVE: To evaluate the costs of bladder tumour treatment and follow-up.
      MATERIAL AND METHODS: The incidence of bladder tumours, both new and recurrences,
      and the cost of bladder tumour treatments with curative intent were registered
      during a 4-year period (1994-97). RESULTS: The incidence of new tumours varied
      from year to year, in contrast to the number of recurrent tumours, which remained
      remarkably stable. The total cost of bladder cancer diagnosis, treatment and
      follow-up was almost 7,000,000 SEK per year (2,800,000 SEK per 100,000
      inhabitants per year). The number of therapeutic events per year remained stable
      at 256 +/- 17 (102 per 100,000 inhabitants per year). Cystectomies were
      responsible for 34% of the expenditure and transurethral procedures for 40%.
      Follow-up cystoscopies accounted for only 13% of the total cost. One-third of the
      routine follow-up cystoscopies resulted in a therapeutic procedure. The cost of
      transurethral resections and extirpations was approximately five times higher
      when performed with the patient hospitalized compared to when performed as day
      care surgery. CONCLUSIONS: A reduction in the number of follow-up cystoscopies
      will only produce marginal economic savings. Further savings could be made if
      more transurethral resections and extirpations/fulgurations were performed on an
      outpatient basis. Another important goal is to reduce the median cost per
      cystectomy.

PMID- 12487737
TI  - An organ-sparing treatment using combined intra-arterial chemotherapy and
      radiotherapy for muscle-invading bladder carcinoma.
AB  - OBJECTIVE: We describe the results of an organ-sparing approach for the treatment
      of non-metastatic, invasive bladder carcinoma. MATERIAL AND METHODS: Twenty-three
      patients (mean age 71 years; age range 47-87 years) with bladder carcinoma of
      clinical stage T2-T3N0M0 and histologically proven muscle invasion were examined
      between 1992 and 1998. The median duration of follow-up was 30 months. The
      treatment protocol for intra-arterial chemotherapy consisted of methotrexate 30
      mg/m(2) and cisplatin 50 mg/m(2) in 7 patients and cisplatin 50 mg/m(2) in 16
      patients, administered in three cycles via catheters inserted in the internal
      iliac arteries. Concomitantly, 41.4 Gy of radiotherapy was given to the lesser
      pelvis. Transurethral biopsy and urine cytology were performed after the
      completion of treatment; patients were followed observationally if residual tumor
      was absent, and underwent radical cystectomy if it was present. RESULTS: At the
      end of treatment, 18 patients (78%) showed a complete response (CR) and the
      bladder was spared in all cases. Radical cystectomy was performed for 4 non-CR
      cases, with the result that 2 cases had residual superficial cancer and the other
      2 had muscle-invading cancer histologically. Among the patients with a CR, 2
      experienced intravesical recurrence. Overall, 2 patients died of cancer, 5 died
      of other causes and 2 died during treatment. The 5-year disease-specific survival
      rate was 70.3% and the overall survival rate 46.4%. CONCLUSIONS: A bladder
      sparing approach for the treatment of muscle-invading bladder carcinoma which
      utilizes combined intra-arterial chemotherapy and radiotherapy may arrest the
      decline in quality of life induced by urinary diversion and yield equivalent
      therapeutic benefit to that of radical cystectomy.

PMID- 12487739
TI  - Demographics of enuresis patients attending a referral centre.
AB  - OBJECTIVE: To study and compare the demography of enuretic children 7-16 years
      old attending a tertiary referral centre for childhood urinary incontinence, with
      that of normal children and what is generally known about enuretics from
      population-based studies. METHODS AND MATERIALS: This was a retrospective
      analysis of data compiled from 298 enuretic patients referred to The Centre of
      Child Incontinence, Aarhus University Hospital, Skejby, Denmark, and 53 healthy
      controls. Data was obtained by conducting standardised questionnaire interviews.
      Patients were stratified according to accompanying symptoms and severity of
      enuresis. Statistical analysis of the results was then performed. RESULTS: Two
      hundred and ninety-three patients had sufficient data registered to allow
      reliable analysis. Male-female ratio was 2.2:1. Primary and secondary enuresis
      was found in 87.4% and 11.6% of the patients respectively. Enuresis was
      associated with a reported history of bronchial asthma (p < 0.05), verified
      allergy (p < 0.05) and a positive family history of the same disorder (p < 0.01).
      No association with psycho-developmental factors was evident. Approximately 98%
      of the patients had undergone some form of therapy at presentation. 74.1% of the
      patients had pure monosymptomatic enuresis, 16.4% had day and night time
      incontinence, while the remaining 9.6% had nocturnal incontinence combined with
      other lower urinary tract symptoms other than daytime wetting. CONCLUSIONS: The
      demography of our patient population was, with a few exceptions, within the
      confines of what has previously been reported. Our results also reaffirmed the
      heterogeneity of enuretic patients.

PMID- 12487740
TI  - Voiding habits and wetting in a population of 4,332 Belgian schoolchildren aged
      between 10 and 14 years.
AB  - OBJECTIVE: To determine the prevalence of daytime- with/without night-time
      wetting, in Belgium, in a group of 10 to 14 year old schoolchildren, and to study
      the voiding habits. SUBJECTS AND METHODS: A questionnaire of 41 questions was
      developed and completed by 4,332 parents at home. RESULTS: Wetting or soiling
      episodes were reported by a total of 528 (12%) of the children: monosymptomatic
      nocturnal enuresis by 62 (1%), daytime wetting with/without night-time wetting by
      343 (8%), and faecal soiling by 123 (3%). We found significantly more girls in
      the wetting group, and the capacity to regularly postpone the voiding was
      significantly lower in this group. Significantly more children had nocturia in
      the group with wetting. CONCLUSIONS: Children with daytime wetting with/without
      night-time wetting have very often bladder-sphincter dysfunctions, which is in
      turn correlated with recurrent urinary tract infections. Eight percent of the 10
      to 12 year old schoolchildren report daytime wetting with/without night-time
      wetting with some frequency. Surprisingly few parents, especially in the daytime
      wetting group, searched for medical help. Physicians and paediatricians should be
      encouraged to be more attentive to wetting in children and initiate discussion
      about urinary en faecal problems with parents and children.

PMID- 12487741
TI  - Clinical experience and results of ESWL treatment for 3,093 urinary calculi with
      the Storz Modulith SL 20 lithotripter at the Singapore general hospital.
AB  - We study the outcome of 2,700 patients treated for 3,093 urinary calculi over a
      period of 60 months. All patients underwent Extracorporeal Shock Wave Lithotripsy
      (ESWL) treatment using the Storz Modulith SL20, predominantly on an outpatient
      basis (99.9% using intravenous pethidine for analgesia). The treatment outcome of
      1,666 renal calculi and 1,427 ureteric calculi were analysed and stratified
      according to size and site. Follow-up status at 3 months was available for 91.8%
      of patients. For renal calculi, the overall success rate was 81% (re-treatment
      rate 29.7%). The majority of failures were stones larger than 2 cm and those
      situated in the lower pole of the renal calyces. The overall success rate for
      ureteric calculi is 85% with similar clearance rates throughout the ureter (re
      treatment rate 22.8%). Failures were predominantly with stones larger than 2 cm.
      For the entire series, the morbidity rate requiring hospital admission was 2.9%,
      there was no mortality. The commonest cause for admission was for pain control
      (1.8%). To our knowledge, our experience with this lithotriptor is the largest to
      date. We have demonstrated that ESWL with Storz Modulith SL20 is safe, well
      tolerated and highly effective for the treatment of urolithiasis.

PMID- 12487742
TI  - The diagnostic value of the phosphate levels in serum and 24-hour urine samples
      in patients with recurrent renal stone disease.
AB  - OBJECTIVE: The aim of this study is to investigate the value of phosphate levels
      in serum and urine in patients with recurrent renal stone disease. MATERIALS AND
      METHODS: The patients (n:60) were divided into two groups as first-time stone
      disease (group 1) and recurrent renal stone disease (group 2). The demographical
      datas and their historical information were recorded and physical examination was
      done. The sera and urine for 24 hr were obtained from patients to measure
      electrolyte levels especially phosphorus. In addition, based on presenting serum
      phosphate levels, patients were divided into the hypophosphatemia group, less
      than 2.5 mg/dl; normophosphatemia group, between 2.5-5.2 mg/dl; and
      hyperphosphatemia group greater than 5.2 mg/dl. RESULTS: The mean age of study
      group was 45 (21-70) years. Thirty-six patients (60%) were in group 1 and 24
      patients (40%) were in group 2. No statistically correlation was found between
      stone recurrence and phosphate levels both in serum and urine. There was only a
      statistical association of K levels in 24-hour urine samples between group 1 and
      2. CONCLUSION: There was no significant association between stone recurrence and
      initial phosphate levels in the serum or in urine. We do not propose to determine
      phosphate levels routinely in management of patients with stone disease.

PMID- 12487743
TI  - Management of vascular access for hemodialysis after successful kidney
      transplantation.
AB  - OBJECTIVE: There is a lack of data concerning the fate of arterio-venous fistulas
      (AVF) after successful kidney transplantation. The objective of this study was to
      assess the evolution of AVF in transplanted patients and to discuss the
      management of such vascular access once dialysis has been stopped. MATERIAL AND
      METHODS: We reviewed 160 renal transplant patients who had undergone an AVF 0 to
      312 months (mean 29) before transplantation. 136 (85%) of AVF were created in the
      forearm/wrist region and 21 (13%) at the elbow. RESULTS: The mean follow-up was
      69 months from renal transplantation and 95 months from constitution of the AVF.
      Vascular access had to be closed in 7.5% of cases. Thrombosis occurred in 31% of
      cases, mainly in distal fistulas (85%). AVF was still functional in 61% of
      patients at the end of follow-up. CONCLUSION: AVF remains functional in the
      majority of patients after renal transplantation and is not usually associated
      with any significant morbidity. Systematic closure of AVF does not seem warranted
      as it would deprive patients of a useful vascular access should dialysis become
      again necessary in the long term.

PMID- 12487744
TI  - Low response to HBsAg vaccine in chronic renal failure patients is not due to
      intrinsic defect of B cells.
AB  - OBJECTIVE: The aim of this study was to investigate whether the inability of
      chronic renal failure patients to mount an adequate antibody response following
      hepatitis B vaccination was due to an inherent defect in the antibody producing
      capacity of their B cells. MATERIAL AND METHODS: Peripheral blood mononuclear
      cells of end stage renal disease (ESRD) patients, who were not on maintenance
      hemodialysis (CRF) and those undergoing long-term hemodialysis (HD) were
      stimulated in vitro with pokeweed mitogen, a B cell mitogen or hepatitis B
      surface antigen. The total immunoglobulin (IgG, IgM and IgA) levels and anti-HBs
      specific IgM and IgG were quantitiated by sandwich ELISA and levels between
      patients who had a good antibody response in vivo and those who failed to mount
      an antibody response were compared. RESULTS: Spontaneous IgG production was
      significantly higher than normals in CRF and HD group; PWM induced IgM, IgG and
      IgA production was comparable to normals in both groups of patients. The
      spontaneous IgG and PWM stimulated IgM and IgG production was significantly
      higher in HD patients as compared to CRF. The in vitro Ig levels in the vaccine
      responders and non-responders was comparable except for the spontaneous IgG which
      was highest in the responders. The in vitro anti-HBs production was comparable in
      HB vaccine responders and non-responders; the in vivo and in vitro anti-HBs
      titers showed a significant correlation coefficient thereby indicating that the
      in vitro assay reflects the in vivo functional status of B cells. CONCLUSION: Our
      results demonstrate that the B cells in ESRD patients are functionally normal and
      cannot be the cause of the compromised vaccine response in these patients.

PMID- 12487745
TI  - Late onset classical seminoma in a sib pair with possible familial aetiology.

PMID- 12487746
TI  - Intrascrotal neurofibroma.

PMID- 12487747
TI  - Testicular seminoma presenting 22 years after treatment for extra-gonadal germ
      cell tumour.
AB  - We report an interesting case of testicular seminoma in a 57-year-old man who had
      received treatment for a pulmonary extra-gonadal seminoma 22 years previously.
      This case indicates that patients with extra-gonadal germ-cell tumours should
      either be followed up for life or, if discharged, should be informed of the
      potential risk of developing testicular tumour in the future and advised of the
      need for regular self-testicular examination.

PMID- 12487748
TI  - Massive peri-renal haemorrhage from ruptured renal artery aneurysm in the
      presence of normal renal function.
AB  - A 65-year-old man presented acutely with a large right peri-nephric haematoma as
      seen on a CT scan. Intravenous urography demonstrated normal function. An
      arteriogram later revealed a 1 cm renal artery tributary aneurysm, which was
      successfully embolized.

PMID- 12487749
TI  - Clinical and radiological evolution of a case of idiopathic retroperitoneal
      fibrosis treated with Tamoxifen.
AB  - The authors report a case of retroperitoneal fibrosis conservatively treated with
      Tamoxifen. The computerized tomography (TC) control at ten months showed the
      persistence of a slight residual of peri-aortic fibrotic tissue. This result
      allowed removal of the double J catheter.

PMID- 12487750
TI  - Immediate improvement of a persistent cough after tumor embolization for renal
      cell carcinoma--a rare manifestation of paraneoplastic syndrome.
AB  - We report an interesting case of a patient with renal cell carcinoma who
      developed a refractory cough, which immediately resolved after tumor
      embolization. Patient's symptoms including low-grade fever, weight loss, and
      abnormal laboratory results also improved shortly after subsequent nephrectomy.
      The clinical manifestations of the patient are most likely representing
      paraneoplastic syndrome secondary to renal cell carcinoma.

PMID- 12487751
TI  - Spontaneous regression of pleural metastases after nephrectomy for renal cell
      carcinoma--a histologically verified case with nine-year follow-up.
AB  - Spontaneous regression of metastatic renal cell carcinoma is a rare but well
      documented event, most often involving pulmonary metastases. A case of
      spontaneous regression of histologically verified pleural metastases after
      nephrectomy is reported.

PMID- 12487752
TI  - Dietary compounds in relation to dietary diversity and human health.
AB  - The human diet contains numerous endocrine-active compounds that influence
      mammalian physiology. The effects of these dietary compounds may be mediated by
      interaction with well-characterized intracellular hormone receptors or by other
      effects on patterns of endogenous hormone production, metabolism, target tissue
      signaling, growth, or differentiation. Because humans evolved as omnivores, the
      spectrum of dietary compounds that can be tolerated at modest levels of intake
      without frank toxicity is broad. Modest intake of these diverse nonnutritive
      endocrine-active compounds offers potential human health benefits through
      modulation of metabolic and hormonal responses, especially in sedentary
      individuals consuming a highly refined diet.

PMID- 12487753
TI  - Synergistic antioxidative properties of phenolics from natural origin toward low
      density lipoproteins depend on the oxidation system.
AB  - Using an approach in line with that of a previous report, we assessed the
      antioxidant activity of several natural, polyphenol- or tocotrienol-rich
      mixtures: extracts from Elaesis Guineensis oil (A) and Vitis vinifera (B), a
      Coffea robusta powder (C), and extracts from Olea europea mill wastewaters (D),
      Solanum melongena (E), and Lycopersicon esculentum (F). The copper- and 2-2'
      azobis(2-amidinopropane) hydrochloride (AAPH)-oxidation systems were used in the
      presence of low-density lipoprotein. For comparison, antioxidant activities of
      chlorogenic acid and catechin, as archetypes of molecules highly efficient with
      the copper- and the AAPH-oxidation system, respectively, were assessed. The aim
      was to establish the occurrence of synergistic antioxidant actions among some of
      these natural mixtures. On a molar basis, the highest specific antioxidant
      activities (SAA) were found for B, chlorogenic acid, and C in the copper system,
      and for A, catechin, and B in the AAPH system. On a mass basis, the highest SAA
      were found, respectively, for chlorogenic acid, B, and catechin, and for
      catechin, chlorogenic acid, and B. These results show that large discrepancies
      take place in the evaluations between the two systems. B and C exhibited a
      synergistic antioxidant efficiency, in the presence or absence of A, but only
      with the copper system. This was also true for the two types of A+B+C mixture
      that were tested. It is thought that this association might provide an ideal
      combination, incorporating both the radical scavenger and the transition-metal
      ion chelation properties of B and C.

PMID- 12487754
TI  - Antioxidant properties of carboxymethyl glucan: comparative analysis.
AB  - Antioxidative capabilities of carboxymethylated (1 --> 3)-beta-D-glucan from
      Saccharomyces cerevisiae cell wall, alpha-tocopherol, and mannitol against lipid
      peroxidation in phosphatidylcholine liposomes induced by OH. radicals produced
      with Fenton's reagent (H(2)O(2)/Fe(2+)) were studied using absorption ultraviolet
      visible spectrophotometry. It was found that (1 --> 3)-beta-D-glucan is an
      antioxidant with the scavenging ability lying between that of alpha-tocopherol,
      which is known to be incorporated in the lipid bilayer, and the water-soluble
      antioxidant, mannitol.

PMID- 12487755
TI  - Growth characteristics and selenium status changes of yeast cells with inorganic
      and organic selenium supplementation: selenium, a chemopreventive agent.
AB  - We attempted to determine the level and form of selenium (Se) that yielded the
      maximum Se status of yeast cells, for their evaluation as a source of Se for
      chemopreventive action. The influence of various Se concentrations from organic
      (selenomethionine) and inorganic (sodium selenite) Se compounds on growth pattern
      and cell viability and the alterations in the antioxidant enzyme system of yeast
      were evaluated. A continuous decrease in cell and colony-forming units counts was
      observed with increasing concentrations of Se from either source. Increasing Se
      status of yeast cells was found with increasing concentrations of Se with both
      forms, with much greater uptake for organic Se at maximum Se concentrations. A
      continuous increase in glutathione peroxidase (GSH-Px) activity with increasing
      Se concentrations in both forms revealed an active Se response in terms of
      antioxidant activity, with a more pronounced percentage increase with
      selenomethionine. A highly significant increase in total glutathione was observed
      with selenomethionine supplementation, compared with sodium selenite. A
      decreasing trend in reduced glutathione was observed with increasing organic or
      inorganic Se concentrations. An increasing trend in glutathione-S-transferase
      activity was observed with increasing Se concentrations for both forms.
      Significantly higher values of glutathione-S-transferase were associated with the
      organic form at higher Se concentrations. There was normal activity of Se in
      mammalian cells. The results showed that an organic Se source more greatly
      enhances the Se status of yeast cells and hence could help in chemoprevention if
      consumed by the population.

PMID- 12487756
TI  - Hypocholesterolemic effect of spirulina in patients with hyperlipidemic nephrotic
      syndrome.
AB  - In nephrotic syndrome, large amounts of plasma proteins are lost in urine,
      causing a decrease in the plasma oncotic pressure. This leads to enhanced hepatic
      synthesis of albumin and other proteins, including lipoproteins, causing a
      secondary hyperlipidemia. Essential fatty acids such as gamma-linolenic acid
      (GLA) can prevent accumulation of cholesterol in the body, and spirulina has an
      appreciable amount of GLA. In this study 23 patients (age 2 to 13 years) with
      nephrotic syndrome received either medication (group I) or medication plus 1
      g/day Spirulina (group II). Height, weight, and serum levels of fasting blood
      sugar, triglycerides, total cholesterol (TC), and low- and high-density
      cholesterol fractions (LDL-C and HDL-C, respectively) were measured before and
      after the 2-month study period. Mean height and weight were normal compared with
      healthy, age-matched Indian children. Lipoprotein cholesterol levels were
      significantly increased at baseline. TC significantly decreased by 116.33 mg/dl,
      LDL-C by 94.14 mg/dl, and triglycerides by 67.72 mg/dl in group II; in control
      group I, these values fell by 69.87, 61.13, and 22.62 mg/dl, respectively. The
      LDL-C:HDL-C ratio also decreased significantly, by 1.66 in group II and 1.13 in
      group I. TC:HDL-C decreased by 1.96 in group II and 1.19 in group I. HDL-C:LDL-C
      also improved significantly in both the groups. It can be concluded that spray
      dried Spirulina capsules, rich in antioxidants, GLA, amino acids, and fatty
      acids, helped reduce the increased levels of lipids in patients with
      hyperlipidemic nephrotic syndrome.

PMID- 12487758
TI  - Fast and accurate phylogeny reconstruction algorithms based on the minimum
      evolution principle.
AB  - The Minimum Evolution (ME) approach to phylogeny estimation has been shown to be
      statistically consistent when it is used in conjunction with ordinary least
      squares (OLS) fitting of a metric to a tree structure. The traditional approach
      to using ME has been to start with the Neighbor Joining (NJ) topology for a given
      matrix and then do a topological search from that starting point. The first stage
      requires O(n(3)) time, where n is the number of taxa, while the current
      implementations of the second are in O(p n(3)) or more, where p is the number of
      swaps performed by the program. In this paper, we examine a greedy approach to
      minimum evolution which produces a starting topology in O(n(2)) time. Moreover,
      we provide an algorithm that searches for the best topology using nearest
      neighbor interchanges (NNIs), where the cost of doing p NNIs is O(n(2) + p n),
      i.e., O(n(2)) in practice because p is always much smaller than n. The Greedy
      Minimum Evolution (GME) algorithm, when used in combination with NNIs, produces
      trees which are fairly close to NJ trees in terms of topological accuracy. We
      also examine ME under a balanced weighting scheme, where sibling subtrees have
      equal weight, as opposed to the standard "unweighted" OLS, where all taxa have
      the same weight so that the weight of a subtree is equal to the number of its
      taxa. The balanced minimum evolution scheme (BME) runs slower than the OLS
      version, requiring O(n(2) x diam(T)) operations to build the starting tree and
      O(p n x diam(T)) to perform the NNIs, where diam(T) is the topological diameter
      of the output tree. In the usual Yule-Harding distribution on phylogenetic trees,
      the diameter expectation is in log(n), so our algorithms are in practice faster
      that NJ. Moreover, this BME scheme yields a very significant improvement over NJ
      and other distance-based algorithms, especially with large trees, in terms of
      topological accuracy.

PMID- 12487757
TI  - Effect of Phaseolus vulgaris on circulatory antioxidants and lipids in rats with
      streptozotocin-induced diabetes.
AB  - The effect of Phaseolus vulgaris, an indigenous plant used in ayurvedic medicine
      in India, on circulatory antioxidants and lipids was studied in rats with
      streptozotocin-induced diabetes. Oral administration of an aqueous extract of P.
      vulgaris pods (PPEt, 200 mg/kg body weight) for 45 days significantly reduced the
      elevated blood glucose, serum triglycerides, free fatty acids, phospholipids,
      total cholesterol, very-low-density lipoprotein cholesterol, and low-density
      lipoprotein cholesterol. The extract also caused a significant decrease in plasma
      thiobarbituric acid-reactive substances (TBARS), hydroperoxides, vitamin E, and
      ceruloplasmin. The decreased serum levels of high-density lipoprotein
      cholesterol, antiatherogenic index (AAI), plasma insulin, vitamin C, and
      glutathione in the diabetic rats were also reversed toward normalization. The
      results show the antioxidant and antihyperlipidemic properties of PPEt in
      addition to its antidiabetic action. PPEt was found to be more effective than
      glibenclamide.

PMID- 12487759
TI  - Mining protein sequences for motifs.
AB  - We use methods from Data Mining and Knowledge Discovery to design an algorithm
      for detecting motifs in protein sequences. The algorithm assumes that a motif is
      constituted by the presence of a "good" combination of residues in appropriate
      locations of the motif. The algorithm attempts to compile such good combinations
      into a "pattern dictionary" by processing an aligned training set of protein
      sequences. The dictionary is subsequently used to detect motifs in new protein
      sequences. Statistical significance of the detection results are ensured by
      statistically determining the various parameters of the algorithm. Based on this
      approach, we have implemented a program called GYM. The Helix-Turn-Helix motif
      was used as a model system on which to test our program. The program was also
      extended to detect Homeodomain motifs. The detection results for the two motifs
      compare favorably with existing programs. In addition, the GYM program provides a
      lot of useful information about a given protein sequence.

PMID- 12487760
TI  - A combinatorial toolbox for protein sequence design and landscape analysis in the
      grand canonical model.
AB  - In modern biology, one of the most important research problems is to understand
      how protein sequences fold into their native 3D structures. To investigate this
      problem at a high level, one wishes to analyze the protein landscapes, i.e., the
      structures of the space of all protein sequences and their native 3D structures.
      Perhaps the most basic computational problem at this level is to take a target 3D
      structure as input and design a fittest protein sequence with respect to one or
      more fitness functions of the target 3D structure. We develop a toolbox of
      combinatorial techniques for protein landscape analysis in the Grand Canonical
      model of Sun, Brem, Chan, and Dill. The toolbox is based on linear programming,
      network flow, and a linear-size representation of all minimum cuts of a network.
      It not only substantially expands the network flow technique for protein sequence
      design in Kleinberg's seminal work but also is applicable to a considerably
      broader collection of computational problems than those considered by Kleinberg.
      We have used this toolbox to obtain a number of efficient algorithms and hardness
      results. We have further used the algorithms to analyze 3D structures drawn from
      the Protein Data Bank and have discovered some novel relationships between such
      native 3D structures and the Grand Canonical model.

PMID- 12487761
TI  - A lower bound on the reversal and transposition diameter.
AB  - One possible model to study genome evolution is to represent genomes as
      permutations of genes and compute distances based on the minimum number of
      certain operations (rearrangements) needed to transform one permutation into
      another. Under this model, the shorter the distance, the closer the genomes are.
      Two operations that have been extensively studied are the reversal and the
      transposition. A reversal is an operation that reverses the order of the genes on
      a certain portion of the permutation. A transposition is an operation that "cuts"
      a certain portion of the permutation and "pastes" it elsewhere in the same
      permutation. In this note, we show that the reversal and transposition distance
      of the signed permutation pi(n) = (-1 -2.-(n - 1)-n) with respect to the identity
      is left floor n/2 right floor + 2 for all n>or=3. We conjecture that this value
      is the diameter of the permutation group under these operations.

PMID- 12487762
TI  - A novel approach to remote homology detection: jumping alignments.
AB  - We describe a new algorithm for protein classification and the detection of
      remote homologs. The rationale is to exploit both vertical and horizontal
      information of a multiple alignment in a well-balanced manner. This is in
      contrast to established methods such as profiles and profile hidden Markov models
      which focus on vertical information as they model the columns of the alignment
      independently and to family pairwise search which focuses on horizontal
      information as it treats given sequences separately. In our setting, we want to
      select from a given database of "candidate sequences" those proteins that belong
      to a given superfamily. In order to do so, each candidate sequence is separately
      tested against a multiple alignment of the known members of the superfamily by
      means of a new jumping alignment algorithm. This algorithm is an extension of the
      Smith-Waterman algorithm and computes a local alignment of a single sequence and
      a multiple alignment. In contrast to traditional methods, however, this alignment
      is not based on a summary of the individual columns of the multiple alignment.
      Rather, the candidate sequence is at each position aligned to one sequence of the
      multiple alignment, called the "reference sequence." In addition, the reference
      sequence may change within the alignment, while each such jump is penalized. To
      evaluate the discriminative quality of the jumping alignment algorithm, we
      compare it to profiles, profile hidden Markov models, and family pairwise search
      on a subset of the SCOP database of protein domains. The discriminative quality
      is assessed by median false positive counts (med-FP-counts). For moderate med-FP
      counts, the number of successful searches with our method is considerably higher
      than with the competing methods.

PMID- 12487764
TI  - Prevention in thyroidology.

PMID- 12487765
TI  - Epidemiology and prevention of clinical and subclinical hypothyroidism.
AB  - Iodine deficiency is the most common cause of hypothyroidism worldwide. In
      persons living in iodine-replete areas, causes are congenital, spontaneous
      because of chronic autoimmune disease (atrophic autoimmune thyroiditis or
      goitrous autoimmune thyroiditis [Hashimoto's thyroiditis]), or iatrogenic because
      of goitrogens, drugs, or destructive treatment for thyrotoxicosis. Screening for
      congenital hypothyroidism exists and its use prevents mental retardation. The
      prevalence of spontaneous hypothyroidism is between 1% and 2% and is more common
      in older women and 10 times more common in women than in men. A significant
      proportion of subjects have asymptomatic chronic autoimmune thyroiditis and 8% of
      women (10% of women over 55 years of age) and 3% of men have subclinical
      hypothyroidism. Approximately one third of patients with newly diagnosed overt
      hypothyroidism have received destructive therapy for hyperthyroidism and
      indefinite surveillance is required. There is not much that can be done to
      prevent the occurrence of spontaneous autoimmune hypothyroidism, but if
      identified early, something can be done to prevent progression to overt disease.
      Controversy exists as to whether healthy adults would benefit from screening for
      autoimmune thyroid disease because a significant proportion of subjects tested
      will have evidence of mild thyroid failure. Case finding in women at menopause or
      visiting a primary care physician with nonspecific symptoms appears justified.

PMID- 12487766
TI  - Reduction of the risk of relapse after withdrawal of medical therapy for Graves'
      disease.
AB  - It has been a continuing challenge to try and identify those patients with
      hyperthyroid Graves' disease likely to remain in remission after an antithyroid
      drug course or to manage the medical treatment so as to increase the chance of
      remission. On average, the overall relapse rate is approximately 50% and any
      significant reduction of this figure would be of practical as well as theoretical
      value. The numerous controlled prospective studies performed in many parts of the
      world, with varying iodine intakes, have all confirmed that the main initial
      features related to the subsequent risk of relapse are: young age, male gender,
      goiter larger than 40 mL, hypoechogenic and hypervascular gland, high level of
      anti-thyrotropin receptor antibody (TRAb), detected either with radioreceptor
      assay (TBII: >40 U/L) or the biologic stimulation assay (thyroid-stimulating
      antibodies [TSAb]; >300%), severity of hyperthyroidism, and possibly the presence
      of ophthalmopathy. Alone, each of these has a low predictive value, but together
      they allow evaluation of the risk of relapse, thus helping treatment choice. As
      to the modalities of antithyroid drug treatment, dose of the drug or addition of
      levothyroxine does not affect posttreatment outcome. In contrast, significantly
      fewer relapses occur for drug courses longer than at least 1 year. Persistence of
      high levels of TRAb after medical treatment is strongly predictive of relapse but
      this is of limited value because in most patients, TRAb levels are low or even
      undetectable at the end of treatment, which does not indicate for further
      outcome. Smoking is a significant independent risk factor for relapse. In
      conclusion, reduction of the risk of relapse in patients with medically treated
      hyperthyroid Graves' disease relies on clinical competence and appropriate
      management taking into account an array of factors none of which alone has
      definite predictive value.

PMID- 12487767
TI  - Epidemiology and prevention of Graves' ophthalmopathy.
AB  - Graves' ophthalmopathy is clinically relevant in approximately 50% of patients
      with Graves' disease, severe forms affecting 3%-5% of patients. Two age peaks of
      incidence are observed in the fifth and seventh decades of life, with slight
      differences between women and men. The disease is more frequent in women than in
      men, although the female-to-male ratio is only 1:4 in severe forms of eye
      disease. The natural history of Graves' ophthalmopathy is incompletely defined,
      but in many instances, especially in mild forms, the disease may remit or improve
      spontaneously. The onset of the ophthalmopathy is in most cases concomitant with
      the onset of hyperthyroidism, but eye disease may precede or follow
      hyperthyroidism. Cigarette smoking plays an important role in the occurrence of
      the ophthalmopathy, and is also associated with a higher degree of disease
      severity and a lower effectiveness of its medical treatment. Primary prevention
      (i.e., avoidance of the occurrence of the ophthalmopathy) is presently not
      feasible, but smoking withdrawal in relatives of patients with Graves' disease
      might be important. In terms of secondary prevention (i.e., avoidance of
      progression of subclinical eye disease into overt and severe ophthalmopathy) in
      addition to refraining from smoking, early and accurate control of thyroid
      dysfunction (both hyperthyroidism and hypothyroidism), as well as early diagnosis
      and treatment of mild eye disease are important. As to the role that management
      of hyperthyroidism may play in the course of Graves' ophthalmopathy, while
      antithyroid drugs and thyroidectomy are not disease-modifying treatments,
      radioiodine therapy causes a progression of the ophthalmopathy in approximately
      15% of patients, especially high-risk patients, who smoke, have severe
      hyperthyroidism or uncontrolled hypothyroidism, high levels of thyrotropin (TSH)
      receptor antibody, or preexisting eye disease. However, the risk of radioiodine
      associated progression of the opthalmopathy can be eliminated by concomitant
      treatment with middle-dose glucocorticoids. In terms of tertiary prevention
      (i.e., avoidance of deterioration and complications of overt disease) early
      immunosuppressive treatment or orbital decompression, as appropriate, are
      essential tools. Smoking withdrawal may increase the effectiveness of
      immunosuppressive treatment.

PMID- 12487768
TI  - Epidemiology and prevention of thyroid disease in pregnancy.
AB  - Pregnancy has variable effects on thyroid hormone concentrations throughout
      pregnancy as well as being associated with goiter. The latter is largely
      preventable by ensuring optimal iodine intake of at least 200 microg/d.
      Immunologic changes in pregnancy include a so-called T(H)2 shift that reverts to
      T(H)1 status around birth or early in the postpartum period. Hyperthyroidism
      during gestation, usually caused by Graves' disease, is rare (0.2%) and is best
      managed medically with propylthiouracil; thyroid-stimulating antibodies should be
      measured. Prevention of the deleterious effects of Graves' disease includes
      adequate preconception advice, adequate monitoring during pregnancy, and total
      avoidance of (131)I therapy during pregnancy. Hypothyroidism during pregnancy has
      an incidence of 2.5% although there is a 10% incidence of thyroid peroxidase
      (TPO)-antibody positivity in early gestation. There are convincing epidemiologic
      data to show that suboptimal thyroid function in pregnancy is associated with
      impaired neurointellectual development (e.g., 19% with IQ < 85 compared to 5% in
      one study). Therefore, there is a case for screening for thyroid function in
      early pregnancy with thyroxine (T(4)) intervention therapy. Maintenance of
      optimal iodine intake is critical to prevent nonautoimmune gestational maternal
      hypothyroxinaemia. Postpartum thyroid dysfunction (PPTD) occurs in 5%-9% of women
      and in up to 50% of TPO-antibody positive women (as ascertained in early
      pregnancy). Prevention of PPTD at this time could only be achieved by
      pregestational ablation of the thyroid. Another approach is to at least improve
      the prediction of postpartum thyroid disease (PPT) because the TPO antibody has a
      sensitivity of only 50%.

PMID- 12487769
TI  - The impact of iron and selenium deficiencies on iodine and thyroid metabolism:
      biochemistry and relevance to public health.
AB  - Several minerals and trace elements are essential for normal thyroid hormone
      metabolism, e.g., iodine, iron, selenium, and zinc. Coexisting deficiencies of
      these elements can impair thyroid function. Iron deficiency impairs thyroid
      hormone synthesis by reducing activity of heme-dependent thyroid peroxidase. Iron
      deficiency anemia blunts and iron supplementation improves the efficacy of iodine
      supplementation. Combined selenium and iodine deficiency leads to myxedematous
      cretinism. The normal thyroid gland retains high selenium concentrations even
      under conditions of inadequate selenium supply and expresses many of the known
      selenocysteine-containing proteins. Among these selenoproteins are the
      glutathione peroxidase, deiodinase, and thioredoxine reductase families of
      enzymes. Adequate selenium nutrition supports efficient thyroid hormone synthesis
      and metabolism and protects the thyroid gland from damage by excessive iodide
      exposure. In regions of combined severe iodine and selenium deficiency,
      normalization of iodine supply is mandatory before initiation of selenium
      supplementation in order to prevent hypothyroidism. Selenium deficiency and
      disturbed thyroid hormone economy may develop under conditions of special dietary
      regimens such as long-term total parenteral nutrition, phenylketonuria diet,
      cystic fibrosis, or may be the result of imbalanced nutrition in children,
      elderly people, or sick patients.

PMID- 12487770
TI  - Risk factors for goiter and thyroid nodules.
AB  - The occurrence of thyroid diseases is determined by interplay between genetic and
      environmental factors. The major environmental factor that determines goiter
      prevalence is iodine status, but other environmental factors influencing entire
      populations have been identified such as goitrogens in food and drinking water.
      Less focus has been on individual environmental factors and the interplay between
      factors. The goiter prevalence is higher in certain groups in the population. The
      variation in goiter prevalence between the genders is well known with a higher
      occurrence among women. The association with age is probably dependent on iodine
      status, because it seems that the zenith of goiter prevalence appears earlier in
      life the more severe iodine deficiency the population is exposed to. The
      association with individual risk factors has been investigated in some studies,
      especially the association with tobacco smoking. In iodine-deficient areas, a
      strong association between tobacco smoking and goiter prevalence is found,
      whereas the association is less pronounced in iodine-replete areas. This was
      predictable from experimental studies showing thiocyanate to be the mediator of
      the goitrogenic effect of tobacco smoke acting as a competitive inhibitor of
      iodine uptake. The association with alcohol intake has only been investigated in
      few studies, but a low occurrence of goiter among alcohol consumers has been
      found. The mechanism of this association is not known. Increased goiter
      prevalence during pregnancy has been reported, and recently a long-term
      goitrogenic effect of pregnancies has also been shown. As demonstrated for
      tobacco smoking, this association is dependent on iodine status, because the
      association has only been found in areas with a suboptimal iodine intake. This
      indicates pregnancy-induced goiter to be the result of exacerbation of existing
      iodine deficiency. Recently, the use of oral contraceptives has been shown to be
      associated with a markedly reduced prevalence of goiter, although experimental
      studies have previously shown proliferative effects of estrogens on thyrocytes.
      Some implications for prevention of thyroid disease could be suggested.
      Discussion of smoking habits should be included in a consultation for goiter with
      a motivation to quit smoking. Iodine deficiency has particularly strong
      goitrogenic effects during pregnancy and for the sake of the mother as well as
      the fetus, sufficient iodine supply should be ensured to all pregnant women. The
      difference in age maximum in goiter prevalence suggests that monitoring of iodine
      deficiency disorders should ideally include a spectrum of age groups.

PMID- 12487771
TI  - Epidemiology and primary prevention of thyroid cancer.
AB  - The purpose of this review is to provide an account of our present knowledge
      about the epidemiology of nonmedullary thyroid carcinoma, to discuss the effects
      of environment, lifestyle and radiation on the risk of developing thyroid cancer,
      and to discuss aspects on primary prevention of the disease. In areas not
      associated with nuclear fallout, the annual incidence of thyroid cancer ranges
      between 2.0-3.8 cases per 100,000 in women and 1.2-2.6 per 100,000 in men, women
      of childbearing age being at highest risk. Low figures are found in some European
      countries (Denmark, Holland, Slovakia) and high figures are found in Iceland and
      Hawaii. Differences in iodine intake may be one factor explaining the geographic
      variation, high iodine intake being associated with a slightly increased risk of
      developing thyroid cancer. In general, lifestyle factors have only a small effect
      on the risk of thyroid cancer, a possible protective effect of tobacco smoking
      has been recently reported. Because of the (small) increase in risk of thyroid
      cancer associated with iodination programs, these should be supervised, so that
      the population does not receive excess iodine. The thyroid gland is highly
      sensitive to radiation-induced oncogenesis. This is verified by numerous reports
      from survivors after Hiroshima and Nagasaki, the Nevada, Novaja Semlja and
      Marshal Island atmospheric tests, and the Chernobyl plant accident, as well as by
      investigations of earlier medical use of radiation for benign diseases in
      childhood. These reports are summarized in the review. There appears to be a dose
      response relation for the risk of developing cancer after exposure to radioactive
      radioiodine. The thyroid gland of children is especially vulnerable to the
      carcinogenic action of ionizing radiation. Thus, the incidence of thyroid cancer
      in children in the Belarus area was less than 1 case per million per year before
      the Chernobyl accident, increasing to a peak exceeding 100 per million per year
      in certain areas after the accident. It is a social obligation of scientists to
      inform the public and politicians of these risks. All nuclear power plants should
      have a program in operation for stockpiling potassium iodide for distribution
      within 1-2 days after an accident.

PMID- 12487772
TI  - Thiocyanate in food and iodine in milk: from domestic animal feeding to improved
      understanding of cretinism.
AB  - Transport of iodine in the mammary gland into breast milk plays a central role in
      various fields of prevention of thyroid diseases. First, a sufficient content of
      iodine in the mother's milk is necessary for normal brain development in the
      breastfed child. This is attained by expression during lactation in the mammary
      gland of the sodium iodide symporter (NIS), also responsible for iodine transport
      in the thyroid. Milk iodine content varies with the iodine intake of the mother,
      and urinary iodine excretion in groups of mothers seems to be a valuable
      indicator of the iodine status of their breastfed children. Second, iodine in
      dairy products provides a considerable part of iodine intake in many populations.
      Thiocyanate from rapeseed feeding of cows decreases milk iodine content, probably
      by competitive inhibition of NIS in the mammary gland. Alterations in feeding of
      dairy cows may alter the iodine content of consumer milk, and this may influence
      the risk of thyroid diseases in the population. Thiocyanate inhibition of iodine
      transport into milk may also be operative in humans with a high thiocyanate
      intake. This could further impair iodine status in breastfed children in low
      iodine intake areas of the world. It can be speculated that a low-iodine content
      of mother's milk because of inhibition of NIS in the mammary gland may be one
      factor of importance for development of myxedematous cretinism.

PMID- 12487773
TI  - Iodine supplementation in Austria: methods and results.
AB  - Until 1963 Austria was an extremely iodine-deficient area with low iodine intake
      and high goiter prevalence. Therefore, for the first time in 1963, salt
      iodination with 10 mg of potassium iodide per kilogram of salt was introduced by
      federal law. Twenty years after this salt iodination, however, investigations in
      schoolchildren demonstrated iodine deficiency grade I to II according to the
      World Health Organization (WHO) (urinary iodine excretion, 42-75 microg/g Crea)
      and goiter prevalence of far more than 10%. In 1990, salt iodination was
      increased to 20 mg of potassium iodide per kilogram of salt. In 1994, further
      investigations in schoolchildren demonstrated an increase of urinary iodine
      excretion (121 microg/g Crea) and a reduction of goiter prevalence below 5%, with
      the exception of pupils ages 14-19 (12%). In the year 2000, 10 years after the
      increase of salt iodination in Austria, 430 nonselected adult inhabitants of
      three communities in Carinthia (a county of Austria) were investigated for iodine
      excretion, goiter prevalence, and prevalence of thyroid autoantibodies. This
      study demonstrated that although iodine supply is sufficient now in Austria
      (males, 163.7 microg of Crea; females, 183.3 microg of iodine per gram of Crea),
      goiter prevalence is still high in the elderly, who lived for a longer period of
      iodine deficiency (34.3% in women and 21.3% in men), whereas goiter prevalence in
      younger people up to age 40 years is below 5%. It could also be shown that the
      percentage of thyroid autoantibodies is now as high as in other countries with
      sufficient iodine supply (3.19% in males, 5.17% in females). In addition to the
      changes of urinary iodine excretion and goiter prevalence because of salt
      iodination, changes of incidence in hyperthyroidism and histologic types of
      thyroid cancer are discussed in this paper. In conclusion, the introduction of
      salt iodination led to an improvement in iodine supply with a marked reduction of
      goiter prevalence in people who were born after 1963, but also to an increase in
      hyperthyroidism and autoimmune thyroid diseases as well as changes in histologic
      types of thyroid cancer.

PMID- 12487774
TI  - Cost estimation of thyroid disorders in Germany.
AB  - To assess the economic effects of thyroid disorder-related morbidity in Germany,
      a systematic review of national and international literature from 1981-2001 was
      performed. Data from insurance companies, the government department of public
      health, and the federal office of statistics helped characterize the situation in
      Germany. Being the most important thyroid disease, endemic iodine-deficiency
      goiter causes economic costs of approximately 2.1 billion DM per year or 1
      billion Euros or 1 billion U.S. dollars. In recent years iodine supplementation
      of food became better accepted by the German population. This should
      significantly reduce the prevalence of goiter from 30%-40% to less than 10%.
      Functional thyroid disorders are observed in 5%-10% of the German population. A
      more differentiated view of these conditions should lead to specific guidelines
      for an economic screening and therapy of subpopulations. Lacking valuable data,
      an actual economic assessment of autoimmune or malignant thyroid diseases cannot
      be performed. On the other hand, with respect to the costs of specific thyroid
      therapy, e.g., radioiodine treatment of thyrotoxicosis (mainly toxic nodular
      goiter), the economic consequences of a new regulation for radiation protection
      in Germany have been demonstrated recently. Using the actual maximum permissible
      level of residual activity on discharge from the hospital after radioiodine
      therapy, length of hospitalization was shortened to 5.1 days in university
      hospitals and to 5.8 days in nonuniversity institutions. Payment per patient for
      radioiodine therapy was 1,856 and 1,530 Euros (median value) in university and
      nonuniversity hospitals, respectively. In conclusion, better prevention of iodine
      deficiency and its long-term consequences should effectively reduce direct as
      well as indirect costs and overall economic impact of endemic goiter as the most
      important thyroid disease in Germany. Sustainable elimination of iodine
      deficiency is technically possible, but it needs further commitment and support
      at all levels.

PMID- 12487775
TI  - Thoughts on prevention of thyroid disease in the United States.
AB  - In the realm of preventive medicine, there are three distinct types of prevention
      that can be defined. Primary prevention is the prevention of new disease in
      previously healthy individuals, usually achieved by decreasing risk factors for
      disease. Secondary prevention is the prevention of progression of mild or latent
      disease to more severe disease, and typically involves screening for occult
      disease. Tertiary prevention is the term used by some to describe medical care
      intended to improve already established disease. The role of primary prevention
      of thyroid disease in the United States is uncertain, because iodine deficiency
      is not clearly known to be a problem. In the case of secondary prevention of
      thyroid disease, this would necessarily involve screening of individuals for
      subclinical hyperthyroidism or hypothyroidism with thyrotropin (TSH) testing.
      Using data from a large prevalence study and from the 2000 U.S. Census, it can be
      calculated that approximately 15 million adults have unrecognized thyroid
      disease, mostly subclinical hypothyroidism. If detected, secondary prevention
      might also entail treatment with antithyroid drugs/radioiodine or thyroxine to
      prevent sequelae or progression to a more advanced degree of thyrotoxicosis or
      thyroid failure, respectively. Over the next 20 years, it can be calculated that
      approximately 5 million people, mostly with subclinical hypothyroidism, will
      progress to overt disease. Tertiary prevention of thyroid disease would involve
      avoiding iatrogenic disease, such as thyroid hormone overdose. From epidemiologic
      data it can be calculated that approximately 600,00 elderly individuals have
      iatrogenic hyperthyroidism from thyroid hormone overdose, putting them at risk
      for atrial fibrillation and osteoporosis. Together, these data suggest that the
      notion of preventive medicine in the United States should be expanded to include
      thyroid disease as a target for secondary and tertiary intervention.

PMID- 12487776
TI  - EDTA inhibits collagen-induced ATP+ADP secretion and tyrosine phosphorylation in
      platelets independently of Mg2+ chelation and decrease in pH.
AB  - The effects of Mg2+ and EDTA on collagen-induced platelet dense granule secretion
      and protein tyrosine phosphorylation were studied in the presence and absence of
      various inhibitors of autocrine agonists that are released from secretory
      granules. Addition of EDTA to gel-filtered platelets in Tyrode's solution caused
      a decrease in pH of 0.7-0.9 pH units, due to chelation of Mg2+, and a marked
      inhibition of cATP+ADP secretion induced by collagen (25 (micro)g/ml). Lowering
      pH of the platelet suspension to the same extent by HCl had no effect on
      secretion which also was the same in the absence of exogenous Mg2+ as in its
      presence. Similarly, secretion induced by collagen per se, i.e., isolated from
      autocrine agonists by inhibitors, which was about 50% less than with autocrine
      agonists, was not affected by the presence or absence of exogenous Mg2+. The
      level of tyrosine phosphorylation of several proteins in resting platelets was
      higher in the absence of Mg2+ than in its presence, but the onset of collagen
      induced phosphorylation and dephosphorylation was more rapid in the absence of
      Mg2+. Tyrosine phosphorylation of p38 was specifically enhanced in the presence
      of inhibitors of autocrine phosphorylation and even more enhanced in the absence
      of Mg2+. EDTA inhibited the protein phosphorylation to the same extent in the
      presence as in the absence of exogenous Mg2+. These results show that EDTA
      inhibits collagen-induced dense granule secretion neither through chelation of
      Mg2+ nor lowering of pH, and thus probably through other effects on the platelet
      by the EDTA2- species that are reflected in protein tyrosine phosphorylation
      signalling.

PMID- 12487777
TI  - Influence of heparin coating of coronary stents and ex vivo efficacy of different
      doses of acetylsalicylic acid and ticlopidine in a pulsed floating model of
      recirculating human plasma.
AB  - Acute occlusion of stented coronary vessels still occurs in up to 3%. Activated
      platelets have been found to play a major role in the pathogenesis of these
      complications. We therefore analyzed the efficacy of a heparin coating of
      coronary stents and investigated the ex vivo efficacy of different antiplatelet
      drugs. Each of seven healthy volunteers was treated with each of the following
      medications for 7 days: ASA 100 mg/day, ASA 300 mg/day, ticlopidine 250 mg/day,
      and ticlopidine 500 mg/day. Three standardized in vitro silicon tubing models,
      one of them containing an uncoated stent, one a heparin-coated stent, and one
      without a stent (control) were filled with PRP and circulation was started. TOS
      in systems with heparin-coated stents was 2.4-times longer compared to systems
      with uncoated stents (P<0.001), and 1.5-times longer compared to the control
      (P<0.01). The increase of CD62p expression within the first 5 min was 2.5-times
      higher in systems with uncoated stents and 1.7-times higher in the control than
      in systems with heparin-coated stents (P<0.05). Aggregometry revealed significant
      medication- and dose-dependent inhibition of platelet aggregability for all
      medications. Heparin-coating of coronary stents reduces their thrombogenicity
      significantly. ASA and ticlopidine effectively reduce platelet activation ex
      vivo. The used in vitro system facilitates a reproducible method to estimate the
      thrombogenicity of coronary stents prior to in vivo trials.

PMID- 12487778
TI  - Absence of compensatory platelet activation in patients with severe haemophilia,
      but evidence for a platelet collagen-activation defect.
AB  - Severe haemophilia is a serious, haemorrhagic disorder of the plasmatic
      coagulation system. In this study we investigated, whether 'compensatory'
      activation of the platelet coagulation system occurs in this situation. Platelet
      function was investigated with aggregation, adhesion and flow cytometric assays.
      In addition, we performed clot and platelet plug formation tests and determined
      endogenous thrombin potentials in patients with severe haemophilia A or B;
      results were compared to those of healthy controls. Platelet aggregation in
      response to stimulation with ADP, ristocetin and epinephrine was similar in
      patients and controls; aggregation in response to collagen was reduced
      significantly in haemophiliacs. Flow cytometric analysis of P-selectin (CD 62P)
      and CD 63, of the conformationally changed GP IIb/IIIa with PAC 1 and of
      thrombospondin bound to CD 36 (GP IV) was performed at baseline and post
      stimulation. Baseline expression of all markers was similar in haemophiliacs and
      controls. After stimulation of the platelet thrombin receptors with the thrombin
      receptor activating peptide (TRAP) 6, the surface expression of all markers
      increased significantly; again, the expression was similar in haemophiliacs and
      controls. With thrombelastography and PFA 100 analysis, clot formation under low
      shear and platelet plug formation under high shear is measured. Both test results
      revealed a significantly reduced clot and platelet plug formation capacity in
      severe haemophiliacs. Our results did not reveal signs of enhanced platelet
      preactivation in haemophiliacs, indicating that baseline platelet reactivity in
      severe haemophilia remains in a neutral state, despite the severely haemorrhagic
      condition. As expected, both thrombin and clot formation capacities were impaired
      significantly in severe haemophilia. The reduced response to collagen-based
      platelet stimulation tests is indicative of a concomitant platelet function
      defect. This defect probably contributes to the intensity of bleeding events in
      patients with severe haemophilia.

PMID- 12487779
TI  - Upstream open reading frames regulate translation of Mona/Gads adapter mRNA in
      the megakaryocytic lineage.
AB  - Mona, also called Gads, is a molecular adapter that plays a key role in T-cell
      and platelet signalling by linking the adaptors Src homology 2 domain-containing
      leukocyte phosphoprotein of 76 kDa (Slp-76) and linker for activation of T cells
      (LAT) upon T-cell receptor and collagen receptor activation. Platelets express a
      specific form of Mona mRNA, called 1B, which is transcribed from a megakaryocyte
      specific promoter. Mona 1B mRNA differ from 1A transcripts found in T cells and
      some myeloid cells only by the 5'UTR. We report here that 1B mRNA expressing
      cells do not express detectable amounts of Mona protein, in contrast to 1A
      expressing cells, and we show that 1B 5'UTR contains upstream open reading frames
      (uORFs). Mutating the corresponding uAUG restored efficient Mona translation, or
      that of an unrelated ORF. This suggested that Mona protein expression in 1B mRNA
      expressing cells is tightly controlled at the translational level. Accordingly,
      Mona protein was not detected in resting platelets. Strikingly, platelet
      activation by thrombin resulted in the rapid induction of Mona protein
      expression, suggesting that translation inhibition of 1B mRNA may be relieved in
      activated platelets.

PMID- 12487780
TI  - Safety, inhibition of platelet aggregation and pharmacokinetics of Fab'2
      fragments of the anti-glycoprotein IIb-IIIa monoclonal antibody FRaMon in high
      risk coronary angioplasty.
AB  - The purpose of the study was to evaluate safety, effects on platelet aggregation
      and pharmacokinetics of F(ab')(2) fragments of anti-glycoprotein (GP) IIb-IIIa
      murine monoclonal antibody FRaMon (F(ab')(2) FRaMon) upon its intravenous
      administration in patients undergoing high-risk coronary angioplasty. Patients
      were treated before angioplasty with F(ab')(2) FRaMon at 0.2 mg/kg (n = 17) and
      0.25 mg/kg (n = 12) bolus or with abciximab at 0.25 mg/kg bolus + 12 h infusion
      at 0.125 microg/kg per min (n = 29). F(ab')(2) FRaMon at both doses decreased
      platelet aggregation induced by 20 microM ADP to <10, <20, <40 and <70% of the
      predrug level at 1, 12, 24 and 72 h after injection, respectively. No significant
      differences were observed between F(ab')(2) FRaMon and abciximab antiaggregatory
      effects. In none of the patients did F(ab')(2) FRaMon cause allergic reactions,
      major bleedings or deep thrombocytopenia. Antibodies against F(ab')(2) FRaMon
      were detected in one patient. Free F(ab')(2) FRaMon was cleared from plasma
      within 12 h, while platelet-bound preparation occupied >95, 70-80 and 40-50% of
      GP IIb-IIIa at 1 and 12-24 h and 3 days after injection, respectively. Thrombotic
      complications within the first month after angioplasty in groups treated with
      F(ab')(2) FRaMon and abciximab were observed in one and two patients,
      respectively. The data obtained have shown that F(ab')(2) FRaMon at bolus
      administration to patients undergoing coronary angioplasty caused no serious side
      effects and at comparative dosage inhibited platelet aggregation with the same
      efficacy as abciximab at bolus + infusion administration.

PMID- 12487781
TI  - Antiplatelet activity of carvedilol in comparison to propranolol.
AB  - The non-selective vasodilating beta-blocker carvedilol was found to inhibit
      platelet aggregation as well as thromboxane B(2) formation more effectively than
      propranolol. The antiaggregatory activity of carvedilol decreased, depending on
      the stimulus used, in the following rank order of potency (in parentheses the
      respective mean inhibitory concentrations of carvedilol and propranolol are given
      in micromol/l): PMA (19 and 34) > thrombin (55 and 77) > Ca(2+)-ionophore A23187
      (58 and 81) > epinephrine (86 and 118). However, aggregation of platelets
      activated with ADP was not affected by carvedilol in concentrations up to 100
      micromol/l. In platelets stimulated with thrombin, carvedilol (10 micromol/l)
      reduced thromboxane B(2) formation by 64%, whereas propranolol was ineffective at
      this concentration. Moreover, A23187-induced formation of thromboxane B(2), not
      affected by propranolol, was completely blocked by 100 micromol/l carvedilol. In
      comparison to propranolol, the molecule of carvedilol is more lipophilic and
      possesses lower dipole moment and higher molar refractivity, thus penetrating
      into platelet membranes readily and in large quantities. The antiplatelet effect
      was assumed to result from interactions of carvedilol with membrane
      macromolecules (phospholipids, ion channels, enzymes, etc.) rather than from
      blockade of alpha- and beta-adrenergic receptors.

PMID- 12487782
TI  - Platelet activation is increased in patients with cardiomyopathy: myocardial
      inflammation and platelet reactivity.
AB  - Thrombotic events are a major complication in patients with cardiomyopathy, in
      which inflammation is often found within the heart. We examined the platelet
      activation in patients with cardiomyopathy with and without myocardial
      infiltrates. Endomyocardial biopsies of 45 patients with cardiomyopathy (CM) were
      immunohistologically assessed for infiltrates. Twenty-three patients had
      myocardial infiltrates (>/= 2 CD3(+) cells/high power field (HPF), CM+) and 22
      patients had no inflammation (< 2 CD3(+) cells/HPF, CM-). Platelet adhesion
      proteins were flow cytometrically quantified (thrombospondin, P-selectin, CD 41)
      and platelet activation in CM compared to 45 healthy controls. Significantly more
      activated platelets were detected in patients with cardiomyopathy than controls
      (for thrombospondin 13.5% [10.3; 22.0] median [25; 75 quartile] vs. 10.6% [8.2;
      16.0], P = 0.002; for P-selectin 12.6% [10.0; 18.6] vs. 7.7% [5.8; 10.9], P <
      0.001). Platelet activation was higher in patients with cardiomyopathy and
      myocardial infiltrates (for thrombospondin 19.0% [11.0; 26.3]) compared to
      patients without inflammation (12.3% [9.9; 16.0], P = 0.018). Platelet GPIIb/IIIa
      expression was also increased in patients with inflammation (290 arbitrary units
      [268, 338]) compared to the controls (215 [188, 248], P < 0.001). In conclusion,
      platelet reactivity was increased in patients with cardiomyopathy and myocardial
      infiltrates. Measurement of platelet reactivity may be useful to identify
      patients with cardiomyopathy at risk for thrombotic events.

PMID- 12487783
TI  - Monitoring of antiplatelet therapy with the PFA-100 in peripheral angioplasty
      patients.
AB  - BACKGROUND: In patients suffering from peripheral arterial occlusive disease
      (PAOD) the risk of restenosis after percutaneous transluminal angioplasty (PTA)
      might be influenced by platelet mediated factors. OBJECTIVE: To look for a
      correlation between the effect of antiplatelet therapy and recurrence of disease
      after PTA by monitoring platelet function in 3-month intervals by the platelet
      function analyzer system, PFA-100, over a period of 1 year. PATIENTS AND METHODS:
      A group of 98 patients (43 females, 55 males) with PAOD, treated with aspirin (n
      = 52), thienopyridine (n = 34) or combination therapy of both (n = 12) were
      followed over a period of 12 months after elective PTA of the lower extremities
      with regard to occurrence of restenosis or reocclusion at the site of
      angioplasty, to demonstrate inhibitory effects on platelets, induced by
      antiplatelet therapy. RESULTS: PFA-100 proved suitable to identify 'non
      responders' to antiplatelet therapy, in a 12-month follow-up period. In 'non
      responders' to clopidogrel therapy, a higher incidence of restenosis or
      reocclusion after PTA of the lower limbs was detected compared with 'responders'.
      CONCLUSION: PFA-100, upon stimulation with ADP, might predict patients under
      clopidogrel therapy with elevated risk for the development of complications
      following PTA of the lower limbs. This could offer the chance to switch to an
      alternative therapy or adapt the dose.

PMID- 12487784
TI  - Comparison of the pharmacological mechanisms involved in the platelet lowering
      actions of anagrelide and hydroxyurea: a review.

PMID- 12487785
TI  - Glanzmann's thrombasthenia: updated.
AB  - Glanzmann's thrombasthenia is an autosomal recessive disorder, rare in a global
      context, but a relatively more common platelet function defect in communities
      where consanguineous marriages are more frequent. On clinical grounds alone, it
      cannot be distinguished from other congenital platelet function defects.
      Epistaxis, gum bleeding, menorrhagia are the common clinical manifestations,
      whereas large muscle hematoma or hemarthrosis seldom occur in these patients.
      Essential diagnostic features are a normal platelet count and morphology, a
      greatly prolonged bleeding time, absence of platelet aggregation in response to
      ADP, collagen, epinephrine, thrombin and to all aggregating agents which
      ultimately depend on fibrinogen binding to platelets for this effect, flow
      cytometry, studies of GPIIb-IIIa receptors on the platelet membrane surface using
      monoclonal antibodies. The present review describes some of the uncommon features
      of the disorders and the currently available options which the treating
      physicians should be aware of during the management of these patients. Although
      by definition all patients with Glanzmann's thrombasthenia have a virtually
      complete failure of platelet aggregation, a number of variant forms of GT have
      been described in which the glycoproteins are present in normal or near normal
      amounts but are functionally defective. Understanding the pathophysiology of the
      disorder by the treating physicians is of utmost importance. Presence of high
      affinity platelet receptors resulting in thrombasthennia-like phenotype may
      require an antagonistic treatment atypical of classical GT management. It has now
      been established that different genetic mutations of either GPIIb or IIIa genes
      results in such a heterogeneity of thrombasthenia phenotype. Glanzmann's
      thrombasthenia is a paradigm for treating coronary artery disease patients with
      GPIIb-IIIa antibody and inhibitors. By using these medicines we create a
      temporary GT-like situation. Hence, understanding this disease is of utmost
      importance to the practicing cardiologist. As mutations for different variant
      forms of GT become known, our understanding of how GPIIb-IIIa molecules can be
      activated to act as a receptor for fibrinogen molecules will be increased. Such
      understanding undoubtedly will help us to devise better drugs with GPIIb-IIIa
      inhibitors. Molecular biology techniques have enabled us to equivocally detect
      heterozygote carriers who are clinically asymptomatic. However, there may be
      several laboratories in the developing world, which have no access to molecular
      biology techniques. Development of more robust techniques of quantitation of
      platelet receptors has enabled an accurate diagnosis of heterozygote carriers or
      an unborn fetus in the second trimester. The importance of the GPIIb-IIIa
      polymorphisms in carrier and prenatal diagnosis has not been properly studied.
      Nowadays the less direct method of PLA1 typing (determination of the levels of
      platelet antigen) of the foetal platelets as early as 16 weeks of intrauterine
      life can be used for prenatal diagnosis of GT.

PMID- 12487786
TI  - Thrombopoietin inside the pulmonary vessels in patients with and without
      pulmonary hypertension.
AB  - There is substantial evidence that platelet production and release take place in
      the lungs. Thrombopoietin (Tpo) stimulation can cause platelet release in the
      pulmonary vasculature. On the other hand, myelofibrosis can occur in Tpo
      overexpressing transgenic mice models, and there is unexplained pulmonary
      hypertension in chronic myeloproliferative disorders including primary
      myelofibrosis. In this study, we aimed to assess local Tpo concentrations inside
      the pulmonary artery and associated vessels in humans. We measured Tpo
      concentrations in plasma samples taken concurrently from the right ventricle, the
      pulmonary artery, and the left ventricle during cardiac catheterization in
      patients with and without pulmonary hypertension. The study group comprised 10
      patients with normal pulmonary arterial pressure (Group A, male/female 4/6, mean
      age 48 +/- 19) and 14 patients with pulmonary hypertension (Group B, male/female
      9/5, mean age 57 +/- 16). The Tpo levels inside the right ventricle, the
      pulmonary artery and the left ventricle were 33.3 +/- 15.6, 47.2 +/- 33.9, and
      34.4 +/- 18.6 pg/ml, respectively, in Group A; and 85.0 +/- 39.8, 128.4 +/- 50.4,
      and 81.5 +/- 35.5 pg/ml, respectively, in Group B. Levels of the Tpo were
      significantly higher in all three localizations in Group B compared to Group A.
      Moreover, the Tpo concentration inside the pulmonary artery is significantly
      higher than the Tpo concentrations in the right and left ventricles in Group B
      patients. There were positive correlations between the Tpo levels and pulmonary
      artery systolic pressure over the whole patient group. In conclusion, there could
      be an association between pulmonary hypertension and Tpo level. Moreover, lung
      vasculature holding the major regulatory thrombopoietic hormone, Tpo, may be an
      important place for megakaryocytopoiesis.

PMID- 12487787
TI  - The GPIIb/IIIa antagonist eptifibatide markedly potentiates platelet-leukocyte
      interaction and tissue factor expression following platelet activation in whole
      blood in vitro.
AB  - Tissue factor (TF) is the most important initiator of intravascular coagulation.
      Activated platelets are able to adhere to leukocytes and this heterotypic cell
      cell interaction results in a CD62P-dependent TF expression on monocytes.
      GPIIb/IIIa antagonists are inhibitors of the common pathway of platelet
      aggregation and they are widely used in patients with acute coronary syndromes
      undergoing coronary interventions. As GPIIb/IIIa antagonists do not prevent
      platelet activation we investigated the effect a GPIIb/IIIa antagonist,
      eptifibatide, on the formation of platelet-leukocyte conjugates and leukocyte TF
      expression. Flow cytometry was used to detect conjugates and TF. When platelets
      in citrated human blood were stimulated for 30 min with collagen there was a
      increase in the number of both neutrophils and monocytes with the platelet
      specific antigen CD42a, indicating the formation of platelet-neutrophil (P/N) and
      platelet-monocyte (P/M) conjugates. P/M formation was associated with about a 2.5
      fold increase in TF expression on monocytes, whereas P/N formation changed TF
      expression neutrophils only by about 10%. Eptifibatide enhanced dose-dependently
      (0.0625-1.5 microg/ml) both collagen-induced P/M formation and monocyte TF
      expression. Maximum enhancement by about 60 and 120%, respectively, was observed
      at 0.5 microg/ml eptifibatide. In contrast, eptifibatide had only a minor effect
      on P/N formation and no effect on neutrophil TF expression. The augmented P/M
      formation and monocyte TF expression in the presence of a GPIIb/IIIa antagonist
      may be relevant to the poor antithrombotic efficiency of oral GPIIb/IIIa
      antagonists as shown in recent large clinical trials.

PMID- 12487788
TI  - Comparison of the pharmacodynamic effects of the platelet ADP receptor
      antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease.
AB  - We compared the antiplatelet effects of clopidogrel and the intravenous platelet
      P2Y(12) receptor antagonist AR-C69931MX, which acts on the same receptor as
      clopidogrel by a different and reversible mechanism and, unlike clopidogrel, is
      active in vitro. Thirteen patients with acute coronary syndromes entered into a
      phase II study of intravenous AR-C69931MX (Group 1) and eight patients undergoing
      intracoronary stent implantation and treated with clopidogrel (Group 2) were
      studied using a whole blood single-platelet counting aggregation assay. Group 2
      patients were also studied using turbidimetry with ADP and TRAP as agonists and
      whole blood [(14)C]5HT release to study dense granule secretion in response to
      ADP, collagen and TRAP. In Group 2 studies, a therapeutic concentration of AR
      C69931MX was added in vitro before and after clopidogrel administration. AR
      C69931MX in Group 1 achieved greater inhibition of ADP-induced platelet
      aggregation than clopidogrel in Group 2 and AR-C69931MX in vitro added to the
      effects of clopidogrel on ADP-induced aggregation. AR-C69931MX but not
      clopidogrel inhibited TRAP-induced aggregation and granule secretion and AR
      C69931MX had a more consistent inhibitory effect on collagen-induced responses.
      In conclusion, therapeutic administration of clopidogrel moderately inhibits
      platelet P2Y(12) receptor activation and substantially greater P2Y(12) receptor
      blockade can be achieved with AR-C69931MX.

PMID- 12487789
TI  - Phospholipase A2 activity in platelets of patients with uremia.
AB  - Platelets of patients with uremia develop a defective platelet function and have
      a decreased production of thromboxane B2 (TxB2). Activated platelets generate
      thromboxane from free arachidonate that is previously released from the membrane
      phospholipids (PLs) by phospholipases. Phospholipase A2 (PLA2) release up to 70%
      of the arachidonate in normal platelets, and to date, the activity of this enzyme
      in uremia is unknown. This work studied the PLA2 activity in the platelets of
      nine uremic patients and nine healthy volunteers. Washed platelets were labelled
      with [(14)C]arachidonic acid and activated with calcium ionophore A-23187 (4
      microgr/ml). Lipids were resolved by TLC and identified by autoradiography. The
      distribution of [(14)C]arachidonic acid in the five major platelet phospholipids
      was found to be normal. Uremic platelets released more radioactivity than normal
      platelets (19.0 +/- 5.2% versus 11.3 +/- 1.6%, P = 0.001). The production of
      both, radioactive thromboxane B2 and hydroxyheptadecatrienoic acid was normal
      (2.6 +/- 1.2% and 3.5 +/- 1.6% of total radioactivity respectively), but the
      formation of the lipoxygenase metabolite hydroxyeicosatetraenoic acid was
      increased with respect to the controls (12.9 +/- 4.6% vs 7.0 +/- 1.3% of total
      radioactivity, P = 0002). In conclusion, platelets of patients with uremia have
      an increased activity of phospholipase A2 and produce increased amounts of
      hydroxyeicosatetraenoic acid, an inhibitor of the platelet function.

PMID- 12487790
TI  - Polysaccharide part of Proteus mirabilis lipopolysaccharide may be responsible
      for the stimulation of platelet adhesion to collagen.
AB  - Lipopolysaccharide (LPS, endotoxin) is a well-known causative agent of septic
      shock and disseminated intravascular coagulation. The action of LPS is related to
      the activation of many types of cells, including blood platelets. We examined the
      effects of different LPSs from Proteus mirabilis (smooth form LPS S1959 and rough
      forms LPSs R110 and R45) and fragments of LPS structure (lipid A and
      polysaccharide part) on platelet adhesion to collagen in the presence or absence
      of the phoinositide 3-kinase (PI 3-K) inhibitor, wortmannin. We found that all
      forms of LPS and its fragments caused the stimulation of platelet adhesion to
      collagen, but the polysaccharide part (PS S1959) was the most important in this
      action. Wortmannin had no effect on LPS-stimulated platelet adhesion to collagen.
      We conclude that both lipid A and PS S1959 play important roles in LPS-stimulated
      platelet adhesion to collagen independent on the PI 3-K action.

PMID- 12487791
TI  - New types of granulocyte inclusions in hereditary macrothrombocytopenias.

PMID- 12487792
TI  - Professor Ernst F. Luscher (Berne, 1916-Muri, 2002): a personal tribute to a
      founding member of ETRO.

PMID- 12487793
TI  - A new platelet preservative.
AB  - A new platelet preservative, ViaCyte trade mark (balanced salt solution,
      physiological buffer, D-ribose, bovine serum albumin, D-glucose, sterile water)
      was tested against the presently used storage solution (citrate-phosphate
      dextrose; CPD) and results revealed that ViaCyte demonstrated added protection
      for platelets during storage-induced activation. Following five days of storage
      at room temperature, only 12.2% of platelets stored in ViaCyte exhibited P
      selectin expression at rest and, upon thrombin challenge, 64.2% were activated,
      an increase of 42%. In control platelets (platelets stored in CDP), 44.4% were
      activated due to storage-induced lesions, and thrombin stimulation resulted in
      47.9% P-selectin expression, an increase of only 2.5%. ViaCyte storage maintained
      the resting state and preserved platelet function, making more platelets
      available for activation upon agonist challenge. This preliminary study
      demonstrated that the presently used standard preservative does not offer
      protection from storage-induced lesions. Partially dysfunctional platelets do not
      contribute significantly to hemostasis in vivo and play little role, if any, in
      clot retraction and wound healing processes.

PMID- 12487794
TI  - On different facets of regularization theory.
AB  - This review provides a comprehensive understanding of regularization theory from
      different perspectives, emphasizing smoothness and simplicity principles. Using
      the tools of operator theory and Fourier analysis, it is shown that the solution
      of the classical Tikhonov regularization problem can be derived from the
      regularized functional defined by a linear differential (integral) operator in
      the spatial (Fourier) domain. State-of-the-art research relevant to the
      regularization theory is reviewed, covering Occam's razor, minimum length
      description, Bayesian theory, pruning algorithms, informational (entropy) theory,
      statistical learning theory, and equivalent regularization. The universal
      principle of regularization in terms of Kolmogorov complexity is discussed.
      Finally, some prospective studies on regularization theory and beyond are
      suggested.

PMID- 12487795
TI  - Biophysiologically plausible implementations of the maximum operation.
AB  - Visual processing in the cortex can be characterized by a predominantly
      hierarchical architecture, in which specialized brain regions along the
      processing pathways extract visual features of increasing complexity, accompanied
      by greater invariance in stimulus properties such as size and position. Various
      studies have postulated that a nonlinear pooling function such as the maximum
      (MAX) operation could be fundamental in achieving such selectivity and
      invariance. In this article, we are concerned with neurally plausible mechanisms
      that may be involved in realizing the MAX operation. Different canonical models
      are proposed, each based on neural mechanisms that have been previously discussed
      in the context of cortical processing. Through simulations and mathematical
      analysis, we compare the performance and robustness of these mechanisms. We
      derive experimentally verifiable predictions for each model and discuss the
      relevant physiological considerations.

PMID- 12487796
TI  - Self-regulation mechanism of temporally asymmetric Hebbian plasticity.
AB  - Recent biological experimental findings have shown that synaptic plasticity
      depends on the relative timing of the pre- and postsynaptic spikes. This
      determines whether long-term potentiation (LTP) or long-term depression (LTD) is
      induced. This synaptic plasticity has been called temporally asymmetric Hebbian
      plasticity (TAH). Many authors have numerically demonstrated that neural networks
      are capable of storing spatiotemporal patterns. However, the mathematical
      mechanism of the storage of spatiotemporal patterns is still unknown, and the
      effect of LTD is particularly unknown. In this article, we employ a simple neural
      network model and show that interference between LTP and LTD disappears in a
      sparse coding scheme. On the other hand, the covariance learning rule is known to
      be indispensable for the storage of sparse patterns. We also show that TAH has
      the same qualitative effect as the covariance rule when spatiotemporal patterns
      are embedded in the network.

PMID- 12487797
TI  - Associative memory with dynamic synapses.
AB  - We have examined a role of dynamic synapses in the stochastic Hopfield-like
      network behavior. Our results demonstrate an appearance of a novel phase
      characterized by quick transitions from one memory state to another. The network
      is able to retrieve memorized patterns corresponding to classical ferromagnetic
      states but switches between memorized patterns with an intermittent type of
      behavior. This phenomenon might reflect the flexibility of real neural systems
      and their readiness to receive and respond to novel and changing external
      stimuli.

PMID- 12487798
TI  - Adaptive spatiotemporal receptive field estimation in the visual pathway.
AB  - The encoding properties of the visual pathway are under constant control from
      mechanisms of adaptation and systems-level plasticity. In all but the most
      artificial experimental conditions, these mechanisms serve to continuously
      modulate the spatial and temporal receptive field (RF) dynamics. Conventional
      reverse-correlation techniques designed to capture spatiotemporal RF properties
      assume invariant stimulus-response relationships over experimental trials and are
      thus limited in their applicability to more natural experimental conditions.
      Presented here is an approach to tracking time-varying encoding dynamics in the
      early visual pathway based on adaptive estimation of the spatiotemporal RF in the
      time domain. Simulations and experimental data from the lateral geniculate
      nucleus reveal that subtle features of encoding properties can be captured by the
      adaptive approach that would otherwise be undetected. Capturing the role of
      dynamically varying encoding mechanisms is vital to our understanding of vision
      on the natural setting, where there is absence of a true steady state.

PMID- 12487799
TI  - Global convergence rate of recurrently connected neural networks.
AB  - We discuss recurrently connected neural networks, investigating their global
      exponential stability (GES). Some sufficient conditions for a class of recurrent
      neural networks belonging to GES are given. Sharp convergence rate is given too.

PMID- 12487800
TI  - Locality of global stochastic interaction in directed acyclic networks.
AB  - The hypothesis of invariant maximization of interaction (IMI) is formulated
      within the setting of random fields. According to this hypothesis, learning
      processes maximize the stochastic interaction of the neurons subject to
      constraints. We consider the extrinsic constraint in terms of a fixed input
      distribution on the periphery of the network. Our main intrinsic constraint is
      given by a directed acyclic network structure. First mathematical results about
      the strong relation of the local information flow and the global interaction are
      stated in order to investigate the possibility of controlling IMI optimization in
      a completely local way. Furthermore, we discuss some relations of this approach
      to the optimization according to Linsker's Infomax principle.

PMID- 12487801
TI  - On unique representations of certain dynamical systems produced by continuous
      time recurrent neural networks.
AB  - This article extends previous mathematical studies on elucidating the redundancy
      for describing functions by feedforward neural networks (FNNs) to the elucidation
      of redundancy for describing dynamical systems (DSs) by continuous-time recurrent
      neural networks (RNNs). In order to approximate a DS on R(n) using an RNN with n
      visible units, an n-dimensional affine neural dynamical system (A-NDS) can be
      used as the DS actually produced by the above RNN under an affine map from its
      visible state-space R(n) to its hidden state-space. Therefore, we consider the
      problem of clarifying the redundancy for describing A-NDSs by RNNs and affine
      maps. We clarify to what extent a pair of an RNN and an affine map is uniquely
      determined by its corresponding A-NDS and also give a nonredundant sufficient
      search set for the DS approximation problem based on A-NDS.

PMID- 12487802
TI  - Descartes' rule of signs for radial basis function neural networks.
AB  - We establish versions of Descartes' rule of signs for radial basis function (RBF)
      neural networks. The RBF rules of signs provide tight bounds for the number of
      zeros of univariate networks with certain parameter restrictions. Moreover, they
      can be used to infer that the Vapnik-Chervonenkis (VC) dimension and
      pseudodimension of these networks are no more than linear. This contrasts with
      previous work showing that RBF neural networks with two or more input nodes have
      superlinear VC dimension. The rules also give rise to lower bounds for network
      sizes, thus demonstrating the relevance of network parameters for the complexity
      of computing with RBF neural networks.

PMID- 12487803
TI  - Approximation bounds for some sparse kernel regression algorithms.
AB  - Gaussian processes have been widely applied to regression problems with good
      performance. However, they can be computationally expensive. In order to reduce
      the computational cost, there have been recent studies on using sparse
      approximations in gaussian processes. In this article, we investigate properties
      of certain sparse regression algorithms that approximately solve a gaussian
      process. We obtain approximation bounds and compare our results with related
      methods.

PMID- 12487804
TI  - Scaling HIV vaccine attitudes among gay men in Sydney, Australia.
AB  - This study aimed to develop reliable scales of HIV vaccine attitudes. Gay men
      were recruited at the 2001 Sydney Gay and Lesbian Mardi Gras Fair Day, a large
      gay community gathering of thousands of people. A total of 776 participants
      completed a questionnaire containing 38 items about HIV vaccines. Factor analysis
      of the responses of 585 HIV-negative/untested men revealed four distinct factors
      (accounting cumulatively for 24.5% of the variance): I, Comfort with
      Participation in HIV Vaccine Trials, Cronbach alpha = 0.81; II, Confidence in HIV
      Vaccines/Vaccine Trials, Cronbach alpha = 0.71; III, Sexual Freedom, Cronbach
      alpha = 0.64; IV, Willingness to Participate in HIV Vaccine Trials, Cronbach
      alpha = 0.59. Of the HIV-negative/untested men, 162 (27.7%) were likely/very
      likely to volunteer for HIV vaccine trials, and 422 (72.3%) were unlikely/very
      unlikely to do so. As preliminary evidence of construct validity, the 162 men had
      a higher mean score on scale I (2.79), indicating greater comfort with trial
      participation than their 422 counterparts (2.47, p < 0.001). As preliminary
      evidence of concurrent validity, the 162 men had a higher mean score on scale IV
      (2.79), indicating greater willingness to participate than the rest (2.22, p <
      0.001). Alongside HIV vaccine trials, these scales may be a useful adjunct to
      social research in gay communities; to monitor and be responsive to community
      concerns about HIV vaccine trials as well as their potential to undermine safe
      sex practices.

PMID- 12487805
TI  - Molecular Epidemiology of HIV Type 1 in Ecuador, Peru, Bolivia, Uruguay, and
      Argentina.
AB  - Surveillance for HIV infection among people at increased risk was conducted in
      five countries in South America. Seroprevalence studies were conducted in more
      than 36,000 people in Ecuador, Peru, Boliva, Uruguay, and Argentina, along with
      genetic analysis of the HIV-1 strains. In all countries, the prevalence of HIV-1
      among men who have sex with men (MSM) was high (3-30%), whereas the prevalence
      among female commercial sex workers (FCSMs) was low (0.3-6%). By envelope
      heteroduplex mobility assay, subtype B predominated in MSM communities and in
      FCSWs in Ecuador, Bolivia, and Peru. A new genetic screening assay, the
      multiregion hybridization assay for subtypes B and F (MHA-bf), was developed to
      improve large-scale genetic screening in South America. MHA-bf can screen four
      regions of the genome for subtype B or subtype F, and thus can detect most
      recombinants. The sensitivity of MHA-bf when applied to a panel of pure subtypes
      and CRF12_BF was 100%, and 88% of unique recombinants were also detected as
      recombinant. Using MHA-bf, more than 80% of samples from Ecuador, Peru, and
      Bolivia were classified as pure subtype B, whereas in Uruguay and Argentina this
      proportion was only 30 to 40%. BF recombinants were the most prevalent form of
      HIV-1 in Uruguay and Argentina. Subtype B is the most common subtype in countries
      lacking injecting drug use (IDU) epidemics, whereas BF recombinants are more
      common in countries where extensive IDU epidemics have been documented,
      suggesting the ontogeny of recombinant strains in particular risk groups in South
      America.

PMID- 12487806
TI  - Immune activation in patients infected with HIV type 1 and maintaining
      suppression of viral replication by highly active antiretroviral therapy.
AB  - Immune activation associated with HIV infection declines after highly active
      antiretroviral therapy (HAART), but may persist or recur in some patients. It is
      not clear whether this reflects a resurgence of HIV replication or another cause
      of immune activation, such as inflammatory reactions to opportunistic pathogens
      (immune restoration disease [IRD]). Here, we studied plasma and cellular immune
      activation markers in adult HIV-1 patients who had received HAART for >12 months
      and maintained plasma HIV RNA levels of <400 copies/ml for >6 months. Plasma
      interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels
      were similar in patients and HIV-negative control subjects, but the highest
      levels occurred mainly in patients with a history of IRD. In contrast, expression
      of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in
      patients than in control subjects. Thus, cellular markers of immune activation
      are abnormal in some patients with a good virological response to HAART, and
      abnormalities of plasma immune activation markers correlate with a history of
      IRD.

PMID- 12487807
TI  - Phase I trial of a therapeutic HIV type 1 vaccine, Vacc-4x, in HIV type 1
      infected individuals with or without antiretroviral therapy.
AB  - Highly active antiretroviral therapy (HAART) can effectively suppress HIV-1
      replication but, as soon as the drugs are withdrawn, there is a rapid rebound of
      replicating virus. Severe metabolic toxicities and therapy failures due to the
      appearance of resistant virus are becoming an increasing problem that precludes
      long-term continuous medication. Therapeutic immunizations represent a feasible
      and attractive means of supplementing or, alternatively, replacing current
      therapies, thereby reducing the potential for emergence of drug-resistant HIV-1
      strains. We have performed an open, single-center, phase I safety study of a
      candidate therapeutic HIV-1 vaccine, Vacc-4x, given to 11 HIV-1-infected
      individuals with or without antiretroviral therapy. The immunogen consists of
      four synthetic peptides based on the major core protein p24. To ensure optimal
      exposure of the immunogen to the antigen-presenting cells (APCs), the vaccine was
      given intradermally together with granulocyte-macrophage colony-stimulating
      factor (GM-CSF). Responses to the immunization protocol were determined by
      delayed-type hypersensitivity (DTH) reaction, interferon gamma-secreting cells in
      the enzyme-linked immunospot (ELISpot) assay, and antibody production to the p24
      protein and the peptides. The vaccine was safe and in general well tolerated.
      Plasma HIV RNA levels and CD4(+) cell counts did not change appreciably during
      the study. All patients showed a positive DTH response. For two of the patients,
      the immunization protocol induced responses to one or two of the tested peptides
      whereas a third patient showed reactivity to one of the peptides before
      immunization. A weak antibody response in the peptide-specific enzyme-linked
      immunosorbent assay could be seen in seven patients.

PMID- 12487808
TI  - Peripheral blood cell-specific cytokines in persons with untreated HIV infection
      in Malawi, Africa.
AB  - Human immunodeficiency virus (HIV) infection is the primary cause of morbidity
      and mortality in Malawi, Africa, because of its many effects on the immune
      system. Immune cells communicate through cytokines; therefore, we examined the
      relationships between HIV serostatus and cell-specific cytokine production for 40
      asymptomatic, employed adults and 312 acutely ill, hospitalized patients in
      Malawi. We also measured the plasma HIV-1 RNA levels of 13 asymptomatic persons
      and 83 patients found to be HIV(+). We incubated peripheral whole blood with
      brefeldin-A +/- phorbol 12-myristate 13-acetate and ionomycin and then
      permeabilized, fixed, fluorescently stained, and examined the mononuclear cells
      with four-color, six-parameter flow cytometry. The percentage of lymphocytes
      expressing CD4 did not differ significantly between the HIV(+) and HIV(-) healthy
      adults (medians, 35.2 vs. 40.8%, respectively), but a wide array of cytokine
      parameters were lower in the HIV(+) than in the HIV(-) asymptomatic persons, for
      example, median percentages of T cells producing induced interleukin 2 (IL-2)
      (8.7 vs. 16.5%, respectively) and spontaneously producing IL-6 (0.7 vs. 11.0%,
      respectively). Also, four T cell parameters reflecting type 2-to-type 1 cytokine
      balances (T2/T1) were higher in the HIV(+), versus HIV(-), asymptomatic persons.
      Unlike the healthy adults, for patients with mycobacteremia/fungemia or malaria,
      the HIV(+) patients had higher median percentages of T cells and CD8(+) T cells
      producing induced interferon gamma than did the HIV(-) PATIENTS: For both
      asymptomatic and acutely ill persons, HIV-1 plasma levels were positively
      correlated with T2/T1 parameters. Cell-specific cytokine effects of HIV infection
      may precede measurable effects on CD4 expression. Cytokine therapies, even beyond
      periodic administration of IL-2, may improve the responses of HIV-infected
      persons to both HIV and coinfections.

PMID- 12487809
TI  - Differences in cellular activation and apoptosis in HIV-infected patients
      receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors.
AB  - The mechanism of CD4(+) T cell depletion seen in HIV infection is largely
      mediated by increased apoptosis of these cells. The benefit of protease inhibitor
      (PI)-based antiretroviral therapy to CD4(+) T cell recovery seems to involve more
      than its antiviral activity, and a direct antiapoptotic effect of PIs has been
      proposed to explain it. To test this hypothesis we have analyzed directly, ex
      vivo, the effects of two different highly active antiretroviral therapy (HAART)
      regimens on the levels of activation and apoptosis of T lymphocytes. A total of
      126 subjects (43 receiving PIs, 35 receiving NNRTIs, 27 untreated HIV carriers,
      and 21 uninfected control subjects) was included in the study. Apoptosis was
      measured in blood lymphocytes by flow cytometry, using annexin V labeling. A
      broad panel of monoclonal antibodies was used to characterize the different
      CD4(+) and CD8(+) lymphocyte subsets. Apoptosis was significantly increased in
      HIV-untreated subjects, whereas apoptosis levels did not differ when comparing
      HIV-positive subjects undergoing HAART and uninfected control subjects. Likewise,
      markers of activation were elevated in HIV-positive untreated patients, and
      declined in subjects receiving treatment. However, activated-memory CD8(+) T
      cells remained significantly higher in treated patients with respect to
      uninfected control subjects. No differences in the level of apoptosis or in
      immune activation markers were recognized when comparing subjects receiving PIs
      and those receiving NNRTIs. Antiretroviral therapy reduces apoptosis of CD4(+)
      and CD8(+) lymphocytes to normal levels without differences when comparing
      subjects receiving PI and NNRTI triple combinations. Despite complete suppression
      of viral replication, activated memory CD8(+) T cells remain significantly
      elevated in subjects receiving HAART, suggesting the persistence of residual HIV
      replication. If PIs provide a positive effect on CD4(+) counts beyond an
      antiviral effect, mechanisms other than apoptosis should be involved.

PMID- 12487810
TI  - Consistent subtype-specific anti-HIV type 1 T lymphocyte responses in Indian
      subjects recently infected with HIV type 1.
AB  - Anti-HIV-1-specific T cell responses in early HIV-1 infection have been found to
      be important in deciding the course of disease progression. But there are few
      data concerning nonsubtype B HIV infection. HIV-1 subtype C is the most prevalent
      subtype in India. HIV-1 Gag-specific T cell responses in 12 Indian subjects with
      recent HIV-1 infection were characterized by an ELISpot assay at two consecutive
      visits and their correlation with plasma viral load and CD4(+) T lymphocyte
      counts was studied. Ten of the 12 subjects demonstrated T cell responses to
      either one or both Gag B and C peptides, on at least one visit. Five of 10
      responders showed a consistent response (response at both visits): 4 exhibited a
      Gag C-specific consistent response and 1 showed a consistent response to Gag B.
      The remaining five patients, showing response at only one of the two visits, were
      considered inconsistent responders. None of the individuals showed a consistent
      response to both B and C Gag peptides. Marginally significant correlation was
      observed between consistency of the response and lower plasma viral load (p =
      0.062). The subtype-specific Gag C response was also found to be correlated with
      lower viral load as compared with the response to Gag B (r = -0.336, p = 0.054
      for subtype C and r = -0.234, p = 0.13 for subtype B). The data suggest that the
      patients exhibiting consistent subtype-specific responses to HIV-1 Gag might have
      better control of viral replication in early HIV infection.

PMID- 12487811
TI  - Characterizing immune reconstitution after long-term highly active antiretroviral
      therapy in pediatric AIDS.
AB  - In this study, we sought to characterize the T lymphocyte recovery in vertically
      HIV-1-infected children who respond to long-term highly active antiretroviral
      therapy (HAART). A 3-year longitudinal retrospective study was used to perform a
      cross-sectional study of 32 children rated according to the time course of CD4(+)
      T cell percentages in response to antiretroviral therapy and CDC clinical
      classification: (1) long-term asymptomatic (LTA group): 8 children in A1 during
      the whole follow-up period; (2) responsive to HAART (Rec group): 13 children in
      C3 before HAART who achieved CD4(+) T cell counts of > 500 cells/mm(3) after 3
      years of HAART; and (3) nonresponsive to HAART (Non-Rec group): 11 children in C3
      during the whole follow-up period despite 3 years of HAART. We also studied 17
      healthy age-matched uninfected children as controls. Lymphoproliferative
      responses (LPRs) were evaluated by incorporation of [(3)H]thymidine,
      identification of T cell subsets by three-color flow cytometry, and determination
      of thymic production of T cells by quantification of T cell receptor
      rearrangement excision circles (TRECs). Interestingly, the Rec group showed an
      increase in percentage of CD4(+) T cells and a decrease in viral load, and
      recovered LPRs to mitogens and recall antigens, with values similar to those of
      the LTA group. Moreover, the Rec group produced similar percentages and absolute
      counts of naive (CD45RA(+)CD62L(+)) CD4(+) and CD8(+) T cells, and TRECs similar
      to those of the LTA group. In particular, the Rec group produced similar
      percentages of CD8(+)CD28(-)CD57(+) and CD8(+)CD28(-)CD57(-) T cell subsets
      compared with controls. Our data indicate that among children who have already
      progressed to AIDS and severe immunodeficiency but who respond to HAART, the
      immune system can recover and resemble those of nonprogressors or even uninfected
      children, in quantitative as well as in functional terms.

PMID- 12487812
TI  - The effects of different HIV type 1 strains on human thymic function.
AB  - Studies of HIV-1-infected humans indicate that the thymus can be infected by HIV
      1. In some of these patients, there is a significant CD4(+) T cell decline and a
      faster disease progression. This phenomenon is more evident in pediatric patients
      who depend heavily on their thymus for generation of new T cells. We hypothesize
      that HIV-1 causes T cell regenerative failure within the thymus, which has a
      profound impact on disease progression. Building on our established human
      thymopoiesis model, we include dynamic interactions between different HIV-1
      strains (R5 and X4) and thymocytes. Our results predict that thymic infection
      with different HIV-1 strains induces thymic dysfunction to varying degrees,
      contributing to differences in disease progression as observed in both HIV-1
      infected children and adults. Thymic infection in children is more severe than in
      adults, particularly during X4 infection. This outcome is likely due to both a
      higher viral load and a more active thymus in pediatric patients. Our results
      also indicate that a viral strain switch from R5 to X4 induces further
      deterioration in thymopoiesis. We predict that both viral and host factors play
      key roles in controlling thymic infection, including strain virulence and health
      status of the thymus.

PMID- 12487813
TI  - Processing of the HTLV-II envelope precursor glycoprotein gp63 by furin is
      essential for cell fusion activity.
AB  - To investigate the relationship between the fusogenic properties of HTLV-II and
      the processing of the envelope precursor glycoprotein gp63, recombinant cowpox
      virus expressing this protein was used to infect a range of cell lines derived
      from different species. Syncytium formation and gp63 processing were observed in
      all cells with the exception of LoVo cells, which are known to have a
      dysfunctional form of the endoprotease, furin. Furin has been shown to be
      necessary for the processing of a number of viral envelope glycoproteins, and
      gp63 contains a consensus sequence (305)Arg-Arg-Arg-Arg, which is a furin
      substrate motif. Pulse-chase studies demonstrated gp63 processing in Vero but not
      in LoVo cells. In addition it could be shown that expression of recombinant furin
      restored the processing of gp63 to gp46 in LoVo cells, and this resulted in
      syncytium formation. Our findings suggest that furin plays a pivotal role in
      cleavage of the HTLV-II envelope gp63, which in turn is a prerequisite for the
      fusogenic properties of the virus.

PMID- 12487814
TI  - High frequency of recombinant genomes in HIV type 1 samples from Brazilian
      southeastern and southern regions.
AB  - We describe the genetic variability of HIV-1 subtypes and recombinant genomes in
      samples from southeastern and southern Brazilian regions. Phylogenetic analysis
      of a subset of 34 samples (8F, 7B, 7C, 2D, 1A, and 9 B" variant) based on the DNA
      sequencing of the env gp120 and gp41, gag p17, and nef regions confirmed the
      presence of nine (26.5%) potentially HIV-1 recombinant genomes. From the eight C2
      V3 gp120 subtype F samples, only two seem to be pure F. One of the samples,
      classified as B" in the C2-V3 gp120 and as B in gp41 had the gag and nef regions
      clustering with subtype C. Two of seven C2-V3 subtype C samples presented
      distinct recombinant patterns as Bgag/Cenv/Bnef and Bgag/Cenv/Cnef. Putative
      recombinant breakpoints were obtained for three samples presenting discordant
      subtypes (F/B) between gp120 and gp41 env fragments showing that similar
      breakpoints could be observed between two unlinked samples (95BRRJ014 and
      96BRRJ101). A higher degree of polymorphism was verified in the analysis of a
      subtype A sample (98BRRS058) in the C2-V3/gp41 env fragment. The intrasubtype C
      distance was found to be lower than that found for the other subtypes for all
      genomic regions. These data confirm that distinct HIV-1 subtypes and recombinant
      forms are actively participating in the Brazilian AIDS epidemic, and that the
      subtype C was introduced more recently into southern Brazil.

PMID- 12487815
TI  - Subcompartmentalization of HIV-1 quasispecies between seminal cells and seminal
      plasma indicates their origin in distinct genital tissues.
AB  - The mononuclear cells and plasma components of semen from HIV-infected subjects
      have been shown to contain HIV-1. However, there is very little information as to
      whether distinct HIV-1 population are present in these two seminal compartments
      or as to their tissue of origin. Phylogenetic analysis of nucleotide sequences of
      the C2-V5 region of the HIV-1 gp120 from HIV-1 RNA isolated from seminal cells
      and seminal plasma of five subjects indicates that the HIV-1 population derived
      from seminal plasma was distinct from that present in seminal cells. Such
      subcompartmentalization of HIV-1 between seminal cells and seminal plasma was
      detected as early as 3 months after seroconversion and persisted up to 38 months
      following seroconversion. Furthermore, comparison of HIV-1 sequences between
      testis and prostate tissues showed distinct HIV-1 populations in these tissue
      compartments. In situ real-time (Taqman) PCR analysis of prostate and testis
      tissues indicated that T lymphocytes were the predominant cells infected with HIV
      1 in both of these tissues. Since seminal plasma is derived from prostate and
      most of the seminal cells originate from the rete testis and epididymis, these
      results are consistent with the idea that HIV-1 in seminal plasma is derived from
      the prostate, while HIV-1-infected cells in semen originate mostly from the rete
      testis and epididymis. These findings provide for the first time evidence of
      subcompartmentalization of HIV-1 in male genital organs and suggest that
      intervention strategies such as vasectomy may not prevent sexual transmission.

PMID- 12487816
TI  - Among 46 near full length HIV type 1 genome sequences from Rakai District,
      Uganda, subtype D and AD recombinants predominate.
AB  - The impact of HIV-1 genetic diversity on candidate vaccines is uncertain. To
      minimize genetic diversity in the evaluation of HIV-1 vaccines, vaccine products
      must be matched to the predominant subtype in a vaccine cohort. To that end, full
      genome sequencing was used to detect and characterize HIV-1 subtypes and
      recombinant strains from individuals in Rakai District, Uganda. DNA extracted
      from peripheral blood mononuclear cells (PMBC) was PCR amplified using primers in
      the long terminal repeats (LTRs) to generate nearly full length genomes.
      Amplicons were directly sequenced with dye terminators and automated sequencers.
      Sequences were phylogenetically analyzed and recombinants were detected and
      mapped with distance scan and bootscan. Among 46 sequences, 54% were subtype D,
      15% were subtype A, and 30% were recombinant. All recombinants were individually
      unique, and most combined subtypes A and D. Subtype D comprised more than 70% of
      all the HIV-1 genomes in Rakai when both pure subtypes and recombinants were
      considered. Candidate vaccines based on HIV-1 subtype D would be appropriate for
      evaluation in Rakai District, Uganda.

PMID- 12487817
TI  - Detection of mucosal antibodies in HIV type 1-infected individuals.
AB  - HIV-1-specific mucosal IgA antibodies may correlate with protection in highly
      exposed but uninfected individuals, but have been detected at highly variable
      levels in HIV-1-infected individuals. To determine the best assays for detection
      of IgA antibodies in mucosal samples, rectal washes from 16 HIV-1-infected and 14
      uninfected individuals were distributed to six laboratories experienced in
      detection of mucosal antibodies. Assays for HIV-1-specific IgA and IgG were
      performed in a blinded fashion by each of the laboratories using modifications of
      ELISA and chemiluminescence-enhanced Western blotting. Rectal washes contained
      easily detectable total IgA levels that did not differ between HIV-1-infected and
      uninfected groups. Irrespective of the assay used, HIV-1-specific IgA antibodies
      were absent in most samples; only one laboratory identified a higher frequency of
      positive samples from HIV-1-infected than uninfected individuals. In spite of 10
      fold lower levels of total IgG than IgA, all but one laboratory identified HIV-1
      specific IgG in most rectal washes of HIV-1-infected individuals. Comparable and
      readily detectable levels of influenza-specific IgA antibodies were present in
      nasal, salivary, and rectal secretions from both HIV-1-infected and uninfected
      individuals. These observations suggest a selective alteration in the production
      of HIV-1-specific IgA antibodies in HIV-1-infected individuals.

PMID- 12487818
TI  - Increased proliferation within T lymphocyte subsets of HIV-infected adolescents.
AB  - Proliferation within T lymphocyte subsets of HIV-infected adolescents was
      quantified by detection of Ki-67, a nuclear antigen found in cells in late G(1),
      S, or G(2) phases of the cell cycle. Median percentages and absolute counts of Ki
      67(+) cells for all subsets tested (CD4 naive and memory, CD8 naive and memory)
      were significantly higher for HIV-infected adolescents compared to uninfected
      controls. CD8 naive cells of HIV-infected adolescents had the greatest increase
      in rate of proliferation and number of proliferating cells compared to uninfected
      controls. In HIV-infected adolescents, the percentage and absolute number of
      proliferating CD4 naive cells were considerably lower than corresponding values
      for the other subsets. CD4 percent correlated inversely with Ki-67 expression in
      CD4 memory, CD8 naive, and CD8 memory cells, while Ki-67 expression in CD4 and
      CD8 memory cells correlated directly with average CD38 molecules/CD8 cell and
      absolute number of CD8/CD38/HLA-DR cells, consistent with T cell activation.
      These results indicate that in adolescents, HIV infection is associated with
      increased proliferation within CD4 and CD8 naive and memory subsets.
      Proliferation within the CD8 naive subset was higher than that observed
      previously for HIV-infected adults, suggesting that adolescents have a greater
      ability to regenerate and/or expand CD8 naive cells. CD4 naive cells of HIV
      infected adolescents had a low rate of proliferation, and the total number of CD4
      naive cells was low, suggesting that regeneration and/or peripheral expansion are
      limited and may contribute to the reduced size of this subset. The Ki-67 assay
      provided new and useful information on in vivo lymphocyte proliferation in HIV
      infected adolescents.

PMID- 12487819
TI  - High mannose glycans and sialic acid on gp120 regulate binding of mannose-binding
      lectin (MBL) to HIV type 1.
AB  - Mannose-binding lectin (MBL) is a C-type lectin of the innate immune system that
      binds to carbohydrates on the surface of certain microorganisms. Previous studies
      showed that MBL binds to gp120, the envelope glycoprotein of HIV-1. gp120 is
      extensively glycosylated, with N-linked complex and high mannose carbohydrates
      accounting for about half of the molecular weight. The objectives of this study
      were to determine the types of glycans on gp120 important for MBL binding and to
      determine if alteration of complex glycans with neuraminidase (NA) could enhance
      the interaction of MBL with virus. Lectin blot analyses revealed that MBL
      interacted with recombinant gp120 (rgp120) from both T cell-tropic and M-tropic
      virus strains. Treatment of rgp120 with endoglycosidase H (eH) or endoglycosidase
      F1 (eF1) abrogated binding of MBL, but did not decrease binding of wheat germ
      agglutinin indicating that high mannose and/or hybrid N-linked glycans were
      required for MBL binding. Removal of sialic acids from rgp120 with NA enhanced
      MBL binding. Treatment of intact virus from T cell lines or primary isolates with
      eF1 also significantly decreased HIV binding to MBL, while treatment with NA
      substantially increased binding. Treatment of virus with both eF1 and NA did not
      decrease binding compared to NA alone suggesting that NA treatment exposed
      binding sites on gp120 that are not high mannose glycans. These studies provide
      evidence that MBL binds to HIV via high mannose carbohydrates on gp120 and shows
      that the interaction of MBL with virus is regulated by sialylation.

PMID- 12487820
TI  - HIV type 1 abrogates TAP-mediated transport of antigenic peptides presented by
      MHC class I. Transporter associated with antigen presentation.
AB  - Downregulation of MHC class I expression following human immunodeficiency virus 1
      (HIV-1) infection is thought to play an important role in viral escape from
      immune recognition by cytotoxic T-lymphocytes (CTLs). Since exogenous addition of
      HIV-1-derived peptides restores susceptibility of HIV-1-infected cells to CTL
      mediated lysis, we tested whether endogenous peptide loading is impaired in these
      cells. Our results show that in HIV-1-infected cells the ability of the
      transporter associated with antigen presentation (TAP) to translocate antigenic
      peptides from the cytosol to the lumen of the ER for presentation on MHC class I
      molecules is abolished. These data suggest that interference with the supply of
      antigenic peptides to the MHC class I pathway provides an additional mechanism by
      which HIV-1 evades the CTL-mediated immune response.

PMID- 12487821
TI  - Novel evolutionary analyses of full-length HIV type 1 subtype C molecular clones
      from Cape Town, South Africa.
AB  - Understanding the origin, distribution, and evolving dominance of HIV-1 subtype C
      strains is an important component in the design and evaluation of a globally
      effective AIDS vaccine. To better understand subtype C viruses, we constructed
      complete molecular clones of primary, CCR-5-using isolates from South Africa and
      analyzed the molecular phylogenies of these clones using best fitting
      evolutionary substitution models. Analyses were performed on three full-length
      sequences, and on the individual genes. All clones were nonrecombinant, and
      although two of three had open reading frames and intact splice sites, they were
      not infectious. At the genomic level, the models demonstrated the increasing
      variability of subtype C in South Africa. At the subgenomic level, they revealed
      marked differences in the evolutionary patterns of individual genes, a finding
      that suggests that the genes are under different selective pressures and
      constraints. These data underscore the dynamic nature of the subtype C epidemic
      and emphasize the need for continuous monitoring of local strains.

PMID- 12487822
TI  - Low level viremia and high CD4% predict normal survival in a cohort of HIV type-2
      infected villagers.
AB  - A community-based study of human immunodeficiency virus type 2 (HIV-2) infection
      was conducted in a rural village in northern Guinea Bissau, West Africa to assess
      the relationship between plasma HIV-2 RNA levels, CD4 lymphocyte percentage, and
      survival over an 8-year period. The cohort of 133 HIV-2-infected individuals and
      160 HIV-uninfected controls enrolled in 1991 were followed up at home until 1998.
      Thirty-one (23%) HIV-2-infected and 24 (16%) HIV-uninfected individuals died over
      the follow-up period (mortality hazard ratio 1.7, 95% CI 1.0, 2.9; p= 0.06). In
      HIV-2-infected individuals, the median HIV-2 RNA level was 347 copies/ml and the
      mean CD4% was 28.6. Both plasma viremia and CD4% were independent predictors of
      survival, with hazard ratios increasing by 1.6 (95% CI, 1.1, 2.3) for each
      log(10) increase of plasma viremia and 1.7 (1.1, 2.6) for each 10% decrease of
      CD4%. Infected subjects with a plasma viral load >or= the median (347 copies/ml)
      and a CD4% <or= the mean (28.6%) had a mortality hazard ratio of 3.1 (95% CI 1.7,
      5.8) compared to uninfected controls, whereas the remaining infected subjects had
      a mortality rate similar to uninfected controls, the mortality hazard ratio being
      1.0 (95% CI, 0.5, 2.1.) In those who survived between 1991 and 1996, HIV-2 RNA
      levels were unchanged overall and CD4 lymphocyte counts remained high. In
      conclusion, baseline HIV-2 RNA levels predicted a normal survival for the
      majority, with low and stable levels of plasma viremia characterizing HIV-2
      infections in this rural West African community.

PMID- 12487823
TI  - Rapid disease progression in human immunodeficiency virus type 1-infected
      seroconverters in India.
AB  - To determine if the early immunological and virological events of HIV infection
      are unique in a setting with limited access to health care and HIV-1 subtype C
      infection, we undertook a prospective cohort study to characterize the early
      natural history of HIV viral load and CD4(+) T lymphocyte counts in individuals
      with recent HIV seroconversion in India. CD4(+) T lymphocyte counts were
      prospectively measured for up to 720 days in 46 antiviral drug-naive persons with
      very early HIV infection, documented by HIV antibody seroconversion. HIV viral
      RNA levels were measured subsequently on reposited plasma samples from these same
      time points. The median viral load "set point" for Indian seroconverters was
      28,729 RNA copies/ml. The median CD4(+) cell count following acute primary HIV
      infection was 644 cells/mm(3). Over the first 2 years since primary infection,
      the annual rate of increase in HIV viral load was +8274 RNA copies/ml/year and
      the annual decline in CD4 cell count was -120 cells/year. Although the viral "set
      point" was similar, the median trajectory of increasing viral load in Indian
      seroconverters was greater than what has been reported in untreated HIV
      seroconverters in the United States. These data suggest that the more rapid HIV
      disease progression described in resource-poor settings may be due to very early
      virological and host events following primary HIV infection. A rapid increase in
      viral load within the first 2 years after primary infection may have to be
      considered when applying treatment guidelines for antiretroviral therapy and
      opportunistic infection prophylaxis.

PMID- 12487824
TI  - Therapeutic responses to AZT + 3TC + EFV in advanced antiretroviral naive HIV
      type 1-infected Ugandan patients.
AB  - Convenient, non-food-dependent dosing, low tablet volume, and relatively low cost
      have made nonnucleoside reverse transcriptase inhibitors a first choice for both
      clinicians and patients in Uganda. Concerns exist as to their efficacy in
      patients with viral loads (VL) above 100,000 copies/ml, a feature common to about
      75% of HIV-1-infected patients presenting at the Joint Clinical Research Center
      (JCRC) in Uganda. Furthermore, there are few data on the response to such therapy
      of non-B subtypes, A and D, predominant in Uganda. Presented here is a
      retrospective analysis of therapeutic responses in 11 antiretroviral (ARV) naive
      HIV-1-infected Ugandan patients who had been initiated on zidovudine (AZT),
      lamivudine (3TC), and efavirenz (EFV). Laboratory assessments subsequent to
      initiation of ARV therapy, done at 11.6 +/- 3.9 weeks and 30.6 +/- 5.9 weeks,
      showed 88.9 and 71.4% patients achieved undetectable viral load, respectively.
      Virological suppression to below detection occurred in 85.7% of patients at 11.6
      weeks despite baseline VL >or= 100,000 copies/ml. At 31 weeks there was a median
      increment of +183 cells/mm(3) in CD4(+) T lymphocytes. These findings reflect
      significant efficacy in the use of AZT + 3TC + EFV in advanced ARV naive non-B
      subtype HIV-1-infected patients. The therapeutic responses were comparable to
      those previously described in the western world.

PMID- 12487825
TI  - Mechanisms of HIV type 1-induced cognitive impairment: evidence for hippocampal
      cholinergic involvement with overstimulation of the VIPergic system by the viral
      coat protein core.
AB  - HIV-1 is associated with a neuroAIDS syndrome that includes cognitive impairment.
      Several components of HIV-1 are capable of affecting cognition, but which of
      these is the major mediator is unknown. We injected into the lateral cerebral
      ventricle of mice HIV-1 pseudoviruses expressing the full viral genome with or
      without the viral coat glycoproteins, gp120/gp41. Only virus possessing
      gp120/gp41 induced defects in memory as assessed in an active avoidance T-maze
      footshock paradigm. By itself, gp120 also induced impairments that were reversed
      by hippocampal cholinergic stimulation. Paradoxically, low doses of gp120 could
      improve memory. Such low-dose, paradoxic improvement is a characteristic of
      substances that impair memory by overstimulating pathways that normally sustain
      memory. Consistent with this, a low, but not a high, dose of gp120 reversed
      memory impairment induced by overstimulation of the VIPergic system, a memory
      sustaining pathway. Further characterization showed that two strains of gp120 (SF
      and MN) were equally effective at improving memory and that, unlike other actions
      of gp120, glycation was not required. We conclude that (1) the predominant
      cognitive-impairing component of HIV-1 is its viral coat glycoproteins, (2) gp120
      impairs memory by overstimulating pathways that normally sustain memory, (3) the
      cognitive effect of gp120 is mediated by its protein core, and (4) gp120 likely
      impairs memory by affecting the cholinergic/VIPergic system.

PMID- 12487826
TI  - Sustained antibody-dependent cell-mediated cytotoxicity (ADCC) in SIV-infected
      macaques correlates with delayed progression to AIDS.
AB  - Although several in vitro lines of evidence support the potential power of
      antibody-dependent cell-mediated cytotoxicity (ADCC) in controlling HIV
      infection, the role of ADCC in the pathogenesis of HIV infection in vivo remains
      uncertain. There are few studies to date that longitudinally determine the plasma
      ADCC activity in HIV-infected subjects. We sought to establish an SIV/macaque
      model to perform such a longitudinal study. In the rhesus macaque cohort studied
      here, three of five macaques (designated Group 1) maintained higher plasma ADCC
      activity for at least 1 year after inoculation with SIV/17E-Br. The ADCC activity
      of the two remaining macaques (Group 2) fell 12 weeks after inoculation. There
      were also differences in longitudinal measurements of anti-SIV envelope IgG
      titers and CD4 counts. Group 1 macaques maintained higher antienvelope IgG titers
      and higher CD4(+) T cell numbers as late as 60 weeks postinoculation, while Group
      2 macaques had significantly lower titers at 1 year postinoculation and lower
      CD4(+) T cell counts by 30 weeks postinoculation. Our study shows a correlation
      between humoral response, ADCC activity, and disease progression (as measured by
      CD4(+) T cell counts). In these animals, ADCC activity is associated with delayed
      progression to AIDS. Further studies are underway to determine if ADCC is a
      protective immune response in SIV infection or if ADCC is a marker of intact
      cellular and humoral immune responses.

PMID- 12487827
TI  - Characterization of CD4-induced epitopes on the HIV type 1 gp120 envelope
      glycoprotein recognized by neutralizing human monoclonal antibodies.
AB  - The entry of human immunodeficiency virus (HIV-1) into target cells typically
      requires the sequential binding of the viral exterior envelope glycoprotein,
      gp120, to CD4 and a chemokine receptor. CD4 binding exposes gp120 epitopes
      recognized by CD4-induced (CD4i) antibodies, which can block virus binding to the
      chemokine receptor. We identified three new CD4i antibodies from an HIV-1
      infected individual and localized their epitopes. These epitopes include a highly
      conserved gp120 beta-strand encompassing residues 419-424, which is also
      important for binding to the CCR5 chemokine receptor. All of the CD4i antibodies
      inhibited the binding of gp120-CD4 complexes to CCR5. CD4i antibodies and CD4
      reciprocally induced each other's binding, suggesting that these ligands
      recognize a similar gp120 conformation. The CD4i antibodies neutralized
      laboratory-adapted HIV-1 isolates; primary isolates were more resistant to
      neutralization by these antibodies. Thus, all known CD4i antibodies recognize a
      common, conserved gp120 element overlapping the binding site for the CCR5
      chemokine receptor.

PMID- 12487828
TI  - Presence of prolonged dispersion of qt intervals in late survivors of childhood
      anthracycline therapy.
AB  - To determine the incidence of abnormal dispersion of QT intervals on an ECG the
      authors measured these intervals in long-term survivors after anthracycline
      treatment for childhood malignancies and compared the incidence to the
      traditional markers, prolonged QT and QTc intervals. Prolonged QT dispersion
      (QTd) and corrected QT dispersion (QTcd) have been associated with serious
      arrhythmias and sudden death in many forms of heart disease. The above intervals
      and shortening fraction (SF) on echocardiogram were determined in 64 late
      survivors who were 4-22 years post anthracycline therapy. They were divided into
      2 groups: group I, 39 patients with normal function with SF >or= 29%, and group
      II, 15 patients with SF < 29%. An additional 10 patients had died and had SF <
      29% at the time of death. They were divided into 2 groups: group III, 5 patients
      who died with heart failure after a mean of 12 years from of therapy, and group
      IV, 5 patients who had a sudden cardiac death after a mean of 9 years from end of
      therapy. In group I patients, the incidence of prolonged QT and QTc intervals was
      < 6%, whereas that of QTd and QTcd was > 38%. In group II patients, the presence
      of prolonged QT and QTc intervals was < 16%, whereas that of QTd and QTcd was >
      40%. The QTc (p =.01), QTd (p =.02), and QTcd (p =.01) were significantly higher
      and SF (<.01) significantly lower in group IV compared to those alive (group I
      and II patients) with no significant difference in age, number of years of follow
      up, precordial radiation dose, or anthracycline dose between the two. The
      combination of QTcd > 110 ms and diminished SF < 29% was found to be associated
      with sudden death. In summary, the long-term survivors of anthracycline therapy
      had a high incidence (>38%) of abnormally prolonged QT dispersion intervals, QTd
      and QTcd, even in those with normal QT and QTc on an ECG and normal shortening
      fraction on an echocardiogram.

PMID- 12487829
TI  - Investigation of TT virus in the etiology of pediatric acute lymphoblastic
      leukemia.
AB  - Infectious agents have been implicated in the pathogenesis of pediatric acute
      lymphoblastic leukemia (ALL). A novel human DNA virus, TT virus (TTV), has been
      identified in children possessing characteristics as an etiologic agent, making
      the virus a potential candidate. Analysis of specimens from children with ALL was
      performed to determine if an association exists. Archived specimens (79
      peripheral blood mononuclear cells, PBMC/bone marrow cells, BMC, and 125
      cerebrospinal fluid, CSF) obtained at diagnosis and during therapy from 28
      pediatric patients were tested for TTV. All of the diagnostic BMC/PBMC were
      negative for TTV, but 7 patients had follow-up specimens that converted to TTV
      positivity. TTV was not detected in any CSF. The absence of TTV at diagnosis
      suggests TTV is unlikely to be causally associated with ALL in the cases
      analyzed. However, the data support TTV transmission through blood products and
      suggest that the CNS is not a sanctuary site for TTV.

PMID- 12487830
TI  - The efficacy of heparinization in prolonging patency of arterial and central
      venous catheters in children: a randomized double-blind trial.
AB  - This study evaluates the efficacy of heparinization in prolonging patency of
      arterial and central venous catheters in children. A randomized double-blind
      trial in a tertiary 10-bed pediatric intensive care unit was used to evaluate 300
      children (age older than 4 weeks, younger than 18 years). Trial medication
      consisted of either NaCl 0.9% infusion or NaCl 0.9% infusion to which 1 IU of
      heparin per milliliter was added. The number of nonpatent arterial and central
      venous catheters and the duration of stay of patent arterial and central venous
      catheters were measured. There was a significant risk increase for nonpatency in
      the nonheparinized arterial catheters (relative risk [RR]: 3.54; 95% confidence
      interval [CI]: 1.01-12.42). No significant risk increase for nonpatency could be
      demonstrated for the nonheparinized central venous catheters (RR: 7.63; 95% CI:
      0.40-145). The median duration of stay of the patent arterial and central venous
      catheters was similar for both treatment groups. These results indicate that the
      use of normal saline in arterial catheters is associated with an increased
      frequency of catheter nonpatency as compared with heparinized saline.

PMID- 12487831
TI  - Endogenous pro-inflammatory cytokines in children and adolescents during
      chemotherapy-induced neutropenia.
AB  - Monocyte-derived pro-inflammatory cytokines such as GM-CSF, IL-12, and IP-10
      might protect patients with chemotherapy-induced neutropenia against infections.
      In settings with abundant neutrophils, G-CSF has been described as a suppressor
      of IL-12, but also as an inducer of GM-CSF. In 25 pediatric patients with
      chemotherapy-induced neutropenia the authors measured plasma levels of these four
      cytokines. GM-CSF was detectable in only a minority of patients (6/25). It was,
      however, positively correlated with high plasma levels of IL-12 and IP-10. G-CSF
      levels, however, were in no way correlated with the levels of any of these three
      cytokines.

PMID- 12487832
TI  - Red blood cell indexes in patients in patients with hereditary spherocytosis and
      beta-thalassemia combination.
AB  - The spontaneous occurrence of hereditary spherocytosis (HS) and beta-thalassemia
      in the same patient is a rare event. The mean corpuscular hemoglobin
      concentration is elevated above the reference range in half to two-thirds of
      patients with HS, but there are no data for the HS/beta-thal combinations for the
      red blood cell indexes. This study reassessed these values in these particular
      patients. Hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular
      hemoglobin concentration (MCHC), red cell distribution (RDW), and reticulocyte
      count were documented from 43 HS patients, 13 of which were from 10 families with
      the combination of beta-thal and HS; 28 controls were also included. Patients
      with HS/beta-thal have a significantly lower MCV, mean corpuscular hemoglobin,
      and MCHC and a significantly higher RDW than normal control subjects; 95% of beta
      thalassemia carriers are free of clinical symptoms. When red blood cell indexes
      reveal a possibility of a beta-thalassemia carrier state with the symptoms of
      hemolytic anemia, HS should be considered.

PMID- 12487833
TI  - Centrofacial malignant T-cell lymphoma exhibiting recurrent fever and skin ulcer
      in a 3-year-old girl.
AB  - A rare case of undetermined fever and skin ulcers is reported. The patient had an
      8-month history of recurrent fever, destructive ulceration of the midline facial
      tissue, and symmetrical skin ulcer in the cheeks and the back of the hand.
      Pathological examination revealed that the patient had lethal midline granuloma
      (centrofacial malignant T-cell lymphoma), which is very rare in childhood.
      Centrofacial malignant T-cell lymphoma should be considered as a differential
      diagnosis of unexplained fever and skin ulcer in children.

PMID- 12487834
TI  - Hematological abnormalities in inborn errors of metabolism--how frequent are
      they? The Cretan experience.
AB  - This study aimed to ascertain the frequency and type of hematological findings in
      a defined group of patients with inborn errors on Crete. The key role of these
      hematological findings in the diagnosis of the inborn errors in daily practice
      was explored. A variety of hematological findings were obtained from 31 of the
      132 subjects who had been referred to the University Hospital of Heraklion. A
      diagnosis of inborn errors of metabolism (IEM) was confirmed in 21 subjects, but
      in 12 of them the diagnosis was combined with hematological findings. The
      hematological findings consist of a neglected area in the diagnosis of the IEM,
      and cooperation of primary care physicians and neurologists could help
      hematologists in the management of people with unexplained hematological symptoms
      and signs.

PMID- 12487835
TI  - Incidental diagnosis and tempestive therapy in a case of neonatal alloimmune
      thrombocytopenia due to anti-HPA-5b.
AB  - Neonatal alloimmune thrombocytopenia (NAIT) is usually attributable to HPA-1a
      antibodies. The authors report a case of incidentally diagnosed thrombocytopenia
      in a small for gestational age infant. A NAIT was suspected and she was
      successfully treated with intravenous IgG. The direct and indirect platelet
      suspension immunofluorescence test (PSIFT) in maternal blood suggested
      alloimmunization to HPA-5b. Empiric treatment with IgG could be useful in case of
      clear suspect even in absence of confirmed diagnosis.

PMID- 12487836
TI  - High levels of FVIII and FIX in a pediatric patient with retinal artery
      occlusion.
AB  - A 13-year-old female patient with the diagnosis of retinal artery occlusion was
      evaluated for thrombophilia. The data revealed high FVIII and FIX levels. The
      patient had familial clustering. The data indicate that elevated FVIII and FIX
      could be a risk factor for thrombosis.

PMID- 12487837
TI  - Bilateral exopthalmus due to retro-orbital chloromas in a boy with t(8;21)-
      positive acute myeloblastic acute leukemia.
AB  - Exophthalmus is an infrequent finding in pediatrics. The differential diagnoses
      include chloromas, tumors of immature hematopoietic precursor cells. The case of
      a child with acute myeloid leukemia is reported. The presenting signs had
      included exophthalmus and nasal speech due to retro-orbital and sinusoidal
      chloromas, respectively. As in most cases of pediatric acute myeloid leukemia
      with chloroma, the AML1/ETO fusion gene was found, which portended a not
      unfavorable prognosis. This child was treated according to the AML-BFM 98
      protocol and achieved an ongoing remission. The exophthalmus resolved completely.

PMID- 12487838
TI  - Antithrombin supplementation III in childhood acute lymphoblastic leukemia
      treated with L-asparaginase.
AB  - The change of plasma antithrombin III (AT) levels after supplementation of AT
      concentrates was examined in ALL children with acquired AT deficiency following L
      asparaginase (ASP) administration. The patients received AT concentrates of 34.5
      +/- 7.6 U/kg. The increase of plasma AT activity and antigen was 2.07 +/- 0.62%
      and 0.70 +/- 0.16 mg/dL per unit AT infused per kilogram of body weight,
      respectively. The activity decreased to 62.0 +/- 7.7% of the peak values by 48
      hours after supplementation. The administration of AT concentrates constantly
      increased the plasma AT activity in ALL children treated with ASP, which may
      minimize the acquired prothrombotic state.

PMID- 12487840
TI  - 'Floating support': implications for interprofessional working.
AB  - This article describes a floating support scheme, provided by a local housing
      association, which enables single vulnerable people to live independently in
      their own homes. The study aimed to explore the impact of the scheme from the
      perspectives of clients, floating support workers and representatives from
      health, social care and voluntary agencies. It was found that the majority of
      clients had long-term mental health problems and were supported by a range of
      professionals. Floating support was flexible in responding to individual needs. A
      number of themes of relevance to interprofessional working emerged from the data.
      These included: floating support as a community resource, links with other
      agencies and confidentiality, information sharing and risk management. Floating
      support workers worked closely with professionals from health, social care,
      voluntary and educational services. Although the scheme's contribution to client
      care was highly valued, a number of barriers to effective interagency working
      were evident. This study highlighted the need for discussion and presented a
      forum for developing an ongoing collaborative process to address the specific
      issues which emerged in focus group discussions.

PMID- 12487841
TI  - Assessing risk: professional perspectives on work involving mental health and
      child care services.
AB  - The assessment of risk is central to work with families where parental mental
      health needs and child care concerns coexist. This article reports on the
      findings of three interprofessional focus groups which examined professionals'
      experiences of working with such families. Specialisation and differing
      thresholds and codes were identified as factors which contributed to difficulties
      for practitioners and families and scepticism was expressed concerning the
      feasibility of a key worker system for this group. The issue of psychiatric
      diagnosis evoked ambivalent responses and was both valued as offering direction
      for planning interventions and seen as a means of labelling and excluding
      individuals from services. The focus group participants were aware that assessing
      risk placed families under considerable pressure, but practitioners themselves
      also appeared to experience an emphasis on risk as restrictive.

PMID- 12487842
TI  - Evidence-based practice in health and social care: where are we now?
AB  - This paper explores evidence-based practice (EBP) in health and social care in
      the UK from the individual perspectives of professionals in physiotherapy,
      midwifery, nursing and social care. The present interest in EBP emerges as a
      natural derivative of contemporary economic, social and political trends and
      concerns. There is optimism and broad acceptance of the overall philosophy of EBP
      and each profession demonstrates a concerted organisational attempt to bridge the
      research--practice divide. This includes the interpretation of research outcomes
      in the form of practice guidelines, protocols and standards. However, adherence
      to these is poor and resistance to EBP is growing. This is attributed to
      practical and philosophical tensions common to all of the professions. These
      include the continued dominance of randomised controlled trials (RCTs) in the
      hierarchy of evidence. RCTs often fail to capture the multi-faceted
      individualistic nature of health and social care interactions or the development
      of qualitative methodologies within the professions. Concern is expressed that
      professional autonomy and the art of practice will be eroded by the enforcement
      of guidelines and protocols. EBP is currently located within individual
      professions rather than the broader context of interprofessional practice. The
      future of EBP is dependent, at least in part, on educational initiatives,
      organisational commitment and support, patient/client involvement and the
      development of a broader interprofessional perspective.

PMID- 12487843
TI  - Learning to plan? A critical fiction about the facilitation of professional and
      practice development plans in primary care.
AB  - A shift from continuing medical education towards professional and organisational
      development policies, coupled with the introduction of accountability frameworks
      (clinical governance), has generated interest in professional and practice
      development plans (PPDPs) in general practice. The problems of implementing this
      change in an independent contractor-based service remain unexplored and the aims
      of this study were to focus on the facilitator's experience of the issues that
      hampered or fostered development in general practice. Facilitators of PPDPs were
      asked to document their experience of supporting 12 practices in an all Wales
      feasibility study. In order to maintain organisational anonymity while reporting
      accurate accounts of the obstacles encountered, a method known as critical
      fiction was employed. This method allowed the authors to write detailed
      reflective accounts that were then fictionalised. The culture of general practice
      reflects the development of an independent contractor service that has developed
      into partnerships that employ some professionals (practice nurses, managers and
      administrative staff) and collaborate with others in variable arrangements
      (community nurses, health visitors, midwives and others). Developing organisation
      wide systems in so-called 'primary health care teams' is a difficult exercise,
      given the ethos of autonomous decision-making processes and the lack of
      experience of 'whole systems' approaches in primary care. The potential for
      multiprofessional synergy and the evidence that systematic changes lead to
      sustained health care improvements are well established. But the implementation
      issues of these concepts have not been addressed. Existing educational policies
      are based in uniprofessional paradigms and the protected time requirements and
      funding streams required for PPDPs have not been clarified.

PMID- 12487844
TI  - Balancing professional and team boundaries in mental health services: pursuing
      the holy grail in Somerset.
AB  - The overcoming of professional boundaries to collaboration in patient care has
      become one of the goals of mental health service policy in England over the past
      25 years, predominantly through the creation of community mental health teams.
      However, research has shown that these boundaries have been slow to come down,
      and some commentators have pointed to the benefits of appropriate boundaries.
      This paper introduces a theoretical framework, which seeks to categorise boundary
      activity in organisations and then examines the boundary activity of professional
      groups and community teams during the integration of mental health and social
      care service provision in one locality in the southwest of England. The paper
      identifies the ways in which this integration impacted on boundary activity and
      draws out the messages for mental health policy and practice that emerge.

PMID- 12487845
TI  - The impact of the Bristol Royal Infirmary disaster and inquiry on public services
      in the UK.
AB  - The inquiry into the services provided by the paediatric cardiac surgical team at
      Bristol Royal Infirmary between 1984 and 1995 marks a watershed in the
      development of health and social care services in the UK. There was an
      organisational failure of foresight based on a series of systemic and
      communication failures which contributed to oversight of an 'incubating' hazard
      which ultimately led to disaster. The recommendations of the Bristol inquiry have
      provided a major stimulus to the modernisation programme and especially of
      governance in health and social care which aims to restore public confidence and
      create 'high-trust' organisations. While it is premature to evaluate the impact
      of the changes, there is little evidence at present to indicate that they will
      improve the quality of professional decision making and the safety of users or
      enhance user and public confidence in the NHS and other public services.

PMID- 12487846
TI  - In our own image--a multidisciplinary qualitative analysis of medical education.
AB  - One aim of reform of undergraduate medical education is to achieve a better
      balance between an emphasis on scientific knowledge and an enhancement of
      desirable professional attitudes: for example, reducing the core curriculum in
      biochemistry in order to increase learning opportunities in ethics. This study
      was based on qualitative data collected from stakeholders involved in community-
      and primary care-based medical education. Its aim was to consider whether
      different participants agreed on the desired outcomes of basic medical training,
      and the contribution of community and primary care settings. Analysis of the data
      showed that the professional identity of the future doctor is contested, its
      goals reflective of the 'world view' of the stakeholder, and seen as being highly
      dependent on the contexts in which students learn. Themes which emerged suggest
      that medical education may not achieve its goals unless student experiences
      become less dominated by the context of secondary care and its predominantly
      technical practice of medicine, and more attention is paid to the personal
      development of the students. The discussion considers the implications for
      further reform, and emphasises the role of multidisciplinary tutoring in
      remodelling the world view of 'tomorrow's doctors'.

PMID- 12487847
TI  - The state of the world's pharmacy: a portrait of the pharmacy profession.
AB  - Pharmacy is the health profession that has the responsibility for ensuring the
      safe, effective and rational use of medicines. As such it plays a vital part in
      the delivery of health care world-wide. However, there remain wide variations in
      the practice of pharmacy, not only between countries but also within countries.
      Nevertheless, in recent years there has been significant convergence, driven by a
      number of key factors. These include World Health Organization declarations
      concerning the role of pharmacists, changes in the political climate of many
      countries, and the pursuit by pharmacists themselves of the goals of medicines
      management and pharmaceutical care. This paper considers the main activities
      undertaken by pharmacists, describes their education and regulation, and explores
      the current state of pharmacy around the world.

PMID- 12487848
TI  - Developing consensus and interprofessional working in cancer services: the case
      of user involvement.

PMID- 12487849
TI  - [Preoperative high-dose chemotherapy with peripheral blood stem cell support in
      breast cancer: report of 3 cases].
AB  - OBJECTIVE: To investigate the possibility and short-term effect of high dose
      chemotherapy with peripheral blood stem cell support in the preoperative therapy
      of breast cancer, and-its influence on the following operation and would healing.
      METHODS: Three patients with T(3)N(1)M(0) (III(a)), T(4)N(1)M(0) (III(b)),
      T(4)N(1)M(1) (IV) of breast cancer were diagnosed histopathologically. After
      receiving HDC/APBSCT, the 3 patients were operated on. HDC/APBSCT process
      included 2 cycles of FEC induction chemotherapy; PBSC mobilization, APBSC
      collection and cryopreservation and PBSC infusion; and high-dose chemotherapy,
      APBSC infusion and supportive therapy. The therapy consisted of CTX2.5 g/m(2), VP
      16 600 mg/m(2), and cerboplatin 600 mg/m(2) delivered on day 1, APBSC infusion 48
      h later, rhG-CSF (150 microg, BID) was administered 4 h after infusion of APBSC
      until WBC was higher than 10 x 10(9)/L. During HDC/APBSCT, the patients were
      protected in the air laminar flow room with supportive therapy of antibiotics,
      anti-virus and anti-fungus drugs. They left the air laminar flow room after their
      WBC was greater than 2 x 10(9)/L. Case 1 was treated by radical mastectomy, Case
      2 by improved radical mastectomy, Case 3 by improved radical mastectomy and
      transplantation of skin for the large area. RESULTS: Rapid recovery of bone
      marrow function was observed in all 3 patients. Operation was performed 4 weeks
      after HDC/PBSCT in Cases 1, 2 and 33 days in Case 3. No influence was seen on
      operative procedure and would healing, especially in Case 3 with a large area of
      skin transplantation. Two patients with stage III(a) and III(b) have been alive
      since the treatment for 30 months and the other with stage IV died of brain
      metastasis 16 months later. CONCLUSIONS: HDC/APBSCT as a preoperative therapy for
      breast cancer has no influence on the coming surgery and would healing, even on
      skin transplantation for a large area. It has a practical response in stage
      III(a) and III(b), but it is still controversial in stage IV. This method as a
      salvage therapy for patients with breast cancer of intemuediate or stage.

PMID- 12487850
TI  - [Transdifferentiating of adult human pancreatic stem cells into islet cells].
AB  - OBJECTIVE: To understand and improve the transdifferentiation of pancreatic stem
      cells into islet cells through isolation, cultivation and transdifferentiation of
      adult human pancreatic duct cells. METHODS: A portion of adult human pancreas was
      digested with collagenase, followed by incontinuous density gradient to separate
      islets from the acinar and ductal tissue. Duct epithelial cells were cultivated
      in CMRL1066 and then in serum-free DMEM/F12 medium with the addition of growth
      factors for 27 days. Samples were taken at different time points for light and
      electron microscopic examination and for immunocytochemical study with antibodies
      against transdifferentiation gene PDX-1 and protein CK-19. Amylase and insulin
      contents in the medium were assayed. RESULTS: A large number of duct epithelial
      cells were harvested after the isolation of islets. Some duct epithelial cells
      were PDX-1 and CK-19 positive at day one and duct epithelial cells proliferated
      and expanded rapidly and then transdifferentiated into stem cells and finally 3D
      islets. 760 islets were harvested from each gram of pancreatic tissue on day 27.
      CONCLUSIONS: Adult pancreatic duct cells are potential stem cells and could be
      transdifferentiated into islet cells in vitro under appropriate conditions.

PMID- 12487851
TI  - [Double promoters induct suicide gene target killing of 5-FU drug-fast cancer
      cells].
AB  - OBJECTIVE: To study target killing of 5-FU drug-fast cancer cells with
      thymidylate synthase (TS) and p16 gene promoters inducting TK gene expression.
      METHODS: TS promoter was inserted to 5' end and p16 promoter inserted to 3' end
      of TK cDNA sequence, constructing recombinant plasmid of pXJ41. Human rectal
      cancer cell lines of HR-8348 and normal peripheral blood mononuclear cells (PBMC)
      were transfected with the recombinant plasmid. Plating efficiency was counted and
      survival rates of cells were tested with MTT method. And suppression rates of
      xenograft tumors in nude mice were examined. RESULTS: Recombinant pXJ41 with
      double promotors and TK gene was transfected into HR-8348, and positive
      expression of TS and TK was observed. The expression of TK gene was consistent
      with TS expression. Plating efficiency was 9/300, 92/300 in transfected HR-8348
      and contrast cells respectively (t = 33.885, P < 0.01). Cancer cell growth rate
      reduced markedly in the transfected group. The suppression rate of xenograft
      tumor growth was 74.5%. With the recombinant pXJ41 to transfect PBMC, p16
      expression was positive, but TK and TS expressions were negative. No
      damnification was observed in PBMC. CONCLUSIONS: TS and p16 double promoters are
      capable of inducting TK target killing of 5-FU drug-fast cancer cells, thus
      protecting normal cells and improving safety of gene therapy.

PMID- 12487852
TI  - [Radiotherapy with (186)Re-lipiodol II for primary liver cancer patients].
AB  - OBJECTIVE: To analyze the biodistribution of (186)Re-lipiodol (RL) in patients
      with primary liver cancer (PLC) after hepatic arterial injection in attempt to
      assess the potential of RL as a radiopharmaceutical for the treatment of PLC.
      METHODS: RL was synthesized from (186)Rhenium and Lipiodol by a series of
      physical and chemical procedures. Doses of RL ranged from 1 110 MBq to 2 220 MBq
      per patient depending on the volume of tumor. Quantitative gamma camera imaging
      (ECT) and gamma counting of serum and urine were used to obtain data for
      dosimetry estimation. Serum tumor marker (AFP) level and shrinkage of tumor were
      used to evaluate the therapeutic efficacy of RL. RESULTS: In the hepatic tumor,
      RL was selectively retained and radioactivity was very high throughout this
      study. The ratio of tumor concentration to the normal liver tissue concentration
      (T/NT ratio) was 10 - 14 at 48 hours after injection of RL. The main side effects
      of this therapy were transient fever and anorexia. No unacceptable toxicity was
      observed. In 100% of the patients, the therapy resulted in a significant decrease
      of AFP level and reduction of tumor volume. CONCLUSION: The biodistribution and
      imaging results demonstrated RL localized selectively in tumor, and that RL may
      be a potential internal radiopharmaceutical agent for the treatment of primary
      liver cancer.

PMID- 12487853
TI  - [Microarray in screening for differentially expressed genes of cellular cycle and
      apoptosis in abdominal aortic aneurysms].
AB  - OBJECTIVE: To analyze the functions of differentially expressed genes between
      abdominal aortic aneurysm and normal aortic tissue by cDNA microarray. METHODS:
      Total RNAs were respectively isolated from the normal aorta and aortic aneurysm,
      purified into mRNAs by oligotex. Subsequently they were reverse-transcribed into
      cDNAs incorporated with fluorescent dUTP to make hybridization probes, which were
      hybridized as the cDNA microarray for scanning of fluorescent signals and
      differentially expressed genes between the normal aortic and aortic aneurysm by
      using GenePix Pro 3.0 software. RESULTS: A total of 18 differentially expressed
      genes were detected, accounting for 0.44% of total genes. Among these genes, 11
      were related to cell cycle and the remaining 7 to cell apoptosis. The number of
      upregulated genes in the aortic aneurysm was 9 (mean ratio: 3.860) and that of
      the downregulated 9 (mean Ratio: 0.294). Bio-informative analysis showed that
      these 18 genes might influence the growth and apoptosis of smooth muscle cells in
      abdominal aortic aneurysms. CONCLUSIONS: During the development of abdominal
      aortic aneurysms, modulations of multi-gene expression would undergo various
      changes. Cell cycle and apoptosis-related genes were related to the growth and
      apoptosis of smooth muscle cells in abdominal aortic aneurysms. Further research
      into these genes will clarify the mechanisms of abdominal aortic aneurysms.

PMID- 12487854
TI  - [Comparison of local recurrence of rectal cancer after two radical operations
      using total mesorectal excision].
AB  - OBJECTIVE: To compare the difference in local recurrence Dixon and Miles groups
      after total mesorectal excision. METHODS: One hundred and seventy-three patients
      with rectal cancer were divided into two groups (Dixon group, 123 patients; Miles
      group 50 patients). Total mesorectal excision was made according to Heald's
      method. RESULTS: The local recurrence in the Dixon and Miles groups was 4.8%
      (6/123) and 18.0% (9/50) respectively (P < 0.05), and in the Miles group before
      and after 1997 was 36.8% (7/19) and 6.5% (2/31) respectively (P < 0.05), 4.8% in
      LRR (P < 0.01). No significant difference was observed in the local recurrence
      between the two groups (P > 0.05). CONCLUSION: Total mesorectal excision is an
      important factor reducing local recurrence after radical operation for rectal
      cancer.

PMID- 12487855
TI  - [Percutaneous radiofrequency ablation combined with transcatheter arterial
      chemoembolization for hepatocellular carcinoma].
AB  - OBJECTIVE: To assess the significance of the method of percutaneous
      radiofrequency ablation (PRFA) combined with transcatheter arterial
      chemoembolization for hepatocellular carcinoma. METHODS: Thirty patients with
      hepatocellular carcinoma were divided into PRFA group and TACE + PRFA group
      between January 2000 and July 2001. All patients were followed up to examine the
      value of AFP, MRI or CT. Kaplan-Meier estimation was used for the analysis of
      disease-free survival and the cumulative survival rate. RESULTS: The complete
      necrosis rates were 86.7% (13/15) and 26.7% (4/15) in the TACE + PRFA group and
      group PRFA group respectively. The rates of AFP positive down to negative were
      66.7% (6/9) for the former and 20% (2/10) for of the latter, and the six-month
      disease-free survival rates were 100% (13/13) and 75% (3/4) in the two groups.
      The 1-, 1.5- and 2-year survival rates of the group TACE + PRFA were 100%, 100%
      and 66.7% respectively. The survival rates of 1 and 1.5 years of the group PRFA
      only were 80% and 40%. CONCLUSIONS: For those hepatocellular carcinomas over 3 cm
      in size, located in the porta hepatis, or with indistinct boundary or the
      presence of foci, TACE can be performed first and then followed by PRFA in
      suitable time. This method can enlarge the necrosis range and increase the rate
      of complete necrosis of tumors, thereby decrease the recurrence and improve the
      disease-free survival and total survival of patients.

PMID- 12487856
TI  - [Depressive disorder in patients undergoing general surgical operations].
AB  - OBJECTIVE: To investigate the prevalence of depressive disorder in patients
      undergoing general surgical operations. METHODS: One hundred and four patients
      who had undergone general surgical operations were investigated. Each patient
      filled in the self rating depression scale (SDS) as the baseline data. RESULTS:
      Among these patients 40.4% of them had depressive disorder. The major factors for
      the prevalence of depression were sex, educational background and malignant
      diseases. CONCLUSIONS: A certain proportion of patients undergoing general
      surgical operations have depressive disorder. It is important to recognize and
      treat for this disorder.

PMID- 12487857
TI  - [Long-term results of selective vagotomy plus antrectomy in treatment of duodenal
      ulcer].
AB  - OBJECTIVES: To study the long-term results of selective vagotomy plus antrectomy
      in treatment of duodenal ulcer. METHODS: One hundred and ninety-three patients
      with duodenal ulcer were subjected to selective vagotomy plus antrectomy from
      November 1977 to November 2001. These patients included 28 patients with
      refractory ulcer, 112 with recurrent bleeding, 41 with pylori obstruction, and 12
      with duodenal and gastric ulcer. RESULTS: BAO, IMAO, PMAO and serum gastrin were
      decreased significantly after an 1 - 24-year follow-up after selective vagotomy
      plus antrectomy. The characteristics of inhibitory secretive were observed in
      parietal cells. Follow-up after operation for 1 - 10 years and 11 - 24 years
      showed that 95.60% and 96.61% of patients belonged to Visick grade I and II, and
      4.40% and 3.39% of patients belonged to Visick grade III, respectively. No ulcer
      recurrence was seen during the 1 - 24 year follow-up after the operation.
      CONCLUSION: SV + A is an effective method for duodenal ulcer, especially for
      complicated duodenal ulcer, with permanent reduction of gastric acid and no
      recurrence.

PMID- 12487858
TI  - [Clinical and pathological analysis collision carcinoma: report of 7 patients].
AB  - OBJECTIVE: To study the epidemiological, pathological, clinical features and
      therapy of collision carcinoma. METHODS: Seven patients were studied
      retrospectively against the background of the literature from 1980 to 2001,
      including the incidence, age of onset, sex ratio, predilection sites, clinical
      signs, pathological features and therapies. RESULTS: Collision carcinoma is rare,
      but more common in males than in females. The peak onset age is more than 65
      years. It is found frequently in the stomach, liver, uterine, esophagogastric
      junction, and lung. Without special clinical features, it is difficult to
      diagnose. Pathological findings are the only way to make a correct diagnosis
      before operation. Operation is the major therapy, assisted by chemotherapy or/and
      radiotherapy when necessary. Collision carcinoma represents a coexistence of two
      adjacent but histologically different malignant neoplasmas without histological
      admixture in an organ. CONCLUSIONS: Collision carcinoma is rare but composed of
      mosaics of two malignant tumours. The clinical features of collision carcinoma
      need further investigation.

PMID- 12487859
TI  - [Preliminary experience of video-mediastinoscopy in clinical application].
AB  - OBJECTIVE: To determine the value of video-mediastinoscopy in clinical
      application. METHODS: The clinical data of 54 patients receiving video
      mediastinoscopy were reviewed retrospectively. This operation consisted of
      cervical mediastinoscopy in 44 patients, parasternal mediastinoscopy in 6, and
      combined procedures in 4. Of these patients, 18 underwent video-mediastinoscopy
      for the evaluation of undifferentiated mediastinal disease. Thirty-six patients
      with suspected lung cancer showed enlarged mediastinal lymph nodes
      radiographically in the chest and underwent video-mediastinoscopy. RESULTS:
      Seventeen of 18 patients with undetermined mediastinal diseases had a definitive
      pathologic diagnosis, with an accuracy of 94.4% (17/18). In the 36 patients with
      suspected lung cancer, 22 were positive, and 14 negative. In the negative
      patients who underwent thoracotomy with resection, mediastinal lymph nodes
      revealed no evidence of metastasis. There were no postoperative complication and
      deaths. CONCLUSION: Video-mediastinoscopy as a highly effective and safe
      procedure could be used in the diagnosis and staging of thoracic diseases.

PMID- 12487860
TI  - [A new technique for transmyocardial laser revascularization].
AB  - OBJECTIVE: To investigate the effects of traditional transmyocardial laser
      revascularization (T-TMLR) and non-transmural myocardial laser revascularization
      (N-TMLR) on myocardial ischemic and necrotic areas and angiogenesis. METHODS: In
      30 rabbit models, Evans blue -TTC staining and HE staining were used for
      measuring ischemic and necrotic areas and observing angiogenesis. RESULTS: The
      ischemic areas in the MI + T-TMLR (30.6 +/- 1.0)% and the MI + N-TMLR group (30.2
      +/- 0.4)% were significantly decreased compared with the MI group (37.2 +/- 0.2)%
      (F = 21.04, P < 0.01). The necrotic areas in the MI + T-TMLR (17.0 +/- 0.7)% and
      the MI + N-TMLR group (16.9 +/- 0.6)% was not different from that in the MI group
      (17.9 +/- 0.5)% (F = 1.73, P > 0.05). The angiogenesis in the MI + T-TMLR (1.8)
      and the MI + N-TMLR (1.6) was significantly increased compared with that in the
      MI group (0.6) (F = 15.32, P < 0.01). CONCLUSIONS: MI + N-TMLR can achieve the
      same effects of MI + T-TMLR. Inducing angiogenesis via laser channels and
      decreasing ischemic area may be one of the predominant mechanisms of TMLR,
      whereas whether laser channels themselves are patent is not relation to the
      effects of TMLR.

PMID- 12487861
TI  - [Valve repair of congenital mitral regurgitation in infants and young children].
AB  - OBJECTIVE: To summarize the experience of mitral valve (MV) repair in infants and
      young children with congenital mitral malformation. METHODS: Thirty-eight
      consecutive infants and young children with this disease, aged (2.3 +/- 1.2)
      years, weighted (12.6 +/- 3.9) kg, underwent mitral repair from January 1996 to
      March 2002. The procedure included partial annuloplasty, repair of the cleft of
      the mitral leaflet, chordal shortening, chordal transfer, artificial chordae and
      reconstruction of the posterior leaflet. The modified annuloplasty allows natural
      growth of the annulus. The associated cardiac anomalies were totally corrected.
      RESULTS: In these patients, no early and late deaths were observed, nor
      reoperation and severe complications. No or trivial regurgitation occurred in 11
      patients, mild regurgitation in 22, and moderate and greater regurgitation in 5.
      Thirty-seven patients were asymptomatic. CONCLUSIONS: Mitral repair procedure may
      be effective in infants and children with early or intermediate mitral
      regurgitation.

PMID- 12487862
TI  - [Interventional treatment of 126 patients with anterior communicating artery
      aneurysm].
AB  - OBJECTIVES: To analyse the characteristics of interventional treatment for
      anterior communicating artery aneurysm (AcoAA) and improve curative effects.
      METHODS: In 126 patients, detachable microcoils were used to embolize the AcoAA
      via endovascular approach. Those patients failed to be embolized were treated by
      surgical clipping. RESULTS: Of the 109 patients who were embolized successfully,
      97 were achieved 100% occlusion, 12 95% - 98% occlusion. In the other 17 patients
      who failed to interventional treatment 15 were treated surgically and 2 no
      treatment because of cerebral vascular spasm. 123 patients were cured, one died,
      and 2 had aneurysms disappeared without any operations, as proved by follow-up
      for 5 months to 1 years. Of 32 patients checked by cerebral angiography 3 weeks
      to 30 months after operation, 30 showed disappeared of aneurysms and 2 had
      recurrence. The recurred aneurysms were successfully reembolized. CONCLUSIONS:
      Most of AcoAAs can be cured by endovascular interventional treatment. Those who
      failed to be treated by embolization can be cured surgically. Few patients may be
      healed spontaneously. The long term effects of treatment should be followed-up
      for a long time.

PMID- 12487863
TI  - [Electronic fiberesophagoscopy in video-assisted thoracoscopic surgery for benign
      esophageal diseases].
AB  - OBJECTIVE: To evaluate the effect of electronic fiberesophagoscopy in video
      assisted thoracoscopic surgery for benign esophageal diseases. METHODS: We
      determined the position of lesion, separated the lesion from the esophageal wall,
      resected the lesion and protected the esophageal mucosa during the process of
      video-assisted thoracoscopic surgery for benign esophageal diseases. RESULTS:
      Thirty-six patients with benign esophageal disease underwent the operation
      successfully and recovered uneventfully. There was no operative death or severe
      perioperative complications such as esophago pleural fistula. Two patients were
      changed to undergo thoracotomy. CONCLUSIONS: Electronic fiberesophagoscopy is an
      essential equipment in video-assisted thoracoscopic surgery for benign esophageal
      diseases. It should be adopted as a routine equipment to ensure the accuracy,
      safety, reliability and convenience of this kind of operations.

PMID- 12487864
TI  - [Unilateral external fixator combined with simple internal fixation for severe
      open tibia-fibular fracture].
AB  - OBJECTIVE: To improve the treatment for severe open tibia-fibular fracture.
      METHODS: From 1994 to 2000, 146 patients with severe open tibia-fibular fracture
      were treated. According to Gustilo classification, all patients were of type III.
      Among them, 96 patients belonged to III A, 36 III B, and 18 III C. One hundred
      and eight patients were male and 38 female, aged from 11 to 68 years, with an
      average of 31. All patients were treated with unilateral external fixator
      combined with simple internal fixation (general screw or Kirschner wire). Thirty
      patients were treated with secondary flap operation. Among them, 19 patients
      received pedicle gastrocnemius muscle flaps, 9 free vastus lateralis muscle
      flaps, and 2 free latissimus dorsi muscle flaps. RESULTS: Three patients of type
      IIIB were subjected to amputation because of advanced age and associated cerebral
      or thoraco-abdominal injury. Five patients of type III C had amputation because
      of insufficient postoperative blood supply and necrosis. The rupture of other 138
      patients was well reduced, and firmly fixed. They were followed up for 6 months-6
      years, with an average of 2.5 years. The average time of fracture-union was 27
      weeks, and the average time for removal of fixtors was 28 weeks. The motion of
      knee joint ranged from 0 to 120 degree in 110 patients; from 0 to 100 degrees in
      25, and from 0 to 90 degrees. The motion of ankle joint was approximately normal.
      CONCLUSIONS: For patients with severe open tibia-fibular fracture, comprehensive
      analysis should be made for preservation of the wounded limb or amputation as for
      elderly patients with vessel-nerve injury or with cerebral- thoracoabdominal
      injury, emergency amputation should be done. Unilateral external fixator combined
      with simple internal fixation (general screw or Kirschner wire) for severe open
      tibia-fibular fracture is advantageous for a simple and reliable fixation. It is
      less traumatic.

PMID- 12487865
TI  - [Nitric oxide and cytokine levels in the seminal plasma of infertile men].
AB  - OBJECTIVE: To evaluate the effect of nitric oxide (NO), TNF alpha, IL-6, IL-8 on
      the pathogenesis of infertile men. METHODS: NO, TNF alpha, IL-6 and IL-8 levels
      were assayed in 80 infertile men and 26 normal men. RESULTS: The levels of NO,
      TNF alpha, IL-6 and IL-8 in infertile men were all significantly higher than
      those in controls (P < 0.01 or P < 0.05). NO was positively correlated with TNF
      alpha, IL-6 and IL-8 (P < 0.01). CONCLUSION: NO, TNF alpha, IL-6 and IL-8 might
      play an important role in the pathogenic process of infertile.

PMID- 12487867
TI  - [Protection effect of nerve implantation after peripheral nerve injury to rats].
AB  - OBJECTIVE: To investigate the protection effect of nerve implantation to the
      neurons after sciatic nerve injury to adult rats. METHODS: Thirty male Sprague
      Dawley rats weighing 180 - 220 g (8 - 9 weeks of age) were randomly divided into
      four groups. Group A consisted of normal rats without operation. In group B, the
      sciatic nerve of rats was transected, with the proximal stump of the sciatic
      nerve ligated to inhibit nerve regeneration. In group C, a sciatic nerve crushed
      model was set up. In group D, a sciatic nerve implantation model was established.
      The rats were sacrificed on postoperative days 7, 14 and 28 respectively. The
      L(4)-L(6) segments of the spinal cord were harvested. TUNEL technique was used to
      detect apoptotic motor neurons. HE and Toluidine Blue staining was used for
      counting motor neurons. RESULTS: The apoptotic neurons detected on the 28th
      postoperative day were significantly fewer in the implantation group than in the
      other groups (P < 0.05). The number of motor neurons was significantly higher in
      the implantation group than in other two control groups (P < 0.05). CONCLUSIONS:
      Nerve implantation exerts protective effect on neurons after nerve injury.

PMID- 12487866
TI  - [Influence of intraoperative implantation of radioactive (125)I seeds on healing
      of surgical anastomosis].
AB  - OBJECTIVE: To investigate the influence of intraoperative implantation of
      radioactive (125)I seeds on healing of surgical anastomosis. METHODS: The jejunum
      was cut, and end-to-end anastomosis was made in 12 healthy dogs. In the
      experimental group (n = 8), the (125)I seeds were implanted into the two sides of
      the anastomosis. The total radiation dosage at the anastomosis was 116 Gy. The
      other 4 dogs were in the included control group. At the 7th, 14th postoperative
      day, specimens were obtained from 4 dogs in the experimental group and 2 dogs in
      the control group respectively. The healing of the anastomosis was observed
      grossly; hydroxyproline content, as well as histopathological and ultrastructural
      changes of the anastomotic tissue were studied. RESULTS: Gross observation showed
      healing of the anastomosis of the experimental animals. The hydroxyproline
      contents were 0.578 +/- 0.020 microg/mg proteins in the experimental group and
      0.631 +/- 0.012 microg/mg proteins in the control group (P > 0.05).
      Histopathological and ultrastructural changes of the anastomotic tissue were not
      significant in healing as compared to the control group. One of 29 patients had
      anastomotic leakage. CONCLUSIONS: Intraoperative implantation of (125)I has no
      adverse effect on healing of surgical anastomosis; it is safe and feasible in
      clinical practice.

PMID- 12487868
TI  - [Surgical treatment of lumbar spinal stenosis associated with unstable
      degenerative spondylolisthesis].
AB  - OBJECTIVES: To assess surgical treatment of lumbar spinal stenosis associated
      with unstable degenerative spondylolisthesis. METHODS: In 86 patients with lumbar
      spinal stenosis associated with unstable degenerative spondylolisthesis. (30 men
      and 56 women, aged from 30 to 77 years), 63 patients complained of lower back
      pain with both lower extremity pain, 10 patients pain in one leg, and 13 patients
      only lower back pain. Seventy-two of these patients complained of intermittent
      claudication, with a walking distance ranging from 10 to 1 000 m. Thirty-two
      patients had some changes in sensation, motion and reflexes of the foot.
      According to White' critera, all patients showed dynamic instability of the
      lesion. Meyerding criteria showed degree 1 in 79 patients, and degree 2 in 7. CT
      scan was made in 56 patients, MRI in 24 and MRM in 6 before operation.
      Myelography was performed in 61 patients, and CTM in 6. Stenosis and
      spondylolisthesis located between L(4) and L(5) in 49 patients, between L(3) and
      L(4) in 6, between L(5) and S(1) in 25, between L(3) and L(4) and between L(4)
      and L(5) in 2, and from L(3) to S(1) in 4. The patients with pathological
      spondylolisthesis were excluded. Lateral recess stenosis of one leg was observed
      in 10 patients, lateral recess of both legs in 22, and central canal stenosis in
      54, of whom 12 patients were associated with protrusion of the lumbar disc.
      Decompression and autograft with iliac bone and various internal fixation were
      performed in all patients. RESULTS: The patients were followed up from 8 months
      to 13 years, longer than 1 year (average 5.6 years) in 81 patients. According to
      Amundsen et al, excellent results were obtained in 78 patients, good in 5, and
      fair in 3. Spondylolisthesis was completely reduced in 70 patients of degree 1
      (89.9%), and in 6 patients of degree 2 (85.7%). No patient showed slippage
      aggravated. 74 patients gained bone graft fusion within 3 months and 10 patients
      within 6 months. Two patients showed pseudoarthrosis during the follow-up.
      Complications included internal fixation breakage in 1 patient, and delayed
      infection in 1. CONCLUSIONS: Complete decompression and bone graft fusion are the
      key to treatment. Decompression and internal fixation improve the symptoms of
      patients with lumbar spinal stenosis associated with spondylolisthesis.
      Transpedicle instrumentation can reduce spondylolisthesis and maintain the
      physical curve of the lumbar.

PMID- 12487869
TI  - [Bone graft repair of adolescence spondylolysis with lag screw and tension band
      fixation].
AB  - OBJECTIVE: To investigate direct bone graft repair with lag screw and tension
      band fixation technique and its value for the treatment of adolescence
      spondylolysis. METHODS: Lysis was prepared and the fibrous tissue within the gap
      was removed in 12 patients from 12 to 26 years (average 18.4). 1 - 2 mm extra
      bony element was resected on both sides with fresh interface with the bone graft
      harvested from the iliac crest. From the entry point 8 mm away from the midline
      at the inferior margin of the lamina, titanium lag screws of 35 - 45 mm long and
      3.5 mm in diameter were placed at 300 upward and outward and tighted through the
      lysis, bone graft and the superior and lateral aspect of the pedicle. Extra match
      bone graft was placed around the surface of defect, an high intensity Nilon wire
      tension band between the cap of the screw and the basis of transverse process was
      constructed before wound closure and suction drainage. The patients were
      immobilized with plaster brace of Paris for 2 months. RESULTS: Average operation
      time was (10 +/- 55) minutes, and average blood loss was 170 ml. Follow-up ranged
      from 12 to 36 months (mean 17 months), and cases of 22 lysis healed within 3
      months. CONCLUSIONS: Technique of direct bone graft repair with lag screw and
      tension band fixation for the treatment of adolescence spondylolysis is simple,
      safe and reliable. Combined biomechanical and biological processes, it is less
      invasive but advantageous in preserving the motion in the affected segment.

PMID- 12487870
TI  - [The effect of cervical spine instability on sympathetic cervical spondylosis].
AB  - OBJECTIVE: To investigate the effect of cervical spine instability on sympathetic
      cervical spondylosis. METHODS: Twelve patients with cervical spondylosis showing
      sympathetic symptoms from 1992 to 2 000 were evaluated for cervical spine
      instability, immobilization of collar brace, MRI and surgical results. RESULTS:
      Radiologic evaluation cervical instability was observed radiologically in 7 of
      the 12 cases. Collar brace was obviously effective in 5 of the 12 cases and
      slightly effective in 7 cases. MRI showed abnormal signal for instability of the
      cervical spine in 7 cases. Surgery was markedly effective in 7 cases and
      moderately effective in 4 cases. CONCLUSION: Cervical spine instability was an
      important factor for sympathetic cervical spondylosis, which can be improved
      effectively by surgery.

PMID- 12487871
TI  - [Extraforaminal lumbar disc herniation: anatomical study and surgical treatment].
AB  - OBJECTIVES: To provide the anatomical basis for surgical treatment of
      extraforaminal lumbar disc herniation (EFLDH) by paraspinous muscle splitting
      approach and to investigate the effect of its application. METHODS: The
      relationship among the intertransverse processes, lateral margin of the pars
      interarticularis, anterior ramus of the lumbar nerve, and anterior ramus of the
      lumbar artery was studied in 34 cadaveric specimens. From October 1993 to October
      1999, eleven cases of extraforaminal lumbar disc herniation were treated by
      paraspinous muscle splitting approach and retroperitoneal approach. RESULTS: In
      the extraforaminal region, the anterior ramus of the lumbar artery and venus
      locate ventrally to the superior half of the intertransverse space, and the
      anterior ramus of the lumbar artery runs downward behind the nerve. The distance
      from the lateral margin of the pars interarticularis to the nerve root and the
      angle between the nerve root and midline sagittal plane were 1.0 - 2.0 cm and 7
      degrees - 25 degrees respectively which increased gradually from L(1) to L(5).
      The period of follow up in 10 of 11 cases was 23 - 98 months. Evaluation
      according to Low Back Outcome Score showed excellent results in 8 cases, and good
      in 2. CONCLUSION: Surgical treatment of EFLDH by paraspinous muscle splitting
      approach is safe, effective and minimal invasive.

PMID- 12487872
TI  - [Stability analysis of an enhanced load sharing dynamic pedicle screw fixation
      device and its equivalent rigid device].
AB  - OBJECTIVES: To compare the stability of an enhanced load sharing dynamic pedicle
      screw fixation device with its equivalent rigid device and to evaluate
      biomechanical roles of the dynamic fixation. METHODS: A model of L(1) body
      fracture was produced on seven specimens of fresh adult cadaver spine from T(10)
      to L(4). Both dynamic and rigid devices were applied in the specimens to strength
      the injured level. Ranges of three dimensional movements and stiffness under
      flexion-compression were measured in intact, injured and stabilized specimens.
      RESULTS: Both dynamic and rigid devices were found to provide significant
      stability for injured segment in flexion-extension and lateral bending. In axial
      rotation, the devices could restore the stability to levels similar to those in
      an intact spine. Results indicated 40% increase in range of motion in flexion
      extension and 24.1 Nmm reduction in stiffness of flexion-compression for dynamic
      device, compared with the rigid device. CONCLUSION: The dynamic device offers a
      design that may enhance load sharing without sacrificing the stability and will
      decrease stress-shielding and stress concentration.

PMID- 12487873
TI  - [Surgical treatment of De Bakey type III aortic dissection].
AB  - OBJECTIVE: To summarize the experience in surgical treatment of De Bakey type III
      aortic dissection and discuss the operative indications, techniques, and methods
      for spinal cord protection. METHODS: From January 1994 to January 2000, 49
      patients with De Bakey type III aortic dissection were operated on. Of these
      patients, 35 were subjected to partial thoratical aorta replacement, 4 partial
      thoratical aorta replacement and plasty, 8 total thoratical aorta replacement,
      and 2 thoracoabdominal aorta replacement. In the 35 patients, the operations were
      performed by using the technique which preserved blood was transfused back by
      pump via the femoral artery. RESULTS: Hospital mortality in this group was 6.1%
      (3/49). Eight patients received emergence operation, and 1 patient died.
      Paraparesis developed in one patient (2.0%). Other complications included re
      exploration for bleeding in 3 patients, and wound infection in 5. CONCLUSIONS:
      The rate of mortality and complication is high in patients with De Bakey type III
      aortic dissection. Appropriate operative techniques and methods of spinal cord
      protection are essential to resolve this problem.

PMID- 12487874
TI  - [Endoscopic ultrasonography guided fine-needle aspiration in diagnosis of lung
      neoplasm and mediastinal lymph node metastasis].
AB  - OBJECTIVE: To access the feasibility, safety and accuracy of endoscopic
      ultrasonography guided fine-needle aspiration (EUS-FNA) in patients with
      suspected lung neoplasm and metastatic mediastinal lymph nodes. METHODS: Using a
      linear array scanning endosonography (Pentax FG32-UA) and a 22-guage GIP (Medi
      Globe) needle, we performed EUS-FNA in 10 patients including 6 patients with lung
      mass and enlarged mediastinal lymph nodes, 1 patient with a mass in the right
      lung, 1 patient with a mass near the esophagus, and 2 patients with extensive
      enlarged mediastinal lymph nodes. The data collected included lesions types,
      complications and diagnostic accuracy. RESULTS: EUS-FNA revealed small cell
      carcinoma in 5 patients, squamous cell carcinoma in 1, adenocarcinoma in 1, and
      benign lymph nodes in 2. Malignancy was confirmed by follow-up in 7 patients, and
      benign tumor was confirmed by mediastinoscopy, thoracoscopy or follow-up in 2
      patients. In 1 patient, FNA sample was not diagnosed because of inadequate
      specimen. None of the patients had complications caused by any procedures.
      CONCLUSION: EUS-FNA is safe, reliable and accurate in diagnosis of suspicious
      lung neoplasm and mediastinal lymph node.

PMID- 12487875
TI  - [Vision deterioration after transsphenoidal surgery for removal of pituitary
      adenoma].
AB  - OBJECTIVE: To explore the mechanism and strategies of prevention and treatment of
      vision deterioration after transsphenoidal surgery for removal of pituitary
      adenoma. METHODS: From January 1980 to February 2001, 1 412 patients were
      operated on by transsphenoidal surgery to remove pituitary adenoma. Fourteen
      patients experienced vision deterioration after operation. Clinical data from the
      14 patients with vision deterioration were analyzed retrospectively. RESULTS: In
      this group, the incidence of vision deterioration was 0.99%. Over packing of the
      adenoma bed was seen in 5 patients, apoplexy of residual tumor in 3, high
      intracranial pressure in 2, vascular spasm in 2, injury of the optic nerve in the
      cannel in 1 and unknown reason in 1. CONCLUSIONS: Vision deterioration is a
      severe complication after transsphenoidal surgery. Early diagnosis and treatment
      can greatly improve the vision.

PMID- 12487876
TI  - [Intravertebral canals vascular malformations treated by superselective
      embolization].
AB  - OBJECTIVE: To assess the feasibility superselective embolization using
      microcatheters in treatment of intravertebral canal vascular malformation.
      METHODS: In 128 patients with intravertebral canals vascular malformation, their
      AVMS or fistulae were treated with silk thread, Ivalon microspheres or tungsten
      microcoils. RESULTS: In the 128 patients, 120 fistulae disappeared completely,
      but 8 were embolized 60% - 80%. Symptoms were improved in 113 patients. Improved
      muscular strength from grade I to IV was obtained in 8 patients, from grade II to
      III in 32, from grade III to IV in 32, and from grade IV to V in 41. The symptoms
      did not change in 15 patients. CONCLUSION: Superselective embolization through
      microcatheter is effective in the treatment of intraspinal canal vascular
      malformations.

PMID- 12487877
TI  - [Venous hypertensive myelopathy caused by narrowing of ascending lumbar vein].
AB  - OBJECTIVE: To assess the diagnosis and treatment of venous hypertensive
      myelopathy (VHM) caused by narrowing of the ascending lumbar vein. METHOD: The
      data from 3 patients with VHM caused by narrowing of the ascending lumbar vein
      were analyzed retrospectively. RESULTS: Once the narrowed site of the lumbar
      ascending vein was determined by myelographic or angiographic technique, an
      undetachable balloon was introduced and advanced to the proximal part of the
      narrowed segment. Satisfactory results were obtained in these patients.
      CONCLUSION: Narrowing of the ascending lumbar vein is one of the causes for VHM,
      and endovascular balloon angioplasty is an optimal treatment.

PMID- 12487878
TI  - [Diagnosis and treatment of subclinical pituitary apoplexy: report of 21 cases].
AB  - OBJECTIVES: To evaluate clinical manifestations of 21 patients with subclinical
      pituitary apoplexy and their diagnosis and treatment. METHOD: Clinical data from
      21 patients with subclinical pituitary apoplexy treated from October 1989 to
      November 2001 were analyzed retrospectively. RESULTS: Their clinical
      manifestations included chronic headache, visual deficit and field cut. Three
      patients showed no clinical signs. Microsurgery was performed in 20 patients, of
      whom 3 were treated by emergency operation. Microsurgery included transsphenoidal
      decompression in 17 patients, and transpterioral approach in 3. One patient was
      given conservative therapy, and 12 were given endocrine replacement therapy.
      Nineteen patients recovered with marked visual improvement (7), partial
      improvement (8), no changes (4); deterioration was noted in 1. CONCLUSIONS:
      Subclinical pituitary apoplexy characterized by atypical clinical manifestations
      may be misdiagnosed or in appropriately treated. MRI is superior to CT scan for
      the diagnosis of subclinical pituitary apoplexy. Patients with persistent
      chiasmatic syndromes are indicated for emergency surgery. Endocrine replacement
      and transsphnoidal decompression are effective for the improvement of severe
      visual disturbance.

PMID- 12487879
TI  - [Multimodal approach to clinical liver transplantation].
AB  - OBJECTIVE: To sum up the clinical experience of liver transplantation. METHOD: A
      retrospective study was made in 11 patients receiving living donor liver
      transplantation (LDLT)/and 14 patients having orthotopic liver transplantation
      (OLT), including one time operation of reduced size liver retransplantation and
      one time operation of cadaveric liver retransplantation. RESULTS: The voluntary
      donors were a sister and 10 mothers of recipients. The location of graft included
      3 patients of segment II, III, part of IV (not including intermediate hepatic
      veins), 6 patients of segment II, III, IV (including intermediate hepatic veins),
      and 2 patients of V, VI, VII, VIII (not including intermediate hepatic veins).
      The weight range of graft was 270 - 620 g. Twenty-four recipients achieved a long
      term survival and retained normal liver function during the follow-up. Only 1
      patient died from serious rejection on the 72nd day postoperatively. Ten patients
      with hepatitis B cirrhosis were treated with lamivudine and anti-HBVIg, and HBV
      DNA in serum was negative during the follow-up for 4 approximately 21 months.
      Copperoxidase, ceruloplasmin and main indexes of liver function became normal in
      all patients with Wilson's Disease. Postoperative complications included
      abdominal hemorrhage (2 patients), acute respiratory distress syndrome (5), acute
      rejection (4), and acute renal function failure (2). CONCLUSIONS: The wise
      solution to improve the result of liver transplantation and optimize liver
      resources is the "multimodal approach", by which all kinds of techniques for
      liver transplantation including CLT, LDLT and RSLT should well developed.

PMID- 12487880
TI  - [Life quality of patients after cholecystectomy].
AB  - OBJECTIVE: To evaluate the quality of life in patients who underwent laparoscopic
      and open cholecystectomy for chronic cholecystolithiasis. METHODS: A prospective
      survey was made on 25 patients receiving laparoscopic cholecystectomy (LC group)
      and 26 patients receiving open cholecystectomy (OC group). The quality of life
      was measured with the gastrointestinal quality of life index (GLQI)
      preoperatively, and at 2, 5, 10 and 16 weeks after the operation. RESULTS: The
      mean preoperative GLQI scores of all dimensions of the quality of life were 112.5
      and 110.3 in the LC and OC groups respectively. In the LC group, the quality of
      life was not considerably reduced at 2 weeks after operation, with a mean GLQI
      score of 110. There was a significant improvement both in total mean score and in
      the aspects of symptomatology, emotional and physiological status from 5 to 16
      weeks after LC operation. In the OC group, the GLQI score reduced to 102.0 at 2
      weeks after surgery (P < 0.05). There were significant reductions in the aspects
      of symptomatology, physiological and social status as well. The GLQI scores
      reached to the preoperative level of 115.6 at 10 weeks after the operation (P >
      0.05). The patients experienced significant improvements of GLQI at 16 weeks
      after OC operation (P < 0.01 or P < 0.05). The LC group showed better GLQI scores
      than did the OC group for up to 10 weeks postoperatively (P < 0.05). CONCLUSIONS:
      LC is betler or more rapidly than OC is improving the quality of life
      postoperatively. The assessment of the quality of life is valuable for measuring
      the outcome of surgical treatment.

PMID- 12487881
TI  - [Uncinate process carcinoma of the pancreas: clinical features and diagnosis and
      treatment].
AB  - OBJECTIVE: To summarize the clinical features and diagnosis and treatment of
      uncinate process carcinoma of the pancreas. METHODS: From January 1998 to
      December 2000, 41 patients of pancreas uncinate process carcinoma were
      retrospectly analysed. RESULTS: Upper abdominal pain accompanied with back
      pain,weight loss and jaundice were the main symptoms. Thirty-six patients were
      subjected to regional pancreaticoduodenectomy (RP), 11 to SMV-PV or SMA lateral
      wall partial resection or partial vascular resection and reconstruction, of which
      PV reconstruction with PTEE grafts was performed in 2 patients. Two
      cholecystojejunostomy Roux-en-Y. Alcohol injection was made in the nerve plexus
      of the trunks of both celic axes and the superior mesenteric artery and regional
      chemotherapy via chemotherapy pump and liver biopsy in one case. Abdominal
      exploration was performed in 1 case and no-operation in another. None of the
      cases died perioperatively. Postoperation survival 2 - 44 months and was 1 the
      median survival was 11.2 months. Four patients are still alive, the longest
      surviving have been 44 months. The 1-year and 3-year survival rate was 37.0% and
      3.7%. CONCLUSIONS: Pancreas uncinate process carcinoma has a tendency to invade
      adjacent SMV/SMA-PV and is difficult to diagnose early. Since those are related
      to its location and not to its invading behaviors, the tumon is highly resecable
      (87.8%).

PMID- 12487882
TI  - [Laparoscopic colorectomy for colorectal cancer].
AB  - OBJECTIVE: To evaluate the result of laparoscopic colorectomy in treatment of
      colorectal cancer. METHODS: Laparoscopic colorectal surgery was performed in 78
      patients with colorectal cancer. Operative procedures, complications and
      postoperative recovery were studied. RESULT: None of the 78 patients died of
      laparoscopic colorectal surgery or complications. Eleven patients died from tumor
      metastasis and 2 from other causes. Twenty-one, 17, 8 patients for 1, 3, 5 years
      survived respectively. In nine patients who had received operation less than 1
      year, no tumor recurrence or metastasis was found except in 1 patient 11 months
      after operation. CONCLUSION: Laparoscopic colorectal cancer resection is
      essential to colectomy for colon and rectum cancer when indicated.

PMID- 12487883
TI  - [Expression and clinical significance of osteopontin in colorectal cancer and
      liver metastatic tissues].
AB  - OBJECTIVE: To investigate the possible association of osteopontin (OPN) with
      liver metastasis in colorectal cancer. METHODS: RNA was quantitated by RT-PCR
      from colorectal cancer and surrounding normal tissues, also from liver metastatic
      tissues and normal liver tissues. ISH was utilized to detect OPN mRNA in
      colorectal cancer and liver metastatic tissues. RESULTS: In 44 cases, the
      expressions of OPN mRNA in colorectal cancer tissues were higher than those in
      the surrounding normal tissues (t = 4.89, P = 0.000). The expression of OPN mRNA
      in colorectal cancer was as high as 18.2%, but in liver metastasis was 80%
      (chi(2) = 22.42, P = 0.000). In ISH, OPN mRNA located in the cytoplasm of
      colorectal cancer cells. CONCLUSIONS: The expressions of OPN mRNA were the
      highest in liver metastatic tissues, moderate in colorectal cancer tissues, and
      lowest in surrounding normal tissues, indicating that OPN is a potential marker
      for liver metastasis of colorectal cancer.

PMID- 12487884
TI  - [Loss of heterozygosity analysis to define putative region involved in tumor
      differentiation and metastases in sporadic colorectal cancer patients].
AB  - OBJECTIVE: To detect putative suppressor loci involved in tumor progressing or
      metastases. METHODS: Thirty microsatellite marker primers were employed to amply
      the corresponding loci of the genome DNA from 83 patients with sporadic
      colorectal cancer. The PCR products were electrophoresed on a 377 PRISM sequencer
      and the fluorescent signals were analyzed by Genotyper and Genescan software.
      RESULTS: The data were obtained from 24 loci, with an average LOH frequency of
      15.16%. The LOH at D2S206 and D2S364 was more frequent than 30%, and was less
      than 20% at the rest loci. Significant difference was observed between the
      percentage of LOH and tumor staging or differentiation at D2S142 (2q24.1), D2S126
      (2q35), D2S2211 (2p24.2), D2S305 (2p23.3). Occarrence of deletion at the later
      two loci was correlative. CONCLUSIONS: Frequent LOH was not observed at the loci
      around known mismatch repair genes on chr. 2. The region between D2S305 (2p23.3)
      and D2S2211 (2p24.2) deleted holistically, and was correlated to the stage and
      differentiation of tumor attended by D2S142 (2q24.1) and D2S126 (2q35) on 2q. It
      is suggested that unknown genes associated with tumor progressing or metastases
      reside in the two loci on 2q or the region on 2p.

PMID- 12487885
TI  - [Bladder controller in bladder function reconstruction of paraplegic dogs].
AB  - OBJECTIVE: To observe whether bladder controller can restore bladder function in
      paraplegic dogs. METHODS: Four dogs were studied after their T(10) spinal cord
      was transected. Electrodes implanted around S(2) bilaterally were connected to
      subcutaneous recievers. Microsurgical techniques were employed in dorsal
      rhizotomy at S(1 - 3) intradural segment. After daily stimulation, the results of
      bladder controller were evaluated by micturition and vesicography. RESULTS:
      Micturition was given under electrical stimulation with a urine volume of 80 -
      140 ml per time. The mode of micturition was post-stimulus voiding. Vesicography
      showed that the bladder was filled and bladder neck was open in the micturition
      course of electric stimulation. Residual urine volume was 15 - 20 ml. CONCLUSION:
      Bladder controller together with a sacral deafferentation procedure can restore
      bladder function of paraplegic dogs.

PMID- 12487886
TI  - [Long-term culture and differentiation of neural stem cells of embryonic mice].
AB  - OBJECTIVES: To assess the culture and differentiation of neural stem cells in
      embryonic mice and set up a basis for further research in to neural stem cells.
      METHODS: Embryonic cortices of mice were dissociated and single cell suspensions
      were achieved by mechanical methods in sterile conditions, and cells were seeded
      in uncoated plate in N2 medium. The cells were passaged by mechanical methods,
      frozen and thawed by general procedure. They were identified by
      immunocytochemical techniques. RESULTS: Neural stem cells from embryonic mice
      were successfully cultured forming typical neurospheres in suspension. Neurons,
      astrocytes and oligodendrocytes were differentiated from neural stem cells, with
      a ratio of 7%, 85% - 90% and 2% - 4% respectively. CONCLUSIONS: Neural stem
      cells, which can be cultured and passaged steadily in vitro and they are the
      ideal cell sources for cell transplantation and gene therapy.

PMID- 12487887
TI  - [Effect of cholesterol in bile on cholecystokinin receptor in the gallbladder].
AB  - OBJECTIVE: To assess the effect of cholesterol in bile on cholecystokinin
      receptor (CCK-R) in the gallbladder. METHODS: One hundred Guinea pigs were
      randomly divided into four groups, 25 animals for each. The control group was fed
      a standard diet, and the cholesterol group fed a diet containing 2% cholesterol.
      After taking the 2% cholesterol diet for two weeks, the natural group persisted
      on the standard diet, and the treated group was perfused by traditional Chinese
      medicine. Serum cholecystokinin (CCK) level in the portal vein and maximal
      binding capacity (B(max)) and Kd of CCK-R in the gallbladder were measured in the
      four groups by RIA and RBA, and the concentrations of cholesterol in bile were
      also observed. RESULTS: Compared with the control group, after high-cholesterol
      feeding for two weeks, the gallbladder emptying rate [(65.83 +/- 7.32)%
      approximately (47.22 +/- 5.24)%] and B(max) of CCK-R [(60 +/- 27) approximately
      (32 +/- 13) fmol/mg protein] and in decreased fasting gallbladder volume (FV)
      [(0.89 +/- 0.26) approximately (1.34 +/- 0.61) cm(3)] and concentration of
      cholesterol [(0.44 +/- 0.11) approximately (0.60 +/- 0.13) mmol/L] in bile
      increased, but no change was in the serum CCK level and Kd of CCK-R in the
      cholesterol group. Compared with the natural group, after two-week in take of
      herb decoction of qingre lidan and liqi huoxue, FV [(1.27 +/- 0.60) approximately
      (0.90 +/- 0.27) cm(3)], RV [(0.85 +/- 0.45) approximately (0.32 +/- 0.12) cm(3)],
      FB [(0.92 +/- 0.35) approximately (0.73 +/- 0.21) cm(3)], RB [(0.76 +/- 0.34)
      approximately (0.29 +/- 0.08) cm(3)] in the treated group decreased
      significantly; but gallbladder emptying rate [(43.06 +/- 4.27)% approximately
      (67.01 +/- 6.82)%] increased significantly. The concentration of cholesterol in
      bile was lower in the treated group than in the natural group [(0.59 +/- 0.14)
      approximately (0.43 +/- 0.10) mmol/L], but no change was found in the serum CCK
      level. Bmax of CCK-R in the treated group increased significantly [(39 +/- 19)
      approximately (59 +/- 11) fmol/mg protein], Kd of CCK-R showed no significant
      changes between the treated group and natural group. CONCLUSION: High cholesterol
      in gallbladder bile causes defective muscle contraction by down-regulating CCK-R
      in the gallbladder, so the reduction of cholesterol concentration of bile may
      contribute to gallbladder contraction.

PMID- 12487888
TI  - [The in vivo antitumor activity of murine liver tumor vaccine expressing MIP
      1alpha].
AB  - OBJECTIVE: To observe the in vivo antitumor activity of murine liver tumor
      vaccine expressing MIP-1alpha mediated by recombinant adenoviral vector. METHODS:
      The infection efficacy was measured by GFP expression 48 hours after infection of
      Hepa1-6, and the number of cells was counted daily for 14 days. 5 x 10(6)
      modified Hepa1-6 cells were inoculated subcutaneously to C57BL/6 mice and the
      tumor-free animals were rechallenged by 2 x 10(6) wild-type Hepa1-6 cells or
      syngenic EL4 cells four weeks later. The tumor volume was measured twice a week.
      RESULTS: Adenoviral vectors could efficiently infect Hepa1-6 cells in vitro, and
      the in vitro growth rate of AdmMIP-1alpha modified Hepa1-6 cells was not
      affected; however the in vivo tumorigenicity was significantly decreased,
      compared with that of control vector modified Hepa1-6. Rechallenge of the tumor
      free mice four weeks after administration of AdmMIP-1alpha with the parental
      Hepa1-6 cells resulted in significant inhibition of tumor growth, but there was
      no significant difference when rechallenged with EL4. CONCLUSIONS: The liver
      cancer cells expressing mMIP-1alpha mediated by recombinant adenoviral vector
      decrease tumorigenicity and elicit specific immunological protection, and could
      be used as an effective liver tumor vaccine.

PMID- 12487889
TI  - [Late reconstruction and repositioning of enophthalmos of orbital blow-out
      fractures].
AB  - OBJECTIVE: To investigate the surgical technique for late reconstruction and
      reposition of enophthalmos of orbital blow-out fractures (BOF) and its efficacy,
      and to evaluate the effectiveness of hydroxyapatite (HA) composite material as
      orbital implant material. METHODS: Twenty-one patients with enophthalmos of BOF
      were randomly assigned into 2 groups in which autogenous bone and HA composite
      material as orbital grafting material were used. Computer orbital three
      dimensional measuring technique, Hertel exophthalmometer and Lancaster test were
      applied. Late reconstruction of the orbit and reposition of the globe were
      performed on 21 cases during three months to 2 years after injury.
      Postoperatively, they were followed up for an average of 8 months. RESULTS: In
      the 21 cases with enophthalmos of BOF, 15 patients presented moderate
      enophthalmos (3 - 4 mm) and 6 patients presented severe enophthalmos (5 - 6 mm).
      Three months after operation, the measurements demonstrated that 3 patients had
      no enophthalmos, 15 patients had mild enophthalmos (1 - 2 mm) and 3 patients had
      no effect. Sixteen of 21 patients had diplopia preoperatively. Eight patients had
      satisfactory result, and 8 patients had no change. There was no significant
      difference between orbital implants of autogenous bone and HA composite material.
      CONCLUSIONS: Late reconstruction of orbit and reposition of globe for
      enophthalmos of BOF may obtain satisfactory results. HA composite material is a
      useful orbital implant material.

PMID- 12487890
TI  - [Surgical treatment of orbital blow-out fracture].
AB  - OBJECTIVE: To evaluate the effect of surgical treatment for blow-out fractures.
      METHODS: Fifty-six cases with blow-out fracture treated by surgery from 1994 to
      1999 were reviewed and summarized, and their surgical effects were analyzed.
      RESULTS: The surgical approaches were as follows: anterior orbitotomy in 52
      cases, through brow in 2 cases, anterior orbital with oral approach in 2 cases.
      The enophthalmos was from the mean of 3.4 mm to 1.2 mm after operation. The
      diplopia completely disappeared in 18 cases and partly disappeared in 25 cases
      after operation. Diplopia was still presented in 9 cases post-operatively. There
      were 4 cases with inferior orbital nerve anesthesia after operation. CONCLUSIONS:
      Surgical management is an effective means of blow-out fractures. The effect is
      related to the time selected for surgery. Transconjunctival approach has
      advantages of easy operation, full exposure and invisible scar. This is the key
      method to eliminate diplopia since it may fully loose the incarcerated muscle and
      reduce secondary adhesion.

PMID- 12487891
TI  - [The surgical management of late complex posttraumatic enophthalmos].
AB  - OBJECTIVE: To study the surgical management of late complex posttraumatic
      enophthalmos. METHOD: According to the X-ray film and CT examination, the
      displaced orbital bone fragments was repositioned after osteotomy and rigid fixed
      by mini-plate and screws, then the orbital walls were repaired. RESULT: From July
      1996 to June 2001, 42 cases were treated and the enophthalmos were obviously
      corrected or improved. CONCLUSION: The late complex posttraumatic enophthalmos
      can be corrected or obviously improved through reconstruction of the normal shape
      and volume by the reduction of displaced bone fragments and precise orbit wall
      repair.

PMID- 12487892
TI  - [Surgical treatment of traumatic suprachoroidal hemorrhage].
AB  - OBJECTIVE: To evaluate the methods and effects of surgery for traumatic
      suprachoroidal hemorrhage (SH). METHODS: Seventeen cases with SH caused by ocular
      rupture underwent secondary surgery. With BSS irrigating into vitreous cavity, we
      drained SH through pars plana incisions and performed routine vitrectomy with gas
      or silicone oil tamponade. RESULTS: SH drainage was effective in 17 cases. During
      the follow-up of 3 - 27 months, the eye balls survived and the visual acuities
      were improved in 15 eyes (88.2%). CONCLUSION: With the surgical treatment of
      vitrectomy combined with SH drainage, most of the eyes with traumatic SH can be
      saved and their visual acuities recover for some degrees.

PMID- 12487893
TI  - [The surgical treatment of traumatized eyes with no light perception].
AB  - OBJECTIVE: To assess the efficacy of surgical treatment for traumatized eyes with
      no light perception (NLP). METHOD: We performed surgical treatment of vitrectomy
      on 11 eyes with NLP of 11 patients. The patients with LP or more than LP after
      the operations were followed up from 6 to 24 months (mean, 11 months). RESULTS:
      Postoperatively, 7 of 11 patients had visual acuities of light perception to 0.2.
      Four remained NLP, in which one had enucleation. CONCLUSIONS: The serious opacity
      of refractive media, the damaged or detached retina and the choroid edema are the
      main reasons of NLP. Some patients of NLP may get some visual acuities after
      surgical treatment of vitrectomy.

PMID- 12487894
TI  - [The change of immunoglobulin in patients with eyeball perforation at high
      altitude].
AB  - OBJECTIVE: To explore the change of tear immune function on eyeballs with
      perforating injury at high altitude. METHODS: In 51 patients (53 eyes) with
      eyeball perforating injury at high altitude (sea level 3658 m), by using single
      agar immune diffusion test, IgG, IgA, IgM, C(3) and C(4) values of tears were
      separately measured before and after clinical cure. RESULTS: The Ig values of
      tears increased universally. The IgA value increased especially in the 7th day.
      The IgG and IgM value in the serum increased in the 3rd day after injury (P <
      0.05), and the IgG, IgA and IgM of tears increased especially on the 7th day (P <
      0.01). The C(3) and C(4) value of tears did not change significantly (P < 0.05).
      CONCLUSIONS: The change of Ig value is a useful detective means to evaluate the
      treatment effect.

PMID- 12487895
TI  - [The effect of internal limiting membrane removal on healing of idiopathic
      macular hole].
AB  - OBJECTIVE: To prospectively investigate the effect on macular hole healing after
      internal limiting membrane (ILM) removal during idiopathic macular hole (IMH)
      surgery. METHODS: Forty-one consecutive patients (forty-one eyes) with idiopathic
      macular hole underwent pars plana vitrectomy (PPV) combined with surgical removal
      of the epiretinal membranes overlying the hole, gas/fluid exchange and C(3)F(8)
      intraocular tamponade. The patients were randomly divided into two groups, group
      A 19 patients in non-ILM-peeling group, group B 22 patients in ILM peeling group
      who underwent the removal of internal limiting membrane surrounding the hole.
      RESULTS: Among the 41 cases, IMHs were completely closed in 37 eyes (90.2%). In
      the ILM removal group, IMHs were closed in 22 cases (22/22, 100%). In the non-ILM
      removal group, IMHs were closed only in 15 eyes (15/19, 78.9%). There was a
      significant difference between the two groups (P < 0.05). CONCLUSION: PPV is a
      valid treatment for IMH and the removal of ILM may help IMH close after surgery.

PMID- 12487896
TI  - [The observation on detachment of posterior hyaloid membrane in idiopathic
      macular holes by optical coherence tomography].
AB  - OBJECTIVE: To investigate the relationship of the detachment of posterior hyaloid
      membrane and idiopathic macular hole by optical coherence tomography (OCT).
      METHODS: Fundus examination after dilatation of pupil and OCT were performed on
      223 eyes of 193 patients with idiopathic macular hole. All macular holes were
      graded according to the classification proposed by Gass. RESULTS: According to
      Gass classification, there were 21 eyes of stage I macular hole, 74 eyes of stage
      II, 97 eyes of stage III and 31 eyes of stage IV. OCT showed the detachment of
      posterior hyaloid membrane in 15 eyes (71.4%) in stage I, 38 eyes (51.4%) in
      stage II and 46 eyes (47.4%) in stage III. There were three kinds of imaging
      characteristics: (1) Perifoveal detachment of posterior hyaloid membrane
      (hyporeflective band) with a cyst (hyporeflective cavity) in the center of fovea
      and the elevating or flattening of fovea by the traction of posterior hyaloid.
      (2) The posterior hyaloid (hyporeflective band) adhered to the partially detached
      operculum (hyporeflective band) that was pulled forward. (3) The complete
      detachment of posterior hyaloid from the retina was seen. In some cases, the OCT
      image showed the development of macular hole from stage I to stage III. A scan
      along the papillomacular axis showed that the posterior vitreous detachment was
      dome shaped with the adhesion to fovea and disc. CONCLUSIONS: The occurrence of
      posterior hyaloid detachment at the fovea is in accordance with the formation of
      macular hole.

PMID- 12487897
TI  - [Observation on therapeutic effect of intraocular lens exchange surgery].
AB  - OBJECTIVE: To explore the causes, surgical principle and effect of lens exchange
      surgery. METHODS: The causes for 30 cases (30 eyes) of lens exchange were
      retrospectively analyzed, which included 11 cases with eccentric or dislocated
      intraocular lens (IOL, 36.7%), 8 cases with lens opacification (26.7%), 8 cases
      with incorrect power (26.7%) and 3 cases with iris capture (10.0%). There were 16
      males and 14 females aged 32 to 80 years (average, 62). RESULTS: After extraction
      of the original implant, the second IOL was inserted in the lens bag in 11 cases
      (36.7%), in the ciliary sulcus in 13 cases (43.3%), in the anterior chamber in 1
      case (3.3%) and with scleral fixation in 5 cases (16.7%). In the follow-up of 1 -
      24 months, the best corrected visual acuity over 0.5 was achieved in 23 cases
      (76.7%), 0.3 - 0.4 in 5 cases (16.7%), under 0.2 in 2 cases (6.6%). The surgical
      complications included astigmatism in 4 cases, cystoid macular edema 1 case,
      hyphema 1 case and posterior capsular opacification 1 case. CONCLUSIONS: The
      eccentric or dislocated IOL, lens opacification and incorrect power are the major
      causes of lens exchange. Proper IOL selected and meticulous operative technique
      can avoid the abnormality of IOL, and the lens exchange is an effective way to
      manage the situation.

PMID- 12487898
TI  - [Visual outcome and complications after posterior capsule rupture during
      phacoemulsification].
AB  - OBJECTIVE: To determine the visual outcome and incidence of complications after
      posterior capsule rupture during phacoemulsification. METHODS: Sixty-six eyes of
      66 patients which sustained posterior capsule rupture were retrospectively
      studied. RESULT: Fifty-two out of 66 eyes had best corrected visual acuity of
      20/40 or better. The complications included corneal edema (42 eyes), iris injury
      (1 eye), pupil decentration (5 eyes), intraocular hypertension (4 eyes),
      intraocular lens dislocation (1 eye), cystoid macular edema (3 eyes), remain of
      lens material (2 eyes) and retinal detachment (2 eyes). CONCLUSIONS:
      Phacoemulsification, even if complicated by posterior capsule rupture, is
      compatible with good visual outcome. Immediate proper management of complications
      is important.

PMID- 12487899
TI  - [Contrast sensitivity function in myopic LASIK].
AB  - OBJECTIVE: To evaluate near contrast sensitivity function before and after myopic
      laser in situ keratomileusis (LASIK). METHODS: With FACT 101 test chart, static
      near contrast sensitivity was measured in randomly selected 47 subjects (93 eyes)
      before, 1 month and 6 months after LASIK. The contrast sensitivity was measured
      at 1.5, 3.0, 6.0, 12.0 and 18.0 cycles per degree (c/d) spatial frequency
      respectively and made comparison in them. RESULTS: The patients achieved the mean
      uncorrected visual acuity (UCVA) of 1.07 +/- 0.18 and 1.12 +/- 0.20 at
      postoperative 1-month and 6-months respectively. There was a general reduction in
      near contrast sensitivity in all spatial frequencies at postoperative 1-month
      when they were compared with the preoperative contrast sensitivity. The
      difference at 12 and 18 c/d spatial frequency was statistically significant (t
      test, P < 0.01). By the 6-month visit, all eyes showed a recovery of static
      contrast sensitivity function. The group of high myopia (preoperative > or = 
      6.00 D) and group with complaining of glare and halos after the surgery had a
      higher decrease rate of contrast sensitivity compared with that of the group
      preoperative < - 6.00 D and the group of patients without such complaints
      respectively. The differences at 6.0, 12.0 and 18.0 c/d spatial frequency at 1
      month visit was statistically significant (t test, P < 0.05). CONCLUSIONS: The
      contrast sensitivity function test offers a more sensitive and comprehensive
      measure of functional vision than does standard Snellen acuity. The near contrast
      sensitivity in post-LASIK patients at early stage is reduced despite normal
      visual acuity and this can affect the quality of vision.

PMID- 12487900
TI  - [A study on localization of an autosomal dominant retinitis pigmentosa gene].
AB  - OBJECTIVE: To report the localization of a gene for an autosomal dominant
      retinitis pigmentosa (ADRP) family. METHODS: We studied a large ADRP family,
      collected 3 - 5 ml of venous blood samples from some family members, and genomic
      DNA was extracted from the blood. Then two-point linkage analysis between the
      known markers and the disease locus was performed. RESULTS: Linkage analysis
      showed the maximum LOD score reaches 2.732852 at marker D3S1292 (at recombination
      fraction theta = 0.1). CONCLUSION: Since D3S1292 was localized at 3q21, we
      roughly localized the disease gene on 3q21. In the mean time, the rhodopsin gene
      had been reported as linked to 3q21 adjacent to D3S1292, thus we think the
      disease gene may be the rhodopsin gene.

PMID- 12487901
TI  - [Telomerase expression in tarsal gland carcinoma].
AB  - OBJECTIVE: To investigate the roles of telomerase activity (TA) and human
      telomerase RNA (hTR) in tarsal gland carcinoma. METHODS: The telomerase repeated
      amplification protocol (TRAP) was used to demonstrate telomerase activity in 12
      tarsal gland carcinomas. In situ hybridization (ISH) was used to demonstrate the
      expression of hTR in 55 cases of paraffin-embedded tarsal gland carcinoma, and
      the results were compared with the proliferative index determined by Mib-1
      immunolabeling, histological patterns and recurrence of the tumor. RESULTS: The
      telomerase activity was revealed in 12 tarsal gland carcinomas with different
      degrees. The positive expression of hTR was 85.5% (47/55) and observed in tumor
      cells, but not in the adjacent tissues. The expression of hTR was correlated with
      the proliferative activity (as assessed by Mib-1 immunolabelling, r = 0.942, P <
      0.001) and the differentiation of tarsal gland carcinoma (chi(2) = 17.621, P <
      0.001), but no significant relationship with tumor recurrence. The level of hTR
      expression had a gradually raised tendency along with the decrease of
      differentiation of tarsal gland carcinoma. CONCLUSION: The results suggest that
      up-regulation of telomerase expression play some roles in tarsal gland
      carcinogenesis, and the expression of hTR be a useful marker for malignant degree
      of tarsal gland carcinoma.

PMID- 12487902
TI  - [Influence of low molecular weight heparin on proliferation of bovine lens
      epithelial cells on the surface of intraocular lens].
AB  - OBJECTIVE: To investigate the anti-proliferation effect of low molecular weight
      heparin (LMWH) on bovine lens epithelial cells (BLEC) on the surface of
      polymethylmethacrylate (PMMA) intraocular lens (IOL). METHODS: BLECs were
      incubated in vitro on the surface of PMMA IOLs. The cultural media contained LMWH
      (1 x 10(5) U/L) or normal heparin (1 x 10(5) U/L) or none of them (control).
      Cells were counted by flow cytometry. RESULTS: The heparin or LMWH treated BLECs
      on the surface of PMMA IOLs showed immature appearance, while the BLECs in the
      control group showed a tendency of fibrosis. The numbers of BLECs (per ml) in the
      digested solution from the surface of IOLs were 878.2 +/- 107.8 (control), 545.5
      +/- 58.2 (heparin) and 407.8 +/- 36.6 (LMWH). The comparisons among the three
      groups showed significant differences (P < 0.001). CONCLUSION: Low molecular
      weight heparin inhibits proliferation of lens epithelial cells on the surface of
      intraocular lens, which could be used as a potential drug to prevent the
      occurrence of postoperative capsular opacification after IOL implantation.

PMID- 12487903
TI  - [Preparation of anti-human retinoblastoma monoclonal antibody by solid tumor cell
      immunization and study on characteristics of its antigen].
AB  - OBJECTIVE: To prepare anti-human retinoblastoma (Rb) monoclonal antibody (McAb)
      by immunization with solid tumor cells and preliminarily study the
      characteristics of its antigen. METHODS: Three Balb/C mice were immunized by
      intraperitoneal injection of Rb solid tumor cells acquired from enucleation.
      Spleen lymphocytes were separated from them and fused with myeloma cell line
      SP2/0. The anti-human Rb McAb was selected by Rb solid tumor cell, SO-Rb(50), SO
      Rb(70), etc as antigens. The characteristics of its antigen were preliminarily
      studied by immunofluorescence, immunohistochemistry and Western blot. RESULTS:
      After repeatedly cloning them with micro-manipulation equipment, we successfully
      established 3 hybridoma cell lines secreting anti-human Rb McAb. Of all, 3C6
      hybridoma cells could steadily secrete anti-human Rb McAb after they were frozen,
      resuscitated and passaged repeatedly for 2 years. Its subgroup was IgG(1). Both
      immunofluorescence and immunohistochemistry examinations demonstrated that the
      corresponding antigen of McAb 3C6 was specifically and highly expressed in Rb
      tumor cell membrane and cytoplasm. The other tumor tissues and human normal eye
      tissues were negative. Western blot analysis preliminarily demonstrated that McAb
      3C6 could bind 25 000 protein band of Rb antigen. CONCLUSIONS: The anti-human Rb
      McAb 3C6 established by immunization of solid tumor cells is specifically and
      highly expressed in Rb tumor cells and has no cross-response with other tumor
      tissues and normal eyeballs. The antigen molecular weight bounded to this
      antibody is 25 000 or so, which further shows that it is a possibility for a new
      unidentified gene to be concerned with the tumor formation of Rb.

PMID- 12487904
TI  - [Epidemiology survey of rhegmatogenous retinal detachment in Beijing districts,
      Shanghai].
AB  - OBJECTIVE: To investigate the recent incidence and related risk factors of
      rhegmatogenous retinal detachment (RD) in Chinese people. METHODS: This incidence
      survey was based on 108 132 persons in Beijing districts, Shanghai, P. R. China.
      Rhegmatogenous RD patients came from inpatient, outpatient service data and the
      local health net databank composed of health data of 97.5% of all local
      residents. A contrast group was set up. The previous population data can be used
      to estimate the whole and specific incidence of rhegmatogenous RD. Some factors
      relevant to rhegmatogenous RD incidence were found by comparing the patient group
      and the contrast group. RESULTS: In Dec 1996 to Dec 1999, 61 cases with
      rhegmatogenous RD newly happened. The patients were 29 males and 32 females. The
      annual incidences of rhegmatogenous RD in these 4 years were 11.3/10(5),
      14.1/10(5), 14.1/10(5) and 17.6/10(5) respectively, and the average annual
      incidence was 14.4/10(5) (95% confidence interval 10.0 - 18.6). There was a high
      incidence of rhegmatogenous RD in persons older than 40 years, especially between
      40 and 59. When compared with the contrast group, the proportion of high myopia
      (more than -6.00 D) was significantly higher in rhegmatogenous RD patients group
      (P < 0.001). CONCLUSIONS: The annual incidence of rhegmatogenous RD of local
      Chinese population in these 4 years is increasing. It is strongly associated with
      high myopia and age, but not with gender.

PMID- 12487905
TI  - [Epidemiology of rhegmatogenous retinal detachment in Beijing, China].
AB  - OBJECTIVE: To investigate the incidence and epidemiological characteristics of
      rhegmatogenous retinal detachment (RD) in Beijing, China. METHODS: A prospective
      population-based study of the incidence of rhegmatogenous RD diagnosed between
      October 1999 and September 2000 was performed. The study group of Epidemiology of
      Rhegmatogenous Retinal Detachment in Beijing, China was made-up by the Department
      of Health Care Epidemiology of Peking University and all 35 hospitals with
      conditions of diagnosis and treatment for rhegmatogenous RD in Beijing city.
      Standard questionnaire and diagnostic guidelines for rhegmatogenous RD were
      adopted. All patients diagnosed for rhegmatogenous RD the first time in this
      period (included in-patients and out-patients) and resided in Beijing city proper
      and nearby suburbs were registered and recorded. The record included the age,
      sex, residing district, month rhegmatogenous RD occurring, refraction, eye or
      eyes of illness, history of blunt trauma, history of cataract extraction, history
      of rhegmatogenous RD on the contra-lateral eye, etc. Cases with recurrence,
      retinal break without retinal detachment and without patient's compliant and
      subclinical RD were excluded. Exudative RD, tractional RD, secondary detachment
      of retina after vitrectomy or strabismus operation or excision of ocular tumor
      and mixed retinal detachment were also excluded. RESULTS: A total of 526 patients
      were diagnosed in the city proper and the nearby suburbs. The annual incidence of
      rhegmatogenous RD was 7.98 per 100 000 population [95% confidence interval (CI),
      7.3 - 8.7]. The incidence of blunt traumatic, aphakic or pseudophakic, and
      nontraumatic phakic cases being 0.93/10(5) (95% CI, 0.7 - 1.2), 0.80/10(5) (95%
      CI, 0.6 - 1.0), and 6.25/10(5) (95% CI, 5.7 - 6.9), respectively. The incidence
      of traumatic detachment for males was 1.55/10(5) (95% CI, 1.1 - 2.0), which was
      higher than that for females 0.30/10(5) (95% CI, 0.1 - 0.5), (Z test based on the
      Poisson distribution, P < 0.001). But there was no significant difference between
      males and females in the incidences of nontraumatic phakic detachment and aphakic
      detachment (Z test based on the Poisson distribution, 0.5 < P < 0.7). There were
      two peak incidences, one occurred in 60 - 69-age-group, and the other occurred in
      20 - 29-age-group. No seasonal variations in the occurrence of retinal detachment
      was found (Z test based on the Poisson distribution, 0.8 < P < 0.9). There was no
      difference of incidence between the left and the right eye (Z test based on the
      Poisson distribution, P > 0.05). The proportion of bilateral detachment was 5.82%
      in that myopia was found in 66.5% of the patients. The proportion of high myopia
      in bilateral retinal detachment was greater than that of the unilateral retinal
      detachment (Chi-square test, 0.01 < P < 0.02). CONCLUSIONS: The annual incidence
      of rhegmatogenous RD in Beijing city proper and its nearby suburbs of China
      between Oct 1999 and Sept 2000 was 7.98 per 10(5) population (95% CI, 7.3 - 8.7).

PMID- 12487906
TI  - [Prevalence of blindness among adults aged 40 years or above in Linzhou county of
      Lasa].
AB  - OBJECTIVE: To estimate the prevalence of blindness among older adults aged >/= 40
      years in Linzhou county, Lasa, China. METHODS: Cluster sampling was used in
      randomly selecting individuals aged >/= 40 years in 44 villages in Linzhou county
      in May, 2000. A total of 3 153 individuals were examined for visual acuity and
      eye condition. The prevalence of blindness was calculated according to the
      pinhole vision with WHO blindness criterion (criterion A) and presenting vision
      with blindness criterion (criterion B). RESULTS: The individuals examined were
      enumerated. The response rate was 97.4% (3 071/3 153). When the bilateral pinhole
      vision < 3/60 was defined as the blindness criterion, the prevalence of blindness
      was 2.3% [95% confidence interval (CI), 1.8 - 2.8]. The blindness prevalence was
      increased with age (P < 0.001). Men had a higher prevalence of blindness than
      women (P > 0.05). After adjusting for age, the difference had statistical
      significance (P < 0.05). Prevalence of blindness was higher among the illiterate
      persons than among those with 1 or more years of schooling (P < 0.001). But after
      adjusting for age, the difference had no statistical significance (P > 0.05).
      When the bilateral presenting vision < 6/60 was defined as the blindness
      criterion, the prevalence of blindness was 3.2% (95% CI, 2.6 - 3.8). The
      blindness prevalence was increased with age (P < 0.001). Men had a higher
      prevalence of blindness than women. The crude male-to-female odds ratio for
      moderate and severe blindness was 1.17 (P > 0.05). After adjusting for age, the
      difference had no significance too (P > 0.05). Prevalence of blindness was higher
      among the illiterate persons than among those with 1 or more years of schooling
      (P < 0.001). But after adjusting for age, the difference had no statistical
      significance (P > 0.05). CONCLUSIONS: The prevalence of blindness is higher in
      the area of plateau. The principal cause of blindness is cataract.

PMID- 12487907
TI  - [Quality of life assessment of cataract surgery in elderly population of Doumen
      County, Guangzhou Province].
AB  - OBJECTIVE: To evaluate the outcome of cataract surgery in elderly population in
      Doumen County, Guangdong Province by assessment of subjective visual function and
      quality of life. METHODS: All the cataract postoperative subjects were identified
      in the population-level. Visual Function and Quality of Life (VF/QOL)
      questionnaire developed by National Eye Institute, USA in developing countries
      was used as the instrument. This Questionnaire was administered by four trained
      interviewers in all subjects with visual acuity less than 0.1 in either eye
      (treated as visual impairment cases), One in every 20 persons with visual acuity
      better than 0.3 (treated as normal control cases) in both eyes (un-operated
      group) and all cataract postoperative cases (operated group). RESULTS: In 5 342
      cross-sectional examined persons, individuals who could be successfully
      interviewed included 99 (90.8%) cataract postoperative cases, 535 (85.5%) visual
      impairment cases and 119 normal control ones. On a 0 - 100 scale, medium total
      scores of VF and QOL diminished from 92 to 2 and from 100 to 19 respectively
      along with visual status from normal to severe blindness in the un-operated
      group. Similar findings on visual status and VF/QOL scores were found in the
      operated group. The overall scores of VF and QOL were 40 and 56 for operated one
      and 56 and 72 for un-operated one. After adjusted the confounding effect of
      visual status, age, sex and education by multivariate regression model, the
      difference of QOL scores between un-operated and operated group was significant
      (P = 0.015), while no significant difference (P = 0.199) was found in VF scores.
      CONCLUSIONS: The scores of VF and QOL are significantly correlated with the
      visual status. Subjective visual function and quality of life could not be
      significantly improved after cataract surgery in this target population. Concerns
      should be paid in postoperative follow-up, aphakic correction and social
      psychological rehabilitation.

PMID- 12487908
TI  - [Simultaneous intraocular lens implantation during vitreous surgery for treatment
      of proliferative diabetic retinopathy].
AB  - OBJECTIVE: To evaluate the efficacy of cataract extraction and simultaneous
      intraocular lens (IOL) implantation during vitreous surgery for treatment of a
      series of patients with proliferative diabetic retinopathy (PDR) and cataract.
      METHODS: A consecutive series of PDR treated with vitrectomy and simultaneous IOL
      implantation during February 1997 and October 2001 was retrospectively analyzed.
      RESULTS: The series included 37 cases (12 males and 25 females) 44 eyes (OD 13;
      OS 17 and OU 7) with diabetic history for 1 - 30 years and eye symptoms for 40
      days to 10 years. Surgical techniques included lensectomy or phacofragmentation
      via the pars plana. The anterior capsule was preserved and the epithelium was
      suctioned and scraped off. After vitreous surgery and endolaser, IOL was inserted
      via the corneoscleral incision on the anterior capsule, of which the center area
      5 mm in diameter was cut. The patients was followed-up for 3 months to 4.5 years,
      mean (16 +/- 13) months. Visual acuity was light perception, hand motion, finger
      count, 0.02, and 0.1 - 0.2 in 5, 14, 11, 6, and 8 (18.2%) eyes, respectively
      before operation. Postoperatively, visual improvement was achieved in 41 eyes
      with 0.1 - 1.0 in 35 eyes (79.5%). Visual acuity remained unchanged in 2 eyes and
      decreased in one eye. Eyes with lower vision were associated with marked macular
      edema, hard exudates and severe ischemia. Six eyes had mild corneal edema 2
      approximately 5 days after operation. Corneal ulcer or neovascular glaucoma
      occurred in 2 eyes 5 months after surgery. CONCLUSION: Cataract extraction and
      simultaneous IOL implantation during vitreous surgery for PDR may improve the
      visual outcome in the majority of selected eyes without significant
      complications.

PMID- 12487909
TI  - [Analysis of intraocular pressure after myopic photorefractive keratectomy].
AB  - OBJECTIVE: To explore the factors related to intraocular pressure (IOP) after
      excimer laser photorefractive keratectomy (PRK). METHODS: Two hundred and nine
      cases (364 eyes) of myopia were studied with Goldmann applanation tonometer. All
      the patients were followed up for 12 months. RESULTS: After PRK, a decrease was
      observed in the IOP. The IOP reading in the 12(th) month was lower than that in
      the 6(th) month (P < 0.001). A positive correlation was found between IOP and
      corneal thickness or corneal curvature (r = 0.172, P < 0.001, r = 0.182, P <
      0.001). Regression equation for IOP drop (mmHg) = 1.156 + 0.22X(1) + 0.052X(2),
      [X(1) = decrease in corneal thickness ( micro m), X(2) = decrease in corneal
      curvature (D)]. CONCLUSION: The IOP measured after PRK for myopia is influenced
      by the corneal thickness, corneal curvature and steroid.

PMID- 12487910
TI  - [A clinical study of posterior capsular opacification after implantation of
      foldable intraocular lenses with different edges of optics].
AB  - OBJECTIVE: To study the influence of intraocular lens (IOL) optics with a square
      truncated edge on the incidence of posterior capsular opacification (PCO).
      METHODS: This consecutive series of 140 eyes (140 cases) underwent
      phacoemulsification with implantation of a foldable IOL with a square truncated
      edges (n = 90) or a foldable IOL with a round tapered edges (n = 50). We
      evaluated visual acuity, overall incidence of PCO and the incidence of PCO under
      different continuous curvilinear capsulorrhexis (CCC) conditions after surgeries.
      The mean postoperative follow-up was (14 +/- 8) months (range, 6 to 48 months)
      and (18 +/- 8) months (range, 6 to 48 months) respectively. RESULTS: Posterior
      capsular opacification occurred in 8.9% (8/90 eyes) of eyes in the square
      truncated edge designed group and 38.0% (19/50 eyes) of eyes in the round tapered
      edge designed group. The difference between the 2 groups was statistically
      significant (P < 0.01). Moderate CCC with the diameter slightly smaller than that
      of the IOL optic was achieved in 76 eyes in the square truncated edge group and
      no PCO was found. In the round tapered edge group, moderate CCC was achieved in
      41 eyes in which 10 eyes developed PCO. Amonhad a large or decentered CCC, 8 out
      of 14 eyes (57.1%) in the square truncated group developed PCO, and 9 out of 9
      eyes (100.0%) in the round tapered group developed PCO. The difference is also
      significant (P < 0.05). Nd: YAG laser capsulotomy rate was lower in the square
      truncated edge group (1.1%) than that in the round tapered edge group (10.0%) (P
      < 0.05). CONCLUSION: Moderate CCC and IOL optic design with a square truncated
      edge are the two important factors for prevention of posterior capsular
      opacification.

PMID- 12487911
TI  - [Clinical significance of accumulated energy complex parameter in
      phacoemulsification].
AB  - OBJECTIVE: The accumulated energy complex parameter [AECP, AECP = actual power
      (AP) x time (T)] was put forward and used to analyze the correlation between
      phacoemulsification energy and postoperative complication. METHODS: Ninety-two
      cases with senile cataract who underwent phacoemulsification were observed. The
      correlation between AECP and postoperative corneal edema rate (CER) was analyzed.
      The difference of AECP between the method of divided-conque and that of epi
      capsular rotated-chipping was compared for the same hard nucleus (IV) cataract
      extraction. RESULTS: The positive correlation was observed between AECP and CER
      (r = 0.974, t = 5.643, P < 0.05). The difference of the average AECP values
      existed between the two methods (t = 2.947, P < 0.01). The AECP and CER were
      lower in the method of divided-conque than that in epi-capsular rotated-chipping.
      CONCLUSION: AECP can be used as a dynamic index to control the
      phacoemulsification energy in order to decrease CER predictably. Our study
      suggests that AECP provide an important integrated energy index to evaluate
      phacoemulsification.

PMID- 12487912
TI  - [Synthetic plastic surgery for hemilateral facial deformity after retinoblastoma
      operation].
AB  - OBJECTIVE: To evaluate the effect of correcting complex deformity of the orbital
      region and contraction of the eye socket that caused by enucleation and
      postoperative irradiation for the treatment of retinoblastoma. METHODS:
      Depressive deformity of the orbitozygoma was corrected, and a large permanent eye
      socket was achieved in two-stage operation. First-stage surgery: Orbitozygomatic
      deformity reconstruction with hydroxyapatite (HA) and a temporoparietal fascial
      flap and a HA implant for correction of anophthalmos. Second-stage: Free radial
      forearm flap was adopted for eye socket reconstruction. RESULTS: Excellent
      cosmetic results of this method in 8 cases were demonstrated. CONCLUSION: This
      method is effective for management of complex deformities of orbitozygoma and
      contraction of eye socket.

PMID- 12487913
TI  - [Effects of adenovirus-mediated HSV-tk/GCV system on lens epithelium].
AB  - OBJECTIVE: To investigate the efficiency of adenovirus-mediated herpes simplex
      virus thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy system on
      calf lens epithelial cells and analyze the mechanism of cell death. METHODS: Calf
      lens epithelial cells were infected in vitro by the recombinant adenoviral vector
      containing HSV-tk gene (suicide gene) and followed by the treatment of GCV.
      Finally the efficiency was observed. In addition, the E(1) deleted empty
      adenoviral vector was used as the control. The conditions of cell necrosis and
      apoptosis were detected by electron microscope and staining with TUNEL and AO-EB
      (acridine orange-ethidium bromide) methods. RESULTS: Calf lens epithelial cells
      trans-infected by adenoviral vector containing HSV-tk gene were significantly
      inhibited in vitro by GCV treatment. And the phenomenon of bystander effect was
      confirmed. By comparison, there was no obvious toxin on the cells infected by
      empty adenoviral vector. Under the treatment of various dosages of GCV, a
      significant difference of the cell survival rate existed between the ADV/HSV-tk
      group and the ADV/Empty group (t = 4.94, P < 0.01). The killing efficiency of GCV
      increased with the prolongation of time. And the cell survival rate of the
      ADV/HSV-tk group was much lower than that of the ADV/Empty group (t = 11.28, P <
      0.001). Many lens epithelial cells were found in the group of ADV/HSV-tk. The
      levels of necrosis (t = 14.72, P < 0.001) and apoptosis (t = 7.28, P < 0.01) of
      lens epithelial cells in the ADV/HSV-tk group were greatly higher than those in
      the group of ADV/Empty. CONCLUSIONS: Adenoviral vector may successfully transduct
      HSV-tk gene (suicide gene) into calf lens epithelial cells. The lens epithelium
      expressing HSV-tk gene can be effectively killed by GCV. The mechanism of cell
      death caused by HSV-tk/GCV is probably necrosis and apoptosis. Therefore,
      adenovirus-mediated HSV-tk/GCV suicide gene therapy system may provide an
      effective approach to the treatment of posterior capsule opacification (PCO).

PMID- 12487915
TI  - [Analysis of complications about gynecologic endoscopic procedures in 14
      hospitals of Shanghai during 1992-2001].
AB  - OBJECTIVE: To investigate the objective law of complication in endoscopic
      operation of gynecology. METHOD: We retrospectively reviewed and analyzed the
      complications of endoscopic surgery during the decade occurred in 9 municipal or
      teaching hospitals and 5 district hospitals in Shanghai. RESULTS: There were
      total 10,263 cases of operative laparoscopy and 18,306 cases of hysteroscopy. The
      laparoscopic complication rate was 1.51% (155/10,263) and incidence of
      hysteroscopic complication was 0.09% (16/18,306). The major common complications
      in laparoscopic procedures were bleedings (70/10,263, 0.68%), 18 infections
      (18/10,263, 0.18%) and 12 organic injuries (12/10,263, 0.12%). The complication
      rate in laparoscopic surgery made by the inexperienced was six times greater than
      that by the experienced (P < 0.01). Complication rate decreased to 0.90% in 2001
      from 7.25% in 1992. The complications in hysteroscopy were 6 uterine
      perforations, 3 hyperhydration syndromes, 3 postoperative bleedings, 2 cardio
      brain syndrome, 1 organic injury, and 1 died. The mortality was 0.005%. The
      complication rate in the hospital developing hysteroscopic surgery less than
      1,000 cases was 16 times greater than in that over 1,000 cases (P < 0.01).
      CONCLUSIONS: It is suggested by our data that the complication in laparoscopy
      showed downward year by year and some serious complications were increased with
      extension of operative surgery. Complication has to do with the experience of
      surgeons. To decrease complication, surgeons should pay a great attention to the
      indication chosen correctly, training step by step and basic skills.

PMID- 12487914
TI  - [Effect of Smad 4 mRNA on the proliferation of rabbit epithelial cells].
AB  - OBJECTIVE: To assess the effects of Smad 4 mRNA on the proliferation and
      transformation of rabbit lens epithelial cells (LECs). METHODS: The expressions
      of Smad 4 mRNA and proliferating cell nuclear antigen (PCNA) in rabbit LECs in
      different periods after lens cortex absorption were detected by in situ
      hybridization (ISH) and immuno-histochemical methods respectively. RESULTS: (1)
      The expression of Smad 4 mRNA in the cytoplasm of normal rabbit lens epithelial
      cells was weakly positive. (2) The expression in the equatorial region and
      anterior subcapsular region on the postoperative first day was negative, and the
      light absorbance (A) was 0.39 and 0.36 respectively, P < 0.01 in comparison with
      the preoperative ones. (3) The expression of Smad 4 appeared again on the
      postoperative third day, and then increased gradually along with the prolongation
      of time. The expression of Smad 4 mRNA of cells in anterior subcapsular region
      reached its peak in the postoperative one month. The percentage of positive area
      was 1.31 and the average A value was 0.54. In the equatorial region, the
      expression was strongest in the postoperative one week, the percentage of
      positive area was 0.77 and the A value was 0.53, P < 0.01 in comparison with that
      before the operation. (4) In 1 - 2 months postoperatively, transformed
      fibroblasts appeared in the equatorial region. The expression of Smad 4 mRNA was
      positive in the cytoplasm of the transformed fibroblasts. The expression of PCNA
      was strongest on the postoperative first day, and afterwards it was gradually
      decreased. Until the postoperative one month, it restored to its preoperative
      level. CONCLUSIONS: The expression of Smad 4 mRNA presents in normal lens
      epithelial cells. Smad 4 mRNA participates in the proliferation and metabolism of
      lens epithelial cells. Smad 4 mRNA possibly participates in the procedure of
      transformation from lens epithelial cells to fibroblasts.

PMID- 12487916
TI  - [Clinical study of severe complications during hysteroscopic surgeries].
AB  - OBJECTIVE: To investigate the clinical characteristics, treatment and prevention
      methods of severe complications during hysteroscopic procedures. METHODS: From
      January 1995 to January 2001, seventeen cases with uterine perforation, heavy
      bleeding and fluid overload respectively were encountered during hysteroscopic
      procedures. This analysis focuses on their diagnosis and clinical management as
      well as prevention methods. RESULTS: Three cases with uterine perforation and
      seven with incomplete perforation followed transcervical resection of myoma
      (TCRM), transcervical resection of adhesion, transcervical resection of septum
      and transcervical removal of foreign body respectively, which were diagnosed by
      both B ultrasonography and laparoscopy and treated laparoscopically. Four cases
      with heavy bleeding were encountered during TCRM. Foley catheter was inserted
      into uterine cavity to stop the bleeding successfully. Three cases with fluid
      overload were cured by diuretic agent and saline infusion. There were no serious
      consequence happened. CONCLUSIONS: It is a potential high risk factor of
      resulting in complications that performing complicated procedures inside uterine
      cavity during hysteroscopic operations. Pre-treatment with gonadotropin-releasing
      a and guiding with B ultrasound/laparoscopy as well as controlling irrigation
      pressure are necessary for preventing above complications.

PMID- 12487917
TI  - [Laparoscopic surgery in patients with hypovolemic shock due to ectopic
      pregnancy].
AB  - OBJECTIVE: To evaluate the feasibility and safety of operative laparoscopy for
      ectopic pregnancy with hypovolemic shock. METHODS: Two hundred and fifteen women
      with ectopic pregnancy underwent operative laparoscopy. These patients were
      divided into two groups. Group I included 21 patients of ectopic pregnancy with
      shock and intraperitoneal hemorrhage more than 1,000 ml, and group II included
      194 hemodynamically stable patients with blood loss less than 1,000 ml. The
      clinical data of perioperative periods in two groups were analyzed. RESULTS: All
      patients were tube pregnancies. The rate of tube rupture was higher in group I
      than that in group II (81% versus 16%), the difference was statistically
      significant (P < 0.01). Intraabdominal blood loss was significantly higher in
      group I (1,775 +/- 531) ml than that in group II (133 +/- 176) ml, autologous
      blood transfusions were given to 95% and 9% of patients in group I and II
      respectively (P < 0.01). Laparoscopic salpingectomy was performed to 86% and 51%
      of patients in group I and II, the difference was significant. The operating time
      was longer in group I than in group II (50 +/- 24) and (43 +/- 24) min, but the
      difference was not significant. All patients had no perioperative complications.
      CONCLUSIONS: Operative laparoscopy in patients with hypovolemic shock can be
      safely and effectively performed by experienced laparoscopists with the aid of
      optimal anesthesia, advanced cardiovascular monitoring and autologous blood
      transfusion.

PMID- 12487918
TI  - [Clinical analysis of laparoscopic pelvic and paraaortic lymphadenectomy treated
      patients with gynecological malignancies].
AB  - OBJECTIVE: To investigate the possibility and value of laparoscopic radial
      hysterectomy with lymphadenectomy in patients with gynecology malignancies.
      METHODS: From July 2000 through June 2002, we performed laparoscopic radial
      hysterectomy with lymphadenectomy on 56 patients with biopsy-proven endometrial
      or cervical carcinoma (21 endometrial cancer and 35 cervical cancers). Pelvic,
      para-aortic, and combinations of both pelvic and para-aortic lymphadenectomies
      were performed depending on the primary site of the disease and indication for
      lymph node dissection. RESULTS: Laparoscopic procedure required an average of 3.1
      h, with an average blood loss of 198 ml. The average number of nodes was 16.
      Patients undergoing laparoscopic assisted vaginal radical hysterectomy and
      lymphadenectomy alone were admitted for 9.6 days on average. There were 5
      patients with intraoperative complications. Two patients were bladder injury and
      other two patients with venous injury. One patient was colon injury and converted
      to an abdominal procedure. There were no ureteral or intestinal injuries.
      Postoperative complications occurred in 3% of patients and only one was
      considered ureteral constriction 1 month after operation. There has been one
      patient with trocar site recurrences 4 weeks after operation. Three patients have
      retention of urine. CONCLUSIONS: Laparoscopic assisted vaginal radical
      hysterectomy and lymphadenectomy was feasible and safe for treatment of cervical
      or endometrial cancer. Also it was a less invasive, and recovery time was
      reduced. This was reliable and accurate method for evaluating lymph node
      metastasis of cervical or endometrial carcinoma.

PMID- 12487919
TI  - [Expression of nicotinamide edenine dinucleotide dehydrogenase gene in placenta
      of patients with pregnancy induced hypertension].
AB  - OBJECTIVE: To investigate the expression of nicotinamide edenine dinucleotide
      (NADH) dehydrogenase gene in the placenta of patients with pregnancy induced
      hypertension (PIH) and the role of NADH dehydrogenase in PIH pathogenesis.
      METHODS: Using (32)P dATP labeled human NADH dehydrogenase cDNA probe, the
      expression of NADH dehydrogenase gene in placental tissues of 10 normal late
      pregnant (NLP) women and 10 PIH patients was detected by dot blot. Mean A of each
      hybridization dot was measured by image analysis system to compare NADH
      dehydrogenase mRNA level in PIH placentae with that in NLP placenta. RESULTS: The
      NADH dehydrogenase gene values in patients with PIH and NLP were 21 +/- 6 and 56
      +/- 16. The level of NADH dehydrogenase mRNA in PIH placenta was significantly
      higher than that in normal placenta (P < 0.05). CONCLUSION: Elevated expression
      of NADH dehydrogenase gene may play a role in PIH pathogenesis.

PMID- 12487920
TI  - [Relationship of nitric oxide with intrauterine human cytomegalovirus active
      infection during early pregnancy].
AB  - OBJECTIVE: To study the relationship of nitric oxide (NO) with intrauterine human
      cytomegalovirus (HCMV) active infection during early pregnancy. METHODS: Reverse
      transcript polymerase chain reaction (RT-PCR) was used to screen HCMV-mRNA of
      chorionic villi during early pregnancy in 81 cases who had poor pregnant history.
      The serum HCMV-IgM was measured by enzyme linked immunoadsorbent assay (ELISA)
      and the expression of decidual iNOS-mRNA was investigated with in situ
      hybridization (ISH). RESULTS: (1) Six cases were HCMV-mRNA positive in chorionic
      villous tissues and 14 cases with serum HCMV-IgM positive among cases, the
      positive rate of serum HCMV-IgM was 17.3% (14/81). All cases were divided into
      three groups according to HCMV-mRNA and serum HCMV IgM. Group I: 5 cases with
      HCMV-mRNA positive and IgM positive, and the transmission rate between pregnant
      women and fetus was 35.7% (5/14); Group II: 9 cases with HCMV-mRNA negative and
      IgM positive, Group III: 66 cases with HCMV-mRNA and IgM negative; In addition, 1
      case with HCMV-mRNA positive but IgM negative. (2) The expressive quantity of
      decidual iNOS-mRNA in group I was significantly higher than those in group II and
      III (P < 0.05). The case with HCMV-mRNA positive and serum IgM negative also has
      a strong staining of decidual iNOS-mRNA. CONCLUSIONS: NO may play a critical role
      in intrauterine HCMV active infection, NO could be served as an assistant marker
      of HCMV infection.

PMID- 12487921
TI  - [Predictive value of umbilical artery lactate levels and fetal heart rate
      monitoring for fetal distress].
AB  - OBJECTIVE: Measuring umbilical artery lactate levels to evaluating the predictive
      value of abnormal fetal heart rate (FHR) monitoring patterns for fetal distress.
      METHODS: There were 73 neonates with abnormal fetal heart monitoring patterns in
      the distress group. The abnormal patterns included abnormal baseline FHR, severe
      variable decelerations, mild variable decelerations and tachycardia. There were
      118 normal neonates (Apgar score > or = 9) in the control group. Twenty min fetal
      heart monitoring was performed at the time of admitting, laboring and in labor
      and in active phase. Continuous fetal heart monitoring was performed during the
      second stage of labor. All neonatal umbilical artery lactate levels were measured
      at delivery. RESULTS: The rate of using forceps in distress group was
      significantly higher than that of the control (P < 0.01), the rate of spontaneous
      labor was significantly lower than the control group (P < 0.01). In the distress
      group, severe variable decelerations were generally emerged in the second stage
      of labor. The incidence of neonatal Apgar score < or = 7 in neonates with
      abnormal baseline FHR was higher than those with severe variable decelerations,
      mild variable decelerations and tachycardia (P < 0.05). As for neonatal umbilical
      artery lactate levels, the neonatatuses with abnormal baseline FHR was (4.55 +/-
      0.23) mmol/L, the neonatatuses with severe variable decelerations was (3.84 +/-
      0.40) mmol/L, all significantly higher than the control group's (P < 0.01). The
      neonatatuses with mild variable decelerations was (2.63 +/- 0.32) mmol/L, the
      neonatatuses with tachycardia was (2.55 +/- 0.46) mmol/L, and there are no
      significant differences between the neonatatuses with mild variable decelerations
      and tachycardia and the control group's (P > 0.05). CONCLUSIONS: Measuring
      umbilical artery lactate levels is an efficient and accurate technique for fetal
      distress diagnosis. There was a close correlation between baseline FHR with
      abnormal changes and severe variable deceleration with fetal distress. There was
      no certainly correlation between mild variable decelerations and tachycardia with
      fetal distress. It should be evaluated later.

PMID- 12487922
TI  - [Relationship of vascular endothelial growth factor with bile acid in
      intrahepatic cholestasis of pregnancy].
AB  - OBJECTIVE: To investigate the relationship of vascular endothelial growth factor
      (VEGF) with bile acid in intrahepatic cholestasis of pregnancy patients (ICP).
      METHODS: Thirty three ICP patients and 30 normal pregnant women in late pregnancy
      were studied, maternal serum VEGF concentrations were examined by enzyme linked
      immunoadsorbent assay (ELISA). Capillaries density in placenta are detected by s
      ABC immunohistochemistry, radio-immunity method is used to assay the maternal
      serum glycocholic acid. RESULTS: Serum VEGF in ICP (2 072 +/- 17) ng/L has
      negative correlation with glycocholic acid (47.9 +/- 14.2) ng/L, however,
      positive correlation with capillaries density in placenta (68 +/- 5)/HP; The
      serum VEGF in normal pregnant woman (2 256 +/- 30) ng/L does not have
      relationship to glycocholic acid (1.6 +/- 0.7) ng/L but it has positive
      correlation with capillaries density in placenta (74 +/- 7)/HP. CONCLUSION:
      Cytotoxicity of high concentration bile acids impairs vascular endothelial cells
      resulting in lower excretion of VEGF in vascular endothelial cells of ICP, which
      lead to placental blood capillaries dysplasia and lower permeability, it may be
      one of reasons of fetal distress and fetal death in uteri in ICP.

PMID- 12487923
TI  - [Effect of traditional Chinese medicine on expression of extracellular signal
      regulating kinase-1 and mitogen activated protein kinase phosphatase-1 in brain
      and liver of fetal rats with fetal growth restriction].
AB  - OBJECTIVE: To investigate the effect of reinforcing kidney, replenishing Qi and
      blood activating prescription (RKRQBAP) on extracellular signal regulating kinase
      1 (ERK-1) and mitogen activated protein kinase phosphatase-1 (MKP-1) of fetal
      rats with fetal growth restriction (FGR). METHODS: Passive smoking was used to
      establish animal model of FGR. All pregnant rats were divided into four groups:
      FGR group, L-arg group: rats with FGR treated with L-arginine, Chinese medicine
      group (CHM group): rats with FGR treated by traditional Chinese medicine and
      normal control group. The expression of ERK-1 and MKP-1 in brain and liver were
      measured by western-blot. RESULTS: (1) According to FGR group, L-arg group, CHM
      group and normal group, the expression of ERK-1 in brain was 7.63 +/- 0.22, 10.03
      +/- 0.41, 11.03 +/- 0.30, 11.44 +/- 0.09 and MKP-1 was 7.41 +/- 0.38, 10.35 +/-
      0.60, 10.60 +/- 0.14, 11.60 +/- 0.62. (2) The expression of ERK-1 in liver was
      4.73 +/- 0.54, 5.83 +/- 0.17, 11.37 +/- 0.12, 12.34 +/- 0.14 accordingly and MKP
      1 was 9.07 +/- 0.61, 10.66 +/- 0.08, 14.27 +/- 0.73, 14.92 +/- 0.17. (3) The
      expression of ERK-1 and MKP-1 in brain and liver was much lower in FGR group than
      in normal group (P < 0.01), and that of CHM group was much higher than in FGR
      group (P < 0.01) and closed to normal group (P > 0.05). The expression of ERK-1
      in brain was much higher in CHM group than in L-arg group (P < 0.05), the
      expression of MKP-1 was almost the same (P > 0.05); Both of them in liver were
      higher in CHM group than in L-arg group (P < 0.01). CONCLUSION: The possible
      mechanism which the RKRQBAP cure FGR is to affect the expression of ERK-1 and MKP
      1 and to promote growth- related genes expression and restrain apoptosis. In
      addition, RKRQBAP is superior to L-arginine in treatment of FGR.

PMID- 12487924
TI  - [Preimplantation genetic diagnosis].
AB  - OBJECTIVE: To evaluate the clinical effectiveness of preimplantation genetic
      diagnosis (PGD) for the couples having a higher risk of genetic diseases with
      fluorescence in situ hybridization (FISH). METHODS: Ovarian hyperstimulation,
      oocyte retrieval and in vitro fertilization were performed in 4 cases. Blastomere
      biopsy were performed from the embryos at the 6 - 8 cell stage. Genetic diagnosis
      was identified by single blastomere FISH. The female embryos or normal embryos
      were transferred into uterus. RESULTS: Twelve embryos were available for embryo
      biopsy. Twenty cells were collected. Seventeen nuclei were found after fixation.
      Hybridization signals of 11 embryos were clear and 8 embryos were transferred
      into uterus. One clinical pregnancy was achieved, and 1 normal female infant was
      delivered on september 14, 2001. CONCLUSION: PGD is very valuable for avoiding
      selective abortion and birth of affected child of the couples having a higher
      risk of genetic diseases by detecting embryo sex and chromosome number using
      FISH.

PMID- 12487925
TI  - [Evaluation of myometrial invasion in endometrial carcinoma].
AB  - OBJECTIVE: To determine the value of preoperative ultrasound, intraoperative
      gross visual inspection and postoperative bulk specimen measurement in evaluating
      the diagnosis of myometrial invasion in endometrial carcinoma. METHODS: A total
      of 133 cases of women with endometrial carcinoma were analyzed focusing on
      evaluating the diagnosis of myometrial invasion by preoperative ultrasound,
      intraoperative gross visual inspection and postoperative bulk specimen
      measurement. The relationship between CA(125) and endometrial carcinoma of 91
      cases of endometrial carcinoma was also analyzed. RESULTS: In the diagnosis of
      myometrial invasion and deep myometrial invasion, ultrasound showed a sensitivity
      of 62.6% and 47.8% and a specificity of 67.7% and 90.0%, respectively, and
      intraoperative gross visual inspection showed a sensitivity of 59.6% and 73.9%
      and a specificity of 76.5% and 94.6%, respectively. The sensitivity of
      postoperative bulk specimen measurement was 70.0% and 94.4% and the specificity
      was 92.0% and 97.7%, respectively. The levels of CA(125) had no correlation with
      depth of myometrial invasion in endometrial carcinoma, but they had correlation
      with International Federation of Gynecology and Obstetrics (FIGO) stage.
      CONCLUSIONS: Preoperative ultrasound, intraoperative gross visual inspection and
      postoperative bulk specimen measurement were helpful to the diagnosis of depth of
      myometrial invasion in endometrial carcinoma, and postoperative bulk specimen
      measurement seems to be better. CA(125) could not evaluate depth of myometrial
      invasion in endometrial carcinoma.

PMID- 12487926
TI  - [Experimental study of anti-vascular endothelial growth factor hairpin ribozyme
      gene inhibiting growth of xenografted tumor of ovarian cancer cells].
AB  - OBJECTIVE: We propose to block the autocrine and (or) paracrine pathway of
      vascular endothelial growth factor (VEGF) in ovarian cancer by using anti-VEGF
      hairpin ribozyme gene to see whether the growth of tumor cells could be inhibited
      and to further exploit its mechanisms. METHODS: Anti-VEGF hairpin ribozyme gene
      eukaryotic expression vector was introduced into ovarian cancer cells SKOV(3) by
      using lipofectin mediation and positive clones were screened by genticin (G418);
      ribozyme (RZ) expression was confirmed by RNA dot blot; the VEGF expression of
      SKOV(3) cells before or after transfection were detected by reverse transcription
      polymerase chain reaction (RT-PCR) method, transmission electron microscopy
      demonstrated the morphologic changes of ribozyme-generating SKOV(3) cells; the
      growth of transfected cells in nude mice were detected. RESULTS: VEGF expression
      was decreased distinctly in SKOV(3) cells transfected by RZ (SKOV(3)-RZ) cells.
      Apoptosis cells were observed; the formation rate and growth speed of xenografted
      tumor slowed down. CONCLUSIONS: Anti-VEGF hairpin ribozyme gene can inhibit the
      expression of VEGF mRNA and VEGF in SKOV(3) cells. The growth of xenografted
      tumor in nude mice was inhibited by reduced angiogenesis. This provides an
      experimental basis for curing human ovarian cancer with antiangiogenesis method.

PMID- 12487927
TI  - [Relationship between cyclooxygenase-2 protein expression, prostaglandins levels
      and biologic behavior in ovarian carcinoma tissue].
AB  - OBJECTIVE: To study the relationship between cyclooxygenase-2 (COX-2) protein
      expression, prostaglandins levels assay and ovarian carcinoma biologic behavior
      in ovarian carcinoma tissue. METHODS: The levels of COX-2 protein, prostaglandin
      (PG) E(2), 6-keto-PGF(1 alpha) and thromboxane (TX) B(2) in 54 biopsy specimens
      from patients with ovarian serous tumor which included three groups: 33 samples
      of ovarian serous carcinomas; 10 samples of borderline ovarian serous tumors and
      11 samples of benign ovarian serous tumors and 10 samples of normal ovarian
      tissues were detected by western blot analysis and radioimmunoassay to
      investigate their clinical significance. RESULTS: (1) The levels of COX-2 protein
      expression (82%, 27/33) and relative quantity (20.08 +/- 3.53) in ovarian serous
      tumor tissues were statistically higher than those in benign ovarian serous tumor
      tissues and in normal ovary tissues [0 and (15.04 +/- 0.12), 0 and (15.33 +/-
      0.60), P < 0.05]. The level of COX-2 protein expression in borderline ovarian
      serous tumor tissues (90%, 9/10) and relative quantity (20.61 +/- 3.03) were
      statistically higher than those in benign ovarian serous tumor and normal ovary
      tissues (P < 0.05). The levels of COX-2 protein expression and relative quantity
      were found no significant differences in different clinical stages (I to II and
      III to IV), different histological grades, with or without ascites and lymphatic
      metastasis. (2) The levels of PGE(2), 6-keto-PGF(1 alpha) and TXB(2) in ovarian
      serous carcinoma tissues were statistically higher than in borderline ovarian
      serous tumor, benign ovarian serous tumor or normal ovarian tissues (P < 0.05).
      No significant differences of the levels were found among borderline tissues,
      benign tissues or normal ovarian tissues (P > 0.05). PGE(2), 6-keto-PGF(1 alpha)
      and TXB(2) were found no significant differences in different clinical stages (I
      to II and III to IV), different histological grades, with or without ascites and
      lymphatic metastasis. (3) COX-2 expression was correlated with PGE(2), 6-keto
      PGF(1 alpha) and TXB(2) (P < 0.01). CONCLUSIONS: (1) Our data suggest that COX-2
      overexpression leads to increased PGE(2), 6-keto-PGF(1 alpha) and TXB(2)
      biosynthesis, which may be mechanisms underlying the contribution of COX-2 to the
      development of ovarian serous carcinoma. (2) PGE(2), 6-keto-PGF(1 alpha) and
      TXB(2) may be helpful parameters of diagnosis and differentiate diagnosis in
      ovarian serous carcinoma.

PMID- 12487928
TI  - [Clinical value of antenatal diagnosis of intrauterine active human
      cytomegalovirus infection with reverse transcription polymerase chain reaction].
AB  - OBJECTIVE: To study the clinical value of antenatal diagnosis of intrauterine
      active human cytomegalovirus (HCMV) infection with reverse transcription
      polymerase chain reaction (RT-PCR). METHODS: The active HCMV infection of
      pregnant women was diagnosed with enzyme-linked immunosorbent assay (ELISA),
      serum Nest-PCR (N-PCR) and RT-PCR. The methods of antenatal diagnosis include
      villus sampling, amniocentesis and cordocentesis under ultrasound guidance. RT
      PCR and N-PCR was used to screen fetal active infection. RESULTS: The infection
      rate of chorionic villi and cord blood whose mother was in active infection is
      53.3% (16/30) and 47.8% (33/69) respectively, whereas that whose mother just had
      infectious history is 8.3% (4/48), 9.7% (6/62) respectively, the differences are
      statistically significant respectively (P < 0.001). The active infection rate of
      chorionic villi and cord blood in maternal active infection group is 30.0% (9/30)
      and 29.0% (20/69) respectively, whereas that with infectious history is 4.2%
      (2/48) and 4.8% (3/62), the differences are statistically significant
      respectively (P < 0.001). In the active intrauterine infection, the incidence of
      abortion and premature delivery was 41.2% (14/34), significantly higher than that
      of the latent infection 8.0% (2/25, P < 0.01). CONCLUSIONS: Antenatal diagnosis
      of intrauterine active HCMV infection with RT-PCR and the means of sampling
      described are of safety and reliability. It has a great clinical value in
      management of the fetus whose mother had been in active HCMV infection.

PMID- 12487929
TI  - [Clinical study on efficacy and safety of labor analgesia with inhalation of
      nitrous oxide in oxygen].
AB  - OBJECTIVE: To investigate the efficacy and safety of labor analgesia with
      inhalation of 50% nitrous oxide in oxygen. METHODS: A total of 1300 cases of term
      primiparous women in labor were divided into two groups. Study group (n = 658)
      50% nitrous oxide in oxygen was inhaled during labor for relieving labor pain.
      Control group (n = 642) intermittent inhalation of 50% oxygen was carried out
      during labor. Two groups were compared with following indices: duration of the
      labor, delivery mode, meconium stained of amniotic fluid, postpartum bleeding
      volume, neonatal Apgar score, side effect of nitrous oxide, and blood gas
      analysis of samples from maternal radius artery and fetal umbilical blood.
      RESULTS: The efficiency of relieving labor pain in study group was much better
      than that of control group (80.9% vs 0.9%, P < 0.001). Rate of cesarean section
      in study group was lower than control group (11.6% vs 19.3%, P < 0.05). The
      active phase of labor in study group was shorter than control group (153 min vs
      187 min, P < 0.05). There was side effect of dizziness in 39.4% cases of study
      group but there were no any complaint in the control group cases. There were no
      significantly differences in duration of the labor, meconium stained amniotic
      fluid, postpartum bleeding volume, neonatal Apgar score, and blood gas analysis
      between two groups (P > 0.05). CONCLUSION: Inhalation of 50% nitrous oxide in
      oxygen was safe and effective labor analgesia. It is acceptable. The measure of
      relieving labor pain may increase the vaginal birth rate. There is no severe side
      effect on mother and baby.

PMID- 12487930
TI  - [Relationship between vaginal sialidase bacteria vaginosis and chorioammionitis].
AB  - OBJECTIVE: To study the relationship among vaginal sialidase, bacterial vaginosis
      (BV), chorioammionitis and subsequent adverse outcome of pregnancy. METHODS:
      Vaginal sialidase was measured by colorimetry in samples of vaginal discharges
      from 80 pregnant women with BV (study group) and 60 normal pregnant women at same
      gestation weeks (control group). Color turning blue means positive of sialidase
      activity, and no color changing means negative. The diagnosis of chorioammionitis
      was based on pathological examination. RESULTS: Ninety six dot three percent,
      3.3% exhibited sialidase activities in study group and control group,
      respectively. There were significant differences between these two groups (P <
      0.001). By measuring vaginal sialidase activity, the sensitivity, specificity,
      positive and negative predictive value in diagnosing BV were 96.3%, 96.7%, 97.5%
      and 95.1%, respectively. Chorioammionitis, premature rupture of membranes,
      premature delivery and puerperal infection in sialidase positive group were
      significantly higher than the negative group. Sensitivity, specialty of sialidase
      activity for chorioammionitis were 87.5%, 50.0%, respectively. CONCLUSION:
      Vaginal sialidase activity has strong relation with bacterial vaginosis.
      Measuring vaginal sialidase activity is a fast, easy, and useful method to
      diagnose bacterial vaginosis. It also has relation with chorioammionitis and
      subsequent adverse outcome of pregnancy.

PMID- 12487931
TI  - [Study on the effects of various dosage of dexamethasone in accelerating fetal
      lung maturation and the accompanied side effects in rats].
AB  - OBJECTIVE: To compare the effect of various dosage of dexamethasone (Dex) in
      accelerating fetal lung maturation and the accompanied side effects. METHOD:
      Sixty time-bred Wistar rats were randomly assigned to one of the four groups (15
      rats each group). They were given normal saline 0.8 ml (group A); Dex 0.2 mg
      (group B); Dex 0.4 mg (group C); Dex 0.8 mg (group D) IH, separated for 4 times
      on gestational day 15, 16. ten rats in each group were killed and hysterectomy
      were made immediately on day 17. The neonate breathing scale and their lung were
      observed and scored; the amniotic lamellar bodies (LB) were counted to assess the
      preterm fetal lung maturation. The remaining 5 rats in each group delivered
      naturally. The mother rats' condition in perinatal period, the birth weight of
      their neonates, and the structure of the livers and adrenal glands of the
      neonates were recorded to assess the side effects of the drug. RESULTS: The
      scores of neonatal breathing scale in group A to D were: 1.4 +/- 0.5, 3.6 +/-
      0.7, 4.2 +/- 0.5, 4.5 +/- 0.5; their lung histologic maturation degree: 1.4 +/-
      0.6, 3.9 +/- 0.9, 4.2 +/- 0.7, 4.4 +/- 0.6; and the account of their amniotic LB
      were: (8.6 +/- 3.0), (30.2 +/- 4.2), (33.0 +/- 3.4), (35.8 +/- 2.7) x 10(9)/ml
      respectively. All the indexes in the three Dex groups were higher than group A,
      and there were no statistical difference among in the three Dex groups except the
      neonatal breathing scale scores, which were higher in the high dose group D than
      the low dose group B. When high dose Dex was used, there was a reductive tendency
      in mother rats weight and its ability to resist infectious disease; meanwhile,
      the birth weight of their neonates reduced, the number of stillbirth and neonate
      liver necrosis increased. CONCLUSION: By the preterm gravid rat model, low dosage
      of antenatal dexamethasone administration accelerate fetal lung maturation to the
      extent equally to the middle even high doses of the drug. When high dosage of Dex
      was administered, the increasing side effects on the mother rats and their
      fetuses were accompanied.

PMID- 12487932
TI  - [Clinical analyses of 42 cases of urinary tract injury in gynecologic surgery].
AB  - OBJECTIVE: To determine the clinical characteristics and management of urinary
      tract injuries incidental to gynecologic surgery. METHODS: During the study
      period from Jan. 1, 1990 to Dec. 31, 2001, forty-two patients with urinary tract
      injuries in gynecologic surgery were analyzed retrospectively focusing on type
      and time of injury, diagnostic methods and managements of urinary fistula.
      RESULTS: Forty-two urological injuries were incurred during the performance of 12
      849 gynecologic surgical procedures, an incidence of 0.33% including of 11
      ureteral injuries and 31 bladder injuries, an incidence of 0.09% and 0.24%
      respectively. Of the 11 ureteral injuries 5 occurred in the lower ureter, 4
      occurred at the level of vecical entrance and 2 were in the region of the
      infundibulopelvic ligaments. Of the bladder injuries, all 31 occurred at the
      bottom or back of the bladder. Urinary tract injury was made intraoperatively in
      32 patients (76%) and made postoperatively in 10 patients (24%). Urinary fistulae
      occurred in 14 patients (33%). Ten patients with urinary fistulae were diagnosed
      by comparing the concentration of electrolyte, urea nitrogen and creatine in
      drainage fluid with those in urine and blood. Infusion of methylene blue and/or
      cystoscopy were checked in 9 patients and 4 bladder fistulae were found positive
      results. All 8 ureteral fistulae were diagnosed by intravenous pyelography. An
      appropriate repair during operation, putting the double J-catheter and/or
      catheterization was useful. Forty-one patients were healed. CONCLUSION: Most of
      urinary tract injuries in gynecologic surgery had optimal results when they were
      diagnosed early and managed correctly.

PMID- 12487933
TI  - [Effect of hormone replacement therapy on homocysteine and echocardiography in
      postmenopausal women].
AB  - OBJECTIVE: To observe the effects of hormone replacement therapy (HRT) on fasting
      total plasma homocysteine levels and echocardiography in postmenopausal women.
      METHODS: Subjects were assigned to four groups. Group I: 30 postmenopausal women
      were assigned to sequentially combined daily 0.625 mg conjugated equine estrogen
      (CEE) plus 2 mg medroxyprogesterone acetate (MPA) or plus 4 mg MPA daily for 14
      days in a 28 day cycle for 3 months. Group II: 30 postmenopausal women did not
      received HRT. Group III: 20 postmenopausal women who took HRT for 1.5 years.
      Group IV: 20 postmenopausal women who never took HRT. Measurement of fasting
      total plasma homocysteine was performed before and after 3 months treatment in
      group I and group II. Fasting total plasma homocysteine was determined and
      echocardiography was taken in group III and group IV. RESULTS: Fasting total
      plasma homocysteine concentrations were not altered significantly after 3 months
      in group I and group II [before HRT: (9.3 +/- 2.5) micro mol/L, (9.4 +/- 2.9)
      micro mol/L; after HRT: (9.1 +/- 2.8) micro mol/L, (9.8 +/- 3.6) micro mol/L,
      respectively (P > 0.05)]. Compared with women of group III, women of group IV had
      statistically significant lower plasma homocysteine [(8.0 +/- 1.3) micro mol/L,
      (10.3 +/- 3.2) micro mol/L, respectively (P < 0.05)]. Echocardiography was not
      found any difference between those two groups. CONCLUSIONS: Three months HRT has
      no effect on plasma homocysteine levels in postmenopausal women but the
      postmenopausal women using HRT 1.5 years have lower plasma homocysteine levels
      than those who never received HRT. Echocardiography showed no detectable changes
      between women received 1.5 years HRT and those who received no HRT.

PMID- 12487934
TI  - [Impact of high response of ovary to gonadotropin stimulation on the outcome of
      in vitro fertilization and embryo transfer or intracytoplasmic sperm injection].
AB  - OBJECTIVE: To evaluate the impact of elevated peak estradiol (E(2)) levels and a
      high number of retrieved oocytes on implantation and pregnancy rate in patients
      undergoing in vitro fertilization-embryo transfer (IVF-ET) and intracytoplasmic
      sperm injection (ICSI). METHODS: Retrospectively analyzed 474 infertile women
      undergoing 510 cycles for IVF-ET/ICSI treatment during the period of March 1999
      to December 2000. Using a standard long protocol/flare-up protocol [(gonadotropic
      hormone releasing hormone agonist/high pure follicle-stimulating hormone (FSH
      HP)/human chorionic gonadotropin (hCG)] for ovarian stimulation. High responders
      were defined as those who had peak E(2) levels of > 11 010 pmol/L on the day of
      hCG administration (n = 160) or > 15 retrieved oocytes (n = 148). Normal
      responders were defined as those who had peak E(2) levels of </= 11 010 pmol/L on
      the day of hCG administration (n = 350) or </= 15 retrieved oocytes (n = 362).
      RESULTS: There were statistically significant differences in age, infertile
      years, basal FSH level and the ampules of FSH-HP required between high and normal
      responders (P < 0.01 and P < 0.05). Ovarian hyperstimulation syndrome (OHSS)
      increased significantly in the high responders (P < 0.01). There were no
      statistically significant differences in implantation rate or pregnancy rate
      between high and normal responders. CONCLUSION: Elevated peak E(2) levels and
      high oocytes retrieved were not detrimental to IVF outcome, but had high
      incidence of OHSS.

PMID- 12487935
TI  - [Expression of matrix metalloproteinase-2, 9 and it's tissue inhibitor-1, 2 in
      endometrial carcinoma].
AB  - OBJECTIVE: To study the expression of matrix metalloproteinase (MMP)-2, 9 and
      tissue inhibitor of metalloproteinase (TIMP)-1, 2 protein in human endometrial
      carcinoma tissue and its relation to the invasion and metastasis of endometrial
      carcinoma. METHODS: Immunocytochemistry and zymography techniques were used to
      measure the MMP-2, MMP-9, TIMP-1, TIMP-2 protein levels and activities in
      endometrial carcinoma tissue of 37 patients and control group composed of 7
      normal postmenstrual endometrial samples. RESULTS: The MMP-2, MMP-9, TIMP-1 and
      TIMP-2 proteins mainly expressed in endometrial carcinoma cells, glandular cells
      and endothelial cells. The strongly positive expression proportions of MMP-2, 9
      and TIMP-1 proteins in grade III carcinoma cells were respectively 73%, 20% and
      67%, which were higher than those in grade II (13%, 0, 27%) and grade I (0) ones
      (P < 0.05). They were also higher in endometrial carcinoma with deep layer
      invasion ones (63%, 16%, 68%) and lymph node metastasis ones (4/4, 3/4, 4/4).
      TIMP-2 did not show different expression with the tumor invasion and metastasis.
      In endothelial cells of grade III carcinoma tissue the strongly positive
      expression proportions of MMP-2 (60%) and TIMP-1 (60%) proteins, not MMP-9, were
      found in higher amount comparing with those in grade II (20%) and grade I (1/7)
      tumor tissues (P < 0.05). The density of above four proteins were all found very
      low in the normal postmenopausal endometrial tissues (P < 0.05). By zymography
      test the active MMP-2 was the main protein form in adenocarcinoma tissue.
      CONCLUSIONS: MMP-2 and MMP-9 expression levels in adenocarcinoma tissue correlate
      with the histologic grade and invasion/metastasis trend. Active MMP-2 is the main
      form in endometrial cancer.

PMID- 12487936
TI  - [Study of the mutation and expression of PTEN gene in endometrial carcinoma and
      epithelial ovarian cancer].
AB  - OBJECTIVE: To study the relationship between the mutation and protein expression
      of PTEN and carcinogenesis of endometrial carcinoma and epithelial ovarian
      cancer. METHODS: The mutations of Exon5, 8 of PTEN in epithelial ovarian cancer
      tissues and endometrial carcinoma tissues were examined by polymerase chain
      reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequence
      analysis; and immunohistochemistry was used to evaluate the expression of PTEN
      protein in corresponding tissues. RESULTS: The mutation rate (25%) in endometrial
      carcinomas was higher than that of normal tissue (0, P < 0.05) and the mutation
      rate had significant relationship with pathological grade, histological type and
      depth of myometrial invasion (P < 0.05). PTEN protein expression deletion rate
      (60%) in endometrial carcinoma tissues was higher than that of normal tissue (0,
      P < 0.05). The protein expression deletion was significantly associated with
      pathological grade and histological type (P < 0.05), but was irrelevant to stage
      and depth of myometrial invasion (P > 0.05). The mutation frequency in epithelial
      ovarian carcinomas (5%) had no significant difference compared with those of
      normal ovarian tissues (0) and benign epithelial ovarian tumors (0). PTEN protein
      expression deletion in epithelial ovarian cancers (23%) was higher than those of
      normal ovarian tissues (0) and benign epithelial ovarian tumors (0, P < 0.05).
      The expression level of PTEN protein varied between different stages and
      differential grades. There was no difference between the expression levels of two
      different histological types and different ages. CONCLUSION: The mutation and
      expression deletion of PTEN played a role in the carcinogenesis of endometrial
      cancers, however, in epithelial ovarian cancers PTEN gene played its role by
      expression deletion other than mutation.

PMID- 12487937
TI  - [What is the Nursing Certificate and what is it for in critical patient care].

PMID- 12487938
TI  - [Endotrachael aspiration protocol in patients with serious cranial trauma. study
      of neurophysiological variables].
AB  - Aspiration of tracheobronchial secretions can cause noxious effects on
      neurophysiological variables. Different studies that refer to aspiration of
      secretions in Serious Cranial Trauma use hyperinsuflation and hyperoxygenation to
      minimize its repercussion on Intracranial Pressure and thus try to not contribute
      to the secondary lesion. After reviewing these studies, a protocol of
      tracheobronchial secretion aspiration was performed in our ICU in patients with
      serious cranial trauma subjected to mechanical ventilation in order to assess the
      effect of the aspiration of secretions in the neurophysiological variables
      following homogeneous and standardized guidelines. Neurological, hemodynamic,
      oxygenation and ventilation variables were analyzed before, during and after
      aspiration of secretions. When the results were compared before and during this,
      we observed a decrease in the Intracranial Pressure with increase of Cerebral
      Perfusion Pressure (due to increase of Mean Blood Pressure), maintaining the
      levels of PaCO2 and jugular saturation of O2, with an increase in the airway
      pressures. After finishing the aspiration process, all the affected values
      recovered. It is concluded that the aspiration of tracheobronchial secretions in
      patients with Severe Cranial Trauma, after standardized hyperinsuflation and
      hyperoxygenation, does not alter the hydrodynamics or brain use of O2.

PMID- 12487939
TI  - [Utilization of the nine equivalents of nursing manpower use score (NEMS) in a
      pediatric intensive care unit].
AB  - In 1994, sponsored by the European Communities Commission and the FRICE
      (Foundation for Research on Intensive Care in Europe), the EURICUS proyect was
      born, which, among other objectives, sets out to know objectively the work loads
      of the nursing staff in the intensive medicine services. As a consequence, the
      FRICE developed and validated a new therapeutic index, the nine equivalents of
      nursing manpower use score, NEMS. This scale (NEMS) can determine the therapeutic
      effort required by critically ill patients in a simple way and only using nine
      therapeutic variables. The objectives of this study are: to know if the NEMS
      scale reflects the therapeutic effort of the pediatric critical patients and
      validate if the NEMS scale measures the health care effect of the nursing staff
      in a pediatric intensive care unit (PICU). The study was performed in the
      Pediatrics Intensive Care Unit of the Hospital Sant Joan de Deu in Barcelona. The
      population studied was made up by the patients admitted to the PICU during a
      three week period (January 17 to February 6, 2001). Eight nurses from the unit
      having different shifts participated in the data collection. The NEMS scale was
      measured at 7 am.m. and 7 p.m. respectively in all the patients and then a
      qualitative assessment of the data obtained was performed. During this period,
      there were 50 admissions in the unit: 2.2 admissiions per day. The occupancy rate
      during the days of the study was 75%. A total of 389 measurements were performed,
      obtaining a mean value of 26.1 on the NEMS scale. Principal contributions of the
      nurses participating in the study were:They believe that use of the health care
      effort scales is useful in the intensive care units. The NEMS scale is easy to
      use and requires little time to be filled out. The NEMS scale reflects the
      therapeutic effort of the pediatric critically ill patients, but does not reflect
      the nursing staff cares. In a pediatric ICU, the age of the patient who is
      hospitalized influences the requirements of the nursing staff. Depending on at
      what time the scale is measured, not all the nursing activity is reflected, due
      to the high number of daily admissions and discharges. The NEMS scale is simple
      to use and reflects the therapeutic effort of the patients admitted to a PICU;
      however it only measures those cares delegated from therapeutic intervention and
      does not reflect the basic nursing cares.

PMID- 12487940
TI  - [Intensive care: need for intermediate care].

PMID- 12487943
TI  - [Mirtazapine in the treatment of cocaine-dependence in patients with methadone].
AB  - OBJECTIVE: To evaluate efficacy, interactions and adherence to treatment in
      cocaine-dependent patients (according to DSM- IV criteria). Its impact on
      reducing/quitting both cocaine and especially benzodiazepines (BZP) is of a great
      concern. PATIENTS AND METHODS: Thirty-one patients with an average age of 35
      years, mean methadone dose of 155 mg/day and an average staying time on MMP of 21
      months started treatment with MTZ, 60 mg/day as a single dose. One patient had to
      take 90 mg/day. One patient was excluded because of poor performance in the
      methadone maintenance program (MMP). In the pre-treatment evaluation, 22% of the
      patients did not use BZP and 40% used only cocaine. Sixty three percent used
      cocaine in higher dose than 0.5 g/day. (Range: 0.5-2 g). Abusive alcohol drinkers
      or patients with severe organic or psychiatric impairment were discarded.
      RESULTS: MTZ is well tolerated and its adverse effects are welcome in this kind
      of patients. Adherence to treatment was quite good for these reasons and because
      MTZ has a short latency time. No dose adjustments or interactions with other
      prescriptions (e.g., HAART), were shown. Hamilton-17, GCI, stress and craving
      scales were employed. Drug use was monitored with enzyme immune assay. At the end
      of the study, seven patients (23%) managed to quit cocaine. No BZP use was
      reported in 20 patients (80%). CONCLUSION: MTZ has shown good results in ceasing
      street BZP abuse, as well as reducing cocaine abuse though in the minor abusers.
      Treatment adherence was quite good and no evidence of interactions with drug
      related treatments was reported.

PMID- 12487944
TI  - [Eating disorders among Spanish university students].
AB  - OBJECTIVE: This present work assesses the prevalence of anorexia nervosa, its
      partial syndromes, bulimia nervosa and binge eating in a university sample of
      Galician students (Spain). METHOD: The sample is made up of 298 women and 157
      men. The scales used were: Eating Disorders Inventory (EDI) and a Questionnaire
      on eating behavior. RESULTS: Women had higher scores in drive for thinness,
      bulimia, interoceptive awareness, body dissatisfaction and ineffectiveness than
      men; furthermore the women had lower scores in BMI. We find a very high
      prevalence, a total of 6.4% of cases of eating disorders. CONCLUSIONS: The high
      values of probable eating disorders make it especially necessary to carry out
      primary and secondary prevention programs in university students populations.

PMID- 12487945
TI  - [Implementation and evaluation of case management in Catalonia: the ISP-SMD
      program].
AB  - INTRODUCTION: The pilot study of the Individualized Service Program for people
      with Severe Mental Disorders (ISP-SMD) consists of the implementation of case
      management services in Catalonia. METHODOLOGY: The ISP-SMD has been implemented
      in two health care sectors and will be expanded to the rest of Catalonia in the
      next years. The program serves people with persistent mental disorders who have
      serious social or family problems and/or who have inadequate mental health
      service use (high use of inpatient services, no use of community services). The
      ISP-SMD is a community intervention program that focuses its activities on direct
      care and coordination between services. Thirty patients have been included in the
      evaluation. RESULTS: The results of the pilot study have shown that, compared to
      the year before entering the program, the patients show better clinical status,
      they decrease their unmet need level, they have more appropriate use of health
      services and have lower treatment costs. Satisfaction of the patients, family
      members and professionals with the program is very high. CONCLUSION: It is
      possible to adapt and implement case management services in Catalonia. When
      implemented, they improve patient quality of life.

PMID- 12487946
TI  - [Evaluation of the combination of psychosocial and pharmacological treatment in
      schizophrenic patients].
AB  - INTRODUCTION: The present treatment of schizophrenia should initially focus on
      bringing psychotic symptoms under control with the use of antipsychotic
      medication, but it also should include the psychosocial management of the
      illness, with the implementation of psychosocial treatment. The purpose of the
      present study is to describe the results of the comparison of two groups
      (experimental and control) of schizophrenic out-patients of The National
      Institute of Psychiatry Ramon de la Fuente in Mexico City. The experimental group
      received a combination of psychosocial and pharmacological treatment, while the
      control group received the pharmacological treatment alone. MATERIAL AND METHODS:
      A quasi-experimental design which included the two groups under study,
      experimental (n=25) and control group (n=22), was used. Both groups were assessed
      at the beginning and at the end of a one-year interventions considering variables
      such as: symptomatology, psychosocial functioning, global functioning, compliance
      with antipsychotic medication, relapses, rehospitalizations, therapeutic non
      compliance, and adherence. RESULTS: Experimental patients, in comparison with
      control patients, improved their symptomatology, psychosocial functioning and
      global functioning considerably. They also presented the following: lower relapse
      frequency - 12% versus 31,8% of the controls as well as low rehospitalizacion
      rate - 0% versus 13.6% of the control patients, higher antipsychotic medication
      compliance (90%) when compared with patients under the control condition (80%), a
      reduced rate of therapeutic non-compliace (19.3%) and a higher degree of
      adherence (80.7%). On the other hand, control patients remained stabilized in
      their symptomatology, but did not improved in any of the psychosocial variables.
      CONCLUSIONS: The results show that the combination of psychosocial and
      pharmacological therapy is a more effective form of treatment in comparison with
      the other approach of pharmacotherapy alone. It may be concluded that there is
      sound evidence that indicates that combined psychosocial and pharmacological
      therapy combined report beneficial effects for the patients; therefore, it should
      be considered as an important therapeutic alternative in the treatment of
      schizophrenic patients.

PMID- 12487947
TI  - [Predictive variables of adherence to treatment in alcoholics].
AB  - OBJECTIVE: This paper aims to study the predictive potential of the stage of
      change, type of treatment followed and other variables regarding adherence to
      therapy. METHODOLOGY: A longitudinal and multicentre study has been carried out
      in three drug-addiction treatment centres within the Valencia Region, Spain. The
      sample included 172 alcohol-addicted clients (152 men and 20 women). Adherence to
      treatment was measured at one, 3, 6, 9, 12, 18, and 24 months. RESULTS: The most
      successful variable predicting treatment adherence is the type of program
      followed associated to all the time cutoffs. The fact of attending the centre
      with some relative or friend is a sign of potential adherence to treatment at the
      3 and 6 months. The longer the withdrawal period previous to treatment, the
      greater the chances of adherence at the 6, 9 and 12 months of treatment.
      CONCLUSIONS: Those variables directly associated with treatment are potentially
      better predictors of adherence than the stage of change. We have found it
      necessary to assess it throughout the therapeutic process.

PMID- 12487948
TI  - [Eating behavior, body attitudes and psychopathology in morbid obesity].
AB  - INTRODUCTION: Obesity is an ever more frequent health problem. An assessment of
      eating habits, attitudes towards the body and presence and degree of
      psychopathology in morbid obese subjects is presented. METHOD: Eighty subjects
      with morbid obesity (BMI > 40), candidates for bariatric surgery, were
      systematically studied. A semistructured interview was carried out, including
      demographic and anthropometric data, eating habits, family history of obesity and
      family and personal background of psychiatric illness. The following tests were
      also administered: BITE, EDI and GHQ-28. RESULTS: Most of the subjects were women
      (90%), married (67.5%), with medium educational and professional levels. Mean age
      was 38 years, weight 131.3 kg, and BMI 50.17 kg/m2. A high frequency of familial
      history of obesity (82.5%) was observed, with fewer familial antecedents of
      depression (37.5%) and personal history of psychiatric illness (36.3%). A total
      of 27.5% admitted binge eating, 60% were nibblers and 46.3% sweet eaters. BITE
      results shows a medium level of bulimia (12.25), with 22.5% high scorers. A high
      level of body dissatisfaction (mean score of 21.5), with a significant drive for
      thinness stood out in the EDI. GHQ detects the existence of psychopathology in
      low degree (mean total score of 8.64), especially anxiety-insomnia, with a high
      proportion of possible psychopathologic disorders (46.2%). CONCLUSIONS: Morbid
      obese subjects have a significant frequency of binge eating, and show a high
      level of body dissatisfaction, an important drive for thinness and medium
      frequency of low degree psychopathology, mainly anxiety.

PMID- 12487949
TI  - [Estrangement in psychopathology: depersonalization, derealization, disorders of
      the self?].
AB  - The history of estrangement as a clinical object is very recent and concrete. It
      is negatively defined through the following syndromes: depersonalization,
      derealization and disturbances of the self. The limits that are established for
      its definition are very lax and unsuitable. The models that have been applied to
      these phenomena are explained in this paper: the model of the psychology of
      faculties, the model of the self-awareness as a reflective structure and the
      model of the consciousness as a passive synthesis. The authors propose to recover
      estrangement as a primary experience and to concentrate on the concepts of
      subject and person's re-examination.

PMID- 12487950
TI  - [Rheumatic fibromyalgia: psychiatric features].
AB  - Rheumatic fibromyalgia, also known as fibrositis or myofascial pain, is a common
      syndrome whose diagnoses, founded mainly on physical examination, usually delays
      due to symptom unspecificity, amount of complementary tests requested and
      intercourse with psychiatric disorders. Psychyatrists and psychologists get often
      involved in fibromyalgia treatment. Its proper knowledge prevents not only
      physicians and patients' psychological discourage but also development of
      depression and mental health expenses, as well as allows designing a treatment
      plan according to the main symptoms which may offer improvement chances to
      fibromyalgia patients. This article intends to offer an up-to-date and complete
      information about this entity, focused on psychiatric aspects, to better identify
      and manage such a puzzling disease.

PMID- 12487951
TI  - [Relationship between clozapine plasma levels and withdrawal symptoms].
AB  - Discontinuation of clozapine and an attempt to change his medication to sertindol
      has led to serious psychotic and somatic symptoms in an schizophrenic patient
      treated with clozapine for five years, however after readministration of
      clozapine these symptoms rapidly disappeared. To further analyse the case we have
      developed an HPLC method for the measurement of plasma levels of clozapine and
      its main metabolite N-desmethyl clozapine in order to monitor the plasma levels
      of clozapine and to correlate with the clinical symptoms. The present results
      confirmed that after discontinuation of clozapine no measurable amount of drug or
      its main metabolite were present in the plasma of the patient. The correlation
      between the plasma levels of clozapine and the changes in the clinical state of
      the patient confirmed that the patient's severe psychotic and somatic symptoms
      were the result of discontinuation of clozapine treatment. The clozapine plasma
      concentration of the patient reported here was low (100 ng/ml) compared to the
      generally accepted plasma levels for antipsychotic action of clozapine (350
      ng/ml), however the somatic and psychotic clozapine withdrawal symptoms rapidly
      and completely disappeared.

PMID- 12487952
TI  - [Psoriasis and lithium treatment: a common physiopathology?].
AB  - INTRODUCTION: Lithium is the main treatment of bipolar disorder. Lithium may
      produce several dermatological side effects including psoriasis. PATIENT: A 42
      years old female with bipolar disorder and psoriasis produced by lithium. The
      evolution of psoriasis was parallel to treatment with lithium. RESULT: Psoriasis
      was resolved when lithium was replaced with carbamazepine and valproic acid.
      These medication shave different pharmacodynamic effects than lithium.
      CONCLUSIONS: The effect of lithium on second messengers as etiological factor in
      the evolution of psoriasis in this patient were discussed.

PMID- 12487953
TI  - [Safety of zolpidem].

PMID- 12487955
TI  - [Nonsystemic vasculitic neuropathies].

PMID- 12487957
TI  - [Satisfaction and recovery of normal activity with rizatriptan 10 mg. Results
      from the open, prospective, observational 4M study].
AB  - BACKGROUND: To evaluate the impact of the treatment with rizatriptan 10 mg
      (Maxalt) on the return to normal activity and satisfaction with treatment in the
      general population with migraine. PATIENTS AND METHOD: We conducted an open,
      prospective study in patients with migraine (International Headache Society [IHS]
      criteria) who were followed for up to 3 migraine attacks. We measured the degree
      of functional disability at 0 and 2 hours after treatment, and satisfaction at 24
      hours. Other domains of satisfaction were evaluated after three migraine attacks.
      The relationship between baseline pain severity, satisfaction after 24 hours and
      functional disability was analyzed. RESULTS: 2,469 patients were enrolled who
      experienced 6,323 migraine attacks. A return to normal activity was achieved two
      hours after treatment in 67% of all attacks treated with rizatriptan 10 mg. The
      percentage of attacks causing severe functional disability decreased from 39%
      before therapy to 3.6% two hours after treatment. In more than 90% of moderate or
      severe attacks, a normal or slightly impaired functional capacity was restored
      two hours after treatment. In 76.3% of the attacks the patients were fully or
      very satisfied 24 hours after treatment with rizatriptan 10 mg. After treating
      three migraine attacks, the proportion of patients fully or very satisfied with
      rizatriptan was over 79% for all the domains explored. CONCLUSIONS: The patients
      were highly satisfied after 24 hours and following three migraine attacks treated
      with rizatriptan 10 mg. In more than two-thirds of the attacks treated with
      rizatriptan 10 mg, the patients returned to normal activity two hours after
      treatment.

PMID- 12487956
TI  - [Nonsystemic vasculitic neuropathy].
AB  - BACKGROUND: Nonsystemic vasculitic neuropathy (NSVN) is an infrequent type of
      vasculitic neuropathy that evolves without manifestations of vasculitis in other
      organs and in the absence of serological abnormalities. There are non clarified
      conjectures about the pathogenesis, outcome and treatment approach. PATIENTS AND
      METHOD: A retrospective study of a series of six patients diagnosed of NSVN
      during a period of 12 years. Clinical, electrophysiological and pathological
      features, as well as the response to therapy and outcome are analysed. RESULTS:
      Four cases presented with a pattern of multiple mononeuropathy, evolving towards
      a symmetrical sensory and motor polyneuropathy in two of them. One patient
      presented with an acute sensory neuropathy and another had a subacute asymmetric
      sensory and motor neuropathy. No signs of accompanying systemic vasculitis were
      observed during the follow-up (mean 35 months) and the only outstanding
      serological abnormality was the presence of antibodies against hepatitis B virus
      in four of them. The nerve conduction studies showed typical features of axonal
      degeneration. The diagnostic was obtained due to the presence of a necrotizing
      vasculitis in the sural nerve biopsy in all cases. The mean time from symptom
      onset to diagnosis was 11 months. All patients were treated with
      immunosuppressive therapy presenting a favourable response, except the case of
      the sensory neuropathy that remained stable. CONCLUSIONS: NSVN is a benign type
      of vasculitic neuropathy with a variable clinical pattern of presentation and
      favourable response to immunosuppression. This neuropathy requires a high index
      of suspicion for diagnosis, so nerve biopsy must be carried out in all neuropathy
      of unknown etiology. Careful follow-up of patients is necessary, so that life
      threatening systemic vasculitis neuropathy can be diagnosed early.

PMID- 12487958
TI  - [Hashimoto's encephalopathy].
AB  - Hashimoto's autoimmune thyroiditis is a common cause of thyroid disease.
      Neurological dysfunction related to thyroid hypo or hyperfunction is well known.
      Not so is autoimmune thyroid disease-associated or Hashimoto's encephalopathy,
      which includes different neurological manifestations appearing in the context of
      autoimmune thyroiditis with normal hormone levels. Around fifty cases have been
      reported since the first description by Brain in 1966. Pathogenesis is unknown,
      although the most accepted theory points out to an autoimmune cerebral
      dysfunction. There are two different clinical presentations. The vasculitic type
      is characterized by relapsing-remitting stroke-like episodes. The diffuse
      progressive type shows insidious cognitive impairment, confusion, psychosis,
      somnolence and coma. Cerebrospinal fluid is abnormal in more than 80% of
      patients, with high protein levels and mononuclear pleocytosis. Steroids are the
      treatment of choice, although favourable evolution have been reported
      spontaneously or after thyroxine treatment.

PMID- 12487959
TI  - [Pareidolia in Beato de Liebana's illuminated Visigothic codes].
AB  - The visual perception alterations constitute a characteristic etymological field
      in some neurological and psychiatric processes (such as hallucinations,
      hallucinosis, etc.) that can also appear in healthy people (metamorphosias,
      pareidolias). The pareidolia is a phenomenon characterized by the non auto
      provoked visualization of a perception in which reality and daydream are
      combined. It constitutes a source of inspiration for different artistic
      manifestations, is the basis of some common psychological explorations (such as
      Rorcharch test) and it even can be the explication to some situations considered
      as paranormals, for example the vision of faces in the Moon or in Mars or the
      apparition of sacred figures either in spots or shades... Beato of Liebana was a
      cantabrian presbyter, author in the eight century of the Comments of the
      Apocalypse exegesis, copied and illuminated repeated times all through the
      following centuries. Given the marked revealing and eschatological component of
      the Apocalypse, starting from the Leon's School (known also as Mozarabic since
      the Ninth Century), the original was enriched adding another texts with their own
      illustrations. From them, the Comments to Daniel's Book, from Saint Jeronimus,
      stands out. The whole of the illuminated Hispanic manuscripts constitutes a
      "corpus" of amazing codices international known today as Beatos. We have
      demonstrated that the first History's graphic representation of a pareidolia
      phenomenon is found in the miniature Visigoth Hispanic manuscripts known as
      Beatos; we have arrived to this conclusion studying two facsimiles from the x
      Century (Beato of Valcavado and Beato of Gerona) specially the miniature called
      Baltasar's Feast; in both codices, is illustrated how this Babylon king perceives
      the way a phantasmagoric hand spurts up from a candlestick flame and writes in
      the adjacent wall three mysterious words: MANE, TECEL, FARES, which were only
      interpreted by Prophet Daniel, requested ad hoc. Baltasar mixed up
      unintentionally the perceived and the daydreamed starting from a visual field
      barely structured, we conclude that he suffered from a pareilolia phenomenon,
      graphically represented by the first time in History in the Beatos.

PMID- 12487960
TI  - [Spyglass-type cerebral ischemia].

PMID- 12487961
TI  - [Electrocardiographic abnormalities consistent with acute myocardial infarction
      associated with ischemic stroke].
AB  - Patients with acute cerebrovascular diseases may present a great variety of
      electrocardiographic abnormalities. Electrocardiographic pattern consistent with
      acute myocardial infarction (AMI) without biochemical evidence of myocardial
      necrosis associated with ischemic stroke is exceptional. It is described a 86
      year-old woman with an electrocardiographic pattern consistent with AMI, with
      normal creatinkinase and troponin I levels, associated with a right hemispheric
      ischemic stroke.

PMID- 12487962
TI  - [Cerebrotendinous xanthomatosis without tendinous xanthomas: presentation of two
      cases].
AB  - Cerebrotendinous xanthomatosis (CTX) is a genetic disorder caused by a 27
      hydroxilase enzyme deficiency, leading to beta-cholestanol storage in many body
      tissues. Clinically, the disease is characterised by the presence of tendinous
      xanthomas, juvenile cataracts and progressive neurologic dysfunction. The
      diagnosis requires beta-cholestanol quantification in serum. We report two
      siblings with a history of photosensitive epilepsy of childhood onset, who
      developed progressive spastic paraparesis and cataracts in their third decade of
      life. They were diagnosed to have CTX in spite of the absence of tendinous
      xanthomas. Cranial and spinal MRI only showed bilateral high intensity signal in
      the dentate nuclei in the T2-weighted and proton-density sequences. Our patients
      presented with a progressive spastic paraparesis. The delay in the diagnosis in
      our case could be due to the absence of tendinous xanthomas and late-onset
      cataracts. The recognition of the disease is important, because the treatment
      with chenodeoxycholic acid induces a decrement of beta-cholestanol levels in
      serum and could prevent the progression of the disease.

PMID- 12487963
TI  - [Sensory neuropathy and primary biliary cirrhosis].
AB  - Primary biliary cirrhosis (PBC) may associate an axonal neuropathy, a somatic and
      autonomic neuropathy and a very infrequently sensory neuropathy (with or without
      xanthomata). The aim of this paper is to describe the case of a 46 year old man
      diagnosed with PBC in stage I-II and a progressive sensory neuropathy
      (axonopathy) confined to his upper limbs with distal predominance. It had
      progressed slowly an began asymmetrically. A complete clinical study excluded
      other causes of neuropathy. We followed him clinically and electromyographically
      and he remains stable after two years evolution. The sensory neuropathy in this
      case, a primary biliary cirrhosis, is compatible with an assymetric sensory
      neuropathy limited to the upper limbs with assymmetric beginning.

PMID- 12487964
TI  - [Conservative treatment of paucisymptomatic cerebral venous thrombosis].

PMID- 12487965
TI  - Protein 14.3.3 in pellagra encephalopathy.

PMID- 12487966
TI  - [Retrospective epidemiological study on the durability of the treatment of HIV
      infection or AIDS in Spain].
AB  - BACKGROUND AND OBJECTIVE: To know the durability of consecutive regimens of
      antiretroviral treatment is important to design a long-term therapy, but there is
      not much information about this subject. PATIENTS AND METHOD: Retrospective
      epidemiological study of a sample of 401 patients who began antiretroviral
      treatment between January 1997 and April 2000 at ten Spanish hospitals. The
      duration of each consecutive antiretroviral regimen was calculated and the
      reasons for modification and discontinuation were described. RESULTS: In the 3
      years and 3 months covered by the study, 48.6% of the patients received more than
      one regimen of therapy. Seventy five of the initial prescribed combinations
      included protease inhibitors. Median duration of consecutive lines of therapy was
      decreasing: 560, 360, 330 and 202 days for the first, second, third and fourth
      regimens, respectively. The main reason to modification was intolerance or
      toxicity (46.2, 49.1 and 47.1% for the first, second and third modification). A
      fifth of changes was originated by difficulties to follow the therapy.
      Virological failure was the reason for modification in 21.8, 24.5 and 26.5% of
      first, second and third changes. CONCLUSIONS: Duration of consecutive
      antiretroviral regimens progressively decreases. Intolerance or drug toxicity
      were the main reasons conditioning the change of treatment.

PMID- 12487967
TI  - [Responses to antiretroviral treatments in vertically HIV-1-infected children].
AB  - BACKGROUND AND OBJECTIVE: Our goal was to determine the probability of achieving
      a fall-off of viral load (VL) and an increase of CD4+T-lymphocytes by 36 months
      from the initiation of antiretroviral therapy (ART) in a cohort of HIV-infected
      children according to their baseline data. PATIENTS AND METHOD: This was
      retrospective multicenter observational study of virologic and immunologic
      markers in 128 HIV-1-vertically infected children on ART: 55 HIV-infected
      children on combination therapy (CT), and 73 HIV-infected children on highly
      active antiretroviral therapy (HAART). Viral load (VL) was quantified using a
      standard molecular assay. CD4+ and CD8+ T-cells subsets were determined by flow
      cytometry. RESULTS: The median time for a 10% rise of CD4+ T-lymphocytes was 35.7
      months (95% confidence interval [95% CI], 15.5-55.9) after starting CT, and 11
      months (95% CI, 7,7-14.3) after starting HAART. The median time for a VL fall to
      < 400 copies/ml was 29.6 months (95% CI, 9.4-49.7) after starting CT, and the
      median time for a VL fall to < 400 copies/ml was 10.9 months (95% CI, 0-21.9)
      after starting HAART. A 10% increase of CD4+ T-cells over baseline was associated
      with HAART, low CD4+ T-cells and high VL. On the other hand, a VL fall lower than
      400 copies/ml was associated with HAART and low baseline VL. CONCLUSIONS: Our
      data indicate that HAART was better than CT in the control of VL and CD4+ T-cell
      increase. Also, baseline CD4+ T-cell and VL values helped to determine the
      response to ART in HIV-1 infected children.

PMID- 12487968
TI  - [Effect of weight reduction on lipids and lipoprotein (a) serum levels].
AB  - BACKGROUND AND OBJECTIVE: A quasi-experimental study to determine the effects of
      a body weight reduction treatment on lipids and lipoprotein (a) serum levels.
      PATIENTS AND METHOD: Ponderal and lipidogram values were determined in 69
      premenopausic obese women before and after treatment. Differences were determined
      at a given time and at intervals. RESULTS: Apart from a high fasting HDLc, a
      reduction of the lipid values was observed. CONCLUSIONS: Our results suggest that
      weight reduction modifies favourably the lipid profile in premenopausic obese
      women.

PMID- 12487969
TI  - [New drugs for therapy of congestive heart failure].

PMID- 12487970
TI  - [Therapeutic value of humor].

PMID- 12487971
TI  - [Current therapy of lupus nephritis].

PMID- 12487972
TI  - [New anthithrombotic drugs].

PMID- 12487973
TI  - [Narcolepsy].

PMID- 12487974
TI  - [Raised factor VIII and ABO system as thrombotic risk factors].

PMID- 12487976
TI  - [Methicillin-resistant Staphylococcus aureus].

PMID- 12487977
TI  - [Home therapy for type 1 Gaucher disease in Spain].

PMID- 12487978
TI  - [Cytomegalovirus enteritis after autologous peripheral blood stem cell
      transplantation].

PMID- 12487979
TI  - [Neuralgic amyotrophy induced by Epstein-Barr virus infection].

PMID- 12487980
TI  - [Complete response of cerebral metastasic melanoma after a combined treatment of
      radiotherapy and temozolomide].

PMID- 12487981
TI  - [Pica and iron-deficiency anemia as presenting symtoms in celiac disease].

PMID- 12487982
TI  - Curriculum vitae: John A. Schellman.

PMID- 12487983
TI  - John Schellman and his scientific work.

PMID- 12487984
TI  - Focal contributions to molecular biophysics and structural biology: a personal
      view. Part II.

PMID- 12487985
TI  - My life with John A. Schellman.

PMID- 12487986
TI  - An apprentice in a sorcerer's laboratory.

PMID- 12487987
TI  - Mutational studies of protein stability and folding of the hyperstable MYL Arc
      repressor variant.
AB  - The Arc-MYL variant is hyperstable and has an earlier transition state than wild
      type as a consequence of replacing the wild-type salt-bridge triad formed by R31,
      E36 and R40 with hydrophobic interactions formed by M31, Y36 and L40. Amino acid
      substitution mutations were constructed at 16 positions in the Arc-MYL background
      and the equilibrium stabilities of the corresponding mutant proteins were
      determined. At three positions, mutations were found to be less destabilizing in
      MYL than in wild-type Arc, and, at one position, the opposite result was
      obtained. The kinetics of refolding and unfolding were determined for a subset of
      the Arc-MYL core mutants. Three mutations--VA18, LA19 and LA40--had their major
      energetic effects on the refolding rate. The interactions perturbed by these
      mutations appear to be substantially formed in the transition state. V18 and L19
      are in the N-terminal turn of helix A and L40 is in the center of helix B. The
      remaining mutations--VA22, MA31, VA33, YA36, VA41, MA42 and FA45--had some
      effects on refolding but exerted their major effects on the unfolding rate.
      Approximately 30% of the energetic interactions mediated by these latter side
      chains seem to be present in the transition state of Arc-MYL.

PMID- 12487988
TI  - A helix initiation signal in T4 lysozyme identified by polyalanine mutagenesis.
AB  - To better understand the relation between sequence and structure, and in an
      attempt to simplify the protein folding problem, a series of alanine
      substitutions was introduced into bacteriophage T4 lysozyme. In contrast to
      previous studies in this system, which were restricted to single alpha-helices,
      the present analysis included a helix-turn-helix region, a loop-helix region, and
      two alpha-helices that were well separated in the three-dimensional structure. It
      was shown previously that T4 lysozyme is very tolerant of alanine substitutions
      within alpha-helices, especially at solvent-exposed sites. The present study
      shows that the protein is also tolerant of such substitutions in turn and loop
      regions, although less than in helices. The results confirm that the structural
      information in the amino acid sequence is highly redundant. For example, the
      protein with the sequence 127AAAAAALAAAAWAAA141 folds normally, has melting
      temperature only 0.8 degrees C lower than wildtype, and has a crystal structure
      that is also very similar to wildtype. Polyalanine substitutions within turns or
      loops can, however, lead to differences in structure and in folding. In one
      example the triple substitution K35A/S36A/P37A caused this region of the molecule
      to change to a more helical conformation. In a second case the mutant with the
      sequence 34AAAAALAAAKAALAAA49, which spans a loop-helix region, had a
      dramatically altered thermal unfolding transition, suggesting that this region
      may tend to form a single, uninterrupted, helix. Substitution of Ala38 in the
      above construct with aspartic acid caused the unfolding to be more like wildtype,
      suggesting that residue 38, which is at a helix-capping position in the wildtype
      structure, provides an initiation signal that is essential in the polyalanine
      mutant for the correct formation of alpha-helix 39-50. In a typical protein, the
      information that codes for the 3D structure is presumably distributed over many
      amino acids. The present results suggest that in simplified sequences the key
      folding information may be restricted to a subset of critical residues, and so be
      more readily accessible to experimental analysis.

PMID- 12487989
TI  - Submolecular cooperativity produces multi-state protein unfolding and refolding.
AB  - Hydrogen exchange experiments show that cytochrome c and other proteins under
      native conditions reversibly unfold in a multi-step manner. The step from one
      intermediate to the next is determined by the intrinsically cooperative nature of
      secondary structural elements, which is retained in the native protein. Folding
      uses the same pathway in the reverse direction, moving from the unfolded to the
      native state through relatively discrete intermediate forms by the sequential
      addition of native-like secondary structural units.

PMID- 12487990
TI  - Hydrogen exchange, core modules, and new designed proteins.
AB  - A strategy for design of new proteins that mimic folding properties of native
      proteins is based on peptides modeled on the slow exchange cores of natural
      proteins. We have synthesized peptides, called core modules, that correspond to
      the elements of secondary structure that carry the very slowest exchanging amides
      in a protein. The expectation is that, if soluble in water, core modules will
      form conformational ensembles that favor native-like structure. Core modules
      modeled on natural bovine pancreatic trypsin inhibitor have been shown by NMR
      studies to meet this expectation. The next step toward production of a native
      state mimic is to further shift the conformational bias of a core module toward
      more ordered structure by promoting module-module interactions that are mutually
      stabilizing. For this, two core modules were incorporated into a single molecule
      by means of a long cross-link. From a panel of several two-module peptides, one
      very promising lead emerged; it is called BetaCore. BetaCore is monomeric in
      water and forms a new fold composed of a four-stranded, antiparallel beta-sheet.
      The single, dominant conformation of BetaCore is characterized by various NMR
      experiments. Here we compare the individual core module to the two-module
      BetaCore and discuss the progressive stabilization of intramodule structure and
      the formation of new intermodule interactions.

PMID- 12487991
TI  - Protein substructures and folded stability.
AB  - Protein substructures detected in proton-exchange experiments can be described in
      quantitative detail with the Debye-Waller temperature factors from diffraction
      studies. The smallest substructures, in mesophilic proteins approximately 12% of
      the total residues, determine thermodynamic as well as kinetic stability by
      electrostatic synergism of a few tightly packed clusters about central peptide
      peptide hydrogen bonds. Fixed positions of the clusters establish genetic
      stability of a protein family. The normal product of thermal denaturation above
      280 K in dilute buffers, a compact but motile bubble, is formed with positive
      free-energy change in step from native state the single transition state and
      smaller negative change in the step from transition state to product. The largest
      substructures, approximately 80% of the residues, undergo changes in atom free
      volumes in function that are small relative to coordinate errors in protein
      diffraction studies but nevertheless describe the most important conformation
      changes. The criterion of precision in protein construction is approximately 0.05
      A and may be found to be smaller when precision in X-ray diffraction improves.
      The ratio of residues in the two substructures is fixed in mesophiles.

PMID- 12487992
TI  - Parsimony in protein evolution.
AB  - Pohl found the activation enthalpy and entropy for melting of his mesophilic
      proteins to be linear in the total number of residues and Privalov and colleagues
      found this same linearity for the standard heat-capacity, enthalpy and entropy
      changes in the overall melting equilibria. Despite the small samples these
      results suggest that mesophiles individually, and as a class, are related through
      a single standard representative. If so, very extensive convergent evolution has
      provided both great simplification and very sophisticated goals for genome
      decoding and quantitative description of protein substructures [R. Lumry, The
      protein primer, http://www.umn.edu.chem. /groupslumry].

PMID- 12487993
TI  - Thermodynamic binding and site occupancy in the light of the Schellman exchange
      concept.
AB  - An analysis of Schellman's treatment of preferential interactions is presented,
      as viewed by a laboratory practitioner of the art. Starting with an intuitive
      description of what binding is in terms of the distribution of molecules of water
      and of a weakly interacting ligand (co-solvent), Schellman proceeded to a
      rigorous thermodynamic definition in which he showed that classical, dialysis
      equilibrium, binding is a purely thermodynamic quantity. Putting water and the co
      solvent on an equivalent footing, he showed that the classical binding treatment
      is inadequate for weakly interacting systems, in which the replacement of water
      by ligand and exclusion of co-solvent are symmetrical concepts. Analyzing
      specifically the simple model of a single independent site, Schellman
      demonstrated how a positive binding constant can give rise to a measured negative
      binding stoichiometry. He showed that the origin of the complicated binding
      isotherms is the non-idealities of water and co-solvent, and went further to
      analyze critically the effect of site heterogeneity on the ligand concentration
      dependencies of site occupancy, preferential binding and the thermodynamic
      quantities, enthalpy, entropy and Gibbs free energy. This exposition of the
      Schellman treatment is accompanied by illustrations drawn from the experimental
      results obtained in this author's laboratory.

PMID- 12487994
TI  - Sequential vs. parallel protein-folding mechanisms: experimental tests for
      complex folding reactions.
AB  - The recent emphasis on rough energy landscapes for protein folding reactions by
      theoreticians, and the many observations of complex folding kinetics by
      experimentalists provide a rationale for a brief literature survey of various
      empirical approaches for validating the underlying mechanisms. The determination
      of the folding mechanism is a key step in defining the energy surface on which
      the folding reactions occurs and in interpreting the effects of amino acid
      replacements on this reaction. Case studies that illustrate methods for
      differentiating between sequential and parallel channel folding mechanisms are
      presented. The ultimate goal of such efforts is to understand how the one
      dimensional information contained in the amino acid sequence is rapidly and
      efficiently translated into three-dimensional structure.

PMID- 12487995
TI  - Quantitative urea gradient gel electrophoresis for studies of dissociation and
      unfolding of oligomeric proteins.
AB  - Urea gradient gel electrophoresis combined with quantitative image processing of
      stained gels was used to analyze the dissociation and unfolding of the catalytic
      subunit of aspartate transcarbamoylase. The subunit, composed of three identical
      polypeptide chains, dissociates reversibly at high urea concentrations into
      unfolded chains. A comparison of the complex, but reproducible, gel patterns
      obtained for the native subunit and for the denatured protein in 6 M urea
      revealed significant differences at intermediate urea concentrations due to the
      presence of a transient kinetic intermediate identified as a relatively compact
      monomer. Mass transport equations based on a three state model were used to
      describe the urea gradient gel electrophoresis experiments, and a numerical
      solution yielded estimates of the population of molecular species and kinetic
      constants for the unfolding and refolding reactions as well as the dissociation
      and reconstitution reactions.

PMID- 12487996
TI  - Structure and zymogen activation of caspases.
AB  - Apoptosis is primarily executed by active caspases, which are derived from the
      inactive zymogens. Structural and biochemical studies of caspases-1, -3, -7, -8
      and -9 have greatly enhanced our understanding of the structure, function, and
      specificity of the active form of these enzymes. Only recently, the structures of
      procaspase-7 and biochemical studies of procaspase-9 and -8 have provided insight
      into the process of procaspase activation. The mechanism of zymogen activation
      requires limited proteolysis as for many other proteases. In addition, self
      activation through oligomerization has been demonstrated for the initiator
      caspases-8, -9 and -10. These studies provide a structural mechanism for caspase
      activation, substrate/inhibitor binding, and contribute to the understanding of
      the biological role of caspases in the processes of apoptosis.

PMID- 12487997
TI  - Efficacy of macromolecular crowding in forcing proteins to fold.
AB  - The intrinsically unstructured protein, reduced and carboxyamidated RNase T1
      (TCAM) was used to determine the degree to which macromolecular crowding agents
      increase the equilibrium constant for folding. TCAM is not catalytically active
      in an aqueous assay system alone, but becomes catalytically active on addition of
      400 mg/ml dextran 70. The activity observed accounts for approximately 16% of the
      total available TCAM in solution. We interpret this result to mean that 16% of
      the TCAM becomes folded protein in the presence of the 400 mg/ml dextran 70, and
      this translates into an approximately five-fold increase in the equilibrium
      constant for folding. Sarcosine-induced folding of TCAM was performed in the
      presence of 0, 100, 200 and 300 mg/ml dextran 70, and apparent deltaG(o)(N-D)
      values determined from the linear extrapolation method provide an estimated 22%
      folded TCAM formed in the limit of zero sarcosine concentration and in presence
      of 400 mg/ml dextran 70. The increase in TCAM folding equilibrium constant using
      this method of determination is approximately 7.5-fold. Overall, the results
      indicate that macromolecular crowding agents are only modestly effective in
      promoting folding of this intrinsically unstructured protein.

PMID- 12487998
TI  - Methinks it is like a folding curve.
AB  - Most often, the unfolded state of peptides and proteins has been modeled as a
      statistical random coil. Here, we suggest an alternative model based on the
      presence of a significant, temperature-dependent conformational bias in the
      unfolded population. Conformational bias is suggested by our calculations [Proc.
      Natl. Acad. Sci. USA 96 (1999) 14258-14263], and it is found in recent studies of
      both proteins and peptides. The imposition of even a modest bias would transform
      our assessment of the folding problem.

PMID- 12487999
TI  - Hydration entropy change from the hard sphere model.
AB  - The gas to liquid transfer entropy change for a pure non-polar liquid can be
      calculated quite accurately using a hard sphere model that obeys the Carnahan
      Starling equation of state. The same procedure fails to produce a reasonable
      value for hydrogen bonding liquids such as water, methanol and ethanol. However,
      the size of the molecules increases when the hydrogen bonds are turned off to
      produce the hard sphere system and the volume packing density rises. We show here
      that the hard sphere system that has this increased packing density reproduces
      the experimental transfer entropy values rather well. The gas to water transfer
      entropy values for small non-polar hydrocarbons is also not reproduced by a hard
      sphere model, whether one uses the normal (2.8 A diameter) or the increased (3.2
      A) size for water. At least part of the reason that the hard sphere model with
      2.8 A size water produces too small entropy change is that the size of water is
      too small for a system without hydrogen bonds. The reason that the 3.2 A model
      also produces too small entropy values is that this is an overly crowded system
      and that the free volume introduced in the system by the addition of a solute
      molecule produces too much of a relief to this crowding. A hard sphere model, in
      which the free volume increase is limited by requiring that the average surface
      to-surface distance between the solute and water molecules is the same as that
      between the increased-size water molecules, does approximately reproduce the
      experimental hydration entropy values.

PMID- 12488000
TI  - Evidence of turn and salt bridge contributions to beta-hairpin stability: MD
      simulations of C-terminal fragment from the B1 domain of protein G.
AB  - We ran and analyzed a total of eighteen, 10 ns molecular dynamics simulations of
      two C-terminal beta-hairpins from the B1 domain of Protein G: twelve runs for the
      last 16 residues and six runs for the last 15 residues, G41-E56 and E42-E56,
      respectively. Based on their CalphaRMS deviation from the starting structure and
      the pattern of stabilizing interactions (hydrogen bonds, hydrophobic contacts,
      and salt bridges), we were able to classify the twelve runs on G41-E56 into one
      of three general states of the beta-hairpin ensemble: 'Stable', 'Unstable', and
      'Unfolded'. Comparing the specific interactions between these states, we find
      that on average the stable beta-hairpin buries 287 A(2) of hydrophobic surface
      area, makes 13 hydrogen bonds, and forms 3 salt-bridges. We find that the
      hydrophobic core prefers to make some specific contacts; however, this core does
      not require optimal packing. Side-chain hydrogen bonds stabilize the beta-hairpin
      turn with strong stabilizing interactions primarily due to the carboxyl of D46
      with contributions from T49 hydroxyl. Buoyed by the strength of the hydrophobic
      core, other hydrogen bonds, primarily main-chain, guide the beta-hairpin into
      registration by forming a loose network of interactions, making an approximately
      constant number of hydrogen bonds from a pool of possible candidates. In
      simulations on E42-E56, where the salt bridge closing the termini is not favored,
      we observe that all the simulations show no 'Stable' behavior, but are 'Unstable'
      or 'Unfolded'. We can estimate that the salt-bridge between the termini provides
      approximately 1.3 kcal/mol. Altogether, the results suggest that the beta-hairpin
      folds beginning at the turn, followed by hydrophobic collapse, and then hydrogen
      bond formation. Salt bridges help to stabilize the folded conformations by
      inhibiting unfolded states.

PMID- 12488001
TI  - Relation between peptide backbone solvation and the energetics of peptide
      hydrogen bonds.
AB  - The H-bond inventory approach is used commonly to interpret data involving
      changes in the number or types of protein hydrogen bonds. I point out here that
      this approach gives an incorrect answer either for the standard free energy or
      enthalpy of the reaction between simple amides and water. On the other hand, an
      electrostatic solvation approach fits almost within error the polar solvation
      free energies of small molecules, including amides. The electrostatic solvation
      approach is used here to discuss the relation between peptide backbone solvation
      and the enthalpy change for forming an alanine helix.

PMID- 12488002
TI  - Charge-charge interactions are the primary determinants of the pK values of the
      ionizable groups in Ribonuclease T1.
AB  - Coulomb's law and a finite difference Poisson-Boltzmann based analysis are used
      to predict the pK values for 15 ionizable side chains (6 Asp, 6 Glu and 3 His) in
      ribonuclease T1. These predicted values are compared to the measured pK values to
      gain insight into the most important factors that influence the pK values of the
      ionizable groups in proteins. Charge-charge interactions are clearly the most
      important factor that determines the pK values of most ionizable groups in
      ribonuclease T1. However, pK values can be shifted by several pK units by the
      Born self energy associated with burying ionizable groups and by favorable
      intramolecular hydrogen bonding.

PMID- 12488003
TI  - Relationships between the temperature dependence of solvent denaturation and the
      denaturant dependence of protein stability curves.
AB  - We have used a simple binding model to consider how the thermodynamics of
      denaturant-protein interactions might influence the shape of protein stability
      curves (free energy change as a function of temperature), and how these effects
      translate into a temperature dependence of the apparent m-value (sensitivity of
      unfolding free energy to denaturant). We find that for an exothermic binding
      reaction with no binding heat capacity increment, increasing denaturant
      concentrations produces an apparent increase in curvature in the protein
      stability curve, giving rise to an increase in the heat capacity increment of
      unfolding. Similar increases are seen if the binding heat capacity increment is
      taken as positive. However, for a negative binding heat capacity increment,
      increasing denaturant concentrations decreases the curvature of the stability
      curve, giving rise to a decrease in the heat capacity of unfolding. At very high
      denaturant concentrations (above which the heat capacity of denaturation becomes
      negative) the stability curve becomes dimpled, showing two separate maxima rather
      than one. These three models result in very different temperature dependencies of
      apparent m-values. For urea-induced unfolding of the ankyrin-domain of the
      Drosophila Notch protein, we find a dependence of experimental m-values on
      temperature that is similar to that produced by a negative binding heat capacity
      increment. This temperature dependence is consistent with the observed decrease
      in heat capacity of unfolding as denaturant is added.

PMID- 12488004
TI  - Binding affinities and geometries of various metal ligands in peptide deformylase
      inhibitors.
AB  - Removal of the N-terminal formyl group from newly synthesized proteins by the
      enzyme peptide deformylase (PDF) is essential for normal growth of bacteria but
      not higher organisms. Recently, PDF has been explored as a target for novel
      antibiotics. Screening a collection of natural products for antimicrobial
      activity identified actinonin and two matlystatin analogs as potent PDF
      inhibitors. A number of synthetic analogs of these natural products were prepared
      and their inhibitory potency determined. Previous work has shown that PDF is an
      iron metalloproteinase also containing a catalytic glutamic acid residue.
      Ligation of the ferrous cation is an essential feature of potent inhibitors. The
      structures of actinonin, a matlystatin analog and a synthetic inhibitor complexed
      with PDF were determined by crystallography. A quantum mechanics/molecular
      mechanics (QM/MM) method was used to reproduce the geometry of known complexes,
      to predict the protonation state in the active site and to predict the geometry
      of additional complexes. The requirement for protonation of the active site
      glutamate anion is an important factor in understanding the potency of inhibitors
      with acidic iron-ligating groups such as hydroxamate and carboxylate. Even though
      potent inhibitors of PDF have been discovered, their bacteriostatic mechanism of
      action and the rapid development of resistance in vitro may limit their potential
      as antibacterial drugs.

PMID- 12488005
TI  - A hypothesis concerning diffusion-limited protein-ligand interactions.
AB  - A simple assumption allows the prediction of the numerical value for a
      'universal' limiting kinetic rate for wholly diffusion-limited reactions between
      small neutral molecules and macromolecules. This prediction is compared with
      appropriate experimental data for binding of ligands to myoglobin and to enzymes.
      It is shown that in the absence of electrostatic effects, this limit is
      approached but not exceeded. The model also makes very specific predictions
      concerning the viscosity and temperature dependence of such reactions.

PMID- 12488006
TI  - Helix-coil transitions re-visited.
AB  - The thermally-induced helix-coil transition in polyamino acids is a good model
      for determining the helix-forming propensities of amino acids but not for the two
      state folding/unfolding transition in globular proteins. The equilibrium and
      kinetic treatments of the helix-coil transition are summarized here together with
      a description of applications to various types of homopolymers and copolymers.
      Attention is then focused on the helix-coil transition in poly-L-alanine as an
      example of a non-polar polyamino acid. To render such a non-polar polymer water
      soluble, it is necessary to introduce polar amino acids such as lysines, but care
      must be taken as to the location of such polar residues. If they are attached as
      end groups, as in a triblock copolymer, they do not perturb the helix-forming
      tendency of the central poly-L-alanine block significantly, but if they are
      introduced within the sequence of alanine residues, then the hydration properties
      of the lysines dominate the behavior of the resulting copolymer, thereby leading
      to erroneous values of the parameters characterizing the helix-forming tendency
      of the alanines. Neutral but polar residues, such as glutamines, also exhibit
      hydration-dominating properties but less so than charged lysines. Some details of
      the calculations for an alanine/glutamine copolymer are presented here. It is
      concluded that random copolymers based on a neutral water-soluble host provide
      reliable information about the helix-forming tendencies of amino acid residues
      that are introduced as guests among such neutral host residues.

PMID- 12488007
TI  - Non-classical helix-stabilizing interactions: C-H...O H-bonding between Phe and
      Glu side chains in alpha-helical peptides.
AB  - The classical picture of H-bonds has evolved considerably. In contrast to earlier
      expectations, C-H...O H-bonds are now known to be prevalent in both small organic
      and large biological systems. However, there are few reports on the energetic
      contribution of C-H...O H-bonds in protein or polypeptide systems and we do not
      know whether such interactions are stabilizing. Here we investigate C-H...O H
      bonding interactions between Phe and Glu side chains by determining their effects
      on the helicity of model alpha-helical peptides using a combination of CD and NMR
      spectroscopy. The results suggest that Glu/Phe C-H...O H-bonding interactions
      stabilize helical structure, but only in the orientation Glu --> Phe (N --> C).
      Each Glu --> Phe (N --> C) interaction can contribute approximately -0.5 kcal
      mol(-1) to the stability of helical peptide. In the reverse orientation, Phe -->
      Glu (N --> C) appears to contribute negligibly. pH titrations provide further
      evidence for the existence of C-H...O H-bonds. The C-H...O H-bonding interactions
      in these peptides are insensitive to the screening effect of added neutral salt.
      Our results provide quantitative energetic information on C-H...O H-bonds that
      should be useful for empirical force-field calibration.

PMID- 12488008
TI  - Recent advances in helix-coil theory.
AB  - Peptide helices in solution form a complex mixture of all helix, all coil or,
      most frequently, central helices with frayed coil ends. In order to interpret
      experiments on helical peptides and make theoretical predictions on helices, it
      is therefore essential to use a helix-coil theory that takes account of this
      equilibrium. The original Zimm-Bragg and Lifson-Roig helix-coil theories have
      been greatly extended in the last 10 years to include additional interactions.
      These include preferences for the N-cap, N1, N2, N3 and C-cap positions, capping
      motifs, helix dipoles, side chain interactions and 3(10)-helix formation. These
      have been applied to determine energies for these preferences from experimental
      data and to predict the helix contents of peptides. This review discusses these
      newly recognised structural features of helices and how they have been included
      in helix-coil models.

PMID- 12488009
TI  - Potential of mean force between two hydrophobic solutes in water.
AB  - We study the potential of mean force between two nonpolar solutes in the Mercedes
      Benz model of water. Using NPT Monte Carlo simulations, we find that the solute
      size determines the relative preference of two solute molecules to come into
      contact ('contact minimum') or to be separated by a single layer of water
      ('solvent-separated minimum'). Larger solutes more strongly prefer the contacting
      state, while smaller solutes have more tendency to become solvent-separated,
      particularly in cold water. The thermal driving forces oscillate with solute
      separation. Contacts are stabilized by entropy, whereas solvent-separated solute
      pairing is stabilized by enthalpy. The free energy of interaction for small
      solutes is well-approximated by scaled-particle theory.

PMID- 12488010
TI  - Molecular recognition--viewed through the eyes of the solvent.
AB  - The binding of a ligand L to a specific site on an adsorbent molecule P is
      usually studied within the lock-and-key model. In this article we argue that the
      presence of an aqueous solvent may change dramatically the means by which a
      ligand recognizes its binding site. The main factor, originating from the
      specific property of water, is the ability of a water molecule to form a hydrogen
      bond-bridge between a functional group on L and a functional group on P. This
      factor will change the criterion for selecting the best binding site.

PMID- 12488011
TI  - Hypothesis: the RNase-sensitive restraint to unfolding of spermidine nucleoids
      from Escherichia coli is composed of cotranslational insertion linkages.
AB  - The genomic DNA of bacteria is highly localized in one or a few bodies known as
      nucleoids. A number of restraints to the unfolding of the DNA of spermidine
      nucleoids from Escherichia coli were previously associated with characteristic
      urea concentrations (U(m) values). The dominant restraint to unfolding was
      sensitive to pancreatic RNase and underwent a cooperative transition at U(m) =
      3.2 M urea. The losses of the RNase-sensitive restraint caused by urea or
      pancreatic RNase appear to result from breakage of cotranslational insertion
      linkages which joined the nucleoid to the cell envelope in growing cells. This
      conclusion is based upon effects from exposures of cells to antibiotics
      (chloramphenicol, rifampicin, streptomycin), treatment of nucleoid preparations
      with formaldehyde or concentrated NaCl solutions, and effects of urea on purified
      ribosomes. The specific RNase-sensitive and urea-sensitive components of the
      spermidine nucleoids are suggested to be the mRNA and ribosomes, respectively, of
      cotranslational insertion linkages.

PMID- 12488012
TI  - Effect of neutral lipids on coexisting phases in monolayers of pulmonary
      surfactant.
AB  - We previously established that compression of monolayers containing the lipids in
      pulmonary surfactant, with or without the surfactant proteins, initially leads to
      phase separation. On further compression, however, phase coexistence terminates
      at a critical point that requires the presence of cholesterol. The studies
      reported here address the changes in the phospholipid phase diagram produced by
      cholesterol. We used the two systems of the lipids from calf surfactant with and
      without the surfactant proteins. For both systems, we began with the postulate
      that cholesterol had no effect on the composition of other constituents in the
      two phases, and then used the known behavior of interfacial tension at a critical
      point to test the two extreme cases in which the cholesterol partitions
      exclusively into condensed domains or into the surrounding film. Measurements of
      surface potential along with the fraction of the nonfluorescent area and the
      radius of the domains, both obtained by fluorescence microscopy, for films with
      and without cholesterol allowed calculation of the interfacial tension between
      the two phases. Only the model that assumes the presence of cholesterol within
      the domains accurately predicts a decreasing line tension during film compression
      toward the critical point. That model, however, also predicts an unlikely
      decrease during compression of the dipole moment density for the condensed phase.
      Our results are best explained in terms of cholesterol partitioning predominantly
      into the condensed domains, with a resulting partial redistribution of the
      phospholipids between the two phases.

PMID- 12488013
TI  - Listeria monocytogenes phosphatidylinositol-specific phospholipase C: activation
      and allostery.
AB  - The animal and human pathogen Listeria monocytogenes secretes several virulence
      factors, including a phosphatidylinositol-specific phospholipase C (PI-PLC).
      Sufficient quantities of L. monocytogenes PI-PLC for biophysical studies were
      obtained by overexpression of the enzyme in Escherichia coli. The purified PI-PLC
      was examined in enzyme kinetics experiments using a new fluorogenic substrate,
      methyl-FLIP. Methyl-FLIP is a water-soluble monomeric substrate cleaved in a
      manner similar to the natural aggregate substrate, phosphatidylinositol (PI).
      Michaelis-Menten kinetics were observed with K(M) = 61 +/- 7 microM and V(max) =
      120 +/- 5 micromol min(-1) mg(-1), corresponding to k(cat) = 66+/-3 s(-1). The
      catalysis is activated by the addition of a short-chain phospholipid, dihexanoyl
      phosphatidylcholine (diC(6)PC). The kinetics were fitted to a two-site model in
      which the substrate binds to the active site and diC(6)PC binds to a second site,
      with an interaction between the two sites. The result is a decrease in K(M) and
      an increase in V(max), producing an overall four to five-fold increase in
      catalytic efficiency (k(cat)/K(M)). The interaction is not a regulatory
      mechanism, as is the case for multimeric enzymes; rather, it suggests interfacial
      cooperativity between the active site and a lipid-binding subsite, presumably
      adjacent to the active site.

PMID- 12488014
TI  - The dynamic behavior of CheW from Thermotoga maritima in solution, as determined
      by nuclear magnetic resonance: implications for potential protein-protein
      interaction sites.
AB  - Measurements of the 15N relaxation parameters have been used to characterize the
      backbone dynamics of CheW from Thermotoga maritima. The dynamic nature of
      residues that appeared disordered in our recent solution structure of CheW is
      confirmed by these dynamics measurements. We have interpreted the data in terms
      of the Lipari and Szabo 'model-free' approach. The derived order parameter, S(2),
      the [1H]-(15)N heteronuclear nuclear Overhauser effect (NOE) values, the chemical
      exchange rate, R(ex), and the internal correlation time, tau(e), show that CheW
      exhibits considerable motional freedom from the picosecond to millisecond time
      scales. These regions of the protein cluster within the framework of the three
      dimensional structure and may indicate possible binding sites for other protein
      components of the bacterial chemotaxis receptor-signaling complex. The structure
      of CheW consists of two five-stranded beta-barrel domains that pack together with
      an extensive hydrophobic core between the domains. Regions highlighted by
      dynamics measurements co-localize to specific regions of the three-dimensional
      structure of CheW previously implicated in the formation of bacterial chemotaxis
      receptor signaling complex. The motional properties of domain 2 of CheW suggest
      that this domain may be able to experience structural rearrangements that allow
      the exposure of a hydrophobic surface area that could be used as a binding
      surface for the other members of the receptor complex. Residues within domain 2
      have been implicated in binding interactions for two chemotaxis proteins, CheA
      and the receptor. We further propose that domain 1 interacts with other
      components of the chemotaxis machinery, such as CheZ, or in the formation of
      clusters of signaling components.

PMID- 12488015
TI  - Lifson-Roig nucleation for alpha-helices in trifluoroethanol: context has a
      strong effect on the helical propensity of amino acids.
AB  - We have investigated the effect of substituting each of 19 common amino acids
      (excluding P) at the X position in the peptide acetyl-Y-VAEAK-TSXSR-VAEAK-NH(2).
      This very different peptide is of interest because, in previous work, we showed
      that nucleation in the strong alpha-helix-forming pentamers VAEAK was unable to
      propagate the helix structure through the sequence TSDSR, which is neither a
      helix-forming sequence nor a breaker, but is indifferent to helix formation.
      Substitution in the center of the indifferent sequence reveals an interesting
      measure of the helical propensity for the 19 amino acids. CD spectra were
      measured in various mixtures of buffer and 2,2,2-trifluoroethanol (TFE), and then
      analyzed for helix propensity of the amino acids using the Lifson-Roig model.
      However, the nucleation parameter in the Lifson-Roig model has never been
      measured for TFE. We have empirically found that the nucleation parameter for a
      solvent can be determined from the data normally used to determine only the
      propagation parameters. The results of the analysis of the CD show that most
      amino acids are excellent or good helix formers in 90% TFE, while amino acids D,
      W, F and G are poor helix formers for the indifferent pentamer sequence. The
      helix propensity of the 19 amino acids is quite different from the helix
      propensity measured in other peptide sequences, demonstrating the context
      dependence of this property. The results as a function of alcohol concentration
      confirm that the relative order of helical propensity of amino acids changes with
      solvent environment. Clearly, the prediction of alpha-helical secondary structure
      from protein sequence requires more than a single helical propensity for each
      amino acid.

PMID- 12488016
TI  - Metabolism of pyrrolizidine alkaloids by Peptostreptococcus heliotrinreducens and
      a mixed culture derived from ovine ruminal fluid.
AB  - A mixed culture of ovine ruminal microbes metabolizes the macrocyclic
      pyrrolizidine alkaloids present in the plant Senecio jacobaea, including jacobine
      and seneciphylline. Previous attempts to identify metabolites of these alkaloids
      have not been successful. The objective of this study was to compare the
      metabolism of pyrrolizidine alkaloids by a mixed culture of ovine ruminal
      microbes to the metabolism of pyrrolizidine alkaloids by the known organism
      Peptostreptococcus heliotrinreducens. P. heliotrinreducens metabolizes the
      pyrrolizidine alkaloids heliotrine and lasiocarpine to 7alpha-hydroxy-1-methylene
      8alpha-pyrrolizidine and 7alpha-angelyl-1-methylene-8alpha-pyrrolizidine,
      respectively. This organism does not metabolize the pyrrolizidine alkaloids
      jacobine or seneciphylline. A mixed culture of ovine ruminal microbes also
      metabolized heliotrine and lasiocarpine to identical methylene compounds. This
      mixed culture also metabolized jacobine and seneciphylline, with the production
      of very low levels of the corresponding 1-methylene compounds. Samples were
      analyzed by TLC and GC/MS.

PMID- 12488017
TI  - Reaction pathways in transcript elongation.
AB  - Transcription of DNA into RNA is a central part of gene expression, and is highly
      regulated in all organisms. In order to approach transcription control systems on
      a molecular basis we must understand the mechanisms used by the transcription
      complex to discharge its various functions, which include transcript initiation,
      elongation, editing, and termination. In this article we describe recent progress
      in sorting out the multiple reaction pathways that are, at least in principle,
      available to the transcription complex at each DNA template position, and show
      how transcription control systems partition active complexes into these pathways.
      Understanding these regulatory processes requires an elucidation of the molecular
      details of how sequence- and factor-dependent changes in the conformations,
      stabilities, and reaction rates of the complexes determine function. Recent
      progress in unraveling these issues is summarized in this article and emerging
      principles that govern the regulation of the elongation phase of transcription
      are discussed.

PMID- 12488018
TI  - Extensions of counterion condensation theory. I. Alternative geometries and
      finite salt concentration.
AB  - The counterion condensation theory originally proposed by Manning is extended to
      take account of both finite counterion concentration (m(C)) and the actual
      structure of the array of discrete changes. Counterion condensation is treated
      here as a binding isotherm problem, in which the unknown free volume is replaced
      by an unknown local binding constant beta', which is expected to vary with m(C)
      and polyion structure. The relation between the condensed fraction of counterion
      charge, r, beta' and m(C) is obtained from the relevant grand partition function
      via the maximum term method. In the case of the single polyion in a large salt
      reservoir, the result is practically identical to Manning's equation. In order to
      determine the values of beta' and r at arbitrary m(C), a second relation between
      r, beta' and m(C) is required. We propose an alternative auxiliary relation that
      is equivalent to previous assumptions near m(C) = 0, but which yields
      qualitatively correct and quantitatively useful results at finite m(C). Simple
      expressions for r vs. m(C) and beta' vs. m(C) are obtained by simultaneously
      solving the binding isotherm and auxiliary equations. Then r and beta' are
      evaluated for five different linear arrays of infinite extent with different
      geometries: (1) a straight line of charges with uniform axial spacing; (2) two
      parallel lines of in-phase uniformly spaced charges; (3) a single-helix of
      discrete charges with uniform axial spacing; (4) a double-helix of discrete
      charges with uniform axial spacing of pairs of charges; (5) a cylindrical array
      of many parallel charged lines, chosen to simulate a uniformly charged cylinder.
      In all cases, the computed binding isotherms exhibit qualitatively correct
      behavior. As m(C) approaches zero, r approaches the Manning limit, r = 1
      1/(L(B)/b) where b is the average axial spacing of electronic charges in the
      array and L(B) is the Bjerrum length. However, beta' varies with polyion
      geometry, even in the zero salt limit, and matches the Manning value only in the
      case of a single straight charged line. With increasing m(C), r declines
      significantly below its limiting value whenever lambda(b) > or approximately
      equal 0.3, where lambda is the Debye screening parameter. In the case of
      cylindrical arrays containing either 2 or 100 parallel charged lines, r also
      decreases, whenever lambda(d) > or approximately equal 2.0, where d is the
      diameter of the array. In the case of two parallel charged lines, each with axial
      charge spacing b=3.4 A, which are separated by d = 200 A, r exhibits a plateau
      value, 0.76, characteristic of the two combined lines, when lambda(d)<<2.0, and
      declines with increasing m(C) to a shelf value, 0.52, characteristic of either
      single line, when lambda(d) > or approximately equal 2.0 and the lines become
      effectively screened from one another. beta' behaves in a roughly similar
      fashion. In the case of a cylindrical array of charged lines with the diameter
      and linear charge density of DNA, the r-values predicted by the present theory
      agree fairly well with those predicted by non-linear Poisson-Boltzmann theory up
      to 0.15 M uni-univalent salt.

PMID- 12488019
TI  - Wall effects on DNA stretch and relaxation.
AB  - Hydrodynamic wall effects are treated with an image or reflection method. This
      method uses a mirror image of the molecule, with the opposite velocity, to
      satisfy the non-slip boundary condition of zero velocity of the liquid at the
      wall. Molecules moving inside a slit require an infinite series of images, or
      reflections from both walls, whose effects converge slower for thinner slits. It
      is shown that, with the same external field, wall effects increase the
      electrophoretic stretch of DNA, more so for thinner slits. The theory is in
      fairly good agreement with stretch experiments on T4 DNA in slits of width 5,
      0.3, and 0.09 microm by Bakajin et al. (Phys. Rev. Let. 80 (1998) 2737). For the
      same slits relaxation data are available for T4 DNA first hooked around an
      obstacle, stretched in a U-shape in an external electric field, and sliding off
      until the stretched molecule moves away in free electrophoresis. The theory
      approximates the relaxation of the molecule, after detachment from the obstacle,
      as the relaxation of tethered DNA stretched in a temporary electric field. The
      theory agrees fairly well with the experiments. The significance of
      electroosmotic flow is discussed for electrophoretic experiments. An Appendix
      gives numerical data on the free electrophoresis of unstained and stained DNA,
      and discusses problems of the kinetic diameter of DNA.

PMID- 12488020
TI  - Electrostatic free energy of the DNA double helix in counterion condensation
      theory.
AB  - Polyelectrolyte theory based on counterion condensation is extended from the
      standard line charge model to helical and double helical charge arrays. The
      number of condensed counterions turns out to be the same as for a line charge
      with charge density equal to the axial charge density of the helix. Also, the
      logarithmic salt dependence of the electrostatic free energy is the same in the
      range of lower salt concentration, so that the limiting laws remain unchanged.
      However, the internal free energy of the condensed layer of counterions and the
      overall electrostatic free energy depend on the helical parameters. At higher
      salt, the free energies of both single and double helix are negative, indicating
      electrostatic stabilization of the helical charge lattices due to the mixing
      entropy of the condensed counterions. Except at very low salt, the free energy of
      a single helix is higher than the free energy of a double helix with twice the
      charge density. With B-DNA parameters and single strands modeled as single
      helices, the predicted salt dependence of the free energy of transition from
      double helix to separated single strands has a maximum at approximately 0.2 M
      salt, close to the location in the laboratory of this well-known feature of the
      DNA strand separation transition. We also calculate the electrostatic free energy
      for the transition of the DNA double helix from the B to the A conformation. The
      B form is electrostatically stable over most of the salt range, but there is a
      spontaneous electrostatic transition to A near 1 M salt. The electrostatic free
      energy values are close to the experimental values of the overall (electrostatic
      plus non-electrostatic) transition free energies for A-philic base pair
      sequences. We are led to suggest that the experimentally observed B-to-A
      transition for A-philic sequences near 1 M salt in water is governed by the
      polyelectrolyte properties of these two conformations of the DNA double helix.
      The effect of ethanol, however, cannot be attributed to lowering of the bulk
      dielectric constant.

PMID- 12488021
TI  - Investigation of viral DNA packaging using molecular mechanics models.
AB  - A simple molecular mechanics model has been used to investigate optimal spool
      like packing conformations of double-stranded DNA molecules in viral capsids with
      icosahedral symmetry. The model represents an elastic segmented chain by using
      one pseudoatom for each ten basepairs (roughly one turn of the DNA double helix).
      Force constants for the various terms in the energy function were chosen to
      approximate known physical properties, and a radial restraint was used to confine
      the DNA into a sphere with a volume corresponding to that of a typical
      bacteriophage capsid. When the DNA fills 90% of the spherical volume, optimal
      packaging is obtained for coaxially spooled models, but this result does not hold
      when the void volume is larger. When only 60% of the spherical volume is filled
      with DNA, the lowest energy structure has two layers, with a coiled core packed
      at an angle to an outer coaxially spooled shell. This relieves bending strain
      associated with tight curvature near the poles in a model with 100% coaxial
      spooling. Interestingly, the supercoiling density of these models is very similar
      to typical values observed in plasmids in bacterial cells. Potential applications
      of the methodology are also discussed.

PMID- 12488022
TI  - Maximum-entropy calculation of free energy distributions in tRNAs.
AB  - We have previously shown that the distribution function describing the
      probability that a biological macromolecule picked at random has a particular
      enthalpy value can be calculated from the temperature dependence of the heat
      capacity of the macromolecule. The free energy as a function of enthalpy (free
      energy distribution) can then be determined from the enthalpy probability
      distribution. In addition, the free energy distribution at an arbitrary
      temperature can be calculated from the free energy distribution at a reference
      temperature. Here we apply this approach to a family of similar macromolecules,
      namely a set of transfer RNAs, specifically tRNA(Phe), tRNA(Val), tRNA(Met),
      tRNA(Ser), tRNA(Asp) and tRNA(Ile). Using published heat-capacity data, we
      calculate the enthalpy probability distribution functions for all of these
      molecules at five different temperatures covering the range from 30 to 80 degrees
      C. We then use these distributions to give a reference free-energy distribution,
      from which the thermodynamics at any temperature can be calculated for each
      species. We compare the reference free-energy distribution for the five tRNAs and
      find that, while the overall form of the distributions is similar, the local
      behavior of the functions varies considerably between the species.

PMID- 12488023
TI  - Generalized derivation of an exact relationship linking different coefficients
      that characterize thermodynamic effects of preferential interactions.
AB  - In solutions consisting of solvent water (component '1') and two solute
      components ('2' and '3'), various thermodynamic effects of differences between
      solute-solute and solute-solvent interactions are quantitatively characterized by
      state functions commonly called 'preferential interaction coefficients':
      gamma(mu(1),mu(3)) triple bond (delta(m3)/delta(m2))(T,mu(1),mu(3)) and
      gamma(mu(k)) triple bond (delta(m3)/delta(m2))(T,P,mu(k)), where k = 1,2 or 3.
      These different derivatives are not all directly accessible to experimental
      determination, nor are they entirely equivalent for analyses and interpretations
      of thermodynamic and molecular effects of preferential interactions.
      Consequently, various practical and theoretical considerations arise when, for a
      given system, different kinds of preferential interaction coefficients have
      significantly different numerical values. Previously we derived the exact
      relationship linking all three coefficients of the type gamma(mu(k), and hence
      identified the physical origins of the differences between gamma(mu(1)) and
      gamma(mu(3)) that have been experimentally determined for each of various common
      biochemical solutes interacting with a protein [J. Phys. Chem. B, 106 (2002) 418
      433]. Continuing our investigation of exact thermodynamic linkages among
      different types of preferential interaction coefficients, we present here a
      generalized derivation of the relationship linking gamma(mu(1),mu(3)),
      gamma(mu(3)) and gamma(mu(1)), with no restrictions on m(2), m(3) or any physical
      characteristic of either solute component (such as partial molar volume). Hence,
      we show that (gamma(mu(1),mu(3)) - gamma(mu(3))) is related directly to
      (gamma(mu(3)) - gamma(mu(1))), for which the physical determinants have been
      considered in detail previously, and to a factor dependent on the ratio of the
      partial molar volumes V3/V1. Our generalized expression also provides a basis for
      calculating gamma(mu(1),mu(3)), even in situations where preferential
      interactions could not be investigated by equilibrium dialysis. To demonstrate
      this applicability, we analyze isopiestic distillation data for aqueous solutions
      containing urea and NaCl, two small solute components that cannot be selectively
      dialyzed.

PMID- 12488024
TI  - The effect of force on thermodynamics and kinetics of single molecule reactions.
AB  - The usual variables chemists use to affect a chemical reaction are temperature
      and pressure. We consider here an additional variable: force, F. By attaching a
      molecule to the tip of a cantilever of an atomic force microscope, or to a bead
      in a laser light trap, we can control the force on a single molecule. This
      mechanical force can drive a reaction to completion, or stabilize the reactants.
      Force changes the thermodynamic stability of a molecule; it can thus increase or
      decrease the free energy change for the reaction. Force can also speed or slow
      rates of reactions; it changes the free energy of activation of the reaction.

PMID- 12488025
TI  - Recent developments in the electronic spectroscopy of amides and alpha-helical
      polypeptides.
AB  - Recent experimental and theoretical advances in understanding the electronic
      excited states of simple amides are reviewed. Polarized reflection spectroscopy
      of single crystals of N-acetylglycine shows that the direction of the first pipi*
      (NV(1)) transition dipole moment of a secondary amide differs by approximately 15
      degrees from that of a primary amide. Ab initio calculations on simple amides
      support this conclusion. Ab initio studies of di- and tri-amides demonstrate that
      several inter-amide charge-transfer (CT) transitions occur in the 150-175-nm
      region, between the NV(1) and NV(2) transitions. When the correct dipole
      transition moment direction for peptides is used in calculations of the circular
      dichroism of the alpha-helix, the results are much improved over those from
      earlier calculations that used the direction for primary amides. Studies that
      consider the mixing of the NV(1) transition with CT transitions are reviewed.
      These indicate that such mixing is likely to have a significant effect on the
      absorption and CD spectra of the alpha-helix and other types of peptide
      conformation. Nevertheless, the independent systems model gives a reasonable
      first approximation to the absorption and CD spectra of the alpha-helix.

PMID- 12488026
TI  - Temperature jump kinetic study of the stability of apo-calmodulin.
AB  - Temperature-jump relaxation spectrometry has been used to study the unfolding
      properties of Ca(2+)-free Drosophila calmodulin from 278 to 336 K, monitored by
      absorption of Tyr-138. The T-jump amplitude data are well fitted throughout with
      a melting temperature T(m) = 315.7 K, deltaH(o)(m) = 140.5 kJ mol(-1) and
      deltaC(p)(o) = 3.28 kJ K(-1) mol(-1), giving deltaG(o)(293) = 7.36 kJ mol(-1) for
      the C-domain, in good agreement with other data. The relaxation rate observed
      (time range 1 micros-1 ms) obeys a simple two-state kinetic mechanism throughout.
      The activation energy for unfolding is nearly temperature-independent, in
      contrast to that for refolding, and hence the transition state is relatively
      compact, resembling the folded state, and the relaxation time, tau, shows complex
      temperature dependence. The domain unfolding is a two-state process occurring
      with tau of approximately 100 micros at the T(m). At 296 K, when the C-domain is
      approximately 6% unfolded, k(unfolding) approximately 305 s(-1), k(refolding)
      approximately 4660 s(-1) and tau approximately 200 micros. This closely resembles
      the rate and extent of a reported C-domain exchange process, inferred from NMR
      line-broadening at 296 K. The inherent instability of the apo-C-domain of
      calmodulin indicates that the unfolded form significantly contributes to the
      physical properties of apo-calmodulin at normal temperatures, and this
      instability is enhanced by low ionic strength conditions.

PMID- 12488027
TI  - Single-molecule enzymology: stochastic Michaelis-Menten kinetics.
AB  - We provide a stochastic analysis of single-molecule enzymatic reactions that
      follow Michaelis-Menten kinetics. We show that this system can exhibit
      oscillatory behavior in the non-equilibrium steady-state at appropriate substrate
      concentrations. The stochastic model includes both enzyme dynamics and substrate
      turnover kinetics. The relationship between the probability of substrate survival
      and the time-correlation of enzyme conformation trajectories is discussed.
      Deterministic kinetics at large substrate concentrations are obtained as a limit
      of the stochastic model. We suggest that in addition to fluctuating enzyme
      conformation, the stochastic nature of substrate concentration fluctuations is
      another possible source of the complex behavior of single-molecule enzyme
      kinetics.

PMID- 12488028
TI  - Interaction of bombolitin II with a membrane-mimetic environment: an NMR and
      molecular dynamics simulation approach.
AB  - Bombolitins are five natural heptadecapeptides originally isolated from the venom
      of a bumblebee. They induce lysis of erythrocytes and liposomes and increase the
      activity of phospholipase A(2) (PLA(2)), that plays an important role in the
      early steps of the inflammatory process. It has been proposed that PLA(2)
      activation depends on the alteration of the physical state of the membrane.
      Bombolitin II folds into an alpha-helix in a membrane mimicking environment
      constituted by sodium dodecyl sulfate micelles (Macromol. Chem. Phys., 196 (1995)
      2827). In the present work, the topological orientation of the peptide relative
      to the micelle was determined, using three spin probes localized in different
      positions of the water/micelle system. The reduction in intensity of the 1H NMR
      signals clearly demonstrated that the peptide is located on the surface of the
      micelle, with its helical axis parallel to the interface. Only a small portion of
      the helix is exposed to the aqueous environment. Results from NMR experiments
      were confirmed by molecular dynamics simulations, performed using a two-phase
      water/decane simulation cell. The timescale for the reorientation of the peptide
      was between 120 and 450 ps, depending on the starting position of the peptide.

PMID- 12488029
TI  - Use of T4 lysozyme charge mutants to examine electrophoretic models.
AB  - The electrophoretic mobility of a macro-ion is affected in a complex manner by a
      variety of forces that arise from the applied field. Coupling of the macro-ion
      and small-ion flows gives rise to non-conserved forces that are greater than
      those expected from ordinary hydrodynamic considerations. It is difficult to
      separate the steady-state hydrodynamic and electrodynamic contributions to the
      macro-ion mobility. Membrane-confined electrophoresis (MCE), a free solution
      technique, provides an experimental means by which to gain insight into these
      contributions. In this work we used MCE steady-state electrophoresis (SSE) of a
      series of T4 lysozyme charge mutants to investigate these effects and to examine
      the existing theoretical descriptions. These experiments isolate the effects of
      charge on electrophoretic mobility and permit a unique test of theories by Debye
      Huckel-Henry, Booth and Allison. Our results show that for wild type (WT) T4,
      where divergence is expected to be greatest, the predicted results are within 15,
      8 and 1%, respectively, of experimental SSE results. Parallel experiments using
      another free-solution technique, capillary electrophoresis, were in good
      agreement with MCE results. The theoretical predictions were within 20, 13 and 5%
      of CE mobilities for WT. Boundary element modeling by Allison and co-workers,
      using continuum hydrodynamics based on detailed structural information, provides
      predictions in excellent agreement with experimental results at ionic strengths
      of 0.11 M.

PMID- 12488030
TI  - Atomic force microscopy reveals kinks in the p53 response element DNA.
AB  - p53 is a 53 kDa nuclear phosphoprotein. Its function as a tumor suppressor
      critically lies in its ability to recognize its target DNA response elements as a
      tetramer. Here, we report the structural theme intrinsic to the response element
      DNA that governs this recognition phenomenon. The intrinsic flexibility or
      dynamic bending between two distinctly different, but naturally occurring p53
      response elements has been compared by ring closure. Results show that DNA
      binding sites containing helically phased d(CATG.CATG) tetra-nucleotide sequences
      at the centers of quasi-dyad symmetry in each half-response site are more
      intrinsically flexible (i.e. preferentially bent under axial stress) than their
      d(CTTG.CTTG) counterparts. Intriguingly, p53 binding sites containing these more
      flexible d(CATG.CATG) sequence elements also exhibit a stronger tendency for
      tetrameric binding of the p53 DNA binding domain peptide. Examination of the
      shapes of DNA microcircles obtained by circularization of oligomers constructed
      from such flexible p53 target DNA sequences in tandem using MacMode atomic force
      microscopy directly revealed sequence-specific kinks in solution. The tetra
      nucleotide sequence d(CATG.CATG) is highly conserved in most functional p53
      response elements. Consequently, we propose that the sequence-specific kinks
      originating from d(CATG.CATG) sequences could be a common structural theme in p53
      response elements and as evident from the results reported here, could be a
      determinant of binding site recognition by the p53 protein and the subsequent
      stability of the p53-DNA complex.

PMID- 12488031
TI  - Raspberry vesicles.
AB  - We present a method to control the osmotic stress of giant unilamellar vesicles
      (GUV) and we report an original shrinkage mode of the vesicles: the volume
      reduction is accompanied by the formation of inverted daughter vesicles which
      gives the shrunk vesicles the appearance of raspberries. We analyze this peculiar
      shrinkage and we propose some physical origins for the observed phenomena.

PMID- 12488032
TI  - The interaction of alpha-tocopherol with bilayers of 1-palmitoyl-2-oleoyl
      phosphatidylcholine.
AB  - The effect of alpha-tocopherol on the structure and phase behaviour of 1
      palmitoyl-2-oleoyl-phosphatidylcholine was examined by real-time synchrotron X
      ray diffraction and freeze-fracture electron microscopic methods. X-ray
      scattering intensity was recorded from mixed aqueous dispersions of phospholipid
      with 2.5, 5, 10 and 20 mol% alpha-tocopherol during temperature scans at 3
      degrees /min between -25 and 10 degrees C. A ripple structure is induced by the
      presence of alpha-tocopherol that coexists with the ripple phase characteristic
      of the pure phospholipid in mixtures containing 2.5 mol% alpha-tocopherol but
      completely replaces it in mixtures containing greater proportions of alpha
      tocopherol. Freeze-fracture replicas of dispersions containing 5 mol% alpha
      tocopherol indicate a ripple phase with a periodicity of about 9 nm. Increasing
      amounts of alpha-tocopherol result in a progressive reduction in temperature of
      the gel to liquid-crystal phase transition and broadening of the transition. Two
      lamellar phases coexist in the liquid-crystal state, one with a spacing of 6.4 nm
      assigned to an alpha-tocopherol-enriched lamellar structure and the other with a
      lamellar repeat of 6.1 nm corresponding to bilayers of pure phospholipid.

PMID- 12488034
TI  - Evaluation of lipid-based reagents to mediate intracellular gene delivery.
AB  - We characterized different cationic lipid-based gene delivery systems consisting
      of both liposomes and nonliposomal structures, in terms of their in vitro
      transfection activity, resistance to the presence of serum, protective effect
      against nuclease degradation and stability under different storage conditions.
      The effect of lipid/DNA charge ratio of the resulting complexes on these
      properties was also evaluated. Our results indicate that the highest levels of
      transfection activity were observed for complexes prepared from nonliposomal
      structures composed of FuGENE 6. However, their DNA protective effect was shown
      to be lower than that observed for cationic liposome formulations when prepared
      at the optimal (+/-) charge ratio. Our results suggest that lipoplexes are
      resistant to serum up to 30% when prepared at a 2:1 lipid/DNA charge ratio.
      However, when they were prepared at higher (+/-) charge ratios, they become
      sensitive to serum for even lower concentrations (10%). Replacement of dioleoyl
      phosphatidylethanolamine (DOPE) by cholesterol enhanced the resistance of the
      complexes to the inhibitory effect of serum. This different biological activity
      in the presence of serum was attributed to different extents of binding of serum
      proteins to the complexes, as evaluated by the immunoblotting assay. Studies on
      the stability under storage show that lipoplexes maintain most of their
      biological activity when stored at -80 degrees C, following their fast freezing
      in liquid nitrogen.

PMID- 12488033
TI  - Mammalian Pex14p: membrane topology and characterisation of the Pex14p-Pex14p
      interaction.
AB  - Peroxisomal biogenesis is a complex process requiring the action of numerous
      peroxins. One central component of this machinery is Pex14p, an intrinsic
      peroxisomal membrane protein probably involved in the docking of Pex5p, the
      receptor for PTS1-containing proteins (peroxisomal targeting signal 1-containing
      proteins). In this work the membrane topology of mammalian Pex14p was studied.
      Using a combination of protease protection assays and CNBr cleavage, we show that
      the first 130 amino acid residues of Pex14p are highly protected from exogenously
      added proteases by the peroxisomal membrane itself. Data indicating that this
      domain is responsible for the strong interaction of Pex14p with the organelle
      membrane are presented. All the other Pex14p amino acid residues are exposed to
      the cytosol. The properties of recombinant human Pex14p were also characterised.
      Heterologous expressed Pex14p was found to be a homopolymer of variable
      stoichiometry. Finally, in vitro binding assays indicate that homopolymerisation
      of Pex14p involves a domain comprising amino acid residues 147-278 of this
      peroxin.

PMID- 12488035
TI  - Indanedione spin labelling of Na,K-ATPase.
AB  - The indanedione series of vinyl ketone spin-labelling reagents has been extended
      in two ways: by increasing the length of the rigid spacer between the reactive
      centre and the nitroxide ring, or by introducing an electrophilic substituent
      (that could also hinder its rotation) at the bridge head position of the
      nitroxide ring. Three reagents of this new series have been used to spin label
      the Class II thiol groups of membranous Na,K-ATPase from Squalus acanthias. With
      a conjugated diene spacer, the majority of spin labels are strongly held but a
      minor population is relatively mobile at 37 degrees C. With a conjugated triene
      spacer, the nitroxide is still strongly held but a portion of the label is non
      covalently bound. The 4-bromo-pyrroline derivative (with short vinyl spacer) is
      tightly held at the attachment site, and the conventional electron paramagnetic
      resonance (EPR) spectra distinguish between the two enantiomeric structures which
      differ in their mobility at 37 degrees C. Saturation transfer EPR (ST-EPR)
      spectra of this label at 4 degrees C have been used to determine the dependence
      of the protein rotational mobility on ionic strength. Electrostatic repulsion
      contributes to the lateral interactions between Na,K-ATPase molecules.

PMID- 12488036
TI  - Viability of Escherichia coli after combined osmotic and thermal treatment: a
      plasma membrane implication.
AB  - This study investigates the influence of temperature (T) and osmotic pressure
      (Pi) on the viability of Escherichia coli K12 during an osmotic treatment.
      Osmotic shock (dehydration and rehydration within 1 s) in liquid media at
      different temperatures (4, 10, 30 and 37 degrees C) and different levels of
      osmotic pressure (26, 30, 35, 40, 82 and 133 MPa) were realized. Results show
      that a sudden dehydration, below 40 MPa, destroyed up to 80% of the bacterial
      population for each tested temperature, whereas viability was greater than 90%
      for an osmotic pressure less than 26 MPa. The influence of T and Pi on the
      membrane's physical structure is finally considered to explain the results in
      light of FTIR and electron microscopy study of the influence of temperature and
      osmotic pressure on E. coli membrane phospholipids conformation.

PMID- 12488037
TI  - A molecular basis explanation of the dynamic and thermal effects of vinblastine
      sulfate upon dipalmitoylphosphatidylcholine bilayer membranes.
AB  - Differential scanning calorimetry has been employed to study the thermal effects
      of vinblastine sulfate upon aqueous, single and multiple bilayer dispersions of
      1,2-dipalmitoyl-3-sn-phosphatidylcholine (DPPC). The calorimetric results
      summarized to an increase in the gel to liquid-crystalline phase transition
      enthalpy and the abolishment of the L(beta)' (gel phase) to P(beta)' (ripple
      phase) pretransition for the uni- and multilamellar dispersions, as well as an
      increase in the transition temperature T(m) and the transition cooperativity for
      single bilayer DPPC/vinblastine mixed vesicles, are consistent with an induced,
      partially interdigitated, gel phase. Computational analysis has been successfully
      applied to clarify the intermolecular effects and verify the feasibility of the
      proposed interdigitation for the vinblastine sulfate molecules and also for the
      ursodeoxycholic acid (UDCAH) and bromocylated taxanes, which have been shown to
      induce an interdigitated gel phase in DPPC bilayers.

PMID- 12488038
TI  - Identification of lysine-411 in the human reduced folate carrier as an important
      determinant of substrate selectivity and carrier function by systematic site
      directed mutagenesis.
AB  - Site-directed mutagenesis was used to characterize the functional role of lysine
      411, a conserved amino acid located in putative transmembrane domain (TMD) 11 of
      the human reduced folate carrier (hRFC). Lysine-411 was mutagenized to arginine,
      glutamate, and leucine, and the mutant constructs (K411R-, K411E-, and K411L
      hRFC, respectively) were transfected into hRFC-deficient K562 cells. The mutant
      hRFC constructs were all expressed at high levels and restored 22-36% of the
      methotrexate (MTX) transport level in wild-type (K43-6) hRFC transfectants.
      Although 5-formyl tetrahydrofolate (5-CHO-H(4)PteGlu) uptake levels for both the
      K411E- and K411L-hRFCs were also impaired (approximately 33% and 28%,
      respectively), a complete restoration of the wild-type level was observed for
      K411R-hRFC. While loss of MTX transport activity for the K411R-hRFC transfectant
      was associated with an incomplete restoration of MTX sensitivity compared to K43
      6 cells, these cells were similarly sensitive to Tomudex. The K411R-hRFC
      transfectants showed an approximately threefold decreased growth requirement for
      5-CHO-H(4)PteGlu compared to K43-6 cells. The 5-CHO-H(4)PteGlu transport
      stimulation observed for the wild-type carrier in chloride-free buffer was also
      observed for K411R-hRFC, however, this response was decreased for the K411E- and
      K411L-hRFCs. The preservation of low levels of transport for the K411E- and K411L
      hRFCs suggest that the amino acid at position 411 does not directly participate
      in the binding of anionic hRFC substrates. However, a functionally important role
      for a basic amino acid at position 411 was, nonetheless, implied by the increased
      MTX transport for wild-type hRFC over the K411 mutant hRFCs, and the highly
      selective uptake of 5-CHO-H(4)PteGlu over MTX for K411R-hRFC.

PMID- 12488039
TI  - Comparative molecular dynamics simulations of amphotericin B
      cholesterol/ergosterol membrane channels.
AB  - Amphotericin B (AmB) is a very effective anti-fungal polyene macrolide antibiotic
      whose usage is limited by its toxicity. Lack of a complete understanding of AmB's
      molecular mechanism has impeded attempts to design less toxic AmB derivatives.
      The antibiotic is known to interact with sterols present in the cell membrane to
      form ion channels that disrupt membrane function. The slightly higher affinity of
      AmB toward ergosterol (dominant sterol in fungal cells) than cholesterol
      (mammalian sterol) is regarded as the most essential factor on which antifungal
      chemotherapy is based. To study these differences at the molecular level, two
      realistic model membrane channels containing molecules of AmB, sterol
      (cholesterol or ergosterol), phospholipid, and water were studied by molecular
      dynamics (MD) simulations. Comparative analysis of the simulation data revealed
      that the sterol type has noticeable effect on the properties of AmB membrane
      channels. In addition to having a larger size, the AmB channel in the ergosterol
      containing membrane has a more pronounced pattern of intermolecular hydrogen
      bonds. The interaction between the antibiotic and ergosterol is more specific
      than between the antibiotic and cholesterol. These observed differences suggest
      that the channel in the ergosterol-containing membrane is more stable and, due to
      its larger size, would have a higher ion conductance. These observations are in
      agreement with experiments.

PMID- 12488040
TI  - Interfacial tension of bilayer lipid membrane formed from
      phosphatidylethanolamine.
AB  - The dependence of the interfacial tension of a lipid membrane on the pH of the
      aqueous solution has been studied. Interfacial tension measurements of
      phosphatidylethanolamine (PE) were carried out. A theoretical equation is derived
      to describe this dependence in the whole pH range. A maximum corresponding to the
      isoelectric point appears both in the theoretical equation and in the
      experimental data.

PMID- 12488041
TI  - Transepithelial ultrafiltration and fractal power diffusion of D-glucose in the
      perfused rat intestine.
AB  - Despite an enormous body of research investigating the mass transfer of D-glucose
      through biological membranes, carrier-mediated and first-order models have
      remained the prevalent models describing glucose's quantitative behavior even
      though they have proven to be inadequate over extended concentration ranges.
      Recent evidence from GLUT2 knockout studies further questions our understanding
      of molecular models, especially those employing Michaelis-Menten (MM)-type
      kinetic models. In this report, evidence is provided that D-glucose is absorbed
      by rat intestinal epithelium by a combination of convective ultrafiltration and
      nonlinear diffusion. The diffusive component of mass transfer is described by a
      concentration-dependent permeability coefficient, modeled as a fractal power
      function. Glucose and sodium chloride-dependent-induced aqueous convection
      currents are the result of prevailing oncotic and osmotic pressure effects, and a
      direct effect of glucose and sodium chloride on intestinal epithelium resulting
      in enhanced glucose, sodium ion, and water mobility. The fractal power model of
      glucose diffusion was superior to the conventional MM description. A convection
      diffusion model of mass transfer adequately characterized glucose mass transfer
      over a 105-fold glucose concentration range in the presence and absence of sodium
      ion.

PMID- 12488042
TI  - Functional characterization of the human intestinal NaPi-IIb cotransporter in
      hamster fibroblasts and Xenopus oocytes.
AB  - The recently cloned NaPi-IIb cotransporter is an apical membrane protein that is
      involved in the absorption of phosphate in the intestine. To expedite functional
      and structural studies, the human intestinal NaPi-IIb cotransporter was stably
      expressed in hamster fibroblast (PS120) cells. The hNaPi-IIb cDNA stably
      transfected cells exhibited a 1.8-fold higher sodium-dependent phosphate uptake
      than vector DNA transfected cells, and had a K(m) for Pi of approximately 106
      microM and a K(m) for Na(+) of approximately 34 mM. The hNaPi-IIb cotransporter
      was also expressed in Xenopus oocytes and it exhibited a K(m) for Pi of
      approximately 113 microM and a K(m) for Na(+) of approximately 65 mM. The hNaPi
      IIb cotransporter expressed in both PS120 cells and oocytes was inhibited by high
      external pH. Furthermore, the phosphate uptake mediated by the hNaPi-IIb
      cotransporter was inhibited by 5 mM phosphonoformic acid (PFA), 1 mM arsenate and
      100 nM phorbol myristate acetate (PMA). These results demonstrate that the human
      intestinal NaPi-IIb cotransporter is functional when expressed in hamster
      fibroblasts, and that this model system may be useful in the future to identify
      NaPi-IIb cotransporter-specific inhibitors.

PMID- 12488043
TI  - Cellular and molecular aspects of thiamin uptake by human liver cells: studies
      with cultured HepG2 cells.
AB  - The liver is an important site for thiamin metabolism, utilization, and storage.
      Little is known about the mechanism of thiamin uptake by the human liver. In this
      study, we examined cellular and molecular aspects of the human liver thiamin
      uptake process using the human-derived liver HepG2 cells as a model system. Our
      studies showed that the initial rate of thiamin uptake to be: (1) Na(+)
      independent and occurs with no detectable metabolic alterations in the
      transported substrate, (2) highly pH-dependent with diminished uptake upon
      decreasing incubation buffer pH from 8.0 to 5.0, (3) higher following cell
      acidification compared to unacidified control cells, (4) saturable as a function
      of concentration with an apparent K(m) of 7.7+/-1.6 microM, (5) inhibited by the
      thiamin structural analogues oxythiamin and amprolium but not by the unrelated
      organic cations tetraethylammonium (TEA) and N-methylnicotinamide (NMN), and (6)
      inhibited in a concentration-dependent manner by the membrane transport inhibitor
      amiloride. Both of the recently cloned human thiamin transporters, i.e., SLC19A2
      and SLC19A3, were found to be expressed in liver HepG2 cells with the former
      being the predominant form. High promoter activity of the predominant form, i.e.,
      SLC19A2, was detected in HepG2 cells, and the minimal region of the SLC19A2
      promoter required for its basal activity in these cells was found to be encoded
      in a sequence between -356 and -36 and has multiple putative cis-regulatory
      elements. Mutation of a number of these putative cis-elements diminished promoter
      activity of the SLC19A2 minimal region. These results show the involvement of a
      specialized carrier-mediated mechanism for thiamin uptake by human liver HepG2
      cells. In addition, SLC19A2 was found to be the predominant thiamin uptake
      carrier expressed in these cells and its promoter displays a high level of
      activity in them.

PMID- 12488044
TI  - Estimation of the radius of the pores formed by the Bacillus thuringiensis Cry1C
      delta-endotoxin in planar lipid bilayers.
AB  - Pore formation constitutes a key step in the mode of action of Bacillus
      thuringiensis delta-endotoxins and various activated Cry toxins have been shown
      to form ionic channels in receptor-free planar lipid bilayers at high
      concentrations. Multiple conductance levels have been observed with several
      toxins, suggesting that the channels result from the multimeric assembly of a
      variable number of toxin molecules. To test this possibility, the size of the
      channels formed by Cry1C was estimated with the non-electrolyte exclusion
      technique and polyethylene glycols of various molecular weights. In symmetrical
      300 mM KCl solutions, Cry1C induced channel activity with 15 distinct conductance
      levels ranging from 21 to 246 pS and distributed in two main conductance
      populations. Both the smallest and largest conductance levels and the mean
      conductance values of both populations were systematically reduced in the
      presence of polyethylene glycols with hydrated radii of up to 1.05 nm, indicating
      that these solutes can penetrate the pores formed by the toxin. Larger
      polyethylene glycols had little effect on the conductance levels, indicating that
      they were excluded from the pores. Our results indicate that Cry1C forms clusters
      composed of a variable number of channels having a similar pore radius of between
      1.0 and 1.3 nm and gating synchronously.

PMID- 12488045
TI  - A cholesterol-binding and transporting protein from rat liver mitochondria.
AB  - In this communication, we present results indicating a protein isolated from rat
      liver mitochondrial intermembrane space that is capable of binding cholesterol
      and transporting it between the inner and outer mitochondrial membranes. This
      protein has a molecular weight of 57.5 kDa by SDS-PAGE; however, under native
      conditions, there is cholesterol-binding capability only as a 115 kDa dimer. Our
      data show that this dimeric protein may play a role in the regulation of
      mitochondrial membrane cholesterol levels, a prerequisite for the optimal
      activity of inner mitochondrial membrane-associated enzyme complexes. In
      addition, it appears that this protein is largely responsible for the differences
      in membrane cholesterol levels observed in normal and hepatoma mitochondria, a
      discrepancy which may help to explain the lack of energy production via oxidative
      phosphorylation in malignant tumor mitochondria.

PMID- 12488046
TI  - Functional analysis of candidate ABC transporter proteins for sitosterol
      transport.
AB  - Two ATP-binding cassette (ABC) proteins, ABCG5 and ABCG8, have recently been
      associated with the accumulation of dietary cholesterol in the sterol storage
      disease sitosterolemia. These two 'half-transporters' are assumed to dimerize to
      form the complete sitosterol transporter which reduces the absorption of
      sitosterol and related molecules in the intestine by pumping them back into the
      lumen. Although mutations altering ABCG5 and ABCG8 are found in affected
      patients, no functional demonstration of sitosterol transport has been achieved.
      In this study, we investigated whether other ABC transporters implicated in lipid
      movement and expressed in tissues with a role in sterol synthesis and absorption,
      might also be involved in sitosterol transport. Transport by the multidrug
      resistance P-glycoprotein (P-gp; Abcb1), the multidrug resistance-associated
      protein (Mrp1; Abcc1), the breast cancer resistance protein (Bcrp; Abcg2) and the
      bile salt export pump (Bsep; Abcb11) was assessed using several assays.
      Unexpectedly, none of the candidate proteins mediated significant sitosterol
      transport. This has implications for the pathology of sitosterolemia. In
      addition, the data suggest that otherwise broad-specific ABC transporters have
      acquired specificity to exclude sitosterol and related sterols like cholesterol
      presumably because the abundance of cholesterol in the membrane would interfere
      with their action; in consequence, specific transporters have evolved to handle
      these sterols.

PMID- 12488047
TI  - Syringotoxin pore formation and inactivation in human red blood cell and model
      bilayer lipid membranes.
AB  - The effect of syringotoxin (ST), a member of the cyclic lipodepsipeptides family
      (CLPs) produced by Pseudomonas syringae pv. syringae on the membrane permeability
      of human red blood cells (RBCs) and model bilayer lipid membranes (BLMs) was
      studied and compared to that of two recently investigated CLPs, syringomycin E
      (SRE) and syringopeptin 22A (SP22A) [Biochim. Biophys. Acta 1466 (2000) 79 and
      Bioelectrochemistry 52 (2000) 161]. The permeability-increasing effect of ST on
      RBCs was the least among the three CLPs. A time-dependent ST pore inactivation
      was observed on RBCs at 20 and 37 degrees C but not at 8 degrees C. From the
      kinetic model worked out parameters as permeability coefficient of RBC membrane
      for 86Rb(+) and pores mean lifetime were calculated. A shorter pores mean
      lifetime was calculated at 37 degrees C then at 20 degrees C, which gave us an
      explanation for the unusual slower rate of tracer efflux measured at 37 degrees C
      then that at 20 degrees C. The results obtained on BLM showed that the pore
      inactivation was due to a decrease in the number of pores but not to a change of
      their dwell time or conductance.

PMID- 12488048
TI  - Doxorubicin induces early lipid peroxidation associated with changes in glucose
      transport in cultured cardiomyocytes.
AB  - Doxorubicin (DOX) has not only chronic, but also acute toxic effects in the
      heart, ascribed to the generation of reactive oxygen species (ROS). Focusing on
      the DOX-induced early biochemical changes in rat cardiomyocytes, we demonstrated
      that lipid peroxidation is an early event, in fact conjugated diene production
      increased after 1-h DOX exposure, while cell damage, evaluated as lactate
      dehydrogenase (LDH) release, was observed only later, when at least one third of
      the cell antioxidant defences were consumed. Cell pre-treatment with alpha
      tocopherol (TC) inhibited both conjugated diene production and LDH release. In
      cardiomyocytes, DOX treatment caused a maximal increase in glucose uptake at 1 h,
      demonstrating that glucose transport may represent an early target for DOX. At
      longer times, as the cell damage become significant, the glucose uptake
      stimulation diminished. Immunoblotting of glucose transporter isoform GLUT1 in
      membranes after 1-h DOX exposure revealed an increase in GLUT1 amount similar to
      the increase in transport activity; both effects were inhibited by alpha TC.
      Early lipid peroxidation evokes an adaptive response resulting in an increased
      glucose uptake, presumably to restore cellular energy. The regulation of nutrient
      transport mechanisms in cardiomyocytes may be considered an early event in the
      development of the cardiotoxic effects of the anthracycline.

PMID- 12488049
TI  - Identification of a conserved domain of the HIV-1 transmembrane protein gp41
      which interacts with cholesteryl groups.
AB  - A soluble form of the HIV-1 envelope glycoprotein gp160 devoid of the
      transmembrane anchor domain was found to bind to cholesteryl-hemisuccinate
      agarose. The external subunit gp120 failed to bind to the resin, suggesting that
      the site responsible for the binding to cholesterol was located in the
      transmembrane protein gp41. We constructed a series of maltose binding protein
      (MBP) fusion proteins representing overlapping fragments of the gp41 molecule and
      we studied their capacity to bind to cholesteryl beads. The domain responsible
      for binding to cholesterol was localised within the residues 668 to 684
      immediately adjacent to the membrane spanning domain. We identified a short
      sequence (LWYIK, aa 678-683) comparable to the cholesterol interaction amino acid
      consensus pattern published by Li and Papadopoulos [Endocrinology 139 (1998)
      4991]. We demonstrated that the sequence LWYIK synthesized fused to the MBP was
      able to bind to cholesteryl groups. A synthetic peptide containing the sequence
      LWYIK was found to inhibit the interaction between cholesteryl beads and MBP44,
      an MBP fusion HIV-1 envelope protein that contains the putative cholesterol
      binding domain. Human sera obtained from HIV-1 seropositive patients did not
      react in ELISA to the LWYIK sequence, suggesting that this region is not exposed
      to the immune system. The biological significance of the interaction between gp41
      and cholesterol is discussed.

PMID- 12488050
TI  - Differential localization of glucose transporter isoforms in non-polarized
      mammalian cells: distribution of GLUT1 but not GLUT3 to detergent-resistant
      membrane domains.
AB  - The hexose transporter family, which mediates a facilitated uptake in mammalian
      cells, consists of more than 10 members containing 12 membrane-spanning segments
      with a single N-glycosylation site. However, it remains unknown how these
      isoforms are functionally organized in the membrane domains. In this report, we
      describe a differential distribution of the glucose transporter isoforms GLUT1
      and GLUT3 to detergent-resistant membrane domains (DRMs) in non-polarized
      mammalian cells. Whereas more than 80% of cellular proteins containing GLUT3 in
      HeLa cell lines was solubilized by a non-ionic detergent (either Triton X-100 or
      Lubrol WX) at 4 degrees C, GLUT1 remained insoluble together with the DRM
      associated proteins, such as caveolin-1 and intestinal alkaline phosphatase
      (IAP). These DRM-associated proteins and the ganglioside GM1 were shown to float
      to the upper fractions when Triton X-100-solubilized cell extracts were
      centrifuged on a density gradient. In contrast, GLUT3 as well as most soluble
      proteins remained in the lower layers. Furthermore, perturbations of DRMs due to
      depletion of cholesterol by methyl-beta-cyclodextrin (m beta CD) rendered GLUT1
      soluble in Triton X-100. Immunostaining patterns for these isoforms detected by
      confocal laser scanning microscopy in a living cell were also distinctive. These
      results suggest that in non-polarized mammalian cells, GLUT1 can be organized
      into a raft-like DRM domain but GLUT3 may distribute to fluid membrane domains.
      This differential distribution may occur irrespective of the N-glycosylation
      state or cell type.

PMID- 12488051
TI  - Phosphatidylserine content is a more important contributor than transmembrane
      potential to interactions of merocyanine 540 with lipid bilayers.
AB  - Several factors, including the exposure of the negatively charged PL and
      transmembrane potential (TMP), may affect the binding of merocyanine 540 dye
      (MC540) to membrane lipids. Our aim was to quantify the significance of each of
      these two determinants in MC540 interactions with
      phosphatidylserine:phosphatidylcholine (PS/PC) vesicles. The effects of the
      altered PS content (PS/PC molar ratio: 5:95, 10:90 and 20:80) and TMP on MC540
      binding were monitored using flow cytometry. Rapid [K(+)] flux across the vesicle
      membrane lipid bilayer was generated using valinomycin. We showed that the
      increased PS content leads to attenuated MC540 binding, while having no influence
      on the dynamic parameters of PS/PC vesicle membranes (electron spin resonance
      (ESR) spectrometry). Higher [K(+)](out) makes PS/PC liposomes bind more MC540,
      which implies that TMP-which becomes more positive inside the vesicles-favours
      the interactions of MC540 with the PL bilayer. Overall, the variability
      attributed to MC540-PL interactions is explained only to a minor extent by the
      generated TMP (7%) and largely by the variations in PS content (by up to 60%). In
      conclusion, the content of negatively charged PL is more important than TMP in
      determining the interactions of MC540 with PS/PC membranes.

PMID- 12488052
TI  - Erythrocyte ghost cell-alkaline phosphatase: construction and characterization of
      a vesicular system for use in biomineralization studies.
AB  - Alkaline phosphatase is required for the mineralization of bone and cartilage.
      This enzyme is localized in the matrix vesicle, which plays a role key in
      calcifying cartilage. In this paper we standardize a method to construction a
      resealed ghost cell-alkaline phosphatase system to mimic matrix vesicles and
      examine the kinetic behavior of the incorporated enzyme. Polidocanol-solubilized
      alkaline phosphatase, free of detergent, was incorporated into resealed ghost
      cells. This process was time-dependent and practically 50% of the enzyme was
      incorporated into the vesicles in 40 h of incubation, at 25 degrees C. Alkaline
      phosphatase-ghost cell systems were relatively homogeneous with diameters of
      about 300 nm and were more stable when stored at -20 degrees C. Alkaline
      phosphatase was completely released from the resealed ghost cell-system using
      only phospholipase C. These experiments confirm that the interaction between
      alkaline phosphatase and the lipid bilayer of resealed ghost cell is exclusively
      via glycosylphosphatidylinositol (GPI) anchor of the enzyme. An important point
      shown is that an enzyme bound to resealed ghost cell does not lose the ability to
      hydrolyze ATP, pyrophosphate and p-nitrophenyl phosphate (PNPP), but the presence
      of a ghost membrane, as a support of the enzyme, affects its kinetic properties.
      Moreover, calcium ions stimulate and phosphate ions inhibit the PNPPase activity
      of alkaline phosphatase present in resealed ghost cells.

PMID- 12488053
TI  - Ion transport across a phospholipid membrane mediated by the peptide trichogin GA
      IV.
AB  - Trichogin GA IV is a special member of a class of peptaibols that are linear
      peptide antibiotics of fungal origin, characterised by the presence of a variable
      number of alpha-aminoisobutyric acid residues, an acyl group at the N-terminus
      and a 1,2-amino alcohol at the C-terminus. Most of the peptaibols display ion
      channel-forming or at least membrane-modifying properties. The 11-residue-long
      trichogin GA IV is not only one of shortest peptaibols, but it is also unique for
      its n-octanoyl group instead of the more common found acetyl group at the N
      terminus. For the first time we have found that this lipopeptaibol is able to
      enhance conduction of monovalent cations through membranes of large unilamellar
      vesicles (LUVs). The influence of the [Leu-OMe]trichogin GA IV analogue (TRI) on
      ion permeation was studied under a variety of conditions (lipid composition,
      lipid-to-peptide ratio and a transmembrane potential). Parallel experiments were
      performed with the 16-residue long, channel-forming peptaibol, zervamicin (ZER).
      For the two peptides, the permeability between K(+) and Na(+) was found to be
      different. In addition, the ion diffusion rate dependencies on the peptide
      concentration are observed to be different. This might indicate that a different
      number of aggregated molecules are involved in the rate-limiting step, i.e. 3-4
      (TRI) and 4-7 (ZER). In the presence of TRI, dissipation of the transmembrane
      potential, Delta psi, was observed with a rate to be dependent on the magnitude
      of both initial Delta psi and peptide concentration. Both peptides were activated
      by a cis-positive but not by cis-negative Delta psi. Under identical conditions
      the ion-conducting efficiency of zervamicin was 100-200 times higher than that of
      trichogin. Our results show that, unlike for zervamicin, the membrane-modifying
      activity of trichogin is not associated with a channel mechanism.

PMID- 12488054
TI  - Attaching histidine-tagged peptides and proteins to lipid-based carriers through
      use of metal-ion-chelating lipids.
AB  - The therapeutic potential of selected peptides and proteins is enormous, with
      applications ranging from use as therapeutic vaccines, as modulators of
      intracellular signaling pathways and as highly selective agents capable of
      recognizing unique extracellular targets. We have been pursuing development of
      hybrid lipid-based carrier formulations designed to take advantage of the
      therapeutic benefits of peptides selected for their ability to act in a
      complementary fashion with the carrier system. In this regard, it is critical to
      have simple and versatile methods to promote and control the binding of diverse
      peptides to a broad range of carrier formulations. As demonstrated here,
      recombinant proteins and synthetic peptides containing poly-histidine residues (4
      to 10) can be specifically bound to liposomes containing a metal-ion-chelating
      lipid, DOGS-NTA-Ni. The potential of this approach is demonstrated using two
      functional peptides, AntpHD-Cw3 (applications for vaccine production) and AHNP
      (specificity for Her-2 expressing cells).

PMID- 12488055
TI  - Characterization of the macrocyclic carbon suboxide factors as potent Na,K-ATPase
      and SR Ca-ATPase inhibitors.
AB  - Recently discovered macrocyclic carbon suboxide (MCS) factors with the general
      formula (C(3)O(2))(n) were found to strongly inhibit rabbit and rat Na,K-ATPase
      as well as SR Ca-ATPase. Highly active MCS factors were obtained by a base/acid
      treatment of their lipophilic precursor isolated from plants. In the ESI-MS
      spectra, the dominant molar mass ion of 431 Da corresponds to a 1:1 complex of
      the carbon suboxide hexamer (n=6; M(r)=408 Da) with a Na(+) ion. Additional mass
      ions identified in positive and negative ion mode were assigned as complexes of
      the MCS hexamer (n=6) and octamer (n=8) with Na(+) or with TFA(-) in various
      ratios. The dominant mass ion values of these active MCS factors from plants are
      also found in mass spectra of previously described endogenous digitalis-like
      factors (EDLF) from animals. This would suggest that ubiquitously distributed MCS
      factors may function as putative endogenous regulatory substances of Na,K-ATPase
      and possibly of other ATPases. With the symmetric display of several equivalent
      carbonyl or hydroxy groups, the structure of MCS factors is particularly suited
      for interactions with proteins and other bio-molecules. This could explain the
      high biological activity and the unusual properties of the MCS factors.

PMID- 12488056
TI  - Structural changes are induced in human neutrophil cytochrome b by NADPH oxidase
      activators, LDS, SDS, and arachidonate: intermolecular resonance energy transfer
      between trisulfopyrenyl-wheat germ agglutinin and cytochrome b(558).
AB  - Anionic amphiphiles such as sodium- and lithium dodecyl sulfate (SDS, LDS), or
      arachidonate (AA) initiate NADPH oxidase and proton channel activation in cell
      free systems and intact neutrophils. To investigate whether these amphiphiles
      exert allosteric effects on cytochrome b, trisulfopyrenyl-labeled wheat germ
      agglutinin (Cascade Blue-wheat germ agglutinin, CCB-WGA) was used as an extrinsic
      fluorescence donor for resonance energy transfer (RET) to the intrinsic heme
      acceptors of detergent-solubilized cytochrome b. In solution, cytochrome b
      complexed with the CCB-WGA causing a rapid, saturable, carbohydrate-dependent
      quenching of up to approximately 55% of the steady-state fluorescence. Subsequent
      additions of SDS, LDS, or AA to typical cell-free oxidase assay concentrations
      completely relaxed the fluorescence quenching. The relaxation effects were
      specific, and not caused by dissociation of the CCB-WGA-cytochrome b complex or
      alterations in the spectral properties of the chromophores. In contrast, addition
      of the oxidase antagonist, arachidonate methyl ester, caused an opposite effect
      and was able to partially reverse the activator-induced relaxation. We conclude
      that the activators induce a cytochrome b conformation wherein the proximity or
      orientation between the hemes and the extrinsic CCB fluorescence donors has
      undergone a significant change. These events may be linked to NADPH oxidase
      assembly and activation or proton channel induction.

PMID- 12488058
TI  - Decrease in genu of the corpus callosum in medication-naive, early-onset
      dysthymia and depressive personality disorder.
AB  - BACKGROUND: The purpose of this study was to detect differences in regional areas
      of the corpus callosum (CC) in subjects with early-onset minor depression
      (dysthymia or depressive personality disorder) and healthy comparison subjects.
      Based on previous reports that have suggested reduced frontal lobe volume and
      reduced hemispheric lateralization in the frontal regions of the brain in
      depression, we hypothesized that the area of the CC that interconnects the
      frontal regions of the brain, i.e., the genu, will be smaller compared to that of
      healthy comparison subjects. METHODS: Forty female subjects with early-onset
      dysthymia or depressive personality disorder, as defined by the Structured
      Clinical Interview for DSM-III-R and the Diagnostic Interview for Depressive
      Personality, respectively, and age- and gender-matched healthy comparison
      subjects (n = 42) were recruited (age: 21.4 +/- 2.1 and 20.9 +/- 2.8 years,
      respectively). All subjects were psychotropic medications-naive and right-handed.
      A 1.5T GE Sigma scanner was used to acquire 124 1.5-mm-thick contiguous coronal
      images. Midsagittal slice images were carefully selected from reconstructed
      magnetic resonance images both from native and stereotaxic space to measure seven
      regional areas of the CC. RESULTS: There were significant diagnosis by CC region
      interactions [F(6,480) = 4.06, p <.001; F(6,480) = 3.30, p =.003, native and
      stereotaxic space, respectively]. Early-onset minor depression subjects had a
      9.9% (native space) and 6.9% (stereotaxic space) smaller genu of the CC compared
      to the healthy comparison subjects (the Newman-Keuls post hoc test, p =.005
      and.019, native and stereotaxic space, respectively). Early-onset minor
      depression subjects also had a 7.8% smaller posterior midbody relative to the
      comparison subjects (the Newman-Keuls post hoc test, p =.033) only in the native
      space. Severity of current depressive symptoms or duration of illness did not
      correlate with the size of the genu or the posterior midbody parts of the CC.
      CONCLUSIONS: These results suggest frontal lobe structural, and possibly
      functional, abnormalities in the brain in young female adults with a milder
      spectrum of depression, i.e., DSM-IV early-onset dysthymia or depressive
      personality disorder. The present findings point out the possible role of frontal
      lobe abnormality in pathophysiology of early-onset minor depression.

PMID- 12488057
TI  - Glia pathology in the prefrontal cortex in alcohol dependence with and without
      depressive symptoms.
AB  - BACKGROUND: Reductions in glial density and enlargement of glial nuclei have been
      reported in the dorsolateral prefrontal cortex (dlPFC) in mood disorders. In
      alcohol dependence, often comorbid with depression, it is unclear whether there
      are changes in the density and size of glial cells in the dlPFC. METHODS: The
      packing density and size of Nissl-stained glial cell nuclei were analyzed
      postmortem in the cortical layers of the dlPFC from 21 control and 17 alcohol
      dependent (Alc) subjects without Wernicke or Korsakoff syndromes. Eight Alc
      subjects had depressive symptoms. The density of glial cells was measured with a
      three-dimensional cell counting method, and the areal fraction of glial
      fibrillary acidic protein immunoreactivity (GFAP) was also determined. RESULTS:
      Glial density was reduced by 11-14% in layers V and VI and in all layers combined
      in the Alc group. The size of glial nuclei was decreased by 3.2% in Alc subjects.
      The Alc subjects with depressive symptoms showed the lowest values of density and
      size. There was no difference in GFAP immunoreactivity, although the lowest
      values were in the Alc group. CONCLUSIONS: Alcohol dependence is characterized by
      decreases in both density and size of glia in the dlPFC. Glial pathology may be
      more severe in Alc subjects with depressive symptoms.

PMID- 12488059
TI  - Linkage disequilibrium between dopamine D1 receptor gene (DRD1) and bipolar
      disorder.
AB  - BACKGROUND: Based on the dopamine hypothesis, the dopamine D1 receptor gene
      (DRD1) is considered to be a good candidate gene for bipolar disorder (BP).
      METHODS: In our study, three polymorphisms of the DRD1 gene, -800T/C, -48A/G, and
      1403T/C, were analyzed in 286 BP trios. Both the transmission disequilibrium test
      (TDT) and haplotype TDT were performed on the genotype data to test for the
      presence of linkage disequilibrium between DRD1 and bipolar disorder. With the
      extended transmission disequilibrium test (ETDT), we also calculated the maternal
      transmission and paternal transmission for each allele. RESULTS: Although no
      association was found for each individual polymorphism, there is a significant
      association between DRD1 and BP for haplotype TDT analysis (chi(2) = 16.068, df =
      3, p =.0011). CONCLUSIONS: These results indicate that DRD1 may play a role in
      the etiology of bipolar disorder.

PMID- 12488060
TI  - A genotype-controlled analysis of plasma dopamine beta-hydroxylase in healthy and
      alcoholic subjects: evidence for alcohol-related differences in noradrenergic
      function.
AB  - BACKGROUND: Norepinephrine and dopamine mediate important aspects of alcoholism
      and alcohol withdrawal. Dopamine-beta-hydroxylase (DbetaH) converts dopamine to
      norepinephrine. A recent study demonstrated a strong association between variance
      in plasma DbetaH activity and a novel polymorphism (DBH-1021C-->T) at the
      structural locus (DBH) encoding DbetaH protein. METHODS: Our study investigated
      whether the DBH-1021C-->T polymorphism and plasma DbetaH activity were associated
      with alcoholism or with delirium tremens (DT) during alcohol withdrawal by
      analyzing 207 German alcoholic and 102 healthy control subjects. We also examined
      the influence of the polymorphism on enzyme activity. RESULTS: Mean (+SD) plasma
      DbetaH activity measured in alcoholic subjects abstinent was significantly lower
      than that observed in control (27.7 + 16.7 vs. 35.6 + 18.8; p =.01). It did not
      differ between subjects with DT during withdrawal and subjects with mild
      withdrawal symptoms. The T allele of the DBH-1021C-->T polymorphism was
      significantly associated with lower plasma DbetaH activity. None of the alleles
      or genotypes were associated with alcoholism or DT. CONCLUSIONS: The data
      indicate that the alcoholism-related reduction in plasma DbetaH activity is
      independent of genotype at DBH-1021C-->T and replicate the finding that DBH-1021C
      ->T is strongly associated with plasma DbetaH activity in a native Western
      European population.

PMID- 12488061
TI  - Lack of association between suicidal ideation and enhanced platelet 5-HT2A
      receptor-mediated calcium mobilization in cancer patients with depression.
AB  - BACKGROUND: Increased density of 5-HT2A receptors was observed in the platelets
      of depressive patients with suicidal ideation. Enhanced 5-HT2A receptor-mediated
      platelet calcium mobilization has been proposed as a biological marker for the
      pathophysiology of major depression in cancer patients as well as in physically
      healthy patients. To examine whether depressive cancer patients with suicidal
      ideation have enhanced 5-HT2A receptor-mediated platelet response compared with
      those without suicidal ideation, we compared 5-HT-induced platelet calcium
      mobilization in depressive cancer patients with and without suicidal ideation.
      METHODS: 5-HT-induced platelet calcium mobilization was examined in 24 cancer
      patients diagnosed as having major depression according to the DSM-IV criteria.
      Suicidal ideation was evaluated by the Hamilton Depression Rating Scale and
      Zung's Self Depression Scale, as well as by the DSM-IV criteria. RESULTS: There
      was no significant differences in 5-HT-induced platelet calcium response between
      the depressive cancer patients with (n = 8) and without suicidal ideation (n =
      16). 5-HT-induced platelet calcium response was also not significantly associated
      with the severity of suicidal ideation or with the severity of depression
      assessed by Hamilton Depression Rating Scale and Zung's Self Depression Scale.
      CONCLUSIONS: These findings suggest that enhanced 5-HT2A receptor-mediated
      response was not associated with suicidal ideation in cancer patients with
      depression.

PMID- 12488062
TI  - Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients
      with depression.
AB  - BACKGROUND: Serotonergic and adrenergic enhancement may be synergistic and more
      effective than serotonergic enhancement alone in treating depression. The dual
      serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine is a dual reuptake
      inhibitor that may therefore offer greater efficacy than selective serotonin
      reuptake inhibitors (SSRIs). METHODS: Data from eight randomized, double-blind,
      controlled studies were pooled to compare efficacy in depressed patients
      receiving venlafaxine/venlafaxine extended release (XR), SSRIs, or placebo for
      </=8 weeks. The mean changes from baseline in the 21-item Hamilton Rating Scale
      for Depression (HAM-D(21)), Montgomery-Asberg Depression Rating Scale (MADRS),
      and Clinical Global Impressions-Global Improvement (CGI-I) and CGI-Severity of
      Illness (CGI-S) item scores were compared, as were response rates derived from
      these scales. RESULTS: Statistically significant differences in mean HAM-D(21)
      score decrease between venlafaxine (14.5) and SSRIs (12.6) and between the active
      treatments and placebo (11.3) were observed. Venlafaxine significantly decreased
      the mean MADRS scores more than SSRIs (17.8 vs. 15.9), and both treatments were
      significantly better than placebo (12.9). The same pattern of significance for
      CGI-I, HAM-D(21), and MADRS response rates between venlafaxine (71%, 64%, and
      67%, respectively), SSRIs (64%, 57%, and 59%, respectively), and placebo (50%,
      42%, and 41%, respectively) was observed. CONCLUSIONS: Venlafaxine was
      significantly more effective than SSRIs in improving depression, perhaps due to
      enhancing both serotonin and norepinephrine.

PMID- 12488063
TI  - Neuropsychological performance in schizotypal personality disorder: evidence
      regarding diagnostic specificity.
AB  - BACKGROUND: Individuals with schizotypal personality disorder (SPD) share
      cognitive deficits with schizophrenic patients, suggesting that these deficits
      represent a core feature of the schizophrenia spectrum. We investigated the
      neuropsychological profile in SPD patients compared with two comparison groups:
      healthy volunteers (HV) and patients who met criteria for another non
      schizophrenia spectrum personality disorder (NSS). METHODS: We tested 48 DSM-III
      R SPD patients, 22 NSS and 32 HV on a neuropsychologic battery that included the
      California Verbal Learning Test (CVLT), Trail Making A and B, the DOT test of
      working memory, the Stroop Color-Word Interference, the Paced Auditory Serial
      Addition Test (PASAT), the Wechsler Memory Scale Visual Reproduction Test (WMSV
      R), and the Wechsler Adult Intelligence Scale vocabulary and block design.
      RESULTS: Normative standards for performance were created using the HV group. SPD
      patients performed significantly worse compared with HVs; specifically, SPD
      patients demonstrated impaired performance on the PASAT and the WMSV-R immediate
      and delayed recall compared to HV. Moreover, SPD patients were impaired in the
      PASAT and the WMSV-R immediate condition compared with the NSS group. The NSS
      patients did not differ from HV on any of the cognitive tasks. The interpersonal
      factor of the schizotypal symptoms inversely correlated with the PASAT score (r =
      -.32, p <.006). CONCLUSIONS: Compared with HVs, SPD patients demonstrate modest
      cognitive impairment. These differences reached statistical significance for the
      PASAT (an auditory working memory task), and the WMSV-R immediate and delayed
      recall (a learning-recall test). In contrast, performance of NSS patients did not
      differ from that of HVs. The types of deficits observed in SPD patients are
      qualitatively similar to but milder than those seen in patients with
      schizophrenia.

PMID- 12488064
TI  - Pentagastrin-induced sleep panic attacks: panic in the absence of elevated
      baseline arousal.
AB  - BACKGROUND: It has been suggested that pharmacological challenges that induce
      panic attacks are confounded by effects of environmental stress, elevated
      baseline arousal, and expectancy bias. METHODS: To control for effects of arousal
      and cognition on the panicogenic effects of pentagastrin, pharmacological
      challenges were conducted during sleep in seven patients with panic disorder or
      social phobia. All patients had previously experienced pentagastrin-induced panic
      while awake. Infusions of normal saline and pentagastrin (0.6 microg/kg) were
      administered in fixed order and timed so that pentagastrin infusions took place
      during the transition from Stage 2 to Stage 3 sleep. Long intravenous lines were
      placed for remote blood sampling and subsequent analysis of plasma
      adrenocorticotropic hormone and cortisol. Measures of anxiety and panic were
      obtained at baseline and upon awakening after pharmacological challenge. RESULTS:
      All seven subjects awoke within seconds following pentagastrin infusion. Four
      patients reported symptoms that met criteria for panic. Neither baseline anxiety
      nor neuroendocrine measures were predictive of panic. CONCLUSIONS: These data
      demonstrate the ability to induce panic during a period of diminishing arousal
      and indicate that panic attacks can occur in the absence of elevated arousal and
      environmental stress.

PMID- 12488066
TI  - Equid herpesvirus (EHV-1) live vaccine strain C147: efficacy against respiratory
      diseases following EHV types 1 and 4 challenges.
AB  - The temperature sensitive and host range mutant clone 147 of equine herpesvirus 1
      (EHV-1) was assessed for its ability to protect conventional, susceptible adult
      horses against respiratory infection by EHV-1 and equine herpesvirus 4 (EHV-4).
      Intranasal (IN) vaccination with 5.2 log(10) TCID(50) did not cause adverse
      clinical reactions although a limited virus shedding and viraemia (leukocytes)
      was observed in 11 of 15 and 10 of 15 vaccinated horses respectively. All 15
      vaccinated horses showed a significant seroresponse to both EHV-1 and EHV-4 for
      virus neutralising (VN) antibody. None of 14 control horses shed virus or became
      viraemic or seroconverted prior to challenge. EHV-1 challenge (dose 6.0 log(10))
      6 weeks after vaccination resulted in pyrexia in all eight control horses while
      eight vaccinated horses remained unaffected. Six control horses developed nasal
      discharge, five of which were mucopurulent nasal discharge (mean duration 3.2
      days) which also occurred in four vaccinated horses for 1 day. All eight control
      horses shed challenge EHV-1 at a significantly higher level (group mean titre
      2.6+/-0.4 log(10) TCID(50) per sample) and for much longer (mean duration 4.8+/
      1.5 days) than that (group mean titre 1.4+/-0.8 log(10) TCID(50) per sample and
      mean duration 1.5+/-0.5 days) in six vaccinated horses. Furthermore, all eight
      control horses became viraemic (mean duration 2.9 days) but viraemia did not
      occur in eight vaccinated horses. Following EHV-1 challenge, all eight control
      horses showed a significant VN antibody rise to both EHV-1 and EHV-4 but this
      occurred in only one vaccinated horse and to EHV-4 only. In EHV-4 challenge (dose
      of 4.2 log(10) TCID(50)) of a separate pair of seven vaccinated and six control
      horses, 6 weeks after EHV-1 vaccination resulted in pyrexia (mean duration 2.3
      days) and nasal discharge (mean duration 1.8 days) in three and five control
      horses respectively but the only reaction observed in the vaccinated group was
      nasal discharge for 1 day in one animal. All six control animals shed virus (mean
      titre 2.5+/-0.6 log(10) TCID(50) per sample and mean duration 2+/-0.6 days)
      compared to one vaccinated animal. Although EHV-4 viraemia is rare, 3 of 6
      control horses became viraemic after EHV-4 challenge but this was not observed in
      vaccinated horses. After EHV-4 challenge 3 and 5 of 6 control horses
      seroconverted for VN antibody to EHV-1 and EHV-4 respectively; a non-responsive
      control horse had high level of pre-existing VN antibody to EHV-4. However, only
      1 of 7 vaccinated horses showed a significant antibody rise and only to EHV-4.

PMID- 12488067
TI  - Survival and immunization of raccoons after exposure to pseudorabies (Aujeszky's
      disease) virus gene-deleted vaccines.
AB  - In a controlled experiment, 16 wild-trapped raccoons were exposed to 1 of 2
      genetically modified live pseudorabies virus (PRV) vaccines used in swine. One
      vaccine had genes deleted for thymidine kinase (TK(-)) and glycoprotein G (gG(
      )); the other had an additional deletion for glycoprotein E (gE(-)). These
      vaccines were administered orally and intranasally at four dose levels: 10(3),
      10(4), 10(5), and 10(6) TCID(50). The 21 days survival rate was 37.5% for the gG(
      )TK(-) vaccine; all of the survivors developed antibodies to PRV. All animals
      receiving the gG(-)gE(-)TK(-) vaccine survived; 75% (all except the lowest dose)
      developed anti-PRV antibodies. Survivors were challenged intranasally with a
      3.2x10(3) TCID(50) dose of the virulent wildtype PRV Shope strain. Two of the
      remaining three gG(-)TK(-) vaccinated raccoons survived the challenge; for the
      gG(-)gE(-)TK(-) vaccine, the survival rate was 50% (4/8). The raccoons with
      higher vaccine-induced antibody titers were more likely to survive the challenge
      with the virulent PRV; there was a 100% mortality rate for raccoons lacking
      detectable anti-PRV antibodies. This experiment indicates that exposure of
      raccoons to modified live gene-deleted PRV vaccines may result in an immune
      response, and that this immunity provides some protection against exposure to
      virulent virus.

PMID- 12488068
TI  - Serotype C foot-and-mouth disease virus isolates from India belong to a separate
      so far not described lineage.
AB  - Complete 1D gene sequences of 13 Indian foot-and-mouth disease virus (FMDV) type
      C field isolates and a vaccine strain (C-Bombay/64) were determined. All the
      field isolates showed a greater genetic homogeneity (95-100%) among themselves
      and were 19.7-21.2% divergent from the vaccine strain. In the phylogenetic
      analysis, the Indian field isolates formed a separate lineage (lineage VII)
      different from the previously identified six lineages (lineage I-VI) in type C
      FMDV [J. Virol. 66 (1992) 3557]. The vaccine strain was grouped with European
      lineage (lineage II). Comparison of the deduced amino acid sequences of antigenic
      sites A and C of field isolates showed no significant variation from the vaccine
      strain. One-way serological relationship determined in ELISA showed antigenic
      closeness of the field isolates with C-Bombay/64.

PMID- 12488069
TI  - Prevalence and distribution of the insertion element ISMag1 in Mycoplasma
      agalactiae.
AB  - In characterising Mycoplasma agalactiae strains from various European countries
      and from Africa, a new insertion sequence (IS), ISMag1, which is related to IS of
      the family of IS30 insertion elements, has been identified by DNA sequence
      analysis and Southern blot hybridisation. ISMag1 has a size of 1515bp, and
      contains inverted repeats of 3bp and a gene encoding the putative transposase on
      a single open reading frame. ISMag1 is present only in the rarely isolated
      serotypes E, F, G and H of M. agalactiae, where it is found in 1 to approximately
      30 copies. The different patterns obtained by hybridisation of a labelled probe
      of ISMag1 to genomic DNA cut with various restriction enzymes correlate to some
      extent to the different serotypes and to variations of the nucleotide sequences
      of the uvrC genes of the different strains. Based on uvrC sequences, the strains
      of M. agalactiae carrying ISMag1 form a cluster, separate from the other strains.
      IS patterns obtained with ISMag1 allow a fine subtyping of the serotypes E, F, G
      and H of M. agalactiae for epidemiological studies. The potential role of ISMag1
      and of its copy numbers on virulence and persistence of the respective strains
      requests further studies.

PMID- 12488070
TI  - Comparison of intestinal invasion and macrophage response of Salmonella
      Gallinarum and other host-adapted Salmonella enterica serovars in the avian host.
AB  - The purpose of this investigation was to study the host specific infection of
      Salmonella Gallinarum in chickens and to determine the contribution of intestinal
      invasion and macrophage survival in relation to systemic infection in the host.
      This was carried out by comparing the kinetics of infection of S. Gallinarum to
      that of other Salmonella host-adapted (S. Cholerae-suis, S. Dublin and S.
      Typhimurium) and host-specific (S. Pullorum and S. Abortus-ovis) serovars.
      Establishment of the rate of colonisation in intestinal tissue, bursa and
      systemic sites was carried out by oral infection in day-old and week-old birds.
      Salmonella Gallinarum was the only serovar capable of causing systemic infection
      in chickens, however, general colonising ability in the intestine and bursa
      demonstrated no apparent selective advantage for S. Gallinarum. Further
      quantification of gastrointestinal invasion was carried out using ligated loops
      in the small intestine. Invasion in the jejunum of the chicken intestine over 3h
      demonstrated that Salmonella Typhimurium invasion was statistically higher
      (P<0.01) when compared with S. Gallinarum. Specific sites of high lymphoid tissue
      concentration in the chicken, including the bursa of Fabricius and caecal
      tonsils, were also targeted in invasion assays to investigate possible areas of
      tissue tropism. S. Typhimurium demonstrated significantly higher (P<0.01)
      invasion at these sites when compared with S. Gallinarum. Infection of chicken
      macrophages with S. Gallinarum did not demonstrate increased multiplication and
      survival intracellularly when compared with other Salmonella serotypes. The only
      difference seen was with S. Abortus-ovis, which demonstrated a significantly
      lower (P<0.05 to 0.001) intracellular survival. Together these data suggest that
      although S. Gallinarum host specificity in the chicken correlates with systemic
      infection, intestinal and lymphoid tissue invasion in the bursa and caeca, and
      macrophage survival does not influence this outcome.

PMID- 12488071
TI  - Evaluation of a PCR test for the diagnosis of Brucella ovis infection in semen
      samples from rams.
AB  - The sensitivity and specificity of a PCR assay with primers derived from the
      insertion sequence IS6501 was compared with that of bacteriological culture and
      serological tests for the diagnosis of Brucella ovis infection in rams. No
      amplifications were detected with DNAs from the strains phylogenetically related
      to Brucella and from the seven bacterial species considered as the main etiologic
      agents of epididymitis in rams. In addition, the specificity of the PCR was 100%
      when testing semen samples from Brucella-free rams. The comparison of the semen
      culture and PCR results from 192 semen samples tested, showed a proportion of
      agreement of 0.91 between both tests. The PCR-based test described has
      sensitivity similar to that of semen culture and could be used as a complementary
      test for the direct diagnosis of Brucella ovis in semen samples of rams.

PMID- 12488072
TI  - Infection and re-infection of domestic cats with various Bartonella species or
      types: B. henselae type I is protective against heterologous challenge with B.
      henselae type II.
AB  - Four Bartonella species have been isolated from domestic cats, of which two
      serotypes/genotypes of Bartonella henselae and possibly B. clarridgeiae are human
      pathogens, causing cat scratch disease (CSD).Our objectives were to evaluate
      infection and potential cross-protection during re-infection in domestic cats
      with various Bartonella species or types.Thirty-six cats were primarily
      inoculated with B. henselae type I (n=16), B. henselae type II (n=10), B.
      clarridgeiae (n=6) or B. koehlerae (n=4). They were challenged with B. henselae
      type I (n=15), B. henselae type II (n=13) or B. clarridgeiae (n=8). All 36 cats
      became bacteremic (1.25x10(2)-1.44x10(6)CFU/ml) and bacteremia lasted from 37 to
      582 days. Duration of bacteremia for cats inoculated with B. henselae type I was
      shorter than for cats inoculated with either B. henselae type II (P=0.025) or B.
      clarridgeiae (P=0.011). After challenge, 26 cats became bacteremic. Among the
      nine cats primarily inoculated with B. henselae type I and challenged with B.
      henselae type II, six cats stayed abacteremic. The three bacteremic cats had a
      transient low-level bacteremia. No bacteremia was observed in three cats
      primarily inoculated with B. henselae type I and challenged with another strain
      of B. henselae type I. Bacteremia levels in the 26 cats were significantly lower
      than for primary inoculation (P=0.022) and its duration was shorter (P=0.012).
      Among the eight cats challenged with B. clarridgeiae, duration of bacteremia in
      the four cats primarily inoculated with B. henselae type I was shorter than in
      the four cats primarily inoculated with B. henselae type II (P=0.01). Bartonella
      clarridgeiae inoculated cats were more likely to have relapses for both primary
      and secondary infections. This is the first demonstration of cross-protection,
      evidenced by absence of bacteremia, in cats primarily infected with B. henselae
      type I and challenged with B. henselae type II, whereas no cross-protection was
      previously shown for cats primarily infected with B. henselae type II and
      challenged with B. henselae type I. Such results are of major importance for
      future feline Bartonella vaccine development.

PMID- 12488073
TI  - Non-pathogenic Actinobacillus isolates antigenically and biochemically similar to
      Actinobacillus pleuropneumoniae: a novel species?
AB  - Two unusual Actinobacillus isolates were recovered from pigs with no clinical
      signs, no lesions and no history of swine pleuropneumonia. Two representative
      strains (9953L55 and 0347) analyzed in this study were initially biochemically
      and antigenically identified as A. pleuropneumoniae serotypes 1 and 9,
      respectively, by traditional identification methods. Both strains presented,
      however, negative results with three A. pleuropneumoniae-specific PCR tests and
      revealed in particular the absence of the apxIV toxin genes. However, both
      strains produced and secreted ApxII toxin although they only harbored the toxin
      genes apxIICA, which is an uncommon feature for any of the known A.
      pleuropneumoniae serotypes. Upon experimental inoculation of pigs, these strains
      proved to be totally non-pathogenic. Animals infected with one of the strains
      produced antibodies that cross-react with A. pleuropneumoniae serotypes 1-9-11
      specific LC-LPS ELISA. Phylogenetic analysis based on 16S rRNA gene sequence
      analysis revealed that these strains form a separate phylogenetic group that is
      distinct from other Actinobacillus species and is particularly different from A.
      pleuropneumoniae.

PMID- 12488074
TI  - Survey of restriction-modification systems and transformation in Mannheimia
      haemolytica and Pasteurella trehalosi.
AB  - A significant obstacle to molecular studies of Mannheimia (Pasteurella)
      haemolytica, has been its resistance to genetic transformation. The lack of
      competence of many M. haemolytica strains has been attributed to the presence of
      restriction modification systems. In this study, representative strains of 12 M.
      haemolytica serotypes and four Pasteurella trehalosi serotypes were successfully
      transformed by electroporation using a recombinant vector derived from the native
      M. haemolytica A1 serotype plasmid pNSF2176. Transformation was achieved despite
      PCR-based evidence for the presence of genes encoding a type I restriction
      enzyme, phaI, and a type II restriction enzyme hsdM, in each of the M.
      haemolytica strains.

PMID- 12488075
TI  - Interaction between probiotic lactic acid bacteria and canine enteric pathogens:
      a risk factor for intestinal Enterococcus faecium colonization?
AB  - Selected probiotic lactic acid bacteria (LAB) have been shown to elicit positive
      health effects particularly in humans. Competitive exclusion of pathogens is one
      of the most important beneficial health claims of probiotic bacteria. The effect
      of probiotic LAB on competitive exclusion of pathogens has been demonstrated in
      humans, chicken and pigs. In this study we evaluated the ability of certain LAB
      strains (Lactobacillus rhamnosus GG, Bifidobacterium lactis Bb12, Lactobacillus
      pentosus UK1A, L. pentosus SK2A, Enterococcus faecium M74 and E. faecium SF273)
      to inhibit the adhesion of selected canine and zoonotic pathogens (Staphylococcus
      intermedius, Salmonella Typhimurium ATCC 14028, Clostridium perfringens and
      Campylobacter jejuni) to immobilised mucus isolated from canine jejunal chyme in
      vitro. Adhesion of C. perfringens was reduced significantly by all tested LAB
      strains, between 53.7 and 79.1% of the control without LAB, the LAB of canine
      origin yielding the best reduction. The adhesion of S. Typhimurium and S.
      intermedius were not significantly altered by any of the LAB included in the
      study. Both enterococci tested significantly enhanced the adhesion of C. jejuni,
      to 134.6 and 205.5% of the control without LAB. E. faecium may thus favor the
      adhesion and colonization of C. jejuni in the dog's intestine, making it a
      potential carrier and possibly a source for human infection. Enhanced C. jejuni
      adhesion is a new potential risk factor of enterococci. Our results further
      emphasize the importance of safety guidelines to be established for the
      probiotics intended for animal use.

PMID- 12488076
TI  - Cloning and characterisation of type 4 fimbrial genes from Actinobacillus
      pleuropneumoniae.
AB  - Actinobacillus pleuropneumoniae is the cause of porcine pleuropneumoniae. Little
      is known about the mechanisms by which A. pleuropneumoniae colonises the
      respiratory tract. Fimbriae are common mediators of bacterial adherence to
      mucosal epithelia and have been observed on the surface of A. pleuropneumoniae
      cells. Here we report the identification and characterisation of the type 4
      fimbrial structural gene (apfA) from A. pleuropneumoniae. In addition a number of
      open reading frames were identified in A. pleuropneumoniae that have significant
      homology to type 4 fimbrial biogenesis genes from other species, including a
      putative leader specific peptidase (apfD). A. pleuropneumoniae apfA codes for a
      predicted polypeptide of approximately 16kDa, removal of the leader sequence at
      the predicted cleavage site would yield a 14.5kDa polypeptide. The first 30
      residues of the mature polypeptide are well conserved with other members of the
      group A type 4 fimbriae family. The signal sequence of ApfA is 13 amino acids in
      length and, unusually, the residue that precedes the cleavage site is alanine
      rather than glycine which is found in most other type 4 fimbriae. The C-terminus
      of ApfA possesses cysteine residues that are conserved in type 4 fimbriae of many
      species. In other type 4 fimbriae the distal C-terminal cysteines form a
      disulphide bond that produces a loop, which is important for the function of
      fimbriae and also comprises a major antigenic determinant. A motif within the
      predicted loop in ApfA was found to be highly conserved in type 4 fimbriae of
      other HAP organisms (Haemophilus, Actinobacillus, Pasteurella). The A.
      pleuropneumoniae type 4 fimbrial biogenesis genes showed the strongest homology
      to putative type 4 fimbrial genes of Haemophilus ducreyi. A. pleuropneumoniae
      apfA gene was shown to be present and highly conserved in different serotypes of
      A. pleuropneumoniae. Recombinant ApfA was produced and used to raise anti-ApfA
      antisera.

PMID- 12488077
TI  - Detection by immunomagnetic PCR of Mycobacterium avium subsp. paratuberculosis in
      milk from dairy goats in Norway.
AB  - Milk samples from 340 individual goats in 34 dairy herds throughout Norway were
      examined for Mycobacterium avium subsp. paratuberculosis (M.a. paratuberculosis)
      by culture and immunomagnetic separation combined with PCR (IMS-PCR). The samples
      included three categories; (A) vaccinated dairy goats in herds with
      paratuberculosis; (B) vaccinated dairy goats in herds with no history of
      paratuberculosis; (C) unvaccinated goats in herds with no history of
      paratuberculosis. Viable M.a. paratuberculosis were not detected by culture in
      any sample, but 24 samples (7.1%) tested positive by IMS-PCR when the PCR
      products were visualised by dot blot hybridisation. PCR products from five milk
      samples originating from five different herds were sequenced; all showed 99%
      homology with the IS900 sequence from M.a. paratuberculosis.M.a. paratuberculosis
      were detected in all sampled categories. The percentage of IMS-PCR positive
      samples from herds where paratuberculosis had previously been reported was
      significantly lower than from herds where the infection had never been diagnosed
      (3.3 and 9.1%, respectively, P=0.048). Similar proportions of milk samples from
      vaccinated and non-vaccinated goats tested positive for the presence of M.a.
      paratuberculosis. Vaccinated goats older than 4 years tested positive more often
      than vaccinated animals less than 2 years old. Samples collected in May tested
      significantly more often positive than milk sampled during February-March (13.8
      and 2.9%, respectively, P=0.001). This study showed that raw goats' milk in
      Norway might be contaminated with M.a. paratuberculosis.

PMID- 12488078
TI  - Phylogenetic analysis of the erythrocytic Anaplasma species based on 16S rDNA and
      GroEL (HSP60) sequences of A. marginale, A. centrale, and A. ovis and the
      specific detection of A. centrale vaccine strain.
AB  - Phenotypic criteria for the identification of erythrocytic ruminant Anaplasma
      species has relied on subjective identification methods such as host
      pathogenicity (virulence for cattle or sheep) and/or the location of Anaplasma
      inclusion bodies within the host's red cells. Sequence comparisons of new and
      available GenBank Accessions were investigated to elucidate the relationships
      among these closely related Anaplasma species. Twenty-one 16S rDNA and GroEL
      (HSP60) sequences from 13 Anaplasma marginale (South Africa, Namibia, Zimbabwe,
      Israel, USA, Australia and Uruguay), three A. centrale (South Africa and Japan),
      two A. ovis (USA and South Africa), and two unknown Anaplasma species isolated
      from wild ruminants (South Africa), were compared. 16S rDNA maximum-likelihood
      and distance trees separated all A. marginale (and the two wild ruminant
      isolates) from the two South African A. centrale (including original vaccine
      strain, Theiler, 1911). The Japanese A. centrale (Aomori) demonstrated the lowest
      sequence identity to the remaining erythrocytic Anaplasma species. A. ovis inter
      species relationships could not be resolved through the 16S rDNA analyses,
      whereas strong bootstrap branch support is demonstrated in the GroEL distance
      tree using A. ovis OVI strain. All erythrocytic Anaplasma species and isolates
      were confirmed to belong to the same cluster showing strong branch support to
      Anaplasma (Ehrlichia) phagocytophilum with Ehrlichia (Cowdria) ruminantium and
      Rickettsia rickettsii serving as appropriate out-groups. Based on groEL
      sequences, a specific PCR method was developed which amplified A. centrale
      vaccine (Theiler, 1911) specifically. This study confirms the suitability of 16S
      rDNA sequences to define genera and demonstrates the usefulness of GroEL
      sequences for defining species of erythrocytic Anaplasma.

PMID- 12488079
TI  - Host cell specific activity of RTX toxins from haemolytic Actinobacillus equuli
      and Actinobacillus suis.
AB  - We assessed and compared host cell specificity of the haemolytic and cytotoxic
      activity of the RTX toxins from Actinobacillus equuli, an equine pathogen, and
      Actinobacillus suis, which is pathogenic for pigs. The two bacterial species are
      closely related, phenotypically as well as phylogenetically, sharing the same 16S
      rRNA gene sequence. Both species contain specific protein toxins from the family
      of pore-forming RTX toxins, however, the two species differ in their RTX toxin
      profiles. Haemolytic A. equuli contains the operon for the Aqx toxin, whereas A.
      suis harbours genes for ApxI and ApxII. We tested the toxic activity of the
      corresponding proteins on erythrocytes as well as on lymphocytes isolated from
      horse and pig blood. The strength of the haemolytic activity for each of the
      toxins was independent of the origin of erythrocytes. When testing cytotoxic
      activity, the Aqx protein showed a higher toxic effect for horse lymphocytes than
      for porcine lymphocytes. On the other hand, ApxI and ApxII showed a strong
      cytotoxic effect on porcine lymphocytes and a reduced toxicity for horse
      lymphocytes; the toxicity of ApxII was generally much lower than ApxI. Our
      results indicate a host species specificity of the toxic activity of RTX toxins
      Aqx of A. equuli and ApxI and ApxII of A. suis.

PMID- 12488080
TI  - Transformation-mediated serogroup conversion of Dichelobacter nodosus.
AB  - Dichelobacter nodosus is the essential causative agent of footrot in sheep. The
      type IV fimbriae of D. nodosus are required for virulence, are highly immunogenic
      and immunoprotective, and can be divided into 10 major serogroups. Fimbrial
      variation has been postulated to have arisen because of genetic recombination
      within the fimbrial gene region perhaps as a means of evading the immune response
      invoked by infection. To show that antigenic variation in these fimbriae could
      occur after natural transformation and subsequent homologous recombination, a
      suicide plasmid containing the fimbrial subunit gene, fimA, of a serogroup G
      strain was used to convert a serogroup I strain to serogroup G. The resultant
      mutants were shown by Western blotting and slide agglutination to produce
      serogroup G fimbriae, but by two independent methods to still have the genotype
      of the parent type I strain. These data have significant implications for the use
      of fimbrial vaccines for the control of ovine footrot and suggest that benign
      strains of D. nodosus could play an important role as a reservoir of alternative
      fimbrial antigens.

PMID- 12488081
TI  - Phenotypic and genotypic characterization of bovine mastitis isolates of
      Staphylococcus aureus for biofilm formation.
AB  - Staphylococcus aureus is one of the most common pathogens responsible for
      contagious mastitis in ruminants. The ability of S. aureus to form biofilm in
      vivo is considered to be a major virulence factor influencing its pathogenesis in
      mastitis. The objectives of the study were to examine in vitro slime production,
      biofilm formation, and the presence of the ica gene locus and icaA and icaD genes
      in S. aureus isolates from bovine mastitis. Thirty-two of the 35 isolates tested
      produced slime on Congo red agar, whereas only 24 of the isolates were found to
      produce biofilm in vitro. However, all the 35 isolates possessed the ica locus,
      icaA and icaD genes. This study indicates a high prevalence of the ica genes
      among S. aureus mastitis isolates, and their presence is not always associated
      with in vitro formation of slime or biofilm. A combination of phenotypic and
      genotypic tests is recommended for investigating biofilm formation in S. aureus.

PMID- 12488082
TI  - The influence of maternal immunity on the efficacy of a classical swine fever
      vaccine against classical swine fever virus, genogroup 2.2, infection.
AB  - In Thailand, where vaccination is routinely employed, there has been an increased
      incidence of chronic classical swine fever (CSF) outbreaks during the past
      decade. The major causative virus has been identified to be the moderate
      virulence, classical swine fever virus (CSFV) of the genogroup 2.2. An
      investigation was made into the efficacy of a CSF vaccine against this genogroup
      2.2 challenge. Five-week-old pigs, grouped by their level of passive antibody
      titer were immunized with lapinized Chinese-strain CSF vaccine and challenged
      with CSFV genogroup 2.2, 13 days after vaccination. The group containing passive
      titers of lower than 64 at the time of immunization, had significantly higher
      number of CSFV-specific IFN-gamma secreting cells and was completely protected
      against the challenge. Interestingly, both cellular and antibody responses were
      inhibited in the pigs with the higher passive titer. Furthermore, following
      challenge, CSFV could be isolated from 50% of the pigs in this group. It was
      demonstrated that the CSF vaccine could induce complete protection in pigs,
      provided that the maternal derived titer at the time of vaccination was lower
      than 64. The result implied that an increase in CSFV outbreaks might be due to
      the inappropriate timing of vaccination as well as the nature of the CSFV
      genogroup 2.2.

PMID- 12488083
TI  - Mechanisms that contribute to differences in motor performance between young and
      old adults.
AB  - This paper examines the physiological mechanisms responsible for differences in
      the amplitude of force fluctuations between young and old adults. Because muscle
      force is a consequence of motor unit activity, the potential mechanisms include
      both motor unit properties and the behavior of motor unit populations. The force
      fluctuations, however, depend not only on the age of the individual but also on
      the muscle group performing the task, the type and intensity of the muscle
      contraction, and the physical activity status of the individual. Computer
      simulations and experimental findings performed on tasks that involved single
      agonist and antagonist muscles suggest that differences in force fluctuations are
      not attributable to motor unit twitch force, motor unit number, or nonuniform
      activation of the agonist muscle, but that they are influenced by the variability
      and common modulation of motor unit discharge in both the agonist and antagonist
      muscles. Because the amplitude of the force fluctuations does not vary linearly
      with muscle activation, these results suggest that multiple mechanisms contribute
      to the differences in force fluctuations between young and old adults, although
      the boundary conditions for each mechanism remain to be determined.

PMID- 12488084
TI  - Interpretation of EMG changes with fatigue: facts, pitfalls, and fallacies.
AB  - Failure to maintain the required or expected force, defined as muscle fatigue, is
      accompanied by changes in muscle electrical activity. Although studied for a long
      time, reasons for EMG changes in time and frequency domain have not been clear
      until now. Many authors considered that theory predicted linear relation between
      the characteristic frequencies and muscle fibre propagation velocity (MFPV),
      irrespective of the fact that spectral characteristics can drop even without any
      changes in MFPV, or in proportion exceeding the MFPV changes. The amplitude
      changes seem to be more complicated and contradictory since data on increased,
      almost unchanged, and decreased amplitude characteristics of the EMG, M-wave or
      motor unit potential (MUP) during fatigue can be found in literature. Moreover,
      simultaneous decrease and increase in amplitude of MUP and M-wave, detected with
      indwelling and surface electrodes, were referred to as paradoxical. In spite of
      this, EMG amplitude characteristics are predominantly used when causes for
      fatigue are analysed. We aimed to demonstrate theoretical grounds for pitfalls
      and fallacies in analysis of experimental results if changes in intracellular
      action potential (IAP), i.e. in peripheral factors of muscle fatigue, were not
      taken into consideration. We based on convolution model of potentials produced by
      a motor unit and detected by a point or rectangular plate electrode in a
      homogeneous anisotropic infinite volume conductor. Presentation of MUP in the
      convolution form gave us a chance to consider power spectrum (PS) of MUP as a
      product of two terms. The first one, PS of the input signal, represented PS of
      the first temporal derivative of intracellular action potential (IAP). The second
      term, PS of the impulse response, took into account MFPV, differences in instants
      of activation of each fibre, MU anatomy, and MU position in the volume conductor
      in respect to the detecting electrode. PS presentation through product means that
      not only changes in MFPV could be responsible for PS shift as is usually assumed.
      Changes in IAP duration and IAP after-potential magnitude, affecting the first
      term of the product, influence the product and thus MUP PS. Moreover, the
      interrelations between the two spectra and thus sensitivity of spectrum to
      different parameters change with MU-electrode distance because the second term
      depends on it. Thus, we have demonstrated that theory does not predict a linear
      relation between the characteristic frequencies (maximum, mean and median) and
      MFPV. IAP duration and after-potential magnitude are among parameters affecting
      MUP or M-wave PS and thus, EMG PS detected by monopolar and bipolar electrodes.
      Usage of single fibre action potential models instead of MUP ones can result in
      false dependencies of frequency characteristics. The MUP amplitude
      characteristics are determined not only by amplitude of IAP, but also by the
      length of the IAP profile and source-electrode distance. Due to the IAP profile
      lengthening and an increase in the negative after-potential, surface detected EMG
      amplitude characteristics can increase even when IAP amplitude decreases
      considerably during fatigue. Increase in surface detected MUP or M-wave amplitude
      should not be attributed to a weaker attenuation of the low-frequency components
      with distance. Simultaneous decrease and increase in amplitude of MUP and M-wave
      detected with indwelling and surface electrodes are regular, not paradoxical.
      Corner frequency of the high pass filter should be 0.5 or 1 Hz when muscle
      fatigue is analyzed. The area of MUP or M-wave normalized in respect of the
      amplitude of the terminal phase (that is produced during extinction of the
      depolarized zones at the ends of the fibres) could be useful as a fatigue index.
      Analysing literature data on IAP changes due to Ca(2+) increasing, we
      hypothesised that the ability of muscle fibres to uptake Ca(2+) back into the
      sarcoplasmic reticulum could be the limiting site for fatigue. If this hypothesis
      is valid, IAP changes are not a cause of fatigue; they are due to it.

PMID- 12488085
TI  - The linear electrode array: a useful tool with many applications.
AB  - In this review we describe the basic principles of operation of linear electrode
      arrays for the detection of surface EMG signals, together with their most
      relevant current applications. A linear array of electrodes is a system which
      detects surface EMG signals in a number of points located along a line. A spatial
      filter is usually placed in each point for signal detection, so that the
      recording of EMG signals with linear arrays corresponds to the sampling in one
      spatial direction of a spatially filtered version of the potential distribution
      over the skin. Linear arrays provide indications on motor unit (MU) anatomical
      properties, such as the locations of the innervation zones and tendons, and the
      fiber length. Such systems allow the investigation of the properties of the
      volume conductor and its effect on surface detected signals. Moreover, linear
      arrays allow to estimate muscle fiber conduction velocity with a very low
      standard deviation of estimation (of the order of 0.1-0.2 m/s), thus providing
      reliable indications on muscle fiber membrane properties and their changes in
      time (for example with fatigue or during treatment). Conduction velocity can be
      estimated from a signal epoch (global estimate) or at the single MU level. In the
      latter case, MU action potentials are identified from the interference EMG
      signals and conduction velocity is estimated for each detected potential. In this
      way it is possible, in certain conditions, to investigate single MU control and
      conduction properties with a completely non-invasive approach. Linear arrays
      provide valuable information on the neuromuscular system properties and appear to
      be promising tools for applied studies and clinical research.

PMID- 12488086
TI  - Motor mechanisms of balance during quiet standing.
AB  - The purpose of this paper is to highlight the motor mechanisms involved in
      balance as the human, as a biped, continuously defends against gravitational and
      internal forces to maintain a safe posture. The search for these mechanisms needs
      precise and valid 3D measurements including both limbs plus valid biomechanical
      models. The literature shows the need for two force platforms to separate the
      mechanisms at the ankle and hip (load/unload mechanism). Also, precise measures (
      approximately 0.03 mm) of markers on a multi-segment 3D bilateral model are
      required to record the minute trajectories of all segments and joints. The
      controlled variable, center-of-mass, is seen to be virtually in phase with the
      controlling variable, the center-of-pressure, which suggests a 0th order system
      where a simple series elastic spring could maintain balance. The first model
      involves a mass/spring/damper of medial/lateral balance: the stiffness was varied
      with stance width and the predicted sway from a spring controlled inverted
      pendulum closely matched the experimentally measured stiffness and sway. The
      second was a non-linear model of the plantarflexor series elastic elements which
      resulted in three closely validated predictions of anterior/posterior balance:
      the locus of the gravitational load line, the predicted ankle moment and the
      ankle stiffness at the operating point.

PMID- 12488087
TI  - Cortical reorganization in training.
AB  - Plasticity within the human central motor system occurs and has been studied with
      transcranial magnetic stimulation in patients with amputations, spinal cord
      injuries, and ischemic nerve block. These studies have identified a pattern of
      motor system reorganization that results in enlarged muscle representation areas
      and large motor evoked potentials (MEPs) for muscles immediately proximal to the
      lesion. Some of these changes are apparent minutes after ischemic nerve block,
      weeks after spinal cord injury, and as early as six months after amputation.These
      studies motivated us to study the cortical motor reorganization after finger
      movement training in normals and after anastomosis of intercostal nerves to the
      musculocutaneous nerve in young patients with cervical root avulsions due to a
      traumatic motorcycle injury.

PMID- 12488088
TI  - Crosstalk in surface electromyography of the proximal forearm during gripping
      tasks.
AB  - Electromyographic (EMG) crosstalk was systematically analyzed to evaluate the
      magnitude of common signal present between electrode pairs around the forearm.
      Surface EMG was recorded and analyzed from seven electrode pairs placed
      circumferentially around the proximal forearm in six healthy individuals. The
      cross-correlation function was used to determine the amount of common signal,
      which was found to decrease as the distance between electrode pairs increased,
      but was not significantly altered by forearm posture (pronation, neutral,
      supination). Overall, approximately 40% common signal was detected between
      adjacent electrode pairs (3 cm apart), dropping to about 10% at 6 cm spacing and
      2.5% at 9 cm. The magnitude of common signal approached 50% between adjacent
      electrode pairs over the extensor muscles, while over 60% was observed between
      neighbouring sites on the flexor aspect of the forearm. Although flexor and
      extensor EMG amplitude was similar, less than 2% common signal was present
      between flexor and extensor electrode pairs during both pinch and grasp tasks.
      Maximum grip force production was not affected by forearm rotation for pinch, but
      reduced 18% from neutral (mid-prone) to pronation during grasp (p=0.01). In spite
      of differences in grip force, mean muscle activity did not vary between the three
      forearm postures during maximum pinch or grasp trials. While this study improved
      our knowledge of crosstalk and electrode spacing issues, further examination of
      forearm EMG is required to improve understanding of muscle loading, EMG
      properties and motor control during gripping tasks.

PMID- 12488089
TI  - Measuring movement irregularity in the upper motor neurone syndrome using
      normalised average rectified jerk.
AB  - Movement irregularity is a feature of the upper motor neurone (UMN) syndrome
      which is difficult to measure. Average rectified jerk (ARJ) has been proposed as
      a measure of this movement irregularity, but ARJ depends upon the duration of
      movement. Since movements may be slower in UMN patients, duration dependence
      compromises ARJ as a measure of irregularity. A normalisation technique is
      proposed that generates a measure of movement irregularity which is independent
      of movement duration: normalised average rectified jerk (NARJ). This paper
      presents a validation of NARJ in the UMN syndrome. Nine control subjects, nine
      left hemiparetic stroke patients and nine right hemiparetic stroke patients were
      studied. Test movements comprised elbow extension/flexion in the horizontal
      plane; these were recorded with an electro-goniometer and accelerometer. The
      effectiveness of the normalisation technique has been demonstrated using
      trajectories of various durations; some of these were artificially generated from
      participants' trajectories, in order to preserve the movement profile. The
      variability of NARJ and ARJ have been compared in a sample of control subjects.
      NARJ has been criterion validated by correlation with expert subjective rating of
      irregularity in a heterogeneous set of trajectories. Construct validity has been
      tested by discrimination between movements of control subjects, left hemiparetic
      stroke patients and right hemiparetic stroke patients. When comparing
      trajectories of identical profile but two-fold difference in movement duration,
      NARJ differed only 2.6% whereas ARJ differed 706%. NARJ was less reproducible in
      healthy participants than ARJ: median non-parametric coefficients of variation
      for repeated movements were 55% and 41%, respectively. Spearman rank correlation
      coefficient for NARJ and expert rating was 0.92 (p<0.01). NARJ measurements on
      right hemiparetic patients differ significantly from those made on the control
      group (p<0.02); corresponding ARJ measurements do not attain statistical
      significance. NARJ is a valid measure of movement irregularity in the UMN
      syndrome.

PMID- 12488090
TI  - EMG frequency content changes with increasing force and during fatigue in the
      quadriceps femoris muscle of men and women.
AB  - The purpose of this study was to determine the effect of gender on changes in
      electromyographic (EMG) signal characteristics of the quadriceps muscles with
      increasing force and with fatigue. A total of fourteen healthy adults (seven men,
      seven women) participated in the study. Subjects had to perform isometric ramp
      contractions in knee extension with the force gradually increasing from 0 to 100%
      of the maximal voluntary contraction (MVC) in a 6-s period. Subjects then
      performed a fatigue task, consisting of a sustained maximum isometric knee
      extension contraction held until force decreased below 50% of the pre-fatigue
      MVC. Subjects also performed a single ramp contraction immediately after the
      fatigue task. The Root Mean Square (RMS) amplitude, mean power frequency (MPF)
      and median frequency (MF) of EMG signals obtained from the vastus lateralis,
      vastus medialis and rectus femoris were calculated at nine different force levels
      from the ramp contractions (10, 20, 30, 40, 50, 60, 70, 80 and 90% MVC), as well
      as every 5 s during the fatigue task. The main results were a more pronounced
      increase in EMG RMS amplitude for the three muscles and in MPF for the VL muscle
      with force in men compared with women. No significant effect of gender was found
      with regards to fatigue. These observations most likely reflect a moderately
      greater type II fiber content and/or area in the VL muscle of men compared to
      that of women.

PMID- 12488091
TI  - Motor unit activation patterns during isometric, concentric and eccentric actions
      at different force levels.
AB  - Motor unit activation patterns were studied during four different force levels of
      concentric and eccentric actions. Eight male subjects performed concentric and
      eccentric forearm flexions with the movement range from 100 degrees to 60 degrees
      in concentric and from 100 degrees to 140 degrees elbow angle in eccentric
      actions. The movements were started either from zero preactivation or with
      isometric preactivation of the force levels of 20, 40, 60 and 80% MVC. The
      subjects were then instructed to maintain the corresponding relative force levels
      during the dynamic actions. Intramuscular and surface EMG was recorded from
      biceps brachii muscle. Altogether 28 motoneuron pools were analyzed using the
      intramuscular spike-amplitude frequency (ISAF) analysis technique of Moritani et
      al. The mean spike amplitude was lower and the mean spike frequency higher in the
      isometric preactivation phase than in the consequent concentric and eccentric
      actions. When the movements started with isometric preactivation the mean spike
      amplitude increased significantly (P<0.001) up to 80% in isometric and concentric
      actions but in eccentric actions the increase continued only up to 60% (P<0.01).
      The mean spike frequency in isometric preactivation and in concentric action with
      preactivation was lower only at the 20% force level (P<0.01) as compared to the
      other force levels while in eccentric action with preactivation the increase
      between the force levels was significant (P<0.01) up to 60%. When the movement
      was started without preactivation the mean spike amplitude at 20% and at 40%
      force level was higher (P<0.01) in eccentric action than in concentric actions.
      It was concluded that the recruitment threshold may be lower in dynamic as
      compared to isometric actions. The recruitment of fast motor units may continue
      to higher force levels in isometric and in concentric as in eccentric actions
      which, on the other hand, seems to achieve the higher forces by increasing the
      firing rate of the active units. At the lower force levels mean spike amplitude
      was higher in eccentric than in concentric actions which might indicate selective
      activation of fast motor units. This was, however, the case only when the
      movements were started without isometric preactivation.

PMID- 12488092
TI  - The single nuclear lamin of Caenorhabditis elegans forms in vitro stable
      intermediate filaments and paracrystals with a reduced axial periodicity.
AB  - The lamins of the tunicate Ciona intestinalis and the nematode Caenorhabditis
      elegans show unusual sequence features when compared to the more than 35 metazoan
      lamin sequences currently known. We therefore analyzed the in vitro assembly of
      these two lamins by electron microscopy using chicken lamin B2 as a control.
      While lamin dimers usually appear as a rod carrying two globules at one end,
      these globules are absent from Ciona lamin, which lacks the central 105-residue
      region of the tail domain. The deletion of 14 residues or two heptads from the
      coiled coil rod domain of the single C.elegans lamin results in a 1.5-nm
      shortening of the dimer rod. Similarly, the paracrystals assembled from the
      C.elegans lamin exhibit a 3.1-nm reduction of the true axial repeat compared to
      that of chicken lamin B2 paracrystals. We speculate that the banding pattern in
      the C.elegans lamin paracrystals arises from a relative stagger between dimers
      and/or a positioning of the globular tail domain relative to the central rod that
      is distinct from that observed in chicken lamin B2 paracrystals. Here we show
      that a nuclear lamin can assemble in vitro into 10-nm intermediate filaments
      (IFs). C.elegans lamin in low ionic strength Tris-buffers at a pH of 7.2-7.4
      provides a stable population of lamin IFs. Some implications of this filament
      formation are discussed.

PMID- 12488093
TI  - Amyloid-forming peptides from beta2-microglobulin-Insights into the mechanism of
      fibril formation in vitro.
AB  - Beta(2)-Microglobulin (beta(2)m) is one of over 20 proteins known to be involved
      in human amyloid disease. Peptides equivalent to each of the seven beta-strands
      of the native protein, together with an eighth peptide (corresponding to the most
      stable region in the amyloid precursor conformation formed at pH 3.6, that
      includes residues in the native strand E plus the eight succeeding residues
      (named peptide E')), were synthesised and their ability to form fibrils
      investigated. Surprisingly, only two sequences, both of which encompass the
      region that forms strand E in native beta(2)m, are capable of forming amyloid
      like fibrils in vitro. These peptides correspond to residues 59-71 (peptide E)
      and 59-79 (peptide E') of intact beta(2)m. The peptides form fibrils under the
      acidic conditions shown previously to promote amyloid formation from the intact
      protein (pH <5 at low and high ionic strength), and also associate to form
      fibrils at neutral pH. Fibrils formed from these two peptides enhance
      fibrillogenesis of the intact protein. No correlation was found between secondary
      structure propensity, peptide length, pI or hydrophobicity and the ability of the
      peptides to associate into amyloid-like fibrils. However, the presence of a
      relatively high content of aromatic side-chains correlates with the ability of
      the peptides to form amyloid fibrils. On the basis of these results we propose
      that residues 59-71 may be important in the self-association of partially folded
      beta(2)m into amyloid fibrils and discuss the relevance of these results for the
      assembly mechanism of the intact protein in vitro.

PMID- 12488094
TI  - Characterization of the ABCA transporter subfamily: identification of prokaryotic
      and eukaryotic members, phylogeny and topology.
AB  - An alignment of the mammalian ABCA transporters enabled the identification of
      sequence segments, specific to the ABCA subfamily, which were used as queries to
      search for eukaryotic and prokaryotic homologues. Thirty-seven eukaryotic half
      and full-length transporters were found, and a close relationship with
      prokaryotic subfamily 7 transporters was detected. Each half of the ABCA full
      transporters is predicted to comprise a membrane-spanning domain (MSD) composed
      of six helices and a large extracellular loop, followed by a nucleotide-binding
      domain (NBD) and a conserved cytoplasmic 80-residue sequence, which might have a
      regulatory function. The topology predicted for the ABCA transporters was
      compared to the crystal structures of the MsbA and BtuCD bacterial transporters.
      The alignment of the MSD and NBD domains provided an estimate of the degree of
      residue conservation in the cytoplasmic, extracellular and transmembrane domains
      of the ABCA transporter subfamily. The phylogenic tree of eukaryotic ABCA
      transporters based upon the NBD sequences, consists of three major clades,
      corresponding to the half-transporter single NBDs and to the full-transporter
      NBDls and NBD2s. A phylogenic tree of prokaryotic transporters and the eukaryotic
      ABCA transporters confirmed the evolutionary relationship between prokaryotic
      subfamily 7 transporters and eukaryotic ABCA half and full-transporters.

PMID- 12488095
TI  - The N-terminal domain of the regulatory subunit is sufficient for complete
      activation of acetohydroxyacid synthase III from Escherichia coli.
AB  - We have previously proposed a model for the fold of the N-terminal domain of the
      small, regulatory subunit (SSU) of acetohydroxyacid synthase isozyme III. The
      fold is an alpha-beta sandwich with betaalphabetabetaalphabeta topology,
      structurally homologous to the C-terminal regulatory domain of 3-phosphoglycerate
      dehydrogenase. We suggested that the N-terminal domains of a pair of SSUs
      interact in the holoenzyme to form two binding sites for the feedback inhibitor
      valine in the interface between them. The model was supported by mutational
      analysis and other evidence. We have now examined the role of the C-terminal
      portion of the SSU by construction of truncated polypeptides (lacking 35, 48, 80,
      95, or 112 amino acid residues from the C terminus) and examining the properties
      of holoenzymes reconstituted using these constructs. The Delta35, Delta48, and
      Delta80 constructs all lead to essentially complete activation of the catalytic
      subunits. The Delta80 construct, corresponding to the putative N-terminal domain,
      has the highest level of affinity for the catalytic subunits and leads to a
      reconstituted enzyme with k(cat)/K(M) about twice that of the wild-type enzyme.
      On the other hand, none of these constructs binds valine or leads to a valine
      sensitive enzyme on reconstitution. The enzyme reconstituted with the Delta80
      construct does not bind valine, either. The N-terminal portion (about 80 amino
      acid residues) of the SSU is thus necessary and sufficient for recognition and
      activation of the catalytic subunits, but the C-terminal half of the SSU is
      required for valine binding and response. We suggest that the C-terminal region
      of the SSU contributes to monomer-monomer interactions, and provide additional
      experimental evidence for this suggestion.

PMID- 12488096
TI  - Tyr212: a key residue involved in strand discrimination by the DNA mismatch
      repair endonuclease MutH.
AB  - The molecular mechanism of how the dam-methylation status of the DNA is
      recognized during DNA mismatch repair by the strand discrimination endonuclease
      MutH is not known. A comparison of the crystal structure of MutH with those of co
      crystal structures of several restriction endonucleases, together with a multiple
      sequence alignment of MutH and related proteins suggested that Phe94, Arg184 and
      Tyr212 could be involved in discrimination between a methylated or unmethylated
      adenine in the d(GATC) sequence. A mutational analysis revealed that the variants
      R184A and Y212S, but not F94A, were substantially reduced in their ability to
      complement a mismatch repair deficiency in a mutH(-) Escherichia coli strain. In
      vitro, R184A displayed a strongly reduced endonuclease activity, whereas the
      Y212S variant has almost completely lost its preference for cleaving the
      unmethylated strand at hemimethylated d(GATC) sites. Furthermore, the Y212
      variant can cleave fully methlyated d(GATC) sites at a comparable rate to
      unmethylated d(GATC) sites. This demonstrates that Tyr212 is an important, if not
      the only amino acid residue in MutH for sensing the methylation status of the
      DNA.

PMID- 12488097
TI  - Genomic structure and functional characterisation of the promoters of human and
      mouse nogo/rtn4.
AB  - The reticulon-family member Nogo-A is a potent neurite growth inhibitory protein
      in vitro and may play a role in the restriction of axonal regeneration after
      injury and of structural plasticity in the CNS of higher vertebrates. Of the
      three major isoforms of Nogo, Nogo-A is mostly expressed in the brain, Nogo-B is
      found in a ubiquitous pattern, and Nogo-C is most highly expressed in muscle.
      Seven additional splice-variants derived both from differential splicing and
      differential promoter usage have been identified. Analysis of the TATA-less Nogo
      A/B promoter (P1) shows that conserved GC-boxes and a CCAAT-box within the first
      500bp upstream of the transcription start are responsible for its regulation. No
      major differences in the methylation status of the P1 CpG-island in tissues
      expressing or not expressing Nogo-A/B could be detected, suggesting that silencer
      elements are involved in the regulation. The specific expression pattern of Nogo
      A/B is due to differential splicing. The basal Nogo-C promoter (P2) is regulated
      by a proximal and a distal element. The 5'UTR of Nogo-C harbours a negative
      control element. These data may help to identify factors that can modulate Nogo
      transcription, thus offering an alternative approach for Nogo neutralisation.

PMID- 12488098
TI  - Rabbit immune repertoires as sources for therapeutic monoclonal antibodies: the
      impact of kappa allotype-correlated variation in cysteine content on antibody
      libraries selected by phage display.
AB  - The rabbit immune repertoire has long been a rich source of diagnostic polyclonal
      antibodies. Now it also holds great promise as a source of therapeutic monoclonal
      antibodies. On the basis of phage display technology, we recently reported the
      first humanization of a rabbit monoclonal antibody. The allotypic diversity of
      rabbit immunoglobulins prompted us to compare different rabbit immune repertoires
      for the generation and humanization of monoclonal antibodies that bind with
      strong affinity to antigens involved in tumor angiogenesis. In particular, we
      evaluated the diversity of unselected and selected chimeric rabbit/human Fab
      libraries that were derived from different kappa light chain allotypes. Most
      rabbit light chains have an extra disulfide bridge that links the variable and
      constant domains in addition to the two intrachain disulfide bridges shared with
      mouse and human kappa light chains. Here we evaluate the impact of this increased
      disulfide bridge complexity on the generation and selection of chimeric
      rabbit/human Fab libraries. We demonstrate that rabbits with mutant bas and wild
      type parental b9 allotypes are excellent sources for therapeutic monoclonal
      antibodies. Featured among the selected clones with b9 allotype is a rabbit/human
      Fab that binds with a dissociation constant of 1nM to both human and mouse Tie-2,
      which will facilitate its evaluation in mouse models of human cancer. Examination
      of 228 new rabbit antibody sequences allowed for a comprehensive comparison of
      the LCDR3 and HCDR3 length diversity in rabbits. This study revealed that rabbits
      exhibit an HCDR3 length distribution more closely related to human antibodies
      than mouse antibodies.

PMID- 12488099
TI  - Analysis of the antigen combining site: correlations between length and sequence
      composition of the hypervariable loops and the nature of the antigen.
AB  - It has long been suggested that the overall shape of the antigen combining site
      (ACS) of antibodies is correlated with the nature of the antigen. For example,
      deep pockets are characteristic of antibodies that bind haptens, grooves indicate
      peptide binders, while antibodies that bind to proteins have relatively flat
      combining sites. In 1996, MacCallum, Martin and Thornton used a fractal shape
      descriptor and showed a strong correlation of the shape of the binding region
      with the general nature of the antigen.However, the shape of the ACS is
      determined primarily by the lengths of the six complementarity-determining
      regions (CDRs). Here, we make a direct correlation between the lengths of the
      CDRs and the nature of the antigen. In addition, we show significant differences
      in the residue composition of the CDRs of antibodies that bind to different
      antigen classes. As well as helping us to understand the process of antigen
      recognition, autoimmune disease and cross-reactivity, these results are of direct
      application in the design of antibody phage libraries and modification of
      affinity.

PMID- 12488100
TI  - Granulysin crystal structure and a structure-derived lytic mechanism.
AB  - Our crystal structure of granulysin suggests a mechanism for lysis of bacterial
      membranes by granulysin, a 74-residue basic protein from human cytolytic T
      lymphocyte and natural killer cells. We determined the initial crystal structure
      of selenomethionyl granulysin by MAD phasing at 2A resolution. We present the
      structure model refined using native diffraction data to 0.96A resolution. The
      five-helical bundle of granulysin resembles other "saposin folds" (such as NK
      lysin). Positive charges distribute in a ring around the granulysin molecule, and
      one face has net positive charge. Sulfate ions bind near the segment of the
      molecule identified as most membrane-lytic and of highest hydrophobic moment. The
      ion locations may indicate granulysin's orientation of initial approach towards
      the membrane. The crystal packing reveals one way to pack a sheet of granulysin
      molecules at the cell surface for a concerted lysis effort. The energy of binding
      granulysin charges to the bacterial membrane could drive the subsequent lytic
      processes. The loosely packed core facilitates a hinge or scissors motion towards
      exposure of hydrophobic surface that we propose tunnels the granulysin into the
      fracturing target membrane.

PMID- 12488101
TI  - Evidence for sequential barriers and obligatory intermediates in apparent two
      state protein folding.
AB  - Many small proteins fold fast and without detectable intermediates. This is
      frequently taken as evidence against the importance of partially folded states,
      which often transiently accumulate during folding of larger proteins. To get
      insight into the properties of free energy barriers in protein folding we
      analyzed experimental data from 23 proteins that were reported to show non-linear
      activation free-energy relationships. These non-linearities are generally
      interpreted in terms of broad transition barrier regions with a large number of
      energetically similar states. Our results argue against the presence of a single
      broad barrier region. They rather indicate that the non-linearities are caused by
      sequential folding pathways with consecutive distinct barriers and a few
      obligatory high-energy intermediates. In contrast to a broad barrier model the
      sequential model gives a consistent picture of the folding barriers for different
      variants of the same protein and when folding of a single protein is analyzed
      under different solvent conditions. The sequential model is also able to explain
      changes from linear to non-linear free energy relationships and from apparent two
      state folding to folding through populated intermediates upon single point
      mutations or changes in the experimental conditions. These results suggest that
      the apparent discrepancy between two-state and multi-state folding originates in
      the relative stability of the intermediates, which argues for the importance of
      partially folded states in protein folding.

PMID- 12488102
TI  - Analysing six types of protein-protein interfaces.
AB  - Non-covalent residue side-chain interactions occur in many different types of
      proteins and facilitate many biological functions. Are these differences
      manifested in the sequence compositions and/or the residue-residue contact
      preferences of the interfaces? Previous studies analysed small data sets and gave
      contradictory answers. Here, we introduced a new data-mining method that yielded
      the largest high-resolution data set of interactions analysed. We introduced an
      information theory-based analysis method. On the basis of sequence features, we
      were able to differentiate six types of protein interfaces, each corresponding to
      a different functional or structural association between residues. Particularly,
      we found significant differences in amino acid composition and residue-residue
      preferences between interactions of residues within the same structural domain
      and between different domains, between permanent and transient interfaces, and
      between interactions associating homo-oligomers and hetero-oligomers. The
      differences between the six types were so substantial that, using amino acid
      composition alone, we could predict statistically to which of the six types of
      interfaces a pool of 1000 residues belongs at 63-100% accuracy. All interfaces
      differed significantly from the background of all residues in SWISS-PROT, from
      the group of surface residues, and from internal residues that were not involved
      in non-trivial interactions. Overall, our results suggest that the interface type
      could be predicted from sequence and that interface-type specific mean-field
      potentials may be adequate for certain applications.

PMID- 12488103
TI  - Evidence for structural integrity in the undecameric c-rings isolated from sodium
      ATP synthases.
AB  - The Na(+)-translocating ATP synthases from Ilyobacter tartaricus and
      Propionigenium modestum contain undecameric c subunit rings of unusual stability.
      These c(11) rings have been isolated from both ATP synthases and crystallized in
      two dimensions. Cryo-transmission electron microscopy projection maps of the c
      rings from both organisms were identical at 7A resolution. Different crystal
      contacts were induced after treatment of the crystals with
      dicyclohexylcarbodiimide (DCCD), which is consistent with the binding of the
      inhibitor to glutamate 65 in the C-terminal helix on the outside of the ring. The
      c subunits of the isolated c(11) ring of I.tartaricus were modified specifically
      by incubation with DCCD with kinetics that were indistinguishable from those of
      the F(1)F(o) holoenzyme. The reaction rate increased with decreasing pH but was
      lower in the presence of Na(+). From the pH profile of the second-order rate
      constants, the pK of glutamate 65 was deduced to be 6.6 or 6.2 in the absence or
      presence of 0.5mM NaCl, respectively. These pK values are identical with those
      determined for the F(1)F(o) complex. The results indicate that the isolated c
      ring retains its native structure, and that the glutamate 65, including binding
      sites near the middle of the membrane, are accessible to Na(+) from the cytoplasm
      through access channels within the c-ring itself.

PMID- 12488104
TI  - Biogenesis of rat mitochondrial citrate carrier (CIC): the N-terminal presequence
      facilitates the solubility of the preprotein but does not act as a targeting
      signal.
AB  - Most mitochondrial preproteins carry a cleavable N-terminal presequence that
      mediates targeting to mitochondria and translocation across the mitochondrial
      membranes. In this study, we characterized the presequence of the citrate carrier
      (CIC, tricarboxylate carrier) of rat liver mitochondria. The CIC presequence was
      found to be dispensable both for targeting to mitochondria and insertion into the
      inner membrane. Unlike the presequence of the related phosphate carrier, fusion
      of the CIC presequence to the cytosolic enzyme dihydrofolate reductase did not
      confer mitochondrial targeting, indicating that the CIC presequence does not act
      as a targeting signal. However, the presequence was required to keep the CIC in a
      soluble state. Mature CIC lacking the presequence was prone to aggregation. We
      conclude that mitochondrial presequences do not necessarily act as mediators of
      targeting. In the case of the CIC, the presequence appears to determine the
      folding state of the preprotein.

PMID- 12488105
TI  - Masculinized finger length patterns in human males and females with congenital
      adrenal hyperplasia.
AB  - The ratio of the length of the second digit (2D) to the length of the fourth
      digit (4D) is greater in women than in men. Since androgens are involved in most
      somatic sex differences and since the sexual dimorphism in 2D:4D is stable from 2
      years of age in humans, it was hypothesized that finger length pattern
      development might be affected by early androgen exposure. Human females with
      congenital adrenal hyperplasia (CAH) are exposed prenatally to higher than normal
      levels of adrenal androgens, providing an opportunity to test the effects of
      early androgen exposure on digit ratios. The 2D:4D was calculated for females
      with CAH, females without CAH, males with CAH, and males without CAH. Females
      with CAH had a significantly smaller 2D:4D on the right hand than did females
      without CAH. Males with CAH had a significantly smaller 2D:4D on the left hand
      than did males without CAH. A subset of six males with CAH had a significantly
      smaller 2D:4D on both hands compared with their male relatives without CAH. These
      results are consistent with the idea that prenatal androgen exposure reduces the
      2D:4D and plays a role in the establishment of the sex difference in human finger
      length patterns. Finger lengths may therefore offer a retrospective marker of
      perinatal androgen exposure in humans.

PMID- 12488106
TI  - Associations between stress reactivity and sexual and nonsexual risk taking in
      young adult human males.
AB  - Release of the hormone cortisol represents a distress response to novel or
      stressful situations. Individual differences in such reactivity have been
      conceptualized as representing a relatively enduring, generalizable trait. In
      this study, cortisol responses to two experimentally manipulated "sexual" and
      "nonsexual" stressors were used to examine whether stress reactivity is related
      to sexual and nonsexual risk behavior in young adult males. Analyses were based
      on 150 males 18 to 25 years old; risk behavior was assessed in confidential, self
      administered questionnaires. Analyses indicated that both stressors effectively
      elicited cortisol increases. Generalized reactivity, defined as a cortisol
      response to both stressors, was inversely associated with deviance (e.g., theft,
      substance use) and with two indicators of sexual risk taking (lifetime number of
      intercourse partners and frequency of condom use). Findings are discussed in
      terms of cross-situational consistency of stress responses, the utility of stress
      reactivity for understanding individual differences in risk taking, and the
      interpretive limitations imposed by study design.

PMID- 12488107
TI  - Testosterone and prolactin are associated with emotional responses to infant
      cries in new fathers.
AB  - To determine the responsiveness of new fathers and non-fathers toward infant
      cues, we exposed fathers and non-fathers to infant cries and to control stimuli
      and we measured affective, heart-rate, and endocrine responses, including
      salivary testosterone and cortisol and plasma prolactin concentrations prior to
      and after cry presentations. We found that (1) fathers hearing the cry stimuli
      felt more sympathetic and more alert compared to groups who did not hear the
      cries or to non-fathers who heard the cries; (2) fathers and non-fathers with
      lower testosterone levels had higher sympathy and/or need to respond to the
      infant cries than fathers with higher testosterone levels; (3) fathers with
      higher, as opposed to lower, prolactin levels were also more alert and more
      positive in response to the cries; (4) fathers hearing the cry stimuli showed
      greater percentage increase in testosterone than fathers not hearing the cry
      stimuli; (5) experienced fathers hearing the cries showed a greater percentage
      increase in prolactin levels compared to first-time fathers or to any group of
      fathers hearing control stimuli; finally, (6) partial correlations with parity
      and experience entered as a covariates indicated that both experience and
      testosterone contributed to the variance in fathers' affective responses to
      infant cries. Taken together, these results indicate that, as with a number of
      other biparental species, human fathers are more responsive to infant cues than
      are non-fathers and fathers' responses to infant cues are related to both
      hormones and to caregiving experience.

PMID- 12488108
TI  - Statistical analysis of hormonal influences on arousal measures in ovariectomized
      female mice.
AB  - In a previous article (J. Frohlich, M. Morgan, S. Ogawa, L. Burton, and D. Pfaff,
      2001, Horm. Behav. 39, 39-47) an experiment to explore the structure of
      behavioral arousal in female mice was described. The present study extends this,
      to investigate the roles of thyroid hormone and estradiol in altering the
      statistical structure of arousal measures. Each of four groups of ovariectomized
      female mice was administered either thyroxine (T4), estradiol benzoate (EB), both
      (T4 + EB), or neither (control). They were then subjected to the same rigid
      protocol of tests bearing on arousal concepts used in our previous study. T4
      treated mice manifested significantly increased freezing behavior relative to
      control mice in a fear-conditioning paradigm. When compared with EB mice, T4
      treated mice evinced significantly increased acoustic startle and open-field
      behavior. T4 mice were also significantly more active in the open field than EB +
      T4-treated mice. Mice administered EB demonstrated significantly decreased
      acoustic startle and open-field performance than controls. Evidence for increased
      anxiety in the open-field test was obtained in the EB condition. Factor and
      cluster analysis indicated the statistical structure of arousal measures to be
      reasonably robust across hormonal conditions. Hormone effects on arousal
      components are of interest because of their likely contributions to emotional
      states and cognitive performance.

PMID- 12488109
TI  - Salivary hormone concentrations in mothers and fathers becoming parents are not
      correlated.
AB  - A time- and date-matched set of saliva samples (N = 229) from nine couples first
      expecting, and then caring for, their first child were used to test whether
      hormone changes in the father could be predicted by the hormonal status of the
      mother. Testosterone, cortisol, and estradiol were quantified from saliva.
      Neither testosterone nor estradiol concentration was correlated within couples
      before or after the birth, although there was a positive correlation for cortisol
      concentration in the mother and father before the birth. As the hormone that
      might be influenced by chemical signals, that already played a similar role in
      men and women, and that had been empirically linked to paternal behavior,
      cortisol concentration was also compared with sex steroid concentrations. The
      mother's cortisol concentration was positively correlated to the father's
      testosterone concentration, and the mother's testosterone concentration was
      positively correlated with the father's cortisol concentration. However, both
      effects were similar in magnitude to the cortisol to cortisol correlation, and
      all could parsimoniously be explained by similar responses to a shared
      environment. Thus, this analysis rejects parallels in peripheral hormone
      concentrations of estradiol, testosterone, and cortisol in mothers and fathers.
      However, the available data were not able to test or reject hypotheses about
      local neuroendocrine homology, nor to control for masking effects of other
      hormonal demands on men and women, nor to determine the relative importance of
      shared environment versus mother-father signaling.

PMID- 12488110
TI  - Prenatal stress alters seizure thresholds and the development of kindled seizures
      in infant and adult rats.
AB  - Stressful events during gestation and in the neonatal period have important
      effects on the later physical and mental health of the offspring. The present
      study tested the hypothesis that pre- and/or postnatal stress would affect
      seizure susceptibility in infant and adult rats, using the hippocampal kindling
      model. Prenatal stress consisted of daily restraint of the dam under bright light
      (for 45 min, 3 x / day) during either early gestation or mid/late gestation. Pups
      were compared to pups born to unstressed dams. Postnatal stress (administered on
      Days 4 and 5 after birth) consisted of either separation from the dam and
      placement in the bedding of a strange male for 1 h or injection of dexamethasone.
      Pups were compared to nonstressed siblings of the same litter. Both early and
      mid/late-gestation prenatal stress significantly lowered the after-discharge
      threshold (ADT) in infant, 14-day-old rat offspring, as compared to nonstressed
      control offspring. This effect on ADT was lost by adulthood. Mid/late-gestation
      stress increased the rate of kindled seizure development in infant rats and in
      their adult male, but not female, siblings. Postnatal stress had no significant
      effect on ADT or kindling rate. These findings indicate that prenatal stress,
      particularly during the latter half of pregnancy, may play an important role in
      increasing seizure vulnerability in the unborn offspring. These effects are more
      pronounced in infancy, but can also extend to adulthood.

PMID- 12488111
TI  - Testosterone rapidly reduces anxiety in male house mice (Mus musculus).
AB  - Eight experiments supported the hypotheses that reflexive testosterone release by
      male mice during sexual encounters reduces male anxiety (operationally defined in
      terms of behavior on an elevated plus-maze) and that this anxiolysis is mediated
      by the conversion of testosterone to neurosteroids that interact with GABA(A)
      receptors. In Experiment 1, a 10-min exposure to opposite-sex conspecifics
      significantly reduced both male and female anxiety 20 min later (as indexed by
      increased open-arm time on an elevated plus-maze) compared to control mice not
      receiving this exposure. In contrast, locomotor activity (as indexed by enclosed
      arm entries on the elevated plus-maze) was not significantly affected. The
      remaining experiments examined only male behavior. In Experiment 2, exposure to
      female urine alone was anxiolytic while locomotor activity was not significantly
      affected. Thus, urinary pheromones of female mice likely initiated the events
      leading to the male anxiolysis. In phase 1 of Experiment 3, sc injections of 500
      microg of testosterone significantly reduced anxiety 30 min later while locomotor
      activity was not significantly affected. Thus, testosterone elevations were
      associated with reduced male anxiety and the time course consistent with a
      nongenomic, or very rapid genomic, mechanism of testosterone action. In phase 2
      of Experiment 3, the anxiolytic effect of testosterone was dose dependent with a
      250 microg sc injection required. Thus, testosterone levels likely must be well
      above baseline levels (i.e., in the range induced by pulsatile release) in order
      to induce anxiolysis. In Experiment 4, a high dosage of 5alpha
      dihydrotestosterone was more anxiolytic than a high dosage of estradiol benzoate,
      suggesting that testosterone action may require 5alpha-reduction. In Experiments
      5 and 6, 3alpha,5alpha-reduced neurosteroid metabolites of testosterone
      (androsterone and 3alpha-androstandione) were both anxiolytic at a lower dosage
      (100 microg/sc injection) than testosterone, supporting the notion that
      testosterone is converted into neurosteroid metabolites for anxiolytic activity.
      Experiments 7 and 8 found that either picrotoxin or bicucculine, noncompetitive
      and competitive antagonists of the GABA(A) receptor, respectively, blocked the
      anxiolytic effects of testosterone. However, conclusions from these 2 experiments
      must be tempered by the reduction in locomotor activity that was also seen. The
      possible brain locations of testosterone action as well as the possible adaptive
      significance of this anxiolytic response are discussed.

PMID- 12488112
TI  - Cyclic estradiol treatment normalizes body weight and restores physiological
      patterns of spontaneous feeding and sexual receptivity in ovariectomized rats.
AB  - Hypothalamic-pituitary-gonadal axis function strongly influences feeding and body
      weight in cycling females in many species. To test the sufficiency of cyclic
      variations in plasma estradiol to reproduce normal patterns of spontaneous
      feeding, food intake, and body weight, ovariectomized Long-Evans rats were
      subcutaneously injected every fourth day with 2 microg estradiol benzoate or with
      the oil vehicle alone. Cyclic estradiol treatment completely normalized the
      trajectory of body weight gain and total food intake through seven treatment
      cycles. The hyperphagia of ovariectomized rats was expressed as an increase in
      spontaneous meal size. Meal frequency decreased, but not enough to compensate for
      the increase in meal size. Estradiol treatment normalized both parameters. In
      addition, cyclic estradiol treatment produced a further phasic decrease in meal
      size (and increase in meal frequency) and a decrease in food intake during the
      second night after injection. This phasic change is similar to the feeding
      changes occurring during estrus in intact rats. Sexual receptivity was measured
      during the eighth estradiol treatment cycle, 4 h after injection of 0.5 mg
      progesterone. Lordosis scores at the time of the treatment cycle modeling estrus
      were maximal, and scores at the time modeling diestrus were slightly increased
      over those of rats that did not receive estradiol. Finally, plasma estradiol
      levels, measured during the ninth treatment cycle, revealed a near-normal cyclic
      pattern of plasma estradiol levels. These results provide the first demonstration
      that the induction of a cyclic, near-physiological pattern of plasma estradiol is
      sufficient to maintain normal levels of body weight, spontaneous feeding
      patterns, total food intake, and (together with progesterone) sexual receptivity
      in ovariectomized rats.

PMID- 12488113
TI  - Prenatal stress alters reproductive responses of rats in behavioral estrus and
      paced mating of hormone-primed rats.
AB  - Adult female offspring of dams exposed to gestational stress (prenatal stress,
      PNS) may show altered reproductive behavior, exploration in novel environments,
      and/or social interactions than do their non-PNS counterparts. These behavioral
      differences may be more readily observed in a seminatural, paced mating paradigm,
      in which females have greater control of their sexual contacts, than in a
      standard mating situation. Adult offspring of dams exposed to restraint and
      lights for 45 min on Gestational Days 14-20 (PNS) were compared with those not
      subjected to stress (non-PNS, control condition). The motor, reproductive, and
      sociosexual behaviors of hormone-primed (Experiment 1) or cycling adult offspring
      in behavioral estrus (Experiment 2) were examined following 20 min of restraint
      stress under bright lights (postnatal stress). Hormone-primed PNS rats displayed
      less motor behavior in a novel arena than did non-PNS rats. In a standard mating
      test, hormone-primed PNS females tended to be more aggressive toward the male
      than were non-PNS rats. In a seminatural mating situation, hormone-primed PNS
      females showed increased avoidance behavior, such as longer latencies to the
      initial intromission, greater return latencies following mounts and
      intromissions, and more exiting subsequent to mounts and intromissions, than did
      non-PNS rats. PNS rats in behavioral estrus had decreased incidence and intensity
      of lordosis, and fewer solicitation behaviors, in both standard or paced mating
      situations, in which latency to and number of mounts were also increased. Thus,
      hormone-primed PNS rats exposed to restraint showed more avoidance behaviors in
      paced mating situations, while cycling PNS rats in behavioral estrus had greater
      disruption of reproductive responses in standard or paced mating paradigms than
      did non-PNS control rats.

PMID- 12488114
TI  - Estrogen receptor alpha influences socially motivated behaviors.
AB  - Male mice lacking estrogen receptor alpha (ERalphaKO) show reduced social
      behaviors. We hypothesized that this might be due to either socially elicited or
      generalized anxiety. Male ERalphaKOs and wild type (WT) mice were given a series
      of behavioral tests: elevated plus maze, T-maze, and social recognition. Each
      test included a social dimension by exposing males to ovariectomized (OVX)
      females. In addition plasma concentrations of corticosterone were measured, and
      open field activity was assessed. In the elevated plus maze, WT males exposed to
      an OVX female 1 min prior to the test were more anxious than WT controls.
      ERalphaKO males showed anxiety in this test whether or not they were preexposed
      to a female. In the T-maze, WT males increased exploration of a novel arm when it
      contained an OVX female. The presence or absence of a female in a novel arm did
      not affect behavior of ERalphaKO males. In social recognition tests, ERalphaKO
      males spent less time than WT littermates investigating an OVX female that was
      repeatedly introduced into their home cage. On the final trial, when a novel
      female was introduced, WT males increased their chemo-investigation but
      ERalphaKOs did not. Plasma corticosterone levels were lower in ERalphaKO than in
      WT males when plasma was taken directly after a brief (control) cage disturbance.
      In the open field WT and ERalphaKO males behaved essentially the same. Taken
      together, the results of these experiments suggest the ERalphaKO males avoid
      contact with other conspecifics, perhaps due to an inability to be aroused by
      social cues.

PMID- 12488115
TI  - Relative lengths of fingers and toes in human males and females.
AB  - Digital scans of the hands and feet were obtained from 62 heterosexual females
      and 60 heterosexual males. Scans only of the hands were obtained from 29
      homosexual females and 35 homosexual males. The lengths of the individual fingers
      and toes were estimated from those images by two experienced judges, and length
      ratios were constructed for all possible pairs of fingers (or toes) on each hand
      (or foot). Thumbs were not measured, but the great toe was measured and used to
      construct length ratios. Past research had concentrated on the relative lengths
      of the index and ring fingers (the 2D:4D ratio). This ratio is close to 1.0 in
      females and smaller than 1.0 in males. Here 2D:4D did exhibit the largest sex
      difference, for both hands, followed by 2D:5D and 3D:4D. The sex differences were
      larger for the right hand than for the left. For both homosexual females and
      homosexual males, nearly all of the length ratios for fingers were intermediate
      to those for heterosexual females and heterosexual males; that is, the ratios of
      homosexual females were masculinized and those of homosexual males were
      hypomasculinized, but few of these differences were significant. Because many
      toes were substantially arched, acceptable estimates of length often could not be
      obtained from the two-dimensional scans, meaning that conclusions about toes are
      much less certain than those for fingers. Nevertheless, the length ratios were
      generally larger for toes than for fingers, and the sex differences were
      generally smaller for toes.

PMID- 12488116
TI  - Cognitive predictors of posttraumatic stress disorder in children: results of a
      prospective longitudinal study.
AB  - The present study explored whether cognitive factors specified in the Ehlers and
      Clark model (Behav. Res. Ther. 38 (2000) 319) of posttraumatic stress disorder
      (PTSD) predict chronic PTSD in children who had experienced a road traffic
      accident. Children were assessed at 2 weeks, 3 months, and 6 months after the
      accident. Data-driven processing during the accident, negative interpretation of
      intrusive memories, alienation from other people, anger, rumination, thought
      suppression and persistent dissociation at initial assessment predicted PTSD
      symptom severity at 3 and 6 months. On the basis of sex and stressor severity
      variables, 14% of the variance of PTSD symptoms at 6 months could be explained.
      The accuracy of the prediction increased to 49% or 53% when the cognitive
      variables measured at initial assessment or 3 months, respectively, were taken
      into account.

PMID- 12488117
TI  - Two different types of obsession: autogenous obsessions and reactive obsessions.
AB  - We propose that obsessions are categorized into two subtypes, i.e. autogenous
      obsessions and reactive obsessions, which are different in terms of
      identifiability of their evoking stimuli, subjective experiences, contents, and
      subsequent cognitive processes. Autogenous obsessions tend to come abruptly into
      consciousness without identifiable evoking stimuli, which are perceived as ego
      dystonic and aversive enough to be repelled, and include sexual, aggressive, and
      immoral thoughts or impulses. On the other hand, reactive obsessions are evoked
      by identifiable external stimuli, which are perceived as relatively realistic and
      rational enough to do something toward the stimuli, and include thoughts about
      contamination, mistake, accident, asymmetry, loss, etc. Through three empirical
      studies, we confirmed the differences between the two types of obsessional
      intrusion in their frequency, subjective experiences, subsequent appraisal and
      control strategy. In particular, autogenous obsessions led to high appraisal on
      'control over thought' and 'importance of thought' and frequent use of 'avoidant
      control strategies', while reactive obsessions linked with high appraisal on
      'responsibility' and frequent use of 'confrontational control strategies'. These
      findings are expected to provide a basis for classifying and explaining the
      heterogeneous phenomena of obsessive-compulsive disorder.

PMID- 12488118
TI  - Behavioral treatment of insomnia in older adults: an open clinical trial
      comparing two interventions.
AB  - Fifty-five insomniacs, 60 years or above, participated in a behavioral treatment
      program, comparing two interventions (sleep hygiene+stimulus control vs sleep
      hygiene+relaxation tape). Half of the subjects were randomized to a waiting-list
      condition prior to treatment. No significant changes were observed during the
      waiting-list period. During the treatment period however, the subjects improved
      on several sleep parameters, and treatment gains were maintained at a 6-month
      follow-up. The effects of treatment were greater for nocturnal measures (e.g.
      sleep onset latency and total sleep time) as compared to daytime measures (e.g.
      life satisfaction, daytime alertness) and not-targeted behavior (medication use).
      There were no differences in treatment effects for the two interventions.

PMID- 12488119
TI  - Posttraumatic stress disorder in the emergency room: exploration of a cognitive
      model.
AB  - Ehlers and Clark (Behav. Res. Ther., 38 (2000) 319) recently proposed a cognitive
      model of posttraumatic stress disorder (PTSD). In this study, we examined two
      facets of this model, appraisal and peritraumatic dissociation, in the context of
      a hospital emergency room. Fifty-one emergency room personnel completed
      questionnaires measuring posttraumatic stress symptoms, interpretations of
      traumatic events experienced while working in the emergency room and subsequent
      intrusive recollections, and peritraumatic dissociation. Twelve percent of
      participants met formal diagnostic criteria for PTSD, and 20% met PTSD symptom
      criteria. As predicted, both negative appraisals of the trauma and of intrusive
      recollections were associated with increased PTSD severity. Although
      peritraumatic dissociation did not correlate with overall PTSD symptom severity,
      it was associated with the reexperiencing symptom cluster. Discussion focuses on
      the factors associated with PTSD in emergency room professionals and implications
      for intervention.

PMID- 12488120
TI  - Peritraumatic dissociation and posttraumatic stress after pregnancy loss: a
      prospective study.
AB  - This study examined (1). predictors for peritraumatic dissociation, (2). its
      relations with acute and chronic symptoms of posttraumatic stress disorder
      (PTSD), and (3). pathways regarding these relations in response to pregnancy
      loss. In early pregnancy, about 1370 women volunteers completed questionnaires
      for neuroticism, control over emotions, dissociative tendencies, absorption, and
      prior life events. Of these, 126 subsequently experienced pregnancy loss and most
      of them completed measures 1 month (N = 118) and 4 months (N = 104) later. At 1
      month, peritraumatic dissociation, memory of pregnancy loss (degree of
      fragmentation, sensory impressions, and emotional intensity), thought
      suppression, and PTSD symptoms were assessed, and at 4 months, PTSD symptoms were
      re-assessed. Peritraumatic dissociation was predicted by prior low control over
      emotions, dissociative tendencies, and lower education. It was not predicted by
      neuroticism, absorption, and prior life events. Peritraumatic dissociation was
      related to acute PTSD symptoms and LISREL analyses indicated that self-reported
      memory fragmentation and thought suppression of pregnancy loss mediated this
      relation. It also predicted chronic PTSD symptoms, and this relation was mediated
      by acute PTSD symptoms.

PMID- 12488121
TI  - A controlled evaluation of cognitive behavioural therapy for posttraumatic stress
      in motor vehicle accident survivors.
AB  - Seventy-eight motor vehicle accident survivors with chronic (greater than 6
      months) PTSD, or severe sub-syndromal PTSD, completed a randomized controlled
      comparison of cognitive behavioral therapy (CBT), supportive psychotherapy
      (SUPPORT), or a Wait List control condition with two detailed assessments. Scores
      on the CAPS showed significantly greater improvement for those in CBT in
      comparison to the Wait List and to the SUPPORT conditions. The SUPPORT condition
      in turn was superior (p=0.012) to the Wait List. Categorical diagnostic data
      showed the same results. An analysis of CAPS scores including drop-outs (n=98)
      also showed CBT to be superior to Wait List and to SUPPORT with a trend for
      SUPPORT to be superior to Wait List. The CBT condition led to significantly
      greater reductions in co-morbid major depression and GAD than the other two
      conditions. Results held up well at a 3-month follow-up on the two active
      treatment conditions.

PMID- 12488122
TI  - How to suppress obsessive thoughts.
AB  - Thought suppression (i.e. consciously trying to avoid certain thoughts from
      entering consciousness) has been argued to be an inadequate strategy in case of
      unwanted intrusions. That is, thought suppression seems to result in more rather
      than less intrusions. Although this experimental finding has been explained in
      terms of failing attempts to distract oneself from the target thought, the White
      Bear Suppression Inventory (WBSI; a scale that measures chronic thought
      suppression tendencies) does not address the means by which respondents try to
      suppress unwanted thoughts. To examine which strategies of mental control people
      use to suppress unwanted thoughts, obsessive-compulsive disorder patients (N=47)
      completed the WBSI, the Thought Control Questionnaire, and two measures of
      psychopathology. Results suggest that the crucial mechanism in thought
      suppression may not be distraction, but self-punishment.

PMID- 12488123
TI  - The influence of comorbidity on treatment outcome for children and adolescents
      with anxiety disorders.
AB  - There have been a growing number of studies showing that cognitive behavioural
      treatment packages for children with anxiety disorders are highly effective.
      Clinically, it is often assumed that treatment outcome is less successful, or
      that treatment needs to be altered when faced with the existence of comorbid
      conditions. To date, only one study has directly addressed this question in the
      child anxiety literature. The present study compared the treatment outcome and
      maintenance following a brief, group program for the reduction of child and
      adolescent anxiety disorders in anxious children with versus without comorbid
      disorders. There was no significant difference in response to treatment at the
      end of the program and few differences at 12-month follow-up. The only indication
      of an impact of comorbidity was a suggestion that children with a comorbid
      condition did not do as well at follow-up. However, this result was only shown on
      some parent-report measures and not on self-report measures. Overall, the results
      indicate that treatment for child and adolescent anxiety disorders produces
      broadly comparable results regardless of the existence of comorbid disorders.

PMID- 12488124
TI  - Fear information and social phobic beliefs in children: a prospective paradigm
      and preliminary results.
AB  - This paper presents a first attempt to develop a prospective paradigm to test
      Rachman's (Behav. Res. Ther. 15 (1977) 375) theory of fear acquisition for social
      fears. Following the prospective paradigm for animal fears developed by Field et
      al. (Behav. Res. Ther. 39 (2001) 1259) an attempt is made to adapt this paradigm
      to look at the effect of fear information in the development of social fears. A
      large group of normal children (N=135) who were at an age (10-13 years) at which
      social concerns are most pertinent were tested using this paradigm. They were
      given positive, negative or neutral information about three social situations:
      public speaking, eating in public, and meeting a new group of children.
      Children's fear beliefs were measured before and after the information was given
      and the information was given by a teacher, a same age peer or no information was
      given (a control). The results indicate that although information can change
      social fear beliefs it is dependent upon the type of social activity and who
      provides the information. The implications of these initial results for our
      understanding of both the role of fear information in the development of social
      fear beliefs, and the limitations of this current paradigm are discussed.

PMID- 12488129
TI  - Progress in the analysis of urinary oxidative DNA damage.
AB  - Oxidative DNA damage has been implicated to be important in the pathogenesis of
      many diseases, including cancer and heart disease. The assessment of damage in
      various biological matrices, such as DNA, serum, and urine, is vital to
      understanding this role and subsequently devising intervention strategies.
      Despite the numerous techniques to measure oxidative DNA damage products in
      urine, it remains unclear what these measurements truly represent. Sources of
      urinary lesions may include the diet, cell death, and, of most interest, DNA
      repair. Were it possible to exclude the two former contributions, a noninvasive
      assay for DNA repair would be invaluable in the study of DNA damage and disease.
      This review highlights that, although progress has been made, significant work
      remains. Diet, cell death, and repair need continued examination to further
      elucidate the kinetics of lesion formation and clearance in vivo. Studies from
      our laboratory and others are making appreciable progress towards the
      interpretation of urinary lesion measurements along with the development of
      urinary assays to evaluate DNA repair. Upon establishment of these details,
      urinary oxidative DNA damage measurements may become more than a reflection of
      generalized oxidative stress.

PMID- 12488130
TI  - Effect of high-glucose levels on protein oxidation in cultured lens cells, and in
      crystalline and albumin solution and its inhibition by vitamin B6 and N
      acetylcysteine: its possible relevance to cataract formation in diabetes.
AB  - Diabetic patients have elevated levels of glucose in their blood and other body
      fluids. This project studied the effect of high-glucose concentrations (HG) on
      the protein oxidation in cultured lens cells and in crystalline protein solution.
      In addition, we also examined the effect of HG on the oxidation and turbidity
      (aggregation) of albumin protein solution. This study also examined whether
      vitamin B6 [pyridoxine (P), pyridoxamine (PM)] or n-acetylcysteine (NAC) is
      capable of preventing protein oxidation similar to that seen in cataracts. For
      cell culture studies, rabbit lens cells were cultured in control or HG medium at
      37 degrees C for 2 d. For studies with protein solution, a buffered solution of
      serum albumin or crystalline protein was incubated with normal glucose (5 mM) or
      HG (50-100 mM) in a water bath at 37 degrees C for 4 d. All treatments were
      carried out with and without the addition of P, PM, or NAC. We found
      significantly higher levels of carbonyl protein (an index of protein oxidation)
      in HG-treated compared with normal glucose-treated lens cells and in crystalline
      protein solution. P, PM, and NAC significantly decreased the protein oxidation in
      lens cells and crystalline protein solution. We also found significantly higher
      levels of protein oxidation and turbidity (an index of protein aggregation) and
      its inhibition by P, PM, and NAC in HG-treated compared with normal glucose
      treated albumin solution. This suggests that HG can cause the oxidation and
      modification of proteins in the lens, and that vitamin B6 and NAC supplementation
      may be helpful in slowing the oxidation of lens proteins. This study explains the
      cause of early cataract development and the potential benefit of supplementation
      with vitamin B6 and NAC in the prevention of the development of cataract among
      the diabetic population.

PMID- 12488131
TI  - Chromium(III)-induced apoptosis of lymphocytes: death decision by ROS and Src
      family tyrosine kinases.
AB  - Apoptosis is an active process induced by a variety of physiological and external
      stimuli, in which elimination of damaged cells are effected through a genetically
      controlled process. In this study, we have examined the mechanism of
      chromium(III) [Cr(III)]-induced cytotoxicity with respect to its relationship to
      oxidative stress. Morphology, flow cytometry, and DNA fragmentation studies show
      that tris-(1,10-phenanthroline)chromium(III) [Cr(III)-phen], tris-(2,2'
      bipyridyl)chromium(III) [Cr(III)-bpy], trans-diaqua[1,2
      bis(salicylideneamino)ethanechromium(III)] [Cr(III)-salen], and trans-diaqua[1,3
      bis(salicylideneamino)propanechromium(III)] [Cr(III)-salprn] induced apoptosis of
      lymphocytes. Pentaammineaquachromium(III) [Cr(III)-hpa] does not induce
      apoptosis. Apoptosis induced by these complexes involves the generation of
      reactive oxygen species (ROS) as seen by increased fluorescence of
      dichloroflourescein (DCF) observed through flow cytometry. Pretreatment of
      lymphocytes with antioxidants completely abrogate apoptosis. Cr(III) treatment
      also increased the expression and activation of Src-family tyrosine kinases viz.
      p56lck, p59fyn, and p53/56lyn, as seen by immunoblotting and immune complex
      kinase assay. PP2, a selective Src-family tyrosine kinase inhibitor, abolishes
      apoptosis, indicating that Src-family tyrosine kinases are directly involved in
      eliciting apoptosis. Interestingly, a one-to-one correlation between the
      expression of Src-family tyrosine kinases and ROS is observed, since antioxidants
      pretreatment inhibits the expression and the activation of these kinases. These
      results further indicate that Cr(III)-induced apoptosis is mediated through
      production of ROS, which in turn activates the Src-family tyrosine kinases. The
      increased activation of Src-family tyrosine kinases may be a mechanism involved
      in apoptosis of lymphocytes elicited by various other physiological stimuli that
      exploit ROS as a second messenger.

PMID- 12488132
TI  - Oxidative stress induces the expression of Fas and Fas ligand and apoptosis in
      murine intestinal epithelial cells.
AB  - Intestinal epithelial cell function is compromised by local immune and
      inflammatory responses. In this study, we examined the possibility that
      intestinal epithelial cell injury occurs in the presence of activated
      inflammatory cells, such as neutrophils and macrophages, via production of
      reactive oxygen species (ROS). Following exposure to 50-150 microM H2O2 levels of
      mRNA and protein for Fas and, to a lesser degree, Fas-L were increased and
      intestinal epithelial cells underwent apoptosis. Treatment of H2O2-exposed cells
      with agonistic anti-Fas antibody, but not isotype control antibody, significantly
      enhanced apoptosis. Apoptosis was associated with the activation of caspase 8,
      while Z-IETD, an inhibitor of caspase 8, blocked apoptosis of H2O2-exposed
      intestinal epithelial cells. Thus, ROS induced Fas and Fas-L expression in
      association with intestinal epithelial cell apoptosis. These data support the
      hypothesis that, following exposure to oxidative stress, enterocytes are primed
      for cell death via Fas-mediated pathways.

PMID- 12488133
TI  - Serum protein acrolein adducts: utility in detecting oxidant stress in
      hemodialysis patients and reversal using a vitamin E-bonded hemodialyzer.
AB  - Accumulating evidence indicates that protein modification by acrolein is one of
      the major hallmarks of atherosclerosis. The purpose of the present study was to
      evaluate the serum acrolein-modified protein adduct (Acr) level in end-stage
      renal disease (ESRD), and to elucidate the efficacy of vitamin E-bonded
      hemodialyzer in reducing Acr in a crossover trial. A significant increase in Acr
      was found in ESRD patients compared with healthy controls (p <.001). In ESRD, the
      Acr level of those patients with type 2 diabetes mellitus (DM) was significantly
      higher compared with the non-DM group (p <.05). Forty-one ESRD patients who
      exhibited Acr levels higher than the mean value in ESRD were treated by vitamin E
      bonded hemodialyzer for 6 months. After 6 months of treatment, Acr levels were
      decreased to those found in healthy individuals (p <.001). When hemodialyzers
      were switched back from vitamin E bonded to the original regular ones, Acr levels
      increased to nearly their initial levels after 3 months (p <.001), compared with
      the 6 month time point. These results suggest the potential of Acr as an
      oxidative stress marker in ESRD, and that vitamin E-bonded hemodialyzer treatment
      is a reasonable approach to reduce oxidative stress in ESRD.

PMID- 12488134
TI  - Hemodynamic effects of metalloporphyrin catalytic antioxidants: structure
      activity relationships and species specificity.
AB  - Superoxide plays a role in blood pressure regulation in certain vascular
      diseases, however, its involvement in regulating basal blood pressure is
      uncertain. Vascular superoxide concentrations are limited by extracellular
      superoxide dismutase (EC-SOD), which is highly expressed in the vasculature of
      most animal species. Metalloporphyrins are low molecular weight, synthetic, redox
      active, catalytic antioxidants that act as SOD mimetics. We evaluated the effects
      of metalloporphyrins on blood pressure in different animal species. The
      metalloporphyrin AEOL10113 (5-10 micro /kg iv), but not native or polyethylene
      glycol-CuZnSOD, caused a dose-dependent reduction in blood pressure in
      anesthetized rats. AEOL10113 had no effect on blood pressure in mice (wild-type
      or EC-SOD knockouts), guinea pigs, dogs, or baboons at doses up to 5 mg/kg iv
      Structure-activity studies indicated that metalloporphyrins with high SOD
      activity were more effective in lowering rat blood pressure than low-activity
      analogs. The blood pressure effect of AEOL10113 was not attributable to the
      release of manganese, nor was it affected by inhibitors of nitric oxide synthase
      (L-NAME) and guanylate cyclase (ODQ, 8-bromo-cGMP, and methylene blue) or nitric
      oxide scavengers (HbAo). Chlorpheniramine attenuated the effect, suggesting that
      the blood pressure response in rats is related to histamine release rather than
      the protection of nitric oxide.

PMID- 12488135
TI  - (+)-Catechin inhibits platelet hyperactivity induced by an acute iron load in
      vivo.
AB  - Reactive oxygen species and platelets are thought to be involved in the
      pathogenesis of cardiovascular disease. Epidemiological data have indicated that
      high consumption of fruits and vegetables is associated with a lower incidence of
      vascular events. Polyphenols were proposed to provide such a protection. In the
      present study performed in rats, we investigated the influence of (+)-catechin
      (Cat), a polyphenol identified in tea, cocoa, and red wine, on an acute iron load
      induced model of platelet hyperactivity. We found that platelet function was
      significantly enhanced in iron-loaded rats. These changes were associated with
      impairment of the antioxidative defense including ex vivo free radical-induced
      hemolysis. Pretreatment with Cat (10 mg/kg, ip, 4 d) normalized biomarkers of
      antioxidative status and platelet hyperactivity. The benefits of Cat treatment
      were only observed in iron-loaded animals and not in control animals. In light of
      the known antioxidant properties of Cat (or its metabolites), we suggest that
      oxidative injury-induced modification of platelet calcium homeostasis may have
      explained the iron load-induced platelet hyperactivity. The protective effect of
      Cat appears to work probably through normalization of the antioxidative status.

PMID- 12488136
TI  - Geometrical isomerism of monounsaturated fatty acids: thiyl radical catalysis and
      influence of antioxidant vitamins.
AB  - Thiyl radicals generated either from thiols or disulfides act as the catalyst for
      the cis-trans isomerization of a variety of monounsaturated fatty acid methyl
      esters in homogeneous solution. Similar results have also been obtained using
      alpha-lipoic acid and its reduced form. The effectiveness of the isomerization
      processes in the presence of the most common antioxidants has been addressed. The
      ability of thiyl radical scavenging was found to increase along the series alpha
      tocopherol < ascorbic acid < all-trans retinol. The cis-trans isomerization of
      fatty acid residues in multilamellar vesicles of dioleoyl phosphatidyl choline by
      thiyl radical, in the absence and presence of the various antioxidants, has also
      been studied in detail. The influence of the isomerization process on the
      phospholipid bilayer has been tested by permeability measurements of vesicles and
      it is clearly shown that trans fatty acid-containing membranes have intermediate
      properties between those formed by all-cis and saturated components. This study
      contributes to the understanding of radical processes that can alter or protect
      the naturally occurring cis geometry of unsaturated lipids in cell membranes and
      demonstrates a new role of essential antioxidants.

PMID- 12488137
TI  - Uptake and metabolism of epicatechin and its access to the brain after oral
      ingestion.
AB  - Epicatechin is a flavan-3-ol that is commonly present in green teas, red wine,
      cocoa products, and many fruits, such as apples. There is considerable interest
      in the bioavailability of epicatechin after oral ingestion. In vivo studies have
      shown that low levels of epicatechin are absorbed and found in the circulation as
      glucuronides, methylated and sulfated forms. Recent research has demonstrated
      protective effects of epicatechin and one of its in vivo metabolites, 3'-O-methyl
      epicatechin, against neuronal cell death induced by oxidative stress. Thus, we
      are interested in the ability of ingested epicatechin to cross the blood brain
      barrier and target the brain. Rats were administered 100 mg/kg body weight/d
      epicatechin orally for 1, 5, and 10 d. Plasma and brain extracts were analyzed by
      HPLC with photodiode array detection and LC-MS/MS. This study reports the
      presence of the epicatechin glucuronide and 3'-O-methyl epicatechin glucuronide
      formed after oral ingestion in the rat brain tissue.

PMID- 12488138
TI  - Inhibition of human surfactant protein A function by oxidation intermediates of
      nitrite.
AB  - NitraNitration of protein tyrosine residues by peroxynitrite (ONOO - ) has been
      implicated in a variety of inflammatory diseases such as acute respiratory
      distress syndrome (ARDS). Pulmonary surfactant protein A (SP-A) has multiple
      functions including host defense. We report here that a mixture of hypochlorous
      acid (HOCl) and nitrite (NO 2 - ) induces nitration, oxidation, and chlorination
      of tyrosine residues in human SP-A and inhibits SP-A's ability to aggregate
      lipids and bind mannose. Nitration and oxidation of SP-A was not altered by the
      presence of lipids, suggesting that proteins are preferred targets in lipid-rich
      mixtures such as pulmonary surfactant. Moreover, both horseradish peroxidase and
      myeloperoxidase (MPO) can utilize NO 2 - and hydrogen peroxide (H 2 O 2 ) as
      substrates to catalyze tyrosine nitration in SP-A and inhibit its lipid
      aggregation function. SP-A nitration and oxidation by MPO is markedly enhanced in
      the presence of physiological concentrations of Cl - and the lipid aggregation
      function of SP-A is completely abolished. Collectively, our results suggest that
      MPO released by activated neutrophils during inflammation utilizes physiological
      or pathological levels of NO 2 - to nitrate proteins, and may provide an
      additional mechanism in addition to ONOO - formation, for tissue injury in ARDS
      and other inflammatory diseases associated with upregulated *NO and oxidant
      production.

PMID- 12488139
TI  - Catalysis of catechol oxidation by metal-dithiocarbamate complexes in pesticides.
AB  - Dithiocarbamate (DTC)-based pesticides have been implicated in Parkinson's
      disease (PD) through epidemiological links to increased risk of PD, clinical
      reports of parkinsonism following occupational exposure to the DTC-based
      pesticide maneb, and experimental studies showing dopaminergic neurodegeneration
      with combined exposure of rats to maneb and paraquat. We hypothesize that the
      manganese-ethylene-bis-dithiocarbamate (MnEBDC) complex in maneb may produce
      oxidative stress by catalyzing catechol oxidation. We tested this hypothesis by
      performing a structure-function analysis of metal-EBDC and metal
      diethyldithiocarbamate (DEDC) complexes of Mn2+, Zn2+, and Cu2+ to catalyze
      oxidation of N-acetyldopamine (NA-DA) and 3,4-dihydroxyphenylacetic acid (DP) in
      the presence and absence of N-acetylcysteine (NAC), a model of glutathione. Both
      Mn-DTCs retained the capacity of the parent ion to catalyze one-electron
      oxidation of NA-DA, but lost the ability to catalyze DP oxidation. Strikingly,
      while Zn2+ did not catalyze catechol oxidation, both Zn-DTCs catalyzed one
      electron oxidation of NA-DA but not DP. While Cu2+ catalyzed oxidation of both
      catechols, Cu-DTCs were inert. Similar results were obtained with MnEBDC and
      dopamine or norepinephrine; however, zinc-ethylene-bis-dithiocarbamate was less
      efficient at catalyzing oxidation of these catechols. Our results point to the
      potential for manganese- and zinc-containing EBDC pesticides to promote oxidative
      stress in catecholaminergic regions of the brain.

PMID- 12488140
TI  - Design, synthesis, and antioxidant activity of FeAOX-6, a novel agent deriving
      from a molecular combination of the chromanyl and polyisoprenyl moieties.
AB  - Several lines of evidence suggest potential benefits by a combination of
      carotenoids and tocopherols in chronic diseases. Therefore, we have designed
      FeAOX-6, a novel antioxidant that combines into a single molecule the chroman
      head of tocopherols and a fragment of lycopene, consisting of a polyisoprenyl
      sequence of four conjugated double bonds. The ability of FeAOX-6 in inhibiting
      lipid peroxidation and reactive oxygen species (ROS) production induced by
      different sources of free radicals (t-BOOH, AAPH, and H2O2) in arachidonic acid
      solution and in isolated thymocytes was investigated. Its antioxidant efficiency
      was also compared with that of alpha-tocopherol, lycopene, and a mixture of the
      two antioxidants. The results strongly suggest that FeAOX-6 can act as a potent
      antioxidant in our models, by inhibiting malondialdehyde production and ROS
      generation in a dose- and a time-dependent manner. In the cell model, the
      compound also provides a higher antioxidant capacity than alpha-tocopherol and
      lycopene, alone or in combination, suggesting the possibility of an oxidative
      intramolecular cooperation.

PMID- 12488141
TI  - Pair-wise linear and 3D nonlinear relationships between the liver antioxidant
      enzyme activities and the rate of body oxygen consumption in mice.
AB  - Relationships between the rate of body oxygen consumption (VO2) and the liver key
      antioxidant enzyme activities were assessed in female CBA mice. The pair-wise
      linear regression and correlation demonstrated significant correlative links
      between VO2 and activity of catalase (CAT). Nonlinear 3D plotting revealed a
      complementary pattern of CAT and glutathione peroxidase (GP) relation. CAT
      activity was elevated in mice with proportionally high VO2 and superoxide
      dismutase (SOD), whereas GP activity was high in animals with low or
      disproportional VO2 and SOD.

PMID- 12488142
TI  - Breast cancer-treatment for the future based on lessons from the past.

PMID- 12488143
TI  - Advances in the surgical management of sarcomas in children.
AB  - The management of children with soft tissue sarcomas has changed and survival has
      improved markedly during the past three decades. This is, in large part, due to
      the multi-modal approach to pediatric malignancies; decreasing the need for
      radical surgical procedures, while improving survival and decreasing morbidity.
      The management of patients with rhabdomyosarcomas (RMS) and nonrhabdomyosarcomas
      soft-tissue sarcomas (NRSTS) as well as neurofibromatosis and related tumors is
      best accomplished in an organized and systematic fashion with the surgeon
      involved early in the planning, diagnostic, and treatment phases. Cooperative
      trials for rhabdomyosarcoma, as part of the Intergroup Rhabdomyosarcoma Study,
      have led to improved survival with less radical surgery. Ongoing trials of the
      Soft Tissue Sarcoma Group of the Children's Oncology Group are under way. Since
      these tumors are rare, cooperative trials are essential to answering the
      remaining questions regarding extent of surgery and adjuvant therapy.

PMID- 12488144
TI  - Frequency of sentinel lymph node metastases in patients with favorable breast
      cancer histologic subtypes.
AB  - BACKGROUND: The need for axillary nodal staging in favorable histologic subtypes
      of breast cancer is controversial. METHODS: Patients with clinical stage T1-2, N0
      breast cancer were enrolled in a prospective, multi-institutional study. All
      patients underwent sentinel lymph node (SLN) biopsy followed by completion level
      I/II axillary dissection. RESULTS: SLN were identified in 3,106 of 3,324 patients
      (93%). Axillary metastases were found in 35% and 40% of patients with
      infiltrating ductal carcinoma and infiltrating lobular carcinoma, respectively.
      Among tumor subtypes, positive nodes were found in 17% of patients with pure
      tubular carcinoma, 7% of patients with papillary cancer, 6% of patients with
      colloid (mucinous) carcinoma, 21% of patients with medullary carcinoma, and 8% of
      patients with DCIS with microinvasion. CONCLUSIONS: Patients with favorable
      breast cancer subtypes have a significant rate of axillary nodal metastasis.
      Axillary nodal staging remains important in such patients; SLN biopsy is an ideal
      method to obtain this staging information.

PMID- 12488146
TI  - Reoperation on the abdomen encased in adhesions.
AB  - PURPOSE: To determine outcome after lysis of intestinal adhesions, relief of
      obstruction, closure of fistulas and drainage of abscesses in patients with an
      abdominal cavity obliterated by chronic postoperative adhesions. METHODS: Among
      40 patients with an abdomen encased in dense adhesions after a mean of 5 previous
      operations, 31 patients also had intestinal obstruction, 25 enteric fistulas and
      20 abdominal abscesses. Reoperation was done and outcome assessed from the
      medical records and by a mailed questionnaire. RESULTS: Only 1 postoperative
      death occurred, but 24 early complications appeared. At hospital discharge,
      obstruction, fistula and abscess were completely resolved in all but 3 patients
      (P <0.001). Only 2 of 16 patients on parenteral nutrition before operation (TPN)
      still required it (P = 0.004). At late follow-up (mean, 4.6 years) the patients'
      quality of life (mean score +/- SD, 8.6 +/- 2.1) was similar to that of a healthy
      control population (9.2 +/- 1.2, P = 0.17). CONCLUSIONS: Reoperation on the
      abdomen encased in adhesions restores most patients to good health and an
      excellent long-term quality of life.

PMID- 12488148
TI  - Is laparoscopic umbilical hernia repair with mesh a reasonable alternative to
      conventional repair?
AB  - BACKGROUND: Laparoscopic mesh repair has been advocated as treatment of choice
      for ventral hernias. The term "ventral hernia" refers to a variety of abdominal
      wall defects and laparoscopic papers have not reported defect specific analysis.
      The purpose of this study was to determine any advantages to laparoscopic mesh
      repair of umbilical hernias. METHODS: A retrospective review (January 1998 to
      April 2001) was made of patients undergoing umbilical hernia repair. Patients
      were categorized into three groups: laparoscopic repair with mesh, open repair
      with mesh, and open repair without mesh. Comparative analysis was performed.
      RESULTS: One-hundred and sixteen umbilical hernia repairs were performed in 112
      patients: 30 laparoscopic mesh repairs, 20 open mesh repairs, and 66 open nonmesh
      repairs. The laparoscopic technique was used for larger defects and took more
      time with a trend toward fewer postoperative complications and recurrences.
      CONCLUSIONS: Laparoscopic umbilical hernia repair with mesh presents a reasonable
      alternative to conventional methods of repair.

PMID- 12488150
TI  - Is thyroid frozen section too much for too little?
AB  - BACKGROUND: The role of frozen section (FS) in thyroid disease is controversial.
      The goal of this study was to identify a cohort of patients who may or may not
      benefit from FS. METHODS: Two hundred thirty-one patients who underwent
      thyroidectomy were evaluated in regard to fine-needle aspiration (FNA), FS, and
      the extent of surgery. RESULTS: In all, 155 patients underwent FNA, 140 patients
      underwent FS, and 103 patients had both. A final diagnosis of malignancy was
      obtained in 47 of 231 patients. FNA had a sensitivity of 50% and a specificity of
      99%, and FS had a sensitivity of 50% and a specificity of 100% for diagnosing
      malignancy. Accounting for the clinical findings and FNA results, FS results
      altered the extent of thyroidectomy in 1 of 103 patients. CONCLUSIONS: The
      increased costs for the operative time and the pathologists needed to obtain
      routine FS are not supported with any substantial benefit in patient outcome.

PMID- 12488152
TI  - Predicting failure of outpatient laparoscopic cholecystectomy.
AB  - BACKGROUND: Outpatient laparoscopic cholecystectomy (LC) is safe and feasible,
      but factors related to the failure of outpatient surgery are poorly defined. We
      hypothesized that patients in whom same day discharge (SDD) is unlikely may be
      identified preoperatively. METHODS: Three hundred eighty-seven consecutive
      patients scheduled for elective LC were prospectively enrolled in an outpatient
      clinical pathway. RESULTS: In all, 269 (70%) patients successfully underwent
      outpatient LC. Factors related to failure of SDD were age, American Society of
      Anesthesiology (ASA) class, surgery start time, and duration of surgery. Body
      mass index, liver function tests, and ultrasound findings did not predict failure
      of SDD. Three factors were able to predict more than 50% failure of SDD: age more
      than 50 years, ASA class 3 or more, and surgery start time later than 1:00 PM.
      CONCLUSIONS: Outpatient LC is feasible in a large county hospital. These data may
      be used in scheduling cases and counseling patients.

PMID- 12488154
TI  - Patterns of early recurrence after sentinel lymph node biopsy for melanoma.
AB  - BACKGROUND: Patterns of early recurrence after sentinel lymph node (SLN) biopsy
      for melanoma was determined from the Sunbelt Melanoma Trial, which includes
      patients with Breslow thickness > or =1.0 mm and nonpalpable regional lymph
      nodes. METHODS: SLN were evaluated by routine histology and S-100 protein stain.
      Overall, there were 1,183 patients with a median follow-up of 16 months. RESULTS:
      SLN were positive in 233 of 1,183 patients (20%). The recurrence rate was greater
      among patients with histologically positive SLN than those with negative SLN
      (15.5% versus 6.0%, respectively, P <0.05). Patients with positive SLN were more
      likely to have distant metastases (as opposed to locoregional recurrence) than
      those with negative SLN (67% versus 46%, respectively, P <0.05). By multivariate
      analysis, SLN status, Breslow thickness, Clark level, and ulceration were
      significant independent factors associated with early recurrence. Of patients
      with negative SLN, 14 of 950 (1.5%) experienced metastatic disease in lymph node
      basins which were staged as negative for tumor by SLN biopsy initially.
      CONCLUSIONS: Early regional lymph node recurrence was very uncommon after
      positive SLN biopsy and completion lymphadenectomy. Patients with positive SLN
      are more likely than those with negative SLN to develop both local/in-transit
      recurrence and distant metastases within a short follow-up period.

PMID- 12488156
TI  - Development of a continuous renal replacement program in critically ill patients.
AB  - BACKGROUND: Critically ill patients encounter many obstacles, such as acute renal
      failure, that increases length of stay as well as hospital cost. Dialysis in
      these patients is often ineffective thereby prolonging the inevitable and
      significantly increasing the cost of care. A dialysis program that could improve
      patient care, potentially improve outcome and be "revenue neutral" would be
      ideal. METHODS: A continuous renal replacement therapy (CRRT) program was
      developed to significantly impact the care of critically ill patients Using the
      latest CRRT equipment along with an innovative hands-on CRRT training program, a
      specialized CRRT team was created. Working in conjunction with the hospital
      business office, new revenue charge codes were created and existing codes were
      updated. Patients who underwent CRRT had their financial records reviewed for:
      hospital cost to perform CRRT, total hospital billing to the payer, CRRT revenue
      881 (billing units) charged to the payer, total charges and reimbursement for the
      account, percentage of reimbursement, collected revenue, and payer. RESULTS: From
      April 2000 to February 2002, 39 critically ill patients underwent CRRT. Initial
      set-up cost was US$79,622.80 and the cost of CRRT was US$222,323.98. The hospital
      billed for US$656,090.63 and assuming 100% reimbursement, the potential profit
      was US$427,678.50. However, loss of revenue, mainly from noncompliance with
      charge capture resulted in the hospital billing only US$386,794.32 with a total
      reimbursement of US$165,779.86. The 21 burn patients who underwent CRRT yielded a
      net profit of US$10,294.12, with the highest reimbursement from workman's
      compensation and private payers. The overall mortality rate was 59% and 65% for
      the burn patients; significantly lower than published national averages.
      CONCLUSIONS: An in-house CRRT program improved patient care by providing dialysis
      in patients who normally would not tolerate the procedure. Although there was a
      loss of revenue, CRRT in the burn patients appeared "revenue neutral." Although
      not specifically studied in this review, based on published data, mortality rates
      in this population were lower than expected especially in critically ill burn
      patients.

PMID- 12488158
TI  - Atypical ductal hyperplasia of the breast diagnosed by 11-gauge directional
      vacuum-assisted biopsy.
AB  - BACKGROUND: Small nonpalpable mammographic abnormalities are frequently diagnosed
      by percutaneous stereotactically guided core needle biopsy. The reliability of
      the histologic diagnosis of atypical ductal hyperplasia (ADH) made from tissue
      obtained by 11-gauge directional, vacuum-assisted biopsy of these nonpalpable
      breast lesions is unknown. METHODS: The records of 31 patients who were found to
      have ADH by 11-gauge directional vacuum-assisted biopsy were reviewed. All of
      these patients subsequently underwent surgical excision with needle localization
      biopsy of the ADH and they are the subjects of this retrospective study. RESULTS:
      Eleven of the 31 patients with ADH on 11-gauge directional vacuum-assisted biopsy
      were upgraded to ductal carcinoma in situ or infiltrating carcinoma by the
      excisional biopsy. This was a 35% underestimation of malignancy in our patients.
      CONCLUSIONS: When the histologic diagnosis of ADH is made from tissue harvested
      by an 11-gauge directional vacuum assisted biopsy, surgical excision of the
      entire abnormality is recommended to avoid underdiagnosis of breast cancer.

PMID- 12488160
TI  - Secondary abdominal compartment syndrome is an elusive early complication of
      traumatic shock resuscitation.
AB  - BACKGROUND: The term secondary abdominal compartment syndrome (ACS) has been
      applied to describe trauma patients who develop ACS but do not have abdominal
      injuries. The purpose of this study was to describe major trauma victims who
      developed secondary ACS during standardized shock resuscitation. METHODS: Our
      prospective database for standardized shock resuscitation was reviewed to obtain
      before and after abdominal decompression shock related data for secondary ACS
      patients. Focused chart review was done to confirm time-related outcomes.
      RESULTS: Over the 30 months period ending May 2001, 11 (9%) of 128 standardized
      shock resuscitation patients developed secondary ACS. All presented in severe
      shock (systolic blood pressure 85 +/- 5 mm Hg, base deficit 8.6 +/- 1.6 mEq/L),
      with severe injuries (injury severity score 28 +/- 3) and required aggressive
      shock resuscitation (26 +/- 2 units of blood, 38 +/- 3 L crystalloid within 24
      hours). All cases of secondary ACS were recognized and decompressed within 24
      hours of hospital admission. After decompression, the bladder pressure and the
      systemic vascular resistance decreased, while the mean arterial pressure, cardiac
      index, and static lung compliance increased. The mortality rate was 54%. Those
      who died failed to respond to decompression with increased cardiac index and did
      not maintain decreased bladder pressure. CONCLUSIONS: Secondary ACS is an early
      but, if appropriately monitored, recognizable complication in patients with major
      nonabdominal trauma who require aggressive resuscitation.

PMID- 12488162
TI  - Ambulatory mastectomy.
AB  - BACKGROUND: Ambulatory mastectomy has been a topic of heated political debate
      with little analysis of clinical data. METHODS: Based on extensive satisfaction
      surveys, an ideal surgical treatment experience was developed that decreased
      nausea, increased preoperative education, and reduced perioperative narcotic
      usage. Using this new algorithm, patients treated by a single surgeon were given
      the choice of overnight stay versus discharge to home with visiting nurse care.
      RESULTS: From March 1 to October 31, 2001, 92 mastectomies or lumpectomy/axillary
      dissections were performed in 87 patients. One patient chose to remain in the
      center overnight. All others were discharged in less than 2.5 hours
      postoperatively. Perioperative complications fell to 20% of those of the prior
      year. Hospital charges fell 79.5%. CONCLUSIONS: Despite lay reservations about
      ambulatory mastectomy, a detailed approach can result in markedly reduced health
      care costs without incurring additional morbidity or mortality.

PMID- 12488164
TI  - Percutaneous excisional breast biopsy.
AB  - BACKGROUND: The utility of the vacuum-assisted breast biopsy device (VABB) under
      stereotactic guidance is well established. We hypothesized that the complete
      removal of small benign lesions under ultrasonography guidance in an outpatient
      setting could be obtained with minimal morbidity with the multidirectional hand
      held vacuum-assisted biopsy. METHODS: Patients enrolled in this study underwent
      an ultrasound-guided minimally invasive excisional breast biopsy through a 3-mm
      incision. Removal of the abnormality was accomplished with a handheld 8- or 11
      gauge Mammotome. RESULTS: Eighty-one patients had 101 lesions excised. The
      average (+/- SD) age of the participants was 46.8 +/- 15.4 years. The average
      size of the lesions was 1.15 +/- 0.43 cm (range 0.5 cm to 2.0 cm). Ninety-four
      lesions (93%) had benign pathology, five lesions (5%) were malignant, and two
      (2%) lesions had atypical hyperplasia. Six-month baseline mammogram performed in
      71% of patients more than 40 years old documented resolution of percutaneously
      removed lesions. CONCLUSIONS: Vacuum-assisted excisional breast biopsy under
      ultrasound guidance is an effective technique for the therapeutic management of
      benign lesions.

PMID- 12488166
TI  - Is hypotension a reliable indicator of blood loss from traumatic injury in
      children?
AB  - BACKGROUND: Traditional surgical teaching stresses that hypotension is an
      indicator of loss of circulating blood volume. The purpose of this study is to
      critically evaluate hypotensive injured children for evidence of a hemorrhagic
      insult. METHODS: Over a 2-year period, data were collected prospectively from
      children injured via a blunt mechanism. Systolic blood pressure (SBP) was
      recorded in the field and on arrival to the emergency department. RESULTS: In
      all, 194 injured children were identified as hypotensive. Only 82 (42%) had
      identifiable injuries to account for significant volume loss. Children 0 to 5
      years old had a 61% incidence of isolated head injury (46 of 76) and only a 34%
      incidence of hemorrhagic insult (26 of 76). Children 6 to 12 years old had a 31%
      incidence of isolated head injury (22 of 72) and a 52% incidence of hemorrhagic
      insult (38 of 72). Finally, patients more than 12 years old had a 33% incidence
      of isolated head injury (15 of 46) and a 39% incidence of hemorrhagic insult (18
      of 46). CONCLUSIONS: Hypotension should not be viewed only as a potential marker
      of loss of circulating volume, but also as a possible indicator of head injury in
      young trauma victims.

PMID- 12488168
TI  - Mid-term results of patients undergoing endovascular aortic aneurysm repair.
AB  - BACKGROUND: The utilization of endovascular aneurysm repair (EAR) is increasing
      significantly; however, few papers have outlined mid-term outcomes. METHODS:
      Patients undergoing EAR with an AneuRx endograft between September 1997 and May
      2001 were evaluated. Mean follow-up was 20.7 +/- 11.9 (SD) months. RESULTS: In
      all, 101 EAR devices were successfully deployed in 105 attempts. Four open
      conversions (2 acute, 2 delayed) were performed for complications of EAR.
      Technical, clinical, and 1 to 3 year continuing success rates were 75%, 73%, and
      78% to 83%. When divided by the median date, significantly fewer patients in the
      later group required secondary procedures compared with the early group. Vascular
      insufficiency occurred in 12 patients; 11 were treated with a secondary
      procedure. For 9 type I and 9 type II persistent endoleaks, secondary procedures
      were attempted and successful in 10 patients. Of successful EAR deployments,
      including secondary interventions, 85% demonstrated no persistent leak, rupture,
      increase in aneurysm size, or migration at most recent follow-up. CONCLUSIONS:
      EAR is successful in selected individuals; however, continuing follow-up is of
      paramount importance.

PMID- 12488170
TI  - Vascular ultrasonography prior to dialysis access surgery.
AB  - BACKGROUND: Native arterial venous fistulas (NAVF) are generally considered
      preferable to synthetic grafts for chronic dialysis access. As increasing numbers
      of diabetic and elderly patients are treated, adequate NAVFs become more
      difficult to establish. Vascular ultrasonography (US) prior to NAVF surgery has
      received little attention. METHODS: Patients with questionable venous or arterial
      status underwent 47 US evaluations by the operating surgeon prior to AV fistula
      surgery. Veins were evaluated for compressibility, size and distensibility.
      Arterial and venous occlusive lesions were identified. RESULTS: In all, 74.5% of
      patients were diabetic. More than half the patients had at least one previous
      access operation. Ultrasonography examination detected venous occlusions,
      stenoses, or fibrotic segments in addition to atheromatous disease in the radial
      artery. CONCLUSIONS: The use of the origin of the radial artery for anastomotic
      inflow was frequently helpful. Only once in 47 procedures was placement of a
      prosthetic graft required. One patient had early thrombosis. There were no
      infections or ischemic complications. The use of preoperative US by the operating
      surgeon aids in selection of site and feasibility for NAVFs. Almost all patients
      can have a NAVF created and avoid the problems associated with synthetic graft
      material.

PMID- 12488172
TI  - Aortic suspension (aortopexy) for severe tracheomalacia in infants and children.
AB  - BACKGROUND: Tracheomalacia with anterior great vessel compression is a common
      disorder in infants and children, which can lead to life-threatening airway
      occlusion. In this study, a large number of patients underwent anterior aortopexy
      to provide a more normal distal airway. METHODS: Thirty-two infants and children
      with tracheomalacia associated with esophageal atresia-tracheoesophageal fistula
      (18), vascular ring (8), abnormal innominate artery takeoff (4), and primary (2)
      were evaluated with bronchoscopy, magnetic resonance imaging, and pulmonary
      functions. Aortopexy was accomplished through left thoracotomy and suture
      fixation of the aorta and innominate artery to the posterior sternum. RESULTS:
      Intraoperative bronchoscopy showed marked improvement in airway caliber and
      rigidity, and no patients had further obstructive episodes. Forced expiratory
      volume improved from 52% +/- 4% of predicted to 82% +/- 3%. CONCLUSIONS:
      Aortopexy is a simple procedure for the treatment of distal tracheomalacia that
      is immediately effective and provides permanent relief of obstructive episodes.

PMID- 12488174
TI  - Comparison of quick parathyroid assay for uniglandular and multiglandular
      parathyroid disease.
AB  - BACKGROUND: The quick intraoperative parathyroid assay (qPTH) has been proposed
      as an effective tool in the surgical management of hyperparathyroidism. This
      assay may facilitate directed, unilateral exploration for uniglandular disease;
      however, its role in the management of multiglandular disease remains unclear.
      The purpose of this study is to evaluate the use of qPTH in parathyroid surgery,
      and to compare the results for uniglandular and multiglandular disease. METHODS:
      A prospective analysis of 63 consecutive patients explored for
      hyperparathyroidism using the qPTH assay was performed. Preoperative localization
      studies including ultrasonography and sestamibi scan were routinely obtained.
      Blood samples for qPTH were routinely drawn prior to the surgical incision, prior
      to gland excision, as well as 5 and 10 minutes after gland excision. Patients
      with primary or secondary hyperplasia had blood samples drawn relative to a 3-1/2
      gland resection. Additional samples were drawn as needed for patients with a
      double adenoma. A qPTH decline of greater than or equal to 50% of the highest
      preincision or gland preexcision level was considered successful. Unilateral neck
      exploration was routinely performed unless multiglandular disease was identified.
      Patients were followed up postoperatively with serum calcium levels and an 8
      month median follow-up was recorded. RESULTS: Forty-nine of 63 (78%) patients
      were found to have a solitary parathyroid adenoma. The qPTH assay was successful
      in 48 (97%) patients with uniglandular disease. Forty-four of these 48 patients
      showed an appropriate assay decline 5 minutes after adenoma excision. One patient
      with a single adenoma showed a delayed 50% decline in qPTH at 20 minutes.
      Fourteen (22%) patients were found to have multiglandular disease: 6 patients
      with primary hyperplasia, 4 patients with hyperplasia secondary to renal failure,
      and 4 patients with double adenomas. All patients with multiglandular disease
      demonstrated a successful decrease in qPTH levels. All patients with hyperplasia
      secondary to renal failure showed a successful assay decline 5 minutes after 3
      1/2 gland resection. Eight of 14 (57%) patients with multiglandular disease (4
      double adenomas, and 4 hyperplasia) were suspected to have solitary adenomas
      preoperatively. Overall, 62 of 63 (98%) patients showed an appropriate assay
      decline within 10 minutes after gland excision. Postoperatively, all patients
      were normocalcemic with a median follow-up of 8 months. CONCLUSIONS: These data
      suggest that qPTH can accurately facilitate unilateral, directed neck exploration
      for uniglandular parathyroid disease, as well as guide the extent of gland
      resection for multiglandular disease. This assay reliably eliminates the most
      common cause of parathyroidectomy failure, which is unrecognized multiglandular
      disease. The qPTH assay can reliably be used with similar accuracy for patients
      with multiglandular disease as has been shown for uniglandular parathyroid
      disease.

PMID- 12488176
TI  - Adverse effects of liver dysfunction and portal hypertension on intestinal
      adaptation in short bowel syndrome in children.
AB  - BACKGROUND: The effects of liver dysfunction and portal hypertension on
      intestinal adaptation in short bowel syndrome are generally unknown. The presence
      of these disorders may adversely affect the ability to wean these patients from
      parenteral nutrition. METHODS: Forty-two infants with short bowel syndrome were
      placed in one of three Child's classifications, depending on serum bilirubin,
      prothrombin time, ascites, albumin, and liver biopsy, and compared for time to
      diet tolerance, time required for parenteral nutrition, and survival. A subgroup
      of these patients also underwent portal pressure measurement, which was combined
      with liver biopsy results to compare three groups for the same parameters.
      RESULTS: Survival was Child's class A 100%, B 84%, C 61%, while time to feeding
      tolerance was A 16.3 days, B 20.0 days, C 28 days, and total parenteral nutrition
      time was A 80.0 days, B 98.0 days, C 100.0 days. In the groups that underwent
      portal pressure measurement, the survival was group I (normal biopsy and
      pressure) 100%, group II (abnormal biopsy and normal pressure) 90%, group III
      (abnormal biopsy and pressure) 66%, while time to feeding tolerance was I 15.0
      days, II 18.0 days, III 24.0 days, and total parenteral nutrition time was I 72.0
      days, II 94.0 days, III 184.0 days. CONCLUSIONS: Cholestatic liver disease,
      especially associated with portal hypertension adversely affects bowel adaptation
      in short bowel syndrome.

PMID- 12488178
TI  - The use of abdominal computed tomography scan decreases the frequency of
      misdiagnosis in cases of suspected appendicitis.
AB  - BACKGROUND: Despite considerable experience the reported frequency of
      misdiagnosis in patients undergoing appendectomy continues in the range of 20% to
      40% in some populations. METHODS: We developed a clinical guideline that
      recommended abdominal computed tomography (CT) for all nonpregnant adults in whom
      the diagnosis of appendicitis was suspected unless the diagnosis could be ruled
      out clinically. The records of adult patients that underwent appendectomy from
      July 1998 through October 2001 were reviewed. The clinical guideline was
      developed in July 2000. RESULTS: There were 194 appendectomies performed, 114
      prior to the guideline and 80 after the development of the guideline. The rate of
      misdiagnosis decreased from 25% to 6% (P <0.05), the rate of CT use increased
      from 32% to 84% (P <0.05), and the perforation rate remained unchanged.
      CONCLUSIONS: These results support the effectiveness of a clinical guideline that
      encourage the use of abdominal CT in decreasing the frequency of misdiagnosis in
      cases of suspected appendicitis.

PMID- 12488180
TI  - Increased laparoscopic experience does not lead to improved results with acute
      cholecystitis.
AB  - BACKGROUND: As laparoscopic experience increases, ever more challenging cases are
      attempted. Enlarged surgeon experience, along with better technology, has been
      lauded as improving outcomes. The purpose of this study is to see if this applies
      to the management of acute cholecystitis. METHODS: We reviewed our experience
      over a 7 and a half year period. Information was obtained from a prospectively
      maintained computer database containing patient presentation, demographics,
      workup, laboratory values, and outcomes. Diagnosis of gangrene was based on
      pathologic examination of the specimen. RESULTS: There were 305 patients admitted
      to our institution with acute cholecystitis. Group I (n = 111) was admitted
      during the first half of the study and group II (n = 194) during the second half.
      Demographics were similar in the two groups. While slightly more patients were
      attempted laparoscopically in group II (90% versus 82%), conversion rates were
      virtually identical (27.1% versus 27.5%). There was a trend toward improved
      results with group II versus group I in mortality (3% versus 4%) and morbidity
      (14% versus 21%; P = not significant). Deaths were divided between sepsis and
      cardiac events. Gangrenous cholecystitis was less frequent in group II patients
      (29% versus 40%; P = 0.06). Analysis of gangrene versus non-gangrene patients
      within each group showed that conversion rates remained twice as high (40% versus
      20%; P < 0.05) in those with gangrene. Interestingly, gangrene had no effect on
      morbidity or mortality. CONCLUSIONS: Morbidity and mortality for acute
      cholecystitis remain relatively high. These seem to be determined by the degree
      of acute and chronic illness present at the time of diagnosis. As conversion
      rates remain unchanged, increased surgeon experience and further advances in
      laparoscopic technology are unlikely to dramatically affect results. Efforts to
      improve outcomes for this common disease should therefore focus on better and
      earlier identification of patients for operation.

PMID- 12488182
TI  - Gastric emptying time, not enterogastric reflux, is related to symptoms after
      upper gastrointestinal/biliary surgery.
AB  - BACKGROUND: It has been suggested that symptoms from bile reflux gastritis are
      related to the frequency and degree of enterogastric reflux (EGR). METHODS:
      Patients with history of upper gastrointestinal surgery or cholecystectomy as
      well as control patients were studied. Presence of EGR, degree of EGR, and
      gastric bile emptying time were assessed and quantified via 99mTC scintillation
      imaging and then compared between symptomatic and asymptomatic patients. RESULTS:
      Patients with vagotomy and pyloroplasty, Billroth I, Billroth II, and
      cholecystectomy demonstrated statistically higher degrees of EGR compared with
      controls. Although asymptomatic and symptomatic patients with a history of upper
      gastrointestinal or biliary surgery demonstrated no statistically significant
      differences between incidence of EGR and degree of EGR, there was a statistically
      significant difference in gastric emptying time. CONCLUSIONS: Delayed gastric
      emptying time, not frequency or extent of EGR, was associated with the symptoms
      of bile reflux in patients who had previous upper gastrointestinal or biliary
      operations.

PMID- 12488184
TI  - Preoperative evaluation of hepatic lesions for the staging of hepatocellular and
      metastatic liver carcinoma using endoscopic ultrasonography.
AB  - BACKGROUND: Noninvasive imaging techniques, such as dynamic computed tomography
      (CT), magnetic resonance imaging and transabdominal ultrasonography are limited
      in their ability to detect hepatic lesions less than one cm. Intraoperative
      ultrasonography (IOUS) is currently the most sensitive modality for the detection
      of small hepatic lesions. However, IOUS is invasive requiring laparoscopy or
      formal laparotomy. We sought to evaluate the feasibility of using endoscopic
      ultrasonograhpy (EUS) for the detection and diagnosis of hepatic masses in
      patients with hepatocellular cancer (HCCA) and metastatic lesions (ML). We
      hypothesized that EUS could detect small (<1.0 cm) hepatic lesions undetectable
      by CT scan and could be used for biopsy of deep-seated hepatic lesions. METHODS:
      Consecutive patients referred for EUS with suspected liver lesions were evaluated
      between July 2000 and October 2001. All patients underwent EUS using an Olympus
      (EM30) radial echoendoscope. If liver lesions were confirmed and fine needle
      aspiration (FNA) was deemed necessary, a linear array scope was used and an FNA
      performed with a 22-gauge needle. Two passes were made for each lesion. RESULTS:
      14 patients underwent evaluation with dynamic CT scans and EUS. In all 14
      patients, EUS successfully identified hepatic lesions ranging in size from 0.3 cm
      to 14 cm (right lobe: n = 3, left lobe: n = 1, bilobar: n = 8). Moreover, EUS
      identified new or additional lesions in 28% (4 of 14) of the patients, all less
      than 0.5 cm in size (HCCA: n = 2, ML: n = 2), influencing the clinical
      management. In 2 of 14 patients EUS identified liver lesions, previously
      described as suspicious by CT scan, to be hemangiomas. Nine patients underwent
      EUS-guided FNA of hepatic lesions (deep seated: n = 3, superficial: n = 6). All
      FNA passes yielded adequate specimens (malignant: n = 8, benign: n = 1).
      CONCLUSIONS: Our preliminary experience suggests that EUS is a feasible
      preoperative staging tool for liver masses suspected to be HCCA or metastatic
      lesions. EUS can detect small hepatic lesions previously undetected by dynamic CT
      scans. Furthermore, EUS-guided FNA can confirm additional HCCA liver lesions or
      liver metastases, in deep-seated locations, upstaging patients and changing
      clinical management.

PMID- 12488186
TI  - Splenectomy versus medical treatment for idiopathic thrombocytopenic purpura.
AB  - BACKGROUND: Treatment strategies for idiopathic thrombocytopenic purpura (ITP)
      are still uncertain and its management is primarily empirical. The aim of this
      study was to investigate the role of splenectomy in the therapy of ITP and to
      evaluate whether medical or surgical treatment is superior. METHODS: Ninety-two
      patients with ITP were included in the study. All of these patients had medical
      therapy and 38 of them underwent splenectomy subsequently. Follow-up was
      completed in 91 patients after a median of 64 months. RESULTS: Side effects of
      medical therapy were noticed in 32 patients (35%), whereas after surgery only 2
      patients (5%) had minor complications. A complete or partial remission was
      achieved in 35 patients (92%) after splenectomy, whereas this was achieved in
      only 27 patients (30%) after medical therapy. On multivariate analysis
      splenectomy and age were the only significant independent factors for complete
      and partial remission. CONCLUSIONS: Splenectomy is highly effective and safe in
      the treatment of ITP and is superior over medical therapy. These results should
      stimulate the discussion about splenectomy for ITP, possibly establishing
      evidence-based guidelines for surgical treatment in hematology.

PMID- 12488188
TI  - Open Roux-en-Y gastric bypass for the morbidly obese in the era of laparoscopy.
AB  - BACKGROUND: Roux-En-Y gastric bypass (RYGB) has been the preferred operative
      treatment for morbid obesity. Recently, laparoscopic RYGB has been described. We
      reviewed our data and believe that open RYGB is still the better option. METHODS:
      One hundred three consecutive cases were retrospectively reviewed for
      preoperative conditions, perioperative outcomes, and postoperative complications
      with weight/health changes. RESULTS: The mean follow-up was 5 months. The mean
      percent excess body weight loss was 33%. Comorbidities improved 50% of the time.
      The mean operative time was 117 minutes with blood loss averaging 208 cc. The
      mean intensive care unit stay was 1.3 days, with a total hospital stay of 4.4
      days. There was an 8% major complication rate and a 1% mortality rate.
      CONCLUSIONS: The health improvement and complication rates are comparable to
      published series on laparoscopic RYGB. With the technical complexity of the
      laparoscopic technique, open RYGB should remain the current standard of care, in
      most centers.

PMID- 12488190
TI  - Establishing a laparoscopic gastric bypass program.
AB  - OBJECTIVE: To evaluate the outcomes for laparoscopic Roux-en-Y gastric bypass in
      a newly developed bariatric surgery program. METHODS: A prospective analysis of
      the initial 100 patients who underwent laparoscopic Roux-en-Y gastric bypass at a
      community based teaching hospital between December 2000 and October 2001 was
      performed. Study endpoints included operative time, early (less than 7 days) and
      late complication rates, hospital length of stay (LOS), time to initiation of
      oral diet, and percentage of excess body weight loss. RESULTS: There were 91
      women and 9 men with a mean age of 39 years (range 21 to 57). Mean preoperative
      weight was 126.4 kg (range 92.3 kg to 214 kg), with a mean preoperative body mass
      index of 47.4 (range 37.3 to 75.7). Ninety (90%) patients had at least one
      significant medical comorbidity (median = 6 per patient). Mean operative time was
      2.4 hours (range 1.0 to 6.5; 3.0 hours for the first 50 patients and 1.8 hours
      for the last 50 patients). Three patients required conversion to open gastric
      bypass, all due to equipment failure (two harmonic scalpel failures and one
      linear stapler malfunction). Seven patients had early complications, 3 with
      anastomotic hemorrhage requiring transfusion, 3 with intestinal leaks requiring
      reoperation, and 1 with transected nasogastric tube. Eleven patients had late
      complications: 5 patients with small bowel obstruction, all due to herniation
      through the transverse colon mesentery (these occurred early in the series,
      prompting a change in technique, with no subsequent occurrences), 3 with
      gastrojejunostomy strictures requiring endoscopic dilation, 2 superficial wound
      infections, and 1 port-site incisional hernia. No complications occurred in the
      last 40 patients. No deaths occurred. Median hospital stay was 2 days (range 1 to
      37); 3 days in the first 50 cases and 1 day in the last 50 cases. The median
      number of days to the start of an oral diet was 1 day. Average excess body weight
      loss was 34% (median follow-up 4 months). CONCLUSIONS: Laparoscopic Roux-en-Y
      gastric bypass is a technically challenging procedure that can be safely
      integrated into a bariatric treatment program with good results. Improved
      outcomes, shorter operative times, and fewer complications are associated with
      increased surgical experience.

PMID- 12488192
TI  - Contemporary surgical management of pheochromocytoma.
AB  - BACKGROUND: The availability of laparoscopic adrenalectomy led us to review our
      experience and management of adrenal and extraadrenal pheochromocytoma. METHODS:
      Seventeen patients undergoing pheochromocytoma resection from January 1997 to
      August 2001 were categorized as open, laparoscopic, or laparoscopic assisted
      depending on the surgical approach. Hospital records were reviewed. RESULTS:
      There was no significant difference between the groups in patient age, weight or
      preoperative blockade. Operative times for open, laparoscopic, and laparoscopic
      assisted adrenalectomies were 202, 218, and 260 minutes, respectively. Estimated
      blood loss was 562 cc, 187 cc, and 925 cc. The average hospital length of stay
      was 6.2, 3.0, and 5.8 days. CONCLUSIONS: Laparoscopic removal resulted in longer
      operative times than open, but less operative blood loss and a shorter hospital
      stay. The laparoscopic assisted approach did not save time nor did it lead to
      earlier discharge. Laparoscopic adrenalectomy was comparable to the open
      approach, and is preferential in tumors less than 6 cm. An open approach remains
      our choice for larger or extraadrenal tumors.

PMID- 12488194
TI  - Housestaff performance is improved by participation in a laparoscopic skills
      curriculum.
AB  - BACKGROUND: After the implementation of a laparoscopic skills curriculum, we
      studied two questions: (1) can skills curriculum participation improve
      performance and (2) can we identify housestaff who may benefit from early
      instruction in laparoscopic technical skills? METHODS: We administered a six-task
      laparoscopic skills curriculum to postgraduate year (PGY) 2 and PGY3 surgical
      housestaff. Six laparoscopic tasks were divided into two groups: generalized
      skills and task specific skills. All participants were evaluated during a pretest
      and were placed in the novice group (total score less than 600) or in the
      intermediate skill (IS) group (total score 600 or more). Each participant had two
      1-hour practice/instruction sessions and 2 weeks for independent practice. After
      these sessions, a posttest was administered. RESULTS: Novices and intermediate
      skill participants demonstrated significant improvement in general skills and
      task specific skills. However, comparison of novice and IS group learners
      revealed that IS group learners were significantly more proficient in the
      performance of general skills, but the performance of task specific skills failed
      to demonstrate a difference between the two groups. On posttest, there was no
      significant difference in overall score between novices and IS participants.
      CONCLUSIONS: Overall ability and performance of generalized skills by all
      housestaff are improved with a laparoscopic skills curriculum; however, the
      performance of novices improved the greatest. Task specific skills did not
      discriminate novices from more advanced learners. Early testing of housestaff may
      identify those individuals who could benefit from intervention and instruction
      prior to performing the laparoscopic skills in the operating room.

PMID- 12488196
TI  - Portal vein thrombosis after splenectomy.
AB  - BACKGROUND: Portal vein thrombosis (PVT) has been described after splenectomy,
      but the factors associated with its development and the clinical outcomes are
      poorly characterized. METHODS: Case logs of four surgeons from 1996 to 2001 were
      retrospectively reviewed to identify cases of postsplenectomy PVT. RESULTS: Eight
      cases of PVT (8%) among 101 splenectomies were identified. Indications for
      splenectomy in patients with PVT were myeloproliferative disease (n = 4),
      hemolytic anemia (n = 3), and myelodysplastic disorder (n = 1). All patients had
      splenomegaly (mean 1698 g, range 360 to 3150 g). Among 10 patients with
      myeloproliferative disease (MP), 4 patients (40%) developed PVT, compared with 4
      of 12 patients (25%) with hemolytic anemia. Three of 4 patients (75%) with MP
      disease and spleen weight greater than 3,000 g developed PVT. Five patients
      developed PVT despite receiving prophylactic subcutaneous heparin
      postoperatively. Presenting symptoms included anorexia in 7 (88%), abdominal pain
      in 6 (75%), and both elevated leukocyte and platelet counts in 8 patients (100%).
      All diagnoses were made by contrast-enhanced computed tomography scan, and
      anticoagulation was initiated immediately. One patient died of intraabdominal
      sepsis; the others are alive with no clinical sequelae at 38 months of follow-up.
      CONCLUSIONS: PVT is a relatively common complication of splenectomy in patients
      with splenomegaly. A high index of suspicion, early diagnosis by contrast
      enhanced computed tomography, and prompt anticoagulation are key to a successful
      outcome.

PMID- 12488198
TI  - Education of medical students in clinical breast examination during surgical
      clerkship.
AB  - BACKGROUND: Medical student training in clinical breast examination is deficient
      at most medical schools. The use of silicone breast models may allow the
      education of abnormal and normal findings. This study examines the efficacy of
      silicone breast models to educate medical students in clinical breast
      examinations during their third-year surgical rotation. METHODS: Medical students
      were randomly selected to participate in formalized training sessions in clinical
      breast examination or as a control group. Presession and postsession testing with
      silicone breast models were performed. True positives (masses that were present
      and documented by the student) and false positives (masses that were not present
      but were documented by the student) were recorded. RESULTS: Medical students
      undergoing the training sessions demonstrated improved true positive scores (2.2
      to 2.8; P <0.05) as well as improved false positive scores (3.0 to 2.0; P = 0.30)
      and total scores (-0.8 to 0.8; P = 0.07). Students who documented an increase in
      the number of breast examinations during their rotations had statistically lower
      false positive scores. CONCLUSIONS: Students after formalized clinical breast
      examination sessions do improve their ability to detect breast masses, although
      they continue to detect masses that are not present. Experience of actual breast
      examinations during their surgical rotations may refine their clinical skills.

PMID- 12488200
TI  - Increased expression of alpha-1-antitrypsin, glutathione S-transferase pi and
      vascular endothelial growth factor in human pancreatic adenocarcinoma.
AB  - BACKGROUND: This study was designed to investigate abnormalities in gene
      expression in ductal adenocarcinoma of the pancreas using cDNA arrays. METHODS:
      Gene expression in pancreatic ductal adenocarcinoma was compared with normal
      pancreatic tissue controls. Specimens from 5 patients with pancreatic
      adenocarcinoma were taken fresh at operation and analyzed using commercially
      prepared cDNA arrays evaluating approximately 2,000 genes. Immunohistochemical
      staining was used to confirm protein expression of selected genes. RESULTS: Alpha
      1-antitrypsin (A1AT) and glutathione S-transferase pi (GSTP) were significantly
      up-regulated in all 5 tumors. Vascular endothelial growth factor (VEGF) was up
      regulated in 4 of the 5 patients. Immunohistochemical staining verified the
      overexpression of each of these genes. CONCLUSIONS: A1AT, GSTP, and VEGF are
      overexpressed in human pancreatic adenocarcinoma specimens taken fresh at
      operation. To our knowledge, this is the first study of human pancreatic ductal
      adenocarcinoma demonstrating the up-regulation of these genes using gene
      expression arrays.

PMID- 12488202
TI  - The adrenal response after severe trauma.
AB  - BACKGROUND: The integrity of the hypothalamic-pituitary-adrenal axis is a major
      determinant of the host response to stress. Relative adrenal insufficiency has
      been implicated in poor outcome from systemic inflammatory states; however,
      whether low endogenous glucocorticoid levels are adaptive or pathologic remains
      controversial. The purpose of this study was to prospectively evaluate the
      cortisol response and determine the incidence of occult adrenal insufficiency
      after severe trauma. METHODS: Over an 18-month period, 22 severely injured
      patients admitted to the surgical intensive care unit of our level 1 trauma
      center were prospectively identified and followed. Demographic and outcome data
      were tabulated. In addition, random serum cortisol levels were obtained on days
      0, 5, and 10 after injury. Relative adrenal insufficiency was defined as a random
      serum cortisol level less than 18 microg/dL. RESULTS: Mean baseline cortisol
      levels were elevated (35 +/- 3 microg/dL) and significantly declined over the
      next 10 days (day 5: 24 +/- 2 microg/dL; and day 10: 22 +/- 2 microg/dL; P
      <0.01). Thirteen of 22 (60%) patients had random serum cortisol levels less than
      18 microg/dL. Only 1 of the 2 patients who died had a serum cortisol level less
      than 18 microg/dL. The mean cortisol levels at baseline were higher in the 2
      patients who died compared with those who survived but this was not statistically
      significant (43.4 +/- 8.8 microg/dL versus 35.0 +/- 3.6 microg/dL, P = 0.5).
      CONCLUSIONS: Serum cortisol levels increased immediately and gradually returned
      towards normal after severe trauma. Occult adrenal insufficiency was common (60%)
      in this small group of severely injured patients. This did not, however, affect
      mortality in these patients. Further study is needed to delineate the role of
      occult adrenal insufficiency after severe injury.

PMID- 12488208
TI  - Is it time to change the rules for resuscitation?

PMID- 12488210
TI  - Breast cancer in young Latinos.

PMID- 12488213
TI  - Cell invasion by Theileria sporozoites.

PMID- 12488214
TI  - Trends in teaching parasitology: the American situation.

PMID- 12488215
TI  - Arginases in parasitic diseases.

PMID- 12488216
TI  - Dicrocoeliosis of ruminants: a little known fluke disease.

PMID- 12488217
TI  - Understanding parasite strategies.

PMID- 12488219
TI  - GATEWAY vectors for Plasmodium falciparum transfection.

PMID- 12488220
TI  - Neospora caninum: pregnancy, parasites and prolactin.

PMID- 12488221
TI  - Etiology of Chagas disease myocarditis: autoimmunity, parasite persistence, or
      both?

PMID- 12488222
TI  - Plasmodium falciparum: sacrificing membrane to grow crystals?

PMID- 12488223
TI  - Canine hepatozoonosis: two disease syndromes caused by separate Hepatozoon spp.

PMID- 12488224
TI  - Evolutionary ideas about genetically manipulated mosquitoes and malaria control.

PMID- 12488225
TI  - Do disturbances within the folate pathway contribute to low birth weight in
      malaria?

PMID- 12488226
TI  - Chagas disease control in Venezuela: lessons for the Andean region and beyond.

PMID- 12488227
TI  - Use of A-bomb survivor studies as a basis for nuclear worker compensation.

PMID- 12488230
TI  - Aging and neural control of the GI tract: V. Aging and gastrointestinal smooth
      muscle: from signal transduction to contractile proteins.
AB  - The object of this theme is to offer new perspectives on the effect of aging on
      signal-transduction pathways associated with agonist-induced contraction of
      smooth muscle cells from the colon. Smooth muscle cells from old rats (32 mo old)
      exhibit limited cell length distribution and diminished contractility. The
      observed reduced contractile response may be due to the effect of aging on signal
      transduction pathways, especially an inhibition of the tyrosine kinase-Src kinase
      pathway, a reduced activation of the PKC pathway, and a reduced association of
      contractile proteins [heat shock protein 27 (HSP27)-tropomyosin, HSP27-actin,
      actin-myosin]. Levels of HSP27 phosphorylation are also reduced compared with
      adult rats.

PMID- 12488231
TI  - Musings on the wanderer: what's new in our understanding of vago-vagal reflexes?:
      II. Integration of afferent signaling from the viscera by the nodose ganglia.
AB  - To understand vago-vagal reflexes, one must have an appreciation of the events
      surrounding the encoding, integration, and central transfer of peripheral
      sensations by vagal afferent neurons. A large body of work has shown that vagal
      afferent neurons have nonuniform properties and that distinct subpopulations of
      neurons exist within the nodose ganglia. These sensory neurons display a
      considerable degree of plasticity; electrophysiological, pharmacological, and
      neurochemical properties have all been shown to alter after peripheral tissue
      injury. The validity of claims of selective recordings from populations of
      neurons activated by peripheral stimuli may be diminished, however, by the recent
      demonstration that stimulation of a subpopulation of nodose neurons can enhance
      the activity of unstimulated neuronal neighbors. To better understand the
      neurophysiological processes occurring after vagal afferent stimulation, it is
      essential that the electrophysiological, pharmacological, and neurochemical
      properties of nodose neurons are correlated with their sensory function or, at
      the very least, with their specific innervation target.

PMID- 12488232
TI  - Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning.
AB  - Ischemia-reperfusion injury is, at least in part, responsible for the morbidity
      associated with liver surgery under total vascular exclusion or after liver
      transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a
      number of mechanisms that contribute to various degrees in the overall injury.
      Some of the topics discussed in this review include cellular mechanisms of
      injury, formation of pro- and anti-inflammatory mediators, expression of adhesion
      molecules, and the role of oxidant stress during the inflammatory response.
      Furthermore, the roles of nitric oxide in preventing microcirculatory
      disturbances and as a substrate for peroxynitrite formation are reviewed. In
      addition, emerging mechanisms of protection by ischemic preconditioning are
      discussed. On the basis of current knowledge, preconditioning or pharmacological
      interventions that mimic these effects have the greatest potential to improve
      clinical outcome in liver surgery involving ischemic stress and reperfusion.

PMID- 12488233
TI  - Physiological effects of enteral and parenteral feeding on pancreaticobiliary
      secretion in humans.
AB  - In the nutritional management of digestive disorders, it is important to know the
      relative secretory and metabolic responses to enteral and parenteral feeding.
      Twenty-seven healthy volunteers were studied while receiving either oral drinks
      or duodenal infusions of a complex formula diet, duodenal or intravenous
      infusions of elemental (protein as free amino acids, low fat) formulae, or
      saline. Pancreaticobiliary secretory responses were measured by nasoduodenal
      polyethylene glycol perfusion and aspiration, while monitoring blood hormone and
      nutrient levels. Diets were matched for protein (1.5 g x kg(-1) x d(-1)) and
      energy (40 kcal x kg(-1) x d(-1)). Compared with placebo, all oroenteral diets
      stimulated amylase, lipase, trypsin, and bile acid secretion and increased plasma
      concentrations of gastrin and cholecystokinin, whereas intravenous feeding did
      not. The complex formula produced a similar response whether given as drinks or
      duodenal infusions. Changing the duodenal formula to elemental reduced enzyme
      secretion by 50%, independently of CCK. Higher increases in plasma insulin,
      glucose, and amino acids were noted with intravenous feeding. Delivering food
      directly to the intestine by a feeding tube does not reduce pancreaticobiliary
      secretion. Enteral "elemental" formulae diminish, but only intravenous feeding
      avoids pancreatic stimulation. Intravenous administration impairs metabolic
      clearance.

PMID- 12488234
TI  - Chronic EtOH administration alters liver Mg2+ homeostasis.
AB  - Ethanol (EtOH) administration to rats for 4 wk markedly decreased Mg(2+) content
      in several tissues, including liver. Total cellular Mg(2+) accounted for 26.8 +/-
      2.4 vs. 36.0 +/- 1.4 nmol Mg(2+)/mg protein in hepatocytes from EtOH-fed and
      control rats, respectively, and paralleled a 13% decrease in cellular ATP
      content. Stimulation of alpha(1)- or beta-adrenergic receptor or acute EtOH
      administration did not elicit an extrusion of Mg(2+) from liver cells of EtOH-fed
      rats while releasing 5% of total tissue Mg(2+) content from hepatocytes of
      control rats. Despite the 25% decrease in Mg(2+) content, hepatocytes from EtOH
      fed rats did not accumulate Mg(2+) following stimulation of protein kinase C
      signaling pathway, whereas control hepatocytes accumulated approximately 2 nmol
      Mg(2+). mg protein(-1). 4 min(-1). Together, these data indicate that Mg(2+)
      homeostasis and transport are markedly impaired in liver cells after prolonged
      exposure to alcohol. The inability of liver cells, and possibly other tissues, to
      accumulate Mg(2+) can help explain the reduction in tissue Mg(2+) content
      following chronic alcohol consumption.

PMID- 12488235
TI  - Regulation of atrial natriuretic peptide secretion by cholinergic and PACAP
      neurons of the gastric antrum.
AB  - Atrial natriuretic peptide (ANP) released from enterochromaffin cells helps
      regulate antral somatostatin secretion, but the mechanisms regulating ANP
      secretion are not known. We superfused rat antral segments with selective neural
      agonists/antagonists to identify the neural pathways regulating ANP secretion.
      The nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) stimulated ANP
      secretion; the effect was abolished by hexamethonium but doubled by atropine.
      Atropine's effect implied that DMPP activated concomitantly cholinergic neurons
      that inhibit and noncholinergic neurons that stimulate ANP secretion, the latter
      effect predominating. Methacholine inhibited ANP secretion. Neither bombesin nor
      vasoactive intestinal polypeptide stimulated ANP secretion, whereas pituitary
      adenylate cyclase-activating polypeptide (PACAP)-27, PACAP-38, and maxadilan
      [PACAP type 1 (PAC1) agonist] each stimulated ANP secretion. The PAC1 antagonist
      M65 1) abolished PACAP-27/38-stimulated ANP secretion; 2) inhibited basal ANP
      secretion by 28 +/- 5%, implying that endogenous PACAP stimulates ANP secretion;
      and 3) converted the ANP response to DMPP from 109 +/- 21% above to 40 +/- 5%
      below basal, unmasking the cholinergic component and indicating that DMPP
      activated PACAP neurons that stimulate ANP secretion. Combined atropine and M65
      restored DMPP-stimulated ANP secretion to basal levels. ANP secretion in the
      antrum is thus regulated by intramural cholinergic and PACAP neurons; cholinergic
      neurons inhibit and PACAP neurons stimulate ANP secretion.

PMID- 12488236
TI  - Stimulation of gastrin-CCKB receptor promotes migration of gastric AGS cells via
      multiple paracrine pathways.
AB  - Responses to G protein-coupled receptor stimulation may be mediated by paracrine
      factors. We have developed a coculture system to study paracrine regulation of
      migration of gastric epithelial (AGS) cells after stimulation of gastrin-CCK(B)
      receptors. In cells expressing this receptor, G-17 stimulated migration by
      activation of protein kinase C. However, G-17 also stimulated the migration of
      cells expressing green fluorescent protein, but not the receptor, when they were
      cocultured with receptor-expressing cells consistent with activation of paracrine
      signals. The use of various pharmacological inhibitors indicated that gastrin
      stimulated migration via activation of the EGF receptor (EGR-R), the erbB-2
      receptor tyrosine kinase, and the MAP kinase pathway. However, gastrin also
      released fibroblast growth factor (FGF)-1, and migration was inhibited by the FGF
      receptor tyrosine kinase inhibitor SU-5402. Flow cytometry indicated that in both
      cell types, gastrin increased MAP kinase via activation of EGF-R but not FGF-R1
      or erbB-2. We conclude that gastrin-CCK(B) receptors stimulate epithelial cell
      migration partly via paracrine mechanisms; transactivation of EGF-R is only one
      component of the paracrine pathway.

PMID- 12488238
TI  - Increased activity and expression of matrix metalloproteinase-9 in a rat model of
      distal colitis.
AB  - Matrix metalloproteinases may play a role in tissue remodelling and destruction
      associated with inflammation. We investigated activity and expression of matrix
      metalloproteinases in a rat model of colitis and tested the therapeutic potential
      of a synthetic inhibitor (CGS-27023-A). Colitis was induced by dextran sulphate
      sodium (at 5% in drinking water for 5 days) in a group of eight rats, whereas a
      matched control group received plain water. Activity and expression of matrix
      metalloproteinases were measured in colonic tissue homogenates using zymography
      and Western blot on days 3 and 5 after induction of colitis. In another set of
      experiments, two groups of colitic rats (20 per group) were treated with CGS
      27023-A (20 mg/kg) or vehicle, respectively. On days 5 and 14, colonic mucosal
      lesions were blindly scored by microscopic examination. Induction of colitis led
      to a significant upregulation of matrix metalloproteinase-9 protein and its
      activity, but no change in matrix metalloproteinase-2 activity was observed.
      Treatment with CGS-27023-A significantly decreased the extent and severity of
      epithelial injury but did not influence mucosal repair. We conclude that
      increased activity of matrix metalloproteinases may contribute to epithelial
      damage in this model of colitis.

PMID- 12488237
TI  - Curcumin ameliorates ethanol and nonethanol experimental pancreatitis.
AB  - Treatments for pancreatitis are limited. Activation of transcription factor NF
      kappaB, a key regulator of inflammatory molecule expression, is an early event in
      experimental pancreatitis and correlates with the inflammatory response. We
      report here that curcumin, a natural phytochemical known to inhibit NF-kappaB and
      activator protein (AP)-1, another important proinflammatory transcription factor,
      ameliorates pancreatitis in two rat models. In both cerulein pancreatitis and
      pancreatitis induced by a combination of ethanol diet and low-dose CCK, curcumin
      improved the severity of the disease as measured by a number of parameters
      (histology, serum amylase, pancreatic trypsin, and neutrophil infiltration).
      Curcumin markedly inhibited NF-kappaB and AP-1 activation, assessed by DNA
      binding and degradation of inhibitory IkappaB proteins, and the induction of
      mRNAs for cytokines IL-6 and TNF-alpha, the chemokine KC, and inducible nitric
      oxide synthase in pancreas. Curcumin also blocked CCK-induced NF-kappaB and AP-1
      activation in isolated pancreatic acini. Our findings indicate that blocking key
      signals of the inflammatory response ameliorates pancreatitis in both ethanol and
      nonethanol models. They suggest that curcumin, which is currently in clinical
      trials for cancer prevention, may be useful for treatment of pancreatitis.

PMID- 12488239
TI  - Selective effects of serotonergic psychoactive agents on gastrointestinal
      functions in health.
AB  - This study evaluated the effects of serotonergic psychoactive agents on
      gastrointestinal functions in healthy human subjects. Participants received one
      of four regimens in a randomized, double-blind manner: buspirone, a 5-HT(1A)
      receptor agonist (10 mg twice daily); paroxetine, a selective serotonin reuptake
      inhibitor (20 mg daily); venlafaxine-XR, a selective serotonin and norepinephrine
      reuptake inhibitor (75 mg daily); or placebo for 11 days. Physiological testing
      performed on days 8-11 included scintigraphic assessment of gastrointestinal and
      colonic transit, the nutrient drink test, and assessment of the postprandial
      change in gastric volume. Fifty-one healthy adults (40 females, 11 males)
      participated in this study. No effects on gastric emptying or colonic transit
      were identified with any agent. Small bowel transit of a solid meal was
      accelerated by paroxetine. Buspirone decreased postprandial aggregate symptom and
      nausea scores. Venlafaxine-XR increased the postprandial change in gastric
      volume. Buspirone, paroxetine, and venlafaxine-XR affect upper gastrointestinal
      functions in healthy humans. These data support the need for clinical and
      physiological studies of these agents in functional gastrointestinal disorders.

PMID- 12488240
TI  - Serine metabolism in human pregnancy.
AB  - Serine plays an important role in intermediary metabolism as a source of one
      carbon pool for nucleotide biosynthesis, as a precursor for glycine and glucose,
      and as a contributor to cysteine biosynthesis. A unique serine-glycine cycling
      between the liver and the placenta has been demonstrated in the sheep fetus. We
      hypothesized that, because of serine's role in growth and development,
      significant changes in serine metabolism will occur in pregnancy with advancing
      gestation. The rate of appearance (R(a)) of serine and its metabolism were
      quantified in healthy women longitudinally through pregnancy with a [2
      (15)N(13)C]serine tracer. The contribution of serine N to urea and the rate of
      oxidation of serine were measured using the precursor-product relation. Plasma
      serine concentrations and serine R(a) were lower in pregnant (P) women, in both
      early and late gestation, compared with nonpregnant (NP) women [plasma serine:
      NP, 113 +/- 24.5; P early, 71.9 +/- 6.2; P late, 68.5 +/- 9.6 micromol/l; serine
      R(a): NP (n = 7), 152.9 +/- 42.8; P early (n = 12), 123.7 +/- 21.5; P late (n =
      8), 102.8 +/- 18.2 micromol x kg(-1) x h(-1)]. Serine contributed approximately
      6% to urea N and 15-20% to the plasma glycine pool, and oxidation of serine
      represented approximately 8% of R(a). There was no significant difference between
      P and NP subjects. Glucose infusion, at 3 mg x kg(-1) x min(-1) in P subjects,
      resulted in a decrease in serine R(a) and an increase in oxidation. The decrease
      in serine turnover in pregnancy may represent a decrease in alpha-amino nitrogen
      turnover related to a decreased rate of branched-chain amino acid transamination
      and caused by pregnancy-related hormones aimed at nitrogen conservation and
      accretion.

PMID- 12488241
TI  - Adipose tissue sensitization to insulin induced by troglitazone and MEDICA 16 in
      obese Zucker rats in vivo.
AB  - The putative role played by insulin sensitizers in modulating adipose tissue
      lipolysis in the fasting state was evaluated in obese conscious Zucker rats
      treated with troglitazone or beta,beta'-tetramethylhexadecanedioic acid (MEDICA
      16) and compared with nontreated lean and obese animals. The rates of appearance
      (R(a)) of glycerol and free fatty acid (FFA), primary intra-adipose
      reesterification, and secondary reuptake of plasma FFA in adipose fat were
      measured using constant infusion of stable isotope-labeled [(2)H(5)]glycerol,
      [2,2-(2)H(2)]palmitate, and radioactive [(3)H]palmitate. The overall lipolytic
      flux (R(a) glycerol) was increased 1.7- and 1.4-fold in obese animals treated
      with troglitazone or MEDICA 16, respectively, resulting in increased FFA export
      (R(a) FFA) in the troglitazone-treated rats. Primary intra-adipose
      reesterification of lipolysis-derived fatty acids was enhanced twofold by insulin
      sensitizers, whereas reesterification of plasma fatty acids was unaffected by
      either treatment. Despite the unchanged R(a) FFA in MEDICA 16 or the increased
      R(a) FFA induced by troglitazone, very low density lipoprotein production rates
      were robustly curtailed. Total adipose tissue reesterification, used as an
      estimate of glucose conversion to glyceride-glycerol, was increased 1.9-fold by
      treatment with the insulin sensitizers. Our results indicate that, in the fasting
      state, insulin sensitizers induce, in vivo, a significant activation rather than
      suppression of adipose tissue lipolysis together with stimulation of glucose
      conversion to glyceride-glycerol.

PMID- 12488242
TI  - Effect of weight loss on muscle lipid content in morbidly obese subjects.
AB  - The purpose of this study was to test the hypothesis that weight loss results in
      a reduction in intramuscular lipid (IMCL) content that is concomitant with
      enhanced insulin action. Muscle biopsies were obtained from morbidly obese
      individuals [body mass index (BMI) 52.2 +/- 2.5 kg/m(2); n = 6] before and after
      gastric bypass surgery, an intervention that improves insulin action. With
      intervention, there was a 47% reduction (P < 0.01) in BMI and a 93% decrease in
      homeostasis model assessment, or HOMA (7.0 +/- 1.9 vs. 0.5 +/- 0.1).
      Histochemically determined IMCL content decreased (P < 0.05) by approximately
      30%. In relation to fiber type, IMCL was significantly higher in type I vs. type
      II fibers. In both fiber types, there were reductions in IMCL and trends for
      muscle atrophy. Despite these two negating factors, the IMCL-to-fiber area ratio
      still decreased by approximately 44% with weight loss. In conclusion, despite
      differing initial levels and possible atrophy, weight loss appears to decrease
      IMCL deposition to a similar relative extent in type I and II muscle fibers. This
      reduction in intramuscular triglyceride may contribute to enhanced insulin action
      seen with weight loss.

PMID- 12488243
TI  - Sumoylation of Pdx1 is associated with its nuclear localization and insulin gene
      activation.
AB  - Pancreatic duodenal homeobox-1 (Pdx1) is a transcription factor, and its
      phosphorylation is thought to be essential for activation of insulin gene
      expression. This phosphorylation is related to a concomitant shift in molecular
      mass from 31 to 46 kDa. However, we found that Pdx1 was modified by SUMO-1 (small
      ubiquitin-related modifier 1) in beta-TC-6 and COS-7 cells, which were
      transfected with Pdx1 cDNA. This modification contributed to the increase in
      molecular mass of Pdx1 from 31 to 46 kDa. Additionally, sumoylated Pdx1 localized
      in the nucleus. The reduction of SUMO-1 protein by use of RNA interference (SUMO
      iRNAs) resulted in a significant decrease in Pdx1 protein in the nucleus. A 34
      kDa form of Pdx1 was detected by the cells exposed to SUMO-iRNAs in the presence
      of lactacystin, a proteasome inhibitor. Furthermore, the reduced nuclear
      sumoylated Pdx1 content was associated with significant lower transcriptional
      activity of the insulin gene. These findings indicate that SUMO-1 modification is
      associated with both the localization and stability of Pdx1 as well as its effect
      on insulin gene activation.

PMID- 12488244
TI  - Protein anabolic effects of insulin and IGF-I in the ovine fetus.
AB  - We determined the effect of insulin and/or recombinant human (rh)IGF-I infusion
      on ovine fetal phenylalanine kinetics, protein synthesis, and phenylalanine
      accretion. The chronically catheterized fetal lamb model was used at 130 days
      gestation. All studies were performed while fetal glucose and amino acid
      concentrations were held constant. Experimental infusates were 1). saline, 2).
      rhIGF-I plus a replacement dose of insulin (40 nmol), 3). insulin (890 mIU/h),
      and 4). IGF-I plus insulin (40 nmol IGF-I/h and 890 mIU insulin/h). Both hormones
      increased glucose and amino acid utilization, with insulin having a greater
      effect. The major effect on phenylalanine kinetics was a pronounced fall in
      phenylalanine hydroxylation, again with insulin having the greatest effect. Whole
      body protein breakdown was not significantly altered by either hormone; whole
      body protein synthesis was significantly increased during the combined infusion.
      Protein accretion was increased by both hormones, with the greatest increase
      during combined infusion. The fractional synthetic rate (FSR) of circulating
      albumin was increased by IGF-I but not by insulin. Both hormones significantly
      increased skeletal muscle FSR without a synergistic effect. The anabolic effects
      of insulin and IGF-I were more pronounced in these studies than in previous
      studies where amino acid concentrations were not maintained. The present data
      also suggest that insulin and IGF-I promote fetal growth through distinct, organ
      specific mechanisms.

PMID- 12488245
TI  - Regulation of 5'AMP-activated protein kinase activity and substrate utilization
      in exercising human skeletal muscle.
AB  - The metabolic role of 5'AMP-activated protein kinase (AMPK) in regulation of
      skeletal muscle metabolism in humans is unresolved. We measured isoform-specific
      AMPK activity and beta-acetyl-CoA carboxylase (ACCbeta) Ser(221) phosphorylation
      and substrate balance in skeletal muscle of eight athletes at rest, during
      cycling exercise for 1 h at 70% peak oxygen consumption, and 1 h into recovery.
      The experiment was performed twice, once in a glycogen-loaded (glycogen
      concentration approximately 900 mmol/kg dry wt) and once in a glycogen-depleted
      (glycogen concentration approximately 160 mmol/kg dry wt) state. At rest, plasma
      long-chain fatty acids (FA) were twofold higher in the glycogen-depleted than in
      the loaded state, and muscle alpha1 AMPK (160%) and alpha2 AMPK (145%) activities
      and ACCbeta Ser(221) phosphorylation (137%) were also significantly higher in the
      glycogen-depleted state. During exercise, alpha2 AMPK activity, ACCbeta Ser(221)
      phosphorylation, plasma catecholamines, and leg glucose and net FA uptake were
      significantly higher in the glycogen-depleted than in the glycogen-loaded state
      without apparent differences in muscle high-energy phosphates. Thus exercise in
      the glycogen-depleted state elicits an enhanced uptake of circulating fuels that
      might be associated with elevated muscle AMPK activation. It is concluded that
      muscle AMPK activity and ACCbeta Ser(221) phosphorylation at rest and during
      exercise are sensitive to the fuel status of the muscle. During exercise, this
      dependence may in part be mediated by humoral factors.

PMID- 12488246
TI  - Male gender increases sensitivity to renal injury in response to cholesterol
      loading.
AB  - Males are at greater risk for renal injury than females. This may relate to
      nitric oxide (NO) availability, because female rats have higher renal endothelial
      NO synthase (NOS) levels. Previously, our laboratory found susceptibility to
      proteinuria induced by NOS inhibition in male compared with female rats.
      Dyslipidemia and hypercholesterolemia dose dependently decreased renal NOS
      activity and caused renal injury in female rats. We hypothesized that exposure of
      male rats to hypercholesterolemia would lead to more renal injury in male than in
      female rats due to an a priori lower renal NO system. Female and male rats were
      fed no, low-dose, or high-dose cholesterol for 24 wk. Cholesterol feeding dose
      dependently increased proteinuria in both female and male rats, but male rats
      developed more proteinuria at similar plasma cholesterol (P < 0.001). Control
      males had lower renal NOS activity than control females (4.44 +/- 0.18 vs. 7.46
      +/- 0.37 pmol. min(-1). mg protein(-1); P < 0.05), and cholesterol feeding
      decreased renal NOS activity in males and in females (P < 0.05). Cholesterol-fed
      males developed significantly more vascular, glomerular, and tubulointerstitial
      monocyte/macrophage influx and injury than females. Thus under baseline
      conditions, male rats have lower renal NOS activity than female rats. This may
      explain why male rats are more sensitive to renal injury by factors that decrease
      NO availability, such as hypercholesterolemia.

PMID- 12488247
TI  - Characterization of a type IIb sodium-phosphate cotransporter from zebrafish
      (Danio rerio) kidney.
AB  - Zebrafish (Danio rerio) express two isoforms of the type IIb Na-dependent P(i)
      cotransporter (NaPi). Type NaPi-IIb1 has previously been cloned and
      characterized. Here, we report the cloning of the NaPi-IIb2 transcript from
      zebrafish kidney, its localization, and its functional characterization. RT-PCR
      with renal RNA and degenerate NaPi-IIb-specific primers resulted in a specific
      fragment. 3'-Rapid amplification of cDNA ends yielded a product that contained
      typical NaPi-IIb characteristics such as a cysteine-rich COOH terminus and a PDZ
      (PSD95- Dlg-zona occludens-1) binding motif. Several approaches were unsuccessful
      at cloning the 5' end of the transcript; products lacked an in-frame start codon.
      The missing information was obtained from an EST (GenBank accession number ). The
      combined clone displayed a high degree of homology with published type IIb
      cotransporter sequences. Specific antibodies were raised against a COOH-terminal
      epitope of both NaPi-IIb1 and NaPi-IIb2 isoforms. Immunohistochemical mapping
      revealed apical expression of both isoforms in zebrafish renal and intestinal
      epithelia, as well as in bile ducts. The novel clone was expressed in oocytes,
      and function was assayed by the two-electrode voltage-clamp technique. The
      function of the new NaPi-IIb2 clone was found to be significantly different from
      NaPi-IIb1 despite strong structural similarities. NaPi-IIb2 was found to be
      strongly voltage sensitive, with higher affinities for both sodium and phosphate
      than NaPi-IIb1. Also, NaPi-IIb2 was significantly less sensitive to external pH
      than NaPi-IIb1. The strong structural similarity but divergent function makes
      these zebrafish transporters ideal models for the molecular mapping of
      functionally important regions in the type II NaPi-cotransporter family.

PMID- 12488248
TI  - Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly
      coupled to the Na+ gradient.
AB  - Basolateral uptake of organic anions in renal proximal tubule cells is indirectly
      coupled to the Na(+) gradient through Na(+)-dicarboxylate cotransport and organic
      anion/dicarboxylate exchange. One member of the organic anion transporter (OAT)
      family, Oat1, is expressed in the proximal tubule and is an organic
      anion/dicarboxylate exchanger. However, a second organic anion carrier, Oat3, is
      also highly expressed in the renal proximal tubule, but its mechanism is unclear.
      Thus we have assessed Oat3 function in Xenopus laevis oocytes and rat renal
      cortical slices. Probenecid-sensitive uptake of p-aminohippurate (PAH, an Oat1
      and Oat3 substrate) and estrone sulfate (ES, an Oat3 substrate) in rat Oat3
      expressing oocytes was significantly trans-stimulated by preloading the oocytes
      with the dicarboxylate glutarate (GA). GA stimulation of ES transport by oocytes
      coexpressing rabbit Na(+)-dicarboxylate cotransporter 1 and rat Oat3 was
      significantly inhibited when the preloading medium contained Li(+) or
      methylsuccinate (MS) or when Na(+) was absent. All these treatments inhibit the
      Na(+)-dicarboxylate cotransporter, but not rat Oat3. Li(+), MS, and Na(+) removal
      had no effect when applied during the ES uptake step, rather than during the GA
      preloading step. Concentrative ES uptake in rat renal cortical slices was also
      demonstrated to be probenecid and Na(+) sensitive. Accumulation of ES was
      stimulated by GA, and this stimulation was completely blocked by probenecid,
      Li(+), MS, taurocholate, and removal of Na(+). Thus Oat3 functions as an organic
      anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the
      Na(+) gradient.

PMID- 12488250
TI  - Interesting idea-prove it!

PMID- 12488251
TI  - The OPA1 gene and optic neuropathy.

PMID- 12488252
TI  - Weaning children with accommodative esotropia out of spectacles: a pilot study.
AB  - BACKGROUND/AIM: Many children with accommodative esotropia must continue
      spectacle use throughout life. This study was undertaken to determine which
      factors are predictive of successfully weaning children with accommodative
      esotropia out of spectacles. METHODS: A retrospective review of 10 children with
      accommodative esotropia, who were gradually weaned from their hyperopic
      correction, and three age matched controls was performed. The main outcome
      measure was resolution or non-resolution of esotropia following weaning and
      eventual discontinuation of spectacles. Secondary outcome measures were final
      refractive error and the final esotropic or esophoric angle without correction.
      RESULTS: Six patients were successfully weaned from spectacles. At the completion
      of the weaning period one child was orthophoric and the other five children had
      well controlled esophorias. The other four patients remained spectacle dependent
      because of persistent esotropia or decreased vision without spectacles. The
      baseline and final refractive errors were significantly lower in the children
      successfully weaned from spectacles (p = 0.014). While the children who were
      successfully weaned from spectacles were older when initially diagnosed with
      accommodative esotropia (4.6 v 2.5 years), this difference was not statistically
      significant (p = 0.09). CONCLUSION: Some children with accommodative esotropia
      may be weaned out of spectacles during the grade school years with resolution of
      their esotropia. It is likely that gradual reduction of the hyperopic correction
      increases divergence amplitudes, but it is unclear whether this facilitates
      emmetropisation.

PMID- 12488253
TI  - Quality of life with macular degeneration: perceptions of patients, clinicians,
      and community members.
AB  - BACKGROUND/AIMS: Age related macular degeneration (ARMD) is a common
      ophthalmological disorder that can significantly impair a patient's ability to
      function independently and potentially have a dramatic impact on health related
      quality of life. The aim of this study is to evaluate the quality of life of
      patients with ARMD, through the use of utility evaluation, and assess whether
      clinicians and healthy volunteers appreciate the impact of ARMD on health related
      quality of life. METHODS: A standardised questionnaire using the time-tradeoff
      method of utility analysis was created to assess health related quality of life.
      This questionnaire was distributed to 115 patients with ARMD. A similar
      questionnaire was distributed to 142 healthy volunteers and 62 clinicians who
      were asked to assume that they had ARMD. Comparisons were made among the
      responses from the members of the three groups. RESULTS: There was a significant
      difference in the utility scores among respondents with mild, moderate, and
      severe ARMD when compared to members of the general public and clinicians who
      were asked to assume they had each severity of ARMD. For mild ARMD the mean
      utility scores were 0.932, 0.960, and 0.832, for the general public, clinicians,
      and patients respectively (F = 21.7; p <0.001). No significant difference was
      found between the community members and clinicians (p <0.166); however, the
      patient group differed significantly from the general public (p<0.001) and
      clinician (p <0.001) groups. The utility scores for moderate ARMD for the general
      public, clinicians, and patients were 0.918, 0.877, and 0.732, respectively. (F =
      34.6, p <0.001). There was no significant difference between the general public
      and clinicians (p <0.143); however, the patient group differed significantly
      compared with the general public (p <0.001) and clinician (p <0.001) groups. The
      utility scores for people with severe ARMD in the general public, clinician, and
      patient groups were 0.857, 0.821, and 0.566, respectively (F = 45.5; p <0.001).
      No significant difference was shown between the community members and clinicians
      (p <0.386); however, a significant difference was seen when comparing the patient
      group with the community member and clinician (p<0.001) groups. CONCLUSION:
      Clinicians and community members may greatly underestimate the impact of mild,
      moderate, and severe ARMD on health related quality of life.

PMID- 12488254
TI  - Paediatric cataract blindness in the developing world: surgical techniques and
      intraocular lenses in the new millennium.
AB  - Paediatric cataract blindness presents an enormous problem to developing
      countries in terms of human morbidity, economic loss, and social burden. Managing
      cataracts in children remains a challenge: treatment is often difficult, tedious,
      and requires a dedicated team effort. To assure the best long term outcome for
      cataract blind children, appropriate paediatric surgical techniques need to be
      defined and adopted by ophthalmic surgeons of developing countries. The high cost
      of operative equipment and the uneven world distribution of ophthalmologists,
      paediatricians, and anaesthetists create unique challenges. This review focuses
      on issues related to paediatric cataract management that are appropriate and
      suitable for ophthalmic surgeons in the developing world. Practical guidelines
      and recommendations have also been provided for ophthalmic surgeons and health
      planners dealing with childhood cataract management in the developing world.

PMID- 12488255
TI  - Causes of childhood blindness: results from schools for the blind in south
      eastern Nigeria.
AB  - AIM: This cross sectional study was undertaken to identify the major causes of
      childhood severe visual impairment/blindness (SVI/BL) among students in schools
      for the blind in south eastern Nigeria with a view to offering treatment to those
      with remediable blindness. METHODS: 142 students attending three schools for the
      blind in the study area were interviewed and examined using the World Health
      Organization programme for prevention of blindness (WHO/PBL) childhood blindness
      proforma. RESULTS: By anatomical classification, the major causes of SVI/BL
      identified in the children (aged 15 years or less) were lesions of the lens
      (30.4%), corneal lesions (21.7%), whole globe lesions (mainly phthisis bulbi)
      (17.4%), and glaucoma/buphthalmos (10.9%). For the young adults (more than 15
      years) these lesions accounted for 31.9%, 21.3%, 23.4%, and 8.5% of SVI/BL,
      respectively. For all the students, the commonest single diagnoses were cataract
      (23.5%) and corneal scarring (21.4%), of which 86.7% were caused by measles. By
      aetiological classification, childhood factors (38.6%) constituted the major
      cause of blindness: 37.0% in the children and 39.4% in the young adults. In 74.5%
      of all the students, blindness was considered avoidable. CONCLUSIONS: A high
      proportion of childhood blindness in schools for the blind in south eastern
      Nigeria is avoidable. Development of paediatric ophthalmology in Nigeria to
      manage childhood cataract and glaucoma is advocated.

PMID- 12488256
TI  - Intraocular pressure after intravitreal injection of triamcinolone acetonide.
AB  - AIM: To investigate the intraocular pressure (IOP) response after intravitreal
      injections of triamcinolone acetonide as treatment of intraocular neovascular or
      oedematous diseases. METHODS: The prospective consecutive non-comparative
      interventional case series study included 71 patients (75 eyes) with progressive
      exudative age related macular degeneration (n = 64 eyes) or diffuse diabetic
      macular oedema (n = 11 eyes), who received an intravitreal injection of 25 mg
      triamcinolone acetonide. Mean follow up time was 6.86 (SD 2.52) months (range 3.1
      14.47 months). RESULTS: IOP increased significantly (p<0.001) from 15.43 (3.26)
      mm Hg preoperatively to a mean maximum of 23.38 (8.37) mm Hg (range 13-64 mm Hg)
      postoperatively. An IOP rise to values higher than 21 mm Hg was observed in 39
      (52%) eyes. Elevation of IOP occurred about 2 months after the injection.
      Preoperative predictive factor for the rise in IOP was younger age (p=0.013). It
      was statistically independent of refractive error, presence of diabetes mellitus,
      and indication for the injection. In all but one eye, IOP could be lowered to the
      normal range with topical medication, without development of glaucomatous optic
      nerve head changes. In the eyes with an elevation of IOP, IOP normalised about 6
      months after the injection, without further medication. Eyes undergoing
      repeatedly intravitreal injections of triamcinolone acetonide showed only an
      elevation of IOP, if after the first injection a rise of IOP had occurred.
      CONCLUSIONS: After intravitreal injections of 25 mg of triamcinolone acetonide,
      an IOP elevation can develop in about 50% of eyes, starting about 1-2 months
      after the injection. In the vast majority, IOP can be normalised by topical
      medication, and returns to normal values without further medication about 6
      months after the injection.

PMID- 12488257
TI  - A multicentre randomised double masked clinical trial of a new formulation of
      topical cysteamine for the treatment of corneal cystine crystals in cystinosis.
AB  - AIM: To evaluate the safety and efficacy of a new topical cysteamine formulation,
      stable at room temperature, for the treatment of corneal cystine crystals in
      cystinosis. METHODS: 20 study subjects were enrolled in the safety study and 16
      in the efficacy study. Both studies were randomised and double blind. The primary
      outcome for the safety study was the occurrence of predefined serious adverse
      reactions over 6 months and for the efficacy study the reduction of corneal
      cystine crystal score (CCCS) by 1.00 or more units on photographs graded by a
      reading centre using a standardised protocol. RESULTS: No study subject developed
      any serious adverse reactions. In the efficacy study, 47% of eyes receiving the
      standard formulation experienced a reduction in the CCCS of >/=1.00 after 1 year,
      while 7% of eyes on the new formulation experienced such a decrease (p=0.04).
      CONCLUSION: Although no serious adverse reactions were observed with either
      formulation, the new formulation was not as effective as the standard
      formulation.

PMID- 12488259
TI  - Quantitative analysis of axonal loss in band atrophy of the optic nerve using
      scanning laser polarimetry.
AB  - AIMS: To measure axonal loss in patients with band atrophy from optic chiasm
      compression using scanning laser polarimetry (GDx, Laser Diagnostic Technologies,
      Inc, San Diego, CA, USA) and to evaluate the ability of this instrument to
      identify this pattern of retinal nerve fibre layer (RNFL) loss. METHODS: 19 eyes
      from 17 consecutive patients with band atrophy of the optic nerve and permanent
      temporal hemianopia due to chiasmal compression, and 19 eyes from an age and sex
      matched control group of 17 healthy individuals were prospectively studied. All
      patients were submitted to an ophthalmic examination including Goldmann perimetry
      and evaluation of the RNFL using scanning laser polarimetry. Mean RNFL thickness
      around the optic disc were compared between the two groups. The diagnostic
      performance of the deviation from normal analysis provided by the GDx software
      was also assessed. RESULTS: The peripapillary RNFL thickness (mean (SD)) of eyes
      with band atrophy was 47.9 (7.63) micro m, 37.1 (8.48) micro m, 57.0 (9.31) micro
      m, and 37.2 (8.86) micro m in the superior, temporal, inferior, and nasal
      regions, respectively. The total average was 43.7 (12.0) micro m. In the control
      group, the corresponding values were 71.1 (12.2) micro m, 40.4 (10.9) micro m,
      85.4 (14.0) micro m, and 49.8 (10.1) micro m. The total average measured 67.9
      (11.2) micro m. The measurements from eyes with optic atrophy were significantly
      different from those in the control group in all regions but the temporal. The
      deviation from normal analysis provided by the GDx software failed to identify
      the majority of abnormalities in the temporal and nasal regions of patients with
      band atrophy. CONCLUSIONS: Scanning laser polarimetry was able to identify axonal
      loss in the superior, inferior, and nasal regions, but failed to detect it in the
      temporal region of the optic disc, despite the fact that this area was clearly
      altered in eyes with band atrophy. This examination also showed poor sensitivity
      to detect axonal loss in the nasal region when GDx software analysis was used.
      The results of this study emphasise that RNFL evaluation using scanning laser
      polarimetry should be interpreted with caution in the study of eye diseases that
      lead to axonal loss predominantly in the nasal and temporal areas of the optic
      disc.

PMID- 12488260
TI  - Orbital myositis in scleritis.
AB  - AIMS: To investigate the association between scleritis and myositis. METHODS:
      Retrospective, non-comparative case series. Records and ultrasonograms were
      examined of 132 patients, with a diagnosis of episcleritis or scleritis, who
      attended the ophthalmology department at Leiden University Medical Center between
      1997 and 2000. 103 were eligible for comprehensive examination. Medical records
      were evaluated. Ultrasonography was performed in all patients diagnosed with
      episcleritis or scleritis. Clinical features, precipitating factors, systemic
      associations, ocular complications, treatment, and outcome of each patient were
      assessed. RESULTS: Of the 103 patients, 27 (26.2%) had episcleritis and 76
      (73.8%) had scleritis. Myositis was found to be present in 11 patients. It was
      present in 14.5% of all patients with scleritis and 30.5% of those in whom the
      posterior sclera was affected. The presence of the associated myositis did not
      worsen the visual prognosis and the presence of myositis was not associated with
      other systemic diseases. There were no cases of unilateral scleritis with
      bilateral orbital myositis. During an attack ocular complications were more
      common in patients with scleritis and myositis (64%) than in patients with
      scleritis alone (30.4%), indicating a more diffuse and potentially dangerous
      inflammation. There was no evidence that the inflammatory changes in the orbit
      had spread to involve the sclera, so it is assumed that the muscle changes are an
      extension of a generalised response to intense inflammation of the episclera and
      sclera. CONCLUSION: This study found a frequent association between myositis and
      scleritis. Prognosis for vision was not affected by coexistence of myositis.

PMID- 12488261
TI  - Mechanical endonasal dacryocystorhinostomy with mucosal flaps.
AB  - AIMS: To describe and assess the efficacy of mechanical endonasal
      dacryocystorhinostomy (MENDCR). This is a new technique that involves creation of
      a large rhinostomy and mucosal flaps. The study involved a prospective non
      randomised interventional case series with short perioperative follow up. METHOD:
      A prospective series of 104 consecutive endonasal DCRs performed from January
      1999 to December 2001 were entered into the study. Patients included in the study
      had nasolacrimal duct obstruction and had not had previous lacrimal surgery. The
      technique involved anastomosis of nasal mucosal and lacrimal sac flaps and a
      large bony ostium. Surgery was performed by two surgeons (AT/PJW). Follow up
      assessment included nasoendoscopy as well as symptom evaluation. Success was
      defined as anatomical patency with fluorescein flow on nasoendoscopy and patency
      to lacrimal syringing. The average follow up time was 9.7 months (range 2-28, SD
      6.7 months). RESULTS: There were 104 DCRs performed on 86 patients (30 male, 56
      female). The average age of the patients was 59 years (range 3-89, SD 24.1
      years). Common presentations were epiphora (77%) and/or mucocele (19%).
      Septoplasty (SMR) was required in 48 DCRs (46%) and 13 DCRs (12.5%) needed other
      endoscopic surgery in conjunction with the lacrimal surgery. The surgery was
      successful in 93 cases (89%). Of the 11 cases that were classified as a failure
      six patients was anatomically patent but still symptomatic and another two had
      preoperative canalicular problems. The anatomical patency with this new technique
      was thus 95% (99 of 104 DCRs). CONCLUSION: MENDCR involves creation of a large
      ostium and mucosal preservation for the construction of flaps. The anatomical
      success is 95% and is similar to external DCR and better then other endonasal
      approaches. The authors suggest that creation of a large ostium as well as
      mucosal flaps improves the efficacy of this endonasal technique.

PMID- 12488262
TI  - Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy.
AB  - BACKGROUND/AIMS: Patients with autosomal dominant optic atrophy (ADOA) are
      genetically heterogeneous, but all have disc pallor. A degree of cupping in ADOA
      can make the distinction from normal tension glaucoma (NTG) clinically difficult.
      This study aimed to clarify the features of the optic nerve of patients with ADOA
      at the OPA1 locus. METHODS: 29 patients (58 eyes), from 12 families, were
      identified in a prospective observational study of patients with ADOA examined by
      a single observer between 1995 and 1998, in whom genetic analysis showed either
      evidence for linkage to chromosome 3q28 or mutations in the ADOA gene, OPA1. All
      of the patients had disc and fundal photographs available for retrospective
      analysis. Clinical data collected included disc appearance, intraocular pressure,
      Snellen visual acuity, Hardy-Rand-Rittler colour vision plates, and Humphrey 30-2
      visual fields. RESULTS: Mean age at time of examination was 37 years and mean
      visual acuity was 6/24. Disc morphology showed temporal disc pallor in 30 eyes
      (52%) and total disc pallor in 28 eyes (48%). At least one disc showed a cup to
      disc ratio of more than 0.5 in 18 patients (28 discs, 48%). The temporal
      neuroretinal rim always showed pallor and shallow shelving (or saucerisation) was
      seen in 46 eyes (79%). Only 12 discs (21%) had deep excavation and baring of
      blood vessels. All of the patients had normal intraocular pressure and no family
      history of glaucoma. There was a temporal grey, pigmentary crescent in 12
      patients (18 eyes, 31%) and peripapillary atrophy in 20 patients (40 eyes, 69%),
      but disc margin haemorrhages were not seen. There was no maculopathy or
      retinopathy. CONCLUSION: The optic disc morphology, described for the first time
      in this genetically homogeneous population of patients with OPA1 ADOA, shows a
      distinctive absence of a healthy neuroretinal rim and shallow saucerisation of
      the optic disc cup, with frequent peripapillary atrophy.

PMID- 12488263
TI  - Botulinum toxin A treatment in patients suffering from blepharospasm and dry eye.
AB  - BACKGROUND: Many patients with essential blepharospasm also show dry eye signs
      and symptoms. Botulinum toxin A is an effective treatment for reducing spasms in
      these patients. In this investigation, the effect of botulinum toxin A injections
      on tear function and on the morphology of the ocular surface in patients
      suffering from blepharospasm in combination with a dry eye syndrome was
      investigated. METHODS: Botulinum toxin A injections were applied to 16 patients
      with blepharospasm. All patients complained of dry eye symptoms and had reduced
      tear break up time values. A subjective questionnaire and ocular examinations
      including tear break up time, Schirmer test without local anaesthesia, and rose
      bengal staining were evaluated before, 1 week, 1 month, and 3 months after
      injection. Impression cytology was performed before, 1 month, and 3 months after
      botulinum toxin A treatment. RESULTS: Although all patients were relieved of
      blepharospasm after botulinum toxin injections, only three noticed an improvement
      in dry eye symptoms. Eight patients noticed no difference and five complained of
      worsening. Tear break up time was found to be increased 1 week and 1 month after
      injections. Schirmer test measurements were reduced up to 3 months. Rose bengal
      staining slightly increased 1 week after injections. Impression cytology showed
      no definite change in conjunctival cell morphology 1 month and 3 months after
      botulinum toxin A injections. CONCLUSION: In the patients presented here
      suffering from blepharospasm and dry eye, botulinum toxin A injections were
      effective in relieving blepharospasm but were not successful in treating dry eye
      syndrome.

PMID- 12488264
TI  - A randomised, double masked, multicentre clinical trial comparing bimatoprost and
      timolol for the treatment of glaucoma and ocular hypertension.
AB  - AIM: To evaluate the safety and efficacy of bimatoprost 0.03% once daily or twice
      daily compared with timolol 0.5% twice daily in patients with glaucoma or ocular
      hypertension. METHODS: Multicentre, double masked, randomised, parallel group, 3
      month trial comparing bimatoprost once daily (n=240), bimatoprost twice daily
      (n=240), and timolol twice daily (n=122). The primary efficacy end point was
      diurnal intraocular pressure (IOP) (8 am, 10 am, 4 pm). Safety measures included
      adverse events, ocular parameters, and systemic variables. RESULTS: Bimatoprost
      once daily provided significantly lower mean IOP than timolol twice daily at all
      times and follow up visits (p<0.001). At month 3, mean IOP reductions from
      baseline at 10 am (peak timolol effect) were bimatoprost once daily, 8.0 mm Hg
      (32.4%); bimatoprost twice daily, 6.3 mm Hg (25.2%); timolol, 5.5 mm Hg (22.7%).
      Bimatoprost twice daily was also more effective than timolol, but was not as
      effective as bimatoprost once daily. A higher percentage of patients achieved low
      target pressures with bimatoprost once daily than with timolol. The most frequent
      side effects with bimatoprost were eyelash growth and mild conjunctival
      hyperaemia. Systemic safety parameters were not affected by bimatoprost.
      CONCLUSIONS: Bimatoprost 0.03% once daily demonstrated superior efficacy compared
      with timolol 0.5% twice daily in patients with elevated IOP. Bimatoprost once
      daily was more effective than twice daily dosing.

PMID- 12488265
TI  - Clinical experience of e-PTFE membrane implant surgery for refractory glaucoma.
AB  - AIMS: To evaluate the clinical efficacy of membrane tube implant made of expanded
      polytetrafluoroethylene (e-PTFE, Gore-Tex) membrane and silicone tube in treating
      refractory glaucoma. METHODS: A retrospective chart review was performed on 43
      eyes of 40 patients who underwent glaucoma tube shunt implant surgery using
      double layered e-PTFE membrane and silicone tube to treat refractory glaucoma.
      The surgeries were performed from May 1991 to September 1995, and the subjects
      were patients with terminal glaucoma without useful vision on the study eye.
      RESULTS: The mean follow up period was 32.9 months. The Kaplan-Meier survival for
      intraocular pressure (IOP) control (IOP between 6 and 21mm Hg without significant
      complication) was 80.9% at 1 year, 73.9% at 2 years, and 62.2% at 3 years after
      surgery. After excluding three eyes of three patients who were dropped within 3
      months after surgery and did not have any serious complication or problem in IOP
      control, the average preoperative IOP was 42.5 (SD 14.6) mm Hg and IOP on the
      last visit was 17.3 (10.2) mm Hg (p = 0.000, n = 40). The number of antiglaucoma
      medications before surgery (2.2 (0.6)) was reduced to 0.5 (0.8) on the last visit
      (p = 0.000). The IOP was controlled within the range of 6-21 mm Hg in 26 eyes
      (65.0%). In the remaining 14 eyes (35%), we could not control the IOP or
      additional surgery was needed to control the IOP or to treat severe
      complications. Two cases of endophthalmitis and three of phthisis were found as
      serious complications. The other complications were similar to those of other
      commercially available glaucoma implants. CONCLUSION: A comparable clinical
      result was obtained with this new implant as with the other commercially
      available implants. This implant with a thin and non-rigid reservoir has a
      potential to reduce some complications associated with the large volume and rigid
      consistency of the other implants, although it is not yet proved. This membrane
      tube implant may be considered as another substitute in the surgery of refractory
      glaucoma.

PMID- 12488266
TI  - Indocyanine green assisted retinal internal limiting membrane removal in stage 3
      or 4 macular hole surgery.
AB  - AIMS: To determine surgical outcome in primary idiopathic stage 3 or 4 macular
      holes with indocyanine green (ICG) assisted retinal internal limiting membrane
      (ILM) peeling. METHODS: A prospective, consecutive, interventional case series
      with 41 eyes of 40 patients was included. No patient defaulted follow up. Besides
      a standard macular hole surgery, all eyes received ICG assisted ILM removal of 3
      4 disc diameters around macular holes. At the end of the surgery, 12%
      perfluoropropane gas was used. A face down posture for 2 weeks was required
      postoperatively. RESULTS: The mean follow up period was 15.1 months (range 6-24
      months). Twenty (48.8%) eyes had stage 3 macular holes and 21 (51.2%) had stage 4
      macular holes. The overall median duration of holes was 11 months. 19 (46.3%)
      were chronic macular holes of more than 12 months' duration. The anatomical
      success rates after one surgery was 87.8% (36 eyes), while that of chronic and
      non-chronic ones was 78.9% and 95.5%, respectively. The median preoperative and
      postoperative visual acuity was 20/200 (range 20/60 to counting fingers) and
      20/100 (range 20/20 to 20/400), respectively. 24 (58.5%) eyes had improvement of
      two or more Snellen lines. The mean was 3.2 lines (range two to nine lines), with
      3.6 lines and 2.7 lines for non-chronic and chronic holes, respectively. For all
      the 41 eyes, 16 (39%) eyes had a final visual acuity of 20/50 or better.
      CONCLUSION: ICG assisted retinal ILM removal, in idiopathic primary chronic and
      non-chronic stage 3 or 4 macular hole surgery, appears to give a promising
      anatomical closure rate without compromising the visual result.

PMID- 12488267
TI  - A matched study of primary scleral buckle placement during repair of posterior
      segment open globe injuries.
AB  - AIMS: To compare the visual and anatomical outcomes of patients who underwent
      primary scleral buckle (SB) placement during posterior segment open globe repair
      with matched control patients who did not undergo primary SB placement. METHODS:
      Patients who underwent open globe repair alone or with SB placement at Duke
      University Eye Center (November 1994-September 1997) and the Massachusetts Eye
      and Ear Infirmary (July 1993-July 1997) were identified. 19 open globe patients
      who received primary SB placement were matched with control patients who did not
      receive a primary SB based on three important prognostic factors: (1) visual
      grade; (2) zone of injury; and (3) mechanism of injury. The outcomes of interest
      were: (1) visual outcome; (2) anatomical outcome; (3) subsequent retinal
      detachment (RD); and (4) number of subsequent surgeries. RESULTS: Baseline
      characteristics between the groups were similar. Patients who received primary SB
      placement had a better final visual grade (p = 0.02), logMAR vision (p = 0.007),
      and anatomical grade (p = 0.01) compared with control patients. Primary SB
      patients had an average final vision of 20/270, whereas control patients had an
      average final vision of hand movement. Primary SB placement also resulted in
      fewer subsequent RDs (26% versus 53%), but this difference did not reach
      statistical significance (p = 0.10). There were no complications associated with
      primary SB placement. CONCLUSION: Primary SB placement during posterior segment
      open globe repair may decrease the risk of subsequent RD and improve final visual
      and anatomical outcome.

PMID- 12488268
TI  - Polymerase chain reaction analysis of aqueous humour samples in necrotising
      retinitis.
AB  - AIM: To evaluate the diagnostic value of polymerase chain reaction (PCR)
      performed on aqueous humour for the detection of viral DNA in patients with
      necrotising herpetic retinitis. METHODS: The clinical features and laboratory
      results of 22 patients (29 eyes) presenting with necrotising herpetic retinitis
      between March 1999 and June 2001 were reviewed retrospectively. Aqueous humour
      was obtained after anterior chamber paracentesis and PCR was performed in all
      cases. RESULTS: Viral DNA was detected in the aqueous humour of 19 patients
      (86.4%). Epstein-Barr virus (EBV) seroconversion was evidenced in one additional
      patient. In the acute retinal necrosis (ARN) group (n = 19), varicella zoster
      virus (VZV) DNA was identified in six patients, herpes simplex virus 1 (HSV-1)
      DNA in two patients, herpes simplex virus 2 (HSV-2) DNA in four patients, and
      cytomegalovirus (CMV) genome in four patients. In the progressive outer retinal
      necrosis (PORN) group (n = 3), VZV DNA was detected in all patients. No sample
      was positive for more than one virus. CONCLUSIONS: PCR analysis of aqueous humour
      in patients with clinical features of necrotising viral retinitis can provide
      specific aetiological orientation and the method appears to be safe and highly
      sensitive.

PMID- 12488269
TI  - Photodynamic therapy using verteporfin in circumscribed choroidal haemangioma.
AB  - AIM: To investigate the safety and efficacy of photodynamic therapy with
      verteporfin in patients with choroidal haemangioma. METHODS: A non-randomised,
      prospective clinical investigation of 19 patients with symptomatic circumscribed
      choroidal haemangioma was performed. Unsuccessful pretreatment (external beam
      irradiation, laser photocoagulation) was performed in four patients. Patients
      were included when (1) subretinal exudation involving the fovea, (2) a decrease
      in visual function, and (3) additional symptoms (for example, metamorphopsia)
      were present. Photodynamic therapy (PDT) was performed with verteporfin at a
      concentration of 6 mg/m(2) body surface area and a light dose of 100 J/cm(2) at
      692 nm. RESULTS: The mean follow up time was 10.6 months (2-24 months). The mean
      number of treatment sessions was 2.15 (range 1-5). Visual acuity improved by at
      least one line in 73.3%, by at least two lines in 42.1%, was stable in 21.1%, and
      decreased by one line in 5.2% of the patients. Exudation was completely resolved
      in 94.8% of the cases. Regression of tumour height was documented in all 19
      tumours. Patients receiving any pretreatment before PDT, a visual acuity of 0.1
      and less, a history of more than 30 months, and no significant response after the
      first PDT session, did not show any significant improvement. Cox regression
      analysis revealed that the number of PDT treatment sessions was inversely
      associated with the improvement in visual acuity of at least two lines. No
      recurrences and no local or systemic side effects were observed during the follow
      up time. CONCLUSION: PDT using verteporfin is a safe and effective therapy for
      the treatment of symptomatic choroidal haemangioma even in tumours located
      beneath the fovea.

PMID- 12488270
TI  - Thermochemotherapy in hereditary retinoblastoma.
AB  - BACKGROUND/AIM: The combination of chemotherapy and transpupillary thermotherapy,
      thermochemotherapy (TCT) has become an established part of the treatment plan in
      advanced retinoblastoma. The aim of this study was to identify safe indications,
      the complications as well as the limitations of this new treatment for
      retinoblastoma. METHODS: Tumour response and side effects of TCT with an indirect
      laser ophthalmoscope (spot size about 400 micro m) in 55 tumours of 26 children
      with bilateral retinoblastoma were analysed. Using the Reese-Ellsworth
      classification system, nine of 35 eyes were classified as type I, 13 eyes as type
      II, 10 eyes as type III, and three eyes as type V. The mean age of the children
      was 0.74 (SD 0.61) years. The mean tumour height was 3.5 (2.3) mm with a mean
      diameter of 6.1 (4.1) mm. Treatment parameters were 4.3 (1.6) (median 5)
      thermochemotherapy sessions with a mean energy of 539 (211) mW and a mean
      duration of 13.5 (5.6) minutes. Chemotherapy courses (vincristine, etoposide, and
      carboplatin) were repeated every 3 weeks. The mean follow up period was 1.25
      (0.6) years. RESULTS: Local recurrence occurred in 21 tumours (38%), with a mean
      onset of 3.2 (2.9) months after TCT. The risk of tumour recurrence was correlated
      with tumour height. The recurrence rate was 17% for tumours with a height less
      than 2 mm, 37% for tumours with a height between 2 and 4 mm, and 63% for larger
      retinoblastomas. Multivariate analysis identified fish flesh regression after TCT
      (p = 0.0007) as the most important risk factor for tumour recurrence besides
      tumour height (p = 0.001) and the necessity of increased laser power during TCT
      sessions (p = 0.018). Complications during therapy included transient corneal
      opacification in two eyes (6%), focal iris atrophy (three eyes, 8.5%), peripheral
      lens opacity (two eyes, 6%), circumscribed transient retinal detachment (one eye,
      3%) and diffuse choroidal atrophy (one eye, 3%). CONCLUSION: TCT using an
      indirect laser ophthalmoscope with a spot size of about 400 micro m was efficient
      for retinoblastoma with a tumour height less than 4 mm. In larger tumours, the
      recurrence rate was unacceptably high. Fish flesh regression after TCT correlates
      with a higher rate of local tumour recurrence. Treatment related complications
      occurred in less than 9% of the treated eyes.

PMID- 12488271
TI  - Epilepsy patients treated with vigabatrin exhibit reduced ocular blood flow.
AB  - BACKGROUND/AIM: Reduced cerebral blood flow and decreased glucose metabolism have
      been identified in epilepsy patients receiving vigabatrin. It is likely that such
      a change may extend to the eye and may be linked to previously reported
      irreversible visual field defects. The aim of this study was to determine whether
      patients who have undergone anti-epileptic drug (AED) therapy with vigabatrin
      have altered ocular haemodynamics. METHODS: The study cohort comprised 11 normal
      subjects (mean age 42.6 (SD 12.7) years and 17 epilepsy patients, of which 10
      were either currently or previously treated with vigabatrin (38.6 (11.7) years)
      and seven were treated with AEDs excluding vigabatrin (46.0 (9.8) years). The
      three groups were matched at baseline for pulse rate, diastolic and systolic
      blood pressure, and intraocular pressure (IOP). At a single visit, the ocular
      blood flow analyser (OBFA; Paradigm Medical Instruments Inc, UT, USA) was used to
      measure pulsatile ocular blood flow (POBF) and pulse amplitude (PA) in each eye
      of all subjects. One way ANCOVA (with age as a covariate) was used to identify
      differences in POBF and PA between the groups. For the vigabatrin group only,
      Pearson's product moment correlation coefficient was used to explore potential
      interactions between ocular blood flow parameters and cumulative vigabatrin dose,
      duration, and maximum dose. RESULTS: Both the vigabatrin treated epilepsy group
      and conventionally treated epilepsy group exhibited significantly reduced POBF
      (p=<0.001, p=0.040) and PA (p=<0.001, p=0.005) compared to normal subjects.
      Patients treated with vigabatrin exhibited a further reduction in POBF (p=0.046)
      and PA (p=0.034) compared to conventionally treated epilepsy patients. No
      significant correlations were found between drug dosage and POBF and PA for the
      vigabatrin treated epilepsy group. CONCLUSIONS: A significant reduction in POBF
      and PA is apparent in epilepsy patients treated with AEDs when compared to normal
      subjects. A further reduction in POBF and PA is apparent between vigabatrin
      treated and conventionally treated patients. The reduction in ocular perfusion,
      which is more pronounced in patients previously treated with vigabatrin, may have
      implications in the impairment of visual function associated with the drug.

PMID- 12488272
TI  - Pericyte recruitment in human corneal angiogenesis: an ultrastructural study with
      clinicopathological correlation.
AB  - BACKGROUND/AIM: During angiogenesis-that is, the outgrowth of new from pre
      existing blood vessels, new capillaries undergo a period of "fine tuning" when
      vascular endothelial cells become apoptotic if sufficient supply of angiogenic
      factors is lacking. Morphologically, this period correlates with the absence of
      pericyte coverage of new vessels. Mature, pericyte covered vessels, in contrast,
      do not depend on elevated levels of angiogenic factors for survival. This study
      analyses whether, and if so when, pathological vessels in human corneal
      neovascularisation (CN) acquire pericyte coverage. This can be of importance for
      future angioregressive therapeutic strategies. METHODS: Vascularised human
      corneas obtained by keratoplasty were evaluated by electron microscopy for
      pericyte coverage of new vessels. These data were correlated with the duration of
      CN (mean 73 (SD 95) (range 0.5-360) months; n = 15). CN was secondary to
      keratitis, transplant rejection, aniridia, or trauma. RESULTS: Overall, 196 blood
      vessels were analysed ultrastructurally (72 (37%) capillaries, 122 (62%) venules,
      and two (1%) arterioles). Electron microscopically, 170 (87%) vessels were
      covered by pericytes and two (1%) in addition by smooth muscle cells. Pericyte
      recruitment increased with time, evolving between clinically noted onset of CN
      and keratoplasty. Already 2 weeks after onset of CN, more than 80% of new vessels
      were covered by pericytes. CONCLUSION: Pathological new vessels in human corneal
      angiogenesis are rapidly covered by pericytes. Therapeutic strategies aimed at
      regression of immature, not yet pericyte covered vessels by antagonising
      angiogenic factors should thus be most effective if applied very early in the
      course of corneal neovascularisation.

PMID- 12488273
TI  - Measurement error of visual field tests in glaucoma.
AB  - AIM: Psychophysical strategies designed for clinical visual field testing produce
      rapid estimates of threshold with relatively few stimulus presentations and so
      represent a trade-off between test quality and efficiency. The aim of this study
      was to determine the measurement error of a staircase algorithm similar to full
      threshold with standard automated perimetry (SAP) and frequency doubling
      perimetry (FDP) in glaucoma patients. METHODS: Seven patients with early open
      angle glaucoma (OAG) were prospectively recruited. All were experienced in
      laboratory based psychophysics. Three matched test locations were examined with
      SAP (externally driven Humphrey field analyser) and FDP (CRT) in a single
      arbitrarily selected eye of each subject. Each location was tested twice with a 4
      2-2 dB staircase strategy, similar to full threshold, and then with the method of
      constant stimuli (MOCS). Accuracy (threshold estimation error) was quantified by
      determination of differences between "true" threshold measurements made by MOCS
      and single staircase threshold estimates. Precision (repeatability) was
      quantified by the differences between repeated staircase threshold estimates.
      RESULTS: Precision was relatively high for both tests, although higher for FDP
      than SAP at depressed sensitivity levels. The staircase strategy significantly
      underestimated threshold sensitivity for both test types, with the mean
      difference (95% CI) between staircase and MOCS thresholds being 4.48 dB (2.35 to
      7.32) and 1.35 dB (0.56 to 1.73) for SAP and FDP respectively. Agreement levels
      (weighted kappa) between MOCS and staircase thresholds were found to be 0.48 for
      SAP and 0.85 for FDP. Although this "bias" appeared constant for FDP across all
      sensitivity levels, this was not the case for SAP where accuracy decreased at
      lower sensitivity levels. CONCLUSION: Estimations of threshold sensitivity made
      using staircase strategies common to clinical visual field test instrumentation
      are associated with varying degrees of measurement error according to visual
      field test type and sensitivity. In particular, SAP significantly overestimates
      the "true" level of sensitivity, particularly in damaged areas of the visual
      field, suggesting that clinical data of this type should be interpreted with
      caution.

PMID- 12488275
TI  - Eyelid skin adenoid cystic carcinoma: a clinicopathological study of one case
      simulating sebaceous gland carcinoma.

PMID- 12488274
TI  - Why HID headlights bother older drivers.
AB  - Driving requires effective coordination of visual, motor, and cognitive skills.
      Visual skills are pushed to their limit at night by decreased illumination and by
      disabling glare from oncoming headlights. High intensity discharge (HID)
      headlamps project light farther down roads, improving their owner's driving
      safety by increasing the time available for reaction to potential problems. Glare
      is proportional to headlamp brightness, however, so increasing headlamp
      brightness also increases potential glare for oncoming drivers, particularly on
      curving two lane roads. This problem is worse for older drivers because of their
      increased intraocular light scattering, glare sensitivity, and photostress
      recovery time. An analysis of automobile headlights, intraocular stray light,
      glare, and night driving shows that brightness rather than blueness is the
      primary reason for the visual problems that HID headlights can cause for older
      drivers who confront them. The increased light projected by HID headlights is
      potentially valuable, but serious questions remain regarding how and where it
      should be projected.

PMID- 12488276
TI  - Congenital trichomegaly (Oliver-McFarlane syndrome): a case report with 9 years'
      follow up.

PMID- 12488277
TI  - Adult orbital xanthogranuloma with periosteal infiltration.

PMID- 12488278
TI  - Acute keratoconus with perforation in a patient with Down's syndrome.

PMID- 12488279
TI  - Tacrolimus.

PMID- 12488280
TI  - Visual symptoms in patients on cyclophosphamide may herald sight threatening
      disease.

PMID- 12488281
TI  - Assessment of endothelium from donor corneas.

PMID- 12488282
TI  - Retinal vein occlusion and cardiovascular risk assessment.

PMID- 12488283
TI  - A randomised controlled trial of written information.

PMID- 12488285
TI  - Off label use--label off use?

PMID- 12488286
TI  - Pegfilgrastim: the promise of pegylation fulfilled.

PMID- 12488287
TI  - Evidence-based management options for women at increased breast/ovarian cancer
      risk.
AB  - Recent developments in our ability to predict breast cancer risk necessitates
      primary care physicians learn to evaluate breast cancer risk and its importance
      in shaping decisions concerning surveillance and risk reduction measures. This
      article reviews the current opinion on risk assessment and management of women
      with an increased risk of breast/ovarian cancer. Management options are given for
      women at slightly, moderately and highly elevated breast cancer risk, as well as
      for BRCA1/2 carriers, based on currently available evidence.

PMID- 12488288
TI  - The Snark is a Boojum: the continuing problem of drug resistance in the
      antiangiogenic era.
AB  - If your Snark be a Snark, that is right: Fetch it home by all means-you may serve
      it with greens, And it's handy for striking a light. "But oh, beamish nephew,
      beware of the day, If your Snark be a Boojum! For then You will softly and
      suddenly vanish away, And never be met with again!" Lewis Carroll The Hunting of
      the Snark

PMID- 12488289
TI  - A randomized double-blind multicenter phase III study of fixed-dose single
      administration pegfilgrastim versus daily filgrastim in patients receiving
      myelosuppressive chemotherapy.
AB  - BACKGROUND: We evaluated the efficacy of a single fixed 6 mg dose of
      pegfilgrastim (a pegylated version of filgrastim) per cycle of chemotherapy,
      compared with daily administration of filgrastim, in the provision of neutrophil
      support. PATIENTS AND METHODS: Patients (n = 157) were randomized to receive
      either a single 6 mg subcutaneous (s.c.) injection of pegfilgrastim or daily 5
      mg/kg s.c. injections of filgrastim, after doxorubicin and docetaxel chemotherapy
      (60 mg/m(2) and 75 mg/m(2), respectively). Duration of grade 4 neutropenia, depth
      of neutrophil nadir, incidence of febrile neutropenia, time to neutrophil
      recovery and safety information were recorded. RESULTS: A single 6 mg injection
      of pegfilgrastim was as effective as daily injections of filgrastim for all
      efficacy measures for all cycles. The mean duration of grade 4 neutropenia in
      cycle 1 was 1.8 and 1.6 days for the pegfilgrastim and filgrastim groups,
      respectively. Results for all efficacy end points in cycles 2-4 were consistent
      with the results from cycle 1. A trend towards a lower incidence of febrile
      neutropenia was noted across all cycles with pegfilgrastim compared with
      filgrastim (13% versus 20%, respectively). A single fixed dose of pegfilgrastim
      was as safe and well tolerated as standard daily filgrastim. CONCLUSIONS: A
      single fixed dose of pegfilgrastim administered once per cycle of chemotherapy
      was comparable to multiple daily injections of filgrastim in safely providing
      neutrophil support during myelosuppressive chemotherapy. Pegfilgrastim may have
      utility in other clinical settings of neutropenia.

PMID- 12488290
TI  - Evaluation of the nutritional and inflammatory status in cancer patients for the
      risk assessment of severe haematological toxicity following chemotherapy.
AB  - BACKGROUND: The toxicity outcome of cancer patients receiving chemotherapy is
      difficult to predict. In this study the influence of malnutrition and
      inflammation on acute haematological toxicity was investigated. PATIENTS AND
      METHODS: Between January 1999 and January 2000, 48 consecutive cancer patients
      experienced severe haematological toxicity (SHT), either neutropenic fever or
      severe thrombocytopenia, following various chemotherapy regimens. Their baseline
      characteristics were compared with those of 59 control patients. Previous
      chemotherapy regimens, type of chemotherapy, performance status (PS), calculated
      creatinine clearance, bilirubin, C-reactive protein (1), alpha-1 acid
      glycoprotein (2), albumin (3), pre-albumin (4) and the nutritional and
      inflammatory status (NIS) ratio [NIS = (1 x 2)/(3 x 4)] were studied. Statistical
      analysis was carried out using either a t-test or a chi-square test. A receiver
      operating characteristic (ROC) curve determined the cut-off value for NIS.
      RESULTS: Patients experiencing SHT had a higher PS (P <0.001), inflammatory serum
      protein levels (P <0.001) and NIS ratio (P <0.0001), but lower haemoglobin (P
      <0.05) and serum-albumin levels (P <0.0001). Using a cut-off of 0 or 1 for PS and
      1 for NIS, sensitivity was 98%, 43% and 89%; specificity was 38%, 90% and 66%,
      respectively. In 37 patients treated with topotecan as single agent, the
      determinants for SHT were PS (P <0.0001) and NIS (P <0.0001). CONCLUSIONS:
      Altered nutritional and inflammatory status correlates with increased risk of
      severe haematological toxicity following anticancer chemotherapy.

PMID- 12488291
TI  - Unlicensed and off label drug use in acute lymphoblastic leukaemia and other
      malignancies in children.
AB  - BACKGROUND: The need to use unlicensed and off label drugs in children due to the
      lack of suitable, licensed formulations with appropriate prescribing information
      creates many problems on an everyday basis for healthcare professionals, carers
      and children. PATIENTS AND METHODS: This prospective study was designed to
      examine the incidence and nature of unlicensed and off label prescribing, in
      paediatric oncology patients with acute lymphoblastic leukaemia and other
      malignancies. Inpatient and outpatient prescriptions were analysed for a 4-week
      period. RESULTS: All patients received at least one unlicensed or off label drug.
      Fifty-five per cent of prescriptions were licensed, 19% were unlicensed and 26%
      were licensed drugs used in an off label manner. Unlicensed preparations were
      used in 40% of prescriptions for cytotoxic agents, due to a lack of commercially
      available formulations suitable for the paediatric patient. These drugs included
      mercaptopurine and methotrexate which have been used in the treatment of
      paediatric leukaemia for many years, their efficacy having been demonstrated by
      on-going Medical Research Council trials. CONCLUSIONS: It is disappointing that
      drugs, which are the mainstay of therapy for paediatric leukaemia and other
      malignancies, are unavailable in appropriate licensed formulations to facilitate
      their administration to children. This needs to be urgently addressed.

PMID- 12488292
TI  - Psychological responses of patients receiving a diagnosis of cancer.
AB  - BACKGROUND: Current recommendations on how to break bad news are primarily based
      on expert opinion. Little is known about the association between communication
      practices and patients' psychological response. PATIENTS AND METHODS: One-hundred
      and thirty-one patients with newly diagnosed melanoma were surveyed 4 months
      after the initial consultation at the Sydney Melanoma Unit regarding their
      communication experiences and their satisfaction with these experiences. They
      completed the Hospital Anxiety and Depression Scale (HADS) at this time, and 4
      and 13 months later. RESULTS: Both patients' satisfaction with communication and
      their psychological morbidity were found to be associated with particular
      communication practices. Practices linked to lower anxiety included preparing the
      patient for a possible diagnosis of cancer; having the people wanted by the
      patient present to hear the diagnosis; giving the patient as much information
      about the diagnosis as desired; providing written information; presenting the
      information clearly; discussing the patient's questions the same day; talking
      about the patient's feelings; and being reassuring. Practices linked with lower
      levels of depression included using the word 'cancer'; discussing the severity of
      the situation, life expectancy and how the cancer might affect other aspects of
      life; and encouraging the patient to be involved in treatment decisions.
      CONCLUSIONS: This study provided preliminary evidence that communication
      strategies recommended in the literature produce positive patient outcomes.
      Further studies are needed which document actual communication.

PMID- 12488293
TI  - Oncology health care professionals' attitudes to cancer: a professional concern.
AB  - BACKGROUND: Despite the known benefits of screening, early detection and advances
      in treatment modalities, negative attitudes to cancer persist among health care
      professionals, and cancer remains the most feared disease in modern society.
      Attitudes to cancer may create a barrier to communication between patients and
      health care professionals, hinder early detection, treatment and rehabilitation,
      and may influence decision making about referral to specialist services and the
      selection of appropriate treatments. DESIGN: A descriptive survey was conducted,
      within a Regional Cancer Centre, to evaluate oncology health care professionals'
      attitudes towards cancer. Attitudes were measured using the Burns' Cancer Belief
      Scales. RESULTS: Regardless of gender, profession and clinical experience, all
      health care professionals displayed persistently negative attitudes towards
      cancer. No statistically significant difference was detected between gender,
      profession, clinical experience or specialist education, and although small in
      number, no major differences were found between group means. CONCLUSIONS:
      Oncology health care professionals hold negative attitudes towards cancer and
      changing these attitudes presents a significant challenge. Educational programmes
      and supportive strategies may alleviate fears and promote a more positive image
      of cancer. However, such strategies must be based on an understanding of current
      attitudes towards this phenomenon.

PMID- 12488294
TI  - Double-blind randomised trial comparing the non-steroidal aromatase inhibitors
      letrozole and fadrozole in postmenopausal women with advanced breast cancer.
AB  - BACKGROUND: To compare the efficacy, safety and tolerability of letrozole, an
      advanced non-steroidal aromatase inhibitor, and fadrozole hydrochloride, an older
      generation drug in this class, we conducted a randomised double-blind trial in
      postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: One
      hundred and fifty-seven postmenopausal women with advanced breast cancer were
      enrolled and randomly assigned to receive letrozole or fadrozole in a
      multicentre, randomised double-blind trial in Japan. One hundred and fifty-four
      eligible patients were treated with either letrozole 1.0 mg once daily (n = 77)
      or fadrozole 1.0 mg twice daily (n = 77), for a minimum of 8 weeks. RESULTS:
      Letrozole showed a significantly higher overall objective response rate [complete
      response (CR) + partial response (PR)] than fadrozole (31.2% and 13.0%,
      respectively; P = 0.011, Fisher's exact test). Clinical benefits defined as CR,
      PR and stable disease (no change in status for more than 24 weeks) were also
      higher in patients treated with letrozole (50.6%) than fadrozole (35.1%).
      Letrozole was significantly superior to fadrozole in terms of the dominant lesion
      in soft tissue, bone and viscera (P = 0.011, stratified Mantel-Haenszel test).
      Median time to progression was 211 days in the letrozole group and 113 days in
      the fadrozole group with no significant difference (P = 0.175, log-rank test).
      Letrozole markedly reduced the estradiol, estrone and estrone sulfate levels in
      peripheral blood within 4 weeks. The suppressive effect of fadrozole on these
      hormone levels was insufficient. Adverse drug reactions were observed in 35.9% of
      the patients treated with letrozole and in 39.5% of those treated with fadrozole
      with no significant difference between the two groups (P = 0.74, Fisher's exact
      test). Most of the adverse drug reactions were rated as grade 1 or 2.
      CONCLUSIONS: The results show letrozole at a dose of 1.0 mg once daily to be more
      effective in treating postmenopausal women with advanced breast cancer than
      fadrozole at 1.0 mg twice daily, with similar safety and tolerability profiles.

PMID- 12488295
TI  - Cancer risk in women with previous breast cancer.
AB  - BACKGROUND: Excess risks of several second neoplasms following breast cancer have
      been reported. However, these risks have still to be quantified. PATIENTS AND
      METHODS: We considered 9,729 breast cancer patients registered by the Swiss
      Cancer Registries of Vaud and Neuchatel (covering about 786,000 inhabitants) and
      followed up from 1974 to 1998. RESULTS: Overall, 443 second primary neoplasms
      (other than second primary breast cancers) were observed versus 389 expected
      [standardised incidence ratio (SIR): 1.14; 95% confidence interval (CI) 1.04
      1.25]. The SIRs were above unity for endometrium (SIR = 1.5), ovary (1.3),
      colorectum (1.1), gallbladder (1.4), cutaneous malignant melanoma (1.4), kidney
      (1.4), lymphomas (1.4) and leukaemias (1.2), as well as for selected tobacco
      related neoplasms. The largest excess risk was found for soft tissue sarcomas
      (STS) with 10 cases observed versus 3.1 expected (SIR = 3.2; 95% CI 1.5-5.9). Of
      these, eight occurred in potentially irradiated areas. CONCLUSIONS: This analysis
      confirms the existence of a modest excess in several neoplasms occurring after
      breast cancer. The substantial excess of STS confirms the strong association
      between irradiation and STS.

PMID- 12488296
TI  - Results of interval debulking surgery in advanced stage ovarian cancer: an
      exposed-non-exposed study.
AB  - BACKGROUND: To study the results of interval debulking surgery (IDS) in patients
      treated for 'unresectable' advanced stage ovarian cancer compared with primary
      debulking surgery (PDS) followed by chemotherapy. PATIENTS AND METHODS: An
      exposed-non-exposed study including a group of 34 patients who underwent an IDS
      and were matched to an historic control group of 34 patients treated with PDS.
      RESULTS: Optimal cytoreductive surgery was achieved in 94% (32 out of 34) of
      patients in both groups. The rates of post-operative morbidity, blood transfusion
      and median length of hospitalisation were significantly reduced in the study
      (IDS) group, but survival did not differ in both groups. CONCLUSIONS: IDS in
      patients with advanced stage ovarian cancer offers the same chance of survival as
      PDS, but it is better tolerated.

PMID- 12488297
TI  - Dietary glycemic index, glycemic load and ovarian cancer risk: a case-control
      study in Italy.
AB  - BACKGROUND: Dietary carbohydrates vary in their ability to raise blood glucose
      and insulin levels, which, in turn, influence levels of sex hormones and insulin
      like growth factors. We analyzed the effect of type and amount of carbohydrates
      on ovarian cancer risk, using the glycemic index (GI) and the glycemic load (GL)
      measurement in a large case-control study conducted in Italy. MATERIALS AND
      METHODS: Cases included 1031 women with incident, histologically confirmed
      epithelial ovarian cancer, from four Italian regions. Controls included 2411
      women admitted to the same hospital networks for acute, non-neoplastic
      conditions. Average daily GI and GL were calculated from a validated food
      frequency questionnaire. Odds ratios (OR) and the corresponding 95% confidence
      intervals (CI) were computed using multiple logistic regression. RESULTS: Ovarian
      cancer was directly associated with dietary GI (OR for highest versus lowest
      quartile = 1.7, 95% CI 1.3-2.1) and GL (OR = 1.7, 95% CI 1.3-2.1). The
      associations were observed in pre- and postmenopausal women, and they remained
      consistent across strata of major covariates identified. CONCLUSIONS: This study
      supports the hypothesis of a direct association between GI and GL and ovarian
      cancer risk and, consequently, of a possible role of hyperinsulinemia/insulin
      resistance in ovarian cancer development.

PMID- 12488298
TI  - Expression and prognostic significance of LIVIN, SURVIVIN and other apoptosis
      related genes in the progression of superficial bladder cancer.
AB  - BACKGROUND: It has been suggested that progression of superficial bladder cancer
      may be regulated at the molecular level by a typical pattern of expression of
      genes involved in apoptosis. Recently LIVIN, belonging to the inhibitors of
      apoptosis (IAP) family, has been found to be expressed in most solid tumors,
      where its expression is suggested to have prognostic significance. No data are
      available concerning the significance of LIVIN in the progression of bladder
      tumors. PATIENTS AND METHODS: In the present paper we used RT-PCR to investigate
      the expression of LIVIN isoforms alpha and beta, SURVIVIN, BCL-X and BCL-2/BAX
      expression ratio both in normal and tumoral bladder tissues, and correlated their
      expression with the emergence of early relapses in a follow-up of 4 years. This
      study shows that only the alpha isoform of LIVIN, which is not expressed in
      normal bladder tissue, is expressed in a proportion of tumors with a high risk of
      relapse. RESULTS: LIVIN was found in 7/30 patients (23%), SURVIVIN in 9/30 (30%),
      BCL-2/BAX ratio >1 in 16/30 (53%), BCL-2/BAX expression ratio <1 in 14/30 (46.6%)
      and BCL-X, only in isoform BCL-X(L), in 11/30 (36.6%). When we evaluated the
      dependence between each gene expression and relapse free time of patients, we
      found that LIVIN, high BCL-2/BAX ratio and BCL-X(L), but not SURVIVIN, reached
      statistical significance in order to predict relapses. CONCLUSIONS: Our findings
      suggest that LIVIN may be involved in the progression of superficial bladder
      cancer and used as a marker of early recurrence; while the expression of SURVIVIN
      cannot be used to identify patients with high risk of relapse.

PMID- 12488299
TI  - Predicting the risk of bleomycin lung toxicity in patients with germ-cell
      tumours.
AB  - BACKGROUND: Bleomycin pulmonary toxicity (BPT) has been known since the early
      clinical trials of bleomycin in the 1960s. Postulated risk factors include
      cumulative bleomycin dose, reduced glomerular filtration rate (GFR), raised
      creatinine, older age and supplemental oxygen exposure. PATIENTS AND METHODS:
      From our prospectively collected testicular cancer research database, we reviewed
      835 patients treated at the Royal Marsden NHS Trust (Sutton, UK) with bleomycin
      containing regimens for germ-cell tumours between January 1982 and December 1999,
      to identify those with BPT. RESULTS: Fifty-seven (6.8%) patients had BPT, ranging
      from X-ray/CT (computed tomography) changes to dyspnoea. There were eight deaths
      (1% of patients treated) directly attributed to BPT. The median time from the
      start of bleomycin administration to documented lung toxicity was 4.2 months
      (range 1.2-8.2). On multivariate analysis, the factors independently predicting
      for increased risk of BPT were GFR <80 ml/min [hazard ratio (HR) 3.3], age >40
      years (HR 2.3), stage IV disease at presentation (HR 2.6) and cumulative dose of
      bleomycin >300,000 IU (HR 3.5). CONCLUSIONS: Patients with poor renal function
      are at high risk of BPT, especially if they are aged >40 years, have stage IV
      disease at presentation or receive >300,000 IU of bleomycin. In such cases
      alternative drug regimens or dose restriction should be considered.

PMID- 12488300
TI  - Biweekly high-dose gemcitabine alone or in combination with capecitabine in
      patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial.
AB  - BACKGROUND: Gemcitabine is an active antitumor agent in the treatment of advanced
      pancreatic cancer, and has shown potential synergistic activity with the oral
      fluoropyrimidine capecitabine in previous phase I/II trials. Based on this
      background and in order to define the therapeutic potential and tolerance of this
      combination more precisely, the present randomized multicenter phase II trial was
      initiated. PATIENTS AND METHODS: We prospectively randomized 83 patients to
      treatment with biweekly gemcitabine 2,200 mg/m(2) given as a 30 min intravenous
      infusion on day 1, or the same treatment plus oral capecitabine 2,500 mg/m(2)
      given from days 1 to 7. In both arms, chemotherapy was administered for a
      duration of 6 months unless there was prior evidence of progressive disease. The
      efficacy of the two treatment arms was evaluated according to standard criteria,
      i.e. objective response, progression-free survival (PFS) and overall survival
      (OS), as well as by analysis of clinical benefit response. RESULTS: The overall
      objective response rate among the 42 patients treated with gemcitabine alone was
      14% compared with 7/41 (17%) among those treated with the combination arm.
      Similar to response rates, there was no apparent difference between the two
      groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus
      9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients
      with tumor-related symptoms, who were considered evaluable for clinical benefit
      response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the
      gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in
      both arms with only four versus six patients experiencing WHO grade 3 symptoms.
      Apart from the occurrence of hand-foot syndrome in 10 patients, no major increase
      in incidence and/or degree of adverse reactions was noted in the combination arm.
      CONCLUSIONS: Results of this trial suggest a fairly good therapeutic index for
      the combination of biweekly high-dose gemcitabine and capecitabine for the
      treatment of advanced pancreatic cancer. Despite a somewhat superior clinical
      benefit response rate, no advantage over single-agent gemcitabine, however, was
      noted in terms of objective efficacy parameters.

PMID- 12488301
TI  - An endogastric capsule for measuring tumor markers in gastric juice: an
      evaluation of the safety and efficacy of a new diagnostic tool.
AB  - BACKGROUND: In gastric juice, high levels of the carcinoembryonic antigen (CEA)
      and the carbohydrate antigen 19-9 (CA 19-9) have been found to correlate with
      precancerous lesions and gastric cancer. So far, sampling of gastric juice has
      required upper endoscopy. In place of this invasive procedure, we investigated a
      new tool for the quantitation of tumor markers in gastric juice. MATERIALS AND
      METHODS: The study population consisted of healthy controls and consecutive
      subjects with suspected gastric cancer or dyspepsia/epigastric distress. Patients
      were asked to swallow a small gelatine capsule (14 mm in length and 5 mm in
      diameter) containing a pierced plastic cover and surrounding a piece of absorbent
      paper. The capsule was left in the gastric cavity for 60 min to allow saturation
      of the absorbent paper with gastric juice. A 45-50 cm length of nylon thread
      connected to the inner capsule was used to remove the device from the gastric
      cavity. After processing the absorbent paper for radioimmunoassay, CEA and CA 19
      9 levels were correlated to the findings of upper endoscopy and biopsies of
      gastric mucosa or suspected lesions. RESULTS: The endogastric capsule did not
      cause any side-effects and 62 participants were fully compliant to the procedure.
      Assessable gastric juice samples were taken from 23 patients with gastric cancer,
      15 patients with intestinal metaplasia or dysplasia, 12 patients with gastritis
      and 12 controls without gastric diseases. In the 12 samples of gastric juice from
      control patients, mean values of CEA and CA 19-9 were 1.1 +/- 0.9 ng/ml and 16 +/
      7.5 ng/ml, respectively. The mean levels of both markers were found to increase
      according to the severity of gastric lesions and in patients with cancer, mean
      CEA and CA 19-9 levels were 513 +/- 627 ng/ml and 545 +/- 510 ng/ml,
      respectively. Patients with precancerous lesions and cancer showed higher levels
      of CEA and CA 19-9 than patients with normal findings or gastritis (P <0.001).
      CONCLUSIONS: The endogastric capsule is a simple, non-invasive tool for the
      measurement of CEA and CA 19-9 levels in gastric juice. These values may
      discriminate between normal or minor pathologic changes and precancerous lesions
      or carcinomas. Further investigations are warranted, since this may represent a
      new method for gastric cancer screening.

PMID- 12488302
TI  - Neoadjuvant radiochemotherapy for locally advanced gastric cancer: a phase I-II
      study.
AB  - BACKGROUND: To study in a phase I-II trial the maximum tolerated dose, the
      toxicity, and the tolerance of adding radiotherapy to systemic chemotherapy
      administered preoperatively in patients with locoregionally advanced gastric
      adenocarcinoma. PATIENTS AND METHODS: Patients with adenocarcinoma of the stomach
      (T(3)(-)(4)N(any) or T(any)N+), performance status </=1, normal hematological,
      hepatic and renal functions received two cycles of cisplatin 100 mg/m(2) on day
      1, 5-FU 800 mg/m(2) on days 1 to 4 and leucovorin 60 mg b.i.d. on days 1 to 4
      q3w, concomitantly with radiation therapy escalated in three dose tiers (31.2,
      38.4 and 45.6 Gy). RESULTS: Nineteen patients were accrued and 18 completed
      neoadjuvant therapy. Major toxicity consisted of grade 3/4 leucopenia and
      mucositis in 89% and 36% of the patients, respectively. Only one episode of
      febrile neutropenia was recorded. Dose level number 2 (38.4 Gy) with the
      chemotherapy given q4w is the recommended dose level. All patients were
      subsequently operated and no fatalities occurred. Pathological assessment showed
      one complete and eight partial responses. Two- and 3-year relapse-free survival
      rates were 57% and 50%, respectively. Only one patient relapsed locally. The
      peritoneum was the most frequent site of relapse. CONCLUSIONS: This neoadjuvant
      therapeutic program is relatively well tolerated, does not seem to increase the
      operative risk, and might increase the locoregional control of the disease. The
      frequency of peritoneal involvement in relapsing patients underscores the need
      for a more effective systemic treatment.

PMID- 12488303
TI  - Docetaxel as neoadjuvant therapy for radically treatable stage III non-small-cell
      lung cancer: a multinational randomised phase III study.
AB  - BACKGROUND: Docetaxel (Taxotere) is a potent anticancer agent, with proven
      efficacy as first-line therapy in non-small-cell lung cancer (NSCLC). The aim of
      this large randomised multicentre phase III study was to evaluate docetaxel in
      the neoadjuvant (pre-operative) setting. PATIENTS AND METHODS: Patients with
      stage IIIA or locally treatable IIIB NSCLC were randomly assigned to receive
      neoadjuvant docetaxel (n = 134) or no chemotherapy (n = 140) before
      surgery/curative-intention radiotherapy. Patients received up to three 3-weekly
      cycles of docetaxel (100 mg/m(2)) as 1-h intravenous infusions. RESULTS: Median
      survival was 14.8 months in the docetaxel group and 12.6 months in the control
      group. Median times to disease progression were 9.0 months (docetaxel arm) and
      7.6 months (control arm). There were three complete responses and 25 partial
      responses in patients treated with docetaxel who were evaluable for response (n =
      101). Docetaxel was well-tolerated: 103 patients (77%) received all three planned
      cycles. The major toxicity was grade 4 neutropenia (69 patients, 55%) and
      neutropenic fever (eight patients, 6%). Radiotherapy was well-tolerated after
      docetaxel administration. CONCLUSIONS: Neoadjuvant docetaxel is generally well
      tolerated and shows a promising trend towards longer survival in patients with
      NSCLC.

PMID- 12488304
TI  - Early detection of relapse by whole-body positron emission tomography in the
      follow-up of patients with Hodgkin's disease.
AB  - BACKGROUND: Relapse after treatment of Hodgkin's disease (HD) is usually
      identified as a result of the investigation of symptoms. We undertook this study
      to examine the value of whole-body positron emission tomography (PET) for the
      detection of preclinical relapse. PATIENTS AND METHODS: Thirty-six patients
      underwent 2-[fluorine-18]fluoro-2-deoxy-D-glucose ((18)F-FDG) PET at the end of
      treatment and than every 4-6 months for 2-3 years after the end of
      polychemotherapy and/or radiotherapy. In those cases of abnormal (18)F-FDG
      accumulation a confirmatory study was performed 4-6 weeks later. RESULTS: One
      patient had residual tumor and four patients relapsed during a follow-up of 5-24
      months. All five events were correctly identified early by (18)F-FDG PET.
      Residual tumor or relapse was never first diagnosed based on clinical
      examination, laboratory findings or computed tomography (CT) studies. Two
      patients presented B symptoms and the three others were asymptomatic at the time
      of residual disease or relapse. Confirmation of residual disease or relapse was
      obtained by biopsy in four patients 1, 1, 5 and 9 months after PET and by
      unequivocal clinical symptoms and CT studies in one patient 3 months after PET.
      False-positive (18)F-FDG PET studies incorrectly suggested possible relapse in
      six other patients, but the confirmatory PET was always negative. Our study also
      provides important information about physiological (18)F-FDG uptake in the
      thymus. CONCLUSIONS: Our data suggest the potential of (18)F-FDG PET to detect
      preclinical relapse in patients with HD. This could help identify patients
      requiring salvage chemotherapy at the time of minimal disease rather than at the
      time of clinically overt relapse. Further studies are warranted to determine the
      impact of PET on treatment management and outcome. In fact, the aim of follow-up
      procedures is not only to detect preclinical relapse but mainly to obtain better
      results by starting salvage treatment earlier. A cost-benefit analysis will also
      be necessary before (18)F-FDG PET can be used routinely in the follow-up of
      patients with HD.

PMID- 12488305
TI  - Primary extranodal non-Hodgkin's lymphoma (NHL): the impact of alternative
      definitions tested in the Comprehensive Cancer Centre West population-based NHL
      registry.
AB  - BACKGROUND: The definition of primary extranodal non-Hodgkin's lymphoma (NHL) is
      a controversial issue, especially in patients where both nodal and extranodal
      sites are involved. PATIENTS AND METHODS: The impact of different definitions of
      primary extranodal NHL on incidence and prognosis is explored using data from a
      population-based NHL registry. RESULTS: Using liberal criteria, 389 (34%) cases
      were classified as primary extranodal NHL. Overall survival (OS) rates of nodal
      and extranodal NHL patients defined this way were comparable; however, extranodal
      NHL patients had a better disease-free survival (DFS). When strict criteria were
      applied, 231 cases (20%) were classified as primary extranodal NHL. OS and DFS
      rates of extranodal NHL patients defined this way were superior to nodal NHL
      patients; however, the difference in OS was reversed after correction for
      differences in International Prognostic Index and malignancy grade. CONCLUSION:
      This study illustrates the selection bias that is introduced when a strict
      definition of primary extranodal NHL, that excludes cases with disseminated
      disease, is used. Patients with primary extranodal NHL were found to have a
      superior DFS, irrespective of which definition of primary extranodal NHL was
      used.

PMID- 12488306
TI  - High-dose therapy in diffuse large cell lymphoma: results and prognostic factors
      in 452 patients from the GEL-TAMO Spanish Cooperative Group.
AB  - BACKGROUND: The purpose of this study was to analyse the results and prognostic
      factors influencing overall survival (OS) and disease-free survival (DFS) in 452
      patients diagnosed with diffuse large cell lymphomas (DLCL) treated with high
      dose therapy (HDT) included in the Grupo Espanol de Linfomas/Trasplante Autologo
      de Medula Osea (GEL-TAMO) Spanish registry. PATIENTS AND METHODS: At
      transplantation, median age was 42 years (range 15-73), 146 patients (32%) were
      transplanted in first complete remission (1st CR), 19% in second CR (2nd CR) and
      47% had active disease: sensitive disease in 157 (35%) patients [95 were in first
      partial remission (1st PR) and 62 in second PR (2nd PR)] and refractory disease
      in 55 (12%) patients. Age-adjusted International Prognostic Index (IPI) was 2 or
      3 in 51 patients (12%). Conditioning regimen consisted of BEAM (carmustine,
      etoposide, cytarabine and melphalan) in 39% of patients, BEAC (carmustine,
      etoposide, cytarabine and cyclophosphamide) in 33%, CBV (carmustine, etoposide
      and cyclophosphamide) in 10% and cyclophosphamide plus total body irradiation
      (TBI) in 12%. RESULTS: Estimated overall survival (OS) and disease-free survival
      (DFS) at 5 years were 53% and 43%, respectively. The transplant-related mortality
      was 11% (53 cases). By multivariate analysis three variables significantly
      influenced OS and DFS: number of protocols to reach 1st CR, disease status at
      transplant and TBI in the conditioning regimen. Age-adjusted IPI at
      transplantation also influenced OS. CONCLUSIONS: Prolonged OS and DFS can be
      achieved in patients with DLCL after HDT and our results suggest that the best
      line of chemotherapy should be used up-front in patients considered as candidates
      for HDT in order to obtain an early CR. Resistant patients are not good
      candidates for HDT and they should be offered newer strategies. Finally,
      polichemotherapy conditioning regimens offer better results compared with TBI.

PMID- 12488307
TI  - Detection of malignant bone marrow involvement with dynamic contrast-enhanced
      magnetic resonance imaging.
AB  - BACKGROUND: The purpose of this study was to evaluate the role of dynamic
      contrast-enhanced magnetic resonance imaging (dMRI) in detecting bone marrow
      involvement in cancer patients. PATIENTS AND METHODS: We studied 50 consecutive
      patients with histologically confirmed malignant dissemination to the bone
      marrow, using dMRI of the lumbosacral spine. Time-signal intensity curves were
      generated from regions of interest (ROIs) obtained from areas of obvious bone
      marrow disease (group B). In 16 patients from group B with focal disease, ROIs
      were also placed on areas with apparently normal bone marrow on static magnetic
      resonance images (group C). Twenty-two patients with no history of malignancy
      were used as a control group (group A). Wash-in (WIN) and wash-out (WOUT) rates,
      time to peak (TTPK), time to maximum slope (TMSP) values and WIN/TMSP ratios were
      calculated for each patient. Mean values for the three groups were compared
      statistically. Six patients from group B had follow-up dMRI after chemotherapy:
      four patients achieved a clinical partial response and two had resistant disease.
      RESULTS: A significant difference was found between groups A and B for all
      values. Between groups A and C, in spite of the similar static MRI appearance,
      all values were significantly different. Between groups B and C, a significant
      difference was found for WIN, WOUT rates and WIN/TMSP ratio. Follow-up dMRI data
      analysis correlated well with clinical staging. CONCLUSIONS: dMRI can distinguish
      normal from malignant bone marrow. It may identify malignant bone marrow
      infiltration in patients with negative static MRI and serve as both a diagnostic
      and prognostic tool for patients with bone marrow malignancies.

PMID- 12488308
TI  - Lung cancer mortality in European regions (1955-1997).
AB  - BACKGROUND: The different spread of tobacco smoking across European countries has
      caused a substantial variability in lung cancer mortality. The objective of this
      investigation was to analyse the trends in lung cancer mortality rates in three
      broad European regions (Northern and Western countries, Eastern countries, and
      Mediterranean countries) during the second half of the 20th century. PATIENTS AND
      METHODS: Mortality data were obtained from the World Health Organisation
      database. Lung cancer mortality rates were age-standardised by the direct method
      to the world standard population. Trends from 1955 to 1997 were assessed by means
      of joinpoint regression analysis. RESULTS: In men, rates in Eastern Europe
      increased to reach in the 1990s the highest values ever registered, while
      downward trends were observed in Northern and Western Europe since 1979, and in
      Mediterranean countries since the 1990s. In women, upward trends were observed in
      the three regions considered for the whole period. CONCLUSIONS: Different smoking
      prevalences over time explain the shift of almost one decade in the trends in
      Mediterranean men as compared with Northern and other Western European men. The
      persisting upward trends in women in the three regions are of concern.

PMID- 12488309
TI  - Fibre intake and laryngeal cancer risk.
AB  - BACKGROUND: Consumption of vegetables, fruit and whole grain cereals has been
      inversely related to laryngeal cancer risk. Among the potential protective agents
      found in these foods, information on dietary fibres and laryngeal cancer risk are
      scanty. PATIENTS AND METHODS: A multi-centric, hospital-based case-control study
      was conducted on 527 patients with squamous-cell carcinoma of the larynx and
      1,297 non-neoplastic controls. Cases and controls, frequency matched by age, sex
      and study centre, were interviewed using a validated food frequency
      questionnaire. RESULTS: Compared with the lowest quintile of fibre intake, the
      odds ratios (ORs) for the highest quintile were 0.3 [95% confidence interval (CI)
      0.2-0.4] for total fibre, 0.3 (95% CI 0.2-0.5) for soluble non-cellulose
      polysaccharides (NCP) and for total insoluble fibre, including cellulose (OR =
      0.3, 95% CI 0.2-0.4) and insoluble NCP (OR = 0.4, 95% CI 0.3-0.7). The ORs were
      0.2 (95% CI 0.1-0.4) for fibre from vegetables, 0.5 (95% CI 0.3-0.7) from fruit
      and 1.1 (95% CI 0.6-1.9) from grains. The inverse association observed was
      similar among different subsites of laryngeal cancer, and consistent across
      strata of various covariates. CONCLUSIONS: This study found a strong inverse
      association between fibre intake and laryngeal cancer risk, which points to fibre
      as one of the beneficial components of vegetables and fruit.

PMID- 12488310
TI  - High-dose methotrexate clearance following prior vancomycin administration: no
      significant interaction in the absence of overt renal impairment.

PMID- 12488311
TI  - Comment on "A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and
      paclitaxel in patients with chemorefractory small-cell lung cancer", by C. M.
      Rudin et al. (Ann Oncol 2002; 13: 539-545).

PMID- 12488312
TI  - Rituximab monotherapy in nodular lymphocyte-predominant Hodgkin's disease.

PMID- 12488313
TI  - Absolute lymphocyte count as a predictive factor for response to monoclonal anti
      CD20 antibody therapy.

PMID- 12488314
TI  - Conformational changes in hemoglobin S (betaE6V) imposed by mutation of the beta
      Glu7-beta Lys132 salt bridge and detected by UV resonance Raman spectroscopy.
AB  - The impact upon molecular structure of an additional point mutation adjacent to
      the existing E6V mutation in sickle cell hemoglobin was probed spectroscopically.
      The UV resonance Raman results show that the conformational consequences of
      mutating the salt bridge pair, betaGlu(7)-betaLys(132), are dependent on which
      residue of the pair is modified. The betaK132A mutants exhibit the spectroscopic
      signatures of the R --> T state transition in both the "hinge" and "switch"
      regions of the alpha(1)beta(2) interface. Both singly and doubly mutated
      hemoglobin (Hb) betaepsilon7Alpha exhibit the switch region signature for the R -
      > T quaternary state transition but not the hinge signature. The absence of this
      hinge region-associated quaternary change is the likely origin of the observed
      increased oxygen binding affinity for the Hb betaepsilon7Alpha mutants. The
      observed large decrease in the W3 alpha14beta15 band intensity for doubly mutated
      Hb betaepsilon7Alpha is attributed to an enhanced separation in the A helix-E
      helix tertiary contact of the beta subunits. The results for the Hb A betaGlu(7)
      betaLys(132) salt bridge mutants demonstrate that attaining the T state
      conformation at the hinge region of the alpha(1)beta(2) dimer interface can be
      achieved through different intraglobin pathways; these pathways are subject to
      subtle mutagenic manipulation at sites well removed from the dimer interface.

PMID- 12488315
TI  - Two-dimensional NMR study of the heme active site structure of chloroperoxidase.
AB  - The heme active site structure of chloroperoxidase (CPO), a glycoprotein that
      displays versatile catalytic activities isolated from the marine mold
      Caldariomyces fumago, has been characterized by two-dimensional NMR spectroscopic
      studies. All hyperfine shifted resonances from the heme pocket as well as
      resonances from catalytically relevant amino acid residues including the heme
      iron ligand (Cys(29)) attributable to the unique catalytic properties of CPO have
      been firmly assigned through (a) measurement of nuclear Overhauser effect
      connectivities, (b) prediction of the Curie intercepts from both one- and two
      dimensional variable temperature studies, (c) comparison with assignments made
      for cyanide derivatives of several well characterized heme proteins such as
      cytochrome c peroxidase, horseradish peroxidase, and manganese peroxidase, and
      (d) examination of the crystal structural parameters of CPO. The location of
      protein modification that differentiates the signatures of the two isozymes of
      CPO has been postulated. The function of the distal histidine (His(105)) in
      modulating the catalytic activities of CPO is proposed based on the unique
      arrangement of this residue within the heme cavity. Contrary to the crystal
      state, the high affinity Mn(II) binding site in CPO (in solution) is not
      accessible to externally added Mn(II). The results presented here provide a
      reasonable explanation for the discrepancies in the literature between
      spectroscopists and crystallographers concerning the manganese binding site in
      this unique protein. Our study indicates that results from NMR investigations of
      the protein in solution can complement the results revealed by x-ray diffraction
      studies of the crystal form and thus provide a complete and better understanding
      of the actual structure of the protein.

PMID- 12488316
TI  - Pathways accessory to proteasomal proteolysis are less efficient in major
      histocompatibility complex class I antigen production.
AB  - Degradation of cytosolic proteins depends largely on the proteasome, and a
      fraction of the cleavage products are presented as major histocompatibility
      complex (MHC) class I-bound ligands at the cell surface of antigen presenting
      cells. Proteolytic pathways accessory to the proteasome contribute to protein
      turnover, and their up-regulation may complement the proteasome when proteasomal
      proteolysis is impaired. Here we show that reduced reliance on proteasomal
      proteolysis allowed a reduced efficiency of MHC class I ligand production,
      whereas protein turnover and cellular proliferation were maintained. Using the
      proteasomal inhibitor adamantane-acetyl-(6-aminohexanoyl)3-(leucinyl)3-vinyl
      (methyl)-sulphone, we show that covalent inhibition of all three types of
      proteasomal beta-subunits (beta(1), beta(2), and beta(5)) was compatible with
      continued growth in cells that up-regulate accessory proteolytic pathways, which
      include cytosolic proteases as well as deubiquitinating enzymes. However, under
      these conditions, we observed poor assembly of H-2D(b) molecules and inhibited
      presentation of endogenous tumor antigens. Thus, the tight link between protein
      turnover and production of MHC class I ligands can be broken by enforcing the
      substitution of the proteasome with alternative proteolytic pathways.

PMID- 12488317
TI  - V-1, a protein expressed transiently during murine cerebellar development,
      regulates actin polymerization via interaction with capping protein.
AB  - V-1 is a 12-kDa protein consisting of three consecutive ANK repeats, which are
      believed to serve as the surface for protein-protein interactions. It is thought
      to have a role in neural development for its temporal profile of expression
      during murine cerebellar development, but its precise role remains unknown. Here
      we applied the proteomic approach to search for protein targets that interact
      with V-1. The V-1 cDNA attached with a tandem affinity purification tag was
      expressed in the cultured 293T cells, and the protein complex formed within the
      cells were captured and characterized by mass spectrometry. We detected two
      polypeptides specifically associated with V-1, which were identified as the alpha
      and beta subunits of the capping protein (CP, alternatively called CapZ or beta
      actinin). CP regulates actin polymerization by capping the barbed end of the
      actin filament. The V-1.CP complex was detected not only in cultured cells
      transfected with the V-1 cDNA but also endogenously in cells as well as in murine
      cerebellar extracts. An analysis of the V-1/CP interaction by surface plasmon
      resonance spectroscopy showed that V-1 formed a stable complex with the CP
      heterodimer with a dissociation constant of 1.2 x 10(-7) m and a molecular
      stoichiometry of approximately 1:1. In addition, V-1 inhibited the CP-regulated
      actin polymerization in vitro in a dose-dependent manner. Thus, our results
      suggest that V-1 is a novel component that regulates the dynamics of actin
      polymerization by interacting with CP and thereby participates in a variety of
      cellular processes such as actin-driven cell movements and motility during
      neuronal development.

PMID- 12488318
TI  - Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a
      cell survival response to multiple types of environmental stress stimuli in
      mammary epithelial cells.
AB  - The effects of multiple stress stimuli on the cellular utilization of the serum-
      and glucocorticoid-inducible protein kinase (Sgk) were examined in NMuMg mammary
      epithelial cells exposed to hyperosmotic stress induced by the organic osmolyte
      sorbitol, heat shock, ultraviolet irradiation, oxidative stress induced by
      hydrogen peroxide, or to dexamethasone, a synthetic glucocorticoid that
      represents a general class of physiological stress hormones. Each of the stress
      stimuli induced Sgk protein expression with differences in the kinetics and
      duration of induction and in subcellular localization. The environmental
      stresses, but not dexamethasone, stimulated Sgk expression through a p38/MAPK
      dependent pathway. In each case, a hyperphosphorylated active Sgk protein was
      produced under conditions in which Akt, the close homolog of Sgk, remained in its
      non-phosphorylated state. Ectopic expression of wild type Sgk or of the
      T256D/S422D mutant Sgk that mimics phosphorylation conferred protection against
      stress-induced cell death in NMuMg cells. In contrast, expression of the
      T256A/S422A Sgk phosphorylation site mutant has no effect on cell survival. Sgk
      is known to phosphorylate and negatively regulate pro-apoptotic forkhead
      transcription factor FKHRL1. The environmental stress stimuli that induce Sgk,
      but not dexamethasone, strongly inhibited the nuclear transcriptional activity
      and increased the cytoplasmic retention of FKHRL1. Also, the conditional IPTG
      inducible expression of wild type Sgk, but not of the kinase dead T256A mutant
      Sgk, protected Con8 mammary epithelial tumor cells from serum starvation-induced
      apoptosis. Taken together, our study establishes that induction of enzymatically
      active Sgk functions as a key cell survival component in response to different
      environmental stress stimuli.

PMID- 12488319
TI  - Biochemical evidence for interaction between the two nucleotide binding domains
      of ArsA. Insights from mutants and ATP analogs.
AB  - ArsA, the peripheral membrane component of the anion-translocating ATPase ArsAB,
      consists of two nucleotide binding domains (A1 and A2), which are connected by a
      linker sequence. Previous studies on ArsA have focused on the function of each
      nucleotide binding domain and the role of the linker, whereas the present study
      looks at the interactions between the binding domains and their interactions with
      the linker. It has previously been shown that the A1 domain of ArsA carries out
      unisite catalysis in the absence of antimonite, while A2 is recruited in
      multisite catalysis by antimonite in the presence of a functional A1 domain.
      Multisite catalysis thus seems to result from an interaction between A1 and A2
      brought about by antimonite. In the present study, we provide direct biochemical
      evidence for interaction between the two nucleotide binding domains and show that
      the linker region acts as a transducer of the conformational changes between
      them. We find that nucleotide binding to the A2 domain results in a significant,
      detectable change in the conformation of the A1 domain. Two ATP analogs, FSBA and
      ATP gamma S, used in this study, were both found to bind preferentially to the A2
      domain, and their binding resulted in changing the otherwise compact A1 domain
      into an open conformation. Point mutations in the A2 domain and the linker region
      also produced a similar effect on the conformation of A1, thus suggesting that
      events at A2 are relayed to A1 via the linker. We propose that nucleotide binding
      to A2 produces a two-tiered conformational change. The significance of these
      changes in the mechanism of ArsA is discussed.

PMID- 12488320
TI  - The proline-rich domain of dynamin-2 is responsible for dynamin-dependent in
      vitro potentiation of endothelial nitric-oxide synthase activity via selective
      effects on reductase domain function.
AB  - The GTPase dynamin-2 (dyn-2) binds and positively regulates the nitric oxide
      generating enzyme, endothelial nitric-oxide synthase (eNOS) (Cao, S., Yao, Y.,
      McCabe, T., Yao, Q., Katusic, Z., Sessa, W., and Shah, V. (2001) J. Biol. Chem.
      276, 14249-14256). Here we demonstrate, using purified proteins, that this occurs
      through a selective influence of the dyn-2 proline-rich domain (dyn-2 PRD) on the
      eNOS reductase domain. In vitro studies demonstrate that dyn-2 PRD fused with
      glutathione S-transferase (GST) binds recombinant eNOS protein specifically and
      with binding kinetics comparable with that observed between dyn-2 full-length and
      eNOS. Additionally, GST-dyn-2 PRD binds the in vitro transcribed (35)S-eNOS
      reductase domain but not the (35)S-eNOS oxygenase domain. Furthermore GST-dyn-2
      PRD binds a (35)S-labeled eNOS reductase domain fragment (amino acids 645-850)
      that partially overlaps with the FAD binding domain of eNOS. A recombinant form
      of the SH3-containing protein Fyn competes the binding of recombinant eNOS
      protein with dyn-2 PRD, thereby implicating the SH3-like region contained within
      this reductase domain fragment as the dyn-2 binding region. Mammalian two-hybrid
      screen corroborates these interactions in cells as well. Functional studies
      demonstrate that dyn-2 PRD selectively potentiates eNOS activity in a
      concentration-dependent manner in an order of magnitude similar to that observed
      with dyn-2 full-length and in a manner that requires calmodulin. Although dyn-2
      PRD does not influence eNOS oxygenase domain function or ferricyanide reduction,
      it does potentiate the ability of recombinant eNOS to reduce cytochrome c,
      supporting an influence of dyn-2 PRD on electron transfer between FAD and FMN.
      (These data indicate that the binding domains of dyn-2 and eNOS reside within the
      dyn-2 PRD domain and the FAD binding region of the eNOS reductase domains,
      respectively, and that dyn-2 PRD is sufficient to mediate dyn-2-dependent
      potentiation of eNOS activity, at least in part, by potentiating electron
      transfer.)

PMID- 12488322
TI  - Gonadotropin-releasing hormone II: is this neuropeptide important for mammalian
      reproduction?

PMID- 12488323
TI  - Tissue inhibitor of metalloproteinase-1 (TIMP-1) deficient mice display reduced
      serum progesterone levels during corpus luteum development.
AB  - TIMP-1 is a multifunctional protein that is abundantly expressed within the ovary
      during the period of early corpus luteum formation. TIMP-1 has been suggested to
      play a role in progesterone production, but reports are conflicting. To more
      thoroughly examine the role of TIMP-1 in steroidogenesis during early luteal
      development in vivo, immature wild-type and TIMP-1 null female mice were primed
      with gonadotropins. Mice were sacrificed at 0, 24, and 48 h post hCG
      administration and serum was collected for determination of estradiol (E(2)) or
      progesterone (P(4)) concentrations. In the 24 h hCG groups, ovulation was
      assessed by counting the number of shed ova. Serum P(4) concentrations were
      significantly lower in the TIMP-1 null mice, both at 24 and 48-h post hCG
      compared to wild-type counterparts. No differences were detected in the number of
      ovulations between genotypes at the 24 h time point. In both the 24 and 48 h post
      hCG groups, null mice had significantly higher ovarian wet weights.
      Interestingly, ovarian MMP activity was greater in the null mice at 24 h post hCG
      but higher in the wild-type at 48 h post hCG administration. These observations
      suggests that expression of TIMP-1 during early luteal development may
      participate in regulation of progesterone production via its ability to regulate
      ovarian MMP activity.

PMID- 12488324
TI  - Evidence for genetic modifiers of ovarian follicular endowment and development
      from studies of five inbred mouse strains.
AB  - The laboratory mouse is the model of choice for genetic studies in mammals due to
      the availability of many genetically defined inbred strains and inbred congenic
      strains, as well as the ability to study the effects of over-expression
      (transgenics) or inactivation (knockouts) of a given gene on cells or tissues.
      During our studies using these technologies to uncover the importance of various
      genes to apoptosis in the ovary, we observed that the size of the primordial
      oocyte reserve was affected by mouse strain in the absence of any other genetic
      manipulation. To determine if genetic modifiers of oocyte endowment truly exist,
      herein we examined follicle numbers in one outbred (CD-1) and several inbred
      (129/Sv, DBA/2, C57BL/6, FVB, AKR/J) strains of mice at day 4 (neonatal) and day
      42 (young adult) postpartum. In neonatal life, ovaries of AKR/J females had the
      lowest total number of follicles, whereas 129/Sv females possessed the highest
      total number of follicles (P < 0.05 for AKR/J versus 129/Sv). There were more
      primordial follicles in 129/Sv compared with DBA/2 (P < 0.05), C57BL/6 (P <
      0.05), FVB (P < 0.05) or AKR/J (P < 0.05) females, and in CD-1 compared with
      AKR/J (P < 0.05) females. Although no significant strain-dependent differences in
      primary follicle numbers were noted, C57BL/6 females had the fewest number of
      small preantral follicles (P < 0.05 versus all other strains). Evaluation of
      ovaries at 42 days of age revealed the persistence of strain-dependent
      differences in early follicle growth patterns, although the total numbers of
      follicles were comparable. Of interest, marked strain-dependent differences in
      the rate of primordial follicle growth activation, as well as in the rate of
      follicle loss (atresia), between days 4 and 42 were observed. These results
      indicate that genetic modifiers play a major role in follicle endowment,
      development and atresia in the mouse ovary.

PMID- 12488325
TI  - An evolutionarily conserved form of gonadotropin-releasing hormone coordinates
      energy and reproductive behavior.
AB  - GnRH is the master neuropeptide that coordinates and regulates reproduction in
      all vertebrates and in some nonvertebrate species. Sixteen forms of GnRH have
      been isolated in brain. In the vast majority of species, two or more forms occur
      in anatomically and developmental distinct neuronal populations. In mammalian
      brain, two GnRH forms, mammalian (GnRH-I) and chicken-II (GnRH-II), exist. The
      distribution and functions of GnRH-I have been well characterized and intensively
      studied. However, the function of GnRH-II, which is the most evolutionarily
      conserved form of GnRH, has been elusive. Here we demonstrate that in a primitive
      mammal, the musk shrew (Suncus murinus), GnRH-II activates mating behavior in
      nutritionally challenged females within a few minutes after administration. In
      addition GnRH-II immunoreactive cell numbers and fibers increase in food
      restricted females. Furthermore, GnRH type II receptor immunoreactivity was
      detected in musk shrew brain in regions associated with mating behavior. Our
      results lead us to hypothesize that the role of the evolutionarily conserved GnRH
      II peptide is to coordinate reproductive behavior as appropriate to the
      organism's energetic condition.

PMID- 12488326
TI  - Anandamide activity and degradation are regulated by early postnatal aging and
      follicle-stimulating hormone in mouse Sertoli cells.
AB  - Anandamide (AEA), a prominent member of the endogenous ligands of cannabinoid
      receptors (endocannabinoids), is known to adversely affect female fertility.
      However, a potential role of AEA in male reproductive functions is unknown. Here
      we report evidence that immature mouse Sertoli cells have the biochemical tools
      to bind and inactivate AEA, i.e. a functional type-2 cannabinoid receptor (CB2R),
      a selective AEA membrane transporter, and an AEA-degrading enzyme fatty acid
      amide hydrolase. We show that, unlike CB2R, the activity of AEA membrane
      transporter and the activity and expression of FAAH decrease, whereas the
      apoptosis-inducing activity of AEA increases with age during the neonatal period.
      We also show that FSH reduces the apoptotic potential of AEA, but not that of its
      nonhydrolyzable analog methanandamide. Concomitantly, FSH enhances FAAH activity
      in a manner dependent on mRNA transcription and protein synthesis and apparently
      involving cAMP. These data demonstrate that Sertoli cells partake in the
      peripheral endocannabinoid system, and that FSH reduces the apoptotic potential
      of AEA by activating FAAH. Taken together, it can be suggested that the
      endocannabinoid network plays a role in the hormonal regulation of male
      fertility.

PMID- 12488327
TI  - Follicle-stimulating hormone-responsive cytoskeletal genes in rat granulosa
      cells: class I beta-tubulin, tropomyosin-4, and kinesin heavy chain.
AB  - FSH regulates gene expression for granulosa cell differentiation and follicular
      development. Therefore, FSH-responsive genes are crucial, but only a few genes
      have been identified for the early stage of follicular development. In
      particular, little is known about cytoskeletal genes, which likely play essential
      roles in the morphological changes such as the antrum formation, a major
      landmark. FSH is also known to induce the differentiation of an immature,
      undifferentiated rat ovary granulosa (ROG) cell line. Our data show that FSH
      induced massive yet distinct reorganization of microtubules and the actin
      cytoskeletons as well as morphological changes. To identify those genes
      responding to FSH during the differentiation, differential display was performed
      on ROG cells. Of the 80 FSH-responsive genes identified, there were three
      cytoskeleton-related genes (class I beta-tubulin, tropomyosin 4, and kinesin
      heavy chain), which are crucial for intracellular morphogenesis, transport, and
      differentiation. Northern blots show that the level of these gene transcripts
      reached a peak at 6 h after FSH treatment and subsided at 24 h. FSH induced the
      similar temporal expression not only in granulosa cells isolated from immature
      rats, but also in vivo. For instance, in situ hybridization showed that beta
      tubulin mRNA was transiently expressed in the granulosa cells of large preantral
      and early antral follicles. Despite the same temporal expression, the regulatory
      mechanisms of the three genes were strikingly different. As an example,
      cycloheximide blocked the beta-tubulin mRNA expression, whereas it increased
      tropomyosin-4 (TM4) mRNA. Yet, it did not impact kinesin heavy chain (Khc) mRNA.
      In conclusion, FSH induces the massive reorganization of the cytoskeletons and
      morphological changes by the selective regulation of the gene expression, protein
      synthesis, and rearrangement of the cytoskeletal proteins in the ROG cells and
      probably, specific follicles and granulosa cells.

PMID- 12488328
TI  - Skeletal effects of cyclosporin A are gender related in rats.
AB  - The immunosuppressive drug cyclosporin A (CsA) is thought to be involved in the
      pathogenesis of posttransplantation osteoporosis. To evaluate further the
      skeletal effects of CsA, we treated aged male and female sham-operated and
      gonadectomized rats with low doses of CsA for 4 months. Here, we show that CsA is
      antiresorptive and bone-sparing in aged female rats but increases bone resorption
      and reduces bone mass in aged male rats. However, even in male rats, CsA
      treatment, at clinically relevant doses, increased bone resorption only
      transiently and did not result in pronounced long-term cancellous bone loss. The
      gender-specific skeletal effects of CsA were not modulated by sex hormones or
      gonadectomy. CsA did not influence sex steroid metabolism in male or female rats.
      However, endogenous estradiol in sham-operated female rats (and especially,
      exogenous administration of 17beta-estradiol in ovariectomized rats) markedly
      diminished blood levels of CsA, probably by increasing hepatic CsA metabolism.
      Although the mechanism for the gender-specific skeletal effects of CsA is still
      obscure, our findings may have important implications for clinical therapy with
      CsA.

PMID- 12488329
TI  - p53 Is required for 1,25-dihydroxyvitamin D3-induced G0 arrest but is not
      required for G1 accumulation or apoptosis of LNCaP prostate cancer cells.
AB  - 1,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is an effective agent for
      inhibiting the growth of prostate cancer cells including LNCaP and PC-3 cell
      lines. However, the extent of growth inhibition in these cell lines differs
      because LNCaP cells are much more responsive than PC-3 cells. Previous studies in
      LNCaP cells have shown that 1,25-(OH)(2)D(3) treatment results in G(0)/G(1) cell
      cycle accumulation, loss of Ki67 expression, and induction of apoptosis. One
      difference between the two cell lines is that PC-3 cells lack functional p53, a
      protein that plays roles both in cell cycle regulation and induction of
      apoptosis. In this study, the role of p53 in 1,25-(OH)(2)D(3) action was examined
      using the p53-negative PC-3 cells and a line of LNCaP cells, called LN-56, in
      which p53 function was shut off using a dominant negative p53 fragment. We found
      that treatment with 1,25-(OH)(2)D(3) extensively inhibits growth of LN-56
      prostate cancer cells lacking p53, but in contrast to the parental LNCaP cells,
      the LN-56 cells recover rapidly. Moreover, in prostate cancer cells, the
      synergism between 1,25-(OH)(2)D(3) and 9-cis retinoic acid appears to be
      dependent on the presence of functional p53; however, 1,25-(OH)(2)D(3)-mediated
      induction of G(1) cell cycle accumulation and induction of apoptosis is not.

PMID- 12488330
TI  - Regulation of oxytocin receptor expression in cultured human myometrial cells by
      fetal bovine serum and lysophospholipids.
AB  - Oxytocin receptor (OTR) expression in human myometrium increases over 150-fold
      from the beginning of pregnancy to the end. In the present studies, we examined
      potential mechanisms of OTR up-regulation, using myometrial cells in primary
      culture from women in late gestation. OTR ligand-binding sites and steady-state
      mRNA levels were down regulated by serum starvation, and up-regulated by
      restoration of fetal bovine serum (FBS). Transcriptional activity of the OTR gene
      was the same with or without FBS treatment, but FBS increased OTR mRNA half-life
      about 5-fold. Lysophospholipids (lysophosphatidic acid and sphingosine 1
      phosphate), which are present in serum, had similar effects as FBS.
      Lysophospholipid receptor mRNAs of the endothelial differentiation gene (Edg)
      family (Edgs 1, 3, 4, and 5) were demonstrated in myometrial cells by RT-PCR.
      These G protein-coupled receptors have been shown to be coupled to G(i/o) and to
      mediate activation of phosphoinositol 3-phosphate kinase. Indeed, the effects of
      the lysophospholipids and FBS were completely blocked by pertussis toxin, a
      G(i/o) inhibitor. Likewise, inhibition of G(i/o) signaling by elevation of
      intracellular cAMP or inhibition of phosphoinositol 3-phosphate kinase blocked
      FBS effects on OTR mRNA stability. We do not presently understand the mechanisms
      of OTR up-regulation in human myometrium in vivo, but the present studies might
      lead to the description of mRNA-stabilizing factors whose activity can be
      quantified in tissue samples during pregnancy to elucidate the process of OTR up
      regulation.

PMID- 12488331
TI  - Bax, caspase-2, and caspase-3 are required for ovarian follicle loss caused by 4
      vinylcyclohexene diepoxide exposure of female mice in vivo.
AB  - The industrial chemical, 4-vinylcyclohexene diepoxide (VCD), kills oocytes within
      immature follicles in the ovaries of mice and rats and is considered a potential
      occupational health hazard. It has been reported that VCD-induced follicle loss
      occurs via a cell death process involving elevated expression of Bax, a
      proapoptotic Bcl-2 family member, and increased caspase-3-like activity. We have
      previously shown that oocytes lacking acid sphingomyelinase (ASMase; an enzyme
      that generates the proapoptotic stress sensor ceramide), the aromatic hydrocarbon
      receptor (Ahr), Bax, or caspase-2 are resistant to apoptosis induced by other
      chemical toxicants. Therefore, this study was designed to investigate the
      functional importance of ASMase, Ahr, Bax, and caspase-2 as well as the related
      executioner enzyme caspase-3 to VCD-induced ovotoxicity in mice using gene
      knockout technology. For each gene mutant mouse line, wild-type and homozygous
      null female siblings derived from heterozygous matings were given once-daily ip
      injections of either vehicle (sesame oil) or VCD (80 mg/kg body weight) for 15 d
      (three or four mice per treatment group per genotype). Ovaries were collected 24
      h after the final injection and analyzed for the total number of nonatretic
      primordial and primary follicles remaining per ovary. No differences in the
      extent of primordial or primary follicle destruction resulting from VCD exposure
      were observed in wild-type vs. ASMase- or Ahr-deficient mice. By contrast, the
      extent of VCD-induced primordial follicle depletion in Bax-deficient mice (45 +/-
      11%) was significantly (P < 0.05) lower than that in wild-type females (85 +/-
      2%). The extent of primary follicle loss in bax-null mice exposed to VCD (3 +/-
      22%) was also significantly (P < 0.05) lower than that in their wild-type sisters
      (86 +/- 4%). In caspase-2-deficient mice, significantly (P < 0.05) fewer oocyte
      containing primary follicles were destroyed by VCD (17 +/- 19%) vs. wild-type
      controls (71 +/- 6%); however, no significant difference in the extent of VCD
      induced primordial follicle destruction was observed in caspase-2-null vs. wild
      type females. Finally, in caspase-3-deficient mice, significantly (P < 0.05)
      fewer oocyte-containing primary follicles were destroyed by VCD (33 +/- 3%) vs.
      wild-type controls (71 +/- 2%); however, no significant difference in the extent
      of VCD-induced primordial follicle destruction was observed in caspase-3-null vs.
      wild-type females. We conclude that Bax, caspase-2, and caspase-3, but not ASMase
      or Ahr, are functionally important in VCD-induced follicle loss. However, as a
      loss of Bax, caspase-2, or caspase-3 function conveyed only partial protection
      from the ovotoxic effects of VCD, other cell death pathways that either function
      independently of Bax, caspase-2, and caspase-3 or are not apoptotic in nature are
      also involved.

PMID- 12488332
TI  - Immunolesion of norepinephrine and epinephrine afferents to medial hypothalamus
      alters basal and 2-deoxy-D-glucose-induced neuropeptide Y and agouti gene-related
      protein messenger ribonucleic acid expression in the arcuate nucleus.
AB  - Neuropeptide Y (NPY) and agouti gene-related protein (AGRP) are orexigenic
      peptides of special importance for control of food intake. In situ hybridization
      studies have shown that NPY and AGRP mRNAs are increased in the arcuate nucleus
      of the hypothalamus (ARC) by glucoprivation. Other work has shown that
      glucoprivation stimulates food intake by activation of hindbrain glucoreceptor
      cells and requires the participation of rostrally projecting norepinephrine (NE)
      or epinephrine (E) neurons. Here we determine the role of hindbrain catecholamine
      afferents in glucoprivation-induced increase in ARC NPY and AGRP gene expression.
      The selective NE/E immunotoxin saporin-conjugated antidopamine-beta-hydroxylase
      (anti-dbetah) was microinjected into the medial hypothalamus and expression of
      AGRP and NPY mRNA was analyzed subsequently in the ARC under basal and
      glucoprivic conditions using (33)P-labeled in situ hybridization. Saporin
      conjugated anti-dbetah virtually eliminated dbetah-immunoreactive terminals in
      the ARC without causing nonspecific damage. These lesions significantly increased
      basal but eliminated 2-deoxy-D-glucose-induced increases in AGRP and NPY mRNA
      expression. Results indicate that hindbrain catecholaminergic neurons contribute
      to basal NPY and AGRP gene expression and mediate the responsiveness of NPY and
      AGRP neurons to glucose deficit. Our results also suggest that catecholamine
      neurons couple potent orexigenic neural circuitry within the hypothalamus with
      hindbrain glucose sensors that monitor brain glucose supply.

PMID- 12488333
TI  - Estrogen receptor-alpha gene deficiency enhances androgen biosynthesis in the
      mouse Leydig cell.
AB  - Leydig cells, which produce the primary male steroid hormone testosterone (T),
      express the two estrogen receptor (ER) subtypes, ERalpha and ERbeta, and have the
      capacity to convert testosterone to the natural estrogen 17beta-estradiol. Thus,
      Leydig cells are subject to estrogen action. The development of transgenic mice
      that are homozygous for targeted deletion of genes encoding the ER subtypes
      provides an opportunity to examine the role of estrogen in Leydig cell function.
      In this study androgen biosynthesis was analyzed in Leydig cells from mice that
      were homozygous for targeted deletion of the ERalpha gene (alphaERKO). T
      production by alphaERKO Leydig cells was 2-fold higher than that in wild-type
      (WT) cells. Serum T levels were accordingly higher in alphaERKO compared with WT
      mice (5.1 +/- 1.1 vs. 2.2 +/- 0.4 ng/ml; P </= 0.01) as were serum LH levels
      (1.31 +/- 0.3 vs. 0.45 +/- 0.08 ng/ml; P </= 0.01). Mice that were treated with
      the pure antiestrogen ICI 182,780 at 100 micro g/kg.d for 7 d, effectively
      abrogating ER-mediated activity, also had 2-fold elevations in the serum levels
      of LH (1.15 +/- 0.3 vs. 0.45 +/- 0.2 ng/ml) and T (4.3 +/- 1.1 vs. 2.2 +/- 0.2
      ng/ml; P </= 0.01). Increased androgen biosynthesis by alphaERKO Leydig cells was
      associated with higher steroidogenic enzyme activity, especially of cytochrome
      P450 17alpha-hydroxylase/17-20 lyase (P450(17alpha)) and 17beta-hydroxysteroid
      dehydrogenase (17beta-HSD), as measured by conversion of radiolabeled steroid
      substrates to T or its precursors. The largest increases in enzymatic activity
      were observed for P450(17alpha) (423 +/- 45 pmol/min.10(6) cells in alphaERKO
      Leydig cells vs. 295 +/- 27 pmol/min.10(6) cells in WT cells; P < 0.01).
      Consistent with steroidogenic enzyme activity, the testis of alphaERKO mice
      expressed higher steady state mRNA levels for steroidogenic acute regulatory
      protein and two enzymes involved in androgen biosynthesis, P450(17alpha) and
      17beta-HSD type III, as determined by semiquantitative RT-PCR. Compared with the
      controls, higher steady state mRNA levels for steroidogenic acute regulatory
      protein and P450(17alpha) were also measured in the testis of ICI 182,780-treated
      mice. In a second set of experiments estrogen administration reduced serum LH and
      T levels in WT controls, whereas alphaERKO mice were unaffected. Although
      exposure of WT and alphaERKO Leydig cells to estrogen in vitro did not affect
      androgen biosynthesis, incubation with ICI 182,780 reduced T production by WT,
      but not alphaERKO, Leydig cells. These observations indicate that abrogation of
      the ERalpha gene by targeted deletion or treatment with an antiestrogen increases
      Leydig cell steroidogenesis in association with elevations in the serum levels of
      LH, which presumably is the result of estrogen insensitivity at the level of the
      hypothalamus and/or pituitary gonadotropes. Furthermore, the decrease in T
      production by WT Leydig cells and not alphaERKO Leydig cells occasioned by
      incubation with ICI 182,780 suggests that of the ER subtypes, ERalpha has a
      regulatory role in Leydig cell steroidogenic function.

PMID- 12488334
TI  - Natriuretic peptides suppress protein kinase C activity to reduce evoked dopamine
      efflux from pheochromocytoma (PC12) cells.
AB  - The observation that natriuretic peptides and protein kinase C activators
      influence evoked neurotransmitter efflux by diametrically opposed mechanisms
      prompted an investigation of the influence of natriuretic peptides on protein
      kinase C activity and the potential involvement of this pathway in
      neuromodulatory responses to natriuretic peptides. C-Type natriuretic peptide
      attenuated both evoked dopamine efflux and protein kinase C activity in a
      concentration-dependent manner consistent with a 10% diminution in protein kinase
      C activity producing a 4.6-6.2% reduction in evoked dopamine efflux. The ability
      of C-type natriuretic peptide to suppress evoked dopamine efflux was abolished by
      treatment with the protein kinase C inhibitors chelerythrine (10 micro M) and
      staurosporine (10 nM). Both chelerythrine and staurosporine attenuated protein
      kinase C activity at the concentrations used. The natriuretic peptide C receptor
      (NPR-C) appeared to mediate the attenuation of protein kinase C activity, because
      the effect was mimicked by a pentadecapeptide fragment of the NPR-C, and the
      effect of C-type natriuretic peptide was attenuated by an antibody generated
      against the same region of the receptor. These data suggest that C-type
      natriuretic peptide attenuates neurotransmitter efflux by a mechanism involving
      suppression of neuronal protein kinase C activity via an interaction with the NPR
      C.

PMID- 12488335
TI  - Sex difference in hepatic peroxisome proliferator-activated receptor alpha
      expression: influence of pituitary and gonadal hormones.
AB  - Peroxisome proliferator-activated receptor (PPAR) alpha is a nuclear receptor
      that is mainly expressed in tissues with a high degree of fatty acid oxidation
      such as liver, heart, and skeletal muscle. Unsaturated fatty acids, their
      derivatives, and fibrates activate PPARalpha. Male rats are more responsive to
      fibrates than female rats. We therefore wanted to investigate if there is a sex
      difference in PPARalpha expression. Male rats had higher levels of hepatic
      PPARalpha mRNA and protein than female rats. Fasting increased hepatic PPARalpha
      mRNA levels to a similar degree in both sexes. Gonadectomy of male rats decreased
      PPARalpha mRNA expression to similar levels as in intact and gonadectomized
      female rats. Hypophysectomy increased hepatic PPARalpha mRNA and protein levels.
      The increase in PPARalpha mRNA after hypophysectomy was more pronounced in
      females than in males. GH treatment decreased PPARalpha mRNA and protein levels,
      but the sex-differentiated secretory pattern of GH does not determine the sex
      differentiated expression of PPARalpha. The expression of PPARalpha mRNA in heart
      or soleus muscle was not influenced by gender, gonadectomy, hypophysectomy, or GH
      treatment. In summary, pituitary-dependent hormones specifically regulate hepatic
      PPARalpha expression. Sex hormones regulate the sex difference in hepatic
      PPARalpha levels, but not via the sexually dimorphic GH secretory pattern.

PMID- 12488336
TI  - Prolactin regulation of neonatal ovine uterine gland morphogenesis.
AB  - Uterine gland development or adenogenesis in the neonatal ovine uterus involves
      budding, proliferation, and branching morphogenesis of the glandular epithelium
      (GE) from the luminal epithelium (LE) between birth (postnatal day or PND 0) and
      PND 56. This critical developmental event is coincident with increases in serum
      PRL and expression of long and short PRL receptors specifically in the nascent
      and proliferating GE. In study one, ewes were treated with a placebo pellet as a
      control (CX) or a bromocryptine mesylate pellet from PNDs 0-56. On PND 56, the
      endometrium of bromocryptine mesylate ewes contained fewer glands, particularly
      in the stratum spongiosum that contained numerous coiled and branched glands in
      CX uteri. In study two, ewes were treated with saline as a CX or recombinant
      ovine PRL from PNDs 0-56. Treatment with PRL increased gland number and density
      on PND 14 and PND 56. In study three, expression of signal transducers and
      activators of transcription (STAT) 1, 3, and 5 proteins was detected in the
      developing glands from PNDs 7-56. In study four, Western blot analyses indicated
      that PRL increased levels of phosphorylated STATs 1 and 5, but not STAT 3, and
      phosphorylated ERK 1 and 2 MAPKs and c-Jun N-terminal kinase/stress-activated
      protein kinase proteins in explanted PND 28 ovine uteri. Collectively, results
      indicate that PRL regulates endometrial adenogenesis in the neonatal ovine
      uterus.

PMID- 12488337
TI  - Nongenomic activity and subsequent c-fos induction by estrogen receptor ligands
      are not sufficient to promote deoxyribonucleic acid synthesis in human
      endometrial adenocarcinoma cells.
AB  - Estrogen 17beta-estradiol (E2) rapidly modulates several signaling pathways
      related to cell growth, preservation, and differentiation. The physiological role
      of these nongenomic effects with regard to downstream outcomes, and the
      relationship with transcriptional estrogen activity are unclear. Furthermore, the
      ability of selective estrogen receptor modulators (SERMs) to trigger nongenomic
      actions is largely unknown. To determine whether estrogen receptor (ER) ligands
      exert nongenomic activity in endometrial adenocarcinoma cells, and whether this
      activity affects transcription and DNA synthesis, we challenged human Ishikawa
      cells with E2 or partial ER agonists 4-hydroxytamoxifen (OHT) and raloxifene
      (ral). Serum-starved Ishikawa cells exposed for 5 min to 0.1 nM E2 showed induced
      phosphorylation of MAPK (ERK1/2). Ral and 4-OHT each at 1 nM also stimulated ERK
      in a rapid transient manner. E2 and 4-OHT induced proto-oncogene c-fos mRNA
      expression in Ishikawa cells within 30 min, but ral had no effect. In contrast to
      nongenomic action, only E2 stimulated expression of an estrogen response element
      (ERE)-driven luciferase (LUC) reporter gene. To examine DNA synthesis, [(3)H]
      thymidine incorporation was measured in serum-starved cultures exposed to E2 or
      partial agonists for 2 d. E2 at 1 nM stimulated thymidine uptake in an ERK
      dependent manner, but 1 nM 4-OHT, 1 nM ral, and 0.1-nM concentrations of E2 had
      no significant effects. Taken together, these data indicate that both nongenomic
      and direct transcriptional ER effects are likely required to promote DNA
      synthesis.

PMID- 12488338
TI  - Specificity of cognate ligand-receptor interactions: fusion proteins of human
      chorionic gonadotropin and the heptahelical receptors for human luteinizing
      hormone, thyroid-stimulating hormone, and follicle-stimulating hormone.
AB  - The family of glycoprotein hormones and their homologous heptahelical receptors
      represent an excellent system for comparative structure-function studies. We have
      engineered single chain molecules of human chorionic gonadotropin (hCG) fused to
      its cognate receptor, LH receptor (LHR), and to the noncognate receptors, TSH
      receptor (TSHR) and FSH receptor (FSHR; N-beta-alpha-receptor-C), to create the
      yoked (Y) complexes YCG/LHR, YCG/TSHR, and YCG/FSHR. The expression and
      bioactivity of these fusion proteins were examined in transiently transfected HEK
      293 cells. Western blot analysis and antibody binding assays demonstrated that
      each of the proteins was expressed. In the case of YCG/LHR, minimal binding of
      exogenous hormone was observed due to the continued occupation of receptor by the
      fused ligand. The presence of hCG in the YCG/TSHR and YCG/FSHR, however, did not
      prevent binding of exogenous cognate ligand, presumably due to the lower affinity
      of hCG. The basal cAMP levels in cells expressing the YCG/LHR complex was
      approximately 20-fold higher than that in cells expressing LHR. Increases in
      basal cAMP production were also observed with YCG/TSHR and YCG/FSHR, e.g. 13- and
      4-fold increases, respectively. Whereas the affinity and specificity of hCG for
      LHR are extraordinarily high, the hormone is capable of binding to and activating
      both TSHR and FSHR under these conditions that mimic high ligand concentrations.
      These findings were confirmed by adding high concentrations of hCG to cells
      expressing TSHR and FSHR. Although the functional interaction of hCG and TSHR has
      been recognized in gestational hyperthyroidism, there are no reports linking hCG
      to FSHR activation. This study, however, suggests that such a functional
      interaction is capable of occurring under conditions of high circulating levels
      of hCG, e.g. the first trimester of pregnancy and in patients with hCG-secreting
      tumors.

PMID- 12488339
TI  - Failure of normal Leydig cell development in follicle-stimulating hormone (FSH)
      receptor-deficient mice, but not FSHbeta-deficient mice: role for constitutive
      FSH receptor activity.
AB  - Previous studies have suggested that FSH may be involved in regulation of Leydig
      cell function. We have examined this directly using two mouse models with null
      mutations in either the FSH beta-subunit (FSHbetaKO mice) or the FSH receptor
      (FSHRKO mice). Circulating LH levels were normal in adult FSHbetaKO mice, but
      were significantly increased in FSHRKO mice. Intratesticular testosterone levels
      increased normally in FSHbetaKO mice from birth to adulthood, whereas
      testosterone levels in FSHRKO mice failed to increase normally after puberty and
      were significantly reduced in adult animals. This was associated with reduced
      levels of mRNA encoding cytochrome P450 side-chain cleavage, 3beta-hydroxysteroid
      dehydrogenase type VI, and steroidogenic acute regulatory protein in FSHRKO mice.
      Leydig cell number was normal in FSHbetaKO mice during development, but in FSHRKO
      mice Leydig cell number increased slowly after puberty and was significantly
      reduced in the adult animal. Transfection studies showed that the FSHR exhibits
      constitutive activity in the absence of agonist stimulation. The results
      indicate, therefore, that Sertoli cells regulate the development of Leydig cell
      number and that constitutive activity within the FSHR is sufficient to stimulate
      this process. The presence of the hormone itself is not required when circulating
      LH levels are adequate.

PMID- 12488340
TI  - Peroxisome proliferator-activated receptor-alpha activation during pregnancy
      attenuates glucose-stimulated insulin hypersecretion in vivo by increasing
      insulin sensitivity, without impairing pregnancy-induced increases in beta-cell
      glucose sensing and responsiveness.
AB  - We investigated the effects of acute (24-h) peroxisome proliferator-activated
      receptor (PPAR)alpha activation by WY14,643 (pirinixic acid) treatment on glucose
      stimulated insulin secretion (GSIS) during pregnancy, in the rat, in relation to
      insulin sensitivity. GSIS after iv glucose challenge (500 mg/kg) was increased at
      d 15 of pregnancy but was attenuated by WY14,643 treatment in vivo, with
      decreases in acute insulin response (51%; P < 0.001) and total suprabasal 30-min
      area under the insulin curve (deltaI) (55%; P < 0.001). GSIS was unaffected by
      WY14,643 treatment in unmated rats. Islet perifusions were employed to identify
      persistent effects of PPARalpha activation. GSIS was enhanced, and the glucose
      threshold was reduced in perifused islets from pregnant rats, but WY14,643
      treatment failed to reverse these effects. WY14,643 treatment of 15-d-pregnant
      rats significantly lowered (by 63%; P < 0.01) the insulin resistance index [total
      suprabasal 30-min area under insulin curve x suprabasal 30-min area under glucose
      curve (deltaI x deltaG)]. A strong positive linear relationship (r = 0.92)
      between acute insulin response and deltaI x deltaG was evident between groups.
      Our studies show that acute PPARalpha activation reverses the augmented GSIS
      evoked by pregnancy in vivo, whereas the isolated islets retain pregnancy-induced
      enhancement of beta-cell glucose sensing and responsiveness. Normalization of
      maternal GSIS to that found in the nonpregnant state is observed in association
      with alleviation of maternal insulin resistance.

PMID- 12488341
TI  - Lysyl oxidase gene expression and enzyme activity in the rat ovary: regulation by
      follicle-stimulating hormone, androgen, and transforming growth factor-beta
      superfamily members in vitro.
AB  - Lysyl oxidase (LOX) catalyzes the final enzymatic reaction required for cross
      linking of collagen and elastin fibers and therefore has a crucial role in
      regulating the formation and maintenance of extracellular matrix in the ovary.
      LOX mRNA is abundantly expressed in rat granulosa cells. To examine how
      regulation of LOX in the ovary might influence follicular development, we studied
      LOX mRNA expression and enzyme activity in rat granulosa cells from late
      preantral/early antral follicles in vitro. FSH dose dependently inhibited LOX
      mRNA and enzyme activity (50% reduction at 10 ng/ml) in vitro, and FSH action was
      mimicked by 8-bromo-cAMP, suggesting FSH action via elevation of cAMP.
      Dihydrotestosterone alone enhanced LOX mRNA and enzyme activity, but potentiated
      the effect of FSH, causing a further reduction. TGFbeta1 alone dose dependently
      enhanced LOX mRNA (5-fold increase at 10 ng/ml) and activity (1.5-fold increase).
      FSH dose dependently inhibited the increase in LOX mRNA and activity caused by
      TGFbeta1 (by up to 84% and 80%, respectively). Growth differentiation factor-9
      (GDF-9) and activin A, at the same concentration as TGFbeta1 (10 ng/ml),
      stimulated LOX mRNA and activity within 6 h, although overall expression was
      higher at 48 h. All three factors when combined with FSH further reduced both
      mRNA and enzyme activity (by up to 60%) compared with FSH alone. These findings
      indicate control of LOX at endocrine, paracrine, and autocrine levels within the
      ovary and suggest coordinated regulation of ovarian extracellular matrix during
      follicular development, with FSH determining whether local factors act as
      stimulators or inhibitors of LOX.

PMID- 12488342
TI  - Pubertal acceleration of pulsatile gonadotropin-releasing hormone release in male
      rats as revealed by microdialysis.
AB  - A microdialysis technique was used in male rats to directly assess the postulate
      that pubertal maturation is associated with accelerated GnRH pulsatility.
      Juvenile male rats, postnatal d 43 or 45 (n = 4) were stereotaxically fitted with
      guide cannulas directed toward the lateral median eminence, and repeated
      microdialysis experiments were conducted over 4-6 d. In each session, samples
      were collected continuously over 12 h (0900-2100 h) at 5-min intervals Results
      from individual peripubertal animals were pooled into two time bins for postnatal
      d 45-47 and 48-50, respectively, and GnRH characteristics were compared between
      the two epochs. The GnRH pulse frequency and mean GnRH concentration were
      significantly elevated at 48-50 d compared with 45-47 d. The GnRH pulsatility
      characteristics for 45-47 d vs. 48-50 d were as follows: pulse frequency, 0.74 +/
      0.16 vs. 1.79 +/- 0.19 pulses/h (P < 0.05); pulse amplitude, 254.1 +/- 22.3 vs.
      347.2 +/- 15.8 deltapg/ml (difference in value from trough to peak); and mean
      release, 0.55 +/- 0.03 vs. 2.04 +/- 0.04 pg/5 min (P < 0.05). An additional two
      rats were dialyzed only once on postnatal d 50 to assess the effects of repeated
      sampling; the GnRH pulse characteristics in these animals were similar to those
      in rats sampled for a third or fourth time on postnatal d 48-50. To further
      assess the possible effects of repeated sampling on GnRH release profiles, a
      group of adult male rats (postnatal d 95-105; n = 3) was also dialyzed on four
      consecutive days. In these rats no significant alteration in GnRH pulse generator
      activity was observed over the four sessions. Moreover, the increase in GnRH
      pulse frequency observed in the peripubertal rats was found to be sustained in
      adult animals. To better understand the temporal relationship of GnRH pulse
      generator activity to reproductive maturation, groups of male rats were killed
      from postnatal d 45-56 along with an adult group at 95-105 d (n = 5/group) and
      examined for physiological signs of reproductive development. Gradual increases
      in serum levels of LH and testosterone and decreases in FSH and inhibin B were
      seen from postnatal d 45-56 to adulthood. Mature spermatozoa were found in the
      vas deferens by postnatal d 53. Our results demonstrate that in the late juvenile
      stage of male rat development, GnRH pulse generator activity is gradually
      accelerated over the course of consecutive days. This acceleration occurs over a
      period during which serum LH and testosterone are rising to adult levels, and it
      precedes the presence of mature spermatozoa in the vas deferens by 3 d. Our
      observations provide direct support for the hypothesis that an acceleration of
      GnRH pulsatility is the critical neural stimulus for the initiation of pubertal
      maturation in males. The peripheral and central cues that prompt the pubertal
      activation of the GnRH pulse generator remain to be characterized.

PMID- 12488343
TI  - Growth differentiation factor-9 stimulates inhibin production and activates Smad2
      in cultured rat granulosa cells.
AB  - Ovarian inhibin production is stimulated by FSH and several TGFbeta family
      ligands including activins and bone morphogenetic proteins. Growth
      differentiation factor-9 (GDF-9) derived by the oocyte is a member of the
      TGFbeta/activin family, and we have previously shown that GDF-9 treatment
      stimulates ovarian inhibin-alpha content in explants of neonatal ovaries.
      However, little is known about GDF-9 regulation of inhibin production in
      granulosa cells and downstream signaling proteins activated by GDF-9. Here, we
      used cultured rat granulosa cells to examine the influence of GDF-9 on basal and
      FSH-stimulated inhibin production, expression of inhibin subunit transcripts, and
      the GDF-9 activation of Smad phosphorylation. Granulosa cells from small antral
      follicles of diethylstilbestrol-primed immature rats were cultured with FSH in
      the presence or absence of increasing concentrations of GDF-9. Secreted dimeric
      inhibin A and inhibin B were quantified using specific ELISAs, whereas inhibin
      subunit RNAs were analyzed by Northern blotting using (32)P-labeled inhibin
      subunit cDNA probes. Similar to FSH, treatment with GDF-9 stimulated dose- and
      time-dependent increases of both inhibin A and inhibin B production. Furthermore,
      coincubation of cells with GDF-9 and FSH led to a synergistic stimulation of both
      inhibin A and inhibin B production. GDF-9 treatment also increased mRNA
      expression for inhibin-alpha and inhibin-beta subunits. To investigate Smad
      activation, granulosa cell lysates were analyzed in immunoblots using
      antiphosphoSmad1 and antiphosphoSmad2 antibodies. GDF-9 treatment increased
      Smad2, but not Smad1, phosphorylation with increasing doses of GDF-9 leading to a
      dose-dependent increase in phosphoSmad2 levels. To further investigate inhibin
      alpha gene promoter activation by GDF-9, granulosa cells were transiently
      transfected with an inhibin-alpha promoter-luciferase reporter construct and
      cultured with different hormones before assaying for luciferase activity.
      Treatment with FSH or GDF-9 resulted in increased inhibin-alpha gene promoter
      activity, and combined treatment with both led to synergistic increases. The
      present data demonstrate that oocyte-derived GDF-9, alone or together with
      pituitary-derived FSH, stimulates inhibin production, inhibin subunit mRNA
      expression, and inhibin-alpha promoter activity by rat granulosa cells. The
      synergistic stimulation of inhibin secretion by the paracrine hormone GDF-9 and
      the endocrine hormone FSH could play an important role in the feedback regulation
      of FSH release, thus leading to the modulation of follicle maturation and
      ovulation.

PMID- 12488344
TI  - Selective estrogen receptor modulators regulate phasic activation of hippocampal
      CA1 pyramidal cells by estrogen.
AB  - Previous studies demonstrated that estrogen induces two sequential waves of CA1
      pyramidal cell activation, evidenced by induction of c-Fos at 2 and 24 h after a
      single estrogen treatment. The second wave of activation is paralleled by
      suppression of immunoreactivity for glutamic acid decarboxylase-65kD (GAD65) in
      CA1 and decreased synaptic inhibition of CA1 pyramidal cells. Here, we report
      that pretreatment with either of the selective estrogen receptor (ER) modulators,
      tamoxifen (T) or CI628, has no effect on the first wave of c-Fos expression at 2
      h but completely blocks the second wave of c-Fos and the suppression of GAD65 at
      24 h. Interestingly, T, given 4 h after estrogen, failed to block c-Fos
      expression or suppression of GAD65 at 24 h. Electrophysiological experiments
      showed that the T metabolite, 4OH-T, or CI628 can inhibit the so-called rapid
      estrogen effect, to potentiate excitatory postsynaptic currents (EPSCs) in CA1
      pyramidal cells. Thus, estrogen seems to act within 4 h via classical ERs and/or
      a rapid estrogen effect, such as EPSC potentiation, to produce
      activation/disinhibition of pyramidal cells 24 h later. In contrast, the initial
      activation of pyramidal cells, at 2 h after estrogen, seems to involve neither
      classical ERs nor rapid potentiation of EPSCs.

PMID- 12488345
TI  - Menkes protein contributes to the function of peptidylglycine alpha-amidating
      monooxygenase.
AB  - Menkes protein (ATP7A) is a P-type ATPase involved in copper uptake and
      homeostasis. Disturbed copper homeostasis occurs in patients with Menkes disease,
      an X-linked disorder characterized by mental retardation, neurodegeneration,
      connective tissue disorders, and early childhood death. Mutations in ATP7A result
      in malfunction of copper-requiring enzymes, such as tyrosinase and copper/zinc
      superoxide dismutase. The first step of the two-step amidation reaction carried
      out by peptidylglycine alpha-amidating monooxygenase (PAM) also requires copper.
      We used tissue from wild-type rats and mice and an ATP7A-specific antibody to
      determine that ATP7A is expressed at high levels in tissues expressing high
      levels of PAM. ATP7A is largely localized to the trans Golgi network in pituitary
      endocrine cells. The Atp7a mouse, bearing a mutation in the Atp7a gene, is an
      excellent model system for examining the consequences of ATP7A malfunction.
      Despite normal levels of PAM protein, levels of several amidated peptides were
      reduced in pituitary and brain extracts of Atp7a mice, demonstrating that PAM
      function is compromised when ATP7A is inactive. Based on these results, we
      conclude that a reduction in the ability of PAM to produce bioactive end-products
      involved in neuronal growth and development could contribute to many of the
      biological effects associated with Menkes disease.

PMID- 12488346
TI  - pp60c-Src Kinase mediates growth effects of the full-length precursor progastrin1
      80 peptide on rat intestinal epithelial cells, in vitro.
AB  - Growth factor effects of precursor forms of gastrins have become evident in
      recent years. However, intracellular pathways that mediate growth effects of the
      precursor molecules are not known. In previous studies, we reported an increase
      in Tyr phosphorylation of pp60(c-Src) in intestinal epithelial cells (IEC) in
      response to the fully processed form of gastrin [gastrin(1-17) (G17)]. We have
      now examined whether c-Src kinase is similarly phosphorylated and activated in
      response to the full-length precursor molecule, progastrin (PG)(1-80),
      (recombinant human PG) in IEC cells. We found a significant increase in pp60(c
      Src) kinase activity in response to both G17 and PG (0.1-1.0 nM), suggesting that
      growth effects of both the precursor and fully processed gastrin molecules may be
      mediated via similar pathways. On the other hand, pp62(c-Yes) was not
      phosphorylated or activated in response to either G17 or PG. To examine whether c
      Src kinase mediates proliferative effects of PG, IEC cells were microinjected
      with anti-Src-IgG and (3)H-thymidine ((3)H-Tdr) uptake of the cells measured.
      Control cells received nonimmune IgG. The (3)H-Tdr uptake of cells stimulated
      with 1.0 nM PG was significantly reduced in cells microinjected with anti-c-Src
      IgG; control IgG had no effect. In cells stimulated with 1.0% fetal calf serum,
      microinjection with c-Src-IgG had no effect on (3)H-Tdr uptake. The specificity
      of the effect was further confirmed by blocking the inhibitory effect of anti-c
      Src-IgG with antigenic Src peptide. These results suggest that activation of c
      Src kinase likely represents a critical step in mediating proliferative effects
      of both the precursor and fully processed forms of gastrins on IEC.

PMID- 12488347
TI  - Temporally sensitive trophic responsiveness of the adrenalectomized rat anterior
      pituitary to dexamethasone challenge: relationship between mitotic activity and
      apoptotic sensitivity.
AB  - Depending on timing and dose, exogenous glucocorticoids induce a wave of
      apoptosis in the adult rat anterior pituitary, a response that is enhanced by
      adrenalectomy. In this study, we show that the size of the glucocorticoid
      sensitive apoptotic population progressively increases during the week following
      surgical adrenalectomy, plateaus for a further week, then spontaneously declines
      to levels seen in intact animals by 4 wk. Mitotic activity, in contrast, rises
      rapidly post adrenalectomy but returns to baseline within 2 wk. Increased mitotic
      activity precedes the increase in the population of cells that undergo
      glucocorticoid-induced apoptosis and the subsequent decline in mitotic activity
      precedes the decline in apoptotic sensitivity despite persistent elevation of
      hypothalamic CRH and pituitary proopiomelanocortin transcripts. If glucocorticoid
      exposure is delayed until 4 wk post adrenalectomy when the apoptotic response has
      returned to baseline, glucocorticoid withdrawal, by transiently increasing
      mitotic activity, again primes the formation of an expanded glucocorticoid
      sensitive apoptotic cell population. These data suggest that apoptotic
      sensitivity is largely confined to cells that have recently entered the cell
      cycle. This observation is further corroborated by demonstrating an abrupt
      glucocorticoid-induced step-down in the bromodeoxyuridine-labeling index to basal
      levels in rats given daily injections of bromodeoxyuridine during the week
      following adrenalectomy.

PMID- 12488348
TI  - New evidence of similarity between human and plant steroid metabolism: 5alpha
      reductase activity in Solanum malacoxylon.
AB  - The physiological role of steroid hormones in humans is well known, and the
      metabolic pathway and mechanisms of action are almost completely elucidated. The
      role of plant steroid hormones, brassinosteroids, is less known, but an
      increasing amount of data on brassinosteroid biosynthesis is showing unexpected
      similarities between human and plant steroid metabolic pathways. Here we focus
      our attention on the enzyme 5alpha-reductase (5alphaR) for which a plant ortholog
      of the mammalian system, DET2, was recently described in Arabidopsis thaliana. We
      demonstrate that campestenone, the natural substrate of DET2, is reduced to
      5alpha-campestanone by both human 5alphaR isozymes but with different affinities.
      Solanum malacoxylon, which is a calcinogenic plant very active in the
      biosynthesis of vitamin D-like molecules and sterols, was used to study 5alphaR
      activity. Leaves and calli were chosen as examples of differentiated and
      undifferentiated tissues, respectively. Two separate 5alphaR activities were
      found in calli and leaves of Solanum using campestenone as substrate. The use of
      progesterone allowed the detection of both activities in calli. Support for the
      existence of two 5alphaR isozymes in S. malacoxylon was provided by the
      differential actions of inhibitors of the human 5alphaR in calli and leaves. The
      evidence for the presence of two isozymes in different plant tissues extends the
      analogies between plant and mammalian steroid metabolic pathways.

PMID- 12488349
TI  - Estrogen increases locomotor activity in mice through estrogen receptor alpha:
      specificity for the type of activity.
AB  - Estrogens are known to increase running wheel activity of rodents primarily by
      acting on the medial preoptic area (mPOA). The mechanisms of this estrogenic
      regulation of running wheel activity are not completely understood. In
      particular, little is known about the separate roles of two types of estrogen
      receptors, ERalpha and ERbeta, both of which are expressed in mPOA neurons. In
      the present study the effects of continuous estrogen treatment on running wheel
      activity were examined in male and female mice specifically lacking either the
      ERalpha (alphaERKO) or the ERbeta (betaERKO) gene. Mice were gonadectomized and 1
      wk later implanted with either a low dose (16 ng/d) or a high dose (160 ng/d) of
      estradiol benzoate (EB) or with a placebo control pellet. Home cage running wheel
      activity was recorded for 9 d starting 10 d after EB implants. The same mice were
      also tested for open field activity before and after EB implants. In both female
      and male alphaERKO mice, running wheel activity was not different from that in
      corresponding wild-type (alphaWT) mice in placebo control groups. In both females
      and males it was increased by EB only in alphaWT, not alphaERKO, mice. In
      betaERKO mice, on the other hand, both doses of EB equally increased running
      wheel activity in both sexes just as they did in betaWT mice. Absolute numbers of
      daily revolutions of EB-treated groups, however, were significantly lower in
      betaERKO females compared with betaWT females. Before EB treatment,
      gonadectomized alphaERKO female were significantly less active than alphaWT mice
      in open field tests, whereas betaERKO females tended to be more active than
      betaWT mice. In male mice there were no effect of ERalpha or ERbeta gene knockout
      on open field activity. Unlike its effect on running wheel activity, EB treatment
      induced only a small increase in open field activity in female, but not male,
      mice. These findings indicate that 1) in both sexes estrogenic regulation of
      running wheel activity is primarily mediated through the ERalpha, not the ERbeta;
      and 2) hormone/genotype effects are specific to the type of locomotor activity
      (i.e. home cage running wheel activity and open field activity) measured.

PMID- 12488350
TI  - Lysophosphatidic acid inhibits C-type natriuretic peptide activation of guanylyl
      cyclase-B.
AB  - C-type natriuretic peptide (CNP), found in endothelial cells, chondrocytes, and
      neurons, binds its cognate transmembrane receptor, natriuretic peptide receptor-B
      (NPR-B/GC-B), and stimulates the synthesis of the intracellular signaling
      molecule, cGMP. The known physiologic consequences of this binding event are
      vasorelaxation, inhibition of cell proliferation, and the stimulation of long
      bone growth. Here we report that 10% fetal bovine serum markedly reduced CNP
      dependent cGMP elevations in NIH3T3 fibroblast. The purified serum components
      platelet-derived growth factor and lysophosphatidic acid (LPA) mimicked the
      effect of serum on CNP-dependent cGMP elevations, but the latter factor resulted
      in the most dramatic reductions. The LPA-dependent inhibition was rapid and dose
      dependent, having t(1/2) and IC(50) values of approximately 5 min and 3.0 micro M
      LPA, respectively. The decreased cGMP concentrations resulted from reduced CNP
      dependent NPR-B guanylyl cyclase activity that did not require losses in receptor
      protein or activation of protein kinase C, indicating a previously undescribed
      desensitization pathway. These data suggest that NPR-B is repressed by LPA and
      that one mechanism by which LPA exerts its effects is through the heterologous
      desensitization of the CNP/NPR-B/cGMP pathway. We hypothesize that cross-talk
      between the LPA and CNP signaling pathway maximizes the response of fibroblasts
      in the wound-healing process.

PMID- 12488351
TI  - Anion selectivity by the sodium iodide symporter.
AB  - The iodide transporter of the thyroid (NIS) has been cloned by the group of
      Carrasco. The NIS-mediated transport was studied by electrophysiological methods
      in NIS-expressing Xenopus oocytes. Using this method, the anion selectivity of
      NIS was different from that previously reported for thyroid cells, whereas
      perchlorate and perrhenate were found not transported. In this study we compared
      the properties of human NIS, stably transfected in COS-7 cells to those of the
      transport in a thyroid cell line, the FRTL5 cells, by measuring the transport
      directly. We measured the uptake of (125)I(-), (186)ReO(4)(-), and (99m)TcO(4)(-)
      and studied the effect on it of known competing anions, i.e. ClO(4)(-), SCN(-),
      ClO(3)(-), ReO(4)(-), and Br(-). We conclude that the properties of the NIS
      transporter account by themselves for the properties of the thyroid iodide
      transporter as described previously in thyroid slices. The order of affinity was:
      ClO(4)(-) > ReO(4)(-) > I(-) >/= SCN(-) > ClO(3)(-) > Br(-). NIS is also
      inhibited by dysidenin (as in dog thyroid).

PMID- 12488352
TI  - Dehydroepiandrosterone down-regulates the expression of peroxisome proliferator
      activated receptor gamma in adipocytes.
AB  - Dehydroepiandrosterone (DHEA) is expected to have a weight-reducing effect. In
      this study, we evaluated the effect of DHEA on genetically obese Otsuka Long
      Evans Fatty rats (OLETF) compared with Long-Evans Tokushima rats (LETO) as
      control. Feeding with 0.4% DHEA-containing food for 2 wk reduced the weight of
      sc, epididymal, and perirenal adipose tissue in association with decreased plasma
      leptin levels in OLETF. Adipose tissue from OLETF showed increased expression of
      peroxisome proliferator-activated receptor gamma (PPARgamma) protein, which was
      prevented by DHEA treatment. Further, we examined the effect of DHEA on PPARgamma
      in primary cultured adipocytes and monolayer adipocytes differentiated from rat
      preadipocytes. PPARgamma protein level was decreased in a time- and concentration
      dependent manner, and DHEA significantly reduced mRNA levels of PPARgamma,
      adipocyte lipid-binding protein, and sterol regulatory element-binding protein,
      but not CCAAT/enhancer binding protein alpha. DHEA-sulfate also reduced the
      PPARgamma protein, but dexamethasone, testosterone, or androstenedione did not
      alter its expression. In addition, treatment with DHEA for 5 d reduced the
      triglyceride content in monolayer adipocytes. These results suggest that DHEA
      down-regulates adiposity through the reduction of PPARgamma in adipocytes.

PMID- 12488353
TI  - Contrasting activities of thyrotropin receptor antibodies in experimental models
      of Graves' disease induced by injection of transfected fibroblasts or
      deoxyribonucleic acid vaccination.
AB  - The development of experimental models of autoimmune hyperthyroid Graves' disease
      has proved a difficult challenge, but recently two novel methods have led to
      their successful development in mice. We describe our studies on replicating the
      adjuvant modified, human TSH receptor (TSHR) and major histocompatibility complex
      class II transfected fibroblast injection system, and the plasmid DNA vaccination
      method as models resembling the human disorder. The fibroblast injection model in
      female AKR/N (H-2k) mice led to 70% of the animals developing thyroid-stimulating
      antibodies and their thyroid glands showed large goiters with histological
      features of thyroid cell activation characteristic of Graves' glands. Consistent
      with the clinical homolog, there was no inflammatory cell infiltrate of the
      thyroid gland. Detailed studies on the anti-TSHR antibodies such as thyroid
      stimulating blocking antibody, antibodies to the native TSHR by flow cytometry,
      and TSH-binding inhibiting Ig showed that they were heterogeneous and did not
      correlate with disease activity, thus resembling those present in patients with
      Graves' disease. In contrast, the plasmid DNA vaccination model in female BALB/c
      (H-2d) mice led to the generation of low levels of anti-TSHR antibodies by flow
      cytometry, which were undetectable for thyroid-stimulating antibodies, TSH
      stimulating blocking antibodies, and TSH-binding inhibiting Ig activity.
      Moreover, this model too was not accompanied by lymphocytic cell infiltration.
      The data demonstrate the high incidence of hyperthyroid disease induced in the
      adjuvant modified, transfected fibroblast model in AKR/N mice to allow
      pathological mechanisms of disease to be studied.

PMID- 12488354
TI  - Androgen receptors in gonadotrophs in pituitary cultures from adult male monkeys
      and rats.
AB  - There is substantial evidence demonstrating that the principal feedback action of
      androgens to decrease LH secretion in male primates, including man, is to slow
      the GnRH pulse generator, whereas in male rats androgens not only decrease GnRH
      but also suppress LH synthesis and secretion through a direct pituitary effect.
      Previous experiments in our laboratory revealed that testosterone (T) suppresses
      LH secretion and decreases alpha-subunit mRNA levels in male rat pituitary cell
      cultures perifused with pulses of GnRH but not in pituitary cells from adult male
      monkeys. In the present study, we sought to determine whether the lack of
      responsiveness of gonadotrophs to androgens in the primate is androgen receptor
      (AR) related. Primary cultures were prepared from the anterior pituitary glands
      of adult male monkeys and rats. Cells were identified as gonadotrophs if they
      were immunoreactive for LH-beta or FSH-beta. Of these cells in the monkey, 80%
      contained both gonadotropins, 17% contained only LH-beta, and 3% contained only
      FSH-beta. AR immunoreactivity (IR) was nuclear in 22% and 15%, respectively, of
      monkey and rat FSH-beta-positive cells in the absence of T. Following T
      treatment, nuclear AR IR was identified in 79% of monkey and 81% of rat
      gonadotrophs. T treatment similarly intensified AR IR in mouse gonadotroph
      alphaT3-1 and LbetaT2 cells and in monkey and rat fibroblasts. Single-cell RT-PCR
      confirmed coexpression of LH-beta and AR mRNA as well as LH-beta and GH mRNA in
      monkey gonadotrophs. Our data reveal that most monkey, as well as rat,
      gonadotrophs are AR-positive with nuclear localization in the presence of T. GH
      expression is not required for AR expression in gonadotrophs. We conclude that
      the failure of T to inhibit LH secretion and decrease alpha-subunit mRNA
      expression in the male primate is not due a disturbance in AR nuclear shuttling.

PMID- 12488355
TI  - The morphometry of astrocytes in the rostral preoptic area exhibits a diurnal
      rhythm on proestrus: relationship to the luteinizing hormone surge and effects of
      age.
AB  - The morphometry of astrocytes in the arcuate nucleus exhibits cyclic changes
      during the estrous cycle leading to dynamic changes in the communication between
      neurotransmitters and neuropeptides that regulate pituitary hormone secretion.
      Data suggest that remodeling of direct and/or indirect inputs into GnRH neurons
      may influence the timing and/or amplitude of the preovulatory LH surge in young
      rats. We have previously found that aging alters the timing and amplitude of the
      LH surge. Therefore, the purpose of this study was to focus on the rostral
      preoptic area where GnRH cell bodies reside. We assessed the possibility that the
      morphometry of astrocytes in the rostral preoptic area displays time-related and
      age-dependent changes on proestrus. Our results demonstrate that, in young rats,
      astrocyte cell surface area decreases between 0800 h and 1200 h, before the
      initiation of the LH surge. Changes in surface area over the cycle were specific
      to astrocytes in close apposition to GnRH neurons. In contrast, in middle-aged
      rats astrocyte surface area was significantly less than in young rats and did not
      change during the day. These findings suggest that a loss of astrocyte plasticity
      could lead to the delayed and attenuated LH surge that has been previously
      observed in middle-aged rats.

PMID- 12488356
TI  - Central administration of neuropeptide Y reduces alpha-melanocyte-stimulating
      hormone-induced cyclic adenosine 5'-monophosphate response element binding
      protein (CREB) phosphorylation in pro-thyrotropin-releasing hormone neurons and
      increases CREB phosphorylation in corticotropin-releasing hormone neurons in the
      hypothalamic paraventricular nucleus.
AB  - Neuropeptide Y (NPY) has a potent inhibitory effect on TRH gene expression in the
      paraventricular nucleus (PVN) and contributes to the fall in circulating thyroid
      hormone levels during fasting mediated by a reduction in serum leptin levels.
      Because alpha-MSH activates the TRH gene by increasing the phosphorylation of
      CREB in the nucleus of these neurons, we raised the possibility that at least one
      of the mechanisms by which NPY reduces TRH mRNA in hypophysiotropic neurons is by
      antagonizing the ability of alpha-MSH to phosphorylate CREB. As NPY increases CRH
      mRNA in the hypothalamus, we further determined whether intracerebroventricular
      (i.c.v.) administration of NPY regulates the phosphorylation of CREB in
      hypophysiotropic CRH neurons. NPY [10 micro g in artificial CSF (aCSF)] was
      administered into the lateral ventricle i.c.v. 30 min before the i.c.v.
      administration of aCSF or alpha-MSH (10 micro g in aCSF), the latter in a dose
      previously demonstrated to increase proTRH mRNA and phosphorylate CREB in TRH
      neurons. By double-labeling immunocytochemistry, only few TRH neurons in the PVN
      contained phosphoCREB (PCREB) in animals treated only with aCSF (4 +/- 0.2%) or
      with NPY followed by aCSF (9.7 +/- 2.5), whereas alpha-MSH-infused animals
      dramatically increased the percentage of TRH neurons containing PCREB (75.3 +/-
      6.9%). Pretreatment with NPY before alpha-MSH infusion, however, significantly
      reduced the percentage of TRH neurons containing PCREB (40.8 +/- 3.5%) compared
      with alpha-MSH infused animals (P = 0.01). Only 12.2 +/- 0.9% of CRH neurons of
      the medial parvocellular neurons contained PCREB nuclei in vehicle-treated
      animals, whereas 30 min following NPY infusion, the number of CRH neurons
      containing PCREB increased dramatically to 88 +/- 2.9%. Whereas alpha-MSH
      infusion increased the percentage of CRH neurons that contained PCREB to 56 +/-
      2.2% compared with control, animals pretreated with NPY further increased the
      number of CRH neurons colocalizing with PCREB to 87 +/- 2.5%. These data
      demonstrate a functional interaction between NPY and alpha-MSH in the regulation
      of proTRH neurons in the PVN, suggesting that NPY can antagonize alpha-MSH
      induced activation of the TRH gene by interfering with melanocortin signaling at
      the postreceptor level, preventing the phosphorylation of CREB. In contrast, NPY
      infusion increases the phosphorylation of CREB in CRH neurons, indicating that
      NPY has independent effects on discrete populations of neurons in the PVN,
      presumably mediated through different signaling mechanisms.

PMID- 12488357
TI  - Trafficking of mutant carboxypeptidase E to secretory granules in a beta-cell
      line derived from Cpe(fat)/Cpe(fat) mice.
AB  - We have reinvestigated the stability and intracellular routing of mutant
      carboxypeptidase E in NIT3 cells, a pancreatic beta-cell line derived from the
      Cpe(fat)/Cpe(fat) mouse. Pulse-chase experiments demonstrated that this protein
      has a half-life of approximately 3 h in these cells and that up to 45% of the
      proCPE(202) can escape degradation by the proteosome. In double-label
      immunofluorescence microscopy, a portion of the mutant CPE did not colocalize
      with calnexin, an endoplasmic reticulum marker, but was found in prohormone
      convertase 2-containing secretory granules, demonstrating that it had escaped
      degradation and arrived at a post-Golgi compartment. The mutant CPE as well as
      prohormone convertase 2 were secreted into the medium in a stimulated manner by
      treatment with the physiological secretagogue, glucagon-like peptide-1,
      consistent with its presence in granules of the regulated secretory pathway. The
      presence of mutant carboxypeptidase E in granules supports a potential role for
      its involvement as a sorting/retention receptor in the trafficking of proinsulin
      to the regulated secretory pathway.

PMID- 12488358
TI  - Colocalization and hormone regulation of estrogen receptor alpha and N-methyl-D
      aspartate receptor in the hypothalamus of female rats.
AB  - Effects of N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation on
      neuroendocrine function can be modulated by the steroid hormone milieu. For
      example, the hypothalamic GnRH neurons, the primary cells regulating reproductive
      function, are stimulated by NMDAR agonists, and this is greatly potentiated by
      estrogen. We hypothesized that the actions of glutamate and estrogen may converge
      at target cells in the brain in which the NMDA and estrogen receptors (ERs) are
      coexpressed. To this end, we used quantitative stereological techniques to
      determine the colocalization of the obligatory NMDAR subunit, NR1, and the
      ERalpha, in the anteroventral periventricular nucleus and the medial preoptic
      nucleus, two critical regions for reproductive physiology and behavior. We
      observed extensive colocalization of ERalpha and NR1 in these brain regions
      (approximately 80%). In the anteroventral periventricular nucleus, treatment of
      ovariectomized rats with estrogen up-regulated the coexpression, whereas in the
      medial preoptic nucleus, estrogen had no effect, demonstrating a regional
      specificity to the estrogen sensitivity. The number of ERalpha cells that did not
      express NR1 was not altered by estrogen treatment in either brain region. Thus,
      we speculate that the extensive colocalization of ERalpha and the NMDAR provides
      an anatomical level at which estrogen and glutamate can act at target cells, and
      potentially synergize, to influence neuroendocrine and autonomic functions.

PMID- 12488359
TI  - Estrogen receptor-mediated neuroprotection from oxidative stress requires
      activation of the mitogen-activated protein kinase pathway.
AB  - It is well documented that estrogen mediates responses by both genomic and
      nongenomic mechanisms, both of which are important for cell survival. Because
      direct evidence showing that the estrogen receptors (ERs) alpha and/or beta can
      activate rapid signaling that may mediate neuroprotection is lacking, the
      hippocampal-derived cell line, HT22, was stably transfected with ERalpha
      (HTERalpha), ERbeta (HTERbeta), or a mutated form of ERalpha (HTERalphaHE27),
      which lacks the ability to mediate ER element-mediated transcription. Treatment
      of HT22, HTERalpha, HTERbeta, and HTERalphaHE27 cells with glutamate (5 mM)
      resulted in a significant decrease in cell viability. Pretreatment for 15 min
      with 10 nM 17beta-estradiol resulted in a 50% increase in the number of living
      cells in HTERalpha and HTERbeta cells but not in HT22 cells. The ER antagonist
      ICI 182,780 and the MEK inhibitor PD98059 prevented 17beta-estradiol-mediated
      protection. In HTERalphaHE27 cells, 17beta-estradiol rapidly phosphorylated ERK2
      (within 15 min), in the absence of estrogen response element-mediated
      transcription. Treatment of HTERalphaHE27 cells with 10 nM 17beta-estradiol
      partially reversed the cell death produced by glutamate treatment. This study
      demonstrates that activation of either ERalpha or ERbeta can result in
      neuroprotection and that activation of the MAPK pathway is an important part of
      the neuroprotective mechanism.

PMID- 12488360
TI  - The mouse prolactin gene family locus.
AB  - In the mouse, there is a large family of paralogous genes closely related to PRL.
      The objective of this report was to investigate the organization of the mouse PRL
      gene family locus. PRL family genes reside on chromosome 13 of the mouse genome.
      The PRL gene family members were localized to a series of overlapping bacterial
      artificial chromosome clones and arranged based on structural relationships.
      Additionally, several new members of the PRL gene family were identified.
      Placental lactogen I (PL-I) was found to be encoded by three closely related
      (>98% exon sequence identity) contiguous genes (termed: PL-Ialpha, PL-Ibeta, and
      PL-Igamma). Two previously unidentified mouse orthologs for members of the rat
      PRL family, PRL-like protein-I (PLP-I) and PLP-K were discovered, as were two new
      members of the PLP-C subfamily, PLP-Cgamma and PLP-Cdelta, and two new entirely
      unique members of the PRL family, PLP-N and PLP-O. Amino acid sequences predicted
      from the latter two genes most closely resembled proliferin-related protein. Each
      of the nine newly discovered genes is expressed in trophoblast cells of the mouse
      placenta in a gestationally specific pattern. In summary, elucidation of the
      mouse PRL gene family locus provides new insights into the expansion of the mouse
      PRL family and new tools for studying the genetics and biology of its members.

PMID- 12488361
TI  - Soluble vascular endothelial growth factor receptor 1 inhibits edema and
      epithelial proliferation induced by 17beta-estradiol in the mouse uterus.
AB  - The uterine response to 17beta-estradiol (E2) includes increased water retention,
      enhanced vascular permeability, DNA and RNA synthesis, and increased cellular
      mitosis. We have used the natural antagonist of vascular endothelial growth
      factor A (VEGF-A), sflt-1 (soluble form of flt-1), to determine whether the
      edematous and proliferative effects of E2 in the uterus are mediated by VEGF-A.
      Female BALB/c mice were ovariectomized and treated with E2 (10 micro g/kg) in the
      absence or presence of sflt-1 (0.8 and 4.0 mg/kg) for 24 h. E2 induced increases
      in uterine mass from 25.3 to 36.8 mg, in total cross-sectional uterine area from
      771 to 1133 micro m(2), in cross-sectional endometrial area from 268 to 569 micro
      m(2), and in the mitotic index of lumenal epithelial cells from 0% to 53%.
      Antagonism with sflt-1 reduced the E2-induced increases in total uterine area to
      779 micro m(2), endometrial area to 398 micro m(2) and the mitotic index of
      lumenal epithelial cells to 25%, but the E2-induced increase in uterine mass was
      not significantly reduced. From these data we conclude that the edematous
      response and proliferation of lumenal epithelial cells in the murine uterus are
      mediated in part through VEGF-A. These data suggest that sflt-1 could be a useful
      anti-VEGF-A agent and may be effective in modifying uterine biology.

PMID- 12488362
TI  - Mitochondrial dysfunction is involved in apoptosis induced by serum withdrawal
      and fatty acids in the beta-cell line INS-1.
AB  - The potential toxic effects of high extracellular concentrations of fatty acids
      were tested in beta(INS-1)-cells cultured in the absence of serum, a condition
      known to alter cell survival in various systems. This may in part mimic the
      situation in type 1 or 2 diabetes where beta-cells are already insulted by
      various stressful conditions, such as cytokines and oxidative stress. Serum
      removal caused, over a 36-h period, oxidative stress and an early impairment of
      mitochondrial function, as revealed by increased superoxide production and
      markedly reduced mitochondrial membrane potential, but a lack of cytochrome c and
      apoptosis-inducing factor release in the cytosol. The fatty acids palmitate and
      oleate considerably accelerated the apoptosis process in serum-starved cells, as
      revealed by fluorescence-activated cell sorting analysis, morphological changes,
      chromatin condensation, DNA laddering, poly(ADP-ribose) polymerase cleavage,
      cytochrome c and apoptosis-inducing factor release, and increased levels of Bax
      and cytosolic caspase-2. The fatty acids also increased nitric oxide production,
      apparently independently of inducible nitric oxide synthase induction. Under the
      same experimental conditions, elevated glucose alone had only a marginal effect
      on beta-cell apoptosis. Together the results indicate that elevated
      concentrations of fatty acids are particularly efficient in accelerating the rate
      of apoptosis of already stressed beta(INS-1)-cells displaying altered
      mitochondrial function, and that the mitochondrial arm of the apoptosis process
      is involved in beta-cell lipotoxicity.

PMID- 12488363
TI  - Diabetes interferes with the bone formation by affecting the expression of
      transcription factors that regulate osteoblast differentiation.
AB  - Type 1 diabetes in humans has as one of its complications inadequate bone
      formation, resulting in osteopenia and delayed fracture healing. To investigate
      the mechanisms by which diabetes affects bone formation, experiments were
      performed in a marrow ablation model. Mice were made diabetic by multiple low
      dose streptozotocin treatment, and controls were treated with vehicle alone.
      Killing occurred 0, 2, 4, 6, 10, and 16 d following marrow ablation. Histologic
      analysis demonstrated that the amount of immature mesenchymal tissue was
      equivalent in both the experimental and control groups on d 4. On d 6 a burst of
      bone formation occurred in the control group that was significantly reduced in
      the diabetic group. This deficit was evident at the molecular level as shown by
      diminished expression of osteocalcin, collagen types I. When transcription
      factors were examined, core-binding factor alpha1 (Cbfa1)/runt domain factor-2
      (Runx-2) and human homolog of the drosophila distal-less gene (Dlx5) expression
      were substantially reduced in the diabetic, compared with control, groups on d 4
      and 6. C-fos but not c-jun expression was also suppressed in the diabetic group
      but not closely linked to bone formation. Insulin treatment substantially
      reversed the effect of diabetes on the expression of bone matrix osteocalcin and
      collagen type I and transcription factors Cbfa1/Runx2 and Dlx5. These results
      indicate that diabetic animals produce sufficient amounts of immature mesenchymal
      tissue but fail to adequately express genes that regulate osteoblast
      differentiation, Cbfa1/Runx-2 and Dlx5, which in turn, leads to decreased bone
      formation.

PMID- 12488364
TI  - Ghrelin protects against ethanol-induced gastric ulcers in rats: studies on the
      mechanisms of action.
AB  - Ghrelin, the endogenous ligand for GH secretagogue receptors, has been reported
      to influence acid gastric secretion and motility, but its potential
      gastroprotective effect is unknown. The aims of this study were 1) to examine the
      effects of central and peripheral administration of ghrelin on ethanol-induced
      gastric ulcers in conscious rats, and 2) to investigate the possible roles of
      nitric oxide (NO), vagal nerve, and sensory fibers in the gastric effects of
      ghrelin. Ghrelin was administered either intracerebroventricularly or sc 30 min
      before ethanol, and mucosal lesions were examined macroscopically. Additionally,
      rats were either treated with the inhibitor of NO synthesis N(omega)-nitro-L
      arginine methyl ester (L-NAME) or underwent bilateral cervical vagotomy or
      capsaicin-induced sensory denervation. Conventional histology and
      immunohistochemistry for ghrelin, gastrin, and somatostatin were performed on
      gastric specimens from representative rats. Central ghrelin (4-4,000 ng/rat) dose
      dependently reduced ethanol-induced gastric ulcers by 39-77%. Subcutaneous
      ghrelin administration (80 micro g/kg) reduced ulcer depth only. L-NAME and
      capsaicin, but not vagotomy, prevented the gastroprotective effect of central
      ghrelin (4000 ng/rat). This is the first evidence that ghrelin exerts a potent
      central gastroprotective activity against ethanol-induced lesions. The
      gastroprotective effect of ghrelin is mediated by endogenous NO release and
      requires the integrity of sensory nerve fibers.

PMID- 12488365
TI  - Alpha-melanocyte stimulating hormone prevents lipopolysaccharide-induced
      vasculitis by down-regulating endothelial cell adhesion molecule expression.
AB  - The neuroendocrine hormone alpha-melanocyte stimulating hormone (MSH) has
      profound antiinflammatory and immunomodulating properties. Here we have examined
      the possibility that alpha-MSH may interfere with the expression and function of
      cell adhesion molecules (CAMs) expressed by human dermal microvascular
      endothelial cells (HDMECs) in response to lipopolysaccharide (LPS) or TNFalpha in
      vitro and in vivo. In HDMEC, alpha-MSH (10(-8)/10(-12) M) profoundly reduced the
      mRNA and protein expression of E-selectin, vascular CAM (VCAM)-1, and
      intercellular CAM (ICAM)-1 induced by LPS or TNFalpha as determined by
      semiquantitative RT-PCR, ELISA, and fluorescence-activated cell sorter analysis.
      In addition, alpha-MSH significantly impaired the LPS-induced ICAM-1 and VCAM-1
      mediated adhesion of lymphocytes to HDMEC monolayer in a functional adhesion
      assay. Likewise, alpha-MSH effectively inhibited the transcription factor nuclear
      factor-kappaB activation in HDMEC, which is required for CAM gene expression.
      Importantly in vivo, in murine LPS-induced cutaneous vasculitis (local Shwartzman
      reaction), a single ip injection of alpha-MSH significantly suppressed the
      deleterious vascular damage and hemorrhage by inhibiting the sustained expression
      of vascular E-selectin and VCAM-1. This persistent expression has been implicated
      in the dysregulation of diapedesis and activation of leukocytes, which
      subsequently leads to hemorrhagic vascular damage. Our findings indicate that
      alpha-MSH may have an important therapeutical potential for the treatment of
      vasculitis, sepsis, and inflammatory diseases.

PMID- 12488366
TI  - The interplay of collagen IV, tumor necrosis factor-alpha, gelatinase B (matrix
      metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal
      lamina regulates Sertoli cell-tight junction dynamics in the rat testis.
AB  - During spermatogenesis, preleptotene and leptotene spermatocytes must translocate
      across the blood-testis barrier formed by inter-Sertoli cell-tight junctions
      (TJs) from the basal compartment of the seminiferous epithelium adjacent to the
      basement membrane to the adluminal compartment at stages VIII-IX for further
      development. Because of the close proximity between extracellular matrix (ECM)
      that constitutes the basement membrane and the blood-testis barrier, we sought to
      investigate the role of ECM in Sertoli cell TJ dynamics. When Sertoli cells were
      cultured in vitro to initiate the assembly of the Sertoli cell TJ-permeability
      barrier, the presence of an anticollagen IV antibody indeed perturbed the
      barrier. Because ECM is known to maintain a pool of cytokines and TNFalpha has
      been shown to regulate TJ dynamics in other epithelia, we investigated whether
      TNFalpha can regulate Sertoli cell TJ function via its effects on collagen
      alpha3(IV) and other proteins that maintain the homeostasis of ECM. As expected,
      recombinant TNFalpha perturbed the Sertoli cell TJ-barrier assembly in vitro dose
      dependently. TNFalpha also inhibited the timely induction of occludin, which is
      known to associate with the Sertoli cell TJ-barrier assembly. Furthermore,
      TNFalpha induced the expression of Sertoli cell collagen alpha3(IV), gelatinase B
      (matrix metalloprotease-9, MMP-9) and tissue inhibitor of metalloproteases-1 but
      not gelatinase A (matrix metalloprotease-2), and promoted the activation of pro
      MMP-9. These results thus suggest that the activated MMP-9 induced by TNFalpha is
      used to cleave the existing collagen network in the ECM, thereby perturbing the
      TJ-barrier. This in turn creates a negative feedback that causes TNFalpha to
      induce collagen alpha3(IV) and tissue inhibitor of metalloproteases-1 expression
      so as to replenish the collagen network in the disrupted TJ-barrier and limit the
      activity of MMP-9. Taken collectively, these observations strengthen the notion
      that ECM is involved in the regulation of junction dynamics in addition to its
      structural role in the testis.

PMID- 12488367
TI  - Stimulation of combinatorial expression of prolactin and glycoprotein hormone
      alpha-subunit genes by gonadotropin-releasing hormone and estradiol-17beta in
      single rat pituitary cells during aggregate cell culture.
AB  - Previously we showed the existence of rat and mouse anterior pituitary cells
      coexpressing mRNA from two or more hormone genes in which production and/or
      storage of the corresponding hormones were not detectable. To substantiate a
      putative function for these cells, we investigated whether these phenotypes were
      retained during long-term reaggregate cell culture and whether protagonist
      regulatory factors could expand cell populations expressing particular hormone
      mRNA combinations. After 4-wk culture and treatments, aggregates were trypsinized
      and single cells collected by means of a fluo-rescence-activated cell sorter.
      Hormone mRNAs were detected by single-cell RT-PCR. Combinatorial hormone mRNA
      expression was retained in culture. Both estradiol (E2) and GnRH (1 nM) markedly
      augmented the proportion of cells expressing prolactin (PRL) mRNA together with
      other hormone mRNAs and cells expressing glycoprotein subunit (GSU)-alpha mRNA
      together with other hormone mRNAs. GnRH strongly increased the proportion of
      cells containing alphaGSU mRNA alone, but E2 did not. GnRH and (E2) affected the
      expansion of a population (approximately 20% of all cells) coexpressing PRL and
      alphaGSU mRNA without betaGSUs. Immunostaining of stored hormone on tissue
      sections revealed colocalization of PRL and alphaGSU in the E2- but not in the
      GnRH-treated cells. The present findings suggest that cells coexpressing
      different pituitary hormone mRNAs form a distinct population that survives
      without extrapituitary factors. Their occurrence can be markedly modified by
      regulatory factors. Certain hormone regimens favor unique coexpressions
      distinctly at mRNA and protein level. These peculiar characteristics support the
      notion that combinatorial expression of hormone genes in the pituitary serves a
      biological role.

PMID- 12488368
TI  - Variant Creutzfeldt-Jakob disease and disposable anaesthetic equipment-balancing
      the risks.

PMID- 12488369
TI  - Outreach critical care--cash for no questions?

PMID- 12488370
TI  - Electronic manuscript submission to the BJA: keeping abreast of the times, or
      keeping up with the Jones'?

PMID- 12488371
TI  - Randomized evaluation of the performance of single-use laryngoscopes in simulated
      easy and difficult intubation.
AB  - BACKGROUND: Single-use laryngoscopes are becoming used more widely. METHODS: We
      compared six types of single-use laryngoscope with the standard Macintosh
      laryngoscope using the Laerdal SimMan patient simulator. Twenty anaesthetists
      attempted to intubate the simulator with standardized airway settings allowing a
      full view of the vocal cords ('easy intubation'). The airway settings were then
      changed so that only the posterior part of the glottis was visible ('difficult
      intubation') and the anaesthetists were asked to intubate the simulator again.
      RESULTS: The time to intubate with the standard laryngoscope was less in both
      easy (P<0.05) and difficult (P<0.01) intubations. The performance of five
      laryngoscopes during easy intubation (P<0.01) and four during difficult
      intubation (P<0.001) was significantly worse than that of the Macintosh. There
      was a significant difference in Cormack and Lehane grading between the
      laryngoscopes tested in both easy (P<0.05) and difficult (P<0.05) intubation. The
      percentage of glottic opening visible (POGO score) also differed between
      laryngoscopes in both the easy (P<0.01) and difficult (P<0.001) groups. The
      highest POGO scores were obtained with the Macintosh laryngoscope. During the
      difficult intubation simulation, the reusable Macintosh laryngoscope needed less
      use of a bougie and had fewer failed intubations than the single-use
      laryngoscopes, but these differences did not reach statistical significance.
      CONCLUSIONS: Of the laryngoscopes tested, the standard reusable Macintosh
      laryngoscope performed best. The Europa was the best single-use laryngoscope.
      Some single-use laryngoscopes tested were significantly inferior to the
      Macintosh. This raises concern over their use in clinical practice, particularly
      if intubation is difficult.

PMID- 12488372
TI  - Propofol requirement for insertion of cuffed oropharyngeal airway versus
      laryngeal mask airway with and without fentanyl: a dose-finding study.
AB  - BACKGROUND: The cuffed oropharyngeal airway (COPA) is a modified Guedel-type oral
      airway with a cuff at its distal end. The objectives of this prospective,
      randomized study were to compare the COPA and the laryngeal mask airway (LMA) in
      terms of propofol requirement with and without fentanyl pretreatment for smooth
      insertions. METHODS: Seventy-five patients undergoing general anaesthesia were
      randomly assigned to either a COPA (n=38) or LMA (n=37) group for airway
      management, and each group was further randomized to a saline-propofol or
      fentanyl-propofol group for anaesthesia induction. The saline-propofol group
      received i.v. saline and the fentanyl-propofol group received i.v. fentanyl 1
      micro g kg(-1) followed 30 s later by i.v. propofol. Insertion of the device was
      attempted 90 s after propofol administration without the use of neuromuscular
      blocking agents or other adjuvants, and the responses of 'movement' or 'no
      movement' were judged by three observers blinded to the drug dose. Each dose of
      propofol at which insertion was attempted was predetermined by modification of
      Dixon's up-and-down method with 0.5 mg kg(-1) as the step size, and 2 mg kg(-1)
      as an initial dose. RESULTS: Without fentanyl pretreatment, propofol requirement
      [mean (SD), 95% CI] for COPA placement [2.17 (0.38), 1.77-2.56 mg kg(-1)] was
      significantly less than for LMA insertion [3.42 (0.26), 3.15-3.69 mg kg(-1),
      P<0.001]. In contrast, propofol requirements after fentanyl were comparable
      between the COPA and LMA groups [1.50 (0.42), 1.06-1.94 and 1.42 (0.26), 1.15
      1.69 mg kg(-1), respectively], but were less than for the placebo group with both
      devices (P<0.05). Haemodynamic changes and duration of apnoea were similar with
      both devices irrespective of fentanyl pretreatment. CONCLUSIONS: Insertion of the
      COPA can be accomplished with a smaller bolus dose of propofol compared with the
      LMA, but propofol requirements are similar with both devices after a small dose
      of fentanyl.

PMID- 12488373
TI  - Progressive changes in arterial oxygenation during one-lung anaesthesia are
      related to the response to compression of the non-dependent lung.
AB  - BACKGROUND: Arterial oxygenation can change during one-lung ventilation for
      reasons that are not fully understood. METHODS: We studied patients during
      anaesthesia and one-lung ventilation, with an inspiratory oxygen fraction of 0.8.
      Arterial blood gas values were recorded every 10 s with a continuous intra
      arterial sensor. The non-dependent lung was compressed several times during the
      surgical procedure, using a retractor. The change in Pa(O(2)) during and after
      compression of the non-dependent lung was measured. RESULTS: Pa(O(2)) increased
      significantly when the non-dependent lung was compressed, and decreased when the
      compression was released. The first compression of the non-dependent lung
      transiently increased Pa(O(2)), but the effect of the second compression on
      oxygenation was more marked and persistent. Pa(O(2)) increased by more than 13
      kPa at 10 min after the second compression in four patients (responder group).
      Arterial oxygenation improved markedly in patients in this group during the
      surgical procedure. CONCLUSION: Oxygenation can improve during one-lung
      ventilation in some patients. This improvement is partly related to a marked
      increase in Pa(O(2)) during compression of the non-dependent lung.

PMID- 12488374
TI  - Effect of preoperative beta-blockade on perioperative mortality in coronary
      surgery.
AB  - BACKGROUND: Many preoperative factors can influence perioperative mortality in
      cardiac surgery. Because the perioperative use of beta-blocking agents may reduce
      perioperative cardiac complications in non-cardiac surgery, we considered the
      possibility that beta-blocking agents could improve survival in coronary surgery
      patients. METHODS: In a retrospective study on 1586 patients undergoing coronary
      bypass surgery, the relative risk of 30-day mortality was determined in relation
      to preoperative risk factors and medication. Factors included patient
      characteristics, pre-existing illness, specific cardiovascular risk factors,
      cardiac status and urgency of surgery. Treatment with beta-blocking agents,
      calcium antagonists, angiotensin-converting enzyme inhibitors, nitrates, anti
      arrhythmic agents, diuretics and antithrombotic agents was taken into account.
      RESULTS: Sex, age, chronic obstructive pulmonary disease, urgency and the
      preoperative use of diuretics and chronic beta-blocking therapy were found to be
      linked to mortality (P<0.05). Backward stepwise regression testing identified
      age, urgency and beta-blocking therapy as independent factors that could predict
      mortality. CONCLUSIONS: Increasing age and urgency of surgery are associated with
      greater mortality, whereas preoperative beta-blocking therapy is associated with
      less mortality. The characteristics of patients who received chronic beta
      blockade did not differ significantly from those of patients who did not. The
      results suggest that chronic preoperative beta-blocker therapy reduces 30-day
      mortality in coronary surgery.

PMID- 12488375
TI  - Comparison of the effects of sevoflurane and propofol on cooling and rewarming
      during deliberate mild hypothermia for neurosurgery.
AB  - BACKGROUND: Because the time available for cooling and rewarming during
      deliberate mild hypothermia is limited, studies of the rate of the cooling and
      rewarming are useful. The decrease in core hypothermia caused by heat
      redistribution depends on the anaesthetic agent used. We therefore investigated
      possible differences between sevoflurane and propofol on the decrease and
      recovery of core temperature during deliberate mild hypothermia for neurosurgery.
      METHODS: After institutional approval and informed consent, 26 patients were
      assigned randomly to maintenance of anaesthesia with propofol or sevoflurane.
      Patients in the propofol group (n=13) received propofol induction followed by a
      continuous infusion of propofol 3-5 mg kg(-1) h(-1). Patients in the sevoflurane
      group (n=13) received propofol induction followed by sevoflurane 1-2%. Nitrous
      oxide and fentanyl were also used for anaesthetic maintenance. After induction of
      anaesthesia, patients were cooled and tympanic membrane temperature was
      maintained at 34.5 degrees C. After surgery, patients were actively rewarmed.
      RESULTS: There was no difference in the rate of decrease and recovery of core
      temperature between the groups. There was also no difference in skin surface
      temperature gradient (forearm to fingertip), heart rate and mean arterial blood
      pressure between the groups. CONCLUSIONS: Sevoflurane-based anaesthesia did not
      affect cooling and rewarming for deliberate mild hypothermia compared with
      propofol-based anaesthesia.

PMID- 12488376
TI  - Raised intracranial pressure and seizures in the neurological intensive care
      unit.
AB  - BACKGROUND: The relationship between changes in intracranial pressure and
      incidence of subclinical seizures in patients requiring neurological intensive
      care is not fully understood. The aim of this study was to investigate if acute
      increases in intracranial pressure were accompanied by subclinical seizures.
      METHODS: We prospectively studied 17 intensive care patients (11 male, aged 3-66
      yr) who were selected from 85 patients requiring intracranial pressure
      measurement. Patients were selected to have a 30 min, 16-channel
      electroencephalogram (EEG) recorded when intracranial pressure remained increased
      despite preliminary treatments. RESULTS: Diagnoses included head injury,
      intracranial haemorrhage, subarachnoid haemorrhage and sagittal sinus thrombosis.
      All patients had at least one acute episode of intracranial pressure increase.
      Pressures ranged from 90 to 440 mm H(2)O. Encephalopathic features (delta/theta
      rhythms and burst suppression) were noted on all EEGs. No seizure activity was
      recorded. CONCLUSIONS: We conclude from this pilot study that seizures are an
      uncommon cause of acute raised intracranial pressure. To determine whether raised
      intracranial pressure causes seizures, long-term monitoring in a large cohort of
      intensive care patients would be necessary, studying patients with similar
      diagnoses and ages.

PMID- 12488377
TI  - Evaluation of high fidelity patient simulator in assessment of performance of
      anaesthetists.
AB  - BACKGROUND: There is increasing emphasis on performance-based assessment of
      clinical competence. The High Fidelity Patient Simulator (HPS) may be useful for
      assessment of clinical practice in anaesthesia, but needs formal evaluation of
      validity, reliability, feasibility and effect on learning. We set out to assess
      the reliability of a global rating scale for scoring simulator performance in
      crisis management. METHODS: Using a global rating scale, three judges
      independently rated videotapes of anaesthetists in simulated crises in the
      operating theatre. Five anaesthetists then independently rated subsets of these
      videotapes. RESULTS: There was good agreement between raters for medical
      management, behavioural attributes and overall performance. Agreement was high
      for both the initial judges and the five additional raters. CONCLUSIONS: Using a
      global scale to assess simulator performance, we found good inter-rater
      reliability for scoring performance in a crisis. We estimate that two judges
      should provide a reliable assessment. High fidelity simulation should be studied
      further for assessing clinical performance.

PMID- 12488378
TI  - Assessment of a simple artificial neural network for predicting residual
      neuromuscular block.
AB  - BACKGROUND: Postoperative residual curarization (PORC) after surgery is common
      and its detection has a high error rate. Artificial neural networks are being
      used increasingly to examine complex data. We hypothesized that a neural network
      would enhance prediction of PORC. METHODS: In 40 previously reported patients,
      neuromuscular function, neuromuscular block/antagonist usage and time intervals
      were recorded throughout anaesthesia until tracheal extubation by an observer
      uninvolved in patient care. PORC was defined as significant 'fade' (train of four
      <0.7) at extubation. Neuromuscular function was classified as PORC (value=1) or
      no PORC (value=0). A back-propagation neural network was trained to assign
      similar values (0, 1) for prediction of PORC, by examining the impact of (i) the
      degree of spontaneous recovery at reversal, and (ii) the time since
      pharmacological reversal, using the jackknife method. Successful prediction was
      defined as attainment of a predicted value within 0.2 of the target value.
      RESULTS: Twenty-six patients (65%) had PORC at tracheal extubation. Clinical
      detection of PORC had a sensitivity of 0 and specificity of 1, with an
      indeterminate positive predictive value and a negative predictive value of 0.35.
      Using the artificial neural network, one patient with residual block and one with
      adequate neuromuscular function were incorrectly classified during the test
      phase, with no indeterminate predictions, giving an artificial neural network
      sensitivity of 0.96 (chi(2)=44, P<0.001) and specificity of 0.92 (P=1), with a
      positive predictive value of 0.96 and a negative predictive value of 0.93
      (chi(2)=12, P<0.001). CONCLUSIONS: Neural network-based prediction, using readily
      available clinical measurements, is significantly better than human judgement in
      predicting recovery of neuromuscular function.

PMID- 12488379
TI  - Comparison between patient-controlled analgesia and subcutaneous morphine in
      elderly patients after total hip replacement.
AB  - BACKGROUND: The goal of this study was to evaluate the effectiveness on
      postoperative pain, and cognitive impact, of patient-controlled analgesia (PCA)
      compared with subcutaneous (s.c.) injections of morphine in elderly patients
      undergoing total hip replacement (THR). METHODS: Forty patients older than 70 yr
      were randomly assigned to two different postoperative analgesic techniques for 48
      h: i.v. PCA morphine (dose, 1 mg; lockout interval, 8 min; PCA group) or regular
      s.c. morphine injections (SC group). Postoperative pain was assessed at rest and
      when moving, using a visual analogue scale (VAS) every 4 h. A Mini Mental Status
      (MMS) examination was used to assess cognitive functions before surgery, at 2 h,
      24 h and 48 h after surgery, and at hospital discharge. Side-effects were also
      recorded systematically during the first 48 h after surgery. RESULTS: The PCA
      group showed significantly lower pain scores than the SC group both at rest and
      during mobilization. However, the clinical significance of pain scores was weak.
      There was no intergroup difference in postoperative MMS scores. The incidence of
      side-effects was similar in both groups. CONCLUSIONS: We conclude that in healthy
      elderly subjects undergoing THR, the flexibility of the analgesic regimen is more
      important than the route of administration with regard to efficacy, adverse
      effects and recovery of cognitive function.

PMID- 12488380
TI  - Effect of preoperative amino acid infusion on thermoregulatory response during
      spinal anaesthesia.
AB  - BACKGROUND: Intravenous amino acid infusion during general anaesthesia prevents
      decreases in core temperature resulting from increased energy expenditure and
      heat accumulation. METHODS: We investigated whether such stimulation also occurs
      during spinal anaesthesia, which blocks sympathetic nervous activity. We examined
      the effect of i.v. amino acid infusion on changes in core temperature during
      spinal anaesthesia. Thirty-five patients were divided into two groups: an i.v.
      amino acid infusion group (4 kJ kg(-1) h(-1) starting 2 h before surgery); and a
      saline infusion group. Tympanic membrane core temperature, forearm-fingertip
      temperature gradient (an index of peripheral vasoconstriction) and mean skin
      temperature were measured for 90 min after the onset of spinal anaesthesia.
      RESULTS: Changes in mean arterial pressure and heart rate did not differ
      significantly between the groups during the study period. Mean final core
      temperature 90 min after induction of spinal anaesthesia was 35.8 (SEM 0.1)
      degrees C in the saline group and 36.6 (0.1) degrees C in the amino acid group
      (P<0.05). The increased level of oxygen consumption in the amino acid group
      compared with the saline group was preserved even after the onset of spinal
      anaesthesia. The thermal vasoconstriction threshold, defined as the tympanic
      membrane temperature that triggered a rapid increase in forearm-fingertip
      temperature gradient, was increased in the amino acid group [36.8 (0.1) degrees
      C] compared with the saline group [36.5 (0.1) degrees C] (P<0.05). CONCLUSIONS:
      Preoperative infusion of amino acids effectively prevents spinal anaesthesia
      induced hypothermia by maintaining a higher metabolic rate and increasing the
      threshold core temperature for thermal vasoconstriction.

PMID- 12488381
TI  - The 'swoosh' test--an evaluation of a modified 'whoosh' test in children.
AB  - BACKGROUND: Caudal analgesia is widely used in paediatric anaesthetic practice.
      In adults, the 'whoosh' test has been recommended as a guide to successful needle
      insertion, but it has not been extensively studied in paediatric patients. We
      have investigated a modification of the 'whoosh' test, which we have christened
      the 'swoosh' test. It avoids the injection of air by performing auscultation
      during injection of the local anaesthetic solution. We have compared it with
      clinical judgement of correct placement. METHODS: We studied 113 children
      undergoing elective surgery. During insertion of the caudal block, a stethoscope
      was placed over the lower lumbar spine and the presence or absence of an audible
      'swoosh' noted. The operator's clinical impression of successful insertion was
      also recorded. RESULTS: The overall success rate of caudal anaesthesia was 95.6%.
      Of the 108 patients with a successful block, 98 had a positive 'swoosh' test.
      There were no false positive results. Calculations show the 'swoosh' test to have
      a sensitivity of 91%, a specificity of 100% and a positive predictive value of
      100%. CONCLUSIONS: The 'swoosh' test is a simple and accurate test to confirm
      successful caudal insertion in children, and is especially useful as a teaching
      aid for anaesthetists new to the technique.

PMID- 12488382
TI  - Effects of epinephrine and phosphodiesterase III inhibitors on bupivacaine
      induced myocardial depression in guinea-pig papillary muscle.
AB  - BACKGROUND: This study was designed to investigate the effects of epinephrine and
      the phosphodiesterase III inhibitors amrinone and milrinone on bupivacaine
      induced myocardial depression in guinea-pig papillary muscles using an
      electrophysiological method. METHODS: Electrophysiological studies of the effects
      of bupivacaine, epinephrine, amrinone and milrinone in normal and high K(+)
      Tyrode's solution were measured with guinea-pig papillary muscles. Specifically,
      epinephrine, amrinone and milrinone reversal of bupivacaine-induced depression
      was measured. RESULTS: Bupivacaine reduced the action potential duration (APD),
      the maximum rate of rise of the AP (V(max)) and contractile force. Although
      epinephrine increased the contractile force similarly to amrinone and milrinone,
      it shortened the APD at 50% repolarization (APD(50)) and 90% repolarization
      (APD(90)). A high concentration of amrinone shortened APD, while milrinone did
      not affect APD except for a prolongation of APD(20). In high K(+) Tyrode's
      solution (25 mM), epinephrine, amrinone and milrinone increased the APD and the
      contractile force. Epinephrine reversed bupivacaine depression of APD and
      contractile force to control levels. Amrinone and milrinone restored not only the
      contractile force but also APD. There was an incomplete recovery of APD(50) for
      amrinone and the prolongation of APD(20) for milrinone. CONCLUSIONS: Our results
      suggest that bupivacaine decreases the Ca(+) current (I(Ca)) and Na(+) current
      (I(Na)). Epinephrine and amrinone may increase I(Ca) and the delayed outward
      current (I(k)), whereas milrinone may increase I(Ca). The profound cardiovascular
      depression caused by bupivacaine was effectively reversed by amrinone and
      milrinone in a manner similar to epinephrine.

PMID- 12488383
TI  - Severe meningococcal disease in childhood.
AB  - Meningococcal disease remains an important cause of illness in the UK (Commun Dis
      Rep CDR Suppl 1999; 9: S5), and is the commonest infective cause of death in
      children outwith the neonatal period. Although most common in children, adults
      are also affected. Meningococcal vaccines offer long-term protection only against
      Group C disease, which causes less than half of invasive meningococcal disease
      (Commun Dis Rep CDR Wkly 1998; 8: 2) in the UK.

PMID- 12488385
TI  - Comparison of measured and estimated angles of table tilt at Caesarean section.
AB  - BACKGROUND: Lateral maternal tilt reduces aortocaval compression and the
      consequent cardiovascular instability. METHODS: We measured the angle of table
      tilt used by 16 anaesthetists during uncomplicated, elective Caesarean section.
      After initiating anaesthesia, they were asked to position the patient and
      estimate the angle of tilt, which was then measured. RESULTS: Almost every
      anaesthetist positioned the patient less than 15 degrees because they
      overestimated the angle of tilt. When questioned on their knowledge of the
      current advice for lateral tilt, 11 of the 16 anaesthetists were aware of the 15
      degrees recommendation. CONCLUSION: Estimation of the angle of table tilt is
      unreliable.

PMID- 12488384
TI  - Cerebrospinal fluid and blood propofol concentration during total intravenous
      anaesthesia for neurosurgery.
AB  - BACKGROUND: The aim of this paper is to compare the propofol concentration in
      blood and cerebrospinal fluid (CSF) in patients scheduled for different
      neurosurgical procedures and anaesthetized using propofol as part of a total
      intravenous anaesthesia technique. METHODS: Thirty-nine patients (ASA I-III)
      scheduled for elective intracranial procedures, were studied. Propofol was
      infused initially at 12 mg kg(-1) h(-1) and then reduced in steps to 9 and 6 mg
      kg(-1) h(-1). During anaesthesia, bolus doses of fentanyl and cis-atracurium were
      administered as necessary. After tracheal intubation the lungs were ventilated to
      achieve normocapnia with an oxygen-air mixture (FI(O(2))=0.33). Arterial blood
      and CSF samples for propofol examination were obtained simultaneously directly
      after intracranial drainage insertion and measured using high-performance liquid
      chromatography. The patients were divided into two groups depending on the type
      of neurosurgery. The Aneurysm group consisted of 13 patients who were surgically
      treated for ruptured intracranial aneurysm. The Tumour group was composed of 26
      patients who were undergoing elective posterior fossa extra-axial tumour removal.
      RESULTS: Blood propofol concentrations in both groups did not differ
      significantly (P>0.05). The propofol concentration in CSF was 86.62 (SD 37.99) ng
      ml(-1) in the Aneurysm group and 50.81 (26.10) ng ml(-1) in the Tumour group
      (P<0.005). CONCLUSIONS: Intracranial pathology may influence CSF propofol
      concentration. However, the observed discrepancies may also result from
      quantitative differences in CSF composition and from restricted diffusion of the
      drug in the CSF.

PMID- 12488386
TI  - Nitrous oxide decreases shivering threshold in rabbits less than isoflurane.
AB  - BACKGROUND: Comparable minimum alveolar concentration (MAC) fractions of volatile
      anaesthetics produce similar thermoregulatory impairment. Nitrous oxide, however,
      decreases the vasoconstriction threshold less than sevoflurane or isoflurane. We
      tested the hypothesis that nitrous oxide also decreases shivering threshold less
      than isoflurane alone or in combination. METHODS: Twenty-four rabbits were
      assigned randomly to one of three 0.3 MAC anaesthetic regimens: (i) nitrous oxide
      69%; (ii) nitrous oxide 35% and isoflurane 0.3%; or (iii) isoflurane 0.6%. Body
      temperature was lowered by perfusing 10 degrees C water through a U-shaped
      thermode positioned in the colon. Shivering was evaluated by inspection. RESULTS:
      The rabbits anaesthetized with nitrous oxide alone shivered at 37.0 (0.5) degrees
      C (P<0.01 vs other groups). In those given the nitrous oxide and isoflurane
      combination, the shivering threshold was 36.4 (0.5) degrees C and that in the
      isoflurane group was 35.9 (0.4) degrees C. CONCLUSION: This study indicates that
      nitrous oxide reduces the shivering threshold less than isoflurane.

PMID- 12488387
TI  - Postoperative extracorporeal membrane oxygenation for severe intraoperative SIRS
      10 h after multiple trauma.
AB  - A 34-yr-old male suffered multiple trauma in a road traffic accident. He required
      right thoracotomy and laparotomy to control exanguinating haemorrhage, and
      received 93 u blood and blood products. Intraoperatively, he developed severe
      systemic inflammatory response syndrome (SIRS) with coagulopathy and respiratory
      failure. At the end of the procedure, the mean arterial pressure (MAP) was 40 mm
      Hg, arterial blood gas analysis showed a pH of 6.9, Pa(CO(2)) 12 kPa, and
      Pa(O(2)) 4.5 kPa, and his core temperature was 29 degrees C. There was
      established disseminated intravascular coagulation. The decision was made to
      stabilize the patient on veno-venous extracorporeal membrane oxygenation (ECMO)
      only 10 h after the accident, in spite of the high risk of haemorrhage. The
      patient was stabilized within 60 min and transferred to the intensive care unit.
      He was weaned off ECMO after 51 h. He had no haemorrhagic complications, spent 3
      weeks in the intensive care unit, and has made a good recovery.

PMID- 12488388
TI  - Double respiratory sequelae of head injury: subglottic stenosis and bilateral
      pneumothoraces.
AB  - An 18-yr-old man with insulin-dependent diabetes developed severe subglottic
      stenosis after a very brief period of intubation. Emergency tracheostomy was
      complicated by the development of bilateral pneumothoraces. This case highlights
      the importance of making an early diagnosis to minimize the risk of complications
      and examines postintubation subglottic stenosis in the context of poorly
      controlled insulin-dependent diabetes mellitus.

PMID- 12488389
TI  - Anaesthetic management of acute gastric volvulus in an adult.
AB  - We describe an adult patient with gastric volvulus caused by a congenital
      diaphragmatic hernia. Anaesthetic management was complicated by cardiovascular
      instability, respiratory distress and unexpectedly difficult intubation.

PMID- 12488390
TI  - Postpartum cerebral ischaemia after accidental dural puncture and epidural blood
      patch.
AB  - Puerperal women are reported to have a rate of cerebral infarction 13 times
      greater than non-pregnant females. We report a case of cerebral ischaemia in a 30
      yr-old healthy parturient after epidural analgesia for labour, complicated by
      dural puncture treated with two epidural blood patches. Investigations showed the
      development of cerebral ischaemia on postpartum day 14. A transcranial Doppler
      ultrasonography showed vasospasm of the left middle cerebral artery still present
      at 3-month follow-up. At 1-yr follow-up, the patient had homonymous hemianopsia.
      We discuss the possible causative mechanism of the cerebral ischaemia in relation
      to the dural puncture and epidural blood patch.

PMID- 12488391
TI  - Exhaled nitric oxide as a marker of lung injury in coronary artery bypass
      surgery.

PMID- 12488392
TI  - Anaphylactic reaction to isosulphan blue.

PMID- 12488393
TI  - Allergic reaction to nanocolloid during lymphoscintigraphy for sentinel lymph
      node biopsy.

PMID- 12488394
TI  - Treatment of biological and chemical casualties in the UK.

PMID- 12488395
TI  - Ultrasound-guided infraclavicular brachial plexus block.

PMID- 12488396
TI  - Intrathecal diamorphine or intrathecal fentanyl to supplement spinal anaesthesia
      for Caesarean section?

PMID- 12488397
TI  - Sub-Tenon's infiltration using bupivacaine 0.5% decreases acute postoperative
      pain and opioid requirement after posterior segment surgery.

PMID- 12488398
TI  - Early postoperative vomiting and volatile anaesthetics or nitrous oxide.

PMID- 12488399
TI  - Another case of obstruction to an anaesthetic circuit.

PMID- 12488400
TI  - Digital ischaemia after ulnar artery cannulation.

PMID- 12488402
TI  - Adjuvant therapy for premenopausal women with breast cancer: is it time for
      another paradigm shift?

PMID- 12488403
TI  - Primary central nervous system lymphoma: time to ask the question.

PMID- 12488404
TI  - "The guard dies, it does not surrender!" progress in the management of small-cell
      lung cancer?

PMID- 12488405
TI  - Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide,
      methotrexate, and fluorouracil: evidence for the superiority of treatment with
      endocrine blockade in premenopausal patients with hormone-responsive breast
      cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5.
AB  - PURPOSE: Effective adjuvant treatment modalities in premenopausal breast cancer
      patients today include chemotherapy, ovariectomy, and tamoxifen administration.
      The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to
      compare the efficacy of a combination endocrine treatment with standard
      chemotherapy. PATIENTS AND METHODS: Assessable trial subjects (N = 1,034)
      presenting with hormone-responsive disease were randomized to receive either 3
      years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide,
      methotrexate, and fluorouracil (CMF). Stratification criteria included tumor
      stage and grade, number of involved nodes, type of surgery, and steroid hormone
      receptor content. Relapse-free survival (RFS) was defined as time from
      randomization to first relapse, local recurrence, or contralateral incidence, and
      overall survival (OS) as time to date of death. RESULTS: With a 60-month median
      follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing
      chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%,
      respectively. RFS and local recurrence-free survival differed significantly in
      favor of endocrine therapy (P =.037 and P =.015), with a similar trend observed
      in OS (P =.195). CONCLUSION: Overall, our data suggest that the goserelin
      tamoxifen combination is significantly more effective than CMF in the adjuvant
      treatment of premenopausal patients with stage I and II breast cancer.

PMID- 12488406
TI  - Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant
      therapy in premenopausal patients with node-positive breast cancer: The Zoladex
      Early Breast Cancer Research Association Study.
AB  - PURPOSE: Current adjuvant therapies have improved survival for premenopausal
      patients with breast cancer but may have short-term toxic effects and long-term
      effects associated with premature menopause. PATIENTS AND METHODS: The Zoladex
      Early Breast Cancer Research Association study assessed the efficacy and
      tolerability of goserelin (3.6 mg every 28 days for 2 years; n = 817) versus
      cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (six 28-day
      cycles; n = 823) for adjuvant treatment in premenopausal patients with node
      positive breast cancer. RESULTS: Analysis was performed when 684 events had been
      achieved, and the median follow-up was 6 years. A significant interaction between
      treatment and estrogen receptor (ER) status was found (P =.0016). In ER-positive
      patients (approximately 74%), goserelin was equivalent to CMF for disease-free
      survival (DFS) (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.84 to
      1.20). In ER-negative patients, goserelin was inferior to CMF for DFS (HR, 1.76;
      95% CI, 1.27 to 2.44). Amenorrhea occurred in more than 95% of goserelin patients
      by 6 months versus 58.6% of CMF patients. Menses returned in most goserelin
      patients after therapy stopped, whereas amenorrhea was generally permanent in CMF
      patients (22.6% v 76.9% amenorrheic at 3 years). Chemotherapy-related side
      effects such as nausea/vomiting, alopecia, and infection were higher with CMF
      than with goserelin during CMF treatment. Side effects related to estrogen
      suppression were initially higher with goserelin, but when goserelin treatment
      stopped, reduced to a level below that observed in the CMF group. CONCLUSION:
      Goserelin offers an effective, well-tolerated alternative to CMF in premenopausal
      patients with ER-positive and node-positive early breast cancer.

PMID- 12488407
TI  - Population-based assessment of hospitalizations for toxicity from chemotherapy in
      older women with breast cancer.
AB  - PURPOSE: There are no population-based data on hospitalization rate for toxicity
      from breast cancer chemotherapy, and even large clinical trials often do not
      report this information. Medicare data, linked to the Surveillance, Epidemiology,
      and End-Results (SEER) tumor registries, are now used to assess rates of
      hospitalization for chemotherapy-related toxicity in a population-based setting.
      PATIENTS AND METHODS: A total of 35,060 women diagnosed with stages I through IV
      breast cancer aged >or= 65 from 1991 through 1996 were identified from the SEER
      Medicare linked program and studied. Patients were defined as being hospitalized
      for adverse effects of chemotherapy if there was a Medicare inpatient claim for
      neutropenia, fever, thrombocytopenia, or adverse effect of systemic therapy less
      than 7 months after diagnosis of breast cancer. RESULTS: More than 9% of women
      with breast cancer who received chemotherapy were admitted with the diagnosis of
      neutropenia, fever, thrombocytopenia, or adverse effect of systemic therapy,
      compared with 0.5% of women with breast cancer who did not receive chemotherapy.
      The rates for stage I to IV were 6.3%, 8.1%, 12.3%, and 13.2% in those treated
      with chemotherapy, and 0.4%, 0.6%, 0.7%, and 1.5% in women not treated with
      chemotherapy. The hospitalization rates for adverse effects increased
      significantly with comorbidity score and varied more than two-fold across the
      nine SEER areas but did not vary by age. Use of anthracycline-containing
      chemotherapy agents was associated with greater odds of these toxicities (eg,
      odds ratio, 2.53 for neutropenia; 95% confidence interval, 1.97 to 3.26).
      CONCLUSION: This study demonstrated the feasibility of using Medicare data to
      assess rates of hospitalization for serious toxicity associated with cancer
      chemotherapy. Rates in actual practice were higher than those reported in
      clinical trials and did not vary by age.

PMID- 12488408
TI  - Combination chemotherapy and radiotherapy for primary central nervous system
      lymphoma: Radiation Therapy Oncology Group Study 93-10.
AB  - PURPOSE: Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor.
      Cranial irradiation alone rarely results in long-term disease control or
      prolonged survival. We prospectively studied the use of combination chemotherapy
      plus cranial irradiation in newly diagnosed patients with PCNSL. PATIENTS AND
      METHODS: We enrolled 102 newly diagnosed, immunocompetent patients with PCNSL; 98
      were assessable. Patients first received five cycles of methotrexate 2.5 g/m(2),
      vincristine, procarbazine, and intraventricular methotrexate (12 mg). Whole-brain
      radiotherapy (RT) was administered to a total dose of 45 Gy and all patients
      received high-dose cytarabine after RT. RESULTS: Fifty-eight percent of patients
      with measurable disease had a complete response to preirradiation chemotherapy
      and 36% had a partial (> 50%) response, for a 94% response rate. Median
      progression-free survival was 24.0 months and overall survival was 36.9 months.
      Age was an important prognostic factor; median survival was 50.4 months in
      patients younger than 60 and only 21.8 months in those aged 60 or older (P
      <.001). Fifty-three percent of patients had grade 3 or 4 toxicity during
      induction chemotherapy, half of which was hematologic. However, 12 patients (15%)
      experienced severe delayed neurologic toxicity, eight of whom died. CONCLUSION:
      This is the first multicenter trial demonstrating improved survival with the
      combination of chemotherapy plus RT compared with previous reports of RT alone. A
      high-dose methotrexate-based regimen produced a high response rate before RT was
      administered. High-dose methotrexate combined with cranial irradiation is an
      effective therapeutic approach to PCNSL, but neurotoxicity is a delayed risk of
      this approach.

PMID- 12488409
TI  - Randomized phase III study of fludarabine phosphate versus cyclophosphamide,
      vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's
      lymphoma previously treated with an alkylating agent or alkylator-containing
      regimen.
AB  - PURPOSE: To compare in a phase III study the safety and efficacy of fludarabine
      to that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low
      grade, non-Hodgkin's lymphoma after previous response to systemic treatment.
      PATIENTS AND METHODS: Patients were randomized to fludarabine (25 mg/m(2)
      intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m(2)
      and vincristine 1.2 mg/m(2) both intravenously on day 1 and prednisone 40 mg/m(2)
      orally on days 1 to 5, every 21 days). The primary outcome assessed was
      progression-free survival (PFS); secondary outcomes included treatment-free
      survival (TFS), overall survival (OS), treatment-related toxicity, and quality of
      life (QoL) according to the European Organization for Research and Treatment of
      Cancer's Quality of Life Questionnaire C-30 version 1.0 instrument. RESULTS:
      Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was
      no difference in response rates, with 64% (complete response [CR], 9%) for
      fludarabine versus 52% (CR, 7%) for CVP (P =.72). With a median follow-up of 42
      months, median PFS (11 months v 9.1 months; P =.03) and TFS (15 months v 11
      months; P =.02) were superior in patients receiving fludarabine. No difference in
      median overall survival was detected (57 months for fludarabine v 44 months for
      CVP; P =.95). Three patients receiving fludarabine died of treatment-related
      toxicity compared with none of the patients receiving CVP. Peripheral neuropathy
      and alopecia were more common with CVP. Patients receiving fludarabine had higher
      scores for social function (P =.008); no other differences in QoL were detected.
      CONCLUSION: In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and
      social function scores in comparison with CVP but does not improve OS.

PMID- 12488410
TI  - Transplantation of peripheral blood stem cells as compared with bone marrow from
      HLA-identical siblings in adult patients with acute myeloid leukemia and acute
      lymphoblastic leukemia.
AB  - PURPOSE: Several studies show that allogeneic peripheral blood stem cells (PBSCs)
      engraft more rapidly than bone marrow (BM). However, the data are inconsistent
      with regard to acute and chronic graft-versus-host disease (GVHD), relapse,
      transplant-related mortality (TRM), and leukemia-free survival (LFS). PATIENTS
      AND METHODS: Between January 1994 and December 2000, 3,465 adult patients (older
      than 15 years of age) were reported to the European Group for Blood and Marrow
      Transplantation Registry from 224 centers. Among acute myeloid leukemia (AML)
      patients, 1,537 patients received BM and 757 patients received PBSC. In acute
      lymphoblastic leukemia (ALL) patients, the corresponding figures were 826 versus
      345 patients who were analyzed for engraftment, GVHD, TRM, relapse, LFS, and
      survival. RESULTS: In multivariate analysis, the recovery of neutrophils and
      platelets was faster with PBSC than with BM (P <.0001). Chronic GVHD was
      associated with PBSC in patients with AML (relative risk [RR], 2.11; 95%
      confidence interval, 1.66 to 2.7; P <.0001) and ALL (RR, 1.56; 95% confidence
      interval, 1.09 to 2.27; P =.02). PBSC versus BM in patients with AML or ALL was
      not significantly associated with acute GVHD, TRM, relapse, survival, or LFS. In
      multivariate analysis of patients with AML, factors significantly associated with
      improved LFS included first remission at transplant (P <.0001), promyelocytic
      leukemia (M3) versus other French-American-British types (P <.0001), and donor
      age below median 37 years (P =.02). In patients with ALL, first remission (P
      <.0001) and methotrexate included in the immunosuppressive regimen (P =.001) were
      associated with improved LFS. CONCLUSION: Allogeneic PBSC results in faster
      neutrophil and platelet engraftment and a higher incidence of chronic GVHD than
      BM. However, acute GVHD, TRM, relapse, survival, and LFS were similar in patients
      receiving PBSCs versus BM.

PMID- 12488411
TI  - Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and
      vincristine regimen in small-cell lung cancer: results from a randomized phase
      III trial with 5 years' follow-up.
AB  - PURPOSE: To investigate whether chemotherapy with etoposide and cisplatin (EP) is
      superior to cyclophosphamide, epirubicin, and vincristine (CEV) in small-cell
      lung cancer (SCLC). PATIENTS AND METHODS: A total of 436 eligible patients were
      randomized to chemotherapy with EP (n = 218) or CEV (n = 218). Patients were
      stratified according to extent of disease (limited disease [LD], n = 214;
      extensive disease [ED], n = 222). The EP group received five courses of etoposide
      100 mg/m(2) intravenously (IV) and cisplatin 75 mg/m(2) IV on day 1, followed by
      oral etoposide 200 mg/m(2) daily on days 2 to 4. The CEV group received five
      courses of epirubicin 50 mg/m(2), cyclophosphamide 1,000 mg/m(2), and vincristine
      2 mg, all IV on day 1. In addition, LD patients received thoracic radiotherapy
      concurrent with chemotherapy cycle 3, and those achieving complete remission
      during the treatment period received prophylactic cranial irradiation. RESULTS:
      The treatment groups were well balanced with regard to age, sex, and prognostic
      factors such as weight loss, and performance status. The 2- and 5-year survival
      rates in the EP arm (14% and 5%, P =.0004) were significantly higher compared
      with those in the CEV arm (6% and 2%). Among LD patients, median survival time
      was 14.5 months versus 9.7 months in the EP and CEV arms, respectively (P =.001).
      The 2- and 5-year survival rates of 25% and 10% in the EP arm compared with 8%
      and 3% in the CEV arm (P =.0001). For ED patients, there was no significant
      survival difference between the treatment arms. Quality-of-life assessments
      revealed no major differences between the randomized groups. CONCLUSION: EP is
      superior to CEV in LD-SCLC patients. In ED-SCLC patients, the benefits of EP and
      CEV chemotherapy seem equivalent, with similar survival time and quality of life.

PMID- 12488412
TI  - Clinical characteristics and outcomes from an institutional series of acinar cell
      carcinoma of the pancreas and related tumors.
AB  - PURPOSE: Acinar cell carcinoma is a rare tumor of the exocrine pancreas. Clinical
      features such as prognostic information, survival, and treatment outcomes are
      unknown. We present the largest retrospective review to date. PATIENTS AND
      METHODS: Thirty-nine patients with pathologically confirmed acinar neoplasms of
      the pancreas were identified between August 1981 and January 2001. Demographic
      data, tumor characteristics, and treatment information were obtained by chart
      review. Survival probabilities were estimated by using the Kaplan-Meier method
      and compared using the log-rank test. RESULTS: The median survival for all
      patients was 19 months. On the basis of a univariate analysis, the patients'
      stage of disease correlated significantly with survival. The median survival of
      patients with localized disease was 38 months, versus 14 months for those
      presenting with metastases (P = 0.03). Patients who could be treated with surgery
      as first-line therapy had a longer survival time (36 months) compared with those
      who did not have surgery (14 months). Two of 18 patients who received
      chemotherapy and three of eight patients who received radiation had a major
      response. CONCLUSION: The survival curves suggest a more aggressive cancer than
      pancreatic endocrine neoplasms but one that is less aggressive than ductal
      adenocarcinoma of the pancreas. Those patients who present with localized disease
      have a much better prognosis than those who present with metastases. There is a
      high recurrence rate after complete surgical resection, suggesting that
      micrometastases are present even in localized disease and that adjuvant therapies
      may be indicated. Chemotherapy and radiation afford disappointing results,
      however, and novel therapies are needed.

PMID- 12488413
TI  - Development and validation of a prognostic model to predict the length of
      survival in patients with carcinomas of an unknown primary site.
AB  - PURPOSE: To identify clinical and biologic variables with significant impact on
      survival in patients with carcinomas of an unknown primary site and to develop a
      simple prognostic model for the selection of patients in prospective clinical
      trials. PATIENTS AND METHODS: Univariate and multivariate prognostic factor
      analyses were conducted in a population of 150 unselected patients and led to the
      construction of two successive classification schemes. An external data set of
      116 patients enrolled onto two prospective trials was used for validation.
      RESULTS: When studying clinical variables only, poor performance status (2 or 3)
      and presence of liver metastases were retained in the multivariate analysis. The
      first classification scheme consisted of three subgroups of patients with median
      survivals of 10.8, 6.0, and 2.4 months, according to the number of adverse
      prognostic factors. With the introduction of serum lactate dehydrogenase (LDH)
      levels in a further step, liver metastases were no longer significant. The second
      classification scheme therefore included poor performance status (relative risk
      [RR], 2.1) and elevated serum LDH level (RR, 2.1). Good-risk and poor-risk
      patients were identified, with median survivals of 11.7 months and 3.9 months,
      respectively (P <.0001). The 1-year survival rates were 45% and 11%,
      respectively. This second classification scheme was validated in an external data
      set: the median survival rates of patients assigned to the good-risk group and
      the poor-risk group were 12 months and 7 months, respectively (P =.0089). The 1
      year survival rates were 53% and 23%, respectively. CONCLUSION: A simple
      prognostic model using performance status and serum LDH levels was developed and
      validated. It allows the assignment of patients into two subgroups with divergent
      outcome. Further prospective trials will be designed using this prognostic model.

PMID- 12488414
TI  - Temozolomide in malignant gliomas of childhood: a United Kingdom Children's
      Cancer Study Group and French Society for Pediatric Oncology Intergroup Study.
AB  - PURPOSE: To determine the response rate of the malignant gliomas of childhood to
      an oral, daily schedule of temozolomide. PATIENTS AND METHODS: A multicenter,
      phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m(2) on 5
      consecutive days) was undertaken in children with relapsed or progressive, biopsy
      proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem
      glioma (arm B). Evidence of activity was defined by radiologic evidence of a
      sustained reduction in tumor size on serial magnetic resonance imaging scans.
      RESULTS: Fifty-five patients were recruited (34 to arm A and 21 to arm B) and
      received 215 cycles of chemotherapy. Grade 3/4 thrombocytopenia was the most
      frequent toxic event (7% of cycles). Prolonged myelosuppression resulted in
      significant treatment delays and dose reductions (17% and 22% of cycles,
      respectively). Two toxic deaths were documented and were related to
      myelosuppression and sepsis in one patient and pneumonia in a second. The overall
      (best) response rate was 12% for arm A (95% confidence interval [CI], 3 to 28 in
      the study cohort, and 2 to 31 for eligible patients) and 5% and 6%, respectively,
      for arm B (95% CI, 0 to 26 in the study cohort, and 0 to 27 for eligible
      patients). Stabilization of disease was also documented and was most noteworthy
      for brainstem gliomas, where two patients achieved both radiologic static disease
      and discontinued steroid medication. CONCLUSION: Despite moderate toxicity,
      objective response rates to temozolomide have been low, indicating that
      temozolomide has minimal activity in the high-grade gliomas of childhood.

PMID- 12488415
TI  - The Minneapolis-Manchester Quality of Life instrument: reliability and validity
      of the Adolescent Form.
AB  - PURPOSE: With improvement in survival after childhood cancer, increasing emphasis
      is being placed on the impact of treatment and its sequelae on the health-related
      quality of life (HRQL) of survivors. The Minneapolis-Manchester Quality of Life
      Instrument (MMQL) is a standardized patient self-report instrument designed to
      assess HRQL in survivors of childhood cancer. The MMQL is being developed for
      three age groups to address the changing developmental need of different ages:
      MMQL-Youth (8 to 12 years), MMQL-Adolescent (13 to 20 years), and MMQL-Young
      Adult (21 to 45 years). This report focuses on the development and testing of the
      MMQL-Adolescent Form. PATIENTS AND METHODS: To validate the instrument, the MMQL
      Adolescent Form was administered to 397 adolescents (129 healthy individuals, 110
      patients with cancer undergoing therapy, and 158 subjects off therapy for
      cancer). Factor analysis was conducted to refine the instrument. Construct
      validity was conducted by comparing similar constructs in the MMQL-Adolescent
      Form and the Child Health Questionnaire (CHQ). Discriminate validity was
      determined by comparing healthy children with children with cancer either on or
      off therapy. Stability of the MMQL was tested by readministering the MMQL
      Adolescent Form 2 weeks later. RESULTS: Internal consistency reliability was in
      the acceptable range for this instrument. The MMQL was able to discriminate
      between the three study populations. There were high correlations between the
      MMQL scales and similar CHQ domains. Test-retest reliability of the MMQL
      Adolescent Form demonstrated that the instrument was extremely stable in all
      scales tested. CONCLUSION: Overall, the data provide evidence for the validity
      and reliability of the MMQL-Adolescent Form as a comprehensive, multidimensional
      self-report instrument for measuring HRQL among adolescent survivors of childhood
      cancer.

PMID- 12488416
TI  - Attitudes of Japanese physicians toward terminal dehydration: a nationwide
      survey.
AB  - PURPOSE: To clarify physician attitudes toward terminal dehydration and identify
      the physician-related factors contributing to their attitudes. METHODS: A cross
      sectional survey of Japanese physicians with a self-reported questionnaire was
      used. RESULTS: A total of 584 responses were analyzed (response rate, 53%). In
      the vignette of a gastric cancer patient with an estimated survival of 1 month
      and almost impossible oral intake due to intestinal obstruction, 50% chose
      intravenous hydration of 1,000 mL/d, while 24% selected more than 1,500 mL/d. For
      a lung cancer patient with cachexia, 58% chose 1,000 mL/d, while 26% selected no
      hydration or 500 mL. Multivariate analyses revealed that the physicians with more
      positive attitudes toward intravenous hydration were significantly less involved
      in end-of-life care, more likely to regard the physiologic requirement of fluid
      and nutrition as important in initiating intravenous hydration, more likely to
      believe that intravenous hydration is effective for symptom palliation, and more
      likely to believe that intravenous hydration is the minimum standard of care.
      CONCLUSION: Physicians have considerably divergent attitudes toward intravenous
      hydration for terminally ill cancer patients. To resolve the discrepancy, the
      priority in hydration research should be to clarify the appropriate physiologic
      requirements of fluid and nutrition in dying patients, the effects of intravenous
      hydration on patient symptoms, and the reasons why physicians consider
      intravenous hydration to be the minimum standard of care.

PMID- 12488417
TI  - Multidisciplinary systems approach to chemotherapy safety: rebuilding processes
      and holding the gains.
AB  - PURPOSE: The problem of medication safety came to public attention largely
      through a chemotherapy error, and the high toxicity and low therapeutic index of
      anticancer medications make safety in their prescription and administration
      critical. We have undertaken a thorough revision of our systems for inpatient
      chemotherapy. METHODS: We participated in a multi-institutional collaborative
      effort of the Institute for Healthcare Improvement, and used their rapid cycle
      change method. Particularly powerful systems change concepts were driving out
      fear, "trapping" errors and learning from them, focusing on outcome rather than
      on input, simplifying and standardizing, using constraints and "forcing
      functions," reducing handoffs, and paying attention to human factors. RESULTS:
      Applying these concepts to our chemotherapy delivery system, we have achieved an
      84% decrease in the number of chemotherapy errors that actually reach patients
      per 1,000 chemotherapy doses, and have sustained that improvement for 5 years.
      CONCLUSION: Factors contributing to our success include the rapid cycle change
      method, strong support from hospital administration, grassroots participation,
      and a tradition of interdisciplinary cooperation. Computerized direct physician
      order entry and cooperative group participation have had mixed effects. Continued
      efforts at improvement have been key to holding our gains. Although specific
      problems and changes may not be relevant to other organizations, the concepts and
      methods we used are generally applicable.

PMID- 12488418
TI  - Model of chemotherapy-induced myelosuppression with parameter consistency across
      drugs.
AB  - PURPOSE: To develop a semimechanistic pharmacokinetic-pharmacodynamic model
      describing chemotherapy-induced myelosuppression through drug-specific parameters
      and system-related parameters, which are common to all drugs. PATIENTS AND
      METHODS: Patient leukocyte and neutrophil data after administration of docetaxel,
      paclitaxel, and etoposide were used to develop the model, which was also applied
      to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan
      (CPT-11), and vinflunine administrations. The model consisted of a proliferating
      compartment that was sensitive to drugs, three transit compartments that
      represented maturation, and a compartment of circulating blood cells. Three
      system-related parameters were estimated: baseline, mean transit time, and a
      feedback parameter. Drug concentration-time profiles affected the proliferation
      of sensitive cells by either an inhibitory linear model or an inhibitory E(max)
      model. To evaluate the model, system-related parameters were fixed to the same
      values for all drugs, which were based on the results from the estimations, and
      only drug-specific parameters were estimated. All modeling was performed using
      NONMEM software. RESULTS: For all investigated drugs, the model successfully
      described myelosuppression. Consecutive courses and different schedules of
      administration were also well characterized. Similar system-related parameter
      estimates were obtained for the different drugs and also for leukocytes compared
      with neutrophils. In addition, when system-related parameters were fixed, the
      model well characterized chemotherapy-induced myelosuppression for the different
      drugs. CONCLUSION: This model predicted myelosuppression after administration of
      one of several different chemotherapeutic drugs. In addition, with fixed system
      related parameters to proposed values, and only drug-related parameters
      estimated, myelosuppression can be predicted. We propose that this model can be a
      useful tool in the development of anticancer drugs and therapies.

PMID- 12488419
TI  - American Society of Clinical Oncology 2001 Presidential Initiative: impact of
      regulatory burdens on quality cancer care.
AB  - PURPOSE: This study was conducted as part of the American Society of Clinical
      Oncology (ASCO) 2001 Presidential Initiative to assess the administrative burden
      of payer documentation requirements and their impact on oncology practice.
      METHODS: The study consisted of a physician questionnaire and an activity log.
      Site visits were conducted to support survey data. Analysis included 2,493
      questionnaires and 1,115 activity logs; data were also collected from site visits
      to 10 oncology practices. RESULTS: Increased documentation was the greatest
      concern among respondents, greater even than the stress of dealing with death and
      dying. More than 97% of survey respondents reported an increase in documentation
      (averaging 1.4 h/d) and 77% reported an increase in work hours because of
      documentation in the past 5 years. As a result, more than 40% of respondents
      reported decreases in key aspects of patient care and decreases in teaching (48%)
      and research (39%). Site visit data demonstrate similar trends. CONCLUSION: It is
      critical to find ways to decrease physician burden without decreasing the ability
      to prevent fraud and abuse. Reforms include provisions in a recently passed bill
      in the United States House of Representatives to streamline Medicare regulation
      and increase physician education. To address oncology-specific concerns, changes
      also should be made to supervision requirements for residents and fellows and
      evaluation and management documentation for oncology follow-up visits.

PMID- 12488423
TI  - A full complement of receptors in immune complex diseases.

PMID- 12488422
TI  - Remission of renal disease: recounting the challenge, acquiring the goal.

PMID- 12488424
TI  - Unexpected news in renal fibrosis.

PMID- 12488425
TI  - Getting peptide vaccines to work: just a matter of quality control?

PMID- 12488426
TI  - Calcitonin and bone formation: a knockout full of surprises.

PMID- 12488428
TI  - Functional repair of a mutant chloride channel using a trans-splicing ribozyme.
AB  - RNA repair has been proposed as a novel gene-based therapeutic strategy. Modified
      Tetrahymena group I intron ribozymes have been used to mediate trans-splicing of
      therapeutically relevant RNA transcripts, but the efficiency of the ribozyme
      mediated RNA repair process has not been determined precisely and subsequent
      restoration of protein function has been demonstrated only by indirect means. We
      engineered a ribozyme that targets the mRNA of a mutant canine skeletal muscle
      chloride channel (cClC-1) (mutation T268M in ClC-1 causing myotonia congenita)
      and replaces the mutant-containing 3' portion by trans-splicing the corresponding
      4-kb wild-type sequence. Repair efficiency assessed by quantitative RT-PCR was
      1.2% +/- 0.1% in a population of treated cells. However, when chloride channel
      function was examined in single cells, a wide range of electrophysiological
      activity was observed, with 18% of cells exhibiting significant functional
      restoration and some cells exhibiting complete rescue of the biophysical
      phenotype. These results indicate that RNA repair can restore wild-type protein
      activity and reveal considerable cell-to-cell variability in ribozyme-mediated
      trans-splicing reaction efficiency.

PMID- 12488427
TI  - Collagen-binding integrin alpha1beta1 regulates intestinal inflammation in
      experimental colitis.
AB  - Central to inflammatory responses are the integrin-mediated adhesive interactions
      of cells with their ECM-rich environment. We investigated the role of the
      collagen-binding integrin alpha(1)beta(1) in intestinal inflammation using the
      mouse model of colitis induced by dextran sodium sulfate (DSS). mAb's directed
      against murine alpha(1) were found to significantly attenuate inflammation and
      injury in DSS-treated wild-type mice; similar protection was seen in mice
      deficient for alpha(1)beta(1) integrin. Blockade or loss of alpha(1)beta(1) was
      also associated with decreased mucosal inflammatory cell infiltrate and cytokine
      production. Importantly, we demonstrated that development and alpha(1)-mediated
      inhibition of DSS-induced colitis occurred independently of lymphocytes (Rag-2(-/
      ) mice), and identified the monocyte as a key alpha(1)beta(1)-expressing cell
      type involved in the development of colitis in this model. In response to DSS,
      both alpha(1) deficiency and anti-alpha(1) mAb treatment significantly reduced
      monocyte accumulation and activation within the lamina propria. In summary, the
      data demonstrate that engagement of leukocyte-associated alpha(1)beta(1)
      receptors with ECM plays a pivotal role in mediating intestinal inflammation via
      promotion of monocyte movement and/or activation within the inflamed
      interstitium. Therapeutic strategies designed to disrupt such interactions may
      prove beneficial in treating intestinal inflammation.

PMID- 12488429
TI  - Targeted disruption of H3 receptors results in changes in brain histamine tone
      leading to an obese phenotype.
AB  - Histamine is an aminergic neurotransmitter that is localized in the CNS and in
      peripheral tissues. To date, four histamine receptors have been identified, and
      the H3 receptor, which was recently cloned, is predominantly expressed in the
      CNS. The peripheral functions of histamine have been investigated intensively
      using available molecular and pharmacological tools, and the molecular
      identification of the H3 receptor opens up new possibilities for investigating
      the role of histamine in central tissues. To understand the biological function
      of the histamine presynaptic autoreceptor H3, we inactivated the receptor through
      homologous recombination. H3(-/-) mice manifest mild obese phenotypes that are
      characterized by increases in body weight, food intake, and adiposity and by
      reductions in energy expenditure. Consistent with these observations, homozygous
      null mice have insulin and leptin resistance, increased levels of plasma leptin
      and insulin, and decreased levels of histamine in the hypothalamic/thalamic
      region of their brains coupled with increased histamine turnover. The expression
      of UCP1 in brown adipose tissue and of UCP3 in brown adipose tissue, white
      adipose tissue, and skeletal muscle is decreased in H3(-/-) mutants, and the
      anorexigenic activity of thioperamide is not observed. These results suggest that
      neuronal histamine is a mediator of body-weight homeostasis and that neuronal
      histamine functions through H3 receptors in mice.

PMID- 12488430
TI  - Pregnancy alters glucose-6-phosphate dehydrogenase trafficking, cell metabolism,
      and oxidant release of maternal neutrophils.
AB  - Pregnancy is associated with changes in host susceptibility to infections and
      inflammatory disease. We hypothesize that metabolic enzyme trafficking affects
      maternal neutrophil activation. Specifically, immunofluorescence microscopy has
      shown that glucose-6-phosphate dehydrogenase (G-6-PDase), the rate-controlling
      step of the hexose monophosphate shunt (HMS), is located near the cell periphery
      in control neutrophils but is found near the microtubule-organizing centers in
      cells from pregnant women. Cytochemical studies confirmed that the distribution
      of the G-6-PDase antigen is coincident with functional G-6-PDase activity.
      Metabolic oscillations within activated pregnancy neutrophils are higher in
      amplitude, though lower in frequency, than activated control neutrophils,
      suggesting limited HMS activity. Analysis of radioisotope-labeled carbon flux
      from glucose to CO(2) indicates that the HMS is intact in leukocytes from
      pregnant women, but its level is not enhanced by cell stimulation. Using
      extracellular fluorescent markers, activated pregnancy neutrophils were found to
      release reactive oxygen metabolites (ROMs) at a lower rate than activated control
      neutrophils. However, basal levels of ROM production in polarized pregnancy
      neutrophils were greater than in control neutrophils. Microtubule-disrupting
      agents reversed the observed changes in G-6-PDase trafficking, metabolic
      oscillations, and ROM production by maternal neutrophils. G-6-PDase trafficking
      appears to be one mechanism regulating ROM production by maternal neutrophils.

PMID- 12488431
TI  - Multiepitope CD8(+) T cell response to a NY-ESO-1 peptide vaccine results in
      imprecise tumor targeting.
AB  - The cancer-testis antigen NY-ESO-1 is one of the most promising candidates for
      generic vaccination of cancer patients. Here we analyzed the CD8(+) T cell
      response to a NY-ESO-1 peptide vaccine composed of the two previously defined
      peptides 157-165 and 157-167, administered with GM-CSF as a systemic adjuvant.
      The NY-ESO-1 peptide vaccine elicited a CD8(+) T cell response directed against
      multiple distinct epitopes in the 157-167 region, as revealed by using A2/peptide
      multimers incorporating overlapping A2 binding peptides in this region. However,
      only a minor fraction of the elicited CD8(+) T cells, namely those recognizing
      the peptide 157-165 with sufficiently high functional avidity, recognized the
      naturally processed target on NY-ESO-1(+) tumor cells. In contrast, the majority
      of peptide 157-165-specific CD8(+) T cells exhibited lower functional avidity and
      no tumor reactivity. In addition, vaccine-elicited CD8(+) T cells specific for
      other overlapping epitopes in the 157-167 region failed to significantly
      recognize NY-ESO-1-expressing tumor targets. Thus, because of the complexity of
      the CD8(+) T cell repertoire that can be elicited by vaccination with synthetic
      peptides, a precise definition of the targeted epitope, and hence, of the
      corresponding peptide to be used as immunogen, is required to ensure a precise
      tumor targeting.

PMID- 12488432
TI  - C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs
      in immune complex-induced lung disease.
AB  - IgG Fc receptors (FcgammaRs, especially FcgammaRIII) and complement (in
      particular, C5a anaphylatoxin) are critical effectors of the acute inflammatory
      response to immune complexes (ICs). However, it is unknown whether and how these
      two key components can interact with each other in vivo. We use here a mouse
      model of the acute pulmonary IC hypersensitivity reaction to analyze their
      potential interaction. FcgammaRIII and C5aR are coexpressed on alveolar
      macrophages (AMs), and both FcgammaRIII and C5aR mutant mice display impaired
      immune responses. We find that recombinant human C5a (rhC5a) can control inverse
      expression of various FcgammaRs, and costimulation of ICs with rhC5a results in
      strong enhancement of FcgammaRIII-triggered cellular activation in vitro and in
      vivo. Moreover, we show here that early IC-induced bioactive C5a, and its
      interaction with C5aR, causes induction of activating FcgammaRIII and suppression
      of inhibitory FcgammaRII on AMs that appears crucial for efficient cytokine
      production and neutrophil recruitment in lung pathology. Therefore, C5a, which is
      a potent chemoattractant, has a broader critical function in regulating the
      inhibitory/activating FcgammaRII/III receptor pair to connect complement and
      FcgammaR effector pathways in immune inflammation.

PMID- 12488433
TI  - The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane
      type matrix metalloproteinase-1 and cyclooxygenase-2 expression.
AB  - Hepatocellular carcinoma is strongly associated with chronic infection by the
      hepatitis B virus (HBV) and has poor prognosis due to intrahepatic metastasis.
      HBx is often the only HBV protein detected in hepatic tumor cells; however, its
      contribution to tumor invasion and metastasis has not been established so far. In
      this work, we show that HBx enhances tumor cell invasion, both in vivo and in
      vitro. The increased invasive capacity induced by HBx is mediated by an
      upregulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression,
      which in turn activates matrix metalloproteinase-2. Induction of both MT1-MMP
      expression and cell invasion by HBx is dependent on cyclooxygenase-2 (COX-2)
      activity. In addition, HBx upregulates the expression of COX-2, which is mediated
      by the transcriptional activation of the COX-2 gene promoter in a nuclear factor
      of activated T cell-dependent (NF-AT-dependent) manner. These results demonstrate
      the ability of HBx to promote tumor cell invasion by a mechanism involving the
      upregulation of MT1-MMP and COX-2 and provide new insights into the mechanism of
      action of this viral protein and its involvement in tumor metastasis and
      recurrence of hepatocellular carcinoma.

PMID- 12488434
TI  - The forkhead transcription factor Foxo1 links insulin signaling to Pdx1
      regulation of pancreatic beta cell growth.
AB  - Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of
      insulin-producing beta cells. The mechanisms governing replication of terminally
      differentiated beta cells and neogenesis from progenitor cells are unclear. Mice
      lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting
      that insulin signaling is required to maintain an adequate beta cell mass. We
      report that haploinsufficiency for the forkhead transcription factor Foxo1
      reverses beta cell failure in Irs2(-/-) mice through partial restoration of beta
      cell proliferation and increased expression of the pancreatic transcription
      factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually
      exclusive patterns of nuclear localization in beta cells, and constitutive
      nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression.
      We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3beta-dependent)
      expression from the Pdx1 promoter. We propose that insulin/IGFs regulate beta
      cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset
      of cells embedded within pancreatic ducts.

PMID- 12488435
TI  - Increased bone mass is an unexpected phenotype associated with deletion of the
      calcitonin gene.
AB  - Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene-related
      peptide-alpha (CGRPalpha), produced by alternative RNA processing of the CT/CGRP
      gene, has no clearly defined role in bone. To better understand the physiologic
      role of the CT/CGRP gene we created a mouse in which the coding sequences for
      both CT and CGRPalpha were deleted by homologous recombination. The CT/CGRP(-/-)
      knockout (KO) mice procreated normally, there were no identifiable developmental
      defects at birth, and they had normal baseline calcium-related chemistry values.
      However, KO animals were more responsive to exogenous human parathyroid hormone
      as evidenced by a greater increase of the serum calcium concentration and urine
      deoxypyridinoline crosslinks, an effect reversed by CT and mediated by a greater
      increase in bone resorption than in controls. Surprisingly, KO mice have
      significantly greater trabecular bone volume and a 1.5- to 2-fold increase in
      bone formation at 1 and 3 months of age. This effect appears to be mediated by
      increased bone formation. In addition, KO mice maintain bone mass following
      ovariectomy, whereas wild-type mice lose approximately one-third of their bone
      mass over 2 months. These findings argue for dual roles for CT/CGRP gene
      products: prevention of bone resorption in hypercalcemic states and a regulatory
      role in bone formation.

PMID- 12488436
TI  - Absence of angiotensin II type 1 receptor in bone marrow-derived cells is
      detrimental in the evolution of renal fibrosis.
AB  - We examined the in vivo function of the angiotensin II type 1 receptor (Agtr1) on
      macrophages in renal fibrosis. Fourteen days after the induction of unilateral
      ureteral obstruction (UUO), wild-type mice reconstituted with marrow lacking the
      Agtr1 gene (Agtr1(-/-)) developed more severe interstitial fibrosis with fewer
      interstitial macrophages than those in mice reconstituted with Agtr1(+/+) marrow.
      These differences were not observed at day 5 of UUO. The expression of
      profibrotic genes - including TGF-beta1, alpha1(I) collagen, and alpha1(III)
      collagen - was substantially higher in the obstructed kidneys of mice with Agtr1(
      /-) marrow than in those with Agtr1(+/+) marrow at day 14 but not at day 5 of
      UUO. Mice with Agtr1(-/-) marrow were characterized by reduced numbers of
      peripheral-blood monocytes and macrophage progenitors in bone marrow. In vivo
      assays revealed a significantly impaired phagocytic capability in Agtr1(-/-)
      macrophages. In vivo treatment of Agtr1(+/+) mice with losartan reduced
      phagocytic capability of Agtr1(+/+) macrophages to a level comparable to that of
      Agtr1(-/-) macrophages. Thus, during urinary tract obstruction, the Agtr1 on bone
      marrow-derived macrophages functions to preserve the renal parenchymal
      architecture, and this function depends in part on its modulatory effect on
      phagocytosis.

PMID- 12488438
TI  - Selective proteolytic processing of rat hepatic sterol regulatory element binding
      protein-1 (SREBP-1) and SREBP-2 during postnatal development.
AB  - Sterol regulatory element-binding protein-1c (SREBP-1c) plays a major role in
      hepatic lipogenic gene expression. In adult animals, insulin and oxysterols
      induce SREBP-1c gene transcription, whereas polyunsaturated fatty acids suppress
      the nuclear content of SREBP-1c through pre-translational regulatory mechanisms.
      A decline in nuclear SREBP-1 is associated with suppression of hepatic
      lipogenesis. In contrast to adult rats, hepatic lipogenesis in preweaned neonatal
      rats is low. Ingestion of milk fat by the neonate may contribute to low hepatic
      lipogenesis. In this report, we tested the hypothesis that low lipogenic gene
      expression prior to weaning correlates with low mRNA(SREBP-1c), as well as low
      precursor and nuclear forms of SREBP-1. In contrast to expectations, levels of
      mRNA(SREBP-1c) and the 125-kDa SREBP-1 precursor in livers of preweaned rats was
      comparable with adult levels. Despite high levels of SREBP-1 precursor, mature
      (65 kDa) SREBP-1 was not detected in rat liver nuclei prior to 18 days
      postpartum. Weaning rats at 21 days postpartum was accompanied by a rise in
      nuclear SREBP-1 levels as well as increased lipogenic gene expression. In
      contrast, SREBP-2 was present in rat liver nuclei, and its target gene, HMG-CoA
      reductase, was expressed above adult levels prior to weaning. These studies
      indicate that, prior to weaning, SREBP-2 but not SREBP-1 is proteolytically
      processed to the mature form. As such, SREBP-2-regulated genes are active.
      Failure of SREBP-1 to be processed to the mature form <18 days postpartum
      correlates with low hepatic lipogenic gene expression. This mechanism differs
      from the hormonal and fatty acid-mediated pre-translational control of SREBP-1c
      in adult liver.

PMID- 12488437
TI  - Removal of anti-Galalpha1,3Gal xenoantibodies with an injectable polymer.
AB  - Preformed and elicited Ab's against the Galalpha1,3Gal terminating carbohydrate
      chains (alphaGal Ab's) are the primary cause of hyperacute and acute vascular
      xenograft rejection in pig-to-primate transplantation. alphaGal Ab's are produced
      by long-lived Ab-producing cells that are not susceptible to pharmacological
      immunosuppression. We reasoned that antigen-specific elimination of alphaGal Ab's
      might be achieved in vivo by systemic administration of nonimmunogenic polyvalent
      alphaGal structures with high avidity for alphaGal Ab's. We devised GAS914, a
      soluble trisaccharide-polylysine conjugate of approximately 500 kDa that
      effectively competes for alphaGal binding by alphaGal IgM (IC(50), 43 nM) and IgG
      (IC(50), 28 nM) in vitro. Injections of GAS914 in cynomolgus monkeys, at the dose
      of 1 mg/kg, resulted in the immediate decrease of more than 90% of circulating
      alphaGal Ab's and serum anti-pig cytotoxicity. In baboons, repeated injections of
      GAS914 effectively reduced both circulating alphaGal Ab's and cytotoxicity over
      several months. Studies with [(14)C]GAS914 in rhesus monkeys and Gal(-/-) mice
      indicate that GAS914 binds to circulating alphaGal Ab's and that the complex is
      quickly metabolized by the liver and excreted by the kidney. Remarkably,
      posttreatment alphaGal Ab titers never exceeded pretreatment levels and no
      sensitization to either alphaGal or the polylysine backbone has been observed.
      Furthermore there was no apparent acute or chronic toxicity associated with
      GAS914 treatment in primates. We conclude that GAS914 may be used therapeutically
      for the specific removal of alphaGal Ab's.

PMID- 12488439
TI  - Multiple regions of internalin B contribute to its ability to turn on the Ras
      mitogen-activated protein kinase pathway.
AB  - Internalin B (InlB) is a protein present on the surface of Listeria monocytogenes
      that mediates bacterial entry into mammalian cells. It is thought that InlB acts
      by binding directly to the hepatocyte growth factor (HGF) receptor, present on
      the surface of host cells. Binding of InlB to the HGF receptor results in mitogen
      activated protein (MAP) kinase and phosphoinositide 3-kinase activation, followed
      by changes in the organization of the actin cytoskeleton. Here we have compared
      signaling by HGF and InlB. Whereas stimulation with equivalent concentrations of
      HGF and InlB elicits similar activation of the HGF receptor, we observed striking
      differences in downstream activation of MAP kinase. InlB leads to a greater
      activation of the Ras-MAP kinase pathway than does HGF. The leucine-rich repeat
      region, which was previously shown to be sufficient for binding and activation of
      the HGF receptor, lacks the ability to super-activate the Ras-MAP kinase pathway.
      Analysis of a series of deletion mutants suggests that it is the B repeat region
      between the leucine-rich repeat and GW domains that endows InlB with an increased
      ability to turn on the Ras-MAP kinase pathway. These unexpected observations
      suggest that HGF and InlB use alternative mechanisms to turn on cellular
      signaling pathways.

PMID- 12488440
TI  - Glycolysis and glutamate accumulation into synaptic vesicles. Role of
      glyceraldehyde phosphate dehydrogenase and 3-phosphoglycerate kinase.
AB  - Glucose is the major source of brain energy and is essential for maintaining
      normal brain and neuronal function. Hypoglycemia causes impaired synaptic
      transmission. This occurs even before significant reduction in global cellular
      ATP concentration, and relationships among glycolysis, ATP supply, and synaptic
      transmission are not well understood. We demonstrate that the glycolytic enzymes
      glyceraldehyde phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate kinase (3
      PGK) are enriched in synaptic vesicles, forming a functional complex, and that
      synaptic vesicles are capable of accumulating the excitatory neurotransmitter
      glutamate by harnessing ATP produced by vesicle-bound GAPDH/3-PGK at the expense
      of their substrates. The GAPDH inhibitor iodoacetate suppressed GAPDH/3-PGK
      dependent, but not exogenous ATP-dependent, [(3)H]glutamate uptake into isolated
      synaptic vesicles. It also decreased vesicular [(3)H]glutamate content in the
      nerve ending preparation synaptosome; this decrease was reflected in reduction of
      depolarization-induced [(3)H]glutamate release. In contrast, oligomycin, a
      mitochondrial ATP synthase inhibitor, had minimal effect on any of these
      parameters. ADP at concentrations above 0.1 mm inhibited vesicular glutamate and
      dissipated membrane potential. This suggests that the coupled GAPDH/3-PGK system,
      which converts ADP to ATP, ensures maximal glutamate accumulation into
      presynaptic vesicles. Together, these observations provide insight into the
      essential nature of glycolysis in sustaining normal synaptic transmission.

PMID- 12488441
TI  - Determination of relative chlorophyll binding affinities in the major light
      harvesting chlorophyll a/b complex.
AB  - The major light-harvesting complex (LHCIIb) of photosystem II can be
      reconstituted in vitro from its recombinant apoprotein in the presence of a
      mixture of carotenoids and chlorophylls a and b. By varying the chlorophyll a/b
      ratio in the reconstitution mixture, the relative amounts of chlorophyll a and
      chlorophyll b bound to LHCIIb can be changed. We have analyzed the chlorophyll
      stoichiometry in recombinant wild type and mutant LHCIIb reconstituted at
      different chlorophyll a/b ratios in order to assess relative affinities of the
      chlorophyll-binding sites. This approach reveals five sites that exclusively bind
      chlorophyll b. Another site exhibits a slight preference of chlorophyll b over
      chlorophyll a. The remaining six sites are filled preferentially with chlorophyll
      a but also tolerate chlorophyll b when this is offered at a large excess. Three
      of these chlorophyll a-affine sites could be assigned to distinct positions
      defined by the three-dimensional LHCIIb structure. Exclusive chlorophyll b sites
      complemented by chlorophyll a sites that are selective only to a certain extent
      are consistent with the observation that chlorophyll b but not chlorophyll a is
      essential for reconstituting stable LHCIIb. These data offer an explanation why a
      rather constant chlorophyll a/b ratio is observed in native LHCIIb despite the
      apparent promiscuity of some binding sites.

PMID- 12488442
TI  - Loss of G protein gamma 7 alters behavior and reduces striatal alpha(olf) level
      and cAMP production.
AB  - The G protein beta gamma-dimer is required for receptor interaction and effector
      regulation. However, previous approaches have not identified the physiologic
      roles of individual subtypes in these processes. We used a gene knockout approach
      to demonstrate a unique role for the G protein gamma(7)-subunit in mice. Notably,
      deletion of Gng7 caused behavioral changes that were associated with reductions
      in the alpha(olf)-subunit content and adenylyl cyclase activity of the striatum.
      These data demonstrate that an individual gamma-subunit contributes to the
      specificity of a given signaling pathway and controls the formation or stability
      of a particular G protein heterotrimer.

PMID- 12488443
TI  - Palmitoylation of the human prostacyclin receptor. Functional implications of
      palmitoylation and isoprenylation.
AB  - We have previously established that isoprenylation of the prostacyclin receptor
      (IP) is required for its efficient G protein coupling and effector signaling
      (Hayes, J. S., Lawler, O. A., Walsh, M. T., and Kinsella, B. T. (1999) J. Biol.
      Chem. 274, 23707-23718). In the present study, we sought to investigate whether
      the IP may actually be subject to palmitoylation in addition to isoprenylation
      and to establish the functional significance thereof. The human (h) IP was
      efficiently palmitoylated at Cys(308) and Cys(311), proximal to transmembrane
      domain 7 within its carboxyl-terminal (C)-tail domain, whereas Cys(309) was not
      palmitoylated. The isoprenylation-defective hIP(SSLC) underwent palmitoylation
      but did not efficiently couple to G(s) or G(q), confirming that isoprenylation is
      required for G protein coupling. Deletion of C-tail sequences distal to Val(307)
      generated hIP(Delta307) that was neither palmitoylated nor isoprenylated and did
      not efficiently couple to G(s) or to G(q), whereas hIP(Delta312) was
      palmitoylated and ably coupled to both effector systems. Conversion of Cys(308),
      Cys(309), Cys(311), Cys(308,309), or Cys(309,311) to corresponding Ser residues,
      while leaving the isoprenylation CAAX motif intact, did not affect hIP coupling
      to G(s) signaling, whereas mutation of Cys(308,311) and Cys(308,309,311)
      abolished signaling, indicating that palmitoylation of either Cys(308) or
      Cys(311) is sufficient to maintain functional G(s) coupling. Although mutation of
      Cys(309) and Cys(311) did not affect hIP-mediated G(q) coupling, mutation of
      Cys(308) abolished signaling, indicating a specific requirement for
      palmitoylation of Cys(308) for G(q) coupling. Consistent with this, neither
      hIP(C308S,C309S), hIP(C308S,C311S), nor hIP(C308S,C309S,C311S) coupled to G(q).
      Taken together, these data confirm that the hIP is isoprenylated and
      palmitoylated, and collectively these modifications modulate its G protein
      coupling and effector signaling. We propose that through lipid modification
      followed by membrane insertion, the C-tail domain of the IP may contain a double
      loop structure anchored by the dynamically regulated palmitoyl groups proximal to
      transmembrane domain 7 and by a distal farnesyl isoprenoid permanently attached
      to its carboxyl terminus.

PMID- 12488444
TI  - Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of
      oncoprotein Mdm2.
AB  - Oncoprotein Mdm2 is a master negative regulator of the tumor suppressor p53 and
      has been recently shown to regulate the ubiquitination of beta-arrestin 2, an
      important adapter and scaffold in signaling of G-protein-coupled receptors
      (GPCRs). However, whether beta-arrestin 2 has any effect on the function of Mdm2
      is still unclear. Our current results demonstrated that the binding of Mdm2 to
      beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of
      GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs
      and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of
      beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and
      consequently reduced the Mdm2-mediated p53 degradation and ubiquitination.
      Further experiments revealed that overexpression of beta-arrestin 2 enhanced the
      p53-mediated apoptosis while suppression of endogenous beta-arrestin 2 expression
      by RNA interference technology considerably attenuated the p53-mediated
      apoptosis. Our study thus suggests that beta-arrestin 2 may serve as a cross-talk
      linker between GPCR and p53 signaling pathways.

PMID- 12488445
TI  - Microtubule disruption utilizes an NFkappa B-dependent pathway to stabilize HIF
      1alpha protein.
AB  - Hypoxia-inducible factor (HIF)-1alpha levels are elevated in normoxic cells
      undergoing physiological processes involving large scale microtubule
      reorganization, such as embryonic development, wound healing, and tumor cell
      metastasis. Although alterations in microtubules affect numerous cellular
      responses, no data have yet implicated microtubule dynamics in HIF-1alpha
      regulation. To investigate the effect of microtubule change upon HIF-1alpha
      regulation, we treated cells with the microtubule-depolymerizing agents (MDAs)
      colchicine, vinblastine or nocodazole. We demonstrate that these agents are able
      to induce transcriptionally active HIF-1. MDA-mediated induction of HIF-1alpha
      required microtubule depolymerization, since HIF-1alpha levels were unchanged in
      cells treated with either the microtubule-stabilizing agent paclitaxel, or an
      inactive form of colchicine, or in colchicine-resistant cells. HIF-1 induction
      was dependent upon cellular transcription, as transcription inhibitors abrogated
      HIF-1alpha protein up-regulation. The ability of transcriptional inhibitors to
      interfere with HIF-1alpha accumulation was specific to the MDA-initiated pathway,
      as they were ineffective in preventing hypoxia-mediated HIF-1 induction, which
      occurs by a distinct post-translational pathway. Moreover, we provide evidence
      implicating a requirement for NFkappaB transcription in the HIF-1 induction
      mediated by MDAs. The ability of MDAs to induce HIF-1alpha is dependent upon
      activation of NFkappaB, since inhibition of NFkappaB either pharmacologically or
      by transfection of an NFkappaB super-repressor plasmid abrogated this induction.
      Collectively, these data support a model in which NFkappaB is a focal point for
      the convergence of MDA-mediated signaling events leading to HIF-1 induction, thus
      revealing a novel aspect of HIF-1alpha regulation and function.

PMID- 12488446
TI  - RAG1-DNA binding in V(D)J recombination. Specificity and DNA-induced
      conformational changes revealed by fluorescence and CD spectroscopy.
AB  - The RAG1 and RAG2 proteins together constitute the nuclease that initiates the
      assembly of immunoglobulin and T cell receptor genes in a reaction known as V(D)J
      recombination. RAG1 plays a central role in recognition of the recombination
      signal sequence (RSS) by the RAG1/2 complex. To investigate the parameters
      governing the RAG1-RSS interaction, the murine core RAG1 protein (amino acids 377
      1008) fused to a short Strep tag has been purified to homogeneity from bacteria.
      The Strep-RAG1 (StrRAG1) protein exists as a dimer at a wide range of protein
      concentrations (25-500 nM) in the absence of DNA and binds with reasonably high
      affinity and specificity (apparent K(D) = 41 nM) to the RSS. Both electrophoretic
      mobility shift assays and polarization anisotropy experiments indicate that only
      a single StrRAG1-DNA species exists in solution. Anisotropy decay measured by
      frequency domain spectroscopy suggests that the complex contains a dimer of
      StrRAG1 bound to a single DNA molecule. Using measurements of protein intrinsic
      fluorescence and circular dichroism, we demonstrate that StrRAG1 undergoes a
      major conformational change upon binding the RSS. Steady-state fluorescence and
      acrylamide quenching studies reveal that this conformational change is associated
      with a repositioning of intrinsic protein fluorophores from a hydrophobic to a
      solvent-exposed environment. RSS-induced conformational changes of StrRAG1 may
      influence the interaction of RAG1 with RAG2 and synaptic complex formation.

PMID- 12488447
TI  - High conservation of the Set1/Rad6 axis of histone 3 lysine 4 methylation in
      budding and fission yeasts.
AB  - Histone 3 lysine 4 (H3 Lys(4)) methylation in Saccharomyces cerevisiae is
      mediated by the Set1 complex (Set1C) and is dependent upon ubiquitinylation of
      H2B by Rad6. Mutually exclusive methylation of H3 at Lys(4) or Lys(9) is central
      to chromatin regulation; however, S. cerevisiae lacks Lys(9) methylation.
      Furthermore, a different H3 Lys(4) methylase, Set 7/9, has been identified in
      mammals, thereby questioning the relevance of the S. cerevisiae findings for
      eukaryotes in general. We report that the majority of Lys(4) methylation in
      Schizosaccharomyces pombe, like in S. cerevisiae, is mediated by Set1C and is
      Rad6-dependent. S. pombe Set1C mediates H3 Lys(4) methylation in vitro and
      contains the same eight subunits found in S. cerevisiae, including the homologue
      of the Drosophila trithorax Group protein, Ash2. Three additional features of S.
      pombe Set1C each involve PHD fingers. Notably, the Spp1 subunit is dispensable
      for H3 Lys(4) methylation in budding yeast but required in fission yeast, and
      Sp_Set1C has a novel proteomic hyperlink to a new complex that includes the
      homologue of another trithorax Group protein, Lid (little imaginal discs). Thus,
      we infer that Set1C is highly conserved in eukaryotes but observe that its links
      to the proteome are not.

PMID- 12488448
TI  - Sensitizing anthrax lethal toxin-resistant macrophages to lethal toxin-induced
      killing by tumor necrosis factor-alpha.
AB  - Macrophages from different inbred mouse strains exhibit striking differences in
      their sensitivity to anthrax lethal toxin (LeTx)-induced cytolysis. Although LeTx
      induced cytolysis of macrophages plays an important role in the outcome of
      anthrax infection, the sensitivity of macrophages in vitro does not correlate
      with in vivo susceptibility to infection of Bacillus anthracis. This divergence
      suggests that additional factors other than LeTx are involved in the cytolysis of
      LeTx-resistant macrophages in vivo. We found that LeTx-resistant macrophages
      became sensitive to LeTx-induced cytolysis when these cells were activated by
      bacterial components. Tumor necrosis factor-alpha induced by bacterial components
      was a key factor that cooperated with LeTx in inducing LeTx-resistant macrophage
      death. Tumor necrosis factor-alpha/LeTx-induced death of LeTx-resistant
      macrophages was dependent on mTor (mammalian target of rapamycin), but
      independent of caspases. Our data indicate that host responses to anthrax
      infection contribute to cytolysis of LeTx- resistant macrophages.

PMID- 12488449
TI  - Conformational change in aspartate aminotransferase on substrate binding induces
      strain in the catalytic group and enhances catalysis.
AB  - Aspartate aminotransferase has been known to undergo a significant conformational
      change, in which the small domain approaches the large domain, and the residues
      at the entrance of the active site pack together, on binding of substrates.
      Accompanying this conformational change is a two-unit increase in the pK(a) of
      the pyridoxal 5'-phosphate-Lys(258) aldimine, which has been proposed to enhance
      catalysis. To elucidate how the conformational change is coupled to the shift in
      the aldimine pK(a) and how these changes are involved in catalysis, we analyzed
      structurally and kinetically an enzyme in which Val(39) located at both the
      domain interface and the entrance of the active site was replaced with a bulkier
      residue, Phe. The V39F mutant enzyme showed a more open conformation, and the
      aldimine pK(a) was lowered by 0.7 unit compared with the wild-type enzyme. When
      Asn(194) had been replaced by Ala in advance, the V39F mutation did not decrease
      the aldimine pK(a), showing that the domain rotation controls the aldimine pK(a)
      via the Arg(386)-Asn(194)-pyridoxal 5'-phosphate linkage system. The maleate
      bound V39F enzyme showed the aldimine pK(a) 0.9 unit lower than that of the
      maleate-bound wild-type enzyme. However, the positions of maleate, Asn(194), and
      Arg(386) were superimposable between the mutant and the wild-type enzymes;
      therefore, the domain rotation was not the cause of the lowered aldimine pK(a)
      value. The maleate-bound V39F enzyme showed an altered side-chain packing pattern
      in the 37-39 region, and the lack of repulsion between Gly(38) carbonyl O and
      Tyr(225) Oeta seemed to be the cause of the reduced pK(a) value. Kinetic analysis
      suggested that the repulsion increases the free energy level of the Michaelis
      complex and promotes the catalytic reaction.

PMID- 12488450
TI  - Genetic and biochemical characterization of EshA, a protein that forms large
      multimers and affects developmental processes in Streptomyces griseus.
AB  - The 52-kDa protein, EshA, whose expression is controlled developmentally, is
      produced during the late growth phase of Streptomyces spp. We found that
      disruption of the eshA gene, which encodes the EshA protein, abolishes the aerial
      mycelium formation and streptomycin production in Streptomyces griseus when grown
      on an agar plate. The eshA disruptant KO-390 demonstrated a reduced amount of
      expression of the transcriptional activator strR, thus accounting for the failure
      to produce streptomycin. KO-390 was found to accumulate deoxynucleoside
      triphosphates at high levels, including dGTP, at late growth phase. The
      accumulation of dGTP was a cause for the impaired ability of KO-390 to produce
      aerial mycelium, because the ability to form aerial mycelium was completely
      repaired by addition of decoyinine, an inhibitor of GMP synthetase. The
      accumulation of dNTP in KO-390 coincided with a reduced rate of DNA synthesis.
      The developmental time frame of these phenomena in KO-390 matched a burst of EshA
      expression in the wild-type strain. In contrast to S. griseus, the eshA
      disruption did not affect the ability for Streptomyces coelicolor to form aerial
      mycelium and did not result in the aberrant accumulation of dNTP accompanied by
      arrest of DNA synthesis, implying qualitative differences in addition to
      quantitative differences between the two EshA proteins. We propose that the S.
      griseus EshA protein somehow positively affects (or regulates) the replication of
      DNA in wild-type cells at late growth phase but leads to aberrant phenotypes in
      mutant cells due to the disturbed DNA replication. The EshA protein was found to
      exist as a multimer ( approximately 20-mers) creating a cubic-like structure with
      a diameter of 27 nm and located predominantly in cytoplasm.

PMID- 12488451
TI  - The class A scavenger receptor binds to proteoglycans and mediates adhesion of
      macrophages to the extracellular matrix.
AB  - The class A scavenger receptor (SR-A) binds modified lipoproteins and has been
      implicated in cholesterol ester deposition in macrophages. The SR-A also
      contributes to cellular adhesion. Using SR-A(+/+) and SR-A(-)/- murine
      macrophages, we found SR-A expression important for both divalent cation
      dependent and -independent adhesion of macrophages to the human smooth muscle
      cell extracellular matrix. The SR-A mediated 65 and 85% of macrophage adhesion to
      the extracellular matrix in the presence and absence of serum, respectively. When
      EDTA was added to chelate divalent cations, the SR-A mediated 90 and 95% of the
      macrophage adhesion without and with serum, respectively. SR-A-mediated adhesion
      to the extracellular matrix was prevented by fucoidin, an SR-A antagonist.
      Biglycan and decorin, proteoglycans of the extracellular matrix, were identified
      as SR-A ligands. Compared with control cells, Chinese hamster ovary cells
      expressing the SR-A showed 5- and 6-fold greater cell association (binding and
      internalization) of (125)I-decorin and -biglycan, respectively. In competition
      studies, unlabeled proteoglycan or fucoidin competed for binding of (125)I
      labeled decorin and -biglycan, and biglycan and decorin competed for the SR-A
      mediated cell association and degradation of (125)I-labeled acetylated LDL, a
      well characterized ligand for the SR-A. These results suggest that the SR-A could
      contribute to the adhesion of macrophages to the extracellular matrix of
      atherosclerotic plaques.

PMID- 12488452
TI  - The growth hormone-binding protein is a location-dependent cytokine receptor
      transcriptional enhancer.
AB  - In the rat, a growth hormone-binding protein (GHBP) exists that is derived from
      the growth hormone (GH) receptor gene by an alternative mRNA splicing mechanism
      such that the transmembrane and intracellular domains of the GH receptor are
      replaced by a hydrophilic carboxyl terminus. In isolation, the GHBP is inactive,
      although it does compete with the receptor for ligand binding in the
      extracellular space and therefore inhibits the cellular response to GH. The GHBP
      is also located intracellularly and is translocated to the nucleus upon ligand
      stimulation. We show here that endogenously produced GHBP, in contrast to
      exogenous GHBP, was able to enhance the STAT5-mediated transcriptional response
      to GH. Interestingly, when the GHBP was targeted constitutively to the nucleus by
      the addition of the nuclear localization sequence of the SV40 large T antigen,
      greater enhancement of STAT5-mediated transcription was obtained. The
      transcriptional enhancement did not require GH per se and was not specific to the
      GH receptor, since similar enhancement of STAT5-mediated transcription by nuclear
      localized GHBP was obtained with specific ligand stimulation of both prolactin
      and erythropoietin receptors. Thus, the GHBP exerts divergent effects on STAT5
      mediated transcription depending on its cellular location. The use of a soluble
      cytokine receptor as a location-dependent transcriptional enhancer and the ligand
      independent involvement of the extracellular domain of a polypeptide ligand
      receptor in intracellular signal transduction provide additional novel mechanisms
      of transcriptional control.

PMID- 12488453
TI  - Calmodulin mediates brain-derived neurotrophic factor cell survival signaling
      upstream of Akt kinase in embryonic neocortical neurons.
AB  - As a calcium-sensing protein, calmodulin acts as a transducer of the
      intracellular calcium signal for a variety of cellular responses. Although
      calcium is an important regulator of neuronal survival during development of the
      nervous system and is also implicated in the pathogenesis of neurodegenerative
      disorders, it is not known if calmodulin mediates these actions of calcium. To
      determine the role of calmodulin in regulating neuronal survival and death, we
      overexpressed calmodulin with mutations in all four Ca(2+)-binding sites (CaM(1
      4)) or with disabled C-terminal Ca(2+)-binding sites (CaM(3,4)) in cultured
      neocortical neurons by adenoviral gene transfer. Long-term neuronal survival was
      decreased in neurons overexpressing CaM(1-4) and CaM(3,4), which could not be
      rescued by brain-derived neurotrophic factor (BDNF). The basal level of Akt
      kinase activation was decreased, and the ability of BDNF to activate Akt was
      completely abolished in neurons overexpressing CaM(1-4) or CaM(3,4). In contrast,
      BDNF-induced activation of p42/44 MAPKs was unaffected by calmodulin mutations.
      Treatment of neurons with calmodulin antagonists and a phosphatidylinositol 3
      kinase inhibitor blocked the ability of BDNF to prevent neuronal death, whereas
      inhibitors of calcium/ calmodulin-dependent protein kinase II did not. Our
      findings demonstrate a pivotal role for calmodulin in survival signaling by BDNF
      in developing neocortical neurons by activating a transduction pathway involving
      phosphatidylinositol 3-kinase and Akt. In addition, our findings show that the C
      terminal Ca(2+)-binding sites are critical for calmodulin-mediated cell survival
      signaling.

PMID- 12488454
TI  - The central helices of ApoA-I can promote ATP-binding cassette transporter A1
      (ABCA1)-mediated lipid efflux. Amino acid residues 220-231 of the wild-type ApoA
      I are required for lipid efflux in vitro and high density lipoprotein formation
      in vivo.
AB  - We have mapped the domains of lipid-free apoA-I that promote cAMP-dependent and
      cAMP-independent cholesterol and phospholipid efflux. The cAMP-dependent lipid
      efflux in J774 mouse macrophages was decreased by approximately 80-92% by apoA
      I[delta(185-243)], only by 15% by apoA-I[delta(1-41)] or apoA-I[delta(1-59)], and
      was restored to 75-80% of the wild-type apoA-I control value by double deletion
      mutants apoA-I[delta(1-41)delta(185-243)] and apoA-I[delta(1-59)delta(185-243)].
      Similar results were obtained in HEK293 cells transfected with an ATP-binding
      cassette transporter A1 (ABCA1) expression plasmid. The double deletion mutant of
      apoA-I had reduced thermal and chemical stability compared with wild-type apoA-I.
      Sequential carboxyl-terminal deletions showed that cAMP-dependent cholesterol
      efflux was diminished in all the mutants tested, except the apoA-I[delta(232
      243)] which had normal cholesterol efflux. In cAMP-untreated or in mock
      transfected cells, cholesterol efflux was not affected by the amino-terminal
      deletions, but decreased by 30-40% and 50-65% by the carboxyl-terminal and double
      deletions, respectively. After adenovirus-mediated gene transfer in apoA-I
      deficient mice, wild-type apoA-I and apoA-I[delta(1-41)] formed spherical high
      density lipoprotein (HDL) particles, whereas apoA-I[delta(1-41)delta(185-243)]
      formed discoidal HDL. The findings suggest that although the central helices of
      apoA-I alone can promote ABCA1-mediated lipid efflux, residues 220-231 are
      necessary to allow functional interactions between the full-length apoA-I and
      ABCA1 that are required for lipid efflux and HDL biogenesis.

PMID- 12488455
TI  - Na+ promotes the dissociation between Galpha GDP and Gbeta gamma, activating G
      protein-gated K+ channels.
AB  - G protein-gated K(+) channels (GIRK, or Kir3) are activated by the direct binding
      of Gbetagamma or of cytosolic Na(+). Na(+) activation is fast, Gbetagamma
      independent, and probably via a direct, low affinity (EC(50), 30-40 mm) binding
      of Na(+) to the channel. Here we demonstrate that an increase in intracellular
      Na(+) concentration, [Na(+)](in), within the physiological range (5-20 mm),
      activates GIRK within minutes via an additional, slow mechanism. The slow
      activation is observed in GIRK mutants lacking the direct Na(+) effect. It is
      inhibited by a Gbetagamma scavenger, hence it is Gbetagamma-dependent; but it
      does not require GTP. We hypothesized that Na(+) elevates the cellular
      concentration of free Gbetagamma by promoting the dissociation of the
      Galphabetagamma heterotrimer into free Galpha(GDP) and Gbetagamma. Direct
      biochemical measurements showed that Na(+) causes a moderate decrease
      (approximately 2-fold) in the affinity of interaction between Galpha(GDP) and
      Gbetagamma. Furthermore, in accord with the predictions of our model, slow Na(+)
      activation was enhanced by mild coexpression of Galpha(i3). Our findings reveal a
      previously unknown mechanism of regulation of G proteins and demonstrate a novel
      Gbetagamma-dependent regulation of GIRK by Na(+). We propose that Na(+) may act
      as a regulatory factor, or even a second messenger, that regulates effectors via
      Gbetagamma.

PMID- 12488456
TI  - The co-activator p300 associates physically with and can mediate the action of
      the distal enhancer of the FGF-4 gene.
AB  - Distal enhancers commonly regulate gene expression. However, the mechanisms of
      transcriptional mediation by distal enhancers remain largely unknown. To better
      understand distal enhancer-mediated transcription, we examined the regulation of
      the FGF-4 gene. The FGF-4 gene is regulated during early development by a
      powerful distal enhancer located downstream of the promoter in exon 3. Sox-2 and
      Oct-3 bind to the enhancer and are required for the activation of the FGF-4 gene.
      Previously, we implicated the co-activator p300 as a mediator of Sox-2/Oct-3
      synergistic activation of a heterologous promoter, suggesting that p300 may play
      a role in mediating enhancer activation of the FGF-4 gene. In this study, we
      provide both functional and physical evidence that p300 plays an important role
      in the action of the FGF-4 enhancer. Specifically, we show that E1a, but not a
      mutant form of E1a that is unable to bind p300, inhibits enhancer activation of
      the FGF-4 promoter. We also demonstrate that Gal4/p300 fusion proteins can
      stimulate the FGF-4 promoter when bound to the FGF-4 enhancer. Additionally, we
      present evidence that p300 mediation of the FGF-4 enhancer requires
      acetyltransferase activity. Importantly, we also show that Sox-2 and p300 are
      physically associated with the endogenous FGF-4 enhancer but weakly associated
      with the endogenous FGF-4 promoter. These results are consistent with a model of
      transitory interaction between the distal enhancer and the FGF-4 promoter. Our
      results also suggest that intragenic distal enhancers may use mechanisms that
      differ from extragenic distal enhancers.

PMID- 12488457
TI  - Regulation of lipocalin-type prostaglandin D synthase gene expression by Hes-1
      through E-box and interleukin-1 beta via two NF-kappa B elements in rat
      leptomeningeal cells.
AB  - The promoter function of the rat lipocalin-type prostaglandin D synthase (L-PGDS)
      gene was characterized in primary cultures of leptomeningeal cells prepared from
      the neonatal rat brain. Luciferase reporter assays with deletion and site
      directed mutation of the promoter region (-1250 to +77) showed that an AP-2
      element at -109 was required for activation and an E-box at +57, for repression.
      Binding of nuclear factors to each of these cis-elements was demonstrated by an
      electrophoretic mobility shift assay. Several components of the Notch-Hes
      signaling pathway, Jagged, Notch1, Notch3, and Hes-1, were expressed in the
      leptomeningeal cells. Human Hes-1 co-expressed in the leptomeningeal cells bound
      to the E-box of the rat L-PGDS gene, and repressed the promoter activity of the
      rat L-PGDS gene in a dose-dependent manner. The L-PGDS gene expression was up
      regulated slowly by interleukin-1 beta to the maximum level at 24 h. The reporter
      assay with deletion and mutation revealed that two NF-kappa B elements at -1106
      and -291 were essential for this up-regulation. Binding of two NF-kappa B
      subunits, p65 and c-Rel, to these two NF-kappa B elements occurred after the
      interleukin-1 beta treatment. Therefore, the L-PGDS gene is the first gene
      identified as the target for the Notch-Hes signal through the E-box among a
      variety of genes involved in the prostanoid biosynthesis, classified to the
      lipocalin family, and expressed in the leptomeninges. Moreover, the L-PGDS gene
      is a unique gene that is activated slowly by the NF-kappa B system.

PMID- 12488458
TI  - Characterization of the transforming growth factor-beta 1-induced apoptotic
      transcriptome in FaO hepatoma cells.
AB  - We have previously shown that transforming growth factor-beta(1) (TGF-beta(1))
      induced apoptosis in FaO hepatoma cells is mediated by cytochrome c release,
      apoptosome formation, and caspase activation. Although TGF-beta(1) acts via the
      SMAD signaling pathway to initiate de novo gene transcription, little is known
      about the downstream gene targets that are involved in the regulation of
      apoptosis. Therefore, in this study, we used in-house microarrays (approximately
      5500 genes) to identify pathway-specific gene clustering in TGF-beta(1)-treated
      cells. A total of 142 genes showed time-dependent changes in expression during
      TGF-beta(1)-induced apoptosis. The polycaspase inhibitor benzyloxycarbonyl-VAD
      fluoromethyl ketone, which, on its own, had no effect on gene transcription,
      blocked TGF-beta(1)-induced cell death and significantly altered the expression
      of 261 genes, including 185 down-regulated genes. Cluster analysis identified up
      regulation of early response genes (0-4 h) encoding for the extracellular matrix
      and cytoskeleton, including the pro-apoptotic CTGF gene, and delayed response
      genes (8-16 h), including pro-apoptotic genes. A second delayed response cluster
      (44 genes) was also observed when TGF-beta(1)-induced caspase activation was
      blocked by benzyloxycarbonyl-VAD-fluoromethyl ketone. This cluster included genes
      encoding stress-related proteins (e.g. Jun, ATF3, TAB1, and TANK), suggesting
      that their up-regulation may be in response to secondary necrosis. Finally, we
      identified an early response set of nine down-regulated genes that are involved
      in antioxidant defense. We propose that the regulation of these genes by TGF
      beta(1) could provide a molecular mechanism for the observed elevation in
      reactive oxygen species after TGF-beta(1) treatment and may represent the primary
      mechanism through which TGF-beta(1) initiates apoptosis.

PMID- 12488459
TI  - Myristoyl-CoA:protein N-myristoyltransferase, an essential enzyme and potential
      drug target in kinetoplastid parasites.
AB  - Co-translational modification of eukaryotic proteins by N-myristoylation aids
      subcellular targeting and protein-protein interactions. The enzyme that catalyzes
      this process, N-myristoyltransferase (NMT), has been characterized in the
      kinetoplastid protozoan parasites, Leishmania and Trypanosoma brucei. In
      Leishmania major, the single copy NMT gene is constitutively expressed in all
      parasite stages as a 48.5-kDa protein that localizes to both membrane and
      cytoplasmic fractions. Leishmania NMT myristoylates the target acylated
      Leishmania protein, HASPA, when both are co-expressed in Escherichia coli. Gene
      targeting experiments have shown that NMT activity is essential for viability in
      Leishmania. In addition, overexpression of NMT causes gross changes in parasite
      morphology, including the subcellular accumulation of lipids, leading to cell
      death. This phenotype is more extreme than that observed in Saccharomyces
      cerevisiae, in which overexpression of NMT activity has no obvious effects on
      growth kinetics or cell morphology. RNA interference assays in T. brucei have
      confirmed that NMT is also an essential protein in both life cycle stages of this
      second kinetoplastid species, suggesting that this enzyme may be an appropriate
      target for the development of anti-parasitic agents.

PMID- 12488460
TI  - Biosynthesis, glycosylation, and enzymatic processing in vivo of human
      tripeptidyl-peptidase I.
AB  - Human tripeptidyl-peptidase I (TPP I, CLN2 protein) is a lysosomal serine
      protease that removes tripeptides from the free N termini of small polypeptides
      and also shows a minor endoprotease activity. Due to various naturally occurring
      mutations, an inherited deficiency of TPP I activity causes a fatal lysosomal
      storage disorder, classic late infantile neuronal ceroid lipofuscinosis (CLN2).
      In the present study, we analyzed biosynthesis, glycosylation, transport, and
      proteolytic processing of this enzyme in stably transfected Chinese hamster ovary
      cells as well as maturation of the endocytosed proenzyme in CLN2 lymphoblasts,
      fibroblasts, and N2a cells. Human TPP I was initially identified as a single
      precursor polypeptide of approximately 68 kDa, which, within a few hours, was
      converted to the mature enzyme of approximately 48 kDa. Compounds affecting the
      pH of intracellular acidic compartments, those interfering with the intracellular
      vesicular transport as well as inhibition of the fusion between late endosomes
      and lysosomes by temperature block or 3-methyladenine, hampered the conversion of
      TPP I proenzyme into the mature form, suggesting that this process takes place in
      lysosomal compartments. Digestion of immunoprecipitated TPP I proenzyme with both
      N-glycosidase F and endoglycosidase H as well as treatment of the cells with
      tunicamycin reduced the molecular mass of TPP I proenzyme by approximately 10
      kDa, which indicates that all five potential N-glycosylation sites in TPP I are
      utilized. Mature TPP I was found to be partially resistant to endo H treatment;
      thus, some of its N-linked oligosaccharides are of the complex/hybrid type.
      Analysis of the effect of various classes of protease inhibitors and mutation of
      the active site Ser(475) on human TPP I maturation in cultured cells demonstrated
      that although TPP I zymogen is capable of autoactivation in vitro, a serine
      protease that is sensitive to AEBSF participates in processing of the proenzyme
      to the mature, active form in vivo.

PMID- 12488461
TI  - The human plasma proteome: history, character, and diagnostic prospects.
AB  - The human plasma proteome holds the promise of a revolution in disease diagnosis
      and therapeutic monitoring provided that major challenges in proteomics and
      related disciplines can be addressed. Plasma is not only the primary clinical
      specimen but also represents the largest and deepest version of the human
      proteome present in any sample: in addition to the classical "plasma proteins,"
      it contains all tissue proteins (as leakage markers) plus very numerous distinct
      immunoglobulin sequences, and it has an extraordinary dynamic range in that more
      than 10 orders of magnitude in concentration separate albumin and the rarest
      proteins now measured clinically. Although the restricted dynamic range of
      conventional proteomic technology (two-dimensional gels and mass spectrometry)
      has limited its contribution to the list of 289 proteins (tabulated here) that
      have been reported in plasma to date, very recent advances in multidimensional
      survey techniques promise at least double this number in the near future.
      Abundant scientific evidence, from proteomics and other disciplines, suggests
      that among these are proteins whose abundances and structures change in ways
      indicative of many, if not most, human diseases. Nevertheless, only a handful of
      proteins are currently used in routine clinical diagnosis, and the rate of
      introduction of new protein tests approved by the United States Food and Drug
      Administration (FDA) has paradoxically declined over the last decade to less than
      one new protein diagnostic marker per year. We speculate on the reasons behind
      this large discrepancy between the expectations arising from proteomics and the
      realities of clinical diagnostics and suggest approaches by which protein-disease
      associations may be more effectively translated into diagnostic tools in the
      future.

PMID- 12488462
TI  - Structural models of osteogenesis imperfecta-associated variants in the COL1A1
      gene.
AB  - Osteogenesis imperfecta (OI) is a genetic disease in which the most common
      mutations result in substitutions for glycine residues in the triple helical
      domain of the chains of type I collagen. Currently there is no way to use
      sequence information to predict the clinical OI phenotype. However, structural
      models coupled with biophysical and machine learning methods may be able to
      predict sequences that, when mutated, would be associated with more severe forms
      of OI. To build appropriate structural models, we have applied a high throughput
      molecular dynamic approach. Homotrimeric peptides covering 57 positions in which
      mutations are associated with OI were simulated both with and without mutations.
      Our models revealed structural differences that occur with different substituting
      amino acids. When mutations were introduced, we observed a decrease in helix
      stability, as caused by fewer main chain backbone hydrogen bonds, and an increase
      in main chain root mean square deviation and specifically bound water molecules.

PMID- 12488463
TI  - Changes in the proteome associated with the action of Bcr-Abl tyrosine kinase are
      not related to transcriptional regulation.
AB  - Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease, the hallmark
      of which is the Bcr-Abl protein tyrosine kinase (PTK). Without intervention the
      disease progresses from a benign chronic phase to a rapidly fatal blast crisis.
      To identify the molecular mechanisms underlying disease progression we used two
      dimensional gel electrophoresis on a model we have previously described using the
      expression of a conditional mutant of Bcr-Abl PTK in a multipotent stem cell
      line, FDCP-Mix. Long term exposure of FDCP-Mix cells to Bcr-Abl mimics disease
      progression in CML. Four major differences were observed as a consequence of long
      term exposure to the Bcr-Abl PTK compared with cells exposed short term. The
      proteins were identified using matrix-assisted laser desorption ionization-time
      of flight mass spectrometry-generated peptide mass fingerprint data and liquid
      chromatography-tandem mass spectrometry-generated sequence information.
      Leukotriene A4 hydrolase, an enzyme known to be deregulated in CML, was found to
      be up-regulated. Annexin VI, vacuolar ATP synthase catalytic subunit A, and
      mortalin were found to be down-regulated. Poly(A) PCR cDNA analysis showed there
      was no correlation between the protein expression changes and mRNA levels.
      Western blot analysis also indicated no change in the levels of mortalin or
      leukotriene A4 hydrolase, indicating that post-translational events may modify
      protein content of the specific spots. Leukotriene B4 levels (product of
      leukotriene A4 hydrolase) were, however, reduced in cells exposed long term to
      Bcr-Abl activity. This study demonstrates the potential of proteomic analysis to
      define novel effects of oncogenes.

PMID- 12488464
TI  - Attomole detection of in vivo protein targets of benzene in mice: evidence for a
      highly reactive metabolite.
AB  - Modified proteins were detected in liver and bone marrow of mice following
      treatment with [(14)C]benzene. Stained sections were excised from one-dimensional
      and two-dimensional gels and converted to graphite to enable (14)C/(13)C ratios
      to be measured by accelerator mass spectrometry. Protein adducts of benzene or
      its metabolites were indicated by elevated levels of (14)C. A number of proteins
      were identified by in-gel proteolysis and conventional mass spectrometric methods
      with the low molecular weight proteins identified including hemoglobin and
      several histones. The incorporation of (14)C was largely proportional to the
      density of gel staining, giving little evidence that these proteins were specific
      targets for selective labeling. This was also true for individual histones
      subfractionated with Triton-acid-urea gels. A representative histone, H4, was
      isolated and digested with endopeptidase Asp-N, and the resulting peptides were
      separated by high performance liquid chromatography. (14)C levels in collected
      fractions were determined, and the peptides were identified by conventional mass
      spectrometry. The modifications were distributed throughout the protein, and no
      particular amino acids or groups of amino acids were identified as selective
      targets. Thus chemical attack by one or more benzene metabolites upon histones
      was identified and confirmed, but the resulting modifications appeared to be
      largely nonspecific. This implies high reactivity toward proteins, enabling such
      attack to occur at multiple sites within multiple targets. It is not known to
      what extent, if any, the modification of the core histones may contribute to the
      carcinogenicity of benzene.

PMID- 12488465
TI  - Chromatographic isolation of methionine-containing peptides for gel-free proteome
      analysis: identification of more than 800 Escherichia coli proteins.
AB  - A novel gel-free proteomic technology was used to identify more than 800 proteins
      from 50 million Escherichia coli K12 cells in a single analysis. A peptide
      mixture is first obtained from a total unfractionated cell lysate, and only the
      methionine-containing peptides are isolated and identified by mass spectrometry
      and database searching. The sorting procedure is based on the concept of diagonal
      chromatography but adapted for highly complex mixtures. Statistical analysis
      predicts that we have identified more than 40% of the expressed proteome,
      including soluble and membrane-bound proteins. Next to highly abundant proteins,
      we also detected low copy number components such as the E. coli lactose operon
      repressor, illustrating the high dynamic range. The method is about 100 times
      more sensitive than two-dimensional gel-based methods and is fully automated. The
      strongest point, however, is the flexibility in the peptide sorting chemistry,
      which may target the technique toward quantitative proteomics of virtually every
      class of peptides containing modifiable amino acids, such as phosphopeptides,
      amino-terminal peptides, etc., adding a new dimension to future proteome
      research.

PMID- 12488466
TI  - A new method to estimate ligand-receptor energetics.
AB  - In the discovery of new drugs, lead identification and optimization have assumed
      critical importance given the number of drug targets generated from genetic,
      genomics, and proteomic technologies. High-throughput experimental screening
      assays have been complemented recently by "virtual screening" approaches to
      identify and filter potential ligands when the characteristics of a target
      receptor structure of interest are known. Virtual screening mandates a reliable
      procedure for automatic ranking of structurally distinct ligands in compound
      library databases. Computing a rank score requires the accurate prediction of
      binding affinities between these ligands and the target. Many current scoring
      strategies require information about the target three-dimensional structure. In
      this study, a new method to estimate the free binding energy between a ligand and
      receptor is proposed. We extend a central idea previously reported (Bock, J. R.,
      and Gough, D. A. (2001) Predicting protein-protein interactions from primary
      structure. Bioinformatics 17, 455-460; Bock, J. R., and Gough, D. A. (2002) Whole
      proteome interaction mining. Bioinformatics, in press) that uses simple
      descriptors to represent biomolecules as input examples to train a support vector
      machine (Smola, A. J., and Scholkopf, B. (1998) A Tutorial on Support Vector
      Regression, Neuro-COLT Technical Report NC-TR-98-030, Royal Holloway College,
      University of London, UK) and the application of the trained system to previously
      unseen pairs, estimating their propensity for interaction. Here we seek to learn
      the function that maps features of a receptor-ligand pair onto their equilibrium
      free binding energy. These features do not comprise any direct information about
      the three-dimensional structures of ligand or target. In cross-validation
      experiments, it is demonstrated that objective measurements of prediction error
      rate and rank-ordering statistics are competitive with those of several other
      investigations, most of which depend on three-dimensional structural data. The
      size of the sample (n = 2,671) indicates that this approach is robust and may
      have widespread applicability beyond restricted families of receptor types. It is
      concluded that newly sequenced proteins, or those for which three-dimensional
      crystal structures are not easily obtained, can be rapidly analyzed for their
      binding potential against a library of ligands using this methodology.

PMID- 12488467
TI  - Ethical significance of ethics-related empirical research.

PMID- 12488468
TI  - Body surface area in dosing anticancer agents: scratch the surface!

PMID- 12488469
TI  - Erbitux trial flawed from the beginning, committee finds.

PMID- 12488471
TI  - Guilt by association? Some cancer epidemiology favorites.

PMID- 12488472
TI  - Designer molecule may lead to new treatments for ocular cancers.

PMID- 12488473
TI  - Incidence of cancers of the eye and orbit, 1995-1999.

PMID- 12488474
TI  - RNA-based therapy unlocks drugs within cancer cells.

PMID- 12488476
TI  - New associations of human papillomavirus, Simian virus 40, and Epstein-Barr virus
      with human cancer.

PMID- 12488477
TI  - Cancer screening practices from National Health Interview Surveys: past, present,
      and future.
AB  - The National Health Interview Survey (NHIS) has provided data about health
      behaviors at the national level since 1957. The 1987 and 1992 Cancer Control
      Supplements to the NHIS, along with other supplemental surveys administered
      intermittently on self-reported cancer-related behaviors, have contributed to
      important research and public health purposes. In this article, we reviewed 73
      papers published between 1980 and 2001 that used NHIS data, including the first
      report from the 1998 NHIS, to examine what has been learned from past surveys.
      Our goal was to facilitate future analyses of recently released data on cancer
      screening practices from the Cancer Control Supplement to the 2000 NHIS, which is
      now known as the Cancer Control Module. We categorized the papers according to
      which of the following three study approaches they used: trends in screening
      rates, correlates of these rates with factors that may influence screening, and
      linkages or comparisons of NHIS data with other surveys or sources of
      information. We summarize knowledge gained in cancer screening for each of these
      three categories and identify areas that could benefit from more research. We
      highlight some of the new information available for the first time on the Cancer
      Control Module of the 2000 NHIS as fresh opportunities for cancer control
      research. Finally, we describe how the Cancer Control Supplements to the NHIS are
      integrated with the objectives of and developments in national cancer
      surveillance research that have emerged from federal planning efforts and
      collaborations with national partners in cancer surveillance in recent years.

PMID- 12488478
TI  - Views of American oncologists about the purposes of clinical trials.
AB  - BACKGROUND: Many research subjects believe incorrectly that the primary purpose
      of clinical trials is to benefit the participants rather than to improve therapy
      for future patients. However, few data are available about how physicians view
      trials. METHODS: We mailed surveys to a stratified random sample (n = 1120) of
      U.S. medical, pediatric, and other oncology specialists who were selected from
      the American Society of Clinical Oncology Membership Directory. Respondents were
      asked to select, from a list of options, their reasons for enrolling individual
      patients in trials and what they thought the main societal purposes of clinical
      trials are. We used logistic regression models to evaluate which demographic and
      clinical practice characteristics were associated with responses to these
      questions. All statistical tests were two-sided. RESULTS: Of the 547 physicians
      (48.8%) who responded, 40.5% of the medical oncologists, 32.3% of the pediatric
      oncologists, and 62.6% of the other oncology subspecialists reported enrolling
      individual patients in clinical trials to improve future therapy. Most of the
      other respondents reported enrolling patients to ensure that they received state
      of-the-art treatment. When asked about the main societal purpose of clinical
      trials, 72.7% of the medical oncologists, 59.4% of the pediatric oncologists, and
      81.9% of the other oncology subspecialists cited improving future therapy; most
      of the other respondents cited ensuring state-of-the-art treatment for
      participants. In multivariable analysis, medical oncologists (odds ratio [OR] =
      0.6, 95% confidence interval [CI] = 0.3 to 0.9) and pediatric oncologists (OR =
      0.3, 95% CI = 0.2 to 0.5) were less likely than other oncologists to identify
      improving future therapy as the main societal purpose of clinical trials, whereas
      industry physicians (OR = 4.6, 95% CI = 1.1 to 20.5) chose this option more often
      than physicians who did not work for industry. CONCLUSIONS: Many respondents
      viewed the main societal purpose of clinical trials as benefiting the
      participants rather than as creating generalizable knowledge to advance future
      therapy. This view, which was more prevalent among specialists such as pediatric
      oncologists that enrolled greater proportions of patients in trials, conflicts
      with established principles of research ethics.

PMID- 12488479
TI  - Inhibition of human cancer cell growth and metastasis in nude mice by oral intake
      of modified citrus pectin.
AB  - BACKGROUND: The role of dietary components in cancer progression and metastasis
      is an emerging field of clinical importance. Many stages of cancer progression
      involve carbohydrate-mediated recognition processes. We therefore studied the
      effects of high pH- and temperature-modified citrus pectin (MCP), a
      nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that
      specifically inhibits the carbohydrate-binding protein galectin-3, on tumor
      growth and metastasis in vivo and on galectin-3-mediated functions in vitro.
      METHODS: In vivo tumor growth, angiogenesis, and metastasis were studied in
      athymic mice that had been fed with MCP in their drinking water and then injected
      orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary
      fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum.
      Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by
      assessing the effect of MCP on capillary tube formation by human umbilical vein
      endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin-3-induced
      HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied
      using Boyden chamber and labeling assays, respectively. The data were analyzed by
      two-sided Student's t test or Fisher's protected least-significant-difference
      test. RESULTS: Tumor growth, angiogenesis, and spontaneous metastasis in vivo
      were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited
      HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In
      vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of
      0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 micro g/mL) to HUVECs
      by 72.1% (P =.038) and 95.8% (P =.025), respectively, and at a concentration of
      0.25% it inhibited the binding of galectin-3 (1 micro g/mL) to HUVECs by 100% (P
      =.032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent
      manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at
      0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which
      express galectin-3, to HUVECs in a dose-dependent manner. CONCLUSIONS: MCP, given
      orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis
      in vivo, presumably via its effects on galectin-3 function. These data stress the
      importance of dietary carbohydrate compounds as agents for the prevention and/or
      treatment of cancer.

PMID- 12488480
TI  - Effect of RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle
      formation in human cancer cells.
AB  - BACKGROUND: Expression of polo-like kinase-1 (PLK1), which has several functions
      in mitotic progression, is elevated in a broad range of human tumors. To
      investigate the role of PLK1 in neoplastic proliferation, we used the technique
      of RNA interference. METHODS: Cells from several different cancer cell lines (MCF
      7 breast cancer cells, HeLa S3 cervical cancer cells, SW-480 colon cancer cells,
      and A549 lung cancer cells) were transfected with small interfering (si) RNAs
      targeted against the human PLK1 or lamin genes. Northern and western blot
      analyses were used to examine PLK1 gene expression in transfected cancer cells
      and normal cells (human mammary epithelial cells [HMECs]). The phenotype,
      proliferation, and cell cycle distribution of cells transfected with siRNAs were
      also monitored by fluorescence microscopy and fluorescence-activated cell sorting
      analysis. RESULTS: All cancer cell lines transfected with low doses of siRNAs
      targeted to PLK1 had greatly decreased levels of PLK1 mRNA and protein. siRNA4,
      which had the strongest inhibitory effect, reduced PLK1 mRNA in MCF-7 cells by
      70% and PLK1 protein in MCF-7 cells by 95% 24 hours after transfection. Cell
      proliferation was reduced by between 66% and 99% 48 hours after transfection, and
      apoptosis was increased from 1%-5% to 13%-50% in transfected cells. Transfected
      SW-480 cells were mitotically arrested, and their centrosomes had lost the
      ability to nucleate microtubules. HMECs took up siRNAs less efficiently than
      cancer cells, and transfection with siRNAs targeted to PLK1 did not inhibit their
      proliferation. CONCLUSIONS: PLK1 function appears to be essential for centrosome
      mediated microtubule events and, consequently, for spindle assembly. siRNAs
      targeted against human PLK1 may be valuable tools as antiproliferative agents
      that display activity against a broad spectrum of neoplastic cells at very low
      doses.

PMID- 12488481
TI  - Alcohol consumption and risk of lung cancer: the Framingham Study.
AB  - BACKGROUND: Reports on the association between alcohol consumption and the risk
      of lung cancer have been inconsistent. The purpose of this study was to assess
      this association in a cohort study. METHODS: This study included 4265
      participants in the original population-based Framingham Study cohort and 4973
      subjects in the offspring cohort. Alcohol consumption data were collected
      periodically for both cohorts. We used the risk sets method to match control
      subjects to each case patient based on age, sex, smoking variables, and year of
      birth. We used a conditional logistic regression model to estimate the relative
      risk of lung cancer according to alcohol consumption. RESULTS: Alcohol
      consumption was generally light to moderate (i.e., <12 g/day) in both cohorts.
      During mean follow-ups of 32.8 years in the original and 16.2 years in the
      offspring cohorts, 269 cases of lung cancer occurred. In categories of total
      alcohol consumption of 0, 0.1-12, 12.1-24, and greater than 24 g/day, the crude
      incidence rates of lung cancer were 7.4, 13.6, 16.4, and 25.2 cases per 10 000
      person-years, respectively, in the original cohort and 6.6, 4.3, 7.9, and 12.3
      cases per 10 000 person-years, respectively, in the offspring cohort. However,
      after adjustment for age, sex, pack-years of smoking, smoking status, and year of
      birth in a multivariable conditional logistic regression model, relative risks
      for lung cancer from the lowest to the highest category of alcohol consumption
      were 1.0 (referent), 1.0 (95% confidence interval [CI] = 0.5 to 2.1), 1.0 (95% CI
      = 0.5 to 2.3), and 1.1 (95% CI = 0.5 to 2.3), respectively, in the original
      cohort and 1.0, 1.4 (95% CI = 0.5 to 3.6), 1.1 (95% CI = 0.3 to 3.6), and 2.0
      (95% CI = 0.7 to 5.7), respectively, in the offspring cohort. CONCLUSION: Alcohol
      consumption among subjects in the Framingham Study, most of whom were light to
      moderate drinkers, was not statistically significantly associated with the risk
      of lung cancer.

PMID- 12488482
TI  - Role of body surface area in dosing of investigational anticancer agents in
      adults, 1991-2001.
AB  - The prescribed dose of anticancer agents is most commonly calculated using body
      surface area as the only independent variable, and it has been shown that this
      approach still results in large interpatient variability in drug exposure. Here,
      we retrospectively assessed the pharmacokinetics of 33 investigational agents
      tested in phase I trials from 1991 through 2001, as a function of body surface
      area in 1650 adult cancer patients. Twelve of the drugs were administered orally,
      19 were administered intravenously, and two were administered by both routes.
      Body surface area-based dosing was statistically significantly associated with a
      reduction in interpatient variability in drug clearance for only five of the 33
      agents: docosahexaenoic acid (DHA)-paclitaxel, 5-fluorouracil/eniluracil,
      paclitaxel, temozolomide, and troxacitabine. These results do not support the use
      of body surface area in dose calculations and suggest that alternate dosing
      strategies should be evaluated. We conclude that body surface area should not be
      used to determine starting doses of investigational agents in future phase I
      studies.

PMID- 12488483
TI  - Inorganic arsenite-induced malignant transformation of human prostate epithelial
      cells.
AB  - Although several epidemiologic studies show an association between arsenic
      exposure and prostate cancer, it is still unknown whether human prostate
      epithelial cells are directly susceptible to arsenic-induced transformation. This
      study was designed to determine whether the nontumorigenic human prostate
      epithelial cell line RWPE-1 could be malignantly transformed in vitro by
      arsenite. RWPE-1 cells were continuously exposed to 5 micro M arsenite and
      monitored for signs of transformation, assessed as changes in matrix
      metalloproteinase-9 levels. After 29 weeks of exposure, the arsenite-exposed RWPE
      1 cells (referred to as CAsE-PE) showed a marked increase in matrix
      metalloproteinase-9 secretion, a common finding in prostate malignancies.
      Malignant transformation was confirmed when CAsE-PE cells produced aggressive
      undifferentiated malignant epithelial tumors in nude mice. The tumors stained
      positive for human prostate-specific antigen, confirming their origin. These
      results are the first report of arsenite-induced malignant transformation of a
      human epithelial cell line and provide an important in vitro model for studying
      the mechanisms underlying arsenic-induced carcinogenesis in humans.

PMID- 12488484
TI  - Re: Risk of subsequent cancer following breast cancer in men.

PMID- 12488486
TI  - Re: Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors
      of advanced-stage prostate cancer.

PMID- 12488488
TI  - The immune system and prion diseases: a relationship of complicity and blindness.
AB  - In most documented infectious forms of transmissible spongiform encephalopathies,
      prions must transit through the lymphoreticular compartment before invading the
      central nervous system. A major goal has been to identify the cell susbsets that
      support replication and propagation of prions from sites of penetration to sites
      of neuroinvasion. The conclusions, still fragmentary and confusing, point at a
      few candidates: follicular dendritic cells (FDCs) and more recently, dendritic
      cells (DCs). It is clear, however, that lymphoinvasion does not depend on a
      single-cell type but needs a coordinated network of cells. Discrepancies between
      models suggest that the actors may vary according to prion strains. A second
      center of interest has emerged following reports that anti-prion protein (PrP)
      antibodies blocked in vitro cell conversion of normal PrP into pathological PrP
      and cured infected cell lines. As isoform conversion is a critical event in prion
      propagation and formation of lesions, the identification of immune agents capable
      of inhibiting the reaction is of major importance. In vivo experiments suggest
      that antibodies produced in transgenic mice or an ongoing immune reaction induced
      by peptides can prevent PrP conversion and retard disease progression. These
      results do not say whether clinical disease can be durably delayed and if
      immunological tolerance to PrP can be easily broken in infected individuals.
      Altogether, these results suggest that the unconventional relationship between
      prions and the immune system is on the eve of new and fascinating developments.
      Whether they will provide innovative strategies for early diagnosis and
      preventive treatments is still an open question.

PMID- 12488489
TI  - HMGB1 as a DNA-binding cytokine.
AB  - HMGB1 (high mobility group box chromosomal protein 1), historically known as an
      abundant, nonhistone architectural chromosomal protein, is extremely conserved
      across species. As a nuclear protein, HMGB1 stabilizes nucleosomes and allows
      bending of DNA that facilitates gene transcription. Unexpectedly, recent studies
      identified extracellular HMGB1 as a potent macrophage-activating factor,
      signaling via the receptor for advanced glycation end-products to induce
      inflammatory responses. It is released as a late mediator during inflammation and
      participates in the pathogenesis of systemic inflammation after the early
      mediator response has resolved. HMGB1 occupies a critical role as a
      proinflammatory mediator passively released by necrotic but not apoptotic cells.
      Necrotic Hmgb1(-/-) cells mediate minimal inflammatory responses. Stimulated
      macrophages actively secrete HMGB1 to promote inflammation and in turn, stimulate
      production of multiple, proinflammatory cytokines. HMGB1 mediates endotoxin
      lethality, acute lung injury, arthritis induction, activation of macrophages,
      smooth muscle cell chemotaxis, and epithelial cell barrier dysfunction. HMGB1 is
      structurally composed of three different domains: two homologous DNA-binding
      sequences entitled box A and box B and a highly, negatively charged C terminus.
      The B box domain contains the proinflammatory cytokine functionality of the
      molecule, whereas the A box region has an antagonistic, anti-inflammatory effect
      with therapeutic potential. Administration of highly purified, recombinant A box
      protein or neutralizing antibodies against HMGB1 rescued mice from lethal sepsis,
      even when initial treatment was delayed for 24 h after the onset of infection,
      establishing a clinically relevant therapeutic window that is significantly wider
      than for other known cytokines.

PMID- 12488490
TI  - Signal transduction during Fc receptor-mediated phagocytosis.
AB  - Phagocytosis is the process whereby cells engulf large particles, usually over
      0.5 micro m in diameter. Phagocytosis is triggered by the interaction of opsonins
      that cover the particle to be internalized with specific receptors on the surface
      of the phagocyte. The best-studied phagocytic receptors include the Fc receptors
      (FcR) that bind to the Fc portion of immunoglobulins. Cross-linking of FcR on the
      phagocyte initiates a variety of signals, which lead through the reorganization
      of the actin cytoskeleton, and membrane remodeling, to the formation of the
      phagosome. From recent data, it is becoming clear that FcR-mediated phagocytosis
      occurs as a series of steps that are regulated in a nonlinear manner and that
      signaling for phagocytosis does not terminate when the phagosome is formed.
      Several lipid molecules localize around the nascent phagosome and function as
      initiators of important signaling pathways for the late stages of phagolysosome
      formation. In addition, the use of particular signaling molecules may change for
      different receptors and may also vary depending on the activation or
      differentiation state of the cell. This review focuses on this new information
      and presents a model of our present understanding of the signal transduction
      events that regulate phagocytosis mediated by FcR.

PMID- 12488491
TI  - Chronic ethanol consumption by mice results in activated splenic T cells.
AB  - Previous studies have shown that T cells from human alcoholics overexpress
      activation or memory markers such as human leukocyte antigen-DR, CD45RO, CD57,
      and CD11b and may have reduced levels of CD62L. In those studies, we demonstrated
      that the increased CD57(+) T cell population rapidly produces interferon-gamma
      (IFN-gamma) and tumor necrosis factor alpha, independent of a second signal
      requirement, consistent with an increased effector T cell population. In contrast
      to the length of alcohol abuse by human alcoholics, most work with mice has
      involved 2-week ethanol exposures or less, which result in decreased IFN-gamma
      responses. In the present work, we have evaluated C57Bl/6 or BALB/c mice, which
      were administered 20% w/v ethanol in water for 3-13 weeks. In these mice, rapid
      cytoplasmic IFN-gamma expression by T cells after stimulation through the T cell
      receptor was significantly increased versus normals. Studies of surface
      activation markers showed that T cells from chronically ethanol-fed mice had
      reduced CD62L expression and an increased percentage of CD44(hi) T cells. The
      CD44(hi) subset was largely second signal-independent for secreted IFN-gamma and
      interleukin (IL)-4 production at early times after stimulation. The enriched T
      cells of chronic ethanol mice secreted more IFN-gamma and IL-4 than controls and
      equivalent IL-2 at early times after stimulation (6-24 h). The overall results
      support the concept that in humans and mice, chronic alcohol exposure of
      sufficient duration results in T cell activation or sensitization in vivo and an
      increased percentage of the effector/memory subset.

PMID- 12488492
TI  - Diminution of experimental autoimmune uveoretinitis (EAU) in mice depleted of NK
      cells.
AB  - To evaluate the potential role of NK1.1 (CD161c) cells in autoimmune
      uveoretinitis, we treated experimental autoimmune uveoretinitis (EAU)-susceptible
      mice with anti-CD161c antibodies (PK136) to deplete natural killer (NK) cells.
      Injection of anti-CD161c antibodies deleted NK cells from the peripheral blood of
      EAU-susceptible mice. The T cell proliferative response against the ocular
      autoantigen K2 was not suppressed in mice treated with anti-CD161c antibody when
      compared with T cells from control mice. Although mice treated with anti-CD161c
      developed EAU, the clinical severity on days 17 and 19 after induction of EAU was
      significantly mild in anti-CD161c-treated mice compared with control mice. In
      addition, the histopathological severity of EAU was significantly milder in mice
      treated with anti-CD161c antibodies than controls 21 days after induction of EAU.
      Our results indicate that the severity of EAU is augmented by NK1.1(+) NK cells.

PMID- 12488493
TI  - Acute mast cell-dependent neutrophil recruitment in the skin is mediated by KC
      and LFA-1: inhibitory mechanisms of dexamethasone.
AB  - This study examined adhesive and signaling pathways and anti-inflammatory
      mechanisms of dexamethasone in acute mast cell-dependent neutrophil recruitment
      in the skin in mice. Mast cell activation dose- and time-dependently triggered
      influx of predominately neutrophils and secretion of cytokine-induced neutrophil
      chemoattractant (KC). Neutralization of KC attenuated neutrophil recruitment upon
      mast cell activation. Mast cell activation- and KC-induced neutrophil responses
      were significantly decreased in lymphocyte function-associated antigen-1 (LFA-1)
      deficient mice. Dexamethasone inhibited neutrophil accumulation elicited by mast
      cell activation. It is interesting that dexamethasone significantly reduced the
      mast cell-dependent secretion of KC, whereas neutrophil recruitment induced by
      exogenous KC was insensitive to dexamethasone treatment. Thus, KC is a
      fundamental mediator of neutrophil recruitment in acute mast cell-dependent skin
      inflammation, and mast cell activation- and KC-induced neutrophil responses are
      LFA-1-dependent. Moreover, dexamethasone inhibits mast cell-regulated skin
      infiltration of neutrophils mainly by attenuating KC secretion. Thus, this study
      elucidates important interactions between chemokines and adhesion molecules in
      mast cell-dependent neutrophil recruitment and provides new insight into
      mechanisms of dexamethasone in skin inflammation.

PMID- 12488494
TI  - Involvement of CD44 in leukocyte trafficking at the blood-retinal barrier.
AB  - In the present study, we investigated the involvement of CD44 in leukocyte
      trafficking in vivo at the blood-retinal barrier using experimental autoimmune
      uveoretinitis (EAU) as a model system. Leukocyte trafficking was evaluated using
      adoptive transfer of calcein-AM (C-AM)-labeled spleen cells harvested from
      syngeneic mice at prepeak severity of EAU to mice at a similar stage of disease.
      CD44 and its ligand hyaluronan were up-regulated in the eye during EAU. CD44
      positive leukocytes were found sticking in the retinal venules and postcapillary
      venules but not in the retinal arterioles nor in mesenteric vessels.
      Preincubation of in vitro C-AM-labeled leukocytes with anti-CD44 monoclonal
      antibodies (mAb; IM7) or high molecular weight hyaluronic acid (HA) before
      transfer significantly suppressed leukocyte rolling but not sticking in retinal
      venules and also reduced cell infiltration in the retinal parenchyma.
      Administration of the HA-specific enzyme hyaluronidase to mice before cell
      transfer also reduced leukocyte infiltration, suggesting that CD44-HA
      interactions are involved in leukocyte recruitment in EAU. This was further
      supported by the observation that disease severity was reduced by administration
      of anti-CD44 mAb (IM7) at the early leukocyte-infiltration stage. Further studies
      also indicated that CD44 activation was associated with increased levels of
      apoptosis, and this may also be in part responsible for the reduction in disease
      severity. These findings demonstrate that CD44 is directly involved in leukocyte
      endothelial interaction in vivo and influence the trafficking of primed
      leukocytes to the retina and their overall survival.

PMID- 12488495
TI  - Ethanol-induced inhibition of cytokine release and protein degranulation in human
      neutrophils.
AB  - Ethanol impairs immune responses in humans and animal models, in vivo and in
      vitro. In particular, ethanol inhibits some key functions of human
      polymorphonuclear neutrophils (PMN). We investigated the impact of ethanol on
      cytokine production by highly purified PMN. In a time- and concentration
      dependent manner, ethanol inhibited the production of interleukin (IL)-8 protein
      and mRNA and also hindered tumor necrosis factor alpha (TNF-alpha) release by
      modulating the expression of the TNF-alpha-converting enzyme involved in TNF
      alpha shedding. This disruption of PMN cytokine release by ethanol may contribute
      to the increased risk of infection in alcoholic patients. Degranulation of
      hepatocyte growth factor (HGF) was also impaired by a clinically relevant ethanol
      concentration (0.8%), an action that may delay the repair of alcoholic liver
      damage. These findings suggest that ethanol may modulate three major cytokines
      involved in alcoholic liver diseases, IL-8, TNF-alpha, and HGF, via three
      different mechanisms.

PMID- 12488496
TI  - Monocyte-derived dendritic cells release neopterin.
AB  - Increased neopterin concentrations in body fluids are found in diseases
      associated with activated, cell-mediated immunity including infections,
      autoimmune diseases, and certain malignancies. Monocytes/macrophages are known to
      secrete large amounts of neopterin upon stimulation with interferon-gamma (IFN
      gamma). Ontogenetically, the major part of dendritic cells (DC) belongs to the
      myeloid lineage. Therefore, we investigated whether cultured monocyte-derived DC
      can elaborate neopterin. Cells were treated with cytokines in the presence or
      absence of monocyte-conditioned medium as a maturation stimulus. DC secreted an
      average 3.5 nmol/l neopterin. In response to IFN-gamma, cells significantly
      increased their output of neopterin. In distinction to monocytes/macrophages,
      neopterin production in DC was highly sensitive to IFN-alpha and IFN-beta.
      Further, lipopolysaccharides (LPS) enhanced neopterin synthesis, whereas tumor
      necrosis factor alpha, interleukin (IL)-1beta, IL-2, IL-10, and IL-18 were
      ineffective. Simultaneously, tryptophan degradation by induction of indoleamine
      (2,3)-dioxygenase (IDO) was tested in stimulated cells. Our results showed that
      IFN-gamma as well as LPS are inducers of IDO in DC.

PMID- 12488497
TI  - Inhibition of murine dendritic cell activation by synthetic phosphorothioate
      oligodeoxynucleotides.
AB  - Depending on sequence and backbone structure, DNA can inhibit as well as
      stimulate immune responses. As previously shown, single-base phosphorothioate
      (Ps) oligodeoxynucleotides (ODN) can inhibit murine macrophage activation. To
      determine whether these compounds can also affect dendritic cells (DC), the
      effects of 30-mer Ps ODN (SdA, SdT, SdG, and SdC) on DC activation were assessed
      in an in vitro system. With DC preparations obtained from murine bone marrow
      cultured in granulocyte macrophage-colony stimulating factor, the Ps ODN blocked
      the production of interleukin-12 and nitric oxide induced by bacterial DNA, an
      immunostimulatory cytosine phosphate guanosine dinucleotide (CpG) ODN and
      lipopolysaccharide (LPS). Furthermore, these compounds inhibited up-regulation of
      costimulatory molecules CD40 and CD86 as well as major histocompatibility complex
      II molecules, indicating an effect on DC maturation. Although the Ps ODN limited
      uptake of CpG ODN as assessed by flow cytometry, the Ps ODN did not affect LPS
      uptake, suggesting that these compounds inhibit DC responses by effects on
      downstream signaling pathways. Together, these observations extend the range of
      action of inhibitory ODN to DC and suggest a role of these compounds as
      immunomodulatory agents.

PMID- 12488498
TI  - Optimal induction of antigen-specific CD8+ T cell responses requires bystander
      cell participation.
AB  - Efficient activation of specific immune responses requires a concerted
      interaction between T cells and antigen-presenting cells. A requirement for
      bystander participation of CD4+ T cells for expansion and maintenance of memory
      CD8+ T cells has been noted in several models, but a role with regard to effector
      CD8+ T responses has not been well-defined. In this report, the requirement of
      bystander participation for optimal induction of antigen-specific CD8+ T cell
      effector function was determined by directly quantitating antigen-specific
      interferon-gamma (IFN-gamma) CD8+ T cell responses by enzyme-linked immunospot
      assays, and by indirectly evaluating induction of the chemokine monokine induced
      by IFN-gamma as a marker for IFN-gamma-mediated effector function. Our results
      demonstrate that bystander cell participation, mediated by CD4+ T cell and
      natural killer (NK) cells, is required for optimal induction of antigen-specific
      CD8+ T cell effector responses. Our data further establish a novel role for NK
      cells in the activation of antigen-specific immune responses.

PMID- 12488499
TI  - Immune complex stimulation of human neutrophils involves a novel Ca2+/H+
      exchanger that participates in the regulation of cytoplasmic pH: flow cytometric
      analysis of Ca2+/pH responses by subpopulations.
AB  - The activation of human phagocytic leukocytes by immune complexes (IC) or
      opsonized microbes via their Fc and complement receptors has been well-described.
      The mechanisms involved in this process are complex and depend on the receptors
      involved. The biochemical events that lead to the destruction of invading
      organisms in turn display varying degrees of interdependence, but the controlling
      elements that lead to the ultimate killing of ingested organisms within
      phagosomes by lysosomal enzymes and reactive oxygen intermediates are still not
      completely understood. We have addressed these mechanisms by following and
      correlating the kinetics of responses by individual cells, using multiparameter
      flow cytometry. Using nonopsonized IC as stimuli, we document here the presence
      of a novel Ca(2)(+)/H(+) voltage-independent channel in human neutrophils, which
      helps to control their cytoplasmic pH.

PMID- 12488500
TI  - CD40 ligation and phagocytosis differently affect the differentiation of
      monocytes into dendritic cells.
AB  - That monocytes can differentiate into macrophages or dendritic cells (DCs) makes
      them an essential link between innate and adaptive immunity. However, little is
      known about how interactions with pathogens or T cells influence monocyte
      engagement toward DCs. We approached this point in cultures where granulocyte
      macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 induced
      monocytes to differentiate into immature DCs. Activating monocytes with soluble
      CD40 ligand (CD40L) led to accelerated differentiation toward mature CD83(+) DCs
      with up-regulated human leukocyte antigen-DR, costimulatory molecules and CD116
      (GM-CSF receptor), and down-regulation of molecules involved in antigen capture.
      Monocytes primed by phagocytosis of antibody-opsonized, killed Escherichia coli
      differentiated into DCs with an immature phenotype, whereas Zymosan priming
      yielded active DCs with an intermediate phenotype. Accordingly, DCs obtained from
      cultures with CD40L or after Zymosan priming had a decreased capacity to
      endocytose dextran, but only DCs cultured with CD40L had increased capacity to
      stimulate allogeneic T cells. DCs obtained after E. coli or Zymosan priming of
      monocytes produced high levels of proinflammatory tumor necrosis factor alpha and
      IL-6 as well as of regulatory IL-10, but they produced IL-12p70 only after
      secondary CD40 ligation. Thus, CD40 ligation on monocytes accelerates the
      maturation of DCs in the presence of GM-CSF/IL-4, whereas phagocytosis of
      different microorganisms does not alter and even facilitates their potential to
      differentiate into immature or active DCs, the maturation of which can be
      completed upon CD40 ligation. In vivo, such differences may correspond to DCs
      with different trafficking and T helper cell-stimulating capacities that could
      differently affect induction of adaptive immune responses to infections.

PMID- 12488501
TI  - An essential role of macrophage inflammatory protein 1alpha/CCL3 on the
      expression of host's innate immunities against infectious complications.
AB  - Sepsis was induced by well-controlled cecal ligation and puncture (CLP) in
      macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3 knockout (CCL3(-/-)) and
      severe combined immunodeficiency (SCID) mice. CCL3(-/-) mice and their
      littermates (CCL3(+/+) mice) treated with anti-CCL3 monoclonal antibodies were
      susceptible (0-20% survival) to CLP-induced sepsis, and CCL3(-/-) mice
      supplemented with recombinant (r)CCL3 (250 ng/mouse) and CCL3(+/+) mice were
      resistant (70-80% survival). The resistance of SCID mice to CLP was markedly
      improved by the rCCL3 administration (88% survival), and SCID mice treated with
      saline were shown to be middling resistant to the same CLP (45% survival).
      However, the resistance of SCID-M mice (SCID mice depleted of the macrophage
      function) to CLP was not improved by the rCCL3 administration (11% survival), and
      41% of SCID-M mice reconstituted with normal peritoneal macrophages and 79% of
      SCID-M mice inoculated with CCL3-treated peritoneal macrophages survived. In
      addition, the resistance of SCID-MN mice (SCID mice depleted of functional
      macrophages and neutrophils) to CLP was improved by the inoculation of CCL3
      treated macrophages (78% survival), and all of SCID-MN mice inoculated with CCL3
      treated neutrophils died. CCL3 is shown to be essential to the host resistance
      against bacterial sepsis. Macrophages but not neutrophils are highlighted as the
      major effector cells when protective innate immunities against sepsis are
      improved by CCL3.

PMID- 12488502
TI  - Interleukin-10 differently regulates monocyte chemoattractant protein-1 gene
      expression depending on the environment in a human monoblastic cell line, UG3.
AB  - Interleukin (IL)-4, IL-10, and IL-13 affect monocyte/macrophage functions
      including regulation of cytokine production. We analyzed the regulatory effects
      of these cytokines on cytokine production using a human monoblastic cell line,
      UG3. It is interesting that IL-10 up-regulated, whereas IL-4 and IL-13 down
      regulated monocyte chemoattractant protein-1 (MCP-1) production by unstimulated
      UG3 cells. IL-10-induced expression of MCP-1 mRNA occurred without de novo
      protein synthesis at transcriptional and post-transcriptional levels. The
      enhancement of binding activity of nuclear factor Sp1 (Sp-1) and signal
      transducer and activators of transcription (STAT)1 and 3 but not nuclear factor
      kappaB (NF-kappaB) was associated with this IL-10-induced MCP-1 expression.
      Furthermore, IL-10 suppressed lipopolysaccharide (LPS)-induced NF-kappaB binding
      but not Sp-1. The present results suggest IL-10 has two contrasting actions on
      the MCP-1 production of monocytes/macrophages, between the resting and activated
      conditions. The combination of activated Sp-1 and STATs is important for IL-10
      induced MCP-1 expression in resting monocytes/macrophages, and the inhibition of
      LPS-induced NF-kappaB binding is crucial for down-regulation of MCP-1 by IL-10 in
      stimulated monocytes/macrophages.

PMID- 12488503
TI  - CXCR4 heterogeneity in primary cells: possible role of ubiquitination.
AB  - The chemokine receptor CXCR4 is a primary coreceptor for the HIV-1 virus. The
      predicted molecular weight (MW) of glycosylated CXCR4 is 45-47 kDa. However,
      immunoblots of whole cell lysates from human lymphocytes, monocytes, macrophages,
      and the Jurkat T-lymphocyte line revealed multiple MW isoforms of CXCR4. Three of
      the bands could be precipitated by anti-CXCR4 monoclonal antibodies (101 and 47
      kDa) or coprecipitated with CD4 (62 kDa). Expression of these isoforms was
      enhanced by infection with a recombinant vaccinia virus encoding CXCR4. In
      immunoblots of two-dimensional gels, antiubiquitin antibodies reacted with the 62
      kDa CXCR4 species from monocytes subsequent to coprecipitation with anti-CD4
      antibodies. Culturing of monocytes and lymphocytes with lactacystin enhanced the
      amount of the 101-kDa CXCR4 isoform in immunoblots by three- to sevenfold. In
      lymphocytes, lactacystin also increased cell-surface expression of CXCR4, which
      correlated with enhanced fusion with HIV-1 envelope-expressing cells. Similar
      increases in the intensity of the 101-kDa isoform were seen after treatment with
      the lysosomal inhibitors monensin and ammonium chloride. Antiubiquitin antibodies
      reacted with multiple proteins above 62 kDa, which were precipitated with anti
      CXCR4 antibodies. Our data indicate that ubiquitination may contribute to CXCR4
      heterogeneity and suggest roles for proteasomes and lysosomes in the constitutive
      turnover of CXCR4 in primary human cells.

PMID- 12488504
TI  - Identification and characterization of a novel mouse gene encoding a Ras
      associated guanine nucleotide exchange factor: expression in macrophages and
      myocarditis elicited by Trypanosoma cruzi parasites.
AB  - The ability of Trypanosoma cruzi to activate macrophages is, at least in part,
      attributed to the glycosylphosphatidylinositol-anchored mucin-like glycoproteins
      (GPI-mucins) expressed in the surface of the trypomastigote stage of the
      parasite. The differential display reverse transcriptase-polymerase chain
      reaction and the reverse Northern blot were used to study modulation of gene
      expression in murine macrophages exposed to GPI-mucins and in cardiac tissues
      from mice infected with T. cruzi. Among several cDNAs that were more abundant in
      lanes corresponding to macrophages stimulated with GPI-mucins as compared with
      resting cells, we confirmed the differential expression of A1, interleukin-18,
      and GPIgamma4. Some of these genes were also shown to have enhanced expression in
      the cardiac tissue (DAP-12, A1, and GPIgamma4) from infected animals. The
      expression of GPIgamma4 was also enhanced in human monocytes stimulated with GPI
      mucins or bacterial lipopolysaccharides. The complete sequence of the GPIgamma4
      transcript and its gene including the 5' upstream region was defined. GPIgamma4
      was encoded by a novel, single copy gene present in mouse as well as human
      genomes and showed conserved homology to different members of the guanine
      nucleotide exchange factor family.

PMID- 12488505
TI  - The effect of GPI-anchor deficiency on apoptosis in mice carrying a Piga gene
      mutation in hematopoietic cells.
AB  - Glycosyl phosphatidylinositol (GPI) anchors are used by a variety of proteins to
      link to the cell surface. GPI-anchored proteins are deficient on a proportion of
      blood cells from patients with paroxysmal nocturnal hemoglobinuria. This is
      caused by the expansion of a cell clone that has acquired a mutation in a gene,
      PIGA, which is essential in the synthesis of GPI anchors. The nature of the
      growth/survival advantage permitting the expansion of PIGA(-) cells is unknown. A
      decreased susceptibility to apoptosis has been found in blood cells from
      patients, but the contribution of the PIGA gene mutation to this finding remained
      controversial. Therefore, we investigated apoptosis in mice that harbor a
      targeted Piga gene mutation in hematopoietic cells. When exposed to a variety of
      apoptotic stimuli, apoptosis in PIGA(-) thymocytes, granulocytes, and
      hematopoietic progenitor cells was similar to apoptosis induced in PIGA(+) cells
      from the same mouse or from wild-type controls. Similarly, whole-body gamma
      irradiation did not produce an in vivo survival advantage of PIGA(-)
      hematopoietic stem cells. Our findings imply that a Piga gene mutation does not
      alter susceptibility to cell death, indicating that other factors in addition to
      the PIGA gene mutation are necessary to promote the clonal outgrowth of PIGA(-)
      cells.

PMID- 12488506
TI  - Regulation of gene expression in mouse macrophages stimulated with bacterial CpG
      DNA and lipopolysaccharide.
AB  - CpG-DNA is known as a potent immunostimulating agent and may contribute in
      therapeutic treatment of many immune disorders. CpG-DNA triggers innate and
      acquired immune responses through activated expression of various genes in immune
      cells, including macrophages. To define the molecular mechanism(s) by which CpG
      DNA activates immune cells, we studied macrophage gene expression following CpG
      DNA exposure using high-density oligonucleotide microarrays. As CpG-DNA receptor
      Toll-like receptor 9 (TLR9) shares homology with the lipopolysaccharide (LPS)
      TLR4 receptor, we compared gene expression profiles in macrophages stimulated by
      LPS versus CpG-DNA. CpG-DNA and LPS modulate expression of many genes encoding
      cytokines, cell surface receptors, transcription factors, and proteins related to
      cell proliferation/differentiation. However, LPS modulated expression of
      significantly more genes than did CpG-DNA, and all genes induced or repressed by
      CpG-DNA were induced or repressed by LPS. We conclude that CpG-DNA signaling
      through TLR9 activates a subset of genes induced by LPS-TLR4 signaling.

PMID- 12488507
TI  - Functional cross-talk between cytokine receptors revealed by activating mutations
      in the extracellular domain of the beta-subunit of the GM-CSF receptor.
AB  - Several reports have suggested an interaction between the erythropoietin receptor
      (EpoR) and the shared signaling subunit (hbeta(c)) of the human granulocyte
      macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5
      receptors, although the functional consequences of this interaction are unclear.
      We previously showed that in vivo expression of constitutively active
      extracellular (EC) mutants of hbeta(c) induces erythrocytosis and Epo
      independence of erythroid colony-forming units (CFU-E). This occurs despite an
      apparent requirement of these mutants for the GM-CSF receptor alpha-subunit
      (GMRalpha), which is not expressed in CFU-E. Here, we show that coexpression of
      hbeta(c) EC mutants and EpoR in BaF-B03 cells, which lack GMRalpha, results in
      factor-independent proliferation and JAK2 activation. Mutant receptors that
      cannot activate JAK2 fail to produce a functional interaction. As there is no
      detectable phosphorylation of hbeta(c) on intracellular tyrosine residues, EpoR
      displays constitutive tyrosine phosphorylation. These observations suggest that
      JAK2 activation mediates cross-talk between EC mutants of hbeta(c) and EpoR. The
      implications of these data are discussed as are our findings that activated
      hbeta(c) mutants can functionally interact with certain other cytokine receptors.

PMID- 12488509
TI  - Mono-ADP-ribosylation: a tool for modulating immune response and cell signaling.
AB  - Mono-ADP-ribosylation is a posttranslational modification of cellular proteins
      that has the potential to regulate various cell functions. This reaction consists
      of the enzymatic transfer of ADP-ribose to specific acceptor amino acid residues
      (predominantly arginine and cysteine). The best-known cellular ADP
      ribosyltransferases (the enzymes that catalyze this reaction) are the seven
      ectoenzymes, members of the ART family. Recently, ADP-ribosylated human
      neutrophil-derived peptide (HNP-1, an antimicrobial peptide secreted by immune
      cells) has been identified in the bronchoalveolar lavage fluid from individuals
      who smoke cigarettes. This demonstrates that ADP-ribosylation of HNP-1 occurs in
      vivo. In vitro experiments have indicated that ART-1, an enzyme also present in
      the airway epithelium, specifically modifies Arg(14) of the HNP-1, causing the
      loss of the peptide's antimicrobial and cytotoxic activity, while preserving its
      chemotactic activity. From a functional point of view, these data support a role
      of ADP-ribosylation in the innate immune response. Additional functions proposed
      for the ADP-ribosylation reaction involve the intracellular ADP
      ribosyltransferases, which are molecularly unrelated to the ARTs and intervene in
      cell signaling and metabolism cascades. The growing understanding of the
      biological roles of protein and peptide ADP-ribosylation represents a powerful
      tool for novel pharmacological interventions.

PMID- 12488510
TI  - Insights into Dahl salt-sensitive hypertension revealed by temporal patterns of
      renal medullary gene expression.
AB  - Dahl salt-sensitive SS and consomic, salt-resistant SS-13(BN)/Mcw rats possess a
      highly similar genetic background but exhibit substantial differences in blood
      pressure salt sensitivity. We used cDNA microarrays to examine sequential changes
      of mRNA expression of approximately 2,000 currently known rat genes in the renal
      medulla (a tissue critical for long-term blood pressure regulation) in SS and SS
      13(BN)/Mcw rats in response to a high-salt diet (16 h, 3 days, or 2 wk).
      Differentially expressed genes in each between-group comparison were identified
      based on a threshold determined experimentally using a reference distribution
      that was constructed by comparing rats within the same group. A difference
      analysis of 54 microarrays identified 50 genes that exhibited the most distinct
      temporal patterns of expression between SS and SS-13(BN)/Mcw rats over the entire
      time course. Thirty of these genes could be linked to the regulation of arterial
      blood pressure or renal injury based on their known involvement in functional
      pathways such as renal tubular transport, metabolism of vasoactive substances,
      extracellular matrix formation, and apoptosis. Importantly, the majority of the
      30 genes exhibited temporal expression patterns that would be expected to lower
      arterial pressure and reduce renal injury in SS-13(BN)/Mcw compared with SS rats.
      The phenotypic impact of the other 20 genes was less clear. These 50 genes are
      widely distributed on chromosome 13 and several other chromosomes. This suggested
      that primary genetic defects, although important, are unlikely to be solely
      responsible for the full manifestation of this type of hypertension and
      associated injury phenotypes. In summary, the results of this study identified a
      number of pathways potentially important for the amelioration of hypertension and
      renal injury in SS-13(BN)/Mcw rats, and these results generated a series of
      testable hypotheses related to the role of the renal medulla in the complex
      mechanism of salt-sensitive hypertension.

PMID- 12488512
TI  - Reviewing peer review in Occupational Medicine.

PMID- 12488511
TI  - Efficient large-scale production and concentration of HIV-1-based lentiviral
      vectors for use in vivo.
AB  - The aim of this study was to develop an efficient method for packaging and
      concentrating lentiviral vectors that consistently yields high-titer virus on a
      scale suitable for in vivo applications. Transient cotransfection of 293T
      packaging cells with DNA plasmids encoding lentiviral vector components was
      optimized using SuperFect, an activated dendrimer-based transfection reagent. The
      use of SuperFect allowed reproducible and efficient production of high-titer
      lentiviral vector at concentrations greater than 1 x 10(7) transducing units per
      ml (TU/ml) and required less than one-third of the total amount of DNA used in
      traditional calcium phosphate transfection methods. Viral titers were further
      increased using a novel concentration protocol that yielded an average final
      titer of 1.4 x 10(10) TU/ml. Lentiviruses produced using these methods exhibited
      efficient transduction of central nervous system and peripheral tissues in vivo.
      The method is reproducible and can be scaled up to facilitate the use of these
      vectors in animal studies.

PMID- 12488513
TI  - Occupational health in British agriculture.

PMID- 12488514
TI  - Musculoskeletal disorders in farmers and farm workers.
AB  - Farming is a physically arduous occupation and this places farm workers at
      potential risk of musculoskeletal disorders such as osteoarthritis (OA) of the
      hip and knee, low back pain (LBP), neck and upper limb complaints, and hand-arm
      vibration syndrome (HAVS). This review considers the epidemiological evidence
      concerning such risks. The strongest evidence relates to OA of the hip, for which
      the public health impact is likely to be considerable. There is also weaker, but
      suggestive evidence that farmers more often have knee OA and LBP than workers in
      occupations with fewer physical demands. Tractor drivers, in particular, seem to
      have more LBP. Relatively little information exists on the risks of soft tissue
      rheumatism in the limbs and neck. For some outcomes, the link with occupational
      risk factors (such as heavy loading of joints and whole-body vibration) is
      sufficient to suggest the course that future prevention should take, but for
      several outcomes more research is first needed.

PMID- 12488515
TI  - Respiratory illness in agricultural workers.
AB  - Respiratory diseases have long been recognized in association with work in
      farming. Overall, only a small proportion of the population is employed in
      agriculture, so respiratory disease in farmers is not a major public health
      issue. However, farmers are known to have high morbidity and mortality from
      certain respiratory diseases, as shown by routinely collected statistics. Despite
      this, knowledge of the frequency, nature and risk factors for some respiratory
      disorders in agricultural workers is incomplete. Multiple exposures are common
      and some exposures can give rise to more than one specific disease. Moreover, the
      most common respiratory symptoms reported by farm workers (wheeze, dyspnoea and
      cough) are relatively non-specific and can be associated with several
      occupational respiratory disorders. This review describes the main occupational
      respiratory illnesses in farming and summarizes the current literature about
      epidemiology and prevention. The most important diseases are rhinitis and asthma,
      which, although common, are not usually fatal. Some non-allergic conditions, e.g.
      asthma-like syndrome and organic toxic dust syndrome, are not yet fully
      understood, but appear to be common among farm workers. The most serious
      respiratory diseases are hypersensitivity pneumonitis and respiratory infections,
      but these are rare. Most importantly, respiratory diseases are preventable by
      controlling harmful exposures to organic dust, toxic gases and chemicals on farms
      through improvements in animal rearing techniques, ventilation of animal
      accommodation, careful drying and storage of animal feed-stuffs, crops and other
      products, and use of personal protective equipment.

PMID- 12488516
TI  - Accidental injuries in agriculture in the UK.
AB  - The rate of occupational accidents in British agriculture is higher than in most
      other industries. The most common fatal accidents are those involving vehicles
      and machinery, falls from a height and electrocution. A substantial proportion of
      reported non-fatal injuries in agricultural employees is attributable to manual
      handling, but among self-employed farmers the contribution is much smaller. Few
      data are available on longer-term determinants of risk, but accidental deaths are
      most frequent in July, August and September. The main approaches to preventing
      agricultural accidents are through engineering improvements, and education and
      training of the workforce. The introduction of roll-over protection structures
      for tractors has been an important development in recent decades. Other
      engineering controls include guards for power take off shafts, guard rails to
      prevent falls, better handling facilities for animals and closed transfer systems
      for pesticides. Training on safety is available from several sources, but its
      effectiveness in reducing accidents is uncertain.

PMID- 12488517
TI  - Work with pesticides and organophosphate sheep dips.
AB  - Pesticides are an important hazard in agriculture. In developed countries their
      use is strictly regulated. Risk assessment for new pesticides includes comparison
      of the potential exposures of spray operators and other farm workers with a
      reference value. Usually, this is derived from toxicological studies in animals
      with allowance for the uncertainties in extrapolating between and within species.
      Older pesticides undergo periodic reviews, for which epidemiological data may
      also be available. Unintentional fatal poisoning by pesticides is extremely rare
      in Britain. Documented reports of non-fatal acute poisoning are also uncommon,
      but there may be substantial under-ascertainment of minor incidents. Pesticides
      have been linked with various chronic diseases, but few associations have been
      clearly established. A particular concern recently in Britain has been the
      possibility that organophosphate insecticides can cause chronic neuropsychiatric
      illness.

PMID- 12488518
TI  - The mental health of farmers.
AB  - Farmers are subject to a number of unique occupational stressors, many of which
      have been aggravated in recent years by changes in farming practice and by
      economic factors. These are probably part of the explanation for the high rates
      of suicide in farmers and farm workers, which in the UK account for the largest
      number of suicides in any occupational group. Suicide is usually associated with
      mental illness, which, in farming communities, appears to be particularly
      stigmatized and poorly understood. This affects health-seeking behaviour, which
      is compounded by the geographical isolation and inaccessibility of many services
      in rural areas. Our current understanding of these issues suggests a number of
      potentially valuable interventions.

PMID- 12488519
TI  - Demonstrating the economic value of occupational health services.
AB  - Many large companies operate some form of occupational health service (OHS). More
      companies now require specific evaluative information to justify the continued
      provision of an in-house OHS. This is in the face of increased pressure to
      control costs, combined with an awareness that the service itself can induce
      activity (supplier-induced demand) and could be substituted with health care
      provided or even funded outside the company. The lack of routinely collected data
      and the conceptual difficulty in defining and measuring the outcomes of an OHS
      provide challenges for economic evaluation. A purely human capital approach,
      where people are valued by their wage rates, is likely to be insufficient, since
      OHSs have multiple objectives. These objectives include fulfilling statutory
      obligations, contributing to the creation of a culture of partnership, reduction
      of potential costs to the company (sickness benefit, production loss, poor
      performance, litigation, insurance) and providing a suitable environment for the
      cost-effective reduction of the social and health service costs of illness at
      work. Evidence is needed to quantify some of these arguments and demonstrate to
      decision makers the value generated by OHSs. The aim of this paper is to consider
      the practicality of different economic evaluation methodologies, specifically
      cost models, contingent valuation (willingness-to-pay) and development of OHS
      specific outcome measures. In considering different approaches, we present the
      results of our research in two UK companies.

PMID- 12488520
TI  - Measuring sick leave: a comparison of self-reported data on sick leave and data
      from company records.
AB  - The objective of this study was to compare sick leave data obtained from
      questionnaires with data from company records. During a period of 12 months,
      questionnaires were completed monthly for 6 months and then at 9 and 12 months.
      The sensitivity and specificity of questionnaires for detecting an episode of
      sick leave were determined, using the company records as a reference standard. In
      addition, the duration of sick leave episodes reported in the two data sets was
      compared. In this analysis, company records were not assumed to be superior, and
      agreement was assessed with intraclass correlation coefficients (ICCs). The
      sensitivity of questionnaires for detecting an episode of sick leave was 55% (95%
      CI = 0.50-0.60) and the specificity 83% (95% CI = 0.72-0.94). The ICC for all
      episodes was 0.58 (95% CI = 0.47-0.67). The only satisfactory ICC (0.87; 95% CI =
      0.74-0.93) was found for the questionnaires at 9 and 12 months. No large
      systematic differences were found between the duration of episodes reported in
      the two data sets. In conclusion, in our study, the sensitivity of questionnaires
      for detecting an episode of sick leave was very low. Furthermore, when episodes
      were recalled, there was little agreement on the duration of the episode between
      questionnaire data and data in the company records. Based on these results and
      considering the risk of missing questionnaires, data on sick leave gathered from
      company records are clearly preferable as an outcome measure in research.

PMID- 12488521
TI  - Comparison of outcomes of untreated carpal tunnel syndrome and asymptomatic
      controls in meat packers.
AB  - Our objectives were to determine the reporting of symptoms, the medical outcome
      and the work status of meat plant workers diagnosed with clinical carpal tunnel
      syndrome (CTS). Forty-seven cases of CTS were identified from a previously
      reported study, and were matched by age, gender and hand use. Cases and controls
      were followed up for 24 months. The Provincial Workers' Compensation Board and
      company health records were used to determine the reporting of symptoms,
      interventions and work status. Thirty-one study cases and all control cases were
      followed for the full 24 months (16 study cases were lost to follow-up). In
      total, 12 cases reported symptoms of CTS during the 24 months (eight study cases
      and four controls). Of the eight study cases, one required surgical release of
      the carpal tunnel. After a period of work modification, five of the eight study
      cases returned to regular duty and the remainder were placed on permanent job
      restrictions. Of the four controls, one subject had a surgical release and
      returned to regular work, two subjects' jobs were permanently modified, and the
      fourth returned to regular duty. Occupation-related CTS in meat packers appears
      to be transient and responsive to conservative measures, with a surgical rate
      comparable to other occupations.

PMID- 12488522
TI  - Implementation of statutory occupational respiratory health surveillance.
AB  - Health surveillance is required by UK regulations in certain circumstances, and
      is usually provided through an occupational health organization. Although there
      are studies assessing the provision of health surveillance across the country,
      there are no published studies addressing the practical application of
      legislation, guidelines and medical research to respiratory health surveillance
      programmes. An audit of a multidisciplinary health surveillance programme was
      carried out, using review of occupational health records, occupational hygiene
      reports and managers' risk assessments, to compare the implementation of health
      surveillance in different organizations and under different contractual
      relationships. Sixty-six per cent of National Health Service (NHS) and 56% of
      industrial workplaces were able to provide risk assessments but were unable to
      link these with appropriate health surveillance. Twenty-seven per cent of NHS
      employees potentially exposed to respiratory sensitizers had baseline
      surveillance, compared with 87% in industry. Fifty-five per cent of Medical
      Research Council questionnaires were inappropriately administered by the employee
      themselves, rather than an interviewer as recommended. Other follow-up
      questionnaires in use had not been formally validated. Non-regular lung function
      assessment using spirometry was the predominant tool used for follow-up
      surveillance. There was no overall strategic approach to respiratory health
      surveillance in the organization studied. Health surveillance programmes should
      focus on disease prevention without becoming a repetitious application of
      unvalidated tools. Clinical governance demands quality assurance standards that
      will effectively implement a coordinated approach to health surveillance.

PMID- 12488524
TI  - Compensable injuries and health outcomes.

PMID- 12488523
TI  - Generic task-related occupational requirements for Royal Naval personnel.
AB  - Physical tests and selection criteria have historically been used by many
      military organizations. However, the standards associated with them have come
      under increasing scrutiny in recent years. This paper describes a series of
      experiments that were conducted to establish task-related occupational tests and
      standards (TBTs) for Royal Naval (RN) personnel. A total of 172 (106 male and 66
      female) RN personnel volunteered for these experiments, which were designed to:
      identify the anthropometric requirements for operating various safety hatches and
      doors on board a RN Frigate (TBT1); quantify the metabolic demands of shipboard
      firefighting tasks and establish an aerobic fitness standard (TBT2); and identify
      a battery of tests to predict performance of shipboard casualty-carrying tasks
      (TBT3). Whilst all subjects completed the criterion tasks during TBT1,
      performance of the bulkhead door (BD) escape task was related to height (r = 0.50
      0.62, P < 0.05) and vertical reach (r = 0.42-0.54, P < 0.05), with shorter
      subjects struggling to perform the task. During TBT2, the mean metabolic demand
      of representative firefighting tasks was 38 ml/min/kg, which must be sustained
      for 20-30 min. Finally, a battery of tests incorporating measures of lean body
      mass, fat mass, standing broad jump, 20 m sprint, press-ups, sit-ups and grip
      strength produced a high correlation (r = 0.89, P < 0.01) with casualty-carrying
      task performance. From the results of these experiments, it is recommended that
      RN personnel perform the BD simulation task at the recruitment stage (TBT1), to
      prove that they possess the anthropometric characteristics commensurate with
      survival at sea. Secondly, personnel should be frequently screened to ascertain
      whether they have the maximal aerobic power (41 ml/min/kg) commensurate with
      shipboard firefighting for 20-30 min (TBT2). Finally, they should perform the
      battery of proposed tests and score at least 34 points, in order to establish
      whether they have the anaerobic and strength capacity commensurate with shipboard
      casualty-carrying tasks (TBT3).

PMID- 12488525
TI  - The problem with material safety data sheets.

PMID- 12488530
TI  - Tonically activated GABAA receptors in hippocampal neurons are high-affinity, low
      conductance sensors for extracellular GABA.
AB  - In the hippocampus, two distinct forms of GABAergic inhibition have been
      identified, phasic inhibitory postsynaptic currents that are the consequence of
      the vesicular release of GABA and a tonic conductance that is activated by low
      ambient concentrations of extracellular GABA. It is not known what accounts for
      the distinct properties of receptors that mediate the phasic and tonic inhibitory
      conductances. Moreover, the physiological role of the tonic inhibitory
      conductance remains uncertain because pharmacological tools that clearly
      distinguish tonic and phasic receptors are lacking. Here, we demonstrate that
      GABAA receptors that generate a tonic conductance in cultured hippocampal neurons
      from embryonic mice have different pharmacological properties than those in
      cerebellar granule neurons or pyramidal neurons in the dentate gyrus. The tonic
      conductance in cultured hippocampal neurons is enhanced by the benzodiazepine,
      midazolam, and is insensitive to the inhibitory effects of the competitive
      antagonist, gabazine (< or =10 microM). We also identify penicillin as an
      uncompetitive antagonist that selectively inhibits the synaptic but not tonic
      conductance. GABA was applied to hippocampal neurons to investigate the
      properties of synaptic and extrasynaptic receptors. GABA-evoked current was
      composed of two components: a rapidly desensitizing current that was blocked by
      penicillin and a nondesensitizing current that was insensitive to penicillin
      blockade. The potency of GABA was greater for the penicillin-insensitive
      nondesensitizing current. Single-channel studies show that the gabazine
      insensitive GABAA receptors have a lower unitary conductance (12 pS) than that
      estimated for synaptic receptors. Thus, specialized GABAA receptors with an
      apparent higher affinity for GABA that do not readily desensitize mediate the
      persistent tonic conductance in hippocampal neurons. The receptors underlying
      tonic and phasic inhibitory conductances in hippocampal neurons are
      pharmacologically and biophysically distinct, suggesting that they serve
      different physiological roles.

PMID- 12488531
TI  - Regulation of G protein-coupled receptor kinases and arrestins during receptor
      desensitization.

PMID- 12488532
TI  - The selective activation of the glutamate receptor GluR5 by ATPA is controlled by
      serine 741.
AB  - Only a few agonists exhibit selectivity between the AMPA and the kainate subtypes
      of the glutamate receptor. The most commonly used kainate receptor preferring
      agonist, (S)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid [(S)
      ATPA], is an (R,S)-2-amino-3-(5-methyl-3-hydroxy-4-isoxazolyl)propionic acid
      (AMPA) derivative in which the methyl group at the 5-position of the isoxazole
      ring has been replaced by a tert-butyl group. When characterized by the two
      electrode voltage clamp method in Xenopus laevis oocytes, ATPA exhibits at least
      50-fold higher potency on the kainate receptor subtype, GluR5, compared with the
      AMPA receptors. Through mutagenesis studies of GluR5 and the AMPA receptor
      subtype, GluR1, we demonstrate that this pronounced selectivity for ATPA can be
      ascribed to Ser741 in GluR5 and Met722 in GluR1. Examination of other aliphatic
      substitutions at the 5-position of the isoxazole ring revealed that (R,S)-2-amino
      3-(5-isopropyl-3-hydroxy-4-isoxazolyl)propionic acid (isopropyl-AMPA) displayed a
      6-fold higher potency for GluR5 than for GluR1, whereas the analogs, propyl-AMPA
      and isobutyl-AMPA, did not exhibit significantly different potencies. Our study
      suggests that the GluR5 selectivity was a result not only of steric interference
      between the bulky tert-butyl group in ATPA and the methionine (Met722) in GluR1
      but also a serine-dependent stabilization of the active conformation of GluR5
      induced by ATPA. The stabilization was agonist-dependent and observed only for
      ATPA and isopropyl-AMPA, not for other AMPA analogs with bulky substitutions at
      the 5-position of the isoxazole ring.

PMID- 12488533
TI  - Chemical synthesis of MT1 and MT7 muscarinic toxins: critical role of Arg-34 in
      their interaction with M1 muscarinic receptor.
AB  - Two muscarinic toxins, MT1 and MT7, were obtained by one-step solid-phase
      synthesis using the 9-fluorenylmethoxycarbonyl-based method. The synthetic and
      natural toxins, isolated from the snake venom or recombinantly expressed, display
      identical physicochemical properties and pharmacological profiles. High protein
      recovery allowed us to specify the selectivity of these toxins for various
      muscarinic receptor subtypes. Thus, sMT7 has a selectivity for the M1 receptor
      that is at least 20,000 times that for the other subtypes. The stability of the
      toxin-receptor complexes indicates that sMT1 interacts reversibly with the M1
      receptor, unlike sMT7, which binds it quasi-irreversibly. The effect of the
      synthetic toxins on the atropine-induced [3H]N-methylscopolamine (NMS)
      dissociation confirms that sMT7 targets the allosteric site on the M1 receptor,
      whereas sMT1 seems interact on the orthosteric one. The great decreases in the
      binding potencies observed after the R34A modification in sMT1 and sMT7 toxins
      highlight the functional role of this conserved residue in their interactions
      with the M1 receptor. Interestingly, after the R34A modification, the sMT7 toxin
      binds reversibly on the M1 receptor. Furthermore, the potency of sMT7-R34A for
      the NMS-occupied receptor is lower compared with unmodified toxin, supporting the
      role of this residue in the allosteric interaction of sMT7. All these results and
      the different charge distributions observed at the two toxin surfaces of their
      structure models support the hypothesis that the two toxins recognize the M1
      receptor differently.

PMID- 12488534
TI  - Molecular basis of partial agonism: orientation of indoleamine ligands in the
      binding pocket of the human serotonin 5-HT2A receptor determines relative
      efficacy.
AB  - Based on experiment and computational simulation, we present a structural
      explanation for the differing efficacies of indole agonists at the human
      serotonin 5-HT2A receptor (5HT2AR). We find that serotonin [5-hydroxytryptamine
      (5-HT)] forms hydrogen-bonds with Ser3.36 in helix 3 and Ser5.46 in helix 5.
      Disruption of these hydrogen bonds by methyl-substitution of the cationic primary
      amine or of the backbone N1-amine, respectively, leads to a reduction in agonist
      efficacy. Computational simulation predicts that mutation of Ser3.36 to Ala
      should allow a similar interaction with helix 3 both for agonists that have
      unmodified cationic amine side chains and for those with substituted amines.
      Experimentally, this mutation was found to largely eliminate the differences in
      efficacy caused by cationic amine substitution for a series of indole congeners.
      Similarly, substitution of the N1-amine, which interacts with Ser5.46, reduced
      efficacy more markedly at the wild-type (WT) than at the Ser5.46Ala mutant
      receptor. Computational modeling of binding pocket interactions of ligands with
      WT and mutant receptor constructs demonstrate how the Ser3.36 and Ser5.46
      interactions serve to modify the agonist's favored position in the binding
      pocket. A striking correlation was found between differences in the position
      assumed by the indole ring and differences in agonist activity. These data
      support the hypothesis that the position of the agonist interacting with the
      receptor is influenced by specific interactions in helices 3 and 5 and determines
      the degree of receptor activation by agonist through a mechanism that is likely
      to be shared by other G-protein coupled receptors in this class.

PMID- 12488535
TI  - Involvement of a calcineurin cascade in amygdala depotentiation and quenching of
      fear memory.
AB  - If fear memory is expressed by a long-term potentiation (LTP) of synaptic
      transmission in the amygdala, then reversal of LTP (depotentiation) in this area
      of the brain may provide an important mechanism for amelioration of anxiety and
      post-traumatic stress disorder. Herein, we show that low-frequency stimulation
      (LFS) of the external capsule elicits a depotentiation in the lateral nucleus of
      the amygdala. The induction of depotentiation requires activation of N-methyl-D
      aspartate receptors and voltage-dependent calcium channels but is independent of
      adenosine A(1) and metabotropic glutamate group II receptors. Extracellular
      perfusion or loading cells with protein phosphatase (PP) 2B (calcineurin)
      inhibitors prevents depotentiation. The same stimulating protocol applied to the
      amygdala in vivo attenuates the expression of fear memory measured with fear
      potentiated startle and reduces conditioning-elicited phosphorylation of Akt and
      mitogen-activated protein kinase (MAPK). This is paralleled by an increase in the
      activity of calcineurin. In addition, application of calcineurin inhibitor blocks
      LFS-induced extinction of fear memory and MAPK dephosphorylation. Taken together,
      this study characterizes the properties of LFS-induced depotentiation in the
      amygdala and suggests an involvement of calcineurin cascade in synaptic
      plasticity and memory storage.

PMID- 12488536
TI  - Withdrawal from chronic intermittent ethanol treatment changes subunit
      composition, reduces synaptic function, and decreases behavioral responses to
      positive allosteric modulators of GABAA receptors.
AB  - One of the pharmacological targets of ethanol is the GABAA receptor (GABAR),
      whose function and expression are altered after chronic administration of
      ethanol. The details of the changes differ between experimental models. In the
      chronic intermittent ethanol (CIE) model for alcohol dependence, rats are exposed
      to intermittent episodes of intoxicating ethanol and withdrawal, leading to a
      kindling-like state of behavioral excitability. This is accompanied by presumably
      causal changes in GABAR expression and physiology. The present study investigates
      further the effect of CIE on GABAR function and expression. CIE is validated as a
      model for human alcohol withdrawal syndrome (AWS) by demonstrating increased
      level of anxiety; diazepam improved performance in the test. In addition, CIE
      rats showed remarkably reduced hypnotic response to a benzodiazepine and a
      steroid anesthetic, reduced sensitivity to a barbiturate, but not propofol.
      Immunoblotting revealed decrease in alpha1 and delta expression and increase in
      gamma2 and alpha4 subunits in hippocampus of CIE rats, confirmed by an increase
      in diazepam-insensitive binding for ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H
      imidazo(1,5-alpha)(1,4)benzodiazepine-3-carboxylate (Ro15-4513). Elevated mRNA
      levels were shown for the gamma2S and gamma1 subunits. Recordings in hippocampal
      slices from CIE rats revealed that the decay time of GABAR-mediated miniature
      inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal cells was decreased,
      and potentiation of mIPCSs by positive modulators of GABAR was also reduced
      compared with control rats. However, mIPSC potentiation by the alpha4-preferring
      benzodiazepine ligands bretazenil and Ro15-4513 was maintained, and increased,
      respectively. These data suggest that specific alterations in GABAR occur after
      CIE and may underlie the development of hyperexcitability and ethanol dependence.

PMID- 12488537
TI  - Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV
      1 nucleoside reverse transcriptase inhibitors.
AB  - Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP- binding
      cassette transporters, which induce multidrug resistance in cancer cells. We
      found that a high level of BCRP expression in CD4+ T cells conferred cellular
      resistance to human immunodeficiency virus type-1 (HIV-1) nucleoside reverse
      transcriptase inhibitors. The cell line MT-4/DOX 500 was established through the
      long-term culture of MT-4 cells in the presence of doxorubicin (DOX) and had
      reduced sensitivity to not only DOX but also zidovudine (AZT). MT-4/DOX 500 cells
      showed reduced intracellular accumulation and retention of DOX and increased ATP
      dependent rhodamine 123 efflux. The cells were also resistant to several
      anticancer agents such as mitoxantrone, 7-ethyl-10-[4-(1-piperidino)-1
      piperidino]carbonyloxycamptothecin, and 7-ethyl-10-hydroxycamptothecin. AZT was
      7.5-fold less inhibitory to HIV-1 replication in MT-4/DOX 500 cells than in MT-4
      cells. Furthermore, the anti-HIV-1 activity of lamivudine was severely impaired
      in MT-4/DOX 500 cells. In contrast, the antiviral activity of non-nucleoside
      reverse transcriptase inhibitors and protease inhibitors was not affected in the
      cells. MT-4/DOX 500 cells expressed glycosylated BCRP but not P-glycoprotein
      (ABCB1), multidrug resistance protein 1, 2, or 4 (ABCC1, -2, or -4), or lung
      resistance-related protein. In addition, the BCRP-specific inhibitor
      fumitremorgin C completely abolished the resistance of MT-4/DOX 500 cells to AZT
      as well as to DOX. An analysis for intracellular metabolism of AZT suggests that
      the resistance is attributed to the increase of ATP-dependent efflux of its
      metabolites, presumably AZT 5'-monophosphate, in MT-4/DOX 500 cells.

PMID- 12488538
TI  - Evidence that the coactivator CBP/p300 is important for phenobarbital-induced but
      not basal expression of the CYP2H1 gene.
AB  - We have previously identified an upstream 556-bp enhancer domain for the chicken
      CYP2H1 gene that responds to phenobarbital and binds several transcription
      factors, including the orphan chicken xenobiotic receptor (CXR). By contrast, the
      promoter lacks a CXR site and is not inducible by phenobarbital. Although it has
      been established that CXR can interact with the coactivator SRC-1, there are no
      reports as to whether other coactivators may be important for phenobarbital
      mediated inducibility. Our studies using the adenovirus E1A wild-type protein,
      which inhibits the coactivators cAMP response element binding protein (CBP) and
      CBP associated factor (p/CAF), provide evidence for the involvement of one or
      both of these coactivators at the enhancer but not at the promoter of the CYP2H1
      gene. The observations that mutant E1A proteins did not affect the enhancer
      activity and that inhibition by wild-type E1A was reversed by CBP and p/CAF
      confirmed the involvement of these coactivators in the induction process. We
      propose that the intrinsic histone acetyl transferase activity of one or both of
      these coactivators participates in chromatin remodeling thereby stimulating drug
      induction of the promoter. This proposal was supported by experiments with the
      histone deacetylase inhibitor, trichostatin A, which resulted in the
      superinduction of the drug response but had little effect on basal expression of
      the CYP2H1 gene. The work provides evidence for the first time for the
      involvement of the coactivators CBP and p/CAF in the phenobarbital-mediated
      induction of the CYP2H1 gene.

PMID- 12488539
TI  - The effect of insulin on expression level of nucleoside transporters in diabetic
      rats.
AB  - Evidence that the time course of insulin-induced changes in adenosine level in
      diabetic rats is different from that observed for expression of adenosine kinase
      prompted us to study the insulin effect on expression of nucleoside transporters
      in tissues of diabetic rats. RNase protection assay demonstrated that mRNA levels
      of equilibrative (rENT) and Na+-dependent nucleoside transporters (rCNT) were
      altered in diabetic tissues. The rENT1 mRNA level with respect to values obtained
      in age- and sex-matched nondiabetic rats was decreased by 45, 32, and 10% in
      diabetic heart, liver, and kidney, respectively. The level of rENT2 mRNA was
      lowered by 40% in diabetic kidney and heart, and by 24% in diabetic liver.
      Changes in the expression pattern of rCNT1 and rCNT2 in diabetic tissues differed
      significantly from that observed for rENT. The levels of rCNT1 and rCNT2 mRNA did
      not change significantly in diabetic kidney. In diabetic heart, the mRNA levels
      of rCNT1 and rCNT2 increased 1.7- and 2-fold, respectively. Changes in expression
      of nucleoside transporters were accompanied by alterations in adenosine content.
      Administration of insulin to diabetic rats resulted in a drop in adenosine
      concentration in examined tissues and return of the rCNT1, rCNT2, and rENT2 but
      not rENT1 mRNA levels to values observed in nondiabetic rats. In summary, these
      data demonstrate that insulin affects expression of nucleoside transporters in a
      cell-specific manner. We conclude that change in the expression level of the
      nucleoside transporters occurring in tissues of diabetic rat is an important
      factor influencing adenosine levels in the cell.

PMID- 12488540
TI  - Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes
      the functional response to micro agonists from inhibitory to excitatory.
AB  - GH3 cells show spontaneous activity characterized by bursts of action potentials
      and oscillations in [Ca 2+]i. This activity is modulated by the activation of
      exogenously expressed opioid receptors. In GH3 cells expressing only micro
      receptors (GH3MOR cells), the micro receptor-specific ligand [D-Ala2,N-Me
      Phe4,Gly5-ol]-enkephalin (DAMGO) inhibited spontaneous Ca 2+ signaling by the
      inhibition of voltage-gated Ca 2+ channels, activation of inward-rectifying K+
      channels, and inhibition of adenylyl cyclase. In contrast, in cells expressing
      both micro and delta receptors (GH3MORDOR cells), DAMGO had an excitatory effect
      on Ca 2+ signaling that was mediated by phospholipase C and release of Ca 2+ from
      intracellular stores. The excitatory effect of DAMGO was also inhibited by
      pretreatment with pertussis toxin. Despite the excitatory effect on Ca 2+
      signaling, DAMGO inhibited Ca 2+ channels and activated inward-rectifying K+
      channels in GH3MORDOR cells, although to a lesser extent than in GH3MOR cells.
      Long-term treatment with the delta receptor-specific ligand [D-Pen2,D-Pen5]
      enkephalin reduced the excitatory effect of DAMGO in the majority of GH3MORDOR
      cells and restored the inhibitory response to DAMGO in some cells. The inhibitory
      effect of somatostatin on Ca 2+ signaling was not different in GH3MORDOR versus
      GH3MOR cells. These results indicate that interaction between micro- and delta
      opioid receptors causes a change in the functional response to micro ligands,
      possibly by the formation of a micro/delta heterodimer with distinct functional
      properties.

PMID- 12488541
TI  - Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in
      African green monkeys after long-term nicotine administration.
AB  - Nicotine metabolism is decreased in smokers compared with nonsmokers, but the
      mechanism(s) responsible for the slower metabolism are unknown. Nicotine is
      inactivated to cotinine by CYP2A6 in human liver [nicotine C-oxidation (NCO)].
      CYP2B6 also metabolizes nicotine to cotinine but with lower affinity than CYP2A6.
      To evaluate the effects of long-term nicotine treatment on hepatic levels of
      CYP2A6 and CYP2B6, and nicotine metabolism, an African green monkey (AGM) model
      was developed. As in humans, approximately 80 to 90% of in vitro hepatic NCO is
      mediated by a CYP2A6-like protein (CYP2A6agm) in this species, as determined by
      inhibition studies. Male AGM (n = 6 per group) were treated for 3 weeks with
      nicotine (s.c., 0.3 mg/kg, b.i.d.), phenobarbital (oral, 20 mg/kg, as a positive
      control for P450 induction), and/or saline (s.c., b.i.d.). Immunoblotting
      demonstrated a 59% decrease (p < 0.05) in hepatic CYP2A6agm protein in nicotine
      treated animals. A CYP2B6-like protein (CYP2B6agm) was modestly and
      insignificantly decreased (14%, p = 0.11). In vitro NCO was decreased by 41% in
      the nicotine-treated group (p < 0.05), mediated by a decrease in CYP2A6agm, as
      demonstrated using inhibitory antibodies. CYP2A6agm mRNA (33%, P < or = 0.05) and
      CYP2B6agm (35%, p < 0.01) mRNA were also significantly decreased in the nicotine
      treated group. Phenobarbital-treated animals demonstrated an increase in
      CYP2B6agm (650%, p < 0.001), but not CYP2A6agm (20%, p = 0.49). NCO was increased
      in the phenobarbital-treated group (55%, p < 0.05) by an increase in CYP2B6agm
      mediated NCO. Consistent with the slower nicotine metabolism observed in smokers,
      nicotine may decrease its own metabolism in primates by decreasing the expression
      of the primary nicotine-metabolizing enzyme CYP2A6.

PMID- 12488542
TI  - Assessment of the effect of phosphorylated metabolites of anti-human
      immunodeficiency virus and anti-hepatitis B virus pyrimidine analogs on the
      behavior of human deoxycytidylate deaminase.
AB  - Deoxycytidylate deaminase, catalyzing the conversion of dCMP to dUMP, is an
      important enzyme in the de novo synthesis of thymidine nucleotides. It also may
      be involved in the action, as well as the metabolism of anticancer agents.
      Recently, several L- and D-configuration pyrimidine deoxynucleoside analogs were
      found to be potent antiviral and antitumor agents. Their interaction with dCMP
      deaminase as a monophosphate or a triphosphate metabolite is not clear. These
      include D-nucleoside analogs such as beta-D-2',3'-dideoxycytidine (ddC), beta-2'
      fluoro-5-methyl-arabinofuranosyluracil (FMAU), 3'-azido-2',3'-dideoxythymidine
      (AZT), and 2',3'-didehydro-2',3'-dideoxythymidine (D4T) as well as L-nucleoside
      analogs such as beta-L-dioxolane-cytidine (L-OddC), beta-L-2',3'-dideoxy-3'
      thiacytidine, beta-L-2',3'-dideoxy-5'-fluoro-3'-thia-cytidine (L-FSddC), beta-L
      2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine, and L-FMAU. None of the L
      deoxycytidine analog monophosphates act as substrates or inhibitors. Among these
      pyrimidine deoxynucleoside analog monophosphates, D-FMAU monophosphate (MP) is
      the most potent competitive inhibitor, whereas L-FMAUMP has no inhibitory
      activity. Interestingly, AZTMP and D4TMP also have potent inhibitory activities
      on dCMP deaminase. Among the dCTP and TTP analogs examined, D- and L-FMAUTP were
      the most potent inhibitors and had the same extent of inhibitory effect. These
      results suggest that a chiral specificity for the substrate-binding site may
      exist, but there is no chiral specificity for the regulator-binding site. This is
      also supported by the observation that L-OddC and L-FSddC have inhibitory
      activities as triphosphates but not as monophosphates. None of the D- and L-dCTP
      analogs activated dCMP deaminase as dCTP. The biological activities of AZT and
      D4T could be partially attributable to their inhibitory activity against dCMP
      deaminase by their phosphorylated metabolites, whereas that of ddC and the L
      deoxycytidine analogs may not involve dCMP deaminase directly.

PMID- 12488543
TI  - Parathyroid hormone-related peptide is induced by stimulation of alpha 1A
      adrenoceptors and improves resistance against apoptosis in coronary endothelial
      cells.
AB  - Parathyroid hormone-related peptide (PTHrP) is expressed throughout the vascular
      system, including coronary endothelial cells. The regulation of endothelial PTHrP
      expression and the role of PTHrP expression in endothelial cells is not clear.
      This study investigates the question of whether the stimulation of alpha
      adrenergic or angiotensin II receptors increases endothelial expression of PTHrP
      and whether endogenously expressed PTHrP exerts intracrine effects in coronary
      endothelial cells. We found that the stimulation of alpha 1A-adrenoceptors, but
      not that of angiotensin II, increases cellular expression of PTHrP in growing,
      but not in growth-arrested, coronary endothelial cells. Angiotensin II increases
      the expression of PTHrP in smooth muscle cells but not in endothelial cells.
      PTHrP enters the nucleus of endothelial cells at the stadium of confluence, which
      suggests an intracrine effect of PTHrP. It was further investigated whether the
      down-regulation of endogenous PTHrP expression by transfection with antisense
      oligonucleotides alters cell proliferation or apoptosis resistance in growing or
      nongrowing endothelial cells. Down-regulation of PTHrP did not modify cell
      proliferation, but it increased the amount of UV-induced apoptosis. An increased
      expression of PTHrP in cells pretreated with an alpha-adrenoceptor agonist
      reduced the basal rate of apoptosis and improved resistance against UV-induced
      apoptosis. These results indicate a novel intracrine effect of PTHrP in coronary
      endothelial cells that improves cell survival. In endothelial cells, its
      expression is regulated by alpha-adrenoceptor stimulation in a cell-cycle
      dependent and cell-type-specific manner.

PMID- 12488544
TI  - Mechanism of rat UDP-glucuronosyltransferase 1A6 induction by oltipraz: evidence
      for a contribution of the Aryl hydrocarbon receptor pathway.
AB  - The utility of oltipraz as a cancer chemopreventive agent is thought to depend on
      the induction of enzymes involved in phase 2 xenobiotic detoxification. Although
      studies of some enzymes induced by oltipraz implicate a novel transcriptional
      activating pathway involving Nrf2 and antioxidant-response elements (AREs), the
      mechanism of phenol UGT induction has remained unclear. Previous work showed that
      UGT1A6 is transcribed from two promoters, P1 and P2, that are both induced by
      oltipraz in rat liver. The effect also occurs in rat hepatocytes treated with
      oltipraz (concentrations >3 microM). To investigate the mechanism, luciferase
      reporter plasmids under the control of P1 [p(-1078/+27)1A6P1-luc] or P2 [p(
      1354/+65)1A6P2-luc] were transfected into rat hepatocytes and tested for
      inducibility. P1, but not P2, showed responsiveness to oltipraz (2- to 5-fold
      increase) and 3-methylcholanthrene (10- to 30-fold increase). Because P1
      contained no visible AREs, the role of a xenobiotic response element (XRE)
      centered between bases -134 and -129 was evaluated. Mutation of the XRE core
      reduced the effects of both oltipraz and 3-methylcholanthrene on the P1 reporter.
      The 1A6 XRE conferred oltipraz responsiveness on the simian virus 40 promoter of
      pGL3-Promoter. Comparative effects of oltipraz and 3-methylcholanthrene on
      transfected cytochrome P4501A1 reporters support the general but relatively weak
      XRE-stimulating activity of oltipraz. The involvement of the aryl hydrocarbon
      receptor (AHR) and aryl hydrocarbon nuclear translocator (ARNT) in mediating the
      effects of oltipraz on the XRE is supported by electrophoretic mobility
      supershift data and AHR/ARNT overexpression studies. These data raise questions
      about the contribution of AHR and other secondary induction pathways in the
      mechanism of oltipraz.

PMID- 12488546
TI  - Activation of microsomal glutathione s-transferase by peroxynitrite.
AB  - Peroxynitrite (ONOO-) toxicity is associated with protein oxidation and/or
      tyrosine nitration, usually resulting in inhibition of enzyme activity. We
      examined the effect of ONOO- on the activity of purified rat liver microsomal
      glutathione S-transferase (GST) and found that the activity of reduced
      glutathione (GSH)-free enzyme was increased 4- to 5-fold by 2 mM ONOO-; only 15%
      of this increased activity was reversed by dithiothreitol. Exposure of the
      microsomal GST to ONOO- resulted in concentration-dependent oxidation of protein
      sulfhydryl groups, dimer and trimer formation, protein fragmentation, and
      tyrosine nitration. With the exception of sulfhydryl oxidation, these
      modifications of the enzyme correlated well with the increase in enzyme activity.
      Nitration or acetylation of tyrosine residues of the enzyme using
      tetranitromethane and N-acetylimidazole, respectively, also resulted in increased
      enzyme activity, providing additional evidence that modification of tyrosine
      residues can alter catalytic activity. Addition of ONOO--treated microsomal GST
      to microsomal membrane preparations caused a marked reduction in iron-induced
      lipid peroxidation, which raises the possibility that this enzyme may act to
      lessen the degree of membrane damage that would otherwise occur under
      pathophysiological conditions of increased ONOO- formation.

PMID- 12488545
TI  - Cell-specific extracellular signal-regulated kinase activation by multiple G
      protein-coupled receptor families in hippocampus.
AB  - Several families of G protein-coupled receptors (GPCR) have been shown to
      activate extracellular signal-regulated kinase (ERK) in transfected cells and non
      neuronal systems. However, little is known about GPCR activation of ERK in brain.
      Because ERK is an important component in the regulation of synaptic plasticity,
      in this study we examined ERK activation by three families of GPCR that respond
      to major neuromodulatory neurotransmitters in the hippocampus. We used an
      immunocytochemical approach to examine ERK activation by muscarinic acetylcholine
      (mAChR), metabotropic glutamate (mGluR), and beta-adrenergic (beta-AR) receptors
      in CA1 neurons of mouse hippocampal slices. Because these GPCR families comprise
      receptors coupling to each of the major heterotrimeric G proteins, we examined
      whether ERK activation differs according to G-protein coupling. By using
      immunocytochemistry, we were able to examine not only whether each family of
      receptors activates ERK, but also the cellular populations and subcellular
      distributions of activated ERK. We demonstrated that M1 mAChRs and group I
      mGluRs, both of which are Gq-coupled receptors, activate ERK in CA1 pyramidal
      neurons, although activation in response to mAChR is more robust. The G(i/o)
      coupled group II mGluRs activate ERK in glia scattered throughout CA1, and Gs
      coupled beta-AR receptors activate ERK in scattered interneurons. Thus, we
      demonstrated that GPCR coupling to Gq, G(i/o), and Gs all activate ERK in the
      hippocampus, although each does so with unique properties and distributions.

PMID- 12488547
TI  - Cell-level pharmacokinetic model of granulocyte colony-stimulating factor:
      implications for ligand lifetime and potency in vivo.
AB  - The cytokine granulocyte colony-stimulating factor (GCSF) is of great clinical
      importance, with primary application to rapidly elevate the peripheral neutrophil
      levels of chemotherapy patients through accelerated granulopoiesis. However,
      these mature bloodstream neutrophils express the GCSF receptor (GCSFR),
      presenting a significant and specific clearance mechanism of circulating GCSF
      that increases with time. Here, we formulate a mathematical model that describes
      these cell-level GCSF/GCSFR dynamics and correlate the effect of these endocytic
      trafficking processes to ligand depletion in an in vitro culture. We further
      incorporate this cell-level model into an existing
      pharmacokinetic/pharmacodynamic (PK/PD) model, to gain insight into the effects
      that specific molecular and cellular parameters may have on overall PK/PD effects
      in vivo. Our cell-level model suggests that ligand depletion may be reduced in
      vitro by decreasing the endosomal affinity of endocytosed GCSF/GCSFR complexes,
      matching experimental findings. Additionally, our modified PK/PD model suggests
      that a GCSF analog with a modification that effectively eliminates renal
      clearance should have a significantly longer half-life in vivo and should
      therefore improve peripheral neutrophil counts. This is consistent with clinical
      studies on a polyethylene glycol chemical conjugate of GCSF termed SD/01. The
      model predicts that a GCSF analog that eliminates renal clearance and has reduced
      endosomal binding affinity may result in an even longer ligand half-life and
      increased neutrophil counts at a lower dose than either wild-type GCSF or SD/01.
      More generally, this type of hierarchical model provides a correlation between
      the molecular and pharmacological properties of a drug and may elucidate design
      goals for such protein therapeutics.

PMID- 12488548
TI  - Growth inhibition by the farnesyltransferase inhibitor FTI-277 involves Bcl-2
      expression and defective association with Raf-1 in liver cancer cell lines.
AB  - Farnesyltransferase inhibitors (FTIs) block the growth of tumor cells in vitro
      and in vivo with minimal toxicity toward normal cells. In general, inhibition of
      protein farnesylation results in G0/G1 cell cycle block, G2/M cell cycle arrest,
      or has no effect on cell cycle progression. One aspect of FTI biology that is
      poorly understood is the ability of these drugs to induce cancer cell growth
      arrest at the G2/M phase of cell cycle. In the present study, we investigated the
      effects of the farnesyltransferase inhibitor FTI-277 on two human liver cancer
      cell lines, HepG2 and Huh7. Treatment of these cells with FTI-277 inhibited Ras
      farnesylation in a dose-dependent manner. Both HepG2 and Huh7 cell growth was
      inhibited by FTI-277 and cells accumulated at the G2/M phase of the cell cycle.
      In HepG2 and Huh7 cells, FTI-277 induced an up-regulation of the cyclin-dependent
      kinase inhibitor p27(Kip1) without affecting the cellular levels of p53 and
      p21(Waf1). This event correlated with reduced activity of the cyclin-dependent
      kinase 2 and cyclin-dependent kinase 1. Moreover, increased expression of Bcl-2
      protein was observed in HepG2 and Huh7 cells treated with FTI-277, and this was
      coincidental with reduced association between Raf-1 and Bcl-2. Finally, transient
      transfection of a dominant-negative Ras allele induced Bcl-2 expression and
      reduced Bcl-2/Raf-1 association demonstrating a requirement for Ras. Taken
      together, these findings show that increased expression of p27(Kip1) and Bcl-2 is
      concomitant with altered association between Ras, Raf-1 and Bcl-2 and suggest
      that this is responsible for the growth-inhibitory properties of FTI-277.

PMID- 12488549
TI  - Detection of thymidylate synthase modulators by a novel screening assay.
AB  - Thymidylate synthase (TS), a key cancer chemotherapeutic target, catalyzes the
      conversion of deoxyuridylate to thymidylate. TS can serve as a repressor of its
      own synthesis by binding to its own mRNA through TS-specific binding elements
      (TBEs). In this report, we describe the use of a luciferase reporter plasmid
      containing two TBEs that can be used as a tool for the identification and initial
      profiling of compounds that modulate TS activity, levels, or ability to bind
      mRNA. To validate this model, we evaluated several groups of drugs. Thus, cells
      were exposed to the pyrimidine analogs 5-fluorouracil (5-FU), 5-fluorouridine
      (FUrd), 5-fluoro-2'-deoxyuridine (FUdR), trifluorothymidine (TFT); to the
      nonpyrimidine TS-inhibitors AG-331, nolatrexed (AG337), and raltitrexed (ZD1694);
      or to drugs with other primary sites of action (methotrexate, actinomycin D, 5
      azacytidine, 8-thioguanosine). Except for 5-azacytidine and 8-thioguanosine, all
      compounds examined induced luciferase activity compared with untreated cells.
      Effects of luciferase activity inducing drugs through TS-affected translation
      were confirmed by examinations of TS protein and mRNA levels. Treatment of H630
      C6 cells with 5-FU, FUrd, FUdR, TFT, AG331, AG337, ZD1694, and methotrexate up
      regulated TS levels as determined by Western blot analysis, although TS mRNA
      levels remained unchanged as determined by reverse transcription-polymerase chain
      reaction. Our studies demonstrate a novel application of a TBE-dependent reporter
      plasmid that could be used for the high-throughput identification of potential
      chemotherapeutic agents that modulate TS RNA-binding activity, either directly or
      indirectly.

PMID- 12488550
TI  - Structural characteristics that govern binding to, and modulation through, the
      cardiac ryanodine receptor nucleotide binding site.
AB  - Comparative molecular field analysis (CoMFA) predicts that the large
      electrostatic field around the phosphate groups of ATP plays a crucial role in
      stabilizing the open state of the cardiac ryanodine receptor (RyR) channel. We
      therefore investigated the effects of adenosine-5'-(beta,gamma
      methylenetriphosphate) (AMP-PCP), an ATP analog with lower negative charge in
      this region, on the gating of the cardiac RyR channel. In the presence of 10
      microM cytosolic Ca2+, AMP-PCP exhibited approximately 50% of the efficacy of ATP
      and optimal doses increased open probability (Po) to only 0.441 +/- 0.156 (n =
      4), thus confirming the predictive ability of our preliminary CoMFA model. We
      also reveal that AMP-PCP has a higher affinity than ATP for the cardiac RyR,
      demonstrating that the structural properties required for tight binding to RyR
      differ from those necessary for recruiting long open states and high Po values.
      CoMFA identified very strong correlations between the structures of adenine-based
      ligands and their affinity for RyR and different (but also highly significant)
      correlations between structure and the ability to activate the channel. Analysis
      indicates that ATP may be more effective than other adenine nucleotides because
      it can convert the greatest amount of binding energy into conformational changes
      that stabilize the open channel state.

PMID- 12488551
TI  - Specificity of metabotropic glutamate receptor 2 coupling to G proteins.
AB  - Metabotropic glutamate receptor 2 (mGluR2) is a class 3 G protein-coupled
      receptor and an important mediator of synaptic activity in the central nervous
      system. Previous work demonstrated that mGluR2 couples to pertussis toxin (PTX)
      sensitive G proteins. However, the specificity of mGluR2 coupling to individual
      members of the G(i/o) family is not known. Using heterologously expressed mGluR2
      in rat sympathetic neurons from the superior cervical ganglion (SCG), the
      mGluR2/G protein coupling profile was characterized by reconstituting coupling in
      PTX-treated cells expressing PTX-insensitive mutant Galpha proteins and
      Gbetagamma. By employing this method, it was demonstrated that mGluR2 coupled
      strongly with Galphaob, Galphai1, Galphai2, and Galphai3, although coupling to
      Galphaoa was less efficient. In addition, mGluR2 did not seem to couple to the
      most divergent member of the G(i/o) family, Galphaz, although Galphaz coupled
      strongly to the endogenous alpha2 adrenergic receptor. To determine which Galpha
      proteins may be natively expressed in SCG neurons, the presence of mRNA for
      various Galpha proteins was tested using reverse transcription-polymerase chain
      reaction. Strong bands were detected for all members of the G(i/o) family
      (Galphao, Galphai1, Galphai2, Galphai3, Galphaz) as well as for Galpha11 and
      Galphas. A weak signal was detected for Galphaq and no Galpha15 mRNA was
      detected.

PMID- 12488552
TI  - Inhibition of telomerase increases resistance of melanoma cells to temozolomide,
      but not to temozolomide combined with poly (adp-ribose) polymerase inhibitor.
AB  - In the present study, we have investigated the influence of telomerase inhibition
      in chemosensitivity of melanoma cells to temozolomide (TMZ), a methylating agent
      with promising antitumor activity against metastatic melanoma. In fact,
      telomerase, a ribonucleoprotein enzyme expressed in the majority of tumors, is
      presently considered an attractive target for anticancer therapy, with the double
      aim of reducing tumor growth and increasing chemosensitivity of cancer cells.
      Susceptibility to TMZ and to other antitumor agents used for treatment of
      metastatic melanoma was initially assessed in melanoma lines with different basal
      levels of telomerase activity. Thereafter, chemosensitivity was investigated
      after inhibition of telomerase by means of stable transfection of a catalytically
      inactive, dominant-negative mutant of hTERT (DN-hTERT). This study shows for the
      first time that: a) susceptibility to TMZ of melanoma lines derived from the same
      patient did not depend on basal telomerase activity; b) inhibition of telomerase
      by DN-hTERT resulted in reduced growth rate and increased resistance to TMZ and
      to the chloroethylating agent carmustine, increased sensitivity to cisplatin, and
      no change in response to tamoxifen or to a selective N3-adenine methylating
      agent; c) inhibition of poly(ADP-ribose) polymerase (PARP), an enzyme involved in
      the repair of N-methylpurines, restored sensitivity of DN-hTERT clones to TMZ.
      These results indicate that a careful selection of the antitumor agent has to be
      made when antitelomerase therapy is combined with chemotherapy. Moreover, the
      data presented here suggest that TMZ + PARP inhibitor combination is active
      against telomerase-suppressed and slowly growing tumors.

PMID- 12488553
TI  - The Anti-HIV potency of cyclotriazadisulfonamide analogs is directly correlated
      with their ability to down-modulate the CD4 receptor.
AB  - 9-Benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododecane (CADA)
      has been identified as a novel antiviral lead compound with significant anti
      human immunodeficiency virus and anti-human herpesvirus 7 activity. Surprisingly,
      this compound selectively decreased the expression of the CD4 glycoprotein, the
      primary receptor needed for the entry of both viruses. Herein, we describe the
      CD4 down-modulating and antiviral potencies of more than 25 CADA derivatives.
      Flow cytometric evaluation of cellular CD4 receptor expression in T cells
      demonstrated the specific CD4 down-modulating capacity of the CADA derivatives,
      with IC(50) values similar to those obtained in the antiviral assays. The close
      correlation observed between the CD4 down-regulating and anti-HIV potencies of
      the CADA derivatives further points to CD4 receptor down-modulation as the
      primary mode of antiviral action for this group of compounds.

PMID- 12488555
TI  - All-trans-retinoic acid binds to and inhibits adenine nucleotide translocase and
      induces mitochondrial permeability transition.
AB  - We investigated the effects of retinoic acids on mitochondrial permeability
      transition (MPT) measured as changes in rhodamine 123 fluorescence from both
      isolated heart mitochondria and HeLa cells. We report that all-trans-retinoic
      acid (atRA), 9-cis-retinoic acid, and 13-cis-retinoic acid induce a drop in
      mitochondrial membrane potential in isolated mitochondria. The atRA effect was
      done through the induction of MPT because it was dependent on Ca(2+), in a
      synergic mechanism, and inhibited by cyclosporin A (CsA). Furthermore, atRA also
      opened MPT in vivo, because treatment of HeLa cells with atRA results in a CsA
      sensitive drop of mitochondrial membrane potential. We demonstrated for the first
      time that retinoic acids inhibit adenine nucleotide translocase (ANT) activity in
      heart and liver mitochondria. Kinetic studies revealed atRA as an uncompetitive
      inhibitor of ANT. Photoaffinity labeling of mitochondrial proteins with [3H]atRA
      demonstrated the binding of a 31-kDa protein to atRA. This protein was identified
      as ANT because the presence of carboxyatractyloside, a specific ANT inhibitor,
      prevented labeling. The specific photolabeling of ANT was also prevented in a
      concentration-dependent manner by nonlabeled atRA, whereas palmitic acid was
      ineffective. This study indicates that specific interaction between atRA and ANT
      takes place regulating MPT opening and adenylate transport. These observations
      establish a novel mechanism for atRA action, which could control both energetic
      and apoptotic mitochondrial processes in situations such as retinoic acid
      treatment.

PMID- 12488554
TI  - Key structural features of nonsteroidal ligands for binding and activation of the
      androgen receptor.
AB  - The purposes of the present studies were to examine the androgen receptor (AR)
      binding ability and in vitro functional activity of multiple series of
      nonsteroidal compounds derived from known antiandrogen pharmacophores and to
      investigate the structure-activity relationships (SARs) of these nonsteroidal
      compounds. The AR binding properties of sixty-five nonsteroidal compounds were
      assessed by a radioligand competitive binding assay with the use of cytosolic AR
      prepared from rat prostates. The AR agonist and antagonist activities of high
      affinity ligands were determined by the ability of the ligand to regulate AR
      mediated transcriptional activation in cultured CV-1 cells, using a
      cotransfection assay. Nonsteroidal compounds with diverse structural features
      demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly
      from the bicalutamide-related series, showed a binding affinity superior to the
      structural pharmacophore from which they were derived. Several SARs regarding
      nonsteroidal AR binding were revealed from the binding data, including
      stereoisomeric conformation, steric effect, and electronic effect. The functional
      activity of high-affinity ligands ranged from antagonist to full agonist for the
      AR. Several structural features were found to be determinative of agonist and
      antagonist activities. The nonsteroidal AR agonists identified from the present
      studies provided a pool of candidates for further development of selective
      androgen receptor modulators (SARMs) for androgen therapy. Also, these studies
      uncovered or confirmed numerous important SARs governing AR binding and
      functional properties by nonsteroidal molecules, which would be valuable in the
      future structural optimization of SARMs.

PMID- 12488557
TI  - Monomeric and dimeric byproducts are the principal functional elements of higher
      order P2X1 concatamers.
AB  - Heteromultimeric assembly of ion channel subunits generates high diversity in ion
      channel subtypes with distinct pharmacological and functional properties. To
      determine the subunit stoichiometry and order of ion channels, constructs with
      several concatenated subunits have been widely used in electrophysiological
      studies. Here we used primarily biochemical techniques to analyze the synthesis,
      assembly, and surface expression of P2X1 concatamers. We found that full-length
      concatamers consisting of two to six contiguous copies of the P2X1 subunit,
      although readily synthesized in Xenopus laevis oocytes, were entirely retained as
      aggregates in the endoplasmic reticulum. In contrast, minute levels of lower
      order byproducts, such as monomers and dimers, that were inherently formed with
      all the concatamers combined to form defined protein complexes equal in mass to
      the homotrimeric P2X1 receptor assembled from P2X1 monomers. Besides these
      complexes consisting of three monomers or one monomer plus one concatenated
      dimer, only small amounts of concatenated P2X1 trimers reached the plasma
      membrane. Complexes comprising more than three subunits were not observed in the
      plasma membrane. The byproduct complexes can account fully for the ATP-gated
      currents arising from expression of concatenated P2X1 subunits. These results
      strongly corroborate a trimeric architecture for P2X receptors yet indicate that
      formation of lower order by-products can be a pitfall of the concatamer approach.

PMID- 12488556
TI  - Bryostatin 1 and UCN-01 potentiate 1-beta-D-arabinofuranosylcytosine-induced
      apoptosis in human myeloid leukemia cells through disparate mechanisms.
AB  - The effects of the PKC activator and down-regulator bryostatin 1 and the PKC and
      Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) were compared with respect to
      potentiation of 1-beta-D-arabinofuranosylcytosine (ara-C)-induced apoptosis in
      human myelomonocytic leukemia cells (U937). Whereas bryostatin 1 and UCN-01 both
      markedly enhanced ara-C-induced mitochondrial injury (e.g., cytochrome c and
      Smac/DIABLO release, loss of mitochondrial membrane potential), caspase
      activation, and apoptosis, ectopic expression of an N-terminal loop-deleted Bcl-2
      mutant protein protected cells from ara-C/UCN-01- but not ara-C/bryostatin 1
      mediated lethality. Conversely, ectopic expression of CrmA or dominant-negative
      caspase-8 abrogated potentiation of ara-C-mediated apoptosis by bryostatin 1 but
      not by UCN-01. Exposure of cells to ara-C and bryostatin 1 (but not UCN-01)
      resulted in sustained release of tumor necrosis factor (TNF) alpha; moreover,
      potentiation of ara-C lethality by bryostatin 1 (but not by UCN-01) was reversed
      by coadministration of TNF soluble receptors or the selective PKC inhibitor
      bisindolylmaleimide (1 microM). Finally, similar events were observed in the
      human promyelocytic leukemia cell line HL-60. Together, these findings suggest
      that potentiation of ara-C lethality in human myeloid leukemia cells by
      bryostatin 1 but not UCN-01 involves activation of the extrinsic, receptor
      mediated apoptotic pathway, and represents a consequence of bryostatin 1-mediated
      release of TNF-alpha. They also argue that the mechanism by which bryostatin 1
      promotes ara-C-induced mitochondrial injury, caspase activation, and apoptosis
      involves factors other than or in addition to PKC down-regulation or modulation
      of Bcl-2 phosphorylation status.

PMID- 12488559
TI  - Live attenuated vaccine for the prevention of varicella-zoster virus infection:
      does it work, is it safe and do we really need it in the UK?

PMID- 12488558
TI  - Cloning, sequencing and tissue distribution of rat flavin-containing
      monooxygenase 4: two different forms are produced by tissue-specific alternative
      splicing.
AB  - The nucleotide sequence of rat flavin-containing monooxygenase 4 (FMO4) mRNA was
      obtained by reverse transcription-polymerase chain reaction (RT-PCR) and 5'/3'
      terminal extension. Complete cDNA was amplified, cloned, and sequenced from the
      mRNA obtained from rat kidney and brain. Two different transcripts (short and
      long) stemming from the splicing of an internal region of 189 bases pair,
      corresponding to exon 4 were identified. This alternative splicing seems to be
      specific of the brain. The long cDNA encodes a protein of 560 amino acids with a
      predicted molecular mass of 63,395 Da. The short cDNA encodes a protein of 497
      amino acids with a predicted molecular mass of 55,871 Da. Both of these encoded
      sequences contain the NADPH- and FAD-binding sites and a hydrophilic carboxyl
      terminus. These sequences are 80 and 79% identical to the sequences of human and
      rabbit FMO4. By Northern blotting and/or RT-PCR, the long-form FMO4 mRNA was
      detected in the rat kidney, intestine, and liver and the short form particularly
      in the brain. For the first time, the expression of FMO4 protein was
      demonstrated. By Western blotting using the two different forms of FMO4
      antibodies, a long FMO4 protein was detected in the rat kidney, whereas in the
      rat brain, only the short form of FMO4 was observed.

PMID- 12488560
TI  - Human herpesvirus 6: molecular biology and clinical features.
AB  - Human herpesvirus 6 (HHV-6) exists as distinct variants HHV-6A and HHV-6B. The
      complete genomes of HHV-6A and HHV-6B have been sequenced. HHV-6B contains 97
      unique genes. CD46 is the cell receptor for HHV-6, explaining its broad tissue
      tropism but its restricted host-species range. HHV-6 utilizes a number of
      strategies to down-regulate the host immune response, including molecular mimicry
      by production of a functional chemokine and chemokine receptors.
      Immunosuppression is enhanced by depletion of CD4 T lymphocytes via direct
      infection of intra-thymic progenitors and by apoptosis induction. Infection is
      widespread in infants between 6 months and 2 years of age. A minority of infants
      develop roseola infantum, but undifferentiated febrile illness is more common.
      Reactivation from latency occurs in immunocompromised hosts. Organ-specific
      clinical syndromes occasionally result, but indirect effects including
      interactions with other viruses such as human immunodeficiency virus type 1 and
      human cytomegalovirus or graft dysfunction in transplant recipients may be more
      significant complications in this population. Recent advances in quantitative PCR
      are providing additional insights into the natural history of infection in
      paediatric populations and immunocompromised hosts.

PMID- 12488562
TI  - Relative importance of STAT4 in murine tuberculosis.
AB  - This study was designed to determine the roles of STAT proteins in defence
      against mycobacterial infection. Airborne infection of STAT4 knockout (KO) mice
      with a Mycobacterium tuberculosis strain induced large granulomas with massive
      neutrophil infiltration over time, while that in STAT6 KO mice did not. The STAT4
      KO mice succumbed to mycobacterial infection by the 80th day after infection.
      Compared with the levels in wild-type (WT) and STAT6 KO mice, pulmonary inducible
      nitric oxide synthase, interferon-alpha, -beta and -gamma mRNA levels were
      significantly lower in STAT4 KO mice, but expression of interleukin-2, -6, -12
      and -18 mRNAs was slightly higher up to the fifth week after aerial infection.
      Therefore, STAT4, but not STAT6, appears to be a critical transcription factor in
      mycobacterial regulation.

PMID- 12488561
TI  - Role of RsmA in the regulation of swarming motility and virulence factor
      expression in Proteus mirabilis.
AB  - Swarming by Proteus mirabilis involves differentiation of typical short
      vegetative rods into filamentous hyper-flagellated swarm cells that undergo
      cycles of rapid and co-ordinated population migration across surfaces and exhibit
      high levels of virulence gene expression. RsmA (repressor of secondary
      metabolites) and CsrA, its homologue in Escherichia coli, control many phenotypic
      traits, such as motility and pathogenesis in Erwinia species, glycogen
      biosynthesis, cell size and biofilm formation in Escherichia coli and swarming
      motility in Serratia marcescens. To investigate the role of RsmA in Proteus
      mirabilis, the rsmA gene from Proteus mirabilis (hereafter referred to as
      rsmA(Pm)) was cloned. RsmA(Pm) showed high sequence similarity to Escherichia
      coli CsrA and RsmA cloned from Erwinia carotovora subsp. carotovora, Serratia
      marcescens, Haemophilus influenzae and Bacillus subtilis and could complement an
      Escherichia coli csrA mutant in glycogen synthesis. A low-copy-number plasmid
      carrying rsmA(Pm) expressed from its native promoter caused suppression of
      swarming motility and expression of virulence factors in Proteus mirabilis. mRNA
      stability assays suggested that RsmA(Pm) inhibited virulence factor expression
      through promoting mRNA degradation. RsmA homologues cloned from Serratia
      marcescens and Erwinia carotovora subsp. carotovora could also inhibit swarming
      and virulence factor expression in Proteus mirabilis.

PMID- 12488563
TI  - Evaluation of protection against Chlamydophila abortus challenge after DNA
      immunization with the major outer-membrane protein-encoding gene in pregnant and
      non-pregnant mice.
AB  - The protective effect of DNA vaccination with the gene encoding the major outer
      membrane protein (MOMP) of Chlamydophila abortus has been studied in non-pregnant
      and pregnant mouse models after chlamydial challenge. OF1 outbred mice were
      vaccinated intramuscularly three times every 3 weeks, mated and challenged with
      C. abortus 2 weeks after the last injection of DNA. In non-pregnant mice, the
      MOMP DNA vaccine elicited a specific humoral response with predominantly IgG2a
      antibodies, suggesting a Th1-type immune response. The induced antibodies showed
      no in vitro neutralizing effect on C. abortus infectivity. Moreover, immunization
      with the momp gene showed no reduction in the mean splenic bacterial counts of
      non-pregnant or pregnant mice or in the mean placental bacterial counts of
      pregnant mice after the C. abortus challenge. Nevertheless, the MOMP DNA
      immunization induced a non-specific and partial protection in fetuses against
      challenge.

PMID- 12488564
TI  - Human beta-defensin-2 induction in Helicobacter pylori-infected gastric mucosal
      tissues: antimicrobial effect of overexpression.
AB  - The objective of this study was to understand more of the innate immune response
      to Helicobacter pylori by determining the expression of human beta-defensin-2
      (hBD-2) in various gastric mucosal tissues and MKN45 gastric cancer cells with or
      without H. pylori. Semi-quantitative TaqMan RT-PCR and immunohistochemistry were
      carried out. The antimicrobial effects of a transfected hBD-2 gene against H.
      pylori were also evaluated. The results showed that hBD-2 was expressed in
      inflamed gastric mucosal tissues with H. pylori infection, but not in the absence
      of H. pylori infection. Expression was also detected in gastric cancers in
      patients with H. pylori infection. Expression was induced in the MKN45 gastric
      cancer cell line by H. pylori in a manner dependent on the abundance of bacteria.
      hBD-2-transfected 3T3J2-1 cells secreted hBD-2 protein into the culture medium
      and this protein inhibited growth of H. pylori completely. The results suggest
      that hBD-2 may be involved in the pathophysiology of H. pylori-induced gastritis.

PMID- 12488565
TI  - Identification of Bacillus anthracis by a simple protective antigen-specific mAb
      dot-ELISA.
AB  - A simple protective antigen (PA)-reactive mAb dot-ELISA was standardized for
      confirmation of toxin-producing strains of Bacillus anthracis. Twenty-seven
      clinical isolates were collected from patients clinically suspected of having
      anthrax. PA was elaborated from these isolates using Casamino acids medium and
      the culture medium was boiled to kill the cells. PA in boiled culture
      supernatants was detected using a dot-ELISA. Of the 27 clinical isolates tested,
      PA was detected in 24 isolates. This was further confirmed by amplifying the PA
      gene by PCR. This testing procedure is simple to perform, specific and safer than
      existing procedures, which are added advantages over existing methods of
      identification of B. anthracis. This test system could be a valuable tool in
      confirming clinical and environmental isolates of B. anthracis.

PMID- 12488566
TI  - Detection and genotyping of meningococci using a nested PCR approach.
AB  - An effective vaccine against Neisseria meningitidis serogroup B is required.
      Outer-membrane protein vaccines have been developed, which may provide protection
      against common circulating serotypes and serosubtypes in some countries. However,
      limited genosubtyping data are available because most laboratories use mAbs
      directed against a limited number of specific serotypes and serosubtypes and
      laboratories do not genosubtype directly from body fluids due to the lack of a
      sensitive PCR method. A nested PCR was therefore developed that enables the
      amplification of the porA gene directly from clinical samples and has the
      required sensitivity for nucleotide sequencing of the three main variable
      regions, VR1, VR2 and VR3. Data were compared with those from culture-based
      nucleotide sequencing, and the use of this method increased the availability of
      genosubtype information by 45 %, thereby indicating the impact that this
      methodology has on the data provided and the implications for vaccine design.

PMID- 12488567
TI  - Characterization and comparison of Pasteurella multocida strains associated with
      porcine pneumonia and atrophic rhinitis.
AB  - One hundred and fifty-eight porcine strains of Pasteurella multocida, recovered
      primarily from cases of pneumonic pasteurellosis or progressive atrophic rhinitis
      (PAR) in England and Wales, were characterized by determination of their capsular
      types, presence or absence of the toxA gene and molecular mass heterogeneity of
      the heat-modifiable (OmpA) and porin (OmpH) proteins. Eighteen groups (clones) of
      strains were identified on the basis of specific combinations of capsular type,
      toxA status and outer-membrane protein (OMP)-type. The data provided evidence
      that different subpopulations of P. multocida are responsible for pneumonia and
      PAR in pigs. The majority (88 %) of cases of pneumonia were associated
      exclusively with non-toxigenic capsular type A strains of OMP-types 1.1, 2.1, 3.1
      and 5.1 and capsular type D isolates of OMP-type 6.1. These strains were
      recovered from widespread geographical locations within England and Wales over a
      12-year period and represented mostly single sporadic cases. The association of a
      small number of P. multocida variants with the majority of cases of porcine
      pneumonia suggests that these strains are not opportunistic pathogens of low
      virulence but represent primary pathogens with a relatively high degree of
      virulence. In contrast, the majority (76 %) of cases of PAR were associated with
      toxA-containing capsular type D strains of OMP-type 4.1 and capsular type A and D
      strains of OMP-type 6.1. Toxigenic capsular type A strains associated with PAR
      and non-toxigenic capsular type A strains associated with pneumonia represent
      distinct subpopulations of P. multocida that can be differentiated by their OMP
      types. The association of capsular types A and D with strains of the same OMP
      types, and the absence and presence of the toxA gene in strains of the same OMP
      types, suggest that horizontal transfer of capsular biosynthesis and toxA genes
      has occurred between strains representing certain subpopulations of P. multocida.

PMID- 12488568
TI  - Production by Bacillus pumilus (MSH) of an antifungal compound that is active
      against Mucoraceae and Aspergillus species: preliminary report.
AB  - A compound produced by Bacillus pumilus (MSH) that inhibits Mucoraceae and
      Aspergillus species is described. Fungicidal activity was demonstrated by lawn
      spotting and by diffusion through 0.45 microm Millipore membranes placed on 5 %
      sheep-blood agar, nutrient agar, trypticase soy agar and Mueller-Hinton agar,
      followed by spore inoculation of the bacterium-free underlying agar surface. With
      either technique, zones of fungal inhibition correlated with the zone of
      haemolysis produced by B. pumilus (MSH). The active compound inhibited Mucor and
      Aspergillus spore germination and aborted elongating hyphae, presumably by
      inducing a cell-wall lesion. Antifungal activity was stable in agar for a minimum
      of 8 days, resistant to Pronase degradation, and partially inactivated by
      chloroform exposure and at pH 5.6. Its molecular mass was determined by diffusion
      through dialysis membrane to be 500-3000 Da. Attempts at further isolation of the
      compound have proven unsuccessful to date.

PMID- 12488569
TI  - Impact of meningococcal vaccination with combined serogroups A and C
      polysaccharide vaccine on carriage of Neisseria meningitidis C.
AB  - Two studies of meningococcal carriage state were carried out in Galicia (Spain)
      before and after a mass vaccination campaign between December 1996 and January
      1997 against Neisseria meningitidis serogroup C with meningococcal serogroups A
      and C polysaccharide vaccine. The studies covered two areas with different
      incidence rates of meningococcal disease in 1996 (high and low incidence).
      Carriage rates of serogroup C showed a decrease in both areas, 47 and 65 %
      respectively, before and after the vaccination. Results showed a decrease in
      carrier state in the age groups 10-14- and 15-19-year-olds, but not in the 5-9
      year-olds. These results demonstrate the effect of immunization on the reduction
      of the carriage state.

PMID- 12488570
TI  - Application of terminal RFLP analysis to characterize oral bacterial flora in
      saliva of healthy subjects and patients with periodontitis.
AB  - Terminal restriction fragment-length polymorphism (T-RFLP) analysis was applied
      to characterize oral bacterial flora in saliva from 18 healthy subjects and 18
      patients with periodontitis. The 16S rRNA genes (rDNAs) of oral bacteria and
      spirochaetes in saliva were amplified by PCR with a 6'carboxy-fluorescein (6-FAM)
      labelled universal forward primer (27F) and a universal reverse primer (1492R) or
      the Spirochaeta-selective reverse primer. The 16S rDNAs were digested with
      restriction enzymes with 4 bp recognition sites (HhaI or MspI) and analysed by
      using an automated DNA sequencer. T-RFLP patterns were numerically analysed using
      a computer program. From analysis of the oral bacterial community, patterns
      derived from periodontally healthy subjects and patients with periodontitis were
      grouped into different clusters, though with some uncertainty. Samples from
      patients with periodontitis tended to cluster into their respective types
      (aggressive and chronic periodontitis), although this was not very clear.
      Analysis of spirochaetal community using T-RFLP showed that the patterns derived
      from patients with periodontitis were grouped more as compared with the analysis
      of the oral bacterial community. These results suggest that samples from patients
      with periodontitis contain an unexpected diversity. T-RFLP patterns of 16S rDNAs
      from saliva samples of two periodontally healthy subjects over a 5-week period
      showed host-specific relatively stable oral bacterial flora. Our study indicates
      that T-RFLP analysis is useful for the assessment of diversity of oral bacterial
      flora and rapid comparison of the community structure between subjects with and
      without periodontitis.

PMID- 12488573
TI  - All We Are Saying Is Give Plants a Chance!

PMID- 12488571
TI  - Lack of flagella disadvantages Salmonella enterica serovar Enteritidis during the
      early stages of infection in the rat.
AB  - The roles of flagella and five fimbriae (SEF14, SEF17, SEF21, pef, lpf) in the
      early stages (up to 3 days) of Salmonella enterica serovar Enteritidis (S.
      Enteritidis) infection have been investigated in the rat. Wild-type strains LA5
      and S1400 (fim+/fla+) and insertionally inactivated mutants unable to express the
      five fimbriae (fim-/fla+), flagella (fim+/fla-) or fimbriae and flagella (fim
      /fla-) were used. All wild-type and mutant strains were able to colonize the gut
      and spread to the mesenteric lymph nodes, liver and spleen. There appeared to be
      little or no difference between the fim-/fla+ and wild-type (fim+/fla+) strains.
      In contrast, the numbers of aflagellate (fim+/fla- or fim-/fla-) salmonella in
      the liver and spleen were transiently reduced. In addition, fim+/fla- or fim-/fla
      strains were less able to persist in the upper gastrointestinal tract and the
      inflammatory responses they elicited in the gut were less severe. Thus,
      expression of SEF14, SEF17, SEF21, pef and lpf did not appear to be a
      prerequisite for induction of S. Enteritidis infection in the rat. Deletion of
      flagella did, however, disadvantage the bacterium. This may be due to the
      inability to produce or release the potent immunomodulating protein flagellin.

PMID- 12488572
TI  - Staphylococcus cohnii septicaemia in a patient with colon cancer.
AB  - A coagulase-negative staphylococcal strain was isolated from peripheral blood and
      central venous catheter blood of a febrile patient with cancer. This isolate,
      initially classified by a commercial test as Staphylococcus kloosii, was
      definitively assigned to Staphylococcus cohnii by physiological and molecular
      tests. The strain lacked virulence factors, such as biofilm production and
      haemagglutination, and was sensitive to the antibiotics tested. The data suggest
      that rare micro-organisms with low pathogenic potential can cause severe illness
      in cancer patients; reference identification is required, however, to describe
      correctly the epidemiological characteristics and virulence factors of these
      clinical isolates.

PMID- 12488574
TI  - Vectorial Transcellular Calcium Transport in Intestine: Integration of Current
      Models.
AB  - In spite of decades of research, the exact subcellular pathway for calcium
      transport in intestine has not been elucidated. In this mini-review, we present
      three models for vectorial movement of calcium across the cell: facilitated
      (cytoplasmic) diffusion, vesicular/lysosomal transport, and tunneling through the
      endoplasmic reticulum compartment. We conclude by offering one way to integrate
      elements of these three models.

PMID- 12488575
TI  - Alzheimer Disease and Oxidative Stress.
AB  - Research in Alzheimer disease has recently demonstrated compelling evidence on
      the importance of oxidative processes in its pathogenesis. Cellular changes show
      that oxidative stress is an event that precedes the appearance of the hallmark
      pathologies of the disease, neurofibrillary tangles, and senile plaques. While it
      is still unclear what the initial source of the oxidative stress is in Alzheimer
      disease, it is likely that the process is highly dependent on redox-active
      transition metals such as iron and copper. Further investigation into the role
      that oxidative stress mechanisms seem to play in the pathogenesis of Alzheimer
      disease may lead to novel clinical interventions.

PMID- 12488576
TI  - The Promise of Integrins as Effective Targets for Anticancer Agents.
AB  - This review will briefly describe integrin function, address why integrins are
      attractive targets for chemotherapeutic drug design, and discuss some ongoing
      studies aimed at inhibiting integrin activity. Integrins are cell surface
      heterodimeric receptors. They modulate many cellular processes including: growth,
      death (apoptosis), adhesion, migration, and invasion by activating several
      signaling pathways. Many potential chemotherapeutic agents target integrins
      directly (eg, polypeptides, monoclonal antibodies, adenovirus vectors). These
      agents may be clinically useful in controlling the metastatic spread of cancer.

PMID- 12488577
TI  - Playing Tag with HIF: The VHL Story.
AB  - Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL
      is the cause of inherited VHL disease and is associated with sporadic kidney
      cancer. pVHL is found in a multiprotein complex with elongins B/C, Cul2, and Rbx1
      forming an E3 ubiquitin ligase complex called VEC. This modular enzyme targets
      the alpha subunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated
      destruction. Consequently, tumour cells lacking functional pVHL overproduce the
      products of HIF-target genes such as vascular endothelial growth factor (VEGF),
      which promotes angiogenesis. This likely accounts for the hypervascular nature of
      VHL-associated neoplasms. Although pVHL has been linked to the cell-cycle,
      differentiation, and the regulation of extracellular matrix assembly,
      microenvironment pH, and tissue invasiveness, this review will focus on the
      recent insights into the molecular mechanisms governing the E3 ubiquitin ligase
      function of VEC.

PMID- 12488578
TI  - Perillyl Alcohol Inhibits Breast Cell Migration without Affecting Cell Adhesion.
AB  - The monoterpene d-limonene exhibits chemotherapeutic and chemopreventive
      potential in breast cancer patients. D-limonene and its related compounds,
      perillyl alcohol and perillyl aldehyde, were chosen as candidate drugs for
      application in a screen for nontoxic inhibitors of cell migration. Using the
      nontumorigenic human breast cell line MCF-10A, we delineated the toxicity as
      greatest for the perillyl aldehyde, intermediate for perillyl alcohol, and least
      for limonene. A noncytotoxic concentration of 0.5 mmol/L perillyl alcohol
      inhibited the migration, while the same concentration of limonene failed to do
      so. Adhesion of the MCF-10A cell line and the human breast cancer cell line MDA
      MB 435 to fibronectin was unaffected by 1.5 mmol/L perillyl alcohol. 0.4 mmol/L
      perillyl alcohol inhibited the growth of MDA-MB 435 cells. All migration
      inhibiting concentrations of perillyl alcohol for MDA-MB 435 cells proved to be
      toxic. These results suggest that subtoxic doses of perillyl alcohol may have
      prophylactic potential in the treatment of breast cancer.

PMID- 12488579
TI  - Randomly Amplified DNA Fingerprinting: A Culmination of DNA Marker Technologies
      Based on Arbitrarily-Primed PCR Amplification.
AB  - Arbitrarily-primed DNA markers can be very useful for genetic fingerprinting and
      for facilitating positional cloning of genes. This class of technologies is
      particularly important for less studied species, for which genome sequence
      information is generally not known. The technologies include Randomly Amplified
      Polymorphic DNA (RAPD), DNA Amplification Fingerprinting (DAF), and Amplified
      Fragment Length Polymorphism (AFLP). We have modified the DAF protocol to produce
      a robust PCR-based DNA marker technology called Randomly Amplified DNA
      Fingerprinting (RAF). While the protocol most closely resembles DAF, it is much
      more robust and sensitive because amplicons are labelled with either radioactive
      33P or fluorescence in a 30-cycle PCR, and then separated and detected on large
      polyacrylamide sequencing gels. Highly reproducible RAF markers were readily
      amplified from either purified DNA or alkali-treated intact leaf tissue. RAF
      markers typically display dominant inheritance. However, a small but significant
      portion of the RAF markers exhibit codominant inheritance and represent
      microsatellite loci. RAF compares favorably with AFLP for efficiency and
      reliability on many plant genomes, including the very large and complex genomes
      of sugarcane and wheat. While the two technologies detect about the same number
      of markers per large polyacrylamide gel, advantages of RAF over AFLP include: (i)
      no requirement for enzymatic template preparation, (ii) one instead of two PCRs,
      and (iii) overall cost. RAF and AFLP were shown to differ in the selective basis
      of amplification of markers from genomes and could therefore be used in
      complementary fashion for some genetic studies.

PMID- 12488580
TI  - Quantitative Trait Loci Associated with Foliar Trigonelline Accumulation in
      Glycine Max L.
AB  - The objective of this study was to utilize a Glycine max RIL population to (1)
      evaluate foliar trigonelline (TRG) content in field-grown soybean, (2) determine
      the heritability of TRG accumulation, and (3) identify DNA markers linked to
      quantitative trait loci (QTLs) conditioning variation in TRG accumulation.
      Frequency distributions of 70 recombinant inbred lines showed statistically no
      significant departure from normality (P >.05) for TRG accumulation measured at
      pod development stage (R4). Six different molecular linkage groups (LGs) (B2, C2,
      D2, G, J, and K) were identified to be linked to QTLs for foliar TRG
      accumulation. Two unique microsatellite markers (SSR) on two different linkage
      groups identified QTL significantly associated with foliar TRG accumulation: a
      region on LG J (Satt285) (P =.0019, R(2) = 15.9%) and a second region on LG C2
      (Satt079) (P =.0029, R(2) = 13.4%).

PMID- 12488581
TI  - Analysis of Dystrophin Gene Deletions by Multiplex PCR in Moroccan Patients.
AB  - Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked diseases
      resulting from a defect in the dystrophin gene located on Xp21. DMD is the most
      frequent neuromuscular disease in humans (1/3500 male newborn). Deletions in the
      dystrophin gene represent 65% of mutations in DMD/BMD patients. We have analyzed
      DNA from 72 Moroccan patients with DMD/BMD using the multiplex polymerase chain
      reaction (PCR) to screen for exon deletions within the dystrophin gene, and to
      estimate the frequency of these abnormalities. We found dystrophin gene deletions
      in 37 cases. Therefore the frequency in Moroccan DMD/BMD patients is about 51.3%.
      All deletions were clustered in the two known hot-spots regions, and in 81% of
      cases deletions were detected in the region from exon 43 to exon 52. These
      findings are comparable to those reported in other studies. It is important to
      note that in our population, we can first search for deletions of DMD gene in the
      most frequently deleted exons determined by this study. This may facilitate the
      molecular diagnosis of DMD and BMD in our country.

PMID- 12488582
TI  - DNA Damage, Repair, and Diseases.

PMID- 12488583
TI  - Werner Syndrome.
AB  - Werner syndrome is a premature aging disease caused by the mutation in the WRN
      gene. The cloning and characterization of the WRN gene and its product allows
      investigators to study the disease and the human aging process at molecular
      level. This review summarizes the recent progresses on various aspects of the WRN
      research including functional analysis of the protein, interactive cloning,
      complexes formation, mouse models, and SNPs (single nucleotide polymorphisms).
      These in depth investigations have greatly advanced our understanding of the
      disease and elucidated future research direction for Werner syndrome and the
      human aging process.

PMID- 12488584
TI  - Nucleotide Excision Repair, Genome Stability, and Human Disease: New Insight from
      Model Systems.
AB  - Nucleotide excision repair (NER) is one of several DNA repair pathways that are
      universal throughout phylogeny. NER has a broad substrate specificity and is
      capable of removing several classes of lesions to the DNA, including those that
      accumulate upon exposure to UV radiation. The loss of this activity in NER
      defective mutants gives rise to characteristic sensitivities to UV that, in
      humans, is manifested as a greatly elevated sensitivity to exposure to the sun.
      Xeroderma pigmentosum (XP), Cockaynes syndrome (CS), and trichothiodystrophy
      (TTD) are three, rare, recessively inherited human diseases that are linked to
      these defects. Interestingly, some of the symptoms in afflicted individuals
      appear to be due to defects in transcription, the result of the dual
      functionality of several components of the NER apparatus as parts of
      transcription factor IIH (TFIIH). Studies with several model systems have
      revealed that the genetic and biochemical features of NER are extraordinarily
      conserved in eukaryotes. One system that has been studied very closely is the
      budding yeast Saccharomyces cerevisiae. While many yeast NER mutants display the
      expected increases in UV sensitivity and defective transcription, other
      interesting phenotypes have also been observed. Elevated mutation and
      recombination rates, as well as increased frequencies of genome rearrangement by
      retrotransposon movement and recombination between short genomic sequences have
      been documented. The potential relevance of these novel phenotypes to disease in
      humans is discussed.

PMID- 12488585
TI  - Ku and the Stability of the Genome.
AB  - Ku proteins are associated with a variety of cellular processes such as repair of
      DNA-double-strand breaks, telomere maintenance and retrotransposition. In recent
      years, we have learned a lot about their cellular and molecular functions and it
      has turned out that Ku-dependent processes affect the stability of the genome,
      both positively and negatively, in several ways. This article gives an overview
      on the role of Ku in determining the shape of the genome.

PMID- 12488586
TI  - Answering the Call: Coping with DNA Damage at the Most Inopportune Time.
AB  - DNA damage incurred during the process of chromosomal replication has a
      particularly high possibility of resulting in mutagenesis or lethality for the
      cell. The SOS response of Escherichia coli appears to be well adapted for this
      particular situation and involves the coordinated up-regulation of genes whose
      products center upon the tasks of maintaining the integrity of the replication
      fork when it encounters DNA damage, delaying the replication process (a DNA
      damage checkpoint), repairing the DNA lesions or allowing replication to occur
      over these DNA lesions, and then restoring processive replication before the SOS
      response itself is turned off. Recent advances in the fields of genomics and
      biochemistry has given a much more comprehensive picture of the timing and
      coordination of events which allow cells to deal with potentially lethal or
      mutagenic DNA lesions at the time of chromosomal replication.

PMID- 12488588
TI  - Recombinational DNA Repair in Cancer and Normal Cells: The Challenge of
      Functional Analysis.
AB  - A major goal of current cancer research is to understand the functional
      consequences of mutations in recombinational DNA repair genes. The introduction
      of artificial recombination substrates into living cells has evolved into a
      powerful tool to perform functional analysis of DNA double strand break (DSB)
      repair. Here, we review the principles and practice of current plasmid assays
      with regard to the two major DSB repair pathways, homologous recombination and
      nonhomologous end-joining. A spectrum of assay types is available to assess
      repair in a wide variety of cell lines. However, several technical challenges
      still need to be overcome. Understanding the alterations of DSB repair in cancers
      will ultimately provide a rational basis for drug design that may selectively
      sensitize tumor cells to ionizing radiation and chemotherapy, thereby achieving
      therapeutic gain.

PMID- 12488587
TI  - Homologous Recombination and Its Role in Carcinogenesis.
AB  - Cancer develops when cells no longer follow their normal pattern of controlled
      growth. In the absence or disregard of such regulation, resulting from changes in
      their genetic makeup, these errant cells acquire a growth advantage, expanding
      into precancerous clones. Over the last decade, many studies have revealed the
      relevance of genomic mutation in this process, be it by misreplication,
      environmental damage, or a deficiency in repairing endogenous and exogenous
      damage. Here, we discuss homologous recombination as another mechanism that can
      result in a loss of heterozygosity or genetic rearrangements. Some of these
      genetic alterations may play a primary role in carcinogenesis, but they are more
      likely to be involved in secondary and subsequent steps of carcinogenesis by
      which recessive oncogenic mutations are revealed. Patients, whose cells display
      an increased frequency of recombination, also have an elevated frequency of
      cancer, further supporting the link between recombination and carcinogenesis.

PMID- 12488589
TI  - Regulation of repair by the 26S proteasome.
AB  - Cellular processes such as transcription and DNA repair may be regulated through
      diverse mechanisms, including RNA synthesis, protein synthesis, posttranslational
      modification and protein degradation. The 26S proteasome, which is responsible
      for degrading a broad spectrum of proteins, has been shown to interact with
      several nucleotide excision repair proteins, including xeroderma pigmentosum B
      protein (XPB), Rad4, and Rad23. Rad4 and Rad23 form a complex that binds
      preferentially to UV-damaged DNA. The 26S proteasome may regulate repair by
      degrading DNA repair proteins after repair is completed or, alternatively, the
      proteasome may act as a molecular chaperone to promote disassembly of the repair
      complex. In either case, the interaction between the proteasome and nucleotide
      excision repair depends on proteins like Rad23 that bind ubiquitin-conjugated
      proteins and the proteasome. While the iteration between Rad4 and Rad23 is well
      established, it will be interesting to determine what other proteins are
      regulated in a Rad23-dependent manner.

PMID- 12488591
TI  - DNA Microarrays in Medicine: Can the Promises Be Kept?

PMID- 12488592
TI  - Gene Therapy: Fighting against the Next Plateau.

PMID- 12488590
TI  - XRCC2 is Required for the Formation of Rad51 Foci Induced by Ionizing Radiation
      and DNA Cross-Linking Agent Mitomycin C.
AB  - XRCC2 protein shares weak amino acid sequence similarity with Rad51, which is a
      central player in homologous recombinational repair (HRR). Rad51 proteins
      assemble at the sites of HRR and form visible nuclear foci in response to DNA
      damage. Xrcc2 hamster mutant irs1 cells are incapable of forming Rad51 foci after
      ionizing irradiation or DNA cross-linking agent mitomycin C treatment, though the
      Rad51 protein level is normal in the mutant. The defect can be corrected in an
      XRCC2 transformant. Time course study showed that the irs1 cells primarily lacked
      the early response (2 hours after irradiation) to form small Rad51 foci (type 1)
      and later response (8 hours after irradiation) to form large foci (type 2). These
      results suggested that XRCC2 is essential for the assembly of the DNA damage
      induced Rad51 foci and that XRCC2 may play an important role in the early stage
      of HRR.

PMID- 12488593
TI  - Picking Some News about the Retroviral Vector World from the 9th Symposium of the
      European Society of Gene Therapy.
AB  - The 9th symposium of the European Society of Gene Therapy (ESGT) organized by
      Murat Tuncer (President of the Meeting), Bernd Gansbacher (President of the
      ESGT), and Meral Ozguc (Secretary of the Meeting) took place in Antalya, South
      Turkey, on 2-4 November 2001. Although the international political context made
      difficult the coming of some researchers, this symposium has drawn an interesting
      picture of the works in progress in Europe and in the Mediterranean area.

PMID- 12488594
TI  - Antitumorigenic Evaluation of Thalidomide Alone and in Combination with Cisplatin
      in DBA2/J Mice.
AB  - Thalidomide's reported ability to inhibit angiogenesis has led to clinical trials
      determining its effectiveness in combating various types of cancer. This study
      explored thalidomide's antitumorigenic potential when administered alone and in
      combination with cisplatin to DBA2/J mice whose tumors were induced by murine
      erythroleukemic cells. Thalidomide treatment alone produced no significant
      inhibitory effect on tumor development and metastasis. Mice that received both
      drugs had significantly lower incidences of both primary and secondary tumors as
      compared to the untreated control group. Cisplatin, administered alone or in
      combination with thalidomide, led to a significant delay in tumor formation and a
      longer life span than was recorded in untreated mice. However, the combination
      treatment results were not significantly different from those of cisplatin
      treatment used as a single agent. In in vitro cell multiplication studies using
      murine erythroleukemic and murine endothelial cells, thalidomide failed to
      inhibit cell proliferation. However, cisplatin treatment with or without
      thalidomide, significantly inhibited the multiplication of both cell lines in a
      dose dependent manner. Thalidomide does not appear to be a beneficial adjuvant to
      cisplatin treatment.

PMID- 12488595
TI  - CD36 mRNA and Protein Expression Levels Are Significantly Increased in the Heart
      and Testis of apoE Deficient Mice in Comparison to Wild Type (C57BL/6).
AB  - CD36, an 88kd-adhesion molecule, plays a major role as a scavenging receptor
      implicated in cellular lipid metabolism. Secretory mammary epithelium,
      microvasculature endothelium, adipocytes, smooth muscle cells, and platelets
      express CD36. In addition, CD36 expression is significantly enhanced in
      macrophages differentiating into foam cells. The effect of pathological levels of
      cholesterol, as observed in apoE(-/-), on vascular CD36 expression is, at this
      stage, not known. In this study, a quantitative analysis of CD36 transcription
      and protein expression levels, present in tissues of male C57BL/6 and
      apolipoprotein-E (apoE) deficient mice was carried out by Northern and Western
      blots. Four-week-old animals were fed a chow diet over different periods of time
      (0, 6, 16, or 20 weeks). Immunohistochemistry was used to localize CD36 protein
      expression in the heart and testis. Results indicate that CD36 transcription is
      increased in hearts of apoE deficient animals (100% higher at 6 weeks, and 30%
      higher at 16 and 20 weeks) in comparison to wild type. This was confirmed at the
      protein level, which showed an increase of at least 100% at 6 weeks, and between
      40% to 50% increase at 16 and 20 weeks of apoE(-/-) mice compared to controls. In
      addition, CD36 transcription levels were significantly increased in testis of
      apoE animals (at least 100% at 6, 16, and 20 weeks) compared to C57BL/6 wild
      type. Such an increase was also confirmed at the protein level (65% increase at
      16 weeks in apoE mice compared to control). Finally, localization of CD36 protein
      expression by immunohistochemistry showed that it was expressed in the
      capillaries of heart and testis endothelial cells and also at the head of
      spermatozoid during spermatogenesis. These results indicate that high circulating
      cholesterol levels, in apoE deficient mice, significantly enhance the expression
      of CD36 in the heart and testis. Such enhanced CD36 expression might lead to
      organ remodeling and/or dysfunction.

PMID- 12488596
TI  - Different Forms of Vanadate on Sugar Transport in Insulin Target and Nontarget
      Cells.
AB  - The effects of several vanadates (ie, orthovanadate, pervanadate, and two stable
      peroxovanadium compounds) on basal and insulin-stimulated 2-DG transport in
      insulin target and nontarget cell lines are reported, herein. In nontarget cells,
      exposure to vanadates (5 x 10(-6) to 10(-4) mol/L) resulted in 2-DG transport
      stimulatory responses similar to those observed in 2-DG transport post exposure
      to 667 nmol/L insulin alone, or insulin in combination with vanadates. In 3T3-L1
      adipocytes and L6 myotubes, exposure to a vanadate compound or 67 nmol/L insulin,
      stimulated 2-DG transport dramatically. Again, this effect on stimulated
      transport was similar to 2-DG transport post-treatment with the effective
      vanadates in combination with insulin. While pervanadate or stable
      peroxovanadates stimulated 2-DG transport at 10(-5) to 10(-6) mol/L,
      orthovanadate up to 10(-4) mol/L was not effective in stimulating 2-DG transport
      in any of the cell lines tested. The data indicate that the various
      peroxovanadates are clearly superior insulin mimetics while a more limited
      insulin mimesis is observed with orthovanadate over a wide variety of cell types.

PMID- 12488597
TI  - Diversity of the Brain Dystrophin-Glycoprotein Complex.
AB  - Duchenne muscular dystrophy (DMD), the most common inherited neuromuscular
      disorder, is characterized by progressive muscle wasting and weakness. One third
      of Duchenne patients suffer a moderate to severe, nonprogressive form of mental
      retardation. Mutations in the DMD gene are thought to be responsible, with the
      shorter isoforms of dystrophin implicated in its molecular brain pathogenesis. It
      is becoming clear that region-specific variations in dystrophin isoforms delegate
      the composition of the dystrophin-glycoprotein complex in brain, and hence, the
      function of the specific membrane assembly. Here we summarize the recent advances
      in the understanding of brain dystrophin, dystrophin-related proteins and
      dystrophin-associated proteins.

PMID- 12488598
TI  - Olfactory Ensheathing Glia: Drivers of Axonal Regeneration in the Central Nervous
      System?
AB  - Olfactory ensheathing glia (OEG) accompany olfactory growing axons in their entry
      to the adult mammalian central nervous system (CNS). Due to this special
      characteristic, considerable attention has been focused on the possibility of
      using OEG for CNS regeneration. OEG present a large heterogeneity in culture with
      respect to their cellular morphology and expressed molecules. The specific
      characteristics of OEG responsible for their regenerative properties have to be
      defined. These properties probably result from the combination of several
      factors: molecular composition of the membrane (expressing adhesion molecules as
      PSA-NCAM, L1 and/or others) combined with their ability to reduce glial scarring
      and to accompany new growing axons into the host CNS. Their capacity to produce
      some neurotrophic factors might also account for their ability to produce CNS
      regeneration.

PMID- 12488600
TI  - The Human Genome Revolution or Evolution?

PMID- 12488599
TI  - A Tragic Compromise on Stem Cell Derivation.

PMID- 12488601
TI  - UNESCO Chair of Biophysics and Molecular Neurobiology.

PMID- 12488602
TI  - In Vitro Investigations on the Toxicity and Cell Death Induced by Tamoxifen on
      Two Non-Breast Cancer Cell Types.
AB  - Tamoxifen, a potent anticancer agent known to interrupt the enhanced estrogen
      activity of malignant mammary gland cells, was recently approved by the Food and
      Drug Administration (FDA)for the treatment of breast cancer. In this
      investigation, the toxic effects of tamoxifen were evaluated through cell
      multiplication, and cytological, surface ultrastructural, and biochemical studies
      on human cervical carcinoma cells (HeLa)and/or murine erythroleukemic (MEL) cells
      (BB-88). Tamoxifen treatment demonstrated an inhibitory effect on HeLa cell
      multiplication at lower concentrations and toxicity at higher concentrations and
      longer treatment durations. The drug also triggered morphological and biochemical
      changes as revealed by light microscopy, scanning electron microscopy (SEM),
      fluorescence microscopy, Nucleosome ELISA, and the DNA smear pattern. Cytological
      observations showed nuclear condensation, cell shrinkage, multinucleation, and
      apoptotic bodies. Surface ultrastructure of tamoxifen treated cells examined
      under the SEM revealed abnormalities such as membrane blebbing, holes, and
      cytoplasmic extrusions, all of which are characteristics of programmed cell death
      (apoptosis). Redistribution of the membrane phospholipid phosphatidylserine (PS)
      from the protoplasmic surface of the plasma membrane to the cell surface was
      identified using annexin V-enhanced green fluorescent protein (EGFP) in tamoxifen
      treated MEL BB-88 cells, a general feature of cells undergoing apoptosis.
      Tamoxifen treated cells demonstrated internucleosomal damages of the genomic DNA
      and DNA fragmentations, evidenced by an increase in free nucleosomes, and
      distinctive DNA smear patterns on the agarose gel.

PMID- 12488603
TI  - Interaction Between Mevalonate Pathway and Retinoic Acid-Induced Differentiation.
AB  - All trans retinoic acid (ATRA) is a potent inducer of differentiation of HL-60
      cell line. The pretreatment of the cells by compactin, a competitive inhibitor of
      3-hydroxy-3-methylglutaryl (HMG) CoA reductase, during 24 hours, enhances the
      ATRA-induced cell differentiation. At 50 nM, the percentage of cell
      differentiation is 34.9% +/- 2 and 73% +/- 2.96 in the control and compactin
      treated cells, respectively. The removal of compactin boosts the level of HMG-CoA
      reductase and therefore the biosynthesis of sterol and nonsterol isoprenoid
      compounds. The participation of sterol and nonsterol pathway was then
      investigated. The supply of an excess of cholesterol (up to 80 &mgr;g/ml of LDL)
      leads to a significant decrease of cell differentiation by ATRA from 78% +/-0.1
      to 54% +/-2.8. A concomitant decrease of cell growth (51% +/- 6.4) was observed.
      The pretreatment of cells by the geranylgeranyltransferase inhibitor (GGTI-298)
      has no effect on the cell differentiation process. By contrast, the
      farnesyltransferase inhibitors (FTI-II and FTI-277) completely abolish theATRA
      induced differentiation, thus confirming the involvement of farnesylated proteins
      in the differentiation mechanism.

PMID- 12488604
TI  - Two Novel Frame Shift, Recurrent and De Novo Mutations in the ITGB2 (CD18) Gene
      Causing Leukocyte Adhesion Deficiency in a Highly Inbred North African
      Population.
AB  - We have identified four different mutations causing leukocyte adhesion Deficiency
      (LAD) in the ITGB2 gene of patients from a highly inbred population. Two were
      novel single-bp deletions (1497delG and 1920delG) causing frame shift and the two
      others were the missense mutations G284S and R593C. In our study, the G284S was a
      recurrent mutation while the R593C occurred de novo. We have also characterized a
      novel Xba1 polymorphic site located at the 5' end of the ITGB2 locus. Family
      studies showed that the 1497delG mutation segregated with this marker and the
      intragenic AvaII polymorphic marker, suggesting the presence of a founder effect.
      The observation of a heterogeneous spectrum including de novo and recurrent
      mutations causing LAD in a highly inbred population is rather unexpected. In view
      of the literature published on the molecular genetics of LAD and considering the
      ethnic origin of the patients studied, our findings confirm the heterogeneity of
      the mutations causing LAD and point out potential mutational hot spots in the
      ITGB2 gene.

PMID- 12488605
TI  - A C-Terminal Hydrophobic Region is Required for Homo-Oligomerization of the
      Hepatitis E Virus Capsid (ORF2) Protein.
AB  - Hepatitis E virus (HEV) is the causative agent of hepatitis E, an acute form of
      viral hepatitis. The open reading frame 2 (ORF2) of HEV encodes the viral capsid
      protein, which can self-oligomerize into virus-like particles. To understand the
      domains within this protein important for capsid biogenesis, we have carried out
      in vitro analyses of association and folding patterns of wild type and mutant
      ORF2 proteins. When expressed in vitro or in transfected cells, the ORF2 protein
      assembled as dimers, trimers and higher order forms.While N-terminal deletions
      upto 111 amino acids had no effect, the deletion of amino acids 585-610 led to
      reduced homo-oligomerization. This deletion also resulted in aberrant folding of
      the protein, as determined by its sensitivity to trypsin. This study suggests
      that a C-terminal hydrophobic region encompassing amino acids 585-610 of the ORF2
      protein might be critical for capsid biogenesis.

PMID- 12488606
TI  - The Spectrum of beta-Thalassemia Mutations in the Arab Populations.
AB  - The Arab countries encompass a wide region stretching from the Persian Gulf to
      the Atlantic Ocean. The Arab population is quite heterogeneous and has
      experienced various invasions and migrations throughout history. beta-thalassemia
      is endemic in all countries of the Arab world. Our review of the molecular basis
      of beta-thalassemia in various Arab countries reveals the presence of 52
      mutations, which are mostly of Mediterranean and Asian origin. The distribution
      of mutations reflects the geographical and historical backgrounds of each region.
      However, no specific mutation is confined to the Arabs, although some Arab
      countries do have unique mutations.

PMID- 12488608
TI  - Sunlight and Skin Cancer.

PMID- 12488607
TI  - Identification of Stem Cell Units in the Terminal End Bud and Duct of the Mouse
      Mammary Gland.
AB  - The mouse mammary gland may undergo cycles of proliferation, terminal
      differentiation, tissue remodeling, and more importantly malignant
      transformation.Mammary epithelial stem cells and their progeny participate in
      these processes.Mammary epithelial stem cells are multipotent, exhibit properties
      of self renewal (up to 7 divisions)and may exist either as long-lived nondividing
      cells or as proliferating-differentiating cells. The focus of this study was to
      locate stem cells by identifying them as long-lived, label-retaining mammary
      epithelial cells (LRCs)in growth active (developing)or growth static
      (aged)mammary ducts. Initially, primary epithelial cells were pulse labeled with
      either fluorescent tracker dye and/or BrdU. Cells were then transplanted into
      cleared juvenile syngeneic mammary fat pads and held for 5 weeks or 8 weeks. In
      this study, we demonstrate that LRCs are stem cells and their progeny
      (transitional cells)are arranged as transitional units (TUs). Additionally, TUs
      are located every 250 +/- 75 &mgr;m in ducts or in the terminal end bud 200-600
      &mgr;m in diameter. Molecules expressed in TUs were Zonula Occludens-1 and alpha
      catenin proteins which were significantly detected in 75%-91% (P <0.001)of the
      LRCs cells that make up the TU. These data suggest that transitional units may be
      a group of label-retaining stem cells and maybe involved in the developmental or
      cancer process.

PMID- 12488609
TI  - Some Provocative Thoughts on Damage and Repair of DNA.

PMID- 12488610
TI  - Induction of Apoptosis in Rat Peripheral Blood Lymphocytes by the Anticancer Drug
      CI-994 (Acetyldinaline)(*).
AB  - CI-994 (acetyldinaline) is an investigational anticancer drug currently in
      clinical trials. In preclinical safety studies in rats and dogs, CI-994 resulted
      in significant toxicity to bone marrow and lymphoid tissue. To determine if
      apoptosis was involved in CI-994 toxicity, peripheral blood lymphocytes were
      isolated from untreated male Wistar rats and exposed to CI-994 (1, 3, 10, or 30
      &mgr;M) in vitro for up to 24 hours. Morphological and biochemical features of
      apoptosis were evaluated using several techniques, and lactate dehydrogenase
      (LDH) release was measured as an indicator of cell necrosis. No evidence of
      apoptosis or necrosis was detected in lymphocytes exposed to CI-994 for 4 hours.
      After 24 hours, concentration-dependent increases in apoptosis characterized by
      DNA condensation, DNA fragmentation, and/or externalization of phosphatidyl
      serine were seen at CI-994 concentrations as low as 1 &mgr;M and were
      statistically significant beginning at 10 &mgr;M. Ultrastructural analysis
      confirmed the presence of DNA condensation, DNA fragmentation, cell shrinkage,
      and membrane blebbing in cells exposed to 30 &mgr;M CI-994. After 24 hours, the
      percent of maximum LDH release from lymphocytes treated with 10 and 30 &mgr;M CI
      994 was 7% and 15%, respectively, compared with 0% in the controls. In
      comparison, morphological changes of apoptosis detected by fluorescent microscopy
      were observed in 79% of the lymphocytes at these two concentrations.
      Additionally, apoptosis was seen in more than 24% of lymphocytes exposed to 1 and
      3 &mgr;M CI-994, whereas maximum LDH release was less than or equal to 1% at
      these concentrations. These results show that apoptosis is the primary mode of
      cell death in rat lymphocytes exposed to CI-994 in vitro.

PMID- 12488611
TI  - The Thermal Stability of the Fusarium solani pisi Cutinase as a Function of pH.
AB  - We have investigated the thermal stability of the Fusarium solani pisi cutinase
      as a function of pH, in the range from pH 2-12. Its highest enzymatic activity
      coincides with the pH-range at which it displays its highest thermal stability.
      The unfolding of the enzyme as a function of pH was investigated by
      microcalorimetry. The ratio between the calorimetric enthalpy (DeltaH(cal)) and
      the van't Hoff enthalpy (DeltaH(v)) obtained, is far from unity, indicating that
      cutinase does not exhibit a simple two state unfolding behaviour. The role of pH
      on the electrostatic contribution to the thermal stability was assessed using
      TITRA. We propose a molecular interpretation for the pH-variation in enzymatic
      activity.

PMID- 12488612
TI  - Somatic Embryogenesis, Rhizogenesis, and Morphinan Alkaloids Production in Two
      Species of Opium Poppy.
AB  - A study of somatic embryogenesis and rhizogenesis and their influence on
      production of morphinan alkaloids on two species of opium poppy is presented. We
      identified the ratios of auxin and cytokinin that caused somatic embryogenesis
      and rhizogenesis in hypocotyl and cotyledons of Papaver somniferum album and
      Papaver orientale splendidissimum. The hypocotyls and cotyledons both show
      somatic embryogenesis in Papaver somniferum album whereas only the cotyledons
      were embryogenic in Papaver orientale splendidissimum. For rhizogenesis, the most
      important response is on the cotyledons and leaves in these two species.
      Histology showed characteristic stages of somatic embryo: Globular, cotyledonous,
      and heart cotyledonary. High performance liquid chromatography analysis showed
      that the roots of both species synthesized codeine, thebaine, and papaverine.
      Morphine was only detected in aerial parts of Papaver somniferum album. Codeine
      and thebaine were detected in the rhizogenous but no embryonic callus. These
      results suggest that root organogenesis is causally related to alkaloid
      biosynthesis.

PMID- 12488613
TI  - Response of Escherichia coli Containing Mycobacterial Carotene Genes to UV
      Radiation.
AB  - The plasmid pC5, which encodes biogenesis of lycopene in Mycobacterium aurum
      A(+), was partially digested by restriction endonucleases and generated fragments
      were cloned. After transformation of Escherichia coli (colorless bacteria) with
      the plasmids so constructed, seven orange clones were detected and found to carry
      the same recombinant plasmid (pC51). E. coli cells containing this plasmid
      synthesize neurosporene and lycopene, and were more resistant to ultraviolet
      irradiation than non pigmented strain.

PMID- 12488614
TI  - High-Pressure Biotechnology in Medicine and Pharmaceutical Science.
AB  - High-pressure (HP) biotechnology is an emerging technique initially applied for
      food processing and more recently in pharmaceutical and medical sciences.
      Pressure can stabilize enzymes and modulate both their activity and specificity.
      HP engineering of proteins may be used for enzyme-catalyzed synthesis of fine
      chemicals, pharmaceuticals, and production of modified proteins of medical or
      pharmaceutical interest. HP inactivation of biological agents is expected to be
      applicable to sterilization of fragile biopharmaceuticals, or medical compounds.
      The enhanced immunogenicity of some pressure-killed bacteria and viruses could be
      applied for making new vaccines. Finally, storage at subzero temperatures without
      freezing is another potential application of HP for cells, animal tissues, blood
      cells, organs for transplant, and so forth.

PMID- 12488615
TI  - The Role of Neuraminidase Inhibitors in the Treatment and Prevention of
      Influenza.

PMID- 12488616
TI  - CD26 Immuno-Expression and Periodontal Disease Progression.
AB  - Immunological mechanisms participate in the pathogenesis of human chronic
      inflammatory periodontal disease (CIPD). Human CD4(+) lymphocytes express
      functionally heterogeneous profiles of cytokine production. CD26 is an integral
      membrane glycoprotein, that is, a marker of Th1-like cytokine development. The
      purpose of the present study was to compare the immuno-expression of CD26
      receptor in periodontal sites with and without clinical attachment loss (CAL).
      Five patients with rapidly progressing periodontitis and one with juvenile
      periodontitis were investigated. Each patient presented at least one site with
      and without CAL. Ten sites with CAL and nine without any CAL were biopsied,
      followed by the immunohistochemical identification of the CD26 receptor using the
      MIB-DS2/7 antibody. The results demonstrated that the percentage of positive
      cells for this antigen in the periodontal sites with CAL was not significantly
      different from those without attachment loss. Therefore, Th1 cell impairment may
      not be directly involved with periodontal attachment loss.

PMID- 12488617
TI  - Journal of Biomedicine and Biotechnology.

PMID- 12488618
TI  - Telomeres in Cancer Therapy.

PMID- 12488619
TI  - A Model for UV-Induction of Skin Cancer.

PMID- 12488620
TI  - Genetic Stabilization by p53 Involves Growth Regulatory and Repair Pathways.
AB  - p53 performs a plethora of activities, which are directed towards the maintenance
      of the genomic integrity and constitute its universal role as a tumor suppressor.
      1000 to 10000 latent p53 molecules are permanently available in order to monitor
      DNA exchange processes in mitotically growing cells. After the introduction of
      major DNA injuries the levels of posttranslationally modified p53 proteins rise,
      which in turn transcriptionally signal transient cell cycle arrest or apoptotic
      cell death, depending on the extent of damage. Taken together, p53 inhibits the
      manifestation of genomic instabilities at different control levels both during
      naturally occurring metabolic processes and in response to genotoxic treatments.

PMID- 12488621
TI  - Trypanosoma cruzi-Induced Host Immune System Dysfunction: A Rationale for
      Parasite Immunosuppressive Factor(s) Encoding Gene Targeting.
AB  - An intense suppression of T cell proliferation to mitogens and to antigens is
      observed in a large number of parasitic infections. The impairment of T cell
      proliferation also occurred during the acute phase of Chagas' disease, caused by
      the intracellular protozoan parasite Trypanosoma cruzi. A wealth of evidence has
      accumulated that illustrates the ability of T. cruzi released molecules to
      influence directly a variety of diverse immunological functions. In this paper,
      we review the data concerning the immunoregulatory effects of T. cruzi Tc24 (a B
      cell activator antigen) and Tc52 (an immunosuppressive protein) released
      molecules on the host immune system. The gene targeting approach developed to
      further explore the biological function(s) of Tc52 molecule, revealed interesting
      unexpected functional properties. Indeed, in addition to its immunusuppressive
      activity a direct or indirect involvement of Tc52 gene product alone or in
      combination with other cellular components in T. cruzi differentiation control
      mechanisms have been evidenced. Moreover, targeted Tc52 replacement allowed the
      obtention of parasite mutants exhibiting low virulence in vitro and in vivo.
      Thus, the generation of a complete deficiency state of virulence factors by gene
      targeting should provide a means to assess the importance of these factors in the
      pathophysiological processes and disease progression. It is hoped that such
      approaches might allow rational design of tools to control T. cruzi infections.

PMID- 12488622
TI  - The Human Y Chromosome: The Biological Role of a "Functional Wasteland"
AB  - "Functional wasteland," "Nonrecombining desert" and "Gene-poor chromosome" are
      only some examples of the different definitions given to the Y chromosome in the
      last decade. In comparison to the other chromosomes, the Y is poor in genes,
      being more than 50% of its sequence composed of repeated elements. Moreover, the
      Y genes are in continuous decay probably due to the lack of recombination of this
      chromosome. But the human Y chromosome, at the same time, plays a central role in
      human biology. The presence or absence of this chromosome determines gonadal sex.
      Thus, mammalian embryos with a Y chromosome develop testes, while those without
      it develop ovaries (Polani, 1981). What is responsible for the male phenotype is
      the testis-determining SRY gene (Sinclair, 1990) which remains the most
      distinguishing characteristic of this chromosome. In addition to SRY, the
      presence of other genes with important functions has been reported, including a
      region associated to Turner estigmata, a gene related to the development of
      gonadoblastoma and, most important, genes related to germ cell development and
      maintenance and then, related with male fertility (Lahn and Page, 1997). This
      paper reviews the structure and the biological functions of this peculiar
      chromosome.

PMID- 12488623
TI  - Breaching the Kinetic Barrier to In Vitro Somatic Stem Cell Propagation.
AB  - Here we have reviewed the conventional definitions and fundamental
      characteristics of the two basic types of stem cells, embryonic stem cells (ESCs)
      and somatic stem cells (SSCs). By taking into account the often-overlooked
      asymmetric cell kinetics of SSCs, we consider the evidence that should SSCs
      retain these growth kinetics in vitro, a natural kinetic barrier to SSC
      propagation exists. Recent discoveries showing that the tumor suppressor gene p53
      can act as a regulator of asymmetric cell kinetics provide a target pathway for
      in vitro SSC propagation strategies.

PMID- 12488625
TI  - Genomic Regions That Underlie Soybean Seed Isoflavone Content.
AB  - Soy products contain isoflavones (genistein, daidzein, and glycitein) that
      display biological effects when ingested by humans and animals, these effects are
      species, dose and age dependent. Therefore, the content and quality of
      isoflavones in soybeans is a key to their biological effect. Our objective was to
      identify loci that underlie isoflavone content in soybean seeds. The study
      involved 100 recombinant inbred lines (RIL) from the cross of 'Essex' by
      'Forrest,' two cultivars that contrast for isoflavone content. Isoflavone content
      of seeds from each RIL was determined by high performance liquid chromatography
      (HPLC). The distribution of isoflavone content was continuous and unimodal. The
      heritability estimates on a line mean basis were 79% for daidzein, 22% for
      genistein, and 88% for glycitein. Isoflavone content of soybean seeds was
      compared against 150 polymorphic DNA markers in a one-way analysis of variance.
      Four genomic regions were found to be significantly associated with the
      isoflavone content of soybean seeds across both locations and years. Molecular
      linkage group B1 contained a major QTL underlying glycitein content (P = 0.0001,
      R(2) = 50.2%), linkage group N contained a QTL for glycitein (P = 0.0033, R(2) =
      11.1%) and a QTL for daidzein (P = 0.0023, R(2) = 10.3%) and linkage group A1
      contained a QTL for daidzein (P = 0.0081, R(2) = 9.6%). Selection for these
      chromosomal regions in a marker assisted selection program will allow for the
      manipulation of amounts and profiles of isoflavones (genistein, daidzein, and
      glycitein) content of soybean seeds. In addition, tightly linked markers can be
      used in map based cloning of genes associated with isoflavone content.

PMID- 12488624
TI  - Cellular Senescence: Ex Vivo p53-Dependent Asymmetric Cell Kinetics.
AB  - Although senescence is a defining property of euploid mammalian cells, its
      physiologic basis remains obscure. Previously, cell kinetics properties of normal
      tissue cells have not been considered in models for senescence. We now provide
      evidence that senescence is in fact the natural consequence of normal in vivo
      somatic stem cell kinetics extended in culture. This concept of senescence is
      based on our discovery that cells engineered to conditionally express the well
      recognized tumor suppressor protein and senescence factor, p53, exhibit
      asymmetric cell kinetics. In vivo, asymmetric cell kinetics are essential for
      maintenance of somatic stem cells; ex vivo, the same cell kinetics yield
      senescence as a simple kinetic endpoint. This new "asymmetric cell kinetics
      model" for senescence suggests novel strategies for the isolation and propagation
      of somatic tissue stem cells in culture.

PMID- 12488626
TI  - The Impact of Genetic Diseases on Jordanians: Strategies Towards Prevention.

PMID- 12488627
TI  - Add new technology to your wish list.

PMID- 12488628
TI  - Time to get healthy.

PMID- 12488629
TI  - Can room and board lead to hidden revenue?
AB  - Review how a hospital's financial department builds inpatient room and board
      charges.

PMID- 12488630
TI  - New year, new compliance issues.
AB  - Ensure your department's continued compliance with the Joint Commission's
      standards.

PMID- 12488631
TI  - Avoid the pitfalls of progress.
AB  - As health care technology options increase--namely, infrared ID systems--so do
      your legal liabilities.

PMID- 12488632
TI  - Leapfrog Group jumps over nursing.

PMID- 12488634
TI  - Guide nursing's next generation.

PMID- 12488635
TI  - Achieve best practice with an evidence-based approach. Create a collaborative
      environment that improves patient care through consistent outcomes measurement.
AB  - Ensure quality and identify room for growth within your progressive care unit
      with pointed outcomes measurement.

PMID- 12488636
TI  - Safeguarding patient privacy. Establish department compliance with new federal
      regulations on individually indentifiable health information.
AB  - New patient privacy standards require managers to rethink daily unit policies and
      procedures. Here's what you need to know to comply with the impending federal
      mandates.

PMID- 12488637
TI  - Match critical care situations with savvy devices. High-tech solutions give a new
      twist to familiar procedures.
AB  - Advances in cardiac resynchronization therapy, stents, robotics, and monitoring
      offer patients new treatment options.

PMID- 12488638
TI  - Infection control risks "engineered out". Engineering controls foster better hand
      hygiene, aseptic techniques, and management of invasive devices.
AB  - Health care providers remain in an ideal position to discover and implement new
      methods of infection prevention and control.

PMID- 12488639
TI  - Eyeing IT trends and challenges. To predict healthcare's future, look at the
      industry's current business environment.
AB  - General health care industry business objectives and goals drive technology
      implementation within the hospital setting.

PMID- 12488640
TI  - Advancing vascular access. Improve safety through heightened device performance.
AB  - Federal law mandates the use of safety intravenous (I.V.) equipment in most U.S.
      health care settings. In response, I.V. device manufacturers offer a wider
      variety of safety products that target reduction of site incidents.

PMID- 12488641
TI  - Scan your way to a comprehensive electronic medical record. Augment medication
      administration accuracy and increase documentation efficiency with bar coding
      technology.
AB  - As a pioneer of patient safety, the Department of Veterans Affairs continues to
      develop a variety of computerized tools to reduce medication errors.

PMID- 12488642
TI  - Protecting perineal skin integrity. Incontinent patients present unique
      challenges to successful skin care management.
AB  - Improve your understanding of the factors that contribute to perineal skin
      breakdown in incontinent patients and how to prevent or manage this condition.

PMID- 12488643
TI  - Intravascular ultrasound assessment of longitudinal plaque distribution patterns
      in patients with angiographically silent coronary artery disease after heart
      transplantation.
AB  - AIMS: The purpose of this three-dimensional intracoronary ultrasound (ICUS) study
      was to assess longitudinal plaque distribution patterns in patients with
      angiographically silent coronary artery disease (CAD) after heart transplantation
      (HTX). METHODS AND RESULTS: Out of 334 patients without diameter stenosis >/=25%
      determined by coronary angiography, 321 underwent successful three-dimensional
      ICUS (30 MHz) of the left main coronary artery (LMCA) and all segments of the
      left anterior descending coronary artery (LAD). Early plaque formation was found
      in 296 patients (92.2%). Single (focal CAD, n = 65) or multiple (polyfocal CAD, n
      = 77), discrete coronary lesions were found in 142 patients and continuous plaque
      formation of at least one entire coronary segment (diffuse CAD) in 154 patients.
      Using multivariate regression analysis, male sex (P = 0.01), increasing post
      transplantation time (P = 0.003) and increasing donor age (P = 0.001) were
      independent clinical predictors for diffuse CAD. Both focal and diffuse CAD most
      frequently affected the proximal LAD (88% compared with 89.6%, NS). The mean
      intimal index of each LAD segment was significantly higher in patients with
      diffuse CAD (P < 0.001) and showed a proximal-to-distal decline in patients with
      focal/polyfocal (LMCA, 10.1 +/- 14.3, LAD-6, 30.1 +/- 17.4%, LAD-7, 16.3 +/-
      14.1%, LAD-8, 4.6 +/- 11.1%; P < 0.001) and diffuse (LMCA, 27.0 +/- 16.0, LAD-6,
      47.8 +/- 16.1%, LAD-7, 41.9 +/- 14.5%, LAD-8, 24.9 +/- 23.3%; P < 0.01) CAD.
      CONCLUSION: Evaluation of longitudinal plaque distribution after HTX by three
      dimensional ICUS revealed a time-dependent increase in the incidence of diffuse
      CAD and a proximal-to-distal decline in frequency and magnitude of early plaque
      formation.

PMID- 12488644
TI  - Decrease of vascular smooth muscle cell locomotion by abciximab, but not
      tirofiban: a possible role of different affinity to alpha v beta 3 integrins.
AB  - AIM: The EPISTENT and EPIC studies demonstrated a reduction of clinically driven
      re-interventions after percutaneous transluminal coronary angioplasty (PTCA) and
      stent implantation in patients treated with abciximab, while for tirofiban no
      similar effects could be demonstrated. This may be explained by the different
      effects on the migratory and invasive potential of vascular smooth muscle cells
      (VSMCs) by integrin alpha v beta 3 blockade. Therefore, the objective of this
      study was to compare the effectiveness of abciximab and tirofiban to affect VSMC
      migration and invasion. METHODS: Vascular smooth muscle cells were treated with
      abciximab (0.1-1 microg/ml), tirofiban (0.1-1 microg/ml), and the alpha v beta 3
      specific antibody LM609 (1-5 microg/ml), that was used as a positive control
      during the assay (treatment) over 24 h before the assay (pre-treatment), or
      before and during the assay (combined treatment). Sodium 3'-[1
      (phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxyy-6-nitro) benzene sulfonic
      acid (XTT)-assay and cell counting measured the influence of the substances on
      VSMC proliferation. Using a Boyden Chamber model, the capability of VSMCs for
      migration and invasion was tested with different chemo-attractants and barriers.
      RESULTS: Any influence of the platelet glycoprotein (GP) IIb/IIIa receptor
      (integrin alpha IIb beta 3) antagonists on VSMC proliferation could be excluded.
      After combined treatment, abciximab demonstrated a dose-dependent inhibition of
      migration (IC50 = 33 microg/ml) and invasion (IC50 = 0.5 microg/ml) of VSMCs.
      Administration during the assay without pre-treatment inhibited migration
      similarly (IC50 = 32 microg/ml) but invasion to a significant lower extent (IC50
      = 44 microg/ml). Administration of tirofiban during the assay with or without pre
      treatment had no inhibitory effect on VSMC migration and invasion. Pre-treatment
      alone with one of the substances also did not alter VSMC migration or invasion.
      CONCLUSION: Abciximab administration in physiological concentrations was capable
      of significantly inhibiting the migratory and invasive potential of VSMCs, while
      for tirofiban no similar effect could be demonstrated.

PMID- 12488645
TI  - Magnetic resonance imaging versus Doppler guide wire in the assessment of
      coronary flow reserve in patients with coronary artery disease.
AB  - BACKGROUND: Coronary flow velocity reserve (CFVR), defined as the ratio of
      maximal hyperaemic to baseline flow velocity, has been validated as a marker of
      physiological significance of a coronary lesion. Clinically, this parameter is
      measured invasively during X-ray angiography using the Doppler guide wire. With
      magnetic resonance (MR) imaging it is possible to quantify CFVR non-invasively.
      DESIGN: The purpose of the study was to compare CFVR, acquired with MR imaging
      and the Doppler guide wire in patients with coronary artery disease. METHODS:
      Twenty-two patients suffering from one- or two-vessel coronary artery disease as
      derived from diagnostic X-ray coronary angiography were included. Coronary flow
      velocity reserve was measured at baseline and during maximal hyperaemia, obtained
      by intravenous administration of adenosine using MR phase contrast velocity
      quantification. Within 2 weeks CFVR was measured invasively with a Doppler guide
      wire. RESULTS: In 26 coronary arteries CFVR was acquired with both techniques.
      Mean CFVR in the stenosed and healthy reference arteries was 1.5 +/- 0.7 and 2.7
      +/- 1.0 (P < 0.01) respectively for MR measurements and 1.9 +/- 0.7 and 3.1 +/-
      0.6 (P < 0.01) respectively for Doppler measurements. Bland-Altman analysis
      revealed a non-significant mean difference between the two techniques of 0.4 +/-
      1.2. CONCLUSION: In a selected group of stable patients with coronary artery
      disease MR flow velocity quantification provides non-invasive data equivalent to
      the invasive Doppler guide wire data. Variability in both the MR and Doppler
      ultrasound measurement resulted in a significant scatter of data without
      systematic difference.

PMID- 12488646
TI  - Treatment of totally occluded saphenous vein grafts using self-expanding stents.
AB  - Patients with saphenous vein graft (SVG) disease represent an increasing
      proportion of those referred for percutaneous coronary intervention. The success
      of treatment of occluded SVG with percutaneous intervention has been limited by
      frequent occurrence of no-reflow phenomenon. Use of self-expanding stents with
      low pressure pre- and post-dilation may improve success by limiting embolism of
      atherothrombotic debris. The self-expanding stents provide a meshed design that
      helps to trap the atherothrombotic debris between the vessel wall and stent
      struts. Results with two patients are described to illustrate the proposed
      technique that appears to limit no-reflow during and immediately after the
      procedure. Adjunctive treatment with a GP IIb-IIIa inhibitor is likely to be of
      benefit as well. Additional studies are required to demonstrate definitively the
      potential benefits of this approach.

PMID- 12488647
TI  - Pravastatin promotes coronary collateral circulation in patients with coronary
      artery disease.
AB  - BACKGROUND: Previous studies suggested that hydroxymethylglutaryl coenzyme A
      reductase inhibitor (statin) promotes collateral circulation in ischemic limbs of
      rabbits. The present study was designed to determine the association between
      treatment with pravastatin and the development of coronary collateral circulation
      as assessed by the Rentrop Score in patients with coronary artery disease (CAD)
      in a case-control study. DESIGN: The study included patients who had one (1-V),
      two (2-V) or three (3-V) significantly stenosed vessels. Patients who did and did
      not receive pravastatin were defined as case participants (n = 42) and control
      participants (n = 100), respectively. RESULTS: The case participants included a
      higher percentage of 3-V patients with a Rentrop Score 1 compared to the control
      participants but there was no difference among 1-V and 2-V patients, suggesting
      that pravastatin was associated with coronary collateral circulation independent
      of the number of stenosed vessels. Patients with 3-V disease who were treated
      with pravastatin were most likely [odds ratio (confidence interval), 17.4 (4.4
      115)] to develop collateral circulation, as assessed by multiple logistic
      regression analysis. CONCLUSIONS: Treatment with pravastatin was associated with
      the development of collateral circulation in patients with CAD, suggesting that
      such action constitutes part of the pleiotropic effects of statin.

PMID- 12488648
TI  - What is the white-coat effect and how should it be measured?
AB  - The white coat effect is conceived as a measure of the blood pressure response to
      a clinic visit, but there is no agreement as to exactly how it should be defined.
      The most widely used definition is the difference between the average clinic and
      daytime ambulatory blood pressures, but other methods that have been used include
      the difference between clinic and home pressures, measurements using ambulatory
      blood pressures only, clinic measurements only, and laboratory (reactivity)
      testing. Few studies have compared the different methods, but the reactivity
      method has reported bigger changes of blood pressure and heart rate than the
      others. The effect tends to be greater in older than younger patients, in women
      than in men, but is present to a greater or lesser degree in almost all
      hypertensive patients. It is diminished but not obliterated by drug treatment. It
      is not closely related to overall blood pressure variability, and does not
      predict cardiovascular risk. The white coat effect appears to be idiosyncratic to
      the clinic setting.

PMID- 12488649
TI  - Blood pressure variability in obstructive sleep apnea: role of sympathetic
      nervous activity and effect of continuous positive airway pressure.
AB  - BACKGROUND: Many studies support a link between obstructive sleep apnea (OSA),
      increased blood pressure (BP) and/or BP variability, and sympathetic nervous
      system (SNS) activity. We assessed the relationship between SNS activity and 24-h
      BP variability in patients with OSA, and the effect of continuous positive airway
      pressure (CPAP) on BP variability. DESIGN: Forty-one patients with a respiratory
      disturbance index (RDI) > 15 were randomized into CPAP or CPAP placebo groups for
      a 1-week trial. METHODS: Ambulatory BP, 24-h urine norepinephrine (NE) and
      polysomnography were measured prior to treatment and after 1 and 7 days of
      treatment. RESULTS: Neither RDI nor 24-h urine NE levels were related to 24-h
      mean BP levels. While RDI was associated only with night-time BP variability,
      daytime urine NE levels were associated with both night-time and daytime BP
      variability. After treatment, the BP variability decreased significantly but
      equally in both active and placebo CPAP groups. CONCLUSIONS: Obstructive sleep
      apnea is more related to BP variability than BP. Sympathetic nervous activity, as
      inferred from daytime urine NE, is related to changes in BP variability in OSA
      patients. BP variability is not specifically affected by CPAP.

PMID- 12488650
TI  - Hidden errors of aneroid sphygmomanometers.
AB  - BACKGROUND: Measurement of blood pressure remains the most commonly performed
      screening test in medical practice. With the likely removal of mercury
      sphygmomanometers from the workplace alternative devices are required. Of these
      the aneroid sphygmomanometer is popular both in the community and hospital
      setting. We investigated the accuracy of all the aneroid and mercury
      sphygmomanometers during dynamic calibration within a tertiary referral maternity
      hospital. METHODS: We compared the accuracy of 39 aneroid and 36 mercury
      sphygmomanometers to a recently calibrated and serviced mercury sphygmomanometer
      (the accepted gold standard). All devices were in current clinical use. Using
      three blinded, trained observers, 30 different pressures were checked throughout
      the pressure range following British Hypertension Society protocol guidelines.
      RESULTS: Only 31 (86%) of the mercury devices and 36 (92%) of the aneroid devices
      were in adequate working condition and suitable for analysis. Significantly more
      aneroid devices had systematic errors of > 5 mmHg (19 versus 3%, < 0.05). Fifty
      percent of aneroid devices had at least one reading > 10 mmHg out compared to
      only 10% of mercury devices (chi square programme). CONCLUSIONS: Aneroid
      sphygmomanometers in apparent good working order are inaccurate compared to
      mercury devices. Some of these faults can only be detected during dynamic
      testing. To minimize the risk of erroneous blood pressure recording, aneroid
      devices should be regularly checked for accuracy using dynamic calibration
      methods as recommended in validation protocols.

PMID- 12488651
TI  - Limitations of current validation protocols for home blood pressure monitors for
      individual patients.
AB  - BACKGROUND: Automatic blood pressure monitoring conducted at home is increasingly
      used in the diagnosis and management of hypertension. We assessed the adequacy of
      existing British Hypertension Society (BHS) and Association for the Advancement
      of Medical Instrumentation (AAMI) validation standards for automatic blood
      pressure monitoring devices. SUBJECT AND METHODS: A theoretical study and an
      empirical test are presented to estimate the proportion of persons for whom a
      blood pressure monitor validated according to existing BHS and AAMI standards
      would be inaccurate. RESULTS: The results suggest that a major limitation of both
      protocols is the lack of attention given to the number of individual patients for
      whom a monitor may be inaccurate. A blood pressure monitor that meets the AAMI
      and BHS validation criteria may report blood pressures in error by more than 5
      mmHg for more than half of the people. CONCLUSIONS: A validation standard that
      does not take account of the person-effects on error will lead to a substantial
      proportion of persons using self-monitors that are systematically inaccurate for
      that person.

PMID- 12488652
TI  - Validation of the Microlife BP 3BTO-A oscillometric blood pressure monitoring
      device according to a modified British Hypertension Society protocol.
AB  - BACKGROUND: The market for devices for the self-measurement of blood pressure is
      growing, and as accuracy is of prime importance, there is increasing pressure for
      manufacturers to provide evidence of independent testing. Recent reviews have
      shown that only five automated upper arm devices for self-measurement of blood
      pressure have been recommended for use. We tested the Microlife BP 3BTO-A, a
      lightweight, upper arm, automated oscillometric device, according to a modified
      version of the British Hypertension Society protocol and also analysed the
      computer-generated oscillograms for possible causes of inaccuracy. METHODS: One
      hundred and twenty-six subjects were recruited from general medical and
      specialist clinics and from amongst the staff at Guy's and St Thomas' Hospital,
      London, UK. Only 85 of these were included in the final analysis. Nine sequential
      readings were taken by two trained observers alternating between the mercury
      sphygmomanometer and the device. The last seven readings were analysed according
      to the British Hypertension Society protocol. Modifications to the protocol were:
      (1) the exclusion of patients whose blood pressure varied by more than 15 mmHg
      between sequential observer readings and (2) limited testing in the low systolic
      pressure range. RESULTS: The Microlife achieved a grade A for both systolic and
      diastolic pressure according to the British Hypertension Society protocol. The
      mean differences (standard deviation) between the observers and the device were 
      1.6 (7.7) mmHg and -2.1 (6.3) mmHg for systolic and diastolic blood pressure,
      respectively, therefore also fulfilling the criteria set by the Association for
      the Advancement of Medical Instrumentation. Sub-analysis for different pressure
      ranges showed that the device was less accurate in the high-pressure range
      (>160/100 mmHg). CONCLUSION: The Microlife can be recommended for clinical use in
      an adult population.

PMID- 12488653
TI  - Inflationary oscillometric blood pressure monitoring: validation of the OMRON
      MIT.
AB  - BACKGROUND: To evaluate the accuracy of the OMRON-MIT, (an automated inflationary
      oscillometric blood pressure monitoring device) for use in the general population
      by direct comparison to standard auscultatory mercury sphygmomanometry. DESIGN:
      Two trained, blinded observers taking simultaneous blood pressure measurements
      alternating between a mercury sphygmomanometer and the OMRON-MIT. METHODS: The
      evaluation was carried out according to the revised British Hypertension Society
      protocol. The validation data was also classified by the American Association for
      the Advancement of Medical Instrumentation (AAMI). RESULTS: The OMRON-MIT device
      achieved a BHS grade A for both systolic blood pressure (SBP) and diastolic blood
      pressure (DBP). It also met the criteria for the AAMI protocol, the mean
      difference between the MIT and standard was -2.0 +/- 7 mmHg for SBP and -2.0 +/-
      6 mmHg for DBP. CONCLUSIONS: Inflationary oscillometry is a valid technique for
      the measurement of blood pressure. The OMRON-MIT, which uses this technique, is
      accurate and can be recommended for clinical use in the adult population.

PMID- 12488654
TI  - Diagnostic value of simultaneous non-invasive continuous, ambulatory finger blood
      pressure and electrocardiogram monitoring in a patient with hypertrophic
      obstructive cardiomyopathy.
AB  - BACKGROUND: The pathophysiology of hypertrophic obstructive cardiomyopathy (HOCM)
      is complex and heterogeneous, and it may be difficult to disentangle the various
      pathophysiologic properties leading to complaints. OBJECTIVES: To elucidate the
      sequence of acute pathophysiologic changes leading to complaints in a patient
      with HOCM. METHODS: Cardiopres measurements [the combination of non-invasive,
      continuous finger artery blood pressure monitoring, and three-lead
      electrocardiogram (ECG) recordings] were performed during physiologic, supine
      exercise--before and after replacement of metoprolol by verapamil. Within 24 h of
      the Cardiopres measurement standard Doppler echocardiography was performed.
      Finger artery pressure wave was analysed using Beatscope software (BMI-TNO,
      Amsterdam, The Netherlands), ST analysis was performed with H-Scribe (Mortara
      Instrument, Bilt, The Netherlands). RESULTS: Exercise under metoprolol: finger BP
      decreased from 130/65 mmHg to 90/60 mmHg, heart rate increased from 65 bpm to 100
      bpm and ST analysis revealed significant ST depression in all leads. The
      occurrence of ST depression preceded the hypotension. Echocardiography showed a
      dynamic gradient of 70 mmHg. Exercise under verapamil: the patient had less
      complaints, BP increased from 125/60 mmHg to 165/65 mmHg, heart rate increased
      from 75 bpm to 107 bpm and ST analysis showed no ST depression > 1 mm.
      Echocardiography showed no change. CONCLUSIONS: The use of the Cardiopres during
      a physiological stimulus showed improvement in exercise capacity in a patient
      with HOCM, while the standard test, stress-echocardiography, showed no
      correlation with clinical status. The Cardiopres is a useful diagnostic and
      research tool, allowing non-invasive, ambulatory monitoring of blood pressure and
      ECG changes.

PMID- 12488655
TI  - Clinical evaluation of a self blood pressure monitor according to the First
      International Consensus Conference on Self Blood Pressure Measurement.
AB  - BACKGROUND: The Calor TensioSense Bras automatic blood pressure monitor has
      obtained European Union certification, but the clinical validity of this new
      oscillometric device when handled by lay subjects has yet to be evaluated.
      DESIGN: The design employed prospective and blinded blood pressure measurements
      and a validation procedure according to the criteria set out by the First
      International Consensus Conference on Self Blood Pressure Measurement (1999).
      METHODS: Thirty-three subjects were recruited, 11 in each of three strata of
      systolic blood pressure (<130, 130-160 and >160 mmHg). Blood pressure was
      measured sequentially seven times, alternating observer and lay measurements. Two
      certified observers used two mercury columns and a double stethoscope; the
      subjects used the automatic device. All blood pressure readings and recordings
      were blinded. Adequate cuff sizes were used, and the subjects' position was
      standardized. Discrepancy analysis between manual and automatic measurements was
      carried out using VAPA software. RESULTS: Dispersion of the discrepancies between
      manual and automatic measurements showed no specific trend. Out of the 99
      systolic blood pressure measurements, 53, 76 and 89 discrepancies were less than
      5, 10 and 15 mmHg, respectively. Of the 99 diastolic blood pressure measurements,
      62, 86 and 97 discrepancies were less than 5, 10 and 15 mmHg, respectively. The
      mean inter-observer discrepancy was 1 mmHg for both systolic and diastolic blood
      pressure comparisons. CONCLUSION: This evaluation showed that this device
      complies with the international validation protocol requirements. Thus, the
      device can, providing adequate instruction is given in the clinic, be recommended
      for self-measurement by patients at home, as well as for clinical or
      epidemiological research.

PMID- 12488657
TI  - Clinical manifestations of rotavirus infection in the neonatal intensive care
      unit.
AB  - OBJECTIVES: This report describes clinical signs of rotavirus infection (RVI)
      among neonates admitted to a neonatal intensive care unit (NICU), compares these
      signs between term and preterm neonates and assesses the seasonal distribution of
      RVI in the NICU with that of the community. METHODS: After an initial prevalence
      study of 28 days, a prospective longitudinal study in the NICU was conducted.
      During the next 48 months from December 1, 1991 to November 30, 1995, term and
      preterm NICU patients were evaluated daily for pre-defined deviations in their
      baseline gastrointestinal status. Fecal specimens of neonates who fulfilled the
      entry criteria were tested for rotavirus by a monoclonal antibody-based enzyme
      immunoassay and by immunoelectron microscopy. Demographic and outcome data for
      these neonates were collected. In addition data assessing RVI in the community
      were collected during this period. RESULTS: The prevalence of RVI among NICU
      patients was 18.4%. Of 194 neonates included in the longitudinal study, 95 had
      RVI. Neonates with RVI differed from those without RVI with respect to frequent
      stooling (P = 0.0005), higher percentage of bloody mucoid stools (P = 0.003) and
      higher percentage of watery stools (P = 0.023). The odds of these three clinical
      outcomes were approximately 2.5 times higher in neonates with RVI than in
      neonates without RVI. Among neonates included in the study advanced necrotizing
      enterocolitis occurred at the same rate (15%) among those with and without RVI.
      Comparisons between term and preterm neonates with RVI showed that frequent
      stooling (P = 0.003) and watery stools (P = 0.0001) occurred more often among
      term neonates, whereas bloody mucoid stools (P = 0.001), abdominal distention (P
      = 0.03) and intestinal dilatation (P = 0.016) were more common in preterm
      neonates. The seasonal distribution of RVI in NICU paralleled its distribution in
      the community. CONCLUSION: RVI appears prevalent in the NICU setting. An absence
      of watery stools in a neonate should not preclude consideration of RVI when
      evaluating gastrointestinal signs among neonates. The clinical spectrum of RVI
      differs in term and preterm infants.

PMID- 12488658
TI  - Outbreak of Acinetobacter baumannii bacteremia in a neonatal intensive care unit:
      clinical implications and genotyping analysis.
AB  - BACKGROUND: Outbreaks of sepsis associated with have been rarely reported in
      neonatal intensive care units (NICUs). We describe such an outbreak in a NICU,
      and the results of molecular epidemiologic investigations are presented.
      MATERIALS AND METHODS: Between August and September 2000, 6 premature infants
      hospitalized in a pediatric NICU developed sepsis. Three additional cases had
      infections during November and December. For an environmental culture survey, 94
      environmental specimens and hand washings of all 43 health care workers involved
      in this unit were examined for the presence of this organism. Two genotyping
      methods, pulsed field gel electrophoresis of genomic DNA digested with I and
      infrequent restriction site polymerase chain reaction, were used to analyze the 9
      bacteremic isolates and any isolates obtained from the environmental survey and
      the hand washings. Another 3 bacteremic isolates of collected in the same NICU in
      1999 were incorporated as controls. RESULTS: The 9 infants were premature and had
      birth weights of <1,500 g. Before onset of sepsis 9 infants had received total
      parenteral nutrition, and 8 infants had had central venous catheters and received
      intrafat emulsion. Five (5.3%) environmental specimens and 10 (23.3%) hand
      washing specimens were positive for the organism. Except for the strain from Case
      9, the results of both genotyping methods were concordant; 11 patterns were
      identified by infrequent restriction site polymerase chain reaction and 10
      patterns by pulsed field gel electrophoresis. One major genotype was demonstrated
      in the first 6 bacteremic isolates as well as 3 hand washing isolates. The
      genotypes of the other 3 bacteremic isolates, the 3 control strains, the 5
      environmental isolates and 7 other hand washing isolates were distinct from the
      genotype of outbreak strains. CONCLUSION: An outbreak of bacteremia in a NICU was
      clearly demonstrated by the molecular epidemiologic investigation and was
      possibly transmitted via the hands of health care workers.

PMID- 12488659
TI  - Tympanostomy tube placements, sociodemographic factors and parental expectations
      for management of acute otitis media in Iceland.
AB  - BACKGROUND: Widespread antimicrobial use is a risk factor for development of
      antimicrobial resistance. Antimicrobial treatment of acute otitis media (AOM) may
      not always be necessary. Little is known about the influence of parental
      expectations on physicians' decision-making in relation to treatment of AOM.
      Evidence is insufficient as to whether tympanostomy tube placement reduces
      antibiotic consumption. METHODS: We randomly selected 1,030 children 1 to 6 years
      old living in 4 geographic areas in Iceland to be invited to participate in the
      study. Information about sociodemographic factors, antimicrobial prescriptions
      and their indications during the preceding 12 months, tympanostomy tube
      placements and parental views on antimicrobial use and bacterial resistance were
      obtained from a questionnaire completed by the parents and medical records.
      RESULTS: The incidence of AOM episodes resulting in antimicrobial prescription
      for 804 children recruited into the study was 0.7 (95% confidence interval, 0.6
      to 0.8) per child per year, highest among children age 1 year, i.e. 1.8
      prescriptions (95% confidence interval, 1.4 to 2.2). The cumulative incidence of
      tympanostomy tube placements was approximately 30%. Antimicrobial use during the
      preceding 8 weeks for children with and without tubes did not differ (P = 0.36).
      Fifteen percent of children with tubes had received antimicrobials during the
      preceding 8 weeks at last once for AOM compared with 14% of those without tubes
      (P = 0.97). Parents in the area where antimicrobial consumption was lowest were
      less likely to accept antimicrobial treatment than parents in the other areas (P
      = 0.005). Parents of children who had previously received antimicrobials for AOM
      were more likely to accept antimicrobials (P = 0.04). CONCLUSIONS: Parental
      expectations to antimicrobial treatment and awareness about resistance
      development appear to influence treatment strategies for AOM. The high rate of
      tympanostomy tube placement in preschool children does not result in reduced
      antimicrobial consumption.

PMID- 12488660
TI  - Population-based surveillance for hospitalized and ambulatory pediatric invasive
      pneumococcal disease in Santiago, Chile.
AB  - BACKGROUND: Nine- and 11-valent pneumococcal conjugate vaccines under development
      may control pediatric pneumococcal disease in nonindustrialized countries.
      Because these vaccines are expensive, population-based surveillance of
      pneumococcal disease in children <36 months of age was undertaken in Santiago,
      Chile to provide health authorities with reliable data on the burden of invasive
      pneumococcal disease and causative serotypes, including those in outpatients with
      high fever. METHODS: Automated blood culture machines were introduced into 9
      hospitals that admit 85% of all hospitalized children in Santiago. Acutely ill
      pediatric febrile ambulatory patients are attended at 8 emergency rooms (ERs) and
      36 urgent primary care services. After a 12-month pilot study in 3 ERs, health
      authorities collected blood cultures from children <36 months of age with high
      fever seen in the ER as standard practice. isolates were serotyped. RESULTS:
      Blood cultures of 18 (1.2%) of 1,503 outpatients 6 to 35 months of age with high
      fever in the pilot study yielded S. In the ensuing 24 months 236 children <36
      months old were hospitalized with invasive pneumococcal disease (incidence, 33.9
      cases/10(5) children), and 188 bacteremias were detected among ambulatory ER
      patients with high fever (incidence, 27.0 cases/10(5) children). Although
      serotypes were similar among hospitalized and ambulatory cases (except 18C, which
      was more common in the latter), case fatality was 9.5% in hospitalized (21 of
      236) 0% in ambulatory cases (0 of 188) (P = <0.0001). High level resistance to
      penicillin (25.8% vs 10.1%) and cefotaxime (19.5% vs 6.2%) was observed more
      often among pneumococcal isolates from hospitalized than among ambulatory cases
      (P < 0.001). CONCLUSIONS: ER surveillance detected approximately one case of
      pneumococcal bacteremia among febrile ambulatory patients for each hospitalized
      invasive case. Because 71% of cases were caused by vaccine serotypes (and 87% by
      vaccine serogroups), 9- and 11-valent pneumococcal conjugate vaccines could
      prevent most invasive pediatric pneumococcal disease in Chile.

PMID- 12488661
TI  - Turicella otitidis and Corynebacterium auris do not cause otitis media with
      effusion in children.
AB  - BACKGROUND: The recently described coryneform bacteria and were first detected in
      the middle ear of patients with acute otitis media and chronic otitis media.
      Whether these bacteria play an essential role in the pathogenesis of otitis media
      with effusion (OME) is unclear. METHODS: In a prospective study 60 children with
      OME and 205 controls were evaluated to determine the incidence of and. Swabs from
      the external auditory canal (EAC) and the middle ear effusion (MEE) of OME
      children undergoing tympanotomy, ventilation tube insertion or both were
      cultured. Swabs from the EAC from healthy children served as controls. RESULTS:
      In control children was found in EAC swabs from 23 of 205 (11.2%) and in 32 of
      205 (15.6%). was isolated from 14 of 60 (23.3%) OME patients from the EAC only
      and in 6 of 60 (10.0%) OME patients from both EAC and MEE. was isolated in 2 of
      60 (3.3%) from the EAC only and in 1 of 60 (1.7%) from both EAC and MEE. In no
      patient did or grow exclusively from MEE. CONCLUSION: and may be part of the
      normal bacterial flora of the EAC in some children. Neither organism seems to
      cause OME in children.

PMID- 12488662
TI  - A season of aseptic meningitis in Germany: epidemiologic, clinical and diagnostic
      aspects.
AB  - OBJECTIVE: We assessed epidemiologic, clinical and laboratory features of aseptic
      meningitis during one season of multiserotype enteroviral meningitis in East
      Germany in 70 consecutive patients with aseptic meningitis admitted to the
      Children's University Hospital Leipzig. RESULTS: Patients, age 1 to 16 years,
      typically presented with headache, emesis and fever, whereas signs of meningeal
      irritation were only moderately expressed in one-half of the patients. The median
      number of leukocytes in the CSF was 151 cells/mm(3) (range, 2 to 1,820) with a
      high percentage of polymorphonuclear cells (PMNs). Initial blood counts showed
      mild leukocytosis and pronounced PMN predominance (78.9 +/- 1.3%). The percentage
      of PMNs in the peripheral blood decreased in favor of mononuclear cells after 3
      days to a pattern more compatible with viral infection as opposed to that
      suggestive for bacteria in the beginning. Mean cerebrospinal fluid values of
      protein, glucose and lactate and the C-reactive protein were mildly elevated or
      normal. Nonpolio enteroviruses were detected in 30 of 70 patients. Subsequent
      serotyping revealed echovirus type 13 (13 patients), type 6 (2), type 30 (1) and
      coxsackie B virus type 5 (2). There were no differences in demographic or
      clinical data between enterovirus positive and negative patients. CONCLUSIONS:
      Even though individual laboratory values do not solely allow discrimination
      between viral and bacterial meningitis, the combined epidemiologic, clinical and
      laboratory data facilitate the diagnosis of aseptic meningitis in most cases.
      Viral diagnostics, identifying echovirus type 13 that thus far has not been
      associated with epidemics of meningitis, adds important epidemiologic
      information.

PMID- 12488663
TI  - Human fetal infection with parvovirus B19: maternal infection time in gestation,
      viral persistence and fetal prognosis.
AB  - OBJECTIVE: To clarify the relation between the time of parvovirus B19 (B19)
      infection in pregnancy and fetal outcome, including the viral persistence in the
      fetus. METHODS: Among 57 pairs showing serologic and/or virologic evidence of
      maternal and fetal B19 infection between 1986 and 1999 in Japan, 13 maternal
      fetal pairs with the time of maternal B19 infection documented were
      retrospectively evaluated for fetal outcome and viral persistence. RESULTS:
      Nonimmune hydrops occurred at 23, 21 and 26 gestational weeks (gw) in three
      fetuses as a result of their mothers' symptomatic infection (erythema
      infectiosum) at 3, 16 and 19 gw, respectively. Spontaneous abortion without
      hydrops and intrauterine growth retardation resulting in small-for-gestational
      age (SGA) classification occurred in two fetuses whose mothers had developed
      erythema infectiosum at 5 and 16 gw, respectively. Eight fetuses were
      asymptomatic as a result of their mothers' infection at 6, 9, 12, 15, 18, 23, 23
      and 33 gw, respectively. B19 DNA was detected in neonatal serum in all nine cases
      tested. CONCLUSION: Maternal B19 infection throughout gestation including the
      early stage after fertilization caused fetal infection that persisted until
      intrauterine fetal death with or without nonimmune hydrops or until the neonatal
      period after birth.

PMID- 12488664
TI  - Multicenter, randomized, double blind clinical trial of short course versus
      standard course oral ciprofloxacin for Shigella dysenteriae type 1 dysentery in
      children.
AB  - BACKGROUND: Shigella dysenteriae type 1 (Sd1) dysentery is associated with
      serious morbidity and mortality. Treatment is either costly or complicated by the
      emergence of bacterial resistance. This study compared the efficacy and safety of
      short course (3 days) and standard course (5 days) oral ciprofloxacin in children
      with Sd1 dysentery. METHODS: A multicenter, randomized, double blind, controlled
      clinical trial. Children between 1 and 12 years of age with Sd1 dysentery were
      randomized to receive oral ciprofloxacin suspension 15 mg/kg every 12 h for 3
      days followed by placebo for 2 days or ciprofloxacin suspension for 5 days.
      Treatment success was defined as either resolution of illness or marked
      improvement on Day 6 of study. Bacteriologic cure was defined as failure to grow
      Sd1 on a stool sample collected on Day 6. Clinical assessments and joint
      examinations were performed at baseline, at discharge and 2 weeks later. RESULTS:
      Of 253 patients enrolled 128 were assigned to short course ciprofloxacin and 125
      to standard course ciprofloxacin. The success rates were 65 and 69% for short and
      standard course ciprofloxacin, respectively. All patients had bacteriologic cure,
      and all Sd1 isolates were susceptible to ciprofloxacin. No bacteriologic relapses
      occurred during the study period. Eight patients reported arthralgia. All
      patients had normal joint function including at follow-up. CONCLUSION: In this
      study twice daily ciprofloxacin for 3 days achieved clinical cure rates similar
      to those for the same dosage given for 5 days in children with Sd1 dysentery.

PMID- 12488665
TI  - Successful treatment of neuroborreliosis with ten day regimens.
AB  - BACKGROUND: There have been few large reports of the treatment and outcome of
      neuroborreliosis in children. METHODS: All 203 children with symptoms,
      cerebrospinal fluid and serologic findings compatible with neuroborreliosis and
      treated at one of the four pediatric hospitals in Stockholm from 1994 through
      1996 were included. Children were treated with intravenous beta-lactam
      antibiotics or oral doxycycline for 10 days and followed until the resolution of
      symptoms. RESULTS: At the end of treatment 58% and after 2 months 92% of the
      children had no symptoms. Cerebrospinal fluid findings had no statistically
      significant influence on the outcome. Facial paralysis persisted longer than
      other symptoms. CONCLUSIONS: The prognosis of neuroborreliosis in children 2
      months after treatment seems to be excellent with 10-day treatment regimens.

PMID- 12488667
TI  - Epidemiologic characteristics of children hospitalized for Kawasaki disease in
      California.
AB  - OBJECTIVE: To evaluate the epidemiologic pattern of Kawasaki disease (KD) in
      California. METHODS: Statewide hospital discharge data from California from 1995
      through 1999 were used. Children 0 through 17 years old who had a discharge
      diagnosis of KD (by ICD9-CM code 446.1) were identified. Precipitation and
      temperature data of climate divisions of the state were used to determine their
      possible association with incidences of KD. Multiple regression analysis was
      performed to evaluate factors related to the KD incidence of the counties.
      RESULTS: There were 2,325 patients admitted to 194 California hospitals during
      the 5-year study period. The male-to-female ratio was 1.62. Median age was 30
      months; peak incidence by year of age was in the second year of life. Overall
      annual incidence was 15.3 cases per 100,000 children <5 years old and 3.2 cases
      per 100,000 children 5 through 9 years old. Compared with 1995 and 1996, the
      incidence for children <5 years old increased by 30% in 1997 and 1998 (P < 0.01).
      In contrast the incidence for children 5 through 9 years old remained relatively
      unchanged. Asians had the highest incidence of 35.3 cases per 100,000 children <5
      years old, followed by blacks (24.6) and whites (14.7) (P < 0.01). The number of
      cases peaked in March and had its nadir in September. In a multiple regression
      analysis, no association was found between KD incidence and temperature or
      precipitation. KD incidence was not related to average family size, proportion of
      Asians in the population, population density or whether the county is in northern
      or southern California. There was no in hospital death. The median length of
      hospital stay was 2 days. CONCLUSIONS: The incidence of Kawasaki disease in
      patients <5 years old increased in 1997 and 1998. Asians had the highest KD
      incidence compared with other races. Peak incidence was in March, and the lowest
      incidence was in September. KD incidence was not associated with temperature,
      precipitation, family size or population density.

PMID- 12488666
TI  - Hospitalizations during a measles epidemic in the Netherlands, 1999 to 2000.
AB  - BACKGROUND: A measles epidemic occurred in the Netherlands in 1999 to 2000. We
      collected data on hospitalized and deceased cases to inform the public about the
      risks associated with measles infection. METHODS: From the National Medical
      Registration we extracted hospital discharge diagnoses for measles-related
      hospitalizations (International Classification of Diseases, 9th revision,
      Clinical Modification Code 055) during the measles epidemic (April 1999 to May
      2000). We also reviewed hospital records to assess reasons for hospitalization
      and severity of disease as a result of measles infection during this epidemic. In
      addition we estimated the total number of hospitalized cases by a capture
      recapture approach using two surveillance sources. RESULTS: Measles without
      mention of complication (39%) and postmeasles pneumonia (33%) were most often
      registered as main discharge diagnoses for the 130 cases in the National Medical
      Registration. Forty-seven (96%) of the 49 patients whose hospital charts were
      reviewed were not vaccinated. Median admission period was 5 (range, 1 to 26)
      days, 19 (38%) required mechanical ventilation and 14 (29%) had sequelae at the
      time of discharge but none was permanent. Three patients died as a result of
      complications. No association was observed between preexisting illness and either
      reason for admission (P = 0.5) or residual symptoms at discharge (P = 0.5). The
      estimated total number of hospitalized measles patients was 157 (95% confidence
      interval, 145 to 179), leading to an estimated 825 admission days during an
      epidemic in which 3,292 cases were reported. CONCLUSIONS: Measles infection can
      still run a severe course even in a prosperous country.

PMID- 12488668
TI  - Periorbital versus orbital cellulitis.

PMID- 12488669
TI  - Macrolide resistance in group A Streptococcus.

PMID- 12488670
TI  - Ecthyma gangrenosum: considerations in a previously healthy child.
AB  - Ecthymagangrenosum is a skin lesion that is most commonly caused by. Although
      ecthyma gangrenosum usually develops in patients with underlying
      immunodeficiencies or chronic diseases, there have been reports of its appearance
      in previously healthy children. A review of such patients in the English
      literature showed that most of them had either previously undetected
      immunodeficiencies or transient risk factors that predisposed them to the
      development of ecthyma gangrenosum. We report a patient without apparent
      antecedent predisposing risk factors for ecthyma gangrenosum who developed
      chronic neutropenia 1 week after presentation. It is important for the primary
      care provider to recognize ecthyma gangrenosum, treat it with appropriate
      antimicrobial agents and investigate the patient for occult immunodeficiencies.

PMID- 12488671
TI  - Recommendations for parents adopting an infant with chronic hepatitis B.

PMID- 12488673
TI  - The newest home care accreditation agency--ACHC.

PMID- 12488675
TI  - Help on the net: internet support groups for people dealing with cancer.

PMID- 12488676
TI  - When your patient complains of hair loss.

PMID- 12488677
TI  - An exploratory study of motor vehicle use in home visiting nurses.

PMID- 12488678
TI  - Implementing your HIPAA plan.

PMID- 12488679
TI  - Evidence-based practice: basic strategies for success.

PMID- 12488680
TI  - PPS reimbursement numbers effective October 1, 2002: changes rates published in
      May 2002 issue of HHN.

PMID- 12488681
TI  - Frequently asked questions about computer technology for clinicians.

PMID- 12488682
TI  - Ten tips for working with home care clients who reside in assisted living
      facilities.

PMID- 12488683
TI  - Conference on using technology to enhance patient care delivery.

PMID- 12488684
TI  - Investing in the future: facilitating student experiences in the gastroenterology
      setting.

PMID- 12488685
TI  - What you need to know about Barrett's esophagus.
AB  - The incidence of Barrett's esophagus is increasing and this diagnosis is being
      seen more frequently in endoscopy units. Barrett's esophagus is a premalignant
      condition where the cells that normally line the esophagus are replaced with
      specialized columnar cells. Patients with Barrett's require close surveillance to
      monitor their condition and screen for the development of esophageal
      adenocarcinoma. This article provides an overview of Barrett's esophagus to
      better prepare gastroenterology nurses for educating and caring for this
      population of patients. Included is a discussion of the pathophysiology, signs
      and symptoms, and diagnostics of this disease entity. Current treatment options
      including medical management with proton pump inhibitors, endoscopic mucosal
      ablation techniques such as photodynamic therapy, and surgical intervention are
      also discussed. Current patient education approaches are also discussed.

PMID- 12488686
TI  - The basics of ostomies.
AB  - Basic ostomy care can be intimidating because nurses don't often see colostomies,
      ileostomies, or urostomies. While there are as many different ostomies as there
      are people who have them, there are some commonalities in the care of the stoma.
      These can be generalized to all stomas, regardless of the type of output. Some
      care, however, is specific to the placement of the stoma and the type of effluent
      flowing from the opening. This article will provide the gastroenterology nurse an
      overview of the basic features of ostomies as well as routine ostomy care.

PMID- 12488687
TI  - An assessment of social support in people with inflammatory bowel disease.
AB  - The purpose of this descriptive study was to assess the perceived level of social
      support in a sample of people with inflammatory bowel disease. This assessment
      was to serve as the basis for the development and evaluation of a program of
      social support. The Personal Resource Questionnaire (PRQ-85), which measures
      perceived level of social support, was mailed to all members (n = 300) of the
      Northwestern Society for Intestinal Research. Adults who met the eligibility
      criteria were invited to participate. Questionnaires and consent forms were
      completed and returned by 97 subjects. Results indicated that subjects would use
      a variety of resources if confronted with situations that required social
      support. The perceived level of social support was high, with mean scores for
      this inflammatory bowel disease sample reported at 143.86 of a possible 175. A
      two-tailed t-test suggests there is no significant difference in perceived level
      of social support between those subjects with Crohn disease and those with
      ulcerative colitis at the 0.05 level of significance. Because the level of social
      support was so high in this sample, plans to develop a program of support were
      abandoned. The meaning of these results including an analysis of the scores and a
      critique of the questionnaire are discussed.

PMID- 12488688
TI  - Teenage constipation: a case study.
AB  - Constipation is a problem of significant magnitude. It can have a devastating
      impact on a patient's personal life. There are many causes of constipation. Among
      them are dietary factors such as decreased fiber and low fluid intake, decreased
      activity, lack of privacy for defecation, pharmacologic agents, physiologic
      problems such as bowel obstruction or metabolic disorders, and psychosocial
      distress. A young teenage boy is followed through a series of emergency room
      visits, office visits, and a hospitalization related to his experiences with
      constipation. A bowel program was identified and instituted with successful
      outcomes.

PMID- 12488689
TI  - Development of a new pain scale: Colorado Behavioral Numerical Pain Scale for
      sedated adult patients undergoing gastrointestinal procedures.
AB  - A limited number of studies have addressed pain assessment among sedated patients
      undergoing a gastrointestinal examination. The Colorado Behavioral Numerical Pain
      Scale is a quick, simple tool that can provide an estimation of the patient's
      comfort level while sedated. Multiple studies completed in intensive care unit
      and postanesthesia care unit settings provide ample evidence of the accuracy of
      behavioral pain scales ratings. In developing the Colorado Behavioral Numerical
      Pain Scale, experienced endoscopy nurses provided suggestions and modifications
      of descriptive words for behavioral assessment of pain selected from the relevant
      literature. Three nurses simultaneously rated pain using the scale for 30
      procedures. Interrater reliability was high with 82% of observations in total
      agreement and 17% having one of the three persons disagreeing on the rating.
      Nurses from four hospitals and one ambulatory facility also evaluated the
      Colorado Behavioral Numerical Pain Scale tool. In this evaluation, 98% of the 52
      respondents agreed that the words described what they observed during a
      gastrointestinal examination and 94% felt it was a better descriptor of pain than
      a patient self-report numerical scale. Assessment of pain for the sedated patient
      undergoing gastrointestinal procedures is often difficult due to the patient's
      inability to report pain levels. The sedated patient undergoing painful
      procedures depends on the nurse to interpret physical signs to quantify his or
      her distress. The Acute Pain Management Guidelines (AHCPR, 1992) promotes the use
      of both physiological and behavioral responses to pain for assessment when self
      report is absent. While an individual's self-report of pain intensity and
      distress is the most accurate assessment measurement, the validity of a sedated
      patient's elicited response about pain is questionable. It is the nurse, through
      observation, who attempts to assess the sedated individual's pain levels.

PMID- 12488690
TI  - Developing a diverse nursing workforce.

PMID- 12488691
TI  - End-of-life nursing care.

PMID- 12488692
TI  - SGNA position statement on minimal registered nurse staffing for patient care in
      the gastrointestinal endoscopy unit.

PMID- 12488693
TI  - SGNA position statement on the role of the nurse/associate in the placement of
      percutaneous endoscopic gastrostomy (PEG) tube.

PMID- 12488694
TI  - Is your practice based on fact or fiction?

PMID- 12488696
TI  - Defining subtypes of Crohn's disease patients: the ground work for translational
      research in inflammatory bowel disease.

PMID- 12488697
TI  - Saccharomyces: is it a probiotic or a pathogen and what is the significance of an
      elevated anti-S. cerevisiae antibody?

PMID- 12488698
TI  - Borderline enteropathies.

PMID- 12488699
TI  - Clinical and demographic characterization of Jewish Crohn's disease patients in
      Israel.
AB  - BACKGROUND: Crohn's disease (CD) is a chronic transmural inflammatory disease of
      unknown etiology. Genetic background may influence the nature of disease. The
      Jewish population in Israel is composed of Ashkenazi and Sephardic Jews, who
      differ in their genetic background. Previous studies have reported that the
      prevalence of CD in Sephardic Jews is lower than in Ashkenazi Jews; however, no
      information is available regarding disease characteristics in these patient
      populations. GOALS: To assess the demographic and clinical characteristics of CD
      in Israeli Jewish patients. STUDY: We studied 189 CD patients who were observed
      in our department. Demographic and clinical data were collected and analyzed.
      RESULTS: Forty-eight percent of the patients had ileum-only disease. Fistulizing
      disease was more frequently seen in ileocolonic than in ileal ( p= 0.04) or
      colonic ( p= 0.01) disease, whereas strictures occurred more often in ileal than
      in colonic disease (22% and 3%, respectively, p= 0.007). No association was found
      between current smoking and disease severity. Sephardic patients more frequently
      had extraintestinal disease than did Ashkenazi patients (35% vs. 17%,
      respectively, = 0.019). CONCLUSION: Jewish Israeli patients show a predilection
      for ileum-only disease. Disease severity appears not to be influenced by smoking.
      These differences in disease behavior may be related to genetic factors.

PMID- 12488700
TI  - The symptomatic and histologic response to a gluten-free diet in patients with
      borderline enteropathy.
AB  - GOALS: A clinical problem is posed by patients with symptoms suggestive of gluten
      sensitivity (diarrhea, weight loss, unresponsive iron-deficiency anemia, etc.);
      however, small intestinal biopsies reveal only minor abnormalities, such as
      lymphocytosis with or without crypt hyperplasia (Marsh I-II). Our aim was to
      assess the benefit of a gluten-free diet (GFD) in patients with these small bowel
      mucosal abnormalities. STUDY: We studied 35 patients (11 men, 24 women; mean age,
      28 years; range, 22-51 years) referred to us for gastrointestinal symptoms or
      unexplained or unresponsive diseases. Because celiac disease was suspected to be
      the underlying pathology, small intestinal biopsies were taken. These revealed
      only minor abnormalities: 11 patients showed Marsh I type lesions, whereas 24
      patients demonstrated Marsh II type lesions. Although the histologic lesions were
      inconsistent for celiac disease and a suspicion of a borderline celiac disease
      persisted, all patients were motivated to adhere to GFD. RESULTS Only 23 patients
      adhered to our advice and followed a GFD; follow-up biopsies were taken after 8
      to 12 months. In the Marsh I lesion group (seven patients), five patients showed
      mucosal normalization to Marsh 0 and two showed persistence of Marsh I lesions.
      In the Marsh II lesion group (16 patients), 9 patients revealed mucosal
      normalization, 5 improved to a Marsh I lesion, and 3 revealed persistence of
      Marsh II lesions. A dramatic clinical improvement in symptoms was noted in all
      patients who were on a GFD, with symptoms virtually disappearing in all patients.
      Seven patients who refused GFD were reevaluated 8 to 12 months later. Symptoms
      and histologic lesions were unchanged in six, all of whom refused again to adhere
      to a GFD. One of the seven with Marsh I lesions had a worsening of symptoms and
      of histologic lesions (from Marsh I to Marsh IIIa); so, this last patient adhered
      to a GFD. CONCLUSIONS: Symptoms disappeared after GFD in patients suspected to
      have celiac disease but with slight histologic lesions. Although Marsh I-II
      lesions cannot be classified as celiac lesions (ESPGAN criteria), the patients'
      symptoms at presentation and the clear improvement of symptoms when on GFD, with
      or without improvement of histologic lesions, supports the assumption that these
      patients are sensitive to gluten and may justify treatment with a GFD.

PMID- 12488701
TI  - The diagnosis and treatment of adult intussusception.
AB  - BACKGROUND: Intussusception in adults is often diagnosed on computed tomography
      (CT), and the optimal treatment of this entity is not universally agreed upon. We
      report our experience in an attempt to clarify the usefulness of CT scan and the
      optimal treatment of this entity. STUDY: Seven cases of adult intussusception
      were encountered at our institute between 1991 and 2001. Data related to
      presentation, diagnosis, treatment, and pathology were analyzed. RESULTS:
      Preoperative diagnosis was made in four patients by CT scan and/or
      ultrasonography. Two patients had colonic cancer and one had jejunal cancer.
      Three of four patients with small bowel intussusception underwent reduction
      before resection and the other one underwent resection without reduction because
      of severe ischemic bowel. CONCLUSIONS: The CT scan is most useful in making the
      diagnosis of intussusception. Colonic lesions should be resected without
      reduction. Small bowel lesions should be reduced only in patients in whom a
      benign diagnosis has been strongly suggested preoperatively or in patients in
      whom resection may result in short gut syndrome.

PMID- 12488702
TI  - Possible protective effect of 5-aminosalicylic acid on Helicobacter pylori
      infection in patients with inflammatory bowel disease.
AB  - GOALS: To evaluate the prevalence of (Hp) infection in a group of inflammatory
      bowel disease (IBD) outpatients and the possible influence of treatment.
      BACKGROUND: The low prevalence of Hp infection in these patients is usually
      attributed to environmental factors; the role of drugs has not been fully
      investigated. STUDY: Seventy-two consecutive outpatients underwent a C13-urea
      breath test for Hp: 32 with Crohn's disease (13 men; mean age, 48 years; range,
      20-72 years) and 40 with ulcerative colitis (25 men; mean age, 49 years; range,
      25-71 years). Thirty-one patients were treated with sulfasalazine and 41 with 5
      ASA. The control group consisted of 72 age- and sex-matched subjects. RESULTS:
      The prevalence of Hp infection was 47% in the IBD patients and 61% in the
      controls (p = 0.089; odds ratio = 0.55; 95% CI = 0.283-1.089) with a
      statistically significant increase for each year of age ( p= 0.044; odds ratio =
      1.02; 95% CI = 1.001-1.052). Among the IBD patients, age and gender, the type,
      activity, duration, extent of the disease, or the calendar year of diagnosis, had
      no influence on Hp infection. was detected in 65% of the patients treated with
      sulfasalazine and in 34% treated with 5-ASA (p = 0.017). CONCLUSIONS: Although
      low, the prevalence of Hp infection in our patients was not significantly
      different from that in the controls. 5-ASA, and not sulfasalazine, may have a
      protective effect against Hp infection.

PMID- 12488703
TI  - Carditis is associated with Helicobacter pylori-induced gastritis and not reflux
      esophagitis.
AB  - Pathogenesis of chronic inflammation at the gastric cardia is not yet clear. It
      is controversial whether cardiac-type mucosa is normal structure at the cardiac
      region. Therefore, we studied the existence of correlations between carditis,
      infection, and gastroesophageal reflux disease, and determined the prevalence of
      cardiac mucosa at the endoscopically defined cardiac region. Gastric biopsy
      specimens were analyzed from 27 patients with reflux esophagitis and 30 subjects
      without reflux esophagitis. Carditis was not associated with reflux esophagitis,
      but with infection. Moreover, the degree of gastritis and atrophy at the cardia
      were closely related to those of the antrum and body. Cardiac mucosa was not
      always present in the endoscopically defined cardiac region, and its prevalence
      was positively correlated with gastritis and atrophy grade of the cardia and age.
      In conclusion, -induced pangastritis may lead to the development of carditis,
      which is associated with occurrence of cardiac-type mucosa at the cardiac region.

PMID- 12488704
TI  - Clinicopathologic characteristics and prognoses of gastric cancer in patients
      with a positive familial history of cancer.
AB  - BACKGROUND: There is a significant association between a positive family history
      of cancer and gastric cancer risk; however, the clinicopathologic characteristics
      and prognoses of gastric cancer patients with a positive family history of cancer
      are not clear. GOALS: To define the clinicopathologic characteristics and
      prognoses of gastric cancer patients with a positive family history of cancer.
      STUDY: We reviewed 548 patients with pathologically confirmed primary gastric
      cancer who had undergone a gastrectomy between 1990 and 1996. The average age was
      59.7 years, and the male-to-female ratio was 1.7. The familial cancer histories
      of these patients were reviewed, and the various clinicopathologic
      characteristics of those patients with a positive family history of cancer were
      compared with those with a negative history. RESULTS: Among this cohort, 74
      (13.5%) patients had a positive family history of cancer in their primary or
      secondary relatives. The most common cancer was gastric cancer in 29 patients,
      followed by colorectal cancer in 10 and lung cancer in 7. Patients with a
      positive family history of cancer were associated with bigger tumors, and more
      patients received a total gastrectomy than did patients with a negative family
      history. Immunopathologic study disclosed a higher rate of p53 overexpression but
      not of neu or c-met in patients with a positive family history of cancer. There
      were no differences in the mean age, gender, site, depth of invasion, or TNM
      stage. The survival curve of patients with a positive family history of
      malignancy was similar to that of patients without a family cancer history.
      CONCLUSION: Patients with gastric cancer with a positive family history of cancer
      appeared to have bigger tumors with a higher rate of p53 overexpression, and more
      patients required a total gastrectomy compared with those with a negative family
      history. This study suggests a genetic component in the aggressiveness of gastric
      cancer and indicates that higher caution should be exercised with people who have
      a positive family history of cancer.

PMID- 12488705
TI  - Temporal trends over ten years in formal inpatient gastroenterology consultations
      at an inner city hospital.
AB  - GOALS: Inpatient consultation is an important, but poorly understood, component
      of medical subspecialty practices. In a time when all services strive for cost
      effective and efficient treatments, little is known about the epidemiology of
      inpatient subspecialty consultation. This study is designed to describe the
      nature and trends of formal inpatient gastroenterology consultations during the
      past decade. STUDY: All inpatient gastroenterology consultations at Grady
      Memorial Hospital in Atlanta, GA, in 1998 and 1988 were retrospectively reviewed.
      Percentages of inpatient gastroenterology consultations were calculated for each
      year accordingly. Top ten reasons for inpatient gastroenterology consultations
      were compared. RESULTS: Formal inpatient gastroenterology consultations have
      steadily increased in the past 10 years (2.8% of all admissions in 1988 to 4.8%
      in 1998, < 0.0001). Inpatient gastrointestinal endoscopic procedures have
      significantly increased over the past decade (30.9% of the total consultations in
      1988 to 36.1% in 1998, = 0.008). The leading reasons for formal inpatient
      gastroenterology consultations in 1998 were hematemesis, abnormal liver tests,
      hematochezia, anemia, and melena. Consultations for abnormal liver tests have
      significantly decreased in the past 10 years (27% of the total consultations in
      1988 to 16% in 1998, < 0.001). CONCLUSIONS: Formal inpatient gastroenterology
      consultations and inpatient gastrointestinal endoscopic procedures have
      significantly increased over the past 10 years, despite pressures to decrease
      costs of inpatient care. The main reason for formal inpatient gastroenterology
      consultations shifted from abnormal liver tests to gastrointestinal bleeding.

PMID- 12488706
TI  - Saccharomyces cerevisiae-associated diarrhea in an immunocompetent patient with
      ulcerative colitis.
AB  - Infectious diarrhea is common in cases of ulcerative colitis (UC), caused by
      resistance to treatment. In particular, it has been associated with
      cytomegalovirus or infection has rarely been observed in human beings, but has
      never been seen in immunocompetent patients. We report a case of intestinal
      infection presenting as acute diarrhea in a patient with a 10-year history of UC
      who was never treated with immunosuppressants.

PMID- 12488707
TI  - Saccharomyces cerevisiae fungemia after Saccharomyces boulardii treatment in
      immunocompromised patients.
AB  - Saccharomyces cerevisiae is widely used as a probiotic compound. Clinical data
      suggest that this agent is safe and effective. We report two cases of fungemia
      caused by S. cerevisiae occurring in immunosuppressed patients treated orally
      with S. boulardii Molecular typing confirmed clonality in isolate strains from
      patients and the capsule. Physicians caring for immunosuppressed patients must be
      aware of this potential serious complication of probiotic use.

PMID- 12488708
TI  - Verocytotoxin-producing Escherichia coli EH 0157:H7 colitis.
AB  - 0157:H7 is a known etiologic agent of hemorrhagic colitis. The clinical and
      histologic picture of colitis is largely similar to that of ischemic colitis,
      with areas of submucosal hemorrhage and edema, erosions, and ulcerations. We
      present a case report and review of the literature. A 52-year-old HIV-positive
      man, in apparently good immunologic condition, developed severe hemorrhagic
      colitis characterized by the onset of multiple colonic perforations and an
      unfavorable outcome. The diagnosis of 0157:H7 colitis should therefore be
      considered in all patients with indeterminate hematic diarrhea. Further studies
      are warranted to verify whether HIV infection may play a determinant role in the
      clinical course of 0157:H7 infection.

PMID- 12488709
TI  - The epidemiology of hepatitis C virus infection.
AB  - The prevalence of hepatitis C virus (HCV) infection varies in different
      populations, ranging from as low as 0.6% in volunteer blood donors to as high as
      80% in injection drug users. The prevalence of HCV in a population can be
      predicted by risk factors associated with the transmission of infection. These
      risk factors include injection drug use, blood product transfusion, organ
      transplantation, hemodialysis, occupational injury, sexual transmission, and
      vertical transmission. We review the literature regarding the incidence and
      prevalence of HCV infection and the evidence supporting various modes of HCV
      transmission.

PMID- 12488710
TI  - Issues in hyperlipidemic pancreatitis.
AB  - Hypertriglyceridemia (HTG) is a rare cause of pancreatitis. Pancreatitis
      secondary to HTG, presents typically as an episode of acute pancreatitis (AP) or
      recurrent AP, rarely as chronic pancreatitis. A serum triglyceride (TG) level of
      more than 1,000 to 2,000 mg/dL in patients with type I, IV, or V hyperlipidemia
      (Fredrickson's classification) is an identifiable risk factor. The typical
      clinical profile of hyperlipidemic pancreatitis (HLP) is a patient with a
      preexisting lipid abnormality along with the presence of a secondary factor
      (e.g., poorly controlled diabetes, alcohol use, or a medication) that can induce
      HTG. Less commonly, a patient with isolated hyperlipidemia (type V or I) without
      a precipitating factor presents with pancreatitis. Interestingly, serum
      pancreatic enzymes may be normal or only minimally elevated, even in the presence
      of severe pancreatitis diagnosed by imaging studies. The clinical course in HLP
      is not different from that of pancreatitis of other causes. Routine management of
      AP caused by hyperlipidemia should be similar to that of other causes. A thorough
      family history of lipid abnormalities should be obtained, and an attempt to
      identify secondary causes should be made. Reduction of TG levels to well below
      1,000 mg/dL effectively prevents further episodes of pancreatitis. The mainstay
      of treatment includes dietary restriction of fat and lipid-lowering medications
      (mainly fibric acid derivatives). Experiences with plasmapheresis, lipid
      pheresis, and extracorporeal lipid elimination are limited.

PMID- 12488711
TI  - Hepatic resection and percutaneous ethanol injection as treatments of small
      hepatocellular carcinoma: a Cancer of the Liver Italian Program (CLIP 08)
      retrospective case-control study.
AB  - BACKGROUND: Patients with small hepatocellular carcinoma (HCC) are usually
      treated with hepatic resection or percutaneous ethanol injection (PEI). GOALS: To
      compare the effects of hepatic resection versus PEI on survival in a matched case
      control study. STUDY Patients with single-nodule HCC (<or=5 cm) who were treated
      with hepatic resection (cases) or PEI (controls) were eligible. Matching criteria
      were date of diagnosis, Child-Pugh stage, and age at diagnosis. Kaplan-Meier
      survival curve of the control group was drawn weighing each stratum by the
      inverse of its size. Treatments were compared by a stratified Cox's model,
      adjusted by CLIP score. RESULTS: Of 912 patients, 197 were eligible and 82 (17
      cases and 65 controls) were matched, creating 17 strata. Nine (53%) cases and 41
      (63%) controls died. Cox model showed no survival difference between the two
      groups; hazard ratio of PEI versus hepatic resection was 1.04 (95% CI = 0.43
      2.52). One- and 3-year survival rates in the hepatic resection and PEI groups
      were 82% versus 91% and 63% versus 65%, respectively. CONCLUSIONS: Patients with
      small HCC treated with hepatic resection or PEI have similar survival rates. In
      view of the higher cost and morbidity of hepatic resection, a prospective
      randomized study is warranted.

PMID- 12488712
TI  - Endoscopic injection sclerotherapy for esophageal varices in cirrhotic patients
      with hepatocellular carcinoma: risk factors for survival.
AB  - GOALS: We previously showed that endoscopic injection sclerotherapy (EIS)
      prolonged survival in patients with esophageal varices complicated by
      hepatocellular carcinoma (HCC) and liver cirrhosis. Here, we evaluated risk
      factors that affect EIS outcomes. Among factors, the difference between
      prophylactic and emergency EIS was of interest, and we analyzed precisely. STUDY:
      Subjects were 134 patients with esophageal varices complicated by HCC and liver
      cirrhosis: 38 underwent emergent therapy for bleeding varices and 96 underwent
      prophylactic sclerotherapy. RESULTS: During 2-year observation, 22 of the 38
      (57.9%) and 38 of the 96 (39.6%) died. Analysis by univariate Cox's proportional
      hazard model indicated that prognosis of patients receiving emergency EIS was
      inferior to those with prophylactic EIS. However, multivariate Cox's analysis
      showed that emergency EIS itself extended survivals of those with esophageal
      varices complicated by HCC and liver cirrhosis. Patients' hepatic function (Child
      Pugh classes) and tumor sizes were also statistically significant factors for
      survival. Neither prophylactic nor emergency EIS prolonged survival of patients
      with Child C hepatic function or those with HCCs larger than 5 cm. CONCLUSIONS:
      The prophylactic sclerotherapy for esophageal varices prolongs long-term survival
      of patients with liver cirrhosis and HCC, better than emergency therapy. However,
      EIS itself had no beneficial effect on patients with poor disease status.

PMID- 12488713
TI  - Endoscopic retrograde cholangiopancreatography is safe and effective in patients
      90 years of age and older.
AB  - GOALS: To review our experience of endoscopic retrograde cholangiopancreatography
      (ERCP) in patients 90 years and older. BACKGROUND: ERCP is effective in the
      investigation and treatment of biliary disease; however, in the very elderly, a
      perception of high procedural risk and lack of efficacy may limit its use. STUDY:
      Retrospective analysis of ERCPs performed on patients 90 years of age and older
      from one institution. RESULTS: Between 1987-2000, 23 ERCPs were performed on
      patients 90 years of age and more (16 women; age range, 90-96 years). The primary
      indications were obstructive jaundice (16 patients), pancreatitis (2),
      cholangitis (1), unexplained abdominal pain (1), and planned follow-up (3). The
      main endoscopic findings were common bile duct (CBD) stone (15 patients),
      pancreatic carcinoma (2), cholangiocarcinoma (2), and dilated duct (only 1).
      Sixteen sphincterotomies were performed, with successful common duct clearance in
      10 patients. Seven biliary stents were inserted for benign disease and three, for
      malignancy. In two patients, CBD cannulation was unsuccessful. Three minor
      hemorrhages were controlled endoscopically. Three patients died of nonprocedural
      causes. CONCLUSIONS: ERCP is safe and effective in the very elderly. The decision
      to undergo ERCP should be determined by clinical need.

PMID- 12488714
TI  - Low complement levels and opsonic activity in hepatic hydrothorax: its
      relationship with spontaneous bacterial empyema.
AB  - GOALS: To analyze the pleural fluid factors that might cause spontaneous
      bacterial empyema (SBEM) in patients with cirrhotic hydrothorax. BACKGROUND:
      Pathogenic mechanism of SBEM of cirrhotic patients is probably similar to that of
      spontaneous bacterial peritonitis, but local factors affecting pleural fluid have
      not been studied. STUDY: Determination of C3, C4, and opsonic activity levels of
      pleural fluid in a cohort of patients with pleural effusions of different causes.
      RESULTS: Forty-eight patients had hepatic hydrothorax; 8, heart failure and 45,
      exudates (9, tuberculosis; 21, malignancies; 10, other). Of the 48 cirrhotic
      patients, 15 developed SBEM on admission. The pleural fluid of cirrhotic patients
      showed significantly lower levels of total protein, complement, and opsonic
      activity than did the fluids of patients with other causes of SBEM. Patients who
      developed SBEM had lower concentrations of pleural fluid total protein and C3 and
      had a higher Child-Pugh score than patients who did not develop the infection.
      CONCLUSION: Cirrhotic patients with hepatic hydrothorax have lower pleural fluid
      opsonic activity and C3 levels than those found in the pleural fluid of patients
      with other causes. Patients who develop SBEM have lower levels of pleural fluid
      C3, pleural fluid total protein, and a higher Child-Pugh score than those who do
      not develop SBEM.

PMID- 12488715
TI  - Severe esophagitis healed in less than a week with intravenous pantoprazole.

PMID- 12488716
TI  - Hyperprolactinemia caused by azathioprine.

PMID- 12488717
TI  - Patient compliance for endoscopic procedures.

PMID- 12488718
TI  - Use of stent retrieval rat tooth forceps for percutaneous endoscopic
      gastrostomy/jejunostomy tube placement.

PMID- 12488719
TI  - Celiac disease presenting during puerperium.

PMID- 12488720
TI  - Does high albumin gradient ascites accompany tuberculous peritonitis?

PMID- 12488721
TI  - Autoimmune thrombotic thrombocytopenic purpura: a severe complication of
      inflammatory bowel disease.

PMID- 12488722
TI  - Sclerosing cholangitis associated with systemic sarcoidosis.

PMID- 12488723
TI  - Use of mycophenolate mofetil in the treatment of primary sclerosing cholangitis.

PMID- 12488724
TI  - Reversal of protein-losing enteropathy by liver transplantation.

PMID- 12488725
TI  - Carcinoid crisis induced by external manipulation of liver metastasis.

PMID- 12488726
TI  - Gadopentetate dimeglumine is potentially an alternative contrast agent for three
      dimensional computed tomography angiography with multidetector-row helical
      scanning.
AB  - OBJECTIVE: To demonstrate that gadopentetate dimeglumine is potentially an
      alternative contrast medium for computed tomographic angiography (CTA). METHODS:
      One 12.2-kg Beagle dog was studied as proof of principle; the cervical vessels of
      three adult human patients were imaged for presurgical planning of the neck.
      Gadopentetate dimeglumine, 0.5 mol/l (Berlex Laboratories, Wayne, NJ, U.S.A.), a
      LightSpeed QX/i CT (General Electric Medical Systems, Milwaukee, WI, U.S.A.), and
      an Ultra Sparc II (SUN Microsystems, Santa Clara, CA, U.S.A.) running Advantage
      Windows 3.1 (General Electric Medical Systems) were used. RESULTS: Sufficient
      enhancement for CTA of the thoracic aorta, cervical vessels, and abdominal
      vessels was produced in the experimental dog, and the cervical vessels were
      clearly defined in all three patients. CONCLUSION: In that subset of patients
      with contraindications to iodinated contrast medium and for whom magnetic
      resonance angiography is inappropriate, gadopentetate dimeglumine may be an
      alternative contrast medium for CTA.

PMID- 12488727
TI  - Gadolinium-enhanced multidetector CT angiography of the thoracoabdominal aorta.
AB  - A 93-year-old patient with a cardiac pacemaker and biochemical renal failure
      presented with back pain suspicious for dissection. We performed gadolinium
      enhanced thoracoabdominal multidetector CT angiography using eight-channel
      multidetector CT. Uniform aortic enhancement of 140 HU was sufficient to exclude
      aortic dissection and defined an unruptured infrarenal abdominal aortic aneurysm.

PMID- 12488729
TI  - Coronary artery calcium scoring using multicardiac computed tomography.
AB  - OBJECTIVES: To test the hypothesis that multicardiac-phase computed tomography
      (CT) improves the quantification of coronary artery calcium. METHODS: Calcium
      phosphate on a cardiac phantom and 108 calcified plaques from 50 patients were
      scanned, and multicardiac-phase images were obtained. Motion artifacts and
      calcium scores of the calcified plaques were compared between cardiac phases and
      CT scanners. RESULTS: In the phantom images, motion artifacts differed between
      cardiac phases; thus, the calcium scores were either higher or lower than the
      score from the static state. In the patient study, motion artifacts of
      calcifications on the various coronary branches varied with the cardiac cycle,
      which profoundly influenced the calcium scores. CONCLUSION: Multicardiac-phase CT
      has the potential to improve the quantification of coronary artery calcium by
      determining the cardiac phase where motion artifacts are the least on individual
      calcified plaques.

PMID- 12488728
TI  - Gadolinium-enhanced three-dimensional electron beam coronary angiography.

PMID- 12488730
TI  - Ability of calibration phantom to reduce the interscan variability in electron
      beam computed tomography.
AB  - OBJECTIVE: To test the hypothesis that a calibration phantom would improve
      interpatient and interscan variability in coronary artery calcium (CAC) studies.
      METHODS: We scanned 144 patients twice with or without the calibration phantom
      and then scanned 93 patients with a single calcific lesion twice and, finally,
      scanned a cork heart with calcific foci. RESULTS: There were no linear
      correlations in computed tomography Hounsfield unit (CT HU) and CT HU interscan
      variation between blood pool and phantom plugs at any slice level in patient
      groups (p > 0.05). The CT HU interscan variation in phantom plugs (2.11 HU) was
      less than that of the blood pool (3.47 HU; p < 0.05) and CAC lesion (20.39; p <
      0.001). Comparing images with and without a calibration phantom, there was a
      significant decrease in CT HU as well as an increase in noise and peak values in
      patient studies and the cork phantom study. CONCLUSION: The CT HU attenuation
      variations of the interpatient and interscan blood pool, calibration phantom
      plug, and cork coronary arteries were not parallel. Therefore, the ability to
      adjust the CT HU variation of calcific lesions by a calibration phantom is
      problematic and may worsen the problem.

PMID- 12488731
TI  - Postmortem intravascular high-density fluid level (hypostasis): CT findings.
AB  - PURPOSE: To evaluate postmortem CT (PMCT) finding of hypostasis. METHODS: PMCT
      examinations were performed within 2 hours of death in 126 patients who arrived
      at our institution in nontraumatic cardiopulmonary arrest. RESULTS: PMCT showed
      hypostasis as high-density fluid level in the lumen of the heart or great vessels
      in 66 of 126 patients (52%). CONCLUSION: Hypostasis is observed as an
      intravascular high-density fluid level on PMCT.

PMID- 12488732
TI  - Age-dependent change in metabolic response to photic stimulation of the primary
      visual cortex in infants: functional magnetic resonance imaging study.
AB  - The blood oxygen level-dependent (BOLD) response to photic stimulation in the
      primary visual cortex (V1) reverses from positive to negative around 8 weeks of
      age. This phenomenon may be caused by increased oxygen consumption during
      stimulation as the result of a rapid increase of synaptic density at this age. To
      test this hypothesis, we applied existing mathematic models of BOLD signals to
      the experimental data from infants. When the stimulus-related increments of
      cerebral blood flow and cerebral blood volume were fixed at 60% and 20%,
      respectively, the mean estimated increment of the cerebral metabolic rate of
      oxygen of the V1 in the elder infant group (57.1% +/- 8.8%) was twice as large as
      that in the younger infant group (32.2% +/- 4.7%), which corresponds to the
      reported difference in synaptic density. The present data confirmed that a change
      in oxygen consumption could explain a transition from a positive to a negative
      BOLD response.

PMID- 12488733
TI  - Comparison of MR signal intensities of cerebral perivascular (Virchow-Robin) and
      subarachnoid spaces.
AB  - PURPOSE: The purpose of this work was to compare quantitatively the T2-weighted
      MR signal intensity values of the perivascular (Virchow-Robin) spaces and the
      cerebrospinal fluid (CSF). METHOD: Coronal 3D T2-weighted turbo spin echo MR
      images of the brain were evaluated in 44 subjects without any significant
      cerebral pathology. MR signal intensity values of the perivascular spaces around
      the anterior commissure and the CSF in the ventricles and the subarachnoid space
      were measured. RESULTS: A statistically significant difference between the mean
      MR signal intensity values of the perivascular spaces and the CSF both in the
      ventricles and in the subarachnoid space was found. The intensity values in the
      ventricles and in the subarachnoid space were not statistically significantly
      different. CONCLUSION: The perivascular spaces have a different MR signal
      intensity than the CSF-containing structures within and around the brain. This
      finding is in keeping with the statement that the perivascular spaces represent
      entrapments of interstitial fluid and are not the invagination of CSF-filled
      subarachnoid sheaths.

PMID- 12488734
TI  - Hemichorea-hemiballism in primary diabetic patients: MR correlation.
AB  - PURPOSE: The purpose of this work was to describe the characteristic imaging
      findings and clinical presentations in patients with hemichorea-hemiballism (HC
      HB) associated with nonketotic hyperglycemia (NKH) in primary diabetes mellitus
      (DM). METHOD: The MR findings from six patients with HC-HB associated with NKH in
      primary DM were evaluated. Their ages ranged from 43 to 81 years. CT was
      performed on three patients, one of whom underwent a SPECT exam and another who
      had follow-up MRI. RESULTS: A high-signal putaminal lesion was evident on the T1
      weighted images in all cases without edema or mass effect. Three of the six cases
      also showed high-signal intensities in the caudate. Two cases revealed high
      signal intensities in the globus pallidus, and the lesions extended to the
      midbrain in one patient. The T2-weighted and FLAIR images were more variable. One
      diffusion-weighted image showed increased signal intensity. All three patients
      who had postcontrast MRI showed no enhancement. Two of the three patients who had
      CT studies showed high attenuation and the other isodensity. The SPECT study
      showed decreased perfusion. In all our patients, the chorea resolved within days
      to weeks after correction of the underlying hyperglycemia. CONCLUSION: In
      patients with HC-HB with NKH in primary DM, T1-weighted MR images showed
      hyperintense lesions of the putamen or caudate. Early recognition of these
      imaging characteristics may facilitate the diagnosis of primary DM with
      hyperglycemia and lead to prompt and appropriate therapy.

PMID- 12488735
TI  - Enhanced four-detector row computed tomography imaging of laryngeal and
      hypopharyngeal cancers.
AB  - PURPOSE: Four-detector row computed tomography (4D CT) enables imaging of the
      larynx and hypopharynx with high temporal resolution and rapid reformatting of
      coronal planes. The aim of our study was to assess the usefulness of postcontrast
      biphasic 4D CT in diagnosing tumor extent. METHODS: Forty-seven patients with
      laryngeal or hypopharyngeal cancer were investigated using 4D CT. Two
      radiologists retrospectively evaluated transverse and reformatted coronal images
      in both the early and late phases. RESULTS: Images in the late phase were
      superior to those in the early phase in the conspicuity of the depicted lesions.
      The coronal images facilitated assessment of the craniocaudal extension of tumors
      and obliteration of the paraglottic space. The maximal diameter of tumors tended
      to be larger on the coronal image than on the transverse image. CONCLUSIONS:
      Images in the late phase were more informative than images in the early phase to
      demonstrate tumor extension. Reformatted coronal imaging was useful in evaluating
      craniocaudal extension.

PMID- 12488736
TI  - Dynamic multislice helical CT of ameloblastoma and odontogenic keratocyst:
      correlation between contrast enhancement and angiogenesis.
AB  - PURPOSE: The purpose of this study was to assess whether the enhancement
      characteristics of dynamic multislice helical CT (MS-CT) could help in the
      differential diagnosis of ameloblastomas and odontogenic keratocysts. The
      correlation between enhancement characteristics and immunohistochemical findings,
      especially with regard to angiogenesis, was also evaluated. METHOD: Dynamic MS-CT
      was performed in 13 consecutive patients (8 ameloblastoma cases and 5 odontogenic
      keratocyst cases). The percentage of density increase (Enh%) was measured in
      dynamic MS-CT images taken during the arterial phase, and microvessel density
      (MVD) was analyzed using immunohistochemical study with anti-CD31 antibody. The
      Mann-Whitney U test was used to evaluate the significance of the Enh% or the MVD
      values between lesion subtypes, and the Spearman correlation coefficient was used
      to evaluate the correlation between the Enh% and the MVD in ameloblastomas and
      odontogenic keratocysts. RESULTS: The Enh% in ameloblastomas was significantly
      higher than that of odontogenic keratocysts (P < 0.005). The MVD of
      ameloblastomas was also significantly higher than that of odontogenic keratocysts
      (P < 0.005). The Enh% values for ameloblastomas and odontogenic keratocysts were
      positively correlated with the respective MVD values (r = 0.92, P < or = 0.000).
      CONCLUSION: Dynamic MS-CT is useful tool for differentiating between
      ameloblastomas and odontogenic keratocysts on the basis of the contrast
      enhancement values of intratumoral vascularities during the arterial phase.
      Furthermore, the Enh% obtained by dynamic MS-CT is correlated with the MVD in
      ameloblastomas and odontogenic keratocysts.

PMID- 12488737
TI  - Automatic brain tissue extraction method using erosion-dilation treatment (BREED)
      from three-dimensional magnetic resonance imaging T1-weighted data.
AB  - To improve the efficiency of brain image analysis, we propose a full-automatic
      method for extracting brain tissue from three-dimensional magnetic resonance
      imaging of T1-weighted data on the human head (brain tissue extraction method
      using erosion-dilation treatment [BREED]). The extraction processing is realized
      by combining signal intensity thresholding by means of the discriminant analysis
      method and an erosion-dilation treatment of the image. The accuracy of BREED is
      evaluated using both simulated and subject data. BREED can extract brain tissues
      with high accuracy (approximately 97%) for either simulated or subject data.

PMID- 12488738
TI  - Cartilaginous endplates of the spine: MRI with anatomic correlation in cadavers.
AB  - PURPOSE: The purpose of this work was to describe the MR appearance of
      cartilaginous endplates (CEPs) with close anatomic correlation in cadavers
      derived from elderly subjects. METHOD: High-resolution MRI was performed on five
      cadaveric lumbar spines, and a total of 48 CEPs were studied with T1-weighted
      spin echo, T2-weighted fast spin echo, and fat-suppressed 3D spoiled GRASS
      gradient echo (SPGR) MR images. All specimens underwent anatomic sectioning, and
      gross anatomic findings were correlated with those of MRI. RESULTS: Conventional
      MR images allowed gross morphologic evaluation of the integrity of the CEPs and
      demonstrated cartilaginous nodes. In all specimens, fat-suppressed 3D-SPGR images
      invariably improved visualization of the fine anatomic structures at the
      diskovertebral junction (p < 0.01). Various morphologic abnormalities of the CEPs
      demonstrated on MR images, including thinning, irregularity, erosions,
      cartilaginous defects, and Schmorl nodes, were confirmed on anatomic inspection.
      CONCLUSION: Results in our study indicate that MRI may delineate the normal
      anatomy of CEPs and demonstrate morphologic changes occurring at the
      diskovertebral junction. Dedicated high-resolution technique and fat-suppressed
      3D-SPGR images may significantly improve the diagnostic capabilities of MRI of
      this particular anatomic region.

PMID- 12488739
TI  - Translocation of Broca's area to the contralateral hemisphere as the result of
      the growth of a left inferior frontal glioma.
AB  - We report a case of a patient with a left inferior frontal glioma in whom
      language functional magnetic resonance imaging (fMRI) paradigms produced
      activation of Broca's area on the right and Wernicke's area on the left. We
      propose that tumor invasion of the left frontal operculum led to cortical
      reorganization and interhemispheric transfer of Broca's area. This case
      emphasizes the importance of preoperative fMRI in assessing the location of
      eloquent cortices adjacent to a tumor and in guiding neurosurgical decision
      making.

PMID- 12488740
TI  - A rare sign of intracranial internal carotid artery dissection causing cerebral
      infarction: a case report and review of the literature.
AB  - We describe a patient with CT-proven ischemic infarction of the left middle
      cerebral artery (MCA) territory. The emergency CT, on admission, was suggestive
      of intracranial internal carotid artery dissection by demonstrating gaseous gap
      defects in the arterial wall and a subsequent thromboembolic process in the MCA.
      To our knowledge, there is no previous report regarding radiologically detected
      gas within the vessel wall or lumen secondary to dissection. We discuss this
      uncommon radiologic sign and its possible pathogenesis with a review of the
      literature.

PMID- 12488741
TI  - Reversible MR imaging and MR spectroscopy abnormalities in association with
      metronidazole therapy.
AB  - We present a report of MRI and proton MR spectroscopy (MRS) findings in an
      adolescent patient with Down syndrome and Crohn disease treated with
      metronidazole. MRI revealed signal abnormalities within the corpus callosum,
      basal ganglia, and brainstem. Proton MRS examination demonstrated a persistent
      lactate elevation during metronidazole treatment. Clinical, spectroscopic, and
      imaging abnormalities resolved with discontinuation of metronidazole.

PMID- 12488742
TI  - Tensor diffusion imaging in B12 leukoencephalopathy.
AB  - Anisotropy measurements were obtained from periventricular foci of T2
      prolongation and adjacent normal-appearing white matter in a case of B12
      leukoencephalopathy. Measurements were compared with mean values from two age
      matched control subjects. Anisotropy was greatly reduced in the lesions evident
      on T2-weighted images and in the normal-appearing adjacent white matter (WM),
      indicating that the extent of WM tract disruption was greater than could be
      identified on routine MR sequences.

PMID- 12488743
TI  - Spiral CT following the Whipple procedure: distinguishing normal postoperative
      findings from complications.
AB  - Following a Whipple procedure for a patient with pancreatic cancer, postoperative
      imaging with CT is essential to exclude complications and to identify recurrence.
      Accurate interpretation of these examinations requires knowledge of the type of
      surgery performed and the normal appearance of the abdomen on CT following this
      complex surgery. The purpose of this pictorial essay is to illustrate the normal
      appearance of the bowel following a Whipple procedure as well as some of the
      complications.

PMID- 12488744
TI  - Limits of Couinaud's liver segment classification: a quantitative computer-based
      three-dimensional analysis.
AB  - PURPOSE: Traditionally, liver surgery relies on Couinaud's liver segment
      classification. As the position and shape of these segments are variable and
      their borders are hidden within the homogeneous liver mass, the accuracy of
      segment identification methods needs computer-aided reevaluation. METHOD: The
      segmental liver anatomy of 23 patients receiving diagnostic helical CT scans
      because of suspected intrahepatic lesion was analyzed with the aid of a computer
      based operation-planning system. We compared the standard Couinaud
      classification, which depends particularly on the main stems of portal and
      hepatic veins, with a method that calculates the segment borders by analyzing the
      complete portal venous tree. Volume, shape, and position of the liver segments
      found by each method were compared. RESULTS: With reference to the portal vein
      based method, segmental volumes were overestimated by the classic Couinaud method
      by up to 24% and underestimated to 13%. Volumes of Couinaud segments 4a, 7, and 8
      were generally larger compared with those obtained by the portal vein-based
      method, whereas segments 3 and 6 were smaller. Gross variations were found in
      segments 5, 7, and 8. When shape and position were considered, poor correlation
      was found for five segments (median kappa = 0.35-0.45). Only segments 2, 7, and 8
      had kappa values clearly above 0.45 in the majority of cases. The plane that
      divides the two hemilivers along the middle hepatic vein and the border between
      the left sector (segments 2 and 3) and the medial sector (4a and 4b) were found
      in both methods with very good conformity (kappa > 0.75). CONCLUSION: Couinaud's
      method of dividing the liver into eight autonomous liver segments has to be
      accepted as a good approximation. Nevertheless, the volume, position, and shape
      of these segments and their segmental borders show significant variability.

PMID- 12488745
TI  - Multiple biliary papillomatosis: comparison of MR cholangiography with endoscopic
      retrograde cholangiography.
AB  - PURPOSE: The purpose of this work was to compare MR cholangiography with
      endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of
      multiple biliary papillomatosis (MBP). METHOD: Nine patients with pathologically
      proven MBP underwent MR cholangiography and ERCP. A comparison was made between
      ERCP, multislice HASTE, and single-shot RARE. Each biliary tract was divided into
      five sections for assessment; therefore, 45 biliary duct areas were used for
      lesion detection and determination of quality of depiction. RESULTS: Of the 35
      segments detected by percutaneous transhepatic cholangioscopy, pathologic
      examinations were performed in 31 segments: papillary adenocarcinoma was proved
      in 28 and papillary adenoma in 3. The multislice HASTE sequence showed bile duct
      branches with biliary papillomatosis better than did ERCP (p = 0.0029) and single
      shot RARE sequence (p = 0.0558). The multislice HASTE procedure had the highest
      number of lesions detected, followed by single-shot RARE and ERCP, but there was
      no significant difference between the imaging techniques. CONCLUSION: Our
      preliminary data suggest that MR cholangiography can replace ERCP for the
      detection of MBP.

PMID- 12488746
TI  - Peritumoral rim enhancement of liver metastasis: hemodynamics observed on single
      level dynamic CT during hepatic arteriography and histopathologic correlation.
AB  - PURPOSE: The purpose of this work was to clarify the mechanism of peritumoral rim
      enhancement of metastatic liver cancer. METHOD: Twenty-nine liver metastases of
      colon cancer were examined by single-level dynamic CT during hepatic
      arteriography, which was performed without table feed. We analyzed these findings
      and correlated them with the histopathologic findings. RESULTS: Eleven metastases
      were hypervascular and 18 were hypovascular. Early appearance of rim enhancement
      was seen in 3 of 10 hypervascular metastases and 17 of 18 hypovascular metastases
      (p < 0.01). The time of appearance and thickness of peritumoral rim enhancement
      showed no apparent correlation with the desmoplastic reaction or inflammation in
      the surrounding hepatic parenchyma. CONCLUSION: Two types of intra- and
      peritumoral enhancement were observed. Peritumoral rim enhancement was considered
      to be due mainly to the drainage of blood flow from the tumor to the surrounding
      hepatic parenchyma in hypervascular metastasis or increased arterioportal shunts
      surrounding the tumor in hypovascular metastasis.

PMID- 12488747
TI  - Detection of hypervascular hepatocellular carcinoma by dynamic magnetic resonance
      imaging with double-echo chemical shift in-phase and opposed-phase gradient echo
      technique: comparison with dynamic helical computed tomography imaging with
      double arterial phase.
AB  - PURPOSE: The technique of double-echo chemical shift gradient echo magnetic
      resonance imaging (MRI) with the fast low-angle shot (double-echo FLASH) sequence
      provides in-phase and opposed-phase images in a single breath hold. The purpose
      of this study was to evaluate the efficacy of dynamic MRI with double-echo FLASH
      imaging for the detection of hypervascular hepatocellular carcinoma by comparing
      it with dynamic helical computed tomography (CT) imaging with double arterial
      phase. MATERIALS AND METHODS: Twenty-nine patients with 67 hypervascular
      hepatocellular carcinoma nodules who underwent both dynamic MRI with double-echo
      FLASH imaging (repetition time/echo time/flip angle: 160/3.6, 7.0/80 degrees )
      and dynamic helical CT imaging with double arterial phase were enrolled in the
      study. For dynamic MRI, precontrast, arterial, portal venous, and equilibrium
      phase images were obtained before and approximately 19, 60, and 120 seconds,
      respectively, after intravenous injection of 0.1 mmol/kg of gadopentetate
      dimeglumine at a rate of 2 ml/s. For dynamic CT imaging, quadraphase images,
      including early arterial, late arterial, portal venous, and equilibrium phases,
      were obtained serially approximately 20, 30, 70, and 180 seconds, respectively,
      after intravenous administration of 2 ml/kg of 300 mgI/ml of nonionic contrast
      medium at a rate of 5 ml/s. Three masked observers independently interpreted
      images obtained with each technique in random order, separately and without
      patient identifiers. Sensitivity and positive predictive values as well as the
      area below the alternative-free response receiver operating characteristic curve
      (Az) for each imaging technique were calculated and compared statistically.
      RESULTS: Mean sensitivity and positive predictive values of MRI for hypervascular
      hepatocellular carcinoma were 48% and 94%, respectively, and those of CT imaging
      were 47% and 91%, respectively. In 11 (38%) of the 29 patients, at least one
      observer judged dynamic MRI to be superior, whereas in 5 patients (17%), dynamic
      CT was judged to be superior. There was no significant difference in the
      sensitivity and positive predictive values between these techniques (p > 0.05).
      There was no significant difference either in mean Az values between CT (0.55)
      and MRI (0.57) (p = 0.61). CONCLUSION: Dynamic MRI with double-echo FLASH imaging
      can detect hypervascular hepatocellular carcinoma as well as dynamic helical CT
      imaging with double arterial phase.

PMID- 12488748
TI  - Hepatic iron deposition on magnetic resonance imaging: correlation with
      inflammatory activity.
AB  - PURPOSES: To define the relation between pathologic inflammatory activity and
      magnetic resonance imaging (MRI) grades of iron deposition in patients with liver
      cirrhosis. PATIENTS AND METHODS: In 53 patients with biopsy-proven liver
      cirrhosis, T2*-weighted gradient echo MRI (echo time > or =6 milliseconds) was
      reviewed. Grading of parenchymal iron deposition and siderotic nodules in the
      liver and liver-to-skeletal muscle signal intensity ratios were compared with
      pathologically defined inflammatory activity. RESULTS: The MRI grade of hepatic
      siderotic nodules correlated significantly with the grade of periportal
      inflammation (r = 0.301, P < 0.05) but not with the grade of piecemeal necrosis.
      The grade of parenchymal iron deposition was not correlated with the grade of
      periportal inflammation or piecemeal necrosis. There was a nonsignificant trend
      toward correlation between the histologic grade of hepatic iron content and the
      grades of periportal inflammation and piecemeal necrosis. CONCLUSION: MRI grading
      of siderotic nodules correlates with inflammatory activity in cirrhotic patients.

PMID- 12488749
TI  - Do patients with primary sclerosing cholangitis have a greater frequency of
      pancreatic abnormalities at MRI than patients with other liver diseases?
AB  - PURPOSE: It has been proposed that there is an increased frequency of pancreatic
      abnormalities in patients with primary sclerosing cholangitis (PSC). Our purpose
      is to compare the frequency of pancreatic abnormalities detected at MRI in
      patients with PSC and to compare these findings with those found in a matched
      cohort with other liver diseases. METHOD: We identified 29 patients who had
      either a histologic or an endoscopic retrograde cholangiopancreatography
      diagnosis of PSC and 29 age- and gender-matched patients with liver disease
      without PSC who underwent MRI at 1.5 T. The protocol included breath-hold T1
      weighted gradient echo, echo train, fast spin echo, T2-weighted images and
      dynamic gadolinium-enhanced MRI. Two blinded readers retrospectively evaluated
      the MR images for abnormalities of pancreatic size and morphology, T1 and T2
      signal intensity, duct size and irregularities, arterial-phase contrast
      enhancement, focal pancreatic masses, cystic lesions, peripancreatic fluid/edema,
      ascites, and capsular-like rim surrounding the pancreas. RESULTS: The prevalence
      of pancreatic and peripancreatic abnormalities was 10 of 29 (35%) in PSC patients
      and 14 of 29 (48%) in control patients. MR findings included ascites (9 PSC, 12
      controls), peripancreatic edema (7 PSC, 11 controls), atrophy (4 PSC, 3 control),
      increased T2 signal (3 PSC, 4 controls), cystic lesions (2 PSC, 3 controls),
      abnormal T1 signal (1 PSC, 2 controls), and dilated pancreatic ducts (3 PSC, 2
      controls). Quantitative parameters were not significantly different between PSC
      patients and the control subjects with pancreatic findings. CONCLUSION: There is
      no significant difference in pancreatic abnormalities detected on MRI between
      patients with PSC and those with other liver diseases.

PMID- 12488750
TI  - Dropped gallstones post laparoscopic cholecystectomy mimicking peritoneal
      seeding: CT and ultrasound features.
AB  - PURPOSE: The purpose of this work was to investigate the ultrasound (US) and CT
      features of dropped gallstones mimicking peritoneal seeding in patients after
      laparoscopic cholecystectomy (LCC). METHOD: We describe the US and CT features of
      dropped gallstones mimicking peritoneal seeding in eight patients who underwent
      LCC. We also conducted a retrospective study of consecutive LCC patients who
      subsequently had CT to determine the prevalence of this condition. RESULTS AND
      CONCLUSION: The density of dropped gallstones on CT ranged from hypodense to
      partially or completely calcified nodules. Some stones did not have visible
      surrounding reaction, whereas others showed an enhancing halo. All stones were
      echogenic and demonstrated shadowing on US. The stones were located mostly on the
      right side of the abdomen, and the majority were around the liver. The prevalence
      of dropped gallstones post laparoscopic cholecystectomy was 4.2%.

PMID- 12488751
TI  - Sensitivity and specificity of CT in the diagnosis of inflammatory abdominal
      aortic aneurysms.
AB  - PURPOSE: The purpose of this study is to assess the diagnostic ability
      (sensitivity and specificity) of CT in the diagnosis of inflammatory abdominal
      aortic aneurysm (IAAA) and to quantitatively evaluate its features. METHOD: A
      retrospective survey of 355 consecutive patients with abdominal aortic aneurysm
      and iliac artery aneurysm who underwent CT examination and surgical repair
      yielded 18 patients with operatively confirmed IAAA. The sensitivity,
      specificity, and diagnostic accuracy of CT were evaluated in this review.
      Eighteen IAAAs were then analyzed in terms of distribution and degree of
      perianeurysmal fibrosis as well as time-dependent change of CT values of the
      aneurysmal wall on contrast-enhanced CT. Complications related to IAAA were also
      determined. RESULTS: Fifteen of the 18 cases of IAAA could be easily diagnosed on
      CT prior to surgical repair. Three false-negative and one false-positive case
      were found. This gives a sensitivity rate of 83.3% for this imaging technique,
      with specificity and accuracy rates of 99.7 and 93.7%, respectively. Thickening
      of the aortic wall was noticed mostly in the anterolateral wall of the aneurysm
      as compared with the posterior wall. The thickness of the perianeurysmal fibrosis
      correlated neither with the size of aneurysm nor with the inflammatory reaction
      such as erythrocyte sedimentation rate, C-reactive protein level, and white blood
      cell count. CT indicated the complications in 7 of 18 patients with IAAA. These
      included hydronephrosis, aortoenteric fistula, and infected iliac aneurysm.
      CONCLUSION: CT scan with contrast enhancement was a highly reliable imaging
      modality for the diagnosis of IAAA.

PMID- 12488752
TI  - Computer-aided detection of polyps in a colon phantom: effect of scan
      orientation, polyp size, collimation, and dose.
AB  - PURPOSE: To determine the importance of polyp size, orientation to the scan
      plane, collimation, scanner type (single or multislice helical), and radiation
      dose on computed tomography (CT) colonography computer-aided detection. MATERIALS
      AND METHODS: Eight tissue-equivalent simulated polyps were placed into the
      interior of an air-filled acrylic tube placed within a water-filled box. Their
      sizes, expressed by diameter and height in millimeters, were 10 x 10, 10 x 7, 10
      x 5, 10 x 3, 7 x 7, 7 x 5, 7 x 3, and 5 x 5. Detection of the polyps was
      performed by applying our prototype automated polyp detector software to 48 CT
      colonography data sets of the phantom acquired with different CT scanner
      settings. RESULTS: We detected at least six of the eight polyps in 47 of 48
      experiments. The two most frequently undetected polyps (7 x 7 and 5 x 5) had
      extreme eccentricity (their height was twice the radius of the base) and were
      most commonly missed for 90 degrees tube orientation, 5-mm collimation, and high
      table speed. False-positive detections occurred in only 5 of 48 experiments.
      CONCLUSION: Clinically significant 10-mm polyps can be detected with 100%
      sensitivity in all orientations, doses, collimations, and modes that we examined.

PMID- 12488753
TI  - Heterotopic paragonimiasis in the omentum.
AB  - Paragonimus westermani is a lung fluke but may be found in organs other than the
      lungs. A case of omental paragonimiasis was found incidentally by plain
      radiography and computed tomography and showed multiple, irregularly shaped,
      conglomerated calcifications in the intraperitoneum. Many P. westermani ova were
      detected in the resected omentum. This uncommon calcification on the plain
      abdominal radiography and computed tomography scan was considered to represent
      radiologic findings of ectopic paragonimiasis.

PMID- 12488754
TI  - CT during arterial portography: effects of precontrast injection of prostaglandin
      E1 into the superior mesenteric artery.
AB  - Prostaglandin E1 (PGE1) is a vasodilator that increases portal venous flow.
      Hepatic CT during arterial portography (CTAP) was performed in 42 patients with
      and without PGE1 to compare peak hepatic enhancement and nontumorous
      abnormalities. Although no significant differences in peak hepatic enhancement
      were observed (71 +/- 12 HU for CTAP with PGE1; 74 +/- 34 HU for CTAP without
      PGE1), the number of nontumorous abnormalities for CTAP with PGE1 (n = 11) was
      significantly lower than that for CTAP without PGE1 (n = 24) (p < 0.01, Wilcoxon
      signed rank test). CTAP combined with PGE1 therefore represents a useful method
      to study lesions of the liver, as the number of nontumorous abnormalities
      observed is significantly reduced and liver parenchyma can be scanned more
      evenly.

PMID- 12488755
TI  - Air-containing space in lung adenocarcinoma: high-resolution computed tomography
      findings.
AB  - OBJECTIVE: To disclose imaging features of air-containing spaces other than air
      bronchograms in lung adenocarcinoma on high-resolution computed tomography
      (HRCT). MATERIALS AND METHODS: We retrospectively reviewed HRCT scans of 42
      consecutive patients with surgically proved lung adenocarcinoma correlating with
      pathologic specimens. RESULTS: Air-containing spaces were seen in 17 (40%) of
      cases on HRCT. The air-containing spaces appeared as multiple air densities (16
      cases [94%]) with variable shapes and had a relatively larger size than that of
      air bronchograms. Internal septi were often noted (11 cases [65%]). CONCLUSION:
      Our results demonstrate that multiplicity, larger diameter, and internal septi
      are the features of air-containing spaces. These findings could be a key to the
      definitive diagnosis of lung adenocarcinoma, distinguishing it from the mimics
      such as organizing pneumonia, tuberculoma, or malignant lymphoma.

PMID- 12488756
TI  - Percutaneous radiofrequency ablation of a lung metastasis: delayed cavitation
      with no infection.
AB  - A 64-year-old man presented with a lung metastasis of the lower left lobe. After
      partial response with chemotherapy, a thoracotomy was performed that did not
      allow a wedge resection, and lobectomy was contraindicated by the patient's
      ventilatory function. Radiofrequency ablation of this lung metastasis was thus
      performed, followed by a delayed cavitation with no infection, which, to our
      knowledge, has not yet been described.

PMID- 12488757
TI  - Cross-sectional imaging of amyloidosis: an organ system-based approach.
AB  - Systemic amyloidosis--whether primary or secondary--can involve any organ or
      organ system and imparts significant morbidity and mortality. Unfortunately,
      imaging findings are only rarely specific, manifesting in a variety of ways
      (e.g., mass-like lesions, micronodular or diffusely infiltrative process).
      Sensitivity can be improved by being familiar with these varied image
      manifestations of amyloidosis and aware of the patient's medical history, because
      there is a significant association between this and other systemic diseases.

PMID- 12488758
TI  - Diffusion-weighted half-Fourier single-shot turbo spin echo imaging in breast
      tumors: differentiation of invasive ductal carcinoma from fibroadenoma.
AB  - PURPOSE: The purpose of this investigation is to evaluate the usefulness of
      diffusion-weighted half-Fourier single-shot turbo spin echo (DW-HASTE) imaging in
      differentiating invasive ductal carcinoma from fibroadenoma. METHOD: The DW-HASTE
      imaging was performed in patients with invasive ductal carcinoma (n = 16) and
      fibroadenoma (n = 6). Images were obtained with diffusion-sensitizing gradients
      of 0 and 700 mm(2)/s. The apparent diffusion coefficient (ADC) was calculated.
      RESULTS: The DW-HASTE imaging was not affected with susceptibility and chemical
      shift artifacts usually present in DW echo planar imaging. The DW-HASTE imaging
      had low tumor detectability (62%), however. The difference in mean ADC of
      invasive ductal carcinoma (1.216 +/- 0.189 x 10(-3)mm(2)/s) and fibroadenoma
      (1.495 +/- 0.181 x 10(-3)mm(2)/s) was statistically significant. CONCLUSION:
      Apparent diffusion coefficient measurement using DW-HASTE imaging is helpful in
      differentiating invasive ductal carcinoma from fibroadenoma. Nevertheless, DW
      HASTE imaging has low detectability at present; therefore, more technologic
      improvement is desired.

PMID- 12488759
TI  - Quantitative differentiation of breast lesions based on three-dimensional
      morphology from magnetic resonance imaging.
AB  - OBJECTIVE: The purpose of this study was to develop geometric indices, based on
      morphologic measurements, of contrast-enhanced breast lesions using three
      dimensional magnetic resonance imaging (MRI) that can statistically differentiate
      between benign and malignant lesions. METHODS: Thirty-three patients with
      abnormal mammograms were scanned using three-dimensional MRI. The lesion was then
      extracted from the volume data set using interactive volume-rendering software.
      From the extracted region of interest, the surface boundary corresponding to the
      lesion was extracted using an isosurface method. The boundary was represented as
      a triangular mesh, from which the surface area and volume enclosed by the surface
      were computed. The following variables were tested for discrimination ability
      between benign and malignant lesions: 1) the volume-to-surface area (V/S) ratio,
      2) spherical shape index (SSI), and 3) resolution reduction for V/S and SSI
      values (100%, 16%, 8%, 4%, 2%, and 1% resolution). In addition, comparisons were
      made between the V/S and SSI values at 100% versus their reduced resolutions.
      RESULTS: Thirty-three subjects (15 malignant tumors and 18 benign tumors) were
      studied. The SSI index (P = 0.0063) was a significant discriminator for
      malignancy. The V/S ratio (P = 0.9280) did not seem to be a useful variable in
      distinguishing benign and malignant masses. The V/S resolution comparisons (P >
      0.5897) and the SSI resolution comparisons (P > 0.05) were also not useful
      discriminating variables. CONCLUSION: The SSI seems to be a useful factor in
      differentiating between benign and malignant lesions. Current clinical
      interpretation of breast lesions using MRI may be enhanced by the adjunctive use
      of this objective postanalysis method.

PMID- 12488760
TI  - MR finding of seat belt injury in the breast.

PMID- 12488761
TI  - Emission tomography with a large-hole collimator (CACAO): a possible new way to
      improve radionuclide imaging.
AB  - This work aims to improve the quality of scintigraphy. It evaluates the use of a
      large-hole collimator, the Computer Aided Collimation Gamma Camera Project
      (CACAO), in SPECT. Acquisition data from the same object were simulated for CACAO
      and for a conventional collimator. Better signal-to-noise ratios were found for
      CACAO images, whatever the number of emitted photons. This work demonstrates that
      high-resolution images may be obtained with large-hole collimators. The
      combination of CACAO and pixilated detectors may further improve radionuclide
      imaging.

PMID- 12488762
TI  - Atypical benign lipomatous tumors in the soft tissue: radiographic and pathologic
      correlation.
AB  - This article describes the characteristic imaging findings and correlates them
      with the pathology in the nonfatty regions of benign atypical lipomatous tumors,
      which have different findings compared with typical lipomas and well
      differentiated liposarcomas. For differentiating these tumors from typical
      lipomas and well-differentiated liposarcomas, it may be helpful to analyze
      nonfatty regions in benign atypical lipomatous tumors.

PMID- 12488763
TI  - Adult cranial dura I: intrinsic vessels.
AB  - This is the first of two articles designed to provide user-friendly schematics of
      the adult dural vascular anatomy. It describes the intrinsic meningeal arteries
      and veins of the skull base/cranial vault and the dural partitions (the
      tentorium, falx cerebelli, and falx cerebri). The discussion of this anatomy is
      supplemented by illustrative pathologic insights. The second article focuses on
      the dural sinuses and their remaining tributaries from the brain, diploe, and
      emissary veins from the extracranial soft tissues. This information will assist
      in interpreting neuroimaging studies, communications with clinicians, and
      teaching of this difficult subject.

PMID- 12488764
TI  - Major lower limb congenital shortening: a mini review.
AB  - Major congenital limb deficiencies are rare and the experience of most
      orthopaedic surgeons of their management will be small. The suggestion of the
      establishment of special limb deficiency clinics seems a sensible way of
      collecting the necessary expertise together in one place in order to advise
      patient and parents on the long-term management, throughout life, of their
      problems. Advances in imaging have led to prenatal diagnosis, which produces very
      significant problems in counselling parents before their child is born. More
      sophisticated methods of imaging after birth such as magnetic resonance imaging
      allow more accurate assessment of the deficiency. Early classifications based on
      plain radiology in the first year of life are being superseded by classifications
      relevant to the modern methods of reconstruction particularly the circular
      (Ilizarov) fixator. Similarly the remarkable advances in molecular biology are
      increasing our understanding of the fundamental causes of these deficiencies and
      the ultimate aim of their prevention. The rapid advances in reconstruction
      particularly using circular fixators has made reconstruction rather than
      amputation and a prosthesis possible, particularly in the milder forms of
      deficiency. However, the surgeon must remember that these conditions represent a
      field defect so that reconstruction cannot produce a normal limb. One of the
      hardest things to explain to patients and parents is that however well
      reconstruction is performed the result is not a normal limb. In the more severe
      forms of deficiency frequently the best advice is still amputation and a modern
      prosthesis. For some patients and parents this is very difficult if not
      impossible to accept. However, life with a good amputation and modern prosthesis
      may be better than attempting a long and arduous reconstruction, which still
      results in an abnormal and imperfect limb.

PMID- 12488765
TI  - Nail-patella syndrome: long term evolution.
AB  - Nail-patella syndrome is a rare dysplasia characterized by a typical tetrad:
      hypoplasic nails, hypoplasic or absent patella, radial head dislocation and iliac
      horns. We review eight patients, four men and four women, aged from 20 to 70
      years. The main complaint at consultation was with their knees due to patellar
      instability and pain. Five of them required surgical treatment due to patellar
      dislocation and three patients were not treated. The Krogius-Lecene procedure was
      performed in four patients with a good result following the Insall classification
      of pain and instability and with an average follow-up of 24 years (range, 18-28
      years). Patellectomy was performed in the eldest patient due to femoropatellar
      arthritis present at first consultation. No patients presented with elbow or nail
      disorders or with iliac horns.

PMID- 12488766
TI  - Reconstruction of forearm deformities in multiple cartilaginous exostoses.
AB  - The management of complex forearm deformities in patients with multiple
      cartilaginous exostoses is controversial. The objective of this study is to look
      into the outcome of treatment with the combined use of ulna lengthening, radial
      osteotomy, and excision of exostosis in our six patients, who all had Masada type
      1 deformity of the forearm. Clinical assessment was performed using the pre- and
      postoperative range of motion of the wrist, forearm and elbow. The chief symptom
      each patient had was noted as well as the demographic data of all patients.
      Radiological assessment was performed by checking the degree of negative ulna
      variance, the radial articular angle, and the degree of carpal slip. The degree
      of satisfaction of the patients and their parents were noted. Good clinical and
      radiological results were obtained at a mean follow-up of 2.5 years. All patients
      and parents were satisfied and there was no recurrence of deformity in the latest
      follow-up. The authors believe in early and aggressive treatment of Masada type 1
      deformity of the wrist and forearm for multiple cartilaginous exostoses with a
      combination of excision of exostosis, ulna lengthening and radial osteotomy.

PMID- 12488767
TI  - The orthopaedic manifestations of Smith-Magenis syndrome.
AB  - Smith-Magenis syndrome is a rare condition, which occurs due to interstitial
      deletion of chromosome 17. In order to evaluate the various orthopaedic
      characteristics of this syndrome, we examined 22 patients in the UK. The
      orthopaedic characteristics included brachydactily, short stature, flat feet and
      scoliosis. We found that 30% of our patients had significant scoliosis and some
      of them required corrective surgery. The objective of this paper is to describe
      the general orthopaedic and spinal manifestations of the syndrome and provide an
      overview of the other medical characteristics that an orthopaedic surgeon might
      encounter. We highlight this condition as a rare cause of progressive scoliosis
      that is not reported in the orthopaedic or spinal literature. As a result of this
      study we recommend a screening programme for scoliosis in children with Smith
      Magenis syndrome.

PMID- 12488768
TI  - Bending osteotomy through the distal tibial physis in fibular hemimelia for
      stable reduction of the hindfoot.
AB  - Fibular hemimelia is associated with a deformity of the distal tibial epiphysis
      resulting in a convexity with lateral and posterior slope of the distal joint
      surface. The deformity results into an equinovalgus position of the foot and
      ankle and frequently consecutive dislocation of the foot. A new procedure is
      presented, in with a metaphyseal ostotomy is performed towards the physis in
      order to bend the postero-lateral third of the distal tibial epiphysis forming a
      concave distal tibial joint surface. This procedure was done in four feet in
      three patients at ages between 7 and 20 months combined with soft tissue releases
      and rebalancing the tendons. At a follow-up between 6 and 42 months the position
      of the feet is well retained.

PMID- 12488769
TI  - The adult hip after femoral varus osteotomy in patients with unilateral Legg
      Calve-Perthes disease.
AB  - Femoral varus osteotomy in unilateral Legg-Calve-Perthes disease was reviewed at
      a mean of 18 years (10-27 years) after surgery. Forty-four patients (mean age
      24.5 years) received a clinical and radiographic evaluation. The range of motion
      index revealed good and very good results in 84.1% of the patients. The age at
      surgery was a significant predictor of joint congruence and mature trochanteric
      position. The Catterall classification correlated with the mature leg-length
      difference. The extent of osteotomy and age at surgery showed significant
      influence on the mature femoral head diameter. Femoral varus osteotomy proved to
      be an adequate treatment. Satisfied patients and hips without osteoarthritis and
      with good function for a long period of time can be expected.

PMID- 12488770
TI  - Distal transfer of the greater trochanter in acquired coxa vara. Clinical and
      radiographic results.
AB  - Relative overgrowth of the greater trochanter is a problem related to proximal
      femoral growth cartilage damage. Eleven hips in 10 patients aged 4-13 years with
      acquired coxa vara were retrospectively reviewed. Distal and lateral transfer of
      the greater trochanter was performed in all patients. The average follow-up was
      42.7 months. The causes of the overgrowth were Perthes disease, avascular
      necrosis after treatment of developmental dysplasia of the hip, septic arthritis
      and rheumatoid arthritis. Radiological assessment revealed an improvement of both
      the articulotrochanteric distance and the greater trochanter relative overgrowth.
      Values referred to the acetabulum or the neck-shaft angle remained unmodified.
      Clinical improvement was achieved. A fracture of the transferred greater
      trochanter was observed. We believe that this procedure is a simple technique,
      with good results and few complications.

PMID- 12488771
TI  - Medial synovial plica syndrome of the knee: a diagnostic pitfall in adolescent
      athletes.
AB  - Medial plica syndrome is usually a rare cause of anterior knee pain, but in
      adolescent athletes it is more common. A prospective investigation of clinical
      criteria for the diagnosis of medial plica syndrome was carried out.
      Investigating the stress test for the diagnosis of medial plica syndrome, we used
      active extension as a kick test and flexion to test blocking of swinging of the
      shank. The aim of this investigation was to examine these two new tests. The
      tests we used improved the accuracy of the clinical examination and allowed
      diagnosis of the symptomatic medial plica.

PMID- 12488772
TI  - Clinical and functional outcome of relapse surgery in severe congenital talipes
      equinovarus.
AB  - From a cohort of 110 idiopathic clubfeet, 26 feet in 18 children requiring
      surgery for severe relapse have been studied. Surgery comprised a lateral column
      shortening procedure (Lichtblau) plus or minus a plantarmedial release. Surgery
      was staged to avoid wound complications. Preoperatively feet were prospectively
      categorized, according to a system reported by Dimeglio, into one of four grades.
      This grading system provides a clinical assessment. Children were reviewed on two
      subsequent occasions. At review feet were again graded and in addition appearance
      and functional outcome were analysed. This included an assessment of gait,
      activity and functional limitation. Three children were lost to follow-up leaving
      22 feet in seven male and eight female patients available for review. The mean
      age at surgery was 43 months (23-82 months). The mean time from surgery to first
      and second reviews was 35 and 56 months respectively. There was a significant
      improvement in grading at first review compared with preoperative grading
      (Wilcoxon signed ranks test). Although there remained a significant improvement
      in grading at second review compared with the preoperative grading, there was a
      significant reduction in the number of feet in which grading had improved when
      compared with first review. There was no significant change in function between
      the two postoperative reviews, with the majority of children experiencing little
      functional limitation. There were no wound complications. We conclude that
      relapse surgery, involving a lateral column shortening procedure for severe
      clubfoot, results in a significant initial improvement when assessed using a
      grading system. This improvement in grading subsequently decreases over time.
      However, the functional outcome in such cases remains favourable.

PMID- 12488773
TI  - Fibular shortening in clubfeet.
AB  - Seventy-eight children (105 feet) operated on for congenital clubfoot with two
      different procedures - limited posteromedial-lateral release and complete
      subtalar release - were analysed. For all of them the age at operation ranged
      from 3 to 76 months (mean 17 months) and follow-up from 41 to 84 months (mean 58
      months). The control group consisted of 42 opposite feet from the patients with a
      unilateral deformity. In all the feet operated on, a higher positioning of the
      fibula in relation to the talar dome was found. A correlation between the high
      positioning of the fibula and the strength of the plantar flexors was noted in
      children operated on by limited posteromedial-lateral release (the weaker the
      strength of the plantar flexors the higher the position of the fibula in the
      ankle). There was no correlation between the position of the fibula and the
      hindfoot valgus, the limited range of motion within the talo-calcaneo-navicular
      joint, and the talo-calcaneal angle in the anteroposterior view. In the same
      group, the difference in the distance between lateral malleolus and talar dome in
      the healthy and affected foot did not increase with age, but in the group
      operated on by complete subtalar release, there was a tendency for increasing
      shortening.

PMID- 12488774
TI  - Effect of the Denis Browne splint in conservative treatment of congenital club
      foot.
AB  - In order to discover whether or not a Denis Browne splint is an effective
      orthosis in the conservative treatment of congenital club foot, we investigated
      clinically and radiologically 34 congenital club feet treated with full-time
      splint wearing after serial manipulations and casts. We found objectively that
      the correction achieved by the initial treatments was not improved but was at
      least maintained. However, the age when the splint was applied statistically
      influenced the changes in radiological measurements. The Denis Browne splint with
      a well-molded heel is an effective orthosis to maintain clinical and radiological
      results after initial treatments, especially when it is applied at an early age.

PMID- 12488775
TI  - Fracture of the radial head and neck of Mason types II and III during growth: a
      14-25 year follow-up.
AB  - Twenty-four individuals, who were 16 years of age or younger when they sustained
      a fracture of the radial head or neck, were examined at a mean of 19 years (range
      14-25 years) after injury. The 12 girls and 12 boys were a mean age of 11 years
      (range 5-16 years) when the fracture was sustained. Two were excluded due to late
      resection of the radial head following persisting pain. The fractures, which were
      of Mason type II in 19 and type III in three cases, were treated by mobilization
      in eight cases, plaster in eight, open reduction and internal fixation in three
      and closed reduction and plaster in three. At the follow-up examination, 19 (86%)
      had no complaints, while three (14%) had occasional pain. Flexion was decreased
      in the formerly injured compared with the uninjured elbow (139 +/- 8 degrees
      versus 142+/-5 degrees; P<0.05). None had developed elbow osteoarthritis.
      Isolated, closed fracture of the radial head and neck during growth has a
      favourable, long-term outcome.

PMID- 12488776
TI  - Percutaneous epiphysiodesis for leg length discrepancy.
AB  - This study presents a retrospective evaluation of 57 patients who underwent a
      percutaneous epiphysiodesis for leg length discrepancy. Of these patients, 68.5%
      presented with a good result with a final leg length discrepancy of less than 1.5
      cm, 14% with a fair result with a discrepancy of between 1.5 and 2 cm, and 17.5%
      showed a poor result with a leg length discrepancy of more than 2 cm. The
      percutaneous epiphysiodesis was found to be a safe and reliable technique. There
      were very few technical errors. The causes of failure were analyzed and compared
      with a previous study from the same department. Error in timing remains the main
      problem.

PMID- 12488778
TI  - Correspondence.

PMID- 12488777
TI  - Solitary cystic tuberculosis of long tubular bones in children.
AB  - Five children (mean age 3.4 years) with solitary cystic tuberculosis of proximal
      femur or proximal tibia were treated by surgical debridement and curettage
      combined with anti-tuberculosis anti-biotherapy. The mean follow-up period was
      4.3 years and clinical and radiological healing was observed in all cases. It was
      concluded that solitary cystic tuberculosis of long tubular bones, which was a
      rare manifestation in children, should be kept in mind especially for metaphyseal
      lesions in the lower limbs and should be differentiated from several osseous
      lesions including infections and bone tumours.

PMID- 12488780
TI  - Physiology of sleep and wakefulness as it relates to the physiology of epilepsy.
AB  - This paper reviews the present knowledge about the cellular origins of vigilance
      states (wakefulness and slow-wave sleep) from the perspective of their
      involvement in the triggering of epileptic seizures. The data stem from
      intracellular recordings (most of them dual impalements of pairs of neurons and
      glia), extracellular ionic concentrations (mainly K and Ca ) and simultaneous
      intracortical field potentials from the cortex of cats. These data were
      corroborated with recordings from naturally sleeping animals and humans. It is
      shown that sleep is dominated by a cortically generated slow (<1 Hz) oscillation
      resulting from the complex interplay within networks of neurons and glia, which
      are modulated by the more diffuse action of extracellular currents of ions.
      Wakefulness is produced through the activation of brainstem and basal forebrain
      structures, which disrupt sleep oscillations and elicit a global change of the
      extraneuronal milieu, with profound modifications of glial and cerebral blood
      flow parameters. Paroxysmal events arising during quiet sleep evolve within the
      cortex from normal slow sleep oscillations. The synchronization of large cortical
      and eventually subcortical territories relies on the propagation of increased
      currents of K through the glial syncytium, which compensate for the reduced
      synaptic efficacy due to the depletion of extracellular Ca.

PMID- 12488781
TI  - Effect of sleep on epilepsy.
AB  - There is an extremely intimate relationship between sleep and epilepsy. In this
      manuscript I will review the influence that sleep has on epilepsy. Sleep is a
      potent activator of interictal epileptiform discharges. Sharp waves are
      infrequent during wakefulness in benign focal epilepsy of childhood, but may
      occur in runs of several discharges per page in sleep. The interictal discharges
      become almost continuous in non-REM sleep in the syndrome of encephalopathy with
      electrical status epilepticus during slow wave sleep. In some patients with West
      syndrome a hypsarrhythmia pattern may only appear in sleep whereas in others
      there may be an increase in discharges in a semiperiodic fashion resulting in a
      burst-suppression like pattern. Seizures appear to have a very close relationship
      with sleep in certain epilepsy syndromes. In benign focal epilepsy of childhood
      the seizures occur almost exclusively in sleep, while supplementary
      sensorimototor area seizures tend to occur in clusters during sleep. Juvenile
      myoclonic epilepsy has a close relationship with the sleep-wake cycle with
      seizures tending to occur predominantly on awakening. I also discuss the role of
      sleep and sleep deprivation in the EEG evaluation of epilepsy.

PMID- 12488782
TI  - Sleep complaints and epilepsy: the role of seizures, antiepileptic drugs and
      sleep disorders.
AB  - Patients with epilepsy commonly complain of daytime sleepiness and poor sleep
      quality. These problems are frequently attributed to antiepileptic drugs and
      seizures. Antiepileptic drugs and seizures have effects on sleep architecture
      often leading to daytime sleepiness. However, sleep symptoms may also be caused
      by poor sleep hygiene and primary sleep disorders. Primary sleep disorders should
      be suspected in patients with persistent daytime sleepiness, particularly those
      on AED monotherapy or with low serum drug concentrations and well-controlled
      seizures. Treatment of sleep disorders and improved sleep hygiene may improve
      seizure control and quality of life.

PMID- 12488783
TI  - Paroxysmal events in sleep.
AB  - This review describes the wide spectrum of episodic phenomena that can occur
      during sleep. These phenomena include arousal disorders of nonrapid eye movement
      (NREM) sleep, rapid eye movement (REM) sleep behavior disorder, movement
      disorders, psychiatric disorders, and epileptic seizures. Each of these entities
      is discussed in detail, focusing on their clinical manifestations, diagnosis, and
      treatment. Essential historic elements that distinguish these events and the role
      of video-EEG-polysomnography in their differential diagnosis are emphasized.

PMID- 12488784
TI  - Clinical and radiologic correlates of frontal intermittent rhythmic delta
      activity.
AB  - To assess the clinical and radiologic correlates of frontal intermittent rhythmic
      delta activity (FIRDA), the authors reviewed the hospital charts of patients
      whose EEGs depicted this EEG finding, and recorded their past medical and
      neurologic history, the reason for hospital admission, and their neurologic
      status both on admission and during EEG recordings. Laboratory results on
      admission and concomitant to the EEG recording, computed tomography, or MRI
      findings during hospital admission were also reviewed. Sixty-eight patients were
      assessed. The gender ratio was 1:1; mean age was 56 years. Chronic disease
      occurred in 78% of patients, including hypertension (34%), diabetes (32%), and
      renal failure (18%). On admission, renal failure (n = 34) and hyperglycemia (n =
      22) were most prominent. The majority of patients had at least one abnormal
      laboratory result. Thirty-eight of 51 patients in whom the level of consciousness
      was stated during EEG were described as awake. More than half of 58 patients
      whose EEG background activity was stipulated demonstrated diffuse slowing, mostly
      in the theta range. MRI was abnormal in 15 of 17 patients. Intrahemispheric
      lesions, particularly ischemic and hemorrhagic, were most common (n = 10),
      followed by basal ganglia lacunae (n = 4). Computed tomography was abnormal in 29
      of 44 patients. Hemispheric pathology, diffuse or localized, occurred in 22
      patients. Frontal intermittent rhythmic delta activity is associated with mild to
      moderate encephalopathy and is detected principally in awake patients. Most
      patients in this series had chronic systemic illness. Old ischemic structural
      brain lesions may predispose some patients to develop FIRDA during acute
      metabolic derangement, such as uremia and hyperglycemia. Frontal intermittent
      rhythmic delta activity was not associated with EEG epileptiform activity. Deep
      midline lesions, posterior fossa tumors, and hydrocephalus were not detected in
      this series of patients with FIRDA.

PMID- 12488785
TI  - Early restitution of electrocorticogram predicts subsequent behavioral recovery
      from cardiac arrest.
AB  - Previous studies have shown that parameters of EEG restitution reflect the
      severity of global hypoxic-ischemic brain injury. Here, the hypothesis is tested
      that patterns of EEG restitution during the first 4 hours predict later
      behavioral recovery. Time course and correlations between behavior,
      electrocorticogram (EcoG), and neuronal injury were investigated in a rodent
      model of asphyctic cardiac arrest. Forty Wistar rats were subjected to 5 minutes
      of asphyxia and cardiopulmonary resuscitation. Behavior was assessed by repeated
      scoring of neurodeficits and open field activity until euthanasia at 48 hours.
      Electrocorticographic bursting occurred at 13.2 +/- 4 minutes after
      resuscitation. Bursts increased in frequency and duration until the EcoG reverted
      to a continuous signal. The resuscitation-continuous EcoG interval correlated
      with the first appearance of spontaneous movements (r = 0.80, P < 0.05). Larger
      intervals were associated with hyperactivity in the open field at 24 hours (r =
      0.61, P < 0.05), indicating a more severe behavioral deficit. Larger intervals
      were also associated with worse 48-hour neurodeficit scores (P < 0.05). Neuronal
      damage in the hippocampus correlated with the degree of open field hyperactivity
      at 14 hours (P < 0.05). These findings demonstrate a close temporal and
      prognostic relationship between electrical and behavioral recovery after hypoxic
      ischemic brain injury.

PMID- 12488786
TI  - Spindle activity in children during cardiac surgery and hypothermic
      cardiopulmonary bypass.
AB  - Hypothermia has marked effects on the electrical activity of the brain, which has
      been shown in animals as well as in humans. The aim of this study was to
      investigate EEG spindle activity in children during cardiac surgery and
      hypothermic cardiopulmonary bypass. The authors obtained intraoperative 21
      channel EEG recordings in 36 children (mean age, 22 months; range, 6 days to 69
      months) with congenital heart disease. Bipolar EEG derivations were analyzed
      visually for rhythmic spindle activity based on morphology, frequency, duration,
      and amplitude. Linear regression analysis for duration, frequency, and amplitude
      versus rectal temperature was performed in each individual. Spindle activity was
      observed in 17 children (16 children < 12 months of age). Progressive slowing of
      spindle frequency with decreasing rectal temperature was found (mean decrease,
      0.54 +/- 0.31 Hz/ degrees C). Spindle duration increased on average by 0.69 +/-
      0.39 second/ degrees C during cooling procedures. Spindle amplitude did not show
      any correlation to changes in rectal temperature. The current study demonstrates
      spindle activity during hypothermic cardiopulmonary bypass with temperature
      dependent spindle modifications of frequency and duration. Although the
      temperature-dependent changes in this study confirm temperature coefficients of
      other EEG studies, the reasons for the clear age relationship and the "nature" of
      these spindles remain unknown.

PMID- 12488787
TI  - Motor circuitry re-organization after pallidotomy in Parkinson disease: a
      neurophysiological study of the bereitschaftspotential, contingent negative
      variation, and N30.
AB  - The aim of the study was to evaluate the reorganization changes in the motor
      circuitry of the basal ganglia following unilateral posteroventral pallidotomy in
      Parkinson disease (PD) patients using neurophysiological paradigms. Eight
      advanced PD patients received a neurophysiological battery 2 months prior and 6
      months after unilateral pallidotomy. Examinations were all performed in the
      practically defined "off" situation. Bereitschaftspotential (BP) and N30 were
      recorded for each hand alternately. Contingent negative variation (CNV) was
      obtained using a visual Go/no-Go paradigm. ANOVAs (electrode position; surgery)
      were applied for BP and CNV results. N30 data were analyzed using Wilcoxon
      matched-pair tests. A significant increase in amplitude of the late component
      (NS') of the BP was evidenced with patient performing with the hand contralateral
      to pallidotomy. No significant amplitude differences were found in CNV after
      surgery in any lead, or in any of the time windows tested. A trend toward
      significance was observed corresponding to a postsurgical numerical increase in
      amplitude of the N30 peak in the hand contralateral to pallidotomy. These results
      suggest that neurophysiological changes after pallidotomy are mainly in the last
      stages of movement preparation and execution.

PMID- 12488788
TI  - Generalized synchronization of MEG recordings in Alzheimer's Disease: evidence
      for involvement of the gamma band.
AB  - The purpose of this study was to investigate interdependencies in whole-head
      magnetoencephalography (MEG) of Alzheimer patients and healthy control subjects.
      Magnetoencephalograms were recorded in 20 Alzheimer patients (11 men; mean age,
      69.0 years [standard deviation, 8.2 years]); Mini-Mental State Examination score,
      21.3 points; range, 15 to 27 points) and 20 healthy control subjects (9 men; mean
      age, 66.4 years [standard deviation, 9.0 years]) during a no-task eyes-closed
      condition with a 151 channel whole-head MEG system. Synchronization likelihood (a
      new measure for linear as well as nonlinear interdependencies between signals)
      and coherence were computed for each channel in different frequency bands (2 to
      6, 6 to 10, 10 to 14, 14 to 18, 18 to 22, 22 to 40 Hz). Synchronization was lower
      in Alzheimer patients in the upper alpha band (10 to 14 Hz), the upper beta band
      (18 to 22 Hz), and the gamma band (22 to 40 Hz). In contrast, coherence did not
      show significant group differences at the p<0.05 level. The synchronization
      likelihood showed a spatial pattern (high synchronization central, parietal and
      right frontal; low synchronization, occipital and temporal). This study confirms
      a widespread loss of functional interactions in the alpha and beta bands, and
      provides the first evidence for loss of gamma band synchronization in Alzheimer's
      disease. Synchronization likelihood may be more sensitive to detect such changes
      than the commonly used coherence analysis.

PMID- 12488790
TI  - Monkeys--a great asset to reveal human cognitive functions.

PMID- 12488789
TI  - Small fiber dysfunction predominates in Fabry neuropathy.
AB  - Fabry disease is an X-linked recessive disease with a reduction of lysosomal
      alpha galactosidase A and consecutive storage of glycolipids e.g., in the brain,
      kidney, skin, and nerve fibers. Cardinal neurologic findings are hypohidrosis,
      painful episodes, and peripheral neuropathy. So far, the neurophysiological
      findings regarding the extent of large and small fiber dysfunction are
      contradictory. This study evaluated large and small nerve fiber function in a
      homogeneous group of Fabry patients. In 24 of 30 Fabry patients with creatinine
      below 194.7 mmol/L the authors assessed median, ulnar, and peroneal motor
      conduction velocity (MCV) and median, ulnar, and sural sensory conduction
      velocity (SCV) nerve conduction to study the function of thickly myelinated nerve
      fibers. In addition, the authors studied sympathetic skin responses (SSR) at both
      hands and feet in 24 patients. To evaluate A beta nerve fiber function, the
      authors determined vibratory detection thresholds (VDT) at the first toe in 30
      patients. Function of A delta and C fibers was assessed by quantitative sensory
      testing of cold detection threshold (CDT) and heat-pain detection thresholds
      (HPDT). Nerve conduction studies showed significantly decreased amplitudes of
      MCVs and SCVs in Fabry patients as compared to controls. However, individual
      results of MCV and SCV studies were only mildly impaired. SSRs were present in
      all tested patients but SSR amplitudes were significantly decreased in Fabry
      patients in comparison to controls. VDT, CDT, and HPDT were significantly
      elevated in Fabry patients as compared to controls. However, only six patients
      had pathologic VDT, 19 had increased CDT, and 25 had elevated HPDT at a high
      level of stimulation. In Fabry patients, small fiber dysfunction is more
      prominent than large fiber dysfunction, confirming previous findings of sural
      nerve biopsies. The results suggest a higher vulnerability of small-diameter
      nerve fibers than of the thickly myelinated fibers.

PMID- 12488791
TI  - Lysophosphatidic acid in neural signaling.
AB  - The physiological and pathological importance of lysophosphatidic acid (LPA) in
      the nervous system is underscored by its presence, as well as the expression of
      its receptors in neural tissues. In fact, LPA produces responses in a broad range
      of cell types related to the function of the nervous system. These cell types
      include neural cell lines, neural progenitors, primary neurons, oligodendrocytes,
      Schwann cells, astrocytes, microglia, and brain endothelial cells. LPA-induced
      cell type-specific effects include changes in cell morphology, promotion of cell
      proliferation and cell survival, induction of cell death, changes in ion
      conductance and Ca2+ mobilization, induction of pain transmission, and
      stimulation of vasoconstriction. These effects are mediated through a number of G
      protein-coupled LPA receptors that activate various downstream signaling
      cascades. This review provides a current summary of LPA-induced effects in neural
      cells in vitro or in vivo in combination with our current understanding of the
      signaling pathways responsible for these effects.

PMID- 12488792
TI  - Dual effects of 5-HT4 receptor activation on GABA release from guinea pig
      hippocampal slices.
AB  - The effects of BIMU-8, a 5-HT4 receptor agonist, were studied on GABA release in
      guinea pig hippocampal slices. BIMU-8 did not modify GABA outflow at rest but did
      display a complex action in electrically stimulated slices: at low concentrations
      it increased, and at higher concentrations inhibited, GABA release. These
      responses were competitively counteracted by GR 125487, a selective 5-HT4
      receptor antagonist. The dual effects of BIMU-8 are consistent with its indirect
      cholinergic action since the M1 and M3 antagonist, 4-DAMP, prevented BIMU-8
      elicited GABA facilitation, whereas the M2 antagonist AFDX-116 cancelled GABA
      inhibition. These results provide evidence that serotonin exerts a complex
      modulation on the GABAergic system, via 5-HT4 receptors, and suggest that the
      amine releases acetylcholine which, in turn, bidirectionally modulates GABA
      release.

PMID- 12488793
TI  - Decreased activity in inferotemporal cortex during explicit memory: dissociating
      priming, novelty detection, and recognition.
AB  - Studies of non-human primates have shown that activity in inferotemporal (IT)
      brain regions decrease over repeated stimulus exposure, a phenomenon known as
      repetition suppression. In the present study, repetition suppression was examined
      during recognition of personally experienced events (explicit memory). Brain
      activity was measured while subjects encoded and subsequently recognized scenic
      pictures. First, two recognition conditions were compared; one that mainly
      included familiar pictures and one that mainly included novel pictures. Responses
      derived from this contrast may reflect recognition memory, perceptual priming, or
      novelty detection. To test specifically for responses associated with recognition
      memory, subjects encoded a new set of pictures followed by two recognition tests.
      All test pictures had been presented during the course of the experiment, and the
      subjects identified pictures that appeared in the second encoding list. Since all
      pictures were familiar, repetition suppression was specifically associated with
      recognition memory. In the first contrast, relative change in brain activity was
      observed in inferotemporal, extra-striate, and hippocampal regions during
      recognition of familiar versus novel pictures. In the second contrast, decreased
      activity in IT cortex was found. The location of this region overlapped with that
      for the region identified in the first contrast, and a conjunction analysis
      showed that reduced activity in left IT cortex was common to both contrasts.
      These results suggest that repetition suppression in IT cortex reflects
      recognition memory, and that such a response is not a simple function of stimulus
      repetition but can be modulated by top-down processing.

PMID- 12488794
TI  - Superior digit memory of abacus experts: an event-related functional MRI study.
AB  - Abacus experts exhibit superior short-term memory for digits, but the underlying
      neurophysiological mechanism remains unknown. Using event-related fMRI, we
      examined the brain activity of abacus experts and non-experts during the memory
      retention period of a delayed match-to-sample task using digits as stimuli. In
      controls, activity was greater in cortical areas related to verbal working
      memory, including Broca's area. In contrast, in experts, activity was greater in
      cortical areas related to visuo-spatial working memory, including the bilateral
      superior frontal sulcus and superior parietal lobule. This provides
      neurophysiological evidence that abacus experts utilize a visuo-spatial
      representation for digit memory.

PMID- 12488795
TI  - Oxytocin within auditory nuclei: a neuromodulatory function in sensory
      processing?
AB  - Oxytocin (OT) plays an important role in social bonding, ultrasonic vocalizations
      and other sexual behaviors in mammalian species. Although its presence within
      neuroendocrine regions in the forebrain is well established, its association with
      sensory nuclei remains unclear. We report here the presence of oxytocin
      immunoreactive neurons within several nuclei in the auditory brain stem of the
      mustached bat, Pteronotus parnellii. Immunocytochemical procedures revealed OT
      immunoreactive perikarya and/or fiber terminals in restricted areas of the
      inferior colliculus (IC), superior olivary complex (SOC), including the medial
      and ventral nuclei of the trapezoid body, and in the cochlear nucleus. Perikarya
      were labeled predominantly in the IC and SOC and both perikarya and fiber
      terminals were labeled extensively in the cochlear nucleus.

PMID- 12488796
TI  - VEGF is increased in serum but not in spinal cord from patients with amyotrophic
      lateral sclerosis.
AB  - Homogenates of postmortem spinal cord from seven patients with amyotrophic
      lateral sclerosis (ALS) and six controls together with serum from 13 patients
      with ALS and 13 controls were analysed for vascular endothelial growth factor
      (VEGF) using an immunoassay (ELISA). There was no significant difference in VEGF
      levels in the spinal cord between the ALS patients and the controls. In serum the
      VEGF levels were significantly higher in the ALS group than in the control group.
      There was a moderate inverse relation between the duration of the disorder and
      the serum VEGF levels. The findings indicate that the capacity to synthesize VEGF
      is preserved even in the late stages of ALS. The results might also be consistent
      with a transient hypoxic component during the course of ALS, but not with a
      persistant spinal hypoxia in the late stages of the disorder.

PMID- 12488797
TI  - Temporal resolution of the human primary auditory cortex in gap detection.
AB  - The temporal resolution of the primary auditory cortex was studied by recording
      the magnetic middle latency fields (MAEF) evoked by gaps of 3, 6 and 9 ms
      inserted in the middle of 600 ms broadband noise bursts. Spatio-temporal source
      modelling showed that a significant neural representation as reflected by MAEF
      responses is present at gap durations as low as 3 sms. The comparison of the MAEF
      waveforms elicited by the onset, gap and offset of the noise bursts indicates
      that the gap related response near threshold is largely determined by the onset
      to the burst following the gap. The electro-physiologically derived minimum
      detectable gap closely resembled the psychoacoustic threshold of 2.0 ms obtained
      in the same subjects.

PMID- 12488798
TI  - Stepping out of the spotlight: MMN attenuation as a function of distance from the
      attended location.
AB  - In this report we present neurophysiological evidence that spatial separation
      between attended and unattended sound sources influences a listener's ability to
      register changes in sounds presented outside the focus of attention. Standard and
      deviant stimuli were presented at three azimuth locations. Participants were
      asked to press a key whenever they heard a deviant at a designated location.
      Mismatch negativity waves were generated for deviants at the attended location
      and were attenuated for deviants occurring 30 degrees away from the attended
      location. Mismatch negativities were not observed at distances of 60 degrees or
      more. The results are consistent with a spotlight model of auditory attention in
      which the processing of stimuli outside the attentional focus is attenuated as a
      function of increasing distance from the focus.

PMID- 12488799
TI  - Repeated access to sucrose augments dopamine turnover in the nucleus accumbens.
AB  - Dopamine in the nucleus accumbens has been implicated in motivated behavior,
      including feeding. Normal feeding occurs in patterns, but little is known about
      how these schedules influence this neural system. We hypothesized that repeated
      access to preferred foods would augment dopamine clearance. Rats on a restricted
      feeding schedule had access to 0.3 M sucrose or water followed 2 h later by chow.
      The rats were kept on this regimen for 7 days, with microdialysis performed on
      the last day. During the chow period, dopamine turnover in the nucleus accumbens
      was higher when preceded by sucrose than by water. This finding suggests that,
      under some dietary conditions, neuroadaptation occurs in response to feeding and
      these changes may, in turn, influence future meals.

PMID- 12488800
TI  - MMP-9 and EBA immunoreactivity after papaverine mediated opening of the blood
      brain barrier.
AB  - Papaverine is a non-specific vasodilatory drug, which was found to unexpectedly
      cause opening of the blood-brain barrier (BBB). We studied the expression of two
      endothelial cell related markers, endothelial barrier antigen (EBA) as a marker
      of BBB intactness, and matrix metalloproteinase-9 (MMP-9), an extracellular
      matrix molecule, the activation of which results in BBB opening. Immunoreactivity
      was quantified after intra-carotid injection of papaverine in rats. BBB opening
      was identified at 1 h, but had been reversed by 24 h. Reduction in EBA
      immunoreactivity occurred at 3 h, whereas MMP-9 was not observed until 24 h. The
      activation of MMP-9 thus occurred much later than BBB opening, which suggests a
      different role for MMP-9 when selective and reversible opening of the BBB is
      produced by pharmacological manipulation.

PMID- 12488801
TI  - Neurons of the superior olivary complex do not excite startle-mediating neurons
      in the caudal pontine reticular formation.
AB  - The acoustic startle response is an important mammalian model for studying the
      cellular mechanisms of emotions and learning. Lesions in the superior olivary
      complex have been shown to attenuate the amplitude of the acoustic startle
      response, thus a substantial contribution of these neurons to the startle
      response was proposed. We here explored the putative connection of olivary
      neurons to the startle-mediating giant neurons in the reticular formation in rat
      brain slices in vitro. Tracing studies and electrical stimulation in the superior
      olivary complex revealed a strong connection; however it was not possible to
      distinguish between olivary neurons and traversing auditory fibres. Glutamate
      uncaging in the olivary complex excited a subpopulation of olivary neurons but
      never PnC giant neurons, as shown by patch-clamp recordings. This clearly
      contradicts an excitatory connection from olivary neurons to PnC giant neurons
      and thus an involvement of the superior olivary complex in eliciting a startle
      response.

PMID- 12488802
TI  - Pulse configuration-dependent effects of repetitive transcranial magnetic
      stimulation on visual perception.
AB  - Transcranial magnetic stimulation (TMS) is a noninvasive technique for direct
      stimulation of the neocortex. In the last two decades it is successfully applied
      in the study of motor and sensory physiology. TMS uses the indirect induction of
      electrical fields in the brain generated by intense changes of magnetic fields
      applied to the scalp. It encompasses two widely used waveform configurations:
      mono-phasic magnetic pulses induce a single current in the brain while biphasic
      pulses induce at least two currents of inverse direction. As has been shown for
      the motor cortex, efficacy of repetitive transcranial magnetic stimulation (rTMS)
      may depend on pulse configuration. In order to clarify this question with regard
      to visual perception, static contrast sensitivities (sCS) were evaluated before,
      during, immediately after and 10 minutes after monophasic and biphasic low
      frequency (1 Hz) rTMS applied to the occipital cortex of 15 healthy subjects. The
      intensity of stimulation was the phosphene threshold of each individual subject.
      Using 4 c/d spatial frequency, significant sCS loss was found during and
      immediately after 10 min of monophasic stimulation, while biphasic stimulation
      resulted in no significant effect. Ten minutes after the end of stimulation, the
      sCS values were at baseline level again. However, reversed current flow direction
      resulted in an increased efficacy of biphasic and decreased efficacy of
      monophasic stimulation. Our results are in agreement with previous findings
      showing that primary visual functions, such as contrast detection, can be
      transiently altered by low frequency transcranial magnetic stimulation. However
      the effect of modulation significantly depends on the current waveform and
      direction.

PMID- 12488803
TI  - Effects of glutamate agonists on the isolated neurons from the locomotor network
      of the mollusc Clione limacina.
AB  - In the pteropod mollusc, locomotor rhythm is produced by the central pattern
      generator (CPG), mainly by the reciprocal activity of interneurons, groups 7 and
      8, which are active in the phases of the dorsal and ventral flexion of the wings,
      respectively. Both groups produce excitation in the CPG neurons controlling the
      same phase of the locomotor cycle, and inhibition in the neurons of the opposite
      phase. As previously suggested, the connections of the group 7 interneurons to
      the follower CPG neurons are glutamatergic. However, the properties of the
      glutamatergic receptors in the postsynaptic cells are unknown. In this work, the
      identified CPG motoneurons of the antagonistic groups 1 and 2 were isolated from
      the CNS, and their responses to the local application of glutamate agonists were
      examined. Glutamate elicited opposite effects in the neurons of these two groups,
      reproducing excitatory and inhibitory influence of the group 7 interneurons.
      Interestingly, micromolar concentrations of glutamate agonists kainate, domoate
      and AMPA elicited excitation in both types of the motoneurons. To test for the
      possible of the NMDA receptors, NMDA was applied, as well as an equimolar mixture
      of NMDA and glycine. The isolated motoneurons showed excitatory response to these
      applications only at high (millimolar) concentrations. These results suggest that
      the motoneurons of group 1 possess excitatory glutamate receptors and that
      motoneurons of group 2 may posses a composite population of receptors, which are
      responsible for the inhibitory action of glutamate and excitatory action of its
      AMPA/kainate agonists.

PMID- 12488804
TI  - Differential response of two subdivisions of lateral amygdala to aversive
      conditioning as revealed by c-Fos and P-ERK mapping.
AB  - Rats were subjected to two aversive learning protocols: either classical (fear
      conditioning) or instrumental (two-way active avoidance training). Next,
      immunocytochemical mapping of phosphorylated extracellular signal-regulated
      kinase (P-ERK) and c-Fos transcription factor protein was performed, and the
      expression pattern of both markers within the dorsal nucleus of lateral amygdala
      (LaD) was analyzed. As immunocytochemical studies revealed, aversive training
      induced ERK phosphorylation and c-Fos expression specifically in ventral but not
      dorsal tip of LaD. These data show for the first time molecular distinction
      between subdivisions of LaD as well as they also strengthen the idea of Repa that
      the neurons in the ventral tip of LaD are involved in storage of long-lasting
      changes associated with formation of fear memories.

PMID- 12488805
TI  - Dual regulation of cryptochrome 1 mRNA expression in chicken retina by light and
      circadian oscillators.
AB  - The localization and regulation of chicken cryptochrome 1 (cCry1) mRNA expression
      in retina was investigated by laser capture microdissection and quantitative real
      time RT-PCR. Laser capture microdissection (LCM) of retinal cell layers showed
      the highest level of cCry1 expression in the ganglion cell and photoreceptor
      layers. In both layers, expression was high during the daytime and low at night
      in subjects exposed to a 12:12 h light:dark cycle. Robust circadian oscillations
      of cCry1 mRNA levels were observed in constant (24 h day) light, but not in
      constant darkness, with the highest expression during daytime at zeitgeber time
      (ZT) 8. Unlike cCry1, circadian rhythms of the melatonin-synthesizing enzyme,
      arylalkylamine N-acetyltransferase, persisted in constant darkness, suggesting
      that rhythmic cCry1 expression is not essential for circadian clock function or
      output. On the second day of constant darkness, when cCry1 expression is
      arrhythmic, light exposure for 2 h significantly increased retinal cCry1 mRNA
      levels at ZT 4 and 8, times that cCry1 expression is induced in LD and LL.
      Similar light exposure ending at ZT 20 had no significant effect. Thus,
      expression of cCry1 mRNA is regulated dually by light and circadian clocks.

PMID- 12488807
TI  - My eyes want to look where your eyes are looking: exploring the tendency to
      imitate another individual's gaze.
AB  - In this study we investigated the tendency of humans to imitate the gaze
      direction of other individuals. Distracting gaze stimuli or non biological
      directional cues (arrows) were presented to observers performing an instructed
      saccadic eye movement task. Eye movement recordings showed that observers
      performed less accurately when the distracting gaze and the instructed saccade
      had opposite directions, with a substantial number of saccades matching the
      direction of the distracting gaze. Static (Experiment 1) and dynamic (Experiment
      2) gaze distracters, but not pointing arrows (Experiment 3), produced the effect.
      Results show a strong predisposition of humans to imitate somebody else's
      oculomotor behaviour, even when detrimental to task performance. This is likely
      linked to a strong tendency to share attentional states of other individuals,
      known as joint attention.

PMID- 12488806
TI  - The orbitofrontal cortex in methamphetamine addiction: involvement in fear.
AB  - We used Tellegen's Multidimensional Personality Questionnaire (MPQ) harm
      avoidance (fear) scale and the constraint superfactor as personality measures of
      inhibitory control and examined their association with glucose metabolism in the
      orbitofrontal gyrus at rest in 14 recently abstinent methamphetamine-dependent
      subjects and 22 comparison subjects. Higher MPQ scores were associated with
      higher relative orbitofrontal gyrus metabolism in the methamphetamine-dependent
      subjects. There was a tendency towards a negative association for the comparison
      subjects (test of coincidence of regression lines for the two subject groups: F =
      3.3, df = 2,32; = 0.051). These results suggest that the role of the
      orbitofrontal cortex in inhibitory control can be manifested in stable
      personality predispositions and further implicate this region in the core
      characteristics of drug addiction.

PMID- 12488808
TI  - Molecular basis underlying GABA(A) responses in rat mesencephalic trigeminal
      neurons.
AB  - We studied the molecular basis of GABA(A) receptor (GABA(A)R) expressed in the
      rat mesencephalic trigeminal (Vmes) sensory neuron using the immunohistochemical
      and single-cell RT-PCR methods. Using anti-GABA(A)R alpha2 subunit antibody,
      abundant GABA(A)Rs were visualized in Vmes neurons. A single-cell RT-PCR
      clarified that GABA(A)Rs expressed in Vmes neurons were predominantly composed of
      alpha2, alpha5, beta1, gamma1 and gamma2 subunits. Novel splicing variants in
      both alpha5 and beta1 were found invariably, and they lacked multiple amino acid
      sequence in the extracellular N-terminal portion. Known functional roles of both
      beta and gamma subunits in regulating the expression at the cell surface suggest
      that the unique subunit composition of GABA(A)Rs may be involved in the
      characteristics of GABA(A) response in Vmes neurons.

PMID- 12488809
TI  - Expression disparity of brain-derived neurotrophic factor immunoreactivity and
      mRNA in ischemic hippocampal neurons.
AB  - We studied the spatial and temporal expression of BDNF immunoreactivity and mRNA
      in the hippocampal formation after transient forebrain ischemia in gerbils. Our
      study demonstrated that in the vulnerable CA1 neurons, there was a prolonged
      expression disparity between BDNF immunoreactivity and mRNA and the BDNF level
      was reduced, in contrast to the ischemia-resistant dentate gyrus neurons that
      showed transient expression disparity and maintained the BDNF level. This
      expression disparity of the neurotrophic factor may be related to delayed
      neuronal death. Double immunostaining showed that reactive astroglia and
      microglia could express BDNF, suggesting a possible involvement of these cells in
      the mechanism of neuronal survival after ischemia.

PMID- 12488810
TI  - Sex differences in rapid auditory processing deficits in ectopic BXSB/MpJ mice.
AB  - Prior research with rodent models, performed predominantly in males, has
      demonstrated a significant association between focal neocortical malformations
      (e.g. ectopias and microgyria) and rate-specific auditory processing deficits. In
      the current study and consistent with prior findings, we report that ectopic male
      BXSB/MpJ mice exhibit impairments in detecting a two-tone oddball stimulus at
      short but not long inter-stimulus interval durations when compared to non-ectopic
      male littermates. However, ectopic female littermates showed no rapid auditory
      processing deficit when compared to non-ectopic females on this same task.
      Current results add growing support to: (1) an association between focal cortical
      malformations and impaired auditory processing in males; and (2) the existence of
      sex differences in the behavioral consequences of focal cortical malformations.

PMID- 12488811
TI  - Morphology and morphometry of the corpus callosum in Williams syndrome: a T1
      weighted MRI study.
AB  - Williams syndrome (WS) is characterised by a defined genetic aetiology and a
      specific cognitive profile. It provides an opportunity to examine associations
      between neuroanatomy, behaviour, and genetics. High-resolution T1-weighted MRI of
      the brain of 12 patients with WS and 12 normal control subjects were used to
      estimate the shape and volume of the corpus callosum (CC), as well as the voxel
      intensity values as a measure its water content. The CC of patients with WS was
      more convex than that of normal control subjects and overall smaller in volume,
      particularly in the splenium and in the caudal part of the callosal body. In
      addition, there were higher ratio values of voxel intensity (i.e. less water
      content) in the mid-section of the body and the caudal part of the body of the
      CC. These combined features indicate an aberrant development of the CC in
      patients with WS and document some of the anatomical abnormalities that may
      underlie some of the cognitive impairments observed in subjects with WS.

PMID- 12488812
TI  - An fMRI study of music sight-reading.
AB  - The brain areas involved in music reading were investigated using fMRI. In order
      to evaluate the specificity of these areas we compared reading music notation to
      reading verbal and number notations in a task that required professional pianists
      to play the notes (in musical and verbal notations) and the numbers displayed on
      a 5-key keyboard. Overall, the three tasks revealed a similar pattern of
      activated brain areas. However, direct contrasts between the music notation and
      the verbal or the numerical notation tasks also revealed specific major foci of
      activation in the right occipito-temporal junction, superior parietal lobule and
      the intraparietal sulcus. We interpret the right occipito-temporal difference as
      due to differences at the encoding level between notes, words and numbers. This
      area might be analogous to one described for words, called the visual word form
      area. The parietal activations are discussed in terms of visuo-motor transcoding
      pathways that differ for the three types of notations used. Finally, we present a
      model of music reading that can possibly explain our findings.

PMID- 12488813
TI  - Lumbar motoneuron fate in a mouse model of amyotrophic lateral sclerosis.
AB  - Onuf's nucleus, a collection of motoneurons within the spinal cord, is often
      spared in the neurodegenerative disorder amyotrophic lateral sclerosis. To assess
      whether these cells survive in a rodent model of this disease, motoneurons were
      counted in the spinal nucleus of the bulbocavernosus (an homologous structure to
      Onuf's), as well as in two other cell groups at the same level of the spinal
      cord, the dorsolateral nucleus and the retrodorsolateral nucleus. In mice
      displaying signs of neurodegeneration, both the dorsolateral and
      retrodorsolateral nuclei displayed significant motoneuron loss compared to
      controls; this cell loss was particularly exaggerated in the retrodorsolateral
      nucleus of animals displaying a rapid disease progression. However, no
      significant decline in motoneuron number was observed in the spinal nucleus of
      the bulbocavernosus, and the perineal muscle bulbocavernosus, which is innervated
      by this nucleus, appeared to be unaffected. This was in stark contrast to the
      thigh muscles, which displayed significant atrophy. Overall, these data indicate
      that the spinal nucleus of the bulbocavernosus is spared from degeneration in an
      animal model of amyotrophic lateral sclerosis, paralleling observations in
      patients suffering from this disease. Further study of this resistance to
      motoneuron loss may provide useful insights into the pathophysiology of the
      degenerative process.

PMID- 12488814
TI  - Somatosensory evoked potentials correlate with genetics in Huntington's disease.
AB  - Abnormalities of somatosensory evoked potentials (SEPs) have been reported in
      Huntington's disease, a neuropsychiatric disorder caused by the expansion of a
      CAG trinucleotide repeat. The aim of our study was to determine the relationship
      between these electrophysiological changes and the length of the nucleotide
      repeat. We found a striking correlation between the decrease in the early
      component amplitudes (N20 and N30) of the median nerve SEP and the repeat length,
      suggesting that these SEP alterations are indeed related to the genetically
      determined pathological process. The cortical components of the tibial nerve SEP
      exhibited a dramatic alteration in the patient group and were the only SEP
      changes found in the group of asymptomatic carriers of the mutation, being more
      sensitive than the median nerve SEPs.

PMID- 12488815
TI  - Diffusion tensor in posterior cingulate gyrus: correlation with cognitive decline
      in Alzheimer's disease.
AB  - To determine whether the diffusion abnormalities in brains with Alzheimer's
      disease (AD) correlate with disease severity, we studied 34 AD patients using
      diffusion tensor MRI. Mean diffusivity and fractional anisotropy (FA) as well as
      three eigenvalues (lambda1, lambda2, and lambda3) of the diffusion tensor of the
      posterior cingulate white matter correlated with the Mini-Mental State
      Examination (MMSE) score. The mean diffusivity and the three eigenvalues showed
      significant correlation with the MMSE score. On the other hand, no significant
      correlation was seen between the FA and MMSE score. Our results suggested that
      mean diffusivity and the eigen-values, but not FA, reflect progression of AD
      related histopathlogical changes in the posterior cingulate white matter and may
      be useful biological indices to monitor AD.

PMID- 12488816
TI  - Localization of premotoneurons for an NMDA-induced repetitive rhythmical activity
      to TMNs.
AB  - The localization or characteristics of the premotoneurons for trigeminal
      rhythmical activity have not been clarified. We investigated the localization of
      premotoneurons generating an NMDA-induced repetitive rhythmical activity to
      trigeminal motoneurons (TMNs). The minimal circuitry for this rhythmical activity
      was determined using a fragmented slice preparation of the isolated brain stem
      from neonatal rats (0-3 days old). We recorded rhythmical neural activities from
      TMNs using whole and fragmented brainstem slices preparation including the
      trigeminal motor nucleus in the presence of the excitatory amino acid agonist NMA
      and the GABAA receptor antagonist, bicuculline methiodide (BIC). TMNs receive
      projections from premotoneurons for an NMDA-induced rhythmical activity, which
      can be located in the area 300 microm surrounding the trigeminal motor nucleus.
      NMA (20 microM) and BIC (10 microM) induced repetitive rhythmical activities on
      TMNs.

PMID- 12488817
TI  - Mutation of linotte causes behavioral defects independently of pigeon in
      Drosophila.
AB  - The Drosophila linotte1 mutation was isolated from a genetic screen designed to
      identify learning and memory genes. For some authors, this mutation affects a
      novel gene specifically involved in adult learning and memory, whereas for
      others, it is an allele of the derailed receptor tyrosine kinase gene (the
      linotte/derailed gene) involved in nervous system development. Here, we show that
      the original derailed mutation induces a memory phenotype. We also report that a
      new null mutation, lioexc21, affecting specifically the linotte/derailed gene
      causes behavioral defects, which can be partially rescued by expression of a
      lio+/drl+ transgene. The data presented here suggest that the memory phenotype of
      linotte and derailed mutants is a consequence of abnormal brain development due
      to loss of function of the linotte/derailed encoded receptor tyrosine kinase.

PMID- 12488818
TI  - beta-Agkistrodotoxin inhibition of Ca2+-dependent release of glutamate,
      aspartate, glycine and gamma-aminobutyric acid from cerebrocortical synaptosomes
      following its binding to synaptic membrane.
AB  - The binding properties of beta-AgTX, a snake pre-synaptic toxin, membranes and
      its effect on transmitter release from cerebrocortical synaptosomes were
      investigated. Assay of [125I]-beta-AgTX binding to rat synaptic membrane revealed
      a high affinity binding site for the toxin within the synaptic membrane.
      Preincubation with beta-AgTX inhibited K+-evoked Ca2+-dependent glutamate release
      from synaptosomes in a concentration-dependent manner, as determined by an on
      line enzyme-linked fluorometric assay. The toxin also blocked the Ca2+-dependent
      release of other transmitters, aspartate, glycine, and GABA induced by K+
      depolarization. However, Ca2+-ionophore, ionomycin-stimulated Ca2+-dependent
      transmitter release was not significantly affected by beta-AgTX, indicating that
      the toxin inhibits transmitter release by reducing the entry of Ca2+ into
      cytoplasm. It is suggested that beta-AgTX-binding site in synaptic membrane is
      related to the release of a variety of transmitters.

PMID- 12488819
TI  - Time-dependent contribution of the hippocampal complex when remembering the past:
      a PET study.
AB  - Previous studies of brain-damaged patients and functional neuro-imaging have
      consistently shown the importance of the hippocampal complex, i.e. the
      hippocampus and parahippocampal gyrus, in episodic memory retrieval. We wished to
      determine whether patterns of brain activation during memory retrieval as
      measured by PET are same or different when the oldness of a to-be-retrieved
      episode is manipulated. Using cue words, subjects remembered related episodes
      from three periods of their life, childhood, adolescence and recent period. The
      results showed an increase of parahippocampal activities during recall of
      episodes from childhood and recent period, but not from adolescence. These data
      suggest a possibility of time-dependent hippocampal contribution in episodic
      recall, which cannot be understood in simple terms of recent remote memory
      dichotomy.

PMID- 12488820
TI  - Limb flexion reflex-related areas in human cerebellum.
AB  - Numerous studies have shown that the cerebellum is involved in classical
      conditioning of specific aversive reactions. Only few studies, however, have
      examined the exact localization of cerebellar areas involved in the control of
      unconditioned reflex responses. The present study investigated cerebellar areas,
      which are activated during eliciting of the limb flexion reflex in healthy
      controls using [15O]H2O PET. Limb flexion reflex related areas were found in
      vermal lobules III-VI with the local maximum in vermal lobule V. Areas of
      activation were more widespread compared to a voluntary foot movement and a
      sensory foot stimulation condition. Limb flexion reflex areas probably reflect
      efferent reflex modulation as well as sensory inputs from the stimulus itself
      and/or the reflex response.

PMID- 12488821
TI  - A neural network elicited by parametric manipulation of the attention load.
AB  - We used a parametric experimental design to identify the rCBF variations related
      to a continuous variation of the attention load. The experiment involved goal
      directed visual tasks. The length of time during which the subject's attention
      was engaged toward the external stimulus was taken as the factor of interest. The
      neural network revealed areas that positively (left cerebellum, bilateral MT/V5
      complex and superior parietal lobule, right inferior temporal lobe and
      dorsolateral prefrontal cortex) or negatively (precuneus, anterior cingulate and
      medial superior frontal cortex) correlate with the attention load. Results
      demonstrate that the activity of these areas varies continuously as a function of
      the variation in the attention load.

PMID- 12488822
TI  - Selective attention regulates spatial and intensity information processing in the
      human primary somatosensory cortex.
AB  - Attention-related cognitive processes in the primary somatosensory cortex (SI)
      were studied by measuring somatosensory evoked magnetic fields (SEFs). Twenty-one
      normal adult human subjects participated in this study for investigating effects
      of attention and stimulus intensity on cortical finger representation in the SI
      cortex. Electric stimuli at low and high intensity were delivered to the index or
      middle finger in finger discrimination and non-discrimination task. For the low
      intensity stimulation at 1.25 times sensory threshold, an early component (M50)
      showed clear segregation of the sources for the two fingers and an increase of
      the amplitude specific to the finger discrimination task. Such an attentional
      effect on the SI cortex was masked by the high intensity stimulation (2.5 times
      sensory threshold); the M50 source separation by the fingers was induced
      irrespective of the discrimination or non-discrimination task. The results
      suggest that a conscious regulation of stimulus intensity coding in the SI cortex
      underlies the attention-dependent enhancement of spatial finger information
      processing.

PMID- 12488823
TI  - The effect of D-aspartate on luteinizing hormone-releasing hormone, alpha
      melanocyte-stimulating hormone, GABA and dopamine release.
AB  - Since D-aspartate stimulates prolactin and LH release, our objective was to
      determine whether D-aspartate modifies the release of hypothalamic and posterior
      pituitary factors involved in the control of their secretion and whether its
      effects on these tissues are exerted through NMDA receptors and mediated by
      nitric oxide. In the hypothalamus, D-aspartate stimulated luteinizing hormone
      releasing hormone (LHRH), alpha-melanocyte-stimulating hormone (alpha-MSH) and
      GABA release and inhibited dopamine release through interaction with NMDA
      receptors. It increased nitric oxide synthase (NOS) activity, and its effects on
      LHRH and hypothalamic GABA release were blunted when NOS was inhibited. In the
      posterior pituitary gland, D-aspartate inhibited GABA release but had no effect
      on dopamine or alpha-MSH release. We report that D-aspartate differentially
      affects the release of hypothalamic and posterior pituitary factors involved in
      the regulation of pituitary hormone secretion.

PMID- 12488824
TI  - Effect of the novel sigma1 receptor ligand and putative atypical antipsychotic E
      5842 on BDNF mRNA expression in the rat brain.
AB  - Changes in the expression of brain-derived neurotrophic factor (BDNF) have been
      implicated in some neuropsychiatric disorders. Several antipsychotic drugs affect
      the expression of BDNF mRNA in different areas of the rat brain. We examined the
      effect of single or repeated administration of 4-[4-fluorophenyl]-1,2,3,6-tetra
      hydo-1-[4-[1,-2,4-triazol-1-il]butyl]pyridine citrate) (E-5842), a sigma1
      receptor ligand and putative atypical antipsychotic drug on the expression of
      BDNF mRNA in rats. Acute treatment with E-5842 induced a down-regulation of BDNF
      mRNA levels in the frontal cortex and hippocampus, while a chronic treatment had
      no effect. Levels of another neurotrophin, nerve growth factor (NGF), remained
      unaltered after either acute or chronic treatment. The effects suggest that any
      therapeutic properties of E-5842 are not mediated by stimulation of BDNF or NGF,
      whereas the regulation of these trophic factors may be part of the mechanism of
      action of sigma1 receptor ligands.

PMID- 12488825
TI  - Macaque prefrontal activity associated with extensive tool use.
AB  - Macaques can utilize tools sequentially on a single object or they can modify
      functions effectively in a relevant context. Two Japanese macaques were scanned
      by positron emission tomography with H(2)15O during a tool combination task and
      two control tasks (single tool task and simple stick-waving task). In the tool
      combination task, monkeys were required to use two identical tools properly in
      different functions. We found increased activity in the bilateral prefrontal
      cortex (area 9/46), bilateral intraparietal sulcus regions, right cerebellum, and
      bilateral early visual cortices during the tool combination task with the right
      hand, compared with the single tool task. These results suggest that interactions
      between the fronto-cerebellar and the fronto-parietal circuit are responsible for
      appropriate and effective modifications of tools in their functions.

PMID- 12488826
TI  - alpha5 Subunit-containing GABA(A) receptors form clusters at GABAergic synapses
      in hippocampal cultures.
AB  - We have used triple-label fluorescence immunocytochemistry to demonstrate that
      alpha5 subunit-containing GABA(A) receptors (GABA(A)Rs) form large clusters at
      GABAergic synapses in dendrites and axon initial segment of cultured hippocampal
      neurons. The large synaptic clusters of alpha5 subunit-containing GABA(A)Rs also
      contained alpha1, beta2/3, gamma2 GABA(A)R subunits and gephyrin. The alpha5
      subunit-containing GABA(A)Rs also formed small clusters. The small clusters were
      not associated with GABAergic synapses and often did not co-localize with
      gephyrin.

PMID- 12488827
TI  - SUMO-1 co-localized with mutant atrophin-1 with expanded polyglutamines
      accelerates intranuclear aggregation and cell death.
AB  - To investigate the implication of small ubiquitin-related modifier-1 (SUMO-1) in
      the formation of neuronal intranuclear inclusions in polyglutamine diseases, we
      examined the localization of SUMO-1 in dentatorubral-pallidoluysian atrophy
      (DRPLA) brain tissues and PC12 cells expressing truncated atrophin-1 with
      expanded poly-glutamine stretches. SUMO-1 was co-localized with neuronal
      intranuclear inclusions in DRPLA brain and the DRPLA model cells, which showed
      that the aggregates formed by expanded polyglutamine stretches were highly
      SUMOlylated. In addition, to examine the role of SUMO-1 in nuclear aggregate
      formation and cell death, either SUMO-1 or DeltaSUMO-1, which is a SUMOlylation
      defective mutant lacking the C-terminal motif, was co-transfected with atrophin-1
      with expanded polyglutamine stretches. Co-transfection of DeltaSUMO-1 decreased
      number of the cells with nuclear aggregates and consequent apoptosis of PC12
      cells, both of which were markedly enhanced by co-transfection of SUMO-1 with
      atrophin-1 with expanded polyglutamine stretches. These results suggest that SUMO
      1 is implicated in the pathogenesis of DRPLA and accelerates aggregate formation
      and cell death.

PMID- 12488828
TI  - 5-HT2A receptors are expressed by catecholaminergic neurons in the rat nucleus
      tractus solitarii.
AB  - Within the nucleus tractus solitarii (NTS), serotonin (5-HT) exerts modulatory
      effects on central mechanisms controlling autonomic functions, notably through
      the stimulation of 5-HT2 receptors. Using double immunocytochemical labeling with
      specific anti-5-HT2A receptor antibodies and antibodies directed against the
      catecholamine (CA) synthesizing enzymes, i.e. tyrosine hydroxylase, dopamine beta
      hydroxylase (DBH) and phenylethanolamine N-methyltransferase, we investigated
      whether 5-HT effects could be mediated by 5-HT2A receptors located on CA
      perikarya and/or processes within the NTS. A relatively high density of 5-HT2A
      immunoreactive processes was observed throughout the NTS. 5-HT2A neuronal
      perikarya were also found within the NTS except in its rostrolateral part. Double
      immunolabeling experiments revealed many 5-HT2A receptors on CA processes but
      only few 5-HT2A/TH and 5-HT2A/DBH perikarya. These data support the idea that,
      within the NTS, 5-HT2A-mediated control of autonomic functions involves CA
      neurons.

PMID- 12488829
TI  - Brain size and grey matter volume in the healthy human brain.
AB  - Magnetic resonance imaging was used to evaluate the influence of sex and brain
      size on compartmental brain volumes (grey matter, white matter, CSF) in a large
      and well-matched sample of neurologically normal women (n = 50) and men (n = 50).
      As expected, we found a significant sex difference for the absolute volumes of
      total brain, grey matter, white matter and CSF, with greater volumes for men.
      Relating these compartmental volume measures to brain volume resulting in
      proportional volume measures revealed a higher proportion of grey matter in
      women. No significant sex differences were found for white matter and CSF
      proportions. However, when the influence of sex was partialized out by regression
      analyses, brain volume explained 40-81% of the variance of the absolute grey
      matter, white matter and CSF volumes. Performing these regression analyses for
      the proportional volume measures revealed that brain volume explained
      approximately 16% of the variance in grey matter proportion. Sex or the
      interaction between sex and brain volume revealed no additional predicitve
      values. Interestingly, the correlation between brain volume and grey matter
      proportion was negative, with larger brains exhibiting relatively smaller
      proportions of grey matter. Thus, sex is not the main variable explaining the
      variability in grey matter volume. Rather, we suggest that brain size is the main
      variable determining the proportion of grey matter.

PMID- 12488830
TI  - N-terminal Slit2 promotes survival and neurite extension in cultured peripheral
      neurons.
AB  - To investigate the effect of the N-terminal Slit2 protein on neuronal survival
      and development, recombinant human N-terminal Slit2 (N-Slit2) was assayed against
      isolated embryonic chick dorsal root ganglion sensory, ciliary ganglion and
      paravertebral sympathetic neurons. N-Slit2 promoted significant levels of
      neuronal survival and neurite extension in all of these populations. The protein
      was also assayed against postnatal mouse dorsal root ganglion neurons and found
      to promote neuronal survival in a similar manner. These findings suggest the Slit
      proteins may play an important role during development of the nervous system,
      mediating cellular survival in addition to the well documented role these
      proteins play in axonal and neuronal chemorepulsion.

PMID- 12488831
TI  - Characteristics of nonurgent emergency department use in the first 3 months of
      life.
AB  - OBJECTIVES: To determine the characteristics of nonurgent emergency department
      (ED) visits in the first 3 months of life. METHODS: The study cohort consisted of
      full-term newborns admitted to and discharged from one newborn nursery from
      September 1, 1992, to May 1, 1994. All visits in the first 90 days of life to one
      large urban ED were analyzed to determine whether they were nonurgent, based on
      history of present illness and final diagnosis or disposition. The principal
      outcomes of interest were the frequency and pattern of nonurgent ED visits. Risk
      factors for nonurgent ED use were also studied. RESULTS: A total of 2137 patients
      with 965 ED visits were analyzed; 20.4% of the patients had nonurgent visits, and
      60.1% of all visits were nonurgent. Of all patients with nonurgent visits, 24.1%
      had more than one. Younger maternal age, Medicaid, maternal parity, and nonwhite
      race all resulted in increased nonurgent ED use. One third of all ED visits were
      made when the primary care physician's offices were open, and 57.6% of these
      visits were nonurgent. CONCLUSIONS: Maternal and economic factors affected
      nonurgent ED utilization. Other critical factors still need to be explored.
      Interventions focused on decreasing nonurgent ED use in early infancy should be
      targeted at patients with the identified risk factors.

PMID- 12488832
TI  - Tolerance of family presence during pediatric cardiopulmonary resuscitation: a
      snapshot of military and civilian pediatricians, nurses, and residents.
AB  - BACKGROUND: Family presence during cardiopulmonary resuscitation is becoming a
      more common and accepted practice. OBJECTIVES: We wanted to determine the views
      held by pediatricians on family presence during pediatric cardiopulmonary
      resuscitation. We hypothesized that physicians who had more experience with
      critical illness and death would be more willing to allow parental presence.
      Additionally, we hypothesized that recently trained physicians, who may have had
      more educational exposure to family presence, would be more open to the practice
      than physicians who had been practicing longer. METHODS: A 10-question survey was
      distributed to attendees of the American Academy of Pediatrics annual Uniformed
      Services Pediatric Seminar meeting, as well as pediatric staff and residents at
      both Tripler Army Medical Center and Kapiolani Women's and Children's Medical
      Center, Honolulu, Hawaii. Responses were compared using chi analysis, with
      significance indicated by a value < 0.05. RESULTS: Of the 245 respondents, 65%
      indicated that they would not allow parental presence. There was no significant
      difference in the responses based on gender, military affiliation, or years of
      experience. Those involved in inpatient-oriented specialties and residents were
      significantly more likely to allow parental presence during resuscitation than
      respondents involved in outpatient-oriented specialties (57.5%, 50%, and 26.4%,
      respectively; < 0.01). Although only one third of respondents had been involved
      in a resuscitation during which parents were allowed to be present, the majority
      (63%) indicated that they would be willing to repeat the practice. CONCLUSIONS:
      Although in the minority, one third of the pediatricians surveyed are comfortable
      allowing parental presence during cardiopulmonary resuscitation. We conclude that
      pediatricians who have more frequent contact with seriously ill children are more
      likely to accept parental presence. Additionally, the exposure to parental
      presence during resuscitation efforts increases the likelihood of allowing
      parental presence in future resuscitation efforts.

PMID- 12488833
TI  - Evaluation of a Capno-Flo resuscitator during transport of critically ill
      children.
AB  - OBJECTIVES: Critically ill children often require endotracheal intubation prior
      to transport to a tertiary care center. Correct endotracheal tube (ETT) placement
      (trachea vs esophagus) and maintenance of ETT position during transport are of
      utmost importance. We evaluated the use of a Capno-Flo resuscitator (ventilation
      bag with a pH-sensitive colorimetric strip in the patient connector; Kirk
      Specialty Systems, Carrollton, TX) during transport of critically ill children.
      METHODS: Thirty-nine intubations were evaluated in 38 patients (one patient was
      intubated twice) aged 1 day to 19 years (median age, 13 mo) and weighing 0.9 to
      80 kg (median weight, 11 kg) who were intubated and transported by air ( = 26,
      68%) and ground ambulance ( = 12, 32%). ETT position was confirmed by physical
      examination, pulse oximetry, and in some patients, arterial blood gases and chest
      roentgenograms. ETT position was also assessed using the Capno-Flo after six
      breaths after intubation and was read as positive if the color changed from
      purple to yellow (tracheal tube position) and negative if the strip remained
      purple (esophageal tube position). The Capno-Flo ambu-bag was used continuously
      during transport and evaluated by the nurses or respiratory therapists, who also
      completed a brief questionnaire. RESULTS: Two esophageal and 37 tracheal tube
      positions were correctly identified by the device. There were no false-positive
      or false-negative results; the device was 100% sensitive and specific for the
      initial reading. It sometimes took longer to obtain this initial reading (> six
      breaths) in three patients. During transport, most personnel (36/38) noted
      minimal or no color change during inspiration and expiration, and therefore, it
      was not helpful in the continued verification of ETT position. CONCLUSIONS: The
      Capno-Flo resuscitator is useful in the initial confirmation of ETT position but
      not for continuous evaluation of ETT position during transport.

PMID- 12488835
TI  - Evaluation of the performance of general emergency physicians in pediatric
      emergencies: Obstructive airway diseases, seizures, and trauma.
AB  - BACKGROUND: In the Lubeck region, as is usual in Germany, hospital-based
      emergency physicians are called for outside emergencies. They evaluate and
      stabilize patients and transfer them to hospital facilities of their choice (no
      emergency department system). These physicians are mainly anesthesiologists,
      surgeons, and internists-not pediatricians. Numerous quality management studies
      have shown an overall excellent performance of this system, but it has not been
      evaluated for pediatric emergencies. PATIENTS AND METHODS: In a prospective,
      observational study conducted over a 1-year period, all pediatric emergencies
      (patient age < 15 y) treated by the emergency physician service were studied. A
      syllabus with standards of care for children with trauma, obstructive airway
      disease, and seizures was distributed. In accordance with this syllabus, the
      actions taken were documented by the emergency physicians, and the cases were
      documented as life threatening or not and were classified as "trauma,"
      "obstructive airway disease," "seizures," or "other" by the admitting pediatric
      intensivists and surgeons. The admitting attending physician compared these data
      and evaluated whether the standard management required by the syllabus was
      followed. RESULTS: A total of 422 pediatric cases out of 11,605 emergencies
      (3.5%) were recorded (147 [34.8%] trauma patients, 41 [9.7%] patients with
      obstructive airway disease, and 108 [25.6%] patients with seizures). Of the
      pediatric patients, 20.5% had life-threatening conditions; three children died
      before arrival, and the others required treatment in the intensive care unit. In
      25% of trauma patients, deficiencies in primary treatment were observed: no
      documentation of neurologic status in 10.6%, no cervical immobilization in 15% of
      head trauma patients, and no adequate analgesia in 7%. In 25% of seizure
      patients, neurologic status was not documented, although treatment was in
      accordance with the standard of care. The worst results were observed in infants
      with obstructive airway disease: no documentation of oxygen saturation in 71.4%,
      no oxygen therapy despite hypoxemia in seven of 12 patients, and overall therapy
      not in accordance with the standard of care in 50%. CONCLUSIONS: The high quality
      of the emergency physician service documented for adults is not reproduced in the
      pediatric population. Trauma and seizures with similarities to adult cases are
      handled in a fair manner. However, the most important pediatric diagnostic entity
      of obstructive airway disease is often not treated adequately. Intensified
      educational programs for emergency physicians are warranted.

PMID- 12488834
TI  - Rapid sequence intubation for pediatric emergency airway management.
AB  - OBJECTIVES: To characterize current practice with respect to pediatric emergency
      airway management using a multicenter data set. METHODS: A multicenter
      collaboration was undertaken to gather data prospectively regarding emergency
      intubation. Analysis of data on adult emergency department (ED) intubations
      clearly demonstrated that rapid sequence intubation (RSI) was the method used
      most often. We then conducted an observational study of the prospectively
      collected database of pediatric ED intubations (EDIs) using the National
      Emergency Airway Registry Phase One data, gathered in 11 participating EDs over a
      16-month time period. A data form completed at the time of EDI enabled analysis
      of patients' ages, weights, and indications for EDI; personnel; methods employed
      to facilitate EDI; success rates; and adverse events. Data forms were analyzed
      regarding the methods of intubation employed, and frequencies, success rates, and
      adverse event rates among various intubation modalities were compared. RESULTS:
      Of 1288 EDIs, there were 156 documented pediatric patients. Initial intubation
      attempts were all oral, including rapid sequence intubation in 81%, without
      medications (NOM) in 13%, and sedation without neuromuscular blockade (SED) in
      6%. Older children and trauma patients were more likely to be intubated with RSI
      compared to younger children and patients presenting with medical illnesses.
      Intubation using RSI was more successful on the first attempt (78%) compared with
      either NOM (47%, < 0.01) or SED (44%, < 0.05), though this finding is likely
      explainable by the age differences among groups. Intubation was successfully
      performed by the initial intubator in 85% of RSI, 75% of NOM, and 89% of SED
      attempts ( = NS for both comparisons vs RSI). Overall, successful intubation
      occurred in 99% of RSI and 97% of non-RSI intubation attempts ( = NS). Only one
      of 156 patients required surgical airway management. True complications occurred
      in 1%, 5%, and 0% of RSI, NOM, and SED attempts, respectively ( = NS for both
      comparisons vs RSI). The majority of initial intubation attempts were by
      emergency medicine residents (59%), pediatric emergency medicine fellows (17%),
      and pediatrics residents (10%). These groups were 77%, 77%, and 50% successful,
      respectively, on the first laryngoscopy attempt, and 89%, 89%, and 69% successful
      overall. CONCLUSIONS: A large, prospective, multicenter observational study of
      pediatric EDIs was conducted at university-affiliated EDs. RSI is the method of
      choice for the majority of pediatric emergency intubations; it is associated with
      a high success rate and a low rate of serious adverse events. Pediatric
      intubation as practiced in academic EDs, with most initial attempts by emergency
      and pediatrics residents and fellows under attending physician supervision, is
      safe and highly successful.

PMID- 12488836
TI  - Aseptic meningitis due to administration of intravenous immunoglobulin with an
      unusually high number of leukocytes in cerebrospinal fluid.

PMID- 12488837
TI  - Cervical necrotizing fasciitis caused by Serratia marcescens in a 2 year old.
AB  - We report an unusual, life-threatening complication of producing fulminant
      cervical necrotizing fasciitis in a previously healthy 2-year-old girl. We
      reviewed the literature for necrotizing fasciitis in children and its morbidity,
      mortality, and treatment. This case illustrates the necessity of prompt
      recognition and aggressive management in patients presenting with cervical
      necrotizing fasciitis.

PMID- 12488838
TI  - Hematuria due to urolithiasis in a child with chronic immune thrombocytopenic
      purpura.
AB  - Hematuria is an uncommon manifestation of chronic immune thrombocytopenic
      purpura. The occurrence of urolithiasis in children with chronic immune
      thrombocytopenic purpura has not been described. We report a case of hematuria
      due to urolithiasis in an 8-year-old boy with chronic immune thrombocytopenic
      purpura. This child, who had a history of immune thrombocytopenic purpura of 1
      year's duration, presented to the emergency department with gross hematuria. The
      cause of hematuria was initially attributed to his primary disease process. A
      careful history, examination, and pertinent investigations revealed that the
      hematuria was secondary to urolithiasis. This report highlights the need to keep
      an open mind and to search for specific causes of bleeding, even in children with
      known bleeding disorders.

PMID- 12488839
TI  - Procedural training for pediatric and neonatal transport nurses: Part 2
      procedures, skills assessment, and retention.

PMID- 12488840
TI  - beta2-Agonists in acute asthma: the evolving state of the art.

PMID- 12488841
TI  - Academic dilemmas.

PMID- 12488842
TI  - Pediatric emergency medicine: legal briefs.

PMID- 12488843
TI  - Recurrent stabbing chest pain.

PMID- 12488844
TI  - Pediatric defibrillation: concerns and opportunities.

PMID- 12488845
TI  - Tooth preparations designed for posterior resin-bonded fixed partial dentures: a
      clinical report.
AB  - Numerous designs for posterior resin-bonded fixed partial dentures have been
      reported in the dental literature, but a methodical technique is still lacking. A
      groove, plate, and strut approach involving minimal preparation of posterior
      abutments to receive a resin-bonded fixed partial dentures is presented. The
      essential clinical and laboratory procedures are illustrated.

PMID- 12488846
TI  - Fabrication of one-piece all-ceramic coronal post and laminate veneer
      restoration: a clinical report.
AB  - The procedure used for the restoration of maxillary right and left lateral
      incisors with all-ceramic one-piece coronal post and laminate veneer restorations
      is described in this clinical report. The proposed treatment technique conserves
      the remaining tooth structure, reestablishes function, offers satisfactory
      esthetics, and represents an alternative to traditional restoration procedures
      with the use of adhesive bonding techniques.

PMID- 12488847
TI  - Surgical and prosthodontic treatment alternatives for children and adolescents
      with ectodermal dysplasia: a clinical report.
AB  - Ectodermal dysplasia with oligodontia and anodontia is characterized by absence
      or deficiency of the alveolar ridges. The optimal surgical and prosthetic
      approach varies in relation to patient age and the amount of bone that is
      present. This clinical report presents rehabilitation alternatives for ectodermal
      dysplasia in children and adolescents.

PMID- 12488848
TI  - Application of cast magnetic attachments to sectional complete dentures for a
      patient with microstomia: a clinical report.
AB  - Patients with microstomia who must wear removable dental prostheses often state
      that they are unable to insert or remove the prosthesis because of the
      constricted opening of the oral cavity. This article presents a cast iron
      platinum magnetic attachment system applied to sectional collapsed complete
      dentures for an edentulous patient with microstomia. With the use of lingual and
      palatal midline hinges and a cast iron-platinum magnetic attachment, the
      sectional prosthesis was successfully and easily inserted and provided adequate
      function in the patient's mouth.

PMID- 12488849
TI  - Computer-based evaluation of gender identification and morphologic classification
      of tooth face and arch forms.
AB  - STATEMENT OF PROBLEM: In prosthodontics, sex-related differences in tooth forms
      are assumed, and optimal esthetics is further assumed to be achieved only if the
      face, arch, and tooth forms are in harmony. However, there is no universally
      accepted rule or mathematical method to define these morphologic features.
      PURPOSE: The purpose of this study was to evaluate whether anterior tooth from
      reflected gender and to question the hypothesis that there was a correlation
      among face, arch, and tooth forms on the basis of dentists' perceptions.
      MATERIALS AND METHODS: Photographic records including full face, dental arch, and
      anterior tooth images of 60 dental students were made by use of digital
      photography. A database was arranged as a questionnaire for evaluation by
      prosthodontists who were asked to define the sex and morphologic features of the
      subjects by examining stored images of the subjects. Thirteen prosthodontists,
      all with at least 10 years of experience, served as experts and performed these
      evaluations twice at 2-week intervals. Kappa statistic was used to measure
      intraobserver and interobserver agreement. RESULTS: The average correctly
      identified values in females and males were 53% and 58%, respectively. However,
      the proportions of females and males who were identified correctly and completely
      the same in both the first and second evaluations were 36% for females and 41%
      for males. According to the observations of the experts, face-to-arch form (54%)
      and face-to-tooth form (51%) correlations were higher than the tooth-to-arch form
      correlation. The overall correlation among face, arch, and tooth forms was 31%.
      The experts were in fair agreement in defining tooth forms. CONCLUSIONS: The
      results of gender identification of the subjects showed that the experts were
      unsuccessful in distinguishing the actual sex by the visual assessment of
      anterior tooth segment alone, with a fair agreement between 2 evaluation
      sessions. There were also significant interobserver and intraobserver differences
      in classifying face, arch, and especially tooth forms. Furthermore, the
      correlation among these forms was not highly defined.

PMID- 12488850
TI  - The repeatability of an intraoral dental colorimeter.
AB  - STATEMENT OF PROBLEM: Characterizing and reproducing color remain one of the most
      challenging aspects of dentistry. A relatively new intraoral colorimeter measures
      the color of natural teeth and metal-ceramic restorations and prints out a color
      recipe for the Vintage Halo Porcelain System. The reliability of the colorimeter
      is unknown. PURPOSE: The purpose of this study was to evaluate the reliability of
      a contact dental colorimeter and to correlate the shade registered by the
      colorimeter with the shade selected by experienced clinicians. MATERIALS AND
      METHODS: In part I of the study, 2 examiners (A and B) took 2 colorimeter
      measurements from the maxillary right central incisors of 11 subjects. The
      examiners were blinded to their own data and those of other investigators. The
      readings were repeated 3 weeks later with the same protocol. The Cronbach alpha
      reliability coefficient was used to analyze the collected data. In part II of the
      study, 2 experienced clinicians (examiners D and E) selected a shade from the
      classic Vita Lumin Vacuum shade guide for the maxillary right central incisors of
      the same 11 subjects. The clinicians were blinded to each other's selections and
      the colorimeter readings. It should be noted that the manufacturer of the
      colorimeter uses the terms shade, value, and hue to represent chroma, value, and
      hue, respectively, as defined in the Glossary of Prosthodontic Terms (J Prosthet
      Dent 1999;81:39-110). RESULTS: The reliability analysis results for each of the
      combined trials for shade, value, and hue were all >.94. The interexaminer
      reliability alpha values were >.9 for shade and value and.64 to.74 for hue. The
      interexaminer alpha represented the value range of each of 4 measurements. The
      intraexaminer reliability alpha values for shade, value, and hue were.99,.95,
      and.96 for examiner A and.99,.93, and.97 for examiner B, respectively. In part II
      of the study, the colorimeter agreed with itself 82% of the time, whereas
      clinicians agreed with each other on the selected shade 73% of the time.
      Selections made by the colorimeter and the clinicians matched 55% to 64% of the
      time. CONCLUSIONS: Within the limitations of this study, the colorimeter reliably
      measured the color of natural teeth.

PMID- 12488851
TI  - Influence of tab and disk design on shade matching of dental porcelain.
AB  - STATEMENT OF PROBLEM: Given the complexity of tooth color, the variations of
      shade within each tooth, and translucency, it is difficult to view only one small
      area and select a shade match for restorations. PURPOSE: This study tested the
      effect of specimen design on porcelain shade matching, hypothesizing that flat
      disks would be matched to one another with more accuracy than tooth-shaped tabs
      to tabs. MATERIALS AND METHODS: All testing was conducted in a Macbeth
      SpectraLight booth with D65 illumination. Seventy-three senior dental students
      (25 women and 48 men; mean age, 27 years) were asked to match selected Vita
      porcelain disks and Vita shade tabs to like specimens. The design order, namely
      matching tabs or disks first, was alternated for each observer. The specimens
      were handed to the observer individually. No time limit for matching was imposed,
      although each observer was given explicit instructions related to the observation
      and handling of the specimens. Upon completion of the matching exercises, each
      student received his or her standardized test results and reviewed the matching
      results. The time for testing and review was approximately 20 minutes per
      observer. An analysis of variance, with gender and order as 2 factors that could
      affect matching scores, was performed (P <.05). RESULTS: The mean matching scores
      were 78.4% for disks and 73.6% for tabs (P=.119). Female observers matched 76.5%
      of the disks and 77.5% of the tabs, whereas male observers matched 79.4% of the
      disks and 71.6% of the tabs (P=.054). Matching disks before tabs yielded
      equivalent levels of shade matching (disks, 77.6%; tabs, 77.1%). When tabs were
      matched first, the scores were as follows: disks, 79.8%, and tabs, 67.3%
      (P=.010). CONCLUSIONS: Within the limitations of this study, there was no
      significant difference in shade-matching accuracy between the 2 shapes, although
      the order of design matching resulted in a difference in shade-matching ability.
      When tabs were matched first and disks second, improved matching was evident on
      the second test. The reverse was not true; no learning was demonstrated when the
      tabs were matched after the disks.

PMID- 12488852
TI  - Comparison of microleakage of three acid-base luting cements versus one resin
      bonded cement for Class V direct composite inlays.
AB  - STATEMENT OF PROBLEM: Demineralized dentin beneath set cement may adversely
      affect microleakage under fixed restorations. PURPOSE: Microleakage of direct
      composite inlays cemented with acid-base cements and a methyl methacrylate resin
      cement were evaluated to determine their effect on the integrity of the
      underlying hybridized dentin. MATERIALS AND METHODS: Sixty Class V box
      preparations (3 mm x 3 mm x 1.5 mm) were precisely prepared in previously frozen
      bovine teeth with one margin in enamel and another margin in dentin. Direct
      composite inlays (EPIC-TMPT) for each preparation were divided into 4 groups of
      15 specimens each and cemented with 3 acid-base cements (control group): Elite,
      Ketac-Cem, Hy-Bond Carbo-Cem, and 1 adhesive resin cement: C&B Metabond. All
      specimens were stored in distilled water for 24 hours at 37 degrees C before
      immersion in 0.5% basic fuchsin for 24 hours. The dye penetration was measured on
      the sectioned specimens at the tooth-cement interface of enamel and cementum
      margins and recorded with graded criteria under light microscopy (Olympus Vanox
      T) at original magnification x 50, 100, and 200. A Kruskal-Wallis and the Mann
      Whitney test at P<.05 were used to analyze leakage score. RESULTS: All cementum
      margins of the 3 acid-base cements tested demonstrated significantly higher
      leakage scores than cementum margins for inlays cemented with the resin cement
      tested(P<.01). No leakage along the tooth-cement interface was found for inlays
      retained with the adhesive resin cement. CONCLUSIONS: Within the limitations of
      this study, the 3 acid-base cements tested exhibited greater microleakage at the
      cementum margins than did the adhesive resin cement that was tested.

PMID- 12488853
TI  - Fatigue resistance of two implant/abutment joint designs.
AB  - STATEMENT OF PROBLEM: Because of reported mechanical failures, alternative
      implant system components with suggested optimized strength have been
      manufactured. However, the endurance of these products has not been well
      investigated. PURPOSE: This study was designed to assess the effect of joint
      design on the fatigue strength and failure mode of 2 single-tooth implant
      systems: Branemark and ITI, in which a hex mediated-butt joint and 8-degree
      internal conical implant/abutment interface are used, respectively. MATERIALS AND
      METHODS: Seven 10-mm implants from each implant system were embedded to a depth
      of 7 mm in cylindrical acrylic resin blocks. CeraOne and Solid abutments with
      cement-retained castings were assembled to the Branemark and ITI implants,
      respectively. The assembled units were mounted in a lever-type-testing machine
      that was equipped with an automatic counting device and shutoff sensors, enabling
      the recording of the number of cycles till failure. A cyclic load of 100 N was
      applied perpendicular to the long axis of the assemblies at a rate of 75
      cycles/min. To investigate specimen resistance to fatigue during 6 years of
      simulated function, a target of 1,800,000 cycles was defined. Specimen
      preparation and testing was performed by the same operator. The association of
      the joint design with the occurrence of failure was verified by Fisher's exact
      probability test (P<.05). RESULTS: For the Branemark group, the gold alloy
      abutment screw in all specimens fractured between 1,178,023 and 1,733,526 cycles
      with a standard deviation of 224,477 cycles. For the ITI group, all specimens had
      no failure until 1,800,000 cycles. Statistical analysis showed a highly
      significant difference between the 2 groups (P=.000582). CONCLUSIONS: Within the
      limitations of this in vitro study, the effect of joint design on the fatigue
      strength and failure mode of the ITI single tooth implant system was
      significantly better (P>.001) than the Branemark single-tooth implant system
      tested.

PMID- 12488854
TI  - Effect of a heat-treatment on the linear dimensional change of a hard chairside
      reline resin.
AB  - STATEMENT OF PROBLEM: Little data are available regarding the effect of heat
      treatments on the dimensional stability of hard chairside reline resins. PURPOSE:
      The objective of this in vitro study was to evaluate whether a heat-treatment
      improves the dimensional stability of the reline resin Duraliner II and to
      compare the linear dimensional changes of this material with the heat-polymerized
      acrylic resin Lucitone 550. MATERIALS AND METHODS: The materials were mixed
      according to the manufacturer's instructions and packed into a stainless steel
      split mold (50.0 mm diameter and 0.5 mm thickness) with reference points (A, B,
      C, and D). Duraliner II specimens were polymerized for 12 minutes in water at 37
      degrees C and bench cooled to room temperature before being removed from the
      mold. Twelve specimens were made and divided into 2 groups: group 1 specimens
      (n=6) were left untreated, and group 2 specimens (n=6) were submitted to a heat
      treatment in a water bath at 55 degrees C for 10 minutes and then bench cooled to
      room temperature. The 6 Lucitone specimens (control group) were polymerized in a
      water bath for 9 hours at 71 degrees C. The specimens were removed after the mold
      reached the room temperature. A Nikon optical comparator was used to measure the
      distances between the reference points (AB and CD) on the stainless steel mold
      (baseline readings) and on the specimens to the nearest 0.001 mm. Measurements
      were made after processing and after the specimens had been stored in distilled
      water at 37 degrees C for 8 different periods of time. Data were subjected to
      analysis of variance with repeated measures, followed by Tukey's multiple
      comparison test (P<.05). RESULTS: All specimens exhibited shrinkage after
      processing (control, -0.41%; group 1, -0.26%; and group 2, -0.51%). Group 1
      specimens showed greater shrinkage (-1.23%) than the control (-0.23%) and group 2
      (-0.81%) specimens after 60 days of storage in water (P<.05). CONCLUSIONS: Within
      the limitations of this study, a significant improvement of the long-term
      dimensional stability of the Duraliner II reline resin was observed when the
      specimens were heat-treated. However, the shrinkage remained considerably higher
      than the denture base resin Lucitone 550.

PMID- 12488855
TI  - Wetting characteristic of ceramic to water and adhesive resin.
AB  - STATEMENT OF PROBLEM: Maximum wetting of ceramic by adhesive resin is required to
      achieve optimal adhesion of the resin to ceramic. It is unknown whether the
      adhesion of the resin to the ceramic is affected by the surface topography and
      wetting by water or the adhesive resin. PURPOSE: This study was designed to
      characterize the effect of surface topography on the wetting of ceramics by water
      and adhesive resin. MATERIALS AND METHODS: Three materials, a veneering ceramic,
      Eris (ERV), and 2 core ceramics, Empress 1 core ceramic (E1C) and an experimental
      core ceramic (EXC), were used. Four surface-roughening procedures were used. They
      included polishing through 1200-grit SiC paper (P), air abrasion with 50 microm
      Al(2)O(3) (A), etching with 5% hydrofluoric acid gel (E), and a combination of
      airborne particle abrasion and etching (A/E). Forty bar specimens (15 x 10 x 1.5
      mm) were prepared from each material (N=120). Twelve groups of 10 specimens each
      were prepared for the 4 surface-roughening procedures. Advancing (theta(A)) and
      receding (theta(R)) contact angles were measured with a CAHN Dynamic Contact
      Analyzer, on the basis of the Wilhelmy plate technique, with water and adhesive
      resin. The work of adhesion (W(A)) by the probing media was calculated by use of
      advancing contact angle data. The data were analyzed by t testing, analysis of
      variance, and Duncan's tests (alpha=0.05) to determine the statistical
      significance of differences in the contact angles between ceramic and water or
      resin as a function of surface roughening. RESULTS: In general, the mean theta(A)
      values were higher than the mean theta(R) values except for groups of E or A/E
      specimens with water used as a probing medium. E and A/E treatments yielded the
      lowest contact angle values, followed by A and P treatments (P<.001). The E1C
      exhibited the highest mean contact angles, whereas EXC exhibited the lowest mean
      contact angle except for the theta(R) with resin. The corresponding values for
      ERV were between those of E1C and EXC except for theta(R) values with resin. The
      resin medium yielded higher mean contact angles than the water medium for the
      same surfaces. W(A) ranged from 62.9 to 145.2 mJ/m(2). CONCLUSIONS: Within the
      limitations of this study, etching or a combination of air abrasion and etching
      were comparably effective in increasing the surface area for bonding. The most
      wettable surface as measured by the resin medium was EXC, followed by ERV and
      E1C.

PMID- 12488856
TI  - Comparing maximum intercuspal contacts of virtual dental patients and mounted
      dental casts.
AB  - STATEMENT OF PROBLEM: Quantitative measures of occlusal contacts are of paramount
      importance in the study of chewing dysfunction. A tool is needed to identify and
      quantify occlusal parameters without occlusal interference caused by the
      technique of analysis. PURPOSE: This laboratory simulation study compared
      occlusal contacts constructed from 3-dimensional images of dental casts and
      interocclusal records with contacts found by use of conventional methods.
      MATERIALS AND METHODS: Dental casts of 10 completely dentate adults were mounted
      in a semi-adjustable Denar articulator. Maximum intercuspal contacts were marked
      on the casts using red film. Intercuspal records made with an experimental vinyl
      polysiloxane impression material recorded maximum intercuspation. Three
      dimensional virtual models of the casts and interocclusal records were made using
      custom software and an optical scanner. Contacts were calculated between virtual
      casts aligned manually (CM), aligned with interocclusal records scanned seated on
      the mandibular casts (C1) or scanned independently (C2), and directly from
      virtual interocclusal records (IR). Sensitivity and specificity calculations used
      the marked contacts as the standard. Contact parameters were compared between
      method pairs. Statistical comparisons used analysis of variance and the Tukey
      Kramer post hoc test (P=<.05). RESULTS: Sensitivities (range 0.76-0.89) did not
      differ significantly among the 4 methods (P=.14); however, specificities (range
      0.89-0.98) were significantly lower for IR (P=.0001). Contact parameters of
      methods CM, C1, and C2 differed significantly from those of method IR (P<.02).
      The ranking based on method pair comparisons was C2/C1 > CM/C1 = CM/C2 > C2/IR >
      CM/IR > C1/IR, where ">" means "closer than." CONCLUSIONS: Within the limits of
      this study, occlusal contacts calculated from aligned virtual casts accurately
      reproduce articulator contacts.

PMID- 12488857
TI  - Treating the modern complete denture patient: a review of the literature.
AB  - This article reviews the physical and mental compromises of today's patients,
      techniques, materials, occlusion, impressions, and soft liners and makes
      recommendations as to managing these compromises when fabricating complete
      dentures. References used were primarily from the "classical literature," and an
      effort was made to ascertain whether these treatment recommendations are
      appropriate for today's more difficult patients. An effort was made to
      incorporate recent recommendations where appropriate.

PMID- 12488858
TI  - Veneering technique for a Ti-6Al-7Nb framework used in a resin-bonded fixed
      partial denture with a highly filled indirect composite.
AB  - This article presents a veneering technique for fixed partial denture frameworks
      made from a Ti-6Al-7Nb alloy. The fixed partial denture framework was prepared
      with a magnesia-based mold material and a centrifugal casting machine. An
      esthetic veneer was fabricated with a highly filled dual-polymerized composite
      material and a metal-conditioning agent. This technique can be applied as a
      standardized veneering procedure for the titanium alloy, for which porcelain
      fusing is currently difficult.

PMID- 12488859
TI  - A dual-purpose guide for optimum placement of dental implants.
AB  - Correct placement of implants is a requirement for implant treatment. The use of
      computed tomography and precise surgical guides is required when inadequate bone
      support is anticipated. This article describes the fabrication and use of an
      acrylic resin dual-purpose guide for radiographic evaluation of recipient sites
      and implant placement, which uses internally stacked stainless steel surgical
      guide channels. The drill guides are machined to allow consecutive surgical
      drills to be used without changing the implant angulation during surgery.

PMID- 12488860
TI  - An alternative procedure for discrimination of contacts in centric occlusion and
      lateral excursion.
AB  - An alternative procedure for discrimination of contacts in centric occlusion and
      lateral excursion was introduced for eliminating premature contacts in lateral
      excursion without the alteration of other intercuspations. This procedure
      involves the application of red paper for the evaluation of lateral excursive
      contacts and blue paper for centric occlusion holding contacts to provide
      improved visibility of occlusal contacts.

PMID- 12488862
TI  - Guidelines for digital scientific presentations.
AB  - In the world of scientific and professional presentations, the digital age has
      made an immense transformation. With these advances, digital media can be used to
      assist and enhance communication without losing the message. This article
      discusses guidelines for the presenter of scientific presentations with digital
      media.

PMID- 12488861
TI  - Developing an optimal emergence profile of the definitive restoration with a
      modified impression cap technique for ITI solid abutment.
AB  - There appears to be no convenient method for fabricating an optimal emergence
      profile for the definitive restoration of an ITI solid abutment when the implant
      is installed subgingivally. This article describes an efficient technique to
      solve this problem and reviews its advantages and disadvantages.

PMID- 12488865
TI  - Making a difference: connecting research to practice.

PMID- 12488866
TI  - Incorporating health services research into nursing doctoral programs.
AB  - Despite the successes of the US health care system, problems associated with
      access, affordability, and quality of care remain to be solved. Health services
      research (HSR) has the potential to aid nurses in addressing these issues; yet
      the importance of its inclusion in the academic preparation of nurse researchers
      has not been consistently recognized. This article discusses the relevance of HSR
      to nursing, provides a brief review of the history of HSR and its imperatives,
      and presents rationale for nursing's involvement in HSR. Problems identified by
      the Re-envisioning PhD project conducted by the University of Washington are
      assessed for relevance to HSR and nursing doctoral preparation. Recommendations
      are included for integrating HSR into nursing doctoral programs and meeting HSR
      capacity building needs for the future.

PMID- 12488867
TI  - Columbia University's competency and evidence-based Acute Care Nurse Practitioner
      Program.
AB  - New clinical information is being generated faster than practicing clinicians can
      effectively assimilate it. Since the gold standard of clinical information is
      evidence-based information, tools and techniques that facilitate both the
      building of evidence for practice and the application of evidence to practice are
      essential for practicing clinicians. As such, the Acute Care Nurse Practitioner
      (ACNP) program at Columbia University's School of Nursing was reconfigured to
      incorporate both theoretically based competency evaluation standards and
      strategies to foster an evidence-based practice approach to clinical care. The
      purpose of this article is to describe a curriculum and set of learning
      activities used to foster both development of clinical competency and evidence
      based practice in students in the Acute Care Nurse Practitioner program.

PMID- 12488868
TI  - Faculty practice: what do the data show? Findings from the NONPF Faculty Practice
      Survey. National Organization of Nurse Practitioner Faculties.
AB  - This article reports on the findings of the NONPF (National Organization of Nurse
      Practitioner Faculties) Faculty Practice Survey regarding promotion and tenure.
      Relevant issues related to tenure for practicing faculty are identified and
      discussed. Faculty practice has become an increasingly important and complex
      issue for academic institutions in relation to promotion and tenure. The purpose
      of this article is to examine the role and patterns of practice among tenured and
      nontenured faculty in academic nursing institutions and the variables associated
      with faculty promotion and tenure in these institutions. METHOD: A survey was
      mailed to the membership of the National Organization of Nurse Practitioner
      Faculties to examine the differences between practicing faculty who were tenured
      and those who were nontenured and to identify predictors of tenure. A 50%
      response rate (N = 452) was obtained. Findings indicate that only 37% of the
      practicing faculty were tenured, and more than half (51%) reported that practice
      was not considered in promotion and tenure decisions at their institutions. The
      predictors of tenure included practice being considered in promotion and tenure
      and support for practice at the school of nursing level. Data on reasons faculty
      practice are also presented. Recommendations for including practice in promotion
      and tenure guidelines are discussed as well as the ramifications of
      administrative support for practice.

PMID- 12488869
TI  - A theoretical framework for specialty certification in nursing practice.

PMID- 12488872
TI  - A new age is challenging the foundations of nursing practice and education.

PMID- 12488870
TI  - Virginia Cleland: an oral history by her colleagues and mentorees.
AB  - PURPOSE: The purpose of this study, an oral history, was to create a documented
      account of how Virginia Cleland was experienced by her colleagues and those she
      mentored. DESIGN: Data were collected for 8 months by snowball sampling of
      colleagues and mentorees. Nineteen individuals from across the United States were
      contacted and interviewed via telephone. METHODS: An oral history method was used
      to allow selected colleagues and mentorees of Cleland to talk about their
      experiences with her as a nurse scholar, academic, advocate for women, and
      visionary. The following 5 predominant themes were identified: (1) keeping
      boundaries clear; (2) "outspoken" leadership; (3) intense commitment to potential
      growth of others; (4) pragmatic, creative ideas, and action; and (5) equal rights
      for women. CONCLUSIONS: The oral history method is an effective way to
      demonstrate the characteristics of nurse leaders who contribute to successes in
      their careers. Nurses are given the opportunity to evaluate the qualities of
      leadership, especially in turbulent and challenging times.

PMID- 12488873
TI  - May extinction not become the future of our profession.

PMID- 12488874
TI  - [Towards a policy for science, technology, and innovation in health].

PMID- 12488875
TI  - [A literature review on pharmacists' interventions in the use of medication by
      elderly patients].
AB  - The total proportional geriatric population in Brazil is projected to increase
      from 9.05% in 1999 to approximately 13% in 2020. Non-communicable diseases are
      common in this age group, and medication is used frequently. Inadequate
      prescription and improper use of drugs can produce undesirable outcomes, leading
      to avoidable hospitalization and increasing health care costs. The objective of
      this paper was to conduct a literature review of pharmacists' interventions and
      their influence on use of medication by elderly patients, based on five databases
      from 1970 to 1999. The sample consisted of 76 studies, of which 15 were analyzed
      and discussed. Research on this subject is scarce, and limited to developed
      countries. In general, the interventions presented favorable outcomes. Most
      actions were limited to counseling patients and their physicians, and there was a
      lack of interventions to adjust the medication to the user.

PMID- 12488876
TI  - Homicides among teenagers in the city of Porto Alegre, Rio Grande do Sul State,
      Brazil: vulnerability, susceptibility, and gender cultures.
AB  - The authors present a quantitative and qualitative study on homicides among
      teenagers in Porto Alegre, Rio Grande do Sul State, Brazil, based on a historical
      series during the 1990s and the life and death histories in this group, with a
      special focus on 1997. In that year there were 68 homicides in which the victims
      were from 10 to 19 years old. Of the 68, 62 were males and only 6 females, or a
      ratio of 10:1, showing that young males are more vulnerable and susceptible to
      being murdered. The data indicate that cause of death is influenced by gender
      culture and that homicides are based on power and status symbols characterizing a
      kind of virility. This expression of virility in the shaping of violence also
      appears in the domination of the female body observed in homicides with young
      women as the victims. The life and death histories of these teenagers highlight
      the pertinence of the gender-based analysis as a theoretical-analytical category,
      in addition to analyses considering socioeconomic aspects and social inequity.

PMID- 12488877
TI  - Preventable infant mortality and quality of health care: maternal perception of
      the child's illness and treatment.
AB  - This study used a qualitative methodology to analyze the discourse of mothers
      from Greater Metropolitan Belo Horizonte, Minas Gerais, Brazil, whose infant
      children had died from what were considered avoidable causes (diarrhea,
      malnutrition, and pneumonia), seeking to elucidate the factors associated with
      utilization of health care services. Identification of the illness by the mother
      was related to perception of specific alterations in the child's state of health.
      Analysis of the alterations helped identify the principal characteristics
      ascribed to each alteration and their relationship to the search for treatment.
      The authors also studied the mother's assessment of treatment received at health
      care facilities; 43.0% of the cases involved problems related to the structure of
      health care services or the attending health care professionals. In 46.0% of the
      cases, mothers associated the child's death with flaws in the health care
      service. The study group showed a variety of interpretations of illness, often
      distinct from the corresponding biomedical concepts. The fact that attending
      health care personnel overlooked or underrated the mother's perception of the
      illness and the lack of communications between health care personnel and the
      child's family had an influence on the child's evolution and subsequent death.

PMID- 12488878
TI  - Evaluation of the residual effect of temephos on Aedes aegypti (Diptera,
      Culicidae) larvae in artificial containers in Manaus, Amazonas State, Brazil.
AB  - Trial tests and container observations were conducted in households to verify the
      residual effect of temephos in Manaus, Amazonas State, Brazil. Three plastic
      buckets, three tin cans, and three tires filled with water from an artesian well
      and larvicide were used in the experiment, with twenty-five third-instar larvae,
      which remained exposed for 24h, followed by mortality readings. The same types of
      containers were selected from common households. Collection and counts followed
      by chemical treatment were carried out on the larvae that were found. Follow-up
      was performed weekly to verify recolonization by Aedes aegypti. The experiment
      showed 100% mortality in the plastic buckets until day 90, and 80% in the tin
      cans until day 30, decreasing from day 45 onwards. Mortality in the tires
      decreased to 35% in the first month. Household results showed 100% mortality for
      all containers after 24h and differentiated values in the subsequent readings.
      Larvae were observed on day 35 in a tin can and on day 21 in a gallon can. There
      was a large diversity of results in the tires, with recolonization observed from
      day 7 onwards.

PMID- 12488879
TI  - [Trachoma prevalence in preschoolers and schoolchildren in Botucatu, Sao Paulo
      State, Brazil, 1992].
AB  - Trachoma dispensaries were created in the State of Sao Paulo in 1938, when the
      incidence of trachoma was 10.9% in Botucatu. During the 1970s trachoma ceased to
      pose a public health problem. The disease reappeared in the 1980s, leading the
      Sao Paulo State Health Department to establish a control program as new cases
      were being detected in various parts of the State, including Botucatu. This study
      aimed to determine the prevalence of trachoma in preschoolers and schoolchildren
      and to implement a program to control the disease in Botucatu. A cluster sample
      of children were submitted to external ocular examination to detect signs of
      trachoma according to WHO criteria. Trachoma prevalence was 11.9% among the 1,393
      children examined. All cases were treated with 1.0% tetracycline ointment and
      followed up periodically. Loss to follow-up increased from 1.6% for the first
      return visit to 62.4% for the last visit. The results showed the need to
      investigate the causes of non-compliance with the control program and the impact
      and effectiveness of treatment.

PMID- 12488880
TI  - [Health education for triatomine control in an area under epidemiological
      surveillance in Parana State, Brazil].
AB  - This paper describes a health education project targeting a rural community and
      health professionals from counties undergoing epidemiological surveillance for
      Chagas disease vectors in the State of Parana, Brazil. A group of technicians
      from the Brazilian National Health Foundation (FUNASA) was trained, together with
      teachers, workers, and students from the State University of Maringa, who
      prepared an instructions manual and drew up guidelines for reporting presence of
      triatomines or suspected cases of Trypanosoma cruziinfection. From June 1996
      through February 2000, the activities reached 742 families, 2,300 schoolchildren,
      and 27 teachers from 18 elementary schools, and included a meeting between FUNASA
      members and 40 participants, 21 meetings in health centers, and provision of a
      set of preserved triatomine specimens for use in vector surveillance and
      identification. After three years of health education activities and insecticide
      treatment (cipermetrina 125 mg i.a./m2), there was a reduction of 80.6% in
      households infested with triatomines and increased awareness among rural
      residents and health workers. The authors discuss the need to train professionals
      committed to changing Brazil's prevailing health model.

PMID- 12488881
TI  - [Different forms of payment systems for dental services and their impact on
      care].
AB  - The Brazilian dental care sector is facing a paradoxical crisis characterized by
      a surplus of dentists and a large contingent of people lacking dental care, thus
      highlighting the need to improve management strategies. One necessary step is to
      analyze the various payment schemes for dental services. This paper reviews two
      important approaches, fee for service and capitation, and considers the impacts
      and consequences of payment strategies on the dental care system.

PMID- 12488882
TI  - [Quality and subjectivity in the evaluation of health services and programs].
AB  - This essay focuses on the evaluation of health programs and services, emphasizing
      the subjectivity emerging from the evaluation process. The text is a theoretical
      construction that targets the various meanings of evaluation, the influence of
      the positivist paradigm on the field of health program and service evaluation,
      the polysemous nature of the term "quality", and its close overlapping with
      subjectivity. In addition, the authors highlight the importance of studies that
      incorporate the perspectives of social actors into the evaluation processes,
      recommending qualitative social research methodology as a productive instrument.

PMID- 12488883
TI  - A case-control study on alcohol and psychiatric disorders as risk factors for
      drug abuse pattern.
AB  - We evaluated alcohol and psychiatric disorders as risk factors for the pattern of
      drug abuse/dependence in a matched case-control study (370 adults). Cases (drug
      abusers) and controls were selected in the community using the snowball technique
      and matched by sex, age, and friendship. Information was gathered using the
      "Composite International Diagnostic Interview" (CIDI). Three patterns of drug
      abuse/dependence were evaluated: any drug abuse/dependence, only cannabis, and
      cocaine and other drugs. Logistic conditional regression showed that alcohol
      dependence was strongly associated with pattern of drug abuse/dependence. Thus,
      compared to the "no drug abuse group", the odds ratio for association with
      diagnosis of abuse/dependence on cocaine and other drugs was 10.2 (95% CI: 4.9
      21.2), whereas for abuse/dependence on cannabis only, the odds ratio was 1.0. For
      affective disorders, the odds ratio was 2.0 (95% CI: 1.10-3.64) for the group
      that received a diagnosis of abuse/dependence on cocaine and other drugs, whereas
      no association was found for those with abuse/dependence on cannabis only. In
      conclusion, there is not a homogeneous group of "drug users", and the role of
      risk factors depends on the drug use pattern.

PMID- 12488884
TI  - [Hospital costs due to violence against children and adolescents in Pernambuco
      State, Brazil, during 1999].
AB  - This study focused on expenditures under the Brazilian National Unified Health
      System (SUS) due to hospitalization of children and adolescents as the result of
      violence in Pernambuco State in 1999. Data were collected from the Hospital
      Admittance Forms covering the State of Pernambuco. Some 9,220 hospital admissions
      due to external causes were identified, with a cost of R$3,659,558.62. Mean cost
      of hospitalization for children and adolescents in Pernambuco State in 1999 was
      R$306.49. Mean cost of hospitalization due to external causes was R$396.91.
      Traumatic lesions were the most common reason for hospital admission (84.7%).
      Violence against children and adolescents in Greater Metropolitan Recife
      accounted for 65.1% of hospital admissions and 77.9% of all hospital costs in
      Pernambuco State.

PMID- 12488885
TI  - [What is garbage, anyway? The opinions of women from an outlying neighborhood in
      a large Brazilian city].
AB  - Domestic solid waste is cause for current environmental concern in large cities
      around the world. Little is known about the human health consequences of solid
      waste disposal in open-air dumps. In addition, there are few studies on people's
      health practices in relation to solid waste. As the initial step in
      epidemiological research on the relationship between solid waste and diarrhea,
      this study describes women's perception of the definition of garbage and the
      popular understanding of the relationships between garbage and disease, and
      between garbage and the environment. The study used a qualitative approach in a
      slum neighborhood in Salvador, Bahia. A total of 13 women were interviewed using
      a semi-structured questionnaire in 1999. The FileMaker "diaricamp" application
      was used for data analysis. Interviewees defined garbage as anything useless and
      considered it a problem whenever it accumulated in the surroundings producing a
      bad smell or visual pollution, attracted animals, caused disease in children or
      adults, or was shifted from the individual to the collective/institutional sphere
      of action to solve the problem.

PMID- 12488886
TI  - [Emerging and reemerging rickettsiosis in an endemic area of Minas Gerais State,
      Brazil].
AB  - This article describes a serological survey for rickettsiosis in the county of
      Novo Cruzeiro, Minas Gerais State, Brazil, in 1998, testing schoolchildren and
      dogs. Sera included 331 samples from schoolchildren from an endemic area and 142
      samples from schoolchildren from a non-endemic area in the county. All children
      examined were healthy and had not reported clinical symptoms of Brazilian spotted
      fever prior to the serological survey. Some 35 children in the endemic area were
      reactive to Rickettsia rickettsiiby indirect fluorescent antibody (IFA) with a
      titer of 1:64, corresponding to 10.6%. Sera from 73 dogs were tested, showing
      seroreactivity (IFA 1:64) to Rickettsia rickettsi, Ehrlichia chaffeensis, and
      Ehrlichia canisin 3 (4.11%), 11 (15.07%), and 13 (17.81%), respectively. The
      results in schoolchildren and the presence of canine seroreactivity to
      Ehrlichiaspecies that are potentially pathogenic to humans suggests the risk of
      transmission of other Rickettsiaein the study area.

PMID- 12488887
TI  - [A study of groundwater contamination with organic fuels and potential public
      health impact in Itaguai, Rio de Janeiro State, Brazil].
AB  - Increasing attention is current focused on urban groundwater contamination with
      gasoline hydrocarbon compounds in Brazil. The compounds benzene, toluene,
      ethylbenzene, and xylenes (BTEX) contained in fuels are highly toxic and can have
      severe public health consequences, besides posing the risk of intake from the
      water table by way of contamination. After two years of a steady gasoline storage
      tank leak, water samples from private household wells in the district of Brisa
      Mar, Itaguai, Rio de Janeiro State, were analyzed and the concentration of BTEX
      compounds was evaluated. Two out of ten water samples from the study area
      presented BTEX concentrations above the National Water Quality Standard
      (Brazilian Health Ministry Ruling No. 1469/2000), in which the maximum
      permissible benzene concentration is 5 micro g.L-1. Four others wells were also
      contaminated with nitrate, responsible for the induction of methemoglobinemia.
      Natural attenuation (intrinsic biodegradation) mechanisms through electron
      acceptors was also investigated in this study.

PMID- 12488888
TI  - [Sexuality of women living with HIV/AIDS in Sao Paulo].
AB  - The social and cultural setting which increases female vulnerability to HIV does
      not disappear when women living with HIV/AIDS discover that they are infected.
      Following diagnosis, new challenges arise in their emotional lives, an issue
      which has received little attention in the literature. This study interviewed
      1068 women living with HIV/AIDS using a questionnaire consisting of both open and
      closed questions, aimed at describing aspects of their sexual and reproductive
      lives and how they perceive counseling at Reference Centers in two cities in the
      State of Sao Paulo, where they have access to free antiretroviral therapy. Of the
      women with stable sexual partners, 63% used condoms in all their sexual
      relations, or three times the national average; 43% of the partners were HIV
      negative and 14% had unknown serological status; 73% of the women had children
      and 15% were considering becoming pregnant. Knowledge on mother-to-child
      transmission was less than expected, and the interviewees complained of limited
      space and receptiveness for discussing sexuality, especially with regard to their
      childbearing wishes. Counseling on sexuality should be a continuing process and
      requires interdisciplinary training for the professional team working in health
      care services, with an emphasis on sexual and reproductive rights.

PMID- 12488889
TI  - [Dialogue and participation in a local health council in the State of Santa
      Catarina, Brazil].
AB  - Although we are accustomed to believing that dialogue must involve participation,
      actual practice shows that it can occur in different ways. In this study,
      conducted in a municipal health council in the State of Santa Catarina, Brazil,
      the discursive mechanisms and strategies that appear as "obstacles" to this
      dialogue were analyzed, based on the minutes from 39 council meetings. Dialogue
      remained absent even though the council was intended as a forum for
      participation. Among the strategies, certain expressions which Umberto Eco refers
      to as "hypercodifications" were identified. Such expressions apparently act to
      block any debate in the council. The hypercodifications identified in this study
      were expressions of technical, administrative, and political jargon. Through
      these discursive strategies, the authors observed that language is used as a
      ruse, closing off possibilities for democratic interlocution, effectively cutting
      off dialogue. Thus, there is little transitivity in the power wielded by various
      segments in the council, which ended up concentrating primarily in the government
      sector.

PMID- 12488890
TI  - [The interdiction of disease: a cultural construction of schistosomiasis in an
      endemic area in Minas Gerais, Brazil].
AB  - This study was conducted in a rural area endemic for schistosomiasis in Minas
      Gerais, Brazil. The objective was to determine the relationship between an
      environmental and health education program for schistosomiasis, implemented for
      teachers and students from the state secondary school in the village of Boa
      Uniao, and the subsequent actions of its participants in regards to the
      environment and the illness. An important difference in this program is its
      perspective that it is not merely the implementation of instrumental and
      cognitive knowledge of the environment and illness, but an approach in which
      subjects are asked to question and investigate their perception of reality, the
      environment, and the illness. The study demonstrated that a change in attitude
      could occur from reflection on one's experience in relation to both the
      environment and diseases endemic it.

PMID- 12488891
TI  - [Community-based health workers: building the identity of this hybrid, polyphonic
      character].
AB  - This article analyzes the identity-building process for community-based health
      workers in the context of their role in the Health Family Program team and their
      interaction with the residents of communities where they work. Based on this
      analysis we specifically emphasize conflicts of interpretation, power
      relationships between both sides of identity-building for community-based health
      workers from three perspectives: that included in the official training of these
      workers, that produced by workers concerning themselves, and that transmitted by
      the community. The fact that community-based health workers live the reality of
      health practices in the neighborhoods where they live and work and are trained
      with biomedical references makes them actors that convey both the contradictions
      and the possibility for a deep dialogue between these two forms of knowledge and
      practice.

PMID- 12488892
TI  - [Changes in child health indicators in a municipality with community health
      workers: the case of Itapirapua Paulista, Vale do Ribeira, Sao Paulo State,
      Brazil].
AB  - Twelve community health workers (CHWs) were trained to offer basic health care
      for children under five years of age through household visits in Itapirapua
      Paulista, a municipality in Vale do Ribeira, Sao Paulo State, Brazil. Their tasks
      included diagnosis, initial treatment, and management of diarrhea and acute
      respiratory diseases at the household level, growth monitoring, incentives to
      complete basic immunization, and counseling on infant food supplementation. An
      average of 409 (396-417) children were visited weekly by CHWs in their homes over
      the course of three years. In this period, the hospitalization rate dropped
      drastically, and the use of oral rehydration therapy during bouts of diarrhea
      increased greatly. However, prevalence of stunting and incidence of low birth
      weight did not change. Child health indicators (CHI) in this municipality were
      better than those in a municipality chosen as a control. CHWs may have
      contributed to improved local CHI, but the results should be interpreted with
      caution for two reasons: (1) CHI is improving in Brazil countrywide and (2) it is
      a small program implemented in an area with high morbidity and mortality rates
      and low availability of health services.

PMID- 12488893
TI  - [Financial incentives for employees as part of a policy to upgrade care in a
      public hospital in Volta Redonda, Rio de Janeiro State, Brazil].
AB  - The authors present and analyze six years of regular and steady application of an
      institutional evaluation policy based on financial incentives in a public
      hospital in Volta Redonda, Rio de Janeiro State, Brazil, as a part of the
      hospital's administrative modernization policy. This type of policy is considered
      implicitly capable of developing a sequence of strategic wagers: (1) release of
      financial resources for payment of bonuses; (2) creation of an operationally
      feasible and sensitive evaluation instrument; (3) creation of adequate management
      mechanisms to improve evaluation policy; (4) employee adherence to the hospital
      upgrading policy based on the bonus system; and (5) maintenance of the effects of
      evaluation policy over time. The article discusses the "degree of success" of
      each of these wagers in an attempt to portray possible gains throughout the
      process, while also identifying inherent difficulties in such a policy.

PMID- 12488894
TI  - [From miasmas to microorganisms: hygienic lower-class housing].
AB  - By analyzing the influence of early Pasteurian thought on health discourse and
      practice, this paper discusses the thesis postulating an opposition between pre-
      and post- Pasteurian hygiene. Focusing on an analysis of the sanitary strategies
      to control lower-class housing that were proposed by Argentine and Brazilian
      hygienists, the author identifies the breaks and continuities between classical
      hygiene and hygiene reorganized by microbiology.

PMID- 12488895
TI  - [Chromosome instability induced by agrochemicals among farm workers in Passo
      Fundo, Rio Grande do Sul, Brazil].
AB  - A major share of the grain farming (wheat and soybeans) in the State of Rio
      Grande do Sul is in the Passo Fundo area. For crop pest control, large amounts of
      agrochemicals (fungicides, insecticides, and herbicides) are used. To evaluate
      the genotoxicity of these products, the micronucleus test was performed in farm
      workers directly exposed to these chemicals. Heparinized blood samples were drawn
      by venipuncture from 30 exposed workers and 30 non-exposed controls. Micronuclei
      frequency was evaluated by counting 1,000 binucleated cells per individual in
      both groups. Smoking habits, age, and duration of exposure showed no effect on
      the frequency of micronuclei in both groups. However, statistical analysis showed
      significantly higher mean numbers of binucleated cells with micronuclei in
      exposed individuals (14.3/1,000 cells) as compared to controls (7.1/1,000 cells),
      allowing the authors to conclude that the micronucleus test is an efficient
      biological assay for monitoring population exposure to mixtures of agrochemicals.

PMID- 12488896
TI  - [Hospital leaflets and the dynamics of constructing their meanings: the
      perspective of health professionals].
AB  - Based on interviews in a hospital in Rio de Janeiro, the authors analyze
      strategies, interests, assumptions, and concerns among producers of patient
      information leaflets on infectious diseases. Most such publications followed a
      linear communications model, according to which health messages produce a sole
      and single effect on their audience. Visual communications are seen as a field of
      knowledge over which physicians have no "command", but which raises great
      expectations on their part, principally in light of the limits of written
      language for an illiterate patient population. The most frequent concerns relate
      to the "adequacy of the language" (a denotative, non-semantic function of
      language) and on the increase in "dissemination". Leaflets are generally linked
      to the professional experience of providing health care, but the lack of
      pertinent research prior to the production of such publications leads to
      simplifications and generalizations concerning the patients' most common doubts
      and questions, reinforcing the stereotyping of the clientele based on their lacks
      and needs. In two exceptional leaflets, interaction with the clientele appears
      and expands the relationship between the health care professionals and the values
      and decisions made in distinct sociocultural contexts.

PMID- 12488897
TI  - [The Chagas Disease Control Program of the Sao Paulo State: the contribution of
      serology to the epidemiological investigation of triatomine-infested domiciliary
      units during the 1990s].
AB  - The Chagas Disease Control Program in Sao Paulo State, Brazil, now in the
      entomological surveillance phase, includes a serological examination of
      individuals residing in domiciliary units infested with vector triatomines
      infected with Trypanosoma cruzi. From 1990 to 1999, this action included area in
      which triatomine searches were conducted either as a routine procedure, according
      to their levels of intra- or peridomiciliary infestation, or at the request of
      local residents. Among residents of the 1,415 UDs inspected, we collected 5,587
      blood samples for serological examination, 87 of which (1.56%) tested positive,
      seven of which from individuals under 29 years of age. The species most
      frequently captured were Panstrongylus megistus, Triatoma sordida, and Triatoma
      tibiamaculata in the adult stage. No association was found between presence of
      seropositive residents and triatomines infected with Tr. cruzi (OR = 1.498; 0.875
      < OR < 2.564, 95% C.I.). Our purpose was to use serological testing to
      investigate the situation of areas identifiable as being at risk of Chagas
      disease transmission and to compare the results with extant data about Tr. cruzi
      infection both in humans and vector triatomines.

PMID- 12488898
TI  - [Pre-menopausal simple hysterectomy and post-menopausal female bone mineral
      density].
AB  - This study aimed to evaluate the bone mineral density (BMD) of post-menopausal
      women with previous pre-menopausal hysterectomy including bilateral ovarian
      conservation compared to a group of non-hysterectomized women with natural
      menopause. Data from a cross-sectional study of 30 pre-menopausally
      hysterectomized women evaluated in the post-menopause were compared with 102
      naturally post-menopausal women, analyzing their respective bone densitometry,
      measuring the femoral and lumbar spinal BMD. Multiple regression analysis of the
      132 women showed that age and body mass index (BMI) were heavily associated with
      femoral and lumbar spinal BMD, BMI directly associated, and age inversely
      associated with BMD. In addition, 30 hysterectomized women were matched by age
      and BMI to the 30 non-hysterectomized women, and bone densitometry did not show
      significant differences in BMD. These findings suggest that pre-menopausal
      hysterectomy with bilateral ovarian conservation does not appear to cause an
      additional reduction in bone mass when evaluated in the post-menopausal phase.

PMID- 12488899
TI  - [Relationship between water supply, sanitation, public health, and environment:
      elements for the formulation of a sanitary infrastructure planning model].
AB  - The understanding of sanitation infrastructure, public health, and environmental
      relations is a fundamental assumption for planning sanitation infrastructure in
      urban areas. This article thus suggests elements for developing a planning model
      for sanitation infrastructure. The authors performed a historical survey of
      environmental and public health issues related to the sector, an analysis of the
      conceptual frameworks involving public health and sanitation systems, and a
      systematization of the various effects that water supply and sanitation have on
      public health and the environment. Evaluation of these effects should guarantee
      the correct analysis of possible alternatives, deal with environmental and public
      health objectives (the main purpose of sanitation infrastructure), and provide
      the most reasonable indication of actions. The suggested systematization of the
      sanitation systems effects in each step of their implementation is an advance
      considering the association between the fundamental elements for formulating a
      planning model for sanitation infrastructure.

PMID- 12488900
TI  - [Infant mortality estimation in Brazil: what do Ministry of Health data on deaths
      and live births say?].
AB  - A methodological approach to infant mortality estimation in Brazil based on vital
      information provided by Ministry of Health systems is presented. The study
      evaluated the available data to establish criteria for identifying municipalities
      with serious data deficiencies, proposing an adequacy index. All municipalities
      were classified in strata according to geographic region and adequacy of
      information. To estimate infant mortality by macro-geographic region, in 1998,
      direct calculation was performed in strata with adequate information. The United
      Nations model was used in the other geographic strata. The Brazilian North
      presented the most deficient information, with 63% of the municipalities
      presenting inadequate reporting (35% of the regional population), followed by the
      Northeast (29% of the population). In the South, only 1% of the population showed
      inadequate information. For the whole country, 12% of the population presented
      serious problems in completeness of death reports. The adequacy index varied from
      -28% in Maranhao to 94% in Rio de Janeiro. The infant mortality rate was
      estimated in the interval 30.7-32.6 per 1,000 live births and the completeness of
      infant deaths from 61.8% to 65.6%.

PMID- 12488901
TI  - [Implementation process evaluation of the Integrated Management Childhood Illness
      strategy in the Family Health Program, Pernambuco State, Brazil].
AB  - This evaluative study attempts to define the contextual determinants of the
      degree of implementation in the Integrated Management of Childhood Illnesses
      strategy in Pernambuco State, Brazil. A total of 33 Family Health Program teams
      were selected from 10 municipalities. In order to define the degree of
      implementation, the study used a specific score system and the process indicators
      provided by the strategy. Municipalities were classified as critical,
      unsatisfactory, and acceptable. All municipalities except for one presented an
      acceptable degree of implementation in relation to the structure. In relation to
      process evaluation, two municipalities received one follow-up visit and their
      scores were unsatisfactory. Four municipalities received two visits, and one was
      classified as unsatisfactory on the second follow-up visit, while another
      presented a critical score on the first follow-up visit. Among four
      municipalities that received three follow-up visits, one was classified as
      unsatisfactory in the three evaluations. Four municipalities achieved mean
      unsatisfactory scores, when considering the mean scores acquired in the three
      follow-up visits. There was no association between the organizational context and
      degrees of implementation.

PMID- 12488902
TI  - [Assessment of the food list and serving size of a Food Frequency Questionnaire
      in an adult population].
AB  - This study examined both the food list and portion size values from a Food
      Frequency Questionnaire (FFQ) among participants in a case-control study in Sao
      Paulo, Brazil. Two hundred adult respondents to a case-control study were
      randomly selected (101 men and 99 women; age range: 35-69 years). FFQ food items
      were examined on the basis of their contribution to total population nutrient
      intake estimated by 24-hour dietary recall (1-DR). We examined the frequency
      distribution of equivalent-gram weights of each selected food from the 1-DR and
      identified the portion sizes as small, medium, and large in the distribution
      (percentiles 25, 50, and 75, respectively). The FFQ provided close estimation of
      total fat, saturated fatty acids, cholesterol, total fiber, vitamin B6, and folic
      acid compared to the 1-DR (paired t-test; p < 0.05). The FFQ food list covered
      the study population's main dietary nutrient sources.

PMID- 12488903
TI  - [Anemia in public school first graders in the city of Maceio, Alagoas, Brazil].
AB  - A cross-sectional study was conducted in a representative sample of 426 randomly
      selected first graders (ages 6 to 10 years) from public schools in Maceio, State
      of Alagoas, Brazil. The aim was to determine the prevalence of anemia, as well as
      its association with growth retardation. Data were collected from May to July
      2000, and determination of hemoglobin (HGB) employed an STKS Coulter counter. Two
      cut-off points were used to classify anemia, both established by the World Health
      Organization: HGB < 11.5g/dl and HGB < 12.0g/dl. The indicators height/age (H/A),
      weight/age (W/A), and weight/height (W/H) below -2.0 standard deviations from the
      NCHS reference were diagnosed as growth retardation. Prevalence of anemia was
      9.9% when HGB < 11.5g/dl was used, and 25.4% when the cut-off point was HGB <
      12.0g/dl. Growth retardation was detected in 6.2% of children according to H/A,
      4.0% for W/A, and 3.0% for W/H. There was no statistically significant
      association between the variables in the study. These findings confirm results of
      previous surveys where prevalence of anemia was much higher than that of growth
      retardation. The severe consequences of anemia in this age group justify the
      implementation of broad public policies to overcome this nutritional deficiency.

PMID- 12488904
TI  - [Chagas' disease seroprevalence among school-age children in Espirito Santo
      State, Brazil, 1999-2000].
AB  - Although the Brazilian State of Espirito Santo is not considered endemic for
      Chagas' disease, the sylvatic triatomines occurring there frequently invade
      houses, increasing the chances of Trypanosoma cruzi transmission to man. The
      epidemiological pattern of the disease in Espirito Santo was evaluated by a
      serological survey of 5,243 schoolchildren ages 7 to 14 years, residents of 17
      municipalities. Indirect immunofluorescence, indirect hemagglutination, and
      immunoenzymatic (ELISA) tests were positive in only one person, representing only
      0.019% of the total. This result was similar to those found by other authors in
      previous studies. Based on the results of serological tests it is concluded that
      the epidemiological pattern of Chagas' disease in Espirito Santo remains stable,
      despite the intensive destruction of the Atlantic Forest that has occurred in
      recent decades.

PMID- 12488905
TI  - [Health sector reform in Colombia and its effects on tuberculosis control and
      immunization programs].
AB  - This paper analyzes the effects of health reform in Colombia on public health
      programs at the local level, particularly the Expanded Program of Immunization
      (EPI) and the tuberculosis control program. The research was developed in three
      health districts in two States by analysis of documents, direct observation, and
      longitudinal follow-up of the transition process. The health districts were
      unprepared for the change, resulting in insufficient technical skills among staff
      as well as lack of awareness of important elements in the new system, associated
      with a reduction in immunization coverage and tuberculosis case detection.
      Structural problems in the new system included loss of immunization opportunities
      and lack of examination of tuberculosis contacts. The potentialities of the new
      system were the local development of a new organizational structure and the
      improvement of the information system; a limiting factor was exposure of the
      health system to local political interests. The general conclusion is that the
      transition period takes far longer than anticipated and requires a much greater
      information flow to both the local level and the community. There are transitory
      but also structural maladjustments that require a political response.

PMID- 12488906
TI  - Globalization and disease: in an unequal world, unequal health!
AB  - In this paper, originally presented at an event held by the National Institutes
      of Health (NIH) in the United States, the author analyzes the repercussions of
      globalization on various health aspects: the spread of infectious and parasitic
      diseases, bioterrorism, and new behavioral patterns in health, among others. He
      goes on to examine the positive and negative effects of international agreements
      on health, particularly in the trade area, including the TRIPS Agreement on
      medicines in the area of public health. The paper concludes that the resumption
      of cooperation among nations is the best way to achieve world progress in public
      health.

PMID- 12488907
TI  - [Accreditation and its implementation in graduate studies in Public Health].
AB  - This article aims to contribute to a better understanding of the establishment
      and implementation of accreditation in graduate courses in public health and to
      encourage discussions to improve quality in this area. The term accreditation is
      defined, and two of its main thrusts are discussed: quality and competence. The
      basis for establishing and implementing an accreditation system is described, and
      some of the key characteristics of the Brazilian experience are presented.

PMID- 12488908
TI  - [Mutations in the methylene-tetrahydrofolate reductase gene and Down syndrome].
AB  - Down syndrome (DS) is a complex genetic and metabolic disorder attributed to the
      presence of three copies of chromosome 21. The extra chromosome derives from the
      mother in 93% of cases and is due to abnormal chromosome segregation during
      meiosis (nondisjunction). Except for advanced age at conception, maternal risk
      factors for meiotic nondisjunction are not well established. A recent preliminary
      study suggested that abnormal folate metabolism and the 677 (C-->T) mutation in
      the methylene-tetrahydrofolate reductase (MTHFR) gene may be maternal risk
      factors for DS. Frequency of the MTHFR 677 (C-->T) and 1298 (A-->C) mutations was
      evaluated in 36 mothers of children with DS and in 200 controls. The results are
      consistent with the observation that the MTHFR 677 (C-->T) and 1298 (A-->C)
      mutations are more prevalent among mothers of children with DS than controls. In
      addition, the most prevalent genotype was the combination of both mutations. The
      results suggest that mutations in the MTHFR gene are associated with maternal
      risk for DS

PMID- 12488909
TI  - [Screening program for hemoglobinopathies based on blood donors from Braganca
      Paulista, Sao Paulo, Brazil].
AB  - Screening programs for hemoglobinopathies target different population groups such
      as neonates, students, pregnant women, military personnel, recruits, and blood
      donors. The feasibility and efficiency of these programs basically depend on the
      population's receptivity, which in turn is related to highly complex economic,
      psychological, and sociocultural factors. The purpose of this study was to
      evaluate the population of Braganca Paulista, Sao Paulo, based on results from
      the blood donors' group and to compare these results with those previously
      obtained in a group of students from the same city. The sample consisted of 1,846
      donors who had given blood at the Sao Francisco University Hematology Center,
      Braganca Paulista, Sao Paulo, from October 1998 to April 1999. Analysis of the
      1,846 donors identified 31 individuals who were hemoglobinopathy carriers
      (1.68%). The result was quite similar to that obtained in the group of students
      and demonstrated that the two methods are similar in relation to detection of
      hemoglobinopathies; however, the blood donor approach is more practical.

PMID- 12488910
TI  - [Census of hospitalized patients in a psychiatric institution of Rio de Janeiro
      State: preliminary data].
AB  - Rio de Janeiro State has one of the largest networks of psychiatric hospitals in
      Brazil, one of them the Dr. Eiras Paracambi Hospital (CSDE-P). In late 2000, the
      current Mental Health Advisory Division of the Rio de Janeiro State Health
      Department conducted a clinical and psychosocial census of patients hospitalized
      in the CSDE-P. The hospital population consisted of 1,494 individuals, the
      majority men (53.4%), single (81.6%), working-age (66.4%), and with limited
      schooling (only 11.5% with a complete primary education or more). Most had been
      in hospital for at least two years (77.6%), received visits from relatives
      (60.5%), but did not have hospital leave (73.8%). The predominant diagnoses were
      schizophrenia (53.6%) and mental retardation (26.4%). The main therapeutic
      approach was psychiatric (84.1%). Only 13.3% took part in systematic activities
      during the day, although 36% were in a condition to do so. CSDE-P is a mega
      hospital where most patients have precarious social links, demanding treatment
      strategies which take this characteristic into account.

PMID- 12488911
TI  - [Education in reproductive health: proposal or reality in the Family Health
      Program?].
AB  - As supervisors of primary health care units in the State of Ceara, Brazil, we
      have observed a low supply of health education services. As part of the
      activities under the Family Health Program (FHP), we attempted to investigate the
      causes of this short supply and identify flaws in the development of such
      activities. Interviews and participatory observation were adopted as the research
      method. The following causes were defined in the lack of health education
      practices: disorganization of demand, insufficient coverage of the population by
      FHP teams, resistance by both health professionals and the population to
      educational activities, absence of adequate floor space for conducting such
      activities, and lack of support materials. The following flaws were identified in
      the implementation of activities: limited exchange of experiences among
      participants; limited focus on the group's needs; frequent use of scientific
      language; transfer of outdated information; and inadequate utilization of
      teaching materials. The conclusion is that there is a need to retrain health
      professionals and to improve the availability of physical resources and teaching
      materials in order for education in reproductive health to become a reality in
      the FHP.

PMID- 12488912
TI  - [Seasonal distribution of malaria vectors in Machadinho d'Oeste, Rondonia State,
      Amazon Region, Brazil].
AB  - The objective of this study was to describe the seasonal distribution of malaria
      vectors in Machadinho d'Oeste, Rondonia State, Brazil. The study was based on
      data from the Brazilian National Health Foundation (FUNASA) for the period from
      April 1993 to November 1994. A total of 97 field visits were conducted, and 93
      intradomiciliary and 95 peridomiciliary collections were performed. The most
      frequently captured species in both the intra- and peridomiciles was Anopheles
      darlingi, followed by Anopheles triannulatus, among other species. Only An.
      darlingi was captured throughout the study period, and it was more abundant
      during the transition from the dry to the rainy season and vice versa. The
      elaboration of scientific studies based on secondary entomological data from
      FUNASA has been reinforced, since these results are comparable to those from the
      literature, taken from studies using primary data.

PMID- 12488914
TI  - [Prevalence and risk factors for smoking among adolescents].
AB  - OBJECTIVE: Tobacco smoking is one of the main causes of preventable disease and
      premature disability. The study was aimed at measuring smoking prevalence and
      related risk factors among adolescents. METHODS: A population-based cross
      sectional study was carried out in a representative sample of 1,187 adolescents
      aged 10 to 19 years living in the urban area of Pelotas, southern Brazil. All
      adolescents were interviewed separately using a confidential coded questionnaire.
      Kaplan-Meier test was performed for survival curve analysis. RESULTS: The overall
      smoking prevalence rate in the sample was 12.1% (95% CI 10.3%-14%). Boys and
      girls had similar prevalence rates. The following were the risk factors for
      smoking found in the multivariate logistic regression analysis: older age
      (OR=28.7; 95% CI 11.5-71.4), older smoking siblings (OR=2.4; 95% CI 1.5-3.8),
      three or more smoking friends (OR=17.5; 95% CI 8.8-34.8) and low schooling
      (OR=3.5; 95% CI 1.5-8.0). CONCLUSIONS: The prevalence of smoking among
      adolescents in the city of Pelotas was high. Campaigns against tobacco use should
      be aimed at the community and families, targeting adolescents. The government
      must adopt legal actions in order to prevent adolescents to have access to to
      smoking.

PMID- 12488915
TI  - [Sexual violence and its prevalence among adolescents, Brazil].
AB  - OBJECTIVE: To assess the prevalence o sexual violence among adolescents of public
      schools. METHODS: Fifty-two public elementary schools of Porto Alegre, Brazil,
      were selected through random sampling stratified by school size. An 8th grade
      class was selected in each school through simple random sampling and all
      adolescents attending the classes who agreed to participate were included in the
      study. The Screening Survey of Children's Exposure to Community Violence was used
      to identify adolescents who were victims, witnesses or knew someone who had been
      a victim of sexual violence. RESULTS: There were 1,193 adolescents included in
      the study, representing 10.3% of all students enrolled on 8th grade classes in
      the city's public schools. Twenty-seven adolescents (2.3%) reported being victims
      of sexual violence, 54 (4.5%) reported witnessing some episode of sexual violence
      and 332 (27.9%) reported knowing someone who was a victim of sexual violence.
      CONCLUSIONS: Exposure to sexual violence in any of the three forms of contact was
      a common event among the studied adolescents. Studies focusing sexual violence as
      a broad social phenomenon with multiples associated factors are necessary to
      support preventive and treatment strategies at the community level.

PMID- 12488916
TI  - [Experiencing motherhood in early adolescence].
AB  - OBJECTIVE: Although still scarcely studied in Brazil, motherhood in early
      adolescence among girls aged 10 to 14 years is mostly unwanted and it is an
      important public health issue. Most investigations are based on biomedical
      paradigms and few take into consideration the adolescent's point of view. This
      study aimed to explore the different patterns of experiencing early motherhood
      from the adolescent's own point of view. METHODS: William Stephenson's Q
      methodology was applied. The study population was selected from 2 public mother
      and child health units in Rio de Janeiro, Brazil, and comprised 20 adolescents
      who became pregnant at the age of 10 to 14 years and were followed up for a
      period of 6 to 24 months after giving birth. Q-sorts underwent factor analysis
      and then the factors were interpreted. RESULTS: Four qualitatively and
      statistically (p<0.01) perception patterns were found. Two factors were well
      defined: Factor I - Satisfied with motherhood/ Dependent on the child's
      affection: motherhood is a positive and rich experience; and Factor II -
      Depressed/ Stressed out: motherhood is a negative and stressful experience. Other
      two potential factors need confirmation in further studies with a larger sample
      size. CONCLUSIONS: It was observed that motherhood's experience is distinct and
      heterogeneous. For some adolescents, motherhood could be a rewarding experience

PMID- 12488917
TI  - [Hypercholesterolemia and its risk factors among schoolchildren].
AB  - OBJECTIVE: To identify the risk factors of hypercholesterolemia among
      schoolchildren aged 7 to 10 years, Brazil. METHODS: A case-control study was
      conducted among 172 children matched by sex and age +/-3 months in Campinas,
      Brazil. Cases were defined as hypercholesterolemia when cholesterol (3)200 mg/dL
      and controls when cholesterol 140 and 170 mg/dL. Besides drawing a blood sample
      for cholesterol, blood pressure, body mass index and family history of
      cardiovascular diseases were documented. Data were analyzed through bivariate
      correlation using t-test for quantitative variables and Chi-square for family
      history of cardiovascular diseases. Odds ratio was used to estimate the risk of
      hypercholesterolemia. RESULTS: On average, a cholesterol of 215 mg/dL for cases
      and 154 mg/dL for controls was found. The mean systolic blood pressure was 107
      mmHg for cases and 106 mmHg for controls. The mean of diastolic blood pressure
      was 67 mmHg for cases and 68 mmHg for controls. The mean body mass index was 18.2
      kg/m(2) in the case-group and 17.1 kg/m(2) in the control group. Bivariate
      analysis showed an association between hypercholesterolemia and body mass index
      (p=0.048). The odds ratio revealed obesity as a risk factor in this study
      population (OR=2.17; CI=1.05 to 4.45). CONCLUSIONS: The results showed obesity as
      a risk factor for hypercholesterolemia.

PMID- 12488918
TI  - [Sexuality in Down syndrome individuals].
AB  - OBJECTIVE: To evaluate parents and health professionals' opinions on the
      sexuality of Down syndrome individuals and to describe how these individuals see
      their own sexuality. METHODS: Both quantitative and qualitative analyses have
      been applied in the study. A total of 809 questionnaires were to parents and
      health professionals (348). Twelve focal groups' sessions were carried out
      separately with parents, professionals and DS individuals. Chi-square test was
      performed in the analysis. RESULTS: Parents see their children as eternal kids as
      they are afraid of the utmost outcome of their children's sexual life: unwanted
      pregnancy, and risk of syndrome recurrence. Health professionals revealed to be
      unprepared to provide sexual advice for DS individuals and adequate parents'
      attitude to their children's sexual drive. CONCLUSIONS: Down syndrome sexuality
      develops similarly to other individuals, but DS individuals experience
      restrictions depending on their social context.

PMID- 12488919
TI  - [Determinant factors of functional status among the elderly].
AB  - OBJECTIVE: To investigate the impact of health-related demographic and
      socioeconomic factors, as well as the impact of factors associated to social
      activity and the subjective health evaluation on the functional status of elderly
      people. METHODS: A cross-sectional multicentric study was conducted in a
      representative population sample in the city of Sao Paulo, Brazil, in 1989.
      Functional status was evaluated using a scale of activities of personal and
      instrumental daily living. It was studied as a dichotomous variable: absence of
      dependency - disability/difficulty in none of the activities in contrast with
      moderate/severe dependency - disability/difficulty in 4 or more activities.
      Multiple regression analysis was applied to hierarchically clustered factors.
      RESULTS: Those with the following features were more associated to
      moderate/severe dependency: illiterate, retired, pensioner, house keeper, living
      in a rented home, age over 65 years, multigenerational family composition,
      hospitalization in the last 6 months, mental health screening case, no visiting
      friends, and having a pessimistic perception of his/her own health when compared
      to their peers. CONCLUSIONS: The identified features associated to
      moderate/severe dependency suggest a complex net of causes for the declining
      functional status. However, one can assume that preventive measures directed to
      specific factors can benefit these population by improving their well-being.

PMID- 12488920
TI  - [Chagas' disease in the southern coastal region of Brazil].
AB  - OBJECTIVE: To analyze serological data collected in two different periods, from
      the late 1960's to 1983, when these data was first added to the available
      information about vector triatomines found in the state of Sao Paulo, and from
      1984 to 1999, a period when serology was used to describe endemic Chagas' disease
      in the state. METHODS: Serological surveillance data from schoolchildren (during
      the late 1960s and between 1973 and 1983), and the general population (between
      1980 and 1982) of the municipalities of Cananeia, Iguape and Peruibe were
      analyzed together with data collected on the vectors. RESULTS: Seropositivity
      among schoolchildren remained low and constant in the period from 1973 to 1982,
      and was no more detected in 1983. Cananeia showed titer distribution patterns
      typical of a non-endemic area, while Iguape and Peruibe indicated low endemicity.
      Most of the cases came from other states; autochthonous cases were suggestive of
      oral transmission. There were reports of infestation by vector triatomines in
      1,261 domiciliary units (main species: Panstrongylus megistus and Triatoma
      tibiamaculata). A total of 5,338 blood samples were collected and 40 were
      seropositive (0.75%). Triatomines captured within domiciles were mostly adults,
      and about half of them having fed upon human blood. Serological results of
      residents living in households where triatomines infected with Trypanosoma cruzi
      had been found did not differ from those living in houses infested only with non
      infected insects. CONCLUSIONS: In addition to educational activities aimed at the
      local population, there is a need to develop a collaboration between scientific
      institutions to isolate and characterize trypanosoma strains from vectors,
      reservoirs (sylvatic or other) and humans. Thus, evolutional, ecological,
      pathological and other pertinent characteristics of different strains of such
      parasites could be better understood.

PMID- 12488921
TI  - [Chagas' disease epidemiology in the province of General Paz, Argentina].
AB  - OBJECTIVE: The aim of this study was to evaluate triatomine colonization in
      domestic and peridomestic ecotopes and to assess the seroprevalence of Chagas'
      disease in rural areas. METHODS: The study was carried out in the province of
      General Paz, Corrientes, Argentina. Human dwellings and peridomestic ecotopes
      were randomly selected. Triatomines were collected using the man/hour/capture
      method. The insects were taxonomically determined and classified by age and sex.
      Trypanosoma cruzi infection was detected through direct microscopy of feces and
      polymerase chain reaction (PCR). Diagnosis of Chagas infection in volunteer
      residents was performed using indirect hemagglutination (IHA) and immunoenzimatic
      assay (ELISA). Infestation, density, colonization, natural infection and
      dispersion indexes were recorded. RESULTS; A total of 42 households and 50
      peridomestic areas were examined. Triatoma infestans domestic infestation and
      infection indexes were 23.8 and 19.4; respectively. Density, colonization and
      dispersion indexes were 2.1; 47.0 and 50.0; respectively. Of all, 5.9% of
      peridomiciles were infested by T. infestans and 11.8% by Triatoma sordida.
      Trypanosoma cruzi infection was observed in 2.0% of T. sordida. The
      seroprevalence rate obtained from 85 human sera analyzed was 22.3%. CONCLUSIONS:
      The results suggest a halt in T. cruzi transmission in the study area.
      Nevertheless the presence of seroreactive individuals and infected T. infestans
      vectors might facilitate the resurgence of the transmission cycle. Control
      actions with the use of insecticides might be considered in order to eliminate
      vector populations.

PMID- 12488922
TI  - [Housemaids and non-fatal occupational injuries].
AB  - OBJECTIVE: To estimate the annual incidence of non-fatal work injuries according
      to sociodemographic and occupational variables among housemaids. METHODS: A
      community-based survey was conducted in a population of 1,650 women aged 10 to 65
      years who reported a paid occupation randomly selected in a household sample of
      the city of Salvador, Brazil. Data was collected through individual
      questionnaires on living and work conditions and health status. Fisher Exact test
      was performed for frequency analysis. RESULTS: It was estimated an overall annual
      incidence of non-fatal work injuries in the study population of 5.0%, which was
      statistically significant (p<0.05) higher among housemaids (7.3%) than in the
      group with other occupations (4.5%). Half of the injuries among housemaids were
      not related with long-term disabilities, and 38.1% women referred not being able
      to work for two weeks on average after the injury. CONCLUSIONS: Housemaids
      represent a major contingent of the work force in Brazil and other Latin America
      countries. The high incidence of non-fatal work injuries in this working group
      reveals its public health relevance and the need for preventive programs.

PMID- 12488923
TI  - [Reported morbidity and use of health services by working women, Brazil].
AB  - OBJECTIVE: Inclusion in the work force has become part of women's daily lives,
      and they have to cope with multiple tasks and manage double working shifts. A
      study was carried out to assess working women's morbidity and their use of health
      services. METHODS: By means of a household survey, chronic and acute morbidity
      (i.e. within 30 days of data collection) was reported by 1,157 women aged 10 to
      49 years living in the southern area of the city of Sao Paulo, Brazil. Data were
      collected from January 1992 to January 1993. The relationship between employment
      and marital status, educational level and socioeconomic status was evaluated.
      RESULTS: Women who had a paid job were more likely to complain of acute or
      chronic morbidity. Also, these women tended to be less likely to seek medical
      services for their health problem. The most prevalent acute illnesses were:
      respiratory illnesses, especially influenza or colds (72/1,000), abdominal and
      pelvic pain (13.2/1,000), headaches (11.4/1,000), and hypertension (9.5/1,000).
      Regarding chronic complaints, hypertension (39.7/1,000), back pain (26.5/1,000),
      gastritis or inflammation of duodenum (24.6/1,000), and bronchitis (24.6/1,000)
      were the most prevalent conditions. CONCLUSIONS: Although employed women reported
      more health complaints than women who were not employed, their use of health
      services was equal to or less than that of women who were not employed for most
      health conditions studied.

PMID- 12488924
TI  - [Household insecticides: pattern of use according to per capita income].
AB  - OBJECTIVE: Although insecticides are widely used in many countries, few studies
      of their use in households have been conducted. This study was carried out to
      describe the household use of insecticides according to per capita income.
      METHODS: From October 1999 to January 2000, questionnaires on the use of
      household insecticides were applied to 2,039 households in the urban area of
      Pelotas, Brazil. Data was collected on income, use of insecticides in the 12
      months prior to the interview, product type and chemical group of the
      insecticides found in the households and, mechanical protection used for insect
      control. Chi-square test for trends was used to assess relationships, prevalence
      rates and confidence intervals. RESULTS: Household insecticides were used in 89%
      of the households visited at least in one occasion in the 12 months prior to the
      interview. In 79% one or more units of insecticides were found in the household
      at the time of the interview. The most common types were aerosols and tablet
      refills for electric devices of the pyrethroid chemical group. Mechanical
      protection against insects was not widely used. CONCLUSIONS: Higher income
      households most frequently had insecticides in the form of pyrethroid aerosols
      while organophosphate sprays were more frequently found in lower income
      households.

PMID- 12488925
TI  - Probabilistic linkage in household survey on hospital care usage.
AB  - OBJECTIVE: To evaluate the potential advantages and limitations of the use of the
      Brazilian hospital admission authorization forms database and the probabilistic
      record linkage methodology for the validation of reported utilization of hospital
      care services in household surveys. METHODS: A total of 2,288 households
      interviews were conducted in the county of Duque de Caxias, Brazil. Information
      on the occurrence of at least one hospital admission in the year preceding the
      interview was obtained from a total of 10,733 household members. The 130 records
      of household members who reported at least one hospital admission in a public
      hospital were linked to a hospital database with 801,587 records, using an
      automatic probabilistic approach combined with an extensive clerical review.
      RESULTS: Seventy-four (57%) of the 130 household members were identified in the
      hospital database. Yet only 60 subjects (46%) showed a record of hospitalization
      in the hospital database in the study period. Hospital admissions due to a
      surgery procedure were significantly more likely to have been identified in the
      hospital database. The low level of concordance seen in the study can be
      explained by the following factors: errors in the linkage process; a telescoping
      effect; and an incomplete record in the hospital database. CONCLUSIONS: The use
      of hospital administrative databases and probabilistic linkage methodology may
      represent a methodological alternative for the validation of reported utilization
      of health care services, but some strategies should be employed in order to
      minimize the problems related to the use of this methodology in non-ideal
      conditions. Ideally, a single identifier, such as a personal health insurance
      number, and the universal coverage of the database would be desirable.

PMID- 12488926
TI  - [Cervical cancer screening: knowledge of Pap smear benefits and utilization in
      Mexico].
AB  - OBJECTIVE: To identify and evaluate the predisposing factors regarding the
      utilization of the Pap smears in the population seen in the Cervical Cancer
      Screening Program in Mexico METHODS: A cross-sectional study was conducted from
      January 1997 through December 1998 in Mexico city. A questionnaire was applied to
      a total of 2,107 women of reproductive age who attended a family planning program
      and data was collected regarding the following topics: social-demographics,
      reproductive risk factors associated with cervical cancer, sexual behavior and
      partner history, birth control, knowledge about Pap smear' benefits, and its
      utilization. Statistic analysis was conducted using Student' s test and non
      conditional multiple logistic regression model for determining significance.
      RESULTS: The predisposing factors were: knowledge about Pap smear's benefits
      (OR=6.00, CI 95% 4.70-7.67), history of using at least two birth control methods
      (OR=2.38, CI 95% 1.75-3.24), previous history of vaginal infection (OR=2.18, CI
      95% 1.73-2.75), sexual partner's approval of gynecological examinations (OR=1.56,
      CI 95% 1.07-2.29). CONCLUSIONS: Educational programs on cancer prevention in this
      population should include the benefits of screening tests. Pap smears for Mexican
      women of reproductive age are mostly offered opportunely. The previous use of
      health services is a determinant factor for the utilization of the Cervical
      Cancer Screening Program. These results show the need to strengthen health
      promotion programs to women at high risk of cervical cancer and their sexual
      partners.

PMID- 12488927
TI  - [Chronic Chagas' disease: from xenodiagnosis and hemoculture to polymerase chain
      reaction].
AB  - Although there has been an improvement in the diagnosis of chronic Chagas'
      disease, the low sensitivity of indirect parasitological tests is a drawback to
      its application in diagnosis and post-therapeutic control. Polymerase chain
      reaction (PCR) has limited use in routine diagnosis due to the need of specific
      laboratory facilities, common DNA cross-contamination, and high costs. At the
      same time, the high variability of PCR results found in different regions of
      Brazil raises some questions concerning its applicability for diagnosis. PCR's
      high specificity is indicative that it can be used as a confirmation method in
      inconclusive serology diagnosis as well as an auxiliary method in pos-therapeutic
      control of chronic Chagas' disease when comparing to serology and parasitological
      techniques. It is discussed here the applicability of molecular and indirect
      parasitological methods in the diagnosis and post-therapeutic control of chronic
      Chagas' disease based on the literature published from 1954 to 2001.

PMID- 12488928
TI  - [Chronic occupational metallic mercurialism].
AB  - This is a review on current knowledge of chronic occupational mercurialism
      syndrome. Major scientific studies and reviews on clinical manifestation and
      physiopathology of mercury poisoning were evaluated. The search was complemented
      using Medline and Lilacs data. Erethism or neuropsychological syndrome,
      characterized by irritability, personality change, loss of self-confidence,
      depression, delirium, insomnia, apathy, loss of memory, headaches, general pain,
      and tremors, is seen after exposure to metallic mercury. Hypertension, renal
      disturbances, allergies and immunological conditions are also common. Mercury is
      found in many different work processes: industries, gold mining, and dentistry.
      As prevention measures are not often adopted there is an increasing risk of
      mercury poisoning. The disease has been under diagnosed even though 16 clinical
      forms of mercury poisoning are described by Brazilian regulations. Clinical
      diagnosis is important, especially because abnormalities in the central nervous,
      renal and immunological systems can be detected using current medical technology,
      helping to develop the knowledge and control measures for mercurialism.

PMID- 12488930
TI  - [Association of children's consumption of processed foods and family income in
      the city of Sao Paulo, Brazil].
AB  - OBJECTIVE: To describe children's consumption of processed foods and its
      relationship with per capita family income based on a household survey. METHODS:
      Food consumption was studied in a statistical sample of 718 children living in
      the city of Sao Paulo in the period 1995-1996. A 24-hour dietary recall was used.
      Data regarding the association of children's consumption of 24 processed foods
      and per capita family income (arranged in quartiles) was analyzed. RESULTS:
      Consumption of sugar was higher among children of low income families whereas the
      consumption of chocolate powder, chocolate, yogurt, infant formula and soft
      drinks was higher among children of high income families (p< 0.05). CONCLUSIONS:
      It seems that per capita family income affects the consumption of some processed
      foods.

PMID- 12488931
TI  - [Newborn feeding in the immediate pospartum period].
AB  - OBJECTIVE: To describe the type of newborn feeding in public and private
      institutions and to investigate its relationship with health practices during
      delivery and in the puerperium and sociodemographic characteristics. METHODS:
      Three hundred and forty-seven representative binomials mother - child of births
      that occurred in public and private maternity wards in the city of Cordoba,
      Argentina, were studied. Mothers were interviewed between 24 to 48 hours after
      delivery. By means of logistic regression analysis the association between health
      care practices and the type of newborn feeding in public and private institutions
      was studied, controlling for the effect of sociodemographic and perinatal
      factors. Statistical analysis was performed using logistic regression, odds
      ratio, and 95%CI. RESULTS: Of the total, 60.4% newborns in public institutions
      and 2.9% in private institutions were exclusively breastfed. In the public
      institutions, the risk of partial breastfeeding in the immediate postpartum was
      significantly higher in children who were not initially fed with mother's milk
      [odds ratio (OR)=149; confidence interval (CI): 95%: 16.7-1332], the first mother
      child contact was delayed for more than 45 minutes (OR:4.43; IC 95%: 1.02-19.20)
      and mother's intention was to breastfeed her child for less than 6 months (OR:
      5.80; IC: 95% 1.32-25.52); and in private institutions when children were not
      initially fed with mother's milk (OR: 9.88; IC 95%: 1.07-91.15). CONCLUSIONS:
      Labor and postpartum care does not comply with the current recommendations and it
      affects the type of feeding regardless of other factors studied.

PMID- 12488932
TI  - [Self-assessment of STD/AIDS vulnerability among women, Brazil].
AB  - OBJECTIVE: To investigate risk behaviors and self-assessment of the vulnerability
      to sexually transmitted diseases (STD) and acquired immunodeficiency syndrome
      (AIDS) among women. METHODS: A systematic sample including 48 of 281 census
      tracts in the urban area of Pelotas, Brazil, was selected. There were interviewed
      1,543 women, aged between 15 and 49 years, who had ever been sexually active.
      Risk behaviors were assessed using a confidential questionnaire that consisted of
      three sections: socioeconomic profile, interviewers' and self-administered
      questions. Data analysis was conducted using Epi-Info software, version 6.0.
      Statistical analysis was carried out using Kappa test and odds ratio. RESULTS: Of
      all women in the sample, 64% considered impossible or almost impossible for them
      to acquire an STD or AIDS. The main risk behaviors were non-use of condoms in
      their last intercourse (72%); onset of sexual activity before age 18 years (47%);
      drug or alcohol use by the partner (14%) or the woman (7%) before their last
      intercourse; two or more partners in the last three months (7%); and anal sex in
      the last intercourse (3%); 44% reported two or more risk behaviors. Using a risk
      score of two or more points as the gold standard, sensitivity and specificity of
      self-assessment were 41% and 67%, respectively. CONCLUSIONS: Self-assessment of
      vulnerability is not an adequate indicator of STD and AIDS vulnerability since
      women do not have an appropriate perception of their risks.

PMID- 12488933
TI  - [A sociodemographic analysis of the AIDS epidemic in Brazil, 1989-1997].
AB  - OBJECTIVE: To describe the temporal evolution of AIDS epidemic analyzed from a
      socio-demographic and behavioral perspective and focusing on the individual's
      educational level. METHODS: All AIDS cases aged 20 to 69, diagnosed with more
      than 7 days of difference between the dates of death and of diagnosis and
      reported to the Ministry of Health's Case Report Data Center from 1989 to 1997
      were analyzed. Three educational levels were considered: "level I" (less or
      equivalent to 8 years of schooling), "level II" (more than 8 years of schooling)
      and "unknown" (no available information). A descriptive analysis of the temporal
      evolution of the distribution of AIDS cases during the study period was carried
      out for both sexes and categorized by educational levels, geographic region,
      county population size, and exposure categories. Multivariate logistic analysis
      was performed to assess the variables combined effect. RESULTS: Information on
      educational level was not available in 22% of the cases. Where there was
      available information, higher percentages of "level I" were observed among
      females, in the southeast and south regions, municipalities with less than
      500,000 inhabitants, and in the "heterosexual" and "IDU" exposure categories. For
      all variables analyzed, it was observed a gradual reduction on the percentages of
      cases with a higher level of education, in the time period analyzed, for both
      sexes, less intense among the cases in "homosexual or bisexual" exposure
      category. CONCLUSIONS: The AIDS epidemic in Brazil started in social strata of
      higher educational level, spreading to populations with low educational level,
      especially among females, as well as to smaller population counties, through
      heterosexual contacts and use of injecting drugs.

PMID- 12488934
TI  - Fuzzy linguistic model for evaluating the risk of neonatal death.
AB  - OBJECTIVE: To introduce a fuzzy linguistic model for evaluating the risk of
      neonatal death. METHODS: The study is based on the fuzziness of the variables
      newborn birth weight and gestational age at delivery. The inference used was
      Mamdani's method. Neonatologists were interviewed to estimate the risk of
      neonatal death under certain conditions and to allow comparing their opinions and
      the model values. RESULTS: The results were compared with experts' opinions and
      the Fuzzy model was able to capture the expert knowledge with a strong
      correlation (r=0.96). CONCLUSIONS: The linguistic model was able to estimate the
      risk of neonatal death when compared to experts' performance.

PMID- 12488935
TI  - [Noise-induced hearing loss and high blood pressure among city bus drivers].
AB  - OBJECTIVE: To estimate the prevalence of occupational noise-induced hearing loss
      and arterial hypertension among city bus drivers. METHODS: A cross-sectional
      study was carried out on a probability random sample of 108 city bus drivers
      taken out of a total of 1,529 estimated professionals in the city of Campinas,
      Brazil, in 1991. Drivers were interviewed using questionnaires on job history,
      shift work and vacation schedules and underwent clinical and laboratory
      examinations including measures of blood pressure, pure-tone audiometry, speech
      audiometry, and anthropometric data analysis after an informed consent was
      obtained. RESULTS: The prevalence of noise-induced hearing loss was 32.7%.
      According to Merluzzi's classification, 91.2% (31 cases) were classified as first
      and second-degree losses and the most affected frequencies were 6 kHz in 61.3%,
      and 4 kHz in 38.7%. There were no differences in the laterality of the first
      affected ear. The prevalence of arterial hypertension was 13.2% (PAD > or =90
      mmHg; PAS > or =140 mmHg). CONCLUSIONS: The risk of noise-induced hearing loss
      was greater for drivers in job for more than 6 years, after controlling for age
      related hearing loss. An odds ratio of 19.25 was found for those aged 45 or more
      (1.59<OR<386.75; p<0.01).

PMID- 12488936
TI  - [Scenarios of typical occupational injuries in lumber industry].
AB  - OBJECTIVE: To describe the scenarios of typical occupational injuries in lumber
      industry. METHODS: All occupational injuries reported to a INSS (National
      Institute of Social Security) center in Lages, SC, Brazil from January 1997 to
      January 1999 were identified. A descriptive cross-sectional study was carried out
      and 254 injury report forms were analyzed. Multivariate analysis was conducted
      using Factorial Analysis of Correspondence (FAC), Hierarchical Ascendant
      Classification (HAC) and Partition to identify the scenarios of typical
      occupational injuries. RESULTS: There were identified five scenarios of
      occupational injuries: 1) workers' falls (40 reports); 2) overexertion in lifting
      or pushing objects (5 reports); 3) objects or machine parts falling or being
      ejected from running machines (76 reports); 4) crushing of soft tissue body parts
      (56 reports); and 5) body contact with running saw machines (77 reports).
      CONCLUSIONS: Multivariate analysis allowed describing the most typical injuries
      related to specific types of accidents, and provided a better understanding of
      the circumstances for their occurrence.

PMID- 12488937
TI  - [Fall-related factors in a cohort of elderly community residents].
AB  - OBJECTIVE: To identify factors associated to fall and recurrent fall episodes
      among elderly living in a community, and to determine the relative risk of each
      factor as a fall predictor. METHODS: A two-year follow-up study with two segments
      of multi-dimensional household surveys (1991-1992 and 1994-1995) was carried out
      in a cohort of 1,667 elderly, aged 65 or older, living in a community in the city
      of Sao Paulo, Brazil. The instrument used for data collection was the BOMFAQ, the
      Brazilian version of the Multidimensional Functional Assessment Questionnaire
      (OARS). A stepwise logistic regression analysis was conducted with p<0.05 and 95%
      CI. RESULTS: About 31% of the elderly referred a fall episode and around 11%
      referred two or more fall episodes in the previous year of the first survey.
      After follow-up, 53.4% didn't refer any fall episodes, 32.7% referred a fall
      episode either in the first survey or in the second one and almost 14% referred
      fall episodes in both surveys. The predictive model of recurrent falls was
      composed by the following variables: absence of a spouse (OR=1.59 95% CI 1.00
      2.52), not having a reading habit (OR= 1.56 95% CI 1.03-2.37), history of
      fractures (OR=4.6 95% CI 2.23-9.69 difficulty to perform one to three activities
      of daily life (OR=2.37 95% CI 1.49-3.78), difficulty to perform four or more
      activities of daily life (OR=3.31 95%CI 1.58-6.93) and among those whose sight is
      most impaired (OR=1.53 95%CI 1.00-2.34). CONCLUSIONS: Population ageing and
      increase in life expectancy demand preventive and rehabilitation actions in order
      to reduce risk factors for falls, such as impaired functional capacity, impaired
      eye sight and lack of cognitive stimulation.

PMID- 12488938
TI  - [Comparative study of surgical wound infection diagnosed in-hospital and post
      discharge].
AB  - OBJECTIVE: Surgical wound infection (SWI) is a serious hospital infection due to
      its incidence, morbidity and mortality. Because of the short hospital stay, the
      majority of SWI appears post-discharge, and its incidence is often underreported
      when there is no follow-up of the surgical patient post discharge. The need of a
      surveillance system for surgical patient after discharge is critical for
      infection control. The study objective was to determine the incidence of SWI in
      surgical patients and to compare the frequency of SWI diagnosed in-hospital and
      after discharge. METHODS: A prospective cohort study was carried out in a
      university hospital. Patients admitted to the general surgery unit (504) and
      underwent digestive tract surgery in the first semester of the year 2000 were
      followed up during their hospital stay and after discharge. RESULTS: Of 504
      surgical patients, 398 (79.0%) returned to follow up in the post discharge
      outpatient clinic. Of the total surgical wound infections diagnosed, most (62.9%)
      was detected in the post discharge outpatient clinic, and 88% of SWI diagnosed
      were classified as superficial, and 67% reported up to day 7 after discharge.
      CONCLUSIONS: This study showed the importance of following up surgical patients
      after discharge to achieve reliable incidence data on surgical wound infection
      because of the late occurrence of infection in the majority of cases, which
      results in underreporting when the patient is followed up only during the
      hospital stay.

PMID- 12488939
TI  - Hippuric acid in urine: reference values.
AB  - OBJECTIVE: To establish reference values for hippuric acid (HA) excreted in the
      urine, and to evaluate the impact of age, gender, alcohol, and tobacco, on these
      levels in a population nonexposed to toluene. METHODS: Reference values for
      hippuric acid in urine were determined in 115 toluene nonexposed healthy
      volunteers, from Alfenas city, Southeastern Brazil. A questionnaire was applied
      to each volunteer and data on occupational and personal habits were collected.
      Biochemical and hematological analyses were used to confirm the volunteers' good
      health condition. Reference values were expressed in g HA/g urine creatinine, as
      mean +/- standard deviation (x +/- SD), median, 95% confidence interval (95%CI),
      95th percentile, and upper reference value (URV, mean +2 SD). RESULTS: Reference
      values of hippuric acid in urine were: mean +/- standard deviation =0.18+/-0.10;
      median =0.15; 95% confidence interval =0.16+/-0.20; 95th percentile = 0.36 and
      upper reference value (URV, mean +2 SD) =0.38. Statistically significant
      differences in urinary HA (Wilcoxon - Mann/Whitney, p<0.05) were observed for
      different genders and age groups. Alcohol ingestion and smoking habit did not
      significantly affect the results. CONCLUSIONS: The reference values of hippuric
      acid in urine can be used in biomonitoring programs of workers occupationally
      exposed to toluene, especially in the southern region of the state of Minas
      Gerais. Age and gender may affect the HA reference values.

PMID- 12488940
TI  - [A sixteen-year epidemiological profile of a pediatric intensive care unit,
      Brazil].
AB  - OBJECTIVE: To review epidemiological data from patients admitted to a Pediatric
      Intensive Care Unit (PICU), Brazil, and to compare them to medical aspects
      associated to disease severity and mortality. Also, to profile these patients,
      including demographic data, disease prevalence, mortality rates and associated
      factors. METHODS: Retrospective data were collected from all patients admitted in
      a PICU of a university hospital between 1978 and 1994. Data were presented as
      percentages and compared using Chi-square, and calculating the relative risk (RR)
      with a 95% confidence interval, p<0.05. RESULTS: Of 13, 101 patients selected,
      most of them were boys (58.4%), younger than 12 months of age (40.4%), well
      nourished (69.5%), and with clinical disease (73.1%). The general mortality rate
      was 7.4%. Patients aged less than 12 months showed a RR of 1.86 (CI 1.65 - 2.10;
      p<0.0001), while the RR of malnutrition was 2.98 (CI 2.64 - 3.36; p<0.0001).
      CONCLUSIONS: The epidemiological survey showed that the mortality is higher in
      malnourished children younger than 12 months of age. Sepsis was the most main
      cause of death.

PMID- 12488942
TI  - Schizophrenia in males of cognitive performance: discriminative and diagnostic
      values.
AB  - OBJECTIVE: To evaluate the discriminative and diagnostic values of
      neuropsychological tests for identifying schizophrenia patients. METHODS: A cross
      sectional study with 36 male schizophrenia outpatients and 72 healthy matched
      volunteers was carried out. Participants underwent the following
      neuropsychological tests: Wisconsin Card Sorting test, Verbal Fluency, Stroop
      test, Mini Mental State Examination, and Spatial Recognition Span. Sensitivity
      and specificity estimated the diagnostic value of tests with cutoffs obtained
      using Receiver Operating Characteristic curves. The latent class model (diagnosis
      of schizophrenia) was used as gold standard. RESULTS: Although patients presented
      lower scores in most tests, the highest canonical function for the discriminant
      analysis was 0.57 (Verbal Fluency M). The best sensitivity and specificity were
      obtained in the Verbal Fluency M test (75 and 65, respectively). CONCLUSIONS: The
      neuropsychological tests showed moderate diagnostic value for the identification
      of schizophrenia patients. These findings suggested that the cognitive impairment
      measured by these tests might not be homogeneous among schizophrenia patients.

PMID- 12488941
TI  - [Social performance expectations in psychiatric patients of a general hospital
      ward].
AB  - OBJECTIVE: To prospectively assess the performance of socially expected
      activities of psychiatric patients in the first year after their discharge from a
      psychiatric ward of a general hospital. Also, to evaluate the patients' and their
      family' expectations on the former's performance. METHODS: The study was carried
      out in a general hospital in Ribeirao Preto, Brazil. The Katz Scale was applied
      to the patient and their family informer at the time of hospitalization regarding
      to the week preceding admission, and at one, six and 12 months after hospital
      discharge, regarding to the preceding week. Of the 86 pairs who were initially
      included in the study, 55 patients (33 women and 22 men) and their respective
      family informers completed the study. Performance scores and expectations were
      compared using variance (ANOVA) and t-student test. RESULTS: Expectation did not
      show significant variations either in the patient's evaluation or in the family's
      evaluation. According to both evaluations, expectation was significantly higher
      than performance. A significant improvement in the performance of socially
      expected activities was observed as early as one month after discharge compared
      to the pre-admission period and was unchanged along the first year in both
      evaluations of the patient and their family. CONCLUSIONS: These results suggest
      that admission to a psychiatric ward of a general hospital, in addition to
      reducing the psychiatric symptoms, contributed to improving the performance of
      socially expected activities. The average level of performance was unchanged
      throughout the first year after discharge, although demographic and medical
      variables can influence these results.

PMID- 12488943
TI  - [Microbiological analysis of mineral water and drinking water of reservoir
      supplies, Brazil].
AB  - The aim of this study was to evaluate the microbiological quality of different
      commercial mineral water brands, wells and reservoir supplies in surrounding
      areas of the city of Marilia, Brazil, to determine the amount of total and fecal
      coliforms. Eighteen samples of each source (mineral and reservoir supplies) were
      analyzed using Colilert Technique in cellophane. The results revealed that one
      sample of mineral water and one sample collected from the reservoir supply had
      been contaminated by a bacterium of the total coliform group, and there were
      found one bacterium/100 ml of water. None of the water samples showed
      contamination by fecal coliforms.

PMID- 12488944
TI  - [Self-perception of fluorosis due to fluoride exposure to drinking water and
      dentifrice].
AB  - The impact of dental fluorosis in children exposed to fluoride in drinking water
      and dentifrice was evaluated. Dental fluorosis was found in 72% of the children,
      but the children's well-being was not affected. It was concluded that although
      dental fluorosis due to the intake of optimally fluoridated drinking water and
      dentifrice did not affect the dental aesthetics of this studied population
      sample, there is a need of further studies on the subject.

PMID- 12488945
TI  - [Chagasic cardiopathy in endemic area versus sporadically infected patients].
AB  - The aim of the study was to compare the degree of cardiac compromise between two
      patient groups infected with Chagas' disease, A) those permanently residing in
      endemic areas and B) those sporadically exposed to the parasite and indirectly
      (non-vector) infected (transfusion, mother-to-child transmission, etc.). The
      results show that patients sporadically infected presented a lower prevalence of
      cardiopathy, and when they do present cardiopathy, there is a lower prevalence of
      dilation when compared to infected patients residing in endemic areas. Also, the
      role of the parasite, number of reinfections, immunopathogenic mechanisms,
      quality of life and occupation are considered in the study of disease progression
      in each patient.

PMID- 12488946
TI  - [Perinatal mortality and evitability: a review].
AB  - This is a literature review onperinatal mortality focusing its evitability. A
      Medline and Lilacs (Latin-America and Caribbean) search was conducted for the
      90s. There are few research studies on this subject in Brazil due to the great
      number of underreported fetal deaths and the low quality information provided in
      death certificates. Different proposals for perinatal death classification are
      presented. Most are based on grouping the underlying causes of deaths in a
      functional system in order to facilitate the analysis. In the Wigglesworth
      classification system, one of the most recommended methods, deaths are related to
      the different stages of care for pregnant women and children, evidencing the
      possibilities of their prevention. The evitability approach of perinatal deaths
      in Brazil is highly recommended, as mortality rates are still very high and most
      of the deaths are considered avoidable. Premature deaths could be avoided
      improving the quality of health care. Besides improving the medical assistance,
      the organization of health care regarding pre-natal, birth and neonatal care must
      also be better developed to ensure access to qualified assistance.

PMID- 12488947
TI  - [Epidemiological research on dementia in developing countries].
AB  - As the world population is ageing, dementia becomes an important public health
      problem, particularly in developing countries. Epidemiological research in these
      settings is scarce and present additional methodological difficulties, mainly
      regarding the socio-cultural adequacy of instruments used to identify cases of
      dementia. As a result of these concerns the 10/66 Dementia Research Group was
      founded to fill this gap. This is an international network of investigators,
      mostly from developing countries, and the group's name was based on the paradox
      that less than 10% of the population-based studies on dementia are directed to
      2/3 or more cases of people with dementia living in developing countries. The aim
      of the paper is to update data in the literature regarding the differences in
      dementia prevalence and incidence seen in developed and developing countries.

PMID- 12488948
TI  - Effects of delta9-THC and WIN-55,212-2 on place preference in the water maze in
      rats.
AB  - RATIONALE: Cannabinoids such as delta(9)-tetrahydrocannabinol (delta(9)-THC) or
      WIN-55,212-2 (WIN-2) have psychoactive effects on cognition. As a result, the
      reinforcing properties of delta(9)-THC or WIN-2 may confound learning and memory
      tests with false negative results. It therefore seems advisable to assess the
      reinforcing properties of the drugs in the same behavioural model used for
      learning experiments. OBJECTIVE: We therefore developed conditioned place
      preference protocols in the open-field water maze and tested both delta(9)-THC (2
      mg/kg) and WIN-2 (1 mg/kg and 3 mg/kg). Given that previous reports on
      cannabinoids have revealed conflicting data and that this was a novel behavioural
      test, we also tested the benzodiazepine receptor agonist diazepam (2.5 mg/kg).
      Some methodical refinements were appropriate in order to determine the
      behavioural strategy implemented by the animals. METHODS: All animals were
      injected intraperitoneally 30 min prior to training/testing. In experiment 1,
      male hooded Lister rats injected with drug were repeatedly placed on the drug
      related platform and subsequently tested for place preference. In experiment 2,
      rats were trained to swim to the drug platform on drug days and to the vehicle
      platform on vehicle days. A series of probe trials was introduced to delineate
      what had been learned. Experiment 3 studied the effect of WIN-2 on spatial
      learning in the water maze. RESULTS: Neither WIN-2 nor delta(9)-THC induced place
      preference in the water maze. When trained in the swim procedure, however, WIN-2
      was neutral, but Delta(9)-THC resulted in place aversion. Conversely, diazepam
      consistently produced place preference in both procedures. WIN-2 (3 mg/kg),
      however, produced a small learning deficit in the spatial water maze task.
      CONCLUSION: It appears that the reinforcing properties of delta(9)-THC and WIN-2
      in the doses used here are different, despite them both being agonists at
      cannabinoid receptors within the central nervous system. The fact that delta(9)
      THC may be aversively related to a particular context has implications for
      previous work reporting deficits in spatial learning.

PMID- 12488949
TI  - The delivery rate of dietary carbohydrates affects cognitive performance in both
      rats and humans.
AB  - RATIONALE: Glucose is the main metabolic fuel of the brain. The rate of glucose
      delivery from food to the bloodstream depends on the nature of carbohydrates in
      the diet, which can be summarized as the glycaemic index (GI). OBJECTIVES: To
      assess the benefit of a low versus high GI breakfast on cognitive performances
      within the following 4 h. METHODS: The influence of the GI of the breakfast on
      verbal memory of young adults was measured throughout the morning in parallel to
      the assessment of blood glucose levels. The learning abilities of rats performing
      an operant-conditioning test 3 h after a breakfast-like meal of various GI was
      also examined. RESULTS: A low GI rather than high GI diet improved memory in
      humans, especially in the late morning (150 and 210 min after breakfast).
      Similarly, rats displayed better learning performance 180 min after they were fed
      with a low rather than high GI diet. CONCLUSION: Although performances appeared
      to be only remotely related to blood glucose, our data provide evidence that a
      low GI breakfast allows better cognitive performances later in the morning.

PMID- 12488950
TI  - Asymmetric dimethylarginine (ADMA): a potential link between endothelial
      dysfunction and cardiovascular diseases in insulin resistance syndrome?
AB  - Endothelium-derived nitric oxide plays a major role in the regulation of vascular
      tone and in the maintenance of vascular homeostasis. Endothelial dysfunction with
      impaired nitric oxide biosynthesis and decreased bioavailability has been
      implicated in insulin resistance syndrome and Type II (non-insulin-dependent)
      diabetes mellitus. Nitric oxide is synthesised by nitric oxide synthase.
      Asymmetric dimethylarginine is a major endogenous nitric oxide synthase
      inhibitor. Increased circulating asymmetric dimethylarginine was initially found
      in patients with chronic renal failure and subsequently many other disease
      states. Increased asymmetric dimethylarginine plasma concentrations could
      contribute to the development of insulin resistance and coronary heart disease.
      Understanding of the pathophysiological role of asymmetric dimethylarginine could
      lead to novel therapies in the prevention of arteriosclerosis and coronary heart
      disease.

PMID- 12488951
TI  - Diabetic retinopathyA clinical update.
AB  - Easy observation of the fundus oculi makes retinopathy the most frequently
      reported chronic complication of diabetes and, consequently, the one we know best
      in terms of epidemiology and natural history. Achieving near-normal levels of
      blood glucose and blood pressure provides empirical though powerful tools for
      clinicians to delay the onset and progression of diabetic retinopathy. Even when
      these measures have failed and retinopathy becomes sight-threatening, laser
      photocoagulation has proven remarkably effective. Nonetheless, retinopathy
      remains a leading cause of blindness and there is little evidence that diabetes
      related visual loss is decreasing in industrialized countries. This may result
      from the mixed blessing of prolonged survival of patients who had become diabetic
      when metabolic control was pursued less fastidiously than today. Screening for
      sight-threatening retinopathy is the most cost-effective medical procedure known
      and should help optimise the use of diagnostic and therapeutic resources, but its
      widest deployment still meets with inertia and lack of interest within most
      health care systems. Improving clinical skills and technology, however, allow us
      to take a more optimistic look at the future, as pathogenesis-targeted forms of
      treatment are being developed and tested through appropriately powered clinical
      trials.

PMID- 12488952
TI  - Prevalence and 7-year incidence of Type II diabetes mellitus in a Japanese
      Brazilian population: an alarming public health problem.
AB  - AIMS/HYPOTHESIS: In 1993, the prevalence of glucose intolerance was studied in a
      sample of 647 first-generation and second-generation Japanese-Brazilians. Their
      cohort was followed until 2000, when a second survey was conducted, this included
      the first and second generations, aged 30 or more years. The aims were to
      estimate the prevalence of glucose intolerance and 7-yr incidence of Type II (non
      insulin-dependent) diabetes mellitus in this population. METHODS: Prevalence
      rates were obtained for 1330 subjects examined in 2000. The incidence of diabetes
      mellitus was calculated for those classified as normal glucose tolerant in 1993
      (n=253). A Student's t test and the Cox proportional hazard model were used in
      data analysis. RESULTS: In the year 2000, higher proportions of subjects were
      observed in all categories of glucose intolerance than those found in 1993. The
      overall incidence of diabetes was 30.9 per 1000 per year. A worse profile was
      observed among incident cases of diabetes, characterized by higher baseline
      values of anthropometric and metabolic variables as compared to those who had not
      developed diabetes. Analysis considering the simultaneous effects of demographic,
      nutritional and metabolic variables and physical activity levels for the
      development of diabetes showed that age, sex, waist circumference, fasting and 2
      h plasma glucose concentrations were independent predictors.
      CONCLUSION/INTERPRETATION: Our data point towards a worsening of glucose
      tolerance status among Japanese-Brazilians, who show one of the highest
      prevalence rates of diabetes mellitus worldwide. This could reflect their strong
      genetic susceptibility associated with unfavourable environmental conditions.

PMID- 12488953
TI  - First-phase insulin response in young healthy children at genetic and
      immunological risk for Type I diabetes.
AB  - AIMS/HYPOTHESIS: A reduced first-phase insulin response to intravenous glucose is
      perceived as a sign of far-advanced deterioration of beta-cell function during
      the development of Type I (insulin-dependent) diabetes mellitus, but data on
      insulin responses at the onset of diabetes-related autoimmunity are lacking. We
      studied the first-phase insulin responses of small children soon after observed
      seroconversion to autoantibody positivity. METHODS: In the Type I Diabetes
      Prediction and Prevention Study newborn infants are screened for HLA-DQB1
      associated genetic risk for Type I diabetes and those with increased risk are
      followed-up for the emergence of islet-cell antibodies. If antibodies are
      detected, autoantibodies to three other antigens (insulin, GAD65 and IA-2) are
      also measured. To measure first-phase insulin responses, intravenous glucose
      tolerance tests were carried out in 52 (1 to 5-year-old) children who had
      recently seroconverted to islet-cell antibody positivity. RESULTS: The first
      phase insulin response was subnormal (<38 mU/l, the 5(th) percentile of insulin
      responses of 20 islet-cell antibody negative healthy children at this age) in 22
      of the 52 children (42%). Stepwise multiregression analysis showed that islet
      cell antibody greater than 20 JDFU (p=0.0005), insulin autoantibodies (p=0.0009)
      and an increasing number of positive autoantibodies (p=0.0011) were independent
      predictors of low first-phase insulin response. CONCLUSION/INTERPRETATION: A
      decreased first-phase insulin response could be an early phenomenon in the course
      of prediabetes in young children, implying a rapid autoimmune destruction or loss
      of function of beta cells as well as possible metabolic compensation mechanisms,
      since 11 out of the 22 high risk children remain nondiabetic for a considerable
      period of time despite low insulin responses.

PMID- 12488954
TI  - Age-dependent impact of zygosity and birth weight on insulin secretion and
      insulin action in twins.
AB  - AIMS/HYPOTHESIS: Study the influence of age, zygosity and birth weight on insulin
      action and insulin secretion in twins. METHODS: In vivo insulin action and
      insulin secretion were measured using the euglycaemic, hyperinsulinaemic clamp
      technique and intravenous glucose tolerance test, respectively. We examined 104
      monozygotic (MZ) twins and 88 dizygotic (DZ) twins in two age groups (25-34 and
      57-66 years). RESULTS: There were no differences in birth weight, body mass
      index, waist to hip ratio or lean body mass between monozygotic and dizygotic
      twins. Younger monozygotic twins had a slightly higher insulin-stimulated glucose
      uptake (M) than younger dizygotic twins. In contrast, elderly monozygotic twins
      had a lower insulin-stimulated glucose uptake value compared with elderly
      dizygotic twins. Elderly monozygotic twins had a reduced insulin secretion
      relative to insulin resistance compared to dizygotic twins during oral glucose
      tolerance test (OGTT). Birth weight per se was not associated with insulin
      secretion or action in the twins. However, correcting for the genetic influence
      on birth weight using intrapair differences among monozygotic twin pairs, low
      birth weight was associated with insulin resistance and low insulin secretion
      after both oral and intravenous glucose administration in elderly MZ twins.
      CONCLUSION/INTERPRETATION: Zygosity status has a major age (or time) dependent
      impact on in vivo insulin secretion and insulin action in twins independent of
      birth weight and adult antropometry. An additional non-genetic impact of low
      birth weight on insulin secretion and insulin action was found in elderly
      monozygotic twins. Ageing could play an important role by unmasking the influence
      of an adverse intrauterine environment on insulin resistance and low insulin
      secretion in twins.

PMID- 12488955
TI  - IA-2 autoantibodies predict impending type I diabetes in siblings of patients.
AB  - AIMS/HYPOTHESIS: Multiple islet autoantibody positivity is currently believed to
      best predict progression to Type I (insulin-dependent) diabetes mellitus. We
      compared its predictive value with that of positivity for a particular type of
      islet autoantibody, directed against the IA-2 antigen. METHODS: Autoantibodies
      against islet cell cytoplasm (ICA), insulin (IAA), GAD (GADA) and IA-2 (IA-2A)
      were measured at initial sampling in 1724 non-diabetic siblings (median age
      [range]:16 [0-39] years) of Type I diabetic patients with a median follow-up of
      50 months. RESULTS: On initial sampling 11% of siblings were positive for one
      antibody type or more and 2.1% for three of more types. During follow-up, 27
      antibody-positive siblings developed diabetes. Using survival analysis, the risk
      for clinical onset within 5 years was 34% in subjects positive for three or more
      types compared with 13% in those with one type or more. Progression to diabetes
      amounted to 12% within 5 years among siblings positive for IAA, 20% for ICA, 19%
      for GADA but 59% for IA-2A (p<0.001 vs absence of the respective antibody). IA-2A
      were detected in 1.7% of all siblings and in 56% of the prediabetic subjects on
      first sampling. Initial positivity for two or three antibody markers was
      associated with a higher progression rate in IA-2A positive as compared to IA-2A
      negative siblings (p=0.001). In absence of IA-2A initial positivity for another
      antibody (IAA, ICA or GADA) conferred a low (<10% within 5 years) risk of
      diabetes compared to subjects lacking this antibody. CONCLUSIONS/INTERPRETATION:
      In siblings of Type I diabetic patients, IA-2A positivity is a more direct
      predictor of impending clinical onset than multiple antibody positivity per se.
      Assessment of IA-2A status allows us to select subjects with homogeneously high
      risk of diabetes for participation in prevention trials.

PMID- 12488956
TI  - Anti-CD38 autoantibodies: characterisation in new-onset type I diabetes and
      latent autoimmune diabetes of the adult (LADA) and comparison with other islet
      autoantibodies.
AB  - AIMS/HYPOTHESIS: Serum anti-CD38 autoantibodies (aAbs) have been reported in 17
      to 19% of patients with long-standing Type I (insulin-dependent) diabetes
      mellitus and Type II (non-insulin-dependent) diabetes mellitus. Whether these
      aAbs are also found in new-onset Type I diabetes and in Latent Autoimmune
      Diabetes in Adults (LADA) is not known, as is their relationship with
      conventional islet aAbs. METHODS: These issues were addressed by studying new
      onset Type I and LADA diabetic cohorts with a recently developed anti-CD38
      enzymatic immuno-assay. RESULTS: Anti-CD38 aAb prevalence among new-onset Type I
      patients (3.8%) was lower than previously found in long-standing Type I diabetes
      (11.7%, as defined with the 97.5 percentile cutoff; p=0.01), suggesting a late
      appearance of these aAbs. Among LADA patients, 14.9% were anti-CD38(+). Anti-CD38
      were only associated with anti-GAD aAbs in new-onset Type I diabetes. Although
      the CD38 target molecule was expressed in human pancreatic islets, anti-CD38 aAbs
      did not contribute to the islet cell antibody (ICA) immunofluorescence
      reactivity. All the positive sera analysed for Ca(2+) release were found to
      mobilise it. In agreement with these agonistic features, anti-CD38(+) new-onset
      Type I patients showed higher fasting C-peptide values as compared to negative
      counterparts; the association was stronger when the analysis was limited to the
      agonistic anti-CD38(+) sera. A similar trend was found among LADA patients.
      CONCLUSION/INTERPRETATION: Anti-CD38 aAbs are distinct markers of islet
      autoimmunity which are more prevalent in long-standing disease, as opposed to the
      other known islet aAbs. Their in vitro agonistic properties could be operating in
      vivo as well, as they identify sub-groups of patients with higher residual beta
      cell function.

PMID- 12488957
TI  - TNF-related apoptosis-inducing ligand death pathway-mediated human beta-cell
      destruction.
AB  - AIMS/HYPOTHESIS: The aim of this study is to investigate whether apoptosis in
      human beta cells can be related to the induction of the tumor necrosis factor
      related apoptosis-inducing ligand (TRAIL) pathway. METHODS: We examined the
      expression of TRAIL and TRAIL receptors in two human pancreatic beta-cell lines
      and in human primary islet cells using RT-PCR assays and flow cytometric analyses
      and tested TRAIL-mediated beta-cell destruction in (51)Cr release cytotoxicity
      assays, Annexin-V and APO-DIREC assays. RESULTS: Most of the human beta cells
      express TRAIL receptors-R1, -R2, -R3, -R4 and/or TRAIL. TRAIL induced much
      stronger cytotoxicity and apoptosis to beta-cell lines CM and HP62 than did FasL,
      TNF-alpha, LTalpha1beta2, LTalpha2beta1, LIGHT, and IFN-gamma. The cytotoxicity
      and apoptosis induced by TRAIL to beta-cell lines CM were inhibited competitively
      by soluble TRAIL receptors, R1, R2, R3 or R4. Treatment of these beta cells with
      antibodies against TRAIL receptors was able to block the cytotoxicity of TRAIL to
      these cells. Beta-cell antigen-specific CTL (CD4(+) and CD8(+)) clones express
      TRAIL, suggesting that these cells are potential sources of TRAIL-inducing beta
      cell destruction. Normal primary islet cells from most donors are resistant to
      the cytotoxicity mediated by TRAIL. However, treatment with an inhibitor of
      protein synthesis (cycloheximide) or with an enzyme (PI-PLC) that can remove
      TRAIL-R3 from the islet-cell membrane was able to increase the susceptibility of
      TRAIL-resistant primary islet cells to the TRAIL death pathway.
      CONCLUSION/INTERPRETATION: The TRAIL death pathway is present and can function in
      human islet beta cells, but unidentified inhibitors of the TRAIL death pathway
      are present in normal islet cells.

PMID- 12488958
TI  - Detrimental effect of protracted hyperglycaemia on beta-cell neogenesis in a
      mouse murine model of diabetes.
AB  - AIMS/HYPOTHESIS: Previous studies have shown that new beta cells differentiate
      from intra-islet precursors in pancreatic islets of mice in which diabetes is
      induced by injecting a high dose of the beta-cell toxin streptozotocin. Moreover,
      the re-establishment of euglycaemia by insulin therapy 1 day after streptozotocin
      treatment improved the process of regeneration. We sought to assess whether a 1
      week delay in the restoration of euglycaemia would affect beta-cell regeneration.
      METHODS: Adult CD-1 mice were injected with 200 mg/kg of streptozotocin. One
      group of mice remained hyperglycaemic throughout the experiment while a second
      group became normoglycaemic following the administration of insulin therapy 1
      week after the injection of streptozotocin. Pancreata removed at different times
      after treatment were processed for visualization ofbeta precursor-cell markers
      and insulin by confocal microscopy. RESULTS: New beta cells appeared in islets of
      streptozotocin-treated mice after restoration of normoglycaemia. Like islets of
      streptozotocin mice in which blood glucose concentrations were rapidly restored,
      islets of mice that became normoglycaemic 1 week after streptozotocin treatment
      also had two potential insulin precursor cell types. Protracted hyperglycaemia
      however, had several harmful effects on insulin cell neogenesis, such as a
      reduction in the number of euglycaemic mice with successful beta-cell
      regeneration and a decrease in the number and survival of the newly
      differentiated insulin-containing cells. CONCLUSION/INTERPRETATION: These results
      indicate that islets gradually lose their regenerative potential when they are
      exposed to high circulating glucose concentrations for an extended period of
      time.

PMID- 12488959
TI  - Absence of functional insulin receptor substrate-3 (IRS-3) gene in humans.
AB  - AIM/HYPOTHESIS: Insulin receptor substrate (IRS) proteins play important roles in
      insulin action and pancreatic beta-cell function. At least four mammalian IRS
      molecules have been identified. Although genes and cDNAs encoding human IRS-1,
      IRS-2, and IRS-4 have been cloned, IRS-3 has been identified only in rodents.
      Thus, we have attempted to clone the human IRS-3 gene. METHODS: Insulin
      stimulated rat or human adipocytes were subjected to Western blot analysis to
      assess IRS-3 tyrosine phosphorylation. Human liver and adipose cDNA libraries
      were screened in an effort to clone IRS-3 cDNA. A PCR-based approach was designed
      to amplify IRS-3 cDNA. Reverse transcription PCR was carried out using mRNA from
      adipose tissue, liver, and skeletal muscle as templates in combination with an in
      silico screen using mouse IRS-1, IRS-2 and IRS-3 in a tblastn search of the draft
      public human genome. RESULTS: In human adipocytes we did not detect a M(r) 60 000
      phosphoprotein corresponding to IRS-3, whereas in rat adipocytes IRS-3 protein
      and insulin-stimulated tyrosine phosphorylation was readily observed. None of the
      molecular approaches provided evidence for a functional IRS-3gene in human
      tissue. Two deletions in human IRS-3 gene were identified using bioinformatics.
      The human IRS-3 gene product is predicted to lack a phosphotyrosine binding
      domain and also the sequence corresponding amino acid 353-407 of murine IRS-3.
      The contiguous sequence of genomic DNA between these two homologous regions does
      not have the coding information for human IRS-3. CONCLUSION/INTERPRETATION: In
      silico screening of the human IRS-3 genome region, combined with further
      biological and molecular validation, provides evidence against a functional IRS-3
      in humans.

PMID- 12488960
TI  - Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha
      (MODY3) gene.
AB  - AIMS/HYPOTHESIS: Maturity onset diabetes of the young type 3 (MODY3) is a
      monogenic form of diabetes mellitus caused by mutations in the gene encoding for
      hepatocyte nuclear factor 1 alpha, HNF1 alpha. In this study we have examined the
      in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and
      dimerization domains in the N terminal part of the HNF1 alpha gene. METHODS: Beta
      cell function of the affected family members was assessed by an oral glucose
      tolerance test. Functional tests were carried out to explain the role of the
      mutation in vitro by transcriptional activity assay, Western blotting, DNA
      binding assays and subcellular localization experiments. RESULTS: Affected family
      members showed an 86% decreased insulin response to glucose when compared to age
      matched healthy control subjects. In vitro the mutation showed a 79% decrease in
      transcriptional activity as compared to wild type HNF1 alpha in HeLa cells
      lacking HNF1 alpha. The transcriptional activity was not suppressed when the
      mutant was co-expressed with wild type HNF1 alpha suggesting that the decreased
      activity was not mediated by a dominant negative mechanism. The L107I/HNF1alpha
      protein showed normal nuclear targeting but impaired binding to an HNF1 alpha
      consensus sequence. CONCLUSION/INTERPRETATION: Our results suggest that the L107I
      substitution represents a MODY3 mutation which impairs beta-cell function by a
      loss-of-function mechanism.

PMID- 12488961
TI  - High frequency of mutations in the HNF-1alpha gene in non-obese patients with
      diabetes of youth in Japanese and identification of a case of digenic
      inheritance.
AB  - AIMS/HYPOTHESIS: There is an emerging epidemic of Type II (non-insulin-dependent)
      diabetes mellitus of youth in Japan and in many other developed countries. The
      aim of this study was to determine the prevalence of mutations in the hepatocyte
      nuclear factor (HNF)-1alpha gene (TCF1) in a large group of Japanese patients
      with early-onset non-Type I (insulin-dependent) diabetes mellitus. Since
      approximately 20% of Caucasian patients with HNF-1alpha mutations have been shown
      to be obese or overweight, we also examined the association of genetic variations
      in TCF1 with body weight in Japanese subjects. METHODS: We examined 203 patients
      with non-Type 1 diabetes who had been diagnosed before they reached 15 years of
      age. Ten exons and flanking introns of TCF1 of these patients were directly
      sequenced for mutations. RESULTS: We found 14 different mutations in 18 patients
      (8.9%), including one that was found to be de novo. The patients with the
      mutations had lower BMI (20.1+/-3.0 kg/m(2)) at diagnosis than the patients
      without them (24.5+/-6.0 kg/m(2)) (p=0.0024). All of the patients with the
      mutations, except for one, Y120, had normal body weight (BMI<25 kg/m(2)); the
      frequency of HNF-1alpha mutations in the non-obese patients of this study was 17%
      (17/101). Patient Y120, who had atypical symptoms of mild obesity and insulin
      resistance at diagnosis, was found to have inherited an additional mutation in an
      obesity-related gene. CONCLUSION/INTERPRETATION: A considerable number of non
      obese Japanese patients with non-Type 1 diabetes of youth have HNF-1alpha
      deficient diabetes. Lack of obesity could well be a characteristic feature of
      this form of diabetes.

PMID- 12488962
TI  - Identification of three new mutations of the HNF-1 alpha gene in Japanese MODY
      families.
AB  - AIM/HYPOTHESIS: We analysed Japanese MODY patients for mutations in the HNF-1
      alpha gene. METHODS: Fifty unrelated Japanese patients with early-onset diabetes
      (diagnosed at 25 years of age or younger) or with a strong family history of
      diabetes were screened for mutations in the HNF-1 alpha gene. Functional studies
      of the mutant HNF-1alpha were carried out. RESULTS: We identified three new
      mutations in the HNF-1 alpha gene in the families with a strong family history
      for diabetes. One mutation (L518P519fsTCC --> A) was identified in three
      unrelated families, while the other two mutations (T521I and V617I) were
      identified in one family. We also identified the A site of the promoter (+102G-to
      C), which was reported previously. We examined the functional properties of the
      mutant HNF-1alpha. By increasing the amount of L518P519fsTCC-->A-HNF-1alpha,
      increasing inhibition of the transcription of human transthyretin (TTR) was
      observed (up to 61% of the control). Increasing amounts of T521I-HNF-1alpha or
      V617I-HNF-1alpha mutant proteins increased TTR promoter transcription up to 4.3
      fold and 2.4-fold, respectively, whereas both increased transcription up to 12.4
      fold of the control. CONCLUSION/INTERPRETATION: The L518P519fsTCC --> A was
      identified for the first time and this mutation might be a common cause of
      Japanese MODY3 in Okinawa area. In addition, both the T521I and V617I mutations
      were present in two patients in the same family. Since the prevalence of these
      mutations is relatively high (10%, 5/50), the HNF-1 alpha gene needs to be
      screened for mutations in patients either with early-onset diabetes or with a
      strong family history for diabetes.

PMID- 12488964
TI  - Patient education - evaluation of a complex intervention.
AB  - Diabetes education or self-management programmes are complex interventions. Their
      evaluation is difficult because of problems in identifying and separately
      assessing the effect of the various components of the intervention. A phased
      approach defining sequential stages of a continuum of increasing evidence has
      been proposed as a framework for the design and evaluation of such complex
      interventions. As an example we present the available evidence for diabetes
      treatment and teaching programmes implemented in Germany. Evidence is compiled
      for structured group treatment and teaching programmes for Type I diabetes, non
      insulin dependent Type II diabetes, and hypertension according to the following
      sequential stages of increasing evidence: (i) preclinical or theoretical phase;
      (ii) modelling the components of the intervention; (iii) exploratory trials; (iv)
      randomized controlled trials; (v) phase of implementation including replication
      and transfer to different settings. Evidence for most of these phases has been
      generated for the three programmes, although individual studies do not fulfill
      all important quality criteria by today's standards. The time span for gathering
      the evidence from the theoretical phase to surveillance after implementation was
      about 20 years. It can only be speculated which parts of the programmes are the
      most active ones. The presentation of a continuum of increasing evidence for
      diabetes education or self-management programmes could provide useful information
      for the appraisal of such complex interventions. Since this evidence cannot be
      readily extracted from databases we suggest that other research groups present
      their data in a similar way.

PMID- 12488963
TI  - Severe clinical onset of diabetes and increased prevalence of other autoimmune
      diseases in children with coeliac disease diagnosed before diabetes mellitus.
AB  - AIMS/HYPOTHESIS: To analyse whether the time of diagnosis of coeliac disease with
      respect to the clinical onset of diabetes could differentiate subgroups of
      varying severity in patients with both diseases. METHODS: We investigated 383
      patients with Type I (insulin-dependent) diabetes mellitus for coeliac disease.
      Sex distribution, age at diagnosis of diabetes, prevalence of ketoacidosis at the
      onset of diabetes and prevalence of other autoimmune diseases were compared in
      patients. We divided these patients according to whether coeliac disease was
      diagnosed before (Group A, n=8) or after (Group B, n=24) diabetes onset and
      whether they had presented clinical symptoms of coeliac disease. Group C (n=351)
      included diabetic patients without coeliac disease. RESULTS: Out of 383 Type I
      diabetic patients we found 32 coeliac subjects (8.3%). There was a higher number
      of girls (p=0.003), but similar age and prevalence of ketoacidosis compared with
      Group C; 18.7% had a third autoimmune disorder. The higher number of girls was
      confirmed in Groups A and B in comparison to Group C (p=0.013), while higher
      prevalence of both ketoacidosis (p=0.009) and other autoimmune diseases (p=0.001)
      was found only in Group A. Compared with symptomatic patients, asymptomatic
      subjects in Group B had a lower number of girls, older age at diabetes onset,
      lower prevalence of ketoacidosis and no other associated autoimmune disease.
      CONCLUSIONS/INTERPRETATION: A wide clinical spectrum characterises the
      association of coeliac disease and diabetes mellitus, with a severe clinical
      presentation (higher prevalence of ketoacidosis at the onset and occurrence of
      other autoimmune diseases) when coeliac disease is diagnosed before diabetes.
      Distinct phenotypes might imply the contribution of a peculiar genetic
      background.

PMID- 12488966
TI  - Association of the implementation of PACS with hospital revenue.
AB  - The purpose of this study is to assess the association of implementation of PACS
      with the inpatient and outpatient revenue of a general hospital. The authors
      analyzed the in- and outpatient revenue data of all general hospitals (212) in
      South Korea obtained from the Korean National Health Insurance Corporation
      (KNHIC) during the period from 1996 through 1999 using the mixed model for
      repeated measure data. The following variables were used in the analysis: status
      of picture archiving and communication systems (PACS) implementation, population
      size, state of competition, inhabitant's income, hospital location, hospital
      size, whether a tertiary hospital, whether public or private, the effect of year.
      The revenues from both in- and outpatient departments were significantly higher
      one year after the introduction of PACS while controlling for the confounding
      variables. Although the causality needs to be clarified, the implementation of
      PACS was correlated significantly to the increased amount of inpatient and
      outpatient revenue.

PMID- 12488967
TI  - Species-specific pheromonal compounds induce distinct conformational changes of
      pheromone binding protein subtypes from Antheraea polyphemus.
AB  - We have investigated the structural features of three pheromone binding protein
      (PBP) subtypes from Antheraea polyphemus and monitored possible changes induced
      upon interaction with the Antheraea pheromonal compounds 4E,9Z-14:Ac [(E4,Z9)
      tetradecadienyl-1-acetate], 6E,11Z-16:Ac [(E6,Z11)-hexadecadienyl-1-acetate], and
      6E,11Z-16:Al [(E6,Z11)-hexadecadienal]. Circular dichroism and second derivative
      UV-difference spectroscopy data demonstrate that the structure of subtype PBP1
      significantly changes upon binding of 4E,9Z-14:Ac. The related 6E,11Z-16:Ac was
      less effective and 6E,11Z-16:Al showed only a small effect. In contrast, in
      subtype PBP2 pronounced structural changes were only induced by the 6E,11Z-16:Al,
      and the subtype PBP3 did not show any considerable changes in response to the
      pheromonal compounds. The UV-spectroscopic data suggest that histidine residues
      are likely to be involved in the ligand-induced structural changes of the
      proteins, and this notion was confirmed by site-directed mutagenesis experiments.
      These results demonstrate that appropriate ligands induce structural changes in
      PBPs and provide evidence for ligand specificity of these proteins.

PMID- 12488968
TI  - Thoracic leg motoneurons in the isolated CNS of adult Manduca produce patterned
      activity in response to pilocarpine, which is distinct from that produced in
      larvae.
AB  - In the hawkmoth, Manduca sexta, thoracic leg motoneurons survive the degeneration
      of the larval leg muscles to innervate new muscles of the adult legs. The same
      motoneurons, therefore, participate in the very different modes of terrestrial
      locomotion that are used by larvae (crawling) and adults (walking). Consequently,
      changes in locomotor behavior may reflect changes in both the CNS and periphery.
      The present study was undertaken to determine whether motor patterns produced by
      the isolated CNS of adult Manduca, in the absence of sensory feedback, would
      resemble adult specific patterns of coordination. Pilocarpine, which evokes a
      fictive crawling motor pattern from the isolated larval CNS, also evoked robust
      patterned activity from leg motoneurons in the isolated adult CNS. As in the
      larva, levator and depressor motoneurons innervating the same leg were active in
      antiphase. Unlike fictive crawling, however, bursts of activity in levator or
      depressor motoneurons of one leg alternated with bursts in the homologous
      motoneurons innervating the opposite leg of the same segment and the leg on the
      same side in the adjacent segment. The most common mode of intersegmental
      activity generated by the isolated adult CNS resembled an alternating tripod
      gait, which is displayed, albeit infrequently, during walking in intact adult
      Manduca. A detailed analysis revealed specific differences between the patterned
      motor activity that is evoked from the isolated adult CNS and activity patterns
      observed during walking in intact animals, perhaps indicating an important role
      for sensory feedback. Nevertheless, the basic similarity to adult walking and
      clear distinctions from the larval fictive crawling pattern suggest that changes
      within the CNS contribute to alterations in locomotor activity during
      metamorphosis.

PMID- 12488969
TI  - Ultrastructure of electrical synapses between nociceptive and anterior pagoda
      neurons in the CNS of the leech (Whitmania pigra).
AB  - We have used electron microscopy to measure quantitatively the morphology of
      electrical synapses in a circuit that has been proposed to account for the
      positional discrimination of the leech. Injection of a presynaptic nociceptive
      sensory neuron and the postsynaptic anterior pagoda neuron with HRP showed gap
      junctions in the neuropil. After double labeling, La(3+)-treated ganglia revealed
      labeled gap junctions from 2.0 to 3.5 nm wide. Between the labeled axon
      terminals, there were innexons with diameters of 8 to 10 nm. The innexon's
      central pore diameter was 2 nm, and the mean of the center-to-center distance
      between two innexons was 30 nm. Except for the gap junction areas of nociceptive
      sensory neuron axon terminals, the other ultrastructural parameters measured by
      freeze fracture were similar to those of samples labeled with HRP and filled with
      La(3+). These data suggested that the gap width, innexon diameter, and its
      central pore do not on their own account for the mechanism of positional
      discrimination, which may depend rather on the differences in distribution and
      number of gap junctions.

PMID- 12488970
TI  - Ingestion motor programs of Aplysia are modulated by short-term synaptic
      enhancement in cerebral-buccal interneuron pathways.
AB  - In the sea slug Aplysia, buccal synapses of cerebral-buccal interneurons (CBIs)
      CBI-2 and CBI-12 exhibit short-term synaptic enhancement (STE), including
      frequency-dependent facilitation and augmentation/post-tetanic potentiation
      (AUG/PTP). The STE that results from driving CBI-2 or CBI-12 is associated with
      significantly decreased latency to burst onset in buccal premotor neurons and
      motor neurons, increased cycle frequency of ingestion buccal motor programs
      (iBMPs) and increased intraburst firing frequency of buccal neurons during iBMPs.
      Tests of paired-pulse facilitation during AUG/PTP suggest that the locus for this
      plasticity is presynaptic. The AUG/PTP is not elicited by heterosynaptic
      pathways, indicating that its origin is homosynaptic. At low CBI-2 and CBI-12
      firing frequencies, STE is likely to contribute to iBMP initiation, while at
      higher firing frequencies, STE is correlated with increased cycle frequency of
      iBMPs. Thus, STE is an important component of the mechanisms whereby cerebral
      neurons regulate cyclic feeding programs and likely contributes to observed
      variations in behavioral responses, including feeding arousal.

PMID- 12488971
TI  - Recombinant aequorin as a reporter for receptor-mediated changes of intracellular
      Ca2+ -levels in Drosophila S2 cells.
AB  - The bioluminescent Ca(2+)-sensitive reporter protein, aequorin, was employed to
      develop an insect cell-based functional assay system for monitoring receptor
      mediated changes of intracellular Ca(2)(+)-concentrations. Drosophila Schneider 2
      (S2) cells were genetically engineered to stably express both apoaequorin and the
      insect tachykinin-related peptide receptor, STKR. Lom-TK III, an STKR agonist,
      was shown to elicit concentration-dependent bioluminescent responses in these S2
      STKR-Aeq cells. The EC(50) value for the calcium effect detected by means of
      aequorin appeared to be nearly identical to the one that was measured by means of
      Fura-2, a fluorescent Ca(2)(+)-indicator. In addition, this aequorin-based method
      was also utilised to study receptor antagonists. Experimental analysis of the
      effects exerted by spantide I, II and III, three potent substance P antagonists,
      on Lom-TK III-stimulated S2-STKR-Aeq cells showed that these compounds antagonise
      STKR-mediated responses in a concentration-dependent manner. The rank order of
      inhibitory potencies was spantide III > spantide II > spantide I.

PMID- 12488972
TI  - Developmental regulation of alternative exon usage in the house fly Vssc1 sodium
      channel gene.
AB  - Sequence analysis of cDNA clones amplified by PCR from house fly ( Musca
      domestica L.) Vssc1 voltage-sensitive sodium channel alpha subunit transcript
      templates identified 11 putative alternatively spliced exons. Nine of these
      corresponded to the 7 optional exons (designated a, b, e, f, h, i, and j) and 2
      mutually exclusive exons (designated c/d) identified previously in the
      orthologous para sodium channel alpha subunit genes of Drosophila melanogaster
      and Drosophila virilis, whereas two segments represented new mutually exclusive
      exons in Vssc1 (designated k/l) located in a region not previously identified as
      a site of alternative splicing in para. Diagnostic PCR assays on individual Vssc1
      cDNA templates detected the presence or absence of each putative alternative exon
      in multiple partial cDNAs (42-96 individual clones per cDNA pool) from newly
      emerged first instar larvae, pupae, day 1 adult heads, and day 1 adult bodies.
      Exons h and i were present in all cDNA clones from all developmental stages. Exon
      d was also present in all clones from all developmental stages that encoded full
      length amino acid sequences; however, 1 of 42 clones from adult head contained an
      exon c-like segment in which the coding sequence was terminated by a premature
      stop codon. In contrast, the frequencies of exons a, b, e, f, j, k, and l
      differed between developmental stages and adult anatomical regions. Analysis of
      the Vssc1 region containing alternative exons a, b, c/d, e, f, h, and i as a
      single amplified cDNA segment identified nine Vssc1 splice variants involving
      these exons. The splice variant containing exons a, d, h, and i was the most
      abundant form in all cDNA pools examined, but the observed patterns of splice
      variant expression were specific to each developmental stage and adult anatomical
      region. Our results document the strong conservation of alternative exon location
      and structure between the Vssc1 gene of the house fly and the para gene of D.
      melanogaster but identify marked differences in exon usage between these species.

PMID- 12488973
TI  - Lead toxicity, locomotion and feeding in the freshwater snail, Lymnaea stagnalis
      (L.).
AB  - The effects of lead (5 or 10 ppm) on the survival of the freshwater snail Lymnaea
      stagnalis (L.) collected from lead contaminated or uncontaminated environments
      were evaluated under controlled laboratory conditions. The animals from the
      contaminated environment had significantly greater survivability than those from
      the unpolluted environment to subsequent acute (up to 24 days) exposure to lead.
      Acute (72 h) exposure to lead inhibited several behavioural activities including
      locomotion, feeding, tentacle extension and emergence from the shell. Lead
      bioaccumulated in the snail tissues, especially the buccal mass and stomach. The
      freshwater snail provides a valuable system for studying the bioaccumulation and
      development of tolerance to environmental lead.

PMID- 12488974
TI  - Arterial cells and CNS sheath cells from Aplysia californica produce factors that
      enhance neurite outgrowth in co-cultured neurons.
AB  - Substrate-bound and soluble factors regulate neurite outgrowth and synapse
      formation during development, regeneration, and learning and memory. We report
      that sheath cells from CNS connectives and arterial cells from the anterior aorta
      of the sea slug, Aplysia californica, enhance neurite outgrowth from co-cultured
      Aplysia neurons. Sheath and arterial cell cultures contain several cell types,
      including fibrocytes, myocytes, and amoebocytes. When compared to controls
      (neurons with defined growth medium alone), the percentage of neurons with growth
      and the average neurite lengths are significantly enhanced by sheath and arterial
      cells at 48 h after plating of the neurons; these parameters are comparable to
      those of neurons cultured in medium containing hemolymph. Our results indicate
      that sheath cells produce substrate-bound factor(s) and arterial cells produce
      diffusible factor(s) that promote growth. These growth factors likely promote
      neuron survival and neurite outgrowth during neural plasticity exhibited in the
      adult CNS.

PMID- 12488975
TI  - Evidence against the presence of NMDA receptors at a central glutamatergic
      synapse in leeches.
AB  - The N-methyl- D-aspartate (NMDA) receptor, able to detect the coincidence of pre-
      and postsynaptic events, is considered to be the molecular analogue of
      associative learning. Associative learning is well known in leeches, particularly
      for reflexive shortening. The neuronal circuits underlying shortening have been
      documented and include neurons that release glutamate. Is this type of learning
      in leeches also mediated by NMDA receptors? The synapse between the P sensory
      neuron and the motoneuron-like AP cell was examined and: (1) NMDA failed to
      elicit a response in the AP cell, (2) the NMDA receptor antagonist 2-amino-5
      phosphopentanoic acid affected synaptic transmission only at high, non-specific
      levels, and (3) the antagonist for the glycine-binding site 7-chloro-kynurenic
      acid at 20 microM did not inhibit transmission. Therefore, there are evidently no
      NMDA receptors at the P to AP synapse, suggesting other mechanisms of associative
      learning in leeches.

PMID- 12488976
TI  - The anatomy of the nervous system of the hydrozoan jellyfish, Polyorchis
      penicillatus, as revealed by a monoclonal antibody.
AB  - Dissociated cells from the margin and tentacles of the hydromedusa Polyorchis
      penicillatus were centrifuged in a Percoll gradient to remove cnidocytes. The
      resulting formaldehyde-fixed cells were used to inoculate mice to produce
      monoclonal antibodies. One of the hybridomas, which secreted antibodies against
      all neurons, was cloned and designated as mAb 5C6. Immunohistochemical labelling
      with mAb 5C6 of whole-mount preparations and paraffin sections provided a far
      more complete picture of the organisation of the hydromedusan nervous system than
      was previously available when using neuronal labelling techniques that restrict
      labelling to certain neuronal types. Besides confirming anatomical features
      described in earlier studies these techniques allowed us to discover a number of
      new structures and to determine connections that were only suspected. Such
      findings included:1. The discovery of an arch-like connection between the
      swimming motor neuron network at the apices of the subumbrellar muscle sheets 2.
      An orthogonal network connecting each pair of radial nerves in each radius 3.
      Continuity of a central branch of the radial nerve with the radial innervation of
      the manubrium 4. Details of the sensory neuronal contribution to the microanatomy
      of the ocelli and cnidocyte batteries 5. Presence of specialised receptor cells
      in the margin at the bases of tentacles 6. Neurons apparently innervating the
      radial muscles of the velum 7. Isolated neurons in the peduncle and gonads

PMID- 12488977
TI  - Synaptic differentiation between two phasic motoneurons to a crayfish fast
      muscle.
AB  - Synaptic differentiation among crustacean phasic motoneurons was investigated by
      characterizing the synaptic output and nerve terminal morphology of the two axons
      to the adductor exopodite muscle in the crayfish uropod. The muscle is of the
      fast type with short sarcomeres (2-3 micro m) and a low thin to thick filament
      number (6:1). On single muscle fibers, excitatory postsynaptic potentials
      generated by the large-diameter axon are significantly larger than those by the
      small-diameter axon suggesting a presynaptic origin for these differences. Nerve
      terminals arising from these two axons have typical phasic features, filiform
      shape and a low (6-8%) mitochondrial density. Synaptic contacts are similar in
      size between the two axons as is the length and number of active zone dense bars
      at these synapses. The large-diameter axon, however, exhibits a twofold larger
      area of nerve terminal than the small-diameter axon resulting in a higher density
      of synapses per muscle fiber. Hence, differences in synaptic density may in part
      account for differences in synaptic output between these paired phasic axons.

PMID- 12488978
TI  - DSC1 channels are expressed in both the central and the peripheral nervous system
      of adult Drosophila melanogaster.
AB  - DSC1 encodes a putative voltage-sensitive sodium channel alpha subunit in
      Drosophila melanogaster. We generated polyclonal antibodies raised against part
      of the DSC1 sequence to characterize the size and the distribution of these
      channels in the adult fly. Immunoblotting experiments indicated that the protein
      has a molecular weight of about 270 kDa. We also showed that DSC1 channels are
      found only in the neurons of the fly. The density of channels was high in
      synaptic regions and in most of the axonal processes that connect the various
      structures of the CNS. No signal was observed in the cortical cell bodies where
      the para channels are mainly present. The most striking result concerns the
      widespread distribution of DSC1 channels in the PNS, as confirmed by experiments
      done with the monoclonal antibody 22C10. These results strongly suggest that DSC1
      and para channels may have complementary roles, at least in the adult stage.

PMID- 12488979
TI  - Distribution and partial characterization of CREB-like immunoreactivity in the
      medicinal leech Hirudo.
AB  - The presence and distribution of immunoreactivity to the cyclic AMP response
      element binding protein (CREB) were determined in the central nervous system
      (CNS) and in peripheral tissues of the medicinal leech Hirudo. Western blots
      revealed several CREB-immunoreactive (CREB-IR) bands including one whose
      molecular weight (43-44 kDa) was similar to mammalian CREB. The 43-44 kDa CREB
      like protein was detected in nuclear extracts of the ventral nerve cord and was
      not observed following preincubation of the primary antiserum with the epitope
      sequence. CREB-like immunoreactivity was detected in extracts from each of six
      regions of the leech CNS, and in extracts from leech body wall musculature, crop,
      intestine, jaw musculature, pharynx, and salivary tissues. Whole mounts of leech
      ganglia revealed specific CREB-IR in a restricted population of neurons
      distributed throughout the leech CNS. Apparent homologues to a pair of CREB-IR
      dorsolateral neurons were observed in most ganglia along the ventral nerve cord.
      Several CREB-IR neurons exhibited segmental specificity. A number of neurons
      stained with an antiserum to the cyclic AMP response element modulator (CREM).
      These neurons showed no overlap in location with CREB-IR neurons, and this
      staining was not eliminated with a preabsorption control. Possible roles for a
      CREB-like protein in the leech are discussed.

PMID- 12488980
TI  - Neuronal and non-neuronal responses to nerve crush in a pulmonate snail, Melampus
      bidentatus.
AB  - Immunohistochemical and ultrastructural techniques were used to study sequelae of
      nerve injury in the pulmonate snail Melampus bidentatus. Either pedal or tentacle
      nerves were crushed, severing all axons, and recovery was monitored over 15 days.
      The axons regenerated from the segment attached to the soma, with no evidence of
      fusion of proximal and distal segments. The medium to large axons of central
      neurons, including those monitored with serotonin immunohistochemistry, grow
      distally across the path of smaller axons extending centrally from peripheral
      somata. The regions into which the growing axons projected were a focus of
      phagocytic activity. Cells previously labeled by PKH-26PCL, a fluorescent marker
      for phagocytic activity, were attracted to the crushed nerve within 6 h and were
      a consistent feature in the vicinity of the injury for at least 9 days, gradually
      extending their range as repair progressed in both directions from the crush.
      Repair proceeded within an intact sheath, and many sheath cells survived the
      crush, although the nuclear dye Hoechst 33258 revealed an initial distortion of
      their nuclei. The concentration of cells in the sheath in the crushed region
      increases after the crush, with the packing of nuclei peaking at 3 days and
      gradually returning to control conditions; this probably reflects migration of
      resident sheath cells. Cell division is rare in the sheath of intact nerves, but
      labeling with bromodeoxyuridine increases at the crush site between 4 and 9 days,
      indicating that cell replacement also occurs at the site.

PMID- 12488981
TI  - Secretory component, J chain, and immunoglobulins in human embryos and fetuses of
      the first trimester of pregnancy: immunohistochemical study.
AB  - In our previous studies, we described the development of the secretory (mucosal)
      immune system (SIS) in human fetuses in the second trimester of pregnancy. In the
      present study, we examined the presence and distribution of components of this
      system in human embryos and early fetuses in the first trimester. An
      immunohistochemical study was performed on 17 embryos and 9 fetuses (4 to 12 wk
      of development) using antibodies against secretory component (SC), joining (J)
      chain, immunoglobulins (IgA, IgM, IgG), subsets of T and B lymphocytes, and
      macrophages. Cells positive for SC, J chain, and IgG were found in epithelial
      tissues from wk 4 of pregnancy. In the internal organs, such as the myocardium
      and endocardium, capillary endothelium, epithelium of the kidney tubules and some
      others, only J chain and immunoglobulins were seen. IgA was weakly reactive in
      tissues where SC and/or J chain were presented. IgM was very weak or absent.
      Among the cellular components of the SIS, only macrophages were seen in 4-wk-old
      embryos. CD3+ and CD20+ lymphocytes were found at wk 7 to 8. IgA- and IgM
      positive lymphocytes appeared at the end of wk 9. The SIS is widespread in
      embryonic and early fetal periods and begins to function before the appearance of
      the common immune system in the developing organism. The first functional
      components of the SIS, such as IgG and IgA observed in this study, are most
      probably of maternal origin.

PMID- 12488982
TI  - Podocytes, parietal cells, and glomerular pathology: the role of cell cycle
      proteins.
AB  - Podocytes are highly differentiated cells that play a central role in glomerular
      function. Cell cycle quiescence sustained by the tight regulation of cell cycle
      molecules seems to be the basis of podocyte differentiation, as reflected in
      reciprocal expression of cyclins and cyclin kinase inhibitors (CKIs) during
      glomerulogenesis, concurrent with the expression of podocyte-specific markers. In
      addition, cell cycle re-entry by podocytes, accompanied by down-regulation of
      CKIs, leads to either nuclear division without cytokinesis or to marked cell
      proliferation, both of which result in heavy proteinuria and progressive
      glomerulosclerosis. These observations suggest that proper cell cycle regulation
      in podocytes is pivotal for their role in glomerular function and that
      dysregulation of this system plays a role in glomerular pathology. This review
      discusses the role of cell cycle molecules in the differentiation, function, and
      pathology of podocytes.

PMID- 12488983
TI  - Embryonal hyperplasia of Bowman's capsular epithelium in patients with WT1
      mutations.
AB  - Embryonal hyperplasia of Bowman's capsular epithelium (EHBCE) is a rare
      condition, observed in patients with end-stage renal disease when treated with
      long-term dialysis. Immunohistochemical studies have suggested that EHBCE
      originates from the visceral epithelium of the Bowman's capsule. Here we report
      two patients with WT1 missense mutations in exon 7, who received continuous
      ambulatory peritoneal dialysis and developed EHBCE without Wilms tumor. One
      patient showed manifestations of Denys-Drash syndrome (DDS), while the other
      patient exhibited rapid progress into end-stage renal disease, but no
      genitourinary anomaly. Recently, abnormal expression of WT1 and PAX2 was shown in
      the podocytes in diffuse mesangial sclerosis (DMS) associated with DDS and
      isolated DMS. We hypothesize that EHBCE is a reversion of Bowman's capsular
      epithelial cells to an earlier cell differentiation state, which has the
      characteristics of a progenitor cell of both Bowman's capsular epithelia and
      podocytes. Immunohistochemical analysis of WT1, PAX2, vimentin, cytokeratin, and
      epithelial membrane antigen was performed in the kidney specimens obtained at
      autopsy or surgery. Abnormal expression of WT1 and PAX2 in the EHBCE was observed
      in both patients, supporting our hypothesis. The nephropathy associated with
      constitutional WT1 mutations might therefore be associated with EHBCE.

PMID- 12488984
TI  - What is biparietal diameter/kidney length ratio in cases with renal
      hyperechogenicity?
AB  - The object of this study was to investigate the fetal biparietal diameter/kidney
      length ratio in normal and hyperechogenic kidneys during the 3rd trimester of
      gestation. Screened pregnancies were chronically hypoxic [i.e. intrauterine
      growth retardation (IUGR)]. Depending on the renal manifestation of the
      intrauterine chronic hypoxia, the cases were divided into two study groups. Group
      I was composed of 28 fetuses with IUGR and hyperechogenic renal medullae. Group
      II consisted of 62 fetuses with IUGR and normal echoic kidney. Both study groups
      included pregnant women from the 3rd trimester. Fetal renal hyperechogenicity is
      an indicator of depression of fetal renal perfusion, correlated with pathological
      growth in the fetal kidney development. The fetal biparietal diameter/kidney
      length ratio was significantly higher in hyperechogenic cases. This may also be
      an in utero indicator of subsequent intrauterine and neonatal complications.
      Detailed ultrasound examinations of renal parenchyma and length appear to be
      useful in the prenatal diagnosis of reduced renal perfusion and of intrauterine
      hypoxia, allowing detection of possible pathological fetal conditions in utero.

PMID- 12488985
TI  - Cystosonography and voiding cystourethrography in the diagnosis of vesicoureteral
      reflux.
AB  - The availability of US (ultrasonography) contrast media in the last few years has
      prompted investigation into their use in the diagnosis of vesicoureteral reflux
      (VUR) in children, a common cause of urinary tract infections (UTI) or
      pyelonephritis. We performed voiding cystourethrography (VCUG) and
      cystosonography (CSG) in the same session in 158 children (M/F 97/61, mean age
      3.9 years, age range 0.1-12.7 years) with clinical suspicion of VUR, studied over
      a year with an ATL plus 3000 real-time scanner (ATL Ultrasound, Bothell, USA),
      equipped with 2- to 4- and 4- to 7-MHz convex transducers. US contrast medium
      Levovist (Schering, Berlin, Germany) was used. VCUG and CSG diagnosed 74 (24.2%)
      and 77 (25.2%) cases of VUR, respectively. There was no agreement in 67 cases
      (22%). The percentage of false negatives was similar and high with both
      techniques. CSG seems to be more sensitive in detecting intermediate (second- and
      third-degree) VUR. In spite of the moderate relative diagnostic adequacy of both
      methods, we believe that CSG is an alternative to VCUG, avoiding the risk of
      ionizing radiation, in the following conditions: (1) first diagnosis in females
      (not in males, due to the poor vesical and urethral anatomical detail it
      provides), (2) VUR follow-up, (3) VUR diagnosis in megaureters and/or in
      ureteroceles, and (4) VUR diagnosis in transplanted kidneys. Further improvements
      of CSG, both in US contrast media and in US technique, could possibly increase
      its sensitivity.

PMID- 12488986
TI  - Hepatitis-B virus associated nephropathies: a clinicopathological study in 14
      children.
AB  - Hepatitis B virus (HBV)-associated glomerulonephritides have been increasingly
      reported, and the association between HBV and glomerulopathy is striking,
      especially in children. In this study, we investigated clinical and
      immunohistological features of HBV-associated glomerulonephritis in 14 children
      aged from 2.5 to 16 years (mean 10 years). The nephrotic syndrome was present in
      9 (64%) and the nephritic syndrome in 8 children (57%). Five children had both
      nephrotic and nephritic syndrome together (35%). Renal insufficiency was
      determined in 4 of 14 patients (28%). Surface antigen (HBsAg) was present in all,
      with no history of clinically apparent hepatitis. Investigation of all renal
      tissue samples with light and immunofluorescence microscopy confirmed the
      diagnosis of membranous glomerulonephritis (MGN) in 6, membranoproliferative
      glomerulonephritis (MPGN) in 7, and IgA nephropathy (IgAN) in 1 child. Renal
      tissue samples were studied by the immunoperoxidase method for HBsAg in all
      cases; only in 4 children was HBsAg detected in the glomeruli. Examination of
      liver tissue samples was available in 4 cases, revealing chronic hepatitis in
      all, with additional development of cirrhosis in 1 and the presence of HBsAg in
      hepatocytes in all. Of the patients, 8 received corticosteroid treatment; 1 of
      them achieved a complete remission, while 4 had a partial remission with
      persistent proteinuria and hematuria. Four patients who received no treatment had
      a spontaneous remission within 5 months to 10 years following the onset of the
      renal disease. Two patients died of renal failure, while 1 died of intercurrent
      sepsis. The patient with IgAN received interferon-alpha 2a and lamuvidine, which
      resulted in a remission and a marked decrease in HBV DNA titer. The remaining 2
      were lost to follow-up. Although MGN has been reported as the nephropathy most
      commonly associated with HBsAg antigenemia in adults, our study revealed that
      MPGN could occur in children as well as MGN, without any clinical or historical
      evidence of hepatitis. The present study provides further evidence for a causal
      relationship between HBV hepatitis and HBs antigenemia-related
      glomerulonephritides in the pediatric age group. It also indicates the prognosis
      (71%) of the associated nephropathies with or without treatment is quite
      favorable in childhood.

PMID- 12488987
TI  - Continuous venovenous renal replacement therapy using a pulsatile blood pump.
AB  - The objective of this study was to evaluate the efficacy of a pulsatile pump for
      continuous renal replacement therapy in a pediatric-size animal model. A vacuum
      driven, tubular, blood-pumping device was used in 13 pigs weighing 10.4+/-1.5 kg,
      connected to a neonatal hemofiltration circuit with an FH22 filter and a flow
      sensor. Three different flow rates [30 ml/min (8 cases), 15 ml/min (3 cases), and
      5 ml/min (2 cases] were used over 2-h periods. Aspiration pressure, frequency of
      pulsation, blood flow rate, ultrafiltrate volume, pre- and post-filter pressures,
      heart rate, arterial blood pressure, temperature, pH, sodium, potassium,
      chloride, urea, creatinine, glucose, and hematocrit were measured at 30-min
      intervals. The mean ultrafiltrate flow was 0.54+/-0.33 ml/kg per min. The
      aspiration pressure and pulsation frequency needed to maintain blood flow
      remained stable throughout the experiment. There were no complications secondary
      to the use of this technique and no significant changes in heart rate, blood
      pressure, or analytical determinations. In conclusion, in this animal model, the
      pulsatile pump has been shown to be an effective method for continuous venovenous
      renal replacement therapy.

PMID- 12488988
TI  - Varicella vaccination in children with chronic renal failure. A report of the
      Southwest Pediatric Nephrology Study Group.
AB  - Children with kidney disease are at risk for serious varicella-related
      complications. To evaluate the safety and immunogenicity of a two-dose regimen of
      varicella vaccine in children (aged 1-19 years) with chronic renal insufficiency
      and on dialysis, the Southwest Pediatric Nephrology Study Group (SPNSG) undertook
      an open-label, multi-center, prospective 3-year clinical trial. Ninety-six
      patients without history of varicella were enrolled. Fifty (mean age 4.2 years)
      had no detectable varicella zoster virus (VZV) antibody; 98% seroconverted after
      the two-dose regimen. At 1, 2, and 3 years' follow-up, all patients studied
      maintained VZV antibody, including 16 who received a transplant. No significant
      vaccine-associated adverse events were seen. One subject developed mild varicella
      (10-50 maculopapular lesions) 16 months post transplant. In multivariate
      regression analysis, patients vaccinated after age 6 years had VZV antibody
      levels 73% (95% confidence interval 33%-89%) lower than patients vaccinated
      before age 6 years after controlling for gender, estimated glomerular filtration
      rate, and dialysis treatment. Adjusted analysis also showed that VZV antibody
      levels were lower after kidney transplantation, but this appeared to be a
      transient phenomenon. In this study, varicella vaccination with a two-dose
      regimen of varicella vaccine was generally well tolerated and highly immunogenic
      in children with chronic kidney disease.

PMID- 12488989
TI  - Oral health in children with chronic renal failure.
AB  - Seventy children with chronic renal failure (CRF) aged 4-13.6 years were
      recruited from the Renal Unit of the Great Ormond Street Hospital for Children.
      Indices were recorded for dental caries, dental plaque, gingival inflammation,
      gingival enlargement, and enamel defects. Salivary urea, buffering capacity, and
      the oral streptococcal flora were determined for 25 of the children. A
      significantly greater proportion of the CRF children was caries free, 40%
      compared with 8.5% of the controls. The mean plaque score was significantly
      greater in the CRF group for both the primary 12.7 (16) and permanent dentition
      22.0 (18.2) compared with the controls, 5.3 (7.6) and 15.5 (13.3), respectively.
      Eight CRF children had gingival enlargement. Enamel defects affecting the
      permanent teeth were observed in 57% of the CRF children compared with 33% of the
      controls. The buffering capacity was significantly greater in the CRF group, pH
      6.4 (0.5) compared with the controls pH 5.6 (0.8). The mean salivary urea level
      (mmol/l) was significantly greater in the CRF children, 11.6 (5.9) compared with
      3.6 (1.4) for the controls. The isolation frequency of Streptococcus mutans was
      significantly greater from controls compared with the CRF children ( P=0.002). An
      integrated dental service needs to be developed with emphasis on tooth brushing
      to prevent gingival hyperplasia and periodontal disease after puberty.

PMID- 12488990
TI  - Renal function and effect of aminoglycoside therapy during the first ten days of
      life.
AB  - The effect of aminoglycoside administration on kidney functional maturation was
      evaluated in groups of 30 preterm and 30 fullterm infants who were treated for 7
      days because of suspected infection. One of three different aminoglycosides was
      administered to each subgroup of ten preterm and ten fullterm infants. Changes in
      tubular function in groups of ten preterm and ten fullterm infants who were not
      given antibiotics were also compared. The mean gestational age for preterm
      infants from 32.5 to 33.6 weeks and for fullterm infants between 39.2 and 39.5
      weeks. The renal tubular function was assessed by examining the fractional
      excretion of sodium (FENa), potassium (FEK), phosphorus (FEP), magnesium (FEMg)
      and uric acid (FEUA) as well as by the urinary excretion of calcium as the
      calcium/creatinine (UCa/UCr) ratio. Gentamicin affected the normal plasma
      creatinine (PCr) decline in both treated groups (fullterm and preterm).
      Disturbances in FENa and UCa/UCr were more pronounced in treated preterm than in
      fullterm infants especially after netilmicin and gentamicin administration. FEMg
      was significantly affected in preterm infants treated with gentamicin. The
      findings of this study indicate that the effect of aminoglycosides on tubular
      function is dependent upon kidney maturity and the type of the aminoglycoside
      used for therapy.

PMID- 12488991
TI  - Standards for renal biopsies: comparison of inpatient and day care procedures.
AB  - There are no national standards for the adequacy and complications of
      percutaneous renal biopsies. We developed local standards that have been used in
      a prospective audit of biopsies undertaken in a tertiary pediatric nephrology
      unit between January 1997 and December 2000. We compared outcomes of biopsies
      performed on inpatients with day care procedures. A total of 251 biopsies (113
      transplant) were undertaken, 114 (46%) as day care procedures. Adequate tissue
      for diagnosis was obtained in 245 (97.6%), with a standard set at >95%. This was
      also achieved for a mean number of passes in native (<3 in 80%) and transplanted
      (<2 in 80%) kidneys. Eleven patients (4%) developed macroscopic hematuria
      (standard <5%) and none required transfusion. Delay in discharge occurred in 4
      patients, and a further 4 returned to the ward post discharge. There was no
      significant difference in complication rates between inpatient and day care
      patients. Our local biopsy standards were met in this audit. Such standards could
      provide useful comparisons between units in national audit programs, as well as
      permitting the monitoring of individual performance as part of clinical
      governance. Day care procedures benefit the patient and family, as well as
      significantly reducing costs.

PMID- 12488993
TI  - Pneumothorax and transient pseudohypoaldosteronism in an infant with
      hydronephrosis.
AB  - Pneumothorax and transient pseudohypoaldosteronism have been noted as
      complications of obstructive uropathy in infancy. However, they are rare
      complications, and there have been no reports of a patient with both pneumothorax
      and pseudohypoaldosteronism in obstructive uropathy. Here we describe a case of
      pneumothorax and transient pseudohypoaldosteronism in an infant with bilateral
      hydronephrosis due to ureteropelvic junction obstruction. Nephrostomy improved
      the patient's condition and laboratory findings rapidly. While the exact
      pathogenic mechanism of pneumothorax in patients with obstructive uropathy is
      unclear, some biochemical defects due to obstructive uropathy might impair fetal
      lung maturation, which results in pneumothorax.

PMID- 12488992
TI  - Recombinant human growth hormone therapy in autosomal recessive polycystic kidney
      disease.
AB  - Patients with autosomal recessive polycystic kidney disease (ARPKD) may have
      growth retardation that is disproportionate to the degree of renal dysfunction.
      We treated growth-retarded ARPKD patients with recombinant growth hormone (rhGH)
      and document the response to therapy and effect of rhGH on the rate of
      progression of renal failure. The diagnosis of ARPKD and congenital hepatic
      fibrosis was made on the basis of clinical findings and by abdominal ultrasound
      examinations. Seventeen patients (6 girls/11 boys) aged 0.3-18.3 years were
      studied. Diagnosis was made prenatally in 6, after birth in 3, and in 8 between
      0.33 and 10 years. Follow-up was 2 months to 14.3 years (median 6.9 years).
      Growth, growth velocity, weight, and bone age were measured before and after
      treatment with rhGH. Insulin-like growth factor-1 and IGF binding protein 3 were
      measured prior to rhGH therapy. Five children (1 girl/4 boys) with height Z
      scores < or =1.2 (5/17) aged 4.5-11.9 years received rhGH therapy. Duration of
      rhGH therapy was 0.3-5.4 years. All responded to rhGH (Z-score before -2.8 vs. 
      1.26 after treatment, P=0.03). An increase in height Z-score was noted 0.5-1.5
      years after starting rhGH therapy. There were no side effects from rhGH therapy.
      The initial Z-score in the untreated group was -0.35 and the final score was 
      0.64. Initial glomerular filtration rate (GFR) in the treated group was 77 versus
      104 ml/min per 1.73 m(2) in the non-treated group. GFR in 3 of 6 growth-retarded
      patients (<5th percentile) was 38, 65, and 30 ml/min per 1.73 m(2). GFR in 2 of
      11 non-growth-retarded patients was 30 and 26 ml/min per 1.73 m(2). The change
      from initial GFR and final GFR in treated patients was 77 versus 76 ml/min per
      1.73 m(2), and non-treated patients 104 versus 89 ml/min per 1.73 m(2) ( P>0.05).
      Growth failure in ARPKD may be attributable to factors other than chronic renal
      insufficiency alone. Use of rhGH therapy in ARPKD is safe, effective, and has the
      potential to improve the physical and psychological well-being of these children.

PMID- 12488994
TI  - Fetal urinoma as a sign of a dysplastic kidney.
AB  - We describe a female neonate in whom a urinoma was first diagnosed at 20 weeks of
      gestation without any evidence of underlying urinary tract obstruction. The
      urinoma became apparent following the performance of a "bloody tap"
      amniocentesis. Sequential ultrasonography, both fetal and up to 3 months after
      birth, showed eventual resorption of the urinoma in parallel with the development
      of a shrunken, non-functioning kidney. Except for the onset of high-renin
      hypertension, which spontaneously remitted at 1 year of age, the baby's postnatal
      course was uneventful. Renal function was normal. The presence of a fetal urinoma
      as a sign of a dysplastic kidney is discussed.

PMID- 12488995
TI  - Systemic anticoagulation and bleeding in children with hemodialysis catheters.
AB  - Hemodialysis catheters are routinely flushed with high-concentration heparin
      solutions to maintain intradialytic patency. The safety of this practice has
      never been established. This report describes five patients with hemodialysis
      catheters who were found to be inadvertently systemically anticoagulated
      perioperatively and had bleeding complications. These patients all had normal
      preoperative coagulation panels drawn peripherally. Smaller children managed by
      hemodialysis may be at greater risk for systemic anticoagulation and bleeding
      than older children and adults from high-concentration heparin flush solutions,
      particularly during the perioperative period. Guidelines are presented to prevent
      hemorrhagic complications from inadvertent systemic anticoagulation.

PMID- 12488996
TI  - Laparoscopic repair of two unusual traumatic colorectal injuries.
AB  - Although the role of laparoscopy in the repair of iatrogenic colonic perforations
      in prepared bowel is well established, the use of laparoscopy as a therapeutic
      tool in the management of patients with traumatic intraabdominal injuries remains
      unclear. We report two cases of traumatic colorectal injuries that were managed
      successfully by therapeutic laparoscopy. Both patients sustained traumatic
      perforations to the large bowel as a result of unusual accidents in the home.
      Laparoscopic repair of the perforations with interrupted sutures and peritoneal
      lavage were performed with good results in both cases. We believe that the
      laparoscopic repair of traumatic colonic injuries is feasible in selected
      patients and offers a number of accepted advantages over formal laparotomy.

PMID- 12488997
TI  - Black esophagus induced by severe vomiting in a healthy young man.
AB  - Black esophagus is an uncommon entity that has been described only a few times
      previously. It is defined as a dark pigmentation of the esophagus associated with
      histologic mucosal necrosis. Most cases have no known etiology, although
      ischemia, nasogastric tube trauma, infection, gastric outlet obstruction, gastric
      volvulus, and hypersensitivity to antibiotics have all been suggested as possible
      causes. Herein we report the case of a young, healthy, athletic man who developed
      black esophagus due to severe vomiting after alcohol overindulgence and summarize
      the other published cases to date.

PMID- 12488998
TI  - Unusual course of colonic tattooing with India ink.
AB  - We here report the successful but unusual course of colonic tattooing in a
      patient with a carcinoma in situ in a polyp. A 70-year-old woman was admitted for
      persistent diarrhea, occult fecal blood, and anemia. During colonoscopy, a
      pedunculated large polyp in the sigmoid colon occluding the lumen was removed
      successfully. Histopathological examination revealed a carcinoma in situ with a
      resection of the peduncle in sano. At the second sigmoidoscopy, the polypectomy
      site was marked with India ink to facilitate the recovery of the polypectomy site
      in follow-up endoscopies. Three months later, the India ink had spread in the
      submucosal layer and a segment measuring 15 cm was colored dark blue. At the
      original polypectomy site, an uncolored flat mucosal proliferation was found
      above the dark colonic wall. After mucosectomy, the tissue was classified as
      hyperplastic. Six weeks later, a second control sigmoidoscopy did not show any
      suspicious mucosal alterations.

PMID- 12488999
TI  - Large bowel ischemia following laparoscopic inguinal hernioplasty.
AB  - The adverse physiological effects of pneumoperitoneum are well understood.
      However, the clinical implications of compromised mesenteric circulation through
      several mechanical and physiological mechanisms are not as well recognized. We
      describe a fatal case of large bowel ischemia following an elective laparoscopic
      transperitoneal inguinal hernioplasty. The patient was a 78-year-old man who died
      within 30 h after an uneventful anesthesia and laparoscopic surgery. An autopsy
      revealed thrombosis of the inferior mesenteric artery and an infrarenal aortic
      aneurysm with thrombotic plaque on its wall. We reviewed the relevant literature
      on laparoscopic procedures and mesenteric ischemia. To our knowledge, this is the
      first reported case of large bowel ischemia following pneumoperitoneum. We
      conclude that the presence of an aortic aneurysm is an added risk factor in
      laparoscopy.

PMID- 12489000
TI  - Laparoscopic resection of a retroperitoneal schwannoma.
AB  - We report a case of a successfully resected retroperitoneal benign schwannoma
      using laparoscopic surgery. A 62-year-old woman presented with an asymptomatic
      retroperitoneal mass. Computed tomography (CT) scan revealed a solid tumor
      compressing the inferior vena cava (IVC). First, we performed an intraoperative
      biopsy analysis, which revealed a benign neurologic tumor. We then proceeded with
      the complete laparoscopic resection of the tumor. Pathology revealed a benign
      schwannoma 8 x 5 cm in size. To our knowledge, only three other cases of the
      laparoscopic resection of retroperitoneal schwannoma have been reported. In our
      case, despite the large size of the tumor and the high level of compression of
      the IVC, a totally laparoscopic resection was feasible.

PMID- 12489001
TI  - Laparoscopic resection of a congenital liver cyst and simultaneous closure of a
      diaphragmatic defect in a 5-month-old infant.
AB  - Congenital liver cysts are an unusual finding and present a difficult diagnostic
      challenge. In a 5-month-old infant, routine echocardiography detected a cystic
      lesion (3 cm in diameter) just below the diaphragm. All conventional diagnostics,
      including magnetic resonance imaging (MRI), failed to clarify its etiology
      definitively. Moreover, a phrenic irregularity was suspected at the site of
      Morgagni. Finally, laparoscopy (5-mm scope and instruments) confirmed the
      diagnosis of a solitary liver cyst and a diaphragmatic defect. Using a Harmonic
      scalpel, the cyst was resected and the diaphragmatic defect was closed with
      interrupted nonabsorbable sutures. The patient's postoperative course was
      uneventful. Pathological analysis showed a true liver cyst with mesothelial
      lining and hepatic residues. Retrospective speculation suggests a common
      embryologic origin for both malformations. In conclusion, laparoscopy allowed
      final diagnosis and simultaneous treatment of an infant with the rare combination
      of a liver cyst and a diaphragmatic defect. To our knowledge, this case
      represents the first endosurgical experience of such a simultaneous procedure.

PMID- 12489002
TI  - Result of 310 consecutive patients undergoing laparoscopic Nissen fundoplication
      as hospital outpatients or at a free-standing surgery center.
AB  - Recently, several studies were published regarding the safety and feasibility of
      laparoscopic Nissen fundoplication as an outpatient procedure. However, in these
      studies the patients were discharged within 24 h and considered to be
      outpatients. In our study, the author performed 310 procedures on an outpatient
      basis at a hospital or free-standing surgery center. The study analyzed
      intraoperative complications, readmission after discharge, length of dysphagia,
      resumption of regular diet, effectiveness, and the use of antireflux medications
      after the procedure. The study concluded that with the outpatient procedure,
      there is no increase in morbidity, mortality, readmission, or long-term
      effectiveness, as compared with inpatient procedures. Outpatient laparoscopic
      Nissen fundoplication makes the procedure much more attractive to most patients.

PMID- 12489003
TI  - Laparoscopic surgery in sickle cell disease.

PMID- 12489004
TI  - Asexual multiplication of larval parasitic worms: a predictor of adult life
      history traits in Taeniidae?
AB  - The hypothesis that asexual multiplication inside the intermediate host and adult
      life-history traits within the final host are independent is tested among
      Cestoda. Using phylogenetic relationships among the Cestoda species, we can show
      that asexual multiplication appears to have been lost and recovered several times
      throughout Taeniidae evolution; this allows a comparison of the adult life
      history traits of species with and without asexual multiplication at the larval
      stage. The adult trait considered is the size of the parasite, since numerous
      life-history traits, such as fecundity and longevity, are correlated with size.
      If adult traits are independent of whether the larval stage reproduced asexually
      or not, we expect no difference in the adult size of the proliferative (i.e. with
      asexual multiplication) and non-proliferative species. The results are
      inconsistent with this hypothesis. In contrast, species with asexual
      multiplication in the intermediate host seem to have smaller adult size,
      reflecting a trade-off. We propose that ecological factors involving
      intraspecific and interspecific competition in the final host might be
      responsible for this trade-off. The role of these parameters in the evolution of
      life-history traits and more precisely in the acquisition of asexual
      multiplication is investigated with comparative analysis and discussed in the
      context of host-parasite interactions.

PMID- 12489005
TI  - A method to obtain axenic Angiostrongylus vasorum first-stage larvae from dog
      feces.
AB  - An improved method to obtain a large number of axenic larvae of Angiostrongylus
      vasorum from fecal samples was developed in the present study. The procedure here
      in reported consisted of obtaining larvae using a modified Baermann technique,
      followed by an additional filtration step. This isolation technique recovered
      almost 90% of the living larvae in a clean preparation. Isolated larvae were
      submitted to decontamination treatments with either sodium hypochlorite or
      antibiotic cocktail solutions. The axenic status, as confirmed by oral
      inoculation of decontaminated larvae into germ-free mice, was only achieved using
      larvae treated with 0.5% sodium hypochlorite solution for 10 min. The isolation
      and decontamination treatment did not affect larval viability. Treated larvae
      remained viable and infective to the invertebrate host.

PMID- 12489006
TI  - Expansion of the Asiatic parasite Ashworthius sidemi (Nematoda,
      Trichostrongylidae) in wild ruminants in Polish territory.
AB  - The abomasa of 40 wild ruminants (18 red deer, 9 roe deer, 13 European bison)
      shot in the Bieszczady Mountains and another 8 European bison shot in Bialowieza
      Primeval Forest, were examined for worms. Ashworthius sidemi was found in all of
      the animals from the Bieszczady Mountains, and the intensity of infection was
      usually massive. In Bialowieza Forest few specimens of A. sidemi were noted among
      three bison. Wild ruminants were infected by A. sidemi from June to September.
      The nematodes originating from this infection only attained sexual maturity in
      June of the following year, and from September the process of expelling the
      parasites of that generation began. From June to autumn, two generations of
      nematodes, one consisting of mature individuals from the previous year and the
      other of the current year comprising fourth stage larvae as well as juveniles,
      occur in these hosts. In the winter and spring periods until June, only one
      generation of the parasite, arrested fourth-stage larvae and juveniles, occurs in
      the hosts.

PMID- 12489007
TI  - Parasite-susceptibility phenotypes of F1 Biomphalaria glabrataprogeny derived
      from interbreeding Schistosoma mansoni-resistant and -susceptible snails.
AB  - In an effort to investigate the 'flow' of parasite-resistance genes through
      laboratory snail populations, we determined the susceptibility of progeny snails
      from freely interbreeding parasite-susceptible and parasite-resistant parents.
      Five parental populations of Biomphalaria glabrata were used to generate the
      progeny snails. Three of them contained different proportions of Schistosoma
      mansoni-susceptible albino snails (NMRI stock) and S. mansoni-resistant pigmented
      snails (BS-90), while single stock controls comprised the other two parental
      populations. F(1) snails from each parental population were exposed to S. mansoni
      miracidia. Some of the progeny snails were exposed as juveniles, others as
      adults. According to Hardy-Weinberg principle predictions, the F(1) generation
      from the three pigmented/albino parental populations displayed higher than
      expected numbers of pigmented (resistant) snails and lower than expected numbers
      of albino (susceptible) snails. Among the assumptions of the Hardy-Weinberg
      principle that were not met within these populations could include non-random
      mating, unequal fecundity, different hatching and survival rates of different
      genotypes, or other life-history differences between snail stocks. It is clear,
      though, that for these two laboratory snail stocks there is no fitness cost
      attached to genetic resistance to the parasite.

PMID- 12489008
TI  - Biological control of infective larvae of a gastro-intestinal nematode
      (Teladorsagia circumcincta) and a small lungworm (Muellerius capillaris) by
      Duddingtonia flagrans in goat faeces.
AB  - The high prevalence of benzimidazole-resistant nematodes in French grazing dairy
      goat flocks led to a search for nematode-control schemes based on integrated
      approaches with non-chemical options, like vaccination, grazing management, or
      biological control using nematophagous fungi. The effect of the daily feeding of
      goats with spores of the nematophagous fungus Duddingtonia flagrans on third
      stage larvae (L3) of Teladorsagia circumcincta was examined in faecal cultures.
      In addition, the effect of D. flagrans on the survival of first-stage larvae (L1)
      of Muellerius capillaris was tested. Twenty-two culled dairy goats previously
      raised in a zero-grazing system were twice infected at monthly intervals with
      5,000 and then 7,500 T. circumcincta L3. Eight animals were infected with a
      benzimidazole-susceptible (BZs) strain while the remainder received a
      benzimidazole-resistant one (BZr). Six culled goats naturally infected with M.
      capillaris were purchased from private farms. All the goats were divided in two
      groups, one group receiving daily 5 x 10(5) chlamydospores of D. flagrans/kg body
      weight per goat for seven consecutive days in the food, the other group acting as
      control. For T. circumcincta-infected goats, individual egg counts and
      coprocultures (13 days, 25 degrees C) followed by L3 extraction with the Baermann
      method were performed. For M. capillaris-infected goats, extraction of L1 with
      the Baermann apparatus was individually performed on day 0 and after
      coprocultures on days 7, 10 and 14. Reductions in percentage development of T.
      circumcincta L3 in fungus groups compared with control groups ranged from 84%
      (BZs strain) to 90% (BZr strain). A decrease in M. capillaris L1 recovery was
      noted on days 7 and 10 (a reduction of 70% compared with day 0) and on day 14
      (85%), but this pattern was similar in both groups, whether receiving the fungus
      or not. At the dosage of 5 x 10(5) spores/kg body weight, D. flagrans was highly
      effective in reducing the larval development of T. circumcincta in goats faeces.
      In contrast, the fungus did not reduce M. capillaris L1 survival in faeces in our
      conditions.

PMID- 12489009
TI  - Accumulation of human waterborne parasites by zebra mussels (Dreissena
      polymorpha) and Asian freshwater clams (Corbicula fluminea).
AB  - Zebra mussels (Dreissena polymorpha) and Asian freshwater clams (Corbicula
      fluminea) are nonindigenous invasive bivalves present in North American fresh
      waters that are frequently contaminated with human enteric parasites,
      Cryptosporidium parvum and Giardia lamblia. Six-week laboratory exposure of D.
      polymorpha and Corbicula fluminea to both parasites seeded daily at
      concentrations reported from surface waters demonstrated efficient removal of
      Cryptosporidium parvum oocysts and G. lamblia cysts by both bivalve species. The
      number of parasites in mollusk tissue progressively increased in relation to the
      concentration of waterborne contamination, and decreased after cessation of the
      contamination. Oocysts outnumbered cysts in the tissue of both bivalves, and more
      parasites were identified in D. polymorpha than in Corbicula fluminea; overall
      35.0% and 16.3% of the parasites seeded, respectively. Because C. fluminea and D.
      polymorpha can accumulate human waterborne parasites in proportion to ambient
      concentrations, these species of bivalves can be effective bioindicators of
      contamination of freshwater habitats with Cryptosporidium and Giardia.

PMID- 12489010
TI  - Gene expression changes in Schistosoma mansoni sporocysts induced by Biomphalaria
      glabrata embryonic cells.
AB  - Biomphalaria glabrataembryonic (Bge) cells have been shown to provide favourable
      environmental conditions for the development of Schistosoma mansoni sporocysts.
      We investigated the effect of Bge excretory-secretory products on metabolic
      activity and gene transcription in S. mansoni mother sporocysts. Using the
      differential-display technique, we identified several sporocyst transcripts
      regulated by exposure to Bge soluble components. Research in databases indicated
      that six of the eight differential products analysed were homologous to sequences
      already present in databases. Two transcripts appeared of interest for
      schistosome development since they could be associated with cell division and
      protein synthesis in developing sporocysts. Their up-regulation following contact
      with cell products was confirmed by semi-quantitative RT-PCR. The first fragment
      coded for a part of the chaperonin containing T-complex protein gamma subunit
      like protein of S. mansoni (SmTCP 1-C). The second one represented a new S.
      mansoni expressed sequence tag encoding a protein homologous to various
      glutaminyl-tRNA synthetases (GlnRS). The full-length sequence of SmGlnRS was
      cloned from adult schistosomes and its primary sequence was compared to other
      GlnRS. The overexpression of SmTCP-1 and SmGlnRS could be correlated with the
      metabolic changes observed in Bge-exposed sporocysts.

PMID- 12489011
TI  - Eprinomectin in goat: assessment of subcutaneous administration.
AB  - Eprinomectin is only available as a topically applied anthelmintic for dairy
      cattle. To determine whether eprinomectin can be administered in the goat as an
      injectable formulation, it was subcutaneously delivered to six goats and measured
      in the plasma at different times after administration. The area under the
      concentration-time curve (AUC) reported after subcutaneous administration of 0.2
      mg kg(-1) eprinomectin (68.5+/-23.2 ng day(-1) ml(-1)) was similar to the AUC
      previously reported for goats after a pour-on administration of 0.5 mg kg(-1)
      eprinomectin. Thus, our results clearly show that subcutaneous administration is
      2.5 times more effective than pour-on administration, in terms of amount of drug
      present in the organism. This work should encourage the development of a
      subcutaneous formulation of eprinomectin and should contribute to defining
      optimal therapeutic conditions for goat anthelmintic treatment.

PMID- 12489012
TI  - Biochemical analysis of proteins and lipids found in parasitophorous vacuoles
      containing Leishmania amazonensis.
AB  - One fundamental step of Leishmania-macrophage interaction is the phase of
      parasite internalization through an endocytic process, with the formation of the
      parasitophorous vacuole (PV). The present study analyzed this process using two
      approaches. First, to investigate the host cell proteins which take part in this
      compartment, the macrophage surface was biotinilated and allowed to interact with
      both Leishmania forms, the PV was then isolated, and the biotinilated proteins
      were analyzed by Western blot. The results obtained showed that the isolated PV
      from macrophages infected for 60 min with infective promastigotes displayed high
      molecular weight proteins, 220 kDa and 180 kDa, contrary to the isolated PV
      obtained from amastigotes. The isolated PV from amastigotes, after 60 min
      interaction, displayed a faint, biotinilated protein profile, in contrast to the
      PV containing amastigote which, after 30 min interaction, displayed a strong
      protein profile in the range of 120 kDa and 40-60 kDa. The biotinilated protein
      profile may represent proteins distributed in the PV membrane and may also
      correspond to biotinilated proteins incorporated by the intracellular parasite,
      as observed by confocal microscopy. In a second approach, to investigate the PV
      phospholipid composition, macrophages were incubated with (32)P, allowed to
      interact with the parasites, and the isolated PV was then processed for
      phospholipid analysis by thin layer chromatography and scintillation counting. An
      increase in the levels of lysophosphatidylcholine was observed in infected
      macrophages. The isolated PV from infective promastigotes and amastigotes, after
      60 min interaction, displayed high levels of phosphatidylcholine. Then the PV was
      ruptured and the intravacuolar parasite's (32)P phospholipid composition was
      analyzed by TLC; and labeling of the parasites was found, suggesting that
      phospholipids from the macrophage are transferred to the parasite. Taken
      together, the results obtained show that several proteins and phospholipids found
      in the plasma membrane of the macrophage are also found in the PV compartment.

PMID- 12489013
TI  - Oestrus cycle perturbations and hypotrophy of clitoral glands in malaria-infected
      female BALB/c mice.
AB  - An experimental host-parasite association involving BALB/c female mice infected
      with Plasmodium vinckei petteri was used with the aim of investigating the
      morphological and physiological alterations induced by the parasite in the
      genital tract of the host. The vaginal oestrous cycle was monitored as a daily
      clue to the sexual physiology of the female mice, and a complete histological
      analysis of the genital tract was performed 36 days following parasite
      inoculation. The oestrous cycle showed strong transitory alterations during the
      first 30 days following infection. The occurrence of oestrus days increased
      during the first 10 days post-infection and then decreased to a subnormal value
      during the following 20 days. Infected mice also showed a remarkable hypotrophy
      of their clitoral glands 30 days after the beginning of the malarial infection. A
      probable cause of such perturbations is a significant hormonal imbalance
      triggered by the erythrocytic proliferation of the Plasmodium. The relationship
      between the immune response of the host and these physiological and morphological
      alterations, as well as the outcomes of these alterations on the sexuality of the
      rodent host are discussed.

PMID- 12489014
TI  - Contamination of Atlantic coast commercial shellfish with Cryptosporidium.
AB  - Shellfish (oysters and/or clams) were obtained from 37 commercial harvesting
      sites in 13 Atlantic coast states from Maine to Florida and one site in New
      Brunswick, Canada. Gill washings from each of 25 shellfish at each site were
      examined by immunofluorescence microscopy (IFA) for oocysts of Cryptosporidium.
      Gill washings from another 25 shellfish at each site were grouped into five pools
      of five shellfish each. DNA from each pool was utilized for PCR and genotyping.
      Oocysts were found in 3.7% of 925 oysters and clams examined by IFA in shellfish
      from New Brunswick and 11 of 13 states. Cryptosporidium DNA was detected by PCR
      in 35.2% of 185 pools. Cryptosporidium parvum genotypes 1 and 2, and
      Cryptosporidium meleagridis,all of which have been identified in infected humans,
      were identified at 37.8% of the sites. Gill washings from every site were tested
      for the presence of infectious oocysts by biological assay in neonatal BALB/c
      mice but no mice were found infected, suggesting that either the oocysts were no
      longer infectious or infections in mice were below the level of detection.
      Collectively, these findings indicate that Cryptosporidium species, indicative of
      pollution from human and animal feces and potentially infectious for humans, were
      found in commercial shellfish from 64.9% of sites examined along the Atlantic
      coast by either microscopy or molecular testing. Previous reports link periods of
      high rainfall with the elevated numbers of pathogen contaminated shellfish.
      Because shellfish in the present study were examined during a period of
      exceptionally low precipitation, the data are thought to underestimate the number
      of Cryptosporidium contaminated shellfish likely to be found during periods of
      normal or above normal precipitation.

PMID- 12489015
TI  - Nitric oxide inhibits cysteine proteinases and alcohol dehydrogenase 2 of
      Entamoeba histolytica.
AB  - Nitric oxide is involved in the neutrophil and macrophage killing of the
      protozoan parasite Entamoeba histolytica. In the present study, we found that
      cysteine proteinases, significant contributors to amebic virulence and alcohol
      dehydrogenase 2, an enzyme absolutely required for the survival of the parasite,
      are both significantly inhibited by S-nitroso-glutathione, a physiological nitric
      oxide donor, within the concentration range 0.5-2.0 m M.

PMID- 12489016
TI  - Intestinal granuloma formation in normal and SCID BALB/c mice infected with
      Angiostrongylus costaricensis.
AB  - We studied the histomorphology of granuloma formation and cytokine production in
      Angiostrongylus costaricensis-infected immunocompetent and immunodeficient BALB/c
      mice. Histological examination of the infected intestine showed well developed
      granulomas in BALB/c mice. In contrast, in SCID mice, clusters of eggs and larvae
      and a progression of infiltration of inflammatory cells were also observed, but
      little fibroblastic activity was seen. Analysis of plasma of the infected mice
      demonstrated a dramatic contrast in the cytokine profile between normal and SCID
      mice. Normal mice infected with A. costaricensis showed highly elevated plasma
      IFN-gamma levels at week 3 of infection, but plasma IL-4 remained close to the
      background levels obtained from non-infected mice. In contrast, the amount of
      those cytokines in the plasma of SCID animals was little affected by this
      parasitic infection. These results suggest that Th1-mediated immunity is required
      for granuloma formation in response to A. costaricensis infection in mice.

PMID- 12489017
TI  - A new reporter gene for transient transfection of Plasmodium falciparum.
AB  - Transfection of Plasmodium falciparum has remained difficult and laborious due to
      a lack of suitable reporter genes and low transfection efficiency. Therefore, the
      luciferase gene of Renilla reniformis, a sensitive mammalian reporter gene, was
      evaluated as a reporter gene in this system. Our studies indicate that the R.
      reniformis luciferase gene can be expressed in P. falciparum and is easily
      detected by luminometry. P. falciparum extracts do not contain endogenous R.
      reniformis luciferase activity, which is essential for its use as a reporter gene
      in this organism. Moreover, both firefly and R. reniformis luciferase genes can
      be co-expressed in P. falciparum and their respective enzyme activities can be
      measured from the same sample. Thus, the R. reniformis luciferase gene can be
      used as an experimental reporter gene and/or used in conjunction with the firefly
      luciferase gene where one gene would be used to control transfection efficiency.
      The R. reniformis luciferase gene thus provides a valuable tool to facilitate
      transient transfection analysis in P. falciparum.

PMID- 12489018
TI  - Lung tissue mitochondrial benzodiazepine receptors increase in a model of
      pulmonary inflammation.
AB  - Pulmonary inflammation induced in the rabbit lung by the intravenous injection of
      complete Freund's adjuvant (CFA) increases the lung uptake of 14C-diazepam from
      the pulmonary circulation. The objective of this study was to determine the
      extent to which mitochondrial (or peripheral) benzodiazepine receptors (mBRs) may
      contribute to this increased uptake. To this end, we measured the pulmonary
      venous effluent concentration versus time for 14C-diazepam following its
      injection into the pulmonary artery of isolated perfused normal and CFA inflamed
      lungs with and without an inhibitor (PK11195) of diazepam binding to mBRs. The
      results demonstrate that this model of pulmonary inflammation is associated with
      an increase in lung tissue mBR. Lung tissue caspase-3 activity was also measured
      as one index of lung inflammation, and we found that in inflamed lungs, there was
      an inverse correlation between mBR density and lung tissue capase-3 activity.
      This is consistent with observations in other organs and a role for mBRs in
      apoptotic elimination of inflammatory cells in the resolution of this
      inflammatory response. The results suggest the potential utility of mBR ligands
      for noninvasive detection and/or characterization of pulmonary inflammation,
      e.g., via nuclear medicine methods.

PMID- 12489019
TI  - Possible involvement of C-C chemokines in functional augmentation of adhesion
      molecules in asthmatic patients.
AB  - Adhesion molecules and C-C chemokines play an important role in the accumulation
      of eosinophils in allergic inflammation. In the present study, the expression and
      function of adhesion molecules on eosinophils from asthmatic patients and
      involvement of RANTES and eotaxin were examined. Eosinophils isolated by the CD16
      negative selection method were stimulated with or without RANTES or eotaxin.
      Expression of b integrins on eosinophils and the functional adherence to
      recombinant soluble intercellular adhesion molecule-1 (r-sICAM-1)-coated plates
      were examined. Compared with normal subjects, eosinophils from asthmatic patients
      showed increased expression of b2 integrins and functional adherence to r-sICAM-1
      coated plates. RANTES and eotaxin augmented the functional adherence of
      eosinophils without a significant upregulation of b2 integrins. Anti-b2 integrin
      antibody inhibited the augmentative effect on eosinophil adherence of RANTES and
      eotaxin. Pertussis toxin, wortmannin, and genistein inhibited chemokine-induced
      adherence. RANTES and eotaxin are closely related to eosinophil accumulation not
      only as chemotactic agents but also as augmentative agents for eosinophil
      adherence through involvement in functional eosinophil adherence to ICAM-1 by a
      possible qualitative change of b2 integrins. Pertussis toxin-sensitive G
      proteins, PI3 kinase, and tyrosine kinase are involved in signal transduction
      leading to activation of b2 integrins on eosinophil following stimulation with
      RANTES and eotaxin.

PMID- 12489020
TI  - Correlation between polymorphonuclear leukocyte counts and levels of tumor
      necrosis factor-a in pleural fluid of patients with parapneumonic effusion.
AB  - High concentrations of tumor necrosis factor-a (TNF), as well as excess of
      polymorphonuclear leukocytes (PMNs), are present in pleural fluid of patients
      with complicated parapneumonic effusion (CPPE). Several studies have shown that
      PMNs are capable of secreting TNF. However, the correlation between levels of TNF
      and PMN counts in pleural fluid of patients with parapneumonic effusion has not
      been previously evaluated. This study was undertaken to evaluate this
      correlation. Using a commercially available high sensitivity ELISA kit, levels of
      TNF were measured in pleural fluid of patients with UCPPE (n = 22), and CPPE (n =
      14), and were compared with PMN count in pleural fluid of these patients. The
      mean +/- SD values of pleural fluid TNF and PMN count in the UCPPE group the
      group were 10.15 +/- 6.48 pg/mL and 3,452 +/- 2,878 cells/mm3, respectively, and
      in the CPPE group the values were 55.51 +/- 29.49 pg/mL and 25,261 +/- 11,733
      cells/mm3, respectively. Levels of pleural fluid TNF and PMN counts in the CPPE
      group were significantly higher than in the UCPPE group (p <0.0001). A
      significant correlation was found between levels of pleural fluid TNF and PMN
      counts in the CPPE group (r = 0.57, p = 0.03) and also in the UCPPE group (r =
      0.44, p = 0.04). The results of this study indicate that in pleural fluid of
      patients with UCPPE or CPPE, levels of TNF correlate positively with PMN counts,
      and PMNs might be an important source of TNF production in pleural fluid of these
      patients, particularly in those with CPPE.

PMID- 12489021
TI  - Monitoring cytokeratin fragment 19 (CYFRA 21-1) serum levels for early prediction
      of recurrence of adenocarcinoma and squamous cell carcinoma in the lung after
      surgical resection.
AB  - The purpose of this study was to evaluate the markers' clinical usefulness for
      early prediction of recurrence, by serial and simultaneous measurements of serum
      cytokeratin fragment 19 (CYFRA 21-1), before and after surgery on patients with
      non-small cell lung cancers (NSCLC). The 48 patients enrolled in this study had
      adenocarcinoma of the lung (adenoCa) (including 24 patients with recurrence and
      24 patients without recurrence 1 year after surgery) and 48 patients with
      squamous cell carcinoma of the lung (SCC) (including 24 cases with recurrence and
      24 without recurrence 1 year after surgery). Serial serum levels of CYFRA 21-1
      were measured before the operation and 1 week, 1 month, 3 months, 6 months, 9
      months, and 12 months after surgery for the early detection of recurrence. The
      results revealed that (1) the mean serum values of CYFRA 21-1 were significantly
      higher beginning at 1 month after surgery in the 24 patients with recurrent
      adenoCa compared with the 24 patients without recurrent adenoCa, (2) mean serum
      values of CYFRA 21-1 were significantly higher beginning at 1 month after surgery
      in 24 patients with recurrent SCC when compared with 24 patients without
      recurrent SCC, and (3) mean serum values of CYFRA 21-1 were significantly higher
      beginning at 1 month after operation in the total 48 patients with recurrent
      NSCLC when compared with 48 patients without recurrent NSCLC. We conclude that
      CYFRA 21-1 is not a good marker for early prediction of NSCLC recurrence
      including adenoCa and SCC after surgery.

PMID- 12489022
TI  - Sarcoidosis: impact of other illnesses on the presentation and management of
      multi-organ disease.
AB  - Sarcoidosis remains a fascinating illness that almost always affects the
      respiratory tract but often involves many other organs as well. Although many
      patients seem to have only an intrathoracic illness, with perhaps one other site
      or organ involved, others can experience a severe multi-organ disease. The
      inciting stimulus, even if unknown, can elicit an immunologic host response-the
      non-caseating granuloma-in almost every organ. It is intriguing that this
      stimulus can be so widespread throughout the body, while the biology of the
      disease can be so variable. Many series of patients with sarcoidosis have
      reported the multiple organs involved and the clinical presentation. Our series
      of 67 patients (40 female, 27 male, mean age 38.7 years +/- 13.2 (SD) at time of
      diagnosis) generally mirrors the clinical pattern found in five comparison series
      that span the past 60 years. However, more emphasis is given in this series to
      associated medical conditions that can complicate the presentation of
      sarcoidosis, as well as to co-morbid illnesses that must be managed in addition
      to the patient's sarcoidosis. Although most patients had intrathoracic
      sarcoidosis diagnosed at initial evaluation (40%), many had other organs or
      bodily sites involved in addition (or subsequently) as the illness evolved.
      Confounding the initial patient evaluation were two factors: (1) the presence of
      an occupational respiratory exposure(s) (n = 25 or 37% of patients); (2) a
      previously diagnosed malignancy (n = 6 or 9%) that heightened the possibility of
      a primary malignancy presenting in the chest, or the reactivation of a prior
      malignancy (breast, thyroid, and lymphoma) that could metastasize to the lung.
      Symptoms present when a patient's diagnosis was established usually
      differentiated respiratory and/or abdominal organ involvement. Although
      respiratory symptoms could be absent (n = 18 or 27%) for many patients with
      incidental thoracic findings, most had typical ones, including exertional
      dyspnea. For patients with an abdominal presenting illness (n = 11 or 16%),
      nonspecific digestive and abdominal symptoms were experienced as well as
      arthralgias. Almost every patient had at least one important other illness that
      factored significantly into the management of their sarcoidosis. Older patients
      had more illnesses, such as cardiovascular illness, diabetes mellitus, neurologic
      problems, and functional gastrointestinal symptoms. Depression affected all ages
      and was probably underrecognized; more emphasis on this illness is needed.
      Obesity was associated with disordered sleep syndromes, but not invariably so, as
      half the subjects had a good body habitus. Thus, many of the other illnesses
      experienced by sarcoidosis patients are common problems that middle-aged people
      develop. However, digestive and gastroenterological symptoms seemed
      disproportionately frequent in this series. This is a component of multi-organ
      sarcoidosis that has not received extensive coverage in the literature.
      Approximately one-third of sarcoidosis patients had one of two very common
      problems-gastroesophageal reflux or irritable bowel syndrome. But these are
      common problems, and it is thus necessary to separate these symptoms from those
      associated with abdominal visceral involvement of sarcoidosis. Although liver
      and/or splenic involvement with sarcoidosis do not cause organ dysfunction or
      insufficiency, they can contribute to abdominal symptoms. Finally, it remains of
      interest whether inflammatory bowel disease-Crohn's disease in particular-is
      another organ manifestation of sarcoidosis, or is it unrelated?

PMID- 12489023
TI  - Prospects for CD40-directed experimental therapy of human cancer.
AB  - CD40, a member of the tumor necrosis factor receptor (TNF-R) family, is a surface
      receptor best known for its capacity to initiate multifaceted activation signals
      in normal B cells and dendritic cells (DCs). CD40-related treatment approaches
      have been considered for the experimental therapy of human leukemias, lymphomas,
      and multiple myeloma, based on findings that CD40 binding by its natural ligand
      (CD40L), CD154, led to growth modulation of malignant B cells. Recent studies
      also exploited the selective expression of the CD40 receptor on human epithelial
      and mesenchymal tumors but not on most normal, nonproliferating epithelial
      tissues. Ligation of CD40 on human breast, ovarian, cervical, bladder, non small
      cell lung, and squamous epithelial carcinoma cells was found to produce a direct
      growth-inhibitory effect through cell cycle blockage and/or apoptotic induction
      with no overt side effects on their normal counterparts. CD154 treatment also
      heightened tumor rejection immune responses through DC activation, and by
      increasing tumor immunogenicity through up-regulation of costimulatory molecule
      expression and cytokine production of epithelial cancer cells. These
      immunopotentiating features can produce a "bystander effect" through which the
      CD40-negative tumor subset is eliminated by activated tumor-reactive cytotoxic T
      cells. However, the potential risk of systemic inflammation and autoimmune
      consequences remains a concern for systemic CD154-based experimental therapy. The
      promise of CD154 as a tumor therapeutic agent to directly modulate tumor cell
      growth, and indirectly activate antitumor immune response, may depend on
      selective and/or restricted CD154 expression within the tumor microenvironment.
      This may be achieved by inoculating cancer vaccines of autologous cancer cells
      that have been transduced ex vivo with CD154, as documented by recently clinical
      trials. This review summarizes recent findings on CD154 recombinant protein- and
      gene therapy-based tumor treatment approaches, and examines our understanding of
      the multifaceted molecular mechanisms of CD154-CD40 interactions.

PMID- 12489024
TI  - The rat sodium iodide symporter gene permits more effective radioisotope
      concentration than the human sodium iodide symporter gene in human and rodent
      cancer cells.
AB  - Expression of the sodium iodide symporter (NIS) gene in tumor cells may provide a
      novel mechanism for treating cancer. The NIS mediates the normal physiological
      transport of iodide across the thyroid cell membrane. This mechanism of iodide
      uptake has been used to both diagnose and treat thyroid cancer. Tissue expression
      of the NIS is largely limited to the thyroid; therefore, expression of the NIS
      gene in cancer cells would allow for specific iodine uptake, radioisotope
      accumulation, and treatment. In this study, we directly compared the human and
      rat NIS (rNIS) for their ability to concentrate radioisotope into human and
      rodent cancer cells. Perchlorate-sensitive (125)I uptake in multiple cell lines
      was demonstrated following transduction with retroviral vectors expressing either
      the human or rNIS gene. Surprisingly, iodine uptake was consistently higher with
      the rNIS gene, up to 5-fold greater, when compared to the human gene, even within
      a variety of human tumor cell lines. This iodine uptake allowed for cell killing
      following (131)I treatment in NIS-transduced cells when assayed by in vitro
      clonogenic assays. These results demonstrate that the rNIS gene provides superior
      iodine uptake ability, and may be preferable for use in designing anticancer gene
      therapy approaches.

PMID- 12489025
TI  - Antitumor activity of 2-fluoro-2'-deoxyadenosine against tumors that express
      Escherichia coli purine nucleoside phosphorylase.
AB  - The selective expression of Escherichia coli purine nucleoside phosphorylase
      (PNP) in solid tumors has been successfully used to activate two purine
      nucleoside analogs [9-(2-deoxy-beta-D-ribofuranosyl)-6-methylpurine (MeP-dR) and
      9-beta-D-arabinofuranosyl-2-fluoroadenine (F-araA)] resulting in lasting tumor
      regressions and cures. E. coli PNP also cleaves 2-fluoro-2'-deoxyadenosine (F
      dAdo) to 2-F-adenine, which is the toxic purine analog liberated from F-araA that
      has high bystander activity and is active against nonproliferating tumor cells.
      As F-dAdo is 3000 times better than F-araA as a substrate for E. coli PNP, we
      have evaluated its antitumor activity against D54 gliomas that express E. coli
      PNP and have characterized its in vivo metabolism in order to better understand
      its mechanism of action with respect to the other two agents. Like MeP-dR and F
      araA-5'-monophosphate (F-araAMP, a prodrug of F-araA), treatment of mice bearing
      D54 tumors that express E. coli PNP with F-dAdo resulted in excellent antitumor
      activity. Although F-dAdo was as active as MeP-dR and better than F-araAMP, it
      was not dramatically better than either compound because of its short plasma half
      life and the limited activation of F-adenine to toxic metabolites. Regardless,
      these results indicated that F-dAdo was also an excellent prodrug for use with
      gene vectors that deliver E. coli PNP to tumor cells.

PMID- 12489026
TI  - Replicative retroviral vectors for cancer gene therapy.
AB  - Poor efficiency of gene transfer into cancer cells constitutes the major
      bottleneck of current cancer gene therapy. We reasoned that because tumors are
      masses of rapidly dividing cells, they would be most efficiently transduced with
      vector systems allowing transgene propagation. We thus designed two replicative
      retrovirus-derived vector systems: one inherently replicative vector, and one
      defective vector propagated by a helper retrovirus. In vitro, both systems
      achieved very efficient transgene propagation. In immunocompetent mice,
      replicative vectors transduced >85% tumor cells, whereas defective vectors
      transduced <1% under similar conditions. It is noteworthy that viral propagation
      could be efficiently blocked by azido-thymidine, in vitro and in vivo. In a model
      of established brain tumors treated with suicide genes, replicative retroviral
      vectors (RRVs) were approximately 1000 times more efficient than defective
      adenoviral vectors. These results demonstrate the advantage and potential of RRVs
      and strongly support their development for cancer gene therapy.

PMID- 12489027
TI  - Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N.
AB  - The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been
      shown to enhance the antitumor effects of radiation and chemotherapy drugs. We
      have investigated the role of cytochrome P450 3A4 (CYP3A4) in increasing the
      metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy.
      RIF-1 murine tumor cells were transfected with a mammalian expression vector
      containing CYP3A4 cDNA. In vitro AQ4N metabolism, DNA damage, and clonogenic cell
      kill were assessed following exposure of transfected and parental control cells
      to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and
      significantly enhanced the ability of the drug to cause DNA strand breaks and
      clonogenic cell death. Cotransfection of CYP reductase with CYP3A4 showed a small
      enhancement of the effect in the DNA damage assay only. A single injection of
      CYP3A4 into established RIF-1 murine tumors increased the metabolism of AQ4N, and
      when used in combination with radiation, three of nine tumors were locally
      controlled for >60 days. This is the first demonstration that CYPs alone can be
      used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is
      the only CYP-activated bioreductive agent in clinical trials. Combination with a
      GDEPT strategy may offer a further opportunity for targeting radiation-resistant
      and chemo-resistant hypoxic tumor cells.

PMID- 12489028
TI  - The herpesvirus saimiri ORF 73 regulatory region provides long-term transgene
      expression in human carcinoma cell lines.
AB  - Herpesvirus saimiri (HVS) is capable of establishing a persistent infection in a
      variety of human carcinoma cell lines, by virtue of episomal maintenance.
      Moreover, the viral episome provides expression of a transgene in both in vitro
      and in vivo environments. At present, HVS vectors utilize heterologous promoters
      such as the IE hCMV promoter. However, this promoter maybe unsuitable for long
      term expression in vivo, as promoter silencing has been observed in this and
      other herpesvirus-based vector systems. Ideal regulatory regions would be
      functional when the herpesvirus genome is maintained as a latent episome. We have
      previously shown that gene expression in an HVS-persistently-infected human
      carcinoma cell line is limited to an adjacent set of genes encoding ORFs 71-73.
      These genes are transcribed as a polycistronic mRNA species from a common
      regulatory region upstream of the ORF 73 gene. In this report, we assess the
      potential of the ORF 73 regulatory region to provide heterologous gene expression
      in a wide variety of human cancer cell lines. We demonstrate, utilizing transient
      transfection assays, that the ORF 73 regulatory region can provide transgene
      expression in a variety of human carcinoma cell lines, although levels of
      transgene expression are not as high as achieved under the control of
      heterologous promoters such as the IE hCMV promoter. Furthermore, incorporation
      of the minimal ORF 73 regulatory region in a recombinant HVS-based vector
      provides sustained expression of the green fluorescent protein in both in vitro
      and in vivo environments. These results suggest that the ORF 73 regulatory region
      may be suitable for use in HVS-based cancer gene therapy applications.

PMID- 12489029
TI  - Recombinant adenoviruses expressing dominant negative insulin-like growth factor
      I receptor demonstrate antitumor effects on lung cancer.
AB  - The continuous growth of tumors depends on the altered regulation of the cell
      cycle, which is in turn modulated by signals from growth factors and their
      receptors. Blockade of insulin-like growth factor (IGF)-I and IGF-IR by antisense
      or dominant negative plasmid transfection can suppress tumorigenicity and induce
      regression of established tumors. We have constructed two recombinant
      adenoviruses: an adenovirus expressing truncated IGF-IR (ad-IGF-IR/950) with an
      engineered stop codon at amino acid residue 950, and an adenovirus expressing the
      soluble extracellular domain of IGF-IR (ad-IGF-IR/482) with an engineered stop
      codon at amino acid residue 482. Ad-IGF-IR/950 produces a defective receptor with
      an intact alpha subunit and a defective beta subunit lacking the tyrosine kinase
      domain. Dominant negative inhibition results from competition of the defective
      receptor with normal IGF-IR subunits, or the competition with normal IGF-IR for
      ligand by the soluble receptor. We were able to show here that ad-IGF-IR/950
      induced the increased expression of IGF-IR on the cell surface and ad-IGF-IR/482
      induced the secretion of the soluble fragment of IGF-IR. The transduction of both
      ad-IGF-IR/950 and ad-IGF-IR/482 could blunt the growth-stimulatory effect of IGF
      I on human lung cancer cell lines. Both ad-IGF-IR/950 and ad-IGF-IR/482
      effectively blocked IGF-I-induced Akt kinase activation. Intratumoral injection
      of ad-IGF-IR/482 virus showed significant growth suppression in established lung
      cancer xenografts. These findings suggest that these ad-IGF-IR/dn (950, 482) have
      the potential to be effective and practical cancer gene therapy strategies.

PMID- 12489030
TI  - Transcellular transfer of active HSV-1 thymidine kinase mediated by an 11-amino
      acid peptide from HIV-1 Tat.
AB  - Suicide gene therapy using herpes simplex virus type-1 (HSV-1) thymidine kinase
      (TK) is a widely exploited approach for gene therapy of cancer and other
      hyperproliferative disorders. Despite its popularity, clinical success has been
      so far hampered mostly by the relative inefficiency of TK gene transfer and its
      limited bystander effect. Here we report that fusion of TK to an 11-amino-acid
      peptide from the basic domain of the HIV-1 Tat protein (Tat11) imparts cell
      membrane translocating ability to the enzyme and significantly increases its
      cytotoxic efficacy. In cells expressing Tat11-TK, this protein is found
      extracellularly, associated with cell surface heparan sulfate proteoglycans, and
      is released into the cell culture medium. Based on its interaction with HSPGs,
      the protein is then internalized by neighboring, nonexpressing cells, which
      become susceptible to cell death when treated with the nucleoside analogue
      acyclovir. As a consequence, co-cultures of wild-type cells with cells expressing
      Tat11-TK show increased sensitivity to ACV through a mechanism involving
      apoptosis. Modification of TK by fusion with Tat11 might constitute an important
      step for the optimization of TK suicide gene strategy for gene therapy of
      cellular proliferation.

PMID- 12489032
TI  - An Integrative Review of Patient Medication Compliance from 1990-1998.
AB  - PURPOSE: The purpose of the integrated review was to summarize studies about
      medication compliance and identify their implications for research and practice.
      Thirty research studies exploring patient medication compliance were reviewed.
      Study variables related to patients included characteristics that affect
      compliance, common medication errors, and strategies used by patients to remember
      to take their medication. Other studies evaluated methods for measuring
      compliance and interventions for improving compliance. CONCLUSIONS: There has not
      been a "gold standard" identified for measuring compliance, therefore it is
      difficult to compare results due to differences in operational definitions.
      Dosage frequency, patient's confidence in their provider, belief in the efficacy
      of a drug along with acceptance of illness have been shown to have a positive
      effect on compliance. IMPLICATIONS: Nurses and other health care providers can
      promote medication compliance by developing a collaborative relationship with the
      patient. Education and reminders are especially important at the beginning of
      treatment. Further research is needed to assess the efficacy of nursing
      interventions to promote compliance.

PMID- 12489031
TI  - Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of
      oral cancer.
AB  - Current clinical success rates of adenoviral vector (Adv)-based gene therapy of
      squamous cell carcinoma (SCC) of the head and neck remain unsatisfactory. A major
      problem with this approach is thought to be related to low Adv transduction
      efficiency due to weak expression of the adenovirus receptor, coxsackie
      adenovirus receptor (CAR), in SCC. To improve the limited infectivity of Adv in
      oral SCC, we constructed mutated Adv incorporating the integrin-binding motif,
      RGD, in the HI loop of the fiber knob. The mutated Adv infected target cells
      through integrins commonly expressed in oral SCC. LacZ marker gene expression
      after infection with this mutated Adv (Adv-F/RGD) in oral SCC cell lines that
      showed reduced expression of CAR was approximately 5-10 times higher than that
      obtained with the parental Adv containing wild-type fiber knob (Adv-F/wt). In an
      in vitro study, transduction of oral cancer cell lines with Adv-F/RGD expressing
      human IL-2 (AxCAhIL2-F/RGD) resulted in greater production of cytokine than
      AxCAhIL2-F/wt infection. In an in vivo therapeutic xenograft model of oral SCC in
      nude mice, AxCAhIL2-F/RGD demonstrated antitumor effects superior to those of
      AxCAhIL2-F/wt. These data suggest that exploitation of genetically altered
      adenovirus vectors with integrin-binding motifs may offer significant
      improvements in oral SCC gene therapy.

PMID- 12489033
TI  - A Synthesis of What We Know About the Use of Physical Restraints and Seclusion
      with Patients in Psychiatric and Acute Care Settings.
AB  - PURPOSE: This article synthesizes research findings on the use of restraint and
      seclusion with patients in psychiatric and acute care settings. CONCLUSIONS: The
      little that is known about restraint/seclusion use with these populations is
      inconsistent. Attitudes and perceptions of patients, family, and staff differ.
      However, all patients had very negative feelings about both, whether they were
      restrained/secluded or observed by others who were not restrained. The reasons
      for restraint/seclusion use vary with no accurate use rate for either. What
      precipitates the use of restraint/seclusion also varies but professionals claim
      they are necessary to prevent/treat violent or unruly behavior. Some believe
      seclusion/restraint is effective but there is no empirical evidence to support
      this belief. Many less restrictive alternatives have been tested with varying
      outcomes. Several educational programs to help staff learn about different ways
      to handle violent/confused patients have been successful. IMPLICATIONS: Until
      more is known about restraint/seclusion use from prospective controlled research,
      the goal to use least restrictive methods must be pursued. More staff educational
      programs must be offered and the evaluation of alternatives to
      restraint/seclusion pursued. When seclusion/restraint is necessary it should be
      used less arbitrarily, less frequently, and with less trauma.

PMID- 12489034
TI  - Using the OJKSN as a Teaching Tool with RN/BSN Students.

PMID- 12489035
TI  - Bilateral Head Flattening in Hospitalized Premature Infants.
AB  - Asymmetrical headshape in infants has increased markedly since the 1992
      recommendation of the American Academy of Pediatrics to reduce the risk of sudden
      infant death syndrome by avoiding the prone sleeping position. Cranial molding
      correlated to restrictive intrauterine environment, birth trauma, torticollis,
      positioning, lack of full bone mineralization, neurological deficits, and any
      combination of the above. Nursing interventions to prevent cranial molding
      include alternative mattress surfaces and repositioning. The research strongly
      supports repositioning of infants to improve cranial vault symmetry.

PMID- 12489036
TI  - Exposure Risk in the Handling and Administration of Chemotherapy Agents: A Review
      and Synthesis of the Literature.
AB  - PURPOSE: This paper synthesizes research findings on known exposure risks to and
      compliance among health care professionals in the handling of neoplastic agents
      and suggests implications for practice and future research. CONCLUSIONS: The
      exposure risk for experiencing mutagenicity and alterations in fertility from
      chemotherapy agents among health care professionals has been extensively studied.
      Exposure risk and its relationship to health care professionals' compliance to
      established protocols for the safe handling and administration of chemotherapy
      agents continues to be a concern for health care institutions. Research in this
      area has been mainly retrospective and most studies have used a causal
      comparative design; the degree of mutagenicity has been quantified for an
      identified exposed group and compared with a group that has not been exposed to
      antineoplastic agents. The evaluation of exposure has been found to be a complex
      problem because of the considerable mediating factors that are multifactorial and
      interactive in nature. Despite these confounding factors, the findings of past
      studies suggest that unsafe practice leads to an increased risk of exposure.
      IMPLICATIONS: Findings from existing research indicate that compliance with
      established safety guidelines offers adequate protection to those health care
      workers involved in the handling, administration and care of patients receiving
      chemotherapy agents.

PMID- 12489037
TI  - Exercise in Heart Failure: A Synthesis of Current Research.
AB  - Exercise intolerance, as a hallmark symptom in patients with heart failure, has
      been the focus of numerous research initiatives in recent years. The purpose of
      this review is to synthesize the current literature in order to provide the
      clinician with an understanding of the state of knowledge regarding the role of
      exercise in treatment of heart failure. Many studies speak to the effect of
      exercise training in this population. While sample sizes have been small and
      restricted predominantly to male subjects with ischemic cardiomyopathies, strong
      support has been documented in favor of beneficial effects of exercise in heart
      failure. Future research should target more representative subject pools (i.e.,
      females, non-ischemic cardiomyopathies, cultural minorities, frail elderly, and
      NYHA class IV), evaluation of impact on quality of life outcomes, exploration of
      different types and intensity of exercise, and formulation of specific activity
      prescription tools which can guide practitioners in making activity and/or
      exercise recommendations to those patients who have no access, or limited access,
      to cardiac rehabilitation programs.

PMID- 12489038
TI  - Smoking Relapse During Postpartum.
AB  - PURPOSE: While many women quit smoking when learning of their pregnancy, the
      majority relapses within one year of giving birth. This paper provides an
      integrative review of studies that assess the contributing factors to maternal
      smoking relapse within the first year of giving birth. The framework for this
      review is the relapse prevention model, which seeks to uncover the contributing
      factors, or high-risk situations, that lead to relapse. Additionally, this paper
      examines existing practice interventions aimed at reducing postpartum relapse and
      provides recommendations for best practice. CONCLUSIONS: Research evidence to
      date shows that two main factors are associated with smoking relapse among
      postpartum women: (1) their association with other smokers and (2) their choosing
      not to breastfeed. Since maternal smoking results in poor health outcomes for
      both mothers and children, relapse prevention is a health issue worthy of
      examination. Nurses can use this information in planning, implementing, and
      evaluating smoking prevention and cessation programs for pregnant and postpartum
      women.

PMID- 12489039
TI  - Evidence-Based Best Practice: The Common Knowledge of Ethical Clinical
      Scholarship.

PMID- 12489040
TI  - Convergence of Science and Health.

PMID- 12489041
TI  - Distribution patterns of postmortem damage in human mitochondrial DNA.
AB  - The distribution of postmortem damage in mitochondrial DNA retrieved from 37
      ancient human DNA samples was analyzed by cloning and was compared with a
      selection of published animal data. A relative rate of damage (rho(v)) was
      calculated for nucleotide positions within the human hypervariable region 1
      (HVR1) and cytochrome oxidase subunit III genes. A comparison of damaged sites
      within and between the regions reveals that damage hotspots exist and that, in
      the HVR1, these correlate with sites known to have high in vivo mutation rates.
      Conversely, HVR1 subregions with known structural function, such as MT5, have
      lower in vivo mutation rates and lower postmortem-damage rates. The postmortem
      data also identify a possible functional subregion of the HVR1, termed "low
      diversity 1," through the lack of sequence damage. The amount of postmortem
      damage observed in mitochondrial coding regions was significantly lower than in
      the HVR1, and, although hotspots were noted, these did not correlate with codon
      position. Finally, a simple method for the identification of incorrect
      archaeological haplogroup designations is introduced, on the basis of the
      observed spectrum of postmortem damage.

PMID- 12489042
TI  - Characterization of genetic miscoding lesions caused by postmortem damage.
AB  - The spectrum of postmortem damage in mitochondrial DNA was analyzed in a large
      data set of cloned sequences from ancient human specimens. The most common forms
      of damage observed are two complementary groups of transitions, termed "type 1"
      (adenine-->guanine/thymine-->cytosine) and "type 2" (cytosine-->thymine/guanine-
      >adenine). Single-primer extension PCR and enzymatic digestion with uracil-N
      glycosylase confirm that each of these groups of transitions result from a single
      event, the deamination of adenine to hypoxanthine, and cytosine to uracil,
      respectively. The predominant form of transition-manifested damage varies by
      sample, though a marked bias toward type 2 is observed with increasing amounts of
      damage. The two transition types can be used to identify the original strand,
      light (L) or heavy (H), on which the initial damage event occurred, and this can
      increase the number of detected jumping-PCR artifacts by up to 80%. No bias
      toward H-strand-specific damage events is noted within the hypervariable 1 region
      of human mitochondria, suggesting the rapid postmortem degradation of the
      secondary displacement (D-loop) H strand. The data also indicate that, as damage
      increases within a sample, fewer H strands retain the ability to act as templates
      for enzymatic amplification. Last, a significant correlation between
      archaeological site and sample-specific level of DNA damage was detected.

PMID- 12489043
TI  - A mutation in the fibroblast growth factor 14 gene is associated with autosomal
      dominant cerebellar ataxia [corrected].
AB  - Hereditary spinocerebellar ataxias (SCAs) are a clinically and genetically
      heterogeneous group of neurodegenerative disorders for which >/=14 different
      genetic loci have been identified. In some SCA types, expanded tri- or
      pentanucleotide repeats have been identified, and the length of these expansions
      correlates with the age at onset and with the severity of the clinical phenotype.
      In several other SCA types, no genetic defect has yet been identified. We
      describe a large, three-generation family with early-onset tremor, dyskinesia,
      and slowly progressive cerebellar ataxia, not associated with any of the known
      SCA loci, and a mutation in the fibroblast growth factor 14 (FGF14) gene on
      chromosome 13q34. Our observations are in accordance with the occurrence of
      ataxia and paroxysmal dyskinesia in Fgf14-knockout mice. As indicated by protein
      modeling, the amino acid change from phenylalanine to serine at position 145 is
      predicted to reduce the stability of the protein. The present FGF14 mutation
      represents a novel gene defect involved in the neurodegeneration of cerebellum
      and basal ganglia.

PMID- 12489045
TI  - Infectious complications of venous access devices.
AB  - Infection represents one of the most common venous access device (VAD)-related
      complications requiring catheter removal. Recognition of such complications is
      essential to provide appropriate therapy in the setting of active infection. This
      article reviews the definition of various types of infections, as well as
      reviewing the diagnosis, prevention, and treatment of VAD-related infections.

PMID- 12489046
TI  - Management of catheter-induced venous thrombosis.
AB  - Catheter-induced venous thrombosis remains a significant problem in current
      clinical practice. A high level of biocompatibility of the materials used to
      manufacture the existing venous access devices has not eliminated catheter
      induced venous thrombosis. Similarly, catheter bonding with anticoagulants or
      their systemic use, while in some instances having a favorable effect on the
      incidence, has not eliminated this problem. The focus of this article is on
      discussion of the various factors that influence formation of catheter-induced
      venous thrombosis. Also discussed is the management of this clinical problem, and
      a useful algorithm is outlined.

PMID- 12489047
TI  - Fibrin sheaths and central venous catheter occlusions: diagnosis and management.
AB  - Central venous catheter malfunction diagnosis and treatment is a growing
      component of the field of interventional radiology. A thorough understanding of
      the causes of catheter malfunction and the technical skills needed to treat these
      problems are necessities to appropriate management. In long-standing central
      venous catheters, the formation of a fibrin sheath can and often does contribute
      to catheter malfunction. Differentiating a sheath from thrombus is imperative to
      appropriate therapy. The purpose of this article is to provide an understanding
      of the causes of fibrin sheaths and how to treat them.

PMID- 12489048
TI  - Pediatric interventional venous access.
AB  - Venous access for therapy in sick children is very important, but sometimes also
      extremely challenging. With several advances in imaging modalities, the
      interventional radiologist can certainly help in these situations. This article
      reviews the indications, technique, and complications related to short-
      (peripherally inserted central catheter) and long-term (central venous lines,
      Port-a-catheters) venous accesses in children. A brief commentary is also made
      about retrieval of fragmented lines.

PMID- 12489049
TI  - Percutaneous peritoneal dialysis catheter placement for the management of end
      stage renal disease: technique and comparison with the surgical approach.
AB  - As the incidence of end-stage renal disease is increasing, so is the pressure on
      the health care system to promote less expensive and burdensome management
      solutions. Peritoneal dialysis (PD) has been increasingly used and is especially
      suited for patients who, in exchange for meticulous care and technique, enjoy
      more independence and fewer clinic visits than their counterparts on
      hemodialysis. Both the efficiency and the complication profile of the
      percutaneously placed PD catheters are comparable to that of surgically implanted
      ones. Percutaneous procedures have the added advantage of being less expensive
      and requiring shorter hospitalization. Radiologists are in an advantageous
      position to provide fluoroscopic placement of PD catheters promptly and safely.
      We describe this technique step by step and compare its complication profile to
      that of the surgical approach as reported in the literature.

PMID- 12489050
TI  - Dialysis ports: a new totally implantable option for hemodialysis access.
AB  - Current options for hemodialysis access have significant limitations. Chronic
      central venous catheters have even more problems. In an effort to surmount many
      of the problems associated with chronic central venous catheters, totally
      implantable access systems have been designed. This article reviews the 2 devices
      currently available or under investigation for use as dialysis ports. Operational
      principles are described, and insertion technique is highlighted. Performance
      characteristics are then addressed.

PMID- 12489051
TI  - Unconventional venous access.
AB  - Venous access is commonly thought of as the bread and butter of interventional
      radiologic procedures. However, in those patients who have undergone multiple
      previous central venous catheter placements, venous access can be a technical
      challenge for even the most seasoned interventional radiologist. Conventional
      access sites include the internal jugular veins (IJV) and subclavian veins (SCV).
      The former should be considered as the primary access site for all patients who
      will be catheter dependent for whatever reason. Before utilization of the SCV,
      the external jugular veins (EJV) should be used, especially in the dialysis
      population. Only after surgical hemodialysis access is no longer an option in the
      upper extremity should cannulation of the SCV be entertained. Once these usual
      access sites are no longer available, it may necessary to use an unconventional
      access method, including catheterization of the common femoral vein,
      catheterization of enlarged collateral vessels, recanalization of occluded veins,
      translumbar inferior vena cava (IVC) catheter placement, and transhepatic
      catheter placement. This chapter serves as a review of these techniques.

PMID- 12489053
TI  - Management of stage I nonseminomatous germ-cell tumors.
AB  - Following orchiectomy in patients with stage 1 nonseminomatous germ-cell tumors
      (NSGCT), there are three treatment options. Retroperitoneal lymph-node dissection
      (RPLND) is currently the treatment of choice in the United States and can be both
      diagnostic and therapeutic but is associated with surgical morbidities.
      Surveillance is the least invasive but carries the highest potential for relapse
      and can be timely and costly for both patient and physician. Primary chemotherapy
      avoids the morbidity of surgery while achieving similar survival rates, albeit
      with potentially significant side effects. The advantages and disadvantages of
      each treatment modality are discussed.

PMID- 12489054
TI  - Controversies in the management of testicular seminoma.
AB  - Tremendous progress has been made in the treatment of testicular seminoma over
      the past 25 years. The advent of curative cytotoxic chemotherapy, even for
      patients with advanced metastatic disease, has led to a paradigm shift toward
      minimizing additional oncologic therapies and their potential side effects.
      Despite these advances, controversial issues still exist in managing patients
      with this disease. Patients with stage I disease can now be managed successfully
      with close surveillance or postoperative radiotherapy (RT). Although deemed safe,
      considerable debate persists about surveillance including issues of compliance,
      cost, and secondary effects of routine RT. Aside from RT, patients with stage I
      disease also can be managed with one- or 2-dose single-agent carboplatin.
      Although this appears safe and efficacious, an ongoing randomized study is
      underway to compare its effectiveness with that of RT. Residual mass after
      chemotherapy for seminoma is not uncommon and therapeutic options include
      observation, RT, or retroperitoneal lymphadenectomy. Although most agree that
      patients with small (<3 cm) or ill-defined masses can be observed, debate
      persists as to the optimal management of patients with well-defined masses
      greater than 3 cm. For many years, patients with bulky retroperitoneal disease
      (>5 cm) were treated with up-front radiotherapy and chemotherapy at relapse. The
      high failure rate outside the treatment field has now changed this paradigm to
      one of up-front chemotherapy.

PMID- 12489055
TI  - Contralateral testicular biopsy procedure in patients with unilateral testis
      cancer: is it indicated?
AB  - About 5% of all patients with unilateral testis cancer harbor testicular
      intraepithelial neoplasia (TIN) in their contralateral testicle, which will
      progress into an invasive germ-cell tumor over time. Accurate diagnosis of TIN by
      a random surgical testis biopsy examination and effective therapy by local
      radiation has led to the concept of a contralateral screening biopsy procedure in
      all testis cancer patients. Screening and preventive treatment, however, only are
      indicated if (1) therapeutic outcome of the screened population is improved and
      (2) physiologic function of the affected organ might be maintained. Based on a
      critical review of the literature, some drawbacks of this policy have to be
      considered and the routine indication for contralateral testis biopsy procedure
      has to be questioned: (1) all TIN-negative patients still have to undergo
      meticulous follow-up evaluation for metachronous testis cancer owing to a false
      negative biopsy diagnosis rate of 0.3%; (2) testis biopsy procedure is associated
      with a 15% to 20% complication rate, which might a negative impact on endocrine
      and exocrine testicular function; (3) local radiation of TIN results in
      irreversible infertility owing to eradication of spermatogenesis; (4) local
      radiation of TIN results in an impairment of endocrine Leydig cell function in
      25% of patients; (5) therapeutic outcome and prognosis will not be improved in
      irradiated patients as compared with patients on surveillance; (6) local tumor
      resection for the management of metachronous testicular cancer represents an
      effective and viable option. The current literature does not support the strategy
      to perform contralateral testis biopsy procedures in all patients with unilateral
      testicular germ-cell tumors. Testis biopsy procedures might, however, be offered
      to high-risk (34%) patients for contralateral TIN with a testicular volume less
      than 12 mL, a history of cryptorchidism, and an age less than 30 years.

PMID- 12489056
TI  - Adjuvant chemotherapy for stage II nonseminomatous germ-cell tumors.
AB  - Management options for patients with stage II nonseminomatous germ-cell tumors
      (NSGCT), completely resected at retroperitoneal lymph node dissection (RPLND),
      include 2 cycles of adjuvant cisplatin-based chemotherapy, or close surveillance,
      with chemotherapy reserved for patients who relapse. Both options are associated
      with cure in an equally high percentage of patients. The decision to choose one
      of these options over the other is influenced by the extent of the tumor resected
      and patient compliance. Surveillance is a strong consideration for patients with
      low-volume nodal disease at RPLND (pN1), because the relapse proportion is 30% or
      less. In contrast, patients with high-volume nodal involvement at RPLND (pN2)
      have a relapse rate of 50% to 90% with surveillance alone. Adjuvant chemotherapy
      is the preferable option in the latter group. A prospective trial of 2 cycles of
      etoposide plus cisplatin adjuvant chemotherapy for patients with pN2 tumors
      showed that this regimen was highly effective in achieving relapse-free survival.

PMID- 12489057
TI  - Chemotherapy for good-risk germ-cell tumors.
AB  - Patients with good-risk germ-cell tumors have a high likelihood of cure with an
      approach that integrates cisplatin-based chemotherapy, surgery, radiation, and
      observation. This article addresses risk group allocation as well as the
      controversies regarding the composition, number of cycles, and dosages of
      chemotherapy regimens used in this population. Recent data from randomized trials
      demonstrate that carboplatin is inferior to cisplatin and that the dose of
      etoposide should be 500 mg/m(2) per course. Bleomycin remains controversial in
      good-risk germ-cell tumors, but the literature suggests that both E(500)P for
      four cycles or BE(500)P for three cycles may be considered standard.

PMID- 12489058
TI  - Poor prognosis germ-cell tumors: An unresolved challenge.
AB  - The prognostic classification developed by the International Germ Cell Consensus
      group (IGCCC) enables appropriate choice of initial treatment, and provides
      consistent eligibility criteria for clinical trials and more accurate assessment
      of published results. The standard therapy for IGCCC poor- and intermediate
      prognosis germ-cell tumors is 4 cycles of bleomycin, etoposide, and cisplatin
      chemotherapy followed by surgical resection of residual masses, if the serum
      tumor markers have returned to normal. Improved outcomes are achieved by centers
      that treat a larger number of cases. The unsatisfactory results achieved with
      current therapy warrant entry of these patients into appropriate clinical trials.
      Future improvements in therapy are likely to require a better understanding of
      the molecular mechanisms of resistance and the development of novel therapeutic
      approaches that target these mechanisms.

PMID- 12489059
TI  - The role of adjunctive postchemotherapy surgery for nonseminomatous germ-cell
      tumors: current concepts and controversies.
AB  - Adjunctive surgical resection of residual disease after chemotherapy is a
      critical part of the comprehensive management of patients with advanced
      nonseminomatous germ-cell tumor (NSGCT). Surgical resection is indicated in the
      presence of residual radiographic abnormalities and normal serum tumor markers.
      Necrosis, teratoma, and viable carcinoma can be found at any resected site. After
      induction chemotherapy, necrosis comprises approximately 50% of histologic
      findings, teratoma 40%, and viable GCT the remaining 10%. A number of
      investigators have attempted to predict the presence of necrosis in an effort to
      obviate surgery. A number of variables predictive of necrosis have been
      identified and tested prospectively, including: degree of tumor shrinkage, size
      of pre- and posttreatment mass(es), prechemotherapy markers, and teratomatous
      components in the orchiectomy specimen. However, the risk for a false-negative
      prediction remains approximately 20%. The most rigorous approach remains a
      retroperitoneal lymph node dissection (RPLND). Furthermore, the histologic
      discordance between different sites ranges from 29% to 46%; thus, all sites of
      residual disease should be resected. The patient's prognosis is influenced by:
      (1) completeness of resection, and (2) biology of the tumor (histology of
      residual mass(es), marker status at the time of RPLND, and prior burden of
      therapy). Surgical boundaries and completeness of dissection should not be
      compromised in an attempt to preserve ejaculation.

PMID- 12489060
TI  - Serum plant sterols as a potential risk factor for coronary heart disease.
AB  - In patients with the inherited disease of phytosterolemia, elevated
      concentrations of plant sterols (eg, campesterol and sitosterol) have been
      implicated as a risk factor for premature atherosclerosis. Whether plasma
      concentrations of campesterol and sitosterol are risk factors for coronary heart
      disease (CHD) in nonphytosterolemia subjects has not been established. Therefore,
      the present study examined the role of plant sterols in patients admitted for
      elective artery coronary bypass graft (ACBG). Serum concentrations of campesterol
      and sitosterol, as well as lathosterol, desmosterol, cholestanol, and
      lipoproteins were analyzed in 42 men and 11 women without lipid-lowering
      treatment during the past. Twenty-six patients reported a positive family history
      in their first-degree relatives for CHD. Lipid profile and other risk factors
      were comparable in both groups. Patients with a positive family history for CHD
      had significant higher plasma levels of campesterol (.50 +/-.17 v.38 +/-.16
      mg/dL; P =.011), sitosterol (.40 +/-.11 v.31 +/-.11 mg/dL; P =.004) and their
      ratios to cholesterol. Lathosterol, desmosterol, cholestanol, and their ratios to
      cholesterol were not significantly different. Analysis of covariance (ANCOVA)
      analysis showed no influence of sex, age, triglycerides, total-, low-density
      lipoprotein (LDL)-, and high-density lipoprotein (HDL)-cholesterol on the
      results, but confirmed a strong influence of plant sterols. These findings
      support the hypothesis that plant sterols might be an additional risk factor for
      CHD.

PMID- 12489061
TI  - Brain glucose levels are elevated in chronically hyperglycemic diabetic rats: no
      evidence for protective adaptation by the blood brain barrier.
AB  - Recent evidence suggests that brain function may be impaired by prolonged
      elevations of blood glucose, such as those that occur in poorly controlled
      diabetes. However, little is known about the effects of such hyperglycemia on
      brain metabolic substrate levels. Using microdialysis in awake, freely moving
      rats, we directly measured brain extracellular fluid (ECF) glucose, lactate, and
      beta-hydroxybutyrate (betaOHB) levels in the inferior colliculus in chronically
      hyperglycemic BB/wor diabetic rats and in control (Sprague-Dawley) rats during
      euglycemia and acute hyperglycemia. The ECF:plasma glucose ratio (0.27 to 0.34)
      was remarkably similar in animals from all 3 groups, resulting in proportional
      elevations of brain ECF glucose in the hyperglycemic groups. Moreover, brain ECF
      levels of lactate and beta-OHB were increased in diabetic (DM) rats as compared
      with controls. Our results suggest that no significant protective adaptation of
      the blood brain barrier (BBB) transfer of glucose occurs in chronic
      hyperglycemia. Hence, brain tissue may be chronically exposed to markedly
      elevated levels of glucose and other metabolic fuels during poorly controlled
      diabetes, and therefore it may be subject to the same long-term adverse effects
      of hyperglycemia seen in peripheral tissues.

PMID- 12489062
TI  - Repetitive deformation and pressure activate small bowel and colonic mucosal
      tyrosine kinase activity in vivo.
AB  - Physical forces like deformation and pressure modulate signaling and phenotype in
      cultured cells. However, it is more difficult to establish that such phenomena
      occur in vivo. We studied the effects of 0 to 10 minutes of rhythmic distension
      with an isotonic electrolyte and polyethylene glycol solution to 30 cm H(2)O
      pressure on defunctionalized small and large bowel segments in adult male Sprague
      Dawley rats. Mucosa was harvested at 0, 1, and 10 minutes and assayed for
      tyrosine kinase activity. Rhythmic distension caused a time-dependent increase in
      colonic mucosal tyrosine kinase activity, which was statistically significant at
      10 minutes (140% +/- 41% increase, n = 5, P <.05). Small bowel tyrosine kinase
      activity was markedly lower than that observed in the colon, but achieved a
      statistically significant increase at 5 minutes after initiation of rhythmic
      distension. (115% +/- 44% increase, n = 5, P <.05).

PMID- 12489063
TI  - Physiologic changes after diet combined with structured aerobic exercise or
      lifestyle activity.
AB  - Moderate intensity physical activity achieved through changes in lifestyle may
      promote weight management. However, little is known about changes in physiologic
      and metabolic variables when patients lose weight using moderate intensity
      lifestyle activity instead of traditional structured vigorous aerobic exercise.
      To compare changes in resting metabolic energy expenditure (REE), fat mass (FM),
      and fat-free mass (FFM) associated with a 12-week weight loss program combined
      with either: (1) aerobic exercise (AER); or (2) lifestyle activity (LIFE), we
      randomized 39 overweight adults (mean body mass index [BMI] = 30.9 +/- 2.8
      kg/m(2)) to either diet plus AER (N = 18) or diet plus LIFE (N = 21). Both groups
      consumed a self-selected diet of 1,200 to 1,800 kcal/d (5,021 to 7,531 kJ/d). The
      AER group performed vigorous aerobic exercise for up to 45 minutes 3 to 4 d/wk.
      The LIFE group accumulated 30 minutes of moderate intensity physical activity on
      most days of the week. Compliance with the respective protocols was monitored on
      a weekly basis. REE was measured before and after treatment via open-circuit
      spirometry. The AER group decreased body weight by 8.4% (P<.001)while the LIFE
      had a reduction of 6.7% (P <.001) after treatment. Over the course of the
      interventions, the AER and LIFE groups experienced 10.9% (P <.001) and 10.2% (P
      <.001) reductions in REE, respectively. Aerobic exercise did not prevent
      reductions in REE to a greater extent than did lifestyle activity in patients
      consuming a reduced calorie diet. Change in REE was not related to changes in FFM
      or FM for either group, and there were no differences between groups in
      reductions of REE, weight, FM, or FFM. A program of diet plus lifestyle physical
      activity may be a suitable alternative for dieting adults who have difficulty
      adhering to a program of vigorous activity.

PMID- 12489064
TI  - Replacement of dietary saturated fat with trans fat reduces serum paraoxonase
      activity in healthy men and women.
AB  - A high intake of saturated fat and of trans isomers of unsaturated fat is
      associated with increased risk of cardiovascular disease. Recently, we found that
      replacement of saturated fat by trans fat in a dietary controlled study with 32
      men and women decreased serum high-density lipoprotein (HDL)-cholesterol and
      impaired endothelial function, suggesting that trans fats have stronger adverse
      effects than saturated fats. To investigate this further, we measured the
      activity of serum paraoxonase (PON1) in serum samples of the same volunteers
      after consumption of both diets. PON1 protects lipoproteins from oxidative
      damage, and higher PON1 activity appears to be related to lower cardiovascular
      disease risk. PON1 activity (mean +/- SD) was 195.9 +/- 108.9 U/L after 4 weeks
      of consuming a diet with 22.9% of energy (en%) from saturated fat and 184.5 +/-
      99.3 U/L when 9.3 en% from saturated fat was replaced by trans fat (P =.006).
      Thus, replacement of dietary saturated fat by trans fat not only decreased serum
      HDL-cholesterol and impaired endothelial function, but also decreased the
      activity of serum paraoxonase. Whether the changes in serum paraoxonase activity
      caused the changes in endothelial function needs to be further investigated.

PMID- 12489065
TI  - Long-term fructose intake: biochemical consequences and altered renal histology
      in the male rat.
AB  - The use of fructose as a pure sugar has considerably increased in the last 3
      decades, especially as a sweetener in carbonated beverages. Our previous studies
      showed that long-term fructose intake adversely affected several age-related
      metabolic parameters. The purpose of the present study was to compare the
      consequences of long-term fructose intake with those of glucose or sucrose on
      renal morphology and on several biochemical parameters used to estimate renal
      function. Male rats were fed a commercial diet for 16 months, and had free access
      either to water (control) or to 250 g/L solutions of fructose, glucose, or
      sucrose. Fructose-drinking rats exhibited higher liver weights compare to the
      other dietary groups. Control rats excreted significantly less urinary output
      than all sugar groups, which did not differ from each other. No differences were
      observed in fasting plasma fructose, glucose, and creatinine levels, or in
      urinary glucose levels. Fructose consumption resulted in elevated urinary
      fructose levels, higher creatinine clearance, and marked proteinuria. The tested
      sugars had influence on the molecular weight distribution of urinary proteins in
      the ranges of 10 to 16, 25 to 35, and 75 to 85 kd. Histological examination
      revealed that fructose consumption led to the formation of foci of cortical
      tubular necrosis with chronic inflammatory infiltrate, accumulation of tubular
      hyaline casts, thickening of the Bowman's capsule, mesangial thickening due to
      collagen deposits, and the occurrence of hemosiderin in tubular cells. These data
      suggest that fructose has a negative impact on kidney function and morphology.
      Further research is required to elucidate the precise mechanisms by which long
      term fructose consumption hampers renal metabolism.

PMID- 12489066
TI  - Combination therapy of alpha-glucosidase inhibitor and a sulfonylurea compound
      prolongs the duration of good glycemic control.
AB  - The aim of this study was to investigate whether combination therapy of alpha
      glucosidase inhibitor and a sulfonylurea (SU) drug can prolong the duration of
      good glycemic control compared with SU alone in patients with type 2 diabetes.
      The open prospective study included 124 Japanese patients with type 2 diabetes
      and inadequate glycemic control (hemoglobin A(1c) [HbA(1c)] gt; 7.0%). Patients
      were given either voglibose plus a SU compound (glibenclamide or gliclazide, n =
      61) or SU drug alone (n = 63). The first 6-month run-in period (targeted to
      HbA(1c) </= 7.0%) was followed by treatment for 3 years. The endpoint was
      deterioration of glycemic control (HbA(1c) >/= 8.0%). Fifty patients on
      combination therapy and 48 patients on SU alone completed the trial. During the
      follow-up, 21 patients on combination therapy and 30 patients on SU alone showed
      deterioration of glycemic control and reached the endpoint (P =.04). The
      combination therapy significantly prolonged the duration of good glycemic control
      (HbA(1c) < 8.0%) compared with SU alone by Kaplan-Meier estimated survival
      analysis using a log-rank test (P =.02). Thus, combination therapy with voglibose
      and a SU agent prolongs the duration of good glycemic control compared with SU
      alone in patients with type 2 diabetes.

PMID- 12489067
TI  - Altered renal microvascular response in Zucker obese rats.
AB  - Although available evidence demonstrates that obesity manifests insulin
      resistance and causes glomerular sclerosis, it has not been determined whether
      insulin resistance alters the renal microvascular reactivity. This study examined
      whether insulin- and acetylcholine (ACH)-induced vasodilation was impaired in
      Zucker obese rats, and attempted to clarify the change in myogenic afferent
      arteriolar constriction, a determinant of glomerular pressure. Isolated perfused
      hydronephrotic rat kidneys were used to visualize the renal microcirculation. In
      Zucker lean rats, insulin (10 to 300 microU/mL) inhibited norepinephrine (NE)
      induced afferent and efferent arteriolar constriction in a dose-dependent manner,
      with 112 % +/- 8% and 98% +/- 8% reversal at 300 microU/mL Similarly, ACH
      elicited dose-dependent dilation of these vessels. In Zucker obese rats, by
      contrast, afferent and efferent arterioles failed to dilate in response to
      insulin, and manifested diminished vasodilator responses to acetylcholine In the
      presence of nitro-L-arginine methylester (LNAME; 100 micromol/L), ACH (10
      micromol/L) induced transient afferent arteriolar dilation (121% +/- 9% reversal)
      in Zucker lean rats, whereas this response was blunted in obese rats (72% +/- 8%
      reversal) Furthermore, myogenic afferent arteriolar constriction by elevating
      renal arterial pressure to 180 mm Hg was diminished in Zucker obese rats (-14% +/
      3% decrement in diameter), compared with that in lean rats (-23% +/- 2%
      decrement) Finally, the impairment in these vasodilator and vasoconstrictor
      responses was partially prevented by troglitazone, an insulin-sensitizing agent.
      Collectively, in insulin resistance, renal microvessels are refractory to the
      vasodilator action of insulin. Furthermore, "renal insulin resistance" is
      associated with the impaired vasodilator responses to ACH-induced nitric oxide
      (NO) and the diminished vasoconstrictor responses to pressure. The blunted
      myogenic afferent arteriolar constriction would allow glomerular hypertension,
      and in concert with the impaired endothelium-dependent vasodilation, could be
      responsible for the development of glomerular injury in obesity.

PMID- 12489068
TI  - Chronic alcohol feeding and its influence on c-Fos and heat shock protein-70 gene
      expression in different brain regions of male and female rats.
AB  - Excessive ingestion of the macronutrient, alcohol, causes devastating
      complications in the brain leading to atrophy and impaired cognitive function
      with corresponding increases in morbidity and mortality and, consequently,
      reduced quality of life measures. The pathogenic mechanisms are unknown, but
      various studies have shown that the immediate early genes and heat shock (ie,
      stress or chaperone) proteins are increased in alcohol-exposed tissue. However,
      many of these studies have been performed in vitro or have failed to consider
      either the nutritional elements in the experimental design by appropriate use of
      pair-feeding or whether there are regional and/or gender differences. We
      hypothesized that (1) increased expression of heat shock proteins and/or
      oncogenes occur as a consequence of alcohol-feeding in vivo, and sensitivities
      are related to different (2) gender and (3) brain regions. To test this, we fed
      male and female rats nutritionally complete diets containing ethanol as 35% of
      total calories (treated) or isocaloric amounts of the same diet in which ethanol
      was replaced by isocaloric glucose (controls). At the end of 6 weeks, rats were
      killed and c-Fos and heat shock protein-70 (HSP70) mRNA analyzed in midbrain,
      cortex, brainstem, and cerebellum by reverse transcription-polymerase chain
      reaction (RT-PCR) with an endogenous internal standard, beta-actin. The results
      showed that there were distinct regional differences (P at least <.05) in both c
      Fos (cerebellum > cortex > midbrain and brainstem) and HSP70 (brainstem and
      cerebellum > cortex and midbrain). However, the only significant effect of
      alcohol feeding occurred in the HSP70 mRNA in midbrain of male rats, which was
      reduced by approximately 50% (P <.01). In contrast, no corresponding effect of
      alcohol feeding was observed in c-Fos mRNA levels in either midbrain or other
      regions of female rats. These data show that chronic ethanol feeding has no
      demonstrable effect on c-Fos mRNA expression in the brain when using
      nutritionally complete liquid diet regimens with concomitant pair-feeding. HSP70
      mRNA, in contrast, is reduced by alcohol feeding and appears to be regional and
      gender dependent.

PMID- 12489069
TI  - Fetal nutrition and muscle oxygen supply in childhood.
AB  - Fetal undernutrition may increase the risk of insulin resistance syndrome in
      adult life and low birth weight carries with it the risk of endothelial
      dysfunction. We studied 59 prepubertal and adolescent children whose birth weight
      exceeded 2.5 kg. We related their birth weight and ponderal index (PI)
      (weight/length(3)) at birth to muscle oxygen supply (assessed by near infrared
      spectroscopy [NIRS]) and to variables associated with increased risk of
      developing the insulin resistance syndrome (ie, abdominal subcutaneous and
      visceral fat volumes, percentage body fat, fasting leptin, insulin, and glucose
      levels). Birth weight was not associated with muscle oxygen supply or any other
      independent variable measured. In the prepubertal group, there was a significant
      inverse relation between PI and muscle reoxygenation half-time in both the male
      (R =.58, P =.03) and female (R =.72, P =.009) groups. This relationship was not
      present in either the male (R =.03, P =.90) or female (R =.09, P =.75) adolescent
      groups. In a population in which low birth weight subjects were excluded, low PI
      at birth is associated with poor muscle oxygen supply in early childhood, but
      this relationship is not present in adolescence.

PMID- 12489070
TI  - The relationship between psychological risk attributes and the metabolic syndrome
      in healthy women: antecedent or consequence?
AB  - The metabolic syndrome is an important risk factor for major chronic diseases in
      women. A key component of the syndrome, central adiposity, is correlated with
      psychological risk factors associated with coronary artery disease in prior
      epidemiological studies. We evaluated if psychological risk factors predicted the
      metabolic syndrome and if the metabolic syndrome predicted psychological
      distress. A population-based cohort of 425 women who were middle-aged, and pre-,
      peri-, and postmenopausal was followed for an average 7.4 years. Psychological
      risk factors, including depression, anxiety, tension, current perceived stress,
      and anger, and biological components of the metabolic syndrome, including
      glucose, triglycerides, high-density lipoprotein (HDL)-cholesterol, waist
      circumference, and blood pressure (BP) were measured at baseline and at
      examinations 1 to 8 years postmenopause. Women were classified according to the
      National Heart, Lung, and Blood Institute (NHLBI) criteria for metabolic
      syndrome. Women who exhibited high levels of depression, tension, and anger at
      baseline, and increased in anger during the follow-up had elevated risk for
      developing the metabolic syndrome during follow-up, P <.04. The metabolic
      syndrome at baseline, in turn, predicted increasing anger and anxiety 7.4 years
      later, P <.001. Psychological risk factors affect the development of the
      metabolic syndrome. The association between anger and the metabolic syndrome is
      reciprocal. Reduction in the level of psychological distress may prevent the
      development of the metabolic syndrome in women.

PMID- 12489071
TI  - C-reactive protein and insulin resistance in non-obese Japanese type 2 diabetic
      patients.
AB  - The aim of the present study was to investigate the relationship between C
      reactive protein (CRP) and insulin resistance in non-obese Japanese type 2
      diabetic patients. A total of 135 non-obese Japanese type 2 diabetic patients (96
      men and 39 women, aged 36 to 83 years, with a body mass index [BMI] of 16.2 to
      26.8 kg/m2) were studied. BMI, glycosylated hemoglobin (HbA(1c)), fasting
      concentrations of plasma glucose, serum lipids (triglycerides, low-density
      lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and
      total cholesterol), CRP, and fibrinogen were measured. LDL cholesterol was
      calculated using the Friedewald formula. Insulin resistance was estimated by the
      insulin resistance index of homeostasis model assessment (HOMA-IR). Univariate
      regression analysis showed that CRP value was positively correlated to age (r =
      0.218, P =.012), BMI (r = 0.239, P =.006), HOMA-IR (r = 0.397, P <.0001),
      triglycerides (r= 0.310, P <.005), LDL cholesterol (r= 0.179, P =.038), and
      fibrinogen (r = 0.371, P <.0001) levels and inversely correlated to HDL
      cholesterol (r = 0.174, P =.044) level in our diabetic patients. Multiple
      regression analysis showed that CRP was independently predicted by HOMA-IR
      (P<.0001, F = 11.6) and fibrinogen (P<.0001, F = 34.2), which explained 23.5% of
      the variability of CRP in our non-obese Japanese type 2 diabetic patients. These
      results indicate that insulin resistance and fibrinogen level are independent
      predictors of CRP in non-obese Japanese type 2 diabetic patients.

PMID- 12489072
TI  - Comparison of insulin sensitivity and glucose effectiveness determined by the one
      and two-compartment-labeled minimal model in late prepubertal children and early
      adolescents.
AB  - Multiple methods are used to determine insulin sensitivity. Most commonly used in
      children are euglycemic-hyperinsulinemic clamp and frequently sampled intravenous
      glucose tolerance (FSIVGTT) with minimal modeling (MinMod). The parameters S(G)
      and S(I) of MinMod are related to insulin sensitivity and glucose effectiveness,
      respectively, but inappropriate modeling of glucose kinetics causes inaccuracies.
      Glucose tracer use may mitigate such inaccuracies, allowing use of multiple
      modeling approaches, including a 2-compartment model (2CMM). This study was
      designed to compare the 1-compartment model (1CMM) and 2CMM in a pediatric
      population. Twenty-three children were studied 4 times using FSIVGTT with [6,6]
      D(2) glucose. Glucose effectiveness and insulin sensitivity were calculated by
      1CMM (S*(G1) and S*(I1)) and 2CMM (S*(G2) and S*(I2)). Indices were reliably
      estimated in 86 of 87 tests for 1CMM, but only in 49 for 2CMM. S*(G1)
      overestimated S*(G2), but they were positively related. S*(I1) and S*(12) were
      not different and were positively related. This suggests that inadequate modeling
      by the 1CMM has a smaller impact on glucose tolerance indices in children than in
      adults. Comparison with classical MinMod gave results analogous to those in
      adults (MinMod S(G) was larger than S*(G1), MinMod S(I) was smaller than S*(I1)).
      These results demonstrate significant differences in glucose effectiveness, but
      not insulin sensitivity, as measured by 1CMM and 2CMM in early adolescents. Thus,
      when insulin sensitivity is the primary interest, the 1CMM is more robust because
      its parameters are more reliably estimated than those of 2CMM and is the logical
      choice in pediatric population-based studies.

PMID- 12489073
TI  - Exercise training does not reduce hyperlipidemia in pigs fed a high-fat diet.
AB  - The pig is often used as a model for studying lipoprotein metabolism as it
      relates to human atherosclerosis, but few studies have examined the complete
      lipoprotein profile and related enzymes in swine ingesting an atherogenic diet.
      We examined whether exercise training would moderate the effects of an
      atherogenic diet on lipoproteins and lipoprotein lipase (LPL) activity in
      miniature swine. Male (n = 30) and female (n = 32) swine were initially divided
      into 2 dietary groups: one consumed low-fat (8%) pig chow, and one consumed pig
      chow supplemented with 2% cholesterol, 17.1% coconut oil, 2.3% corn oil, and.7%
      sodium cholate (46% kcal from fat). Following 30 days on the diets, pigs from
      each diet group were further divided into sedentary and exercise trained
      subgroups, each cell with 6 to 8 pigs. Training occurred 5 days per week on a
      treadmill in which the intensity and duration were progressively increased during
      the 16- to 20-week training period to 75 minutes of aerobic running per session.
      A 4-way analysis of variance (ANOVA) with repeated measures on time indicated
      that at the conclusion of the study the atherogenic diet caused significantly (P
      <.05) increased cholesterol, triglyceride (TG), high-density lipoprotein
      cholesterol (HDL-C) and subfractions, low-density lipoprotein cholesterol (LDL-C)
      and subfractions, and LPL activity in both genders. For cholesterol, TG, HDL-C,
      HDL(2)-C, LDL-C, LDL(1&2)-C, and hepatic lipase, the female response to the diet
      was exaggerated compared to the male response. Exercise training produced no
      group differences or interactions on any lipoprotein variable. These results
      suggest that an atherogenic diet has a greater impact on the lipoproteins of
      female miniature swine than males. Furthermore, under the conditions of this
      study, exercise training does not moderate the effects of an atherogenic diet on
      lipoproteins.

PMID- 12489074
TI  - A dietary portfolio approach to cholesterol reduction: combined effects of plant
      sterols, vegetable proteins, and viscous fibers in hypercholesterolemia.
AB  - Plant sterols, soy proteins, and viscous fibers are advised for cholesterol
      reduction but their combined effect has never been tested. We therefore assessed
      their combined effect on blood lipids in hyperlipidemic subjects who were already
      consuming a low-saturated fat, low-cholesterol diet before starting the study.
      The test (combination) diet was 1 month in duration and was very low in saturated
      fat and high in plant sterols (1 g/1,000 kcal), soy protein (23 g/1,000 kcal),
      and viscous fibers (9 g/1,000 kcal) obtained from foods available in supermarkets
      and health food stores. One subject also completed 2 further diet periods: a low
      fat control diet and a control diet plus 20 mg/d lovastatin. Fasting blood
      lipids, blood pressure, and body weight were measured prior to and at weekly
      intervals during the study. The combination diet was rated as acceptable and very
      filling. The diet reduced low-density lipoprotein (LDL)-cholesterol by 29.0% +/-
      2.7% (P <.001) and the ratio of LDL-cholesterol to high-density lipoprotein (HDL)
      cholesterol by 26.5% +/- 3.4% (P <.001). Near maximal reductions were seen by
      week 2. In the subject who took Mevacor and control diets each for 4 weeks, the
      reduction in LDL:HDL-cholesterol on Mevacor was similar to the combination diet.
      We conclude that acceptable diets of foods from supermarkets and health food
      stores that contain recognized cholesterol-lowering dietary components in
      combination (a dietary portfolio) may be as effective as the starting dose of
      older first-line drugs in managing hypercholesterolemia.

PMID- 12489075
TI  - Upregulation of fatty acid synthase gene expression in experimental chronic renal
      failure.
AB  - Hypertriglyceridemia associated with chronic renal failure (CRF) and elevated
      plasma concentration of very-low-density lipoprotein (VLDL) are thought to be a
      consequence of the depressed lipoprotein lipase and hepatic lipase activities and
      impaired clearance of lipoproteins. However, there is some evidence that the
      lipoproteins overproduction might also contribute to hypertriglyceridemia in CRF.
      This study was performed to test the hypothesis that the increased rate of
      lipogenesis consequent to upregulation of fatty acid synthase (FAS), a key
      lipogenic enzyme, gene expression could contribute to overproduction of
      triacylglycerols and to hypertriglyceridemia in CRF. FAS activity, FAS protein
      mass (Western blot analysis), and FAS mRNA level (Northern blot analysis) in
      liver and epididymal white adipose tissue (WAT) were measured in male Wistar rats
      6 weeks after subtotal (5 of 6) nephrectomy or sham operation. Moreover, the rate
      of lipogenesis in WAT was determined. The CRF group showed significant increase
      in FAS gene expression (measured as activity, mRNA, and protein abundance) in
      both liver and WAT. This was associated with the increase in the lipogenesis rate
      and with the increase in plasma triacylglycerol and VLDL concentrations. Our
      results suggest that not only decreased removal, but also an increase of
      triacylglycerol production could contribute, in part, to the CRF-associated
      hyperlipidemia. Upregulation of FAS gene expression, shown in this report for the
      first time, reveals another factor involved in disturbed lipid metabolism in CRF.
      It seems that elevated plasma insulin and cytokine concentration could play an
      important role in the mechanism responsible for the increased FAS gene expression
      in CRF.

PMID- 12489076
TI  - Gene expression profiling using advanced mass spectrometric approaches.
AB  - In the era of systems biology, computational and high-throughput experimental
      biological approaches are increasingly being combined to provide global snapshots
      of entire genomes and proteomes under tissue- and disease-specific conditions.
      The aim is to identify proteins changing in concentration and/or post
      translational state and/or location, and develop a better molecular level
      understanding of the operation of biological systems. Here we describe an
      approach for comparative proteomics that builds upon the combination of high
      performance nano-scale separations with the high-mass measurement accuracy, mass
      resolving power and sensitivity of Fourier transform ion cyclotron resonance mass
      spectrometry to provide broad dynamic range, comprehensive and quantitative
      proteome measurements.

PMID- 12489077
TI  - Proceedings of the 20th Informal Meeting on Mass Spectrometry. May 12-16, 2002.
      Fiera di Primiero, Italy.

PMID- 12489078
TI  - A new external EI/CI source-ion trap system devoted to the study of ion-molecule
      reactions.
AB  - A new instrumental arrangement dedicated to the study of ion-molecule reactions
      and consists of by an electron impact/chemical ionization source mounted 420 mm
      away from an ion trap is described. It has been designed and developed to exclude
      diffusion into the ion trap of the neutral reactants from the EI/CI source and so
      to avoid undesired side-reactions. Its instrumental parameterization is described
      and some preliminary results are illustrated that show promise for the successful
      application of the system to the study of ion-molecule reactions.

PMID- 12489079
TI  - Gas-phase ion chemistry in the ternary SiH4-C3H6-NH3 system.
AB  - The gas-phase ion chemistry of propene-ammonia and silane-propene-ammonia
      mixtures was studied by ion trap mass spectrometry. As far as the binary mixture
      is concerned, the effect of different molar ratios of the reactants on the trend
      of ion species formed was evaluated, the ion-molecule reaction processes were
      identified and the rate constants for the main processes were measured. The
      results were compared with the collisional rate constants to determine the
      reaction efficiencies. In the ternary silane-propene-ammonia mixture the
      mechanisms of formation of Si(m)C(n)N(p)H(q)(+) clusters were elucidated and the
      rate constants of the most important steps were measured. For some species,
      selected by double isolation (MS/MS), the low abundance of the ions allowed us to
      determine the reaction paths but not the rate constants. Ternary ions are mainly
      formed by reactions of Si(m)C(n)H(q)(+) ions with ammonia, whereas a minor
      contribution comes from reactions of Si(m)N(p)H(q)(+) ions with propene. On the
      other hand, the C(n)N(p)H(q)(+) ions showed a very low reactivity and no step
      leading to ternary ion species was identified. The formation of hydrogenated
      ternary ions with Si, C and N has a basic importance in relation to their
      possible role as precursors of amorphous silicon carbides doped with nitrogen
      obtained by deposition from silane-propene-ammonia mixtures properly activated.

PMID- 12489080
TI  - Capillary electrophoresis/mass spectrometry: a promising tool for the control of
      some physiologically hazardous compounds. I-derivatives of 3-quinuclidinol.
AB  - A method based on the coupling of capillary electrophoresis with mass
      spectrometry (CE/MS) was developed for the monitoring of 3-quinuclidinol and its
      four N-alkyl derivatives (methyl, ethyl, propyl and isopropyl derivatives). A
      fragmentation study (collision-induced dissociation of ions in an ion trap) and
      optimization of the ion optics set-up for CE/MS experiments using direct infusion
      of a methanolic solution of the standards into the mass spectrometer were carried
      out in advance. Molecular ions of all quaternary compounds and the quasi
      molecular ion [M + H]+ of free 3-quinuclidinol prevail in the mass spectra. In
      the MS/MS of propyl and isopropyl derivatives, the elimination of the alkyl chain
      dominates, leading to the ion at m/z 128. The fragmentation of the other
      compounds is more complex. Previous CE separation of the mixture of isobaric
      propyl and isopropyl derivatives is necessary for their unambiguous
      identification. A 10 mM ammonium acetate buffer (pH 4.0) is the optimum running
      electrolyte, allowing the CE separation of methyl, ethyl, propyl and isopropyl
      derivatives. A 0.5% (v/v) solution of acetic acid in methanol provides sufficient
      detection sensitivity when used as the sheath liquid. Limits of detection of 0.1
      ppm for 3-quinuclidinol and 0.05 ppm for quaternary derivatives were achieved
      under the optimum conditions. The optimized method was applied to the
      determination of 3-quinuclidinol and related quaternary derivatives spiked into a
      sample of pond water. The experimental set-up for CE/MS/MS was investigated,
      which strongly increases the identification capability of the technique.

PMID- 12489081
TI  - Detoxification of cytotoxic alpha,beta-unsaturated aldehydes by carnosine:
      characterization of conjugated adducts by electrospray ionization tandem mass
      spectrometry and detection by liquid chromatography/mass spectrometry in rat
      skeletal muscle.
AB  - Oxidation of polyunsaturated fatty acids containing phospholipids in tissue
      generates lipid hydroperoxides, which are further degraded to several products,
      among which unsaturated aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) play an
      important role in mediating the pathological effects of oxidative stress. While
      the reaction of HNE with glutathione (GSH) is a well recognized pathway of
      detoxification in biological systems, no data are available on HNE interactions
      with carnosine, a dipeptide (beta-alanyl-L-histidine) present in high
      concentration in skeletal muscle. The aim of this work was to study the quenching
      ability of carnosine towards HNE and to characterize the reaction products by
      electrospray ionization tandem mass spectrometry (ESI-MS/MS), using GSH as a
      model peptide. GSH incubation with HNE in 1 mM phosphate buffer (pH 7.4) results
      in the complete disappearance of HNE within 1 h owing to the formation of a
      Michael adduct, S-(4-hydroxynonanal-3-yl)glutathione. The reaction of HNE with
      carnosine was studied in different molar ratios and monitored up to 24 h by high
      performance liquid chromatography (HPLC) (HNE consumption), MS/MS (infusion) and
      liquid chromatography mass spectrometry (LC/MS) experiments. Carnosine, although
      less reactive than GSH, significantly quenched HNE (48.2 +/- 0.9% HNE consumption
      after 1 h; carnosine:HNE molar ratio 10 : 1). Two reaction products were
      identified: the Michael adduct, N-(4-hydroxynonanal-3-yl)carnosine involving the
      imidazolic nitrogen of histidine, and the imine adduct, involving the amino group
      of the beta-alanine residue. Definitive structure assignment was achieved by
      chemical reduction with NaBH(4) and multinuclear magnetic resonance experiments.
      To understand whether carnosine acts as a quencher of unsaturated aldehydes in
      biological matrices, rat skeletal muscle homogenate was incubated with HNE and
      the formation of conjugated adducts was determined by LC/MS analysis. Three main
      products were detected and identified as Michael adducts of HNE with GSH,
      carnosine and anserine (the N-methylated derivative of carnosine, present in high
      concentrations in rat muscle). The results indicate that beside GSH, histidine
      containing dipeptides could be involved in the detoxification pathway of reactive
      aldehydes from lipid peroxidation generated in skeletal muscle during physical
      endurance.

PMID- 12489082
TI  - Solid-phase microextraction gas chromatography/ion trap mass spectrometry and
      multistage mass spectrometry experiments in the characterization of germacrene D.
AB  - Germacrene D is a vegetable pheromone utilized in interactions among organisms
      belonging to different species. For the first time, using solid-phase
      microextraction/gas chromatography/ion trap mass spectrometry, the presence of
      this compound was detected in an in vitro mycorrhizal synthesis system where the
      mycelium of the ectomycorrhizal fungus Tuber borchii Vittad. interacts with the
      plant Tilia Americana L. From this symbiosis, a new structure, called
      ectomycorrhiza, is formed where the two symbionts exchange nutrients and
      metabolites. It seems that only after this interaction can the mycelium develop
      the fruitbody, commonly known as truffle. The results obtained allowed us to
      ascertain that germacrene D was synthesized by the plant exclusively in the
      presence of T. borchii. The originality of these data prompted us to hypothesize
      that this compound could be involved in the first step of ectomycorrhiza
      formation, as it is able to stimulate specific fungi receptors. In fact, plants
      release hundreds of secondary metabolites that are important in their
      interactions with other organisms.

PMID- 12489083
TI  - Mass spectrometric investigation of gallium and zirconium complexes with
      octaethylporphyrin and tetraphenylporphyrin.
AB  - Gallium and zirconium octaethylporphyrin (OEP) and tetraphenylporphyrin (TPP)
      were examined by electrospray ionization (ESI) mass spectrometry. All systems
      were prepared in dichloromethane with addition of a stabilizing lipophilic
      anionic agent, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB). In
      the solutions examined both monomeric and dimeric metalloporphyrins were
      observed. In the gallium-OEP mass spectrum the ion registered at m/z 601 was
      attributed to monomeric [Ga(OEP)](+) and that at m/z 1219 to the dimeric form,
      [[Ga(OEP)](2)OH](+). Peaks appearing in the ESI mass spectra of zirconium systems
      were substantially less intense, probably owing to the relatively low stability
      of complexes of this metal caused by its different geometry preferences. The most
      abundant monomeric zirconium-OEP complexes were [[Zr(OEP)OH]](+) (m/z 639) and
      [Zr(OEP)Cl](+) (m/z 657), and dimeric [[Zr(OEP)OH](2)](2+) (m/z 639). Analogous
      species were observed in the Zr(TPP) system: monomeric [[Zr(OEP)OH]](+) (m/z 719)
      and [Zr(TPP)Cl](+) (m/z 737) and dimeric [[Zr(TPP)OH](2)](2+) (m/z 719). In both
      cases series of other dimers, e.g. [[Zr(OEP)](2)O(2)H](+) (m/z 1277),
      [[Zr(OEP)OH](2)Cl](+) (m/z 1313), [Zr(TPP)(2)O(2)H](+), (m/z 1437),
      [[Zr(TPP)OH](2)OH](+) (m/z 1455) and [[Zr(TPP)OH](2)Cl](+) (m/z 1473), appeared.
      The results obtained confirmed the hypothesis concerning the formation of dimeric
      metalloporphyrins in solutions containing stabilizing lipophilic anions. It also
      allowed us to explain the super-Nernstian slopes of the calibration curves
      towards primary anions of ion-selective electrodes with membranes containing the
      examined metalloporphyrins.

PMID- 12489084
TI  - Atmospheric pressure ionization mass spectrometry of purine and pyrimidine
      markers of inherited metabolic disorders.
AB  - Purines and pyrimidines are of interest owing to their significance in processes
      in living organisms. Mass spectrometry is a promising analytical tool utilized in
      their analysis. Two atmospheric pressure ionization (API) methods (electrospray
      ionization (ESI) and atmospheric pressure chemical ionization (APCI)) in both
      negative and positive modes applied to selected purine and pyrimidine metabolites
      (markers of inherited metabolic disorders) were studied. APCI is less sensitive
      to alkali metal cations present in a sample and offers higher response than ESI
      for studied compounds. Both of the techniques afford quasi-molecular ions, but
      fragmentation also occurs to a certain extent. However, the application of
      collision-induced dissociation of quasi-molecular ions is essential to confirm a
      certain metabolite in a sample. Fragmentation of both positive and negative ions
      was evaluated using multi-stage mass spectrometric experiments. Typical neutral
      losses correspond to molecules NH(3), H(2)O, HCN, CO, H(2)NCN, HNCO and CO(2).
      The ion [NCO](-) arises in the negative mode. The cleavage of the glycosidic C-N
      bond is characteristic for relevant metabolites. Other neutral losses (CH(2)O,
      C(2)H(4)O(2) and C(3)H(6)O(3)) originate from fragmentation of the glycosidic
      part of the molecules. In addition to fragmentation, the formation of adducts of
      some ions with applied solvents (H(2)O, CH(3)OH) was observed. The composition of
      the solution infused into the ion source affects the appearance of the mass
      spectra. Tandem mass spectra allow one to distinguish compounds with the same
      molecular mass (uridine-pseudouridine and adenosine-2'-deoxyguanosine). Flow
      injection analysis APCI-MS/MS was tested on model samples of human urines
      corresponding to adenosine deaminase deficiency and xanthine oxidase deficiency.
      In both cases, the results showed potential diagnostic usefulness.

PMID- 12489085
TI  - Development of a gas chromatographic/ion trap mass spectrometric method for the
      determination of levoglucosan and saccharidic compounds in atmospheric aerosols.
      Application to urban aerosols.
AB  - We developed and validated a gas chromatographic/ion trap mass spectrometric
      method for the determination of levoglucosan and the related monosaccharide
      anhydrides, mannosan, galactosan and 1,6-anhydro-beta-D-glucofuranose in urban
      atmospheric aerosols collected on quartz fiber filters. The method is based on
      extraction with dichloromethane-methanol (80 : 20, v/v), trimethylsilylation,
      multiple reaction monitoring in the tandem mass spectrometric mode using the ion
      at m/z 217, and the use of an internal standard calibration procedure with the
      structurally related compound methyl beta-L-arabinopyranoside. In addition, the
      method allows the quantification of other saccharidic compounds, arabitol,
      mannitol, glucose, fructose, inositol and sucrose, which were found to be
      important in summer aerosols. The recovery of levoglucosan was estimated by
      spiking blank filters and was better than 90%. The precision evaluated by
      analyzing parts of the same filters was about 2% for the monosaccharide
      anhydrides and 7% for the other saccharidic compounds in the case of a winter
      aerosol sample, and the corresponding values for a summer aerosol sample were 5%
      and 8%. The method was applied to urban PM(10) (particulate matter of <10 microm
      aerodynamic diameter) aerosols collected at Ghent, Belgium, during a 2000-2001
      winter and a 2001 summer episode and revealed interesting seasonal variations.
      While monosaccharide anhydrides were relatively more important during the winter
      season owing to wood burning, the other saccharidic compounds were more prevalent
      during the summer season, with some of them, if not all, originating from the
      vegetation.

PMID- 12489086
TI  - An unusual rearrangement of Zofenopril, a new ACE inhibitor drug: mass
      spectrometric and conformational studies.
AB  - Zofenopril (1) is a new ACE inhibitor, used in therapy for hypertension and post
      myocardial infarction. The protonated quasi-molecular ion (m/z 430) of 1,
      obtained under positive electrospray ionization conditions, loses a benzoic acid
      molecule (m/z 308), which in turn decomposes via loss of CO (m/z 280) when low
      energy collisional-induced dissociation (CID) and in-source experiments are
      performed. This rearrangement is the main fragmentation process and can be
      observed both in-source and in the product ion tandem mass spectra, using either
      an ion trap or a triple quadrupole instrument. Other known diastereoisomers of 1,
      an impurity with an acetyl in the place of the benzoyl group (2) and an impurity
      with two propanoyl chains in series (3), give the same rearrangement. On the
      other hand, the mass spectra of the methyl ester (4) and an impurity with two
      proline moieties (5) do not show this unusual fragmentation. Time-resolved CID
      spectra of 1 show that the rearrangement occurs after about 2 ms, a time scale
      comparable to those of the other non-rearrangement cleavages. These experiments
      suggest a conformation in the gas phase for 1 in which the benzoyl group is close
      to the hydroxyl of the carboxylic acid group, from which the rearrangement could
      readily occur. Since compounds 4 and 5 do not show the same behaviour, the
      presence of a carboxylic acid in the proline ring seems to play a crucial role in
      the rearrangement, probably due to an intramolecular hydrogen bond. To confirm
      this hypothesis, deuterium exchanges in mass spectrometric experiments and a
      conformational analysis via computational methods were performed.

PMID- 12489087
TI  - Determination of 17beta-estradiol in bovine plasma: development of a highly
      sensitive technique by ion trap gas chromatography-tandem mass spectrometry using
      negative chemical ionization.
AB  - A novel approach to the determination of 17beta-estradiol in bovine plasma is
      presented. The observed enhanced sensitivity is gained by the application of
      tandem mass spectrometry (MS) fragmentation to a stable, well characterized
      negative ion produced by chemical ionization (methane as reagent gas). A specific
      derivatizing reactant is employed (pentafluorobenzyl bromide), combined with bis
      trimethylsilyltrifluoroacetamide, to favor the formation of a diagnostic
      precursor negative ion. Plasma samples are purified through a C18 solid phase
      extraction column and derivatized before gas chromatography-MS analysis. The
      accuracy and the precision of the method, tested over a set of spiked samples,
      were satisfactory. The limit of detection was found to be 5 pg ml(-1) and the
      limit of quantification was fixed at 20 pg ml(-1). The fragmentation pattern is
      fully explained and the method is applicable for the official analysis of bovine
      plasma for the detection of 17beta-estradiol according to the European criteria
      256/93 and to the draft SANCO/1805/2000 rev. 3. The quantification of incurred
      positive samples was performed according to the proposed procedure and compared
      with the results obtained by standardized radio immuno assay; the estimated
      concentrations were significantly similar.

PMID- 12489088
TI  - Direct stereochemical assignment of hexose and pentose residues in flavonoid O
      glycosides by fast atom bombardment and electrospray ionization mass
      spectrometry.
AB  - Mass spectrometric methods have been developed which allow the direct
      stereochemical assignment of terminal monosaccharide residues in flavonoid O
      glycosides without the need for chemical hydrolysis. Standards containing a
      glucose, galactose, mannose, xylose, arabinose or apiose residue were examined
      because these monosaccharides are by far the most commonly encountered in
      flavonoid glycosides. Following acetylation, the major peracetylated sugar
      related fragments, generated by fast atom bombardment (FAB) or electrospray
      ionization (ESI), were selected for collisional activation employing a broad
      range of collision energies. Both FAB and ESI proved to be useful as ionization
      techniques. Stereoselective fragmentation was achieved and allowed us clearly to
      differentiate and characterize isomeric monosaccharide residues. The method
      developed was successfully applied to an unknown flavonoid containing a terminal
      pentose and hexose residue which was isolated from Farsetia aegyptia.

PMID- 12489089
TI  - Isomerization and dissociation of C2X5+ and C2X4+* ions (X = Cl, F) from
      chlorofluoroethanes in an ion trap mass spectrometer.
AB  - The collision-induced dissociation of C(2)X(5)(+) (C(2)Cl(2)F(3)(+),
      C(2)Cl(3)F(2)(+) and C(2)Cl(4)F(+)) and C(2)X(4)(+.) ions (C(2)ClF(3)(+*),
      C(2)Cl(2)F(2)(+*), and C(2)ClF(3)(+*)) derived from three chlorofluoroethanes
      (the isomeric 1,1,1- and 1,1,2-trichlorotrifluoroethane and 1,1,1,2
      tetrachlorodifluoroethane) was investigated by means of multi-stage mass
      spectrometric (MS(n)) experiments in an ion trap mass spectrometer. The
      observation of a common dissociation pattern for ions of any given elemental
      composition suggests that the experiments could not differentiate isomeric
      C(2)X(5)(+) ions formed from different neutral precursors and originally having
      different structures. For any given elemental composition, a common dissociation
      pattern was observed, suggesting that energy barriers for isomer interconversion
      are lower than for dissociation. For ions containing two or more fluorine atoms,
      the major (in some cases unique) dissociation involves C-C cleavage to form
      CX(3)(+) and CF(2). Energetically, CF(2) loss is always the most favorable
      reaction; mechanistically it implies, at least in some cases, rearrangement via
      halogen transfer from one carbon to the other (for example, in the case of the
      C(2)Cl(2)F(3)(+) species derived from 1,1,1-trichlorotrifluoroethane, which
      should have initially the Cl(2)C(+)-CF(3) structure). Similar behavior was
      observed with C(2)X(4)(+*) ions produced both from the three chlorofluoroethanes
      and from model alkenes (trifluorochloroethene and tetrachloroethene). The
      dissociation behavior of these C(2)X(4)(+*) species is characteristic of the ion
      composition, with no memory of the original neutral precursor structure.
      Specifically, C(2)Cl(2)F(2)(+*) ions dissociate uniquely via loss of CF(2),
      C(2)ClF(3)(+*) ions eliminate preferentially CF, with CF(2) loss being only a
      minor reaction, whereas C(2)Cl(3)F(+*) and C(2)Cl(4)(+*) dissociate exclusively
      via Cl elimination.

PMID- 12489090
TI  - Analyses of gas composition in vacuum systems by mass spectrometry.
AB  - Analyses of the composition of residual gases for diagnostic purposes, analyses
      of the atmosphere enforced by the introduction of gases for technological
      purposes and analyses of gases released from analyte materials in numerous
      analytical methods (e.g. TSD, SIMS) are frequently carried out in vacuum systems.
      There is only a small amount of gas available, in the vacuum system so the most
      important property of a mass spectrometer is high sensitivity. As a consequence,
      the mass resolution is usually low. Moreover, a low outgassing rate of the mass
      spectrometer itself and all parts connecting it to the vacuum system is required.
      Dynamic mass spectrometry satisfies these demands best. Quadrupole mass
      spectrometers are almost solely utilized in applications, although the time-of
      flight mass spectrometer has come into use recently. The main disadvantage of the
      quadrupole mass spectrometer is a strong dependence of the sensitivity and the
      mass discrimination factor on the stability of the supply voltages. Together with
      the necessity to use multipliers for detection of the ion current, this leads to
      a requirement for frequent recalibration. Another serious problem, that is met in
      such applications is the estimation of the gas composition from the measured mass
      spectra. Usually, the analyte gas mixtures consist of various individual gases,
      or at least are measured on a background of such mixtures. This implies a
      requirement for the exact knowledge of the fragmentation pattern of the gases,
      and again the necessity for frequent calibration over a satisfactorily wide range
      of mass numbers. Some theoretical considerations and some experimental results
      obtained by the authors are presented.

PMID- 12489091
TI  - An investigation on the role of 5-hydroxytryptophan in the biosynthesis of
      melanins.

PMID- 12489092
TI  - Current literature in mass spectrometry.

PMID- 12489093
TI  - From the diffusion coefficient to the diffusion tensor.
AB  - With diffusion tensor MRI one has access to the organization in space of tissue
      microstructural components. This outstanding potential adds, however, another
      layer of complexity to the diffusion MRI data acquisition and analysis processes.
      Over the last few years many articles have been published dealing with those
      matters. This special issue is thus timely to provide readers with the synthesis
      and the overall viewpoints from leading contributors to the field.

PMID- 12489094
TI  - The basis of anisotropic water diffusion in the nervous system - a technical
      review.
AB  - Anisotropic water diffusion in neural fibres such as nerve, white matter in
      spinal cord, or white matter in brain forms the basis for the utilization of
      diffusion tensor imaging (DTI) to track fibre pathways. The fact that water
      diffusion is sensitive to the underlying tissue microstructure provides a unique
      method of assessing the orientation and integrity of these neural fibres, which
      may be useful in assessing a number of neurological disorders. The purpose of
      this review is to characterize the relationship of nuclear magnetic resonance
      measurements of water diffusion and its anisotropy (i.e. directional dependence)
      with the underlying microstructure of neural fibres. The emphasis of the review
      will be on model neurological systems both in vitro and in vivo. A systematic
      discussion of the possible sources of anisotropy and their evaluation will be
      presented followed by an overview of various studies of restricted diffusion and
      compartmentation as they relate to anisotropy. Pertinent pathological models,
      developmental studies and theoretical analyses provide further insight into the
      basis of anisotropic diffusion and its potential utility in the nervous system.

PMID- 12489095
TI  - Diffusion-tensor MRI: theory, experimental design and data analysis - a technical
      review.
AB  - This article treats the theoretical underpinnings of diffusion-tensor magnetic
      resonance imaging (DT-MRI), as well as experimental design and data analysis
      issues. We review the mathematical model underlying DT-MRI, discuss the
      quantitative parameters that are derived from the measured effective diffusion
      tensor, and describe artifacts that arise in typical DT-MRI acquisitions. We also
      discuss difficulties in identifying appropriate models to describe water
      diffusion in heterogeneous tissues, as well as in interpreting experimental data
      obtained in such issues. Finally, we describe new statistical methods that have
      been developed to analyse DT-MRI data, and their potential uses in clinical and
      multi-site studies.

PMID- 12489096
TI  - Fiber tracking: principles and strategies - a technical review.
AB  - The state of the art of reconstruction of the axonal tracts in the central
      nervous system (CNS) using diffusion tensor imaging (DTI) is reviewed. This
      relatively new technique has generated much enthusiasm and high expectations
      because it presently is the only approach available to non-invasively study the
      three-dimensional architecture of white matter tracts. While there is no doubt
      that DTI fiber tracking is providing exciting new opportunities to study CNS
      anatomy, it is very important to understand its limitations. In this review we
      therefore assess the basic principles and the assumptions that need to be made
      for each step of the study, including both data acquisition and the elaborate
      fiber reconstruction algorithms. Special attention is paid to situations where
      complications may arise, and possible solutions are reviewed. Validation issues
      and potential future directions and improvements are also discussed.

PMID- 12489097
TI  - A framework based on spin glass models for the inference of anatomical
      connectivity from diffusion-weighted MR data - a technical review.
AB  - A family of methods aiming at the reconstruction of a putative fascicle map from
      any diffusion-weighted dataset is proposed. This fascicle map is defined as a
      trade-off between local information on voxel microstructure provided by diffusion
      data and a priori information on the low curvature of plausible fascicles. The
      optimal fascicle map is the minimum energy configuration of a simulated spin
      glass in which each spin represents a fascicle piece. This spin glass is embedded
      into a simulated magnetic external field that tends to align the spins along the
      more probable fiber orientations according to diffusion models. A model of spin
      interactions related to the curvature of the underlying fascicles introduces a
      low bending potential constraint. Hence, the optimal configuration is a trade-off
      between these two kind of forces acting on the spins. Experimental results are
      presented for the simplest spin glass model made up of compass needles located in
      the center of each voxel of a tensor based acquisition.

PMID- 12489098
TI  - Diffusion tensor fiber tracking of human brain connectivity: aquisition methods,
      reliability analysis and biological results.
AB  - We present a description, biological results and a reliability analysis for the
      method of diffusion tensor tracking (DTT) of white matter fiber pathways. In DTT,
      diffusion-tensor MRI (DT-MRI) data are collected and processed to visualize the
      line trajectories of fiber bundles within white matter (WM) pathways of living
      humans. A detailed description of the data acquisition is given. Technical
      aspects and experimental results are illustrated for the geniculo-calcarine tract
      with broad projections to visual cortex, occipital and parietal U-fibers, and the
      temporo-calcarine ventral pathway. To better understand sources of error and to
      optimize the method, accuracy and precision were analyzed by computer
      simulations. In the simulations, noisy DT-MRI data were computed that would be
      obtained for a WM pathway having a helical trajectory passing through gray
      matter. The error vector between the real and ideal track was computed, and
      random errors accumulated with the square root of track length consistent with a
      random-walk process. Random error was most dependent on signal-to-noise ratio,
      followed by number of averages, pathway anisotropy and voxel size, in decreasing
      order. Systematic error only occurred for a few conditions, and was most
      dependent on the stepping algorithm, anisotropy of the surrounding tissue, and
      non-equal voxel dimensions. Both random and systematic errors were typically
      below the voxel dimension. Other effects such as track rebound and track recovery
      also depended on experimental conditions. The methods, biological results and
      error analysis herein may improve the understanding and optimization of DTT for
      use in various applications in neuroscience and medicine.

PMID- 12489099
TI  - High b-value q-space analyzed diffusion-weighted MRS and MRI in neuronal tissues 
      a technical review.
AB  - This review deals with high b-value q-space diffusion-weighted MRI (DW-MRI) of
      neuronal tissues. It is well documented that at sufficiently high b-values (and
      high q-values) neuronal water signal decay in diffusion experiments is not mono
      exponential. This implies the existence of more than one apparent diffusing
      component or evidence for restriction. The assignment of the different apparent
      diffusing components to real physical entities is not straightforward. However,
      the apparent slow diffusing component that was found to be restricted to a
      compartment of a few microns, if originating mainly from a specific pool and if
      assigned correctly, may potentially be used to obtain more specific MR images
      with regard to specific pathologies of the CNS. This review examines the utility
      of analyzing high b-value diffusion MRS and MRI data using the q-space approach
      introduced by Callaghan and by Cory and Garroway. This approach provides
      displacement probability maps that emphasize, at long diffusion times, the
      characteristics of the apparent slow diffusing component. Examples from excised
      spinal cord, where the experimental conditions for which the q-space analysis of
      MR diffusion data was developed can be met or approached will be presented. Then
      examples from human MS patients, where q-space requirement for the short gradient
      pulse is clearly violated, are presented. In the excised spinal cord studies,
      this approach was used to study spinal cord maturation and trauma, and was found
      to be more sensitive than other conventional methods in following spinal cord
      degeneration in an experimental model of vascular dementia (VaD). High b-value q
      space DWI was also recently used to study healthy and MS diseased human brains.
      This approach was found to be very sensitive to the disease load in MS, compared
      with other conventional MRI methods, especially in the normal appearing white
      matter (NAWM) of MS brains. Finally, the potential diagnostic capacity embedded
      in high b-value q-space analyzed diffusion MR images is discussed. The potentials
      and caveats of this approach are outlined and experimental data are presented
      that show the effect of violating the short gradient pulse (SGP) approximation on
      the extracted parameters from the q-space analysis.

PMID- 12489100
TI  - Diffusion tensor imaging of normal and injured developing human brain - a
      technical review.
AB  - The application of diffusion tensor imaging (DTI) to the evaluation of developing
      brain remains an area of active investigation. This review focuses on the changes
      in DTI parameters which accompany both brain maturation and injury. The two
      primary pieces of information available from DTI studies-water apparent diffusion
      coefficient and diffusion anisotropy measures-change dramatically during
      development, reflecting underlying changes in tissue water content and
      cytoarchitecture. DTI parameters also change in response to brain injury. In this
      context, not only does DTI offer the possibility of detecting injury earlier than
      conventional imaging methods, but also appears more sensitive to disruption of
      white matter than any other imaging method. DTI offers unique insight into brain
      injury and maturation, and does so in a fashion that can be readily applied in a
      clinical setting.

PMID- 12489101
TI  - Diffusion tensor imaging and aging - a review.
AB  - Diffusion-tensor imaging (DTI) non-invasively provides maps of microscopic
      structural information of oriented tissue in vivo, which is finding utility in
      studies of the aging population. In contrast to the white matter maturation
      process, investigators have observed significant declines in the white matter
      ordering in normal as well as in abnormal aging. These studies suggest that water
      proton non-random, anisotropic diffusion measured by DTI is highly sensitive to
      otherwise subtle disease processes not normally seen with conventional MRI tissue
      contrast mechanisms.

PMID- 12489102
TI  - The role of diffusion tensor imaging in the evaluation of ischemic brain injury -
      a review.
AB  - Water diffusion in brain tissue is affected by the presence of barriers to
      translational motion such as cell membranes and myelin fibers. The measured water
      apparent diffusion coefficient (ADC) value is therefore frequently anisotropic
      and varies depending upon the orientation of restricting barriers (such as white
      matter tracts) relative to the diffusion-sensitive-gradient direction.
      Anisotropic water diffusion can be specified using indices of diffusion
      anisotropy [e.g. standard deviation of the individual ADC values, fractional
      anisotropy (FA), lattice index (LI)], which are derived from measurements of the
      full diffusion tensor. The rotationally invariant nature of particular diffusion
      anisotropy indices (e.g. FA, LI) allows orientation-independent comparisons of
      these parameters between different subjects. Pathophysiological processes (such
      as cerebral ischemia) that modify the integrity of the tissue microstructure
      result in significant alterations in tissue anisotropy and make this metric a
      useful endpoint for characterizing the temporal evolution of the disease.
      Diffusion-tensor imaging (DTI) studies of both experimental and human stroke
      suggest that DTI may provide additional information about the evolution of the
      disease that is not available from diffusion-weighted MRI (DWI) alone. Acute
      reductions in the average diffusivity [<D> = (lambda(1) + lambda(2) +
      lambda(3))/3 where lambda(1), lambda(2), and lambda(3) are the eigenvalues of the
      diffusion tensor] following the onset of cerebral ischemia are often accompanied
      by increases in diffusion anisotropy. In the transition from acute to sub-acute
      and chronic stroke, <D> renormalizes and subsequently increases whereas diffusion
      anisotropy measures (e.g. FA) decline and remained reduced in chronic infarcts.
      Overall isotropic ADC changes during infarct evolution have been observed to be
      greater in white matter (WM) than in gray matter (GM) lesions (although there
      have been conflicting reports on this issue) and GM lesions tend to renormalize
      prior to WM lesions as the infarct evolves. Ischemic WM exhibits a significant
      decrease in diffusion anisotropy (relative to normal WM) during ischemic
      evolution whereas that of ischemic GM remains statistically unchanged.
      Furthermore, the percentage decrease in ischemic WM <D> is largely determined by
      reductions in lambda(1), the eigenvalue that coincides with the long axis of the
      WM fiber tract. Variations in unidirectional ADC or <D> over the ischemic time
      course limit the usefulness of this parameter alone as a predictor of ischemic
      injury. Consequently, ADC information has been combined with that of other MR
      parameters (including DTI) to unambiguously stage and predict ischemic brain
      injury over its entire temporal evolution. Combined <D> and diffusion anisotropy
      measurements have identified three phases of diffusion abnormality: (1) reduced
      <D> and elevated anisotropy; (2) reduced <D> and reduced anisotropy; and (3)
      elevated <D> and reduced anisotropy. However, variations in the differential
      patterns of <D> and diffusion anisotropy evolution have been observed by a number
      of investigators and more work is needed to clarify the role of these
      measurements in characterizing the severity of the ischemic insult as well as the
      potential outcome in response to the initial ischemic injury. The use of DTI, in
      combination with more sophisticated analysis methods for performing
      multiparametric segmentation, such as multispectral analysis, may enhance the use
      of MRI for accurate diagnosis and prognosis of stroke. Furthermore, these
      techniques may also play an important role in the clinical evaluation of new
      stroke treatments.

PMID- 12489103
TI  - Applications of diffusion-weighted and diffusion tensor MRI to white matter
      diseases - a review.
AB  - This paper reviews the current applications of diffusion-weighted and diffusion
      tensor MRI in diseases of the brain white matter. The contribution that diffusion
      weighted imaging has made to our understanding of white matter diseases is
      critically appraised. The quantitative nature of diffusion MRI is one of its
      major attractions; however, this is offset by the more advanced hardware required
      to collect diffusion-weighted images reliably, and the more complex processing to
      produce quantitative parametric diffusion images. With the now common
      availability of scanners equipped to perform echo-planar imaging, the acquisition
      of diffusion tensor images is sure to become more widespread and routine.

PMID- 12489104
TI  - Diffusion tensor imaging in spinal cord: methods and applications - a review.
AB  - The spinal cord is a clinically eloquent site within the central nervous system,
      containing important sensorimotor tracts confined within a small cross-sectional
      area. Damage to the spinal cord may be caused by a wide range of pathologies, and
      can result in profound functional disability. Characterization of the structural
      integrity of the spinal cord can be assessed using diffusion tensor imaging
      methods. Development and application of this technique may improve our
      understanding of the nature and evolution of structural damage in spinal cord
      disease. Possible developments include improved detection of ischaemic lesions,
      clarification of the relationship between clinical disability and structural
      damage to the cord and monitoring of anti-inflammatory or neuroprotective
      therapies. In this review current technical aspects, clinical applications and
      the suggested future development of spinal cord diffusion imaging are discussed.

PMID- 12489105
TI  - Neuropsychiatric applications of DTI - a review.
AB  - Psychiatric disorders are common throughout the world and are a leading cause of
      disability. There is a growing appreciation of the importance of connectivity to
      brain function. Disruption of this connectivity can result in brain dysfunction
      manifested in impaired cognitive functioning and the development of clinical
      symptoms. White matter forms the basis of anatomical connectivity. Diffusion
      tensor imaging (DTI) is a useful tool for examining and quantifying white matter
      microstructure. Clinical research studies in alcoholism, HIV-1 infection,
      geriatric depression and schizophrenia using DTI have revealed abnormalities in
      white matter microstructure. The use of complementary imaging methods may be
      helpful in further characterizing these abnormalities. Other psychiatric
      disorders may also have white matter involvement amenable to study with DTI.
      Advances in acquisition and analysis methods will be necessary to further advance
      work in this field. The study of animal models and postmortem tissue may be
      helpful in elucidating the neurobiological underpinnings of abnormalities
      observed with DTI.

PMID- 12489107
TI  - Modulation of JB6 mouse epidermal cell transformation response by the
      prostaglandin F2alpha receptor.
AB  - Prostaglandin F(2alpha) (PGF(2alpha)) modulates clonal selection processes in the
      mouse skin model of carcinogenesis. In this study we investigated whether JB6
      mouse epidermal cells expressed a functional PGF(2alpha) receptor (FP) coupled
      with a cell-transformation response. Treatment of JB6 cells with an FP agonist
      (fluprostenol) potently (pM-nM) increased anchorage-dependent and anchorage
      independent growth. Inositol phospholipid accumulation and extracellular signal
      regulated kinase (Erk) activity were increased in cells treated with FP agonists,
      consistent with established FP-related signal transduction. FP mRNA was detected
      by reverse transcription-polymerase chain reaction, and the average specific
      [(3)H]PGF(2alpha) binding was 8.25 +/- 0.95 fmol/mg protein. Erk activity and
      colony size were increased by cotreatment of JB6 cells with epidermal growth
      factor (EGF) and fluprostenol to a greater extent than with either treatment
      alone, whereas the cotreatment effect on colony number appeared to be simply
      additive. Collectively, our data indicated that JB6 cells expressed a functional
      FP coupled with transformation-related signal transduction and the regulation of
      clonal selection processes. Erk activity appears to be a convergence point in the
      EGF and FP pathways. The data raise the possibility that the FP contributes to
      clonal selection processes but probably plays a more important role as a response
      modifier.

PMID- 12489106
TI  - Mechanism of action of a dominant negative c-jun mutant in inhibiting activator
      protein-1 activation.
AB  - The dominant negative c-jun TAM-67 has been shown to inhibit tumor promotion
      induced by 12-O-tetradecanoylphorbol-13-acetate and okadaic acid (OA). To better
      understand this phenomenon, we investigated the mechanism of action of TAM-67 in
      response to OA. To identify the mechanism of action, we used a 6xHis-tagged TAM
      67 as well as chimeric constructs of TAM-67 that either cannot bind DNA or cannot
      heterodimerize with wild-type transcription factors. The results of these studies
      indicated that TAM-67 acts by blocking or squelching. The results of
      elecrophoretic mobility-shift assays showed that TAM-67 must act by squelching in
      response to OA, as TAM-67 cannot be found in DNA-binding complexes. We then
      identified some of the proteins with which TAM-67 interacts. They include all
      members of the jun and fos families as well as the cAMP response element binding
      protein, activating transcription factor-1, activating transcription factor-2,
      and RelA (p65). Thus, we have shown that TAM-67 squelches the induction of
      activating transcription factor-1 transactivation in response to OA and that TAM
      67 is capable of interacting with proteins that control transactivation by
      binding to the 12-O-tetradecanoylphorbol-13-acetate response element, cAMP
      response element and nuclear factor-kappaB sites.

PMID- 12489108
TI  - Downregulation of expression of a novel cadherin molecule, T-cadherin, in basal
      cell carcinoma of the skin.
AB  - T-cadherin appears to act as a tumor-suppressor factor in various cancers.
      Downregulation of T-cadherin is caused by a combination of allelic loss and
      hypermethylation of the T-cadherin promoter region and is related to cancer
      invasion. To elucidate the molecular mechanism of invasiveness of basal cell
      carcinoma of the skin, T-cadherin expression was investigated in archival
      pathological tissue sections made up of normal counterparts of skin and various
      types of basal cell carcinoma. Immunohistochemical staining showed that T
      cadherin was not expressed in 38 of 51 (75%) basal cell carcinoma specimens,
      whereas normal counterparts of the skin appeared to express abundant T-cadherin.
      Loss of heterozygosity in intron 1 of the T-cadherin gene was found in four of 20
      informative cases that did not express T-cadherin. Aberrant methylation of the T
      cadherin promoter region also was found in six of 25 basal cell carcinomas by
      methylation-specific polymerase chain reaction. In contrast, no structural
      alternations were found in two loss of heterozygosity-positive basal cell
      carcinomas on sequence analysis. These findings indicated that T-cadherin
      expression was downregulated by a combination of allelic loss and aberrant
      methylation in basal cell carcinoma of the skin. Loss of T-cadherin expression
      might be related to the biological behavior of basal cell carcinoma. In addition,
      results of the present study suggested that downregulation of T-cadherin in
      various cancers might be related to tumor invasiveness rather than metastasis,
      because basal cell carcinoma of the skin principally lacks metastatic activity.

PMID- 12489109
TI  - Expression, localization, and activity of glycogen synthase kinase 3beta during
      mouse skin tumorigenesis.
AB  - Glycogen synthase kinase 3 (GSK-3) is a protein kinase that plays essential roles
      in the control of several developmental, metabolic, and apoptotic processes.
      Owing to its negative actions on several oncogenic insults, it has been
      considered a putative functional tumor suppressor. We studied the expression,
      activity, and localization of GSK-3beta during the process of chemically induced
      two-stage mouse skin carcinogenesis and also in the tumors generated upon
      subcutaneous injection of Akt-transformed keratinocytes. We found that GSK-3
      activity was downregulated at the later stages of promotion by tyrosine 216
      dephosphorylation and serine 9 phosphorylation. The data obtained with Akt
      transformed keratinocytes clearly suggested the involvement of Akt in serine 9
      phosphorylation of GSK-3beta. Finally, besides functional inactivation,
      significant basal activity of GSK-3beta was detected in all cases, indicating
      that this enzyme provides essential functions to malignant keratinocytes.

PMID- 12489110
TI  - Gradual deregulation and loss of PCPH expression in the progression of human
      laryngeal neoplasia.
AB  - PCPH is a gene involved in the regulation of eukaryotic cell proliferation and
      stress response. Recently, analyses of human and animal solid tumors and cell
      lines suggested that PCPH protein deregulation may participate in neoplastic
      progression. To test this possibility, we first examined PCPH expression in
      several laryngeal carcinoma cell lines by Western analysis. The results showed
      the presence of altered PCPH polypeptides in these cells, accompanied by the loss
      of the PCPH form present in normal laryngeal epithelial cells, a deregulated
      expression pattern similar to that reported previously. We then analyzed PCPH
      expression in 59 dysplastic lesions of the human larynx, representative of the
      mild, moderate, and severe stages of the disease. Immunohistochemical data showed
      that, compared with normal laryngeal mucosa, PCPH expression in the dysplastic
      samples was associated with areas of epithelial cell maturation rather than with
      regions of increased proliferation. Furthermore, PCPH expression decreased
      parallel to the increase in cellular atypia of the dysplastic samples: PCPH
      either was expressed at very low levels or not expressed in cases of severe
      dysplasia/carcinoma in situ. This trend toward loss of PCPH expression along
      malignant progression of the larynx was confirmed by the low to null expression
      of PCPH in samples of invasive laryngeal carcinoma and by the complete absence of
      PCPH immunostaining in a laryngeal carcinoma-derived liver metastasis. These
      results indicated that PCPH protein analysis might allow for the distinction
      between grades of laryngeal dysplasia. In addition, detection of altered PCPH
      polypeptides by Western analysis potentially can be applied to the early
      identification of laryngeal squamous cell carcinoma.

PMID- 12489111
TI  - Generation of free radicals and induction of DNA adducts by activation of
      heterocyclic aromatic amines via different metabolic pathways in vitro.
AB  - Food-derived heterocyclic aromatic amines (HCAs) have proved to be carcinogenic
      in both rodents and nonhuman primates. Two different metabolic pathways are
      suggested for the metabolic activation of HCA. The hepatic pathway proceeds via a
      two-step process involving N-hydroxylation by cytochrome P4501A2 and subsequent O
      acetylation by N-acetyltransferase-2. An alternative pathway may be of particular
      interest in extrahepatic tissues and proceeds via one-electron oxidation
      catalyzed by prostaglandin H synthase (PHS), rendering free-radical metabolites.
      In this study, we investigated the metabolic activation of two HCAs, 2-amino-3
      methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5
      b]pyridine (PhIP), by two different enzyme systems in vitro, generating different
      primary and secondary reactive metabolites. Rat liver S9 mix and PHS were used as
      the activating system and represent the hepatic and extrahepatic pathways,
      respectively. Electron-spin resonance spectroscopy showed that both IQ and PhIP
      exerted inhibiting effects on PHS-mediated formation of hydroxyl radicals during
      the conversion of arachidonic acid to prostaglandins. Evidence for the formation
      of HCA free radicals was presented in an indirect way by the formation of
      glutathione-derived thiyl radicals, with purified PHS as the activating system.
      Activation by S9 mix did not result in the formation of detectable radical
      metabolites, showing that the two metabolic routes primarily led to the formation
      of different metabolites. In all electron-spin resonance experiments, IQ appeared
      to be more effective than PhIP. In contrasts, DNA adduct analysis by means of
      (32)P-postlabeling showed similar adduct patterns for S9 and PHS in single
      stranded and double-stranded salmon testes DNA after incubation with PhIP,
      indicating the ultimate formation of a common reactive intermediate. For IQ,
      activation by PHS led to an additional adduct spot that was not present after S9
      activation. Furthermore, activation of IQ resulted in higher adduct levels
      compared with PhIP for both activation pathways. Overall, adduct levels were
      higher in single-stranded DNA than double-stranded DNA. Our results showed that
      the hepatic and extrahepatic pathways resulted in different primary metabolites,
      while the ultimate formation of a similar reactive intermediate for PhIP,
      possibly an arylnitrenium ion, suggested that both pathways could play an
      important role in the onset of carcinogenesis.

PMID- 12489112
TI  - Genotoxicity biomonitoring in regions exposed to vehicle emissions using the
      comet assay and the micronucleus test in native rodent Ctenomys minutus.
AB  - Exposure to motor vehicle emissions represents an important concern for possible
      long-term health effects. The present report describes: 1) the application and
      verification of the alkaline comet assay in Ctenomys minutus to detect the
      possible genotoxicity of automobile emissions; 2) a comparison of the comet assay
      results with peripheral blood micronucleus (MN) assay results performed in the
      same animals; and 3) the identification of agents involved in the responses and
      in the seasonal variation of the effects. Ctenomys minutus (Octodontidae
      Rodentia) were captured in two different fields from both sides of RS/030, a
      highway on the coastal plain of the Brazilian state of Rio Grande do Sul.
      Reference animals were obtained from a nearby field that was about 3 km distant
      from any road. By the end of this study, 123 rodents (73 females and 50 males)
      were live-trapped. Our results indicate that there was an increase in cells with
      DNA damage for C. minutus environmentally exposed to automobile emissions, as
      demonstrated by the alkaline comet assay, but there was no increase in
      micronucleated cells. The alkaline comet assay showed age and gender differences
      in the response. The comet assay results suggest that adult females are the
      principal population affected by air pollutants from vehicle emissions. Chemical
      data were also collected from areas exposed to automobile exhaust and these
      indicated that elevated levels of hydrocarbons, metals, and NO(2) were associated
      with the elevated levels of damaged cells observed in the wild rodent C. minutus.
      Our results agree with previous data on engine and fuel components, where weak
      increases in damage for native rodents exposed to emissions have been observed.
      Other larger, controlled studies are needed to better understand how the
      metabolism of C. minutus affects its response to emission exposure.

PMID- 12489113
TI  - Effects of heat shock protein 70 (Hsp70) on arsenite-induced genotoxicity.
AB  - Arsenic, a human carcinogen, is genotoxic, although its mechanism(s) of action
      for tumorigenesis is not well understood. Among the toxicity-related properties
      of this chemical are its clastogenic and aneugenic activities, as well as its
      capacity for inducing stress-response in the form of elevated heat shock protein
      (HSP) expression. In the present study, we evaluated the effects of Hsp70
      expression on arsenite (As)-induced structural and numerical chromosome anomalies
      in human cells. Human MCF-7 Tet-off cells stably transfected with a pTRE/Hsp70-1
      transgene construct were used to regulate Hsp70 levels prior to in vitro As
      exposures. Separate cultures of relatively high vs. low Hsp70-expressing cells
      were established. A cytokinesis block micronucleus assay with kinetochore
      immunostaining was used to detect micronuclei (MN) derived from chromosome
      breakage (K-MN) or loss (K+MN). These studies demonstrated significant increases
      in micronucleus frequencies in response to As following either a long exposure (5
      or 10 microM for 46 hr), or short exposure (10 or 40 microM for 8 hr) protocol.
      Overall, the long protocol was more efficient in producing K+MN and cells with
      multiple MN. Overexpressing Hsp70 resulted in significant reductions in the
      percent of cells positive for MN for both the long and short As exposure
      protocols. Both K+ and K- types of As-induced MN were lower in cells with
      elevated Hsp70 as compared to cells without overexpression of Hsp70. We conclude
      that the dose and duration of As exposure influence the type as well as amount of
      chromosomal alteration produced and that inducible Hsp70 protects against both
      the clastogenic and aneugenic effects of this chemical.

PMID- 12489114
TI  - Msh2 deficiency increases the mutation frequency in all parts of the mouse colon.
AB  - The Msh2 DNA mismatch repair gene is one of five genes implicated in the
      pathogenesis of hereditary nonpolyposis colorectal cancer (HNPCC). To address the
      possible mechanisms of the site-specific occurrence of HNPCC, the effect of Msh2
      deficiency on mutations in different parts of the colon was investigated using
      the BC-1(lacI)/Msh2 double transgenic mouse. Compared to the Msh2(+/+) mice,
      Msh2(-/-) mice had an 8-9-fold increase of mutation frequency (MF) in the lacI
      gene from the cecum and the proximal and distal colon. The mutational spectra
      were also significantly different between Msh2(+/+) and Msh2(-/-) mice, with a
      significant increase in the frequency of -1 frameshifts and G:C-->A:T base
      substitutions in the repair-deficient mice. However, in spite of the site
      specific predisposition of HNPCC in humans, we found no significant difference in
      the MF or mutation spectrum between the three parts of the colon in Msh2(+/+),
      Msh2(+/-), or Msh2(-/-) mice. In addition, 11 independent mutants harboring
      complex mutations within the lacI gene were recovered in the Msh2(-/-) mice.
      Interestingly, while the Msh2(+/-) mice displayed an overall MF similar to that
      observed in the wild-type mice, sequencing revealed a significantly different
      mutational spectrum between Msh2(+/+) and Msh2(+/-) mice, mainly characterized by
      an increase in -1 frameshifts. Due to the prevalence of frameshift mutations in
      HNPCC patients, this haploinsufficiency effect of the Msh2 gene in safeguarding
      genomic integrity may have important implications for human carrier status.

PMID- 12489115
TI  - Transmission of mutations in the lacI transgene to the offspring of ENU-treated
      Big Blue male mice.
AB  - The purpose of the study was to determine: 1) if male germ cells of Big Blue mice
      carrying newly induced mutations in the lacI transgene were effective in
      fertilization; 2) if offspring arising from such mutant sperm had the mutation in
      germ cells and multiple somatic tissues; and 3) how the frequency of mutants
      induced in the lacI transgene compared to the frequency induced in endogenous
      genes traditionally employed to study germ cell mutagenesis in mice. Male
      B6C3F(1) mice hemizygous for the lambda/lacI transgene were treated weekly with
      100 mg/kg body weight of the mammalian germ cell mutagen N-ethyl-N-nitrosourea
      (ENU). The cumulative dose for each treated animal was 300 mg ENU/kg body weight.
      Ten weeks later the treated mice were mated to T stock females and the resulting
      offspring were screened for specific-locus mutations at six loci affecting
      external appearance, as well as for mutations in the lacI transgene in multiple
      somatic tissues and germ cells. Five offspring carrying recessive specific-locus
      mutations were observed among 597 offspring screened (mutant frequency = 139.6 x
      10(-5) per locus). Four offspring carrying lacI mutations were observed among 280
      offspring screened (mutant frequency = 35.7 x 10(-5) per locus (assuming 40
      target loci)). Each of the four lacI mutant offspring carried a different
      mutation. Three of the mutations were A:T-->G:C transitions and one a G:C-->A:T
      transition. Consistent with the expectation that a mutation induced in a parental
      germ cell and transmitted to a conceptus would exist in every cell of the
      offspring, each mutant mouse had identical mutations in all somatic tissues
      sampled, as well as in its germ cells. These data provide preliminary evidence
      for the biological validity of assessing induced, heritable mutations using
      transgenic mice, without the need for generating an F(1) generation.

PMID- 12489116
TI  - Overexpression of heme oxygenase-1 (HO-1) in V79 cells results in increased
      resistance to hyperbaric oxygen (HBO)-induced DNA damage.
AB  - Heme oxygenase (HO) catalyzes the rate-limiting step in the oxidative degradation
      of heme to biliverdin. The isoform HO-1 is inducible by a variety of agents
      causing oxidative stress and has been suggested to play an important role in
      cellular protection against oxidant-mediated cell damage. Using treatment of cell
      cultures with hyperbaric oxygen (HBO) as a model for oxidative stress, we have
      shown an induction of HO-1 in isolated human lymphocytes after a single HBO
      exposure and protection of these cells against DNA damage by subsequent oxidative
      stress. In contrast, V79 Chinese hamster cells showed neither a comparable
      adaptive protection nor an induction of HO-1 after HBO exposure, which makes this
      cell line an attractive model system for a further characterization of HO-1
      mediated protection. In the present study, we investigated whether overexpression
      of HO-1 renders V79 cells more resistant to DNA damage induced by HBO. Transient
      transfection of V79 cells with a full-length human HO-1 cDNA resulted in a 2-3
      fold increase in HO-1 protein levels. Comet assay experiments with and without
      FPG posttreatment for the determination of oxidative DNA base damage showed that
      HO-1 overexpressing V79 cells were significantly protected against oxidative DNA
      damage induced by a single HBO exposure. Furthermore, HO-1-transfected cells
      exhibited a clearly reduced induction of micronuclei after HBO treatment. Since
      the observed protective effects were abolished by cotreatment with the HO-1
      inhibitor tin-mesoporphyrin, our study suggests that a low-level overexpression
      of HO-1 provides protection against oxidative DNA damage induced by HBO.

PMID- 12489117
TI  - Evaluation of the clastogenic, DNA intercalative, and topoisomerase II
      interactive properties of bioflavonoids in Chinese hamster V79 cells.
AB  - Bioflavonoids are naturally occurring polyphenols with intriguing and varied
      therapeutic and chemoprotective activities generally ascribed to their
      antioxidant properties. However, many flavonoids have also been shown to be
      genotoxic in a variety of prokaryotic, eukaryotic, and in vivo systems. The
      mechanistic basis for this genotoxicity has not been fully elucidated, although
      structure-activity relationship studies have identified requisite flavonoid
      structural features. We utilized Chinese hamster V79 cells to evaluate the
      relationships between DNA intercalation ability, topoisomerase II interactions,
      reactive oxygen species (ROS) generation, and clastogenicity in a series of 14
      bioflavonoids. Five of the flavonoids examined, luteolin, quercetin, genistein,
      apigenin, and acacetin, were strongly clastogenic. This clastogenicity was shown
      to require DNA intercalation (with the exception of genistein) and was
      substantially reduced by catalytic inhibitors of DNA topoisomerase II. The
      transition metals Cu(II) and Mn(II) formed chelates with and/or modified the
      structure and biological activity of some flavonoids but no consistent
      relationship could be demonstrated between metal reactivity and clastogenicity.
      There was no clear association between generation of ROS and clastogenicity. The
      data presented herein are consistent with a model in which the genotoxicity of
      most flavonoids arises via DNA intercalation and topo II poisoning, likely
      mediated through metabolism to flavonoid quinones. Interestingly, other
      flavonoids such as myricetin, daidzein, baicalein, fisetin, and galangin were
      catalytic topo II inhibitors, rather than poisons. These studies further validate
      the use of cell-based approaches for detecting drug/topo II interactions and
      raise interesting questions relating to biological and chemical mechanisms of
      flavonoids.

PMID- 12489118
TI  - Induction of epithelial tumors in Drosophila melanogaster heterozygous for the
      tumor suppressor gene wts.
AB  - The imaginal disk cells of Drosophila have a cell cycle that is very similar to
      that of mammalian cells. Data concerning factors inducing tumors in these cells
      may directly relate to the risk of these factors for inducing cancer in humans.
      One of the genes involved in the regulation of cell cycle control is wts (warts),
      the Drosophila homolog of the mammalian tumor suppressor gene LATS1. The
      Drosophila wts mutations are recessive lethal. However, homozygous clones that
      arise in heterozygous flies in the imaginal disk cells lead to epithelial tumors,
      spectacular outgrowths visible on the cuticle of the adult. We have treated
      Drosophila larvae, heterozygous for wts, with the chemical mutagen MMS (methyl
      methanesulfonate) or with X-rays and measured the appearance of epithelial tumors
      in the eclosing adult flies. This test is a variation of the well-known
      Drosophila somatic mutation and recombination test (SMART), where mostly
      recessive markers have been used leading to visible phenotypes in the eyes and
      wings of the fly. We show that the sensitivity of this test is far greater than
      the comparable test system using the recessive eye marker white.

PMID- 12489119
TI  - Mutagenic activity of cisplatin in the lacZ plasmid-based transgenic mouse model.
AB  - Cis-diamminedichloroplatinum (II) (cisplatin) is a well characterized antitumor
      drug used for the treatment of a variety of human cancers. The cytotoxicity of
      cisplatin is mainly mediated through the formation of DNA adducts, which are also
      believed to be responsible for the secondary malignancies produced by the drug.
      The aim of this study was to determine the in vivo mutagenic activity of
      cisplatin in the lacZ plasmid-based transgenic mouse model. The mutant frequency
      (MF) and the spectrum of mutations induced by cisplatin in the mouse liver were
      analyzed and compared to controls. The mean MF in the lacZ gene was increased 2
      fold in mice treated with a single 6 mg/kg body weight dose of cisplatin and
      sacrificed after 17 and 28 days (P = 0.001 and P < 0.0001). Restriction analysis
      and sequencing of mutant DNA showed that cisplatin was able to induce both large
      deletions and point mutations. A specific profile of base substitution and
      frameshift mutations was identified in treated mice, consisting primarily of G:C-
      >A:T transitions at GpG and ApG sites, the preferential DNA binding sites of
      cisplatin, and single basepair deletions/insertions. The present results provide
      the first evidence that cisplatin has mutagenic activity in vivo and induces a
      characteristic pattern of mutations in the mouse liver. This mutagenicity may be
      responsible for its tumorigenic activity.

PMID- 12489120
TI  - Mouse lymphoma thymidine kinase gene mutation assay: follow-up International
      Workshop on Genotoxicity Test Procedures, New Orleans, Louisiana, April 2000.
AB  - The Mouse Lymphoma Assay (MLA) Workgroup of the International Workshop on
      Genotoxicity Test Procedures held a second harmonization meeting just prior to
      the U.S. Environmental Mutagen Society Meeting in New Orleans, LA, in April 2000.
      The discussion focused on several important aspects of the MLA, including: 1)
      cytotoxicity measures and their determination, 2) use of a 24-hr treatment, 3)
      the ability of the assay to detect aneugens, and 4) concentration selection.
      Prior to the meeting the group developed Microsoft Excel Workbooks for data
      entry. Ten laboratories entered their data into the workbooks (primarily as coded
      chemicals). The Excel Workbooks were used to facilitate data analysis by
      generating an extensive set of graphs that were evaluated by the meeting
      participants. Based on the Workgroup's previous agreement that a single
      cytotoxicity measure should be established for both the microwell and soft agar
      versions of the assay, the Workgroup analyzed the submitted data and unanimously
      agreed that the relative total growth (RTG) should be used as the cytotoxicity
      measure for concentration selection and data evaluation. The Workgroup also
      agreed that the various cytotoxicity measures should be calculated using the same
      methods regardless of whether the soft agar or microwell version of the assay was
      used. In the absence of sufficient data to make a definitive determination, the
      Workgroup continued to endorse the International Committee on Harmonization
      recommendation for the use of 24-hr treatment and made some specific 24-hr
      treatment protocol recommendations. The Workgroup recognized the ability of the
      MLA to detect at least some aneugens and also developed general guidance and
      requirements for appropriate concentration selection.

PMID- 12489121
TI  - Studies of yeast Kluyveromyces lactis mutations conferring super-secretion of
      recombinant proteins.
AB  - We have isolated mutants responsible for a super-secretion phenotype in
      Kluyveromyces lactis using the gene coding for a Bacillus amyloliquefaciens alpha
      amylase as a marker for secretion. These mutations defined two groups, dominant
      and recessive. The recessive mutant strain, which secreted the heterologous
      protein in five-fold excess compared to the wild-type strain, was used for the
      cloning of genes, restraining the super-secreting phenotype. In screening for
      genes affecting super-secreting phenotype, we found that multiple copies of 10
      different independently isolated DNA sequences suppressed the super-secreting
      phenotype. The first among the genes characterized, named KlSEL1 ('secretion
      lowering') showed homology to Saccharomyces cerevisiae ORF YML013w. The KlSEL1
      gene is predicted to encode a polypeptide of 620 amino acid residues containing a
      putative transmembrane domain and UBX domain, characteristic for the ubiquitin
      regulatory proteins. We demonstrated that the disruption of the SEL1 orthologues
      in K. lactis and S. cerevisiae conferred the super-secreting phenotype. SEL1
      isolated from S. cerevisiae suppressed the super-secretion phenotype in K. lactis
      klsel1 strain, likewise homologous KlSEL1. No other phenotypic features for
      strains lacking the SEL1 gene were noticed except for the S. cerevisiae mutant
      growth being notably slower than in a wt strain. No growth changes were observed
      in the K. lactis klsel1 mutant. The set of genes (suppressors of over-secreting
      phenotype) could be attractive for further analysis of gene functions, super
      secreting mechanisms and construction of new strains. This collection could be
      useful for the expedient construction of reduced yeast genomes, optimized for
      heterologous protein secretion.

PMID- 12489122
TI  - The acetyl co-enzyme A synthetase genes of Kluyveromyces lactis.
AB  - Two Kluyveromyces lactis genes encoding acetyl co-enzyme A synthetase isoenzymes
      were isolated. One we named KlACS1, as it has high similarity to the ACS1 gene of
      Saccharomyces cerevisiae. The other gene, KlACS2, showed more similarity to S.
      cerevisiae ACS2 than to KlACS1 or ScACS1. This suggests that divergence of the
      two isogenes occurred before the evolutionary separation of the species and that
      the different functions have been conserved. In line with this idea is the
      regulation of transcription of the genes. The mode of regulation appeared to be
      maintained between ScACS1 and KlACS1 and between ScACS2 and KlACS2. The KlACS1
      transcript was absent in glucose-grown cells, whereas transcription levels in
      ethanol- and acetate-grown cells were high. Disruption of the KlACS1 gene did not
      result in growth defects on glucose or ethanol. The growth rate on acetate,
      however, was reduced by a factor of two. KlACS2 was expressed at similar levels
      during growth on glucose and acetate, whereas expression on ethanol was slightly
      higher. A null mutant in this gene showed a reduced growth rate on all three
      carbon sources. Taken together, these data suggest that KlACS2 is used during
      growth on glucose and that KlACS1 is most dominant during growth on acetate.
      Strains in which both ACS genes are deleted could only be retrieved when a
      plasmid containing the ACS2 gene was present, suggesting that the double mutant
      is lethal. Tetrad analysis confirmed that non-viable spores with a deduced
      Klacs1Klacs2 genotype germinated but could not divide further. It therefore
      appears that, as in S. cerevisiae, the pyruvate dehydrogenase bypass formed by
      the enzymes pyruvate decarboxylase, acetaldehyde dehydrogenase and acetyl co
      enzyme A synthetase is essential for growth. These results are in apparent
      contradiction with the growth on glucose of a strain with a disruption in the
      only structural pyruvate decarboxylase gene of K. lactis. Residual enzyme
      activity might, however, account for this discrepancy, or Acs fulfils an
      additional as yet unknown function, separate from its enzymatic activity.

PMID- 12489123
TI  - Real-time imaging of the surface topography of living yeast cells by atomic force
      microscopy.
AB  - Atomic force microscopy (AFM) was used to image the surface topography of living
      Saccharomyces cerevisiae cells at high resolution and to monitor enzyme digestion
      of the cell wall in real time. Apart from the presence of bud scars, the surface
      of native cells imaged in aqueous solution was homogeneous and smooth.
      Topographic images of the surface were recorded to a lateral resolution of 2 nm
      without significant modification of the surface morphology. Successive images of
      single cells were collected at fixed time intervals following addition of
      protease and amyloglucosidase solutions. Protease caused a progressive increase
      of surface roughness. Large depressions surrounded by protruding edges,
      approximately 50 nm in height, were formed and attributed to the erosion of the
      mannoprotein outer layer. By contrast, no modification of the cell surface was
      noted upon addition of amyloglucosidase, which was consistent with the cell wall
      biochemical composition. These results indicate that AFM is a complementary tool
      to electron microscopy in that it allows the surface of living cells to be
      explored directly in real time.

PMID- 12489124
TI  - The role of the GATA factors Gln3p, Nil1p, Dal80p and the Ure2p on ASP3
      regulation in Saccharomyces cerevisiae.
AB  - The role of Gln3p, Nil1p, Dal80p and Ure2p in the nitrogen regulation of ASP3,
      which codes for the periplasmic Saccharomyces cerevisiae asparaginase II, was
      investigated. Analysis of enzyme levels and mRNA(ASP3) in two wild-type strains
      and gln3, nil1, gln3nil1, gln3ure2, nil1ure2, nil1dal80, ure2, dal80 and
      ure2dal80 mutant cells allowed the study of the qualitative and quantitative
      regulatory role of the GATA factors and Ure2p on ASP3 expression. The
      simultaneous presence of Gln3p and Nil1p is a required condition for full gene
      transcription. Enzyme activity doubled upon nitrogen starvation of either
      ammonium-grown (possibly due to Nil2p/Deh1p derepression) or proline-grown (due
      to Dal80p derepression) cells. The ure2 mutation increased enzyme levels five
      fold in fresh ammonium-grown cells and ten-fold in fresh proline-grown cells. The
      combined effects of the ure2 mutation and nitrogen starvation on ammonium- or
      proline-grown cells resulted in an overall 10-20-fold enzyme activity increase,
      respectively, in comparison with the wild-type cells.

PMID- 12489125
TI  - Analysis of the hypoxia-induced ADH2 promoter of the respiratory yeast Pichia
      stipitis reveals a new mechanism for sensing of oxygen limitation in yeast.
AB  - We introduced a reporter gene system into Pichia stipitis using the gene for the
      artificial green fluorescent protein (GFP), variant yEGFP. This system was used
      to analyse hypoxia-dependent PsADH2 regulation. Reporter gene activity was only
      found under oxygen limitation on a fermentable carbon source. The promoter was
      not induced by oxygen limitation in the Crabtree-positive yeast Saccharomyces
      cerevisiae. Promoter deletions revealed that a region of 15 bp contained the
      essential site for hypoxic induction. This motif was different from the known
      hypoxia response elements of S. cerevisiae but showed some similarity to the
      mammalian HIF-1 binding site. Electrophoretic mobility shift assays demonstrated
      specific protein binding to this region under oxygen limitation. Similar to the
      S. cerevisiae heme sensor system, the promoter was induced by Co(2+). Cyanide was
      not able to mimic the effect of oxygen limitation. The activation mechanism of
      PsADH2 also, in this respect, has similarities to the mammalian HIF-1 system,
      which is inducible by Co(2+) but not by cyanide. Thus, the very first promoter
      analysis in P. stipitis revealed a hitherto unknown mechanism of oxygen sensing
      in yeast.

PMID- 12489126
TI  - Automated screening in environmental arrays allows analysis of quantitative
      phenotypic profiles in Saccharomyces cerevisiae.
AB  - A methodology for large-scale automated phenotypic profiling utilizing
      quantitative changes in yeast growth has been tested and applied to the analysis
      of some commonly used laboratory strains. This yeast-adjusted methodology is
      based on microcultivation in 350 microl liquid medium, where growth is frequently
      optically recorded, followed by automated extraction of relevant variables from
      obtained growth curves. We report that cultivation at this micro-scale displayed
      overall growth features and protein expression pattern highly similar to growth
      in well aerated medium-scale (10 ml) culture. However, differences were also
      encountered, mainly relating to the respiratory potential and the production of
      stress-induced proteins. Quantitative phenotypic profiles for the laboratory
      yeast strains W303, FY1679 and CEN-PK.2 were screened for in environmental
      arrays, including 98 different conditions composed of low, medium and high
      concentrations of 33 growth inhibitors. We introduce the concepts phenotypic
      index(rate) and phenotypic index(stationary), which relate to changes in rate of
      growth and the stationary phase optical density increment, respectively, in a
      particular environment relative a reference strain. The laboratory strains
      presented selective phenotypic profiles in both phenotypic indexes and the two
      features appeared in many cases to be independent characteristics. We propose the
      utilization of this methodology in large-scale screening of the complete
      collection of yeast deletion mutants.

PMID- 12489127
TI  - Cloning and characterization of a second alpha-amylase gene (LKA2) from Lipomyces
      kononenkoae IGC4052B and its expression in Saccharomyces cerevisiae.
AB  - Lipomyces kononenkoae secretes a battery of highly effective amylases (i.e. alpha
      amylase, glucoamylase, isoamylase and cyclomaltodextrin glucanotransferase
      activities) and is therefore considered as one of the most efficient raw starch
      degrading yeasts known. Previously, we have cloned and characterized genomic and
      cDNA copies of the LKA1 alpha-amylase gene from L. kononenkoae IGC4052B
      (CBS5608T) and expressed them in Saccharomyces cerevisiae and Schizosaccharomyces
      pombe. Here we report on the cloning and characterization of the genomic and cDNA
      copies of a second alpha-amylase gene (LKA2) from the same strain of L.
      kononenkoae. LKA2 was cloned initially as a 1663 bp cDNA harbouring an open
      reading frame (ORF) of 1496 nucleotides. Sequence analysis of LKA2 revealed that
      this ORF encodes a protein (Lka2p) of 499 amino acids, with a predicted molecular
      weight of 55,307 Da. The LKA2-encoded alpha-amylase showed significant homology
      to several bacterial cyclomaltodextrin glucanotransferases and also to the alpha
      amylases of Aspergillus nidulans, Debaryomyces occidentalis, Saccharomycopsis
      fibuligera and Sz. pombe. When LKA2 was expressed under the control of the
      phosphoglycerate kinase gene promoter (PGK1(p)) in S. cerevisiae, it was found
      that the genomic copy contained a 55 bp intron that impaired the production of
      biologically active Lka2p in the heterologous host. In contrast to the genomic
      copy, the expression of the cDNA construct of PGK1p-LKA2 in S. cerevisiae
      resulted in the production of biologically active alpha-amylase. The LKA2-encoded
      alpha-amylase produced by S. cerevisiae exhibited a high specificity towards
      substrates containing alpha-1,4 glucosidic linkages. The optimum pH of Lka2p was
      found to be 3.5 and the optimum temperature was 60 degrees C. Besides LKA1, LKA2
      is only the second L. kononenkoae gene ever cloned and expressed in S.
      cerevisiae. The cloning, characterization and co-expression of these two genes
      encoding these highly efficient alpha-amylases form an important part of an
      extensive research programme aimed at the development of amylolytic strains of S.
      cerevisiae for the efficient bioconversion of starch into commercially important
      commodities.

PMID- 12489128
TI  - Disruption of 12 ORFs located on chromosomes IV, VII and XIV of Saccharomyces
      cerevisiae reveals two essential genes.
AB  - We describe the generation of null-mutants of 12 open reading frames (ORFs),
      discovered during the systematic sequencing of the Saccharomyces cerevisiae
      genome. These ORFs are located on chromosome IV (YDL183c), on chromosome VII
      (YGL139w, YGL140c, YGL141w, YGR280c and YGR284c) or on chromosome XIV (YNL006w,
      YNR004w, YNR007c, YNR008w, YNR009w and YNR013c). Disruptants were generated using
      the PCR-based short flanking homology (SFH) strategy in yeast strain FY1679.
      Tetrad analysis, following sporulation of the heterozygous disruptants, revealed
      that YGR280c and YNL006w are essential genes for vegetative yeast growth in rich
      medium. The lethality of the two genes was confirmed by gene complementation
      analysis. The protein encoded by YNL006w (LST8) is now known to be involved in
      transport of permeases from the Golgi to the plasma membrane. Basic phenotypic
      analyses were performed on haploid disruptants from both mating types of 10 non
      essential genes. One disruptant (YNR004w) revealed a slow growth rate on glucose
      minimal medium at 15 degrees C. For each of the individual ORFs, a disruption
      cassette and the corresponding cognate gene were cloned into appropriate
      plasmids.

PMID- 12489129
TI  - Eicosanoids in insect immunity: bacterial infection stimulates hemocytic
      phospholipase A2 activity in tobacco hornworms.
AB  - Intracellular phospholipase A(2) (PLA(2)) is responsible for releasing
      arachidonic acid from cellular phospholipids, and is thought to be the first step
      in eicosanoid biosynthesis. Intracellular PLA(2)s have been characterized in fat
      body and hemocytes from tobacco hornworms, Manduca sexta. Here we show that
      bacterial challenge stimulated increased PLA(2) activity in isolated hemocyte
      preparations, relative to control hemocyte preparations that were challenged with
      water. The increased activity was detected as early as 15 s post-challenge and
      lasted for at least 1 h. The increased activity depended on a minimum bacterial
      challenge dose, and was inhibited in reactions conducted in the presence of
      oleyoxyethylphosphorylcholine, a site-specific PLA(2) inhibitor. In independent
      experiments with serum prepared from whole hemolymph, we found no PLA(2) activity
      was secreted into serum during the first 24 h following bacterial infection. We
      infer that a hemocytic intracellular PLA(2) activity is increased immediately an
      infection is detected. The significance of this enzyme lies in its role in
      launching the biosynthesis of eicosanoids, which mediate cellular immune
      reactions to bacterial infection.

PMID- 12489130
TI  - Positive and negative modulation of Bombyx mori adenylate cyclase by 5
      phenyloxazoles: identification of octopamine and tyramine receptor agonists.
AB  - Nineteen 5-phenyloxazoles (5POs) were examined for their ability to modulate
      adenylate cyclase by measuring cAMP produced in head membrane homogenates of
      fifth instar larvae of the silkworm Bombyx mori. Among the compounds tested, 5-(4
      methoxyphenyl)oxazole (9) and the 2,6-dichlorophenyl congener showed the highest
      activation of adenylate cyclase; both compounds produced approximately half the
      level of cAMP produced by the action of octopamine (OCT). The OCT receptor
      antagonists chlorpromazine, mianserin, and metoclopramide attenuated 9-stimulated
      cAMP production. In contrast, 5-(4-hydroxyphenyl)oxazole (8) and the 4
      cyanophenyl congener attenuated both OCT-stimulated and basal cAMP production.
      The tyramine (TYR) receptor antagonist yohimbine inhibited the negative effect of
      8. These findings indicate that the 5PO class of compounds includes both positive
      and negative modulators of adenylate cyclase in the heads of B. mori larvae, and
      that 9 and 8 are OCT and TYR receptor agonists, respectively. These compounds
      might prove useful for a pharmacological dissection of biogenic amine receptors.

PMID- 12489131
TI  - Monoclonal antibodies to elongation factor-1alpha inhibit in vitro translation in
      lysates of Sf21 cells.
AB  - Elongation factor-1alpha (EF-1alpha) is an enzyme that is essential for protein
      synthesis. Although EF-1alpha offers an excellent target for the disruption of
      insect metabolism, agents known to interfere with EF-1alpha activity are toxic to
      humans. In this article, we describe the development of monoclonal antibodies
      (MAbs) that can disrupt the activity of insect EF-1alpha without cross-reacting
      with the human enzyme. MAbs were generated to EF-1alpha from Sf21 cells derived
      from the fall armyworm, Spodoptera frugiperda, by immunizing mice with EF-1alpha
      eluted from SDS-PAGE gels. The MAbs reacted with EF-1alpha in eggs and first
      through fifth instars of the fall armyworm in immunoblots of SDS-PAGE gels, but
      did not recognize EF-1alpha in human carcinoma cells and normal tissues. MAbs
      with the ability to recognize EF-1alpha in its native conformation, identified
      through immunoprecipitation experiments, were added to Sf21 cell lysates to
      determine whether the antibodies could inhibit incorporation of [(35)S]methionine
      into newly synthesized in vitro translation products. Of the four EF-1alpha
      specific MAbs tested, three significantly inhibited protein synthesis when
      compared to the negative control antibody (P < 0.001, one-way ANOVA; followed by
      Dunnett's test, P < 0.05).

PMID- 12489132
TI  - Entomogenous fungus Nomuraea rileyi inhibits host insect molting by C22-oxidizing
      inactivation of hemolymph ecdysteroids.
AB  - The entomogenous fungus Nomuraea rileyi reportedly secretes a proteinaceous
      substance inhibiting larval molt and metamorphosis in the silkworm Bombyx mori.
      We studied the possibility that N. rileyi controls B. mori development by
      inactivating hemolymph molting hormone, ecdysteroids. Incubation of ecdysone (E)
      and 20-hydroxyecdysone (20E) in fungal-conditioned medium resulted in their rapid
      modification into products with longer retention times in reverse-phase HPLC.
      Each modified product from E and 20E was purified by HPLC, and identified by NMR
      as 22-dehydroecdysone and 22-dehydro-20-hydroxyecdysone. Some other ecdysteroids
      with a hydroxyl group at position C22 were also modified. Injection of the fungal
      conditioned medium into Bombyx mori larvae in the mid-4th instar inhibited larval
      molt but induced precocious pupal metamorphosis, and its injection into 5th
      instar larvae just after gut purge blocked pupal metamorphosis. In hemolymph of
      injected larvae, E and 20E disappeared and, in turn, 22-dehydroecdysone and 22
      dehydro-20-hydroxyecdysone accumulated. These results indicate that N. rileyi
      secretes a specific enzyme that oxidizes the hydroxyl group at position C22 of
      hemolymph ecdysteroids and prevents molting in B. mori larvae.

PMID- 12489133
TI  - Hemolymph ecdysteroids do not affect vitellogenesis in the lubber grasshopper.
AB  - The role of hemolymph ecdysteroids in the reproduction of non-dipteran insects is
      unclear. We examine the role(s) of hemolymph ecdysteroids during egg production
      in the lubber grasshopper, Romalea microptera. In all individuals, hemolymph
      ecdysteroids rose to a sharp peak with similar maxima and then fell to
      undetectable levels. The time from the adult molt to the maximum ecdysteroid
      titer (E(max) titer) varied in response to food availability, whereas the time
      from E(max) titer to oviposition was unrelated to food availability. Because both
      the timing of egg production and the timing of E(max) responded similarly to
      environmental changes, ecdysteroids may be involved in egg production. We
      hypothesized that this role is the stimulation of vitellogenesis. Ovariectomized
      females had vitellogenin but no ecdysteroids, so ecdysteroids are not necessary
      for vitellogenin production. In addition, treatment of females with ecdysteroids
      altered neither Vg titers nor ovarian growth. Ovarian ecdysteriods increased at
      the same age in development as hemolymph ecdysteroids. In contrast to hemolymph
      ecdysteroids, ovarian ecdysteroids persisted until oviposition. Despite this,
      [(3)H]ecdysone injected into the hemolymph was detected later only at very low
      levels in the ovary, suggesting that hemolymph ecdysteroids are not sequestered
      by the ovary. In summary, our studies indicate that hemolymph ecdysteroids in
      adult females of the lubber grasshopper are associated with the timing of egg
      production, but they neither regulate vitellogenesis nor act as a source of
      ecdysteroids for the ovary.

PMID- 12489134
TI  - Postmarital residence and biological variation at Pueblo Bonito.
AB  - Although the social organization of many of the present-day pueblos of the
      American Southwest is well-described in the anthropological literature, many
      aspects of prehistoric Puebloan social organization have received limited
      attention since initial investigations of postmarital residence in the 1960s and
      1970s. This paper examines postmarital residence at the Chaco Canyon great house
      of Pueblo Bonito, using biological data. Our findings are inconsistent with the
      previously well-accepted hypothesis that the Pueblo II and Pueblo III occupants
      of the San Juan Basin conformed to a socially prescribed pattern of matrilocal
      residence with matrilineal descent. Univariate variance differences for nine
      craniometric variables indicate a pattern of increased female variability
      consistent with patrilocal/bilocal residence. The results of multivariate
      determinant ratio analyses are in agreement with the univariate results,
      suggesting the possibility of a patrilocal or bilocal residence preference at
      Pueblo Bonito. These findings are inconsistent with the notion that the female
      based system of matrilocal residence with matrilineal descent observed among the
      present-day Western Pueblos was the ancestral Anasazi condition.

PMID- 12489135
TI  - Long bone articular and diaphyseal structure in Old World monkeys and apes. II:
      Estimation of body mass.
AB  - Body mass estimation equations are generated from long bone cross-sectional
      diaphyseal and articular surface dimensions in 176 individuals and 12 species of
      hominoids and cercopithecoids. A series of comparisons is carried out to
      determine the best body mass predictors for each of several taxonomic/locomotor
      groupings. Articular breadths are better predictors than articular surface areas,
      while cross-sectional shaft strengths are better predictors than shaft external
      breadths. Percent standard errors of estimate (%SEEs) and percent prediction
      errors for most of the better predictors range between 10-20%. Confidence
      intervals of equations using sex/species means are fairly representative of those
      calculated using individual data, except for sex/species means equations with
      very low %SEEs (under about 10%), where confidence intervals (CIs) based on
      individuals are likely to be larger. Given individual variability, or biological
      "error," this may represent a lower limit of precision in estimating individual
      body masses. In general, it is much more preferable to determine at least broad
      locomotor affinities, and thus appropriate modern reference groups, before
      applying body mass estimation equations. However, some structural dimensions are
      less sensitive to locomotor distinctions than others; for example, proximal
      tibial articular M-L breadth is apparently "locomotor blind" regarding body mass
      estimation within the present study sample. In other cases where locomotor
      affiliation is uncertain, mean estimates from different reference groups can be
      used, while for some dimensions no estimation should be attempted. The techniques
      are illustrated by estimating the body masses of four fossil anthropoid specimens
      of Proconsul nyanzae, Proconsul heseloni, Morotopithecus bishopi, and
      Theropithecus oswaldi.

PMID- 12489136
TI  - Scaling relationships between craniofacial sexual dimorphism and body mass
      dimorphism in primates: implications for the fossil record.
AB  - Craniofacial remains (the most abundant identifiable remains in the fossil
      record) potentially offer important information about body size dimorphism in
      extinct species. This study evaluates the scaling relationships between body mass
      dimorphism and different measures of craniofacial dimorphism, evaluating
      taxonomic differences in the magnitude and scaling of craniofacial dimorphism
      across higher taxonomic groups. Data on 40 dimensions from 129 primate species
      and subspecies demonstrate that few dimensions change proportionally with body
      mass dimorphism. Primates show general patterns of greater facial vs.
      neurocranial and orbital dimorphism, and greater dimorphism in lengths as opposed
      to breadths. Within any species, though, different craniofacial dimensions can
      yield very different reconstructions of size dimorphism. There are significant
      taxonomic differences in the relationships between size and craniofacial
      dimorphism among primate groups that can have a significant impact on
      reconstructions of body mass dimorphism. Hominoids tend to show lower degrees of
      facial dimorphism proportional to size dimorphism than other primates. This in
      turn implies that strong craniofacial dimorphism in Australopithecus africanus
      could imply very strong body size dimorphism, conflicting with the relatively
      modest size dimorphism inferred from postcrania. Different methods of estimating
      the magnitude of size dimorphism from craniofacial measurements yield similar
      results, and yield comparatively low percent prediction errors for a number of
      dimensions. However, confidence intervals for most estimates are so large as to
      render most estimates highly tentative.

PMID- 12489137
TI  - Localized hypoplasia of the primary canine in bonobos, orangutans, and gibbons.
AB  - This paper extends observations by Lukacs ([1999] Am. J. Phys. Anthropol. 110:351
      363; [2001] Am. J. Phys. Anthropol. 116:199-208) of localized hypoplasia of the
      primary canine (LHPC) among large apes to gibbons, bonobos, and orangutans. LHPC
      is a roughly circular area of deficient enamel on the labial surface of primary
      canine teeth which, on current evidence from humans, forms several months after
      birth due to malnutrition-induced craniofacial osteopenia, leading to crypt
      fenestration that exposes the dental follicle and more deep-sited ameloblasts to
      minor physical traumata during normal motor infant development. Our goal was to
      determine the prevalence of LHPC among a variety of apes which differ in body
      mass and socioecology, with a view to elucidating the etiology of the defect. We
      examined juvenile dentitions from 122 animals from three taxa: 8 Hylobates lar,
      75 Pongo pygmaeus from Borneo and Sumatra, and 39 Pan paniscus from central
      Africa. Reported variables include taxon, sex, arcade, side, and tooth size.
      Presence/absence and ordinal severity of defect expression were recorded by
      description, microphotography, and scanning electron microscopy. Molds were taken
      in high-resolution dental impression materials and cast in epoxy resin. There are
      clear taxonomic, but no sex, differences. Prevalence ranged from 0.0% in gibbons
      to 61.5% in bonobos and 85.3% in orangutans. The result for orangutans is similar
      to that reported by Lukacs ([1999] Am. J. Phys. Anthropol. 110:351-363), while
      bonobos are much more affected than were the common chimpanzees (22%) described
      by Lukacs ([1999] Am. J. Phys. Anthropol. 110:351-363). There are no significant
      antimeric differences, but the lower canine is much more affected than the upper
      by LHPC. We show that larger teeth are more affected by LHPC and have more severe
      defects. Also, we encountered several instances of patent or healing canine crypt
      fenestrations, occasionally in direct association with LHPC. Location of the
      defect indicates that LHPC may occur perinatally but more usually several months
      postnatally. Histological examination showing the neonatal line and LHPC is
      required to resolve the issue of timing. We concur with Lukacs ([1999] Am. J.
      Phys. Anthropol. 110:351-363) that taxonomic, anatomical, and environmental
      variables combine to determine the occurrence and appearance of LHPC.
      Nevertheless, we conclude that LHPC probably reflects deficient growth of the
      arcades in infant apes and humans.

PMID- 12489138
TI  - Analysis of colored teeth from Precolumbian Tlatelolco: postmortem transformation
      or intravitam processes?
AB  - The etiological basis of the abnormal coloration of archaeological teeth has been
      an unsolved question for a long time. Differences in the appearance of some
      archaeological teeth from Precolumbian adult and infant skeletons, detected by
      external optical inspection, led us to study this problem. A blue stain is
      visible in a few of the deciduous erupted teeth, and a brown color in various
      unerupted teeth in the collection, while brown spots appear on some permanent
      teeth. Several processes or factors that may occur during one's life, others
      around the time of death, and still others resulting from postmortem alterations
      have been reported as potential causes of abnormal tooth coloration.A sample of
      35 colored teeth and two soil layers taken from Tlatelolco were analyzed by
      particle-induced X-ray emission (PIXE) as well as selective dissolution
      techniques. Concentrations of total and extractable elements in enamel and soil
      layers (Cg1-Cg2) were obtained. This paper describes the occurrence and
      implications of a substantial secondary concentration of Zinc (Zn), manganese
      (Mn), strontium (Sr), and iron (Fe) in the deciduous erupted and nonerupted teeth
      as compared to that in the adult teeth. Our interpretation is that, in this
      archaeological context, the brown spots and blue stains on the teeth are due to
      differences in tooth enamel porosity and to a postmortem biogeochemical process.
      The alterations involve cumulization and diagenesis of iron, manganese, and
      organic matter solutions that were eluviated from the soil and are not the result
      of antemortem or perimortem conditions such as trauma or disease.

PMID- 12489139
TI  - Life history and the competitive environment: trajectories of growth, maturation,
      and reproductive output among chacma baboons.
AB  - The social environment is a key feature influencing primate life histories.
      Chacma baboons (Papio hamadryas ursinus) are a female-bonded species with a
      strict linear dominance hierarchy. In this species, the allocation of energy to
      competing demands of growth and reproduction is hypothesized to vary as a
      function of competitive ability, which in turn increases with social rank. Since
      growth rate is a major component of life history models, measures of age-specific
      growth were used to analyze variation in life history traits across social ranks.
      Weights of 42 immature baboons were obtained without sedation or baiting from a
      troop of well-habituated chacma baboons in the Okavango Delta, Botswana. Using
      demographic and weight data from this wild population, five main findings
      emerged: 1) Weight for age and growth rate of infant and juvenile females are
      positively associated with maternal rank. 2) Male growth is not influenced by
      maternal rank. 3) Female growth shows smaller variation across feeding conditions
      than male growth. 4) Low-ranking adult females continue investment in offspring
      through prolonged lactation until they reach a weight comparable to that of high
      ranking infants. 5) The benefit of rank to reproductive success shown in this
      study is 0.83 additional offspring. Reproductive span determined predominantly by
      age at maturation contributes 27-38% to the difference in expected number of
      offspring by rank, vs. 62-73% due to reproductive rate. These findings have major
      implications for understanding the role of social environment in phenotypic
      plasticity of life history traits, and in the evolution of primate life
      histories.

PMID- 12489140
TI  - An address to young research workers: Inconsequences and blindness to the facts
      and unpublished observations.
AB  - The critical remembrance of my research activity displays aspects of
      inconsequence and mental rigidity. Particular probative examples are called to
      mind. Unpublished observations concerning immortalized dental cells are
      summarized. As a consequence, if I could start again, I would improve several
      aspects of my behavior and attitude of mind.

PMID- 12489141
TI  - Teeth and paleoanthropology.
AB  - Teeth have a very significant place in paleoanthropology. Their number is one of
      the keys of the primate taxonomy and classification. They have been used for
      systematics, phylogeny, paleobiology, or paleoenvironment. Some examples are
      given on the use of dental formula, morphology, wear or microwear, and
      biogeochemistry in paleoanthopologic studies.

PMID- 12489142
TI  - Enamel hypoplasia in a pliocene hominid from Chad.
AB  - Abel is the first Australopithecine known west of the East African Rift Valley.
      The fossil finds include a perisymphyseal fragment of an adult mandible with well
      preserved crowns of the right I2-P4 and the left C-P4. Abel's dentition displays
      many enamel defects, which are described in detail for each tooth. Pitting
      affected every tooth, while larger, shallow depressions were observed on the
      canines alone. From two to four pit bands occurred on the different teeth, each
      resulting from a separate hypoplastic episode. In modern humans, a large number
      of causes, both environmental and genetic, have been suggested for such enamel
      defects. It seems probable that Abel's pathology was systemic. However, the
      occurrence of a number of bands and the variable intensity of the attacks make it
      difficult to say whether there was a single, repetitive cause or different
      etiologies. Possible causes discussed here include recurrent fevers and seasonal
      nutritional deficiencies.

PMID- 12489143
TI  - Fish dentitions as paradigms for odontogenic questions.
AB  - Bony fish, and in particular teleosts, represent a morphologically extremely
      diverse group of vertebrates, well suited to study certain problems in
      odontogenesis. In this article we address some questions that can benefit much
      from the use of fish dentitions as paradigms, such as endodermal participation in
      tooth formation and epithelial primacy in initiation events. Next, we highlight
      some results recently obtained in our laboratory with respect to two models, the
      zebrafish (Cyprinidae), and selected species of cichlids (Cichlidae). Finally, we
      pinpoint some questions that lend themselves admirably to be examined using fish
      models, such as the factors that control renewed initiation of teeth, and the
      relationship (or absence thereof) between Hox genes and tooth formation.

PMID- 12489144
TI  - Tooth shape differences analyzed by biometric and morphometric approaches: a case
      study on two morphologically very similar lacustrine cichlid species.
AB  - Tooth shape is generally considered to be under strong genetic control, and
      highly species specific. It is therefore widely used for taxonomic studies. The
      tooth shape-based morphological classification of the Eretmodini (a tribe of
      closely related cichlids endemic to Lake Tanganyika), has, however, been shown to
      be in conflict with recent molecular data, which suggests the occurrence of
      parallel evolution. A detailed biometric and morphometric analysis of tooth shape
      has been undertaken for two genetic lineages of the taxon Eretmodus cyanostictus.
      The use of both landmark-based measurements and elliptic Fourier analysis reveals
      differences between both lineages and supports the molecular phylogeny. These
      differences further endorse the interpretation of parallel evolution. In
      addition, we here present a powerful tool for the analysis of tooth shape.

PMID- 12489145
TI  - Developmental differences between cranial bones in the zebrafish (Danio rerio):
      some preliminary light and TEM observations.
AB  - To test whether cartilage bones and dermal bones, which belong to two different
      units of the vertebrate skeleton, have distinct developmental programs possibly
      reflected in a different molecular control of their ossification process, we
      currently investigate the development of some selected cranial bones in the
      zebrafish, Danio rerio. Here we present some light microscopical and
      ultrastructural findings with respect to the maxillary bone (a dermal bone that
      is edentulous in the zebrafish) and the basioccipital bone (a cartilage bone,
      i.e., with a perichondral phase followed by endochondral invasion). The two bones
      differ in (a) the area where matrix is first deposited--an unstructured
      extracellular domain in the former versus intermingling of bone matrix elements
      with cartilage matrix in the latter--and (b) the progression of ossification-
      continuously from an initium in the former versus through fusion of separate
      anlagen in the latter. These findings seem to support the hypothesis that the two
      types of bone have at least some distinctive features in their developmental
      programs.

PMID- 12489146
TI  - Developmental constraints conserve evolutionary pattern in an osteichthyan
      dentition.
AB  - The lungfish dentition is different from other osteichthyan fish because it has a
      characteristic and unique pattern of teeth arranged as toothplates. Growth,
      addition of teeth, and retention as part of a statodont dentition are determined
      by the initiation pattern. In adult lungfish new teeth are only added laterally
      to each radial row in the dentition. This is in marked contrast to marginal rows
      of teeth with regular, alternating replacement in most osteichthyans. We analyze
      development from fossil hatchling forms of the Late Devonian dipnoan
      Andreyevichthys and compare with those of Neoceratodus, the Australian lungfish.
      The specific pattern of development, unique within lungfish, is also present in
      the transitory, marginal, anterior dentition in both, reflecting a strongly
      conserved developmental pattern. These marginal teeth form but are then lost in
      both, so that also this program of development is conserved within lungfish for
      360 million years, from the earliest known form.

PMID- 12489147
TI  - Development of the vestigial tooth primordia as part of mouse odontogenesis.
AB  - The mouse functional dentition comprises one incisor separated from three molars
      by a toothless diastema in each dental quadrant. Between the incisor and molars,
      the embryonic tooth pattern also includes vestigial dental primordia, which
      undergo regression involving apoptosis in their epithelium. Apoptosis appears to
      play an important role in achieving the specific tooth pattern in the mouse. We
      documented similarities in the folding mechanism allowing the formation of the
      dental lamina in mice as well as in reptiles. While further budding on this
      dental lamina gives rise to many individual simple tooth primordia in crocodiles
      and lizards, budding morphogenesis of several simple tooth primordia appears to
      be integrated in the mouse, giving rise to enamel organs of a complex nature. The
      differentiation of a mammalian tooth germ during both ontogeny and phylogeny
      might thus include the concrescence (connation) of more primordia, putatively
      corresponding to simple teeth in mammalian ancestors.

PMID- 12489148
TI  - Evolutionary implications of the occurrence of two vestigial tooth germs during
      early odontogenesis in the mouse lower jaw.
AB  - The study of closely-spaced developmental stages reveals the occurrence of three
      distinct dental segments during early odontogenesis in the ICR mouse lower jaw:
      the mesial (MS), the second rudimentary (R2), and the molar segments. At
      embryonic day (ED) 12.5, the MS displays an accessory bud, which regresses
      rapidly and disappears at ED 13.5. The R2 segment reaches a wide bud stage at ED
      13.5 and then merges with the mesial end of the emerging first lower molar (M1)
      cap before ED 15.0. The MS and R2 segments never develop into functional teeth
      and are classified as vestigial tooth germs. Depending on their developmental
      chronology and on the position they occupy along the prospective mandibular tooth
      row, MS and R2 segments are putatively assigned to primordia of a third (dP3) and
      fourth (dP4) lower deciduous premolar, respectively. Evolutionary implications of
      these developmental data are discussed.

PMID- 12489149
TI  - Proliferating cell nuclear antigen (PCNA) expression in tooth primordia in the
      field vole (Microtus agrestis, Rodentia).
AB  - Cell proliferation in developing tooth germs has been studied particularly using
      bromodeoxyuridine (BrdU) incorporation into growing tooth primordia and by
      counting and three-dimensional (3D) reconstruction of mitoses in serial sections
      of developing teeth. PCNA has been proposed as an alternative marker of
      proliferation activity. The aim of our study was to detect immunohistochemically
      locations of PCNA-positive cells in developing tooth germs of Microtus agrestis
      (Rodentia). PCNA expression could be distinguished in oral epithelium and
      mesenchyme before first signs of dental lamina elevation. During bud, cap, and
      bell stages, positive immunostaining could be observed at defined sites in enamel
      organ, tooth papilla, and dental follicle. Rudimental tooth germs of the upper
      diastema, enamel knots, and inner enamel epithelium at day of ontogeny 18 and 19
      showed negative reaction. PCNA marks cycling and early G0 cells and can be used
      successfully as a proliferation marker even in collection material.

PMID- 12489150
TI  - Expression and regulation of hedgehog-interacting protein during early tooth
      development.
AB  - Sonic hedgehog (Shh) expression is highly localized to the epithelium at the
      future sites of tooth development. This restricted expression suggests that
      inhibition of Shh in areas where teeth do not form may be an important mechanism
      in tooth germ localization. Recently, Hip, a putative vertebrate antagonist of
      Shh, has been identified. We have investigated the expression of Hip during early
      tooth development and found it not to be localized in cells immediately adjacent
      to Shh-expressing cells, but rather at a distance, separated by cells expressing
      Ptc1. Hip is also regulated by Shh in the first branchial arch. Shh-soaked
      agarose beads are able to induce the expression of Hip in odontogenic mesenchyme.
      A role for Hip might be to prevent the spread of excess Shh ligand beyond an
      immediate Ptc1-induced zone in odontogenic mesenchyme. This mechanism would
      therefore restrict Shh signaling specifically to those regions along the oral
      axis that are destined to form teeth.

PMID- 12489151
TI  - Msx1 homeogene antisense mRNA in mouse dental and bone cells.
AB  - Msx1 plays a key role in early dental and cranio-facial patterning. A systematic
      screening of Msx1 transcripts during late postnatal stages of development
      evidenced not only sense mRNA but also antisense mRNA in the skeleton. Natural
      antisenses are able to bind their corresponding sense RNAs and block protein
      expression. Specific reverse-transcription polymerase chain reaction (RT-PCR)
      Northern-blotting using riboprobes and primer extension analysis allowed to
      identify and sequence a mouse 2184-base Msx1 antisense transcript. The
      transcription start site was located in a region including a consensus TATA box.
      In situ hybridization evidenced an increase in antisense mRNA expression during
      dental and bone cell differentiation in prenatal (Theiler stages E15.5-18.5) and
      newborn mice. This upregulation was related to Msx1 protein downregulation in
      cells expressing Msx1 sense mRNA. In vitro, transient Msx1 sense and antisense
      mRNA overexpression was performed in MO6-G3 cells, which pertain to the
      odontoblast lineage (polarization and dentin sialoprotein and phosphoprotein
      synthesis). The balance between antisense and sense Msx1 mRNAs appeared to
      control Msx1 protein levels. These data suggest that a bidirectional
      transcription of Msx1 homeogene may control Msx1 protein levels, and therefore
      may be critical in cell communication and differentiation during dental and
      cranio-facial development and mineralization.

PMID- 12489152
TI  - Msx1 is a regulator of bone formation during development and postnatal growth: in
      vivo investigations in a transgenic mouse model.
AB  - The present study is devoted to Msx1 distribution and function from birth to 15
      months, events and periods still unexplored in vivo using Msx1 knock in
      transgenic mice. The study is focused on the mandible, as an exemplary model
      system for Msx1-dependent neural crest-derived skeletal unit. The transgenic line
      enabled study of morphological abnormalities in Msx1 null mutation mice and Msx1
      protein expression in Msx1+/- heterozygous mice. In Msx1 null mutation, the most
      striking feature was an inhibition of the mandibular basal convexity, the absence
      of teeth and alveolar bone processes, and absence of endochondral ossification in
      the mandibular condyle. At birth, in Msx1+/- heterozygous animals, we identified
      for the first time a double Msx1 aboral-oral and disto-proximal gradient field
      developmental pattern located in the low border of the mandibular bone in
      relation with this bone segment modeling. Msx1 expression involved both
      osteoblast and osteoclast cells. A distinct pattern characterized bone surfaces:
      Periosteum osteoblast differentiation was related to Msx1 down-regulation, while
      in the endosteum both differentiated osteoblasts and osteoclasts expressed the
      homeoprotein. In postnatal stages, Msx1 expression was maintained in the alveolar
      bone processes and dento-alveolar cells in relation with tooth function. Our data
      suggest that Msx1 play a role in a site-specific manner not only in early
      patterning but also in skeletal growth and modeling by acting on heterogenous
      bone cell populations.

PMID- 12489153
TI  - Krox-26 is a novel C2H2 zinc finger transcription factor expressed in developing
      dental and osteogenic tissues.
AB  - The development of teeth through epithelial-mesenchymal interactions is mediated
      on a molecular level by a network of secreted growth factors and responsive
      transcription factors. Although zinc finger transcription factors constitute by
      far the largest class of transcriptional regulators with an estimated number of
      approximately 1000 genes present in mammals [14], little is known about their
      role in the regulation of mineralized tissue formation. A fragment (Y150) of the
      novel C2H2 zinc finger transcription factor Krox-26 has initially been isolated
      from highly proliferative dental pulp tissue in rats [19]. The objective of this
      study was to clone the full-length cDNA sequence of the murine homologue and to
      determine its mRNA and protein expression pattern during mouse embryonic
      development. Mouse Krox-26 contains five C2H2 zinc finger repeats. Its expression
      was found to be most prominent in the developing craniofacial bones and dental
      organs. These results suggest Krox-26 as a potential regulator of gene
      transcription during the development of teeth and the craniofacial skeleton.

PMID- 12489154
TI  - Porcine N-acetylgalactosamine 6-sulfatase (GALNS) cDNA sequence and expression in
      developing teeth.
AB  - Mucopolysaccharidosis type IVA (Morquio A syndrome, MPS IVA) is a rare, autosomal
      recessive disorder with a prevalence of 1 in 170,000 live births. It is caused by
      a deficiency of N-acetylgalactosamine 6-sulfatase (GALNS), a lysosomal hydrolase
      encoded by a gene on human chromosome 16q24.3. Mucopolysaccharidosis type IVA is
      the only known MPS that is associated with structural defects in dental enamel.
      GALNS cleaves the sulfate group from N-acetylgalactosamine 6-sulfate and
      galactose 6-sulfate, which are specifically found in keratan sulfate and
      chondroitin 6-sulfate. A pathologic absence of GALNS activity results in the
      accumulation of these glycosaminoaglycans in the urine and in the lysosomes of
      tissues that turn them over. There is currently no animal model for MPS IVA. To
      learn more about how a GALNS deficit could lead to enamel defects, we have cloned
      and characterized a full-length pig GALNS cDNA. GALNS mRNA was localized in
      developing teeth by in situ hybridization, Northern blot, and reverse
      transcription polymerase chain reaction analyses, while GALNS substrates were
      localized using immunohistochemistry. We report that secretory ameloblasts were
      positive for GALNS mRNA, as well as for keratan sulfate and chondroitin 6
      sulfate. We conclude that enamel defects associated with the loss of GALNS
      activity in persons with MPS IVA are likely to result from the pathological
      accumulation of keratan sulfate and chondroitin 6-sulfate in the lysosomes of
      secretory stage ameloblasts.

PMID- 12489155
TI  - Analysis of cDNAs from a mouse embryo tooth library: identification of novel
      genes during tooth development.
AB  - Signaling molecules, their receptors, and target genes from pathways and networks
      regulate the development of the tooth from initiation through cell
      differentiation. In order to identify genes involved in odontoblast and
      ameloblast differentiation, we constructed a cDNA library from E19.5 mouse
      molars. In this work, we report the partial cDNA sequences of 10 noncharacterized
      genes and we show cell expression of the transcripts on mouse embryo molars by in
      situ hybridization.

PMID- 12489156
TI  - Misexpression of genes in mouse tooth germs using in vitro electroporation.
AB  - Mouse mandible primodia in vitro explant cultures are an excellent model for
      investigating tooth development. Mandibular arch epithelial-mesenchymal tissue
      recombinations and implantation of beads soaked in signaling proteins have
      revealed much about the early events of odontogenesis. These approaches do,
      however, suffer from several disadvantages, in particular the nonphysiological
      nature of beads soaked in very high concentrations of proteins and the inability
      to directly manipulate receptor and transcription factor gene expression. We have
      utilized the technique of DNA electroporation to deliver targeted gene expression
      to defined areas of mandibular arch epithelium or mesenchyme. This approach is
      being used to (a) ectopically express epithelial signals such as Shh and Bmp-4,
      (b) inhibit BMP and FGF signaling by expression of dominant negative receptors
      and antagonists, and (c) misexpress transcriptional factors in the mesenchyme.
      The technical aspects of electroporation are discussed, as well as preliminary
      findings.

PMID- 12489157
TI  - Body weight in mouse embryos specifies staging of tooth development.
AB  - Great intra- and interlitter variation in morphological stages is known to exist
      among mouse embryos of the same strain at a similar chronological stage. With the
      aim of searching for an easily measurable parameter that correlates well with
      tooth development, the morpho- and histodifferentiation of teeth were compared in
      embryos classified according to the embryonic day (ED) specified by wet body
      weight. The embryos and fetuses were harvested at 12-h intervals from ED12.5
      until birth, weighed, fixed, and processed histologically. The tooth age was
      determined according to the developmental progress of the first molar, evaluated
      based on morpho- and histodifferentiation criteria. The data documented a better
      correlation between tooth morpho-histodifferentiation with the age/weight staging
      than with only the embryonic day. The cyto-differentiation of odontoblasts
      exhibited a high interlitter variability and was similar within specimens of the
      same litter, regardless of their body weight differences.

PMID- 12489158
TI  - Cell-cell and cell-matrix interactions during initial enamel organ
      histomorphogenesis in the mouse.
AB  - Relationships between cell-cell/cell-matrix interactions and enamel organ
      histomorphogenesis were examined by immunostaining and electron microscopy.
      During the cap-bell transition in the mouse molar, laminin-5 (LN5) disappeared
      from the basement membrane (BM) associated with the inner dental epithelium
      (IDE), and nondividing IDE cells from the enamel knot (EK) underwent a tooth
      specific segregation in as many subpopulations as cusps develop. In the incisor,
      the basement membrane (BM) in contact with EK cells showed strong staining for
      LN5 and integrin alpha 6 beta 4. LN5 seems to provide stable adhesion, while its
      proteolytic processing might facilitate cell segregation. In both teeth,
      immunostaining for antigens associated with desmosomes or adherens junctions was
      similar for EK cells and neighboring IDE cells. Outside the EK, IDE cell-BM
      interactions changed locally during the initial molar cusp delimitation and on
      the labial part of the incisor cervical loop. Conversely, cell-cell junctions
      stabilized the anterior part of the incisor during completion of morphogenesis.
      Time and space regulation of cell-matrix and cell-cell interactions might thus
      play complementary roles in allowing plasticity during tooth morphogenesis and
      stabilization at later stages of epithelial histogenesis.

PMID- 12489159
TI  - FGF10 maintains stem cell population during mouse incisor development.
AB  - Mouse incisors have a cervical loop that gives rise to dental epithelium in the
      apical region of the tooth germ, in contrast to molars. In a study of formation
      of the stem-cell compartment, we focused on expression patterns of fibroblast
      growth factor (Fgf) 10 and Fgf3 in developing mice incisors. At E14, Fgf10 and
      Fgf3 were coexpressed in the dental papilla. After E16 mesenchymal cells
      underlying cervical loop expressed Fgf10 but not Fgf3. To illustrate the role of
      FGF10, we analyzed incisor development of Fgf10-deficient mice. The germs of
      FGF10-null mice proceeded to cap stage normally. However, at a later stage, the
      cervical loop was not formed. Functional disorder of FGF10 by a neutralizing anti
      FGF10 antibody induced apoptosis in the cervical loop of incisor explants.
      Recombinant FGF10 rescued the cervical loop from apoptosis. These results show
      that FGF10 maintains the stem-cell compartment in the developing incisor tooth
      germ.

PMID- 12489160
TI  - Temperospatial expression of matrix metalloproteinases 1, 2, 3, and 9 during
      early tooth development.
AB  - Odontogenesis involves a complex series of processes including epithelial
      mesenchymal interactions, morphogenesis, differentiation, fibrillogenesis, and
      mineralization. Extracellular (ECM) remodeling plays a critical role in the rapid
      morphological changes that accompany these events. It is proposed that matrix
      metalloproteinases (MMPs) participate in the remodeling of tooth-specific
      matrices that accompanies the developmental events. MMPs are zinc-requiring
      endopeptidases that are centrally involved in the controlled turnover of ECM
      components and are key to a varied range of developmental processes. Thus, the
      aim of this study was to examine the expression of MMPs 1, 2, 3, and 9 within the
      developing tooth germ of Wistar rats, using immunohistochemical localisation.
      During the bud stage, MMPs 1, 2, 3, and 9 were expressed within both epithelial
      and mesenchymal cells. Later on, during the cap stage, differential expression
      was observed; of note was the expression of MMP 3 within the enamel knot. This
      study reports the temperospatial expression of MMPs 1, 2, 3, and 9 during early
      tooth development, and points to them having a key role during this important
      developmental period.

PMID- 12489161
TI  - Expression of the neural cell adhesion molecule during mouse tooth development.
AB  - The neural cell adhesion molecule (NCAM) is a molecule that mediates calcium
      independent cell-cell adhesion, and is expressed during development in a variety
      of tissues including nonneuronal ones. Expression of NCAM during molar tooth
      development was analyzed in this present study. In the enamel organ, NCAM
      expression was detected from the embryonic day 13 onward in restricted areas,
      including a part of the stratum intermedium of the tooth germ at the bell stage.
      Mesenchymal cells also expressed NCAM from the bud stage of the first molar
      onward. In addition to the strong expression in the dental follicle, weak and
      transient expression was detected in the dental papilla. The second and the third
      molars appeared to initiate their development by the interaction between the
      epithelial cells and NCAM-expressing mesenchymal cells. Comparison of the
      expression patterns of NCAM and transcription factor Barx1 revealed a possibility
      that Barx1 negatively regulates NCAM expression.

PMID- 12489162
TI  - Col1a1-GFP transgene expression in developing incisors.
AB  - Previous studies have shown that terminal differentiation of odontoblasts is
      accompanied by dramatic increases in type I collagen synthesis. Recently
      transgenic mice in which green fluorescent protein (GFP) expression is under the
      control of the rat 3.6 (pOBCol3.6GFPtpz) and 2.3 (pOBCol2.3GFPemd) Col1a1
      promoter fragments were generated. Our analysis of these GFP-expressing
      transgenic mice shows that the 2.3-kb promoter fragment directs strong expression
      of GFP only to bones and teeth, whereas the 3.6-kb fragment of promoter directs
      strong expression of GFP in bone and tooth, as well as in other type I collagen
      producing tissues. Our observations of incisors in these transgenic mice show
      high levels of GFP expression in functional odontoblasts and in differentiated
      osteoblasts. These observations show that expression of GFP reporter genes
      closely follow the patterns of expression of alpha 1(I) collagen in various
      tissues including odontoblasts.

PMID- 12489163
TI  - Expression of heat-shock protein 25 immunoreactivity in the dental pulp and
      enamel organ during odontogenesis in the rat molar.
AB  - The present immunocytochemical study reports on the expression of heat-shock
      protein (Hsp) 25 during odontogenesis in rat molars from postnatal 1 to 100 days.
      Hsp 25 immunoreactivity (IR) appeared in the immature dental mesenchymal cells
      and the differentiating and differentiated odontoblasts. At 30 days, the coronal
      odontoblasts retained intense Hsp25-IR, whereas the odontoblasts in the root and
      floor pulp were initially weak or negative but increased in IR in the later
      stages, indicating that the expression of Hsp 25 reflects the differentiation
      status of odontoblasts. During amelogenesis, the secretory ameloblasts were Hsp
      25 immunopositive and the enamel free area (EFA) cells showed intense Hsp 25-IR
      when they developed a ruffled border. Ruffle-ended ameloblasts (RA) also
      consistently showed intense Hsp 25-IR, but smooth ended ameloblasts (SA) showed
      weak IR. These data suggest that Hsp 25 is related to the formation and
      maintenance of the ruffled border of RA and EFA cells.

PMID- 12489164
TI  - Polypeptides translated from alternatively spliced transcripts of the amelogenin
      gene, devoid of the exon 6a, b, c region, have specific effects on tooth germ
      development in culture.
AB  - Recombinant proteins have been produced from cDNAs corresponding to alternatively
      spliced transcripts comprised from exons 2,3,4,5,6d,7 and 2,3,5,6d,7 of the rat
      amelogenin gene. These peptides, designated as [A + 4] and [A - 4], respectively,
      induce embryonic muscle fibroblasts in culture in vitro to express proteins
      characteristic of the chondrogenic and osteogenic phenotypes, and in matrix
      supported implants into rat muscle, in vivo, induce typical bone matrix proteins.
      The aim of the present work was to examine the potential role of these proteins
      on the development of odontogenic tissue. The lower first molars were collected
      from Charles River CD-1 mice at postnatal days 1 and 2 and were grown on
      semisolid, serum-free medium supplemented with ascorbic and retinoic acids and
      transferin. The peptides were added to the serum-free media at 10 ng/ml. As
      controls, the medium was either 20% fetal bovine serum or the supplemented serum
      free medium without either amelogenin peptide. The tooth germs were cultured for
      6 days, then fixed and paraffin embedded by standard procedures. The tissue
      blocks were serially sectioned and stained with hematoxylin-eosin (H&E), or
      antibodies to collagen 1 (Col1), phosphophoryn (DMP2), or cementum attachment
      protein (CAP). CAP, DMP2, and Col1 expression was enhanced by the addition of the
      amelogenin peptides, as compared to the 0% fetal bovine serum (FBS) controls, but
      the peptides showed different effects. Expression of DMP2, characteristic of
      dentin matrix, was upregulated by [A + 4], whereas CAP, characteristic of
      cementum, was upregulated by [A - 4]. Since the recombinant peptides are active,
      their corresponding tissue forms may be important in the stimulation of
      mesenchymal tissue differentiation. Thus, these specific amelogenin proteins may
      be involved in tooth morphogenesis.

PMID- 12489165
TI  - In vivo and in vitro expression of connexin 43 in human teeth.
AB  - Gap junctions are composed of transmembrane proteins belonging to the connexin
      family. These proteins permit the exchange of mall regulatory molecules directly
      between cells for the control of growth, development and differentiation.
      Although the presence of gap junctions in teeth has been already evidenced, the
      involved connexins have not yet been identified in human species. Here, we
      examined the distribution of connexin 43 (Cx43) in embryonic and permanent intact
      and carious human teeth. During tooth development, Cx43 localized both in
      epithelial and mesenchymal dental cells, correlated with cytodifferentiation
      gradients. In adult intact teeth, Cx43 was distributed in odontoblast processes.
      While Cx43 expression was downregulated in mature intact teeth, Cx43 appeared to
      be upregulated in odontoblasts facing carious lesions. In cultured pulp cells,
      Cx43 expression was related to the formation of mineralized nodules. These
      results indicate that Cx43 expression is developmentally regulated in human
      dental tissues, and suggest that Cx43 may participate in the processes of dentin
      formation and pathology.

PMID- 12489166
TI  - Ultrastructural characterization of the mesenchyme of the facial processes during
      development of the rat intermaxillary segment.
AB  - This study quantifies ultrastructural changes within the mesenchyme of the
      maxillary and medial/lateral nasal processes before and after formation of the
      intermaxillary segment. At both day 11 and day 13 of development, 4 fetal rat
      heads were fixed with 3% glutaraldehyde and processed for electron microscopy.
      Differences between cells within the facial processes were discerned at day 11 of
      gestation. Significantly more rough endoplasmic reticulum was present in the
      cells of the maxillary processes than in the lateral nasal processes (p < .05),
      and a greater number of cell projections was found in the maxillary processes
      than in the medial nasal processes (p < .05). At day 13, no significant
      differences were found in the facial processes. Of particular note, a consistent
      increase in the number of cell projections within all the facial processes was
      found on day 13 when compared with day 11 (p < .05). This change may be related
      to intercellular signaling between the mesenchymal cells at the time of onset of
      major histogenic changes.

PMID- 12489167
TI  - Pathways and fate of migratory cells during late tooth organogenesis.
AB  - Tissue recombination experiments and cell lineage analyses of the developing
      neural crest have documented the role and central pathways of migratory cells
      during early craniofacial development. In the present study, regional pathways of
      cells during late peripheral morphogenesis were investigated using the crown
      stage tooth organ as a model. Homing targets during tooth integument formation
      were analyzed to understand the fate of migratory cells involved in late tooth
      organogenesis and the developmental origin of periodontal tissues. After surgical
      removal of the oral mucosa, the oral aspect of the dental follicle of lower first
      mouse molar teeth was labeled using a fluorescent contact dye. Following
      sacrifice after 0, 2, 4, and 6 days, labeled cells were detected in the dental
      follicle, in the alveolar bone, and in the periodontal ligament adjacent to the
      molar root. The distribution of labeled tissues was reconstructed three
      dimensionally via confocal microscopy. Using a tooth molar organ culture system,
      labeled cells within the dental follicle were documented traveling in the apical
      direction. Our results indicated that cell migration during tooth organogenesis
      was following specific pathways and that cells within the circumference of the
      dental follicle were migrating in the apical direction. We speculate that
      migratory cells passing through the dental follicle connective tissue may
      contribute to the formation of the periodontium. The present documentation
      visualizes pathways, role, and dynamics of extensive cell movements during late
      tooth organogenesis.

PMID- 12489168
TI  - Bone morphogenetic protein 2 induces the expression of cementum attachment
      protein in human periodontal ligament clones.
AB  - Cementum is continuously formed during the lifetime of a tooth. The paravascular
      zones in the adult periodontal ligament (PL) comprise the progenitors for the
      fibroblastic (Fb) lineage and mineralized tissue-forming (MTF) cell lineages--the
      osteoblastic (Ob) and cementoblastic (Cb) lineages. Recent studies indicate that
      cementum attachment protein (CAP) is related to the differentiation of the Cb
      lineage and is instrumental in differentiating between the three periodontal cell
      lineages. The purpose of this study was to assess the effect of bone
      morphogenetic protein 2 (BMP2) on the expression of cementum attachment protein
      (CAP) and on the differentiation of cloned PL progenitors. The effect of BMP2 on
      CAP expression and on the differentiation of cloned Fb and MTF progenitors was
      tested by assessing the expression of alkaline phosphatase (ALP), CAP, and bone
      sialoprotein (BSP) by immunochemistry and by determining the CAP-binding capacity
      of these clones. Untreated Fb clones were negative for all tested markers and had
      low CAP-binding capacity. Untreated MTF clones had a high CAP-binding capacity
      and were positive for the three markers. BMP2 enhanced the CAP-binding potential
      of both Fb and MTF clones. BMP2 induced the expression of CAP, ALP, and BSP in
      the Fb clones and enhanced the expression of CAP and BSP in the MTF clones. These
      results indicate for the first time that BMP2 can recruit progenitors to the Cb
      lineage and regulate the differentiation of the Cb lineage by inducing and
      enhancing the expression of CAP, a cell lineage-specific regulator. Furthermore,
      the results suggest that the MTF and Fb lineages may originate from a common
      early progenitor cell.

PMID- 12489169
TI  - Apoptosis in the connective tissues of the periodontal ligament and gingivae of
      rat incisor and molar teeth at various stages of development.
AB  - Apoptosis in the periodontal connective tissues was studied using the TUNEL
      technique, supported by electron microscopy. For 16 rats (aged 3, 8, or 104
      weeks), nuclear fragmentation was assessed using the TUNEL technique (for 4 of
      the animals aged 8 weeks, incisor eruption was experimentally increased by
      trimming of teeth to the gingival margin--unimpeded eruption). A further 8 rats
      (aged 8 and 104 weeks) were employed for electron microscopy. For the incisor,
      prior to aging, and regardless of eruptive behavior (i.e., for both impeded and
      unimpeded incisors), there was little evidence of apoptosis in the periodontal
      ligament or gingival connective tissues. For the molar, apoptosis was also not
      usually detected when the teeth were erupting or in the mature, erupted state. In
      the aged animals, however, there was a marked increase in apoptosis (as assessed
      by the TUNEL technique) within the periodontal ligament and gingivae of both the
      molars and incisors (where eruption rates also increased). Nevertheless, electron
      microscopy indicated that significant numbers of apoptotic cells were only in the
      incisor periodontium. These findings are not consistent with the view that the
      periodontal fibroblasts provide a component of the force(s) responsible for
      eruption.

PMID- 12489170
TI  - The effects of aging on the eruptive behavior of the mandibular incisor in male
      rats.
AB  - Several studies have highlighted the lack of age changes in the extracellular
      matrix of the periodontal ligament, but more needs to be known about cellular and
      functional changes (including the effects upon eruption). For this study, impeded
      and unimpeded eruption rates were measured over a 2-week period for the
      mandibular incisors of a group of 24-month-old rats. The technique used for
      measuring eruption was similar to that described by Bryer [15]. Both impeded and
      unimpeded eruption rates were found to be significantly increased (p < .01)
      compared with those obtained from a group of rats aged 8 weeks. These changes
      might be related to changes in the mechanism(s) responsible for the generation of
      the eruptive force(s) or to changes in the resistance of the tissues to such
      forces.

PMID- 12489171
TI  - Postnatal lower jaw dentition in different phenotypes of tabby mice.
AB  - The tabby (Ta) syndrome in mouse is homologous to human anhidrotic ectodermal
      dysplasia, including defective development of hair, teeth, and glands. To
      complete the available data on the functional dentition in the Ta mice, we
      analyzed the mandibular cheek teeth in 261 postnatal specimens arranged in
      several phenotype/genotype groups: 51 Ta-hemizygous males, 56 Ta-homo/hemizygous
      females, 64 Ta-heterozygous females, and 40 and 50 wild-type control males and
      females, respectively. We evaluated tooth number, size, shape and eruption and
      compared these parameters in the different groups. In any individual group of Ta
      mice, there was variability mainly in the size and shape of the most mesial tooth
      and in the tooth patterns. The incidence of a reduction in tooth number in
      homozygous and hemizygous mice was dependent on the breeding scheme.

PMID- 12489172
TI  - Further studies of a model for the etiology of anomalies of tooth number and size
      in humans.
AB  - A multifactorial model based on an underlying continuous distribution of tooth
      size, with thresholds determining hypodontia and supernumeraries, has been
      proposed [1]. Our aim is to investigate this model by comparing tooth morphology
      of affected patients and their first degree relatives with normal controls. An
      image analysis system [2] was used to measure teeth on study models of controls,
      patients with hypodontia of varying degrees and location, first-degree relatives
      of hypodontia index cases, and patients with supernumerary teeth in the maxillary
      incisor region. Mesio-distal crown size in hypodontia patients was smaller than
      controls, and this difference was significant for all tooth types. There was a
      general pattern: the more severe the hypodontia, the smaller the size of the
      tooth formed. Patients with supernumerary teeth had permanent maxillary central
      and lateral incisors and canines that were significantly larger in mesio-distal
      width than controls. The maxillary central incisors also differed in taper in
      supernumerary patients compared to controls. Hypodontia prevalence was higher in
      first-degree relatives (22%) of hypodontia index cases than in the general
      population (4.4%), and unaffected relatives had smaller teeth than controls.
      Thus, there were generalized and localized effects within the dentition, and
      these findings are compatible with the statistical expectations of the proposed
      multifactorial model.

PMID- 12489173
TI  - Mutational analysis of families affected with molar oligodontia.
AB  - Oligodontia, the congenital absence of six or more permanent teeth, is a common
      developmental anomaly of human dentition whose genetic basis is poorly
      understood. We recently reported a nonsyndromic form of oligodontia involving
      mostly all permanent molars in a large kindred, caused by a frameshift mutation
      in exon 2 of the human PAX9 gene [3]. To better understand the genotype/phenotype
      correlation in non-syndromic familial oligodontia, we identified additional
      families with a similar pattern of molar oligodontia. We hypothesize that molar
      oligodontia is due to allelic heterogeneity involving different mutations in
      PAX9. To test this hypothesis, we performed pedigree analysis followed by
      mutational analysis. Pedigree analysis revealed that the oligodontia trait is
      inherited in an autosomal dominant fashion. Mutational analysis of PAX9 thus far
      excludes the presence of the previously identified frameshift mutation.

PMID- 12489174
TI  - Extracellular matrix proteins and the dynamics of dentin formation.
AB  - Dentinogenesis involves controlled reactions that result in conversion of
      unmineralized predentin to dentin when apatite crystals are formed. This process
      is dynamic: Maturation events occur within predentin beginning at the proximal
      layer and progressing to the predentin-dentin (PD) border. One type of controlled
      reaction is the proteolytic processing of dentin sialophosphoprotein (DSPP) to
      dentin sialoprotein (DSP) and dentin phosphoprotein (DPP), by cleavage of at
      least three highly conserved peptide bonds. We postulate that this processing
      event represents an activation step, resulting in release of DPP, which is active
      in its effects on formation and growth of apatite crystals. Dentin matrix protein
      1 (DPM1), present as a processed fragment (57-kD protein) in bone, is seen in
      dentin on sodium dodecyl sulfate polyacrylamide gel electrophoresis as one intact
      protein of 150-200 kD. Anti-57-kD antibodies elicit immunoreactivity in bone,
      dentin, and cellular cementum. In bone, the reactivity is associated with
      osteocytes and their cell processes. Similarly, dentin shows reactivity in
      odontoblasts, predentin, and the odontoblast processes. In summary, the
      processing of large sialic acid-rich proteins into smaller fragments may be an
      important part of the controlled conversion of predentin to dentin and osteoid to
      bone.

PMID- 12489175
TI  - Novel functions of the matricellular proteins osteopontin and osteonectin/SPARC.
AB  - Osteopontin (OPN) and osteonectin/SPARC (ON/SPARC) are prominent matricellular
      components of the extracellular matrix of mineralized tissues of bones and teeth
      in which they can regulate the formation and growth of hydroxyapatite crystals
      and influence a variety of cell activities. OPN regulates cell responses through
      several integrin receptors and is also a ligand for the CD44 receptor, through
      which it acts as a chemoattractant. Although a cell-surface receptor for SPARC
      has not been identified it can block cell-cell and cell-matrix interactions and
      inhibit cell migration and chemotaxis. OPN and SPARC also appear to function
      inside cells. Thus, OPN appears to exist in association with the CD44 receptor
      inside migratory cells, while intracellular SPARC is associated with axonemal
      tubulin in ciliated epithelial cells. Analyses of fibroblasts and peritoneal
      macrophages from OPN-null and CD44-null cells show impaired functionality
      involving migration and cell fusion required for osteoclast formation, while
      disruption of SPARC expression leads to developmental defects in Xenopus. To gain
      further insights into the intracellular functions of OPN and SPARC, we have used
      the yeast two-hybrid system to identify potential interacting molecules. Using
      full-length SPARC as bait the carboxy-terminal domain, which contains two EF
      hand, high-affinity binding sites, was found to have transcriptional activity,
      while several novel proteins that interact with the amino-terminal domains of
      SPARC and full-length OPN have been identified. The identification of OPN and
      SPARC inside specialized cells introduces a novel concept in cellular regulation
      by matricellular proteins.

PMID- 12489176
TI  - MEPE/OF45, a new dentin/bone matrix protein and candidate gene for dentin
      diseases mapping to chromosome 4q21.
AB  - Substantial progress has been made regarding the molecular etiology of the dentin
      diseases dentinogenesis imperfecta types II and III, and dentin dysplasia type
      II. Genetic linkage studies have identified the critical loci for these diseases
      on human chromosome 4q21. Located within an overlapping segment of these disease
      loci is a dentin/bone gene cluster that includes osteopontin, bone sialoprotein,
      dentin matrix protein 1, dentin sialophosphoprotein, and a new gene MEPE also
      known as OF45, renamed osteoregulin. In this paper, we report the location of
      MEPE/OF45 in relationship to the other members of the dentin/bone gene cluster as
      well as the genomic organization of the human gene. For the first time, MEPE/OF45
      expression was shown in dental tissue, in particular odontoblasts, by reverse
      transcription polymerase chain reaction (RT-PCR) amplification and
      characterization of a partial mouse cDNA. Our data provide the first evidence
      that MEPE/OF45 is expressed during odontogenesis and should be considered as a
      candidate gene for dentin structural diseases mapping to human chromosome 4q21.

PMID- 12489177
TI  - The conservation and regulation of rat DSP-PP gene.
AB  - Two highly expressed noncollagenous proteins associated with dentin
      mineralization, dentin sialoprotein (DSP) and phosphophoryn (PP), are encoded by
      a single DSP-PP transcript. To better understand how DSP-PP transcripts are
      regulated, we have determined the DSP-PP transcription start site, sequenced its
      5' flanking region, and analyzed the transcriptional activity of the gene
      promoter out to -1615 bp. Comparison of the rat cDNA sequence with the mouse, rat
      and human genes clearly indicates high sequence conservation within the DSP-PP 5'
      flanking region, implicating the possible presence of highly conserved gene
      regulatory cis elements. Among a number of conserved transcription sites
      identified in the 5' flanking region, we demonstrate that the conserved Y box
      sequence (ATTGG) can specifically bind nuclear extracts from mouse MDPC23 cells.
      This sequence (located within the -57 bp/-52 bp 5' flanking region) therefore
      likely represents one DSP-PP transcriptional regulatory sequence.

PMID- 12489178
TI  - Spatial expression of Cbfa1/Runx2 isoforms in teeth and characterization of
      binding sites in the DSPP gene.
AB  - Cbfa1/Runx2 is an essential transcription factor for osteoblast and odontoblast
      differentiation. Heterogeneous mutations of Cbfa1 gene result in cleidocranial
      dysplasia, an autosomal dominant syndrome, characterized by abnormal skeletal
      genesis and dental disorders. Recently three Cbfa1/Runx isoforms (Pebp2 alpha
      A/type I, til-1/type II, and Osf2/type III) have been identified that differ in
      their amino-terminal sequences. The precise roles of Cbfa1/Runx2 isoforms in
      odontoblast development are not known. The purpose of this study was to determine
      and compare expression patterns of the three Cbfa1/Runx2 isoforms in newborn
      tooth organs. Toward this aim, we developed three probes: type I and type II,
      which specifically hybridize with Pebp2 alpha A and til-1, respectively, and type
      II/III, which hybridizes with osf2 and partially with til-1. In addition,
      Cbfa1/Runx2 binding sites were identified in the regulatory elements of mouse
      dentin sialophosphoprotein (mDSPP) gene, which encodes a matrix protein expressed
      during odontogenesis. In situ hybridization performed with the specific
      Cbfa1/Runx2 isoform probes demonstrated that all isoforms are expressed in teeth
      and bone. The type I isoform was expressed at higher levels than isoforms type II
      and type II/III in developing newborn mouse incisors. Genomic mDSPP clones were
      isolated and characterized containing approximately 2.6 kb of the promoter
      region. Computer analysis of the promoter segment and intron 1 revealed a number
      of potential transcriptional factor binding sites including five Cbfa1/Runx2
      binding sites, three in the promoter region and two within intron 1. DNA-protein
      assay and antibody supershift experiments showed that these binding sites
      interact with nuclear extracts isolated from the mouse odontoblast cell line MO6
      G3. Further characterization of the functional role of Cbfa1/Runx2 in the
      regulation of the mDSPP gene expression is being investigated.

PMID- 12489179
TI  - TGF beta 1 signaling and stimulation of osteoadherin in human odontoblasts in
      vitro.
AB  - Transforming growth factor beta 1 (TGF beta 1) is generally considered to be a
      potent inducer of dentin formation. In order to further assess this role, we
      studied the influence of this factor in human dental pulp cells on the expression
      of osteoadherin (OSAD), a newly described proteoglycan found in bone and dentin
      and suspected to play a role in mineralization events. We performed TGF beta 1
      stimulation both in cultures of human tooth thick slices including mature
      odontoblasts and in pulp explant cultures giving rise to early secretory
      odontoblasts or pulpal fibroblasts. We first showed by immunohistochemistry that
      molecules involved in TGF beta 1 signal transduction, that is, membrane receptors
      T beta RI and T beta RII and intracellular proteins SMAD-2, SMAD-3, and SMAD-4,
      were present in human dental cells in vivo and were all maintained after culture
      of thick-sliced teeth in cells undergoing TGF beta 1 stimulation. In this culture
      system, OSAD synthesis was increased in mature odontoblasts close to the TGF beta
      1 delivery system. In explant cultures, semiquantitative reverse-transcription
      polymerase chain reaction (RT-PCR) analysis indicated that the growth factor
      stimulated OSAD gene expression in early secretory odontoblasts and in pulpal
      fibroblasts. Taken together, these results indicate that OSAD expression is
      stimulated by TGF beta 1 in pulpal fibroblasts and in early secretory and mature
      odontoblasts. We suggest that TGF beta 1 in this way could control the
      organization and the mineralization of the extracellular matrix deposited by
      these cells during dentin formation.

PMID- 12489181
TI  - Genomic organization and localization of mouse Nma/BAMBI: possible implications
      related to ameloblastoma formation.
AB  - Our laboratory has determined the DNA sequence and transcriptional expression
      pattern of a mouse cDNA clone termed Nma/BAMBI. This clone encodes a highly
      conserved protein with 89% identity to the human homologue (termed Nma) and 78%
      similarity to the Xenopus homologue (termed BAMBI) at the predicted amino acid
      level. Nma/BAMBI encodes a 260-amino-acid transmembrane protein that has homology
      to the transforming growth factor (TGF) beta type I receptor family. This protein
      contains an extracellular ligand binding domain, a 24-amino-acid transmembrane
      domain, and a short intracellular domain that lacks a functional serine/threonine
      kinase domain. It is believed that Nma/BAMBI is important in the negative
      regulation of TGF beta signal transduction pathways during development and has
      implications in tumor progression. We have determined the genomic organization of
      the mouse Nma/BAMBI gene and confirmed the chromosomal mapping to human
      chromosome 10 and mouse chromosome 2. Furthermore, we report the production and
      utilization of an anti-peptide antibody in preliminary immunohistochemical
      analysis of an ameloblastoma.

PMID- 12489180
TI  - TGF beta-1 downregulates DMP-1 and DSPP in odontoblasts.
AB  - Transforming growth factor beta-1 (TGF beta-1) is a multifunctional growth factor
      that is expressed in numerous cell types. It has been shown to induce secretion
      of dentin extracellular matrix components associated with primary dentinogenesis
      and to play a role in tertiary or reparative dentinogenesis. In this study, we
      investigated the potential transcriptional regulation by TGF beta-1 of two dentin
      matrix proteins: dentin matrix protein 1 (DMP-1), and dentin sialophosphoprotein
      (DSPP). In vitro promoter studies were performed using plasmid constructs
      containing mouse DMP-1 and DSPP promoter sequences fused to the luciferase
      reporter gene. Constructs were transiently transfected in the mouse odontoblast
      cell line M06-G3 and cultured in the presence or absence of TGF beta-1. The
      integrity of the TGF beta-1 signaling pathway was investigated in the M06-G3
      cells by identifying known key effectors of TGF beta-1 signal transduction.
      Transient transfection studies demonstrate for the first time that TGF beta-1
      downregulates both DMP-1 and DSPP genes. Our findings indicate that the TGF beta
      1 type I receptor ALK5 is expressed by odontoblasts as well as the signal
      transduction proteins Smad2, Smad3, and Smad4. These results suggest that TGF
      beta-1 regulates two key dentin proteins involved in matrix mineralization most
      likely mediated through the type I ALK5 receptor and transduced by Smads 2, 3,
      and 4.

PMID- 12489182
TI  - Transcriptional regulation of dentin matrix protein 1 (DMP1) by AP-1 (c-fos/c
      jun) factors.
AB  - Dentin matrix protein 1 (DMP1) is an extracellular matrix phosphoprotein whose
      expression is precisely controlled temporally and spatially during the
      differentiation of the odontoblasts. Odontoblasts are postmitotic cells that
      differentiate to mature polarized cells and are responsible for the synthesis of
      a calcified dentin matrix. Although the DMP1 promoter has been isolated from the
      mouse and the rat, little is actually known about their control by specific
      transcription factors. Analysis of the rat DMP1 promoter has identified several
      regulatory transcription factors. These factors include AP-1 family members, SP1
      and ETS. Therefore the transcription of DMP1 may be controlled positively or
      negatively by a variety of stimuli resulting in a developmentally regulated gene
      expression. This study demonstrates the role of c-fos and c-jun on the
      transcriptional regulation of DMP1 gene.

PMID- 12489183
TI  - Differential epithelial and mesenchymal regulation of tooth-specific matrix
      proteins expression by 1,25-dihydroxyvitamin D3 in vivo.
AB  - Enamel defects have been reported in rickets and related to disturbed expression
      of amelogenin in ameloblasts. The present study is devoted to amelogenin,
      enamelin, ameloblastin, and dentin sialophosphoprotein (DSPP) expression in both
      the epithelium and mesenchyme of vitamin D-deficient rat incisors. Quantitative
      Northern blotting analysis (relatively to glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH) mRNA steady-state levels) was performed on microdissected
      cells of rachitic (-D) and control (+D) 56 day old rats. Steady-state levels of
      amelogenin and enamelin mRNA were significantly reduced in the -D epithelium
      versus the +D epithelium ones. In contrast, ameloblastin expression was slightly
      increased in -D epithelium. In the same samples, DSPP mRNA levels remained
      unchanged in -D dental mesenchyme. Comparative electron microscopy studies
      between +D and -D animals showed a dramatic decrease of intraprismatic enamel
      (amelogenin and enamelin immunoreactive) consistent with our molecular results.
      In conclusion, tooth formation results from the coordinated expression of several
      matrix proteins that may be controlled by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3].

PMID- 12489184
TI  - Analysis of odontoblast gene expression using a novel approach, laser capture
      microdissection.
AB  - Studying the mechanisms of molecular interactions in developing tissues demands
      sensitive molecular biological in vivo and in vitro techniques. Laser capture
      microdissection (LCM) allows for the isolation of mRNA in histological sections
      even from single cells, thus enabling the identification of in vivo gene
      expression products in closely circumscribed tissue areas. The aims of this study
      were to assess the optimal fixation, processing, and staining conditions to
      retrieve RNA from microdissected odontoblasts. Fluorometric assays and RT-PCR
      analysis of alpha 1(I) collagen, dentin sialophosphoprotein (Dspp), and
      osteocalcin (OC) confirmed that the total RNA isolated from day 0 and day 3
      captured odontoblasts was sufficient in quantity and quality. Our results
      indicate that individual odontoblasts obtained by LCM are morphologically intact
      and chemically unaltered, allowing accurate molecular and biochemical analyses.

PMID- 12489185
TI  - TGF-beta latency-associated peptides (LAPs) in human dentin matrix and pulp.
AB  - Transforming growth factor (TGF)-beta s in dentin matrix provide a pool of
      bioactive molecules, but association with latency-associated peptides (LAPs) may
      influence their activity. We investigated TGF-beta 1, -beta 2, and -beta 3 LAP
      expression in sound and carious human teeth. Teeth were fixed and processed
      immediately following extraction prior to staining with rabbit polyclonal
      antibodies to the TGF-beta LAPs. A soluble dentin matrix fraction was prepared
      from dissected human dentin and sequential extraction of pulpal ECM was performed
      prior to purification. Fractions were Western blotted and probed with the LAP
      antibodies. All three LAPs were present in odontoblasts, cells of the pulp, and
      predentin; however, no staining of mineralized dentin matrix was seen. Similar
      patterns of expression were seen in carious tissue. Expression of TGF-beta LAPs
      in cells and pulpal matrix of healthy and carious teeth will be important in
      regulation of TGF-beta activity and may modulate the tissue response to injury.

PMID- 12489186
TI  - Effects of alginate hydrogels and TGF-beta 1 on human dental pulp repair in
      vitro.
AB  - The objective of this study was to investigate the use of alginate hydrogels to
      present either exogenous or endogenous transforming growth factor (TGF)-beta 1 to
      the dentin-pulp complex to signal reparative processes. Hydrogels were prepared,
      applied to cultured human tooth slices and the effects on tertiary dentinogenesis
      examined histologically. Both TGF-beta 1-containing and acid-treated alginate
      hydrogels, but not untreated hydrogels, upregulated dentin matrix secretion and
      induced odontoblast-like cell differentiation with subsequent secretion of
      regular tubular dentin matrix on cut pulpal surfaces. It is concluded that TGF
      beta 1 can signal both induction of odontoblast-like cell differentiation and
      upregulation of their matrix secretion in the human dentin-pulp complex. Alginate
      hydrogels provide an appropriate matrix in which dental regeneration can take
      place and may also be useful for delivery of growth factors, including TGF-beta
      s, to enhance the natural regenerative capacity of the dental pulp.

PMID- 12489187
TI  - Experimental dentin-based approaches to tissue regeneration in vital pulp
      therapy.
AB  - The potential direct induction of odontoblastlike cell differentiation at the
      surface of implanted dentin matrix has been tested in a series of capping
      experiments. Pieces of Teflon (control) or autogenous dentin matrix were placed
      in contact with the wound surface at a conventional capping situation, or at the
      dentinal base of the cavity at a distance from the exposed pulp periphery. Tissue
      responses were studied by light microscopy after periods of 2 and 4 weeks.
      Partial degradation of the dentin matrix implants was seen. Formation of a
      tubular calcified matrix, occasionally followed by tubular reparative dentin, was
      consistently detected in association with dentinal particles. The area between
      the traumatized dental pulp periphery and the capping material had been occupied
      by a well-vascularized tissue, regardless of the capping material and
      postoperative time period. Traces of calcified matrix were detected along the cut
      dentinal walls. The present data indicate that dentin matrix is limited in its
      ability to directly induce odontoblastlike cell differentiation and reparative
      dentin formation at the surface of mechanically exposed pulp of mature teeth.
      Furthermore, it seems that the traumatized mature pulp maintains the ability to
      grow, while a calcifying potential could be expressed by this growing part of the
      pulp core.

PMID- 12489188
TI  - Two- versus three-dimensional in vitro differentiation of human pulp cells into
      odontoblastic cells.
AB  - The spatial organization of the pulp cells may modify the cytodifferentiation
      process. The purpose of this study was to compare the two- versus three
      dimensional cell culture systems for differentiation of human odontoblastic cells
      in vitro. Pulpal cores from freshly extracted human third molars were cultured in
      vitro in a perfusion device on two types of membranes: polyester membrane (two
      dimensional [2D] cell culture) and nylon mesh (three-dimensional [3D] cell
      culture). The cells were incubated with minimum essential medium containing (a)
      substitute serum, (b) 10% fetal calf serum (FCS), (c) 10% fetal calf serum + 2 mM
      beta-glycerophosphate (beta GP), and (d) 10% fetal calf serum + transforming
      growth factor (TGF) beta 1. Immunohistochemistry was used to evaluate the
      expression of collagen I, osteonectin, and nestin. Small differences were
      observed between 2D and 3D cell culture systems. This was particularly evident in
      the 10% FCS group. beta-Glycerophosphate in the 3D system seems to stimulate the
      osteogenic cell phenotype, as a considerable induction of osteonectin is
      observed.

PMID- 12489189
TI  - Odontoblast dysfunction in osteogenesis imperfecta: an LM, SEM, and
      ultrastructural study.
AB  - The inherited dentin defect dentinogenesis imperfecta (DI), while clinically
      obvious in osteogenesis imperfecta (OI) Types IB and IC, II, III, and IVB, is now
      thought to be present in all children with OI, in a continuum from minimal to
      severe dentin pathology. This collaborative study further clarifies the
      structural and ultrastructural dentin changes in the teeth of OI children with
      clinically obvious DI, and attempts to explain these in terms of odontoblast
      dysfunction. Collaborative studies were carried out in Melbourne, Australia, and
      Strasbourg, France, using light and polarized-light microscopy, scanning and
      transmission electron microscopy (SEM, TEM), selected-area diffraction (SAD), and
      x-ray spectroscopy (EDX). These showed structurally normal enamel (but containing
      long and broad lamellae) and a normally scalloped dentino-enamel junction (DEJ),
      but severe pathologic changes in the dentin. An initial narrow band of normal
      appearing dentin tubules (including the mantle layer) ceased abruptly and was
      replaced by a wavelike laminar zone parallel to the DEJ with occluded tubules.
      Multiple parallel channels of 5-10 microns diameter were present at right angles
      to the DEJ indenting this zone, some terminating in retro-curved "processes." The
      abnormal dentin containing these channels almost completely occluded the pulp
      chamber. The structural and ultrastructural changes seen can be explained on the
      basis of the collagen defect in OI resulting in odontoblast dysfunction, which
      produces a distinct phenotype and one that is different from that in bone.

PMID- 12489190
TI  - Progenitor cells from dental follicle are able to form cementum matrix in vivo.
AB  - To address the molecular mechanisms of cementogenesis, we have isolated dental
      follicle cells and examined them to see if they contain cementoblast progenitors.
      Dental follicle tissue was dissected from the root surface of bovine tooth germ
      and cells were released by digestion with bacterial collagenase. The released
      cells were maintained as a bovine dental follicle cells (BDFC). To elucidate the
      differentiation capacity of BDFC, they were transplanted into severe combined
      immunodeficiency (SCID) mice for 4 weeks. Transplanted BDFC formed cementumlike
      matrix; in contrast, bovine alveolar osteoblast (BAOB) transplants formed
      bonelike matrix, and bovine periodontal ligament cells (BPDL) formed a small
      amount of the cementumlike matrix. Immunohistochemical analysis showed that
      cementumlike matrix was positive for anti-cementum attachment protein monoclonal
      antibody, whereas bone-like matrix was negative. These results indicated that the
      BDFC contained cementoblast progenitors that were able to differentiate to
      cementoblasts in vivo. They also indicated that the BDFC are phenotypically
      distinct from BAOB and BPDL, and provide a useful model for investigating
      molecular mechanisms of cementogenesis.

PMID- 12489191
TI  - Establishment of dental epithelial cell line (HAT-7) and the cell differentiation
      dependent on Notch signaling pathway.
AB  - Rat incisors grow continuously throughout life. Producing a variety of dental
      epithelial cells is performed by stem cells located in the cervical loop of the
      incisor apex. To study the mechanisms for cell differentiation, we established a
      dental epithelial cell line (HAT-7) originating from a cervical loop epithelium
      of a rat incisor. Immunochemical studies showed that HAT-7 produced the cells
      expressing amelogenin, ameloblastin, or alkaline phosphatase (ALP). To illustrate
      a role of Notch signaling in the determinant of the cell fate, we examined
      expression patterns of Notch1 and Jagged1 in HAT-7 density dependently. At lower
      cell density, Notch1- or Jagged1-expressing cells were not seen. However, when
      they were fully confluent, cells began to express Notch1 or Jagged1 strongly.
      Some ALP-positive cells were almost consistent with Notch1-expressing cells but
      not Jagged1-expressing cells. These results suggested that the determinant of
      direction of differentiation was associated with Notch signaling pathway.

PMID- 12489192
TI  - Immunolocalization of inducible nitric oxide synthase in localized juvenile
      periodontitis patients.
AB  - Localized juvenile periodontitis (LJP) is associated with a destruction of
      periodontal tissues and the presence of Actinobacillus actinomycetemcomitans
      (AA). Lipopolysaccharide (LPS) from AA was found to induce a significant
      macrophage production of nitric oxide (NO). Increased nitric oxide synthase (NOS)
      activity was found to be negatively correlated with the neutrophil chemotactic
      response. The aim of this study was to determine the occurrence and distribution
      of inducible NOS (iNOS) in human gingival tissue from LJP patients. The
      distribution of iNOS was assessed by monoclonal antibody against iNOS. Cellular
      markers (CD 3, CD 20, and CD 68) were used to determine the cellular origin of
      iNOS. The immunostaining revealed the appearance of iNOS in inflamed compared to
      noninflamed gingival tissues. Macrophages expressed high levels of iNOS that may
      cause some damage to the periodontal tissues. This study suggests that iNOS
      activity in macrophages may modify abnormalities of neutrophil function.

PMID- 12489193
TI  - S100A8 and S100A9 calcium-binding proteins: localization within normal and
      cyclosporin A-induced overgrowth gingiva.
AB  - S100A8 and S100A9, also called myeloid related protein (MRP) 8 and 14, are
      calcium-binding proteins highly expressed in neutrophils, in which they play a
      key role in the inflammatory progression. In this study, we looked at the
      expression of S100A8/A9 within gingiva from normal and Cyclosporin A (CsA)
      induced overgrowth gingiva. In gingiva from the CsA group, several positive
      S100A8/A9 cells were seen within the connective tissue, whereas in normal gingiva
      very few positive S100A8/A9 cells were detected. These cells correspond either to
      activated macrophages or to neutrophils, reflecting the well-known gingival
      inflammatory status associated with the CsA-treated group. In addition, in both
      the normal and drug-treated group, the gingival epithelia appeared S100A8/A9
      immunopositive. More specifically, S100A8/A9 appeared in the majority within the
      spino-cellular layer and located extracellularly within the desmosomes. In
      addition, S100A8/A9 also appeared sporadically intracellularly, located within
      the cytoplasm and the nuclei, reflecting S100A8/A9 translocations.

PMID- 12489194
TI  - The human tuftelin gene and the expression of tuftelin in mineralizing and
      nonmineralizing tissues.
AB  - Tuftelin has been suggested to play an important role during the development and
      mineralization of enamel, but its precise function is still unclear. This article
      reviews major milestones in the discovery, structural characterization,
      expression, localization, and conservation of tuftelin in different vertebrate
      species. It focuses on the structure of the human tuftelin gene, which has
      recently been deciphered [12]. It describes the exon-intron organization, sizes
      and structure, the promoter structure, and the newly discovered alternatively
      spliced human tooth-bud tuftelin mRNA transcripts. It also examines information
      on the structural motifs in the human-derived tuftelin protein and how they
      relate to tuftelin from other species. It reviews our recent results on the
      transcription of tuftelin mRNA and protein expression in several nonmineralizing
      soft tissues, using reverse-transcription polymerase chain reaction (RT-PCR)
      followed by DNA cloning and sequencing, indirect immunohistochemistry,
      immunohistochemistry combined with confocal microscopy, and in situ
      hybridization. These results and earlier Northern blot results show that
      tuftelin, in addition to being expressed in the developing and mineralizing
      tooth, is also expressed in several nonmineralizing soft tissues, suggesting that
      tuftelin has a universal function and/or a multifunctional role.

PMID- 12489195
TI  - Pig amelogenin gene expresses a unique exon 4.
AB  - The pig amelogenin gene was isolated from a Lambda genomic library, and a 6.3 kb
      SalI/XbaI restriction fragment, inclusive of exons 3 through 7, was subcloned
      into a plasmid vector. DNA sequencing revealed two putative exon 4 sequences. The
      derived amino acid sequence of exon 4a, KSGRWGARLTAFVSSVQ, had previously been
      identified in a 190-amino-acid amelogenin isoform by protein sequencing. Exon 4b
      encoded the peptide DLYLEAIRIDRTAF, which is homologous to exon 4-encoded
      segments reported for human, mouse, and rat. Oligonucleotides from both of these
      exons were used to amplify cDNA generated from developing teeth. Amplification
      products were analyzed by agarose gel electrophoresis, cloned, and characterized
      by DNA sequencing. Exon 4a was found in transcripts encoding amelogenin isoforms
      having 190 and 73 amino acids. Exon 4b was found only in apparent splicing
      intermediates that retained intron 3, but was not detected in any final mRNA
      transcripts. Pig amelogenin having apparent molecular mass of 23 kD were isolated
      from the enamel matrix and characterized by mass spectrometry. Two mass values,
      18,512.5, and 18,571.2 Da, were measured that match the values predicted for the
      162-amino-acid cleavage product of the 173-amino-acid amelogenin, and the 165
      amino-acid cleavage product of the 190-amino-acid amelogenin, which includes 17
      amino acids encoded by exon 4a. We conclude that the pig amelogenin gene
      expresses a unique exon 4 that is not homologous to, or evolved from, the exon 4
      segment expressed in humans and rodents.

PMID- 12489196
TI  - Expression, structure, and function of enamel proteinases.
AB  - Proteinases serve two important functions during dental enamel formation: They
      (a) process and (b) degrade enamel proteins. Different enzymes carry out these
      functions. Enamelysin (MMP-20) is the foremost enamel matrix-processing enzyme.
      Its expression initiates prior to the onset of dentin mineralization and
      continues throughout the secretory stage of amelogenesis. In vitro, enamelysin
      catalyzes all of the amelogenin cleavages that are known to occur during the
      secretory stage in vivo, and it is probably the enzyme responsible for the
      processing of all enamel proteins. There is evidence suggesting that enamelysin
      activity is critical for proper enamel formation. Uncleaved and processed enamel
      proteins often segregate into different compartments within the developing enamel
      layer, suggesting that they may have different functions. Intact ameloblastin and
      its C-terminal cleavage products localize in the superficial rod and interrod
      enamel, while its N-terminal cleavage products congregate in the sheath space.
      Intact enamelin is only present at the mineralization front within a micrometer
      of the enamel surface, while its cleavage products concentrate in the rod and
      interrod enamel. Processed enamel proteins accumulate during the secretory stage,
      but disappear early in the maturation stage. Enamel matrix serine proteinase 1
      (EMSP1), now officially designated kallikrein 4 (KLK4), is believed to be the
      predominant degradative enzyme that clears enamel proteins from the matrix during
      maturation. KLK4 expression initiates during the transition stage and continues
      throughout maturation. KLK4 concentrates at the enamel surface when the enamel
      matrix disappears, and aggressively degrades amelogenin in vitro. During tooth
      development, proteinases are secreted by ameloblasts into the extracellular
      space, where they cleave enamel proteins by catalyzing the hydrolysis of peptide
      bonds. Enamel proteinases are present in low abundance and are not likely to
      participate directly in the mineralization process. Two major enamel proteinases
      have been identified: enamelysin (MMP20) and kallikrein 4 (KLK4). These
      proteinases are expressed at different times and have different functions. Their
      roles are to modify and/or to eliminate enamel matrix proteins, which affects the
      way enamel proteins interact with each other and with the developing enamel
      crystallites. A brief review of dental enamel formation is presented, followed by
      a more detailed analysis of enamelysin and KLK4 expression, structure, and
      function.

PMID- 12489197
TI  - Limited proteolysis of amelogenin: toward understanding the proteolytic processes
      in enamel extracellular matrix.
AB  - This article is a short review of our recent study on controlled proteolysis of
      amelogenins by a series of commercially available proteinases as well as the
      tooth-specific metalloproteinase enamelysin. A limited proteolysis approach and
      mass spectrometry were applied in order to determine the surface accessibility of
      conserved domains of amelogenin nanospheres. Furthermore, this study was aimed at
      exploring the factors that affect the activity of enamel proteases to process
      amelogenins and at providing insight into the mechanisms of amelogenin
      degradation during amelogenesis. We found that, under limited conditions, certain
      amino acid residues at both the C- and N-termini of amelogenin are accessible to
      proteolytic action by a series of proteinases, suggesting that these regions are
      exposed on the surface of amelogenin nanospheres. Recombinant enamelysin cleaved
      amelogenin at the C-terminal region, showing a preference of the enzyme to cleave
      the S/M and F/S bonds. This result of enamelysin activity on amelogenin explains
      the abundance of the p148 (20k) pig amelogenin during the secretory stage of
      amelogenesis.

PMID- 12489198
TI  - Fluoride enhances intracellular degradation of amelogenins during secretory phase
      of amelogenesis of hamster teeth in organ culture.
AB  - Amelogenins are the major protein species synthesized by secretory ameloblasts
      and are believed to be involved in enamel mineralization. During enamel
      formation, amelogenins are progressively degraded into smaller fragments by
      protease activity. These amelogenin fragments are removed from the enamel
      extracellular space, thereby enabling full mineralization of the dental enamel.
      Enamel from fluorotic teeth is porous and contains more proteins and less mineral
      than sound enamel. In this study we examined the hypothesis that fluoride (F-) is
      capable of inhibiting the proteolysis of amelogenins in enamel being formed in
      organ culture. Hamster molar tooth germs in stages of secretory amelogenesis were
      pulse labeled in vitro with [3H]- or [14C] proline and subsequently pulse chased.
      The explants were exposed to F- at different days of chase (i.e., during
      secretory amelogenesis early after labeling, later after labeling or at stages
      just beyond secretory amelogenesis). Exposure of secretory stage explants to F-
      enhanced the release of radiolabeled fragments when F- was applied early after
      labeling but progressively less if applied later. In contrast, F- had no such
      effect in stages beyond secretion. The enhanced release of radiolabeled fragments
      in secretory stages was associated with a reduction of radioactivity in the soft
      tissue enamel organ indicating that fragmentation of enamel matrix proteins
      (mainly amelogenins) occurred intracellularly. Analysis by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that the fluorotic
      enamel contained less radiolabeled parent amelogenins (M(r) 28 kD and 26 kD) but
      more low-molecular-mass fragments than enamel from control explants. Our data
      indicate that F- promotes intracellular degradation of the newly synthesized
      parent amelogenins during secretory stage. Our in vitro data do not support the
      concept that F- impairs extracellular proteolysis of amelogenins, either in the
      secretory phase or in the stage just beyond the secretory phase.

PMID- 12489199
TI  - Inheritance pattern and elemental composition of enamel affected by
      hypomaturation amelogenesis imperfecta.
AB  - Hypomaturation amelogenesis imperfecta (AI) is characterized clinically by enamel
      of normal thickness that is hypomineralized, mottled, and detaches easily from
      the underlying dentin. Autosomal dominant, autosomal recessive, X-linked, and
      sporadic modes of inheritance have been documented. The present study
      investigated the elemental composition of the enamel of teeth from individuals
      demonstrating clinical hypomaturation AI from families representing three of
      these patterns of inheritance. The aim of the study was to determine if there was
      any commonality in microscopic phenotype of this defect between families
      demonstrating the various inheritance patterns. One section from each tooth was
      microradiographed and then viewed in a scanning electron microscope (SEM)
      equipped with an ultrathin window energy-dispersive x-ray spectroscopy (EDX)
      detector. In the SEM, prisms and constituent crystals in discrete areas appeared
      to be largely obscured by an amorphous material. EDX analysis showed enamel
      outside these areas to have a composition indistinguishable from control teeth.
      However, within these affected areas there was a large increase in carbon content
      (up to a fivefold increase). In some teeth there was also a detectable but
      smaller increase in the relative amounts of nitrogen or oxygen. The results
      suggest the defect in these teeth with a common clinical phenotype, irrespective
      of the pattern of inheritance, demonstrates a commonality in microscopic
      phenotype. The large increase in carbon content, not matched by an equivalent
      increase in nitrogen or oxygen, suggests a possible increased lipid content. In
      those teeth with elevated nitrogen levels there may also be retained protein.

PMID- 12489200
TI  - Characterization of a porcine amelogenin preparation, EMDOGAIN, a biological
      treatment for periodontal disease.
AB  - EMDOGAIN is derived from porcine developing enamel matrix and has been shown to
      facilitate regeneration of the periodontium, although its mechanism of action is
      unknown. The aim of the present study was to identify enamel matrix proteins and
      proteolytic enzymes present in EMDOGAIN and compare them with those extracted
      from developing porcine enamel itself. Sodium dodecyl sulfate polyacrylamide gel
      electrophoresis (SDS-PAGE), Western blotting, and zymography were used to
      identify the proteins present and to determine their enzyme activity. The results
      showed that developing enamel contained amelogenins, albumin, amelin, and
      enamelin. EMDOGAIN, however, contained only amelogenins. Both
      metalloendoproteases and serine protease activity were revealed in both EMDOGAIN
      and developing enamel. The roles of the amelogenin and enzyme components, if any,
      in periodontal regeneration are unknown.

PMID- 12489201
TI  - Enamelin compartmentalization in developing porcine enamel.
AB  - The tissue compartmentalization of enamelin-processing products has been
      investigated in developing pig enamel using a sequential extraction procedure.
      Only trace amounts of enamelin-processing products were detected in simulated
      enamel fluid extracts, suggesting that enamelins are not solubilized in the
      matrix to any great extent. Subsequent phosphate buffer extraction desorbed and
      extracted several enamelin-processing products that were presumably bound to the
      mineral phase. A 35-kD processing product dominated the phosphate extract,
      suggesting that enamelin processing leads to an accumulation of this mineral
      bound molecule. Dissociative extraction with urea subsequently extracted the
      remainder of the enamelin-processing products present. This material was
      presumably present in the tissue in an aggregated insoluble state. Several
      enamelin-processing products were only extracted by specific extraction
      procedures, suggesting that different enamelin-processing products are
      differentially compartmentalized. This may indicate that specific enamelin
      processing products have different functions. In contrast to amelogenins, which
      are processed in the deeper tissue to generate products having a low affinity for
      the mineral, enamelin processing appears to produce products (those enamelins
      desorbed by phosphate buffer) that have a high affinity for the mineral. These
      products, appearing in the deeper enamel layers, may serve to influence crystal
      growth kinetics in the absence of any mineral-binding amelogenins.

PMID- 12489202
TI  - The dentino-enamel junction revisited.
AB  - The dentino-enamel junction is not an simple inert interface between two
      mineralized structures. A less simplistic view suggests that the dentino-enamel
      junctional complex should also include the inner aprismatic enamel and the mantle
      dentin. At early stages of enamel formation, fibroblast growth factor (FGF)-2 is
      stored in and released from the inner aprismatic enamel, possibly under the
      control of matrix metalloproteinase (MMP)-3. The concentration peak for MMP-2 and
      -9 observed in the mantle dentin coincided with a very low labeling for TIMP-1
      and -2, favoring the cross-talk between mineralizing epithelial and connective
      structures, and as a consequence the translocation of enamel proteins toward
      odontoblasts and pulp cells, and vice versa, the translocation of dentin proteins
      toward secretory ameloblasts and cells of the enamel organ. Finally, in X-linked
      hypophosphatemic rickets, large interglobular spaces in the circumpulpal dentin
      were the major defect induced by the gene alteration, whereas the mantle dentin
      was constantly unaffected. Altogether, these data plead for the recognition of
      the dentino-enamel junctional complex as a specific entity bearing its own
      biological characteristics.

PMID- 12489203
TI  - Development of enamel defects in rat mandibular incisor after thyro
      parathyroidectomy.
AB  - Previous studies with scanning electron microscopy (SEM) demonstrated the
      presence of small hypoplastic defects in the incisal third of incisors and deep
      hypoplasia in the apical third of the incisors after thyro-parathyroidectomy in
      the rat. These studies provided a morphological description of the defects, but
      uncertainty remained concerning their development throughout amelogenesis. The
      aim of the present investigation was to study, with SEM operated in the
      backscattered mode, the development of the hypoplastic defects, from the
      beginning of the secretion to the end of the maturation zone of the enamel, in
      the lower incisor of thyroparathyroidectomized rats. The results of the present
      study showed that the large and small defects developed are separate entities
      that do not develop into the other. The distribution of large defects might be
      linked to a reduction of the eruption rate in these rats. The pathogenesis of
      these defects needs further investigation.

PMID- 12489204
TI  - TEM observations on the ameloblast/enamel interface in the rat incisor.
AB  - The structure of rat incisor enamel is established at the topographically complex
      interface between secretory ameloblasts and forming enamel. The aim of this study
      was to gain additional information on this interface by sectioning parallel with
      the rows and the long axis of Tomes' processes and prisms. Rats were sacrificed
      and fixed by glutaraldehyde/paraformaldehyde perfusion. After dissection,
      demineralization and embedding transverse jaw/incisor segments were cut,
      reembedded, and reoriented. Sections were prepared for and observed in the
      transmission electron microscopy (TEM). The intraenamel part of Tomes' process
      was about 18 microns long. The forming prism occupied a longitudinally grooved
      invagination on its apical aspect. The parts of Tomes' process forming the side
      walls of the groove were attenuated and showed variation in extent and outline.
      Prism growth occurred over the whole grooved area. An estimation of Tomes'
      process secretory area in rat compared with data from humans suggests that there
      may be a relationship between secretory area and rate of prism formation. Prism
      crystals were oriented obliquely or parallel to the secretory surface of Tomes'
      process. At interprism growth sites matrix deposition was irregular and required
      some redistribution to conform to the pattern of interprism sheets.

PMID- 12489205
TI  - Fine structure and Ca-ATPase activity of the stratum intermedium cells during
      odontogenesis in gars, Lepisosteus, Actinopterygii.
AB  - This is the first report on the stratum intermedium in vertebrates other than
      mammals. The aim of this study is to elucidate the fine structure and
      cytochemical features of the stratum intermedium during the stages of enameloid
      formation in Lepisosteus. Inner dental epithelium, stratum intermedium, stellate
      reticulum, and outer dental epithelium are consistently present in the tooth
      germs of Lepisosteus. The stratum intermedium cells are oval in shape, contain
      elliptical nuclei, and extend many small processes. It is implied that the
      structure of the enamel organ is different among actinopterygians, and that
      constitution of the enamel organ in Lepisosteus resembles that in higher
      vertebrates. Marked Ca-ATPase activity is observed at the cell membrane of the
      stratum intermedium cells, suggesting that the cells are involved in calcium
      transport during the stages of enameloid formation.

PMID- 12489206
TI  - Cross-talk between Msx/Dlx homeobox genes and vitamin D during tooth
      mineralization.
AB  - Rickets is associated with site-specific disorders of enamel and dentin
      formation, which may reflect the impact of vitamin D on a morphogenetic pathway.
      This study is devoted to potential cross-talk between vitamin D and Msx/Dlx
      transcription factors. We raised the question of a potential link between tooth
      defects seen in mice with rickets and Msx2 gene misexpression, using mutant mice
      lacking the nuclear vitamin D receptor as an animal model. Our data showed a
      modulation of Msx2 expression. In order to search for a functional impact of this
      Msx2 misexpression secondary to rickets, we focused our attention on osteocalcin
      as a target gene for both vitamin D and Msx2. Combining Msx2 overexpression and
      vitamin D addition in vitro, we showed an inhibitory effect on osteocalcin
      expression in immortalized MO6-G3 odontoblasts. Finally, in the same cells, such
      combinations appeared to modulate VDR expression outlining the existence of
      complex cross-regulations between vitamin D and Msx/Dix pathways.

PMID- 12489207
TI  - Bone formation in the context of growth retardation induced by hIGFBP-1
      overexpression in transgenic mice.
AB  - In humans, intrauterine growth retardation (hIUGR) is correlated with an
      overexpression of insulin-like growth factor binding protein 1 (IGFBP-1). The
      affected children also present a delay in bone mineralization. In this study,
      transgenic 12-day-old mutant mice overexpressing human IGFBP-1 hepatospecifically
      showed a severe growth retardation. Alcian blue and alizarin red S staining of
      the skeleton revealed mineralization defects at the posterior level of the skull
      (delayed suture closure) and in appendicular and axial skeleton. Furthermore,
      microradiographic analysis showed a reduced bone density in the same areas. Thus,
      overexpressing of hIGFBP-1 demonstrates early postnatal life growth retardation
      and a delay in mineralization in transgenic mutant mice. These data show the
      involvement of the IGF/IGFBP system and more particularly IGFBP-1 in the
      biomineralization process.

PMID- 12489208
TI  - Inhibition of BMP-induced ectopic bone formation by an antiangiogenic agent
      (epigallocatechin 3-gallate).
AB  - Epigallocatechin 3-gallate (EGCG), which is one of the components of green tea,
      was recently shown to inhibit endothelial cell growth in vitro and angiogenesis
      in vivo [5]. We have previously shown that bone and cartilage formation by bone
      morphogenetic protein (BMP) is highly dependent on the geometry of the carrier
      (vasculature-inducing or -inhibiting geometry [2]. To verify the function of
      angiogenesis in the BMP induction system, we examine in this article whether
      inhibition of angiogenesis enhances chondrogenesis and suppresses osteogenesis.
      Fibrous glass membrane used as a BMP carrier was mixed with 1.2 micrograms rhBMP
      2 and 1-10 micrograms of EGCG and was implanted into rats subcutaneously. As the
      dose of EGCG increased, alkaline phosphatase activity and calcium content were
      decreased, whereas the type II collagen content was increased. The results
      clearly indicated that inhibition of vascularization enhanced chondrogenesis and
      suppressed osteogenesis.

PMID- 12489209
TI  - The biomimetics of bone: engineered glass-ceramics a paradigm for in vitro
      biomineralization studies.
AB  - In this study, we investigated the behavior of fetal rat osteoblasts cultured up
      to 23 days on a bioactive apatite-wollastonite glass-ceramic (AW) and on the same
      material on which a carbonated apatite layer was formed by a biomimetic process
      (AWa). The specific activity of alkaline phosphatase activity was about 30%
      increased on AWa compared to AW disks at the last day of culture. Scanning
      electron microscopic (SEM) observations of the material surfaces after scrapping
      off the cell layers revealed that mineralized bone nodules remained attached to
      both surfaces but in larger numbers on AWa. The AWa/bone interfaces were also
      analyzed after fracturing the disks and by transmission electron microscopy
      (TEM). All these results indicated the importance of the surface composition in
      supporting differentiation of osteogenic cells and the subsequent apposition of
      bone matrix. Furthermore, prefabrication of a biological apatite layer by a
      biomimetic method could improve our knowledge of biomineralization processes and
      could find application as bone-repairing material.

PMID- 12489210
TI  - Geometry of artificial ECM: sizes of pores controlling phenotype expression in
      BMP-induced osteogenesis and chondrogenesis.
AB  - This study aims to elucidate the feasible geometry of the scaffolds in bone and
      periodontal tissue engineering. Several biomaterials with different geometries
      are compared in terms of their patterns of ectopic BMP-induced chondrogenesis and
      osteogenesis. The materials include a honeycomb-shaped hydroxyapatite (HCHAP)
      with different tunnel sizes, a laser-perforated collagen membrane (LPM), and CPSA
      bioglass fibers. Implanted pellets were removed at 1-4 weeks and analyzed for
      bone and cartilage formation histologically and biochemically. Porous particles
      of hydroxyapatite (PPHAP), porous blocks of hydroxyapatite (PBHAP), and LPM did
      not induce detectable cartilage formation. In straight tunnel structures with
      various diameters in honeycomb-shaped hydroxyapatite (HCHAP), tunnels with
      smaller diameters (approximately 0.1 mm) induced cartilage followed by bone
      formation, while one with a larger diameter (0.35 mm) directly induced bone
      formation within the tunnels. It is concluded that the "vasculature-inducing
      geometry" of the carrier as an ECM is crucially important for osteogenesis.

PMID- 12489211
TI  - Changes in bone remodeling rate influence the degree of mineralization of bone.
AB  - Mineralization of bone matrix implies two successive steps, a primary
      mineralization on the calcification front followed by a slow process of secondary
      mineralization progressively adding about 50-60% of the mineral content on bone
      matrix. Our model is that antiresorptive agents prolong the lifetime of the basic
      structural units (BSUs) by causing a marked reduction in the birth rate of basic
      multicellular units (BMUs), and increase the degree of mineralization of bone
      (DMB) by allowing a more complete secondary mineralization. Conversely, agents or
      events provoking an augmentation of the birthrate of BMUs and a decrease of the
      lifetime of BSUs lead to resorption of new BSUs before they have fully completed
      their secondary mineralization, leading to the presence of incompletely
      mineralized BSUs and a low mean DMB value, as measured by quantitative
      microradiography. Measurements of DMB (distribution and mean value) under
      circumstances with various remodeling activities favor our model. In
      postmenopausal osteoporotic women treated during 2 or 3 years with alendronate
      (10 mg/day), an increase of the mean DMB of approximately 7 to 10% was found, due
      to a marked reduction in the bone remodeling. In contrast, an activation of bone
      remodeling as in primary hyperparathyroidism lowered the mean DMB.

PMID- 12489212
TI  - Biodendrimers: new polymeric biomaterials for tissue engineering.
AB  - Dendrimers composed entirely of building blocks known to be biocompatible or
      degradable in vivo to natural metabolites were synthesized using a high yield
      divergent approach. This synthesis is amenable to the design and development of
      new biomaterials that are of interest for a variety of medical applications,
      including tissue engineering. In a novel application, photocross-linkable
      dendrimers are used to seal large corneal lacerations.

PMID- 12489213
TI  - Substituent effects on edge-to-face aromatic interactions.
AB  - Chemical double mutant cycles have been used to measure the magnitude of edge-to
      face aromatic interactions in hydrogen-bonded zipper complexes as a function of
      substituents on both aromatic rings. The interaction energies vary depending on
      the combination of substituents from +1.0 kJ mol-1 (repulsive), to -4.9 kJ mol-1
      (attractive). The results correlate with the Hammett substituent constants which
      indicates that electrostatic interactions are responsible for the observed
      differences in interaction energy. The experiments can be rationalised based on
      local electrostatic interactions between the protons on the edge ring and the pi
      electron density on the face ring as well as global electrostatic interactions
      between the overall dipoles on the two aromatic groups.

PMID- 12489214
TI  - An evaluation of force-field treatments of aromatic interactions.
AB  - Experimental measurements of edge-to-face aromatic interactions have been used to
      test a series of molecular mechanics force fields. The experimental data were
      determined for a range of differently substituted aromatic rings using chemical
      double mutant cycles on hydrogen-bonded zipper complexes. These complexes were
      truncated for the purposes of the molecular mechanics calculations so that
      problems of conformational searching and the optimisation of large structures
      could be avoided. Double-mutant cycles were then carried out in silico using
      these truncated systems. Comparison of the experimental aromatic interaction
      energies and the X-ray crystal structures of these truncated complexes with the
      calculated data show that conventional molecular mechanics force fields (MM2,
      MM3, AMBER and OPLS) do not perform well. However, the XED force field which
      explicitly represents electron anisotropy as an expansion of point charges around
      each atom reproduces the trends in interaction energy and the three-dimensional
      structures exceedingly well. Collapsing the XED charges onto atom centres or the
      use of semi-empirical atom-centred charges within the XED force field gives poor
      results. Thus the success of XED is not related to the methods used to assign the
      atomic charge distribution but can be directly attributed to the use of off-atom
      centre charges.

PMID- 12489215
TI  - Modification of carbon nanofibres for the immobilization of metal complexes: a
      case study with rhodium and anthranilic acid.
AB  - The immobilisation of the rhodium/anthranilic acid complex onto fishbone carbon
      nanofibres (CNFs) was executed by means of the following steps: 1) surface
      oxidation of the fibres, 2) conversion of the oxygen-containing surface groups
      into acid chloride groups, 3) attachment of anthranilic acid and 4) complexation
      of rhodium by the attached anthranilic acid. The immobilisation process was
      followed and the resulting surface species were characterised by IR, X-ray
      absorption fine structure (XAFS) and X-ray photoelectron spectroscopy (XPS), and
      by molecular modelling. Anthranilic acid bonds to the CNFs by an amide linkage to
      the carboxyl groups that are present after surface oxidation of the fibres. The
      immobilised anthranilic acid coordinates to rhodium through the nitrogen atom and
      the carboxyl group. The assynthesised RhIII complex itself is not active in the
      liquid-phase hydrogenation of cyclohexene. Reduction with sodium borohydride
      yields small particles (d = 1.5-2 nm) of rhodium metal that are highly active.
      The results indicate that different activation procedures for the immobilised
      Rh/anthranilic acid system should be applied, such as reduction with a milder
      reducing agent or direct complexation of the rhodium in the RhI state.

PMID- 12489216
TI  - Synthesis and self-association of syn-5,10,15-trialkylated truxenes.
AB  - syn-Trialkylated truxenes have been synthesized by alkylation of the truxene
      trianion followed by base-catalyzed isomerization of the anti isomers. 1H NMR
      studies, including a determination of diffusion coefficients, as well as
      molecular mechanics calculations, demonstrate that these derivatives self
      associate in solution through arene-arene interactions. The benzyl derivatives
      show the strongest associations, which are a result of both benzyl-benzyl and
      truxene-truxene interactions.

PMID- 12489217
TI  - Metallocene-DNA: synthesis, molecular and electronic structure and DNA
      incorporation of C5-ferrocenylthymidine derivatives.
AB  - Ferrocenylthymidine derivatives have been prepared by Pd-catalysed cross-coupling
      between ethynylferrocene or vinylferrocene and 5-iodo-2'-deoxyuridine. In the
      latter case a mixture of trans (2a) and gem (2b) isomers was obtained. The cis
      vinylferrocenyl (2c), and ethylferrocenyl (3) derivatives were obtained by
      catalytic hydrogenation of ethynylferrocenyl-dT (1a), and 2c respectively. Single
      crystal X-ray data for 1a, the ferrocenyl-2'furano-pyrimidone 1b, and 2a show
      that the nucleobase is essentially co-planar with the substituted Cp ring of the
      metallocene. The selective reduction of the linkage between the ferrocenyl and
      thymidine moieties, from -C identical to C- to -CH2CH2-, causes a shift in the
      reduction potential of -124 mV. DFT calculations for the one-electron oxidised
      species indicate that the diminished conjugation reduces the spin transfer onto
      the bridging C2 group, but has less effect on the extent transferred to the
      nucleobase from the ferrocenyl group. Compound 1a was incorporated site
      specifically into DNA oligonucleotides by using automated solid-phase methods.
      However, some interconversion of 1a-->1b occurs, even under rapid mild conditions
      of deprotection.

PMID- 12489218
TI  - Structural and energetic aspects of the protonation of phenol, catechol,
      resorcinol, and hydroquinone.
AB  - The various protonated forms of phenol (1), catechol (2), resorcinol (3), and
      hydroquinone (4) were explored by ab initio quantum chemical calculations at the
      MP2/6-31G(d) and B3LYP/6-31G(d) levels. Proton affinities (PA) of 1-4 were
      calculated by the combined G2(MP2,SVP) method, and their gas-phase basicities
      were estimated after calculation of the change in entropy on protonation. These
      theoretical data were compared with the corresponding experimental values
      determined in a high-pressure mass spectrometer. This comparison confirmed that
      phenols are essentially carbon bases and that protonation generally occurs in a
      position para to the hydroxyl group. Resorcinol is the most effective base (PA =
      856 kJ mol-1) due to the participation of both oxygen atoms in the stabilization
      of the protonated form. Since protonation is accompanied by a freezing of the two
      internal rotations, a significant decrease in entropy is observed. The basicity
      of catechol (PA = 823 kJ mol-1) is due to the existence of an intramolecular
      hydrogen bond, which is strengthened upon protonation. The lower basicity of
      hydroquinone (PA = 808 kJ mol-1) is a consequence of the fact that protonation
      necessarily occurs in a position ortho to the hydroxyl group. When the previously
      published data are reconsidered and a corrected protonation entropy is used, a
      proton affinity value of 820 kJ mol-1 is obtained for phenol.

PMID- 12489219
TI  - Easy access to phosphonothioates.
AB  - A new and particularly mild method for the formation of phosphorus-sulfur bonds
      has been achieved through base-catalyzed addition of thiocyanate to the
      corresponding H-phosphine oxide, phosphinate, or phosphonate. This reaction
      procedure offers many advantages: the use as starting material of a stable and
      not oxygen-sensitive phosphorus(v) species, particularly mild and nonaqueous
      reaction conditions and workup (a pivotal point for these sensitive
      phosphonothioates), and, through optimized access to thiocyanates, a wider scope
      of substrates. This method has been applied to achieve the synthesis of substrate
      analogues for the study of antibody-catalyzed hydrolysis of acetylcholinesterase
      inhibitor PhX (11).

PMID- 12489220
TI  - Generation and use of an equivalent of difluoroacetamide or difluoroacetate
      anions.
AB  - Ethers of trifluoroacetaldehyde hemiaminals can undergo dehydrofluorination under
      basic conditions to provide ethers of difluoroketene hemiaminals. The latter
      behave as equivalents of difluoroacetamide or difluoroacetate anions towards
      various electrophiles, yielding a range of difluoromethylcarbonyl products.

PMID- 12489221
TI  - Synthesis of eight- and nine-membered carbocycles through a ring-closing
      metathesis/ring fragmentation strategy: a rapid and versatile approach to
      bicyclo[6.4.0]- and bicyclo[7.4.0]alkene ring systems.
AB  - Ring-closing metathesis (RCM) of cis-2,6-dialkenyl-2-hydroxy-1-cyclohexanones
      affords bicyclo[3.n.1]alkenones that are easily converted into eight- or nine
      membered carbocycles by oxidative cleavage of the keto-bridging tether. Since the
      starting cyclohexanones are readily assembled from commercially available 1,2
      cyclohexanedione, the overall process constitutes a rapid and versatile route to
      medium-sized carbocycles, which are otherwise difficult compounds to assemble
      using currently available procedures. If one of the alkenes of the cyclohexanone
      chains is replaced by an alkyne, the subsequent RCM produces 1,3-diene systems
      capable of undergoing stereoselective Diels-Alder reaction with activated
      dienophiles. Oxidative cleavage of the keto bridge of the resulting tricycles
      leads to 8-6 and 9-6 fused bicarbocycles with up to four stereocenters.

PMID- 12489222
TI  - Enantioselective transport by a steroidal guanidinium receptor.
AB  - The cationic steroidal receptors 9 and 11 have been synthesized from cholic acid
      3. Receptor 9 extracts N-acetyl-alpha-amino acids from aqueous media into
      chloroform with enantioselectivities (L:D) of 7-10:1. The lipophilic variant 11
      has been employed for the enantioselective transport of N-acetylphenylalanine, a)
      through dichloromethane (DCM) and dichloroethane (DCE) bulk liquid membranes (U
      tube apparatus), and b) through 2.5% (v/v) octanol/hexane via hollow fibre
      membrane contactors. Significant enantioselectivities and multiple turnovers were
      observed for both types of apparatus.

PMID- 12489223
TI  - Control of the morphogenesis of barium chromate by using double-hydrophilic block
      copolymers (DHBCs) as crystal growth modifiers.
AB  - A systematic morphosynthesis of barium chromate particles has been performed by
      using double-hydrophilic block copolymers (DHBCs), which consist of a hydrophilic
      solvating block and a hydrophilic binding block, as crystal growth modifiers to
      direct the controlled precipitation of barium chromate from aqueous solution.
      Several kinds of DHBCs with different functional groups -COOH, -PO3H2, -SO3H, -SH
      as well as PEG-poly(aminoamine) block-dendrimer copolymers were explored for
      crystallization and morphology control of barium chromate. Well-defined
      morphologies of BaCrO4 particles can be produced, such as more or less dendritic
      X-shaped, elongated X-shaped, or rodlike particles, flower-like plates,
      ellipsoids, spheres, nanofiber bundles, nanofibers, and other more complex
      morphologies. In the presence of the phosphonated copolymer PEG-b-PMAA-PO3H2
      (degree of phosphonation: 21%) at pH 5, large conelike bundles of nanofibers
      ranging from 10 to 20 nm in diameter with lengths up to 150 microns can be
      produced at room temperature, whereas replacement of the covalently bound
      phosphonate groups by the ionic salt analogue dopant fails to produce this
      structure, indicating the importance of the functional polymer block structures.
      The time-resolved formation process of the bundles of nanofibres was
      investigated, showing a remarkable self-similarity. At temperatures higher than
      50 degrees C, in plastic flasks or when undergoing continuous stirring, only
      ellipsoids or nearly spherical particles can be obtained. This shows that the
      fiber formation relies on heterogeneous nucleation and is in agreement with a
      recently published mechanism where fiber formation is due to the vectorially
      directed self-assembly of primary particles. Our results demonstrate that the
      integration of DHBCs, taking advantage of the experimental conditions such as
      crystallization sites, temperature, pH, and reactant concentration, will extend
      the possibilities for controlling the shape, size, and microstructures of the
      inorganic crystals by means of a simple mineralization process.

PMID- 12489224
TI  - Hexagonal terpyridine--ruthenium and -iron macrocyclic complexes by stepwise and
      self-assembly procedures.
AB  - Methods for the self-assembly, as well as directed construction, of hexaruthenium
      metallomacrocycles employing bisterpyridine building blocks are described. Self
      assembly is effected by a combination of equimolar mixtures of bismetalated and
      nonmetalated bis(terpyridinyl) monomers each possessing the requisite planar, 60
      degrees, terpyridine-metal-terpyridine connectivity. Stepwise synthesis of the
      identical hexamer is also discussed and used to aid in verification of the self
      assembled product. Preparation and analysis of the related FeII metallomacrocycle
      are detailed and its TEM image confirms the hexameric structure. Characterization
      of the metalated products includes cyclic voltammetry along with the routine
      analytical techniques.

PMID- 12489225
TI  - Ruthenium-catalyzed transfer hydrogenation of imines by propan-2-ol in benzene.
AB  - Transfer hydrogenation of a variety of different imines to the corresponding
      amines by propan-2-ol in benzene catalyzed by [Ru2(CO)4(mu-H)(C4Ph4COHOCC4Ph4)]
      (1) has been studied. The reaction is highly efficient with turnover frequencies
      of over 800 per hour, and the product amines were obtained in excellent yields. A
      remarkable concentration dependence of propan-2-ol was observed when the reaction
      was run in benzene as cosolvent. An optimum was obtained at 24 equivalents of
      propan-2-ol to imine, and further increase of the propan-2-ol led to a dramatic
      decrease in rate. Also the use of polar cosolvents with 24 equivalents of propan
      2-ol gave a low rate. It was found that ketimines react faster than aldimines and
      that electron-donating substituents on the imine increase the rate of the
      catalytic transfer hydrogenation. Electron-withdrawing substituents decreased the
      rate. An isomerization was observed with imines having an alpha-hydrogen at the N
      alkyl substituent, which is in accordance with a mechanism involving a ruthenium
      amine intermediate. It was demonstrated that the ruthenium-amine complex from
      alpha-methylbenzylamine, corresponding to the postulated intermediate, can
      replace 1 as catalyst in the transfer hydrogenation of imines. A primary
      deuterium isotope effect of kCH/CD = 2.7 +/- 0.25 was observed when 2-deuterio
      propan-2-ol was used in place of propan-2-ol in the transfer hydrogenation of N
      phenyl-(1-phenylethylidene)amine.

PMID- 12489226
TI  - Highly chemoselective hydrogenation of 2-ethylanthraquinone to 2
      ethylanthrahydroquinone catalyzed by palladium metal dispersed inside highly
      lipophilic functional resins.
AB  - Most hydrogen peroxide is currently produced by the selective hydrogenation of 2
      ethylanthraquinone (EAQ) to 2-ethylanthrahydroquinone (EAHQ), followed by
      treatment with dioxygen; this produces hydrogen peroxide and regenerates 2
      ethylanthraquinone. We have developed novel catalysts for this process that are
      based on palladium supported on very lipophilic functional resins and that are
      able to promote a chemoselectivity for EAHQ slightly but definitely superior to
      that provided by an industrial catalyst under identical conditions. This finding
      demonstrates the potential of variations of the lipophilic/hydrophilic character
      of the support as a tool for the improvement of the chemoselectivity of resin
      based metal catalysts.

PMID- 12489227
TI  - Novel asymmetric michael addition of alpha-cyanopropionates to acrolein by the
      use of a bis(oxazolinyl)phenylstannane-derived rhodium(III) complex as a chiral
      Lewis acid catalyst.
AB  - The rhodium complex prepared in situ by simply mixing [[RhCl(c-octene)2]2] and
      [(Phebox)SnMe3] (1) (Phebox = 2,6-bis(oxazolinyl)phenyl) was found to serve as an
      efficient catalyst for the asymmetric Michael addition of alpha-cyanopropionates
      (4) to acrolein under mild and neutral conditions. In the present catalytic
      system, both the temperature of catalyst preparation and the order of the
      addition of the substrates were very important for the catalytic efficiency and
      enantioselectivity. Detailed mechanistic studies of this catalytic system
      revealed that the [(Phebox)RhIII(SnMe3)Cl] complex (9), generated by oxidative
      addition of [[RhCl(c-octene)2]2] to 1, is an active catalyst and the turnover
      number (TON) of the present actual catalyst existing in a reaction mixture is
      greater than 10,000. The obtained (R) stereochemistry of the Michael adducts 5
      can be explained by N-bonded enol intermediates C', which are formed by
      enolization of 4 bound to the Lewis acidic rhodium complex 9. We also found that
      the active catalyst 9 gradually decomposed in the presence of the remaining
      [[RhCl(c-octene)2]2] in the reaction mixture to form the catalytically nonactive
      [(Phebox)RhCl2] fragment A, whose structure was characterized by an X-ray
      crystallographic study after converting to the tBuNC complex 10.

PMID- 12489228
TI  - Synthesis of a novel potential tridentate anthracene ligand, 1,8
      bis(dimethylamino)-9-bromoanthracene, and its application as chelate ligand for
      synthesis of the corresponding boron and palladium compounds.
AB  - A novel potential tridentate ligand, 1,8-bis(dimethylamino)-9-bromoanthracene,
      was synthesized. The key steps are as follows: 1) dimethylamination of 1,8
      dibromo-9-methoxyanthracene by a modified Buchwald's method to afford 1,8
      bis(dimethylamino)-9-methoxyanthracene, and 2) reduction of the methoxy group by
      LDBB (lithium di-tert-butylbiphenylide) followed by treatment with BrCF2CF2Br.
      The corresponding 1,8-bis(dimethylamino)-9-lithioanthracene, which should be a
      useful versatile tridentate ligand, could be generated by treatment of the
      bromide with one equivalent of nBuLi. The lithioanthracene reacted with B
      chloroborane derivatives to give three 9-boryl derivatives. Although we recently
      reported that the crystal structure of 1,8-dimethoxy-9-B
      catecholateborylanthracene was a symmetrical compound with the almost identical
      two O-B distances (2.379(2) and 2.441(2) A), the newly prepared 1,8
      bis(dimethylamino)-9-borylanthracene derivatives clearly have unsymmetrical
      structures with coordination of only one NMe2 group toward the central boron
      atom. However, the energy difference between the unsymmetrical and symmeterical
      structures was found to be very small based on 1H NMR measurements, in which
      symmetrical anthracene patterns in the aromatic region (two kinds of doublets and
      a triplet) and a sharp singlet signal of the two NMe2 groups were observed even
      at -80 degrees C. 1,8-Bis(dimethylamino)-9-bromoanthracene itself can be a
      versatile ligand for transition metal compounds. In fact, direct palladation of
      the bromide took place by the reaction with [Pd2(dba)3].CHCl3 in THF to give the
      9-palladated product. X-ray crystallographic analysis of the Pd compound showed
      that the square planar palladium atom was coordinated in a symmetrical fashion by
      both NMe2 groups (Pd-N bonds are 2.138(5) and 2.146(5) A).

PMID- 12489229
TI  - Interlocking inorganic screw helices: synthesis, structure, and magnetism of the
      novel framework uranium orthothiophoshates A11U7(PS4)13 (A = K, Rb).
AB  - The novel quaternary uranium thiophosphate K11U7(PS4)13 has been synthesized by
      reacting uranium metal, K2S, S, and P2S5 at 700 degrees C in an evacuated silica
      tube. The crystal structure was determined by single crystal X-ray diffraction
      techniques. K11U7(PS4)13 crystallizes in the tetragonal space group I42d (a =
      32.048(2) A, c = 17.321(1) A, Z = 8). The structure contains a tunnel framework
      composed of eight interlocking uranium U7(PS4)13 screw helices, with alkali metal
      cations residing inside the framework channels. The uranium atoms are coordinated
      in a bi- or tricapped trigonal prismatic fashion. The screw helices are built up
      from uranium atoms interconnected by PS4 tetrahedral units. Magnetic
      susceptibility measurements indicate modified Curie-Weiss-type behavior between
      300 and 70 K, with an effective magnetic moment of 2.54 microB per U atom at room
      temperature and C = 3.78, theta = -14.54, chi 0 = 0.01. The isostructural
      compound Rb11U7(PS4)13 (a = 32.1641(11) A, c = 17.7244(9) A, Z = 8) was prepared
      by heating a mixture of the formal composition UPS5 in eutectic LiCl/RbCl melts
      at 700 degrees C.

PMID- 12489230
TI  - Large oligosaccharide-based glycodendrimers.
AB  - Carbohydrate-based dendritic structures composed of 21 and 27 monosaccharide
      residues have been synthesized in a convergent manner from trisaccharide building
      blocks. The oligosaccharide AB2 monomers are based on a maltosyl beta(1-
      >6)galactose structure, which has been modified to include two methylamino groups
      at the primary positions of the glucosyl residues. Reductive alkylation of the
      secondary amino groups, with the innate formyl function of a second
      oligosaccharide monomer, allows for the chemoselective construction of dendritic
      wedges, while employing a minimal number of protecting groups. The first
      generation dendron can be coupled either to another AB2 monomer, to give a second
      generation dendron, or to a tris[2-(methylamino)ethyl]amine-based core moiety, to
      provide a carbohydrate-based dendrimer. Alternating alpha- and beta-glucosyl
      residues in the monomers and dendrons, simplifies 1H NMR spectra as a consequence
      of spreading out the anomeric proton signals. Monomers and dendrons were
      characterized by extensive one- and two-dimensional NMR spectroscopy in addition
      to FAB, electrospray, and MALDI-TOF mass spectrometry. Molecular dynamics
      simulations revealed similar conformations in the dendrons as in the isolated
      trisaccharide repeating units.

PMID- 12489231
TI  - alpha-L-LNA (alpha-L-ribo configured locked nucleic acid) recognition of DNA: an
      NMR spectroscopic study.
AB  - We have used NMR and CD spectroscopy to study and characterise two alpha-L
      LNA:DNA duplexes, a nonamer that incorporates three alpha-L-LNA nucleotides and a
      decamer that incorporates four alpha-L-LNA nucleotides, in which alpha-L-LNA is
      alpha-L-ribo-configured locked nucleic acid. Both duplexes adopt right-handed
      helical conformations and form normal Watson-Crick base pairing with all
      nucleobases in the anti conformation. Deoxyribose conformations were determined
      from measurements of scalar coupling constants in the sugar rings, and for the
      decamer duplex, distance information was derived from 1H-1H NOE measurements. In
      general, the deoxyriboses in both of the alpha-L-LNA:DNA duplexes adopt S-type (B
      type structure) sugar puckers, that is the inclusion of the modified alpha-L-LNA
      nucleotides does not perturb the local native B-like double-stranded DNA (dsDNA)
      structure. The CD spectra of the duplexes confirm these findings, as these
      display B-type characteristic features that allow us to characterise the overall
      duplex type as B-like. The 1H-1H NOE distances which were determined for the
      decamer duplex were employed in a simulated annealing protocol to generate a
      model structure for this duplex, thus allowing a more detailed inspection of the
      impact of the alpha-L-ribo-configured nucleotides. In this structure, it is
      evident that the malleable DNA backbone rearranges in the vicinity of the
      modified nucleotides in order to accommodate them and present their nucleobases
      in a geometry suitable for Watson-Crick base pairing.

PMID- 12489232
TI  - Anion exchange in the channels of a robust alkaline earth sulfonate coordination
      network.
AB  - The barium sulfonate network presented herein, [[Ba2(L)(H2O)5]Cl]infinity (1),
      represents the first metal sulfonate compound to possess a cationic framework.
      The network is layered with channels between pillaring ligands in which chloride
      ions reside. Compound 1 contracts slightly upon dehydration but retains its
      overall structural motif to 420 degrees C. Significantly, the chloride ions of
      the structure can be exchanged in 80% yield for fluoride ions in a facile manner.
      This exchange is quantified by elemental analyses, gravimetric determination, and
      19F NMR spectroscopy. Confirmation of retention of structure is provided by
      standardized powder X-ray diffraction experiments. This last point is notable as
      the F-analogue of the structure is not attainable by a direct synthesis. These
      results illustrate one of the hallmark features of supramolecular chemistry, that
      a robust and functional framework can result through cooperative interactions
      between more weakly interacting units.

PMID- 12489233
TI  - Crowded piperidines with intramolecularly hydrogen-bonded nitrogen: synthesis and
      conformation study.
AB  - 2,2,6,6-Tetramethyl substituted piperidines with a beta-branched N-alkyl
      substituent were synthesized by the photoreaction of N-Me precursors with
      ketones. The main conformation features of these sterically-hindered amines
      (established by NMR and IR spectroscopy) are a ring in the chair form, an
      eclipsed conformation for the N-substituent and an intramolecular OH...N bond.
      High barriers for the geminal substituent topomerization were measured for these
      piperidines at different temperatures by means of line-shape analysis of the
      temperature-dependent 13C and 1H NMR spectra. An MM3-derived conformation scheme
      indicated that, for one of the studied analogues, the rotation of the N
      substituent determines a slow topomerization rate. A new mechanism of nitrogen
      inversion--a concerted hydrogen-bond dissociation/nitrogen inversion process--is
      considered for hydrogen-bonded amines.

PMID- 12489234
TI  - Synthesis of oligothiophene-bridged bisporphyrins and study of the linkage
      dependence of the electronic coupling.
AB  - A set of twelve porphyrin dimers has been prepared to give information on how the
      type of connectivity between a porphyrin core and a bridge can influence the
      interporphyrin electronic interaction. The new porphyrin systems are substituted
      directly at the meso position with an oligothiophene chain tethered either with a
      single C-C sigma bond, a trans ethylenyl group, or a acetylenyl group. The
      compounds are easily obtained by palladium-catalyzed cross-coupling reactions
      (Stille, Heck, and Sonogashira) between 5-iodo-10,15,20-(3,5-ditert
      butylphenyl)porphyrin and the appropriate oligothiophene derivative. This
      synthetic approach is straightforward and very effective for preparing
      oligothiophene-based prophyrin systems. The absorption spectra and the
      fluorescence properties of the dimers demonstrated the crucial importance of the
      characteristics of the chemical bond used to connect the bridge to the porphyrin
      unit. The magnitude of the electronic communication can thus be significantly
      modulated by altering the type of bond connectivity used to link the chromophore
      to the bridge. The present work shows that an oligothiophene spacer is a viable
      class of linker for connecting porphyrins, and that a quaterthiophene appended
      with ethynyl linkages affords a high electronic interaction over a distance as
      large as 28 A. A detailed computational study of these dimers has clarified the
      conditions needed for a conjugated system to behave as a molecular wire. These
      conditions are full planarity of the molecule and proper energy matching between
      the frontier orbitals of the bridge and the porphyrin. Intermolecular energy
      transfer in asymmetrical dyads composed of a zinc porphyrin and a freebase
      porphyrin has been studied by fluorescence spectroscopy. In all systems, this
      process is more than 98% efficient, and its rate constant decreases steadily in
      the order 4ZH > 1ZH > 3ZH approximately 2ZH. Thus, the largest rate (kEnT = 1.2 x
      10(11) s-1) was found in the dyad linked with bisethynyl quaterthiophene, which
      represents the longest bridge within the series. These results clearly
      demonstrate that strong communication and also efficient photoinduced processes
      can be promoted over a large distance if the electronic structure of the
      molecular connector is appropriately chosen.

PMID- 12489235
TI  - Ruthenium alkylidenes: modulation of a new class of catalysts for controlled
      radical polymerization of vinyl monomers.
AB  - Air-stable and readily available ruthenium benzylidene complexes of the general
      type [RuCl2(=CHPh)(L)(L')] (L, L' = PCy3 and/or N-heterocyclic carbene)
      constitute a new class of catalyst precursors for atom-transfer radical
      polymerization (ATRP) of methyl methacrylate and styrene, and provide an
      unprecedented example for the involvement of ruthenium alkylidenes in radical
      reactions. They promote the polymerization of various monomers with good to
      excellent yields, and in a controlled way with methyl methacrylate and styrene.
      Variations of their basic structural motif provide insights into the essential
      parameters responsible for catalytic activity. The ligands L (PCy3 and/or N
      heterocyclic carbene) turned out to play a particularly important role in
      determining the rate of the polymerizations. A similarly pronounced influence is
      exerted by the substituents on the N-heterocyclic carbene. Our results indicate
      that the catalysts decompose quickly under ATRP conditions, and polymerizations
      are mediated by both [RuCl2(=CHPh)(L)(L')] complexes and ruthenium species bereft
      of the benzylidene moiety, through a pathway in which both tricyclohexylphosphane
      and/or N-heterocyclic carbene ligands remain bound to the metal center.
      Polymerization of n-butyl acrylate and vinyl acetate is not controlled and most
      probably takes place through a redox-initiated free-radical process.

PMID- 12489236
TI  - Kinetics of MTO-catalyzed olefin epoxidation in ambient temperature ionic
      liquids: UV/Vis and 2H NMR study.
AB  - The kinetics of oxygen-atom transfer from the peroxo complexes of
      methyltrioxorhenium (MTO) to alkenes in ionic liquids have been investigated.
      Noncatalytic conversions of alkenes to epoxide were monitored by UV/Vis at 360
      nm, where the monoperoxorhenium (mpRe) and diperoxorhenium (dpRe) complexes
      absorb. Water- and peroxide-free dpRe was prepared in situ by the reaction of MTO
      and urea hydrogen peroxide (UHP) in dry THF. The observed biexponential time
      profiles in conjunction with kinetic modeling allow the assignment of the fast
      step to the reaction of olefin with dpRe (k4) and the slow step to the analogous
      reaction with mpRe (k3). In most of the tudied ionic liquids, k4 approximately 5
      x k3. 2H NMR experiments conducted with [D3]dpRe under non-steady-state
      conditions confirm the speciation of the catalytic system in ionic liquids and
      assert the validity of the UV/Vis kinetics. Deuteriated alkenes were used to
      study the catalytic epoxidation and dihydroxylation of alkenes by 2H NMR
      spectroscopy. The values of k4 for alpha-methylstyrene in several ionic liquids
      exceed what is observed in acetonitrile by an order of magnitude. While the rate
      of olefin epoxidation is unaffected by the nature of the ionic liquid cation, a
      discernible kinetic effect is observed with coordinating anions such as nitrate.

PMID- 12489237
TI  - The problem with premenstrual syndrome.

PMID- 12489238
TI  - Tertiary research applied to primary care.

PMID- 12489239
TI  - Know your "MeSH" terms.

PMID- 12489240
TI  - Overdrugged patients: enough is enough.

PMID- 12489241
TI  - Influenza vaccination during pregnancy.
AB  - QUESTION: A 27-year-old patient of mine recently learned she is pregnant. She
      took the influenza vaccine offered at work when she was 7 weeks pregnant. Is her
      fetus at risk of malformations? ANSWER: No evidence indicates that killed
      influenza vaccine is teratogenic, even if given during the first trimester. Since
      1996, Health Canada's Centre for Disease Control and Prevention has recommended
      that pregnant women in their second and third trimesters be vaccinated. This
      should not be interpreted as evidence that the vaccine is teratogenic in the
      first trimester because such evidence does not exist.

PMID- 12489242
TI  - Ophthaproblem. Ocular myasthenia gravis.

PMID- 12489243
TI  - Just the berries. Management of community-acquired pneumonia. Evidence-based
      update.

PMID- 12489244
TI  - Premenstrual syndrome. Evidence-based treatment in family practice.
AB  - OBJECTIVE: To evaluate the strength of evidence for treatments for premenstrual
      syndrome (PMS) and to derive a set of practical guidelines for managing PMS in
      family practice. QUALITY OF EVIDENCE: An advanced MEDLINE search was conducted
      from January 1990 to December 2001. The Cochrane Library and personal contacts
      were also used. Quality of evidence in studies ranged from level I to level III,
      depending on the intervention. MAIN MESSAGE: Good scientific evidence shows that
      calcium carbonate (1200 mg/d) and selective serotonin reuptake inhibitors are
      effective treatments for PMS. The most commonly used therapies (including vitamin
      B6, evening primrose oil, and oral contraceptives) are based on inconclusive
      evidence. Other treatments for which there is inconclusive evidence include
      aerobic exercise, stress reduction, cognitive therapy, spironolactone, magnesium,
      nonsteroidal anti-inflammatory drugs, various hormonal regimens, and a complex
      carbohydrate-rich diet. Although evidence for them is inconclusive, it is
      reasonable to recommend healthy lifestyle changes given their overall health
      benefits. Progesterone and bromocriptine, which are still widely used, are
      ineffective. CONCLUSION: Calcium carbonate should be recommended as first-line
      therapy for women with mild-to-moderate PMS. Selective serotonin reuptake
      inhibitors can be considered as first-line therapy for women with severe
      affective symptoms and for women with milder symptoms who have failed to respond
      to other therapies. Other therapies may be tried if these measures fail to
      provide adequate relief.

PMID- 12489245
TI  - [The patient-centered interview and the way it is taught. What do family
      physicians who have recently received their degree think?].
AB  - OBJECTIVE: To describe how family physicians perceive the patient-centred
      interview (PCI) and the way in which it is taught during residency training.
      DESIGN: Mailed survey. SETTING: Family physicians from a variety of practice
      settings in Quebec. PARTICIPANTS: Ninety-one family physicians who graduated from
      Laval University between 1996 and 1998. METHOD: Survey was conducted in 1999
      using the modified Dillman method. The original questionnaire had mainly open
      ended questions on perception of the PCI and learning activities associated with
      it during residency training. All qualitative data were subject to content
      analysis using triangulation strategies. MAIN FINDINGS: A PCI mainly involves
      exploring patients' experience of their illnesses; this helps physicians to
      better understand patients. Patients are more content with this type of interview
      and are, therefore, more likely to follow physicians' recommendations.
      Respondents reported the main drawback to be longer interview times; this was
      particularly true for emergency and walk-in care. The most useful learning
      activities during residency were reported to be supervision by direct observation
      and observation of supervisor-patient consultations. CONCLUSION: Patient-centred
      interviews enabled physicians to understand and help their patients better.
      Results of this study can help teachers who are developing and consolidating
      activities to teach residents how to conduct PCIs and how to integrate them into
      practice.

PMID- 12489246
TI  - Patients with eating disorders. How well are family physicians managing them?
AB  - OBJECTIVE: To assess the attitudes and behaviour of family physicians toward
      patients with eating disorders (EDs) and to assess these physicians' ongoing
      learning needs. DESIGN: Confidential survey by mail. SETTING: Family practices in
      London, Ont. PARTICIPANTS: Two hundred thirty-six general FPs. MAIN OUTCOME
      MEASURES: Proportion of FPs seeing patients with EDs, screening and management
      practices, learning needs. RESULTS: Survey response rate was 87.7%; 64% of
      respondents were male, 36% were female, and 54% had completed a family medicine
      residency program. Overall, FPs were more comfortable with diagnosis, and less
      comfortable with management, of EDs. Most respondents shared care with other
      professionals, usually psychiatrists and nutritionists. Female physicians had
      identified a larger number of ED patients in their practices and were more likely
      to screen routinely for EDs. Three quarters of FPs rated their undergraduate
      training in EDs as poor, and 59% thought their postgraduate training was poor.
      Outpatient services, diagnostic issues, screening needs, and management planning
      were identified as important learning needs. Family physicians thought these
      needs could be best addressed in interactive workshops or peer-led case
      discussion groups. CONCLUSION: Family physicians are important in first-line
      treatment of EDs, but many barriers prevent effective diagnosis and management.
      Validated screening tools and management strategies could assist FPs in caring
      for patients with EDs.

PMID- 12489247
TI  - Synthesis and anticonvulsant activity of 1-acetyl-5-arylidenyl-3-(2'
      oxo/thiobarbiturinyl)-2-pyrazolines.
AB  - 1-(2'-Oxo/thiobarbiturinyl)-3-arylidenylchalcones (3-14) were synthesized by the
      condensation of different aromatic aldehydes with 5-acetyl-2-oxo/thiobarbituric
      acid (1 resp. 2) and various 1-acetyl-5-arylidenyl-3-(2'-oxo/thiobarbiturinyl)-2
      pyrazolines (15-26) were synthesized by cyclisation of compounds 3-14 with
      hydrazine hydrate. The newly synthesized compounds showed anticonvulsant activity
      ranging from 40% to 90%. Compound 23 showed the maximum activity being more
      potent than the reference drug 1-acetyl-5-(P-methoxyphenyl)-3-(2'
      thiobarbiturinyl)-2-pyrazoline.

PMID- 12489248
TI  - Synthesis and alpha 1-adrenoceptor antagonistic activity of some 4-amino-5,7
      dimethyl-2-(substituted) aminopyrido (2,3-d) pyrimidines.
AB  - A series of new 4-amino-5,7-dimethyl-2- (substituted)aminopyrido(2,3
      d)pyrimidines (5) have been synthesized and tested for selective alpha 1
      adrenoreceptor antagonistic activity. Some of the compounds were found to
      antagonize alpha 1-adrenoreceptor in a competitive and reversible manner. When
      screened on rat anococcygeus muscle some of the compounds exhibited significant
      alpha 1-adrenoreceptor antagonistic activity (pA2 values in the range of 5.2
      7.8). The most potent compound (5j) was evaluated by an in vivo method and was
      found to reduce the systolic and diastolic blood pressure of spontaneously
      hypertensive rats. The percentage reduction in blood pressure by test compound 5j
      was found to be higher than that of the standard drug prazosin (CAS 19216-56-9)
      at the same dose level (1 mg/kg p.o.). Chemically, prazosin is a 4
      aminoquinazolin derivative. Pyridopyrimidine is a known bioisostere of
      quinazoline. The study revealed that isosteric replacement of the benzene ring of
      prazosin by a pyridine ring increases the potency.

PMID- 12489250
TI  - Effects of direct and indirect activation of G protein of adenylyl cyclase on the
      subsequent response to beta-adrenergic receptor agonists in human trachealis.
AB  - To examine the response to beta-adrenergic receptor agonists (beta-agonists)
      following prolonged activation of the stimulatory G protein of adenylyl cyclase
      (Gs), relaxation by isoproterenol (isoprenaline, CAS 949-36-0) and formoterol
      (CAS 73573-87-2), a long-acting beta-agonist, after exposure to formoterol was
      measured in human tracheal smooth muscle, using isometric tension records. Prior
      exposure to formoterol (0.3-30 nmol/l) for 45 min reduced the subsequent
      relaxation induced by this drug in a concentration-dependent manner, but only
      modestly reduced that induced by isoproterenol. Next, the effects of cholera
      toxin (CTX, CAS 9012-63-9) an irreversible direct activator of Gs and formoterol
      on the reduced responsiveness to isoproterenol after continuous and repeated
      exposure to isoprotenerol were examined. Preincubation with cholera toxin (0.02-2
      micrograms/ml) caused concentration-dependent inhibition of the desensitization
      induced by isoproterenol, but preincubation with formoterol did not. These
      results indicate that prolonged activation of Gs via beta-adrenergic receptors
      does not cause cross-desensitization to short-acting beta-agonists. However, it
      also fails to inhibit the desensitization of beta-adrenergic receptors after
      excessive exposure to short-acting beta-agonists. Activation of Gs via a pathway
      that bypasses the receptors may be beneficial for the prevention of this
      phenomenon.

PMID- 12489249
TI  - Blood pressure lowering effect of an olive leaf extract (Olea europaea) in L-NAME
      induced hypertension in rats.
AB  - A specially prepared olive leaf extract (EFLA 943) has been tested for its blood
      pressure lowering activity in rats rendered hypertensive by daily oral doses of L
      NAME (NG-nitro-L-arginine methyl ester, 50 mg/kg) for at least 4 weeks. Oral
      administration of the extract at different dose levels at the same time as L-NAME
      for a period of 8 weeks showed a dose dependent prophylactic effect against the
      rise in blood pressure induced by L-NAME, best effects being induced by a dose of
      100 mg/kg of the extract. In rats previously rendered hypertensive by L-NAME for
      6 weeks and then treated with that dose of the extract for a further 6 weeks
      without discontinuation of L-NAME, normalisation of the blood pressure was
      observed. The findings confirm previous reports on the hypotensive effects of
      olive leaf. The special extract, EFLA 943, was shown to give consistent results
      with little individual variability. The antihypertensive effect of the extract
      may be related to a variety of factors involving reversal of vascular changes
      involved in the L-NAME induced hypertension.

PMID- 12489251
TI  - Evaluation of the combined effect of pranlukast during high-dose steroid
      inhalation.
AB  - In 40 patients with moderate to severe persistent adult asthma who had been
      requiring more than 1200 micrograms/day of beclomethasone dipropionate (CAS 5534
      09-8, BDP) inhalation, the present study evaluated the combined effects of
      pranlukast (CAS 103177-37-3, Onon) during highdose steroid inhalation (20 in the
      pranlukast group and 20 in the control group). In the pranlukast group, 450
      mg/day of pranlukast was administered. The course of these patients was monitored
      for 6 weeks during which the dose of BDP was decreased to 1/2 of the initial dose
      2 weeks later and to 1/4 of the initial dose additional 4 weeks later. The dose
      of BDP was also decreased in the control group. The concomitant use of pranlukast
      significantly improved asthmatic symptoms and respiratory functions in asthmatic
      patients receiving high-dose steroid inhalation. Furthermore, the concomitant use
      of pranlukast significantly inhibited worsening of asthmatic symptoms,
      respiratory functions and parameters, which are frequently observed when the dose
      of inhalation steroids is decreased.

PMID- 12489252
TI  - Synthesis, spectral studies and anti-inflammatory activity of glycolamide esters
      of niflumic acid as potential prodrugs.
AB  - In order to reduce the gastric irritation caused by direct contact mechanism of
      the carboxylic acid group, a series of glycolamide esters of niflumic acid (CAS
      4394-00-7) (1) have been prepared as bio-labile prodrugs by reacting appropriate
      2-chloroacetamides with niflumic acid. The required 2-chloroacetamides were
      obtained by the condensation of chloroacetyl chloride and corresponding amine.
      Their structures were confirmed by UV, IR and 1H NMR spectra. Selected compounds
      were evaluated for anti-inflammatory activity in carrageenan induced paw oedema
      in rats at the doses of 45, 90 and 150 mg/kg b.w. Prodrugs showed comparable anti
      inflammatory activity (67.1-79.4%) at 150 mg/kg b.w. with respect to niflumic
      acid (70.3%) at 45 mg/kg b.w., indicating moderate release of niflumic acid in
      vivo. The highest activity was observed with diethylamine (4) and pyrrolidine (9)
      derivatives.

PMID- 12489253
TI  - Tissue absorption and distribution of ketoprofen after patch application in
      subjects undergoing knee arthroscopy or endoscopic carpal ligament release.
AB  - The diffusion into the target tissues of ketoprofen (CAS 22071-15-4), a widely
      used nonsteroidal anti-inflammatory drug, from a new topical patch has been
      studied after repeated patch application in comparison with its plasma level. Ten
      patients (5 women and 5 men) with a mean age of 45.0 +/- 12.3 years (mean +/-
      SD), scheduled for arthroscopic meniscectomy (5 subjects) or endoscopic carpal
      tunnel decompression (5 subjects), were asked to apply one patch with 100 mg
      ketoprofen on the affected body site once a day during the 6 days before the
      scheduled surgery. The last patch was kept for 6 h, and removed just a few
      minutes before surgery, when venous blood was drawn. Biopsies of the synovial
      tissue of the medial compartment and of the anterior fat pad (Hoffa's tissue) or
      of the ulnar bursa were taken during knee arthroscopy or endoscopic carpal tunnel
      release, respectively. An average plasma value of 52.8 +/- 30.1 (SD) ng/ml of
      ketoprofen was obtained in the 10 patients. The tissue concentrations of
      ketoprofen in the 5 subjects undergoing knee arthroscopy were 27.9 +/- 26.1 ng/g
      (range 7.2-67.1 ng/g) in the anterior fat pad and 239.0 +/- 163.0 ng/g (range
      20.0-430.5 ng/g) in the synovial tissue. Drug concentrations up to 1000 times
      higher were found in the tendon sheath tissue of the ulnar bursa of the five
      patients undergoing endoscopic carpal tunnel release: average values of 20,107 +/
      7359 ng/g (range 13,004-32,578 ng/g) were obtained in this tissue. Data observed
      in this trial are consistent with those previously published by other authors,
      and demonstrate that ketoprofen applied on the skin is able to enter the
      subcutaneous and intra-articular tissues, reaching concentrations markedly higher
      than in plasma, and is further able to produce the desired pharmacological
      activity in situ, whereas plasma concentrations are too low to produce any
      systemic activity or side effect.

PMID- 12489254
TI  - Effects of the anti-ulcer agents ecabet sodium, cimetidine and sucralfate on
      acetylsalicylic acid-induced gastric mucosal damage deteriorated by renal failure
      in rats.
AB  - Renal failure including post-renal transplantation increases the susceptibility
      of the upper gastrointestinal mucosa to injury. The aim of this study was to
      confirm the influence of renal failure on gastric mucosal barrier and the
      protective effect of various anti-ulcer agents in rats. Renal failure (RF) was
      induced by 45-min left renal artery clamping and right-uninephrectomy. Four days
      after surgery, gastric mucosal lesions were induced by intragastric
      administration of acetylsalicylic acid (ASA, CAS 50-78-2) (100 mg/kg). Anti-ulcer
      agents were given orally 30 min before ASA administration. RF induced moderate
      gastric mucosal damages, but significantly worsened the ASA-induced gastric
      lesions. Ecabet sodium (CAS 86408-72-2) and cimetidine (CAS 51481-61-9)
      significantly inhibited ASA-induced gastric lesions in RF rats, whereas
      sucralfate (CAS 54182-58-0) tended to inhibit it. ASA and all of these anti-ulcer
      agents had no effect on the serum creatinine and blood urea nitrogen levels
      increased by RF. The gastric mucosa of RF rats is more susceptible to damage
      induced by ASA. Ecabet and cimetidine potently inhibited gastric lesions in RF
      rats suggesting its utility for the gastric mucosal damage in patients with RF
      including post-renal transplant.

PMID- 12489255
TI  - Synthesis and evaluation of anti-HIV-1 and anti-HSV-1 activities of 4H-[1,2,4]
      triazolo[1,5-a]pyrimidin-5-one derivatives.
AB  - In a one pot procedure, 18 compounds of 7-(substituted phenyl)-2-substituted-6,7
      dihydro-4H-[1,2,4]triazolo[1,5-a] pyrimidin-5-one derivatives (16-33) have been
      synthesized. 3(5)-Amino-5(3)-substituted-1,2,4-triazole derivatives (7-12) were
      used as synthomes which were cyclo-condensed by fusion with substituted methyl
      cinnamate esters (13-15) to afford the target compounds (16-33). In an effort to
      develop new non-nucleoside antiviral agents, compounds 16-33 were evaluated for
      their anti-HIV-1 and anti-HSV-1 activities. Complete inhibition of the
      proliferation of HIV-1 viruses was achieved by compounds 22, 23 and 24 at
      concentrations of 25, 25 and 50 micrograms/ml, respectively. 7-Phenyl-2-(n
      pentyl)-6,7-dihydro-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one (19) exhibited
      potential activity against HSV-1 with 88% reduction in the viral plaques. The
      suggested marked specificity of this class of compounds as anti-HIV-1 and HSV-1
      agents is discussed.

PMID- 12489256
TI  - Cytotoxic activities of some mono and bis Mannich bases derived from acetophenone
      in brine shrimp bioassay.
AB  - Some mono Mannich bases (1-phenyl-3-amino-1-propanone salts) and bis Mannich
      bases (1-phenyl-3-amino-2-amino-methyl-1-propanone salts) derived from
      acetophenone and a few representative quaternary derivatives were synthesised and
      their cytotoxicity was tested using the brine shrimp bioassay. This assay may
      serve as an intermediate test before further in vivo animal experiments in large
      scale, since brine shrimp nauplii as whole organisms were used in this test. Mono
      Mannich bases were generally more cytotoxic than their corresponding bis Mannich
      bases. Mannich bases synthesised were cytotoxic in both brine shrimp bioassay in
      this study and cell culture tests using Jurkat and Renca cells in a previous
      study. However, the order of the cytotoxic potency of the compounds were reverse,
      which may result from faster deamination of bis derivatives than optimal level,
      and different species and test media used in the two test systems. Faster
      deamination of bis derivatives might have led to elimination of active
      metabolites before reaching its target. The cytotoxicity of the compounds might
      have been altered by amino acids and proteins present in cell culture medium but
      not in sea water used in brine shrimp bioassay affecting their transport through
      the cell membrane and metabolism in the cell by binding with the compounds. With
      higher cytotoxic activity compared with 5-fluorouracil (CAS 51-21-8) in brine
      shrimp bioassay, mono Mannich base 1 and its quaternary derivative 4 and
      quaternary bis derivative 8 seem to be candidate compounds for further drug
      design.

PMID- 12489257
TI  - Mediation of the schistosomicidal effect of praziquantel through nitric oxide.
AB  - The effect of praziquantel (CAS 55268-74-1) on serum nitrate/nitrite level (a
      marker for nitric oxide (NO) synthesis) in S. mansoni infected mice was studied.
      The effects of the NO precursor (L-arginine) and NO-synthase inhibitor (NG-nitro
      L-arginine methyl ester, L-NAME) on the effect of praziquantel on nitrate/nitrite
      level as well as on its antischistosomal activity were also evaluated.
      Praziquantel increased nitrate/nitrite level in serum of infected mice in a dose
      dependent manner. An oral dose of 75 mg/kg praziquantel produces a significant (p
      < 0.05) increase in serum nitrate/nitrite level by about 3.5 fold. Administration
      of L-arginine (200 mg/kg orally) induced a significant (p < 0.05) increase in
      nitrate/nitrite level (to about 5 fold) compared to praziquantel 75 mg/kg alone.
      Praziquantel-induced increase in nitrate/nitrite level was significantly reduced
      by administration of L-NAME 100 mg/kg. The antischistosomal activity of
      praziquantel was evaluated using two models: hepatic shift model and reduction of
      worm burden. In the hepatic shift model, praziquantel increased the percentage of
      worms in the liver (from 5% in control to 60%). Praziquantel-induced hepatic
      shift was not significantly affected by concurrent L-arginine or L-NAME
      administration. In the second model, praziquantel induced a significant decrease
      of the worm burden (p < 0.05) and the action of praziquantel was significantly
      increased by L-arginine and reduced by L-NAME administration. In conclusion, NO
      is possibly involved in the antibilharzial effect of praziquantel and
      administration of L-arginine with praziquantel produces beneficial antibilharzial
      effect.

PMID- 12489258
TI  - Effects of interleukin-11 on the hematopoietic action of granulocyte colony
      stimulating factor.
AB  - Interleukin-11 (IL-11, CAS 145941-26-0) is a cytokine that ameliorates
      thrombocytopenia induced by chemotherapy. Granulocyte colony-stimulating factor
      (G-CSF) is frequently used clinically as an adjuvant therapy to ameliorate
      neutropenia. In this study, it has been investigated whether IL-11 influences the
      hematopoietic action of G-CSF in vitro. IL-11 alone did not stimulate CFU-Meg
      colony formation in the absence of interleukin-3 (IL-3), but did in the presence
      of IL-3. However, IL-11 alone stimulated the formation of CFU-E, BFU-E and CFU-GM
      colonies, which were further enhanced by IL-3. G-CSF alone stimulated in a
      concentration dependent manner colony formation of CFU-GM and CFU-E, but not BFU
      E or CFU-Meg. The addition of IL-11 enhanced the stimulatory effect of G-CSF on
      CFU-GM colony formation, and enabled G-CSF to stimulate colony formation of BFU
      E, but not CFU-E. The addition of IL-3 further enhanced the stimulatory effect of
      G-CSF on CFU-E, BFU-E, and CFU-GM colony formation. However, G-CSF was unable to
      stimulate CFU-Meg colony formation for any of the cytokine combinations tested.
      These studies demonstrate that IL-11 has significant stimulatory effects on G-CSF
      induced CFU-GM colony formation, suggesting that the therapeutic combination of
      the two growth factors could be beneficial for the treatment of myelosuppression
      induced by chemotherapy.

PMID- 12489259
TI  - Direct electrochemical oxidation of polyacrylates.
AB  - A promising elimination treatment of non-biodegradable organic pollutants is the
      direct electro-oxidation. In this work has been proposed the electrochemical
      elimination of polyacrylates by using boron-doped diamond (BDD) as anodic
      material. The complete elimination of organic contaminants has been obtained and
      this is the first case of successful electrochemical treatment of polymeric and
      bio-refractory species. The tests of the electrochemical oxidation have been
      conducted at constant current conditions and a complete elimination of organic
      species has been reached. The decrease of the COD value with time follows the
      behaviour of an ideal anode as in the case of low molecular organic compounds.

PMID- 12489260
TI  - rH-metric controls and primary standardization in aqueous-organic media.
AB  - The rationale for the extension of the rH-metric standardization and measurements
      to aqueous-organic solvent mixtures is here introduced, and examples of
      establishment of the ranges of conventional rH-metric scales as well as primary
      standards rHs in some typical aqueous-organic solvent mixtures are described.

PMID- 12489261
TI  - Surfactant effects on electrokinetic processes in clay-rich soils remediation.
AB  - The present work concerns the realisation of an equipment suitable for the choice
      of surfactants to be employed in the remediation of polluted soils by soil
      washing processes. The experimental activity has been focused to verify the
      surfactants efficiency in electrokinetic processes applied in low porosity soils,
      polluted with used vehicle oil. The equipment consents to estimate low
      electroosmotic permeabilities, electrical current and to analyse the electrolytic
      solutions. The concentration of the chemical species reached in both anodic and
      cathodic cells allows a more accurate evaluation of the ion mobility through the
      soil. The apparatus realised has been shown to be a useful instrument capable of
      providing directions for the choice of surfactants in electrokinetic soil
      remediation. The choice of an anionic surfactant for the oil removal has shown
      promising result.

PMID- 12489262
TI  - Selective electrodehalogenation of bromophenols on Ag electrocatalyst.
AB  - Among the innovative technologies for the detoxification and disposal of
      industrial effluents, our recently described electroreductive dehalogenation of
      organic halides on silver electrocatalyst provides a promising route, to be
      easily "plugged-in" into integrated waste treatments. Although electroreductions
      do not lead to total substrate mineralization, complete and selective
      dehalogenation may be achieved by the appropriate choice of the cathode material,
      thus decreasing the biotoxicity of the waste. In particular the use of silver as
      electrocatalyst greatly reduces the energy demand, and ensures higher yields and
      no by-products also when treating highly toxic aromatic halides. In the present
      work the electrocatalytic role of silver in the electroreductive dehalogenation
      process has been studied on mono- and polyhalogenated bromophenols, taken as
      model substrates, both in terms of selectivity of the reaction pathway and of
      reactivity of the position on the aromatic ring of the bromo leaving group. The
      results point to the possibility of effectively extending the methodology also to
      the more common and less reactive chlorinated derivatives.

PMID- 12489263
TI  - Sandwich liquid membrane in the separation and concentration of Cu++.
AB  - Some tests of mass transport on a sandwich liquid membrane (SwLM) for separation
      and concentration of Cu++ ion are reported and the results compared with the
      traditional supported liquid membrane (SLM) system both in terms of stability and
      flux. Moreover a chemical-physical model was developed evidencing the differences
      in the mass transport between the two systems studied. The obtained results
      showed an higher Cu++ flux in the SwLM (110.4 vs. 52.4 mmol/h.m2 referred to the
      effective pore surface) while lifetime was lower (6 vs. 15 h). The model
      evidenced a lower overall resistance to Cu++ ions transport through the SwLM than
      the SLM because the transport in the free solution did not suffer of the pores
      presence. Use of permanent hydrophilic membranes can improve the SwLM lifetime in
      view of industrial applications.

PMID- 12489264
TI  - Electrokinetic filtration in clays: theory and experiments.
AB  - The main aspects and results of some electrokinetic filtration tests are
      presented. Both theory and tests show the key role played by the electrochemical
      boundary phenomena, such as the electrode reactions, and by the mineralogy of the
      soil. The aforementioned results show the necessity to run long duration tests.
      Indeed the macroscopic properties of the soil can change widely during the tests,
      therefore affecting the expected results in terms of environmental remediation or
      consolidation but also in terms of energy consumption and efficiency.

PMID- 12489265
TI  - Electrochemical oxidation of phenol at boron-doped diamond electrode. Application
      to electro-organic synthesis and wastewater treatment.
AB  - The electrochemical behaviour of a synthetic boron-doped diamond thin film
      electrode (BDD) has been studied in acid media containing phenol using cyclic
      voltammetry and bulk electrolysis. The results have shown that in the potential
      region of water stability direct electron transfers can occur on BDD surface
      resulting in electrode fouling due to the formation of a polymeric film on its
      surface. During electrolysis in the potential region of oxygen evolution, complex
      oxidation reactions can take place due to electrogenerated hydroxyl radicals.
      Electrode fouling is inhibited under these conditions. Depending on the
      experimental conditions, the electrogenerated hydroxyl radicals can lead to the
      combustion of phenol or to the selective oxidation of phenol to benzoquinone. The
      experimental results have also been compared to a theoretical model that permits
      the prediction of the evolution with time of phenol concentration, during its
      combustion, or during its selective oxidation to benzoquinone.

PMID- 12489266
TI  - Experimental assessment of electrochemical processes in the remediation of
      atrazine contaminated soils.
AB  - The electrochemical oxidation of an atrazine solution obtained from a flushing
      treatment of a contaminated soil was investigated. The influence of ethanol on
      atrazine oxidation was studied. Results show that the electrogenerated Fenton's
      reagent provides a complete degradation of atrazine and its main chlorinated by
      products via N-dehalkylation and dechlorination. This process therefore presents
      an effective alternative to the chemical oxidation treatment which necessarily
      needs a further biological state.

PMID- 12489267
TI  - Electrochemical oxidation of p-hydroxybenzoic and protocathecuic acids at a
      dimensional stable anode (DSA) in the presence of NaCl.
AB  - This work is part of a wider research programme on innovative technologies for
      industrial wastewater treatment. Results from electrolyses at DSA commercial
      anodes of synthetic solutions with composition analogous to that of agro
      industrial wastes are presented. The results obtained indicate that the rate of
      degradation of phenolic compounds is high, provided that chloride ions are
      present in solution. Oxidation of phenolic compounds is faster than that of
      biodegradable substances, such as sugars or amminoacids. Moreover, investigation
      on the trend of toxicity during the treatment, seems to exclude that toxic
      intermediates persist in solution when phenolic compounds are removed.
      Experiments on olive oil mill wastewater (OMW) samples show that the results
      obtained from synthetic solutions are extensible to real wastewater. When
      phenolic compounds are completely removed, the toxicity of the solution is very
      low; the initial dark colour of the solution, due to the brown pigment which
      characterises OMW, is nearly completely disappeared.

PMID- 12489268
TI  - Electrocoagulation of textile wastewater bearing disperse dyes.
AB  - The paper describes a study on the removal of colour from textile wastewater
      bearing a mixture of three disperse dyes. The experiments were carried out in a
      reactor equipped with an Al sacrificial anode (100 cm2) and a stainless steel
      cathode of the same dimensions. Decolorisation occurred as a result of
      destabilisation of colloids due to an effect of an electric field generated
      between the electrodes (polarisation coagulation) and the reactions with
      coagulating compounds, formed in situ during anode oxidation (volumetric
      coagulation), followed by a subsequent flotation of agglomerates of the
      particles. During the study the following parameters were varied: initial pH of
      the solution, current density (between 100 and 300 A m-2) and an initial
      concentration of the dyes. The best results of elimination of colour, equal to
      99%, were obtained during 5 minutes of treatment under the conditions of pH of 9
      and the G factor equal to 41.

PMID- 12489269
TI  - Colorectal cancer prevention and detection. Introduction.

PMID- 12489270
TI  - Modifiable risk factors for colon cancer.
AB  - Although many mechanisms remain unclear, a large body of evidence indicates that
      several dietary and lifestyle factors are likely to have a major influence on the
      risk of colon cancer. Physical inactivity, excess body weight, and a central
      deposition of adiposity are consistent risk factors. Overconsumption of energy is
      likely to be one of the major contributors to the high rates of colon cancer in
      Western countries. Beyond their influence on energy balance, the independent role
      of specific macronutrients remain controversial. Red meat, processed meats, and
      perhaps refined carbohydrates contribute to risk. Recent evidence indicate that
      chronic hyperinsulinemia may increase risk of colon cancer. As insulin resistance
      and subsequent hyperinsulinemia is induced by excess energy intake and some
      aspects of the Western diet (e.g., saturated fats and refined carbohydrates),
      insulin may be a focus of factors influencing colon cancer risk. Recent evidence
      also points to a role of IGF-1, but our understanding of modifiable factors that
      influence levels of these is poor at present. Of note is that hyperinsulinemia
      increases free IGF-1 exposure [25]. High alcohol consumption, probably in
      combination with a diet low in some micronutrients such as folate and methionine,
      and smoking early in life are likely to increase risk of colon cancer. Recent
      epidemiologic studies have tended not to support a strong influence of fiber;
      instead, some micronutrients or phytochemicals in fiber-rich foods may be
      important. Folate is one such nutrient that has received attention lately and is
      being studied in randomized intervention trials. Agents with chemopreventive
      properties, such as aspirin and postmenopausal estrogens, have potential adverse
      effects so a careful consideration of the risk-benefit ratio is required before
      general recommendations can be made. Other NSAIDs with a potential for reduced
      toxicity, such as celecoxib, are currently being evaluated for efficacy and
      toxicity. The overwhelming evidence indicates that primary prevention of colon
      cancer is feasible. At least 70% of colon cancers may be preventable by moderate
      changes in diet and lifestyle [197]. Secondary prevention, through screening by
      sigmoidoscopy and colonoscopy, is also critically important to prevent mortality
      from colon cancer; however, many of the diet and lifestyle risk factors for colon
      cancers are the same for cardiovascular disease and for some other cancers, so
      focusing on the modifiable risk factors for colon cancer is likely to have many
      additional benefits beyond this cancer.

PMID- 12489271
TI  - Hypermethylation pathways to colorectal cancer. Implications for prevention and
      detection.
AB  - Epigenetic changes play an important role in the development and progression of
      colorectal cancer. The best characterized of these changes is the promoter region
      methylation of CpG islands of genes that play key roles in this disease. These
      changes compliment and lead to genetic changes that are well established as
      central to colorectal cancer progression. They may also prove useful in molecular
      detection approaches.

PMID- 12489272
TI  - Colorectal polyps and other precursor lesions. Need for an expanded view.
AB  - The traditional understanding of adenomas serving as precursors for a homogeneous
      group of adenocarcinomas is being assailed from all sides. Clearly, the
      relationship between precursor lesions and adenocarcinomas with defective DNA
      mismatch repair is much more complex and appears to include right-sided
      hyperplastic polyps as precursor lesions in some cases. Additional data will be
      forthcoming regarding this risk of adenocarcinoma development in right-sided
      hyperplastic polyps, both through defective DNA mismatch repair and methylation
      of the MGMT gene. This will likely be accompanied by an attempt to reclassify at
      least some larger hyperplastic polyps as serrated adenomas either on subtle
      morphologic or molecular grounds.

PMID- 12489273
TI  - Chemoprevention of colorectal cancer: problems, progress, and prospects.
AB  - Chemoprevention holds great promise as a complement to traditional CRC screening
      and treatment. Effective chemopreventive agents might improve patient outcomes by
      reducing the number of missed lesions, the morbidity associated with their
      identification and treatment, and their malignant potential. In addition,
      chemoprevention may reduce neoplastic potential simultaneously in several organs
      and improve clinical outcomes for persons at risk for cancers at multiple sites
      (e.g., colorectal and extracolonic cancers in HNPCC cohorts). Complex molecular
      circuits underlie the disease mosaic that is associated with aging. Several of
      these diseases share common mechanisms against which preventive interventions
      appear to be effective, such as NSAIDs for colorectal neoplasia and
      neurodegenerative disease, and statins for cardiovascular disease and colorectal
      neoplasia. Understanding these mechanisms and effects could raise prevention
      science to an entirely new level. The number of trials that are investigating
      chemopreventives against CR neoplasia is relatively small; if these agents live
      up to a fraction of their promise, the public health impact may be great (see
      Table 6).

PMID- 12489274
TI  - Immunoprevention of colorectal cancer: a future possibility?
AB  - Immunoprevention of colorectal cancer remains a largely untested possibility. The
      success demonstrated by immunopreventive approaches in mammary carcinoma suggest
      that this new cancer preventive modality should be investigated for other types
      of cancer. The design of a successful strategy for colorectal cancer will have to
      incorporate general concepts that have already been developed for dealing with
      other tumors, and intestine-specific immunologic strategies.

PMID- 12489275
TI  - Flexible sigmoidoscopy for colorectal cancer screening: valid approach or short
      sighted?
AB  - Flexible sigmoidoscopy is a safe, effective test that may be delivered feasibly
      on a large scale for mass colorectal cancer screening. Flexible sigmoidoscopy is
      67% to 80% as sensitive as colonoscopy in a screening population, but is probably
      10 to 20 times safer than colonoscopy in terms of complications. Several national
      guidelines recommend combining flexible sigmoidoscopy with fecal occult blood
      tests. There is limited evidence to support this practice, and the added benefit
      to an existing flexible sigmoidoscopy screening program although real, may be
      marginal. In the future, it is likely that flexible sigmoidoscopy screening among
      patients aged 50 to 65 will be supplemented with total colonic screening, using
      molecular-based fecal tests or virtual colonoscopy, after age 65.

PMID- 12489276
TI  - Screening colonoscopy in balance. Issues of implementation.
AB  - Although colonoscopy is currently considered an option for colon cancer
      screening, its choice as a preferred screening test is not supported by data,
      recommendations, or cost-effectiveness analysis. The use of colonoscopy in
      postpolypectomy surveillance constitutes a huge potential effort that should be
      appropriately anticipated and managed. Noninvasive methods for colon cancer
      screening may reduce the need for colonoscopy in the future.

PMID- 12489277
TI  - The future of colorectal imaging: computed tomographic colonography.
AB  - The development of colorectal cancer screening alternatives that are attractive
      to patients and effective for screening is critical for reducing this too-common
      and deadly disease. CTC is an exciting technique that is the only imaging
      alternative developed since the barium enema for colon screening. In the past few
      years, many obstacles to clinical implementation of CTC have been eliminated. For
      example, there is no longer any post-processing time, which was previously as
      long as 8 to 10 hours, and the interpretation time has been drastically reduced
      from 4 hours to 15 to 20 minutes. The majority of studies have demonstrated
      excellent results for detection of lesions > or = 1 cm, with few false positives.
      This examination will continue to improve with the development of automated
      (computer) detection programs and automated 3D rendering algorithms. In addition,
      cathartic bowel preparation, one of the biggest obstacles to patient compliance
      with colorectal cancer screening, may be eliminated if successful fecal tagging
      can be developed. The most important issue that remains is its performance in a
      screening population, and studies are currently underway to answer that important
      question.

PMID- 12489278
TI  - Barriers to preventive intervention.
AB  - A spectrum of colorectal cancer screening studies identified barriers to
      screening adherence, although definitive and comprehensive conclusions cannot be
      drawn. Barriers can be intrinsic (demographic, medical, psychological, and
      knowledge/attitudes/beliefs) or extrinsic (access to health care, health care
      provider knowledge and motivation, and lifestyle issues). Certain consistent
      patterns are emerging. Lower adherence is generally seen in persons who have less
      knowledge and lower perceived risk of colorectal cancer, as well as when health
      care providers do not recommend screening. Remedies that reduce intrinsic and
      extrinsic barriers to screening adherence are needed.

PMID- 12489279
TI  - Cost-effectiveness in the prevention of colorectal cancer.
AB  - In cost-effectiveness analyses of cancer prevention, the ratio of cost and
      medical effectiveness serves as the primary measure for comparing various
      strategies, effectiveness being measured in terms of (quality adjusted) life
      years gained through medical intervention. Such analyses are reliable in
      comparing different medical management strategies and revealing the most
      important factors to influence their cost-effectiveness ratios, but less helpful
      in judging the general merit of a given medical strategy. Models of medical
      decision making are used to simulate the natural history of colorectal cancer and
      test how it becomes affected by various means of screening and prevention. The
      analyses suggest that, compared with no prevention, a single colonoscopy at age
      65 is the most cost-effective means of cancer prevention in the general
      population, followed by screening colonoscopy every ten years or screening
      colonoscopy every ten years plus chemoprevention with daily aspirin. Other means
      of prevention, involving annual fecal occult blood testing or flexible
      sigmoidoscopy every 5-10 years, are dominated by cheaper and more effective
      strategies. Economic and decision models do not obviate the primacy of clinical
      data gathered through controlled clinical trials, since they cannot account for
      all factors that may eventually determine the cost-effectiveness of actual
      screening and cancer prevention.

PMID- 12489280
TI  - Endoscopic ultrasound for rectal cancer.
AB  - The application of EUS has improved the way we evaluate and manage patients with
      rectal cancer. EUS has substantially greater sensitivity than CT in detecting
      advanced T stage tumors. Such improved sensitivity results in changes in
      preoperative therapy that would not otherwise have occurred without EUS. Although
      the addition of FNA provides little incremental effect on patient management, it
      carries the most potential for impacting management in those patients with early
      T stage disease, and its use should be considered in this subgroup of patients.
      Whether the accurate staging ability of EUS translates into improved outcomes in
      terms of reduced recurrence rates and ultimately prolonged survival remains
      uncertain. This will require further long-term outcome studies focusing on the
      endpoint of tumor recurrence and patient survival.

PMID- 12489281
TI  - Heritable colorectal cancer syndromes: recognition and preventive management.
AB  - Familial CRC syndromes account for a small yet important portion of colorectal
      malignancies. HNPCC, FAP, JPS, and Peutz-Jeghers syndrome are the four major
      conditions to r to consider if an hereditary condition is suspected in an
      individual with CRC. A multidisciplinary team comprised of a medical geneticist,
      gastroenterologist, pathologist, radiologist, and colorectal surgeon with
      expertise in recognizing and establishing the diagnosis of a specific familial
      cancer condition is crucial to implementing the proper management and prevention
      strategies unique to each of these syndromes. Genetic testing for each of these
      coniditions is available and useful for presymptomatic diagnosis and for
      indicated surveillance regimens. Vigilant endoscopic surveillance and careful
      timing of surgery are the mainstays of prevention for gastrointestinal
      malignancies. But with the advancement of genetic evaluation, improved cancer
      surveillance for intestinal as well as extraintestinal cancer, and
      chemopreventive strategies, the management of patients with  a familial CRC
      syndrome will continue to evolve and, hopefully, significantly reduce their
      cancer burden.

PMID- 12489282
TI  - Cancer prevention in patients with inflammatory bowel disease.
AB  - Colorectal cancer is an important, and often dreaded, consequence of long
      standing UC and Crohn's colitis. Surveillance colonoscopy, despite its
      limitations, is beneficial for detecting earlier stage cancers and, probably,
      mortality reduction. Agents such as anti-inflammatory medications, folic acid,
      and ursodeoxycholic acid show promise for chemoprevention in this disease. Future
      research will help to define better the natural history of dysplasia in IBD, and
      to determine how molecular approaches may be integrated into surveillance
      programs to reduce CRC risk.

PMID- 12489283
TI  - Evolving microbes and re-emerging streptococcal disease.
AB  - Microbes will evolve and the epidemics they cause will continue to occur in the
      future as they have in the past. Microbes emerge from the evolutionary stream as
      a result of genetic events and selective pressures that favor new over old. It is
      nature's way. Microbes and vectors swim in the evolutionary stream, and they swim
      much faster than humans. Bacteria reproduce every 30 minutes and, for them, a
      millennium is compressed into a fortnight. They are "fleet afoot," and the pace
      of research must keep up with them or they will overtake. Microbes were here on
      Earth 2 billion years before humans arrived, learning every trick of the trade
      for survival, and they are likely to be here 2 billion years after we depart.
      Current research on the rise and decline of epidemics is broadly based and
      includes evolutionary and population genetics of host-microbe relationships.
      Within this context, the 19th century pandemic of scarlet fever has been
      described. The possibility is raised that the GAS, which currently cause STSS,
      possess some of the virulence factors that caused pandemic scarlet fever.
      Furthermore, the GAS isolated during the recent outbreaks of ARF in certain
      locales in the United States have the virulence properties of the GAS frequently
      isolated in the first half of the 20th century. Finally, it is suggested that the
      strategy to confront emerging infectious diseases should be the study of
      infectious diseases from all points of view. They remain the greatest threats to
      our society.

PMID- 12489284
TI  - Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy.
AB  - Strong epidemiologic and laboratory evidence indicate that a novel, variant form
      of Creutzfeldt-Jakob disease (vCJD) first reported in the United Kingdom in 1996
      is causally linked with bovine spongiform encephalopathy (BSE). BSE was first
      identified in the early 1980s in the United Kingdom, and has since spread to
      other European countries and recently to Japan and Israel. Although the United
      Kingdom BSE epizootic is on the decline, widespread exposure of humans to
      infected cattle products may have already occurred, raising concerns about the
      ultimate magnitude of the vCJD outbreak which, as of October 2002, has already
      affected 138 patients worldwide, including 128 patients in the United Kingdom.

PMID- 12489285
TI  - Influenza.
AB  - Influenza remains an important cause of morbidity and mortality in the United
      States. Although signs and symptoms of individual influenza cases are
      nonspecific, the epidemiology is characteristic, and a clinical diagnosis can be
      made accurately during epidemics. Several tests can be used to confirm influenza
      infection. Antiviral medications may be used for both treatment and prophylaxis,
      but prevention of influenza is most reliably achieved through vaccination.

PMID- 12489286
TI  - Human herpesvirus 8, Kaposi's sarcoma, and associated conditions.
AB  - HHV-8 is a recently identified human herpes virus that can produce tumors, most
      often in immune compromised hosts. The virus is most closely associated with
      Kaposi's sarcoma, but is also clearly associated with primary effusion lymphomas
      and multicentric Castleman's disease. The prevalence of HHV-8 infection varies
      considerably, but is highest among men who have sex with men and others with
      histories of sexually transmitted diseases and high numbers of lifetime sexual
      partners. HHV-8 is shed in saliva, and less commonly in genital secretions.
      Treatment of HHV-8 associated diseases includes reversal of immune compromise
      either via discontinuation of immunosuppressives or immune reconstitution via
      antiretroviral regimens. Specific antiviral drug inhibit HHV-8 replication, and
      can result in responses in certain HHV-8-associated conditions.

PMID- 12489287
TI  - Diagnosis of nontuberculous mycobacterial infections.
AB  - This section discusses the methods of laboratory diagnosis of nontuberculous
      mycobacteria (NTM) using conventional biochemical and nutritional requirements,
      acid-fast smear microscopy, high performance liquid chromatography (HPLC),
      antibiotic susceptibility testing, and newer genetic methods such as molecular
      probes, polymerase chain reaction restriction fragment length polymorphism
      analysis (PRA), and 16S rDNA sequence analysis. This article discusses how
      laboratory results are applied by clinicians, and some of the difficulties and
      controversies regarding the diagnosis of NTM disease after the laboratory work is
      complete.

PMID- 12489288
TI  - Cyclospora cayetanesis.
AB  - The novelty of C cayetanensis has led to some misconceptions about how best to
      detect its presence in stool examinations. Some reports have implied that the
      organism can only be seen on stained specimens, which is not true. The unstained
      organism can easily be identified by its characteristic size and internal
      structures. However, not doing a concentration procedure can reduce the chances
      of detecting C cayentanensis by up to 40%. Finally, there have been false
      positive reports of C cayetanensis when stained artifacts were mistaken for the
      real organism. The best way to become comfortable with the laboratory diagnosis
      of C cayentanensis is to obtain some known positive samples and practice
      identifying the oocysts using a variety of methods. The clinical syndrome
      associated with C cayentanensis is recognizable. The patient will usually have
      prominent anorexia, fatigue, nausea, and gas. Diarrhea, after the initial severe
      bout, is often intermittent, and submitted specimens may be formed despite a
      persistent feeling of being unwell.

PMID- 12489289
TI  - Laboratory diagnosis of Bartonella infections.
AB  - Bartonella species are pathogens of emerging and reemerging significance, causing
      a wide array of clinical syndromes. In North America and Europe, they are
      increasingly recognized as a cause of culture negative endocarditis,
      neuroretinitis, and disease among homeless, HIV-infected, and other
      immunosuppressed individuals. In South America, bartonellosis continues to plague
      those in endemic regions and poses a significant threat to travelers in these
      areas. As the clinician is increasingly faced with these illnesses, which may be
      difficult to diagnose, laboratory techniques to confirm or refute the diagnosis
      are becoming increasingly important. Culture methods have improved over the past
      decade demonstrating increased sensitivity, but still require prolonged periods
      before isolation of the organism. Specimen handling, media selection, and growth
      conditions all may affect results and must be optimized in order to provide the
      highest likelihood of recovering the organism. Pure culture of the bacteria not
      only provides morphologic information, but also provides material for further
      diagnostic testing. Work with liquid media, which may provide a more rapid means
      of cultivation has shown some promise and should continue to be pursued. Improved
      blood culture techniques were a primary factor in the discovery of Bartonella
      endocarditis and continued improvements will likely demonstrate further clinical
      insights. Serologic testing for B henselae infections has become the cornerstone
      of clinical diagnosis, replacing the skin test that was poorly standardized and
      posed a potential risk to the patient. Immunofluorescence assays have been well
      characterized and validated in clinical trials, however they are not universally
      available. Vero cell cocultivated antigens appear to provide higher sensitivity
      and specificity when compared with agar-derived antigens. IFA assays are
      inherently difficult to perform, requiring significant expertise to provide
      reproducible results. On the contrary, enzyme immunoassays offer ease of use and
      a high level of reproducibility, however ideal antigens for use in the diagnosis
      of Bartonella infections have not been clearly identified. Continued work to
      define antigenic targets of the human response to infection and incorporation of
      these into a widely available EIA will provide a cost-effective tool for the
      clinician and epidemiologist alike. Due to the close phylogenetic relationship of
      B henselae and B quintana, differentiation between these species by serologic
      means may prove difficult. Molecular techniques including PCR offer high
      sensitivity and specificity, rapid availability of information, and the ability
      to differentiate Bartonella organisms at the highest level. Results of studies to
      date are promising and as methods are refined it will be important to conduct
      clinical studies to define the role of these assays. In disseminated Bartonella
      infections such as bacillary angiomatosis, peliosis, endocarditis, and urban
      trench fever, PCR currently offers the ability to establish the diagnosis when
      other tests may be unrevealing. For CSD, this technique should be used as a
      confirmatory technique when the diagnosis is unclear by other means. PCR analysis
      of blood specimens offers a minimally invasive approach to diagnosis, but
      clinical data are scarce and further studies are needed. As DNA microarrays move
      into the clinical arena, specific hybridization probes may allow improved
      identification and differentiation of Bartonellae at the molecular level.

PMID- 12489290
TI  - Progress in the development of a preventive HIV-1 vaccine.
AB  - Control of human immunodeficiency virus type-1 (HIV-1) infection is the foremost
      public health challenge at the turn of the millennium. Two decades, 22 million
      fatalities, and 40 million living victims after its discovery, HIV-1 continues
      its inexorable spread. Over the past few years, scientists have made tremendous
      progress in understanding the immunopathogenesis of HIV-1 infection and
      identifying potential targets for intervention with vaccines. Future progress
      will require a coordinated and proactive response to foster understanding of the
      benefits of vaccines and to encourage a receptive atmosphere for community
      vaccine testing and implementation.

PMID- 12489291
TI  - Viral hemorrhagic fevers including hantavirus pulmonary syndrome in the Americas.
AB  - The term viral hemorrhagic fever refers to an acute systemic illness with a
      propensity for bleeding and shock. The viral hemorrhagic fevers endemic in the
      Americas include yellow fever, dengue hemorrhagic fever, the South American
      hemorrhagic fevers, hantavirus pulmonary syndrome, and hemorrhagic fever with
      renal syndrome. Because these diseases are primarily zoonotic, the distribution
      of any given virus is generally restricted by the distribution of its natural
      reservoir or arthropod vector. A high index of suspicion, detailed investigation
      of the travel and exposure history of the patient, and a basic understanding of
      the incubation periods and distributions of the various reservoirs of hemorrhagic
      fever viruses are imperative, as are prompt notification and laboratory
      confirmation. Clinical management is largely supportive, with a special emphasis
      on safe nursing practices to prevent nosocomial transmission.

PMID- 12489292
TI  - Scientific basis of laser energy.
AB  - Lasers are intense beams of energy generated through the stimulation of
      radiation. Their clinical appeal in arthroscopic applications is based on their
      preferential absorption by water-containing tissues. Laser-tissue interaction
      includes reflection, scattering, transmission, and absorption. Clinical effects
      occur through tissue heating by absorption of laser energy. When power density is
      sufficient to achieve the ablation threshold, vaporization of tissue results with
      minimal collateral thermal damage. Further developments in the field of laser
      medicine may provide us with arthroscopic tools of even greater precision and
      safety.

PMID- 12489293
TI  - Electrothermal assisted shoulder capsulorraphy--monopolar.
AB  - Monopolar electrothermal stabilization of the shoulder shows considerable promise
      as a treatment alternative in athletes and patients with recurrent instability.
      Range of motion is preserved, recovery is faster than with open procedures, there
      is little disruption or alteration of inherent anatomy, and, most importantly,
      results at 2 years appear comparable to other surgical procedures in high-demand
      populations. The procedure is technically easy to perform, and the complication
      rate is low. Success depends on surgeon's understanding of the applications of RF
      energy, the use of proper surgical technique, careful patient selection,
      attention to the rehabilitation program, and the patient's compliance with
      postoperative protocol. Long-term follow-up is necessary to determine if results
      for this procedure deteriorate over time, especially in patients with
      multidirectional instability.

PMID- 12489294
TI  - The basic science of thermally assisted chondroplasty.
AB  - Thermal chondroplasty provides a visually enticing effect on articular cartilage,
      but the long-term effects of thermal modification and injury to articular
      cartilage must be understood before the technology is applied to cartilage and
      chondrocytes in a clinical setting.

PMID- 12489295
TI  - Histologic analysis of radiofrequency energy chondroplasty.
AB  - Two types of radiofrequency energy are currently used for chondroplasty: thermal
      and ablative. The primary mode of operation for monopolar radiofrequency energy
      is thermal, whereas the primary mode for bipolar radiofrequency energy is
      ablation. The safety of radiofrequency energy in articular cartilage is
      investigated because these treatment modalities can result in injury of target
      and surrounding tissues. Histologic analysis is used to assess this degree of
      damages and the efficacy of these techniques, but the accuracy and relevance of
      the results are affected by the design and duration of the analysis. A review of
      recent studies using different methods of histologic analysis of articular
      cartilage subject to radiofrequency energy techniques is presented.

PMID- 12489296
TI  - Electrothermal chondroplasty--monopolar.
AB  - Despite the lack of clinical studies, monopolar RF energy is currently used for
      the treatment of grade 2, 3, and 4 chondromalacia. Basic science studies have
      confirmed that monopolar RF can mechanically debride the articular surface by
      smoothing, potentially reducing further delamination. However, a zone of thermal
      injury in the areas of treatment has been observed with loss of chondrocyte
      viability. Therefore, further use of this procedure lies in the surgeon's
      understanding of the potential deleterious effects of temperature on chondrocyte
      viability and the limitations of alternate treatment options. Monopolar RF energy
      is a potential alternative to other cartilage removal or smoothing techniques,
      but more science is needed to define optimal parameters for thermal
      chondroplasty. Great care is currently proposed in the selection of operative
      parameters by clinicians when using monopolar RF chondroplasty until safety and
      efficacy are confirmed.

PMID- 12489297
TI  - Electrothermal chondroplasty--bipolar.
AB  - The use of bRF for the debridement of degenerative AC appears safe and at least
      as effective as mechanical debridement. The benefit of a residual smooth surface,
      improved surgical access, and minimal collateral damage makes its use on AC
      attractive. As with any surgical cutting device, improper use, such as prolonged
      exposure on AC, may cause significant damage. Much research still needs to be
      done, especially with regards to ideal power setting and the mechanical
      alterations to AC that occur as a result of its use.

PMID- 12489298
TI  - Laser-assisted chondroplasty.
AB  - Laser-assisted chondroplasty is a controversial issue in arthroscopy. Some
      preliminary research has demonstrated that laser energy can stimulate DNA
      synthesis and matrix production in articular cartilage. Other studies cite the
      dangers of thermal energy with laser use on articular cartilage. Commonly used
      lasers and their current research are discussed in this chapter. It is unclear
      whether or not the laser will remain in the arthroscopists' arsenal for
      chondroplasty, and further research is warranted.

PMID- 12489299
TI  - Anterior cruciate ligament thermal shrinkage.
AB  - Heat has been used as a therapeutic form of treatment in the field of medicine
      since ancient times. Electrothermal energy delivered by radiofrequency has the
      advantages of being able to be used by even the casual arthroscopist and being
      relatively inexpensive. One of the expanded uses is treating ligament laxity,
      including the anterior cruciate.

PMID- 12489300
TI  - Thermal treatment of anterior cruciate ligament injury and laxity with its
      imaging characteristics.
AB  - The use of radiofrequency or laser to treat lax anterior cruciate ligaments is at
      its infancy. The imaging results of such treated ligaments using MRI are
      undocumented in the literature. This article reviews the basic science behind
      thermal treatment of ligaments and previously published and unpublished data on
      this therapy and its imaging implications.

PMID- 12489301
TI  - The use of thermal energy in ankle instability.
AB  - With appropriate indications, ankle arthroscopy can be of significant benefit to
      both the patient and physician. The additional use of thermal energy
      significantly enhances surgical techniques. Midterm follow-up of thermal
      treatment of ankle instability demonstrates excellent patient satisfaction, with
      preserved stability, good overall function, and return to sports. Further long
      term follow-up studies will continue to provide us with data that will help guide
      the expansion of uses of thermal energy about the ankle in a safe and efficacious
      manner.

PMID- 12489302
TI  - Thermal energy in arthroscopic surgery of the wrist.
AB  - Thermal energy in arthroscopic surgery needs further follow-up evaluation to
      clarify the potential benefits, specifically with respect to thermal shrinkage.
      Although the initial findings are promising, the long-term results need to be
      compared with other accepted standards of management. Preliminary findings seem
      to show that the addition of these surgical instruments and expanding operative
      techniques have definite roles in arthroscopic wrist surgery, as demonstrated
      through meticulous synovectomies and precise tissue debridement, along with the
      possible thermal shrinkage potential.

PMID- 12489303
TI  - Complications of thermal energy in knee surgery--Part I.
AB  - The use of thermal energy in knee surgery has many potentially exciting and
      useful applications. There is a growing body of literature that demonstrates the
      effects of these energy probes on different types of tissue. When contemplating
      the use of these surgical interventions in patients, it is important to recognize
      the potential limitations and complications that may arise.

PMID- 12489304
TI  - Complications of thermal energy in knee surgery--Part II.
AB  - With the theoretical and reported complications of thermal energy use in the
      knee, an analysis of potential risks and benefits should be done on a case-by
      case basis. Many of the basic science studies may not be directly applicable to
      clinical practice because they use normal (i.e., not diseased) tissues in animal
      models. Clinical studies are also dependent on surgical technique and equipment
      settings. With the benefits listed previously, however, it is likely that thermal
      energy will continue to play an important role in arthroscopic orthopedic
      surgery, and there are studies that strongly support its safety and efficacy.
      Janecki performed a retrospective review of 504 laser chondroplasties to
      determine safe parameters for Ho:YAG laser use in the knee [10]. In their series,
      they found an 88% patient satisfaction rate, no significant changes in the
      articular cartilage lesions in the failure group who underwent repeat
      arthroscopy, and no new cases of osteonecrosis. They concluded that the Ho:YAG
      laser was safe and recommended energy settings of less than or equal to 1 joule
      when performing chondroplasties, noncontact and tangential delivery of the laser
      beam, and maximizing laser spot size as methods for further decreasing
      complication rates. We agree with the above recommendations and with using the
      minimal power settings required to afford the desired surgical result. More
      studies are required to fully define the indications and consequences of thermal
      energy use in the knee.

PMID- 12489305
TI  - Future trends in thermal energy.
AB  - Current research is focusing on the parameters that affect tissue response to
      thermal energy. A clearer understanding of the interaction between thermal
      delivery systems, technique, and tissue response will allow for advancement. The
      future use of thermal energy in orthopedics depends on continued basic science
      and clinical research to ensure safe and efficacious results.

PMID- 12489306
TI  - Thermal capsular shrinkage in the throwing athlete.
AB  - The role of thermal capsular shrinkage in treating various forms of pathology
      continues to evolve. The addition of thermal capsular shrinkage to the treatment
      regimen of standard pathologies in the thrower's shoulder has increased the rate
      of return to play even at the highest levels. Our data indicate an approximate
      20% improvement in the rate of return to play with the addition of thermal
      capsular shrinkage to traditional treatments. These data represent relatively
      short-term follow-up. Longer duration of follow-up and increased numbers of
      patients will further enable us to make recommendations regarding the future use
      of this technology. As our understanding of the pathology that occurs in the
      thrower's shoulder continues to improve, so too will our understanding of the
      effect of applying thermal energy to the joint capsule.

PMID- 12489307
TI  - Maladaptive personality functioning within the big five and the five-factor
      model.
AB  - The five-factor model (FFM) of general personality functioning was derived
      originally from lexical studies of trait terms within the English language. Many
      studies have been conducted on the relationship of the FFM to personality
      disorder symptomatology but, as yet, no lexical study of the representation of
      maladaptive personality functioning within a language has been conducted. The
      current study identified the distribution of socially undesirable trait terms
      within each of the poles of the Big Five and compared this distribution to
      findings obtained with FFM personality disorder measures. The implications of the
      results for a FFM of personality disorders and for the FFM assessment of
      maladaptive personality functioning are discussed.

PMID- 12489308
TI  - A comparative study of the dimensions and facets of the five-factor model in the
      diagnosis of cases of personality disorder.
AB  - Two national samples of psychologists (n = 92, n = 89) rated personality disorder
      cases using either the five factors (domains) or the 30 facets of the five-factor
      model (FFM) to examine reliability and clinical utility of the model when used as
      a diagnostic tool. The cases were prototypic and nonprototypic cases representing
      the three clusters of personality disorders in the DSM-IV. Although confidence
      was higher using the factors rather than the facets to rate the cases, interrater
      reliability was similar and the facets were rated more useful for professional
      communication, case conceptualization, and treatment. Mean ratings for the
      prototypic cases supported the theorized relationships between those personality
      disorders and the FFM. Principal components factor analysis of the facet ratings
      largely replicated the structure of the FFM with only a few facets failing to
      load with their superordinate dimension in the model. Implications for use of the
      FFM with personality disorder are discussed.

PMID- 12489309
TI  - Dependency, impulsivity, and self-harm: traits hypothesized to underlie the
      association between cluster B personality and substance use disorders.
AB  - Cluster B personality disorders (PDs) (i.e., antisocial, borderline, histrionic,
      and narcissistic) typically show a high degree of comorbidity with substance use
      disorders (SUDs). Previous research suggests that the broad-based personality
      domains of Disinhibition and Negative Temperament/Neuroticism may be common
      factors to both types of disorders. Using a two-phase process (i.e., screening
      and follow-up), this study examined three lower-order personality traits (i.e.,
      dependency, impulsivity, and self-harm) that fall within the Disinhibition and
      Neuroticism domains. The study evaluated the hypotheses that these traits (a) are
      related both to cluster B PDs and to SUDs; and (b) underlie the association
      between the two types of disorders. Results indicate that impulsivity and self
      harm play a significant role in cluster B PDs and SUDs, as well as in their
      association with each other. However, dependency was not associated with either
      type of disorder. These results indicate that sets of individual traits can be of
      significant utility in understanding the comorbidity between PDs and SUDs.

PMID- 12489310
TI  - Impaired social functioning and symptoms of personality disorders assessed by
      peer and self-report in a nonclinical population.
AB  - Data regarding the connection between personality disorders (PDs) and impaired
      social functioning are often difficult to interpret because both sets of
      variables are influenced by depressed mood and both are usually assessed using
      self-report instruments. We studied PD symptoms in a nonclinical population and
      examined whether these symptoms are associated with social dysfunction, after
      controlling for current mental state. Participants were 577 undergraduate
      students who completed self-report measures of social functioning, PD symptoms,
      depression, and anxiety, as well as a peer-report PD inventory. As expected, self
      reported PD scores and social dysfunction were both correlated with current
      levels of anxiety and depression. Both self- and peer-reported PD symptoms
      contributed to the prediction of level of social functioning above and beyond the
      influence of depressed mood. Overall, our results complement those from clinical
      samples and provide further evidence that there is an association between PD
      traits and impaired social functioning.

PMID- 12489311
TI  - MCMI-II profiles of women with eating disorders: a cluster analytic
      investigation.
AB  - A three-factor model of personality pathology was investigated in a clinical
      sample of 183 female patients in an outpatient eating disorders treatment
      program. Cluster analysis of MCMI-II personality scales (Millon, 1987) yielded
      three distinct personality profiles, which were consistent with previous studies.
      First, 16.9% of the sample comprised a High Functioning cluster, which manifested
      no clinical elevations on the MCMI-II and had significantly lower scores on the
      Eating Disorder Inventory (EDI; Garner; 1991) scales than the other two clusters.
      Second, 49.1% of the sample comprised an Undercontrolled/Dysregulated cluster.
      Finally, the remaining 34% of the sample comprised an Overcontrolled/Avoidant
      cluster. This final cluster had significantly higher EDI Ineffectiveness scale
      scores than the Undercontrolled/Dysregulated cluster group. Cluster membership
      was not associated with eating disorder subtype, suggesting that there is
      considerable variance in personality pathology within eating disorder diagnostic
      categories.

PMID- 12489313
TI  - The structure of traits delineating personality disorder in a Chinese sample.
AB  - The present study examined the factorial structure of a Chinese language version
      of the self-report Dimensional Assessment of Personality Pathology Questionnaire
      in 581 adults. Four factors were extracted (Emotional Dysregulation, Dissocial,
      Inhibition, and Compulsivity) that are similar to the factors extracted in the
      scales' normative clinical and general population samples from North America
      (factor comparability coefficients range from .88 to .96), supporting the idea
      that this trait structure is invariant across diverse populations. The internal
      consistency of the scales (Cronbach's alpha) was satisfactory across age and
      gender groups with the exception of the Intimacy Problems scale. Possible
      explanations for the poor internal consistency of the Intimacy Problems scale,
      such as cultural differences in social factors influencing marital and romantic
      relationships in Chinese populations, as opposed to other populations are
      discussed.

PMID- 12489312
TI  - Gender role and personality disorders.
AB  - Many researchers have hypothesized relationships between personality disorders
      and gender role (i.e., masculinity and femininity). However, research has not
      addressed if people who are masculine or feminine more often meet the criteria
      for personality disorders. The present study examined whether college students (N
      = 665, 60% women) higher in masculinity or femininity more often exhibited
      features of the 10 DSM-IV personality disorders. Feminine men exhibited more
      features of all the personality disorders except antisocial. Dependent traits
      were associated with higher femininity and lower masculinity. Antisocial traits
      were associated with masculinity. Both men and women who typically behaved
      consistent with their gender had more narcissistic and histrionic features,
      whereas participants who typically behaved unlike their gender had more features
      of the Cluster A personality disorders.

PMID- 12489315
TI  - [Antibiotics, controlling misuse].

PMID- 12489314
TI  - [Awareness of the influence of progestin contraceptives on bone mineral content].

PMID- 12489316
TI  - [Suspicious pigmented skin lesions. Screening campaign by occupational physicians
      in the Provence-Alpes-Cote d'Azur region].
AB  - OBJECTIVE: Cutaneous melanoma prevention has become a public health issue. The
      incidence of this cancer has been steadily growing for 50 years, and the related
      death ratio is not decreasing. Today, the surgical resection of a thin lesion is
      the only validated curative treatment. The early detection of melanoma represents
      a major line in the management of such tumours. METHODS: Occupational physicians
      of the PACA area were invited to participate in a campaign for the screening of
      pigmented suspect cutaneous lesions for 2 years. Voluntary physicians were
      trained to use the ABCDEF diagnostic criterion. Lesions were detected during
      regular yearly consultations (1998/1999) and the data concerning the development
      and care of these lesions was collected during consultations over the following
      year (1999/2000). RESULTS: Two hundred and fifty occupational physicians of the
      PACA area participated in the campaign. Two pre-cancerous lesions and 10 cancers
      (5 melanoma and 5 pigmented basocellular carcinoma) were found among the 487
      suspect lesions detected. Each melanoma had a Breslow score of less than 0.9 mm
      and were of good or even excellent prognosis. CONCLUSION: The cutaneous
      examination, although rapid, during the occupational medicine consultations, is
      an effective means of detecting the early onset tumoral lesions which, at that
      stage may potentially be cured. The ABCDEF criterion is a useful diagnostic tool
      and should be taught to the all the medical and paramedical staff.

PMID- 12489317
TI  - [Primary acute disseminated encephalomyelitis in the adult. Study of 6 year
      follow-up of 2 patients].
AB  - INTRODUCTION: The relationship between acute disseminated encephalomyelitis
      (ADEM), a monophasic disease, and multiple sclerosis (MS), a potentially
      progressive disease with periods of recurrence or remission, remains debatable.
      In a large number of patients, the diagnosis initially retained is that of ADEM,
      whilst the progression is subsequently towards a defined MS. This has incited
      some authors to consider that there is a continuum between these two diseases and
      to underline the frailty of the criteria retained for the diagnosis of ADEM.
      Further interest has presently been paid to this subject and the question of
      whether a basic treatment of MS should be started after the first episode has
      been raised, although such a treatment is obviously not justified if the
      diagnosis retained is an ADEM. OBJECTIVES: Two cases observed in adults, followed
      up for 6 years, contribute to the validation of a number of clinical, biological
      and radiological arguments which are all in favor of the diagnosis of ADEM versus
      that of an initial episode of MS. CLINICAL ARGUMENTS: These are the absence of
      any neurological past history, the existence of a multi-focal neurological
      symptomatology right from the start and, particularly in children, the presence
      of a meningeal syndrome. BIOLOGICAL ARGUMENTS: Presence in the cephalo-spinal
      liquid, of an increase in cells and cervicospinal proteins to levels not usually
      found in MS. RADIOLOGICAL ARGUMENTS: MRI reveals multi-focal, extensive and
      bilateral lesions, beneath the cortex rather than peri-ventricular, which may
      extensively involve the thalamus and the bone marrow; these lesions are of the
      same age and often regress.

PMID- 12489318
TI  - [Peripheral facial paralysis in a patient infected with HTLV-1 virus. 2 case
      reports].
AB  - INTRODUCTION: Facial nerve palsy is a frequent situation of varying etiology and
      the former concept of frozen facial nerves is progressively being abandoned. The
      HTLV-1 virus, endemic to some tropical areas, is one of the most recent causes
      discovered. OBSERVATIONS: We present two HTLV-1 seropositive patients of
      Caribbean origin who developed facial palsy and several complications related to
      this retrovirus. COMMENTS: When confronted with facial palsy, the presence of
      risk factors for HTLV-1 infection (particularly when native in high
      seroprevalence areas) must lead to serological examinations in the search for
      this retrovirus.

PMID- 12489319
TI  - [Gonadal deficiency in relation to age, also in men].

PMID- 12489320
TI  - [Andropause and its management in the aged male].
AB  - THE "ANDROPAUSE": Also called the "male menopause" or "partial androgen
      deficiency of the aging male" etc., corresponds to the age at which the
      progressive decrease in androgen activity reaches a pathogenic threshold. Surveys
      made in various countries since the seventies conclude that testosterone blood
      levels start to decrease after the age of 25 and that 20 to more than 50% of the
      male population no longer benefit from optimal androgen stimulation after the age
      of 60. THE CONSEQUENCES OF HYPOANDROGENISM: The subsequent progressive
      hypoandrogenism participates in inducing the commonly-observed clinical symptoms
      (fatigue, morosity, weight loss, lack of interest in sexual activity); the most
      specific of which is the disappearance or rarification of "automatic" nocturnal
      or matinal erections. This appears to influence the prostatic pathology and the
      frequent cardiovascular risk factors, which, far more than a problem of erection,
      is a major public health issue. A COMPLEX BIOLOGICAL DIAGNOSIS: Added to the
      abnormalities in production and transport of testosterone are the abnormalities
      in its metabolisation by the target tissues. These abnormalities are often
      undetected in present day blood controls and may explain the elevation in the
      hepatocyte of SHBG synthesis, the relative inhibition of GnRH pulses and LH
      secretion in the hypothalamus and the pituitary gland and, in the arterial wall
      (including penile vascularisation) and the prostate, some of the frequent
      functional and histological disorders. In current practice today, the best
      approximation of androgen potential is obtained by the comparison of total
      testosterone concentrations and SHBG, measurements that require relatively
      reliable standardised kits. THERAPEUTIC CHOICE: Optimal replacement therapy, for
      some authors, must mimic the physiology of the young man and above all maintain
      or reinforce the estrogenic effects of testosterone, related to its aromatisation
      into estradiol and supposedly beneficial for the cardiovascular system and the
      bone. For other, the androgenic effects, enhanced by the 5 alpha reduction into
      dihydrotestosterone (DHT), should be reinforced in older men because the
      estrogenic effects are ineffective on bone and most of the other targets, and are
      probably pathogenic for the prostate. This debate is extremely important since
      the various formulations of androgens authorized by the French Medicines agency
      (AFSSAPS) induce clearly differing estradiol/DHT plasma ratios.

PMID- 12489321
TI  - [Osteoporosis in the aged male].
AB  - A MAJOR PROBLEM: Osteoporosis in elderly men is a public health problem. However,
      the criteria for its diagnosis remain to be defined. With the aging of the male
      population, the number of osteoporotic fractures is increasing together with the
      incidence of fractures per age range. These fractures create handicaps and an
      excess of mortality and generate great expense for the health budget. VARIOUS
      PHYSIOPATHOLOGICAL MECHANISMS: In the pathogenesis of osteoporosis of the elderly
      men, various elements must be taken into account: hormone factors (decreased
      testicular secretion, vitamin D deficiency), life style (chronic alcoholism,
      smoking, lack of exercise), certain diseases (rheumatoid arthritis) and certain
      drugs (corticosteroids, anti-androgenes). THE PROGRESSION OF BONE MINERAL DENSITY
      (BMD) WITH AGE: Depending on the area measured, the BMD peak is reached before
      the age of 30 in the hip and in the trabecular bone areas, whilst it is reached
      around the age of 40 in the cortical bone areas. Bone loss accelerates after the
      age of 70. After the age of 80, the BMD peak is around 16 to 20% lesser, except
      for the lumbar spine where the arthrosic calcifications artificially increase the
      BMD value. Bone formation marker blood levels remain stable in elderly men
      whereas the urinary excretion of deoxypyridinoline (bone resorption marker)
      increases after the age of 60. THE DIAGNOSIS OF OSTEOPOROSIS IN ELDERLY MEN:
      Osteoporosis must be evoked when confronted with a recent fracture, notably of
      the vertebra, or following moderate trauma and the diagnosis is confirmed by the
      measurement of a low BMD score (T-score < -2.5). WITH REGARD TO TREATMENT: There
      are few studies on the treatment of male osteoporosis. In the elderly man,
      documented hypogonadism justifies testosterone replacement therapy, although its
      anti-fracture efficacy has not been studied. In elderly men, particularly those
      living in homes, vitamin D deficiency and the subsequent hyperthyroidism justify
      treatment with vitamin D and calcium. The new bisphosphonates appear promising.
      In a randomised study, alendronate increased BMD and reduced the incidence of
      vertebral fractures. Alendronate and risedronate were also effective in the
      prevention and treatment of cortisone-induced osteoporosis in men.

PMID- 12489322
TI  - [Apropos of reform of residency].

PMID- 12489323
TI  - [The clinician's point of view: decision aids].

PMID- 12489325
TI  - [Lower respiratory tract infections in the adult. The microbiologist's point of
      view ].

PMID- 12489324
TI  - [The microbiologist's point of view].

PMID- 12489326
TI  - [Lower respiratory tract infections in the adult. The clinician's point of view].

PMID- 12489327
TI  - [Lower respiratory tract infections in the child. The microbiologist's point of
      view].

PMID- 12489328
TI  - [Lower respiratory tract infections in the child. The clinician's point of view].

PMID- 12489329
TI  - [Upper respiratory tract infections in the adult, excluding otitis. The
      microbiologist's point of view].

PMID- 12489330
TI  - [Upper respiratory tract infections in the adult, excluding otitis. The
      clinician's point of view].

PMID- 12489331
TI  - [Upper respiratory tract infections in the child: suppurative otitis. The
      microbiologist's point of view].

PMID- 12489332
TI  - [Infections of the upper respiratory tract in the child: suppurative otitis. The
      clinician's point of view].

PMID- 12489333
TI  - [Johann Friedrich Meckel the Younger (1781-1833), an extremely important
      naturalist and scholar].
AB  - Johann Friedrich Meckel the Younger (1781-1833) belongs to the famous scientists
      of the 19th century. His research work is enormous. Important termini e.g.
      diverticulum Meckelii, cartilago Meckelii, Meckel syndrome and Meckel Serres law
      reflect the scientific results obtained by Meckel. He worked as a professor of
      anatomy, pathology and zoology at the University of Halle, a town in the Central
      Germany. Meckel founded the scientific teratology. In the literature he is also
      referred to the German Cuvier. On 8 April 1802, J. F. Meckel defended his
      doctoral thesis "De cordis conditionibus abnormibus". On occasion of the 200th
      anniversary of this event, we like to honor J. F. Meckel the famous German
      anatomist. Therefore, during the 97th session of the Anatomische Gesellschaft at
      Halle, a satellite symposium "From Meck el to genom" was held.

PMID- 12489334
TI  - [The "Meckel-Serres Statute", its origin and relation to evolutionary theories of
      the 19th Century]].

PMID- 12489335
TI  - [The scholarly program of Johann Friedrich Meckel the Younger (1781-1833) and it
      importance for the development of life sciences].
AB  - Although Johann Friedrich Meckel the Younger was one of the most famous
      anatomists, his research work has been severely neglected in the recent
      historiographical literature on the German morphology. The goal of our study is
      to approach a general characterization of his research program. Our analysis
      reveals that Meckel introduced the Cuvierian empiricism in Germany, but he also
      considered the "Abstraktion" as a main component of the scientific knowledge.
      According to his epistemology on nascent organisms and transmutable species,
      both, variability and relatedness of the organic forms are important to the same
      degree. Meckel explicitly adopted the Jean-Baptiste de Lamarcks (1744-1829)
      evolutionary theories. Even though in Meckel's discourse about diversity the
      Cuvierian notion of "functional adaptation" was preserved, the main goal of his
      research program was to demonstrate empirically the "Allgemeinheit des
      Bildungstypus". For this purpose, he considered the entire variety of the animal
      kingdom: normal as well as abnormal organisms, adult specimens and above all
      embryos. Moreover, he believed that the abnormal development is due to the same
      laws as the normal development. He applied parallelisms to a new domain, the
      study of malformation. With Meckel's researches on teratology, a new era in the
      analyses of the anomalies was opened. They became an integral part of the natural
      diversity and thus a highly exploited subject of biomedical researches. Meckel's
      empirical and epistemological writings on the embryology, comparative embryology,
      teratology, pathology, systematics and comparative anatomy have largely
      contributed to the foundation of the biological research.

PMID- 12489336
TI  - Ernst Haeckel's ontogenetic recapitulation: irritation and incentive from 1866 to
      our time.
AB  - Ernst Haeckel (1834-1919) must count among the most widely known biologists of
      his time. His monographs on radiolarian skeletons, sponges and medusae
      immediately became standard works, owing partly to lavish illustrations that
      later on culminated in his "Art Forms in Nature", which markedly influenced the
      "art nouveau" of the early 20th century. Haeckel's main impact, however, came
      from his numerous popular books that were crucial in transferring Darwin's ideas
      to continental Europe. Haeckel's main addition was his claim that ontogeny
      recapitulates phylogeny. It was partly founded on pre-Darwinian observations by
      J.F. Meckel and K.E. v. Baer who noticed that vertebrate embryos of different
      species resemble each other more strongly during early ontogenesis than later on.
      Wishing to illustrate this clearly, Haeckel clandestinely generalized some
      figures showing early embryos of animals and Man. This "fraud" provided
      ammunition for his many adversaries, most of whom felt provoked by his
      antireligious campaigns. The resulting controversies continued well into the 20th
      century but then subsided. Quite recently, however, they have flared up again,
      perhaps in connection with progress in molecular embryology that revealed an
      amazing evolutionary conservation of genes and their cooperation in signal
      transduction chains. The scientific publications that triggered this flare, and a
      selection of "Letters to the Editor" in both international science magazines and
      the German popular press, serve here to show that Haeckel's idea of
      recapitulation, while having proven its heuristic value, is still causing
      considerable irritation. This results from the widespread intuition that the
      marvels of ontogenesis and other biological phenomena must reflect some
      "intelligent design" rather than Darwinian evolution.

PMID- 12489337
TI  - [Johann Friedrich Meckel the Younger (1781-1833) and modern teratology].
AB  - Among other special topics Johann Friedrich Meckel the Younger concentrated his
      scientific researches on the systematic investigations of the human and animal
      malformations. He explored many samples which were part of his private anatomical
      collection. Today, the Institute of Anatomy and Cell Biology possesses a number
      of important teratological preparations which Meckel and his graduate students
      minutely investigated (e.g. the individuals to the Meckel, Klippel Feil and
      Hanhart syndrome). The goals of our studies are to identify the samples
      originating from the Meckel Collections, and to reinvestigate them with modern
      methods. Two objects (brainless malformation, Halle I, and neural tube defect,
      Halle II) were analysed by comparative genomic hybridization (CGH). These results
      obtained are published in Toennies et al. (2002).

PMID- 12489338
TI  - [Molecular-cytogenetic analysis of ancient DNA (aDNA) from preparations from the
      Meckel collection in Halle (Saale)].

PMID- 12489339
TI  - [Dr. Gustav Wilhelm Munter (1804-1870)--the "unknown" assistant of the Meckel
      collection].
AB  - For 48 years of his life, Dr. Gustav Wilhelm Munter was a diligent, skillful,
      reliable and indispensable assistant of the Meckel Collections. He was a loyal
      worker under famous superiors as Johann Friedrich Meckel the Younger (1781-1833),
      Eduard d'Alton (1803-1854) and Alfred Wilhelm Volkmann (1801-1877). Munter's aim
      was to get scientific acknowledgement and the position of a "Prosector". But he
      reached none of it. However, A. W. Volkmann, who often criticized Munter's work,
      was obligated to say: "It is true, that a very large part of the Meckel
      Collections had been prepared and put up by him." Today the Anatomical
      Collections of Halle include a large number of very nice preparations produced by
      Munter.

PMID- 12489340
TI  - [Genealogy of the Meckel anatomy family (from Hem[b]sbach)].
AB  - The main goal of our investigations is to complete the genealogy of the famous
      Meckel dynasty. It is important to answer a lot of questions which have remained
      unanswered until now. During the investigations we were able to find the names of
      three children who died early and were dissected by their father Philipp
      Friedrich Theodor Meckel (1755-1803). Besides, it was possible to extend
      distinctly our knowledge of the various genealogical lines of the Meckel family.

PMID- 12489341
TI  - [The anatomy of Johann Samuel Eduard d'Alton (1803-1854)--his life and work in
      Halle (Saale)].
AB  - After the death of Johann Friedrich Meckel (1781-1833), Eduard d'Alton was
      appointed to be his successor. From 1834 to 1854, he was Professor of Anatomy and
      head of the "Anatomisches Theater" at the University of Halle. In the literature
      we can only find little details about him. The aim is to investigate his life and
      work. Before he came to Halle, he was first professor at the Academy of Arts in
      Berlin. Then few years later he received the professorship of anatomy and
      physiology at the Friedrich-Wilhelm-University in Berlin. During his work as
      anatomist and physiologist in Halle he was rector twice, in 1845 and 1846.
      d'Alton worked very accurately and highly engaged. He supported the students'
      education very conscientiously but, since he was strict and exacting at the same
      time, he was not very popular. His extraordinary drawings of human and
      comparative anatomy earned him great recognition. In 1850, he published the
      "Handbuch der menschlichen Anatomie". d'Alton was mainly engaged in comparative
      anatomy, embryology and teratology and performed experimental embryological
      tests. In 1853, he published a catalogue of teratological preparations many of
      which can still be found in the Anatomical Collections in Halle.

PMID- 12489342
TI  - [Inauguration speech].

PMID- 12489343
TI  - Patterning is initiated before cleavage in the mouse.
AB  - Once experimental embryological studies revealed the striking ability of mammals
      to regulate their early development, the notion that pattern-formation might
      depend on information already present in the egg before cleavage was generally
      regarded as untenable. Mammals were therefore assumed to differ from almost all
      other animals in the way in which their embryonic patterning was set up. This
      view was justified by the profound way in which their early development is
      modified to meet the requirements of viviparity. However, it ignored various
      findings showing that exposure of gametes and very early conceptuses to altered
      conditions could perturb organisation of the fetus. Recent studies that place
      particular emphasis on non-invasive approaches have revealed hitherto overlooked
      regularities in early mouse development. They clearly show that specification of
      embryonic axes normally begins before cleavage in this species. Moreover, the
      relevant patterning processes seem to depend on intrinsic organisation of the egg
      rather than, as claimed recently, the site of entry of the fertilizing sperm.
      These new findings are of interest for two reasons. First, from an evolutionary
      perspective, it means that mammals retain common features with other animals in
      how their early development is controlled. Second, it raises the practical
      question whether the increasing use of in vitro manipulation of gametes and
      zygotes for assisting human reproduction carries a risk of perturbing
      development.

PMID- 12489344
TI  - [Chrono-endocrinology--quo vadis?].
AB  - The present review deals with important new chronobiological results especially
      in the field of chronoendocrinology, shedding new light on the circadian
      organisation of mammals including man. In vitro studies have shown that the
      concept of the existence of a single circadian oscillator located in the
      suprachiasmatic nucleus has to be extended. Circadian oscillators have also been
      found to exist in the retina, islets of Langerhans, liver, lung, and fibroblasts.
      Another major result is the detection of a new photopigment, melanopsin, present
      in a subpopulation of retinal ganglion cells which are lightsensitive and project
      to the suprachiasmatic nucleus, acting as zeitgeber for the photic entrainment of
      the circadian rhythm. We are only beginning to understand how the circadian
      oscillator transmits the circadian message to the endocrine system. The
      generation of circadian and seasonal rhythms of hormone synthesis is best
      understood in the pineal gland and its hormone melatonin. Seasonal changes of
      melatonin synthesis are transduced in the pars tuberalis of the adenohypophysis
      which is now entering the limelight of chronoendocrinological research.
      Currently, the elucidation of the genetic basis and the molecular organisation of
      the circadian oscillator within individual cells is a major thrust in
      chronobiological research.

PMID- 12489345
TI  - A histologic study of extralobar pulmonary sequestration and its anomalous artery
      as a clue to its development.
AB  - In 1997, an anomalous small mass of soft tissue was found in the left thoracic
      cavity of a Japanese male cadaver during student dissection practice. It was
      linked only by branches from the thoracic aorta, hemiazygos vein and greater
      splanchnic nerve, with no connection to the normal lung by vessels or airway.
      Examination of cut sections clarified that this anomalous small tissue mass was
      an extralobar pulmonary sequestration (EPS). Many cases of pulmonary
      sequestration have been reported from the clinical aspect, but there are few from
      a purely anatomical viewpoint. In the present case, detailed gross anatomical and
      histologic observations clarified that the anomalous artery supplying the
      sequestration resembled an elastic artery. In view of the findings of other
      reports, the anomalous arteries are divided into two types, the elastic type such
      as the pulmonary artery and the muscular type such as the bronchial artery. So it
      is thought that the histologic observation of an anomalous artery in comparison
      with normal pulmonary and bronchial arteries may offer an important clue to
      consider in elucidating the origin and development of pulmonary sequestration.

PMID- 12489346
TI  - Electromyographic validation of the trapezius and serratus anterior muscles in
      rowing exercises with closed grip.
AB  - Because the lack of specialized textbooks, the select of basic exercises for
      physical conditioning programmes is based on empirical knowledge. This fact led
      the authors to propose the study on electromyographic activity of the trapezius
      (upper portion) (TS) and the serratus anterior (lower portion) (SI) muscles in
      rowing exercises with closed grip in three different modalities. The tests were
      carried out with 24 male volunteers, 18 to 25 years old, by using a two-channel
      TECA TE 4 electromyograph and Hewlett Packard surface electrodes. For exercises
      execution, a long bar made of light wood was used. TS acted significantly in the
      three different modalities, that is, upright, sitting and bent over, while SI
      acted preferentially in upright and sitting rowing exercises, justifying their
      inclusion as basic exercises in physical conditioning programmes.

PMID- 12489347
TI  - Changes in alpha-motoneuron excitability with positions that tension neural
      tissue.
AB  - The slump test assesses the contribution of neural tissue to the referred
      symptoms associated with spinal pain and musculo-skeletal injuries of the lower
      limb. The limitation to full range of movement in performing this test has, in
      the past, been attributed to a mechanical restriction in mobility of neural
      tissue. Recent literature suggests that the limitation may be caused by
      protective reflex muscle action. The purpose of this study was to establish
      whether the slump test was associated with an increase or a decrease in
      excitability of alpha-motoneurons and, therefore, an alteration in muscle
      activity at the end of the range of movement of the test. Forty-three normal
      subjects and eight subjects with abnormal neural tension participated in this
      study. Changes in alpha-motoneuron excitability in neck flexion, moderate slump,
      and maximum slump positions were assessed by observing changes in H-reflex
      recruitment curves. Linear regression analysis on the rising portion of the H
      reflex recruitment curve enabled calculation of the dependent variable Hslp for
      statistical analysis. Normal subjects in the moderate and maximum slump positions
      demonstrated a significant decrease (p < 0.05) in the slope of the H-reflex
      recruitment curve. Subjects with abnormal neural tension showed a non-significant
      increase in slope when in these positions. Subject flexibility had a significant
      influence on motoneuron excitability in the moderate neural tension position with
      inflexible subjects demonstrating a significant inhibition of motoneurons. The
      difference between the flexible or moderately flexible subjects and inflexible
      subjects was not significant in the maximum neural tension position. These
      findings have important implications for the rationale for treatment selection
      and success of treatment outcomes in the clinical setting.

PMID- 12489349
TI  - Relative incidence of needle EMG abnormalities in the anterior tibial and
      gastrocnemius muscles.
AB  - Foot drop resulting from weakness of the anterior tibial muscle is commonly
      encountered in clinical practice. We analyzed the incidence of needle
      electromyographic (EMG) abnormalities in the anterior tibial and gastrocnemius
      muscles from traumatic injuries to the sciatic nerve and also from different non
      traumatic lower motor neuron conditions. In both traumatic and non-traumatic
      cases, the anterior tibial muscle showed relatively more EMG abnormalities
      compared to the gastrocnemius. It appears that the anterior tibial muscle is more
      susceptible to injury from a variety of pathologic conditions, as opposed to the
      gastrocnemius muscle.

PMID- 12489348
TI  - Electromyographic validation of the double pulley equipment during movements of
      the lower limbs.
AB  - The double pulley equipment was tested on ten male volunteers during contraction
      of the semitendinosus and biceps femoris (caput longum) muscles in the following
      movements of the lower limbs: 1) hip extension with extended knee and erect
      trunk, 2) hip extension with flexed knee and erect trunk, 3) hip extension with
      flexed knee and erect trunk, 3) hip extension with extended knee and inclined
      trunk, 5) hip abduction along the midline, 7) hip abduction with extension beyond
      the midline, 8) adduction with hip flexion beyond the midline, 8) adduction with
      hip flexion beyond the midline, and 9) adduction with hip extension beyond the
      midline. The myoelectric signals were taken up by Lec Tec surface electrodes
      connected to a 6-channel Lynx electromyographic signal amplifier coupled with a
      computer equipped with a model CAD 10/26 analogue digital conversion board and
      with a specific software for signal recording and analysis. The semitendinosus
      and biceps femoris muscles presented the highest potentials in movements 1; 2; 7,
      8 and 9, whereas the potentials in the remaining movements were negligible. The
      pattern of activity of the semitendinosus and the biceps femoris was similar in
      exercises 1, 2, 3, 4 and 8. The potentials of the semitendinosus prevailed in
      movements 5, 6 and 7, and the strongest potentials observed in movement 9 were
      those of the biceps femoris.

PMID- 12489350
TI  - An improved approach to the evaluation of the deep motor branch of the ulnar
      nerve.
AB  - The detection of ulnar nerve lesions at Guyon's canal requires evaluation of the
      distal ulnar sensory and distal motor latency to the abductor digiti minimi
      (ADM). In addition precision in the measurement of distal motor latencies (DL) to
      the first dorsal interosseous (1DI) muscle and response amplitude is necessary.
      This study examines a standardized technique assessing distal ulnar nerve
      conduction aimed to provide a more sensitive evaluation of these lesions. Fifty
      normals and eighteen subjects with hand symptoms were assessed to determine DL to
      the ADM and 1DI and response amplitudes. These standard values were then compared
      to values obtained from clinically proven cases of distal ulnar lesions over the
      previous 2 years. The main outcome measures were elimination of premotor
      potentials and prolongation of 1DI DL. The results revealed that the standardized
      technique consistently eliminates premotor potentials (PMP) and provides a
      significantly narrowed range of normal DL values. This enhanced precision allows
      for more accurate normative values, making recognition of more subtle lesions
      possible. Normative data compared to values from a 2 year chart review of distal
      ulnar lesions shows predictive trends toward prolonged 1DI DL and diminution of
      1DI amplitudes (AMP).

PMID- 12489351
TI  - "Functional-QEMG" a new reliable method in daily routine investigation.
AB  - In classical quantitative analysis motor unit action potentials (MUAPs)
      parameters are useful in establishing diagnosis, but not in monitoring the
      functional status as expressed by clinical sings. This drawback is overcome by
      our new method called "Functional-QEMG", where the analysis is based on
      structural and functional changes of all acting motor units (MUs). The automatic
      classification of normal versus myogenic or neurogenic disorder together with the
      assessment of their severity is performed by special computer-assisted diagnostic
      procedures. The classification is based on individual MUAPs size (structure) and
      their functional properties determined in unique "Mapping-MUAP" program. This
      classification is further confirmed by the adequate to a given pathology the
      structural reorganisation of all acting MUs. In consequence theirs functional
      properties are changing as the compensatory mechanisms to generate the optimal
      force in structurally changed acting MUs. Thus, the effectiveness of compensatory
      process is used for quantitative assessment of severity of the disease from
      simultaneously recorded maximal effort pattern. Our experience during last ten
      years shown that such dynamical analysis is very useful in correlation with the
      clinical picture of examined patient to make the final conclusion of EMG
      investigation.

PMID- 12489352
TI  - Inter-trial variation of soleus H reflex in humans: implication for supraspinal
      influence.
AB  - Inter-trial variation in soleus H reflex amplitude for different effort modes,
      elicited at different test-stimulus intensities, was studied in fifteen healthy
      subjects. Regardless of test-stimulus intensity, weak isometric plantarflexion
      and dorsiflexion at 20% of maximum voluntary contraction caused significant
      potentiation and depression of the H reflex amplitude. In addition, both
      facilitation and inhibition of the soleus H reflex was associated with
      considerable inter-trial variability of the H reflex amplitude that varied
      proportionally with test-stimulus intensity. As inter-variability of the H reflex
      was independent of that of M response, the results indicate that: 1) supra-spinal
      input influences loop-gain fluctuations of the monosynaptic-reflex arc; and 2)
      smaller test stimuli may be more efficacious for exploration of motoneuronal
      excitability because of reduction in variability in H reflex amplitude.

PMID- 12489353
TI  - The problem with men.

PMID- 12489354
TI  - Key developments in men's health.

PMID- 12489355
TI  - Diagnosing testicular pain.

PMID- 12489356
TI  - Sexual disease in male patients.

PMID- 12489357
TI  - Managing benign prostate disease.

PMID- 12489358
TI  - Current and future asthma therapies.

PMID- 12489359
TI  - Preparing for the written paper.

PMID- 12489361
TI  - NIH conference addresses hormone therapy issues.

PMID- 12489360
TI  - Outsourced compounding can be problematic.

PMID- 12489362
TI  - Blood pressure guidelines call for lifestyle modifications.

PMID- 12489363
TI  - Shared governance builds leaders, aids patient care.

PMID- 12489364
TI  - Urokinase to return to market.

PMID- 12489365
TI  - FDA reporting program is key to safety information.

PMID- 12489366
TI  - Understanding and preparing for clinical drug trial audits.

PMID- 12489367
TI  - Unit dose packaging and patient safety.

PMID- 12489368
TI  - Measuring medication safety in hospitals. Introduction.

PMID- 12489369
TI  - Observation method of detecting medication errors.

PMID- 12489370
TI  - Using information technology to screen for adverse drug events.

PMID- 12489371
TI  - Practitioner intervention-reporting systems for measuring the quality of drug
      use.

PMID- 12489373
TI  - Voluntary reporting of medication errors.

PMID- 12489372
TI  - Using chart review to screen for medication errors and adverse drug events.

PMID- 12489374
TI  - Using technology to enhance measurement of drug-use safety.

PMID- 12489375
TI  - Workshop summaries.

PMID- 12489376
TI  - Pharmacist time requirements for counseling in an outpatient pharmacy.
AB  - The correlation between the pharmacist time required for counseling patients and
      the characteristics of the services provided was studied. Data from the Kaiser
      Permanente/USC Patient Consultation Study were used to examine the relationship
      between pharmacist time and potential problems, actions to resolve the problems,
      and disposition of prescriptions. A regression model was estimated with
      pharmacist time as the dependent variable. An encounter consisting of patient
      contact to monitor adverse effects, duplicate therapy, or compliance took an
      estimated three minutes on average. Problems related to appropriateness of
      therapy or drug interactions required an additional 1.8 and 0.5 minutes,
      respectively. Four additional minutes were required for provider contact unless
      the contact involved a simple clarification (an additional 2.6 minutes). Patient
      referrals required an additional 2.5 minutes. The time requirements related to
      the problem addressed and action taken were not additive. The incremental time
      requirements across alternative problem-action clusters ranged from 2.9 to 9
      minutes. A fee-for-service payment system appears to be feasible for pharmacist
      counseling services.

PMID- 12489377
TI  - Analysis of medication management activities for home-dwelling patients.

PMID- 12489378
TI  - International Pharmaceutical Abstracts: what's new and what can IPA do for you?

PMID- 12489379
TI  - Stability of cefazolin sodium in icodextrin-containing peritoneal dialysis
      solution.

PMID- 12489380
TI  - Insulin resistance, diabetes, and the adipocyte.
AB  - The etiology, natural history, and relationship of insulin resistance to type 2
      diabetes mellitus and the effects of insulin-sensitizing agents are described.
      Insulin resistance results from a combination of genetic and environmental
      factors and contributes to type 2 diabetes mellitus, dyslipidemia, hypertension,
      central (abdominal) obesity, and cardiovascular disease. Insulin resistance does
      not necessarily progress to impaired glucose tolerance or diabetes because
      insulin secretion by normal pancreatic beta cells can increase to compensate for
      reduced physiological activity. Diabetes may develop in insulin-resistant persons
      with inherited secretory and glucose-sensing defects in beta cells. The
      pathogenesis of diabetes appears to involve a progressive decrease in beta-cell
      mass, potentially triggered by abnormalities in adipocytokine release from
      intraabdominal fat cells. Metformin and the thiazolidinediones are used to treat
      insulin resistance, but their actions differ. Metformin reduces free-fatty-acid
      efflux from fat cells, thereby suppressing hepatic glucose production, and
      indirectly improves peripheral insulin sensitivity and endothelial function.
      Thiazolidinediones improve peripheral insulin sensitivity by reducing circulating
      free fatty acids but also by suppressing adipocytokines, which increase insulin
      resistance. Thiazolidinediones also improve endothelial function and may prevent
      or delay the onset of diabetes. Insulin is intrinsically antiatherogenic but may
      mediate arterial inflammation in insulin-resistant patients. Unlike metformin,
      the thiazolidinediones suppress this inflammatory pathway and may indirectly help
      preserve beta-cell function. Insulin resistance, resulting from a combination of
      genetic and environmental factors, plays a central role in type 2 diabetes
      mellitus. Diabetes may develop in insulin-resistant persons with inherited
      secretory and glucose-sensing defects in beta cells. Metformin and
      thiazolidinediones are insulin-sensitizing agents with different mechanisms of
      action and effects in patients with type 2 diabetes mellitus.

PMID- 12489381
TI  - Treating dual defects in diabetes: insulin resistance and insulin secretion.
AB  - The therapeutic goals in patients with type 2 diabetes mellitus and the
      mechanisms of insulin resistance and secretion are discussed. Sulfonylureas
      improve glycemic control, restore the acute insulin response, and help improve
      beta-cell function in the short term. Meglitinides and phenylalanine derivatives
      and alpha-glucosidase inhibitors may be useful for elderly patients and others
      with normal fasting blood glucose levels and postprandial hyperglycemia, but they
      are less effective in achieving goal HbA1c levels in patients with marked fasting
      hyperglycemia. Metformin and thiazolidinediones act on hepatic, muscle, and
      adipose tissue through different mechanisms to improve glycemic control, beta
      cell function, and the lipid profile. Thiazolidinediones have a greater impact on
      free fatty acids than metformin. They may have an additive effect with
      sulfonylureas, metformin, or insulin in improving glycemic control and the lipid
      profile. Many patients require combination therapy with one or more insulin
      sensitizers and an insulin secretagogue to achieve therapeutic goals. Insulin
      therapy should be initiated in patients in whom an HbA1c level less than 7.0%
      cannot be maintained with other therapies. This is vital in preventing diabetes
      complications. Insulin sensitizers should be continued during insulin therapy to
      reduce insulin resistance and treat the insulin resistance syndrome. Therapeutic
      goals for patients with type 2 diabetes mellitus include improvement in glycemic
      control and prevention of diabetes complications. Elevated levels of fasting
      blood glucose should be addressed before postprandial levels to reduce HbA1c
      levels and glucotoxicity to the beta cell. Dyslipidemia, hypertension, and
      hypercoagulability should be treated to minimize the increased cardiovascular
      risk seen in people with diabetes, which is responsible for the majority of
      deaths.

PMID- 12489382
TI  - Economic considerations in treating patients with type 2 diabetes mellitus.
AB  - Economic considerations in treating patients with type 2 diabetes mellitus are
      reviewed. Glycemic control, lipid profiles, and adherence to standards of care
      are less than optimal in many patients with type 2 diabetes mellitus. Diabetes
      has an enormous economic impact, and its related costs in the United States are
      expected to increase as the frequency of the disease increases. A substantial
      portion of diabetes-related health care expenditures is allotted to the treatment
      of cardiovascular disease, a major complication of diabetes. Significant health
      care resources are spent in a reactive manner (i.e., after complications have
      developed), with little emphasis on preventive care. One large study conducted in
      the United Kingdom demonstrated that providing intensive blood glucose control
      significantly reduced the risk of microvascular complications, such as
      retinopathy, nephropathy, and neuropathy, in patients with type 2 diabetes
      mellitus. Factors to consider in selecting pharmacotherapy for these patients
      include the magnitude of change in measures of glycemic control provided by the
      medication, other desired metabolic changes and outcomes (e.g., blood pressure
      and lipid changes), mechanism of action, adverse effects, contraindications,
      patient adherence, and cost. Early interventions, such as annual urinalysis and
      screening for microalbuminemia, annual comprehensive eye examination by an
      ophthalmologist or optometrist, and screening for neuropathy and foot problems
      are cost-effective ways of reducing diabetes-related complications. Interventions
      recommended for reducing the risk for cardiovascular complications in patients
      with type 2 diabetes mellitus include lipid control, blood pressure control,
      aspirin therapy, smoking cessation, and weight loss. Achieving and maintaining
      glycemic control in patients with type 2 diabetes mellitus improves quality of
      life and is cost-effective, especially among patients with comorbid heart
      disease, hypertension, or both.

PMID- 12489383
TI  - Role of the pharmacist in diabetes management.
AB  - The role of pharmacists in diabetes management, including patient identification,
      assessment, education, referral, and monitoring, is described. Pharmacists can
      help identify patients with diabetes through screening and should target patients
      at high risk, people with a family history of the disease, and women with a
      history of gestational diabetes or who delivered a baby weighing more than nine
      pounds. Patient education should be provided immediately after diagnosis, at a
      second stage at which time a patient assessment can be performed, and at a third
      stage during which patients can receive continuing education to reinforce
      concepts and a motivational boost. One of the pharmacist's most important roles
      is the referral of patients to other members of the diabetes care team. Although
      the role of the pharmacist in monitoring diabetes is not well defined, it might
      include such things as ascertaining whether physician visits and testing to
      assess long-term glycemic control. Obtaining certification as a diabetes educator
      is recommended. This process requires at least 1000 hours of experience in
      providing disease-state management for patients with diabetes and successful
      completion of an examination. Implementing diabetes management services requires
      a commitment of time, effort, and resources and may necessitate training of staff
      and changes in work patterns. The pharmacist can play an important role in
      diabetes care by screening patients at high risk for diabetes, assessing patient
      health status and adherence to standards of care, educating patients to empower
      them to care for themselves, referring patients to other health care
      professionals as appropriate, and monitoring outcomes. Providing diabetes
      management services requires market savvy, communication skills, and a commitment
      of time, effort, and resources. Pharmacists who obtain training in diabetes
      management reap rewards in professional satisfaction and financial reimbursement.

PMID- 12489384
TI  - Integrated departments: can CMs and social workers get along?

PMID- 12489385
TI  - The three levels of case management integration.

PMID- 12489386
TI  - CCMC announces changes to CCM credential.

PMID- 12489387
TI  - Clinical pathways program presents challenges.

PMID- 12489388
TI  - Clinical pathway for colorectal procedures.

PMID- 12489389
TI  - Cutting-edge strategies go beyond staffing ratios.

PMID- 12489390
TI  - JCAHO unveils major changes to survey process.

PMID- 12489391
TI  - Population dynamics of calyptrate Diptera (Muscidae and Sarcophagidae) at the Rio
      Zoo Foundation, Rio de Janeiro, RJ, Brazil.
AB  - Twenty-seven species of calyptrate muscoids (Muscidae and Sarcophagidae) were
      collected from December 1993 to November 1994 with wind oriented traps (W.O.T.)
      baited with decomposing beef liver at the Rio de Janeiro Zoo. The most abundant
      species found were Musca domestica (57.84%), Peckia chrysostoma (28.16%), Ophyra
      aenescens (17.11%), Oxysarcodexia thornax (17.82%), Synthesiomyia nudiseta
      (13.05%), and Oxysarcodexia diana (14.52%).

PMID- 12489392
TI  - Birds of a central Sao Paulo woodlot: 1. Censuses 1982-2000.
AB  - Some 263 birds were recorded near and in a 230-ha patch of semideciduous forest
      in cane fields of central Sao Paulo, Brazil. Subtracting 67 open-area species, 22
      of marshes or creeks, 10 vagrants and 12 recorded later, 152 forest and border
      species were recorded in 1982-86, much like what was observed in a similar
      woodlot near Campinas. Both woodlots lost species gradually over the years. Some
      birds avoided hard cane-field edges, preferring soft bushy edges. Of open-area
      species, 22 seemed to have disappeared by 1997 due to earlier high El Nino rains
      or rare permanently open habitats in the sugar cane; 17 new species were mostly
      nocturnal ones not noted earlier, or occasional visitors. Forest and borders lost
      31 species, gaining five of dry regions and one winter visitor. Several migrants
      from the south appeared only in wet years before recent greenhouse effects, some
      resident birds were hunted, and canopy hummingbirds were perhaps still present.
      Dry-forest travel-prone or "metapopulational" species moved their centers of
      distribution, partly concealing loss of moist-forest diversity.

PMID- 12489393
TI  - Spatial and temporal distribution of larvae and juveniles of Hoplias aff.
      malabaricus (Characiformes, Erythrinidae) in the Upper Parana River floodplain,
      Brazil.
AB  - Spatial and temporal distribution of larvae and juveniles of trahira, Hoplias
      aff. malabaricus (Erythrinidae), and their relationship with environmental
      parameters in the Upper Parana River floodplain were analyzed. Sampling of larvae
      and juveniles of H. aff. malabaricus has been conducted during the period from
      November 1991 through February 1995, with 42 sampling stations distributed in
      four sub-areas: Ivinhema I, Ivinhema II, Baia, and Parana. During the same
      period, data were obtained for water temperature, dissolved oxygen, pH,
      electrical conductivity, river level, precipitation index, and photoperiod. The
      largest catches of larvae were in the Ivinhema I sub-area (47.06%), and of
      juveniles in the Parana sub-area (54.55%). Larvae and juveniles were caught from
      October to February. Larvae were mainly collected at night and in all types of
      environments sampled (lotic, semi-lotic, and lentic). Principal Component
      Analysis of the environmental parameters and larval density showed that the
      largest catches were obtained in dry season months, with low values for
      temperature, electrical conductivity, river level, and photoperiod, and with high
      concentrations of dissolved oxygen and pH. This reproductive strategy may
      minimizes predation and maximizes food utilization, as it enables the fish to
      reach advanced developmental stages, while most other species are spawning.

PMID- 12489394
TI  - Effect of butanolic fraction of Desmodium adscendens on the anococcygeus of the
      rat.
AB  - The chemical composition of plants can vary according to factors such as soil and
      time of collection. Desmodium adscendens (Sw.) D.C. var. adscendens
      (Papillionaceae) is a plant employed in the treatment of asthma in Ghana, Africa.
      Studies have shown that butanolic extract inhibits contraction of the ileum and
      trachea in guinea pigs. In Mato Grosso, this plant is used only in the treatment
      of ovarian inflammation. The objective of this work was to verify if the plant
      found in Mato Grosso also relaxes smooth muscle and to understand better its
      action. The cumulative application of the butanolic fraction relaxed the
      contraction maintained in the isolated anococcygeus of a rat, induced by high
      potassium, but not that induced by phenylephrine. Relaxation was not altered by
      methylene blue. The butanolic fraction reduced in a concentration-dependent way
      the maximum response of concentration-response curve to calcium in the
      anococcygeus muscle. The results suggest that the butanolic fraction acts, at
      least partly, through the blockade of voltage-sensitive Ca+2 channels.

PMID- 12489395
TI  - Photophase influence on the reproductive diapause, seasonal morphs, and feeding
      activity of Euschistus heros (Fabr., 1798) (Hemiptera: Pentatomidae).
AB  - Laboratory studies were conducted to verify the influence of photophase on
      diapause incidence in the Neotropical brown stink bug, Euschistus heros (Fabr.,
      1798), fed with soybean [Glycine max (L.)] Merrill pods. Nymphs were maintained
      at three different photophases: 10 h, 12 h, and 14 h, with constant temperature
      of 25 +/- 1 degree C and relative humidity of 65 +/- 5%. With 14 h, approximately
      100% of the adults showed mature reproductive organs; the shoulder (spine) length
      was significantly greater (2.96 and 2.79 mm for females and males, respectively)
      than those of bugs maintained at the photophase of 12 h (2.60 mm for females and
      males) and 10 h (2.59 and 2.53 mm for females and males). At the longer
      photophase (14 h), E. heros showed better reproductive performance and greater
      feeding activity than insects reared at 10 h and 12 h; in all photophases bugs
      tended to reduce feeding from the 1st to the 6th week of life. Body color was
      considered an unreliable parameter to indicate diapause incidence. However, at 14
      h, 60% of the insects were dark brown and 40% were reddish brown. These results
      indicate that E. heros enters reproductive diapause with photophase of 12 hours
      or less, showing immature reproductive organs or with intermediate development,
      with shoulder (spine) less developed and reduced feeding activity.

PMID- 12489396
TI  - Aspects of the reproductive biology of the shortfin Mako, Isurus oxyrinchus
      (Elasmobranchii Lamnidae), in the southeastern region of Brazil.
AB  - Uteri from four pregnant females and two newborn of shortfin mako, Isurus
      oxyrinchus, were collected in the southeastern region of Brazil, during
      September, October, and November of 1993 and 1994. All embryos were near-term
      with developing dentition and inner organs. Total length ranged from 64.5 to 72.0
      cm, and the maximum number of embryos observed in a litter was 20. These
      observations further confirmed oophagy as a form of nutrition in this species,
      and its periodicity. The presence of teeth in the embryos' stomachs suggest that
      tooth replacement begins in the uterine phase.

PMID- 12489397
TI  - Social behavior between mothers x young of sloths Bradypus variegatus Schinz,
      1825 (Xenarthra: Bradypodidae).
AB  - This study is a contribution to the ex situ and in situ conservation and
      preservation of Sloths. The behavioral records of the social interaction between
      mothers and offspring allow the detection of important learning interactions and
      psychomotor development. The results provide valuable information that may assist
      in improving management conditions of captive orphan progeny. They also favor a
      more effective monitoring of released or transferred specimens. Age is of
      fundamental importance in deciding what is important during the release,
      transfer, or reintroduction of the species.

PMID- 12489398
TI  - The gross anatomy of the nervous system of Bothriurus bonariensis (L. C. Koch,
      1842). (Scorpiones, Bothriuridae).
AB  - The nervous system of the order Scorpiones appears to have a common
      organizational structure. The combination of an anatomical study using methylene
      blue as the contrast medium together with a histological analysis using
      hematoxylin-eosin and Heindenhain's iron hematoxylin techniques permitted the
      identification of a large number of nerves in B. bonariensis. Many of these are
      also present in a variety of other species of scorpions, belonging to distinct
      families of the order Scorpiones. Nevertheless, two pairs of nerves from B.
      bonariensis originating in the cheliceral ganglion, one pair of esophageal nerves
      and one pair of nerves from the aortic arch, appear to diverge from this basic
      organization. They have not been previously described, nor have any equivalents
      been reported in research on other scorpion species, in which the current
      homological criteria have been employed.

PMID- 12489399
TI  - The occurrence of amphibians in bromeliads from a southeastern Brazilian restinga
      habitat, with special reference to Aparasphenodon brunoi (Anura, Hylidae).
AB  - Five species of anuran amphibians, all belonging to the family Hylidae, were
      collected at Praia das Neves, municipality of President Kennedy, southeastern
      Brazil. The species were represented by four genera: Scinax, Hyla,
      Aparasphenodon, and Trachycephalus. Four species (A. brunoi, Hyla albomarginata,
      Scinax altera, and S. cuspidatus) were found during the dry season (August 1999),
      and two (A. brunoi and Trachycephalus nigromaculatus) in the rainy season
      (February 2000). Aparasphenodon brunoi was the most abundant species in Praia das
      Neves. Some reproductive aspects and feeding habits of this hylid were
      investigated. Aparasphenodon brunoi was found mainly inside the bromeliad Aechmea
      lingulata, the largest plant analyzed. Fifteen specimens were collected during
      the dry season (August 1999) (11 males and 4 females). During the rainy season
      (February 2000), we collected 14 specimens (3 males, 10 females, and 1 juvenile).
      Sex-ratio was 1:1. Frogs ranged in snout-vent length from 31.2 to 69.3 mm.
      Females were larger than males. One female had 1,451 fully developed oocytes in
      her ovaries. The major groups of prey found in the stomachs were: Insecta,
      Myriapoda, and Arachnida. Blattodea, Orthoptera, Lepidoptera, and Hymenoptera
      (only ants) were the main food types in frequency, number, and weight.
      Aparasphenodon brunoi is a threatened species in many habitats of southeastern
      Brazil. Only natural vegetation protection may guarantee its survival during the
      immediate future.

PMID- 12489400
TI  - Natural enemies of the gall-maker Eugeniamyia dispar (Diptera, Cecidomyiidae):
      predatory ants and parasitoids.
AB  - Natural enemies of the gall maker Eugeniamyia dispar (Diptera: Cecidomyiidae)
      were studied on the urban area of Porto Alegre, RS, Brazil from October 1993 to
      March 1996. Galls and associated arthropods were followed weekly in the field on
      individual host plants (Eugenia uniflora, Myrtaceae) and also in the laboratory.
      Three species of ants attacked the galls, the most common being Pseudomyrmex sp.
      A proportion of galls was parasitised by Rileya sp. (Eurytomidae). The adults of
      this solitary ectoparasitoid were also attacked by the ants and fell prey to
      spider webs.

PMID- 12489401
TI  - Life history of the gall-maker Eugeniamyia dispar Maia, Mendonca-Jr. &
      Romanowski, 1996 (Diptera, Cecidomyiidae).
AB  - The development of the galls of the midge Eugeniamyia dispar Maia, Mendonca-Jr. &
      Romanowski, 1996 (Diptera: Cecidomyiidae) was monitored weekly on its host plant,
      Eugenia uniflora (Myrtaceae). The work was carried out in the urban area of Porto
      Alegre, RS, Brazil, from October 1993 to September 1995. Galls were collected
      from the field and raised in the laboratory to obtain adults. The females
      oviposit on young leaves of the host plant, with the first instar larvae inducing
      the gall, which is unilocular. The last instar larvae drop to the soil to pupate
      and later emerge as adults. The galls occur from late August to early June, when
      young leaves of the host can be found, with populations peaking during the
      summer. So far this species is only known from the two southernmost states of
      Brazil (RS and SC).

PMID- 12489402
TI  - The terrestrial reptile fauna of the Abrolhos Archipelago: species list and
      ecological aspects.
AB  - We have studied the terrestrial reptile fauna of the Abrolhos Archipelago (a
      group of five islands located ca. 70 km off the southern coast of the State of
      Bahia, Brazil) and analyze here some of its ecological aspects such as diet,
      thermal ecology, activity, and some reproductive parameters. Three lizards
      comprise the archipelago's terrestrial reptile fauna: Tropidurus torquatus
      (Tropiduridae), Mabuya agilis (Scincidae), and Hemidactylus mabouia (Gekkonidae).
      The first two are diurnal and the latter is crepuscular/nocturnal (initiating
      activity at ca. 17:30). The activity period of T. torquatus extended from 5:30 to
      18:30 h. Mean field body temperatures of active T. torquatus, M. agilis, and H.
      mabouia were, respectively, 34.0 +/- 3.7 degrees C (range 23.8-38.0 degrees C; N
      = 75), 34.5 +/- 2.2 degrees C (range 30.8-37.0 degrees C; N = 6), and 26.3 +/-
      1.1 degrees C (range 24.8-28.0 degrees C; N = 8). The predominant prey items in
      the diet of T. torquatus were ants, coleopterans, and hemipterans. In the diet of
      M. agilis, coleopterans were the most frequent prey items. For H. mabouia, the
      most important dietary items were orthopterans. Clutch size of T. torquatus
      averaged 4.1 +/- 1.1 (range 2-6; N = 15) and was significantly related to female
      size (R2 = 0.618; p = 0.001; N = 15). Clutch size for H. mabouia was fixed (two)
      and mean litter size of the viviparous M. agilis was 3.3 +/- 0.6 (range 3-4; N =
      3). Tropidurus torquatus and H. mabouia deposit their eggs under rocks in the
      study area, with the former burying them but not the latter; in both species,
      more than one female often oviposit under the same rock.

PMID- 12489403
TI  - Field experimental evaluation of secondary metabolites from marine invertebrates
      as antifoulants.
AB  - The crude organic extracts of the endemic gorgonian Phyllogorgia dilatata and two
      sponge species Aplysina fulva and Mycale microsigmatosa were evaluated for anti
      fouling properties through field experiments. To investigate this property in
      ecologically meaningful conditions, crude extracts from these invertebrates were
      incorporated at concentrations naturally found in these marine organisms into a
      stable gel used as a substratum for fouling settlement. Crude extract from A.
      fulva showed no significant anti-fouling property at the natural concentrations
      used in the field experiments. In fact, fouling organisms settled significantly
      more on gels treated with A. fulva extract than on the control gel. On the other
      hand, both M. microsigmatosa and P. dilatata yielded crude extracts that
      exhibited a selective action inhibiting only the settlement of barnacles. The
      evidences obtained here by means of field experiments can provide a basis for
      future development of one kind of natural antifoulant technology to prevent
      marine biofouling.

PMID- 12489404
TI  - Geographical variation in larval host-plant use by Heliconius erato (Lepidoptera:
      Nymphalidae) and consequences for adult life history.
AB  - Adult body size, one of the most important life-history components, varies
      strongly within and between Heliconius erato phyllis (Lepidoptera: Nymphalidae)
      populations. This study determines if this variation is caused by geographical
      changes in host-plant used by the larval stage, whose reproductive parameters are
      influenced by female body size, with estimates of the corresponding heritability.
      The variation in adult body size was determined together with a survey of passion
      vine species (Passifloraceae) used by the larvae in seven localities in Rio
      Grande do Sul State: three located in the urban area of Porto Alegre and Triunfo
      Counties, two within Eucalyptus plantations (Barba Negra Forest, Barra do Ribeiro
      County, and Aguas Belas Experimental Station-Viamao County), one in a Myrtaceae
      Forest (Itapua State Park-Itapua County) and one in the Atlantic Rain Forest
      (Maquine Experimental Station-Maquine County). Effects of female body size on
      fecundity, egg size and egg viability were determined in an outdoor insectary.
      Size heritability was estimated by rearing in the laboratory offspring of
      individuals maintained in an insectary. The data showed that adults from
      populations where larvae feed only upon Passiflora suberosa are smaller than
      those that feed on Passiflora misera. The larvae prefer P. misera even when the
      dominant passion vine in a given place is P. suberosa. Fecundity increases
      linearly with the increase in size of females, but there is no size effect on egg
      size or viability. Size heritability is null for the adult size range occurring
      in the field. Thus, the geographical variation of H. erato phyllis adult size is
      primarily determined by the type, corresponding availability and quality of host
      plants used by the larval stage. Within the natural size range of H. erato
      phyllis, the variation related to this character is not genetically based, thus
      being part of H. erato phyllis phenotypic plasticity.

PMID- 12489405
TI  - The genus Plesiophysa, with a redescription of P. ornata (Haas, 1938)
      (Gastropoda: Planorbidae).
AB  - A redescription of conchological and anatomical characters of the planorbidae
      mollusc Plesiophysa ornata (Haas, 1938) is presented, based on topotypic material
      and specimens from 14 additional localities in the Brazilian states of Rio Grande
      do Norte, Paraiba, Sergipe, Bahia, Espirito Santo and Minas Gerais. Due to the
      close similarity of their shells, a sure discrimination of the five species of
      Plesiophysa described so far (P. pilsbryi, P. granulata, P. guadeloupensis, P.
      ornata and P. hubendicki) is only possible through their anatomical features. The
      present study points to the high probability of synonymy of P. hubendicki with P.
      ornata. Investigations on the anatomy of P. pilsbryi and P. guadeloupensis are
      needed to define their taxonomic relation with the other nominal species.

PMID- 12489406
TI  - Fruiting phenology and consumption by birds in Ficus calyptroceras (Miq.) Miq.
      (Moraceae).
AB  - Figs are a remarkable food resource to frugivores, mainly in periods of general
      fruit scarcity. Ficus calyptroceras Miq. (Moraceae) is the only fig species in a
      type of dry forest in western Brazil. In this study I examined the fruiting
      pattern as well as fig consumption by birds in F. calyptroceras. Although
      rainfall was highly seasonal, fruiting was aseasonal, since the monthly
      proportion of fruiting trees ranged from 4% to 14% (N = 50 trees). I recorded 22
      bird species feeding on figs. In the wet season 20 bird species ate figs, while
      in the dry season 13 did. Parrots were the most important consumers. This group
      removed 72% and 40% of the figs consumed in the wet and dry seasons,
      respectively. No bird species increases fig consumption from dry to wet season.
      However, a group of bird species assumed as seed dispersers largely increases fig
      consumption from wet to dry season, suggesting the importance of this resource in
      the period of fruit scarcity. The results of this study points out the remarkable
      role that F. calyptroceras plays to frugivorous birds, in such a dry forest,
      since its fruits were widely consumed and were available all year round.

PMID- 12489407
TI  - Longitudinal processes in Salto Grande Reservoir (Americana, SP, Brazil) and its
      influence in the formation of compartment system.
AB  - Studies on the longitudinal processes in reservoirs, involving physical, chemical
      and biological processes have been thoroughly appraised, suggesting the existence
      of a longitudinal organization controlled by the entrance and circulation of
      water which inserts modifications in the structuring of the system. To evaluate
      this effect, the Salto Grande reservoir (Americana, SP) was analyzed in 11
      sampling stations in its longitudinal axis, in the rainy and dry seasons of 1997
      considering the physical chemical and biological variables. Analyzing the results
      in agreement with the declining concentration degree of the river-barrage
      direction, a more significant correlation was verified in the dry period for
      total phosphorus (r2 = 0.86), dissolved total phosphate (r2 = 0.83), nitrite (r2
      = 0.93), inorganic phosphate (r2 = 0.89), ammonium (r2 = 0.84) and suspended
      material (r2 = 0.85). In the rainy period, only nitrite (r2 = 0.90) and
      conductivity (r2 = 0.89) presented correlation with the distance of the dam,
      which demonstrates the effects of precipitation and the operational mechanism of
      the dam, as well as the distinction among the physical (sedimentation), chemical
      (oxidation) and biological (decomposition) processes in spatial heterogeneity of
      the system. These factors were decisive in the organization of these communities,
      with higher occurrence of rotifers and copepods in relation to cladocerans, the
      first ones being more abundant in the entrance of the Atibaia river, decreasing
      towards the dam direction, while copepods presented an inverse pattern. A
      distribution pattern similar to Copepoda was also verified for the Cladocera,
      evidencing a tendency to increase the density of organisms in the stations
      distant to the entrance of the Atibaia river, not being registered, however, a
      distribution gradient in the longitudinal axis, as observed for rotifers and
      copepods. In relation to the trophic degree a longitudinal gradient was also
      verified from eutrophic to oligotrophic depending on the location of the sampling
      station in relation to the longitudinal axis and period of analysis. The
      differences obtained, relating to the distribution of the environmental
      variables, demonstrate a characteristic pattern for reservoirs, with a
      longitudinal gradient in the sense river-barrage that inserts changes in the
      physical and chemical composition of the water, contributing to the
      differentiated establishing of biological communities.

PMID- 12489408
TI  - Screening for exopolysaccharide-producing bacteria from sub-tropical polluted
      groundwater.
AB  - A selection of exopolysaccharide (EPS)--producing bacterial strains was conducted
      in groundwater adjacent to an old controlled landfill in the City of Sao Carlos
      (Sao Paulo, Brazil). The strains were isolated in P and E media under aerobic and
      microacrophilic conditions at 25 degrees C. A total of 26 strains were isolated
      and based on the mucoid mode of the colonies, 6 were selected and their
      morphological, physiological and biochemical aspects were characterized. All
      strains presented pigmentation, ranging from yellow to orange and from pink to
      salmon, with a shiny glistening aspect in all tested media. Strains Lb, Lc and
      Lg, which excelled the others with regard to the mucoid mode of the colonies,
      were selected to be cultured in E medium with alternate sucrose and glucose as
      carbon sources in anaerobiosis at 25 degrees C to analyze the production of EPS.
      Strains Lc and Lg were classified as being of order Actinomycelates, suborder
      Corynebacterineae. Lg strain was identified as Gordonia polyisoprenivorans and Lc
      strain did not correspond to a known description and therefore a more detailed
      study is under preparation. Considering all ecological aspects and the metabolic
      potential associated with the microorganisms of the environment studied, as well
      as the capacity to produce pigment and EPS, and the presence of G.
      polyisoprenivorans, a rubber degrader bacterium, the potential of the groundwater
      analyzed is evident as a source of microorganisms to be utilized in studies
      related to environmental remediation.

PMID- 12489409
TI  - Protection of Vochysia elliptica (Vochysiaceae) by a nectar-thieving ant.
AB  - Vochysia elliptica (Vochysiaceae) is a shrubby plant, which does not have EFNs.
      Camponotus ants thieve nectar, and can decrease plant fitness by making flowers
      less attractive to pollinators. However, ants remove herbivores, wHich can be
      beneficial. Results show that plants from which ants were excluded had lower
      rates of termite (simulated herbivore) removal than did plants visited by ants.
      Plants accessible to ants showed higher rates of termite removal in the base of
      leaves and in the inflorescence, than in the tip of leaves. This occurs because
      ants must pass through the principal axis to reach the inflorescence. Conclusive
      results of this cost/benefit analysis of the Camponotus sp. presence for V.
      elliptica can be obtained, with experimental manipulations.

PMID- 12489410
TI  - Mandibular ramus flexure and gonial eversion as morphologic indicators of sex.
AB  - Recently, two mandibular traits--ramus flexure and gonial eversion--have come
      under close scrutiny (Loth & Henneberg 1996, 2000). The present study
      investigates the reliability of these two traits when each is applied as a single
      and independent indicator of sex, including the question of repeatability. The
      investigation was designed to give insights into possible confounding factors
      such as age and remodeling after tooth loss. Two samples, one of forensic (N =
      153) and one of archaeological provenance (N = 80), were examined. The forensic
      sample was evaluated by a single observer while the archaeological sample was
      independently scored by three different observers. The results document that age
      and localized tooth loss seriously reduce the accuracy of these traits. For ramus
      flexure, male accuracy was only 66%, while female accuracy was even lower (32%).
      Overall accuracy was 59%. It is believed that the original scoring system devised
      by Loth and Henneberg (1996) creates an inherent bias in favor of males. For
      gonial eversion, a similar picture emerged (75.4% for males, 45.2% for females
      and 69.3% overall accuracy). Furthermore, both indicators are prone to intra- as
      well as inter-observer bias. While both possess some merit as sex indicators,
      they show marked functional and adaptive responses and may not be suitable for
      all samples.

PMID- 12489411
TI  - The role of occlusal stress and gingival infection in the formation of exostoses
      on mandible and maxilla from Neolithic China.
AB  - Exostoses on the mandible and maxilla is a frequently observed bone growth of
      controversial aetiology. The aim of this study is to analyse environmental
      factors that may stimulate the formation of exostoses on different regions of the
      maxilla and mandible. Sixty-six well-preserved crania from Neolithic China were
      studied for the presence of buccal exostoses on the maxilla (BE) and lingual
      exostoses on the mandible (LME). Other oral health indicators, such as occlusal
      wear on molars, pathology of temporomandibular joint (TMJ), carious lesions,
      calculus accretion, periodontal disease, and antemortem tooth loss were recorded.
      Buccal maxillary exostosis was unusually common on the Neolithic skulls from
      China, which thus resemble the Sinantropus crania described by Weidenreich
      (1943). We report a significant Spearman correlation between BE and LME (rho =
      0.54, P < 0.00001), suggesting a partially shared aetiology of these two types of
      exostoses. The highest correlations between either form of exostoses and any oral
      indicator of stress were found for pathology at TMJ (rho = 0.46, P < 0.0001 for
      both types of exostoses). Smaller but significant correlations were observed
      between LME and the age adjusted wear rate on lower molars, as well as between BE
      and indicators of oral/dental pathology, e.g. caries, calculus, periodontoses,
      and antemortem tooth loss. Both types of exostoses tended to increase in
      frequency with age, although a significant trend was observed only for BE. We
      conclude that formation of exostoses is a complex process that can be invoked by
      any agent causing damage and inflammation of gingival tissue. However, severe
      occlusal stress, which is often manifested in TMJ disorder, is the main
      environmental factor leading to exostosis development in genetically pre-disposed
      individuals.

PMID- 12489412
TI  - An assessment of the health status and physical characteristics of an early 20th
      century community a +  Maroelabult in the north west province, South Africa.
AB  - As a result of mining activities, two related graveyards dating from the last
      decade of the 19th century and first half of the 20th century had to be
      relocated. This provided the opportunity to study 47 skeletons of black South
      Africans, with the aim of obtaining information on the health status and life
      style of people from a rural area in a mostly pre-antibiotic era. Although the
      sample is too small to do a proper palaeodemographic analysis, the age spread of
      the individuals indicates a high infant mortality rate and generally low life
      expectancy. Medical services were available, as could be seen from the surgically
      treated forearm fracture of one individual. One individual had signs of a
      possible treponemal infection, while subperiosteal bone growth on the ribs of
      another may indicate tuberculosis. High incidences of arthritic disease and joint
      degeneration probably indicate a high work load. Enlarged fontanelles with
      delayed closure were noted in some of the infants. Data on long bone lengths also
      indicate that the growth of the children may have been retarded in comparison to
      other similarly aged children. It thus seems as though this was a community under
      considerable stress. A surprising find was the unusually high incidence of
      individuals with dental abnormalities and variations.

PMID- 12489413
TI  - Relationship between parameters of early growth in Israeli infants.
AB  - A sample of 1931 Israeli infants was measured for body weight (WT), length (HT)
      and head circumference (HC) for approximately 2 years. The Count model with 3
      parameters was chosen as the best fitting and most parsimonious function to
      approximate growth of all 3 studied traits. In the model parameter a relates to
      birth indices, b--to velocity of growth, and c--to rapid early childhood growth,
      or acceleration. Assuming a difference in growth patterns in the periods of
      different length, the whole sample was divided into 3 groups: 1) infants with
      last measurement around the age of 12 months; 2) infants with last measurement
      around the age of 18 months, and 3) infants with last measurement around the age
      of 24 months. The individuals measured up to 12 months were presented in all
      three groups. 27 curve fitting parameters, corresponding to 3 different follow-up
      intervals for WT, HT and HC were computed for each individual. A high correlation
      was detected between the a parameters regardless of time interval for 3 measured
      traits. A negative correlation was found between b and c parameters within the
      same time interval. A consistent positive correlation was indicated between a and
      b parameters, especially for body length and head circumference. A principal
      component analysis extracted five independent factors explaining 88.1% of the
      total variance. Three first factors retained parameters b and c, describing
      growth rate and pattern of each trait separately, namely, F1 was responsible for
      head circumference, F2 was a body length factor, F3 was a body weight factor. F4
      extracted all birth indices, observed (HC0, HT0 and WT0) and expected (parameters
      a). The composition of principal factors allowed us to assume that there might be
      a strong involvement of a pleiotropic genetic source in determination of birth
      size traits and an independent genetic source controlling the pattern of growth
      for each trait separately.

PMID- 12489414
TI  - Systemic changes in body structure of 17-18-year-old schoolboys.
AB  - The purpose of this study was to assess the systemic structural changes in the
      body build of 17-18-year-old schoolboys in the final years of Tartu secondary
      schools within a height-weight classification dividing anthropometric variables
      into 5 SD-classes. Weight and height, 9 length, 8 breadth and 2 depth
      measurements, 16 circumferences and 12 skinfolds were measured. From these 5
      length measurements and 53 indices were computed, which characterise the ratios
      of various parts of the body to body height, to upper and lower limbs' length and
      body composition. The subjects (n = 253) were divided into five standard
      deviation classes according to height and weight (Kaarma 1981, 1995). In the
      first three classes height and weight were proportional: (1) small height--small
      weight, (2) medium height--medium weight and (3) big height--big weight. In the
      fourth and the fifth class height and weight were non-proportional. In the fourth
      class weight was preponderant over height, and in the fifth class height was
      preponderant over weight. It was proved that a statistical difference exists
      between the opposite classes--the fourth and the fifth class. It was also
      revealed that the three proportional classes differ from each other
      significantly. Increase in body height and weight leads also to an increase in
      length, breadth and depth measurements, bone thicknesses, circumferences and
      skinfolds. Rohrer index, body mass index, total percentage of fat by Siri,
      absolute and relative mass of fat tissue increased from the small to the large
      class. The relationship of the length, width, and depth measurements,
      circumferences and bone thicknesses to height remains almost unchanged throughout
      the proportional classes. These investigations support the position that the
      whole body model may be reconstructed from body height and weight.

PMID- 12489415
TI  - Genetic marker variation in coastal populations of Chile.
AB  - Gene frequencies for nine genetic marker systems are presented for the following
      Chilean coastal populations: Paposo, Carelmapu, Laitec and Ukika. Historical and
      anthropological data suggest the presence of descendants of the Amerindian
      populations, specifically of Changos, Cuncos, Chonos and Yamanas in these
      populations. Results indicate that the studied groups maintain an important
      aboriginal genetic composition. According to Amerindian admixture estimates, the
      genetic isolation of coastal populations is lower than that of inland
      populations, suggesting that proximity to the sea facilitated gene flow. Genetic
      distances and dendrograms were obtained for these populations and another four
      Chilean Indian populations. Results agree with expectations, taking geographic
      isolation and non-aboriginal admixture into account.

PMID- 12489417
TI  - SDS polyacrylamide gel electrophoresis for N-terminal protein sequencing.

PMID- 12489416
TI  - Strategies for handling polypeptides on a micro-scale.

PMID- 12489418
TI  - Two-dimensional polyacrylamide gel electrophoresis for the separation of proteins
      for chemical characterization.

PMID- 12489419
TI  - Electroblotting of proteins from polyacrylamide gels for chemical
      characterization.

PMID- 12489420
TI  - Enzymatic cleavage of proteins.

PMID- 12489421
TI  - Chemical cleavage of polypeptides.

PMID- 12489422
TI  - Enzymatic preparation and isolation of glycopeptides.

PMID- 12489423
TI  - Analytical and micropreparative capillary electrophoresis of peptides.

PMID- 12489424
TI  - High-performance liquid chromatography on-line derivative spectroscopy for the
      characterization of peptides with aromatic amino acid residues.

PMID- 12489426
TI  - Amino acid analysis. Precolumn derivatization methods.

PMID- 12489425
TI  - Hydrolysis of samples for amino acid analysis.

PMID- 12489427
TI  - Post column amino acid analysis.

PMID- 12489428
TI  - Amino acid analysis using pre-column derivatization with 6-aminoquinolyl-N
      hydroxysuccinimidyl carbamate. Analysis of hydrolyzed proteins and electroblotted
      samples.

PMID- 12489429
TI  - Amino acid analysis in protein hydrolysates using anion exchange chromatography
      and IPAD detection.

PMID- 12489430
TI  - D-amino acid analysis.

PMID- 12489431
TI  - Validation of amino acid analysis methods.

PMID- 12489432
TI  - Electrospray mass spectrometry of peptides, proteins, and glycoproteins.

PMID- 12489433
TI  - Peptide mass fingerprinting using MALDI-TOF mass spectrometry.

PMID- 12489434
TI  - Nanoelectrospray tandem mass spectrometry and sequence similarity searching for
      identification of proteins from organisms with unknown genomes.

PMID- 12489435
TI  - Direct identification of proteins in ultracomplex mixtures. Applications to
      proteome analysis.

PMID- 12489436
TI  - Identification of PTH-amino acids by HPLC.

PMID- 12489437
TI  - Protein sequencer maintenance and troubleshooting.

PMID- 12489438
TI  - N-terminal protein sequencing for special applications.

PMID- 12489439
TI  - Identification of phosphorylation sites by Edman degradation.

PMID- 12489440
TI  - Validation of protein sequencing in a regulated laboratory.

PMID- 12489441
TI  - Automated C-terminal protein sequence analysis using the alkylated-thiohydantoin
      method.

PMID- 12489442
TI  - Chemical modifications of proteins as an aid to sequence analysis.

PMID- 12489443
TI  - Deblocking of N-terminally modified proteins.

PMID- 12489444
TI  - Deblocking of proteins containing N-terminal pyroglutamic acid.

PMID- 12489445
TI  - Identification of sites of glycosylation.

PMID- 12489446
TI  - Analysis of sites of protein phosphorylation.

PMID- 12489447
TI  - Quantitation and location of disulfide bonds in proteins.

PMID- 12489448
TI  - Getting the most from your protein sequence.

PMID- 12489449
TI  - Letter codes, structures, masses, and derviatives of amino acids.

PMID- 12489450
TI  - Protein consensus sequence motifs.

PMID- 12489451
TI  - Superantigens. Structure, function, and diversity.

PMID- 12489452
TI  - Expression, purification, and detection of novel streptococcal superantigens.

PMID- 12489453
TI  - Flow cytometric detection of MMTV superantigens.

PMID- 12489454
TI  - Spectrophotometric methods for the determination of superantigen structure and
      stability.

PMID- 12489455
TI  - Binding kinetics of superantigen with TCR and MHC class II.

PMID- 12489456
TI  - Directed evolution of T-cell receptors for binding superantigens.

PMID- 12489457
TI  - Analysis of superantigen binding to soluble T-cell receptors.

PMID- 12489458
TI  - Role of accessory molecules in the superantigen-induced activation of peripheral
      blood T cells.

PMID- 12489459
TI  - T-lymphocyte activation induced by staphylococcal enterotoxin superantigens.
      Analysis of protein tyrosine phosphorylation.

PMID- 12489460
TI  - Measurement of proinflammatory cytokines and T-cell proliferative response in
      superantigen-activated human peripheral blood mononuclear cells.

PMID- 12489462
TI  - Staining protocol for superantigen-induced cytokine production studied at the
      single-cell level.

PMID- 12489461
TI  - RNase protection assay for the study of the differential effects of therapeutic
      agents in suppressing staphylococcal enterotoxin B-induced cytokines in human
      peripheral blood mononuclear cells.

PMID- 12489463
TI  - Assessment of specific T-cell activation by superantigens.

PMID- 12489464
TI  - Superantigen-induced changes in epithelial ion transport and barrier function.
      Use of an in vitro model.

PMID- 12489465
TI  - Pyrogenic, lethal, and emetic properties of superantigens in rabbits and
      primates.

PMID- 12489466
TI  - Gastroesophageal reflux disease revisited.
AB  - GERD should be viewed as three distinct groups of patients: NERD, erosive
      esophagitis, and Barrett's esophagus. This new paradigm will shift our focus to
      mechanisms leading to symptom generation in each group and foster specific
      therapeutic modalities that benefit each individual group of patients.

PMID- 12489467
TI  - Central mechanisms of lower esophageal sphincter control.
AB  - Lower esophageal sphincter (LES) tone is decreased during swallowing, during
      transient LES relaxations (TLESRs), and before emesis, and this decrease is due
      primarily to increasing inhibitory vagal output to the LES. Reflex-evoked
      relaxation of the LES is mediated by long-loop vagovagal reflexes that are
      coordinated by the dorsal vagal complex in the hindbrain medulla. A sequence of
      events occurs. Central control of TLESRs has not been studied directly; the
      information on how drugs may work centrally to reduce TLESRs is extrapolated from
      knowledge of how the brain evokes LES relaxation. Reduction of the frequency of
      TLESRs by a GABAB agonist, baclofen, is due to inhibition of vagal afferents,
      information transfer between the nucleus tractus solitarius and dorsal motor
      nucleus of the vagus, and vagal efferent outflow. Preliminary data show that
      cannabinoid receptor activation reduces information transfer between the nucleus
      tractus solitarius and dorsal motor nucleus of the vagus. The potential
      therapeutic usefulness of these types of agents that reduce TLESRs by acting
      centrally is promising.

PMID- 12489468
TI  - Peripheral mechanisms affecting the lower esophageal sphincter tone.
AB  - LES tone is influenced by central and peripheral mechanisms. Peripheral factors
      influencing the LES tone include inhibitory reflexes originating from the
      stomach, esophagus, pharynx, and larynx. Although the role of LES relaxation and
      its associated reflux events induced by gastric distention has been extensively
      studied, the LES relaxations triggered by stimulation of the aerodigestive tract
      have only recently been the focus of systematic investigation and have resulted
      in documentation of the intricate reflex relationship between the upper
      gastrointestinal tract and the aerodigestive tract.

PMID- 12489469
TI  - Pathogenesis of gastroesophageal reflux disease.
AB  - The pathophysiology of GERD involves contact of the esophageal epithelium with
      acid/pepsin in the refluxate. For this contact to occur with sufficient duration,
      there must be a combination of defects in antireflux and luminal clearance
      mechanisms for acid/pepsin to overwhelm an intact epithelium, or defects within
      the epithelium develop that subsequently enable normal acid contact times to
      become damaging to the epithelium. In either case, the final common pathway is
      damage to the esophageal epithelium--damage that is reflected in the development
      of heartburn, esophageal necrosis and inflammation, or both.

PMID- 12489470
TI  - Assessment of relationship between acid reflux and heartburn using receiver
      operating characteristic curves.
AB  - Arguments proposed in this article may explain why a subgroup of patients, having
      so-called "functional heartburn," does not respond to acid inhibition therapy
      [19,20]. It is highly likely that acid is not the cause of heartburn in this
      group of subjects. These conclusions are supported further by observations of
      Wiener et al [2] and Howard et al [21], who found that a subgroup of patients
      with high SI have a negative Bernstein test, which suggests that the presence of
      acid in the esophagus at the time of spontaneous heartburn may be coincidental
      and does not reflect a cause-and-effect relationship between the two. The motor
      events responsible for the occurrence of acid reflux (longitudinal muscle
      contraction of the esophagus [SEC] associated with transient LES relaxation) may
      be the cause of heartburn sensation.

PMID- 12489471
TI  - Natural history of nonerosive reflux disease. Is all gastroesophageal reflux
      disease the same? What is the evidence?
AB  - Currently not much can be said about the natural history of NERD. The existing
      data show that GERD symptoms are common, affecting one out of five adults on a
      weekly basis, but they fluctuate dramatically and are associated with other forms
      of gastrointestinal symptoms. Clinic-based studies suggest that the natural
      history of NERD and GERD is the same in regard to symptom duration and ratings of
      symptom severity. These studies show some transition between NERD and erosive
      reflux disease. At present, there is a need to establish more accurately the
      clinical condition to be labeled as NERD. This condition should be defined by
      noninvasive tests. A true natural history study could be performed and address
      the question in more detail.

PMID- 12489472
TI  - Decision making in gastroesophageal reflux disease. What are the critical issues?
AB  - This article has identified several crucial decision points in the management of
      GERD. Although there seems to be a strong epidemiologic association with
      esophageal adenocarcinoma, the clinical and economic benefits of screening
      endoscopy are not clear. Given the low incidence of this cancer, it is
      conceivable that screening programs in these patients, such as colon cancer
      screening and breast cancer screening, may provide a greater health benefit at a
      lower incremental cost. Surveillance endoscopy in BE is another contentious
      issue, with the surveillance interval and cost-effectiveness hinging on the
      cancer risk. As more precise estimates of cancer risk, accounting for publication
      bias, are derived, the economics of surveillance will require further evaluation.
      Finally, several, management strategies seem to improve outcomes for patients
      with uninvestigated GERD, but the incremental costs of the more effective step
      down approach seem minimal. More important than the initial strategy may be the
      ability to implement a systematic approach to care that ensures that patients
      attempt step-down when symptoms are resolved and do not remain on potent therapy
      indefinitely when it is not necessary. The results of prospective effectiveness
      trials are anticipated to validate the findings of these economic analyses.

PMID- 12489473
TI  - Persistent gastroesophageal reflux disease symptoms on standard proton-pump
      inhibitor therapy.
AB  - Eight patients with refractory GERD symptoms were controlled over a mean of 15.4
      years only by the addition of a benzodiazepine to once-daily or twice-daily PPI
      therapy. In selected patients with refractory GERD, as defined by continued
      reflux symptoms despite twice-daily PPIs, the addition of a benzodiazepine to the
      PPI regimen may provide additional control of GERD symptoms.

PMID- 12489474
TI  - Novel methods of using proton-pump inhibitors.
AB  - On-demand therapy with PPIs is a new strategy that has been shown to be effective
      in patients with nonerosive reflux disease or mild erosive reflux disease. This
      strategy can reduce the cost of maintenance therapy substantially and is
      particularly appealing in patients with no evidence of mucosal disease. The long
      term efficacy and safety of this form of therapy have not been established.
      Nocturnal reflux may be important in patients with complicated reflux disease or
      Barrett's esophagus. Data on combining PPIs with H2RAs suggest that nocturnal
      gastric pH can be controlled by the administration of H2RAs at bedtime. There are
      few data on nocturnal symptoms, and some studies suggest that tachyphylaxis may
      develop with H2RA therapy. More data are required on the clinical effectiveness
      of combination therapy administered long-term.

PMID- 12489475
TI  - Surgical and endoscopic treatment of gastroesophageal reflux disease.
AB  - There is no evidence to advocate medical or surgical therapy as the best therapy
      for GERD. The decision to have antireflux surgery must be individualized. All
      patients taking long-term medications for GERD should receive advice on the
      safety and wisdom of staying on that therapy and information on antireflux
      surgery. Fundoplication should be considered in three circumstances [4]: 1.
      Patients who are intolerant of PPI therapy because of side effects should be
      considered for surgery. This situation will be less common now with five PPIs,
      however. 2. Patients who are poorly responsive to PPI therapy should be
      considered for surgery. This situation is probably not common, given the
      effectiveness of the currently available PPIs. It is more common in patients with
      atypical GERD. The gastroenterologist should be as certain as possible that the
      patient not only has GERD, but also that the patient's symptoms are reflux
      related. 3. Surgery should be considered when patients desire a permanent
      solution to free them of the need to take medications. These patients must be
      warned about the potential suboptimal results, including the frequent need for
      medication within a few years of having the procedure and the small but real
      possibility of becoming worse after the operation. Even in experienced hands, 1%
      to 2% of patients are worse after the procedure. A careful preoperative
      evaluation to ensure that the patient's symptoms are reflux related and that the
      right operative procedure is performed offers the patient the best opportunity
      for success. Widespread use of endoscopic therapy for GERD is probably still
      several years away. The best endoscopic therapy is yet to be determined, but it
      will need to be safe, effective, and easy to use.

PMID- 12489476
TI  - Novel medical therapies for gastroesophageal reflux disease beyond proton-pump
      inhibitors.
AB  - The control of TLESRs is a novel pharmacologic approach to the treatment of GERD.
      It is applicable in most reflux patients characterized as having nonerosive
      disease or patients with mild erosive disease. Currently, only the GABAB agonist
      baclofen is available for oral therapy, although side effects may be a limiting
      factor. Future drug development requires a better understanding of the central
      and peripheral mechanisms controlling TLESRs.

PMID- 12489477
TI  - [Anemia induced by solid tumor chemotherapy].
AB  - Cancer patients frequently experience anemia as a complication of chemotherapy.
      Recent advances in assessing the relationships between anemia, fatigue and
      quality of life (QOL) in such patients have resulted in a new multidimensional
      perspective of these parameters. Clinical data suggest that even a mild-to
      moderate chemotherapy-induced anemia results in a significant reduction in a
      patient's energy level and QOL. As recombinant human erythropoetin has recently
      become available for the treatment of this condition, we performed a review of
      the incidence and severity of anemia associated with commonly employed
      chemotherapy regimens in the major non-hematologic malignancies. Although evident
      flaws in the grading and reporting of treatment-related anemia have limited
      analysis, the results clearly indicate a relatively high incidence of mild-to
      moderate anemia. Research in progress is likely to result in a new classification
      of chemotherapy-induced anemia that can guide therapeutic interventions on the
      basis of outcomes and hemoglobin levels. The once widespread belief that lesser
      degrees of anemia must be endured without treatment may be overcome as greater
      emphasis is placed on the QOL of the oncology patient. Further insights into the
      relationships between hemoglobin levels, patient well-being and symptoms may lead
      to a refinement of current strategies of approaching the treatment of anemia.

PMID- 12489478
TI  - [Innovative treatment in oncology].
AB  - The improved knowledge of the key molecular mechanisms involved in cell
      transformation and tumor progression allows to the identification of new
      therapeutic targets for anticancer therapy. Several molecular-targeting compounds
      have been developed, capable to selectively interfire with tumorangiogenesis,
      receptors with tyrosin-chinase activity, specific tumor growth factors. A
      rationale selection of the patients as well as an appropriate monitoring of
      pharmacodynamics effects of molecular-targeting compounds need of the
      availability of surrogate markers, assessable in tumor tissue of circulating
      blood.

PMID- 12489479
TI  - [Tumor-correlated asthenia].
AB  - Fatigue is one of the most common complaints of people with cancer. In this
      setting, fatigue is to be defined as a chronic form of tiredness, which is
      perceived by the patient as being unusual or abnormal, and absolutely
      disproportionate with respect to the amount of exercise or activity he/she has
      carried out and which is not removed by resting or sleeping. It affects the
      majority of patients actively undergoing cancer related therapies, but also a
      meaningful number of those who successfully completed therapy and are disease
      free and potentially cured at the end of the treatments. The exact cause of
      fatigue is not known. There is no standard of care for the assessment or
      treatment of fatigue in patients with cancer. The evaluation of fatigue is
      intrinsically multidimensional, and a number of methods have been developed to
      assess it. Treatment of fatigue should depend on its cause, but presently it is
      still addressed against the associated symptoms rather than fatigue itself. In
      this article some of the crucial issues related to fatigue in people with cancer
      are reviewed.

PMID- 12489480
TI  - [Primary centrofollicular cutaneous cell lymphoma. Clinical description,
      treatment results, and follow up of 21 cases].
AB  - BACKGROUND: The goal of this study was to describe the clinical, biological,
      features and the outcome of 21 patients with primary cutaneous centro-follicular
      lymphoma (PCL-CF). PATIENTS AND METHODS: A group of 21 consecutive patients with
      PCL-CF (median age 56 years) presenting with single (11/21) or multiple (10/21)
      cutaneous lesions observed between January 1980 and June 2000 were described. The
      histologic features, treatment modalities and outcome were shown. RESULTS: The
      patients mainly presented with cutaneous lesions on the head and trunk (19/21).
      Histological findings were grade I, II and III (REAL/WHO classification) in 4, 8
      and 9 patients respectively. Pattern was follicular (12/21) and diffuse (9/21).
      Treatment of PCL-CF consisted in restricted field radiotherapy (RT), chemotherapy
      (CHT) and combined modalities (CM) in 11, 5 and 5 cases respectively. The
      response to treatment was: 17 complete responses, CR (13 RT, 2CHT, 2CM), 3
      partial responses, PR (1 CHT, 2 CM) and 1 non response, NR (1CHT). The relapse
      rate was 23.8% with a median follow-up of 48 months; the estimated 4 years event
      free survival (EFS) and overall survival (OS) were 68% and 90% respectively.
      DISCUSSION AND CONCLUSIONS: Our experience demonstrates that PCL-CF are
      lymphoproliferative disorders with a good prognosis after adequate therapy and
      that the histologic features did not influence significantly both response and
      survival.

PMID- 12489481
TI  - [Porocarcinoma of the parotid area. Report of a case].
AB  - The Authors describe the case of a 55 years old man, affected by
      ipercolesterolemy, ipertension and glaucoma, observed because of an important
      left parotid and laterocervical erythema with a small brown area measuring less
      than 1 cm inside. In the last two years the patient underwent resection of two
      basaliomas and of a porocarcinoma, with infiltration of margins, in the same
      region. Clinical and instrumental findings indicated the presence of reactive
      parotid's nodes; no evident lesions appeared at the examination of the ENT
      regions. The Authors describe and support their therapeutic approach.

PMID- 12489482
TI  - [Clinical postoperative surveillance of gastric carcinoma].
AB  - Up to today no agreement has been reached in relation with gastric remnant
      surveillance. In the cases of partial gastrectomy for benign pathology, most of
      the Authors agree in believing that in the asymptomatic subject a follow-up is
      necessary after 15-20 years only from the surgical intervention. Differently, for
      the cases of partial gastrectomy for malignant neoplasia, it has not been well
      defined yet the clinical surveillance. Certainly, a surgical intervention in case
      of relapse presents remarkable difficulties. The relapses are often located in
      lymphnodes site or metastasis are present and, therefore, the relapses are local
      in a low percentages. Besides, sometimes the local relapses cannot be re
      operated. In spite of such considerations, the personal opinion is that to act in
      asymptomatic subjects a regular follow-up, in patients operated for early cancer
      above all. That is justified by the possibility to notice, by means of endoscopy
      with multiple biopsies, of pre-neoplastic (epithelial dysplasia) or precocious
      neoplasia lesions, with the aim of obtaining a satisfactory radical surgical
      intervention.

PMID- 12489483
TI  - [Clinical postoperative surveillance of colorectal carcinoma].
AB  - Post-operative follow-up after "curative" surgery for patients affected by colon
      rectal carcinoma depends upon multiple variables such as type of operation
      (conservative or wide surgery), adoption of neo-adjuvant or adjuvant treatments
      (i.e. radiotherapy and/or chemotherapy) to surgery, the availability of anatomo
      pathological or biological parameters predictive of unfavourable prognosis. Even
      though an international agreement on follow-up policy has not still reached,
      patients with colon-rectum cancer should be intensively (every 6 months) checked
      in the first 3 years from surgery and every 12 months afterwards. An early
      detection of asymptomatic pelvic recurrences or abdominal neoplastic progression
      may help prolong survival of patients and improve their quality of life.

PMID- 12489484
TI  - [Clinical postoperative surveillance of breast carcinoma].
AB  - The problem of post-surgical clinical follow-up for breast cancer patients is
      still open. A lot of comparative studies between intensive and minimal follow-up
      showed no advantage of the former vs. the latter modality. The above data have
      been confirmed also from sistematic revisions and from pharmaco-economic studies.
      The ASCO guidelines confirm the importance of clinical surveillance, together
      with annual mammography and pelvic examination, while no blood tests or other
      instrumental examinations are indicated in absence of specific symptoms. The
      follow-up program needs to be realized under the supervision of a specialist with
      specific experience in the oncologic evaluation. Concerning the patients with
      high risk of recurrence, there is no agreement, even if no advantage seems to
      exist with an intensive follow-up program in terms of quality or quantity of
      life. The Authors suggest that the standard follow-up program should include a
      thoracic X-ray picture and an abdominal USG, in order to detect early a small
      number (< or = 2 sites) of visceral metastases, amenable of a treatment. The
      above program should be realized from a multidisciplinary team (surgeon, medical
      oncologist, radiotherapist) gaining in terms of quality and sparing time and
      resources.

PMID- 12489485
TI  - [Chemokines and tumors].
AB  - Chemokines are cytokines which induce chemotaxis on many cell types, thus
      regulating cell migration within inflammatory and allergic sites, and leucocyte
      homing. Also, they play a crucial role in inflammatory and tumor-associated
      angiogenesis, as well as in tumor progression. Chemokines are grouped into: 1)
      alpha or CXC; 2) beta or CC; 3) gamma or C; 4) delta or CX3C molecules. Each of
      them recognizes one or more cell surface receptors, named CXCR, CCR, XCR, CX3CR
      respectively, according to the corresponding subfamily. Many chemokines have been
      identified within tumor tissues, as a secretory product of tumor cells and/or
      inflammatory cells. The CXC chemokines (such as IL-8, IP10, Mig, SDF-1 alpha) or
      CC chemokines (such as MCP-1, MIP-1 alpha, eotaxin, RANTES) have been frequently
      harvested from tumor tissues or the biological fluids of patients. Some
      chemokines inhibit tumor growth and progression by activating immunocompetent
      cytolytic cells or inhibiting tumor-associated angiogenesis. In contrast, other
      chemokines induce tumor progression by interacting with the specific receptor
      expressed on the tumor cells and hence by activating chemotaxis and secretion of
      proteolytic enzymes, or by inducing angiogenesis and metastatic spreading.
      Sometimes neoplastic cells express chemokine receptors which are not expressed on
      their normal counterpart. Data from this lab show the CXCR3 expression by cells
      from lymphoproliferative diseases, such as multiple myeloma and lymphoma, and the
      stimulation of an invasive phenotype following interaction with specific
      chemokines.

PMID- 12489486
TI  - Polymorphisms in glucosylceramide (glucocerebroside) synthase and the Gaucher
      disease phenotype.
AB  - BACKGROUND: Gaucher disease results from the accumulation of glucosylceramide
      (glucocerebroside) in tissues of affected persons. Patients sharing the same
      genotype present with widely varying degrees of lipid storage and of clinical
      manifestations. OBJECTIVES: To determine whether variation in the
      glucosylceramide synthase (UDPGlucose ceramide glucosyltransferase) gene, which
      encodes the enzyme that regulates the synthesis of glucocerebroside, could
      account for the variability and clinical manifestations. METHODS: Patients
      homozygous for the 1226G (N370S) mutation, the most common in the Ashkenazi
      Jewish population, were investigated. The exons and flanking sequences of the
      gene were sequenced using DNA derived from five very mild Gaucher disease
      patients and four patients with relatively severe Gaucher disease. RESULTS: One
      polymorphism was found in the coding region, but this did not change any amino
      acids. Seven other polymorphisms were found in introns and in the 5' untranslated
      region. Some of these were single nucleotide polymorphisms; others were
      insertions. The mutations appear to be in linkage equilibrium and none were found
      with a significantly higher frequency in either severe or mildly affected
      individuals. CONCLUSIONS: Mutations in the glucosylceramide synthase gene do not
      appear to account for the variability in expression of the common Jewish Gaucher
      disease mutation.

PMID- 12489487
TI  - Cryopreserved fetal human liver hematopoietic progenitor cells for repopulating
      immune-deficient mouse bone marrow.
AB  - BACKGROUND: Experimental and clinical protocols are being developed for the
      cryopreservation of human hematopoietic progenitor cells. However, the effect of
      these procedures on the potential for HPC to repopulate bone marrow is unknown.
      OBJECTIVES: To examine the effect of cryopreservation on the ability of fetal
      human liver HPC, which include CD34+ cells and long-term culture-initiating
      cells, to repopulate immunodeficient non-obese diabetic/severe combined
      immunodeficiency mouse bone marrow. METHODS: Groups of sublethally irradiated
      NOD/SCID mice were injected intravenously with cryopreserved or freshly isolated
      fetal human liver HPC. RESULTS: Seven weeks after transplantation, flow
      cytometric analysis of bone marrow samples showed that mice that received the
      transplanted cells (either cryopreserved or freshly isolated) demonstrated both
      lymphoid and myeloid differentiation as well as the retention of a significant
      fraction of CD34+ cells. CONCLUSIONS: Cryopreserved fetal human liver-derived HPC
      appear to be capable of initiating human cell engraftment in NOD/SCID mouse bone
      marrow and open the possibility of using cryopreserved fetal human liver HPC for
      gene manipulation, gene transfusion therapy, and transplantation purposes.

PMID- 12489488
TI  - Fibrinogen: intra-individual variability in patients with arterial disease and in
      patients with cardiac valve replacements.
AB  - BACKGROUND: Elevated fibrinogen, considered an independent risk factor for
      coronary disease, stratifies an individual as high risk for coronary disease. A
      risk marker requires little intra-individual variability during a long period.
      OBJECTIVES: To establish intra-individual variability of fibrinogen levels in
      patients with coronary disease. METHODS: We investigated fibrinogen levels
      prospectively in four blood samples drawn from 267 patients with a history of
      arterial disease (arterial group) and from 264 patients with cardiac valve
      replacements (valvular group). The samples were taken during the course of 78.7
      and 78.8 days from the arterial and valvular groups respectively. RESULTS: Marked
      intra-individual dispersion with a reliability coefficient of 0.541 was found in
      the arterial group and 0.547 in the valvular group. The Bland-Altman test showed
      low probability to obtain similar results in different samples from the same
      individual. These results show large intra-individual variability, with
      similarities in the arterial as well as in the valvular group. CONCLUSIONS: It is
      not possible to stratify a patient by a specific fibrinogen dosage.

PMID- 12489489
TI  - Involvement of human heparanase in the pathogenesis of diabetic nephropathy.
AB  - BACKGROUND: Decreased heparan sulfate proteoglycan content of the glomerular
      basement membrane has been described in proteinuric patients with diabetic
      nephropathy. Heparanase is an endo-beta-D-glucuronidase that cleaves negatively
      charged heparan sulfate side chains in the basement membrane and extracellular
      matrix. OBJECTIVES: To investigate whether urine from type I diabetic patients
      differs in heparanase activity from control subjects and whether resident
      glomerular cells could be the source of urinary heparanase. METHODS: Using
      soluble 35S-HSPG and sulfate-labeled extracellular matrix we assessed heparanase
      activity in human glomerular epithelial cells, rat mesangial cells, and urine
      from 73 type I diabetic patients. Heparanase activity resulted in the conversion
      of a high molecular weight sulfate-labeled HSPG into heparan sulfate degradation
      fragments as determined by gel filtration analysis. RESULTS: High heparanase
      activity was found in lysates of both epithelial and mesangial cells.
      Immunohistochemical staining localized the heparanase protein to both glomeruli
      capillaries and tubular epithelium. Heparanase activity was detected in the urine
      of 16% and 25% of the normoalbuminuric and microalbuminuric diabetic patients,
      respectively. Urine from 40 healthy individuals did not possess detectable
      heparanase. Urinary heparanase activity was associated with worse glycemic
      control. CONCLUSION: We suggest that heparanase enzyme participates in the
      tunover of glomerular HSPG. Hyperglycemia enhances heparanase activity and/or
      secretion in some diabetic patients, resulting in the loss of albumin
      permselective properties of the GBM.

PMID- 12489490
TI  - Treatment of venous thromboembolism with the oral thrombin inhibitor,
      ximelagatran.
AB  - BACKGROUND: Venous thromboembolic diseases are treated initially with low
      molecular weight heparin followed by oral coumarins. OBJECTIVES: To investigate
      an orally available direct thrombin inhibitor for the acute treatment of venous
      thromboembolism as well as for prophylaxis of recurrent events. METHODS: The
      direct thrombin inhibitor ximelagatran was compared with subcutaneous LMW
      heparins followed by oral warfarin in a double-blind randomized prospective
      multicenter trial in patients with acute VTE. A pharmacokinetic study was
      performed in the VTE patients. For assessing the prevention of recurrent VTE,
      double-blind prospective randomized studies were conducted as follows: a)
      ximelagatran compared to warfarin for 6 months, and b) prolonged anticoagulation
      of ximelagatran vs. placebo for 18 months after termination of 6 months coumarin
      therapy. RESULTS: Two dose-finding studies and the pharmacokinetic analysis of
      ximelagatran in acute VTE were completed. About 2,500 patients were randomized to
      investigate 2 x 36 mg ximelagatran versus 2 x 1 mg/kg body weight enoxaparin
      followed by warfarin. The study hypothesized that the efficacy was equal in both
      treatment regimens for recurrent VTE documented by objective methods. The second
      study, with 1,234 patients, aimed to demonstrate a reduced incidence of recurrent
      thromboembolic events documented by objective methods after 18 months of
      treatment with 2 x 24 mg ximelagatran daily compared to placebo. CONCLUSION:
      These large-scale clinical trials will soon yield the results of the comparison
      between oral ximelagatran and subcutaneous LMW heparin for treatment of acute
      VTE, and of warfarin for prophylaxis of recurrent events for 6 months and for a
      prolonged prophylaxis for another 18 months.

PMID- 12489491
TI  - Rituximab for refractory childhood autoimmune hemolytic anemia.
AB  - BACKGROUND: Chronic childhood autoimmune hemolytic anemia is an uncommon disorder
      that is associated with significant morbidity. Treatment with high dose steroids,
      splenectomy and frequent blood transfusions results in a myriad of complications
      including growth failure, bone demineralization, Cushing's syndrome,
      immunosuppression, and transfusional hemosiderosis. OBJECTIVES: To investigate
      the efficacy of the monoclonal anti-CD20 antibody, rituximab, in treating
      children with AIHA. METHODS: Four children with chronic AIHA, including two with
      prior splenectomy, who were dependent on high dose steroids and refractory to
      other immunosuppressive regimens were treated with four to six weekly doses of
      rituximab at a dose of 375 mg/m2. RESULTS: All four patients became transfusion
      independent and were taken off prednisone completely. Adverse effects included
      infusion-related reactions that were mild, and infectious complications of
      Pneumocystis carinii pneumonia and varicella pneumonia. CONCLUSIONS: Treatment
      with rituximab appears promising for refractory AIHA; if may obviate the need for
      prednisone and may result in sustained disease remissions in some patients.

PMID- 12489492
TI  - Characteristics and functional outcome of traumatic hyphema without routine
      administration of epsilon-aminocaproic acid.
AB  - BACKGROUND: The prevalence of traumatic hyphema as well as the distribution of
      its severity varies among different patient populations. Treatment
      recommendations in the literature differ significantly among various published
      reports. This lack of a uniformly accepted treatment probably reflects the
      different characteristics of this pathology among the populations investigated
      and cells for a population-adjusted treatment recommendation. OBJECTIVES: To
      report the characteristics and functional outcome of patients with traumatic
      hyphema and to discuss possible recommendations regarding the use of epsilon
      aminocaproic acid. METHODS: A prospective, non-randomized study was conducted in
      154 consecutive patients with traumatic hyphema, including data collection of
      ophthalmic status at various time points, the presence or absence of secondary
      hemorrhage, and final visual acuity. RESULTS: Of the 154 eyes studied over 3
      years, nearly 90% had hyphema of grade 1 or less, 5 (3.25%) experienced
      rebleeding, and 2 (1.3%)--neither of which rebled--needed surgical intervention.
      None of the four patients who experienced final visual acuity of 6/40 or less
      suffered rebleeding. CONCLUSION: The use of epsilon-aminocaproic acid in the
      studied population was unjustified and routine use of epsilon-aminocaproic acid
      in our patient population is probably not indicated. A treatment policy regarding
      epsilon-aminocaproic acid use should be adjusted to the population being treated.

PMID- 12489493
TI  - Malignant myeloid transformation in congenital forms of neutropenia.
AB  - BACKGROUND: Granulocyte colony-stimulating factor has had a major impact on the
      management of severe chronic neutropenia--a collective term referring to
      congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G
      CSF with increased neutrophils, reduced infections, and improved survival. Some
      responders with congenital neutropenia (termed Kostmann's syndrome herein) and
      Shwachman-Diamond syndrome have developed myelodysplastic syndrome and acute
      myeloid leukemia, which raises the question of the role of G-CSF in pathogenesis.
      The issue is complicated because both disorders have a propensity for MDS or AML
      as part of their natural history. OBJECTIVE AND METHODS: To address this, the
      Severe Chronic Neutropenia International Registry used its large database of
      chronic neutropenia patients treated with G-CSF to determine the incidence of
      malignant myeloid transformation in the two disorders, and its relationship to
      treatment and to other patient characteristics. RESULTS: As of January 2001, of
      the 383 patients with congenital forms of neutropenia in the Registry, 48 had MDS
      or AML (crude rate, about 12.5%). No statistically significant relationships were
      found between age at onset of MDS or AML and patient gender, G-CSF dose, or
      duration of G-CSF therapy. What was observed, however, was the multistep
      acquisition of aberrant cellular genetic changes in marrow cells from Kostmann's
      syndrome patients who transformed, including activating ras oncogene mutations,
      clonal cytogenetic abnormalities, and G-CSF receptor mutations. The latter in
      murine models produces a hyperproliferative response to G-CSF, confers resistance
      to apoptosis, and enhances cell survival. CONCLUSIONS: Since Kostmann's syndrome
      and Shwachman-Diamond syndrome are inherited forms of bone marrow failure, G-CSF
      may accelerate the propensity for MDS/AML in the genetically altered stem and
      progenitor cells, especially in those with G-CSF receptor and ras mutations (82%
      and 50% of Kostmann's syndrome patients who transform, respectively).
      Alternatively, and equally plausible, G-CSF may simply be an innocent bystander
      that corrects neutropenia, prolongs patient survival, and allows time for the
      malignant predisposition to declare itself. Only careful long-term follow-up of
      the cohort of patients receiving G-CSF will provide the answer.

PMID- 12489494
TI  - The involvement of peripheral polymorphonuclear leukocytes in the oxidative
      stress and inflammation among cigarette smokers.
AB  - BACKGROUND: Cigarette smoking is a well-known risk factor for the development of
      endothelial dysfunction and the progression of atherosclerosis. Oxidative stress
      and inflammation have recently been implicated in endothelial dysfunction.
      OBJECTIVES: To assess the concomitant contribution of polymorphonuclear
      leukocytes to systemic oxidative stress and inflammation in cigarette smokers.
      METHODS: The study group comprised 41 chronic cigarette-smoking, otherwise
      healthy males aged 45.0 +/- 11.5 (range 31-67 years) and 41 male non-smokers aged
      42.6 +/- 11.3 (range 31-65) who served as the control group. The potential
      generation of oxidative stress was assessed by measuring the rate of superoxide
      release from separated, phorbol 12-myristate 13-acetate-stimulated PMNL and by
      plasma levels of reduced (GSH) and oxidized (GSSG) glutathione. Inflammation was
      estimated indirectly by: a) determining the in vitro survival of PMNL, reflecting
      cell necrosis; b) in vivo peripheral PMNL counts, reflecting cell recruitment;
      and c) plasma alkaline phosphatase levels, indicating PMNL activation and
      degranulation. RESULTS: PMA-stimulated PMNL from cigarette smokers released
      superoxide at a faster rate than PMNL from the controls. Smokers had decreased
      plasma GSH and elevated GSSG levels. In vitro incubation of control and smokers'
      PMNL in sera of smokers caused necrosis, while control sera improved smoker PMNL
      survival. Smokers' PMNL counts, although in the normal range, were significantly
      higher than those of controls. Plasma ALP levels in smokers were significantly
      higher than in controls and correlated positively with superoxide release and
      PMNL counts. CONCLUSIONS: Our study shows that PMNL in smokers are primed in
      vivo, contribution concomitantly to systemic oxidative stress and inflammation
      that predispose smokers to endothelial dysfunction, and explains in part the
      accelerated atherosclerosis found in smokers.

PMID- 12489495
TI  - Long distance flights and the risk of venous thromboembolism--a real threat or
      just another flight hysteria?

PMID- 12489496
TI  - The leukocyte NADPH oxidase.
AB  - The leukocyte NADPH oxidase catalyzes the reduction of oxygen to O2- (superoxide)
      at the expense of NADPH. The O2- then dismutes to H2O2, which serves to oxidize
      Cl- to HOCl, a potent microbicidal agent that is used by leukocytes to kill
      invading microorganisms. This oxidation is catalyzed by myeloperoxidase. O2 is
      also used to make other microbicidal oxidants, some in reactions with nitric
      oxide. The oxidase itself is highly complex, consisting of four unique subunits
      and Rac2. In the resting cell, two of the subunits, p22PHOX and gp91PHOX, are
      located in the membrane, and the other two, p47PHOX and p67PHOX, are in the
      cytosol. The electron-carrying components of the oxidase are located in gp91PHOX;
      the NADPH binding site is generally regarded to be in gp91PHOX as well, but there
      is some evidence that it may be in p67PHOX. When the oxidase is activated,
      p47PHOX is phosphorylated at specific sites, and the cytosolic components plus
      Rac2 migrate to the membrane to assemble the active oxidase.

PMID- 12489498
TI  - Diagnostic evaluation of the chronic myeloproliferative disorders.

PMID- 12489497
TI  - Chemokine receptor-8: potential role in atherogenesis.
AB  - Chemokines and their receptors play regulatory roles in inflammatory reactions.
      Lipoprotein(a) is an atherogenic lipoprotein, however the mechanisms of its
      actions are not defined. Our interest in chemokines and their receptors was
      stimulated by the finding that incubation of Lp(a) with human umbilical vein
      endothelial cells produced a conditioned medium that was chemotactic for human
      monocytes. Since infiltration of monocytes into the vessel wall is an early
      lesion in atherosclerosis, this finding provided a novel mechanism to explain the
      relationship between Lp(a) and atherosclerosis. The chemoattractant produced by
      HUVEC was identified as CCL1/I-309, a CC chemokine previously reported to be
      secreted by stimulated monocytes/macrophages and T lymphocytes. CCR8, the CCL1
      receptor, was identified on endothelial cells, and CCL1 was found to be a
      chemoattractant for these cells. Most recently we demonstrated functional CCR8 on
      human vascular smooth muscle cells and found that the Lp(a)-HUVEC conditioned
      medium is a chemoattractant for these cells. CCL1 increased metalloproteinase-2
      production by HUVEC, an activity that enables these cells to remodel the vascular
      matrix. These studies suggest that CCR8 may play an important role in arterial
      wall pathology.

PMID- 12489499
TI  - Granulocyte colony-stimulating factor receptor signaling defects from neutropenia
      to leukemia.

PMID- 12489500
TI  - Patient self-testing and patient self-management of oral anticoagulation: is it
      too late?

PMID- 12489501
TI  - Risk factors for venous thromboembolism in general surgical patients.

PMID- 12489502
TI  - Risk factors for venous thromboembolism in orthopedic surgery.

PMID- 12489503
TI  - The role of hepcidin in iron sequestration during infections and in the
      pathogenesis of anemia of chronic disease.
AB  - Systemic infection or inflammation causes a decrease in intestinal iron
      absorption and impairs the release of recycled iron from macrophages. Decreased
      availability of iron may deny this essential element to invading pathogens and
      may inhibit their multiplication and other metabolic processes but also results
      in anemia of chronic disease. This article reviews recent discoveries that shed
      light on the regulation of iron metabolism during infection and iron overload,
      and point to the central role of a newly discovered peptide, hepcidin. Evidence
      to date indicates that hepcidin is a negative regulator of intestinal iron
      absorption, placental iron transport, and the release of iron from macrophages
      that recycle iron from senescent red cells. It may also be the central mediator
      of iron sequestration during infections and inflammatory states and the mediator
      of anemia of chronic disease. Rapid progress in this area is a good example of
      the beneficial effects of improvements in peptide analysis and chemistry,
      advances in genomics, and the increasing use of transgenic mice to determine the
      function of newly discovered genes and proteins.

PMID- 12489504
TI  - Heparinoids: integrated control of hemostasis and metastasis.

PMID- 12489505
TI  - Methotrexate-related neurotoxicity in the treatment of childhood acute
      lymphoblastic leukemia.
AB  - The addition of methotrexate to treatment protocols in children with acute
      lymphoblastic leukemia has been found beneficial in preventing central nervous
      system relapse. However, MTX itself may be associated with neurologic
      morbidities, the most significant of which is leukoencephalopathy. The present
      study describes the clinical spectrum of leukoencephalopathy, which ranges from a
      subclinical disease manifested only radiologically to a progressive, devastating
      encephalopathy. The interaction of MTX with other components of the treatment
      protocol is discussed, as is the effect of leucovorin. A summary is presented of
      the metabolic pathways that may be involved in the development of MTX toxicity.
      Researchers are still seeking a biochemical marker to aid in the determination of
      the amount of MTX that may be safely administered.

PMID- 12489506
TI  - Potential role of chemokines in immune therapy of cancer.

PMID- 12489507
TI  - Leukocytes and acute myocardial infarction.

PMID- 12489508
TI  - Methylation of gene promoters in leukemogenesis.

PMID- 12489509
TI  - Erythropoietin and its receptor: signaling and clinical manifestations.

PMID- 12489510
TI  - Cigarette smoking and endothelial damage.

PMID- 12489511
TI  - Air flights and venous thromboembolism--a preventable condition.

PMID- 12489512
TI  - Electronic blood cell counters are by no means perfect.

PMID- 12489513
TI  - Post-splenectomy veno-occlusive priapism in a child with idiopathic
      thrombocytopenic purpura.

PMID- 12489514
TI  - Hemolytic anemia in a G6PD-deficient man after inhalation of amyl nitrite
      ("poppers").

PMID- 12489515
TI  - Hemorrhage caused by invasive procedures and trauma in patients treated with low
      molecular weight heparin.

PMID- 12489516
TI  - Remember the blood smear: a clinical laboratory vignette.

PMID- 12489517
TI  - Implementing medical ethics.
AB  - How to place medical ethics more firmly into medical practice continues to be a
      central concern of physician training and practice. One strategy is to make
      medical ethics an explicit focus of attention in the medical record. A separate
      section of the medical chart, one integral to clinical evaluations and ongoing
      progress notes, should be devised to articulate both the obvious and less
      apparent ethical issues pertinent to each patient. This so-called Ethical
      Concerns section is designed to proactively identify such problems and thereby
      raise these issues as part of routine evaluation and care. The historical
      developments and ethical challenges leading to the need for such a revision in
      record-keeping is reviewed.

PMID- 12489518
TI  - Effects of simulated weightlessness on Calbindin D-28K-immunoreactivity in rat
      soleus muscle spindle.
AB  - Objective. To analyze the mechanism involved in muscle spindle deterioration
      during simulated weightlessness. Method. Using the immunoperoxidase reaction
      utilizing the ABC (avidin-biotin-complex) method, Calbindin D28K-like
      immunoreactivity (CaBP-LI) of intrafusal fibres in soleus muscle were detected in
      7 d, 14 d tail-suspended rats and compared with control rats. Result. The
      extrafusal muscle fibres and nerve fibres did not exhibit immunoreactivity to
      CaBP. CaBP-LI was found in some of the intrafusal muscle fibres in all the muscle
      spindles. After 14 d suspension, the immunoreactivity to CaBP of the intrafusal
      fibres decreased markedly. Conclusion. Simulated weightlessness could induce
      changes in the immunoreactivity of rat soleus muscle spindle to CaBP, which may
      contribute to the deterioration of muscle spindle.

PMID- 12489519
TI  - Guidelines for legalized euthanasia in Canada.

PMID- 12489520
TI  - Out of the laboratory and into the bathroom cabinet: designing and implementing
      clinical trials.

PMID- 12489521
TI  - An overview of the drug approval process.

PMID- 12489522
TI  - Accelerated approval: where are we now?

PMID- 12489523
TI  - The need for novel targets and approaches to HIV therapy.

PMID- 12489524
TI  - Will immune-based therapies ever be approved?

PMID- 12489525
TI  - AIDS activism's message in a bottle.

PMID- 12489527
TI  - The museum of the profession.

PMID- 12489528
TI  - [The use of a therapeutic toy, as a tool for nursing intervention, in the
      preparation of children for blood sampling].
AB  - This study is almost an experiment with the objective to verify the effect of the
      Therapeutic Play on preschool children during blood collect for laboratory tests.
      The sample consisted of 42 children divided into control and experimental groups.
      All the children had their behavior observed and only the children of the
      experimental group were prepared for the Therapeutic Play. The results were
      analyzed comparing the children's behavior with the groups and showed that
      arrangement with the Therapeutic Play was effective in the comprehension of the
      procedure and in the control of their behavioral reactions.

PMID- 12489526
TI  - Isolation and expression analysis of the testis-specific gene, STRA8, stimulated
      by retinoic acid gene 8.
AB  - Retinoids are known to be required for vertebrate reproduction, and in the male,
      for the maintenance of normal testicular structure and function. Previously
      several novel retinoic acid responsive genes, collectively designated as the Stra
      genes, had been isolated in the mouse. The Stra8 gene encodes a cytoplasmic
      protein and is expressed specific to the developing male gonad during mouse
      embryogenesis. In adult mouse, its expression is restricted to the premeiotic
      germ cells. Thus it has been suggested that the mouse Stra8 protein may play a
      role in the premeiotic phase of spermatogenesis. Recently a lot of genes that are
      expressed only in male germ cells have been isolated in the mouse. The mouse
      Stra8, Rnh2, Piwil2, Tex17, and Tuba7 were identified as testis-specific
      expressed genes. In addition, the Figla was known to be a testis- and ovary
      specific gene. Recently we had reported the isolation of the human RNH2 cDNA and
      its expression, which is limited to the human testis. In the present study, we
      have isolated full-length cDNA of S TRA8 and partial cDNAs of PIWIL2, FIGLA,
      TEX17, and TUBA7, and analyzed their expression patterns in human tissues.

PMID- 12489529
TI  - Estrogenic effects of apigenin, kaempferol and bisphenol A in immature Wistar
      female rats and in MCF-7 cells.

PMID- 12489530
TI  - [Breast Cancer Conference. Trastuzumab and capecitabine in the treatment of
      advanced breast cancer. Milano, 6-7 June 2002].

PMID- 12489531
TI  - Pelvimetry revisited.

PMID- 12489532
TI  - A spin transition molecular material with a wide bistability domain.
AB  - [Fe(hyptrz)3](4-chloro-3-nitrophenylsulfonate)22 H2O (1; hyptrz=4-(3
      hydroxypropyl)-1,2,4-triazole) has been synthesized and its physical properties
      have been investigated by several physical techniques including magnetic
      susceptibility measurements, calorimetry, and Mossbauer, optical, and EXAFS
      spectroscopy. Compound 1 exhibits a spin transition below room temperature,
      together with a very wide thermal hysteresis of about 50 K. This represents the
      widest hysteresis loop ever observed for an FeII-1,2,4-triazole spin transition
      material. The cooperativity is discussed on the basis of temperature-dependent
      EXAFS studies and of the structural features of a CuII analogue. The EXAFS
      structural model of (1) in both spin states is compared to that obtained for a
      related material whose spin transition occurs above room temperature. EXAFS
      spectroscopy suggests that 1,2,4-triazole chain compounds retain a linear
      character whatever the spin state of the iron(II).

PMID- 12489534
TI  - A new method for distinguishing between enantiomers and racemates and assignment
      of enantiomeric purity by means of solid-state NMR. Examples from
      oxazaphosphorinanes.
AB  - It is shown that enantiomers and racemates that have identical isotropic NMR
      chemical shift as well as anisotropic chemical-shift tensor parameters can be
      easily distinguished by means of the ODESSA (One Dimensional Exchange
      Spectroscopy by Sideband Alternation) technique. The method is based on the fact
      that the molecular symmetries and packing of enantiomers and racemates are
      usually significantly different. The power of the proposed approach is
      demonstrated by employing as model compounds P-chiral oxazaphosphorine
      derivatives, which are widely used in clinical oncology. Correlation of the
      amplitude of the ODESSA decay (AOD) with enantiomeric excess is also presented.

PMID- 12489533
TI  - Bond angle versus torsional deformation in an overcrowded alkene: 9-(2,2,2
      triphenylethylidene)fluorene.
AB  - Competition between bond angle and torsional strain in sterically crowded alkenes
      generally causes twisting in tetrasubstituted alkenes, while most structurally
      characterized trisubstituted alkenes are planar. To investigate structural
      effects of steric repulsion between a planar aromatic ring and a vicinal
      triphenylmethyl (trityl) group, 9-(2,2,2-triphenylethylidene)fluorene (1 a) was
      synthesized by reaction of 9-bromomethylenefluorene with triphenylmethyllithium.
      For comparison with a less strained analogue, 9-ethylidenefluorene (1 b) was
      prepared by reaction of fluorenone with ethylmagnesium bromide. The X-ray crystal
      structures show that the difference between bond angles at the 9-fluorenyl carbon
      atom is much larger for 1 a (12.9 degrees) than 1 b (2.6 degrees). Bond angle and
      torsional deformations were compared theoretically (HF/6-31+G*) with the tert
      butyl analogue (1 c), 1,2,2-tri-tert-butylethene (7), and 2,4,4-trimethyl-2
      pentene (8) and crystallographically with six known 1,1-diaryl-2-tert
      alkylethenes (2). The trisubstituted alkenes formed three groups with 1) large
      angle distortion with moderate twisting (1 a, 1 b, and 7), 2) moderate bending
      with a large range of torsional angles (2), and 3) little bending or twisting (1
      b and 8). For the entire series, there appears to be a delicate balance between
      angle and torsional deformation, but twisting appears to produce smaller relief
      from steric strain than angle bending. In the crystallographically characterized
      trisubstituted alkenes, the choice between the two is mainly determined by more
      subtle packing forces.

PMID- 12489535
TI  - Efficient preparation of highly optically active (S)-(-)-2,3-allenols and (R)-(+)
      2,3-allenyl acetates by a clean novozym-435-catalyzed enzymatic separation of
      racemic 2,3-allenols.
AB  - Novozym-435 has been found to be an effective biocatalyst for the kinetic
      resolution of a series of racemic 2,3-allenols, affording highly optically active
      (S)-(-)-2,3-allenols and (R)-(+)-2,3-allenyl acetates in high yields and with
      excellent ee values. The reaction of 3-(n-butyl)-3,4-pentadien-2-ol (1 a) was
      successfully performed on a 10 g scale to afford the corresponding (S)-(-)-2,3
      allenol (1 a) and (R)-(+)-2,3-allenyl acetate (2 a) in synthetically useful
      amounts and with high ee values. The advantages of this reaction are the ready
      availability of the starting materials, high stereoselectivities for both (-)-2,3
      allenols and (+)-2,3-allenyl acetates, the use of a relatively high substrate
      concentration, and a lower catalyst loading. The resulting (S)-(-)-2,3-allenol 1
      a can be converted into the corresponding chiral 2,5-dihydrofuran and the vinylic
      epoxide.

PMID- 12489536
TI  - DFT description of the magnetic properties and electron localization in dinuclear
      di-mu-oxo-bridged manganese complexes.
AB  - Density functional theory (DFT) was applied to describe the magnetic and electron
      transfer properties of dinuclear systems containing the [MnO2Mn]n+ core, with
      n=0,1,2,3,4. The calculation of the potential energy surfaces (PESs) of the mixed
      valence species (n=1,3) allowed the classification of these systems according to
      the extent of valence localization as Class II compounds, in the Robin-Day
      classification scheme. The fundamental frequencies corresponding to the
      asymmetric breathing vibration were also computed.

PMID- 12489537
TI  - Design of coordination polymer as stable catalytic systems.
AB  - Here we report the first example of catalytic metallogels, which are formed
      irreversibly in dimethylsulfoxide via the creation of cross-linked, three
      dimensional coordination polymer networks by using transition-metal ions with
      multiple sites available for coordination and multidentate ligands.
      Conformational flexibility of the ligands and slow formation of the coordination
      polymers apparently favor the gelation. These metallogels are stable in water and
      most organic solvents and can catalyze the oxidation of benzyl alcohol to
      benzaldehyde by using their PdII moieties as the catalytic centers. The best
      catalytic turnover of the metallogel is twice that of [Pd(OAc)2] under similar
      reaction conditions.

PMID- 12489538
TI  - Dramatically synergetic effect of carboxylic acid additive on tridentate titanium
      catalyzed enantioselective hetero-diels-alder reaction: additive acceleration and
      nonlinear effect.
AB  - This paper describes the successful development of a group of highly efficient
      chiral tridentate titanium catalysts for hetero-Diels-Alder reaction of
      Danishefsky's diene and a variety of aldehydes through ligand and additive
      diversity. Dramatically synergetic effect of carboxylic acid additives and
      influence of substituent in chiral Schiff base ligands on the
      enantioselectivities of the reaction are reported. It was found that a chiral
      drug Naproxen (A21) was a highly efficient additive for Ti-catalyzed HDA
      reaction, affording 2-substituted 2,3-dihydro-4H-pyran-4-one in up to 97 % ee and
      >99 % yields. Quantitative study of the effect of chiral carboxylic acid A21
      revealed that the reaction could be accelerated by one order of magnitude.
      Another interesting feature of present catalytic system is the existence of
      significant positive nonlinear effect, which indicates that the heterochiral
      Schiff base-titanium complexes may have higher stability than their homochiral
      counterparts. As a result, the homochiral Schiff base-titanium complexes with
      higher ee than that of starting ligand will react with carboxylic acid additive
      to form the more active species and predominate the catalytic process. The
      isolation and characterization of stable heterochiral ((+/-)-L1)2Ti complex has
      also been successful, which strongly supported the explanation for positive
      nonlinear effect observed in the catalytic system.

PMID- 12489539
TI  - Computational investigation of the role of fluoride in Tamao oxidations.
AB  - The Tamao oxidation of alkoxysilanes was investigated computationally to
      determine the role of fluoride, a key additive, in this reaction. A sequence of
      fluoride equilibria as well as possible transition states, mediated by basic and
      neutral peroxide, respectively, were examined, and a potential energy surface was
      calculated which was consistent with the typical synthetic methods required for
      the conversion of alkoxysilanes to alcohols.

PMID- 12489540
TI  - Politically active nurses.

PMID- 12489541
TI  - Stealing words.

PMID- 12489542
TI  - Meningococcal meningitis in Africa.

PMID- 12489543
TI  - Healthy children and flu complications.

PMID- 12489544
TI  - Living well but poorly.

PMID- 12489546
TI  - Finally, privacy regulations finalized.

PMID- 12489547
TI  - A protective effect from breastfeeding.

PMID- 12489548
TI  - Scientific criteria for evaluating health effects of food components. ILSI North
      American Technical Committee on Food Components for Health Promotion.

PMID- 12489549
TI  - Abstracts of the Royal Academy of Medicine in Ireland sections and society
      meetings 1998-2001.

PMID- 12489550
TI  - Abstracts of the 21st Annual European Society for Therapeutic Radiology and
      Oncology Meeting. Praha, Czech Republic, 17-21 September 2002.

PMID- 12489552
TI  - Abstracts of the 4th International Symposium on Preimplantation Genetics.
      Limassol, Cyprus, 10-13 April 2002.

PMID- 12489551
TI  - Abstracts of the 5th European Congress on Epileptology. Madrid, Spain, 6-10
      October 2002.

PMID- 12489553
TI  - Abstracts of the 55th Annual Meeting of the Gerontological Society of America. 22
      26 November 2002, Boston, Massachusetts, USA.

PMID- 12489554
TI  - Methods in Enzymology cumulative subject index, volumes 321-354.

PMID- 12489555
TI  - Proteine 2002. Abstracts of the XVI Meeting of the Protein Workgroup. L'Aquila,
      Italy, 6-8 June 2002.

PMID- 12489556
TI  - Spare parts for the rich? Everybody seems to have a view on embryo research. But
      stem cell treatments raise moral dilemmas that few have even started to consider.

PMID- 12489557
TI  - Abstracts of the 42nd American Society for Cell Biology Annual Meeting. 14-18
      December 2002, San Francisco, California, USA.

PMID- 12489558
TI  - British Maternal and Fetal Medicine Society 7th Annual Conference. Cambridge,
      United Kingdom, 11-12 April 2002. Abstracts.

PMID- 12489559
TI  - European Human Genetics Conference 2002 in conjunction with the European Meeting
      on Psychosocial Aspects of Genetics 2002. Strasbourg, France, 25-29 May 2002.
      Abstracts.

PMID- 12489560
TI  - Proceedings and abstracts of the annual meeting of the Israel Association of
      Allergy and Clinical Immunology.

PMID- 12489561
TI  - Duplicate publication.

PMID- 12489562
TI  - Aromatase in primate pregnancy: a review.
AB  - Aromatase enzyme is a cytochrome P450 protein that can catalyze the aromatization
      of C 19 androgens and thus their conversion into estrogens. It is tissue
      specifically expressed in primate placenta, connective tissue, ovary, and brain
      through alternative splicing of tissue selective promoters. Human aromatase
      activity is critical for maintenance of early and mid pregnancy and in regulating
      parturition in late pregnancy. It is also important in the development of fetal
      gonadocytes and the sexual differentiation of brain, especially the hypothalamic
      gonadal axis. Exposure to aromatase inhibitors in primates significantly impairs
      pregnancy outcome. Recent case reports have described syndromes associated with
      rare autosomal recessive mutations in aromatase genes.

PMID- 12489563
TI  - Assessing pregnancy risks of azole antifungals using a high throughput aromatase
      inhibition assay.
AB  - Human aromatase (CYP19) converts C19 androgens to aromatic C18 estrogenic
      steroids. Its activity is critical for early and mid pregnancy maintenance and in
      regulating parturition in late pregnancy. Past studies have utilized placental
      microsome tritiated water release assay to assess drug-hormone interactions with
      estrogen synthesis. We compared data from human placental assays with BD
      Gentest's high throughput recombinant CYP19 enzyme assay using the fluorometric
      substrate dibenzylfluorescein. We tested a panel of azole antifungal agents that
      are commonly administered to women of childbearing potential, for their potential
      to inhibit aromatase. Potency varied by several orders of magnitude. Plasma and
      tissue levels of some azole drugs following oral or topical administration are at
      or above these IC50 values. These include the oral agents fluconazole and
      ketoconazole, and the topical agents econazole, bifonazole, clotrimazole,
      miconazole, and sulconazole. CONCLUSIONS: 1. Recombinant enzyme assay data are
      comparable to the human placental assay data in both SAR rank order and potency.
      2. Plasma and tissue levels of some azole drugs following oral or topical
      administration are at or above these IC50 values. Therefore, some azole drugs may
      disrupt estrogen production in pregnancy, affecting pregnancy outcome. 3.
      Recombinant CYP19 assay using the fluorometric substrate dibenzylfluorescein,
      demonstrates rapid screening potential for chemicals that may affect pregnancy
      outcome as a result of CYP19 inhibition.

PMID- 12489564
TI  - Adverse effects of neonatal hypothyroidism on Wistar rat spermatogenesis.
AB  - The effect of neonatal hypothyroidism on spermatogenesis was studied in Wistar
      rats of different age groups. Hypothyroidism was induced in newborn male rats
      from day one postpartum up to day 60 postpartum by daily administration of 0.05%
      methimazole (MMI) to the nursing mothers or directly through drinking water. The
      animals were killed at days 10, 15, 30, 40, and 60 postpartum, blood plasma was
      collected, and testes, epididymides, prostates, and seminal vesicles were
      separated and weighed. Testes were fixed in formalin for histological studies.
      Plasma testosterone (T), estradiol (E2), and sex hormone binding globulin (SHBG)
      were measured by radioimmunoassay. Hypothyroidism significantly reduced
      seminiferous tubule and lumen diameter. Control rats showed active
      spermatogenesis whereas in hypothyroid rats, the proliferation and
      differentiation of germ cells were arrested and their number was decreased.
      Plasma T, E2, and SHBG levels were significantly decreased at all ages for
      hypothyroid rats. The absolute weight of testes was decreased irrespective of age
      (except day 10 postpartum), however ventral, dorsolateral prostate, and
      epididymis weights were decreased at 30, 40, and 60 days postpartum. Coagulating
      gland weight was decreased in all age groups of hypothyroid rats. Hypothyroid
      rats of day 40 and 60 postpartum showed a decrease in absolute seminal vesicle
      weight. Relative testicular weights of hypothyroid rats decreased by postpartum
      day 15, 30, 40, and 60 whereas the opposite effect was observed by postpartum day
      10. Relative organ weights were increased in epididymides (day 15 and 30
      postpartum), seminal vesicles (day 30 and 40 postpartum), and dorsolateral
      prostates (day 15, 30, and 40 postpartum) and decreased in 10 and 60 day old
      hypothyroid rat. Ventral prostate relative weight was decreased in 40 and 60 day
      old rats. Th coagulating gland weight was decreased in 10, 15, and 60 days
      postpartum and an opposite effect was observed in 30 and 40 days hypothyroid
      rats. The present study clearly indicates that hypothyroidism adversely affects
      spermatogenesis; it also indicates that thyroid hormones are essential for normal
      spermatogenesis. Their effect may either be direct or indirect.

PMID- 12489565
TI  - Cyclic estrogen-progestin hormone therapy as a new therapeutic approach in the
      treatment of functional alterations of the hypothalamus-pituitary-ovary axis:
      case reports.
AB  - Amenorrhea is a clinical condition characterized by failure of menarche or by the
      absence of menstruation for six months in a woman with previous periodic menses.
      We report a first case of a 30 year-old woman affected by polycystic ovarian
      disease (PCOD) whose amenorrhea ceased after a 6-month combination treatment with
      cyclic estradiol-norethisterone acetate. After the withdrawal of the hormone
      therapy, a stable recovery of periodic menses was observed. We describe a second
      case of a 23 year-old woman whose amenorrhea was caused by a hypogonadotropic
      hypogonadism due to a non-functioning pituitary adenoma. After the administration
      of the previously described therapy both a disappearance of the adenoma and a
      recover of periodic menses were observed. We hypothesized that the outcomes in
      our cases could be the consequence of a balancing action induced by the exogenous
      hormone administration. The exogenous hormones may have reset the feedback
      between the hypothalamus and pituitary gland through mimicking the physiological
      hormones pattern of the 28-day cycle.

PMID- 12489566
TI  - Bio-available testosterone levels fall acutely following myocardial infarction in
      men: association with fibrinolytic factors.
AB  - The effect of acute myocardial infarction on plasma levels of testosterone in men
      is unclear. No previous studies have evaluated the bio-available fraction of
      testosterone. Low plasma testosterone levels have been associated with several
      risk factors for myocardial infarction, including an unfavorable fibrinolytic
      profile. In a prospective, case control study, we examined changes in plasma
      levels of sex hormones, including bio-available testosterone, in patients with
      acute myocardial infarction and in control subjects. In addition, changes in
      hormone levels in patients were compared with alterations in the fibrinolytic
      profile. Thirty male patients admitted with chest pain were studied. Twenty two
      had acute myocardial infarction and eight had non-specific chest pain. Plasma
      levels of total and bio-available testosterone, 17beta-estradiol, sex hormone
      binding globulin and insulin were measured at baseline and throughout admission.
      In addition, fibrinolytic factors (plasminogen activator inhibitor-1 (PAI-1),
      tissue plasminogen activator (tPA) and fibrinogen) were measured in patients who
      received fibrinolysis. Height and weight, and the subsequent development of heart
      failure or myocardial dysfunction were also recorded. Patients had lower levels
      of bio-available testosterone (2.07 +/- 0.75 nmol/L vs. 5.3 +/- 1.7 nmol/L, p <
      0.05) and higher levels of 17beta-estradiol (87.9 +/- 39.5 pmol/L vs. 48.1 +/-
      18.4 pmol/L, p < 0.001) than controls. Total and bio-available testosterone
      levels fell acutely following myocardial infarction (11.9 +/- 3.8 nmol/L to 9.7
      +/- 3.3 nmol/L, p < 0.05; 1.95 +/- 0.76 nmol/L to 1.55 +/- 0.67 nmol/L, p <
      0.05). This reduction was associated with elevation of PAI-I activity and
      reduction of tPA activity, independent of changes in plasma insulin levels.
      Patients with lower baseline levels of testosterone and higher levels of 17beta
      estradiol had a relatively pro-thrombotic fibrinolytic profile and increased risk
      of complications. In conclusion, total and bio-available levels of testosterone
      fall following acute myocardial infarction in men, in association with adverse
      changes in fibrinolytic profile. It is not clear whether this association
      represents a direct effect of testosterone on thrombotic tendency but warrants
      further investigation.

PMID- 12489567
TI  - Sex steroids regulate intermediary metabolism in Oreochromis mossambicus.
AB  - The effect of long-term administration of testosterone, progesterone, and a
      synthetic estrogen, diethylstilbestrol (DES), on intermediary metabolism was
      studied in a freshwater fish Oreochromis mossambicus. The present study reveals
      that testosterone, progesterone, and Des specifically control key enzymes
      involved in carbohydrate, protein and lipid metabolism in the liver of O.
      mossambicus implying a general influence of sex steroids on intermediary
      metabolism. The activities of malic enzyme (ME), glucose-6-phosphate
      dehydrogenase (G6PDH), isocitrate dehydrogenase (ICDH), glucose 6 phosphatase (G
      6-Pase), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are
      either stimulated or inhibited following the administration of sex steroids. The
      long-term in vivo i.p. injection of sex steroids intensely reveals that
      testosterone and progesterone are hyperglycemic, DES is hypoglycemic,
      testosterone and DES lipogenic, and progesterone antilipogenic (lipolytic) in the
      present study. It is also established that amino acid catabolism, mostly that of
      alanine, may be a major source of substrate for gluconeogenesis. A genomic mode
      of action is proposed for sex steroids for long term treatment, as their action
      is sensitive to transcription and translation inhibitors.

PMID- 12489568
TI  - The changes of serum leptin and soluble leptin receptor levels in patients
      undergoing mobilization of peripheral blood stem cells before autologous stem
      cells transplantation.
AB  - BACKGROUND AND OBJECTIVES: Leptin was demonstrated to stimulate the proliferation
      of hematopoietic stem cells in vitro, but there is scarce information concerning
      serum leptin levels in patients with hematological diseases. The aim of our study
      was to measure serum leptin levels in patients undergoing mobilization of
      peripheral blood stem cells (PBSC) before autologous stem cell transplantation
      (ASCT). DESIGN AND METHODS: Eighteen patients indicated for ASCT were included in
      the study. The blood samples were obtained before the initiation of mobilization
      chemotherapy, at the phase of maximal leukopenia and on the second day of stem
      cell harvest. Serum leptin levels, soluble leptin receptor, cortisol, insulin,
      tumor necrosis factor alpha (TNFalpha), and interleukin-1 receptor antagonist (IL
      1ra) levels were measured in the withdrawn samples. RESULTS: The basal values of
      parameters measured except for higher levels of IL-1ra in mobilized group did not
      differ significantly from those of a control group of healthy subjects. Serum
      leptin levels decreased significantly at the leukopenia phase and remained
      suppressed in the stem cell harvest phase (means +/- standard error means (SEM):
      12.2 +/- 2.4 vs. 7.7 +/- 1.5 vs. 9.3 +/- 1.9 ng mL(-1)). No significant changes
      were found in soluble leptin receptor, insulin, cortisol, and TNFalpha levels
      throughout three measurements, while IL-1ra levels increased significantly in the
      SC harvest phase compared to the previous two measurements. INTERPRETATION AND
      CONCLUSIONS: As no metabolic variations explaining suppressed leptin levels were
      found, this suppression could be the result either of G-CSF administration or
      increased leptin consumption by activated stem cells.

PMID- 12489569
TI  - Soluble leptin receptor levels in patients with anorexia nervosa.
AB  - OBJECTIVE: To examine whether changes of serum soluble leptin receptor levels (S
      LEPR) can modify leptin half-life and its tissue effects. The aim of our study
      was to measure S-LEPR levels in patients with anorexia nervosa (AN) before and 6
      weeks after partial refeeding. METHODS: Anthropometric variables, serum leptin, S
      LEPR, insulin, cortisol and TNF-alpha were measured in 15 AN patients before and
      after partial refeeding and 15 healthy control women. RESULTS: S-LEPR levels in
      AN patients were significantly higher than in healthy subjects (26.8 +/- 8.1 vs.
      16.36+/-2.6U/mL, p < 0.01) and were not affected by partial refeeding (26.8 +/-
      8.1 vs. 24.2 +/- 6.1 U/mL). In contrast, body mass index (BMI), body fat content,
      and serum leptin levels in AN patients increased significantly after partial
      refeeding. Except for the inverse relationship of S-LEPR levels to BMI and body
      fat content no clear relationship of this parameter to serum leptin, cortisol,
      insulin or TNF-alpha was found. CONCLUSION: S-LEPR levels are significantly
      increased in AN patients and this increase is unaffected by partial refeeding.
      The possibility of etiological role of increased S-LEPR levels in AN patients by
      affecting leptin central and/or peripherial effects should be further elucidated.

PMID- 12489570
TI  - Purine metabolism in leukocytes and erythrocytes in Graves' or Hashimoto's
      disease.
AB  - INTRODUCTION: Adenosine deaminase (ADA), purine nucleoside phosphorylase
      (PNPase), S-adenosylhomocysteine hydrolase (SAHH), 5'-nucleotidase (5N), and
      deoxycytidine kinase (dCK) are involved in purine salvage metabolism. Changes of
      the activities of the above enzymes have been observed in blood cells in patients
      with immunological disorders. MATERIALS AND METHODS: The activities of ADA,
      PNPase, SAHH, 5'N, and dCK in lysates of leukocytes and erythrocytes, obtained
      from patients with Graves' or Hashimoto's disease, were measured, using
      chromatographic analysis. Serum concentrations of antithyroglobulin (Tg Ab) and
      antithyroperoxidase (TPO Ab) antibodies were measured by an immunoenzymatic
      method. RESULTS: (1) ADA activity in leukocytes, obtained from patients with
      Hashimoto's disease, was significantly higher than in control leukocytes, as well
      as in leukocytes from patients with Graves' disease; (2) dCK activities in
      leukocytes from patients with both Graves' and Hashimoto's diseases were
      approximately four and five times higher, respectively, than in leukocytes of
      control subjects; (3) a positive correlation was observed between dCK activity in
      leukocytes and serum Tg Ab concentration in patients with Graves' disease. In
      conclusion, the increased ADA and dCK activities in leukocytes from patients with
      Graves' and Hashimoto's diseases may be regarded as indicators of
      autoimmunological thyroid diseases.

PMID- 12489571
TI  - Mutations flanking the polyglutamine repeat in the modulatory domain of rat
      glucocorticoid receptor lead to an increase in affinity for hormone.
AB  - A polyglutamine repeat in the N-terminus of the rat glucocorticoid receptor shows
      polymorphism, with variants of Q2RQ5, Q2RQ15-21. We investigated whether these
      natural polymorphisms affect receptor function, and whether alleles with
      polyglutamine repeats shorter than Q2RQ5, between Q2RQ6-14, or longer than Q2RQ21
      are not found naturally because they encode a dysfunctional receptor. Ligand
      binding and transactivation properties of sets of natural (Q2RQ5-Q2RQ21) and
      artificial (Q4-Q80) alleles were compared following expression in CV-1 cells. The
      sequence of artificial alleles at sites flanking the repeat region was altered
      slightly to facilitate cloning. Western blotting showed that all constructs
      expressed GR protein in CV-1 cells. When co-expressed with an MMTV-lacZ reporter
      plasmid, all GR proteins were shown to be transcriptionally active in the
      presence of hormone. Scatchard analysis of ligand binding curves showed that
      affinities for dexamethasone and corticosterone were not affected by variation in
      the polyglutamine repeat either the natural or artificial sets of alleles.
      However, affinities were greater for the artificial compared with the natural
      alleles (2-3-fold for dexametasone, p < 0.001; and 4-fold for corticosterone,p <
      0.001). These differences provide evidence of a direct or indirect interaction
      within GR between the ligand binding domain and residues flanking the
      polyglutamine repeat of the N-terminal domain.

PMID- 12489572
TI  - Tc-99m-tetrofosmin thyroid scan in patients with low I-131 thyroid uptake.
AB  - Low 24-hour thyroid uptake of I-131 (I-131 uptake) is a common finding that
      influences evaluation of the thyroid gland. METHODS: We studied 20 female
      patients aged 16-82 years with low I-131 uptake. The following causes of reduced
      I-131 uptake were defined as (A) six cases with subacute thyroiditis, (B) seven
      cases with T4 suppression therapy, and (C) seven cases with iodinated
      pharmaceuticals use. Thirty-minute Tc-99m tetrofosmin thyroid scan was performed
      within 24 hours of the I-131 thyroid study. RESULTS: The results were correlated
      with neck ultrasound, serum TSH and biopsy histopathological findings. Tc-99m
      tetrofosmin thyroid scans revealed 10 normal thyroids, five diffuse goiters, four
      multinodular goitres, and one solitary thyroid nodule. CONCLUSIONS: Our results
      suggest that Tc-99m tetrofosmin thyroid scans may provide additional information
      to diagnose thyroid pathology in patients with low 24-hour I-131 uptake.

PMID- 12489573
TI  - Modulation by polyamines of gamma-glutamyl transpeptidase activity and lactate
      production in cultured Sertoli cells from immature and adult regressed golden
      hamster.
AB  - Polyamines are involved in cellular growth and differentiation. To analyze a
      possible role of polyamines on the regulation of Sertoli cell function, we
      studied the effect of putrescine, spermidine, and spermine on gamma-glutamyl
      transpeptidase (gamma-GTP) activity and lactate production on Sertoli cell
      cultures obtained from immature and adult-regressed golden hamsters. Sertoli
      cells were cultured for 7 days. The 72 hour conditioned media obtained on day 6
      were used to evaluate lactate levels. Gamma glutamyl transpeptidase activity was
      determined in the cells harvested on day 7. Cultured Sertoli cells isolated from
      immature and adult-regressed golden hamsters exhibited a clear morphological
      response to follicle-stimulating hormone (FSH) and to spermine. Gamma glutamyl
      transpeptidase activity increased in response to FSH in a dose-dependent manner.
      Dose-dependent stimulation of lactate production by FSH was also observed. For
      each functional parameter, a similar ED50 value of FSH stimulation was observed
      in both groups of animals. Spermine increased basal and FSH-stimulated gamma-GTP
      activity in immature and adult-regressed Sertoli cell cultures. A stimulatory
      effect of spermidine and putrescine on gamma-GTP activity was exclusively
      observed in adult-regressed Sertoli cell cultures. In Sertoli cells obtained from
      immature hamsters, spermine exerted a stimulatory effect on basal and FSH
      stimulated lactate production. These results suggest that, in addition to the
      known effects of hormones and paracrine factors, polyamines may influence the
      functionality of Sertoli cells.

PMID- 12489574
TI  - Biological variability of biochemical markers of bone turnover in healthy women.
AB  - To investigate day-to-day biological change of biochemical makers of bone
      turnover, we measured eight markers for 5 days in 10 healthy women. They aged 26
      41 years (mean age; 31.1 years old), and had regular menstrual cycles. Fasting
      second void urine and blood was collected from them on five successive days. As
      serum marker, Estradiol (E2), intact PTH (i-PTH), Bone-specific alkaline
      phosphatase (BAP), and serum C-telopeptide (S-CTX) were measured. As urinary
      markers, urinary CTX (U-CTX), N-telopeptide (NTX), pyridinoline (Pyr) and
      deoxypyridinoline (Dpyr) were measured. Day-to-day physiological variations were
      different between bone markers. Variability of serum markers was less than that
      of urinary markers. Moreover, in the comparison of the same molecular marker,
      CTX, the variability of S-CTX was less than U-CTX. One should consider
      physiological variation of the marker to evaluate whether the change of the
      biochemical marker of bone turnover is significant or not.

PMID- 12489575
TI  - Prediction of asymptomatically poor muscle perfusion of lower extremities in
      patients with type II diabetes mellitus using an objective radionuclide method.
AB  - Foot problems are the most common cause of hospital admission in patients with
      type II diabetes mellitus (DM). Poor muscle perfusion of lower extremities is
      thought to be the major component in the pathogenesis of foot problems. We used a
      well-established and non-invasive radionuclide method to objectively evaluate the
      anterior tibial muscle perfusion of 120 type II DM patients without
      symptoms/signs of peripheral vascular disease (PVD) in the lower extremities. The
      patients were separated into groups according to the duration of the disease and
      condition of blood sugar control. Meanwhile, 60 normal control males with a
      matched age distribution were also included for comparison. The muscle perfusion
      were of significant difference between (1) 120 type II DM patients and 60 normal
      controls, (2) 72 patients with good sugar control and 48 patients with poor sugar
      control, as well as (3) 64 patients with short disease duration and 56 patient
      with long disease duration. Based on the objective radionuclide method, we
      concluded that the muscle perfusion in the lower extremities of type II DM
      patients without symptoms/signs of PVD is significantly decreased and related to
      the duration of the disease and condition of blood sugar control.

PMID- 12489576
TI  - Functional MRCP in pancreatic and periampullary disease.
AB  - BACKGROUND: The magnetic resonance (MR) evaluation of the pancreatic and biliary
      tree has undergone an important evolution because the introduction of the
      technique of MR cholangiopancreatography (MRCP). AIM: To describe and illustrate
      the technique of secretin-enhanced MRCP (S-MRCP) and discuss its use in
      pancreatic and periampullary disease. METHODS: Results are based on 6 years
      experience using MRCP with secretin infusion in hundreds of patients in a
      tertiary referral center. RESULTS: Secretin improves pancreatic duct and side
      branch delineation and the detection of anatomic variants such as pancreas
      divisum and abnormal common bilio-pancreatic channel. It allows monitoring of
      pancreatic flow dynamics and evaluation of pancreatic exocrine function that has
      been previously unavailable. In advanced inflammatory disease, it is useful in
      monitoring the course of the disease, for planning therapy and for follow-up
      studies after therapeutic endoscopy. CONCLUSION: Combining morphology and
      function into one non-invasive and comprehensive diagnostic modality has expanded
      the clinical applications of MRCP beyond the diagnostic ERCP that it replaces.

PMID- 12489578
TI  - EUS diagnosis of cystic lesions of the pancreas.
AB  - BACKGROUND: Cystic tumors of the pancreas are composed of benign, premalignant,
      malignant, and inflammatory lesions that are traditionally difficult to diagnose.
      Most of the tumors are initially detected on CT/US scanning, but often the
      morphological characteristics are insufficient for making a definitive diagnosis.
      Endoscopic ultrasound (EUS) may be an ideal tool for imaging of these lesions
      because it can provide highly detailed imaging without interference by bowel or
      air. Furthermore, EUS can direct fine needle aspiration of the lesions, providing
      cyst fluid for cytologic examination. The findings of cyst fluid cytology can be
      complemented by the use of cyst fluid tumor makers such as CEA. Using the
      morphologic appearance by endosonography, the results of cytology, and tumor
      marker analysis, EUS can often differentiate between benign, malignant, and
      inflammatory cystic lesions of the pancreas.

PMID- 12489577
TI  - Magnetic resonance imaging of pancreatic adenocarcinoma.
AB  - BACKGROUND: Magnetic resonance imaging (MRI) should be considered essential to
      the presurgical evaluation of pancreatic adenocarcinoma, to accurately detect
      resectable lesions and to spare patients with non-resectable tumors the
      morbidity, mortality, and expense of unnecessary surgery. This article is a
      review of the MRI characteristics of pancreatic adenocarcinoma, the features that
      determine its resectability, and the optimal MR sequences needed for its
      effective evaluation. The role of MRI imaging is contrasted with other imaging
      and invasive modalities for the diagnosis and staging of pancreatic
      adenocarcinoma.

PMID- 12489579
TI  - Endoscopic ultrasonography in the diagnosis and staging of pancreatic neoplasms.
AB  - BACKGROUND: Pancreatic cancer is the fourth leading cause of death among
      Americans. Twenty-eight thousand cases of pancreatic cancer are diagnosed
      annually and about the same number of patients die of pancreatic cancer every
      year. Most patients with pancreatic cancer are diagnosed when the tumor is 3 cm
      or more in diameter. Most pancreatic cancers are metastatic at the time of
      diagnosis and the median survival is only 18-20 mo. Overall, actual 5-yr survival
      is about 10% and has not changed much over several decades. Curative surgical
      resection is currently believed to offer the only chance of long-term survival in
      these patients. Difficulty in the early diagnosis of pancreatic cancer remains a
      major obstacle in improving outcomes in these patients. Screening for pancreatic
      cancer is currently not recommended. However, recent developments in endoscopic
      ultrasound (EUS) and cytological EUS-guided fine-needle aspiration (FNA) allow
      early diagnosis of pancreatic cancer with histological confirmation. EUS-FNA in
      conjunction with helical CT also provides reliable preoperative staging of
      pancreatic tumors. EUS with FNA therefore appears to be a promising tool in the
      fight against pancreatic cancer.

PMID- 12489580
TI  - Intraductal papillary-mucinous tumor and mucinous cystic neoplasm: CT and MR
      findings.
AB  - Cystic lesions of the pancreas are increasingly detected by imaging at daily
      clinical practice. Among them mucinous cystic tumor and intradcutal papillary
      mucinous tumor of the pancreas are clinically important since they are latently
      or overtly malignant and still have potentially good prognosis after resection.
      In this review article we describe history, clinicopathology and differential
      diagnosis of two entities, and findings and role of CT and MR imaging as well as
      MR cholangiopancreatography in the diagnosis and evaluation of intraductal
      papillary-mucinous tumor.

PMID- 12489581
TI  - Advanced 3-D imaging for the evaluation of pancreatic cancer with multidetector
      CT.
AB  - BACKGROUND: Pancreatic cancer remains the fourth leading cause of cancer-related
      death. Surgery is the only option for cure. Multidetector computed tomography
      (CT) and advanced postprocessing techniques, can provide solutions for difficult
      problems in diagnosing and staging disease, and can aid radiologists in
      communicating findings to surgeons and oncologists. Multiplanar reformats can
      provide additional information on involvement of the portal vein, hepatic artery,
      and common bile duct. Maximum intensity projection (MIP) images and volume
      rendered images can aid in identification of important vascular variants. MIP
      images can show the relationship of tumor to the pancreatic duct or biliary tree.
      Curved reformatted images can show the relationship of tumor to the pancreatic
      duct or vascular structures.

PMID- 12489582
TI  - Imaging of neuroendocrine tumors of the pancreas.
AB  - BACKGROUND: Neuroendocrine tumors of the pancreas are uncommon neoplasms of the
      pancreas that can occur sporadically or in association with various syndromes
      such as multiple endocrine neoplasia type 1 (MEN I). Patients can present with a
      specific clinical syndrome related to biochemically functioning tumors or with
      nonspecific symptoms related to mass effect or metastases. The size, function,
      consistency, and malignant behavior of neuroendocrine tumors are integrally
      related. Imaging has a major role in the preoperative localization of the primary
      tumor and detection of metastases. Several techniques are available including
      ultrasound, endoscopic ultrasound, computed tomography (CT), MR, somatostatin
      receptor scintigraphy, angiography, and arterial stimulation with venous
      sampling; each with unique advantages and limitations. The reported performance
      for these techniques vary widely, and as a result, recommended imaging algorithms
      are controversial. Recent technical advances in ultrasound, CT, and MRI have
      occurred that may improve the sensitivity of some of the techniques. Further
      improvements are likely in the future. In this chapter we will review imaging
      techniques used to study the pancreas as it relates to the detection of
      neuroendocrine tumors, imaging findings of these tumors using various imaging
      modalities, and the advantages, limitations and results obtained with each
      technique.

PMID- 12489583
TI  - Vascular anatomy of the pancreas and clinical applications.
AB  - The development of recent technology, especially the helical computed tomography
      (CT) scan, allows us to observe small peripancreatic vessels which previously
      could be demonstrated only by angiography (1), and therefore make three
      dimensional (3-D) volume rendered CT angiographic reconstruction possible (2).
      The neighboring structures as well as the pancreatic vessels are clearly
      visualized on the axial CT scan. Therefore, it is necessary to define the
      peripancreatic vessels on the axial images, as well as on angiography to make an
      accurate diagnosis of pancreatic disease so that we can also estimate the dynamic
      flow of the peripancreatic vessels. In this chapter, I would like to use the
      cadaver dissections of pancreatic vessels to explain each pancreatic vessel based
      on previous anatomic and radiologic references and finally demonstrate the
      clinical cases in terms of the pancreatic vessels. The pancreatic arteries and
      veins are explained based on the anatomic and radiologic references. Principal
      pancreatic vessels are demonstrated on cadaver dissection. The pancreas head is
      supplied by the anterior and posterior pancreaticoduodenal arteries forming
      arcades in the pancreaticoduodenal sulcus and is drained by the
      pancreaticoduodenal veins. The pancreas body and tail are supplied by the dorsal,
      inferior, and caudate pancreatic arteries, and are drained by the inferior and
      left pancreatic veins. Clinical applications in terms of the pancreatic vessels
      such as basis for interpretation of the angiography and the CT scan, treatment of
      pancreatitis and pancreatic cancer, detection of small insulinoma are stated.

PMID- 12489584
TI  - Arteriovenous fistula for chronic hemodialysis in children.
AB  - Each year, three to five children per million develop chronic renal failure. Of
      these one to two will require long-term hemodialysis support. From July 1992 to
      July 2000, we performed 19 surgical procedures to provide chronic hemodialysis
      access for a group of 14 children. There were 8 boys and 6 girls, with a mean age
      of 7.9 years (range 2.5-13). Ten of the children were between 2.5 and 10 years
      old. The mean weight of the children was 20.3 kg (range 12-49). Four children
      were only 12 kg in weight. The mean follow-up period was 42.1 months (range 10
      96). Surgical technique was varied. Polytetrafluoroethylene (PTFE) grafts were
      used in 5 cases. The overall mean functional primary patency of the fistula was
      30.2 months and secondary patency 31.6 months. Primary and secondary patency were
      better with autologous (39 and 40.6 months) than with PTFE graft (3.75 and 4.75
      months). Providing dialysis access in the pediatric population is a time
      consuming and frustrating challenge. We advocate the use of autologous material
      whenever possible. In children less than 12 kg in weight, brachiobasilic fistula
      is our first choice for angioaccess.

PMID- 12489585
TI  - Evaluation and treatment of obesity.

PMID- 12489586
TI  - Hypertension in the elderly. Part II.

PMID- 12489587
TI  - Vascular disorders of the upper extremities. Part II. Venous disorders.

PMID- 12489588
TI  - Infections and antiphospholipid antibodies.

PMID- 12489589
TI  - Hearing preservation mastoidectomy in otogenic meningitis secondary to an
      enlarged vestibular aqueduct. Case report.
AB  - In pyogenic meningitis resulting from a life-threatening ear infection,
      mastoidectomy is performed as part of the management of the disorder. A dilemma
      arises when the active ear is the only hearing ear. An active unsafe ear can lead
      to sensorineural hearing loss whereas ear surgery carries the risk of inner ear
      damage. We present the case of a 40-year-old woman admitted for severe purulent
      meningitis and sub-coma secondary to a left mastoiditis with mixed hearing loss
      on the left side and complete deafness on the right side. The study of this case
      shows that the intracranial complication was secondary to an abnormally enlarged
      left vestibular aqueduct. Because of the failure to control meningitis with
      medical treatment using highly specific antibiotherapy for two weeks, we
      proceeded with a left side mastoidectomy and closure of the external aperture of
      the vestibular aqueduct with a muscle graft. This surgery saved the patient's
      life, cured the meningitis and brought a recovery of a near normal hearing to the
      only hearing ear. Although demonstrating a rare etiology of intracranial
      complication, this case confirms that mastoidectomy, even on the only hearing
      ear, has to be done as early as possible to remove the source of infection, to
      prevent further intracranial complication, to arrest the progress of the ear
      disease and preserve or even recover almost normal hearing.

PMID- 12489590
TI  - Cisapride: questions and answers.

PMID- 12489591
TI  - A modeling and convolution method to measure compositional variations in strained
      alloy quantum dots.
AB  - We have developed a method to quantitatively measure the absolute composition of
      nanometer sized capped quantum dots in semiconductor alloys. The method uses
      spatially resolved electron energy-loss spectroscopy in a scanning transmission
      electron microscope to measure compositional profiles across the center of the
      quantum dot and the adjacent nanometer wide wetting layer. The measurements from
      the wetting layer are used to derive a spatial broadening function which includes
      the effects of probe size, instabilities and beam spreading in the sample. This
      broadening function is employed to simulate compositional profiles from the
      quantum dots. Information on the dimensions of dots is extracted from annular
      dark-field images. The method is applied to In(y)Ga(1-y)As (y = 0.5) quantum dots
      grown on a GaAs substrate. In this system, a simple truncated cone model is found
      to give an adequate description of the compositional variations across the dot.
      We find a substantial enrichment in In at the center of the dots, in agreement
      with theoretical predictions.

PMID- 12489592
TI  - Theoretical analysis of the atomic force microscopy characterization of columnar
      thin films.
AB  - In this paper, the theoretical analysis of the influence of finite linear
      dimensions of an atomic force microscope tip on profiles of the upper boundaries
      of columnar thin films and their statistical quantities is performed. This
      analysis is based on a numerical evaluation of the main statistical quantities,
      i.e. the standard deviations of the heights and slopes, one-dimensional
      distributions of the probability density of heights and slopes and power spectral
      density function, corresponding to a simulated columnar structure of the thin
      films. It is shown that the strongest misrepresentation of the measured profiles
      of the upper boundaries of the columnar films originates in the cases when the
      linear dimensions of the columns are smaller or comparable with the linear
      dimensions of the tip. Further, it is shown that using a surface reconstruction
      procedure one can correct (improve) the boundary profiles and their statistical
      quantities partially. The results of this analysis enable us to perform rough
      estimation of the errors achieved within atomic force microscopy studies of the
      real columnar thin films. Moreover, these results allow to estimate the
      corrections of the statistical quantities mentioned above to be obtained using
      the surface reconstruction.

PMID- 12489593
TI  - Mean free paths for inelastic electron scattering in silicon and poly(styrene)
      nanospheres.
AB  - The mean free paths for inelastic electron scattering, lambda(in), in silicon
      [Si] and poly(styrene) [PS] have been measured using off-axis electron holography
      in a field-emission transmission electron microscope (FEG TEM). The holographic
      imaging method determines both quantitative wave phase information as well as
      elastic energy-filtered wave amplitude information. Using the energy-filtered
      amplitude data, two-dimensional t/lambda(in) images are reconstructed. The
      present work uses spherical nanoparticles as samples, so the sample thickness at
      any point in a two-dimensional image can be calculated knowing the center and
      radius of the projected nanosphere. The thickness contribution to t/lambda(in) is
      removed to obtain quantitative lambda(in) values. This work finds values of
      lambda(i)Si = 53.8 +/- 5.5 and 88.6 +/- 6.9 nm, and lambda(PS) = 78.1 +/- 3.4 and
      113.0 +/- 5.9 nm for 120 and 200 keV incident electron energies, respectively.

PMID- 12489594
TI  - A comparison of EDS microanalysis in FIB-prepared and electropolished TEM thin
      foils.
AB  - This paper reports the results of a fine-probe EDS microanalytical study of
      cellular precipitation in a Cu-Ti binary alloy. Compositional profiles across the
      solute depleted Cu-rich FCC lamellae and the Cu4Ti lamellae within isothermally
      formed cellular colonies were measured in a FEG-TEM from thin-foil specimens
      prepared by conventional electropolishing and by a technique using a Ga+ focused
      ion-beam (FIB). The Cliff-Lorimer ratio method, with an absorption correction,
      was employed to quantify the compositions. Two FIB samples were prepared with
      different orientations of the lamellae with respect to the ion-milling direction.
      The compositional profiles across the Cu-rich FCC lamellae and the Cu4Ti compound
      lamellae in both the FIB-prepared samples and the electropolished sample were,
      within experimental error, numerically equivalent. The composition of the Cu4Ti
      compound phase lamellae was very close to the ideal stoichiometric composition of
      20 at % Ti. It is concluded that for this system, and for the specimen
      preparation procedures used in this study, the Ga+ ion-milling process has had no
      detectable effect on the chemistry changes across the interlamellar interface at
      the scale studied. These results indicate that the possible sources of chemical
      artifacts which include redeposition, preferential sputtering and ion-induced
      atomic migration can be minimized if several precautions are taken during milling
      in the FIB. Consistent with previous investigators, it was also found that the
      ion-milling process does introduce significant structural artifacts (e.g.,
      dislocations) into the softer FCC Cu-rich phase compared with a specimen produced
      by conventional electropolishing.

PMID- 12489595
TI  - Thermal behaviour modelling of tapered optical fibres for scanning near-field
      microscopy.
AB  - A simple model allowing the calculation of the thermal field inside a metal
      coated fibre tip is presented. The approach has been based on previous
      temperature measurements which operated in steady state and periodic rate. The
      modelhas been inspired from the general theory of heat transfer inside fins,
      after having divided the taper into a set of layers. The advantage of the method
      is the possibility to consider any taper shapes. Moreover, any kind of coating
      thickness and external heat transfer distributions can be considered. As a mean
      of comparison with some previous works, results obtained for simple
      configurations are presented. Then, a study of the main governing parameters
      provides the basic thermal behaviour analysis of optical tips and a comparison
      with experience is given in order to confirm the validity of our approach.

PMID- 12489596
TI  - A historical overview of enhanced external counterpulsation.
AB  - Angina remains a significant health problem in the United States and the world.
      Although there are a variety of pharmacologic and interventional therapies to
      treat angina, many patients are not adequately helped by these treatments.
      Enhanced external counterpulsation (EECP) is an effective, noninvasive technique
      designed to decrease the frequency and duration of anginal episodes, as well as
      increase exercise duration in patients with acute angina. Since the early 1960s,
      the technology of EECP has been thoroughly refined. In addition, a number of
      important clinical trials have provided evidence for its effectiveness.
      Continuing research is needed to determine the best patients for EECP and its
      appropriate clinical application.

PMID- 12489597
TI  - A review of enhanced external counterpulsation clinical trials.
AB  - A variety of clinical trials of enhanced external counterpulsation (EECP) have
      been conducted since the 1960s. The vast majority of these studies have
      investigated the use of EECP in patients with angina pectoris. Only one of these
      trials was randomized. These clinical trials have demonstrated the benefits of
      EECP in terms of reduction in anginal episodes, increased exercise times, and
      improvement in health-related quality of life scores. The International EECP
      Patient Registry, through its phase I and II enrollment, is expanding the data
      set on outcomes after EECP treatment.

PMID- 12489598
TI  - Enhanced external counterpulsation: mechanism of action.
AB  - The mechanisms accounting forthe salutary benefits of enhanced external
      counterpulsation (EECP) remain largely unknown. Emerging data now point to three
      possible hypotheses to explain its efficacy. These possible explanations include
      enhanced diastolic flow, changes in the neurohumoral milieu, and changes in
      ventricular function independent of changes in cardiac load. While each of these
      three hypotheses may help explain the mechanism behind EECP's effects, more
      clinical studies are required to refine these proposed explanations.

PMID- 12489599
TI  - Current use of enhanced external counterpulsation and patient selection.
AB  - Most patients who receive enhanced external counterpulsation (EECP) have
      symptomatic coronary artery disease. These patients have either responded poorly
      to pharmacologic therapy or are poor candidates for revascularization procedures.
      Such patients receive a variety of consistent benefits from EECP treatment. As
      more is learned about EECP, patients once excluded from early clinical trials are
      now able to take advantage of EECP. Nevertheless, EECP is not suitable for some
      patients. It has a favorable adverse event profile for most patients undergoing
      the treatment. Medicare reimbursement coverage limitations remain an obstacle to
      having a broad cross-section of patients benefit from EECP.

PMID- 12489600
TI  - Treatment options for angina pectoris and the future role of enhanced external
      counterpulsation.
AB  - Patients with coronary artery disease have a variety of treatment options
      available to them. These include medications to control anginal episodes and,
      when appropriate, revascularization interventions in the form of coronary artery
      bypass graft and angioplasty. Despite advances in the treatment of angina, a
      substantial number of patients continue to have symptoms that can significantly
      impair their quality of life. These patients may benefit from enhanced external
      counterpulsation (EECP). With recent results of the latest clinical trial of
      EECPjust published, the role of EECP, including its position in the hierarchy of
      treatment options, needs to be seriously considered.

PMID- 12489601
TI  - Ongoing and planned studies of enhanced external counterpulsation.
AB  - There is strong, continued interest in enhanced external counterpulsation (EECP)
      as evidenced by current, ongoing clinical trials. Many of these have been
      designed to support the current indications of EECP, mainly its application in
      the treatment of symptomatic coronary artery disease. An exciting area in this
      regard ishow EECP may help control blood glucose in patients with angina and
      diabetes mellitus. A variety of planned or ongoing exploratory studies are also
      helping to explain the mechanism of action behind EECP. Two clinical trials are
      now investigating a new indication for EECP in patients with congestive heart
      failure, including the important randomized Prospective Evaluation of EECP in
      Congestive Heart failure (PEECH) trial.

PMID- 12489602
TI  - Preventing blood-borne infections through pharmacy syringe sales and safe
      community syringe disposal.

PMID- 12489603
TI  - Injection drug users and pharmacists: a call for compassion, cooperation, and
      care.

PMID- 12489604
TI  - The legality of selling or giving syringes to injection drug users.
AB  - OBJECTIVES: Laws limiting access to sterile syringes impede the public health
      goal that injection drug users (IDUs) use a new, sterile syringe for every
      injection to reduce blood-borne disease transmission. We sought to determine the
      legality of selling or giving syringes to IDUs to prevent disease. DESIGN: We
      used standard legal research methods to identify and analyze laws and regulations
      influencing the distribution of syringes in the 50 states, the District of
      Columbia, Puerto Rico, and the Virgin Islands. RESULTS: A total of 51
      jurisdictions had drug paraphernalia laws; 14 had syringe prescription laws or
      regulations; 11 required purchasers to show identification; 13 had legislation
      authorizing syringe exchange programs (SEPs). Since the beginning of the human
      immunodeficiency virus epidemic, 11 states have fully or partially deregulated
      syringe sales. Nonprescription retail syringe sales to IDUs for disease
      prevention purposes are clearly legal in 20 states, and have a reasonable claim
      to legality in 22 more. Sales to IDUs with a prescription are clearly illegal in
      only 3 jurisdictions. SEPs can operate legally in at least 21 states. CONCLUSION:
      Syringe access laws in most states may reasonably be interpreted to allow
      pharmacists to sell syringes to IDUs to prevent disease. In practice, however,
      unclear laws and pharmacist uncertainty as to their interpretation may constitute
      continuing barriers to syringe access for IDUs. A comprehensive public policy of
      ensuring syringe access for IDUs requires eliminating legal barriers to the sale,
      possession, and disposal of syringes, and educating pharmacists and law
      enforcement officials about the legality and public health importance of sterile
      syringe access.

PMID- 12489605
TI  - Deregulation of syringe sale and possession in New Hampshire, 1991-2000.

PMID- 12489606
TI  - The Minnesota Pharmacy Syringe Access Initiative: a successful statewide program
      to increase injection drug user access to sterile syringes.

PMID- 12489607
TI  - Increasing legal and regulatory support for pharmacy syringe sales to injection
      drug users, Washington State, 1999-2002.

PMID- 12489608
TI  - Maine Board of Pharmacy strongly supports unrestricted sale of sterile syringes.

PMID- 12489609
TI  - Encouraging pharmacy sale and safe disposal of syringes in Seattle, Washington.

PMID- 12489610
TI  - Mobilizing public and private partners to support New York's Expanded Syringe
      Access Demonstration Program.

PMID- 12489611
TI  - Maximizing the benefits of expanded syringe access and safe disposal for persons
      with diabetes.

PMID- 12489612
TI  - Encouraging pharmacy sale of syringes to injection drug users in New Mexico.

PMID- 12489613
TI  - Pharmacy student knowledge, attitudes, and beliefs about selling syringes to
      injection drug users.
AB  - OBJECTIVE: To explore pharmacy school education and pharmacy students' knowledge,
      attitudes, and beliefs about human immunodeficiency virus (HIV) and acquired
      immunodeficiency syndrome (AIDS), drug use, and syringe sales to injection drug
      users (IDUs). DESIGN: Qualitative study of a convenience sample of pharmacy
      school students. SETTING: A pharmacy school in the southeastern United States.
      INTERVENTION: Two focus groups and nine in-depth interviews were conducted about
      HIV/AIDS education and counseling, syringe sales to possible IDUs, and related
      pharmacy school education. PARTICIPANTS: 19 Doctor of Pharmacy students,
      including 88 students in their third professional year and 11 in their fourth
      professional year. RESULTS: Most participants believed that they would benefit
      from more class time on HIV/AIDS topics, including AIDS treatment medications and
      HIV prevention. Most participants believed that the laws and regulations
      governing syringe sales in their state were vague, leaving syringe sale decisions
      to pharmacists' discretion. Nine study participants supported selling syringes to
      possible IDUs, five opposed it, and five were undecided or ambivalent. Classroom
      education focused on addiction to prescription drugs, with limited attention to
      illicit drug use. CONCLUSION: Pharmacy students have divided opinions about
      selling syringes to IDUs. To prepare students for helping their patients with
      drug-use problems, pharmacy schools should increase training about HIV/AIDS and
      addiction. Policy makers should consider changing laws and regulations of syringe
      sales to recognize prevention of blood-borne infections as a legitimate medical
      purpose for selling syringes to IDUs.

PMID- 12489614
TI  - Individual and structural influences shaping pharmacists' decisions to sell
      syringes to injection drug users in Atlanta, Georgia.
AB  - OBJECTIVE: To better understand the individual (e.g., attitudes and beliefs) and
      structural (e.g., laws and regulations) factors that influence and shape
      pharmacists' decisions about selling syringes to injection drug users (IDUs).
      DESIGN: Qualitative research. SETTING: Metropolitan Atlanta. PARICIPANTS: 20
      practicing pharmacists who work in or near areas of high drug use in Atlanta, and
      nine pharmacists who are considered leaders in their profession in Georgia.
      INTERVENTIONS: Semistructured, in-depth interviews. MAIN OUTCOME MEASURES:
      Individual and structural factors that influence pharmacists' decisions about
      selling syringes to IDUs. RESULTS: Pharmacists reported that they use their
      professional discretion in making syringe sale decisions and that these decisions
      are influenced by individuals factors such as their personal attitudes and
      beliefs about the nature and causes of drug use, and by structural factors such
      as the Georgia Board of Pharmacy regulation stating that syringes cannot be sold
      if they will be used for an "unlawful purpose." CONCLUSIONS: IDUs' access to
      sterile syringes from pharmacies in Atlanta, would likely be increased by (1)
      providing practicing pharmacists with professional education programs that
      describe the broad professional support for IDU access to sterile syringes and
      why blood-borne infection prevention is a legitimate medical purpose for selling
      syringes and (2) removing or modifying the restrictive Board of Pharmacy
      regulation governing syringe sales.

PMID- 12489615
TI  - Pharmacists' attitudes and concerns regarding syringe sales to injection drug
      users in Denver, Colorado.
AB  - OBJECTIVE: To identify factors influencing pharmacists' decisions about selling
      syringes to injection drug users (IDUs). DESIGN: Audiotaped interviews. SETTING:
      Denver, Colorado. PARTICIPANTS: Thirty-two pharmacists at 24 pharmacies.
      INTERVENTION: One-hour semistructured interviews. MAIN OUTCOME MEASURES:
      Practices regarding syringe sales to IDUs and factors influencing the practices.
      RESULTS: Of the 32 pharmacists interviewed, 16 indicated that they sold syringes
      to all customers ("pro-sell"), 11 refused to sell unless shown proof of diabetic
      status ("no-sell"), and 5 were "undecided." Several factors influenced the
      decision to sell. A perceived conflict between prevention of disease and
      prevention of drug abuse most clearly distinguished the three categories, with
      pro-sell pharmacists more likely than others to prioritize disease prevention and
      believe that syringe sales would not increase drug abuse. Business concerns, such
      as the effect of the presence of IDUs on other customers and the possibility of
      discarded syringes around the store, were especially prevalent among no-sell and
      undecided pharmacists. Seventeen pharmacists did not know about Colorado laws
      governing syringe sales. Four no-sell pharmacists used the laws to justify their
      decision not to sell, and two undecided pharmacists said they used the law when
      they did not want to sell syringes to IDU. All pharmacists supported syringe
      exchange programs. CONCLUSION: One-half of the pharmacists sold syringes to IDUs,
      and several more indicated that they would do so if certain concerns were
      addressed. These data suggest that improved syringe disposal options, continuing
      education programs, and clarification of existing laws and regulations would
      encourage more pharmacists in Denver to sell syringes to IDUs.

PMID- 12489616
TI  - Pharmacist ambivalence about sale of syringes to injection drug users.
AB  - OBJECTIVE: To examine pharmacists' attitudes and practices surrounding human
      immunodeficiency virus (HIV) prevention among injection drug users. DESIGN: Focus
      groups. SETTING: Urban and rural sites in Colorado, Connecticut, Kentucky, and
      Missouri. PATIENTS OR OTHER PARTICIPANTS: Eight focus groups, with 4 to 11
      pharmacists participating in each group. INTERVENTIONS: Transcripts of focus
      group discussions were evaluated for common themes by the authors and through the
      use of NUD*IST. MAIN OUTCOME MEASURES: Willingness to sell syringes to all
      customers, views on syringe exchange programs (SEPs), knowledge of laws governing
      syringe sales and racial, ethnic, or gender biases in syringe selling practices.
      RESULTS: Two pharmacists established their own policies of selling syringes to
      everyone, and three expressed a willingness to have their pharmacies serve as
      SEPs. A total of 20% of the pharmacists expressed an interest in learning more
      about the efficacy of SEPs and distribution of syringes by pharmacists, and were
      willing to change their views based on this information. Many also indicated a
      general willingness to work with SEPs or to participate in the effort to curb the
      spread of HIV. However, a majority of pharmacists opposed having SEPs in their
      pharmacies and reported selling syringes only within specific limits: to known
      diabetics, to individuals who looked reasonable, or to individuals who presented
      a logical explanation. No racial, ethnic, or gender bias was observed.
      CONCLUSION: Opinions among pharmacists varied across and within sites. While a
      majority of pharmacists would not establish SEPs in their own pharmacies, nearly
      all would participate in other HIV-prevention programs. Educational programs for
      pharmacists may be valuable in HIV-prevention efforts.

PMID- 12489617
TI  - Pharmacist support for selling syringes without a prescription to injection drug
      users in Rhode Island.
AB  - OBJECTIVE: To examine pharmacists' attitudes and obstacles to syringe sales to
      IDUs without prescriptions in Rhode Island, around the time that such sales
      became legal in the state. DESIGN: Self-administered written survey. SETTING:
      Rhode Island. PARTICIPANTS: 400 randomly selected pharmacist members of the Rhode
      Island Pharmacists Association. MAIN OUTCOME MEASURES: Responses to survey items.
      RESULTS: Of the 400 pharmacists contacted, 131 (33%) completed and returned the
      survey; of these, 101 (77%) were pharmacists who worked in stores that provided
      direct nonprescription syringe sales to the public. The majority of these 101
      pharmacists were willing to sell syringes to a suspected IDU without a
      prescription (65%), favored providing free sharps containers for disposal (68%),
      and supported providing pamphlets on safer injection practices (88%). Willingness
      to sell syringes to IDUs without a prescription was significantly correlated with
      various beliefs about possible consequences of sales. CONCLUSION: The high level
      of support for nonprescription syringe sales to IDUs is promising. The
      correlation between the willingness to sell syringes to IDUs without a
      prescription and various beliefs suggests that future educational interventions
      might encourage pharmacists to sell syringes to this population without a
      prescription to decrease HIV and hepatitis transmission.

PMID- 12489618
TI  - More pharmacists in high-risk neighborhoods of New York City support selling
      syringes to injection drug users.
AB  - OBJECTIVE: To document changes in pharmacists' opinions and practices from the
      time of passage to implementation of a law permitting selling syringes without a
      prescription (the Expanded Syringe Access Demonstration Program [ESAP]). DESIGN:
      Two cross-sectional randomized telephone surveys. SETTING: High-risk
      neighborhoods of New York City. SUBJECTS: Pharmacists. MAIN OUTCOME MEASURES:
      Support for selling syringes without a prescription to injection drug users
      (IDUs). RESULTS: We completed 130 surveys at baseline (BL) in August 2000, from
      neighborhoods with high numbers of injection-related acquired immunodeficiency
      syndrome (AIDS) cases and 231 surveys at law change (LC) in January 2001. To
      correct for differences in sampling, we limited the analysis to pharmacies in ZIP
      Codes represented in both samples and weighted results to adjust for the median
      income level of those postal codes. From BL (n = 83) to LC (n = 84), law
      awareness increased (43% to 90%, P < .001), as did personal support for selling
      syringes without a prescription to IDUs (36% to 63%, P < .001). From BL to LC, a
      larger proportion of supporters believed that selling syringes was an important
      part of human immunodeficiency virus (HIV) prevention and would help decrease HIV
      transmission, and a smaller proportion was concerned about customer discomfort
      and increased drug use. A total of 40% of respondents were ESAP registered at LC
      but registration was not associated with support for selling syringes to IDUs.
      CONCLUSIONS: Support for ESAP among pharmacists increased in high-risk
      neighborhoods as the program was implemented. The finding that some pharmacists
      were ESAP registered but did not support selling syringes to IDUs and others were
      supportive, but not ESAP registered, may have program implications.

PMID- 12489619
TI  - Injection drug users report good access to pharmacy sale of syringes.
AB  - OBJECTIVE: To examine injection drug users (IDUs) opinions and behavior regarding
      purchase of sterile syringes from pharmacies. DESIGN: Focus groups. SETTING:
      Urban and rural sites in Colorado, Connecticut, Kentucky, and Missouri. PATIENTS
      OR OTHER PARTICIPANTS: Eight focus groups, with 4 to 15 IDU participants per
      group. INTERVENTIONS: Transcripts of focus group discussions were evaluated for
      common themes by the authors and through the use of the software program NUD*IST.
      MAIN OUTCOME MEASURES: Knowledge of human immunodeficiency virus (HIV), pharmacy
      use, barriers to access from pharmacies, high-risk and risk-reducing behavior,
      and rural/urban difference. RESULTS: Almost all participants knew the importance
      of using sterile syringes for disease prevention and reported buying syringes
      from pharmacies more than from any other source. Two IDUs believed pharmacists
      knew the syringes were being used for injecting drugs and perceived pharmacists'
      sales of syringes to be an attempt to contribute to HIV prevention. Most IDUs
      reported that sterile syringes were relativity easy to buy from pharmacies, but
      most also reported barriers to access, such as having to buy in packs of 50 or
      100, being made to sign a book, having to make up a story about being diabetic,
      or having the feeling that the pharmacists were demeaning them. While the
      majority of IDUs reported properly cleaning or not sharing syringes and safely
      disposing of them, others reported inadequate cleaning of syringes and instances
      of sharing syringes or of improper disposal. There were few differences in IDUs'
      reported ability to buy syringes among states or between urban and rural sites,
      although the data suggest that IDUs could buy syringes more easily in the urban
      settings. CONCLUSION: For the most part, participants understood the need for
      sterile syringes in order to protect themselves from HIV, hepatitis B virus, and
      hepatitis C virus and saw pharmacies as the best source of sterile syringes.
      Although these data are not generalizable, they suggest that pharmacists can and
      do serve as HIV-prevention service providers in their communities.

PMID- 12489621
TI  - Impact of increased syringe access: preliminary findings on injection drug user
      syringe source, disposal, and pharmacy sales in Harlem, New York.
AB  - OBJECTIVE: To evaluate the New York State Expanded Syringe Access Demonstration
      Program (ESAP) through injection drug user (IDU) surveys, discarded needles and
      syringes studies, and pharmacy sales and experiences surveys. DESIGN: Pre-post
      comparison. SETTING: In Harlem, New York City, risk surveys among street
      recruited IDUs, needle/syringe street counts on 27 systematically sampled city
      blocks, and Harlem pharmacist reports of sales and experiences. MAIN OUTCOME
      MEASURES: Number and types of IDU syringe sources, block mean counts of discarded
      needles and syringes, level of pharmacy nonprescription syringe sales (NPSS), and
      pharmacists' experiences. RESULTS: Comparing 209 pre-ESAP with 396 post-ESAP
      IDUs, pharmacies as a primary syringe source increased: 3.4% to 5.3% (P < .001,
      and ever pharmacy use increased: 4.9% to 12.5% (P < .001), respectively. Compared
      with pre-ESAP IDUs, post-ESAP IDUs tended to be younger and more often black.
      Harlem pharmacy participation in ESAP increased considerably from March 1, 2001,
      to March 1, 2002, 49% to 79%, respectively. Among three Harlem pharmacies, there
      was a modest increase in NPSS; pharmacists reported no problems, and no discarded
      needles and syringes were observed in pharmacy areas. In the three pharmacies,
      the proportion of syringe sales that were NPSS was 46% (110 to 240 NPSS/month),
      3% (25 to 90 NPSS/month), and 0%. The mean ratios of needles/syringes to
      background trash have not increased in Harlem since ESAP began. CONCLUSION: To
      date, no evidence of harmful effects discarded needles/syringes, pharmacy
      altercations) resulting from ESAP were observed. While NPSS have increased in
      Harlem, pharmacy use among IDUs remains low. In Harlem, efforts are underway to
      increase ESAP awareness and reduce socioenvironmental barriers to ESAP.

PMID- 12489622
TI  - Pharmacy syringe sale practices during the first year of expanded syringe
      availability in New York City (2001-2002).
AB  - OBJECTIVE: [corrected] To assess the role that customer characteristics,
      including race, age, and gender and pharmacy characteristics, including type and
      location, play on actual syringe-selling practice by pharmacies registered to
      sell syringes under the New York State Expanded Syringe Access Demonstration
      Program (ESAP). DESIGN: 89 syringe-purchasing visits were made in randomly
      selected ESAP-registered pharmacies, stratified by chain and independent status.
      SETTING: Visits were conducted in 14 New York City neighborhoods. Three
      neighborhoods (two with high need for human immunodeficiency virus [HIV]
      prevention services and one with low need) were selected in each of New York
      City's five boroughs (except Staten Island, where only two neighborhoods were
      visited, as only one exists with high need for HIV prevention services).
      PARTICIPANTS: Visits were conducted by syringe-purchasing testers with different
      demographic characteristics, including age (< or = 25 and > 25), race/ethnicity
      (white, black, Latino), and gender (men, women). RESULTS: Testers were able to
      purchase syringes in 69% of visits. Tester race, age, and gender did not
      significantly affect sales of syringe-selling practices. Location of pharmacy was
      statistically significant, with only 33% of the registered pharmacies selling
      syringes in the Bronx, but 67% to 89% selling in other four boroughs.
      CONCLUSIONS: ESAP has been widely implemented among registered pharmacies in four
      of New York City's five boroughs. The program's effectiveness could be enhanced
      through pharmacy-based efforts focused broadly on the ESAP goal of preventing the
      transmission of HIV and other blood-borne infections among injection drug users.

PMID- 12489620
TI  - Legal syringe purchases by injection drug users, Brooklyn and Queens, New York
      City, 2000-2001.
AB  - OBJECTIVE: To assess preliminary results of the Expanded Syringe Access
      Demonstration Program (ESAP) in New York City. DESIGN: Temporal trends of
      pharmacy use among injection drug users (IDUs) in Brooklyn and Queens were
      analyzed from December 2000 through December 2001. SETTING: Brooklyn and Queens,
      New York City. PARTIPANTS: IDUs. MAIN OUTCOME MEASURES: Attempts to purchase
      syringes from pharmacies and success in doing so. RESULTS: Of the 1,072 IDUs
      interviewed from December 2000 through December 2001, the majority were daily
      heroin injectors, but there was also substantial speedball and cocaine injection.
      There was a clear increase over time in both the percentage of subjects who
      attempted to purchase syringes in pharmacies and in the percentage who
      successfully purchased syringes. Among IDUs interviewed 4 or more months after
      ESAP began, large majorities of those who attempted to purchase syringes were
      successful in doing so. No differences in use of ESAP by IDUs were identified in
      Brooklyn versus Queens: 27% of IDUs interviewed in Queens reported that they had
      attempted to purchase syringes in pharmacies versus 28% in Brooklyn. Persons who
      reported injecting on a daily or more frequent basis were more likely to have
      attempted pharmacy purchases than persons who reported injecting less frequently,
      32% versus 21%. CONCLUSIONS: The ESAP program has led to an increase in the use
      of pharmacies as sources of sterile injection equipment among IDUs in New York
      City. The extent to which pharmacies become an important source of sterile
      injection equipment and the effect of legal pharmacy sales on risk behaviors for
      human immunodeficiency virus (HIV) infection remain to be determined.

PMID- 12489623
TI  - Limited access to syringes for injection drug users in pharmacies in Denver,
      Colorado.
AB  - OBJECTIVE: To determine the availability of syringes for injection drug users
      (IDUs) from pharmacies in Denver. DESIGN: Single-group, uncontrolled,
      noncomparative study. SETTING: Denver, Colorado. PATIENTS OR OTHER PARTICIPANTS:
      23 randomly selected pharmacies in the Denver metropolitan area and 3 additional
      pharmacies located near drug-buying locations. INTERVENTION: Attempt by eight
      trained IDU "research assistants" to purchase packages of 10 U-100 insulin
      syringes without a prescription from pharmacies. MAIN OUTCOME MEASURES:
      Successful purchase of syringes; reasons for refusal. RESULTS: Of 26 pharmacies,
      4 reported not stocking syringes, 3 did not sell syringes to any research
      assistants, 10 sold to some research assistants but not to others, and 9 sold to
      all research assistants. Of 206 purchase attempts, 54% were successful. In 37.9%
      of 95 refusals, the pharmacist reported that syringes were not sold at the store,
      and in 28.4% the pharmacist refused to sell because the research assistant did
      not produce diabetic identification or answer insulin-related questions. No
      differences in pharmacy response were found with respect to the racial or ethnic
      characteristics of the research assistant. Price varied substantially within and
      among stores. No pharmacies that sold syringes to research assistants were open
      24 hours per day. CONCLUSION: While IDUs who live near a pharmacy that regularly
      sells syringes and IDUs with a convincing diabetes story may have adequate access
      to syringes, others face inconsistent availability. Price fluctuations and
      limited hours of those pharmacies that sell syringes may be additional barriers
      to access to sterile syringes for IDUs in Denver.

PMID- 12489624
TI  - Needle sightings and on-the-job needle-stick injuries among New York City
      Department of Sanitation Workers.

PMID- 12489625
TI  - State syringe and drug possession laws potentially influencing safe syringe
      disposal by injection drug users.
AB  - OBJECTIVE: To review state laws and judicial decisions for potential barriers to
      proper syringe disposal by injection drug users (IDUs). DESIGN: Using standard
      legal research methods, this study reviewed drug paraphernalia, syringe
      prescription, drug possession, and syringe exchange laws and relevant case
      decisions in 59 jurisdictions. MAIN OUTCOME MEASURES: Drug paraphernalia, syringe
      prescription, and drug possession laws. RESULTS: Drug paraphernalia laws prohibit
      all possession of syringes by IDUs in 31 jurisdictions. Syringe prescription laws
      prohibit possession in 7 jurisdictions. In 53 jurisdictions, IDUs may be subject
      to prosecution for the possession of drug residue in used syringes. Only two
      states (HI, RI) have no legal barriers to safe syringe disposal by IDUs. Sixteen
      jurisdictions that have tried to expand syringe access for IDUs by authorizing
      SEPs or by deregulating pharmacy sale of syringes continue to have criminal law
      provisions that could pose barriers to proper disposal. CONCLUSION: IDUs are a
      significant source of syringes disposed of outside the health care system.
      Involving IDUs in safe community sharps disposal programs is an important public
      health goal, but may be frustrated by legal barriers. Although this study looked
      only at law on the books, and not law as actually applied, ethnographic and
      survey research indicates that criminal laws do influence the syringe possession
      behavior of IDUs. The findings of this study suggest that syringe and drug
      possession laws could deter IDUs from participating in safe syringe disposal
      programs.

PMID- 12489626
TI  - Community syringe collection and disposal policies in 16 states.
AB  - OBJECTIVE: To review laws, regulations, and guidelines that affect the collection
      and disposal of hypodermic needles, syringes, and lancets used outside of
      professional health care settings (hereafter referred to as "community
      syringes"). DESIGN: Law and policy analysis. SETTING: Alabama, California,
      Florida, Georgia, Hawaii, Massachusetts, Michigan, Minnesota, New Jersey, New
      York, Ohio, Oregon, Rhode Island, South Carolina, Washington, and Wisconsin.
      INTERVENTION: Information on syringe collection and disposal in the community was
      gathered from federal and state records and state agency personnel. MAIN OUTCOME
      MEASURES: Legally permissible means of syringe collection and disposal available
      to persons in the community injecting medical treatments and injection drug
      users. RESULTS: Laws, regulations, or guidelines in 13 states allowed community
      syringes to be legally discarded in household trash; guidelines for in-trash
      disposal varied among the states. Only 6 states had laws or regulations that
      specifically addressed community syringe collection. In 10 states, infectious
      waste laws and regulations that apply to medical facilities such as clinics would
      also apply to community syringe collection sites. CONCLUSION: In the 16 states
      studied, laws, regulations, and guidelines relating to community syringe
      collection and disposal were somewhat inconsistent and confusing and presented
      potential barriers to safe disposal. States should consider amending laws,
      regulations, and guidelines to promote community syringe collection programs. A
      national effort is needed to achieve consistent community syringe collection and
      disposal laws and guidelines for all states. Pharmacists can aid in safe syringe
      disposal by counseling their patients about safe disposal, providing or selling
      sharps containers, and accepting used syringes for safe disposal. Pharmacists can
      join other interested groups in advocating clarification of disposal laws and
      regulations that favor community programs designed to keep syringes out of the
      trash so that they can be disposed of as infectious waste.

PMID- 12489627
TI  - Promoting safe syringe disposal goes "hand in hand" with expanded syringe access
      in New York State.

PMID- 12489628
TI  - Community needle collection and disposal programs in Florida.

PMID- 12489629
TI  - Eureka--implementing safe community needle disposal in Rhode Island.

PMID- 12489630
TI  - How Wisconsin promotes household sharps collection.

PMID- 12489631
TI  - Household sharps collection program in Brown County, Wisconsin.

PMID- 12489632
TI  - San Francisco Safe Needle Disposal Program, 1991-2001.

PMID- 12489633
TI  - Community sharps disposal program in Council Bluffs, Iowa.

PMID- 12489634
TI  - Safe sharps disposal in public restrooms, Bush Intercontinental Airport, Houston,
      Texas.

PMID- 12489635
TI  - Nitric oxide and Mycobacterium leprae pathogenicity.
AB  - Leprosy is an old, still dreaded infectious disease caused by the obligate
      intracellular bacterium Mycobacterium leprae. During the infectious process, M.
      leprae is faced with the host macrophagic environment, where the oxidative stress
      and NO release, combined with low pH, low pO2, and high pCO2, contribute to limit
      the growth of the bacilli. Comparative genomics has unraveled massive gene decay
      in M. leprae, linking the strictly parasitic lifestyle with the reductive genome
      evolution. Compared with Mycobacterium tuberculosis and Mycobacterium bovis, the
      leprosy bacillus has lost most of the genes involved in the detoxification of
      reactive oxygen and nitrogen species. The very low reactivity of the unique
      truncated hemoglobin retained by M. leprae could account for the susceptibility
      of this exceptionally slow-growing microbe to NO.

PMID- 12489636
TI  - The complementary membranes forming the blood-brain barrier.
AB  - Brain capillary endothelial cells form the blood-brain barrier. They are
      connected by extensive tight junctions, and are polarized into luminal (blood
      facing) and abluminal (brain-facing) plasma membrane domains. The polar
      distribution of transport proteins allows for active regulation of brain
      extracellular fluid. Experiments on isolated membrane vesicles from capillary
      endothelial cells of bovine brain demonstrated the polar arrangement of amino
      acid and glucose transporters, and the utility of such arrangements have been
      proposed. For instance, passive carriers for glutamine and glutamate have been
      found only in the luminal membrane of blood-brain barrier cells, while Na
      dependent secondary active transporters are at the abluminal membrane. This
      organization could promote the net removal of nitrogen-rich amino acids from
      brain, and account for the low level of glutamate penetration into the central
      nervous system. Furthermore, the presence of a gamma-glutamyl cycle at the
      luminal membrane and Na-dependent amino acid transporters at the abluminal
      membrane may serve to modulate movement of amino acids from blood-to-brain.
      Passive carriers facilitate amino acid transport into brain. However, activation
      of the gamma-glutamyl cycle by increased plasma amino acids is expected to
      generate oxoproline within the blood-brain barrier. Oxoproline stimulates
      secondary active amino acid transporters (Systems A and B(o)+) at the abluminal
      membrane, thereby reducing net influx of amino acids to brain. Finally, passive
      glucose transporters are present in both the luminal and abluminal membranes of
      the blood-brain barrier. Interestingly, a high affinity Na-dependent glucose
      carrier has been described only in the abluminal membrane. This raises the
      question whether glucose entry may be regulated to some extent. Immunoblotting
      studies suggest more than one type of passive glucose transporter exist in the
      blood-brain barrier, each with an asymmetrical distribution. In conclusion, it is
      now clear that the blood-brain barrier participates in the active regulation of
      brain extracellular fluid, and that the diverse functions of each plasma membrane
      domain contributes to these regulatory functions.

PMID- 12489637
TI  - In vitro selection of self-interacting transmembrane segments--membrane proteins
      approached from a different perspective.
AB  - The principles underlying the folding of integral membrane proteins are uncovered
      in an increasingly detailed way. Experimental determination of high-resolution
      structures followed by analysis of packing reveal structural similarities as well
      as differences to soluble globular proteins. At the same time, protein/protein
      interactions at the level of membrane-embedded domains have been investigated for
      different model proteins. More recently, self-interacting transmembrane helices
      have been selected from combinatorial libraries in vitro to study the mechanistic
      basis of protein/protein interaction in membranes in a systematic way. With an
      emphasis on the latter approach, this review discusses insights emerging from an
      integrated view on the recent advances.

PMID- 12489638
TI  - In vivo studies on mouse erythrocytes linked to transferrin.
AB  - Transferrin (Tf), a plasma protein with numerous, highly specific receptors in
      proliferating and differentiating cells was already discussed as a targeting
      ligand for drugs and liposomes in previous studies. In this paper, we deal with
      erythrocytes linked to Tf as possible physiological targeting carrier systems for
      delivering anticancer drugs. For that purpose we have used glutaraldehyde (0.1%)
      as a coupling agent between Tf and erythrocytes. The highest amount of Tf linked
      to erythrocytes turned out to be 0.76 +/- 0.13 microg Tf/10(6) cells, while
      reaching 65% of cell recovery. After 13 days, the Tf-erythrocytes hemolysis
      reached 50%, with transferrin still coupled to erythrocytes. The in vivo kinetic
      behaviour of intravenously injected 51Cr-Tf-erythrocytes showed a reduced half
      life to hours as compared to days of controls. However, a considerable percentage
      of Tf-erythrocytes (close to 20%) remained circulating for a relatively long
      period (around 2 days), which made possible the specific targeting by these
      carrier systems. In vivo biodistribution studies indicated that 51Cr-Tf
      erythrocytes rapidly accumulated in the different studied organs (liver, spleen,
      lungs, kidneys, femur-tibia, and heart), suggesting a selective removal of Tf
      erythrocytes by the cells of the mononuclear phagocytic system present mainly in
      liver and spleen. On the other hand, Tf-erythrocytes showed a poor targeting of
      heart tissue, therefore a reduced cardiac toxicity should be expected after
      administration of erythrocyte-encapsulated drugs. The presence of Tf-erythrocytes
      in femur-tibia and spleen could be related to the Tf-specific binding to the
      hematopoietic cells containing Tf receptors. The final results of this study
      encourage additional research on Tf-erythrocyte to investigate the relationship
      between transferrin-mediated targeting by carrier erythrocytes and uptake of
      different erythrocyte-encapsulated drugs. Consequently, the current study showed
      possible use of these carriers as a potential therapeutic tool for drug targeting
      in animal models with alterations affecting mononuclear phagocytic system or
      carcinomas of various origins whose cells show elevated number of Tf receptors.

PMID- 12489640
TI  - Down-regulation of organic anion transporter 2 mRNA expression by nitric oxide in
      primary cultured rat hepatocytes.
AB  - Role of nitric oxide (NO) on the expression of organic anion transporter 2 (OAT2)
      located in sinusoidal domain of hepatocytes has been investigated. Effect of NO
      generated in vivo in rat and delivered in vitro to hepatocytes was determined.
      Lipopolysaccharide (LPS) and spermine NONOate (SPER/NO) were selected as the NO
      donors for in vivo and in vitro experiments, respectively. Constitutive basal
      expression of rOAT2 mRNA was detected in the normal rat liver and the level of
      its expression was decreased by intraperitoneal administration of LPS. This LPS
      induced decrement did not occur when aminoguanidine (AG), an inhibitor of iNOS,
      was co-administered with LPS. The expression of rOAT2 mRNA was detected in
      hepatocytes, but not in the nonparenchymal cells. In the primary cultured
      hepatocytes obtained from normal rats (normal hepatocytes), a time-dependent
      decline of rOAT2 mRNA expression was observed, but not in the hepatocytes
      obtained from rats pretreated with gadolinium chloride (GdCl3, Gd-hepatocytes),
      an inhibitor of Kupffer cell activation. The decline of rOAT2 mRNA expression
      observed in the normal hepatocytes was enhanced by LPS treatment, but not in the
      Gd-hepatocytes. The LPS-dependent enhancement in the decline of rOAT2 mRNA
      expression did not occur when the normal hepatocytes were treated with AG or
      actinomycin D. When the Gd-hepatocytes were treated with SPER/NO, an NO donor,
      the rOAT2 mRNA expression declined markedly. Combined, our results suggest that
      rOAT2 mRNA expression in hepatocytes is down-regulated by NO at least at the
      transcriptional step.

PMID- 12489639
TI  - Thymocyte apoptosis induced by phosphorylation of histones is associated with the
      change in chromatin structure to allow easy accessibility of DNase.
AB  - The inhibitors of protein phosphatase such as calyculin A and okadaic acid induce
      the apoptotic cell death in rat thymocytes. To clarify the molecular mechanism of
      these inhibitor-induced apoptosis, the effect of calyculin A on DNA fragmentation
      in the isolated nuclei were studied. A significant increase in DNA fragmentation
      was observed in the nuclei prepared from the cells treated with calyculin A that
      caused histone hyperphosphorylation. No changes of the activities of caspase-8
      and -3 were observed in the extract from the cells treated with calyculin A. The
      circular dichroism analysis of soluble chromatin from calyculin A-treated
      thymocyte nuclei indicated that phosphorylation of histones decreased its alpha
      helical content. Thus, the change in the chromatin structure may be due to the
      chemical modification of histones. Moreover, the structural change in chromatin
      preceded DNA fragmentation in the nuclei. Therefore, these results suggest that
      the change of chromatin structure allow easy accessibility of nuclear DNase to
      chromosomal DNA.

PMID- 12489641
TI  - Unification for the expression of the monophenolase and diphenolase activities of
      tyrosinase.
AB  - In order to unify and generalize, we define the International Units used to
      express the monophenolase and diphenolase activity of mushroom tyrosinase acting
      on different monophenol/diphenol pairs and establish a quantitative relation.
      Similarly, the activity units to express tyrosinase activity proposed by
      suppliers are discussed and compared with the above International Units. Lastly,
      we study the relation between International Units of diphenolase activity and of
      monophenolase activity for other biological sources of tyrosinase.

PMID- 12489642
TI  - What is the function of GTP produced in the Krebs citric acid cycle?

PMID- 12489643
TI  - How I became a biochemist.

PMID- 12489644
TI  - My friendship with Africa.

PMID- 12489645
TI  - To revise or retreat--your choice.

PMID- 12489646
TI  - Effect of physical vapor deposition on cutting efficiency of nickel-titanium
      files.
AB  - The purpose of this study was to investigate possible changes in cutting
      efficiency of nickel-titanium K-files that had undergone physical vapor
      deposition coating. Titanium nitride coatings were deposited using different
      process parameters. A total of 84 nickel-titanium K-files (size 35) were randomly
      divided into 7 groups of 12 instruments each. Groups A to F (experimental):
      instruments were coated with titanium nitride using different process parameters
      regarding substrate temperature, applied voltage, coating thickness, and ion
      bombardment. Group K (control): samples were not coated with titanium nitride.
      The cutting efficiency of all instruments was determined in a rotary working
      motion by means of a computer-driven testing device. Special plastic samples with
      a cylindrical canal were used, and the maximum penetration depth of the
      instruments into the lumen was the criterion for cutting efficiency. Instruments
      of groups A, F, and C achieved significantly greater penetration depths than the
      uncoated instruments of the control group (p < 0.05). Cutting efficiency of
      physical vapor deposition-coated nickel-titanium files was increased by up to
      26.2% in comparison with uncoated instruments.

PMID- 12489647
TI  - Regulation of tissue inhibitors of metalloproteinase-1 gene expression by
      cytokines in human gingival fibroblasts.
AB  - Tissue inhibitors of metalloproteinase (TIMP) are important participants in
      various physiological processes that involve tissues remodeling. They help
      maintain a delicate balance between physiological degradation and synthesis of
      the extracellular matrix. A better understanding of TIMP activity will be helpful
      in understanding the etiology of periapical lesions and their means of treatment.
      The fibroblast is a prominent cellular component of the periapical tissues. The
      potential implications of cytokine-mediated tissue destruction still remain to be
      elucidated. The purpose of this study was to determine the effects of interleukin
      (IL)-1alpha and transforming growth factor (TGF)-beta on the expressing of TIMP-1
      by primary gingival fibroblast cultures. After exposure to cytokines for 8 h,
      total RNA in gingival fibroblasts was isolated and evaluated by reverse
      transcriptase polymerase chain reaction. Densitometric analysis of the TIMP-1
      mRNA gene expression, after normalization by beta-actin, demonstrated that
      exposure to IL-1alpha resulted in a decreased level of TIMP-1 mRNA compared with
      the control groups. However, the TIMP-1 mRNA was up-regulated by TGF-beta. In
      addition, when the cells were cultured in combination with TGF-beta (1 ng/ml) and
      IL-1alpha for 8 h, the level of TIMP-1 mRNA was dramatically reduced. These
      results demonstrated that in human periapical tissue cytokines differentially and
      specifically regulate expression of TIMP-1 mRNA. An understanding of the actions
      of cytokines on gingival fibroblasts may result in new therapies to augment
      current treatment of periapical lesions.

PMID- 12489648
TI  - Effects of parachlorophenol and camphorated parachlorophenol on the phagocytic
      activities of a murine macrophage cell line (RAW264.7).
AB  - The aim of this study was to determine whether the phagocytic functions of a
      murine macrophage cell line (RAW264.7 cells) may be altered by parachlorophenol
      (PCP) and camphorated parachlorophenol (CMCP). The adherence capacities of PCP-
      or CMCP-treated cells on plastic surfaces were much lower than those of untreated
      cells. When the PCP- or CMCP-treated cells were incubated with Actinobacillus
      actinomycetemcomitans, phagocytosis of these cells was significantly reduced in a
      dose-dependent fashion compared with that of untreated cells. Preactivation with
      bacterial lipopolysaccharide on PCP- or CMCP-treated cells failed to completely
      restore the phagocytosis of this periodontopathogen. The phagocytic functions of
      PCP- or CMCP-treated cells to this periodontopathogen opsonized with anti-A.
      actinomycetemcomitans were also reduced compared with those of untreated cells
      but were comparable with those of untreated cells incubated with unopsonized
      bacteria. The results of this study indicated, therefore, that both PCP and CMCP
      may, indeed, reduce the phagocytic activities of murine macrophages.

PMID- 12489649
TI  - In vitro cytotoxicity evaluation of endodontic sealers exposed to heat before
      assay.
AB  - During warm-vertical condensation of gutta-percha, endodontic sealers are exposed
      to temperatures that potentially alter their cytotoxicity profiles. This study
      investigated the effects of heat on sealer toxicity by using the CyQuant assays
      for cell adhesion and proliferation of human gingival fibroblasts. Seven sealers
      were exposed to one of the following temperatures for 10 min before assay: 23
      degrees C, 43 degrees C, or 100 degrees C. Adhesion data were used to determine
      percentage of cells bound, and proliferation data were used to determine
      percentage of change in cell number from 24 to 72 h, for each sealer at each
      temperature. The temperatures of 23 degrees C, 43 degrees C, and 100 degrees C
      were significantly different in both the adhesion and proliferation assays.
      Sealer type and temperature were significant variables in both assays. The
      changes in toxicity measured by adhesion and proliferation for each sealer were
      not always similar. Roth 801 and Roth 811, after exposure to 100 degrees C,
      showed enhanced adhesion but not proliferation, whereas Kerr PCS and Dentalis,
      after exposure to 100 degrees C, showed decreased adhesion but enhanced
      proliferation. AH Plus and AH26 showed an increase in adhesion and proliferation
      after heat exposure, whereas Sealapex remained virtually unaffected.

PMID- 12489650
TI  - EM evaluation of bacterial biofilm and microorganisms on the apical external root
      surface of human teeth.
AB  - The aim of this study was to evaluate the presence of bacterial biofilm on the
      external surface of the root apex in teeth with pulp necrosis, with and without
      radiographically visible periapical lesions, and in teeth with a vital pulp.
      Twenty-one teeth were extracted, eight with pulp necrosis and periapical lesions,
      eight with pulp necrosis without radiographically visible periapical lesions, and
      five with a vital pulp. The roots were sectioned, and the root apexes (+/- 3 mm)
      were processed for scanning electron microscope evaluation. The surface of the
      apical root was evaluated for the presence of microorganisms, root resorption,
      and biofilm. There were no microorganisms on the apical root surface of either
      teeth with pulp vitality or with pulp necrosis with no radiographically visible
      periapical lesions. Microorganisms were always present in teeth with pulp
      necrosis and radiographically visible periapical lesions. These included cocci,
      bacilli, and filaments and the presence of an apical biofilm. Apical biofilm is
      clinically important because microbial biofilms are inherently resistant to
      antimicrobial agents and cannot be removed by biomechanical preparation alone.
      This may cause failure of endodontic treatment as a consequence of persistent
      infection.

PMID- 12489651
TI  - Quality of life and satisfaction outcomes of endodontic treatment.
AB  - The purpose of this study was to assess quality of life and satisfaction in
      relation to endodontic treatment in two Canadian populations and the association
      of these outcomes with the treatment providers' level of training (generalist or
      endodontist). New patients aged 25 to 40, presenting at the dental faculties in
      Toronto and Saskatoon were screened. Patients with radiographically identifiable
      endodontic treatment were invited for interviews conducted using a questionnaire
      that measured changes in quality of life after endodontic treatment and semantic
      differential scales that measured satisfaction with endodontic treatment. Data
      were analyzed using Chi-square, multiple and logistic regression (p < 0.05), and
      Mann-Whitney U test (p < 0.02). Subjects reported preoperative factors (e.g.,
      pain, sleep disturbances) impacting quality of life, which improved after
      endodontic treatment, significantly more in the Toronto than in the Saskatoon
      population. Satisfaction was significantly better when endodontic treatment was
      provided by endodontists.

PMID- 12489652
TI  - The effect of three commonly used endodontic materials on the strength and
      hardness of root dentin.
AB  - The purpose of this study was to determine if calcium hydroxide, mineral trioxide
      aggregate, or sodium hypochlorite caused a change in the force required to
      fracture root dentin. Ten bovine central and lateral incisors were machined using
      various saws and drills to produce a cylinder of dentin with a 6.0-mm outer
      diameter 3.5-mm inner diameter and a length of 10 mm. The cylinders were cut
      lengthwise into four symmetrical pieces. The canal sides of the sections were
      then placed into Petri dishes containing a 1-mm depth of calcium hydroxide,
      mineral trioxide aggregate, sodium hypochlorite, or physiologic saline (control).
      The samples remained in the dishes for 5 weeks and were then shear tested by
      using an Instron machine. Data were analyzed using an ANOVA test for comparison
      of the groups as a whole, and a t test was used to compare each quarter section
      with its control from the same tooth. A 32% mean decrease in strength was
      discovered for calcium hydroxide, a 33% decrease in strength for mineral trioxide
      aggregate, and a 59% decrease for sodium hypochlorite. All decreases in strength
      were statistically significant: p < 0.001 for calcium hydroxide, p = 0.027 for
      mineral trioxide aggregate, and p < 0.001 for sodium hypochlorite. Results
      indicated that root dentin was weakened after 5 weeks of exposure to calcium
      hydroxide, mineral trioxide aggregate, or sodium hypochlorite.

PMID- 12489653
TI  - Effect of electronic apex locators on cardiac pacemaker function.
AB  - The purpose of this study was to assess the effects of five electronic apex
      locators on pacemaker function in vitro. A Biotronik Actros DR+ pacemaker was
      evaluated at maximum sensitivity on a flat bench top. The pacemaker lead,
      electronic apex locator, and oscilloscope were connected across a 150-ohm
      resistor. Pace monitoring was carried out with a Biotronik EPR 1000 programmer
      and a Tektronix TDS 220 2-channel digital real-time oscilloscope. Four of five
      electronic apex locators tested did not cause inhibition or interfere with normal
      pacemaker function. It seems that electronic apex locators can be used safely in
      patients with pacemakers.

PMID- 12489654
TI  - Contemporary endodontic retreatments: an analysis based on clinical treatment
      findings.
AB  - A prospective in vivo investigation was conducted to determine radiographic and
      clinical factors associated with contemporary nonsurgical endodontic
      retreatments. Approximately 1,100 failing endodontically treated teeth were
      screened to determine an appropriate treatment plan. Using magnification, 337
      consecutive retreatment cases were evaluated and treated. The vast majority of
      the retreated cases involved multiple factors. Eighty-five percent of the cases
      presented with periradicular radiolucencies. Sixty-five percent of the cases
      demonstrated poor radiographic obturation quality. Associated pain was noted 51%
      of the time. Forty-two percent of the teeth had untreated canal space. It was
      statistically significant (Chi-square, p < or = 0.05) that additional canal space
      was located and treated in 89% of the cases that had previous radiographic
      asymmetrical obturations. Evidence of coronal leakage was noted in 13% of the
      retreated teeth. Tooth number, obturation materials, overfills, and previous
      surgical retrofillings were also recorded. Recommendations were made that might
      improve the rate of clinical success.

PMID- 12489655
TI  - Efficacy of irrigation with rotary instrumentation.
AB  - The purpose of this study was to evaluate the efficacy of a handpiece-mounted
      irrigation device and compare it to irrigation with a syringe and needle in the
      apical 5 mm of the root canal system. Twenty matched pairs of extracted teeth
      were used. The only variable within each matched pair was the method of
      irrigation. A syringe and needle were used in group A and the handpiece-mounted
      system in group B. Sections 1, 3, and 5 mm from the working length were examined
      microscopically, and images of the slides were digitized. The percentage of canal
      space occupied by pulpal and dentinal debris was calculated to be 6% +/- 12.7% in
      group A, versus 3.8% +/- 7% in group B (p = 0.264). The percentages at each level
      were as follows: 1 mm from the working length, 14.1% +/- 19% for group A and 5%
      +/- 7.5% for group B; 3 mm from working length, 1.8% +/- 5.4% for group A and
      3.9% +/- 6.9% for group B; and 5 mm from working length, 3.1% +/- 7.7% for group
      A and 2.6% +/- 7.3% for group B. In group A, there was significantly more debris
      in the 1-mm section than in the 3- or 5-mm sections. In group B, the differences
      between levels were not significant. There was no significant difference in the
      amount of debris remaining in the apical 5 mm of canals when comparing the
      handpiece-mounted irrigation device to irrigation with a syringe and needle. The
      average times for instrumentation in group A (needle irrigation) and group B
      (Quantec-E irrigation system) were 8.7 +/- 2.7 min and 6.5 +/- 1.9 min,
      respectively. Group B was associated with statistically significant shorter
      instrumentation time (p < 0.0005). An average of 12.5 +/- 4.9 ml of irrigant was
      used in group A and 17.3 +/- 4.8 ml in group B. The difference was statistically
      significant (p < 0.0005).

PMID- 12489657
TI  - The AAE door is open!

PMID- 12489656
TI  - Diagnostic acuity versus negligence.

PMID- 12489658
TI  - Object-based selection within and beyond the focus of spatial attention.
AB  - In a series of experiments, we examined the effect of perceptual objects on
      visual attentional processing in the presence of spatially cued attentional
      selection. Subjects made speeded judgments about two visual elements that were
      either both on the same object or on two different objects. Judgments were faster
      when the elements were on the same object than when they were on different
      objects, revealing an object advantage. Importantly, the object advantage
      remained even when either exogenous or endogenous spatial cues were used to
      direct the subjects' attention to a part of the display, contrary to earlier
      findings of other researchers. The object advantage, however, did disappear when
      the stimulus duration was shortened substantially. The results show that object
      based selection is pervasive and is not diminished by the act of selective
      attention. The results are discussed in terms of their implications for the
      mechanisms that underlie attentional selection.

PMID- 12489659
TI  - Attend to it now or lose it forever: selective attention, metacontrast masking,
      and object substitution.
AB  - Metacontrast masking occurs when the visibility of a brief target stimulus is
      decreased by the subsequent appearance of another nearby visual stimulus. Early
      explanations of the phenomenon involved low-level mechanisms, but subsequent
      studies have suggested a role for selective attention. The results of three
      experiments presented here extend previous findings to the metacontrast paradigm.
      It is shown that the strength of metacontrast masking increases with the number
      of distractor items in a display, decreases when the target location is validly
      but not invalidly precued, and is eliminated when search for the target is
      efficient (pop-out search) but not when search is inefficient (serial search). A
      connection between metacontrast masking and object substitution masking is
      considered.

PMID- 12489660
TI  - Early computation of part structure: evidence from visual search.
AB  - The visual system represents object shapes in terms of intermediate-level parts.
      The minima rule proposes that the visual system uses negative minima of curvature
      to define boundaries between parts. We used visual search to test whether part
      structures consistent with the minima rule are computed preattentively--or at
      least, rapidly and early in visual processing. The results of Experiments 1 and 2
      showed that whereas the search for a non-minima-segmented shape is fast and
      efficient among minima-segmented shapes, the reverse search is slow and
      inefficient. This asymmetry is expected if parsing at negative minima occurs
      obligatorily. The results of Experiments 3 and 4 showed that although both minima
      and non-minima-segmented shapes pop out among unsegmented shapes, the search for
      minima-segmented shapes is significantly slower. Together, these results
      demonstrate that the visual system segments shapes into parts, using negative
      minima of curvature, and that it does so rapidly in early stages of visual
      processing.

PMID- 12489661
TI  - Is visual short-term memory object based? Rejection of the "strong-object"
      hypothesis.
AB  - Is the capacity of visual short-term memory (VSTM) limited by the number of
      objects or by the number of features? VSTM for objects with either one feature or
      two color features was tested. Results show that capacity was limited primarily
      by the number of colors to be memorized, not by the number of objects. This
      result held up with variations in color saturation, blocked or mixed conditions,
      duration of memory image, and absence or presence of verbal load. However,
      conjoining features into objects improved VSTM capacity when size-orientation and
      color-orientation conjunctions were tested. Nevertheless, the number of features
      still mattered. When feature heterogeneity was controlled, VSTM for conjoined
      objects was worse than VSTM for objects made of single features. Our results
      support a weak-object hypothesis of VSTM capacity that suggests that VSTM is
      limited by both the number of objects and the feature composition of those
      objects.

PMID- 12489662
TI  - Attentional limitations in processing sequentially presented vibrotactile
      targets.
AB  - In seven experiments, participants experienced rapid, serially presented streams
      of vibrations and responded to specific targets in the streams. In visual (and
      sometimes auditory) streams presented in this manner, it is typical to find a
      deficit in reporting the second of two targets when both must be reported and the
      second appears within a short temporal interval of the first, but not when
      identical displays are presented but only the second target must be reported
      (e.g., the attentional blink, or AB). This conventional AB pattern was found in
      the last experiment, in which judgments were about target location. However in
      the first six experiments reported here, in which judgments were about frequency,
      intensity, duration, or location of targets, accuracy was dependent on target
      separation regardless of whether or not the first target was reported. This
      unconventional pattern could represent an AB if the first target was attended
      even when it was not reported. The evidence for this claim and an alternative
      possibility that location judgments are especially sensitive to attention
      manipulations are discussed.

PMID- 12489663
TI  - Visuo-tactile links in covert exogenous spatial attention remap across changes in
      unseen hand posture.
AB  - We investigated the effect of unseen hand posture on cross-modal, visuo-tactile
      links in covert spatial attention. In Experiment 1, a spatially nonpredictive
      visual cue was presented to the left or right hemifield shortly before a tactile
      target on either hand. To examine the spatial coordinates of any cross-modal
      cuing, the unseen hands were either uncrossed or crossed so that the left hand
      lay to the right and vice versa. Tactile up/down (i.e., index finger/thumb)
      judgments were better on the same side of external space as the visual cue, for
      both crossed and uncrossed postures. Thus, which hand was advantaged by a visual
      cue in a particular hemifield reversed across the different unseen postures. In
      Experiment 2, nonpredictive tactile cues now preceded visual targets. Up/down
      judgments for the latter were better on the same side of external space as the
      tactile cue, again for both postures. These results demonstrate cross-modal links
      between vision and touch in exogenous covert spatial attention that remap across
      changes in unseen hand posture, suggesting a modulatory role for proprioception.

PMID- 12489664
TI  - Relative roles of spatial and intensive cues in the discrimination of spatial
      tactile stimuli.
AB  - Two psychophysical measures of tactile sensitivity--grating-orientation (GO) and
      smooth-grooved (SG) discrimination--were used to determine tactile spatial acuity
      with and without an intermediate surface (latex glove) interposed between the
      contactor and the skin. Measures were made at three locations that varied in
      sensitivity and in density of innervation of the primary afferent fibers: the
      index fingerpad (fingertip), palmar surface of the proximal phalanx (fingerbase),
      and the thenar eminence (palm). Neurophysiological studies have suggested that
      the density of innervation of SAI fibers is a limiting factor in spatial acuity.
      In the present study, without a glove, the GO thresholds varied as a function of
      location. With the glove, increases in the GO thresholds were relatively uniform
      and modest. Without a glove, however, the SG thresholds were well below the GO
      thresholds, and changing the site of stimulation had little effect on the
      threshold. With a glove, the SG thresholds increased by 100% to more than 300% as
      in comparison with those in the no-glove condition. The largest increases
      occurred at the less sensitive locations. The results of the GO task are
      consistent with the view that GO is a valid measure of spatial acuity. The
      results of the SG task, however, are inconsistent with previous results and
      suggest that both spatial and intensive factors are involved in this task.

PMID- 12489665
TI  - Active haptic detection and discrimination of shape.
AB  - In previous research, we have shown that detection thresholds for Gaussian shapes
      increase with a power of 1.3 of spatial width. In the present three experiments,
      we generalized this finding to more complex shapes and to discrimination tasks.
      In Experiment 1, we found that the slope of the psychometric function for
      detection (i.e., distinguishing curved from flat surfaces) was independent of
      surface shape. In Experiment 3, we found the same result for discrimination of
      two different curved shapes. In Experiment 2, we found that detection and
      discrimination functions had the same dependence on spatial width, except that
      discrimination thresholds were two to four times larger. Possible neural
      mechanisms underlying these results are discussed.

PMID- 12489666
TI  - Simple rotary motion is integrated across fixations.
AB  - Participants were shown a line rotating at a constant angular velocity and were
      asked to judge whether motion was continuous or whether the line jumped (i.e.,
      moved either forward or backward in the rotary cycle). In two experiments, the
      participants were significantly better than chance in detecting these jumps in
      simple rotary motion even when the jumps occurred during a saccade. Moreover, in
      Experiment 2, when the jump occurred during a saccade followed by a masking
      flash, perception of the jump was at least as good as when it occurred during a
      fixation followed by a masking flash. These results complement and extend the
      findings of Verfaillie and co-workers, who found that perceptions of some changes
      in biological motion were as good across fixations as when they occurred during a
      fixation. These findings are in contrast to the common finding, in the reading
      literature, that people are consciously "blind" to many changes in the text and
      to those, in the scene perception literature, in which detection of static
      changes across fixations is above chance but plausibly well below the level that
      would be expected if the change occurred during a fixation.

PMID- 12489667
TI  - What determines the eyes' landing position in words?
AB  - The place at which the eyes first fixate in a word during continuous reading,
      called the preferred landing position (PLP), is usually located halfway between
      the beginning and the middle of the word. To propose a mechanism that might
      account for the off-center location of the PLP, six eye movement experiments were
      conducted using a lexical decision task (Experiment 1) and a stimulus bisection
      task (Experiments 2-6). The type of stimulus--linguistic (words and nonwords)
      versus nonlinguistic (strings of hashes, dotted lines, and solid lines)--and the
      stimulus presentation side (left vs. right) were manipulated. The results showed
      that (1) stimulus discreteness versus continuousness is an important factor in
      saccade computation and (2) PLP asymmetry can be explained in terms of
      attentional and/or oculomotor processes.

PMID- 12489668
TI  - The perception and discrimination of local 3-D surface structure from deforming
      and disparate boundary contours.
AB  - In a series of four experiments, we evaluated observers' abilities to perceive
      and discriminate ordinal depth relationships between separated local surface
      regions for objects depicted by static, deforming, and disparate boundary
      contours or silhouettes. Comparisons were also made between judgments made for
      silhouettes and for objects defined by surface texture, which permits judgment
      based on conventional static texture gradients, conventional stereopsis, and
      conventional structure-from-motion. In all the experiments, the observers were
      able to detect, with relatively high precision, ordinal depth relationships, an
      aspect of local three-dimensional (3-D) structure, from boundary contours or
      silhouettes. The results of the experiments clearly demonstrate that the static,
      disparate, and deforming boundary contours of solid objects are perceptually
      important optical sources of information about 3-D shape. Other factors that were
      found to affect performance were the amount of separation between the local
      surface regions, the proximity or closeness of the regions to the boundary
      contour itself, and for the conditions with deforming contours, the overall
      magnitude of the boundary deformation.

PMID- 12489669
TI  - Perception of acceleration with short presentation times: can acceleration be
      used in interception?
AB  - To investigate whether visual judgments of acceleration could be used for
      intercepting moving targets, we determined how well subjects can detect
      acceleration when the presentation time is short. In a differential judgment
      task, two dots were presented successively. One dot accelerated and the other
      decelerated. Subjects had to indicate which of the two accelerated. In an
      absolute judgment task, subjects had to adjust the motion of a dot so that it
      appeared to move at a constant velocity. The results for the two tasks were
      similar. For most subjects, we could determine a detection threshold even when
      the presentation time was only 300 msec. However, an analysis of these thresholds
      suggests that subjects did not detect the acceleration itself but that they
      detected that a target had accelerated on the basis of the change in velocity
      between the beginning and the end of the presentation. A change of about 25% was
      needed to detect acceleration with reasonable confidence. Perhaps the simplest
      use of acceleration for interception consists of distinguishing between
      acceleration and deceleration of the optic projection of an approaching ball to
      determine whether one has to run backward or forward to catch it. We examined the
      results of a real ball-catching task (Oudejans, Michaels, & Bakker, 1997) and
      found that subjects reacted before acceleration could have been detected. We
      conclude that acceleration is not used in this simple manner to intercept moving
      targets.

PMID- 12489670
TI  - Functional localization and mechanisms of sequential effects in serial reaction
      time tasks.
AB  - Reaction times (RTs) to randomly ordered stimuli are influenced in various ways
      by the sequence of preceding events. Depending on the response-stimulus interval
      and stimulus-response compatibility, cost-only or cost-benefit patterns can be
      observed. In order to localize these effects within the information-processing
      system, different sequential patterns were induced in overt performance. RTs and
      amplitude developments of the lateralized readiness potential (LRP) across
      several trials indicated the accumulation of residual traces as a possible
      mechanism underlying sequential effects. Analysis of LRP onsets indicated two
      possible loci of action of such traces. Whereas in motoric stages trace
      accumulation appeared to produce processing advantages only for continued event
      repetitions, without corresponding costs for discontinuations, cost-benefit
      patterns were consistently observed in premotoric stages.

PMID- 12489671
TI  - B cell non-Hodgkin cerebral lymphoma associated with an anaplastic
      oligodendroglioma.
AB  - Primary central nervous system lymphomas and anaplastic oligodendrogliomas are
      not uncommon; however, no association between the 2 has been documented to date.
      We describe a unique case, whereby a patient presenting with seizures and slight
      impairment of higher functions, underwent frontal lobectomy for a mass lesion.
      The histology revealed dual pathology of anaplastic oligodendroglioma and B cell
      non-Hodgkin lymphoma. Postoperatively, the patient received whole brain
      radiotherapy. The patient remained well after 18 months of follow-up with no
      radiological progression of a known tumor residuum.

PMID- 12489672
TI  - Germinoma with a granulomatous reaction. Problems of differential diagnosis.
AB  - The patient was a 6 year-old girl with a progressive loss of visual acuity.
      Magnetic resonance imaging showed a suprasellar mass lesion with enhanced
      gadolinium which was resected. Histopathological study showed a remarkable
      granulomatous reaction, but a diagnosis was difficult. However,
      immunohistochemical study showed a few cells that were positive for placental
      alkaline phosphatase and it was diagnosed as germinoma. Intracranial germinoma
      with a remarkable granulomatous reaction is rare. However, when germinoma is
      suspected clinically, an immunohistochemical study is able to identify germinoma
      even if granulomatous disease is diagnosed histopathologically.

PMID- 12489673
TI  - Diagnostic and prognostic role of Ki67 immunostaining in human astrocytomas using
      four different antibodies.
AB  - OBJECTIVE: Astrocytomas have an inherent tendency to progress, and
      histopathological examination and grading do not always identify these subsets of
      tumors. The aim of this study was therefore to investigate whether different Ki67
      antibodies could assist in the diagnostic and prognostic evaluation of these
      tumors. MATERIAL AND METHODS: Forty-one cerebral astrocytomas, graded according
      to the latest criteria of the World Health Organization, were included in the
      study: 22 diffuse fibrillary astrocytomas, 10 anaplastic astrocytomas and 9
      glioblastomas. Standard immunohistochemical analyses were performed using 4
      different commercially available Ki67 antibodies. The immunohistochemical data
      were correlated with the clinical course. RESULTS: There were positive
      correlations between the proliferation indices (PI) obtained with the different
      Ki67 antibodies. The Ki67 PIs increased significantly with increasing malignancy
      grade, and the antibodies discriminated well between low- (grade II) and high
      grade tumors (grade III and IV). For the entire tumor material, the use of median
      values as cutoff divided the astrocytomas into 2 groups: those tumors with the
      higher Ki67 PIs had significantly poorer prognosis than those with lower indices.
      CONCLUSIONS: Ki67 immunostaining serves as an important supplementary tool in the
      diagnostic and prognostic evaluation of human astrocytomas.

PMID- 12489674
TI  - Biphasic malignant meningioma: a comparative genomic hybridization study.
AB  - To ascertain if a carcinoma-like component within a fibroblastic meningioma
      represented a metastatic carcinoma to a meningioma or malignant progression, we
      employed traditional immunohistochemical methods as well as comparative genomic
      hybridization (CGH) which compares chromosomal alterations. Vimentin and
      epithelial membrane antigen were strongly immunoreactive in both the fibroblastic
      and carcinoma-like components. The CGH profile in both components had similar
      chromosomal alterations, including losses of 1p, 14, 16p13-->p10 and 22. However,
      the CGH profiles from the fibroblastic component showed losses of 4p, 10q23-->q24
      and 18, along with gains of 1q, 6q25-->qter and 13q32-->qter. The profile of the
      carcinoma-like component showed losses of chromosome 4, in addition to gains of
      3p12-->q13.11, 5q14.3-->q23.2, 6pter-->p23, and 13q14.2-->qter. CGH analysis of a
      biphasic malignant meningioma confirmed that the disparate histologic components
      were genetically related and likely derivative from a common precursor,
      demonstrating genetic instability and clonal expansion. Furthermore, CGH showed
      that the histologically appearing low-grade fibroblastic component had not solely
      the characteristic alterations of a benign meningioma but had already progressed
      to an atypical meningioma.

PMID- 12489675
TI  - X-linked myotubular myopathy with probable germline mosaicism.
AB  - X-linked myotubular myopathy is a disorder characterized by severe neonatal
      hypotonia and respiratory insufficiency. The mutation of MTMI gene results in a
      defective production of myotubularin, which is responsible for the maturational
      arrest of muscle development. An identical mutation in the carrier mother and the
      diseased child establishes the inheritance. We report the disease in a neonate
      with a mutation on exon 6 of the MTMI gene. Surprisingly, the mother was healthy
      and did not carry this mutation, she is likely to have germline mosaicism.

PMID- 12489676
TI  - Dementia with Lewy bodies showing advanced Lewy pathology but minimal Alzheimer
      pathology--Lewy pathology causes neuronal loss inducing progressive dementia.
AB  - The present study concerns an autopsied case of dementia with Lewy bodies (DLB)
      showing advanced Lewy pathology but minimal Alzheimer pathology. The patient was
      a 50-year-old Japanese male without inheritance. His initial symptoms at the age
      of 43 suggested the diagnosis ofjuvenile idiopathic Parkinson's disease (PD), but
      were followed by memory disturbance 1 year later. He showed parkinsonism,
      dementia, personality change, fluctuating cognition and visual hallucinations 3
      years later. Neuroradiological examination revealed moderate brain atrophy,
      predominantly in the frontal and temporal lobes. Neuropathological examination
      demonstrated a widespread occurrence of Lewy bodies (LB) with LB-related neurites
      not only in the brainstem but also in the cerebrum. The present case showed Lewy
      pathology which corresponded to stage IV by our staging and was parallel to
      neuronal loss. There was marked neuronal loss with many LB-related neurites in
      the CA2 of the hippocampus. Neurofibrillary tangles (NFT) were almost restricted
      to the entorhinal cortex, while senile plaques were absent. Consequently, the
      present case was pathologically diagnosed as having DLB of the neocortical type,
      pure form. In the present study, we suggest that Lewy pathology in the cerebral
      cortex could be responsible for progressive dementia.

PMID- 12489677
TI  - Castleman's disease of the leptomeninges--immunohistochemical findings in 2
      cases.
AB  - OBJECTIVE: Castleman's disease is an uncommon benign lymphoproliferative disorder
      that arises in lymph nodes. Few cases of Castleman's disease affecting the
      central nervous system have been described. CASE HISTORY: We report 2 new cases
      of Castleman's disease confined solely to the leptomeninges. The patients were
      referred to neurosurgery with presumptive clinical diagnosis of meningiomas.
      Histological investigation of the operative specimens taken from the abnormal
      leptomeninges revealed nodular lymphoid areas with multiple germinal centers
      surrounded by concentrically layered proliferations of small lymphocytes.
      Histologically, these 2 cases fulfilled the classification criteria for the mixed
      and for the hyaline-vascular type of Castleman's disease. The immunohistochemical
      analysis revealed a polyclonal B cell proliferation in the lesions with
      perifollicular T cell proliferation with the T helper cell predominance.
      CONCLUSIONS: The authors conclude that Castleman's disease involving the
      leptomeninges have a similar immunological pattern reported for the disease in
      extracranial locations and that, though being rare, Castleman's disease should be
      considered as a differential diagnosis when dealing with mass lesions of
      leptomeninges.

PMID- 12489678
TI  - Spatial patterns of the vacuolation in subcortical white matter in sporadic
      Creutzfeldt-Jakob disease (sCJD).
AB  - OBJECTIVE: To study the spatial patterns of the vacuolation ("spongiform change")
      in the subcortical white matter in the "classical" form of sporadic Creutzfeldt
      Jakob disease (sCJD). MATERIAL: Frontal, parietal, occipital and temporal lobes
      of 11 cases of sCJD. METHOD: Spatial patterns were studied across the white
      matter at the base of the gyri using spatial pattern analysis. RESULTS: In the
      white matter of all gyri studied, vacuoles were aggregated into clusters, 50 to >
      800 microm in diameter and in 22/37 (59%) of gyri, the clusters of vacuoles
      exhibited a regular distribution across the base of the gyri. In the remaining
      gyri, the vacuoles were aggregated into large clusters, at least 400 microm or
      800 microm in diameter, but without evidence of a regular distribution. In a
      significant proportion of gyri, the spatial patterns of the vacuolation were
      similar to those reported previously for spongiform change and prion protein
      (PrP) deposits in the corresponding grey matter. CONCLUSIONS: Degeneration of the
      white matter and the formation of clusters of vacuoles may occur before the
      degeneration of the grey matter or could be a consequence of pathology affecting
      the cortico-cortical pathways.

PMID- 12489679
TI  - Recent advances in molecular diversity.

PMID- 12489680
TI  - An overview of the diversity represented in commercially-available databases.

PMID- 12489681
TI  - Filtering databases and chemical libraries.

PMID- 12489682
TI  - Current trends in lead discovery: are we looking for the appropriate properties?
AB  - The new drug discovery paradigm is based on high-throughput technologies, both
      with respect to synthesis and screening. The progression HTS hits --> lead series
      --> candidate drug --> marketed drug appears to indicate that the probability of
      reaching launched status is one in a million. This has shifted the focus from
      good quality candidate drugs to good quality leads. We examined the current
      trends in lead discovery by comparing MW (molecular weight), LogP (octanol/water
      partition coefficient, estimated by Kowwin) and LogSw (intrinsic water
      solubility, estimated by Wskowwin) for the following categories: 62 leads and 75
      drugs; compounds in the development phase (I, II, III and launched), as indexed
      in MDDR; and compounds indexed in medicinal chemistry journals, categorized
      according to their biological activity. Comparing the distribution of the above
      properties, the 62 lead structures show the lowest median with respect to MW
      (smaller) and LogP (less hydrophobic), and the highest median with respect to
      LogSw (more soluble). By contrast, over 50% of the medicinal chemistry compounds
      with activities above 1 nanomolar have MW > 425, LogP > 4.25 and LogSw < -4.75,
      indicating that the reported active compounds are larger, more hydrophobic and
      less soluble when compared to time-tested quality leads. In the MDDR set, a
      progressive constraint to reduce MW and LogP, and to increase LogSw, can be
      observed when examining trends in the developmental sequence: phase I, II, III
      and launched drugs. These trends indicate that other properties besides binding
      affinity, e.g., solubility and hydrophobicity, need to be considered when
      choosing the appropriate leads.

PMID- 12489683
TI  - Multiobjective optimization of combinatorial libraries.
AB  - Combinatorial chemistry and high-throughput screening have caused a fundamental
      shift in the way chemists contemplate experiments. Designing a combinatorial
      library is a controversial art that involves a heterogeneous mix of chemistry,
      mathematics, economics, experience, and intuition. Although there seems to be
      little agreement as to what constitutes an ideal library, one thing is certain:
      only one property or measure seldom defines the quality of the design. In most
      real-world applications, a good experiment requires the simultaneous optimization
      of several, often conflicting, design objectives, some of which may be vague and
      uncertain. In this paper, we discuss a class of algorithms for subset selection
      rooted in the principles of multiobjective optimization. Our approach is to
      employ an objective function that encodes all of the desired selection criteria,
      and then use a simulated annealing or evolutionary approach to identify the
      optimal (or a nearly optimal) subset from among the vast number of possibilities.
      Many design criteria can be accommodated, including diversity, similarity to
      known actives, predicted activity and/or selectivity determined by quantitative
      structure-activity relationship (QSAR) models or receptor binding models,
      enforcement of certain property distributions, reagent cost and availability, and
      many others. The method is robust, convergent, and extensible, offers the user
      full control over the relative significance of the various objectives in the
      final design, and permits the simultaneous selection of compounds from multiple
      libraries in full- or sparse-array format.

PMID- 12489684
TI  - Predictive QSAR modeling based on diversity sampling of experimental datasets for
      the training and test set selection.
AB  - One of the most important characteristics of Quantitative Structure Activity
      Relashionships (QSAR) models is their predictive power. The latter can be defined
      as the ability of a model to predict accurately the target property (e.g.,
      biological activity) of compounds that were not used for model development. We
      suggest that this goal can be achieved by rational division of an experimental
      SAR dataset into the training and test set, which are used for model development
      and validation, respectively. Given that all compounds are represented by points
      in multidimensional descriptor space, we argue that training and test sets must
      satisfy the following criteria: (i) Representative points of the test set must be
      close to those of the training set; (ii) Representative points of the training
      set must be close to representative points of the test set; (iii) Training set
      must be diverse. For quantitative description of these criteria, we use molecular
      dataset diversity indices introduced recently (Golbraikh, A., J. Chem. Inf.
      Comput. Sci., 40 (2000) 414-425). For rational division of a dataset into the
      training and test sets, we use three closely related sphere-exclusion algorithms.
      Using several experimental datasets, we demonstrate that QSAR models built and
      validated with our approach have statistically better predictive power than
      models generated with either random or activity ranking based selection of the
      training and test sets. We suggest that rational approaches to the selection of
      training and test sets based on diversity principles should be used routinely in
      all QSAR modeling research.

PMID- 12489685
TI  - Reactant- and product-based approaches to the design of combinatorial libraries.

PMID- 12489687
TI  - New methods in predictive metabolism.

PMID- 12489686
TI  - Towards a new age of virtual ADME/TOX and multidimensional drug discovery.
AB  - With the continual pressure to ensure follow-up molecules to billion dollar
      blockbuster drugs, there is a hurdle in profitability and growth for
      pharmaceutical companies in the next decades. With each success and failure we
      increasingly appreciate that a key to the success of synthesized molecules
      through the research and development process is the possession of drug-like
      properties. These properties include an adequate bioactivity as well as adequate
      solubility, an ability to cross critical membranes (intestinal and sometimes
      blood-brain barrier), reasonable metabolic stability and of course safety in
      humans. Dependent on the therapeutic area being investigated it might also be
      desirable to avoid certain enzymes or transporters to circumvent potential drug
      drug interactions. It may also be important to limit the induction of these same
      proteins that can result in further toxicities. We have clearly moved the
      assessment of in vitro absorption, distribution, metabolism, excretion and
      toxicity (ADME/TOX) parameters much earlier in the discovery organization than a
      decade ago with the inclusion of higher throughput systems. We are also now faced
      with huge amounts of ADME/TOX data for each molecule that need interpretation and
      also provide a valuable resource for generating predictive computational models
      for future drug discovery. The present review aims to show what tools exist today
      for visualizing and modeling ADME/TOX data, what tools need to be developed, and
      how both the present and future tools are valuable for virtual filtering using
      ADME/TOX and bioactivity properties in parallel as a viable addition to present
      practices.

PMID- 12489689
TI  - Chemoinformatics methods for systematic comparison of molecules from natural and
      synthetic sources and design of hybrid libraries.
AB  - Until recently, the field of diversity and library design has more or less
      ignored natural products as a compound source. This is probably due to at least
      two reasons. First, combinatorial and reaction-based approaches have been major
      focal points in the early days of computational library design. In addition, a
      widespread view is that natural products are often highly complex and not
      amenable to medicinal chemistry efforts. This contribution introduces recent
      computational approaches to systematically analyze natural molecules and bridge
      the gap between natural products and synthetic chemistry programs. Large scale
      comparisons of natural and synthetic molecules are discussed as well as studies
      designed to identify 'synthetic mimics' of natural products with specific
      activity. In addition, a concept for the design of natural/synthetic hybrid
      libraries is introduced. Although research in this area is still in its early
      stages, an important lesson to be learned from computational analyses is that
      there is no need to a priori 'shy away' from natural products as a source for
      molecular design.

PMID- 12489688
TI  - Exploring privileged structures: the combinatorial synthesis of cyclic peptides.
AB  - Head-to-tail cyclic peptides have been reported to bind to multiple, unrelated
      classes of receptor with high affinity. They may therefore be considered to be
      privileged structures. This review outlines the strategies by which both
      macrocyclic cyclic peptides and cyclic dipeptides or diketopiperazines have been
      synthesised in combinatorial libraries. It also briefly outlines some of the
      biological applications of these molecules, thereby justifying their inclusion as
      privileged structures.

PMID- 12489690
TI  - Poly(A)-binding protein and eRF3 are associated in vivo in human and Xenopus
      cells.
AB  - An interaction between human poly(A)-binding protein (PABP) et human eRF3 has
      been demonstrated using a double-hybrid approach and in vitro assays. Here, we
      show that the binding of both proteins is conserved through evolution. We also
      demonstrate that the last 39 C-terminal amino acids of PABP contain the interface
      that interacts with eRF3. This region includes helix 5, identified by RMN, which
      is conserved in all known PABPs. Lastly, we demonstrate that eRF3 et PABP
      molecules interact in vivo.

PMID- 12489691
TI  - Characterization of the poly(A) binding proteins expressed during oogenesis and
      early development of Xenopus laevis.
AB  - During vertebrate oogenesis and early embryogenesis, gene expression is governed
      mainly by translational control. The recruitment of Poly(A) Binding Protein
      (PABP) during poly(A) tail lengthening appears to be the key to translational
      activation during this period of development in Xenopus laevis. We showed that
      PABP1 and ePABP proteins are both present during oogenesis and early development.
      We selected ePABP as an eRF3 binding protein in a two-hybrid screening of a X.
      laevis cDNA library and demonstrated that this protein is associated with
      translational complexes. It can complement essential functions of the yeast
      homologue Pab1p. We discuss specific expression patterns of the finely tuned
      PABP1 and ePABP proteins.

PMID- 12489693
TI  - Elemental characterization of microorganism granules by EFTEM in the tube wall of
      a deep-sea vent invertebrate.
AB  - Microorganisms colonizing the exoskeletons of the tube worm Riftia pachyptila are
      described at the ultrastructural level. The prokaryotic cells from the worm tube
      wall differ from those colonizing the exoskeleton outer surface in the presence
      of an electron dense granule. The morphology and distribution of these bacteria
      like cells are described. Prokaryotic organisms are assembled in nodules which
      increased in size in the oldest part of the exoskeleton. The aspect, location and
      elemental composition of the intracellular granules are determined. Most of them
      (100 nm in diameter) are located close to the cell membrane and exhibit a
      homogeneous and amorphous content. EDX and EFTEM microanalyses show that these
      structures contain phosphorus, oxygen and iron. All together these data suggest
      that these granules are iron polyphosphates. These structures may act as energy
      sources for making ATP during anoxic conditions as existing in hydrothermal
      environments.

PMID- 12489692
TI  - Permeability changes induced by polylysines in rat spermatids.
AB  - High molecular weight (HMW, >15 kDa) but not low molecular weight (LMW, <15 kDa)
      polylysines (PLs) bound and induced permeability changes in rat spermatid plasma
      membranes, estimated by Mn2+ quenching of intracellular indo-1 fluorescence
      (K(1/2) = 3.3 +/- 0.5 microg/ml) and Co2+ quenching of intracellular calcein. The
      pharmacology of the Mn2+ entry pathway activated by HMW PL does not suggest that
      Ca2+ channels are involved in this phenomenon. Concentrations of HMW PL that
      induced divalent ion entry did not induce the entry of ethidium bromide,
      suggesting that HMW PL first bound and perturbed the plasma membrane structure
      inducing a non-specific increase in membrane permeability. High concentrations of
      HMW PL induced cell lysis (K(1/2) = 23 microg/ml). The binding of HMW PL,
      initially homogenous on the cell surface, subsequently progressed to a segregated
      pattern resembling a clustering phenomenon.

PMID- 12489694
TI  - Arachidonic acid cytotoxicity in leukocytes: implications of oxidative stress and
      eicosanoid synthesis.
AB  - Arachidonic acid (AA)-induced cytotoxicity was evaluated in leukocytes: the human
      leukemia cell lines HL-60, Jurkat and Raji and in rat lymphocytes. Such
      cytotoxicity was dose- and time-dependent. At concentrations below 5 microM, AA
      was not toxic; at 10-400 microM, AA induced apoptosis and at concentrations
      beyond 400 microM, necrosis. The minimum exposure time to trigger cell death was
      of around 1 h, but the effect was increased by longer exposure times until 6-24
      h. Apoptosis was morphologically characterized by a decrease in cell and nuclear
      volume, chromatin condensation and DNA fragmentation and the presence of lipid
      bodies, without changes in organelle integrity. Biochemically, AA-induced
      apoptosis was associated with internucleosomal fragmentation and caspase
      activation, evaluated by PARP cleavage and the use of a caspase inhibitor.
      Necrosis was characterized by increased cell volume, presence of loose chromatin,
      appearance of vacuoles, loss of membrane integrity and of the definition of
      organelles. The apoptotic effect of AA was studied as to oxidative-reductive
      imbalance and the participation of eicosanoids. Apoptotic AA treatment was
      accompanied by an increase in the quantity of thiobarbituric acid reactive
      substances (TBARS), low-level chemiluminescence and in the glutathione
      disulfide/reduced glutathione ratio, indicating oxidative stress. The addition of
      tocopherol, ascorbate, prostaglandin E2 and lipoxygenase inhibitors delayed cell
      death, whereas the inhibition of cyclooxygenase promoted AA-induced cell death.
      Cell treatment with AA was accompanied by increased cellular production of LTB4.
      AA, therefore, is cytotoxic at physiological and supraphysiological
      concentrations, causing apoptosis and necrosis. Cell treatment with apoptotic
      concentrations of AA involves oxidative stress and changes in eicosanoid
      biosynthesis.

PMID- 12489695
TI  - Nuclear transcription factor GATA-1 is activated during aclacinomycin-induced
      erythroid differentiation.
AB  - Anthracycline antitumor drugs induce erythroid differentiation of the K562
      erythroleukemic cell line at subtoxic concentrations. Aclacinomycin (ACM)
      stimulates this process by activating the erythroid transcription factor GATA-1,
      that controls genes involved in hemoglobin biosynthesis. To investigate the
      implication of GATA-1 in this process, we used a specific anti-GATA-1 polyclonal
      antibody that we produced in our laboratory. The GATA-1 transcription factor was
      then monitored during erythroid differentiation induced by aclacinomycin. Here we
      show that a cellular redistribution and a modification of the phosphorylation
      state of this transcription factor occurred during ACM-mediated cell
      differentiation. It suggests that anthracyclines can induce the erythroid
      differentiation of neoplastic cells by activating the transcription factor GATA
      1, probably via its clustering into nuclear foci.

PMID- 12489696
TI  - Centrosome separation: respective role of microtubules and actin filaments.
AB  - In mammalian cells, the separation of centrosomes is a prerequisite for bipolar
      mitotic spindle assembly. We have investigated the respective contribution of the
      two cytoskeleton components, microtubules and actin filaments, in this process.
      Distances between centrosomes have been measured during cell cycle progression in
      Xenopus laevis XL2 cultured cells in the presence or absence of either network.
      We considered two stages in centrosome separation: the splitting stage, when
      centrosomes start to move apart (minimum distance of 1 microm), and the
      elongation stage (from 1 to 7 microm). In interphase, depolymerisation of
      microtubules by nocodazole significantly inhibited the splitting stage, while the
      elongation stage was, on the contrary, facilitated. In mitosis, while nocodazole
      treatment completely blocked spindle assembly, in prophase, we observed that 55%
      of the centrosomes separated, versus 94% in the control. Upon actin
      depolymerisation by latrunculin, splitting of the interphase centrosome was
      blocked, and cells entered mitosis with unseparated centrosomes. Cells
      compensated for this separation delay by increasing the length of both prophase
      and prometaphase stages to allow for centrosome separation until a minimal
      distance was reached. Then the cells passed through anaphase, performing proper
      chromosome separation, but cytokinesis did not occur, and binuclear cells were
      formed. Our results clearly show that the actin microfilaments participate in
      centrosome separation at the G2/M transition and work in synergy with the
      microtubules to accelerate centrosome separation during mitosis.

PMID- 12489697
TI  - Nucleus behavior during the closed mitosis of Tritrichomonas foetus.
AB  - We present observations on the fine structure and the division process of the
      nucleus in the protist Tritrichomonas foetus, parasite of the urogenital tract of
      cattle. The nucleus was followed by immunofluorescence and electron microscopy
      during interphase and mitosis. Conventional karyotyping coupled to image
      processing and bright field Panotic staining were used to follow nucleus
      modifications, chromosome number and condensation pattern along the whole cell
      cycle. Confocal laser scanning microscopy (CLSM) using DNA fluorescent probes,
      followed by image processing in the SURF-Driver program, produced three
      dimensional reconstruction data of the mitotic nucleus under each phase of the
      division process. Immunocytochemistry in thin-sections revealed the chromosome
      spatial arrangement after bromodeoxyuridine incorporation and immunogold labeling
      using anti-DNA monoclonal antibodies. Our results indicate that: (1) the nucleus
      assumes different size and shapes along mitosis: it appears oval in interphase,
      becoming lobed or concave in prophase, then undergoing torsion and constriction,
      displaying an 'S' shape (metaphase). Next, it becomes elongated and it is finally
      separated in two nuclei at the transition of anaphase to telophase; (2) T. foetus
      nucleus harbors five chromosomes; (3) chromosomes become condensed in a pre
      mitotic phase; (4) the nucleolus persists during the mitosis.

PMID- 12489698
TI  - Crossing the secular divide: government and faith-based organizations as partners
      in health.
AB  - Recent debate over the relationship between government and faith-based
      organizations has renewed interest in the opportunities and challenges that are
      associated with change in this area of health care policy. Experience exists
      already that faith-based organizations can provide effective health education and
      services in the community. Limited infrastructure and liability are among the
      important barriers to their expansion. Spurred by the demographics of an aging
      population and increasing health care costs, we argue the necessity of further
      partnering, within well-defined limits, to maximize the availability of health
      care education and services throughout this nation.

PMID- 12489699
TI  - Anxiety and poor glycemic control: a meta-analytic review of the literature.
AB  - OBJECTIVE: To determine whether anxiety is associated with poor glycemic control
      in adults with type 1 or type 2 diabetes. METHOD: MEDLINE, PubMed, and PsycINFO
      databases were used to locate studies that measured the association of anxiety
      with glycemic control. Meta-analytic procedures were used to convert the findings
      to a common metric, compute effect sizes (ES), and statistically analyze the
      collective data. RESULTS: The search procedures identified 12 studies, 11 (92
      percent) of which satisfied the criteria for inclusion in the meta-analysis. In
      this overall group, anxiety was not associated with glycemic control (p = 0.19),
      although the ES was marginally statistically significant (ES = .09, 95 percent CI
      = 0.04 to 0.14). In studies that determined anxiety from diagnostic interviews,
      anxiety was associated with hyperglycemia (p = 0.003) and the ES was also
      statistically significant (ES: 0.25, 95 percent CI = 0.10 to 0.38). CONCLUSIONS:
      The existing literature suggests that anxiety disorders are associated with
      hyperglycemia in diabetic patients. Additional studies are required to confirm
      the magnitude of the relationship, to elucidate moderating and causal factors,
      and to determine whether successful treatment of anxiety improves glycemic
      control.

PMID- 12489700
TI  - Clinically relevant behaviors in elderly hip fracture inpatients.
AB  - OBJECTIVE: To examine the range of behaviors documented by inpatient
      rehabilitation staff and the association of these behaviors with functional
      outcome, in elderly persons undergoing rehabilitation after hip fracture. METHOD:
      Subjects were 137 patients, aged 60 and older, admitted to a rehabilitation
      hospital after a hip fracture, defined as having either a good or poor
      rehabilitation outcome based on change in Functional Independence Measure motor
      subscale scores during the course of their admission. Their charts were
      systematically reviewed for nursing and therapy staff documentation of behaviors.
      Prevalence of behaviors was compared between good and poor rehabilitation outcome
      group. RESULTS: Disturbances in cognition and rehabilitation participation were
      common and were associated with poorer rehabilitation outcome. Behaviors
      reflective of depression and anxiety were relatively uncommon and not associated
      with rehabilitation outcome. CONCLUSION: Rehabilitation staff frequently detect
      and document disturbances in cognition and participation that are associated with
      poorer rehabilitation outcome. It is recommended that staff observations be
      routinely added to mental health evaluations. Additionally, routine mental health
      screening and required staff documentation of behaviors would improve case
      detection rate.

PMID- 12489701
TI  - National prescribing patterns in the management of extrapyramidal symptoms among
      patients with schizophrenia.
AB  - PURPOSE: Antipsychotics, particularly typical agents, have been shown to cause
      extrapyramidal symptoms (EPS). We hypothesized a negative association between
      concomitant (at same visit) prescriptions for atypical antipsychotics and
      prescriptions for medications to manage EPS. METHOD: We combined National
      Ambulatory Medical Care Survey (NAMCS) data from 1993 through 1999 for visits by
      patients with a diagnosis of schizophrenia (ICD-9 295.0-295.9), that included a
      prescription for either an atypical or typical antipsychotic (but not both). We
      also constructed two, scale-weighted logistic regression models to separately
      estimate the odds and probabilities of receiving prescriptions for an
      antipsychotic and for a medication used to treat EPS. RESULTS: From 1993 through
      1999, there were an estimated 10,475,507 office visits with schizophrenia as a
      diagnosis; 7,371,625 (70.4 percent) included a prescription for a conventional
      (typical) antipsychotic. Thirty-four percent of visits included a prescription
      for a medication used to treat EPS. Being in the older age group, having Medicaid
      as primary coverage, belonging to an HMO, and being female significantly reduced
      the probability of receiving an atypical antipsychotic by 12.6 percent, 10.9
      percent, 15.1 percent and 10.2 percent, respectively. Caucasian patients were 14
      percent more likely to be prescribed an atypical. Antipsychotic type had a
      clinically and statistically significant effect on EPS management prescribing. A
      prescription for an atypical antipsychotic reduced the probability of receiving a
      concomitant prescription for EPS management by 26.8 percent. CONCLUSION: As
      expected, we observed the hypothesized joint prescribing pattern. The results
      ofthis study suggest that atypical antipsychotic prescriptions strongly predict
      fewer prescriptions for EPS treatment, and, by implication, reduced need for EPS
      treatment in actual ambulatory care practices throughout the nation.

PMID- 12489702
TI  - Screening for somatization and depression in Saudi Arabia: a validation study of
      the PHQ in primary care.
AB  - OBJECTIVES: Somatization, the tendency to seek treatment for medically
      unexplained physical symptoms, is an important issue in primary care practice.
      This study examines the somatoform, depression, and anxiety modules of the
      Patient Health Questionnaire (PHQ), a screening instrument for the identification
      of somatoform and other mental disorders. We also utilized the PHQ to measure the
      prevalence of somatization and co-morbid depression in Saudi Arabian primary care
      patients. METHODS: This is a cross sectional study of 431 male and female Saudi
      Arabian primary care patients with a two stage design for purposes of validation
      of the somatoform, depression and anxiety modules of the PHQ. The self
      administered Patient Health Questionnaire was given to 431 primary care patients
      and, of this group, the first, consecutive 173 patients (40 percent) were
      interviewed by mental health professionals using the Structured Clinical
      Interview (SCID-R) as the criterion standard for validation of the PHQ in the
      Saudi population. The PHQ was then used to measure the prevalence of somatization
      and depression in the remaining 258 patients. RESULTS: The somatoform and
      depression modules of the PHQ were found to be valid in a Saudi population using
      the criterion standard of SCID based psychiatric interviews. Agreement between
      the PHQ and psychiatric interviews was (kappa = .65) for both somatoform
      disorders and depression but the anxiety module was weak in terms of sensitivity
      (.37) and agreement with the criterion standard (k = .37). Clinically significant
      rates of somatization (19.3 percent) and depression (20 percent) were identified
      in this population. CONCLUSIONS: The prevalence of somatization and co-morbid
      depression in a primary care population in Saudi Arabia is similar to published
      rates in the U.S. and worldwide. It is possible to screen primary care patients
      for mental disorders in international settings and the PHQ is valid instrument
      for that purpose.

PMID- 12489703
TI  - Psychological problems in Christian and Moslem primary care patients in Greece.
AB  - OBJECTIVE: Psychiatric problems are often expressed through, or coexist with,
      somatic symptoms. Cultural factors may influence this association. This study
      aims to 1) estimate the prevalence of mental health problems in a sample of
      primary care attendees in a rural area of Greece, and 2) investigate the
      differences in psychiatric symptomatology among patients from different
      religious/cultural backgrounds. METHOD: Over a three-month period, 300
      consecutive adult patients (Christians and Moslems) at the rural Primary Care
      Health Centre of Iasmos in Thrace, Greece, were assessed with the 28-item General
      Health Questionnaire. RESULTS: The probable prevalence of mental health problems
      was estimated at 32 percent. Only for a small minority of the patients (3.3
      percent) psychological problems were the presenting complaint. Moslems scored
      significantly higher than Christians in the somatic complaints subscale (p <
      0.001). CONCLUSION: Mental health problems are common in primary care although
      they rarely constitute a reason for consultation. Sociocultural background may
      affect the presentation of psychological distress. Primary health care staff have
      a significant role in identifying hidden psychiatric morbidity.

PMID- 12489704
TI  - Behavioral characteristics in delusional pregnancy: a matched control group
      study.
AB  - OBJECTIVE: False pregnancy or delusional pregnancy, is the condition of believing
      one is pregnant despite factual evidence to the contrary. This is the first study
      to utilize a standardized mental disorder assessment tool, The Brief Psychiatric
      Rating Scale (BPRS) to evaluate a group of women with delusional pregnancy
      compared to a group of controls. METHOD: Eleven-women with delusional pregnancy
      (DP) were compared to a control group matched for age, race and DSM-IV
      psychiatric diagnosis. All patients were receiving care in a state psychiatric
      hospital setting. RESULTS: Compared to matched controls, women with DP had
      significantly higher levels of hostility (p < .05), higher rates of prescribed
      polypharmacy (p < .05) and a trend toward higher antipsychotic medication dosages
      (t = 1.48, df = 20, p = .08). These findings may be suggestive of greater
      resistance to treatment in women with DP. CONCLUSIONS: Biologic and
      psychotherapeutic treatment interventions for women with DP may need to address
      factors of hostility and treatment resistance. Preliminary treatment issues
      include selection of specific categories of psychotropic agents, as well as
      psychotherapies that are cognitive and lead to modification of belief paradigm.

PMID- 12489705
TI  - Insight into the psychosocial aspects of Huntington's disease in Chinese society.
AB  - OBJECTIVE: To review the psychosocial aspects of Chinese families with
      Huntington's disease (HD) in Hong Kong. METHOD: The psychosocial aspects of five
      Chinese families in Hong Kong were studied with in-depth interviews and detailed
      analysis of case records. RESULTS: Patients with HD are found to suffer from
      certain specific psychosocial adversities, including marital disharmony, social
      stigma and increased suicidal risk in those with relatively well-preserved
      cognitive function. A low request rate for presymptomatic testing for HD is also
      observed among these cases. CONCLUSIONS: Though the genetic defect in HD is
      universal and cuts across cultures, the problems faced by these patients and
      their families are never the same. Despite limited local experience due to a much
      lower prevalence, Chinese HD patients in Hong Kong are found to have specific
      needs that emerge from their ethno-historical background.

PMID- 12489706
TI  - An adolescent in Istanbul with Munchausen's syndrome.
AB  - This article presents the treatment period for a 16-year-old girl with
      Munchausen's syndrome. She was initially referred to the hospital with emphysema
      of the face, which turned out to be due to self-injection of air. She had an
      eight-month hospitalization period for the diagnosis of her condition. After the
      diagnosis was established she was treated by our psychiatric team and followed
      for 21 months successfully without recurrence.

PMID- 12489707
TI  - Natural distemper in vaccinated and unvaccinated dogs in Warsaw.
AB  - Two hundred and twenty-four dogs with clinical signs of distemper were examined
      for the presence of canine distemper virus (CDV) in mucous membranes by direct
      immunofluorescence assay. The study showed that 22% of the animals were CDV
      positive. Most (33/50; 66%) of the infected dogs had never been vaccinated
      against distemper, whereas only 11 of 50 (22%) CDV-positive animals were
      immunized at least once. The difference in the infection rate between vaccinated
      and unvaccinated animals was statistically significant (P < 0.001), as assessed
      by the chi2 test. It is concluded that distemper is an important disease among
      dogs in Warsaw and the vaccination significantly reduces the risk of this
      disease.

PMID- 12489708
TI  - Identification of acid fast bacteria from caseous lesions in cattle in Sudan.
AB  - One-hundred-and-twenty caseous lesions collected from slaughtered cattle at
      selected slaughterhouses in Sudan were processed for the detection of acid-fast
      bacteria (AFB). Sixty-four of the 120 samples showed AFB on microscopic
      examination after staining with the Ziehl-Neelsen method. Accordingly, it was
      estimated that 64 (53.3%) of the 120 caseous (purulent) lesions among the samples
      were due to AFB whereas 56 (46.7%) were due to other causes. Growth on Lowenstein
      Jensen slants was obtained in 54 of the 120 samples. The isolated AFB were
      tentatively identified using microscopic and cultural characteristics.
      Confirmation of the phenotypic clusters was achieved by analysing the mycolic
      acids contents and PCR-amplification of the IS6110 insertion sequences. The above
      two methods have allowed the identification of Mycobacterium bovis and M.
      farcinogenes, the major AFB isolated from cattle in Sudan. The remaining AFB,
      which were negative for the above two tests, were further identified by
      sequencing the 16S rRNA gene. The above strategy thus allowed the identification
      of the isolated strains as follows: 25 (46%) M. bovis; 21 (39.9%) M.
      farcinogenes; 4 (7.4%) M. tuberculosis; 1 (1.9%) M. avium; 1 (1.9%) Nocardia sp.,
      2 (3.7%) unidentified AFB. The isolation of M. farcinogenes and M. tuberculosis,
      from pulmonary lymph nodes represented important findings.

PMID- 12489709
TI  - Identification and antimicrobial susceptibility of coagulase positive
      staphylococci isolated from healthy dogs and dogs suffering from otitis externa.
AB  - A total of 67 strains of coagulase positive staphylococci isolated from healthy
      dogs and dogs suffering from otitis externa were studied. Twenty-two isolates
      were from healthy dogs (five from hound dogs and 17 from companion dogs) and 45
      from dogs suffering otitis externa (14 from hound dogs and 31 from companion
      dogs). Presumptive identification was attempted using the following tests:
      production of acetoin, anaerobic utilization of mannitol, acid production from
      mannitol, presence of beta-galactosidase, and growth on P agar supplemented with
      different concentrations of acriflavine. Susceptibility of staphylococci to 16
      antibiotics was determined. Most effective antibiotics were imipenem,
      amoxycillin/clavulanic acid, ciprofloxacin, tobramycin, gentamicin and
      marbofloxacin. Penicillin, ampicillin and polymyxin B showed the lowest activity.
      There were no significant differences in antimicrobial susceptibility among
      isolates from healthy dogs and dogs suffering from otitis externa.

PMID- 12489711
TI  - Effects of various applications of lipopolysaccharides on blood parameters of
      pigs.
AB  - In five experiments, lipopolysaccharides (LPS) of Escherichia coli O26:B6 and
      O111:B4 were applied intravenously, intramuscularly, subcutaneously or
      intrabronchially in doses of 5000-15,000 U/kg body mass to a total of 47 weaner
      pigs and compared with the application of sodium chloride. Different parameters
      of blood cells were investigated, including cell numbers, in vivo interleukin
      secretion, radical formation, phagocytosis capacity and IL-6 as well as TNFalpha
      formation ex vivo. Non-specific effects and dependencies on the type of
      application and LPS dose are discussed.

PMID- 12489710
TI  - Assessment of respiratory herd health in weaner pigs by measuring cellular
      composition of bronchoalveolar lavage fluid.
AB  - Cell differentiation of bronchoalveolar lavage fluid (BALF) was compared among 11
      herds having a history of recurrent respiratory disease in weaner pigs and nine
      herds lacking such a history. In every herd, 20 pigs aged 8-10 weeks were
      lavaged. The two groups differed significantly on median percentage of
      macrophages, neutrophils and lymphocytes, but not on white blood cell count of
      the BALF. Logistic regression showed the percentage of samples per herd exceeding
      the reference value for neutrophils of 0-8% to be the most promising parameter to
      assess the health status in weaner pigs.

PMID- 12489712
TI  - Estimating the prevalence of Salmonella spp. in swine herds--influence of
      sensitivity and specificity of Salmonella detection.
AB  - Information about the proportion of truly Salmonella-free herds is required for
      an evaluation of the epidemiological situation, the development of control
      strategies and their implementation. Findings regarding the presence of
      salmonellas in faeces and intestinal lymph nodes as well as the presence of
      Salmonella antibodies in meat juice from slaughtered pigs were obtained in the
      context of a study conducted by a number of institutes. These data were used for
      an analysis of the validity of data on the prevalence of infected animals within
      herds and on the prevalence of infected herds. The proportion of batches or herds
      with exclusively negative individual findings was found to depend not only on the
      true proportion of truly Salmonella-free animals within herds but quite
      essentially also on the distribution of the proportion of infected animals within
      herds, the sensitivity of the methods of examination and sample sizes. When
      taking into account the existing dependencies, it was found that among the swine,
      the real numbers of Salmonella carriers were much higher than shown by
      bacteriological and serological examination. Regarding salmonellosis in swine,
      also a number of contaminated herds must be expected which is far higher than
      that shown by the number of herds with positive findings in at least one animal.
      Even a low contamination of all or almost all herds would result in the numbers
      of 'negative' batches observed, i.e. batches with exclusively negative individual
      findings. A rating of the salmonella exposure of herds as high, low, or very low
      is possible and may, and should be, used for measures of consumer protection,
      irrespective of the proportion of truly Salmonella-free herds.

PMID- 12489714
TI  - An experimental infection to investigate the indirect transmission of classical
      swine fever virus by excretions of infected pigs.
AB  - In this experiment transmission of classical swine fever (CSF) virus via
      excretions of infected pigs was investigated under experimental conditions. Five
      pairs of pigs were experimentally infected with CSF virus. Eight days after
      experimental infection, when all pigs were viraemic for at least 3 days, the pens
      were depopulated and 20 h later, restocked with five pairs of susceptible pigs
      which stayed in these pens for 35 days. During the first 3 weeks of the
      experiment, the pens were neither cleaned nor disinfected. During the observation
      period, none of the susceptible pigs became infected. This result indicates that
      CSF virus spread via excretions is of minor importance in the early stages of
      infection. For extrapolation of these findings to the field situation and to
      increase the validity of the conclusions further research is needed to evaluate
      the effect of factors like virus strain, interval, ..., that may influence the
      outcome of the experiment.

PMID- 12489713
TI  - Avian paramyxovirus serotype 1 isolates from the spinal cord of parrots display a
      very low virulence.
AB  - The spinal cord of 32 psittacines suffering from proventricular dilatation
      disease (PDD) was investigated. In six cases, a virus was isolated which upon
      electron microscopic examination revealed morphological details typical of
      members of the Paramyxoviridae. All isolates were subsequently characterized as
      avian paramyxovirus serotype 1 (APMV-1) by type-specific polyclonal antisera.
      According to their reactivity with APMV-1 specific monoclonal antibodies, the six
      isolates shared epitopes within the haemagglutinin-neuraminidase spike protein,
      distinct from pigeon-type paramyxoviruses and the LaSota vaccine strain. This
      grouping was further corroborated by properties of the haemagglutinin: all
      isolates showed a very thermosensitive haemagglutination activity and were rapid
      eluters. Virulence of the APMV-1 isolates in 1-day-old specific pathogen free
      (spf) chicken was very low, with intracerebral pathogenicity indices between 0
      and 0.1. In embryonated spf chicken eggs, psittacine isolates replicated to high
      titres (10(8.6)-10(10.7) EID50/ml). However, they exhibited a reduced lethality
      over an observation time of 7 days (10(6.1)-10(8.3) ELD50/ml). In a
      haemagglutination inhibition test with parrot sera from birds with no history of
      APMV-1 vaccination, sera reacted preferentially with two isolates compared with
      APMV-1 vaccine strains LaSota and B1. The other four isolates exhibited a
      differentiated reaction pattern with the parrot sera, indicating an antigenic
      inhomogeneity. This is the first report of isolating very low virulent APMV-1
      from neuronal tissue of parrots and implications for a possible role in slow
      progressing disease will be discussed.

PMID- 12489715
TI  - Minimum inhibitory concentrations of 20 antimicrobial agents against
      Staphylococcus aureus isolated from bovine intramammary infections in Japan.
AB  - Minimum inhibitory concentrations (MICs) of 20 antimicrobial agents were
      determined against 51 isolates of Staphylococcus aureus from bovine intramammary
      infections. Fourteen (27.4%) isolates were resistant to benzylpenicillin, but
      none of the isolates was resistant to cloxacillin, nafcillin, or cephems. Among
      aminoglycosides, gentamicin was the most active, with an MIC50 of 0.2 microg/ml,
      followed by kanamycin, with an MIC50 of 0.78 microg/ml. Five isolates (9.8%) were
      resistant to dihydrostreptomycin, three isolates (5.9%) to kanamycin and two
      isolates (3.9%) to gentamicin. Resistance to erythromycin was observed in two
      isolates (3.9%). Tylosin was less active than erythromycin, with MIC50s of 1.56
      microg/ml versus 0.39 microg/ml, but none of the isolates was resistant to this
      antibiotic. Oxytetracycline MICs were situated in the range of 0.39-1.56
      microg/ml for 48 susceptible isolates. Although 19 (37.3%) isolates were
      resistant to one or more antimicrobial agents, a single resistance pattern was
      most frequent: benzylpenicillin (12 isolates), dihydrostreptomycin (two isolates)
      and kanamycin (one isolate). There were no isolates resistant to antimicrobial
      agents such as methicillin, lincomycin, clindamycin, chloramphenicol, florfenicol
      and virginiamycin, which have not been approved for use in cattle husbandry in
      Japan.

PMID- 12489716
TI  - Copper complexation by dissolved organic matter and uncertainty assessment of
      their stability constants.
AB  - The interaction of Cu with dissolved organic matter (DOM, extracted from an
      organic forest floor) was investigated and the resulting data was evaluated in
      terms of their uncertainty. The speciation of Cu over 'free' Cu (as analysed by
      diffusive gradients in thin films (DGT)), dissolved Cu-DOM complexes and
      precipitated Cu-DOM was determined as a function of pH (3.5, 4.0 and 4.5) and
      Cu/C ratio. The dissolved organically bound fraction was highest at pH 4.5, but
      this fraction decreased with increasing Cu/C ratio, which was observed for all pH
      levels. In the range of Cu/C = 7 x 10(-5) -2.3 x 10(-2) (mol/mol) the
      precipitated fraction was very small. The speciation of both Al and Fe was not
      affected by increasing Cu concentrations. From a continuous distribution model
      using the Scatchard approach, we calculated the optimal fit and corresponding
      upper and lower 95% uncertainty bounds of the overall stability constants (K(o))
      with the shuffled complex evolution Metropolis (SCEM) algorithm. Although the
      optimal equation fitted the data very well, the uncertainty of the, according to
      literature, most reliable approach to establish stability constants, was still
      large. Accordingly, the usually reported intrinsic stability constants exhibited
      large uncertainty ranging from log K(i) = 6.0-7.1 (optimal 6.7) for pH 3.5, log
      K(i) = 6.5-7.1 (optimal 6.8) for pH 4.0, and log K(i) = 6.4-7.2 (optimal 6.8) for
      pH 4.5 and showed only little effect of pH.

PMID- 12489717
TI  - Comparative assessment of methods to develop QSARs for the prediction of the
      toxicity of phenols to Tetrahymena pyriformis.
AB  - Quantitative structure-activity relationships (QSARs) for the toxicity of 200
      phenols to the ciliated protozoan Tetrahymena pyriformis, and the validation of
      the QSARs using a test set of a further 50 compounds, are reported. The phenols
      are structurally heterogeneous and represent a variety of mechanisms of toxic
      action including polar narcosis, weak acid respiratory uncoupling,
      electrophilicity, and those compounds capable of being metabolised or oxidised to
      quinones. For each compound, a total of 108 physico-chemical descriptors have
      been calculated. A variety of methods were utilised to develop QSARs and are
      compared. The response-surface, or two parameter, approach was found to be
      successful, but only following the removal of compounds known to form quinones.
      Stepwise regression produced a seven parameter QSAR with good statistical fit,
      but was less interpretable and transparent than the response-surface. Partial
      least squares produced a good model for phenolic toxicity following supervised
      selection of parameters, this, however, was the least transparent of all
      approaches attempted. In all approaches, a large number of outliers were
      observed, typically these were compounds capable of being metabolised to
      quinones. The strengths and weaknesses of each of the approaches to predict the
      toxicity of the validation (test) set of phenols to T. pyriformis are discussed.

PMID- 12489718
TI  - Azo-dyes photocatalytic degradation in aqueous suspension of TiO2 under solar
      irradiation.
AB  - The photodegradation of two common and very stable azo-dyes, i.e. methyl-orange
      (C14H14N3SO3Na) and orange II (C16H11N2SO4Na), is reported. The photocatalytic
      oxidation was carried out in aqueous suspensions of polycrystalline TiO2
      irradiated by sunlight. Compound parabolic collectors, installed at the
      "Plataforma Solar de Almeria" (PSA, Spain) were used as the photoreactors and two
      identical reacting systems allowed to perform photoreactivity runs for the two
      dyes at the same time and under the same irradiation conditions. The
      disappearance of colour and substrates together with the abatement of total
      organic carbon content was monitored. The main sulfonate-containing intermediates
      were found to be in lower number in respect to those obtained under artificial
      irradiation. In particular there were no more evidence of the presence of
      hydroxylated transients. The dependence of dye photooxidation rate on: (i)
      substrate concentration; (ii) catalyst amount; and (iii) initial pH was
      investigated. The influence of the presence of strong oxidant species (H2O2,
      S2O8(2-)) and some ions (Cl-, SO4(2-)) on the process was also studied.

PMID- 12489719
TI  - Resistant sorption of in situ chlorobenzenes and a polychlorinated biphenyl in
      river Rhine suspended matter.
AB  - The desorption kinetics of in situ chlorobenzenes (dichlorobenzenes,
      pentachlorobenzene and hexachlorobenzene) and 2,4,4'-trichlorobiphenyl (PCB-28)
      were measured with a gas-purge technique for river Rhine suspended matter sampled
      in Lobith, The Netherlands. This suspended matter is the main source of sediment
      accumulation in lake Ketelmeer. In lake Ketelmeer sediment earlier observations
      showed that slow and very slow fractions dominate the desorption profile. For the
      river Rhine suspended matter, only for PCB-28 a fast desorbing fraction of around
      1.6% could be detected. The observed rate constants were on the average 0.2 h(-1)
      for fast desorption, 0.004 h(-1) for slow desorption, and 0.00022 h(-1) for very
      slow desorption. These values are in agreement with previous findings for the
      sediment from lake Ketelmeer and with available literature data on fast, slow,
      and very slow desorption kinetics. The results from this study show the
      similarity of desorption profiles between river Rhine suspended matter, and the
      top layer sediment from lake Ketelmeer. This indicates that slow and very slow
      fractions are already present in material forming the top layer of lake
      Ketelmeer, and were not formed after deposition of this material in the lake. The
      absence of detectable fast fractions for most compounds could be caused by the
      absence of recent pollution of the suspended matter. But, the observations may
      also be explained by a rapid disappearance of compounds from the fast fraction
      due to a combination of a high affinity of very slow sites for these compounds,
      and their relatively high volatility.

PMID- 12489720
TI  - Behavior of PAHs during cold storage of historically contaminated soil samples.
AB  - The stability of historically polycyclic aromatic hydrocarbon (PAH)-contaminated
      soils during cold storage was investigated. Samples from two former manufactured
      gas plants exhibited quantitative recoveries of PAHs over the whole period of
      sample holding at 4 degrees C in the dark (8-10 months), whereas significant
      losses of PAHs were observed for soils received from a former railroad sleeper
      preservation plant with low molecular weight compounds being notably more
      affected compared to heavier PAHs. Already after 2 weeks of holding time, 3-ring
      PAHs in one of theses samples were down to 29-73% of the initial concentration
      and significant losses were observed for up to 5-ring compounds. Dissipation of
      PAHs was found to be predominantly due to aerobic microbial metabolism since
      sodium azide poisoned samples showed quantitative recoveries for all PAHs over
      the entire storage time of 3 months. A similar stabilizing effect was observed
      for freezing at -20 degrees C as means of preservation. Except for acenaphthene,
      no significant loss for any of the PAHs was observed over 6 weeks of holding
      time. Eventually, selected chemical, physical, and biological parameters of two
      soils were investigated and identified as potential indicators for the stability
      of PAH-contaminated soil samples.

PMID- 12489721
TI  - Monoterpene emissions and carbonyl compound air concentrations during the
      blooming period of rape (Brassica napus).
AB  - An increasing percentage of agricultural land in Germany is used for oil seed
      plants. Hence, rape has become an important agricultural plant (in Saxony 1998:
      12% of the farmland) in the recent years. During flowering of rape along with
      intensive radiation and high temperatures, a higher production and emission of
      biogenic VOC was observed. The emissions of terpenes were determined and more
      importantly, high concentrations of organic carbonyl compounds were observed
      during this field experiment. All measurements of interest have been carried out
      during two selected days with optimal weather conditions. It is found that the
      origin or the mechanism of formation of different group of compounds had strong
      influence on the day to day variation of their concentrations. The emission flux
      of terpenes from flowering rape plants was determined to be 16-32 microg h(-1) m(
      2) (30-60 ng h(-1) per g dry plant-540-11080 ng h(-1) per plant), in total.
      Limonene, alpha-thujene and sabinene were the most important compounds (about 60%
      of total terpenes). For limonene and sabinene reference emission rates (Ms) and
      temperature coefficients were determined: beta(limonene) = 0.108 K(-1) and Ms =
      14.57 microg h(-1) m(-2) beta(sabinene) = 0.095 K(-1) and Ms = 5.39 microg h(-1)
      m(-2). The detected carbonyl compound concentrations were unexpectedly high
      (maximum formaldehyde concentration was 18.1 ppbv and 3.4 ppbv for butyraldehyde)
      for an open field. Possible reasons for these concentrations are the combination
      of primary emission from the plants induced by high temperature and high ozone
      stress, the secondary formation from biogenically and advected anthropogenically
      emitted VOC at high radiation intensities and furthered by the low wind speeds at
      this time.

PMID- 12489722
TI  - Laboratory shake flask batch tests can predict field biodegradation of aniline in
      the Rhine.
AB  - The aim of this study was to compare degradation rates of aniline in laboratory
      shake flask simulation tests with field rates in the river Rhine. The combined
      events of a low flow situation in the Rhine and residual aniline concentrations
      in the effluent from the BASF treatment plant in Ludwigshafen temporarily higher
      than normal, made it possible to monitor aniline at trace concentrations in the
      river water downstream the wastewater outlet by means of a sensitive GC headspace
      analytical method. Aniline was analyzed along a downstream gradient and the
      dilution along the gradient was calculated from measurements of conductivity,
      sulfate and a non-readily biodegradable substance, 1,4-dioxane. Compensating
      dilution, field first-order degradation rate constants downstream the discharge
      of BASF were estimated at 1.8 day(-1) for two different dates with water
      temperatures of 21.9 and 14.7 degrees C, respectively. This field rate estimate
      was compared with results from 38 laboratory shake flask batch tests with Rhine
      water which averaged 1.5 day(-1) at 15 degrees C and 2.0 day(-1) at 20 degrees C.
      These results indicate that laboratory shake flask batch tests with low
      concentrations of test substance can be good predictors of degradation rates in
      natural water bodies--at least as ascertained here for short duration tests with
      readily degradable compounds among which aniline is a commonly used reference.

PMID- 12489723
TI  - The effect of particle size reduction by grinding on subsampling variance for
      explosives residues in soil.
AB  - Efforts to characterize the surface soil contamination on military training
      ranges have been compromised by the inability to obtain representative subsamples
      of soils submitted to analytical laboratories for determination of explosives
      residues. Two factors affecting subsampling error for explosives residues were
      examined using soils collected from hand grenade and anti-tank ranges. These
      factors were increased subsample size and particle size reduction prior to
      subsampling of soils. Increasing the subsample size from 2 to 50 g did not reduce
      the soil subsampling error because of the extreme heterogeneous distribution of
      the solid contaminants. Alternatively, particle size reduction by machine
      grinding on a ring mill reduced subsampling error to less than 10% relative
      standard deviation for replicate analyses using 10-g subsamples.

PMID- 12489724
TI  - Quality of roof runoff waters from an urban region (Gdansk, Poland).
AB  - The paper presents the results of testing of roof runoff waters from buildings in
      the city of Gdansk (Poland), carried out as a part of a broader research project
      aimed at the determination of pollutant levels in precipitation. The analytes
      determined included volatile organohalogen compounds, petroleum hydrocarbons,
      Na+, K+, NH4+, Mg2+, Ca2+, F-, Cl-, NO2-, NO3-, PO4(3-), SO4(2-) ions, as well as
      organonitrogen, organophosphorus and organochlorine pesticides. In addition, the
      toxicity and pH of the samples were examined. The samples were collected over a
      period of six months, during or immediately following precipitation events. More
      than half of the samples (25) were found to be toxic, with inhibition exceeding
      20%. The toxicity was weakly correlated to the levels of organonitrogen and
      organophosphorus pesticides in runoff waters. It was established that at least in
      some cases the roofing material affected the levels of the pollutants found in
      the samples.

PMID- 12489725
TI  - Sorption of lambda-cyhalothrin, cypermethrin, deltamethrin and fenvalerate to
      quartz, corundum, kaolinite and montmorillonite.
AB  - Sorption to mineral surfaces may be important for retention and degradation of
      hydrophobic pesticides in subsoils and aquifers poor in organic matter. In this
      work the title pyrethroids have been used to investigate selective interactions
      with the surfaces of four minerals. Sorption of the four pyrethroids was
      quantified in batch experiments with initial pyrethroid concentrations of 1-100
      microg/l. Sorption to centrifuge tubes used in the batch experiments accounted
      for 25-60% of total sorption. Net sorption was obtained from total sorption after
      subtracting the amounts of pyrethroids sorbed to centrifuge tubes used. All
      isotherms could be fitted by the Freundlich equation with n ranging between 0.9
      and 1.1. Bonding affinities per unit surface area decreased in the order:
      corundum > quartz > montmorillonite approximately equal kaolinite. A similar
      sequence as found for the total surface tension of the minerals. All minerals
      showed the same selectivity order with respect to sorption affinity of the four
      pyrethroids: lambda-cyhalothrin > deltamethrin > cypermethrin > fenvalerate,
      which shows that the most hydrophobic compound is sorbed most strongly.
      Stereochemical properties of the four pyrethroid formulations may also contribute
      to the selectivity pattern.

PMID- 12489727
TI  - Distribution of heavy metal contents of urban soils in parks of Seville.
AB  - Several metals in urban soils of Seville were extracted by two methods, which
      respectively give estimates of the available and 'quasi total' contents. Although
      the soils did not show strong heterogeneity in their general properties, high
      dispersion of the contents in those metals with greater relative availability,
      Cu, Pb and Zn, as compared to others suggested that pollution with these three
      metals could occur in some sampling sites. It was shown that the contents in
      these metals tend to increase as the historic quarters of the city are
      approached. Using reference values given by the Quebec Ministry of Environment it
      was shown that those green areas closer to the historic centre present contents
      in Pb, Zn and particularly Cu that often exceed the acceptable limits for
      residential, recreational and institutional sites. From background contents for
      Seville soils estimated from a park located on the outskirts, a pollution load
      index (PLI) for each sampling site was calculated for the set of these three
      metals. It was shown that the PLI tends to increase as traffic density increases
      and as distance from main traffic decreases, but poor regressions were obtained,
      suggesting that other variables different from traffic should be considered.

PMID- 12489726
TI  - Occurrence and microbial degradation of phthalate esters in Taiwan river
      sediments.
AB  - Concentrations and microbial degradation rates were measured for eight phthalate
      esters (PAEs) found in 14 surface water and six sediment samples taken from
      rivers in Taiwan. The tested PAEs were diethyl phthalate (DEP), dipropyl
      phthalate (DPP), di-n-butyl phthalate (DBP), diphenyl phthalate (DPhP),
      benzylbutyl phthalate (BBP), dihexyl phthalate (DHP), dicyclohexyl phthalate
      (DCP), and di-(2-ethylhexyl) phthalate (DEHP). In all samples, concentrations of
      DEHP and DBP were found to be higher than the other six PAEs. DEHP concentrations
      in the water and sediment samples ranged from ND to 18.5 microg/l and 0.5 to 23.9
      microg/g, respectively; for DBP the concentration ranges were 1.0-13.5 microg/l
      and 0.3-30.3 microg/g, respectively. Concentrations of DHP, BBP, DCP and DPhP
      were below detection limits. Under aerobic conditions, average degradation half
      lives for DEP, DPP, DBP, DPhP, BBP, DHP, DCP and DEHP were measured as 2.5, 2.8,
      2.9, 2.6, 3.1, 9.7, 11.1 and 14.8 days, respectively; under anaerobic conditions,
      respective average half-lives were measured as 33.6, 25.7, 14.4, 14.6, 19.3,
      24.1, 26.4 and 34.7 days. In other words, under aerobic conditions we found that
      DEP, DPP, DBP, DPhP and BBP were easily degraded, but DEHP was difficult to
      degrade; under anaerobic conditions, DBP, DPhP and BBP were easily degraded, but
      DEP and DEHP were difficult to degrade. Aerobic degradation rates were up to 10
      times faster than anaerobic degradation rates.

PMID- 12489728
TI  - Simultaneous sorption of lead and chlorobenzene by organobentonite.
AB  - Clays or organoclays have been used as a barrier to prevent the transport of
      hazardous contaminants in landfills. However, clays are known to effectively sorb
      mostly inorganic contaminants, while organoclays are mainly used for organic
      contaminants. Since the organoclays are basically clay particles modified with
      cationic surfactants, there might exist an optimal coverage of cationic
      surfactant on the clay particles to sorb both inorganic and organic contaminants.
      In order to determine the optimal mass of cationic surfactants on the bentonites,
      sodium bentonites were treated with various ratios of hexadecyltrimethylammonium
      (HDTMA) to bentonites. Chlorobenzene and lead were selected as representative
      contaminants. When either chlorobenzene or lead exists as a single contaminant,
      chlorobenzene sorption increased with increasing HDTMA to bentonite ratios, and
      lead sorption decreased with increasing HDTMA to bentonite ratios. Sorption of
      chlorobenzene was a function of HDTMA coverage on the bentonites, while lead
      sorption was much more influenced by the initial lead concentration rather than
      the mass of HDTMA added to the bentonites.

PMID- 12489729
TI  - Reverse quantitative structure-activity relationship for modelling the sorption
      of esfenvalerate to dissolved organic matter. A multivariate approach.
AB  - The sorption of the pyrethroid, esfenvalerate, to the dissolved and/or dispersed
      fraction of eight different natural humic compounds has been investigated. The
      dissolved organic matters (DOMs) included in this study originate from ground
      water, soil pore water, and surface waters. Sorption was modelled at DOM
      concentration levels where equilibrium partitioning of esfenvalerate between DOM
      and the aqueous bulk phase prevails. The inherent characteristics of the eight
      different humic materials, quantified in the preceding paper by Thomsen et al.
      (2002, this issue (PII: S0045-6535(02)00335-1)), have been used as explanatory
      variables for modelling this equilibrium partitioning. Using a reverse QSAR
      approach based on by projection-into-latent-structure regression (PLS-R) inherent
      sorbent properties determining for the sorption affinity of esfenvalerate to DOM
      were analysed. For all humic substances a decrease in the DOM-normalised
      equilibrium-partitioning coefficient, K(DOM), with increasing concentration of
      DOM was observed. Significant variations in K(DOM) values, as function of the
      inherent characteristics of the individual humic substances, were found at DOM
      concentrations of 75 and 100 ppm, respectively. The latter is a strong indication
      of variations in sorption mechanisms of esfenvalerate to DOM of varying inherent
      properties. Groupings in the principal property space quantifying DOMs may
      indicate that separate models are needed for quantifying the equilibrium
      partitioning to different classes of DOM.

PMID- 12489730
TI  - Characterisation of humic materials of different origin: a multivariate approach
      for quantifying the latent properties of dissolved organic matter.
AB  - The inherent chemical properties of eight different dissolved organic matters
      (DOMs) originating from soil, surface and groundwater have been analysed. The
      samples consist of isolated fulvic acids (FA), humic acids (HA), and humic
      substances (HS), i.e. natural mixtures containing a humic and a fulvic fraction.
      The humic substances have been characterised by elemental analysis, size
      exclusion chromatography, E2/E3 and E4/E6 UV absorption ratios, and liquid-state
      13C-NMR spectroscopy. The information contents of the different analytical
      methods have been investigated by pattern recognition, i.e. cluster analysis and
      principal component analysis (PCA). A comparative study of the information
      contents of DOM descriptors derived from different analytical methods is
      presented. Through extraction of information content of the individual analytical
      methods the inherent properties of DOM are quantified. Pattern recognition
      revealed significant quantitative differences in the inherent properties of DOM
      of different origin and type. PCA based on the NMR descriptors showed highest
      explained variance. However, all models showed low robustness due to the limited
      number of samples. The supervised pattern recognition, i.e. PCA, indicates a
      classification of DOMs into groups of similar properties by an increase in the
      number of samples. Furthermore that the number of groups may be higher and more
      continuously distributed than the conventional classification into fulvic acids,
      humic acids or humic substances.

PMID- 12489731
TI  - Enantiomer fractions of chiral organochlorine pesticides and polychlorinated
      biphenyls in standard and certified reference materials.
AB  - Enantiomeric ratios (ERs) and enantiomeric fractions (EFs) of a number of chiral
      organochlorine pesticides and PCB atropisomers were measured by chiral gas
      chromatography/mass spectrometry (GC/MS) in five standard (SRM) and certified
      (CRM) reference materials: SRM 1588a (organics in cod liver oil), SRM 1945
      (organics in whale blubber), Marine Mammal Quality Assurance Exercise Control
      Material IV (NIST IV, organics in whale blubber), CRM trout, and CRM EC-5
      (sediment). Target analytes were cis- and trans-chlordane, heptachlor exo
      epoxide, oxychlordane, U82, MC5, MC6, MC7, o,p'-DDT, and PCB congeners 91, 95,
      136, 149, 174, 176, and 183. Measured ERs and EFs are in close agreement with the
      few literature values reported for some of these analytes in SRMs and CRMs.
      Chiral PCB ERs and EFs measured by one-dimensional chiral GC/MS were similar to
      values measured using multidimensional chiral GC/MS. Non-racemic chiral
      compositions are in agreement with known uptake and biotransformation in the
      respective environmental matrices. These values should aid in the quality
      assurance/quality control methodologies for chiral environmental chemistry using
      standardized reference materials.

PMID- 12489732
TI  - Solid-phase microextraction coupled with atomic emission spectroscopy--rapid
      screening for volatile chlorinated compounds.
AB  - Solid-phase microextraction (SPME) coupled with atomic emission spectroscopy was
      evaluated as a rapid screening tool for volatile halogenated compounds in water
      samples. After extraction, the SPME fiber was introduced to the injector where
      the analytes were rapidly and efficiently desorbed. The analytes entered the
      detector over a short period of time and produced one well-defined analyte
      signal. Element selective responses were measured to confirm the presence and to
      roughly estimate the content of volatile compounds. The total time for extraction
      and detection was approximately 5 min, which makes this method a rapid and
      promising technique for determination of total amount of volatile halogenated
      compounds. The proposed technique may prove useful as a screening test in order
      to pinpoint the samples that need further assessment by capillary gas
      chromatography.

PMID- 12489733
TI  - Pesticide residues in biological waste.
AB  - The aim of this study was to detect crop protection products (CPP) in single
      fractions of biological waste and to estimate pesticide concentrations in
      biological waste, depending on its composition. The composition of biological
      waste was determined from the literature, which provided information on its local
      and seasonal variability. The residue analysis included 17 pesticides for the
      analysis of tropical fruit peels and 48 pesticides for other fractions, e.g.
      vegetables, other fruits and ornamental flowers. The freeze-dried samples were
      extracted ultrasonically and purified by means of gel permeation chromatography.
      The analysis was carried out using gas chromatography with a mass selective
      detector in the selected ion monitoring mode. All tropical fruit peels contained
      CPP-residues. Thiabendazole was the most important contaminant with respect to
      the concentration and frequency of occurrence. The vegetables, other fruits and
      flowers also contained CPP-residues, such as the fungicides captan and dodemorph
      and the insecticide endosulfan. Based on import data and the composition of
      biological waste, the CPP-content of biological waste was estimated for rural and
      urban areas in summer and winter. Due to the higher percentage of tropical fruit
      peels, thiabendazole was the main contaminant in winter. The total concentration
      of CPP, summed up over all substances, ranged between 828 and 1829 microg(kg ww)(
      1).

PMID- 12489734
TI  - Distribution coefficients (Kd) and desorption rates of 137Cs and 241Am in Black
      Sea sediments.
AB  - The distribution coefficients (Kd) and desorption rates of 137Cs and 241Am
      radionuclides in bottom sediments at different locations in the Black Sea were
      studied under laboratory conditions. The Kd values were found to be 500 for 137Cs
      and 3800 for 241Am at the steady state and described exponential curves. Rapid
      uptake of the radionuclides occurred during the initial period and little
      accumulation happened after four days. The desorption rates for 137Cs in
      different bottom sediments were best described by a three-component exponential
      model. The desorption half-times of 137Cs ranged from 26 to 50 d at the slow
      components. However, the desorption rate of 241Am described one component for all
      sediment samples and desorption half-time was found to be 75 d. In general, the
      results showed that the 241Am radionuclide is more effectively transferred to
      bottom sediment and has longer turnover time than 137Cs under Black Sea
      conditions.

PMID- 12489735
TI  - Abiotic behavior of entrapped petroleum products in the subsurface during
      leaching.
AB  - Petroleum products are generally volatile hydrocarbon mixtures. These mixtures
      may contaminate land surfaces, the unsaturated zone and ground waters at numerous
      sites and thus represent a long-term source of environmental subsurface
      pollution. Based on laboratory and field evidence obtained by our research groups
      and others we emphasize in the present review paper the effect of leaching on the
      abiotic processes controlling the fate of volatile petroleum hydrocarbon mixtures
      (VPHMs) in the soil environment. The modification of petroleum hydrocarbon
      mixtures due to changes in the soil water content is considered the result of a
      "leaching phenomenon". The experimental evidence of VPHM behavior in the porous
      media is linked to four major processes: retention, redistribution and
      attenuation in the subsurface, and dissolution in the soil water. Once VPHMs
      reach the soil surface, their residual concentration and composition is
      influenced by the amount and quality of the leaching water. The transport and
      natural attenuation of the VPHMs in the unsaturated zone is affected by the
      amount and rate of leaching. Since VPHM are a mixture of volatile and non
      volatile hydrocarbons whose components differ by several orders of magnitude in
      their vapor pressure and water solubility, their fates in the soil environment
      under leaching will be diverse too. This will influence the temporal
      concentrations of the VPHM components and their distributions with depth, as
      vapors, solutes, or water-immiscible solutions. Wetting the soil before or after
      the VPHMs reach it, differentially affects the abiotic processes governing
      petroleum products behavior into the porous media.

PMID- 12489736
TI  - Nitrogen trace gas emissions from a riparian ecosystem in southern Appalachia.
AB  - In this paper, we present two years of seasonal nitric oxide (NO), ammonia (NH3),
      and nitrous oxide (N2O) trace gas fluxes measured in a recovering riparian zone
      with cattle excluded and adjacent riparian zone grazed by cattle. In the
      recovering riparian zone, average NO, NH3, and N2O fluxes were 5.8, 2.0, and 76.7
      ng N m(-2) S(-1) (1.83, 0.63, and 24.19 kg N ha(-1) y(-1)), respectively. Fluxes
      in the grazed riparian zone were larger, especially for NO and NH3, measuring
      9.1, 4.3, and 77.6 ng N m(-2) S(-1) (2.87, 1.35, and 24.50 kg N ha(-1) y(-1)) for
      NO, NH3, and N2O, respectively. On average, N2O accounted for greater than 85% of
      total trace gas flux in both the recovering and grazed riparian zones, though N2O
      fluxes were highly variable temporally. In the recovering riparian zone,
      variability in seasonal average fluxes was explained by variability in soil
      nitrogen (N) concentrations. Nitric oxide flux was positively correlated with
      soil ammonium (NH4+) concentration, while N2O flux was positively correlated with
      soil nitrate (NO3-) concentration. Ammonia flux was positively correlated with
      the ratio of NH4+ to NO3-. In the grazed riparian zone, average NH3 and N2O
      fluxes were not correlated with soil temperature, N concentrations, or moisture.
      This was likely due to high variability in soil microsite conditions related to
      cattle effects such as compaction and N input. Nitric oxide flux in the grazed
      riparian zone was positively correlated with soil temperature and NO3-
      concentration. Restoration appeared to significantly affect NO flux, which
      increased approximately 600% during the first year following restoration and
      decreased during the second year to levels encountered at the onset of
      restoration. By comparing the ratio of total trace gas flux to soil N
      concentration, we show that the restored riparian zone is likely more efficient
      than the grazed riparian zone at diverting upper-soil N from the receiving stream
      to the atmosphere. This is likely due to the recovery of microbiological
      communities following changes in soil physical characteristics.

PMID- 12489737
TI  - An experimental ecotoxicological study and its application to the behavioural
      study of organic mercury (CH3HgCl) in the environment: influence of temperature
      and pH.
AB  - Laboratory experiments were carried out to study the influence of temperature
      (24, 28 and 30 degrees C) and pH (1-10) on organic mercury (CH3HgCl) transfer and
      accumulation in an experimental ecotoxicological model. We followed the evolution
      of CH3HgCl in a basic model (water + air) by varying temperature and pH. In a
      second step, we completed the model by adding sediment and fish. We added CH3HgCI
      to water at the beginning of each experiment which was repeated at least three
      times. Results demonstrated that mercury was released from methylmercury into the
      air regardless of water pH and its concentration in the air increased with
      increasing pH. By contrast, in presence of sediment, almost all the mercury was
      fixed onto the sediment and no mercury was traced in air or in water.
      Interestingly, in the presence of sediment, the life span of fish under
      methylmercury exposure lasted longer despite their higher mercury body level
      content at their death. These results indicate that water is a bad exposure
      indicator for aquatic pollution. In case of chronic pollution, sediments, fish
      and aquatic plants are more appropriate indicators.

PMID- 12489738
TI  - What is your diagnosis? Testicular torsion.

PMID- 12489739
TI  - Rupture of the cranial pubic tendon in the cat.
AB  - Seven cats with rupture of the cranial pubic tendon (CPT) were presented to the
      authors between 1992 and 2001. The causal aetiology was unclear in each case.
      Diagnosis was made on physical examination (five animals) or surgical exploration
      (two animals). Concurrent injuries were present in four cats, including injury to
      the urinary tract and musculoskeletal system. All ruptures were surgically
      explored and primary repair of the CPT rupture was performed in five cats. Repair
      was not possible in two cats, and follow-up examination showed that scar tissue
      had apparently formed to support the deficit. All cats were asymptomatic at
      follow-up examination. The prognosis for CPT rupture in the cat is favourable.

PMID- 12489740
TI  - Evaluation of two point-of-care analysers for measurement of fructosamine or
      haemoglobin A1c in dogs.
AB  - Measurement of glycosylated proteins such as fructosamine and haemoglobin A1c
      (HbA1c) can be used to assess glycaemic control in canine diabetic patients. Two
      point-of-care analysers, designed for human diabetics, were evaluated for use in
      dogs. Blood samples were collected from 50 normoglycaemic dogs, 100 diabetic
      patients and five dogs with insulinoma and tested using the In Charge
      fructosamine meter and the Haemaquant/Glycosal HbA1c meter. Readings were
      obtained in all cases except for 21 of 50 diabetics, which were above the upper
      limit of the In Charge meter. Diabetic dogs had higher fructosamine and HbA1c
      concentrations compared to controls. However, there was poor agreement between
      the In Charge meter readings and serum fructosamine concentrations, suggesting
      that there are problems associated with the use of this device in dogs. HbA1c
      concentrations showed a high degree of correlation with glycosylated haemoglobin
      measured at an external laboratory, suggesting that the Haemaquant/Glycosal meter
      warrants further evaluation for veterinary use.

PMID- 12489741
TI  - Eosinophilic diseases in two Cavalier King Charles spaniels.
AB  - This report describes the clinical presentation of two Cavalier King Charles
      spaniels with different eosinophilic diseases. The first case presented with
      dyspnoea and a non-productive cough, and investigations demonstrated eosinophilic
      bronchopneumonopathy. The second dog was referred for the investigation of
      haemorrhagic vomiting and diarrhoea and was eventually diagnosed with
      eosinophilic enteritis. Both dogs had concurrent eosinophilic stomatitis, and
      both responded completely to immunosuppressive glucocorticoid therapy. This
      report is the first to describe the concurrence of eosinophilic stomatitis and
      systemic eosinophilic disease in Cavalier King Charles spaniels, and suggest that
      this breed may be predisposed to eosinophilic syndromes.

PMID- 12489742
TI  - Clinical and pathological findings of acute zinc intoxication in a puppy.
AB  - This report describes the clinical and pathological findings in a case of acute
      zinc poisoning in a young dog. The puppy suffered four days of progressively more
      severe vomiting and diarrhoea. Jaundice and pale mucous membranes, severe
      haematemesis and haemoglobinuria were other findings. Despite intensive therapy,
      the dog died a few hours after hospitalisation. Postmortem examination revealed a
      metallic foreign body in the stomach, catarrhal gastritis, hepatomegaly and
      enlarged, dark kidneys. Histology showed hepatic centrilobular vacuolar
      degeneration, haemoglobinuric nephrosis with early tubular necrosis,
      haemosiderosis and extramedullary haematopoiesis, as well as neuronal damage. The
      foreign body was mainly composed of zinc. Plasma zinc values were markedly raised
      (34.5 microg/ml; normal range 0.8 to 1.0 microg/ml). Pathophysiological
      mechanisms of zinc poisoning are discussed.

PMID- 12489743
TI  - Spontaneous pneumoperitoneum in two cats.
AB  - Spontaneous pneumoperitoneum is an infrequently observed presentation in cats.
      This report details two cases of pneumoperitoneum in the cat. The first case was
      suspected to have been caused by a gastric perforation secondary to gastric
      lymphoma. The second case was caused by a perforated gastric ulcer in a cat that
      had been recently treated with corticosteroids and a non-steroidal anti
      inflammatory drug.

PMID- 12489745
TI  - Sacrotuberal ligament transposition in the dog.

PMID- 12489744
TI  - Closure of large patent ductus arteriosus with a self-expanding duct occluder in
      two dogs.
AB  - Of the different catheterisation methods described for closure of patent ductus
      arteriosus (PDA), coil embolisation is most commonly used in dogs. However, for a
      PDA larger than 4 to 5 mm in diameter, coil implantation is difficult. For these
      cases, the Amplatzer duct occluder (ADO) offers an alternative method. This
      report describes the successful implantation of an ADO in two dogs with large
      PDAs of approximately 6 mm diameter. The self-expandible device attached to an
      implantation wire was advanced through a long sheath antegrade to the femoral
      vein through the right heart and pulmonary artery to the duct and delivered into
      the PDA. Thereafter the device was released by unscrewing it from the delivery
      cable. The large PDA in both dogs was totally occluded by these means without any
      residual shunt. Thus, the ADO is a controlled release implant that also allows
      occlusion of a large PDA. Its high costs limit its general use in veterinary
      medicine at the present time.

PMID- 12489746
TI  - BSAVA's position on electronic training devices for dogs and cats. British Small
      Animal Veterinary Association.

PMID- 12489747
TI  - Brushing up on dentistry.

PMID- 12489748
TI  - Keeping track of microchip adverse reactions.

PMID- 12489749
TI  - Welfare issues in surgical training.

PMID- 12489750
TI  - Cellular regulatory mechanisms influencing the activity of the cochlear nucleus:
      a review.
AB  - The cochlear nucleus is the site in the auditory pathway where the primary
      sensory information carried by the fibres of the acoustic nerve is transmitted to
      the second-order neurones. According to the generally accepted view this
      transmission is not a simple relay process but is considered as the first stage
      where the decoding of the auditory information begins. This notion is based on
      the diverse neurone composition and highly ordered structure of the nucleus, on
      the complex electrophysiological properties and activity patterns of the
      neurones, on the activity of local and descending modulatory mechanisms and on
      the presence of a highly sophisticated intracellular Ca2+ homeostasis. This
      review puts emphasis on introducing the experimental findings supporting the
      above statements and on the questions which should be answered in order to gain a
      better understanding of the function of the cochlear nucleus.

PMID- 12489751
TI  - New trends in studying structure and function of biological membranes.
AB  - Thirty years ago Singer and Nicolson constructed the "fluid mosaic model" of the
      membrane, which described the structural and functional characteristics of the
      plasma membrane of non-polarized cells like circulating blood lymphocytes as a
      fluid lipid phase accommodating proteins with a relatively free mobility. It is a
      rare phenomenon in biology that such a model could survive 30 years and even
      today it has a high degree of validity. However, in the light of new data it
      demands some modifications. In this minireview we present a new concept, which
      revives the SN model, by shifting the emphasis from fluidity to mosaicism, i.e.
      to lipid microdomains and rafts. A concise summary of data and key methods is
      given, proving the existence of non-random co-distribution patterns of different
      receptor kinds in the microdomain system of the plasma membrane. Furthermore we
      present evidence that proteins are not only accommodated by the lipid phase, but
      they are integral structural elements of it. Novel suggestions to the SN model
      help to develop a modernized version of the old paradigm in the light of new
      data.

PMID- 12489752
TI  - Renal nuclear angiotensin II receptors in normal and hypertensive rats.
AB  - Accumulation of Angiotensin II (Ang II) in the kidneys of hypertensive rats
      infused chronically with Ang II occurs by AT1 receptor mediated internalization
      of Ang II, which may interact with intracellular targets, including nuclear
      binding sites. The aims of this study were to determine if kidney cell nuclei
      have specific Ang II binding sites and if chronic infusion of Ang II (70 ng/min;
      n=9) influences the nuclear Ang II binding capacity. Kidneys were harvested from
      control and Ang II infused rats and the renal cortexes were homogenized to obtain
      crude membrane preparations and nuclear fractions. Ang II binding sites were
      measured with a single point assay by incubating each fraction with 10 nM 125I
      Sar-Ile-Ang II in the absence (total binding sites) or presence of either 2.5 M
      Sar-Leu-Ang II or 25 microM losartan to detect specific AT or AT1 binding sites.
      Both fractions exhibited specific Ang II binding sites that were displaced by
      both saralasin and losartan. In control rats, crude membrane preparations had 792
      +/- 218 and the nuclear fraction had 543 +/- 222 fmol/mg protein AT1 receptors.
      AT1 receptor levels in membrane (885 +/- 170 fmol/mg protein) and nuclear
      fractions (610 +/- 198 fmol/mg protein) were not significantly different in Ang
      II infused rats. These data support the presence of nuclear Ang II receptors
      predominantly of the AT1 subtype in renal cells. Chronic Ang II infusion did not
      alter overall Ang II receptor densities.

PMID- 12489753
TI  - The specificity of Ca2+ signalling.
AB  - A calcium signal is a sudden increase in concentration of calcium ions (Ca2+) in
      the cytosol. Such signals are crucial for the control of many important functions
      of the body. In the brain, for example, Ca2+ signals are responsible for memory,
      in muscle cells they switch on contraction, whereas in gland cells they are
      responsible for regulation of secretion. In many cases Ca2+ signals can control
      several different processes in the same cell. As an example, we shall deal with
      one particular cell type, namely the pancreatic acinar cell, which is responsible
      for the secretion of the enzymes essential for the digestion of food. In this
      cell, Ca2+ signals do not only control the normal enzyme secretion, but also
      regulate growth (cell division) and programmed cell death (apoptosis). Until
      recently, it was a mystery how the same type of signal could regulate such
      diverse functions in one and the same cell. 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.

PMID- 12489754
TI  - Evaluation of the involvement of nitric oxide and substance P in reducing
      baroreflex gain in the genetically hypertensive (GH) rat.
AB  - The attenuation of baroreflex gain associated with hereditary hypertension could
      involve abnormal signalling by nitric oxide or substance P. Baroreflex gain was
      measured in age-matched male genetically hypertensive (GH) and nonnotensive (N)
      anaesthetised rats from heart rate changes in response to i.v. phenylephrine or
      sodium nitroprusside. In subgroups of these animals, nitric oxide synthesis was
      inhibited using NG-nitro-L-arginine methyl ester (L-NAME, 30 mg x kg(-1) i.v.),
      substance P transmission was blocked using the antagonist SR 140333 (360 nmoles x
      kg(-1) i.v.) or substance P release was inhibited with resiniferatoxin (4 doses
      of 0.3 microg x kg(-1) i.v. at 4 min intervals). Baroreflex gain was markedly
      reduced in GH compared to N animals (N -0.37 +/- 0.04 beat x min(-1) x mm Hg(-1),
      GH -0.17 +/- 0.02 beat x min(-1) x mm Hg(-1), p < 0.0001). Inhibition of nitric
      oxide synthase increased baroreflex gain in each strain, but the inter-strain
      difference in gain persisted (post-treatment N -0.57 +/- 0.07 beat x min(-1) x mm
      Hg(-1), GH -0.24 +/- 0.05 beat x min(-1) x mm Hg(-1) (p < 0.001). Blockade of
      receptors or inhibition of substance P release did not affect gain in either
      strain. Nitric oxide, but not substance P, appears to play an inhibitory role in
      the rat arterial baroreflex. Impairment of baroreflex gain in GH rats is not
      secondary to altered nitric oxide signaling.

PMID- 12489755
TI  - Effect of single neonatal treatment with the soy bean phytosteroid, genistein on
      the sexual behavior of adult rats.
AB  - Hormonal imprinting develops during the perinatal critical period, when the
      target hormone meets the yet unmatured receptor. As a consequence of imprinting
      the receptor accomplishes its maturation reaching the binding capacity
      characteristic to adults. In this period in the presence of foreign molecules
      similar to the target hormone faulty imprinting may occur with life-long
      consequences. Soy bean contains phytosteroids which can mimic estrogen effects.
      In the present experiments single genistein (20 microg) or combined genistein +
      benzpyrene (20 microg) treatments were done neonatally and the sexual behavior of
      male and female adult animals was studied. Genistein significantly increased the
      lordosis quotient of females, which was compensated by neonatal benzpyrene
      treatment. Genistein also enhanced the sexual activity of males, and this was
      significantly not reduced by parallel benzpyrene treatment. The results show that
      neonatal genistein exposure can imprint sexual activity for life and the presence
      of a second imprinter can modify genistein's behavioral effect.

PMID- 12489756
TI  - Bone adaptation to load: microdamage as a stimulus for bone remodelling.
AB  - Mechanical loading in the proximal radius was increased by ulnar osteotomy (Group
      O), altered by Steinmann pinning (Group P) or unaltered in sham operated controls
      (Group C) in skeletally mature female sheep, aged 2-4 years. A series of
      intravenous fluorochromes were given to label bone formation and fuchsin-stained
      microdamage assessed at intervals of up to 24 weeks. Microcracks were present in
      all groups and were found in the original cortex near the periosteal surface. No
      microcracks were found in the new, fibrolamellar bone laid down at periosteal or
      endosteal surfaces. Mean microcrack length (49 microm, SD 10 microm) did not
      differ between groups or overtime. Microcrack numerical and surface densities and
      resorption cavity density peaked in all groups at 6 weeks, consistent with a
      regional acceleratory phenomenon (RAP), but the peaks were significantly greater
      in Group O. The density of refilling or secondary osteons peaked at 10 weeks and
      the mean time required for the formation of an osteon was 7.51 +/- 0.59 weeks.
      Fatigue-induced microdamage is normally present in bone and is increased due to
      repetitive loading of the mechanically overloaded radius. The location and timing
      of microcracks, resorption cavities and secondary osteons are consistent with the
      activation-resorption-formation remodelling cycle and suggest that microdamage is
      a stimulus for bone remodelling.

PMID- 12489757
TI  - Quantifying temporal bone morphology of great apes and humans: an approach using
      geometric morphometrics.
AB  - The hominid temporal bone offers a complex array of morphology that is linked to
      several different functional systems. Its frequent preservation in the fossil
      record gives the temporal bone added significance in the study of human
      evolution, but its morphology has proven difficult to quantify. In this study we
      use techniques of 3D geometric morphometrics to quantify differences among humans
      and great apes and discuss the results in a phylogenetic context. Twenty-three
      landmarks on the ectocranial surface of the temporal bone provide a high level of
      anatomical detail. Generalized Procrustes analysis (GPA) is used to register
      (adjust for position, orientation and scale) landmark data from 405 adults
      representing Homo, Pan, Gorilla and Pongo. Principal components analysis of
      residuals from the GPA shows that the major source of variation is between humans
      and apes. Human characteristics such as a coronally orientated petrous axis, a
      deep mandibular fossa, a projecting mastoid process, and reduced lateral
      extension of the tympanic element strongly impact the analysis. In phenetic
      cluster analyses, gorillas and orangutans group together with respect to
      chimpanzees, and all apes group together with respect to humans. Thus, the
      analysis contradicts depictions of African apes as a single morphotype. Gorillas
      and orangutans lack the extensive preglenoid surface of chimpanzees, and their
      mastoid processes are less medially inflected. These and other characters shared
      by gorillas and orangutans are probably primitive for the African hominid clade.

PMID- 12489758
TI  - Elastic fibre organization in the intervertebral discs of the bovine tail.
AB  - Elastic fibres have been revealed by both elastin immunostaining and conventional
      histological orcein-staining in the intervertebral discs of the bovine tail.
      These fibres are distributed in all regions of the disc but their organization
      varies from region to region. In the centre of the nucleus, long (> 150 microm)
      elastic fibres are orientated radially. In the transitional region between
      nucleus and annulus, the orientation of the elastic fibres changes, producing a
      criss-cross pattern. In the annulus itself, elastic fibres appear densely
      distributed in the region between the lamellae and also in 'bridges' across the
      lamellae, particularly in the adult. Elastic fibres are apparent within the
      lamellae, orientated parallel to the collagen fibres of each lamella,
      particularly in the young (12-day-old) discs. In the region between the disc and
      the cartilaginous endplate, elastic fibres appear to anchor into the plate and
      terminate there. The results of this study suggest that elastic fibres contribute
      to the mechanical functioning of the intervertebral disc. The varying
      organization of the elastic fibres in the different regions of the disc is likely
      to relate to the different regional loading patterns.

PMID- 12489759
TI  - Apoptosis in the cortex of the developing mouse kidney.
AB  - Published levels of apoptosis in developing rat kidney (approximately 2.5%) seem
      large for a tissue with no obvious need for continual cell death. This paper
      examines the levels and patterns of apoptosis and mitosis in the cortical region
      of the developing metanephros of the mouse, the standard mammalian model embryo.
      Using confocal microscopy on specimens stained with propidium iodide to highlight
      nuclear morphology, optical sections of wholemount kidneys to a depth of
      approximately 50 microm were analysed and mitotic, apoptotic and interphase
      nuclei counted in the various compartments. Of the approximately 200 000 cells
      examined over E11.5-16.5, 2-3% were mitotic, confirming observations based on
      cryosections; the mitotic index peaked at E14.5, dropping to approximately 0.5%
      by P14. The mean apoptotic index during this period was 0.28%; this figure from
      wholemounts was approximately 10% of that earlier reported in cryosectioned rat
      kidneys. One possible explanation for the difference is that cryosectioning turns
      out to create small nuclear fragments that can stain strongly with propidium.
      Such fragments are not seen in wholemounts and do not stain with TUNEL.
      Wholemount mouse E11.5 tails and E16.5 lungs were also analysed and both their
      mitotic and their apoptotic indexes were similar to those in wholemount
      developing kidneys. These results show that the level of apoptosis in wholemount
      embryonic mouse kidney cortex is far less than previously reported in
      cryosectioned rat embryonic kidneys, and typical of that in other mouse embryonic
      tissues whose development seems not to require apoptosis.

PMID- 12489760
TI  - Cerebellar connections to the rostral reticular nucleus of the thalamus in the
      rat.
AB  - We studied the cerebellar connections to the reticular nucleus thalamus (RNT) by
      means of retrograde axonal transport of horseradish peroxidase (HRP) in the rat.
      Specific HRP pressure injections to the rostral RNT (1.6-1.8 mm caudal to bregma)
      resulted in retrograde labelling of neurones in the cerebellar nuclei. The
      rostral RNT showed specific topographical organization of its cerebellar
      connections. Microinjections into the rostral RNT, 1.6 mm caudal to bregma,
      produced numerous HRP-labelled neurones within the anterior interposed
      (emboliform nucleus) and scarce HRP-labelled neurones within the lateral (dentate
      nucleus) cerebellar nuclei, whereas injections into the rostral RNT, 1.8 mm
      caudal to bregma, produced numerous HRP-labelled neurones within the posterior
      interposed (globose nucleus) and scarce lightly HRP-labelled neurones within the
      lateral (dentate nucleus) cerebellar nuclei. Cerebellar connections with the
      rostral RNT were exclusively ipsilateral to the injection site. No HRP-labelled
      cells were detected in the medial (fastigial nucleus) cerebellar nucleus. The
      cerebellar connections reach the RNT via the superior cerebellar peduncle. By
      contrast, HRP injections into the anterior, posterior interposed and lateral
      cerebellar nuclei produced no labelled cells within the RNT. This study
      demonstrates the existence of direct cerebello-RNT but not RNT-cerebellar
      connections. The presence of the cerebello-RNT connections introduces a new route
      through which the cerebellum may influence RNT and thus cerebral cortical
      activity.

PMID- 12489761
TI  - An anatomical and electrophysiological study of the genitofemoral nerve and some
      of its targets in the male rat.
AB  - Anatomical descriptions of the genitofemoral nerve (GFn) innervating the lower
      pelvic area are contradictory. Here we re-examine its origin and innervation by
      its various branches of principal target organs in the male rat. Using gross
      dissection, electrophysiological techniques and retrograde tracing of
      motoneurones with horseradish peroxidase, we confirm that the GFn originates from
      lumbar spinal nerves 1 and 2, and that at the level of the common iliac artery it
      divides into a lateral femoral and a medial genital branch. In contrast to
      previous studies, we report that the genital and not the femoral branch
      innervates the abdominal-inguinal skin, and not only the genital but also the
      femoral branch innervates the cremaster muscle (Cm) surrounding the testes.
      Motoneurones innervating the Cm proper are located in the ventral nucleus of L1
      and L2, and those innervating the muscular transition region of the rostral Cm
      are located in the ventral nucleus in L1 and the ventrolateral nucleus in L2. The
      GFn may contribute to male reproductive performance by transmitting cutaneous
      information during copulation and, via contraction of the Cm to promote
      ejaculation, the protective displacement of the testes into the abdominal cavity
      during fighting and as a sperm-protecting thermoregulatory measure.

PMID- 12489762
TI  - Recombinant human alpha-2a interferon promotes an atypical process of mast cell
      secretion with ultrastructural features suggestive for piecemeal degranulation.
AB  - Purified mast cells (MC), isolated from the rat peritoneum, were stimulated in
      vitro with recombinant human IFN-alpha 2a (rhIFN-alpha 2a) and studied
      ultrastructurally. Quantitative determination of histamine release was also
      performed. The following ultrastructural features were observed: (1) dilation of
      single granules, leading to the formation of cytoplasmic cavities filled with
      dissolved or eroded matrices; (2) induction of partially empty, nonfused granule
      containers close to unaltered resting granules, a process very suggestive of
      piecemeal degranulation; (3) focal exocytosis, characterized by opening of single
      granules to the cell exterior and/or fusion of a few granules into small
      secretory channels. Histamine release was slightly increased in rhIFN-alpha 2a
      treated MC, although not to significant levels. These results indicate that rhIFN
      alpha 2a induces a characteristic pattern of degranulation in rat peritoneal MC
      and that a small proportion of rhIFN-alpha 2a-stimulated MC shows ultrastructural
      features suggestive for piecemeal degranulation.

PMID- 12489763
TI  - Coracoclavicular joint: osteologic study of 1020 human clavicles.
AB  - We examined 1020 dry clavicles from cadavers of Italian origin to determine the
      prevalence of the coracoclavicular joint (ccj), a diarthrotic synovial joint
      occasionally present between the conoid tubercle of the clavicle and the superior
      surface of the horizontal part of the coracoid process. Five hundred and nine
      clavicles from individuals of different ages were submitted to X-ray examination.
      Using radiography, we measured the entire length and the index of sinuosity of
      the anterior lateral curve, on which the distance between the conoid tubercle and
      the coracoid process depends. We also used radiography to record the differences
      in prevalence of arthritis in two neighbouring joints, the acromioclavicular and
      sternoclavicular joints. Of the 1020 clavicles, eight (0.8%) displayed the
      articular facet of the ccj. No statistical correlation was found between
      clavicular length and the index of sinuosity of the anterior lateral curve. The
      prevalence of arthritis in clavicles with ccj was higher than that revealed in
      clavicles without ccj. The prevalence of ccj in the studied clavicles is lower
      than that observed in Asian cohorts. Furthermore, ccj is not conditioned by
      either length or sinuosity of the anterior lateral curve of the clavicle.
      Finally, the assumption that ccj is a predisposing factor for degenerative
      changes of neighbouring joints is statistically justified.

PMID- 12489764
TI  - Laminar bone as an adaptation to torsional loads in flapping flight.
AB  - Using a new histometric method, the orientation of primary osteons was measured
      in the main long bones of adult mallards (Anas platyrhynchos). In the light of
      previous biomechanical and ontogenetic studies, a functional hypothesis is
      proposed, explaining the histological differences observed between long bones;
      laminar bone tissue, mainly found in the wing bones, may be a biomechanical
      adaptation to torsional loads caused by flapping flight.

PMID- 12489765
TI  - Where art, optics, and vision intersect.

PMID- 12489766
TI  - How do the internal details of the object contribute to recognition?
AB  - Object recognition becomes difficult when the main axis of the object is
      foreshortened. It has previously been reported that this so-called foreshortened
      disadvantage is larger when the silhouette of the object is presented than when
      the line drawing of the object is presented. The pronounced foreshortened
      disadvantage in silhouette recognition indicates that the internal details of the
      object, which are absent in the silhouette, provide useful information,
      particularly when the main axis is foreshortened. But the role of these internal
      details remains controversial. One account for the pronounced disadvantage is
      that the internal details contribute to the derivation of the main axis. The
      other account is that internal details provide the distinctive features that are
      directly matched to the object represented in memory. The aim in the present
      study was to determine which of these two explanations best accounts for the
      differential foreshortened disadvantage between line drawings and silhouettes. To
      reduce the uncertainty regarding the axis orientation, a 3-D arrow indicating the
      orientation of the main axis was presented as a cue before the object itself was
      presented. As a result, the difference in the foreshortened disadvantage between
      silhouettes and line drawings disappeared. This indicated that the pronounced
      foreshortened disadvantage for silhouettes was caused by a lack of axis
      information. In other words, the internal details provided the information
      necessary for axis derivation when the axis was foreshortened.

PMID- 12489767
TI  - Effects of occlusion on pigeons' visual object recognition.
AB  - Casual observation suggests that pigeons and other animals can recognize occluded
      objects; yet laboratory research has thus far failed to show that pigeons can do
      so. In a series of experiments, we investigated pigeons' ability to 'name'
      shaded, textured stimuli by associating each with a different response. After
      first learning to recognize four unoccluded objects, pigeons had to recognize the
      objects when they were partially occluded by another surface or when they were
      placed on top of another surface; in each case, recognition was weak. Following
      training with the unoccluded stimuli and with the stimuli placed on top of the
      occluder, pigeons' recognition of occluded objects dramatically improved.
      Pigeons' improved recognition of occluded objects was not limited to the trained
      objects but transferred to novel objects as well. Evidently, the recognition of
      occluded objects requires pigeons to learn to discriminate the object from the
      occluder; once this discrimination is mastered, occluded objects can be better
      recognized.

PMID- 12489768
TI  - The eyes have it: a perceptual investigation of eyespots.
AB  - Previous work with non-human species has shown that eyespots function as sign
      stimuli for defensive behaviour. But it is unknown to what extent eyespots are a
      dominant feature of objects for human perceptual responses. We examined whether
      young children perceive eyespots as a dominant object feature. One hundred and
      nineteen children from the first, second, and third grades were presented with
      small manikins, called "Joopes" that varied in the number, type, and arrangement
      of facial features. Four kinds of Joope heads were used: single element (eyes,
      mouth, or beak only), monovalent (spatially concordant eyes and mouth, or eyes
      and beak), ambivalent (asymmetrical eyes and beak, or eyes and mouth), and
      cyclopean (single eye with orthogonal beak). Two task groups (Peepers and Gobs)
      'helped' the Joopes to either 'see' their food or 'eat' it, by placing food in
      one of 24 feeding dishes. Results indicated that responses made to the ambivalent
      Joopes differed, with greater 'drift' shown by the 'eating' group towards the
      'seeing' responses than by the 'seeing' group towards the 'eating' responses. The
      dominant role of eyespots was thus confirmed for children in the second and third
      grades, but response inconsistencies in the youngest group suggested difficulties
      in handling incongruent stimuli. The implications of these results for
      understanding basic perceptual processes are discussed.

PMID- 12489769
TI  - Vertical disparity can alter perceived direction.
AB  - It has been well established that vertical disparity is involved in perception of
      the three-dimensional layout of a visual scene. The goal of this paper was to
      examine whether vertical disparities can alter perceived direction. We
      dissociated the common relationship between vertical disparity and the stimulus
      direction by applying a vertical magnification to the image presented to one eye.
      We used a staircase paradigm to measure whether perceived straight-ahead depended
      on the amount of vertical magnification in the stimulus. Subjects judged whether
      a test dot was flashed to either the left or the right side of straight-ahead. We
      found that perceived straight-ahead did indeed depend on the amount of vertical
      magnification but only after subjects adapted (for 5 min) to vertical scale (and
      only in five out of nine subjects). We argue that vertical disparity is a factor
      in the calibration of the relationship between eye-position signals and perceived
      direction.

PMID- 12489770
TI  - Feature integration across parts in visual search.
AB  - In the present study, participants searched for a conjunction of color and
      orientation either from the same part of an object (same-part display), or from
      different parts of an object (different-part display). While no difference was
      found between the two display conditions in single feature searches, conjunction
      search in the same-part display was significantly faster than that in the
      different-part display. This same-part advantage applies to both the inner part
      as well as the outer part of an object. These results suggest that features are
      more readily integrated if they are from the same part of an object than if they
      are from different parts of an object. The formation of object part
      representations thus influences how features are integrated and encoded during
      visual information processing.

PMID- 12489771
TI  - Is the acquisition of basic-colour terms in young children constrained?
AB  - We investigated whether the learning of colour terms in childhood is constrained
      by a developmental order of acquisition as predicted by Berlin and Kay [1969
      Basic Color Terms (Berkeley, CA: University of California Press)]. Forty-three
      children, aged between 2 and 5 years and grouped according to language ability,
      were given two tasks testing colour conceptualisation. Colour comprehension was
      assessed in a spoken-word-to-colour-matching task in which a target colour was
      presented in conjunction with two distractor colours. Colour naming was measured
      in an explicit naming task in which colours were presented individually for oral
      naming. Results showed that children's knowledge of basic-colour terms varied
      across tasks and language age, providing little support for a systematic
      developmental order. In addition, we found only limited support for an advantage
      for the conceptualisation of primary (red, green, blue, yellow, black, white)
      compared to non-primary colour terms across tasks and language age. Instead, our
      data suggest that children acquire reliable knowledge of nine basic colours
      within a 3-month period (35.6 to 39.5 months) after which there is a considerable
      lag of up to 9 months before accurate knowledge of the final two colours (brown
      and grey) is acquired. We propose that children acquire colour term knowledge in
      two distinct time frames that reflect the establishment of, first, the exterior
      (yellow, blue, black, green, white, pink, orange, red, and purple) and, second,
      the interior structure (brown and grey) of conceptual colour space. These results
      fail to provide significant support for the order predicted by Berlin and Kay,
      and suggest, instead, that the development of colour term knowledge is largely
      unconstrained.

PMID- 12489772
TI  - The color of two alphabets for a multilingual synesthete.
AB  - Interviews with a multilingual synesthete (MLS), who experiences colored letters
      for Roman and Cyrillic alphabets and for digits, revealed stable synesthetic
      experiences over 2 1/2 - 5 years. Colors of Cyrillic letters were based on Roman
      letters. Four Stroop tests involving both types of letters showed that MLS was
      able to name print color faster if the colors matched her synesthetic colors,
      showing that synesthesia is automatic. Letter-naming times for blocks of color
      were slower than those of actual letters, supporting unidirectionality of
      synesthesia. Stroop tests with Roman, but not Cyrillic, letters showed MLS
      acquired new temporary letter-color pairings and her color-naming times for these
      were not different from those for her original synesthetic colors.

PMID- 12489773
TI  - A comparison of the effects of differences in temporal gating and ear of
      presentation on profile discrimination.
AB  - The aim of the study was to examine the effects of differences in temporal gating
      and ear of presentation (both separately and in combination) on listeners'
      ability to detect an increment in the level of a 1 kHz component (the target)
      relative to that of four spectrally flanking components. The flanking components
      were always presented to the listeners' right ear, while the target component was
      either presented to the same ear (monaural presentation) or to the left ear
      (dichotic presentation). Similarly, the target and flanking components were
      either gated on and off at the same time (synchronous presentation), or else the
      target component began 100 ms before and terminated 100 ms after the four
      flanking components (asynchronous presentation). On average, thresholds were
      lowest in the synchronous, monaural condition, and highest in the two
      asynchronous conditions. Ear differences alone did result in elevated thresholds
      for most listeners. However, combining differences in gating and ear of
      presentation produced thresholds that were indistinguishable from those obtained
      when gating differences alone were employed. These results are consistent with
      the suggestion that differences in temporal gating lead to more complete
      segregation of concurrent frequency components than differences in spatial
      location.

PMID- 12489774
TI  - A rare glimpse of the eye in motion.

PMID- 12489776
TI  - Diversity of endophytic fungi in the roots of mangrove species on the west coast
      of India.
AB  - Because mangrove plant species are a valuable source of useful metabolites, their
      endophytes have gained more importance. Randomly sampled surface-sterilized whole
      root segments of four mangrove plant species, Acanthus ilicifolius, Avicennia
      officinalis, Rhizophora mucronata, and Sonneratia caseolaris from the mangroves
      of Udyavara (Karnataka) on the west coast of India, were characterized for fungal
      communities by direct plating, damp chamber, and bubbling chamber incubation
      methods. The richness of endophytic fungal species from whole root segments after
      direct plating and damp chamber incubation was greatest for R. mucronata than for
      other plants (18 vs. 8-13). Incubation of whole root segments in bubbling
      chambers yielded conidia of two freshwater hyphomycetes: Mycocentrospora acerina
      (in Avicennia officinalis) and Triscelophorus acuminatus (in R. mucronata and in
      S. caseolaris). Surface-sterilized whole root and root bark segments of R.
      mucronata sampled from the mid-tide level on direct plating yielded more fungi
      than that of the root segments sampled from low-tide and high-tide levels. The
      greatest number of isolates, species richness, and diversity of fungi were shown
      by the whole root segments of R. mucronata from the mid-tide level. Rarefaction
      indices also revealed the highest expected number of species out of 150 random
      isolations from the mid-tide level samples of whole root and root bark segments
      of R. mucronata. The present study showed that fungi in mangrove roots are
      composed of a consortium of soil, marine, and freshwater fungi.

PMID- 12489775
TI  - Lignin degrading system of white-rot fungi and its exploitation for dye
      decolorization.
AB  - With global attention and research now focused on looking for the abatement of
      pollution, white-rot fungi is one of the hopes of the future. The lignin
      degrading ability of these fungi have been the focus of attention for many years
      and have been exploited for a wide array of human benefits. This review
      highlights the various enzymes produced by white-rot fungi for lignin
      degradation, namely laccases, peroxidases, aryl alcohol oxidase, glyoxal oxidase,
      and pyranose oxidase. Also discussed are the various radicals and low molecular
      weight compounds that are being produced by white-rot fungi and its role in
      lignin degradation. A brief summary on the developments in research of
      decolorization of dyes using white-rot fungi has been made.

PMID- 12489777
TI  - Ultrastructure and properties of Paecilomyces lilacinus spores.
AB  - Strains of the filamentous soil fungus Paecilomyces lilacinus are currently being
      developed for use as biological control agents against root-knot, cyst, and other
      plant-parasitic nematodes. The inoculum applied in the field consists mainly of
      spores. This study was undertaken to examine the size, ultrastructure, and rodlet
      layers of P. lilacinus spores and the effect of the culture method on structural
      and functional spore properties. A rodlet layer was identified on aerial spores
      only. Other differences noted between aerial spores and those produced in
      submerged culture included the size and appearance of spores and thickness of
      spore coat layers when examined with transmission electron microscopy. The two
      spore types differed in UV tolerance, with aerial spores being less sensitive to
      environmentally relevant UV radiation. Also, viability after drying and storage
      was better with the aerial spores. Both spore types exhibited similar
      nematophagous ability.

PMID- 12489778
TI  - Effect of a combination therapy between IL-12 and soluble IL-4 receptor (sIL-4R)
      on Candida albicans and herpes simplex virus type I infections in thermally
      injured mice.
AB  - The effectiveness of a combination using IL-12 and soluble IL-4 receptor (sIL-4R)
      to treat severe infections of herpes simplex virus type 1 (HSV-1) and Candida
      albicans in thermally injured mice was investigated. Although sIL-4R decreased
      burn-associated type 2 T-cell responses, the effect of sIL-4R was minimal on the
      morbidity and mortality of thermally injured mice exposed to 250 times LD50 of
      HSV-1 or 10 times LD50 of C. albicans. Compared with 100% mortality in control
      mice, mortality for HSV-1 and C. albicans was 40 and 20%, respectively, in
      thermally injured mice that received IL-12 and sIL-4R in combination. After
      stimulation with anti-CD3 monoclonal antibody, splenic T cells from thermally
      injured mice exposed to large amounts of HSV-1 or C. albicans did not produce
      gamma interferon (IFN-gamma) into their culture fluids. However, IFN-gamma was
      produced by splenic T cells from thermally injured and infected mice treated with
      IL-12 and sIL-4R in combination. These results suggest that therapeutic treatment
      with a combination of IL-12 and sIL-4R may be effective by inducing type 1 T-cell
      responses in thermally injured mice exposed to large amounts of HSV-1 or C.
      albicans.

PMID- 12489779
TI  - The aerobic electron transport system of Eikenella corrodens.
AB  - The respiratory system of the fastidious beta-proteobacterium Eikenella corrodens
      grown with limited oxygen was studied. Membranes showed the highest oxidase
      activity with ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) or
      succinate and the lowest activity with NADH and formate. The presence of a bc1
      type complex was suggested by the inhibition exerted by 2-heptyl-4
      hydroxyquinoline-N-oxide (HOQNO), myxothiazol, and antimycin A on respiration
      with succinate and by the effect of the latter two inhibitors on the succinate
      reduced difference spectra. Respiration with succinate or ascorbate-TMPD was
      abolished by low KCN concentrations, suggesting the presence of a KCN-sensitive
      terminal oxidase. Cytochromes b and c were spectroscopically detected after
      reduction with physiological or artificial electron donors, whereas type a and d
      cytochromes were not detected. The CO difference spectrum of membranes reduced by
      dithionite and its photodissociation spectrum (77 K) suggested the presence of a
      single CO compound that had the spectral features of a cytochrome o-like pigment.
      High-pressure liquid chromatography analysis of membrane haems confirmed the
      presence of haem B; in contrast, haems A and O were not detected. Peroxidase
      staining of membrane type c cytochromes using SDS-PAGE revealed the presence of
      five bands with apparent molecular masses of 44, 33, 30, 26, and 14 kDa. Based on
      our results, a tentative scheme of the respiratory chain in E. corrodens,
      comprising (i) dehydrogenases for succinate, NADH, and formate, (ii) a
      ubiquinone, (iii) a cytochrome bc1, and (iv) a type-cbb' cytochrome c oxidase, is
      proposed.

PMID- 12489780
TI  - Phylogenetic study and identification of human pathogenic Vibrio species based on
      partial hsp60 gene sequences.
AB  - The use of hsp60 gene sequences for phylogenetic study and identification of
      pathogenic marine vibrios was investigated. A 600-bp partial hsp60 gene was
      amplified by PCR and sequenced from 29 strains representing 15 Vibrio species
      within the family Vibrionaceae. Sequence comparison of the amplified partial
      hsp60 gene revealed 71-82% sequence identity among different Vibrio species and
      96-100% sequence identity among epidemiologically distinct strains with the same
      species designation. This degree of discrimination allows unambiguous
      differentiation of all Vibrio species included in the current study from each
      other, as well as from Aeromonas hydrophila and Plesiomonas shigelloides, which
      are often misidentified as Vibrio species by conventional biochemical methods.
      Based on the hsp60 gene sequences, two previously unidentified shrimp isolates
      were found to be more closely related to Vibrio alginolyticus (93-94% sequence
      identity) than to Vibrio parahaemolyticus (89% sequence identity), whereas 16S
      rRNA gene analysis was unable to differentiate among these closely related
      species (95-97% sequence identity). Our results indicate that the hsp60 gene may
      be a useful alternative target for phylogenetic analysis and species
      identification of marine Vibrios to complement more conventional identification
      systems.

PMID- 12489781
TI  - Lotus corniculatus condensed tannins decrease in vivo populations of proteolytic
      bacteria and affect nitrogen metabolism in the rumen of sheep.
AB  - Condensed tannins in forage legumes improve the nutrition of sheep by reducing
      ruminal degradation of plant protein and increasing crude protein flow to the
      intestine. However, the effects of condensed tannins in forage legumes on rumen
      bacterial populations in vivo are poorly understood. The aim of this study was to
      investigate the specific effects of condensed tannins from Lotus corniculatus on
      four proteolytic rumen bacteria in sheep during and after transition from a
      ryegrass (Lolium perenne)-white clover (Trifolium repens) diet (i.e., low
      condensed tannins) to a Lotus corniculatus diet (i.e., higher condensed tannins).
      The bacterial populations were quantified using a competitive polymerase chain
      reaction. Lotus corniculatus was fed with or without ruminal infusions of
      polyethylene glycol (PEG), which binds to and inactivates condensed tannins,
      enabling the effect of condensed tannins on bacterial populations to be examined.
      When sheep fed on ryegrass-white clover, populations of Clostridium
      proteoclasticum B316T, Butyrivibrio fibrisolvens C211a, Eubacterium sp. C12b, and
      Streptococcus bovis B315 were 1.5 x 10(8), 1.1 x 10(6), 4.6 x 10(8), and 7.1 x
      10(6) mL(-1), respectively. When the diet was changed to Lotus corniculatus, the
      average populations (after 8-120 h) of C. proteoclasticum, B. fibrisolvens,
      Eubacterium sp., and S. bovis decreased (P < 0.001) to 2.4 x 10(7), 1.1 x 10(5),
      1.1 x 10(8), and 2.5 x 10(5) mL(-1), respectively. When PEG was infused into the
      rumen of sheep fed Lotus corniculatus, the populations of C. proteoclasticum, B.
      fibrisolvens, Eubacterium sp., and S. bovis were higher (P < 0.01-0.001) than in
      sheep fed Lotus corniculatus without the PEG infusion, with average populations
      (after 8-120 h) of 4.9 x 10(7), 3.8 x 10(5), 1.9 x 10(8), and 1.0 x 10(6),
      respectively. Sheep fed the Lotus corniculatus diet had lower rumen proteinase
      activity, ammonia, and soluble nitrogen (P < 0.05-0.001) than sheep that were fed
      Lotus corniculatus plus PEG. The Lotus corniculatus diet reduced rumen nitrogen
      digestibility (P < 0.05) and ammonia pool size and increased the flow of
      undegraded feed nitrogen to the abomasum. The nitrogen intake, rumen non-ammonia
      nitrogen pool size, rumen microbial non-ammonia nitrogen pool size, and abomasal
      microbial non-ammonia nitrogen fluxes were similar both in sheep fed only Lotus
      corniculatus and in sheep fed Lotus corniculatus plus PEG, but nonmicrobial non
      ammonia nitrogen flux to the abomasum was higher (P < 0.01) for the sheep fed
      only Lotus corniculatus. Although condensed tannins in Lotus corniculatus reduced
      the populations of some proteolytic bacteria, total ruminal microbial protein and
      microbial protein outflow to the abomasum were unchanged, suggesting a species
      specific effect of condensed tannins on bacteria in the rumen.

PMID- 12489782
TI  - The glcB locus of Rhizobium leguminosarum VF39 encodes an arabinose-inducible
      malate synthase.
AB  - In the course of a study conducted to isolate genes upregulated by plant cell
      wall sugars, we identified an arabinose-inducible locus from a transcriptional
      fusion library of Rhizobium leguminosarum VF39, carrying random insertions of the
      lacZ transposon Tn5B22. Sequence analysis of the locus disrupted by the
      transposon revealed a high similarity to uncharacterized malate synthase G genes
      from Sinorhizobium meliloti, Agrobacterium tumefaciens, and Mesorhizobium loti.
      This enzyme catalyzes the condensation of glyoxylate and acetyl-CoA to yield
      malate and CoA and is thought to be a component of the glyoxylate cycle, which
      allows microorganisms to grow on two carbon compounds. Enzyme assays showed that
      a functional malate synthase is encoded in the glcB gene of R. leguminosarum and
      that its expression is induced by arabinose, glycolate, and glyoxylate. An
      Escherichia coli aceB glcB mutant, complemented with the R. leguminosarum PCR
      amplified gene, recovered malate synthase activity. A very similar genome
      organization of the loci containing malate synthase and flanking genes was
      observed in R. leguminosarum, S. meliloti, and A. tumefaciens. Pea plants
      inoculated with the glcB mutant or the wild-type strain showed no significant
      differences in nitrogen fixation. This is the first report regarding the
      characterization of a mutant in one of the glyoxylate cycle enzymes in the
      rhizobia.

PMID- 12489783
TI  - Biochemical evidence against protein-mediated uptake of myristic acid in the
      bioluminescent marine bacterium Vibrio harveyi.
AB  - The bioluminescent marine bacterium, Vibrio harveyi, can utilize exogenous
      myristic acid (14:0) for beta-oxidation, phospholipid and lipid A synthesis, and
      as an source of myristyl aldehyde for light emission in the V. harveyi dark
      mutant M17. A variety of genetic and biochemical strategies were employed in an
      attempt to isolate V. harveyi mutants defective in myristate uptake and to
      characterize proteins involved in this process. Although [3H]myristate uptake in
      a tritium suicide experiment decreased the survival of nitrosoguanidine-treated
      M17 cells by a factor of 10(5), none of the surviving cells characterized were
      defective in either incorporation of exogenous myristate into phospholipid or
      stimulation of light emission. These parameters were also unaffected when intact
      M17 cells were treated with proteases. Moreover, M17 double mutants selected on
      the basis of diminished luminescence response to myristate all incorporated
      [3H]myristate into lipids normally. Finally, no resistant colonies were obtained
      using the bacteriocidal fatty acid analogue, 11-bromoundecanoate, and experiments
      with decanoate (10:0) indicated that the V. harveyi cell envelope is very
      sensitive to physical disruption by fatty acids. Taken together, these results
      support an unfacilitated uptake of myristic acid in V. harveyi, in contrast with
      the regulated vectorial transport and activation of long chain fatty acids in
      Escherichia coli.

PMID- 12489784
TI  - Effective dose of a microbial inoculant is one to four cells in the rhizosphere.
AB  - A single-cell approach for studying the growth potential and the establishment of
      bacteria in the barley phytosphere is presented, using Pseudomonas fluorescens
      strain with the capability for biological control. The incidence of growth of one
      to four bacterial cells dispersed to the young rhizosphere approximated to 100%,
      and specific growth rate averaged 0.05. Net growth occurred for cells added to
      the rhizosphere at densities between 1 and 100,000 cells, while at higher
      densities population sizes declined, but always approached 10(5)-10(6) cells per
      rhizosphere. No net growth was observed in bulk soil, and cells died in the
      phyllosphere. Our results showed that bacterial establishment was more related to
      the availability of microhabitats supporting growth, than related to the number
      of bacteria released.

PMID- 12489785
TI  - Structure of the mammalian kinin receptor gene locus.
AB  - The genes encoding the two kinin receptors, B1 and B2, are closely linked on the
      same chromosome in human, mouse, and rat. In this article, we present the
      organisation of the B B2 locus in these mammals. This organisation was obtained
      by comparing the kinin receptor mRNA sequences of man and mouse with the sequence
      of chromosomes 14 and 12, respectively. We found that the two genes are located
      in tandem orientation, separated by only 7.8 kb in mice and 12 kb in humans. The
      distance of the two genes on rat chromosome 6 was determined by long-range PCR to
      be 9.5 kb. The organisation of the two genes encoding the kinin receptors is
      similar in the three species, except that the human B1 gene harbors an additional
      exon, which may originate from the insertion of an Alu repetitive sequence during
      evolution. Moreover, the human and rat, but not the murine, B2 genes carry an
      alternatively spliced exon between exons 2 and 3, termed exon 2b.

PMID- 12489786
TI  - Kinin receptors: functional aspects.
AB  - Two types of receptors (B1R, B2R) for kinins are defined in mammalian species.
      Comparative experiments involving recombinant fusion proteins consisting of
      rabbit B1R or B2R fused to GFP-related proteins are exploited to study the
      regulation of the response to kinins at the receptor level. The following points
      will be briefly reviewed and supported by some novel data. (1) The constitutive
      B2Rs are internalized upon agonist stimulation, but completely recycled to the
      cell surface; however, B2R destruction can be achieved following limited
      proteolysis (extracellular trypsin, neutrophil proteases), a plausible down
      regulation mechanism in pathology. (2) The inducible B1Rs, stimulated by des-Arg9
      kinins, are not phosphorylated nor internalized upon agonist stimulation, but
      rather undergo a reversible redistribution to caveolae-related rafts. B2Rs are
      also subjected to this translocation, but only transiently (before endocytosis).
      (3) Based on the analysis of rabbit aortic smooth muscle cells, B1R induction by
      cytokines is dependent on nuclear factor KB in rabbit vascular tissue, but
      exogenous kinins acting on either receptor type do not induce B1R expression.

PMID- 12489787
TI  - The kinin system: suggestions to broaden some prevailing concepts.
AB  - The existence and importance of the kallikrein-kinin-kininase system, especially
      in the circulation, has taken over three-quarters of a century to be established.
      Finding the multiple components derived from renin-angiotensin and their
      functions stretched over a century [Erdos EG. Perspectives on the early history
      of angiotensin-converting enzyme-recent follow-ups. In: Giles TD, editor.
      Angiotensin-converting enzyme (ACE): clinical and experimental insights. Fort
      Lee: Health Care Communications; 2001, p. 3-16]. Although the discoveries were
      made independently, it was shown in 1970 that the angiotensin I-converting enzyme
      (ACE) is identical with kininase II, previously discovered by us, thus, a single
      protein can regulate either the activation or inactivation of the two peptide
      products. It followed that inhibitors of ACE can affect both processes [Bhoola
      KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and
      kininases. Pharmacol Rev 1992;44:1-80]. After being engaged for a long time in
      characterizing the metabolism of various bio-active peptides, we, as well as
      others, noticed that the effect of ACE inhibitors go beyond simply blocking
      angiotensin (Ang) II release and bradykinin (BK) inactivation by the enzyme
      (Kaplan AP, Joseph K, Silverberg M. Pathways for bradykinin formation and
      inflammatory disease. J Allergy Clin Immunol 2002; 109(2):195-209, Yamada K,
      Erd6s EG. Kallikrein and prekallikrein of the isolated basolateral membrane of
      rat kidney. Kidney Int 1982;22:331-7]. It also became apparent to us that in the
      complex multistep reactions needed to activate the kallikrein-kinin system, there
      should be some shortcuts-shunts-to accelerate and simplify important processes.
      Thus, some basic tenets developed after decades of intensive laboratory
      investigations-and by now generally accepted-can be challenged. For example, it
      should be considered that the activities of BK and Lys BK (kallidin) can be
      substantially different, and that sequentially linked reactions, starting with
      prokallikrein activation and leading to kinin release from kininogen and
      inhibition of kininases, may be only one way to activate kinin receptors. A
      summary of some suggested alterations on prevailing concepts is given below.

PMID- 12489788
TI  - Molecular and pharmacological diversity of the kinin B1 receptor.
AB  - The pharmacological properties of the kinin B1 receptor in binding the endogenous
      kinin peptides are known to differ across species. Molecular cloning has revealed
      that these pharmacological differences arise from the diversity within the BDKRB
      gene. In this report, the molecular diversity of the human BDKRB1 gene is
      expanded by the identification of eight single nucleotide polymorphisms (SNPs) in
      the coding sequence of the receptor, three of which change the amino acid
      sequence of the receptor. The molecular cloning and pharmacological
      characterization of two primate B1 receptors, rhesus and African Green monkey,
      reveals that they exhibit the same high degree of selectivity for des-Arg10
      kallidin (Lys-bradykinin) relative to des-Arg9 bradykinin that is observed with
      the human kinin B1 receptor. Previous mutagenesis studies of the human B1
      receptor have implicated extracellular domain (EC) IV in conferring this
      selectivity for des-Arg10 kallidin, by interacting with the N-terminal Lys
      residue of the peptide. The pharmacological analysis of chimeric B1 receptors, in
      which EC-IV of the human B1 receptor is replaced with the corresponding domain of
      either rat or dog, supports the proposal that EC-IV is an important determinant
      in conferring ligand selectivity.

PMID- 12489789
TI  - Post-translational mechanisms of endothelial nitric oxide synthase regulation by
      bradykinin.
AB  - The endothelial nitric oxide synthase (eNOS) plays a key role in blood pressure
      regulation and vascular homeostasis. Among the more potent inducers of eNOS
      activity in vascular endothelial cells is bradykinin (BK). This brief review
      summarizes the current state of knowledge with regard to regulation of eNOS
      through several distinct molecular mechanisms, each of which acts in concert with
      Ca2+-calmodulin (CaM) signaling in post-translational activation of eNOS. These
      mechanisms include alterations in protein-protein interactions with caveolin-1,
      the BK B2 receptor, and heat shock protein 90 (Hsp90). In addition, BK stimulates
      an increase in eNOS activity through phosphorylation of the enzyme at three
      specific amino acid residues as well as through dephosphorylation at a fourth
      residue.

PMID- 12489790
TI  - Intramolecular signal transduction by the bradykinin B2 receptor.
AB  - To study the intramolecular signal transduction, we performed single point and
      cassette mutations in transmembranal and intracellular regions of the bradykinin
      B2 receptor. We studied the influence of the two intramembranal Cys residues at
      positions 304 and 348, the role of Arg at position 177 in the highly conserved
      tripeptide sequence Asp-Arg-Tyr, the cytosolic G-protein binding area, and
      attempted to verify the general hypothesis of an ion tunnel-like interface in
      GPCRs. Wild type receptor, His-tagged receptor, and His-tagged mutant receptors
      were expressed in COS-7 cells and functionally compared by bradykinin-induced
      formation of inositolphosphate and arachidonic acid. To investigate the
      expression, all mutants were modified at the N-terminus by insertion of two
      successive His-tags and detected with an anti-poly-His antibody. Replacement of
      the second and third cytosolic loop by a loop from another membrane protein as
      well as single replacement of Arg at position 177 by Ala leads to a fully
      inactive receptor mutant without any ligand binding affinity and stimulatory
      activity. Mutants with replacement of Cys residues 304 and 348 by Ser showed only
      moderate effects. Regardless of the replacement of Asp 407 by Ala, the receptor
      is able to increase the agonist-induced levels of inositolphosphate and of
      arachidonic acid, indicating that our studies can not verify the postulated ion
      tunnel hypothesis.

PMID- 12489791
TI  - Diabetes modulates the expression of glomerular kinin receptors.
AB  - The localization of kinin receptors within the kidney implicates this system in
      the regulation of glomerular hemodynamics. We reported that diabetes alters the
      activity of the renal kallikrein-kinin system, and that these alterations
      contribute to the development of microvascular complications of diabetes. The
      present study examined the influence of diabetes on the expression of glomerular
      B1 and B2-kinin receptors, and assessed the cellular signaling of kinin receptor
      activation. Rats made diabetic with streptozocin (85 mg/kg), displayed plasma
      glucose levels in the range of 350-500 mg/dl. At 3, 7, and 21 days, B1 and B2
      kinin receptor mRNA levels were measured in isolated glomeruli from control and
      diabetic rats by RT-PCR. Glomeruli revealed a differential pattern of expression
      between the two kinin receptors. The constitutively expressed B2-receptor was
      increased three-fold at day 3, but returned to normal levels at day 7; whereas,
      the inducible B1-receptor was maximally expressed (20-fold) at day 7 and remained
      elevated (10-fold) at day 21. To test whether the induction of kinin receptors by
      diabetes translates into increased responsiveness, we measured mitogen-activated
      protein kinase (MAPK) phosphorylation (p42, p44) in glomeruli isolated from
      control and diabetic rats stimulated with B1-receptor agonist (des-Arg9
      bradykinin, 10(-8) M). A three-fold increase in phosphorylation of MAPK was
      observed in response to B1-receptor agonist challenge in glomeruli isolated form
      diabetic rats compared to controls. These findings demonstrate for the first time
      that glomerular kinin receptors are induced by diabetes, and provide a rationale
      to study the contribution of these receptors to the development of glomerular
      injury in diabetes.

PMID- 12489792
TI  - Bradykinin antagonists as new drugs for prostate cancer.
AB  - Bradykinin (BK) is an autocrine growth factor for lung and prostate cancers. BK
      also facilitates tumor extension by increasing tissue permeability and
      stimulating angiogenesis. Peptide BK antagonists are in development as potential
      new drugs for lung cancer. Newer nonpeptide BK antagonists have even higher
      potency against lung cancer, in vitro and in vivo. These compounds have now been
      applied to the study of prostate cancers, and have been found to be effective.
      Prostate cancer cell line PC3 is derived from a late-stage, hormone-independent,
      metastatic tumor; its growth is difficult to inhibit. Our established BK
      antagonists, while less effective against this line of prostate cancer in
      xenografts in nude mice than against lung cancer, are active and have led the way
      to development of new peptide and nonpeptide agents for prostate cancer. In
      addition to inhibiting cancer cell growth directly, they inhibit angiogenesis
      mediated by vascular endothelial growth factor, and inhibit increased tissue
      permeability mediated by membrane metalloproteases in these tumors. This class of
      compounds offers hope for development of new drugs for refractory prostate
      cancer.

PMID- 12489793
TI  - Activation of bradykinin B1 receptor by ACE inhibitors.
AB  - ACE or kininase II inhibitors are very important, widely used therapeutic agents
      for the treatment of a variety of diseases. Although they inhibit ACE, thus,
      angiotensin II release and bradykinin (BK) inactivation, this inhibition alone
      does not suffice to explain their successful application in medical practice.
      Enalaprilat and other ACE inhibitors at nanomolar concentrations activate the BK
      B1 receptor directly in the absence of ACE and the peptide ligands, des-Arg
      kinins. The inhibitors activate at the Zn-binding pentameric consensus sequence
      HEXXH (195 -199) of B1, a motif also present in the active centers of ACE but
      absent from the BK B2 receptor. ACE inhibitors, when activating the B1 receptor,
      elevate intracellular calcium [Ca2+]i and release NO from cultured cells.
      Activation by ACE inhibitor was abolished by Ca-EDTA, a B1 receptor antagonist,
      by a synthetic undecapeptide representing the 192-202 sequence in the B1
      receptor, and by site-directed mutagenesis of H195 to A. With the exception of
      the B1 receptor blocker, these agents and the mutation did not affect the actions
      of the peptide ligand des-Arg10-Lys1-BK. Ischemia and inflammatory cytokines
      induce B1 receptors and elevate its expression. Direct activation of the B1
      receptor by ACE inhibitors can contribute to their therapeutic efficacy, for
      example, by releasing NO in vascular beds, or to some of their side effects.

PMID- 12489794
TI  - Kallikreins when activating bradykinin B2 receptor induce its redistribution on
      plasma membrane.
AB  - The bradykinin (BK) B2 receptor (R) is directly activated by kallikreins and
      other serine proteases independent of BK release. Both the Galpha(i) and
      Galpha(q) proteins are involved, shown by the release of arachidonic acid and
      [Ca2+]i elevation. Site-directed mutagenesis of the receptor and the lack of
      heterogeneous desensitization of the human B2R by the BK and kallikrein emphasize
      among others the differences between activation by the proteases and the peptide.
      To characterize further the mechanism thereby kallikreins activate and
      desensitize the B2R we investigated the distribution of the human B2R tagged with
      the green fluorescent protein (B2-GFP(Ct)) on the plasma membrane of stably
      transfected Chinese hamster ovary (CHO) cells. We visualized the movement of B2
      GFP(Ct) R with confocal fluorescence microscopy after activation by BK or a by
      serine protease. Continued exposure of the cells to BK led to B2R internalization
      within 15-20 min. Porcine pancreatic and human recombinant tissue kallikreins
      induced a rapid definite redistribution of receptors on the plasma membrane
      within 5 min, prior to internalization. These effects of kallikrein were blocked
      by the B2R antagonist HOE 140 and by the kallikrein inhibitor, aprotinin. The B2R
      was also activated by endoproteinases LysC and ArgC and trypsin, but these
      enzymes did not induce redistribution, only internalization. In control
      experiments, kallikrein had no effect on cells transfected to stably express the
      angiotensin-converting enzyme-green fluorescent protein (GFP). Thus, kallikreins
      when activating the BK B2R also trigger its redistribution on plasma membrane.

PMID- 12489795
TI  - Hybrid formation between the intracellular faces of the bradykinin B2 and
      angiotensin II AT1 receptors and signal transduction.
AB  - Most frequently, the physiologic functions of the angiotensin II (Ang II) type 1
      receptor (AT1R) and bradykinin B2 receptor (BKB2R) are antagonistic, particularly
      with respect to the regulation of vascular tone. Despite major differences in
      their physiologic actions, the receptors share sequence similarities. Both link
      to Galpha(i) and Galpha(q) and transduce very similar signal paths, not only
      those relating to the traditional G-protein associated second messengers, but
      also those involved in transactivation mechanisms involving receptor tyrosine
      kinases. With respect to these paths, some differences in signaling may be
      accounted for by cell type specificity. However, alternative signal cascades for
      these two receptors are becoming increasingly evident. One such is the
      recruitment of signaling molecules upon receptor translocation and
      internalization. The AT1R translocates into clathrin-coated pits and internalizes
      upon recruitment of beta-arrestin 2 which then recruits ASK1 and JNK3. The BKB2R
      translocates and internalizes mainly via caveolae. Another signaling divergence
      may be due to the direct activation of small G-proteins by both receptors. AT1R
      activates the RhoA, Rac1, Cdc42 while BKB2R couples only with Rac1 and Cdc42.
      Both receptors may serve as docking stations for intracellular proteins. One such
      example is the YIPP motif within the C-terminus of the ATIR which associates with
      the JAK/STAT pathway. Another potential alternative is the activation of
      tyrosine/serine kinase phosphatases by BK. This mechanism may directly oppose
      some of the protein tyrosine/ serine kinase paths activated by AT1R. These
      alternative mechanisms in sum are potentially responsible for the diversion in
      signal transduction between these two receptors. Regardless of the route of
      action, our results suggest that in Rat-1 fibroblasts stably transfected with
      BKB2R, BK slightly decreases connective tissue growth factor (CTGF) mRNA level
      while in ATIR transfected cells Ang II increases CTGF mRNA markedly. To determine
      whether mutant hybrids can be formed between these two receptors which encompass
      some of the function of the donor receptor but bind the ligand of the recipient
      receptor, a series of hybrids were formed with BKB2R the recipient and AT1R the
      donor receptor. Some of these hybrids show resistance to exchanges with the AT1R
      and form receptors which either do not bind (IC1 exchanges) or demonstrate poor
      function but normal internalization (proximal C-terminus exchanges). However,
      other hybrids have proven very functional. For example, the IC2, IC3 and distal C
      terminus of the BKB2R IC face can be replaced simultaneously with the AT1R
      resulting in an hybrid which binds BK, continues to signal, is internalized and
      resensitized. Formation of this and other less extensive hybrids is discussed.
      Some of these hybrids possess the capacity to function as the AT1R as exemplified
      by their ability to upregulate CTGF expression as wild-type (WT) AT1R.

PMID- 12489796
TI  - Regulation of cardiac bradykinin B1- and B2-receptor mRNA in experimental
      ischemic, diabetic, and pressure-overload-induced cardiomyopathy.
AB  - Although kinins have been associated with the regulation of cardiovascular
      function in left ventricular hypertrophy (LVH) as a consequence of hypertension,
      myocardial infarction (MI), and/or diabetic cardiomyopathy, less is known about
      their receptor regulation under these conditions. We have therefore investigated
      the bradykinin B1-receptor (B1R) and B2-receptor (B2R) mRNA expression in rat
      models of MI, LVH and diabetes mellitus (DM). Sprague-Dawley rats (SD) were
      submitted to permanent ligation of the left descending coronary artery (LAD) to
      induce a MI, whereas DM was induced by a single injection of streptozotocin
      (STZ). LVH was induced after thoracic aortic banding (AB). Three weeks after MI,
      six weeks after STZ injection or six weeks after AB, left ventricular (LV)
      function was characterized using a Millar-tip catheter. Cardiac B1R- and B2R-mRNA
      expression were analyzed by specific RNase-protection assays (RPA). LV
      contractility (dP/dt max) was impaired by 40-48% in rats after induction of MI or
      DM compared to their controls. However, despite an enormous increase in LV end
      diastolic pressure (LEVDP) to 310% after AB, LV contractility did not differ
      compared to the controls. These hemodynamic changes were accompanied by an up
      regulation of cardiac B1R- (MI, 288%; STZ, 215%; AB, 4180%) and B2R-mRNA
      expression (MI, 122%; STZ, 288%; AB, 96%). Up-regulation of both BK-receptor
      (BKR) types in early stages of cardiac wound healing induced by ischemia and in
      chronic stages of cardiac remodeling induced by pressure-overload or by
      hyperglycemia indicates that kinins play a major role in the complex processes of
      cardiac tissue injury and repair.

PMID- 12489797
TI  - Bradykinin receptor modulation in cellular models of aging and Alzheimer's
      disease.
AB  - Human fibroblast cell culture systems have been used to model both molecular
      events associated with the aging process and the biochemical anomalies found in
      the aging-associated neurodegenerative disorder Alzheimer's disease (AD). We
      demonstrate modulation of bradykinin (BK) B2 receptors that results in
      Intermediate (I, Kd 2.5-5 nM) and Low (L, Kd 44 nM) receptor affinity states in
      two cellular model systems that target aging and aging-associated disorders: the
      human lung fibroblast cell line WI-38 model for cellular aging and a skin
      fibroblast cell line from a patient with early onset familial Alzheimer's
      disease. In both cellular models the generation of I and L BK B2 receptors is
      extremely rapid, occurring within 1 min of activation of protein kinase C (PKC)
      by phorbol ester. Blocking phosphoprotein phosphatase activity further augments
      the cellular content of I and L receptors in the Alzheimer's skin fibroblast cell
      line. These two lines of evidence suggest that a phosphorylation cascade
      modifying the receptors is responsible for the I and L states. The I and L
      receptors remain biologically active and enhance cellular responsiveness to
      elevated levels of BK that are found in tissue injury, one of the major risk
      factors for development of Alzheimer's disease. The Alzheimer's disease skin
      fibroblast cell line presents a cellular environment highly enriched in the
      amyloid Abeta1-42 peptide that is the hallmark of Alzheimer's plaque lesions in
      the brain. This Abeta-rich environment may serve to foster the signal
      transduction mechanism that generates I and L BK B2 receptors.

PMID- 12489798
TI  - Assembly and activation of the plasma kallikrein/kinin system: a new
      interpretation.
AB  - Understanding the importance and physiologic activity of the plasma
      kallikrein/kinin system (KKS) has been thwarted by the absence of an inclusive
      theory for its assembly and activation. The contact activation hypothesis
      describes the assembly and activation of this system in test tubes and disease
      states, but not under physiologic circumstances. Recent investigations have
      indicated a new cohesive hypothesis for understanding physiologic activation of
      this system. Prekallikrein (PK) and factor XI (FXI) through high molecular weight
      kininogen (HK) assemble on a co-localized, multiprotein receptor complex on
      endothelial cells that consists of at least cytokeratin 1 (CKI), gClqR, and
      urokinase plasminogen activator receptor (muPAR). When assembled on these
      proteins, prekallikrein becomes activated to kallikrein by the membrane-expressed
      enzyme prolylcarboxypeptidase (PRCP). Formed kallikrein then activates factor XII
      (FXII) for amplification of its activation and single chain urokinase. The plasma
      kallikrein/kinin system may serve as a physiologic counterbalance to the plasma
      renin angiotensin system (RAS) by lowering blood pressure and preventing
      thrombosis. Insights into the integrated role of these two systems may afford the
      development of novel therapeutic drugs to manage hypertension and thrombosis.

PMID- 12489799
TI  - Activation of the bradykinin-forming cascade on endothelial cells: a role for
      heat shock protein 90.
AB  - Bradykinin is a major mediator of swelling in C1 inhibitor deficiency as well as
      the angioedema seen with ACE inhibitors and may contribute to bronchial hyper
      reactivity in asthma. Formation of bradykinin occurs in the fluid phase and along
      cell surfaces requiring interaction of Factor XII, prekallikrein and high
      molecular weight kininogen (HK). The mechanism by which initiation occurs is
      uncertain. Recent data suggest that activation of the kinin-forming cascade can
      occur on the surface of endothelial cells, even in the absence of Factor XII. We
      demonstrate herein that during a 2-h incubation time, plasma deficient in either
      Factor XII or high molecular weight kininogen (HK) fail to activate kinin-forming
      cascade as compared to normal plasma. With more prolonged incubation, Factor XII
      deficient plasma gradually activates and HK deficient plasma does not. Our data
      support both Factor XII-dependent (rapid) and Factor XII-independent (slow)
      mechanisms; the latter may require a cell-derived protein (possibly protease) to
      activate prekallikrein in the presence of zinc ion and HK. To further define this
      cellular factor, we demonstrated that both cytosolic and membrane fractions from
      endothelial cells possessed the ability to catalyze prekallikrein conversion to
      kallikrein in the presence of HK and zinc ion. We purified this factor from
      cytosol by affinity chromatography employing corn trypsin inhibitor (CTI) as
      ligand. The fractions with peak activity were subjected to SDS-PAGE analysis,
      ligand blotted with biotinylated CTI, and positive bands were sequenced. Heat
      shock protein 90 (Hsp90) was identified as one of the proteins. Zinc-dependent
      activation of the prekallikrein-HK complex on endothelial cells was inhibited
      upon the addition of polyclonal antibody to Hsp90 in a dose-dependent manner.
      Although the mechanism by which Hsp90 activates the kinin-forming cascade is not
      yet clear, this protein represents the cellular contribution to the reaction and
      may become the dominant mechanism in pathologic circumstances in which Hsp90 is
      highly expressed or secreted.

PMID- 12489800
TI  - Glycosaminoglycans affect the action of human plasma kallikrein on kininogen
      hydrolysis and inflammation.
AB  - Human plasma kallikrein (huPK) is a serine proteinase involved in many biological
      processes including those of the kallikrein-kinin system. The action of huPK on
      kininogen results in bradykinin (BK) release, a potent mediator of inflammatory
      responses. BK generation may be influenced by several agents, and the aim of this
      work was to investigate the effect of glycosaminoglycans (GAGs) on human high
      molecular-weight kininogen (HK) hydrolysis by huPK and on inflammation. huPK was
      pre-incubated in the absence and presence of different GAGs, followed by the
      addition of kininogen. Bradykinin released at different times was measured by
      radioimmunoassay, and KM and kcat were calculated. Tuna and bovine dermatan
      sulfates, the most potent GAGs studied, reduced by 80% and 68%, respectively, the
      catalytic efficiency of huPK (control = 4. x 10(4) M(-1) s(-1) in BK release. The
      effect of bovine dermatan sulfate (BDS) on inflammatory response was studied in
      rat paw edema induced by carrageenin and hourly determined (1-4 h) by
      plethysmography. BDS significantly reduced the inflammatory response in the first
      and second hours of measurements (24% and 28%, respectively), p < 0.05. GAGs were
      shown to reduce bradykinin release "in vitro" and in an inflammation model. This
      reduction may play a role in the control or maintenance of some pathological and
      physiological processes.

PMID- 12489801
TI  - Fine mapping of the H-kininogen binding site in plasma prekallikrein apple domain
      2.
AB  - Plasma prekallikrein (PPK), the zymogen of the contact phase protease plasma
      kallikrein, forms a non-covalent complex with its substrate H-kininogen (HK). HK
      binds to cell surface proteoglycans, indirectly anchoring this bradykinin
      generating protease to endothelial cells. The heavy chain of PPK consisting of
      four apple domains designated A1 to A4. Previous studies indicated that a major
      HK binding site on PPK is within the A2 domain, with additional contributions to
      binding provided by the N-terminal portion of Al and the central part of A4. To
      precisely map the relevant binding segments in A2, we employed a monoclonal anti
      PPK antibody (PKH6) that binds to A2 and blocks HK-PPK complex formation with an
      apparent IC50 of 8 nM. Using recombinant A2 C-terminal deletion mutants, we
      mapped the target epitope of PKH6 to the N-terminal portion of A2, residues 92
      153. C-terminal deletion of A2 to residue 145 resulted in a loss of PKH6 binding,
      as did proteolytic cleavage of A2 at Lys140-Arg141. A comparison of HK binding to
      various A2 deletion mutants revealed that the major HK binding site is localized
      to residues 145-153 in the central portion of A2, where it overlaps with the PKH6
      epitope. This sequence is conserved in the A2 domain of the related protease
      factor XI, explaining the unusual strong cross-reactivity of PHK6 with factor XI,
      as well as the similar HK-binding characteristics of PPK and factor XI.

PMID- 12489802
TI  - Inhibition of angiogenesis by a monoclonal antibody to kininogen as well as by
      kininostatin which block proangiogenic high molecular weight kininogen.
AB  - High molecular weight kininogen (HK) exhibits two activities with respect to
      angiogenesis after cleavage by plasma kallikrein. Cleaved HK (HKa) and its cell
      binding domain 5 (D5), kininostatin, are potent antiangiogenic polypeptides. They
      inhibit endothelial cell migration, proliferation and tube formation. HKa and D5
      inhibit angiogenesis in the chicken chorioallantoic membrane (CAM) assay. D5
      stimulates apoptosis and interferes with the cell cycle. In contrast, intact HK
      is proangiogenic by liberating bradykinin. A monoclonal antibody to HK can
      inhibit angiogenesis in the CAM assay, human colon carcinoma growing as a
      xenograft in nude mice, and murine hybridomas growing in syngeneic hosts. Not
      only are the tumors decreased in volume and weight to isotype controls but the
      mean vascular density is decreased. Thus, both D5 and its constituent peptide and
      monoclonal antibody have potential for inhibiting angiogenesis and tumor growth
      in human therapy.

PMID- 12489803
TI  - Chronic intestinal inflammation and angiogenesis in genetically susceptible rats
      is modulated by kininogen deficiency.
AB  - Genetically susceptible Lewis rats injected in the intestinal wall with
      peptidoglycan-polysaccharide (PG-APS) polymers develop chronic granulomatous
      enterocolitis associated with activation of the kallikrein-kinin system. To
      elucidate the role of high-molecular-weight kininogen (HK), we backcrossed Brown
      Norway rats having an HK deficiency with Lewis rats for five generations. Two new
      strains were produced, wild-type F5 (F5WT) and HK deficient (F5HKd), each with a
      approximately 97% Lewis genome. The HK values of F5WT rat plasma and F5HKd rat
      plasma were 0.62 +/- 0.20 and 0.08 +/- 0.03 U/ml, respectively. Among the
      inflammatory changes, the mean gross gut, total intestinal histologic and liver
      granuloma score and the white blood count were significantly lower in the F5HKd
      than the F5WT rats. Plasma T-kininogen was significantly less in F5HKd.
      Angiogenesis (mean vascular density) in the cecum was decreased significantly in
      F5HKd compared to F5WT. These results indicate the importance of the kallikrein
      kinin system in this model of chronic enterocolitis and systemic inflammation.

PMID- 12489804
TI  - Structural characterization of the human carboxypeptidase D gene and its
      promoter.
AB  - Human carboxypeptidase D (CPD) is a 180-kDa type I membrane protein with three
      tandem active site domains. CPD is a B-type (or kininase I-type) carboxypeptidase
      that cleaves C-terminal basic residues from proteins and peptides, such as Arg9
      from bradykinin. The human carboxypeptidase D (CPD) gene was found to encompass
      approximately 88.3 kb of genomic sequence, containing 21 exons ranging in size
      from 65 to 1813 bp, and 21 introns ranging in size from 112 bp to 35.6 kb.
      Although CPD and CPM belong to the same metallocarboxypeptidase subfamily, their
      intron/exon structures differ significantly. Multiple transcription start sites
      were found in the CPD gene within a GC-rich sequence lacking the typical TATA
      box, but containing three GC boxes. Luciferase reporter assays with various size
      constructs containing the promoter region upstream of the start sites showed that
      it was active in three different cell lines, especially in the human hepatoma
      cell line HepG2 and the human monocytic cell line THP-1, which have high
      constitutive expression of CPD.

PMID- 12489805
TI  - APP, Notch, and presenilin: molecular pieces in the puzzle of Alzheimer's
      disease.
AB  - Deposition of the amyloid-beta protein (Abeta) in the form of cerebral plaques is
      a defining pathological feature of Alzheimer's disease (AD), and all AD-causing
      genes identified to date affect Abeta production or deposition. For these
      reasons, the two proteases, beta- and gamma-secretases, that cut out Abeta from
      the amyloid-beta precursor protein (APP) are considered important targets for the
      development of therapeutics for AD. AD-causing mutations in the presenilin genes
      alter y-secretase activity, increasing production of the more deleterious 42
      residue form of Abeta. Pharmacological profiling, site-directed mutagenesis,
      knockout studies, affinity labeling, and activity-dependent chromatography all
      strongly support the hypothesis that presenilin is an integral component of gamma
      secretase, a founding member of an emerging class of polytopic membrane
      proteases. Gamma-Secretase/ presenilin also cleaves other proteins that are
      important for critical signaling events (the Notch family of receptors), raising
      concerns about mechanism-based toxicities that might arise as a consequence of
      inhibiting this protease. In light of these findings, the potential of gamma
      secretase vis-a-vis beta-secretase as therapeutic targets for the prevention or
      treatment of AD will be discussed.

PMID- 12489806
TI  - Kininostatin as an antiangiogenic inhibitor: what we know and what we do not
      know.
AB  - High-molecular-weight kininogen (HK) is a plasma protein consisting of six
      domains (designated D1-D6). It was first characterized as a precursor of
      bradykinin, a bioactive peptide that regulates many cardiovascular processes. HK
      can bind to endothelial cells where it can be cleaved by plasma kallikrein to
      release bradykinin contained within domain 4. The remaining portion of the
      molecule, cleaved HK, is designated HKa. While bradykinin has been intensively
      studied, the physiological implication of the generation of HKa is not clear. HKa
      has recently been shown to inhibit the important steps required for angiogenesis
      such as proliferation and migration of endothelial cells. The antiangiogenic
      activity of HKa has further been demonstrated in animal models in which HKa
      inhibits neovascularization. Because domain 5 (D5) of HKa reproduces the
      antiangiogenic effect of HKa, D5 is named kininostatin for this novel function.
      In this review, we will briefly discuss the recent progress in the studies of the
      molecular mechanisms that mediate the antiangiogenic effect of HKa and D5.

PMID- 12489807
TI  - The development of insulitis and the kallikrein-kinin system.
AB  - Data derived from animals and humans suggest that the onset of diabetes is
      associated with hemodynamic changes in the renal circulation leading to increased
      renal plasma flow (RPF), glomerular capillary hyperfusion, and an increased
      glomerular transcapillary hydraulic pressure gradient. The duration of diabetes
      is one of the most important factors in predicting the development of diabetic
      nephropathy. On the other hand, diabetic nephropathy has been associated with the
      degree of hyperglycemia; thus, hyperglycemia may therefore contribute to
      alterations in structure and function of the kidney. In the present paper, we
      investigated early alterations of renal function in C57BL/KSJ mdb male mice that
      were injected with sub-diabetogenic doses of STZ. Urinary protein excretion (UPE)
      increased significantly at 12 and 18-20 days after STZ with a glucose level of 4
      6 mm/l; the progressive increase of glycemia was followed by a progressive
      increase of UPE. In a similar way, urinary nitrite (NO2-) was also significantly
      increased. Urinary kallikrein excretion started to increase at a level of 4-6
      mmol/l blood glucose concentration (BGC) 8 days after administration of STZ, and
      kidney vascular permeability also increased following the increment of BGC. These
      results confirm the presence of early modifications of renal function prior to
      the clinical detection of diabetic hyperglycemia.

PMID- 12489808
TI  - Increased activity of the renal kallikrein-kinin system in autosomal dominant
      polycystic kidney disease in rats, but not in humans.
AB  - The kallikrein-kinin system (KKS) was investigated in autosomal dominant
      polycystic kidney disease (ADPKD)-affected rats (PKD) and compared to unaffected
      controls (SD) and 5/6 nephrectomized rats (5/6 Nx). In addition, patients with
      ADPKD compared to patients with nonpolycystic kidney disease and healthy controls
      have been investigated. Plasma and urine samples for determination of creatinine,
      protein, kallikrein (KAL) and bradykinin (BK) were taken in male 3- and 9-month
      old PKD, SD and 9-month-old 5/6 Nx. The same parameters were determined in young
      (age: 20-40 years) and old (41-65 years) male patients with ADPKD and compared to
      age-matched patients with nonpolycystic kidney disease and age-matched healthy
      controls. Plasma and urine KAL were measured by chromogenic peptide substrate,
      and kininswere determined by radioimmunoassay. Urine KAL and BK levels were
      increased i n PKD compared to age-matched SD. No differences with respect to
      serum KAL were found between PKD and SD. In 5/6 Nx, urinary BK levels showed a
      trend towards higher compared to old SD (p = 0.06). KAL and BK were not increased
      in serum and urine of patients with ADPKD, in contrast to rats. Urinary KAL
      excretion was reduced in patients with ADPKD and advanced renal failure. Our
      results demonstrate an age-dependent activation of the renal KKS in rats with
      ADPKD, whereas the KKS is not activated in patients with ADPKD and advanced renal
      failure. These data indicate that there are fundamental differences in the
      factors influencing the course of the disease in human and rat ADPKD.

PMID- 12489809
TI  - Potassium-induced increase in renal kallikrein secretion is attenuated in
      dissected renal connecting tubules of young spontaneously hypertensive rats.
AB  - It is suggested that attenuation of the renal kallikrein-kinin system (KKS)
      involved the development of hypertension in young spontaneously hypertensive rats
      (SHR). In the present study, a comparison was made between young SHR and Wistar
      Kyoto rats (WKY) to examine the ability to secrete renal kallikrein from the
      microdissected connecting tubules (CNT) by potassium or an ATP-sensitive
      potassium channel blocker, 4-morpholinecarboximidine-N-1-adamantyl-N'
      cyclohexylhydrochloride (PNU-37883A), both of which are renal kallikrein
      secretagogues. Maximum effect of potassium on kallikrein secretion was observed
      10 min after placing the tubules at concentration of 20 mM. Kallikrein secretion
      was also increased concentration-dependently by PNU-37883A (0.1, 1, 10, and 100
      microM). In the presence of EDTA, NiCl2, verapamil, xestspongin C (an inositol
      1,4,5-trisphosphate (IP3) receptor-selective antagonist), or ruthenium red (a
      ryanodine-sensitive receptor blocker), potassium-induced increase in renal
      kallikrein secretion was inhibited. Augmentation of renal kallikrein secretion by
      potassium or PNU-37883A was diminished in SHR compared to WKY. These results
      indicate that the ability to secrete renal kallikrein by potassium was attenuated
      in young SHR compared with WKY. Furthermore, it is suggested that the potassium
      induced renal kallikrein secretion requires an extracellular Ca2+ entry through
      Ca2+ channels including L-type Ca2+ channels and Ca2+ release from intracellular
      Ca2+ stores through IP3 receptor and ryanodine receptor.

PMID- 12489811
TI  - Regulatory effects of salt diet on renal renin-angiotensin-aldosterone, and
      kallikrein-kinin systems.
AB  - The interaction of the renin-angiotensin-aldosterone system (RAAS) and the
      kallikrein-kinin system (KKS) was investigated in rats fed on a low, normal, and
      high-salt diet for 2 weeks. At the beginning of the second week, either a B2
      receptor antagonist (icatibant), or an AT1-receptor antagonist (losartan), or an
      aldosterone receptor antagonist (spironolactone) was applied via osmotic pump
      delivering a constant amount of drug for 7 days. The urinary bradykinin (BK)
      levels corresponded with increasing NaCl diet and the activity of urinary
      kallikrein. However, in agreement with other investigators we found a down
      regulation of the renal kallikrein gene expression in response to an increasing
      NaCl diet. Renal kinins are able to stimulate the renal kallikrein expression as
      well as the renal excretion of active kallikrein via the B2-receptor. The release
      of renal kallikrein is also mediated by angiotensin II (AngII). After high-salt
      diet the blood pressure was significantly increased. Losartan and spironolactone
      were not effective in reducing this increase, as AngII and aldosterone should be
      low during high-salt diet. However, low-salt diet also yielded an increase in
      blood pressure, which, however, could be abolished following losartan infusion.
      The data suggest that the expression of renal kallikrein mRNA is mainly regulated
      by dietary salt intake. However, kinins are able to stimulate the kallikrein gene
      expression, as well as the renal kallikrein release. Angll mediates only a
      stimulatory effect on the urinary kallikrein release. In contrast to the general
      belief, our data support the opinion that low-salt diet is able to mediate an
      increase in blood pressure, as the RAAS is stimulated in response to a marked
      salt deficiency.

PMID- 12489810
TI  - Activation of a renin-angiotensin system in ischemic cardiac sympathetic nerve
      endings and its association with norepinephrine release.
AB  - We had reported that in the ischemic heart, locally formed bradykinin (BK) and
      angiotensin II (Ang II) activate B2- and AT1-receptors on sympathetic nerve
      terminals (SNE), promoting reversal of the norepinephrine (NE) transporter in an
      outward direction (i.e., carrier-mediated NE release). Although both BK and Ang
      II contribute to ischemic NE release, Ang II is likely to play a more important
      role. Since BK is formed by ischemic SNE, we questioned whether cardiac SNE also
      contribute to local Ang II formation, in addition to being a target of Ang II.
      SNE were isolated from surgical specimens of human right atrium and incubated in
      ischemic conditions. These SNE released large amounts of endogenous NE via a
      carrier-mediated mechanism, as evidenced by the inhibitory effect of desipramine
      on this process. Moreover, two renin inhibitors, pepstatin-A and BILA 2157 BS,
      the ACE inhibitor enalaprilat and the AT1-receptor antagonist EXP3174 prevented
      ischemic NE release. Western blot analysis revealed the presence of renin in
      cardiac SNE. Renin abundance increased more than three-fold during ischemia.
      Thus, renin is present in cardiac SNE and is activated during ischemia,
      eventually culminating in Ang II formation, stimulation of AT1-receptors and
      carrier-mediated NE release. Our findings uncover a novel autocrine mechanism, by
      which Ang II, formed at SNE in myocardial ischemia, elicits carrier-mediated NE
      release by activating prejuntional AT1-receptors.

PMID- 12489812
TI  - Visualization of the sequential changes in immunolabelled tissue kininogenase
      which accompany follicular development and luteinization of angiogenic granulosa
      cells of the ovary.
AB  - The serine protease, tissue kininogenase (kallikrein), belongs to a unique family
      of enzymes that cleaves the decapeptide, kallidin, from the endogenous substrate
      kininogen. By analysis of genealogy patterns, rat KLK gene family members have
      been detected in ovarian luteinizing granulosa cells of both gonadotrophin
      treated and nontreated control rats. Preliminary experiments suggest that when
      granulosa and endothelial cells are co-cultured, granulosa cells participate in
      the formation of vascular capillary tubes. This inherent capacity of granulosa
      cells to behave and respond like endothelial cells may be of importance in the
      aetiology of ovarian angiogenesis, which drives new blood vessel formation in the
      ovary. Recently, we demonstrated that tissue kininogenase showed intense
      immunolabelling in angiogenic endothelial cells isolated from bovine mature and
      regressing corpora lutea. Therefore, the question to answer was whether granulosa
      cells possess the same capacity to express the kallikrein-kinin cascade as do
      microvascular endothelial cells. As a first step, experiments were designed to
      determine the expression and visualization of tissue kininogenase (both active
      and pro-forms) as well as kininogen and kinin receptors in granulosa cells of
      different developmental stage and segments of the ovarian follicle by
      immunoperoxidase, fluorescent microscopy (confocal) and in situ hybridization.

PMID- 12489813
TI  - Utilization of a radioimmunoassay to detect the generation of Arg-Pro-Pro-Gly
      Phe, a stable endproduct of bradykinin metabolism (from cultured rat aortic
      smooth muscle cells exposed to bradykinin).
AB  - The peptide hormone bradykinin is a mediator in many physiological and
      pathological processes. The generation and, to a limited extent, metabolism occur
      at the sites of action. The short half-life of bradykinin (approximately 15 s)
      renders measurements of its concentration in bodily fluids difficult. As a
      result, recent methods utilizing either ELISA or HPLC/mass spectrometry, have
      been developed for the measurement of the stable metabolic endproduct of
      bradykinin, i.e., the pentapeptide Arg-Pro-Pro-Gly-Phe (RPPGF; BK[1-5]). Both
      have been successfully used to quantitate levels of RPPGF in plasma, pulmonary
      and nasal exudates. In this study, we demonstrate the characterization and
      utility of a radioimmunoassay for the measurement of RPPGF, using a newly
      synthesized radioiodinated analogue of RPPGF, i.e., RPPG(125I)F. This
      radioimmunoassay shows an IC50 of 80.5 +/- 7.4 pg/tube (n = 23) with a linear
      range of detection between 10 and 500 pg/tube. The assay was used to demonstrate
      the time-dependent generation of RPPGF by cultured rat aortic vascular smooth
      muscle cells exposed to bradykinin (100 ng/ml). Peak generation of RPPGF was 74.5
      +/- 9.7 pmol/well (n = 5) after 24 h of incubation. Captopril, an inhibitor of
      angiotensin-converting enzyme (kininase II), inhibited generation in a
      concentration-dependent manner. The results characterize a new radioimmunoassay
      for the stable metabolic endproduct of bradykinin, RPPGF.

PMID- 12489814
TI  - Role of kinin and prostaglandin in cutaneous thermal nociception.
AB  - Involvements of kinin and prostaglandin and their interaction in noxious thermal
      stimuli were investigated in noninflamed and inflamed rats. The nociceptive
      response was evaluated from the escape latency of foot withdrawal to the thermal
      stimuli with a beam of light. The escape latency in kininogens-deficient Brown
      Norway (B/N-) Katholiek rats was significantly longer than that in the normal
      strain, B/N-Kitasato rats. The latency in B/N-Kitasato rat was prolonged by
      administration of a bradykinin (BK) B2 receptor antagonist, FR173657 (30 mg/kg,
      p.o.), whereas it was shortened by pretreatment with a kininase II inhibitor,
      captopril (10 mg/kg, i.p.). Both agents did not affect the latency in B/N
      Katholiek rats. In normal Sprague-Dawley (SD) rat, administration of indomethacin
      did not change the escape latency against the thermal stimuli. In contrast,
      administration of indomethacin or a relatively cyclooxygenase-1-selective
      inhibitor, mofezolac (10 mg/kg, p.o.) significantly reduced numbers of writhing
      reaction in mice induced by acetic acid solution. Injection of lipopolysaccharide
      (1 mg/kg, i.v.) resulted in shortening escape latency at 8 h after the injection
      in B/N-Kitasato rats. This hyperalgesia could be reversed by pretreatment of the
      rats with indomethacin, a cyclooxygenase-2-selective inhibitor JTE-522 (10 mg/kg,
      p.o.), or FR173657, but not with mofezolac. The hyperalgesia was not seen in B/N
      Katholiek rats. These results indicate that kinin has major participation in
      peripheral skin thermal nociception under noninflamed condition, although
      cyclooxygenases may have little participation. Prostaglandins produced by
      cyclooxygenase-2 could coordinate with BK to elicit hyperalgesia during
      inflammation induced by lipopolysaccharide.

PMID- 12489815
TI  - Dietary restriction downregulates free radical and lipid peroxide production:
      plausible mechanism for elongation of life span.
AB  - Dietary restriction elongates life span by suppressing age-related diseases in
      experimental animals. It has received a great deal of attention in connection
      with the relationship between aging, nutrition, and oxidative stress because
      oxidative injury in several tissues is a prominent feature in the aging process.
      Although the oxidative stress theory of aging has currently gained popularity,
      the premise from which this hypothesis was derived is paradoxical because the
      same oxygen, that supports life in one hand threatens survival and promotes aging
      in the other. Until recently, no single experimental paradigm could offer
      satisfactory mechanistic explanations for this complex issue. Recent
      investigations using the life-extending dietary restriction regimen could offer
      satisfactory mechanistic explanations for this apparent self-contradiction to
      life. The modulation of free radical-induced oxidative stress provided sufficient
      data to support the notion that dietary restriction's antiaging effect may come
      from its ability to tightly regulate the oxidative status of an organism. The
      result is the maintenance of cellular homeostasis, a hallmark of dietary
      restriction's action in the extension of life span. To date, we reported that
      dietary restriction (maintained on 60% of ad libitum feeding) suppresses age
      related oxidative damage by modulating the amount as well as the fatty acid
      composition of tissue phospholipids. These remarkable findings have been
      incorporated into the new "membrane peorxidation cycle" concept. The intervention
      of this cycle appears to be an evolutionary process that the dietary restricted
      rats have adapted as a strategy to protect the membrane in an oxidative
      environment.

PMID- 12489816
TI  - Effects of the thyroid hormone on differentiation, growth, and proteolysis in
      cultured muscle cells during serum deprivation.
AB  - The actions of the thyroid hormone (T3) are modified by other hormones.
      Therefore, in the normal cell culture system, with serum as a medium ingredient,
      it is difficult to eliminate the influences of other hormones derived from the
      serum. In the present study, two experiments were conducted to clarify the
      effects of T3 on differentiation, growth and proteolysis (experiment 1), and
      concerted effects of T3 and insulin (experiment 2) in a serum-free culture with
      the use of muscle cells originated from chick embryo. Protein content and
      creatine kinase (CK) activity were examined as indices of growth and
      differentiation of the muscle cells, respectively, and N(tau)-methylhistidine
      (MeHis) release was examined as an index of myofibrillar proteolysis. It was
      observed that T3 suppressed both the muscle differentiation and proteolysis in
      the serum-free medium (experiment 1), though in our previous experiment they were
      enhanced by T3 in the serum-supplemented normal medium. On the other hand, T3
      increased myofibrillar proteolysis and had no effect on muscle differentiation
      when insulin was included in the serum-free medium (experiment 2). These results
      clearly show that the effects of thyroid hormones on muscle differentiation and
      proteolysis are apparently different when serum is deprived from the medium, and
      these differential effects of thyroid hormone could be partially explained by an
      interaction with insulin, one of the growth factors in the serum.

PMID- 12489817
TI  - Effects of ethanol administration at a high-dose level on the stimulatory action
      by bradykinin in vascular permeability.
AB  - The effects of ethanol (EtOH) administration at a high-dose level on the
      stimulatory action by bradykinin in vascular permeability were examined in rats,
      as compared with the effects of histamine and hyaluronidase. Oral administration
      (7.5 g/kg) and intraperitoneal injection (5 g/kg) of EtOH markedly potentiated
      the vascular permeability accelerated by bradykinin, but they suppressed in
      reverse such effects induced by histamine and hyaluronidase. EtOH did not affect
      the stimulatory action of bradykinin on the vascular permeability when
      intracutaneous injection was done under the coexistence with bradykinin. The
      blood pressure was found to descend 30 min later, though there was a transient
      rise immediately after the oral administration of EtOH (7.5 g/kg). The oral
      administration of EtOH (7.5 g/kg) caused no change in both enzyme activities of
      aspartic acid aminotransferase and alanine aminotransferase in blood for 3 h. The
      intraperitoneal injection of EtOH (5 g/kg) lowered the blood bradykinin level and
      increased the blood hyaluronidase activity. In vitro, EtOH elicited a
      concentration-dependent increase in the kallikrein activity, trypsin activity,
      and bradykinin-decomposed activity in plasma. These results strongly suggest that
      vascular permeability results from elevation in the bradykinin level, direct
      action of EtOH on inflamed skin site, and actions of EtOH or its metabolites on
      bradykinin-regulator, which involves bradykinin receptor and NO and endothelin
      productions.

PMID- 12489818
TI  - HDL3 exerts a more powerful antiperoxidative and protective effect against
      peroxidative modification of LDL than HDL2 does.
AB  - The objective of the present study was to establish that HDL3 has a greater
      antiperoxidative effect on the peroxidative modification of LDL than HDL2 has.
      The protective influence of HDL subfractions on this form of LDL modification was
      examined in samples by measuring the concentration of thiobarbituric acid
      reactive substance (TBARS), as well as the electrophoretic mobility of LDL. LDL
      was incubated for 96 hours in phosphate-buffered saline (PBS) alone, without the
      addition of transition-metal ions or in the presence of PBS and HDL2 or HDL3. All
      samples were subjected to agarose gel electrophoresis. Both HDL2 and HDL3
      significantly inhibited peroxidative modification of LDL, as assessed by
      electrophoretic mobility, but this effect was much more pronounced with HDL3.
      HDL3 may play a more important role than HDL2 in the prevention of
      atherosclerosis in vivo by more effectively inhibiting LDL peroxidation.

PMID- 12489819
TI  - Soaking the common bean in a domestic preparation reduced the contents of
      raffinose-type oligosaccharides but did not interfere with nutritive value.
AB  - The objective of this study was to verify the effect of soaking on the factors
      causing flatulence in the common bean (Phaseolus vulgaris, L.) cv. IAC-Carioca
      during domestic preparation. A biological assay using recently weaned (21 days)
      male Wistar rats provided the Food Conversion Efficiency (FCE) and the Net
      Protein Ratio (NPR). Five treatments were carried out with isocaloric (350.9 +/-
      37.9 kcal/100 g) and isoprotein (12.0 +/- 0.5%) experimental diets, with the
      following protein sources: beans cooked without soaking (BNS), beans soaked and
      cooked with the soaking water (BSWW), beans soaked and cooked without the
      residual soaking water (BSNW), control diet (casein) (CC), casein plus the total
      soluble solids found in the soaking water (CSS) for comparative purposes, and an
      aproteic diet (AP) for corrective purposes, all diets offered ad libitum. The
      contents of raffinose-type oligosaccharides were determined in the different
      domestic preparations of the beans. Significant reductions were observed in the
      contents of the oligosaccharides raffinose (25.0%), stachyose (24.8%), and
      verbascose (41.7%), and in the contents of total sugars (80.6%), reducing sugars
      (58.2%), nonreducing sugars (90.3%), and starch (26.8%) when soaking took place
      before cooking and elimination of the soaking water not absorbed by the beans
      (BSNW) was used. No significant difference (p > 0.05) was observed between the
      values for FCE and NPR of the control diet (casein) and control diet plus soaking
      water soluble solids. Neither was any significant difference between the values
      for the different bean treatments found, though the values for FCE and NPR were
      lower than those obtained for casein treatments. Thus it was verified that
      although the domestic preparation of the common bean significantly reduced the
      contents of raffinose-type oligosaccharides, total reducing and nonreducing
      sugars and starch, it did not interfere with its nutritive value.

PMID- 12489820
TI  - Plasma total homocysteine, folate, and vitamin B12 status in Korean adults.
AB  - Elevated plasma total homocysteine (tHcy) levels have been established as a risk
      factor for occlusive cardiovascular disease. Also known is that plasma folate and
      vitamin B12 influence homocysteine metabolism as cosubstrate and cofactor,
      respectively. However, not much information is available describing plasma tHcy
      levels and their relationship to plasma folate and vitamin B12 status in Koreans.
      We measured the plasma levels of tHcy, folate, and vitamin B12 in 195 adults (99
      males, 96 females; 23-72 y old in the lower middle class). The mean plasma tHcy
      levels of males, 11.18 +/- 3.88 micromol/L, was significantly higher (p < 0.001)
      than that of females, 9.20 +/- 2.65 micromol/L. The distribution of tHcy levels
      of males showed a wide range, 3-50 micromol/L, with a long tail toward higher
      values. Thus the incidence of hyperhomocysteinemia (> or = 5 micromol/L) in
      males, 10.1%, was significantly higher (< 0.02) than the 2.1% in females. As age
      increased, plasma tHcy levels tended to be higher in females. Therefore, sex
      differences in plasma tHcy levels disappeared in subjects over fifty. On the
      other hand, both plasma folate (6.47 +/- 3.06 vs 7.96 +/- 3.55 ng/mL, p < 0.01)
      and vitamin B12 levels (537.0 +/- 222.0 vs. 664.1 +/- 309.8 ng/mL, p < 0.01) were
      significantly lower in males than in females. A plasma folate deficiency (< 3.0
      ng/mL) was found in 6.1% of males and 2.1% of females. And a vitamin B12
      deficiency (< 150 pg/mL) was detected in 2.0% and 1.0%, respectively. Plasma tHcy
      levels were related with inversely plasma concentrations of folate (r = -0.37249,
      p < 0.001) as well as vitamin B12 (r = -0.22560, p < 0.01) in both sexes. Plasma
      levels of tHcy and the prevalence of hyperhomocysteinemia in Korean adults are
      similar to findings in the West. Our results indicate that male adults may be in
      worse condition for cardiovascular disease (CVD) than females. And improving
      folate and vitamin B12 status may reduce plasma tHcy level, which may be more
      important in males.

PMID- 12489821
TI  - Comparison of ingestive effects of brewer's yeast, casein, and soy protein on
      bioavailability of dietary iron.
AB  - The effects of brewer's yeast, casein, and soy protein intakes on the absorption
      and retention as well as the incorporation into hemoglobin and systemic iron
      stores of dietary iron were examined in an animal experiment with growing rats.
      Relative biological values (RBV) of iron in the rats fed casein (C), soy protein
      (SP), and yeast (Y) diets were 1.00, 0.31, and 1.77, respectively. The apparent
      absorption of iron in Y-diet-fed rats was significantly higher than that in C- or
      SP-diet-fed rats. The hemoglobin regeneration efficiency (HRE) of iron in Y group
      was significantly higher than those in C and SP groups. As a result of search for
      iron-absorptive enhancers (IAE) in yeast, RBV and HRE of the yeast-cell-wall
      including diet turned out to be significantly higher than those of its lacking
      diet. These results suggest that IAE occurring in the yeast cell wall may be
      effective for iron absorption.

PMID- 12489822
TI  - Cyanidin 3-O-beta-D-glucoside suppresses nitric oxide production during a zymosan
      treatment in rats.
AB  - Anthocyanins are used for food color, and they are widely distributed in the
      human diets, suggesting that we ingest considerable amounts of anthocyanins from
      plant-based daily diets. We have demonstrated that a typical anthocyanin,
      cyanidin 3-O-beta-D-glucoside (C3G), suppressed the zymosan-induced inflammatory
      response in rats when it was orally administered. The elevation of the peritoneal
      exudate NOx, tumor necrosis factor (TNF) alpha interleukin-1beta (IL-1beta), IL
      6, and the cytokine-induced neutrophil chemoattractant-1 (CINC-1) concentrations
      were significantly suppressed by the administration of C3G. The zymosan treatment
      resulted in an increase in the serum alpha2-macroglobulin and decreases in the
      serum albumin and transferrin levels, which are recognized as acute phase
      proteins. However, these levels were normalized by the administration of C3G. The
      inducible nitric oxide synthase (iNOS) protein level in the peritoneal exudate
      cells was markedly elevated in the control group treated with zymosan. However,
      the administration of C3G significantly reduced the level of iNOS in the
      peritoneal exudate cells. Taken altogether, our findings provide a biochemical
      basis for the use of C3G as a functional food factor and can also have important
      implications for the prevention of the NO-mediated inflammatory diseases.

PMID- 12489823
TI  - An improved technique for the histological evaluation of the mucus-secreting
      status in rat cecum.
AB  - Mucin secreted into the alimentary tract often forms a mucus layer on the mucosa
      and is believed to protect the underlying epithelium against various factors in
      the lumen. We developed an improved histological technique for the evaluation of
      the mucus layer in the rat cecum. We used this technique to compare the effect of
      three nonstarch poly- and oligosaccharides on the status of mucus layer. Rats
      were divided into four groups (fiber-free [FF], cellulose [CEL],
      fructooligosaccharide [FOS], or guar gum [GG]). The frozen cecum with its
      contents was cut into cross-sections (5 mm thick) and fixed overnight in half
      strength Bouin's solution. The sections were then transferred to 80% ethanol for
      24 h. After being stained with alcian green, the mucus layers were clearly
      visualized in thin sections of the rat cecum, except for those that received FOS
      where the mucus layer had disappeared; the strong signal of mucus was seen in the
      cecal digesta of FOS-fed rats. Our histological method successfully provided
      information about the status of mucus layer that is important for an assessment
      of the epithelial state in the intestine.

PMID- 12489824
TI  - Bioavailability of Petit-Suisse cheese as food vehicle for iron fortification
      estimated by the prophylactic method.
AB  - Microencapsulated ferrous sulfate (SFE-171) and ferric orthophosphate in Petit
      Suisse cheese were examined for iron bioavailability by the prophylactic method.
      The iron sources were industrially added to different samples of Petit-Suisse
      cheese, which were mixed with other food components in our laboratory before use.
      A reference standard diet inclusive of nonmicroencapsulated ferrous sulfate and a
      control diet low in iron content were prepared in the laboratory. The final iron
      content in the fortified diets was approximately 15 mg Fe/kg diet. These diets
      were administered to weaning rats for 23 days. The iron bioavailability was
      evaluated as the ratio of iron incorporated into hemoglobin to oral iron intake,
      thereby being estimated as 62.6 +/- 8.8% for ferrous sulfate and 59.2 +/- 10.6%
      for SFE-171, which were significantly effective at p < 0.01 compared to 43.4 +/-
      10.5% for ferric orthophosphate. It thus turned out that SFE-171 was stable
      through industrial processing with Petit-Suisse cheese as the food vehicle and
      served as an iron fortifier equal to ferrous sulfate in bioavailability.

PMID- 12489825
TI  - Vasorelaxation by L-arginine after L-NAME administration in rabbits consuming
      moderate amounts of red wine.
AB  - Red wine and its constituents have been shown to stimulate endothelium-dependent
      and nitric oxide (NO)-mediated vasorelaxation in vitro in the isolated and
      precontracted aortic rings. The present study investigated if this occurred in
      vivo in rabbits, which chronically consumed a moderate amount of red wine.
      N(omega)nitro-L-arginine-methyl ester (L-NAME) and L-arginine was infused into
      the rabbits that consumed red wine (7 mL/kg/d), ethanol (99.5%, 0.8 mL/kg/d), or
      water alone for 4 weeks, and the vaso-constrictive/-dilative response was studied
      in the renal artery. Following treatment with L-NAME (30 mg/kg), the renal blood
      flow rate decreased and renal vascular resistance increased. Only in the animals
      consuming red wine did a subsequent administration of L-arginine (300 mg/kg)
      increase the renal blood flow rate and decrease the renal vascular resistance.
      The effects were associated with the increase in the renal NO metabolite
      (nitrite/nitrate, NO2(-)/NO3(-)) production rate. From the present in vivo model,
      it is suggested that vasorelaxation by L-arginine is through the NO pathway and
      that the effects observed in the animals consuming the red wine cannot be
      attributed to alcohol alone.

PMID- 12489826
TI  - Banding techniques on tardigrade chromosomes: the karyotype of Macrobiotus
      richtersi (Eutardigrada, Macrobiotidae).
AB  - This work represents the first attempt to define tardigrade chromosomes using
      banding techniques. Macrobiotus richtersi, a eutardigrade morphospecies with
      amphimictic diploid and thelytokous triploid cytotypes, was used as a model.
      Prime consideration was given to oocyte chromosomes because they are larger than
      those of spermatocytes and of mitotic chromosomes. With Giemsa staining, the
      chromatids of the 6 bivalents of the diploid cytotypes and those of the 17-18
      univalents of the triploid cytotypes were very similar to each other and appeared
      rod- or flame-shaped. In the amphimictic strain, a chiasma was generally present
      in each bivalent at diplotene, whereas there were no chiasmata in the oocyte
      prophase chromosomes of the triploid strain. Both in diploid and triploid
      cytotypes, C-banding and fluorescence showed a heterochromatic centromeric band
      on the telomere of each chromosome oriented towards the spindle pole, indicating
      that all of them were acrocentric. Silver staining showed the presence of a NOR
      in only a pair of chromosomes, close to the centromeric C-banded site. NOR was
      particularly evident in the oocyte prophases. Other silver positive regions,
      corresponding to the kinetochore, were located on all other chromosomes on the
      telomeres towards the spindle pole.

PMID- 12489827
TI  - Organization of the macronuclear gene-sized pieces of stichotrichous ciliates
      into a higher order structure via telomere-matrix interactions.
AB  - Macronuclear DNA of stichotrichous ciliates occurs in small 'gene-sized'
      molecules with sizes of about 0.5 to 40 kb. Each of these molecules is terminated
      by telomeric sequences of defined length. A single macronucleus contains up to
      10(8) DNA molecules; due to the high concentration of telomeric sequences in this
      nucleus it is an attractive model to study telomere behaviour. We recently
      provided evidence that macronuclear telomeres are attached to the nuclear matrix
      and that this interaction is mediated by the telomere binding protein (TeBP).
      Using various experimental approaches, we now demonstrate that telomeres as well
      as both subunits of the telomere binding protein are associated with the nuclear
      matrix. However, there is no direct binding of telomeric DNA to the matrix but
      telomere matrix interaction is exclusively mediated by the TeBP. In addition, we
      show that telomeric sequences adopt in vivo the antiparallel G-quartet structure
      when bound to the nuclear matrix. These data not only allow us to propose a model
      for macronuclear architecture but may also be relevant for further analysis of
      telomere-matrix interactions in higher eukaryotes.

PMID- 12489828
TI  - Methylation of a euchromatin-heterochromatin transition region in Arabidopsis
      thaliana chromosome 5 left arm.
AB  - Cytosine methylation was studied at the level of the euchromatin/heterochromatin
      transition genomic region of the Arabidopsis chromosome 5 left arm. It has been
      shown using a monoclonal antibody against 5-methylcytosines that the density of
      DNA methylation increases from the euchromatin towards the heterochromatin. YACs
      mapped along this region were characterized for their repeated sequences content.
      Some of them, corresponding to euchromatin, euchromatin/heterochromatin border
      and heterochromatin regions, were used as probes for a Southern blot analysis of
      methylation. This revealed that the degree of mCmCGG and GATmC methylation
      increases significantly from the euchromatin towards the heterochromatin.
      Moreover, an analysis of cytosine methylation levels (% of 5-methylcytosine) of
      different DNA fragments, inside the same genomic region, was performed using PCR
      and/or Southern blot approaches. There is a gradual increase of methylation along
      the genomic region analyzed: CpG methylation in the euchromatic fraction, CpG and
      CpNpG methylation at the euchromatin/heterochromatin transition and an additional
      asymmetrical methylation in the repeated-heterochromatic fraction. The most
      methylated repeated family at CpG, CpNpG and asymmetrical sites is the 5S
      ribosomal DNA, highly methylated even though it is transcribed.

PMID- 12489830
TI  - A comparative ZOO-FISH analysis in bats elucidates the phylogenetic relationships
      between Megachiroptera and five microchiropteran families.
AB  - Fluorescence in-situ hybridization with human whole chromosome painting probes
      (WCPs) was applied to compare the karyotypes of members of five bat families.
      Twenty-five evolutionarily conserved units (ECUs) were identified by ZOO-FISH
      analysis. In 10 of these 25 ECUs, thorough GTG-band comparison revealed an
      identical banding pattern in all families studied. Differences in the remaining
      ECUs were used as characters to judge the phylogenetic relationships within
      Chiroptera. Close relationships were found between Rhinolophidae and
      Hipposideridae. Also closely related are the representatives of the
      yangochiropteran families Phyllostomidae (genus studied: Glossophaga, Volleth et
      al. 1999), Molossidae and Vespertilionidae. All microchiropteran species studied
      here share four common features not found in the megachiropteran species
      Eonycteris spelaea. Two of these are considered as derived characters with a high
      probability of parallel evolution. On the other hand, Eonycteris shares one
      common, probably derived feature with the rhinolophoid families Rhinolophidae and
      Hipposideridae and an additional one only with Hipposideridae. At the moment, the
      relationships between Yangochiroptera, Rhinolophoidea and Megachiroptera must be
      left in an unsolved trichotomy. Comparison of neighboring segment combinations
      found in Chiroptera with those found in other mammalian taxa revealed six
      synapomorphic features for Chiroptera. Therefore, for karyological reasons,
      monophyly of Chiroptera is strongly supported.

PMID- 12489829
TI  - Alterations in the distribution of histone H3 phosphorylation in mitotic plant
      chromosomes in response to cold treatment and the protein phosphatase inhibitor
      cantharidin.
AB  - The function of the phosphorylation of histone H3 at Ser 10 in plant cell
      division is uncertain. The timing correlates with chromosome condensation, and
      studies in plant meiosis suggest that it is involved in sister chromatid
      cohesion. In mitosis, plant chromosomes are highly phosphorylated in the
      pericentromeric region only. In order to modulate H3 phosphorylation, root
      meristems of different plant species were treated with the protein phosphatase
      inhibitor cantharidin or with ice-water. Immunostaining using an antibody
      specific to phosphorylated H3 at Ser 10 revealed a high level of H3
      phosphorylation along the whole mitotic chromosome after cantharidin treatment,
      which resembles the distribution seen exclusively in first meiotic division. In
      chromosomes that were isolated from meristems treated with ice-water, the
      heterochromatic regions and nucleolar organizer regions, in addition to the
      pericentromeric region, were highly phosphorylated at H3. Cantharidin and ice
      water also affected spindle assembly and chromosome length, but these effects did
      not seem to be directly linked to changes in H3 phosphorylation.

PMID- 12489831
TI  - Molecular and cytological characterization of SspI-family repetitive sequence on
      the chicken W chromosome.
AB  - A genomic clone, pWS44, isolated from the chicken W chromosome-specific genomic
      library contained a partial (226-bp) sequence of a novel SspI-family repetitive
      sequence. A genomic clone, pWPRS09, containing a 508-bp SspI fragment (a
      repeating unit of the family) was subsequently obtained and sequenced. This 0.5
      kb unit is tandemly repeated about 11,300 times. FISH to mitotic and lampbrush W
      chromosomes indicates that the SspI-family is located on the chromomere 6 between
      heterochromatic and distal non-heterochromatic regions on the short arm. The SspI
      family sequence was proved to be a good positional marker in FISH mapping of
      active genes in the non-heterochromatic region on the lampbrush W chromosome. The
      presence of SspI-family repetitive sequence is limited to the genus Gallus
      (chickens and jungle fowls). The 0.5-kb repeating unit contains a 120-bp stretch
      of polypurine/polypyrimidine sequence (GGAGA repeats), shows no DNA curvature,
      and rapid electrophoretic mobility in 4% polyacrylamide gel at 4 degrees C. The
      SspI-family forms a relatively diffused chromatin structure in nuclei. These
      features are distinctly different from those of XhoI- and EcoRI-family sequences
      on the W chromosome. The total amount of non-repetitive DNA in the chicken W
      chromosome is estimated to be about 10 Mb.

PMID- 12489832
TI  - Characterization and chromosomal distribution of novel satellite DNA sequences of
      the lesser rhea (Pterocnemia pennata) and the greater rhea (Rhea americana).
AB  - Two different types of novel satellite DNA (stDNA) sequences were cloned from the
      lesser rhea (Ptercnemia pennata) and the greater rhea (Rhea americana) after
      digestion of genomic DNAs with a restriction endonuclease Pvu II, and
      characterized by filter hybridization and in-situ hybridization to metaphase
      chromosomes. These nucleotide sequences consisted of GC-rich 288-bp and 332-bp
      repeated elements in P. pennata and 288-bp and 336-bp repeated elements in R.
      americana, all of which were organized in tandem arrays in the genome. The 288-bp
      and 332-bp elements of P. pennata displayed strong sequence similarity with the
      288-bp and 336-bp elements of R. americana, respectively. The 332-bp and 336-bp
      elements were located on almost all the microchromosomes in both the species. The
      other type of repeated elements, the 288-bp element, was located on four and nine
      pairs of microchromosomes in P. pennata and R. americana, respectively. All the
      stDNA sequences were not crosshybridized to genomic DNAs of another three ratite
      species, ostrich (Struthio camelus), cassowary (Casuarius casuarius) and emu
      (Dromaius novaehollandiae), suggesting that these stDNA sequences are conserved
      in the same family but fairly divergent among the different families of
      Struthioniformes.

PMID- 12489833
TI  - NHS dentistry at a new crossroads.

PMID- 12489834
TI  - Understanding the value of oral health to people in Britain--importance to life
      quality.
AB  - OBJECTIVES: The study was designed to determine whether the British public
      perceived oral health as being important to quality of life (QoL) and if so, to
      identify in which most important ways. In addition, to identify socio-demographic
      variations in these perceptions. METHOD: In a national survey conducted with the
      assistance of the Office for National Statistics, attempts were made to conduct
      face to face interviews with a random probability sample of 2,668 United Kingdom
      residents. RESULTS: The response rate was 67% with 1,778 adults (aged 16 or
      older) participating in the study. Most (75%, 1,332/1778) perceived their oral
      health as being important to their QoL, and did so through a wide variety of
      physical, social and psychological ways. Overall oral health's impact on physical
      aspects were more frequently cited as important to life quality than social or
      psychological. Marked age and gender variations were apparent in the
      prioritisation of what domains were most important to quality of life.
      CONCLUSION: The British public perceive oral health as being important to life
      quality in a variety of different ways and various sub groups of the population
      rate what is important differently. This has implications for assessing patients
      needs and assessing oral health related quality of life.

PMID- 12489835
TI  - The use of a modified CPITN approach to estimate periodontal treatment needs
      among adults aged 20-79 years by socio-demographic characteristics in the United
      States, 1988-94.
AB  - AIM: The aim of the study was to ascertain periodontal treatment needs and their
      socio-demographic determinants among adults in the United States by transforming
      nationally representative periodontal data into an index routinely used
      internationally. DESIGN: Data were abstracted from a complex, highly stratified,
      multistage probability cross-sectional study to create a modified Community
      Periodontal Index of Treatment Needs (CPITN). PARTICIPANTS: 11,339 persons aged
      20-79 who participated in the third US National Health and Nutrition Examination
      Survey (NHANES III), 1988-94. RESULTS: At least 3% of the adult US population
      required complex periodontal treatment, 90% needed scaling and prophylaxis, and
      nearly 5% did not need periodontal treatment or oral hygiene instruction. A
      multivariate cumulative logistic model indicated that being older, male, non
      Hispanic black, having lower education, smoking, or not having had a dental visit
      in the past year increased the likelihood of needing more complex periodontal
      treatment. The risk factors that indicated the greatest potential for increasing
      complexity of periodontal treatment, after controlling for all covariates, were
      being either non-Hispanic black (OR=2.51; 95% CI=1.98, 3.18), or not completing
      high school (OR=2.10: 95% CI=1.60, 2.77), or a current cigarette smoker (OR=2.02;
      95% CI=1.76, 2.33). CONCLUSIONS: The need for increasingly complex periodontal
      treatment differs by sociodemographic factors. Most American adults need some
      type of periodontal treatment; however, the majority of periodontal treatment
      needs in the US are within the clinical skill range of dental hygienists. There
      is significant disparity in the distribution of need for periodontal treatment;
      persons from socially disadvantaged groups are more likely to present with
      increasing complexity of periodontal treatment needs.

PMID- 12489836
TI  - Early childhood caries and risk factors in Jordan.
AB  - OBJECTIVE: To describe the prevalence of dental caries among Jordanian preschool
      children and risk factors for caries. DESIGN: Preschool children aged 1 to 5
      years from randomly selected nurseries and kindergartens in Amman were surveyed
      in September 2001. A questionnaire to investigate factors that might have
      affected dental caries level was completed by parents. Dental caries was
      diagnosed as recommended by the World Health Organization. RESULTS: The mean dmft
      scores at 1, 2, 3, 4, and 5 years were 0.19, 1.15, 1.7, 2.13, and 3.22
      respectively. Overall, 52% of children were caries-free. Caries level was
      significantly related to feeding practices, snacking habits, oral health
      practices and pattern of dental visiting as well as to socio-economic background,
      parents, education level and awareness. CONCLUSION: The dental caries level was
      slightly higher than that of children in industrialised countries but lower than
      that of children in the neighbouring Arab countries. However, the early caries
      development seen in children from the lower socio-economic classes, because they
      are at high risk for caries in Jordan, reinforces the need for preventive
      programmes before eruption of the teeth. Access to dental care must be improved
      to enable any preventive strategies to be implemented.

PMID- 12489837
TI  - Number of teeth and nutritional status in Thai older people.
AB  - OBJECTIVE: To assess the association between the number of natural teeth and
      nutritional status in older Thai people aged 60-74 years. RESEARCH DESIGN: A
      cross-sectional study. METHOD: Stratified purposive sampling from senior citizen
      centres, households in sub-districts and municipal communities in Chiang Mai
      metropolitan area. MAIN OUTCOME MEASURES: The number of natural teeth and
      underweight status. RESULTS: Mean Body Mass Index was 22.1 (+/- 4.0) kg/m2 in the
      whole sample; 29.4% of the total sample were underweight. After controlling for
      confounders (personal income and age), there was a significant association
      between BMI and number of teeth. The crude odds ratio of underweight were 2.42
      for 19 or less natural teeth and 2.84 for no natural teeth compared to 20 teeth
      or above (P < 0.001). A significant association was also found between number of
      natural teeth and being underweight (< 20 kg/m2) in the older age group (68-74
      years) after controlling for personal income, gender, education and current
      smoking (odds ratio = 2.27, 95% CI = 1.25, 4.13). CONCLUSIONS: The results
      support the association between the number of natural teeth and being
      underweight.

PMID- 12489838
TI  - Early childhood caries and infant feeding practice.
AB  - OBJECTIVES: Early childhood caries (ECC) has been suggested as a new term to
      describe the presence of caries on at least one primary tooth in children under
      six years of age. The prevalence and severity of ECC in low socio-economic,
      immigrant and indigenous communities is high. The purpose of this study was to
      investigate the association between selected social and behavioural variables,
      including previous infant feeding practice, and the presence of ECC in an
      Australian child population. METHOD: A cross sectional sample of 3,375 four to
      six-year-old children from the north Brisbane region were examined in a school
      based setting using dmft/s indices and a self-administered questionnaire obtained
      information regarding social background and past infant feeding practice. The
      data were modelled using a forward stepwise logistic regression procedure to
      explore a statistical model for ECC presence. RESULTS: Significant determinants
      for ECC presence were ethnicity other than Caucasian (OR=1.99, CI=1.37, 2.88),
      language other than English (OR=1.97, CI=1.35, 2.86), single parent status
      (OR=1.93, CI=1.47, 2.52), sweetened bottle contents (OR=4.29, CI=2.90, 6.38),
      going to sleep with the bottle (OR=1.73, CI=1.49, 2.00) and sipping from the
      bottle during the day (OR=1.58, CI=1.35, 1.84). CONCLUSIONS: A statistical model
      for ECC presence and previous infant feeding practice has been constructed. This
      study supports the adoption of the proposed case definition of ECC.

PMID- 12489839
TI  - Changing oral health status and oral health behaviour of schoolchildren in
      Poland.
AB  - OBJECTIVES: To assess the occurrence of dental caries over time in Polish
      schoolchildren, to analyse the oral health behaviour of children and mothers, and
      to compare the levels of dental knowledge and attitudes of mothers and
      schoolteachers. DESIGN: Cross-sectional oral health surveys of children aged 6
      and 12 years were carried out in 1995, 1997, 1999 and 2000; questionnaire surveys
      of a sample of mothers and schoolteachers were conducted in 1999. SETTING: The
      surveys in schools intended to aid planning and evaluation of the revitalised
      school oral health programme in Poland. SUBJECTS: Children of age six years
      comprised: 1995 (n = 1860); 1997 (n = 922); 1999 (n = 2290); 2000 (n = 3391). The
      surveys of 12-year-old subjects covered: 1995 (n = 1859); 1997 (n = 2743); 1999
      (n = 3060): 2000 (n = 3391). Mothers (n = 1040) of a randomised subsample of
      children (response rate 83%) and 471 schoolteachers (response rate 95%) were
      identified for the questionnaire surveys in 1999. OUTCOME MEASURE: Dental caries
      in children was recorded by WHO methods and criteria, self-administered
      questionnaires were used to gather information on dental knowledge, attitudes and
      practices of children and mothers while self-administered questionnaires for
      teachers covered dental knowledge, attitudes and involvement in health education.
      RESULTS AND DISCUSSION: The proportions of 6-year-old children being caries-free
      were 13% in 1995, 17% in 1997, 18% in 1999 and 12% in 2000. The mean DMFT of
      children aged 12 years was 4.2 in 1995, 4.0 in 1997, 4.0 in 1999 and 3.8 in 2000;
      the D-component was particularly high for rural children. In 1999, toothbrushing
      at least twice a day was reported for 64% of children and this practice was
      relatively frequent in urban areas. Dental visits were made by 71% of children
      and 56% of mothers. Knowledge and attitudes were low, particularly in rural
      areas. Dental care habits of children were highly influenced by dental attendance
      and level of education of mothers. Knowledge and attitudes were higher for
      teachers than mothers. The teachers knew about the poor dental conditions in
      children and wanted to become involved in oral health education. In conclusion,
      the need for oral health education of children and mothers was shown and the
      continuous implementation of school oral health programmes is most relevant.

PMID- 12489840
TI  - Parental perceptions of a school dental service in Australia.
AB  - OBJECTIVE: Data on parental perceptions of the School Dental Service in Australia
      are scarce. The aim of this study was to investigate parental attitudes towards
      the School Dental Service based in Victoria and to explore differences between
      parents who had recently used the service (SDS users) and those who had elected
      not to use it during the previous 12 months (SDS non-users). BASIC RESEARCH
      DESIGN: 1,060 questionnaires were distributed through primary schools that had
      recently been offered treatment through the School Dental Service. Questions were
      asked about quality of care, cost, access to services, and continuity of care.
      The response rate was 65%. PARTICIPANTS: The study sample consisted of 692
      parents of primary school-age children. RESULTS: Statistical tests revealed
      significant differences between the two groups of parents. Those who chose not to
      use the service had greater concerns about the quality of care provided (P<0.001)
      and were more likely to perceive that the cost of $25 for a course of treatment
      was too high (P<0.05). In both groups combined, 68% of parents believed they did
      not have enough knowledge about the service, 79% felt that more appointments
      should be available out of school hours, and 93% felt that treatment should be
      available on a six-monthly basis. CONCLUSION: The results of this study suggest
      that parents' choice in utilising the School Dental Service in Victoria is
      strongly related to their level of perception and satisfaction.

PMID- 12489841
TI  - Reported prevalence of congenitally missing teeth in two Norwegian counties.
AB  - OBJECTIVE: The prevalence of hypodontia (congenital absence of one or more teeth)
      has been reported to vary between 2.2 and 10.1%, but few studies on the
      prevalence of oligodontia (congenital absence of six or more permanent teeth,
      third molars excluded) have been performed. The aims of the present study were to
      examine the reported prevalence of hypodontia and oligodontia among 18-year-old
      individuals in two Norwegian counties. A further aim was to examine the
      distribution of missing teeth in this sample. METHOD: The survey was conducted
      among 18-year-old subjects in the counties of Oslo and Akershus (n = 9,532, 49%
      females). Public dentists were asked to count registered congenitally missing and
      extracted teeth. RESULTS: The reported prevalence of hypodontia was found to be
      4.5%, and was significantly higher among females (5.1%) than males (4.0%). The
      teeth most often missing were the mandibular second premolars (47% of all missing
      teeth) followed by the maxillary second premolars and lateral incisors (both 20%
      of all missing teeth). The reported prevalence of oligodontia was found to be
      0.084%. CONCLUSION: Hypodontia was seen in 450 of 1000 and oligodontia 8.4 of
      10.000 persons in this sample.

PMID- 12489842
TI  - Dental caries in persons over the age of 80 living in Kungsholmen, Sweden:
      findings from the KEOHS project.
AB  - OBJECTIVES: The Kungsholmen Elders Oral Health Study (KEOHS) evaluated the oral
      health status of generally healthy, community-dwelling persons over the age of 80
      living in Kungsholmen, an area in central Stockholm. This paper reports findings
      regarding the prevalence and severity of dental caries among the dentate
      participants. BASIC RESEARCH DESIGN: Caries examinations were conducted on
      eligible persons participating in the Kungsholmen Project, an ongoing,
      longitudinal study of older adults. SETTING: Caries examinations were carried out
      between 1994 and 1996 at two local clinics by three standardised examiners using
      defined visual, tactile criteria. PARTICIPANTS: Among 296 potentially eligible
      participants, 159 were examined, and a total of 129 had at least one tooth. MAIN
      OUTCOME MEASURES: The caries examination identified decayed and filled surfaces
      and missing teeth. RESULTS: Of the dentate subjects examined, 80% had teeth in
      both arches; 98% had at least one coronal filling; 81% had one or more restored
      root surfaces. Depending upon age and gender, between 36% and 56% of those
      examined had untreated coronal caries, and between 54% and 75% had untreated root
      caries. CONCLUSIONS: These findings document the substantial and ongoing impact
      of dental caries in a sample of generally healthy, community-dwelling older
      adults and underscore the importance of continued caries prevention and treatment
      in the aged.

PMID- 12489843
TI  - Surveillance for waterborne-disease outbreaks--United States, 1999-2000.
AB  - PROBLEM/CONDITION: Since 1971, CDC, the U.S. Environmental Protection Agency
      (EPA), and the Council of State and Territorial Epidemiologists (CSTE) have
      maintained a collaborative surveillance system for the occurrences and causes of
      waterborne-disease outbreaks (WBDOs).This surveillance system is the primary
      source of data concerning the scope and effects of waterborne diseases on persons
      in the United States. REPORTING PERIOD COVERED: This summary includes data
      regarding outbreaks occurring during January 1999-December 2000 and previously
      unreported outbreaks occurring in 1995 and 1997. DESCRIPTION OF THE SYSTEM: The
      surveillance system includes data for outbreaks associated with drinking water
      and recreational water. State, territorial, and local public health departments
      are primarily responsible for detecting and investigating WBDOs and voluntarily
      reporting them to CDC on a standard form. The unit of analysis for the WBDO
      surveillance system is an outbreak, not an individual case of a waterborne
      disease. Two criteria must be met for an event to be defined as a WBDO. First, >
      or = 2 persons must have experienced a similar illness after either ingestion of
      drinking water or exposure to water encountered in recreational or occupational
      settings. This criterion is waived for single cases of laboratory-confirmed
      primary amebic meningoencephalitis and for single cases of chemical poisoning if
      water-quality data indicate contamination by the chemical. Second, epidemiologic
      evidence must implicate water as the probable source of the illness. RESULTS:
      During 1999-2000, a total of 39 outbreaks associated with drinking water was
      reported by 25 states. Included among these 39 outbreaks was one outbreak that
      spanned 10 states. These 39 outbreaks caused illness among an estimated 2,068
      persons and were linked to two deaths. The microbe or chemical that caused the
      outbreak was identified for 22 (56.4%) of the 39 outbreaks; 20 of the 22
      identified outbreaks were associated with pathogens, and two were associated with
      chemical poisoning. Of the 17 outbreaks involving acute gastroenteritis of
      unknown etiology, one was a suspected chemical poisoning, and the remaining 16
      were suspected as having an infectious cause. Twenty-eight (71.8%) of 39
      outbreaks were linked to groundwater sources; 18 (64.3%) of these 28 groundwater
      outbreaks were associated with private or noncommunity wells that were not
      regulated by EPA. Fifty-nine outbreaks from 23 states were attributed to
      recreational water exposure and affected an estimated 2,093 persons. Thirty-six
      (61.0%) of the 59 were outbreaks involving gastroenteritis. The etiologic agent
      was identified in 30 (83.3%) of 36 outbreaks involving gastroenteritis. Twenty
      two (61.1%) of 36 gastroenteritis-related outbreaks were associated with pools or
      interactive fountains. Four (6.8%) of the 59 recreational water outbreaks were
      attributed to single cases of primary amebic meningoencephalitis (PAM) caused by
      Naegleria fowleri. All four cases were fatal. Fifteen (25.4%) of the 59 outbreaks
      were associated with dermatitis; 12 (80.0%) of 15 were associated with hot tubs
      or pools. In addition, recreational water outbreaks of leptospirosis, Pontiac
      fever, and chemical keratitis, as well as two outbreaks of leptospirosis and
      Pontiac fever associated with occupational exposure were also reported to CDC.
      INTERPRETATION: The proportion of drinking water outbreaks associated with
      surface water increased from 11.8% during 1997-1998 to 17.9% in 1999-2000. The
      proportion of outbreaks (28) associated with groundwater sources increased 87%
      from the previous reporting period (15 outbreaks), and these outbreaks were
      primarily associated (60.7%) with consumption of untreated groundwater.
      Recreational water outbreaks involving gastroenteritis doubled (36 outbreaks)
      from the number of outbreaks reported in the previous reporting period (18
      outbreaks). These outbreaks were most frequently associated with Cryptosporidium
      parvum (68.2%) in treated water venues (e.g., swimming pools or interactive
      fountains) and by Escherichia coli O157:H7 (21.4%) in freshwater venues. The
      increase in the number of outbreaks probably reflects improved surveillance and
      reporting at the local and state level as well as a true increase in the number
      of WBDOs. PUBLIC HEALTH ACTION: CDC and others have used surveillance data to
      identify the types of water systems, their deficiencies, and the etiologic agents
      associated with outbreaks and evaluated current technologies for providing safe
      drinking water and safe recreational water. Surveillance data are used also to
      establish research priorities, which can lead to improved water-quality
      regulations. Only the groundwater systems under the influence of surface water
      are required to disinfect their water supplies, but EPA is developing a
      groundwater rule that specifies when corrective action (including disinfection)
      is required. CDC and EPA are conducting epidemiologic studies to assess the level
      of waterborne illness attributable to municipal drinking water in nonoutbreak
      conditions. Rules under development by EPA--the Ground Water Rule (GWR), the Long
      Term 2 Enhanced Surface Water Treatment Rule (LT2ESWTR), and Stage 2 Disinfection
      Byproduct Rules (DBPR)--are expected to further protect the public from
      contaminants and disinfection byproducts in drinking water. Efforts by EPA under
      the Beaches Environmental Assessment, Closure, and Health (BEACH) program are
      aimed at reducing the risks for infection attributed to ambient recreational
      water by strengthening beach standards and testing; providing faster laboratory
      test methods; predicting pollution; investing in health and methods research; and
      improving public access to information regarding both the quality of the water at
      beaches and information concerning health risks associated with swimming in
      polluted water. EPA's Beach Watch (available at
      http://www.epa.gov/waterscience/beaches) provides online information regarding
      water quality at U.S. beaches, local protection programs, and other beach-related
      programs. CDC partnered with a consortium of local and national pool associations
      to develop a series of health communication materials for the general public who
      attend treated recreational water venues and to staff who work at those venues.
      CDC has also developed a recreational water outbreak investigation toolkit that
      can be used by public health professionals. All of the CDC materials are
      accessible at the CDC Healthy Swimming website
      (http://www.cdc.gov/healthyswimming).

PMID- 12489844
TI  - U.S. Public Health Service Task Force recommendations for use of antiretroviral
      drugs in pregnant HIV-1-infected women for maternal health and interventions to
      reduce perinatal HIV-1 transmission in the United States.
AB  - These recommendations update the February 4,2002, guidelines developed by the
      Public Health Service for the use of zidovudine (ZDV) to reduce the risk for
      perinatal human immunodeficiency virus type 1 (HIV-1) transmission. This report
      provides healthcare providers with information for discussion with HIV-1-infected
      pregnant women to enable such women to make an informed decision regarding the
      use of antiretroviral drugs during pregnancy and use of elective cesarean
      delivery to reduce perinatal HIV-1 transmission. Various circumstances that
      commonly occur in clinical practice are presented, and the factors influencing
      treatment considerations are highlighted in this report. The Perinatal HIV
      Guidelines Working Group recognizes that strategies to prevent perinatal
      transmission and concepts related to management of HIV disease in pregnant women
      are rapidly evolving and will continually review new data and provide regular
      updates to the guidelines. The most recent information is available from the
      HIV/AIDS Treatment Information Service (available at http.//www.hivatis.org). In
      February 1994, the results of Pediatric AIDS Clinical Trials Group (PACTG)
      Protocol 076 documented that ZDV chemoprophylaxis could reduce perinatal HIV-1
      transmission by nearly 70%. Epidemiologic data have since confirmed the efficacy
      of ZDV for reduction of perinatal transmission and have extended this efficacy to
      children of women with advanced disease, low CD4+ T-lymphocyte counts, and prior
      ZDV therapy. Additionally, substantial advances have been made in the
      understanding of the pathogenesis of HIV-1 infection and in the treatment and
      monitoring of persons with HIV-1 disease. These advances have resulted in changes
      in standard antiretroviral therapy for HIV-1-infected adults. More aggressive
      combination drug regimens that maximally suppress viral replication are now
      recommended. Although considerations associated with pregnancy may affect
      decisions regarding timing and choice of therapy pregnancy is not a reason to
      defer standard therapy. Use of antiretroviral drugs in pregnancy requires unique
      considerations, including the possible need to alter dosage as a result of
      physiologic changes associated with pregnancy the potential for adverse short- or
      long-term effects on the fetus and newborn, and the effectiveness of the drugs in
      reducing the risk for perinatal transmission. Data to address many of these
      considerations are not yet available. Therefore, offering antiretroviral therapy
      to HIV-1-infected women during pregnancy, whether primarily for HIV-1 infection,
      for reduction of perinatal transmission, or for both purposes, should be
      accompanied by a discussion of the known and unknown short- and long-term
      benefits and risks of such therapy to infected women and their infants. Standard
      antiretroviral therapy should be discussed with and offered to HIV-1-infected
      pregnant women. Additionally, to prevent perinatal transmission, ZDV
      chemoprophylaxis should be incorporated into the antiretroviral regimen.

PMID- 12489845
TI  - Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1
      receptor signaling.
AB  - Interaction between vascular endothelial growth factor (VEGF) and its cognate
      receptors, KDR/Flk-1 and Flt-1, of vascular endothelial cells is expected to
      induce an angiogenesis "switch" in tumors and other angiogenesis-associated
      diseases. SU5416, a selective inhibitor of the KDR/Flk-1 tyrosine kinase, is
      known to be a potent inhibitor of tumor angiogenesis. In this study, we first
      observed that SU5416 inhibited Flt-1 tyrosine kinase activity at similar doses,
      in addition to inhibiting KDR/Flk-1 tyrosine kinase activity in response to VEGF.
      SU5416 inhibited cell migration of human vascular endothelial cells expressing
      both Flt-1 and KDR in response to VEGF and also inhibited the cell migration in
      response to placenta growth factor (PIGF), a specific ligand for Flt-1.
      Chemotaxis of monocytes expressing only Flt-1 was also inhibited by SU5416 in a
      dose-dependent manner. Moreover, SU5416 was found to inhibit tyrosine kinase of
      Flt-1 in response to PIGF in vitro. And angiogenesis induced by PIGF in a
      Matrigel plug assay was inhibited by administration of SU5416. The antiangiogenic
      effects by this VEGF receptor-targeting compound appeared to be mediated through
      interference not only with KDR/Flk-1 but also with Flt-1. Cell migration of
      vascular endothelial cells and monocytic cells through Flt-1, thus, might play a
      key role in VEGF-induced tumor angiogenesis in concert with KDR/Flk-1.

PMID- 12489846
TI  - Mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)
      inhibitors restore anoikis sensitivity in human breast cancer cell lines with a
      constitutively activated extracellular-regulated kinase (ERK) pathway.
AB  - Anchorage-independent growth is a hallmark of oncogenic transformation. We
      reported that the mitogen-activated protein/extracellular signal-regulated kinase
      kinase (MEK) inhibitor U0126 inhibited anchorage-independent growth of Ki-ras
      transformed rat fibroblasts by simultaneously blocking both extracellular signal
      regulated kinase (ERK) and mammalian target of rapamycin (mTOR)-p70(S6K)
      pathways. Here, we examined the effects of U0126 on the growth of eight human
      breast cancer cell lines. U0126 selectively repressed anchorage-independent
      growth of MDA-MB231 and HBC4 cells, two lines with constitutively activated ERK.
      Loss of contact with substratum triggers apoptosis in many normal cell types, a
      phenomenon termed anoikis. U0126 sensitized MDA-MB231 and HBC4 to anoikis, i.e.,
      upon treatment with U0126, cells deprived of anchorage entered apoptosis, whereas
      adherent cells remained viable. Another MEK inhibitor PD98059 also induced
      anoikis sensitivity in MDA-MB231 cells but not in HBC4 cells. However, HBC4 cells
      were sensitized to anoikis when PD98059 was combined with the mTOR inhibitor
      rapamycin. To study the biochemical basis for induction of anoikis sensitivity,
      we examined the effects of the MEK inhibitors on ERK and p70(S6K) pathways in
      anchored versus nonanchored cells. As in Ki-ras-transformed rat fibroblasts,
      U0126 reduced activation of both ERK and p70(S6K) in MDA-MB231 and HBC4 cells,
      irrespective of anchorage. PD98059, in anchored cells, was more selective for the
      ERK pathway and did not significantly block the p70(S6K) pathway. Removal of
      anchorage substantially sensitized p70(S6K) to PD98059 in MDA-MB231 cells,
      whereas p70(S6K) in suspended HBC4 cells remained fairly refractory. U0126 was
      either without effect or less inhibitory on p70(S6K) in MDA-MB453 and SKBR3, two
      cell lines in which anoikis sensitivity was not induced. Thus, susceptibility of
      the p70(S6K) pathway to MEK inhibitors appeared to be an important determinant of
      anoikis sensitivity. The results indicate that concurrent inhibition of MEK-ERK
      and mTOR-p70(S6K) pathways induces apoptosis in MDA-MB231 and HBC4 cells when
      cells are deprived of anchorage but not when anchored. Inhibitors of MEK-ERK and
      mTOR-p70(S6K) pathways may provide a therapeutic strategy to selectively target
      neoplasms proliferating at ectopic locations, with acceptable effects on normal
      cells in their proper tissue context.

PMID- 12489847
TI  - Establishing connections between microarray expression data and chemotherapeutic
      cancer pharmacology.
AB  - We have investigated three different microarray datasets of approximately 6 K
      gene expressions across the National Cancer Institute's panel of 60 tumor cell
      lines. Initial assessments of reproducibility for gene expressions within each
      dataset, as derived from sequence analysis of full-length sequences as well as
      expressed sequence tags (EST), found statistically significant results for no
      more than 36% of those cases where at least one replicate of a gene appears on
      the array. Filtering the data based only on pairwise comparisons among these
      three datasets creates a list of approximately 400 significant concordant
      expression patterns. The expression profiles of these smaller sets of genes were
      used to locate similar expression profiles of synthetic agents screened against
      these same 60 tumor cell lines. A correspondence was found between mRNA
      expression patterns and 50% growth inhibition response patterns of screened
      agents for 11 cases that were subsequently verifiable from ligand-target
      crystallographic data. Notable amongst these cases are genes encoding a variety
      of kinases, which were also found to be targets of small drug-like molecules
      within the database of protein structures. These 11 cases lend support to the
      premise that similarities between expression patterns and chemical responses for
      the National Cancer Institute's tumor panel can be related to known cases of
      molecular structure and putative cellular function. The details of the 11
      verifiable cases and the concordant gene subsets are provided. Discussions about
      the prospects of using this approach as a data mining tool are included.

PMID- 12489848
TI  - A model system for the design of armed replicating adenoviruses using p53 as a
      candidate transgene.
AB  - Cancer gene therapy endeavors to overcome the low therapeutic index of currently
      available therapeutic modalities via the efficient and safe delivery of genetic
      material into tumor cells. However, despite promising preclinical results,
      replication-deficient viral vectors have demonstrated a limited efficacy in the
      clinical setting. To increase vector efficiency, replication-competent viruses
      have been proposed. Clinical trials have shown the safety of locally injected,
      conditionally replicative adenoviruses (Ads) but have underscored the need for
      improved potency. To further increase the therapeutic effect of replicating viral
      vectors, armed therapeutic viruses (ATVs) have recently been used for high
      efficiency transgene expression. However, interference with cellular signaling
      and viral production by constitutive transgene expression may be
      counterproductive for ATV replication, thereby hindering the therapeutic outcome.
      Consequently, studies are equivocal with regard to the potential benefits of
      ATVs. To address this issue, we hypothesized that induction of replication of an
      Ad expressing p53 may be a useful strategy in the context of ATV because p53 does
      not interfere with Ad replication and may even increase its cytolytic effect. We
      show that in our in vitro ATV model system, E1 transcomplementation of a
      replication-deficient Ad encoding p53 resulted in dramatic augmentation of cell
      killing and circumvented resistance to apoptosis. Correlation was found between
      the degrees of cell killing and apoptosis induction, rather than with viral
      burst. Furthermore, both Ad5 E1B 55kDa and E4 orf6 genes were required to enhance
      the cell killing. In conclusion, our p53-ATV model system demonstrates the
      potential utility of therapeutic transgene expression by a replicating Ad after a
      rational selection of a candidate transgene.

PMID- 12489849
TI  - PAGE4 is a cytoplasmic protein that is expressed in normal prostate and in
      prostate cancers.
AB  - PAGE4 is an X chromosome-linked cancer-testis antigen that was identified by
      expressed sequence tags database mining and a functional genomic approach. PAGE4
      is preferentially expressed in normal male and female reproductive tissues and
      also in a variety of cancers including prostate. In the present study, we have
      used in situ hybridization to show that PAGE4 mRNA is expressed only in the
      epithelial cells of normal and prostate-cancer specimens. Analysis of the protein
      product encoded by the PAGE4 mRNA reveals that it encodes a Mr 16,000 protein and
      is detected in tissue extracts from both normal prostate and prostate cancer.
      Cell fractionation analysis of PAGE4 protein indicates that PAGE4 is localized in
      the cytoplasm of the cell. Furthermore, cDNA microarray analysis indicates that
      the expression of lipoprotein lipase, a gene frequently deleted in prostate
      cancer, is down-regulated in a cell line that expresses PAGE4.

PMID- 12489850
TI  - Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv
      immunoliposomes.
AB  - An ideal therapeutic for cancer would be one that selectively targets to tumor
      cells, is nontoxic to normal cells, and that could be systemically delivered,
      thereby reaching metastases as well as primary tumor. Immunoliposomes directed by
      monoclonal antibody or its fragments are promising vehicles for tumor-targeted
      drug delivery. However, there is currently very limited data on gene delivery
      using these vehicles. We have recently described a cationic immunoliposome system
      directed by a lipid-tagged, single-chain antibody Fv fragment (scFv) against the
      human transferrin receptor (TfR) that shows promising efficacy for systemic p53
      tumor suppressor gene therapy in a human breast cancer metastasis model. However,
      the extremely low yield of this lipid-tagged scFv limited further downstream
      development and studies. Here we report a different expression strategy for the
      anti-TfR scFv, which produces high levels of protein without any tags, and a
      different approach for complexing the targeting scFv to the liposomes. This
      approach entails covalently conjugating the scFv to the liposome via a cysteine
      at the 3'-end of the protein and a maleimide group on the liposome. Our results
      show that this conjugation does not impair the immunological activity or
      targeting ability of the scFv. The scFv-cys targets the cationic liposome-DNA
      complex (lipoplex) to tumor cells and enhances the transfection efficiencies both
      in vitro and in vivo in a variety of human tumor models. This scFv-immunoliposome
      can deliver the complexed gene systemically to tumors in vivo, where it is
      efficiently expressed. In comparison with the whole antibody or transferrin
      molecule itself, the scFv has a much smaller size for better penetration into
      solid tumors. It is also a recombinant protein rather than a blood product; thus,
      large scale production and strict quality control are feasible. This new approach
      provides a promising system for tumor-targeted gene delivery that may have
      potential for systemic gene therapy of various human cancers.

PMID- 12489851
TI  - Antisense oligonucleotides: basic concepts and mechanisms.

PMID- 12489852
TI  - Peroxisome proliferator-activated receptor modulators as potential
      chemopreventive agents.
AB  - Peroxisome proliferator-activated receptors (PPARs), members of the superfamily
      of nuclear steroid hormone receptors, have traditionally been studied for their
      role in lipid, glucose, and energy homeostasis. Recent evidence suggests that
      pharmacological activation of PPARgamma and PPARalpha, and inhibition of
      PPARdelta, may prevent cancer. PPARgamma agonists induce differentiation, inhibit
      the growth of established tumor cells in vitro and in vivo, and have
      chemopreventive effects in animal models. PPARalpha has anti-inflammatory and
      differentiating activity and protects against the oxidative damage associated
      with aging. In contrast, PPARdelta expression may be a factor in colorectal
      carcinogenesis. PPARdelta is normally repressed by the adenomatous polyposis coli
      tumor suppressor gene, and impaired adenomatous polyposis coli is strongly
      associated with human colorectal cancer risk. This review presents a rationale
      for using PPAR modulators as cancer chemopreventive drugs.

PMID- 12489853
TI  - Influence of mobile phase acid-base equilibria on the chromatographic behaviour
      of protolytic compounds.
AB  - A review about the influence of mobile phase acid-base equilibria on the liquid
      chromatography retention of protolytic analytes with acid-base properties is
      presented. The general equations that relate retention to mobile phase pH are
      derived and the different procedures to measure the pH of the mobile phase are
      explained. These procedures lead to different pH scales and the relationships
      between these scales are presented. IUPAC rules for nomenclature of the different
      pH are also presented. Proposed literature buffers for pH standardization in
      chromatographic mobile phases are reviewed too. Since relationships between
      analyte retention and mobile phase pH depends also on the pKa value of the
      analyte, the solute pKa data in water-organic solvent mixtures more commonly used
      as chromatographic mobile phase are also reviewed. The solvent properties that
      produce variation of the pKa values with solvent composition are discussed.
      Chromatographic examples of the results obtained with the different procedures
      for pH measurement are presented too. Application to the determination of aqueous
      pKa values from chromatographic retention data is also critically discussed.

PMID- 12489854
TI  - Comparison of different extraction methods for the analysis of fragrances from
      Lavandula species by gas chromatography-mass spectrometry.
AB  - Various sampling techniques including solid-phase trapping solvent extraction
      (SPTE), headspace solid-phase microextraction (HS-SPME), reduced pressure steam
      distillation (RPSD) and simultaneous steam distillation-solvent extraction (SDE)
      were compared for the gas chromatography-mass spectrometry of the fragrances from
      the Lavandula species. Linalyl acetate (35.44%) and linalool (18.70%) were
      predominant components of Hidcote lavender samples obtained by SPTE whereas those
      levels were 2.63-4.04 and 36.80-43.47% in the same samples by RPSD and SDE,
      respectively. The partition coefficients between the headspace gaseous phase and
      HS-SPME fiber, and the relative concentration factors of the four characteristic
      components of the lavender were measured for relative evaluation of the fiber
      efficiency. Five different coatings were evaluated and 100-microm
      poly(dimethylsiloxane) was the most efficient for the successful extraction of
      lavender fragrances. A total of 43 compounds were identified by SPTE and gas
      chromatography-mass spectrometry from four Lavandula species. Lavandula
      angustifolia Hidcote species, which contains a higher level of linalyl acetate
      and linalool but little camphor, was evaluated as the highest quality among the
      four different Lavandula species.

PMID- 12489855
TI  - Surface area determination of a polystyrene-divinylbenzene chromatographic
      packing material via ionic amphiphile adsorption from aqueous mobile phases and
      application of Gouy-Chapman theory.
AB  - A method for the determination of the chromatographically accessible area of a
      reversed-phase column similar to the method of Hagglund and Stahlberg [J.
      Chromatogr. A 761 (1997) 13] is applied to a column containing a polystyrene
      divinylbenzene resin. Its theoretical basis is Gouy-Chapman theory in combination
      with an electrostatically modified linear adsorption isotherm. The surface area
      value determined for the resin, 96 m2/g, is much less than the reported surface
      area value, 400 m2/g, determined by N2 sorptometry and application of Branauer
      Emmett-Teller (BET) theory. The method also provides a value for the number of
      moles of native anionic sites present on the column.

PMID- 12489856
TI  - Breakthrough of polymers in interactive liquid chromatography.
AB  - Two separate peaks are observed for narrow polymer standards in both isocratic
      and gradient HPLC. One peak appears around the solvent front (the "solvent-plug
      peak" or "breakthrough peak"), whereas the second peak is retained significantly-
      or even highly. Although the effect has been observed many times before, it has
      never been rigorously explained. In this paper we provide a detailed explanation
      for the breakthrough peak. The two completely separate peaks are demonstrated not
      to represent to different fractions of the sample (e.g., the low- and high
      molecular-mass parts of the distribution). Both peaks are representative of the
      entire polymeric sample for narrow polymer standard. Because the amount of the
      polymer in the breakthrough peak may vary, the quantitative analysis of the
      polymers by LC is jeopardized. The effects of the sample solvent, the (initial)
      mobile phase composition, the injection volume, the injected sample
      concentration, the column temperature, and the analyte structure and molecular
      mass on the breakthrough peak were investigated in LC experiments involving
      standards of polystyrene and poly(methyl methacrylate). Three necessary and
      sufficient conditionsare suggested for the breakthrough phenomenon to be
      observed. Recommendations to avoid the breakthrough phenomenon are given,
      culminating in a structured method for selecting the best possible sample
      solvents.

PMID- 12489857
TI  - Co-eluent effect in partition chromatography. Rhamnose-xylose separation with
      strong and weak cation-exchangers in aqueous ethanol.
AB  - The effect of ethanol in aqueous eluent on the chromatographic separation was
      studied at 298 K. Two sugars, L-rhamnose and D-xylose, were separated by using
      strong and weak cation-exchangers as a stationary phase. The ionic form of the
      resins was Na+ or Ca2+. The separations were carried out with sugar feed
      concentrations up to 35 wt% and with both low (about 1%) and high (about 10%)
      feed volume to bed volume ratios. The separation of the sugars was improved by
      adding ethanol into the eluent. The separation was also significantly enhanced
      when the weak cation-exchangers with the greatest affinity for water were used
      instead of strong cation-exchangers as a separation medium for the sugars having
      different hydrophilicities. The experimental data were successfully explained
      with a rate-based column model, which accounted for the volume changes of the
      stationary phase. A thermodynamic sorption model was utilized in column
      calculations.

PMID- 12489859
TI  - Determination of quinolones and fluoroquinolones in fish tissue and seafood by
      high-performance liquid chromatography with electrospray ionisation tandem mass
      spectrometric detection.
AB  - A reversed-phase high-performance liquid chromatographic method with tandem mass
      spectrometric detection was developed and validated for the simultaneous analysis
      of eight quinolones and fluoroquinolones (oxolinic acid, flumequine, piromidic
      acid, enrofloxacin, ciprofloxacin, danofloxacin, sarafloxacin and orbifloxacin)
      in trout tissue, prawns and abalone. The analytes were extracted from homogenised
      tissue using acetonitrile and the extracts subjected to an automated two-stage
      solid-phase extraction process involving polymeric reversed-phase and anion
      exchange cartridges. Good recoveries were obtained for all analytes and the limit
      of quantification was 5 microg/kg (10 microg/kg for ciprofloxacin). The limit of
      detection was 1-3 microg/kg, depending on the analyte and matrix. Confirmation of
      the identity of a residue was achieved by further tandem mass-spectrometric
      analysis. A procedure for estimating the uncertainty associated with the
      measurement is presented.

PMID- 12489858
TI  - Mapping of protein:protein contact surfaces by hydrogen/deuterium exchange,
      followed by on-line high-performance liquid chromatography-electrospray
      ionization Fourier-transform ion-cyclotron-resonance mass analysis.
AB  - For protein complexes too large, uncrystallizable/insoluble, or low concentration
      for conventional X-ray diffraction or nuclear magnetic resonance analysis, the
      contact surface(s) may be mapped by comparing H/2H exchange rate (and thus
      solvent accessibility) of backbone amide hydrogens in free vs. complexed
      protein(s). The protein is first exposed to 2H2O, allowed to exchange for each of
      several reaction periods, and then digested with pepsin. The extent and rate of
      H/2H exchange is determined by measuring the increase in mass with H/2H exchange
      period for each of the peptides. Here, we present an experimental protocol that
      combines rapid (to minimize back-exchange) HPLC front-end separation with
      ultrahigh-resolution mass analysis (needed to distinguish the isotopic
      distributions of dozens of peptides simultaneously). The method is used to study
      the assembled human immunodeficiency virus type capsid protein (CA) and its
      soluble form.

PMID- 12489860
TI  - Development of hydrophilic fluorogenic derivatization reagents for thiols: 4-(N
      acetylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole and 4-(N
      trichloroacetylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole.
AB  - Sensitive, reactive, and hydrophilic fluorogenic reagents for thiols with the
      benzofurazan skeleton, 4-(N-acetylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole
      (AcABD-F) and 4-(N-trichloroacetylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole
      (TCAcABD-F) have been developed. These reagents reacted with thiols within 10 min
      at 60 degrees C. AcABD-F and TCAcABD-F themselves do not fluoresce but are
      strongly fluorescent after the reaction with thiol compounds. The generated
      derivatives were highly water-soluble, since they dissociated a proton and
      ionized in the neutral pH region. The derivatives with four biologically
      important thiol compounds were separated on a reversed-phase HPLC column and
      detected fluorometrically at 504 nm with excitation at 388 nm. The detection
      limit attained for homocysteine with AcABD-F was 25 fmol on column (11 nM)
      (signal-to-noise ratio = 3), and that for glutathione with TCAcABD-F was 45 fmol
      on column (20 nM).

PMID- 12489861
TI  - Copolymeric (lR-trans)-N,N'-1,2-cyclohexylene-bisbenzamide oligodimethylsiloxane
      chiral stationary phase for gas chromatography.
AB  - A copolymeric stationary phase, consisting of a chiral selective part, i.e. (1R
      trans)-N,N'-1,2-cyclohexylenebisbenzamide, and an efficient siloxane oligomeric
      part, was successfully applied to open tubular column GC analysis. The efficiency
      and the chiral selectivity of this stationary phase were studied in detail, and
      high capacity and efficiency at elevated GC temperatures were especially noted.
      Several drugs and other enantiomeric pairs were separated. The shown examples
      demonstrate a broad application range for this type of chiral stationary phase in
      GC analysis.

PMID- 12489862
TI  - Determination of nitrated polycyclic aromatic hydrocarbons and their precursors
      in biotic matrices.
AB  - Analytical method for the determination of ultra-trace levels of nitro-PAHs in
      various biotic matrices has been developed. Soxhlet extraction and/or solvent
      extraction enhanced by sonication were used for isolation of target analytes; GPC
      followed by SPE were employed for purification of crude extracts. GC-MS/NCI
      technique was utilised for identification/quantitation of target analytes.
      Performance characteristics of implemented method were obtained through thorough
      in-house validation procedure. The main sources of uncertainties were critically
      evaluated, possible strategies of their elimination/minimisation were considered
      and consequently employed. Examination of real-life samples of various foodstuffs
      (complete human diet, mate tea, pumpkin seed oil, parsley, sausages) was
      performed in this study.

PMID- 12489863
TI  - Sensitive and accurate quantitation of monoepoxy fatty acids in thermoxidized
      oils by gas-liquid chromatography.
AB  - A sensitive and accurate methodology for quantitation of monoepoxy fatty acid
      methyl esters (FAME) by gas-liquid chromatography is proposed. Analytical
      problems of interfering compounds, ie, methyl monoester of azelaic acid and
      methyl docosanoate, were solved by a second methylation step with diazomethane
      and by elimination of nonpolar FAME by adsorption chromatography, respectively.
      Six monoepoxy FAME were identified and quantitated in olive and sunflower oils
      heated at 180 degrees C for 15 h: trans-9,10- and cis-9,10-epoxystearate coming
      from oleate and trans-12,13-, trans-9,10-, cis-12,13- and cis-9,10-epoxyoleate
      coming from linoleate. Results demonstrated total recovery of monoepoxy compounds
      after nonpolar FAME elimination with the additional advantage of sample
      concentration, which allowed quantitation of monoepoxy FAME in the initial oils.
      Also, repeatability was excellent as relative standard deviations ranged from 2.2
      to 5.1% for on-column injection and from 0.1 to 2.0% for automatic split
      injection.

PMID- 12489864
TI  - Simultaneous separation of 11 protease and reverse transcriptase inhibitors for
      human immunodeficiency virus therapy by co-electroosmotic capillary zone
      electrophoresis.
AB  - In the present investigation, a co-electroosmotic capillary zone electrophoretic
      method is shown for the simultaneous separation of protease inhibitors and
      reverse transcriptase inhibitors, which are used as antiretroviral therapy drags
      against the human immunodeficiency virus (HIV). The investigated drugs carry
      basic amino groups, thus the electrophoretic system takes advantage of an acidic
      buffer electrolyte. In order to establish a strong cathodic electroosmotic flow
      (EOF), a poly-anionic surfactant is added to the background electrolyte. Thus,
      fast migration times due to a co-directional migration of analytes and EOF (co
      electroosmotic CE) are obtained. The developed separation system exhibits good
      selectivities for the investigated compounds and sufficient sensitivity to
      monitor drug levels in the low ppm range in HIV positive patients who are treated
      by highly active anitiretroviral therapy.

PMID- 12489865
TI  - Purification of long-chain fatty acid ester of epigallocatechin-3-O-gallate by
      high-speed counter-current chromatography.
AB  - Epigallocatechin-3-O-gallate (EGCG) was modified by catalytic esterification with
      hexadecanoyl chloride. A long-chain fatty acid ester derivative was obtained from
      the purification of this reaction product by high-speedcounter-current
      chromatography using a solvent system composed of n-hexane-ethyl acetate-methanol
      water (1:1:1:1, v/v). The structure of the derivative, epigallocatechin-3-O
      gallate-4'-hexadecanate, was elucidated by IR, MS and 1H NMR.

PMID- 12489866
TI  - Insulin sensitivity and muscle characteristics in calves at different levels of
      physical activity.
AB  - This study was undertaken to investigate insulin sensitivity and muscle
      characteristics in calves at different levels of physical activity. Ten male
      calves of the Swedish Holstein breed were allocated to either an exercise or a
      non-exercise group. The exercise group performed light work on a treadmill, 5-15
      min at 10-12 occasions during 4-5 weeks. The treadmill speed varied from 0.6 to
      1.5 m/s. At the beginning and end of the experimental period, the
      hyperinsulinemic euglycemic clamp technique was used to assess insulin
      sensitivity and gluteus medius muscle biopsies specimens were obtained for
      histochemical and biochemical analyses. There were no significant differences in
      insulin sensitivity, muscle fibre types, enzyme activities or glycogen content
      between the groups before or after the experimental period. The areas of type I,
      IIA, IIB fibres and mean muscle fibre area increased significantly in both groups
      during the experimental period. Muscle fibre characteristics and insulin
      sensitivity varied among the calves. Insulin sensitivity correlated positively to
      the percentage of type I fibres at the start of the experiment, and negatively to
      the mean muscle fibre area at the end of the experimental period. The results
      indicate that insulin sensitivity in young calves is associated with the change
      seen in muscle fibre areas with growth, but not by a short period of light
      physical activity.

PMID- 12489867
TI  - Body condition scores in dairy cows: associations with metabolic and endocrine
      changes in healthy dairy cows.
AB  - Relationships between body condition scores (BCS), metabolic profiles and
      endocrine traits were investigated in 53 healthy Red Holstein cows. Cows were
      categorized into groups based on BCS ante-partum (a.p.: >3.25 or < 3.25) and on
      BCS losses during the first 8 weeks after calving (ABCS8 > 0.75 or < or = 0.75).
      Blood samples were collected 1 week before calving and every 2 weeks post-partum
      (p.p.). Cows with BCS a.p. >3.25 and deltaBCS < or = 0.75 were oldest and cows
      with BCS a.p. < or = 3.25 and deltaBCS < or = 0.75 were youngest. Cows with BCS >
      3.25 a.p. and that lost > 0.75 BCS in the first 2 months of lactation exhibited
      signs of subclinical ketosis. If statistically adjusted for the effect of
      lactation number, average milk yield within the first 8 weeks p.p. and milk fat
      concentrations were similar between BCS groups, whereas milk protein
      concentrations differed significantly between BCS groups. Significant differences
      between groups were observed for blood plasma glucose, bilirubin, beta
      hydroxybutyrate, non-esterified fatty acids and insulin concentrations. No
      differences were seen for albumin, urea, insulin-like growth factor-1, and 3.5.3'
      triiodothyronine concentrations and for plasma activities of glutamate
      oxalacetate transaminase, gamma-glutamyltransferase and glutamate dehydrogenase.
      There was a good agreement between BCS and profiles of metabolites and hormones
      related to energy metabolism in clinically healthy cows. Cows in good body
      condition a.p. had greater risks of metabolic problems because of excessive
      mobilization of body reserves. However, the metabolic status was best in cows
      with a BCS > 3.25 a.p.. if they did not lose much body condition p.p.

PMID- 12489869
TI  - Hepatatis in growth promoter treated cows.
AB  - Adult female beef cattle found positive for stanozolol in the urine were
      investigated for liver pathology. In all the animals toxic hepatitis was found,
      including cholestasis, periportal fibrosis and inflammation, focal necrosis and
      blood filled lacunae. As no clinical data of the cows were available, apart from
      the history of illegal stanozolol abuse, it is not possible to attribute all
      changes to the illegal hormone treatment. Moreover, the cows have probably been
      treated with a cocktail, and apart from stanozolol more anabolic steroids may
      have been used. Management factors, viral and bacterial infections, former
      caesarean sections and especially feeding regime may also be responsible for the
      lesions described. Striking similarities with data from hepatotoxicity found in
      human body builders using similar agents, however, suggest a major role of
      stanozolol as causative agent.

PMID- 12489868
TI  - Expression of calbindin-D9k messenger ribonucleic acid in the gastrointestinal
      tract of dairy cattle.
AB  - The calcium demands of pregnancy and lactation are known to up-regulate
      expression of Calbindin-D9k (CaBP-9k) mRNA in the intestines. The
      gastrointestinal CaBP-9k mRNA expressions has not been studied in dairy cows,
      which are bound to experience several pregnancies and lactation stages. In this
      study, the CaBP-9k mRNA expression were examined in the gastrointestinal tract of
      Holstein dairy cattle by Northern blot analysis. Detectable expression of CaBP-9k
      mRNA was localized in the proximal portion of the small intestines. These
      expressions were higher at the most proximal region of the duodenum and gradually
      decreased distally. The duodenal CaBP-9k mRNA was detected in all dairy cattle
      from 0.4 to 83.4 months old, but was not detectable in foetuses. There were no
      significant correlations between the age and the levels of CaBP-9k mRNA
      expression or between the plasma 1,25-(OH)2D3 concentrations and the levels of
      CaBP-9k mRNA expression.

PMID- 12489870
TI  - Haemolytic-uraemic syndrome in a dog.
AB  - An 11-year-old female German Shepherd dog presented with lethargy and anorexia,
      which progressed to haemorrhagic vomiting, diarrhoea and seizures. Serum
      biochemistry and haematology results showed azotaemia and mild thrombocytopaenia.
      Euthanasia was elected and the dog was submitted for necropsy examination. There
      were widespread serosal and mucosal petechial and ecchymotic haemorrhages within
      the abdomen, with ascites and multiple renal infarcts. The renal infarcts were
      associated with fibrinoid necrosis and thrombosis of inter-lobular arteries and
      arterioles. These arterial lesions and clinical signs are consistent with
      haemolytic-uraemic syndrome, which has not previously been reported in dogs in
      Europe.

PMID- 12489871
TI  - Lectin histochemical study of lipopigments present in the cerebellum of Solanum
      fastigiatum var. fastigiatum intoxicated cattle.
AB  - This study was carried out to investigate the pattern of lectin binding in the
      cerebellum of calves poisoned with Solanum fastigiatum var. fastigiatum. For the
      experimental reproduction of the illness, S. fastigiatum var. fastigiatum was
      collected from farms where the intoxication occurs. The dried ground plant was
      administered to two 1-year-old cattle by a ruminal cannula. The animals received
      5 g/kg b.w. daily, 5 days a week, during periods of 107 and 140 days. After these
      periods the animals were bled to death. For the histological study, transverse
      sections of the cerebellum were used. Paraffin-embedded sections were incubated
      with the following biotinylated lectins with different specificity: Concanavalia
      ensiformis (Con-A). Glycine max (SBA). Dolichos hiflorus (DBA), Ulex europeus-I
      (UEA-I). Triticum vulgaris (WGA), succynyl-WGA (sWGA). Arachis hypogaea (PNA),
      Ricinus communis-I (RCA-I) and Bandeirea simplicifolia-I (BS-I). Avidin-biotin
      peroxidase complex was applied as a detection system. Purkinje cells showed
      vacuolation in the pericaryon. The stored material present in the cells reacted
      strongly with the following lectins: Con-A. sWGA, WGA and RCA-I. An irregular
      affinity was observed with PNA and DBA. The lectin-binding pattern was compatible
      with a glycolipid storage disease.

PMID- 12489872
TI  - Effects of analgesia of the distal interphalangeal joint and navicular bursa on
      experimental lameness caused by solar pain in horses.
AB  - It has been hypothesized that pain originating from the dorsal margin of the sole
      of the hoof in horses can be attenuated by analgesia of either the distal
      interphalangeal (DIP) joint, or of the navicular bursa (NB). To test this
      hypothesis, an experimental lameness was induced in the toe region of the left
      forelimb in six adult horses. After this, both synovial structures were blocked
      and the effects on the lameness were semi-quantitatively scored. Lameness was
      induced by creating pressure on the dorsal margin of the sole with the help of
      set-screws that were screwed into a nut, welded to the inside of each branch of
      the shoe. Gaits were recorded on a videotape before and after application of the
      screws, and after application of either a local anaesthetic or saline into the
      DIP joint or NB. The gaits were independently evaluated by two blinded clinicians
      and scored. Lameness scores were high after application of the screws and
      remained high after the administration of saline, but decreased significantly (P
      < 0.05) after administration of the local anaesthetic. Analgesia of the DIP joint
      as well as the NB appeared to be able to desensitize a portion of the sole. It
      was concluded that pain arising from the toe region of the sole should not be
      excluded as a cause of lameness when lameness is attenuated by analgesia of the
      DIP joint, or of the NB.

PMID- 12489873
TI  - Classification of abomasal displacement in cows according to histopathology of
      the liver and clinical chemistry.
AB  - Histopathological features of livers and blood chemical values in cows with
      abomasal displacement were investigated. Liver biopsy samples were collected
      during redressment operations in 92 cows with abomasal displacement, and the
      samples were stained with haematoxylin and eosin or periodic acid Schiff (PAS).
      Blood was collected for chemical tests. Livers were histopathologically divided
      into the following four types: normal histology cases (21%), fatty degeneration
      cases (36%), cloudy swelling cases (19%) and fatty degeneration cases with cloudy
      swelling (24%). The number of PAS-positive samples was significantly higher in
      the normal histology group and significantly lower in the severe fatty
      degeneration group and severe cloudy swelling group. Cows with fatty degeneration
      had significantly higher levels of serum 3-hydroxybutyric acid, non-esterified
      fatty acid and aspartate aminotransferase than did those with cloudy swelling or
      normal histology. The results indicate that the morbid conditions of cows with
      abomasal displacement can be classified into four types.

PMID- 12489874
TI  - Factors affecting the transfer of porcine parvovirus antibodies from sow to
      piglets.
AB  - The aim of the study was to investigate the effects of a number of environmental,
      behavioural and biological factors on passive immunization of piglets as assessed
      by transfer of porcine parvovirus (PPV) antibodies (ab) from the colostrum of PPV
      vaccinated mothers to the serum of the piglets. Twenty primiparous sows were
      housed in pens with peat, straw and branches for nest building. Half the sows
      were prevented from achieving feedback from a completed farrowing nest by
      repeated removal of the nest from 10 to 12 h after nest building had begun,
      whereas the other half kept their nests. Sow serum PPV-ab titres were positively
      related to colostrum PPV-ab titres at birth of the first piglet (BFP) (P <
      0.001). Litter average piglet PPV-ab titre was positively related to both sow
      serum and colostrum PPV-ab titres (both P < 0.001). In addition, in the
      individual piglets. PPV-ab titres were reduced as time from BFP to birth and time
      from birth to first sucking increased and time spent sucking decreased (all P <
      0.01). There were no effects of treatment, time spent in lateral recumbency by
      the sow, number of times the sow stood or piglet weight on day 1 on piglet serum
      PPV-ab titres. Preventing prolonged farrowing, while at the same time ensuring
      the piglets' access to the udder, is important for transfer of maternal immunity.
      Measurements of specific antibodies in sow serum during the periparturient period
      and in piglet serum at 28 days of age may provide a practical tool for evaluating
      transfer of maternal immunity from sow to piglets.

PMID- 12489875
TI  - Analytical separation techniques for the determination of chemical warfare
      agents.
AB  - Today, the determination of chemical warfare agents (CWAs) is an important area
      of application in analytical chemistry. Chromatographic, capillary
      electrophoretic and mass spectrometric techniques are primarily used for the
      identification and quantification of a broad field of classical CWAs in
      environmental samples and neutralization masses, obtained after destruction of
      CWAs. This overview is illustrative for the state of the art and mainly focuses
      on the literature published since 1996.

PMID- 12489876
TI  - Screening method for polycyclic aromatic hydrocarbons in soil using hollow fiber
      membrane solvent microextraction.
AB  - A fast, inexpensive screening method for polycyclic aromatic hydrocarbons in soil
      has been developed. Using hollow fiber membrane solvent microextraction, 8 microl
      of octane extraction solvent was placed inside a porous, polypropylene fiber.
      Following an 8 min analyte preconcentration step, 4 microl of extract was
      injected into a gas chromatograph. Separation was achieved in less than 10 min
      with a detection limit of 0.13 mg/kg for 2-methylnaphthalene. Results of both
      spiked and real soil samples are presented.

PMID- 12489877
TI  - Prediction of internal standards in reversed-phase liquid chromatography. III.
      Evaluation of an alternative solvation parameter model to correlate and predict
      the retention of ionizable compounds.
AB  - This paper describes the results of the evaluation of an alternative solvation
      parameter model for ionizable compounds. The new model is described as Log(k) =
      Int + rR2 + spi2(H) + asigmaalpha2(H) + bsigmabeta2(H) + mVx + U/(1 + V10 (+/-(pH
      Pk))). The first six terms are the usual solvation parameter equation for neutral
      solutes, and the last term represents the contribution to retention from the
      ionization of solutes. Retention data obtained for 30 solutes in
      acetonitrile/aqueous buffer mobile phases are used to evaluate the capability of
      the function using different pH/pK scales. Because the function is not linear,
      nonlinear least-squares analysis is used to perform the data processing. It is
      concluded that the model function describes similarly the retention of ionizable
      compounds to the literature model without the need to accurately measure the
      mobile phase pH and solute's pK. Accordingly, the function simplifies the
      application of linear solvation energy relationships (LSERs) to ionizable
      compounds, and allows us to easily predict their retention for chromatographic
      optimization.

PMID- 12489878
TI  - Multi-residue method for rapid screening and confirmation of pesticides in crude
      extracts of fruits and vegetables using isocratic liquid chromatography with
      electrospray tandem mass spectrometry.
AB  - A LC-MS-MS method capable of the quantitative determination of a range of
      pesticide residues present in crude extracts from a variety of fruit and
      vegetables has been developed. Isocratic LC conditions have been used in
      conjunction with electrospray ionisation tandem mass spectrometry to detect and
      identify up to 38 pesticides presented as various mixtures in different matrices.
      The utility of the method is demonstrated by the analysis of crude extracts, with
      no sample clean up, from grape, kiwi fruit, strawberry, spinach, lemon, peach and
      nectarine. Mean recoveries ranging from 63 to 96% with relative standard
      deviations < 20% were obtained for 30 of the 38 pesticides following analysis of
      organic produce fortified at concentrations between 0.01 and 0.8 mg/kg. Detected
      residues were quantified from interpolation against calibration data generated
      using matrix-matched standards that covered analyte concentration ranges between
      0.005 and 0.8 microg/ml. Conditions suitable for the qualitative and quantitative
      confirmation of residues detected in samples are specified.

PMID- 12489879
TI  - Direct determination of free amino acids and sugars in green tea by anion
      exchange chromatography with integrated pulsed amperometric detection.
AB  - Determination of amino acids and sugars in green tea by anion-exchange
      chromatography with integrated pulsed amperometric detection was developed. Amino
      acids and sugars were separated on an anion-exchange column at a flow-rate of
      0.25 ml/min by using ternary gradient elution consisting of deionized water, 0.25
      M sodium hydroxide, and 1.0 M sodium acetate. Under optimized conditions,
      theanine was separated from glutamine and three sugars (glucose, fructose, and
      sucrose) were eluted earlier than the neutral amino acids to avoid their
      interference with each other. RSDs of the peak area of analytes were lower than
      4.6%. Detection limits for the analytes ranged from 0.12 to 4.9 pmol. The
      linearities for all analytes were two or three orders of magnitude with the
      correlation coefficients greater than 0.99. This method was applied to
      determination of amino acids and sugars in green tea with satisfactory results.

PMID- 12489880
TI  - Application of inverse gas chromatography to the examination of annealing
      processes of semi-synthetic base oils.
AB  - The Flory-Huggins chi1,2infinity parameter and solubility parameter delta2
      determined by means of inverse gas chromatography (IGC) were successfully used in
      the physicochemical characterisation of oxidation products of mineral oil-poly
      alpha-olefin mixtures. Application of IGC parameters allows one to examine the
      changes occurring during three different oxidation procedures: classical
      oxidation in a stainless steel reactor, in a GC column and separate oxidation of
      the mixture's components. Changes in chi1,2infinity values reflect the changing
      affinity of mixtures to different types (dispersive, polar, hydrogen bonding) of
      intermolecular interactions and their potential miscibility and solubility.

PMID- 12489881
TI  - Improvement in the detection of impurities affecting ethylene glycol UV
      transmittance by gas chromatography-mass spectrometry.
AB  - A method was developed for the detection of trace impurities affecting ethylene
      glycol UV transmittance, using gas chromatography-mass spectrometry in the
      selective ion monitoring mode. Four 1,2-cyclopentanediones were identified in
      commercial ethylene glycol as well as in several ethylene glycol plant streams,
      including 3-methyl-1,2-cyclopentanedione, 3,5-dimethyl-1,2-cyclopentanedione, 3,4
      dimethyl-1,2-cyclopentanedione and 3-ethyl-1,2-cyclopentanedione. Quantification
      of the first three compounds was achieved by monitoring the molecular ion. This
      method requires no sample preparation and can detect the compounds of interest as
      low as 0.1 microg ml(-1). As a simple and rapid method, it can be used in tracing
      these 1,2-cyclopentanediones in glycol plants.

PMID- 12489882
TI  - Determination of maleic anhydride in occupational atmospheres.
AB  - Maleic anhydride has many uses in industry, but workers' exposure to it is poorly
      known. Our new method allows airborne maleic anhydride to be determined with a
      limit of quantification of 1 microg/m3 per 12 1 of air, i.e., the concentration
      of about 0.01 times the occupational exposure standard (0.4 mg/m3). Air samples
      are collected in Tenax tubes containing sodium sulfate as a drying agent. Maleic
      anhydride is eluted with methyl tert.-butyl ether containing 5% acetonitrile and
      0.1% acetic anhydride, and determined by capillary gas chromatography with
      electron-capture detection without interference from generic anhydrides. The
      tested method suits both long-term and short-term measurements.

PMID- 12489883
TI  - Simple method for the determination of trace levels of pesticides in honeybees
      using matrix solid-phase dispersion and gas chromatography.
AB  - A simple multiresidue method for the determination of insecticides in honeybees
      is described. The developed method is based on the matrix solid-phase dispersion
      technique. A total number of 12 insecticides (azinfos-methyl, buprofezin,
      chlorpyriphos, chlorpyriphos-methyl, diazinon, ethion, fenitrothion, fipronil,
      methidathion, phosalone, pirimicarb, propoxur) used on flowering fields are
      determined by this method. The method uses Florisil and silica as dispersing
      agents, alumina and silica as cleanup adsorbents and a low polarity solvent
      system to elute pesticide residues from the honeybee samples. The insecticides
      were quantified using capillary gas chromatography with a nitrogen-phosphorus
      detector. The method has shown good recovery (70-110%) for various levels of
      spiked samples (0.01-1.0 mg/kg). The relative standard deviations were in the
      range of 2-8% for all pesticides studied. The limits of detection were in the
      range of 0.005-0.05 mg/kg. The procedure can be applied for the determination of
      residues of low-polarity and medium polarity pesticides in honeybee samples.

PMID- 12489884
TI  - Investigations of cyclophilin interactions with oligopeptides containing proline
      by affinity capillary electrophoresis.
AB  - Affinity capillary electrophoresis using mobility-shift analysis was utilized to
      characterize the binding of peptide ligands to cyclophilins, which are members of
      the enzyme family of peptidyl-prolyl cis/trans isomerases. Peptides derived from
      the human immunodeficiency virus capsid protein p24 exhibited different
      affinities to the isoenzymes cyclophilin18 and cyclophilin20. For the interaction
      of the peptide hormone bradykinin with cyclophilin18, a dissociation constant of
      1.4 +/- 0.1 mM was determined. Finally, the affinity of cyclophilin20 to peptides
      from a cellulose-bound peptide library scanning the sequence of Drosophila
      melanogaster protein cappuccino was investigated. The affinities of selected
      peptides to cyclophilin20 and a green fluorescent fusion protein with
      cyclophilin20 were compared.

PMID- 12489885
TI  - Interaction between netropsin and double-stranded DNA in capillary zone
      electrophoresis and affinity capillary electrophoresis.
AB  - Capillary zone electrophoresis (CZE) and affinity capillary electrophoresis (ACE)
      were applied to study the interaction between netropsin and a 14mer double
      stranded DNA (dsDNA). The use of a polyacrylamide coated capillary can suppress
      the electroosmotic flow (EOF) and the adsorption of DNA onto the wall. Better
      analysis of the DNA was achieved in a coated capillary upon Tris-acetate. In CZE,
      the peak width broadened due to the affinity interaction between dsDNA and
      netropsin. In ACE, o-toluic acid, a negatively charged molecule was used as the
      indicator to monitor the changes of EOF when netropsin was added to the running
      buffer. The 14mer dsDNA showed different mobilities upon various concentrations
      of netropsin due to the affinity interaction between the dsDNA and netropsin. The
      binding constants of this interaction were (1.07 +/- 0.10) x 10(5) M(-1)
      calculated from CZE and (4.75 +/- 0.30) x 10(4) M(-1) from ACE using a Scatchard
      plot. The binding stoichiometry was 1:1 calculated from CZE which was superior to
      ACE in this study.

PMID- 12489886
TI  - Capillary electrochromatographic separation of non-steroidal anti-inflammatory
      drugs with a histidine bonded phase.
AB  - An open tubular wall-coated capillary column containing histidine functional
      groups was prepared and employed for the capillary electrochromatographic
      separation of non-steroidal anti-inflammatory drugs. The anion exchange along
      with the hydrogen bonding and hydrophobic properties of the surface coating
      allowed the separation of analytes with very similar ionic mobility. Selectivity
      and resolution were studied by changing the pH over the range from 3.5 to 5.0 and
      the concentration of the buffer from 10 to 25 mM, as well as variation of the
      organic modifier, such as methanol, ethanol and 1-propanol over the range 7.5 to
      20%. The optimum experimental conditions for the separation of a drug mixture,
      which consisted of indoprofen, ketoprofen, suprofen, naproxen, flurbiprofen,
      fenoprofen and ibuprofen were using a mixture of acetate buffer (20 mM, pH 5.0)
      ethanol (1:5, v/v) as background electrolyte and an applied voltage of -20 kV
      with UV detection at 220 nm. The separation of these drugs could be achieved with
      an average plate number of 1.0 x 10(5) m(-1).

PMID- 12489887
TI  - Gas chromatography for in situ analysis of a cometary nucleus. IV. Study of
      capillary column robustness for space application.
AB  - As part of the development of the European Space Agency Rosetta space mission to
      investigate a cometary nucleus, the selection of columns dedicated to the gas
      chromatographic subsystem of the Cometary Sampling and Composition (COSAC)
      experiment was achieved. Once the space probe launched, these columns will be
      exposed to the harsh environmental constraints of space missions: vibrations,
      radiation (by photons or energetic particles), space vacuum, and large
      temperature range. In order to test the resistance of the flight columns and
      their stationary phases, the columns were exposed to these rough conditions
      reproduced in the laboratory. The comparison of the analytical performances of
      the columns, evaluated prior and after the environmental tests, demonstrated that
      all the columns withstand space constraints, and that their analytical properties
      were preserved. Therefore, all the selected capillary columns, even having porous
      layer or chiral stationary phases, were qualified for space exploration.

PMID- 12489888
TI  - Microinjection of neostigmine into the pontine reticular formation of C57BL/6J
      mouse enhances rapid eye movement sleep and depresses breathing.
AB  - STUDY OBJECTIVES: The cholinergic model of rapid eye movement (REM) sleep has
      contributed significantly to understanding sleep neurobiology and sleep-dependent
      respiratory depression. The model has been used extensively in cat and rat, but
      no previous studies have demonstrated cholinergic REM sleep enhancement in mouse.
      The present study used microinjection of neostigmine into pontine reticular
      formation of mouse to test the hypothesis that enhancing pontine cholinergic
      neurotransmission would cause increased REM sleep and sleep disordered breathing.
      DESIGN: Mice (n=8) were anesthetized and implanted with electrodes for measuring
      cortical electroencephalogram (EEG). Stainless steel cannulae were
      stereotaxically implanted to permit subsequent microinjections of 50 nl
      neostigmine (0.133 microg; 8.8 mM) or saline into the pontine reticular
      formation. Following recovery, an intensive within-subjects design was used to
      obtain measures of sleep/wake states, breathing, and locomotor activity.
      Inferential statistics were provided by t-tests. A probability value of < 0.05
      indicated statistical significance. SETTING: NA. PATIENTS OR PARTICIPANTS: NA.
      INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Behavioral observations and manual
      scoring of polygraphic recordings showed that neostigmine produced a REM sleep
      like state. EEG power analysis using Fast Fourier Transformation confirmed that
      pontine neostigmine caused EEG activation. Plethysmography demonstrated
      significantly disordered breathing. Compared to waking, pontine microinjection of
      neostigmine decreased respiratory rate (-64%) and minute ventilation (-75%).
      Pontine neostigmine significantly increased duration of inspiration (138%) and
      expiration (140%) above waking levels and decreased inspiratory flow (-69%).
      Additional studies showed that pontine neostigmine significantly depressed
      locomotor activity. CONCLUSIONS: This study is the first to demonstrate
      cholinergic REM sleep enhancement in unanesthetized, intact mouse. The results
      encourage future studies to characterize similarities and differences in
      cholinergic REM sleep enhancement in additional inbred strains and in transgenic
      mice. Such comparisons will help characterize sleep and breathing as intermediate
      phenotypes that are determined, in part, by the lower level phenotype of pontine
      cholinergic neurotransmission.

PMID- 12489889
TI  - Short-term variability of respiration and sleep during unattended nonlaboratory
      polysomnography--the Sleep Heart Health Study. [corrected].
AB  - STUDY OBJECTIVES: To determine the short-term variability of indices of disturbed
      respiration and sleep during 2 nights of unattended nonlaboratory polysomnography
      conducted several months apart. DESIGN: Participants were randomly selected using
      a block design with stratification on preliminary estimates of 2 criteria:
      respiratory disturbance index [RDI3% (apnea or hypopnea events associated with >
      or = 3% O2 desaturation): < 15/hour total sleep time, > or = 15/hour total sleep
      time] and sleep efficiency (SEff: < 85% and > or = 85%). The RDI and sleep data
      from initial and repeated polysomnography were compared. SETTING: NA.
      PARTICIPANTS: A subset of 99 participants in the Sleep Heart Health Study who
      agreed to have a repeat polysomnogram within 4 months of their original study.
      INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Acceptable repeat polysomnograms
      were obtained in 91 subjects (mean study interval: 77 +/- 18 [sd] days; range: 31
      112 days). There was no significant bias in RDI between study nights using
      several different RDI definitions including RDI3% and RDI4% (apnea or hypopnea
      events associated with > or = 4% O2 desaturation). Variability between studies
      estimated using intraclass correlations (ICC) ranged from 0.77 to 0.81. For
      subjects with a RDI3% < 15, variability increased as a function of increasing
      RDI, but for those with a RDI3% > or = 15, variability was constant. Body mass
      index, SEff, gender, or age did not directly predict RDI variability. Using RDI4%
      cutpoints of < or = 5, < or = 10 and < or = 15 events per hour of sleep
      demonstrated that 79.1%, 85.7%, and 87.9% of subjects, respectively, had the same
      classification of SDB status on both nights of study. There also was no
      significant bias in sleep staging, sleep efficiency, or arousal index between
      studies. However, variability was greater with ICC values ranging from 0.37 (%
      time in REM) to 0.76 (arousal index). CONCLUSION: In the Sleep Heart Health
      Study, accurate estimates of the severity of sleep-disordered breathing and the
      quality of sleep were obtained from a single night of unattended nonlaboratory
      polysomnography. These findings may be applicable to other large epidemiologic
      studies provided that similar recording techniques and quality-assurance
      procedures are followed.

PMID- 12489890
TI  - Arterial stiffness increases during obstructive sleep apneas.
AB  - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) appears to be an independent risk
      factor for diurnal systemic hypertension, but the specific biologic markers for
      this association have not been well established. Increased arterial stiffness is
      an important measure of increased left ventricular load and a predictor of
      cardiovascular morbidity and may precede the onset of systemic hypertension in
      humans. However, arterial stiffness has not been measured in association with
      obstructive apneas in patients with OSA, nor related to systemic blood pressure
      (BP) activity in this setting. Our objective was to test the hypothesis that
      arterial stiffness may be utilized as a sensitive measure of arterial vasomotor
      perturbation during obstructive events in patients with OSA, by demonstrating
      that (1) arterial stiffness increases acutely in association with obstructive
      apnea and hypopnea, and that (2) such increased stiffness may occur in the
      absence of acute BP increase. DESIGN: Prospective, cross-sectional. SETTING: A
      tertiary-care university-based sleep and ventilatory disorders center. PATIENTS:
      Forty-four normo- and hypertensive adult patients (11 women, 33 men) with
      polysomnographically diagnosed moderate to severe OSA. INTERVENTIONS: N/A.
      MEASUREMENTS AND RESULTS: Beat-to-beat BP was recorded from the radial artery by
      applanation tonometry during nocturnal polysomnography. Arterial augmentation
      index (AAI), a measure of arterial stiffness, was calculated as the ratio of
      augmented systolic BP (SBP) to pulse pressure and expressed as a percentage for
      the following conditions: awake, the first 10 ("early apnea") and last 10 ("late
      apnea") cardiac cycles of obstructive events, and the first 15 cardiac cycles
      following apnea termination ("post apnea"). Mean AAI (+/-SD) for the group was
      significantly increased during NREM sleep from early apnea to late apnea (12.02
      +/- 2.70% vs 13.35 +/- 3.54%, p<0.05, ANOVA). During REM (analyzed in 20
      patients), MI again significantly increased from early apnea to late apnea (11.75
      +/- 2.81% vs 13.43 +/- 4.97%). Conversely, neither mean SBP nor mean arterial BP
      was significantly changed from early apnea to late apnea in NREM (SBP 130 +/- 14
      mmHg vs 129 +/- 14 mmHg) or REM (SBP 128 +/- 22 mmHg vs 127 +/- 21 mmHg).
      CONCLUSIONS: Arterial stiffness increases acutely during obstructive apneas in
      both NREM and REM sleep, in the absence of measurable BP change. These data
      suggest that arterial stiffness may be a sensitive measure of acute arterial
      vasomotor perturbation in this setting and may have implications concerning
      cardiovascular sequelae in patients with OSA.

PMID- 12489891
TI  - Obstructive sleep apnea can be provocative for right-to-left shunting through a
      patent foramen ovale.
AB  - STUDY OBJECTIVES: Under particular conditions, a patent foramen ovale (PFO) can
      potentially give rise to ischemic stroke by means of paradoxical embolization,
      due to right-to-left shunt. Our study aimed to evaluate the presence of right-to
      left shunt in patients with obstructive sleep apnea syndrome (OSAS) and diagnosed
      PFO during sleep. DESIGN AND SETTING: Assessment of provocative-only PFO and
      concomitant OSAS. Evaluation of right-to-left shunting during sleep by means of
      transcranial doppler with contrast medium injected in the cubital vein.
      PARTICIPANTS: 10 consecutive patients affected by PFO detectable only under
      Valsalva maneuver during wakefulness and affected by OSAS (mean age 52.8 +/- 10.7
      years). INTERVENTIONS: Patients underwent transcranial doppler with injection of
      agitated saline solution mixed with air during normal breathing and during
      periods of apnea/hypopnea in nocturnal sleep. MEASUREMENTS AND RESULTS: Right-to
      left shunt was present in 9 patients out of 10 and appeared during obstructive
      apneas longer than 17 seconds. In 1 out of 10 patients, only hypopneas occurred
      and no right-to-left shunt could be shown. The number of microembolic signals
      detected during periods of nocturnal apnea was positively correlated with the
      number detected during Valsalva maneuver in wakefulness (p<0.0001). CONCLUSIONS:
      In the nocturnal sleep period, right-to-left shunt can occur during single
      obstructive apneas in patients with OSAS and concomitant presence of PFO. This
      can be a risk factor for cerebrovascular diseases. This risk could probably
      increase proportionally to the respiratory disturbance index of these patients.

PMID- 12489892
TI  - Brainstem proton magnetic resonance spectroscopy in idopathic REM sleep behavior
      disorder.
AB  - STUDY OBJECTIVES: Rapid-eye-movement (REM) sleep behavior disorder (RBD) is
      thought to result from a dysfunction of the brainstem structures that regulate
      physiologic REM sleep muscle atonia. Proton magnetic resonance spectroscopy (1H
      MRS) is a noninvasive method that allows detection of in vivo neuronal
      dysfunction in localized brain areas. The aim of our study was to investigate
      whether 1H-MRS can detect brainstem abnormalities in patients with idiopathic
      RBD. DESIGN: 1H-MRS centered on the midbrain and the pontine tegmentum was
      acquired in 15 patients with idiopathic RBD and 15 control subjects matched for
      age and sex. SETTING: University hospital sleep laboratory center. PARTICIPANTS:
      Fifteen untreated patients with chronic RBD diagnosed by history and video
      polysomnography, normal neurologic examination, and normal cranial MRI. Fifteen
      healthy controls with no sleep complaints and normal polysomnography and brain
      MRI. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The metabolic peaks detectable
      with 1H-MRS, N-acetylaspartate (NAA), creatine-phosphocreatine (Cr), choline
      containing compounds (Cho) and myoinositol (mI), and the ratios of NAA, Cho and
      ml to Cr were evaluated both in the midbrain and pontine tegmentum. No
      significant differences in N-acetylaspartate/creatine, choline/creatine and
      myoinosito/creatine ratios were found between patients and controls. CONCLUSIONS:
      The results do not suggest that marked mesopontine neuronal loss or 1H-MRS
      detectable metabolic disturbances occur in idiopathic RBD.

PMID- 12489893
TI  - Arousal reactions in sleepwalking and night terrors in adults: the role of
      respiratory events.
AB  - STUDY OBJECTIVES: The aim of the study was to determine the role of respiratory
      events, assessed by means of esophageal pressure monitoring, during arousals from
      slow wave sleep in adult patients with parasomnias. DESIGN: N/A. SETTING: N/A.
      PATIENTS: Ten patients with parasomnias (sleepwalking, night terrors, or both)
      and 10 control subjects matched for gender and age underwent 3 consecutive nights
      of polysomnography. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: By increasing
      sleep fragmentation, esophageal pressure monitoring has a deleterious effect on
      sleep architecture in patients with parasomnias and in control subjects.
      Respiratory events occur more frequently in parasomniacs than in controls.
      Respiratory effort seems to be responsible for the occurrence of a great number
      of arousal reactions in parasomniacs and is involved in triggering the parasomnia
      episodes. CONCLUSION: Sleep-disordered breathing seems to be frequently
      associated with parasomnias during slow wave sleep, emphasizing the utility of
      performing esophageal pressure monitoring in cases of sleep walking or night
      terrors.

PMID- 12489894
TI  - REM sleep deprivation suppresses acquisition of classical eyeblink conditioning.
AB  - STUDY OBJECTIVES: The aim of this study was to investigate the issue of whether
      REM sleep is involved in implicit learning through the cerebellum-related neural
      circuit via the use of classical eyeblink conditioning (CEC). DESIGN: Subjects
      were divided into three groups: control (sleep without interruption), REM sleep
      deprivation (RD), and slow wave sleep (stage 3+4) deprivation (SD). The CEC was
      performed after 8 hours of ordinary nocturnal sleep or sleep disrupted at a
      selected sleep stage. SETTING: A university-based sleep laboratory. PATIENTS OR
      PARTICIPANTS: Twenty-seven healthy volunteers (all men, aged 23.2+/-0.6 years).
      INTERVENTIONS: The CEC was measured after selective sleep deprivation or ordinary
      nocturnal sleep. MEASUREMENTS AND RESULTS: The eyeblink reflex was conditioned
      using a classical delay conditioning paradigm. The conditioned response (CR) was
      determined by electromyography measurements of the orbicularis oculi muscles. The
      rate of appearance of the CR was compared among the three groups. Compared with
      the control subjects, RD subjects were significantly deficient in their capacity
      to acquire conditioned eyeblinks, while no difference was found among the SD
      subjects. CONCLUSIONS: This study suggests that RD suppresses the cerebellar
      function in CEC and that REM sleep is closely linked with the learning function
      in the cerebellum.

PMID- 12489895
TI  - Increased production of evoked and spontaneous K-complexes following a night of
      fragmented sleep.
AB  - STUDY OBJECTIVES: To determine whether K-complex production is better interpreted
      as being an arousal response or reflective of a sleep protective micro-state.
      DESIGN: A 3-night study--night 1 as a baseline night, night 2 as a sleep
      fragmentation night, followed immediately by night 3 as a recovery night. On
      nights 1 and 3, approximately 400 auditory stimuli were presented during nonREM
      sleep in the first two sleep cycles, using stimulus parameters previously found
      to be optimal for K-complex production. SETTING: The sleep research laboratory at
      the University of Melbourne. PARTICIPANTS: Six young healthy subjects (3 female).
      INTERVENTIONS: One night of sleep fragmentation. Ten-second auditory tones of up
      to 110 dB were presented throughout the entire night at approximately 1-minute
      intervals. MEASUREMENTS AND RESULTS: Sleep drive was increased on the recovery
      night, as indicated by increased amounts of slow wave sleep, increased sleep
      efficiency, and a reduction in stimulus-related alpha activity. The incidence of
      both evoked and spontaneous K-complexes increased significantly on the recovery
      night. When K-complex trials were averaged, neither N550 (Fz) amplitude nor
      latency differed between the 2 nights. When vertex sharp waves were averaged,
      N350 (Cz) amplitude was increased significantly on the recovery night.
      CONCLUSIONS: The increase in K-complex frequency together with the decrease seen
      in stimulus-related alpha activity supports the view that they reflect a sleep
      maintenance, rather than an arousal, response.

PMID- 12489896
TI  - Prevalence of sleep problems and quality of life in an older population.
AB  - STUDY OBJECTIVES: To determine the prevalence of insomnia traits in a population
      and the effect of these traits on health-related quality of life. DESIGN: The
      Epidemiology of Hearing Loss Study is a population-based study in Beaver Dam,
      Wisconsin. SETTING: Participants were interviewed as part of the 5-year follow-up
      examination (1998-2000) of the Epidemiology of Hearing Loss Study. Participants
      were interviewed at the study office in Beaver Dam, WI, by telephone, or at their
      residence. PARTICIPANTS: 2800 adults aged 53-97 years. INTERVENTIONS: N/A.
      MEASUREMENTS AND RESULTS: Participants were asked to what extent they experienced
      difficulty getting to sleep, waking up at night and having a hard time getting
      back to sleep, and waking up repeatedly during the night for any reason. A
      response of "often" or "almost always" was coded as positive for an insomnia
      trait. The SF-36 was administered to assess mental and physical function. Twenty
      six percent of the population reported one insomnia trait, 13% reported two, and
      10% reported three. All eight domains and the Mental and Physical Component
      Summary scores of the SF-36 decreased significantly (F-test for linear trend
      statistically significant at p<0.0001) as the number of reported insomnia traits
      increased. CONCLUSIONS: These results indicate that symptoms of insomnia are
      common among older adults and are associated with a decrease in health related
      quality of life.

PMID- 12489897
TI  - Women's sleep: longitudinal changes and secular trends in a 24-year perspective.
      Results of the population study of women in Gothenburg, Sweden.
AB  - STUDY OBJECTIVES: To present observational data on the frequency of sleep
      problems, sleep duration, and sleep medication in an urban female population.
      DESIGN: A prospective population study, initiated in 1968-69, with follow-ups in
      1974-75, 1980-81, and 1992-93. SETTING: Goteborg, Sweden, with around 445,000
      inhabitants. PARTICIPANTS: 1462 women born in 1908, 1914, 1918, 1922, 1930, and
      205 women born in 1942 and 1954, a representative selection of women of the
      respective age in the general population. INTERVENTIONS: NA. MEASUREMENTS:
      Reported number of hours slept per night, sleep problems, use of sleeping pills,
      and sleep satisfaction. RESULTS: The frequency of sleep problems increased with
      age, as did consultations for sleep problems and the use of sleep medication,
      while no major differences in these parameters could be discerned in a 24-year
      secular trend analysis of 38- and 50-year-old women, except a lower sleeping pill
      use in 50-year-old women in 1992-93. An interesting finding was also that the
      significant reduction of the proportion of 38-year-old women sleeping more than 8
      hours per night between 1968-69 and 1980-81 was not accompanied by a secular
      deterioration in sleep satisfaction in that age group. CONCLUSIONS: Sleep
      duration decreased by approximately 0.4 hours per night between the ages of 38
      and 66. The frequency of sleep problems increased by around 30% between the ages
      of 38 and 84. The use of sleeping pills also increased, except in the 50-year-old
      cohort.

PMID- 12489898
TI  - Relationship of epileptic seizures to sleep stage and sleep depth.
AB  - STUDY OBJECTIVES: Interictal epileptiform discharges (IEDs) are facilitated by
      NREM stages 3 and 4 sleep and as sleep is deepening. To determine whether sleep
      influences seizures in a similar way to IEDs, we examined seizure rates in
      various stages of sleep in epilepsy patients undergoing overnight video-EEG
      polysomnography (VPSG). DESIGN: Cross-sectional study. SETTING: Neurology
      Department. PATIENTS, MEASUREMENTS, AND INTERVENTIONS: We reviewed VPSGs from our
      Sleep and Epilepsy Laboratories to identify patients with recorded seizures
      during sleep. A total of 55 patients having 117 seizures were identified.
      RESULTS: Ninety-five percent of seizures occurred in NREM sleep (61% in stage 2,
      20% in stage 1, 14% in stages 3 and 4 combined), and 5% in REM sleep. Adjusting
      for time spent in each stage of sleep, patients had 0.34 seizures per hour in
      stage 1, 0.38 seizures per hour in stage 2, 0.29 seizures/hr in stage 3 and 4
      combined, and 0.09 seizures per hour in REM sleep. Seizures/hour was higher in
      NREM sleep (0.35 for NREM and 0.09 for REM; p=0.0001). For single seizures
      occurring in 1 night, seizure rate was significantly higher in NREM stages 1 and
      2 as compared to NREM stages 3 and 4 sleep. A significant increase in log delta
      power, an automated measure of sleep depth, was observed in the 10 minutes prior
      to seizures. CONCLUSIONS: Both seizures and IEDs are facilitated by NREM sleep.
      While deeper stages of NREM sleep activate IEDs, lighter stages of NREM sleep
      promote seizures, at least for single seizures occurring in 1 night.

PMID- 12489899
TI  - Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a
      double-blind, randomized, crossover, placebo-controlled polygraphic trial.
AB  - OBJECTIVES: To assess the therapeutic efficacy of modafinil in the treatment of
      increased daytime sleepiness in patients with Parkinson's disease (PD). DESIGN:
      Double-blind, randomized, placebo-controlled crossover study with two 2-week
      treatment blocks, separated by a 2-week washout phase. SETTING: Tertiary
      Parkinson's disease care center and sleep laboratory at university hospital
      neurology department. PATIENTS: Fifteen patients with idiopathic PD and daytime
      sleepiness (Epworth sleepiness score (ESS) 10 or more). INTERVENTIONS:
      Administration of placebo or modafinil as a single morning dose in a randomized
      crossover order. The modafinil dose was 100 mg in the first, and 200 mg in the
      second treatment week. MEASUREMENTS AND RESULTS: At baseline and at the end of
      each treatment block, sleepiness was evaluated using subjective (perceived
      sleepiness with the ESS) and objective measures (maintenance of wakefulness
      test). Twelve patients completed the study (9 male, 3 female; mean age 65.0 +/-
      7.6 years, mean disease duration 6.8 +/- 4.1 years). Epworth scores were
      significantly improved with modafinil (3.42 +/- 3.90) compared to placebo (0.83
      +/- 1.99; p = 0.011). Latency to sleep in the maintenance of wakefulness test was
      not significantly altered by modafinil treatment: 10.9 (3-40)/15.1 (2.5-40)
      minutes before/after placebo and 12 (2.6-40)/17.8 (4.2-40) minutes before/after
      modafinil (p = 0.139) [data given as mean +/- standard deviation or median
      (range)]. CONCLUSIONS: The results of this study suggest that modafinil improves
      daytime sleepiness in PD patients, at least on a subjective or behavioral level.
      Modafinil treatment may be considered for EDS in PD patients, in whom otherwise
      treatable causes of Excessive Daytime Sleepiness (EDS) are absent.

PMID- 12489900
TI  - Left ventricular reconstruction for ischemic cardiomyopathy.
AB  - Used since 1984, left ventricular reconstruction (LVR) by endoventricular
      circular patchplasty (EVCPP) appears useful for pure dyskinesia (true aneurysm)
      or ventricular akinesia. The technique is conducted under a totally arrested
      heart; coronary revascularization is accomplished first. The mitral valve is
      checked by TEE and repaired if necessary. Endocardectomy and cryotherapy are used
      in case of ventricular tachycardia. At the limit between scarred and normal
      tissue, a continuous suture is tied on a balloon inflated at the theoretical
      diastolic volume of the patient, and a patch is fixed inside the ventricle.
      Autologous tissue can be also used. The experience of the author is more than
      1000 cases since 1984. The global hospital mortality of the whole series is 7.3%,
      and 13% in patients with very poor ejection fraction (< 30%). In the series of
      the last 3 years, these mortality rates are 4.8% and 7.9%, respectively. Both
      geometry and performances of the LV are improved, and the mean increase of
      ejection fraction is between 10 and 15 points. Three causes can explain delayed
      impairment; continuum in remodeling, lack in diastolic capacity, or absence of
      mitral repair. After an infarct, with or without successful coronary
      recanalization, that leaves a large asynergic scarred ventricle (50% of LV
      circumference), LVR is recommended to avoid or prevent permanent congestive heart
      failure with global dilatation. In end-stage ischemic cardiomyopathy with
      congestive heart failure, and poor response to full medical therapy, LVR, with
      acceptable risk, could slow down the remodeling and avoid or delay heart
      transplantation.

PMID- 12489901
TI  - The Ross operation.

PMID- 12489902
TI  - From dynamic to cellular cardiomyoplasty.
AB  - Dynamic Cardiomyoplasty. Latissimus dorsi dynamic cardiomyoplasty has been used
      in our institution for heart failure patients refractory to medical therapy; 113
      cases were operated at Broussais and Pompidou Hospitals and 75 patients by our
      team abroad, in the scope of an international cooperative program.
      Cardiomyoplasty has been associated with better results due to technical
      improvements, the most significant mini-invasive techniques, the latest the use
      of growth factors to enhance muscle vascularization. Risk factors have been
      identified, resulting in more precise indications, a lower hospital mortality,
      and a wider use of this operation. There has been a new tendency to associate
      cardiomyoplasty with electrophysiological therapies: implantation of ventricular
      defibrillators and multisite cardiac pacing (for atrioventricular and
      interventricular resynchronization). Cellular Cardiomyoplasty. Adult myocardium
      cannot repair after infarction due to the absence of stem cells. Cell
      transplantation strategies for heart failure have been designed to replace
      damaged cells with cells that can perform cardiac work. Current possibilities in
      cell therapy for heart failure is the transplantation into the infarcted
      myocardium of autologous myoblasts (satellite cells originated from skeletal
      muscle), fetal cardiomyocytes, autologous heart cells, cells derived from bone
      marrow stem cells, and smooth muscle cells. Experimental studies demonstrated
      that cell transplantation into the myocardium was associated with the recovery of
      myocardial contractility and compliance, as well as the diastolic pressure-strain
      relationship in animal models (infarctlike myocardial lesions and dilated
      cardiomyopathy models). Healthy myoblasts and myotubes were observed 2 months
      after myocardial implantation. Clinical studies are now in progress.

PMID- 12489903
TI  - Changes in left ventricular morphology and function in end-stage dilated
      cardiomyopathy after reductive annuloplasty of double mitral and tricuspid
      orifices.
AB  - BACKGROUND AND AIM: The aim of this study is to show the changes in left
      ventricular morphology and function after reductive annuloplasty of double mitral
      and tricuspid orifices (RADO) in ischemic dilated cardiomyopathy (IDCM) and
      primary dilated cardiomyopathy (PDCM) analyzed by intraoperative transesophageal
      echocardiography (TEE). METHODS: There were 274 patients, mean age 50.1 years,
      188 operated due to IDCM with ejection fraction under 30%, and 86 patients due to
      PDCM. Mitral annuloplasty according to A. Carpentier and our own procedure was
      done in 49 and 225 patients, respectively. In 265 cases (97%) our modified De
      Vega's tricuspid annuloplasty was performed. RESULTS:  CONCLUSION: RADO
      significantly changes left ventricular morphology, reverses remodeling of the
      heart, decreases sphericity of the left heart, improves hemodynamic function of
      both ventricles, and slows down progression of cardiac failure. We recommend RADO
      in the early stage of PDCM, immediately after the first decompensation, and as an
      important associated procedure in IDCM.

PMID- 12489904
TI  - Aortic valve replacement under deep hypothermic circulatory arrest.
AB  - BACKGROUND: Aortic valve replacement (AVR) in the presence of a calcified aorta
      or patent grafts may preclude clamping of the ascending aorta. We employed deep
      hypothermic circulatory arrest in order to circumvent this problem. METHODS:
      Between January 1993 and December 2000, 415 patients underwent AVR in our
      department. Eight of these were operated using deep hypothermic circulatory
      arrest. There were 5 males, and mean age was 72 years (range 56-81). Indications
      for using circulatory arrest were reoperation with patent grafts and/or severe
      calcification of the ascending aorta. In six patients, cardiopulmonary bypass was
      achieved via femoro-femoral bypass, and in two via aortic-right atrial
      cannulation. Retrograde cerebral perfusion was employed in five. Mean bypass time
      was 155 minutes (range 122-187), and mean circulatory arrest time was 38 minutes
      (range 31-49). RESULTS: There was no operative mortality, and no patient suffered
      any neurologic sequelae. Echocardiography showed all valves to be functioning
      well. CONCLUSIONS: AVR under deep hypothermic circulatory arrest can be
      accomplished with an acceptable degree of safety. It should be considered as an
      alternative in patients in whom aortic clamping is prohibitive, and might
      otherwise be considered inoperable. The ability to connect the patient to bypass
      and the presence of a "window" to allow aortotomy are prerequisites for employing
      this method.

PMID- 12489905
TI  - Pooled human albumin primes neutrophils.
AB  - Human pooled albumin has traditionally been used both to pacify the artificial
      surfaces in a cardiopulmonary bypass circuit and also for volume repletion
      following surgery. In evaluating the routine use of albumin in multiple phases of
      cardiac surgery, conscientious surgical teams must assess both the physiological
      and financial price of albumin. Albumin indiscriminately binds many plasma
      proteins and lipids. In this series of experiments, we explored the influence of
      highly purified albumin devoid of bound lipids and globulins on both receptor
      dependent (FMLP) and receptor-independent (PMA) priming/activation of human
      neutrophils. We believe that it is important to distinguish the direct influence
      of albumin from the albumin-bound proteins and lipids. We, therefore, also
      examined the effect of clinically accessible human pooled albumin on human
      neutrophils. We observed a dose-dependent priming/activation (elastase release)
      of human neutrophils by both pooled and purified albumin. We conclude that it is
      increasingly difficult to justify the routine use of albumin in cardiac surgical
      patients.

PMID- 12489906
TI  - Glucose metabolism, energetics, and function of rat hearts exposed to ischemic
      preconditioning and oxygenated cardioplegia.
AB  - We examined changes induced during ischemia-reperfusion on myocardial metabolism
      and function by oxygenated warm cardioplegia (CP) and ischemic preconditioning
      (IP). The postischemic hemodynamic recovery was comparable and significantly
      better in IP and CP groups, than in untreated hearts (e.g., LVDP recovery was
      threefold that of the control). The IP hearts reached a pH plateau earlier during
      ischemia and at considerably higher pH value (pH approximately 6) compared to the
      other groups (pH approximately 5.5). Postischemic phosphocreatine (PCr) and ATP
      recoveries were comparable and better in protected groups (approximately 72% and
      approximately 30% vs approximately 25% and approximately 10% in control, p <
      0.0001). Preischemic glycogen was significantly reduced in IP to 49% and
      increased in CP hearts to 127%. However, the lactate levels at the end of
      ischemia were similar in all the groups, indicating glucose utilization from
      extracellular space during ischemia in IP hearts. Thus, similar hemodynamic
      protection by CP and IP is observed despite increased energy depletion during
      ischemia in IP. IP and CP protection is expressed through better energetic status
      and by higher recovery of the TCA cycle activity or enhanced mitochondria-cytosol
      transport of alpha-ketoglutarate on reperfusion in addition to metabolic changes
      during ischemia. Glycogen store recovered significantly better in IP than in CP
      and Control. These results exhibit similar and improved postischemic hemodynamic
      protection by CP and IP. Increased recovery of postischemic glycogen pool is a
      protective feature of IP, whereas slightly higher lactate metabolism during
      reperfusion is a protection component of CP.

PMID- 12489909
TI  - Facilitated insertion of the Hancock II bioprosthesis.

PMID- 12489908
TI  - Acutely dissected aorta: a reliable and leak-proof technique.
AB  - When repairing an acutely dissected aorta, a primary concern is bleeding from the
      anastomotic site. To prevent a hemorrhagic complication, a unique variation of
      wall reinforcement with xenopericardium together with GRF glue was introduced to
      provide a leakproof seal for ascending and descending aortic grafts.

PMID- 12489907
TI  - Posterior mitral annuloplasty with an adjustable homemade ring.

PMID- 12489910
TI  - Repair of partial atrioventricular septal defect through a minimal right vertical
      infra-axillary thoracotomy.
AB  - OBJECTIVE: To report a new minimally invasive and cosmetic approach for partial
      atrioventricular septal defect (PAVSD) repair. METHODS: From November 1997 to
      January 2000, six patients with a mean age of 19.2 +/- 7.7 years underwent
      minimal right vertical infra-axillary thoracotomy (VIAT) for PAVSD repair. Left
      atrioventricular (AV) valve regurgitation was tested on the beating heart before
      and after valvuloplasty. Commissuroplasty of the left AV valve and atrial septum
      repair were done in all patients. RESULTS: There was no operative or late
      mortality, and no morbidity directly related to the thoracotomy approach. The
      average length of the incision was 8.3 +/- 1.3 cm. The arrest times averaged 32.8
      +/- 8.3 minutes, and the cardiopulmonary bypass times averaged 66.0 +/- 9.0
      minutes. One patient had mild-to-moderate left AV valve regurgitation
      postoperatively. All patients were free of symptoms during follow-up. CONCLUSION:
      Minimal right VIAT is a safe, more cosmetic, and less invasive approach than
      median sternotomy for the repair of PAVSD.

PMID- 12489912
TI  - Forest Dewey Dodrill: heart surgery pioneer. Michigan Heart, Part II.

PMID- 12489911
TI  - The Michigan Heart: the world's first successful open heart operation? Part I.

PMID- 12489913
TI  - Is dementia with Lewy bodies the second most common cause of dementia?
AB  - Lewy bodies were originally described in isolated brainstem nuclei in persons
      with Parkinson's disease. They have since been recognized as a widespread and
      common neuropathologic finding in individuals with dementia. Dementia with Lewy
      bodies (DLB) is the preferred term for the dementia syndrome associated with Lewy
      bodies. Although DLB is acknowledged as the second most common degenerative
      dementia, trailing only Alzheimer's disease, its ranking with respect to vascular
      dementia remains controversial. Large, community-based studies of DLB with
      postmortem confirmation are lacking. Available data suggest that DLB is more
      common than pure vascular dementia but not more common than any vascular
      contribution to dementia.

PMID- 12489914
TI  - Dementia with Lewy bodies: clinical characteristics and diagnostic criteria.
AB  - Dementia with Lewy bodies (DLB) is increasingly recognized as a distinct clinical
      and pathologic entity. It is a progressive dementia characterized by persistent
      and well-formed visual hallucinations, marked second-to-second fluctuations in
      attention, and progressive extrapyramidal signs. The diagnostic value of
      additional clinical features such as delusions, depression, falls, anosmia, and
      rapid progression continues to be debated. Despite the growing acceptance of the
      diagnosis, DLB has not yet been included in either International Classification
      of Disease (ICD-10) or Diagnostic and Statistical Manual of Mental Disorders (DSM
      IV) criteria. However, the existing consensus diagnostic criteria continue to be
      validated. Most prospective studies to date indicate that their performance is
      acceptable, with specificity similar to the present diagnostic criteria for
      Alzheimer's disease. Nevertheless, at least one in five patients with DLB will
      continue to be misclassified.

PMID- 12489915
TI  - Idiopathic rapid eye movement sleep behavior disorder is a harbinger of dementia
      with Lewy bodies.
AB  - Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia
      clinically linked with the alpha-synucleinopathies multiple systems atrophy
      (MSA), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Available
      autopsy information is limited but suggests that the pathologic basis of
      idiopathic RBD may be neuronal loss and Lewy bodies in pigmented monoaminergic
      nuclei, including the locus coeruleus and substantia nigra, which project to
      pontine nuclei mediating atonia during REM sleep. Thus, idiopathic RBD may be an
      alpha-synucleinopathy per se and a harbinger of impending PD, DLB, or MSA.
      Inclusion of historical or concurrent idiopathic RBD in the diagnostic criteria
      for DLB may improve their sensitivity, specificity, and clinical utility.

PMID- 12489916
TI  - Neuroimaging in dementia with Lewy bodies: metabolism, neurochemistry, and
      morphology.
AB  - Dementia with Lewy bodies (DLB) is recognized as one of the most common forms of
      neurodegenerative dementia. Neuroimaging contributes to a better understanding of
      the pathophysiology of DLB by examining alterations in brain metabolism,
      neurochemisty, and morphology in living patients. Neuroimaging can provide
      objective and quantifiable antemortem markers for the presence of and the
      progression of DLB and permits differentiation from other dementias. This article
      reviews current neuroimaging findings in DLB with particular attention to
      occipital hypometabolism, dopaminergic and cholinergic deficits, and medial
      temporal lobe atrophy as measured by positron emission tomography, single-photon
      emission computed tomography, and magnetic resonance imaging.

PMID- 12489917
TI  - Dementia with Lewy bodies: neuropathology.
AB  - The pathologic substrate of the clinical syndrome of dementia with Lewy bodies
      (DLB) remains to be determined. Only a few prospective clinicopathologic studies
      have been reported. In those reports, most cases of DLB had neocortical or limbic
      Lewy bodies and Alzheimer-type pathology below threshold for diagnosis of
      Alzheimer's disease. These results are in accord with recent retrospective
      clinicopathologic studies of dementia occurring in Parkinson's disease, in which
      cortical Lewy bodies, rather than concurrent Alzheimer's disease, are
      increasingly recognized as the pathologic substrate of dementia. Additional
      clinicopathologic studies are warranted to address the role of other Lewy-related
      pathology, most notably Lewy neurites, in the cognitive impairment of DLB.

PMID- 12489918
TI  - Familial Lewy body diseases.
AB  - Lewy body disease includes clinically and pathologically defined disorders in
      which Lewy bodies occur in the nervous system. In recent years, the molecular
      features of these disorders have been emerging. Several genetic loci have been
      identified in association with familial Lewy body disease; however, the genetic
      risks underlying most cases of familial Lewy body disease remain to be
      discovered. The fact that Lewy bodies stain strongly with antibodies to
      asynuclein and that mutations in the alpha-synuclein gene lead to syndromes in
      which parkinsonism and dementia occur gives us important clues regarding the
      biologic processes leading to disease. Pursuit of additional mendelian causes of
      familial Lewy body disease and study of the factors contributing to the complex
      phenotypes associated with Lewy body disorders will elucidate underlying disease
      pathways and, thus, possible targets for therapeutic intervention.

PMID- 12489919
TI  - Pharmacologic therapy of dementia with Lewy bodies.
AB  - As a clinicopathologically defined entity, dementia with Lewy bodies (DLB) has
      overlapping features of Alzheimer's disease (AD) and Parkinson's disease (PD).
      Analogous characteristics of DLB offer a provisional rationale for pharmacologic
      therapy based on remediating cholinergic and dopaminergic deficits, respectively.
      However, the distinct clinical manifestations and pathophysiologic substrates of
      DLB pose unique therapeutic opportunities and challenges. More severe cholinergic
      deficits in DLB relative to AD support clinical evidence that cholinergic therapy
      may be particularly beneficial in DLB patients. In contrast, DLB patients are
      generally more sensitive to the adverse effects of antipsychotic agents,
      warranting caution in treating visual hallucinations and other psychotic
      symptoms. Similarly, parkinsonian motor signs in DLB, often manifest as rigidity
      and bradykinesia, may be less amenable to dopaminergic therapies than in PD.
      Increasing recognition of DLB as a common form of dementia in the elderly
      underscores the need for large-scale, placebo-controlled therapeutic trials.

PMID- 12489920
TI  - Which Alzheimer patients are at risk for rapid cognitive decline?
AB  - In the current study of 1062 Alzheimer's disease (AD) patients, we employed
      receiver operating characteristic curve analysis to identify characteristics of
      patients at increased risk for rapid cognitive decline. The patients are
      participants at one of the nine Alzheimer's Disease Research Centers of
      California. Rapid decline was defined as a 3-point or greater loss on the Mini
      Mental State Examination (MMSE) per year, post visit. The independent variables
      were age at clinic visit, age at symptom onset of AD, MMSE at patient visit,
      years of education, gender, ethnicity, living arrangement, presence of aphasia,
      delusions, hallucinations, and extrapyramidal signs. Receiver operating
      characteristic curve analysis indicated that AD patients presenting with moderate
      to severe aphasia, age at clinic visit of 75 years or less, and an MMSE greater
      than 7 were at increased risk for rapid cognitive decline. This information could
      help clinicians target these patients for pharmacologic interventions, facilitate
      long-term care planning, and potentially create savings by delaying or
      stabilizing the course of the disease.

PMID- 12489921
TI  - Capgras' syndrome in dementia with Lewy bodies.
AB  - We report the occurrence of Capgras' syndrome, or the delusion of doubles, in a
      patient with dementia with Lewy bodies. The patient believed that several similar
      looking impostors had replaced his wife of over 50 years. Uncharacteristically,
      he adopted a friendly attitude with these impostors. This unusual convivial
      reaction to the impostors may result from differential involvement of the dual
      visual pathways processing facial recognition and emotional responses to faces.
      The delusion resolved spontaneously, coincident with worsening of the dementia.
      In a retrospective chart review of 18 autopsy-confirmed cases of dementia with
      Lewy bodies, delusions were reported in 5 subjects (27.8%), of whom 1 had
      misidentification delusions much like Capgras' syndrome.

PMID- 12489922
TI  - The contribution of afferent signals from the liver to metabolic regulation
      during exercise.
AB  - The crucial role of the liver as the only organ to produce glucose used by
      skeletal muscle during exercise is well known. Since hepatic glucose production
      is central to blood glucose homeostasis during exercise, it has been postulated
      that the liver may inform the central nervous system and other organs of its
      diminishing capacity to produce glucose from glycogen, before blood glucose
      falls. The sensory role of the liver during exercise would be similar to its role
      in the control of food intake. As a consequence, the experimental approaches used
      to test the hypothesis that afferent signals from the liver contribute to
      metabolic regulation during exercise are inspired by those used to test the same
      hypothesis in the regulation of food intake. In the present review, two questions
      are addressed. The existing evidence for the liver's sensory influence on
      metabolic adjustments to exercise is first reviewed; the nature of the initiating
      stimuli for the afferent contribution of the liver to physical exercise is
      discussed thereafter. The hypothetical construct upon which rests the
      contribution of the liver's afferent signals to metabolic regulation during
      exercise is that a decrease in liver glycogen or a related metabolic intermediate
      is sensed by the liver, and the signal is transduced to the central nervous
      system, most likely through the afferent activity of the hepatic vagus nerve,
      where it contributes to the orchestration of the metabolic and hormonal responses
      to exercise. Support in favour of this construct comes mainly from the
      demonstration that sectioning of the hepatic vagus nerve attenuates the normal
      hormonal response to exercise. It seems that the liver-glucagon axis is
      particularly responsive to this reflex activation. In other respects, the hepatic
      mechanism responsible for linking the metabolic activity in the liver to an
      afferent signal capable of regulating the metabolic response to exercise remains
      speculative. Substrates or derivatives of substrate oxidation, energy-related
      compounds (ATP and Pi), or changes in cell volume may all be related to changes
      in transmembrane potential in the liver cell, which according to the
      "potentiostatic" theory would determine the afferent vagal activity.

PMID- 12489923
TI  - Resistance-training-induced adaptations in skeletal muscle protein turnover in
      the fed state.
AB  - Resistance training changes the balance of muscle protein turnover, leading to
      gains in muscle mass. A longitudinal design was employed to assess the effect
      that resistance training had on muscle protein turnover in the fed state. A
      secondary goal was investigation of the potential interactive effects of creatine
      (Cr) monohydrate supplementation on resistance-training-induced adaptations.
      Young (N = 19, 23.7 +/- 3.2 year), untrained (UT), healthy male subjects
      completed an 8-week resistance-training program (6 d/week). Supplementation with
      Cr had no impact on any of the variables studied; hence, all subsequent data were
      pooled. In the UT and trained (T) state, subjects performed an acute bout of
      resistance exercise with a single leg (exercised, EX), while their contralateral
      leg acted as a nonexercised (NE) control. Following exercise, subjects were fed
      while receiving a primed constant infusion of [d5]- and [15N]-phenylalanine to
      determine the fractional synthetic and breakdown rates (FSR and FBR),
      respectively, of skeletal muscle proteins. Acute exercise increased FSR (UT-NE,
      0.065 +/- 0.025 %/h; UT-EX, 0.088 +/- 0.032 %/h; P < 0.01) and FBR (UT-NE, 0.047
      +/- 0.023 %/h; UT-EX, 0.058 +/- 0.026 %/h; P < 0.05). Net balance (BAL = FSR -
      FBR) was positive in both legs (P < 0.05) but was significantly greater (+65%) in
      the EX versus the NE leg (P < 0.05). Muscle protein FSR and FBR were greater at
      rest following T (FSR for T-NE vs. UT-NE, +46%, P < 0.01; FBR for T-NE vs. UT-NE,
      +81%, P < 0.05). Resistance training attenuated the acute exercise-induced rise
      in FSR (T-NE vs. T-EX, +20%, P = 0.65). The present results demonstrate that
      resistance training resulted in an elevated resting muscle protein turnover but
      an attenuation of the acute response of muscle protein turnover to a single bout
      of resistance exercise.

PMID- 12489924
TI  - Relation between MDR1 mRNA levels, resistance factor, and the efficiency of P
      glycoprotein-mediated efflux of pirarubicin in multidrug-resistant K562 sublines.
AB  - In this work, we sought to investigate the relation existing between MDR1 mRNA
      levels, the resistance factor (RF), and the efficiency of efflux of pirarubicin
      (THP) mediated by P-glycoprotein (P-gp) in multidrug-resistant (MDR) K562
      sublines. The MDR K562 sublines were selected from K562/adr cells by exposure to
      different adriamycin concentrations: 300 nM (K562/300), 1,000 nM (K562/1,000),
      and 10,000 nM (K562/10,000), yielding RF values of 23.2, 26.5, and 39.6,
      respectively. The analysis of the P-gp encoding MDR1 gene overexpression by
      reverse transcriptase - polymerase chain reaction provided evidence of increased
      MDR1 mRNA levels when the adriamycin concentration used for the MDR cell
      selection increased. We used spectrofluorometric methods to determine the
      kinetics of the uptake and P-gp-mediated efflux of THP in the different selected
      MDR K562 sublines. Our data showed that (i) the maximal rate of P-gp-mediated
      efflux of THP, Vmax, increased with increasing RF; (ii) the observed Michaelis
      constant, Km, had the same value for all selected sublines, thus leading to an
      overall increase in the ratio Vmax/Km (5.1 x 10(-3), 6.2 x 10(-3), 6.8 x 10(-3),
      and 9.3 x 10(-3) s(-1) for K562/adr, K562/300, K562/1,000, and K562/10,000 cells,
      respectively), and (iii) the determination of the Hill coefficient (nH) gave
      values close to 2, which suggested a positive cooperative transport of THP with
      the expelling of two molecules of THP per turnover of P-gp. This study
      demonstrated that, in the K562/adr sublines used in our experiments, P-gp played
      a major role in conferring the MDR phenotype. Moreover, under our experimental
      conditions, intracellular acidic organelles were shown to contribute to decreased
      drug-target interaction and, thereby, decreased cytotoxicity. The variation of
      the concentrations of THP accumulated in the acidic organelles as a function of
      the total TFP concentration added to the cells was the same, within the limits of
      experimental errors, whatever the degree of resistance of the studied MDR K562
      sublines. Finally, this study suggested that, in the selected MDR K562 sublines,
      the K+/H+ antiporter exchanger could be activated by the pirarubicin transport,
      leading to a probable acidification of intracellular pH. The P-gp-mediated efflux
      of THP and an accumulation of THP in acidic organelles confer an advantage for
      MDR cells in surviving prolonged exposure to cytotoxic agents and giving rise to
      high degrees of resistance.

PMID- 12489925
TI  - Mucosal inflammation in a genetic model of spontaneous type I diabetes mellitus.
AB  - The BioBreeding (BB) rat provides a model of spontaneous type I diabetes mellitus
      that closely resembles the human disease. Diabetes-prone BB rats demonstrate
      increased intestinal permeability prior to the development of insulinitis.
      Studies suggest that alterations in intestinal permeability can lead to increased
      intestinal inflammatory activity. Diabetes-prone (BBdp) and diabetes-resistant
      (BBdr) BB rats were examined at 45 days and at >70 days of age following the
      development of clinical disease (BBd). In separate experiments, tissue was
      assayed for myeloperoxidase (MPO) or fixed for histological assessment and
      immunohistochemistry. Blood was obtained for leukocyte MPO measurements and
      morphological assessment of circulating leukocytes. MPO activity was
      significantly elevated in the distal small intestine of 45-day-old BBdp rats. In
      contrast, at >70 days of age, MPO activity was significantly increased throughout
      the small intestine of BBd and non-diabetic BBdp rats. Subsequently, all
      measurements were performed in >70-day-old rats. An increase in inflammatory
      infiltrate was noted in the distal small intestine of BBd rats by light
      microscopy. Infiltrating cells were identified as bands (a maturing cell type of
      the neutrophil lineage) and mature neutrophils. The findings suggest diabetes
      susceptibility is associated with an increase in intestinal inflammatory
      activity.

PMID- 12489926
TI  - Stereospecific disposition of fluvastatin in streptozotocin-induced diabetic
      rats.
AB  - The study reports on the stereoselective pharmacokinetics of fluvastatin, a
      racemic mixture of (-)-(3S,5R)- and (+)-(3R,5S)-enantiomers, in streptozotocin
      induced diabetic rats. Wistar (control) and streptozotocin-induced diabetic rats
      (n = 6/time point) received by oral gavage racemic fluvastatin (5 mg/kg), and
      blood samples were collected until 24 h. The enantiomers were analysed by chiral
      HPLC with fluorescence detection. The pharmacokinetic parameters were analysed by
      Wilcoxon and Mann-Whitney tests. The results are reported as means (95% CI). The
      following differences (p < 0.05) were observed between the control and diabetic
      groups, respectively: maximum plasma concentration (Cmax) of (-)-(3S,5R), 410.0
      (310.0-510.0) versus 532.6 (463.5-601.8) ng x mL(-7); area under the plasma
      concentration versus time curve (AUC(0-infinity)) for (-)-(3S,5R), 4342A (3,775.7
      4,909.0) versus 3025.2 (2,218.9-3,831.5) ng x h x mL(-1); apparent total
      clearance (Cl/f) of (-)-(3S,5R), 0.6 (0.5-0.7) versus 0.9 (0.6-1.1) L x h(-1) x
      kg(-1); AUC(0-infinity) for (+)-(3R,5S), 493.5 (376.9-610.1) versus 758.5 (537.1
      980.0) ng x h x mL(-1); and Cl/f of (+)-(3R,5S), 5.3 (3.9-6.8) versus 3.5 (2.6
      4.4) L x h(-1) x kg(-1). Streptozotocin-induced diabetes in rats alters the
      pharmacokinetics of fluvastatin in a stereoselective manner.

PMID- 12489927
TI  - Hippocampal brain amines in methotrexate-induced learning and memory deficit.
AB  - Intrathecal methotrexate in children with leukemia is known to cause seizures,
      dementia, leukoencephalopathy, and cognitive dysfunction after long-term
      treatment. To investigate the cognitive dysfunction, male Wistar rats were given
      multiple intracerebroventricular injections of methotrexate. Its effect on
      behaviour was tested in the two-compartment conditioned avoidance task and dark
      bright arena test. Levels of brain amines in the hippocampal region of the brain
      were estimated by HPLC. The qualitative and quantitative histopathological
      changes in the different regions of the hippocampus were studied by cresyl violet
      staining. Multiple injections (1 or 2 mg/kg) produced convulsions and learning
      and memory impairment but did not induce anxiolytic activity. They also reduced
      concentrations of all three brain amines (norepinephrine, dopamine, and
      serotonin) and the serotonin metabolite 5-hydroxyindoleacetic acid. The CA4
      region of the hippocampus was severely affected by intraventricular methotrexate.
      Disruption of brain monoamines has been proposed as a cause of brain dysfunction
      from this chemotherapy, and that disruption may in turn involve cytotoxic effects
      of methotrexate on brain tissue. The outcomes of this study may have therapeutic
      implications in the management of cancer conditions, particularly in childhood
      lymphoblastic leukemia.

PMID- 12489928
TI  - Calcium-stimulated short-circuit currents in the canine proximal colonic
      epithelium: effects of DK-PGD2, a metabolite of prostaglandin D2.
AB  - Prostaglandin D2 (PGD2) has marked inhibitory effects on the canine proximal
      colonic epithelium set up in Ussing chambers. These effects involved a receptor
      that is pharmacologically distinct from the classical DP, presumably the recently
      identified CRTH2/DP2 variety. The mechanism underlying these effects was studied
      using 13,14-dihydro-15-keto-PGD2 (DK-PGD2), a stable metabolite of the parent
      prostanoid. The metabolite quickly reversed short circuit currents (I(sc))
      stimulated by diverse agonists. Greater inhibitory effects were seen with
      stimulants such as carbachol and cyclopiazonic acid (CPA) rather than with
      forskolin or protein kinase A activators. Since the same stimulants were
      differentially affected by removal and replacement of serosal Ca2+, we tested the
      possibility that the prostanoid inhibited basolateral Ca2+ entry. In the absence
      of serosal Ca2+, tissues primed with CPA demonstrated concentration-dependent
      increases in I(sc), to cumulative additions of Ca2+ or Sr2+, though the former
      was more potent. Cl- removal and pretreatment with bumetanide virtually abolished
      responses, suggesting that the increase in I(sc) reflected Ca2+ dependent Cl-
      secretion. Though responses were insensitive to the L-type channel antagonist,
      verapamil, a marked inhibition was seen in the presence of metal cations (Gd3+,
      Cd2+, and La3+). Pretreatment with DK-PGD2 inhibited responses to Ca2+ in CPA
      primed tissues. Thus, basolateral Ca2+ entry via store-operated Ca2+ channels may
      be the locus for the inhibitory effects of PGD2 in this tissue. These results
      could indicate a potential transduction mechanism for the novel DP receptor
      variously called CRTH2 or DP2.

PMID- 12489929
TI  - Effects of a hypocaloric, low-carbohydrate diet on weight loss, blood lipids,
      blood pressure, glucose tolerance, and body composition in free-living overweight
      women.
AB  - The purpose of the current study was to examine the effects of a very low
      carbohydrate diet on weight loss and biochemical parameters in overweight women.
      Twenty women completed an 8-week trial that reduced their daily carbohydrate
      intake from 232 to 71 g (p < 0.05) and reduced energy by 2,644 kJ/day (8,384 to
      5,740 kJ, p < 0.001). The average weight loss was 5.0 kg (p < 0.0001), with a net
      decrease in body mass index of 1.82 kg/m2, a loss of 3.4% body fat (4 kg, p <
      0.0001), and a loss of 1.0 kg lean mass (p < 0.05). There were no significant
      changes in fasting blood glucose, fasting serum insulin, oral glucose tolerance,
      free or total insulin-like growth factor-1, or total IGFBP-3. Systolicblood
      pressure decreased by an average of 9.0 mmHg (1 mmHg = 133.322 Pa) (p < 0.01) and
      diastolic blood pressure decreased by 7 mmHg (p < 0.05). Total cholesterol
      decreased 1.2 mM (p < 0.001), all of which was accounted for by a decrease in low
      density lipoprotein cholesterol (p < 0.001) with no change in high-density
      lipoprotein cholesterol (baseline, 1.17 mM; week 8, 1.22 mM). Total
      triacylglycerol decreased 0.6 mM (p < 0.01), and the ratio of triacylglycerol/HDL
      also significantly decreased (baseline, 1.40; week 8, 0.87; p < 0.001). Serum
      beta-hydroxybutyrate concentrations rose significantly by week 2 and declined
      thereafter but remained significantly higher than baseline values for the
      duration of the intervention. Therefore, carbohydrate restriction to 70 g or less
      with concomitant energy restriction, without changes in protein or fat
      consumption, promotes weight loss, and improvements in body composition, blood
      pressure, and blood lipids without compromising glucose tolerance in moderately
      overweight women.

PMID- 12489930
TI  - Effect of in vivo nitrate tolerance on hypersensitivity to NO donors after NO
      synthase blockade.
AB  - Animals treated with nitric oxide synthase (NOS) inhibitors exhibit marked
      hypersensitivity to the blood pressure lowering effects of exogenous nitric oxide
      (NO) donors. We used this model as a sensitive index to evaluate the relative
      importance of reduced biotransformation of glyceryl trinitrate (GTN) to NO in the
      development of nitrate tolerance. NOS-blockade hypertension using N(G)-nitro-L
      arginine methyl ester (L-NAME) caused a marked enhancement of the mean arterial
      pressure (MAP) decrease mediated by GTN in nontolerant rats. However, even large
      doses of GTN were unable to change the MAP in GTN-tolerant, NOS-blockade
      hypertensive animals. In contrast, the MAP responses to the spontaneous NO donor
      sodium nitroprusside (SNP) were completely unaltered in either tolerant rats or
      tolerant NOS-blockade hypertensive animals, indicating that NO-dependent
      vasodilatory mechanisms remain intact despite the development of GTN tolerance.
      The MAP-lowering effects of GTN in NOS-blockade hypertensive animals were
      restored 48 h after cessation of chronic GTN exposure. These alterations in the
      pharmacodynamic response to GTN during tolerance development and reversal were
      associated with parallel changes in the pattern of GTN metabolite formation,
      suggesting that the activity of one or more enzymes involved in nitrate
      metabolism was altered as a consequence of chronic GTN exposure. These findings
      suggest that the vasodilation resulting from the vascular biotransformation of
      GTN to NO (or a closely related species) is severely compromised in nitrate
      tolerant animals, and that although other mechanisms may contribute to the
      vascular changes observed following the development of GTN tolerance, decreased
      GTN bioactivation is likely the most important.

PMID- 12489931
TI  - Enhanced accumulation of constitutive heat shock protein mRNA is an initial
      response of eye tissue to mild hyperthermia in vivo in adult Xenopus laevis.
AB  - We have examined the effect of mild hyperthermia in vivo on heat shock
      transcription factor (HSF) binding activity and heat shock protein (hsp) gene
      expression in eye tissue of adult Xenopus laevis. A specific interaction between
      HSF and a synthetic oligonucleotide corresponding to the proximal heat shock
      element of the Xenopus hsp70B gene was greatly enhanced in eyes from hyperthermic
      animals compared with controls. Given these results, we examined the effect of
      hyperthermia in vivo on the expression of five hsp genes (hsp70, hsc70, BiP,
      hsp90, and hsp30) in eye tissue. Interestingly, at 28 degrees C constitutively
      expressed hsp genes hsc70, BiP, and hsp90 were strongly enhanced, with further
      accumulation at 30 degrees C. However, hsp70 and hsp30 mRNA accumulation were not
      detectable at 28 degrees C but were strongly induced at 30 degrees C. No
      enhancement of the relative levels of cytoskeletal actin mRNA was observed in the
      eye tissue of hyperthermic animals. These results suggest that one of the primary
      responses of eye tissue to hyperthermia in vivo is in the elevation of mRNAs
      encoding a set of constitutively expressed molecular chaperones.

PMID- 12489932
TI  - Synthesis and characterization of pi-stacked phenothiazine-labeled
      oligodeoxynucleotides.
AB  - [reaction: see text] A facile procedure for the incorporation of N-methyl
      phenothiazine as the terminal nucleoside in oligodeoxynucleotides is reported.
      The phenothiazine nucleoside analogue is synthesized and then incorporated into
      DNA using an automated DNA solid-phase synthesizer. Phenothiazine-labeled
      oligodeoxynucleotides form stable B-form duplexes with higher melting
      temperatures compared to unlabeled DNA duplexes.

PMID- 12489933
TI  - New and efficient synthesis of azabicyclo[4.4.0]alkane amino acids by Rh
      catalyzed cyclohydrocarbonylation.
AB  - [reaction: see text] Highly efficient syntheses of azabicyclo[4.4.0]alkane amino
      acids were achieved by Rh-catalyzed cyclohydrocarbonylation of dipeptides bearing
      a terminal olefin moiety and a heteroatom nucleophile.

PMID- 12489935
TI  - Evaluation of a pseudoephedrine linker for asymmetric alkylations on solid phase.
AB  - [reaction: see text] Immobilized pseudoephedrine amides have been conveniently
      prepared by attachment of pseudoephedrine to Merrifield resin and acylation on
      nitrogen. Deprotonation and alkylation of the resin bound amides proceeds
      smoothly. Products were cleaved from the resin to give ketones and alcohols in
      high enantiomeric excess and moderate to good overall yield.

PMID- 12489934
TI  - High alpha/beta-anomer selectivity in molecular recognition of carbohydrates by
      artificial receptors.
AB  - [structure: see text] New effective, acyclic, pyridine-based receptors 1-3 show
      remarkable alpha/beta binding selectivity in the recognition of monosaccharides.
      They are able to participate in cooperative and bidentate hydrogen bonds with
      sugar hydroxyls as well as in CH-pi interactions with CH's of sugar molecules.

PMID- 12489936
TI  - Palladium-charcoal-catalyzed reduction of tri-O-acetyl-beta-L-fucopyranosyl
      cyanide: a route to small cluster oligosaccharide mimetics (SCOMs).
AB  - [reaction: see text] Synthesis of glycosyl cyanides was optimized with a new
      catalyst system. Reduction of tri-O-acetyl-beta-L-fucopyranosyl cyanide with Pd
      hydrogen, in the presence of Ac(2)O and Boc(2)O, gave N-protected-mono- and -di
      (2,3,4-tri-O-acetyl-beta-L-fucopyranosylmethyl)-amines, which allow for the
      syntheses of small cluster oligosaccharide mimetics of fucopyranosylomethyl
      substituted ureas. From di-(2,3,4-tri-O-acetyl-beta-L-fucopyranosylmethyl) amine
      was also prepared a carbamoyl chloride as a potentially useful synthon for
      preparation of more complex C-glycosidic conjugates.

PMID- 12489937
TI  - Opening of substituted oxetanes with H(2)O(2) and alkyl hydroperoxides:
      stereoselective approach to 3-peroxyalcohols and 1,2,4-trioxepanes.
AB  - [reaction: see text] Lewis acid-catalyzed opening of oxetanes by hydrogen
      peroxide proceeds regioselectively and with good to moderate stereoselectivity to
      furnish enantiomerically enriched 3-hydroperoxyalkanols. The corresponding
      opening using alkyl hydroperoxides furnishes 3-peroxyalkanols. The
      hydroperoxyalkanols are easily converted into enantiomerically enriched 1,2,4
      trioxepanes, building blocks for antimalarials.

PMID- 12489938
TI  - Determination of absolute configuration using optical rotation calculated using
      density functional theory.
AB  - [structure: see text] We report the first determinations of the absolute
      configurations (ACs) of chiral molecules using discrete frequency, transparent
      spectral region optical rotations calculated using density functional theory
      (DFT). The ACs of 2H-naphtho[1,8-bc]thiophene 1-oxide (3), naphtho[1,8-cd]-1,2
      dithiole 1-oxide (4), and 9-phenanthryl methyl sulfoxide (5) are determined by
      comparison of their specific rotations to values calculated via the time
      dependent DFT/gauge-invariant atomic orbital (TDDFT/GIAO) methodology using the
      B3LYP functional and the aug-cc-pVDZ basis set.

PMID- 12489939
TI  - Synthesis of novel diastereomeric diphosphine ligands and their applications in
      asymmetric hydrogenation reactions.
AB  - [structure: see text] Diastereomeric biaryl diphosphine ligands 10 and 11 with
      added chiral centers on the backbone were synthesized. Substrate-directed
      asymmetric synthesis occurred in the coupling step of the preparation of the
      diastereomeric diphosphine oxides. The diastereomeric diphosphine oxides were
      easily separated by column chromatography with silica gel. Ruthenium catalysts
      containing these ligands were highly effective in the hydrogenation of 2-(6'
      methoxy-2'-naphthyl)propenoic acid and beta-ketoesters. The additional chiral
      centers had a significant influence on the enantioselectivity and activity of the
      catalysts.

PMID- 12489940
TI  - Pyranmycins, a novel class of aminoglycosides with improved acid stability: the
      SAR of D-pyranoses on ring III of pyranmycin.
AB  - [reaction: see text] The synthesis of a novel class of aminoglycosides,
      pyranmycins, is reported along with the structure activity relationship (SAR) of
      their antibacterial activity against Escherichia coli. Two pyranmycins show
      prominent activity (9 microM). Pyranmycins also manifest superior stability in
      acidic media. The SAR information will lead to the future designs of pyranmycin
      against drug resistant bacteria.

PMID- 12489941
TI  - (R)-2,4-Dihydroxybutyramide seco-pseudonucleosides: new versatile homochiral
      synthons for synthesis of modified oligonucleotides.
AB  - [reaction: see text] Two series of seco-pseudonucleoside synthons were
      synthesized from (R)-(+)-alpha-hydroxy-gamma-butyrolactone and (R)-(-)
      pantolactone by aminolysis, side-chain protection, dimethoxytritylation, and
      phosphitylation or solid-phase attachment. The phosphoramidites and solid
      supports were used in automated DNA synthesis to prepare oligonucleotides
      modified with one or more 2,4-dihydroxybutyramide units bearing side-chain
      reporter groups. These new oligonucleotide modification reagents allow the
      introduction of a label into any desired position within an oligonucleotide chain
      during solid-phase assembly.

PMID- 12489942
TI  - A tandem three-phase reaction for preparing secondary amines with minimal side
      products.
AB  - [reaction: see text] A new method for the preparation of secondary amines has
      been reported. Complementary solution-phase and solid-phase synthesis highlight
      the process. Amines are obtained in good yields free from the usual byproducts of
      reductive amination. Secondary amines are unreactive, so overalkylation does not
      occur. The procedure can be used interchangeably for traditional or parallel
      synthesis settings.

PMID- 12489943
TI  - Formal total synthesis of fostriecin.
AB  - [reaction: see text] Addition of magnesium anion 4 (M = MgBr, R(1) = TES) to
      ketone 6 (R(2) = PMB) at -78 degrees C in THF proceeded under chelation control
      to provide alcohol 7, which possesses the full set of the chiral centers of
      fostriecin. Subsequently, 7 was transformed successfully to the known key
      intermediate 2.

PMID- 12489944
TI  - Intramolecular Diels-Alder reactions of ester-tethered 1,7,9-decatrienoates:
      bis[chloro(methyl)aluminum]trifluoromethanesulfonamide as a catalyst.
AB  - [reaction: see text] The intramolecular Diels-Alder reaction of 1,7,9
      decatrienoate derivative with an ester tether is efficiently catalyzed by the
      bidentate Lewis acid, bis-aluminated trifluoromethanesulfonamide.

PMID- 12489945
TI  - Galacto, gluco, manno, and disaccharide-based C-glycosides of 2-amino-2-deoxy
      sugars.
AB  - [reaction: see text] Starting from readily available precursors, selenoglycosides
      derived from GalNAc, GlcNAc, and ManNAc were prepared by either a one- or a two
      step process. The anomeric selenides underwent facile C-Se homolysis to provide
      the corresponding anomeric radicals, which were trapped with alkenes to give C
      glycosides. This provides a general entry to alpha-C-glycosides based on 2-amino
      2-deoxy sugars that is also applicable to disaccharide variants.

PMID- 12489946
TI  - Acyl-lithiation of olefins: formation of cyclopentenones from 1-lithio-butadienes
      and CO.
AB  - [reaction: see text] Intramolecular acyl-lithiation of C=C double bonds proceeds
      following carbonylation of 1-lithio-1,3-dienes with CO to afford 2- or 3
      cyclopentenone derivatives in good to excellent yields after hydrolysis. Addition
      of electrophiles to the carbonylation reaction mixtures affords various multiply
      substituted cyclopentenones.

PMID- 12489947
TI  - Intermolecular rhodium(II)-catalyzed reactions with silicon-substituted carbonyl
      ylides.
AB  - [reaction: see text] The Rh(II)-catalyzed reaction of benzyl 2-trialkylsilyl-2
      diazoacetates with various acyclic and cyclic ketones affords novel dioxolanones
      via silicon-substituted carbonyl ylides in up to 98% yield.

PMID- 12489948
TI  - Efficient sensitized photooxygenation in water by a porphyrin-cyclodextrin
      supramolecular complex.
AB  - [reaction: see text] The 2:1 inclusion complex between (2,3,6-tri-O-methyl)-beta
      cyclodextrin (TMbetaCD) and 5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrin
      (TPPS(4)) behaves as a supramolecular sensitizer in water providing
      photooxygenation with turnover numbers up to 30,000 with a very minor sensitizer
      bleaching (<10%). The protocol, which employs only 4 equiv of the cyclodextrin
      additive with respect to the porphyrin sensitizer (5 x 10(-7) M), leads to high
      yield oxidation of model biomolecules such as l-methionine methyl ester and
      uracil and is also effective for phenol degradation in aqueous solution.

PMID- 12489949
TI  - Steroidal ureas as enantioselective receptors for an N-acetyl alpha-amino
      carboxylate.
AB  - [reaction: see text] Cholic acid has been elaborated into three regioisomeric bis
      carbamoylureas, which have been investigated as enantioselective receptors for N
      acetyl phenylalanine. L/D selectivities, peaking at 5:1, have been determined by
      a sensitive and rapid MS-based extraction method that should be generalizable to
      related systems.

PMID- 12489950
TI  - Intramolecular amidofuran cycloadditions across an indole pi-bond: an efficient
      approach to the aspidosperma and strychnos ABCE core.
AB  - [reaction: see text] The intramolecular Diels-Alder reaction between an
      amidofuran moiety tethered onto an indole component was examined as a strategy
      for the synthesis of Aspidosperma and Strychnos alkaloids. Furanyl carbamate 13
      was acylated using the mixed anhydride 16 to provide amidofuran 12 in 68% yield.
      Further N-acylation of this indole furnished 17 in 88% yield. Cyclization
      precursors were prepared by removing the carbamate moiety followed by N
      alkylation with the appropriate alkyl halides. Thermolysis of 25 provided the
      novel tetracyclic ketone 26 in 74% yield.

PMID- 12489951
TI  - 1,3-Diphenyl-1H-pyrazolo[3,4-b]quinoline: a versatile fluorophore for the design
      of brightly emissive molecular sensors.
AB  - [structure: see text] The 1,3-diphenyl-1H-pyrazolo[3,4-b]-quinoline chromophore
      is a versatile building block for the construction of brightly fluorescent
      molecular sensors. Facile synthetic procedures allow integration of the
      chromophore into fluorophore-spacer-receptor systems as well as fluoroionophores
      operating via intramolecular charge transfer. Whereas the former photoinduced
      electron-transfer probes show strong analyte-induced fluorescence enhancement,
      the latter exhibit bright ratiometric dual emission. Employing prototype
      macrocyclic receptors, the favorable signaling features for metal ion recognition
      are demonstrated.

PMID- 12489952
TI  - Unprecedented highly stereoselective alpha- and beta-C-glycosidation with chiral
      titanium enolates.
AB  - [reaction: see text] Lewis acid mediated addition of chiral titanium enolates to
      glycals provides either alpha- or beta-1'-methyl-substituted C-glycosides. This
      highly stereoselective methodology permits the modular preparation of three of
      the four possible diastereomers.

PMID- 12489953
TI  - Conformational stability of helical peptides containing a thioamide linkage.
AB  - [structure: see text] Thioxo peptide analogues of the alpha-helical peptide GCN4
      p1 were synthesized and evaluated for helicity and oligomeric state.
      Sedimentation equilibrium and CD measurements indicate that the thioxo peptides
      fold into parallel alpha-helical coiled coil structures essentially identical to
      the native structure. This work marks the first incorporation of a thioamide
      linkage into the backbone of an alpha-helix and demonstrates that a thioamide
      linkage is compatible with positions within the helix as well as near the C
      terminus.

PMID- 12489954
TI  - In support of the original medermycin/lactoquinomycin A structure.
AB  - [structure: see text] Herein we report a significant body of spectroscopic data
      that supports the originally proposed structure of medermycin/lactoquinomycin A.
      In addition, we demonstrate that these data are inconsistent with the revised
      structure reported recently in the literature.

PMID- 12489955
TI  - Hydrogen bond-stabilized helix formation of a m-phenylene ethynylene oligomer.
AB  - [reaction: see text] Incorporation of a single hydrogen bonded beta-turn mimic in
      the backbone of a m-phenylene ethynylene oligomer is shown to affect the
      thermodynamic properties of the folding reaction. Oligomers 1 and 2 both undergo
      solvophobic helix formation, but hydrogen bonded oligomer 1 was found to form a
      more stable helix with a higher tolerance to solvent denaturation than isomeric,
      non-hydrogen bonded oligomer 2.

PMID- 12489956
TI  - Olefin cross-metathesis as a tool in natural product degradation. The
      stereochemistry of (+)-falcarindiol.
AB  - [reaction: see text] There are conflicting reports in the literature concerning
      the absolute sterochemistry at C-3 of the common plant polyacetylene oxylipin (+)
      falcarindiol. We have employed olefin cross-metathesis using Grubbs' second
      generation catalyst and ethylene gas to degrade falcarindiol to the symmetrical
      1,9-decadiene-4,6-diyne-3,8-diol. The reaction is completely selective for net
      removal of the aliphatic side chain. Degradation of (+)-falcarindiol from
      Tetraplasandra hawaiiensis yields a meso product as shown by chiral HPLC. Hence,
      (+)-falcarindiol from this source has a (3R,8S)-configuration.

PMID- 12489957
TI  - Novel nucleophilic trifluoromethylation of vicinal diol cyclic sulfates.
AB  - [reaction: see text] A novel method for highly regioselective and stereospecific
      nucleophilic trifluoromethylation of vicinal diol cyclic sulfates, using the
      reagent derived from reduction of trifluoromethyl iodide by
      tetrakis(dimethylamino)ethylene (TDAE), is presented.

PMID- 12489958
TI  - A concise route to structurally diverse DMP 323 analogues via highly
      functionalized 1,4-diamines.
AB  - [reaction: see text] The utility of functionalized 1,4-diamines, produced via a
      temporary phosphorus tether (P-tether)/ring-closing metathesis (RCM)/hydrolysis
      sequence, is demonstrated in the synthesis of structurally diverse DMP 323
      analogues. These 1,4-diamines are transformed into various seven-membered
      heterocycles via insertion of the appropriate nuclei "X". Subsequent
      derivatization generates heterocyclic diols that are similar in structure to DMP
      323, a notable member of a class of highly potent inhibitors of HIV protease.

PMID- 12489959
TI  - Tandem reactions to construct heterocycles via phosphine-catalyzed umpolung
      addition and intramolecular conjugate addition.
AB  - [reaction: see text] A highly efficient method for constructing heterocycles was
      achieved by phosphine-catalyzed tandem umpolung addition and intramolecular
      conjugate addition. This strategy offers a simple and promising method for
      constructing synthetically useful heterocycles under neutral conditions with high
      atom economy.

PMID- 12489960
TI  - Stereospecific, enantiospecific total synthesis of the sarpagine indole alkaloids
      (E)16-epiaffinisine, (E)16-epinormacusine B, and dehydro-16-epiaffinisine.
AB  - [reaction: see text] The first stereospecific total synthesis of the sarpagine
      indole alkaloids (E)16-epiaffinisine (1), (E)16-epinormacusine B (2), and dehydro
      16-epiaffinisine (4) has been completed; this method has also resulted in the
      synthesis of dehydro-16-epinormacusine B (5). The formation of the required ether
      in both 4 and 5 was realized with complete control from the top face on treatment
      of the corresponding alcohols with DDQ/THF in 98% and 95% yields, respectively.

PMID- 12489961
TI  - Osmium tetroxide anchored to porous resins bearing residual vinyl groups: a
      highly active and recyclable solid for asymmetric dihydroxylation of olefins.
AB  - [reaction: see text] OsO(4) was simply immobilized onto resins such as Amberlite
      XAD-4 or XAD-7 bearing residual vinyl groups. The resulting osmylated resins are
      air-stable, nonvolatile, and much easier to handle than their homogeneous
      counterpart (OsO(4)). Moreover, the resin-bound OsO(4) exhibited excellent
      catalytic activity in the asymmetric dihydroxylation of olefins and was easily
      recovered and reused in five consecutive reactions without any significant
      decrease in product yield. Turnover time, however, was significantly increased
      for the fourth and fifth reactions.

PMID- 12489962
TI  - Palladium-catalyzed amination of aryl halides on solid support.
AB  - [reaction: see text] The first examples of the Pd(0)-catalyzed amination of aryl
      halides using Rink-resins as nitrogen source are described. Pd(2)dba(3)/BINAP/NaO
      t-Bu was found to be the most efficient catalyst/base system, while a solvent
      mixture of dioxane and tert-butyl alcohol was shown to enhance the selectivity
      toward the desired monoarylation. Moderate to good yields and excellent purities
      of the amination products were found with electron-poor aryl halides, while
      electon-rich aryl halides failed to react under these conditions.

PMID- 12489963
TI  - Studies directed toward asymmetric synthesis of cardioactive steroids via anionic
      polycyclization.
AB  - [reaction: see text] The use of anionic polycyclization (AP) in constructing the
      steroidal backbone of cardenolides was investigated. The reaction of 2
      carbomethoxy-2-cyclohexenone I with the enolate of Nazarov reagent II gave, after
      decarboxylation and aldol condensation, steroid III with control of
      stereochemistry.

PMID- 12489964
TI  - Double cycloisomerization as a novel and expeditious route to tricyclic
      heteroaromatic compounds: short and highly diastereoselective synthesis of (+/-)
      tetraponerine T6.
AB  - [reaction: see text] Cu-Assisted double cycloisomerization of bis
      alkynylpyrimidines afforded the 5-6-5 tricyclic heteroaromatic skeleton. This
      transformation was used as a key step in the highly diastereoselective total
      synthesis of (+/-)-tetraponerine T6.

PMID- 12489965
TI  - A new, simple, and selective palladium-catalyzed cleavage of triethylsilyl
      ethers.
AB  - [reaction: see text] A simple procedure for the cleavage of triethylsilyl (TES)
      ethers in the presence of 10 wt % Pd/C in methanol or 95% ethanol is reported.
      This method allows selective removal of alkyl TES ethers in the presence of
      aromatic TES ethers or tert-butyldimethylsilyl (TBS) protecting groups.

PMID- 12489966
TI  - Investigation of the diastereoselective cyclization of bis-sulfonyl esters.
AB  - [reaction: see text] The diastereoselective cyclization of bissulfonyl esters was
      investigated by varying both the size and the placement of the substituent on the
      tether adjoining the reacting centers. Substitution at either the alpha or beta
      position relative to the ester moiety gave diastereomeric ratios of (1-3):1,
      while gamma substitution dramatically increased the diastereomeric ratios to (6
      20):1.

PMID- 12489967
TI  - Stereoselective transformation of indole diazabicyclo[3.2.2]nonedione to
      azepinoindole.
AB  - [reaction: see text] The synthesis of an indole diazabicyclo[3.2.2]nonedione
      derivative was achieved in a few steps starting from L-tryptophan. Reduction with
      borane-THF complex leads to fragmentation of the bicycle and the stereoselective
      formation of an azepinoindole derivative was observed.

PMID- 12489968
TI  - Synthesis and application of chiral phosphino-imidazoline ligands: Ir-catalyzed
      enantioselective hydrogenation.
AB  - [reaction: see text] A series of chiral phosphino-imidazolines (PHIM ligands) 1a
      j with different substituents at the stereogenic center, the nitrogen atom of the
      imidazoline ring, and at the phosphorus atom were synthesized. Iridium complexes
      derived from these ligands have been evaluated as catalysts for the
      enantioselective hydrogenation of unfunctionalized olefins. In several cases,
      higher enantiomeric excesses were observed than with analogous phosphino
      oxazoline ligands.

PMID- 12489969
TI  - Practical synthesis of aryl triflates under aqueous conditions.
AB  - [reaction: see text] A practical and efficient synthesis of aryl triflates under
      biphasic basic aqueous conditions is described. The current methodology provides
      entry into these valuable substrates that omits the use of amine bases and allows
      facile isolation by simple solvent evaporation after phase separation. Good
      yields can also be obtained without the use of organic solvent.

PMID- 12489970
TI  - Unsymmetrical diaryl sulfones through palladium-catalyzed coupling of aryl
      iodides and arenesulfinates.
AB  - [reaction: see text] The palladium-catalyzed coupling of aryl iodides and
      arenesulfinates provides a simple and extremely efficient new route to
      unsymmetrical diaryl sulfones, usually isolated in high yield. The reaction
      tolerates a variety of functionalized aryl iodides, including those containing
      ether, ester, and nitro groups. The best results have been obtained by using
      Pd(2)(dba)(3), Xantphos, Cs(2)CO(3), and (n)Bu(4)NCl in toluene at 80 degrees C.

PMID- 12489971
TI  - Dramatic rate acceleration of the Baylis-Hillman reaction in homogeneous medium
      in the presence of water.
AB  - [reaction: see text] In homogeneous H(2)O/solvent medium, the reaction rate of
      aromatic aldehydes and acrylonitrile or acrylate was greatly accelerated, which
      led to shorter reaction time, lower reaction temperature, and higher yield. In
      this reaction, Me(3)N, DMAP, DABCO, and urotropine were good catalysts. Except
      for low-carbon alcohols, tetrahydrofuran, 1,4-dioxane, and acetonitrile could be
      chosen as the solvent. Under this condition, the diastereoselective reaction of
      nitrobenzaldehyde and L-menthyl acrylate was realized with 88-99% de.

PMID- 12489972
TI  - Synthesis of 2-arylbenzo[b]furans via copper(I)-catalyzed coupling of o
      iodophenols and aryl acetylenes.
AB  - [reaction: see text] We report a copper(I)-catalyzed procedure for the synthesis
      of 2-arylbenzo[b]furans. This protocol can be used to synthesize a variety of 2
      arylbenzo[b]furans in good to excellent yields. This method can tolerate a
      variety of functional groups, does not require the use of expensive additives,
      and is palladium-free.

PMID- 12489973
TI  - Propargyloxycarbonyl (Poc) as a protective group for the hydroxyl function in
      carbohydrate synthesis.
AB  - [reaction: see text] The propargyloxycarbonyl (Poc) group can be used for the
      selective protection of the hydroxyl function in carbohydrates and can be removed
      under neutral conditions using tetrathiomolybdate MoS(4)(2-) (1) in CH(3)CN at
      room temperature. Under the conditions of deprotection benzylidine acetals,
      benzyl ethers, acetyl and levulinoyl esters, and allyl and benzyl carbonates are
      left untouched. It has also been shown that the new protective group (Poc) is
      compatible with acidic, basic, and also glycosylation conditions.

PMID- 12489974
TI  - Increased Felkin-Anh selectivity using AlMe(3) in the addition of vinyllithiums
      to alpha-chiral aldehydes: do "ate" complexes play any role?
AB  - [reaction: see text] AlMe(3) dramatically increases the diastereoselectivity of
      addition of vinyllithiums to alpha-chiral aldehydes but decreases that of
      methyllithium. Our results are explained in terms of an addition of the free
      vinyllithium on the Me(3)Al-aldehyde complex.

PMID- 12489975
TI  - Studies on the synthesis of tedanolide. 2. Stereoselective synthesis of a
      protected C(1)-C(12) fragment.
AB  - [reaction: see text] Highly diastereoselective syntheses of diketo esters 6a and
      6b are described. These intermediates undergo efficient aldol reactions with
      protected C(13)-C(21) aldehydes 3 and 23, thereby providing advanced C(1)-C(21)
      tedanolide seco ester precursors 9a and 9b.

PMID- 12489978
TI  - Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute
      treatment of seizures.
AB  - Fosphenytoin is a phosphate ester prodrug developed as an alternative to
      intravenous phenytoin for acute treatment of seizures. Advantages include more
      convenient and rapid intravenous administration, availability for intramuscular
      injection, and low potential for adverse local reactions at injection sites.
      Drawbacks include the occurrence of transient paraesthesias and pruritus at rapid
      infusion rates, and cost. Fosphenytoin is highly bound (93-98%) to plasma
      proteins. Saturable binding at higher plasma concentrations accounts for an
      increase in its distribution volume and clearance with increasing dose and
      infusion rate. Fosphenytoin is entirely eliminated through metabolism to
      phenytoin by blood and tissue phosphatases. The bioavailability of the derived
      phenytoin relative to intravenous phenytoin is approximately 100% following
      intravenous or intramuscular administration. The half-life for conversion of
      fosphenytoin to phenytoin ranges from 7-15 minutes. Faster intravenous infusion
      rates and competitive displacement of derived phenytoin from plasma protein
      binding sites by fosphenytoin compensate for the expected conversion-related
      delay in appearance of phenytoin in the plasma. Unbound phenytoin plasma
      concentrations achieved with intravenous fosphenytoin loading doses of 100-150 or
      50-100mg phenytoin sodium equivalents/min are comparable, and achieved at similar
      times, to those with equimolar doses of intravenous phenytoin at 50 (maximum
      recommended rate) or 20-40 mg/min, respectively. The rapid achievement of
      effective concentrations permits the use of fosphenytoin in emergency situations,
      such as status epilepticus. Following intramuscular administration, therapeutic
      phenytoin plasma concentrations are observed within 30 minutes and maximum plasma
      concentrations occur at approximately 30 minutes for fosphenytoin and at 2-4
      hours for derived phenytoin. Plasma concentration profiles for fosphenytoin and
      total and unbound phenytoin in infants and children closely approximate those in
      adults following intravenous or intramuscular fosphenytoin at comparable doses
      and infusion rates. Earlier and higher unbound phenytoin plasma concentrations,
      and thus an increase in systemic adverse effects, may occur following intravenous
      fosphenytoin loading doses in patients with a decreased ability to bind
      fosphenytoin and phenytoin (renal or hepatic disease, hypoalbuminaemia, the
      elderly). Close monitoring and reduction in the infusion rate by 25-50% are
      recommended when intravenous loading doses of fosphenytoin are administered in
      these patients. The potential exists for clinically significant interactions when
      fosphenytoin is coadministered with other highly protein bound drugs. The
      pharmacokinetic properties of fosphenytoin permit the drug to serve as a well
      tolerated and effective alternative to parenteral phenytoin in the emergency and
      non-emergency management of acute seizures in children and adults.

PMID- 12489977
TI  - Role of variability in explaining ethanol pharmacokinetics: research and forensic
      applications.
AB  - Variability in the rate and extent of absorption, distribution and elimination of
      ethanol has important ramifications in clinical and legal medicine. The speed of
      absorption of ethanol from the gut depends on time of day, drinking pattern,
      dosage form, concentration of ethanol in the beverage, and particularly the fed
      or fasting state of the individual. During the absorption phase, a concentration
      gradient exists between the stomach, portal vein and the peripheral venous
      circulation. First-pass metabolism and bioavailability are difficult to assess
      because of dose-, time- and flow-dependent kinetics. Ethanol is transported by
      the bloodstream to all parts of the body. The rate of equilibration is governed
      by the ratio of blood flow to tissue mass. Arterial and venous concentrations
      differ as a function of time after drinking. Ethanol has low solubility in lipids
      and does not bind to plasma proteins, so volume of distribution is closely
      related to the amount of water in the body, contributing to sex- and age-related
      differences in disposition. The bulk of ethanol ingested (95-98%) is metabolised
      and the remainder is excreted in breath, urine and sweat. The rate-limiting step
      in oxidation is conversion of ethanol into acetaldehyde by cytosolic alcohol
      dehydrogenase (ADH), which has a low Michaelis-Menten constant (Km) of 0.05-0.1
      g/L. Moreover, this enzyme displays polymorphism, which accounts for racial and
      ethnic variations in pharmacokinetics. When a moderate dose is ingested, zero
      order elimination operates for a large part of the blood-concentration time
      course, since ADH quickly becomes saturated. Another ethanol-metabolising enzyme,
      cytochrome P450 2E1, has a higher Km (0.5-0.8 g/L) and is also inducible, so that
      the clearance of ethanol is increased in heavy drinkers. Study design influences
      variability in blood ethanol pharmacokinetics. Oral or intravenous
      administration, or fed or fasted state, might require different pharmacokinetic
      models. Recent work supports the need for multicompartment models to describe the
      disposition of ethanol instead of the traditional one-compartment model with zero
      order elimination. Moreover, appropriate statistical analysis is needed to
      isolate between- and within-subject components of variation. Samples at low blood
      ethanol concentrations improve the estimation of parameters and reduce
      variability. Variability in ethanol pharmacokinetics stems from a combination of
      both genetic and environmental factors, and also from the nonlinear nature of
      ethanol disposition, experimental design, subject selection strategy and dose
      dependency. More work is needed to document variability in ethanol
      pharmacokinetics in real-world situations.

PMID- 12489980
TI  - Dose linearity of lacidipine pharmacokinetics after single and repeated oral
      doses in healthy volunteers.
AB  - OBJECTIVE: To assess the dose proportionality of lacidipine after single and
      repeated oral doses, and to obtain new information on the pharmacokinetics of the
      compound since improvement of the plasma assay method. DESIGN: Open, randomised,
      four-way cross-over trial. PARTICIPANTS: 24 healthy male and female volunteers,
      aged 18-46 years. METHODS: Lacidipine was administered as single doses of 2, 4, 6
      and 8 mg, and as multiple doses of 2, 4 and 6 mg for 8 days. Pharmacokinetic
      evaluations were performed on study days 1 and 8. Plasma concentrations of
      lacidipine were determined by a validated high-performance liquid chromatography
      radioimmunoassay method. The ratios of dose-normalised peak plasma concentration
      (C(max)) and area under the concentration-time curve (AUC) were calculated and
      then compared across dose groups by analysis of variance to assess dose linearity
      against a 4 mg reference dose. A power model was also applied as an alternative
      method for the evaluation of linearity. RESULTS: After repeated 2, 4 and 6 mg
      doses of lacidipine, geometric least square mean values (95% CI) were 1.76 (1.46
      2.12), 3.56 (2.96-4.29) and 5.23 (4.34--6.30) microg/L for C(max) and 5.29 (4.57
      6.11), 11.42 (9.87-13.20) and 17.55 (15.18-20.29) microg x h/L for AUC over the
      administration interval at steady state (AUC(tau)), respectively. Mean half-life
      ranged between 13.2 hours and 18.7 hours. Precision of these estimates was
      limited by the small number of sampling timepoints collected in the final part of
      the curve. After administration of single doses, no statistically significant
      deviation from linearity was found except for the 8 mg dose, but a trend of
      greater than proportional exposure was evident with increasing dose. Following
      repeated administration, dose linearity over the therapeutic range was observed.
      No statistically significant difference was observed between AUC to infinity
      (AUC( infinity)) on day 1 and AUC(tau) on day 8, suggesting time-invariance of
      pharmacokinetics. CONCLUSIONS: Lacidipine exhibited linear kinetics after
      repeated doses in the therapeutic range of 2-6 mg once daily. The two different
      methodologies for assessing linearity gave consistent results. Only the single 8
      mg dose, which is outside the recommended therapeutic range, resulted in greater
      than predicted exposure. After low doses, the analytical method still does not
      allow complete characterisation of kinetics. Time-invariance of lacidipine
      kinetics is suggested.

PMID- 12489981
TI  - Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability.
AB  - LKB1 is a widely expressed serine/threonine protein kinase that is mutated in the
      inherited Peutz-Jeghers cancer syndrome. Recent findings indicate that LKB1
      functions as a tumour suppressor, but little is known regarding the detailed
      mechanism by which LKB1 regulates cell growth. In this study we have purified
      LKB1 from cells and establish that it is associated with the heat-shock protein
      90 (Hsp90) chaperone and the Cdc37 kinase-specific targetting subunit for Hsp90.
      We demonstrate that Cdc37 and Hsp90 bind specifically to the kinase domain of
      LKB1. We also perform experiments using Hsp90 inhibitors, which indicate that the
      association of Hsp90 and Cdc37 with LKB1 regulates LKB1 stability and prevents
      its degradation by the proteasome. Hsp90 inhibitors are being considered as
      potential anti-cancer agents. However, our observations indicate that prolonged
      usage of these drugs could possibly lead to tumour development by decreasing
      cellular levels of LKB1.

PMID- 12489979
TI  - Role of P-glycoprotein in pharmacokinetics: clinical implications.
AB  - P-glycoprotein, the most extensively studied ATP-binding cassette (ABC)
      transporter, functions as a biological barrier by extruding toxins and
      xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P
      glycoprotein plays a significant role in drug absorption and disposition. Because
      of its localisation, P-glycoprotein appears to have a greater impact on limiting
      cellular uptake of drugs from blood circulation into brain and from intestinal
      lumen into epithelial cells than on enhancing the excretion of drugs out of
      hepatocytes and renal tubules into the adjacent luminal space. However, the
      relative contribution of intestinal P-glycoprotein to overall drug absorption is
      unlikely to be quantitatively important unless a very small oral dose is given,
      or the dissolution and diffusion rates of the drug are very slow. This is because
      P-glycoprotein transport activity becomes saturated by high concentrations of
      drug in the intestinal lumen. Because of its importance in pharmacokinetics, P
      glycoprotein transport screening has been incorporated into the drug discovery
      process, aided by the availability of transgenic mdr knockout mice and in vitro
      cell systems. When applying in vitro and in vivo screening models to study P
      glycoprotein function, there are two fundamental questions: (i) can in vitro data
      be accurately extrapolated to the in vivo situation; and (ii) can animal data be
      directly scaled up to humans? Current information from our laboratory suggests
      that in vivo P-glycoprotein activity for a given drug can be extrapolated
      reasonably well from in vitro data. On the other hand, there are significant
      species differences in P-glycoprotein transport activity between humans and
      animals, and the species differences appear to be substrate-dependent. Inhibition
      and induction of P-glycoprotein have been reported as the causes of drug-drug
      interactions. The potential risk of P-glycoprotein-mediated drug interactions may
      be greatly underestimated if only plasma concentration is monitored. From animal
      studies, it is clear that P-glycoprotein inhibition always has a much greater
      impact on tissue distribution, particularly with regard to the brain, than on
      plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated
      drug interactions should be assessed carefully. Because of overlapping substrate
      specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of
      similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug
      interactions involve both P-glycoprotein and CYP3A4. Unless the relative
      contribution of P-glycoprotein and CYP3A4 to drug interactions can be
      quantitatively estimated, care should be taken when exploring the underlying
      mechanism of such interactions.

PMID- 12489982
TI  - Ketone bodies disturb fatty acid handling in isolated cardiomyocytes derived from
      control and diabetic rats.
AB  - According to the current paradigm, fatty acid (FA) utilization is increased in
      the diabetic heart. Since plasma levels of competing substrates such as ketone
      bodies are increased during diabetes, the effect of those substrates on cardiac
      FA handling was explored. Cardiomyocytes were isolated from control and
      streptozotocin-treated diabetic rats and incubated with normal (80 microM) and
      elevated (160 microM) palmitate concentrations in the absence or presence of
      ketone bodies, including acetoacetate (AcAc). Comparing control cardiomyocytes
      under normal conditions (80 microM, no AcAc) with diabetic cardiomyocytes (160
      microM, 3 mM AcAc) showed that palmitate uptake was increased from 35.2 +/- 4.8
      to 60.2 +/- 14.0 nmol x 3 min(-1) x g wet weight(-1) respectively. Under these
      conditions, palmitate oxidation rates were comparable (58.9 +/- 23.6 versus 53.2
      +/- 18.5 nmol x 30 min(-1) x g wet weight(-1)). However, in the absence of AcAc,
      palmitate oxidation was significantly enhanced in diabetic cardiomyocytes,
      indicating that ketone bodies are able to suppress cardiac FA oxidation in
      diabetes. The concomitantly increased FA uptake in diabetic cells, mainly due to
      the elevated extracellular FA levels, may be responsible for the accumulation of
      FA and triacylglycerol, as observed in the diabetic heart in situ.

PMID- 12489983
TI  - Purification and kinetic characterization of the magnesium protoporphyrin IX
      methyltransferase from Synechocystis PCC6803.
AB  - Magnesium protoporphyrin IX methyltransferase (ChlM), catalyses the methylation
      of magnesium protoporphyrin IX (MgP) at the C(6) propionate side chain to form
      magnesium protoporphyrin IX monomethylester (MgPME). Threading methods biased by
      sequence similarity and predicted secondary structure have been used to assign
      this enzyme to a particular class of S-adenosyl-L-methionine (SAM)-binding
      proteins. These searches suggest that ChlM contains a seven-stranded beta-sheet,
      common among small-molecule methyltransferases. Steady-state kinetic assays were
      performed using magnesium deuteroporphyrin IX (MgD), a more water-soluble
      substrate analogue of MgP. Initial rate studies showed that the reaction proceeds
      via a ternary complex. Product (S-adenosyl-L-homocysteine; SAH) inhibition was
      used to investigate the kinetic mechanism further. SAH was shown to exhibit
      competitive inhibition with respect to SAM, and mixed inhibition with respect to
      MgD. This is indicative of a random binding mechanism, whereby SAH may bind
      productively to either free enzyme or a ChlM-MgD complex. Our results provide an
      overview of the steady-state kinetics for this enzyme, which are significant
      given the role of MgP and MgPME in plastid-to-nucleus signalling and their likely
      critical role in the regulation of this biosynthetic pathway.

PMID- 12489985
TI  - Advances in oral health knowledge of Greek navy recruits and their socioeconomic
      determinants.
AB  - BACKGROUND: The aim of the present study was to evaluate temporal changes on oral
      health knowledge and attitudes among two populations of young Greek males (age 19
      29 years) undergoing their military training. A secondary aim was to identify
      socioeconomic trends that may have influenced the above. METHODS: A total of
      2,764 healthy subjects (1511 in 1985, and 1253 in 1996) answered a standardized
      questionnaire of oral health issues. Respondents were stratified in 3 groups,
      according to their educational status (ES); their responses were compared using
      the chi-square statistic. The evaluation of socioeconomic indicators utilized
      longitudinal data from the national Household Expenditures Survey. RESULTS: An
      overall improvement was noted in the majority of "Knowledge" and "Attitudes"
      variables in 1996, as compared to 1985. Education seems to play an important role
      in both knowledge and attitudes. These changes may also be partially attributed
      to a shift in consuming standards from the coverage of main needs to income
      disposal directed towards the achievement of better quality of life.

PMID- 12489984
TI  - Regulation of transcription by the heterogeneous nuclear ribonucleoprotein E1B
      AP5 is mediated by complex formation with the novel bromodomain-containing
      protein BRD7.
AB  - E1B-AP5 was initially identified as a target of the early adenovirus E1B-55 kDa
      protein during the course of lytic infection. E1B-AP5 belongs to the
      heterogeneous nuclear ribonucleoprotein family and was demonstrated to be
      involved in mRNA processing and transport [Gabler, Schutt, Groitl, Wolf, Shenk
      and Dobner (1998) J. Virol. 72, 7960-7971]. In the present paper, we demonstrate
      that E1B-AP5 differentially regulates basic and ligand-dependent transcription.
      We found that E1B-AP5 represses basic transcription driven by several virus and
      cellular promoters, and mapped the repression activity to the N-terminal part of
      the protein. In contrast with basic repression, E1B-AP5 activated the
      glucocorticoid-dependent promoter in the absence of dexamethasone, but did not
      contribute to the dexamethasone-induced activation. Mutant analysis indicated the
      presence of an additional cellular factor that modulates E1B-AP5 transcriptional
      activity. Using yeast two-hybrid screening, we identified a novel chromatin
      associated bromodomain-containing protein, BRD7, as an E1B-AP5 interaction
      partner. We confirmed E1B-AP5-BRD7 complex formation in vivo and in vitro. We
      found that, although BRD7 binds to histones H2A, H2B, H3 and H4 through its
      bromodomain, this domain was not necessary for the interaction with E1B-AP5.
      Indeed, the triple complex formation of E1B-AP5, BRD7 and histones was
      demonstrated. Disruption of the E1B-AP5-BRD7 complex increased E1B-AP5 repression
      activity for basic transcription and converted it from being an activator of the
      hormone-dependent promoter into being a strong repressor. We conclude that
      complex formation between BRD7 and E1B-AP5 links chromatin events with mRNA
      processing at the level of transcriptional regulation.

PMID- 12489986
TI  - Changes in the tear proteins of diabetic patients.
AB  - BACKGROUND: Previous studies have shown a significant increase in tear protein
      peaks in the tears of diabetic patients suffering from dry eye. The aim of this
      study was to analyze the tear protein patterns from patients with diabetes
      mellitus who do not suffer from ocular surface diseases (DIA). METHODS: A total
      of 515 patients were examined in this study (255 healthy subjects (controls) and
      260 patients suffering from diabetes mellitus). Tear proteins were separated by
      sodium-dodecyl-sulfate polyacrylamide gel electrophoresis. After digital image
      analysis densitometric data files were created and subsequently used for
      multivariate statistical procedures. RESULTS: A significant increase in the
      number of peaks was detected in diabetic patients compared to controls (P <
      0.0003). The analysis of discriminance revealed a highly significant
      discrimination between diabetic patients and controls (Wilks lambda: 0.27; P <
      0.000001). Furthermore, a significant difference in the protein pattern of
      diabetic patients could be detected between those suffering from dry eye or not
      (P < 0.002). The changes in protein patterns of diabetic patients increased with
      the duration of the diabetic disease. In diabetic patients with a disease
      duration longer than 10 years the changes were significantly more expressed than
      in patients with a shorter diabetic history (P < 0.003) and in healthy subjects
      (P < 0.0001). CONCLUSIONS: The tear protein patterns of diabetic patients are
      very different in the number and intensity of spots from those of healthy
      subjects. Furthermore, it could be demonstrated that the differences found in the
      tear patterns of diabetic patients are not equal to those found in previous
      studies in patients suffering from dry-eye disease. The alterations in the
      diabetic tears were correlated with the duration of the diabetic disease. With
      longer disease, history changes in the tear protein patterns increased. With the
      course of the disease some protein peaks appeared that are not present in healthy
      persons. Our study shows that the analysis of electrophoretic tear protein
      patterns is a new non-invasive approach in the early diagnosis and analysis of
      the pathogenesis of diabetes induced ocular surface disease.

PMID- 12489988
TI  - Isolation of diallyl trisulfide inducible differentially expressed genes in human
      gastric cancer cells by modified cDNA representational difference analysis.
AB  - Extensive epidemiologic studies indicated protective effects of consumption of
      garlic on reducing human gastric cancer (HGC) incidence. Diallyl trisulfide
      (DATS), a critical organic allyl sulfur component of garlic, was reported to have
      chemopreventive effects in inhibiting tumor process. We used DATS to treat HGC
      cell line BGC823 cells, and showed that DATS induces G1/S arrest and apoptosis in
      BGC823 cells demonstrated by a flow cytometric analysis. To further isolate DATS
      inducible differentially expressed genes in BGC823 cells, we combined a highly
      specific subtractive hybridization of cDNA representational difference analysis
      (cDNA RDA) with a sensitive bidirectional radioactive detection of mRNA
      differential display (mRNA DD) to develop a subtractive hybridization
      differential display (SHDD) method. This modified method adopted a first round of
      bidirectional subtractive hybridization between two sample cDNAs and a second
      round of bidirectional subtractive hybridization between the two resultant first
      round difference products. Bidirectional subtractive hybridizations magnified the
      differences between the two sample cDNAs and favored isolating mRNA species with
      very small expression differences. We employed the SHDD method to detect DATS
      inducible differentially expressed genes in BGC823 cells. A total of 14 cDNA
      fragments (11 upregulated and 3 downregulated by DATS treatment) were isolated
      and confirmed by reverse Northern blot analysis. Our data show that SHDD is a
      powerful technique for identifying differentially expressed mRNA species between
      two sample cDNAs and provide useful cellular and molecular information for
      understanding the effects of garlic against human gastric cancer.

PMID- 12489987
TI  - Infection of cells expressing CXCR4 mutants lacking N-glycosylation at the N
      terminal extracellular domain is enhanced for R5X4-dualtropic human
      immunodeficiency virus type-1.
AB  - BACKGROUND: Infection with human immunodeficiency virus type-1 (HIV-1) requires
      binding of the viral envelope gp120 to CD4 and to the CXCR4 coreceptor. Both,
      gp120 and CXCR4 are subject to N-glycosylation. Here we investigated the
      influence of the N-linked glycans g1 and g2 present on CXCR4 for HIV-1 infection.
      METHODS: The two CXCR4 N-glycosylation sites g1 (NYT) and g2 (NVS) were mutated
      by changing the first or third amino acids N or T/S to Q and A respectively (g1;
      N11Q or T13A; g2, N176Q or S178A). Human osteosarcoma cells (GHOST) expressing
      human CD4 and the various CXCR4 glycosylation mutants were tested for infection
      using NL4-3-based viruses with X4, R5 or R5X4-tropism differing only in the V3
      loop region. RESULTS: All constructed cell lines expressing the various CXCR4
      glycomutants showed similar permissiveness for the X4-monotropic virus and no
      change in the coreceptor specificity that allows infection of a CCR5-dependent R5
      monotropic virus. Interestingly, the removal of glycan g1 significantly enhanced
      the permissiveness of GHOST cells for the R5X4 dualtropic virus. GHOST cells
      expressing the CXCR4-g1 or CXCR4-g1/2 mutants were infected at higher rates by
      the R5X4-dualtropic virus compared to cells expressing CXCR4-wt or CXCR4-g2
      coreceptors. CONCLUSION: Our present observations underscore a role for glycans
      present on the CXCR4 coreceptor in the entry process of HIV-1. The data will help
      to better understand the multifaceted mechanism of HIV infection and the
      selective forces which drive HIV-1 evolution from mono- to dual-tropism.

PMID- 12489989
TI  - Identification of preferentially expressed mRNAs in retina and cochlea.
AB  - To search for genes that could be involved in genetic disorders primarily
      involving the retina and the cochlea, we tried to identify mRNAs preferentially
      expressed in retina and cochlea and to establish their chromosomal localization.
      Two approaches were employed. First, a mouse subtracted library (retina + cochlea
      against liver + brain) was generated. Randomly selected cDNA clones were
      sequenced and compared to databases. Tissue expression of some of them was
      analyzed by RT-PCR. Using radiation hybrid cell lines, the mouse chromosomal
      localization was determined for those showing the highest level in the retina and
      the cochlea. Second, human Expressed Sequence Tags (ESTs) with preferential
      expression in the retina and the cochlea were searched for in databases, and
      chromosomal localization was also established. From 171 sequenced clones, 73 were
      classified as known genes (with 17 clones coding for 6 genes), 86 were homologous
      to ESTs, and 12 were unidentified. Of 108 selected clones, 22 (18.5%) had the
      highest level of expression in the retina and/or the cochlea, while expression
      was higher in another tissue or ubiquitous for 60 (55.5%) and 22 (20.4%) of them,
      respectively. By RT-PCR, one clone similar to the mouse Asic3 cDNA (proton-gated
      channel) was found mainly in the retina and cochlea, but its human ortholog was
      widely expressed. We selected 17 ESTs from the UniGene database with restricted
      expression including in the retina and cochlea. We mapped 10 of these ESTs as
      well as four mouse clones from the subtracted library. Some of them localized to
      morbid intervals. The combined information from expression analysis and
      chromosomal localization allowed for the identification of potential candidate
      genes for retinal diseases (CORD8, CORD9) and syndromic blindness/deafness/renal
      defects.

PMID- 12489990
TI  - A retroviral repetitive element confers tissue-specificity to the human alcohol
      dehydrogenase 1C (ADH1C) gene.
AB  - The human ADH1A, ADH1B, and ADH1C genes encode alcohol dehydrogenases (ADHs) that
      metabolize ethanol. They evolved by recent tandem duplications and have similar
      proximal cis-acting elements, but differ in tissue-specificity. We hypothesized
      that distal cis-acting elements confer tissue-specificity. In this article, we
      identify multiple cis-acting elements in the ADH1C upstream region. Negative
      elements in the fragments from bp -1,078 to -622 and from bp -3,957 to -2,651
      decreased transcription activity to 41 and 14%, respectively. A tissue-specific
      regulatory element in the region between bp -1,503 and -1,053 stimulated
      transcription sixfold in H4IIE-C3 hepatoma cells but reduced transcription to 23%
      in HeLa cells. This regulatory element was mapped to a repetitive sequence that
      is similar to the U3 repeat within the long terminal repeat of human endogenous
      retrovirus ERV9. The 30-fold difference in expression between two cell lines
      demonstrates that this upstream U3 element, which inserted after the duplications
      that created the three class I ADH genes, plays an important role in regulating
      tissue-specificity of ADH1C. The ubiquitous Nuclear factor-Y (NF-Y) and an H4IIE
      C3/liver-specific factor bound to the subrepeat sequence. This result suggested
      that tissue specificity might result from combinatorial regulation by these two
      transcription factors.

PMID- 12489991
TI  - Defects in pre-mRNA processing as causes of and predisposition to diseases.
AB  - Humans possess a surprisingly low number of genes and intensively use pre-mRNA
      splicing to achieve the high molecular complexity needed to sustain normal body
      functions and facilitate responses to altered conditions. Because hundreds of
      thousands of proteins are generated by 25,000 to 40,000 genes, pre-mRNA
      processing events are highly important for the regulation of human gene
      expression. Both inherited and acquired defects in pre-mRNA processing are
      increasingly recognized as causes of human diseases, and almost all pre-mRNA
      processing events are controlled by a combination of protein factors. This makes
      defects in these processes likely candidates for causes of diseases with
      complicated inheritance patterns that affect seemingly unrelated functions. The
      elucidation of genetic mechanisms regulating pre-mRNA processing, combined with
      the development of drugs targeted at consensus RNA sequences and/or corresponding
      proteins, can lead to novel diagnostic and therapeutic approaches.

PMID- 12489992
TI  - Hox proteins activate the IGFBP-1 promoter and suppress the function of hPR in
      human endometrial cells.
AB  - Previous studies have shown that progestin activates the transcription of IGFBP-1
      (insulin-like growth factor binding protein-1). Four regions in the IGFBP-1
      promotor have been identified to enhance the transcription. Two of the regions,
      located at -73 to -65 bp and -319 to -311 bp formed identical DNA-protein
      complexes with the nuclear extracts of endometrial stromal/decidual cells. To
      identify the binding protein(s) in endometrial cells that interact with these two
      regions, we have used the TGTCAATTA repeats (-319 to -11 bp of the IGFBP-1
      promoter) to screen the human decidual cDNA library by yeast one-hybrid system.
      We found that Hox A10, HoxA11, HoxB2, HoxB4, and HoxD11 interacted with the
      TGTCAATTA repeats in yeast cells. Among these hox genes, the full-length coding
      region of HoxA10, HoxA11, and HoxB4 were used for functional analysis in three
      types of endometrial cells, undifferentiated endometrial stromal cells, decidual
      cells (differentiated stromal cells) and endometrial adenocarcinoma cell line
      (HEC1-B). All these endometrial cells produce IGFBP-1. Transient transfection
      assay showed that HoxA10 expression vector increased the promoter activity (the
      IGFBP-1 proximal promoter containing TGC/TCAATTA and two functional PRE sites) in
      endometrial stromal cells and in HEC-1B cells, but not in decidual cells. HoxB4
      enhanced the promoter activity only in decidual cells, while HoxA11 had no
      apparent effect in all three types of cells. To evaluate whether Hox proteins
      would interact with progesterone receptor (hPR), cells were transfected with the
      promoter construct, Hox and hPR expression vectors. hPR alone activated the IGFBP
      1 promoter activity, but expression of Hox gene suppressed the activation. Hox
      proteins also suppressed the hPR enhanced promoter activities of MMTV (containing
      consensus-PRE sites) and glycodelin (GdA, containing Sp1 site which mediates the
      hPR function). These data showed that Hox genes selectively activate the
      transcription of the IGFBP-1 and GdA genes in different types of endometrial
      cells. Hox genes, however, suppress the hPR enhanced activities. In addition, we
      found that HoxB4 expression was induced by estrogen and progestin. Other
      investigators have shown that HoxA10 and 11 were stimulated by progestin. These
      findings show that Hox proteins are molecular mediators of the steroid hormones
      during endometrial cell development.

PMID- 12489993
TI  - The overexpression of copper-zinc superoxide dismutase protects NOS III from
      nitric oxide-mediated inhibition.
AB  - Previously, we have demonstrated that increased superoxide generation plays a
      role in the nitric oxide (NO)-mediated inhibition of endothelial NO synthase (NOS
      III) in endothelial cells (ECs). In this study we demonstrate that the source of
      the superoxide is likely due to both NADPH oxidase and NOS III itself. Further,
      this increase appears to be linked to the activation of PKC, as PMA could mimic
      the increase and PKC inhibition ameliorate the increase. To further investigate
      this phenomenon we determined the effect of overexpression of copper-zinc
      superoxide dismutase (CuZn-SOD) and Manganese-SOD (Mn-SOD) on the inhibitory
      effects of NO. Using adenoviral infection we demonstrated that SOD activity was
      increased and superoxide levels decreased, in both CuZn-SOD and Mn-SOD
      overexpressing cells compared to cells infected with an adenovirus expressing
      bacterial beta-galactosidase protein. However, only the CuZn-SOD overexpression
      reduced the NO-mediated inhibition of NOS III. In addition, the level of NO
      induced peroxynitrite generation and nitrated NOS III protein were reduced only
      in the CuZn-SOD overexpressing cells. In conclusion, our results indicate that
      superoxide and peroxynitrite are involved in the inhibition of NOS III by NO, and
      that the scavenging of superoxide may be necessary to prevent NOS III inhibition
      during treatments that involve inhaled NO or NO donors.

PMID- 12489994
TI  - Endonucleases that may recognize the ssDNA-backbone structure: purification from
      Sf9 cells and characterization.
AB  - Endonucleases that cleave ssDNA under conditions that minimize the formation of
      secondary structures were detected in Spodoptera frugiperda Sf9 cells. One
      endonuclease was purified from Sf9 cells and another from Sf9 cells infected by
      baculoviruses. Polynucleotides containing an A- or T-tract, or a CAP binding
      region were digested in the presence of ATP at low Mg ions with these two
      nucleases. ATP could be replaced by citrate but not by EDTA. The cleavage
      patterns were different from those obtained with endonuclease I and exonuclease
      VII of Escherichia coli. The cleavages were dependent on the sequence of the
      polynucleotides but not associated with specific bases. EndoSfV cleaved mainly AT
      rich regions.

PMID- 12489995
TI  - Cellular gene dose and kinetics of gene expression in mouse livers transfected by
      high-volume tail-vein injection of naked DNA.
AB  - Direct gene transfer to mammalian tissues has significant potential for
      biomedical research and gene therapy. Recently, the efficient transfer of naked
      plasmid DNA to the mouse liver by a rapid high-volume tail-vein injection was
      reported. We carried out a systematic analysis of the dose and time dependence of
      the expression of the Escherichia coli beta-galactosidase gene transferred by
      this technique. Surprisingly, the DNA concentration of the administered solution
      determined primarily the cellular gene dose and, hence, the expression of the
      transgene in individual hepatocytes, while the number of transfected cells was
      largely independent of the supplied plasmid mass. Transgene expression was
      transient: after a rapid onset and a peak at 8 h past injection, it gradually
      declined and was no longer detectable 4 weeks later. Although gene transfer was
      accompanied by tissue damage and subsequent regenerative proliferation, the
      decline in transgene expression was not due to increased hepatocyte turnover or
      to promoter downregulation, but instead cells apparently lost the plasmid DNA.
      Furthermore, we show that "nakedness" of the injected DNA is indeed a
      prerequisite for efficient transfer by the hydrodynamics-based procedure. Our
      data provide important clues for the successful use of this gene transfer
      technique, and may point directions for studies on the underlying mechanisms.

PMID- 12489996
TI  - High-level erythroid lineage-directed gene expression using globin gene
      regulatory elements after lentiviral vector-mediated gene transfer into primitive
      human and murine hematopoietic cells.
AB  - Lentiviral vectors efficiently transduce primitive human hematopoietic cells and
      are capable of transferring complex genomes. Vectors were designed with
      hypersensitive sites containing regulatory elements from the beta-globin locus
      control region linked to the beta-globin gene promoter to drive expression of the
      enhanced green fluorescent protein marker to facilitate analysis of the pattern
      of gene expression in various hematopoietic lineages. Such vectors gave higher
      level, induced expression in mouse erythroleukemia cells than a previously
      described vector that utilized an enhancer from the alpha locus and the ankyrin-1
      promoter [Moreau-Gaudry, F., Xia, P., Jiang, G., Perelman, N.P., Bauer, G.,
      Ellis, J., Surinya, K.H., Mavilio, F., Shen, C.K., and Malik, P. (2001). Blood
      98, 2664-2672]. The addition of gamma-globin intron sequences further augmented
      vector expression. Expression was also effectively targeted to the erythroid
      lineage in cultured human cells from peripheral blood and in mouse red blood
      cells in vivo, although lower levels of expression were also observed in other
      lineages. Thus, these newly described vectors provide a means to achieve high
      level gene expression, predominantly in erythroid cells, an outcome that may have
      potential therapeutic application.

PMID- 12489997
TI  - A model for antimicrobial gene therapy: demonstration of human beta-defensin 2
      antimicrobial activities in vivo.
AB  - We transfected host cells with an antimicrobial peptide/protein-encoding gene as
      a way to enhance host defense mechanisms against infection. The human beta
      defensin 2 (HBD-2) gene was chosen as a model because its protein does not
      require cell type-specific processing. Using a retroviral vector carrying HBD-2
      cDNA, we treated several mouse or human cell lines and primary cell cultures
      including fibroblasts, salivary gland cells, endothelial cells, and T cells. All
      transduced cells produced detectable HBD-2. In Escherichia coli gel overlay
      experiments, secreted HBD-2 from selected cell lines showed potent antimicrobial
      activity electrophoretically identical to that of purified HBD-2. We then used a
      mouse model (nonobese diabetic/severely compromised immunodeficient [NOD/SCID])
      to test HBD-2 antimicrobial activities in vivo. HT-1080 cells carrying HBD-2 or
      control vector were implanted subcutaneously into NOD/SCID mice to allow tumor
      formation. Escherichia coli was then injected into each tumor mass. Tumors were
      resected after 16 hr and homogenized for bacterial colony-forming unit analysis.
      Compared with control tumors, HBD-2-bearing tumors contained only 7.8 +/- 3.3%
      viable bacteria. On the basis of this demonstration of HBD-2 in vivo
      antimicrobial activity, enhancement of antibacterial host defense by HBD-2 gene
      therapy may be feasible.

PMID- 12489998
TI  - A preliminary evaluation of recombinant adeno-associated virus biodistribution in
      rhesus monkeys after intrahepatic inoculation in utero.
AB  - The ability to deliver genes to fetuses in utero may prove crucial for those
      genetic diseases that are associated with severe fetal morbidity and for which
      there is no effective postnatal therapy. In utero therapy may be especially
      useful in diseases that affect the central nervous system because the immature
      blood-brain barrier may facilitate gene delivery to neural target cells. We
      investigated whether in utero inoculation of recombinant adeno-associated virus
      (rAAV) into rhesus monkey fetuses would be a useful method of gene delivery,
      especially to the central nervous system. When the monkeys were sacrificed after
      birth, we found vector genomes distributed in many tissues, including the brain
      and peripheral blood. Pericapillary astrocytes expressing transgene products were
      detected by immunohistochemistry. In addition, we occasionally found vector
      genomes in the maternal blood. No adverse clinical or pathologic effects were
      observed in the inoculated monkeys. We concluded that (1) in utero intrahepatic
      inoculation of rAAV is a potentially safe and useful method of delivering genes
      to many fetal tissues; (2) astrocytes may be the cell type most easily targeted
      in the central nervous system (CNS) after systemic administration; and (3) the
      potential of inadvertent gene transfer to the mother must be considered.

PMID- 12489999
TI  - Analysis of origin and optimization of expansion and transduction of circulating
      peripheral blood endothelial progenitor cells in the rhesus macaque model.
AB  - Adult marrow-derived cells have been shown to contribute to various
      nonhematologic tissues and, conversely, primitive cells isolated from
      nonhematopoietic tissues have been shown to reconstitute hematopoiesis.
      Circulating endothelial progenitor cells (EPCs) have been reported to be at least
      partially donor derived after allogeneic bone marrow transplantation, and shown
      to contribute to neovascularization in murine ischemia models. However, it is
      unknown whether these EPCs are actually clonally derived from the same population
      of stem and progenitor cells that reconstitute hematopoiesis, or from another
      cell population found in the marrow or mobilized blood that is transferred during
      transplantation. To approach this question, we characterized circulating EPCs and
      also endothelial cells from large vessels harvested at autopsy from rhesus
      macaques previously transplanted with retrovirally transduced autologous CD34
      enriched peripheral blood stem cells (PBSCs). Endothelial cells were grown in
      culture for 21-28 days and were characterized as CD31(+) CD14(-) via flow
      cytometry, as acLDL(+) UEA-1(+) via immunohistochemistry, and as Flk-1(+) by
      reverse transcriptase-polymerase chain reaction (RT-PCR). Animals had stable
      vector marking in hematopoietic lineages of 2-15%. Neither cultured circulating
      EPCs collected in steady state (n = 3), nor endothelial cells grown from large
      vessels (n = 2), had detectable retroviral marking. EPCs were CD34(+) and could
      be mobilized into the circulation with granulocyte colony-stimulating factor.
      Under ex vivo culture conditions, in which CD34(+) cells were optimized to
      transduce hematopoietic progenitor and stem cells, there was a marked depletion
      of EPCs. Transduction of EPCs was much more efficient under conditions supporting
      endothelial cell growth. Further elucidation of the origin and in vivo behavior
      of EPCs may be possible, using optimized transduction conditions and a vascular
      injury model.

PMID- 12490000
TI  - Monogene and polygene therapy for the treatment of experimental prostate cancers
      by use of apoptotic genes bax and bad driven by the prostate-specific promoter
      ARR(2)PB.
AB  - We have shown that adenovirus-mediated manipulation of apoptotic genes such as
      bax could be a therapeutic option for prostate cancer. Unfortunately, the
      response of experimental prostate tumors to a single therapeutic gene of the
      apoptotic pathway is short-lived, and most of these tumors relapse after a short
      period of time. In this investigation we present data generated with adenovirus
      AvARR(2)PB-Bad, in which the apoptotic gene bad was placed under the control of
      the dihydrotestosterone (DHT)-inducible third-generation probasin-derived
      promoter ARR(2)PB. This therapeutic virus was given alone or in combination with
      other therapeutic viruses to a variety of in vitro and in vivo experimental
      models of prostate cancer. On infection with AvARR(2)PB-Bad, DHT-induced Bad
      overexpression occurred specifically in androgen receptor-positive (AR(+)) cells
      of prostatic derivation. The apoptotic effect of AvARR(2)PB-Bad (group 1) was
      compared with that of AvARR(2)PB-Bax (which overexpresses the apoptotic protein
      Bax) (group 2), with that of the combination AvARR(2)PB-Bad plus AvARR(2)PB-Bax
      (group 3), and with that of the control virus AvARR(2)PB-CAT (group 4) in the
      cell line LNCaP. In addition to identifying the modality of apoptosis induction
      by overexpressed Bad, the results suggested that group 3 contained more apoptotic
      cells than any other group. In additional studies, AR(+) androgen-dependent LNCaP
      cells or AR(+) and androgen-independent C4-2 cells were injected subcutaneously
      into nude mice. Four groups of six LNCaP or C4-2 tumors were treated with the
      same combinations of viruses discussed above for groups 1, 2, 3, and 4. Treatment
      resulted in decreased tumor size in groups 1, 2, and 3 compared with group 4.
      There was a better response in group 3 compared with group 2, and in group 2
      compared with group 1. A better response in group 3 was confirmed during a 8-week
      follow-up period, in which no treatment was administered. Two LNCaP and C4-2
      tumors of group 3 disappeared at the end of treatment and did not recur after an
      8-week follow-up period. The data suggest that polygene therapy with apoptotic
      molecules is more effective in experimental models of androgen-dependent or 
      independent prostate cancer than monogene therapy.

PMID- 12490001
TI  - Development of catheter-based procedures for transducing the isolated rabbit
      liver with plasmid DNA.
AB  - Rapid systemic injection of naked plasmid DNA (pDNA) in a large volume into a
      mouse tail vein has been shown to result in a high level of gene expression in
      the liver. However, the potential therapeutic benefit to humans embodied in
      hydrodynamic transfection of the liver cannot be realized until a clinically
      viable method for gene delivery is developed. In light of this fact, we have
      devised and evaluated several methods for delivering pDNA to the isolated rabbit
      liver using minimally invasive catheter-based techniques. Using a lobar
      technique, pDNA was delivered hydrodynamically to an isolated hepatic lobe using
      a balloon occlusion balloon catheter to occlude a selected hepatic vein. A whole
      organ technique was used wherein the entire hepatic venous system was isolated
      and the pDNA solution injected hydrodynamically into the vena cava between two
      balloons used to block hepatic venous outflow. Lobar delivery of a plasmid
      encoding a secreted alkaline phosphatase (SEAP) reporter gene resulted in
      significant levels of transgene product in the serum. A nonsecreted transgene
      product, chloramphenicol acetyltransferase (CAT), showed the highest levels of
      expression in the injected lobe distal to the injection site. Compared to lobar
      delivery, whole organ delivery yielded much higher serum levels of SEAP
      expression and a significantly broader hepatic parenchymal distribution of CAT
      expression. These preliminary studies suggest that catheter-mediated hydrodynamic
      delivery of pDNA to the isolated liver may provide a method for human gene
      therapy that is both therapeutically significant and clinically practicable.

PMID- 12490002
TI  - In vivo gene transfer into muscle via electro-sonoporation.
AB  - Among the nonviral techniques for gene transfer in vivo, electroporation is
      simple, potent, inexpensive, and safe. To upregulate the expression levels of the
      transferred gene, we investigated the applicability of in vivo electro
      sonoporation, which consists of a combination of electric pulse and ultrasound,
      for gene transfer using plasmid DNA encoding luciferase and mouse interleukin-12
      (mIL-12). The quadriceps muscles of mice were injected with plasmid DNA, then
      sonoporated for 5 min, and electroporated by a pair of electrode plates at the
      middle of the duration of sonoporation. Three days later, mice that had undergone
      electro-sonoporation demonstrated twofold higher luciferase activity and low
      tissue damage in quadriceps muscle compared to mice having undergone
      electroporation alone. Serum mIL-12 levels in mice that had undergone electro
      sonoporation (peaking at 25.5 ng/ml) were twofold higher after gene transfer than
      were those in mice having undergone electroporation alone (peaking at 14.3
      ng/ml), and maintained high serum level of 13.9 ng/ml at 28 days after gene
      transfer. The efficacy of gene transfer via electro-sonoporation was superior
      when the plasmid DNA solution was 0.85% NaCl compared to albumin microbubble echo
      contrast material. These results demonstrated that gene transfer into muscle via
      electro-sonoporation could provide a new potent nonviral technique for gene
      transfer in vivo.

PMID- 12490003
TI  - Opinion paper on the current status of the regulation of gene therapy in Europe.

PMID- 12490005
TI  - Serum S100B concentrations are increased after closed head injury in children: a
      preliminary study.
AB  - Traumatic brain injury (TBI) is a leading cause of death and disability in
      children. The current gold standards for diagnosis of TBI after closed head
      injury (CHI) have limitations, particularly in cases of inflicted injury. S100B
      is a protein that is specific to astrocytes. Serum S100B concentrations are
      increased in adults after CHI; there are no studies of serum S100B after CHI in
      children. The goal of this study was to measure the serum concentrations of S100B
      in children inflicted and noninflicted mild, moderate, and severe CHI. CHI
      severity was defined by initial Glasgow Coma Scale score. Forty-five children
      aged 0-13 years with mild (n = 27), moderate (n = 6), and severe (n = 12) CHI
      were enrolled prospectively. Blood was obtained as soon as possible after injury
      (range: 0.5-15.25 h) and every 12 h for up to 5 days when vascular access was
      available. Single control samples were obtained from 16 children aged 0-11 years
      with isolated long-bone fractures. Twenty-two patients (49%), including both
      patients with inflicted CHI, had an abnormal initial serum S100B concentration
      where an abnormal concentration was defined as greater than mean control
      concentration plus two standard deviations. S100B was detectable more than 12 h
      after injury only in patients with severe CHI. We conclude that serum S100B is
      increased in almost half of children after mild, moderate, and severe inflicted
      and noninflicted CHI. The increase is transient, lasting less than 12 h after
      injury, except in children with severe injury. Future research will focus on the
      possibility of using serum S100B as a screening test for inflicted CHI.

PMID- 12490006
TI  - Downregulation of matrix metalloproteinase-9 and attenuation of edema via
      inhibition of ERK mitogen activated protein kinase in traumatic brain injury.
AB  - Emerging data suggest that matrix metalloproteinase-9 (MMP-9) plays a critical
      role in the pathophysiology of brain injury. However, the regulatory mechanisms
      involved in vivo remain unclear. In this study, we focus on a mitogen activated
      protein kinase (MAPK) pathway that may trigger MMP-9 after traumatic brain
      injury. We aim to show that inhibition of the extracellular signal regulated
      kinase (ERK) would attenuate MMP-9 levels, reduce blood-brain barrier damage, and
      attenuate edema after trauma induced by controlled cortical impact in mouse
      brain. Western blots showed that phospho-ERK was rapidly upregulated after
      trauma. Treatment with U0126, which inhibits MEK, the kinase upstream of ERK,
      effectively prevented the activation of ERK. After trauma, gelatin zymography
      showed an increase in MMP-9. U0126 significantly reduced trauma-induced MMP-9
      levels. Correspondingly, U0126 ameliorated the degradation of the tight junction
      protein ZO-1, which is an MMP-9 substrate, and significantly attenuated tissue
      edema. At 7 days after trauma, traumatic lesion volumes were significantly
      reduced by U0126 compared with saline-treated controls. These data indicate that
      the ERK MAPK pathway triggers the upregulation in MMP-9 after trauma, and further
      suggest that targeting the upstream signaling mechanisms that regulate
      deleterious MMP-9 activity may reveal new therapeutic opportunities for traumatic
      brain injury.

PMID- 12490008
TI  - Calcium responses to caffeine and muscarinic receptor agonists are altered in
      traumatically injured neurons.
AB  - A fundamental mechanism that is believed to contribute to neuronal injury and
      death following traumatic brain injury (TBI) is a disruption in cellular calcium
      homeostasis. Of primary importance to these homeostatic mechanisms are
      intracellular calcium stores located on the endoplasmic reticulum. These
      intracellular stores play an important role in maintaining normal levels of
      calcium and calcium-mediated signaling through these stores is critical to
      several physiological processes in neurons. Using an in vitro model of stretch
      induced traumatic injury and fura-2 digital calcium imaging, we investigated
      alterations in calcium-induced calcium release (CICR) and inositol (1,4,5)
      trisphosphate (IP(3))-linked signaling through intracellular calcium stores in
      populations of cultured rat cortical neurons. Caffeine, which stimulates CICR,
      produced a rapid elevation of intracellular free calcium ([Ca(2+)](i)) in 70% of
      uninjured neurons. Fifteen min after injury the population of caffeine-responsive
      neurons was reduced to 30%. The IP(3)-linked muscarinic acetylcholine receptor
      agonists, CDD-0097 HCl and McN-A-343, produced elevations in [Ca(2+)](i) in 91%
      and 70% of uninjured neurons, respectively. Following injury the population of
      responders was reduced to 19% and 26%, respectively. Differential responses to
      agonists were also noted after injury, in which the majority of neurons within a
      given culture well were unresponsive to agonists while others elicited a normal
      elevation of calcium. These results suggest disruptions in intracellular calcium
      store-mediated signaling and altered calcium signaling population dynamics
      following injury. These alterations could affect normal neurotransmission in the
      brain and may contribute to some of the pathology of TBI.

PMID- 12490007
TI  - Influence of norepinephrine and dopamine on cortical perfusion, EEG activity,
      extracellular glutamate, and brain edema in rats after controlled cortical impact
      injury.
AB  - Following traumatic brain injury, catecholamines given to ameliorate cerebral
      perfusion may induce brain damage via cerebral arteriolar constriction and
      increased neuronal excitation. In the present study the acute effects of
      norepinephrine and dopamine on pericontusional cortical perfusion (rCBF),
      electroencephalographic (EEG) activity, extracellular glutamate, and brain edema
      were investigated in rats following controlled cortical impact injury (CCI).
      rCBF, cerebral perfusion pressure (CPP), EEG activity, and glutamate were
      determined before, during, and after infusing norepinephrine or dopamine,
      increasing MABP to 120 mm Hg for 90 min at 4 h after CCI. Control rats received
      physiological saline. At 8 h after CCI, hemispheric swelling and water content
      were determined gravimetrically. Following CCI, rCBF was significantly decreased.
      In parallel to elevating MABP and CPP, rCBF was significantly increased by
      norepinephrine and dopamine, being mostly pronounced with norepinephrine (+44%
      vs. +29%). In controls, rCBF remained diminished (-45%). EEG activity was
      significantly increased by norepinephrine and dopamine, while pericontusional
      glutamate was only elevated by norepinephrine (28 +/- 6 vs. 8 +/- 4 microM).
      Brain edema was not increased compared to control rats. Despite significantly
      increasing MABP and CPP to the same extent, norepinephrine and dopamine seem to
      differentially influence pericontusional cortical perfusion and glutamatergic
      transmission. In addition to the pressure-passive increase in CPP local cerebral
      effects seem to account for the sustained norepinephrine-induced increase in
      pericontusional cortical perfusion. The significantly elevated pericontusional
      glutamate concentrations in conjunction with the increased EEG activity suggest a
      sustained metabolically driven increase in cortical perfusion during
      norepinephrine infusion.

PMID- 12490009
TI  - Both MK801 and NBQX reduce the neuronal damage after impact-acceleration brain
      injury.
AB  - To understand the pathogenesis of diffuse axonal injury, we investigated the
      temporal and spatial profiles of neuronal degeneration in impact-acceleration
      injury in rats using Fluoro-Jade (FJ) staining. Impact-acceleration injury was
      produced in Wistar rats by the method described by Marmarou et al. with some
      modifications. Animals were sacrificed 1, 2, 7, 14, or 28 days after injury.
      Paraffin-embedded coronal sections were stained with HE or FJ, or analyzed
      immunohistochemically for GFAP or amyloid precursor protein (APP). FJ-positive
      degenerative neurons were found primarily in the dorsal brainstem and thalamus
      from 1 to 2 days following injury and these were associated with GFAP expression.
      However, FJ-positive cells were rarely found after 7 days. In all rats,
      significant expression of APP was observed primarily in the cingulum, cerebral
      peduncle and pontomedullary junction. FJ also stained these injured axons.
      Intrathecal administration of both NMDA and AMPA/kinate glutamate receptor
      antagonists MK-801 and NBQX, respectively, reduced the neuronal injury. NBQX
      showed more significant effects on axonal injury than MK-801. These observations
      indicate that not only axonal damage, but also primary neuronal damage occurs in
      this impact-acceleration injury model. It is also suggested that NBQX can act
      both directly on neuronal cells and white matter and that NMDA could have a
      significant protective effect against not only neuronal, but also axonal injury.

PMID- 12490010
TI  - Prostaglandins contribute to impaired angiotensin II-induced cerebral
      vasodilation after brain injury.
AB  - This study characterized the effects of fluid percussion brain injury (FPI) on
      angiotensin II (AII)-induced cerebral vasodilation, determined the role of
      prostaglandins in such changes and evaluated the contribution of two subtypes of
      AII receptors (AT(1) and AT(2)) to the effects of AII on cerebrovascular
      regulation. Topical AII (10(-8), 10(-6), 10(-4) M) elicited vasodilation, which
      was attenuated by FPI (10 +/- 1; 18 +/- 2; 27 +/- 1% vs. 2 +/- 1; 4 +/- 1; 7 +/-
      1%). Such changes in diameter were associated with increases in CSF 6-keto
      PGF(1alpha), the stable breakdown product of PGI(2) (1.5 +/- 0.1; 2.1 +/- 0.1;
      4.0 +/- 0.3 fold) and TXB(2), the stable breakdown product of TXA(2) (1.2 +/-
      0.1; 1.4 +/- 0.1; 1.6 +/- 0.1 fold). However, after FPI, increases in 6-keto
      PGF(1alpha) were blocked (1.0 +/- 0.1; 1.0 +/- 0.1; 1.1 +/- 0.1 fold) whereas
      TXB(2) release was enhanced (1.5 +/- 0.1; 1.8 +/- 0.1; 1.9 +/- 0.1 fold).
      Pretreatment with the cyclooxygenase inhibitor indomethacin (5 mg/kg i.v.) in FPI
      animals partially protected AII vasodilation (8 +/- 1; 14 +/- 2; 19 +/- 3%). CGP
      42112A, a putative AT(2) agonist, elicited vasodilation, which was also blunted
      by FPI. Such dilation was not associated with CSF prostaglandin changes, and
      indomethacin did not protect responses altered by FPI. Vasodilatation caused by
      low concentrations of AII was blunted by an AT(1) antagonist ZD 7155 but
      unchanged by an AT(2) antagonist PD 123,319. The high AII concentration produced
      dilation that was blunted by both antagonists. These data show that FPI impairs
      AII-mediated vasodilation. These data suggest that FPI causes these changes via
      alteration in an AT(1)-mediated production of prostaglandins. These data
      additionally suggest that FPI induced impairment of AT(2) mediated vasodilation
      is independent of an altered production of prostaglandins.

PMID- 12490011
TI  - Changes in nitric oxide and expression of nitric oxide synthase in spinal cord
      after acute traumatic injury in rats.
AB  - The aim of this study was to observe the time course of NO production and NOS
      expression in the spinal cord following acute traumatic injury. Rat spinal cord
      was injured by extradural static weight-compression, which resulted in an
      incomplete transverse spinal cord lesion with paralysis of the lower extremities.
      Using this model, measurement of NO by microdialysis and Griess reaction and
      histological and immunohistochemical examinations using polyclonal antibodies to
      nNOS and iNOS were performed from immediately to 14 days after injury. In injured
      cord, the amount of NO markedly increased immediately after injury and gradually
      decreased between 1 and 12 h after injury. A second wave of increase in NO level
      was observed at 24 h and 3 days after injury. Histologically, hematomas and
      necrotic changes were observed after injury and demyelination of nerve fibers
      increased with time in the compressed segment. Immunohistochemically, the number
      of cells with expression of nNOS was increased immediately to 12 h after injury.
      Expression of iNOS was observed from 12 h to 3 days after injury. These findings
      suggested that the initial maximal increase of NO production might be caused
      mainly by nNOS and that the second wave of increase in NO might be due mainly to
      iNOS.

PMID- 12490012
TI  - Functional impact of axonal misdirection after peripheral nerve injuries followed
      by graft or tube repair.
AB  - Accuracy of reinnervation is one of the main factors conditioning functional
      recovery after brain, spinal, or peripheral axonal damage. Using the peripheral
      nerve as an experimental model, we studied the amount of inaccurate muscle
      reinnervation and its consequences on walking. Adult rats were submitted to an 8
      mm resection of the sciatic nerve repaired by autograft (AG, n = 9), silicone
      (SIL, n = 13) or poly-L-lactate-epsilon-caprolactone (PLC, n = 11) single guides,
      and fascicular tubulization of peroneal and tibial branches with a dual silicone
      tube (FSIL, n = 9). At the end of follow-up, the sciatic nerve and its tibial and
      peroneal fascicles were dissected and stimulated by means of a suction electrode.
      In control rats, gastrocnemius and plantar muscles are fully innervated by the
      tibial fascicle and the tibialis anterior muscle by the peroneal nerve. None of
      the groups had noticeable recovery of locomotion assessed by the walking track
      index (SFI around -70 in all groups). After resection, all animals of groups AG,
      SIL, and PLC showed aberrant muscle reinnervation by axons from a non
      corresponding fascicle, whereas in group FSIL only one of six regenerated animals
      showed misdirected activity. The proportion of inaccurate muscle activation was
      similar in group AG (47% for gastrocnemius, 54% for tibialis anterior, and 44%
      for plantar muscles) and in group SIL (42%, 42%, and 42%), and reduced in group
      PLC (26%, 38%, and 27%). In conclusion, fascicular silicone tubulization allowed
      the highest degree of accuracy but the lowest recovery, whereas resorbable PLC
      guides provided for the best balance between amount and accuracy of reinnervation
      after nerve resection.

PMID- 12490013
TI  - Fate of the soma and dendrites of cord-projection central neurons after proximal
      and distal spinal axotomy: an intracellular dye injection study.
AB  - We used rat rubrospinal neurons as a model to study the soma-dendritic morphology
      of cord-projection neurons following spinal axonal injury. We examined lumbar
      projection neurons following both upper cervical and lower thoracic axotomy to
      find out whether changes were dependent on the proximity of the lesion to the
      cell body. Axotomized neurons were marked with retrograde tracer and studied 4
      and 8 weeks later with intracellular dye injection technique. Axotomy resulted in
      prominent shrinkage of their soma and relatively minor reduction of their
      dendritic spreads. The degree of soma shrinkage depended on both the duration of
      survival and the proximity of lesion. In addition, dendritic modification peaked
      4 weeks following proximal lesion, which was also achieved 8 weeks following
      distal axotomy. Tractotomy at upper cervical and lower thoracic levels also
      allowed us to compare the effect of distal axotomy on cervical and lumbar
      projection neurons. Results show that although cervical-projection neurons
      responded more quickly than lumbar-projecting ones, they however showed a similar
      degree of alteration in both their soma and dendrites 8 weeks following distal
      axotomy. In summary, cord-projection neurons survived 8 weeks following either
      upper cervical or lower thoracic axotomy with relatively intact dendritic
      features. Taken together, our data thus far suggest that cord-projection central
      neurons continue to integrate inputs and control supraspinal targets following
      spinal axotomy. The minor dendritic shrinkage within two months of spinal axotomy
      rejuvenates hopes for functional recovery if regeneration of their spinal axons
      can be achieved at least within this time frame.

PMID- 12490014
TI  - Time course of proliferation and elimination of microglia/macrophages in
      different neurodegenerative conditions.
AB  - Ablation of the hindlimb area of the sensorimotor cortex produces degeneration in
      the cortex (invasive traumatic injury) and leads to retrograde and/or anterograde
      degeneration in the thalamus (non-invasive injury, distal reaction). This
      provides an useful model to study the proliferation and elimination of
      microglia/macrophages in different neurodegenerative conditions. Changes in the
      morphology, distribution and numbers of microglia in the affected cortex and
      thalamus were analyzed at various time points (12 h to 30 days) after injury. In
      parallel, proliferation was determined by immunocytochemistry for the
      proliferating cell nuclear antigen and cell death by the TUNEL method.
      Proliferation was an early event in the microglia/macrophage response (from 12 h
      in the cortex and from 2 days post-lesion in the thalamus) and persisted up to 30
      days. The different microglia/macrophage phenotypes proliferated in a specific
      temporospatial pattern. In the lesioned cortex, early activation and
      proliferation of intrinsic microglia was accompanied, from the second post-lesion
      day, by monocyte entrance and proliferation of monocyte-derived cells. In
      contrast, accumulation of cells in the thalamus resulted from proliferation of
      intrinsic microglia, without apparent/significant monocytic recruitment. During
      the subsequent microglia/macrophages removal the majority of the cells in the
      cortex transformed into ameboid cells devoid of cell processes that progressively
      accumulated as fully-developed macrophages tissue within the lesion (3-14 days)
      ultimately migrating out to the meningeal connective tissue (14-30 days). Only
      some process-bearing cells, remaining in the cortical tissue bordering the
      lesion, underwent degeneration by 14-21 days post-lesion. In contrast, in the
      distal affected thalamic nuclei, microglial cell death occurred by 14-30 days
      post-lesion. Altogether, this study shows that both the origin and fate of
      microglia/macrophages depend on the nature of the lesion.

PMID- 12490015
TI  - Minimally invasive management of the small renal tumor: review of laparoscopic
      partial nephrectomy and ablative techniques.
AB  - The most profound change among the many that have occurred in the management of
      renal-cell carcinoma (RCC) in recent years is the advent of nephron-sparing
      surgery for masses <4 cm. The main challenge now is to reduce the morbidity
      associated with such procedures. Because of the problems in obtaining hemostasis,
      only a few highly experienced surgeons are performing partial nephrectomy
      laparoscopically. Numerous techniques and tools have been studied, including
      laparoscopic duplication of the open operation; hand-assisted surgery; double
      loop and cable-tie tourniquets; ultrasonic shears; radiofrequency, microwave, and
      laser energy; the Endosnare; and hydro-jet dissection. Also, ablation with cold,
      radiofrequency energy, or high-intensity focused ultrasound is being explored.
      Just as open surgery for urolithiasis has been all but replaced by extracorporeal
      lithotripsy and endoscopic techniques, treatment of most RCCs will ultimately
      shift from open to minimally invasive methods.

PMID- 12490016
TI  - The Dornier Compact Delta lithotripter: the first 150 ureteral calculi.
AB  - BACKGROUND AND PURPOSE: Shockwave lithotripsy (SWL) is the least invasive
      treatment for ureteral calculi and is the best accepted by patients and
      clinicians. This prospective study was performed to evaluate the results of SWL
      for all ureteral calculi. PATIENTS AND METHODS: Between April 1999 and May 2000,
      there were 150 SWL treatments for ureteral calculi at our center. All patients
      who completed treatment (24 females, 126 males with an average age of 54 +/- 14
      years) were entered in the study and were assessed at 1 and 3 months with a plain
      film of the kidneys, ureters, and bladder and an ultrasound scan or intravenous
      urogram if clinically indicated. The outcome has been analyzed according to stone
      size, location (lower ureter [LU], midureter [MU], and upper ureter [UU], number
      of treatments per stone, number of shocks per stone, and stone-free rate (SFR).
      The analgesia requirements during each treatment and complications have also been
      analyzed. RESULTS: The SFR in the UU was 77% at 1 month and 85% at 3 months. The
      SFR in the MU was 74% at both 1 and 3 months. The SFR in the LU was 65% at 1
      month and 74% at 3 months. Overall, the SFR for all calculi was 72% at 1 month
      and 79% at 3 months. Ureteroscopic extraction was necessary in 19% of the
      patients and conservative management for the remaining asymptomatic fragments,
      which were 2 mm or smaller. All of these asymptomatic fragments were seen to have
      passed spontaneously on follow-up imaging studies. Ureteral stents were not
      placed routinely prior to SWL, but there were 32 calculi (21%) for which stents
      had been placed prior to SWL: 29 (19%) in the UU, 3 (2%) in the MU, and 0 in LU.
      There was no difference in the SFR or ureteroscopy rate in UU calculi treated
      with or without stents and no difference in the number of treatments needed to
      achieve these SFRs. The efficiency quotient for the UU was 55%, 45% for the MU,
      and 45% for the LU. Oral analgesia was given routinely; however, additional
      intravenous analgesia was necessary in 24% of treatments. No serious
      complications were seen. CONCLUSIONS: The Dornier Compact Delta lithotripter
      provides an effective noninvasive treatment for ureteral calculi that is achieved
      with minimal anesthesia and a low complication rate. Placement of ureteral stents
      prior to SWL does not enhance the SFR or obviate intervention if SWL fails. We
      recommend a low threshold for ureteroscopic treatment if significant progress is
      not made in fragmenting the stone with SWL.

PMID- 12490018
TI  - Extraperitoneal laparoscopy-assisted percutaneous nephrolithotomy in a left
      pelvic kidney.
AB  - Treatment of urolithiasis within a pelvic kidney presents a technical challenge.
      We report an extraperitoneal laparoscopy-assisted percutaneous approach to access
      the lower-pole calix of a pelvic kidney for percutaneous nephrolithotomy.

PMID- 12490017
TI  - Antibiotic prophylaxis in percutaneous nephrolithotomy: prospective study in 81
      patients.
AB  - PURPOSE: To compare single-dose and short-course antibiotic prophylaxis protocols
      in percutaneous nephrolithotomy. PATIENTS AND METHODS: Eighty-one patients with
      sterile urine preoperatively who underwent percutaneous nephrolithotomy were
      divided into two groups. The first group (N = 43) received a single intravenous
      dose of antibiotic (200 mg of ofloxacin) during anesthetic induction, and the
      second group (N = 38) received treatment doses of antibiotic (400 mg of ofloxacin
      per day) until the nephrostomy catheter was removed. The two groups were
      identical according to demographic and treatment characteristics. For each
      patient, microbiologic evaluation of extracted stones and urine samples was done.
      If patients developed fever in the postoperative period, blood and urine cultures
      were taken. Factors that might have affected the development of postoperative
      fever and infection were analyzed. RESULTS: Nine patients in the first group had
      postoperative fever. Three had bacteriuria, and one had bacteremia. In the second
      group, eight patients had fever. One had bacteriuria and bacteremia. Nineteen
      patients (eleven in the first group, eight in the second) had positive stone
      cultures. No statistical difference was observed between the two groups in terms
      of bacteriuria, bacteremia, positive stone cultures, or postoperative fever. The
      febrile patients had longer operations with the use of more irrigation fluid and
      longer postoperative hospital stays. CONCLUSIONS: In patients whose preoperative
      urine cultures are sterile, short-term prophylaxis has no advantage over single
      dose prophylaxis as a means of preventing infection. The duration of surgery and
      the amount of irrigation fluid are significant risk factors for postoperative
      fever.

PMID- 12490019
TI  - Laparoscopy-assisted orchidopexy: an ideal treatment for children with intra
      abdominal testes.
AB  - BACKGROUND AND PURPOSE: The investigation of a child with a nonpalpable testis is
      probably the most frequent indication for laparoscopy in pediatric patients. The
      objective of this study was to evaluate the results and advantages of laparoscopy
      assisted orchidopexy performed without dividing the spermatic vessels. PATIENTS
      AND METHODS: During a 3-year period, 85 boys with nonpalpable testes (NPT) (91
      testes overall) underwent laparoscopic diagnostic exploration. Twenty-five
      patients (27.4%) showed an intra-abdominal testis (IAT): 24 underwent a
      laparoscopy-assisted orchidopexy (LAO) without sectioning of the spermatic
      vessels, and one, whose inner spermatic vessels were not adequately long for LAO
      without tension, underwent a two-step Fowler-Stephens (FS) procedure. The
      technique consists of dissection and mobilization of the inner spermatic vessels
      and the vas deferens from the posterior peritoneum, sectioning of the
      gubernaculum attachments, and bringing down of the testis into the scrotum
      through the internal inguinal ring, if open, or through a neo-inguinal ring
      created medial to the epigastric vessels. RESULTS: Surgery lasted between 40 and
      80 minutes (median 60 minutes). All the testes were brought down into the
      scrotum. There was only 1 (4%) intraoperative complication, which occurred in the
      second patient operated on with this procedure. He experienced an iatrogenic
      rupture of the spermatic vessels secondary to excessive traction. CONCLUSION:
      Laparoscopic orchidopexy is the logical extension of diagnostic laparoscopy for
      the evaluation of NPT. Concerning the technique, we believe that LAO with intact
      spermatic vessels could be considered the treatment of choice in the patient with
      IAT, as it does not affect normal testicular vascularization. Alternatively, in
      the case of very high IAT (more than 3 cm from IIR), an FS procedure may be
      considered.

PMID- 12490020
TI  - Cystoscopy-assisted laparoscopic resection of extramucosal bladder endometriosis.
AB  - BACKGROUND AND PURPOSE: Involvement of the bladder is seen in only 1% to 2% of
      patients with endometriosis. The diagnosis of vesical endometriosis is difficult
      to formulate, and it should be confirmed by cystoscopy with biopsy. However, this
      examination is often insufficient because of the submucosal-transmural location
      of the lesion. Therefore, laparoscopic examination represents the gold standard
      for the diagnosis of pelvic endometriosis. We describe a case of recurrent
      bladder endometriosis treated by a combined endoscopy technique. CASE REPORT: A
      43-year-old woman presented with pelvic pain, dysmenorrhea, and persistent
      cystitis. The endometriotic lesion on the posterior wall of the bladder consisted
      in a 2.5-cm nodule growing into the vesical muscularis and raising the overlying
      peritoneum. We performed laparoscopic resection employing a cystoscopy-assisted
      technique in order to preserve the integrity of the vesical mucosa. Resection was
      carried out and monitored from inside the bladder with the cystoscope and
      laparoscope lights turned on during the whole procedure ("light-to-light"
      technique). CONCLUSION: This minimally invasive combined endoscopic procedure
      could represent a good alternative to partial cystectomy for muscle-infiltrating
      bladder endometriosis that does not involve the vesical mucosa.

PMID- 12490021
TI  - Endoluminal ultrasonography with reusable probe: preliminary results.
AB  - BACKGROUND AND PURPOSE: Endoluminal ultrasound probes have been disposable,
      making their regular use costly. We describe the technique and preliminary
      results of a reusable endoluminal ultrasound probe for examining ureteral
      anatomy. PATIENTS AND METHODS: The 2.4-mm (7.2F) or 3-mm (9F) probe (Olympus,
      Tokyo) is passed up the ureter after a retrograde ureteropyelogram has been
      obtained. No intraoperative preparation of the probe is needed. An axial image as
      little as 1 cm or as much as 10 cm around the ureter can be obtained. Over the
      last 20 months, 50 procedures using endoluminal ultrasonography were performed in
      our unit: 36 (72%) for uretero-pelvic junction (UPJ) obstruction, 10 (20%) for
      upper-tract filling defects, and the remaining 4 (8%) for ureteral strictures.
      RESULTS: Endoluminal ultrasonography detected crossing vessels at the UPJ in 19
      (53%) and a septum in 9 (25%) of the 36 renal units with UPJ obstruction. In
      eight of the 36 renal units with UPJ obstruction (22%), endopyelotomy was not
      done because of the presence of crossing vessels. A further 4 renal units (11%)
      had the direction of the incision modified because of the ultrasound findings. In
      the cases with upper-tract transitional-cell carcinoma, images correlated well
      with the nephroureterectomy specimen. The probe had to be replaced twice.
      CONCLUSIONS: This endoluminal ultrasound system produces clear images of the
      ureteral and periureteral anatomy. The reusable aspect of the probe removes an
      important obstacle to its common use for evaluating a variety of upper urinary
      tract abnormalities.

PMID- 12490022
TI  - Laparoscopic partial nephrectomy with a novel electrosurgical snare in a porcine
      model.
AB  - PURPOSE: We evaluated the safety and efficacy of laparoscopic partial nephrectomy
      with an arcing-gap electrosurgical snare in a porcine model. MATERIALS AND
      METHODS: A novel electrosurgical snare, optimizing high current density arcing
      and parenchymal compression, was utilized for laparoscopic renal transection.
      Five farm pigs underwent unilateral laparoscopic polar partial nephrectomy; 6
      weeks later, these same animals underwent contralateral partial nephrectomy just
      prior to sacrifice. Five additional animals underwent chronic (6-week follow-up)
      and acute open partial nephrectomies by the conventional surgical technique.
      RESULTS: The average time for transection with the snare was 5.6 minutes. In 9 of
      10 cases, the snare provided satisfactory hemostasis. In the remaining case,
      additional argon-beam coagulation (ABC) controlled the minimal bleeding present
      after transection. In all 10 animals, the collecting system was transected. In
      six cases, application of the snare alone sealed the collecting system. No
      urinomas developed in the five animals followed for 6 weeks. At 6 weeks, the mean
      depth of injury at the center of the cut surface was 5.1 mm in the laparoscopic
      group and 3.9 mm in the open group. CONCLUSIONS: Laparoscopic partial nephrectomy
      with the arcing-gap electrosurgical snare is feasible in a porcine model.
      Application of the snare provides excellent hemostasis without the need to
      control the renal vasculature.

PMID- 12490023
TI  - Mini-laparoscopy-assisted placement of Tenckhoff catheters: an improved technique
      to facilitate peritoneal dialysis.
AB  - BACKGROUND AND PURPOSE: Despite its overall efficacy and patient satisfaction
      with it, peritoneal dialysis has a history of significant complications, which
      has contributed to the evolution in the technique from open laparotomy to
      minimally invasive placement of the catheters. Our goal was twofold: (1) to
      review our early experience with a technique of mini-laparoscopy-assisted (MLA)
      placement of dialysis catheters compared with open placement and (2) to
      demonstrate that urologists are able to provide a satisfactory procedure while
      concurrently developing and maintaining laparoscopic skills within a residency
      training program. PATIENTS AND METHODS: The charts of the first 14 consecutive
      patients who underwent MLA placement of Tenckhoff dialysis catheters by a single
      surgeon (LCM) from January 1, 2000, through March 31, 2001, were reviewed.
      Postoperative narcotic analgesia, length of hospital stay, operative times, days
      until cycling, and rates of leakage, infection, and malfunction necessitating
      removal of catheters were compared with the corresponding data from 12
      consecutive patients who underwent traditional open placement during the same
      time period. A telephone survey was performed to corroborate and supplement the
      findings from the chart review. RESULTS: Differences in complications
      necessitating catheter removal were not significant. The difference in the mean
      operative times of 41.7 minutes in the MLA group and 55.7 minutes for open
      placement was statistically significant. Postoperatively, the MLA group used less
      narcotic analgesia, had shorter hospital stays, and returned earlier to usual
      activities. The incidence of leakage after catheter placement was greater in the
      open group, although this difference was not statistically significant.
      CONCLUSIONS: The MLA technique of dialysis catheter placement appears to have
      similar or greater efficacy than the open technique. It is a viable teaching
      procedure, and with reusable 3-mm ports and shorter operative times, it is cost
      efficient as well.

PMID- 12490024
TI  - Arteriovenous malformation mimicking a renal-cell carcinoma.
AB  - We describe a renal arteriovenous malformation in a patient with a 1-month
      history of flank pain. Imaging studies were interpreted as being consistent with
      renal-cell carcinoma. However, Doppler ultrasonography demonstrated turbulent
      blood flow, and selective renal angiography confirmed the diagnosis of an
      arteriovenous malformation. Embolization relieved the pain. This case calls
      attention to the need to consider arteriovenous malformations in the differential
      diagnosis of central homogenously enhancing renal lesions.

PMID- 12490025
TI  - Resection of isolated fossa recurrence of renal-cell carcinoma after nephrectomy
      using hand-assisted laparoscopy.
AB  - A 72-year-old woman with a body mass index of 33.6 had an apparently isolated
      renal fossa recurrence of a Grade II, Stage T(3) renal-cell carcinoma. The lesion
      was resected using hand-assisted laparoscopy with rapid recovery and good short
      term results.

PMID- 12490026
TI  - Hypertension secondary to an adrenal pseudocyst cured by laparoscopic partial
      adrenalectomy.
AB  - Resection of a large adrenal cyst does not necessarily imply total adrenalectomy.
      We depict transperitoneal laparoscopic partial adrenalectomy of a pseudocyst in a
      hypertensive adult.

PMID- 12490027
TI  - Transrectal ultrasound-guided puncture, drainage, and minocycline hydrochloride
      sclerotherapy for the symptomatic prostatic cyst.
AB  - PURPOSE: We treated three patients who had symptomatic prostatic cysts by
      transrectal ultrasound-guided puncture, drainage, and sclerotherapy. The
      procedure and the results are described in this report. MATERIALS AND METHODS:
      The patients were 60, 73, and 78 years old and complained of difficult voiding.
      With local anesthesia, transrectal ultrasound-guided puncture and drainage were
      performed, and then 100 mg of minocycline hydrochloride was infused into the
      cavity of the cyst. We evaluated the International Prostate Symptom Score (IPSS),
      urodynamic data, volume of residual urine, complications, and recurrence.
      RESULTS: There were no complications, and improvements of voiding symptoms were
      experienced without any recurrences within the 2 years or more of follow-up.
      CONCLUSION: This minimally invasive treatment by transrectal ultrasound-guided
      puncture, drainage, and minocycline hydrochloride sclerotherapy is suggested to
      be promising for the symptomatic prostatic cyst.

PMID- 12490028
TI  - Global bioheat model for quick evaluation of the human physiological thermal
      profiles under differing conditions.
AB  - The paper presents a physical and mathematical model of the thermoregulatory
      system of the human body. The model takes into account tissue physiology,
      structure and general physiological parameters such as blood flow. The global
      response of the body to underlying physiological variations as well as to any
      change in ambient conditions can be simulated. The analysis is based on a one
      dimensional tissue layer and a two-node core and shell array of the entire body.
      Application of the model indicates that the body is particularly sensitive to
      ambient changes in the cold, where a slight drop in gain produces an adverse
      change in the temperature profile of the physiological system. The gain, G, of
      the feedback system also suggests that it is an essential parameter in
      determining the range of the negative feedback as well as the sensitivity of the
      unacclimizated body to its surroundings. It is also the critical parameter to
      determine how hard the feedback system works to maintain a homeostatic state. At
      temperature extremes, G either will cause the system to attain beyond the
      critical temperatures needed for survival or it will cease to cause the system to
      respond further to any more changes in the external environment.

PMID- 12490029
TI  - Quantitative evaluation of the dynamics of external factors influencing canine
      gastric electrical activity before and after uncoupling.
AB  - Electrical uncoupling could be a major source of gastric motility abnormalities.
      Non-invasive recognition of the onsets of gastric electrical uncoupling could
      become an avenue for early detection of gastric motor abnormalities. Cutaneous
      recordings of gastric electrical activity (GEA), known as electrogastrograms
      (EGG), are dynamically influenced by a variety of external factors, jeopardizing
      their reliability. In the present study the dynamics of external factors
      influencing both internal GEA and EGG during surgically induced gastric
      electrical uncoupling are quantitatively explored. Sixteen anaesthesized dogs
      underwent implantation of six stainless steel pairs of bipolar electrodes,
      positioned among the sites for future divisions of the stomach into three equal
      sections. In the basal state and after each surgical cut, simultaneous 30-min
      recordings of six internal GEA and eight EGG channels were performed in each dog.
      The signals were filtered, conditioned and digitized to obtain their one
      dimensional representations in the sampled time domain. These representations
      were regarded as particular projections of multidimensional dynamic vectors
      located in the phase space, which incorporated both the dynamics of the
      electrical processes taking place in the stomach and the dynamic interactions
      between the external factors influencing the recordings. Embedding dimensions in
      the phase space were considered quantitative expressions of all these factors.
      Comparative statistical evaluation of the dynamics of the embedding dimensions
      for both internal GEA and EGG channels was performed. Although the number of
      embedding dimensions did not change significantly with the introduction of
      gradual uncoupling both in the internal GEA and in the EGG channels, opposite
      tendencies towards increment in the former and decrement in the latter were
      noted. After the introduction of severe uncoupling, cutaneous embedding
      dimensions became very similar to the internal ones. A significant number of
      external factors influencing EGG recordings preclude reliable recognition of mild
      electrical uncoupling from EGG.

PMID- 12490030
TI  - Logarithmic amplifier for computed tomography tasks using fluoroscopic
      projections.
AB  - The image intensifier (II)-based imaging systems, as radiotherapy simulators or C
      arm X-ray units, have also been used for image acquisition in computed
      tomography. When analogue-to-digital conversion is performed on the output signal
      of the television camera, the accuracy for low-amplitude video signals,
      corresponding to X-ray pathways crossing high attenuation structures, is limited.
      To deal with this lack of accuracy, we investigated the benefits of using a
      logarithmic amplifier (LOGAMP) inserted between the television camera output and
      the analogue-to-digital converter (ADC) in the image acquisition chain. Such a
      device was intended to provide better use of the available ADCs of a given
      resolution and actually to reduce the quantization noise. Simulated data were
      used in this study, and cases with and without logarithmic amplifier were
      compared. Based on the simulation results, we formulate requirements for several
      signal and acquisition system parameters where the use of such a circuit is
      recommended.

PMID- 12490031
TI  - Comparison between the analgesic and therapeutic effects of a musically modulated
      electromagnetic field (TAMMEF) and those of a 100 Hz electromagnetic field: blind
      experiment on patients suffering from cervical spondylosis or shoulder
      periarthritis.
AB  - The analgesic-therapeutic efficacy and tolerability of a low-frequency
      electromagnetic field (ELF), modulated at a frequency of 100 Hz with a sinusoidal
      waveform and mean induction of a few gauss, has been demonstrated by the authors
      in numerous previous studies of various hyperalgic pathologies, particularly of
      the locomotor apparatus. In the present study, the authors tested a new type of
      all-inclusive field, denoted TAMMEF, whose parameters (frequency, intensity,
      waveform) are modified in time, randomly varying within the respective ranges, so
      that all the possible codes can occur during a single application. For the
      comparison, 150 subjects (118 women and 32 men, between 37 and 66 years of age)
      were enrolled. They were affected by cervical spondylosis (101 cases) or shoulder
      periarthritis (49 cases). Unbeknownst to them, they were randomly divided into
      three groups of 50 subjects. One group was exposed to the new TAMMEF, another
      group to the usual ELF, and the third group to simulated treatment. The results
      show that the effects of the new TAMMEF therapy are equivalent to those obtained
      with the ELF.

PMID- 12490032
TI  - Early online detection of upper airway obstructions in obstructive sleep apnoea
      syndrome (OSAS) patients.
AB  - The obstructive sleep apnoea syndrome (OSAS) is a diagnosis related to snoring
      and caused by a collapse in the upper airway. OSAS patients suffer from
      desaturated oxygen levels during sleep as well as daytime sleepiness. In this
      paper, we propose a system able to identify and detect respiratory disorders
      online based on monitoring the airflow amplitude from a sleeping OSAS patient. By
      the use of chi(2)-analysis and a Haar wavelet transform on signals performed
      offline, reference templates indicating the specific apnoea pattern for four
      different patients are constructed and used for similarity matching against
      online signals. Detection is performed in the early stages of an upcoming airway
      dysfunction, thus providing an opportunity to alert the patient at sleep. The
      system-testing results indicate robust performance and flexibility for the
      patient. Our proposed solution can in turn operate as an alternative to today's
      OSAS treatment of choice, the continuous positive airway pressure (CPAP).

PMID- 12490033
TI  - A new impact actuator using linear momentum exchange of inertia mass.
AB  - For self-controlled endoscopes, many kinds of systems have been proposed. Among
      these, pneumatic actuators show significant potential. However, existing
      actuators, such as those used in endoscopes, have many weak points. In
      particular, free movement inside the human intestine is difficult because the
      diameter of the intestine varies dramatically along its length. We design and
      test a new method of locomotion of robotic endoscopes which allows safe
      manoeuverability in the human intestine. The actuating mechanism is composed of a
      solenoid at each end of the actuator and a single permanent magnet in the centre
      guide. If current is supplied to the two solenoids, attractive and repulsive
      forces occur between the permanent magnet and solenoid at each end. The permanent
      magnet moves by controlling the current supply period. When the current direction
      for operation is reversed, repulsive and attractive forces at each side are
      changed and the permanent magnet moves in the opposite direction. The collision
      at each period transfers momentum from the moving magnet to the actuator body.
      Furthermore, the moving speed of the actuator can be changed by the control of
      the impact force. Modelling and simulation are carried out to predict the
      performance of the actuator. The results of simulations are verified by
      comparison with experimental results. Finally, the momentum is measured by
      attaching an accelerometer to the solenoid head to define moving characteristics.

PMID- 12490035
TI  - Oxidant-induced cell death in respiratory epithelial cells is due to DNA damage
      and loss of ATP.
AB  - Oxidative stress is considered to be an important pathogenic event in ischemia
      reperfusion injury, leading to apoptosis or necrosis. We show acute cytotoxicity
      upon exposure to hydrogen peroxide (H(2)O(2)) in BEAS-2B cells and A549 cells.
      Single-cell gel electrophoresis showed formation of large comet tails from DNA
      upon oxidant exposure suggestive of DNA damage. The ATP content of the cells
      decreased upon exposure to H(2)O(2). Preincubation with 3-aminobenzamide (3-ABA),
      an inhibitor of poly (ADP-ribosyl) polymerase (PARP), prevented the cytotoxicity.
      The decrease in the ATP content of the cells was also prevented by 3-ABA.
      Increase in PARP activity was further confirmed by measuring incorporation of
      [(32)P]-NAD into nuclear proteins in presence of the cell extracts. Markers of
      apoptosis were not seen in cells treated with H(2)O(2) with or without 3-ABA
      pretreatment. These studies suggest that DNA damage is one of the primary reasons
      for oxidant-induced cell death and that PARP plays an important role in cell
      death due to its consumption of ATP. Further elaboration of this and other
      pathways that consume ATP may help prevent oxidant-mediated acute lung injury.

PMID- 12490036
TI  - Ablation of the heat shock factor-1 increases susceptibility to hyperoxia
      mediated cellular injury.
AB  - High concentrations of oxygen (hyperoxia) are known to cause cellular injury and
      death. The heat shock response is a highly conserved cellular defense mechanism
      that protects cells against various environmental stressors, including hyperoxia.
      Herein we determined the role of heat shock factor-1 (HSF-1), a major component
      of the heat shock response, in protecting cells against hyperoxia. Embryonic
      fibroblasts from HSF-1-null mutant mice (HSF-1 -/- cells) were compared to wild
      type embryonic fibroblasts (HSF-1 +/+ cells) following 24 hours' exposure to room
      air or hyperoxia (95% O(2)). Acute survival in hyperoxia was decreased in HSF-1 
      /- cells as compared to HSF-1 +/+ cells. Intracellular ATP levels were
      significantly lower in the HSF-1 -/- cells as compared to the HSF-1 +/+ cells
      exposed to hyperoxia. Isoprostane levels, a marker of membrane lipid
      peroxidation, were significantly higher in the HSF-1 -/- cells as compared to the
      HSF-1 +/+ cells exposed to hyperoxia. Restoration of HSF-1 in the HSF-1 -/- cells
      by stable transfection with a HSF-1 expression plasmid improved survival in
      hyperoxia when compared to HSF-1 -/- cells stably transfected with the empty
      expression vector. Hyperoxia increased activation of HSF-1 in HSF-1 +/+ cells and
      in HSF-1 -/- cells stably transfected with the HSF-1 expression plasmid. These
      data demonstrate that HSF-1 plays an important role in conferring resistance to
      hyperoxia in vitro.

PMID- 12490037
TI  - Dimeric surfactant protein B peptide sp-b(1-25) in neonatal and acute respiratory
      distress syndrome.
AB  - Surfactant protein B (SP-B) is a constituent surfactant protein critical for
      normal lung function. Monomeric SP-B(1-25) (mSP-B(1-25)), a peptide based on the
      N-terminal domain of human SP-B, mixed in phospholipids partially restores lung
      function in surfactant-deficient animals. Because native SP-B is a homodimer, we
      synthesized and tested dimeric SP-B(1-25) (dSP-B(1-25)). Circular dichroism (CD)
      and Fourier Transform Infrared (FTIR) spectroscopy indicated that the secondary
      conformation of SP-B(1-25) was not significantly perturbed by dimerization. The
      effects on lung function were compared to phospholipids and Survanta in models of
      neonatal respiratory distress syndrome (RDS) and acute RDS (ARDS). Preterm
      rabbits born at 27 days of gestation received 100 mg surfactant / kg at birth and
      were ventilated for 1 hour with a tidal volume of 10 mL / kg. Dynamic compliance
      was monitored every 15 minutes and postmortem pressure-volume curves were
      measured. Adult rats were lavaged to induce surfactant deficiency, treated with
      100 mg surfactant / kg, and ventilated for 2 hours. Lung function was assessed
      using arterial blood gases and dynamic compliance every 15 minutes and postmortem
      pressure-volume curves. Lung volumes in both models and oxygenation in the
      lavaged rats were consistently higher in the dSP-B(1-25) than in the Survanta and
      mSP-B(1-25) surfactant groups. The data suggest that dSP-B(1-25) is more
      efficient in restoring lung function in neonatal RDS and ARDS than mSP-B(1-25)
      surfactant.

PMID- 12490038
TI  - Time course of quartz and TiO(2) particle-induced pulmonary inflammation and
      neutrophil apoptotic responses in rats.
AB  - Apoptosis, or programmed cell death, has been reported to play an important role
      in the resolution of pulmonary inflammation. This study was undertaken to
      investigate the role of apoptosis in resolving particle-induced lung inflammatory
      responses in exposed rats, using a dose-response / time course experimental
      design. Groups of rats were exposed via intratracheal instillation to 0, 0.5, 1,
      5, 10, or 50 mg/kg body weight of quartz (i.e., crystalline silica) particles or
      to 0, 0.5, 1, 5, 10, 20, or 50 mg/kg of pigment-grade titanium dioxide (TiO(2))
      particles and evaluated for lung inflammation parameters and evidence of
      apoptosis of inflammatory cells at 24, 48, 72, or 168 hours post exposure. At
      each post exposure evaluation period, bronchoalveolar lavage (BAL)-recovered
      cells from control and particle-exposed rats were assessed for apoptosis using 4
      different techniques. The results in silica-exposed rats demonstrated a
      significant dose-related increase in inflammation concomitant with apoptosis of
      pulmonary inflammatory cells at 24 to 48 hours post exposure. At later
      postexposure time points, both the silica-induced inflammatory responses and
      apoptotic levels of inflammatory cells at higher doses (i.e., >or= 5 mg/kg) were
      reduced but persisted through 1 week. TUNEL (TdT-mediated dUTP nick end-labeling)
      assay studies confirmed that the vast majority of apoptotic cells were
      neutrophils. In contrast, titanium dioxide particle exposures produced transient
      pulmonary inflammation but only small measurable and nonsignificant apoptotic
      responses at higher exposure concentrations. These results suggest that the
      sustained lung inflammatory response in rats exposed to >or= 5 mg/kg silica may
      be related to the ineffectiveness of the normal apoptotic mechanisms associated
      with resolution of inflammation. However, because quartz particles are known to
      be cytotoxic to alveolar macrophages and other lung cells, normal apoptotic
      mechanisms may have limited utility for resolving particle-induced inflammation,
      particularly because silica may not be representative of other particle-types.
      Alternatively, it seems unlikely that apoptosis served to promote silica-induced
      lung inflammatory responses because the initial increase of apoptosis in
      inflammatory cells was subsequently correlated with a reduction of the pulmonary
      inflammatory response in silica-exposed rats. The findings from this in vivo
      study demonstrate that the neutrophil, and not the alveolar macrophage, is the
      primary inflammatory cell-type that undergoes apoptosis in response to particles.
      Furthermore, at doses causing similar degrees of inflammation at 24 hours post
      exposure, the magnitude of apoptosis induced by silica is significantly larger
      than that induced by TiO(2), indicating that there are potency differences in
      lung inflammation as well as apoptotic responses among different particle-types.

PMID- 12490040
TI  - Dioxins in commercial United States baby food.
AB  - This is the first known study of dioxins, dibenzofurans, and polychlorinated
      biphenyls (PCBs) in commercial American bottled baby foods purchased in the
      United States. Dioxins, persistent chlorinated organics, are inadvertent by
      products of chemical synthesis or combustion and are toxic to humans and other
      animals. Almost all dioxins enter the body through food consumption, specifically
      from food products containing animal fat. Major-brand bottled baby food
      containing meat was purchased at U.S. supermarkets and 12 pooled samples were
      analyzed for dioxins using high-resolution gas chromatography with high
      resolution mass spectrometry. Low levels of dioxins were found in these products.
      The range was from 28 to 226 parts per quadrillion (ppq) dioxin toxic equivalents
      (TEQ). This is reported on a whole or wet weight (as eaten) basis. As a
      comparison, findings of dioxins in U.S. supermarket meat ranged from 28 to 540
      ppq. Although dioxin levels are generally lower in these baby foods than in meat
      or poultry, the presence of dioxins in commercial baby food containing meat is
      cause for concern.

PMID- 12490039
TI  - Hyperoxia increases protein mass of 5-lipoxygenase and its activating protein,
      flap, and leukotriene B(4) output in newborn rat lungs.
AB  - In this study, the authors examined in newborn rat lung tissues the release of
      leukotriene B(4) (LTB(4)) from tissue explants in vitro, the protein expression
      of the LT-synthesizing enzyme, 5-lipoxygenase (5-LO), and its activating protein
      (FLAP), and the effects of in vivo hyperoxic exposure (>95% O(2)) on these
      parameters. Basal LTB(4) output increased from 0.98 ng/mgDNA/30 min at day 1 to
      3.3 ng/mgDNA/30 min at day 28 (P <.05). Exposure of rat pups to >95% O(2) from
      days 1 to 7 and 60% O(2) from days 7 to 28 stimulated a 1.6-fold (P <.05)
      increase in LTB(4) output, compared to normoxic pups (to 1.6 ng/mgDNA/30 min) by
      day 1 and on day 7. The calcium ionophore, A23187, caused an increase in LTB(4)
      output from both exposure groups, but LTB(4) output was consistently greater (P
      <.05) from hyperoxia-exposed pups. Western immunoblotting of lung tissue showed
      that 5-LO and FLAP protein mass increased (P <.05) from days 4 to 14. Hyperoxia
      exposure increased the mass of both proteins (P <.05). Immunohistochemistry
      localized 5-LO and FLAP mainly to alveolar macrophages on day 14, but some
      staining was evident in parenchymal tissue. These data show that hyperoxia
      increases LTB(4) output, as well as protein levels of 5-LO and FLAP, in newborn
      rat lungs during early postnatal life. Elevated LTB(4) may contribute to the
      etiology of newborn lung disease.

PMID- 12490041
TI  - Airborne concentrations of benzene due to diesel locomotive exhaust in a
      roundhouse.
AB  - Concentrations of airborne benzene due to diesel exhaust from a locomotive were
      measured during a worst-case exposure scenario in a roundhouse. To understand the
      upper bound human health risk due to benzene, an electromotive diesel and a
      General Electric four-cycle turbo locomotive were allowed to run for four 30-min
      intervals during an 8-h workshift in a roundhouse. Full-shift and 1-h airborne
      concentrations of benzene were measured in the breathing zone of surrogate
      locomotive repairmen over the 8-h workshift on 2 consecutive days. In addition,
      carbon monoxide was measured continuously; elemental carbon (surrogate for diesel
      exhaust) was sampled with full-shift area samples; and nitrogen dioxide/nitric
      oxide was sampled using full-shift and 15-min (nitrogen dioxide only) area
      samples. Peak concentrations of carbon monoxide ranged from 22.5 to 93 ppm. The
      average concentration of elemental carbon for each day of the roundhouse study
      was 0.0543 and 0.0552 microg/m(3 )for an 8-h workshift. These were considered
      "worst-case" conditions since the work environment was intolerably irritating to
      the eyes, nose, and throat. Short-term nitrogen dioxide concentrations ranged
      from 0.81 to 2.63 ppm during the diesel emission events with the doors closed.
      One-hour airborne benzene concentrations ranged from 0.001 to 0.015 ppm with 45%
      of the measurements below the detection limit of 0.002-0.004 ppm. Results
      indicated that the 8-h time-weighted average for benzene in the roundhouse was
      approximately 100-fold less than the current threshold limit value (TLV) of 0.5
      ppm. These data are consistent with other studies, which have indicated that
      benzene concentrations due to diesel emissions, even in a confined environment,
      are quite low.

PMID- 12490042
TI  - Airborne concentrations of benzene and mineral spirits (stoddard solvent) during
      cleaning of a locomotive generator and traction motor.
AB  - Mineral spirits (also called Stoddard solvent), a petroleum distillate, is often
      used as a degreaser or an industrial cleaning agent. Although several studies
      measured airborne concentrations of mineral spirits in various occupational
      settings, none have characterized the airborne concentrations of benzene from use
      of mineral spirits. Recent case reports have suggested that benzene, as a
      contaminant in mineral spirits, might be responsible for adverse health effects.
      Because some claims of health effects in the railroad industry have been
      attributed to potential historical exposures to mineral spirits and little
      information is available regarding air concentrations in this type of
      occupational setting, a simulation study was conducted to quantitate historical
      exposures a railroad worker might have experienced while spraying mineral spirits
      on locomotive engine parts in the 1970s. To quantitate potential historical
      exposures, worker tasks were simulated under worst-case exposure conditions by
      spraying minerals spirits on a locomotive generator and traction motor. The
      results of both generator and traction motor cleaning events produced
      concentrations of mineral spirits ranging from 34 to 221 ppm and an average 1-h
      concentration of 121 ppm, whereas benzene concentrations associated with the
      spraying and drying tasks were less than the limit of detection (0.002-0.006
      ppm). Results indicate that a railroad worker who cleaned a locomotive traction
      motor and generator with mineral spirits for 2 h each workday under worst-case
      exposure conditions would be exposed to an 8-h time-weighted average (based on
      lapel measurements) of 30.4 ppm airborne mineral spirits. On the basis of the
      conditions under which these concentrations were obtained, the results should be
      the reasonable maximum values that can be achieved in a modern-era (post-1970)
      workplace in the United States.

PMID- 12490043
TI  - Cardiac morphology and function following long-term exposure to carbon monoxide
      at high altitude in rats.
AB  - Although chronic exposure to high altitude or carbon monoxide (CO) induces
      several cardiovascular adaptations in mammals, very little information is
      available on the cardiovascular effects due to exposure to these concomitant
      stresses. In particular, cardiac functional responses to chronic CO inhalation at
      high altitude has never been investigated. Thirty-two male Dark Agouti rats were
      exposed for 10 wk in steel chambers to (1) normoxic conditions (N rats), (2) 4000
      m simulated high altitude (chronic hypobaric hypoxia, CH rats), (3) 50 ppm CO (CO
      rats), or (4) 50 ppm CO at 4000 m simulated high altitude (CH + CO rats). Left
      ventricular (LV) morphology and function were evaluated in normoxic conditions
      (1) using transthoracic Doppler echocardiography, just before as well as after
      exposure to environments, and (2) using transparietal intraventricular
      catheterisms following a short ventilatory-controlled thoracotomy (10 ml/kg
      volume inflow, pO2 ~159 torr) after exposure. Right ventricular (RV) function was
      evaluated using the same catheterism process after exposure. Body weight
      increased in all groups during exposure, but to a lesser extent in CH and CH + CO
      than in N and CO rats. At the end of exposure, hematocrit ratio was higher in CH
      than in CO rats, and in CH + CO than in CH rats. Carboxyhemoglobin levels were
      higher in CH + CO than in CO, CH, or N rats. Although neither a simulated high
      altitude nor CO alone had an effect on LV morphology and function, combined
      environments increased LV + septum weight, interventricular and posterior wall
      thicknesses, relative wall thickness, and LV systolic function. LV diastolic
      function was not altered by environmental conditions in the four groups. CO
      intensified the altitude-induced RV hypertrophy as well as the altitude-induced
      decrease in RV diastolic function. RV systolic function increased in CH rats, but
      adding CO did not amplify this adaptation process. Moreover, significant
      polynomial relationships were obtained between hematocrit ratio and LV + septum
      weight or left ventricular systolic pressure. Our results indicate that CO at
      high altitude induced severe hematological responses that could be involved in
      morphological and functional cardiac adaptations of both ventricles. Data
      indicate that CO at high altitude may be more detrimental to cardiac function
      than CO inhaled at sea level.

PMID- 12490044
TI  - Effect of nitrogen dioxide on ovalbumin-induced allergic airway disease in a
      murine model.
AB  - The effect of exposure to irritant air pollutants on the development of allergic
      airway disease is poorly understood. This study examines the effects of the lower
      respiratory tract irritant, NO(2), on the outcome of ovalbumin (OVA)-induced
      allergic airway disease. Male and female C57Bl/6 mice were sensitized by weekly
      intraperitoneal (ip) OVA injections for 3 wk followed by daily 1-h OVA aerosol
      inhalation challenge for 3 or 10 d. Initially, mice were exposed daily for 3 d to
      air or 0.7 or 5 ppm NO(2) for 2 h following each OVA aerosol challenge. OVA
      exposure resulted in pronounced lower airway inflammation, as evidenced by a
      significant increase in bronchoalveolar lavage (BAL) total cellularity and
      eosinophil levels. BAL eosinophil levels were significantly lower in OVA-NO(2)
      compared to OVA-air animals. The reduction was similar at both NO(2) exposure
      concentrations. In a subsequent study, sensitized animals were exposed for 3 or
      10 d to aerosolized OVA followed by air or 0.7 ppm NO(2). BAL eosinophils were
      again reduced at 3 d by OVA-NO(2) exposure compared to OVA-air mice. At 10 d the
      eosinophilia was virtually abolished. This reduction in OVA-induced cellular
      inflammation by NO(2) was confirmed by histopathological analysis. Contrary to
      expectations, exposure to NO(2) during the aerosol challenge to OVA dramatically
      diminished the outcome of allergic disease in lungs as measured by airway
      cellular inflammation.

PMID- 12490045
TI  - Surface reactivity, cytotoxicity, and transforming potency of iron-covered
      compared to untreated refractory ceramic fibers.
AB  - Untreated and iron-coated refractory ceramic fibers (RCFs) 1, 3, and 4 were
      examined for their potential to generate free radicals and to catalyze hydrogen
      peroxide decomposition in cell-free assays and were compared for cytotoxic and
      transforming potencies in Syrian hamster embryo (SHE) cell system. Coating with a
      high quantity of iron increased the capability of RCFs to generate hydroxyl
      radicals and to catalyze the decomposition of hydrogen peroxide. In the SHE
      cells, the untreated RCFs had varying ability to induce inhibition of cell
      proliferation, cytotoxicity (as measured by the colony-forming efficiency, CE)
      and morphological transformation, in a concentration-dependent manner. According
      to cytotoxic and transforming potencies, they ranged as follows: RCF3 > RCF1 >
      RCF4. The lethal concentration 50 (LC50; decrease of CE to 50% of controls after
      7 d of treatment) expressed per number of RCF3 and RCF1/cm(2) of culture dish was
      2.5 x 10(4) and 3.7 x 10(4), respectively, whereas RCF4 was not cytotoxic up to
      the highest concentration tested (23.7 x 10(4) fibers/cm(2)). At LC50, RCF3 was
      1.4-fold more transforming than RCF1, and the weakest, RCF4, induced less than 1%
      transformation. Iron coating of RCF1 and RCF3 markedly attenuated their
      cytostatic, cytotoxic, and transforming potencies without a linear concentration
      transformation relationship. In contrast, iron coating of RCF4 affected slightly
      its low transforming potency, although the growth inhibitory effect was reduced.
      The observed decrease rather than increase in the cytotoxic and transforming
      potencies of the active samples RCF1 and RCF3 by their coating with large amounts
      of ferric iron suggests that it is not the quantity or any form of iron on the
      surface of fibers but the iron, even in trace, in a particular redox and
      coordinate state that might play a role in the fiber's surface reactivity with
      regard to the biological material. Surface chemical functions involved in the
      interaction with the cell could be inactivated by the deposition of a high
      quantity of Fe(III) on the surface of fibers. Physicochemical studies correlated
      to biological effects is an approach for understanding the properties of solids
      related to a given biological response and for elucidating the cellular and
      molecular mechanisms.

PMID- 12490046
TI  - Distribution and accumulation of a mixture of arsenic, cadmium, chromium, nickel,
      and vanadium in mouse small intestine, kidneys, pancreas, and femur following
      oral administration in water or feed.
AB  - Manufactured gas plant (MGP) sites are contaminated with coal tar and may contain
      metals such as arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), and
      vanadium (V). These metals are known to cause cancer or other adverse health
      conditions in humans, and the extent and cost of remediating MGP sites may be
      influenced by the presence of these metals. Studies assessed the distribution of
      these metals in female B6C3F1 mice ingesting (1) a metal mixture in water or (2)
      an MGP mixture in NIH-31 feed. The highest metal levels were measured in the
      small intestine and kidneys of mice receiving the metal mixture in water. For
      mice receiving the metal mixture in water, levels of As, Cd, and Cr, in the small
      intestine, levels of As, Cd, Cr, and V in the kidneys, levels of As and Cd in the
      pancreas, and levels of Cr and V in the femur were significantly greater than
      controls at 4, 8, 12, 16, and 24 wk. Except for Ni levels in the small intestine
      and femur and Cr levels in the kidneys, levels of metals were much lower in mice
      administered the MGP mixture in feed. The highest concentrations of metals in
      mice ingesting the MGP mixture in feed were found in the small intestine and
      kidneys, but few were significantly greater than controls. Levels of As in the
      small intestine at 6 and 18 wk and levels of Cr in the kidneys at 12, 18, and 24
      wk were significantly greater than in controls. The data suggest that tissue
      burdens in small intestine, kidneys, pancreas, and femur of arsenic, cadmium,
      chromium, and vanadium are less when metals are present as an MGP mixture in feed
      than as a mixture in water. The reduced distribution and accumulation of metals
      in the organs of mice ingesting the MGP mixture in feed compared to the levels in
      organs of mice ingesting the metal mixture in water suggests that metals may be
      less likely to accumulate in humans ingesting MGP mixtures, thereby presenting a
      lower overall human health risk. The data presented indicate that the matrix in
      which metals are present will affect the uptake of individual metals and the
      organ specificity.

PMID- 12490047
TI  - Editorial.

PMID- 12490048
TI  - Executive functions, self-regulation, and learned optimism in paediatric
      rehabilitation: a review and implications for intervention.
AB  - Success for children and adults alike in educational, vocational, and social
      pursuits depends heavily on effective self-regulation of cognitive and social
      behaviour. Our goal in this article has been to summarize recent literature on
      executive self-regulatory functions, their importance, their development during
      childhood, the types of disability associated with EF impairment, and
      intervention approaches that have been shown to be useful for related disability
      groups. We also examined the literature on learned helplessness and learned
      optimism for clues to a comprehensive approach to helping children with EF
      impairment, in particular those with acquired brain injury. The central
      rehabilitation-relevant themes that we have derived from these reviews are: (a).
      although brain injury can directly impair executive self-regulation, aspects of
      the environment and the presence or absence of support behaviours of others can
      reduce or amplify the neurologic impairment; (b). interventions need to be
      context sensitive; (c). everyday routines of instruction and parent-child
      interaction are the ideal context within which to provide EF facilitation; and
      (d). a primary role for rehabilitation specialists is to help everyday people
      effectively organize and modulate their support for and everyday interactions
      with children with disability. In an ideal world, competent and optimistic
      rehabilitation professionals work collaboratively with children and their
      parents, teachers and others to ensure an optimistic vision of the future that
      includes an increasingly autonomous child with the executive self-regulatory
      skill needed to succeed in adult life.

PMID- 12490050
TI  - The Hunterian Lectures on the after-affects of head injuries, The Lancet,
      February 20, 1904.

PMID- 12490051
TI  - A prospective study and review of pre-morbid characteristics in children with
      traumatic brain injury.
AB  - The pre-morbid characteristics of 32 children requiring inpatient rehabilitation
      following moderate or severe head injuries were studied prospectively. Teachers
      completed Rutter and modified Conners questionnaires on the pre-head injury
      behavioural characteristics of each child and also rated the pre-morbid learning
      ability of the children on a four-point scale. The children's socioeconomic
      status was determined using their postcode at the time of the injury. Behavioural
      questionnaires were returned for 25 of the 32 children. Five of the 25 children
      obtained total behaviour problem scores on the Rutter teacher scales indicative
      of pre-morbid psychopathology. The general learning ability of five children was
      rated as being far below average. The children had a higher mean socioeconomic
      deprivation score than for the geographic area in which the rehabilitation unit
      is sited. The incidence of pre-morbid behaviour problems in the study population
      with moderate or severe traumatic brain injury may be somewhat higher than in the
      local population, but this did not appear to be a major risk factor in sustaining
      a head injury. However, adverse environmental conditions, linked to socioeconomic
      deprivation, did appear to be important risk factors that contributed to a
      pedestrian road traffic accident.

PMID- 12490052
TI  - Is early occupational therapy in extremely preterm infants of benefit in the long
      run?
AB  - A total of 126 infants with extremely low birth weight (ELBW; <1000 g) were
      enrolled in a prospective case-control study in order to examine the effect of
      occupational therapy based on sensory integration (SI) and neurodevelopmental
      therapy (NDT) on neurological development. The children were grouped as matched
      pairs on the basis of determined developmental risk scores assessed at the age of
      3 months. The intervention children had a 6-month period of weekly occupational
      therapy from the corrected age of 6-12 months. The follow-up showed that the
      social development of the intervention children was significantly better at the
      age of 12 months, but at the age of 2 years the groups had equal developmental
      scores in neurological, neuropsychological and speech therapy assessments. The
      Miller assessment for pre-schoolers (MAP) performed in a total of 96 (92%) of the
      study children at the age of 4 years failed to demonstrate any significant
      differences between the groups. It is concluded that this amount of occupational
      therapy in ELBW infants does not have any detectable effect on long-term
      neurological development.

PMID- 12490054
TI  - Participation readiness at discharge from inpatient rehabilitation in children
      and adolescents with acquired brain injuries.
AB  - OBJECTIVE: To describe the extent of readiness for participation in home, school
      and community life at discharge from inpatient rehabilitation and selected
      factors associated with participation readiness in children and adolescents with
      acquired brain injuries. METHODS: Staff from eight sites used retrospective
      review to complete a prototype clinical performance measure on up to 10 of their
      most recent discharges. Data were obtained on 65 children and adolescents, aged 6
      months to 18 years (X = 9.5 years). The extent of participation readiness was
      analysed descriptively. Associations between selected variables and participation
      readiness were examined using correlation and multiple regression analyses.
      RESULTS: Only 3-27% of the children were deemed ready for age-expected
      participation at discharge in 15 domains of home, school and community life.
      Social behavioural activity performance at discharge explained 74% of the
      variance associated with participation readiness at discharge. CONCLUSIONS: The
      low percentage of children deemed ready for age-expected participation has
      implications for post-discharge programming, since 82% of the children were
      discharged home. Participation readiness may not be an easily achievable goal or
      may not be fully addressed during inpatient rehabilitation. Preliminary findings
      suggest that social-behavioural activity performance is a key variable to be
      considered in efforts to promote participation readiness.

PMID- 12490053
TI  - Consultation in paediatric rehabilitation for behaviour problems in young
      children with cerebral palsy and/or developmental delay.
AB  - To measure the effectiveness of consultation for behaviour problems in a
      paediatric rehabilitation setting, this paper used longitudinal assessment of
      children who received the intervention through their regularly scheduled
      appointments with their Occupational Therapist (OT), Physical Therapist (PT) or
      Speech and Language Pathologist (SLP) at three paediatric rehabilitation clinics
      in Columbia, South Carolina. The participants were 86 children with cerebral
      palsy (CP), developmental delay (DD) and medical conditions, ages 1-6 years, and
      their families. The intervention consisted of monthly meetings between
      rehabilitation therapists and a team consisting of a Child Psychiatrist,
      Developmental Pediatrician, Psychologists and a Preventive Medicine specialist.
      There were statistically significant improvements in the sub-scales of the
      Vineland adaptive skills assessment and the measures of family stress associated
      with the parent's attitude toward the child with a disability. The magnitude of
      the improvement was greatest for children with Mental Development Indices (MDI)
      less than 50. This assessment of young children with disabilities demonstrates
      the effectiveness of a consultation model in improving adaptive behaviour and
      parent attitude about their child.

PMID- 12490055
TI  - Robertsonian translocations: mechanisms of formation, aneuploidy, and uniparental
      disomy and diagnostic considerations.
AB  - Robertsonian translocations (ROBs) are rearrangements of the acrocentric
      chromosomes 13-15 and 21-22. Cytologically, ROBs between homologous chromosomes
      cannot be distinguished from isochromosomes that originate through duplication of
      a single homologue. Both types of rearrangements can be involved in aneuploidy. A
      conceptus with a trisomy or a monosomy can be rescued, and in a proportion of
      cases, a uniparental disomy (UPD) would result. If there are regions of genome
      imprinting on a uniparental chromosome pair, phenotypic consequences can result.
      Chromosomes 14 and 15 are imprinted, and UPD of these are known to result in
      abnormalities. Thus, prenatal testing should be considered in all pregnancies
      when one of the parents is a balanced carrier of a ROB because of the risk for
      aneuploidy, and UPD testing should be considered in fetuses found to carry a
      balanced ROB or isochromosome that involves chromosomes 14 or 15. Additionally,
      infants or children with congenital anomalies who carry a ROB should also be
      considered for UPD testing.

PMID- 12490056
TI  - Determination of melting temperature for variant detection using dHPLC: a
      comparison between an empirical approach and DNA melting prediction software.
AB  - Detection of DNA sequence variants by the use of denaturing high-performance
      liquid chromatography (dHPLC) is a relatively new method (Underhill et al., 1997)
      and has distinct advantages over other methods such as single-strand conformation
      polymorphism (SSCP), direct sequencing, and DNA chip hybridization. The dHPLC
      based single-nucleotide polymorphism (SNP) screening relies on different DNA
      thermodynamic properties between perfectly matched base pairs in homoduplex
      molecules and single base-pair mismatches in heteroduplex DNAs. Separation of the
      two forms of duplex DNAs by dHPLC is based on ionic forces between the negatively
      charged DNA and the hydrophobic stationary phase, which consists of C(18) chains
      on PSDVB (polystyrene-divinylbenzene) beads coated with a positively charged ion
      pairing agent (TEAA, triethylammonium acetate). Removal of the DNA from the TEAA
      coated beads is dependent upon a mobile organic phase, in the form of a linear
      acetonitrile gradient. The major factor that influences the success of dHPLC to
      detect sequence variation is the thermal stability of the duplex DNA, which is
      determined by the melting temperature (TM(50)), where 50% of the DNA strand is
      single stranded and 50% is double stranded. The TM(50) predicts the best
      probability of detecting a single base-pair change based on the altered
      thermodynamics it imparts to the DNA duplex. Generally, there are two ways to
      determine this melting temperature, either empirically or with the aid of
      predictive DNA melting analysis software. Such programs include the DNAMelt
      program located on the Stanford University DNA Sequencing and Technology Center
      website, MeltCalc (Schutz and von Ahsen 1999), and WAVEMAKER, the proprietary
      melting analysis software provided with the Transgenomic WAVE dHPLC system. The
      goal of the current study was to determine whether currently available predictive
      DNA melting programs could be used to increase efficiency and throughput of SNP
      detection. A wide range of amplicons, differing in both size and GC composition,
      were selected for analysis to simulate the broad spectrum of PCR products that
      may be encountered during a large-scale dHPLC screening project.

PMID- 12490057
TI  - Site-directed mutagenesis of exon 5 of p53: purification, analysis, and
      validation of amplicons for DHPLC.
AB  - Reversed-phase ion-pair chromatography is used in its three modes of operation-
      (1) non-denaturing, (2) partially denaturing, (3) fully denaturing - to isolate
      and characterize five site-directed mutant amplicons of exon 5 of the p53 gene
      (GenBank X54156). The mutant fragments were prepared using a simplified
      mutagenesis procedure without cloning and isolated in high purity under non
      denaturing conditions. Then, under partially denaturing conditions,
      heteroduplices formed by hybridization of each of the five mutants with wild-type
      were all detected by denaturing reversed-phase high-performance chromatography
      (DHPLC). The fidelity of the PCR step was also assessed. Finally, the homogeneity
      of each mutant was confirmed by minisequencing under fully denaturing conditions.
      The versatility and facility of the method for DNA manipulations was exploited to
      demonstrate a strategy for validating amplicons for mutation detection by DHPLC.

PMID- 12490058
TI  - A cost-effective screening test for detecting AZF microdeletions on the human Y
      chromosome.
AB  - PCR-based screening of microdeletions in the azoospermic factor (AZF) on the Yq
      chromosome is an accepted means of identifying a common genetic cause of male
      infertility, responsible for 5-15% of cases associated with a low sperm count
      (</=5 x 10(6) sptz/ml). Based on an extensive analysis of the literature, we have
      established a cost-effective preliminary PCR-based diagnostic screening test,
      with a set of six pairs of primers ("set-of-6") that have the capability of
      detecting up to 95% of the Y microdeletion cases already published. These primers
      are: sY84 in AZFa, sY114, sY129, sY143 in AZFb, and sY149, sY254 in AZFc.
      Initially, the set-of-6 was tested with 13 other pairs of primers covering the
      three AZF subregions. A sample of 114 infertile men was tested and 10 (8.8%)
      microdeletions were found, 3 of which were among the 26 (11.5%) idiopathic
      azoospermic men. These results showed that all detected microdeletions would be
      identified using the set-of-6 only. Another sample of 34 patients was
      subsequently tested using the set-of-6 and 3 (8.8%) microdeletions were found in
      this group. A comparison of our results with those reported in the literature
      showed similar microdeletion detection frequencies, demonstrating that the set-of
      6 primers provides a reliable, simple and cost-effective way of detecting AZF
      deletions.

PMID- 12490059
TI  - Preconception cystic fibrosis carrier couple screening: impact, understanding,
      and satisfaction.
AB  - The impact, understanding of test-results, and satisfaction among participating
      couples in a preconception cystic fibrosis (CF) carrier screening project were
      assessed 6 months after testing. Questionnaire data were obtained from 17/18
      identified carriers, 15 partners of carriers with negative test results, and 794
      (73%) other participants. None of the carriers changed their reproductive plans
      because of their test results. Eight participants were worried about their
      results, including four carriers. Those who attended a general practitioner (GP)
      consultation for pretest education were less worried than those who attended an
      educational session. Seven carriers felt less healthy. Predictors of a correct
      understanding of test results (correct in 62% of participants) were: positive
      test results, high level of knowledge of CF, high level of education, attending
      an educational session, and previously heard of CF. All participants who reported
      that they were worried, all carriers, and 95% of the other participants said that
      they would make the same decision to be tested again. Although couples who were
      educated during a GP consultation were less worried, the results of the study
      suggest that understanding is more correct in couples attending an educational
      session. The results further suggest that since satisfaction with the screening
      was high, worries and feeling less healthy due to the test results are probably
      not a great burden.

PMID- 12490060
TI  - Motivations and concerns of women considering genetic testing for breast cancer:
      a comparison between affected and at-risk probands.
AB  - Since the discovery of the BRCA1 and BRCA2 genes, there has been an increasing
      demand for breast cancer risk assessment programs. In an effort to understand and
      serve the population such programs target better, several studies have identified
      factors influencing high-risk women to pursue breast cancer risk assessment and
      genetic testing services; none, however, has focused on how the motivations and
      concerns of at-risk women may differ from their previously affected counterparts,
      who are typically the initial members of their families to undergo genetic
      testing. The majority of both previously affected and unaffected women felt that
      preventative surgery decisions, surveillance practices, the assessment of
      children's risks, and increased breast cancer anxiety were "more important" or
      "very important" issues regarding their thoughts about genetic testing.
      Significantly more affected women deemed family members' opinions "more" or "very
      important" (p < 0.01). Opinions concerning insurance and employment
      discrimination did not vary significantly between groups; however, a larger
      percentage of affected women felt this issue was of importance. Although all
      issues above should be addressed with women seeking cancer risk assessment and
      genetic testing, this research may help health care providers to gain a greater
      understanding of how the motivators and concerns of high-risk women can differ
      with personal cancer status so that referral, counseling, and education can be
      executed optimally.

PMID- 12490061
TI  - A simplified method for the detection of Y chromosome microdeletions in infertile
      men using a multiplex sequence-tagged site-based amplification.
AB  - Sixteen sequence-tagged sites (STSs) were combined in five amplification
      reactions, to screen for deletions of DNA fragments located within the AZFa,
      AZFb, and AZFc regions of the Y chromosome. This multiplex strategy is fast and
      reliable, and most of the azoospermia-associated deletions reported so far are
      detected with this simplified method. Internal control STSs are included that
      allow discrimination between deletion and failure of amplification.

PMID- 12490062
TI  - Founder mutation R245H of Sanfilippo syndrome type A in the Cayman Islands.
AB  - Sanfilippo A syndrome is an autosomal recessive lysosomal storage disease. This
      disease was reported in the Cayman Islands population with carrier frequency of
      1/7 to 1/10 in the West Bay district of Grand Cayman. The carrier testing of
      Sanfilippo A disease for families at risk was carried out using the thermal
      characteristics of sulfamidase activity. In the present study, a search for
      mutations in the sulfamidase gene in an index family was performed. In addition,
      77 individuals, relatives of children with Sanfilippo A syndrome, were also
      studied by single-strand conformation polymorphism (SSCP), restriction fragment
      length polymorphism (RFLP) analyses, and sequencing. A single mutation, G746A
      (R245H), was found in the family, with the patient being homozygous and both
      parents and 1 of the 3 siblings being carriers. Among the 77 family members of
      the patient with Sanfilippo syndrome, the same mutation was found among carriers
      of the disease. The finding of a single mutation supports the idea of a founder
      effect, which facilitates accurate carrier identification of Sanfilippo A
      syndrome in the population of Cayman Islands.

PMID- 12490063
TI  - Accurate determination of ataxin-2 polyglutamine expansion in patients with
      intermediate-range repeats.
AB  - Spinocerebellar ataxia, type 2 (SCA2), results from an expansion of a stretch of
      polyglutamine repeats within the coding sequence of the ataxin-2 gene (ATX2),
      localized to chromosome 12q23-24. Recent studies have widened the clinical
      phenotype, notably for individuals with repeats of intermediate size, from 32 to
      35 glutamine residues. This narrow range necessitates precise determination of
      repeat size. Diagnostic laboratories most often perform direct genotyping of ATX2
      from polymerase chain-amplified patient DNA with subsequent sizing utilizing slab
      gel polyacrylamide gel electrophoresis (PAGE) or capillary electrophoresis. Using
      cloning and sequencing methods, we have constructed a ladder of ATX2 alleles of
      known size and sequence composition. This freely available size ladder will
      facilitate future quantification of expansions of the ATX2 locus.

PMID- 12490064
TI  - Maternal weight correction for alpha-fetoprotein: mathematical truncations
      revisited.
AB  - The objective of this study was to determine if maternal weight correction as
      implemented 20 years ago for alpha-fetoprotein (AFP) testing is still
      appropriate, and what should be the weight cutoff for correction. AFP
      measurements from 44,951 biochemical screening cases from a single laboratory
      were divided by maternal weight, and separated into high >/=2.5 multiples of the
      median (MOM), and low <0.4 MOM. Without weight correction, AFP values are still
      skewed to lower levels of higher maternal weight (1.1% >/= 2.5 MOM). Using a
      truncated range to 200 lbs. (for women greater than 200), produces more uniform
      results than using an upper cutoff of 250 for truncation (2.7% vs 5.0% >/= 2.5
      MOM). The same relationship is seen for "lows." Without correction, higher weight
      lowers AFP, correction to 250 lbs. overcompensates, and 200 lbs. gives the most
      even distribution, and, therefore, optimizes the distribution of highs.

PMID- 12490065
TI  - A PCR-RFLP test for simultaneous detection of two single-nucleotide insertions in
      the Connexin-26 gene promoter.
AB  - Comparisons of Connexin-26 (GJB2) gene sequences available in the GenBank data
      base indicate the presence of a polymorphism in the promoter, but no easy method
      is available for the detection of this polymorphism. We have developed a PCR-RFLP
      test for simultaneous detection of two single nucleotide insertions (G and A) in
      the GJB2 promoter. The test is based on amplification of a 146-bp DNA fragment,
      which was digested with Mae I to detect the G insertion in the promoter. A
      similar digestion with Hinf I detects the A insertion. The test was validated
      using direct DNA sequencing of amplified DNA from 33 samples. After validation,
      we have used it to investigate DNA samples from 160 control subjects and 51
      unrelated patients with nonsyndromic autosomal recessive deafness. All of the
      samples analyzed using the PCR test and DNA sequencing were found to contain both
      the G and A insertions in the GJB2 gene promoter. This PCR test will be useful in
      studying the prevalence of these two insertions in other populations.

PMID- 12490066
TI  - A PCR-RFLP assay for the A716T mutation in the WFS1 gene, a common cause of low
      frequency sensorineural hearing loss.
AB  - Nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) is an unusual type
      of hearing loss that affects frequencies at 2,000 Hz and below. Recently, we
      reported five different heterozygous missense mutations in the Wolfram syndrome
      gene, WFS1, found to be responsible for LFSNHL in six families. One of the five
      mutations, A716T, may be a common cause of LFSNHL, as it has been reported in
      three families to date (Bespalova et al., 2001; Young et al., 2001). We have
      developed a PCR-based restriction fragment-length polymorphism (RFLP) assay to
      detect the A716T mutation in a simple, specific test. This method was evaluated
      with DNA samples from a family in which the A716T mutation was segregating with
      LFSNHL. This simple assay successfully detected the presence of the A716T
      mutation in all of the individuals predicted to be affected, based on audiologic
      results. Therefore, this assay can be routinely used for initial screening of the
      A716T mutation in patients with LFSNHL, before screening the entire coding region
      of the WFS1 gene.

PMID- 12490067
TI  - Rapid automated simultaneous screening of (G1691A) Factor V, (G20210A)
      prothrombin, and (C677T) methylenetetrahydrofolate reductase variants by
      multiplex PCR using fluorescence scanning technology.
AB  - The Factor V Leiden mutation (G1691A), and mutations in the prothrombin (G20210A)
      and 5,10-methylenetetrahydrofolate reductase (C677T) genes are common hereditary
      risk factors associated with venous thrombosis. The aim of this study was to
      develop an automated, PCR-based genotyping assay for rapid simultaneous screening
      of these three mutations. We adapted multiplex PCR, using primer modifications to
      introduce cleavage sites for restriction endonucleases into the fragments bearing
      each of the mutations. The three mutations were analyzed in a single tube by
      fluorescence scanning. An internal digestion control was introduced to prevent
      false-negative results due to incomplete digestion or a total lack of digestion.
      DNA fragment analysis was carried out using an automated capillary
      electrophoresis instrument (ABI310). This reliable, efficient, easy-to-use assay
      can be applied to specimens from large clinical trials and epidemiological
      surveys.

PMID- 12490068
TI  - Mutation screening of the EXT genes in patients with hereditary multiple
      exostoses in Taiwan.
AB  - Hereditary multiple exostoses (HME) is an autosomal dominant disorder
      characterized by growth of benign bone tumors. This genetically heterozygous
      disease comprises three chromosomal loci: the EXT1 gene on chromosome 8q23-q24,
      EXT2 on 11p11-p13, and EXT3 on 19p. Both EXT1 and EXT2 have been cloned and
      defined as a new family of potential tumor suppressor genes in previous work.
      However, no studies have been conducted in the Taiwanese population. To determine
      if previous results can also be applied to the Taiwanese, we analyzed 5 Taiwanese
      probands with clinical features of HME: 1 of them is a sporadic case, and the
      others are familial cases. Linkage studies were performed in the familial cases
      before the mutation analysis to determine to which of the three EXT chromosomes
      these cases could be assigned. Our results showed that one proband is linked to
      the EXT1 locus and three are linked to the EXT2 locus; the sporadic case was
      subsequently found to involve EXT1. We then identified four new mutations that
      have not been found in other races: two in EXT1--frameshift (K218fsX247) and
      nonsense (Y468X) mutations and two in EXT2-missense (R223P) and nonsense (Y394X)
      mutations. Our results indicate that in familial cases, linkage analysis can
      prove useful for preimplantation genetic diagnosis.

PMID- 12490070
TI  - Thyroid-stimulating hormone induces interleukin-18 gene expression in FRTL-5
      cells: immunohistochemical detection of interleukin-18 in autoimmune thyroid
      disease.
AB  - Interleukin (IL)-18 is a cloned cytokine that was identified originally as a
      factor having potent interferon (IFN)-gamma-inducing activity on Kupffer cells.
      First, we analyzed IL-18 gene expression by reverse transcription-polymerase
      chain reaction (RT-PCR) in rat thyroid FRTL-5 cells and human thyroid tissue
      samples. The expression of IL-18 mRNA in FRTL-5 cells was enhanced by thryoid
      stimulating hormone (TSH) in a dose-dependent manner. 8-Bromo-cyclic adenosine
      monophosphate (cAMP) also increased in IL-18 mRNA levels. Furthermore, TGCT
      clones that exhibited an increase in intracellular cAMP accumulation showed an
      increased IL-18 mRNA signal when compared to controls. Taken together, these data
      suggested that the effect of TSH on IL-18 gene expression was mediated by
      activating protein kinase A. Treatment of FRTL-5 cells with the antithyroid drug,
      methimazole (MMI), suppressed this stimulatory action of TSH on IL-18 gene
      expression. Next, we examined IL-18 expression in human thyroid tissue derived
      from patients with autoimmune thyroid diseases (ATD). RT-PCR and immunohistology
      demonstrated that human thyroid follicular cells expressed IL-18. Especially in
      thyroid tissue from a patient with Hashimoto's thyroiditis, expression was more
      diffuse and extensive, generally observed in close relation to a lymphocytic
      infiltrate. Also, IL-18 protein was distributed in the same follicles that
      express Fas-L and HLA-DR. This study is the first to demonstrate the detection of
      IL-18 in the thyroid gland. The frequent expression of IL-18 in thyrocytes
      suggests that IL-18 itself might be a secreted immunomodulator in ATD.

PMID- 12490071
TI  - Genetics of specific phenotypes of congenital hypothyroidism: a population-based
      approach.
AB  - Congenital hypothyroidism (CH) may cause severe and irreversible neurologic and
      developmental abnormalities when not recognized early. Many millions of newborns
      have now been screened and many thousands of patients with CH have been
      identified. Approximately 80%-85% have defects of thyroid gland development,
      while 15%-20% have congenital errors of thyroid hormone biosynthesis. An entire
      population screened for CH over a long period of time, was studied in the present
      report, using a population-based approach. In particular, two CH phenotypes, both
      presenting with in situ thyroid gland (patients with either goiter or with
      thyroid gland volume ranging from normal to hypoplasic) were analyzed. Mutations
      were searched in some of the most likely candidate genes: thyroperoxidase (TPO)
      in patients with CH goiter, Pax8 and thyrotropin receptor (TSHR) in the other
      group. In the former group (n = 8), four TPO gene mutations were identified in
      three patients. One patient was a compound heterozygous. In two cases an already
      described mutation (1277(insGGCC)) was present; in two other cases mutations not
      previously described (1996(G-->T) and 2295(G-->A)), which induced aminoacid
      variations with a Glu --> Stop and Val --> Ile changes, respectively, were
      identified. In all patients mutations were inherited from one of the parents. In
      the case of the compound heterozygous patient, one mutation was inherited from
      the mother (1277(insGGCC)) and the other from the father (1996(G-->T), Glu -->
      Stop). In the latter group (n = 8), a patient with a 16-base pair C(T)(13)CC
      deletion in TSHR gene intron 8, 42-bp distal to exon/intron 8 splice junction,
      was identified. No mutation was identified in Pax8 gene.

PMID- 12490072
TI  - Vascular endothelial growth factor monoclonal antibody inhibits growth of
      anaplastic thyroid cancer xenografts in nude mice.
AB  - BACKGROUND: Anaplastic thyroid cancer (ATC) does not respond well to any
      treatment and is one of the most aggressive of all human cancers. Based on the
      importance of angiogenesis in solid tumor growth, we hypothesized that angiogenic
      blockade might reduce the growth of ATC. METHODS: We tested the in vivo effect of
      vascular endothelial growth factor monoclonal antibody (VEGF-mAb) and thalidomide
      against ATC (ARO-81) xenografts in nude mice. Mice were injected subcutaneously
      with 1 x 10(6) ARO-81 cells, allowed to implant (1 week), and then given daily
      intraperitoneal injections of vehicle (control; n = 9), VEGF-mAb (200 microg/d; n
      = 9), or thalidomide (200 mg/kg per day; n = 9). Tumors were removed, sectioned,
      and stained for routine histology and immunohistochemistry. RESULTS: At 6 weeks,
      VEGF-mAb-treated tumors were smaller (1603 +/- 296 mm(3)) than either the
      thalidomide-treated (6007 +/- 1498 mm(3); p = 0.008) or the control groups (4040
      +/- 831 mm(3); p = 0.014) and the VEGF-mAb-treated animals maintained greater
      weight (30.4 +/- 0.84 g at week 6 versus thalidomide-treated, 26.0 +/- 0.94 g, p
      = 0.003; and control, 25.8 +/- 0.78 g, p = 0.001 animals). Central necrosis was
      observed in 3 of 9 VEGF-mAb-treated confidence interval (33%; 95% [CI] = 0.12
      0.65) but in none of the control or thalidomide-treated tumors (0/18 total; 95%
      CI = 0.0-0.30; p = 0.029). VEGF staining intensity for VEGF-mAb- (2.0 +/- 0.24; p
      = 0.012) and thalidomide- (2.1 +/- 0.05; p = 0.052) treated tumors was greater
      than control (0.89 +/- 0.31) as was p53 staining grade (VEGF-mAb [1.3 +/- 0.37; p
      = 0.012]; thalidomide [1.0 +/- 0.41; p = 0.05]; and controls [0.11 +/- 0.11]).
      CONCLUSION: We conclude that systemic VEGF-mAb significantly reduces growth of
      ATC xenografts and is associated with increased VEGF and p53 expression.
      Thalidomide has no effect on tumor growth, but is also associated with increased
      VEGF and p53 expression. These observations provide the first evidence that VEGF
      mAb-induced angiogenesis blockade may be of use for the treatment of ATC.

PMID- 12490073
TI  - Mice with a mutation in the thyroid hormone receptor beta gene spontaneously
      develop thyroid carcinoma: a mouse model of thyroid carcinogenesis.
AB  - The molecular genetic basis of thyroid carcinogenesis is not well understood.
      Most of the existing models of thyroid cancer only rarely show metastases, and
      this has limited progress in the understanding of the molecular events in thyroid
      cancer invasion and metastasis. We have recently generated a mutant mouse by
      introducing a dominant negative mutant thyroid hormone nuclear receptor gene,
      TRbetaPV, into the TRbeta gene locus. In this TRbetaPV mouse, the regulation of
      the thyroid-pituitary axis is disrupted, leading to a mouse with high levels of
      circulating thyroid-stimulating hormone and extensive hyperplasia of follicular
      epithelium within the thyroid. As TRbeta(PV/PV) mice, but not TRbeta(PV/+) mice,
      aged, metastatic thyroid carcinoma developed. Histologic evaluation of thyroids
      of 5-14-month-old mice showed capsular invasion (91%), vascular invasion (74%),
      anaplasia (35%), and metastasis to the lung and heart (30%). Previous models of
      thyroid cancer have focused on genes that control initial carcinogenesis, but
      this model provides an unusual opportunity to study the alterations in gene
      regulation that occur with clinically relevant changes during progression and
      metastasis in a predictable fashion.

PMID- 12490074
TI  - Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in
      pediatric thyroid carcinomas around chernobyl.
AB  - Protein-tyrosine kinases (PTKs) play a crucial role in regulating thyroid cell
      growth and differentiation. It is known that PTKs are activated by ionizing
      radiation, but the critical pathways through ionizing radiation-induced malignant
      transformation are not well defined. The Axl protein is a member of a new family
      of receptor tyrosine kinases, which the ligand, Gas6, a protein S-related
      molecule, has recently been identified. We previously clarified the expression of
      Axl and mitogenic action of Gas6 in thyroid carcinoma cells. To investigate the
      involvement of Gas6-Axl signaling in pediatric thyroid carcinoma further, we
      examined tissues obtained from 17 patients with thyroid papillary carcinomas from
      Gomel, Belarus, by immunohistochemistry and in situ hybridization. Axl and Gas6
      were overexpressed in 76.5% and 70.6 % of cases, respectively. Solid component
      and invasive front tended to overexppress Gas6 and Axl in papillary carcinomas.
      Eighty-five percent of Axl positive cases coexpressed Gas6. In situ hybridization
      also confirmed the presence of axl mRNA in thyroid carcinoma tissues. These
      findings suggest that Axl and Gas6 expression might be involved in childhood
      thyroid tumorigenesis around Chernobyl.

PMID- 12490075
TI  - Disease associations with autoimmune thyroid disease.
AB  - Autoimmune thyroid disease (AITD) is common and occurs frequently in conjunction
      with other diseases. Many putative disease associations have been suggested for
      AITD but the validity of these associations is not clear in all cases. It is
      important to define disease associations correctly because this may offer a means
      to rationally screen for true associations, may shed light on shared
      pathophysiologic mechanisms and may be important if the associated disease
      impacts on patient management. This review has examined the evidence base for a
      large number of the suggested associations.

PMID- 12490076
TI  - Radioactive iodine lobe ablation as an alternative to completion thyroidectomy
      for follicular carcinoma of the thyroid.
AB  - We performed a retrospective record review of patients who received large lobar
      remnant ablation after surgery for well-differentiated thyroid carcinoma
      including 30 with papillary carcinoma, 14 with follicular carcinoma, and 6 with
      Hurthle cell carcinoma. We compared these 50 patients to a group of patients who
      underwent total or near-total thyroidectomy for well-differentiated thyroid
      carcinoma. The ablation group was treated with single outpatient doses of 29.9
      mCi (131)I to prepare for whole-body radioiodine scanning. Subsequent serum
      thyrotropin (TSH) concentration during thyroid hormone withdrawal was greater
      than 25 microU/mL in 94% of patients. The mean TSH in this population (76
      microU/mL) was not statistically different from a group of 50 patients who
      underwent total or near-total thyroidectomy (mean, TSH 71 microU/ml p = 0.84).
      Twenty-four hour radioiodine uptake post-29.9 mCi (131)I ablation was less than
      1% in 80% of patients. The mean radioiodine uptake (0.8%) in the lobe ablation
      population was significantly lower than in patients treated with total
      thyroidectomy (mean, 2.4%, p < 0.001). There was minimal morbidity after 29.9 mCi
      (131)I ablation of large lobar remnants. Outpatient 29.9 mCi (131)I ablation is a
      safe, effective, and less costly alternative to completion thyroidectomy in
      selected patients. Although we included patients with both papillary and
      follicular carcinoma in our review, we recommend this method for patients with
      minimally invasive follicular carcinoma requiring whole body scanning, even with
      large postsurgical remnants in place.

PMID- 12490077
TI  - Thyroid dysfunction and autoimmunity in infertile women.
AB  - A prospective study was undertaken in 438 women (ages, 32 +/- 5 years) with
      various causes of infertility, and in 100 age-matched (33 +/- 5 years) healthy
      parous controls with the aim of assessing the prevalence of autoimmune thyroid
      disease (AITD) and hitherto undisclosed alterations of thyroid function. Female
      origin of the infertility was diagnosed in 45% of the couples, with specific
      causes including endometriosis (11%), tubal disease (30%), and ovarian
      dysfunction (59%). Male infertility represented 38% and idiopathic infertility
      17% of the couples. Overall, median thyrotropin (TSH) was significantly higher in
      patients with infertility compared to controls: 1.3 (0.9) versus 1.1 (0.8) mIU/L.
      Serum TSH above normal (>4.2 mIU/L) or suppressed TSH (<0.27 mIU/L) levels were
      not more prevalent in the infertile women than in controls. The prevalence of
      positive thyroid peroxidase antibody (TPO-Ab) was higher in all investigated
      women of infertile couples, compared to controls (14% vs. 8%), but the difference
      was not significant. However, in infertility of female origin, a significant
      higher prevalence of positive TPO-Ab was present, compared to controls: 18%
      versus 8%. Furthermore, among the female causes, the highest prevalence of
      positive antibodies was observed in women with endometriosis (29%). When thyroid
      antibodies were positive, both hypothyroidism and hyperthyroidism were more
      frequent in all women of infertile couples and in the women with a female
      infertility cause, compared to women in the same groups but without positive TPO
      Ab. The present study shows that in infertile women, thyroid autoimmunity
      features are significantly more frequent than in healthy fertile controls and
      this was especially the case for the endometriosis subgroup.

PMID- 12490078
TI  - Circulating levels of oxidized low-density lipoprotein in overt and mild
      hypothyroidism.
AB  - The increased low-density lipoprotein cholesterol (LDL-C) levels in
      hypothyroidism may enhance the formation of oxidized LDL (oxi-LDL) that may
      consequently generate foam cells by their uptake by the macrophages. The goal of
      this study was to investigate whether plasma circulating oxi-LDL levels are
      elevated in mild and in overt hypothyroidism, if the concentration of oxi-LDL is
      influenced in a short-term treatment period by thyroid hormone, and whether
      correlations exist between serum concentration of thyrotropin (TSH), thyroid
      hormone, and cholesterol. Thirty-nine patients with overt hypothyroidism (OH), 41
      patients with mild thyroid failure (MTF), and 57 controls (CNTR) were
      investigated. Serum TSH concentrations were increased in OH (18 +/- 6 mU/L) and
      in MTF (6 +/- 2 mU/L), whereas in CNTR the levels were 1.6 +/- 0.3 mU/L. Plasma
      circulating levels of oxi-LDL were measured by a new enzyme-linked immunosorbent
      assay (ELISA) kit (normal range, 40-75 mU/L) and they were found statistically
      significantly increased in OH compared to MTF (86 +/- 16 mU/L vs. 73 +/- 13 mU/L;
      p < 0.01) and to CNTR (62 +/- 11 mU/L; p < 0.001). Smokers in all groups
      exhibited statistically significant higher plasma oxi-LDL levels compared to
      nonsmokers. The percentage of increase amounted to 17.7% in OH, to 9.8% in MTF,
      and to 8% in CNTR. Replacement treatment with levothyroxine over a period of 3
      months in 12 of 39 patients with OH and in 14 of 41 patients with MTF resulted in
      a statistically significant decrease of oxi-LDL only in the OH group. Thus,
      plasma oxi-LDL decreased in OH from 82 +/- 12 mU/L to 73 +/- 10 mU/L (p < 0.05),
      to the upper normal level, and in MTF from 68 +/- 5 mU/L to 64 +/- 5 mU/L,
      respectively. In conclusion, we can state that circulating oxi-LDL levels are
      elevated in untreated overt hypothyroidism, they tend to be higher in mild
      thyroid failure, they are severely affected by smoking, however, they need a
      longer time course to decrease via thyroxine treatment.

PMID- 12490079
TI  - Socioeconomic factors and the presentation, management, and outcome of patients
      with differentiated thyroid carcinoma.
AB  - To determine whether patients from disadvantaged socioeconomic groups present
      with more advanced thyroid carcinoma or experience differing management and
      clinical outcomes, we retrospectively reviewed the charts of 292 patients seen at
      MD Anderson Cancer Center and Ben Taub General Hospital between 1987 and 1994. At
      diagnosis, the mean age was 42 +/- 16 years, 78% of patients were female, 76% of
      patients were low risk (TNM stage I or II), and 22% high risk (stage III or IV).
      Neighborhood income (+/- standard error of the mean [SEM]) (1990 census data) was
      lower in the high-risk group compared with the low-risk group (US dollars 26200
      +/- 1670 vs. US dollars 30900 +/- 870, p = 0.012). Men were more likely than
      women to present at an older age (47.5 +/- 16.7 vs. 40.2 +/- 16.0, p = 0.0014)
      and in the high-risk group (46% vs. 15%, p < 0.0001). No socioeconomic factor
      (ethnicity, marital status, occupation prestige, neighborhood income, insurance
      type) influenced initial diagnostic assessment. Similarly, no socioeconomic
      factor influenced initial disease management or the type of follow-up received
      over the 12-year period. Married patients had a lower 5-year recurrence rate than
      those unmarried (18% vs. 32%, p = 0.03); however, this did not affect overall or
      disease-specific survival. Similarly, ethnicity, marital status, occupation
      prestige, and insurance type did not influence overall or disease-specific
      survival. Although 10-year overall survival rates were lower in patients in the
      lowest income quartile (57% vs. 70% for upper, p = 0.0024) and in men compared
      with women (39% vs. 76%, p < 0.0001), gender alone influenced 10-year disease
      specific survival (80% for men, 89% for women, p = 0.047). In summary, no
      socioeconomic factor appears to affect initial treatment or follow-up pattern in
      patients with differentiated thyroid cancer. Income and gender may affect stage
      at initial disease presentation and may be risk factors affecting eventual
      clinical outcomes.

PMID- 12490080
TI  - Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a
      cohort of Spanish patients with sporadic medullary thyroid cancer.
AB  - The etiology of sporadic medullary thyroid carcinoma (sMTC) remains elusive.
      While germline gain-of-function mutations in the RET proto-oncogene cause
      hereditary MTC, somatic RET mutations have been described in a variable number of
      sMTC. So far, S836S of RET, is the only variant whose association with sMTC has
      been found in several European cohorts. Because RET variants seem to be
      associated with MTC, it is plausible that variants in genes encoding for RET
      coreceptors may play a role in the pathogenesis of sMTC. Recently, we described
      two possible low penetrance susceptibility alleles in the gene encoding RET
      coreceptor GFRalpha1, -193C > G and 537T > C, in a German series of sMTC. In this
      study, we have genotyped nine polymorphisms within GFRA1-3 genes for 51 Spanish
      sMTC, and 100 normal controls. Our results show that no statistical signification
      was found when Spanish sMTC patients were compared to controls. Taken together
      with the observations in the German sMTC series, the present findings suggest
      that GFRA1-193C > G and 537T > C could be in linkage disequilibrium with other
      loci responsible for the disease with a founder effect in Germany. Alternatively,
      the combined observations might also suggest that, if indeed the polymorphisms
      are functional, the effect is small.

PMID- 12490081
TI  - Acute suppurative thyroiditis caused by Salmonella typhimurium: a case report and
      review of the literature.
AB  - A 79-year-old woman with acute suppurative Salmonella thyroiditis is reported.
      She presented with fever and an enlarged, painful thyroid mass. Diagnosis was
      suspected by clinical symptoms and signs and confirmed by ultrasound, neck
      magnetic resonance imaging, aspiration cytology, and culture. The culture of fine
      needle aspirate yielded Salmonella typhimurium. She was treated by parental
      antibiotics and surgical drainage. The source and route of infection remained
      unclear under a series of examinations. No piriform sinus fistula was evident on
      the imaging study. A hematogenous spread seems to be the most possible route.

PMID- 12490082
TI  - Destructive thyroiditis secondary to a metastasis.

PMID- 12490083
TI  - A collective analysis on 54 cases of human myiasis in China from 1995-2001.
AB  - PURPOSE: To review 54 cases of human myiasis in China reported from 1995-2001 in
      order to characterize the current epidemic situation. DATE SOURCES: All reference
      data originated from some Chinese literature in Chinese medical journals. Twenty
      four short reports published from 1995-2001 were selected according to the stated
      purpose. Due to the varied outcomes of myiasis at different sites in the body,
      the present paper is divided into 7 types of infection: ocular, nasal cavity,
      external auricular, cutaneous, gastrointestinal, urogenital, and traumatic
      myiasis. RESULTS: Of these 54 selected cases of myiasis in China from 1995-2001,
      hypodermic myiasis (31 patients) and ocular myiasis (12 patients) were the most
      common, comprising 43 cases (80%). The cases were equally distributed amongst
      both genders. Furthermore, most of the infected were children and infants,
      totaling 39 cases, or 72%. The regional distribution of myiasis was widespread
      throughout the sixteen provinces and autonomous regions in question. CONCLUSIONS:
      Although not always reported, myiasis is a common zoonotic parasitosis occurring
      in most of China's territories. Due to its prevalence, preventive measures for
      myiasis are urgently needed.

PMID- 12490084
TI  - Protective effect of DNA-mediated immunization with a combination of SAG1 and IL
      2 gene adjuvant against infection of Toxoplasma gondii in mice.
AB  - OBJECTIVE: To characterize the immune response induced by SAG1 encoding plasmid
      combined with IL-2 gene adjuvant in mice and to assess the protective effect of
      this vaccination against toxoplasmosis. METHODS: Mice were co-injected
      intramuscularly with plasmid encoding Toxoplasma gondii SAG1 plus murine IL-2
      expression vector at a dose of 100 microg. Booster immunizations were employed 2
      more times at 3-week interval. As controls, mice were inoculated with PBS or
      empty plasmid pcDNA3. Humoral and cellular responses were assayed using ELISA for
      the determination of Ab, Ab isotype and IFN-gamma, as well as IL-4. To detect the
      integration and dissemination of DNA in the injected mice, PCR and in situ
      hybridization were performed. All mice were then infected with highly virulent RH
      tachyzoites of Toxoplasma gondii intraperitoneally. RESULTS: Significant
      increases in specific IgG levels were observed in mice after immunization three
      times with SAG1 expression plasmid. With respect to the IgG isotype, co
      inoculation of IL-2 expression plasmid enhanced the level of IgG2a and the
      production of IFN-gamma. Challenging mice by vaccinating with combined plasmids
      with RH tachyzoites resulted in prolonged survival. CONCLUSION: Humoral and
      cytokine responses elicited by SAG1 DNA immunization can be modulated by co
      inoculation with IL-2 expression plasmid. The use of DNA vaccine in combination
      with an appropriate cytokine gene to prevent T. gondii infection warrants further
      investigation.

PMID- 12490085
TI  - Establishment of a C57BL/6N mouse model of giardiasis.
AB  - OBJECTIVE: To establish a C57BL/6N mouse model infected with Giardia lamblia (G.
      lamblia) isolates from human origin. METHOD: Two groups of C57BL/6N mouse were
      inoculated with purified cysts of two G. lamblia isolates (CD and XZ) by gavage
      separately. Patterns and curves of cyst excretion of the infected mice were
      observed and summarized. Histopathological changes of the small intestines of the
      infected mice were observed. RESULTS: Thirty-six mice receiving 1 x 10(4) cysts
      each were all infected. The C57BL/6N mouse showed high susceptibility to G.
      lamblia infection. There was no notable distinction between the two groups of the
      mice infected by the cysts of CD and XZ isolates. Cyst excretion occurred with
      intermittence. Of 36 infected mice, 32 (89%) passed cysts intermittently and 4
      (11%) others persistently. The latent period of cyst excretion was 0 - 3 days
      p.i. (post-inoculation). The interruption of cyst excretion ranged from 12 to 20
      days p.i. The fastigium of the cyst excretion was on day 6 p.i. The peak count of
      the cysts passed during a 2 h collection period was 2.3 x 10(7)/g fecal specimen.
      Edema, inflammation, cell infiltration, small blood vessels congestion, mitotic
      figures and mucosa necrosis appeared in sections of intestines. CONCLUSION:
      C57Bl/6N mouse is a suitable animal model of G. lamblia.

PMID- 12490086
TI  - Difference in DNA sequences in SSU rDNA variable regions among pathogens isolated
      from different epidemic foci of visceral leishmaniasis in China.
AB  - OBJECTIVE: To confirm the existence of point mutations in the SSU rDNA variable
      regions of 5 Leishmania donovani (L.d.) isolates from different epidemic foci in
      China. METHODS: Specific SSU rDNA fragments from nuclear DNA of 7 Leishmania
      species/isolates were amplified by PCR and then cloned into pGEM(R)-T Easy
      Vectors. After that, the specific fragments were sequenced by an automated DNA
      sequencer. RESULTS: Sequence analysis showed that the amplified DNA fragments of
      7 Leishmania species/isolates were all 392 bp in length. All 5 point mutations
      were located in two unique sequence blocks (UQ-I and UQ-II), and no insertions or
      deletions were found. The identities of comparison of Leishmania in GeneBank were
      more than 98%. CONCLUSION: Five point mutations exist in the SSU rDNA variable
      region of 5 L.d. isolates from different epidemic foci of visceral leishmaniasis
      (VL) in China. Sequence differences of the SSU rDNA variable region exist among
      L.d. isolates from different foci.

PMID- 12490087
TI  - Non-invasive immunodiagnosis of Schistosomiasis japonica: the detection of
      specific antibodies in saliva.
AB  - OBJECTIVE: To assess the feasibility of using saliva for Schistosomiasis japonica
      diagnosis. METHODS: Schistosoma japonicum infected animal model was established.
      Pairs of saliva and serum samples from rabbits and chronic schistosomiasis
      patients were collected. Anti-schistosoma specific antibodies in saliva and serum
      were detected by indirect ELISA. RESULTS: The specificities of antibody detection
      of rabbit saliva and serum were 93% (28/30) and 97% (29/30), respectively, and
      the sensitivities of antibody detection of rabbit serum and saliva were 100%
      (24/24) and 88% (21/24), respectively. A significant correlation (r = 0.5307, P =
      0.0038 < 0.05) existed between anti-SEA IgG levels in serum and saliva. As with
      those in serum, anti-SEA IgG levels in saliva could reflect the state of
      infection and treatment. The sensitivity of antibody detection was 91% (29/32)
      for patient saliva samples and 100% (32/32) for their sera. 8 samples were
      positive in 140 normal saliva samples (i.e. 6% false positive rate) and 6 samples
      were positive in 156 normal serum samples (4% false positive rate). There was a
      significant correlation (r = 0.4227, P = 0.008 < 0.05) between specific
      antibodies in saliva and serum. CONCLUSION: The detection of specific antibodies
      in saliva can be used as a non-invasive immunodiagnosis method of Schistosomiasis
      japonica.

PMID- 12490088
TI  - Cloning of cDNA encoding Schistosoma japonicum tropomyosin and its expression in
      Escherichia coli.
AB  - OBJECTIVE: To perform cloning of the gene encoding Chinese Schistosoma japonicum
      tropomyosin (SjcTM) and its expression in Escherichia coli. METHODS: SjcTM cDNA
      fragment, except for 14 amino acids at the amino terminus, was obtained by
      reverse transcriptase-polymerase chain reaction (RT-PCR) with total RNA extracted
      from adult worms of S. japonicum. The RT-PCR product was cloned into T vector and
      sequenced. The SjcTM cDNA, derived from the constructed TA clone pGEM-SjcTM, was
      then subcloned into the expressing vector pBV220. After characterization by
      agarose gel electrophoresis, endonucleases digestion and PCR, the resultant
      recombinant plasmid was used for expression under the temperature-dependent
      condition. RESULTS: The RT-PCR product, cloned into a T vector, was sequenced and
      shown to be 96.5% identical at the nuclei acid level and 98.1% identical in
      deduced amino acid sequence to that of S. mansoni tropomyosin. The target DNA
      fragment was then subcloned into a prokaryotic vector pBV220. Induced expression
      in E. coli DH5alpha cells resulted in a constant level of recombinant protein
      production. The results of SDS-PAGE and Western blot revealed that the molecular
      weight of non-fusion recombinant protein (rSjcTM) was approximately 32 kDa and
      could be recognized specifically by a polyclonal antiserum specific for native S.
      japonicum tropomyosin (SjcTM). CONCLUSION: The engineering of the cDNA encoding
      S. japonicum tropomyosin and its bacterial expression was successfully made.

PMID- 12490089
TI  - Inhibition of allergic responsiveness in a murine asthma model via IFN-gamma
      transgene expression.
AB  - OBJECTIVE: To investigate adenoviral vector mediated exogenous gene expression in
      mouse lungs and the effect of mIFN-gamma transgene expression on allergen-induced
      pulmonary eosinophil infiltration in a murine asthmatic model. METHODS: LacZ
      marker gene was transduced into CD-1 mouse airway epithelial cells by
      installation of a replication-deficient adenovirus with LacZ gene (AdCMVLacZ) 5 x
      10(9) plaque forming unit (pfu) in the intratrachea or nostril. C57 mice were
      sensitized intraperitoneally and challenged by aerosol with ovalbumin (OVA) to
      produce an asthmatic model. AdCMVmIFNgamma 5 x 10(9) pfu was administered via
      nostril in asthmatic mice 48 h before OVA challenge. Sera, bronchial alveolar
      lavage (BAL) and lungs were recovered 48 h after OVA challenge. RESULTS: After
      administration with AdCMVLacZ by intratracheal installation or nose-drop, the
      lungs revealed a high level of widespread LacZ transduction with X-gal staining,
      mainly along airways. IFN-gamma via adenoviral vector transduction could be
      overexpressed both in vitro and in vivo (1624.7 +/- 1321.5 pg/ml in BAL 96 h
      after AdCMVIFNgamma infection). In AdCMVIFNgamma treated asthmatic models,
      histological evaluation revealed marked suppression of eosinophil peribronchial
      and perivascular infiltration; the recoverable percentage of eosinophils in BAL
      was an average of 9.00% +/- 4.58%, which was a statistically significant decrease
      versus that of the positive control group (75.13% +/- 6.85%) (P < 0.001). The
      total cell number in BAL ((145 +/- 55.6) x 10(3) cells/ml) in AdCMVmIFNgamma
      treated mice also was tremendously reduced compared to the positive control group
      ((216.6 +/- 71.1) x 10(3) cells/ml). CONCLUSIONS: Adenoviral vector was able to
      overexpress exogenous gene in murine lungs. IFN-gamma overexpression via
      adenoviral vector in pulmonary epithelia in vivo can abrogate allergen-induced
      eosinophilic infiltration in lungs in an asthmatic model, which may suggest a new
      preventively therapeutic method for cytokine immunogenetic transfer in allergic
      asthma.

PMID- 12490090
TI  - Telomerase activity in myelodysplastic syndrome.
AB  - OBJECTIVE: To study telomerase activity (TA) and its variation in bone marrow
      mononuclear cells from patients with myelodysplastic syndrome (MDS) at different
      stages in comparison with normal bone marrow cells and leukemic cells. METHODS:
      The TA was semi-quantitatively determined in mononuclear cells from 20 normal
      bone marrow samples, 21 patients with MDS at different stages and 32 cases of
      acute leukemia by using a polymerase chain reaction-enzyme linked immuno-sorben
      assay (PCR-ELISA) kit. RESULTS: The TA in normal bone marrow cells was in the
      range of 0 to 0.3 units (U) with a mean of 0.11 +/- 0.08 U. Among them, 3 samples
      were considered positive in accordance with the standard recommended by the kit's
      pamphlet. In bone marrow cells from patients with acute leukemia, the TA was
      ranging from 0 to 0.96 U with a mean value of 0.42 +/- 0.26 U. The positive rate
      was 78.1% which was significantly different from that in normal bone marrow (BM)
      (P < 0.01). In case of myelodysplastic syndrome, the average level of TA was 0.27
      +/- 0.19 U (ranging from 0 to 0.97 U) with a positive rate of 66.7%. In
      comparison with normal BM cells, the difference was significant (P < 0.05).
      Particularly, the MDS high-risk subgroup exhibited a significantly higher
      activity of telomerase (P < 0.05). In comparison with INT-1 and INT-2 subgroups
      in MDS patients based on international prognostic scoring system (IPPS), the
      difference in TA was also significant (P < 0.05). The abnormality in cell
      karyotype was not correlated with TA. CONCLUSION: The normal bone marrow cells
      demonstrate TA at a marginal level while a remarkably increasing level may be
      seen in acute leukemia patients. The BM cells from MDS patients display a
      moderate TA among which the high risk MDS subgroup with a poor prognostic IPPS
      score exhibited markedly higher TA.

PMID- 12490091
TI  - Epidemiological and antibiotic resistant study on extended-spectrum beta
      lactamase-producing Escherichia coli and Klebsiella pneumoniae in Zhejiang
      Province.
AB  - OBJECTIVE: To investigate the epidemiological status of extended-spectrum beta
      lactamase (ESBL) producing Escherichia coli (E. coli) and Klebsiella pneumoniae
      (K. pneumoniae) and the drug resistance profiles of such organisms. METHODS: A
      total of 282 clinical isolates of E. coli and 180 of K. pneumoniae were collected
      from different districts of Zhejiang Province. Inhibitor potentiated broth
      dilution tests were performed for detecting extended-spectrum beta-lactamases.
      Etests were performed to detect the drug resistance of these strains against nine
      commonly used antibiotics. RESULTS: The prevalence of extended-spectrum beta
      lactamases in E. coli and K. pneumoniae was 34.0% and 38.3%, respectively. The
      average prevalence of extended-spectrum beta-lactamases in E. coli and K.
      pneumoniae was 35.7%. The resistance prevalence of extended spectrum beta
      lactamase producing strains to ceftazidime and cefotaxime was 40% and 26%
      respectively, so were those to cefepime, cefoxitin, piperacillin-tazobactam,
      cefoperazone-sulbactam, amikacin and ciprofloxacin. All these strains were
      sensitive to imipenem. CONCLUSION: The results in this study showed that the
      prevalence of extended-spectrum beta-lactamases was high, while extended-spectrum
      beta-lactamase producing strains were resistant to most antimicrobial agents
      except imipenem.

PMID- 12490092
TI  - Immunogenicity and safety of a new inactivated hepatitis A vaccine in young
      adults: a comparative study.
AB  - OBJECTIVE: To evaluate the immunogenicity, safety, and dosage of a new
      inactivated hepatitis A vaccine administered to young adults. METHODS: One
      hundred and four normal adult volunteers, seronegative for hepatitis A virus and
      hepatitis B surface antigen, were randomly assigned to one of three groups. The
      high-dose group received a primary dose of 1000 units of the new vaccine, the low
      dose group received a primary dose of 500 units of the same vaccine, and the
      Havrix group received a primary dose of 1440 enzyme-linked immunosorbent assay
      units of Havrix, a licensed inactivated hepatitis A vaccine. All groups received
      a booster dose of the same vaccine 6 months after the primary dose. Local and
      systemic adverse reactions, seroconversion rates, and geometric mean titers of
      hepatitis A virus antibodies were measured in all three groups. RESULTS: Local
      and systemic reaction types and rates were similar in all three groups after
      primary and booster doses, although local reactions were more frequent in the
      Havrix group following the primary dose. No serious adverse reactions occurred.
      One month after the primary dose, the seroconversion rate was 87.5% in the high
      dose group, 70.0% in the low-dose group, and 50.0% in the Havrix group (P =
      0.001, versus the high-dose group). At month 6 (before administration of the
      booster dose), seroconversion rates were 96.9% in the high-dose group, 65.0% in
      the low-dose group (P = 0.0029), and 68.8% in the Havrix group (P = 0.007). All
      subjects in all groups seroconverted by one month after receipt of the booster
      dose. Geometric mean titers were similar in all three groups at month 1, but were
      higher in the high-dose group (264 mIU/ml) than those in the Havrix group (135
      mIU/ml) at month 6 (P = 0.0013). One month after the booster dose, geometric mean
      titers in the high-dose group (2747 mIU/ml) were higher than those in the low
      dose group (1657 mIU/ml) (P = 0.0223) or in the Havrix group (1316 mIU/ml) (P =
      0.01). CONCLUSIONS: This new inactivated hepatitis A vaccine is immunogenic and
      safe; two doses of either 500 or 1000 units can induce hepatitis A virus
      antibodies well above the protection level.

PMID- 12490093
TI  - Inhibitive effects of glucose and free fatty acids on proliferation of human
      vascular endothelial cells in vitro.
AB  - OBJECTIVES: To investigate the effects of glucose and free fatty acids (FFAs) on
      the proliferation and cell cycle of human vascular endothelial cells in vitro,
      and to examine whether the combined presence of elevated FFAs and glucose may
      cross-amplify their individual injurious effects. METHODS: Cultured human
      vascular endothelial cells (ECV304) were incubated with various concentrations of
      glucose and/or FFAs (palmitate and/or oleate) for 24 - 96 h. Morphologic
      alterations were observed using a phase contrast microscope and an electron
      microscope. Inhibition of proliferation was measured by a colorimetric 3-[4, 5
      dimethyl thiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. Cell
      viability was determined using trypan blue exclusion. Distribution of cells along
      phases of the cell cycle was analyzed by flow cytometry. RESULTS: Glucose 15 or
      30 mmol/L, palmitate (PA) 0.25 or 0.5 mmol/L, and oleate (OA) 0.5 mmol/L
      inhibited proliferation and accelerated death of endothelial cells in a dose-and
      time-dependent manner. After treatment with elevated glucose and/or FFAs, the
      G(0)/G(1) phase cells increased, whereas S phase cells decreased, suggesting that
      high glucose and/or FFAs mainly arrested endothelial cells at G(0)/G(1) phase.
      The inhibitive rates of proliferation and population of dead cells in endothelial
      cells incubated with glucose plus FFAs (glucose 30 mmol/L + PA 0.25 mmol/L,
      glucose 30 mmol/L + OA 0.5 mmol/L, glucose 30 mmol/L + PA 0.25 mmol/L + OA 0.5
      mmol/L) increased more markedly than those treated with high glucose or FFAs (PA
      and/or OA) alone. CONCLUSION: Both high ambient glucose and FFAs can inhibit
      proliferation and accelerate death of endothelial cells in vitro. These changes
      were cross-amplified in the combined presence of high levels of glucose and FFAs.

PMID- 12490094
TI  - Alpha-synuclein immunoreactivity and ultrastructural study of glial cytoplasmic
      inclusions in multiple system atrophy.
AB  - OBJECTIVE: To understand the possible pathogenesis of sporadic multiple system
      atrophy (MSA). METHODS: The immunoreactivity and ultrastructural features of
      glial cytoplasmic inclusions (GCIs) in 12 autopsy patients with MSA and 4 normal
      control groups were studied. All regional sections from each subject were
      evaluated with HE staining, Kluver-Barrera (KB), Holzer's, modified Gallyas
      Braak's (GB) methods and immunohistochemical staining with alpha-synuclein and
      ubiquitin antibodies. Pontine white matter with abundant GCIs from case 1 was
      examined, using conventional electron microscopy, Gallyas-Braak's electron
      microscopy and immunoelectron microscopy. RESULTS: The presence of GCIs as
      constantly demonstrated in all MSA patients. Strong alpha-synuclein
      immunoreactivity was observed in all of the ubiquitinated GCIs. However, the
      density of alpha-synuclein positive GCIs differed from case to case, and there
      was no relationship between the density of GCIs and age, sex, or MSA subtype.
      Ultrastructural features indicated that argyrophilic granule-associated filaments
      of about 25 nm in diameter were the predominant constituents of GCIs, and the
      anti alpha-synuclein antibody selectively labeled in these filaments. No GCIs and
      alpha-synuclein immunoreaction were found in control brain tissues. CONCLUSIONS:
      GCI was a pathognomonic change in sporadic MSA patients. Accumulation of alpha
      synuclein in GCIs may occur during the early stags of MSA. Seletcive alpha
      synuclein positive abnormal microtubules in GCIs therefore play an important role
      in the pathogenesis of MSA.

PMID- 12490095
TI  - Retrospective analysis of 67 consecutive cases of pure ovarian immature teratoma.
AB  - OBJECTIVE: To investigate the development regularity, treatment methods and
      prognosis of ovary immature teratoma (POIT). METHODS: Sixty-seven patients with
      POIT, admitted from 1958 to 1998, were retrospectively analyzed. There were 31
      patients with stage I, 4 with stage II, 2 with stage III and 1 with stage IV
      lesions. Twenty-seven patients had recurrences and 2 had distant metastases.
      Unilateral adnexectomy was performed for stage I lesions. From the 1980s, this
      was followed by four-cycles of combination chemotherapy (VAC, PVB or BEP x 3
      cycles) as post-operative adjuvant therapy. Combined chemotherapy and multiple
      operations were performed for advanced and recurrent lesions. RESULTS: The
      overall survival rate was 75% (50/67). However, there was a remarkable difference
      in the results from the various periods. From 1958 to 1983, the 5-year survival
      rate was 40% (6/15), and it was raised to 79% (26/33) from 1984 to 1993. In the
      period 1994 to 1998, 95% (18/19)of patients were rescued. Thirty-five patients
      who had early lesions (stage I and II) had a 5-year survival rate of 91.4%
      (32/35). Thirty-two patients with recurrent or advanced lesions had a 5-years
      survival rate of 56% (18/32). There were 8 patients with grade III tumors and
      their 5-year survival rate was only 25% (2/8). The chief prognostic factors for
      this disease are clinical stage, pathological grade and adequate treatment.
      CONCLUSION: POIT is a potentially curable disease in today's practice. It is
      characterized by the fact that recurrent tumors may be converted back to mature
      ones as time goes on. With chemotherapy, these is a good opportunity to rescue
      those patients with recurrent tumors. At present, treatment of POIT gives the
      most satisfactory results among all malignant ovarian germ cell tumor types.
      Tests of serum specific tumor markers (CA19-9, AFP, CA125, CEA) performed
      preoperatively or before chemotherapy and during follow-up have been found
      helpful in the evaluation of prognosis.

PMID- 12490096
TI  - Effects of anti-HPV16E6-ribozyme on phenotype and gene expression of a cervical
      cancer cell line.
AB  - OBJECTIVE: To investigate the effects of anti-HPV16E6-ribozyme (HRz) on phenotype
      and gene expression of a cervical cancer cell line. METHODS: HRz was designed by
      computer programs. HRz's activity was identified by cleavage experiments in
      vitro. HRz and empty eukaryotic plasmids were transfected into CaSKi cells with
      lipofectin, then renamed CaSKi-R and CaSKi-P, respectively. The expression of
      ribozyme in transfected cells was observed by RNA dot blot. The amounts of E6
      mRNA in three kinds of cells lines were detected by Northern blot. Cell growth
      curves and soft agar forming ability were studied. The ability of each cell line
      to form tumors was assessed in nude mice. Apoptosis rates and expression of c
      myc, bcl-2, p53 and Fas were detected by flow cytometry (FCM). Antigens of tumor
      cells, HLA-1, HLA-2, B7-1 and B7-2 were also detected. NK, LAK, and CD(3)AK cells
      were induced. Their cytotoxicities were detected in CaSKi-R, CaSKi-P, and CaSKi
      cells. RESULTS: In vitro cleavage reaction demonstrated that HRz could cleave
      HPV16E6 mRNA in a site-specific manner. HRz could be expressed stably in
      transfected CaSKi cells. Northern blot analysis showed that E6 mRNA levels were
      lower in CaSKi-R than in CaSKi. The growth rate of CaSKi-R was slower than those
      of CaSKi and CaSKi-P. The soft agar-forming rate of CaSKi-R was lower compared
      with those of CaSKi and CaSKi-P cells. The ability of CaSKi-R to form tumors in
      nude mice was also poor. The apoptosis rate of CaSKi-R cells was much higher than
      those of CaSKi and CaSKi-P. HRz could reduce the expression of E6, c-myc and bcl
      2 proteins, and increase the expression of p53 as well. HRz could increase the
      expression of HLA-2, B7-1 and B7-2 antigens. The cytotoxicity of NK, LAK and
      CD(3)AK cells was much higher in CaSKi-R than in CaSKi-P and CaSKi cells.
      CONCLUSION: HRz not only reverses the malignant phenotype of CaSKi cells
      partially, but also induces apoptosis in the cells, and increases sensitivity of
      CaSKi cells to immune cells.

PMID- 12490097
TI  - Diagnostic value of human cytomegalovirus late mRNA detection in active
      intrauterine infection.
AB  - OBJECTIVE: To study the diagnostic value of human cytomegalovirus (HCMV) late
      mRNA detection in active intrauterine infection. METHODS: The HCMV late mRNA in
      peripheral blood of 42 HCMV IgM positive pregnant women and their fetal
      attachments (such as chorionic villi, amniotic fluid, umbilical blood and
      placenta) were detected by reverse transcription polymerase chain reaction (RT
      PCR). RESULTS: Late mRNA was detected in 23 of 42 HCMV IgM positive cases, a rate
      of 54.3%. Fetal appendages in 13 cases of late mRNA positive mothers were also
      tested, of which 7 were positive, with a vertical transmission rate of 53.8%. In
      12 late mRNA negative mothers, only 1 case of fetal appendages tested was
      positive, with a vertical transmission rate of 8.3%. There was significant
      difference between the transmission rates of these two groups. CONCLUSIONS:
      Positive results of HCMV IgM cannot accurately reflect the activity of HCMV at
      the time of testing. However, the activity of HCMV is closely related to the
      mother-fetus vertical transmission rate. As an indicator of active HCMV
      infection, late mRNA can not only reflect the mother-fetus transmission rate
      during active HCMV infection, but also provide some information about HCMV
      activity in fetal tissue.

PMID- 12490098
TI  - Effect of delivery mode on maternal-infant transmission of hepatitis B virus by
      immunoprophylaxis.
AB  - OBJECTIVE: To study the effect of different delivery modes on immunoprophylaxis
      efficacy so as to clarify whether or not cesarean section reduces
      immunoprophylaxis failure. METHODS: Mothers with positive hepatitis B surface
      antigen (HBsAg) were selected in the third trimester of pregnancy. Their babies
      were inoculated with hepatitis B immunoglobulin at birth and hepatitis B vaccine
      at 1, 2 and 7 months of age. HBsAg and its antibodies (anti-HBs) were tested at
      1, 4, 7, and 12 months of age, then followed up yearly. RESULTS: A total of 301
      babies entered the study, including 144 born by normal spontaneous vaginal
      delivery, 40 by obstetric forceps or vacuum extraction, and 117 by cesarean
      section. The incidence of mother's HBeAg positivity or baby's gender constitution
      was comparable between the three groups. There were no significant differences in
      the positive rate of anti-HBs or HBsAg at follow-up periods among the three
      groups. At 12 months of age, anti-HBs could be detected in 78.9% of the babies
      born by normal vaginal delivery, 84.6% of the babies by forceps or vacuum
      extraction, and 86.4% of the babies by cesarean section. The positive rate of
      HBsAg was 8.1%, 7.7%, 9.7%, and chronic HBV infection incidence was 7.3%, 7.7%,
      6.8% respectively. CONCLUSIONS: There are no significant effects of delivery mode
      on the interruption of HBV maternal-baby transmission by immunoprophylaxis.
      Cesarean section does not reduce the incidence of immunoprophylaxis failure.

PMID- 12490099
TI  - Oral immunization of mice with attenuated Salmonella typhimurium expressing
      Helicobacter pylori urease B subunit.
AB  - OBJECTIVE: To establish attenuated Salmonella typhimurium producing Helicobacter
      pylori (H. pylori) urease subunit B (UreB) and determine whether it could be used
      as an oral vaccine against H. pylori. METHODS: H. pylori (SS1 strain) UreB gene
      fragment amplified by PCR was cloned into the prokaryotic expression vector pTC01
      after sequencing, and then transformed into attenuated Salmonella typhimurium
      SL3261 to acquire SL3261/pTC01-UreB. The expression of H. pylori UreB in SL3261
      was detected by Western blot. Twelve weeks after oral immunization of mice,
      antibody responses were evaluated using serum and intestinal fluid by ELISA
      assay. Interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) in the supernatant
      of spleen cells culture were also assessed by ELISA. In vitro stability of pTC01
      UreB plasmid in SL3261 was confirmed by growing in Luria Broth (LB) medium to 80
      generations. RESULTS: The UreB gene fragment amplified by PCR was consistent with
      the sequence of the H. pylori UreB as evidenced by sequence analysis. Enzyme
      digestion revealed that the correct pTC01-UreB was obtained. Western blot showed
      that a 61kDa protein was expressed in SL3261/pTC01-UreB, which could be
      recognized by anti-H. pylori UreB antiserum. After 80 generations of continuous
      culture, the recombinant plasmid pTC01-UreB was stable in SL3261 and had no
      obvious toxicity. Multiple oral immunizations with SL3261/pTC01-UreB could
      significantly induce H. pylori-specific mucosal IgA response as well as serum IgG
      response. Moreover, there were significant increases of IFN-gamma and IL-10 in
      the SL3261/pTC01-UreB group. Finally, no obvious side effects for mice and no
      change in gastric inflammation were observed. CONCLUSION: Attenuated Salmonella
      typhimurium expressing H. pylori UreB may be used as oral vaccine against H.
      pylori infection.

PMID- 12490100
TI  - Generation and analysis of 113 adult stage Schistosoma japonicum (Chinese strain)
      expressed sequence tags.
AB  - OBJECTIVE: To rapidly and economically obtain knowledge about adult stage
      Schistosoma japonicum (Chinese strain) expressed genes using expressed sequence
      tag (EST). METHODS: A directional cDNA library constructed from Schistosoma
      japonicum (Chinese strain) adult stage RNA was used to generate expressed
      sequence tags (ESTs). These were compared against an EMBL-parasites database and
      GENBANK database by BLASTn and BLASTx. RESULTS: A total of 314 phage clones were
      randomly selected for generating expressed sequence tags (ESTs). From these
      clones, 132 EST-quality sequence were obtained. Among these EST-quality
      sequences, 113 ESTs were successfully submitted to the dbEST at GenBanK. A total
      of 7.6% of these EST-quality sequences were previously identified sequence of
      Schistosoma japonicum, while 4.5% were putatively identified sequences of
      Schistosoma japonicum. A total of 23.5% of these EST-quality sequences were
      putatively identified sequence of Schistosoma mansoni or other organisms. 57.6%
      had no matches in the database and were classified as unknown sequences. Most
      ESTs with the putative protein identified belonged to housekeeping proteins.
      Information about several interesting genes was found. CONCLUSION: Partial cDNA
      sequencing to generate expressed sequence tags (ESTs) has the potential to
      rapidly and economically increase our knowledge about adult stage Schistosoma
      japonicum (Chinese strain) expressed genes.

PMID- 12490101
TI  - Affects of different access routes on autologous satellite cell implantation
      stimulating myocardial regeneration.
AB  - OBJECTIVE: To study the effect of different access routes on autologous satellite
      cell implantation to stimulate myocardial regeneration. METHODS: Satellite cells
      were procured from skeletal muscle (gluteus max) of adult mongrel canine,
      cultured, proliferated and labeled with 4', 6-diamidino-2-phenylindone (DAPI) in
      vitro. The cells were autologously implanted into the site of acute myocardial
      infarction by local injection or perfusion through the ligated distal left
      anterior descending coronary artery. Specimens were harvested 2, 4 and 8 weeks
      later for histological study. RESULTS: The labeling efficiency of satellite cells
      with DAPI was close to 100%. Fluorescent cells were found at the infarcted zone,
      papillary muscle and local injection site. Some of these cells had progressively
      differentiated into striated muscle fibers connected to intercalated discs. The
      infant cells appeared different from the mature myocardium under an electron
      microscope. Satellite cells implanted by perfusion through the coronary artery
      were arranged in order of consistency with host myocardial fibers. The satellite
      cells, implanted by local injection, were found growing in a disordered way.
      CONCLUSION: Satellite cells, implanted by coronary artery perfusion, can
      progressively differentiate into striated muscle fibers, arranging in order and
      disseminating over the infarcted zone. This approach seems more favorable for the
      recovery of myocardial contractile function than that of local injection.

PMID- 12490102
TI  - Expression of epidermal growth factor receptor and related phosphorylation
      proteins in hypertrophic scars and normal skin.
AB  - OBJECTIVE: To study the potential signal pathway involved in pathogenesis of
      hypertrophic scar formation. METHODS: The samples of scar were obtained from
      patients with burn wound scars 6 - 28 months post-burn, while the samples of
      normal control skin came from the donor site of the same patients.
      Immunohistochemistry and light microscopy techniques were used to identify the
      expression of epidermal growth factor receptor (EGFR) and phosphotyrosine
      proteins (p-Tyr), as well as the phosphorylation of signal transducer and
      activator of transcription 3 (Stat3) in both hypertrophic scars (n = 6) and
      normal skin (n = 6). RESULTS: Significant differences were observed in the p-Tyr
      and EGFR positive expression keratinocytes both in hypertrophic scars and normal
      skin. The expression of p-Tyr, EGFR and Stat3 protein was greater in hypertrophic
      scars than in normal skin. However, there was no significant difference in p
      Stat3 expression between scar tissues and normal skin. CONCLUSION: Different
      tyrosine kinase activity occurs in hypertrophic scars and normal cutaneous
      tissues. Initially, varied expression of EGFR is due to different ligand
      stimulations. However, phosphotyrosine protein and Stat3 are subsequently
      activated through phosphorylation. In scar tissues, although EGFR has an
      intrinsic tyrosine kinase activity when activated by EGFR correlated ligand,
      phosphorylation of Stat3 showed no significant changes. Therefore, cellular
      signal pathways are induced by EGFR, which might play a role in hypertrophic scar
      pathogenesis.

PMID- 12490103
TI  - Loss of heterozygosity of chromosome 20 in sporadic colorectal cancer.
AB  - OBJECTIVE: To analyze the loss of heterozygosity (LOH) of chromosome 20 in
      patients with sporadic colorectal cancer to identify additional loci involved in
      colorectal tumorigenesis. METHODS: Polymorphic microsatellite markers were
      analyzed in 83 colorectal cancer patients' tumor and normal DNA by PCR. PCR
      products were electrophoresed on an 377 DNA sequencer. Genescan 2.1 and Genotype
      2.1 software were used in the LOH scanning and analysis. Comparisons between LOH
      frequency and clinicopathological data were performed by chi(2) test. P < 0.05
      was considered statistically significant. RESULTS: The average LOH frequency in
      the long arm, short arm and whole chromosome 20 was 21.1%, 26.7% and 22.8%,
      respectively. Chromosome 20 exhibited relatively high LOH frequency, particularly
      in the regions of 20p and 20q11.1-q13.1. CONCLUSION: There is notable genetic
      instability on chromosome 20 in sporadic colorectal carcinoma patients; that is,
      mutation on chromosome 20 is closely associated with sporadic colorectal
      carcinogenesis. Also, there may be tumor suppressor genes related to sporadic
      colorectal carcinoma near the region 20q11.1-q13.1.

PMID- 12490104
TI  - Experiences relating to management of biliary tract complications following liver
      transplantation in 96 cases.
AB  - OBJECTIVE: To investigate best diagnosing methods and therapy for patients with
      biliary tract complications after liver transplantation and analyze related
      factors. METHODS: A review was made of data collected from 96 patients, and
      confirmed by retrospective case notes examination. RESULTS: A total of 94
      patients (97 grafts) survived more than 2 days after transplantation; of whom, 92
      had an end-to-end biliary anastomosis with a T tube. The average follow-up was
      5.8 months (range: 0.3 - 10.2 months). Among the 94 patients, eight (8.5%, 8/94)
      had complications: leakage during T-tube removal (2 patients), leakage at an
      earlier stage (2), simultaneous stricture and leak (2) and just stricture (2).
      Six patients with biliary tract complications had predisposing factors including
      hepatic artery stenosis (2 patients, including one hepatic artery stenosis
      combined with severe rejection, hepatic artery thrombosis (3), and donor
      recipient bile duct mismatch (1). There was no difference in cold ischemic time.
      With hepatic artery thrombosis and/or stenosis > 50%, five patients were re
      transplanted; without hepatic artery thrombosis and/or stenosis < 50%, three
      patients required endoscopic stenting and radiological percutaneous drainage of
      bile collection with or without balloon dilation. All patients survived.
      CONCLUSIONS: Biliary strictures occur later than leaks after surgery. Without
      hepatic artery thrombosis and/or stricture, there is no need for surgery; with
      hepatic artery thrombosis and/or stricture > 50%, re-transplantation is needed as
      early as possible.

PMID- 12490105
TI  - Multivariate analysis by Cox Proportional Hazards Model on prognoses of patients
      with bile duct carcinoma after resection.
AB  - OBJECTIVE: To evaluate the influence of various clinicopathologic factors on the
      survival of patients with bile duct carcinoma after curative resection. METHODS:
      A retrospective analysis was performed on 86 cases of bile duct carcinoma treated
      from January 1981 to September 1995. Fifteen clinicopathologic factors that could
      possibly influence survival were selected. A multivariate analysis of these
      individuals was performed using the Cox Proportional Hazards Model. RESULTS: The
      overall cumulative survival rate was 73% for 1 year, 32% for 3 years and 19% for
      5 years. The results of univariate analysis showed that the major significant
      prognostic factors for influencing survival of these patients were type of
      histological lesion, lymph node metastasis, pancreatic invasion, duodenal
      invasion, perineural invasion, macroscopic vessel involvement, resected surgical
      margin and depth of cancer invasion (P < 0.05). Pancreatic invasion, perineural
      invasion and lymph node metastases were the three most important prognostic
      factors determined by multivariate analysis using the Cox Proportional Hazards
      Model. CONCLUSION: Pancreatic invasion, perineural invasion and lymph node
      metastases are the most important prognostic factors for bile duct carcinoma
      after curative resection.

PMID- 12490106
TI  - The effects of local anesthetics on intracellular Ca2+ release from ryanodine
      sensitive Ca2+ stores in gerbil hippocampal neurons.
AB  - OBJECTIVE: To examine the effects of procaine and lidocaine on intracellular
      Ca(2+) release from sarcoplasmic reticulum ryanodine-sensitive Ca(2+) stores.
      METHODS: The experiment was performed on hippocampal slices from 60-80 g male
      Mongolian gerbils. Levels of intracellular Ca(2+) concentration in the slices
      were measured by microfluorometry. The slices were perfused with 50 mmol/L KCl
      containing medium for 30 seconds. Then, the medium was switched to physiological
      medium. After 5 min of incubation, the slice was perfused with 20 mmol/L caffeine
      containing physiology medium for 2 min. Following incubation, the slice was
      superfused with physiological medium until the end of the experiment. The effects
      of procaine and lidocanin (100 micro mol/L) on caffeine-evoked Ca(2+) release
      were evaluated by adding them to the medium after high K(+) medium perfusion.
      RESULTS: Caffeine induced a marked increase in intracellular Ca(2+) concentration
      which was then decreased 12% upon the addition of procaine (P < 0.05); however,
      lidocaine, did not induce a similar inhibitory reaction. CONCLUSION: Procaine
      inhibits ryanodine-receptor mediated Ca(2+) release from intracellular Ca(2+)
      stores, while lidocaine may inhibit Ca(2+) release through other mechanisms.

PMID- 12490107
TI  - Lung function imaging under quantitative spirometrically controlled CT.
AB  - OBJECTIVE: To assess the possibility of using spirometrically controlled computed
      tomography (CT) to test pulmonary ventilation function. METHODS: Spiral CT scans
      under the control of a spirometer were performed on 30 healthy adults. Spiral CT
      scan was performed at 50% vital capacity (VC) with an 8 mm slice thickness. Mean
      attenuation values and pixel index (PI) of lung regions were evaluated with
      semiautomatic evaluation software. RESULTS: There were significant differences in
      PI values between four pixel intervals. CONCLUSIONS: Spirometrically controlled
      spiral CT with semiautomatic evaluation software is an accurate and reproducible
      method of measuring lung density and PI, which has the possibility of indicating
      pulmonary ventilation function.

PMID- 12490108
TI  - Combined modality therapy following bladder conservation surgery for bladder
      cancers.
AB  - OBJECTIVE: To analyze the efficacy of recurrence prophylaxis using radiation and
      chemotherapy following bladder conservation surgery for muscle invasive bladder
      cancer. METHODS: 23 patients with muscle invasive bladder cancer were treated
      with radiotherapy combined with bladder mitomycin infusion after bladder
      conservation surgery (study group). Radiotherapy was given using an external beam
      at an average dose of 5148 +/- 462 cGy with conventional fractionation. For
      comparison, 29 similar patients treated with postoperative bladder mitomycin
      infusion without radiation served as control (control group). All patients were
      followed up for more than 3 years, an average of 41.6 months (36 - 60 months).
      RESULTS: The 3-year pelvic recurrent rate of muscle invasive bladder cancer was
      17.4% in the study group and 44.8% (P = 0.036) in the control group. The 3-year
      distant metastasis rates were 17.4% and 24.1%, respectively (P = 0.554). The 3
      year overall survival rates were 81.8% and 86.2%, respectively (P = 0.670). Two
      patients from the study group had their treatment interrupted, one for 3 days and
      the other for one week due to acute cystitis, while the rest of the patients were
      able to complete the treatment according to schedule. CONCLUSION: Radiotherapy
      plus chemotherapy after bladder conservation surgery for muscle invasive bladder
      cancer can decrease the rate of pelvic recurrence effectively and be used as a
      realistic adjuvant treatment.

PMID- 12490109
TI  - A preliminary clinical application of sICAM-1 RIA in three kinds of thyroid
      disease.
AB  - OBJECTIVE: To examine serum levels of sICAM-1 from normal controls and patients
      with thyroid diseases (simple goitre, Graves' disease or Hashimoto's thyroiditis)
      with (125)I-sICAM-1 RIA established in our lab. METHODS: Using (125)I-sICAM-1
      RIA, serum sICAM-1 levels of 400 healthy individuals as the normal group and 1020
      patients with simple goitre (SG), Graves' disease (GD) or Hashimoto's thyroiditis
      (HT) were examined for a comporative chinical study. RESULTS: The serum level of
      sICAM-1 (x +/- s) in the normal group was 168.43 +/- 36.23 micro g/L. There was
      no significant difference between the normal and SG groups (P > 0.05), whereas
      the serum levels of sICAM-1 in autoimmune thyroid diseases (GD or HT) were higher
      than those in the normal or SG groups (P < 0.05, respectively). After GD patients
      received one of three medical treatments, their serum sICAM-1 levels decreased (P
      < 0.05). After GD patients were treated and their thyroid function decreased to
      normal, their serum sICAM-1 levels were lower than those in relapsed GD patients
      (P < 0.05). CONCLUSIONS: sICAM-1 RIA can be used to examine autoimmune thyroid
      diseases. Serum levels of sICAM-1 can be used as a parameter in diagnosing
      autoimmune thyroid disease and in evaluating the effects of therapy, drug
      administration or relapse in GD.

PMID- 12490110
TI  - Clinical application and histological observation of pedicled buccal fat pad
      grafting.
AB  - OBJECTIVE: To introduce the applied anatomy of pedicled buccal fat pad (BFP)
      graft and a series of histological changes in the healing process of BFP as an
      uncovered pedicled graft. METHODS: The healing processes of BFP are demonstrated
      via uncovered pedicled grafts on rabbits in histological examination. Uncovered
      buccal fat pads were used to repair soft tissue defects in rabbit oral cavities.
      RESULTS: The uncovered buccal fat pads showed complete epithelialization of their
      oral surfaces at 6 to 8 weeks after surgery and were slowly replaced by fibrous
      tissue. CONCLUSIONS: Advantages of the pedicled buccal fat pad graft include an
      anatomic region that is consistent and easy to excise. The operation can be
      performed in one incision, affecting neither appearance nor function of the area.
      Use of the buccal fat pad provides a good reconstruction of soft tissue defects
      in the mouth.

PMID- 12490111
TI  - Comparison of pre- and post-operational multifocal electroretinograms of retinal
      detachment.
AB  - OBJECTIVES: To explore the changes of multifocal electroretinograms (mfERG)
      before and after retinal detachment surgery and to evaluate its clinical
      significance. METHODS: Twenty-three patients (23 eyes) with rhegmatogenous
      retinal detachment underwent mfERG before and after surgery. The latencies and
      average response densities of N(1)-wave and P(1)-wave of mfERGs in detached
      areas, attached areas, fovea and the entire tested area were compared before and
      after surgery. RESULTS: Preoperatively, the average response densities of N(1)
      wave and P(1)-wave in the detached area were significantly smaller than those in
      attached areas (t = 3.68, t = 4.26, P < 0.01), and the latencies of N(1)-wave and
      P(1)-wave in detached areas were significantly longer than those in attached
      areas (t = 3.07, t = 3.89, P < 0.01). Postoperatively, the average response
      densities of N(1)-wave and P(1)-wave in detached areas, fovea and the entire
      tested area increased, and there were significant differences pre- and
      postoperatively (P < 0.05). However, the latencies of N(1)-wave and P(1)-wave
      before and after surgery showed no significant differences (P > 0.05).
      CONCLUSIONS: The mfERG is a useful tool to evaluate the recovery of posterior
      retinal function after retinal detachment surgery. The response density is a more
      sensitive index than latency to evaluate retinal function of retinal detachment.

PMID- 12490112
TI  - Expression of CD44V6 and PCNA in squamous cell carcinomas.
AB  - OBJECTIVE: To investigate the expression of cluster of differentiation 44 variant
      6 (CD(44V6)) and proliferating cell nuclear antigen (PCNA) in ocular squamous
      cell carcinomas. METHODS: Streptavidin-biotin complex (SABC) immunohistochemistry
      was used to explore the expression of CD(44V6) and PCNA in 35 cases of ocular
      squamous cell carcinomas, 20 cases of papillomas, and 11 cases of normal eyelid
      tissue. RESULTS: The CD(44V6) positive rate was 62.9% (22/35) in ocular squamous
      cell carcinomas, 15.0% (3/20) in papillomas, but not detectable in the 11 cases
      of normal eyelid tissue. The positive expression rates of CD(44V6) in ocular
      squamous cell carcinomas were significantly higher than in benign tumors (chi(2)
      = 11.57, P < 0.01) or control tissue (P = 0.001), and the positive expression
      rates of CD(44V6) in metastasis were significantly higher than without metastasis
      (P = 0.049). PCNA labeling indexes (PI) in tumors with CD(44V6) expression were
      significantly higher than those without (t = 20.21, P < 0.01). CONCLUSIONS:
      Overexpression of CD(44V6) is correlated with the progress and metastasis of
      ocular squamous cell carcinomas. CD(44V6) protein positive staining is associated
      with high PI. CD(44V6) and PCNA are useful for evaluating prognosis.

PMID- 12490113
TI  - Acyclovir for the treatment and prevention of recurrent infectious herpes simplex
      keratitis.
AB  - OBJECTIVE: To evaluate the role of acyclovir in treatment and prevention of
      herpes simplex keratitis (HSK). METHODS: A total of 105 patients with HSK were
      divided into 4 groups. Group 1 consisted of 79 patients with HSV epithelial
      keratitis. Group 2 consisted of 20 patients with interstitial keratitis. Group 3
      consisted of 6 patients with necrotizing keratitis. Group 4 consisted of 4
      necrotizing keratitis patients with corneal perforation treated with conjunctival
      flap and corneal transplantation. All patients were treated with acyclovir
      systemically and topically. After full recovery, the patients with epithelial HSK
      and stromal HSK were randomly divided into two groups individually. One group was
      constantly treated with oral acyclovir at 300 mg/day for 1 year as a prophylaxis
      group. The other group was designated as control. RESULTS: During the one-year
      treatment and follow-up, 5 cases with epithelial HSK recurred in the prophylaxis
      group and 14 cases in the control group, showing a statistically significant
      difference. One case of stromal HSK recurred in the prophylaxis group and 4
      recurred in the control group. CONCLUSION: Long term and low dose oral acyclovir
      for prophylaxis of recurrent epithelial herpes simplex infection and therapeutic
      doses of oral acyclovir reduce both the rate and duration of recurrences of
      infectious herpes simplex keratitis.

PMID- 12490114
TI  - Study of isolation of fluoroquinolone-resistant Ureaplasma urealyticum and
      identification of mutant sites.
AB  - OBJECTIVE: To study the resistance mechanism of clinical isolates of Ureaplasma
      urealyticum resistant to fluoroquinolones. METHODS: Thirteen isolates of
      Ureaplasma urealyticum resistant to six fluoroquinolones were selected out of 184
      clinical isolates and their QRDRs (quinolone resistance-determining region) gyrA,
      gyrB, parC and parE were amplified by PCR. Sequencing results were compared to
      those susceptible reference strains and a comparison of deduced amino acid
      sequences were performed. RESULTS: Sequence comparison revealed a C to A change
      at 87nt of gyrA QRDR leading to the substitution of Asp95 with glutamic acid and
      a C to T change at 50nt of parC QRDR leading to the substitution of Ser80 with
      leucine. CONCLUSION: These results suggest that a C to A change at 87nt of gyrA
      QRDR and a C to T change at 50nt of parC QRDR are associated with fluoroquinolone
      resistance of Ureaplasma urealyticum.

PMID- 12490115
TI  - Experimental study on a novel compound extracted from Traditional Chinese
      Medicine for treatment of alveolar echinococcosis.
AB  - OBJECTIVE: To evaluate the efficacy of a novel compound derived from Traditional
      Chinese Medicine (TCM) for treatment of alveolar echinococcosis in the Kuming
      mouse. METHODS: The compound was extracted from TCM by serial procedures
      including amalgamation of TCM drugs, boiling in a beaker, cold condensation using
      a reflux instrument, evaporation by mild heating and finally, formation of a deep
      brown powder. An animal model of alveolar echinococcosis was established
      concurrently. A bit of alveococcus tissue derived from alveolar echinococcosis in
      the mouse was transplanted into the peritoneal cavity of the musculus of a Kuming
      mouse. The duration of infection after inoculation was classified as either 1
      week or 10 weeks; the animals were again divided into treated groups and control
      groups. Estimation of the alveococcus inhibitory rate and electron microscopic
      observation served as the main methods for assessment of efficacy. The infected
      mice in the treated groups were intra-gastrically administered once per day with
      the TCM extractive powder at doses of 20 mg.kg(-1) for three months continuously.
      All the animals were sacrificed and examined half a month after the end of TCM
      treatment. RESULTS: Total wet weight of alveococcus collected from the 9 mice in
      the treated group after one week of infection was 37.8 g (x +/- s, 4.196 +/-
      2.090 g), which was markedly lower than the amount collected from 10 mice of the
      control group (121.3 g, x +/- s, 12.1 +/- 4.3 g). Therefore, the inhibitory rate
      of the alveococcus was 65.7% (P < 0.01). Similarly, the total wet weight of
      alveococcus from 7 mice of the treated group after 10 weeks of infection was 4.3
      g (x +/- s, 0.62 +/- 1.21 g), which was much lower than the amount collected from
      6 mice of the control group (17.85 g, x +/- s, 2.93 +/- 3.28 g). The inhibitory
      rate of alveococcus was 80.6% (P < 0.01). Furthermore, the ultrastructural
      appearances of alveococcus showed obvious differences between the two groups.
      CONCLUSION: TCM extractive powder for treatment of murine alveococcosis is
      considered to be a hopeful anti-echinococcus compound; it is a topic for further
      study.

PMID- 12490116
TI  - The cross-reactivity of I-A(g7) and I-A(d) tetramers.
AB  - OBJECTIVE: To investigate the cross-reactivity between glutamic acid
      decarboxylase (GAD)-I-A(g7) and I-A(d) tetramer in diabetes-prone non-obese
      diabetic (NOD) mice (I-A(g7)) and diabetes-free Balb/c mice (I-A(d)). METHODS:
      Two GAD peptide I-A(g7) and I-A(d) tetramers were generated and compared for
      phenotype and function of sorted GAD peptide I-A(g7) and I-A(d) tetramer-positive
      (tet+) T cells. RESULTS: The cross-reactivity is shown in either tetramer
      positive percentage or tetramer staining intensity. The NOD and Balb/c derived
      tet+ T cells were able to be cross-stained by GAD peptide I-A(g7) and I-A(d)
      tetramers, and responded to both irradiated NOD and Balb/c splenotyes under
      stimulation by synthetic and recombinant GAD peptides. CONCLUSION: Although I
      A(g7) and I-A(d) are closely related in biochemical and biological aspects, their
      most notable difference is the presence or absence of a negatively charged
      residue at position beta57 that links to insulin-dependent diabetes mellitus.

PMID- 12490117
TI  - [Epidemiological survey of the incidence of bronchial asthma in occupational
      populations in Beijing area].
AB  - OBJECTIVE: To investigate the correlation of asthma incidence with environmental
      pollution. METHODS: We performed stratified-cluster-disproportional-random
      sampling survey in the occupational populations from 10 professional systems by
      using an uniform protocol, questionnaire and procedure in this multicenter study.
      Original data were processed and statistically analyzed with SPSS 8.0 for
      windows. Prevalence rates were compared by chi(2) test. RESULTS: A total of
      50,558 people supposed to cover more than 200,000 staff and workers were sampled.
      Six hundred and thirty asthmatics were identified and the overall prevalence rate
      in Beijing area was 1.25%. The incidence of asthma in occupational populations
      from urban commercial and trade circles, common chemical plants, and a certain
      petrochemical works was 0.51%, 1.06% and 2.81% respectively. The morbidity of
      asthma in the latter two populations was significantly higher than that in
      peasants (0.43%) in the remote outskirts of Beijing city (P < 0.01). The relative
      risk (RR) of asthma incidence in occupational populations from the commercial and
      trade circles, common chemical plants, the petrochemical works and the students
      in elementary and middle schools was 1.88, 2.79, 5.19 and 3.05 respectively as
      compared to peasants, the differences being statistically significant.
      CONCLUSION: The results suggest that the difference in asthma incidence in
      occupational populations may be attributable to environmental pollution.

PMID- 12490118
TI  - [The expression and regulation of vascular cell adhesion molecules and eotaxin in
      bronchioles and lung tissue from a guinea-pig model of asthma].
AB  - OBJECTIVE: To evaluate the expression of vascular cell adhesion molecules (VCAM
      1) and eotaxin and their transcription factors NF-kappa B and AP-1 in bronchi and
      bronchioles (with surrounded lung tissue), and to investigate the mechanisms for
      eosinophil chemotaxis to the lungs in a guinea pig model of asthma. METHODS: (1)
      The guinea pig model of asthma was established by the ovalbumin challenge method.
      (2) The animal models were divided into six groups: control, asthma day 1, asthma
      day 4, asthma day 14, intraperitoneal dexamethasone, and budesonide inhalation
      groups. (3) The protein expressions of VCAM-1, eotaxin, NF-kappa B and AP-1 in
      segmental bronchi and in bronchioles and lung tissue were measured by
      immunohistochemical techniques. (4) The mRNA expressions of VCAM-1 and eotaxin in
      lung tissue homogenates were determined by RT-PCR. (5) The DNA binding activities
      of NF-kappa B and AP-1 were measured by electrophoretic mobility shift assay
      (EMSA). RESULTS: (1) In all the asthmatic groups, the protein levels of VCAM-1,
      eotaxin, NF-kappa B and AP-1, expressed both in central and peripheral airways
      (26.3 +/- 3.2, 89.0 +/- 8.6, 179 +/- 7 and 76 +/- 6), were significantly elevated
      compared to those in the control group (11.2 +/- 3.7, 5.0 +/- 4.0, 36 +/- 3 and
      27 +/- 5). (2) The mRNA expression levels of VCAM-1 and eotaxin in lung tissue
      homogenates were significantly higher in the asthmatic groups (2.46 +/- 0.38 and
      1.080 +/- 0.080) than those in the control group (1.05 +/- 0.11 and 0.080 +/-
      0.020). (3) The DNA binding activities of NF-kappa B and AP-1 were significantly
      increased in the asthmatic groups (256 +/- 10 and 78 +/- 14), than those in the
      control group (67 +/- 13 and 12 +/- 3). (4) All these parameters in both
      glucocorticoid treated groups were significantly decreased compared to those in
      the asthma day 14 group, and similar to those in the control group. CONCLUSIONS:
      VCAM-1 and eotaxin actively participated in the process of eosinophilic
      inflammation. NF-kappa B and AP-1 may play important roles in the regulation of
      VCAM-1 and eotaxin. The up- regulation of these inflammatory mediators existed
      not only in central airways, but also in small airways and lung tissue,
      indicating that asthma in this model is a disease of whole respiratory system.
      Glucocorticoids, either by systemic use or inhalation, demonstrated
      antiinflammatory effects by inhibiting the expressions and activities of NF-kappa
      B and AP-1 and by down-regulation of VCAM-1 and eotaxin.

PMID- 12490119
TI  - [Changes of plasma interleukin-4, interleukin-10 and interleukin-13 in patients
      with acute respiratory distress syndrome].
AB  - OBJECTIVE: To explore the anti-inflammatory mechanisms of interleukin-4 (IL-4),
      interleukin-10 (IL-10) and interleukin-13 (IL-13) in acute respiratory distress
      syndrome (ARDS). METHODS: Enzyme-linked immunosorbent assay (ELISA) was employed
      to determine the plasma levels of IL-4, IL-10 and IL-13 in patients with ARDS (n
      = 22) and systemic inflammatory response syndrome (SIRS, n = 8). Ten normal
      subjects were enrolled as controls. RESULTS: The plasma levels of IL-4, IL-10 and
      IL-13 were (261 +/- 55) microg/L, (458 +/- 112) microg/L and (5.21 +/- 2.02)
      microg/L, respectively in patients with ARDS; (155 +/- 26) micro g/L, (260 +/-
      54) microg/L and (1.69 +/- 0.39) microg/L respectively in patients with SIRS; and
      (43 +/- 13) microg/L, (135 +/- 15) microg/L and (0.33 +/- 0.10) microg/L,
      respectively in normal controls. They were significantly increased in patients
      with ARDS and SIRS as compared to normal controls, and the levels were higher in
      patients with ARDS than in patients with SIRS. CONCLUSIONS: Increased release of
      anti-inflammatory cytokines, such as IL-4, IL-10 and IL-13, may be one of the
      underlining mechanisms for the development of ARDS and SIRS.

PMID- 12490120
TI  - [Arsenic trioxide induced apoptosis and expression of p53 and bcl-2 genes in
      human small cell lung cancer cells].
AB  - OBJECTIVE: To study the arsenic trioxide (As(2)O(3)) induced apoptosis in a human
      small cell lung cancer cell line (NeI-H cells) and its possible mechanisms.
      METHODS: Apoptotic cells were detected by the TUNEL method. The expression of p53
      and bcl-2 was analyzed with immunohistochemical staining. RESULTS: NeI-H cells
      showed the sub-G(1) peak after treatment with As(2)O(3) (0.5 micromol/L, 1.0
      micromol/L, and 2.0 micromol/L) for 72 hours. The ratio of apoptotic cells
      increased with the increasing concentrations of the drug and the time of culture.
      Immunohistochemical staining of NeI-H cells showed increased expression of p53,
      but decreased expression of bcl-2 with the increasing concentrations of the drug.
      CONCLUSION: The anti-carcinogenic effect of As(2)O(3) is due to the induction of
      cell apoptosis. Up-regulation of the p53 gene and down-regulation of the bcl-2
      gene may be an underlining mechanism.

PMID- 12490121
TI  - [The clinical significance of detection of p53 gene mutation in patients with
      lung cancer].
AB  - OBJECTIVE: To assess the value of detection of p53 gene mutation in bronchial
      biopsy and sputum samples for the diagnosis of lung cancer. METHODS: Bronchial
      biopsy and sputum samples were collected from 120 patients confirmed to have lung
      cancer and 40 patients with benign pulmonary diseases. Polymerase chain reaction
      single strand conformation polymorphism-AgNOS(3) staining method (PCR-SSCP) was
      performed for the detection of point mutation at exon 5 - 8 of the p53 gene.
      RESULTS: The positive rates of p53 point mutation in the carcinomatous tissue,
      the para-carcinomatous tissue, the contralateral bronchial tissue and the sputum
      from patients with lung cancer were 60% (36/60), 17% (10/60), 5% (3/60) and 43%
      (26/60), respectively (P < 0.05). In patients with benign pulmonary diseases, p53
      point mutation in bronchial biopsy sample was detected in only one case (5%). The
      positive rate for the diagnosis of lung cancer increased from 48% (cytology
      alone) to 68% when the detection of p53 point mutation and cytological
      examination for sputum samples were combined. CONCLUSIONS: Detection of p53 gene
      mutation with PCR-SSCP-silver stain combined with cytological examination of
      sputum samples can improve the diagnosis of lung cancer.

PMID- 12490122
TI  - [Clinical application and evaluation of the detection of five drugs resistance
      genes in Mycobacterium tuberculosis].
AB  - OBJECTIVE: To evaluate the clinical application of the detection of the drug
      resistant genes rPOB, katG, rPSL, PncA and embB in M. tuberculosis by using
      polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)
      analysis. METHODS: Gene mutations and anti-tuberculous drug susceptibility test
      were analyzed in 109 M. tuberculosis isolates by PCR-SSCP and the proportion
      method on Lowenstein-Jensen medium, respectively. The therapeutic effect was
      evaluated in patients with tuberculosis. RESULTS: Isolates from more than 50% of
      the patients with pulmonary tuberculosis were resistant to at least two drugs.
      The total rates of drug resistance to rifampin (RFP), isoniazid (INH),
      streptomycin (SM), pyrizinamide (PZA) and ethambutol (EB) were 80.7%, 71.5%,
      78.8%, 57.7%, and 48.6%, respectively. The gene mutation rates of rpoB, katG,
      rpsL, pncA and embB were 76%, 68%, 71%, 51% and 30%, respectively. The gene
      mutations were correlated with the degree of drug-resistance to M. tuberculosis.
      Most of the gene mutations were found in drug-resistant isolates in high
      concentrations. The six month cure rates of MDR-TB, confirmed by drug
      susceptibility test and by PCR-SSCP, were 54.8% and 62.8%, respectively (P >
      0.05). CONCLUSIONS: PCR-SSCP is a sensitive and specific method for rapid
      detection of rpoB, katG, rpsL, pncA and embB gene mutations in M. tuberculosis.
      Drug resistant gene detection may be clinically useful in the therapy of
      tuberculosis.

PMID- 12490123
TI  - [Growth of rifampin-dependent Mycobacterium tuberculosis in conditions without
      rifampin].
AB  - OBJECTIVE: To study the growth of rifampin-dependent Mycobacterium tuberculosis
      in conditions without rifampin. METHODS: A typical rifampin-dependent strain was
      identified and a single colony growing in the optimal concentration of rifampin
      was selected and inoculated (10(-4) mg/ml) to L-J and 12B liquid media, cultured
      at 37 degrees C. The bacterial growth and characteristics were studied. RESULTS:
      In the L-J medium containing rifampin, bacterial growth was observed in two
      weeks, but in the medium without rifampin tiny colonies were not observed until
      three weeks. In the 12B media with and without rifampin, bacterial growth was
      evident on day 9 and day 13 respectively. Thick and larger colonies and
      cauliflower-like growth were observed in media containing rifampin, but smaller
      colonies and fried egg-like growth were observed in media without rifampin.
      Microscopic study showed thick and heavily stained bacteria in media containing
      rifampin, but small and lightly stained bacteria in media without rifampin.
      Transmission electron microscopy demonstrated that bacteria growing in the
      presence of rifampin had complete cell walls, but those growing in the absence of
      rifampin had abnormal cell walls. CONCLUSION: Rifampin-dependent Mycobacterium
      tuberculosis may be changed into bacterial L-forms in media without rifampin.

PMID- 12490124
TI  - [Detecting rpoB gene mutation in rifampin-resistant Mycobacterium tuberculosis by
      using the reverse dot-blot hybridization method].
AB  - OBJECTIVE: To establish a simple, rapid and sensitive hybridization method for
      detecting drug-resistance relevant gene mutation in Mycobacterium tuberculosis.
      METHODS: Fourteen single-strand specific probes designed to detect mutated and/or
      wild rpoB gene in Mycobacterium tuberculosis were spotted and fixed on nylon
      membranes, and PCR products labeled with biotin were obtained by using down
      stream primer labeled with biotin, then hybridized and analyzed with streptavidin
      HRP and TMB. RESULTS: Twenty-three rifampin-resistant Mycobacterium tuberculosis
      isolates and 11 rifampin-sensitive isolates were analyzed. The gene mutations
      were consistent with the DNA sequencing and the in vitro susceptibility test in
      30/34 and 28/34 of the isolates, respectively. Mutations of Ser-531 were present
      in 11 of the 23 rifampin-resistant isolates, followed by His-526, Leu-533, and no
      mutation was found in 13 isolates, including 2 rifampin-resistant isolates.
      Mutations in loci 516 and 513 were not detected. CONCLUSION: Reverse dot-blot
      hybridization may be of potential use for the rapid diagnosis of rifampin
      resistant tuberculosis.

PMID- 12490125
TI  - [A study on the use of mycobacterium vaccine in the treatment of tuberculous
      pleurisy].
AB  - OBJECTIVE: To study the effects of immunotherapy with mycobacterium vaccine in
      patients with tuberculous pleurisy. METHODS: The time for effusion resolution and
      lymphocyte counts in the effusions were observed in patients with tuberculous
      pleurisy who received anti-tuberculous therapy and thoracentesis (group A) or
      anti-tuberculous therapy and thoracentesis plus intramuscularly administered
      polysaccharide nucleic acid fraction of Bacillus Calmette Guerin (PSN-BCG,)
      (group S). In situ end-labeling technique of fragment DNA was used to detect the
      apoptosis of lymphocytes in the effusions. RESULTS: The average resolution times
      in group A and group S were 21.2 days and 28.7 days respectively (P < 0.01). The
      lymphocyte counts in the two groups after 1 week, 2 week, and 3 week therapy were
      1.6 x 10(9)/L (A) and 2.1 x 10(9)/L (S) (P < 0.01), 0.83 x 10(9)/L and 1.52 x
      10(9)/L (P < 0.01), 0.55 x 10(9)/L and 1.16 x 10(9)/L (P < 0.01) respectively.
      The average apoptotic half-time was 94 h (A) and 124 h (S) (P < 0.01), 84 h and
      123 h (P < 0.01), 79 h and 120 h (P < 0.01) respectively. CONCLUSIONS:
      Mycobacterium vaccine was found to prolong lymphocyte activation, inhibit
      lymphocyte apoptosis, and delay the resolution of pleural effusions. It was found
      not helpful as an adjunct therapy for tuberculous pleurisy.

PMID- 12490126
TI  - [Changes of blood vessel active substances in acute pulmonary embolism induced by
      echinococus granulous cyst in rabbits].
AB  - OBJECTIVE: To investigate the role of blood vessel active substances, such as
      endothelin-1 (ET-1), thromboxane B(2) (TXB(2)), and 6-keto-prostaglandin
      F(1alpha) (6-K-PGF(1alpha)) in a rabbit model of acute pulmonary embolism induced
      by echinococus granulous cyst. METHODS: Catheters were placed into the femoral
      artery and the femoral vein. Saline, fresh clear cyst fluid or sand containing
      cyst fluid in a volume of 2 ml/kg were infused through the femoral vein catheter.
      Changes of ET-1, TXB(2) and 6-K-PGF(1alpha) were measured; PaO(2), PaCO(2), pH,
      MAP, heart rate, and respiration rate were recorded; and radionuclide lung
      perfusion scan and the change of heart and lung pathology were studied. RESULTS:
      The changes of the studied parameters were not remarkable in the saline treated
      animals (P > 0.05). TXB(2) and 6-K-PGF(1alpha) were elevated in the cyst fluid
      treated animals (P < 0.05). PaO(2), PaCO(2), and MAP declined in the clear cyst
      fluid group (P < 0.05), but their changes were more significant in animals
      treated with sand containing cyst fluid. Radionuclide lung perfusion scan showed
      radioactivity defect or attenuation. Histological examination of the lungs
      revealed diffuse alveolar damage. CONCLUSIONS: Sand containing cyst fluid caused
      a more severe disease in this rabbit model of acute pulmonary embolism,
      suggesting that it played an important role in the induction of lung damage.

PMID- 12490127
TI  - [Epidemiological survey on bronchial asthma in Liaoning province].
AB  - OBJECTIVE: To survey the prevalence of asthma in urban and rural residents of
      Liaoning province in 1999 and evaluate the risk factors for asthma, providing
      data for research and preventive and therapeutic policies for control of asthma.
      METHODS: Stratified cluster disproportional random sampling survey was performed
      in 116 276 residents by common protocols and questionnaire. Asthma was diagnosed
      based upon case history, clinical signs and lung function tests. Univariate
      analysis was employed to evaluate the risk factors for asthma. RESULTS: The
      overall prevalence of asthma in Liaoning province was 1.25%, the male to female
      ratio being 1:1.64. The prevalence of asthma in adults was 1.39% and that in
      children was 0.48%. The onset of asthma occurring in children under the age of 14
      accounted for 38.63% of the whole patients. The prevalence was higher in
      peasants, animal breeders and government officials. The prevalence in the rural
      area (1.89%) was higher than that in the urban area (0.81%) (P < 0.01). The
      prevalence in Shenyang city (1.66%) was higher than those in Dalian city (0.88%)
      (P < 0.01) and Jinzhou (0.71%) (P < 0.01) city. Risk factor analysis showed that
      24.7% of the asthmatics had family history; 20.4% had allergic history, the OR of
      allergic rhinitis being 6.28; 26.0% had smoking history; the OR of cooking oil
      smoke exposure was 5.94. Asthmatic attack was induced by influenza, cold air,
      irritant gases and cooking oil smoke in 52.3% approximately 63.3% of the
      patients. Asthma induced by exercising, fatigue, emotion and allergy was found in
      more than 41.3% of the patients. CONCLUSIONS: Our epidemiologic data reflected
      the general distribution of asthma in Liaoning province. From the overall
      prevalence rate, it is estimated that there are about 529 700 asthmatics in the
      whole province. The data will be helpful for the mass prevention and treatment of
      asthma.

PMID- 12490128
TI  - [Drug resistance and genotyping of Klebsiella pneumoniae in lower respiratory
      tract infection].
AB  - OBJECTIVE: To understand the current drug resistance of Klebsiella pneumoniae in
      lower respiratory tract infection and the prevalence trend of extended spectrum
      beta-lactamase (ESBLs)-producing Klebsiella pneumoniae. METHODS: Drug resistance
      in 86 strains of Klebsiella pneumoniae and ESBLs-producing strains were genotyped
      by randomly amplified DNA polymorphisms (RAPD). RESULTS: ESBLs-producing strains
      accounted for 20.9% of the 86 strains, and 83.3% of the ESBLs-producing strains
      were from respiratory ICU. The drug resistance rate of ESBLs positive bacteria
      was much higher than that of ESBLs negative bacteria. ESBLs positive bacteria
      were resistant to both the quinolones and a minoglylosides. Eighteen ESBLs
      producing strains were divided into 12 types. 3 strains had the same profile
      (genotype A), and 5 strains had an identical profile (genotype B), but other
      strains had different profiles. CONCLUSIONS: Chromosomal DNA analysis proved that
      certain types of ESBLs-producing Klebsiella pneumoniae were epidemic in
      respiratory ICU. RAPD was an economic, simple but reliable method in epidemic
      study.

PMID- 12490129
TI  - [Retrospective analysis of seven cases of pulmonary cryptococcosis].
AB  - OBJECTIVE: To understand the diagnosis and treatment of pulmonary cryptococcosis.
      METHODS: Patients diagnosed as having pulmonary cryptococcosis in the past 15
      years were retrospectively studied. Their demographic data, respiratory symptoms,
      diagnostic methods, chest radiograph, immune state, antifungal therapy and follow
      up results were analyzed. RESULTS: Thirty cases of cryptococcosis were diagnosed,
      of which 7 were diagnosed as having pulmonary cryptococcosis, one of them
      presented with concomitant meningitis. Of the 7 patients, 4 were male and 3 were
      female, with a median age of 41.8. All were HIV negative; one case was
      immunocompromised with a history of colon cancer and glucocorticoid therapy for 8
      months, while others were immunocompetent. Three patients complained of low fever
      or cough and sputum, while 4 others presented no symptoms. The X-ray and chest CT
      showed unilateral or bilateral patches, nodules or cavities. The diagnosis was
      made by pathology and bacterial culture of sputum or bronchoalveolar lavage
      fluid. Amphotericin B plus flucytosine were initially given to 4 patients, all of
      them developed liver and renal abnormalities to some degree after therapy. Three
      patients were given fluconazole or itraconazole initially. All the 7 patients
      with pulmonary cryptococcosis responded favorably to antifungal therapy and the
      prognosis was good. CONCLUSIONS: Clinically pulmonary cryptococcosis was less
      common than cryptococcal meningitis. Pathology and cryptococcal culture were
      essential to the diagnosis. For immunocompetent patients with pulmonary
      cryptococcosis, the prognosis was good.

PMID- 12490130
TI  - [A study of the expression of CD(44) in pneumocytes in pulmonary sarcoidosis].
AB  - OBJECTIVE: To study the expression of CD(44) in pneumocytes in pulmonary
      sarcoidosis. METHODS: CD(44) and AE(1)/AE(3) were detected by immunostaining in
      lung tissues from 21 cases of pulmonary sarcoidosis, 5 cases of tuberculosis, 4
      cases of idiopathic interstitial fibrosis, 3 cases of Wegener's granulomatosis
      and 8 normal controls. The numbers of CD(44) positive cells and AE(1)/AE(3)
      positive cells (total alveolar epithelial cells) per three high-power fields were
      counted, and the ratio of CD(44) cells to AE(1)/AE(3) cells (84 +/- 6) were
      calculated. RESULTS: The total number of alveolar epithelial cells (110 +/- 32)
      and the density of CD(44) cells were significantly higher in sarcoidosis than in
      the normal lungs. CD(44) (18 +/- 4) staining was localized in the pneumocyte
      membrane and the positive cells were mostly type II pneumocytes as confirmed by
      histology. CONCLUSION: Proliferation of pneumocytes and increased expression of
      CD(44) in pneumocyte membrane, especially in the type II pneumocytes, may play an
      important role in lung inflammation and repair in pulmonary sarcoidosis.

PMID- 12490131
TI  - Effect of chronic methanol administration on amino acids and monoamines in
      retina, optic nerve, and brain of the rat.
AB  - The clinical and electroretinographic features of chronic methanol intoxication
      are scarce, and neurotransmitter studies have not been conducted. In addition,
      most of the studies in the field include results after acute administration. In
      the present work, a chronic methanol intoxication scheme (2 g/kg/day ip for 2
      weeks) was carried out in Sprague-Dawley rats previously depleted of folates with
      methotrexate. Taurine (2%) in drinking water was also administered in two groups
      of animals. Blood formate levels were increased in methotrexate-methanol-treated
      animals with respect to controls (0.98 +/- 0.09 and 0.30 +/- 0.03 mM,
      respectively). Amino acids and monoamines were determined in plasma and in
      retina, optic nerve, hippocampus, and posterior cortex by HPLC with fluorescence
      or electrochemical detection. The main finding was an increased aspartate content
      in the optic nerve in methotrexate methanol-treated animals. Methanol alone
      increased glutamate, aspartate, glutamine, taurine, 5-hydroxytryptamine, and 5
      hydroxyindoleacetic acid levels in the hippocampus and 5-hydroxytryptamine in the
      retina. Taurine administration had no significant effect on changes induced by
      methanol treatment. We concluded that chronic methanol administration produced
      accumulation of aspartate, an excitotoxic amino acid, in the optic nerve. These
      findings contribute to the understanding of methanol neurotoxicity and might
      indicate a relationship between chronic methanol consumption and the development
      of optic neuropathies.

PMID- 12490132
TI  - Doxorubicin induces an increase of nitric oxide synthesis in rat cardiac cells
      that is inhibited by iron supplementation.
AB  - Doxorubicin is an anthracycline antibiotic generally used in the treatment of
      solid tumors, but its use is limited by a severe cardiotoxicity, which has been
      related to the generation of oxygen- and nitrogen-derived free radicals. We have
      demonstrated that doxorubicin induces nitric oxide (NO) synthesis in the rat
      cardiac cells H9c2: the drug, after a 24-h incubation, evoked a dose-dependent
      increase of both NO synthase (NOS) activity in the cells and nitrite levels in
      the culture supernatant; the accumulation of nitrite (a stable derivative of NO)
      was prevented by different NOS inhibitors. The increase of NO production was
      associated with an increased expression of the inducible NOS isoform gene. These
      effects were significantly inhibited by the coincubation of doxorubicin with iron
      nitrilotriacetate, a compound that releases iron into the cells. Our results
      suggest that doxorubicin could induce NO generation in cardiac cells by modifying
      the iron homeostasis.

PMID- 12490133
TI  - Effect of caffeine on acetaminophen hepatotoxicity in cultured hepatocytes
      treated with ethanol and isopentanol.
AB  - Pretreatment of cultured rat hepatocytes with ethanol alone or in combination
      with isopentanol, the major higher chain alcohol in alcoholic beverages,
      significantly increased CYP3A and acetaminophen (APAP) bioactivation, with no
      increase in APAP toxicity. Caffeine has previously been shown to activate CYP3A
      activity in vitro and to increase APAP hepatotoxicity in rodents pretreated with
      prototypic inducers of CYP3A. Here we found that caffeine enhanced APAP toxicity
      in cultured rat hepatocytes pretreated with the alcohols. The caffeine-mediated
      increase in APAP toxicity was similar in cells treated with ethanol or
      isopentanol alone or in combination. These findings suggest that even small
      increases in CYP3A are sufficient to support caffeine-enhanced APAP toxicity.
      Triacetyloleandomycin inhibited CYP3A activity in intact hepatocytes and
      protected alcohol-pretreated cells from caffeine enhancement of APAP toxicity.
      This protection was associated with decreased formation of the toxic metabolite
      of APAP. The results indicate that CYP3A is responsible for the caffeine-mediated
      stimulation of APAP toxicity. Our results suggest that caffeine may be an
      additional risk factor for developing alcohol-mediated APAP hepatotoxicity.

PMID- 12490134
TI  - Induction of anti-metallothionein antibody and mercury treatment decreases bone
      mineral density in mice.
AB  - Mercuric chloride (HgCl2) is an industrial agent with toxic effects on the immune
      system, kidney, lung, and nervous tissue, but little is known about its effect on
      bone. Metallothionein (MT) is a cysteine-rich metal-binding protein that exerts
      cytoprotective effects against heavy metal toxins. It has been reported that the
      susceptibility of renal and pulmonary toxicity of mercury was markedly enhanced
      in MT-null mice compared to control mice. However, there is no report about the
      effects of anti-metallothionein (anti-MT) Ab induction on mercury toxicity. We
      investigated the effect of anti-MT Ab induction on mercury-induced bone injury.
      BALB/c mice were injected with MT (10 microg/mouse ic) five times to induce anti
      MT Ab and then treated with HgCl2 (1 mg/kg sc) three times per week for 3 weeks.
      MT immunization plus HgCl2 treatment dramatically decreased bone mineral density
      (BMD), and the humoral bone formation indices, alkaline phosphatase (ALP)
      activity and osteocalcin. MT immunization or HgCl2 treatment alone did not affect
      either BMD or serum ALP activity and osteocalcin levels. MT immunization impeded
      HgCl2-induced increase of MT expression in the liver and led to an increase of
      mercury in serum and the liver but a decrease in the kidney. Furthermore, serum
      titers of IgE and IgG1 were significantly elevated in the MT-immunized plus HgCl2
      treatment group compared with those in the HgCl2 treatment group. Similar results
      were also observed in splenic secretions of IL-4 and IL-10 based on anti-CD3 Ab
      stimulation. Taken together, our results indicate that anti-MT Ab induction
      causes mercury-induced bone injury in BALB/c mice and also enhances mercury
      related immune disorders.

PMID- 12490135
TI  - Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
      type glutamate receptors elicits neuroprotection after trimethyltin exposure in
      hippocampus.
AB  - The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type
      glutamatergic receptors have been linked to survival signaling, especially when
      the receptors are allosterically modulated by members of the Ampakine family.
      While increased glutamatergic communication through AMPA receptors has been shown
      to protect against toxic conditions that target hippocampal subfield CA1,
      protection in other subfields has not been shown. Accordingly, positive
      modulation of AMPA receptors by Ampakine compounds CX727 and CX516 was tested for
      effects on trimethyltin (TMT) neurotoxicity in rat hippocampal slice cultures.
      TMT was applied for 4 h followed by a rapid washout and antagonistic quenching of
      AMPA and N-methyl-D-aspartate (NMDA) receptors. After a 24-h period, the TMT
      exposed slices exhibited increased levels of calpain-mediated spectrin breakdown
      as well as synaptic deterioration. TMT selectively targeted CA3 pyramidal neurons
      and dentate gyrus (DG) granule cells as evidenced by degeneration and neuronal
      loss. The cytoskeletal and synaptic damage was reduced when Ampakine modulation
      was initiated during the postinsult period. Furthermore, the extent of protection
      was comparable to that produced by the NMDA receptor antagonist AP5. The above
      results were substantiated by histological experiments, revealing that Ampakine
      treatment prevented TMT-induced cell loss in CA3 and DG. These results indicate
      that AMPA receptor signals are part of cellular repair responses following
      exposure to an environmental toxin.

PMID- 12490136
TI  - Death receptor response in rodent testis after mono-(2-ethylhexyl) phthalate
      exposure.
AB  - Apoptosis of testicular germ cells is critical for the maintenance of functional
      spermatogenesis. Previously, we have demonstrated that the Fas (Apo-1, CD95)
      receptor participates in the regulation of germ cell apoptosis, particularly
      after toxicant-induced Sertoli cell injury. In this study, we show that germ
      cells from B6.SMNC3H-Fas(gld,gld) (gld) mice that express a dysfunctional form of
      FasL still undergo significant apoptosis, albeit at a lower incidence than seen
      in B6 mice, following mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell
      injury. In addition, we show the presence of Fas, TRAIL-R1 (Death Receptor-4,
      DR4), and TRAIL-R2 (DR5) in the testis of C57BL/6 (B6) and gld mice (4 weeks
      old), and Sprague-Dawley rats (5 weeks old) and their responsiveness after MEHP
      treatment. More importantly, Western blot analysis of cellular fractions showed
      an increase in death receptor localization on the membrane fractions taken from
      Sprague-Dawley rats. Immunohistochemical analysis indicated localization of Fas
      and DR5 primarily to the spermatocyte subpopulation of germ cells. Examination of
      downstream receptor-mediated signals (i.e., cleavage of procaspase-8 and NFkappaB
      activation) revealed an early increase in NFkappaB-DNA binding and an increase in
      procaspase-8 processing in mutant gld mice. In summary, germ cell-associated
      death receptors, as well as downstream signaling elements, appear to be
      responsive to MEHP-induced Sertoli cell injury. Whether this is directly
      responsible for the increases in germ cell apoptosis after MEHP exposure is yet
      to be determined. The observed robust and early increase in Fas in wild-type
      testis and diminished rates of germ cell apoptosis in mutant testis (gld and
      lpr(cg)) reiterates the importance of the Fas signaling pathway.

PMID- 12490137
TI  - Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial
      butter flavoring.
AB  - As the result of a high prevalence of fixed airways obstruction in workers at a
      microwave popcorn manufacturing plant, we examined the hypothesis that vapors of
      butter flavoring used in the manufacture of microwave popcorn and other foods can
      produce airway injury in rats. Rats were exposed to vapors liberated from heated
      butter flavoring. Rats were exposed for 6 h by inhalation and were necropsied 1
      day after exposure. The exposure was found by GC-MS analysis to be a complex
      mixture of various organic gases with the major peaks consisting of diacetyl (2,3
      butanedione), acetic acid, acetoin (3-hydroxy-2-butanone), butyric acid, acetoin
      dimers, 2-nonanone, and delta-alkyl lactones. Diacetyl was used as a marker of
      exposure concentration. In the lung, butter flavoring vapors containing 285-371
      ppm diacetyl caused multifocal, necrotizing bronchitis, which was most
      consistently present in the mainstem bronchus. Alveoli were unaffected. Butter
      flavoring vapors containing 203-371 ppm diacetyl caused necrosuppurative
      rhinitis, which affected all four levels of the nose. Within the posterior two
      nasal levels (T3 and T4), necrosis and inflammation was principally localized to
      the nasopharyngeal duct. Control rats were unaffected. Therefore, concentrations
      of butter flavoring vapors that can occur during the manufacture of foods are
      associated with epithelial injury in the nasal passages and pulmonary airways of
      rats.

PMID- 12490138
TI  - Aromatic hydrocarbon receptor expression and function in liver of
      hypophysectomized male rats.
AB  - The aromatic hydrocarbon receptor (AHR) acts as a ligand-activated transcription
      factor that mediates many of the biological responses to aromatic hydrocarbons,
      such as 3-methylcholanthrene (MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
      Some toxic effects are thought to be the result of AHR-mediated changes in the
      expression of endocrine-related genes, such as the estrogen receptor and genes
      involved in cell growth and differentiation. Since little is known about
      endocrine factors that regulate AHR expression and function, we evaluated the
      effect of hypophysectomy (hypx) on these parameters in the liver of male rats.
      Cytosolic AHR immunoreactive protein was reduced in hypx rats to 61% of levels in
      sham-operated rats. Sucrose density gradient analysis of cytosolic AHR
      radioligand binding using a saturating concentration of [3H]TCDD showed that
      ligand binding was reduced in hypx rats to 31% of sham levels. TCDD showed
      similar potency for transforming cytosolic AHR from hypx and sham rats to a DNA
      binding form; however, maximal AHR DNA-binding was reduced in hypx rats to 57% of
      sham levels, although this did not achieve statistical significance. These
      changes observed at the protein level were not accompanied by a corresponding
      decrease in hypx rats of mRNA for AHR or the AHR nuclear translocator. Despite
      this change in AHR protein level, hypx rats were not compromised in hepatic
      cytochrome P450 1A1 induction following in vivo administration of MC. These data
      indicate that the AHR signaling pathway is intact in hypx rats and that a
      pituitary factor regulates hepatic AHR expression at the protein level.

PMID- 12490139
TI  - T lymphocytes are direct, aryl hydrocarbon receptor (AhR)-dependent targets of
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): AhR expression in both CD4+ and CD8+
      T cells is necessary for full suppression of a cytotoxic T lymphocyte response by
      TCDD.
AB  - The cellular basis for the potent suppression of T cell-mediated immune responses
      in mice following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is not
      fully understood. Although activation of the aryl hydrocarbon receptor (AhR) is
      required, the specific AhR+ cells that transduce the suppression have been
      difficult to identify in vivo. The recent availability of AhR-/- mutant mice has
      provided a resource for novel approaches to investigate the direct targets of
      TCDD. In our studies, we used an in vivo acute graft versus host (GVH) model of T
      cell immunity to address the direct AhR-dependent effects of TCDD on T cells. In
      this model, T cells from C57B1/6 mice are injected into C57B1/6 x DBA/2 F1 host
      mice. The injected T cells recognize the MHC disparity of the host cells,
      resulting in the generation of an antihost cytotoxic T lymphocyte (CTL) response.
      By comparing the ability of TCDD to suppress the CTL response of T cells obtained
      from AhR+/+ and AhR-/- C57B1/6 mice, the need for AhR expression in T cells
      themselves could be assessed. The results of these studies showed that the CTL
      response of T cells from AhR+/+ mice was highly suppressed when the F1 host mice
      were treated with 15 microg/kg TCDD. TCDD treatment also protected the F1 host
      mice from the loss of body weight that accompanies the induction of the GVH
      response. In contrast, when grafted T cells were derived from AhR-/- mice, there
      was no suppression of the CTL response by TCDD, and the host animals lost
      significant body weight. Furthermore, when T cells from AhR+/+ and AhR-/- mice
      were separated into CD4+ and CD8+ subsets and recombined using one subset from
      each donor prior to injection into the F1 host, suppression of the CTL response
      by TCDD was still apparent, but the degree of suppression was significantly
      reduced when either subset was AhR-/-. These results indicate that direct AhR
      dependent effects of TCDD occur in both CD4+ and CD8+ T cell subsets and both T
      cell subsets contribute to the full suppression of the CTL response by TCDD.

PMID- 12490140
TI  - On-line moisture determination of ore concentrates 'a review of traditional
      methods and introduction of a novel solution'.
AB  - The manual gravimetric drying moisture determination methods currently employed
      by most mineral processing plants fail to provide timely and accurate information
      required for automatic control. The costs associated with transporting and
      handling concentrates still represent a major portion of the overall treatment
      price. When considering the cash flow of a mining operation that is governed by
      both the smelter contract, with moisture penalties and the quantity and quality
      of the concentrates shipped, an efficient method of on-line moisture content
      would be a welcome tool. A novel on-line determination system for ore concentrate
      moisture content would replace the tedious manual procedure. Since the
      introduction of microelectronic-based control systems, operators have strived to
      reduce the treatment costs to the minimum. Therefore, a representative and timely
      determination of on-line moisture content becomes vital for control set points
      and timely feedback. Reliable sensors have long been on the 'wish list' of
      mineral processors since the problem has always been that you can only control
      what you can measure. Today, the task of moisture determination is still done by
      the classical technique of loss in weight utilizing uncontrolled procedures.
      These same methods were introduced in the earliest base metal concentrators.
      Generally, it is acceptable to have ore concentrate moisture content vary within
      a range of 7-9%, but controlling the moisture content below 8% is a difficult
      task with a manually controlled system. Many times, delays in manually achieving
      reliable feedback of the moisture content results in the moisture varying from 5
      12% before corrective actions can be made. This paper first reviews the
      traditional and widely available methods for determining moisture content in
      granular materials by applying physical principles and properties to measure
      moisture content. All methods are in some form affected when employed on mineral
      ore concentrates. This paper introduces and describes a novel on-line moisture
      sensor employed for mineral processing de-watering applications, which not only
      automates the tedious tasks but also results in reliable moisture feedback that
      can be used in the optimization of the de-watering process equipment such as
      pressure or vacuum filters and fuel-fired driers. Finally, two measurement
      applications will be presented which indicate the usefulness and summarizes the
      measurement requirements for the proposed method of employing drag force and
      mechanical properties of the material itself to determine the moisture content.

PMID- 12490141
TI  - Detection of hepatopancreatic parvovirus (HPV) infection in Penaeus monodon using
      PCR-ELISA.
AB  - A rapid and sensitive PCR-ELISA has been developed for detection of
      hepatopancreatic parvovirus (HPV) in Penaeus monodon. The specific primer set
      amplified 156 bp fragment and could detect as a little as 0.01 fg of purified HPV
      DNA which equivalent to three viral particles. No cross-reactivity was observed
      when nucleic acid templates from white spot syndrome virus, yellow-head virus,
      monodon baculovirus and shrimp were tested. The crude DNA simple prepared from
      hepatopancreas can be used as DNA template and provide a favorable result. Using
      this technique for detection of HPV infection in 87 carrier shrimps revealed the
      higher sensitivity and efficiency of detection when compared to histological
      examination and conventional PCR. Sixty-two percent infection was detected by PCR
      ELISA from samples with HPV negative diagnosed by histological examination.
      Therefore, this sensitive and specific method is promisingly useful for early
      detection of HPV infection in broodstock, carriers and for ex situ application
      where large numbers of samples can be analyzed simultaneously.

PMID- 12490142
TI  - Development of a PCR-based method for diagnosis of Leishmania in blood samples.
AB  - Visceral Leishmaniasis (VL) cases reported in Mediterranean countries and in
      Northern Europe are becoming increasingly frequent. The past few years several
      studies have shown Polymerase Chain Reaction to be more effective than the
      classical methods for the diagnosis of VL in clinical samples. The purpose of
      this study was the development of a simple, specific and sensitive PCR-based
      assay for the detection of Leishmania in blood samples. A specific pair of
      oligonucleotides was designed using conserved sequences of the ssu-rRNA
      Leishmania infantum gene. Of the 53 blood samples of patients suspected for
      leishmaniasis that were processed with the newly designed oligonucleotides, 13
      were successfully diagnosed positive. The results were confirmed with sequencing
      and restriction fragment length polymorphism. The lower detection limit of the
      reported assay was 10 parasites per ml in all seeded samples tested and
      considered highly satisfactory for diagnosis of Leishmaniasis in blood samples.

PMID- 12490143
TI  - Variant screening of PRKAB2, a type 2 diabetes mellitus susceptibility candidate
      gene on 1q in Pima Indians.
AB  - The AMP-activated protein kinase (AMPK) is a key enzyme involved in the
      regulation of lipid and glucose metabolism. There are multiple isoforms of the
      three subunits of this enzymatic complex, each encoded by a different gene in
      humans. We have investigated the PRKAB2 gene encoding the beta2 subunit, which is
      located on chromosome 1q within a region linked with type 2 diabetes mellitus
      (T2DM) in the Pima Indians and four different Caucasian populations. The gene
      consists of eight exons spanning about 15 kb, and we detected nine variants in
      the introns and 3' UTR, including eight informative single nucleotide
      polymorphisms (SNPs) and one rare 4 bp insertion/deletion. In an analysis of
      representative markers in selected Pima Indians including 149 diabetic cases
      (onset age < 25 years) and 150 controls (at least 45 years old, with normal
      glucose tolerance), we found no evidence for association of this locus with T2DM.
      We conclude that variants in PRKAB2 are unlikely to contribute to the disease
      susceptibility in Pima Indians.

PMID- 12490144
TI  - Quantitative technologies for allele frequency estimation of SNPs in DNA pools.
AB  - We have compared several genotyping methods to assess their applicability to
      single nucleotide polymorphism (SNP) allele frequency estimation in DNA pools.
      The accuracy of these methods (restriction fragment length polymorphism, real
      time pyrophosphate DNA sequencing, single base extension with fluorescently
      labeled ddNTPs, homogeneous 5'-nuclease assay, and MALDI-TOF mass spectrometry)
      was tested by calculating the standard deviation among heterozygous individuals
      (which are natural DNA pools with 50% representation of each allele) and by
      estimating allele frequency in artificial pools. We show that although the
      methods differ in their accuracy, they can all serve for quantification of allele
      frequency in DNA pools with reasonable accuracy. We found that the influence of
      the error variance attributed to pool construction on quantification accuracy is
      insignificant and is SNP dependent.

PMID- 12490145
TI  - Species-specific detection of three human-pathogenic microsporidial species from
      the genus Encephalitozoon via fluorogenic 5' nuclease PCR assays.
AB  - This study describes fluorogenic 5' nuclease PCR assays suitable for rapid,
      sensitive, high-throughput detection of the human-pathogenic microsporidial
      species Encephalitozoon hellem, E. cuniculi and E.intestinalis. The assays
      utilize species-specific primer sets and a genus-specific dual fluorescent
      labeled probe that anneals to a region within the Encephalitozoon 16S rRNA gene.
      The assay design theoretically permits the probe to be used either with one set
      of primers for species-level determination or with a combination of all three
      primer sets for a genus-level screening of samples. The linear range of all three
      species-specific calibration curves that were developed using serial ten-fold
      dilutions of genomic DNA isolated from hemacytometer counted spores was
      determined to be between 10(4) and 10(-1) spores per PCR sample. The coefficients
      of variation were < or =5.2% over the entire 5-log span of each calibration
      curve. When DNA isolated from flow cytometric enumerated spores from each of the
      three Encephalitozoon species was used to evaluate the quantitative capability of
      the species' respective calibration curves, the results from 34 out of 36 (94%)
      samples were within 2 standard deviations. The species-specificity of each assay
      was confirmed using DNA isolated from 10(4) spores from each of the other two
      Encephalitozoon species as well as DNA extracted from numerous other protozoa,
      algae and bacteria.

PMID- 12490146
TI  - Comparison of DNA and RNA extraction methods for mummified tissues.
AB  - Nucleic acids extracted from mummified tissues are valuable materials for the
      study of ancient human beings. Significant difficulty in extracting nucleic acids
      from mummified tissues has been reported due to chemical modification and
      degradation. The goal of this study was to determine a method that is more
      efficient for DNA and RNA extraction from mummified tissues. Twelve mummy
      specimens were analyzed with 9 different nucleic acid extraction methods,
      including guanidium thiocyanate (GTC) and proteinase K/detergent based methods
      prepared in our laboratory or purchased. Glyceraldehyde 3-phosphate dehydrogenase
      DNA and beta-actin RNA were used as markers for the presence of adequate DNA and
      RNA, respectively, for PCR and RT-PCR amplification. Our results show that 5 M
      GTC is more efficient of releasing nucleic acids from mummified tissue than
      proteinase K/detergent, and phenol/chloroform extraction with an additional
      chloroform step is more efficient than phenol/chloroform along. We were able to
      isolate DNAs from all 12 specimens and RNAs from 8 of 12 specimens, and the
      nucleic acids were sufficient for PCR and RT-PCR analysis. We further tested
      hepatitis viruses including hepatitis B virus, hepatitis C virus, hepatitis G
      virus, and TT virus DNA, and fail to detect these viruses in all 12 specimens.

PMID- 12490147
TI  - EMBO workshop "The functional organization of the cell nucleus" held in Prague,
      Czech Republic, April 18 to 21, 2002.

PMID- 12490148
TI  - Actin in the nucleus: what form and what for?
AB  - Actin is an abundant protein in most nonmuscle cells. It has often been observed
      in isolated nuclei, yet cytoplasmic contamination was of course initially
      regarded as the most plausible origin. Numerous studies on nuclear actin appeared
      in the 1970s and 1980s, but the picture remained rather muddy. The viewpoint at
      that time was that actin-shown to move freely between cytoplasm and nucleus-was a
      mere "thermodynamic wanderer," transiently occupying the nucleus. More recently,
      evidence has been mounting that actin's presence in the nucleus is not simply
      governed by the laws of diffusion. The same holds true for the finding of various
      actin-related proteins in the nucleus, and the case for nuclear myosin,
      specifically myosin I, is now quite convincing. Moreover, the first intimations
      of functional roles of nuclear actin are now emerging. Here we examine the
      overall subject from cell biological and chemical perspectives. The major issue
      is no longer the presence of actin in the nucleus but rather its supramolecular
      organization, intranuclear locations, and, of course, functions. These issues
      interface with recent findings that reveal a surprisingly diverse repertoire of
      actin conformations and oligomer and polymer forms beyond monomeric G-actin and
      polymeric F-actin. We present ideas for advancing the nuclear actin field and
      call for a renewed attack on this major problem in cell biology.

PMID- 12490149
TI  - HP1: facts, open questions, and speculation.
AB  - The demonstration, over a decade ago, that HP1 is a highly conserved constituent
      of heterochromatin was accompanied by the explicit view that this protein plays a
      pivotal role in epigenetic regulation (P.B. Singh, J.R. Miller, J. Pearce, R.
      Kothary, R.D. Burton, R. Paro, T.C. James, and S.J. Gaunt, 1991, Nucleic Acids
      Res. 19, 789-794). Recent studies have confirmed this view, unveiling specific
      interactions of HP1 with a variety of histone and nonhistone proteins. We discuss
      here some of these observations, concentrating on structure-function
      relationships and intracellular dynamics. Integrating the available information,
      we also present a hypothetical model describing how HP1, acting as a bifunctional
      cross-linker, could organize peripheral heterochromatin and contribute in the
      compartmentalization of the cell nucleus.

PMID- 12490150
TI  - Initiation of DNA replication in multicellular eukaryotes.
AB  - Three questions central to understanding the initiation of DNA replication in
      eukaryotes are: (1) Does DNA synthesis begin at a defined place? (2) What
      determines replication initiation sites? (3) What regulates an origin to fire
      only once per cell cycle? A key player in this is the origin recognition complex
      (ORC), required for assembly of the pre-replication complex (pre-RC), that is
      converted later to the initiation complex (IC). In both yeast ARS1 and DNA puff
      II/9A of the metazoan fly Sciara, there is a defined start site of replication
      adjacent to an ORC-binding site. Although ORC has some inherent preference for
      certain DNA sequences, other factors may also modulate its binding to DNA. The
      preferred site where DNA synthesis starts at Sciara II/9A and the boundaries of
      the initiation zone change during development, when DNA puff amplification
      occurs. The position of the initiation zone may be influenced by the
      transcriptional machinery and/or chromatin structure. With regard to the third
      question, rereplication of the whole genome in yeast occurs when components of
      the pre-RC are stabilized by mutation. In contrast, a locus-specific
      amplification factor probably exists to account for site-specific DNA
      amplification in flies.

PMID- 12490151
TI  - The architecture of interphase chromosomes and nucleolar transcription sites in
      plants.
AB  - Fluorescence in situ hybridization (FISH) coupled with confocal microscopy has
      been used to reveal the interphase chromosome organization in plants. In wheat
      and several other related species, we have shown that the interphase chromosomes
      are in a very well-defined organization, with centromeres and telomeres located
      at opposite sides of the nuclear envelope-a classic Rabl configuration. In
      transgenic wheat lines, FISH analysis of metaphase chromosomes has shown that
      multiple transgene copies can be integrated along a single chromosome, with large
      regions of intervening genomic sequence. These multiple copies are often
      colocalized in interphase, suggesting either an ectopic association or a highly
      reproducible interphase chromatin configuration. Bromo-uridine (BrU)
      incorporation has been used to label transcription sites in the nucleolus. Using
      pea root tissue, we have combined BrU incorporation with preembedding 1-nm gold
      detection to image the nucleolar transcription sites by electron microscopy. This
      has revealed many distinct elongated clusters of silver-gold particles. These
      clusters are 200-300 nm in length and are thicker at one end than the other. We
      suggest that each cluster corresponds to a single transcribed gene. Serial
      sectioning of several entire nucleoli has enabled the reconstruction of all the
      nucleolar transcription sites, and we have estimated that there are 200-300
      transcribed genes per nucleolus.

PMID- 12490152
TI  - In vivo functional dissection of human inner kinetochore protein CENP-C.
AB  - CENP-C is a fundamental component of the inner kinetochore plate and contributes
      to the formation of functional centromeres in eukaryotic organisms. Recruitment
      of CENP-C to kinetochore requires other centromere proteins, particularly CENP-A,
      CENP-H, and CENP-I. However, how CENP-C is correctly localized at the kinetochore
      is not clearly determined, mainly due to the functional variety of its domains,
      which hints at a complex recruitment mechanism. Here, by both immunofluorescent
      labeling and chromatin/immunoprecipitation we could show that human CENP-C
      contains two distinct domains, one in the central region, between amino acids 426
      and 537, and the second one in the carboxyl terminal region, between amino acids
      638 and 943, which are both capable of localizing at centromeres and binding
      alpha-satellite DNA. The presence of two domains that iterate the same function
      despite being significantly different in their amino acid sequence and structure
      suggests that CENP-C may target the centromere by establishing multiple contacts
      with both the DNA and protein constituents of the kinetochore.

PMID- 12490153
TI  - Cyclin D-cdk6 complex is targeted by p21(WAF) in growth-arrested lymphoma cells.
AB  - Normal human B lymphocytes are sensitive to the growth-inhibitory action of
      transforming growth factor beta1 (TGFbeta1) whereas malignant B lymphoma cells
      are mostly resistant to TGFbeta1 effects. We examined the phosphorylation status
      of retinoblastoma protein and the activity of G(1) cyclin-dependent kinases (cdk)
      in TGFbeta1-sensitive malignant follicular lymphoma cells during the TGFbeta1
      treatment. The kinase activity of cdk2, cdk4, and cdk6 was significantly reduced
      and hypophosphorylation of pRb on serine 795 (S795) and threonine 373 (T373) was
      observed. We examined the composition of cdk complexes and the level of cdk
      inhibitors to explain the inhibitory action of TGFbeta1 toward cdk activity. Both
      cdk4 and cdk6 were notably dissociated from cyclin D cofactors, while cyclin E
      cdk2 complexes remained coupled in TGFbeta1-treated cells. TGFbeta1-induced
      growth arrest was associated with notably increased binding of p21(WAF1) to cdk4
      and cdk6. No induction of cdk-inhibitor molecules of INK family was observed in
      TGFbeta1-treated DoHH2 cells. As shown, TGFbeta1-induced growth arrest of
      malignant B cells was associated with the activation of CIP/KIP family members of
      cdk inhibitors.

PMID- 12490154
TI  - Expression of ISWI and its binding to chromatin during the cell cycle and early
      development.
AB  - We have characterized Xenopus ISWI, a catalytic subunit of a family of chromatin
      remodeling complexes. We show that ISWI is expressed constitutively during
      development but poorly expressed in adult tissues except oocytes which contain a
      large store of maternal protein. We further analyzed its localization both in
      vivo and in vitro in Xenopus cell cycle extracts and identified that ISWI binds
      to chromatin at the G1-S period. However, its association to chromatin does not
      require ongoing DNA replication. Immunodepletion of ISWI has no effect on either
      sperm chromatin decondensation or the kinetics and efficiency of DNA replication.
      Nucleosome assembly also occurs in ISWI-depleted extracts, but nucleosome spacing
      is disturbed. From these results, we conclude that ISWI is not necessary for
      sperm chromatin decondensation and the accelerated rates of DNA replication that
      characterize early development.

PMID- 12490155
TI  - Temporal regulation of Drosophila salivary gland degeneration by the Broad
      Complex transcription factors.
AB  - The destruction of obsolete larval tissues at the onset of insect metamorphosis
      is a complex process triggered by the steroid hormone ecdysone. Among the genes
      required for the implementation of salivary gland (SG) degeneration the reduced
      bristles on palpus (rbp) gene of the Broad-Complex (BR-C) locus plays a critical
      role. This gene encodes the BR-C Z1 transcription factor and its expression is
      directly regulated by ecdysone through the ecdysone receptor (EcR/Usp). The BR-C
      locus encodes four major protein isoforms, including BR-C Z1, Z2, Z3, and Z4.
      With the exceptions of mutations in BR-C Z1 all mutations affecting the other BR
      C isoforms produce pupal lethality. To gain insight into the function of the
      different BR-C isoforms on the process of SG degeneration, we used transgenes
      expressing each of the four major BR-C isoform proteins. This study revealed
      that, depending upon the period of expression relative to the major peak of
      ecdysone production, BR-C Z1, Z2, and Z4 first inhibited and then stimulated the
      process of SG degeneration. In contrast, BR-C Z3 exerted all time points an
      inhibition on SG degeneration.

PMID- 12490156
TI  - Myosin-like proteins 1 and 2 are not required for silencing or telomere
      anchoring, but act in the Tel1 pathway of telomere length control.
AB  - The positioning of chromosomal domains in interphase nuclei is thought to
      facilitate transcriptional repression in yeast. It has been reported that two
      large coiled-coil proteins of the nuclear envelope, myosin-like proteins 1 and 2,
      play direct roles in anchoring yeast telomeres to the nuclear periphery, thereby
      creating a subcompartment enriched for Sir proteins. We have created strains
      containing complete deletions of mlp1 and mlp2 genes, as well as the double null
      strain, and find no evidence for the disruption of telomere anchoring at the
      nuclear periphery in these cells. We also detect no disruption of telomere
      associated gene silencing. We confirm, on the other hand, that mlp mutants are
      particularly sensitive to DNA-damaging agents, such as bleomycin. Moreover, we
      show that rather than having short telomeres as in yKu-deficient strains, the
      mlp1 mlp2 strains have extended telomeres, resembling phenotypes of mutations in
      rif1. Whereas the mlp1 mlp2 mutations act on a pathway of telomere length
      regulation different from that of yKu70, the effects of the tel1 deletion are
      epistatic to the mlp mutations, suggesting that the Mlp proteins restrict
      telomere length in wild-type cells by influencing the Rif-Tel1 pathway of
      telomerase regulation.

PMID- 12490157
TI  - Quantitation of GFP-fusion proteins in single living cells.
AB  - The green fluorescent protein (GFP) has revolutionized cell biology. The ability
      to observe genetically encoded fluorescently tagged fusion proteins in intact
      cells has made virtually any biological process amenable to investigation in
      living cells. However, most in vivo imaging studies are qualitative and little
      information about the number of fluorescently labeled molecules observed in a
      cell or a cellular structure is available. This deficiency severely limits the
      interpretation of imaging experiments and it impedes the application of in vivo
      imaging methods for biophysical purposes. Here we describe a simple method for
      the quantitative determination of the number of GFP-tagged molecules in cellular
      structures in single living cells. The method is based on the use of rotavirus
      like particles containing a known number of GFP molecules as an internal
      calibration standard during in vivo imaging. We have applied this method to
      estimate in single living cells the number of fluorescent transcription factor
      molecules on RNA polymerase I and polymerase II genes. In addition, we have
      estimated the number of molecules for several proteins in subnuclear compartments
      and in exocytic vesicles. VLP-GFP calibration is a simple, convenient, rapid, and
      noninvasive method for routine quantification of GFP-labeled molecules in single,
      living cells.

PMID- 12490158
TI  - Investigation of nuclear architecture with a domain-presenting expression system.
AB  - We have investigated the topogenic properties of the nucleus by ectopic
      expression of chimeric proteins consisting of a NLS-modified cytoplasmic filament
      forming protein, Xenopus laevis vimentin, and domains of inner nuclear membrane
      proteins. Whereas the "carrier" without cargo, the NLS-vimentin alone, is
      deposited in a few nuclear body-type structures (J.M. Bridger, H. Herrmann, C.
      Munkel, P. Lichter, J. Cell Sci., 111, 1241-1253), the distribution is entirely
      changed upon coupling with the evolutionarily conserved domain of the lamin B
      tail, the entire lamin B tail, the amino-terminal nucleoplasmic segment of the
      lamin B receptor (LBR), and the LEM domain of emerin, respectively. Remarkably,
      every individual chimeric protein exhibits a completely different distribution.
      Therefore, we assume that the chimeric parts are specifically recognized by
      factors engaged in nucleus-specific topogenesis. Thus, the conserved domain of
      the lamin B tail results in the formation of many small accumulations spread all
      over the nucleus. The chimera with the complete lamin B tail is deposited in
      short fibrillar aggregates within the nucleus. It does not mediate the
      integration of the chimeric protein into the nuclear membrane in cultured cells,
      indicating that the lamin tail alone is not sufficient to direct the integration
      of a protein into the lamina in vivo. In contrast, in the nuclear assembly system
      of Xenopus laevis the recombinant NLS-vimentin-lamin tail protein is concentrated
      at the nuclear membrane. The LBR chimera is arranged in a "beaded-chain"-type
      fashion, quite different from the more random deposition of NLS-vimentin alone.
      To our surprise, the LEM domain of emerin induces the retention of most of the
      chimeric proteins within the cytoplasm. Hence, it appears to be engaged in a
      strong cytoplasmic interaction that overrides the nuclear localization signal.
      Finally, the lamin chimera with the conserved part of the lamin B tail is shown
      to recruit LBR to the nuclear vimentin bodies and, vice versa, the LBR chimera
      attracts lamin B in transfected cells, thereby demonstrating their bona fide
      interaction in vivo.

PMID- 12490159
TI  - Conservation of an open-reading frame as an element affecting 5' splice site
      selection.
AB  - Splice site selection is a key element of pre-mRNA splicing and involves specific
      recognition of consensus sequences at the 5(') and 3(') splice sites. Evidently,
      the compliance of a given sequence with the consensus 5(') splice site sequence
      is not sufficient to define it as a functional 5(') splice site, because not all
      sequences that conform with the consensus are used for splicing. We have
      previously hypothesized that the necessity to avoid the inclusion of premature
      termination codons within mature mRNAs may serve as a criterion that
      differentiates normal 5(') splice sites from unused (latent) ones. We further
      provided experimental support to this idea, by analyzing the splicing of pre
      mRNAs in which in-frame stop codons upstream of a latent 5(') splice site were
      mutated, and showing that splicing using the latent site is indeed activated by
      such mutations. Here we evaluate this hypothesis by a computerized survey for
      latent 5(') splice sites in 446 protein-coding human genes. This data set
      contains 2311 introns, in which we found 10490 latent 5(') splice sites. The
      utilization of 10045 (95.8%) of these sites for splicing would have led to the
      inclusion of an in-frame stop codon within the resultant mRNA. The validity of
      this finding is confirmed here by statistical analyses. This finding, together
      with our previous experimental results, invokes a nuclear scanning mechanism, as
      part of the splicing machine, which identifies in-frame stop codons within the
      pre-mRNA and prevents splicing that could lead to the formation of a prematurely
      terminated protein.

PMID- 12490160
TI  - Large nuclear RNP particles--the nuclear pre-mRNA processing machine.
AB  - Processing of nuclear pre-mRNA is an important step in the regulation of gene
      expression and involves 5(')- and 3(')-end processing, splicing, and editing.
      Mammalian nuclear pre-mRNAs are assembled in large ribonucleoprotein (lnRNP)
      complexes, in which the entire population of nuclear pre-mRNA is individually
      packaged until it is exported to the cytoplasm. The lnRNP particles are
      supraspliceosomal complexes. They are composed of four spliceosomal substructures
      and an additional one, which are interconnected by the pre-mRNA, and have an
      overall mass of 21MDa. The additional substructure was proposed to harbor
      additional processing activities, such as editing components that were shown to
      be associated with the lnRNP particles. Here we show that the cap-binding
      proteins (CBPs), CBP20 and CBP80, are associated with the lnRNP particles, as
      well as components of the 3(')-end-processing activity. These results, together
      with our previous demonstration of the association of splicing factors and A-to-I
      editing enzymes with lnRNP particles, support the view that the lnRNP particles
      are the nuclear pre-mRNA processing machine. Such a machine is required to
      execute the nuclear processing steps of the pre-mRNA in an accurate and regulated
      manner. The supraspliceosomal pre-mRNA processing machine, in which each
      substructure represents a functional spliceosome, provides a frame onto which the
      pre-mRNA is folded. It allows juxtaposition of exons about to be spliced, while
      introns are looped out of each of the respective spliceosomes. This model can
      account for regulated alternative splicing, which is a major source of protein
      versatility in mammals.

PMID- 12490161
TI  - Evidence that all SC-35 domains contain mRNAs and that transcripts can be
      structurally constrained within these domains.
AB  - A fundamental question of mRNA metabolism concerns the spatial organization of
      the steps involved in generating mature transcripts and their relationship to SC
      35 domains, nuclear compartments enriched in mRNA metabolic factors and poly A+
      RNA. Because poly A+ RNA in SC-35 domains remains after transcription inhibition,
      a prevailing view has been that most or all SC-35 domains do not contain protein
      encoding mRNAs but stable RNAs with nuclear functions and thus that these
      compartments do not have direct roles in mRNA synthesis or transport. However,
      the transcription, splicing, and transport of transcripts from a specific gene
      have been shown to occur in association with two of these 15-30 nuclear
      compartments. Here we show that virtually all SC-35 domains can contain specific
      mRNAs and that these persist in SC-35 domains after treatment with three
      different transcription-inhibitory drugs. This suggests perturbation of an mRNA
      transport step that normally occurs in SC-35 domains and is post-transcriptional
      but still dependent on ongoing transcription. Finally, even after several hours
      of transcription arrest, these transcripts do not disperse from SC-35 domains,
      indicating that they are structurally constrained within them. Our findings
      importantly suggest a spatially direct role for all SC-35 domains in the coupled
      steps of mRNA metabolism and transport.

PMID- 12490162
TI  - Nuclear structure and intranuclear retention of premature RNAs.
AB  - Eukaryotic cells are highly compartmentalized, each compartment being surrounded
      by a lipid bilayer. This membrane-based organization allows cells to use their
      volumes to encode information. The lack of intranuclear membranes suggested that
      the nucleus was largely devoid of structural organization. However, recent work
      has defined numerous specialized nuclear subdomains. Importantly, RNA processing
      factors do not display random distribution but cluster in defined nuclear bodies.
      Although these structures are well characterized morphologically, their function
      in relation to RNA metabolism remains elusive. In this review, we will discuss
      the putative participation of nuclear substructures in a quality control step of
      RNA biogenesis, the nuclear retention of premature RNA.

PMID- 12490163
TI  - New and old roles of the double-stranded RNA-binding domain.
AB  - RNA-binding proteins can strongly regulate and influence the cellular function
      and fate of an RNA molecule. Of the many described nucleic acid-binding domains,
      the double-stranded RNA-binding domain (dsRBD) is a highly specialized example
      found in a wide variety of proteins with diverse cellular functions. Mostly
      present in multiple copies and highly homologous to one another, the individual
      functional specificity of dsRBDs is now becoming apparent. Here we review recent
      evidence showing that single dsRBDs within individual proteins are capable of
      distinct in vivo functions. Not only does this enable dsRBD-containing proteins
      to increase their functional diversity but it also reveals novel and unexpected
      roles that dsRBDs can perform.

PMID- 12490164
TI  - The distribution of RNA polymerase II largest subunit (RPB1) in the Xenopus
      germinal vesicle.
AB  - We describe the localization of the largest subunit of RNA polymerase II (RPB1)
      in the oocyte nucleus of Xenopus laevis. A single oocyte nucleus contains 18
      lampbrush chromosomes, approximately 1500 extrachromosomal nucleoli, 50-100 Cajal
      bodies (CBs) and hundreds to thousands of B-snurposomes. CBs contain many factors
      involved in RNA transcription and processing, whereas B-snurposomes contain a
      subset of these factors involved in mRNA processing. Immunofluorescent staining
      demonstrates that most RPB1 is in the nucleoplasm and that the heptapeptide
      repeat comprising its carboxy-terminal domain (CTD) is not phosphorylated. A
      minor fraction of RPB1 is associated with the transcription units of the
      lampbrush chromosomes and is phosphorylated on serines 2 and 5 of the CTD.
      Another minor fraction occurs in CBs, which react with antibodies against
      unphosphorylated CTD repeats and repeats phosphorylated on serine 5. Although B
      snurposomes are stained by an antibody against phosphorylated RPB1 (mAb H5), we
      present evidence that this stain is due to cross-reaction with one or more SR
      proteins. We show that constructs consisting of 15-17 CTD heptapeptide repeats
      fused to glutathione-S-transferase are targeted rapidly and specifically to CBs
      but not to B-snurposomes after injection into the nucleus. The staining and
      targeting data define at least three distinct populations of RPB1 in the GV with
      different states of phosphorylation. We suggest that CBs play a unique role in
      RPB1 metabolism, possibly as sites for assembly or modification of transcription
      complexes.

PMID- 12490165
TI  - Cell cycle-dependent association of PML bodies with sites of active transcription
      in nuclei of mammalian cells.
AB  - Promyelocytic leukemia (PML) nuclear bodies constitute one class of intranuclear
      domains that may be directly involved in the expression of specific genes. Here
      we have analyzed the spatial relationship between PML bodies and sites of
      transcriptional activity by indirect immunofluorescence and confocal microscopy
      during the cell cycle. In unsynchronized mammalian cells approx 30% of PML bodies
      are spatially associated with transcription sites. These sites contain
      hyperphosphorylated RNA polymerase II, indicating active mRNA transcription
      tightly associated with the PML body. In G1 phase of the cell cycle more than 70%
      of PML bodies contain active transcription foci. A similarly high degree of
      colocalization (approx 80%) between PML bodies and sites of active transcription
      was also observed when the cells were exposed to interferon-gamma. We also show
      that the hypophosphorylated form of RNA polymerase II and the transcriptional
      coactivator CBP colocalize within PML bodies predominantly in G1. Our
      observations suggest that PML bodies may be recruited to nuclear sites of induced
      or up-regulated mRNA transcription where it may serve as a scaffold for factors
      involved in expression of specific genes.

PMID- 12490166
TI  - Mobile foci of Sp100 do not contain PML: PML bodies are immobile but PML and
      Sp100 proteins are not.
AB  - PML bodies are nuclear organelles that are associated with various diseases and
      are suggested to be involved in multiple cellular activities including
      transcriptional regulation, apoptosis, and antiviral defence. Because many
      proteins with different functions aggregate in PML bodies, it has also been
      suggested that these bodies function as nuclear depots. Some proteins
      consistently found in PML bodies may form a stable scaffold that regulates the
      recruitment of other proteins. Thus, some proteins might be stably integrated
      into PML bodies while others continuously exchange with the nucleoplasm. To study
      the dynamic properties of PML bodies and resident proteins, we constructed fusion
      proteins of Sp100, PML, and CBP with autofluorescent proteins. Using time-lapse
      imaging, we show that PML bodies exhibit little movement but that small foci that
      contain Sp100 but not PML are dynamic and fuse with PML bodies. Furthermore, we
      show by monitoring fluorescence recovery after photobleaching that Sp100, PML,
      and CBP are dynamic components of PML bodies. This suggests that these proteins
      do not play a strict structural role in these bodies but that they function at
      other sites in the nucleoplasm.

PMID- 12490167
TI  - Proteasome-dependent processing of nuclear proteins is correlated with their
      subnuclear localization.
AB  - Although proteasomes are abundant in the nucleoplasm little is known of
      proteasome-dependent proteolysis within the nucleus. Thus, we monitored the
      subcellular distribution of nuclear proteins in correlation with proteasomes. The
      proteasomal pathway clears away endogenous proteins, regulates numerous cellular
      processes, and delivers immunocompetent peptides to the antigen presenting
      machinery. Confocal laser scanning microscopy revealed that histones, splicing
      factor SC35, spliceosomal components, such as U1-70k or SmB/B('), and PML
      partially colocalize with 20S proteasomes in nucleoplasmic substructures, whereas
      the centromeric and nucleolar proteins topoisomerase I, fibrillarin, and UBF did
      not overlap with proteasomes. The specific inhibition of proteasomal processing
      with lactacystin induced accumulation of histone protein H2A, SC35, spliceosomal
      components, and PML, suggesting that these proteins are normally degraded by
      proteasomes. In contrast, concentrations of centromeric proteins CENP-B and -C
      and nucleolar proteins remained constant during inhibition of proteasomes.
      Quantification of fluorescence intensities corroborated that nuclear proteins
      which colocalize with proteasomes are degraded by proteasome-dependent
      proteolysis within the nucleoplasm. These data provide evidence that the
      proteasome proteolytic pathway is involved in processing of nuclear components,
      and thus may play an important role in the regulation of nuclear structure and
      function.

PMID- 12490169
TI  - On the formation of amplified nucleoli during early Xenopus oogenesis.
AB  - In Xenopus the genes for ribosomal RNA are selectively amplified during the early
      stages of oogenesis and give rise to over 1000 extrachromosomal nucleoli. These
      oocyte nucleoli are unique in that they contain very high copy numbers of rRNA
      genes, are not attached to chromosomes, and lack nonribosomal DNA. How the
      amplified rRNA genes induce the formation of multiple nucleoli is as yet poorly
      understood. To gain some more insight into this assembly process we have studied
      nucleolar development in early previtellogenic Xenopus oocytes. By using light
      and electron microscopic immunocytochemistry, in situ hybridization, and the TdT
      method for detection of DNA, we have identified three separate structural
      entities which are related to the three components of the functionally active
      nucleoli present in midsized oocytes. Besides fibrillar and granular bodies we
      describe a novel rod-like structure which contains the pol I-specific
      transcription factor UBF. Notably, rDNA emerges from these rods forming a
      filamentous layer. These results reinforce UBF's role as an architectural element
      involved in the spatial organization of the rRNA genes. We consider the rod-like
      rDNA/UBF complexes as extrachromosomal nucleolar organizers which are first
      juxtaposed to preformed fibrillar bodies before both elements gradually fuse into
      a coherent nucleolar structure.

PMID- 12490168
TI  - MAPKs entry into the nucleus at specific interchromatin domains in plant
      differentiation and proliferation processes.
AB  - Mitogen-activated protein kinases (MAPKs) are involved in the signaling of
      extracellular stimuli in eukaryotes, including plants. Different MAPKs have
      recently been shown to be expressed during plant cell proliferation and
      developmental processes such as pollen development and embryogenesis, but the
      structural subdomain where these MAPKs are targeted in the nucleus has not yet
      been characterized. We have determined the changes in the expression and
      subcellular localization of ERK homologues, proteins belonging to the MAPK
      family, and MAPK-active forms in two plant developmental processes which involved
      differentiation (pollen maturation) and proliferation (the initials of pollen
      embryogenesis). Immunofluorescence and immunogold labeling in the species studied
      showed that the progression of differentiation and proliferation was accompanied
      by an increase in the expression of ERKs and MAPK activation together with a
      translocation to the nucleus. Combining ultrastructural cytochemistry and
      immunogold for RNA and phosphorylated proteins we have identified the nuclear
      sites housing these MAPKs in areas of the interchromatin region enriched in RNA
      and phosphoproteins that include clusters of interchromatin granules. This could
      suggest a role of these MAPKs in the early events of activation of the
      transcription and processing machinery, via phosphorylation, which subsequently
      would be recruited to the transcription sites. The association of the nuclear
      localization of MAPKs with the progression through the cell cycle and the
      commitment toward differentiation in the two plant developmental processes can be
      correlated.

PMID- 12490170
TI  - Searching for active ribosomal genes in situ: light microscopy in light of the
      electron beam.
AB  - Light microscopy (LM) approaches are commonly used to attain a description of the
      cell structure. Even though LM, if compared to electron microscopy (EM),
      represents a very fast approach, its resolution is, in principle, much lower than
      in the case of EM. To improve the LM resolution, computational methods based on
      removal of the image blur are frequently implemented in cell biology studies. One
      of the standard deblurring approaches is image restoration through deconvolution
      algorithms. Even though this method of mathematical remodeling of microscopically
      observed objects represents an efficient tool of current cell biology, it is
      legitimate to ask what the limits of its use are. We demonstrate that, in the
      specific case of the fluorescence mapping of active ribosomal genes in HeLa cell
      nucleoli, restoration generates a biased result. On restoration of model images,
      we demonstrate the difficulties of one of the most effective deconvolution
      algorithms during the restoration of ring-shaped fluorescent objects of a
      diameter comparable to the microscope resolution limit. In the case involving the
      mapping of nucleolar transcription in HeLa cells, not the restored fluorescence
      images, but rather the EM images show the true distribution of active ribosomal
      genes.

PMID- 12490171
TI  - Transmission electron microscope studies of the nuclear envelope in
      Caenorhabditis elegans embryos.
AB  - Nuclear membranes and nuclear pore complexes (NPCs) are conserved in both animals
      and plants. However, the lamina composition and the dimensions of NPCs vary
      between plants, yeast, and vertebrates. In this study, we established a protocol
      that preserves the structure of Caenorhabditis elegans embryonic cells for high
      resolution studies with thin-section transmission electron microscopy (TEM). We
      show that the NPCs are bigger in C. elegans embryos than in yeast, with
      dimensions similar to those in higher eukaryotes. We also localized the C.
      elegans nuclear envelope proteins Ce-lamin and Ce-emerin by pre-embedding gold
      labeling immunoelectron microscopy. Both proteins are present at or near the
      inner nuclear membrane. A fraction of Ce-lamin, but not Ce-emerin, is present in
      the nuclear interior. Removing the nuclear membranes leaves both Ce-lamin and Ce
      emerin associated with the chromatin. Eliminating the single lamin protein caused
      cell death as visualized by characteristic changes in nuclear architecture
      including condensation of chromatin, clustering of NPCs, membrane blebbing, and
      the presence of vesicles inside the nucleus. Taken together, these results show
      evolutionarily conserved protein localization, interactions, and functions of the
      C. elegans nuclear envelope.

PMID- 12490172
TI  - Increased solubility of lamins and redistribution of lamin C in X-linked Emery
      Dreifuss muscular dystrophy fibroblasts.
AB  - Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the gene
      encoding the nuclear membrane protein emerin (X-linked EDMD) or in the gene
      encoding lamins A/C (autosomal dominant EDMD). One hypothesis explaining the
      disease suggests that the mutations lead to weakness of the nuclear lamina. To
      test this hypothesis we investigated lamin solubility and distribution in skin
      fibroblasts from X-EDMD patients. Using in situ extraction of cells and
      immunofluorescence microscopy or biochemical fractionation and immunoblotting, we
      found that all lamin subtypes displayed increased solubility properties in
      fibroblasts from X-EDMD patients compared to normal individuals. Lamin and emerin
      solubility was mildly increased in fibroblasts from an X-EDMD carrier.
      Biochemical fractionation and immunoblotting also indicated that lamin C but no
      other lamin became redistributed from the nuclear lamina to the nucleoplasm in X
      EDMD fibroblasts. Indirect immunofluorescence and confocal microscopy studies
      using lamin A- and lamin C-specific antibodies confirmed that lamin C but not
      lamin A became redistributed to the nucleoplasm. Interestingly, the lamin A/C
      binding protein LAP2alpha was also mislocalized in X-EDMD fibroblasts.

PMID- 12490173
TI  - Domain-specific antibodies reveal multiple-site topology of Nup153 within the
      nuclear pore complex.
AB  - Nup153, one of the best characterized nuclear pore complex proteins
      (nucleoporins), plays a critical role in the import of proteins into the nucleus
      as well as in the export of RNAs and proteins from the nucleus. Initially an
      epitope of Nup153 was found to reside at the distal ring of the NPC, whereas more
      recently another epitope was localized to the nuclear ring moiety of the NPC. In
      an effort to more definitively determine the location of Nup153 within the 3-D
      architecture of the NPC we have generated domain-specific antibodies against
      distinct domains of Xenopus Nup153. With this approach we have found that the N
      terminal domain is exposed at the nuclear ring of the NPC, whereas the zinc
      finger domain of Nup153 is exposed at the distal ring of the NPC. In contrast,
      the C-terminal domain of Nup153 is not restricted to one particular subdomain of
      the NPC but rather appears to be highly flexible. Exogenous epitope-tagged
      hNup153 incorporated into Xenopus oocyte NPCs further underscored these findings.
      Our data illustrate that multiple domain-specific antibodies are essential to
      understanding the topology of a nucleoporin within the context of the NPC.
      Moreover, this approach has revealed new clues to the mechanisms by which Nup153
      may contribute to nucleocytoplasmic transport.

PMID- 12490174
TI  - Nuclear transport kinetics in microarrays of nuclear envelope patches.
AB  - Optical Single Transporter Recording (OSTR) is a technique for analyzing membrane
      transport kinetics at high sensitivity, selectivity, and spatial resolution.
      Cellular membranes are firmly attached to microarrays of small test compartments
      (TCs) with diameters between approximately 0.1 and 100 microm and depths between
      approximately 10 and 100 microm. This permits to generate either "small" membrane
      patches containing few transporters or "large" patches containing many
      transporters. Transport of substrates across membrane patches is recorded by
      confocal microscopy. The present article reviews recent applications of OSTR to
      the nuclear pore complex (NPC). The results show that the transport functions of
      the NPC, previously studied almost exclusively in intact and permeabilized cells,
      are conserved in isolated nuclei and can be fully reconstituted in purified
      nuclear envelopes by addition of recombinant transport factors. This opens new
      avenues to the analysis of nuclear transport including the export of nucleic-acid
      protein and ribosomal particles.

PMID- 12490175
TI  - Patterns of importin-alpha expression during Drosophila spermatogenesis.
AB  - Importin-alpha proteins do not only mediate the nuclear import of karyophilic
      proteins but also regulate spindle assembly during mitosis and the assembly of
      ring canals during Drosophila oogenesis. Three importin-alpha genes are present
      in the genome of Drosophila. To gain further insights into their function we
      analysed their expression during spermatogenesis by using antibodies raised
      against each of the three Importin-alpha proteins identified in Drosophila,
      namely, Imp-alpha1, -alpha2, and -alpha3. We found that each Imp-alpha is
      expressed during a specific and limited period of spermatogenesis. Strong
      expression of Imp-alpha2 takes place in spermatogonial cells, persists in
      spermatocytes, and lasts up to the completion of meiosis. In growing
      spermatocytes, the intracellular localisation of Imp-alpha2 appears to be
      dependent upon the rate of cell growth. In pupal testes Imp-alpha2 is essentially
      present in the spermatocyte nucleus but is localised in the cytoplasm of
      spermatocytes from adult testes. Both Imp-alpha1 and -alpha3 expression initiates
      at the beginning of meiosis and ends during spermatid differentiation. Imp-alpha1
      expression extends up to the onset of the elongation phase, whereas that of Imp
      alpha3 persists up to the completion of nuclear condensation when the spermatids
      become individualised. During meiosis Imp-alpha1 and -alpha3 are dispersed in the
      karyoplasm where they are partially associated with the nuclear spindle, albeit
      not with the asters. At telophase they aggregate around the chromatin. During
      sperm head differentiation, both Imp-alpha1 and -alpha3 are nuclear. These data
      indicate that each Imp-alpha protein carries during Drosophila spermatogenesis
      distinct, albeit overlapping, functions that may involve nuclear import of
      proteins, microtubule organisation, and other yet unknown processes.

PMID- 12490176
TI  - Comparing psychological and sociological approaches to identity: identity status,
      identity capital, and the individualization process.
AB  - Psychologists have been studying identity processes at the intrapsychic level
      that resemble what sociologists have noted at the macro-societal level.
      Specifically, using the identity capital model introduced in previous issues of
      this journal (Cote, Journal of Adolescence, 19, 419-430; 20, 421-437), we explore
      a link between the psychologically oriented identity status paradigm, and the
      sociologically oriented individualization theory. The primary link between these
      two disciplinary approaches appears to be that the individualization process can
      be operationalized in terms of agency in identity formation. The relationship
      between agency and identity formation has been recognized by identity status
      researchers for some time, but primarily in terminology referring to the
      intrapsychic level; hence, in some respects, identity status researchers
      anticipated individualization theory. This link was empirically investigated in
      three studies of ethnically diverse samples. It was concluded, with a high degree
      of replication, that the identity statuses representing identity confusion
      (Diffusion) and identity synthesis (Achievement) appear to represent forms of
      default and developmental individualization, respectively. This comparison of
      similar elements between psychological and sociological perspectives may yield a
      richer understanding of identity formation processes, and help to pave the way
      for future interdisciplinary research..

PMID- 12490177
TI  - Influences of maternal mental illness on psychological outcomes for adolescent
      children.
AB  - The research literature associating maternal mental illness with problematic
      mental health outcomes of adolescent children typically controls for neither the
      effects of family stresses and lack of support, nor the effects of parenting
      style. To address this gap, we explore the effects of maternal psychiatric
      symptoms and community functioning on child outcomes in a diverse sample of
      seriously mentally ill women caring for their teenaged children. In hierarchical
      multiple regression, for youth depression, we find effects for parenting style
      and maternal mental health; for youth anxiety and efficacy, effects involve the
      interplay between maternal symptoms and community functioning.

PMID- 12490178
TI  - Cognitive coping strategies and symptoms of depression and anxiety: a comparison
      between adolescents and adults.
AB  - The present study focused on comparability of adolescents and adults in the
      reporting of cognitive coping strategies and their relationship to symptoms of
      depression and anxiety. Two samples were included: 487 adolescents attending a
      secondary school and 630 adults from a general practitioners practice. Data were
      obtained on symptoms of depression and anxiety and the use of nine cognitive
      coping strategies: acceptance, catastrophizing, other-blame, positive
      reappraisal, putting into perspective, refocus on planning, positive refocusing,
      rumination and self-blame. The results showed that all cognitive coping
      strategies were reported by adolescents to a significantly lesser extent than by
      adults. Further, it was shown that both in adolescents and adults a considerable
      percentage of the variance in symptomatology was explained by the use of
      cognitive coping strategies. Although adolescents and adults differed in relative
      strength of the relationships, generally speaking, conclusions were the same: in
      both groups, the cognitive coping strategies self-blame, rumination,
      catastrophizing and positive reappraisal were shown to play the most important
      role in the reporting of symptoms of psychopathology, showing the importance of
      introducing prevention and intervention programmes at an early stage.

PMID- 12490179
TI  - Gender differences in rates of depression among undergraduates: measurement
      matters.
AB  - Two studies tested for gender differences in rates of depression among
      undergraduates using three conceptualizations of depression (mood, syndrome,
      disorder). The first sample consisted of 325 non-referred undergraduate students,
      who completed pencil-and-paper measures of depressed mood, depressive syndrome
      and a depressive disorder analogue. The second sample consisted of 894
      undergraduate students seeking counselling services, who participated in clinical
      intake interviews assessing depressed mood and depressive disorder. Results of
      analyses provide no evidence of gender differences in rates of depressed mood in
      either samples or of depressive syndrome in the non-referred sample. However, in
      both samples, gender differences in rates of depressive disorder were found, with
      male students more likely than female students to be depressed.

PMID- 12490180
TI  - The theme of disconnection in adolescent girls' understanding of depression.
AB  - Fourteen adolescent girls aged between 14 and 17 were interviewed concerning
      their understanding of depression. Individual interviews were semi-structured and
      included discussion about descriptions of, causes of, and coping with,
      depression. Interviews were transcribed verbatim and were analysed thematically.
      The dominant theme arising from the girls' interviews was that of disconnection
      from relationships. Possible reasons why disconnection seems to play such a large
      part in girls' understanding of depression are discussed.

PMID- 12490181
TI  - The role of religious behaviour in adolescent depressive and anxious
      symptomatology.
AB  - Previous research, conducted primarily with adults, suggests that religious
      behaviour is associated with improved mental health. This study expanded extant
      literature to determine whether a similar relationship exists among adolescents.
      Participants completed the Religious Behaviour Questionnaire, the Children's
      Depression Inventory (CDI), and the Revised Children's Manifest Anxiety Scale.
      Results indicated that more frequent religious behaviour and a greater desire to
      participate in religious activities were associated with lower scores on the CDI.
      Clinical and educational implications of these findings are discussed.

PMID- 12490182
TI  - Family stressors and adolescent cannabis use: a pathway to problem use.
AB  - The extent to which the family environment is characterized by stress may have a
      substantial impact on life-course trajectories of young people. Illicit drug use
      is a fairly common part of these trajectories. This paper estimates the direct
      impact of family stressors on the progression to problem cannabis use, as well as
      their indirect effects via the youth's school experience among adolescents in
      Ontario. The results suggest that family stressors have direct and indirect
      effects increasing the probability of cannabis use outcomes. The implications of
      these more complex associations between factors believed to influence adolescent
      drug use trajectories are discussed.

PMID- 12490183
TI  - Adolescent perceptions of the National Lottery and scratchcards: a qualitative
      study using group interviews.
AB  - Recent research has consistently shown that a small but significant minority of
      youth engage in illegal lottery and scratchcard gambling. It is clear that most
      adolescents experience few gambling-related problems as a result of lotteries and
      scratchcards. However, it is less clear how gambling may be affecting them at a
      more general level. The present study set out to examine in more detail the
      perceptions identified in a previous survey. The study provided an opportunity
      for the participants to articulate and outline what they thought were the most
      salient issues through the use of semi-structured group interviews. Six separate
      group interviews took place (three groups of six adolescents and three groups of
      seven adolescents) aged 11-15 years. Results revealed many salient themes
      including winning money, socialization, different forms of excitement associated
      with these activities (entertainment, the fantasy of winning, and the "buzz"),
      control, (personal choice, luck, chance), and awareness of social problems. These
      are discussed in relation to the previous survey literature.

PMID- 12490184
TI  - Official records of bullying incidents among young offenders: what can they tell
      us and how useful are they?
AB  - The present study describes 107 incidents of bullying recorded by staff on
      "Bullying Incident Reports" (BIRs) at a male Young Offender Institution. The most
      frequently recorded type of bullying was psychological/verbal. Bullies had been
      placed on a governor's report prior to the BIR and found guilty on significantly
      more occasions than victims. Victims were significantly more likely than bullies
      to be seen as at risk of/actually displaying self-injurious behaviour during
      their incarceration. Most bullying incidents took place in cells/accommodation or
      in classrooms/the education block. The results are discussed with reference to
      how useful official records of bullying are as a method of measuring the
      nature/extent of bullying.

PMID- 12490185
TI  - Psychiatric morbidity in children remanded to prison custody-a pilot study.
AB  - Of the 1680 boys aged 15 and 16 remanded into prison custody in England and Wales
      during 1999, approximately 40% had histories of being "looked after". It is known
      that "Looked after" children in the community have very high rates of psychiatric
      disorder. This pilot study aimed to establish the psychiatric morbidity in
      children remanded to prison custody using an age appropriate instrument, the K
      SADS. The 19 boys interviewed showed high rates of affective disorders, substance
      misuse and conduct disorder. As hypothesized those who had been "looked after"
      had significantly higher rates. This study highlights the need to develop child
      and adolescent mental health services for children in prison.

PMID- 12490189
TI  - Nonspecific depolarization of the plasma membrane potential induces cytoskeletal
      modifications of bovine corneal endothelial cells in culture.
AB  - Modifications in the cell membrane potential have been suggested to affect
      signaling mechanisms participating in diverse cellular processes, many of which
      involve structural cellular alterations. In order to contribute some evidence in
      this respect, we explored the effects of several depolarizing procedures on the
      structure and monolayer organization of bovine corneal endothelial cells in
      culture. Visually confluent cell monolayers were incubated with or without the
      depolarizing agent, either in a saline solution or in culture medium for up to 30
      min. Membrane potential was monitored by fluorescence microscopy using oxonol V.
      Fluorescent probes were employed for F-actin, microtubules, and vinculin.
      Depolarization of the plasma membrane, achieved via the incorporation of
      gramicidin D into confluent endothelial cells or by modifications of the
      extracellular saline composition, provoked an increment of oxonol fluorescence
      and changes in cell morphology, consisting mainly of modifications in the
      cytoskeletal organization. In some areas, noticeable intercellular spaces appear.
      The cytoskeleton modifications mainly consist of a marked redistribution of F
      actin and microtubules, with accompanying changes in vinculin localization. The
      results suggest that the depolarization of the plasma membrane potential may
      participate in mechanisms involved in cytoskeleton organization and monolayer
      continuity in corneal endothelial cells in culture.

PMID- 12490190
TI  - Expression of lamin A mutated in the carboxyl-terminal tail generates an aberrant
      nuclear phenotype similar to that observed in cells from patients with Dunnigan
      type partial lipodystrophy and Emery-Dreifuss muscular dystrophy.
AB  - Autosomal dominantly inherited missense mutations in lamins A and C cause
      familial partial lipodystrophy of the Dunnigan-type (FPLD), and myopathies
      including Emery-Dreifuss muscular dystrophy (EDMD). While mutations responsible
      for FPLD are restricted to the carboxyl-terminal tails, those responsible for
      EDMD are spread throughout the molecules. We observed here the same structural
      abnormalities in the nuclear envelope and chromatin of fibroblasts from patients
      with FPLD and EDMD, harboring missense mutations at codons 482 and 453,
      respectively. Similar nuclear alterations were generated in fibroblasts,
      myoblasts, and preadipocytes mouse cell lines overexpressing lamin A harboring
      either of these two mutations. A large variation in sensitivity to lamin A
      overexpression was observed among the three cell lines, which was correlated with
      their variable endogenous content in A-type lamins and emerin. The occurrence of
      nuclear abnormalities was reduced when lamin B1 was coexpressed with mutant lamin
      A, emphasizing the functional interaction of the two types of lamins. Transfected
      cells therefore develop similar phenotypes when expressing lamins mutated in the
      carboxyl-terminal tail at sites responsible for FPLD or EDMD.

PMID- 12490191
TI  - Identification of the molecular mechanisms contributing to polarized trafficking
      in osteoblasts.
AB  - The directionality of matrix deposition in vivo is governed by the ability of a
      cell to direct vesicularflow to a specific target site. Osteoblastic cells direct
      newly synthesized bone matrix proteins toward the bone surface. In this study, we
      dissect the molecular mechanisms underlying the polarized trafficking of matrix
      protein in osteoblasts. We demonstrate using TEM, immunocytochemistry, and cDNA
      analysis, the ability of osteoblastic cells in culture to form tight junction
      like structures and report the expression of the tight junction associated
      proteins occludin and claudins 1-3 in these cells. We identify intercellular
      contact sites and the leading edge of migratory osteoblasts as major target sites
      of vesicular trafficking in osteoblasts. Proteins required for this process,
      rsec6, NSF, VAMP1, and syntaxin 4, as well as the bone matrix protein,
      osteopontin, localize to these sites. We demonstrate that osteoblasts in vivo
      possess VAMP1 and, furthermore, report the expression of two VAMP1 splice
      variants in these cells. In addition, osteoblasts express the NSF attachment
      protein alpha-SNAP and the t-SNARE SNAP23. Thus, cell-to-cell contact sites and
      the leading edge of migratory osteoblasts contain a unique complement of proteins
      required for SNARE mediated membrane fusion.

PMID- 12490192
TI  - Leukemia inhibitory factor induces apoptosis of the mammary epithelial cells and
      participates in mouse mammary gland involution.
AB  - Leukemia inhibitory factor (LIF) is a multifunctional glycoprotein that displays
      multiple biological activities in different cell types, but to date there has
      been no report on its expression in the normal mammary gland. In this study we
      found that LIF is expressed at low but detectable levels in postpubertal, adult
      virgin, and pregnant mouse mammary glands. However, LIF expression drops after
      parturition to become almost undetectable in lactating glands. Interestingly, LIF
      expression shows a steep increase shortly after weaning that is maintained for
      the following 3 days. During this period, known as the first stage of mammary
      gland involution, the lack of suckling induces local factors that cause extensive
      epithelial cell death. It has been shown that Stat3 is the main factor in
      signaling the initiation of apoptosis, but the mechanism of its activation
      remains unclear. Herein, we show that LIF expression in the gland is induced by
      milk stasis and not by the decrease of circulating lactogenic hormones after
      weaning. Implantation of LIF containing pellets in lactating glands results in a
      significant increase in epithelium apoptosis. In addition, this treatment also
      induces Stat3 phosphorylation. We conclude that LIF regulated expression in the
      mouse mammary gland may play a relevant role during the first stage of mammary
      gland involution. Our results also show that LIF-induced mammary epithelium
      apoptosis could be mediated, at least partially, by Stat3 activation.

PMID- 12490193
TI  - Activities of MAP-kinase pathways in normal uroepithelial cells and urothelial
      carcinoma cell lines.
AB  - It is often assumed that MAPK pathways drive proliferation of normal
      uroepithelial (UEC) and urothelial carcinoma (TCC) cells. To check this
      assumption, activities and inducibilities of promoters containing serum-response
      elements (SRE) or AP-1 binding sites were investigated in cultured UEC and seven
      TCC lines. Reporter plasmids dependent on SRE or AP-1 sites were highly active in
      UEC, but significantly less so in TCC lines. Reporter activity in TCC lines could
      be induced by constitutively active MEKK4 or TPA. Accordingly, phosphorylation of
      the MAPK pathway components MEK, ERK, and ELK1 was most pronounced in UEC and
      lower in TCC lines. MAPK-dependent promoter activities and bromodeoxyuridine
      incorporation decreased in UEC upon withdrawal of growth factors, but less so in
      TCC lines, in which serum diminution increased apoptosis. Likewise, E2F-dependent
      promoters responded to growth factors in UEC, but were more serum-independent in
      the TCC lines, which lack either RB1 or p16(INK4A). MEK inhibitors inhibited BrdU
      incorporation in UEC more strongly than in TCC lines. Thus, proliferation of
      normal uroepithelial cells is indeed associated with activation of MAPK pathways.
      However, autonomous proliferation of TCC lines--unexpectedly--appears much less
      dependent on MAPK activation and may rather be promoted by defects in cell cycle
      regulation.

PMID- 12490194
TI  - Runnin' with the Dvl: proteins that associate with Dsh/Dvl and their significance
      to Wnt signal transduction.
AB  - Wnt proteins transmit myriad intercellular signals crucial for the development
      and homeostasis of metazoan animals from Hydra to human. Abnormal Wnt signaling
      causes a growing number of diseases, including cancer and osteoporosis. Depending
      on the context, a given Wnt signal may denote: cell proliferation or apoptosis;
      cell fate determination, differentiation, or stem cell maintenance; a variety of
      changes in cell behavior; and/or coordinated interactions with its neighbors.
      Which event(s) occur in Wnt-responsive cells depends critically on the ability of
      Dishevelled (Dsh)/Dvl proteins to interpret distinct types of intracellular,
      receptor-generated stimuli and transmit them to at least two distinct sets of
      effector molecules, all while apparently ignoring a third type of Wnt-generated
      Ca(2+) signal. The three conserved domains present in Dsh/Dvl proteins uniquely
      function in each Wnt pathway, in part by association with 18 (and counting)
      Dsh/Dvl-associated proteins. The latest data suggest that Dsh/Dvl proteins
      organize dynamic, pathway-specific subcellular signaling complexes that ensure
      correct information routing, signal amplification, and dynamic control through
      feedback regulation. The biochemical and cell biological mechanisms by which
      Dsh/Dvl proteins accomplish these remarkable tasks remain obscure.

PMID- 12490195
TI  - The Drosophila female sterile mutation twin peaks is a novel allele of tramtrack
      and reveals a requirement for Ttk69 in epithelial morphogenesis.
AB  - The Drosophila gene tramtrack (ttk) encodes two transcriptional repressors, Ttk69
      and Ttk88, which are required for normal embryogenesis and imaginal disc
      development. Here, we characterize a novel female sterile allele of tramtrack
      called twin peaks (ttk(twk)) that, unlike othertramtrack alleles, has no effect
      on viability and produces no obvious morphological defects, except during
      oogenesis. Females homozygous for twin peaks produce small eggs with thin
      eggshells and short dorsal respiratory appendages. Complementation analyses,
      immunolocalization, and rescue data demonstrate that these defects are due to
      loss of Ttk69, which is expressed in the follicle cells and is required for
      normal chorion production and dorsal follicle-cell migration. Analyses of
      phenotypes produced by mutations in other loci that regulate eggshell synthesis
      suggest that the chorion production and follicle-cell migration defects are
      independent. We present evidence that twin peaks disrupts a promoter or promoters
      required for late-stage follicle-cell expression of Ttk69. We hypothesize that
      loss of Ttk69 in all follicle cells disrupts chorion gene expression and lack of
      function in dorsal anterior follicle cells inhibits morphogenetic changes
      required for elongating the dorsal appendages.

PMID- 12490196
TI  - Expression profiling of placentomegaly associated with nuclear transplantation of
      mouse ES cells.
AB  - Transplantation of nuclei (NT) from engineered mouse ES cells is a potentially
      powerful and rapid route to create knockout mice, obviating the need for matings
      to obtain germ-line chimeras. However, such an application is currently
      impossible, because NT often results in abnormalities in embryo and placenta.
      Although the epigenetic instability of several imprinted genes in ES cells and ES
      derived NT mice has been demonstrated, it is not clear yet what causes the
      abnormalities. To gain perspective on the extent and types of changes, we have
      done gene expression profiling for mouse placentas produced by NT of ES cells and
      compared them with the expression profiles of placentas produced by NT of one
      cell embryos. Based on microarray studies with the NIA 15K mouse cDNA collection,
      we report five principal aberrant events: (1) inappropriate expression of
      imprinted genes; (2) altered expression of regulatory genes involved in global
      gene expression, such as DNA methyltransferase and histone acetyltransferase; (3)
      increased expression of oncogenes and growth promoting genes; (4) overexpression
      of genes involved in placental growth, such as Plac1; and (5) identification of
      many novel genes overexpressed in ES-derived NT mouse placentas, including
      Pitrm1, a new member of the metalloprotease family. The results indicate that
      placentomegaly in ES-derived NT mice is associated with large-scale dysregulation
      of normal gene expression patterns. The study also suggests the presence of two
      regulatory pathways that may lead to histologically discernable placentomegaly.
      The discovery of groups of genes with altered expression may provide potential
      targets for intervention to mimic natural regulation more faithfully in NT mice.

PMID- 12490197
TI  - PAR-1 is required for morphogenesis of the Caenorhabditis elegans vulva.
AB  - The Caenorhabditis elegans vulva provides a simple model for the genetic analysis
      of pattern formation and organ morphogenesis during metazoan development. We have
      discovered an essential role for the polarity protein PAR-1 in the development of
      the vulva. Postembryonic RNA interference of PAR-1 causes a protruding vulva
      phenotype. We found that depleting PAR-1 during the development of the vulva has
      no detectable effect on fate specification or precursor proliferation, but
      instead seems to specifically alter morphogenesis. Using an apical junction
      associated GFP marker, we discovered that PAR-1 depletion causes a failure of the
      two mirror-symmetric halves of the vulva to join into a single, coherent organ.
      The cells that normally form the ventral vulval rings fail to make contact or
      adhere and consequently form incomplete toroids, and dorsal rings adopt variably
      abnormal morphologies. We also found that PAR-1 undergoes a redistribution from
      apical junctions to basolateral domains during morphogenesis. Despite a known
      role for PAR-1 in cell polarity, we have observed no detectable differences in
      the distribution of various markers of epithelial cell polarity. We propose that
      PAR-1 activity at the cell cortex is critical for mediating cell shape changes,
      cell surface composition, or cell signaling during vulval morphogenesis.

PMID- 12490198
TI  - The step-wise assembly of a functional nucleolus in preimplantation mouse embryos
      involves the cajal (coiled) body.
AB  - After fertilization, ribosomal RNA synthesis is silenced during a period which
      depends on the species. Data concerning the reassembly of a functional nucleolus
      remain scarce. We have examined by immunocytochemistry, Western blots, and BrUTP
      microinjection the dynamics of major nucleolar proteins during the first cycles
      of mouse embryogenesis, in relation to rDNA transcription sites and coilin, a
      marker of Cajal bodies. We show that: (1) the reinitiation of rDNA transcription
      occurs at the two-cell stage, 44-45 h after hCG injection (hphCG), at the surface
      of the nucleolar precursor bodies (NPBs), where the RNA polymerase I (pol I)
      transcription complex is recruited 4-5 h before; (2) the NPBs are not equal in
      their ability to support recruitment of pol I and rDNA transcription; (3)
      maternally inherited fibrillarin undergoes a dynamic redistribution during the
      second cell stage, together with coilin, leading to the assembly of the Cajal
      body around 40 hphCG; and (4) the pol I complex is first recruited to the Cajal
      body before reaching its rDNA template. We also find that fibrillarin and B23 are
      both directly assembled around NPBs prior to ongoing pre-rRNA synthesis.
      Altogether, our results reveal a role of the Cajal bodies in the building of a
      functional nucleolus.

PMID- 12490199
TI  - Neurogenin3 participates in gliogenesis in the developing vertebrate spinal cord.
AB  - To study the role of basic helix-loop-helix (bHLH) transcription factors in
      gliogenesis, we examined whether bHLH transcription factors were expressed in
      glial precursor cells and participated in regulating oligodendrocyte and
      astrocyte development. As assessed by reverse transcription-polymerase chain
      reaction (RT-PCR), Neurogenin3 (Ngn3) was transiently expressed in bipotential
      glial cells fated to become either oligodendrocytes or astrocytes. Mice lacking
      Ngn3 displayed a loss of Nkx2.2 expression, a transcription factor required for
      proper oligodendrogliogenesis. Furthermore, a reduction in the expression of
      myelin basic protein (MBP), proteolipid protein (PLP), and glial fibrillary
      acidic protein (GFAP), markers for mature oligodendrocytes and astrocytes, was
      observed in the Ngn3 null mice. Overexpression of Ngn3 was sufficient to drive
      expression from the PLP promoter in transient cotransfection assays. Overall, the
      data suggest that Ngn3 may regulate glial differentiation at a developmental
      stage prior to the segregation of the oligodendrocyte and astrocyte lineage.

PMID- 12490200
TI  - Opioid receptor-induced GTPgamma35S binding during mouse development.
AB  - Although a large superfamily of G-protein-coupled receptors serves multiple
      functions, little is known about their functional activation during ontogeny. To
      examine the functional activation of the mu-opioid receptor (MOR) and the delta
      opioid receptor (DOR) during development, sections of mouse embryos and fetuses
      from e11.5 until birth were treated with DAMGO and DPDPE, respectively, and the
      ability of these drugs to induce G-protein coupling was assessed by using
      GTPgamma(35)S binding autoradiography. MOR activation was first detected in the
      caudate-putamen (CPU) at e12.5, and by e15.5, activity had not only increased in
      this region but also expanded to include the midbrain, medial habenula,
      hypothalamus, pons, and medulla. DOR activity first appeared at e17.5 in the
      hypothalamus, pons, medial habenula, and medulla and at p1 in the CPU at levels
      noticeably less than those of the MOR. In general, MOR and DOR activation lagged
      only slightly behind the appearance of MOR-1 and DOR-1 mRNA but delayed
      activation was particularly pronounced in the trigeminal ganglia, where MOR-1
      gene expression was first detected at e13.5, but MOR activity was not observed
      even at birth. Thus, the data demonstrate temporal and often region-specific
      differences in the appearance and magnitude of functional activity in cell groups
      expressing either the MOR-1 or DOR-1 genes, suggesting that interaction between
      the opioid receptors, G-proteins, and other signaling cofactors is
      developmentally regulated.

PMID- 12490201
TI  - Patterning of the avian intermediate mesoderm by lateral plate and axial tissues.
AB  - Amniote kidney tissue is derived from the intermediate mesoderm (IM), a strip of
      mesoderm that lies between the somites and the lateral plate. While much has been
      learned concerning the later events which regulate the differentiation of IM into
      tubules and other types of kidney tissue, much less is known concerning the
      earlier events which regulate formation of the IM itself. In the current study,
      the chick pronephros was used as a model system to identify tissues that play a
      role in patterning the IM and the critical time periods during which such
      patterning events take place. Explant studies revealed that the prospective
      pronephric IM is already specified to express kidney genes by stage 6, shortly
      after its gastrulation through the primitive streak, and earlier than previously
      reported. Transplant and explant experiments revealed that the lateral plate
      contains an activity that can repress IM formation in tissues that are already
      specified to express IM genes. In contrast, Hensen's node can promote formation
      of IM in the lateral plate. Paraxial tissues (presomitic mesoderm plus neural
      plate and notochord) were found to influence the morphogenesis of the nephric
      duct, but did not induce IM tissue to an appreciable extent. Combining lateral
      plate and paraxial tissue in vivo or in vitro led to induction of IM genes in the
      paraxial mesoderm but not in the lateral plate mesoderm. Based on these results
      and those of others, we propose a two-step model for the patterning of the IM.
      While tissue is still in the primitive streak, the prospective IM is relatively
      uncommitted. By stage 6, shortly after cells leave the primitive streak, a field
      of cells is generate which is specified to give rise to IM (Step 1).
      Subsequently, competing signals from the lateral plate and axial tissues modulate
      the number of cells that commit to an IM fate (Step 2).

PMID- 12490202
TI  - Nodal signaling in Xenopus gastrulae is cell-autonomous and patterned by beta
      catenin.
AB  - The classical three-signal model of amphibian mesoderm induction and more recent
      modifications together propose that an activin-like signaling activity is
      uniformly distributed across the vegetal half of the Xenopus blastula and that
      this activity contributes to mesoderm induction. In support of this, we have
      previously shown that the activin-response element (DE) of the goosecoid promoter
      is uniformly activated across the vegetal half of midgastrula-stage embryos.
      Here, we further examine the nature of this activity by measuring DE activation
      by endogenous signals over time. We find that the spatiotemporal pattern of DE
      activation is much more dynamic than was previously appreciated and also conclude
      that DE(6X)Luc activity reflects endogenous nodal signaling in the embryo. Using
      both the DE(6X)Luc construct and endogenous Xbra and Xgsc expression as read-outs
      for nodal activity, and the cleavage-mutant version of Xnr2 (CmXnr2) to
      regionally suppress endogenous nodal activity, we demonstrate that nodal signals
      act cell-autonomously in Xenopus gastrulae. Nodal-expressing cells are unable to
      rescue either reporter gene activation or target gene expression in distant nodal
      deficient cells, suggesting that nodals function at short range in this context.
      Finally, we show that DE activation by endogenous signals occurs in the absence
      of dorsal beta-catenin-mediated signaling, but that the timing of dorsal
      initiation is altered. We conclude that nodal signals in Xenopus gastrulae
      function cell autonomously at short ranges and that the spatiotemporal pattern of
      this signaling along the dorsoventral axis is regulated by maternal Wnt-like
      signaling.

PMID- 12490203
TI  - A receptor linked to a Gi-family G-protein functions in initiating oocyte
      maturation in starfish but not frogs.
AB  - The stimulation of oocyte maturation by 1-methyladenine in starfish, and by a
      steroid in frogs, has been proposed to involve G-protein-coupled receptors. To
      examine whether activation of receptors linked to G(i) or G(z) was sufficient to
      cause oocyte maturation, we expressed mammalian G(i)- and G(z)-linked receptors
      in starfish and frog oocytes. Application of the corresponding agonists caused
      meiosis to resume in the starfish but not the frog oocytes. We confirmed that the
      receptors were effectively expressed in the frog oocytes by using a chimeric G
      protein, G(qi), that converts input from G(i)- and G(z)-linked receptors to a
      G(q) output and results in a contraction of the oocyte's pigment. These results
      argue against G(i) or G(z) functioning to cause maturation in frog oocytes.
      Consistently, maturation-inducing steroids did not cause pigment contraction in
      frog oocytes expressing G(qi), and G(z) protein was not detectable in frog
      oocytes. For starfish oocytes, however, our results support the conclusion that
      G(i) functions in 1-methyladenine signaling and suggest the possibility of using
      frog oocyte pigment contraction as an assay to identify the 1-methyladenine
      receptor. To test this concept, we coexpressed G(qi) and a starfish adenosine
      receptor in frog oocytes and showed that applying adenosine caused pigment
      contraction.

PMID- 12490204
TI  - Novel activities of Mafb underlie its dual role in hindbrain segmentation and
      regional specification.
AB  - The bZip transcription factor Mafb is expressed in two segments of the developing
      vertebrate hindbrain: the rhombomeres 5 and 6. Loss of Mafb expression in the
      mouse mutant kreisler leads to elimination of r5 and to alterations of r6
      regional identity. Here, we further investigated the role of Mafb in hindbrain
      patterning using gain-of-function experiments in the chick embryo. Our work has
      revealed novel functions for Mafb, including a positive autoregulatory activity,
      the capacity to repress Hoxb1 expression, and the capacity to synergise with or
      antagonise Krox20 activity. These different activities appear to be spatially
      restricted in the hindbrain, presumably due to interactions with other factors.
      Reinvestigation of the kreisler mutation indicated that it also results in an
      ectopic activation of Mafb in rhombomere 3, accounting for the previously
      described molecular alterations of this rhombomere in the mutant. Together, these
      data allow us to refine our view of the dual function of Mafb in both
      segmentation and specification of anteroposterior identity in the hindbrain.

PMID- 12490205
TI  - Thromboembolic diseases of childhood.
AB  - Over the last decade, pediatric thrombophilia programs have emerged around the
      world as a new discipline in pediatric hematology. These programs specialize in
      the diagnosis, prevention and treatment of children with thromboembolic events
      (TEs) in both the venous and arterial systems. The need for separate pediatric
      programs has been discussed previously. (J Pediatr Hematol Oncol 1997; 19: 7-22.)
      The following article will update previous reviews (Hematol Oncol Clin North Am
      1998; 12: 1283-1312; Thromb Haemost 1997; 78: 715-725) and will concentrate on
      three aspects: (1) The risk factors for acquiring TEs; (2) The confirmatory
      diagnostic tests used in children with TEs; and (3) The different antithrombotic
      agents used for prevention and treatment. The current knowledge in respect to the
      above points is only the "tip of the iceberg". Well-designed prospective trials
      are required to establish the contribution of congenital prothrombotic disorders,
      appropriate diagnostic strategies, and optimal therapy for children with TEs.

PMID- 12490206
TI  - Thrombocytopenia in pregnancy: differential diagnosis, pathogenesis, and
      management.
AB  - Thrombocytopenia in pregnant women may result from a number of diverse
      etiologies. While some of these are not associated with adverse pregnancy
      outcomes, others are associated with substantial maternal and/or neonatal
      morbidity and mortality. However, specific therapies, if instituted promptly, may
      significantly improve the outcomes of affected patients and their offspring.
      Since the clinical features of many of these disorders often overlap, identifying
      a specific cause of thrombocytopenia in a pregnant patient may be difficult.
      However, through familiarity with the more common clinical and laboratory
      features of each of these disorders, accurate diagnosis may be achieved, and
      appropriate treatment instituted in most cases. In this review, we discuss the
      differential diagnosis of the more common causes of pregnancy-associated
      thrombocytopenia, and provide an overview of approaches to hematologic
      management.

PMID- 12490207
TI  - Molecular targets in acute myelogenous leukemia.
AB  - Acute myeloid leukemia (AML) remains the most common form of leukemia and the
      most common cause of leukemia death. Although conventional chemotherapy can cure
      between 25 and 45% of AML patients, most patients will either die of relapse or
      die from the complications associated with treatment. Thus, more specific and
      less toxic treatments for AML patients are needed. Recently, a small molecular
      inhibitor (STI571 or Gleevec) that targets the BCR-ABL gene was found to have a
      dramatic clinical effect in patients with chronic myelogenous leukemia (CML).
      These results have encouraged investigators to search for additional small
      molecular inhibitors and other targeted therapies that may be applicable to other
      forms of leukemia. In this review, we examine some of the signaling pathways that
      are aberrantly regulated in AML, focusing on the tyrosine kinase/RAS/MAP kinase
      and JAK/STAT pathways. After reviewing these two pathways, we explore some of the
      targeted therapies directed at these pathways that are under development for AML,
      many of which are already in clinical trials.

PMID- 12490208
TI  - Monoclonal antibodies combined to chemotherapy for the treatment of patients with
      lymphoma.
AB  - Humanized monoclonal antibodies have transformed the treatment of patients with
      lymphomas. The first application of these new drugs appeared less than 10 years
      ago but currently one patient will certainly receive them once or several time
      during the evolution of his disease. This review will cover the use of these
      monoclonal antibodies alone or in combination with chemotherapy. Rituximab, an
      unconjugated anti-CD20 chimeric antibody, is certainly the most widely used but
      other unconjugated or radiolabeled monoclonal antibodies catch up quickly. If
      there are randomized studies demonstrating the benefit of adding these drugs to
      the treatment of patients with lymphoma, very few studies have compared the
      activity of the different monoclonal antibodies. A lot of questions needs to be
      answered before the best setting of these drugs will be known.

PMID- 12490209
TI  - Structural basis of the fibrinogen-fibrin transformation: contributions from X
      ray crystallography.
AB  - During the past several years, a number of crystal structures have been
      determined of fragments from fibrinogen and fibrin and, most recently, a
      structure of a native fibrinogen. One feature of the fibrinogen molecule that has
      emerged from these studies has to do with its "loose ends," segments of the
      molecule that are extremely mobile and not discernable by X-ray crystallography.
      Some, if not all, of this flexibility is functionally important. Small synthetic
      peptides based on mobile parts of fibrinogen exposed by the action of thrombin
      have contributed significantly to these studies and may yet prove useful
      therapeutically. In the end, although crystal structures have added greatly to
      our understanding of fibrin formation, much still needs to be unraveled about how
      clots form.

PMID- 12490210
TI  - Screening and genetic diagnosis of haemoglobin disorders.
AB  - The inherited haemoglobinopathies are large group of disorders that include the
      thalassaemias and sickle cell disease. Carrier detection methods must be able to
      detect alpha-, beta- and deltabeta-thalassaemias, HPFH disorders and haemoglobin
      variants. Carrier diagnosis involves the accurate measurement of MCH, MCV, Hb
      A(2) and Hb F values in combination with an understanding of the haematological
      characteristics of the different types of thalassaemia genes and their
      interactions. The majority of the common thalassaemia mutations and abnormal
      haemoglobins can be identified by PCR-based techniques. The main applications of
      molecular analysis for carrier diagnosis are: the analysis of alpha-thalassaemia
      mutations by gap-PCR to discriminate between heterozygous alpha-thalassaemia and
      homozygous alpha-thalassaemia; the identification of beta-thalassaemia mutations
      for patients requiring prenatal diagnosis and for the prediction of the severity
      of the clinical phenotype of homozygous beta-thalassaemia; to discriminate
      between deltabeta-thalassaemia and HPFH deletions by gap-PCR.

PMID- 12490211
TI  - Effect of roots aqueous extract of Delphinium denudatum on morphine-induced
      tolerance in mice.
AB  - The aqueous extract of Delphinium denudatum (Dd) roots showed a significant
      effect against morphine- (10 mg/kg) induced tolerance and dependence in mice.
      Oral administration of the extract (200-1600 mg/kg) showed a significant dose
      dependent inhibition of naloxone- (1 mg/kg) induced withdrawal.

PMID- 12490212
TI  - Protective effect of rutin on paracetamol- and CCl4-induced hepatotoxicity in
      rodents.
AB  - Rutin, a well-known flavonoid was investigated for its possible protective effect
      against paracetamol- and CCl(4)-induced hepatic damage. Paracetamol produced 100%
      mortality at the dose of 1 g/kg in mice while pre-treatment of animals with rutin
      (20 mg/kg) reduced the death rate to 40%. Oral administration of a sub-lethal
      dose of paracetamol (640 mg/kg) produced liver damage in rats as manifested by
      the rise in serum level of transaminases (AST and ALT). Pre-treatment of rats
      with rutin (20 mg/kg) prevented the paracetamol-induced rise in serum enzymes.
      The hepatotoxic dose of CCl(4) (1.5 ml/kg; orally) also raised the serum AST and
      ALT levels. The same dose of rutin (20 mg/kg) was able to prevent the CCl(4)
      induced rise in serum enzymes. Rutin also prevented the CCl(4)-induced
      prolongation in pentobarbital sleeping time confirming its hepatoprotectivity.
      These results indicate that rutin possesses hepatoprotective activity and the
      presence of this compound in Artemisia scoparia may explain the folkloric use of
      the plant in liver damage.

PMID- 12490213
TI  - Efficacy of Rhizophora mangle aqueous bark extract in the healing of open
      surgical wounds.
AB  - Thirty-seven patients with open wounds from surgical intervention of pilonidal
      cyst (14; 37.8%) or pilonidal fistula (23; 62.2%) were enrolled on a voluntary
      basis in a comparative blinded clinical trial and randomly assigned to a topical
      treatment with a Rhizophora mangle aqueous bark extract once a day or twice a day
      or mercurocrome twice a day. The efficacy of the treatments was evaluated weekly
      from day 10 to 12 until 6 weeks after surgery by measuring the area of the wounds
      by image digital planimetry and the tolerability by recording adverse effects.
      The initial size of the wounds was taken in consideration as covariable in the
      Generalized Lineal Model used. A thin dark red colored film covering the wound
      was observed in all the cases treated with the extract. The wound areas of the
      groups treated with the extract once or twice per day showed a greater reduction
      (P < 0.05) compared to the group treated with mercurocrome. No differences
      between the two regimes of application of the extract of R. mangle were observed.
      No subject showed any sign of adverse effects and no secondary infections were
      observed.

PMID- 12490214
TI  - Inhibition of Trypanosoma cruzi growth by medical plant extracts.
AB  - This study describes the screening of extracts obtained from 18 plants and two
      fungi used in the Chinese and Mediterranean traditional medicines on epimastigote
      forms of Trypanosoma cruzi. The extracts were tested against epimastigote of T.
      cruzi Bra C15C2 clone in vitro at 27 degrees C and at a concentration of 250
      microg/ml in axenic culture. Angelica dahurica, A. pubescens, A. sinensis,
      Astragalus membranaceus, Coptis chinensis, Haplophyllum hispanicum, Phellodendron
      amurense, Poria cocos, Ranunculus sceleratus and Scutellaria baicalensis showed
      significant effects against the parasite with a percentage of growth inhibition
      between 20 and 100%. C. chinensis and R. sceleratus showed the greatest activity
      with IC(50) values of 1.7 microg/ml for C. chinensis and 10.7 microg/ml for R.
      sceleratus. These activities are greater than that of allopurinol. C. chinesis
      and R. sceleratus extracts did not show cytotoxic effects on rat
      polimorphonuclear cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
      tetrazolium bromide and lactic dehydrogenase assays. These results allowed us to
      suggest that R. sceleratus and C. chinensis could be a source of new compounds
      clinically active against T. cruzi.

PMID- 12490215
TI  - Macrocyclic diterpenoids from Euphorbia hyberna L. subsp. insularis and their
      reaction with oxyphilic reagents.
AB  - The aerial parts of Euphorbia hyberna subsp. insularis from Sardinia contain
      large amounts of macrocyclic diterpenoids of the jatrophane type, while phorboids
      could not be isolated. Treatment of the major constituent (1a) with various
      acidic and oxyphilic reagents was investigated, showing the surprising reluctance
      of the macrocyclic system to undergo transannular reactions. Dehydration,
      isomerization of the exocyclic double and acyl rearrangement were, however,
      observed after reduction of the 9-keto group.

PMID- 12490216
TI  - Identification of Ruscus steroidal saponins by HPLC-MS analysis.
AB  - A novel HPLC-UV method has been developed for the fingerprint analysis of the
      steroidal saponins in the rhizomes of three Ruscus species (Ruscus aculeatus,
      Ruscus hypoglossum and Ruscus colchicus). Saponins were identified by HPLC-ESI
      MS. During the study a new major saponin was detected in the rhizomes of R.
      hypoglossum and R. colchicus. The structure of the new compound was defined as 1
      O-[alpha-L-rhamnopyranosyl-(1-->2)-6-O-acetyl-beta-D-galactopyranosyl]
      1beta,3beta,22xi,26-tetrahydroxy-furost-5(6)-en-26-O-beta-D-glucopyranoside (8)
      by spectral analysis.

PMID- 12490217
TI  - Artoindonesianins N and O, new prenylated stilbene and prenylated arylbenzofuran
      derivatives from Artocarpus gomezianus.
AB  - A new prenylated stilbene, named artoindonesianin N (1) and a new prenylated
      arylbenzofuran, named artoindonesianin O (2), were isolated from Artocarpus
      gomezianus Wall. ex Trec. (Moraceae). Their structures were elucidated as 1 and 2
      on the basis of spectroscopic evidence. Along with these new compounds, a known
      phenolic compound was also isolated from this plant and identified as
      oxyresveratrol (3).

PMID- 12490218
TI  - Antiperoxidative effects of lycopene during N-methyl-N'-nitro-N-nitrosoguanidine
      induced gastric carcinogenesis.
AB  - The effects of lycopene on blood oxidant-antioxidant balance during N-methyl-N'
      nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis in the presence of
      saturated sodium chloride (S-NaCl) as promoting agent were investigated. Enhanced
      lipid peroxidation in the blood of tumour-bearing animals was accompanied by
      significant decreases in the levels of reduced glutathione (GSH), ascorbic acid
      and vitamin E and the activities of glutathione peroxidase (GPx), glutathione-S
      transferase (GST) and glutathione reductase (GR). Administration of lycopene
      significantly lowered the concentrations of lipid peroxides and enhanced
      antioxidant levels. We suggest that the modulatory effects of lycopene on the
      blood oxidant-antioxidant balance may be responsible for its chemopreventive
      potential.

PMID- 12490219
TI  - Antioxidant effects of Gongronema latifolium in hepatocytes of rat models of non
      insulin dependent diabetes mellitus.
AB  - Gongronema latifolium is a rainforest plant, which has been traditionally used in
      the South Eastern part of Nigeria for the management of diabetes. The effects of
      oral administration of aqueous and ethanolic G. latifolium leaf extracts for 2
      weeks on streptozotocin-induced diabetic rats were investigated. Both extracts
      were shown to significantly increase the activity of superoxide dismutase and the
      level of reduced glutathione. The aqueous extract further increased the activity
      of glutathione reductase while the ethanolic extract caused a significant
      increase in the activity of glutathione peroxidase and glucose-6-phosphate
      dehydrogenase and a significant decrease in lipid peroxidation. These results
      suggest that the extracts from G. latifolium leaves could exert their
      antidiabetic activities through their antioxidant properties.

PMID- 12490220
TI  - The effect of Mangifera indica stem bark and Pluchea ovalis roots on tracheal
      smooth muscle in vitro.
AB  - Aqueous extract of the stem bark of Mangifera indica and ethanolic extract of the
      roots of Pluchea ovalis has been studied on rat tracheal smooth muscle in vitro.
      The extract of M. indica at 1, 2 and 4 mg/ml and that of P. ovalis at 0.25, 0.5
      and 1 mg/ml relaxed, dose-dependently, the rat tracheal smooth muscle strip
      previously contracted by acetylcholine at 0.055 mmol/l.

PMID- 12490221
TI  - Hypoglycaemic activity of Alpinia galanga rhizome and its extracts in rabbits.
AB  - This investigation was carried out to study effects of Alpinia galanga rhizome on
      blood glucose levels. In normal rabbits, powdered rhizome and its methanol and
      aqueous extracts significantly lowered the blood glucose. Gliclazide also
      produced a significant decrease in blood glucose in the rabbits. In alloxan
      diabetic rabbits, A. galanga and its methanol and aqueous extracts did not
      produce significant reduction in blood glucose. The hypoglycaemic effect of A.
      galanga in normal rabbits was comparable to gliclazide. The rhizome was found to
      contain high levels of certain minerals. Acute toxicity and behavioral studies
      revealed no visible signs of toxicity and any abnormal behavior in rabbits even
      at high doses. It is concluded that A. galanga produces fall in blood glucose
      levels in normal rabbits and the principles, both organic and inorganic, are
      extractable in methanol and water.

PMID- 12490222
TI  - Enhancement of oxidative response and cytokine production by yam
      mucopolysaccharide in murine peritoneal macrophage.
AB  - Yam (Dioscorea batatas) mucopolysaccharide (YMP) was examined for the ability to
      induce secretory and cellular responses in murine peritoneal macrophages. When
      macrophages were treated with various doses (10-100 microg/ml) of YMP for 48 h, a
      significant cytotoxicity against B 16 cells was observed. YMP also increased the
      myeloperoxidase activity and the production of H(2)O(2), O(2)(-), nitric oxide
      (NO) and tumor necrosis factor (TNF-alpha). However, there was a little
      alteration on the production of IFN-gamma. These results indicate that reactive
      oxygen intermediates (ROI), reactive nitrogen intermediates (RNI) and TNF-alpha
      are likely major mediators of cytotoxic activity of YMP-treated macrophages.

PMID- 12490223
TI  - Carbohydrase activities of the rolC-gene transformed and non-transformed ginseng
      cultures.
AB  - The levels of activity of beta-D-glucosidase, alpha-D-mannosidase, alpha- and
      beta-D-galactosidase, 1,3-, 1,6-, 1,4-beta-D-glucanases, 1,4-alpha-D-glucanase,
      fucoidanhydrolase and agarase were measured in extracts of non-transgenic and
      transgenic Panax ginseng cultures transformed with the rolC gene. Significantly
      increased levels of activity of beta- and alpha-D-galactosidases and 1,3-beta-D
      glucanase were detected in rolC-gene transformed cells, compared to the control
      non-transformed cells, while levels of activity of other enzymes were unchanged.
      These, as well as the gel-permeation experiments, revealed that transformation of
      ginseng cells by the rolC gene could significantly affect activity of some
      carbohydrases and production of their molecular forms.

PMID- 12490224
TI  - Effects of sea buckthorn (Hippophae rhamnoides L.) seed and pulp oils on
      experimental models of gastric ulcer in rats.
AB  - Oils from sea buckthorn (Hippophae rhamnoides L.) seeds and berries have
      traditionally been used in the treatment of disorders of skin and mucosa in
      China. Compared with the negative control, oral administration of CO(2)-extracted
      seed and pulp oils, 7.0 ml x kg(-1) x day(-1) significantly reduced ulcer
      formation in water-immersion (P < 0.05) and reserpine-induced (P < 0.01) models
      in rats. In addition, administration of the two oils, 3.5 ml x kg(-1) x day(-1),
      significantly reduced the index of pylorus ligation-induced gastric ulcer (P <
      0.05) and sped up the healing process of acetic acid-induced gastric ulcer (P <
      0.01). The results suggested that the CO(2)-extracted sea buckthorn seed and pulp
      oils have both preventive and curative effects against experimental gastric
      ulcers in rats.

PMID- 12490225
TI  - Light-mediated activities of some Thai medicinal plant teas.
AB  - Forty-one types of commercially available Thai medicinal teas were tested for
      their light-mediated activities against Bacillus subtilis, Staphylococcus aureus
      K147 methicillin-sensitive (Ms), Escherichia coli DC10, E. coli (wild),
      Pseudomonas aeruginosa 187 (wild), Candida albicans and Aspergillus fumigatus.
      The results represent a first report of the light-mediated antimicrobial
      activities of Thai medicinal teas and suggest that phytochemical investigations
      may be warranted.

PMID- 12490226
TI  - Studies on anti-diarrhoeal activity of Ficus hispida. Leaf extract in rats.
AB  - Methanol extract of Ficus hispida L. showed significant inhibitory activity
      against castor oil-induced diarrhoea and PGE(2)-induced enteropooling in rats. It
      also showed a significant reduction in gastro-intestinal motility on charcoal
      meal test in rats. The results obtained establish the F. hispida leaf extract as
      an anti-diarrhoeal agent.

PMID- 12490227
TI  - Artoindonesianin P, a new prenylated flavone with cytotoxic activity from
      Artocarpus lanceifolius.
AB  - A new prenylated flavone, named artoindonesianin P (1), was isolated from the
      tree bark of Artocarpus lanceifolius, together with three known related
      compounds, artobiloxanthone (2), cycloartobiloxanthone (3) and artonol B (4). The
      structure of artoindonesianin P 1 was determined on the basis of spectral
      evidence (MS, 1H and 13C NMR) and by comparison with known related compounds.
      Compounds 1-4 exhibited significant cytotoxicity against murine P388 leukemia
      cells.

PMID- 12490228
TI  - Antiproliferative effects of Ceratonia siliqua L. on mouse hepatocellular
      carcinoma cell line.
AB  - Extracts from pods and leaves of carob (Ceratonia siliqua L.) were tested for
      their ability to inhibit cell proliferation of mouse hepatocellular carcinoma
      cell line (T1). The two extracts showed a marked alteration of T1 cell
      proliferation in a dose-related fashion reaching the maximal effect at 1 mg/ml.
      Moreover, we demonstrated that leaf and pod extracts were able to induce
      apoptosis in T1 cell lines after 24-h treatment mediating a direct activation of
      the caspase 3 pathway. HPLC analysis revealed the presence of gallic acid, (-)
      epigallocatechin-3-gallate and (-) epicatechin-3-gallate in pod and leaf
      extracts, compounds well known to exert antiproliferative effects. Their
      concentration reached 6.28 mg/g in carob leaves and 1.36 mg/g in carob pods
      extract. The discovery that carob pod and leaf extracts contained
      antiproliferative agents could be of practical importance in the development of
      functional foods and/or chemopreventive drugs.

PMID- 12490229
TI  - Clitoria ternatea root extract enhances acetylcholine content in rat hippocampus.
AB  - Treatment with 100 mg/kg of Clitoria ternatea aqueous root extract (CTR), for 30
      days in neonatal and young adult age groups of rat, significantly increased
      acetylcholine (ACh) content in their hippocampi as compared to age matched
      controls. Increase in ACh content in their hippocampus may be the neurochemical
      basis for their improved learning and memory.

PMID- 12490230
TI  - Trypsin inhibitory activity of Lawsonia inermis.
AB  - The ethanolic extract of Lawsonia inermis leaves and lawsone tested for trypsin
      inhibitory activity showed an IC(50) value of 64.87 and 48.6 microg/ml,
      respectively.

PMID- 12490231
TI  - Antithrombin activity of some constituents from Origanum vulgare.
AB  - Aristolochic acid I, aristolochic acid II, and D-(+)-raffinose were isolated from
      Origanum vulgare. Their inhibition of thrombin and activity against leukemia were
      evaluated. Aristolochic acid I and II have high inhibition of thrombin activity
      and were confirmed to possess activity against cancer.

PMID- 12490232
TI  - Antimicrobial activity of the macrofungus Lepista nuda.
AB  - The 60% methanolic extract of Lepista nuda exhibited antimicrobial activity.

PMID- 12490233
TI  - Antimicrobial activity of Pithecolobium avaremotemo bark.
AB  - The Pithecolobium avaremotemo bark methanolic extract exhibited a broad spectrum
      and high levels of antimicrobial activity.

PMID- 12490234
TI  - Antinociceptive activity of Clausena excavata leaves.
AB  - The ethanolic extract of Clausena excavata leaves, given orally at doses of
      125.25 and 500 mg/kg body weight, showed significant antinociceptive activity on
      acetic acid induced writhing in mice.

PMID- 12490235
TI  - Antinociceptive activity of Polygonum hydropiper.
AB  - The hexane, ethylacetate and methanol extracts of Polygonum hydropiper whole
      plant administered to mice at doses of 250 and 500 mg/kg, showed a significant
      activity on acetic acid-induced writhing. Within the tested extracts, the
      ethylacetate one showed the most significant activity.

PMID- 12490236
TI  - Analgesic activity of Enhydra fluctuans.
AB  - The methanol extract of Enhydra fluctuans, given orally at the dose of 250 and
      500 mg/kg, was evaluated for its analgesic activity using the acetic acid induced
      writhing and the tail-flick methods. The extract showed promising activity in
      both tests.

PMID- 12490237
TI  - Free radical scavenging effect of Diospyros kaki, Laminaria japonica and Undaria
      pinnatifida.
AB  - Diospyros kaki folium, Laminaria japonica thallus and Undaria pinnatifida thallus
      have been used traditionally in Korea to promote maternal health. The scavenging
      activity against DPPH (1,1-diphenyl-2-picrylhydrazyl) radicals of the methanol
      extracts of these plants were investigated. The extract of D. kaki was found to
      be the most potent, with an IC(50) value of 0.11 mg/ml.

PMID- 12490238
TI  - Antimicrobial activity of Psidium guajava L.
AB  - Psidium guajava aqueous bark and methanolic extracts were found to possess anti
      bacterial activity.

PMID- 12490239
TI  - Essential oil composition and antioxidant activity of endemic Ziziphora taurica
      subsp. cleonioides.
AB  - The essential oil of Turkish endemic Ziziphora taurica subsp. cleonioides aerial
      parts was found to contain (+)-pulegone (81.86%), limonene (4.48%) and
      piperitenone (2.30%) activity. The essential oil showed relevant antioxidant
      activity.

PMID- 12490240
TI  - Antimicrobial activity of Pseudognaphalium moritzianum.
AB  - The antimicrobial activity of ethanol, acetone and aqueous extracts of the aerial
      parts of Pseudognaphalium moritzianum was evaluated. Ethanol and acetone extracts
      showed activity against Staphlococcus aureus, Enterococcus faecalis and
      Pseudomonas aeruginosa. The aqueous extract was active against S. aureus and P.
      aeruginosa.

PMID- 12490241
TI  - Biological activity of Glechoma hederacea.
AB  - The n-hexane, dichloromethane and methanol extracts of the aerial parts of
      Glechoma hederacea have been screened for antibacterial and free radical
      scavenging activity. General toxicity (brine shrimp lethality assay) of these
      extracts has also been assessed.

PMID- 12490242
TI  - Estrogenic/antiestrogenic activity of homoisoflavonoids from bulbs of Muscari
      racemosum (L.) Miller.
AB  - The homoisoflavonoid fraction obtained from the Muscari racemosum bulb ether
      extract (MRBEE) exhibited estrogenic activity by inducing proliferation of MCF7
      cells in a dose-dependent manner. In the presence of estradiol MRBEE exhibited a
      dose-dependent antiestrogenic activity.

PMID- 12490243
TI  - Hyaluronidase inhibitory activity from the polyphenols in the fruit of blackberry
      (Rubus fruticosus B.).
AB  - The hyaluronidase inhibitory activity of different fractions obtained from
      aqueous extract of blackberry fruits was evaluated. We found that only fractions
      F3 and F7 inhibit the tested enzyme.

PMID- 12490244
TI  - Tumour inhibitory activity of chicory root extract against Ehrlich ascites
      carcinoma in mice.
AB  - The tumour-inhibitory effect of an ethanolic extract of chicory root was studied
      against Ehrlich ascites carcinoma in mice; significant results were obtained at
      doses from 300 to 700 mg/kg.

PMID- 12490245
TI  - Antibacterial activity of Mappia foetida leaves and stem.
AB  - Successive petroleum ether, chloroform and methanol extracts of Mappia foetida
      leaves and stem were tested for their antibacterial activity. The methanol
      fractions were found to be most effective against all the tested organisms.

PMID- 12490246
TI  - Antimicrobial activity of Terminalia complanata and Flacourtia zippelii.
AB  - A broad spectrum of antibacterial activity was exhibited by the methanol extracts
      of leaves, root and stem barks of Terminalia complanata and Flacourtia zippelii
      and their subsequent fractions (petrol, dichloromethane, ethyl acetate).
      Fractionation enhanced the activity particularly in the ethyl acetate fractions
      of the stem and root barks of T. complanata. No activity was observed against the
      moulds.

PMID- 12490247
TI  - Antimicrobial activity of Calophyllum soulattri.
AB  - The methanol extracts of leaves, root and stem barks of Calophyllum soulattri
      were partitioned with petrol, dichloromethane, ethyl acetate. The extracts
      demonstrated a range of antibacterial activity, improved on fractionation. None
      were found to be active against the moulds.

PMID- 12490248
TI  - Antimicrobial activity of Michelia champaca.
AB  - The methanol extracts of leaves, seeds, stem and root barks, stem and root heart
      woods of Michelia champaca and the obtained fractions (petrol, dichloromethane,
      ethyl acetate, butanol) exhibited a broad spectrum of antibacterial activity.
      Fractionation drastically enhanced the level of activity particularly in all
      fractions of the stem bark and dichloromethane fraction of the root bark. Some
      fractions of the leaves, stem and root barks demonstrated antifungal activity
      against some of the tested moulds. Liriodenine was the active constituent of the
      root bark, with a broader and, in some cases, better level of activity as
      compared to the standard.

PMID- 12490249
TI  - A new phenanthridine alkaloid from Hymenocallis x festalis.
AB  - Investigation of the alkaloid fraction of the bulbs of Hymenocallis x festalis
      yielded a new natural product, 3-methoxy-8,9-methylenedioxy-3,4
      dihydrophenanthridine (1). The structure was elucidated on the basis of
      spectroscopic data.

PMID- 12490252
TI  - The central complex and the genetic dissection of locomotor behaviour.
AB  - The central complex is one of the most prominent, yet functionally enigmatic
      structures of the insect brain. Recently, behavioural, neuroanatomical and
      molecular approaches in Drosophila have joined forces to disclose specific
      components of higher locomotion control in larvae and adult flies, such as those
      that guarantee the optimal length and across-body symmetry of strides and an
      appropriate activity.

PMID- 12490253
TI  - Drugs, flies, and videotape: the effects of ethanol and cocaine on Drosophila
      locomotion.
AB  - Drosophila melanogaster has been introduced recently as a model organism in which
      to study the mechanisms by which drugs of abuse change behavior and by which the
      nervous system changes upon repeated drug exposure. Surprising similarities
      between flies and mammals have begun to emerge at the behavioral, neurochemical
      and molecular levels.

PMID- 12490254
TI  - Voltage-sensitive ion channels in rhythmic motor systems.
AB  - Voltage-sensitive ionic currents shape both the firing properties of neurons and
      their synaptic integration within neural networks that drive rhythmic motor
      patterns. Persistent sodium currents underlie rhythmic bursting in respiratory
      neurons. H-type pacemaker currents can act as leak conductances in spinal
      motoneurons, and also control long-term modulation of synaptic release at the
      crayfish neuromuscular junction. Calcium currents travel in rostro-caudal waves
      with motoneuron activity in the spinal cord. Potassium currents control spike
      width and burst duration in many rhythmic motor systems. We are beginning to
      identify the genes that underlie these currents.

PMID- 12490255
TI  - Comparative neurobiology of postural control.
AB  - In recent years, studies of nervous mechanisms for the control of body posture
      have been performed on animal models of different complexity - cat, rabbit,
      lamprey and the mollusc Clione. These studies have greatly expanded our knowledge
      of how the control system operates, how the system can change the stabilized body
      orientation and how the postural functions are distributed within different parts
      of the CNS. For simpler animal models, the postural network has been analyzed in
      considerable detail and main cell types and their interactions have been
      identified.

PMID- 12490256
TI  - Paralysis recovery in humans and model systems.
AB  - Considerable evidence now demonstrates that extensive functional and anatomical
      reorganization following spinal cord injury occurs in centers of the brain that
      have some input into spinal motor pools. This is very encouraging, given the
      accumulating evidence that new connections formed across spinal lesions may not
      be initially functionally useful. The second area of advancement in the field of
      paralysis recovery is in the development of effective interventions to counter
      axonal growth inhibition. A third area of significant progress is the development
      of robotic devices to quantify the performance level of motor tasks following
      spinal cord injury and to 'teach' the spinal cord to step and stand. Advances are
      being made with robotic devices for mice, rats and humans.

PMID- 12490257
TI  - Intrinsic processing in the mammalian superior colliculus.
AB  - The mammalian superior colliculus receives visual inputs from the retina and
      primary visual cortex in its superficial layers and sends descending motor
      commands from its deeper layers. It is now becoming clear that a connection
      exists between these layers, but the signal transmission through it is not
      robust. The induction of burst discharges in the deeper layer neurons by direct
      visual inputs from the superficial layers may lead to 'express' saccadic eye
      movements with extremely short reaction times in behaving animals.

PMID- 12490258
TI  - Cognitive motor control: spatial and temporal aspects.
AB  - Cognitive motor control refers to processes that blend cognitive and motor
      functions in a seamless, interwoven fashion. Such functions evolve in space and
      time at various levels of complexity. This article focuses on conceptual issues
      regarding spatial and temporal aspects of motor control as well as on methods
      suitable for extracting information from neuronal ensembles.

PMID- 12490259
TI  - Motor control of birdsong.
AB  - One of the challenges when considering the motor control of birdsong is to
      understand how such a wide variety of temporally and spectrally diverse
      vocalizations are learned and produced. A better understanding of central neural
      processing, together with direct endoscopic observations and physiological
      studies of peripheral motor function during singing, has resulted in the
      formation of new theoretical models of song production. Recent work suggests that
      it may be more profitable to focus on the temporal relationship between control
      parameters than to attempt to directly correlate neural processing with details
      of the acoustic output.

PMID- 12490260
TI  - The evolution of feeding motor patterns in vertebrates.
AB  - Despite considerable skepticism, researchers have found that the patterns of
      muscle activation that control feeding behaviors of lower vertebrates have been
      surprisingly conserved during evolution. This tendency for conservation among
      taxa appears in the face of marked flexibility of motor patterns within
      individuals. One interpretation of these apparently conflicting trends is that
      the most effective motor pattern for any given feeding situation is the same
      across substantial phylogenetic distances and morphological differences. The
      novel evolutionary insight provided by this research is that historical changes
      to motor patterns are a relatively infrequent source of trophic innovation. The
      spectacular diversity of feeding abilities and feeding ecology in lower
      vertebrates is based mostly on axes of variation, and on the innovations in the
      organization of muscles and the skeletal linkage systems that they drive.

PMID- 12490262
TI  - Vision in flying insects.
AB  - Vision guides flight behaviour in numerous insects. Despite their small brain,
      insects easily outperform current man-made autonomous vehicles in many respects.
      Examples are the virtuosic chasing manoeuvres male flies perform as part of their
      mating behaviour and the ability of bees to assess, on the basis of visual motion
      cues, the distance travelled in a novel environment. Analyses at both the
      behavioural and neuronal levels are beginning to unveil reasons for such
      extraordinary capabilities of insects. One recipe for their success is the
      adaptation of visual information processing to the specific requirements of the
      behavioural tasks and to the specific spatiotemporal properties of the natural
      input.

PMID- 12490263
TI  - Neural mechanisms in insect navigation: polarization compass and odometer.
AB  - Insect navigation relies on path integration, a procedure by which information
      about compass bearings pursued and distances travelled are combined to calculate
      position. Three neural levels of the polarization compass, which uses the
      polarization of skylight as a reference, have been analyzed in orthopteran
      insects. A group of dorsally directed, highly specialized ommatidia serve as
      polarization sensors. Polarization-opponent neurons in the optic lobe condition
      the polarization signal by removing unreliable and irrelevant components of the
      celestial stimulus. Neurons found in the central complex of the brain possibly
      represent elements of the compass output. The odometer for measuring travelling
      distances in honeybees relies on optic flow experienced during flight, whereas
      desert ants most probably use proprioreceptive cues.

PMID- 12490265
TI  - How lobsters, crayfishes, and crabs locate sources of odor: current perspectives
      and future directions.
AB  - Olfactory orientation poses many challenges for crustaceans in marine
      environments. Recent behavioral experiments lead to a new understanding of the
      role of multiple sensory appendages, whereas application of non-invasive chemical
      visualization techniques and biomimetic robotics have allowed researchers to
      correlate the stimulus environment with behavior and to directly test proposed
      orientation mechanisms in decapod crustaceans.

PMID- 12490264
TI  - Novel schemes for hearing and orientation in insects.
AB  - Severe size constraints are imposed on the hearing organs of insects, yet they
      perform sophisticated tasks of auditory processing. Recent research has shown how
      flies acoustically locate targets in space, how mosquitoes afford highly
      sensitive ears, and how crickets avoid deafening themselves with their songs.
      These findings unveil the exquisite analytical capabilities of highly specialized
      microscale auditory systems.

PMID- 12490266
TI  - Seeing and not seeing.
AB  - Recent studies revealed that although subterranean mammals inhabit a dark
      underground environment, they can still perceive light stimuli and use this to
      entrain their circadian activity rhythm. Regarding spatial orientation, olfactory
      and tactile cues are employed for short-distance; whereas for long-distance,
      subterranean mammals employ the earth's magnetic field and self-generated
      (vestibular and kinestatic) cues. We suggest that seismic signals, utilized for
      long-distance communication, might also be used as an echolocation mechanism to
      determine digging depth and presence of obstacles ahead. Taken together, these
      mechanisms provide an equally efficient means of overall orientation and
      communication as those found in sighted mammals.

PMID- 12490267
TI  - The magnetic sense and its use in long-distance navigation by animals.
AB  - True navigation by animals is likely to depend on events occurring in the
      individual cells that detect magnetic fields. Minimum thresholds of detection,
      perception and 'interpretation' of magnetic field stimuli must be met if animals
      are to use a magnetic sense to navigate. Recent technological advances in animal
      tracking devices now make it possible to test predictions from models of
      navigation based on the use of variations in magnetic intensity.

PMID- 12490268
TI  - Maps in birds: representational mechanisms and neural bases.
AB  - The often extraordinary navigational behavior of birds is based in part on their
      ability to learn map-like representations of the heterogeneous distribution of
      environmental stimuli in space. Whether navigating small-scale laboratory
      environments or large-scale field environments, birds appear to be reliant on a
      directional framework, for example that provided by the sun, to learn how stimuli
      are distributed in space and to represent them as a map. The avian hippocampus
      plays a critical role in some aspects of map learning. Recent results from
      electrophysiological studies hint at the possibility that different aspects of
      space may be represented in the activity of different neuronal types in the avian
      hippocampus.

PMID- 12490270
TI  - Intimal hyperplasia and coronary flow reserve after heart transplantation:
      association with big endothelin-1.
AB  - BACKGROUND: Endothelin, a peptide with strong vasoconstrictive and mitogenic
      properties, has been found to increase after cardiac transplantation. We
      therefore assessed the association between its precursor peptide, big endothelin
      1, and intimal hyperplasia and coronary flow reserve after heart transplantation.
      METHODS: Thirty-five patients without hemodynamically significant coronary artery
      disease after heart transplantation were investigated: Average peak flow velocity
      in the left anterior descending artery (LAD) was assessed by intracoronary
      Doppler at baseline as well as after injection of adenosine; coronary flow
      reserve was calculated as a ratio of both and was corrected for patient age and
      baseline average peak flow velocity. Lumen, intima + media and total vessel area
      were measured by intracoronary ultrasound. The plasma concentration of big
      endothelin-1 in venous blood was determined by radioimmunoassay. RESULTS:
      Patients with elevated big endothelin-1 levels (>2 fmol/ml) tended to have a
      decreased corrected coronary flow reserve (2.60 +/- 0.9 vs 3.21 +/- 1.0, p =
      0.078). They also had a significantly larger intima + media area (5.82 +/- 2.9 vs
      2.37 +/- 2.9 mm(2), p = 0.004) and total vessel area (18.36 +/- 5.8 vs 12.81 +/-
      4.8 mm(2), p = 0.012) than those with normal plasma concentrations. CONCLUSIONS:
      Our study suggests an association between elevated big endothelin-1 plasma levels
      and the development of intimal hyperplasia and reduction of coronary flow reserve
      after cardiac transplantation.

PMID- 12490271
TI  - Short-term angiopeptin therapy and the incidence of graft vessel disease after
      heart transplantation.
AB  - BACKGROUND: Graft vessel disease, the major limitation for long-term success
      after heart transplantation, is triggered by injury to the graft vessel
      endothelium, resulting in the expression of adhesion molecules, the migration of
      leukocytes into the graft, and the release of growth factors. Angiopeptin, a
      stable analog of somatostatin, is a growth-hormone inhibitor with additional anti
      proliferative effects. We evaluated angiopeptin for prevention of graft
      vasculopathy after cardiac transplantation in the first prospective, randomized,
      double-blind, clinical trial. METHODS: Thirty-one patients received treatment
      with either angiopeptin (n = 13) or placebo (n = 18). Patients were randomized
      according to the presence of hypercholesterolemia, recipient cytomegalovirus
      antibody status, and donor age. All patients received standard triple-drug
      immunosuppression. Angiopeptin 1.5 mg or placebo was given subcutaneously
      immediately before surgery and twice a day after transplantation from Day 1 to
      Day 14. Furthermore, 1.5 mg was added to each liter of cardioplegic solution, 1.5
      mg was given intravenously during surgery, and another 3 mg was given during the
      first 6 post-operative hours. During the first post-operative year, angiopeptin
      1.5 mg or placebo was added to each treatment for acute rejection (twice a day
      subcutaneously). Baseline angiography was performed within the first 4 post
      operative weeks and annually thereafter. Twenty-three patients each underwent an
      additional intracoronary ultrasound. RESULTS: One- and 4-year survival rates were
      comparable: 85% and 85% for the group receiving angiopeptin, and 89% and 78% for
      the placebo group, respectively. One patient in the control group died of
      myocardial infarction caused by graft vessel disease. Although the mean number of
      rejection and infection episodes was similar, the overall incidence of newly
      occurring graft vessel disease after 2 and 4 years was greater in the control
      cohort: 9% vs 38% after 2 years and 27% vs 44% after 4 years (p = 0.183, 0.448).
      Comparison of the results of intracoronary ultrasound performed in a sub-group of
      patients confirmed that trend: the modified Stanford score, the mean intimal
      thickness, and the mean intimal index were lower in the angiopeptin group. Again,
      because of the relatively small number of patients available for evaluation, the
      difference did not reach statistical significance. CONCLUSIONS: Short-term peri
      operative angiopeptin treatment along with additional injections during rejection
      episodes within the first year resulted in a marked decrease in graft vessel
      disease 2 and 4 years after heart transplantation. Based on our results,
      continuous, long-term application of slow-release angiopeptin could significantly
      decrease or even prevent graft vessel disease.

PMID- 12490272
TI  - Emergence of ganciclovir-resistant cytomegalovirus in lung transplant recipients.
AB  - BACKGROUND: Since ganciclovir-resistant cytomegalovirus (CMV) disease was
      initially described in a patient with acquired immunodeficiency syndrome (AIDS)
      in 1986, the incidence of ganciclovir-resistant CMV disease appears to be
      increasing in immunocompromised patients. More recently, there have been sporadic
      reports of ganciclovir-resistant CMV disease in solid organ transplantation.
      METHODS: We retrospectively assessed the incidence of ganciclovir-resistant CMV
      disease in all lung transplant recipients transplanted between 6/93 and 6/01 at
      Loyola University Medical Center. All patients underwent routine CMV blood
      culture, shell vial assay as well as phenotypic and genotypic anti-viral
      susceptibility testing according to a pre-determined schedule. The number of CMV
      episodes, intravenous ganciclovir use, acute and chronic rejection and survival
      data were documented for all patients. RESULTS: Twelve of 212 (6%) transplant
      recipients developed ganciclovir-resistant CMV disease. Ganciclovir resistance
      was associated with a higher number of CMV episodes (3.4 +/- 2.3 episodes/patient
      vs 1.7 +/- 0.7 episodes/patient [p < 0.05]) and an increased exposure to
      cumulative intravenous ganciclovir in the primary CMV-mismatched (D(+)R(-))
      population (22 +/- 10 vs 13 +/- 7 days [p < 0.05]) compared with patients who did
      not develop ganciclovir resistance. In addition, the use of daclizumab therapy
      was associated with a 7-fold greater likelihood of developing ganciclovir
      resistance (p < 0.0001). The presence of ganciclovir-resistant CMV disease in our
      population was associated with a decreased survival that could be attributed to
      CMV disease itself (p < 0.05). CONCLUSIONS: By screening all lung transplant
      recipients with CMV disease for ganciclovir resistance, we were able to detect a
      higher incidence of ganciclovir-resistant CMV disease (6%) than previously seen
      in solid organ transplantation. High-risk patients (D(+)R(-) CMV serostatus) who
      receive anti-lymphocytic therapy should be monitored aggressively and treated to
      prevent the development of ganciclovir resistance and avert a negative outcome.

PMID- 12490273
TI  - Heparin-induced thrombocytopenia: a common complication in cardiac transplant
      recipients.
AB  - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an idiosyncratic
      complication of heparin therapy triggered by the development of immunoglobulin G
      (IgG) antibodies to platelet factor 4 heparin. It typically results in a 50%
      decrease in platelet count. Paradoxically, although bleeding is rare, there is a
      high risk of venous or arterial thrombotic events. Given that many patients
      awaiting transplantation are exposed to heparin for prolonged periods, we sought
      to determine the frequency of HIT and its consequences among patients before and
      after cardiac transplantation. METHODS: We reviewed retrospectively the clinical,
      pathologic, and laboratory databases for all patients who underwent heart
      transplantation at our institution between January 1, 1998, and December 31,
      2000. An enzyme-linked immunoabsorption assay (ELISA) that detected IgG, IgA, and
      IgM antibodies directed against platelet factor 4 heparin complex confirmed the
      diagnosis of HIT. We analyzed bleeding and thrombotic complications and
      determined the influence of HIT on post-transplant outcomes. RESULTS: An assay
      for HIT antibody was performed before or after transplantation in 26 of 46
      patients (46% of the entire cohort). In all cases, the clinical indication for
      testing was thrombocytopenia. Among patients screened, HIT antibody was detected
      in 11 patients (39%); HIT developed in 10 of 11 patients before transplantation.
      The mean platelet count at diagnosis was 88,000 +/- 22,000/mm(3). Heparin-induced
      thrombocytopenia with thrombosis syndrome developed in 5 of 11 patients (45%).
      Manifestations included splenic and renal infarctions, renal artery occlusion,
      coronary artery embolism with myocardial infarction, pulmonary embolism, and
      femoral and jugular venous occlusions. Alternative pre-operative anti-coagulation
      included lepirudin (n = 7), argatroban (n = 1), dalteparin (n = 1), and abciximab
      (n = 1). Two deaths occurred in the HIT-positive group; neither bleeding nor
      thrombosis caused either death. Actuarial 36-month survival did not differ
      between HIT-positive and HIT-negative cohorts (78% and 79%, respectively).
      CONCLUSION: Heparin-induced thrombocytopenia is a frequent complication among
      patients hospitalized for heart failure who are awaiting heart transplantation.
      Timely HIT-antibody screening and the use of alternative forms of systemic anti
      coagulation may permit successful transplantation with intermediate survival
      rates comparable to those of HIT-negative recipients.

PMID- 12490274
TI  - Tolerability of carvedilol in patients with heart failure and concomitant chronic
      obstructive pulmonary disease or asthma.
AB  - BACKGROUND: A substantial proportion of the population with congestive heart
      failure (CHF) has concomitant airway disease. Little information exists on the
      tolerability of carvedilol in patients with chronic obstructive pulmonary disease
      (COPD). In this study, we assessed the tolerability and efficacy of carvedilol in
      patients with CHF and concomitant COPD or asthma. METHODS: Between 1996 and 2000,
      a total of 487 patients began receiving open-label carvedilol. Forty-three (9%)
      had COPD (n = 31) or asthma (n = 12). Spirometry supported clinical diagnosis in
      all, and full pulmonary function testing supported diagnosis in 71%. Sixty
      percent began carvedilol therapy in the hospital and underwent measurement of
      peak expiratory flow rates (PEFR) before and after dosing. RESULTS: In patients
      with COPD, mean forced expiratory volume in one second (FEV(1)) was 62% +/- 13%
      predicted, reversibility was 4% +/- 4% with bronchodilators, and FEV(1)/FVC was
      62% +/- 8%. Mean PEFR was 325 +/- 115 liter/min before the dose and increased by
      17% 2 hours after the carvedilol dose (p = 0.04). In patients with asthma, mean
      FEV(1) was 80% +/- 17% predicted, reversibility was 13% +/- 7%, and FEV(1)/FVC
      was 74% +/- 11%. Mean PEFR was 407 +/- 161 liter/min before the dose with no
      significant change 2 hours after the dose. Carvedilol was introduced safely in
      84% of patients with COPD, with only 1 patient withdrawn from therapy for
      wheezing. In contrast, only 50% of patients with asthma tolerated carvedilol.
      Survival at 2.5 years was 72%. In survivors, left ventricular end-diastolic
      diameter decreased from 76 +/- 11 mm to 72 +/- 14 mm (p = 0.01), left ventricular
      end-systolic diameter decreased from 65 +/- 13 mm to 60 +/- 15 mm (p = 0.01), and
      fractional shortening increased from 14% +/- 7% to 17% +/- 7% (p = 0.05) at 12
      months. CONCLUSIONS: Patients with CHF and COPD tolerated carvedilol well with no
      significant reversible airflow limitation, but patients with CHF and asthma
      tolerated carvedilol poorly. The effect of carvedilol on left ventricular
      dimensions and function in patients with concomitant airway diseases was similar
      to that seen in our general group of patients. Asthma remains a contraindication
      to beta-blockade.

PMID- 12490275
TI  - A novel heparin-binding, human chimeric, superoxide dismutase improves myocardial
      preservation and protects from ischemia-reperfusion injury.
AB  - BACKGROUND: The plasma membranes of endothelial cells are sites of physiologic
      injury caused by superoxide attack, whether the radicals are generated within the
      cell (i.e., from enzymatic sources such as xanthine oxidase or from ischemically
      injured mitochondria) or are generated within the interstitial spaces by
      activated neutrophils or macrophages. An extracellular superoxide dismutase
      (ECSOD) electrostatically bound to endothelial surfaces partially protects
      against this oxidative attack. To provide a therapeutic equivalent of this ECSOD
      activity, we evaluated the product of a fusion gene encoding a chimeric manganese
      SOD (chimeric-SOD) and the carboxyl-terminal 26-amino acid basic "tail" from
      ECSOD with high affinity for heparin-like proteoglycans on cell surfaces.
      METHODS: We tested the chimeric-SOD in isolated rabbit hearts during warm and
      cold ischemia. RESULTS: When perfused through an isolated rabbit heart, chimeric
      SOD bound to endothelial surfaces and was displaced by a bolus dose of heparin.
      In an established model of no-flow ischemia followed by reperfusion of the
      isolated rabbit heart, the chimeric-SOD was as protective as native Mn-SOD or
      Cu,Zn-SOD, but at doses nearly 2 orders of magnitude lower. In a rabbit-heart
      preservation model, the chimeric-SOD provided better recovery of function after 4
      hours of cold ischemia than did University of Wisconsin cardioplegia solution.
      CONCLUSION: This chimeric-SOD can bind to cell surfaces and may aid in preventing
      superoxide-mediated endothelial damage and may function as a rational therapeutic
      agent for treating free-radical-mediated diseases.

PMID- 12490276
TI  - Successful treatment with rituximab of lymphoproliferative disorder in a child
      after cardiac transplantation.
AB  - Post-transplantation lymphoproliferative disorders (PTLDs) are life-threatening
      complications. We report the case of a 7-year-old girl in whom a
      lymphoproliferative disorder developed more than 2 years after cardiac
      transplantation. The patient was taking ganciclovir for Epstein-Barr virus
      hepatitis at the time the PTLD occurred. Rituximab, an anti-CD20 monoclonal
      antibody, given in the presence of reduced immunosuppression therapy, resulted in
      a complete response of the PTLD. The Epstein-Barr viral load in the peripheral
      blood, which was extremely high at diagnosis, dropped promptly and remained below
      the detection threshold 11 months after completion of therapy. We observed
      complete depletion of B lymphocytes until 7 months after rituximab therapy, which
      was associated with an important decrease in immunoglobulin levels.

PMID- 12490277
TI  - Use of a donor heart with symptomatic WPW in an alternate donor program.

PMID- 12490278
TI  - PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a
      mouse heterotopic tracheal allograft model.
AB  - The current treatment of obliterative bronchiolitis in lung transplant recipients
      is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of
      action distinct from currently available immunosuppressants, including induction
      of T-cell apoptosis, blockade of fibroblast proliferation/maturation and
      inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We
      hypothesized that triptolide may be helpful in blocking obliterative airway
      disease in lung transplant recipients. We investigated the effect of PG490-88, a
      water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft
      model of obliterative airway disease. We show that PG490-88 attenuates airway
      obliteration in this model and inhibits accumulation of inflammatory cells, and
      therefore may have preventive or therapeutic benefits for patients with
      obliterative airway disease (OAD) following lung transplantation.

PMID- 12490279
TI  - Aortic graft transplantation in mice.

PMID- 12490280
TI  - Low protein Z levels and risk of ischemic stroke: differences by diabetic status
      and gender.
AB  - Protein Z was recently shown to act as an essential cofactor for protein Z
      dependent protease inhibitor, a potent downregulator of coagulation Factor Xa.
      Thus, deficiency of protein Z is hypothesized to lead to a prothrombotic state,
      but two publications reported opposing results for the relationship of protein Z
      levels with ischemic stroke in young European subjects (mean age 33-40 years). We
      performed a study of stroke in a different ethnic population of greater mean age
      (57 years) to further clarify this issue. An ELISA was developed to measure
      protein Z antigen in 154 patients with ischemic stroke and in 206 controls in a
      largely Hispanic population. Low plasma protein Z values were significantly
      associated with ischemic stroke except in diabetic subjects and females. The mean
      protein Z value was significantly lower in stroke cases than in controls for
      nondiabetic subjects [1.78 +/- 0.77 (S.D.) versus 2.28 +/- 0.88 microg/ml, P <
      0.0001] and for males (1.90 +/- 0.90 versus 2.42 +/- 0.99 microg/ml, P = 0.0004).
      Stroke risk was higher in subjects with protein Z levels at or below the
      fifteenth percentile of controls (</=1.46 microg/ml). The odds ratios were: 2.6
      for all subjects (95% C.I. = 1.5-4.3); 3.8 for nondiabetic subjects (95% C.I. =
      2.2-6.8); and 3.6 for males (95% C.I. = 2.0-6.4). This study also revealed high
      protein Z levels associated with high triglyceride levels in controls (P =
      0.015). Protein Z is suggested to be a physiologic downregulator of blood
      coagulation and low protein Z levels are associated with increased risk of
      ischemic stroke, particularly in males and in the absence of diabetes.

PMID- 12490281
TI  - Cloning MafF by recognition site screening with the NFE2 tandem repeat of HS2:
      analysis of its role in globin and GCSl genes regulation.
AB  - The erythroid-specific enhancer within hypersensitivity site 2 (HS2) of the human
      beta-globin locus control region is required for high level globin gene
      expression. We used an oligonucleotide of the NF-E2 tandem repeat, within HS2, as
      recognition site probe to screen a K562 cDNA library for interacting
      transcription factors. A 2.3 kb full length cDNA encoding the b-zip transcription
      factor MafF was isolated. MafF can form both homodimers and high affinity
      heterodimers with Nrf1, Nrf2 and Nf-E2, three members of the CNC-bZip family.
      Despite obvious structural similarities with the other small Maf proteins, MafF
      differs in its tissue distribution and its inability to repress transcription
      when overexpressed as homodimer. In fact, in different cell lines and on
      different promoters (gamma-globin, beta-globin and glutamylcysteine synthetase
      genes) the MafF homodimers do not appreciably affect transcription of target
      promoters, whereas MafF/CNC member heterodimers act as weak transcriptional
      activators. Even though MafF was cloned using probes derived from the globin LCR,
      it is in the context of the GCSl promoter and in combination with Jun that MafF
      shows a rather distinct and specific regulatory role. These observations suggest
      that a complex network of small Maf and CNC-AP1 protein interactions might be
      involved in regulating transcription in diverse tissues or developmental stages.

PMID- 12490282
TI  - The hematopoietic defect in PNH is not due to defective stroma, but is due to
      defective progenitor cells.
AB  - Although paroxysmal nocturnal hemoglobinuria (PNH) is often associated with
      aplastic anemia (AA), the nature of the pathogenetic link between PNH and AA
      remains unclear. Moreover, the PIG-A mutation appears to be necessary but not
      sufficient for the development of PNH, suggesting other factors are involved. The
      ability of PNH marrow cells to form in vitro hematopoietic colonies and the
      ability of PNH marrow to generate stroma that could support hematopoiesis of
      normal or PNH marrow in cross culture were investigated. PNH marrow from both
      post-Ficoll and post-lineage depleted hematopoietic progenitor cells grew
      similarly significantly fewer colonies than normal marrow. Sorting of CD59(+) and
      CD59(-) CD34(+) CD38(-) cells from patients with PNH showed similarly impaired
      clonogenic efficiency, indicating that the hematopoietic defect in PNH does not
      directly relate to GPI-anchored protein expression. PNH marrow readily grew
      stroma similar to marrow from normal donors. Cross culture experiments revealed
      that PNH stroma appears to function normally in vitro; it can support growth of
      normal marrow cells as well as normal stroma does, but neither PNH nor normal
      stroma could support the growth of PNH marrow cells. The hematopoietic defect in
      PNH is not due to defective stroma, but is due to defective progenitor cell
      growth related to additional unknown factors.

PMID- 12490283
TI  - Genetic heterogeneity underlies juvenile hemochromatosis phenotype: analysis of
      three families of northern Greek origin.
AB  - Hereditary hemochromatosis is a genetically heterogeneous disease. Common HFE
      mutations (C282Y and H63D) are related to the majority of hereditary
      hemochromatosis cases in populations of Northern European ancestry (HFE1).
      Juvenile hemochromatosis (JH) is a more severe iron overload disorder, usually
      presenting at the second decade of life. The gene responsible for JH lies on a
      genetic locus at chromosome 1q. We have performed a genetic linkage study in
      three families of Northern Greek origin with typical clinical features of JH. In
      two families results were in accordance with linkage to chromosome 1q. In one
      family linkage of the disease to the genetic loci at 1q21, 7q22, and 6p22 was
      excluded. We suggest that more than one gene may underlie the JH phenotype. This
      genetic type of hemochromatosis may be designated 1q unlinked juvenile
      hemochromatosis. Family studies are necessary to establish the genetic diagnosis
      of JH.

PMID- 12490284
TI  - A novel single nucleotide polymorphism in the 3' untranslated region of human
      glutathione peroxidase 4 influences lipoxygenase metabolism.
AB  - Selenium (Se) is an essential micronutrient for human health. The biological
      roles of the essential micronutrient Se are attributed to its presence in a range
      of 20-30 selenoproteins including the cytosolic and phospholipid hydroperoxide
      glutathione peroxidases (GPX1 and GPX4). It has been suggested that GPX4 may play
      a role in regulation of leukotriene biosynthesis and thus inflammation. In
      eukaryotes Se is incorporated into selenoproteins as the amino acid
      selenocysteine in a process requiring a stem-loop within the 3' untranslated
      region (3'UTR) of the mRNA. In this study the region of the GPX4 gene
      corresponding to the 3'UTR was scanned for mutations in a group of 66 volunteers.
      The data show a T/C variant at position 718. The distribution of this SNP in our
      population was 34% CC, 25% TT and 41% TC; i.e., it is in Hardy-Weinberg
      equilibrium. Individuals of different genotypes exhibited significant differences
      in the levels of lymphocyte 5-lipoxygenase total products, with C718 showing
      increased levels of those products compared to T718 and T/C718 (36% and 44%
      increases, respectively). The data suggest that the SNP718 that we have
      identified has functional effects and support the hypothesis that GPX4 plays a
      regulatory role in leukotriene biosynthesis.

PMID- 12490285
TI  - Gene expression levels of cytokine profile and cytotoxic markers in non-immediate
      reactions to drugs.
AB  - Drugs can induce IgE mediated or T cell dependent immunological reactions. T cell
      dependent reactions are poorly understood, although T lymphocytes have been
      proposed as a protagonist in a number of non-immediate immunological reactions
      (NIR). The objective was to study in vivo different regulatory and
      proinflammatory cytokines and cytotoxic markers in patients with NIR to drugs.
      Twenty patients with NIR after drug intake were classified into two groups: Group
      A (severe), Stevens-Johnson syndrome and toxic epidermal necrolysis; and Group B
      (mild), maculopapular exanthema and desquamative exanthema. Another 25 subjects
      taking the same drugs but without reactions formed a control group. Samples were
      obtained within 24 hours of the reaction and 30 days later. IL-2, IL-4, IFN, TNF,
      perforin, granzyme B (GrB), and FasL mRNA expression levels were determined in
      peripheral blood mononuclear cells by competitive RT-PCR. There were 9 patients
      in Group A and 11 in Group B. The drugs involved were betalactams (8),
      anticonvulsants (6), allopurinol (1), sulfamethoxazole (1), amiodarone (1)
      dypirone (2), and erythromicine+paracetamol (1). At the acute stage there was a
      high increase of IL-2, IFN, and TNF mRNA expression in both groups vs. controls,
      perforin and GrB varied in each group with patients in Group A having the highest
      values, and FasL was only expressed in Group A. Relationships between the
      cytokines were only significant in Group B (p < 0.05). Only the relation between
      IFN-gamma and TNF-alpha was significant in Group A. There was a significant
      correlation between cytotoxic markers in both groups (A: p < 0.001, B: p < 0.01).
      These data demonstrate the complexity of the Th1 phenotype in NIR after drug
      intake. In patients with mild NIR, cytokines appear to play a closely related
      role, whereas cytotoxic markers appear more relevant in severe reactions.

PMID- 12490286
TI  - Activated protein C-dependent and -independent anticoagulant activities of
      protein S have different structural requirements.
AB  - Plasma protein S exhibits multiple anticoagulant activities. About 20% of protein
      S normally circulates in a form that is cleaved in its thrombin-sensitive region
      (TSR, residues 47-72) and this cleaved protein S is inactive as a cofactor for
      activated protein C (APC). To clarify whether the same cleavage(s) in the TSR
      neutralizes both APC-cofactor and APC-independent direct anticoagulant
      activities, protein S was treated with several proteases, and activities and
      cleavages were monitored. Thrombin cleaved protein S first at Arg49, which
      abolished protein S APC-cofactor activity, but not APC-independent activity. A
      slower second thrombin cleavage at Arg70 abolished the direct prothrombinase
      inhibitory activity of protein S and its ability to bind phospholipids. Factor Xa
      cleaved protein S only at Arg60 and abolished APC-cofactor activity but not APC
      independent anticoagulant activity. The snake venom enzyme Protac C efficiently
      cleaved protein S at two sites in the TSR, which impaired both types of protein S
      anticoagulant activity in the presence of phospholipids. Protac C-cleaved protein
      S did not compete with Factor Xa for limiting phospholipid surfaces but could
      still inhibit prothrombinase activity in the absence of phospholipids. Thus, the
      APC-cofactor activity protein S is significantly more sensitive to structural
      changes in the TSR than is the APC-independent activity of protein S.

PMID- 12490287
TI  - The mechanism of loss of CR1 during maturation of erythrocytes is different
      between factor I deficient patients and healthy donors.
AB  - During the in vivo maturation of erythrocytes, the number of CR1 per cell
      decreases by approximately two-thirds in 30 days. The CR1 loss is enhanced in
      several diseases such as SLE, AIDS, and particularly in factor I deficiency.
      Microvesicles enriched in CR1 and DAF are released from erythrocytes matured in
      vitro, leading to the same loss of both molecules. When comparing reticulocytes
      and erythrocytes, CR1 and DAF were lost similarly in 15 normal individuals,
      suggesting that vesiculation may be at the origin of CR1 loss in vivo. However,
      the enhanced loss of CR1 in 3 patients with factor I deficiency was contrasted
      with a normal loss of DAF, raising the possibility that, in this pathological
      condition, CR1 might be proteolytically cleaved, leaving small CR1 fragments on
      the erythrocytes. To answer this question, a rabbit polyclonal antibody was
      raised against the cytoplasmic (tail) domain of CR1, which recognised
      specifically CR1 of erythrocytes and urinary vesicles on Western blots. However,
      no CR1 fragments could be detected on erythrocytes of the factor I deficient
      patients although this antibody was able to recognise CR1 fragments after
      treatment of normal erythrocytes or urinary vesicles with elastase. These data
      suggest that cell surface domains rich in CR1, but not in DAF, are specifically
      lost in factor I deficiency.

PMID- 12490288
TI  - Progesterone upregulates GATA-1 on erythroid progenitors cells in liquid culture.
AB  - Steroids hormones modify the hematological features of homozygous sickle cell
      disease, including the levels of fetal hemoglobin. We used semi-quantitative RT
      PCR analysis of GATA-1, GATA-2, NF-E2, and gamma-globin mRNA levels in a two
      phase liquid culture system of human adult erythroid cells in order to assay the
      effect of progesterone upon gene expression. The levels of expression of GATA-1
      and gamma-globin mRNA were significantly increased in cells treated with
      progesterone compared to untreated cells (1.7- to 2.0-fold). Progesterone
      treatment did not produce any stimulatory effect upon GATA-2 and NF-E2 mRNA
      expression. Differences in the synthesis of HbF protein could not be detected by
      flow cytometry, although we observed a small difference in mean intensity
      fluorescence between cells treated and cells untreated with progesterone on days
      7 and 9. Using anti-transferrin receptor and anti-glycophorin A antibodies, we
      verified that addition of progesterone did not cause any change in erythroid
      proliferation and differentiation. In conclusion, it is possible that the
      increased expression of gamma-globin mRNA after progesterone treatment observed
      in this study may be related to the increased GATA-1 mRNA expression.
      Interactions of the steroid receptors with the basal transcriptional machinery
      and with transcription factors might mediate their transcriptional effects.

PMID- 12490289
TI  - Alterations in skeletal protein, distribution of PKCalpha, and level of
      phospholipids in erythrocyte membranes of women with primary breast cancer.
AB  - The aim of our work was to study the influence of primary breast cancer on mature
      erythrocyte membranes. Blood was sampled from 29 women with primary breast
      cancer, aged 35-86 years, in different stages of clinical progression of the
      disease. In red blood cell membranes an increase of phosphatidylinositol-4
      phosphate and phosphatidylinositol-4,5-diphosphate levels was observed. These
      changes were accompanied by a decrease in phospholipase C activity.
      Simultaneously, a significant decrease in concentration of phosphatidylserine,
      sphingomyelin, and phosphatidylinositol was found. Quantitative protein
      evaluation showed an increase in band 4.1 protein content with no changes in the
      level of constitutive PKCalpha responsible for the phosphorylation of this
      protein and its affinity to glycophorine C. In parallel a greater increase of
      PKCalpha translocation after PMA treatment compared to controls was observed.
      Possible oxidative damage of erythrocyte membranes indicated by an increase in
      malonyldialdehyde level and decrease in SH-group content as well as by an
      increase in the w/ ratio was documented. From the results it is concluded that
      primary breast cancer seems to affect the membranes of mature erythrocytes.

PMID- 12490290
TI  - Characterization of a novel hematopoietic marker expressed from early embryonic
      hematopoietic stem cells to adult mature lineages.
AB  - A novel membrane protein has been identified in the course of screening for
      differentially expressed cDNAs in human embryonic hematopoietic sites. This 37-
      to 38-kDa molecule, designated KLIP-1 (killer lineage protein), consisting of 350
      amino acids and containing five transmembrane domains, is encoded by the 5093-bp
      KLIP-1 gene, composed of nine exons and located on chromosome 6 (6p21.1-6p21.2).
      We found the KLIP-1 protein to be expressed by nucleated hematopoietic cells,
      from early embryonic hematopoietic stem cells through mature adult blood lymphoid
      lineages, either as membrane or as cytoplasmic molecules. In day-30/32 human
      embryo sections, KLIP-1 protein expression is restricted to circulating
      hematopoietic cells at hematopoiesis sites. Membrane KLIP-1 is expressed by fetal
      and adult GP-A(+) erythroblasts, the fetal liver CD34(+) subset, fetal spleen,
      and adult bone marrow CD56(+) NK and CD19(+) B cells. Among mature blood cells,
      surface KLIP-1 expression is restricted to CD56(+) NK cells, indicating KLIP-1 to
      be a novel marker of this population. Altogether, these results indicate that
      membrane export of KLIP-1 antigen is developmentally and ontogenetically
      regulated. The high degree of conservation of the KLIP-1 protein sequence among
      mammals strongly suggests that it plays an important role during hematopoiesis
      and may exercise similar functions in human and mouse blood cells. The KLIP-1
      molecule may therefore constitute a powerful tool for improving knowledge of both
      human hematopoiesis and NK cell ontogeny and immune functions.

PMID- 12490292
TI  - From endoderm formation to liver and pancreas development in zebrafish.
AB  - Recent studies in zebrafish have contributed to our understanding of early
      endoderm formation in vertebrates. Specifically, they have illustrated the
      importance of Nodal signaling as well as three transcription factors,
      Faust/Gata5, Bonnie and Clyde, and Casanova, in this process. Ongoing genetic and
      embryological studies in zebrafish are also contributing to our understanding of
      later aspects of endoderm development, including the formation of the gut and its
      associated organs, the liver and pancreas. The generation of transgenic lines
      expressing GFP in these organs promises to be particularly helpful in such
      studies.

PMID- 12490293
TI  - Mechanisms controlling early development of the liver.
AB  - Over the last decade significant advances have been made in our understanding of
      the molecular mechanisms that control early aspects of mammalian liver
      development. Studies using tissue explant cultures and molecular biology
      techniques as well as the analysis of transgenic and knockout mice have
      identified signaling molecules and transcription factors that are necessary for
      the onset of hepatogenesis. This review presents an overview of these studies and
      discusses the role of individual factors during hepatic development.

PMID- 12490294
TI  - Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse
      embryogenesis.
AB  - Lineage tracing follows the progeny of labeled cells through development. This
      technique identifies precursors of mature cell types in vivo and describes the
      cell fate restriction steps they undergo in temporal order. In the mouse
      pancreas, direct cell lineage tracing reveals that Pdx1- expressing progenitors
      in the early embryo give rise to all pancreatic cells. The progenitors for the
      mature pancreatic ducts separate from the endocrine/exocrine tissues before
      E12.5. Expression of Ngn3 and pancreatic polypeptide marks endocrine cell
      lineages during early embryogenesis, and these cells behave as transient
      progenitors rather than stem cells. In adults, Ngn3 is expressed within the
      endocrine islets, and the NGN3+ cells seem to contribute to pancreatic islet
      renewal. These results indicate the stage at which each progenitor population is
      restricted to a particular fate and provide markers for isolating progenitors to
      study their growth, differentiation, and the genes necessary for their
      development.

PMID- 12490295
TI  - Hedgehog signaling in pancreas development.
AB  - Hedgehog proteins are secreted molecules that bind to their cell surface
      receptors to elicit concentration dependent responses essential for numerous
      tissue patterning and cell differentiation events during embryogenesis. However,
      during early stages of pancreas organogenesis, hedgehog signaling has been shown
      to inhibit tissue morphogenesis and cell differentiation. By contrast, recent
      cell culture studies indicate that an active hedgehog pathway might be required
      for maintenance of adult endocrine cell functions. This review describes our
      current understanding of the requirement of hedgehog signaling during pancreas
      morphogenesis and cell differentiation and discusses how individual hedgehog
      genes might act at various stages to ensure proper pancreas development and organ
      function.

PMID- 12490296
TI  - Role of endothelial cells in early pancreas and liver development.
AB  - Liver and pancreas initially develop by budding from the embryonic endoderm. The
      formation of these organs coincides with the appearance of endothelial cells
      (ECs) adjacent to the endoderm. ECs either develop in situ in organs, or are
      recruited by organs and are induced to form blood vessels. Recent reports on
      liver and pancreas have now shown that ECs also induce essential steps in organ
      formation such as morphogenesis and cell differentiation. This review summarizes
      reports on EC signaling during organogenesis and cell differentiation.

PMID- 12490297
TI  - Gene expression cascades in pancreatic development.
AB  - The specialized endocrine and exocrine cells of the pancreas originally derive
      from a pool of apparently identical cells in the early gut endoderm. Serial
      changes in their gene expression program, controlled by a hierarchy of pancreatic
      transcription factors, direct this progression from multipotent progenitor cell
      to mature pancreatic cell. When the cells differentiate, this hierarchy of
      factors coalesces into a network of factors that maintain the differentiated
      phenotype of the cells. As we develop an understanding of the pancreatic
      transcription factors, we are also acquiring the tools with which we can
      ultimately control pancreatic cell differentiation.

PMID- 12490298
TI  - Development of the biliary tract.

PMID- 12490299
TI  - Embryonic liver cells and permanent lines as models for hepatocyte and bile duct
      cell differentiation.
AB  - Analysis of liver cells during development is facilitated by the possibility of
      complementing in vivo analysis with experiments on cultured cells. In this
      review, we discuss results from several laboratories concerning bipotential
      hepatic stem cells from mouse (HBC-3, H-CFU-C, MMH and BMEL), rat (rhe14321) and
      primate (IPFLS) embryos. Several groups have used fluorescence-activated cell
      sorting to identify clonogenic bipotential cells; others have derived bipotential
      cell lines by plating liver cell suspensions and cloning. The bipotential cells,
      which probably originate from hepatoblasts, can differentiate as hepatocytes or
      bile duct cells, and undergo morphogenesis in culture. Disparities in
      differentiation can be explained by distinct medium compositions, extracellular
      matrix coated culture surfaces, and gene expression detection methods. Potential
      applications of these cell lines are discussed.

PMID- 12490300
TI  - Pancreatic-hepatic switches in vivo.
AB  - The existence of a common endodermal progenitor cell to both pancreas and liver
      is suggested by anatomy of the development of pancreatic and liver buds in
      embryogenesis. Here we review the large body of evidence that pancreas to liver
      and liver to pancreas cell differentiation can also occur in adult life. The
      published data are consistent with the hypothesis that endodermal progenitor
      cells, capable of giving rise to multiple hepatic and pancreatic cell types
      continue to persist. These cells may represent a stem cell reservoir with
      potential in cell therapy applications in the future.

PMID- 12490301
TI  - Transdifferentiation of pancreas to liver.
AB  - Transdifferentiation is the name used to describe the direct conversion of one
      differentiated cell type into another. Cells which have the potential to
      interconvert by transdifferentiation generally arise from adjacent regions in the
      developing embryo. For example, the liver and pancreas arise from the same region
      of the endoderm. The transdifferentiation of pancreas to liver (and vice versa)
      has been observed in animal experiments and in certain human pathologies.
      Understanding transdifferentiation is important to developmental biologists
      because it will help elucidate the cellular and molecular differences that
      distinguish neighbouring regions of the embryo. While the in vivo models for the
      transdifferentiation of liver to pancreas have been valuable, it is more
      difficult to extrapolate from these studies to individual changes at the cellular
      or molecular levels. The recent development of two in vitro systems (AR42J cells
      and embryonic pancreatic cultures) for the transdifferentiation of pancreas to
      liver has shown that an environmental change in the form of an exogenous
      glucocorticoid can cause the conversion of pancreatic exocrine cells into
      hepatocytes. The AR42J cell system has been used to elucidate the cell lineage
      and the molecular basis of transdifferentiation of pancreas to liver.

PMID- 12490302
TI  - The role of hepatocytes and oval cells in liver regeneration and repopulation.
AB  - The liver has the unique capacity to regulate its growth and mass. In rodents and
      humans, it grows rapidly after resection of more than 50% of its mass. This
      growth process, as well as that following acute chemical injury is known as liver
      regeneration, although growth takes place by compensatory hyperplasia rather than
      true regeneration. In addition to hepatocytes and non-parenchymal cells, the
      liver contains intra-hepatic "stem" cells which can generate a transit
      compartment of precursors named oval cells. Liver regeneration after partial
      hepatectomy does not involve intra or extra-hepatic (hemopoietic) stem cells but
      depends on the proliferation of hepatocytes. Transplantation and repopulation
      experiments have demonstrated that hepatocytes, which are highly differentiated
      and long-lived cells, have a remarkable capacity for multiple rounds of
      replication. In this article, we review some aspects of the regulation of
      hepatocyte proliferation as well as the interrelationships between hepatocytes
      and oval cells in different liver growth processes. We conclude that in the
      liver, normally quiescent differentiated cells replicate rapidly after tissue
      resection, while intra-hepatic precursor cells (oval cells) proliferate and
      generate lineage only in situations in which hepatocyte proliferation is blocked
      or delayed. Although bone marrow stem cells can generate oval cells and
      hepatocytes, transdifferentiation is very rare and inefficient.

PMID- 12490303
TI  - Hepatic regeneration from hematopoietic stem cells.
AB  - In recent years, numerous investigators have reported novel cellular fates of
      multipotent stem or progenitor cells. In this review, we discuss the unexpected
      observations that hematopoietic stem cells can contribute to the hepatocyte
      lineage in humans and in rodent models of liver disease and regeneration. A key
      unresolved issue regarding hepatic regeneration from hematopoietic stem cells is
      whether the mechanism occurs through transdetermination, cell fusion, or other
      processes. A better understanding of the various stem or progenitor cells of the
      hepatic lineage may facilitate cellular transplantation approaches for the
      correction of hepatic function in patients with end-stage liver disease.

PMID- 12490304
TI  - Ras superfamily monomeric G proteins in carcinoma cell motility.
AB  - With over 100 members in humans, the Ras superfamily is a diverse group of
      monomeric G proteins participating in many cellular processes. Members of the
      Ras, Rho, and Arf families have been shown to regulate cell motility in
      fibroblasts and epithelial cells. Ras and Rho family members are also widely
      involved in human tumorigenesis, either through activating mutations or by
      overexpression. In this review, tools for studying carcinoma cell migration are
      discussed and evidence for regulation of carcinoma cell motility by specific Ras
      superfamily members is summarized. Novel emerging mechanisms of migration in
      carcinoma cells involving RhoC and Ral are also discussed.

PMID- 12490305
TI  - Role of site-specific promoter hypomethylation in aberrant MUC2 mucin expression
      in mucinous gastric carcinomas.
AB  - In the present work we investigated the methylation levels of mucin gene (MUC)2
      promoter region in normal gastric mucosa and mucinous gastric carcinoma in order
      to access if the observed de novo expression of the intestinal mucin MUC2 in
      mucinous gastric carcinoma is associated with changes in MUC2 promoter
      methylation status. The results obtained by methylation-sensitive single
      nucleotide primer extension suggest that MUC2 expression in gastric cells is
      regulated by promoter methylation and further indicate that two specific cytosine
      guaine dinucleotide (CpG) sites may play a particularly important regulatory
      role.

PMID- 12490306
TI  - Microsatellite alterations in esophageal dysplasia and squamous cell carcinoma
      from laser capture microdissected endoscopic biopsies.
AB  - Esophageal squamous cell carcinoma (ESCC), with a 5 year survival below 15%, is
      one of the most common fatal cancers worldwide. Significant reduction in
      mortality may be achieved by detecting and treating asymptomatic precursor
      lesions and curable early cancers. To explore this possibility and look for
      potential early detection markers, we examined alterations in 16 microsatellite
      markers in laser capture microdissected (LCM) endoscopic biopsies from the
      esophagus, including 15 dysplasias and 22 ESCCs, in patients from Shanxi
      Province, a region in north-central China. We found a significant increase in the
      total frequency of allelic loss with increasing disease severity. Allelic loss
      was seen in 2% of the markers in patients with low grade dysplasia (LGD), 15% of
      the markers in patients with high grade dysplasia (HGD), and 35% of the markers
      in patients with ESCC. Ten different markers (D3S4513, D5S2501, D8S1106, D9S118,
      D9S910, D13S1493, D13S894, D13S796, D15S655, and D17S1303) showed allelic loss in
      one or more of the premalignant lesions tested. The frequency of microsatellite
      instability (MSI) also increased with histological severity, from 22% in LGD to
      33% in HGD and 59% in ESCC. These results indicate that the development of ESCC
      is associated with genetic instability, that this instability can be detected in
      endoscopic biopsies of recognized precursor lesions in patients without invasive
      cancer, and that these markers may be useful as predictive markers in the early
      detection of ESCC. Finally, we also report methodologic/technical modifications
      that enhance the use of LCM for screening endoscopic biopsies.

PMID- 12490307
TI  - Tyrphostins and retinoids cooperate during inhibition of in vitro growth of
      ovarian cancer cells.
AB  - Chemoresistance of ovarian cancer can be overcome by co-administration of
      retinoids, albeit clinical proof of this hypothesis is pending. Moreover, growth
      factor/c-erbB signaling is crucial for ovarian tumor growth/chemosensitivity.
      Retinoids and c-erbB modulators therefore represent promising drugs for ovarian
      cancer. We demonstrate that c-erbB-1 (RG-14620, AG1517) and c-erbB-2 selective
      tyrphostins (AG825, AG879), and all-trans and 9-cis retinoic acid inhibit ovarian
      cancer cell proliferation (HOC-7, OVCAR-3). Unlike retinoids, AG1517 and AG879
      induce apoptosis. The antiproliferative activity of AG1517 is enhanced by all
      trans retinoic acid suggesting that c-erbB and retinoid pathways interact. Thus,
      these agents cooperate during ovarian cancer cell growth inhibition.

PMID- 12490308
TI  - The combined treatment of aspirin and radiation induces apoptosis by the
      regulation of bcl-2 and caspase-3 in human cervical cancer cell.
AB  - The antitumor mechanisms mediated by combined treatment of aspirin and radiation
      on human cervical cancer cells are unclear. In this paper, we studied whether
      aspirin and radiation induced apoptosis and whether the sensitivity to radiation
      was enhanced in aspirin-pretreated HeLa TG, human cervical cancer cells. We
      identified the regulation of apoptosis-responsive genes, bcl-2, caspase-3 and p53
      after combined treatment. To investigate the growth inhibitory effect on HeLa TG
      cells after treatment of various nonsteroidal anti-inflammatory drugs (NSAIDs),
      we performed cell proliferation assay and colony-forming assay. In the presence
      of aspirin, sulindac and indomethacin, cell proliferation and colony formation
      were decreased in a time- and dose-dependent manner. According to flow cytometry
      analysis and Hoechst 33342 staining, we found that aspirin increased sub-G1
      population and nuclear condensation of cervical cancer cells. Remarkably, the
      combined treatment decreased cell proliferation compared with treatment of 1 mM
      aspirin or 6 Gy radiation alone. Pretreatment of aspirin followed by irradiation
      also elevated the population of apoptotic cells. These results revealed that
      sensitivity to radiation was enhanced in aspirin-pretreated HeLa TG cells, and
      aspirin has the additive role for amplifying the radiotherapeutic effect in
      cervical cancer cells. Finally, combined treatment revealed bcl-2 repression and
      caspase-3 induction did not detect any change but p53 expression did. We have
      demonstrated that combined treatment of aspirin and radiation induces the
      antitumor effect mediated by bcl-2 and caspase-3 pathway in cervical cancer
      cells.

PMID- 12490309
TI  - Modulation of vinca-alkaloid induced P-glycoprotein expression by indole-3
      carbinol.
AB  - The over-expression of mdr-1 gene transcript P-glycoprotein (P-gp), responsible
      for multiple drug resistance, is one of the major obstacles in cancer
      chemotherapy. In the present study, indole-3-carbinol (I3C), a well-known
      chemopreventive agent present in cruciferous vegetables, has been evaluated for
      its potential to modulate the over-expression of P-gp induced by vinblastine or
      vincristine, which are known inducers of mdr-1 gene. The results revealed that
      I3C significantly reversed the over-expression of P-gp in vinca-alkaloid induced
      drug resistance as evident by Western blotting using monoclonal antibody (clone
      JSB1). Quantization of immunostained tissue sections using image analysis
      technique revealed that vinblastine/ vincristine induced overexpression of P-gp
      was effectively reversed by I3C. The present investigation suggests that I3C can
      significantly inhibit the P-gp over-expression and may have utility as a dietary
      adjuvant in the treatment of cancer for the reversal of multiple drug resistance.

PMID- 12490310
TI  - Combined effects of gender, skin type and polymorphic genes on clinical
      phenotype: use of rate of increase in numbers of basal cell carcinomas as a model
      system.
AB  - Patients with a basal cell carcinomas (BCC) have an increased risk of further
      tumors. We studied the individual and combined impact of gender, skin type and
      allelic genes cytochrome P450 (CYP2D6), vitamin D receptor (VDR), tumor necrosis
      factor-alpha, TNF-alpha) on the rate of increase in BCC numbers after first
      presentation. Individually, male gender, skin type 1, CYP2D6 EM, VDR TT and TNF
      alpha GG were associated with more BCC/year (rate ratio (RR) 1.20-1.36) while RR
      for associations of combinations of two, three and four variables were greater
      than in their reference categories (RR 1.32-1.90, 2.20-2.84, 3.06-5.49,
      respectively). The data show that different factors mediate the numbers of
      BCC/year in males and females and, the individual contributions of variables to
      risk is modest.

PMID- 12490311
TI  - Interferon, alpha 17 (IFNA17) Ile184Arg polymorphism and cervical cancer risk.
AB  - The aim of this study was to estimate whether the Ile184Arg polymorphism of the
      Interferon, alpha 17 (IFNA17) gene might be correlated with the risk and
      prognosis of cervical squamous cell carcinoma (SCCA). Genomic DNA from 173
      patients with invasive cervical SCCA and from 198 non-cancer controls (NCC) was
      examined for the Ile184Arg polymorphism with a polymerase chain reaction
      restriction fragment length polymorphism-based assay. All P values are from two
      sided tests. The distribution of IFNA17 Ile184Arg genotype among SCCA cases
      (Ile/Ile, 21%; Arg/Ile, 57%; and Arg/Arg, 22%) was different significantly from
      that among NCC (Ile/Ile, 32%; Arg/Ile, 56%; and Arg/Arg, 12%) (P=0.0345). A
      significant increase in 184Ile homozygote frequency was found in the SCCA
      patients compared with the NCC group (odds ratio 2.96; 95% confidence interval
      1.53-5.73; P=0.001). However, differences in clinicopathologic prognostic factors
      and in the 5 year survival rate were not significant among the subjects of each
      genotype group (P>0.05). The results of this study suggest that the 184Ile
      homozygote of the IFNA17 gene may represent an important susceptibility biomarker
      for cervical cancer risk.

PMID- 12490312
TI  - Plasminogen activator inhibitor-1 gene polymorphism and colorectal cancer risk
      and prognosis.
AB  - Plasminogen activator inhibitor-1 (PAI-1) is a factor in urokinase-type
      plasminogen activator proteolytic system, which is important for tumour invasion
      and metastasis. Elevated PAI-1 levels in tumours are associated with poor
      prognosis. An insertion/deletion (4G/5G) promoter polymorphism in the PAI-1 gene
      affects activity of its product, the 4G/4G genotype being related to higher
      transcription levels. We assessed the association between the polymorphism and
      colorectal cancer risk in 206 cancer patients and 355 healthy controls. The
      results indicated that the PAI-1 gene polymorphism did not affect colorectal
      cancer risk. Nevertheless, within the case group, the 4G/4G genotype was
      associated with more advanced tumours (Dukes' C&D), whereas the 5G/5G
      homozygocity was associated with the Dukes' A&B tumours. The association with the
      4G/4G presence was stronger in patients with proximal colon cancers (odds ratio=
      6.02, 95% confidence interval, 1.15-31.54). Our results suggest that PAI-1
      genotype may be a useful prognostic marker for colorectal cancer, however further
      specifically designed studies are needed to assess its value in this respect.

PMID- 12490313
TI  - Apicidin, a histone deacetylase inhibitor, induces differentiation of HL-60
      cells.
AB  - The fungal metabolite apicidin (cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D
      pipecolinyl-L-2-amino-8-oxodecanoyl)) inhibited the growth of HL-60 cells in a
      concentration-dependent manner (100-1000 nM). At higher concentrations (>300 nM),
      cell death was induced. At 100 nM, it induced hyperacetylation of histone H4 time
      dependently, while trichostatin A induced transient hyperacetylation. Apicidin
      (10-100 nM) increased the cells having nitroblue tetrazolium-reducing activity
      and expressing CD11b but not CD14 and CD15. The expression of CD11b by apicidin
      was long lasting, while that by trichostatin A was transient. In K562 cells,
      apicidin at 10-100 nM did not inhibit cell growth nor express CD11b, CD14 and
      CD15. Our findings indicate that apicidin inhibits proliferation and induces the
      early stage of differentiation of HL-60 cells.

PMID- 12490314
TI  - Preferential integration of a transfected marker gene into spontaneously
      expressed fragile sites of a breast cancer cell line.
AB  - Common fragile sites are non-randomly distributed unstable chromosomal regions
      thought to be hot spots for recombination. They appear as gaps, breaks and
      triradial figures when cells are cultured under conditions that inhibit
      replication or repair of DNA. The removal of replication-inhibitory challenges is
      followed by repair activation to restore the DNA damage at the fragile site. The
      breast cancer cell line MDA-MB-436 has a spontaneous and non-random expression
      pattern of fragile sites that appear to be related to the complex pattern of
      chromosomal rearrangements. The high frequency of which fragile sites are
      spontaneously activated should make MDA-MB-436 cells a powerful tool to study in
      greater detail the DNA sequences of a multiplicity of fragile sites. Here, we
      have explored if the DNA at spontaneously activated fragile sites in MDA-MB-436
      cells can be genetically tagged by the repair-mediated insertion of an
      exogenously supplied drug resistance gene. The cells were transfected with
      pSV2Neo, stably transfected clones were selected with neomycin, and the sites of
      pSV2Neo integration were determined by fluorescent in situ hybridization. Eighty
      eight of 100 isolated clones had a non-random distribution of a total of 112
      pSV2Neo integrations. Of these, 95 integrations (85%) coincide with the position
      at which non-random gaps and breaks appear in the MDA-MB-436 cells. Forty-nine
      (44%) of the 112 integrations appeared to be at position of known fragile sites,
      46 (41%) were at the non-random chromosomal sites not previously described as
      "true" fragile sites. It is possible, however, that these non-random
      instabilities signal of genomic regions equivalent to fragile sites, that either
      have not previously been detected due to low level expression or that are
      activated in a tissue- or cell-type-specific manner. Collectively, our results
      show a preferential integration of exogenous DNA into fragile sites and other non
      random regions of high genomic instability in MDA-MB-436 cells. This approach has
      provided a platform for the efficient targeted cloning and characterization of a
      substantial number of both common fragile sites and other non-random instability
      regions possibly related to breast cancer, and possibly also to other types of
      cancer.

PMID- 12490315
TI  - Calpain-induced Bax-cleavage product is a more potent inducer of apoptotic cell
      death than wild-type Bax.
AB  - Wild type (wt) p21 Bax was cleaved to generate p18 Bax during apoptotic processes
      by calpain, which was suggested to recognize a certain motif around amino acids
      30-33 Phe-Ile-Gln-Asp (FIQD). In the present study, analysis of protein
      sequencing revealed that the cleavage site was between Gln28 and Gly29. The
      fragment lacking the NH(2)-terminal amino acids 1-28 (tBax(29)) was more
      apoptotic than wt Bax. The tBax(29)-induced apoptotic cell death was
      substantially resistant to Bcl-x(L)-mediated rescue, compared with wt Bax, in
      spite of the complex formation between these two molecules. Together, the
      tBax(29) would be valuable for the treatment of tumors with high levels of Bcl
      x(L) as well as the understanding of Bax-mediated apoptotic processes.

PMID- 12490316
TI  - Low expression levels of p27 correlate with loco-regional recurrence in
      nasopharyngeal carcinoma.
AB  - To clarify the roles of p27 and c-myc in nasopharyngeal carcinoma (NPC), we used
      immunohistochemical studies to examine the expression of p27 and c-myc proteins
      in 69 patients with NPC. The results show that a low level of expression was
      observed in 47 and 41 cases, respectively. A low level of p27 expression was
      significantly correlated with loco-regional recurrence, and reduction in the c
      myc protein was also correlated with neck metastasis in NPC. Our study indicates
      that a reduction in p27 expression is frequently seen in NPC. Furthermore, low
      expression levels of p27 and c-myc may contribute to the aggressive behavior of
      NPC.

PMID- 12490318
TI  - Two novel human X-linked homeobox genes, hPEPP1 and hPEPP2, selectively expressed
      in the testis.
AB  - The PEPP genes are a recently described subfamily of mouse homeobox genes
      preferentially expressed in reproductive tissues. Pem, the founding member of the
      PEPP subfamily, has undergone rapid divergence due to positive selection,
      rendering the identification of its human orthologue difficult. Here we report
      the isolation and characterization of two human homeobox genes, hPEPP1 and
      hPEPP2, that are related to Pem and other PEPP family members. We identified
      these human genes based on their location in Xq24, which is syntenic to the mouse
      X-chromosome region containing three PEPP genes: Pem, Psx-1, and Psx-2. We found
      that hPEPP1 and hPEPP2 are selectively expressed in the testis, where the mouse
      and rat Pem genes are also expressed. However, unlike all mouse PEPP genes,
      hPEPP1 and hPEPP2 were not expressed in placenta, which suggests the possibility
      that the regulation of PEPP genes has significantly changed since the split
      between hominids and rodents. Although hPEPP1 exhibits highly selective
      expression in normal tissues, it is aberrantly expressed in tumor cell lines from
      several different organs, analogous to the expression pattern of mouse and rat
      Pem but not mouse Psx-1 or Psx-2. We conclude that we identified two human
      homeobox genes from the PEPP subfamily that are good candidates to encode
      transcription factors that regulate downstream genes and biological events in the
      human testis.

PMID- 12490317
TI  - L1 adhesion molecule (CD 171) in development and progression of human malignant
      melanoma.
AB  - The L1 adhesion molecule (CD171) plays an important role in axon guidance and
      cell migration in the nervous system. In the human, L1 is expressed on tumors
      derived from neurocrest and on certain carcinomas. We have analyzed
      immunohistochemically L1 expression on paraffin embedded specimens of acquired
      melanocytic nevi, primary cutaneous melanomas, and cutaneous and lymph node
      metastases of malignant melanomas. We found an increase in L1 immunoreactivity in
      malignant melanomas and metastases of malignant melanomas as compared to acquired
      melanocytic nevi that was statistically significant (P<0.05). Additionally, a
      correlation of L1 immunoreactivity with histological data of prognostic value
      such as Clark level and the expression of alphav-integrins was found. We detected
      soluble L1 in the conditioned medium of cultivated melanoma cells but only in
      1/40 serum samples from a panel of melanoma patients representing various stages
      of disease. Our findings suggest that the presence of L1 might contribute to
      tumor progression by promoting cell adhesion and migration.

PMID- 12490320
TI  - Gene structure and expression of cg-ALR1, a type I activin-like receptor from the
      bivalve mollusc Crassostrea gigas.
AB  - Members of the transforming growth factor beta superfamily of cell signaling
      polypeptides have attracted much attention because of their ability, from
      nematodes to mammals, to control cellular functions that in turn, regulate embryo
      development and tissue homeostasis (the transforming growth factors betas 95
      (1990) 419). To understand the divergent evolution of the structures and
      functions of the transforming growth factor beta receptors (superfamily) we
      report here the cloning and characterization of an activin-like type I receptor
      gene from the oyster Crassostrea gigas (cgALR1). This 6 Kb gene encodes a 534
      amino acid long protein consisting of a signal peptide, an extracellular ligand
      binding domain, a transmembrane region and an intracellular domain. The
      intracellular domain contains sequence motifs such as the GS box and EIF/V and
      RIKKTL boxes that are thought to be hallmarks of activin type I receptors. The
      protein sequence shares 67% amino acid identity with other serine/threonine
      kinase receptors in the most conserved kinase domain and 47-49% similarity with
      vertebrate type I receptors. The temporal expression pattern of cgALR1
      transcripts was examined during early larval developmental stages. To gain
      insight into evolutionary diversification, phylogenetic analysis as well as an
      investigation of the genomic structure, including the promoter region of the
      cgALR1 gene were carried out.

PMID- 12490319
TI  - Characterization of two regulatory genes of the mercury resistance determinants
      from TnMERI1 by luciferase-based examination.
AB  - The broad-spectrum mercury resistance transposon, TnMERI1, of Bacillus megaterium
      strain MB1, contains three proposed operator/promoter (O/P) transcriptional start
      sites and two regulatory genes (merR1 and merR2). A series of luciferase (lux)
      based transcriptional fusion plasmids were studied in Escherichia coli to show
      that both merR1 and merR2 gene products repressed transcription from O/PmerB3,
      O/PmerR1, and O/PmerR2 under uninduced conditions. Derepression occurred when the
      merR1 gene was present and Hg(2+) functioned as an inducer. In the presence of
      organomercurial compounds, basal transcription of merB3 was needed to produce
      inorganic Hg(2+) as the inducer of expression regulated by MerR1 at O/PmerB3. The
      presence of merR2 repressed transcription from all three O/Pmer sites under both
      non-induced conditions and when inorganic Hg(2+) or organomercurials were added.
      These results show that MerR1 functions as a repressor in the absence of Hg(2+)
      and as an activator in the presence of Hg(2+), while MerR2 functions as a
      repressor.

PMID- 12490321
TI  - Matrix metalloproteinase-21, the human orthologue for XMMP, is expressed during
      fetal development and in cancer.
AB  - We have characterized a novel human matrix metalloproteinase (MMP-21) from human
      placenta DNA complementary to RNA (cDNA). The 569 amino acid translation of the
      cDNA includes all the typical features of an MMP family member, namely a signal
      sequence, a prodomain with a PRCGVPD motif, a zinc-binding catalytic domain with
      an HEIGHVLGL sequence, and a hemopexin-like domain flanked by two cysteine
      residues. Furthermore, MMP-21 has a furin activation sequence, but no
      transmembrane sequence nor a cytoplasmic domain. As in Xenopus laevis and Cynops
      pyrrhogaster there is an additional insertion of approximately 30 amino acids
      between the prodomain and the catalytic domain, which is poorly conserved between
      the species and is in human MMP-21 especially proline rich. The MMP-21 gene has
      seven exons and is located in chromosome 10. This new MMP is the human orthologue
      for XMMP and CyMMP expressed during gastrulation of X. laevis and C.
      pyrrhogaster, respectively. A 2.5 kb messenger RNA was observed in fetal liver by
      Northern analysis. By reverse transcription-polymerase chain reaction, MMP-21 is
      expressed in various human fetal and adult tissues as well as in cancer cell
      lines. MMP-21 protein can also be detected in malignancies such as ovarian and
      colon carcinomas by immunohistochemical staining. Our findings suggest that MMP
      21 functions in embryogenesis and tumor progression.

PMID- 12490322
TI  - The human transcription factor activation protein-2 gamma (AP-2gamma): gene
      structure, promoter, and expression in mammary carcinoma cell lines.
AB  - Human activation protein-2 gamma (hAP-2gamma) is a key developmental
      transcription factor. It has been implicated in mammary carcinogenesis through
      its regulation of HER-2/neu proto-oncogene and estrogen receptor gene The hAP
      2gamma gene is located on human chromosome 20q13.2. We cloned this gene, deduced
      its genomic structure, and mapped and analyzed its promoter. The hAP-2gamma gene
      contains seven exons. Primer extension analysis and 5'-rapid amplification of
      complementary DNA ends studies show that there is a single transcription start
      site 232 nt upstream of the translational start codon. The promoter lacks
      canonical binding sites for basal transcription factors such as TATA and CCAAT
      boxes, but contains a cluster of CpG islands and may rely on an initiator element
      for transcription. Deletion analyses of the promoter and chloramphenicol acetyl
      transferase reporter gene assays indicate that the sequence between -746 and -575
      is important for its expression in mammary carcinoma cell lines. The hAP-2gamma
      gene is marginally activated in these cells suggesting that increased
      transcription partly contributes to its abundance. Architecture of the gene and
      promoter strikingly resembles that of hAP-2alpha, which is located on a different
      chromosome, suggesting a cognate origin. hAP-2alpha and hAP-2gamma have some
      common and some distinct roles in cells, and are likely the remarkable results of
      gene duplication, translocation and functional divergence through evolution.

PMID- 12490323
TI  - Gene structure and hemocyanin isoform HtH2 from the mollusc Haliotis tuberculata
      indicate early and late intron hot spots.
AB  - We have cloned and sequenced cDNAs coding for the complete primary structure of
      HtH2, the second hemocyanin isoform of the marine gastropod Haliotis tuberculata.
      The deduced protein sequence comprises 3399 amino acids, corresponding to a
      molecular mass of 392 kDa. It shares only 66% of structural identity with the
      previously analysed first isoform HtH1, and according to a molecular clock, the
      two isoforms of Haliotis hemocyanin separated ca. 320 million years ago. By
      genomic polymerase chain reaction and 5' race, we have also sequenced the
      complete gene of HtH2 (18,598 bp), except of the 5' region in front of the
      secreted protein. It encompasses 15 exons and 14 introns and shows several
      microsatellite-rich regions. It mirrors the modular structure of the encoded
      hemocyanin subunit, with a linear arrangement of eight different functional units
      separated and bordered by seven phase 1 'linker introns'. In addition, within
      regions encoding three of the functional units, the HtH2 gene contains six
      'internal introns'. Comparison to previously sequenced genes of Octopus dofleini
      hemocyanin and Haliotis hemocyanin isoform (HtH1) suggests Precambrian and
      Palaeocoic hot spot of intron gains, followed by 320 million years of absolute
      stasis.

PMID- 12490324
TI  - The arginine deiminase pathway in the wine lactic acid bacterium Lactobacillus
      hilgardii X1B: structural and functional study of the arcABC genes.
AB  - The genes implicated in the catabolism of the amino acid arginine by
      Lactobacillus hilgardii X(1)B were investigated to assess the potential for
      formation of ethyl carbamate precursors in wine. L. hilgardii X(1)B can use
      arginine via the arginine deiminase pathway. The complete nucleotide sequence of
      the arc genes involved in this pathway has been determined. They are clustered in
      an operon-like structure in the order arcABC. No evidence was found for the
      presence of a homologue of the arcD gene, coding for the arginine/ornithine
      antiporter. The arc genes have been expressed in Escherichia coli resulting in
      arginine deiminase (ArcA), ornithine carbamoyltransfera (ArcB) and carbamate
      kinase (ArcC) activities. The results indicate the need for caution in the
      selection of lactic acid bacteria for conducting malolactic fermentation in wine
      since arginine degradation could result in high amounts of ethyl carbamate.

PMID- 12490325
TI  - The sheep (Ovis aries) H19 gene: genomic structure and expression patterns, from
      the preimplantation embryo to adulthood.
AB  - H19, which is one of the most abundantly expressed imprinted genes during
      mammalian embryonic and foetal development, has been cloned from a ruminant. The
      sheep (Ovis aries) gene contains five exons interspersed by four exceptionally
      small introns; only short stretches of the nucleotide sequence, particularly in
      exon 1, show good homology with the human gene. The size of the exons and introns
      and the sequences around the splice junctions however, are well conserved between
      the species. The gene encodes a approximately 2.6 kb transcript which contains
      several potential short open reading frames, none of which is conserved between
      the ovine and human or murine transcripts, supporting a previous hypothesis that
      the gene product is the untranslated RNA itself. H19 mRNA is highly abundant in
      most ovine embryonic and foetal tissues of mesodermal and endodermal origins but
      was not detected in tissues of ectodermal origin such as the trophectoderm and
      the foetal brain. Expression of H19 in the extraembryonic membranes was detected
      only after the ovine conceptus began attachment to the endometrium and the embryo
      itself had undergone early organogenesis. This may be regarded as the first step
      in implantation; thus, in comparison with the mouse, the initiation of H19
      expression appears to be determined by the timing of implantation rather than by
      the stage of development of the embryo itself. In most tissues, H19 expression is
      temporally linked to IGF2, a major foetal growth factor. The exceptions were the
      elongated blastocyst, the trophectoderm and brain, where low levels of IGF2 were
      observed in the absence of detectable H19. The abundance of H19 mRNA was in
      general, directly correlated with IGF2 mRNA abundance in mesodermal and
      endodermal tissues, suggesting that the two ovine genes share common regulatory
      elements that co-ordinately regulate their expression. Though both are generally
      regarded as embryonic and foetal genes, their expression was still maintained at
      a fairly high level in the adult sheep liver, lung, skeletal muscle, adrenal
      gland and kidney, suggesting that these organs are significant sources of IGF II
      in the adult.

PMID- 12490326
TI  - Eyelid myoclonia with absences: an overlooked epileptic syndrome?
AB  - AIM: To identify, among patients referred to our Epilepsy Center, those
      fulfilling eyelid myoclonia with absences (EMA) criteria and to evaluate their
      semiological, electroclinical and evolutive features. In addition, to examine
      some possible causes of underdiagnosis and to stress the role of video-EEG (VEEG)
      recording. MATERIALS AND METHODS: Retrospective analysis of 2780 epileptic
      patients. INCLUSION CRITERIA: Eyelid myoclonia and brief absences, related to EEG
      generalized paroxysmal activity and triggered by eye closure and/or by
      intermittent photic stimulation. RESULTS: 7.46% of our patients with idiopathic
      generalized epilepsy (IGE) could be classified as EMA. Female/male ratio was
      1.7:1. Familial history of epilepsy was present in about half of the patients,
      with two pairs of identical twins in the sample. Rare generalized tonic-clonic
      seizures occurred in most cases. CONCLUSIONS: EMA is a not infrequent condition
      among IGEs. It is likely to be underdiagnosed due to the subtle clinical
      semiology and to masking of EEG changes by the effects of age and anti-epileptic
      drugs. VEEG analysis is often needed for diagnosis of EMA. Most likely, only
      genetic research will be able to clarify whether EMA is a distinct epileptic
      syndrome.

PMID- 12490327
TI  - [Comparison of spectral analysis and non-linear analysis of EEG in patients with
      cognitive decline].
AB  - Twenty-five elder subjects were classified in two groups according to the MMS
      score and the cognitive evoked potentials. Normal subjects (n = 15) had mean MMS
      = 27.6 and mean P3 amplitude = 7.1 uV), while patients with cognitive decline (n
      = 10) had respective values of 18 (MMS) and 3.3 uV (P3). Spectral analysis and
      non-linear analysis of EEG (recurrence plots of dynamical systems) were performed
      and both showed statistically significant differences between groups for all the
      parameters analysed. Subjects' classification with discriminant analysis was
      slightly better using the non-linear parameters. The recurrence plot method
      applied to EEGs, gave similar results as the dimension of correlation (D2)
      calculation, and was in favour of a more constraint and less complex dynamics of
      brain activity associated with cognitive decline.

PMID- 12490328
TI  - [Early cerebral MRI in preterm infants: correlations with EEG and outcome].
AB  - AIM OF THE STUDY: Assess the potential benefits of performing an early cerebral
      MRI to evaluate the gravity of cerebral lesions among premature neonates at risk
      of neurologic sequels and establish correlations between EEG findings, abnormal
      neuroimaging findings and neurodevelopment. METHODS: A MRI was performed in 34
      premature newborn babies with abnormal neurological clinical signs, and/or with
      two abnormal EEG and/or with two abnormal cerebral ultrasound scans. The mean age
      and the adjusted age of our population were 5 weeks (range 1-11 weeks) and 35
      weeks of adjusted age (range 29-40 weeks) respectively. The neuroimaging findings
      were correlated to the results of three EEGs (recorded before 15 days old,
      between 15 days and one month old, and after the first month of life) and to
      neurodevelopment. RESULTS: Two statically significant correlations were found
      between: 1) the severity of brain injuries observed in MRI and the results of the
      latest EEG (sensitivity 100%, specificity 60%), 2) the severity of brain injuries
      observed in MRI and abnormal neurodevelopment (sensitivity 75%, specificity 80%).
      There was no correlation between the abnormal development and the results of EEG
      recordings. CONCLUSION: Early cerebral MRI is justified in a selected premature
      population. It is useful for the diagnosis, the evaluation of the severity of
      brain injury and for the management of these children. The correlation with EEGs
      traces allows the detection of the majority of prematures babies that will
      develop sequels.

PMID- 12490329
TI  - Cognitive effects of precentral cortical stimulation for pain control: an ERP
      study.
AB  - Electrical stimulation of the motor cortex (MCS) is a promising and increasingly
      used neurosurgical technique for the control of refractory neuropathic pain.
      Although its mechanisms of action remain unknown, recent functional imaging data
      suggest involvement of the thalamus, brainstem and anterior
      cingulate/orbitofrontal cortex. Since some of these areas are also implicated in
      higher cognitive functions, notably attentional processes, we analysed cognitive
      ERPs and behavioural performance during an "oddball" auditory detection task in
      patients submitted to this procedure. Eleven consecutive patients undergoing MCS
      because of neuropathic refractory pain, ranging in age from 25 to 71 years, were
      included in the study. ERPs were obtained in all cases both during the
      application ("MCS-on") and within the 10 min that followed discontinuation of the
      procedure ("MCS-off"). In five patients, ERPs could also be obtained just before
      the start of MCS. When the patients' sample was taken as a whole, there were no
      consistent effects of MCS on the ERPs. There was, however, a significant
      interaction of MCS action with the patients' age, reflecting a significant delay
      during MCS of the cognitive responses N2 and P3 (N200 and P300) in the group of
      patients older than 50 years exclusively. This effect was rapidly reversible
      after MCS discontinuation. No MCS-related changes were observed in the N1
      component. At the individual level, the effect of MCS on the endogenous ERPs was
      highly variable, ranging from a total stability of ERPs (mostly in younger
      subjects) to latency differences of tens of milliseconds in the older group.
      These results, together with recent experiments showing P300 alteration during
      repetitive transcranial stimulation, suggest that motor cortex stimulation may
      interfere with relatively simple cognitive processes such as those underlying
      target detection, and that the risk of abnormal cognitive effects related to
      cortical stimulation may increase with age. Although the procedure appears on the
      whole remarkably safe, complementary neuropsychological studies in this category
      of patients are advised, as well as caution to possible adverse cognitive effects
      when using MCS in the elderly, notably in the presence of pre-existent cerebral
      lesions.

PMID- 12490330
TI  - Psychophysiological correlates of affects in human olfaction.
AB  - Pleasantness and arousal have been identified as the main dimensions of affective
      responses to environment. Pleasantness is defined as the degree of favorable
      feelings a subject can experience under given circumstances. Arousal is defined
      as the degree of excitement (general activation) the subject feels under these
      circumstances. In visual and auditory modalities, many studies using measures
      such as facial electromyographic (EMG) activity and skin conductance (SC) have
      found those parameters to vary as a function of either pleasantness or arousal:
      for example, facial corrugator EMG activity covaries with the pleasantness
      dimension, while SC increases together with arousal. The first objective of this
      research is to study the possible covariation between peripheral measures and
      pleasantness/arousal in olfaction. We also examined the effect of odor intensity
      on facial and autonomic variations. The second objective was to investigate
      whether odors could evoke verbally specific emotions (e.g. joy, anger, fear,
      surprise, disgust or sadness) and also induce specific patterns of peripheral
      responses. Participants were exposed to 12 different odors while their facial and
      autonomic parameters were recorded, and estimated their intensity, pleasantness,
      and arousal capacity. Then, they chose between seven words for emotions (fear,
      anger, sadness, surprise, neutral, joy or disgust) to describe their reaction to
      the odor. As in vision, olfactory pleasantness covaries (negatively) with facial
      activity of the corrugator muscle, and arousal (positively) with skin
      conductance. No relationships were observed between physiological changes and
      variations in perceived intensity. Results also showed that emotions of "disgust"
      and "joy" were more frequently evoked verbally than any other emotions, and that
      only facial EMG activity distinguishes them (e.g. "disgust" vs. "joy" and
      "neutral state"). The results are discussed in terms of possible existence of two
      brain systems (defensive and appetitive), each of them being able to vary in
      metabolic arousal.

PMID- 12490332
TI  - [How can we define the modalities and clinical levels of coma to wakefulness?].
AB  - OBJECTIVE: The starting point of the French conference of consensus concerning
      arousal after coma was to answer the following question: "How can we define the
      ways of going from coma to arousal and their clinical levels? MATERIALS AND
      METHOD: A team of readers have picked up in the literature one hundred and fifty
      papers, out of which fifty six have been analysed. RESULTS: From this analysis,
      three points emerged: The concepts of coma and arousal; The conditions of
      evolution from coma to arousal; Various groups of patients depending on their
      expressing arousal. One could not find any consensual model concerning the
      different ways of going from coma to arousal. The variability of the technics and
      the changing validity of all scores did not allow the conditions of arousal to
      reach a satisfactory level of proof. The Glasgow Coma Scale (GCS) is the
      recognised standard for severe wakefulness' impairment, but it is not sensitive
      enough while patients' arousing. The Glasgow Outcome Scale (GOS) takes into
      account the patients' situations far later and does not include situations such
      as Minimally Conscious States (MCS). That's why we face multiple scores, either
      ordinal, or categorial, all tending to evaluate the slow levels of arousal.
      CONCLUSION: Clinical findings concerning arousal are to be completed by non
      clinical data. This would be greatly helpful to define appropriate management
      concerning individualized groups of patients. At this stage, another challenge
      for clinicians is to make the difference between emerging wakefulness and growing
      conscious activity.

PMID- 12490333
TI  - [Traumatic brain injuries in adults: from coma to wakefulness. Neurophysiological
      data].
AB  - OBJECTIVE: To analyse relevant literature and to express an expert point of view
      concerning the interest of electroencephalography and evoked potentials
      recordings in the evaluation of severe head trauma in adults in the context of a
      consensus conference. MATERIAL AND METHODS: Scientific databases have been
      checked on the Internet using key-words. The summaries of 340 papers have checked
      out. Consequently 94 papers have been thoroughly analysed. Fifty-nine of them are
      cited in the text of this paper. RESULTS: Electroencephalography (EEG) and evoked
      potentials (Eps) evaluate the functional status of the brain. They augment the
      clinical examination. They are non invasive and easy to perform at patient's
      bedside. The EEG evaluate globally the functional status of the brain but it is
      very sensitive to sedative and anaesthetic drugs. It can disclose subclinical or
      electroclinical epileptic seizures. When reactivity to sensory stimulations can
      be elicited, this can be considered a prognostic indicator for a good outcome.
      Evoked potentials are less influenced by sedative drugs. There are several types
      of evoked potentials, each one with a different localizing value. Brainstem
      auditory evoked potentials (or short-latency Eps) evaluate the auditory nerve and
      brainstem. When normal they have no specificity. When abnormal they are an
      indicator of a poor or bad outcome. Somatosensory and auditory middle-latency Eps
      evaluate the primary cortex. In coma due to traumatic brain injury the presence
      of primary cortex components is an indicator of a good outcome and its absence is
      an indicator of a poor outcome at least when there is no focal brain lesion as to
      have the primary cortex component to be absent. Event-related potentials evaluate
      associative brain areas. When they are present in a comatose patient they favor
      the idea that some cognitive processes are active and they have a high positive
      predictive value for a return to consciousness. The electrophysiological
      evaluation can help to identify atypical situations and pathologies close to
      coma, disclose nonconvulsive seizures and localize certain complications or
      dysfunctions in atypical cases.

PMID- 12490334
TI  - [Life satisfaction and psychosocial outcome in severe traumatic brain injuries in
      Aquitaine].
AB  - OBJECTIVE: To assess late outcome and satisfaction of life of patients with
      severe traumatic brain injury (TBI) patients who received inpatient
      rehabilitation in Aquitaine. DESIGN AND PATIENTS: Seventy-nine consecutive
      patients out of the 158 who were hospitalized for rehabilitation in 1993 were
      asked for in 2000 by a phone interview including standardised scales and free
      talk as well. RESULTS: The results showed that nine years on average after their
      injury, 65 to 85% of patients were independent for daily living, whereas 35 to
      55% only were independent in social life. Most of them were satisfied with their
      autonomy (67%), family life (66%) and financial status (41%), but they were
      dissatisfied with leisure (36%), vocational adjustment (28%) and sexual life
      (32%). CONCLUSION: Return to work, leisure and sexuality are major parameters of
      satisfaction of life after a severe TBI, and should be emphasized in goal
      directed rehabilitation programs.

PMID- 12490335
TI  - [Outcome and quality of life after three years in a cohort of patients with
      severe traumatic brain injury].
AB  - OBJECTIVES: The late outcome of patients with severe traumatic brain injury
      (STBI) has been investigated by measuring deficits, disability and social
      handicap, but their quality of life (QOL) has been less evaluated, and not by a
      direct analysis of the subjective patient "and relatives" QOL. The aim of this
      study was to investigate this outcome and the QOL, with its predictive factors, 3
      years after STBI, in a homogeneous cohort of patients. MATERIAL AND METHODS: We
      selected all adult patients from the Lille area (north of France) admitted in the
      CHU in 1995 following STBI. Each was evaluated at home, in the presence of a
      close relative, using the EBIS document. This one investigates the medical
      history, initial status and late outcome, as well as the subjective QOL of
      patients (evaluated by the patient and by a close relative: 0-10 on an analogical
      visual scale) and close relatives. Relationships between possible explanatory
      factors and QOL were analysed using correlation tests. RESULTS: Among the 33
      patients, 23 survived at three years. The mean initial GCS score was of 5,6/15
      and the mean coma duration of 18.5 days. At three years, physical deficits were
      usually discrete, intellectual deficits more important and the emotional and
      behavioural problems even more severe. The GOS was of 6 in one patient, 4-5 in
      seven, 2-3 in seven and 0-1 in eight. Dependence in advanced activities was more
      sever than in elementary activities. The subjective QOL of patients was
      discretely lower (m = 5,48/10) than that estimated by close relatives (m = 5,91).
      The relatives QOL was similarly reduced (m = 5,45). The factors most influencing
      the patients QOL were the cognitive and behavioural problems and the dependence
      in the advanced activities and the GOS for the patients QOL, and the behavioural
      problem and the dependence in advanced activities for the relatives QOL.
      CONCLUSION: The reduction of the patients "and relatives" QOL was parallel at
      three years. Emotional and behavioural problem as well as the dependence in
      advanced activities mainly explained these QOL.

PMID- 12490336
TI  - Screening for anxiety in primary care: why bother?

PMID- 12490337
TI  - Screening for post-traumatic stress disorder in female Veteran's Affairs
      patients: validation of the PTSD checklist.
AB  - We evaluated the screening validity of a self-report measure for post traumatic
      stress disorder (PTSD), the PTSD Checklist (PCL), in female Veterans Affairs (VA)
      patients. All women seen for care at the VA Puget Sound Health Care system from
      October 1996-January 1999 (n=2,545) were invited to participate in a research
      interview. Participants (n=282) completed the 17-item PCL, followed by a gold
      standard diagnostic interview for PTSD, the Clinician Administered PTSD Scale
      (CAPS). Thirty-six percent of the participants (n=100) met CAPS diagnostic
      criteria for current PTSD. Receiver Operating Characteristic (ROC) analysis was
      used to evaluate the screening performance of the PCL. The area under the ROC
      curve was 0.86 (95% CI 0.82-0.90). A PCL score of 38 optimized the performance of
      the PCL as a screening test (sensitivity 0.79, specificity 0.79). The PCL
      performed well as a screening measure for the detection of PTSD in female VA
      patients.

PMID- 12490338
TI  - Validation of the PTSD checklist in an HMO sample of women.
AB  - Although Post-traumatic Stress Disorder (PTSD) is common among patients seeking
      care at medical clinics, little is known about the performance of screening
      instruments for this disorder in these settings. Previous studies of acute trauma
      populations using the PTSD Checklist (PCL) have suggested that scores of 45-50
      provide the best discrimination between cases and noncases. We gave the PCL to
      1,225 randomly selected women enrolled in an HMO. After interviewing a sample of
      261 of these women using a structured, clinician-administered PTSD interview, we
      compared the results of the PCL to the clinician interviews over a range of
      possible cut scores using Receiver Operating Characteristic analysis. The optimum
      balance of sensitivity and specificity for this population was a score of 30,
      yielding a sensitivity of.82 and specificity of.76. The positive and negative
      likelihood ratios for this cut score were 3.40 and 0.24, respectively. By
      comparison, the use of 45 as a cut score would result in very low sensitivity
      (.36) in this setting. The lower cut score found in this study may indicate that
      the use of previously published cut scores of 45-50 may not optimize the function
      of the PCL as a screening tool outside of acute trauma settings due to an
      unacceptably high number of false negative cases.

PMID- 12490339
TI  - Race, quality of depression care, and recovery from major depression in a primary
      care setting.
AB  - Racial variations in the use of effective medical care and subsequent clinical
      outcomes have been identified for many medical conditions. Still, it is unclear
      whether racial variations in care and clinical outcomes exist for depressed
      primary care patients. Primary care patients presenting for routine treatment
      were screened for major depression as part of a study to disseminate a depression
      treatment guideline. Primary care physicians (PCPs) were informed of their
      patients' depression via an electronic medical record system and asked whether
      they agreed with the diagnosis. Treatment patterns and depressive symptoms over
      the following six-months were assessed by chart review and the Hamilton Rating
      Scale for Depression, respectively. Over a 20-month period, 8,944 African
      American and Caucasian patients aged 18-64 were approached for screening. African
      Americans were less likely to agree to undergo screening than Caucasians (83% vs.
      88%; P<.0001), but those doing so were more likely to report mood symptoms (26%
      vs. 15%; P<.001). 204 patients, including 52 African-Americans (25%), met
      protocol-eligibility criteria and completed a baseline interview. Baseline
      sociodemographic and clinical characteristics, and PCPs' agreement rate with the
      depression diagnosis were similar. Although PCPs were less likely to counsel
      their African-American than Caucasian patients for depression (P=.03), this
      difference resolved after adjusting for education level, employment, and
      insurance status and we found no other variations in the depression care provided
      or in clinical outcomes by race. We found little racial variation in either
      process measures or clinical outcomes for depression in our sample of African
      American and Caucasian primary care patients.

PMID- 12490340
TI  - Characteristics of primary care visits for individuals with severe mental illness
      in a national sample.
AB  - Individuals with severe mental illness (SMI) are at risk for inadequate general
      medical and preventive care, but little is known about their visits for primary
      care. We performed a cross-sectional analysis of primary care physician visits
      from the National Ambulatory Medical Care Survey (NAMCS) 1993-1998 and compared
      visit characteristics for patients with and without SMI. SMI was defined from ICD
      9 diagnoses and medications. Primary care visits for patients with SMI were more
      likely to be return visits, were longer, and were more likely to have scheduled
      follow-up than for patients without SMI. Obesity, diabetes, and smoking were
      reported approximately twice as frequently in visits for patients with SMI
      compared to patients without SMI. The percent of visits with preventive
      counseling and counseling targeted at chronic medical conditions was similar for
      both groups. Likely appropriate to their complex needs, patients with SMI using
      primary care tend to have more return visits, longer time with the physician and
      are more often scheduled for follow-up care; their preventive counseling appears
      similar to non-SMI visits.

PMID- 12490342
TI  - Challenges and early experiences in the development of an anxiety clinic in the
      public health sector.
AB  - This paper argues the importance of establishing specialist anxiety clinics
      within the public sector of the Australian health system. It describes the
      development of such a service and summarizes the characteristics of the first
      1000 clients. Factors such as staffing, utilization trends, referral patterns,
      assessment and treatment procedures, and the clinical and demographic
      characteristics of the first 1000 cases are reviewed and discussed. The model of
      the clinic, which operates in partnership with community mental health and an
      academic research unit, has proven itself to be a suitable, cost-effective and
      efficient prototype in the treatment of anxiety disorders. Anxiety disorders
      exact a high social and economic cost. At a time of global funding cuts and
      savings in the mental health system, it is vital to think ethically as well as
      cost-efficiently, considerations that require that we offer the most efficient
      treatment to the greatest number of people.

PMID- 12490341
TI  - Reliability and validity of the assessment of depression in general practice: the
      Short Depression Interview (SDI).
AB  - General practitioners (GPs) are recommended to use DSM-IV criteria to diagnose
      major depression in daily clinical practice. This implies the assessment of nine
      depressive symptoms and four additional criteria. A short structured interview
      has been developed to assess these symptoms and criteria, and a study was carried
      out to investigate the reliability and validity with which GPs can assess these
      symptoms and criteria and the DSM-IV diagnosis of major depression. In 14 general
      practices, 52 patients with symptoms of distress and depression were interviewed
      twice by their GP, with an interval of one to four days. Furthermore, the
      patients filled out three depression questionnaires. The reproducibility of eight
      symptoms and three additional criteria was moderate to good (kappa >0.40). The
      reproducibility of the depressive symptom count, that is necessary to arrive at a
      diagnosis of major depression, was such that in 75 percent of the patients the
      test-retest difference did not exceed one symptom. The reproducibility of the
      diagnosis of major depression was good (kappa 0.63). The validity of the
      diagnosis of major depression assessed by the GPs, as compared to results of the
      self-report depression questionnaires, was satisfactory (r 0.35-0.61). Diagnosing
      major depression in patients with depressive symptomatology just above or below
      the threshold of major depression warrants a certain amount of caution in general
      practice.

PMID- 12490343
TI  - General hospital suicides--a psychological autopsy study in Finland.
AB  - Although both severe medical disorders and mental disorders are established risk
      factors for suicide, it is not known if patients who commit suicide in general
      hospitals differ from others. This study investigated current mental disorders
      and other clinical characteristics among general hospital suicide victims and
      compared them with other suicide victims in an unselected nationwide population.
      Drawing on data from a psychological autopsy study of all suicides (N = 1397) in
      Finland during one year, all suicides committed by patients in a general hospital
      setting were identified. Retrospective DSM-III-R consensus diagnoses were
      assigned and general hospital suicide victims were compared with other suicide
      completers in terms of clinical characteristics. Twenty-six general hospital
      suicide victims, 1.9% of all suicides, were identified. Subjects who completed
      suicide during general hospital treatment were older and used more violent
      suicide methods than other suicide victims. One or more diagnoses of psychiatric
      (Axis I) disorders were assigned for 88% of the general hospital suicide victims.
      Overall, the most prevalent disorder was major depression, which was more common
      among the general hospital suicide victims, even when age was controlled for. The
      findings of this study suggest that most people who commit suicide during a spell
      of general hospital treatment suffer from current mental disorder, as do suicide
      victims in general. The recognition and treatment of major depression in
      particular should be improved in order to prevent suicide in general hospitals.

PMID- 12490344
TI  - Topiramate as a treatment for pain in multisomatoform disorder patients: an open
      trial.
AB  - Multisomatoform disorder (MSD), defined as 3 or more medically unexplained,
      currently distressing physical symptoms in addition to a long (> or =2 years)
      history of somatization, is a prevalent and disabling disorder in which few
      pharmacological trials have been referred to in the literature. Thirty-five MSD
      patients from the Somatoform Disorders Unit of the Miguel Servet University
      Hospital, Zaragoza, Spain, with pain of more than 3 months as the main symptom,
      were treated with topiramate in doses ranging from 300-400 mg/day. Patients were
      assessed at baseline and at one and six-months follow-up with the McGill Pain
      Questionnaire (MPQ), Pain Visual Analogue Scale (PVAS), Clinical Global Impresion
      (CGI), Global Assessment Functioning (GAF) and Hospital Anxiety Depression Scale
      (HADS). Eight patients (22.8%) dropped from the study, 3 due to side-effects and
      the other 5 because of lack of efficacy. All the outcome measures showed
      significant improvements at one-month except the ratings on the Hospital Anxiety
      Depression Scale. At six-months follow-up, clinician-rated assessments (CGI and
      GAF) still showed significant differences with baseline but less significant than
      at one-month follow-up. However, patient-rated assessments (MPQ and PVAS) did not
      present significant differences with baseline. Despite limitations of the study,
      topiramate seems to be effective in treating multisomatoform disorder patients
      with pain as the main symptom and a controlled randomized trial in these patients
      appears warranted. A possible "decay effect" in patient-rated assessments with
      any drug in somatoform disorder patients is discussed.

PMID- 12490345
TI  - Implementing a randomized clinical trial on a pediatric psychiatric inpatient
      unit at a children's hospital: the case of clonidine for post-traumatic stress.
AB  - Randomized clinical trials (RCTs) of psychotropic medications are uncommon among
      child and adolescent populations, and even rarer on pediatric, psychiatric
      inpatient units. We mention some of these studies, and then discuss the
      advantages and challenges of conducting a RCT among youngsters on an inpatient
      psychiatric unit in a pediatric hospital, using as an example our ongoing study
      of clonidine for intrusive symptoms of post-traumatic stress. Our purpose is to
      alert potential investigators to the obstacles they may encounter while
      implementing a RCT, while also pointing the way to potential resources.
      Advantages of inpatient units for RCTs include easy access to patients, with the
      potential for careful monitoring of both patients' clinical status and of
      medication administration. Challenges include the need for the psychiatric
      researcher to form liaison with other important areas within the hospital, such
      as the Institutional Review Board, the Pharmacy, and sometimes a General Clinical
      Research Center and a Clinical Research Program. The functions of these
      departments are discussed, and additional support for clinicians in hospital
      settings without these departments is described. Other issues include training
      clinical nurses to conduct research while making adequate provisions for their
      time to do so. Attitudes on a clinical psychiatric inpatient unit toward research
      also merit consideration. Furthermore, as with any study in a hospital setting,
      recruitment presents its own set of challenges. Finally, one must be cognizant of
      how clinical information flows between clinicians and researchers.

PMID- 12490346
TI  - Over-the-counter sleeping pills: a survey of use in Hong Kong and a review of
      their constituents.
AB  - This study examined the composition of over-the-counter (OTC) sleeping pills in
      Hong Kong and reviewed the current knowledge about the hypnotic efficacy and
      safety of their major herbal and dietary supplement constituents. We conducted a
      cross-sectional survey of OTC sleep aids at drug stores in a residential district
      of 0.3 million population and literature search using MEDLINE, EMBASE, PsycINFO,
      China Journal Net, China Biomedical Database and relevant English and Chinese
      literature. We identified 17 brands of OTC sleeping pill: eleven of them were
      composed of mixtures of Chinese and Western herbal agents and six brands
      contained 3 mg of melatonin. The Chinese herbal mixture suanzaorentang,
      comprising zizyphi spinosi semen, poria cocos, ligusticum wallichii, anemarrhenae
      rhizoma and glycyrrhizae radix in ratio of 7:5:2:1:1, was the most common OTC
      sleeping pill available in the survey. Our literature review showed that kava,
      valerian and melatonin were the better-researched herbs and dietary supplements,
      however, the data on hypnotic efficacy and safety was inadequate to support their
      clinical use. More rigorous investigations of the risk-benefit relationship of
      herbal agents and dietary supplements used for insomnia are needed.

PMID- 12490347
TI  - Specific psychiatric morbidity in liver cirrhosis in a Nigerian general hospital
      setting.
AB  - The purpose of this investigation was to explore the psychiatric complications of
      liver cirrhosis in a Nigerian general hospital setting. The mental state of 31
      consecutive patients with liver cirrhosis seen in a gastroenterology unit, from
      July 1996 to August 1998, was assessed using the 30-item General Health
      Questionnaire (GHQ-30) and Present State Examination (PSE) and compared with
      those of 20 hypertensive patients and 20 apparently healthy controls. The socio
      demographic characteristics of patients with liver cirrhosis who developed
      psychiatric complications were compared with those without such complications.
      The mental status of the cirrhosis patients in the present study was also
      compared with those of Chronic Obstructive Pulmonary Disease (COPD) and
      hemodialysis patients in earlier studies. About fifty-five percent of all the
      liver cirrhosis patients developed diagnosable psychiatric morbidity. This was
      significantly higher than that of the hypertensive patients (15%) or healthy
      controls (5%) (P=0.0001). The psychiatric conditions were depressive episode,
      generalized anxiety disorder, delirium and adjustment disorder. No socio
      demographic parameter had a significant effect on the mental state of the
      patients with liver cirrhosis. The same proportion (55%) of hemodialysis and a
      lower proportion (30%) of COPD patients compared with cirrhosis patients had
      psychiatric morbidity. We found a high rate of psychiatric morbidity in the
      patients with liver cirrhosis compared with those of hypertension and normal
      subjects. None of the socio-demographic variables considered was found to be
      associated with psychiatric complications in the liver cirrhosis patients. Poor
      medical conditions seem to be associated with high levels of psychiatric
      morbidity.

PMID- 12490348
TI  - Sickle cell disease -- when opioids and physicians fail.
AB  - An interview with a 32-year-old male with sickle cell anemia and multiple
      sequential admissions for vaso-occlusive crises, receiving high dose narcotic
      analgesics, is presented. The subsequent clinical discussion outlines
      psychiatric, psychosocial and treatment issues. Management of acute vaso
      occlusive crisis is summarized along with a discussion of the value of
      comprehensive care for sickle cell disease patients. This article will be useful
      to physicians and consultation-liaison psychiatrists treating patients with
      sickle cell disease as well as policy makers developing service delivery models
      for this population.

PMID- 12490349
TI  - Exacerbation of panic disorder symptoms following Vicodin exposure.

PMID- 12490350
TI  - Depression improvement with calcium heparin.

PMID- 12490352
TI  - A child who visited the emergency room with stress-related nonpsychotic
      hallucinations.

PMID- 12490351
TI  - Silent thyroiditis associated with short-term lithium therapy.

PMID- 12490353
TI  - Bacterial skin infections: unapproved treatments.

PMID- 12490354
TI  - Parasitic skin infestations II, scabies, pediculosis, spider bites: unapproved
      treatments.

PMID- 12490355
TI  - Purpura and vasculitis: unapproved treatments.

PMID- 12490356
TI  - Scleroderma and sclerotic skin conditions: unapproved treatments.

PMID- 12490357
TI  - Disorders of sweat glands: hyperhidrosis: unapproved treatments.

PMID- 12490358
TI  - Nail disorders: unapproved treatments.

PMID- 12490359
TI  - Disorders of pigmentation: unapproved treatments.

PMID- 12490360
TI  - Hemangiomas and vascular malformations: unapproved treatments.

PMID- 12490361
TI  - Anogenital lesions (viral diseases and ectoparasitic infestations): unapproved
      treatments.

PMID- 12490362
TI  - Adverse drug reactions and graft-versus-host reaction: unapproved treatments.

PMID- 12490363
TI  - Dermatoses of the facial skin: unapproved treatments.

PMID- 12490364
TI  - Cutaneous diseases of the foot: unapproved treatments.

PMID- 12490365
TI  - Lasers in dermatology: unapproved treatments.

PMID- 12490366
TI  - New dressings, including tissue-engineered living skin.

PMID- 12490367
TI  - "No trespassing!" are the pharmacists stepping over the line?

PMID- 12490368
TI  - Advances in drug delivery for articular cartilage.
AB  - The complex structure of articular cartilage, the connective tissue lining
      diarthrodial joints, enables this tissue to dissipate compressive loads but also
      appears to hinder its repair ability. At best, both natural and surgical repair
      attempts replace the highly ordered extracellular matrix of native articular
      cartilage with fibrous repair tissue of inferior mechanical properties. Numerous
      bioactive molecules closely regulate the cellular processes in healthy and
      degenerative articular cartilage. Accordingly, this review outlines the roles of
      important signaling molecules in cartilage tissue. In addition, drug delivery
      strategies, aimed at utilizing these bioactive agents to prevent inflammation, to
      regulate extracellular matrix metabolism, and to control cellular activities, are
      discussed. As scientists gain further insight into the complex signaling cascades
      of articular cartilage, continued refinement of drug delivery systems is
      necessary to develop effective clinical therapies for articular cartilage repair.

PMID- 12490369
TI  - The effect of Pluronic on the protein release kinetics of an injectable drug
      delivery system.
AB  - A new class of injectable controlled release depots has been prepared by
      incorporating materials that preferentially segregate during phase inversion.
      These consist of blends of poly(ethylene oxide) (PEO)/poly(propylene oxide)
      (PPO)/poly(ethylene oxide) (PEO) triblock copolymers (Pluronics) with poly(D,L
      lactide) (PDLA)/1-methyl-2-pyrrolidinone (NMP) solutions. The effects of
      preferential segregation on the phase inversion dynamics and in vitro protein
      release kinetics were examined using dark ground imaging, high performance liquid
      chromatography (HPLC), scanning electron microscopy (SEM), and confocal
      microscopy. Variations in Pluronic concentration and molecular weight had an
      insignificant effect on the internal depot morphologies, however, increasing the
      concentration and molecular weight did result in increased phase separation rates
      and, surprisingly, a decrease in the magnitude of the protein burst, though the
      release profiles still retained a typical burst-type shape. Additionally,
      increasing the Pluronic concentration beyond a critical point resulted in a
      transition from a burst-type profile to an extended-release profile. An
      interpretation of these results in terms of a qualitative model for the protein
      release mechanism is also given.

PMID- 12490370
TI  - Stimulation of spleen cells in vitro by nanospheric particles containing antigen.
AB  - Activation of cells, in primary culture, by nanospheres containing antigen has
      been investigated. Single cell suspensions of spleen cells from primed and nai;ve
      animals were cocultured with escalating quantities of soluble tetanus toxoid (TT)
      or TT encapsulated within nanospheres fabricated from poly(lactide-co-glycolide)
      (PLGA). Concomitantly, spleen cells were also cultured in the presence of 'empty'
      PLGA nanospheres that contained no TT. Nanospheres loaded with antigen were found
      to elicit increased proliferation of splenocytes from preimmunised mice in
      comparison to free antigen during coculture at equivalent doses of immunogen (at
      low and intermediate doses). Interestingly, cellular proliferation was abolished
      if B-cells were removed from the splenocyte cultures. Production of IFN-gamma and
      IL-6 was increased, for formulated as compared to free antigen, in microcultures
      from both nai;ve and pre-immunised animals. Secretion of IFN-gamma or IL-6 was
      not observed when primed or nai;ve spleen cells were stimulated with 'empty'
      polymeric spheres. Some unspecific cytotoxicity was detected if cells were
      cocultured with high concentrations of PLGA particles, although toxic effects
      were not seen at concentrations where maximum levels of cytokine secretion and
      cellular proliferation were recorded. These cell culture data indicate that, at
      least in this in vitro model, nanoparticulate TT is able to elicit cytokine
      production that is probably consistent with increased stimulation. This mechanism
      is likely to be distinct from non-specific effects caused by components of the
      delivery vehicle itself.

PMID- 12490371
TI  - A novel controlled release formulation for the anticancer drug paclitaxel
      (Taxol): PLGA nanoparticles containing vitamin E TPGS.
AB  - Paclitaxel (Taxol) is one of the best antineoplastic drugs found from nature in
      the past decades. Like many other anticancer drugs, there are difficulties in its
      clinical administration due to its poor solubility. Therefore an adjuvant called
      Cremophor EL has to be employed, but this has been found to cause serious side
      effects. However, nanoparticles of biodegradable polymers can provide an ideal
      solution to the adjuvant problem and realise a controlled and targeted delivery
      of the drug with better efficacy and fewer side-effects. The present research
      proposes a novel formulation for fabrication of nanoparticles of biodegradable
      polymers containing d-alpha-tocopheryl polyethylene glycol 1000 succinate
      (vitamin E TPGS or TPGS) to replace the current method of clinical administration
      and, with further modification, to provide an innovative solution for oral
      chemotherapy. In the modified solvent extraction/evaporation technique employed
      in this research, the emulsifier/stabiliser/additive and the matrix material can
      play a key role in determining the morphological, physicochemical and
      pharmaceutical properties of the produced nanoparticles. We found that vitamin E
      TPGS could be a novel surfactant as well as a matrix material when blended with
      other biodegradable polymers. The nanoparticles composed of various formulations
      and manufactured under various conditions were characterised by laser light
      scattering (LLS) for size and size distribution, scanning electron microscopy
      (SEM) and atomic force microscopy (AFM) for morphological properties, X-ray
      photoelectron spectroscopy (XPS) for surface chemistry and differential scanning
      calorimetry (DSC) for thermogram properties. The drug encapsulation efficiency
      (EE) and the drug release kinetics under in vitro conditions were measured by
      high performance liquid chromatography (HPLC). It was concluded that vitamin E
      TPGS has great advantages for the manufacture of polymeric nanoparticles for
      controlled release of paclitaxel and other anti-cancer drugs. Nanoparticles of
      nanometer size with narrow distribution can be obtained. A drug encapsulation
      efficiency as high as 100% can be achieved and the release kinetics can be
      controlled.

PMID- 12490372
TI  - The influence of various methods of cold storage of skin on the permeation of
      melatonin and nimesulide.
AB  - The purpose of this study was to investigate the influence of different methods
      of skin preservation on the percutaneous permeation of two drugs with varied
      physicochemical properties (melatonin and nimesulide). Hairless rat skin was
      freshly excised and immediately stored at three different storage conditions:
      (a). 4 degrees C in minimal essential medium eagle (MEM), (b). frozen at -22
      degrees C and (c) frozen at -22 degrees C in 10% glycerol (as a cryoprotective
      agent). The permeation of melatonin and nimesulide from saturated solutions was
      studied using the skin stored at various cold storage conditions for 6 months. At
      4 degrees C, the flux of melatonin was similar to fresh skin for up to 7 days
      (P>0.05) and increased 2.4-fold at 14 days (P<0.001). The flux of melatonin was
      similar to fresh skin for 14 days with skin at -22 degrees C (P>0.05) and then
      steadily increased from 30 days onwards and at 180 days, the flux was 5-fold
      greater than fresh skin (P<0.001). Freezing of skin at -22 degrees C with 10%
      glycerol showed similar flux values for melatonin up to 60 days and at 180 days
      the flux increased 2.2-fold as compared to fresh skin (P<0.001). In the case of
      nimesulide, the skin stored for 2 days at 4 degrees C showed similar flux as
      compared to fresh skin (P>0.05) and increased steadily from 4 days onwards and at
      14 days the flux was 3.5-fold higher than fresh skin (P<0.001). The skin frozen
      at -22 degrees C with or without 10% glycerol showed no difference in flux up to
      4 days which however increased from 7 days onwards. At 180 days, the skin at -22
      degrees C showed 2.5-fold increase in the flux (P<0.001) whereas the skin frozen
      with 10% glycerol showed 2-fold increase in the flux (P<0.001) as compared to
      fresh skin. The results of the present study demonstrate that the permeability of
      the drugs across the stored skin was dependent on the storage condition, the
      length of storage and the physicochemical properties of the drug under study.
      Overall, the freezing of skin at -22 degrees C with 10% glycerol was found to be
      very helpful for the long-term storage of skin for percutaneous permeation
      studies.

PMID- 12490373
TI  - Nano-encapsulation of furosemide microcrystals for controlled drug release.
AB  - Furosemide microcrystals were encapsulated with polyions and gelatin to control
      the release of the drug in aqueous solutions. Charged linear polyions and gelatin
      were alternatively deposited on 5-microm drug microcrystals through layer-by
      layer (LbL) assembly. Sequential layers of poly(dimethyldiallyl ammonium
      chloride) (PDDA) and poly(styrenesulfonate) (PSS) were followed by adsorption of
      two to six gelatin/PSS bilayers with corresponding capsule wall thicknesses
      ranging from 45 to 115 nm. The release of furosemide from the coated
      microparticles was measured in aqueous solutions of pH 1.4 and 7.4. At both pH
      values, the release rate of furosemide from the encapsulated particles was
      reduced by 50-300 times (for capsules coated with two to six bilayers) compared
      to uncoated furosemide. The results provide a method of achieving prolonged drug
      release through self-assembly of polymeric shells on drug microcrystals.

PMID- 12490374
TI  - Modeling skin permeability to hydrophilic and hydrophobic solutes based on four
      permeation pathways.
AB  - Barrier properties of skin originate from low permeability of stratum corneum.
      The objective of this paper is to compile fundamentally-based analytical
      expressions that can be used to predict skin permeability to hydrophilic as well
      as hydrophobic solutes. Solute permeation through four possible routes in stratum
      corneum including free-volume diffusion through lipid bilayers, lateral diffusion
      along lipid bilayers, diffusion through pores, and diffusion through shunts was
      analyzed. Contribution of free-volume diffusion through lipid bilayers was
      determined using Scaled Particle Theory. This theory relates solute partition and
      diffusion coefficients to the work required to create cavities in a lipid
      bilayers to allow solute incorporation and motion. Contribution of lateral lipid
      diffusion was determined from the literature data. Contribution of pores was
      estimated using hindered transport theory. This theory assumes that hydrophilic
      solutes permeate across the skin through imperfections in the lipid bilayers
      modeled as pores. Finally, contribution of shunts was determined using a simple
      diffusion model. The model yielded a series of equations to predict skin
      permeability based on solute radius and octanol-water partition coefficient.
      Predictions of the model compare well with the experimental data.

PMID- 12490375
TI  - A lipophilic paclitaxel derivative incorporated in a lipid emulsion for
      parenteral administration.
AB  - Paclitaxel is one of the most effective and most widely-used anti-cancer agents.
      However, paclitaxel is difficult to formulate for parenteral administration
      because of its low aqueous solubility and Cremophor EL, the excipient used for
      its formulation, has been shown to cause serious side effects. This study reports
      an alternative administration vehicle involving a lipophilic paclitaxel
      derivative, paclitaxel oleate, incorporated in the core of a nano-size sterically
      stabilized oil-in-water (o/w) lipid emulsion. This lipid emulsion, with a
      particle size of 50 nm, has many favourable properties such as drug-carrier like
      biocompatibility, physical stability and ease of preparation. When paclitaxel in
      Cremophor EL/ethanol and paclitaxel oleate in emulsion were incubated with plasma
      a greater proportion of paclitaxel was found in the lipoprotein pool when
      formulated as paclitaxel oleate in a lipid emulsion compared to unesterified
      paclitaxel. The paclitaxel prodrug, paclitaxel oleate, demonstrated cytotoxic
      activity against cultured HeLa cells and with a marked increase in activity with
      incubation time. The 50% inhibition (IC(50)) was calculated to be 5500, 500, 150,
      and 100 nM for 24, 48, 72, and 96 h, respectively. Pharmacokinetic data, obtained
      with rabbits, showed significantly greater AUC, higher C(max), lower systemic
      clearance and lower V(ss) when paclitaxel was formulated as an oleate prodrug in
      a lipid emulsion than when formulated in Cremophor EL/ethanol. The formulated
      emulsion may be clinically useful not only for eliminating toxic effects of
      Cremophor EL but also for improvement of the pharmacokinetic parameters of
      paclitaxel.

PMID- 12490376
TI  - Liquid formulation of a novel non-fluorinated topical quinolone, T-3912,
      utilizing the synergic solubilizing effect of the combined use of magnesium ions
      and hydroxypropyl-beta-cyclodextrin.
AB  - T3912 is a non-fluorinated topical quinolone antimicrobial agent currently under
      development. Its pK(a1) and pK(a2) values were determined as 5.6 and 7.5,
      respectively, and its intrinsic solubility at pH 7 was found to be approximately
      2 microg/ml. This study evaluates the combined use of Mg(2+) ions, hydroxpyropyl
      beta-cyclodextrin (HPbetaCD) and polyvinylpyrrolidone (PVP) in order to obtain a
      stable aqueous liquid formulation of T-3912. The use of Mg(2+) ions alone
      resulted in the improved solubility of T-3912 at physiological pH, however, it
      became unstable during storage. HPbetaCD increased T-3912 solubility with
      relatively high apparent association constant (K(1:1)=9.6 x 10(3) M(-1)) that was
      determined by a phase-solubility method at pH 7.5. Moreover, a binary system of
      Mg(2+) and HPbetaCD exerted a synergetic effect, such that the solubility of T
      3912 increased a remarkable 500-fold. Furthermore, the addition of PVP prevented
      precipitation during storage, and as a result, the liquid formulation of T-3912
      (1000 microg/ml) showed good stability under various conditions, i.e., in a
      refrigerator at 25 degrees C/60% RH and at 40 degrees C/75% RH for 6 months. The
      effect of light exposure of 1200000 lux.h was also tested. This combined system
      of Mg(2+) ions, HPbetaCD and PVP has potential as a liquid formulation of T-3912
      for topical application, especially for opthalmic use.

PMID- 12490377
TI  - A sulfonamide based glucose-responsive hydrogel with covalently immobilized
      glucose oxidase and catalase.
AB  - A new glucose-sensitive hydrogel, based on sulfonamide chemistry with covalently
      conjugated glucose oxidase and catalase, was synthesized and tested. The pH
      induced full swelling transition of the gel occurred in the range of pH 6.5
      approximately 7.5. In a glucose concentration range of 0-300 mg/dl in an isotonic
      phosphate buffered saline solution (pH 7.4), the pH inside the gel varied from pH
      7.4 to 7.2. At the same glucose concentration range, the gel showed reversible
      glucose dependent swelling without hysteresis from 12 to 8, expressed in water
      (g)/polymer (g).

PMID- 12490378
TI  - Loading of plasmid DNA into PLGA microparticles using TROMS (Total Recirculation
      One-Machine System): evaluation of its integrity and controlled release
      properties.
AB  - Loading plasmid DNA into poly(ester) microparticles usually involves the
      formation of a multiple emulsion, using homogenisation techniques such as
      sonication or Ultra-Turrax. These procedures may negatively affect the integrity
      of the macromolecule and consequently its activity. The aim of this study was to
      prepare and evaluate DNA-loaded microparticles by TROMS (Total Recirculation One
      Machine System), a new procedure that is based on the formation of a multiple
      emulsion by the injection of the phases under a turbulent regime. Microparticles
      were prepared with either Resomer) RG 502 (MP 502) or RG 756 (MP 756) and DNA
      loading was quantified fluorimetrically. DNA loading in MP 756 was almost twice
      as high as in MP 502 (510 vs. 285 ng/mg, respectively). Under both formulations,
      the loaded plasmid was released while maintaining its integrity for at least 24
      days (MP 502) and 40 days (MP 756). Finally, the transfection efficiency was
      studied after injection of the microparticles (MP 502) into rat skeletal muscle
      and compared with naked DNA injection. Injection of naked DNA (150 microg DNA per
      muscle) achieved higher but variable expression levels that decreased after 3
      weeks. In contrast, the muscles injected with microparticles (6.8 microg DNA per
      muscle) showed lower but homogeneous expression values, which were maintained for
      at least 3 weeks.

PMID- 12490379
TI  - Nebulization of biodegradable nanoparticles: impact of nebulizer technology and
      nanoparticle characteristics on aerosol features.
AB  - Nanoparticles may be effective drug delivery systems for use in various pulmonary
      therapeutic schemes. This study investigated the effect of nebulization
      technology and nanoparticle characteristics on the features of aerosol
      generation. Suspensions of biodegradable nanoparticles consisting of commercially
      available poly(lactide-co-glycolide) and novel comb polymers were nebulized with
      a jet, ultrasonic, and piezo-electric crystal nebulizer. The effects of the
      nanoparticle suspensions on the aerosol droplet size, as well as the nanoparticle
      size before and after nebulization, were characterized via laser diffraction.
      While the individual nanoparticle suspensions showed no clinically relevant
      influence on aerosol droplet size, as compared to control experiments, an
      enhanced nanoparticle aggregation within the droplets was observed. This
      aggregation was further characterized by fluorescence and scanning electron
      microscopy. Dependency of aggregation on nebulizer technology and nanoparticle
      characteristics was noted. Nanoparticles exhibiting the highest surface
      hydrophobicity were particularly susceptible to aggregation when nebulized with a
      jet nebulizer. Aggregation was reduced with nanoparticles exhibiting a more
      hydrophilic surface or when using ultrasonic nebulizers. We conclude that the
      biodegradable nanoparticles contained in the suspensions did not affect the
      aerosol droplet size in a clinically relevant manner; however, both the
      nanoparticle characteristics and the technique of aerosol generation influence
      nanoparticle aggregation occurring during aerosolization.

PMID- 12490380
TI  - The in vitro transport of pergolide from surfactant-based elastic vesicles
      through human skin: a suggested mechanism of action.
AB  - This paper reports the in vitro transport of pergolide from L-595-PEG-8-L elastic
      vesicle formulations. Several aspects of vesicular delivery were studied in order
      to elucidate the possible mechanisms of action and to establish the optimal
      conditions and drug candidates for usage with L-595-PEG-8-L elastic vesicles. All
      studies were performed using human skin and flow-through Franz diffusion cells.
      Pergolide was chosen as model drug. The findings show that there was a strong
      correlation between the drug incorporation to saturated levels and the drug
      transport, both of which were influenced by the pH of the drug-vesicular system.
      The optimal pH was found to be 5.0, giving the highest drug incorporation as well
      as the highest drug transport. Non-occlusive co-treatment with elastic vesicles
      improved the skin delivery of pergolide compared to the non-occlusive buffer
      control by more than 2-fold. However, non-occlusive pre-treatment of skin with
      empty vesicles did not enhance drug transport. Occlusion improved drug transport
      from both elastic vesicle as well as buffer solutions due to the fact that water
      is an excellent penetration enhancer for pergolide. However, in contrast to non
      occlusive application, the action of the elastic vesicles themselves was
      diminished, as occlusive treatments with elastic vesicles showed a lower flux
      compared to occlusive treatment with the buffer control. Hence, the highest
      pergolide skin permeation in this study was obtained from an occluded saturated
      buffer solution, giving a steady-state flux of 137.9 ng/h cm(-2). The volume of
      application did not have any effect on the drug transport. In conclusion, these
      results showed no evidence that a penetration enhancing effect is the main
      mechanism of action. The pH of the drug-vesicular system is an important factor
      to consider when optimising elastic vesicle delivery systems. Occlusion reduces
      the actions of elastic vesicles, but could increase the pergolide transport since
      water is a good penetration enhancer for this particular drug. Based on the
      results obtained, a mechanism of action for the elastic vesicles was proposed.

PMID- 12490381
TI  - Controllable delivery of non-viral DNA from porous scaffolds.
AB  - The inductive approach to tissue engineering combines three-dimensional porous
      scaffolds with drug delivery to direct the action of progenitor cells into a
      functional tissue. We present an approach to fabricate scaffolds capable of
      controlled, sustained delivery by the assembly and subsequent fusion of drug
      loaded microspheres using a gas foaming/particulate leaching process. DNA-loaded
      microspheres were fabricated from the copolymers of lactide and glycolide (PLG)
      using a cryogenic double emulsion process. Microspheres were fabricated in four
      populations with mean diameters ranging from 12.3 microm to 92.5 microm.
      Scaffolds fabricated by fusion of these microspheres had an interconnected open
      pore structure, maintained DNA integrity, and exhibited sustained release for 21
      days. Control over the release was obtained through manipulating the properties
      of the polymer, microspheres, and the foaming process. Decreasing the microsphere
      diameter or the molecular weight of the polymer used for microsphere fabrication
      led to increased rates of release from the porous scaffold. Additionally,
      increasing the pressure of CO(2) increased the DNA release rate. The ability to
      create porous polymer scaffolds capable of controlled release rates may provide a
      means to enhance and regulate gene transfer within a developing tissue, which
      will increase their utility in tissue engineering.

PMID- 12490382
TI  - In vitro gene expression by cationized derivatives of an artificial protein with
      repeated RGD sequences, Pronectin.
AB  - The objective of this study is to investigate the efficiency of a non-viral gene
      carrier with RGD sequences, Pronectin F(+) for gene transfection. The Pronectin
      F(+) was cationized by introducing ethylenediamine (Ed), spermidine (Sd), and
      spermine (Sm) to the hydroxyl groups while the corresponding gelatin derivative
      was prepared similarly because gelatin also has one RGD sequence per molecule.
      The zeta potential and molecular size of Pronectin F(+) and gelatin derivatives
      were examined before and after polyion complexation with a plasmid DNA of
      luciferase. When complexed with the plasmid DNA at the Pronectin F(+)/plasmid DNA
      mixing ratio of 50, the complex exhibited a zeta potential of about 10 mV, which
      is similar to that of the gelatin derivative-plasmid DNA complex. Irrespective of
      the type of Pronectin F(+) and gelatin derivatives, their complexation enabled
      the apparent molecular size of plasmid DNA to reduce to about 200 nm, the size
      decreasing with the increased derivative/plasmid DNA weight mixing ratio. The rat
      gastric mucosal (RGM)-1 cells treated with both complexes exhibited significantly
      stronger luciferase activities than free plasmid DNA although the enhanced extent
      was significant for the Sm derivative compared with the corresponding Ed and Sd
      derivatives. Cell attachment was enhanced by the Pronectin F(+) derivative to a
      significant high extent compared with the gelatin derivative. The amount of
      plasmid DNA internalized into the cells was enhanced by the complexation with
      every Pronectin F(+) derivative compared with the gelatin derivative. For both of
      Pronectin F(+) and gelatin carriers, the buffering capacity of Sm derivatives was
      higher than that of Ed and Sd derivatives and comparable to that of
      polyethyleneimine. It is likely that the high efficiency of gene transfection for
      the Sm derivative is due to the superior buffering effect. We conclude that the
      Sm derivative of Pronectin F(+) is promising as a non-viral vector of gene
      transfection.

PMID- 12490383
TI  - On the origin of size-dependent tortuosity for permeation of hydrophilic solutes
      across the stratum corneum.
AB  - Due to their low skin permeabilities, transdermal transport of hydrophilic
      solutes is poorly understood. In this study, we sought to determine the
      dependence of solute tortuosity on solute size and stratum corneum (SC) porosity.
      With porous pathway model, transdermal transport of hydrophilic solutes through
      the SC was modeled as diffusion through imperfections/defects that occur
      between/within the lipid lamellar organization of the SC. In order to seek an
      analytical solution, we assumed that the pores in the SC were cylindrical and
      organized in a cubical pattern. The proposed theoretical model describing the
      dependence of solute tortuosity on solute size and SC porosity is in agreement
      with prior experimentally derived tortuosity values.

PMID- 12490384
TI  - Type 3 reovirus neuroinvasion after intramuscular inoculation: viral genetic
      determinants of lethality and spinal cord infection.
AB  - To better understand the mechanisms by which neurotropic viruses invade
      peripheral nerve pathways and produce CNS disease, we defined the type 3 (T3)
      reovirus genes that are determinants of the capacity of reovirus T3 strain
      Dearing (T3D) and T3 clone 9 (C9) to infect the spinal cord and kill mice after
      hindlimb injection. T3D and C9 viruses are both highly virulent (LD(50) < 10(1)
      PFU) after intracranial injection of neonatal mice. However, C9 is significantly
      more lethal than T3D after either intramuscular injection (LD(50) < 10(1) vs
      LD(50) 10(4) PFU) or peroral injection (LD(50) 10(3.4) vs LD(50) > 10(8.3) PFU).
      Using reassortant viruses containing different combinations of genes derived from
      T3D and C9, we found that the S1 gene, encoding the cell attachment protein sigma
      1 and the nonstructural protein sigma 1s, and the L3 gene, encoding the core
      shell protein lambda 1 were the primary determinants of lethality after
      intramuscular injection. The L3 gene and the L2 gene encoding spike protein,
      lambda 2, determined differences in spinal cord titer after intramuscular
      injection. A C9 x T3D mono-reassortant containing all T3D genes except for the C9
      derived L3 was lethal after peroral injection. These studies indicate that the
      S1, L2, and L3 genes all play a potential role in neuroinvasiveness and provide
      the first identification of a role in pathogenesis for the L3 gene.

PMID- 12490385
TI  - Type 3 reovirus neuroinvasion after intramuscular inoculation: direct invasion of
      nerve terminals and age-dependent pathogenesis.
AB  - Neonatal but not adult mice are vulnerable to reovirus invasion of the central
      nervous system after peripheral inoculation. After hindlimb injection, type 3
      reovirus travels via the sciatic nerve to replicate in spinal cord motor neurons
      before spread to the brain and development of lethal encephalitis. Here we
      provide ultrastructural evidence for direct reovirus invasion of unmyelinated
      neonatal motor nerve terminals within 2 h and replication in spinal cord motor
      neurons within 14 h after hindlimb injection of 1-day-old mice. In adult mice,
      resistance to reovirus lethality after intracranial (IC) injection correlates
      with the restriction of virus growth in cortical neurons. We found that
      neuroinvasion also is age dependent after intramuscular injection. Virus
      lethality and CNS infection decreased sharply during the first postnatal week,
      while lethality after IC injection continued for 2 additional weeks. Mice
      inoculated at 7 days of age with high virus doses suffered paralysis of the
      injected limb, but significant brain infection was not lethal. These results
      suggest that reovirus invasion of the neonatal CNS is restricted by several
      progressive age-dependent mechanisms.

PMID- 12490386
TI  - Mapping interaction sites of the A20R protein component of the vaccinia virus DNA
      replication complex.
AB  - The vaccinia virus A20R protein is required for DNA replication, is associated
      with the processive form of the viral DNA polymerase, and directly interacts with
      the viral proteins encoded by the D4R, D5R, and H5R open reading frames as
      determined by a genome-wide yeast two-hybrid analysis. The purpose of the present
      study was to further analyze the latter protein-protein interactions. Association
      of an epitope-tagged A20R protein with an epitope-tagged D4R or H5R protein,
      expressed in vaccinia virus-infected cells, was demonstrated by binding the
      complex to one mAb followed by Western blotting with another. Interaction between
      the A20R and D5R proteins, which was weakest in the yeast two-hybrid analysis,
      could not be demonstrated by this method. A panel of N- and C-terminal truncated
      forms of the A20R protein was tested for interaction with the D4R, H5R, and D5R
      proteins using the yeast two-hybrid system. These studies revealed that
      nonoverlapping regions of A20R comprising amino acids 1 to 25, 26 to 76, and 201
      to 251 were required for binding of D4R, H5R, and D5R, respectively. By contrast,
      no interaction of A20R with D4R could be detected after deletion of only 25
      codons from either end of the latter open reading frame. A fusion protein
      containing either full-length A20R or only the N-terminal 25 amino acids of A20R
      was sufficient to capture the D4R protein, whereas the fusion protein containing
      A20R amino acids 26 to 426 was not, confirming the results of the yeast two
      hybrid analysis. The distinct protein binding domains of the A20R protein may
      contribute to the assembly or stability of the multiprotein DNA replication
      complex.

PMID- 12490387
TI  - Differential effect of nucleotide substitutions in the 3' arm of the influenza A
      virus vRNA promoter on transcription/replication by avian and human polymerase
      complexes is related to the nature of PB2 amino acid 627.
AB  - Using a genetic system that allows the in vivo reconstitution of active
      ribonucleoproteins, the ability to ensure transcription/replication of a viral
      like reporter RNA harboring the G(3) --> A(3), U(5) --> C(5), and C(8) --> U(8)
      mutations (triple 3-5-8 mutations) in the 3' arm of the promoter was examined
      with core proteins from human or avian strains of influenza A viruses. The
      efficiency of transcription/replication of the viral-like RNA with the triple 3-5
      8 mutations in COS-1 cells was found to be slightly decreased as compared to the
      wild-type RNA when the polymerase was derived from a human virus. In contrast, it
      was found to be considerably increased when the polymerase was derived from an
      avian virus, in agreement with published observations using the avian
      A/FPV/Bratislava virus (G. Neumann and G. Hobom, 1995, J. Gen. Virol. 76, 1709
      1717). This increase could be attributed to the compensation of the defect in
      transcription/replication activity in the COS-1 mammalian cell line due to the
      presence of a glutamic acid at PB2 residue 627, characteristic of avian strains
      of influenza viruses. Our results thus suggest that PB2 and/or cellular proteins
      interacting with PB2 could be involved in RNA conformational changes during the
      process of transcription/replication.

PMID- 12490388
TI  - Expression of a full-length hepatitis C virus cDNA up-regulates the expression of
      CC chemokines MCP-1 and RANTES.
AB  - We had previously reported the cloning of the complete genome of an isolate of
      hepatitis C virus (HCV), HCV-S1, of genotype 1b. We have constructed a full
      length complementary DNA (cDNA) clone of HCV-S1 using nine overlapping cDNA
      clones that encompassed its entire genome. HCV core, E1, E2, NS-3, -4B, -5A, and 
      5B proteins were detected in 293T cells by immunoblot analyses when expression of
      the full-length HCV-S1 was driven under a CMV promoter. Expression of full-length
      HCV-S1 led to induction of the CC chemokines RANTES and MCP-1 at both the mRNA
      and the protein levels in HeLa, Huh7, and HepG2 cells. Reporter gene assays
      showed that a minimal MCP-1 promoter construct containing 128 nucleotides
      upstream of its translational start site was sufficient for optimal HCV-mediated
      activation. HCV induced AP-1 binding activities to this region, as determined
      from electrophoretic mobility shift assays and supershifts with anti-AP-1
      antibodies. Transfection of full-length HCV-S1 up-regulated both AP-1 binding
      activities as well as c-jun transcripts. A minimal promoter construct containing
      181 nucleotides upstream of the RANTES translational start site was sufficient
      for maximal HCV-mediated induction. Gel mobility shift and supershift assays
      showed that HCV induced NF-kappaB and other unknown binding activities to the A/B
      site within this region. In HeLa cells, HCV core and NS5A could separately
      augment promoter activities of both MCP-1 and RANTES. In Huh7 cells, only NS5A
      produced a similar effect, while rather surprisingly, HCV core induced a dramatic
      reduction in promoter activities of these two genes. This study provides the
      first direct evidence for the induction of CC chemokines in HCV infection and
      draws attention to their roles in affecting the progress and outcome of HCV
      associated liver diseases.

PMID- 12490389
TI  - Purified tomato spotted wilt virus particles support both genome replication and
      transcription in vitro.
AB  - Purified Tomato spotted wilt virus particles were shown to support either genome
      replication or transcription in vitro, depending on the conditions chosen.
      Transcriptional activity was observed only upon addition of rabbit reticulocyte
      lysate, indicating a dependence on translation. Under these conditions RNA
      molecules of subgenomic length were synthesized that hybridized to strand
      specific probes for the N and NSs genes. Cloning of these transcripts
      demonstrated the presence of nonviral leader sequences at their 5' ends,
      confirming the occurrence of genuine viral transcription initiation known as "cap
      snatching." Sequence analyses revealed that both alpha- and beta-globin mRNA,
      present in the reticulocyte lysate, as well as added Alfalfa mosaic virus (AMV)
      RNA sequences, were utilized as cap donors. Moreover, an artificially produced N
      mRNA containing an AMV-derived leader was shown to be used as cap donor,
      indicating that resnatching of viral mRNAs takes place in vitro.

PMID- 12490390
TI  - Successful protection by amantadine hydrochloride against lethal encephalitis
      caused by a highly neurovirulent recombinant influenza A virus in mice.
AB  - A mouse model system for a lethal encephalitis due to influenza has been
      established by stereotaxic microinjection with the recombinant R404BP strain of
      influenza A virus into the olfactory bulb of C57BL/6 mice. The virus infection
      spread selectively to neurons in nuclei of the broad areas of the brain
      parenchyma that have anatomical connections to the olfactory bulb, leading to
      apoptotic neurodegeneration. The inflammatory reaction at the extended stage of
      viral infection involved the vascular structures affected by induction of
      inducible nitric oxide synthase and protein nitration; those were related to the
      etiology of fatal brain edema. The intraperitoneal administration of amantadine
      inhibited the viral growth in the brain and saved mice from the lethal
      encephalitis. The severity of neuronal loss paralleled the time lag between the
      virus challenge and the start of amantadine treatment. Thus, early
      pharmacological intervention is essential to minimize neurological deficits due
      to influenza virus-induced neurodegeneration.

PMID- 12490391
TI  - PNA targeting the PBS and A-loop sequences of HIV-1 genome destabilizes packaged
      tRNA3(Lys) in the virions and inhibits HIV-1 replication.
AB  - During assembly of the HIV-1 virions, cellular tRNA(Lys)(3) is packaged into the
      virion particles and is utilized as a primer for the initiation of reverse
      transcription. The 3'-terminal 18 nucleotides of the cellular tRNA(Lys)(3) are
      complementary to nucleotides 183-201 of the viral RNA genome, referred to as the
      primer binding sequence (PBS). Additional sequences (A-Loop) upstream of the PBS
      are essential for tRNA primer selection. We report here that a PNA targeted to
      PBS and A-Loop sequence (PNA(PBS)) exhibits high specificity for its target
      sequence and prevents tRNA(Lys)(3) priming on the viral genome. We also
      demonstrate that PNA(PBS) is able to invade the duplex region of the tRNA(Lys)(3)
      viral RNA complex and destabilize the priming process, thereby inhibiting the in
      vitro initiation of reverse transcription. The endogenously packaged tRNA(Lys)(3)
      bound to the PBS region of the viral RNA genome in the HIV-1 virion is
      efficiently competed out by PNA(PBS), resulting in near complete inhibition of
      initiation of endogenous reverse transcription. Examination of the effect of
      PNA(PBS) on HIV-1 production in CEM cells infected with pseudotyped HIV-1 virions
      carrying luciferase reporter exhibited dramatic reduction of HIV-1 replication by
      nearly 99%. Analysis of the mechanism of PNA(PBS)-mediated inhibition indicated
      that PNA(PBS) interferes at the step of reverse transcription. These findings
      suggest the antiviral efficacy of PNA(PBS) in blocking the process of HIV-1
      replication.

PMID- 12490392
TI  - Characterization of the human cytomegalovirus UL75 (glycoprotein H) late gene
      promoter.
AB  - Glycoprotein H (gH, UL75) of human cytomegalovirus (HCMV) is an essential
      envelope glycoprotein that functions in viral entry and the activation of gene
      expression. To understand the regulation of this important viral gene, the
      promoter of the UL75 late gene was characterized in HCMV-infected cells at the
      late stages of viral infection. Primer extension analysis revealed a single major
      start site located 26 bp downstream of a putative TATA element. Deletion analysis
      showed the presence of a dominant activation domain from +14 to +35 that masked
      regulatory sequences upstream of the TATA element. Mutational analysis
      demonstrated that a PEA3-like element in this downstream domain was important for
      promoter activation. In addition, gel shift analysis revealed direct protein
      binding to the PEA3-like element. Together, these studies reveal that the gH
      promoter is regulated in a complex manner with sequences both upstream and
      downstream of the cap site influencing promoter activation.

PMID- 12490393
TI  - A natural recombinant between the geminiviruses Tomato yellow leaf curl Sardinia
      virus and Tomato yellow leaf curl virus exhibits a novel pathogenic phenotype and
      is becoming prevalent in Spanish populations.
AB  - This work provides evidence of the significant contribution of recombination to
      the genetic diversification of emerging begomovirus populations. In southern
      Spain, Tomato yellow leaf curl Sardinia virus (TYLCSV) and Tomato yellow leaf
      curl virus (TYLCV) are distinct geminivirus species that coexist in the field and
      contribute to the tomato yellow leaf curl disease epidemic. A natural recombinant
      between TYLCSV and TYLCV has been detected and an infectious clone of a
      recombinant isolate (ES421/99) was obtained and characterized. Analysis of its
      genome showed that the recombination sites are located in the intergenic region
      in which a conserved stem-loop structure occurs and at the 3'-end of the
      replication enhancer protein open reading frame. ES421/99 exhibited a novel
      pathogenic phenotype that might provide it with a selective advantage over the
      parental genotypes. This agrees with results from field studies which revealed
      that the recombinant strain is becoming prevalent in the region in which it was
      detected.

PMID- 12490394
TI  - Expression of IL-18 by SIV does not modify the outcome of the antiviral immune
      response.
AB  - Interleukin 18 (IL-18) is a proinflammatory cytokine expressed by several cell
      types, including activated dendritic cells and macrophages, that acts in synergy
      with IL-12 as an important amplifying factor for IFN-gamma production and Th1
      development. To study the immunological and virological effects of IL-18
      expression in the context of a lentiviral infection, we inoculated rhesus
      macaques with a high dose of replication-competent simian immunodeficiency virus
      (SIV) vectors carrying the rhesus IL-18 gene in the sense (SIV(IL-18)) or
      antisense (SIV(FIGI)) orientation. Both vectors behaved as attenuated viruses,
      resulting in low viral loads, induction of low and transient levels of
      inflammatory cytokines, no CD4(+) T cell depletion, and mild activation of T
      lymphocytes. Although IL-18-expressing virus could be isolated from some
      SIV(IL18)-infected macaques for 12 weeks postinfection, the anti-SIV humoral and
      cellular immune responses of macaques inoculated with SIV(IL18) and SIV(FIGI)
      were similar to each other, with the exception of an early IFN-gamma response in
      animals infected with SIV(IL18). In summary, expression of IL-18 during the acute
      phase of SIV infection does not increase viral replication or influence the
      outcome of the antiviral immune response.

PMID- 12490395
TI  - A glycosylation-defective variant of the ecotropic murine retrovirus receptor is
      expressed in rat XC cells.
AB  - The XC rat sarcoma cell line undergoes extensive cell-to-cell fusion (syncytium
      formation) after infection with ecotropic murine leukemia viruses (MLVs) and is
      frequently used to titrate these viruses. This cell line is unique in its
      response to the ecotropic MLV envelope (Env) protein in that it undergoes
      syncytium formation with cells expressing Env protein containing R peptide (R+
      Env), which is known to suppress the fusogenic potential of the Env protein in
      other susceptible cells. To assess whether this property of the XC cell line
      arises from differences in its ecotropic MLV receptor, CAT1, we isolated CAT1
      cDNA clones from XC cells. A variant CAT1 (xcCAT1) was found together with the
      wild-type rat CAT1 (rCAT1). xcCAT1 cDNA encodes a protein with a single amino
      acid change that destroys a conserved N-linked glycosylation site proximal to the
      Env-binding motif. We found that xcCAT1 expressed in Chinese hamster ovary (CHO)
      cells undergoes less glycosylation than rCAT1 and that the expression of xcCAT1
      rendered the CHO cells more susceptible to infection with Moloney MLV. Thus, N
      glycosylation negatively regulates the receptor activity of rCAT1. This is
      supported by the observation that treatment of rat F10 cells with the N
      glycosylation inhibitor tunicamycin enhanced their susceptibility to Mo-MLV.
      However, xcCAT1-expressing CHO cells did not fuse with 293T cells expressing R+
      Env, indicating that xcCAT1 expression is not sufficient to induce the XC cell
      specific characteristic of forming syncytia in response to R+ Env.

PMID- 12490396
TI  - Epstein-Barr virus latent membrane protein-1 induction by histone deacetylase
      inhibitors mediates induction of intercellular adhesion molecule-1 expression and
      homotypic aggregation.
AB  - Epstein-Barr virus (EBV) latent membrane protein (LMP)-1 induces B lymphocyte
      immortalization and activates constitutive signal transduction, including NF
      kappaB, JNK/p38, and JAK/STAT pathways. During EBV latency, LMP-1 expression
      induces several B lymphocyte activation markers, including intercellular adhesion
      molecule (ICAM)-1. We found that various structurally distinct histone
      deacetylase inhibitors (HDACI), as well as phorbol ester treatment, induced
      homotypic aggregation in EBV-positive Burkitt's lymphoma lines. Cell-surface
      expression of ICAM-1 was concurrently strongly up-regulated by both HDACI and
      phorbol ester treatments. Cell-surface expression of ICAM-1 was concurrently
      strongly induced by both HDACI and phorbol ester treatment. Among several ICAM
      family members, only ICAM-1 was up-regulated by both HDACI and phorbol ester
      treatments, suggesting that up-regulated ICAM-1 expression might mediate the
      observed increase in homotypic aggregation. HDACI-induced homotypic aggregation
      was blocked by exposure to a monoclonal antibody specific for the beta-chain
      (CD18) of an ICAM-1 ligand, LFA-1. Unexpectedly, HDAC inhibition, but not phorbol
      ester treatment, induced LMP-1 expression in EBV-positive cell lines, and this
      LMP-1 species was identified by RT-PCR and immunoblot analyses as the latent form
      of LMP-1. Control of EBV LMP-1 gene expression by HDACI inhibition occurs at the
      transcriptional level, as indicated by nuclear runoff studies and analysis of
      steady-state mRNA levels. Dominant-negative LMP-1 efficiently blocked HDACI
      induced ICAM-1 up-regulation, and ectopic expression of LMP-1 activated
      expression of an ICAM-1 promoter-driven reporter gene. The HDACI-induced up
      regulation of ICAM-1, and consequent homotypic aggregation, were efficiently
      blocked by the addition of N-acetyl-L-cysteine and by ectopic expression of a
      super-repressor IkappaBalpha, while LPM-1 induction was unaffected, suggesting
      that these effects are mediated by NF-kappaB. We demonstrate, therefore, that the
      latent isoform of LMP-1 is induced by HDAC inhibition, and that HDACI-induced
      latent LMP-1 expression, through NF-kappaB activation, is responsible for ICAM-1
      expression up-regulation and homotypic adhesion.

PMID- 12490397
TI  - Chimeric arteriviruses generated by swapping of the M protein ectodomain rule out
      a role of this domain in viral targeting.
AB  - Arteriviruses are enveloped, positive-strand RNA viruses for which the two major
      envelope proteins GP(5) and M occur as disulfide-linked heterodimers. These were
      assumed to serve the viral targeting functions, but recent ectodomain swapping
      studies with equine arteritis virus (EAV) indicate that the GP(5) protein does
      not determine arteriviral tropism. Here, we focused on the short, 13- to 18
      residue ectodomain of the M protein. Using an infectious cDNA clone of the
      Lelystad virus isolate of porcine reproductive and respiratory syndrome virus
      (PRRSV), we substituted the genomic sequence encoding the M ectodomain by that of
      murine lactate dehydrogenase-elevating virus, EAV, and the US PRRSV-isolate,
      VR2332. Viable viruses with a chimeric M protein were obtained in all three
      cases, but for the latter two only after removal of the genomic overlap between
      the M and GP(5) genes. Characterization of the chimeric viruses revealed that
      they could be distinguished immunologically from wild-type virus, that they were
      genetically stable in vitro, but that they were impaired in their growth,
      reaching lower titers than the parental virus. The latter appeared to be due to
      an increased particle-to-infectivity ratio of the chimeric virus particles.
      Interestingly, the chimeric viruses had retained their ability to infect porcine
      cells and had not acquired tropism for cells susceptible to the viruses from
      which the foreign ectodomains were derived. We conclude that the surface
      structures composed by the arterivirus M and GP(5) ectodomains do not determine
      viral tropism.

PMID- 12490399
TI  - Mapping of the bovine immunodeficiency virus packaging signal and RRE and
      incorporation into a minimal gene transfer vector.
AB  - Gene transfer systems based on lentiviruses have emerged as promising gene
      delivery vehicles for human gene therapy due to their ability to efficiently
      transduce nondividing target cells. Both primate and nonprimate lentiviruses have
      been used for construction of lentiviral vectors. An early generation of gene
      transfer system based on bovine immunodeficiency virus (BIV) has been developed
      (R. D. Berkowitz, H. Ilves, W. Y. Lin, K. Eckert, A. Coward, S. Tamaki, G. Veres,
      and I. Plavec, 2001, J. Virol. 75, 3371-3382). In this study, we mapped the BIV
      Rev response element (RRE) to 312 bp of the Env coding region. Furthermore, we
      compared transduction efficiencies of vectors containing different portions of
      the BIV Gag coding region and found that the first 104 bp of gag contains a
      functional part of the BIV packaging signal. These findings enabled the
      generation of a minimal BIV-based lentiviral vector. The minimal transfer vector
      construct consists of a self-inactivating long terminal repeats (LTR), minimal
      packaging sequence, putative central polypurine tract, minimal RRE, an internal
      promoter driving the gene of interest, and a woodchuck hepatitis
      posttranscriptional regulatory element. In addition, we constructed a BIV
      packaging construct containing gag/pol, minimal Rev/RRE, and the accessory gene
      vpy. The regulatory gene tat and the accessory genes vif and vpw have been
      inactivated or truncated. The current system has significantly reduced regions of
      homologies between the transfer vector and the packaging constructs. The vectors
      generated from this system achieved a titer of greater than 1 x 10(6) transducing
      units per milliliter and are fully functional as indicated by their ability to
      efficiently transduce both dividing and nondividing cells. These modifications
      should provide improved safety features for the BIV-based gene transfer system.

PMID- 12490398
TI  - Reduced IL-2 and IL-4 mRNA expression in CD4+ T cells from bovine leukemia virus
      infected cows with persistent lymphocytosis.
AB  - The role of T-helper (Th) responses in the subclinical progression of bovine
      leukemia virus (BLV) infection was explored by determining the contribution of
      CD4+ T cells to the expression of mRNAs encoding interferon-gamma (IFN-gamma),
      interleukin-2 (IL-2), interleukin-4 (IL-4), and interleukin-10 (IL-10) in BLV
      infected cattle. Relative levels of mRNA encoding IFN-gamma, IL-2, IL-4, and IL
      10 were measured in fresh and concanavalin A (Con A) activated peripheral blood
      mononuclear cells (PBMCs) and purified CD4+ T cells from cows seronegative to BLV
      (BLV-), seropositive without persistent lymphocytosis (BLV+PL-), and seropositive
      with PL (BLV+PL+) using a semiquantitative reverse transcription-polymerase chain
      reaction (RT-PCR) assay. The expressions of IFN-gamma, IL-2, and IL-4 mRNAs were
      significantly reduced in the PBMCs from BLV+PL+ cows as compared to BLV- cows.
      Reduced levels of IL-2 and IL-4 mRNAs were detected in fresh CD4+ T cells from
      BLV+PL+ cows. In contrast, Con A stimulated PBMCs and CD4+ T cells did not differ
      significantly in expression of IFN-gamma, IL-2, IL-10, or IL-4 mRNAs among the
      BLV infection groups. Using flow-sorted CD4+ T cells and semiquantitative RT-PCR
      the frequencies of CD4+ T cells transcribing IFN-gamma, IL-2, IL-4, and IL-10
      mRNAs in the peripheral blood of BLV-, BLV+PL-, and BLV+PL+ cows were determined.
      There were no significant differences in the frequencies of CD4+ T cells
      expressing these cytokine mRNAs among animals in the different BLV infection
      categories. Thus, the observed differences in IL-2 and IL-4 mRNAs in CD4+ T cells
      were due to changes in steady-state mRNA levels expressed by individual cells and
      not to changes in the frequency of cells transcribing IL-2 and IL-4 mRNAs. These
      results demonstrate that the progression of BLV infection to PL is associated
      with reduced expression of classical Th1 and Th2 cytokines by CD4+ T cells, thus
      suggesting aberrant Th regulation in subclinically infected animals.

PMID- 12490400
TI  - Bovine herpesvirus 1 U(S) ORF8 protein induces apoptosis in infected cells and
      facilitates virus egress.
AB  - The bovine herpesvirus 1 (BHV-1) U(S) ORF8 protein with homology to the Us9
      protein of other alphaherpesviruses induces apoptosis in rabbit kidney (RK13)
      cells without the presence of other BHV-1-encoded proteins. In this article, we
      have characterized the cytotoxicity and growth behavior of a BHV-1 recombinant,
      BHV-1/D8, which fails to express the U(S) ORF8 protein in infected cells. BHV
      1/D8 exhibited a reduced cytotoxicity to RK13 cells when compared to the
      cytotoxicity of control BHV-1 strains. In RK13 cells, the onset of apoptosis was
      not observed during the infection with BHV-1/D8, and the virus multiplication of
      BHV-1/D8 was markedly greater than that of control viruses. However, virus
      release of progeny viruses from the infected RK13 cells into culture supernatant
      was significantly decreased by the loss of the U(S) ORF8 protein. These data
      demonstrate that the U(S) ORF8 protein activates the apoptotic process and
      facilitates virus release from the BHV-1-infected cells.

PMID- 12490401
TI  - Herpesvirus papio 2 encodes a virion host shutoff function.
AB  - Infection of baboons with herpesvirus papio 2 (HVP-2) produces a disease that is
      similar to human infection with herpes simplex viruses (HSV). Molecular
      characterization of HVP-2 has demonstrated that the virion contains a factor
      which rapidly shuts off host cell protein synthesis after infection. Reduction of
      host cell protein synthesis occurs in parallel with the degradation of mRNA
      species. A homolog of the HSV virion host shutoff (vhs) gene was identified by
      Southern and DNA sequence analysis. The sequence of the HVP-2 vhs gene homolog
      had greater than 70% identity with the vhs genes of HSV 1 and 2. Disruption of
      the HVP-2 vhs open reading frame diminished the ability of the virus to shut off
      protein synthesis and degrade cellular mRNA, indicating that this gene was
      responsible for the vhs activity. The HVP-2 model system provides the opportunity
      to study the biological role of vhs in the context of a natural primate host.
      Further development of this system will provide a platform for proof-of-concept
      studies that will test the efficacy of vaccines that utilize vhs-deficient
      viruses.

PMID- 12490402
TI  - Identification and characterization of a baboon reovirus-specific nonstructural
      protein encoded by the bicistronic s4 genome segment.
AB  - All characterized orthoreoviruses encode a characteristic spike-like protein on
      their polycistronic S1 genome segments that mediates virus cell attachment. In
      the case of baboon reovirus (BRV), the polycistronic S-class genome segment
      corresponds to the smallest S4 segment. We recently determined that the 5'
      proximal open reading frame (ORF) of the bicistronic S4 segment encodes a
      nonstructural protein responsible for virus-induced syncytium formation. Current
      analysis indicates that the p16 protein encoded by the 3'-proximal ORF of the BRV
      S4 genome segment shows no sequence similarity to any other protein encoded by
      the orthoreoviruses, including the well-characterized sigma1/sigmaC reovirus cell
      attachment protein. Results indicate that p16 is a BRV-specific nonstructural
      protein that is not required for virus infection in cell culture and is not
      involved in viral cell attachment. In conjunction with previous studies of the
      BRV S1, S2, and S3 genome segments, the current results indicate that, unlike all
      other orthoreoviruses, BRV does not encode a cell attachment protein in its S
      class genome segments. Furthermore, cell binding and infectivity studies
      suggested BRV may not utilize a functional homolog of the prototypical reovirus
      sigma1/sigmaC cell receptor-binding protein to mediate endocytic uptake by cells.

PMID- 12490403
TI  - Transmission of human cytomegalovirus from infected uterine microvascular
      endothelial cells to differentiating/invasive placental cytotrophoblasts.
AB  - Analysis of placentas infected with human cytomegalovirus (CMV) suggested that
      viral transmission could involve differentiating/invasive cytotrophoblasts in
      villi that attach the placenta to the uterine wall. To parse the cellular
      components in this process, we developed a coculture system of polarized uterine
      microvascular endothelial cell (UtMVEC) infection with an endothelial cell-tropic
      pathogenic strain of CMV. Then we evaluated the potential role of neutrophils and
      endothelial cells in the spread of infection to differentiating cytotrophoblasts.
      As shown by immunocytochemistry and analysis of viral replication, CMV
      preferentially infected endothelial cells via apical membranes and disrupted cell
      junction proteins, thereby altering paracellular permeability and cell polarity.
      Neutralizing antibodies to CMV glycoprotein B, an envelope component that
      facilitates virion penetration, blocked plaque formation in polarized UtMVEC.
      Neutrophils transmitted CMV infection to UtMVEC, which in turn infected
      cytotrophoblasts. However, neutrophils did not directly infect cytotrophoblasts.
      These findings implicate endothelial cells from the uterine microvasculature as a
      potential source for CMV infection of endovascular cytotrophoblasts of the
      anchoring villi. Possibly the cytokine/chemokine milieu in the pregnant uterus
      could attract immune cells that infect endothelial cells in hybrid fetal-maternal
      vessels. In turn, these cells could infect endovascular cytotrophoblasts, one
      possible initiation point of a cascade that results in retrograde placental CMV
      infection.

PMID- 12490405
TI  - Functional analysis of a conserved region of the baculovirus envelope fusion
      protein, LD130.
AB  - The envelope fusion protein from a baculovirus pathogenic for Lymantria dispar
      was characterized. N-terminal sequence analysis determined that it was cleaved
      downstream of predicted signal peptide and furin cleavage motifs. Mutation of the
      furin motif resulted in a protein that was not cleaved and did not mediate
      fusion. Mutagenesis of three charged amino acids in a conserved sequence with the
      features of a fusion peptide resulted in significant reduction of the ability of
      the constructs to mediate fusion. None of the mutations inhibited transport of
      the proteins to the cell surface. In addition, the mutations of the predicted
      fusion peptide region yielded no inhibition of cleavage. No difference in
      cleavage was detected between constructs expressed in Spodoptera frugiperda or L.
      dispar cells.

PMID- 12490404
TI  - The N-linked glycan g15 within the V3 loop of the HIV-1 external glycoprotein
      gp120 affects coreceptor usage, cellular tropism, and neutralization.
AB  - We have studied infectivity and neutralization of X4, R5, and R5X4 tropic HIV-1
      mutants, which are lacking N-linked glycosylation sites for glycans g13, g14,
      g15, and g17 in the V3 loop region of gp120. X4-tropic NL4-3 mutants lacking
      combinations of g14/15 or g15/17 showed markedly higher infectivity in CXCR4
      specific infection. The role of g15 in CCR5-specific infection was investigated
      using viruses with high (NL-918, R5-monotropic), medium (NL-991, R5-monotropic),
      and low (NL-952, R5X4-dualtropic) CCR5-specific infectivity. For NL-991, a
      reduction of infectivity on GHOST-CCR5 cells was observed for a mutant lacking
      g15. For NL-952 mutants all lacking g15, a complete loss of CCR5-specificity was
      observed and NL-952 was shifted from R5X4 to X4 tropism. For all mutants of NL4
      3, NL-991, and NL-952, where the lack of g15 markedly influenced infectivity or
      coreceptor usage, neutralization was enhanced. In contrast, NL-918 mutants with
      or without g15 showed no difference in neutralization and no difference in GHOST
      CCR5 infection rates. Thus, for viruses with a low or medium CCR5-specificity the
      role of g15 for changing CCR5-usage and sensitivity to neutralization was more
      significant than for viruses with high infection rates on GHOST-CCR5 cells. Our
      data demonstrate that V3 glycans play an important role in the usage of CXCR4 and
      CCR5. The lack of g15 was relevant for a more efficient use of CXCR4, whereas
      interaction with CCR5 was facilitated in the presence of g15. This study also
      demonstrates that glycan g15 is involved in blocking of neutralizing antibodies
      and shifting HIV tropism from R5X4 to X4.

PMID- 12490406
TI  - Association of influenza virus matrix protein with ribonucleoproteins may control
      viral growth and morphology.
AB  - The matrix protein (M1) of influenza virus plays a central role in viral
      replication. In relation to viral growth and morphology, we studied the RNP
      binding activity of M1s from high-growth strain A/Puerto Rico/8/34 (A/PR8/34) and
      the relatively low-growth wild-type strain A/Nanchang/933/95. The RNP-binding
      strength of M1 was studied by disruption of M1 from M1/RNP complexes with salt
      and acidic condition. Our results indicated that binding of M1 of high-growth
      A/PR8/34 was more difficult to break than the binding of M1 of low-growth
      A/Nanchang/933/95. Consistent with the presence of M1 in A/PR8/34, binding of M1
      of Resvir-9, a reassortant containing P, M, and NS genes from A/PR8/34 and the
      rest of genes from A/Nanchang/933/95 and retaining relative high-growth
      characteristic, was relatively difficult to break than the binding of M1 of
      A/Nanchang/933/95. Physical properties of morphological features of these viruses
      were studied by velocity sucrose gradient centrifugation and transmission
      electron microscopy of purified viral particles, and by immunofluorescence
      staining of hemagglutinin expressed on the surface of infected cells. The results
      demonstrated that high-growth strains, A/PR8/34, and a relative high-growth
      reassortant, Resvir-9, had characteristics associated predominantly with
      spherical particles, while the low-growth strain, A/Nanchang/933/95, had
      characteristics of filamentous particles. These studies indicate that the binding
      between M1 and RNP complex might determine viral growth and morphology.

PMID- 12490407
TI  - Effects of 1,8-diaminooctane on the FIV Rev regulatory system.
AB  - Proper function of the Rev regulatory system is essential for the replication of
      lentiviruses, including feline immunodeficiency virus (FIV) and human
      immunodeficiency virus type 1 (HIV-1). Specifically, Rev affects the overall
      stability of viral mRNAs that encode necessary structural and enzymatic proteins.
      In turn, the eukaryotic initiation factor (eIF-5A) is indispensable for Rev
      function and is the only known protein whose biologically active form requires
      the unique amino acid, hypusine. Because 1,8-diaminooctane blocks the formation
      of hypusine by disrupting the cellular enzyme, deoxyhypusine synthase, thereby
      preventing activation of eIF-5A, we investigated the effects of 1,8-diaminooctane
      on posttranscriptional regulation. These are the first results to demonstrate
      that diaminooctane significantly reduced viral replication in a dose-dependent
      manner, even under conditions of contact inhibition, diminishing the compound's
      effect on cell proliferation. Similarly, the addition of increased concentrations
      of diaminooctane caused a reduction in the expression of a Rev-dependent CAT
      system without affecting a Rev-independent CAT system. At the RNA level, exposure
      of chronically infected CrFK cells to increasing concentrations of diaminooctane
      substantially decreased the levels of unspliced and singly spliced viral mRNAs
      and increased the relative amounts of multiply spliced transcripts in the
      cytoplasm. The findings of this study are the first demonstration that FIV,
      similar to HIV-1, requires eIF-5A for efficient Rev function and that small
      molecule intervention can indirectly target this lentivirus regulatory system.

PMID- 12490408
TI  - Identification of infectious bursal disease virus quasispecies in commercial
      vaccines and field isolates of this double-stranded RNA virus.
AB  - Quasispecies of infectious bursal disease virus (IBDV) vaccine and wild-type
      strains were identified using real-time RT-PCR at a region of the viral genome
      known for sequence variability. The LightCycler (Idaho Technology, Inc.) and
      hybridization probe system (Roche, Molecular Biochemicals) were used. An anchor
      probe labeled with LightCycler Red 640 and mutation probe labeled with
      fluorescein were designed using the Del-E IBDV sequence. The sequence of the
      mutation probe included nucleotides in the hydrophilic B region of VP2 that are
      important to a viral neutralizing epitope. This Del-E mutation probe was allowed
      to hybridize to the RT-PCR products following amplification and its temperature
      of dissociation (T(m)) from each viral template was determined using the
      LightCycler melting peak analysis. The observed T(m) for the Del-E mutation probe
      with its homologous virus, Del-E, was usually 65.5 degrees C but ranged from 65
      to 66.4 degrees C. Peak melting temperatures for the test viruses were inversely
      proportional to the number of mutations observed between the Del-E mutation probe
      and target virus sequence. All the IBDV vaccine strains tested and all but two of
      the wild-type strains exhibited more than one melting peak, indicating that
      genetic subpopulations or quasispecies of the viruses were present in the
      samples. Since the mutation probe was located at a site which encodes a
      neutralizing epitope of the virus, it is possible that the genetic differences
      observed are translated into antigenic changes in this VP2 epitope and contribute
      to antigenic diversity in the quasispecies cloud.

PMID- 12490409
TI  - Down-regulation of spontaneous Epstein-Barr virus reactivation in the P3HR-1 cell
      line by L-arginine.
AB  - We tested the hypothesis that inhibition of Epstein-Barr virus (EBV) reactivation
      is controlled in part by nitric oxide (NO) generated from L-arginine (Arg). The
      spontaneous reactivation of EBV in the Burkitt's lymphoma (BL) cell line P3HR-1
      was inhibited when the cells were cultured in L-Arg-supplemented medium. The
      expression of EBV early antigen (EA), immediate-early BZLF1 mRNA and the protein
      ZEBRA, and production of infectious virus were reduced by L-Arg supplementation
      in a dose-dependent manner. We demonstrated that inducible NO synthase (iNOS)
      mRNA was constitutively expressed in P3HR-1 cells, as quantitated by the reverse
      transcription-polymerase chain reaction. L-Arg supplementation enhanced iNOS and
      NOx expression in the cells. A specific NOS inhibitor, NG-monomethyl-L-Arg
      enhanced the expression of ZEBRA and early BMRF1 protein EA-D in the cells. L-Arg
      supplementation also inhibited the spontaneous EBV reactivation in another BL
      cell line EB1 and a B lymphoblastoid cell line OB. These results indicated that L
      Arg induces iNOS and generates NO, which inhibits EBV reactivation in EBV
      positive cells.

PMID- 12490410
TI  - Equivalent immunogenicity of the highly attenuated poxvirus-based ALVAC-SIV and
      NYVAC-SIV vaccine candidates in SIVmac251-infected macaques.
AB  - Therapeutic immunization of HIV-1-infected individuals may induce and/or enhance
      HIV-1-specific immune responses and decrease the dependency on antiretroviral
      drug treatment. However, repeated immunizations with live-recombinant vectors may
      induce vector-specific immune responses that interfere with the elicitation of
      vigorous immune responses to the desired antigen. Therefore, the use of mixed
      modality vaccinations may be necessary to induce sustained virus-specific immune
      responses in HIV-1-infected individuals treated with antiretroviral therapy
      (ART). Thus, the relative immunogenicity of various vaccine modalities needs to
      be assessed. Here we compared the immunogenicity of two vaccine candidates, the
      canarypox-based ALVAC-SIV-gag-pol-env (ALVAC-SIV-gpe) and the vaccinia-based
      NYVAC-SIV-gag-pol-env (NYVAC-SIV-gpe), in rhesus macaques infected with SIVmac251
      and treated with ART by 2 weeks postinfection. Both ALVAC-SIV-gpe and NYVAC-SIV
      gpe vaccine candidates induced and/or enhanced a virus-specific CD8+ T cell
      response to a similar extent, as demonstrated by tetramer staining of Gag
      specific CD8+ T cells. Similarly, both vaccines elicited comparable
      lymphoproliferative responses (LPRs) to the SIV p27 Gag and gp120 Env proteins.
      Thus, both these vaccine modalities alone or in combination may be suitable
      candidate vaccines for immune therapy of HIV-1-infected individuals.

PMID- 12490411
TI  - Different substitutions at conserved amino acids in domains II and III in the
      Sendai L RNA polymerase protein inactivate viral RNA synthesis.
AB  - The Sendai virus RNA polymerase is a complex of two virus-encoded proteins, the
      phosphoprotein (P) and the large (L) protein, where L is believed to possess all
      the enzymatic activities necessary for viral transcription and replication. The
      alignment of amino acid sequences of L proteins from negative-sense RNA viruses
      shows six regions, designated domains I-VI, of good conservation which have been
      proposed to be important for the various enzymatic activities of the polymerase.
      To directly address the role(s) of domains II and III, site-directed mutations
      were constructed by the substitution of multiple amino acids at 13 highly or
      mostly conserved residues. Analysis of in vitro viral transcription and
      replication showed that the majority of the mutations completely inactivated the
      L protein for all aspects of RNA synthesis, thus conservation correlated with the
      essential nature of the amino acid. At some positions different phenotypes, from
      inactivation to partial activities, were observed which depended on the nature of
      the amino acid that was substituted. Two mutants, K543R and K666V, could
      synthesize some leader RNA, but were defective in mRNA synthesis and replication.
      K666R and G737E had significantly reduced replication compared to transcription
      in vitro, but replicated genome RNA much more efficiently in vivo. K666A gave
      transcription, but no replication. Representative inactive L mutants, however,
      were still able to bind P protein and the polymerase complex was capable of
      binding nucleocapsids, so the defect appeared to be in the initiation of RNA
      synthesis.

PMID- 12490412
TI  - [In vivo activity of amoxicillin in a non-toxigenic Corynebacterium diphtheriae
      rabbit endocarditis experimental model].
AB  - The mortality of non-toxigenic Corynebacterium diphtheriae endocarditis is high
      (27%). One explanation could be tolerance to amoxicillin. The aim of this work
      was to evaluate in vivo the tolerance phenomenon, in a rabbit endocarditis
      experimental model. Two strains of non-toxigenic Corynebacterium diphtheriae were
      compared: a tolerant one and a non-tolerant one. EACH ANIMAL WAS RANDOMLY
      ASSIGNED TO ONE OF THE FOLLOWING GROUPS: no treatment, continuous infusion of
      amoxicillin simulating 200 mg/kg/24 h in humans, or fractionated infusion of
      amoxicillin simulating 66 mg/kg/8 h in humans. Surviving bacteria were counted in
      vegetations after one or three days of treatment. The 24 h fractionated
      amoxicillin infusion was more efficacious on the non-tolerant strain than on the
      tolerant strain. On the tolerant strain, 24 h amoxicillin was more efficacious as
      a continuous infusion than as a fractionated one.

PMID- 12490413
TI  - [Enteroviral meningitis in adults, underestimated illness: description of 30
      observations from 1999 to 2000, and evolution of clinical practices during 2001].
AB  - Enteroviral meningitis is well documented in children but underestimated in
      adults. The analysis of 30 cases of adult meningitis prospectively diagnosed by
      enterovirus genome detection (RT-PCR) in cerebrospinal fluid (CSF) between 1999
      and 2000 in routine practice showed diagnosis to be problematic. Characteristic
      symptoms were inconstant (the association of fever/headache/stiff neck absent in
      41%) and sometimes misleading (the presence of peribuccal lesions). CSF data
      showed a predominance of lymphocytes in only 44% of patients. The most reliable
      criterion was normal constant CSF glucose levels. Thirty three per cent of
      patients were admitted during cold months. Management of patients varied markedly
      between departments, and included computed tomography (33%), and the prescription
      of aciclovir (20%) or antibiotics (53%). A report of positive enterovirus RT-PCR
      had only low impact on management because it took 6 days to obtain the results
      (versus 3 days in children during the same period). These findings were
      communicated to all hospital physicians concerned and as a result, the number of
      RT-PCR in adults increased significantly during 2001. Again, enteroviral
      meningitis was diagnosed in adults despite a much lower incidence of the illness
      in 2001 compared to 2000. Thus this pathology should not be underestimated in
      adults. Considerable medical expenditure might be avoided (cumulative numbers of
      172 days in hospital and 82 days of antibiotics in this study), if rapid and
      accurate diagnostic techniques were available.

PMID- 12490414
TI  - [Endemic heteroresistant glycopeptide intermediate Staphylcoccus aureus (hGISA)
      comprising unrelated clonal types and not associated with vancomycin therapy].
AB  - The detection of methicillin-resistant S. aureus (SA) (MRSA) refractory to
      glycopeptides is a serious clinical issue. The prevalence of hetero-resistant
      GISA (hGISA) strains at H. Marechal Joffre, France is reported.858 non-repeat SA
      were isolated during 1999. 367 (43%) of these, from 257 patients, were MRSA (mean
      incidence 11.9/1000 admissions). All MSRA detected during 1999 were screened for
      vancomycin (VAN) resistance (BHI+4 mg/l VAN). Isolates recovered were retested
      using Etest strips (2 McFarland inoculum on BHI) and population analysis
      profile/area under the curve (PAP-AUC) analysis with hGISA SA Mu3 as a
      comparator. 58 selected strains were screened for teicoplanin resistance(TEI)
      using SFM recommended screen (2 McFarland inoculum on MH+5 mg/L TEI) and MIC (0.5
      MF inoculum swabbed on MH agar) methods. 188 (51.3%) grew on VAN screen agar
      (6.1/1000 admissions). 58 strains (7.6%) possessed Etest VAN MIC > 8 mg/l all
      others being VAN < 8 mg/l. Of these 58 isolates, 10 were stably heterogeneously
      resistant to both VAN and teicoplanin (MIC > 8 mg/l). PAP-AUC showed 12 strains
      to have PAP-AUC ratios > 0.95 but < 1.5 (ie. hGISA, not GISA). All 7 isolates
      defined as hGISA by both Etest and PAP-AUC comprised 1 PFGE clone (< 3 bands
      difference). Additionally 2 distinct PFGE types were detected among the other 5
      hGISA identified PAP-AUC. The 12 hGISAs, were derived from 12 patients with
      severe underlying disease. None were on glycopeptide therapy prior to hGISA
      isolation. This is the first report of endemic hGISA, comprising 3 clonal types.
      The isolation of hVISA seems not to be associated with patient-specific
      glycopeptide therapies.

PMID- 12490415
TI  - [Evaluation of four commercial immunoglobulin G (IgG)- and IgM- specific enzyme
      immunoassays for diagnosis of Mycoplasma pneumoniae infections].
AB  - The four following commercially available enzyme immunoassays (EIAs) were
      assessed and compared for their performance in detecting Mycoplasma pneumoniae
      specific IgG and IgM antibodies: EIA-Platelia, EIA-Bmd, EIA-Sorin and EIA
      Biotest. Three groups of patients were investigated: 39 patients (27 children and
      12 adults) with respiratory infections and a M. pneumoniae PCR-positive in
      respiratory specimens (group I; 52 sera), 61 healthy children and adults (group
      II; 61 sera) and 20 patients with rheumatoid factor, antinuclear antibodies or
      positive antiviral IgM (group III; 20 sera). In group III, the IgM specificity
      for the EIA-Platelia, EIA-Bmd, EIA-Biotest and EIA-Sorin was 100%, 90%, 65% and
      25%, respectively. In the children from group I, the four EIAs had similar IgM
      sensitivity (89 to 92%) but a striking difference in IgM sensitivity was observed
      in adult patients: 16% EIA-Platelia and EIA-Bmd, 50% EIA-Biotest, 58% EIA-Sorin.
      The sensitivity for IgG was greater with EIA-Bmd and EIA-Biotest, especially in
      detection of IgG in acute-phase serum : 61% EIA-Bmd and EIA-Biotest, 15% EIA
      Platelia and 31% EIA-Sorin. Discrepant and unexpected results were observed in
      IgM detection from control healthy patients using EIA-Sorin and EIA-Biotest,
      confirming the lack of specificity of these two EIA-tests and making them
      inaccurate for routine diagnosis. A high IgG seroprevalence were found in healthy
      adults by the four EIAs (43-70%). In healthy children, EIA-Bmd and EIA-Biotest
      gave a higher IgG seroprevalence than EIA-Sorin and EIA-Platelia (45% each for
      the former as compared to 17% and 20%, respectively, for the latter).These
      results confirm that the IgM EIA serology test is a valuable tool for the early
      diagnosis of M. pneumoniae infections in children, as long as the EIA test used
      is specific. In adults, the difficult interpretation of EIA tests suggests that
      paired sera, combined with PCR detection on respiratory tract specimens collected
      on admission of patient, should be required for accurate diagnosis.

PMID- 12490416
TI  - [Evaluation of the efficacy of a multiresistant bacteria control programme in a
      teaching hospital, studying the evolution of methicillin-resistant Staphylococcus
      aureus incidence].
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) constitute the most important
      multiresistant bacteria (MRB) recovered in French hospitals. Our objective was to
      measure these MRSA diffusion in our hospital to evaluate the MRB control
      programme which had been implemented in the beginning of 1999. This study was
      conducted in a teaching hospital containing 1800 beds, from February 1999 to
      January 2001. All MRSA isolated in clinical samples were included. Duplicates
      (same bacteria in the same patient) were excluded. The detection of methicillin
      resistance was performed at 30 degrees C, by disk diffusion method. Incidence
      densities were determined with their 95% confidence interval (CI 95%). Their
      evolution by four-month period was evaluated with the chi-square test for trend.
      During the two-year period, 866 MRSA were isolated. The global incidence was 0,88
      per 1000 patient-days (PD) (IC 95% = left open bracket 0,83-0,93 right open
      bracket ). For cases acquired in our hospital the incidence was 0,66 per 1000 PD,
      whereas it was 0,26 per 1000 PD for imported cases. Concerning the evolution of
      incidences, no significant trend was observed for global incidence. The incidence
      of acquired MRSA decreased during the first year, but increased thereafter. The
      incidence of imported MRSA increased with a significant trend (p < 10(-5)). The
      number of these imported MRSA isolated in our hospital was twice fold higher in
      2000. This study emphasizes an important actual problem : the increase of patient
      colonization pressure at the time of admission in hospitals. This increase, which
      can be due in part to a community transmission, is responsible for a reduction of
      the efficacy of MRSA control programmes.

PMID- 12490417
TI  - [Human immunodeficiency virus and pregnancy: a retrospective study of 124 women].
AB  - The objective is to describe medical and obstetrical prenatal care of 124 HIV
      infected pregnant women in the Hopital Delafontaine, Saint-Denis, France, between
      1995 and 2001.Demographic, clinical and biological characteristics of study
      population were retrospectively collected. Three (2,4%) children were infected.

PMID- 12490418
TI  - [Determination of indicators for non-compliance with guidelines for surgical
      antimicrobial prophylaxis].
AB  - We conducted a prospective study to identify predictors of inappropriateness of
      surgical prophylaxis. A total of 72 surgeon-anaesthesist pairs participated in
      data collection. We assessed practices by addressing 5 questions: did the
      surgical procedure justify the use of antimicrobial prophylaxis, and was it
      provided? Was the correct agent used? Was the timing of prophylaxis optimal? Was
      the duration of prophylaxis correct? Was the dose correct? We reviewed 687
      procedures, 513 (74.7%) of which were included in the analysis. The proportion of
      these procedures with totally compliant prescriptions was 41.7%. Of the 156
      patients who received an inappropriate drug, 133 (85.3%) received a drug with a
      broader spectrum than that recommended. Prophylaxis lasted too long in 81 (89.0%)
      of the 91 patients who received prophylaxis of incorrect duration. Multivariate
      analysis revealed a clear association between non-compliant prophylaxis and two
      operation-specific factors: prosthesis implantation (with a relative risk of
      2.52) and clean-contaminated operations (with a relative risk of 4.19). More than
      50% of patients received inappropriate surgical prophylaxis. Non-observance of
      guidelines was related to factors that did not influence the infectious potential
      of the flora.

PMID- 12490419
TI  - [Bacteremia caused by coagulase-negative staphylococci: incidence, frequency of
      teicoplanin resistance and molecular epidemiology].
AB  - All the patients hospitalised at Besancon Hospital between October 2000 and
      December 2000 were included in a prospective study in order to determine the
      incidence of bloodstream infections caused by coagulase-negative staphylococci
      (CNS), the prevalence of decreased susceptibility to glycopeptides and the
      molecular epidemiology of these pathogens. CNS isolates from bloodstream
      infections were collected and characterised by analysis of antibiotic
      susceptibility and restriction fragment length polymorphism using pulsed field
      gel electrophoresis. Forty-five episodes of CNS bacteremia occurred in 43
      patients. The crude incidence of infected patients was 0,51 per 1,000 days of
      hospitalisation. These 45 bacteremia represented 23.3% of the total number of
      bacteraemia. Forty three of 45 bacteremia were studied, 36 were positive with a
      single PFGE pattern, 5 bacteraemias with 2 PFGE patterns, and 2 bacteraemias with
      3 PFGE patterns. We identified 52 distinct PFGE patterns and 42 major PFGE
      patterns (35 were isolated in a single patient, 5 in 2 patients and 2 in 3
      patients). The dendrogram generated showed deep but limited branching, each large
      branch corresponding to a species. Of these CNS isolates, 28.8% and 25.0% showed
      decreased susceptibility to teicoplanin, with the reference method and E-test
      respectively. The 16 strains belonging to multiple PFGE patterns were not more
      resistant to teicoplanin. Clonal dissemination did not seem to play a major role
      in the spread of glycopeptides resistance among CNS.

PMID- 12490420
TI  - [Antibiotics resistance of Streptococcus pneumoniae. Results from the Brittany
      registry for 1999].
AB  - Throughout 1999, clinical microbiology laboratories of 13 hospitals in Brittany
      have recovered Streptococcus pneumoniae isolates in 832 patients, 312 (37.5%)
      female and 518 (62.2%) male. Two hundred fifty five of them (30.6%) were
      children. One hundred eighty eight isolates were recovered from blood cultures
      (22.6%), 16 from CSF (1.9%), 449 from lungs (54%), and 88 from ear exsudates
      (10.6%).A 5 microgram oxacillin-disk test was used to detect isolates with
      reduced susceptibility to penicillin G. Determination of MICs of penicillin G,
      amoxicillin and cefotaxime were then performed by agar dilution method on 402
      strains previously categorized resistant or intermediate. Five hundred forty six
      isolates were PSDP, 33.5% of them were resistant to penicillin G, 2.2% to
      amoxicillin and 0.2% to cefotaxime. As expected, a decreased susceptibility to
      beta-lactamins was frequently associated with resistance to macrolides,
      cotrimoxazole and tetracycline. Among PSDP, the most prevalent serotypes were 23
      (23.7%), 14 (23.5%) and 19 (19.1%). In Brittany, the constant rise of PSDP (1993
      1994: 28.5%; 1997: 56.4%; 1999: 65.6 %) could be perhaps explain by analysis of
      social and demographic data.

PMID- 12490421
TI  - Experience of a combination including indinavir 400 mg plus ritonavir 200 mg
      twice daily in HIV-infected patients: pharmacokinetic data.
AB  - Low doses of ritonavir, a strong inhibitor of cytochrome P450 3A4, enhances the
      pharmacokinetic profile of indinavir with increased serum levels. We assessed the
      indinavir-ritonavir 400/200 twice daily combination in 17 HIV-infected patients
      focusing on the pharmacokinetic data and the tolerance of this regimen. IDV
      trough and peak concentrations were measured by high-performance liquid
      chromatography. Median indinavir trough and peak concentrations were 553 ng/ml
      and 3626 ng/ml, respectively. A good tolerance was observed except for three
      patients who experienced a major toxicity. Only one dose adjustment was related
      to indinavir toxicity. Considering the fact that Cmax is mainly responsible of
      the adverse effects, particularly renal stones, the indinavir-ritonavir 400/200
      mg twice daily regimen offers a well-tolerated combination with an increased Cmin
      but a lower Cmax compared with both the standard tid regimen and higher dose of
      IDV-RTV regimens.

PMID- 12490422
TI  - [Hepatitis viruses: mother to child transmission].
AB  - The infection by the hepatitis viruses, when appearing during the pregnancy,
      could result in damages for the infant. However, risks differ according to the
      implicated virus. Hepatitis B virus infection, for which prevalence varies
      according to areas, is injurious when the mother is chronic HBsAg carrier. Risk
      consists of neonate's contamination during the labour, and if contaminated, the
      neonate becomes a chronic carrier himself in 80 to 90% of cases. When the mother
      is positive for viral DNA in her serum, transmission rate is estimated at 90%. In
      the opposite, if the mother is negative for viral DNA in the serum, transmission
      rate is about 10 to 30%. HBsAg screening is obligatory in France during the sixth
      month of pregnancy: in case of positivity, serovaccination of the neonate is
      systematically carried out. Protection rate is 100% if the mother had a low viral
      load (<150 pg/ml) at the end of pregnancy, and weaker (about 70%) if the mother
      had a higher level of viral DNA. Transmission risk of hepatitis C virus (HCV) is
      much lesser, since it is about 5% for a woman who is positive for viral RNA at
      the end of her pregnancy, and at least 10% if the woman is moreover positive for
      the HIV. Risk is more important if the woman had an important plasmatic viral
      load (> 10(5) copies/ml) and if the duration between membrane rupture and
      delivery is long. Vaginal delivery and breast-feeding are not advised. Neonates
      from mothers who replicate the HCV at the end of pregnancy are serologically
      evaluated until 12-15 months of age, in order to determine their possible
      contamination.Delta virus transmission from mother to infant is exceptional and
      could be avoided by the HBV serovaccination of the new-born.Intra-utero
      transmission of hepatitis A virus is very rare, but perinatal transmission could
      occur. Materno-fetal transmission of hepatitis E virus has been reported, but the
      virus is essentially dangerous for the mother, resulting in a mortality rate of
      15 to 25% if the acute infection occurs during the third trimester of the
      pregnancy.

PMID- 12490423
TI  - [HIV and pregnancy].
AB  - HIV infection is a complex model of mother-to-child transmission. Antiretroviral
      therapy can induce a dramatic reduction of the risk of transmission, actually the
      rate of transmission is about 1 to 2 % in France. The actual most important stake
      concerns the diagnosis and the follow up of infected women living in countries of
      high endemy where the programs are inappropriate at the moment. The knowledge of
      the mechanisms and the timing of HIV mother-to-child transmission need to be more
      developed in order to design adapted antiretroviral posology and to try to reduce
      infant's exposure to drug toxicity.

PMID- 12490424
TI  - Genomics and the tree physiologist.
AB  - During the last decade, a strong case has been made for viewing trees as model
      systems in plant biology. More recently, forest biologists have argued for the
      sequencing of the genome of a forest tree. Now, the United States Department of
      Energy has announced plans for sequencing the genome of the Populus trichocarpa
      clone, "Nisqually-1." Thus, forest biology is poised to enter an exciting period
      of scientific discovery. Embracing new technology and new research paradigms,
      however, is never easy. It is, therefore, timely to ask how tree physiologists
      will take advantage of the Populus genome data. We contend that the most
      attractive opportunities will arise through genome-wide research designed to:
      (1). examine the differences between trees and herbaceous annuals; (2). explore
      questions relating to the temporal and spatial scales that characterize the life
      histories and growth of trees; and (3). investigate cause-and-effect
      relationships that are intractable to conventional research methodologies. To
      highlight the potential applications of genomics in tree physiology, we briefly
      discuss each of these approaches.

PMID- 12490425
TI  - Spatial distribution of leaf morphological and physiological characteristics in
      relation to local radiation regime within the canopies of 3-year-old Populus
      clones in coppice culture.
AB  - Spatial distributions of leaf characteristics relevant to photosynthesis were
      compared within high-density coppice canopies of Populus spp. of contrasting
      genetic origin. We studied three clones representative of the range in growth
      potential, leaf morphology, coppice and canopy structure: Clone Hoogvorst (Hoo)
      (Populus trichocarpa Torr. & Gray x Populus deltoides Bartr. & Marsh), Clone
      Fritzi Pauley (Fri) (Populus trichocarpa Torr. & Gray) and Clone Wolterson (Wol)
      (Populus nigra L.). Leaf area index ranged from 2.7 (Fri and Wol) to 3.8 (Hoo).
      The clones exhibited large vertical variation in leaf area density (0.02-1.42 m2
      m-3). Leaf dry mass per unit leaf area (DM(A)) increased with increasing light in
      Clones Hoo and Fri, from about 56 g m-2 at the bottom of the canopy to 162 g m-2
      at the top. In Clone Wol, DM(A) varied only from 65 to 100 g m-2, with no
      consistent relationship with respect to light. Conversely, nitrogen concentration
      on a mass basis was nearly constant (around 1.3-2.1%) within the canopies of
      Clones Hoo and Fri, but increased strongly with light in Clone Wol, from 1.4% at
      the bottom of the canopy to 4.1% at the top. As a result, nitrogen per unit leaf
      area (N(A)) increased with light in the canopies of all clones, from 0.9 g m-2 at
      the bottom to 2.9 g m-2 at the top. Although a single linear relationship
      described the dependence of maximum carboxylation rate (17-93 micromol CO2 m-2 s
      1) or electron transport capacity (45-186 micromol electrons m-2 s-1) on N(A),
      for all clones, Clone Wol differed from Clones Hoo and Fri by exhibiting a higher
      dark respiration rate at low N(A) (1.8 versus 0.8 micromol CO2 m-2 s-1).

PMID- 12490426
TI  - The influence of severe shoot pruning on growth, carbon and nitrogen status in
      young peach trees (Prunus persica).
AB  - One-year-old peach trees (Prunus persica (L.) Batsch) were severely pruned in
      July by removing 60% of the shoots. Tree responses were analyzed in terms of
      architecture and nutritional status. Tree growth was recorded from July to
      September by nondestructive (leaf production, thickening and branching of the
      remaining secondary axes) and destructive measurements (biomass partitioning and
      concentrations of total nitrogen (N) and nonstructural carbohydrates (NC) in
      specific tissues). The dry weights of pruned trees were lower than those of
      control trees at the end of the growing season (i.e., 2.5 months after pruning),
      whereas shoot:root ratios were restored to the initial values. Tree response
      occurred in two stages. During the first 24 days following pruning, the growth
      components of the remaining secondary axes were similar to the control, and new
      secondary axes were produced. During the next 17 days, increases in both diameter
      and branching of secondary axes contributed to the maintenance of pruned tree
      growth rate (similar to that of control trees) and restoration of initial
      shoot:root ratios. No significant effect of pruning was observed on NC
      concentrations, whereas N concentrations increased in several organs of the
      pruned trees during the first growth period. The transient increase in internal N
      availability contributed to the initiation of new axes and the restoration of a
      more functional biomass partitioning between shoots and roots.

PMID- 12490427
TI  - Growth of young apple trees in relation to reserve nitrogen and carbohydrates.
AB  - Bench-grafted Fuji/M.26 apple (Malus domestica Borkh.) trees were fertilized with
      a nutrient solution (fertigation) containing 0, 2.5, 5, 7.5, 10, 15 or 20 mM
      nitrogen (N) in a modified Hoagland's solution from June 30 to September 1. In
      mid-October, half of the trees in each N treatment were sprayed twice with 3%
      urea, 1 week apart. The remaining trees served as controls. All trees were
      harvested after leaf fall and stored at 2 degrees C over winter. One group of
      trees from each treatment was destructively sampled before bud break to determine
      amounts of reserve N and total nonstructural carbohydrates (TNC); the remaining
      trees were transplanted to N-free medium in the spring. These trees were supplied
      with Hoagland's solution with or without 10 mM N (from 15N-depleted NH4NO3) for
      60 days, starting from bud break. With increasing N supply from fertigation, tree
      N concentration increased, whereas TNC concentration decreased. Foliar urea
      applications increased tree N concentration and decreased TNC concentration in
      each N fertigation treatment. There was a negative linear relationship between
      tree N concentration and TNC concentration. Irrespective of whether N was
      provided the following spring, trees with high N reserves but low carbohydrate
      reserves produced a larger total leaf area at the end of the regrowth period than
      trees with low N reserves but high carbohydrate reserves. The pooled data on
      reserve N used for new growth showed that, regardless of the spring N supply,
      there was a linear relationship between total N accumulated in the tree during
      the previous season and the amount of reserve N remobilized for new shoot and
      leaf growth. About 50% of tree N content was remobilized to support new shoot and
      leaf growth over the range of tree N status examined. We conclude that the
      initial growth of young apple trees in the spring is determined mainly by reserve
      N, not reserve carbohydrates. The amount of reserve N remobilized for new growth
      in spring was proportional to tree N status and was unaffected by current N
      supply.

PMID- 12490429
TI  - Soil temperature, gas exchange and nitrogen status of 5-year-old Norway spruce
      seedlings.
AB  - Five-year-old Norway spruce (Picea abies (L.) Karst.) seedlings were subjected to
      three simulated growing seasons in controlled environment chambers. Plants were
      acclimated to a soil temperature of 16 degrees C during the first and third
      growing seasons, but were allocated at random to soil temperature treatments of
      9, 13, 18 and 21 degrees C during the second growing season. Low soil temperature
      during the second growing season depressed stomatal conductance and
      photosynthetic rate (A) per unit of projected leaf area, although intercellular
      CO2 concentrations did not differ significantly between treatments. At all soil
      temperatures, total chlorophyll concentration first decreased and then increased,
      although the rate of increase and the final concentration increased with soil
      temperature, which may explain the effect of soil temperature on A. Neither
      chlorophyll a/b ratio nor leaf nitrogen concentration was significantly affected
      by soil temperature. Treatment differences disappeared during the third simulated
      growing season when plants were again acclimated to a soil temperature of 16
      degrees C.

PMID- 12490428
TI  - Nitrogen absorption, translocation and distribution from urea applied in autumn
      to leaves of young potted apple (Malus domestica) trees.
AB  - We studied the absorption, assimilation, translocation and distribution of
      nitrogen (N) from urea applied in autumn to leaves of 1-year-old potted Fuji/M26
      apple (Malus domestica Borkh) trees. In early October, all leaves of each tree
      were painted with either 3% urea (enriched to 10 atom % with 15N) or water
      (control trees). Four trees were harvested before the treatment and N and amino
      acid contents were determined. Four trees from each treatment were harvested at
      2, 4, 7, 10, 15 and 20 days after urea or water application. Total N, amino acids
      and 15N in leaves, bark, xylem, shank and roots were analyzed to determine uptake
      and mobilization of N from urea. Most uptake of 15N by leaves occurred during the
      first 2 days following application of urea. The mean rate of absorption during
      these 2 days was 0.29 g m-2 day-1. Amino acids in leaves, bark and roots
      increased significantly after urea application compared with control values. The
      highest concentrations of amino acids in leaves and bark occurred 4 days after
      application, whereas the highest concentrations of amino acids in roots occurred
      10 days after application. Total 15N content in leaves peaked 2 days after urea
      application and then decreased, whereas 15N content in roots and bark increased
      throughout the experiment. Total 15N content in xylem and shank was low. Leaves
      absorbed 35% of the 15N applied as urea, and 63.6% of absorbed 15N was
      translocated out of leaves within 20 days after urea application. We conclude
      that N from urea was converted to amino acids in leaves after foliar application
      in autumn, and roots and bark were the main sinks of N from urea applied to
      leaves.

PMID- 12490430
TI  - Interdigestive transpyloric fluid transport assessed by intraluminal impedance
      recording.
AB  - Our aim was to explore the use of intraluminal impedance recording for assessment
      of interdigestive transpyloric fluid movements. Twenty healthy volunteers were
      studied with a catheter allowing the recording of five antropyloroduodenal
      impedance signals simultaneously with six pressure signals. Patterns induced by
      air were verified by standard ultrasound. Transpyloric Doppler ultrasound was
      used to validate impedance patterns associated with transpyloric fluid
      transports. Impedance changes caused by air (short-lived increases) occupied 14
      +/- 12% of the time in the antrum and 0.8 +/- 0.5% in the duodenum (P < 0.005).
      All fluid transport events lasting >4 s were recorded by both Doppler and
      impedance techniques. Transpyloric fluid transport was observed in all three
      phases of the antral migrating motor complex. The total number of transport
      events was significantly higher (P < 0.05) in phase II (18 +/- 7) than in phases
      I (2.6 +/- 2) and III (6.1 +/- 3). Retrograde transport was observed mainly in
      antral phase I (54% of fluid movements, compared with 2.5% in phase II and 18.5%
      in phase III, P < 0.05). During phase II, 80 +/- 13% of the impedance changes
      were associated with manometric events and 72 +/- 9% of the antral contractions
      were associated with transpyloric fluid transport. Prolonged assessment of
      interdigestive transpyloric fluid transport events using intraluminal measurement
      of impedance is possible. Manometrically detectable contractions are the most
      frequent, but not the only, driving forces of these events.

PMID- 12490431
TI  - Deficit in nitric oxide production in cirrhotic rat livers is located in the
      sinusoidal and postsinusoidal areas.
AB  - Intrahepatic nitric oxide (NO) production is decreased in cirrhotic livers. Our
      objective was to identify, in cirrhotic rat livers, intrahepatic vascular
      segments where the deficit of NO facilitates the effect of vasoconstrictors. By
      using a modified rat liver perfusion system with measurement of both the
      perfusion and sinusoidal (wedged hepatic vein) pressures, we studied the effect
      of the NO synthase blocker N(omega)-nitro-l-arginine (l-NNA) on the response to
      methoxamine (alpha(1)-adrenoreceptor agonist) in different segments of the
      intrahepatic circulation of normal and cirrhotic rat livers. l-NNA enhanced the
      presinusoidal, sinusoidal, and postsinusoidal responses to methoxamine in normal
      livers as well as the presinusoidal response in cirrhotic livers. However, l-NNA
      did not change the already enhanced sinusoidal/postsinusoidal response to
      methoxamine in cirrhotic livers. The postsinusoidal response to methoxamine was
      higher in cirrhotic rats with ascites than in those without ascites. We concluded
      that NO modulates the presinusoidal, sinusoidal, and postsinusoidal vascular tone
      in normal livers. NO production in cirrhotic rat livers is severely impaired in
      the sinusoidal and postsinusoidal areas but is preserved in the presinusoidal
      area, as evidenced by its normal response to l-NNA. We speculate that an
      increased postsinusoidal response to catecholamines may participate in the
      genesis of ascites in cirrhosis.

PMID- 12490432
TI  - mRNA localization in polarized intestinal epithelial cells.
AB  - An important feature of enterocyte maturation is the asymmetrical distribution of
      cellular functions including protein localization. mRNA sorting is one mechanism
      for establishment and maintenance of this process in other systems, and we have
      previously demonstrated differential localization of mRNAs in human enterocytes.
      To study regulation of mRNA sorting, we established a model in polarized Caco-2
      cells. Proxy cDNA constructs containing beta-galactosidase (beta-gal)/green
      fluorescence protein (GFP) and the 3'-untranslated region (3'-UTR) of either
      human sucrase-isomaltase or villin were transfected transiently or stably. A
      control construct contained poly-A sequence in place of 3'-UTR. Expression of GFP
      was observed by confocal microscopy; intracellular location of the construct mRNA
      was imaged by in situ hybridization. The sucrase-isomaltase mRNA proxy localized
      to an apical position in Caco-2 cells as in native enterocytes; the villin mRNA
      proxy did not show significant localization. The control construct was not
      localized and was found diffusely throughout the cell. Proxy GFP proteins tended
      to localize with their mRNA proxies, but with less precision. This study
      establishes a valuable model for the investigation of mRNA localization in
      intestinal epithelial cells. Mechanisms controlling asymmetrical distribution of
      intestinal mRNAs can be now be elucidated.

PMID- 12490433
TI  - Oxidative stress-induced cell death of human oral neutrophils.
AB  - Polymorphonuclear leukocytes (PMN) play crucial roles in protecting hosts against
      invading microbes and in the pathogenesis of inflammatory tissue injury. Although
      PMN migrate into mucosal layers of digestive and respiratory tracts, only limited
      information is available of their fate and function in situ. We previously
      reported that, unlike circulating PMN (CPMN), PMN in the oral cavity
      spontaneously generate superoxide radical and nitric oxide (NO) in the absence of
      any stimuli. When cultured for 12 h under physiological conditions, oral PMN
      (OPMN) showed morphological changes that are characteristic of those of
      apoptosis. Upon agarose gel electrophoresis, nuclear DNA samples isolated from
      OPMN revealed ladder-like profiles characteristic of nucleosomal fragmentation. l
      cysteine, reduced glutathione (GSH), and herbimycin A, a protein tyrosine kinase
      inhibitor, suppressed the activation of caspase-3 and apoptosis of OPMN. Neither
      thiourea, superoxide dismutase (SOD), nor catalase inhibited the activation of
      caspase-3 and apoptosis. Moreover, N-acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD
      CHO), inhibitor for caspase-3, inhibited the fragmentation of DNA. These results
      suggested that oxidative stress and/or tyrosine-kinase-dependent pathway(s)
      activated caspase-3 in OPMN, thereby inducing their apoptosis.

PMID- 12490434
TI  - Protective role of HSP72 against Clostridium difficile toxin A-induced intestinal
      epithelial cell dysfunction.
AB  - We determined whether the cytoprotective heat shock protein HSP72 protects
      against the injurious effects of Clostridium difficile toxin A (TxA) on
      intestinal epithelial cells. Colonic epithelial Caco-2/bbe (C2) cells were stably
      transfected with HSP72 antisense (C2AS) or vector only (C2VC), resulting in low
      and high HSP72 expression, respectively. Measurements of epithelial barrier
      integrity, mitochondrial function, and apoptosis activation were assessed after
      TxA exposure. HSP72 and RhoA interactions were evaluated with
      immunoprecipitations. In C2AS cells, TxA was associated with a greater decrease
      in transepithelial resistance (TER), an increase in [(3)H]mannitol flux, and
      increased dissociation of perijunctional actin. Although HSP72 binds RhoA, it
      failed to prevent RhoA glucosylation. TxA caused a more rapid decrease in ATP,
      release of cytochrome c, and activation of caspase-9 in C2AS cells. To determine
      whether ATP depletion decreases TER, we treated cells with antimycin A, which
      caused a decline in TER. We conclude that HSP72 may protect intestinal epithelial
      cells from TxA-mediated damage through several mechanisms, including actin
      stabilization, mitochondrial protection, and inhibition of apoptosis activation,
      but not by prevention of RhoA glucosylation.

PMID- 12490435
TI  - Inhibitors of glycosphingolipid biosynthesis reduce transepithelial electrical
      resistance in MDCK I and FRT cells.
AB  - Madin-Darby canine kidney (MDCK) I and Fisher rat thyroid (FRT) cells exhibit
      transepithelial electrical resistance (TER) values in excess of 5,000 Omega.
      cm(2). When these cells were incubated in the presence of various inhibitors of
      sphingolipid biosynthesis, a >5-fold reduction of TER was observed without
      changes in the gate function for uncharged solutes or the fence function for
      apically applied fluorescent lipids. The localization of ZO-1 and occludin was
      not altered between control and inhibitor-treated cells, indicating that the
      tight junction was still intact. Furthermore, the complexity of tight junction
      strands, analyzed by freeze-fracture microscopy, was not reduced. Once the
      inhibitor was removed and the cells were allowed to synthesize sphingolipids, a
      gradual recovery of the TER was observed. Interestingly, these inhibitors did not
      attenuate the TER of MDCK II cells, a cell line that typically exhibits values
      below 800 omega x cm(2.) These results suggest that glycosphingolipids play a
      role in regulating the electrical properties of epithelial cells.

PMID- 12490436
TI  - Increase in cytosolic Ca2+ induced by elevation of extracellular Ca2+ in skeletal
      myogenic cells.
AB  - Cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) variation is a key event in
      myoblast differentiation, but the mechanism by which it occurs is still debated.
      Here we show that increases of extracellular Ca(2+) concentration ([Ca(2+)](o))
      produced membrane hyperpolarization and a concentration-dependent increase of
      [Ca(2+)](i) due to Ca(2+) influx across the plasma membrane. Responses were not
      related to inositol phosphate turnover and Ca(2+)-sensing receptor. [Ca(2+)](o)
      induced [Ca(2+)](i) increase was inhibited by Ca(2+) channel inhibitors and
      appeared to be modulated by several kinase activities. [Ca(2+)](i) increase was
      potentiated by depletion of intracellular Ca(2+) stores and depressed by
      inactivation of the Na(+)/Ca(2+) exchanger. The response to arginine vasopressin
      (AVP), which induces inositol 1,4,5-trisphosphate-dependent [Ca(2+)](i) increase
      in L6-C5 cells, was not modified by high [Ca(2+)](o). On the contrary, AVP
      potentiated the [Ca(2+)](i) increase in the presence of elevated [Ca(2+)](o).
      Other clones of the L6 line as well as the rhabdomyosarcoma RD cell line and the
      satellite cell-derived C2-C12 line expressed similar responses to high
      [Ca(2+)](o), and the amplitude of the responses was correlated with the myogenic
      potential of the cells.

PMID- 12490437
TI  - Bioinformatics: biology by other means.

PMID- 12490438
TI  - Accomplishments and challenges in literature data mining for biology.
AB  - We review recent results in literature data mining for biology and discuss the
      need and the steps for a challenge evaluation for this field. Literature data
      mining has progressed from simple recognition of terms to extraction of
      interaction relationships from complex sentences, and has broadened from
      recognition of protein interactions to a range of problems such as improving
      homology search, identifying cellular location, and so on. To encourage
      participation and accelerate progress in this expanding field, we propose
      creating challenge evaluations, and we describe two specific applications in this
      context.

PMID- 12490439
TI  - The presence of signal peptide significantly affects transmembrane topology
      prediction.

PMID- 12490440
TI  - Computational antisense oligo prediction with a neural network model.
AB  - MOTIVATION: The expression of a gene can be selectively inhibited by antisense
      oligonucleotides (AOs) targeting the mRNA. However, if the target site in the
      mRNA is picked randomly, typically 20% or less of the AOs are effective
      inhibitors in vivo. The sequence properties that make an AO effective are not
      well understood, thus many AOs need to be tested to find good inhibitors, which
      is time consuming and costly. So far computational models have been based
      exclusively on RNA structure prediction or motif searches while ignoring
      information from other aspects of AO design into the model. RESULTS: We present a
      computational model for AO prediction based on a neural network approach using a
      broad range of input parameters. Collecting sequence and efficacy data from AO
      scanning experiments in the literature generated a database of 490 AO molecules.
      Using a set of derived parameters based on AO sequence properties we trained a
      neural network model. The best model, an ensemble of 10 networks, gave an overall
      correlation coefficient of 0.30 (p=10(-8)). This model can predict effective AOs
      (>50% inhibition of gene expression) with a success rate of 92%. Using these
      thresholds the model predicts on average 12 effective AOs per 1000 base pairs,
      making it a stringent yet practical method for AO prediction.

PMID- 12490441
TI  - Comparing expression profiles of genes with similar promoter regions.
AB  - MOTIVATION: Gene regulatory elements are often predicted by seeking common
      sequences in the promoter regions of genes that are clustered together based on
      their expression profiles. We consider the problem in the opposite direction: we
      seek to find the genes that have similar promoter regions and determine the
      extent to which these genes have similar expression profiles. RESULTS: We use the
      data sets from experiments on Saccharomyces cerevisiae. Our similarity measure
      for the promoter regions is based on the set of common mapped or putative
      transcription factor binding sites and other regulatory elements in the upstream
      region of the genes, as contained in the Saccharomyces cerevisiae Promoter
      Database. We pair up the genes with high similarity scores and compare their
      expression levels in time-course experiment data. We find that genes with similar
      promoter regions on the average have significantly higher correlation, but it can
      vary widely depending on the genes. This confirms that the presence of similar
      regulatory elements often does not correspond to similarity in expression
      profiles and indicates that finding transcription factor binding sites or other
      regulatory elements starting with the expression patterns may be limited in many
      cases. Regardless of the correlation, the degree to which the profiles agree
      under different experimental conditions can be examined to derive hypotheses
      concerning the role of common regulatory elements. Overall, we find that
      considering the relationship between the promoter regions and the expression
      profiles starting with the regulatory elements is a difficult but useful process
      that can provide valuable insights.

PMID- 12490442
TI  - Robust estimators for expression analysis.
AB  - MOTIVATION: We consider the problem of estimating values associated with gene
      expression from oligonucleotide arrays. Such estimates should linearly track
      concentration, yield non-negative results, have statistical guarantees of
      robustness against outliers, and allow estimates of significance and variance.
      RESULTS: A hierarchy of simple models is used to design robust estimators meeting
      these goals for both stand alone and comparative experiments. This algorithm has
      been validated against an extensive panel of known spike experiments, and shows
      comparable performance to existing standards.

PMID- 12490443
TI  - Analysis of high density expression microarrays with signed-rank call algorithms.
AB  - MOTIVATION: We consider the detection of expressed genes and the comparison of
      them in different experiments with the high-density oligonucleotide microarrays.
      The results are summarized as the detection calls and comparison calls, and they
      should be robust against data outliers over a wide target concentration range. It
      is also helpful to provide parameters that can be adjusted by the user to balance
      specificity and sensitivity under various experimental conditions. RESULTS: We
      present rank-based algorithms for making detection and comparison calls on
      expression microarrays. The detection call algorithm utilizes the discrimination
      scores. The comparison call algorithm utilizes intensity differences. Both
      algorithms are based on Wilcoxon's signed-rank test. Several parameters in the
      algorithms can be adjusted by the user to alter levels of specificity and
      sensitivity. The algorithms were developed and analyzed using spiked-in genes
      arrayed in a Latin square format. In the call process, p-values are calculated to
      give a confidence level for the pertinent hypotheses. For comparison calls made
      between two arrays, two primary normalization factors are defined. To overcome
      the difficulty that constant normalization factors do not fit all probe sets, we
      perturb these primary normalization factors and make increasing or decreasing
      calls only if all resulting p-values fall within a defined critical region. Our
      algorithms also automatically handle scanner saturation.

PMID- 12490444
TI  - Between-group analysis of microarray data.
AB  - MOTIVATION: Most supervised classification methods are limited by the requirement
      for more cases than variables. In microarray data the number of variables (genes)
      far exceeds the number of cases (arrays), and thus filtering and pre-selection of
      genes is required. We describe the application of Between Group Analysis (BGA) to
      the analysis of microarray data. A feature of BGA is that it can be used when the
      number of variables (genes) exceeds the number of cases (arrays). BGA is based on
      carrying out an ordination of groups of samples, using a standard method such as
      Correspondence Analysis (COA), rather than an ordination of the individual
      microarray samples. As such, it can be viewed as a method of carrying out COA
      with grouped data. RESULTS: We illustrate the power of the method using two
      cancer data sets. In both cases, we can quickly and accurately classify test
      samples from any number of specified a priori groups and identify the genes which
      characterize these groups. We obtained very high rates of correct classification,
      as determined by jack-knife or validation experiments with training and test
      sets. The results are comparable to those from other methods in terms of accuracy
      but the power and flexibility of BGA make it an especially attractive method for
      the analysis of microarray cancer data.

PMID- 12490445
TI  - Calculation of the minimum number of replicate spots required for detection of
      significant gene expression fold change in microarray experiments.
AB  - MOTIVATION: We present statistical methods for determining the number of per gene
      replicate spots required in microarray experiments. The purpose of these methods
      is to obtain an estimate of the sampling variability present in microarray data,
      and to determine the number of replicate spots required to achieve a high
      probability of detecting a significant fold change in gene expression, while
      maintaining a low error rate. Our approach is based on data from control
      microarrays, and involves the use of standard statistical estimation techniques.
      RESULTS: After analyzing two experimental data sets containing control array
      data, we were able to determine the statistical power available for the detection
      of significant differential expression given differing levels of replication. The
      inclusion of replicate spots on microarrays not only allows more accurate
      estimation of the variability present in an experiment, but more importantly
      increases the probability of detecting genes undergoing significant fold changes
      in expression, while substantially decreasing the probability of observing fold
      changes due to chance rather than true differential expression.

PMID- 12490446
TI  - A decomposition model to track gene expression signatures: preview on observer
      independent classification of ovarian cancer.
AB  - MOTIVATION: A number of algorithms and analytical models have been employed to
      reduce the multidimensional complexity of DNA array data and attempt to extract
      some meaningful interpretation of the results. These include clustering,
      principal components analysis, self-organizing maps, and support vector machine
      analysis. Each method assumes an implicit model for the data, many of which
      separate genes into distinct clusters defined by similar expression profiles in
      the samples tested. A point of concern is that many genes may be involved in a
      number of distinct behaviours, and should therefore be modelled to fit into as
      many separate clusters as detected in the multidimensional gene expression space.
      The analysis of gene expression data using a decomposition model that is
      independent of the observer involved would be highly beneficial to improve
      standard and reproducible classification of clinical and research samples.
      RESULTS: We present a variational independent component analysis (ICA) method for
      reducing high dimensional DNA array data to a smaller set of latent variables,
      each associated with a gene signature. We present the results of applying the
      method to data from an ovarian cancer study, revealing a number of tissue type
      specific and tissue type-independent gene signatures present in varying amounts
      among the samples surveyed. The observer independent results of such molecular
      analysis of biological samples could help identify patients who would benefit
      from different treatment strategies. We further explore the application of the
      model to similar high-throughput studies.

PMID- 12490447
TI  - Partial least squares proportional hazard regression for application to DNA
      microarray survival data.
AB  - MOTIVATION: Microarrays are increasingly used in cancer research. When gene
      transcription data from microarray experiments also contains patient survival
      information, it is often of interest to predict the survival times based on the
      gene expression. In this paper we consider the well-known proportional hazard
      (PH) regression model for survival analysis. Ordinarily, the PH model is used
      with a few covariates and many observations (subjects). We consider here the case
      that the number of covariates, p, exceeds the number of samples, N, a setting
      typical of gene expression data from DNA microarrays. RESULTS: For a given vector
      of response values which are survival times and p gene expressions (covariates)
      we examine the problem of how to predict the survival probabilities, when N << p.
      The approach taken to cope with the high dimensionality is to reduce the
      dimension using partial least squares with the response variable as the vector of
      survival times. After dimension reduction, the extracted PLS gene components are
      then used as covariates in a PH regression to predict the survival probabilities.
      We demonstrate the use of the methodology on two cDNA gene expression data sets,
      both containing survival data. The first data set contains 40 diffuse large B
      cell lymphoma (DLBCL) tissue samples and the second data set contains 49 tissue
      samples from patients with locally advanced breast cancer in a prospective study.

PMID- 12490448
TI  - Statistical analysis of high-density oligonucleotide arrays: a multiplicative
      noise model.
AB  - MOTIVATION: High-density oligonucleotide arrays (GeneChip, Affymetrix, Santa
      Clara, CA) have become a standard research tool in many areas of biomedical
      research. They quantitatively monitor the expression of thousands of genes
      simultaneously by measuring fluorescence from gene-specific targets or probes.
      The relationship between signal intensities and transcript abundance as well as
      normalization issues have been the focus of much recent attention (Hill et al.,
      2001; Chudin et al., 2002; Naef et al., 2002a). It is desirable that a researcher
      has the best possible analytical tools to make the most of the information that
      this powerful technology has to offer. At present there are three analytical
      methods available: the newly released Affymetrix Microarray Suite 5.0 (AMS)
      software that accompanies the GeneChip product, the method of Li and Wong (LW; Li
      and Wong, 2001), and the method of Naef et al. (FN; Naef et al., 2001). The AMS
      method is tailored for analysis of a single microarray, and can therefore be used
      with any experimental design. The LW method on the other hand depends on a large
      number of microarrays in an experiment and cannot be used for an isolated
      microarray, and the FN method is particular to paired microarrays, such as
      resulting from an experiment in which each 'treatment' sample has a corresponding
      'control' sample. Our focus is on analysis of experiments in which there is a
      series of samples. In this case only the AMS, LW, and the method described in
      this paper can be used. The present method is model-based, like the LW method,
      but assumes multiplicative not additive noise, and employs elimination of
      statistically significant outliers for improved results. Unlike LW and AMS, we do
      not assume probe-specific background (measured by the so-called mismatch probes).
      Rather, we assume uniform background, whose level is estimated using both the
      mismatch and perfect match probe intensities. RESULTS: We present a new method
      for GeneChip analysis, based on a statistical model with multiplicative noise. We
      demonstrated that this method yields results superior to those obtained by the
      Affymetrix Microarray Suite 5.0 software and to those obtained by the model-based
      method of Li and Wong (Li and Wong, 2001). The present method eliminates the hard
      to-interpret negative expression indices, and the binary 'presence' calls
      (present or absent) are replaced by the statistical significance (p-value) of
      gene expression. We have found that thresholding the p-values at the (0.1)(16)
      level produces about the same number of 'present' calls as the AMS software. By
      testing our method on a pair of replicate GeneChips (hybridized with the same
      cRNA), we found that 95.6% of data points lie within the 1.25-fold interval. In
      other words, our method had a 4.4% type I error rate at the 1.25-fold level. The
      error rate of the LW method was 15%, and that of the AMS method was 29%. There
      were no points outside the 2-fold interval with the present method. Analysis of
      variance (ANOVA) of another experiment with multiple replicates shows that this
      reduction of variance is not accompanied by a corresponding reduction of signal.
      On the contrary, the signal-to-noise ratio (as measured by the distribution of F
      statistics) of the present method is on average 3.4-times better than that of
      AMS, and 1.4-times better than that of Li and Wong.

PMID- 12490449
TI  - Modeling the percolation of annotation errors in a database of protein sequences.
AB  - Public sequence databases contain information on the sequence, structure and
      function of proteins. Genome sequencing projects have led to a rapid increase in
      protein sequence information, but reliable, experimentally verified, information
      on protein function lags a long way behind. To address this deficit, functional
      annotation in protein databases is often inferred by sequence similarity to
      homologous, annotated proteins, with the attendant possibility of error. Now, the
      functional annotation in these homologous proteins may itself have been acquired
      through sequence similarity to yet other proteins, and it is generally not
      possible to determine how the functional annotation of any given protein has been
      acquired. Thus the possibility of chains of misannotation arises, a process we
      term 'error percolation'. With some simple assumptions, we develop a dynamical
      probabilistic model for these misannotation chains. By exploring the consequences
      of the model for annotation quality it is evident that this iterative approach
      leads to a systematic deterioration of database quality.

PMID- 12490450
TI  - Local structure-based sequence profile database for local and global protein
      structure predictions.
AB  - MOTIVATION: A large body of evidence suggests that protein structural information
      is frequently encoded in local sequences-sequence-structure relationships derived
      from local structure/sequence analyses could significantly enhance the capacities
      of protein structure prediction methods. In this paper, the prediction capacity
      of a database (LSBSP2) that organizes local sequence-structure relationships
      encoded in local structures with two consecutive secondary structure elements is
      tested with two computational procedures for protein structure prediction. The
      goal is twofold: to test the folding hypothesis that local structures are
      determined by local sequences, and to enhance our capacity in predicting protein
      structures from their amino acid sequences. RESULTS: The LSBSP2 database contains
      a large set of sequence profiles derived from exhaustive pair-wise structural
      alignments for local structures with two consecutive secondary structure
      elements. One computational procedure makes use of the PSI-BLAST alignment
      program to predict local structures for testing sequence fragments by matching
      the testing sequence fragments onto the sequence profiles in the LSBSP2 database.
      The results show that 54% of the test sequence fragments were predicted with
      local structures that match closely with their native local structures. The other
      computational procedure is a filter system that is capable of removing false
      positives as possible from a set of PSI-BLAST hits. An assessment with a large
      set of non-redundant protein structures shows that the PSI-BLAST + filter system
      improves the prediction specificity by up to two-fold over the prediction
      specificity of the PSI-BLAST program for distantly related protein pairs. Tests
      with the two computational procedures above demonstrate that local sequence
      structure relationships can indeed enhance our capacity in protein structure
      prediction. The results also indicate that local sequences encoded with strong
      local structure propensities play an important role in determining the native
      state folding topology.

PMID- 12490451
TI  - Structure-dependent sequence alignment for remotely related proteins.
AB  - MOTIVATION: The quality of a model structure derived from a comparative modeling
      procedure is dictated by the accuracy of the predicted sequence-template
      alignment. As the sequence-template pairs are increasingly remote in sequence
      relationship, the prediction of the sequence-template alignments becomes
      increasingly problematic with sequence alignment methods. Structural information
      of the template, used in connection with the sequence relationship of the
      sequence-template pair, could significantly improve the accuracy of the sequence
      template alignment. In this paper, we describe a sequence-template alignment
      method that integrates sequence and structural information to enhance the
      accuracy of sequence-template alignments for distantly related protein pairs.
      RESULTS: The structure-dependent sequence alignment (SDSA) procedure was
      optimized for coverage and accuracy on a training set of 412 protein pairs; the
      structures for each of the training pairs are similar (RMSD< approximately 4A)
      but the sequence relationship is undetectable (average pair-wise sequence
      identity = 8%). The optimized SDSA procedure was then applied to extend PSI-BLAST
      local alignments by calculating the global alignments under the constraint of the
      residue pairs in the local alignments. This composite alignment procedure was
      assessed with a testing set of 1421 protein pairs, of which the pair-wise
      structures are similar (RMSD< approximately 4A) but the sequences are marginally
      related at best in each pair (average pair-wise sequence identity = 13%). The
      assessment showed that the composite alignment procedure predicted more aligned
      residues pairs with an average of 27% increase in correctly aligned residues over
      the standard PSI-BLAST alignments for the protein pairs in the testing set.

PMID- 12490452
TI  - PFDB: a generic protein family database integrating the CATH domain structure
      database with sequence based protein family resources.
AB  - MOTIVATION: The PFDB (Protein Family Database) is a new database designed to
      integrate protein family-related data with relevant functional and genomic data.
      It currently manages biological data for three projects-the CATH protein domain
      database (Orengo et al., 1997; Pearl et al., 2001), the VIDA virus domains
      database (Alba et al., 2001) and the Gene3D database (Buchan et al., 2001). The
      PFDB has been designed to accommodate protein families identified by a variety of
      sequence based or structure based protocols and provides a generic resource for
      biological research by enabling mapping between different protein families and
      diverse biochemical and genetic data, including complete genomes. RESULTS: A
      characteristic feature of the PFDB is that it has a number of meta-level entities
      (for example aggregation, collection and inclusion) represented as base tables in
      the final design. The explicit representation of relationships at the meta-level
      has a number of advantages, including flexibility-both in terms of the range of
      queries that can be formulated and the ability to integrate new biological
      entities within the existing design. A potential drawback with this approach-poor
      performance caused by the number of joins across meta-level tables-is avoided by
      implementing the PFDB with materialized views using the mature relational
      database technology of Oracle 8i. The resultant database is both fast and
      flexible. This paper presents the principles on which the database has been
      designed and implemented, and describes the current status of the database and
      query facilities supported.

PMID- 12490453
TI  - A hierarchical approach to aligning collinear regions of genomes.
AB  - MOTIVATION: As a first approximation, similarity between two long orthologous
      regions of genomes can be represented by a chain of local similarities. Within
      such a chain, pairs of successive similarities are collinear (non-conflicting),
      i.e. segments involved in the nth similarity precede in both sequences segments
      involved in the (n+1)th similarity. However, when all similarities between two
      long sequences are considered, usually there are many conflicts between them.
      Although some conflicts can be avoided by masking transposons or low-complexity
      sequences, selecting only those similarities that reflect orthology and, thus,
      belong to the evolutionarily true chain is not trivial. RESULTS: We propose a
      simple, hierarchical algorithm of finding the true chain of local similarities.
      Starting from similarities with low P-values, we resolve each pairwise conflict
      by deleting a similarity with a higher P-value. This greedy approach constructs a
      chain of similarities faster than when a chain optimal with respect to some
      global criterion is sought, and makes more sense biologically.

PMID- 12490454
TI  - SNPper: retrieval and analysis of human SNPs.
AB  - MOTIVATION: Single Nucleotide Polymorphisms (SNPs) are an increasingly important
      tool for the study of the human genome. SNPs can be used as markers to create
      high-density genetic maps, as causal candidates for diseases, or to reconstruct
      the history of our genome. SNP-based studies rely on the availability of large
      numbers of validated, high-frequency SNPs whose position on the chromosomes is
      known with precision. Although large collections of SNPs exist in public
      databases, researchers need tools to effectively retrieve and manipulate them.
      RESULTS: We describe the implementation and usage of SNPper, a web-based
      application to automate the tasks of extracting SNPs from public databases,
      analyzing them and exporting them in formats suitable for subsequent use. Our
      application is oriented toward the needs of candidate-gene, whole-genome and fine
      mapping studies, and provides several flexible ways to present and export the
      data. The application has been publicly available for over a year, and has
      received positive user feedback and high usage levels.

PMID- 12490455
TI  - Oligodb--interactive design of oligo DNA for transcription profiling of human
      genes.
AB  - MOTIVATION: The increasing use of customized oligo-DNA-microarrays has created a
      demand for convenient design of oligo nucleotides. The oligo-nucleotides have to
      serve as specific templates in the hybridization reaction. RESULTS: We have
      devised a web-based system for interactive design of suitable oligos for
      transcription profiling experiments with user-defined parameters. Oligodb is
      based on predicted human gene transcripts from the ENSEMBL project. The web
      interface allows the user to retrieve oligos for human transcripts in a flexible
      manner. Criteria for selecting the oligos are low similarity to all other known
      human genes, the absence of stable secondary structures, the length of the oligo,
      and the absence of low complexity regions. Furthermore, the user may select
      oligos corresponding to the desired position in the 5'-3' direction of the
      transcript, and based on the melting temperature. All data and results are
      tightly web-linked to the corresponding data entries of ENSEMBL project.

PMID- 12490456
TI  - PCR designer for restriction analysis of various types of sequence mutation.
AB  - Restriction analysis is widely used to detect gene mutations such as insertions,
      deletions and single nucleotide polymorphisms (SNPs). Although such mutation
      sites sometimes present some natural restriction sites to differentiate the wild
      type and mutant sequences, mismatches are often needed in order to create
      artificial restriction fragment length polymorphisms (RFLPs). In this report, a
      computer program is described that screens for suitable restriction enzymes,
      introducing mismatches where appropriate and when necessary, designs primers
      using the information of the selected restriction enzymes, their recognition
      sequence and locations as well as the information about the mismatches if any.
      The program, supported by a WWW web interface, is intended to be used online.

PMID- 12490457
TI  - Design of endonuclease restriction sites into primers for PCR cloning.
AB  - I present a software system PCRCLNG that facilitates the design of endonuclease
      restriction sites into the 5'-end of PCR primers. The product amplified using
      these primers can be directly cloned into vectors. The program estimates the
      annealing temperature for each primer and selects the primer pairs with
      comparable annealing temperature. Finally the software determines whether the PCR
      product can be cloned into the vector to generate in-frame gene fusion.

PMID- 12490458
TI  - RED: the analysis, management and dissemination of expressed sequence tags.
AB  - The Rancourt EST Database (RED) is a web-based system for the analysis,
      management, and dissemination of expressed sequence tags (ESTs). RED represents a
      flexible template DNA sequence database that can be easily manipulated to suit
      the needs of other laboratories undertaking mid-size sequencing projects.

PMID- 12490459
TI  - GENECOUNTING: haplotype analysis with missing genotypes.
AB  - A general algorithm is described for haplotype analysis of unrelated individuals
      with missing genotypes. It can handle problems involving multiple polymorphic
      markers with missing data.

PMID- 12490460
TI  - DNACompress: fast and effective DNA sequence compression.
AB  - While achieving the best compression ratios for DNA sequences, our new
      DNACompress program significantly improves the running time of all previous DNA
      compression programs.

PMID- 12490461
TI  - ADME-AP: a database of ADME associated proteins.
AB  - Drug absorption, distribution, metabolism and excretion (ADME) often involve
      interaction of a drug with specific proteins. Knowledge about these ADME
      associated proteins is important in facilitating the study of the molecular
      mechanism of disposition and individual response as well as therapeutic action of
      drugs. It is also useful in the development and testing of pharmacokinetics
      prediction tools. Several databases describing specific classes of ADME
      associated proteins have appeared. A new database, ADME-associated proteins (ADME
      AP), is introduced to provide comprehensive information about all classes of ADME
      associated proteins described in the literature including physiological function
      of each protein, pharmacokinetic effect, ADME classification, direction and
      driving force of disposition, location and tissue distribution, substrates,
      synonyms, gene name and protein availability in other species. Cross-links to
      other databases are also provided to facilitate the access of information about
      the sequence, 3D structure, function, polymorphisms, genetic disorders,
      nomenclature, ligand binding properties and related literatures of each protein.
      ADME-AP currently contains entries for 321 proteins and 964 substrates.

PMID- 12490462
TI  - PoPMuSiC, rationally designing point mutations in protein structures.
AB  - PoPMuSiC is an efficient tool for rational computer-aided design of single-site
      mutations in proteins and peptides. Two types of queries can be submitted. The
      first option allows to estimate the changes in folding free energy for specific
      point mutations given by the user. In the second option, all possible point
      mutations in a given protein or protein region are performed and the most
      stabilizing or destabilizing mutations, or the neutral mutations with respect to
      thermodynamic stability, are selected. For each sequence position or secondary
      structure the deviation from the most stable sequence is moreover evaluated,
      which helps to identify the most suitable sites for the introduction of
      mutations.

PMID- 12490463
TI  - OWEN: aligning long collinear regions of genomes.
AB  - OWEN is an interactive tool for aligning two long DNA sequences that represents
      similarity between them by a chain of collinear local similarities. OWEN employs
      several methods for constructing and editing local similarities and for resolving
      conflicts between them. Alignments of sequences of lengths over 10(6) can often
      be produced in minutes. OWEN requires memory below 20 L, where L is the sum of
      lengths of the compared sequences.

PMID- 12490464
TI  - The GeneAround GO viewer.
AB  - We have developed a system for visualizing the Gene Ontology((TM)) hierarchy. The
      graphical browser interactively displays diagrams of the inheritance relationship
      for each term to help understand the meanings of terms when handling gene
      annotation data.

PMID- 12490465
TI  - Screening mammography: target of opportunity for the media.

PMID- 12490467
TI  - Perfusion CT with iodinated contrast material.

PMID- 12490468
TI  - Is administration of enteric contrast material safe before abdominal CT in
      children who require sedation? Experience with chloral hydrate and pentobarbital.
AB  - OBJECTIVE: It has been common practice to administer enteric contrast material in
      preparation for abdominal CT in children who require sedation to be examined. At
      some institutions, the practice of administering an anesthetic or enteric
      contrast material before sedation is being challenged because it violates the
      "nothing by mouth" status that is otherwise strictly enforced before sedation.
      Our purpose was to review our safety record in administering enteric contrast
      material for CT before sedation. MATERIALS AND METHODS: Radiology reports,
      medical records, and department incident reports were reviewed for the past 5
      years from all patients who required sedation for abdominal CT. Patient age and
      sex, type of sedation, and complications (defined as vomiting with aspiration)
      related to enteric contrast material before the sedation were recorded. For
      routine oral contrast material, diluted Hypaque (meglumine diatrizoate) was
      administered in an age-based amount 1-2 hr before scanning. For sedation,
      depending on the patient's age, either oral chloral hydrate (70-100 mg/kg) or IV
      pentobarbital (3 mg/kg with repeated doses of up to 7 mg/kg) was used. RESULTS:
      Three hundred sixty-seven patients who received oral contrast material before
      sedation for abdominal CT were identified (200 boys, 167 girls; age range, 1
      month-19 years; mean age, 2.9 years). Chloral hydrate was used in 30 patients and
      IV pentobarbital in 337 patients. No complications related to the administration
      of oral contrast material before sedation were identified. CONCLUSION: The
      practice of administering oral contrast material in children before sedation for
      abdominal CT appears to be safe when using the sedation drugs and protocols in
      place at our institution. Further study of the safety of this practice should be
      undertaken.

PMID- 12490470
TI  - Accuracy of MR imaging of the knee in adolescents.
AB  - OBJECTIVE: A report in the orthopedics literature states that MR imaging for
      internal derangement of the knee has a lower accuracy in adolescents than in
      adults and may even provide spurious information that alters clinical management.
      This assertion has not been specifically addressed in the radiology literature.
      The purpose of our study was to determine the accuracy of MR imaging in
      adolescents with regard to injury of the cruciate ligaments and menisci.
      MATERIALS AND METHODS: A database search of our institution's records from
      January 1998 to July 2000 yielded 2140 MR examinations of the knee, all of which
      had been performed with a standard knee protocol on a 1.5-T magnet. Of these 2140
      examinations, 156 included patients younger than 18 years. Fifty-nine of these
      patients underwent surgery, and the orthopedic surgeons' operative reports were
      used as the gold standard with which the MR imaging results were compared. Thirty
      four boys and 25 girls who ranged in age from 11 to 17 years (mean age, 15 years)
      were examined. The clinical notes for the remaining 97 patients were evaluated
      for information about management and clinical improvement. RESULTS: The
      sensitivity and specificity values for MR imaging of the menisci and cruciate
      ligaments in adolescents were as follows: medial meniscus, 92% sensitivity and
      87% specificity; lateral meniscus, 93% sensitivity and 95% specificity; anterior
      cruciate ligament, 100% sensitivity and 100% specificity; and posterior cruciate
      ligament, 0% sensitivity and 100% specificity. CONCLUSION: Our data suggest that
      MR imaging of the knee in adolescents is sensitive, specific, and accurate.

PMID- 12490471
TI  - The most recent breast cancer screening controversy about whether mammographic
      screening benefits women at any age: nonsense and nonscience.

PMID- 12490472
TI  - Abdominal CT screening: inflated promises, serious concerns.

PMID- 12490473
TI  - ACR Blue Ribbon Panel response to the AJR commentary by Shellock and Crues on the
      ACR White Paper on MR Safety.

PMID- 12490474
TI  - Failure to diagnose lung cancer: anatomy of a malpractice trial.

PMID- 12490475
TI  - Exploring and summarizing radiologic data.

PMID- 12490476
TI  - Detection and characterization of intracranial aneurysms with MR angiography:
      comparison of volume-rendering and maximum-intensity-projection algorithms.
AB  - OBJECTIVE: The purpose of this study was to compare volume rendering and maximum
      intensity projection as postprocessing techniques of MR angiography in the
      detection and characterization of intracranial aneurysms. MATERIALS AND METHODS:
      Three-dimensional time-of-flight MR angiography studies performed in 82 patients
      were retrospectively evaluated by two independent reviewers who were unaware of
      digital subtraction angiography findings, the standard of reference. Panoramic
      maximum-intensity-projection and volume-rendered angiograms were produced from
      each data set to investigate the presence of underlying aneurysms. Each detected
      aneurysm was then interactively evaluated with subvolume maximum-intensity
      projection and targeted volume-rendering algorithms to evaluate aneurysm
      morphology and size. Aneurysm detection and characterization were evaluated by
      means of the receiver operating characteristic analysis, and aneurysm size was
      evaluated using the limits-of-agreement method. Image quality, aneurysm neck
      depiction, and vascular delineation were also compared between maximum-intensity
      projection and volume-rendered images. The time required for the generation and
      interpretation of maximum-intensity-projection and volume-rendered images was
      assessed. RESULTS: Volume rendering tended to improve the diagnostic confidence
      (A(z) [area under the receiver operating characteristic curve] = 0.95 vs A(z) =
      0.90 for maximum intensity projection) and yielded a considerable improvement in
      sensitivity (89% vs 71% for maximum intensity projection), particularly in the
      detection of small cerebral aneurysms. Regarding aneurysm morphology, volume
      rendering performed significantly better than maximum intensity projection in
      lobulation detection (p < 0.001) and slightly better in neck categorization (p >
      0.238). Limits-of-agreement analysis showed a trend toward improved assessment of
      the aneurysm size by volume rendering (-0.31 +/- 1.62 mm vs -1.27 +/- 2.84 mm by
      maximum intensity projection). Overall image quality and vascular delineation of
      involved vessels on volume-rendered images were rated better than that obtained
      by maximum intensity projections (p < or = 0.007 and p < or = 0.001,
      respectively). Evaluation of time-of-flight MR angiography data sets was
      significantly facilitated with volume rendering (p < 0.001). CONCLUSION: The
      volume-rendering technique facilitates the evaluation of cerebral time-of-flight
      MR angiography data sets and allows better detection and more reliable
      characterization of intracranial aneurysms than does maximum intensity
      projection.

PMID- 12490477
TI  - Defining thresholds for changes in size of simulated T2-hyperintense brain
      lesions on the basis of qualitative comparisons.
AB  - OBJECTIVE: Our purpose was to define thresholds below which trained reviewers
      cannot detect changes in the size of T2-hyperintense brain lesions. MATERIALS AND
      METHODS: We generated T2-weighted brain MR images (TR/TE, 4000/80) with simulated
      hyperintense lesions derived from a real multiple sclerosis plaque. The size of
      the original multiple sclerosis lesion was varied by scaling up or down the
      lesion using a bicubic interpolation method. Three hundred seventy-eight
      composite images, in which two T2-weighted images containing lesions were paired,
      were presented to three equally trained neuroradiologists to define thresholds
      below which changes in original lesion size could not be detected. Stepwise
      logistic regression was used to evaluate the dependency of size thresholds on the
      original size of the lesion. RESULTS: Thresholds ranged from a 5% to 15% increase
      in the original lesion diameter. For increases greater than 15%, all three
      reviewers detected the change in lesion size irrespective of the diameter of the
      original lesion. There was a dependency of the threshold on the diameter of the
      original lesion (p = 0.02). CONCLUSION: Using an MR simulator, we can define
      thresholds below which changes in original lesion size cannot be reliably
      detected. These results may guide the design of clinical trials that rely on
      trained reviewers to assess change in lesion burden.

PMID- 12490478
TI  - Radiologic-pathologic conferences of the University of Texas M.D. Anderson Cancer
      Center. Delayed cerebral radiation necrosis.

PMID- 12490479
TI  - Diffusion-weighted MR imaging of pyogenic ventriculitis.
AB  - OBJECTIVE: The purpose of this study was to describe the features of pyogenic
      ventriculitis (ventricular empyema, pyocephalus) on diffusion-weighted MR
      imaging. CONCLUSION: Markedly increased signal intensity of dependent
      intraventricular fluid on diffusion-weighted MR imaging and an apparent diffusion
      coefficient that is less than that of normal cerebral white matter indicate
      restricted water diffusion in purulent fluid and suggest the diagnosis of
      pyogenic ventriculitis.

PMID- 12490480
TI  - Transsphenoidal (large craniopharyngeal) canal associated with a normally
      functioning pituitary gland and nasopharyngeal extension, hyperprolactinemia, and
      hypothalamic hamartoma.

PMID- 12490481
TI  - CT changes of an intracranial granulocytic sarcoma on short-term follow-up.

PMID- 12490483
TI  - Additional value of a modified method of intraosseous venography during
      percutaneous vertebroplasty.

PMID- 12490482
TI  - MR imaging of the lumbar spine: relation of posterior soft-tissue edema-like
      signal and body weight.
AB  - OBJECTIVE: Our purpose was to determine the association between posterior lumbar
      spine subcutaneous edema, fluid collections, and body weight on lumbar spine MR
      imaging. MATERIALS AND METHODS: MR images of the lumbar spine obtained at 1.5 T
      of 307 consecutive outpatients (191 female, 116 male) were reviewed on the basis
      of MR imaging signal characteristics for the presence, degree, size, and location
      of presumed subcutaneous posterior soft-tissue edema and fluid collections. The
      patients were divided into three weight groups (<70, 70-85, or > 85 kg) and two
      age groups (<50 or >/=50 years old). Edema was graded on a scale of 0-5 according
      to its length relative to the vertebral bodies. When present, the fluid
      collection volumes were calculated. The vertical epicenter of the signal
      abnormality was noted by vertebral body level. RESULTS: Lumbar soft-tissue edema
      was seen in 121 patients (39%), and discrete fluid collections were seen in 53
      patients (17%). Both degree of edema and volume of fluid collection were
      associated with increasing weight (p < 0.001 and p = 0.002, respectively) and
      increasing age (p < 0.001 and p = 0.01, respectively). The degree of edema in
      females was significantly greater than in males (p = 0.003). However, the sex of
      the patient did not correlate with frequency of fluid collections (p = 0.12) or
      volume of collections (p = 0.08). The mean epicenters of edema in females and
      males were at similar levels (L3.4 and L3.9, respectively, p = 0.54). CONCLUSION:
      The severity of posterior lumbar subcutaneous edema and the volume of fluid
      collections on MR imaging are associated with increased weight.

PMID- 12490485
TI  - Meniscal tear configurations: categorization with MR imaging.
AB  - OBJECTIVE: The purpose of this study was to evaluate the accuracy of MR imaging
      for categorizing the configuration of meniscal tears of the knee. MATERIALS AND
      METHODS: Fast spin-echo MR images obtained at 1.5 T from 110 patients who had
      meniscal tears identified at arthroscopy were retrospectively and independently
      classified by two reviewers into five configurations: horizontal, longitudinal,
      radial, oblique, and complex. MR imaging categorization was compared with
      arthroscopic results as the standard of reference. Data were also analyzed with
      longitudinal and oblique tears combined because these usually are reparable, and
      with horizontal, radial, and complex tears combined because these usually are not
      reparable. Interobserver and intraobserver agreements were calculated using kappa
      coefficients. RESULTS: At arthroscopy, meniscal tears were categorized as
      horizontal (n = 44), longitudinal (n = 34), complex (n = 22), radial (n = 11),
      and oblique (n = 5). Sensitivity, specificity, and accuracy of each reviewer for
      the reparable tears were 82%, 92%, and 89%; and 59%, 97%, and 84%, respectively.
      Interobserver agreements were fair between reviewer 1 and the first and second
      interpretations of reviewer 2 (kappa = 0.25, p < 0.005; and kappa = 0.21, p <
      0.05, respectively). Intraobserver agreement was substantial (kappa = 0.71, p <
      0.001). CONCLUSION: MR imaging was accurate for predicting reparable meniscal
      tears and was sensitive for the determination of nonreparable tears.

PMID- 12490487
TI  - Sonography and MR imaging of selected benign masses in the ankle and foot.

PMID- 12490488
TI  - Mineralization in musculoskeletal leiomyosarcoma: radiologic-pathologic
      correlation.
AB  - OBJECTIVE: Mineralization in leiomyosarcoma, a malignant tumor of smooth muscle,
      has not been widely recognized. In this article, we report our experience with
      four cases of primary leiomyosarcoma of soft tissue or bone in which
      mineralization was visible on either radiography or CT. In none of the cases was
      the diagnosis of leiomyosarcoma considered before biopsy. In one case of a soft
      tissue leiomyosarcoma, the presence of mineralization was a factor that led to
      the misinterpretation of the needle biopsy specimen as soft-tissue osteosarcoma.
      CONCLUSION: Histologically, mineralization in leiomyosarcoma appears to be caused
      by either nonneoplastic ossification or dystrophic mineralization in the tumor.
      This feature can cause leiomyosarcomas to be confused with other neoplasms.

PMID- 12490489
TI  - Imaging of the painful hip arthroplasty.

PMID- 12490490
TI  - MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four
      techniques.
AB  - OBJECTIVE: The aim of our prospective study was to assess the MR imaging
      characteristics of hepatic metastases of neuroendocrine tumors and to determine
      the optimal MR sequence for their detection. SUBJECTS AND METHODS: Thirty-seven
      consecutive patients with liver metastases from neuroendocrine tumors underwent
      1.5-T MR imaging of the liver comprising T2-weighted fast spin-echo with
      respiratory monitoring, breath-hold T2-weighted single-shot fast spin-echo, and
      T1-weighted gradient-recalled echo sequences before and after the injection of
      gadoterate dimeglumine. Images were reviewed independently by three observers for
      the number, location, and pattern of signal and enhancement of metastases.
      RESULTS: A total of 359 metastases were detected, 279 on T2-weighed fast spin
      echo, 231 on T2-weighed single-shot fast spin-echo, 272 on unenhanced T1
      weighted, 322 on hepatic arterial phase, and 228 on portal venous phase images.
      Hepatic arterial phase images revealed the greatest number of metastases in 70%
      of patients, including 35 metastases seen only on this sequence, and was
      significantly superior to the unenhanced T1-weighted and portal venous phase
      sequences (p < 0.01). The lesion-to-liver contrast was significantly greatest
      with T2-weighed fast spin-echo sequences. The enhancement patterns of metastases
      were predominantly hypervascular, hypovascular, peripheral with progressive fill
      in, and delayed in, respectively, 27, four, four, and two patients. Most
      metastases with peripheral enhancement and progressive fill-in were heterogeneous
      on T2-weighted images and were without globular peripheral enhancement.
      CONCLUSION: Hepatic metastases of neuroendocrine tumors had a typical
      hypervascular pattern in 73% of patients. Hepatic arterial phase and fast spin
      echo T2-weighed sequences are the most sensitive.

PMID- 12490491
TI  - Effects of tamoxifen on hepatic fat content and the development of hepatic
      steatosis in patients with breast cancer: high frequency of involvement and rapid
      reversal after completion of tamoxifen therapy.
AB  - OBJECTIVE: A study was conducted on hepatic fat content to investigate the
      frequency and clinical course of hepatic steatosis induced by tamoxifen.
      MATERIALS AND METHODS: Sixty-seven patients with breast cancer treated with
      adjuvant tamoxifen were included. The patients underwent postoperative annual
      abdominal CT, both with and without contrast enhancement, for 5 years. We
      retrospectively reviewed unenhanced CT images and obtained hepatic and splenic CT
      attenuation values to calculate the liver-spleen ratio. Hepatic steatosis was
      defined as a liver-spleen ratio of less than 0:9, and its degree was classified
      as mild (liver-spleen ratio, 0:5-0:9), moderate (0-0:5), or severe (<0). The
      pattern of steatosis was classified as generalized, lobar, segmental, or focal.
      RESULTS: In the study population, hepatic CT values decreased during therapy (p <
      0.0001, t test) and increased after therapy (p < 0.0001, paired t test). Twenty
      nine patients (43.2%) developed hepatic steatosis within the first 2 years; its
      degree was mild in 16, moderate in nine, and severe in four. Seventeen patients
      showed a generalized pattern of steatosis, and the other 12 showed a lobar
      pattern. Twenty-three of these patients showed an increase in the liver-spleen
      ratio after therapy to within the normal range, with a mean recovery time of 1.2
      years after therapy ended. None progressed to steatohepatitis or cirrhosis.
      CONCLUSION: Tamoxifen had a statistically significant influence on hepatic fat
      content and was associated with frequent development of hepatic steatosis.
      Radiologists should be aware of this phenomenon and the possible occurrence of
      hepatic dysfunction and should differentiate steatosis from metastasis in
      postoperative patients with breast cancer.

PMID- 12490492
TI  - Hepatic hemangioma: atypical appearances on CT, MR imaging, and sonography.

PMID- 12490493
TI  - Percutaneous ablation therapy guided by contrast-enhanced sonography for patients
      with hepatocellular carcinoma.
AB  - OBJECTIVE: The newly developed contrast-enhanced harmonic gray-scale sonography
      technique enables us to improve the real-time detectability of viable tumor
      tissue in hepatocellular carcinoma lesions. We evaluated the usefulness of real
      time percutaneous ablation therapy under guidance with this method for patients
      with hepatocellular carcinoma that is not depicted on conventional sonography.
      SUBJECTS AND METHODS: We examined 30 patients with 56 hepatocellular carcinomas
      using real-time contrast-enhanced harmonic gray-scale sonography after injection
      of a galactose-palmitic acid contrast agent and compared the results with the
      findings of contrast-enhanced helical CT. We performed percutaneous ablation
      therapy guided by this modality for treatment of viable hepatocellular carcinoma
      lesions that could not be detected using conventional sonography. RESULTS: High
      detection rates of viable hepatocellular carcinoma lesions were obtained using
      real-time contrast-enhanced harmonic gray-scale sonography (52/56 lesions, 93%);
      these rates were comparable to those of helical CT (54/56 lesions, 96%). Nine
      (90%) of the 10 lesions that were not detected on conventional sonography but
      were depicted on real-time contrast-enhanced harmonic gray-scale sonography
      (incomplete local treatment, n = 4; small new lesion, n = 6) were successfully
      treated with percutaneous ablation therapy guided by this method. CONCLUSION:
      Real-time contrast-enhanced harmonic gray-scale sonography improved the
      sensitivity for the detection of viable hepatocellular carcinoma lesions.
      Percutaneous ablation therapy guided by this modality may be useful in patients
      with hypervascular hepatocellular carcinoma lesions that cannot be detected using
      conventional sonography.

PMID- 12490494
TI  - Power rolloff during interactive radiofrequency ablation can enhance necrosis
      when treating hepatocellular carcinoma.
AB  - OBJECTIVE: The purpose of this study was to compare the efficacy between standard
      and interactive radiofrequency ablation for treatment of hepatocellular
      carcinoma. SUBJECTS AND METHODS: Of 97 patients with 112 nodular hepatocellular
      carcinomas, 59 hepatocellular carcinomas were ablated using a standard algorithm
      and 53 hepatocellular carcinomas, using an interactive algorithm. For the
      procedure using the interactive algorithm, the electrode's array was partially
      retracted or fully deployed depending on the change of impedance. Complete tumor
      necrosis was defined as the lack of enhancement on single-detector helical CT at
      least 4 months after the last radiofrequency ablation. RESULTS: Complete necrosis
      was achieved in 101 (90%) of 112 hepatocellular carcinomas, with complete
      necrosis being achieved more frequently in hepatocellular carcinomas undergoing
      interactive ablation (96%) than standard ablation (85%) (p = 0.034). Power
      rolloff (a clinical end point in which power decreases as impedance increases)
      occurred in all of the 53 hepatocellular carcinomas that underwent interactive
      ablation, whereas power rolloff occurred in 48 (81%) of the 59 hepatocellular
      carcinomas that underwent standard ablation (p = 0.00053). Complete necrosis
      occurred more frequently when rolloff was achieved (96%) than without rolloff
      (36%) (p < 0.0001). Multivariate analysis determined that power rolloff was an
      independent factor in achieving complete necrosis of hepatocellular carcinomas (p
      < 0.0001). CONCLUSION: The use of interactive radiofrequency ablation increased
      the frequency of power rolloff and the rate of complete necrosis in the treatment
      of hepatocellular carcinoma. Power rolloff was a significant determinant of
      whether complete necrosis was achieved in hepatocellular carcinomas treated with
      radiofrequency ablation.

PMID- 12490495
TI  - Percutaneous acetic acid injection for hepatocellular carcinoma: using CT
      fluoroscopy to evaluate distribution of acetic acid mixed with an iodinated
      contrast agent.
AB  - OBJECTIVE: The purpose of our study is to evaluate the distribution of acetic
      acid mixed with iodinated contrast agent during percutaneous acetic acid
      injection on CT fluoroscopy for hepatocellular carcinoma. CONCLUSION: Monitoring
      acetic acid distribution on CT fluoroscopy can detect extratumoral diffusion and
      may optimize the distribution of acetic acid in hepatocellular carcinoma.

PMID- 12490496
TI  - Automated saline-enhanced radiofrequency thermal ablation: initial results in ex
      vivo bovine livers.

PMID- 12490497
TI  - Transjugular biopsy of the liver in pediatric and adult patients using an 18
      gauge automated core biopsy needle: a retrospective review of 410 consecutive
      procedures.
AB  - OBJECTIVE: The aim of our study was to evaluate the safety and efficacy of
      transjugular biopsy of the liver in a large population of patients using an 18
      gauge automated core biopsy needle. MATERIALS AND METHODS: A total of 371
      patients underwent 410 attempted transjugular biopsies of the liver during an 80
      month period. Data collected included the retrospective review of patients'
      computerized medical records, clinical charts, and nursing documents. Patient
      demographic data, indications for liver biopsy, laboratory findings of
      coagulation values, procedural data including number of needle passes performed,
      and histologic description of the specimens were noted. Indications varied and
      included traditional contraindications to the percutaneous approach such as
      coagulopathy (53%) and ascites (29%). In one patient, the hepatic veins could not
      be catheterized because of angulation with the inferior vena cava, and in one
      patient, biopsy was performed using the femoral route because of occlusion of the
      jugular vein. All patients were followed up for a minimum of 24 hr after the
      procedure to determine complications. RESULTS: The mean number of needle passes
      per procedure was 3.4 (range, 0-18). Hepatic tissue was obtained in 409
      procedures via the venous route (408 transjugular and one transfemoral), and a
      tissue diagnosis was achieved in 403 (98%). The six tissue samples were
      nondiagnostic because they were too small (n = 3) or too fragmented (n = 1) or
      because they did not contain hepatic tissue (n = 2). Ten complications (2.4%)
      occurred, including three intraperitoneal hemorrhages that resulted in one death.
      CONCLUSION: Transjugular biopsy of the liver using an automatic core biopsy
      needle is safe and produces adequate tissue specimens in a high percentage of
      patients.

PMID- 12490498
TI  - Anomalous pancreaticobiliary junction shown on multidetector CT.

PMID- 12490499
TI  - Intestinal ischemia versus intramural hemorrhage: CT evaluation.
AB  - OBJECTIVE: We evaluated the capability of CT to depict findings that allowed
      differentiation of small-bowel ischemia from intramural hemorrhage. MATERIALS AND
      METHODS: Findings of 35 CT examinations (19 patients with small-bowel ischemia
      and 16 patients with intramural hemorrhage) were analyzed by two abdominal
      radiologists for the degree of wall thickening, location and length of
      involvement (short, <or = 15 cm; medium, 16-30 cm; or long, >30 cm), presence of
      hemoperitoneum, and pattern of attenuation. Patency and caliber of the superior
      mesenteric artery and vein were noted. Diagnosis was confirmed by laboratory
      findings, clinical parameters, and follow-up examinations, or at surgery. A Mann
      Whitney U or Fisher's exact test was used to compare the two conditions for the
      following features: wall thickening, location and length of involvement, presence
      of hemoperitoneum, and appearance of the target sign. RESULTS: Among the 35
      examinations, 18 abnormal segments with intramural hemorrhage and 19 abnormal
      segments with ischemia were identified. (Two patients with intramural hemorrhage
      each had two segments involved.) Mean bowel wall thickness was 11.7 mm (range, 4
      25 mm) in patients with intramural hemorrhage and 4.0 mm (range, 1-9 mm) in
      patients with ischemia. Length of involvement was short in 14 segments with
      intramural hemorrhage and medium in four segments with intramural hemorrhage;
      none of the segments with intramural hemorrhage had long involvement. Among the
      segments with ischemia, length of involvement was medium in three and long in 16;
      none of the ischemic segments had short involvement. Fifteen (94%) of 16 segments
      with intramural hemorrhage and six (32%) of 19 segments with ischemia had
      hemoperitoneum. Seven of the 18 segments with intramural hemorrhage and nine of
      the 19 with ischemia had a target sign. Segments with intramural hemorrhage
      exhibited a higher statistically significant degree of wall thickening (p <
      0.001), a shorter length of involvement (p < 0.0001), and a higher incidence of
      hemoperitoneum (p < 0.001) than did segments with ischemia. The two groups were
      not statistically different in location of involvement (p = 0.12) or in the
      incidence of the target sign (p = 0.18). CONCLUSION: Although some of the CT
      features overlap, a short segment involvement with wall thickening of 1 cm or
      greater is typical of intramural hemorrhage; a long segment involvement with wall
      thickening of less than 1 cm is typical of ischemia.

PMID- 12490500
TI  - Multidetector CT of high-risk patients with occult gastrointestinal stromal
      tumors.
AB  - OBJECTIVE: Stromal tumors are an important cause of occult gastrointestinal
      bleeding in patients who are middle aged or older. This study evaluated the size
      at which stromal tumors become symptomatic and necrotic and examined the role and
      limitations of multidetector CT in detecting gastrointestinal stromal tumors.
      MATERIALS AND METHODS: Two hundred seventy-one patients with stromal tumors were
      retrospectively studied to examine the size of symptomatic, necrotic, or
      malignant stromal tumors. Next, five asymptomatic family members with germline c
      kit mutations were prospectively screened to evaluate the role and limitations of
      multidetector CT. RESULTS: In this retrospective study, two thirds of the
      patients with stromal tumors had symptoms and signs that were correlated with
      tumor size. Stromal tumors larger than 3 cm were accompanied by necrosis, whereas
      this finding was rare for those smaller than 3 cm. In the prospective screening,
      multidetector CT with IV infusion of contrast material showed gastrointestinal
      stromal tumors of more than 2 cm as slightly enhanced intramural or extramural
      nodules and also detected most gastrointestinal stromal tumors between 1 and 2
      cm. Stromal tumors of less than 3 cm were not accompanied by necrosis and
      appeared as slightly enhanced homogenous tumors with the administration of
      contrast media. CONCLUSION: Screening with multidetector CT should be feasible
      for detecting symptomatic stromal tumors of unknown location in the
      gastrointestinal tract.

PMID- 12490501
TI  - MR imaging of the small bowel using polyethylene glycol solution as an oral
      contrast agent in adults and children with celiac disease: preliminary
      observations.
AB  - OBJECTIVE: The purpose of our report is to describe morphologic abnormalities of
      the small bowel in a population of patients with known celiac disease using MR
      imaging with polyethylene glycol solution as an oral contrast agent. CONCLUSION:
      Polyethylene glycol-enhanced MR imaging is a noninvasive (no ionizing radiation
      is used), feasible, and reproducible imaging technique in both adult and
      pediatric populations. Findings on polyethylene glycol-enhanced MR imaging,
      similar to those of conventional barium studies, may suggest a diagnosis of
      celiac disease because the technique can not only reveal intestinal involvement
      but also show extraintestinal findings.

PMID- 12490502
TI  - Duodenal diverticula mimicking cystic neoplasms of the pancreas: CT and MR
      imaging findings in seven patients.
AB  - OBJECTIVE: Duodenal diverticula are common and are typically asymptomatic. When
      filled with gas or a combination of fluid and gas, duodenal diverticula are
      easily recognized on CT or MR imaging. However, a duodenal diverticulum that is
      entirely filled with fluid may mimic a cystic neoplasm arising from the head of
      the pancreas. We present seven cases of patients with duodenal diverticula in
      whom initial findings on CT or MR imaging were suggestive of a cystic neoplasm in
      the head of the pancreas. In all patients, this structure was ultimately proven
      to be a duodenal diverticula. CONCLUSION: When filled with only fluid, a duodenal
      diverticulum may mimic a cystic neoplasm in the head of the pancreas. Recognizing
      the location in which this entity characteristically arises and identifying small
      amounts of intradiverticular gas when it is present may aid in establishing the
      correct diagnosis in patients with duodenal diverticula.

PMID- 12490503
TI  - Value of bone window settings on CT for revealing appendicoliths in patients with
      appendicitis.
AB  - OBJECTIVE: Our retrospective study was designed to determine whether the use of
      bone window settings increases sensitivity of CT for diagnosing appendicitis and
      for detecting an appendicolith in patients with pathologically confirmed
      appendicitis. CONCLUSION: The use of bone window settings is helpful for
      detecting appendicoliths when evaluating patients for acute appendicitis,
      particularly patients in whom evidence of appendicitis is equivocal. In this era
      of PACS (picture archiving and communication systems), bone window settings
      should be used routinely.

PMID- 12490505
TI  - Epiglottic carcinoma as a cause of laryngeal penetration and aspiration.
AB  - OBJECTIVE. The purpose of our investigation was to review a series of patients
      with epiglottic carcinoma to elucidate the clinical and videofluoroscopic
      findings in these individuals. CONCLUSION. Patients with epiglottic carcinoma
      often present with symptoms of aspiration or pharyngeal dysphagia of relatively
      brief duration in the absence of a preexisting neurologic disease. In this
      clinical setting, barium studies are useful not only for detecting the epiglottic
      carcinoma but also for delineating the presence and mechanism of laryngeal
      penetration or tracheobronchial aspiration.

PMID- 12490506
TI  - Trauma cases from Harborview Medical Center. Tracheoesophageal fistula from a
      gunshot wound to the neck.

PMID- 12490507
TI  - Localized intestinal lymphangiectasia: CT findings.

PMID- 12490508
TI  - Twinkling artifact on color Doppler sonography: dependence on machine parameters
      and underlying cause.
AB  - OBJECTIVE: The objective of our study was to evaluate the color Doppler
      sonographic effect known as twinkling artifact. MATERIALS AND METHODS: Struvite
      (ammonium magnesium phosphate) stone fragments, wire mesh, and a flat surface
      were scanned in a water bath with a sonography scanner using a high-frequency
      linear array probe fixed in a ring clamp. Pulse repetition frequency, color-write
      priority, gray-scale gain, and spectral Doppler gain were varied. Color and
      spectral Doppler modes were used. RESULTS: Twinkling artifact and spectral
      broadening were seen most intensely behind struvite stone fragments, and both
      were seen more strongly behind wire mesh with greater surface roughness than
      behind wire mesh with less surface roughness or a flat surface. The appearance of
      the twinkling artifact is highly dependent on machine settings. System noise
      measured on a flat surface generates a band-limited Doppler shift on spectral
      displays with a mean frequency shift of 0 Hz and a mean (+/- SD) absolute
      fluctuation of 86 +/- 10 Hz over a pulse repetition frequency range of 1250
      10,000 Hz. Rough surfaces increase the spectral bandwidth. CONCLUSION: The
      appearance of the twinkling artifact is highly dependent on machine settings and
      is likely generated by a narrow-band, intrinsic machine noise called phase (or
      clock) jitter. Surface roughness secondarily broadens the noise spectrum. With a
      strongly reflecting, rough surface such as a renal stone, the high amplitude,
      broadband signal appears as random motion in color Doppler sonography.
      Understanding of the twinkling artifact may result in better use of its clinical
      appearance.

PMID- 12490509
TI  - Noninvasive coronary imaging using electron beam CT: surface rendering versus
      volume rendering.
AB  - OBJECTIVE: Three-dimensional data for noninvasive imaging of the coronary
      arteries are acquired from electron beam CT, multidetector CT, or MR imaging.
      Most commonly, surface rendering is used for three-dimensional processing, but
      recent advances in hardware and software technology have made it possible to use
      volume rendering. Our objective was to compare volume rendering with surface
      rendering for the visualization of the coronary artery tree. CONCLUSION: Our
      experience in the comparison of both techniques shows that because of intrinsic
      problems associated with surface rendering, volume rendering produces better
      image quality.

PMID- 12490510
TI  - MR venography using an intravascular contrast agent: results from a multicenter
      phase 2 study of dosage.
AB  - OBJECTIVE: The objective of this study was to determine the optimal dose of the
      iron oxide contrast agent feruglose for contrast-enhanced MR venography of the
      abdominopelvic and lower extremity veins and to evaluate its safety and
      tolerability in patients with deep venous thrombosis. SUBJECTS AND METHODS: We
      enrolled in our study a total of 45 patients at six centers who had lower
      extremity deep venous thrombosis documented on radiographic venography. Forty
      four patients received the study drug; 39 completed the study. Each patient
      received three sequential IV injections of feruglose at doses of 0.75, 1.25, and
      3.0 mg Fe/kg body weight. MR venography at 1.5 T was repeated at three levels
      after each dose. Safety was evaluated. RESULTS: The agreement between contrast
      enhanced MR venography and radiographic venography with regard to deep venous
      thrombosis above the knee was zero at the lowest dose (0.75 mg Fe/kg body
      weight), 43% at the dose 2.0 mg Fe/kg body weight, and 49% at the dose 5.0 mg
      Fe/kg body weight. No significant difference was seen between the two highest
      doses. The highest cumulative dose provided the greatest diagnostic usefulness
      score. No serious adverse events occurred. CONCLUSION: The two highest doses of
      feruglose showed the best agreement between contrast-enhanced MR venography and
      radiographic venography for deep venous thrombosis above the knee. The safety and
      tolerability of feruglose were confirmed.

PMID- 12490511
TI  - Volume-rendered multidetector CT angiography: noninvasive follow-up of patients
      treated with renal artery stents.
AB  - OBJECTIVE: The purpose of our study was to evaluate the role of multidetector CT
      (MDCT) angiography with volume rendering for estimating the patency of renal
      artery stents. SUBJECTS AND METHODS: In 16 patients, 16 renal artery stents were
      evaluated with MDCT renal angiography and digital subtraction angiography (DSA).
      CT data were evaluated using multiplanar volume reformations and the volume
      rendering algorithm with three different volume-rendered parameter settings (low
      to-high, high-to-low, and high-low-high opacity transfer functions: VR(LH),
      VR(HL), and VR(VE), respectively). Targeted images of each stent were rendered in
      paraaxial and paracoronal planes and were interactively interpreted. The overall
      restenosis severity was measured on postprocessed paraaxial and paracoronal
      images and compared with that obtained on DSA using linear regression analysis.
      Image quality and lumen delineation on rendered images were also compared using
      Wilcoxon's signed rank test. RESULTS: Eight restenoses were identified on DSA.
      Correlations between restenosis severity measured with DSA and those measured
      with MDCT were significant (p < 0.001). Volume rendering with VR(HL) allowed the
      best correlation with DSA (reviewer 1, r(2) = 0.86; reviewer 2, r(2) = 0.94) and
      was significantly better than multiplanar volume reformations (p = 0.028).
      Overall image quality was high with all rendering techniques and with no
      significant differences (p > 0.59, for all comparisons). Stent lumen was well
      delineated with volume-rendering modalities; however, VR(HL) was significantly
      better than VR(LH) (p = 0.033). CONCLUSION: Volume-rendered MDCT angiography
      enabled high-quality three-dimensional reproducible evaluation of the patency of
      implanted renal artery stents. Volume rendering with VR(HL) achieved the best
      performance.

PMID- 12490512
TI  - Randomized prospective study comparing routine versus selective use of sonography
      of the complete calf in patients with suspected deep venous thrombosis.
AB  - OBJECTIVE: We compared patient outcomes using two protocols: one routinely and
      the other selectively evaluating the calves completely during sonographic
      assessment of the lower extremities in patients with suspected deep venous
      thrombosis. SUBJECTS AND METHODS: In this randomized prospective study, patients
      were assigned to two groups. In one group, the deep calf veins were routinely
      evaluated in their entirety, and in the other group the calf was not evaluated
      unless the patient had symptoms or physical signs in the calf, in which case only
      the areas of symptoms or physical signs were evaluated. Patients were followed up
      for 3 months by medical record review, physician surveys, and telephone calls. An
      adverse outcome was a propagated deep venous thrombosis into the thigh or a
      pulmonary embolus. Examination times were recorded when possible. RESULTS: Of the
      235 patients in the group in which the deep calf veins were routinely evaluated,
      we saw no adverse outcomes (0.0%; 97.5% one-sided confidence interval [CI], 0.6
      1.6%). Of the 261 patients in the group in which the calf was only evaluated if
      there were signs or symptoms, we saw two adverse outcomes (0.8%; 95% CI, 0.1
      2.7%). CONCLUSION: We found no significant difference in adverse outcomes in
      patients undergoing a protocol in which the deep calf veins were routinely
      evaluated or a protocol in which the calf was evaluated only if physical signs or
      symptoms were present.

PMID- 12490514
TI  - Current concepts in whole-body imaging using turbo short tau inversion recovery
      MR imaging.

PMID- 12490515
TI  - Prescreening mammography by technologists: a preliminary assessment.
AB  - OBJECTIVE: We assessed the ability of technologists to accurately classify
      screening mammograms as either showing negative findings or requiring follow-up.
      SUBJECTS AND METHODS: In a prospective study, 33 technologists at a central
      facility and five satellite breast imaging facilities recorded whether mammograms
      obtained during 3019 examinations showed negative findings or findings that
      indicated that additional procedures were required. The technologists were not
      specifically trained for the experiment. The technologists' interpretations were
      compared with radiologists' interpretations. RESULTS: Technologists and
      radiologists agreed in 82% of the cases (77% negative findings and 5% requiring
      follow-up). Of the 175 cases recommended for follow-up by only the radiologists,
      17 were ultimately biopsied and two were found to be malignant. CONCLUSION: Even
      without undergoing additional training, technologists can perform at reasonable
      levels of accuracy in classifying screening mammograms. The possibility of using
      technologists to group cases after the technologists have undergone training is
      an interesting concept that should be explored further.

PMID- 12490516
TI  - Automated assessment of the composition of breast tissue revealed on tissue
      thickness-corrected mammography.
AB  - OBJECTIVE: Variations in the thickness of a compressed breast and the resulting
      variations in mammographic densities confound current automated procedures for
      estimating tissue composition of breasts from digitized mammograms. We sought to
      determine whether adjusting mammographic data for tissue thickness before
      estimating tissue composition could improve the accuracy of the tissue estimates.
      MATERIALS AND METHODS: We developed methods for locally estimating breast
      thickness from mammograms and then adjusting pixel values so that the values
      correlated with the tissue composition over the breast area. In our technique,
      the pixel values are corrected for the nonlinearity of the combined
      characteristic curve from the film and film digitizer; the approximate relative
      thickness as a function of distance from the skin line is measured; and the pixel
      values are adjusted to reflect their distance from the skin line. To estimate
      tissue composition, we created a backpropagation neural network classifier from
      features extracted from the histogram of pixel values, after the data had been
      adjusted for characteristic curve and tissue thickness. We used a 10-fold cross
      validation method to evaluate the neural network. The averaged scores of three
      radiologists were our gold standard. RESULTS: The performance of the neural
      network was calculated as the percentage of correct classifications of images
      that were or were not corrected to reflect tissue thickness. With its parameters
      derived from the pixel-value histogram, the neural network based on corrected
      images performed better (71% accuracy) than that based on uncorrected images (67%
      accuracy) (p < 0.05). CONCLUSION: Our results show that adjusting tissue
      thickness before estimating tissue composition improved the performance of our
      estimation procedure in reproducing the tissue composition values determined by
      radiologists.

PMID- 12490517
TI  - Efficacy of computerized infrared imaging analysis to evaluate mammographically
      suspicious lesions.
AB  - OBJECTIVE: The purpose of this clinical trial was to determine the efficacy of a
      dynamic computerized infrared imaging system for distinguishing between benign
      and malignant lesions in patients undergoing biopsy on the basis of mammographic
      findings. SUBJECTS AND METHODS: A 4-year clinical trial was conducted at five
      institutions using infrared imaging of patients for whom breast biopsy had been
      recommended. The data from a blinded subject set were obtained in 769 subjects
      with 875 biopsied lesions resulting in 187 malignant and 688 benign findings. The
      infrared technique records a series of sequential images that provides an
      assessment of the infrared information in a mammographically identified area. The
      suspicious area is localized on the infrared image by the radiologist using
      mammograms, and an index of suspicion is determined, yielding a negative or
      positive result. RESULTS: In the 875 biopsied lesions, the index of suspicion
      resulted in a 97% sensitivity, a 14% specificity, a 95% negative predictive
      value, and a 24% positive predictive value. Lesions that were assessed as false
      negative by infrared analysis were microcalcifications, so an additional analysis
      was performed in a subset excluding lesions described only as microcalcification.
      In this restricted subset of 448 subjects with 479 lesions and 110 malignancies,
      the index of suspicion resulted in a 99% sensitivity, an 18% specificity, a 99%
      negative predictive value, and a 27% positive predictive value. Analysis of
      infrared imaging performance in all 875 biopsied lesions revealed that
      specificity was statistically improved in dense breast tissue compared with fatty
      breast tissue. CONCLUSION: Infrared imaging offers a safe noninvasive procedure
      that would be valuable as an adjunct to mammography in determining whether a
      lesion is benign or malignant.

PMID- 12490518
TI  - Steatocystoma multiplex: mammographic and sonographic manifestations.
AB  - OBJECTIVE: This study was performed to identify the typical imaging features of
      steatocystoma multiplex on mammography and sonography. CONCLUSION: Steatocystoma
      multiplex is manifest by multiple clinically palpable skin-colored or yellow
      nodules scattered on the axillae and the anterior chest wall. Steatocystoma
      multiplex is included in the differential diagnoses of lipoma, fat necrosis,
      galactocele, epidermal cyst, and so on, so radiologists need to be aware of its
      distinguishing features. The findings of a well-circumscribed round fat-density
      nodule on mammography or an intradermal hypoechoic nodule on sonography, combined
      with a family history of steatocystoma multiplex (40%) and an extensive bilateral
      spatial distribution of nodules, confirm the diagnosis of steatocystoma
      multiplex.

PMID- 12490519
TI  - Retrieval of lost microcalcifications during stereotactic vacuum-assisted core
      biopsy.
AB  - OBJECTIVE: The purpose of our report was to describe patients in whom
      calcifications in the breast that were unequivocally removed during stereotactic
      core biopsy using the Mammotome device were not detected on the initial specimen
      radiograph. The lost calcifications in each instance were subsequently found when
      the tubing and contents of the debris canister were strained through a
      nonadhering dressing and radiographed. Additional situations in which
      calcifications are not seen on the initial specimen radiograph are described and
      recommendations are made. CONCLUSION: When vacuum-assisted core biopsy procedures
      are performed, it is important to be aware of the possibility that calcifications
      may be aspirated into the debris canister, thus compromising the accuracy of the
      histopathologic diagnosis. We recommend changing the tubing and the debris
      canister after each procedure and, in certain situations, sending the strained
      canister contents to pathology for evaluation.

PMID- 12490520
TI  - Arterial embolization of a bullet.

PMID- 12490521
TI  - Multiple myeloma seen only on multidetector CT.

PMID- 12490522
TI  - Does Blount disease alter the growth of the distal femur?

PMID- 12490523
TI  - Placenta percreta versus ectopic pregnancy.

PMID- 12490524
TI  - Mondor's disease of the breast can also occur after a sonography-guided core
      biopsy.

PMID- 12490525
TI  - Infantile fibromatosis.

PMID- 12490526
TI  - Capturing PACS images.

PMID- 12490527
TI  - Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line
      is associated with degradation of CREB-binding protein.
AB  - Huntington's Disease belongs to the CAG repeat family of neurodegenerative
      diseases and is characterized by the presence of an expanded polyglutamine
      (polyQ) repeat in the huntingtin (htt) gene product. PolyQ-expanded htt
      accumulates within large aggregates that are found in various subcellular
      compartments, but are more often localized within the nucleus. It has been
      suggested that the sequestration of proteins essential to cell viability may be
      one mechanism that accounts for toxicity generated by polyQ-expanded proteins.
      Nuclear inclusions containing polyQ-expanded htt recruit the transcriptional
      cofactor, CREB-binding protein (CBP). PolyQ toxicity appears to involve
      alterations of gene transcription and reduced neuronal cell viability. In the
      HT22 hippocampal cell line, we find that toxicity within individual cells induced
      by polyQ-expanded htt, as revealed by a TUNEL assay, is associated with the
      localization of the mutant htt within either nuclear or perinuclear aggregates.
      However, in addition to CBP recruitment, we show here that CBP ubiquitylation and
      degradation can be selectively enhanced by polyQ-expanded htt. Thus, selected
      substrates may be directed to the ubiquitin/proteasome-dependent protein
      degradation pathway in response to polyQ-expanded htt within the nucleus.

PMID- 12490528
TI  - Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of
      endocochlear potential.
AB  - The gap junction protein connexin30 (Cx30) is expressed in a variety of tissues
      that include epithelial and mesenchymal structures of the inner ear. We generated
      Cx30 (Gjb6) deficient mice by deletion of the Cx30 coding region. Homozygous
      mutants (Cx30((-/-))) were born at the expected Mendelian frequency, developed
      normally and were fertile. However, they exhibit a severe constitutive hearing
      impairment. From the age of hearing onset, these mice lack the electrical
      potential difference between the endolymphatic and perilymphatic compartments of
      the cochlea, i.e. the endocochlear potential, which plays a key role in the high
      sensitivity of the mammalian auditory organ. In addition, after postnatal day 18,
      the cochlear sensory epithelium starts to degenerate by cell apoptosis. This
      degeneration process is likely to account for the concomitant decrease of the
      endolymphatic potassium concentration and the aggravation of the hearing loss in
      adult Cx30((-/-)) mice. The Cx30 ((-/-)) phenotype thus reveals the critical role
      of Cx30 both in generating the endocochlear potential and for survival of the
      auditory hair cells after the onset of hearing. The Cx30 deficient mice may
      represent a valuable model to study the mechanism of the hearing loss in human
      patients carrying a homozygous deletion of the CX30 gene (del Castillo et al.,
      2002, New Engl. J. Med., 346, 243-249).

PMID- 12490529
TI  - Results of a high-resolution genome screen of 437 Alzheimer's disease families.
AB  - Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life
      with complex inheritance. Mutations in three known genes lead to the rare early
      onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in
      the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late
      onset (>60 years) AD. A recent study concluded that there are up to four
      additional genes with an equal or greater contribution to the disease. We
      performed a 9 cM genome screen of 437 families with AD, the full National
      Institute of Mental Health (NIMH) sample, which has been carefully ascertained,
      evaluated and followed by our group over the last decade. Performing standard
      parametric and non-parametric linkage analyses, we observed a 'highly
      significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13,
      which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32,
      5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for
      'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod
      score (MLS) >/=2.2] in at least one of our analyses. Although some of these will
      surely prove to be false positives, these linkage signals should provide a
      valuable framework for future studies aimed at identifying additional
      susceptibility genes for late-onset AD.

PMID- 12490530
TI  - Recombination hotspots rather than population history dominate linkage
      disequilibrium in the MHC class II region.
AB  - Recombination, demographic history, drift and selection influence the extent of
      linkage disequilibrium (LD) in the human genome, but their relative contributions
      remain unclear. To investigate the effect of meiotic recombination versus
      population history on LD, three populations with different demographic histories
      (UK north Europeans, Saami and Zimbabweans) were genotyped for high-frequency
      single-nucleotide polymorphisms (SNPs) across a 75 kb DNA segment of the MHC
      class II region. This region spans three well-characterized recombination
      hotspots and a 60 kb long LD block. Despite a high level of underlying haplotype
      diversity and considerable divergence in haplotype composition between
      populations, all three populations showed very similar patterns of LD.
      Surprisingly, the entire 60 kb LD block was present even in Africans, although it
      was relatively difficult to detect owing to a systematic deficiency of high
      frequency SNPs. In contrast, DNA within recombination hotspots did not show this
      low nucleotide diversity in Africans. Thus, while population history has some
      influence on LD, our findings suggest that recombination hotspots play a major
      global role in shaping LD patterns as well as helping to maintain localized SNP
      diversity in this region of the MHC.

PMID- 12490531
TI  - Genomic context drives SCA7 CAG repeat instability, while expressed SCA7 cDNAs
      are intergenerationally and somatically stable in transgenic mice.
AB  - Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant cerebellar ataxia
      caused by a CAG repeat expansion in the ataxin-7 gene. In humans, SCA7 is
      characterized by marked anticipation due to intergenerational repeat instability
      with a bias toward expansion, and is thus regarded as the most unstable of the
      polyglutamine diseases. To study the molecular basis of CAG/CTG repeat
      instability and its pathological significance, we generated lines of transgenic
      mice carrying either a SCA7 cDNA construct or a 13.5 kb SCA7 genomic fragment
      with 92 CAG repeats. While the cDNA transgenic mice showed little
      intergenerational repeat instability, the genomic fragment transgenic mice
      displayed marked intergenerational instability with an obvious expansion bias. We
      then went on to generate additional lines of genomic fragment transgenic mice,
      and observed that deletion of the 3' genomic region significantly stabilized
      intergenerational transmission of the SCA7 CAG92 repeat. These results suggest
      that cis-information present on the genomic fragment is driving the instability
      process. As the SCA7 genomic fragment contains a large number of replication
      associated motifs, the presence of such sequence elements may make the SCA7 CAG
      repeat region more susceptible to instability. Small-pool and standard PCR
      analysis of tissues from genomic fragment mice revealed large repeat expansions
      in their brains and livers, but no such changes were found in any tissues from
      cDNA transgenic mice that have been shown to undergo neurodegeneration. As large
      somatic repeat expansions are absent from the brains of SCA7 cDNA mice, our
      results indicate that neurodegeneration can occur without marked somatic
      mosaicism, at least in these mice.

PMID- 12490532
TI  - The interval of linkage disequilibrium (LD) detected with microsatellite and SNP
      markers in chromosomes of Finnish populations with different histories.
AB  - Linkage disequilibrium (LD) has been an efficient tool for fine mapping of
      monogenic disease genes in population isolates. Its usefulness for identification
      of predisposing loci for common, polygenic diseases has been challenged on the
      basis of anticipated allelic and locus heterogeneity. We compared the extent of
      LD among marker loci in Finnish subpopulations with divergent but well
      characterized histories. One study sample represents the early settlement Finnish
      population, descended from two immigration events 4,000 and 2,000 years ago. The
      second sample represents the geographically large late settlement region,
      populated 15 generations ago by several small immigrant groups from the early
      settlement region. The third is a restricted regional subpopulation in
      northeastern Finland which was founded 12 generations ago by 39 immigrant
      families from the late settlement region. We genotyped 243 microsatellite markers
      and 68 single nucleotide polymorphisms (SNPs) on chromosomes 1q and 5q. The
      genealogy of the families from the early (n=16) and late settlements (n=54) and
      the isolated settlement (n=54) was studied in detail back to the 1800s.
      Microsatellite data revealed greater LD in the young, founder subpopulation than
      was seen in either of the older populations. Observed linkage disequilibrium
      correlated not only with physical distance between markers but also with the
      information content of the markers. Using biallelic SNP markers, significant LD
      could only be detected up to 0.1 cM. Our results demonstrate the complexity of
      the concept of 'detectable LD' and emphasize the importance of understanding
      population history when designing a strategy for disease gene mapping.

PMID- 12490533
TI  - Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a
      single gene model for human Pelger-Huet anomaly.
AB  - The nature of the wild-type gene product at the mouse ichthyosis (ic) locus has
      been of great interest because mutations at this locus cause marked abnormalities
      in nuclear heterochromatin, similar to those observed in Pelger-Huet anomaly
      (PHA). We recently found that human PHA is caused by mutations in the gene (LBR)
      encoding lamin B receptor, an evolutionarily conserved inner nuclear membrane
      protein involved in nuclear assembly and chromatin binding. Mice homozygous for
      deleterious alleles at the ichthyosis (ic) locus present with a blood phenotype
      similar to PHA, and develop other phenotypic abnormalities, including alopecia,
      variable expression of syndactyly and hydrocephalus. The ic locus on mouse
      chromosome 1 shares conserved synteny with the chromosomal location of the human
      LBR locus on human chromosome 1. In this study, we identified one nonsense
      (815ins) and two frameshift mutations (1088insCC and 1884insGGAA) within the Lbr
      gene of mice homozygous for either of three independent mutations (ic, ic(J) and
      ic(4J), respectively) at the ichthyosis locus. These allelic mutations are
      predicted to result in truncated or severely impaired LBR protein. Our studies of
      mice homozygous for the ic(J) mutation revealed a complete loss of LBR protein as
      shown by immunofluorescence microscopy and immunoblotting. The findings provide
      the molecular basis for the heterochromatin clumping and other distinct
      phenotypes caused by ic mutations. These spontaneous Lbr mutations confirm the
      molecular basis of human PHA and provide a small animal model for determination
      of the precise function of LBR in normal and pathological states.

PMID- 12490535
TI  - Association between Parkinson's disease and polymorphisms in the nNOS and iNOS
      genes in a community-based case-control study.
AB  - Excess of nitric oxide (NO) has been shown to exert neurotoxic impacts in the
      brain. Moreover, inhibition of two NO-synthesizing enzymes, neuronal NOS (nNOS)
      and inducible NOS (iNOS), displays neuroprotective effects in the MPTP model of
      Parkinson's disease (PD). These data suggest a possible involvement of NOS as
      factors controlling the resistance of the nigral dopaminergic neurons to
      environmental insults. Therefore, we investigated whether polymorphisms present
      in these genes could contribute to the risk of developing PD. We carried out a
      community-based case-control study among subjects enrolled in the Mutualite
      Sociale Agricole, the French health insurance organization for workers connected
      to agriculture. Two-hundred and nine PD patients and 488 controls of European
      (mostly French) ancestry and matched for age, sex and region of residency were
      included in this study. Associations were observed with polymorphisms present in
      exon 22 of iNOS (OR for AA carriers=0.50, 95% CI=0.29-0.86, P=0.01) and in exon
      29 of nNOS (OR for carriers of the T allele=1.53, 95% CI=1.08-2.16, P=0.02); no
      association was observed with a polymorphism in exon 18 of nNOS (OR for carriers
      of the T allele=1.20, 95% CI=0.85-1.69, P=0.30). Moreover, a significant
      interaction of the nNOS polymorphisms with current and ever cigarette smoking was
      found (nNOS 18, P=0.05; nNOS 29, P=0.04). All together, these data favour an
      involvement of these two genes as new modifier genes in PD.

PMID- 12490534
TI  - Mutations of SPG4 are responsible for a loss of function of spastin, an abundant
      neuronal protein localized in the nucleus.
AB  - Mutations of spastin are responsible for the most common autosomal dominant form
      of hereditary spastic paraplegia (AD-HSP), a disease characterized by axonal
      degeneration of corticospinal tracts and posterior columns. Generation of
      polyclonal antibodies specific to spastin has revealed two isoforms of 75 and 80
      kDa in both human and mouse tissues with a tissue-specific variability of the
      isoform ratio. Spastin is an abundant protein in neural tissues and
      immunolabeling experiments have shown that spastin is expressed in neurons but
      not in glial cells. These data indicate that axonal degeneration linked to
      spastin mutations is caused by a primary defect of neurons. Protein and
      transcript analyses of patients carrying either nonsense or frameshift spastin
      mutations revealed neither truncated protein nor mutated transcripts, providing
      evidence that these mutations are responsible for a loss of spastin function.
      Identifying agents able to induce the expression of the non-mutated spastin
      allele should represent an attractive therapeutic strategy in this disease.

PMID- 12490536
TI  - Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF-alpha in
      human lens epithelial cells.
AB  - Chronic hyperglycemia and cytokines such as tumor necrosis factor alpha (TNF
      alpha) cause oxidative stress leading to dysregulated cell growth or apoptosis
      that contributes to the development of inflammation and secondary complications
      of diabetes. However, the mechanisms regulating hyperglycemic or cytokine injury
      are not well understood. Herein we report that inhibition of the polyol pathway
      enzyme aldose reductase (AR) by two structurally unrelated inhibitors--sorbinil
      and tolrestat--prevents, in the human lens epithelial cell line B-3, the
      apoptosis and activation of caspase-3 caused by exposure to high glucose levels
      or TNF-alpha. Inhibition of AR attenuated TNF-alpha and hyperglycemia-induced
      activation of protein kinase C (PKC), phosphorylation of the inhibitory subunit
      of nuclear factor-kappaB (NF-kappaB), and stimulation of NF-kappaB, but it did
      not prevent the activation of NF-kappaB and PKC by phorbol ester. Inhibition of
      AR also attenuated the increase in p38 mitogen-activated protein kinase and c-Jun
      N-terminal kinase phosphorylation. These signaling pathways were also inhibited
      in cells in which the expression of AR was reduced by antisense ablation.
      Collectively, these results identify a new participant in apoptotic signaling and
      suggest that AR is an obligatory mediator of the apoptotic events upstream of
      PKC. These observations could provide new insights into the pathophysiology of
      diabetes and the role of aberrant glucose metabolism in apoptotic cell death.

PMID- 12490537
TI  - Abnormalities in intracellular Ca2+ regulation in fetal vascular smooth muscle in
      pre-eclampsia: enhanced sensitivity to arachidonic acid.
AB  - Pre-eclampsia (PE) is a leading cause of maternal and fetal mortality and
      morbidity. As free fatty acid metabolism is abnormally regulated in PE, we
      investigated the intracellular Ca2+([Ca2+]i) response to arachidonic acid (AA) in
      primary cultures of human umbilical artery smooth muscle cells (HUASMC). AA (50
      microM) caused a significantly greater [Ca2+]i elevation in PE than in normal
      HUASMC, with many cells displaying a delayed secondary increase. The
      nonmetabolizable AA analog ETYA did not induce a response, suggesting that the
      augmented PE response depends on an AA metabolite. Inhibition of the AA
      metabolizing cyclooxygenase or lipoxygenase pathways did not affect the AA
      response of PE HUASMC but induced in normal cells the secondary rise of [Ca2+]i
      observed in PE cells. This potentiated response and the response in PE cells were
      blocked by inhibitors of the monooxygenase pathway, a third AA metabolizing
      pathway. We conclude that the [Ca2+]i response of HUASMC is elevated in PE
      because of an increased level of a monooxygenase metabolite that stimulates Ca2+
      influx and that this can be mimicked in normal cells by blocking cyclooxygenase
      or lipoxygenase to divert AA to the monooxygenase. This and our work with fetal
      endothelial cells (FASEB J. 10.1096/fj.01-0916fje) demonstrate phenotypic changes
      in the fetal vasculature in PE.

PMID- 12490538
TI  - Alterations in renal cytosolic phospholipase A2 and cyclooxygenases in polycystic
      kidney disease.
AB  - Cytosolic phospholipase A2 (cPLA2), cyclooxygenase-1 (COX-1), and cyclooxygenase
      2 (COX-2) regulate the formation of physiologically active prostaglandins, the
      production of which is known to be elevated in several renal disorders. We
      studied the relevance of these enzymes in polycystic kidney disease (PKD) by
      using two models of the disease: a model in which decline in renal function
      begins in adulthood (CD1-pcy/pcy mouse) and one in which it occurs early, during
      growth (Han:SPRD-cy rat). Immunoblotting analyses of cytosolic and particulate
      kidney fractions revealed that cPLA2 levels are significantly higher (by 34-131%)
      in the latter stages of the disease in both models. Renal COX enzymes were found
      only in the particulate fractions, with COX-1 87% higher in 6-month-old CD1
      pcy/pcy mice compared with normal controls, and 110% higher in male 70-day-old
      Han:SPRD-cy rats with cystic kidneys compared with controls. Renal COX-2 was
      detected only in the rats and was 58% lower in diseased kidneys of 70-day-old
      male Han:SPRD-cy rats, indicating that cPLA2 is coupled to COX-1 in the kidney.
      The altered levels of these eicosanoid-regulating enzymes has implications for
      the use of NSAIDS and specific COX inhibitors in individuals with this disorder.

PMID- 12490539
TI  - Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell
      populations of different organs.
AB  - Cellular responses to oxygen are increasingly recognized as critical in normal
      development and physiology, and are implicated in pathological processes. Many of
      these responses are mediated by the transcription factors HIF-1 and HIF-2. Their
      regulation occurs through oxygen-dependent proteolysis of the alpha subunits HIF
      1alpha and HIF-2alpha, respectively. Both are stabilized in cell lines exposed to
      hypoxia, and recently HIF-1alpha was reported to be widely expressed in vivo. In
      contrast, regulation and sites of HIF-2alpha expression in vivo are unknown,
      although a specific role in endothelium was suggested. We therefore analyzed HIF
      2alpha expression in control and hypoxic rats. Although HIF-2alpha was not
      detectable under baseline conditions, marked hypoxic induction occurred in all
      organs investigated, including brain, heart, lung, kidney, liver, pancreas, and
      intestine. Time course and amplitude of induction varied between organs.
      Immunohistochemistry revealed nuclear accumulation in distinct cell populations
      of each tissue, which were exclusively non-parenchymal in some organs (kidney,
      pancreas, and brain), predominantly parenchymal in others (liver and intestine)
      or equally distributed (myocardium). These data indicate that HIF-2 plays an
      important role in the transcriptional response to hypoxia in vivo, which is not
      confined to the vasculature and is complementary to rather than redundant with
      HIF-1.

PMID- 12490540
TI  - Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an
      apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade.
AB  - Neurofibrillary tangles comprised of highly phosphorylated tau proteins are a key
      component of Alzheimer's disease pathology. Mice lacking Reelin (Reln), double
      knockouts lacking the VLDL receptor (VLDLR) and ApoE receptor2 (ApoER2), and mice
      lacking disabled-1 (Dab1) display increased levels of phosphorylated tau. Because
      Reln binds to recombinant ApoE receptors, assembly of a Reln/ApoE-receptor/Dab1
      (RAD) complex may initiate a signal transduction cascade that controls tau
      phosphorylation. Conversely, disruption of this RAD complex may increase tau
      phosphorylation and lead to neurodegeneration. To substantiate this concept, we
      mated Reln-deficient mice to ApoE-deficient mice and found that in the absence of
      Reln, tau phosphorylation increased as the amount of ApoE decreased. Paralleling
      the change in tau phosphorylation levels, we found that GSK-3beta activity
      increased in Reln-deficient mice and further increased in mice lacking both Reln
      and ApoE. CDK-5 activity was similar in mice lacking Reln, ApoE, or both. GSK
      3beta and CDK-5 activity increased in Dab1-deficient mice, independent of ApoE
      levels. Further supporting the idea that increased tau phosphorylation results
      primarily from increased kinase activity, the activity of two phosphatases was
      similar in all conditions tested. These data support a novel, ligand-mediated
      signal transduction cascade--initiated by the assembly of a RAD complex that
      suppresses kinase activity and controls tau phosphorylation.

PMID- 12490541
TI  - Impaired monocyte function in cancer patients: restoration with a cyclooxygenase
      2 inhibitor.
AB  - Epidemiological data and animal models have provided evidence that nonsteroidal
      antiinflammatory drugs (NSAIDs) have an anticancer effect. However, the molecular
      mechanisms underlying these antineoplastic effects are not well understood. We
      described previously that expression levels of the chemokine receptor, CCR5, and
      the beta2-integrin, Mac-1, were down-regulated on primary monocytes after
      incubation in supernatants from human carcinoma cell lines, and that this down
      regulation resulted in impaired monocyte function with respect to migration and
      adhesion. We now demonstrate that these impairments are also present in vivo.
      Monocytes from cancer patients displayed significantly reduced CCR5 levels and
      migration capacities in comparison to cells from healthy donors. Because
      migration is necessary for the antitumor activity of monocytes/macrophages, these
      deficits may contribute to the suppressed immune system seen in cancer patients.
      In a clinical study, we analyzed the effect of a selective COX-2 inhibitor,
      Rofecoxib, on the migration of monocytes derived from cancer patients. The
      results revealed significant improvement in migration equal to those levels seen
      in healthy donors. We conclude that in patients with cancer, the intake of
      Rofecoxib for 3 wk leads to significant restoration of monocyte function. These
      data may, at least in part, help explain the anticancer effects of NSAIDs.

PMID- 12490542
TI  - Transforming growth factor alpha-induced expression of type 1 plasminogen
      activator inhibitor in astrocytes rescues neurons from excitotoxicity.
AB  - Although transforming growth factor (TGF)-alpha, a member of the epidermal growth
      factor (EGF) family, has been shown to protect neurons against excitotoxic and
      ischemic brain injuries, its mechanism of action remains unknown. In the present
      study, we used in vitro models of apoptotic or necrotic paradigms demonstrating
      that TGF-alpha rescues neurons from N-methyl-D-aspartate (NMDA)-induced
      excitotoxic death, with the obligatory presence of astrocytes. Because neuronal
      tissue-type plasminogen activator (t-PA) release was shown to potentiate NMDA
      induced excitotoxicity, we observed that TGF-alpha treatment reduced NMDA-induced
      increase of t-PA activity in mixed cultures of neurons and astrocytes. In
      addition, we showed that although TGF-alpha induces activation of the
      extracellular signal-regulated kinases (ERKs) in astrocytes, it failed to
      activate p42/p44 in neurons. Finally, we showed that TGF-alpha, by an ERK
      dependent mechanism, stimulates the astrocytic expression of PAI-1, a t-PA
      inhibitor, which mediates the neuroprotective activity of TGF-alpha against NMDA
      mediated excitotoxic neuronal death. Taken together, we indicate that TGF-alpha
      rescues neurons from NMDA-induced excitotoxicity in mixed cultures through
      inhibition of t-PA activity, involving PAI-1 overexpression by an ERK-dependent
      pathway in astrocytes.

PMID- 12490543
TI  - Pseudo-symmetry of C19 steroids, alternative binding orientations, and
      multispecificity in human estrogenic 17beta-hydroxysteroid dehydrogenase.
AB  - Steroids are implicated in many physiological processes, such as reproduction,
      aging, metabolism, and cancer. To understand the molecular basis for steroid
      recognition and discrimination, we studied the human estrogenic 17beta
      hydroxysteroid dehydrogenase (17beta-HSD1) responsible for the last step in the
      bioactivation of all estrogens. Here we report the first observation of the
      conversion of dihydrotestosterone (DHT) into 3beta,17beta-androstanediol (3beta
      diol) by 17beta-HSD1, an estrogenic enzyme studied for more than half a century.
      Kinetic observations demonstrate that both the 3beta-reduction of DHT into 3beta
      diol (kcat = 0.040 s(-1)1; Km = 32 +/- 9 microM) and the 17beta-oxidation of DHT
      into androstandione (A-dione) (kcat = 0.19 s(-1); Km = 26 +/-6 microM) are
      catalyzed by 17beta-HSD1 via alternative binding orientation of the steroid. The
      reduction of DHT was also observed in intact cells by using HEK-293 cells stably
      transformed with 17beta-HSD1. The high-resolution structure of a 17beta-HSD1-C19
      steroid (testosterone) complex solved at 1.54 A demonstrates that the steroid is
      reversibly oriented in the active site, which strongly supports the existence of
      alternative binding mode. Such a phenomenon can be explained by the pseudo
      symmetric structure of C19-steroids. Our results confirm the role of the Leu149
      residue in C18/C19-steroid discrimination and suggest a possible mechanism of
      17beta-HSD1 in the modulation of DHT levels in tissues, such as the breast, where
      both the enzyme and DHT are present.

PMID- 12490544
TI  - Evidence for a skeletal mechanosensitivity gene on mouse chromosome 4.
AB  - Differences in skeletal mechanical adaptation between C3H/HeJ (C3H) and C57BL/6J
      (B6) mouse strains suggest that these mice can be used to elucidate the genes
      involved in mechanosensitivity regulation. The C3H and B6 skeletons also differ
      in bone size, and several quantitative trait loci (QTL) have been mapped for bone
      size. We hypothesized that genes controlling bone size (external diameter) might
      exert their effect by influencing mechanosensitivity. The hypothesis was tested
      by applying mechanical loads to the ulnae of the B6.C3H-4T (4T) congenic mouse
      strain, which is genetically 98.4% B6 and carries the C3H chromosome 4 (Chr. 4)
      QTL genomic DNA. Mechanical strain was measured at the midshaft ulna in separate
      calibration animals. 4T mice were significantly more responsive to mechanical
      stimulation than B6 control mice, as assessed by changes in bone geometry and
      fluorochrome-derived bone formation rates. Bone formation rates were also greater
      in the ulnae and femora of 6-wk-old 4T mice engaged in normal cage activity
      compared with age-matched B6 mice. Collectively, the results might explain why 4T
      mice have wider femora and ulnae than do B6 control mice and suggest that mouse
      Chr. 4 contains a genetic locus that modulates the mechanosensitivity of bone
      tissue.

PMID- 12490545
TI  - p38 MAP kinase--a molecular switch between VEGF-induced angiogenesis and vascular
      hyperpermeability.
AB  - Vascular endothelial growth factor (VEGF) is not only essential for
      vasculogenesis and angiogenesis but also is a potent inducer of vascular
      permeability. Although a dissection of the molecular pathways between
      angiogenesis- and vascular permeability-inducing properties would be desirable
      for the development of angiogenic and anti-angiogenic therapies, such mechanisms
      have not been identified yet. Here we provide evidence for a role of the p38 MAPK
      as the signaling molecule that separates these two processes. Inhibition of p38
      MAPK activity enhances VEGF-induced angiogenesis in vitro and in vivo, a finding
      that was accompanied by prolonged Erk1/2 MAPK activation, increased endothelial
      survival, and plasminogen activation. Conversely, the same inhibitors abrogate
      VEGF-induced vascular permeability in vitro and in vivo. These dualistic
      properties of p38 MAPK are relevant not only for therapeutic angiogenesis but
      also for reducing edema formation and enhancing tissue repair in ischemic
      diseases.

PMID- 12490546
TI  - AT2 receptor activation regulates myocardial eNOS expression via the calcineurin
      NF-AT pathway.
AB  - The role of AT2-receptors has recently been subject of considerable debate. We
      investigated the influence of AT2-stimulation/inhibition on myocardial
      endothelial NO-synthase (eNOS, NOS-III) promoter activity and eNOS protein
      expression. Stimulation of rat cardiomyocytes with angiotensin II (AngII)
      increased eNOS protein expression 3.3-fold. This was blocked by Cyclosporin A
      (CsA). Inhibition of the AT1-receptor did not reduce AngII-mediated eNOS protein
      expression, whereas AT2 stimulation increased it 2.4-fold and AT2 inhibition
      suppressed it. The modulatory effects of the AT2-receptor on eNOS expression was
      confirmed in mice with a genetic deletion of the AT2-receptor (AT2-KO). In gel
      shift assays two putative NF-AT sites in a 1.6 kb eNOS promoter fragment showed
      NF-AT binding and a supershift by NF-AT2(-c1)-specific antibodies. Stimulation of
      transfected cells with AngII or specific AT2-receptor agonists resulted in a
      significant increase in eNOS promoter activity, which was blocked by CsA, MCIP1,
      and mutation of an upstream NF-AT site. CONCLUSION: 1) AngII-stimulation of the
      myocardium, both in vivo and in vitro, is accompanied by increased expression of
      eNOS. 2) This effect is mediated by the calcineurin pathway and is induced by the
      AT2-receptor. 3) These results define a calcineurin/NF-AT/eNOS pathway as
      downstream effector of AT2-receptor activation in the myocardium.

PMID- 12490547
TI  - Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin
      system in mice.
AB  - The endothelium controls blood flow and pressure by releasing several vasoactive
      factors, among them the vasodilator nitric oxide (NO) and the potent
      vasoconstrictor endothelin-1 (ET-1). Although increased NO levels have been found
      in excessive erythrocytosis, little is known concerning ET-1 expression in this
      condition. Thus, we examined the endothelin system in transgenic mice that due to
      constitutive overexpression of erythropoietin (Epo) reached hematocrit levels of
      approximately 80%. Surprisingly, despite generalized vasodilatation, polycythemic
      mice exhibited a two- to fivefold elevation in ET-1 mRNA levels in aorta, liver,
      heart, and kidney. In line with this, increased expression of ET-1 protein was
      detected in the pulmonary artery by immunohistochemical analysis. Compared with
      their wild-type littermates, aortic rings of Epo transgenic animals exhibited a
      marked reduction in vascular reactivity to ET-1 and big ET-1, but this effect was
      abrogated upon preincubation with the NO synthase inhibitor N-nitro-L-arginine
      methyl ester (L-NAME). Pretreatment of polycythemic mice with the ET(A) receptor
      antagonist darusentan for 3 wk significantly prolonged their survival upon acute
      exposure to L-NAME. Taken together, these results demonstrate for the first time
      that excessive erythrocytosis induces a marked activation of the tissue
      endothelin system that results in increased mortality upon blockade of NO
      mediated vasodilatation. Because ETA antagonism prolonged survival after acute
      blockade of NO synthesis, endothelin may be regarded as a contributor to the
      adverse cardiovascular effects of erythrocytosis and may thus represent a new
      target in the treatment of cardiovascular disease associated with erythrocytosis.

PMID- 12490548
TI  - Identification of novel carrier peptides for the specific delivery of
      therapeutics into cancer cells.
AB  - Cancer therapy is currently limited by the difficulty of achieving efficient
      delivery into target cells. To investigate whether therapeutics can be delivered
      specifically to cancer cells, we have explored the possibility of selecting small
      peptides that bind specifically, or preferentially, to breast cancer cell lines.
      By using random peptide phage libraries and an experimental approach that allows
      the selection of internalized peptides, cell-specific binding peptides have been
      identified. The peptides define a major core motif (LTVXPWY) that was not found
      in negative phages. Phage displaying LTVSPWY peptide sequence exhibited a
      specific binding to breast cancer cells. None of the selected peptides bound to
      human primary cells from different tissue origin (e.g., epithelial, endothelial,
      hematopoetic). The potential of the selected peptides to mediate cellular
      internalization in the context of phages and recombinant GFP-peptide fusions was
      demonstrated. By linking the LTVSPWY peptide to an antisense phosphorothioate
      oligonucleotide against the ErbB2 receptor, specific delivery to cancer cells was
      achieved. In contrast to free antisense, the peptide-antisense conjugates
      inhibited ErbB2 gene expression. Thus, efficient delivery of antisense
      oligonucleotides can be achieved by coupling them to cancer cell-specific
      peptides, identified by a method that did not require any knowledge about their
      corresponding receptors.

PMID- 12490549
TI  - ERG K+ channel blockade enhances firing and epinephrine secretion in rat
      chromaffin cells: the missing link to LQT2-related sudden death?
AB  - The ether-a-go-go-related genes (erg) are expressed in tissues other than heart
      and brain, in which human erg (HERG) K+ channels are known to regulate the
      repolarization of heart action potentials and neuronal spike-frequency
      accommodation. We provide evidence that erg1 transcripts and ERG proteins are
      present in rat chromaffin cells in which we could isolate a K+ current that was
      biophysically and pharmacologically similar to the ERG current. Firing frequency
      and catecholamine release were analyzed at the single-cell level by means of
      perforated patch-clamp and carbon fiber electrochemical detection. It was found
      that the blocking of ERG, KATP, and KCa channels led to hyperexcitability and an
      increase in catecholamine release. Combined immunocytochemical experiments with
      antibodies directed against phenylethanolamine N-methyltransferase and ERG
      channels suggested expression of these channels in epinephrine- but not in
      norepinephrine-containing cells. It is concluded that, in addition to being
      crucial in regulating the QT period in the heart, ERG channels play a role in
      modulating epinephrine, a fundamental neurotransmitter shaping cardiac function.
      This finding suggests that the sudden death phenotype associated with LQT2
      syndrome mutations may be the result of an emotionally triggered increase in
      epinephrine in a long-QT running heart.

PMID- 12490550
TI  - Mbt, a Drosophila PAK protein, combines with Cdc42 to regulate photoreceptor cell
      morphogenesis.
AB  - The Drosophila gene mushroom bodies tiny (mbt) encodes a putative p21-activated
      kinase (PAK), a family of proteins that has been implicated in a multitude of
      cellular processes including regulation of the cytoskeleton, cell polarisation,
      control of MAPK signalling cascades and apoptosis. The mutant phenotype of mbt is
      characterised by fewer neurones in the brain and the eye, indicating a role of
      the protein in cell proliferation, differentiation or survival. We show that
      mutations in mbt interfere with photoreceptor cell morphogenesis. Mbt
      specifically localises at adherens junctions of the developing photoreceptor
      cells. A structure-function analysis of the Mbt protein in vitro and in vivo
      revealed that the Mbt kinase domain and the GTPase binding domain, which
      specifically interacts with GTP-loaded Cdc42, are important for Mbt function.
      Besides regulation of kinase activity, another important function of Cdc42 is to
      recruit Mbt to adherens junctions. We propose a role for Mbt as a downstream
      effector of Cdc42 in photoreceptor cell morphogenesis.

PMID- 12490551
TI  - Functional subdivision of trunk visceral mesoderm parasegments in Drosophila is
      required for gut and trachea development.
AB  - In Drosophila, trunk visceral mesoderm, a derivative of dorsal mesoderm, gives
      rise to circular visceral muscles. It has been demonstrated that the trunk
      visceral mesoderm parasegment is subdivided into at least two domains by
      connectin expression, which is regulated by Hedgehog and Wingless emanating from
      the ectoderm. We now extend these findings by examining a greater number of
      visceral mesodermal genes, including hedgehog and branchless. Each visceral
      mesodermal parasegment appears to be divided into five or six regions, based on
      differences in expression patterns of these genes. Ectodermal Hedgehog and
      Wingless differentially regulate the expression of these metameric targets in
      trunk visceral mesoderm. hedgehog expression in trunk visceral mesoderm is
      responsible for maintaining its own expression and con expression. hedgehog
      expressed in visceral mesoderm parasegment 3 may also be required for normal
      decapentaplegic expression in this region and normal gastric caecum development.
      branchless expressed in each trunk visceral mesodermal parasegment serves as a
      guide for the initial budding of tracheal visceral branches. The metameric
      pattern of trunk visceral mesoderm, organized in response to ectodermal
      instructive signals, is thus maintained at a later time via autoregulation, is
      required for midgut morphogenesis and exerts feedback effect on trachea,
      ectodermal derivatives.

PMID- 12490552
TI  - The role of Grg4 in tectal laminar formation.
AB  - Mature chick optic tecta consist of 16 laminae and receive retinal fiber
      projections in a precise retinotopic manner. Retinal axons arborize in laminae a
      f of the SGFS, but do not cross the border between lamina f and g. In order to
      elucidate molecular mechanisms of tectal laminar formation, we first looked at
      the migration of tectal postmitotic cells. We found that the migration pattern of
      postmitotic cells changes around E5 and that late migratory cells intervened
      laminae that were formed by early migratory cells. The coincident appearance of
      Grg4 expression in the tectal ventricular layer and the change in migration
      pattern suggested an important role for Grg4. Clonal misexpression of Grg4
      resulted in cells migrating to laminae h-j of the SGFS. Massive misexpression of
      Grg4 resulted in disruption of laminae that were formed by early migratory cells,
      in particular lamina g of the SGFS. Application of Grg4 morpholino antisense
      oligonucleotide or the misexpression of a dominant-negative form of Grg4 exerted
      the opposite effect. We concluded that Grg4 may direct tectal postmitotic cells
      to follow a late migratory pathway.

PMID- 12490553
TI  - Sex-lethal splicing autoregulation in vivo: interactions between SEX-LETHAL, the
      U1 snRNP and U2AF underlie male exon skipping.
AB  - Alternative splicing of the Sex-lethal pre-mRNA has long served as a model
      example of a regulated splicing event, yet the mechanism by which the female
      specific SEX-LETHAL RNA-binding protein prevents inclusion of the translation
      terminating male exon is not understood. Thus far, the only general splicing
      factor for which there is in vivo evidence for a regulatory role in the pathway
      leading to male-exon skipping is sans-fille (snf), a protein component of the
      spliceosomal U1 and U2 snRNPs. Its role, however, has remained enigmatic because
      of questions about whether SNF acts as part of an intact snRNP or a free protein.
      We provide evidence that SEX-LETHAL interacts with SANS-FILLE in the context of
      the U1 snRNP, through the characterization of a point mutation that interferes
      with both assembly into the U1 snRNP and complex formation with SEX-LETHAL.
      Moreover, we find that SEX-LETHAL associates with other integral U1 snRNP
      components, and we provide genetic evidence to support the biological relevance
      of these physical interactions. Similar genetic and biochemical approaches also
      link SEX-LETHAL with the heterodimeric splicing factor, U2AF. These studies point
      specifically to a mechanism by which SEX-LETHAL represses splicing by interacting
      with these key splicing factors at both ends of the regulated male exon.
      Moreover, because U2AF and the U1 snRNP are only associated transiently with the
      pre-mRNA during the course of spliceosome assembly, our studies are difficult to
      reconcile with the current model that proposes that the SEX-LETHAL blocks
      splicing at the second catalytic step, and instead argue that the SEX-LETHAL
      protein acts after splice site recognition, but before catalysis begins.

PMID- 12490554
TI  - Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the
      sclerotome.
AB  - We have previously shown that the paired-box transcription factors Pax1 and Pax9
      synergistically act in the proper formation of the vertebral column.
      Nevertheless, downstream events of the Pax1/Pax9 action and their target genes
      remain to be elucidated. We show, by analyzing Pax1;Pax9 double mutant mice, that
      expression of Bapx1 in the sclerotome requires the presence of Pax1 and Pax9, in
      a gene dose-dependent manner. By using a retroviral system to overexpress Pax1 in
      chick presomitic mesoderm explants, we show that Pax1 can substitute for Shh in
      inducing Bapx1 expression and in initiating chondrogenic differentiation.
      Furthermore, we demonstrate that Pax1 and Pax9 can transactivate regulatory
      sequences in the Bapx1 promoter and that they physically interact with the Bapx1
      promoter region. These results strongly suggest that Bapx1 is a direct target of
      Pax1 and Pax9. Together, we conclude that Pax1 and Pax9 are required and
      sufficient for the chondrogenic differentiation of sclerotomal cells.

PMID- 12490555
TI  - Snail precedes slug in the genetic cascade required for the specification and
      migration of the Xenopus neural crest.
AB  - The complex sequence of inductive events responsible for the generation of the
      neural crest at the border between the neural plate and the epidermis, triggers a
      genetic cascade involving several families of transcription factors. Two members
      of the Snail family, Snail and Slug, have both been implicated in this cascade.
      In chick and Xenopus, loss- and gain-of-function experiments have provided
      evidence that Slug plays a key role in neural crest development. However, in
      contrast to the chick, Snail rather than Slug is expressed in the premigratory
      neural crest in the mouse and, in Xenopus, Snail precedes Slug expression in this
      population. Thus, in order to study the function of Snail in neural crest
      development in Xenopus, we have carried out conditional gain- and loss-of
      function experiments using different Snail constructs fused to a glucocorticoid
      receptor element. We show that Snail is able to induce the expression of Slug and
      all other neural crest markers tested (Zic5, FoxD3, Twist and Ets1) at the time
      of specification. This activation is observed in whole embryos and in animal
      caps, in the absence of neural plate and mesodermal markers. We show that Snail
      is required for neural crest specification and migration and that it works as a
      transcriptional repressor. These functions have been previously attributed to
      SLUG: However, Slug alone is unable to induce other neural crest markers in
      animal cap assays, and we show that Snail and Slug can be functionally equivalent
      when tested in overexpression studies. This suggests that, in Xenopus embryos, at
      least some of the functions previously attributed to Slug can be carried out by
      SNAIL: This is additionally supported by rescue experiments in embryos injected
      with dominant-negative constructs that indicate that Snail lies upstream of Slug
      in the genetic cascade leading to neural crest formation and that it plays a key
      role in crest development.

PMID- 12490556
TI  - Functional ablation of the mouse Ldb1 gene results in severe patterning defects
      during gastrulation.
AB  - The LIM domain-binding protein 1 (Ldb1) is found in multi-protein complexes
      containing various combinations of LIM-homeodomain, LIM-only, bHLH, GATA and Otx
      transcription factors. These proteins exert key functions during embryogenesis.
      Here we show that targeted deletion of the Ldb1 gene in mice results in a
      pleiotropic phenotype. There is no heart anlage and head structures are truncated
      anterior to the hindbrain. In about 40% of the mutants, posterior axis
      duplication is observed. There are also severe defects in mesoderm-derived
      extraembryonic structures, including the allantois, blood islands of the yolk
      sack, primordial germ cells and the amnion. Abnormal organizer gene expression
      during gastrulation may account for the observed axis defects in Ldb1 mutant
      embryos. The expression of several Wnt inhibitors is curtailed in the mutant,
      suggesting that Wnt pathways may be involved in axial patterning regulated by
      Ldb1.

PMID- 12490557
TI  - Cell autonomous requirement for PDGFRalpha in populations of cranial and cardiac
      neural crest cells.
AB  - Cardiac and cephalic neural crest cells (NCCs) are essential components of the
      craniofacial and aortic arch mesenchyme. Genetic disruption of the platelet
      derived growth factor receptor alpha (PDGFRalpha) results in defects in multiple
      tissues in the mouse, including neural crest derivatives contributing to the
      frontonasal process and the aortic arch. Using chimeric analysis, we show that
      loss of the receptor in NCCs renders them inefficient at contributing to the
      cranial mesenchyme. Conditional gene ablation in NCCs results in neonatal
      lethality because of aortic arch defects and a severely cleft palate. The
      conotruncal defects are first observed at E11.5 and are consistent with aberrant
      NCC development in the third, fourth and sixth branchial arches, while the bone
      malformations present in the frontonasal process and skull coincide with defects
      of NCCs from the first to third branchial arches. Changes in cell proliferation,
      migration, or survival were not observed in PDGFRalpha NCC conditional embryos,
      suggesting that the PDGFRalpha may play a role in a later stage of NCC
      development. Our results demonstrate that the PDGFRalpha plays an essential, cell
      autonomous role in the development of cardiac and cephalic NCCs and provides a
      model for the study of aberrant NCC development.

PMID- 12490558
TI  - The promoter targeting sequence facilitates and restricts a distant enhancer to a
      single promoter in the Drosophila embryo.
AB  - Transcriptional enhancers in large gene complexes activate promoters over huge
      distances, yet little is known about the mechanism of these long-range
      interactions. We report that the promoter targeting sequence (PTS) from the
      Abdominal-B locus of the Drosophila bithorax complex facilitates the activity of
      a distantly located enhancer in transgenic embryos and that it restricts the
      enhancer to a single promoter. These functions are heritable in all successive
      generations. We also show that the PTS functions only when itself and an
      insulator are located between the enhancer and the promoter. These findings
      suggest that the PTS may facilitate long-range enhancer-promoter interactions in
      the endogenous Abdominal-B locus. We propose that the PTS establishes a stable
      chromatin structure between an enhancer and a promoter, which facilitates yet
      restricts an enhancer to a single promoter.

PMID- 12490559
TI  - The chick oligozeugodactyly (ozd) mutant lacks sonic hedgehog function in the
      limb.
AB  - We have analyzed a new limb mutant in the chicken that we name oligozeugodactyly
      (ozd). The limbs of this mutant have a longitudinal postaxial defect, lacking the
      posterior element in the zeugopod (ulna/fibula) and all digits except digit 1 in
      the leg. Classical recombination experiments show that the limb mesoderm is the
      defective tissue layer in ozd limb buds. Molecular analysis revealed that the ozd
      limbs develop in the absence of Shh expression, while all other organs express
      Shh and develop normally. Neither Ptc1 nor Gli1 are detectable in mutant limb
      buds. However, Bmp2 and dHAND are expressed in the posterior wing and leg bud
      mesoderm, although at lower levels than in normal embryos. Activation of Hoxd11
      13 occurs normally in ozd limbs but progressively declines with time. Phase III
      of expression is more affected than phase II, and expression is more severely
      affected in the more 5' genes. Interestingly, re-expression of Hoxd13 occurs at
      late stages in the distal mesoderm of ozd leg buds, correlating with formation of
      digit 1. Fgf8 and Fgf4 expression are initiated normally in the mutant AER but
      their expression is progressively downregulated in the anterior AER. Recombinant
      Shh protein or ZPA grafts restore normal pattern to ozd limbs; however, retinoic
      acid fails to induce Shh in ozd limb mesoderm. We conclude that Shh function is
      required for limb development distal to the elbow/knee joints, similar to the
      Shh(-/-) mouse. Accordingly we classify the limb skeletal elements as Shh
      dependent or independent, with the ulna/fibula and digits other than digit 1 in
      the leg being Shh dependent. Finally we propose that the ozd mutation is most
      likely a defect in a regulatory element that controls limb-specific expression of
      Shh.

PMID- 12490560
TI  - Genetic rescue of cell number in a mouse model of microphthalmia: interactions
      between Chx10 and G1-phase cell cycle regulators.
AB  - Insufficient cell number is a primary cause of failed retinal development in the
      Chx10 mutant mouse. To determine if Chx10 regulates cell number by antagonizing
      p27(Kip1) activity, we generated Chx10, p27(Kip1) double null mice. The severe
      hypocellular defect in Chx10 single null mice is alleviated in the double null,
      and while Chx10-null retinas lack lamination, double null retinas have near
      normal lamination. Bipolar cells are absent in the double null retina, a defect
      that is attributable to a requirement for Chx10 that is independent of p27(Kip1).
      We find that p27(Kip1) is abnormally present in progenitors of Chx10-null
      retinas, and that its ectopic localization is responsible for a significant
      amount of the proliferation defect in this microphthalmia model system. mRNA and
      protein expression patterns in these mice and in cyclin D1-null mice suggest that
      Chx10 influences p27(Kip1) at a post-transcriptional level, through a mechanism
      that is largely dependent on cyclin D1. This is the first report of rescue of
      retinal proliferation in a microphthalmia model by deletion of a cell cycle
      regulatory gene.

PMID- 12490561
TI  - A re-evaluation of the contributions of Apterous and Notch to the dorsoventral
      lineage restriction boundary in the Drosophila wing.
AB  - The Drosophila limb primordia are subdivided into compartments: cell populations
      that do not mix during development. The wing is subdivided into dorsal (D) and
      ventral (V) compartments by the activity of the selector gene apterous in D
      cells. Apterous causes segregation of D and V cell populations by at least two
      distinct mechanisms. The LRR transmembrane proteins Capricious and Tartan are
      transiently expressed in D cells and contribute to initial segregation of D and V
      cells. Signaling between D and V cells mediated by Notch and Fringe contributes
      to the maintenance of the DV affinity boundary. Given that Notch is activated
      symmetrically, in D and V cells adjacent to the boundary, its role in boundary
      formation remains somewhat unclear. We re-examine the roles of Apterous and
      Fringe activities in DV boundary formation and present evidence that Fringe
      cannot, by itself, generate an affinity difference between D and V cells.
      Although not sufficient, Fringe is required via Notch activation for expression
      of an Apterous-dependent affinity difference. We propose that Apterous controls
      expression of surface proteins that confer an affinity difference in conjunction
      with activated Notch. Thus, we view Apterous as instructive and Notch activity as
      essential, but permissive.

PMID- 12490562
TI  - Transcriptional activation in Drosophila spermatogenesis involves the mutually
      dependent function of aly and a novel meiotic arrest gene cookie monster.
AB  - In Drosophila spermatogenesis, meiotic cell cycle progression and cellular
      differentiation are linked by the function of the meiotic arrest genes. The
      meiotic arrest genes control differentiation by regulating the transcriptional
      activation of many differentiation-specific genes. The meiotic arrest genes have
      been subdivided into aly and can classes, based on the mechanism by which they
      control cell cycle progression. aly has previously been shown to encode a
      chromatin-associated protein. We present the identification, cloning and
      characterisation of a novel Drosophila meiotic arrest gene, cookie monster
      (comr), that has a mutant phenotype indistinguishable from that of aly. A null
      mutant allele of comr is viable but male sterile. Mutant primary spermatocytes
      fail to initiate transcription of a large number of genes, and arrest before
      entry into the meiotic divisions. In adult males, expression of comr is testis
      specific, low levels of transcripts are detected at other stages of development.
      comr encodes a novel acidic protein, which is nuclear and primarily localised to
      regions of chromatin in primary spermatocytes. The nuclear localisation of Aly
      and Comr proteins are mutually dependent. Finally, we show that active RNA
      polymerase II is found in distinct domains in the nucleus that constitute a
      subset of the total Comr stained chromatin.

PMID- 12490563
TI  - Evidence for a direct functional antagonism of the selector genes proboscipedia
      and eyeless in Drosophila head development.
AB  - Diversification of Drosophila segmental and cellular identities both require the
      combinatorial function of homeodomain-containing transcription factors. Ectopic
      expression of the mouthparts selector proboscipedia (pb) directs a homeotic
      antenna-to-maxillary palp transformation. It also induces a dosage-sensitive eye
      loss that we used to screen for dominant Enhancer mutations. Four such Enhancer
      mutations were alleles of the eyeless (ey) gene that encode truncated EY
      proteins. Apart from eye loss, these new eyeless alleles lead to defects in the
      adult olfactory appendages: the maxillary palps and antennae. In support of these
      observations, both ey and pb are expressed in cell subsets of the prepupal
      maxillary primordium of the antennal imaginal disc, beginning early in pupal
      development. Transient co-expression is detected early after this onset, but is
      apparently resolved to yield exclusive groups of cells expressing either PB or EY
      proteins. A combination of in vivo and in vitro approaches indicates that PB
      suppresses EY transactivation activity via protein-protein contacts of the PB
      homeodomain and EY Paired domain. The direct functional antagonism between PB and
      EY proteins suggests a novel crosstalk mechanism integrating known selector
      functions in Drosophila head morphogenesis.

PMID- 12490564
TI  - Wnt2b controls retinal cell differentiation at the ciliary marginal zone.
AB  - The ciliary marginal zone of the vertebrate retina contains undifferentiated
      progenitor cells that continue to proliferate and add new neurons and glia
      peripherally during the embryonic stages - even after the formation of a
      functional retina. To understand the molecular mechanism that controls the
      prolonged progenitor cell proliferation in the ciliary marginal zone, we employed
      a candidate molecule approach, focusing on Wnt2b (formerly know as Wnt13), which
      is expressed in the marginal most tip of the retina. Frizzled 4 and 5, seven-pass
      transmembrane Wnt receptors, were expressed in the peripheral and central part of
      the retina, respectively. LEF1, a downstream Wnt signaling component, was
      expressed at high levels in the ciliary marginal zone with expression gradually
      decreasing towards the central retina. The LEF1-expressing region, which is where
      Wnt signaling is supposedly activated, expressed a set of molecular markers that
      are characteristic of the progenitor cells in the ciliary marginal zone.
      Overexpression of Wnt2b by use of in ovo electroporation in the central retina
      inhibited neuronal differentiation and induced the progenitor cell markers.
      Blocking of the Wnt downstream signaling pathway by a dominant-negative LEF1
      inhibited proliferation of the cells in the marginal area, which resulted in
      their premature neuronal differentiation. The progenitor cells in the ciliary
      marginal zone differentiated into all the neuronal and glial cell types when
      cultured in vitro, and they proliferated for a longer period than did centrally
      located progenitor cells that underwent a limited number of cell divisions. In
      addition, the proliferation of these progenitor cells was promoted in the
      presence of Wnt2b. These results suggest that Wnt2b functions to maintain
      undifferentiated progenitor cells in the ciliary marginal zone, and thus serves
      as a putative stem cell factor in the retina.

PMID- 12490565
TI  - Identification of spatial and temporal cues that regulate postembryonic
      expression of axon maintenance factors in the C. elegans ventral nerve cord.
AB  - Patterns of gene expression are under precise spatial and temporal control. A
      particularly striking example is represented by several members of the zig gene
      family, which code for secreted immunoglobulin domain proteins required for
      maintaining ventral nerve cord organization in Caenorhabditis elegans. These
      genes are coordinately expressed in a single interneuron in the ventral nerve
      cord, known as PVT. Their expression is initiated at a precise postembryonic
      stage, long after PVT has been generated in mid-embryogenesis. We define spatial
      and temporal cues that are required for the precise regulation of zig gene
      expression. We find that two LIM homeobox genes, the Lhx3-class gene ceh-14 and
      the Lmx-class gene lim-6 are coordinately required for zig gene expression in
      PVT. Temporal control of zig gene expression is conferred by the heterochronic
      gene lin-14, a nuclear factor previously implicated in developmental timing in
      various contexts. Loss of the lim-6 and ceh-14 transcription factors and the
      developmental timer lin-14 cause not only a loss of zig gene expression but also
      lead to defects in the maintenance of ventral nerve cord architecture. Overriding
      the normal spatiotemporal control of zig gene expression through expression of
      one of the zig genes under control of heterologous promoters also causes axon
      patterning defects in the ventral nerve cord. Our findings illustrate the
      importance of spatial and temporal control of gene expression in the nervous
      system and, furthermore, implicate heterochronic genes in postmitotic neural
      patterning events.

PMID- 12490566
TI  - Differential effects of cortical neurotrophic factors on development of lateral
      geniculate nucleus and superior colliculus neurons: anterograde and retrograde
      actions.
AB  - Neurotrophins strongly affect visual system development and plasticity. However,
      the mode of delivery and targets of neurotrophin action are still under debate.
      For instance, cortical NT-4/5 (neurotrophin 4/5; Ntf4/5) was shown to rescue
      lateral geniculate nucleus (LGN) neurons from monocular deprivation-induced
      atrophy suggesting a retrograde action on thalamic afferents. It is still unclear
      whether LGN neurons respond to NT-4/5 and other neurotrophins during development
      in animals with normal vision. We now show that infusions of NT-4/5 and NGF
      (nerve growth factor) into visual cortex at the onset and the peak of the
      critical period accelerated LGN neuron growth. BDNF (brain-derived neurotrophic
      factor) was ineffective. The effects of neurotrophin on LGN development were
      clearly dissociated from the effects at cortical level because soma growth of
      cortical layer IV and VI neurons was strongly promoted by BDNF. NT-4/5 was only
      effective at the onset, but no longer at the peak of the critical period
      suggesting a switch in neurotrophin dependency for these cortical cell classes.
      To dissociate retrograde and anterograde effects of the TrkB ligands, we analyzed
      the stratum griseum superficiale (SGS) of the superior colliculus, a target of
      visual cortical efferents. Indeed, TrkB-expressing inhibitory SGS neurons
      responded to cortical NT-4/5 infusion with somatic growth. Strikingly, the TrkB
      expressing excitatory tectothalamic calbindin neurons in the SGS did not respond.
      This demonstrated for the first time a selective cell type-specific anterograde
      action of NT-4/5 and suggested for the LGN that anterograde as well as retrograde
      effects contribute to soma size regulation. Strikingly, cortical infusion of the
      cytokine LIF, which affects development of visual cortex neurochemical
      architecture, transiently inhibited growth of neurons in LGN, cortical layer IV
      and VI and SGS. In summary, the study presents three important results. First,
      central neurons regulate soma size development in an age-and ligand-specific
      fashion. Second, NT-4/5 and NGF accelerate LGN development in rats with normal
      vision while LIF delays growth. Third, anterogradely transported NT-4/5
      effectively promotes neuronal maturation. These differential actions on
      subcortical neurons may contribute to the different effects of neurotrophins on
      visual system development and plasticity.

PMID- 12490567
TI  - Tbx5 is essential for forelimb bud initiation following patterning of the limb
      field in the mouse embryo.
AB  - Transcriptional cascades responsible for initiating the formation of vertebrate
      embryonic structures such as limbs are not well established. Limb formation
      occurs as a result of interplay between fibroblast growth factor (FGF) and Wnt
      signaling. What initiates these signaling cascades and thus limb bud outgrowth at
      defined locations along the anteroposterior axis of the embryo is not known. The
      T-box transcription factor TBX5 is important for normal heart and limb formation,
      but its role in early limb development is not well defined. We report that mouse
      embryos lacking Tbx5 do not form forelimb buds, although the patterning of the
      lateral plate mesoderm into the limb field is intact. Tbx5 is not essential for
      an early establishment of forelimb versus hindlimb identity. In the absence of
      Tbx5, the FGF and Wnt regulatory loops required for limb bud outgrowth are not
      established, including initiation of Fgf10 expression. Tbx5 directly activates
      the Fgf10 gene via a conserved binding site, providing a simple and direct
      mechanism for limb bud initiation. Lef1/Tcf1-dependent Wnt signaling is not
      essential for initiation of Tbx5 or Fgf10 transcription, but is required in
      concert with Tbx5 for maintenance of normal levels of Fgf10 expression. We
      conclude that Tbx5 is not essential for the early establishment of the limb field
      in the lateral plate mesoderm but is a primary and direct initiator of forelimb
      bud formation. These data suggest common pathways for the differentiation and
      growth of embryonic structures downstream of T-box genes.

PMID- 12490568
TI  - Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms
      and strategies for therapeutic intervention.
AB  - Evidence from postmortem analysis implicates the involvement of microglia in the
      neurodegenerative process of several degenerative neurological diseases,
      including Alzheimer's disease and Parkinson's disease. It remains to be
      determined, however, whether microglial activation plays a role in the initiation
      stage of disease progression or occurs merely as a response to neuronal death.
      Activated microglia secrete a variety of proinflammatory and neurotoxic factors
      that are believed to induce and/or exacerbate neurodegeneration. In this article,
      we summarize recent advances on the study of the role of microglia based on
      findings from animal and cell culture models in the pathogenesis of
      neurodegenerative diseases, with particular emphasis on Parkinson's disease. In
      addition, we also discuss novel approaches to potential therapeutic strategies.

PMID- 12490569
TI  - Inhibition of p38 mitogen-activated protein kinase blocks activation of rat
      pancreatic stellate cells.
AB  - Activated pancreatic stellate cells (PSCs) have recently been implicated in the
      pathogenesis of pancreatic fibrosis and inflammation. However, the signal
      transduction pathways in PSCs remain largely unknown. We examined the role of p38
      mitogen-activated protein (MAP) kinase in the activation of PSCs. PSCs were
      isolated from rat pancreas tissue and used in their culture-activated,
      myofibroblast-like phenotype. Activation of p38 MAP kinase was determined by
      Western blotting using anti-phosphospecific antibody. The effects of two p38 MAP
      kinase inhibitors, 4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4
      pyridyl)imidazole (SB203580) and 4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4
      pyridyl)1H-imidazole (SB202190), on the parameters of PSC activation, including
      proliferation, expression of alpha-smooth muscle actin, alpha1(I) procollagen,
      and prolyl 4-hydroxylase (alpha) genes, and monocyte chemoattractant protein-1
      production were evaluated. Interleukin-1beta and platelet-derived growth factor
      BB activated p38 MAP kinase. Platelet-derived growth factor-induced PSC
      proliferation was inhibited by SB203580 and SB202190. These reagents decreased
      alpha-smooth muscle actin protein expression, and alpha1(I) procollagen and
      prolyl 4-hydroxylase (alpha) mRNA levels. Treatment with these p38 MAP kinase
      inhibitors also resulted in inhibition of monocyte chemoattractant protein-1
      expression. In addition, SB203580 inhibited spontaneous activation of freshly
      isolated PSCs in culture on plastic. Thus, inhibition of p38 MAP kinase modulated
      profibrogenic and proinflammatory actions in PSCs, implying a potential
      application of p38 MAP kinase inhibitors for the treatment of pancreatic fibrosis
      and inflammation.

PMID- 12490570
TI  - Withdrawal from repeated cocaine alters dopamine transporter protein turnover in
      the rat striatum.
AB  - Several studies have shown that repeated cocaine administration, followed by
      withdrawal, alters dopamine transporter (DAT) levels in the rat. These changes
      must arise from changes in either transporter protein production or degradation,
      or both. Previously, our laboratory developed an approach to measure the
      synthesis rate, degradation rate constant, and half-life of DAT in the rat
      striatum and nucleus accumbens after administration of the irreversible dopamine
      transporter ligand, RTI-76 [3beta-(3-p-chlorophenyl)tropan-2beta-carboxylic acid
      p-isothiocyanatophenylethyl ester hydrochloride]. Transporter binding was
      measured with [(3)H]GBR12935 [1-(2-[diphenylmethoxy]ethyl)-4-[3
      phenylpropyl]piperazine]. These initial studies showed that: 1) the half-life of
      the transporter was between 2 and 3 days in these two brain regions; 2)
      pretreatment with dopamine D1 and D2 receptor agonists and antagonists over
      several days differentially altered DAT half-lives in the striatum and nucleus
      accumbens; and 3) pretreatment with cocaine for several days increased the half
      life of DAT by decreasing the degradation rate constant in both brain regions. In
      the present study, we determined that repeated pretreatment (10 days) with 20
      mg/kg cocaine (i.p.) and a subsequent withdrawal period (10 days) alters the
      dopamine transporter turnover in the rat striatum, but not in the nucleus
      accumbens. Cocaine pretreatment and withdrawal reduced the half-life of the
      transporter protein from 2.1 days to 0.94 day in the striatum, but did not alter
      the half-life of 2.2 days in the nucleus accumbens. The results indicate the
      complex and long-lasting effects of cocaine administration on cellular processes.
      The mechanism(s) of these effects remains to be elucidated.

PMID- 12490571
TI  - Role of nitric oxide in chronic allergen-induced airway cell proliferation and
      inflammation.
AB  - Chronic cellular inflammation and airway wall remodeling with subepithelial
      fibrosis and airway smooth muscle thickening are features of chronic asthma. We
      determined the role of nitric oxide in the pathogenesis of allergen-induced
      airway cell proliferation and inflammation by studying the effects of a
      relatively selective prodrug inhibitor of nitric-oxide synthase type 2 (NOS2), L
      N6-(1-iminoethyl)-lysine-5-tetrazole amide (SC-51). Brown-Norway rats were
      sensitized to ovalbumin and were exposed to ovalbumin aerosol every 3rd day on
      six occasions and were treated orally with either vehicle or SC-51 (10 mg. kg(
      1); 12 doses). We measured inflammatory cell accumulation in the airways and
      proliferation of cells by incorporation of bromodeoxyuridine. There was an
      increase in the total number of airway smooth muscle cells expressing
      bromodeoxyuridine from 1.3% of airway smooth muscle cells in saline exposed to
      5.4% after allergen-exposure (P < 0.001) and airway epithelial cells from 3.3
      cells/mm basement membrane to 9.6 after allergen-exposure (P < 0.001). SC-51 had
      no effect on airway smooth muscle or epithelial cell proliferation. SC-51
      attenuated the allergen-induced increase in major basic protein (MBP+) eosinophil
      (P < 0.05) and CD4+ T-cell (P < 0.05) accumulation. We conclude that nitric oxide
      derived during allergic inflammation is involved in the expression of
      eosinophilic inflammation and not in epithelial or airway smooth muscle cell DNA
      synthesis induced by chronic allergen exposure.

PMID- 12490572
TI  - Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of
      alcohol and other drugs.
AB  - Enhancement of the activation of GABAA receptors is a common feature of many
      sedative and hypnotic drugs, and it is probable that the GABAA receptor complex
      is a molecular target for these drugs in the mammalian central nervous system. We
      set out to elucidate the role of the two predominant (alpha1 and beta2) subunits
      of GABAA receptor in sedative drug action by studying mice lacking these two
      subunits. Both alpha1 (-/-) and beta2 (-/-) null mutant mice showed markedly
      decreased sleep time induced by nonselective benzodiazepine, flurazepam, and
      GABAA agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol. The sleep time
      induced by the beta-selective drug etomidate was decreased only in beta2 (-/-)
      knockout mice. In contrast, alpha1 (-/-) mice were more resistant to the alpha1
      selective drug zolpidem than beta2 (-/-) or wild-type animals. Knockout mice of
      both strains were similar to wild-type mice in their responses to pentobarbital.
      The duration of loss of the righting reflex produced by ethanol was decreased in
      male mice for both null alleles compared with wild-type mice, but there were no
      differences in ethanol-induced sleep time in mutant females. Deletion of either
      the alpha1 or beta2 subunits reduced the muscimol-stimulated 36Cl36 influx in
      cortical microsacs suggesting that these mutant mice have reduced number of
      functional brain GABAA receptors. Our results show that removal of either alpha1
      or beta2 subunits of GABAA receptors produce strong and selective decreases in
      hypnotic effects of different drugs. Overall, these data confirm the crucial role
      of the GABAA receptor in mechanisms mediating sedative/hypnotic effects.

PMID- 12490573
TI  - c-myc down-regulation induces apoptosis in human cancer cell lines exposed to RPR
      115135 (C31H29NO4), a non-peptidomimetic farnesyltransferase inhibitor.
AB  - A therapeutic strategy that relies on the use of c-myc antisense in combination
      with a farnesyltransferase inhibitor, RPR-115135 (C31H29NO4), was studied in
      human cancer cell lines carrying different mutations (Ras, p53, myc
      amplification). Cell proliferation was strongly inhibited by the combination and
      was observed when c-myc oligo (at a concentration that down-regulates c-myc
      expression) was followed by RPR-115135. Cell cycle analysis demonstrated an
      accumulation in G0-G1 phase and a tendency to apoptosis (not detectable in cells
      treated with a single agent). Morphological examination and DNA fragmentation
      assays (filter binding and enzyme-linked immunosorbent assay DNA fragmentation)
      confirmed the induction of apoptosis. Apoptosis was not p53- and/or p21(waf-1)
      dependent, and the key effector was caspase activation. The combination induced
      Bax expression and Bcl-2 inhibition. Down-regulation of c-myc amplification
      carried out a specific role exclusively when Ras was mutated. Exposure of human
      proliferating lymphocytes to combination did not result in cytotoxicity,
      suggesting that mechanisms regulating c-myc gene expression during normal T cell
      proliferation might not be involved. Because of the high percentage of human
      tumors overexpressing c-myc mRNA and/or protein and, simultaneously, harboring
      oncogenic Ras mutants (i.e., colon cancers), interrupting the myc- and Ras
      signaling pathway would be one of the major focuses on therapy of these types of
      tumors.

PMID- 12490574
TI  - Inhibitory effect of beta3-adrenoceptor agonist in lower esophageal sphincter
      smooth muscle: in vitro studies.
AB  - We investigated the effects of (R,R)-5-[2-[2-3-chlorophenyl)-2-hydroxyethyl] -
      amino]propyl] - 1,3 - benzodioxole - 2, 2 - dicarboxylate (CL 316243) (a typical
      beta3-agonist) on the spontaneously tonic smooth muscle of the lower esophageal
      sphincter (LES). Studies were carried out in smooth muscle strips and smooth
      muscle cells (SMCs) of opossum LES. Isometric tension was recorded in the basal
      state and after CL 316243, and before and after beta3-antagonist (S)-N-[4-[2-[[3
      [-(acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]ethyl]phenyl]benzenesulfonamide
      (L 748337) and nonselective antagonist propranolol. In some experiments, the
      effects of nonadrenergic noncholinergic (NANC) nerve activation by electrical
      field stimulation (EFS) were also examined. The effects of CL 316243 were
      compared with those of nonselective beta-agonist isoproterenol. CL 316243 caused
      a concentration-dependent relaxation of the LES smooth muscle. The relaxant
      action of CL 316243 was determined to be directly at the smooth muscle because it
      remained unmodified by the neurotoxin tetrodotoxin and other neurohumoral
      antagonists, and also was observed in the SMCs. L 748337 selectively antagonized
      the relaxant effect of CL 316243 and, conversely, had no significant effect on
      the inhibitory actions of isoproterenol. CL 316243 (1 x 10(-8) M) caused an
      augmentation of NANC relaxation in the LES. Another beta3-agonist, (S)-4-[hydroxy
      3-phenoxy-propylamino-ethoxy]-N-(2-methoxyethyl)-phenoxyacetamide (ZD 7114), also
      caused concentration-dependent full relaxation of the LES that was selectively
      antagonized by beta3-anatagonist 3-(2-ethylphenoxy)-1-[(1S)1,2,3,4
      tetrahydronaphth-1-ylaminol]-(2S)-2-propanol oxalate (SR 59230A). These studies
      defined the effects of characteristic inhibitory beta3-adrenoceptors in the
      spontaneously tonic LES smooth muscle and suggested a potential therapeutic role
      in the esophageal motility disorders characterized by hypertensive LES.

PMID- 12490575
TI  - The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of
      inflammatory and neuropathic pain.
AB  - Vanilloid receptor type 1 (VR1) (TRPV1) is a ligand-gated ion channel expressed
      on sensory nerves that responds to noxious heat, protons, and chemical stimuli
      such as capsaicin. Herein, we have examined the activity of the VR1 antagonist
      capsazepine in models of inflammatory and neuropathic pain in the rat, mouse, and
      guinea pig. In naive animals, subcutaneous administration of capsazepine (10-100
      mg/kg s.c.) did not affect withdrawal thresholds to noxious thermal or mechanical
      stimuli. However, pretreatment with capsazepine prevented the development of
      mechanical hyperalgesia induced by intraplantar injection of capsaicin, with a
      similar potency in all three species. Capsazepine (up to 100 mg/kg s.c.) did not
      affect mechanical hyperalgesia in the Freund's complete adjuvant (FCA)-inflamed
      hind paw of the rat or mouse. Strikingly, capsazepine (3-30 mg/kg s.c.) produced
      up to 44% reversal of FCA-induced mechanical hyperalgesia in the guinea pig.
      Capsazepine also produced significant reversal of carageenan-induced thermal
      hyperalgesia in the guinea pig at 30 mg/kg s.c., but was ineffective in the rat.
      Similarly, in the partial sciatic nerve ligation model of neuropathic pain,
      capsazepine was surprisingly effective in the guinea pig, producing up to 80%
      reversal of mechanical hyperalgesia (1-30 mg/kg s.c.) but had no effect in the
      rat or mouse. These data show that VR1 antagonists have antihyperalgesic activity
      in animal models of chronic inflammatory and neuropathic pain, and illustrate
      species differences in the in vivo pharmacology of VR1 that correlate with
      differences in pharmacology previously seen in vitro.

PMID- 12490576
TI  - Calpain mediates progressive plasma membrane permeability and proteolysis of
      cytoskeleton-associated paxillin, talin, and vinculin during renal cell death.
AB  - The goal of the present study was to determine the role of calpain in changes in
      plasma membrane permeability and cytoskeleton-associated paxillin, vinculin,
      talin, and alpha-actinin levels during acute renal cell death. The mitochondrial
      inhibitor antimycin A or hypoxia produced graded plasma membrane permeability in
      renal proximal tubules (RPTs), first allowing propidium iodide (PI, molecular
      mass 668 Da) influx and then lactate dehydrogenase (LDH, molecular mass 130 kDa)
      release. Cytoskeleton-associated paxillin levels decreased concomitantly with PI
      influx and before LDH release, whereas cytoskeleton-associated talin and vinculin
      levels decreased concomitantly with LDH release. Cytoskeleton-associated alpha
      actinin levels did not change during antimycin A exposure or hypoxia. Purified
      micro-calpain cleaved paxillin, talin, vinculin, but not alpha-actinin. The
      dissimilar calpain inhibitors 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid
      (PD150606) or chloroacetic acid N'-[6,7-dichloro-4-phenyl)-3-oxo-3,4
      dihydroquinoxalin-2-yl] hydrazide (SJA7029) preserved cytoskeleton-associated
      paxillin, talin, and vinculin levels and prevented PI influx and LDH release in
      antimycin A-exposed or hypoxic RPTs. These results suggest that calpain mediates
      increased plasma membrane permeability and hydrolysis of cytoskeleton-associated
      paxillin, vinculin, and talin during renal cell death.

PMID- 12490577
TI  - Hydrophobic and ionic factors in the binding of local anesthetics to the major
      variant of human alpha1-acid glycoprotein.
AB  - Understanding the interaction of local anesthetics (LAs) with plasma proteins is
      essential to understanding their systemic pharmacology and toxicology. The
      molecular determinants of LA binding to the major variant (F1*S) of human alpha1
      acid glycoprotein (AGP) were therefore investigated spectrofluorometrically using
      whole AGP and a novel, F1*S variant-selective probe previously developed in our
      laboratory. Equilibrium- competitive displacement of this probe by LAs, observed
      by the recovery of AGP's fluorescence as the quenching probe was displaced from
      its high-affinity site, was characterized by inhibitory dissociation constants
      for the various LAs. The importance of electrostatic factors was assessed by
      examining the pH dependent binding of an ionizable LA, lidocaine, using the
      quaternary lidocaine derivative QX-314 [N-(2,6-dimethylphenylcarbamoylmethyl)
      triethylammonium chloride] to control for pH dependent ionization of AGP.
      Uncharged lidocaine bound with at least 8 times the affinity of protonated
      lidocaine (K(D) = 4.0 +/- 0.6 microM and >32 microM, respectively). This result
      is inconsistent with the current model of the AGP-binding site, which depicts a
      buried pocket having a negatively charged region that interacts with the amino
      termini of basic drugs. Consistent with the model, however, two sets of
      structurally homologous LAs (mepivacaine, ropivacaine, bupivacaine, and
      lidocaine, RAD-240, RAD-241, RAD-242, L-30, W-6603) demonstrated a strong
      positive correlation between hydrophobicity (measured as the octanol:buffer
      partition coefficient of the neutral species) and their free energies of
      dissociation. Given that the tertiary structure of AGP has proven refractory to
      resolution, these structure-activity studies should contribute to understanding
      the nature of the binding site on this important protein.

PMID- 12490578
TI  - Pharmacological characterization of N,N-dimethyl-2-(2-amino-4-methylphenyl
      thio)benzylamine as a ligand of the serotonin transporter with high affinity and
      selectivity.
AB  - Serotonin transporter has a key-role in regulation of serotoninergic function,
      and is involved in numerous neurodegenerative and psychiatric disorders. To
      obtain an efficient radioactive ligand allowing the study of this transporter in
      vitro and in vivo, we synthesized a new diphenyl sulfide derivative, N,N-dimethyl
      2-(2-amino-4-methylphenylthio)benzylamine or MADAM. We present here extensive
      pharmacological characterization of this compound. [3H]MADAM bound to serotonin
      transporters with a very high affinity in vitro on rat cortical membranes, at
      least 2 times better than the most commonly used radioactive probes (Kd, 60 pM;
      Bmax, 543 fmol/mg of protein). Competition studies showed few inhibitory effect
      of nisoxetine (Ki = 270 nM), no inhibitory effect of desipramine or 1-[2
      (diphenylmethoxy) ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935) (Ki >1000 nM),
      and strong effect of paroxetine (Ki = 0.32 nM) and citalopram (Ki = 1.57 nM).
      Therefore, MADAM has around 1000-fold better selectivity for the serotonin
      transporter than for other transporters. Autoradiographic studies both on rat and
      postmortem human brain slices demonstrated that the distribution of [3H]MADAM
      parallels the localization of serotonin transporters and is prevented by known
      inhibitors of them. The high affinity and selectivity of [3H]MADAM for the
      serotonin transporter show that it is very valuable for studies using in vitro
      approaches. The high selectivity and low nonspecific binding of [3H]MADAM on the
      postmortem human brain, together with preliminary in vivo results with
      [11C]MADAM, is a new argument for future use of this ligand in in vivo studies of
      the distribution, pharmacology, and pathophysiology of the serotonin transporter
      in the human brain with positron emission tomography.

PMID- 12490579
TI  - Mechanism-based pharmacokinetic/pharmacodynamic modeling of the
      electroencephalogram effects of GABAA receptor modulators: in vitro-in vivo
      correlations.
AB  - A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model for neuroactive
      steroids, comprising a separate characterization of 1) the receptor activation
      process and 2) the stimulus-response relationship, was applied to various
      nonsteroidal GABAA receptor modulators. The EEG effects of nine prototypical
      GABAA receptor modulators (six benzodiazepines, one imidazopyridine, one
      cyclopyrrolone, and one beta-carboline) were determined in rats in conjunction
      with plasma concentrations. Population PK/PD modeling revealed monophasic
      concentration-EEG effect relationships with large differences in potency (EC50)
      and intrinsic activity between the compounds. The data were analyzed on the basis
      of the mechanism-based PK/PD model for (synthetic) neuroactive steroids on the
      assumption of a single and unique stimulus-response relationship. The model
      converged yielding estimates of both the apparent in vivo receptor affinity (KPD)
      and the in vivo intrinsic efficacy (ePD). The values of KPD ranged from 0.41 +/-
      0 ng.ml(-1) for bretazenil to 436 +/- 72 ng.ml(-1) for clobazam and the values
      for e(PD) from -0.27 +/- 0 for methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3
      carboxylate to 0.54 +/- 0.02 for diazepam. Significant linear correlations were
      observed between KPD for unbound concentrations and the affinity in an in vitro
      receptor bioassay (r = 0.93) and between e(PD) and the GABA-shift in vitro (r =
      0.95). The findings of this investigation show that the in vivo effects of
      nonsteroidal GABAA receptor modulators and (synthetic) neuroactive steroids can
      be described on the basis of a single unique transducer function. In this
      paradigm, the nonsteroidal GABAA receptor modulators behave as partial agonists
      relative to neuroactive steroids.

PMID- 12490580
TI  - Antinociceptive effects of interleukin-4, -10, and -13 on the writhing response
      in mice and zymosan-induced knee joint incapacitation in rats.
AB  - The antinociceptive effects of interleukin (IL)-4, -10, and -13 were investigated
      in two different experimental pain models. Our results showed that pretreatment
      (30 min) with IL-4 (1-5 ng/animal), IL-10 (0.4-10 ng/animal), or IL-13 (0.4-2.5
      ng/animal) inhibited the writhing response induced by the i.p. administration of
      acetic acid (53-89%) or zymosan (63-74%) in mice, and the knee joint
      incapacitation induced by i.a. injection of zymosan (49-66%) in rats. Neither of
      the cytokines affected the pain elicited in mice using the hot-plate test. This
      analgesic effect of IL-4, -10, and -13 was not reversed by the combined
      pretreatment with the opioid receptor antagonist naloxone. IL-4, -10, or -13
      significantly inhibited the release of both tumor necrosis factor (TNF)-alpha
      (60, 53, and 100%, respectively) and IL-1beta (80, 100, and 100%, respectively)
      by mice peritoneal macrophages obtained after local (i.p.) injection of zymosan.
      Antisera against IL-4, -10, and -13 potentiated both the zymosan-induced writhing
      response and the articular incapacitation. Our results demonstrate that IL-4, 
      10, and -13 display analgesic activity that is probably not due to endogenous
      opioid release. This analgesic effect could be related to a peripheral mechanism,
      probably via the inhibition of the release of the pro-inflammatory cytokines TNF
      alpha and IL-1beta by resident peritoneal macrophages.

PMID- 12490581
TI  - Discriminative stimulus effects of positive GABAA modulators and other
      anxiolytics, sedatives, and anticonvulsants in untreated and diazepam-treated
      monkeys.
AB  - Positive GABAA modulators and other sedatives, anxiolytics, and anticonvulsants
      were used to evaluate mechanisms underlying the discriminative stimulus effects
      of midazolam in untreated monkeys and of flumazenil in monkeys treated with
      diazepam (5.6 mg/kg/day). Positive GABAA modulators at benzodiazepine (e.g.,
      flunitrazepam and abecarnil) and neuroactive steroid sites (e.g., androsterone)
      substituted for midazolam in all monkeys; the neuroactive steroids
      dihydroandrosterone and epipregnanolone substituted for midazolam in two of three
      monkeys. All positive GABAA modulators attenuated flumazenil in diazepam-treated
      monkeys; doses of flunitrazepam and abecarnil larger than doses substituting for
      midazolam were required to attenuate flumazenil, whereas doses of neuroactive
      steroids smaller than doses substituting for midazolam attenuated flumazenil.
      Drugs with mechanisms that do not predominantly involve allosteric modulation of
      GABA (e.g., buspirone, ketamine, valproic acid, and diphenhydramine) did not
      substitute for midazolam or flumazenil. However, valproic acid enhanced the
      midazolam discriminative stimulus and attenuated the flumazenil discriminative
      stimulus; diphenhydramine attenuated the midazolam discriminative stimulus. These
      results suggest that drugs not sharing a mechanism of action with benzodiazepines
      can modulate the behavioral effects of benzodiazepines. In addition, this study
      demonstrates that endogenous ligands, presumably by acting at neuroactive steroid
      sites on the GABAA receptor complex, share discriminative stimulus effects with
      benzodiazepines. This study also suggests that positive GABAA-modulating
      neuroactive steroids are especially potent in attenuating behavioral effects that
      are related to diazepam withdrawal.

PMID- 12490582
TI  - Mitochondrial dysfunction is an early manifestation of 1,1-dichloroethylene
      induced hepatotoxicity in mice.
AB  - Hepatotoxicity induced by 1,1-dichloroethylene (DCE) is mediated by cytochrome
      P450-dependent metabolism to reactive intermediates, including the epoxide. We
      have tested the hypothesis that mitochondria are a primary target of toxicity by
      investigating dose- and time-dependent effects of DCE on mitochondrial
      respiration. Hepatotoxicity, as assessed by serum alanine aminotransferase (ALT)
      activity, was evaluated. We have also determined the effectiveness of N-acetyl-L
      cysteine (NAC) in protecting against respiratory perturbations and
      hepatotoxicity. Liver mitochondria were isolated 2 h after DCE (50, 75, 100, 125,
      and 150 mg/kg) treatment. Glutamate (complex I)- and succinate (complex II)
      supported mitochondrial respiration was assessed by measurement of state 3 (ADP
      stimulated) and state 4 (resting) rates of oxygen consumption. The corresponding
      respiratory control ratios (RCRs, state 3/state 4) and ADP:O ratios were then
      calculated. A DCE dose of 125 mg/kg significantly inhibited glutamate- and
      succinate-supported state 3 respiration, leading to a significant reduction in
      corresponding RCRs and ADP:O ratios. In time-dependent studies, state 3
      respiration rates and RCRs for glutamate-supported respiration were significantly
      decreased as early as 20 min after DCE (125 mg/kg) treatment, whereas those for
      succinate-supported respiration were significantly decreased at 90 min.
      Additionally, ADP:O ratios for glutamate-supported respiration were significantly
      decreased starting at 60 min, and those for succinate-supported respiration at 90
      min. Alterations in mitochondrial function preceded significant increases in ALT
      activity, which was first manifested at 2 h. Pretreatment with NAC (1200 mg/kg)
      abrogated DCE-induced GSH depletion and inhibited disturbances in mitochondrial
      respiration. Moreover, NAC protected against increased ALT activity, suggesting
      that the protective effect of NAC is due to increased GSH for conjugation
      reactions and/or its antioxidant property. These results showed that DCE-mediated
      mitochondrial dysfunction is an early event that preceded the onset of
      hepatotoxicity.

PMID- 12490583
TI  - Slowing of the inactivation of cardiac voltage-dependent sodium channels by the
      amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran
      (KB130015).
AB  - -Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015 or KB) is a new
      drug, structurally related to amiodarone and to thyroid hormones. Its effects on
      cardiac voltage-dependent Na+ current (I Na) were studied in pig single
      ventricular myocytes at 22 degrees C using the whole-cell (with [Na+]i = [Na+]o =
      10 mM) and cell-attached patch-clamp techniques. KB markedly slowed I Na
      inactivation, due to the development of a slow-inactivating component (tau slow
      approximately equal 50 ms) at the expense of the normal, fast-inactivating
      component (tau fast approximately equal 2-3 ms). The effect was concentration
      dependent, with a half-maximally effective concentration (K0.5) of 2.1 micro M.
      KB also slowed the recovery from inactivation and shifted the voltage-dependent
      inactivation (DeltaV(0.5) = -15 mV; K0.5 > or = 6.9 micro M) and activation to
      more negative potentials. Intracellular cell dialysis with 10 micro M KB had
      marginal or no effect on inactivation and did not prevent the effect of
      extracellularly applied drug. In cell-attached patches, extracellular KB
      prolonged Na+ channel opening. Amiodarone (10 micro M) and 10 micro M 3,5,-diiodo
      L-thyropropionic acid had no effect on inactivation and did not prevent KB
      effects. 3,3',5-Triodo-L-thyronine (T3) also had no effect on inactivation, but
      at 10 micro M it increased I Na amplitude and partially prevented the slowing of
      inactivation by KB. These data suggest the existence of a binding site for KB and
      T3 on Na+ channels.

PMID- 12490584
TI  - Arachidonic acid-induced vasodilation of rat small mesenteric arteries is
      lipoxygenase-dependent.
AB  - We examined the mechanism of arachidonic acid-induced vasodilation in rat small
      mesenteric arteries and determined the primary arachidonic acid metabolites
      produced by these arteries. Responses to arachidonic acid in small mesenteric
      arteries from Sprague-Dawley rats were investigated in vitro in the presence or
      absence of endothelium or after pretreatment with inhibitors of nitric oxide
      (NO), cyclooxygenase, cytochrome P450, lipoxygenase, or K+ channels. In addition,
      the metabolism of arachidonic acid was examined by incubating arteries with
      [3H]arachidonic acid in the presence and absence of cyclooxygenase, cytochrome
      P450, or lipoxygenase inhibitors. Finally, the vascular response to both 12(S)
      hydroxyeicosatetraenoic acid (HETE) and 12(S)-hydroperoxyeicosatetraenoic acid
      (HPETE) was determined. Arachidonic acid induced an endothelium-dependent
      vasodilation that was abolished by lipoxygenase inhibitors [cin-namyl-3,4
      dihydroxy-cyanocinnamate (CDC) or 5,8,11-eicosatriynoic acid (ETI)] and KCl,
      whereas it was partially inhibited by either tetraethylammonium or iberiotoxin.
      In contrast, neither NO nor cytochrome P450 enzyme inhibitors affected
      arachidonic acid-mediated dilation, whereas inhibition of cyclooxygenase enhanced
      dilation. Biochemical analysis revealed that small mesenteric arteries primarily
      produce 12-HETE, a lipoxygenase metabolite. Moreover, CDC and ETI inhibited the
      production of 12-HETE. Finally, both 12(S)-HETE and 12(S)-HPETE induced a
      concentration-dependent vasodilation in mesenteric arteries. These findings
      provide functional and biochemical evidence that the lipoxygenase pathway
      mediates arachidonic acid-induced vasodilation in rat small mesenteric arteries
      through a K+ channel-dependent mechanism.

PMID- 12490585
TI  - Blockage of multidrug resistance-associated proteins potentiates the inhibitory
      effects of arsenic trioxide on CYP1A1 induction by polycyclic aromatic
      hydrocarbons.
AB  - Arsenic is a toxic metalloid known to interact with drug-metabolizing enzymes. In
      the present study, we investigated the effects of arsenic trioxide (As2O3),
      recently used as an anticancer drug, on the expression of human cytochrome P450
      (P450) 1A1, which bioactivates polycyclic aromatic hydrocarbons into mutagenic
      metabolites. Clinically relevant concentrations (0.25-5 microM) of As2O3 were
      demonstrated to inhibit CYP1A activity in primary human hepatocytes and hepatoma
      Hep3B and HepG2 cells coexposed to 3-methylcholanthrene (3MC), benzo(a)pyrene, or
      dioxin and the metalloid for 24 h. Inhibition reached 50 and 90% in Hep3B cells
      treated with 1 and 5 microM As2O3, respectively, and was not due to direct
      interaction of the metalloid with CYP1A1. As2O3 (2.5-5 microM) was demonstrated
      to markedly reduce induction of CYP1A1 mRNA and apoprotein levels and gene
      promotor activity in 3MC-treated Hep3B cells, whereas lower concentrations (0.25
      1 microM) were ineffective. These effects of As2O3 were abrogated by N
      acetylcysteine. Surprisingly, this agent was found 1) to block cellular arsenic
      uptake when coincubated with the metalloid and 2) to increase arsenic efflux
      through multidrug resistance-associated proteins. In addition, blockade of these
      transporters was shown to enhance intracellular amounts of metalloid and to
      potentiate its effects on CYP1A1 gene. Finally, our results have demonstrated
      that As2O3, at low concentrations routinely reached in As2O3-treated patients,
      prevents induction of human CYP1A1 gene expression and that such an effect is
      increased by blocking multidrug resistance-associated proteins.

PMID- 12490586
TI  - The effect of chloroquine on renal function and vasopressin secretion: a nitric
      oxide-dependent effect.
AB  - We have previously reported that chloroquine administration increases plasma
      vasopressin concentration and urinary sodium excretion in Sprague-Dawley rats.
      Because chloroquine has also been shown to stimulate nitric oxide production, the
      aim of this study was to determine whether nitric oxide mediates chloroquine
      induced changes in renal function and secretion of vasopressin. Sprague-Dawley
      rats (n = 6-8/group) were infused with 2.5% dextrose under Intraval anesthesia
      (100 mg kg(-1) i.p.). After 3-h equilibration and a control hour, animals
      received either vehicle, chloroquine (0.04 mg h(-1)), N(omega)-nitro-L-arginine
      methyl ester (L-NAME) (nitric-oxide synthase inhibitor, 60 microg kg(-1) h(-1)),
      or combined chloroquine and L-NAME over the next hour. L-NAME or vehicle infusion
      continued for a further recovery hour. Plasma was collected from a parallel group
      of animals for vasopressin radioimmunoassay. Chloroquine stimulated a significant
      increase (p < 0.05) in urine flow rate, glomerular filtration rate, and sodium
      excretion over the hour of infusion, in comparison with vehicle-infused rats.
      These effects continued after cessation of chloroquine, reaching maxima in the
      following recovery hour. Coadministration of L-NAME abolished these effects,
      returning all parameters to levels comparable with those in vehicle-infused
      animals. Chloroquine administration was accompanied by a significant increase (p
      < 0.05) in plasma vasopressin, which was also reversed by L-NAME. The effects of
      chloroquine on renal function and vasopressin secretion seem to be mediated by
      pathways involving nitric oxide. These data suggest that chloroquine may
      stimulate nitric-oxide synthase both centrally, stimulating vasopressin
      secretion, and within the kidney, where it modulates glomerular hemodynamics and
      tubular function.

PMID- 12490587
TI  - Effects of halothane and propofol on excitatory and inhibitory synaptic
      transmission in rat cortical neurons.
AB  - General anesthetics are thought to act on both excitatory and inhibitory neuronal
      pathways at both post- and presynaptic sites. However, the literature in these
      regards is somewhat controversial. The aim of the present study was to reassess
      the relative importance of the various anesthetic actions using a common
      preparation. Rat cortical neurons in primary culture were used to record
      spontaneous miniature postsynaptic currents by the whole-cell patch-clamp
      technique. Halothane at clinically relevant concentrations prolonged the decay
      phase of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded
      in the presence of tetrodotoxin and at higher concentrations decreased the
      frequency of mIPSCs. The mIPSC amplitudes underwent little change. Spontaneous
      action potential-dependent IPSCs recorded in the absence of tetrodotoxin were
      similarly affected by halothane. Halothane also decreased the frequency of
      spontaneous miniature non-N-methyl-D-aspartate (NMDA) excitatory postsynaptic
      currents (mEPSCs) as well as spontaneous action potential-dependent NMDA EPSCs
      and non-NMDA EPSCs without affecting their decay phase. The halothane effect on
      mIPSC and mEPSC frequency was dependent on the external calcium concentration. In
      contrast to halothane, the only effect of propofol was the prolongation of the
      decay phase of mIPSCs and IPSCs. The prolongation of mIPSCs and IPSCs by
      halothane and propofol coupled with the ineffectiveness on mEPSCs and EPSCs
      suggests a selective postsynaptic modulation of GABA(A) receptors. The additional
      calcium-dependent inhibition of mIPSC and mEPSC frequency by halothane (but not
      propofol) suggests a more general mechanism by this anesthetic on presynaptic
      transmitter release.

PMID- 12490588
TI  - Significant neuroprotection against ischemic brain injury by inhibition of the
      MEK1 protein kinase in mice: exploration of potential mechanism associated with
      apoptosis.
AB  - MEK1/2 is a serine/threonine protein kinase that phosphorylates and activates
      extracellular signal-responsive kinase (ERK)1/2. In the present study we explored
      the role of MEK1/2 in ischemic brain injury using a selective MEK1/2 inhibitor,
      SL327, in mice. C57BL/6 mice were subjected to a 30-min occlusion of the middle
      cerebral artery (MCAO) followed by reperfusion. Western blot analysis
      demonstrated the immediate activation of MEK/ERK after reperfusion (within the
      first 10 min) in the ischemic brain; this activation was dose dependently blocked
      by SL327 (10-100 mg/kg, i.p.). A single dose of SL327 (100 mg/kg) administered 15
      min before or 25 min after the onset of ischemia resulted in 63.6% (n = 18, p <
      0.001) and 50.7% (n = 18, p < 0.01) reduction in infarct size, respectively,
      compared with vehicle-treated mice. Similarly, SL327 significantly reduced
      neurological deficits 1 to 3 days after reperfusion (n = 12, p < 0.01). The
      salutary effect of SL327-induced neuroprotection was independent of mitochondrial
      cytochrome c release or caspase-8-mediated apoptosis; however, SL327 markedly
      suppressed the levels of active caspase-3 and DNA fragmentation (as a measure of
      apoptosis) after ischemia/reperfusion. Our data suggest that the inhibition of
      MEK1/2 results in neuroprotection from reperfusion injury and that this
      protection may be associated with the reduction in apoptosis.

PMID- 12490589
TI  - Potentiation of anandamide effects in mesenteric beds isolated from endotoxemic
      rats.
AB  - The aim of the present experiments was to study the effects of exogenously added
      anandamide on transient norepinephrine (NE)-induced contractions in mesenteric
      beds isolated from adult male Sprague-Dawley rats 6 h after the i.p.
      administration of 5 mg kg(-1) lipopolysaccharide (LPS). LPS treatment induced a 3
      fold increase in total nitric-oxide synthase (NOS) activity without modifying
      either the systolic blood pressure or the vascular reactivity to NE of the
      isolated mesenteric bed. The endocannabinoid anandamide (0.01-10 microM) caused
      concentration-dependent reductions of the contractile responses to NE in the
      isolated mesenteric bed. This effect was significantly potentiated after LPS
      treatment compared with the controls. Anandamide-induced reductions of the
      contractile responses to NE in mesenteric beds isolated from LPS-treated rats
      were unmodified by endothelium removal but significantly diminished by either the
      anandamide amidase inhibitor phenylmethylsulfonyl fluoride (200 microM) or the
      vanilloid receptor antagonist capsazepine (1 microM). The vanilloid receptor
      agonist capsaicin (0.01-100 nM) also caused concentration-dependent relaxations
      that were potentiated in mesenteric beds from LPS-treated rats. Nevertheless,
      they were unmodified by 1 microM capsazepine. It is concluded that the
      potentiation of anandamide relaxations after LPS treatment, which are evident at
      early stages of endotoxic shock, could involve the participation of an anandamide
      metabolite and might be mediated, at least in part, through a vanilloid receptor.

PMID- 12490590
TI  - Human kidney flavin-containing monooxygenases and their potential roles in
      cysteine s-conjugate metabolism and nephrotoxicity.
AB  - The potential roles of human hepatic and renal flavin-containing monooxygenases
      (FMOs) in the metabolism of the cysteine S-conjugates S-allyl cysteine (SAC) and
      S-(1,2-dichlorovinyl)-L-cysteine (DCVC) were investigated. Incubations of human
      cDNA-expressed FMO1, FMO3, FMO4, and FMO5 with SAC resulted in detection of SAC
      sulfoxide, with FMO3 exhibiting approximately 3-, 4-, and 10-fold higher activity
      than FMO1, FMO4, and FMO5, respectively. DCVC sulfoxide formation was only
      detected with FMO3 and was 59-fold lower than SAC sulfoxide formation.
      Incubations of human liver microsomes with SAC or DCVC resulted in detection of
      the corresponding sulfoxides and provided evidence for the involvement of FMO3.
      Incubations of SAC or DCVC with human kidney microsomes, however, led only to the
      detection of SAC sulfoxide. Immunoblots with monospecific antibodies to FMO1,
      FMO3, and FMO5 in kidney microsomes from 26 humans showed that the average
      expression levels for FMO1, FMO3, and FMO5 were 5.8 +/- 2.3, 0.5 +/- 0.4, and 2.4
      +/- 1.4 pmol/mg (means +/- S.D.), respectively. Interestingly, African-American
      kidney samples (n = 8) exhibited significantly higher FMO1 levels than Caucasian
      samples (n = 17), whereas no difference in expression level between males and
      females was observed with any of the examined FMO isoforms. Collectively, the
      results provide evidence for the expression of three FMO isoforms in the human
      kidney and show that the contribution of renal FMOs in cysteine S-conjugate
      metabolism is likely to vary depending upon the cysteine S-conjugate and the
      relative expression levels of the active FMOs.

PMID- 12490591
TI  - Comparison of effect of ethanol on N-methyl-D-aspartate- and GABA-gated currents
      from acutely dissociated neurons: absence of regional differences in sensitivity
      to ethanol.
AB  - In vivo, ethanol alters the effect of N-methyl-D-aspartate (NMDA) and GABA in
      some brain regions but is without effect in others. To determine whether these
      regional differences were due to differences in the effect of ethanol on
      postsynaptic NMDA or GABAA receptors, we examined the effect of ethanol on NMDA-
      and GABA-gated currents from neurons acutely dissociated from the lateral septal
      nucleus, substantia nigra, thalamus, hippocampus, and cerebellum. Ethanol
      decreased the effect of NMDA similarly in all brain areas tested and had similar
      effects on Chinese hamster ovary cells expressing NR2A or NR2B subunits with an
      NR1-1a subunit. However, ifenprodil reduced the inhibition by ethanol of NMDA
      gated currents from neurons isolated from the lateral septum without affecting
      neurons from the substantia nigra. In contrast to the robust effect of ethanol on
      NMDA-gated currents, ethanol (25-300 mM) was without effect on GABA-gated
      currents at all brain sites tested or on Ltk- cells stably expressing the alpha1,
      beta2, and gamma2L or gamma2S subunits. The neuroactive steroid alphaxalone
      profoundly enhanced GABA-gated currents in all brain areas and cell types tested,
      indicating a similar sensitivity to allosteric modulation; however, there was no
      interaction of alphaxalone with ethanol at any site tested. These data suggest
      that the regional differences in the effect of ethanol observed in vivo are not
      due to a differential action of ethanol at the postsynaptic NMDA or GABAA
      receptor subtypes.

PMID- 12490592
TI  - Temporal regulation of agonist efficacy at 5-hydroxytryptamine (5-HT)1A and 5-HT
      1B receptors.
AB  - Coactivation of purinergic (P 2Y) receptors reduces agonist efficacy at serotonin
      1B (5-HT 1B), but not 5-HT 1A receptors. Herein, we report that pretreatment for
      5 min with the P 2Y receptor agonist ATP reduced agonist responsiveness at the 5
      HT 1A, but not at the 5-HT 1B, receptor. The effect of ATP pretreatment on the 5
      HT 1A receptor response rapidly reversed within a 10 min time frame between P 2Y
      receptor and 5-HT 1A receptor activation. ATP pretreatment effects on 5-HT 1A
      agonist responsiveness were blocked by the protein kinase inhibitors
      staurosporine and bisindolylmaleimide, suggesting that the ATP-mediated temporal
      regulation involves activation of protein kinase C (PKC). Moreover, the temporal
      effect of ATP was blocked by incubation with 1% ethanol, suggesting that
      consequences of phospholipase D (PLD) activation play a role. ATP pretreatment
      blocked the inhibitory effect produced by 5-HT 2C receptor activation on the 5-HT
      1A, but not the 5-HT 1B, receptor response, suggesting that the 5-HT 1A receptor
      itself was the target for PLD/PKC action. Finally, ethanol did not block the
      reduction in responsiveness of the 5-HT 1A receptor system produced by activation
      of PKC with phorbol ester treatment, suggesting that PKC activation lies
      downstream of PLD. Taken together, these data suggest that activation of P 2Y
      receptors can reduce responsiveness of the 5-HT 1A receptor system via a PLD/PKC
      dependent mechanism that is highly dependent upon the temporal pattern of
      receptor activation. Moreover, this work underscores the importance of time as a
      variable in receptor signaling cross talk and serves to further illustrate
      differences between the 5-HT 1A and 5-HT 1B receptor systems.

PMID- 12490593
TI  - Effects of prolonged nicotinic ligand exposure on function of heterologously
      expressed, human alpha4beta2- and alpha4beta4-nicotinic acetylcholine receptors.
AB  - Effects of prolonged nicotinic ligand exposure on the function of human
      alpha4beta2- and alpha4beta4-nicotinic acetylcholine receptor (nAChR) subtypes
      were studied using receptors heterologously expressed in SH-EP1 human epithelial
      cells. Magnitudes of acute, nAChR-mediated, specific 86Rb+ efflux responses to 1
      mM carbamylcholine were reduced after pretreatment with specific nAChR ligands in
      effects that depended on pretreatment drug dose, duration of drug pretreatment,
      and duration of drug-free recovery. Fifty percent inhibition of alpha4beta2-nAChR
      function following 5 min of recovery occurred after 1 min of pretreatment with 1
      mM nicotine but also after 1-h pretreatment at 10 nM nicotine. Seventy-five
      percent loss in function persisted 1 h after drug removal following 15 min or
      more of exposure to 1 mM nicotine. However, functional recovery was nearly
      complete after 1 h in drug-free medium following 1 min to 24 h pretreatment with
      0.1 to 1 microM nicotine, i.e., in the range of smoker plasma nicotine levels.
      alpha4beta4-nAChR was similarly sensitive to persistent inactivation by prolonged
      nicotine exposure. Carbamylcholine exhibited slightly lower persistent
      inactivation potency than nicotine at both alpha4beta2- and alpha4beta4-nAChR.
      The nAChR antagonist, mecamylamine, exhibited persistent inactivation potency and
      efficacy similar to nicotine at alpha4beta2-nAChR but had a reduced effect on
      alpha4beta4-nAChR. These studies illustrate persistent inactivation of human
      alpha4beta2- or alpha4beta4-nAChR induced by prolonged exposure to nicotine and
      show that other ligands induce nAChR persistent inactivation in a subtype
      specific manner.

PMID- 12490594
TI  - Activation of epidermal vanilloid receptor-1 induces release of proinflammatory
      mediators in human keratinocytes.
AB  - During dermal injury and the associated trauma a number of compounds are released
      that can mediate the inflammatory response. Determining the cellular mechanisms
      that initiate the inflammatory responses to acute keratinocyte damage is
      important for understanding the regulation of epidermal inflammation. The
      recently cloned vanilloid receptor-1 (VR1) is a polymodal receptor, responding to
      thermal, pH, or vanilloids such as capsaicin stimulation. Although VR1 has been
      localized only on sensory neurons and within the central nervous system, recent
      evidence suggests a functional VR1 is expressed in human skin and epidermal
      cells. Using reverse transcription-polymerase chain reaction and immunoblotting
      we report that human keratinocytes and the human keratinocyte cell line HaCaT
      express VR1. Consistent with neuronal VR1, activation of epidermal VR1 by
      capsaicin induced a calcium influx. Treating HaCaT cells with capsaicin resulted
      in a dose-dependent expression of cyclooxygenase-2 (COX-2), whereas pretreatment
      with the VR1 receptor antagonist capsazepine abolished the capsaicin-stimulated
      increase in COX-2 expression. Furthermore, the capsaicin-induced expression of
      COX-2 was dependent on extracellular calcium. Activation of the epidermal VR1 by
      capsaicin also resulted in an increased release of interleukin-8 and
      prostaglandin E2, and the stimulated release was attenuated by capsazepine. The
      finding that VR1 is expressed by keratinocytes is of great importance because it
      expands the putative role of VR1 beyond that of pain perception. Our results
      suggest that VR1 expression in keratinocytes may have a role in the inflammation
      that occurs secondary to epidermal damage or insult, and thus may function as a
      sensor for noxious cutaneous stimulation.

PMID- 12490595
TI  - Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant
      of rifampin-mediated pregnane X receptor activation.
AB  - Rifampin, a member of the rifamycin class of antibiotics, is well known for its
      ability to induce drug-metabolizing enzymes and transporters, through activation
      of the pregnane X receptor. Available data suggest rifampin entry into
      hepatocytes may be transporter-mediated. Accordingly, it is therefore plausible
      that modulation of the achievable intracellular concentration of rifampin by drug
      uptake transporters would influence the degree of induction. In this study, we
      expressed an array of known hepatic uptake transporters to show the key hepatic
      rifampin uptake transporters are liver-specific members of the organic anion
      transporting polypeptide family (OATP). Indeed, both OATP-C and OATP8 seemed
      capable of mediating rifampin uptake into HeLa cells. OATP-C, however, seemed to
      have far greater affinity and capacity for rifampin transport. In addition,
      several allelic variants of OATP-C known to be present among European and African
      Americans were found to have markedly decreased rifampin transport activity. In
      cell-based, transactivation assays, OATP-C expression was associated with
      increased cellular rifampin retention as well as potentiation of PXR reporter
      gene activity. This is the first demonstration of an uptake transporter such as
      OATP-C, in modulating PXR function, and sheds important new insight into our
      understanding of the molecular determinants of PXR-mediated inductive processes.

PMID- 12490596
TI  - Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and
      phospholipase A2 signaling pathways have different receptor reserves.
AB  - NIH3T3 cells stably expressing the rat 5-hydroxytryptamine 2A (5-HT 2A) receptor
      (5500 fmol/mg) were used to explore further the capacity of structurally distinct
      ligands to elicit differential signaling through the phospholipase C (PLC) or
      phospholipase A 2 (PLA 2) signal transduction pathways. Initial experiments were
      designed to verify that 5-HT 2A receptor-mediated PLA 2 activation in NIH3T3
      cells is independent from, and not a subsequent result of, 5-HT 2A receptor
      mediated PLC activation. In addition, we also explored the extent of receptor
      reserve for the endogenous ligand, 5-HT, for both PLC and PLA 2 activation.
      Finally, we employed structurally diverse ligands from the tryptamine,
      phenethylamine, and ergoline families of 5-HT 2A receptor agonists to test the
      hypothesis of agonist-directed trafficking of 5-HT 2A receptor-mediated PLC and
      PLA 2 activation. To measure agonist-induced pathway activation, we determined
      the potency and intrinsic activity of each compound to activate either the PLA 2
      pathway or the PLC pathway. The results showed that a larger receptor reserve
      exists for 5-HT-induced PLA 2 activation than for 5-HT-induced PLC activation.
      Furthermore, the data support the hypothesis of agonist-directed trafficking in
      NIH3T3-5HT 2A cells because structurally distinct ligands were able to induce
      preferential activation of the PLC or PLA 2 signaling pathway. From these data we
      conclude that structurally distinct ligands can differentially regulate 5-HT 2A
      receptor signal transduction.

PMID- 12490597
TI  - Real-time intracellular Ca2+ mobilization by travoprost acid, bimatoprost,
      unoprostone, and other analogs via endogenous mouse, rat, and cloned human FP
      prostaglandin receptors.
AB  - The ability of a number of prostaglandin F 2 alpha (PGF 2 alpha) analogs to
      mobilize intracellular Ca2+[Ca2+]iand to compete for [3H]PGF 2 alpha binding to
      prostaglandin F 2 alpha receptors (FP) was evaluated. Radioligand binding studies
      measuring displacement of [3H]PGF 2 alpha by a variety of FP prostaglandin
      analogs yielded the following rank order of affinities: travoprost acid [(+)-16-m
      trifluorophenoxy tetranor PGF 2 alpha; (+)-fluprostenol] > bimatoprost acid (17
      phenyl-trinor PGF 2 alpha) >> unoprostone (13,14-dihydro-15-keto-20-ethyl PGF 2
      alpha) = bimatoprost (17-phenyl-trinor PGF 2 alpha ethyl amide) > or = Lumigan
      (bimatoprost ophthalmic solution). In FP functional studies, travoprost acid
      (EC50= 17.5-37 nM, n = 13), bimatoprost acid (EC50= 23.3-49.0 nM, n = 6-12),
      unoprostone (EC50= 306-1270 nM, n = 4-8), bimatoprost (EC50= 3070- 3940 nM, n = 4
      9), and Lumigan (EC50= 1470-3190 nM, n = 5-9) concentration dependently
      stimulated [Ca2+]imobilization via the rat (A7r5 cells), mouse (3T3 cells), and
      cloned human ocular FP prostanoid receptors. The rank order of potency of these
      compounds at the FP receptor of the three species was similar and in good
      agreement with the determined binding affinities. The agonist effects of these
      compounds were concentration dependently blocked by the FP receptor-selective
      antagonist, AL-8810 (11beta-fluoro-15-epi-15-indanyl-tetranor PGF 2 alpha) (Ki=
      0.6-1.3 microM). These studies have demonstrated that bimatoprost, unoprostone,
      and bimatoprost acid possess direct agonist activities at the rat, mouse, and
      human FP prostanoid receptor and that travoprost acid is the most potent of the
      synthetic FP prostaglandin analogs tested.

PMID- 12490598
TI  - High isoproterenol doses are required to activate beta3-adrenoceptor-mediated
      functions in dogs.
AB  - The "in vivo" conditions for beta3-adrenoceptors (beta-AR) activation by
      isoproterenol were investigated in dog. Experiments were carried out in
      anesthetized dogs using isoproterenol as a nonselective beta-AR agonist.
      Intravenous infusion of isoproterenol (0.4 nmol/kg/min) induced arterial
      hypotension and tachycardia with a slight decrease in cutaneous blood flow. At
      this dose, isoproterenol increased glucose, glycerol, and nonesterified fatty
      acid plasma levels. The changes in cardiovascular and endocrine-metabolic
      parameters, induced by the low dose of isoproterenol, were suppressed by
      pretreatment with nadolol (1 mg/kg, i.v.). After nadolol administration, however,
      a 10-fold higher dose (4 nmol/kg/min) of isoproterenol was able to induce a
      decrease in arterial blood pressure with a slight tachycardia and an increase in
      cutaneous blood flow. This high dose of isoproterenol increased nonesterified
      fatty acid and glycerol plasma levels but failed to change glucose plasma levels.
      All these effects were abolished by a pretreatment with nadolol (1 mg/kg, i.v.)
      plus SR59230A [a selective beta3-adrenoceptor antagonist; (3-(2-ethylphenoxy)
      1(1S)-1,2,3,4-tetrahydronaphth-1-ylaminol-(2S)2-propanol oxalate); 1 mg/kg,
      i.v.]. Moreover, as observed with the high dose of isoproterenol under nadolol
      pretreatment, an infusion of SR58611A [a selective beta3-adrenoceptor agonist;
      ((N2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl-(2R)-2-hydroxy-2
      chlorophenyl) ethanamine hydrochloride] induces a decrease in mean arterial blood
      pressure associated with an increase in heart rate, cutaneous blood flow, and
      nonesterified fatty acid and glycerol plasma levels. These results demonstrate
      that the in vivo activation of beta3-adrenoceptors requires higher doses of
      catecholamine than those necessary for beta1- and/or beta2-adrenoceptor
      stimulation. These results also argue for the lack of a beta3-AR involvement in
      the control of heart rate and glycogenolysis in dogs.

PMID- 12490599
TI  - Low concentrations of pyridostigmine prevent soman-induced inhibition of
      GABAergic transmission in the central nervous system: involvement of muscarinic
      receptors.
AB  - This study was designed to investigate the effects of the cholinesterase
      inhibitors soman and pyridostigmine bromide (PB) on synaptic transmission in the
      CA1 field of rat hippocampal slices. Soman (1-100 nM, 10-15 min) decreased the
      amplitude of GABAergic postsynaptic currents (IPSCs) evoked by stimulation of
      Schaffer collaterals and recorded from CA1 pyramidal neurons. It also decreased
      the amplitude and frequency of spontaneous IPSCs recorded from pyramidal neurons.
      Whereas the maximal effect of soman on evoked GABAergic transmission was observed
      at 10 nM, full cholinesterase inhibition was induced by 1 nM soman. After 10-15
      min exposure of hippocampal slices to 100 nM PB, GABAergic transmission was
      facilitated and cholinesterase activity was not significantly affected. At
      nanomolar concentrations, soman and PB have no direct effect on GABA(A)
      receptors. The effects of soman and PB on GABAergic transmission were inhibited
      by the m2 receptor antagonist 11-[[[2-diethylamino-O-methyl]-1-piperidinyl]
      acetyl]-5,11-dihydrol-6H-pyridol[2,3-b][1,4]benzodiazepine-6- one (1 nM) and the
      m3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine (100 nM),
      respectively, and by the nonselective muscarinic receptor antagonist atropine (1
      microM). Thus, changes in GABAergic transmission are likely to result from direct
      interactions of soman and PB with m2 and m3 receptors, respectively, located on
      GABAergic fibers/neurons synapsing onto the neurons under study. Although the
      effects of 1 nM soman and 100 nM PB were diametrically opposed, they only
      canceled one another when PB was applied to the neurons before soman. Therefore,
      PB, acting via m3 receptors, can effectively counteract effects arising from the
      interactions of soman with m2 receptors in the brain.

PMID- 12490600
TI  - Blockade of phencyclidine-induced cortical apoptosis and deficits in prepulse
      inhibition by M40403, a superoxide dismutase mimetic.
AB  - Repetitive administration of phencyclidine (PCP) in the perinatal period results
      in cortical apoptosis and a long-lasting deficit in sensorimotor gating. Because
      these changes are olanzapine-sensitive, we have suggested that the effects of
      perinatal PCP could be used to model certain aspects of schizophrenia. Studies of
      PCP and N-methyl-D-aspartate-induced cell death suggested that superoxide could
      play a role in the pathway leading to death after PCP administration. The purpose
      of the current study was to determine whether the in vivo administration of
      M40403, a superoxide dismutase mimetic, could prevent PCP-induced cortical
      apoptosis and/or deficits in prepulse inhibition. Perinatal rat pups were
      administered 10 mg/kg PCP on postnatal (PN) days 7, 9, and 11 with or without
      treatment with 10 mg/kg M40403. Pups were either killed on PN 12 for analysis of
      various apoptotic markers or they were assessed for prepulse inhibition on PN 24
      to 26. Treatment with M40403 2 and 24 h after each PCP treatment prevented PCP
      induced increases in two measures of apoptosis in the dorsolateral frontal cortex
      and in the olfactory cortex. PCP-induced proapoptotic changes in Bax and Bcl-X(L)
      were also prevented by M40403 treatment. This regimen did not prevent the deficit
      in prepulse inhibition caused by PCP treatment, but when the treatment regimen
      was extended through PN 23, M40403 completely prevented the PCP-induced deficit
      in prepulse inhibition. These data suggest that perinatal PCP treatment leads to
      long-lasting changes in the pathway(s), leading to cell death and behavioral
      deficits, and that the superoxide radical plays a critical role in the underlying
      mechanism.

PMID- 12490601
TI  - Effect of nepadutant, a neurokinin 2 tachykinin receptor antagonist, on immediate
      early gene expression after trinitrobenzenesulfonic acid-induced colitis in the
      rat.
AB  - Tachykinins have been implicated in inflammatory responses such as those
      occurring in inflammatory bowel disease. Accordingly, we investigated the effect
      of a selective neurokinin (NK) 2 receptor antagonist, nepadutant, on proto
      oncogene expression in the L(6)-S(1) spinal cord as well as in dorsal root
      ganglion (DRG) neurons after either non-noxious colorectal distension (CRD) or
      trinitrobenzenesulfonic acid (TNBS)-induced colitis in the adult rat. In both
      preparations, c-fos was expressed in similar spinal cord regions, including
      medial and lateral dorsal horn, dorsal commissure (DCM; laminae X above the
      central canal), and the sacral parasympathetic nucleus (SPN, laminae V-VII).
      However, TNBS-induced colitis produced significantly larger numbers (8-10-fold
      increase over control) of Fos-positive spinal cord neurons. In addition, there
      was also a significant increase (3-4-fold) in the number of Jun-positive colon
      DRG neurons after colitis compared with CRD. Nepadutant had no significant effect
      on proto-oncogene expression induced by CRD in either spinal cord neurons or DRG
      neurons. In contrast, nepadutant significantly decreased (70%) the number of Fos
      positive neurons in dorsal horn, DCM, and SPN spinal cord regions and
      significantly decreased (75%) the number of Jun-positive DRG neurons after TNBS
      induced irritation of the colon. These findings indicate that nepadutant
      suppresses the responses of colonic afferent neurons to nociceptive stimuli and
      that NK2 receptor antagonists may be beneficial in the treatment of sensory
      symptoms of colitis.

PMID- 12490602
TI  - Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated
      with suppression of transforming growth factor-beta1 gene expression but not
      prevention of mitochondrial dysfunction.
AB  - Amiodarone (AM) is an efficacious antidysrhythmic agent that can cause numerous
      adverse effects, including potentially life-threatening pulmonary fibrosis. The
      current study was undertaken to investigate potential protective mechanisms of
      vitamin E against AM-induced pulmonary toxicity (AIPT) in the hamster. Three
      weeks after intratracheal administration of AM (1.83 micromol), increased
      pulmonary hydroxyproline content and histological damage were observed,
      indicative of fibrosis. These effects were preceded by increased pulmonary levels
      of transforming growth factor (TGF)-beta1 mRNA at 1 week post-AM, which remained
      elevated 3 weeks post-AM. Dietary supplementation with vitamin E resulted in
      rapid pulmonary accumulation of the vitamin, and prevention of AM-induced
      increases in TGF-beta1, hydroxyproline, and histological damage. Although dietary
      supplementation also markedly elevated lung mitochondrial vitamin E content, it
      did not attenuate AM-induced inhibition of mitochondrial respiration or
      disruption of mitochondrial membrane potential in vitro, or lung mitochondrial
      respiratory inhibition resulting from in vivo AM administration. These results
      suggest that vitamin E reduces the extent of pulmonary damage after AM
      administration via down-regulating TGF-beta1 overexpression but that it does not
      modify AM-induced mitochondrial dysfunction, a potential initiating event in
      AIPT.

PMID- 12490603
TI  - Attenuation of ischemia/reperfusion-induced renal injury in mice deficient in
      Na+/Ca2+ exchanger.
AB  - Using Na+/Ca2+ exchanger (NCX1)-deficient mice, the pathophysiological role of
      Ca2+ overload via the reverse mode of NCX1 in ischemia/reperfusion-induced renal
      injury was investigated. Because NCX1(-/-) homozygous mice die of heart failure
      before birth, we used NCX1(+/-) heterozygous mice. NCX1 protein in the kidney of
      heterozygous mice decreased to about half of that of wild-type mice. Expression
      of NCX1 protein in the tubular epithelial cells and Ca2+ influx via NCX1 in renal
      tubules were markedly attenuated in the heterozygous mice. Ischemia/reperfusion
      induced renal dysfunction in heterozygous mice was significantly attenuated
      compared with cases in wild-type mice. Histological renal damage such as tubular
      necrosis and proteinaceous casts in tubuli in heterozygous mice were much less
      than that in wild-type mice. Ca2+ deposition in necrotic tubular epithelium was
      observed more markedly in wild-type than in heterozygous mice. Increases in renal
      endothelin-1 content were greater in wild-type than in heterozygous mice, and
      this reflected the difference in immunohistochemical endothelin-1 localization in
      necrotic tubular epithelium. When the preischemic treatment with KB-R7943 was
      performed, the renal functional parameters of both NCX1(+/+) and NCX1(+/-) acute
      renal failure mice were improved to the same level. These findings strongly
      support the view that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange,
      followed by renal endothelin-1 overproduction, plays an important role in the
      pathogenesis of ischemia/reperfusion-induced renal injury.

PMID- 12490604
TI  - Quinine inhibits vascular contraction independent of effects on calcium or myosin
      phosphorylation.
AB  - This report contains results of studies designed to determine whether quinine has
      direct effects on myofilament Ca2+ sensitization in addition to effects on Ca2+.
      Quinine decreased the EC50 value and maximal contraction of intact arterial
      strips to histamine. Incubation of arterial strips with indomethacin or 1H
      [1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one did not alter quinine inhibition,
      suggesting that the effect is not mediated via cyclooxygenase or cGMP.
      Pretreatment of strips with quinine had no effect on the histamine-dependent
      increases in myosin light chain phosphorylation levels. Quinine inhibited Ca2+
      induced contraction in alpha-toxin permeabilized strips, but not the Ca2+-induced
      contraction in Triton X-100 permeabilized strips. Pretreatment of the alpha-toxin
      permeabilized strips with quinine before stimulation with guanosine-5'-O-(3
      thio)triphosphate (GTPgammaS) did not have any effect on the response. In
      conclusion, quinine inhibited Ca2+-dependent contractions of the alpha-toxin
      permeabilized strips, which retain modulatory pathways both upstream and
      downstream from the contractile proteins but did not inhibit GTPgammaS-dependent
      contraction of the alpha-toxin permeabilized preparation important in upstream
      modulation of the contraction. Moreover, quinine did not inhibit the Ca2+
      dependent contractions of the Triton X-100 permeabilized strips, which are devoid
      of all modulatory pathways. This suggests that quinine does not act upstream from
      or directly on the contractile proteins. A more likely site of action may be
      downstream of the contractile proteins and specifically at the coupling of the
      contractile proteins with the physiological endpoint of force development.

PMID- 12490605
TI  - Potency differences for D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 as an antagonist
      of peptide and alkaloid micro-agonists in an antinociception assay.
AB  - D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) is a peptide antagonist that
      demonstrates potent and selective affinity for micro-opioid receptors in
      radioligand binding assays and in vitro bioassays. However, previous studies
      indicate that CTAP may possess unusual pharmacology under certain conditions.
      Therefore, CTAP was evaluated as an antagonist of the antinociceptive effects of
      a range of structurally diverse high- and low-efficacy peptide and alkaloid
      opioid agonists and compared with the traditional antagonist naltrexone. Male
      Sprague-Dawley rats (N = 227) were loosely restrained and the latency for tail
      withdrawal from 55 degrees C water was measured. Morphine s.c. and i.c.v.,
      buprenorphine s.c., etorphine s.c. and i.c.v., [N-Me-Phe3,D-Pro4]-morphiceptin
      and [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin produced antinociceptive effects. CTAP
      was at least 10-fold more potent than naltrexone as an antagonist of the
      antinociceptive effects of all five agonists. High doses of CTAP produced a
      noncompetitive antagonism of etorphine s.c. and morphine s.c. suggesting that
      CTAP may interact with additional opioid receptors in vivo or produce
      insurmountable antagonism at these doses. CTAP was approximately 300-fold more
      potent as an antagonist of DAMGO than the other agonists, indicating that CTAP
      may distinguish some peptide agonists such as DAMGO from other agonists based on
      binding interactions within the micro-opioid receptor or pharmacodynamic
      properties of these peptides. Naltrexone, however, administered by either s.c. or
      i.c.v. routes of administration was approximately equipotent as an antagonist of
      the antinociceptive effects of most agonists. Taken together, these data indicate
      that the peptide antagonist CTAP possesses a unique pharmacology unlike
      traditional opioid antagonists such as naltrexone

PMID- 12490606
TI  - Acquisition, expression, and reinstatement of ethanol-induced conditioned place
      preference in mice: effects of opioid receptor-like 1 receptor agonists and
      naloxone.
AB  - The ability of the two opioid receptor-like receptor 1 (ORL1) agonists nociceptin
      (5 nmol i.c.v.) and synthetic (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1
      yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (Ro 64-6198; 0.1,
      0.3, and 1.0 mg/kg i.p.) and the opioid antagonist naloxone (0.1, 1.0, and 10.0
      mg/kg s.c.) to modify ethanol-induced conditioned place preference was examined
      in NMRI male mice. The ORL1 agonists were found to significantly reduce the
      acquisition, expression, and ethanol-induced reinstatement of conditioned place
      preference. Unlike the ORL1 agonists, naloxone at the doses relevant for opioid
      receptor blockade failed to significantly influence the acquisition of ethanol
      induced conditioned place preference. However, naloxone at 1.0 but not 0.1 mg/kg
      s.c. potently blocked the expression of ethanol-induced conditioned place
      preference and significantly inhibited ethanol-induced reinstatement of the
      conditioned place preference after extinction. Separate experiments indicated
      that nociceptin and Ro 64-6198 are both devoid of reinforcing or aversive
      properties. Naloxone, however, at 1.0 and 10.0 mg/kg, produced conditioned place
      aversion, indicating motivational properties of its own. Both nociceptin and Ro
      64-6198 reduced locomotor activity after acute administration. However, tolerance
      developed very quickly to this effect and already after three i.c.v. (or i.p.)
      injections, there was no significant reduction of locomotor activity. It is
      concluded that ORL1 agonists can modulate the acquisition, expression, and
      reinstatement of the conditioned reinforcing effects of ethanol with no
      reinforcing or aversive properties of their own. This property might be a
      potential advantage in the treatment of alcoholism compared with nonselective
      opioid antagonist naltrexone.

PMID- 12490607
TI  - Neuroinflammatory role of prostaglandins during experimental meningitis: evidence
      suggestive of an in vivo relationship between nitric oxide and prostaglandins.
AB  - Nitric oxide (NO) and prostaglandins are inflammatory mediators produced during
      meningitis. The purpose of the present study was to pharmacologically inhibit
      cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) to 1) explore the
      prostaglandin contribution to blood-cerebrospinal fluid barrier permeability
      alterations and 2) elucidate the in vivo concentration relationship between
      prostaglandin E2 (PGE2) and NO during experimental meningitis. Intracisternal
      injection of lipopolysaccharides (LPSs, 200 microg) induced neuroinflammation.
      Rats were dosed with nimesulide (COX-2 inhibitor), aminoguanidine (iNOS
      inhibitor), or vehicle. Evans blue was used to assess blood-cerebrospinal fluid
      barrier permeability. Meningeal NO and cerebrospinal fluid PGE2 were assayed
      using conventional methods. (Results are expressed as mean +/- S.E.M. of 5-9
      rats/group.) Nimesulide failed to prevent blood-cerebrospinal fluid barrier
      disruption [cerebrospinal fluid Evans blue (micrograms per milliliter): control,
      0.22 +/- 0.22*; LPS, 11.58 +/- 0.66; LPS + nimesulide, 10.58 +/- 0.86; *p < 0.05;
      ANOVA]. Although nimesulide decreased PGE2 (picograms per microliter; p < 0.01)
      in LPS + nimesulide rats (13.9 +/- 1.96) versus LPS + vehicle (73.8 +/- 12.4),
      meningeal NO production (picomoles/30 min/10(6) cells; p < 0.01) increased
      unexpectedly in LPS + nimesulide rats (439 +/- 47) versus LPS + vehicle rats (211
      +/- 31). In contrast, aminoguanidine inhibited meningeal NO (picomoles/30
      min/10(6) cells; p < 0.005) in LPS + aminoguanidine (111 +/- 20) versus LPS (337
      +/- 48) but had no effects (p > 0.05) on PGE2. The in vivo relationship between
      PGE2 and NO was mathematically described by a biphasic, bell-shaped curve (r2 =
      0.42; n = 27 rats; p < 0.0001). Based on these results, inhibition of
      prostaglandin synthesis not only fails to prevent blood-cerebrospinal fluid
      barrier disruption during neuroinflammation and but also promotes increased
      meningeal NO production. The in vivo concentration relationship between PGE2 and
      NO is biphasic, suggesting that inhibition of COX-2 alone may promote NO toxicity
      through enhanced NO synthesis.

PMID- 12490608
TI  - Investigation of CGRP receptors and peptide pharmacology in human coronary
      arteries. Characterization with a nonpeptide antagonist.
AB  - Calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and amylin are
      structurally related peptides mediating vasorelaxation in the coronary
      circulation possibly via CGRP receptors (subtypes 1 or 2). Functional CGRP1
      receptors appear to consist of at least three different kinds of proteins: the
      calcitonin receptor-like receptor (CRLR), receptor-activity-modifying proteins
      (RAMPs) and the receptor component protein (RCP). No CGRP2 receptor has yet been
      cloned. Using reverse transcriptase - polymerase chain reaction, the presence of
      mRNA sequences encoding CRLR, RCP and RAMPs was demonstrated in human coronary
      arteries. Relaxant responses were studied on isolated segments of coronary
      arteries after precontraction with U46619 (9,11-dideoxy-11alpha,9alpha
      epoxymethano-prostaglandin F(2alpha)). The human peptides alphaCGRP, AM, and
      amylin induced relaxation with mean pEC50 values of 8.6, 6.8, and 6.3 M,
      respectively. Preincubation with alphaCGRP(8-37) (10(-7) -10(-5) M) and a novel
      nonpeptide CGRP antagonist "Compound 1" (WO98/11128) (10(-7)-10(-5) M) caused a
      dose-dependent rightward shift of the concentration-response curves for alphaCGRP
      with pA(2) values of 7.0 and 7.1, respectively. Preincubation with alphaCGRP(8
      37) (10(-6) M) and Compound 1 (10(-6) M) caused significant rightward shift of
      the concentration-response curves for AM and amylin as well with pK B values
      between 6.6 and 7.5. Preincubation with AM(22-52) had no antagonistic effect on
      the AM and amylin response, neither did diacetoamidomethyl cysteine CGRP cause
      any concentration dependent (10(-11)-10(-6) M) dilatation. In conclusion, mRNA
      for the components forming CGRP1 and AM receptors was detected in the human left
      anterior descending coronary arteries. alphaCGRP, AM, and amylin mediated
      vasorelaxation via the CGRP1 receptor. Compound 1 acted as a nonpeptide
      antagonist at the CGRP1 receptor and could thus become a tool for the study of
      CGRP-mediated functional responses in human tissue.

PMID- 12490609
TI  - Effects of FK506 on [Ca2+]i differ in mouse and rabbit ventricular myocytes.
AB  - FK506 binding proteins (FKBPs 12 and 12.6) interact with ryanodine receptor (RyR)
      and modulate its functions. FK506 binds to and reverses effects of FKBP on RyR,
      thus increasing RyR sensitivity to Ca2+, decreasing RyR cooperativity, and
      increasing RyR open probability. FK506 would thus be expected to have an effect
      on excitation-contraction coupling, but which of these FK506 effects predominates
      and how the [Ca2+]i transient would be altered are difficult to predict. FK506
      has been reported to increase the [Ca2+]i transient in rat myocytes, but effects
      in other species have not been described. We compared the effects of FK506 on
      [Ca2+]i transients, L-type Ca2+ channel and Na/Ca exchange currents, membrane
      potential, and sarcoplasmic reticulum (SR) Ca2+ content in adult mouse and rabbit
      ventricular myocytes (VM). FK506 (10 microM) increased the [Ca2+]i transient in
      mouse VM (656 +/- 116 to 945 +/- 144 nM, p < 0.001) but decreased the amplitude
      of [Ca2+]i transients in rabbit VM (627 +/- 61 to 401 +/- 37 nM, p < 0.001).
      Similar effects were observed with rapamycin. The effects of FK506 and rapamycin
      on [Ca2+]i transients in VM of both species were reversible upon washout. FK506
      did not alter SR Ca2+ content in mouse VM (0.79 +/- 0.1 versus 0.78 +/- 0.1
      pC/pF) but reduced the SR Ca2+ content in rabbit VM (0.43 +/- 0.05 versus 0.30 +/
      0.04 pC/pF, P < 0.05) [pC = the integral (pA. s) of the caffeine-induced inward
      I(Na/Ca) normalized by cell capacitance (pF)]. FK506 had no effects on membrane
      potential, I(Ca,L) and outward I(Na/Ca) in either mouse or rabbit VM. These
      results indicate that alteration of the functions of RyR by FK506-mediated
      dissociation of FKBP from RyR has different species-dependent effects on SR Ca2+
      load and thus [Ca2+]i transients. This difference may result from the fact that
      [Na+]i is low in rabbit myocytes, allowing extrusion by Na+/Ca2+ exchange of Ca2+
      released by FK506-induced dissociation of FKBP12.6 from SR RyR.

PMID- 12490610
TI  - Presence of diadenosine polyphosphates in the aqueous humor: their effect on
      intraocular pressure.
AB  - Adenine dinucleotides are present in many biological systems and may serve as
      physiological regulators of processes such as neurotransmitter release, vascular
      tone or corneal hydration. The presence of diadenosine polyphosphates was
      investigated in New Zealand White rabbit aqueous humor. Diadenosine
      tetraphosphate (Ap4A) and diadenosine pentaphosphate (Ap5A) were identified and
      quantified in the aqueous humor with concentrations of 0.34 +/- 0.1 and 0.08 +/-
      0.01 microM, respectively. The effects of topical corneal application of
      diadenosine pyrophosphate (Ap2A), diadenosine triphosphate (Ap3A), Ap4A, and Ap5A
      on intraocular pressure in rabbits were also studied. Ap2A, Ap3A, and Ap5A
      increased intraocular pressure with threshold doses of approximately 0.1 to 1.0
      micro g. 10 microl(-1). Ap4A decreased intraocular pressure with an IC50 value of
      0.12 micro g. 10 microl(-1) (or 0.13 nmol). Cross-desensitization studies
      suggested the activation of a P2X receptor for the hypotensive effect of Ap4A and
      a P2Y receptor in the case of Ap5A. The ATP receptor antagonists (all 100 micro
      g. 10 microl(-1)), pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS),
      suramin, and reactive blue 2 (RB-2) alone had no effect on intraocular pressure
      but attenuated responses to diadenosine polyphosphates by approximately 80%. It
      is concluded that Ap2A, Ap3A, and Ap5A increase intraocular pressure, and Ap4A
      decreases intraocular pressure via mechanisms that involve P2 receptors, and that
      Ap4A present in aqueous humor may serve to regulate intraocular pressure.
      Furthermore, we suggest that topical application of Ap4A to the cornea has
      therapeutic potential for lowering intraocular pressure, a major risk factor for
      glaucoma.

PMID- 12490611
TI  - 15R-methyl-prostaglandin D2 is a potent and selective CRTH2/DP2 receptor agonist
      in human eosinophils.
AB  - Prostaglandin D2 (PGD2) is a mast cell-derived mediator that seems to play a role
      in asthma and allergic diseases. It is the only primary prostanoid to activate
      human eosinophils, which it accomplishes through the DP2 receptor/chemoattractant
      receptor-homologous molecule expressed on T helper cell type 2 (Th2) cells
      (CRTH2). In addition, PGD2 has both pro- and anti-inflammatory effects via the
      adenylyl cyclase-coupled DP1 receptor. To attempt to identify potent and
      selective DP2 receptor agonists we compared the abilities of a series of PGD2
      analogs to activate eosinophils via the DP2 receptor with their abilities to
      stimulate adenylyl cyclase in platelets via the DP1 receptor. All of the PGD2
      analogs tested stimulated CD11b expression and actin polymerization with a rank
      order of potency of 15R-methyl-PGD2 > PGD2 > 17-phenyl-18,19,20-trinor-PGD2 > 15S
      methyl-PGD2 approximately equal16,16-dimethyl-PGD2 > 11-keto-fluprostenol.
      Surprisingly, 15R-methyl-PGD2, which has the unnatural R-configuration at carbon
      15, was about 5 times more potent than PGD2 and about 75 times more potent than
      15S-methyl-PGD2. 15R-methyl-PGD2 (EC50 value of 1.7 nM) was also much more potent
      as an eosinophil chemoattractant than PGD2 (EC50 value of 10 nM) and 15S-methyl
      PGD2 (EC50 value of 128 nM). Cross-desensitization experiments indicated that 15R
      methyl-PGD2 acts through the DP2 receptor. None of the PGD2 analogs tested
      elevated platelet cAMP by more than 20% of the maximal level in response to PGD2.
      However, in contrast to eosinophils, the most active was 15S-methyl-PGD2. In
      conclusion, 15R-methyl-PGD2 is the most potent known DP2 receptor agonist, and
      because of its selectivity and resistance to metabolism, should be a useful tool
      in probing the physiological role of this receptor in inflammatory diseases.

PMID- 12490612
TI  - Cyclosporin a and enterohepatic circulation of bile salts in rats: decreased
      cholate synthesis but increased intestinal reabsorption.
AB  - Cyclosporin A (CsA) has been shown to inhibit synthesis and hepatobiliary
      transport of bile salts. However, effects of CsA on the enterohepatic circulation
      of bile salts in vivo are largely unknown. We characterized the effects of CsA on
      the enterohepatic circulation of cholate, with respect to synthesis rate, pool
      size, cycling time, intestinal absorption, and the expression of relevant
      transporters in liver and intestine in rats. CsA (1 mg. 100 g(-1). day(-1) s.c.)
      or its solvent was administered daily to male rats for 10 days. Cholate synthesis
      rate and pool size were determined by a 2H4-cholate dilution technique. Bile and
      feces were collected for determination of cholate and total bile salts,
      respectively. Cycling time and intestinal absorption of cholate were calculated.
      The mRNA levels and corresponding transporter protein levels in liver and
      intestine were assessed by real-time polymerase chain reaction and Western
      analysis, respectively. CsA treatment decreased cholate synthesis rate by 71%,
      but did not affect pool size or cycling time. CsA reduced the amount of cholate
      lost per enterohepatic cycle by approximately 70%. Protein levels of the apical
      sodium-dependent bile salt transporter (Asbt) were 2-fold increased in distal
      ileum of CsA-treated rats, due to post-transcriptional events. In conclusion,
      chronic CsA treatment markedly reduces cholate synthesis rate in rats, but does
      not affect cholate pool size or cycling time. Our results strongly suggest that
      CsA enhances efficacy of intestinal cholate reabsorption through increased Asbt
      protein expression in the distal ileum, which contributes to maintenance of
      cholate pool size in CsA-treated rats.

PMID- 12490613
TI  - Sigma1 receptor agonist-mediated regulation of N-methyl-D-aspartate-stimulated
      [3H]dopamine release is dependent upon protein kinase C.
AB  - We have previously shown that sigma1 receptor agonists inhibit N-methyl-D
      aspartate (NMDA)-stimulated [3H]dopamine from slices of rat striatum in a
      concentration-related manner and that the inhibition is reversed by sigma1
      receptor-selective and nonsubtype-selective sigma receptor antagonists. Based on
      previous evidence from our laboratory as well as other laboratories, we
      hypothesized that sigma1 receptors might use a protein kinase C (PKC) signaling
      pathway to modulate stimulated dopamine release. We tested several inhibitors of
      PKC isozymes, as well as a phospholipase C inhibitor for their effects on sigma1
      receptor agonist-mediated regulation of [3H]dopamine release. Although none of
      the inhibitors tested affected the ability of NMDA to stimulate [3H]dopamine
      release, they all abolished regulation by the sigma1 receptor agonist (+)
      pentazocine in a concentration-related manner. We also found that prior exposure
      to 1 microM phorbol 2-myristate 13-acetate for 30 min abolished regulation by (+)
      pentazocine. We concluded that an intact PKC system was required for sigma1
      agonist-mediated regulation of NMDA-stimulated [3H]dopamine release from rat
      striatal slices. Based on the pharmacological profile of the PKC inhibitors
      tested, as well as reports in the literature on PKC

PMID- 12490614
TI  - Effects of angiotensin-converting enzyme inhibition and angiotensin II type 1
      receptor blockade on beta-adrenoceptor signaling in heart failure produced by
      myocardial Infarction in rabbits: reversal of altered expression of beta
      adrenoceptor kinase and G i alpha.
AB  - Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1
      (AT1) receptor blockers have been demonstrated to improve symptoms and prognosis
      in heart failure (HF). We compared the effects of ACE inhibition and AT1 receptor
      blockade on myocardial beta-adrenoceptor desensitization in rabbits with HF
      established 3 weeks after myocardial infarction (MI) with left circumflex
      coronary artery ligation. Rabbits with MI were randomized to no treatment, the
      ACE inhibitor temocapril (0.5 mg/kg/day) or AT1 receptor blocker valsartan (3
      mg/kg/day). Echocardiographic examinations showed that, relative to rabbits with
      untreated MI, rabbits receiving temocapril or valsartan had a limitation of
      cardiac remodeling and prevention of the development of systolic dysfunction.
      Circulating plasma norepinephrine levels that were markedly elevated in MI
      animals were strongly inhibited by temocapril or valsartan therapy. beta
      Adrenoceptor density, beta-adrenoceptor proportion showing high-affinity agonist
      binding, and basal and isoproterenol-stimulated adenylate cyclase activities were
      significantly reduced in MI rabbits. These defects were similarly reversed by
      temocapril or valsartan. Importantly, as found in human HF, myocardial protein
      levels of beta-adrenoceptor kinase 1 and G(i alpha) were significantly elevated
      in MI rabbits, suggesting that these molecules are contributing to the defects in
      myocardial beta-adrenoceptor signaling. The expression levels of these molecules
      were normalized equally by both treatments. The results suggest that
      pharmacologically different interventions in the renin-angiotensin system can
      equivalently improve the derangements in the beta-adrenoceptor signaling system
      in the failing heart. This may be important for the beneficial effects of these
      agents in HF.

PMID- 12490615
TI  - Constitutive coupling of a chimeric dopamine D2/alpha 1B receptor to the
      phospholipase C pathway: inverse agonism to silent antagonism by neuroleptic
      drugs.
AB  - Neuroleptic drugs have been suggested to act as inverse agonists at the dopamine
      D2 receptor, but no link between therapeutic efficacy and ligand's intrinsic
      activity could be determined. Since the resolving capacity to monitor inverse
      agonism at dopamine D2 receptors is limited, we speculated that receptor
      constitutive activation could be enhanced by constructing chimeric D2/alpha 1B
      receptors. Marked inverse agonist responses with a series of dopamine antagonists
      were obtained by: 1) exchange of the D 2short receptor's 3ICL by that of the
      alpha 1B-adrenoceptor, 2) incorporation of an activating mutation (Ala 279 Glu)
      in the distal portion of its 3ICL, and 3) coexpression with a G alpha11 protein.
      This chimeric D2/alpha 1B receptor construct displayed a ligand binding profile
      comparable to that of the wild-type (wt) D 2short receptor and an effector
      activation profile close to that of the wt alpha 1B-adrenoceptor. Most of the
      dopamine antagonists attenuated by -54 to -59% basal inositol phosphates (IP)
      formation, thus clearly acting as inverse agonists. Ziprasidone behaved as a
      silent antagonist (+5% versus basal IP level) and antagonized both dopamine
      mediated (pK B, 7.61) and tropapride-mediated (pK B, 8.52) IP responses.
      Clozapine, olanzapine, and raclopride displayed partial inverse agonist
      properties (-31, -67, and -71% versus tropapride, respectively), whereas
      bromerguride (+63%) and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino tetralin)
      [(+)-UH 232] (+88%) demonstrated positive agonism. In conclusion, analyses with
      the chimeric D2/alpha 1B Ala 279 Glu 3ICL receptor construct suggest that
      neuroleptic drugs can be differentiated on the basis of their intrinsic activity,
      as they can either activate, inhibit, or be silent at this receptor construct.

PMID- 12490616
TI  - Molecular and behavioral interactions between central melanocortins and cocaine.
AB  - Behavioral and molecular studies have established a link between drugs of abuse
      and the central melanocortin system, particularly the melanocortin 4 receptor
      (MC4-R). The present study expands this line of investigation to characterization
      of the neurochemical and behavioral interactions between MC4-R and the
      psychomotor stimulant, cocaine. The results demonstrate that repeated, but not
      acute, cocaine administration up-regulates MC4-R mRNA expression in the striatum
      and hippocampus, but not cerebral cortex. Pharmacological studies indicate that
      the up-regulation of MC4-R expression occurs via dopamine D1 and D2 receptor
      dependent mechanisms. The D1/D2 antagonist haloperidol and the D2-selective
      antagonist eticlopride mimic the effect of cocaine on MC4-R expression. In
      addition, coadministration of a D1-selective antagonist, SCH 23390 [R-(+)-7
      chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine],
      completely blocks the up-regulation of MC4 mRNA by cocaine, demonstrating that D1
      receptor activation is necessary for this response. Moreover, the results
      demonstrate that cocaine treatment increases behavioral responses (grooming and
      locomotor activity) to infusions of a melanocortin agonist, indicating that up
      regulation of MC4-R expression results in functional consequences. These data
      further support a role for the melanocortin-MC4-R neuropeptide system in the
      biochemical and behavioral effects of cocaine.

PMID- 12490617
TI  - N-n-alkylnicotinium analogs, a novel class of nicotinic receptor antagonists:
      interaction with alpha4beta2* and alpha7* neuronal nicotinic receptors.
AB  - The current study demonstrates that N-n-alkylnicotinium analogs with increasing n
      alkyl chain lengths from 1 to 12 carbons have varying affinity (Ki = 90 nM-20
      microM) for S-(-)-[3H]nicotine binding sites in rat striatal membranes. A linear
      relationship was observed such that increasing n-alkyl chain length provided
      increased affinity for the alpha4beta2* nicotinic acetylcholine receptor (nAChR)
      subtype, with the exception of N-n-octylnicotinium iodide (NONI). The most potent
      analog was N-n-decylnicotinium iodide (NDNI; Ki = 90 nM). In contrast, none of
      the analogs in this series exhibited high affinity for the [3H]methyllycaconitine
      binding site, thus indicating low affinity for the alpha7* nAChR. The C8 analog,
      NONI, had low affinity for S-(-)-[3H]nicotine binding sites but was a potent
      inhibitor of S-(-)-nicotine-evoked [3H]dopamine (DA) overflow from superfused
      striatal slices (IC50 = 0.62 microM), thereby demonstrating selectivity for the
      nAChR subtype mediating S-(-)-nicotine-evoked [3H]DA overflow (alpha3alpha6beta2*
      nAChRs). Importantly, the N-n-alkylnicotinium analog with highest affinity for
      the alpha4beta2* subtype, NDNI, lacked the ability to inhibit S-(-)-nicotine
      evoked [3H]DA overflow and, thus, appears to be selective for alpha4beta2*
      nAChRs. Furthermore, the present study demonstrates that the interaction of these
      analogs with the alpha4beta2* subtype is via a competitive mechanism. Thus,
      selectivity for the alpha4beta2* subtype combined with competitive interaction
      with the S-(-)-nicotine binding site indicates that NDNI is an excellent
      candidate for studying the structural topography of alpha4beta2* agonist
      recognition binding sites, for identifying the antagonist pharmacophore on the
      alpha4beta2* nAChR, and for defining the role of this subtype in physiological
      function and pathological disease states.

PMID- 12490618
TI  - Antisense oligonucleotide blockade of tumor necrosis factor-alpha in two murine
      models of colitis.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine involved in the
      pathogenesis of inflammatory bowel disease. We have developed a second-generation
      antisense oligonucleotide (ISIS 25302) specific for murine TNF-alpha and have
      evaluated this oligonucleotide in two models of gut inflammation of distinct
      etiology. ISIS 25302 decreased TNF-alpha mRNA in a dose- and sequence-dependent
      manner in vitro in the mouse macrophage cell line P388D1. It also reduced TNF
      alpha mRNA in vivo, in whole adipose tissue and in macrophages isolated from the
      adipose tissue of db/db mice, a strain with constitutively high expression of TNF
      alpha. ISIS 25302 significantly reduced disease activity index scores in mice
      with both an acute and a chronic form of dextran sodium sulfate (DSS)-induced
      colitis. It also significantly improved histopathological scores in interleukin
      (IL)-10-deficient mice. This was accompanied by reductions in both the basal and
      lipopolysaccharide-stimulated secretion of TNF-alpha and interferon-gamma in
      colonic organ cultures from IL-10 -/- mice. In this model, efficacy was obtained
      with both a prophylactic treatment regimen or a therapeutic dosing protocol begun
      after colitis was already present. In both the DSS and IL-10 -/- models,
      scrambled and mismatch control oligonucleotides were largely without effect,
      suggesting that ISIS 25302 was exerting its effects through a sequence-dependent
      antisense mechanism.

PMID- 12490619
TI  - Transcellular transport of a highly polar 3+ net charge opioid tetrapeptide.
AB  - Oligopeptides are generally thought to have poor permeability across biological
      membranes. Recent studies, however, suggest significant distribution of
      [Dmt1]DALDA (Dmt-D-Arg-Phe-Lys-NH2; Dmt is 2',6'-dimethyltyrosine), a 3+ net
      charge opioid peptide, to the brain and spinal cord after subcutaneous
      administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the
      uptake of di- and tripeptides across cell membranes, but their ability to
      transport tetrapeptides is not clear. The purpose of this study was to determine
      whether [Dmt1]DALDA can translocate across Caco-2 cell monolayers and whether
      PEPT1 plays a role in the uptake process. Our results show that [3H][Dmt1]DALDA
      can readily translocate across Caco-2 cells, with a permeability coefficient
      estimated to be 1.24 x 10(-5) cm/s. When incubated with Caco-2 cells,
      [3H][Dmt1]DALDA was detected in cell lysates by 5 min. The internalization of
      [Dmt1]DALDA was confirmed visually with a fluorescent [Dmt1]DALDA analog (H-Dmt-D
      Arg-Phe-dnsDap-NH2; dnsDap is beta-dansyl-L-alpha,beta-diaminopropionic acid).
      The uptake of [3H][Dmt1]DALDA was concentration-dependent but temperature- and pH
      independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [14C]glycine
      sarcosine uptake but increased [3H][Dmt1]DALDA uptake 34-fold. These findings
      suggest that PEPT1 is not involved in [Dmt1]DALDA internalization. [Dmt1]DALDA
      uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells,
      and was independent of whether the cells expressed opioid receptors. The efflux
      of [3H][Dmt1]DALDA from Caco-2 cells was temperature-dependent and was inhibited
      by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These
      data show transcellular translocation of a highly polar 3+ charge tetrapeptide
      and suggest that [Dmt1]DALDA may not only distribute across the blood-brain
      barrier but also it may even have reasonable oral absorption.

PMID- 12490620
TI  - Novel small molecule inhibitors of caspase-3 block cellular and biochemical
      features of apoptosis.
AB  - Caspase-3 is an intracellular cysteine protease, activated as part of the
      apoptotic response to cell injury. Its interest as a therapeutic target has led
      many to pursue the development of inhibitors. To date, only one series of
      nonpeptidic inhibitors have been described, and these have limited selectivity
      within the caspase family. Here we report the properties of a series of
      anilinoquinazolines (AQZs) as potent small molecule inhibitors of caspase-3. The
      AQZs inhibit human caspase-3 with Ki values in the 90 to 800 nM range. A subset
      of AQZs are equipotent against caspase-6, although most lack activity against
      this isoform and caspase-1, -2, -7, and -8. The AQZs inhibit endogenous caspase-3
      activity toward a cell permeable, exogenously added substrate in staurosporine
      treated SH-SY5Y cells. The AQZs reduce biochemical and cellular features of
      apoptosis that are thought to be a consequence of caspase-3 activation including
      DNA fragmentation, TUNEL staining, and the various morphological features that
      define the terminal stages of apoptotic cell death. Moreover, the AQZs also
      inhibit apoptosis induced by nerve growth factor withdrawal from differentiated
      PC12 cells. Thus, the AQZs represent a new and structurally novel class of
      inhibitors, some of which selectively inhibit caspase-3 and will thereby allow
      evaluation of the role of caspase-3 activity in various cellular models of
      apoptosis.

PMID- 12490621
TI  - Constitutive expression of p-glycoprotein in normal lung alveolar epithelium and
      functionality in primary alveolar epithelial cultures.
AB  - The multidrug resistant (MDR) transporter P-glycoprotein (P-gp) is constitutively
      expressed in normal tissues, where its spatial distribution defines it as an
      important element reducing the systemic exposure and tissue access of potentially
      harmful xenobiotics. We sought to determine whether P-gp is functionally
      expressed within alveolar epithelium of lung, in particular within the
      predominant cell type of this barrier, the alveolar epithelial (AE) type I cell.
      By immunohistochemistry, MDR-1/mdr-1 P-gp was localized to luminal membranes of
      AE type I epithelium within normal human and rat lung tissue. Using a primary rat
      cell culture model affording study of AE type II to AE type I differentiation, we
      observed increased expression (reverse transcription-polymerase chain reaction
      (RT-PCR), Western blot, and immunoflow cytometry techniques) of mdr-1a and mdr-1b
      P-gp in the cultures as they adopted an AE type I phenotype; freshly isolated AE
      type II cells were negative for mdr-1/P-gp. The functionality of P-gp within the
      AE cultures was demonstrated by a flow cytometric accumulation-retention assay
      using rhodamine-123 as substrate, and also by the polarized transport of
      vinblastine across confluent AE type I monolayers (basal-to-apical permeability
      was 3-fold that of apical-to-basal permeability), which was found to be
      comparable with the P-gp transport barrier presented by Caco-2 cell monolayers.
      The implications of localizing P-gp within alveolar epithelium is of significance
      to studies of fundamental respiratory cell biology as well as to further
      clarifying the nature of the barrier to xenobiotic transfer from alveolar
      airspace to pulmonary interstitium and capillary blood.

PMID- 12490622
TI  - Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of
      taurine and insulin-like growth factor-1.
AB  - A preclinical screening for prompt-to-use drugs that are safer than steroids and
      beneficial in Duchenne muscular dystrophy was performed. Compounds able to reduce
      calcium-induced degeneration (taurine or creatine 10% in chow) or to stimulate
      regeneration [insulin-like growth factor-1 (IGF-1); 50 or 500 microg/kg s.c.]
      were administered for 4 to 8 weeks to mdx mice undergoing chronic exercise on a
      treadmill, a protocol to worsen dystrophy progression. alpha-Methyl-prednisolone
      (PDN; 1 mg/kg) was used as positive control. The effects were evaluated in vivo
      on forelimb strength and in vitro electrophysiologically on the macroscopic
      chloride conductance (gCl), an index of degeneration-regeneration events in mdx
      muscles, and on the mechanical threshold, a calcium-sensitive index of excitation
      contraction coupling. The exercise produced a significant weakness and an
      impairment of gCl, by further decreasing the already low value of degenerating
      diaphragm (DIA) and fully hampering the increase of gCl typical of regenerating
      extensor digitorum longus (EDL) mdx muscle. The already negative voltage
      threshold for contraction of mdx EDL was also slightly worsened. Taurine >
      creatine > IGF-1 counteracted the exercise-induced weakness. The amelioration of
      gCl was drug- and muscle-specific: taurine was effective in EDL, but not in DIA
      muscle; IGF-1 and PDN were fully restorative in both muscles, whereas creatine
      was ineffective. An acute effect of IGF-1 on gCl was observed in vitro in
      untreated, but not in IGF-1-treated exercised mdx muscles. Taurine > PDN > IGF-1,
      but not creatine, significantly ameliorated the negative threshold voltage values
      of the EDL fibers. The results predict a potential benefit of taurine and IGF-1
      for treating human dystrophy.

PMID- 12490623
TI  - Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in
      endotoxemic mice and immunostimulated caco-2 enterocytic monolayers.
AB  - Ethyl pyruvate (EP) solution ameliorates ileal mucosal hyperpermeability and
      decreases the expression of several proinflammatory genes in ileal and/or colonic
      mucosa when it is used instead of Ringer's lactate solution (RLS) to resuscitate
      mice from hemorrhagic shock. To test the hypothesis that EP can ameliorate gut
      barrier dysfunction induced by other forms of inflammation, we incubated Caco-2
      monolayers for 24 to 48 h with cytomix (a mixture of interferon-gamma, tumor
      necrosis factor-alpha, and interleukin-1beta) in the presence or absence of
      graded concentrations of EP or sodium pyruvate. Cytomix increased the
      permeability of Caco-2 monolayers to fluorescein isothiocyanate-labeled dextran
      (FD4; average molecular mass 4 kDa), but this effect was inhibited by adding 0.1
      to 10 mM EP (but not similar concentrations of sodium pyruvate) to the culture
      medium. EP inhibited several other cytomix-induced phenomena, including nuclear
      factor-kappaB activation, inducible nitric oxide synthase mRNA expression, and
      nitric oxide production. Cytomix altered the expression and localization of the
      tight junctional proteins, ZO-1 and occludin, but this effect was prevented by
      EP. Delayed treatment with EP solution instead of RLS ameliorated ileal mucosal
      hyperpermeability to FD4 and bacterial translocation to mesenteric lymph nodes in
      mice challenged with lipopolysaccharide (LPS). These data support the view that
      EP ameliorates cytokine- and/or LPS-induced derangements in intestinal epithelial
      barrier function.

PMID- 12490624
TI  - Analysis of differential substrate selectivities of CYP2B6 and CYP2E1 by site
      directed mutagenesis and molecular modeling.
AB  - Human CYP2B6 and CYP2E1 were used to investigate the extent to which differential
      substrate selectivities between cytochrome P450 subfamilies reflect differences
      in active-site residues as opposed to distinct arrangement of the backbone of the
      enzymes. Reciprocal CYP2B6 and CYP2E1 mutants at active-site positions 103, 209,
      294, 363, 367, and 477 (numbering according to CYP2B6) were characterized using
      the CYP2B6-selective substrate 7-ethoxy-4-trifluoromethylcoumarin, the CYP2E1
      selective substrate p-nitrophenol, and the common substrates 7-ethoxycoumarin, 7
      butoxycoumarin, and arachidonic acid. This report is the first to study the
      active site of CYP2E1 by systematic site-directed mutagenesis. One of the most
      intriguing findings was that substitution of CYP2E1 Phe-477 with valine from
      CYP2B6 resulted in significant 7-ethoxy-4-trifluoromethylcoumarin deethylation.
      Use of three-dimensional models of CYP2B6 and CYP2E1 based on the crystal
      structure of CYP2C5 suggested that deethylation of 7-ethoxy-4
      trifluoromethylcoumarin by CYP2E1 is impeded by van der Waals overlaps with the
      side chain of Phe-477. Interestingly, none of the CYP2B6 mutants acquired
      enhanced ability to hydroxylate p-nitrophenol. Substitution of residue 363 in
      CYP2E1 and CYP2B6 resulted in significant alterations of the metabolite profile
      for the side chain hydroxylation of 7-butoxycoumarin. Probing of CYP2E1 mutants
      with arachidonic acid indicated that residues Leu-209 and Phe-477 are critical
      for substrate orientation in the active site. Overall, the study revealed that
      differences in the side chains of active-site residues are partially responsible
      for differential substrate selectivities across cytochrome P450 subfamilies.
      However, the relative importance of active-site residues appears to be dependent
      on the structural similarity of the compound to other substrates of the enzyme.

PMID- 12490626
TI  - Comparing parental distress, family functioning, and the role of social support
      for caregivers with and without a child with juvenile rheumatoid arthritis.
AB  - OBJECTIVE: To assess parental distress, family functioning, and social support
      among parents of children with a lifetime diagnosis of juvenile rheumatoid
      arthritis (JRA) and comparison families. METHODS: Parents of 64 children with JRA
      (64 mothers, 46 fathers) completed questionnaires and in-home interviews along
      with 64 matched comparison families. Average time since diagnosis for children
      with JRA was 70 months. RESULTS: Families of children with JRA generally reported
      levels of parental distress, family functioning, and social support similar to
      those for comparison families. More mothers of children with JRA exceeded the
      clinical cutoff on the SCL-90-R than comparison mothers. Although disease
      characteristics and social support did not distinguish subgroups of parents at
      greater risk for problems, family supportiveness and conflict were associated
      with caseness for mothers of children with JRA. CONCLUSIONS: Families of children
      with JRA exhibited substantial resilience over the long term. Further multisite
      study of children recently diagnosed and with more severe forms of JRA is
      warranted to determine intervention needs, especially for mothers.

PMID- 12490627
TI  - A controlled longitudinal study of the social functioning of children with
      juvenile rheumatoid arthritis.
AB  - OBJECTIVE: To complete an assessment of social functioning of children with
      juvenile rheumatoid arthritis (JRA) and nonchronically ill controls who had been
      evaluated 2 years earlier (Noll et al., 2000) and to examine the impact of
      disease severity or disease activity over time on the social functioning of
      children with JRA. METHODS: Peer-, teacher-, and self-reports of social
      functioning were obtained from 57 children with JRA and 63 controls. Social
      reputation and social acceptance were examined cross-sectionally and
      longitudinally. RESULTS: Cross-sectional analyses indicated no significant
      differences between children with JRA and controls on measures of social
      functioning. For children with more severe disease, like ratings declined over
      the 2-year period relative to children with mild disease. Children with active
      disease were chosen fewer times over the 2-year period as a best friend than
      children in remission. CONCLUSIONS: Because children with severe or active JRA
      may be at risk for difficulties with social acceptance over time, they are
      appropriate targets for interventions that ameliorate or prevent these
      difficulties.

PMID- 12490628
TI  - Psychological adjustment of children and adolescents with chronic arthritis: a
      meta-analytic review.
AB  - OBJECTIVE: To review studies of psychological adjustment among children and
      adolescents with chronic arthritis to determine whether they are at more risk for
      development of adjustment problems than controls. METHODS: We used meta-analytic
      techniques to review 21 studies reporting overall adjustment problems,
      internalizing symptoms, externalizing symptoms, or self-concept among youths with
      arthritis. RESULTS: Youths with arthritis displayed increased risk for overall
      adjustment problems and internalizing symptoms, but not for externalizing
      symptoms or poor self-concept. Risk was greater in studies making comparisons to
      study controls rather than to norms and in studies including mixed disease
      samples (arthritis plus other rheumatic diseases) rather than samples of youths
      with arthritis only. CONCLUSIONS: Results suggest the importance of assessing for
      internalizing problems among youths with chronic arthritis. Future research may
      benefit from inclusion of child self-report of adjustment problems, diagnostic
      specificity in reporting results, and use of adjustment measures without somatic
      items.

PMID- 12490629
TI  - Commentary: juvenile rheumatic disease as a psychosocial stressor.

PMID- 12490630
TI  - Commentary: Are children with JRA and their families at risk or resilient?

PMID- 12490631
TI  - Pain reactivity and somatization in kindergarten-age children.
AB  - OBJECTIVE: To evaluate predictors of somatization and pain reactivity in
      childhood. METHODS: Facial expressions of children undergoing inoculation were
      scored for pain reactivity. Measures of temperament, pain experience, pain
      models, parental behavior, and parental ability to decode pain were examined for
      their ability to predict pain reactivity and somatization in a structural
      modeling analysis. RESULTS: Pain reactivity was associated positively with
      parental reports of their child's somatization. Child temperament, previous
      negative experiences with medical procedures, and maternal responses to their
      children's pain were positively associated with pain reactivity. CONCLUSIONS:
      Temperament and pain experience may play a role in children's pain reactivity,
      and reactivity may contribute to the development of somatization. Although the
      model that guided the analysis proved to be a reasonable description of the
      outcomes, several anticipated relationships were not significant. We discuss
      implications for a refined model of somatization and for early identification and
      prevention.

PMID- 12490632
TI  - A prospective study of the relationship over time of behavior problems,
      intellectual functioning, and family functioning in children with sickle cell
      disease: a report from the Cooperative Study of Sickle Cell Disease.
AB  - OBJECTIVE: To longitudinally assess the relationship of behavioral problems,
      intellectual functioning, and family functioning in children with sickle cell
      disease (SCD). METHOD: The study sample included 222 children enrolled in the
      Cooperative Study of Sickle Cell Disease (CSSCD). The study protocol included
      intellectual evaluation and brain magnetic resonance imaging (MRI) of the
      children, and mothers completed the Child Behavior Checklist and Family
      Environment Scale. At least two complete sets of measures were obtained across
      four assessment points over the study period of 9 years. RESULTS: Intellectual
      functioning declined, but family functioning and behavior problem scores did not
      change significantly. Consistent behavior problems were reported by mothers for
      9% of the children. The risk of consistent behavior problems was not related to
      MRI classification, gender, education level of mother, or age of the child but
      significantly increased with higher baseline levels of family conflict and
      decreased with higher baseline full-scale IQ. An increase in behavior problems
      was associated with an increase in family conflict. CONCLUSIONS: Maternal
      appraisal of family conflict is a risk factor for the small subgroup of children
      with SCD with consistent mother-reported behavior problems and a salient
      intervention target for fostering adaptation.

PMID- 12490633
TI  - A follow-up study of adherence and glycemic control among Hong Kong youths with
      diabetes.
AB  - OBJECTIVE: To extend longitudinally an earlier study of the pathway from symptoms
      of emotional distress (ED) through self-efficacy (SE) and adherence to glycemic
      control (GC) in youths with diabetes, and to examine the contribution of
      different specific adherence behaviors to changes in GC. METHODS: Fifty-six Hong
      Kong youths with diabetes received a follow-up evaluation 12-24 months after
      initial participation. ED, SE, self-reported adherence to medical regimen (SRA),
      and GC were assessed at both evaluations. RESULTS: The pathway from ED to SE to
      SRA to GC was replicated. Participants' SRA to regular checks on blood glucose
      levels, and taking steps to maintain levels in the recommended range, explained
      significant variance in changes in GC. CONCLUSIONS: The model offers strategies
      to enhance health care in youths with diabetes. Findings support the importance
      of adherence to the medical regimen but emphasize the complexity of the
      relationship between adherence behaviors and GC. Self-regulatory behaviors,
      rather than compliance with fixed instructions, appear to have the most impact on
      GC.

PMID- 12490638
TI  - Objectivity and the neutral expert.

PMID- 12490639
TI  - Science, ethics, and professional public health practice.

PMID- 12490640
TI  - Self care and consumer health. Do we need a public health ethics?

PMID- 12490641
TI  - A glossary for research in occupational health.
AB  - This glossary includes a selection of terms pertaining to the field of research
      in occupational health. The glossary is mostly addressed to readers not
      familiarised with the more specific terms used in the study and protection of
      workers' health. The terms have been ordered according to their logical
      connections, so the glossary can be read from beginning to end giving the reader
      an overview on occupational health research main focuses, methods, and
      applications.

PMID- 12490642
TI  - Health impact assessment of housing improvements: incorporating research
      evidence.
AB  - BACKGROUND: Health impact assessment (HIA) has been widely recommended for future
      social policies and investment, such as housing improvement. However, concerns
      have been raised about the utility and predictive value of an HIA. Use of
      existing research data would add more weight to forecasts by an HIA. METHODS,
      RESULTS, and CONCLUSIONS: A recent systematic review of housing intervention
      studies found a lack of research. The authors recommended that a broader evidence
      base would be needed to support HIA. In response to consultation with
      policymakers and HIA practitioners this paper presents a way in which research
      can be used to inform HIA. Based on the systematic review, the authors have
      developed a table of synthesised findings indicating the expected health effects
      of specific housing improvements. The authors also reviewed observational data of
      housing associated health risks to highlight the key impacts to consider when
      doing a housing HIA. The findings are presented and the authors discuss how they
      should be used to inform evidence based housing HIA. In addition to considering
      the existing research, HIA must consider the local relevance of research.
      Consultation with local stakeholders also needs to be incorporated to the final
      assessment. The lack of data and the difficulties in gathering and reviewing data
      mean that not all HIAs will be able to be informed by research evidence. Well
      conducted prospective validation of HIAs would contribute to the development of
      healthy housing investment by informing future housing HIA.

PMID- 12490643
TI  - Avoidable hospitalisation rates in Singapore, 1991-1998: assessing trends and
      inequities of quality in primary care.
AB  - STUDY OBJECTIVES: To assess avoidable hospitalisation as an indicator of quality
      of primary care by examining trends and gender and ethnic variations. DESIGN AND
      SETTING: Aggregated nationwide data in Singapore from 1991 to1998 were analysed
      for hospitalisations for chronic diseases that are avoidable by timely,
      appropriate, and effective primary care: asthma, congestive heart failure,
      chronic obstructive pulmonary disease, diabetes mellitus, and hypertension
      (avoidable hospitalisations). MAIN RESULTS: Of a total of 1 479 494
      hospitalisations, 6.7% were for ambulatory care sensitive conditions (ACSC). The
      annual rate of avoidable hospitalisation was 29.4 per 10 000 population. Women
      had lower rates of avoidable hospitalisations than men (22.4 versus 29.5 per 10
      000), as well as for total hospitalisations (496.2 versus 515.5 per 10 000).
      Adjusted for total hospitalisation, men were 1.3 times more likely than women to
      be hospitalised for ACSC. With similar adjustments for baseline utilisation,
      Indian and Malays had 1.7 and 1.8 times higher rates of avoidable
      hospitalisations than Chinese. Avoidable hospitalisation decline was -9.1%
      overall; greater in men (-11.8%) than in women (-5.3%); greater for Chinese (
      15.8%), than Malays (-1.1%) and Indians (increase of +4.3%). CONCLUSION: Gender
      and ethnic differences and declining trends in avoidable hospitalisation
      demonstrated in this study suggest that avoidable hospitalisation rates are a
      sensitive indicator for assessing quality of primary ambulatory care.

PMID- 12490644
TI  - Social capital and leisure time physical activity: a population based multilevel
      analysis in Malmo, Sweden.
AB  - OBJECTIVE: To investigate the influence of social capital and individual factors
      on the level of leisure time physical inactivity in the neighbourhoods. METHODS:
      The public health survey in Malmo 1994 is a cross sectional study. A total of
      5600 people aged 20-80 years were invited to answer a postal questionnaire. The
      participation rate was 71%. A multilevel logistic regression model, with
      individuals at the first level and neighbourhoods at the second, was performed.
      The effect (intra-area correlation, cross level modification, and odds ratios)
      was analysed of individual and neighbourhood (the 1993 migration out of an area
      as a proxy for social capital) factors on leisure time physical inactivity after
      adjustment for individual factors. RESULTS: Neighbourhood factors accounted for
      5.0% of the crude total variance in physical inactivity. This effect was
      significantly reduced when the individual factors, especially country of origin,
      education, and social participation, were included in the model. In contrast, it
      was not reduced by the introduction of the contextual social capital variable.
      CONCLUSION: This study suggests that in the neighbourhoods of Malmo leisure time
      physical inactivity is mainly affected by individual factors.

PMID- 12490645
TI  - Differential correlates of physical activity in urban and rural adults of various
      socioeconomic backgrounds in the United States.
AB  - STUDY OBJECTIVES: Few studies have analysed the rates and correlates of physical
      activity in economically and geographically diverse populations. Objectives were
      to examine: (1) urban-rural differences in physical activity by several
      demographic, geographical, environmental, and psychosocial variables, (2)
      patterns in environmental and policy factors across urban-rural setting and
      socioeconomic groups, (3) socioeconomic differences in physical activity across
      the same set of variables, and (4) possible correlations of these patterns with
      meeting of physical activity recommendations. DESIGN: A cross sectional study
      with an over sampling of lower income adults was conducted in 1999-2000. SETTING:
      United States. PARTICIPANTS: 1818 United States adults. MAIN RESULTS: Lower
      income residents were less likely than higher income residents to meet physical
      activity recommendations. Rural residents were least likely to meet
      recommendations; suburban residents were most likely to meet recommendations.
      Suburban, higher income residents were more than twice as likely to meet
      recommendations than rural, lower income residents. Significant differences
      across income levels and urban/rural areas were found for those reporting
      neighbourhood streets, parks, and malls as places to exercise; fear of injury,
      being in poor health, or dislike as barriers to exercise and those reporting
      encouragement from relatives as social support for exercise. Evidence of a
      positive dose-response relation emerged between number of places to exercise and
      likelihood to meet recommendations for physical activity. CONCLUSIONS: Both
      income level and urban rural status were important predictors of adults'
      likelihood to meet physical activity recommendations. In addition, environmental
      variables vary in importance across socioeconomic status and urban-rural areas.

PMID- 12490646
TI  - Children born in the summer have increased risk for coeliac disease.
AB  - STUDY OBJECTIVE: Coeliac disease, also called permanent gluten sensitive
      enteropathy, is being recognised as a widespread health problem. Defining the
      possible role of environmental factors in its aetiology might open doors to
      primary prevention. This study therefore analysed if the risk for coeliac disease
      varies with month of birth as a proxy for a seasonal pattern for possible causal
      environmental exposure(s). DESIGN: A population based incidence register of
      coeliac disease in children below 15 years of age covering the period from 1973
      to 1997. Incidence rates were calculated by month of birth, stratified for age at
      diagnosis. Poisson regression analyses were used to estimate the relative risk
      for coeliac disease for children below 2 years of age by season of birth, also
      taking into account gender and time period of diagnosis. SETTING: Sweden.
      PARTICIPANTS: All 2151 children in the study base with verified coeliac disease.
      MAIN RESULTS: The risk for coeliac disease was significantly higher if born
      during the summer as compared with the winter (RR=1.4, 95% CI 1.2 to 1.7), but
      only in children below 2 years of age at diagnosis. This relative seasonal risk
      pattern prevailed during a 10 year epidemic of coeliac disease, although
      incidence rates varied threefold. The incidence was constantly higher among girls
      as compared with boys, but boys showed a more pronounced seasonal variation in
      risk than girls. CONCLUSIONS: An increased coeliac disease risk in children born
      in the summer compared with the winter reflects causal environmental exposure(s)
      with a seasonal pattern. Infections might be the exposure of importance, either
      by means of a direct causal role and/or through interaction with other exposures,
      for example, gluten intake. However, non-infectious exposures should also be
      explored as possible contributing causal factors.

PMID- 12490647
TI  - Impact of childhood and adulthood socioeconomic position on cause specific
      mortality: the Oslo Mortality Study.
AB  - OBJECTIVE: To study the impact of childhood and adulthood social circumstances on
      cause specific adult mortality. DESIGN: Census data on housing conditions from
      1960 and Personal Register income data for 1990 were linked to 1990-94 death
      registrations, and relative indices of inequality were computed for housing
      conditions in 1960 and for household income in 1990. PARTICIPANTS: The 128 723
      inhabitants in Oslo aged 31-50 years in 1990. MAIN RESULTS: Adulthood mortality
      was strongly associated with both childhood and adulthood social circumstances
      among both men and women. Cardiovascular disease mortality was more strongly
      associated with childhood than with adulthood social circumstances, while the
      opposite was found for psychiatric and accidental/violent mortality. Smoking
      related cancer mortality was related to both adulthood and childhood social
      circumstances in men, but considerably more strongly to adult social
      circumstances. CONCLUSIONS: Childhood social circumstances have an important
      influence on cardiovascular disease risk in adulthood. Current increases in child
      poverty that have been seen in Norway over the past two decades could herald
      unfavourable future trends in adult health.

PMID- 12490648
TI  - Is retirement good or bad for mental and physical health functioning? Whitehall
      II longitudinal study of civil servants.
AB  - BACKGROUND: To determine whether retirement at age 60 is associated with
      improvement or deterioration in mental and physical health, when analysed by
      occupational grade and gender. METHODS: Longitudinal study of civil servants aged
      54 to 59 years at baseline, comparing changes in SF-36 health functioning in
      retired (n=392) and working (n=618) participants at follow up. Data were
      collected from self completed questionnaires. RESULTS: Mental health functioning
      deteriorated among those who continued to work, but improved among the retired.
      However, improvements in mental health were restricted to those in higher
      employment grades. Physical functioning declined in both working and retired
      civil servants. CONCLUSION: The study found that retirement at age 60 had no
      effects on physical health functioning and, if anything, was associated with an
      improvement in mental health, particularly among high socioeconomic status
      groups.

PMID- 12490649
TI  - Effect of short-term exposure to gaseous pollution on asthma hospitalisation in
      children: a bi-directional case-crossover analysis.
AB  - STUDY OBJECTIVE: Assess associations between short-term exposure to gaseous
      pollutants and asthma hospitalisation among boys and girls 6 to12 years of age.
      DESIGN: A bi-directional case-crossover analysis was used. Conditional logistic
      regression models were fitted to the data for boys and girls separately.
      Exposures averaged over periods ranging from one to seven days were used to
      assess the effects of gaseous pollutants on asthma hospitalisation. Estimated
      relative risks for asthma hospitalisation were calculated for an incremental
      exposure corresponding to the interquartile range in pollutant levels, adjusted
      for daily weather conditions and concomitant exposure to particulate matter.
      SETTING: Toronto, Ontario, Canada. PARTICIPANTS: A total of 7319 asthma
      hospitalisations for children 6 to 12 years of age (4629 for boys and 2690 for
      girls) in Toronto between 1981 and 1993. MAIN RESULTS: A significant acute effect
      of carbon monoxide on asthma hospitalisation was found in boys, and sulphur
      dioxide showed significant effects of prolonged exposure in girls. Nitrogen
      dioxide was positively associated with asthma admissions in both sexes. The lag
      time for certain gaseous pollutant effects seemed to be shorter in boys (around
      two to three days for carbon monoxide and nitrogen dioxide), as compared with
      girls (about six to seven days for sulphur dioxide and nitrogen dioxide). The
      effects of gaseous pollutants on asthma hospitalisation remained after adjustment
      of particulate matter. The data showed no association between ozone and asthma
      hospitalisation in children. CONCLUSIONS: The study showed positive relations
      between gaseous pollutants (carbon monoxide, sulphur dioxide, and nitrogen
      dioxide) at comparatively low levels and asthma hospitalisation in children,
      using bi-directional case-crossover analyses. Though, the effects of certain
      specific gaseous pollutants were found to vary in boys and girls.

PMID- 12490650
TI  - Social inequalities in health by individual and household measures of social
      position in a cohort of healthy people.
AB  - STUDY OBJECTIVE: It is increasingly recognised that different dimensions of
      social inequality may be linked to health by different pathways. Furthermore,
      factors operating at the individual level such as employment conditions may
      affect health in a different way from household level factors. The paper examines
      the associations between self rated health and four measures of social position-
      occupational class, household social advantage, personal and household income.
      DESIGN: Multilevel logistic regression models were used to predict self rated
      health using longitudinal data from the British Household panel survey (BHPS)
      with respondents nested within households. Separate analyses were carried out for
      economically active and inactive respondents. SETTING: Interview based surveys of
      adults living within households that are representative of British households.
      PARTICIPANTS: Adult respondents from the BHPS. MAIN RESULTS: Occupational class
      has relatively strong effects on the self rated health of the economically
      active, although household level factors also seem to influence their health.
      Household social advantage has relatively strong effects on the self rated health
      of the economically inactive. CONCLUSIONS: The paper found evidence in support of
      the view that different dimensions of social inequality have different pathways
      to self rated health. There are unexplained similarities in health between
      household members, which require further investigation.

PMID- 12490651
TI  - Low response rate schools in surveys of adolescent risk taking behaviours:
      possible biases, possible solutions.
AB  - STUDY OBJECTIVE: To examine the potential biases introduced when students in low
      response rate schools are dropped from classroom based surveys of adolescent risk
      taking behaviour. DESIGN: Self administered confidential surveys were conducted
      in classrooms, with follow up visits to each school to survey students absent
      during the initial survey administration. Data on students in schools that
      achieved a 70% response rate are compared with data on students in schools that
      did not achieve this level of response. SETTING: New York City, United States.
      PARTICIPANTS: 1854 10th graders in 13 public (state supported) high schools. MAIN
      RESULTS: Students in schools with low response rates resulting from high rates of
      absenteeism have different demographic characteristics and engage in more risk
      behaviours than students in schools with low absenteeism and high response rates.
      Excluding schools with low rates of response can have an effect on estimates of
      risk behaviour, even after data are weighted for individual absences. The
      potential for bias is greatest when, in sampling schools, the proportion of
      schools with low response rates is large, and when such schools represent a large
      share of the students in the area under study. CONCLUSIONS: Excluding schools
      with poor response rates from survey samples using a classroom based approach
      does not improve, and may, under some circumstances, underestimate risky
      behaviour among adolescent populations.

PMID- 12490652
TI  - Collecting behavioural data using the world wide web: considerations for
      researchers.
AB  - OBJECTIVE: To identify and describe advantages, challenges, and ethical
      considerations of web based behavioural data collection. METHODS: This discussion
      is based on the authors' experiences in survey development and study design,
      respondent recruitment, and internet research, and on the experiences of others
      as found in the literature. RESULTS: The advantages of using the world wide web
      to collect behavioural data include rapid access to numerous potential
      respondents and previously hidden populations, respondent openness and full
      participation, opportunities for student research, and reduced research costs.
      Challenges identified include issues related to sampling and sample
      representativeness, competition for the attention of respondents, and potential
      limitations resulting from the much cited "digital divide", literacy, and
      disability. Ethical considerations include anonymity and privacy, providing and
      substantiating informed consent, and potential risks of malfeasance. CONCLUSIONS:
      Computer mediated communications, including electronic mail, the world wide web,
      and interactive programs will play an ever increasing part in the future of
      behavioural science research. Justifiable concerns regarding the use of the world
      wide web in research exist, but as access to, and use of, the internet becomes
      more widely and representatively distributed globally, the world wide web will
      become more applicable. In fact, the world wide web may be the only research tool
      able to reach some previously hidden population subgroups. Furthermore, many of
      the criticisms of online data collection are common to other survey research
      methodologies.

PMID- 12490653
TI  - Comparative analysis of nutrition data from national, household, and individual
      levels: results from a WHO-CINDI collaborative project in Canada, Finland,
      Poland, and Spain.
AB  - STUDY OBJECTIVE: This project determined to what extent data on diet and
      nutrition, which were collected in a non-uniform manner, could be harmonised and
      pooled for international and national comparison. DESIGN: Direct comparisons of
      dietary data between studies were made using food balance sheets (FBS), household
      budget surveys (HBS), and individual dietary data (IDS); comparisons were also
      made within countries. Differences in study design and methodological approaches
      were taken into consideration. Data from research projects from the following
      four World Health Organisation (WHO) Countrywide Integrated Noncommunicable
      Disease Intervention (CINDI) countries were included-Canada, Finland, Poland, and
      Spain. MAIN RESULTS: FBS overestimated food consumption and nutrient intake
      compared to IDS. Results between HBS and IDS were quite similar, except for fish,
      meat, pulses and vegetables, which were underestimated by HBS, and sugar and
      honey and cereals, which were overestimated. Percentages of energy from fat,
      carbohydrates and proteins were higher when estimated from FBS, HBS, and IDS
      respectively. CONCLUSIONS: Results suggest that estimations from these three
      sources of dietary data are difficult to compare because they are measuring
      different levels of dietary information. The understanding of their relations may
      be important in formulating and evaluating a nutrition policy.

PMID- 12490654
TI  - Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death
      ligand-induced apoptosis.
AB  - Somatostatin receptor subtype 2 (sst2) gene expression is lost in 90% of human
      pancreatic adenocarcinomas. We previously demonstrated that stable sst2
      transfection of human pancreatic BxPC-3 cells, which do not endogenously express
      sst2, inhibits cell proliferation, tumorigenicity, and metastasis. These sst2
      effects occur as a consequence of an autocrine sst2-dependent loop, whereby sst2
      induces expression of its own ligand, somatostatin. Here we investigated whether
      sst2 induces apoptosis in sst2-transfected BxPC-3 cells. Expression of sst2
      induced a 4.4- +/- 0.05-fold stimulation of apoptosis in BxPC-3 through the
      activation of tyrosine phosphatase SHP-1. sst2 also sensitized these cells to
      apoptosis induced by tumor necrosis factor alpha (TNFalpha), enhancing it 4.1- +/
      1.5-fold. Apoptosis in BxPC-3 cells mediated by TNF-related apoptosis-inducing
      ligand (TRAIL) and CD95L was likewise increased 2.3- +/- 0.5-fold and 7.4- +/-
      2.5-fold, respectively. sst2-dependent activation and cell sensitization to death
      ligand-induced apoptosis involved activation of the executioner caspases, key
      factors in both death ligand- or mitochondria-mediated apoptosis. sst2 affected
      both pathways: first, by up-regulating expression of TRAIL and TNFalpha
      receptors, DR4 and TNFRI, respectively, and sensitizing the cells to death ligand
      induced initiator capase-8 activation, and, second, by down-regulating expression
      of the antiapoptotic mitochondrial Bcl-2 protein. These results are of interest
      for the clinical management of chemoresistant pancreatic adenocarcinoma by using
      a combined gene therapy based on the cotransfer of genes for both the sst2 and a
      nontoxic death ligand.

PMID- 12490655
TI  - IL-7 induces bone loss in vivo by induction of receptor activator of nuclear
      factor kappa B ligand and tumor necrosis factor alpha from T cells.
AB  - IL-7, a powerful lymphopoietic cytokine, is elevated in rheumatoid arthritis (RA)
      and known to induce bone loss when administered in vivo. IL-7 has been suggested
      to induce bone loss, in part, by stimulating the proliferation of B220(+) cells,
      a population capable of acting as early osteoclast (OC) precursors. However, the
      mechanism by which IL-7 leads to differentiation of precursors into mature OCs
      remains unknown. We previously reported that, in vitro, IL-7 up-regulated T cell
      cytokines including receptor activator of nuclear factor kappaB ligand (RANKL).
      To demonstrate the importance of T cells to the bone-wasting effect of IL-7 in
      vivo, we have now examined IL-7-induced bone loss in T cell-deficient nude mice.
      We show that T cell-replete mice undergo significant osteoclastic bone loss after
      IL-7 administration, concurrent with induction of RANKL and tumor necrosis factor
      alpha (TNF-alpha) secretion by splenic T cells. In contrast, nude mice were
      resistant to IL-7-induced bone loss and showed no detectable increase in either
      RANKL or TNF-alpha, despite an up-regulation of B220(+) cells. Importantly, T
      cell adoptive transfer into nude mice restored IL-7-induced bone loss, and RANKL
      and TNF-alpha secretion, demonstrating that T cells are essential mediators of IL
      7-induced bone loss in vivo.

PMID- 12490656
TI  - Characterization of mouse clonogenic megakaryocyte progenitors.
AB  - Although it has been shown that unfractionated bone marrow, hematopoietic stem
      cells, common myeloid progenitors, and bipotent megakaryocyteerythrocyte
      progenitors can give rise to megakaryocyte colonies in culture, monopotent
      megakaryocyte-committed progenitors (MKP) have never been prospectively isolated
      from the bone marrow of adult mice. Here, we use a monoclonal antibody to the
      megakaryocyte-associated surface protein, CD9, to purify MKPs from the c
      kit(+)Sca-1(-)IL7Ralpha(-)Thy1.1(-)Lin(-) fraction of adult C57BLKa-Thy1.1 bone
      marrow. The CD9(+) fraction contained a subset of
      CD41(+)FcgammaR(lo)CD34(+)CD38(+) cells that represent approximately 0.01% of the
      total nucleated bone marrow cells. They give rise mainly to colony-forming unit
      megakaryocytes and occasionally burst-forming unit-megakaryocytes, with a plating
      efficiency >60% at the single-cell level. In vivo, MKPs do not have spleen colony
      forming activity nor do they contribute to long-term multilineage hematopoiesis;
      they give rise only to platelets for approximately 3 weeks. Common myeloid
      progenitors and megakaryocyteerythrocyte progenitors can differentiate into MKPs
      after 72 h in stromal cultures, indicating that MKPs are downstream of these two
      progenitors. These isolatable MKPs will be very useful for further studies of
      megakaryopoiesis as well as the elucidation of their gene expression patterns.

PMID- 12490657
TI  - Obesity as a disease: etiology, treatment, and management considerations for the
      obese patient.

PMID- 12490658
TI  - The obesity epidemic: pathophysiology and consequences of obesity.
AB  - Obesity has reached epidemic proportions in the United States: more than 20% of
      adults are clinically obese as defined by a body mass index of 30 kg/m(2) or
      higher, and an additional 30% are overweight. Environmental, behavioral, and
      genetic factors have been shown to contribute to the development of obesity.
      Elevated body mass index, particularly caused by abdominal or upper-body obesity,
      has been associated with a number of diseases and metabolic abnormalities, many
      of which have high morbidity and mortality. These include hyperinsulinemia,
      insulin resistance, type 2 diabetes, hypertension, dyslipidemia, coronary heart
      disease, gallbladder disease, and certain malignancies. This underscores the
      importance of identifying people at risk for obesity and its related disease
      states.

PMID- 12490659
TI  - Classification of obesity and assessment of obesity-related health risks.
AB  - The barriers to the evaluation and treatment of obesity by health-care providers
      include a lack of awareness of obesity as an independent risk factor for
      morbidity and mortality and inadequate training in the medical management of
      obesity. However, the increased risk of medical disorders and emotional
      consequences associated with obesity make the disorder a priority for physicians
      to assess and treat. Obesity researchers have published and promoted the use of
      evidence-based, practical guidelines to educate physicians about how best to
      approach obesity as a medical disorder. The guidelines support classification and
      assessment of obesity as an important component of the patient's medical care.
      Assessment begins with classification by body mass index (BMI), with overweight
      and obesity defined as a BMI of 25 and 30 kg/m(2), respectively. Patients with
      high-risk combinations of BMI, waist circumference, and specific cardiovascular
      risk factors should begin a weight-loss program if no contraindications are
      present. Proper assessment also includes evaluation of complicating factors for
      obesity, such as sleep apnea and type 2 diabetes, psychosocial factors, and the
      use of medications that may contribute to obesity. Special attention should be
      paid to elements of the physical examination that often are performed incorrectly
      in obese patients, such as pelvic exams. Gathering this information will allow
      the clinician to tailor a weight-loss program to each patient individually.
      Although this represents the most challenging component of obesity care,
      resources are available to guide the clinician.

PMID- 12490660
TI  - Management of obesity as a chronic disease: nonpharmacologic, pharmacologic, and
      surgical options.
AB  - The successful management of obesity requires a long-term approach that is
      tailored to an individual's lifestyle and needs. Initial treatment should focus
      on lifestyle modifications-dietary interventions and increased physical activity
      with behavioral modification strategies used adjunctively. Several antiobesity
      drugs are approved by the Food and Drug Administration for use in obese patients,
      as well as in overweight individuals with at least one obesity-related
      comorbidity. Most are approved only for short-term weight loss, but sibutramine
      and orlistat are approved for long-term weight loss and maintenance. In addition
      to weight reduction, in clinical trials these drugs provided beneficial actions
      on several cardiovascular risk factors. Several other drugs currently approved
      for other uses show promise in their ability to cause weight loss. Surgical
      options should be reserved for severely obese patients with significant medical
      comorbidities or physical conditions.

PMID- 12490662
TI  - Stepping down as Editor-in-Chief.

PMID- 12490661
TI  - Outpatient management of obesity: a primary care perspective.
AB  - An estimated 64% of the adult population in the United States is either
      overweight or obese. Because obesity affects such a large percentage of the
      population and carries with it numerous health risks, it is essential that
      physicians treat obesity and encourage healthy-weight maintenance within the
      primary care setting. Effective weight management will require providing the
      appropriate physical environment for the overweight or obese patient, properly
      evaluating the impact of a patient's weight on health, evaluating a patient's
      readiness to change, setting appropriate weight-loss goals, and providing
      information and help about how to modify dietary and physical activity patterns.
      Achieving and maintaining weight loss is more likely to be successful when there
      is a physician-patient partnership where the physician provides support and
      motivation for the patient's efforts to initiate and maintain a healthy body
      weight.

PMID- 12490663
TI  - Impact of visceral fat on blood pressure and insulin sensitivity in hypertensive
      obese women.
AB  - OBJECTIVE: The relationship among body fat distribution, blood pressure, serum
      leptin levels, and insulin resistance was investigated in hypertensive obese
      women with central distribution of fat. RESEARCH METHODS AND PROCEDURES: We
      studied 74 hypertensive women (age, 49.8 +/- 7.5 years; body mass index, 39.1 +/-
      5.5 kg/m(2); waist-to-hip ratio, 0.96 +/- 0.08). All patients were submitted to
      24-hour blood pressure ambulatory monitoring (24h-ABPM). Abdominal
      ultrasonography was used to estimate the amount of visceral fat (VF). Fasting
      blood samples were obtained for serum leptin and insulin determinations. Insulin
      resistance was estimated by homeostasis model assessment insulin resistance index
      (HOMA-r index). RESULTS: Sixty-four percent of the women were postmenopausal, and
      all patients showed central distribution of fat (waist-to-hip ratio > 0.85). The
      VF correlated with systolic 24h-ABPM values (r = 0.28, p = 0.01) and with HOMA-r
      index (r = 0.27; p = 0.01). VF measurement (7.5 +/- 2.3 vs. 5.9 +/- 2.2 cm, p <
      0.001) and the systolic 24h-ABPM (133 +/- 14.5 vs. 126 +/- 9.8 mm Hg, p = 0.04),
      but not HOMA-r index, were significantly higher in the postmenopausal group (n =
      48) than in the premenopausal group (n = 26). No correlations were observed
      between blood pressure levels and HOMA-r index, leptin, or insulin levels. In the
      multiple regression analysis, visceral fat, but not age, body fat mass, or HOMA-r
      index, correlated with the 24h-ABPM (p = 0.003). DISCUSSION: In centrally obese
      hypertensive women, the accumulation of VF, more often after menopause, is
      associated with higher levels of blood pressure and insulin resistance. The
      mechanism through which VF contributes to higher blood pressure levels seems to
      be independent of leptin or insulin levels.

PMID- 12490665
TI  - Overnight dexamethasone suppression test: a reliable screen for Cushing's
      syndrome in the obese.
AB  - OBJECTIVE: Reevaluation of the validity of the 1-mg overnight dexamethasone
      suppression test (ODST) as a screening test for Cushing's syndrome in obese
      patients. RESEARCH METHODS AND PROCEDURES: Eighty-six obese patients (body mass
      index, 30 to 53 kg/m(2)) that were referred to a general endocrine outpatient
      clinic for evaluation of simple obesity, diabetes mellitus, hypertension,
      polycystic ovary disease, or pituitary tumor. One milligram dexamethasone was
      administered orally at 11:00 PM, and serum cortisol levels were measured the
      following morning between 8:00 AM and 9:00 AM. Suppression of serum cortisol to
      <80 nM (3 micro g/dL) was chosen as the cut-off point for normal suppression.
      Patients with serum cortisol levels > or =80 nM were evaluated for Cushing's
      syndrome. RESULTS: Suppression of morning cortisol levels to <80 nM occurred in
      79 of the 86 obese patients. Seven patients had serum cortisol levels higher than
      80 nM; five were eventually diagnosed with Cushing's syndrome and two were
      considered false positive results in view of normal 24-hour free urinary cortisol
      and normal suppression on a low dose dexamethasone suppression test (0.5 mg of
      dexamethasone every 6 hours for 2 days). We found a false positive rate of 2.3%
      for the ODST using a cut-off serum cortisol of 80 nM. DISCUSSION: The ODST is a
      valid screening test for Cushing's syndrome in the obese population. The false
      positive rate was 2.3%, even when using a strict cut-off serum cortisol of 80 nM.
      Abnormal cortisol suppression in obese patients should be investigated and not be
      considered false positive results.

PMID- 12490664
TI  - Metabolic response to a mixed meal in obese and lean women from two South african
      populations.
AB  - OBJECTIVE: Lower lipid and insulin levels are found during a glucose-tolerance
      test in obese black than obese white South African women. Therefore, beta-cell
      function and lipid metabolism were compared in these populations during a mixed
      meal. RESEARCH METHODS AND PROCEDURES: Blood concentrations of glucose, free
      fatty acids (FFAs), insulin, lipograms, and in vivo FFA oxidation were determined
      at fasting and for 7 hours after oral administration of a mixed emulsion
      containing glucose-casein-sucrose-lipid and [1-(13)C] palmitic acid in 8 lean
      black women (LBW), 10 obese black women (OBW), 9 lean white women (LWW), and 10
      obese white women (OWW). Subcutaneous and visceral fat mass was assessed by
      computerized tomography. RESULTS: Visceral fat area was higher in OWW (152.7 +/-
      17.0 cm(2)) than OBW (80.0 +/- 6.7 cm(2); p < 0.01). In OBW, 30-minute insulin
      levels were higher (604.3 +/- 117.6 pM) than OWW (311.0 +/- 42.9 pM; p < 0.05).
      Total triglyceride was higher in OWW (706.7 +/- 96.0 mM x 7 hours) than OBW
      (465.7 +/- 48.2 mM x 7 hours; p < 0.05) and correlated with visceral fat area
      (beta = 0.38, p = 0.05). Palmitate oxidation was higher in lean than obese women
      in both ethnic groups and correlated negatively with fat mass (beta = -0.58, p <
      0.005). DISCUSSION: The higher 30-minute insulin response in OBW may reflect a
      higher insulinotropic effect of FFAs or glucose. The elevated triglyceride level
      of OWW may be due to their higher visceral fat mass and possibly reduced
      clearance by adipose tissue.

PMID- 12490666
TI  - Pleiotropic relationships between cortisol levels and adiposity: The HERITAGE
      Family Study.
AB  - OBJECTIVE: To investigate familial basis for the relationship between cortisol
      adiposity at baseline and their training responses. RESEARCH METHODS AND
      PROCEDURES: Bivariate correlation and segregation analyses were employed between
      cortisol and several adiposity measures [body mass index, fat mass (FM), fat-free
      mass, percentage of body fat (% BF), abdominal visceral fat (AVF), abdominal
      subcutaneous fat (ASF), and abdominal total fat (ATF)] from 99 white families and
      105 black families. RESULTS: In both races, significant inverse phenotypic
      correlations were generally observed between cortisol and adiposity measures at
      baseline but not for training responses. Significant cross-trait familial
      correlations were found for cortisol with abdominal fat (ASF, AVF, ATF) and
      overall body adiposity (FM, % BF) measures at baseline, which accounted for 14%
      to 20% of the phenotypic variance in whites. The cross-trait correlations were
      not significant for baseline phenotypes in blacks, perhaps because of the small
      sample size. A bivariate segregation analysis showed evidence of polygenic
      pleiotropy for cortisol with both abdominal fat and overall adiposity measures
      that accounted for 14% to 17% of the phenotypic covariance, but major gene
      pleiotropy was not suggested in whites. However, when ASF, AVF, and ATF were
      additionally adjusted for FM, no familial cross-trait correlations or polygenic
      pleiotropy between cortisol and the abdominal fat measures remained. DISCUSSION:
      Evidence was found for polygenic pleiotropy but not for pleiotropic major gene
      effects between cortisol and overall adiposity in whites. However, the
      covariation of cortisol with abdominal fat phenotypes is dependent on concomitant
      polygenic factors for total-body fat.

PMID- 12490667
TI  - Dopamine transporter genotype as a risk factor for obesity in African-American
      smokers.
AB  - OBJECTIVE: To assess the association between a polymorphism related to dopamine
      function, dopamine transport (SLC6A3), and obesity in smokers. RESEARCH METHODS
      AND PROCEDURES: Logistic regression was used to assess the relationship between
      this genetic polymorphism and obesity (body mass index > or = 30 kg/m(2)) from a
      sample of 510 smokers who smoked at least 10 cigarettes per day and who were
      participating in a study designed to examine genetic and nongenetic predictors of
      response to a pharmacological treatment. RESULTS: The likelihood of obesity in
      African Americans (N = 90) with the 10/10 SLC6A3 genotype was 5.16 times that of
      African Americans with 9/9 or 9/10 SLC6A3 genotypes (odds ratio = 5.16,
      confidence interval = 1.60 to 16.65). There was no association of the SLC6A3
      genotype with obesity for non-Hispanic whites (N = 420). DISCUSSION: These
      results suggest that variants of the dopamine transporter gene may be related to
      obesity in African-American smokers. Possible mechanisms responsible for the
      association between dopamine transport and obesity in African-American smokers
      are discussed.

PMID- 12490668
TI  - Abdominal obesity and ethnic differences in diabetes awareness, treatment, and
      glycemic control.
AB  - OBJECTIVE: To compare racial/ethnic differences in diabetes awareness, treatment,
      and glycemic control between non-Hispanic white, non-Hispanic black, and Hispanic
      Americans. We also determined the impact of abdominal obesity on racial/ethnic
      differences in diabetes awareness, treatment, and glycemic control between these
      population groups. RESEARCH METHODS AND PROCEDURES: Third National Health and
      Nutrition Examination Survey (NHANES III) data were utilized for this study.
      Diabetes awareness was defined as acknowledging diabetic status. Diabetes
      treatment was defined as current use of anti-diabetic medications, good glycemic
      control as HbA(1c) < 8%, and abdominal obesity as waist circumference larger than
      expected. The impacts of abdominal obesity on racial/ethnic differences in
      diabetes awareness, treatment, and glycemic control were assessed using logistic
      regression analyses. Adjustments were made for age, education, smoking, alcohol
      intake, and health insurance. RESULTS: Rates of diabetes awareness in whites,
      blacks, and Hispanics suffering from abdominal obesity were approximately 74%,
      30%, and 21% in men and 77%, 32%, and 19% in women, respectively. Rates of
      diabetes treatment were 70%, 23%, and 14% in men and 57%, 45%, and 23% in women,
      respectively. In men, rates of glycemic control were 64%, 40%, and 30%, and in
      women, they were 62%, 51%, and 27%, respectively. Abdominal obesity was
      associated with decreased diabetes awareness and glycemic control in women.
      DISCUSSION: Subjects with abdominal obesity were found to have poorer glycemic
      controls compared to those without abdominal obesity. Because diabetes
      prevalences were partially explained by racial/ethnic differences in diabetes
      awareness, treatment, and glycemic control, there is a need to craft diabetes
      awareness, treatment, and control programs along racial/ethnic origins.

PMID- 12490669
TI  - Impact of dieting status and dietary restraint on postexercise energy intake in
      overweight women.
AB  - OBJECTIVE: To investigate the unknown relationship between dieting status and
      dietary restraint on postexercise energy intake (PE-EI) in overweight sedentary
      women after a bout of moderate-intensity exercise. Specifically, this was
      investigated in women who were categorized as dieting with high restraint,
      nondieting with high restraint, or nondieting with low restraint. RESEARCH
      METHODS AND PROCEDURES: This study consisted of two experimental conditions,
      exercise (E) and nonexercise (NE) in a counterbalanced-crossover design on 2
      different days. On the E day, the subjects participated in moderate-intensity
      exercise, walking on a treadmill for 60 minutes at 60% to 70% of their maximum
      heart rate. PE-EI at lunch and 12 hours after was compared on the E and an NE
      day. Dietary restraint was determined using the Three-Factor Eating
      Questionnaire. RESULTS: Participants (n = 36) were 26 +/- 7 years of age,
      sedentary, and had a mean body mass index of 27 +/- 3 kg/m(2). There was a
      significant interaction (F((2,33)) = 3.32, p = 0.049) of dieting/restraint status
      and condition (E vs. NE day) on 12-hour EI. The mean difference in 12-hour EI
      between the E and the NE day was significantly higher (p < 0.01) for the dieting
      with high restraint than for the nondieting with high restraint. DISCUSSION: The
      results of this study demonstrate that dieting status, high dietary restraint,
      and higher levels of disinhibition may influence PE-EI in overweight women after
      a bout of moderate-intensity physical activity.

PMID- 12490670
TI  - Association of self-perceived body weight status with dietary reporting by U.S.
      teens.
AB  - OBJECTIVE: Children's self perception of body weight and the medical definition
      of obesity show poor correlation. This study examined the independent
      associations of body mass index (BMI) and self-perceived weight status
      (considered self over-, under-, or right weight) with food reporting, nutrient
      intake estimates, and biomarkers of dietary exposure. RESEARCH METHODS AND
      PROCEDURES: Dietary (one 24-hour recall), anthropometric, and biochemical data
      were from the third National Health and Nutrition Examination Survey (1269 boys
      and 1385 girls, ages 12 to 18 years). Sex-specific multiple regression analyses
      were used to determine the association of BMI and self-perceived body weight
      status with reported intakes of energy, macronutrients, low-nutrient-dense foods,
      micronutrients, and serum concentrations of selected vitamins and carotenoids.
      RESULTS: Reported intakes of energy, macronutrients, number of eating occasions,
      percentage of energy from low-nutrient-dense foods, likelihood of meeting the
      standard of intake of micronutrients, and biomarkers were not different among
      boys and girls who perceived themselves as overweight relative to those who
      perceived themselves at the right weight (p > 0.05). In boys, BMI was a negative
      predictor of percentage of energy from low-nutrient-dense foods (p = 0.004) and
      intake of ascorbic acid (p = 0.04). BMI was inversely related to serum
      concentrations of most carotenoids (p < or = 0.002). DISCUSSION: Perceiving
      oneself as overweight was not associated with reporting of low-nutrient-dense
      foods, macronutrients, micronutrients, and biomarker status; BMI, however, was a
      significant predictor of several outcomes.

PMID- 12490671
TI  - Race, menopause, health-related quality of life, and psychological well-being in
      obese women.
AB  - OBJECTIVE: To investigate the health-related quality of life (HR-QOL) in African
      American (AA) and white (W) obese women. RESEARCH METHODS AND PROCEDURES:
      Participants were 145 obese women (80 AA and 65 W; 87 premenopausal and 58
      postmenopausal) who completed the Medical Outcomes Study short form, the Brief
      Symptom Inventory, the Life Distress Inventory, the Satisfaction With Life Scale,
      and the Rosenberg Self-Esteem Scale before entering a weight-loss study. The mean
      age of the subjects was 46.3 +/- 11.1 years and the mean body mass index was 35.2
      +/- 4.2 kg/m(2). RESULTS: Although AA women were slightly heavier (95.3 +/- 10.3
      kg vs. 91.5 +/- 11.6 kg, p < 0.05) and less educated (14.2 +/- 3.7 years vs. 15.7
      +/- 3.7 years, p < 0.05) than the W women in the sample, there was no difference
      between the two ethnic groups in any of the reported HR-QOL variables. Menopausal
      status had a significant effect on HR-QOL, with premenopausal women being more
      distressed (p = 0.002), having more limitations in social activity (p = 0.007),
      and having less vitality (p < 0.001) than the postmenopausal women. This was
      especially true in the AA women. DISCUSSION: These data show no difference in HR
      QOL between AA and W obese women and suggest that menopausal status may have an
      impact on HR-QOL, especially in AA women.

PMID- 12490672
TI  - Cost of in-patient care over 7 years among surgically and conventionally treated
      obese patients.
AB  - OBJECTIVE: Bariatric surgery improves cardiovascular risk factors and quality of
      life, but few studies have directly addressed the relation between obesity
      treatment and hospitalization costs. This prospective controlled study compares
      in-patient care between surgically and conventionally treated obese patients.
      RESEARCH METHODS AND PROCEDURES: A total of 962 surgically and conventionally
      treated obese patients from the intervention study, Swedish Obese Subjects, were
      followed for 6 years. Changes in days of hospitalization and hospitalization
      costs were analyzed. Information on hospitalizations for each subject were
      obtained from the Swedish Hospital Discharge Register. RESULTS: After 6 years,
      weight change was -16.7% in the surgical group and +0.9% in the control group (p
      < 0.0001). The cumulated hospital stay over 6 years was 23.4 days in the surgical
      group and 6.9 days in the control group (p < 0.0001). The average hospital cost
      for the surgical intervention was US$4300. Incremental costs that could be
      attributable to obesity surgery averaged US$1200 per year. After exclusion of
      hospitalizations for the surgical intervention and conditions common after
      bariatric surgery, there were no significant differences between the groups in
      number of hospital days or hospitalization costs. DISCUSSION: Our experience from
      bariatric surgery indicates that average weight reductions of 16% will not reduce
      hospitalization costs over 6 years. Costs of bariatric surgery are limited and
      seem to be motivated given the marked improvements of cardiovascular risk
      factors, cardiac structure, and function and health-related quality of life.

PMID- 12490673
TI  - Adipose depletion and apoptosis induced by trans-10, cis-12 conjugated linoleic
      Acid in mice.
AB  - OBJECTIVE: To compare the effectiveness of a conjugated linoleic acid (CLA)
      isomer mixture (mCLA) with each main isomer [trans-10,cis-12 CLA (CLA10,12) and
      cis-9,trans-11 CLA (CLA9,11)] in causing body lipid loss and adipose tissue
      apoptosis. RESEARCH METHODS AND PROCEDURES: Mice selected over 16 generations for
      high (MH) or low (ML) energy expenditure and a control group (MC) were fed diets
      containing either soy oil or soy oil plus mCLA, CLA10,12, or CLA9,11 for 5 days
      in one study and 14 days in a second study. RESULTS: Mice fed mCLA or CLA10,12
      had less body lipid (p < 0.05), smaller retroperitoneal fat pads (p < 0.05), and
      ate less (p < 0.01) than mice fed no CLA or CLA9,11 for 5 days. Mice consuming 1%
      mCLA or 0.5% CLA10,12 gained less weight (p < 0.01) and had less body lipid (p <
      0.05) and smaller epididymal (p < 0.05) and retroperitoneal fat pads (p < 0.01)
      than mice consuming either control or 0.5% CLA9,11-containing diets for 14 days.
      Only mCLA and CLA10,12 increased apoptosis in retroperitoneal fat pads (p <
      0.01). The effects of mCLA and CLA10,12 were independent of genetic line except
      for the effect on adipocyte apoptosis. Mice of the MH line were slightly less
      sensitive than MC or ML mice to CLA-induced adipose tissue apoptosis. DISCUSSION:
      CLA10,12, but not CLA9,11, can induce both body fat loss and adipose apoptosis.
      Although mice of a genotype with less body fat and greater metabolic rate and
      feed intake appear less sensitive, these CLA effects are robust for mice of
      varying metabolic background.

PMID- 12490674
TI  - CART gene promoter transcription is regulated by a cyclic adenosine monophosphate
      response element.
AB  - OBJECTIVE: To define the regulatory DNA sequence controlling the expression of
      the cocaine-amphetamine-regulated transcript (CART) gene expression. RESEARCH
      METHODS AND PROCEDURES: A rat genomic library was screened for genomic clones
      containing the CART gene and upstream DNA sequence. A clone containing exons 1
      and 2 of the rat CART gene plus 1.2 kb of upstream sequence was isolated. The 1.2
      kb upstream sequence and truncated segments of this sequence were cloned into a
      luciferase reporter vector for analysis of transcriptional activity in the CART
      expressing pituitary GH3 cell line. Luciferase reporter assays, gel shift assays,
      and site-directed mutagenesis were used to analyze potential regulatory regions
      in the 1.2-kb 5' DNA sequence. RESULTS: Sequence analysis of the 1.2-kb upstream
      sequence reveals several potential regulatory elements. Luciferase reporter
      assays demonstrate that within the first 162 bp of the start codon is a
      functional cyclic adenosine monophosphate (cAMP) response element that can induce
      cAMP-regulated gene expression of the CART promoter in GH3 cells. Mutation of
      this cAMP response element abolishes cAMP-stimulated transcription [corrected].
      Furthermore, the promoter is active in a neuronal cell line where it also
      demonstrates cAMP responsiveness. DISCUSSION: cAMP-mediated transcription of the
      CART promoter may be an important aspect of the regulation of the CART gene.
      However, the cellular context of expression is also important because the CART
      promoter is not responsive to cAMP stimulation in all cell types. Other
      transcription factor binding sequences are likely to play a key role in CART
      promoter regulation.

PMID- 12490675
TI  - Summary of the 2000 Surgeon General's listening session: toward a national action
      plan on overweight and obesity.
AB  - OBJECTIVE: To provide insight into discussions at the Surgeon General's Listening
      Session, "Toward a National Action Plan on Overweight and Obesity," and to
      complement The Surgeon General's Call to Action to Prevent and Decrease
      Overweight and Obesity. RESEARCH METHODS AND PROCEDURES: On December 7 and 8,
      2000, representatives from federal, state, academic, and private sectors attended
      the Surgeon General's Listening Session and were given an opportunity to
      recommend what to include in a national plan to address overweight and obesity.
      The public was invited to comment during a corresponding public comment period.
      The Surgeon General's Listening Session was also broadcast on the Internet,
      allowing others to view the deliberations live or access the archived files.
      Significant discussion points from the Listening Session have been reviewed by
      representatives of the federal agencies and are the basis of this complementary
      document. RESULTS: Examples of issues, strategies, and barriers to change are
      discussed within five thematic areas: schools, health care, family and community,
      worksite, and media. Suggested cooperative or collaborative actions for
      preventing and decreasing overweight and obesity are described. An annotated list
      of some programmatic partnerships is included. DISCUSSION: The Surgeon General's
      Listening Session provided an opportunity for representatives from family and
      community groups, schools, the media, the health-care environment, and worksites
      to become partners and to unite around the common goal of preventing and
      decreasing overweight and obesity. The combination of approaches from these
      perspectives offers a rich resource of opportunity to combat the public health
      epidemic of overweight and obesity.

PMID- 12490679
TI  - Predictive molecular pathology.

PMID- 12490680
TI  - Herbal medicines--what's in the bottle?

PMID- 12490681
TI  - A gene-expression signature as a predictor of survival in breast cancer.
AB  - BACKGROUND: A more accurate means of prognostication in breast cancer will
      improve the selection of patients for adjuvant systemic therapy. METHODS: Using
      microarray analysis to evaluate our previously established 70-gene prognosis
      profile, we classified a series of 295 consecutive patients with primary breast
      carcinomas as having a gene-expression signature associated with either a poor
      prognosis or a good prognosis. All patients had stage I or II breast cancer and
      were younger than 53 years old; 151 had lymph-node-negative disease, and 144 had
      lymph-node-positive disease. We evaluated the predictive power of the prognosis
      profile using univariable and multivariable statistical analyses. RESULTS: Among
      the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis
      signature, and the mean (+/-SE) overall 10-year survival rates were 54.6+/-4.4
      percent and 94.5+/-2.6 percent, respectively. At 10 years, the probability of
      remaining free of distant metastases was 50.6+/-4.5 percent in the group with a
      poor-prognosis signature and 85.2+/-4.3 percent in the group with a good
      prognosis signature. The estimated hazard ratio for distant metastases in the
      group with a poor-prognosis signature, as compared with the group with the good
      prognosis signature, was 5.1 (95 percent confidence interval, 2.9 to 9.0;
      P<0.001). This ratio remained significant when the groups were analyzed according
      to lymph-node status. Multivariable Cox regression analysis showed that the
      prognosis profile was a strong independent factor in predicting disease outcome.
      CONCLUSIONS: The gene-expression profile we studied is a more powerful predictor
      of the outcome of disease in young patients with breast cancer than standard
      systems based on clinical and histologic criteria.

PMID- 12490682
TI  - Effect of dialysis dose and membrane flux in maintenance hemodialysis.
AB  - BACKGROUND: The effects of the dose of dialysis and the level of flux of the
      dialyzer membrane on mortality and morbidity among patients undergoing
      maintenance hemodialysis are uncertain. METHODS: We undertook a randomized
      clinical trial in 1846 patients undergoing thrice-weekly dialysis, using a two-by
      two factorial design to assign patients randomly to a standard or high dose of
      dialysis and to a low-flux or high-flux dialyzer. RESULTS: In the standard-dose
      group, the mean (+/-SD) urea-reduction ratio was 66.3+/-2.5 percent, the single
      pool Kt/V was 1.32+/-0.09, and the equilibrated Kt/V was 1.16+/-0.08; in the high
      dose group, the values were 75.2+/-2.5 percent, 1.71+/-0.11, and 1.53+/-0.09,
      respectively. Flux, estimated on the basis of beta2-microglobulin clearance, was
      3+/-7 ml per minute in the low-flux group and 34+/-11 ml per minute in the high
      flux group. The primary outcome, death from any cause, was not significantly
      influenced by the dose or flux assignment: the relative risk of death in the high
      dose group as compared with the standard-dose group was 0.96 (95 percent
      confidence interval, 0.84 to 1.10; P=0.53), and the relative risk of death in the
      high-flux group as compared with the low-flux group was 0.92 (95 percent
      confidence interval, 0.81 to 1.05; P=0.23). The main secondary outcomes (first
      hospitalization for cardiac causes or death from any cause, first hospitalization
      for infection or death from any cause, first 15 percent decrease in the serum
      albumin level or death from any cause, and all hospitalizations not related to
      vascular access) also did not differ significantly between either the dose groups
      or the flux groups. Possible benefits of the dose or flux interventions were
      suggested in two of seven prespecified subgroups of patients. CONCLUSIONS:
      Patients undergoing hemodialysis thrice weekly appear to have no major benefit
      from a higher dialysis dose than that recommended by current U.S. guidelines or
      from the use of a high-flux membrane.

PMID- 12490684
TI  - Images in clinical medicine. Mycotic aneurysms.

PMID- 12490683
TI  - Comparison of caspofungin and amphotericin B for invasive candidiasis.
AB  - BACKGROUND: Caspofungin is an echinocandin agent with fungicidal activity against
      candida species. We performed a double-blind trial to compare caspofungin with
      amphotericin B deoxycholate for the primary treatment of invasive candidiasis.
      METHODS: We enrolled patients who had clinical evidence of infection and a
      positive culture for candida species from blood or another site. Patients were
      stratified according to the severity of disease, as indicated by the Acute
      Physiology and Chronic Health Evaluation (APACHE II) score, and the presence or
      absence of neutropenia and were randomly assigned to receive either caspofungin
      or amphotericin B. The study was designed to compare the efficacy of caspofungin
      with that of amphotericin B in patients with invasive candidiasis and in a
      subgroup with candidemia. RESULTS: Of the 239 patients enrolled, 224 were
      included in the modified intention-to-treat analysis. Base-line characteristics,
      including the percentage of patients with neutropenia and the mean APACHE II
      score, were similar in the two treatment groups. A modified intention-to-treat
      analysis showed that the efficacy of caspofungin was similar to that of
      amphotericin B, with successful outcomes in 73.4 percent of the patients treated
      with caspofungin and in 61.7 percent of those treated with amphotericin B
      (difference after adjustment for APACHE II score and neutropenic status, 12.7
      percentage points; 95.6 percent confidence interval, -0.7 to 26.0). An analysis
      of patients who met prespecified criteria for evaluation showed that caspofungin
      was superior, with a favorable response in 80.7 percent of patients, as compared
      with 64.9 percent of those who received amphotericin B (difference, 15.4
      percentage points; 95.6 percent confidence interval, 1.1 to 29.7). Caspofungin
      was as effective as amphotericin B in patients who had candidemia, with a
      favorable response in 71.7 percent and 62.8 percent of patients, respectively
      (difference, 10.0 percentage points; 95.0 percent confidence interval, -4.5 to
      24.5). There were significantly fewer drug-related adverse events in the
      caspofungin group than in the amphotericin B group. CONCLUSIONS: Caspofungin is
      at least as effective as amphotericin B for the treatment of invasive candidiasis
      and, more specifically, candidemia.

PMID- 12490686
TI  - Clinical practice. Management of community-acquired pneumonia.

PMID- 12490685
TI  - Effects of a law against early postpartum discharge on newborn follow-up, adverse
      events, and HMO expenditures.
AB  - BACKGROUND: Concern about harm to newborns from early postpartum discharges led
      to laws establishing minimum hospital stays in the mid-1990s. We evaluated the
      effects of an early-discharge protocol (a hospital stay of one postpartum night
      plus a home visit) in a health maintenance organization (HMO) and a subsequent
      state law guaranteeing a 48-hour hospital stay. METHODS: Using interrupted-time
      series analysis and data on 20,366 mother-infant pairs with normal vaginal
      deliveries, we measured changes in length of stay, newborn examinations on the
      third or fourth day of life, and office visits, emergency department visits, and
      hospital readmissions for newborns. We also examined expenditures for
      hospitalizations and home-based care. RESULTS: The early-discharge program
      increased the rate of stays of less than two nights from 29.0 percent to 65.6
      percent (P<0.001). The rate declined to 13.7 percent after the state mandate
      (P<0.001). The rate of newborn examinations on the third or fourth day of life
      increased from 24.5 percent to 64.4 percent with the program (P<0.001), then
      dropped to 53.0 percent after the mandate (P<0.001)--changes that primarily
      reflected changes in the rate of home visits. The rate of nonurgent visits to a
      health center increased from 33.4 percent to 44.7 percent (P<0.001) after the
      reduced-stay program was implemented. There were no significant changes in the
      rate of emergency department visits (quarterly mean, 1.1 percent) or
      rehospitalizations (quarterly mean, 1.5 percent). Results were similar for a
      vulnerable subgroup with lower incomes, younger maternal age, a lower level of
      education, or some combination of these characteristics. Average HMO expenditures
      on hospital and home-based services decreased by $90 per delivery with the early
      discharge program and increased by $100 after the mandate. CONCLUSIONS: Neither
      policy appears to have affected the health outcomes of newborns. After the
      mandate, newborns were less likely to be examined as recommended on day 3 or 4.
      Because of changes in hospital prices, the two policies had minimal effects on
      HMO expenditures for hospital and home-based services.

PMID- 12490687
TI  - Herbal remedies.

PMID- 12490688
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 39-2002--a 35-year-old man with headache, deviation of the
      tongue, and unusual radiographic abnormalities.

PMID- 12490689
TI  - Molecular signatures of breast cancer--predicting the future.

PMID- 12490690
TI  - Success and challenge in dialysis therapy.

PMID- 12490691
TI  - Echinocandins--an advance in the primary treatment of invasive candidiasis.

PMID- 12490692
TI  - Botanical medicines--the need for new regulations.

PMID- 12490693
TI  - New strains of bacteria and exacerbations of COPD.

PMID- 12490694
TI  - Immunosuppression and BKV Nephropathy.

PMID- 12490695
TI  - Voriconazole versus amphotericin B for invasive aspergillosis.

PMID- 12490696
TI  - Paternal inheritance of mitochondrial DNA.

PMID- 12490698
TI  - Polymyalgia rheumatica and giant-cell arteritis.

PMID- 12490697
TI  - Nurses' and social workers' experience with patients who requested assistance
      with suicide.

PMID- 12490699
TI  - Self-cardioversion of paroxysmal lone atrial fibrillation with exercise.

PMID- 12490700
TI  - Neonatal hair analysis as a biomarker for in utero alcohol exposure.

PMID- 12490701
TI  - The phylogenetic distribution of bacterial ribonucleases.
AB  - Ribonucleases play key, often essential, roles in cellular metabolism. Nineteen
      ribonuclease activities, from 22 different proteins, have so far been described
      in bacteria, the majority of them from either Escherichia coli or Bacillus
      subtilis. Here we examine the phylogenetic distribution of all of these
      ribonucleases in 50 eubacterial and archaeal species whose genomes have been
      completely sequenced, with particular emphasis on the endoribonucleases. Although
      some enzymes are very highly conserved throughout evolution, there appears to be
      no truly universal ribonuclease. While some organisms, like E.coli, have a large
      selection of ribonucleases, many with overlapping functions, others seem to have
      relatively few or have many that remain to be discovered.

PMID- 12490702
TI  - Characterization of the fission yeast ribosomal DNA binding factor: components
      share homology with Upstream Activating Factor and with SWI/SNF subunits.
AB  - A ribosomal DNA (rDNA) binding activity was previously characterized in fission
      yeast that recognized the upstream ribosomal RNA (rRNA) gene promoter in a
      sequence specific manner and which stimulated rRNA synthesis. It was found to
      share characteristics with Saccharomyces cerevisiae's Upstream Activating Factor
      (UAF), an RNA polymerase I (pol I) specific transcription stimulatory factor.
      Putative fission yeast homologs of the S.cerevisiae UAF subunits, Rrn5p and
      Rrn10p, were identified. The Schizosaccharomyces pombe rDNA binding
      activity/transcriptional stimulatory activity was found to co-fractionate with
      both SpRrn5h and SpRrn10h. Analysis of polypeptides interacting with SpRrn10h
      uncovered a 27 kDa polypeptide (Spp27) homologous to a SWI/SNF component (now
      known to be homologous to Uaf30p). The contributions of the S.pombe and
      S.cerevisiae upstream rDNA promoter domains were assessed in cross-species
      transcriptional assays. Furthermore, comparative genomic analysis revealed
      putative Rrn5p, Rrn10p, Rrn9p and p27 homologs in multiple non-vertebrates. The
      S.pombe rDNA binding activity is proposed to be an RNA pol I specific SWI/SNF
      type factor.

PMID- 12490703
TI  - Interaction of C5 protein with RNA aptamers selected by SELEX.
AB  - RNA aptamers binding to C5 protein, the protein component of Escherichia coli
      RNase P, were selected and characterized as an initial step in elucidating the
      mechanism of action of C5 protein as an RNA-binding protein. Sequence analyses of
      the RNA aptamers suggest that C5 protein binds various RNA molecules with
      dissociation constants comparable to that of M1 RNA, the RNA component of RNase
      P. The dominant sequence, W2, was chosen for further study. Interactions between
      W2 and C5 protein were independent of Mg2+, in contrast to the Mg2+ dependency of
      M1 RNA-C5 protein interactions. The affinity of W2 for C5 protein increased with
      increasing concentration of monovalent NH4+, suggesting interactions via
      hydrophobic attraction. W2 forms a fairly stable complex with C5 protein,
      although the stability of this complex is lower than that of the complex of M1
      RNA with C5 protein. The core RNA motif essential for interaction with C5 protein
      was identified as a stem-loop structure, comprising a 5 bp stem and a 20 nt loop.
      Our results strongly imply that C5 protein is an interacting partner protein of
      some cellular RNA species apart from M1 RNA.

PMID- 12490704
TI  - Functional second genes generated by retrotransposition of the X-linked ribosomal
      protein genes.
AB  - We have identified a new class of ribosomal protein (RP) genes that appear to
      have been retrotransposed from X-linked RP genes. Mammalian ribosomes are
      composed of four RNA species and 79 different proteins. Unlike RNA constituents,
      each protein is typically encoded by a single intron- containing gene. Here we
      describe functional autosomal copies of the X-linked human RP genes, which we
      designated RPL10L (ribosomal protein L10-like gene), RPL36AL and RPL39L after
      their progenitors. Because these genes lack introns in their coding regions, they
      were likely retrotransposed from X-linked genes. The identities between the
      retrotransposed genes and the original X-linked genes are 89-95% in their
      nucleotide sequences and 92-99% in their amino acid sequences, respectively.
      Northern blot and PCR analyses revealed that RPL10L and RPL39L are expressed only
      in testis, whereas RPL36AL is ubiquitously expressed. Although the role of the
      autosomal RP genes remains unclear, they may have evolved to compensate for the
      reduced dosage of X-linked RP genes.

PMID- 12490705
TI  - A hairpin near the 5' end stabilises the DNA gyrase mRNA in Mycobacterium
      smegmatis.
AB  - RNA is amongst the most labile macromolecules present in the cells. The steady
      state levels of mRNA are regulated both at the stages of synthesis and
      degradation. Recent work in Escherichia coli suggests that controlling the rate
      of degradation is as important as the process of synthesis. The stability of mRNA
      is probably more important in slow- growing organisms like mycobacteria. Here, we
      present our analysis of the cis elements that determine the stability of the DNA
      gyrase message in Mycobacterium smegmatis. The message appears to be stabilised
      by a structure close to its 5' end. The effect is especially pronounced in a
      nutrient-depleted state. These results largely parallel the model proposed in
      E.coli for mRNA degradation/ stability with subtle differences. Furthermore,
      these results suggest that the slow-growing organisms might use stable mRNAs as a
      method to reduce the load of transcription on the cell.

PMID- 12490706
TI  - Comparative analysis of ribosomal proteins in complete genomes: an example of
      reductive evolution at the domain scale.
AB  - A comprehensive investigation of ribosomal genes in complete genomes from 66
      different species allows us to address the distribution of r-proteins between and
      within the three primary domains. Thirty-four r-protein families are represented
      in all domains but 33 families are specific to Archaea and Eucarya, providing
      evidence for specialisation at an early stage of evolution between the bacterial
      lineage and the lineage leading to Archaea and Eukaryotes. With only one specific
      r-protein, the archaeal ribosome appears to be a small-scale model of the
      eukaryotic one in terms of protein composition. However, the mechanism of
      evolution of the protein component of the ribosome appears dramatically different
      in Archaea. In Bacteria and Eucarya, a restricted number of ribosomal genes can
      be lost with a bias toward losses in intracellular pathogens. In Archaea, losses
      implicate 15% of the ribosomal genes revealing an unexpected plasticity of the
      translation apparatus and the pattern of gene losses indicates a progressive
      elimination of ribosomal genes in the course of archaeal evolution. This first
      documented case of reductive evolution at the domain scale provides a new
      framework for discussing the shape of the universal tree of life and the
      selective forces directing the evolution of prokaryotes.

PMID- 12490707
TI  - Helicobacter pylori interstrain restriction-modification diversity prevents
      genome subversion by chromosomal DNA from competing strains.
AB  - Helicobacter pylori, bacteria that colonize the human gastric mucosa, possess a
      large number of genes for restriction-modification (R-M) systems, and
      essentially, every strain possesses a unique complement of functional and partial
      R-M systems. Nearly half of the H.pylori strains studied possess an active type
      IIs R-M system, HpyII, with the recognition sequence GAAGA. Recombination between
      direct repeats that flank the R-M cassette allows for its deletion whereas
      strains lacking hpyIIRM can acquire this cassette through natural transformation.
      We asked whether strains lacking HpyII R-M activity can acquire an active hpyIIRM
      cassette [containing a 1.4 kb kanamycin resistance (aphA) marker], whether such
      acquisition is DNase sensitive or resistant and whether restriction barriers
      limit acquisition of chromosomal DNA. Our results indicate that natural
      transformation and conjugation-like mechanisms may contribute to the transfer of
      large (4.8 kb) insertions of chromosomal DNA between H.pylori strains, that
      inactive or partial R-M systems can be reactivated upon recombination with a
      functional allele, consistent with their being contingency genes, and that
      H.pylori R-M diversity limits acquisition of chromosomal DNA fragments of >/=1
      kb.

PMID- 12490708
TI  - Alpha/gamma transitions in the B-DNA backbone.
AB  - In the crystal structures of protein complexes with B-DNA, alpha and gamma DNA
      backbone torsion angles often exhibit non-canonical values. It is not known if
      these alternative backbone conformations are easily accessible in solution and
      can contribute to the specific recognition of DNA by proteins. We have analysed
      the coupled transition of the alpha and gamma torsion angles within the central
      GpC step of a B-DNA dodecamer by computer simulations. Five stable or metastable
      non-canonical alpha/gamma sub-states are found. The most favourable pathway from
      the canonical alpha/gamma structure to any unusual form involves a counter
      rotation of alpha and gamma, via the trans conformation. However, the
      corresponding free energy indicates that spontaneous flipping of the torsions is
      improbable in free B-DNA. This is supported by an analysis of the available high
      resolution crystallographic structures showing that unusual alpha/gamma states
      are only encountered in B-DNA complexed to proteins. An analysis of the
      structural consequences of alpha/gamma transitions shows that the non-canonical
      backbone geometry influences essentially the roll and twist values and reduces
      the equilibrium dispersion of structural parameters. Our results support the
      hypothesis that unusual alpha/gamma backbones arise during protein-DNA
      complexation, assisting the fine structural adjustments between the two partners
      and playing a role in the overall complexation free energy.

PMID- 12490709
TI  - A directional nucleation-zipping mechanism for triple helix formation.
AB  - A detailed kinetic study of triple helix formation was performed by surface
      plasmon resonance. Three systems were investigated involving 15mer pyrimidine
      oligonucleotides as third strands. Rate constants and activation energies were
      validated by comparison with thermodynamic values calculated from UV-melting
      analysis. Replacement of a T.A base pair by a C.G pair at either the 5' or the 3'
      end of the target sequence allowed us to assess mismatch effects and to delineate
      the mechanism of triple helix formation. Our data show that the association rate
      constant is governed by the sequence of base triplets on the 5' side of the
      triplex (referred to as the 5' side of the target oligopurine strand) and
      provides evidence that the reaction pathway for triple helix formation in the
      pyrimidine motif proceeds from the 5' end to the 3' end of the triplex according
      to the nucleation-zipping model. It seems that this is a general feature for all
      triple helices formation, probably due to the right-handedness of the DNA double
      helix that provides a stronger base stacking at the 5' than at the 3' duplex
      triplex junction. Understanding the mechanism of triple helix formation is not
      only of fundamental interest, but may also help in designing better triple helix
      forming oligonucleotides for gene targeting and control of gene expression.

PMID- 12490710
TI  - Characterisation of the DNA-dependent ATPase activity of human DNA topoisomerase
      IIbeta: mutation of Ser165 in the ATPase domain reduces the ATPase activity and
      abolishes the in vivo complementation ability.
AB  - We report for the first time an analysis of the ATPase activity of human DNA
      topoisomerase (topo) IIbeta. We show that topo IIbeta is a DNA-dependent ATPase
      that appears to fit Michaelis-Menten kinetics. The ATPase activity is stimulated
      44-fold by DNA. The k(cat) for ATP hydrolysis by human DNA topo IIbeta in the
      presence of DNA is 2.25 s(-1). We have characterised a topo IIbeta derivative
      which carries a mutation in the ATPase domain (S165R). S165R reduced the kcat for
      ATP hydrolysis by 7-fold, to 0.32 s(-1), while not significantly altering the
      apparent K(m). The specificity constant for the interaction between ATP and topo
      IIbeta (kcat/K(mapp)) showed a 90% reduction for betaS165R. The DNA binding
      affinity and ATP-independent DNA cleavage activity of the enzyme are unaffected
      by this mutation. However, the strand passage activity is reduced by 80%,
      presumably due to reduced ATP hydrolysis. The mutant enzyme is unable to
      complement ts yeast topo II in vivo. We have used computer modelling to predict
      the arrangement of key residues at the ATPase active site of topo IIbeta. Ser165
      is predicted to lie very close to the bound nucleotide, and the S165R mutation
      could thus influence both ATP binding and ADP dissociation.

PMID- 12490711
TI  - In vivo selection of spectinomycin-binding RNAs.
AB  - The folding of even short RNA molecules in a random library can produce a huge
      number of possible macromolecular structures. Using this principle, we have
      designed selections to seek non-coding RNA transcripts capable of interfering
      with specific macromolecules such as transcription factors in living bacterial
      cells. Here we show that such selections can uncover an unexpected class of RNAs.
      In the present case, we report short RNA transcripts whose expression confers
      bacterial resistance to the antibiotic spectinomycin. We provide evidence that
      such RNAs cause drug resistance by direct antibiotic binding, demonstrating a
      class of spectinomycin-specific functional molecular decoys built from RNA.

PMID- 12490712
TI  - Individual gvp transcript segments in Haloferax mediterranei exhibit varying half
      lives, which are differentially affected by salt concentration and growth phase.
AB  - The mc-gvp genes for gas vesicle formation in Haloferax mediterranei are
      transcribed from two promoters located in front of the mc-gvpA and mc-gvpD genes.
      The different transcripts originating from both promoters show different
      abundances dependent on salt concentration in the medium and growth phase. Here
      we show that the half-lives of these transcripts differ significantly and that
      the small gvp transcripts exhibit higher stabilities than the larger gvp
      transcripts. While the stability of most gvp transcripts is independent of the
      salt concentration in the medium, the gvpA mRNA decays about twice as fast in
      cultures grown at 18% salt compared to cultures grown at 25% salt. The stability
      of the 0.45 kb transcript population derived from the 5' part of the gvpD gene
      depends on the growth phase of the culture. Thus, differences in mRNA stability
      contribute to the salt-dependent and growth phase-dependent abundance of gvp
      transcripts. This implies that, like in bacteria and eukarya, mRNA processing
      contributes to regulated gene expression in archaea.

PMID- 12490713
TI  - Characterization of the interaction between the nucleotide exchange factor EF-Ts
      from nematode mitochondria and elongation factor Tu.
AB  - Caenorhabditis elegans mitochondria have two elongation factor (EF)-Tu species,
      denoted EF-Tu1 and EF-Tu2. Recombinant nematode EF-Ts purified from Escherichia
      coli bound both of these molecules and also stimulated the translational activity
      of EF-Tu, indicating that the nematode EF-Ts homolog is a functional EF-Ts
      protein of mitochondria. Complexes formed by the interaction of nematode EF-Ts
      with EF-Tu1 and EF-Tu2 could be detected by native gel electrophoresis and
      purified by gel filtration. Although the nematode mitochondrial (mt) EF-Tu
      molecules are extremely unstable and easily form aggregates, native gel
      electrophoresis and gel filtration analysis revealed that EF-Tu.EF-Ts complexes
      are significantly more soluble. This indicates that nematode EF-Ts can be used to
      stabilize homologous EF-Tu molecules for experimental purposes. The EF-Ts bound
      to two eubacterial EF-Tu species (E.coli and Thermus thermophilus). Although the
      EF-Ts did not bind to bovine mt EF-Tu, it could bind to a chimeric nematode
      bovine EF-Tu molecule containing domains 1 and 2 from bovine mt EF-Tu. Thus, the
      nematode EF-Ts appears to have a broad specificity for EF-Tu molecules from
      different species.

PMID- 12490714
TI  - Identification of cellular mRNA targets for RNA-binding protein Sam68.
AB  - Sam68 (Src-associated in mitosis, 68 kDa), a nuclear RNA-binding protein, has
      been postulated to play a role in cell-growth control as a modulator of signal
      transduction and activation of RNA metabolism. Although Sam68 was demonstrated to
      bind to the UAAA sequences in synthetic oligoribonucleotides and poly(U)
      homopolymers in vitro, the legitimate cellular mRNA target remained unclear. By
      using the differential display and cDNA-representational difference analysis
      techniques, followed by reverse transcription polymerase chain reaction of RNAs
      co-immunoprecipitated with Sam68 from a HeLa cell lysate, we identified 10 mRNA
      species that bind in vivo to Sam68 in an RNA-binding domain-dependent manner.
      Among them, the mRNA species for hnRNP A2/B1 and beta-actin were found to bind
      prominently in vivo as well as in vitro, suggesting the possible involvement of
      Sam68 in the post- transcriptional regulation of these genes. Mapping of the
      Sam68-binding sequence revealed that Sam68 associates with these mRNAs through
      different nucleotide motifs, UAAA for hnRNP A2/B1 mRNA and UUUUUU for beta-actin
      mRNA, and that both binding sequences must reside in a loop structure for
      recognition by Sam68. The results indicated that Sam68 recognizes both the UAAA
      motif and poly(U) sequences in vivo for binding to cellular target mRNAs.

PMID- 12490715
TI  - The centrosomal kinase Aurora-A/STK15 interacts with a putative tumor suppressor
      NM23-H1.
AB  - Alterations in the activity of the centrosomal kinase, Aurora-A/STK15, have been
      implicated in centrosome amplification, genome instability and cellular
      transformation. How STK15 participates in all of these processes remains largely
      mysterious. The activity of STK15 is regulated by phosphorylation and ubiquitin
      mediated degradation, and physically interacts with protein phosphatase 1 (PP1)
      and CDC20. However, the precise roles of these modifications and interactions
      have yet to be fully appreciated. Here we show that STK15 associates with a
      putative tumor and metastasis suppressor, NM23-H1. STK15 and NM23 were initially
      found to interact in yeast in a two-hybrid assay. Association of these proteins
      in human cells was confirmed by co-immunoprecipitation from cell lysates and
      biochemical fractionation indicating that STK15 and NM23-H1 are present in a
      stable, physical complex. Notably, SKT15 and NM23 both localize to centrosomes
      throughout the cell cycle irrespective of the integrity of the microtubule
      network in normal human fibroblasts.

PMID- 12490717
TI  - Propynyl groups in duplex DNA: stability of base pairs incorporating 7
      substituted 8-aza-7-deazapurines or 5-substituted pyrimidines.
AB  - Oligonucleotides incorporating the 7-propynyl derivatives of 8-aza-7-deaza-2'
      deoxyguanosine (3b) and 8-aza-7-deaza-2'-deoxyadenosine (4b) were synthesized and
      their duplex stability was compared with those containing the 5-propynyl
      derivatives of 2'-deoxycytidine (1) and 2'-deoxyuridine (2). For this purpose
      phosphoramidites of the 8-aza- 7-deazapurine (pyrazolo[3,4-d]pyrimidine)
      nucleosides were prepared and employed in solid-phase synthesis. All propynyl
      nucleosides exert a positive effect on the DNA duplex stability because of the
      increased polarizability of the nucleobase and the hydrophobic character of the
      propynyl group. The propynyl residues introduced into the 7-position of the 8-aza
      7-deazapurines are generally more stabilizing than those at the 5-position of the
      pyrimidine bases. The duplex stabilization of the propynyl derivative 4b was
      higher than for the bromo nucleoside 4c. The extraordinary stability of duplexes
      containing the 7-propynyl derivative of 8-aza-7- deazapurin-2,6-diamine (5b) is
      attributed to the formation of a third hydrogen bond, which is apparently not
      present in the base pair of the purin-2,6-diamine 2'-deoxyribonucleoside with dT.

PMID- 12490716
TI  - Mutations in U5 snRNA loop 1 influence the splicing of different genes in vivo.
AB  - The U5 snRNA loop 1 is characterized by the conserved sequence G1C2C3U4U5U6Y7A8Y9
      and is essential for the alignment of exons during the second step of pre-mRNA
      splicing in Saccharo myces cerevisiae. Despite this sequence conservation the
      size, rather than sequence, of loop 1 is critical for exon alignment in vitro. To
      determine the in vivo requirements for U5 loop 1 a library of loop 1 sequences
      was transformed into a yeast strain where the endogenous U5 gene was deleted.
      Comparison of viable mutations in loop 1 revealed that position 6 was invariant
      and positions 5 and 7 displayed some sequence conservation. These data indicate
      positions 5, 6 and 7 in loop 1 are important for U5 function in vivo. A screen
      for mutations that suppress the temperature-sensitive phenotype of three loop 1
      mutants produced eight intragenic suppressors all containing alterations in loop
      1. Further analysis of these temperature-sensitive mutants revealed that each
      displayed distinct cell cycle arrest phenotypes and pre-mRNA splicing inhibition
      patterns. The cell cycle arrest is likely attributed to inefficient splicing of
      alpha-tubulin pre-mRNA in one mutant and actin pre-mRNA in another. These results
      suggest that various mutations in loop 1 may affect the splicing of different pre
      mRNAs in vivo.

PMID- 12490718
TI  - Synthesis, characterization and solution structure of tethered oligonucleotides
      containing an internal 3'-phosphoglycolate, 5'-phosphate gapped lesion.
AB  - Bleomycins (BLMs) are antitumor antibiotics that in the presence of iron and
      oxygen mediate DNA damage by 4'-hydrogen atom abstraction of pyrimidines 3' to
      guanines. The resulting 4'-deoxyribose radicals can be trapped by O2 and
      ultimately result in the formation of base-propenal and gapped DNA with 3'
      phosphoglycolate (3'-PG) and 5'-phosphate (5'-P) ends. The role of this lesion in
      triggering double-strand cleavage of duplex DNA by a single BLM molecule and the
      mechanism by which this lesion is repaired in vivo remain unsolved problems. The
      structure of these lesions is an essential step in addressing both of these
      problems. Duplex DNAs (13mers containing tethered hexaethylene glycol linkers)
      with GTAC and GGCC cleavage sites have been synthesized in which gaps containing
      3'-PG and 5'-P ends at the sites of BLM cleavage have been inserted. The former
      sequence represents a hot spot for double-strand cleavage, while the latter is a
      hot spot for single-strand cleavage. Analytical methods to characterize the
      lesioned products have been developed. These oligonucleotides have been examined
      using 2D NMR methods and molecular modeling. The studies reveal that the lesioned
      DNAs are B-form and the 3'-PG and 5'-P are extrahelical. The base opposite the
      gap and the base pairs adjacent to the gap remain well stacked in the DNA duplex.
      Titrations of the lesioned GGCC oligomer with HOO-CoBLM leads to a mixture of
      complexes, in contrast to results of a similar titration with the lesioned GTAC
      oligomer.

PMID- 12490719
TI  - Cooperative binding of Sox10 to DNA: requirements and consequences.
AB  - The high-mobility-group (HMG) domain containing transcription factor Sox10 is an
      important regulator of various processes including the development of neural
      crest cells and glial cells. Target gene promoters contain multiple Sox10-binding
      sites, which either support monomeric or cooperative, dimeric binding. The latter
      is unusual for Sox proteins and might contribute to functional specificity of
      Sox10. We find that specific amino acid residues in a conserved region
      immediately preceding the HMG domain of Sox10 are required for cooperative
      binding. These residues cooperate with the HMG domain during dimeric binding in a
      manner dependent on specific determinants within the first two alpha-helices of
      the HMG domain. Cooperativity of DNA binding is surprisingly refractory to
      changes in the overall conformation of the DNA-bound dimer. Whereas maintenance
      of cooperativity is essential for full activation of the promoter of the myelin
      protein zero target gene, dimer-dependent conformational changes such as the
      exact bending angle introduced into the promoter appear to be less important,
      shedding new light on the architectural function of Sox proteins.

PMID- 12490720
TI  - Improving the predictive value of the competence transcription factor (ComK)
      binding site in Bacillus subtilis using a genomic approach.
AB  - Generally, the presence of a consensus sequence in the promoter of a gene is
      taken as indication for regulation by the transcription factor that binds to this
      sequence. In light of the recent developments in genome research, we were
      interested to what extent this supposition is valid. We examined the relationship
      between the presence of a binding site for ComK, the competence transcription
      factor of Bacillus subtilis, and actual transcriptional activation by ComK.
      Bacillus subtilis contains 1062 putative ComK-binding sites (K-boxes) in its
      genome. We employed DNA macroarrays to identify ComK-activated genes, and found
      that the presence of a K-box is an unreliable predictor for regulation. Only
      approximately 8% of the genes containing a K-box in the putative promoter region
      are regulated by ComK. The predictive value of a K-box could be improved by
      taking into consideration the degree of deviation from the K-box consensus
      sequence, the presence of extra ComK-binding motifs and the positions of RNA
      polymerase-binding sites. Finally, many of the ComK-activated genes show no
      apparent function related to the competence process. Based on our findings, we
      propose that the ComK-dependent activation of several genes might serve no
      biological purpose and can be considered 'evolutionary noise'.

PMID- 12490721
TI  - Genome-wide analysis of mRNA decay in resting and activated primary human T
      lymphocytes.
AB  - We used microarray technology to measure mRNA decay rates in resting and
      activated T lymphocytes in order to better understand the role of mRNA decay in
      regulating gene expression. Purified human T lymphocytes were stimulated for 3 h
      with medium alone, with an anti-CD3 antibody, or with a combination of anti-CD3
      and anti-CD28 antibodies. Actinomycin D was added to arrest transcription, and
      total cellular RNA was collected at discrete time points over a 2 h period. RNA
      from each point was analyzed using Affymetrix oligonucleotide arrays and a first
      order decay model was used to determine the half-lives of approximately 6000
      expressed transcripts. We identified hundreds of short-lived transcripts encoding
      important regulatory proteins including cytokines, cell surface receptors, signal
      transduction regulators, transcription factors, cell cycle regulators and
      regulators of apoptosis. Approximately 100 of these short-lived transcripts
      contained ARE-like sequences. We also identified numerous transcripts that
      exhibited stimulus-dependent changes in mRNA decay. In particular, we identified
      hundreds of transcripts whose steady-state levels were repressed following T cell
      activation and were either unstable in the resting state or destabilized
      following cellular activation. Thus, rapid mRNA degradation appears to be an
      important mechanism for turning gene expression off in an activation-dependent
      manner.

PMID- 12490722
TI  - Specificity of Mnt 'master residue' obtained from in vivo and in vitro
      selections.
AB  - Mnt is a repressor from phage P22 that belongs to the ribbon-helix-helix family
      of DNA binding factors. Four amino acids from the N-terminus of the protein,
      Arg2, His6, Asn8 and Arg10, interact with the base pairs of the DNA to provide
      the sequence specificity. Raumann et al. (Nature Struct. Biol., 2, 1115-1122)
      identified position 6 as a 'master residue' that controls the specificity of the
      protein. Models for the interaction have residue 6 of Mnt interacting directly
      with position 5 of the operator. In vivo selections demonstrated that protein
      variants at residue 6 bound specifically to operator mutations at that position.
      Operators in which the wild-type G at position 5 was replaced by T specifically
      bound to several different protein variants, primarily hydrophobic residues. The
      obtained protein variants, plus some others, were used in in vitro selections to
      determine their preferred binding sites. The results showed that the residue at
      position 6 influenced the preference for binding site bases predominantly at
      position 5, but that the effects of altering it can extend over longer distances,
      consistent with its designation as a 'master residue'. The similarities of
      binding sites for different residues do not correlate strongly with common
      measures of amino acid similarities.

PMID- 12490723
TI  - Discovery of novel transcription factor binding sites by statistical
      overrepresentation.
AB  - Understanding the complex and varied mechanisms that regulate gene expression is
      an important and challenging problem. A fundamental sub-problem is to identify
      DNA binding sites for unknown regulatory factors, given a collection of genes
      believed to be co-regulated. We discuss a computational method that identifies
      good candidates for such binding sites. Unlike local search techniques such as
      expectation maximization and Gibbs samplers that may not reach a global optimum,
      the method discussed enumerates all motifs in the search space, and is guaranteed
      to produce the motifs with greatest z-scores. We discuss the results of
      validation experiments in which this algorithm was used to identify candidate
      binding sites in several well studied regulons of Saccharomyces cerevisiae, where
      the most prominent transcription factor binding sites are largely known. We then
      discuss the results on gene families in the functional and mutant phenotype
      catalogs of S.cerevisiae, where the algorithm suggests many promising novel
      transcription factor binding sites. The program is available at
      http://bio.cs.washington.edu/software.html.

PMID- 12490724
TI  - Integrity of duplex structures without hydrogen bonding: DNA with pyrene paired
      at abasic sites.
AB  - DNA polymerases specifically insert the hydrophobic pyrene deoxynucleotide (P)
      opposite tetrahydrofuran (F), an stable abasic site analog, and DNA duplexes
      containing this non-hydrogen-bonded pair possess a high degree of thermodynamic
      stability. These observations support the hypothesis that steric complementarity
      and stacking interactions may be sufficient for maintaining stability of DNA
      structure and specificity of DNA replication, even in the absence of hydrogen
      bonds across the base pair. Here we report the NMR characterization and structure
      determination of two DNA molecules containing pyrene residues. The first is a
      13mer duplex with a pyrene.tetrahydrofuran pair (P.F pair) at the ninth position
      and the second mimics a replication intermediate right after incorporation of a
      pyrene nucleoside opposite an abasic site. Our data indicate that both molecules
      adopt right-handed helical conformations with Watson- Crick alignments for all
      canonical base pairs. The pyrene ring stays inside the helix close to its
      baseless partner in both molecules. The single-stranded region of the replication
      intermediate folds back over the opposing strand, sheltering the hydrophobic
      pyrene moiety from water exposure. The results support the idea that the
      stability and replication of a P.F pair is due to its ability to mimic Watson
      Crick structure.

PMID- 12490725
TI  - Studies on the minimal lengths required for DNA primers to be extended by the
      Tetrahymena telomerase: implications for primer positioning by the enzyme.
AB  - Telomerase is a specialized reverse transcriptase that contains an integral RNA
      subunit including a short template sequence. It extends telomeric 3' overhangs
      and chromosome breakpoints by catalyzing reiterative copying of this internal
      template into single-stranded telomeric DNA repeats. Here we report for the first
      time that in vitro the ciliate Tetrahymena telomerase can efficiently extend very
      short single-stranded DNA primers (<6 nt). These data indicate that interactions
      with nucleotides further upstream are not essential for elongation of longer
      primers. We also report that the minimal lengths required for primers to be
      extended by the telomerase depend on the positions along the template at which
      the primers are initially aligned. At a primer concentration of 2.5 micro M,
      primers aligned in the beginning, middle and next to the end of the template,
      respectively, must consist of at least 4, 5 and 6 nt to be extended by the
      telomerase. At a primer concentration of 50 micro M, the corresponding minimal
      lengths are 3, 4 and 5 nt. The systematic variation of the minimal required
      primer lengths supports the presence of a site within the telomerase
      ribonucleoprotein complex that mediates specific positioning of 3' termini of
      telomeric and non-telomeric DNA in the beginning of the template during telomere
      synthesis.

PMID- 12490727
TI  - Promoter-trapping in Saccharomyces cerevisiae by radiation-assisted fragment
      insertion.
AB  - Non-homologous insertion (NHI) of DNA fragments into genomic DNA is a method
      widely used in insertional mutagenesis screens. In the yeast Saccharomyces
      cerevisiae, the efficiency of NHI is very low. Here we report that its efficiency
      can be increased by gamma-irradiation of recipient cells at the time of
      transformation. Radiation-assisted NHI depends on YKU70, but its efficiency is
      not improved by inactivation of RAD5 or RAD52. In a pilot study, we generated 102
      transformant clones expressing a lacZ reporter gene under standard conditions (30
      degrees C, rich medium). The site of insertion was determined in a subset of
      eight clones in which lacZ expression was altered by UV-irradiation. A comparison
      with published data revealed that three of the eight genes identified in our
      screen have not been targeted by large-scale transposon-based insertion screens.
      This suggests that radiation-assisted NHI offers a more homogeneous coverage of
      the genome than methods relying on transposons or retroviral elements.

PMID- 12490728
TI  - Stochastic processes defining sensitivity and variability of internally
      calibrated quantitative NASBA-based viral load assays.
AB  - For quantitative assessment of virus particles in patient plasma samples various
      assays are commercially available. Typical performance characteristics for such
      assays are sensitivity, precision and the range of linearity. In order to assess
      these properties it is common practice to divide the range of inputs into
      subranges in order to apply different statistical models to evaluate these
      properties separately. We developed a general statistical model for internally
      calibrated amplification based viral load assays that combines these statistical
      properties in one powerful analysis. Based on the model an unambiguous definition
      of the lower limit of the linear range can be given. The proposed method of
      analysis was illustrated by a successful application to data generated by the
      NucliSens EasyQ HIV-1 assay.

PMID- 12490729
TI  - A Y639F/H784A T7 RNA polymerase double mutant displays superior properties for
      synthesizing RNAs with non-canonical NTPs.
AB  - A T7 RNA polymerase in which Tyr639 is mutated to Phe readily utilizes 2'-deoxy,
      2'-NH2 and 2'-F NTPs as substrates and has been widely used to synthesize
      modified RNAs for a variety of applications. This mutant does not readily utilize
      NTPs with bulkier 2'-substituents, nor does it facilitate incorporation of NTPs
      with modifications at other positions. Introduction of a second mutation (H784A)
      into the Y639F background markedly enhances utilization of NTPs with bulky 2'
      substituents (2'-OMe and 2'-N3), and may also enhance use of NTPs with
      modifications at other than the 2'-position. The Y639F/H784A double mutant may
      therefore be exceptionally useful for incorporation of a variety of non-canonical
      NMPs into RNA.

PMID- 12490730
TI  - Random DNA fragmentation with endonuclease V: application to DNA shuffling.
AB  - The enzyme endonuclease V nicks uracil-containing DNA at the second or third
      phosphodiester bond 3' to uracil sites. I applied the enzyme to random
      fragmentation of DNA to revise the complex DNA shuffling protocol. The merit of
      using endonuclease V is that cleavage occurs at random sites and the length of
      the fragments can easily be adjusted by varying the concentration of dUTP in the
      polymerase chain reaction. Unlike the conventional method using DNase I, no
      partial digestion or gel separation of fragments is required. Therefore, labor is
      dramatically reduced and reproducibility ensured. I applied this method to
      recombine two truncated green fluorescent protein (GFP) genes and demonstrated
      successful DNA shuffling by the appearance of the fluorescent full-length GFP
      genes.

PMID- 12490731
TI  - T7 RNA polymerase as a self-replicating label for antigen quantification.
AB  - Enzymes are used widely as labels in binding assays for protein analytes, because
      they provide signal amplification. Efforts at improving the assay sensitivity
      have been focused mainly on the synthesis of novel substrates, e.g. fluorogenic
      and chemiluminogenic ones. We report the investigation of T7 RNA polymerase
      (T7RP) as a label with unique characteristics for antigen quantification. In an
      in vitro, coupled (one-step) transcription/translation reaction, T7RP catalyzes
      the expression of an enzyme-coding DNA template to produce free enzyme
      (luciferase) in solution. We demonstrate that the generated luciferase is
      linearly related to the input T7RP in a range covering over four orders of
      magnitude. It is also shown that T7RP exhibits a significant level of self
      replication (100-fold) in vitro by acting on a DNA template comprising the T7RP
      cDNA downstream of a T7 promoter. By combining the self-replication reaction with
      the expression of luciferase DNA, as low as 1400 T7RP molecules are detectable.
      Furthermore, the T7RP is biotinylated, complexed with streptavidin and used for
      antigen quantification in a microtiter well-based assay with high sensitivity and
      reproducibility.

PMID- 12490726
TI  - Exploring root symbiotic programs in the model legume Medicago truncatula using
      EST analysis.
AB  - We report on a large-scale expressed sequence tag (EST) sequencing and analysis
      program aimed at characterizing the sets of genes expressed in roots of the model
      legume Medicago truncatula during interactions with either of two microsymbionts,
      the nitrogen-fixing bacterium Sinorhizobium meliloti or the arbuscular
      mycorrhizal fungus Glomus intraradices. We have designed specific tools for in
      silico analysis of EST data, in relation to chimeric cDNA detection, EST
      clustering, encoded protein prediction, and detection of differential expression.
      Our 21 473 5'- and 3'-ESTs could be grouped into 6359 EST clusters, corresponding
      to distinct virtual genes, along with 52 498 other M.truncatula ESTs available in
      the dbEST (NCBI) database that were recruited in the process. These clusters were
      manually annotated, using a specifically developed annotation interface. Analysis
      of EST cluster distribution in various M.truncatula cDNA libraries, supported by
      a refined R test to evaluate statistical significance and by 'electronic
      northern' representation, enabled us to identify a large number of novel genes
      predicted to be up- or down-regulated during either symbiotic root interaction.
      These in silico analyses provide a first global view of the genetic programs for
      root symbioses in M.truncatula. A searchable database has been built and can be
      accessed through a public interface.

PMID- 12490734
TI  - Pity the poor consumer.

PMID- 12490732
TI  - Optimization of trans-splicing ribozyme efficiency and specificity by in vivo
      genetic selection.
AB  - Trans-splicing ribozymes are RNA-based catalysts capable of splicing RNA
      sequences from one transcript specifically into a separate target transcript. In
      doing so, a chimeric mRNA can be produced, and new gene activities triggered in
      living cells dependent on the presence of the target mRNA. Based on this ability
      of trans-splicing ribozymes to deliver new gene activities, a simple and
      versatile plating assay was developed in Saccharomyces cerevisiae for assessing
      and optimizing constructs in vivo. Trans-splicing ribozymes were used to splice
      sequences encoding a GAL4-derived transcription activator into a target
      transcript from a prevalent viral pathogen. The transcription activator
      translated from this new mRNA in turn triggered the expression of genes under the
      regulatory control of GAL4 upstream-activating sequences. Two of the activated
      genes complemented metabolic deficiencies in the host strain, and allowed growth
      on selective media. A simple genetic assay based on phenotypic conversion from
      auxotrophy to prototrophy was established to select efficient and specific trans
      splicing ribozymes from a ribozyme library. This simple assay may prove valuable
      for selecting optimal target sites for therapeutic agents such as ribozymes,
      antisense RNA and antisense oligodeoxyribonucleotides, and for optimizing the
      design of the therapeutic agents themselves, in higher eukaryotes.

PMID- 12490733
TI  - Novel retroviral vectors to facilitate expression screens in mammalian cells.
AB  - As tools for functional genomics, expression profiling and proteomics provide
      correlative data, while expression cloning screens can link genes directly to
      biological function. However, technical limitations of gene transfer, expression,
      and recovery of candidate genes have limited wider application of genome-wide
      expression screens. Here we describe the pEYK retroviral vectors, which maintain
      high titers and robust gene expression while addressing the major bottleneck of
      expression cloning--efficient candidate gene recovery. By exploiting schemes for
      enhanced PCR rescue or strategies for direct isolation of proviral DNA as
      plasmids in bacterial hosts, the pEYK vectors facilitate cDNA isolation from
      selected cells and enable rapid iteration of screens and genetic reversion
      analyses to validate gene candidates. These vectors have proven useful to
      identify genes linked to cell proliferation, senescence and apoptosis.

PMID- 12490735
TI  - FDA drug approval summaries: fulvestrant.
AB  - Patients with hormone-sensitive breast cancer who have responded to tamoxifen may
      receive additional benefit from a second endocrine agent following progression or
      relapse after tamoxifen therapy. Fulvestrant (Faslodex((R)), ICI 182780,
      AstraZeneca Pharmaceuticals; Wilmington, Delaware) is a selective antagonist of
      estrogen designed to have no estrogenic effects. Lack of aqueous solubility led
      to the development of a parenteral formulation for monthly intramuscular
      administration. Fulvestrant has been shown to inhibit the proliferative effects
      of estrogen on sensitive tissues in vitro and in vivo, and is without apparent
      measurable estrogenic activity. The data upon which marketing approval for
      fulvestrant was based are summarized below. Eight hundred fifty-one
      postmenopausal women with advanced breast cancer were enrolled in two phase III
      studies, 400 in a North American double-blind study and 451 in a European open
      label study, comparing the efficacy and safety of fulvestrant with anastrozole.
      Four hundred twenty-eight patients were randomized to receive fulvestrant 250 mg
      monthly by intramuscular injection and 423 patients were to receive anastrozole 1
      mg daily. Patients were considered hormone sensitive either by receptor status or
      previous response to endocrine therapy. Over 96% of patients had previously
      received tamoxifen, either in the adjuvant setting or as treatment for metastatic
      disease. The primary study end points were response rate and time to progression.
      Response rates for patients treated with fulvestrant were 17% and 20% in the
      North American and European trials, respectively, compared with 17% and 15% in
      the anastrozole treatment arms. There were no statistically significant
      differences in response rates, time to progression, or survival between treatment
      arms in either study. The most common adverse events attributed to the treatment
      (>10%) were injection-site reactions and hot flashes. Common events (1%-10%)
      included asthenia, headache, and gastrointestinal disturbances (nausea, vomiting,
      and diarrhea), as well as rash and urinary tract infections. A small increase in
      joint disorders was reported in the anastrozole-treated patients. On April 25,
      2002, fulvestrant 250 mg by monthly intramuscular injection was approved by the
      U.S. Food and Drug Administration for the treatment of hormone receptor-positive
      metastatic breast cancer in postmenopausal women with disease progression
      following antiestrogen therapy. Approval was based on similarity of response
      rates and time to progression between fulvestrant and anastrozole.

PMID- 12490736
TI  - The use of zoledronic acid, a novel, highly potent bisphosphonate, for the
      treatment of hypercalcemia of malignancy.
AB  - BACKGROUND: Hypercalcemia of malignancy is a serious complication of cancer that
      affects patients with and without bone metastases. A single infusion of
      pamidronate disodium, a nitrogen-containing bisphosphonate, effectively
      normalizes serum calcium in the majority of patients treated for up to 1 month.
      Zoledronic acid is a new-generation, heterocyclic nitrogen-containing
      bisphosphonate and the most potent inhibitor of bone resorption identified to
      date. METHODS: The natural history, clinical presentation, and treatment of
      hypercalcemia of malignancy are reviewed, with a focus on the mechanisms of
      action and relative efficacy and safety of bisphosphonate therapies. RESULTS: The
      improved efficacy of zoledronic acid compared with pamidronate disodium has been
      demonstrated in a pooled analysis of two randomized clinical trials in patients
      with hypercalcemia of malignancy. In these trials, both zoledronic acid and
      pamidronate disodium were safe and well tolerated; however, zoledronic acid
      treatment resulted in a significantly higher number of complete responses, more
      rapid calcium normalization, and more durable responses compared with pamidronate
      disodium. CONCLUSIONS: Given the superior efficacy and comparable safety profile
      of zoledronic acid compared with pamidronate disodium, zoledronic acid is likely
      to become the treatment of choice for hypercalcemia of malignancy.

PMID- 12490737
TI  - Impact of tumor hypoxia and anemia on radiation therapy outcomes.
AB  - Local recurrence remains a major obstacle to achieving cure of many locally
      advanced solid tumors treated with definitive radiation therapy. The
      microenvironment of solid tumors is hypoxic compared with normal tissue, and this
      hypoxia is associated with decreased radiosensitivity. Recent preclinical data
      also suggest that intratumoral hypoxia, particularly in conjunction with an acid
      microenvironment, may be directly or indirectly mutagenic. Investigations of the
      prognostic significance of the pretreatment oxygenation status of tumors in
      patients with head and neck or cervical cancer have demonstrated that increased
      hypoxia, typically designated in these studies as pO(2) levels below 2.5-10 mm
      Hg, is associated with decreased local tumor control and lower rates of disease
      free and overall survival. Hypoxia-directed therapies in the radiation oncology
      setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen
      breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions
      have shown the potential to increase the effectiveness of curative-intent
      radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a
      viable and important approach. Anemia is common in the cancer population and is
      suspected to contribute to intratumoral hypoxia. A review of the literature
      reveals that a low hemoglobin level before or during radiation therapy is an
      important risk factor for poor locoregional disease control and survival,
      implying that a strong correlation could exist between anemia and hypoxia
      (ultimately predicting for a poor outcome). While having a low hemoglobin level
      has been shown to be detrimental, it is unclear as to exactly what the threshold
      for "low" should be (studies in this area have used thresholds ranging from 9
      14.5 g/dl). Optimal hemoglobin and pO(2) thresholds for improving outcomes may
      vary across and within tumor types, and this is an area that clearly requires
      further evaluation. Nonetheless, the correction of anemia may be a worthwhile
      strategy for radiation oncologists to improve local control and survival.

PMID- 12490738
TI  - A dose-escalation study of weekly topotecan, cisplatin, and gemcitabine front
      line therapy in patients with inoperable non-small cell lung cancer.
AB  - PURPOSE: To determine the optimal dose of combination topotecan, cisplatin, and
      gemcitabine in advanced non-small cell lung cancer patients. MATERIALS AND
      METHODS: This single-center, single-practice, phase I trial enrolled chemotherapy
      naive patients with inoperable stage IIIB/IV disease. Initial treatment was
      topotecan (0.5-2.0 mg/m(2)), cisplatin (20 mg/m(2)), and gemcitabine (1,000
      mg/m(2)) on days 1, 8, and 15 of a 28-day cycle. Dose-limiting thrombocytopenia
      at week 3 necessitated less frequent gemcitabine dosing (days 1 and 15 of each
      cycle). Thereafter, topotecan dose escalation proceeded to the target dose of 2
      mg/m(2). RESULTS: Thirty patients were enrolled and evaluable for toxicity
      assessment. Treatment was extremely well tolerated: only one grade 4 adverse
      event (leukopenia); no hospitalizations for treatment-related toxicities; no
      fever/neutropenia. Although no dose-limiting toxicities developed, 1.75 mg/m(2)
      topotecan is considered optimal and recommended for further study because it was
      well tolerated, active, and did not require dose adjustments or delays in
      therapy. Eleven of 29 (38%) evaluable patients achieved a partial response.
      Median survival was 38 weeks (range 4-110 weeks), median progression-free
      survival was 17 weeks, and the 1-year survival rate was 33%. Two patients remain
      alive after 108-122 weeks of follow-up. CONCLUSION: A 28-day cycle of topotecan
      (1.75 mg/m(2) days 1, 8, 15), cisplatin (20 mg/m(2) days 1, 8, 15), and
      gemcitabine (1,000 mg/m(2) days 1, 15) was a safe and well-tolerated outpatient
      treatment for advanced non-small cell lung cancer. The favorable preliminary
      efficacy and safety of this regimen suggest that further study in phase II
      trials, including quality-of-life end points, is warranted.

PMID- 12490739
TI  - Improvement of oral drug treatment by temporary inhibition of drug transporters
      and/or cytochrome P450 in the gastrointestinal tract and liver: an overview.
AB  - The oral bioavailability of many cytotoxic drugs is low and/or highly variable.
      This can be caused by high affinity for drug transporters and activity of
      metabolic enzymes in the gastrointestinal tract and liver. In this review, we
      will describe the main involved drug transporters and metabolic enzymes and
      discuss novel methods to improve oral treatment of affected substrate drugs.
      Results of preclinical and clinical phase I and II studies will be discussed in
      which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are
      given orally in combination with an inhibitor of drug transport or drug
      metabolism. Future randomized studies will, hopefully, confirm that this strategy
      for oral treatment is at least as equally effective and safe as standard
      intravenous administration of these drugs.

PMID- 12490740
TI  - A phase II and pharmacokinetic study of ecteinascidin 743 in patients with
      gastrointestinal stromal tumors.
AB  - PURPOSE: To assess the efficacy, tolerability, and pharmacokinetics of
      ecteinascidin 743 (ET-743) in patients with advanced gastrointestinal stromal
      tumors (GISTs). PATIENTS AND METHODS: The study was confined to adult patients
      with radiographically measurable GISTs. ET-743 was administered as a 24-hour
      continuous i.v. infusion at a dose of 1.5 mg/m(2) repeated every 3 weeks.
      Pharmacokinetic blood sampling was performed during the first cycle of therapy.
      Tumors were restaged after every second cycle of therapy. RESULTS: A total of 20
      patients was enrolled in the study, 19 of whom were treated with 47 cycles of ET
      743 (median 2, range 1-10). Severe toxicities were limited to reversible grade 3
      transaminitis in 10 patients and grade 3 fatigue in one patient. There were no
      objective responses, and disease stabilization occurred in two patients lasting
      for periods of 4 and 10 months. The 1-year survival rate was 71.1%. Mean +/-
      standard deviation values of the maximum plasma concentration and total plasma
      clearance were 1.1 +/- 0.4 ng/ml and 44 +/- 16 l/h/m(2), respectively, for 19 of
      the 20 patients. CONCLUSION: This study is the first report of a prospective
      phase II trial to evaluate a cytotoxic agent in patients with GISTs. This study
      underscores the primary resistance of GISTS to chemotherapy and stands in stark
      contrast to the encouraging results recently achieved with STI571. The lack of
      response may be associated with a therapeutically ineffective exposure to the
      drug based upon the lower incidence of severe toxicities and greater clearance
      than described in phase I and II trials of ET-743.

PMID- 12490741
TI  - Controversies regarding the use of radiation after mastectomy in breast cancer.
AB  - Despite years of clinical study, there are still many unanswered questions
      regarding postmastectomy radiation. It is clear that radiation therapy plays a
      critical role in the multidisciplinary management of patients with locally
      advanced or inflammatory breast cancer. It is also accepted that postmastectomy
      radiation is not required for most women with noninvasive disease or stage I
      disease. Randomized clinical trials studying radiation treatments for women with
      stage II or III breast cancer have shown that the addition of radiation after
      mastectomy can reduce local-regional recurrence rates, which then improves
      survival. However, other data have indicated that the risk of local-regional
      recurrence after mastectomy and chemotherapy is low for patients with small
      tumors and one to three positive lymph nodes, leading some to question whether
      postmastectomy radiation is useful for this group. A second controversy regards
      the sequencing of postmastectomy radiation and breast reconstruction. In this
      article we discuss these controversies, review the data that are relevant, and
      provide our institutional approaches to these issues.

PMID- 12490742
TI  - Breast cancer in the very young patient: a multidisciplinary case presentation.
AB  - A case is presented that exemplifies many issues and controversies in the
      diagnosis and treatment of breast cancer in the very young. This woman was 22
      years of age at diagnosis; she initially underwent breast-conservation therapy
      and adjuvant chemotherapy, retained fertility, had a subsequent uncomplicated
      pregnancy and delivery, and 7 years later developed a local recurrence in the
      breast. The discussion addresses risk factors, diagnosis, and treatment of breast
      cancer in the young; the impact of treatment on fertility; implications regarding
      pregnancy, and the management of local recurrence after breast conservation.

PMID- 12490743
TI  - Virtual connections: Internet health care.
AB  - Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at
      Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at
      MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and
      advancing compassionate health care delivery that provides hope to the patient,
      support to caregivers, and encourages the healing process. The Center sponsors
      the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers
      reflect on important psychosocial issues faced by patients, their families, and
      their caregivers, and gain insight and support from fellow staff members. The
      20th century success of the Internet is now translating into changes in 21st
      century medical practice. The changes brought about by the Internet have at once
      facilitated and complicated the practice of medicine. Physicians and patients are
      challenged to take advantage of the increased opportunities afforded by Internet
      access while being mindful of its drawbacks and the limitations to virtual
      communication. The case of Karen Parles, one of the authors, is presented. Karen
      developed locally advanced lung cancer and used the Internet to research her
      diagnosis. She found the information on lung cancer limited and confusing, and,
      in response, developed a website devoted to empowering lung cancer patients in
      their search for information and support (http://www.lungcanceronline.org). Here
      we discuss issues surrounding patients' use of the Internet for health
      information and communication with health care providers. The value of
      information-seeking as a coping mechanism is debated, and concerns are raised
      regarding confidentiality of electronic communications and the logistics of
      physicians adopting e-mail as a mechanism for communicating with patients.

PMID- 12490744
TI  - The molecular perspective: VEGF and angiogenesis.

PMID- 12490745
TI  - Capitol report.

PMID- 12490748
TI  - Joining forces to make a difference.

PMID- 12490749
TI  - Connecting the disconnect between hospital and home.
AB  - Mr. D, 76 years old, underwent a colostomy in a local hospital after several
      weeks of preoperative outpatient radiation therapy that caused severe diarrhea.
      The nurses at the hospital managed his colostomy and told him he probably "would
      not need to wear a pouch" after he was taught how to irrigate. They showed him
      how to empty a two-piece system before he was discharged 7 days after his
      surgery. Mr. D was able to manage emptying but did not pay much attention to the
      procedure because he viewed wearing the pouch as a temporary situation. After his
      discharge, the home care nurse informed him that due to the diarrhea he was
      experiencing, colostomy irrigation would not be an option and he would have to
      use a pouching system - one different from the one he had learned to use in the
      hospital. Mr. D was disappointed and bewildered.

PMID- 12490750
TI  - State of the science: pathology and management of the patient with overactive
      bladder.
AB  - A relatively new term, overactive bladder is used to describe urinary frequency,
      urgency, and nocturia with or without urinary incontinence. Normal micturition
      involves coordination among the nervous system, the bladder, and the sphincter.
      Theories about pathogenesis include disorders of the central and peripheral
      nervous system, lowered levels of neurotransmitters, and structural problems of
      the bladder and sphincter. Assessing the patient with overactive bladder
      incorporates a thorough history and focused physical exam. Current treatments for
      this condition include lifestyle changes, behavioral interventions, pharmacologic
      management, and neuromodulation therapy. Research into different medications and
      delivery systems proves promising for the patient with overactive bladder.

PMID- 12490751
TI  - When fiber is not enough: current thinking on constipation management.
AB  - Constipation is a common disorder and many patients fail to respond to the simple
      constipation remedies of increased fiber and fluid intake. When secondary to
      other conditions, medications, or disease processes, the focus of constipation
      management is correction of causative factors. However, primary constipation -
      ie, constipation with no identifiable causative factor - is very common. Patients
      generally present with one of three patterns: constipation-predominant irritable
      bowel syndrome, slow transit constipation, or pelvic floor dysfunction resulting
      in dyssynergic defecation. Baseline evaluation for patients with chronic
      constipation includes a careful history, focused physical examination, and
      limited laboratory studies. Patients with dyssynergic defecation usually respond
      best to biofeedback therapy and pelvic muscle re-education. Constipation
      predominant irritable bowel syndrome is best managed with dietary monitoring and
      modifications, fiber therapy, and education regarding self-monitoring and self
      care. Patients with slow transit constipation may benefit from fiber therapy and
      increased activity, but most also will require laxative therapy. Current
      guidelines for prescribing laxatives suggest bulk agents as first line and
      osmotic agents as second line therapy. Stimulant laxatives should generally be
      reserved for PRN use. Current understanding about the etiology, pathology, and
      classification of different types of constipation are summarized and a stepwise
      approach to evaluation and management is presented.

PMID- 12490752
TI  - An evaluation of two incontinence skin care protocols in a long-term care
      setting.
AB  - Caring for the skin of patients with incontinence is an essential activity in
      long-term care. A prospective descriptive study to compare the effect of two skin
      care protocols on skin condition, pain, and caregiver time was conducted. Thirty
      two (32) skilled nursing facility residents with incontinence participated in the
      3-week study. Patients were randomly assigned to a standard care regimen (soap
      and water cleansing after each incontinence episode, followed by application of a
      moisturizing lotion) or study care protocol (no-rinse skin cleanser after each
      episode and application of a barrier cream with durable properties after the
      first incontinence episode of each shift). Number and type of incontinence
      episodes, skin condition, pain, and caregiver time spent were assessed. Skin
      integrity was maintained in the majority of control (69%) and study group (72%)
      patients and improvement occurred in 8% of control and 17% of the study group
      (NS). Study protocol procedures took less time to complete than control
      procedures (a savings of 79 minutes/patient/day). A positive correlation between
      pain intensity and level of skin impairment was observed (r = 0.88). The results
      of this study suggest that at this facility, use of soap, water, and a
      moisturizer may be less effective and more time-consuming than using a no-rinse
      cleanser and a durable barrier product.

PMID- 12490753
TI  - The impact of urinary incontinence in African American women.
AB  - Urinary incontinence is a major health problem for many individuals, especially
      older women. Research on urinary incontinence is common in Caucasians, but scarce
      in women of diverse cultures. Using data from a previous (parent) descriptive
      correlational study on risk factors for urinary incontinence in African American
      women (N = 233), a descriptive study of the impact of urinary incontinence was
      conducted among 85 college-educated African American women who were members of a
      prestigious African American organization and reported symptoms of urinary
      incontinence. Information about frequency and duration of incontinence,
      activities affected by urinary incontinence, and ratings of how much they were
      bothered by their urinary incontinence was obtained. Mean age of the study group
      was 51.94 years (range 20 to 80 years). Fifty-four of the participants (64%)
      reported one or more vaginal delivery, 33% had undergone a hysterectomy, and
      symptoms of urinary incontinence had been present from 3 months to 30 years.
      Stress, urge, and mixed incontinence were reported. Eleven women (13%) had sought
      treatment for their urinary incontinence, 20% said urinary incontinence bothered
      them a great deal, 8.5% reported behavioral modifications, and a portion of the
      women said they had to spend extra money on incontinence supplies. In this group
      of African American women, urinary incontinence rates were similar to those
      reported in Caucasian women. Research to increase clinician knowledge base and
      improve the care of African American women is needed.

PMID- 12490754
TI  - Evaluating the efficacy of a uniquely delivered skin protectant and its effect on
      the formation of sacral/buttock pressure ulcers.
AB  - Skin breakdown is a common adverse occurrence in healthcare facilities; effective
      management of related risk factors is critical for prevention. Measures focusing
      on the skin care of patients with incontinence are recommended to reduce the
      incidence of pressure ulcers on the sacrum and ischium. However, little research
      exists to support these recommendations. A retrospective study was conducted to
      determine if the use of a skin cleansing/protectant product on residents with
      incontinence decreased the incidence of nosocomial pressure ulcers in the
      sacral/buttock area. Chart data from all residents with incontinence of a 57-bed,
      long-term care, skilled nursing home that employs a comprehensive approach to
      pressure ulcer prevention were collected for a period of 3 months before use of
      the new product and for 3 months following introduction of the new product.
      During the first 3 months, five (14.7%) of the 34 incontinent residents developed
      superficial pressure ulcers (20% were Stage I, 80% were Stage II). Following the
      change in skin care, no pressure ulcers occurred in the 30 residents with
      incontinence. The observed decrease (McNemar's chi-square = 4.786, df = 1, Phi = 
      .273, P =.015) suggests a significant association between the consistent
      application of a skin protectant and the prevention of skin breakdown. The
      results of this study demonstrate that, in this population, and in the presence
      of a comprehensive pressure ulcer prevention program, use of this skin protectant
      can significantly reduce the incidence of nosocomial sacral/buttocks pressure
      ulcers.

PMID- 12490755
TI  - Recent progress in the treatment of myelodysplastic syndrome in adult patients.
AB  - Peripheral blood cytopenias and dysplastic hematopoietic progenitors characterize
      the myelodysplastic syndrome. Patients suffer from the consequences of chronic
      cytopenias or progression to acute myelogenous leukemia. Although allogeneic
      hematopoietic stem cell transplantation is a potentially curative option, the
      standard of care for most patients with myelodysplastic syndrome continues to be
      supportive care, with blood product transfusion and antibiotics for infectious
      complications. Many patients with myelodysplastic syndrome are not candidates for
      allogeneic hematopoietic stem cell transplantation because of advanced age,
      comorbid illnesses, and lack of a histocompatible donor. Increased rates of
      apoptosis in hematopoietic progenitors, altered production of inflammatory
      cytokines, neoangiogenesis, and autoreactive T lymphocytes have all been shown to
      contribute to the phenotype of myelodysplastic syndrome. These recent insights
      into the pathophysiology of myelodysplastic syndrome have been translated into
      therapeutic trials of noncytotoxic agents for this disorder. Although clinical
      responses have been seen with these novel agents, the critical biologic targets
      have not yet been clearly defined.

PMID- 12490756
TI  - Chronic myelogenous leukemia.
AB  - Within the past few years, the introduction of imatinib mesylate (imatinib) has
      profoundly changed the management of patients with chronic myelogenous leukemia.
      This review article addresses the recent advances in the treatment of chronic
      myelogenous leukemia--in particular, maturing data on the use of imatinib in
      different phases of the disease; the optimal therapy of newly diagnosed patients;
      the emergence of resistance to imatinib and potential strategies to overcome this
      problem; and finally, the place of stem cell transplantation in current treatment
      algorithms.

PMID- 12490757
TI  - Chronic lymphocytic leukemia: advances in biology and therapeutics.
AB  - Recent advances in our understanding of the biology of chronic lymphocytic
      leukemia have made it possible to stratify patients according to risk. In
      addition, advances in the therapy of patients have improved responses and have
      for the first time allowed for a risk adapted approach to patients with chronic
      lymphocytic leukemia similar to that which has been used for acute leukemia for
      years. Tumor cell differentiation status and presence of specific somatic and
      immunoglobulin gene mutations have been shown to be reliable predictors of
      disease behaviors. This knowledge could provide clinicians with tools to better
      stratify patients and eventually affect their clinical outcomes. Furthermore, new
      therapeutic agents and treatment combinations that appear to have increased
      efficacy have been developed.

PMID- 12490758
TI  - Recent advances in pediatric acute lymphoblastic and myeloid leukemia.
AB  - Acute leukemia is the most common form of childhood cancer and is the primary
      cause of cancer-related mortality in children. In the United approximately 3250
      cases are diagnosed annually in children and adolescents younger than 20 years,
      of whom 2400 have acute lymphoblastic leukemia (ALL). Treatment results in
      childhood ALL continue to improve, and the expected current cure rates approach
      75 to 80% of all children with ALL, including T-ALL and mature B-cell ALL, the
      two variants that, not too long ago, had a considerably poorer prognosis compared
      with the common form of BpALL. The most significant new development in the past 2
      years has been the development of further evidence for fetal origin of childhood
      leukemias, and additional evidence to support the notion that postnatal events
      modulating the events of immune-mediated elimination of these leukemic clones
      play a major role in the eventual development of clinical disease. Other
      epidemiologic developments include (1) increased appreciation of the role of drug
      metabolizing enzymes, both in determining the predisposition to leukemia and
      response to therapy; and (2) both clinical observations and gene expression
      studies seeming to identify a new approach to the evaluation and treatment of
      children with MLL (11q23) rearrangements. A most remarkable new development in
      the induction therapy of childhood leukemia and lymphoma in the United States is
      the use of urate oxidase for prevention of tumor lysis syndrome and the
      associated uric acid nephropathy. Drug resistance, determined either on leukemic
      blast cells in vitro or by studies of MRD, is being looked at critically in an
      effort to improve the treatment results further. Consolidation with HDMTX has
      gained wider popularity with the realization that effective CNS prophylaxis can
      be achieved with intrathecal therapy plus HDMTX for consolidation. In contrast to
      ALL, the progress in the therapy of acute myeloid leukemia (AML) lags behind,
      with cure rates of approximately 40 to 50%. There is no convincing evidence for
      substitution of daunorubicin with other anthracyclines, nor evidence for using
      high-dose cytarabine during induction in childhood AML. Rather, a 3 + 10 regimen
      with total daunorubicin 180 mg/m2 and cytarabine 100 to 200 mg/2 for 10 days
      appears to yield the best results. The most important component of the
      postremission chemotherapy continues to be several courses of high-dose
      cytarabine. The results from the MRC 10, LAME 89/91 studies and the recent BFM 93
      trial with high-dose cytarabine and mitoxantrone suggest that there may be some
      benefit to including this combination in the postremission phase of AML. Despite
      these improvements in chemotherapy, allogeneic BMT from a matched family donor
      remains the best option for most patients (excluding Down syndrome, APL, and
      possibly those with inv16). Newer prognostic markers of interest include FLT3/ITD
      and minimal residual disease at the end of induction therapy.

PMID- 12490759
TI  - DNA microarray and cancer.
AB  - Since the discovery of the first oncogene 26 years ago, a large body of research
      has convincingly demonstrated that the initiation and progression of cancers
      involve the accumulation of genetic aberrations in the cell. Many techniques have
      been developed to identify these genetic abnormalities. The recent completion of
      human genome sequencing and advances in DNA microarray technology allow rapid
      genetic analysis to take place on a genome-wide scale and have revolutionized the
      way cancers are studied. This ground-breaking approach of studying cancer
      promises to provide a better understanding of the underlying mechanism for
      tumorigenesis, more accurate diagnosis, more comprehensive prognosis, and more
      effective therapeutic interventions.

PMID- 12490760
TI  - Serial analysis of gene expression and cancer.
AB  - Serial analysis of gene expression has been widely used to characterize gene
      expression patterns associated with tumor formation. These studies resulted in
      the identification of tumor-specific markers, transcriptional pathways, or
      therapeutic targets. In this review, recent applications and developments of
      serial analysis of gene expression and their impact on the diagnosis and
      treatment of cancer are discussed. A combination of serial analysis of gene
      expression and small-scale microarray analysis represents a strategy that should
      facilitate the identification and exploitation of tumor-specific gene expression
      for diagnostic or therapeutic purposes. In addition, cancer diagnosis and
      treatment may benefit from a complementation between serial analysis of gene
      expression and quantitative proteomics in the future.

PMID- 12490761
TI  - Mapping genetic alterations in tumors with single nucleotide polymorphisms.
AB  - Single nucleotide polymorphisms are the most abundant genetic markers in the
      human genome whose analyses can be easily conducted on a large scale. Most
      established methods for high-throughput single nucleotide polymorphism analyses
      are qualitative and are not suitable for genetic analysis of archived tumor
      specimens, which have compromised tissue integrity and normal tissue
      contaminations. Recent studies have focused on the development of quantitative
      methods for single nucleotide polymorphism analyses that can tolerate such
      imperfections in archived tissues. These methods have been used to measure the
      rate of allelic imbalance in small adenocarcinomas and to reveal novel
      correlations between allelic imbalance and disease progression in colorectal
      cancer. Therefore, quantitative single nucleotide polymorphism analysis provides
      a powerful tool for the identification of novel tumor markers and for the
      characterization of genetic alterations in human tumors.

PMID- 12490762
TI  - Fluorescence resonance energy transfer in the study of cancer pathways.
AB  - Many different signaling pathways are involved in deregulation of cell
      proliferation leading to cancer. Although genomic approaches successfully
      identified a great variety of molecules associated with cancerogenesis, other
      strategies must be applied to elucidate complex interactions between these
      molecules. One promising approach is fluorescence resonance energy transfer, a
      proximity-dependent fluorescence phenomenon. With the development of spectrally
      different fluorescent proteins and improved technologies for fluorescence
      measurements, this approach gains an enormous potential for future research. The
      fluorescence resonance energy transfer principle can be applied for studying all
      kinds of interactions or conformational changes, and it can also be used for
      microscopic visualization and subcellular localization of biochemical reactions,
      thereby promoting the progress of cancer research. Moreover, it can be exploited
      to develop sensitive and efficient drug screening systems and to design valuable
      diagnostic tools.

PMID- 12490764
TI  - Endocrine tumors: evaluation of the thyroid nodule.
AB  - Thyroid nodules are found in 4 to 7% of the population, and with the increased
      use of radiographic methods, incidental nodules are becoming more prevalent. Only
      5% of all nodules will be malignant, and thyroid cancer accounts for only 0.4% of
      all cancer deaths. The preferred diagnostic approach is early referral, avoidance
      of numerous radiologic evaluations, and early performance fine-needle aspiration.
      This article reviews the literature of the last 12 months and discusses some of
      the new molecular, genetic, and immunostaining techniques in the evaluation of
      thyroid nodules.

PMID- 12490765
TI  - Well differentiated thyroid cancer.
AB  - Cancers of follicular cell origin are the most common of the endocrine
      malignancies. Thyroid cancers are seen with increased frequency after radiation
      exposure and in some familial syndromes. Interestingly, the prognosis of thyroid
      carcinoma is highly dependent on the age of the patient at the time of
      examination: several clinical staging systems facilitate appropriate treatment
      planning. The ability of the follicular cell to take up iodine permits the use of
      radioactive iodine for follow-up and therapy. After thyroidectomy and radioiodine
      ablation, thyroglobulin becomes a sensitive marker for the presence of recurrent
      or metastatic disease. Patients who are thyroglobulin-positive but radioiodine
      negative or who have antithyroglobulin antibodies are a clinical challenge.
      Improvement in imaging studies can help in the treatment of these patients. New
      treatments, such as the use of agents to improve iodine uptake in follicular cell
      tumors, are in early clinical investigation; others are in experimental
      development but hold promise for the treatment of aggressive thyroid
      malignancies.

PMID- 12490766
TI  - Anaplastic thyroid cancer.
AB  - Anaplastic thyroid carcinoma is one of the most aggressive malignancies, with a
      poor prognosis. Although rare, representing only 2% of clinically recognized
      thyroid cancers, the overall median survival is limited to months. Most patients
      are elderly and seek treatment with a rapidly growing mass. Almost half the
      patients seek treatment with distant metastases, with as many as 75% developing
      distant disease during their illness. In most the patients, complete surgical
      resection is not possible. There are, however, a few patients with resectable
      disease reported in the literature who have demonstrated long-term survival with
      aggressive multimodal therapy that included surgery, radiation, and chemotherapy.
      Preclinical studies in human anaplastic thyroid carcinoma cell lines show promise
      that new approaches to the management of this disease will be found in the
      future. Until such time when an effective regimen is found, all patients with
      anaplastic thyroid carcinoma should be evaluated for multimodal therapy in the
      setting of a clinical trial.

PMID- 12490767
TI  - Adrenal incidentaloma.
AB  - Adrenal incidentalomas are incidentally discovered adrenal masses greater than 1
      cm in diameter that appear to be clinically nonfunctioning. They are detected
      during imaging procedures of the abdomen and chest (CT, MRI, and ultrasonography)
      for an unrelated condition or symptom complex. With the widespread escalation in
      the use of these imaging modalities and marked improvements in image resolution,
      the probability of finding an incidentaloma on cross-section imaging is rapidly
      approaching the 6% prevalence of previously reported autopsy studies. All
      incidentalomas greater than 1 cm should be evaluated for hormonal activity,
      including a 1-mg overnight dexamethasone suppression test, total 24-hour urinary
      metanephrines and fractionated catecholamines, and, in the hypertensive patient,
      a serum potassium level and plasma aldosterone concentration to plasma renin
      activity ratio. All hormonally active tumors should be removed. Hormonally
      inactive tumors are resected based on size, imaging phenotype, and interval
      growth. Percutaneous biopsies are generally unwarranted and are potentially
      dangerous. Laparoscopic adrenalectomy has become the surgical procedure of choice
      for most benign functioning and nonfunctioning tumors of the adrenal gland.
      Subclinical metabolic abnormalities associated with adrenal incidentalomas remain
      an area of intense clinical research.

PMID- 12490768
TI  - Adjunctive risperidone treatment in post-traumatic stress disorder: a preliminary
      controlled trial of effects on comorbid psychotic symptoms.
AB  - Positive and negative symptoms of psychosis may be common in patients with
      chronic post-traumatic stress disorder (PTSD), but few studies have investigated
      the use of antipsychotic agents in these patients. This preliminary study
      examined the potential efficacy of risperidone in treating psychotic symptoms
      associated with chronic PTSD. In a 5-week, prospective, randomized, double-blind,
      placebo-controlled trial, adjunctive risperidone treatment was assessed in 40
      combat veterans with chronic PTSD and comorbid psychotic features. Most patients
      were receiving antidepressants and some other psychotics with doses of concurrent
      medications held constant for at least 1 month prior to and during the study.
      Thirty-seven patients completed at least 1 week of treatment with risperidone or
      placebo. The Positive and Negative Syndrome Scale (PANSS) and the Clinician
      Administered PTSD Scale (CAPS) were used to assess symptoms. The PANSS was the
      primary outcome measure. At treatment endpoint, risperidone-treated patients
      showed a significantly greater decrease from baseline, albeit modest, in
      psychotic symptoms (PANSS total scores) than placebo-treated patients (P < 0.05).
      CAPS ratings declined significantly in both groups but did not differ
      significantly between groups. However, CAPS re-experiencing subscale scores had
      greater improvement in the risperidone-treated patients at week 5 (P < 0.05,
      completer analysis) with a trend towards greater improvement versus placebo a
      endpoint (P < 0.1, LOCF). Risperidone was well tolerated with minimal
      extrapyramidal symptoms. These preliminary results support studying the potential
      efficacy of risperidone for treating global psychotic symptoms associated with
      chronic PTSD with a suggestion that core re-experiencing symptoms may also be
      responsive. Further research using randomized, controlled trial designs in larger
      patient groups are needed to define more adequately the role of risperidone and
      other atypical agents in PTSD.

PMID- 12490769
TI  - Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in
      depressed patients.
AB  - Impaired cognitive functioning is often associated with major depressive disorder
      (MDD). Moreover, a number of agents used to treat MDD are known to have negative
      effects on cognitive functioning. We report an assessment of the effects of the
      selective norepinephrine reuptake inhibitor reboxetine, the selective serotonin
      reuptake inhibitor paroxetine, and placebo on a variety of measures of cognitive
      functioning in patients with MDD. Cognitive functioning in 74 adult patients
      (aged 18-65 years) with a confirmed diagnosis of MDD (DSM-IV) was assessed as
      part of two identical, randomized, double-blind, placebo- and active-treatment
      controlled, fixed/flexible dose comparisons of 8 weeks of treatment with
      reboxetine (8-10 mg/day), paroxetine (20-40 mg/day) and placebo. Cognitive
      function was assessed at baseline, day 14 and day 56 using a selection of tasks
      from the Cognitive Drug Research computerized assessment system, including Simple
      Reaction Time, Digit Vigilance, Choice Reaction Time, Numeric Working Memory,
      Word Recognition and Critical Flicker Frequency. The results in the 74 patients
      (reboxetine n = 25, paroxetine n = 23, placebo n = 26) showed that reboxetine
      significantly improved the ability to sustain attention at day 56 compared with
      baseline (P = 0.023). In addition, patients who received reboxetine experienced
      significant improvements in their speed of cognitive functioning when tested at
      day 56 compared to baseline (P = 0.024). No significant changes or trends in this
      direction were seen among patients who received either placebo or paroxetine. The
      results of the present study provide objective data to support the possibility
      that reboxetine favourably affects cognitive processes in depressed patients.

PMID- 12490770
TI  - Treatment of depression with comorbid anxiety disorders: differential efficacy of
      paroxetine versus moclobemide.
AB  - To compare the efficacy and tolerability of moclobemide versus paroxetine for the
      treatment of depression with comorbid anxiety disorders. Outpatients fulfilling
      DSM-III-R criteria for major depression or dysthymia and for a co-occurring
      comorbid anxiety disorder (panic disorder, generalized anxiety disorder or
      obsessive-compulsive disorder) after a 1-week run-in phase were randomly assigned
      to open-label moclobemide (300-600 mg/day) or paroxetine (20-40 mg/day) for 4
      months. Primary criterion for response was a 50% score reduction from baseline on
      Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale scores. Mean
      changes in Clinical Global Impressions Severity of Illness and Improvement Scales
      (CGI-I) were also used to evaluate treatment response. Of the 123 patients
      included in the study, 65 were randomly assigned to moclobemide and 58 to
      paroxetine. At study end, the two treatment groups did not differ significantly
      in terms of proportion of responders. Treatment group differences emerged when
      comorbid anxiety diagnoses were considered. In patients with comorbid panic
      disorder, paroxetine was superior to moclobemide in improving both anxiety and
      depression (five patients out of 18 in the moclobemide group and nine out of 14
      in the paroxetine group were rated as responders according to CGI-I, P = 0.04).
      Neither medication was superior in treating comorbid generalized anxiety
      disorder. These findings indicate that both moclobemide and paroxetine are
      effective for treatment of depression with comorbid anxiety disorders. However,
      in the subgroup with comorbid panic disorder, paroxetine is more effective than
      moclobemide in reducing both depressive and anxiety symptoms.

PMID- 12490771
TI  - Antipsychotic augmentation for treatment resistant obsessive-compulsive disorder:
      what if antipsychotic is discontinued?
AB  - The aim of the present study was to retrospectively review the charts of
      obsessive-compulsive disorder (OCD) patients who responded to the addition of an
      antipsychotic to the seroronin reuptake inhibitor (SRI), and who subsequently
      discontinued the antipsychotic, in order to evaluate whether antipsychotic
      discontinuation resulted in a relapse of the disorder. Charts of patients with a
      principal diagnosis of OCD (DSM-IV) treated with pharmacotherapy were reviewed in
      order to select patients who: (i) did not respond to a trial with a first-line
      drug (clomipramine or a selective SRI); (ii) received an antipsychotic at low
      doses (haloperidol, pimozide, risperidone or olanzapine) in order to potentiate
      the SRI; (iii) responded to this augmentation strategy; and (iv) discontinued the
      antipsychotic drug for any reason while continuing the SRI at the same dose.
      Relapse was defined as a worsening of Yale-Brown Obsessive-Compulsive Scale (Y
      BOCS) total score >/= 35% with respect to last evaluation before antipsychotic
      discontinuation or, for patients with a Y-BOCS < 16 at the end of the combination
      period, as a Y-BOCS total score >/= 16 at any time after antipsychotic
      discontinuation. According to our definition of relapse, 15 patients out of 18
      (83.3%) relapsed after antipsychotic discontinuation, with a mean worsening of
      symptoms of 6.6 +/- 1.7 points in the Y-BOCS total score. Thirteen patients out
      of the 15 who relapsed did so by week 8 after discontinuation. Two subjects
      relapsed at the end of the 1-year study. Although retrospective, our study
      provides initial evidence that antipsychotic augmentation has to be maintained
      for patients who respond to this strategy, because the vast majority of subjects
      who discontinue the antipsychotic relapse within 2 months.

PMID- 12490772
TI  - Effect of a pharmacological intervention on quality of life in patients with
      obsessive-compulsive disorder.
AB  - Patients with obsessive-compulsive disorder (OCD) not only suffer from obsessive
      compulsive symptoms, but also the disorder is associated with aberrant social
      functioning and a diminished quality of life (QoL). Although studies concerning
      the effect of treatment interventions on symptoms are common, studies with regard
      to the effect of treatment interventions on QoL are scarce. We examined the
      effect of a pharmacological intervention on QoL in 150 patients with OCD.
      Furthermore, we studied whether two different drugs, venlafaxine and paroxetine,
      differed in their effect on QoL. Finally, we examined whether any found
      improvement in QoL was related to improvement in symptoms and/or the baseline
      self-directedness score, which is one of the character dimensions of the
      psychobiological model of Cloninger. We demonstrated that QoL, as assessed with
      the Lancashire Quality of Life Profile, improved following pharmacological
      intervention, for which paroxetine and venlafaxine appeared to be equally
      effective. Furthermore, neither improvement in symptoms, nor baseline self
      directedness, was associated with the improvement in QoL.

PMID- 12490773
TI  - Mirtazapine in the treatment of panic disorder: an open-label trial.
AB  - The aim of this open label trial was to evaluate mirtazapine tolerability and
      effectiveness in controlling symptomatology of patients with panic disorder.
      Forty-five patients with panic disorder, with or without agoraphobia, 11 of them
      with a comorbid diagnosis of major depression, were included. Patients were
      assessed with a structured psychiatric interview and their symptomatology
      evaluated with specific psychometric scales. Three study participants dropped out
      due to adverse events. Mirtazapine was administered at an established dose of 30
      mg daily for 3 months. Patients were assessed at weeks 2 and 4, and then at
      monthly intervals. All psychometric measures showed statistically significant
      reductions in total scores at the rated time points, with a pronounced decline in
      number and intensity of panic attacks and anticipatory anxiety throughout the
      study. Mirtazapine was well tolerated as signified by the low discontinuation
      rate (6.3%), and all patients showed a significant symptomatic improvement. The
      improvement did not appear to be linked to the concurrent presence of a
      depressive illness.

PMID- 12490774
TI  - Extrapyramidal symptom profiles assessed with the Drug-Induced Extrapyramidal
      Symptom Scale: comparison with Western scales in the clinical double-blind
      studies of schizophrenic patients treated with either olanzapine or haloperidol.
AB  - The superiority of olanzapine to haloperidol with respect to a decreased
      incidence of treatment-emergent extrapyramidal syndromes (EPS) in patients with
      schizophrenia was demonstrated in studies conducted in both Japan and Western
      countries. EPS measurements used in Western countries included the Simpson-Angus,
      Barnes akathisia and the Abnormal Involuntary Movement Scale, while the Drug
      Induced Extrapyramidal Symptom Scale (DIEPSS) was used in Japan. The aim of this
      study was to clarify how the DIEPSS captures EPS profiles. The baseline
      prevalence and treatment-emergent incidence of EPS in Japanese schizophrenic
      patients treated with olanzapine or haloperidol were retrospectively compared as
      assessed by the DIEPSS to the prevalence and incidence of EPS in primarily
      Caucasian schizophrenic patients who were treated with olanzapine or haloperidol.
      Specifically, the prevalence and incidence of dyskinesia, akathisia and
      parkinsonism were compared between the Japanese trial and an international trial
      to examine if appropriate definitions using the DIEPSS can be derived assuming
      that a comparable prevalence and incidence of the syndromes would be observed
      when any differences in residual antipsychotic exposure at the initiation of
      study treatment were accounted for. For the incidence of all EPS syndromes, odds
      ratios were observed to be similar between the two studies, indicating that
      appropriate criteria for the clinical diagnosis of the EPS syndromes could be
      established based on the DIEPSS. This preliminary and retrospective work suggests
      that the DIEPSS can be used to operationally define the presence or absence, and
      make the clinical diagnosis, of specific EPS syndromes.

PMID- 12490775
TI  - Optimal dose of risperidone and olanzapine for patients with schizophrenia in
      Taiwan.
AB  - Risperidone and olanzapine-administration data were collected for schizophrenia
      patients treated at four Taiwanese medical centres. Only stable patients
      maintained on a medication at a dose that had remained unchanged for more than 1
      month were included in the analysis. Of the 268 cases, 175 were treated with
      risperidone and 93 with olanzapine at mean daily doses of 3.56 +/- 1.54 mg and
      12.21 +/- 4.99 mg, respectively. The majority of the risperidone-treated patients
      (73.2%) received 2-4 mg per day, with another 19.0% receiving 5-6 mg. A daily
      dose of 10-20 mg was received by 82.9% of the olanzapine group. Although the mean
      daily doses for both drugs were slightly higher for inpatients than outpatients,
      statistical significance was not achieved. Further, no gender or age-group dose
      differences were demonstrated for either drug.

PMID- 12490776
TI  - Allopurinol for the treatment of aggressive behaviour in patients with dementia.
AB  - Aggressive behaviour is commonly observed in patients with dementia, and current
      pharmacological treatments are still deficient in terms of efficacy and
      tolerability. Allopurinol is an inhibitor of the enzyme xanthine oxidase, with
      previously suggested anti-aggressive effects. After successful treatment of
      aggression in two patients, we performed a case-series study with allopurinol 300
      mg a day orally for 6 weeks (increasing 300 mg every 2 weeks if the response was
      less than 50%) in six patients with dementia associated with prominent aggressive
      behaviour who failed to respond to two previous treatment strategies. Five
      patients were considerably responsive to allopurinol (four with 300 mg within 2
      weeks and one with 600 mg), apparently without side-effects, which is in
      accordance with its well-established safety and tolerability profile. The
      observed therapeutic effect of allopurinol might be due to the inhibition of the
      enzyme xanthine oxidase, possibly decreasing production of oxygen-free radicals
      or promoting the accumulation of purines. Controlled studies are warranted to
      confirm these preliminary observations.

PMID- 12490777
TI  - Peripheral oedema in patients taking olanzapine.
AB  - Premarketing trials of olanzapine reported an incidence of peripheral oedema of
      3%. Outpatients, who were actively receiving treatment with olanzapine, were
      evaluated for peripheral oedema. Twenty-eight (57%) out of 49 subjects exhibited
      oedema, including five (10.2%) to a severe degree. There were no significant
      differences regarding gender, time/dose on olanzapine, concomitant diagnoses or
      psychotropic medication. There was a tendency (P < 0.10) for older age and
      greater frequency of thyroid abnormalities in those individuals with oedema. In
      the oedema group, there was a positive correlation (P < 0.05) between age and
      severity. Our finding, far from demonstrating that olanzapine causes oedema at
      this frequency, suggests that there maybe patients who are vulnerable to
      developing this side-effect.

PMID- 12490778
TI  - Isolation of precursor endothelial cells from peripheral blood for donor-specific
      crossmatching before organ transplantation.
AB  - BACKGROUND: The clinical importance of endothelial-cell (EC) antibodies (Abs) in
      allo-transplantation (Tx) has been reported. However, lack of a suitable method
      for isolation of donor-specific ECs has prevented routine detection of these Abs
      before Tx. We describe a quick and simple method for the direct isolation of ECs
      from whole blood, for routine crossmatching (XM) to detect anti-EC Abs. METHODS:
      ECs were isolated using magnetic beads coated with Abs against the angiopoietin
      receptor Tie-2 that is expressed on EC precursors. A retrospective analysis of 50
      previously well-characterized XM sera taken immediately before transplantation
      from patients with end-stage kidney disease were tested. RESULTS: Tie-2+ cells
      expressed human leukocyte antigen (HLA) class I, class II, and other EC markers.
      Sera known to contain only EC-specific or EC- and monocyte (EM)-reactive Abs
      reacted positively with Tie-2+ cells but not with Tie-2- cells from the same
      individual. In addition, the Tie-2+ cells reacted with sera containing only HLA
      class I or class II Abs. In all, 3 of 25 sera from patients with stable graft
      outcome and no rejections reacted with Tie-2+ cells. CONCLUSIONS: For the first
      time, with use of a single-target cell population, the detection of clinically
      relevant donor-specific HLA class I, class II, EM, and EC-specific Abs can be
      performed routinely before Tx. This method is promising because it is quick,
      specific, and easy to perform on whole blood samples and can therefore be used to
      perform routine donor-specific EC crossmatching (ECXM) in the future. Routine use
      of ECXM will aid in identifying better donor-recipient combinations and thus have
      a greater impact on transplant survival as compared with lymphocyte crossmatch
      (LXM).

PMID- 12490779
TI  - Tacrolimus pharmacogenetics: polymorphisms associated with expression of
      cytochrome p4503A5 and P-glycoprotein correlate with dose requirement.
AB  - BACKGROUND: There is marked heterogeneity in blood concentrations of tacrolimus
      following standard body-weight-based dosing. This is most apparent in black
      patients, who have a higher dose requirement when compared with other ethnic
      groups. Differences in intestinal P-glycoprotein and hepatic and intestinal
      cytochrome P4503A activity have been postulated as contributing to this problem.
      METHODS: The dose-normalized blood concentrations of tacrolimus at 3 months after
      renal transplantation were related to CYP3AP1 and multiple drug resistance (MDR)
      1 genotypes determined by polymerase chain reaction followed by restriction
      fragment length polymorphism analysis. RESULTS: We found that a single nucleotide
      polymorphism in the CYP3AP1 pseudogene (A/G(44)) that previously has been noted
      to be more common in African Americans and strongly associated with hepatic
      CYP3A5 activity correlated well with the tacrolimus dose requirement. A weaker
      association was found for a polymorphism in the MDR-1 gene, which influences
      intestinal P-glycoprotein expression. CONCLUSIONS: The CYP3AP1 genotype is a
      major factor in determining the dose requirement for tacrolimus, and genotyping
      may be of value in planning patient-specific drug dosing.

PMID- 12490780
TI  - Proapoptotic Bax is hyperexpressed in isolated human islets compared with
      antiapoptotic Bcl-2.
AB  - BACKGROUND: Apoptosis is a well-documented pathway for islet cell death. One
      potential mechanism is overexpression of death-promoting Bax compared with
      antiapoptotic Bcl-2 in islets. METHODS: We isolated islets from 10 human
      pancreata and measured the expression of Bax mRNA and Bcl-2 mRNA by real-time
      quantitative polymerase chain reaction; islet and pancreas expression of Bax, Bcl
      2, activated caspase-3, and cleaved poly (ADP-ribose) polymerase were also
      assessed by immunohistochemistry. Islet cell apoptosis was evaluated by terminal
      deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay and by
      flow cytometry. RESULTS: The mean (+/-SE) level of Bax mRNA was 336+/-79 copies
      per nanogram of total RNA, and the level of Bcl-2 mRNA was 36+/-10 (P=0.001). A
      positive correlation existed between islet expression of Bax mRNA and Bcl-2 mRNA
      (P=0.001). The islet Bax to Bcl-2 ratio was 10.8+/-1.3 and 1.71+/-0.3 for the
      spleens (P=0.0001). Bax mRNA (P=0.04), but not Bcl-2 mRNA, was expressed at a
      higher level in islets compared with spleens. Human islets contained large
      numbers of cells expressing Bax protein, whereas only infrequent islet cells
      expressed Bcl-2 protein, activated caspase-3, and poly (ADP-ribose) polymerase.
      The apoptotic index was 5% by TUNEL assay, and the percentage of apoptotic islet
      cells was 9.7+/-2.5% by flow cytometry. Sections of human pancreas before islet
      isolation showed islet staining for Bax but not Bcl-2. CONCLUSIONS: Our finding
      that isolated human islets express Bax at a higher level compared with Bcl-2
      suggests a molecular mechanism for islet cell death by apoptosis. We hypothesize
      that reducing islet expression of Bax, or regulating its activation, will help
      preserve islet cell mass after islet transplantation.

PMID- 12490781
TI  - BK virus and SV40 co-infection in polyomavirus nephropathy.
AB  - BACKGROUND: Polyomavirus (PV) nephropathy has been attributed to reactivation of
      BK virus (BKV) or more rarely JC virus (JCV). The simian virus (SV) 40 is PV that
      was likely introduced into the human population through contaminated vaccines.
      The purpose of this study was to identify and characterize the PV that is
      associated with PV nephropathy. METHODS: The clinical diagnosis of PV nephropathy
      (PVN) was made in patients with acute deterioration in renal function whose renal
      biopsies showed typical viral cytopathic changes in tubular epithelial cells and
      staining for PV T antigen. Polymerase chain reaction (PCR) amplification of DNA
      from peripheral blood mononuclear cells (PBMC), urinary cells, and renal biopsy
      tissue was performed using specific primers for the transcription control regions
      of BKV, JCV, and SV40, respectively. RESULTS: Six cases of PV nephropathy were
      identified in 91 renal transplant recipients (7%). Immunosuppressive therapy was
      modified in all patients. Renal function stabilized or improved in four patients
      and deteriorated in two patients, and one patient has lost his allograft, after
      follow-up from 2 to 25 months. PCR detection demonstrated BKV genome in three of
      five PBMC samples, six of six urinary cell samples, and two of four renal
      biopsies. SV40 genome was detected in two of five PBMC samples, one of six
      urinary cell samples, and two of four renal biopsies. Infectious SV40 and BKV was
      demonstrated in CV-1 co-cultures using urine from one patient. JCV was not
      detected in any PVN sample. Co-infection with BKV and SV40 was found in two PVN
      patients. Urine samples obtained 12 months after transplant from 26 transplant
      recipients without PVN on simultaneous protocol renal biopsy were analyzed by
      PCR; BKV genome was demonstrated in 5 of 25 samples, JCV genome was demonstrated
      in 3 of 25 samples, and SV40 genome was demonstrated in 0 of 25 samples.
      CONCLUSION: The authors report molecular evidence that co-infection with BKV and
      SV40 occurs in renal transplant patients with PVN, suggesting that SV40 may
      contribute to PVN after renal transplant.

PMID- 12490782
TI  - Modulation of peripheral-type benzodiazepine receptor levels in a reperfusion
      injury pig kidney-graft model.
AB  - BACKGROUND: Ischemia-reperfusion injury is associated with an increased risk of
      acute rejection, delayed graft function, or chronic graft dysfunction.
      Mitochondria play a central role in this process. METHODS: Using an
      autotransplantation pig kidney model, both early (40 min and 7 days) and late (2
      16 weeks) changes in renal function and morphology were determined after
      different periods of cold ischemia in University of Wisconsin or Euro-Collins
      solutions. We have also investigated the expression of the peripheral-type
      benzodiazepine receptor (PBR), which is also critical in maintaining outer
      mitochondrial membrane stability. RESULTS: Function of the kidneys was better
      preserved after 1 hr and 24 hr than after 48 hr and 72 hr in Euro-Collins and
      University of Wisconsin solutions. Medulla injury was reduced in 1 hr-preserved
      and 24 hr-preserved groups. PBR was found to be present in epithelial cells of
      the deep cortical and outer medulla in both normal human and well-preserved pig
      kidneys. PBR expression was modulated by ischemia-reperfusion injury and the
      concurrent tubular injury and repair processes. CONCLUSION: This study indicates
      that PBR expression correlates with the quality of kidney preservation and might
      serve as an index of kidney and mitochondria viability. Moreover, these data
      suggest that PBR might be involved in membrane biogenesis during reperfusion. In
      addition, considering the identical localization of PBR in human and pig kidneys,
      these findings could have a direct application in human clinical settings of
      kidney pathology.

PMID- 12490783
TI  - Local antilaminin antibody treatment alters the rejection pattern of murine
      cardiac allografts: correlation between cellular infiltration and extracellular
      matrix.
AB  - BACKGROUND: Emerging data place extracellular matrix (ECM) proteins as important
      elements in lymphocyte positioning and effector function in alloreactive
      responses. Using a non-vascularized model of allogeneic heart transplantation in
      Swiss mice, we have observed a correlation between the cellular infiltration and
      ECM deposition towards the interior of the graft during the kinetics of
      rejection. METHODS: To confirm the importance of ECM during the rejection process
      in this model, we treated the transplanted animals with local injections of
      antilaminin monoclonal antibody and analyzed, by histology and
      immunohistochemistry, the grafts on day 15, which corresponds to the peak of
      cellular infiltration and ECM deposition. RESULTS: The treatment with mAb
      antilaminin decreased the cellular infiltrate and ECM deposition within the
      grafts, as compared to controls. Moreover, we found a diminished IFN-gamma, TNF
      alpha and IL-2 deposition in the transplant area, and a reduced co-localization
      of these cytokines with laminin. By contrast, the antilaminin treatment increased
      tenascin deposition, a molecule with immunosuppressive properties, and also
      caused an increase in apoptosis of the cellular infiltrate. CONCLUSIONS: These
      data hallmark the importance of laminin, in distinct aspects concerning the
      events leading to allograft rejection, and also reinforce this molecule as a
      potential target for immune intervention in organ transplantation.

PMID- 12490784
TI  - Defining optimal immunosuppression for islet transplantation based on reduced
      diabetogenicity in canine islet autografts.
AB  - BACKGROUND: The recent results of clinical islet transplantation have improved
      substantially with the introduction of a more potent but less diabetogenic
      immunosuppressant protocol. The successful development of this protocol was based
      in part on the outcomes of studies reported herein, addressing the diabetogenic
      potential of a series of immunosuppressant agents used alone or in combination in
      a canine islet autograft model. Although it is recognized that failure to achieve
      long-term insulin independence in human islet allotransplantation has been
      multifactorial, with low engraftment mass, acute or chronic rejection, autoimmune
      recurrence, loss of islet-acinar integrity, heterotopic site, denervation, and
      insulin resistance all being implicated to varying degrees, avoidance of
      diabetogenic immunosuppression has been pivotal to the enhanced outcomes of
      clinical islet transplantation. We here explore the effects of clinically
      relevant doses of cyclosporine or tacrolimus when given alone or in combination
      with glucocorticoids on long-term canine islet autograft function. METHOD: Dogs
      (n=8) underwent total pancreatectomy, islet isolation, and intrasplenic
      autotransplantation and were normoglycemic with stable long-term graft function 3
      months to 8 years posttransplant. The frequently sampled intravenous glucose
      tolerance test (FSIGT) was performed predrug (baseline), at 1 month of therapy
      (on drug), and again 1 month after withdrawal of therapy (postdrug). RESULTS:
      Monotherapy treatments with low- or high-dose prednisone, Neoral, or tacrolimus
      had minimal impact on islet autograft function. The combination of Neoral and
      prednisone led to a marked impairment in glucose decay (25% decline from 1.77+/
      0.2 to 1.24+/-0.2, P<0.05), without significant change in insulin responsiveness
      or glucose effectiveness. However, insulin sensitivity was markedly impaired
      while on therapy (7.10+/-1.2 to 3.10+/-0.5, P<0.01). Importantly, glucose decay
      and insulin sensitivity failed to return to baseline after withdrawal of therapy.
      The combination of tacrolimus and glucocorticoids led to permanent and
      irreversible diabetes in all recipients (n=6, P<0.001). Similar treatment of
      healthy control dogs led to a 44% decrease in glucose decay (P<0.01).
      CONCLUSIONS: Immunosuppression must be specifically tailored for islet
      transplantation and be glucocorticoid free if insulin independence is to be
      sustained clinically.

PMID- 12490785
TI  - The effect of selective inhibition of cyclooxygenase (COX)-2 on acute cardiac
      allograft rejection.
AB  - BACKGROUND: Using a rat (Lewis-Wistar Furth) abdominal heterotopic
      transplantation model, we reported previously that the expression of
      cyclooxygenase (COX)-2 is increased in parallel with that of nitric oxide
      synthase (NOS)-2 during cardiac allograft rejection. METHODS: To investigate
      effects of COX-2 inhibition in this model, allograft recipients were treated
      orally (PO) with 5 mg/kg per day of the tetra substituted furanone selective COX
      2 inhibitor 5,5-dimethyl-3-(3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)
      furanone (DFU) in 1% methyl cellulose solution. RESULTS: In the treated animals,
      allograft survival was increased from 6.3+/-0.5 to 12.6+/-2.6 days (P = .001). At
      days 3 and 5 posttransplantation, there were reductions in the extent of the
      inflammatory infiltrate, endovasculitis, myocardial edema, and cardiomyocyte
      damage in rejecting allografts. The mean numbers of apoptotic cardiomyocytes
      determined with the terminal deoxynucleotide transferase-mediated dUTP nick-end
      labeling (TUNEL) technique were significantly reduced in DFU-treated grafts
      compared with untreated controls (P < 0.05). At day 3 posttransplantation,
      prostaglandin E2 synthesis by myocardial slices incubated with 100 microM
      bradykinin was reduced from 1,097+/-156 to 153+/-63 pg/mg of protein in the
      treated allografts (P < .005). At day 5, COX-2 protein and mRNA together with COX
      2, NOS-2, and nitrotyrosine immunostaining in damaged cardiomyocytes were
      diminished in treated versus control grafts. CONCLUSION: The data indicate that
      the inhibition of COX-2 prolongs allograft survival and reduces myocardial damage
      and inflammation during acute cardiac allograft rejection.

PMID- 12490786
TI  - Variable relationship between chimerism and tolerance after hematopoietic cell
      transplantation without myelosuppressive conditioning.
AB  - BACKGROUND: We have previously described a mixed chimerism protocol that avoids
      myelosuppressive conditioning and permits hematopoietic cell transplantation
      across MHC barriers without the need for whole body irradiation in miniature
      swine. Here, we report our current experience including animals conditioned
      without thymic irradiation, and we attempt to define the relationship between
      long-term chimerism and stable tolerance in these animals. METHODS: Recipient
      swine received in vivo T-cell depletion, with or without thymic irradiation on
      day -2. Cyclosporine was administered for 30 to 60 days beginning on day -1. A
      total of 1 to 2 x 10(10) /kg cytokine-mobilized donor hematopoietic cells were
      infused during 3 days. Chimerism was determined by flow cytometry. In vitro
      tolerance assays and donor-matched kidney transplantation were performed after
      cessation of cyclosporine. RESULTS: Most recipients maintained stable chimerism
      (26 of 35) and were specifically tolerant to donor-matched cells in vitro
      regardless of whether they received thymic irradiation. Donor-matched kidney
      transplantations performed in chimeric animals without in vitro antidonor immune
      responses were accepted without immunosuppression. Some animals developed in
      vitro evidence of antidonor MHC responsiveness despite the persistence of donor
      cells in the peripheral blood. Donor-matched kidney transplantations performed in
      the face of these responses were rejected. CONCLUSIONS: These data indicate that
      this nonmyelosuppressive protocol can induce stable chimerism and robust
      tolerance even in animals conditioned without thymic irradiation. However, the
      data also demonstrate that macrochimerism does not always correlate with
      tolerance. Lack of in vitro antidonor immune responses in chimeric animals is an
      important predictor of renal allograft acceptance in this model.

PMID- 12490787
TI  - Heat shock preconditioning impairs revascularization of freely transplanted
      pancreatic islets.
AB  - BACKGROUND: Revascularization of freely transplanted pancreatic islets is
      essential for appropriate graft function and survival. During the first days
      after transplantation, however, islet transplants are avascular, and successful
      engraftment is believed to be markedly hampered by hypoxia-induced tissue injury.
      Because heat shock has been shown to induce cell resistance against hypoxia, it
      seems reasonable to stress pancreatic islets by heat before transplantation. In
      contrast, hypoxia is a major stimulus for angiogenesis, and thus heat shock
      preconditioning-induced resistance against hypoxia may decrease stimulation of
      angiogenesis. The authors therefore studied in vivo whether heat shock
      preconditioning of isolated islets affects angiogenesis and revascularization
      after free transplantation. METHODS: After collagenase isolation, heat shock
      preconditioned islets (42 degrees C for 30 min) were transplanted syngeneically
      into nontreated skinfold chambers of Syrian hamsters. In a second group of
      animals, nontreated islets were transplanted into heat shock-preconditioned
      chambers. Nontreated islets transplanted into nontreated chambers served as
      controls. Islet angiogenesis and revascularization were quantitatively analyzed
      during 14 days after transplantation using intravital fluorescence microscopy.
      Expression of heat shock proteins (HSP) was confirmed by immunohistochemistry and
      Western blotting. RESULTS: Immunohistochemistry revealed expression of HSP32
      (heme oxygenase [HO]-1), HSP72, and also intracellular insulin in isolated and
      transplanted pancreatic islets. Western blot analysis showed enhanced HSP32 but
      slightly decreased HSP72 expression in heat shock-preconditioned islets when
      compared with controls. Intravital microscopy revealed appropriate
      vascularization of control islets within 14 days after transplantation. Heat
      shock preconditioning of the host tissue (i.e., the skinfold chambers) did not
      affect islet vascularization when compared with controls. In contrast, heat shock
      preconditioning of the isolated islets resulted in a significantly (P < 0.05)
      impaired take rate, a reduced (P < 0.05) size of the newly formed microvascular
      network, and thus a smaller area (P < 0.05) of microvascularly perfused endocrine
      tissue. CONCLUSION: These data suggest that heat shock preconditioning of
      isolated pancreatic islets before transplantation impairs the process of graft
      angiogenesis and revascularization. Therefore, transient exposure of isolated
      islets to heat may not be considered a promising tool to improve the outcome of
      islet transplantation.

PMID- 12490788
TI  - Immune reconstitution at 6 months following T-cell depleted hematopoietic stem
      cell transplantation is predictive for treatment outcome.
AB  - BACKGROUND: Compared with allogeneic bone marrow, in cytokine mobilized blood
      stem cell grafts, the number of hematopoietic progenitors and lymphoid cells is
      higher. Consequently, we compared the immune reconstitution following these two
      transplant modalities in patients receiving T-cell depleted grafts for
      hematological malignancies and studied the impact of lymphocyte subset recovery
      on clinical outcome. METHODS: Conditioning for transplantation was radiation
      based, while graft versus host disease prophylaxis was by ex vivo T-cell
      depletion with Campath-1 antibodies. Clinical parameters of patients receiving
      bone marrow or cytokine-mobilized progenitor cell transplants were reviewed with
      emphasis placed on defining infectious events and on the causes of treatment
      failure (relapse, graft failure, or any cause of death). The blood lymphoid
      subsets, as well as markers for memory and naive T cells, were sequentially
      studied by standard flow cytometry. Serum immunoglobulins (Ig) concentrations
      were also determined. RESULTS: The patient population included 15 females and 27
      males with a median age of 32.5 (range 15-54) years. Source of human leukocyte
      antigen-identical sibling allogeneic grafts was bone marrow in 14 and peripheral
      blood (PBPC) in 28. The median follow-up was of 1,278 (range 47-2,466) days.
      Following hematopoietic recovery, within the first year, 28 patients were
      readmitted for pyrexial episodes, and four died of sepsis. In both groups, while
      the CD8+ subset recuperated rapidly, CD19 and CD4+ T cells remained significantly
      decreased even after 12 months, leading to persistently abnormal CD4:CD8 ratios.
      The median values of CD16+ and CD56+ (natural killer) cells remained normal
      throughout the study period. Despite the patients who were receiving PBPC grafts
      having significantly higher numbers of allogeneic mononuclear cells (x 10(8)/kg;
      median: 6.97; range 4.03-10.10 vs. 0.71; range 0.45-0.99; P<0.001) and colony
      forming unit granulocyte-macrophages (CFU-GMs) (x 10(4)/kg; median: 27.75; range
      0-196, 2 vs. 13.05; range 2.43-57; P<0.05), the recovery rate of B cells or T
      cell subpopulations was similar to those receiving bone marrow transplantation
      (BMT). Double fluorescence studies showed that CD2/CD45RO and RA as well as
      CD4/CD45RO and RA remained subnormal even after 12 months follow-up. During the
      observation period, except for IgA, normal levels of immunoglobulins were
      detected. In all, 18 out of 42 patients failed therapy, and 14 patients died.
      Treatment failure occurred at a median of 270 (range 47-1,638) days and was
      significantly associated with low total lymphocyte count (P = 0.01), CD2 (P =
      0.09), CD8 (P = 0.01), CD19 (P = 0.02), CD45RA (P = 0.05), and CD4/CD45RA (P =
      0.01), when tested at 6 months from transplantation. CONCLUSIONS: After T-cell
      depleted allogeneic PBPC or BMT, no differences in the rate of immune recovery
      were detected. However, patients with specific subset abnormalities at 6 months
      from grafting had a significantly higher risk of treatment failure.

PMID- 12490789
TI  - Improved renal function in sirolimus-treated renal transplant patients after
      early cyclosporine elimination.
AB  - BACKGROUND: Sirolimus (Rapamune; SRL) in combination with cyclosporine (CsA)
      reduces the incidence of acute rejection episodes in renal allograft recipients.
      This study evaluated whether renal function could be improved by elimination of
      CsA from an SRL-based regimen. METHODS: This phase 2, open-label, controlled,
      randomized study was conducted at 17 centers in the United States and Europe. Two
      hundred forty-six first cadaveric renal allograft recipients were enrolled, and
      197 were randomized to full-dose CsA (microemulsion) plus fixed-dose SRL (2
      mg/day; group A, n=97) or reduced-dose CsA plus concentration-controlled SRL
      (troughs 10-20 ng/mL; group B, n=100). Most patients with acute tubular necrosis
      delayed graft function that resolved later than posttransplantation day 7 were
      not randomized but were assigned to a third group (nonrandomized, n=49) and
      received up to 5 mg per day of SRL as part of their individualized treatment
      regimen. All patients received standard doses of corticosteroids. At the end of
      posttransplantation month 2, eligible patients (those not treated for rejection
      within 3 weeks) in group B had CsA tapered and eliminated over the subsequent 4
      to 6 weeks. RESULTS: At 12 months after transplantation, renal function was
      significantly better in the CsA-elimination arm. In patients who were on therapy
      and who had not experienced an acute rejection episode before month 6, serum
      creatinine level was significantly lower (1.38 mg/dL vs. 1.82 mg/dL, P < 0.001)
      and calculated glomerular filtration rate (Nankivell method) was significantly
      higher (73.5 mL/min vs. 57.1 mL/min, P < 0.001) in group B than in group A. In
      the intention-to-treat population, rates of biopsy-confirmed acute rejection at
      12 months were similar between groups A and B (18.6% vs. 22.0%, respectively; P =
      0.598). In addition, graft survival (92.8% and 95.0%) and patient survival (96.9%
      and 96.0%) rates at 12 months were not significantly different between groups A
      and B, respectively. Furthermore, there were no significant differences between
      black and nonblack recipients within treatment groups in terms of rejection rates
      and graft survival at 12 months. Black recipients in group B had better serum
      creatinine levels at 12 months compared with black recipients in group A (1.55
      mg/dL vs. 2.69 mg/dL, respectively, P = 0.011), as did nonblack recipients in
      group B compared with nonblack recipients in group A (1.53 mg/dL vs. 1.75 mg/dL,
      respectively, P = 0.055). Black patients in group A had higher mean serum
      creatinine levels (2.69 mg/dL) than nonblack patients in group A (1.75 mg/dL, P =
      0.028). Hypertension, edema, hypomagnesemia, and dyspnea were reported
      significantly less frequently in patients randomly assigned to undergo CsA
      elimination compared with patients in group A (P < 0.05); group B patients had a
      significantly greater (P < 0.05) incidence of abnormal liver function tests,
      diarrhea, hypokalemia, and thrombocytopenia. CONCLUSION: Concentration-controlled
      SRL with early elimination of CsA is safe and results in improved renal function.
      Reduced exposure to CsA does not result in a clinically significant increase in
      the incidence of acute rejection episodes. This is true for both black and
      nonblack recipients. SRL may be used to reduce the exposure of renal allograft
      recipients to the nephrotoxic effects of CsA.

PMID- 12490790
TI  - Ethnic disparity in clinical outcome after heart transplantation is abrogated
      using tacrolimus and mycophenolate mofetil-based immunosuppression.
AB  - BACKGROUND: Black American heart transplant recipients receiving cyclosporine
      based primary immunoprophylaxis suffer higher rates of allograft rejection with
      hemodynamic compromise, infections, and posttransplant coronary artery disease.
      We examined the hypothesis that a combination of tacrolimus and mycophenolate
      mofetil "resurrects" clinical outcome of black Americans to those seen in white
      heart transplant recipients. METHODS: Sixty-three adult primary heart transplant
      recipients were included in this study. Twenty black American and 21 white
      patients who received tacrolimus-based primary immunoprophylaxis were enrolled in
      this prospective, observational parallel cohort investigation. A separate group
      of 22 black American patients were randomly allocated to receive cyclosporine
      microemulsion-based primary prophylaxis and served as the control population for
      assessing outcomes in the black American group. Adjunctive immunosuppression
      included mycophenolate mofetil and corticosteroids. The primary end-point was the
      freedom from allograft rejection requiring treatment at 1 year. Secondary end
      points included rejection with hemodynamic compromise, and patient or graft
      survival. Adverse events evaluated included development of infections requiring
      hospitalization and nonimmunological outcomes including hyperlipidemia,
      hypertension, and diabetes mellitus (new onset or worsened). RESULTS: Tacrolimus
      treated black American patients had greater freedom from allograft rejection
      requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%,
      P=0.01). No differences were noted between tacrolimus-treated black Americans and
      whites in the primary end point (64% and 67% respectively, P=nonsignificant
      [NS]). Tacrolimus-based immunosuppression was associated with better 1-year
      survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and
      this end point was similar to that achieved in tacrolimus-treated white heart
      transplant recipients (95%). No differences in infection rates were noted among
      either group. Cyclosporine-treated black Americans suffered more hyperlipidemia
      and worse hypertension than tacrolimus-treated patients. CONCLUSIONS: Compared
      with cyclosporine, an immunosuppressive strategy using tacrolimus in black
      Americans achieves superior efficacy with regard to allograft rejection, higher
      allograft survival, and similar safety. Furthermore, tacrolimus-based
      immunosuppression is similar in immunological efficacy and safety in black
      Americans and in white heart transplant recipients.

PMID- 12490791
TI  - Anti-gal A/B, a novel anti-blood group antibody identified in recipients of abo
      incompatible kidney allografts.
AB  - BACKGROUND: The most prevalent anticarbohydrate antibodies in human serum are
      anti-Gal interacting specifically with the alpha-gal epitope (Galalpha1-3Galbeta1
      4GlcNAc-R) and anti-blood group antibodies interacting with blood group A and B
      antigens. The alpha-gal epitope, although absent in humans, comprises part of the
      core of carbohydrate chain in A and B antigens. Therefore, it was of interest to
      determine whether immunoglobulin (Ig) G antibodies, elicited in patients
      rejecting ABO-incompatible kidney allografts, can interact with the alpha-gal
      epitope. METHODS: Anti-A and anti-B antibodies were determined by enzyme-linked
      immunosorbent assay (ELISA) with blood group A or B human red cell membranes, as
      solid phase antigens. Anti-Gal was determined by ELISA with alpha-gal-bovine
      serum albumin as solid-phase antigen. Specific removal of anti-Gal was performed
      by adsorption on fixed rabbit red cells. RESULTS: Blood group O patients who
      underwent transplantation with either A or B kidney produced an antibody that
      bound to all three carbohydrate antigens. This multispecific antibody, designated
      anti-Gal A/B, is specific to the core alpha-gal epitope within A and B antigens.
      Recipients of allograft expressing incompatible blood group B also produce anti
      Gal B antibody, which binds to the core alpha-gal epitope only in the B antigen.
      Anti-Gal A/B and anti-Gal B constitute most of the elicited anti-blood group
      antibody response. Allograft recipients also produced pure anti-A, or pure anti
      B, which require the complete blood group structure for binding. CONCLUSIONS: The
      findings in this study imply that much of the immune response elicited by
      incompatible A or B antigens on kidney allografts results in activation of anti
      Gal B-cell clones producing antibodies to the core alpha-gal epitope in these
      blood group antigens. Only less than 25% of the elicited antibodies interact with
      the complete A or B antigens (i.e., pure anti-A or pure anti-B). These findings
      suggest that prevention of the anti-Gal response may decrease the immune
      rejection of ABO-incompatible allografts.

PMID- 12490792
TI  - Cardiovascular effects of successful renal transplantation: a 1-year sequential
      study of left ventricular morphology and function, and 24-hour blood pressure
      profile.
AB  - BACKGROUND: Cardiovascular disease is the leading cause of death in renal
      transplant recipients. The purpose of this study was to determine the effects of
      a successful renal transplantation on left ventricular morphology and function
      and on the 24-hr blood pressure profile. METHODS: Twenty-four patients with end
      stage renal disease were prospectively studied by ambulatory blood pressure
      monitoring and echocardiography before and at 3, 6, and 12 months after renal
      transplantation. Patients were also analyzed according to their renal function
      after transplantation. RESULTS: We observed a significant drop in the mean values
      of daytime and nocturnal systolic blood pressure and in the 24-hr systolic
      pressure load at 12 months after transplantation. The most frequent
      echocardiographic finding was left ventricular hypertrophy (LVH), for which the
      incidence decreased from 75% before transplantation to 52.1% at 12 months after
      transplantation (P = 0.125). There was a significant decrease in left ventricular
      dilatation, and systolic dysfunction normalized in all patients after 12 months.
      The variables that best independently predicted the decrease in LVH were serum
      creatinine levels and the 24-hr systolic pressure load as registered by
      ambulatory blood pressure monitoring at 12 months after transplantation. We
      observed significant decreases in left ventricular mass and left ventricular mass
      index in the group of patients who had adequate renal function, as compared with
      no changes in patients who did not. CONCLUSIONS: Correction of the uremic state
      by renal transplantation leads to complete resolution of systolic dysfunction,
      regression of LVH, and improvement of left ventricular dilatation. In fact the
      reduction of LVH was dependent on adequate renal function and on a decrease in
      the systolic pressure levels.

PMID- 12490793
TI  - Direct killing of xenograft cells by CD8+ T cells of discordant xenograft
      recipients.
AB  - BACKGROUND: Long-term pig xenografts in monkeys demonstrated the infiltration of
      CD8 T cells into pig cartilage xenografts, transplanted into monkeys. The
      objective of the present study was to determine in an experimental animal model
      whether CD8 T cells in pig xenograft recipients exert any direct cytotoxic effect
      on pig cells. METHODS: The killing of xenograft cells by CD8 T cells, obtained
      from xenograft recipients, was studied in alpha1,3galactosyltransferase knockout
      mice that were repeatedly injected intraperitoneally with pig kidney membranes.
      The pig kidney cell line PK15, which shares many antigens with pig kidney
      membranes, served as a model for xenograft target cells in cytotoxicity assays.
      Cell lines from other species were also studied as target cells. RESULTS:
      Lymphocytes obtained freshly from spleens of mice immunized with pig kidney
      membranes failed to display significant cytotoxic activity against pig cells.
      However, incubation of these lymphocytes with irradiated PK15 cells and addition
      of recombinant interleukin (IL)-2 (100 U/mL), on the third day of incubation,
      resulted in extensive proliferation and expansion of CD8 cytotoxic T lymphocytes
      (CTL). These CTL, obtained after 12 days of incubation, killed nonspecifically
      pig, human, and mouse normal and malignant cells. These CTL were not generated in
      cultures in the absence of stimulatory pig cells or in the absence of IL-2. These
      CTL could not be generated in cultures of lymphocytes from naive mice that were
      incubated with PK15 cells and IL-2. CONCLUSIONS: The data obtained imply that CD8
      T cells from xenograft recipients can be stimulated in vitro by xenoantigens and
      IL-2 to differentiate into highly reactive nonspecific CTL that are capable of
      killing a large variety of xenogeneic and syngeneic cells. Similar in vivo
      microenvironmental conditions within the xenograft may induce the local
      differentiation of infiltrating CD8 T cells into CTL that can destroy
      nonspecifically adjacent xenograft cells. Such cells may not be active outside
      the xenograft because of the absence of IL-2 in sufficiently high concentrations.

PMID- 12490794
TI  - The role of the porcine von Willebrand factor: baboon platelet interactions in
      pulmonary xenotransplantation.
AB  - BACKGROUND: Porcine von Willebrand factor (pvWF) has been shown to bind to human
      glycoprotein Ib (GPIb) and cause activation of human (or primate) platelets in
      the absence of shear stress. Pulmonary xenografts develop disseminated
      intravascular coagulation (DIC) and microvascular thrombosis within hours of
      reperfusion, and the aberrant interaction between pvWF and human platelets may be
      a possible cause of xenograft-associated DIC. METHODS: Experimental baboons (n=3)
      received mouse anti-human GPIb monoclonal antibody before undergoing orthotopic
      pulmonary xenotransplantation with porcine lungs expressing human membrane
      cofactor protein (CD46). RESULTS: Blocking the pvWF-GPIb interaction with a
      monoclonal antibody to GPIb prevented the agglutination of human and baboon
      platelets by pvWF in vitro. In vivo, the anti-GPIb antibody prevented platelet
      deposition and prevented the increases in D-Dimers (P=0.011) seen in control
      xenograft recipients (n=5). However, there was no difference in elevations of
      prothrombin times (PT) or improvement in the vasoconstriction associated with the
      loss of xenograft function. CONCLUSIONS: This study indicates that the DIC
      associated with the hyperacute dysfunction of pulmonary xenografts is a complex
      phenomenon that is affected by, but not solely dependent on, activation of
      platelets. Aberrant interactions between pvWF and GPIb play a significant role in
      DIC associated with pulmonary xenotransplantation.

PMID- 12490795
TI  - High-level expression of viral interleukin-10 in cardiac allografts fails to
      prolong graft survival.
AB  - BACKGROUND: Viral interleukin (vIL)-10, encoded in the Epstein-Barr virus genome,
      shares many of the anti-inflammatory properties of cellular IL-10 but is supposed
      to lack IL-10's immunostimulatory properties. Thus, vIL-10 is expected to offer
      superior immunosuppression. METHODS: We established transgenic mice (vIL-10 Tg)
      that express vIL-10 systemically and transplanted their hearts as vascularized
      allografts into unmodified major histocompatibility complex (MHC) full-mismatch
      or MHC class II-disparate mice. RESULTS: The vIL-10 Tg mice revealed high-level
      expression of vIL-10 in major organs including the heart. However, the heart
      grafts from the vIL-10 Tg mice failed to exhibit prolonged survival in
      combination with either the MHC full-mismatch or the class II-disparate mice. In
      the MHC class II-disparate mice, the vIL-10 Tg heart grafts showed severe CD8 T
      cell infiltration and increased interferon (IFN)-gamma mRNA expression compared
      with non-Tg grafts. CONCLUSION: High level expression of vIL-10 in grafts can
      exacerbate immunological rejection in an allogenic transplantation model.

PMID- 12490796
TI  - Piceatannol in combination with low doses of cyclosporine A prolongs kidney
      allograft survival in a stringent rat transplantation model.
AB  - BACKGROUND: The discovery of new immunosuppressive agents has enhanced short-term
      graft survival. However, current immunosuppressants often induce toxicities that
      limit their clinical use. Thus, there is a need for new immunosuppressants for
      use in clinical transplantation. Piceatannol blocks Syk and ZAP-70, tyrosine
      kinases involved in immune cell activation. We examined whether piceatannol
      prolongs kidney allograft survival in the stringent ACI-to-Lewis rat model.
      METHODS: Kidney recipients were divided into four groups. Group 1 (n=8) received
      piceatannol 30 mg/kg per day intravenously and cyclosporine A (CsA) 2 mg/kg per
      day intramuscularly from day -3 to day 7 after transplantation. At day 8,
      piceatannol was reduced to 10 mg/kg per day and the combined treatment continued
      until day 60. Group 2 (n=9) received 2 mg/kg per day CsA alone from day -3 to day
      60. Group 3 (n=4) received piceatannol alone as in group 1. Group 4 (n=2)
      received only the vehicle dimethyl sulfoxide from day -3 to day 60. Graft
      rejection was defined as either a serum creatinine level more than 2 mg/dL or
      animal death. RESULTS: Group 1 animals survived for at least 115 days (n=8,
      P<0.05), with several animals maintaining their grafts for more than 200 days. In
      contrast, 8 of 9 animals in group 2 rejected their grafts within 10 days of
      transplantation; one animal survived for 71 days. Excellent graft function was
      maintained in group 1 animals despite withdrawal of immunosuppression.
      CONCLUSIONS: These results are the first to show that piceatannol, when combined
      with subtherapeutic dosages of CsA, prevents graft rejection, suggesting that
      targeting Syk and Zap could be useful for preventing graft rejection.

PMID- 12490798
TI  - Lack of donor hyporesponsiveness and donor chimerism after clinical
      transplantation of the hand.
AB  - BACKGROUND: Composite tissue allografts offer great potential in reconstructive
      surgery. However, the risks of immunosuppression and graft-versus-host disease
      (GVHD) after transplantation of vascularized bone in these grafts are
      significant. Transplantation of vascularized bone also may confer donor
      hematopoietic chimerism and, potentially, tolerance. We have followed two hand
      transplant recipients for more than 1 year to determine the level of chimerism
      and possible donor-specific tolerance, in addition to possible GVHD. METHODS: We
      performed kinetic studies on peripheral blood of two subjects after hand
      transplantation that included portions of the radius and ulna. We evaluated donor
      specific reactivity, chimerism, and antibody production. RESULTS: Donor-specific
      tolerance did not develop clinically or in mixed lymphocyte reaction. The first
      subject recovered an excellent in vitro response to phytohemagglutinin, donor and
      third-party alloantigen, and by month 4 and at month 12 also recovered the
      ability to respond to Epstein-Barr virus. The second subject also demonstrated
      good in vitro proliferative responses, which were attenuated by
      immunosuppression. No phenotypic changes in mature hematopoietic lineages were
      detected by four-color flow cytometry other than those expected in response to
      immunosuppression. Donor chimerism was not detectable using four-color flow
      cytometry. Microchimerism (approximately 1:75,000 cells) was observed at the
      level of detection in some of the early posttransplantation specimens and was
      undetectable thereafter. CONCLUSIONS: In this particular transplantation and
      immunosuppressive regimen, the composite tissue allograft with vascularized bone
      marrow did not provide the immunologic benefit of tolerance induction nor cause
      GVHD.

PMID- 12490797
TI  - Role of endogenous vascular endothelial growth factor in tubular cell protection
      against acute cyclosporine toxicity.
AB  - BACKGROUND: Recent studies have shown that exogenous administration of vascular
      endothelial growth factor (VEGF) is protective against cyclosporine A (CsA) renal
      toxicity. No data are available, however, on the possible role of endogenous
      VEGF. Our objective was to examine whether endogenous VEGF has a significant role
      in the renal response against CsA toxicity. METHODS: In vivo, we used high-dose
      (50-150 mg/kg/day) CsA +/- specific goat anti-mouse VEGF blocking monoclonal
      antibody (alpha-VEGF) in mice. In vitro, we exposed mouse tubular cells (MCT) to
      CsA +/- alpha-VEGF. RESULTS: alpha-VEGF markedly enhanced CsA renal toxicity,
      inducing severe tubular damage and increased blood urea nitrogen. In animals
      treated with CsA + alpha-VEGF, damage progressed to generalized tubular injury
      (histology) and apoptosis (terminal deoxynucleotide transferase-mediated dUTP
      nick-end labeling) with associated anemia and reticulocytosis (18 days of
      treatment). CsA + alpha-VEGF treatments strikingly increased tubular VEGF and Bcl
      xL proteins. In vitro, autocrine production of VEGF by MCT was identified by
      Western blot. Of specific interest, CsA toxicity in MCT increased significantly
      in the presence of alpha-VEGF. CONCLUSIONS: Endogenous VEGF has a relevant role
      in the renal tubular defense against CsA toxicity. Blockade of the VEGF effect by
      alpha-VEGF results in clear-cut intensification of the tubular injury and
      appearance of regenerative anemia in the CsA + alpha-VEGF-treated animals. The
      occurrence of both in vivo and in vitro effects of VEGF blockade provides
      evidence of a direct protective effect of VEGF on the tubular cell.

PMID- 12490799
TI  - Narrowband UV-B phototherapy in the treatment of cutaneous graft versus host
      disease.
AB  - Graft versus host disease (GVHD) is an important problem following allogenic bone
      marrow transplantation (BMT). The beneficial effects of photochemotherapy with
      psoralens plus UVA irradiation (PUVA) have been described repeatedly; however,
      PUVA is limited by a wide range of unwanted effects. A novel improved form of UV
      B phototherapy, narrowband UV-B, has been proven to be very effective in T-cell
      mediated dermatoses. Therefore, we investigated the effect of narrowband UV-B
      phototherapy (5 times per week) in 10 patients with cutaneous GVHD (grade 2-3)
      resistant to standard immunosuppressive drugs. It was tolerated well by all
      patients, and no side effects were observed. Skin lesions showed complete
      clearance in 7 out of 10 patients within 3 to 5 weeks. 3 patients showed
      significant improvement of GVHD. We suggest that narrowband UV-B phototherapy is
      a nonaggressive treatment that may benefit patients with cutaneous GVHD who
      already take high doses of immunosuppressive drugs.

PMID- 12490800
TI  - HLA matching and the United Network for Organ Sharing Allocation System: impact
      of HLA matching on African-American recipients of cadaveric kidney transplants.
AB  - BACKGROUND: A recent proposal supports the elimination of allocation points for
      human leukocyte antigen (HLA) mismatches (MM) in cadaveric kidney
      transplantation. The intent is to increase access for some racial groups that
      might be disadvantaged by the representation of race-specific HLA in a largely
      white donor pool. We report our experience from two transplant centers that serve
      a large African American (AA) patient population. METHODS: All cadaveric
      transplants into AA recipients from 1994 to 2000 (n=162) were included in a
      retrospective review. RESULTS: Superior graft survival was observed in AA
      recipients of 0 MM transplants. When induction therapy was used, the graft
      survival at 3 years for the human leukocyte antigen (HLA)-BDR MM grades given
      allocation points (0,1,2 MM) was 82% versus only 49% for BDR MM grades not given
      points (3,4 MM: =0.0022). CONCLUSIONS: Our collective experience demonstrates
      that AA patients having HLA-BDR MM grades given allocation points had better
      graft survival. Removing points for HLA from the national allocation system may
      result in significantly poorer outcome in AA kidney recipients.

PMID- 12490801
TI  - Combined liver and pancreas procurement from a controlled non-heart-beating donor
      with aberrant hepatic arterial anatomy.
AB  - BACKGROUND: The critical shortage of transplantable organs has resulted in the
      use of extended donors, including non-heart-beating donors (NHBDs). Combined
      procurement of both a whole pancreas and a liver from a single cadaver is always
      anatomically feasible. However, when aberrant vasculature is present, the
      potential for vascular injury increases. Because the rapid flush technique is
      used in NHBD procurement, the inability to palpate arterial pulsation may also
      increase the chance of vascular damage. METHODS: We report a case of a successful
      combined procurement of hepatic, pancreatic, and renal grafts from a controlled
      NHBD with right replaced and left accessory hepatic arteries. RESULT: The liver
      and the pancreas were successfully transplanted to two different recipients in
      two different institutions without any complications. All grafts are functioning
      well at 14 months of follow-up. CONCLUSION: Safe procurement of both the liver
      and pancreas is possible from certain controlled NHBDs, even with aberrant
      anatomy.

PMID- 12490802
TI  - Effect of pediatric living-donor liver transplantation on splenomegaly.
AB  - BACKGROUND: The effect of pediatric partial liver transplantation on
      hypersplenism has not yet been clarified. METHODS: Fifty-five consecutive
      pediatric patients who underwent living-donor liver transplantation were
      analyzed. The volume of the spleen was measured by computed tomography, and the
      spleen volume-to-standard spleen volume ratio (R) was calculated in each patient.
      The platelet counts were examined preoperatively and at 1, 6, 12, 18, 24, 36, and
      48 months after the operation. The rate of the decline in this ratio during 1
      year was calculated, and correlations with clinical factors were examined.
      RESULTS: The ratio decreased gradually after the operation in all of the patients
      except for three with an eventful postoperative course. The rate of the reduction
      in R within 1 year after the operation was well correlated with preoperative R
      (R(O); P<0.0001), which led to an equation for R at n months after the operation:
      R(n) =(0.31-0.21R(O) )Ln(3.3n+1)+R(O). The platelet counts increased rapidly in
      the patients with the uneventful postoperative course. CONCLUSIONS: The
      normalization of spleen size can be expected with an uneventful living-donor
      liver transplantation. The spleen volume decreased more rapidly in patients with
      a larger spleen.

PMID- 12490803
TI  - Recurrence of idiopathic pulmonary hemosiderosis in a young adult patient after
      bilateral single-lung transplantation.
AB  - BACKGROUND: Idiopathic pulmonary hemosiderosis (IPH) is a rare disease of unknown
      etiology characterized by hemoptysis, diffuse pulmonary infiltration, and anemia.
      Diagnosis requires a detailed clinical history and transbronchial lung biopsy
      (TLB). METHODS AND RESULTS: A 19-year-old man developed progressive dyspnea,
      hemoptysis, and anemia. The chest x-rays showed bilateral opacities. IPH was
      diagnosed on the basis of clinical findings and TLB. The patient was treated with
      corticosteroidal therapy. His respiratory function worsened, and he underwent
      lung transplantation in 1997. The pathological examination on native lungs
      confirmed the previous histologic diagnosis. In 2000, the patient again developed
      hemoptysis, fever, and hypoxemia. A recurrence of the disease was established by
      TLB. CONCLUSIONS: This is the first report of recurring IPH. The possibility of
      recurrent IPH raises the question whether these patients should be disqualified
      from lung transplantation. This question is unanswerable because incidence of
      recurrence, time course, and impact on the graft function are presently unknown
      and unpredictable.

PMID- 12490804
TI  - Scedosporium apiospermum pneumonia and sternal wound infection in a heart
      transplant recipient.
AB  - BACKGROUND: The most common fungi that cause invasive infection in transplant
      recipients are the spp, spp, and the endemic fungi such as and. Recently,
      however, other fungal pathogens have emerged as important causes of invasive
      disease in these immunocompromised individuals, including the dematiaceous fungi,
      such as and the spp, species of and, and the hyalohyphomycoses, such as
      (Pseudallescheria boydii) (1). METHODS: We present a single patient case report
      and literature review. RESULTS: We illustrate the first reported case of a
      postoperative sternal wound infection and pneumonia caused by in a heart
      transplant recipient and review the significant clinical, microbiologic, and
      therapeutic aspects of infection with this important opportunistic pathogen.
      CONCLUSIONS: Postsurgical wound infection should be added to the growing list of
      infections in the transplant population caused by.

PMID- 12490805
TI  - Posttransplantation lymphoproliferative disorder presenting as a unilateral leg
      mass 10 years after kidney transplantation.
AB  - Epstein-Barr virus (EBV)-associated lymphoproliferative disorder is a well-known
      complication of solid organ transplantation. The risk factors include type and
      degree of immunosuppression and EBV status of the donor and recipient before
      transplantation. The manifestations of posttransplantation lymphoproliferative
      disorders are myriad, from subtle findings such as tonsillar hypertrophy to
      fulminant manifestations such as hepatocellular failure and death. Here we report
      an unusual presentation of posttransplantation lymphoproliferative disorder as
      unilateral leg swelling in a 68-year-old man 10 years after kidney
      transplantation. The patient had detectable EBV-DNA by polymerase chain reaction
      in the peripheral blood and EBV messenger RNA by in situ hybridization in biopsy
      tissue. The patient's tumor did not respond to reductions in immunosuppressive
      medication, intravenous immunoglobulin, ganciclovir, and rituximab. Eventually
      the patient responded to CHOP (cyclophosphamide, Oncovin [vincristine, Eli Lilly,
      Indianapolis, IN], prednisone, and doxorubicin) therapy. He is currently 2 years
      posttreatment, with a serum creatinine of 0.8 mg/dL, on no immunosuppression.

PMID- 12490806
TI  - Fructose-1,6-diphosphate alone and in combination with cyclosporine potentiates
      rat cardiac allograft survival and inhibits lymphocyte proliferation and
      interleukin-2 expression.
AB  - BACKGROUND: Fructose-1,6-diphosphate (FDP) reduces postischemic reperfusion
      injury and is used alone and in combination with cyclosporine A (CsA) as an
      immunosuppressant. METHODS: Wistar-Furth rat hearts were grafted to Lewis rats.
      Activated T-cell proliferation, viability, and interleukin-2 expression were
      determined. RESULTS: Mean survival in days were: saline 7.12+/-0.64, FDP 350
      mg/kg perioperatively 13.5+/-1.4, FDP 350 mg/kg twice daily 11.4+/-0.75, CsA 2.5
      mg/kg daily 12+/-0.81, CsA 5.0 mg/kg daily 12.4+/-0.81, CsA 2.5 mg/kg + FDP 350
      mg/kg twice daily 17.6+/-0.4, and CsA 5 mg/kg + FDP 350 mg/kg twice daily 28.2+/
      0.97. FDP maximally inhibits T-cell proliferation and concomitantly increases
      cell viability at 5,000 to 500 microg/mL, whereas CsA inhibits at 500 ng/mL. FDP
      completely inhibited interleukin-2 expression at 5,000 to 500 microg/mL, whereas
      CsA partially inhibited at 50 to 500 ng/mL. CONCLUSION: FDP + CsA prolongs
      cardiac survival and FDP inhibits T-cell proliferation.

PMID- 12490807
TI  - Living-donor liver transplantation in an HIV-positive patient with hemophilia.

PMID- 12490808
TI  - Clinical study of benign prostatic disease, current concepts and future
      prospects: randomized controlled trials versus real life practice.

PMID- 12490809
TI  - Aetiology and pathogenesis of benign prostatic hyperplasia.
AB  - PURPOSE OF REVIEW: Prostatic hyperplasia predominantly involves the stromal
      compartment of the gland and affects more than 70% of men of 70 years or older
      with or without obstructive symptoms of benign prostatic hyperplasia. A consensus
      view is emerging concerning the factors and control systems that modulate cell
      proliferation and connective tissue biology in the prostate. The purpose of this
      review is to discuss some of the recent work contributing to the latter in the
      context of the aetiology of benign prostatic hyperplasia. RECENT FINDINGS:
      Studies over the last 3-5 years have identified transforming growth factor beta,
      fibroblast growth factor and insulin-like growth factor family members as key
      regulators of cell proliferation and extracellular matrix turnover with
      interrelated activities. Recently, oestrogens, adrenergic signalling and
      inflammatory processes have been shown to impact and potentially perturb the
      balance between the activities of the above factors. These agents are all subject
      to alteration with age and as such are candidates for potential triggers of the
      initiation of stromal hyperplasia. SUMMARY: The current model for the control and
      dysregulation of prostatic stromal growth is discussed in relation to the
      pathogenesis of benign prostatic hyperplasia and future directions for research.

PMID- 12490810
TI  - New innovative therapies for benign prostatic hyperplasia: any advance?
AB  - PURPOSE OF REVIEW: Benign prostatic hyperplasia is the most common human neoplasm
      and it is the most frequent tumour requiring surgical treatment in men. Not
      surprisingly, interest centres on either understanding of prostatic growth during
      ageing or on various medical or interventional treatments. RECENT FINDINGS:
      Recent publications describe the interaction of various 5alpha-reductase
      inhibitors on the two 5alpha-reductase isoforms type 1 and 2, giving a potential
      new insight into the pathogenesis of benign prostatic hyperplasia. Likewise,
      chronic inflammation increases growth patterns of fibromuscular tissue in benign
      prostatic hyperplasia similar to wound healing, and a paracrine loop for chronic
      inflammation with overexpression of interleukin could be identified. This could
      be of particular importance in the further understanding of prostatic
      enlargement. Herbal drug treatment for lower urinary tract symptoms seems to be
      more effective than previously thought. According to recent publications the
      effectiveness is well beyond placebo effects. Likewise, alpha-blockers play an
      important role in treatment of lower urinary tract symptoms with alpha-1
      adrenoreceptor antagonists preventing cell proliferation and apoptotic imbalances
      in prostatic tissue. The effect of alpha-blockers, however, may be limited by
      severe bladder outlet obstruction with patients at increased risk of treatment
      failure. Laser prostatectomy and microwave thermotherapy are under consideration
      as alternative treatments of benign prostatic hyperplasia. The efficacy of
      urodynamically proven de-obstruction as compared with transurethral resection of
      the prostate needs to be evaluated. Newer alternative treatments like ethanol
      installation or bipolar plasma kinetic vaporization have been described, but long
      term results and larger patients cohort are still lacking. SUMMARY: New insights
      into prostatic growth and pathogenesis of benign prostatic hyperplasia are
      presented. Medical treatment and interventional therapies are evaluated for their
      safety and efficacy. Only a few new therapeutical options, however, have been
      published during this review period.

PMID- 12490811
TI  - Investigation of benign prostatic hyperplasia.
AB  - PURPOSE OF REVIEW: This is a concise and timely update of the most recent
      developments in the clinical research on the investigation of benign prostatic
      hyperplasia. RECENT FINDINGS: Analysis of the peer-review literature confirms a
      high level of consensus as to the management of prostatic hyperplasia; analysis
      of practice trends suggests a satisfactory degree of adoption of the proposed
      guidelines. The evaluation of lower urinary tract symptoms remains the mainstay
      in the investigation of prostatic hyperplasia although problems concerning the
      evaluation of nocturia and the differential diagnosis between hyperplasia and
      chronic prostatitis were identified. Lower urinary tract symptoms confirmed their
      value as predictors of disease progression. The extent of patient involvement in
      the decision making process is increasing and new tools to elicit patient
      preference have been developed. A growing consensus as to the concept of disease
      progression has been reached concerning prostatic hyperplasia. Analysis of
      patient sexual function is now considered an important part of patient's
      interview. More sophisticated instruments, such as time trade-off values were
      successfully tested to elicit patient preference in the management of prostate
      disease. The value of serum prostate specific antigen as a predictor on prostate
      volume growth has recently been confirmed also in unselected male population.
      SUMMARY: Current research into the investigation of benign prostatic hyperplasia
      provides new insight into the pathophysiology of lower urinary tract symptoms and
      identifies parameters to predict the natural history of the disease in the
      individual patient, particularly regarding progression of the disease and the
      onset of adverse events.

PMID- 12490812
TI  - Chronic prostatitis.
AB  - PURPOSE OF REVIEW: This review covers recent developments in the classification,
      epidemiology, aetiology, diagnosis and treatment of patients diagnosed with
      chronic prostatitis (NIH classification types II, IIIa/IIIb and IV prostatitis)
      in the period of review (2001-2002). RECENT FINDINGS: Recent studies highlight
      some of the problems with the 1995 NIH classification. Epidemiological studies
      have confirmed that "prostatitis" is common, with a prevalence of 10-15%.
      Associations of prostatitis include benign prostatic hyperplasia, sexually
      transmitted disease, lower urinary tract symptoms, stress, and reduced sunlight
      exposure. Elevated levels of cytokines in the seminal plasma and prostatic
      secretions have been detected in men with chronic prostatitis compared with
      normal individuals, suggesting an active inflammatory process in the male genital
      tract. This inflammatory reaction may be mediated by an adaptive immune response
      directed against a genital tract antigen(s) (autoimmunity). Increased levels of
      bacterial 16S ribosomal DNA in the prostates of men with chronic prostatitis
      compared with controls are compatible with the notion that a bacterial
      inflammatory event initiates an auto-immune process; however, the role of
      bacteria in the continuation of symptoms is unknown. SUMMARY: The aetiology of
      chronic pelvic pain syndrome is still not certain, although an auto-immune
      process is favoured. Further research is required to determine the putative auto
      antigen, the immune responses of patients, the role of bacteria in the
      inflammatory process, and the patients' pain response to genitourinary insults.
      As yet no diagnostic tests (other than to eliminate other pathology) and few
      treatments for chronic prostatitis can be recommended on the basis of scientific
      evidence.

PMID- 12490813
TI  - 5 alpha-reductase inhibitors: what's new?
AB  - PURPOSE OF REVIEW: Medical therapy is now the first-line treatment for most men
      with symptomatic benign prostatic hyperplasia. This review aims to highlight the
      recent contributions to our understanding of 5 alpha-reductase inhibitor usage.
      RECENT FINDINGS: For the last decade, finasteride has been the only available 5
      alpha-reductase inhibitor, acting upon the type 2 isoenzyme of 5-alpha reductase.
      Dutasteride is the first drug that can inhibit both isoenzymes and is soon to be
      available. Biochemically it achieves greater and more rapid dihydrotestosterone
      suppression compared with finasteride. Clinically, it appears to be at least as
      good in terms of improving symptoms and flow rates, and reducing the risk of
      acute urinary retention or the requirement for benign prostatic hyperplasia
      related surgery. However, until these two drugs are formally compared, the true
      benefits of additional type 1 isoenzyme inhibition are unknown. The recently
      reported Medical Therapy of Prostatic Symptoms trial has convincingly
      demonstrated superior outcomes with combination therapy compared with
      monotherapy, unlike previous trials of shorter duration. The ability of 5 alpha
      reductase inhibitors to prevent disease progression was also confirmed. Newer
      roles for 5 alpha-reductase inhibitors are also being defined. Finasteride has
      been shown to reduce and control benign prostatic hyperplasia-related haematuria,
      although its value in controlling perioperative bleeding is less clear. Their
      role as chemopreventive agents for prostate cancer is also under investigation.
      SUMMARY: Recent studies have both clarified and extended the roles of 5 alpha
      reductase inhibitors in benign prostatic hyperplasia, and these may expand
      further if chemopreventive abilities are proved. In addition, dual isoenzyme
      inhibition will soon be available.

PMID- 12490814
TI  - Laser therapy for benign prostatic hyperplasia: a review of recent developments.
AB  - PURPOSE OF REVIEW: Over the past 10-15 years a variety of endoscopic laser
      techniques have evolved for the treatment of benign prostatic hyperplasia. The
      laser is merely an energy source with the ability to coagulate, incise, vaporize,
      resect and dissect (enucleate), all fundamentally different procedures.
      Generalization regarding "laser prostatectomy" is therefore inappropriate. The
      potential for shorter hospital stays and decreased morbidity while maintaining
      the efficacy and durability of transurethral resection of the prostate has been
      the driving force behind the laser techniques that acutely remove tissue, whereas
      the ideal minimally invasive non-tissue removing laser technique is a well
      tolerated office procedure, performed under local anaesthesia. We define the
      various laser techniques currently available for the treatment of benign
      prostatic hyperplasia, and review developments reported during the period July
      2001 to July 2002. RECENT FINDINGS: Although there are few long-term data
      available on laser techniques, more medium-term data is emerging. Issues such as
      cost-effectiveness and applicability to certain sub-groups of patients are being
      investigated as each laser technique aims to find its own niche in the ever
      expanding treatment armamentarium for benign prostatic hyperplasia. SUMMARY:
      Satisfactory moderate term results are now available for several minimally
      invasive laser techniques including interstitial laser coagulation and visual
      laser ablation of the prostate. There are promising early results for holmium
      laser enucleation of the prostate and potassium titanyl-phosphate, which have the
      potential to rival transurethral resection if proved durable in the long-term.
      Holmium laser enucleation is currently a serious contender for the "gold
      standard" for large prostates.

PMID- 12490815
TI  - Thermotherapy and thermoablation for benign prostatic hyperplasia.
AB  - PURPOSE OF REVIEW: From all the available thermoablative methods for the
      treatment of symptomatic benign prostatic hyperplasia, transurethral microwave
      thermotherapy is considered as standard in minimally invasive management. The
      literature is enriched by several new studies on transurethral microwave
      thermotherapy, and thus this review presents up-to-date information about
      thermotherapy. RECENT FINDINGS: New studies have provided significant information
      regarding differences in outcome for devices with different protocols and
      selection criteria, confirming the superiority of high-energy programmes.
      Furthermore, monitoring of the intraprostatic temperature promises better
      clinical results by means of individualization of the treatment. Long-term
      results have been available and allow the evaluation of the fundamental issue of
      treatment durability. Improvement after high-energy transurethral microwave
      thermotherapy remains durable for more than 2.5 years. Randomized studies
      comparing this treatment with other established therapies for benign prostatic
      hyperplasia, including medical treatment and transurethral resection of the
      prostate, have also contributed to an evaluation of the morbidity, and costs of
      treatment. Clinical outcomes with transurethral microwave thermotherapy are in
      the range of those obtained with transurethral resection of the prostate and are
      superior to those of medical management. Retreatment after transurethral
      resection of the prostate emerges because of complications following the
      procedure, whereas retreatment after transurethral microwave thermotherapy is as
      a result of treatment failure. In addition, the rate of failure of medical
      management is almost seven times higher than that for transurethral microwave
      thermotherapy. Thus, the latter seems to play a dominant role in the economic
      models used to assess the cost-efficiency of different treatment modalities for
      benign prostatic hyperplasia. SUMMARY: The recent innovations in high-energy
      transurethral microwave thermotherapy provide better and more durable clinical
      outcomes and lower morbidity, and strengthen its position as an established
      treatment for benign prostatic hyperplasia. However, there is always room for
      improvement, so further research on therapeutic protocols, treatment monitoring
      and selection criteria are to be welcomed.

PMID- 12490816
TI  - Are stents still a useful therapy for benign prostatic hyperplasia?
AB  - PURPOSE OF REVIEW: The use of an endoprosthesis to maintain lumenal patency is a
      well-established concept used in a variety of surgical settings, including
      cardiovascular and gastrointestinal pathologies. However, the utility of self
      retaining endoprosthetics and their application in prostatic pathology and benign
      prostatic hyperplasia is not as clear. This report reviews recent developments in
      the management of symptomatic benign prostatic hyperplasia, particularly the
      current role of intraprostatic stenting in the advent of other minimally invasive
      therapies such as laser prostatectomy. RECENT FINDINGS: Over the past 5 years,
      urology has witnessed the proliferation of minimally invasive surgical therapies
      for benign prostatic hyperplasia. These interventions have enabled the urologist
      to treat a problem whose management was once limited to medical therapy,
      transurethral resection of the prostate, or open, relatively morbid surgery. The
      role of stents as an intermediary in cases of treatment failure, or as definitive
      therapy for benign prostatic hyperplasia and its associated problems is still not
      clear, when compared with newer, minimally invasive options. Current literature
      on stents is relatively sparse. However recent studies demonstrate that permanent
      and temporary prostatic urethral stenting are effective in relieving obstruction
      and urinary retention. Nevertheless larger controlled clinical studies are needed
      to demonstrate the real value of this intervention. SUMMARY: Prostatic stenting
      has a definite role in the management of benign prostatic hypertrophy, but stents
      must be used with caution because complications are still relatively common, and
      their true efficacy and utility in the urological setting has not been
      determined.

PMID- 12490817
TI  - Urinary tract infections in children.
AB  - PURPOSE OF REVIEW: To gain new insights into the epidemiology, imaging and
      conservative management of urinary tract infections based on the peer-reviewed
      literature of the last year. RECENT FINDINGS: It has been estimated that 3% of
      prepubertal girls and 1% of prepubertal boys are diagnosed with urinary tract
      infections. Breastfeeding has been shown to offer significant protection against
      urinary tract infection in infants. Any young child with an acute pyelonephritis
      should be evaluated by dimercaptosuccinic acid renal scan to confirm or rule out
      renal scarring. The voiding cystourethrogram can be performed within the first 7
      days of diagnosis. Amoxicillin, trimethoprim-sulfamethoxazole and cephalosporin
      are the first-line antibiotics to treat children with uncomplicated urinary tract
      infection. SUMMARY: The incidence of urinary tract infections during infancy and
      childhood is high and influenced by the age and sex of the patient. Voiding
      cystourethrogram and dimercaptosuccinic acid renal scan are required for imaging.
      Short-course treatment is sufficient for children with acute uncomplicated lower
      urinary tract infections.

PMID- 12490818
TI  - Infection and urinary stones.
AB  - PURPOSE OF REVIEW: Despite modern antibiotic therapy and technological advances
      in lithotripsy, the presence of infection in urinary stone patients as well as
      infectious stones are still a significant cause of morbidity and mortality. Many
      new investigations are focusing on the pathogenesis and treatment of these
      difficult cases. RECENT FINDINGS: Most of the current literature on the subject
      focuses on pathogenesis of infectious urinary stones. The remaining literature
      highlights difficult cases, outcomes of treatments, and overall reviews of the
      subject. SUMMARY: Recent findings lend more theories as to how infection leads to
      stone formation. Further investigation is critically needed to improve the
      outcomes of patients suffering from infections with urinary stones and infectious
      stones.

PMID- 12490820
TI  - Recent advances in the neurobiology of depression.
AB  - Elucidation of the neurobiological basis of depression and other mood disorders
      is rapidly increasing. Considerable experimental and clinical evidence supports
      the fundamental roles of serotonin and norepinephrine, as well as the
      interactions between these systems in the etiology of depression. Substantial
      evidence has accrued, including changes in neurotransmitter and neurotransmitter
      metabolite concentrations, reuptake sites, and receptors, to support the
      hypothesis that alteration in neuronal serotonergic and noradrenergic function
      occurs in the central nervous system of patients with major depression. Serotonin
      and norepinephrine represent the major targets of current therapeutic
      interventions, which may induce longer-term adaptive changes via modulation of
      the activity of these neurotransmitters. In addition, two neuropeptide
      neurotransmitters--substance P and corticotropin-releasing factor--have been
      implicated in the pathophysiology of mood disorders. Preliminary studies have
      reported the clinical efficacy of a tachykinin NK1 receptor antagonist and a CRF1
      receptor antagonist in depressive disorders. Further clarification of the precise
      neurobiological changes occurring in depression has implications for the use and
      development of novel effective treatments for this disorder.

PMID- 12490821
TI  - New goals in the treatment of depression: moving toward recovery.
AB  - Depression is associated with marked suffering, morbidity, and high risk of
      recurrence and/or chronicity. As a result, the disorder represents a considerable
      public health problem and economic burden on society. Treatment of patients with
      depression to a state of remission is associated with a significantly improved
      long-term outcome, including a reduced risk of relapse and improved functioning.
      Thus, remission (which can be defined as attainment of a total score < or = 7 on
      the Hamilton Rating Scale for Depression) should be the goal of the acute phase
      of pharmacotherapy. Although it is widely assumed that available antidepressants
      are comparably effective, comparisons of the efficacy of antidepressants in
      clinical trials are flawed by a number of factors. Most notable problems are
      higher-than-expected placebo effects and low statistical power. Double-blind,
      comparative studies are also compromised by relatively high attrition rates and
      the often underestimated effects of patient nonadherence. Large study groups (in
      the order of 300 patients per treatment group) are needed to differentiate
      between a good and a potentially better antidepressant. The statistical technique
      of meta-analysis has been used to examine the results of studies of various
      antidepressants; these meta-analyses have shown that the selective serotonin
      reuptake inhibitors (SSRIs) have overall "within group" comparability and,
      overall, an efficacy profile comparable to the previous standard, tricyclic
      antidepressants (TCAs). However, in studies of hospitalized patients, TCAs
      affecting both serotonergic and noradrenergic systems (eg, amitriptyline or
      clomipramine) have been found to have greater efficacy when compared with SSRIs.
      Results of some individual studies, as well as a pooled analysis of the outcomes
      of more than 2,000 depressed patients, indicate that venlafaxine, a selective
      serotonin and norepinephrine reuptake inhibitor, may have a similar advantage
      relative to SSRIs across a broader range of patients. These findings suggest
      antidepressants that affect both serotonergic and noradrenergic neurotransmission
      may be more likely to accomplish the goal of remission. Compared with TCAs, the
      better safety profile of venlafaxine has established the drug as a more
      appropriate first-line treatment option.

PMID- 12490822
TI  - Long-term treatment strategies in affective disorders.
AB  - Unipolar major depression is a disorder with a high incidence of relapse and
      recurrence. Some patients with major depression fail to recover from an episode
      and develop chronic depression. Both episodic and chronic depression are
      associated with considerable morbidity and mortality. An improved long-term
      outcome for patients may be achieved by the use of longer courses of treatment in
      the management of depression, which may ultimately enable recovery from
      depressive symptoms. The data reviewed in this article indicate that both
      selective serotonin reuptake inhibitors (SSRIs) and the serotonin and
      norepinephrine reuptake inhibitor (SNRI) venlafaxine are effective in reducing
      the incidence of relapse during 6 months of continuation therapy for major
      depression. In addition, longer-term treatment using imipramine or venlafaxine
      has shown maintenance therapy to be effective in reducing the risk of recurrence
      of major depression. Pharmacotherapy using sertraline or imipramine for extended
      periods of time has also been shown to be effective in attaining remission from,
      and preventing, recurrence of symptoms in patients with chronic depression. The
      data reviewed suggest that long-term therapy is beneficial in achieving a
      sustained return to complete functioning for patients with depression. The
      significantly higher remission rates attained with venlafaxine treatment as
      compared with some SSRIs warrant further studies of SNRIs for the long-term
      treatment of depression.

PMID- 12490823
TI  - New developments in the neurobiological basis of anxiety disorders.
AB  - Generalized anxiety disorder (GAD) is a chronic disorder that often precedes the
      development of, and is comorbid with, depression. Investigation of the
      neurobiological basis of GAD has provided suggestive evidence to implicate
      dysfunction of serotonergic and noradrenergic systems in the expression of GAD,
      as well as the depressive disorders. Hence, there may be a neurobiological link
      between GAD and depression through the activity of the serotonin and
      norepinephrine systems. The use of various anxiolytics and antidepressants,
      including benzodiazepines, tricyclic antidepressants, selective serotonin
      reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors in the
      treatment of GAD is reviewed. The neurobiological relationship between GAD and
      depression, and the frequent comorbidity of these disorders, suggests that agents
      with a dual action on the serotonin and norepinephrine systems may potentially
      offer superior benefits in the management of patients with anxiety and depressive
      disorders.

PMID- 12490824
TI  - Long-term treatment strategies in anxiety disorders.
AB  - Anxiety disorders are prevalent and associated with increased morbidity and
      mortality. Some chronic anxiety disorders, including generalized anxiety disorder
      (GAD), may be characterized by an underlying high level of anxiety on which
      exacerbations of symptoms are superimposed. Effective treatment of anxiety
      disorders should therefore strive to attain both an acute reduction in the
      symptoms of anxiety (a response) and sustained resolution of the symptoms of any
      underlying chronic anxiety (remission). This strategy may necessitate long-term
      treatment of these disorders by pharmacotherapy and/or psychotherapy. Studies
      using the serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine
      extended release (XR), suggest that these aims may be achieved using this newer
      class of drugs. Studies with venlafaxine XR in patients with GAD have
      demonstrated robust anxiolytic efficacy over placebo, particularly regarding
      worry, cognitive dysfunction, and muscular tension, which are specific to GAD.
      Administration of venlafaxine XR over both short- (8-week) and long-term (6
      month) periods resulted in a significantly greater number of patients achieving
      response and remission than obtained with placebo. Long-term treatment with
      venlafaxine XR in patients with GAD showed greater efficacy than that observed in
      short-term studies. This was achieved without any loss of short-term efficacy and
      patients' social functioning was also restored. While available data indicate
      that venlafaxine XR is an appropriate choice of agent in the long-term treatment
      of GAD, more studies are needed to determine how to further increase remission
      rates and to maintain remission beyond 6 months.

PMID- 12490825
TI  - Optimizing treatment outcomes for patients with depression and generalized
      anxiety disorder.
AB  - The goal of the acute phase of pharmacotherapy of major depressive disorder or
      generalized anxiety disorder is remission (ie, complete resolution of symptoms)
      rather than simply a response (eg, at least a > or = 50% improvement in
      symptoms). Despite treatment, incompletely remitted patients often have
      persistent social and/or functional impairment, and are particularly vulnerable
      to relapse. To optimize outcomes, it is important to continue to adjust and
      refine the treatment plan until there is resolution of residual depressive
      symptoms and normalization of social functioning. Thereafter, prophylactic
      therapy is indicated to lessen the risk of recurrence and/or chronicity.
      Contemporary treatment options include older medications such as tricyclic
      antidepressants, newer compounds, such as selective serotonin reuptake
      inhibitors, the serotonin and norepinephrine reuptake inhibitor, venlafaxine, and
      a number of other medications with novel mechanisms of action. Although it has
      been conventional to assume that all antidepressants are equally effective,
      evidence from a recent pooled analysis of data from eight double-blind,
      randomized, controlled clinical studies suggests that venlafaxine therapy may be
      associated with higher remission rates.

PMID- 12490826
TI  - Coping with somatic comorbidities: striving for complete recovery.
AB  - Depression is increasingly being recognized as a common comorbid disorder in
      patients with severe and chronic medical conditions. However, patients with
      depression and anxiety frequently present with somatic complaints such as aches
      and pains, headache, and chronic fatigue. This leads to underrecognition and
      undertreatment of the psychiatric disorder in an attempt to identify the medical
      cause of the somatic complaint. Reports are demonstrating the efficacy of
      antidepressants in treating disorders other than depression and anxiety.
      Tricyclic antidepressants have shown their usefulness in the treatment of
      diabetic neuropathy, fibromyalgia, and headache. Controlled studies of several
      selective serotonin reuptake inhibitors have been shown to be efficacious in
      relieving the symptoms of premenstrual dysphoric disorder and fibromyalgia. Pilot
      studies have also been conducted with the serotonin and norepinephrine reuptake
      inhibitor venlafaxine for the treatment of diabetic neuropathy, fibromyalgia,
      migraine, premenstrual dysphoric disorder, and stroke. The results encourage
      further controlled studies.

PMID- 12490827
TI  - Depression in the elderly.
AB  - Depression is prevalent in the elderly and associated with increased morbidity
      and mortality. Diagnosis can be complicated by the presence of concomitant
      medical and/or psychiatric disorders, and it is important to exclude a number of
      factors, such as neurological disease, hormonal causes, chronic illness, or
      substance abuse, particularly alcohol. Although comorbid medical illness may
      contribute to depressive illness, depressive disorders are not a consequence of
      aging. Most classes of antidepressants that are effective in adult patients are
      effective in the elderly and, in general, they have shown comparable efficacy in
      terms of response rates. However, antidepressants vary in terms of their
      tolerability profiles, and treatment of the elderly is complicated by their
      sensitivity to medication side effects and the potential for serious adverse
      events, such as falling or delirium. A correct dosing strategy is particularly
      important for the elderly, whose treatment should usually start at low doses of
      antidepressants and increase slowly. It is possible to successfully treat elderly
      patients with depressive disorder, and antidepressant therapy should be selected
      on the basis of prior response to treatment, the adverse-event profile, and the
      potential for drug-drug interactions. Treatment should also take into account the
      likelihood of achieving and maintaining remission of symptoms in order to restore
      the patient to a baseline level of functioning appropriate for their age.

PMID- 12490828
TI  - Mechanism of action of antidepressants.
AB  - A wide range of effective drugs is available for the treatment of major
      depression. The discovery of these agents has not always been the result of
      rational drug design. Tricyclic antidepressants formed the mainstay of treatment
      until the 1990s, and selective serotonin reuptake inhibitors (SSRIs) have
      dominated treatment over the last decade. However, the poor tolerability
      associated with tricyclic antidepressants and concerns about the efficacy of
      SSRIs has led to the search for alternative agents. Attention has focused on
      those drugs that affect norepinephrine and/or serotonin systems, with the recent
      introduction of a number of agents, including venlafaxine, milnacipran,
      nefazodone, mirtazapine, and reboxetine. Venlafaxine, which is the first in a new
      class of drugs known as serotonin and norepinephrine reuptake inhibitors, may be
      associated with an earlier onset of action and higher remission rates than SSRIs.
      It is hoped that the development of drugs with multiple sites of action will
      translate into improved clinical efficacy in the treatment of depression.

PMID- 12490829
TI  - Depression treatment: a lifelong commitment?
AB  - Depression is associated with considerable disability, morbidity, and mortality.
      In many patients, depression follows a course of relapse and/or recurrence.
      However, there is significant evidence that the majority of patients with
      depressive disorders are undertreated and this imposes a substantial economic
      burden on society. The reasons for undertreatment include patient, provider, and
      healthcare system factors. It is vital that treatment be targeted appropriately
      to break the cycle of relapse/recurrence. Rather than short-term improvement of
      symptoms, the optimal outcome of treatment of depressive disorders should be full
      symptom resolution (remission) and long-term recovery. Patients with histories of
      recurrent depressive episodes may require long-term, indefinite treatment with
      antidepressants. Currently, few data exist on the outcome and appropriate
      duration of maintenance pharmacotherapy. The benefits of psychotherapy have
      recently been demonstrated in a 12-week, randomized, controlled study, which also
      includes a maintenance phase that has not yet been completed. Additional well
      designed studies addressing these issues are urgently needed.

PMID- 12490830
TI  - Algorithms in clinical psychiatry: a stepped approach toward the path to
      recovery.
AB  - The use of clinical practice guidelines and treatment algorithms has become
      increasingly prevalent across all fields of medicine. The Texas Medication
      Algorithm Project has developed algorithms for major depressive disorder to
      facilitate clinical decision-making by providing physicians with a detailed, yet
      concise, summary of current clinical data on available pharmacotherapeutic
      interventions, together with specific treatment strategies and tactical
      recommendations. The goal of the algorithm is the attainment of full and
      sustainable remission of symptoms. Clinical experts, practitioners, and
      administrators, as well as patients and their families, all contributed to the
      formulation and implementation of the algorithm in order to ensure an optimum
      level of effectiveness and practicality. It is hoped that algorithm-driven
      pharmacotherapy of depression will increase the quality of care, leading to
      improved patient outcomes, reducing unnecessary practice variation, and
      increasing the overall cost-effectiveness of treatment intervention.

PMID- 12490831
TI  - Unraveling the diagnostic clues of depression and GAD: the primary care
      challenge.
AB  - Anxiety and depression are commonly encountered in primary care, with a
      prevalence ranging from 5% to 10%. These disorders are associated with
      significant and persistent impairment in functioning, risk of suicide, and
      substantial economic cost. Comorbidity of depression and anxiety is frequent and
      intensifies the burden of illness. However, patients with anxiety and depression
      often present to primary care physicians (PCPs) with ill-defined somatic
      symptoms, and both disorders are under-recognized and under-treated. PCPs should
      be aware that the typical presentation of anxiety and depression may not be with
      classical psychological symptoms, but rather with vague somatic symptoms that are
      often hard to treat and result in frequent repeat visits. Once anxiety and
      depression are accurately recognized, most patients can successfully be managed
      in primary care. A wide range of effective drugs is available, allowing selection
      of an optimal treatment for each patient. Antidepressants are effective as
      monotherapy in comorbid patients, and newer agents such as selective serotonin
      reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors have been
      shown to be effective in the treatment of anxiety and depression. Adherence to
      medication can be improved if drug treatment is integrated into a package of
      patient education and support. PCPs have a vital role to play in identifying
      anxiety and depression amongst their patients, and building a therapeutic
      partnership to achieve successful treatment.

PMID- 12490832
TI  - Can we distinguish anxiety from depression?
AB  - It is becoming increasingly apparent that although anxiety and depression are
      separate syndromes and can be identified as such, there is considerable overlap
      of clinical symptoms and pathophysiological processes. Data indicate that
      comorbid anxiety and depression is more common than either disorder alone. A
      large US study found that 58% of individuals with a history of depression also
      had an anxiety disorder, and a study by the World Health Organization showed that
      anxiety and depression were the most common coexisting psychological problems in
      primary care. Generalized anxiety disorder in particular is strongly comorbid
      with, and commonly precedes, major depression. The implications of comorbid
      anxiety and depression are significant, with increased social and psychological
      impairment, and poorer clinical outcomes and prognosis. Anxiety and depression
      coexist at much higher rates than would be expected by chance alone, suggesting
      that the two disorders are closely related and may have a common cause.
      Disturbances of serotonin and norepinephrine neurotransmission are both
      implicated in anxiety and depression, and new evidence suggests that these
      systems may provide a mechanistic link between the two disorders, with changes in
      one system being reflected in the other. Abnormal homeostasis of these two
      systems may result in anxiety and depression. New theories hypothesize a
      continuum of illness, with anxiety and depression possibly being different
      phenotypic expressions of a common neurobiological origin. There is still
      uncertainty regarding the neurobiological cause, but it is probably linked to
      dysregulation in the serotonergic and noradrenergic systems.

PMID- 12490833
TI  - Raising the expectations of long-term treatment strategies in anxiety disorders.
AB  - This article describes the long-term course of anxiety disorders based on the
      findings of the Harvard/Brown Anxiety Research Program (HARP) study--a
      prospective, naturalistic, longitudinal study of patients with anxiety disorders.
      Data from the HARP study emphasize both the chronicity of anxiety disorders and
      their frequent psychiatric comorbidity with other anxiety disorders and
      depression. Social phobia and generalized anxiety disorder are more chronic than
      panic disorder, although the latter has higher rates of relapse following
      recovery. Anxiety disorders have a major impact on the everyday lives of
      sufferers. The detrimental effects on social, psychological, and physical
      functioning are comparable with other chronic medical and psychiatric conditions,
      including diabetes, heart disease, and depression. Comorbidity with depression
      significantly increases the probability of suicide and is associated with poorer
      outcome. Findings from the HARP study have significant implications for
      treatment, which currently tends to focus on short-term outcomes. Future studies
      should emphasize the role of preventive pharmacotherapy to improve the long-term
      course of anxiety and to reduce its associated suffering, suicide, and
      occupational and social impairment.

PMID- 12490835
TI  - Presidential address: Boiling water to iodine--a story of unparalleled
      collaboration.

PMID- 12490836
TI  - Current treatment of nodular goiter with hyperthyroidism (Plummer's disease):
      surgery versus radioiodine.
AB  - BACKGROUND: First described 9 decades ago by H. S. Plummer, thyroidectomy and
      radioiodine remain the 2 therapeutic modalities for toxic nodular goiter. The aim
      of this study was to determine its optimal treatment. METHODS: The presentation,
      operative treatment, pathology, and clinical course of 362 consecutive patients
      treated at our institution for Plummer's disease from 1990 to 1999 were
      retrospectively reviewed. RESULTS: Three hundred forty-six patients (63 men and
      283 women) were treated surgically (181, 53%), with radioiodine (RAI, 157, 45%),
      or a combination of both (8, 2%). Mean age was 62 years (surgical, 55 years; RAI,
      69 years). Nearly half were symptomatic, 51 (15%) with airway or swallowing
      compromise and 110 (32%) with cardiac complications. The estimated goiter size
      was larger (60 g or greater) in surgical (72 patients, 38%) than medically
      treated (45 patients, 29%) patients. RAI treatment dose averaged 28 mCi; 10
      patients (6%) required a second treatment, and 8 patients failed treatment and
      required subsequent thyroidectomy. Types of thyroidectomy included total (29
      patients, 16%), near-total (47 patients, 26%), bilateral subtotal (46 patients,
      25%), and unilateral (58 patients, 32%). One month after treatment,
      hyperthyroidism had resolved in 96% of the surgical patients but only 6% of the
      RAI patients (mean time to resolution, 5.4 months). Only 55 (38%) of the RAI
      patients' goiters reduced in size. Recurrent laryngeal nerve paralysis and
      hypoparathyroidism each occurred in 3 (2%) patients. CONCLUSIONS: Surgical
      treatment results in rapid, reliable resolution of hyperthyroidism and removal of
      the nodular goiter with low morbidity and no mortality. RAI is also safe and
      effective, usually requiring a single dose, but the results are delayed and it
      usually fails to resolve a goiter.

PMID- 12490837
TI  - Intraoperative ultrasonography improves identification of recurrent thyroid
      cancer.
AB  - BACKGROUND: Surgical resection is the only curative treatment option for
      locoregional recurrence of well-differentiated thyroid cancer that does not trap
      radioiodine. We hypothesized that intraoperative ultrasonography would aid in the
      localization of recurrent thyroid cancer and would enhance the ability to perform
      a complete resection. METHODS: Between June 2000 and October 2001, 13 patients
      with recurrent, scan-negative, papillary thyroid cancer were explored by using
      intraoperative ultrasonography. RESULTS: All patients had identification and
      resection of recurrent papillary thyroid cancer. Eleven patients had a complete
      resection, and 2 patients had incomplete resection as a result of local invasion.
      Ultrasound was required for identification of tumor in 7 patients and included
      all patients with a history of external beam radiotherapy. In 6 of these 7
      patients, the tumor was paratracheal or invasive into the trachea or thyroid
      cartilage. In 11 patients with detectable serum thyroglobulin preoperatively, the
      level demonstrated a decline in 10 patients and became undetectable in 7
      patients. CONCLUSIONS: Intraoperative ultrasonography is a useful method to
      identify nonpalpable, locoregional recurrences of thyroid cancer. Ultrasound was
      particularly helpful in patients who had previous external beam radiotherapy and
      in the identification of tumor nodules of 20 mm or less that were invasive or
      adherent to the airway.

PMID- 12490838
TI  - Parathyroidectomy improves concentration and retentiveness in patients with
      primary hyperparathyroidism.
AB  - BACKGROUND: Many patients with primary hyperparathyroidism (PHPT) show symptoms
      of hypercalcemia syndrome, including psychologic and psychiatric disorders. The
      aim of this study was to find out whether parathyroidectomy improves cognitive
      performance with regard to concentration and retentiveness in patients with PHPT.
      METHODS: . Twenty patients with PHPT underwent psychologic testing preoperatively
      as well as 6 and 12 weeks postoperatively. Concentration under stress (timing)
      was proved by the d2-Test of Attention. To evaluate retentiveness, parts of the
      Wilde Intelligence Test were used. Patients were tested under identical
      circumstances with regard to time, location, and tester to minimize exterior
      influences. RESULTS: The patients' concentration enhanced significantly
      postoperatively (P <.001). The same applied to the total number of items
      processed (P <.01). Improvement of patients' ability to memorize numbers reached
      statistical significance when comparing the preoperative with the postoperative
      result (P =.0396); furthermore, there was a tendency to perform the tests more
      carefully and accurately (P =.069). CONCLUSIONS: Parathyroidectomy not only
      betters physical symptoms of PHPT but can also positively influence the patients'
      cognitive performance. These findings reflect the clinical observation of the
      patients' improved mental capacity after parathyroidectomy.

PMID- 12490839
TI  - Rapid insulin assay for intraoperative confirmation of complete resection of
      insulinomas.
AB  - BACKGROUND: Solitary insulinomas are usually the cause of organic hypoglycemia,
      whereas 13% to 24% of patients with hyperinsulinemia have multiple tumors or
      nesidioblastosis. Intraoperative glucose levels confirming complete excision have
      variable accuracy. Intraoperative insulin levels have been shown to predict
      operative outcome. The purpose of this study was to establish criteria for
      predicting operative success by using a new, rapid insulin assay as an
      intraoperative adjunct. METHODS: Eight consecutive patients with organic
      hypoglycemia underwent pancreatic exploration. With an 8-minute
      immunochemiluminescent insulin assay, peripheral blood levels were obtained
      preoperatively, during resection, and at 5-minute intervals after surgical
      excisions. Operative findings and outcome were compared with intraoperative
      insulin/glucose ratios (I/G), glucose, and insulin levels. RESULTS: By using the
      return of insulin levels to normal range and I/G ratios < or = 0.4 15 minutes
      after tumor(s) resection as criteria to predict operative success, 6 patients had
      their outcomes correctly predicted (5 true-positive and 1 true-negative). One
      patient with nesidioblastosis had a false-negative result. One could not be
      evaluated because of diazoxide medication. These criteria predicted postoperative
      absence of hypoglycemia with specificity of 100% and accuracy of 89%.
      CONCLUSIONS: These 8-minute insulin assay and criteria can be a useful adjunct
      for intraoperative assurance of complete insulinoma resection and prediction of
      postoperative outcome.

PMID- 12490840
TI  - Accuracy of selective venous sampling for intact parathyroid hormone in difficult
      patients with recurrent or persistent hyperparathyroidism.
AB  - BACKGROUND: Preoperative noninvasive localization studies of the neck and
      mediastinum are beneficial before reoperation. However, the role of selective
      venous sampling (SVS) for parathyroid hormone (PTH) in reoperative parathyroid
      surgery has never been clearly defined. The purpose of this study was to evaluate
      the accuracy of SVS when applied selectively to the subset of patients with
      indeterminate noninvasive localization studies. METHODS: Between January 1990 and
      December 2001, 64 of 235 (27%) patients with persistent or recurrent
      hyperparathyroidism were considered candidates for SVS in addition to noninvasive
      localization studies. Accuracy of SVS for PTH was retrospectively evaluated.
      RESULTS: Successful surgical treatment was achieved in 86% of these patients. SVS
      for PTH yielded true-positive results in 75% of patients and was not useful for
      the surgeon in 17% (completely false-positive in 12% and indeterminate in 5%). In
      2% of patients, SVS identified successfully 1 gland but failed to locate another
      abnormal gland. In 6% of patients, the location of the abnormal parathyroid
      tissue remained unknown, and the patients have persistent hyperparathyroidism.
      CONCLUSIONS: We showed that SVS is clinically useful in patients with persistent
      or recurrent hyperparathyroidism when the noninvasive localization studies do not
      clearly localize the abnormal parathyroid glands.

PMID- 12490841
TI  - RET proto-oncogene mutations affecting codon 790/791: A mild form of multiple
      endocrine neoplasia type 2A syndrome?
AB  - BACKGROUND: In patients with multiple endocrine neoplasia type 2A syndrome,
      prophylactic thyroidectomy is generally recommended at the age of 5 to 6 years.
      Whether this recommendation is justified for exon 13 mutations is unknown.
      METHODS: We analyzed the clinical data from 40 patients harboring RET codon
      790/791 mutations (exon 13) who had been treated in 4 specialized centers.
      RESULTS: Mean age was 35.2 +/- 21.6 years (range, 5.1-69.0 years). Thirteen
      patients were index patients (mean age, 57.7 +/- 11.3 years), 27 patients were
      screening patients (mean age, 24.4 +/- 16.5 years). In the index group, pT
      category was: T0, n = 2; T1, n = 6; T2, n = 2; T3, n = 1; and T4, n = 2. Lymph
      node metastases were found in 5 patients and distant metastases in 1 patient.
      Postoperatively, 69% of index patients were biochemically cured. In the screening
      group, pT-category was: T0, n = 19; T1, n = 7; and T2, n = 1. Lymph node
      metastases were found in 2 patients. Postoperatively, 93% of screening patients
      were biochemically cured. The youngest patient with medullary thyroid carcinoma
      was 13.8 years, the youngest patient with lymph node metastases was 46.4 years.
      CONCLUSIONS: Patients with RET codon 790/791 mutations seemed to have a less
      aggressive clinical course compared with patients with classic multiple endocrine
      neoplasia type 2A syndrome. Still, index patients had a lower biochemic cure rate
      in comparison with screening patients. Timely total thyroidectomy including lymph
      node dissection is warranted.

PMID- 12490842
TI  - Inhibition of medullary thyroid carcinoma cell proliferation and RET
      phosphorylation by tyrosine kinase inhibitors.
AB  - BACKGROUND: Most medullary thyroid carcinomas (MTCs) result from gain-of-function
      mutations in the RET proto-oncogene, which encodes a transmembrane tyrosine
      kinase receptor. Systemic therapies have not been effective in treating this
      disease. We evaluated the effects of 3 tyrosine kinase inhibitors (TKIs) on MTC
      cell growth and RET tyrosine kinase activity by using an in vitro model. METHODS:
      An MTC cell line (TT cells, RETc634 mutant) cultured in RPMI medium was exposed
      to varying concentrations of STI571, genistein, or allyl-geldanamycin with
      controls (no TKI) for 3 to 48 hours. Cellular protein was analyzed by
      immunoprecipitated Western blot analysis probing with a monoclonal
      antiphosphotyrosine antibody. Cell proliferation was determined by 3-[4,5
      dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'
      deoxyuridine (BrdU) assays. RESULTS: RET phosphorylation was inhibited at 24
      hours of exposure to 5 to 20 micromol/L STI571 and 48 hours of exposure to
      genistein (200 micromol/L) and allyl-geldanamycin (6 micromol/L). RET protein was
      detected in equal concentrations in all experimental conditions. MTT and BrdU
      assays demonstrated a dose-dependent decrease in TT cell proliferation with
      exposure to the 3 TKIs. CONCLUSIONS: These TKIs selectively inhibit cell growth
      and RET tyrosine kinase activity of MTC cells in vitro in a dose manner. This
      study suggests the use of TKIs in human trials as a systemic therapy for MTC.

PMID- 12490843
TI  - Improving the yield of preoperative parathyroid localization: technetium Tc 99m
      sestamibi imaging after thyroid suppression.
AB  - BACKGROUND: Preoperative localization is essential for successful directed,
      minimally invasive or reoperative parathyroidectomy. Standard technetium Tc 99m
      sestamibi imaging is the most sensitive modality for localization. We reviewed
      our experience with (99m)Tc-sestamibi imaging and specifically investigated the
      effect of thyroid suppression on repeat imaging of patients who had initially
      nonlocalizing scans. METHODS: . The records of patients who underwent (99m)Tc
      sestamibi imaging during evaluation for primary hyperparathyroidism were
      reviewed. A subset of patients with initially nonlocalizing scans underwent
      thyroid suppression with either thyroxin or liothyronine and then had their scans
      repeated. RESULTS: Ninety-nine patients with primary hyperparathyroidism
      underwent (99m)Tc-sestamibi imaging followed by parathyroidectomy (initial
      operation, 78; reoperation, 21). Successful parathyroid localization was obtained
      on standard imaging in 67 patients. Fourteen of 32 patients who had nonlocalizing
      (99m)Tc-sestamibi imaging studies underwent an additional scan after thyroid
      suppression. In 10 of 14 patients (71%), repeat (99m)Tc-sestamibi imaging after
      thyroid suppression successfully localized abnormal parathyroid tissue.
      CONCLUSIONS: Thyroid suppression may improve the yield of (99m)Tc-sestamibi
      imaging in patients with hyperparathyroidism who have an initially nonlocalizing
      study. This diagnostic strategy may be helpful in patients motivated to undergo a
      directed, minimally invasive operation, as well as in the evaluation of patients
      for reoperative parathyroidectomy.

PMID- 12490844
TI  - Concurrent resections of pancreatic islet cell cancers with synchronous hepatic
      metastases: outcomes of an aggressive approach.
AB  - BACKGROUND: Pancreatic islet cell cancers are often characterized by the presence
      of endocrinopathies, an indolent clinical course, and a propensity for hepatic
      metastases. Hepatic metastases are associated with a negative impact on survival.
      The role of concurrent resections of pancreatic islet cell cancers and the
      hepatic metastases has not been defined. METHODS: The records of all consecutive
      patients undergoing concurrent resections of pancreatic islet cell cancers and
      their hepatic metastases between 1980 and 1998 were reviewed. Outcomes regarding
      overall progression-free and symptom-free survival and perioperative morbidity
      and mortality were assessed. RESULTS: All 23 patients underwent distal
      pancreatectomy and splenectomy. Six major (> or = 3 segments) and 17 minor (c3
      segments) partial hepatectomies were performed. Complete gross resection of
      cancer (R0/R1) were performed in 9 patients and debulking resections (R2) (<10%
      residual tumor volume) in 14 patients. There were no perioperative deaths. Major
      complications occurred in 4 patients (18%). Overall, progression-free, and
      symptom-free survival was 71% (median: 76 months), 5% (median: 21 months), and
      24% (median: 26 months), respectively, at 5 years. Conclusions. These data
      support aggressive concurrent resection of the pancreatic islet cell cancers and
      synchronic hepatic metastases when technically feasible. Because disease
      progression is frequent and the major cause of death, investigations of adjuvant
      and adjunctive therapies are warranted.

PMID- 12490845
TI  - Increasing the effectiveness of radioactive iodine therapy in the treatment of
      thyroid cancer using Trichostatin A, a histone deacetylase inhibitor.
AB  - BACKGROUND: Radioactive iodine is used to identify and treat recurrent and
      metastatic thyroid cancer of follicular cell origin. Between 30% and 40% of
      thyroid cancers are either resistant or become resistant to radioactive iodine.
      Increased sodium-iodide symporter (NIS) and decreased Pendrin (PDS) activity may
      be associated with increased radioactive iodine effectiveness. In this
      investigation the effects of Trichostatin A (TSA), a histone deacetylating
      inhibitor, on human thyroid NIS and PDS gene expression was investigated. METHOD:
      Cell lines from papillary, Hurthle, and follicular cell carcinomas were treated
      with TSA for 72 hours at concentrations up to 100 ng/mL. NIS and PDS gene
      expression was determined using quantitative RT-polymerase chain reaction.
      RESULTS: . NIS messenger RNA expression in cell carcinomas was increased 107-
      (1.8-307) and 217- (5.7-408) fold in papillary, 39- (20-63) and 58- (37-80) fold
      in Hurthle, and 459- (178-810) and 781- (412-1229) fold in follicular after
      treatment with 50 and 100 ng/mL of TSA, respectively. PDS messenger RNA
      expression in cell carcinomas was decreased 0.22- (0.05-0.45) and 0.27- (0.09
      0.47) fold in papillary, 0.53- (0.46-0.60) and 0.54- (0.44-0.64) fold in Hurthle,
      and 0.32- (0.26-0.39) and 0.56- (0.47-0.64) fold in follicular, after the same
      treatment. CONCLUSIONS: In thyroid cancer cell lines, TSA dramatically increased
      NIS gene expression and reduced PDS expression. The increased NIS expression and
      reduced PDS expression may make radioiodine therapy more effective in patients
      with thyroid cancer, especially when the tumors have no or low uptake of
      radioiodine.

PMID- 12490846
TI  - A new therapeutic approach in medullary thyroid cancer treatment: inhibition of
      oncogenic RET signaling by adenoviral vector-mediated expression of a dominant
      negative RET mutant.
AB  - BACKGROUND: Mutations in the RET proto-oncogene that result in constitutive
      tyrosine kinase activity are the underlying cause for the development of
      medullary thyroid cancer (MTC). To investigate an alternative strategy in MTC
      treatment, we took advantage of a dominant-negative RET (dn-RET) mutant,
      Ret(51)HSCR32, which inhibits oncogenic signal transduction by retaining the
      oncogenic RET protein in the endoplasmic reticulum, thereby reducing the amount
      of oncogenic RET protein from the cell surface. METHODS; We constructed an
      adenoviral (Ad) vector expressing dn-RET under control of the C-cell specific
      synthetic calcitonin promoter TSE2.CP1 (AdTSE2.CP1-RET(51)HSCR32) and
      investigated the effect of dn-RET on cell growth of MTC-derived TT cells.
      RESULTS: Analysis of the subcellular localization of endogenous oncogenic RET
      protein showed a significant dominant-negative effect of Ad vector-delivered dn
      RET in TT cells, resulting in a strong inhibition of cell viability. The observed
      effect is partially dependent on growth inhibition and possibly apoptosis
      induction. CONCLUSIONS: In the present study, growth of human MTC cells was
      successfully inhibited by Ad vector-mediated delivery of RET(51)HSCR32,
      suggesting that inhibition of oncogenic RET receptor tyrosine kinase expression
      by a dn-RET mutant might be a powerful approach for in vivo therapy of MTC.

PMID- 12490847
TI  - Selective estrogen receptor modulators inhibit the effects of insulin-like growth
      factors in hyperparathyroidism.
AB  - BACKGROUND: Primary hyperparathyroidism (HPT) predominantly affects
      perimenopausal women, leading to speculations that an estrogen imbalance may be
      liable. We have previously demonstrated the importance of the insulin-like growth
      factor (IGF) axis in HPT. Because the antiestrogen tamoxifen has been shown to
      modulate the IGF axis, we examined the interactions of selective estrogen
      receptor modulators (SERMs) and IGF in HPT. METHODS; Estrogen receptors were
      evaluated by Western immunoligand blotting. Sixteen parathyroid glands from 19
      patients were included. After adhesion, the cells were treated with IGF (I or II)
      +/- estrogen +/- SERMs (tamoxifen, ICI 182,780) for 96 hours in serum-free media.
      Proliferation was assessed by measuring tritiated thymidine incorporation.
      RESULTS: Both primary and secondary HPT express estrogen receptors alpha and
      beta. Primary and secondary HPT had comparable responses to SERMs, they were
      analyzed together. Compared with control (100%), IGFs (I and II) induced a
      significant increase in DNA synthesis. Estradiol at 10(-8) and 10(-7) mol/L
      (physiologic range) had no significant effects on IGF (I and II, P >.05). Both
      tamoxifen and ICI 182,780 inhibited basal DNA synthesis (P <.05) and abolished
      the effects of both IGF I and II (P <.05). CONCLUSIONS: SERMs are capable of
      reducing basal and IGF-stimulated DNA synthesis. This reduction in proliferation
      has implications for cancer biology and therapeutic potential for SERMs in HPT.

PMID- 12490849
TI  - Do the National Institutes of Health consensus guidelines for parathyroidectomy
      predict symptom severity and surgical outcome in patients with primary
      hyperparathyroidism?
AB  - BACKGROUND: The National Institutes of Health (NIH) consensus guidelines for
      parathyroidectomy in primary hyperparathyroidism were developed addressing only
      the classic symptoms and physiologic markers of hyperparathyroidism. The purpose
      of this study was to assess whether NIH guidelines predict the severity of all
      symptoms and the outcome of operation. METHODS: Symptom severity measurements
      using a disease-specific outcome tool called the parathyroidectomy assessment of
      symptoms (PAS) scores were previously obtained in patients with
      hyperparathyroidism. Patients were retrospectively stratified into 2 groups:
      group A, in which 1 or more of the NIH guidelines were met; and group B. in which
      operation was performed without any of the NIH criteria. For comparison, group C
      consisted of patients with non-toxic thyroid disease. PAS scores were collected
      preoperatively, and at 7 days, 3 months, and 12 months postoperatively. RESULTS:
      There were 95 patients in group A, 22 in group B, and 58 in group C. The median
      preoperative PAS scores for group A (354) and B (301) were not significantly
      different, however, both were more symptomatic than group C (176, P <.01). After
      parathyroidectomy, patients in both group A and B had a significant improvement
      in their PAS scores (A=177 and B=130, P <.05). CONCLUSIONS: Patients with no NIH
      criteria for operation are equally symptomatic compared with those who meet the
      NIH guidelines. Parathyroidectomy significantly improved these symptoms whether
      or not the patient met the NIH consensus guidelines.

PMID- 12490848
TI  - Aldosterone-secreting adrenocortical carcinomas are associated with unique
      operative risks and outcomes.
AB  - BACKGROUND: Adrenocortical carcinoma (ACC) that produces aldosterone is an
      extremely rare, uncharacterized endocrine malignancy. Our aim was to characterize
      this neoplasm in terms of its clinical behavior and patient outcomes. METHODS: A
      retrospective review was made of all patients who had operative management of
      aldosterone-secreting ACC from 1957 to 2000 at the Mayo Clinic. Comparisons were
      made to patients with non-aldosterone-secreting ACC treated during the same
      period. RESULTS: Of 141 patients with ACC, we identified 15 patients with
      aldosterone-secreting ACC. Isolated aldosterone hypersecretion was present in 10
      patients, and mixed hormonal secretion was detected in 5. Mean tumor size and
      weight were 10.8 cm and 453 g, respectively. Surgical management included
      curative resection in 10 patients (67%). Perioperative mortality was 20%. Disease
      recurred in 7 patients (70%) with a median interval of 17 months. Five-year
      survival was 52%. Patients with aldosterone-secreting ACC had an increased risk
      of perioperative mortality (20% vs 5%), yet they had an overall survival of 63
      months compared to 19 months for patients with non-aldosterone-secreting ACC.
      CONCLUSIONS: Aldosterone hypersecretion occurs in 11% of all ACCs and is
      associated with unique operative risk and outcome. Although patients harboring
      aldosterone-secreting ACC appear to have an increased risk of perioperative
      death, survivors may have an improved overall survival rate compared with
      patients with non-aldosterone-secreting ACC.

PMID- 12490850
TI  - Apoptosis regulating genes, bcl-2 and bax, and human telomerase reverse
      transcriptase messenger RNA expression in adrenal tumors: possible diagnostic and
      prognostic importance.
AB  - BACKGROUND: Apoptosis-suppressing gene, bcl-2, and apoptosis-inducing gene, bax,
      are expressed in various tumors. Human telomerase reverse transcriptase (hTERT)
      expression is increased in many cancers. The purpose of this investigation was to
      determine whether bcl-2 or bax gene expression differs between benign and
      malignant adrenal tumors, and whether hTERT gene expression correlates with the
      prognosis of patients with adrenal cancer. METHODS: Expression of bcl-2 and bax
      from 52 adrenal surgical specimens was analyzed by reverse transcription
      polymerase chain reaction. Expression of hTERT was analyzed by real-time
      quantitative reverse transcription-polymerase chain reaction, and expressed using
      the delta-delta threshold cycle method. RESULTS: All normal adrenal tissues (n =
      7) and benign adrenal tumors (n = 41) expressed bcl-2 and bax, whereas all
      adrenocortical cancers (n = 4) expressed bcl-2 but not bax. Expression of hTERT
      was increased in adrenocortical cancers compared with that in normal tissues (P
      <.05), cortical adenomas (n = 17) (P <.05), cortical hyperplasias (n = 4) (P
      <.05), and pheochromocytomas (n = 20) (P <.05). The one patient with an
      adrenocortical cancer without increased hTERT expression is alive with distant
      metastasis 5 years after adrenalectomy. The other 3 patients with adrenocortical
      cancer died 5 to 24 months after adrenalectomy. CONCLUSIONS: Expression of bax
      gene appears to distinguish adrenal cancer from benign adrenal tumors. Gene
      expression of hTERT should be investigated as a prognostic marker in adrenal
      cortical cancers.

PMID- 12490851
TI  - Utility of rapid intraoperative parathyroid hormone assay to predict severe
      postoperative hypocalcemia after reoperation for hyperparathyroidism.
AB  - BACKGROUND: Patients undergoing reoperative parathyroidectomy may develop severe
      transient or permanent hypoparathyroidism. This study's purpose was to determine
      the utility of intraoperative parathyroid hormone (IO-PTH) values in predicting
      the development of severe hypocalcemia for patients undergoing reoperation for
      primary hyperparathyroidism. METHODS: Between March 1999 and October 2001, 68
      patients with persistent or recurrent hyperparathyroidism underwent reoperation
      using IO-PTH measurements. The maximum percent decrease and lowest actual PTH
      value obtained at surgery were compared to determine any correlation with the
      development of postoperative hypocalcemia requiring supplementation. RESULTS: Of
      68 patients, 25 required calcium and calcitriol postoperatively and 43 did not.
      There was a significant difference between the 2 groups with respect to lowest IO
      PTH value (18.4 +/- 2.6 vs 28.0 +/- 3.9 pg/mL; P =.02), percent decrease in IO
      PTH (89% +/- 1% vs 80% +/- 3%; P =.03), and lowest postoperative ionized calcium
      (1.06 +/- 0.01 vs 1.19 +/- 0.01 mmol/L; P <.001). A percent decrease in IO-PTH of
      84% or greater was found to be predictive of patients experiencing hypocalcemia
      requiring supplementation with a positive predictive value of 46% and a negative
      predictive value of 82%. CONCLUSIONS: Although a maximum percent decrease in IO
      PTH of 84% or greater was associated with an increased incidence of postoperative
      hypocalcemia requiring supplementation in the 68-patient cohort, on further
      analysis the association was significant only for patients with multiglandular
      disease and not those with single adenomas. This value may be useful for
      identifying patients who will need closer postoperative monitoring or
      prophylactic supplementation.

PMID- 12490852
TI  - Activation of the ras/raf-1 signal transduction pathway in carcinoid tumor cells
      results in morphologic transdifferentiation.
AB  - BACKGROUND: Recent studies of neuroendocrine tumor cell lines suggest that
      ras/raf-1 activation could be detrimental to tumorigenesis. The mechanism by
      which it alters neuroendocrine tumor cells is unclear. We hypothesize that
      activation of the ras/raf signal transduction pathway may alter gastrointestinal
      carcinoid cells by inducing morphologic transdifferentiation. METHODS: Pancreatic
      carcinoid (BON) cells were transduced in a stable manner with an estrogen
      inducible raf-1 fusion protein (creating "BON-raf cells"). BON and BON-raf cells
      were then treated with either control or 1 micromol/L estradiol (E2). Western
      blots were used to confirm the phosphorylation of extracellular signal-regulated
      kinase 1/2. Morphologic changes were evaluated using light and electron
      microscopy. RESULTS: Western blots using antibodies against phosphorylated and
      unphosphorylated extracellular signal-regulated kinase 1/2. confirmed that
      phosphorylation was only present in the BON-raf E2 cells. BON cells treated with
      control and E2 and BON-raf cells treated with control all looked identical in
      culture. After treatment with E2 to induce raf-1, the BON-raf cells underwent
      dramatic morphologic changes. Under light and electron microscopy the cells
      became flatter and developed much sharper cellular borders mimicking cellular
      differentiation. CONCLUSIONS: Activation of the ras/raf-1 signal transduction
      pathway leads to prominent phenotypic changes that resemble differentiation of
      gastrointestinal carcinoid cells in vitro.

PMID- 12490853
TI  - Pitfalls in the surgical treatment of insulinoma.
AB  - BACKGROUND: In the 75 years since an insulinoma was first described, the
      challenge for the surgeon has been one of localization. The combination of
      endoscopic ultrasound (EUS) or intraoperative ultrasound and operative palpation
      has led to nearly 100% success rate at primary operation in experienced
      institutions. However, 13% of patients at referral centers undergo reexploration,
      which has an increased morbidity. With more successful localization modalities,
      the operative failures have become more challenging than ever. METHODS: During
      the past 35 years, we have treated 118 cases of sporadic insulinoma. Technical
      advances in EUS have led to preoperative identification of more than 90% of
      insulinomas. Despite this success we have become increasingly aware of the
      limitations of EUS in the surgical treatment of insulinoma. We present the
      pitfalls of 6 recent cases. RESULTS: The limitations of EUS include the
      assessment of malignancy, the identification of pedunculated or adjacent lesions,
      the evaluation of distal pancreatic lesions, and the differentiation of larger
      homogeneous tumors from surrounding parenchyma. CONCLUSIONS: The surgical
      challenge in the treatment of insulinomas has transformed from one of
      localization to one of recognizing the limitations of our current localization
      modalities. By sharing our experience with recent difficult cases, we guide the
      surgeon to greater success and the patient to decreased morbidity.

PMID- 12490854
TI  - Limited versus radical parathyroidectomy in familial isolated primary
      hyperparathyroidism.
AB  - BACKGROUND: Familial isolated primary hyperparathyroidism (FIHPT) is
      characterized by earlier onset, higher incidence of multiglandular disease, and
      higher recurrence rate when compared with sporadic primary hyperparathyroidism.
      Excision of 3.5 or 4 glands with autotransplantation has been recommended;
      however, these approaches lead to permanent hypoparathyroidism in 13% to 41% of
      patients. It is reported that many patients with FIHPT return to normocalcemia
      after single-gland excision. The use of preoperative localization and
      intraoperative parathyroid hormone assay permits limited resection of only
      hypersecreting glands. We report the outcome of this operative approach. METHODS:
      Fifteen consecutive patients with FIHPT underwent limited parathyroidectomy with
      resection guided by intact parathyroid hormone secretion in 2 university centers.
      Patients were followed up postoperatively for serum calcium and intact
      parathyroid hormone levels. RESULTS: With an operative success of 93%, 14
      patients had only single-gland excision and 80% had unilateral neck exploration.
      All initial patients had their hypercalcemia corrected. In 4 reoperations,
      permanent hypoparathyroidism occurred in 2 patients. One recurrence was observed
      in 40 (8-122) months of follow-up. CONCLUSION: Limited parathyroidectomy allows
      successful single-gland excision in many patients with FIHPT, thus decreasing the
      risk of hypoparathyroidism. In these patients, a low incidence of
      hypoparathyroidism may be preferable to the possibility of late recurrence.

PMID- 12490855
TI  - VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy
      and inhibited by anti-VEGF antibodies in experimental tumors.
AB  - BACKGROUND: Pheochromocytomas are well-vascularized tumors of the adrenal
      medulla. In human pheochromocytomas, angiogenesis has been associated with tumor
      progression. The mechanisms, however, are unknown. METHODS: Surgical specimens of
      benign, invasive, and metastatic human pheochromocytomas (n = 10/5/5) were
      immunostained for vascular endothelial growth factor (VEGF) and CD34, to
      determine VEGF expression and microvessel density (vascular surface density,
      [VSD]). In PC12-pheochromocytoma cells, VEGF messenger RNA and protein were
      analyzed by Northern blotting and enzyme immunoassay; biologic activity by human
      umbilical vein endothelial cell-proliferation assay. Inhibition of angiogenesis
      of PC12 xenografts by 2 neutralizing anti-VEGF antibodies (C20-pAB, M461-mAB) was
      evaluated by VEGF expression, VSD, and mitotic activity. RESULTS: VEGF expression
      and VSD were significantly higher in metastatic pheochromocytomas (VEGF 37.1 +/-
      10.9% vs 20.7 +/- 9%, VSD 26.2 +/- 8 vs 13.5 +/- 3.3 1/mm). VEGF messenger RNA
      and protein were confirmed in PC12 cells and stimulated by nerve growth factor.
      Conditioned PC12 medium increased human umbilical vein endothelial cell
      proliferation more than 2-fold. Xentrotransplanted PC12 cells had marked VEGF
      expression and angiogenesis, which was inhibited by anti-VEGF antibodies (VEGF
      expression by 29 and 38%, VSD by 43 and 46%, P <.05). CONCLUSION: Higher VEGF
      expression and microvessel density in malignant pheochromocytomas suggest VEGF
      mediated angiogenesis to be related to tumor progression. Angiogenesis of PC12
      xenografts is mediated by VEGF. Neutralizing anti-VEGF antibodies inhibit
      angiogenesis in experimental pheochromocytomas and may have potential for
      treating nonresectable pheochromocytomas.

PMID- 12490856
TI  - Quality of life after laparoscopic bilateral adrenalectomy for Cushing's disease.
AB  - BACKGROUND: Bilateral adrenalectomy to control symptoms of Cushing's disease
      after failed transsphenoidal operation is effective. We examined surgical
      outcomes and quality of life after laparoscopic bilateral adrenalectomy for the
      treatment of Cushing's disease. METHODS: Eighteen patients underwent laparoscopic
      bilateral adrenalectomy from November 1994 through December 2000. Patient data
      were obtained from chart reviews. Patients completed a follow-up survey including
      the SF-36 health survey (QualityMetric Inc, Lincoln, Neb). RESULTS: Laparoscopic
      bilateral adrenalectomy was accomplished in all 18 patients. There was 1
      intraoperative complication of a colotomy, and 2 postoperative complications
      including 1 pancreatic pseudocyst and 1 hemorrhage. Three patients died at 12,
      19, and 50 months after operation. At a median follow-up of 29 months, patients
      reported improvement in all Cushing's-related symptoms. Nine of 11 patients who
      responded to the survey stated their heath was improved after adrenalectomy.
      Results of the SF-36 health survey showed significantly lower scores in all 8
      measured parameters when compared with the general population. CONCLUSIONS:
      Results of laparoscopic bilateral adrenalectomy show this procedure is comparable
      with open adrenalectomy in controlling symptoms of Cushing's disease. Despite
      patient reported improvement in health after adrenalectomy, this patient
      population continues to experience poor health as measured by the SF-36 when
      compared with the general population.

PMID- 12490857
TI  - Minimally invasive video-assisted thyroidectomy for papillary carcinoma: a
      prospective study of its completeness.
AB  - BACKGROUND: The effectiveness of minimally invasive video-assisted thyroidectomy
      (MIVAT) in papillary thyroid carcinoma is still debated. Some are concerned about
      this procedure in patients with thyroid cancer. This prospective study aimed to
      demonstrate that near-total thyroidectomy can be performed by MIVAT with similar
      results compared with open thyroidectomy. METHODS: A total of 33 patients with a
      thyroid nodule proven to be a papillary thyroid carcinoma underwent a near-total
      thyroidectomy. They were randomly assigned to group A (n = 16) or group B (n =
      17) who were treated either by MIVAT or conventional near-total thyroidectomy,
      respectively. Iodine-131 thyroid bed uptake and serum thyroglobulin were measured
      1 month after operation. Data were analyzed by unpaired t test and Mann-Whitney
      statistic methods. RESULTS: . Mean iodine-131 uptake was 5.1 +/- 4.9% in group A
      and 4.6 +/- 6.7% in group B. Mean thyroglobulin serum levels were 5.3 +/- 5.8
      ng/mL in group A and 7.6 +/- 21.7 ng/mL in group B. The differences were not
      statistically significant. CONCLUSIONS: The results of this study showed that the
      completeness obtained with MIVAT is similar to that obtained with open
      thyroidectomy, with the great advantage of a minimal neck wound. No conclusions
      can be drawn in terms of influence of MIVAT on the outcome of the patients with
      small papillary thyroid carcinoma.

PMID- 12490858
TI  - Recovery pattern of patients with osteitis fibrosa cystica in primary
      hyperparathyroidism after successful parathyroidectomy.
AB  - BACKGROUND: After parathyroidectomy, recovery of osteitis fibrosa cystica, which
      continues to dominate presentation of primary hyperparathyroidism in India has
      not been documented objectively. METHODS: We followed up clinical recovery,
      biochemic markers of bone turnover, bone mineral density, and skeletal radiology
      in 51 patients with primary hyperparathyroidism and osteitis fibrosa cystica for
      9 to 124 months (median, 32 months). RESULTS: After parathyroidectomy, 46
      patients had hypocalcemia. During postoperative week 1, bone pain improved in
      71%. During 3 months, appendicular fractures healed in all 33 such patients, and
      6 of 7 patients who were bedridden could walk. Mean bone mineral density
      increments (percent change/y) seen at various sites at 1 week, 3, 6, and 12
      months were distal forearm--37, 28, 23, 21; lumbar spine--165, 104, 101, 106; and
      total hip--168, 157, 166, 133. Follow-up radiographs demonstrated prompt recovery
      though disorderly remineralization. Brown tumors and fractures showed
      hyperdensities within 3 months. Brown tumors regressed partially in 6 of 27
      patients after 6 months. CONCLUSIONS: After parathyroidectomy, patients with
      primary hyperparathyroidism have early, marked, and sustained recovery of
      osteitis fibrosa cystica. Early (1 week) bone mineral density increments of >
      100%/y hint at the skeleton's ability to promptly restore itself. Densitometric
      recovery is prompt at cancellous (lumbar spine), but not at cortical (forearm)
      bone sites. Contour defects and bony tumors persist, and may need corrective
      osteotomies.

PMID- 12490859
TI  - Elevated serum parathormone level after "concise parathyroidectomy" for primary
      sporadic hyperparathyroidism.
AB  - BACKGROUND: Cure after parathyroid exploration is traditionally assessed by serum
      calcium concentration 6 months postoperatively. Postoperative normocalcemic
      elevation of serum parathormone (PTH) level has been described but is of unclear
      significance. METHODS: In a 6-year prospective study of outcomes in 380 patients
      undergoing initial parathyroidectomy for primary sporadic hyperparathyroidism, we
      measured intact serum PTH and calcium levels at more than 5 months. Those with
      normocalcemic high PTH levels were begun on oral calcium + vitamin supplements
      and monitored. RESULTS: At more than 5 months postoperatively, normocalcemic
      elevation in serum PTH level occurred in 28% of patients, was more common after
      resection of double adenomas (P =.01), and predated the onset of recurrent
      hypercalcemia in 3 of 3 patients with unrecognized multiglandular disease.
      Although delayed treatment with calcium and vitamin supplements produced no clear
      benefit, patients who took such supplements from the date of surgery were much
      less likely to have an elevated serum PTH level more than 5 months later (P
      =.0005). CONCLUSIONS: After successful parathyroid surgery, compensatory
      normocalcemic elevation in serum PTH level is frequent and may arise from dietary
      deficiency. Monitored supplemental intake of calcium and vitamin D appears to
      prevent or to normalize the condition in most patients. Patients with
      normocalcemic elevation in serum PTH level should receive evaluation for dietary
      deficiencies as well as follow-up for possible residual disease.

PMID- 12490860
TI  - Expression of kinase genes in primary hyperparathyroidism: adenoma versus
      hyperplastic parathyroid tissue.
AB  - BACKGROUND: Differentiation between parathyroid hyperplasia and adenoma is
      difficult and based on the surgeon's skill. Microarrays and other sophisticated
      research tools generate information about differential gene expression in various
      tissues. Exploration of genes that express differentially in 1 tissue will enable
      identification and perhaps development of new methods of preoperative or
      intraoperative diagnosis. METHODS: RNA was extracted from parathyroid hyperplasia
      and adenoma tissue and hybridized to a microarray containing 359 human
      complementary DNAs of known kinase genes. Signals of exposure were scanned and
      quantified with software for digital image analysis (Atlas-image, v. 2; Clontech
      Labs Inc, Palo Alto, Calif). The program generates a color schematic comparison
      view and numeric data in a tabular format for further analysis. RESULTS: The
      ratio values that are considered significant (< 0.5 or > 1.5) suggest that genes
      up-regulated in parathyroid adenoma are those responsible for angiogenesis and
      production of blood vessels. Genes down-regulated in parathyroid adenoma and
      expressed in hyperplasia are related to a decrease in apoptosis. Moreover, an
      interesting gene expressed only in the hyperplasia sample is increased in
      relation to in vivo proliferation activities. CONCLUSIONS: Parathyroid
      hyperplasia and adenoma are different physiologic conditions. Further analysis of
      kinase genes involved in angiogenesis and apoptosis will enable design of a chip
      that concentrates in the different key genes responsible for the transition
      between hyperplasia and adenoma. Identifying such genes will enable to target
      both diagnostic and therapeutic approaches.

PMID- 12490861
TI  - Computer-assisted evoked electromyography with stimulating surgical instruments
      for recurrent/external laryngeal nerve identification and preservation in thyroid
      and parathyroid operation.
AB  - BACKGROUND: The reported incidence of recurrent laryngeal nerve (RLN)
      palsy/paralysis in thyroid and parathyroid operation ranges from 2% to 13%.
      Injury to the external branch of the superior laryngeal nerve (EBSLN) is less
      clearly documented. We hypothesized that a novel evoked electromyography system
      using an audio warning alarm might be beneficial for detection and preservation
      of the RLN and EBSLN. METHODS: A total of 117 thyroid/parathyroid operations were
      performed using a nerve locator/monitor (Neurovision SE, RLN Systems Inc,
      Jefferson City, Mo). Dissection was performed using a stimulating hemostat with
      conduction to an endotracheal surface electrode. RESULTS: A total of 97
      thyroidectomies (50 total, 47 lobectomies) and 20 parathyroidectomies (16
      directed, 4 bilateral) were performed representing 176 RLN and 152 EBSLN at risk.
      Of 176 RLN, 161 were correctly identified by the nerve stimulator alarm including
      2 nonrecurrent nerves. The cricothyroid space and the superior pole vessels were
      scanned to identify the EBSLN by observing for cricothyroideus contraction or an
      alarm. Fourteen of 152 (8.9%) cases of type 2 anatomy were suggested where
      meticulous dissection of superior pole vessels prevented EBSLN injury.
      CONCLUSIONS: Computer-assisted evoked electromyography with stimulating surgical
      instruments is a useful surgical tool. This technology may be especially useful
      in reoperation in dense scar tissue and preserving the EBSLN in thyroid
      operation.

PMID- 12490862
TI  - Is routine supplementation therapy (calcium and vitamin D) useful after total
      thyroidectomy?
AB  - BACKGROUND: Our goal was to determine whether routine oral calcium (OC) and
      vitamin D (VD) administration can effectively prevent symptoms of hypocalcemia
      after total thyroidectomy. METHODS: Seventy-nine patients who underwent total
      thyroidectomy were randomly allotted to one of the following groups: (1) group A,
      no treatment; (2) group B, OC 3 g per day; (3) group C, OC 3 g + VD 1 mg per day.
      Treatment was started on postoperative (PO) day 1 in groups B and C. RESULTS:
      Fewer patients in groups B and C experienced symptoms when compared with group A
      (P =.005). Patients in groups B and C had only minor symptoms, whereas 2 patients
      in group A experienced major symptoms and 6 required intravenous calcium (P
      <.01). The rate of hypocalcemia was slightly lower in group C (P = not
      significant). Treatment was discontinued by PO day 7 in all but 8 patients. Two
      patients still required treatment 6 months after operation (2.5%). PO parathyroid
      hormone levels did not differ in the 3 groups (P = not significant). CONCLUSIONS:
      Routine supplementation therapy with OC or VD effectively prevents symptomatic
      hypocalcemia after total thyroidectomy and may allow for a safe early discharge.
      Further studies are necessary to determine the best treatment. The combination of
      OC and VD may further reduce the rate of PO hypocalcemia, without inhibiting
      parathyroid hormone secretion.

PMID- 12490863
TI  - Preparation with iopanoic acid rapidly controls thyrotoxicosis in patients with
      amiodarone-induced thyrotoxicosis before thyroidectomy.
AB  - BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) may develop either in
      apparently normal glands (type II AIT) or in the presence of thyroid
      abnormalities (type I AIT). Sometimes AIT is resistant to conventional treatment.
      Thyroidectomy was used in patients with AIT, but in patients who are thyrotoxic
      it may be hazardous. METHODS; Seven patients with AIT (6 type I and 1 type II, 5
      men, 2 women, mean age 70 years [range, 60-82 years]) were prepared for total
      thyroidectomy with a short course of iopanoic acid (1 g/day orally for a mean of
      13 days), an oral iodinated cholecystographic agent inhibiting 5'-deiodinase and
      causing a reduction in the peripheral conversion of thyroxine to
      triiodothyronine. Mean thyroid volume was 64 mL (range, 10-145 mL). RESULTS: Mean
      serum-free triiodothyronine levels decreased from 20 +/- 16.7 pmol/L to 6 +/- 2
      pmol/L (P =.0004), whereas serum-free thyroxine values remained unchanged.
      Euthyroidism was rapidly (7-20 days) restored, allowing an uncomplicated total
      thyroidectomy in all patients and the ability to continue amiodarone therapy in 6
      patients. None had increased surgical bleeding, recurrent nerve palsy, or
      hypoparathyroidism. No cardiovascular complications occurred. CONCLUSIONS:
      Iopanoic acid is an effective drug allowing rapid control of hyperthyroidism in
      AIT.

PMID- 12490864
TI  - Long-term results of less than total parathyroidectomy for hyperparathyroidism in
      multiple endocrine neoplasia type 1.
AB  - BACKGROUND: Our aim was to assess long-term results after less than total
      parathyroidectomy for hyperparathyroidism in multiple endocrine neoplasia type 1.
      METHODS: Of 1888 patients undergoing operation at our institution for primary
      hyperparathyroidism between 1972 and 2001, 83 (4.4%) had multiple endocrine
      neoplasia type 1. Outcome data were available for 79; 66 underwent subtotal
      parathyroidectomy, 55 (83%) of these with bilateral thymectomy. In 13 patients,
      only grossly enlarged glands were resected (mean 1.1 per patient) as the syndrome
      of multiple endocrine neoplasia type 1 was not yet evident or the initial
      exploration was performed elsewhere. RESULTS: Follow-up has been 48 +/- 51 months
      (mean + SD). Intraoperative serum PTH assay decay in 20 patients was suggestive
      of cure in 18 patients, none of whom required reoperation. Nine patients (11%)
      required reoperation (3 required reoperation twice) after a mean interval of 77
      +/- 53 months. Subtotal parathyroidectomy resulted in a lesser reoperation rate
      than resection of grossly enlarged glands (7% vs 30%, P =.02). At the time of
      review, 63 patients (80%) were normocalcemic, 10 (13%) hypocalcemic (2 after
      unsuccessful delayed autograft), and 7% hypercalcemic (none after reoperation).
      By Kaplan-Meier analysis, the rate of surgical cure (patients who are
      nonhypercalcemic) is 60% and 51% at 10 and 15 years, respectively. CONCLUSION:
      Subtotal parathyroidectomy reduces the need for reoperation. Selective
      reoperation leads to long-lasting biochemic cure.

PMID- 12490865
TI  - Cardiac dysfunction in mild primary hyperparathyroidism assessed by radionuclide
      angiography and echocardiography before and after parathyroidectomy.
AB  - BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with increased
      cardiovascular morbidity for reasons that are incompletely understood. The
      present study was undertaken to evaluate the effects of parathyroidectomy on
      cardiac function especially in patients with mild PHPT. METHODS; Fifty patients
      with mild PHPT (serum calcium, 2.55 to 2.95 mmol/L) were randomized to
      parathyroidectomy either directly (group A) or after 1 year of observation (group
      B). Equilibrium radionuclide angiography (ERNA) at rest and at exercise was
      performed in addition to echocardiography on all patients at inclusion in the
      study and 1 and 2 years later. RESULTS: Left ventricular mass index was larger (P
      <.05) in group B compared with group A after 2 years and showed significant
      correlation to the serum concentration of parathyroid hormone (but not serum
      calcium) after 1 year. ERNA showed transient subclinical changes in both systolic
      and diastolic function parameters after parathyroidectomy (decrease of left
      ventricular ejection fraction and peak filling rate, with return to preoperative
      levels within 1 year). CONCLUSIONS: Combined evaluation by ERNA and
      echocardiography has shown previously unknown aspects of parathyroid/myocardial
      interaction, which is consistent with an inotropic influence exerted by
      parathyroid hormone, and is in favor of early surgical treatment for PHPT
      irrespective of serum calcium levels.

PMID- 12490867
TI  - A matter of Class: interpreting subdivision in a malocclusion.
AB  - Confusion exists in the orthodontic community regarding the meaning of
      subdivision in Angle's classification system. The purpose of this study was to
      survey orthodontic educators in the United States to determine their viewpoint on
      the meaning of subdivision and to ascertain the criteria on which they base their
      interpretations. Fifty-seven surveys were mailed to department chairs in the
      United States, asking them to identify the definition to which their orthodontic
      residency program subscribes; 34 surveys were returned. Twenty-two responses
      supported the notion that subdivision refers to the Class II side, 8 responses
      said that it refers to the Class I side, 3 responses supported neither view, and
      1 response indicated that not everyone in the program could agree on the meaning
      of subdivision. Although the prevailing belief appears to be that subdivision
      indicates the side with a molar malocclusion, the orthodontic community does not
      have a consistent standard, and it is time to resolve this controversy.

PMID- 12490868
TI  - Nonprosthodontic management of alveolar clefts with 2 incisors missing on the
      cleft side: a report of 5 patients.
AB  - A treatment combining autotransplantation of developing premolars and orthodontic
      space closure is described as an alternative to prosthodontics in the management
      of patients with alveolar clefts when 2 cleft-side incisors are missing. We
      report on 5 consecutive patients with unilateral clefts in whom 2 cleft-side
      incisors were congenitally missing, severely malformed, ectopically erupting, or
      lost because of trauma. In each instance, a mandibular premolar with a partly
      developed root was transplanted to the central incisor region (3 patients had
      previously undergone alveolar bone grafting). Root growth continued in all
      transplants. After an observation period of 2 years 6 months to 7 years 8 months,
      all transplanted teeth were present and fulfilled the established success
      criteria. The physiologic status of the transplanted premolars compared favorably
      with that of the central incisor on the noncleft side. The appearance of the
      reshaped transplants was found to match the noncleft incisor in 3 patients and
      deviated somewhat in 2. We concluded that an acceptable clinical outcome can be
      obtained by tooth transplantation combined with orthodontic space closure in
      patients with alveolar clefts and 2 missing cleft-side incisors.

PMID- 12490869
TI  - Closing anterior open bites by intruding molars with titanium miniplate
      anchorage.
AB  - The intent of this study was threefold: (1) to validate true intrusion of molars
      in adults, (2) to test the stability of miniplates as anchorage for intruding
      posterior teeth in the maxilla, and (3) to record the skeletal and dental changes
      of open-bite closure. Four adult patients who had anterior open-bite
      malocclusions were selected to undergo posterior intrusion with miniplate
      anchorage to close the open bite; all had true intrusion of the maxillary molars.
      Mean molar intrusion was 1.99 mm (range, 1.45-3.32 mm). No movement of miniplates
      occurred at any time during their use or before intentional clinical removal.
      Open-bite closure was achieved for all 4 patients. Mean closure of incisors was
      3.62 mm (range, 3.0-4.5 mm) as the mandibular plane closed 2.62 degrees (range,
      1.5 degrees -4.5 degrees ), and the occlusal plane decreased 2.25 degrees (range,
      1.0 degrees -3.5 degrees ). Anterior facial heights decreased as the mandible
      closed and B-point rotated anteriorly and upward.

PMID- 12490870
TI  - Prediction of arch perimeter changes due to orthodontic treatment.
AB  - A borderline orthodontic case with mild to moderate space deficiency can be
      treated without extractions. Expansion can be used to relieve space deficiency.
      The prediction of arch perimeter change for a given amount of expansion is
      helpful in planning the treatment of a patient who needs expansion, and it can
      facilitate nonextraction orthodontic treatment. To date, different amounts of
      arch perimeter change have been proposed for the same amount of expansion. A
      computer program is explained in this study, and examples of its uses are given.
      By entering 4 parameters of a dental arch into the computer program before and
      after an orthodontic procedure, one can simply calculate the total and the
      anterior arch perimeters and see the differences between them numerically and
      graphically. The program can save, print, change, and delete the calculated data
      for each patient. For clinicians who do not choose to use the computer program, 2
      regression formulas are also presented to calculate the anterior and the total
      dental arch perimeters. The perimeters of 23 pairs of well-aligned dental arches
      were measured to check the accuracy of the computer program and the formulas.
      Paired t tests did not show statistically significant differences between the
      actual, the computer-derived, and the formula-derived perimeters of the dental
      arches at 95% confidence level.

PMID- 12490871
TI  - Dental arch width in Class II Division 2 deep-bite malocclusion.
AB  - A severe phenotype of Angle's Class II Division 2 (II/2) malocclusion with
      extremely deep overbite has been called cover-bite, or "Deckbiss" in its early
      German descriptions. This distinctive occlusal variation is characterized by
      skeletofacial hypodivergence, mandibular dentoalveolar retrusion, excessive bony
      chin projection, reduced mesiodistal tooth size, maxillary incisor
      retroclination, and at least 100% overbite, covering at least 1 mandibular
      incisor in occlusion. In this study, maxillary and mandibular dental arch widths
      measured at the first molars and the canines were recorded from dental casts of
      23 subjects with II/2 cover-bite malocclusions. The data were compared with a
      control-reference sample of 46 orthodontic patients matched for age and gender.
      In the cover-bite group, the intermolar widths in both arches and the intercanine
      width in the maxilla were comparable with those in the control sample. However,
      mandibular intercanine width in the II/2 cover-bite group was significantly less
      than that of the controls (P =.01). These findings suggest that II/2 deep
      overbite malocclusion is characterized by normalized and relatively compatible
      transverse dimensions in the maxilla and in the mandibular posterior segments.
      The transverse underdevelopment that this study identified in the mandible from
      canine to canine is probably responsible for mandibular incisor compression and
      crowding--natural sequelae of the deep overbite in II/2 cover-bite. Thus, a
      reasonable orthodontic treatment plan for the mandibular dentoalveolar
      compensation often seen in II/2 deep-bite patients would be anterior expansion of
      the mandibular arch width, usually reducing the need for orthodontic tooth
      extractions and increasing the desirability of fixed retention.

PMID- 12490872
TI  - Tooth wear patterns in the deciduous dentition.
AB  - Tooth wear is common in the deciduous dentition. A recent study suggests that
      tooth wear in the deciduous dentition is related to subsequent tooth wear in
      adults, so that early identification of factors related to tooth wear could be of
      long-term benefit. The purposes of this study were to describe patterns of tooth
      wear in the deciduous dentition and to relate tooth wear to occlusal
      characteristics and longitudinal dietary patterns. Data were collected as part of
      a longitudinal study of a cohort of children recruited at birth from Iowa
      hospitals. Stone casts were obtained in the deciduous dentition stage, and 355
      children, 4 to 5 years old, met the selection criteria. Tooth wear was
      categorized for each tooth as none, mild, moderate, or severe, and related to
      occlusal characteristics and longitudinal data on fruit juice and soft drink
      consumption. All children exhibited some tooth wear on at least 1 tooth, and
      nearly 16% of them had at least 1 tooth with severe wear. Tooth wear was
      generally more severe in the maxillary arch and the anterior teeth. Severe tooth
      wear on the molars was significantly related to posterior crossbites, but severe
      tooth wear on the incisors was related to Class III canine relationships. There
      were no statistically significant relationships between tooth wear and soft drink
      or fruit juice consumption. Based on our results, we concluded that mild tooth
      wear is universal in the deciduous dentition, but only a few occlusal factors are
      related to severe tooth wear. Tooth wear was not related to any dietary patterns
      we investigated.

PMID- 12490873
TI  - Craniofacial growth in untreated skeletal Class II subjects: a longitudinal
      study.
AB  - Eighty-five (45 male and 40 female) skeletal Class II untreated subjects with low
      (< 27 degrees ), average (27 degrees - 36 degrees ), and high (> 36 degrees )
      mandibular plane angles (MP-SN) were selected from the Bolton-Brush and the
      Burlington Growth Studies. Cephalograms of each subject at ages 9 and 18 were
      traced, and 28 parameters were measured. The difference in each parameter from
      ages 9 to 18 was calculated, and comparisons were made between the groups with
      low, average, and high angles. Results showed that for children at age 9, the
      high-angle group showed greater convexity, larger Y-axis and gonial angles, and
      greater anterior facial height, and the low-angle group had larger SNA and SNB
      angles, and greater posterior cranial base, mandibular body, ramus height, and
      posterior facial height. From ages 9 to 18, all the low-, average-, and high
      angle groups showed a decrease of convexity (more flattened face) and a
      mandibular forward rotation (decreased MP-SN). The low-angle group displayed
      significantly more facial flattening and more mandibular forward rotation than
      did the high-angle group. Moreover, the mandibular incisors became more
      retroclined in the low-angle group and more proclined in the high-angle group
      with age. Comparisons between males and females showed similar skeletal growth
      patterns in angular measurements. However, a significant sex difference was noted
      in some linear measurements.

PMID- 12490874
TI  - Predicting lower lip and chin response to mandibular advancement and genioplasty.
AB  - The purposes of this retrospective study were to examine the multidimensional
      nature of soft tissue changes associated with mandibular advancement and
      genioplasty and to develop predictive models. Longitudinal lateral cephalograms
      of 62 nongrowing patients (27 men and 35 women) were taken in centric relation
      with the lips in repose within 4 weeks before surgery and at least 6 months
      postoperatively (median postsurgical duration was 11 months). The mandibular
      incisor and pogonion were advanced surgically approximately 6 mm and 11 mm,
      respectively. The lower lip lengthened slightly (2.5 +/- 3.8 mm), and its surface
      contour straightened because of thinning at labrale inferior (-2.8 +/- 2.0 mm);
      there was a slight thickening at the labiomental fold (1.0 +/- 2.3 mm) and a
      slight thinning at soft tissue pogonion (-0.8 +/- 2.2 mm). Multiple regression
      models (explaining from 80% to 94% and 66% to 82% of the variation for horizontal
      and vertical movements, respectively) showed that soft tissue response to
      advancement surgery depended on pretreatment tissue thickness, horizontal
      skeletal movement, vertical skeletal movement, and the position of the maxillary
      incisors. Similar amounts of variation were explained when the models were
      applied to an independent validation sample of 15 subjects. It was concluded that
      lower lip and chin response to mandibular advancement and genioplasty is
      multifactorial but can be accurately and reliably predicted.

PMID- 12490875
TI  - Landmark identification on direct digital versus film-based cephalometric
      radiographs: a human skull study.
AB  - The purpose of this study was to investigate differences in landmark
      identification on vertically scanned, direct digital and conventional (18 x 24
      cm) cephalometric radiographs. Eight observers, all orthodontists or postgraduate
      orthodontic students, recorded 6 landmarks twice on 3 digital and 3 conventional
      cephalograms obtained from 3 human skulls in a standardized fashion. Digital
      images were displayed on a 15.1-in TFT monitor in 3:1 mode (20 x 26 cm).
      Recordings were transferred into standardized coordinate systems and evaluated
      separately for each coordinate. After correcting for magnification, precision was
      assessed with Maloney-Rastogi tests, and intraobserver and interobserver
      reproducibility was calculated from squared differences. Effective magnification
      was larger for the digital images (x, 13%; y, 12%). Significantly different (P
      <.05) precision was found for nasion (N), posterior nasal spine (PNS), sella (S),
      supraspinale (A), and orbitale (Or), but average differences were entirely below
      1 mm. Interobserver and intraobserver reproducibility did not differ
      significantly between the 2 image modes. Squared differences were largest for PNS
      and Or in both modalities. Our results indicate comparable errors in landmark
      recording for both evaluated machines. However, these results must be considered
      in the context of the specific display conditions for digital images, because no
      general standard exists for this purpose.

PMID- 12490876
TI  - Plasma arc curing lights for orthodontic bonding.
AB  - Xenon plasma arc lights were introduced recently for light-cured orthodontic
      bonding. Compared with a conventional tungsten-quartz-halogen light source, these
      high-intensity lights promise a dramatic reduction in curing time. The purpose of
      this in vitro investigation was to evaluate bond strength with 2 commercially
      available plasma arc lights and reduced curing intervals. Brackets were bonded to
      150 extracted human teeth (75 premolars, 75 incisors) with a composite adhesive.
      Intervals of 2 and 6 seconds were used for curing with the plasma arc lights; a
      control group was bonded with a halogen light source and 20 seconds of light
      exposure per bracket. Bond strength testing was performed with a universal
      testing machine. A substantial reduction in curing time was possible with both
      plasma arc units. Significantly lower bond strength values were found for
      premolar brackets bonded with plasma arc curing lights and the shortest curing
      interval of 2 seconds compared with the longer curing time of 6 seconds or the
      standard curing time with the halogen light. Although 2 seconds of curing might
      be adequate to achieve acceptable bond strength values for the incisors, the
      Weibull analysis indicated a higher probability of bond failure for premolar
      brackets in particular. Six seconds of curing time is recommended for bonding
      stainless steel brackets with xenon plasma arc light sources.

PMID- 12490877
TI  - Laser etching of enamel for direct bonding with an Er,Cr:YSGG hydrokinetic laser
      system.
AB  - Irradiation of enamel with laser energy changes the physical and chemical
      characteristics of the enamel surface, and these alterations hold promise for the
      conditioning of enamel for bonding procedures. This laboratory study examined the
      influence of laser irradiation of enamel at 2 different power settings with an
      erbium, chromium: yttrium, scandium, gallium, garnet (Er,Cr:YSGG) hydrokinetic
      laser system (Millennium System, Biolase Technology, Inc; San Clemente, Calif) on
      the shear bond strength of orthodontic appliances and compared these with that of
      acid-etching. The prepared surfaces of 40 noncarious, intact, extracted premolars
      were exposed to laser energy: 20 teeth at 2-W setting (5.6 J/cm(2)) and 20 teeth
      at 1-W setting (2.7 J/cm(2)) of the commercial laser unit. Twenty teeth were
      etched with 37% orthophosphoric acid. Brackets were bonded with an orthodontic no
      mix adhesive, and shear bond strength was determined with a universal testing
      machine. Data were analyzed with Kruskal-Wallis and Mann-Whitney U tests. Etched
      and restored surfaces of an acid-etched tooth and a 2-W laser-irradiated tooth
      were examined with scanning electron microscopy (SEM). Laser treatment under 2 W
      resulted in bond strengths of 7.11 +/- 4.56 megapascals (MPa), which was not
      significantly different from that of acid etching (8.23 +/- 2.30 MPa). Laser
      irradiation at 1 W resulted in bond strengths of 5.64 +/- 3.19 MPa, which was
      significantly different from that of acid etching (P <.05). However, large SD and
      coefficient of variation values of both laser groups made reliability of this
      method as an enamel conditioner questionable. Scanning electron microscopy
      studies of the restored irradiated surfaces showed good surface characteristics,
      whereas the lased surface was still more irregular than the restored acid-etched
      sample. Although laser devices are effectively used in some other areas of
      dentistry, enamel conditioning with an Er,Cr:YSGG laser cannot be considered a
      successful alternative to the conventional methods of increasing bond strengths
      to enamel.

PMID- 12490878
TI  - Concomitant occurrence of canine malposition and tooth agenesis: evidence of
      orofacial genetic fields.
AB  - Certain discrete malpositions of the human canine tooth and agenesis of at least
      1 tooth (hypodontia) are abnormalities known to occur together frequently. This
      study examines the specificity of tooth-agenesis sites associated with the
      occurrence of 3 unambiguous canine malpositions: palatally displaced canine (PDC;
      n = 58), mandibular lateral incisor-canine transposition (Mn.I2.C; n = 60), and
      maxillary canine-first premolar transposition (Mx.C.P1; n = 43). A fourth sample
      was formed from 4 cases of combined occurrence of PDC and Mn.I2.C, the only
      combination-phenotype noted among the 161 subjects. Oral panoramic radiographs
      were used to identify agenesis of at least 1 third molar (M3), mandibular second
      premolar (MnP2), and maxillary lateral incisor (MxI2)-the 3 most frequently
      absent tooth types among people of European descent. PDC and Mn.I2.C
      transposition appear to be associated with significantly increased M3 agenesis (P
      <.01), representing the posterior orofacial field, and Mx.C.P1 transposition
      appears to be associated with conspicuously elevated MxI2 agenesis (P <.001),
      representing the anterior orofacial field. MnP2 agenesis appears to represent an
      intermediate field, found in significantly elevated frequencies with all 3 canine
      positional anomalies. Coupling these new clinical findings with results from
      recent molecular studies, we suggest that transcription factors such as MSX1 and
      PAX9, which have been associated with agenesis of molars, might be involved in
      the genetic control of Mn.I2.C transposition and PDC, tooth malpositions
      connected here with the specific expression of posterior-field (M3) hypodontia.

PMID- 12490879
TI  - Treatment of a patient with a crowded Class I malocclusion and a congenitally
      missing mandibular incisor.
AB  - This case report describes the management of maxillary and mandibular crowding in
      a patient with facial esthetic concerns and a tooth-size discrepancy due to a
      missing mandibular central incisor. The treatment included extracting the
      remaining mandibular central incisor and the 2 maxillary first premolars. The
      mandibular canines were repositioned to substitute for lateral incisors, and the
      mandibular premolars were used as canines.

PMID- 12490880
TI  - New features of PowerPoint 2002.

PMID- 12490882
TI  - 1953 and all that.

PMID- 12490881
TI  - Litigation, legislation, and ethics: malicious prosecution suit upheld.

PMID- 12490883
TI  - Moving across membranes.
AB  - Protein toxins are known to translocate through intracellular membranes to reach
      their cytosolic targets. Results from studies with botulinum neurotoxin suggest
      that the toxin heavy chain functions as both a channel and a chaperone for
      translocation of the catalytically active light chain.

PMID- 12490884
TI  - First bite.
AB  - Dipeptidyl peptidase IV contributes to the regulation of many physiological
      processes, most notably blood sugar homeostasis, by biting a dipeptide off the N
      terminus of specific peptides. A structure of this peptidase in complex with an
      inhibitor will assist efforts to regulate this regulator.

PMID- 12490885
TI  - Getting to the heart of a splicing enhancer.
AB  - Dinucleotide CA repeats of variable length in an intron of the human endothelial
      nitric oxide synthase gene act as regulatory signals for splicing of the gene's
      pre-mRNA. Repeat length-dependent binding of hnRNP L to the repeats provides an
      intriguing link between splicing efficiency, nitric oxide synthesis and
      cardiovascular disease.

PMID- 12490886
TI  - The hitchhiker's guide to the nucleus.
AB  - The hormone-related protein PTHrP travels from the cytosol to the nucleus by
      binding to the transport factor importin . Remarkably, the site of recognition of
      PTHrP is the N-terminal half of importin , which also has Ran-binding and
      nucleoporin-binding capabilities and is, therefore, sufficient by itself to
      function in PTHrP nuclear import.

PMID- 12490887
TI  - Co-transcriptional monitoring of mRNP formation.
AB  - In eukaryotes, newly manufactured mRNA is subject to strict quality control. If
      certain standards are not met, offending messages are retained in the nucleus and
      degraded by the exosome complex. New data suggest that exosome-mediated processes
      are intimately coupled to the transcription machinery, which makes the mRNA in
      the first place.

PMID- 12490888
TI  - From an armadillo to electricity.

PMID- 12490892
TI  - Managing CERN's industries.

PMID- 12490891
TI  - Trust and how to sustain it.

PMID- 12490893
TI  - Stanford announces private plan to get stem-cell research moving.

PMID- 12490894
TI  - CERN collider project back on track.

PMID- 12490895
TI  - Ocean tests raise doubts over use of algae as carbon sink.

PMID- 12490897
TI  - ESA weighs up future after Ariane explosion.

PMID- 12490896
TI  - Mass resignation forces Italian rethink on university funds.

PMID- 12490898
TI  - Australian bushfire centre rises from the flames.

PMID- 12490899
TI  - Neutrino projects are poles apart, says panel.

PMID- 12490900
TI  - Corporate chiefs told to follow animal urges.

PMID- 12490902
TI  - Misconduct: the stars who fell to earth.

PMID- 12490903
TI  - Genomics: sorry, dogs - man's got a new best friend.

PMID- 12490905
TI  - Cosmology: it all adds up.

PMID- 12490904
TI  - Agribiotech: more heat than light.

PMID- 12490906
TI  - Antihydrogen: holding up a mirror to physics' world view.

PMID- 12490907
TI  - Small RNAs: the genome's guiding hand?

PMID- 12490908
TI  - Sustainable development: now we're talking.

PMID- 12490909
TI  - Stem cells: articles of faith adulterated.

PMID- 12490910
TI  - Gene therapy: shining hopes dented - but not dashed.

PMID- 12490911
TI  - Palaeoanthropology: face to face with our past.

PMID- 12490912
TI  - Biodefence: ploughshares into swords.

PMID- 12490913
TI  - Attosecond science: the fast show.

PMID- 12490914
TI  - Neutrino physics: tanked up and ready for action.

PMID- 12490915
TI  - Biometrics was no match for hair-raising tricks.

PMID- 12490916
TI  - Scientific misconduct: the state's role has limits.

PMID- 12490917
TI  - Scientific misconduct: ORI survey is flawed.

PMID- 12490918
TI  - Sounding the alarm on underwater noise.

PMID- 12490919
TI  - Why astronomy is the star of the news show.

PMID- 12490924
TI  - Science in culture: naturally natural. Albrecht Durer's studies of animals have a
      life of their own.

PMID- 12490925
TI  - Multicellularity: evolution and the egg.

PMID- 12490926
TI  - Background comes to the fore.

PMID- 12490927
TI  - Immunology: remembrance of things past.

PMID- 12490928
TI  - Dense ice in detail.

PMID- 12490930
TI  - A light-emitting sandwich filling.

PMID- 12490929
TI  - How hardwired is the brain?

PMID- 12490931
TI  - Plant science: on the slide.

PMID- 12490932
TI  - Genomics: return of a little squirt.

PMID- 12490934
TI  - Computation biology: evolution plays dice.

PMID- 12490935
TI  - Rene Thom (1923-2002).

PMID- 12490936
TI  - Organic chemistry: a digital fluorescent molecular photoswitch.

PMID- 12490937
TI  - Palaeontology: first Devonian tetrapod from Asia.

PMID- 12490938
TI  - Nanotechnology: carbon nanotubes with DNA recognition.

PMID- 12490939
TI  - Secure communication: quantum cryptography with a photon turnstile.

PMID- 12490940
TI  - Measurement of polarization with the Degree Angular Scale Interferometer.
AB  - Measurements of the cosmic microwave background (CMB) radiation can reveal with
      remarkable precision the conditions of the Universe when it was approximately
      400,000 years old. The three most fundamental properties of the CMB are its
      frequency spectrum (which determines the temperature), and the fluctuations in
      both the temperature and polarization across a range of angular scales. The
      frequency spectrum has been well determined, and considerable progress has been
      made in measuring the power spectrum of the temperature fluctuations. But despite
      many efforts to measure the polarization, detection of this property of the CMB
      has hitherto been beyond the reach of even the most sensitive observations. Here
      we describe the Degree Angular Scale Interferometer (DASI), an array of radio
      telescopes, which for the past two years has conducted polarization-sensitive
      observations of the CMB from the Amundsen-Scott South Pole research station.

PMID- 12490941
TI  - Detection of polarization in the cosmic microwave background using DASI. Degree
      Angular Scale Interferometer.
AB  - The past several years have seen the emergence of a standard cosmological model,
      in which small temperature differences in the cosmic microwave background (CMB)
      radiation on angular scales of the order of a degree are understood to arise from
      acoustic oscillations in the hot plasma of the early Universe, arising from
      primordial density fluctuations. Within the context of this model, recent
      measurements of the temperature fluctuations have led to profound conclusions
      about the origin, evolution and composition of the Universe. Using the measured
      temperature fluctuations, the theoretical framework predicts the level of
      polarization of the CMB with essentially no free parameters. Therefore, a
      measurement of the polarization is a critical test of the theory and thus of the
      validity of the cosmological parameters derived from the CMB measurements. Here
      we report the detection of polarization of the CMB with the Degree Angular Scale
      Interferometer (DASI). The polarization is deteced with high confidence, and its
      level and spatial distribution are in excellent agreement with the predictions of
      the standard theory.

PMID- 12490943
TI  - Direct detection of variable tropospheric clouds near Titan's south pole.
AB  - Atmospheric conditions on Saturn's largest satellite, Titan, allow the
      possibility that it could possess a methane condensation and precipitation cycle
      with many similarities to Earth's hydrological cycle. Detailed imaging studies of
      Titan have hitherto shown no direct evidence for tropospheric condensation
      clouds, although there has been indirect spectroscopic evidence for transient
      clouds. Here we report images and spectra of Titan that show clearly transient
      clouds, concentrated near the south pole, which is currently near the point of
      maximum solar heating. The discovery of these clouds demonstrates the existence
      of condensation and localized moist convection in Titan's atmosphere. Their
      location suggests that methane cloud formation is controlled seasonally by small
      variations in surface temperature, and that the clouds will move from the south
      to the north pole on a 15-year timescale.

PMID- 12490942
TI  - Long-term in vivo imaging of experience-dependent synaptic plasticity in adult
      cortex.
AB  - Do new synapses form in the adult cortex to support experience-dependent
      plasticity? To address this question, we repeatedly imaged individual pyramidal
      neurons in the mouse barrel cortex over periods of weeks. We found that, although
      dendritic structure is stable, some spines appear and disappear. Spine lifetimes
      vary greatly: stable spines, about 50% of the population, persist for at least a
      month, whereas the remainder are present for a few days or less. Serial-section
      electron microscopy of imaged dendritic segments revealed retrospectively that
      spine sprouting and retraction are associated with synapse formation and
      elimination. Experience-dependent plasticity of cortical receptive fields was
      accompanied by increased synapse turnover. Our measurements suggest that sensory
      experience drives the formation and elimination of synapses and that these
      changes might underlie adaptive remodelling of neural circuits.

PMID- 12490944
TI  - Charge-ordered ferromagnetic phase in La(0.5)Ca(0.5)MnO3.
AB  - Mixed-valent manganites are noted for their unusual magnetic, electronic and
      structural phase transitions. For example, the La(1-x)Ca(x)MnO(3) phase diagram
      shows that below transition temperatures in the range 100-260 K, compounds with
      0.2 < x < 0.5 are ferromagnetic and metallic, whereas those with 0.5 < x < 0.9
      are antiferromagnetic and charge ordered. In a narrow region around x = 0.5,
      these totally dissimilar ground states are thought to coexist. It has been shown
      that charge order and charge disorder can coexist in the related compound,
      La(0.25)Pr(0.375)Ca(0.375)MnO(3). Here we present electron microscopy data for
      La(0.5)Ca(0.5)MnO(3) that shed light on the distribution of these coexisting
      phases, and uncover an additional, unexpected phase. Using electron holography
      and Fresnel imaging, we find micrometre-sized ferromagnetic regions spanning
      several grains coexisting with similar-sized regions with no local magnetization.
      Holography shows that the ferromagnetic regions have a local magnetization of 3.4
      +/- 0.2 Bohr magnetons per Mn atom (the spin-aligned value is 3.5 micro (B) per
      Mn). We use electron diffraction and dark-field imaging to show that charge order
      exists in regions with no net magnetization and, surprisingly, can also occur in
      ferromagnetic regions.

PMID- 12490945
TI  - Electroluminescence from single monolayers of nanocrystals in molecular organic
      devices.
AB  - The integration of organic and inorganic materials at the nanometre scale into
      hybrid optoelectronic structures enables active devices that combine the
      diversity of organic materials with the high-performance electronic and optical
      properties of inorganic nanocrystals. The optimization of such hybrid devices
      ultimately depends upon the precise positioning of the functionally distinct
      materials. Previous studies have already emphasized that this is a challenge,
      owing to the lack of well-developed nanometre-scale fabrication techniques. Here
      we demonstrate a hybrid light-emitting diode (LED) that combines the ease of
      processability of organic materials with the narrow-band, efficient luminescence
      of colloidal quantum dots (QDs). To isolate the luminescence processes from
      charge conduction, we fabricate a quantum-dot LED (QD-LED) that contains only a
      single monolayer of QDs, sandwiched between two organic thin films. This is
      achieved by a method that uses material phase segregation between the QD
      aliphatic capping groups and the aromatic organic materials. In our devices,
      where QDs function exclusively as lumophores, we observe a 25-fold improvement in
      luminescence efficiency (1.6 cd A(-1) at 2,000 cd m(-2)) over the best previous
      QD-LED results. The reproducibility and precision of our phase-segregation
      approach suggests that this technique could be widely applicable to the
      fabrication of other hybrid organic/inorganic devices.

PMID- 12490946
TI  - Metastable garnet in oceanic crust at the top of the lower mantle.
AB  - As oceanic tectonic plates descend into the Earth's lower mantle, garnet (in the
      basaltic crust) and silicate spinel (in the underlying peridotite layer) each
      decompose to form silicate perovskite-the 'post-garnet' and 'post-spinel'
      transformations, respectively. Recent phase equilibrium studies have shown that
      the post-garnet transformation occurs in the shallow lower mantle in a cold slab,
      rather than at approximately 800 km depth as earlier studies indicated, with the
      implication that the subducted basaltic crust is unlikely to become buoyant
      enough to delaminate as it enters the lower mantle. But here we report results of
      a kinetic study of the post-garnet transformation, obtained from in situ X-ray
      observations using sintered diamond anvils, which show that the kinetics of the
      post-garnet transformation are significantly slower than for the post-spinel
      transformation. Although metastable spinel quickly breaks down at a temperature
      of 1,000 K, we estimate that metastable garnet should survive of the order of 10
      Myr even at 1,600 K. Accordingly, the expectation of where the subducted oceanic
      crust would be buoyant spans a much wider depth range at the top of the lower
      mantle, when transformation kinetics are taken into account.

PMID- 12490947
TI  - SAR11 clade dominates ocean surface bacterioplankton communities.
AB  - The most abundant class of bacterial ribosomal RNA genes detected in seawater DNA
      by gene cloning belongs to SAR11-an alpha-proteobacterial clade. Other than
      indications of their prevalence in seawater, little is known about these
      organisms. Here we report quantitative measurements of the cellular abundance of
      the SAR11 clade in northwestern Sargasso Sea waters to 3,000 m and in Oregon
      coastal surface waters. On average, the SAR11 clade accounts for a third of the
      cells present in surface waters and nearly a fifth of the cells present in the
      mesopelagic zone. In some regions, members of the SAR11 clade represent as much
      as 50% of the total surface microbial community and 25% of the subeuphotic
      microbial community. By extrapolation, we estimate that globally there are 2.4 x
      10(28) SAR11 cells in the oceans, half of which are located in the euphotic zone.
      Although the biogeochemical role of the SAR11 clade remains uncertain, these data
      support the conclusion that this microbial group is among the most successful
      organisms on Earth.

PMID- 12490948
TI  - Macroevolution simulated with autonomously replicating computer programs.
AB  - The process of adaptation occurs on two timescales. In the short term, natural
      selection merely sorts the variation already present in a population, whereas in
      the longer term genotypes quite different from any that were initially present
      evolve through the cumulation of new mutations. The first process is described by
      the mathematical theory of population genetics. However, this theory begins by
      defining a fixed set of genotypes and cannot provide a satisfactory analysis of
      the second process because it does not permit any genuinely new type to arise.
      The evolutionary outcome of selection acting on novel variation arising over long
      periods is therefore difficult to predict. The classical problem of this kind is
      whether 'replaying the tape of life' would invariably lead to the familiar
      organisms of the modern biota. Here we study the long-term behaviour of
      populations of autonomously replicating computer programs and find that the same
      type, introduced into the same simple environment, evolves on any given occasion
      along a unique trajectory towards one of many well-adapted end points.

PMID- 12490949
TI  - Long-term dendritic spine stability in the adult cortex.
AB  - The structural dynamics of synapses probably has a crucial role in the
      development and plasticity of the nervous system. In the mammalian brain, the
      vast majority of excitatory axo-dendritic synapses occur on dendritic
      specializations called 'spines'. However, little is known about their long-term
      changes in the intact developing or adult animal. To address this question we
      developed a transcranial two-photon imaging technique to follow identified spines
      of layer-5 pyramidal neurons in the primary visual cortex of living transgenic
      mice expressing yellow fluorescent protein. Here we show that filopodia-like
      dendritic protrusions, extending and retracting over hours, are abundant in young
      animals but virtually absent from the adult. In young mice, within the 'critical
      period' for visual cortex development, approximately 73% of spines remain stable
      over a one-month interval; most changes are associated with spine elimination. In
      contrast, in adult mice, the overwhelming majority of spines (approximately 96%)
      remain stable over the same interval with a half-life greater than 13 months.
      These results indicate that spines, initially plastic during development, become
      remarkably stable in the adult, providing a potential structural basis for long
      term information storage.

PMID- 12490950
TI  - Glucose transporter recycling in response to insulin is facilitated by myosin
      Myo1c.
AB  - Insulin stimulates glucose uptake in muscle and adipocytes by signalling the
      translocation of GLUT4 glucose transporters from intracellular membranes to the
      cell surface. The translocation of GLUT4 may involve signalling pathways that are
      both independent of and dependent on phosphatidylinositol-3-OH kinase (PI(3)K).
      This translocation also requires the actin cytoskeleton, and the rapid movement
      of GLUT4 along linear tracks may be mediated by molecular motors. Here we report
      that the unconventional myosin Myo1c is present in GLUT4-containing vesicles
      purified from 3T3-L1 adipocytes. Myo1c, which contains a motor domain, three IQ
      motifs and a carboxy-terminal cargo domain, is highly expressed in primary and
      cultured adipocytes. Insulin enhances the localization of Myo1c with GLUT4 in
      cortical tubulovesicular structures associated with actin filaments, and this
      colocalization is insensitive to wortmannin. Insulin-stimulated translocation of
      GLUT4 to the adipocyte plasma membrane is augmented by the expression of wild
      type Myo1c and inhibited by a dominant-negative cargo domain of Myo1c. A decrease
      in the expression of endogenous Myo1c mediated by small interfering RNAs inhibits
      insulin-stimulated uptake of 2-deoxyglucose. Thus, myosin Myo1c functions in a
      PI(3)K-independent insulin signalling pathway that controls the movement of
      intracellular GLUT4-containing vesicles to the plasma membrane.

PMID- 12490951
TI  - Helper T cells regulate type-2 innate immunity in vivo.
AB  - Type-2 immunity requires orchestration of innate and adaptive immune responses to
      protect mucosal sites from pathogens. Dysregulated type-2 responses result in
      allergy or asthma. T helper 2 (T(H)2) cells elaborate cytokines, such as
      interleukin (IL)-4, IL-5, IL-9 and IL-13, which work with toxic mediators of
      innate immune cells to establish environments that are inhospitable to helminth
      or arthropod invaders. The importance of T(H)2 cells in coordinating innate
      immune cells at sites of inflammation is not known. Here we show that polarized
      type-2 immune responses are initiated independently of adaptive immunity. In the
      absence of B and T cells, IL-4-expressing eosinophils were recruited to tissues
      of mice infected with the helminth Nippostrongylus brasiliensis, but eosinophils
      failed to degranulate. Reconstitution with CD4 T cells promoted accumulation of
      degranulated IL-4-expressing cells, but only if T cells were stimulated with
      cognate antigen. Degranulation correlated with tissue destruction, which was
      attenuated if eosinophils were depleted. Helper T cells confer antigen
      specificity on eosinophil cytotoxicity, but not cytokine responses, so defining a
      novel mechanism that focuses tissue injury at sites of immune challenge.

PMID- 12490952
TI  - Chloroplast avoidance movement reduces photodamage in plants.
AB  - When plants are exposed to light levels higher than those required for
      photosynthesis, reactive oxygen species are generated in the chloroplasts and
      cause photodamage. This can occur even under natural growth conditions. To
      mitigate photodamage, plants have developed several protective mechanisms. One is
      chloroplast avoidance movement, in which chloroplasts move from the cell surface
      to the side walls of cells under high light conditions, although experimental
      support is still awaited. Here, using different classes of mutant defective in
      chloroplast avoidance movement, we show that these mutants are more susceptible
      to damage in high light than wild-type plants. Damage of the photosynthetic
      apparatus and subsequent bleaching of leaf colour and necrosis occur faster under
      high light conditions in the mutants than in wild-type plants. We conclude that
      chloroplast avoidance movement actually decreases the amount of light absorption
      by chloroplasts, and might therefore be important to the survival of plants under
      natural growth conditions.

PMID- 12490953
TI  - Role for a Drosophila Myb-containing protein complex in site-specific DNA
      replication.
AB  - There is considerable interest in the developmental, temporal and tissue-specific
      patterns of DNA replication in metazoans. Site-specific DNA replication at the
      chorion loci in Drosophila follicle cells leads to extensive gene amplification,
      and the organization of the cis-acting DNA elements that regulate this process
      may provide a model for how such regulation is achieved. Two elements important
      for amplification of the third chromosome chorion gene cluster, ACE3 and Ori
      beta, are directly bound by Orc (origin recognition complex), and two-dimensional
      gel analysis has revealed that the primary origin used is Ori-beta (refs 7-9).
      Here we show that the Drosophila homologue of the Myb (Myeloblastosis)
      oncoprotein family is tightly associated with four additional proteins, and that
      the complex binds site-specifically to these regulatory DNA elements. Drosophila
      Myb is required in trans for gene amplification, showing that a Myb protein is
      directly involved in DNA replication. A Drosophila Myb binding site, as well as
      the binding site for another Myb complex member (p120), is necessary in cis for
      replication of reporter transgenes. Chromatin immunoprecipitation experiments
      localize both proteins to the chorion loci in vivo. These data provide evidence
      that specific protein complexes bound to replication enhancer elements work
      together with the general replication machinery for site-specific origin
      utilization during replication.

PMID- 12490954
TI  - The RNA processing exosome is linked to elongating RNA polymerase II in
      Drosophila.
AB  - The RNA polymerase II elongation complex contains several factors that facilitate
      transcription elongation and catalyse the processing of precursor messenger RNAs
      (pre-mRNAs). The conserved elongation factor Spt6 is recruited rapidly and
      robustly to sites of active transcription. Here we show that Drosophila Spt6
      (dSpt6) co-purifies with the exosome, a complex of 3' to 5' exoribonucleases that
      is implicated in the processing of structural RNA and in the degradation of
      improperly processed pre-mRNA. Immunoprecipitation assays of Drosophila nuclear
      extracts show that the exosome also associates with the elongation factor dSpt5
      and RNA polymerase II. In vivo, exosome subunits colocalize with dSpt6 at
      transcriptionally active loci on polytene chromosomes during normal development
      and are strongly recruited to heat-shock loci on gene induction. At higher
      resolution, chromatin immunoprecipitation analysis shows that the exosome is
      recruited to transcriptionally active units of heat-shock genes. These data
      provide a physical basis for the hypothesis that exosome-mediated pre-mRNA
      surveillance accompanies transcription elongation.

PMID- 12490955
TI  - A ribozyme composed of only two different nucleotides.
AB  - RNA molecules are thought to have been prominent in the early history of life on
      Earth because of their ability both to encode genetic information and to exhibit
      catalytic function. The modern genetic alphabet relies on two sets of
      complementary base pairs to store genetic information. However, owing to the
      chemical instability of cytosine, which readily deaminates to uracil, a primitive
      genetic system composed of the bases A, U, G and C may have been difficult to
      establish. It has been suggested that the first genetic material instead
      contained only a single base-pairing unit. Here we show that binary informational
      macromolecules, containing only two different nucleotide subunits, can act as
      catalysts. In vitro evolution was used to obtain ligase ribozymes composed of
      only 2,6-diaminopurine and uracil nucleotides, which catalyse the template
      directed joining of two RNA molecules, one bearing a 5'-triphosphate and the
      other a 3'-hydroxyl. The active conformation of the fastest isolated ribozyme had
      a catalytic rate that was about 36,000-fold faster than the uncatalysed rate of
      reaction. This ribozyme is specific for the formation of biologically relevant
      3',5'-phosphodiester linkages.

PMID- 12490957
TI  - Points of control in inflammation.
AB  - Inflammation is a complex set of interactions among soluble factors and cells
      that can arise in any tissue in response to traumatic, infectious, post
      ischaemic, toxic or autoimmune injury. The process normally leads to recovery
      from infection and to healing, However, if targeted destruction and assisted
      repair are not properly phased, inflammation can lead to persistent tissue damage
      by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms
      of its checkpoints, where binary or higher-order signals drive each commitment to
      escalate, go signals trigger stop signals, and molecules responsible for
      mediating the inflammatory response also suppress it, depending on timing and
      context. The non-inflammatory state does not arise passively from an absence of
      inflammatory stimuli; rather, maintenance of health requires the positive actions
      of specific gene products to suppress reactions to potentially inflammatory
      stimuli that do not warrant a full response.

PMID- 12490958
TI  - The inflammatory reflex.
AB  - Inflammation is a local, protective response to microbial invasion or injury. It
      must be fine-tuned and regulated precisely, because deficiencies or excesses of
      the inflammatory response cause morbidity and shorten lifespan. The discovery
      that cholinergic neurons inhibit acute inflammation has qualitatively expanded
      our understanding of how the nervous system modulates immune responses. The
      nervous system reflexively regulates the inflammatory response in real time, just
      as it controls heart rate and other vital functions. The opportunity now exists
      to apply this insight to the treatment of inflammation through selective and
      reversible 'hard-wired' neural systems.

PMID- 12490960
TI  - Inflammation in atherosclerosis.
AB  - Abundant data link hypercholesterolaemia to atherogenesis. However, only recently
      have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma
      formation. Leukocyte recruitment and expression of pro-inflammatory cytokines
      characterize early atherogenesis, and malfunction of inflammatory mediators mutes
      atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a
      late and dreaded complication of atherosclerosis responsible for myocardial
      infarctions and most strokes. The new appreciation of the role of inflammation in
      atherosclerosis provides a mechanistic framework for understanding the clinical
      benefits of lipid-lowering therapies. Identifying the triggers for inflammation
      and unravelling the details of inflammatory pathways may eventually furnish new
      therapeutic targets.

PMID- 12490961
TI  - Mast cells in autoimmune disease.
AB  - Mast cells are known to be the primary responders in allergic reactions,
      orchestrating strong responses to minute amounts of allergens. Several recent
      observations indicate that they may also have a key role in coordinating the
      early phases of autoimmune diseases, particularly those involving auto
      antibodies.

PMID- 12490959
TI  - Inflammation and cancer.
AB  - Recent data have expanded the concept that inflammation is a critical component
      of tumour progression. Many cancers arise from sites of infection, chronic
      irritation and inflammation. It is now becoming clear that the tumour
      microenvironment, which is largely orchestrated by inflammatory cells, is an
      indispensable participant in the neoplastic process, fostering proliferation,
      survival and migration. In addition, tumour cells have co-opted some of the
      signalling molecules of the innate immune system, such as selectins, chemokines
      and their receptors for invasion, migration and metastasis. These insights are
      fostering new anti-inflammatory therapeutic approaches to cancer development.

PMID- 12490962
TI  - Inflammation and therapeutic vaccination in CNS diseases.
AB  - The spectrum of inflammatory diseases of the central nervous system has been
      steadily expanding from classical autoimmune disorders such as multiple sclerosis
      to far more diverse diseases. Evidence now suggests that syndromes such as
      Alzheimer's disease and stroke have important inflammatory and immune components
      and may be amenable to treatment by anti-inflammatory and immunotherapeutic
      approaches. The notion of 'vaccinating' individuals against a neurodegenerative
      disorder such as Alzheimer's disease is a marked departure from classical
      thinking about mechanism and treatment, and yet therapeutic vaccines for both
      Alzheimer's disease and multiple sclerosis have been validated in animal models
      and are in the clinic. Such approaches, however, have the potential to induce
      unwanted inflammatory responses as well as to provide benefit.

PMID- 12490963
TI  - The immunopathogenesis of sepsis.
AB  - Sepsis is a condition that results from a harmful or damaging host response to
      infection. Many of the components of the innate immune response that are normally
      concerned with host defences against infection can, under some circumstances,
      cause cell and tissue damage and hence multiple organ failure, the clinical
      hallmark of sepsis. Because of the high mortality of sepsis in the face of
      standard treatment, many efforts have been made to improve understanding of the
      dysregulation of the host response in sepsis. As a result, much has been learnt
      of the basic principles governing bacterial-host interactions, and new
      opportunities for therapeutic intervention have been revealed.

PMID- 12490964
TI  - Rate-dependence of antiarrhythmic drug action.

PMID- 12490965
TI  - Thiazolidinediones could improve endothelial dysfunction and risk of premature
      coronary heart disease in HIV-infected patients.
AB  - The use of Human Immunodeficiency Virus (HIV) protease inhibitors as part of the
      Highly Active Antiretroviral Therapy (HAART) is associated with atherogenic
      dyslipoproteinemia, insulin resistance, hypertension and endothelial dysfunction,
      all of which contribute to premature coronary heart disease. These abnormalities
      appear to be associated with an increase in cardiovascular events in HIV-infected
      patients. Beneficial metabolic effects of anti-diabetic agents used in HIV
      infected patients have been reported. The thiazolidinediones (TZDs), a new group
      of antidiabetic drugs, may modulate the proliferative and inflammatory cascades
      involved in atherosclerosis. Thus, an increasing totality of evidence suggests
      that TZDs may represent a unique and powerful research tool to find a common
      denominator underlying the pathophysiology and treatment of the metabolic
      cardiovascular risk factors associated with HIV infection.

PMID- 12490966
TI  - The effect of isoproterenol on the class III effect of azimilide in humans.
AB  - BACKGROUND: Many class III antiarrhythmic agents lose efficacy under beta
      adrenergic stimulation and at high heart rates (reverse rate dependence). This
      effect is thought to be due to selective blockade of the rapidly (I(Kr)), but not
      the slowly (I(Ks)), activating component of the delayed inward rectifier
      potassium current. Azimilide is an investigational class III antiarrhythmic agent
      that blocks both IKr and IKs. METHODS: We investigated the electrophysiologic
      effect of azimilide with and without beta-adrenergic stimulation in humans. Right
      ventricular effective refractory period at cycle lengths of 600 and 400
      milliseconds and monophasic right ventricular action potential duration at 90%
      repolarization at cycle lengths of 250, 300, 400, 500 and 600 milliseconds were
      measured in 13 patients at baseline. Isoproterenol was then infused to increase
      the heart rate to 125% of baseline, and the pacing protocol was repeated.
      Patients then received, in a single-blind randomized manner, azimilide
      dihydrochloride (4.5 mg/kg intravenous loading dose followed by 0.625 mg/kg/h)
      plus either isoproterenol at the previous dose, or saline. After measurements
      were taken, treatment groups were crossed over, the azimilide infusion was
      continued and the procedure repeated. RESULTS: Azimilide significantly (P < 0.05)
      prolonged monophasic action potential duration compared to baseline at all cycle
      lengths except for the 250 millisecond cycle length. In the presence of
      isoproterenol, azimilide maintained its class III effect, prolonging the action
      potential duration at 90% repolarization by a mean of 8.7 +/- 3.9 milliseconds,
      (3.7 +/- 1.7%), whereas isoproterenol alone shortened the action potential
      duration at 90% repolarization by -2.6 +/- 3.2 milliseconds (-1.2 +/- 1.4%) (P =
      0.0051). Isoproterenol alone shortened the right ventricular effective refractory
      period by -13.6 +/- 3.4 milliseconds, whereas with isoproterenol in the presence
      of azimilide, the right ventricular effective refractory period was essentially
      unaffected (-1.4 +/- 3.4 milliseconds, P = 0.0085). CONCLUSIONS: Azimilide
      maintained its class III effect in the presence of isoproterenol and at increased
      heart rates, suggesting that IKs block may be of particular benefit in these
      circumstances.

PMID- 12490967
TI  - Effect of ciprofibrate on lipoproteins, fibrinogen, renal function, and hepatic
      enzymes.
AB  - AIM: The action of ciprofibrate in hypertriglyceridemic patients is well
      established. Not only is ciprofibrate able to alter the lipid profile, but it can
      also change the values of fibrinogen, C-reactive protein, creatinine,
      transaminases, gamma-glutamyl transpeptidase and serum alkaline phosphatase.
      However, previous studies focused on the effect of ciprofibrate in
      hypertriglyceridemic patients, leaving unanswered the question of whether
      ciprofibrate exerts the same effect on hyperlipidemic patients with normal
      triglyceride values. The aim of this study is to answer this question. METHODS:
      In this randomized clinical trial, 64 men and women with elevated cholesterol or
      triglyceride levels were included. Two subgroups were formed according to
      triglyceride levels: one (36 patients) with elevated triglyceride levels (> 200
      mg/dL [2.26 mmol/L]) and another (28 patients) with normal triglyceride levels (<
      200 mg/dL [2.26 mmol/l]). After a 6-week period of step 1 diet according to the
      National Cholesterol Education Program, ciprofibrate (100 mg once daily) was
      administered for 16 weeks. Primary efficacy points were the changes of lipid
      parameters (total cholesterol, high density lipoprotein cholesterol, low density
      lipoprotein cholesterol, triglycerides, apoproteins A1, B, E and lipoprotein [a],
      high sensitivity C reactive protein, fibrinogen, glucose, insulin, aspartate
      transaminase, alanine transaminase, gamma-glutamyl transpeptidase, alkaline
      phosphatase, urea and creatinine levels in a fasting blood sample before and
      after treatment with ciprofibrate. RESULTS: The subgroup with triglyceride < 200
      mg/dL (2.26 mmol/L): After the administration of ciprofibrate total cholesterol
      and low-density lipoprotein cholesterol were reduced by 15% (P < 0.001), and 19%
      (P < 0.001), respectively, while high-density lipoprotein cholesterol increased
      by 9% (P = 0.02). Apoproteins B and E levels were reduced by 21% (P < 0.001) and
      11% (P = 0.002), respectively. Subgroup with triglyceride > 200 mg/dL (2.26
      mmol/L): After the administration of ciprofibrate, no significant change in LDL
      cholesterol levels was observed. Total cholesterol levels were reduced by 15% (P
      < 0.001) and high-density lipoprotein cholesterol levels were increased by 13% (P
      = 0.004). Apoprotein B and apoprotein E levels were reduced by 16% (P < 0.001)
      and 30% (P < 0.001), respectively. Apoprotein-A1 levels were increased by 5% (P =
      0.024). In the whole group of patients, the fibrinogen levels fell by 7% (P =
      0.043), and the serum creatinine level increased by 10% (P < 0.001). This rise in
      serum creatinine was more pronounced in patients with low triglyceride levels
      (15% vs 5%, P = 0.009). Ciprofibrate decreased C-reactive protein levels by 26%
      in 44 patients who had C-reactive protein measurements (P < 0.001). gamma
      glutamyl transpeptidase activity was similarly decreased (by approximately 40%)
      in both groups of patients. Alkaline phosphatase activity decreased in both
      groups, a reduction which was greater in hypertriglyceridemics (20% vs 10%, P =
      0.004). CONCLUSIONS: Ciprofibrate improved some of the vascular risk factors,
      such as total cholesterol, low-density lipoprotein cholesterol, high-density
      lipoprotein cholesterol, apoproteins A1, B, and E, and fibrinogen levels in both
      hypertriglyceridemics and normotriglyceridemics. In addition, ciprofibrate raised
      the serum creatinine and improved the activity of the hepatic enzymes in the
      plasma in both patient subgroups.

PMID- 12490968
TI  - Arterial injury in mice with severe insulin-like growth factor-1 (IGF-1)
      deficiency.
AB  - BACKGROUND: Insulin-like growth factor-1 plays a significant role in wound
      healing. Injury to the arterial wall is followed by a marked increase in insulin
      like growth factor-1 expression and inhibition of insulin-like growth factor-1
      action is associated with diminished intimal thickening after injury. METHODS AND
      RESULTS: The role of insulin-like growth factor-1 in arterial response to cuff
      injury was investigated in genetically modified mice with severe insulin-like
      growth factor-1 deficiency ((m/m) mice). Tissue and serum insulin-like growth
      factor-1 was severely decreased, by 40% to 60% before the injury and by 50% to
      60% following the arterial injury in insulin-like growth factor-1 (m/m) mice
      compared to control mice. Nevertheless, following the cuff induced injury to the
      carotid arteries, insulin-like growth factor-1 (m/m) mice had a similar number of
      proliferating medial cells 3 days after injury and similar neointimal thickening
      (0.019 +/- 0.015 C57BL/6J vs. 0.016 +/- 0.014 mm(2), P = 0.26) 21 days after
      injury compared to wild type C57BL/6J mice. The phases of the response to injury
      that are mediated by insulin-like growth factor-1 were studied with recombinant
      human insulin-like growth factor-1 in rats with balloon-injured femoral arteries.
      Treatment of rats with recombinant human insulin-like growth factor-1 increased
      neointimal thickening (0.0265 +/- 0.0099 vs 0.0156 +/- 0.0049 mm(2), P = 0.03),
      intimal smooth muscle cell numbers (195.6 +/- 40.2 vs 145.3 +/- 27.3; P = 0.03),
      and the ratio of proliferating intimal to medial smooth muscle cells (10.7 +/-
      6.9 vs 3.0 +/- 2.1; P = 0.03) 7 days after injury compared to untreated rats. At
      14 days neointimal area was similar in the 2 groups of rats. CONCLUSIONS: The
      data in insulin-like growth factor-1 deficient mice suggest a relatively low
      threshold tissue concentration for insulin-like growth factor-1 to exhibit its
      role in vascular response to injury. The findings in rats treated with
      recombinant human insulin-like growth factor-1 suggest that insulin-like growth
      factor-1 is primarily involved in the early phases of neointimal formation.

PMID- 12490969
TI  - Effects of adrenomedullin on human myocyte contractile function and beta
      adrenergic response.
AB  - BACKGROUND: Adrenomedullin has been demonstrated to cause systemic vasodilation,
      and increased plasma adrenomedullin levels have been observed in cardiovascular
      disease states such as heart failure. While adrenomedullin receptors have been
      localized to the myocardium, the effects of adrenomedullin on human myocyte
      contractility remained unknown. METHODS AND RESULTS: Left ventricular myocytes
      were isolated from myocardial biopsies of patients (n = 16) undergoing elective
      coronary artery bypass surgery with normal left ventricular ejection fractions
      (51 +/- 1%). A total of 233 left ventricular myocytes were studied by
      videomicroscopy. Myocyte shortening velocity (microm/s) was measured at baseline
      and following the addition of either 3 nM, 30 nM, or 60 nM of adrenomedullin. The
      change in myocyte shortening velocity with increasing concentrations of
      adrenomedullin was computed. At all concentrations, adrenomedullin reduced
      myocyte shortening velocity from baseline values (P < 0.05). Next, the potential
      interaction of adrenomedullin with the beta-adrenergic receptor system was
      examined using 25 nM isoproterenol. The beta-adrenergic receptor-mediated
      increase in the myocyte shortening velocity was blunted with adrenomedullin (29
      +/- 7 vs 63 +/- 13 microm/s, P < 0.05). CONCLUSIONS: These unique findings
      demonstrate that adrenomedullin reduced contractility in isolated human left
      ventricular myocytes and exhibited a negative interaction with the beta
      adrenergic receptor system. Past studies have shown that adrenomedullin induces
      nitric oxide synthesis and that nitric oxide can uncouple myocyte metabolism.
      Thus, while adrenomedullin causes systemic vasodilation, this peptide can also
      exert a negative contractile effect in human left ventricular myocytes.

PMID- 12490970
TI  - Metalloproteinase in myocardial adaptation and maladaptation.
AB  - Ventricular remodeling is a compensatory response that comprises the processes of
      apoptosis, muscle cell hypertrophy, and rearrangement of the extracellular matrix
      fibers connecting the muscles. These processes are associated with transformation
      of endothelium and/or fibroblasts to myofibroblasts. Neutral matrix
      metalloproteinases, membrane type matrix metalloproteinases, and disintegrin
      metalloproteinase play a significant role in these processes. The cell
      extracellular matrix connections are important in maintaining and synchronizing
      muscle function. However, a complete extracellular matrix-cell disconnect leads
      to a decrease in muscle cell strength, apoptosis, and hypertrophy.

PMID- 12490971
TI  - Anti-thrombotic effects of atorvastatin--an effect unrelated to lipid lowering.
AB  - Statins (3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have been
      shown to reduce clinical events in excess of what can be explained by altering
      lipid profile. Statins have been shown to possess modest antioxidant and
      antiplatelet aggregatory effect. We postulated that statins may accordingly
      inhibit arterial thrombus formation. To assess the antithrombotic effects of
      atorvastatin, a commonly used statin, in response to an oxidant stimulus, we fed
      Sprague-Dawley rats either regular chow, or chow mixed with atorvastatin (1.25
      mg/kg) for 10 days (n = 16 in each group). Eight rats in each group were also
      given oxidized low-density lipoprotein intravenously prior to the induction of
      thrombus. An occlusive thrombus was created in the abdominal aorta by application
      of Whatman paper soaked in 35% FeCl3. The time to occlusive thrombus formation
      was not altered by administration of oxidized low-density lipoprotein in the rats
      fed regular chow or chow mixed with atorvastatin. However, time to thrombosis was
      increased in the group given chow mixed with atorvastatin (26 +/- 4 minutes vs.
      20 +/- 5 minutes, P < 0.02). To determine the mechanism of atorvastatin's
      antithrombotic effect, we measured the expression of endothelial constitutive
      nitric oxide synthase (cNOS) in rat aortas by Western analysis. The cNOS protein
      expression was enhanced 75% in rats fed chow with atorvastatin (P < 0.01 vs. rats
      fed regular chow). Plasma levels of total cholesterol and low-density lipoprotein
      cholesterol were similar in all groups. This study shows that atorvastatin delays
      thrombus formation in arterial channels exposed to oxidant stress. This effect of
      atorvastatin appears to be related to increased expression of cNOS, which is
      known to inhibit platelet aggregation and induce vasodilatation. The effects of
      atorvastatin are independent of its effects on plasma cholesterol levels.

PMID- 12490972
TI  - Azimilide inhibits multiple cardiac potassium currents in human atrial myocytes.
AB  - BACKGROUND: Studies in animal cell preparations suggest that azimilide may
      produce a more desirable rate-dependent profile of class III action as a result
      of its effects on both the slowly (I(Ks)) and rapidly (I(Kr)) activating
      components of potassium current (I(K)). However, relatively little is known about
      the effects of azimilide on K(+) currents in human atrial cells. The present
      study investigated the effect of azimilide on the inward rectifier potassium
      current (I(K1)), delayed rectifier potassium current (I(K)), ultrarapid delayed
      rectifier current (I(Kur)), and transient outward potassium current (I(to)) in
      isolated single human atrial myocytes. METHODS: The tight-seal, whole-cell
      voltage clamp technique was used to investigate the acute effects of azimilide on
      K(+) currents in single human atrial myocytes. The cells were isolated
      enzymatically from atrial tissues that were obtained from patients undergoing
      open-heart surgeries, with the approval of the local Institutional Review Board.
      RESULTS: The average cell capacitance of the human atrial myocytes was 77.5 +/-
      2.8 pF (Mean +/- standard error of mean, total 28 cells from 17 patients). We
      found that 100 microM of azimilide in the extracellular solution significantly
      inhibited the inward rectifier potassium current (12.3 +/- 3.1 vs 6.7 +/- 2.0
      pA/pF, n = 12, P < 0.05) at the testing potential of -100 mV. Superfusion with
      100 microM of azimilide for 10 minutes inhibited I(K) by 51.7 +/- 5.1% (from 3.4
      +/- 0.5 to 1.6 +/- 0.2 pA/pF, n = 9, P < 0.01) at the clamping membrane potential
      of +40 mV. Human atrial cell I(Kur) was inhibited with 100 microM of azimilide by
      38.6 +/- 4.4% (from 3.9 +/- 0.5 to 2.3 +/- 0.2 pA/pF, n = 9, P < 0.01, test
      potential = 40 mV). We also found that the average peak current amplitude of
      I(to) in these cells was significantly inhibited with 100 microM of azimilide by
      60.3 +/- 5.9% (from 10.3 +/- 1.5 to 3.6 +/- 0.3 pA/pF, n = 6, P < 0.01, test
      potential = 50 mV). CONCLUSION: The present study provides direct evidence that
      azimilide inhibits multiple cellular transmembrane K(+) currents in freshly
      isolated human atrial myocytes. Inhibition of these K(+) currents by azimilide,
      especially of I(Ks) and I(Kur) is likely to be the electrophysiologic basis for
      the prolongation of the action potential duration in the human atria which
      mediates its known antifibrillatory effects in atrial fibrillation and flutter.

PMID- 12490973
TI  - Loss of heterozygosity of p53, BRCA1, VHL, and estrogen receptor genes in breast
      carcinoma: correlation with related protein products and morphologic features.
AB  - Correlation of loss of heterozygosity (LOH) of p53, BRCA1, VHL, and estrogen
      receptor (ER) genes with the expression of related protein products and
      morphologic features predictive of aggressive biologic behavior was investigated
      to determine the significance of LOH in these genes. DNA from 35 formalin-fixed,
      paraffin-embedded breast carcinomas was obtained by microdissection of histologic
      sections. LOH was determined by polymerase chain reaction (PCR) using primers
      TP53, D3S1038, D17S855, and ESR for p53, VHL, BRCA1, and ER genes, respectively.
      p53, ER, and progesterone receptor (PR) protein expression was evaluated by
      immunohistochemistry. Morphologic evaluation included histologic type, and
      histologic and nuclear grades. TP53 LOH was identified in 13 (52%), BRCA1 LOH in
      3 (17%), VHL LOH in 1 (4%), and ER LOH in 4 (21%) of 25, 17, 24, and 19
      informative cases, respectively. p53 and ER protein expression was identified in
      20 (57%) and 25 (71%) cases, respectively. TP53 LOH directly correlated with both
      high histologic and nuclear grade (P<0.01). BRCA1, VHL, and ER LOH was not
      frequent enough for correlation to morphologic features. Although 4 of 4 ER and 7
      of 13 p53 LOH cases expressed related proteins, LOH did not correlate with
      protein expression. TP53 LOH may be an event contributing to aggressive biologic
      behavior since it is strongly associated with high histologic and nuclear grade.
      Missense or nonsense mutations may explain the absence of detectable p53 protein
      in 6 of 13 cases with p53 LOH. All 4 ER LOH cases expressed ER protein. BRCA1 and
      VHL LOH is infrequent in sporadic breast carcinoma.

PMID- 12490974
TI  - c-erb B-2 expression is associated with tumor location and venous invasion and
      influences survival of patients with gastric carcinoma.
AB  - The HER-2/neu gene or c-erb B-2, localized on chromosome 17q, belongs to a family
      of tyrosine kinase receptors and shares extensive homology with the epidermal
      growth factor receptor. c-erb B-2 gene amplification and protein overexpression
      have been reported in several human cancers. The prognostic value of this genetic
      alteration in gastric carcinoma is far from being established. In the present
      study, formalin-fixed, paraffin-embedded gastric carcinoma tissues from 157
      patients were evaluated for c-erb B-2 overexpression, by immunohistochemistry
      using a polyclonal antibody. c-erb B-2 expression was evaluated according to
      clinical and pathological parameters, and to the survival of the patients. Our
      results show that: (1). c-erb B-2 was overexpressed in 15.3% of gastric carcinoma
      cases; (2). c-erb B-2 overexpression was significantly more frequent in cardia
      (23.8%) and fundus/body (25.0%) carcinomas than in antrum (7.2%) carcinomas; (3).
      c-erb B-2 overexpression was significantly associated with venous invasion; (4).
      c-erb B-2 is a prognostic factor for gastric carcinoma.

PMID- 12490975
TI  - Lymphomas of the bone: a pathological and clinical study of 54 cases.
AB  - We examined 28 cases of primary bone lymphomas (PBL; stage IE) and 26 cases of
      systemic lymphomas involving the bone (SBL; stage IIE to IV). Two histologic
      types were prevalent: Diffuse large B-cell lymphomas (DLBCL; 26 PBL and 21 SBL)
      and CD30+ anaplastic large cell lymphomas (ALCL; 1 PBL and 4 SBL). A mature B
      phenotype (CD45+, CD20+, CD79a+, CDw75+/-, CD10-/+) was established in the DLBCL
      group. Bcl-2 immunoreactivity was demonstrated in 13/37 cases (35%), and bcl-6
      immunostaining was observed in 22/32 cases (69%). ALCL showed null/T phenotype
      (CD3-/+; CD43+/-; CD30+), with ALK-1 expression in 3/3 cases. With use of a FR3A
      primer, a monoclonal pattern was demonstrated by PCR analysis in 22/41 lymphomas
      (54%). Bcl-2 translocation was identified in 2/41 cases (5%). This study details
      the clinical and pathological characteristics of bone lymphomas. Our
      immunohistochemical and molecular data suggest that most of them are "de novo"
      DLBCL and support their follicle center origin.

PMID- 12490976
TI  - Can we rely on pathologic parameters to define conservative treatment of
      papillary thyroid carcinoma?
AB  - Papillary thyroid carcinoma is the most common malignant tumor of the thyroid and
      usually behaves in an indolent fashion. At most institutions these tumors are
      treated by near-total or total thyroidectomy followed by radioactive iodine
      ablation. The 2 main reasons for this extensive treatment include high rate of
      multicentricity in papillary carcinoma and difficulty in ablating large thyroid
      remnants with radioactive iodine after partial thyroidectomy. Some authors
      believe, however, that this treatment protocol may not be justified in all cases
      of papillary carcinoma. We analyzed 253 total thyroidectomies performed for
      papillary thyroid carcinoma for the following pathologic variables: tumor size,
      presence of tumor capsular and/or vascular invasion, intrathyroidal spread, tumor
      in the contralateral lobe, and lymph node metastases. Tumors measuring less than
      1 cm and those with extrathyroidal soft tissue extension were excluded from this
      study. Among 253 cases (197 females, 56 males, age range 14-88 years), the
      primary tumor size ranged from 1-9.5 cm; 162 cases were completely encapsulated.
      Tumor capsule invasion was seen in 139 (86%) and vascular invasion was present in
      32 (13%) cases; of these 27 (11% of the total) patients showed both tumor capsule
      and vascular invasion. Seventy-four (29%) patients showed tumor in the
      contralateral lobe; in 35 (47%) of these cases the contralateral tumor measured
      less than 1.0 cm. Lymph nodes were sampled in 106 cases, metastases were present
      in 67 (67/106 = 63%) and only 16 cases with lymph node metastases showed
      contralateral tumors. No significant correlation was noted between tumor size,
      occurrence of contralateral tumors, and lymph node metastases. Seventy-one
      percent of cases included in this study failed to show contralateral tumors.
      Hence, pathologic parameters such as lack of vascular invasion and lack of
      multifocality may be used to identify patients who can benefit from conservative
      therapy alone.

PMID- 12490977
TI  - Long-term prognosis of teenagers with breast cancer.
AB  - We report 4 new cases of breast carcinoma in teenage girls diagnosed by use of
      histochemical and immunohistochemical methods. These cases of breast carcinoma in
      women under 20 years of age were found in the files of our department in the last
      24 years (1976-2000). The patients had operable breast carcinomas corresponding
      to various histologic types (1 invasive ductal carcinoma associated with
      fibroadenoma, 2 secretory carcinomas, and 1 invasive lobular-type carcinoma).
      Simple mastectomy with low axillary lymph node dissection was performed in 2
      postpubertal patients. Only 1 patient received adjuvant chemotherapy (case 4).
      After follow-up ranging from 76 to 126 months, 3 patients are alive and disease
      free and 1 has disseminated metastatic disease. The correlations with prognosis
      related risk factors (stage, age, previous benign lesions, family history,
      histologic types, hormonal receptors, and pregnancy) were examined.

PMID- 12490978
TI  - Multifocal, nascent, and invasive myoepithelial carcinoma (malignant
      myoepithelioma) of the breast: an immunohistochemical and ultrastructural study.
AB  - This report describes the light microscopic (LM), immunohistochemical (IHC), and
      electron microscopic (EM) features of a multifocal, nascent, and invasive
      myoepithelial carcinoma of the breast. By LM, the spindle cells disclosed
      fibrillar acidophilic cytoplasm, mild nuclear atypia, and a low mitotic index.
      Myoepithelial differentiation was established through IHC (single- and double
      labeling techniques) and EM: periductal and infiltrating spindle cells
      coexpressed total muscle actin, alpha-smooth muscle actin, vimentin, cytokeratin
      14, and pankeratin, and their EM features were characteristic of myoepithelial
      cells, i.e., perinuclear tonofilaments, subplasmalemmal bundles of microfilaments
      with dense bodies, intermediate junctions, poorly developed desmosomes, pinocytic
      vesicles, and fragmented external lamina. No invasive epithelial cells disclosed
      luminal differentiation (by LM, IHC, EM), identifying, thus, this neoplasm as a
      pure spindle cell myoepithelial carcinoma of the breast.

PMID- 12490979
TI  - Images in pathology: "Daisy" cells.

PMID- 12490980
TI  - Images in pathology: brunner's gland hamartoma.

PMID- 12490981
TI  - Images in pathology: the hearts of a breast pathologist, a hematopathologist, and
      of a cytotechnologist.

PMID- 12490982
TI  - Images in pathology: a pubic louse in a pap smear.

PMID- 12490984
TI  - Pancreatic cystic dysplasia (dysgenesis) presenting as a surgical pathology
      specimen in a patient with multiple malformations and familial ear pits.
AB  - A peculiar 6 x 5 x 3 cm, multilobed, septated, cystic tumor presented in the tail
      of the pancreas in a 5-month-old infant with left ear pit, bilateral cleft
      palate, brachydactyly type B, and familial ear pits. This combination was not
      found previously reported. The cysts were lined by attenuated epithelium and PAS
      positive, mucus-containing cells. These were keratin 8-, 18-, and 19-positive and
      CA 19.9-negative. Ductuloinsular complexes were present in the adjacent
      pancreatic tissue. Pancreatic cystic dysplasia (dysgenesis) may associate with
      several malformation syndromes. A similar lesion may present isolated as a tumor
      in the first year of life and has been reported under a variety of names
      (hamartoma, cystadenoma, and cyst). The lesion does not fit with the criteria of
      cystadenomas as seen in adults.

PMID- 12490983
TI  - Diffuse nodular lymphoid hyperplasia of the large bowel without
      hypogammaglobulinemia or malabsorption syndrome: a case report and literature
      review.
AB  - Diffuse nodular lymphoid hyperplasia (DNLH) of the intestine is an extremely rare
      lymphoproliferative disorder occasionally associated with non-Hodgkin lymphomas.
      We report an unusual case of DNLH of the entire colon, which resembled malignant
      lymphoma (particularly low-grade B-cell lymphoma) both on clinical and pathologic
      grounds. The patient was a 62-year-old Japanese woman who was found to have
      multiple polypoid lesions along the entire large intestine by colonoscopy.
      Abdominal computed tomography revealed hepatosplenomegaly and multiple mesenteric
      lymphadenopathy. Histologically, the lesion was characterized by numerous
      lymphoid follicles with active germinal centers and a diffuse infiltrate of
      lymphoid cells in the mucosa and submucosa. The present case appears to be an
      essentially benign condition bearing a resemblance, both clinically and
      histologically, to malignant lymphoma, and from which it can be distinguished by
      use of immunohistochemical or molecular analysis.

PMID- 12490985
TI  - Mesectodermal leiomyoma of ciliary body.
AB  - A 37-year-old woman had a mass in her left ocular globe. Uveal melanoma was
      suspected and enucleation was performed. Microscopically, the lesion proved to be
      a typical case of mesectodermal leiomyoma of the ciliary body. According to some
      authors, the peculiar neural appearance of this tumor could be the reflection of
      its probable origin from mesectodermal smooth muscle. Immunohistochemical
      analysis showed reactivity for muscle-specific actin and negativity for desmin, S
      100 protein, HMB-45, EMA, and GFAP. Our results do not support the proposed
      neuroectodermical origin of this tumor, since coexpression of muscular and neural
      markers was not observed.

PMID- 12490986
TI  - Mediastinal rhabdomyoma: a case report and review of the literature.
AB  - An incidental anterior-superior mediastinal rhabdomyoma is reported in a 68-year
      old man who died of hypovolemic shock as a result of massive blood loss due to
      transection of aorta after being hit by a moving motor vehicle. This is the third
      reported case of mediastinal rhabdomyoma in the literature. The
      immunohistochemical evidence of expression of muscle-specific markers supports
      the rhabdomyomatous nature of this neoplasm, and electron microscopic
      demonstration of haphazardly arranged myofilaments with prominent Z bands, "jack
      straws" in the mitochondria, and the absence of desmosomes is supportive of
      extracardiac origin of this rhabdomyoma. The possible histogenesis of
      extracardiac adult rhabdomyoma (EAR) in the anterior-superior mediastinum from
      the thymic myoid cells is also discussed.

PMID- 12490987
TI  - [Dilated cardiomyopathy and growth hormone].
AB  - The data from animal and human in vivo studies suggest that cardiac function is
      dependent in part on the normal function of the GH/IGF-1 axis (growth
      hormone/insulin-like growth factor-1). So far encouraging results from phase II
      and III clinical trials evaluating the effects of intermittent GH treatment in
      patients with chronic congestive heart failure (CHF) due to dilated
      cardiomyopathy (DCM) have been published. In these studies, growth hormone (i.e.,
      DNA-derived recombinant human growth hormone) was not used alone but in addition
      to standard optimal therapy for CHF. The following rationale is the basis of this
      new approach for the treatment of CHF due to DCM: According to Laplace's Law
      cardiac wall stress (i.e., the force acting per unit of cross-sectional area of
      the ventricular wall) is directly related to intraventricular pressure and
      ventricular radius and inversely related to ventricular wall thickness. Cardiac
      (ventricular) wall stress is increased in DCM (mainly because of the dilatation
      of the ventricles and to a minor extent because of the relative reduction in
      ventricular thickness). GH is capable of increasing ventricular wall thickness in
      DCM thus reducing cardiac wall stress which in turn leads to an improvement in
      systolic cardiac performance.

PMID- 12490988
TI  - Highly variable expression of virus receptors in the human cardiovascular system.
      Implications for cardiotropic viral infections and gene therapy.
AB  - Coxsackieviruses and adenoviruses are common agents of viral heart disease. In
      the majority of exposed individuals they do not cause myocardial disease,
      however, since they are not primarily cardiotropic. Until recently the molecular
      basis of their anomalous tropism in patients who develop viral heart disease was
      unknown. An important step towards clarification of the molecular basis of
      cardiotropic viral infections was achieved in 1997, when a common receptor for
      the two structurally unrelated viruses was cloned. This coxsackievirus-adenovirus
      receptor (CAR) is a key determinant for the cellular uptake of both viruses and
      for the molecular pathogenesis of coxsackievirus and adenovirus diseases. We have
      mapped the CAR expression in human hearts and observed highly variable expression
      patterns. Healthy donor hearts had low CAR expression levels, whereas explanted
      hearts of patients with dilated cardiomyopathy (DCM) displayed high CAR
      expression in the myocardium. Remarkably, however, heart failure per se was not
      associated with CAR induction, since in heart failure of non-DCM origin no
      induction was found. Additional studies on the molecular mechanisms of CAR
      induction in cardiomyocytes indicated the existence of a cell-cell contact
      dependent molecular mechanism regulating CAR expression, whereas cellular virus
      uptake and low level replication had no effect. Recombinant expression of human
      CAR in cardiomyocytes strongly increased their virus uptake rate suggesting that
      CAR induction enhances cardiac vulnerability to viral disease, whereas healthy
      myocardium is rather resistant to CAR-dependent viruses. Receptor induction may
      significantly aggravate the clinical course of viral heart disease, so that the
      blockade of receptor expression or receptor-virus interactions opens new
      therapeutic perspectives. Elucidation of the molecular mechanism of CAR induction
      in DCM, but not in heart failure per se, may reveal a particular pathogenetic
      process in this disease. A broader analysis of the cardiovascular expression
      patterns of receptors for other potentially cardiotropic viruses (CMV, EBV, HIV,
      HHV-6, Parvo-B19, etc.) should lead to a better understanding of individual risk
      factors for viral heart diseases and of their highly variable clinical courses,
      and offer new therapeutic options.

PMID- 12490989
TI  - Fabry disease in patients with hypertrophic cardiomyopathy (HCM).
AB  - Fabry disease is an X-linked recessive lysosomal storage disorder with variable
      phenotype characterized by the accumulation of glycosphingolipid in various
      tissues. Unlike patients with the classical systemic Fabry disease entity, who
      present with multiple organ involvement, patients with a cardiac variant of Fabry
      disease are characterized mainly by myocardial hypertrophy. Therefore, the
      cardiac variant of Fabry disease may be defined as a cardiomyocytic storage
      disorder, thus, mimicking the clinical features of hypertrophic obstructive and
      especially non-obstructive cardiomyopathy. In patients with unexplained left
      ventricular hypertrophy the diagnosis of a cardiac variant of Fabry disease is
      performed by light- and electron microscopic evaluation of endomyocardial
      catheter biopsy specimens and/or serologic investigations (decreased activity of
      alpha-galactosidase A in plasma or leucocytes). Several studies show that between
      4% and 8% of unselected patients with the clinical features of hypertrophic non
      obstructive cardiomyopathy have a cardiac variant of Fabry disease. In each
      patient with unexplained myocardial hypertrophy concealed myocardial storage
      disease, especially cardiac Fabry disease has to be considered and should be
      ruled out or confirmed by endomyocardial catheter biopsy. This is important
      because of the recently reported alpha-galactosidase A enzyme replacement therapy
      in Fabry disease. Randomized, multicenter studies are mandatory to test the
      hypothesis that enzyme replacement therapy leads to a beneficial clinical effect
      in the cardiac variant form of Fabry disease and may prevent the progression of
      the disease in asymptomatic patients.

PMID- 12490990
TI  - Heart rate variability enhances the prognostic value of established parameters in
      patients with congestive heart failure.
AB  - This prospective study evaluated whether heart rate variability (HRV) assessed
      from Holter ECG has prognostic value in addition to established parameters in
      patients with congestive heart failure (CHF). The study included 222 patients
      with CHF due to dilated or ischemic cardiomyopathy (left ventricular ejection
      fraction LVEF 21+/-1%; mean+/-SEM). During a mean follow-up of 15+/-1 months, 38
      (17%) patients died and 45 (20%) were hospitalized due to worsening of CHF. The
      HRV parameter SDNN (standard deviation of all intervals between normal beats) was
      significantly lower in non-surviving or hospitalized than in event-free patients
      (118+/-6 vs 142+/-5 ms), as were LVEF (18+/-1 vs 23+/-1%), and peak oxygen uptake
      during exercise (peak VO(2)) (12.8+/-0.5 vs 15.6+/-0.5 ml/min/kg). While each of
      these parameters was a risk predictor in univariate analysis, multivariate
      analysis revealed that HRV provides both independent and additional prognostic
      information with respect to the risk 'cardiac mortality or deterioration of CHF'.
      It is concluded that the determination of HRV enhances the prognostic power given
      by the most widely used parameters LVEF and peak VO(2) in the prediction of
      mortality or deterioration of CHF and thus enables to improve risk
      stratification.

PMID- 12490991
TI  - [Malignomas following heart transplantation].
AB  - Up to 30% of patients with an organ transplantation develop precancerous lesions
      and malignant tumors, especially of the skin. All 241 patients who underwent
      heart transplantation from 1990 to 2000 were evaluated with regard to the
      development of neoplasias. Those alive in September 1999 were referred for a
      standardized dermatological exam (n=156) which detected malignancy in 28 patients
      being transplanted for 4.98 years on average. The skin was the organ most
      frequently involved (64%, n=18). 18% (n=5) of tumors were found in the urinary
      and genital tract, 7% (n=2) each in the respiratory and gastrointestinal tract,
      and 4% (n=1 ) in the breasts. The average age of patients who developed tumors
      was significantly higher as compared to the overall mean age (59.5+/-5 vs 49.8+/
      14.7 years, p=0.00027). There was no correlation between development of
      malignancy and HLA matching, immunosuppressive drugs used, dosage and serum
      levels of immunosuppressive medication, and episodes of transplant rejection. Our
      study shows that the risk to develop tumors is at least doubled after heart
      transplantation. Due to the high incidence of skin tumors, transplant patients
      should undergo dermatological examinations on a regular basis.

PMID- 12490992
TI  - [Alterations of left ventricular systolic and diastolic function in pregnant
      women with insulin-dependent diabetes mellitus].
AB  - BACKGROUND: During pregnancy, major cardiovascular changes occur. The aim of the
      following study was to investigate the course of hemodynamic parameters under the
      increased volume load during pregnancy and delivery in women with insulin
      dependent diabetes mellitus. METHODS: We examined 51 pregnant diabetic and 51
      healthy pregnant women. The control group consisted of 51 healthy non-pregnant
      women. In all women, left ventricular mass and fractional shortening were
      calculated. To evaluate left ventricular diastolic function, mitral inflow and
      pulmonary venous flow profiles were analyzed. RESULTS: During pregnancy left
      ventricular mass increased, fractional shortening decreased and diastolic
      dysfunction was found. While the healthy pregnant women developed signs of
      disturbed relaxation during pregnancy, pregnant diabetic women showed signs of a
      disturbed relaxation already at the beginning of gestation. A total of 29
      pregnant diabetic women developed a restrictive filling pattern already at the
      24th week of gestation. The remaining 22 diabetics had a comparable restrictive
      filling pattern only during vaginal delivery. In 10 of the 29 pregnant diabetic
      women dangerous complications were documented, while there were no complications
      in the healthy pregnant women and the other 22 diabetic pregnant women.
      CONCLUSIONS: In healthy women pregnancy results in a reversible physiologic left
      ventricular hypertrophy, a disturbed relaxation pattern and a temporary decrease
      of left ventricular systolic function. In contrast, pregnant diabetic women
      demonstrated a delayed relaxation at the beginning of pregnancy and developed a
      restrictive filling pattern. The early development of a restrictive filling
      pattern may predispose to complications during delivery in pregnant diabetic
      women.

PMID- 12490993
TI  - [Pulmonary plasma catecholamine levels and pulmonary hypertension in congenital
      heart disease].
AB  - Plasma catecholamines may play a role in the pathogenesis of pulmonary
      hypertension in congenital heart disease with increased pulmonary blood flow. At
      cardiac catheterization, blood samples were obtained before and after passage of
      the lung in patients with congenital heart disease with normal pulmonary blood
      flow (n=39), elevated pulmonary blood flow with normal pulmonary pressure and
      normal pulmonary vascular resistance (PVR) in patients with atrial septal defect
      (ASD) (n=57) or ventricular septal defect (VSD) (n=12), and increased pulmonary
      blood flow, pressure and vascular resistance in patients with ASD, VSD or both
      (n=22), or in patients with primary pulmonary hypertension (n=4). Plasma
      catecholamines were determined by reversed phase high performance liquid
      chromatography and electrochemical detection (HPLC-ECD). In patients with
      elevated PVR elevated norepinephrine levels (NE) were observed. In contrast,
      epinephrine levels (E) were not associated with the development of pulmonary
      hypertension. Patients with primary pulmonary hypertension had the highest levels
      of NE while patients with associated Down's syndrome had significantly lower
      epinephrine levels. Pulmonary plasma norepinephrine levels are increased in
      patients with elevated pulmonary vascular resistance. Whether this phenomena is
      the cause or sequalae of pulmonary hypertension needs further examination. In the
      future, plasma catecholamines may serve as a diagnostic feature or may result in
      further therapeutic options.

PMID- 12490994
TI  - [The Wearable Cardioverter Defibrillator (WCD) for the prevention of sudden
      cardiac death -- a single center experience].
AB  - The Wearable Cardioverter Defibrillator (WCD) is an external defibrillator that
      automatically detects and treats ventricular tachyarrhythmias without the need
      for assistance from a bystander while at the same time allowing the patient to
      ambulate freely. The main components of the system are the defibrillator unit and
      a chest belt with electrodes for arrhythmia detection and therapy delivery.
      Between December 1998 and October 2001, 84 patients used the device at our
      institution. The majority of patients had a history of acute myocardial
      infarction or coronary artery bypass surgery with an increased risk for sudden
      cardiac death or were awaiting heart transplantation. During a mean follow-up of
      116+/-90 days, 7 episodes of ventricular tachyarrhythmias were detected and
      terminated successfully by the WCD in 5 patients. In 9720 days, there was one
      inappropriate shock due to oversensing of electrical noise. Four patients died
      during follow-up; none of them had a cardiac arrest while wearing the device.
      Five patients were excluded because of irregularities in device use. An ICD was
      implanted in 24 patients at the end of the follow-up period. The WCD is effective
      in detecting and treating ventricular tachyarrhythmias in patients with an
      intermittently increased risk for sudden cardiac death. Further use of the system
      in larger patient populations is needed to confirm its safety and cost
      effectiveness.

PMID- 12490995
TI  - [The Lyme carditis as a rare differential diagnosis to an anterior myocardial
      infarction].
AB  - An acute Lyme carditis affects about 0.3-4% of patients with Lyme borreliosis.
      The acute period of the disease may be associated with critical atrioventricular
      conduction abnormalities (complete heart block), supraventricular and ventricular
      arrhythmias as well a left ventricular failure. Normally, Lyme carditis is
      completely reversible. Therefore the prognosis largely depends on the management
      of the acute complications and early antibiotic therapy. Even if the symptoms are
      spontaneously reversible, antibiotic therapy should be applied to prevent a
      chronic cardiomyopathy and other manifestations of Lyme borreliosis. We report on
      a 47-year old patient with acute ECG changes initially suggesting an acute
      coronary syndrome. However, case history and the erythema migrans indicated an
      acute Lyme carditis which was confirmed serologically and by myocardial biopsy
      later.

PMID- 12490996
TI  - [Brugada or not-Brugada: misdiagnosis of recorder-induced artifact].
AB  - The Brugada-Brugada syndrome is a life threatening cardiac arrhythmia that
      features syncopal events or aborted sudden death in combination with
      electrocardiographic characteristics (ST-segment elevation of V(1)-V(3) and right
      bundle branch block). Typical ECG alterations were recorded in a young man who
      was admitted to our hospital after syncope and a Brugada-Brugada syndrome was
      suspected. The following days similar pathological ECG recordings of other
      patients were noticed. The electrocardiographic artifact was diagnosed as being
      caused by incorrect handling of the ECG recorder.

PMID- 12490997
TI  - [Neutral position for the evidence-based expert guidelines "Diabetes and the
      heart" of the German Diabetes Gesellschaft (DDG) as well as the "Recommendations
      for comprehensive reduction of risks for patients with coronary heart disease,
      vascular disease, and diabetes" of the German Cardiac Society (DGK)].

PMID- 12490998
TI  - [Life expectancy in Germany].

PMID- 12490999
TI  - [Active life expectancy: concepts and a new model approach].
AB  - The question about an increasing health burden due to the ongoing aging process
      of the population has been discussed in the scientific community for a very long
      time. The concept of active life expectancy seems to be a suitable instrument to
      test the controversial perceptions about compression or expansion of morbidity in
      old age. A new model is proposed and described based on the Sullivan method which
      does not quantify the change in active life expectancy at a certain age, as is
      common practice. In fact a new model, which measures the difference in active
      life expectancy at a specific general remaining life expectancy over time (DRALE
      model), seems to be much more appropriate. Thus cohort effects can be excluded.
      Finally, possible restrictions in the course of an empirical testing are
      presented and discussed. Main restrictions are the increasing heterogeneity of
      aging populations, the availability of appropriate data, and the high variance of
      raw data in old age.

PMID- 12491000
TI  - [Active life expectancy in Germany and in the United States. A cohort analysis
      based on the "German Socio-Economic Panel" (GSOEP) and the "Panel Study of Income
      Dynamics" (PSID)].
AB  - Using the method of multistate life-tables, the article presents results on
      active life expectancy on the basis of the German Socio-Economic Panel (GSOEP)
      and the Panel Study of Income Dynamics (PSID). The transitions into and out of
      active life are based on event-history analysis and are calculated for different
      cohorts. Compared to cross-sectional analysis, the longitudinal analysis carried
      out here describes active life expectancy with reference to single birth cohorts.
      Results show that in Germany there has been substantial improvement in active
      life expectancy while in the USA there has been some deterioration.

PMID- 12491001
TI  - [Grandparenthood and multigenerational families: are they a social reality or a
      demographic myth?].
AB  - During the last 20 years, there has been growing literature on the consequences
      of population aging. Longer life expectancies mean that current cohorts can
      expect to spend more years as members of a family than was the case 200 years
      ago. The focus of this paper is on how three lineage generations are affected by
      the increase of the life expectancy, especially the increase in a multi
      generational family and the common life time of the family members. Using event
      history analysis and the data of the German Socio-economic panel, it is shown, on
      the basis of different birth cohorts, that both Word Wars and the period after
      World War II have had profound negative effects on the common life time of
      grandfathers and their grandchildren. But there has been only a limited influence
      on the life courses of grandmothers and their grandchildren. One surprising
      result is that grandparenthood in Germany has developed into a broader phenomenon
      of the 20th century -- one that arose especially for children born after World
      War II.

PMID- 12491002
TI  - [Moving into a residential home -- experiences of the elderly and their
      relatives].
AB  - The change of ones habitual living conditions in favor of institutionalized
      living in a residential home is for an old person usually connected with many
      difficulties. Psychological studies support the argument that unprepared or
      sudden relocation leads to dramatic somatic and psychic reactions of the old
      person (anxiety, depression), as well as his care-givers. In this context we
      examined 45 elderly and 34 relatives about their experiences and changes in their
      life during the moving process. The most striking findings the positive
      experiences of the elderly and relatives during the relocation process, the low
      amount of information about residential home especially of the elderly, the
      positive attitude of elderly and relatives towards the residential home and
      finally the well-developed processes of short-term accommodation and subjective
      well-being.

PMID- 12491003
TI  - [Age- and education-specific reference values for the cognitive test of the SIDAM
      (Structured interview for the diagnosis of dementia of the Alzheimer type, multi
      infarct dementia and dementias of other etiology according to ICD-10 and DSM
      IV)].
AB  - The SIDAM (Structured Interview for the diagnosis of Dementia of the Alzheimer
      type, Multi-infarct dementia and dementias of other etiology according to ICD-10
      and DSM-IV) is a standardized interview for the diagnosis of dementia. It can
      also be used as a screening instrument for the diagnosis of different syndromes
      of dementia and mild cognitive impairment. At present there is no age- or
      education-specific standardization. This report presents age- and education
      specific norms for the cognitive assessment of the SIDAM, obtained in a
      population-based sample of elderly people aged 75 and over (n=1001).

PMID- 12491004
TI  - Engaged lifestyle and cognitive function in middle and old-aged, non-demented
      persons: a reciprocal association?
AB  - Some studies have shown that cognitive function is positively affected by an
      engaged and active lifestyle. However, a recent study found evidence for an
      opposite causal direction, i.e., persons with good cognitive function more often
      start to engage in leisure-time activities. Here, we longitudinally examine the
      causal direction of the association between an engaged lifestyle and cognitive
      function in middle and old-aged Dutch men and women. The participants in the
      prospective cohort study "Maastricht Aging Study" (MAAS) were recruited from a
      register of 15 family practices in the South of the Netherlands. There were 830
      non-demented men and women, aged 49 to 81 in 1993-1995 (baseline phase). They
      were re-examined three years later (follow-up phase). During both phases, all
      persons reported on their participation in mental, social, and physical
      activities. Six separate neuropsychological tests, including the Mini-Mental
      State Examination, were used to define cognitive function at baseline and follow
      up. All three activities measured were negatively related to cognitive decline
      between both phases. Effects were moderate, but consistent. Persons participating
      in all three activities were particularly protected against longitudinal decline.
      Furthermore, persons with the best baseline cognitive performance were more
      likely to increase their number of activities during follow-up compared with
      persons with the poorest scores. In summary, an engaged lifestyle and cognitive
      function mutually influence each other in middle and old aged, non-demented
      persons. This reciprocal association is characterized by simultaneous positive
      effects of leisure-time activities and good cognitive function on cognitive
      function and leisure-time activities, respectively. This reciprocal association
      may create a self-reinforcing, beneficial or adverse life-course in middle and
      old age.

PMID- 12491005
TI  - [The image of God in old age].
AB  - The image of God in old age was explored in a group of 32 probands over 65 years
      (18 women, 14 men; mean age 71.4) and a control group of youths between 20 and 29
      years (15 women, 16 men; mean age 20.6) using different questionnaires -- the God
      concept, personal relationship to God and emotional inclinations and feelings
      towards God as well as 3 scales for the determination of mental health status.
      The findings show a tight relationship between the concepts (images) of an
      emotional, protecting God and feelings of being sheltered and being near to God.
      Also there was a highly positive correlation between self reflection, life
      affirmation and stable emotionality and the concepts of a guiding, shelter giving
      God, whose nearness can be directly experienced. The image of God of the older
      probands showed special characteristics like "a God who guides", "an empathetic
      God", and "a God, whose nearness can be experienced", but also "a strict and
      punishing God" and "a God who created everything". An interesting gender
      difference in the image of God was found dominantly in the old aged: while the
      old men stressed a strict law and order God, the old women emphasized the aspects
      of emotionality, care, and nearness. The results of this study show the necessity
      of emphasizing an age- and gender-specific pastoral health care, so that the
      religious dimension could be a constructive coping strategy for successful aging.

PMID- 12491006
TI  - Control of meiotic recombination initiation: a role for the environment?
AB  - Homologous recombination plays a central role during meiosis, ensuring the proper
      segregation of homologous chromosomes during the first meiotic division. In
      addition, meiotic recombination generates genetic variability upon which natural
      selection can act. The frequency of recombination is not evenly distributed
      throughout the genome: regions of high (hotspots) and low (coldspots)
      recombination can be found. Meiotic hotspots exhibit high levels of double-strand
      break formation and these breaks coincide with the upstream regions of genes. In
      many cases, binding of transcription factors has been shown to be required for
      hotspot activity. We review the current knowledge on the mechanisms that
      determine hotspot activity and propose a modified model to account for recent
      observations which show that recombination frequency at hotspots is sensitive to
      environmental conditions.

PMID- 12491007
TI  - The influence of the mismatch-repair system on stationary-phase mutagenesis in
      the yeast Saccharomyces cerevisiae.
AB  - Stationary-phase (also called adaptive) mutation occurs in non-dividing cells
      during prolonged non-lethal selective pressure, e.g. starvation for an essential
      amino acid. Because in such conditions no DNA replication is observed, mutations
      probably arise as a result of inefficient DNA repair. In order to understand the
      role of the yeast mismatch-repair (MMR) system in the mutagenesis of stationary
      phase cells, we studied the effects of deletions in genes encoding MutS- and MutL
      related proteins on the reversion frequency of the lys2 Delta Bgl frameshift
      mutation. We found that the level of Lys(+) reversion was increased in all MMR
      mutants, with the strongest effect observed in a MSH2 (MUTS homologue)-deprived
      strain. Disruption of the MSH3 or MSH6 genes (also MUTS homologues) resulted in
      elevation of the mutation frequency and rate, but to a lesser degree than that
      caused by the inactivation of MSH2. MutL-related proteins were also required for
      mutation avoidance in stationary-phase cells, but to a lesser extent than MutS
      homologues. Among MutL homologues, Mlh1 seems to play the major role in this
      process, while Pms1 and Mlh3 are partially redundant and appear to substitute for
      each other. These data suggest that MMR proteins, particularly MutS homologues,
      are involved in the control of mutability in stationary-phase yeast cells.

PMID- 12491008
TI  - Up-regulation of tRNA biosynthesis affects translational readthrough in maf1
      delta mutant of Saccharomyces cerevisiae.
AB  - Maf1p is a negative effector of RNA polymerase III in yeast. The maf1-delta
      mutation caused an increase in the level of cellular tRNAs, but a decrease of
      translational readthrough at nonsense codons. Using the lacZ- luc dual gene
      reporter system, we detected an almost twofold diminution of UAA and UAG
      readthrough in maf1-delta compared with the parental strain. The maf1-delta
      mutation did not affect the rate of protein biosynthesis and growth at standard
      conditions, but resulted in temperature-sensitive growth on non-fermentable
      carbon sources. We examined the correlation of the temperature sensitive and
      antisuppression phenotypes of maf1- Delta using a colour phenotype assay in the
      ade2-1 SUP11 strain. Antisuppression, but not the temperature-sensitive growth
      defect, was compensated either by increased dosage of SUP11or by [PSI(+)], the
      prion form of the translation termination factor Sup35p. Summarizing, the
      elevated tRNA levels in maf1- Delta increase translational fidelity and,
      independently, affect growth under special conditions.

PMID- 12491009
TI  - Genomic evidence for mating abilities in the asexual pathogen Aspergillus
      fumigatus.
AB  - The filamentous fungus Aspergillus fumigatus is one of the causes of invasive
      lung disease in immunocompromised individuals. It is classified as asexual
      because no direct observation of mating or meiosis has been reported. Sequencing
      of the complete genome by an international collaboration, including the Wellcome
      Trust Sanger Institute (UK) and The Institute for Genomic Research (TIGR, USA),
      has made most of the genomic sequence information from A. fumigatus publicly
      available. By searching the incomplete genome sequence of A. fumigatus, I have
      identified the coding capacity for a set of proteins that could be involved in
      mating and the pheromone response pathway. These include one putative mating-type
      gene, one gene encoding a pheromone and two pheromone-receptor genes. The mating
      type gene encodes a high-mobility group domain protein exhibiting significant
      similarity with mating-type proteins from sexually reproducing filamentous
      ascomycetes. The pheromone gene is predicted to encode a precursor pheromone that
      is processed by a KEX2-like protease to yield a pheromone that is structurally
      similar to the alpha-factor of the yeast Saccharomyces cerevisiae. In addition,
      the deduced gene products of the receptor genes are putative seven-transmembrane
      proteins, which display a high-level amino acid identity with the a-factor
      receptor Ste3p and the alpha-receptor Ste2p of S. cerevisiae, respectively. The
      identification of these homologues suggests the existence of a sexual cycle in A.
      fumigatus.

PMID- 12491010
TI  - Identification of putative genes involved in the development of Tuber borchii
      fruit body by mRNA differential display in agarose gel.
AB  - In order to analyse gene expression during fruit body development of the
      ectomychorrizal fungus Tuber borchii Vittad., a modified differential display
      procedure was set up. The procedure used is easier and faster than the
      traditional one and generates reproducible cDNA banding patterns that can be
      resolved on a standard ethidium bromide-agarose gel. From 16 cDNA fingerprints,
      25 amplicons with apparent differential expression were identified and cloned
      without a previous reamplification. Fifteen clones showed significant similarity
      to known proteins that are involved in dikaryosis and fruiting, cell division,
      transport across membranes, mitochondrial division, intermediary metabolism,
      biosynthesis of isoprenoid compounds and putative RNA/DNA binding. Northern blot
      analyses confirmed that seven cDNAs were indeed differentially expressed during
      fruit body development. The characterisation of these cDNAs represents a starting
      point in understanding the molecular mechanisms of cellular differentiation
      leading to the development of the T. borchii fruit body.

PMID- 12491011
TI  - Inducibility studies with the arbuscular mycorrhizal fungus Glomus mosseae 3
      phosphoglycerate kinase (PGK) gene promoter.
AB  - Arbuscular mycorrhizal (AM) fungi are a multifaceted group of mutualistic
      symbionts that are common to terrestrial ecosystems. The role of AM fungi within
      processes related to carbon (C) dynamics of the plant-root-soil system are of
      global significance. An understanding of the C metabolism of AM fungi within the
      symbiotic and asymbiotic stages of their lifecycle is a necessary pre-requisite
      to understanding the mechanisms of C movement. This investigation studies the
      regulation of the Glomus mosseae (Gm) 3-phosphoglycerate kinase ( PGK) gene
      promoter by different C sources. The suitability of studying the GmPGK promoter
      (P(GmPGK)) within Saccharomyces cerevisiae was confirmed by complementation of a
      S. cerevisiae pgk (-) mutant with an expression vector carrying the P(GmPGK)
      driving the expression of the S. cerevisiae PGK gene. The inducibility of the
      P(GmPGK) to different C sources was studied by creating a P(GmPGK)-luciferase
      fusion, which was introduced into a S. cerevisiae expression vector and used to
      transform S. cerevisiae. The P(GmPGK)-luciferase fusion was tested for expression
      within S. cerevisiae by RT-PCR analysis and was shown to be expressing the
      luciferase gene. C upshift studies were completed to evaluate the inducibility of
      this promoter by different C sources. The sources raffinose, glycerol and glucose
      significantly induced the P(GmPGK), whereas the sources galactose, succinate and
      sucrose had the lowest transcriptional responses. Semi-quantitative RT-PCR was
      used to establish gene expression patterns of GmPGK during spore germination; and
      up-regulation of the GmPGK gene was observed.

PMID- 12491012
TI  - Mitochondrial RNA editing truncates a chimeric open reading frame associated with
      S male-sterility in maize.
AB  - Adjacent mitochondrial open reading frames orf355 and orf77 are associated with S
      cytoplasmic male sterility (CMS-S) in maize, but the mechanisms leading to
      collapse of developing CMS-S pollen are unknown. Sequence similarity between
      orf77 and the mitochondrial ATP synthase subunit 9 (atp9) locus led us to examine
      RNA editing in orf77 and atp9 transcripts of pre-collapse CMS-S microspores.
      Editing of atp9 was not influenced by the presence of orf77 transcripts. Sequence
      analysis of cDNA clones demonstrated that atp9 transcripts are fully edited in
      CMS-S microspores. Orf77 nucleotides corresponding to edited nucleotides in atp9
      were either not edited or edited inefficiently within the context of orf77,
      perhaps due to limited conservation of flanking sequences between orf77 and atp9.
      However, eight of ten orf77 cDNA clones carried an unexpected terminating edit
      that truncated orf77 to predict a peptide of 17 amino acids (ORF17) sharing
      significant identity with the C-terminal transmembrane domain of the ATP9
      protein.

PMID- 12491013
TI  - Percutaneous transluminal angioplasty of dysplastic stenoses of the renal artery:
      results on 70 adults.
AB  - PURPOSE: Retrospective analysis of the dilatation (PTRA) of renal arterial
      dysplastic stenosis (RADS). METHODS: Seventy patients suffering from hypertension
      (87 RADS) were treated at our institution for medial (83%) or non-classified
      fibrodysplasias (17%). Four patients suffered from renal insufficiency. Two
      endoprostheses were implanted. We evaluated blood pressure with the USCSRH
      criteria and renal insufficiency with the Martin criteria. RESULTS: Ninety-five
      percent technical success and 87.9% clinical success for blood pressure were
      obtained, with worse results for patients older than 57 years or with a history
      of hypertension greater than 9 years. Results were better when the RADS was
      responsible for an ipsilateral renal atrophy or for poorly controlled
      hypertension. No renal insufficiency worsened during the follow-up. CONCLUSION:
      PTRA is a first-line treatment for renovascular hypertension caused by RADS. The
      results were encouraging despite a high average age of the subjects and frequent
      associated extrarenal vascular lesions.

PMID- 12491014
TI  - Intracardiac echocardiography evaluation in secundum atrial septal defect
      transcatheter closure.
AB  - PURPOSE: This study was designed to assess the balloon sizing maneuvers and
      deployment of an Amplatzer Septal Occluder (ASO). In addition, intraprocedural
      balloon sizing was compared with off-line intracardiac echocardiographic
      measurements. METHODS: The intracardiac echocardiography (ICE) measurements were:
      maximum transverse and longitudinal atrial septal defect (ASD) diameters in the
      aortic valve and four-chamber planes; area of the ASD and its equivalent circle
      diameter. Thirteen consecutive patients underwent transcatheter implantation of
      an ASO device using ICE guidance under local anesthesia. The device matching the
      balloon sizing diameter of the defect was implanted. Qualitative ICE assessment
      of the ASO devices implanted was performed off line. RESULTS: The mean equivalent
      circle diameter predicted by ICE was 24.40 +/- 5.61 mm and was significantly
      higher (p = 0.027) than the ASD measured by balloon sizing (21.38 +/- 5.28 mm).
      Unlike previous studies we did not find any correlation between the two
      measurements (correlation coefficient = 0.47). Only four of the 13 patients had
      optimal device positioning as shown by the qualitative ICE evaluation, whereas
      the remaining nine patients had inadequate device placement. This resulted in a
      waist diameter that was an average 26.1% undersized in seven patients and 12.7%
      oversized in two patients. Five of the seven patients with an undersized device
      had ASO-atrial septum misalignment with leftward device deviation. CONCLUSION:
      The ICE images allowed careful measurement of the dimensions of the ASD and
      accurately displayed the spatial relations of the ASO astride the ASD. Moreover,
      use of the ICE measurement led to selection of a different size of device in
      comparison with those of balloon sizing. The clinical benefit of this new
      approach needs to be rigorously tested.

PMID- 12491015
TI  - Efficacy of local molsidomine delivery from a hydrogel-coated angioplasty balloon
      catheter in the atherosclerotic porcine model.
AB  - PURPOSE: To evaluate the therapeutic effects of local molsidomine delivery via a
      hydrogel-coated angioplasty balloon catheter during overstretch angioplasty in
      atherosclerotic swine iliac vessels. Molsidomine is retained in the arterial wall
      after local delivery for more than 72 hr and is slowly metabolized into
      linsidomine, releasing nitric oxide (NO). METHODS: A hydrogel-coated angioplasty
      balloon catheter was used to both deliver drug locally (150 mg molsidomine or
      placebo in the contralateral vessel) and dilate iliac vessels in nine Pietrin
      pigs that had been on an atherogenic diet for 5 months. Animals were killed at 3
      hr (n = 2), 24 hr (n = 3) and 3 months (n = 3) after treatment. Iliac arteries
      were examined for wall pulsatility, histomorphometry, cell proliferation and
      platelet aggregation. RESULTS: No significant therapeutic effects were detected 3
      hr after treatment. At 24 hr, wall pulsatility, thromboresistance and vascular
      cell homeostasis were significantly restored in the molsidomine-treated versus
      placebo group. At 3 months, molsidomine inhibited restenotic lesion development,
      except in scarred areas of histologically detectable adventitial/medial
      dissection. CONCLUSION: Local delivery of concentrated molsidomine from a
      hydrogel-coated angioplasty balloon catheter resulted in early NO-dependent
      vasodilation/stress normalization and antithrombotic and antiproliferative
      effects. In the medium term, molsidomine inhibited restenosis in the absence of
      vessel dissection.

PMID- 12491016
TI  - Endovascular treatment of central vein stenoses and/or occlusions in hemodialysis
      patients.
AB  - PURPOSE: To report our experience and results with the endovascular treatment of
      central vein stenoses and occlusions in hemodialysis patients. METHODS: Between
      October 1999 and August 2001 (22 months) we performed 22 interventional
      procedures in 14 hemodialysis patients (8 women, 6 men) ranging in age from 38 to
      87 years (mean 76 years). The indication for intervention was stenosis (n = 10)
      or occlusion (n = 4) of a central vein in the upper arm used for dialysis in
      patients with arm swelling and/or shunt malfunction. All patients had a previous
      history of subclavian vein cannulation. There were six percutaneous transluminal
      angioplasties (PTAs) and eight primary stent placements and eight repeat
      interventions. Seven were for restenoses and one for early occlusion, with two
      secondary stent placements and six PTA of in-stent stenoses. In two patients a
      second stent was implanted. The mean follow-up was 8.5 months (range 1-19
      months). All stents were self-expandable with diameters ranging from 9 to 16 mm.
      RESULTS: All but one of the procedures was technically successful (95%, n = 21).
      The patient with an unsuccessful procedure died 1 month after the procedure, but
      the death was not procedure-related. During follow-up three patients died with a
      patent shunt and central vein, none of them in connection with the procedure. No
      complication occurred during the interventional procedures. One patient was lost
      to follow-up. The primary patency rate at 12 months was 43%, with a primary
      assisted patency rate of 83% and a secondary patency rate of 100% (n = 6).
      CONCLUSION: Central vein stenoses and occlusions are associated with previous
      subclavian vein cannulation. They are a serious problem in hemodialysis patients
      with a shunt on the same arm. Endovascular treatment is a suitable option for
      these patients.

PMID- 12491017
TI  - Renal transplant ureteral stenosis: treatment by self-expanding metallic stent.
AB  - We report the use of a metallic stent in a transplant ureteral stenosis. A 28
      year-old man with chronic renal failure due to chronic pyelonephritis, who
      received a living-donor renal transplant, presented with transplant ureteral
      stenosis. The stenosis was unresponsive to balloon dilation and was treated by
      antegrade placement of a self-expanding Memotherm stent. The stented ureter
      stayed patent for 3 years. It may be reasonable to treat post-transplant ureteral
      stenosis resistant to balloon dilation with self-expanding metallic stents.
      However, long-term follow-up is required to evaluate the efficacy of this
      treatment.

PMID- 12491018
TI  - Nonfunctioning renal allograft embolization as an alternative to graft
      nephrectomy: report on seven years' experience.
AB  - PURPOSE: Graft nephrectomy is the treatment of choice in patients with graft
      intolerance syndrome, but it is associated with high morbidity and mortality
      rates. Renal vascular embolization has been suggested as a possible alternative.
      The aim of this study was to evaluate the efficacy and safety of arterial
      embolization of these nonfunctioning transplanted kidneys. METHODS: Twenty-six
      transplanted kidneys in 25 patients with irreversible renal graft rejection and
      graft intolerance who underwent arterial embolization at our center from August
      1994 to April 2001 were analyzed for procedural success and long-term outcome.
      Embolization was performed with absolute alcohol or with polyvinyl alcohol
      (Ivalon) and coils. RESULTS: Twenty-four of the 26 (92%) procedures were
      technically successful, but in one patient only partial occlusion of one of two
      renal arteries was achieved, and in another the renal artery was already
      completely occluded. There were two major complications: emphysematous
      pyelonephritis necessitating nephrectomy and groin abscess that was drained.
      Follow-up ranged from 8 to 84 months. Clinical success was achieved in 24 of the
      26 procedures (92%), and only in one patient did embolization fail to relieve the
      symptoms, and nephrectomy was performed 3 months later. CONCLUSION: Renal
      vascular embolization is a simple, safe and effective technique for the treatment
      of nonfunctioning renal allografts associated with graft intolerance syndrome. We
      suggest that it be considered the treatment of choice.

PMID- 12491019
TI  - Pancreatitis-associated splenic artery pseudoaneurysm: endovascular treatment
      with self-expandable stent-grafts.
AB  - We present a patient with a splenic artery pseudoaneurysm (SAPA) treated with
      placement of self-expandable stent-grafts. The procedure was complicated by stent
      graft migration, but successful management resulted in lasting exclusion of the
      SAPA, while the patency of the splenic artery was preserved. This is the first
      report of self-expandable stent-graft treatment of SAPA.

PMID- 12491020
TI  - Treatment of lymphangiomas with OK-432 (Picibanil).
AB  - PURPOSE: To determine the efficacy of OK-432 sclerotherapy in the treatment of
      lymphangiomas. METHODS: The treatment was begun for 14 patients with
      lymphangioma. The age range of the patients at the time of the first injection
      was from 10 months to 42 years. Eleven of the lesions involved the head and neck
      region, two the thorax and one was localized in the extremity. Prior to treatment
      all patients were investigated with either magnetic resonance imaging, computed
      tomography, ultrasound or a combination of these modalities. The injections were
      performed with ultrasound and/or fluoroscopic guidance. Eight patients received
      OK-432 as first-line treatment; five were treated after surgery and one after
      medical therapy. On average, 2.2 intracystic injections were performed per
      patient. Nine of the lesions were macrocystic and five were mixed lesions.
      RESULTS: Eleven patients showed complete or marked response to the OK-432
      sclerotherapy, two patients had moderate shrinkage of their lesions and only one
      patient showed no response to therapy. Macrocystic lesions showed the best
      response to therapy. Those patients who received OK-432 as first-line treatment
      showed complete or marked response. CONCLUSION: It was found that treatment of
      lymphangiomas with OK-432 was safe and effective.

PMID- 12491021
TI  - Intraaortic stabilization of the AneuRx stent-graft system: a useful adjunct to
      minimize device migration.
AB  - The deployment of a Medtronic AneuRx stent-graft system for endovascular
      abdominal aortic aneurysm repair requires a series of precise maneuvers that
      include positioning the primary delivery catheter in the infrarenal aorta,
      retracting the graft-covering sheath, and withdrawing the stainless steel
      runners. The last step allows the stent-graft to fully expand and attach to the
      non-aneurysmal aorta and iliac arteries. Such maneuvers may cause the stent-graft
      to move caudally if the device is placed in a severely angulated aortic neck. We
      describe a simple, coaxial, stabilization technique utilizing the contralateral
      introducer sheath which minimizes potential caudal migration of the stent-graft
      in angulated aortic necks during runner withdrawal.

PMID- 12491022
TI  - Percutaneous placement of metallic stents in malignant biliary obstruction: one
      stage or two-stage procedure? Pre-dilate or not?
AB  - The aim of this paper was to evaluate the necessity of percutaneous transhepatic
      catheter drainage and balloon dilation procedures performed before stent
      insertion. One hundred and twenty-six patients with unresectable malignant
      biliary obstruction underwent palliative therapy by means of percutaneous
      transhepatic placement of 183 metallic biliary endoprotheses. Forty-four (35%)
      patients underwent metallic stent insertion in a one-stage procedure and 82 (65%)
      had undergone percutaneous transhepatic catheter drainage before stent insertion.
      Balloon dilation of the stenosis before stent placement (pre-dilation) was
      performed in 53 (42%) of 126 patients. The rate of the 30-day mortality was 11%,
      with no procedure-related deaths. The total rate of early complications was 29%,
      and 84% of these complications were due to percutaneous transhepatic catheter
      drainage and pre-dilation procedures. Percutaneous transhepatic catheter drainage
      and pre-dilation had no clinical or statistically significant effect on the
      patients' survival and stent patency rate. Percutaneous transhepatic catheter
      drainage and balloon dilation increased the cost of stent placement 18% and 19%,
      respectively. Palliation of malignant biliary obstruction with percutaneous
      transhepatic stent insertion should be done directly, in the simplest way,
      without performing percutaneous transhepatic catheter drainage and balloon
      dilation before stent placement. It is more useful, safe, and cost-effective.

PMID- 12491023
TI  - Movement, replication, and emigration rates of individual bacteria in a biofilm.
AB  - Single-cell behavior within a biofilm was observed over a period of several
      hours. The observations were converted into quantitative stochastic rules
      governing the behavior of individual cells within a biofilm. Such a quantitative
      summary provides not only a concise description of the results but also
      information helpful when constructing computer models of dynamic biofilm systems.
      The time to division, emigration, and rate of motility of individual green
      fluorescent protein labeled Pseudomonas aeruginosa PAO1 cells in a 3-10 microm
      thick biofilm containing predominantly non-GFP labeled cells were calculated
      based on images of individual cells collected at 15-min time intervals. The
      biofilms were grown in flow cells and the images captured with a confocal laser
      microscope. Cells destined to emigrate are more active than those that remain;
      the geometric means for velocities in the biofilm are 1.0 microm/h for remaining
      cells and 1.5 microm/h for emigrating cells. The median time to emigration was
      2.0 h. During the experimental observation period, the estimated probability for
      emigration is 0.44, illustrating that a substantial number of bacteria leave the
      field of view. Cells emigrate at a median time one-third that of the median time
      to replication. Specifically, the median time for cells to divide was 6.9 h, and
      it was estimated that 10% of the cells had a time to division greater than 10 h.

PMID- 12491024
TI  - In situ identification by fluorescently labeled oligonucleotide probes of
      morphologically similar, closely related ciliate species.
AB  - Ciliate protozoa are important members of microbial communities in which they
      play specific ecological roles. The determination of single species distribution
      is fundamental for food web analysis, but species recognition, which is mainly
      based on morphological characters, is often difficult between closely related
      species. The use of species-specific, purposely designed, fluorescently labeled
      probes for in situ hybridization is here presented as an easy and fast
      identification method for three closely related species belonging to the
      widespread genus Euplotes, namely E. crassus, E. vannus, and E. minuta, that in
      spite of their remarkable morphological similarity have significant metabolic and
      ecological differences. These three species can be detected simultaneously,
      provided the probes employed are bound to different fluorescent dyes: in this way
      their relative abundance and their population dynamics in the natural environment
      can be evaluated. As more ciliate sequences become available in databases,
      species-specific probes can be designed for other ciliates, thus rendering the
      application of the method of more general importance. The probes used in this
      study may also provide a tool to prevent erroneous species identification in
      future studies.

PMID- 12491025
TI  - Interaction between naltrexone and oral THC in heavy marijuana smokers.
AB  - RATIONALE: Studies in non-human animals suggest that opioid antagonists block the
      reinforcing effects of cannabinoids. OBJECTIVE: The present studies in humans
      investigated how naltrexone modulates (1) the subjective and physiological
      effects of oral THC in comparison to methadone, (2) the reinforcing effects of
      oral THC, and (3) plasma levels of oral THC. METHODS: In study 1, marijuana
      smokers (n=9) received naltrexone (0, 50 mg) followed 30 min later by THC (0, 15,
      30 mg) or methadone (5, 10 mg). Subjective effects, task performance, pupillary
      diameter, and cardiovascular parameters were measured repeatedly. In study 2a,
      marijuana smokers (n=23) were randomly assigned to one THC dose condition (0, 15
      or 30 mg). One set of color-coded capsules containing THC and active naltrexone
      (50 mg) was given in one session, while another set of color-coded capsules
      containing THC and placebo naltrexone was given in another session. In the final
      three sessions, participants chose which color capsules they would receive. In
      study 2b, a subset of participants from study 2a (n=7) received naltrexone (0, 50
      mg) 30 min prior to oral THC (30 mg) administration, and blood was drawn
      repeatedly. RESULTS: Pretreatment with naltrexone significantly increased many of
      the "positive" subjective effects of oral THC (30 mg) e.g. ratings of Good Drug
      Effect and Capsule Liking. Naltrexone tended to increase the reinforcing effects
      of oral THC (30 mg), as indicated by performance in a drug choice test.
      Naltrexone did not alter plasma THC levels. CONCLUSIONS: These studies
      demonstrate that naltrexone increases the subjective effects of oral THC. Thus,
      oral THC's effects are enhanced rather than antagonized by opioid receptor
      blockade in heavy marijuana smokers.

PMID- 12491026
TI  - Neurochemical and behavioral differences between d-methamphetamine and d
      amphetamine in rats.
AB  - RATIONALE: Methamphetamine (METH) and amphetamine (AMPH) are both abused
      psychostimulants. Although METH is generally accepted to be more addictive and
      potent than its analogue AMPH, there are no known neurobiological differences in
      action between the two drugs that may account for such differences. OBJECTIVE:
      METH and AMPH were compared to determine potential mechanisms for such
      differences between the two drugs in order to provide new targets for the
      treatment of METH addiction. METHODS: Using in vivo microdialysis on rats,
      dopamine (DA), DA metabolites, and glutamate (GLU) release in the nucleus
      accumbens (NAC) and prefrontal cortex (PFC) were measured after administration of
      2 mg/kg, IP, of METH or AMPH. Based on the neurochemical differences between METH
      and AMPH, a locomotor activity study was designed to assess differences in
      locomotor activation for a range of doses (1-4 mg/kg, IP) of METH and AMPH and
      after pretreatment with intra-accumbens GLU antagonists. RESULTS: METH and AMPH
      raised NAC DA levels to a similar degree. In the PFC, both METH and AMPH raised
      DA levels, but METH was less effective than AMPH. In the NAC, AMPH raised GLU
      levels but METH did not. In the PFC, METH raised GLU levels but AMPH did not. The
      locomotor activity dose response curve for METH had a lower peak than that of
      AMPH. This difference was blocked by pretreatment with either the GLU NMDA
      antagonist AP5 or the GLU AMPA antagonist DNQX locally in the NAC. CONCLUSIONS:
      This study reveals several previously unknown neurochemical and behavioral
      differences between METH and AMPH. Based on these results, it is suggested that
      new pharmacotherapeutic agents that produce augmentations of NAC GLU or PFC DA
      activity, or perhaps inhibition of PFC GLU activity, may someday be useful for
      the treatment of METH addiction.

PMID- 12491027
TI  - Tacrine-scopolamine interactions on state-dependent retrieval.
AB  - OBJECTIVES: This study examined the effects of tacrine on scopolamine-induced
      state-dependence. METHODS: Rats were trained to complete an FR10 schedule of
      lever presses for milk reward within 120 s after the onset of an operant session
      and were subsequently tested for the retrieval of the response in either the same
      or a different, pharmacologically defined, state. RESULTS: In rats trained with
      2.5 mg/kg scopolamine, the pre-test administration of 10 mg/kg tacrine prevented
      scopolamine from enabling the retrieval that otherwise occurred when animals were
      both trained and tested with scopolamine. However, retrieval of the response was
      also hampered in animals that were trained with tacrine-scopolamine co
      administration and tested with saline, and vice versa, indicating that the co
      administration of tacrine and scopolamine did not induce the saline-associated,
      presumably normal state. At >/=2.5 mg/kg doses, tacrine itself induced state
      dependence with both tacrine-to-saline and saline-to-tacrine state changes.
      CONCLUSION: The findings indicate that tacrine is unable to normalize the
      particular mnesic state induced by scopolamine. The data may elucidate tacrine's
      limited therapeutic efficacy insofar as scopolamine's mnesic actions both model
      human pathology and are due to scopolamine producing state-dependence.

PMID- 12491028
TI  - Salivary cotinine levels in human tobacco smokers predict the attentional
      validity effect size during smoking abstinence.
AB  - RATIONALE: The link between attention and brain cholinergic neurotransmission is
      widely accepted. Human chronic tobacco smokers maintain high levels of nicotine
      in plasma and body tissues and show enhanced attentional orienting and other
      attentional tasks. OBJECTIVE: We wished to test whether abstinence from smoking
      caused levels of the nicotine metabolite cotinine to decline and attentional
      enhancement to be reduced in a correlated manner. METHODS: The levels of salivary
      cotinine and behavioral performance on a cued target detection task were measured
      in chronic, adult tobacco smokers over a 5-day abstinence period. Control groups
      assessed over the same time period include non-smokers, smokers that did not
      abstain from tobacco, and smokers that abstained for 4 days and smoked on the
      last day. RESULTS: In all groups with tobacco exposure, the levels of cotinine
      declined steadily with time after abstinence, reaching near zero levels at day 5.
      During this period, reaction times declined as well for all groups, due in part
      to task practice effects. In contrast, the validity effect, which indexes
      attentional allocation, increased with abstinence and was inversely related to
      cotinine levels in groups exposed to tobacco. CONCLUSIONS: We conclude that 1)
      nicotine abstinence increases the attentional validity effect, and 2) this
      increase is indexed by salivary cotinine, and 3) that control levels of
      attentional performance are achieved after 3-4 days of tobacco abstinence.

PMID- 12491029
TI  - Administration of the D1-like dopamine receptor antagonist SCH-23390 into the
      medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement
      of drug-seeking behavior in rats.
AB  - RATIONALE: A growing literature indicates that increased dopamine transmission in
      the nucleus accumbens contributes to priming-induced reinstatement of cocaine
      seeking behavior. OBJECTIVES: The present experiments were designed to assess the
      role of D(1)-like dopamine receptors in the nucleus accumbens core and shell
      subregions in cocaine priming-induced reinstatement of drug seeking. METHODS:
      Rats were trained to lever press for cocaine using a fixed ratio (FR) 5 schedule
      of reinforcement. Drug-seeking was measured by active lever presses during daily
      2-h sessions. After approximately 30 days of cocaine self-administration, the
      animals underwent an extinction phase during which cocaine was replaced with
      saline. Daily extinction sessions were conducted until responding was
      consistently less than 10% of the response rate maintained by cocaine self
      administration. After the extinction phase, priming-induced reinstatement of
      cocaine-seeking behavior was assessed. RESULTS: Cocaine dose-dependently
      reinstated cocaine seeking, with robust drug seeking at 10 mg/kg cocaine.
      Administration of the D(1)-like dopamine receptor antagonist, SCH-23390 (0.1-1.0
      micro g), directly into the medial nucleus accumbens shell dose-dependently
      attenuated drug seeking induced by 10 mg/kg cocaine. Microinjection of 1.0 micro
      g SCH-23390 into either the nucleus accumbens core or lateral septum had no
      influence on cocaine-seeking behavior. CONCLUSIONS: These results indicate that
      stimulation of D(1)-like dopamine receptors in the medial nucleus accumbens shell
      contributes to drug-induced reinstatement of cocaine-seeking behavior.

PMID- 12491030
TI  - Ultrarapid high-dose methadone detoxification.

PMID- 12491031
TI  - Cannabis is more than simply delta(9)-tetrahydrocannabinol.

PMID- 12491033
TI  - Children as a sensitive subgroup and their role in regulatory toxicology: DGPT
      workshop report.
AB  - There is increasing discussion that children might be considered as a specific
      subgroup in public health regulations which could be more sensitive than the
      average "adult" human being. Differences between children and adults, with regard
      to susceptibility towards toxicants, may result from a combination of
      toxicokinetic, toxicodynamic and exposure factors. Kinetic factors are of
      importance mainly in the early postnatal period, largely as the result of
      immature elimination systems, i.e. metabolising enzymes and/or renal function.
      Specific vulnerability may prevail during several time periods, related to the
      development and maturation of organs (for example, brain, bone, endocrine
      system). For some substances, it has been shown that children at a specific age
      are less sensitive than adults. Specific exposures of toddlers to environmental
      chemicals may be high due to their moving behaviour and hand-to-mouth activities.
      Existing scenarios and models for exposure of children should be improved, in
      particular with respect to different ages. The outcome of model calculations must
      be verified by human biomonitoring analysis. At present, there is ongoing
      discussion of toxicological test models suitable to delineate human postnatal
      development. Experience with infant-orientated test systems is scarce (for
      example in developmental neurotoxicity). In general, tools for predicting
      toxicological sensitivity of children must be further improved. Regulators should
      also be aware that reduction of lifestyle-related toxic exposures such as smoking
      and drug abuse in children and adolescents is now an increasing public health
      problem in many countries.

PMID- 12491034
TI  - Children as a special population at risk--quinolones as an example for
      xenobiotics exhibiting skeletal toxicity.
AB  - The sensitivity of the immature skeletal system during postnatal mammalian
      development was discussed during the workshop "Children as a Sensitive Subgroup
      and their Role in Regulatory Toxicology" (Schwenk et al. 2002, Arch Toxicol, in
      press). As a typical example of xenobiotics exhibiting this extraordinary type of
      toxicity, the quinolone-induced effects on cartilage, bone growth, and tendons
      were considered in depth. Animal experiments indicate that chondrotoxicity of
      quinolones can affect articular cartilage depending on the developmental stage.
      Results from studies with pipemidic acid in dogs at various developmental stages
      from 1 week old to 17 months old showed pronounced effects in the most sensitive
      age groups: 3- to 6-month-old dogs exhibited gait alterations and lameness, but
      signs of toxicity were not observed in 12- or 17-month-old dogs. Similarly,
      experiments performed in rats indicate that they exhibit the highest sensitivity
      for articular cartilage defects at a certain stage of development between 3 and 6
      weeks postnatally; mature articular cartilage does not seem to be a target for
      quinolone-induced toxicity. Some very limited data indicate that in animals at an
      early developmental phase the epiphyseal growth plate can also be damaged by
      quinolones, and that these effects are associated with irreversible bone damage
      and growth inhibition. Another manifestation of toxic effects of quinolones on
      connective tissue structures are tendopathies. For this effect, it is not quite
      clear whether juveniles are more susceptible than adults because clinical and
      experimental data seem to point in different directions. Pathogenesis of both
      effects can probably be explained by the magnesium-chelating properties of these
      drugs, leading to a deficit of functionally available magnesium and,
      subsequently, to radical formation and irreversible connective tissue lesions.
      However, unequivocal explanations for the phase-dependency of the effects are
      lacking.

PMID- 12491035
TI  - Alterations of metallothionein isomers in Hg(0)-exposed rat brain.
AB  - Previously we found that exposure to mercury vapor effectively induced brain
      metallothionein (MT) in rats. Here, using FPLC-gel chromatography, we examined
      time-dependent alterations in the MT isomers, MT-I/II and MT-III, following 3
      weeks of exposure. Rats were exposed to mercury vapor at 8.3 mg/m3 for 15 h in
      total over 5 consecutive days. Total MT levels in rat cerebrum and cerebellum
      increased by 65% and 155%, respectively, 24 h after the final exposure. The
      increased levels in both tissues remained unchanged for at least 2 weeks after
      termination of exposure. Interestingly, most MT in control rat cerebrum and
      cerebellum was accounted for by MT-III, with MT-I/II being less than 10%. Through
      mercury vapor exposure, MT-I/II was quickly induced to a significant extent in
      both tissues, reaching a level comparable to that of MT-III. The induction rate
      of MT-I/II in the cerebellum was somewhat higher than in the cerebrum.
      Chromatograms showed that the MT-I/II thus induced began to decline at an early
      stage in both tissues. In the cerebrum, the amount of MT-I/II on day 22 was about
      30% of the maximum level on day 1. On the other hand, the induction of MT-III was
      not that dramatic, but it did become evident, at least in the latter stage, when
      MT-I/II had begun to decrease. Thus, though the induction rate of MT-III was not
      as high as MT-I/II, it was sustained throughout the experimental period.

PMID- 12491036
TI  - Effect of methylmercury on histamine release from rat mast cells.
AB  - Methylmercury chloride (MeHgCl) is well known as a significant environmental
      hazard, particularly as a modulator of the immune system. As it is acknowledged
      that the critical effector cells in the host response participating in various
      biological responses are mast cells, we tried to define the possible contribution
      of mast cells in the development of methylmercury-evoked effects. We investigated
      the effects of methylmercury on the rat mast cell degranulation induced by non
      immunological stimuli (the selective liberator of histamine, compound 48/80, and
      calcium ionophore A23187) both in vivo and in vitro. Using the cells prepared
      from methylmercury-intoxicated rats through a 5-day treatment of MeHgCl (10
      mg/kg/day), we observed the suppression of calcium ionophore A23187- and 48/80
      induced histamine release, which was enhanced with time after treatment. Similar
      suppression was observed in the ionophore-stimulated release, when cells were
      prepared from rat with a single treatment of MeHgCl (20 mg/kg). It should be
      noted that when cells from the control rat were pre-incubated with methylmercury
      in vitro at a 10(-8) M concentration for 10 min, A23187 and compound 48/80
      stimulated histamine release was significantly enhanced. However, when the pre
      incubation period was prolonged to 30 min, the release was suppressed. An
      increase in the methylmercury concentration to 10(-6) M also suppressed the
      histamine release. These results show that methylmercury treatment can modify
      mast cell function depending on concentration and time, and might provide an
      insight into the role of mast cells in the development of methylmercury
      stimulated effects.

PMID- 12491037
TI  - Standardized extracts of flavonoids increase the viability of PC12 cells treated
      with hydrogen peroxide: effects on oxidative injury.
AB  - Oxidative stress plays an important role in cell death associated with many
      diseases. In the present study, concentration-dependence of hydrogen peroxide on
      rat pheochromocytoma (PC12) cell viability was studied. Preventive effects of
      antioxidants on the viability of these cells treated with 2 mM hydrogen peroxide
      were compared. Trolox and Stobadine, as chain-breaking antioxidants were studied
      in comparison with standardized extracts of flavonoids of Ginkgo biloba and
      Pycnogenol, known as agents effective in several diseases. All antioxidants
      increased the viability of hydrogen peroxide-treated PC12 cells. Flavonoid
      extracts were more effective than Trolox and Stobadine. Antioxidants were most
      effective if present after the oxidative treatment. As expected, the preloading
      with antioxidants was without effect on cell viability. Correlations between
      viability increase induced by antioxidants, and content of oxidation products of
      proteins and lipids were studied at concentrations of antioxidants mostly
      effective in preventing cell death: Trolox (10 microM), Stobadine (30 microM),
      Ginkgo biloba (160 microg/ml), Pycnogenol (100 microg/ml). In these
      concentrations, antioxidants did not statistically significantly decrease the
      content of protein carbonyls, with exception of Stobadine, which had no effect.
      Ginkgo biloba, Trolox and Stobadine intensively decreased the content of
      malondialdehyde, a product of lipid peroxidation. Pycnogenol was without any
      preventive effect. Concentrations of antioxidants with a large effect on
      viability of PC12 cells were not effective in preventing oxygen radical-induced
      injury of proteins. Antioxidants prevented the oxidative injury of lipids more
      effectively than that of proteins.

PMID- 12491038
TI  - Cytometric determination of novel organotellurium compound toxicity in a
      promyelocytic (HL-60) cell line.
AB  - The increasing use of tellurium compounds in organic synthesis, industrial
      applications, and as a possible component in pesticides means that its
      introduction into the environment will increase in the future. Therefore,
      knowledge of the relative toxicity and mode of toxic action of tellurium
      containing compounds is important. The studies detailed here used three model
      compounds: diphenyl ditelluride, 3,3'-diaminodiphenyl ditelluride, and 4,4'
      diisopropyldiphenyl ditelluride. Experiments with human promyelocytic (line HL
      60) cells indicate that all of the organotellurium compounds induce an apoptotic
      form of cell death. The induction of apoptosis occurs in a time- and dose
      dependent manner as assayed by three different analytical methods: fluorescence
      microscopy, gel electrophoresis, and flow cytometry. Apoptotic cells were evident
      as early as 2 h following treatment with 1x10(-6) M concentrations of the
      compounds. Based on these results, future care should be afforded these compounds
      in laboratory as well as industrial settings.

PMID- 12491039
TI  - Association between head and neck cancer and microsomal epoxide hydrolase
      genotypes.
AB  - Tobacco-associated carcinogens are catalyzed by microsomal epoxide hydrolase
      (mEH). Combinations of the Y113H and H139R polymorphic EPHX1 variants have been
      assumed to alter the enzyme activity and thus the risk of squamous cell head and
      neck cancer (SCCHN). Based on in vitro data, a putative low, medium and high mEH
      activity has been associated with combinations of these genotypes, and the
      respective activity categories have been frequently used in the estimation of
      risks for smoking-related cancers. We investigated the SCCHN risk for EPHX1
      genotypes among 280 cases and 289 controls. We could not detect main effects of
      the EPHX1 genotypes, but a smaller risk of the 139HR genotype in smokers (odds
      ratio, OR, 0.57; 95% confidence interval, CI, 0.34-0.95). We could not confirm an
      increase of the SCCHN risk for genotype combinations according to a putative
      medium and high enzyme activity (OR 1.28, 95% CI 0.84-1.96; OR 0.98, 95% CI 0.58
      1.64, respectively), but a significant heterogeneity of the estimated risks for
      the singular genotypes within these categories among smokers ( P=0.02). Further,
      p53 mutations among smoking cases were less frequent in the group with a putative
      high enzyme activity, although insignificant due to small numbers (OR 0.54, 95%
      CI 0.13-2.17). This supports uncertainties in categorizing genotypes with respect
      to limited enzyme activity data, especially when taken from in vitro experiments.

PMID- 12491040
TI  - Hibiscus protocatechuic acid inhibits lipopolysaccharide-induced rat hepatic
      damage.
AB  - Hibiscus protocatechuic acid (PCA), a phenolic compound found in the dried
      flowers of Hibiscus sabdariffa L. (Malvaceae), was demonstrated to have an
      antioxidant effect in vitro and in vivo, and an antitumor property in our
      previous study. In the present study, we used lipopolysaccharide (LPS, an
      endotoxin) to induce rat liver inducible nitric oxide synthase (iNOS), and found
      that pretreatment with PCA decreased the liver iNOS and the serum total nitrite
      induced by LPS. Our investigation showed that pretreatment of rats with PCA (0.2
      and 0.5 mmol/kg dosed by gavage) for 5 days significantly decreased the serum
      levels of the hepatic enzyme markers alanine- and aspartate aminotransferase
      (ALT, alanine aminotransferase; AST, aspartate aminotransferase) induced by the 6
      h treatment with LPS (i.p.; 5 mg/kg). Histopathological evaluation of the rat
      livers revealed that PCA reduced the incidence of liver lesions induced by LPS,
      including neutrophil infiltration, congestion, and liver cell swelling induced by
      LPS in rats. We conclude that PCA, an antioxidant, presents an inhibitory
      potential on iNOS and hepatic damage induced by LPS.

PMID- 12491041
TI  - Thimerosal induces micronuclei in the cytochalasin B block micronucleus test with
      human lymphocytes.
AB  - Thimerosal is a widely used preservative in health care products, especially in
      vaccines. Due to possible adverse health effects, investigations on its
      metabolism and toxicity are urgently needed. An in vivo study on chronic toxicity
      of thimerosal in rats was inconclusive and reports on genotoxic effects in
      various in vitro systems were contradictory. Therefore, we reinvestigated
      thimerosal in the cytochalasin B block micronucleus test. Glutathione S
      transferases were proposed to be involved in the detoxification of thimerosal or
      its decomposition products. Since the outcome of genotoxicity studies can be
      dependent on the metabolic competence of the cells used, we were additionally
      interested whether polymorphisms of glutathione S-transferases (GSTM1, GSTT1, or
      GSTP1) may influence the results of the micronucleus test with primary human
      lymphocytes. Blood samples of six healthy donors of different glutathione S
      transferase genotypes were included in the study. At least two independent
      experiments were performed for each blood donor. Significant induction of
      micronuclei was seen at concentrations between 0.05-0.5 micro g/ml in 14 out of
      16 experiments. Thus, genotoxic effects were seen even at concentrations which
      can occur at the injection site. Toxicity and toxicity-related elevation of
      micronuclei was seen at and above 0.6 micro g/ml thimerosal. Marked individual
      and intraindividual variations in the in vitro response to thimerosal among the
      different blood donors occurred. However, there was no association observed with
      any of the glutathione S-transferase polymorphism investigated. In conclusion,
      thimerosal is genotoxic in the cytochalasin B block micronucleus test with human
      lymphocytes. These data raise some concern on the widespread use of thimerosal.

PMID- 12491042
TI  - A re-assessment of styrene-induced clastogenicity in mice in a subacute
      inhalation study.
AB  - To date, a number of in vivo cytogenetic assays have studied the clastogenicity
      (chromosome aberrations, micronuclei formation) in bone marrow of rodents exposed
      to styrene by various routes. The majority of all these cytogenetic experiments
      yielded negative findings (Scott and Preston, Mutat Res 318:175-203, 1994).
      Recently published data from a micronucleus test in mice exposed via inhalation
      for up to 21 days showed some positive response, but was not fully conclusive
      (Vodicka et al., Chem Biol Interact 137:213-227, 2001). Since this exposure
      regimen has considerable relevance for workplace exposure, the present study was
      performed to further elucidate these findings. NMRI mice were exposed by whole
      body inhalation to styrene concentrations of 750 mg/m3 and 1,500 mg/m3 for 1, 3,
      7, 14 and 21 consecutive days (6 h/day). Animals were killed directly after
      exposure and bone marrow was sampled for analysis of micronucleus induction.
      Under the experimental conditions used in the present investigation, there was no
      evidence of clastogenicity at any concentration or exposure interval.

PMID- 12491043
TI  - [Standardized procedure for suspected bone tumor].
AB  - Real bone tumors are rarely encountered in the daily routine of radiological
      practice. For a general radiologist or surgeon is therefore no need for a
      specialist knowledge on this field.However, he should be able to distinguish
      "leave-me-alone-lesions" in order to avoid unnecessary biopsies.A systematic
      approach towards the interpretation of osteolytic lesions in projection
      radiograms, e.g. according to the classification of Lodwick, is mandatory. CT and
      MRI are additional diagnostic tools and are indicated to clear up the true
      anatomy,e.g. in areas of superposition artefacts in conventional radiology (e.g.
      axial skeleton) and to determine the inner structure of a lesion, e.g. fatty
      tissue, liquid/solid. This paper highlights the advantages and disadvantages and
      the cost-effective use of the imaging modalities including scintigraphy in the
      diagnosis of bon tumors and tumor-like lesions. Guidelines for the management of
      bony lesions will be given in detail. The option and necessity for a specialist
      second opinion is emphasized.

PMID- 12491044
TI  - [Options for surgical treatment of malignant bone tumors].
AB  - Beside the susceptibility to a (neo-) adjuvant therapy, the surgical margin is
      the most important prognostic factor in the treatment of primary malignant bone
      tumors. If adjuvant therapy is not possible, the outcome of the disease depends
      on the selected surgical treatment. Limb salvage has proven to be a safe
      procedure for local tumor control and provides good functional results. The
      surgeon has to consider the best surgical option depending on the site and size
      of the tumor but also depending on the patient's age and the overall prognosis.
      Surgical techniques and possible complications of the most common procedures in
      tumor surgery are described.

PMID- 12491045
TI  - [The role of polychemotherapy in the management of malignant bone tumors].
AB  - Osteosarcoma,chondrosarcoma and Ewing tumors are the most common primary
      malignant bone tumors. Due to early hematogenous dissemination, surgery alone is
      able to cure less than 20% of patients with osteosarcoma. In Ewing-tumors less
      than 10% of patients will be cured with local treatment alone. By the use of
      aggressive polychemotherapy, given both pre- and post-surgery, cure rates of more
      than 50% for Ewing-tumors and about 70% for osteosarcoma could be
      achieved.Thus,chemotherapy is an indispensable part of the multimodal treatment
      of these tumor types. Chondrosarcomas are usually more highly differentiated and
      therefore show a lower rate of metastasis. The use of chemotherapy is not
      established in these tumors.

PMID- 12491046
TI  - [The role of radiotherapy in the treatment of bone neoplasms].
AB  - Primary malignant bone neoplasms are relatively rare. The most common bone tumors
      are osteosarcoma,Ewing's sarcoma,chondrosarcoma, fibrosarcoma,malignant fibrous
      histiocytoma of bone, giant cell tumor, aneurysmal bone cyst and chordoma. These
      tumors are generally considered to be a radioresistant entities, but it has been
      suggested that radiotherapy may be effective in a palliative and in some curative
      situations, if a sufficient dose is given to an adequate volume. Only for the
      management of primary Ewing's sarcoma the radiation therapy is an essential part
      in the multimodal therapy concept. The most common bone neoplasms and the role of
      the radiotherapy are discussed in these chapter.

PMID- 12491047
TI  - [Treatment concepts of benign bone tumors and tumor-like bone lesions].
AB  - The indications for surgical treatment of benign bone tumors and tumor-like
      lesions depend on the biological activity, clinical symptoms and anatomic
      location of the the lesion. Clinically silent lesions ("leave me alone Lesions")
      lacking any scintigraphic enhancement and without danger of pathologic fracture
      or malign transformation only need surveillance and do not require
      surgery.However, tumors becoming symptomatic, displaying progression after
      termination of skeletal growth or radiographic signs of malignancy should be
      scheduled for surgical intervention. For most benign tumors intralesional
      curettage and subsequent bone grafting is the treatment of choice, maintaining
      structural integrity and functional stability of the bone and adjacent joint. In
      case of uncertain histopathological diagnosis an open biopsy should be performed
      followed by definitive either marginal or en-bloc resection, preferably at a
      single procedure. Depending on the tumor-specific risk of recurrence, adjuvant
      measures as phenol instillation or cryotherapy using liquid nitrogen may
      additionally be applied. As for the unicameral juvenile bone cyst or osteoid
      osteoma alternative minimal invasive techniques like corticoid injection and CT
      guided percutaneous eradication of the nidus have been successfully introduced
      into clinical practice. Depending on the activity of the tumor recurrent lesions
      are recommended to be treated by marginal or enbloc resection. The radical and
      aggressive mode of surgical therapy has to be balanced with the treatment-related
      morbidity, i.e. complication rate, possibilities for reconstructive
      stabilizations and resultant functional deficits,making the decision a
      responsible challenge to the orthopedic surgeon.

PMID- 12491048
TI  - [Technical refinements in planning and surgical therapy of pectus carinatum].
AB  - From 1998 to 2002 ten patients underwent surgical correction of pectus carinatum
      using a new diagnostic preoperative three-dimensional volume rendering mode
      computed tomography. Particularly the deformed rib cartilages can now also be
      visualized, which allows exact preoperative planning of the extent of cartilage
      resection and localization of required sternum osteotomies. This additional
      information results in a focused surgical approach and hence minimizes scars. As
      an additional innovation, resorbable plates and screws were used for refixation
      of the osteotomized parts of the sternum. For postoperative thorax immobilization
      and hypertrophic scar circumvention, a special keel chest brace was applied in
      all patients for 6-8 weeks. No complications occurred in any case, and all
      patients were very content with the aesthetic results achieved.

PMID- 12491049
TI  - [Heparin-induced thrombocytopenia and thrombosis. Thrombosis as an early cardinal
      symptom of heparin allergy].
AB  - Apart from bleeding complications, heparin-induced thrombocytopenia (HIT) type II
      is the most severe side effect of heparin therapy. It is widely agreed that its
      most important clinical symptom is thrombocytopenia, with or without
      thromboembolism.Assuming, unlike other authors, that thrombosis is the leading
      clinical symptom of HIT type II, we investigated the frequency of an
      immunological reaction indicative of HIT type II in patients suffering from
      thrombosis. From January 1999 to December 2000, 77% ( n=6713) of our in-patients
      received heparin for more than 5 days as thrombosis prophylaxis. When thrombosis
      was suspected on the grounds of clinical appearances, the patient concerned
      underwent phlebography, and two different serological tests for anti-heparin
      antibodies were also carried out. In such cases, patients were immediately
      switched to hirudin instead of heparin. In 29 out of 101 patients, the clinical
      suspicion of thrombosis was confirmed. Three patients developed pulmonary
      embolism. In 4 patients both serological tests revealed the presence of anti
      heparin antibodies. Three of the remaining 72 patients with negative phlebography
      results were found to have antibodies on serological testing. In none of the 7
      patients with a confirmed diagnosis of HIT type II was the classical sign of
      thrombocytopenia was present. Even with thorough clinical and phlebographic
      examinations, the incidence of HIT type II is only 0.13% in our institution. One
      of the 7 patients with thrombosis was not thrombocytopenic but did show the
      typical immunological reaction. Since the incidence of HIT type II is low and
      thrombocytopenia is not a reliable indicator for HIT II, the need for frequent
      thrombocyte counts (twice weekly) should be reconsidered.However,patients
      developing thrombosis while receiving heparin need to be treated for clinically
      suspected HIT type II until the final diagnosis is made.

PMID- 12491050
TI  - [Risk evaluation in German clinics. Results of a survey].
AB  - INTRODUCTION: Risk evaluation is essential for the choice of individual surgical
      therapy. The aim of this survey was to examine whether preoperative risk analysis
      is routine in surgical therapy. METHODS: A questionnaire was sent to 1,159
      clinics to assess how preoperative risk was evaluated and who carried out the
      evaluation. In addition, the factors used to determine the postoperative course
      and the way in which postoperative complications were observed were established.
      RESULTS: A total of 636 clinics filled out the questionnaire. Preoperative risk
      factors substantially influenced the postoperative course. The ASA classification
      was the most commonly used. Anesthesiologists together with surgeons evaluated
      the preoperative risk in 67% of cases. No preoperative risk evaluation was made
      in 12% of the clinics, and 21% did not record the postoperative complications
      regularly. CONCLUSIONS: Risk evaluation and control of postoperative
      complications are an important part of good clinical practice.

PMID- 12491051
TI  - [The amelanotic melanoma of the rectum].
AB  - The amelanotic melanoma of the rectal mucosa is a very rare, difficult to
      discover tumor. We report on a 65-year-old female patient with an amelanotic
      melanoma of the rectum who underwent several transanal resections and finally,
      after an exact histological diagnosis,was treated by abdominoperineal excision.
      The present case emphasizes the necessity for an obligate histological
      examination of all suspicious alterations of the anorectum. Even with a very
      unfavourable prognosis, the amelanotic melanoma of the anorectum should be
      treated by radical surgical procedures to achieve a significant prolongation of
      life.

PMID- 12491052
TI  - [Multiple recurrent perforated jejunal diverticulitis].
AB  - Jejunal diverticulitis is a very rare cause of acute abdomen. The treatment of
      choice in acute perforated jejunal diverticulitis is intestinal resection with
      primary anastomosis of the affected area. Data on long-term results,
      postoperative complications and the nature of this illness is limited. To our
      knowledge, a recurrent perforated jejunal diverticulitis has never have been
      reported in the literature. In this case,we present a patient who suffered from a
      recurrence of perforated jejunal diverticulitis 13 weeks after the initial
      intestinal resection. After the second intestinal resection (due to the recurrent
      infection), the patient suffered from a third period of jejunal diverticulitis.

PMID- 12491053
TI  - [Distal fractures of the femur].

PMID- 12491054
TI  - [Physical and technical quality assurance and radiation protection in
      transperineal interstitial permanent prostate brachytherapy with 125-iodine
      seeds].
AB  - BACKGROUND: Early stage prostate cancer can be treated successfully by
      interstitial brachytherapy with 125-iodine seeds. A quality-assurance programme
      is presented that was designed for this purpose for internal clinical use.
      Furthermore the requirements of the new German Ordinance Governing Radiation
      Protection (StrlSchV) that came into force on August 1, 2001, are taken into
      account. MATERIAL AND METHODS: For the 125-iodine monotherapy of the prostate we
      used RAPID STRANDS (Amersham Health, Braunschweig, Germany). According to the
      guidelines of the new Ordinance Governing Radiation Protection, the determination
      of the body dose of the staff is made to rely on the new measurement quantities
      H(p) (10) and H(p) (0.07). The nominal air kerma rate of the seeds is measured
      with a calibrated well-chamber of the type HDR 1000 Plus and an electrometer of
      the type MAX 4000 (Standard Imaging Inc., USA). The ultrasound images of the
      prostate are produced by an ultrasound device of the type Falcon 2101 (B-K
      Medical, Denmark). For treatment planning the programme VariSeed (Varian,
      Darmstadt, Germany) was employed. Correct loading of the needles is controlled by
      autoradiography before implantation. After the implantation radiation-protection
      measurements in the operating room are carried out. RESULTS: As regards the
      personnel, for the depth personal dose equivalent Hp(10) and relating to two
      applications each, measurement values between 0 microSv and 14 microSv resulted.
      The control of the radiation exposure of the hands revealed superficial personal
      dose values H(p) (0.07) of up to 1 mSv. The nominal air kerma rates of the RAPID
      STRANDS were all lying within the 95% confidence interval guaranteed by the
      producer. The autoradiographs documented -- except for one case -- the correct
      loading of the needles. The interstitial transperineal prostate implantation of
      the 125-iodine seeds succeeded as planned with all patients. Until now no
      contamination of the operating room was detected by the radiation-protection
      measurements. CONCLUSION: The physical-technical quality assurance programme
      presented here covers the whole physical-technical range of the internal clinical
      quality assurance and could be integrated into the course of the treatment
      without any problems. It has th following advantages: The autoradiographic
      documentation of the correctly loaded needles serves as proof that the
      prerequisite for the production of the prescribed physical dose distribution is
      fulfilled. The internal clinical determination of the nominal air kerma rate is
      the basis for a correct dose application.

PMID- 12491055
TI  - Preoperative hypoxyradiotherapy of colorectal carcinoma.
AB  - AIM: The article focuses on the radioprotective effect of acute hypoxia on
      healthy tissues during preoperative accelerated hypoxyradiotherapy of colorectal
      carcinoma performed as locoregional irradiation including the common iliac lymph
      nodes. Analysis of early and late side effects and complications. PATIENTS AND
      METHODS: In this prospective study, early and late complications were assessed in
      50 patients as a function of hypoxyradiotherapeutic dose increase. The
      preliminary treatment results of this radiotherapeutic modification were
      evaluated after a median follow-up of 48 months using Kaplen-Meier analysis.
      Between April 1991 and February 1997, 50 patients (36 men and 14 women) with
      colorectal carcinoma were treated preoperatively with locoregional accelerated
      hypofractionated hypoxyradiotherapy. The extent of disease was classified
      according to Dukes' criteria (A: four patients, B. 28 patients, C: 18 patients).
      We used a 20-MeV linear accelerator with two parallel opposed fields.
      Hypoxyradiotherapy was performed extending from the perineum to the L4 region.
      Acute hypoxia was induced during irradiation by ventilation of a hypoxic gas
      mixture containing 7.8-8.0% oxygen. Total doses of 24 Gy/8 days, 28 Gy/9 days,
      and 32 Gy/10 days were applied in five, 20, and 25 patients, respectively. Low
      anterior resection or abdominoperineal amputation of the rectum was performed the
      day after completion of preoperative hypoxyradiotherapy. The early reactions
      after irradiation were evaluated according to the Common Toxicity Criteria of the
      National Cancer Institute (CTC-NCI). RESULTS: Early postirradiation proctitis was
      documented in three and early radiation-induced cystitis in two patients only.
      Neither early nor late radiation-associated complications were observed in any of
      the three hypoxyradiotherapy schedules during the follow-up period of 6-105
      months. Based on Kaplan-Meier analysis (median 48 months), a 5-year overall
      survival rate of 61.5% and a local relapse-free survival rate of 84.2% can be
      expected. Treatment failures were predominantly systemic. CONCLUSION: We believe
      it can be concluded that acute hypoxia has a radioprotective effect on normal
      tissues during accelerated hypoxyradiotherapy of colorectal carcinoma.
      Hypoxyradiotherapy permits safe administration of doses higher than those
      tolerated by normoxic, noncanceorus tissue, resulting in the amplification of the
      biological effect of radiation on tumor tissue and contributing to an improved
      outcome after combined radiosurgical treatment of colorectal carcinoma.

PMID- 12491056
TI  - Combined external beam and intraluminal radiotherapy for irresectable Klatskin
      tumors.
AB  - BACKGROUND: In most cases of proximal cholangiocarcinoma, curative surgery is not
      possible. Radiotherapy can be used for palliative treatment. We report our
      experience with combined external beam and intraluminal radiotherapy of advanced
      Klatskin's tumors. PATIENTS AND METHODS: 30 patients were treated for
      extrahepatic proximal bile duct cancer. Our schedule consisted of external beam
      radiotherapy (median dose 30 Gy) and a high-dose-rate brachytherapy boost (median
      dose 40 Gy) delivered in four of five fractions, which could be applied
      completely in twelve of our patients. 15 patients in the brachytherapy and nine
      patients in the non-brachytherapy group received additional low-dose chemotherapy
      with 5-fluorouracil. RESULTS: The brachytherapy boost dose improved the effect of
      external beam radiotherapy by increasing survival from a median of 3.9 months in
      the non-brachytherapy group to 9.1 months in the brachytherapy group. The effect
      was obvious in patients receiving a brachytherapy dose above 30 Gy, and in those
      without jaundice at the beginning of radiotherapy (p < 0.05). CONCLUSIONS: The
      poor prognosis in patients with advanced Klatskin's tumors may be improved by
      combination therapy, with the role of brachytherapy and chemotherapy still to be
      defined. Our results suggest that patients without jaundice should be offered
      brachytherapy, and that a full dose of more than 30 Gy should be applied.

PMID- 12491057
TI  - [Analysis of the actual number of physicians in radiotherapy units in Germany].
AB  - BACKGROUND: Physician workload directly influences the ability of an institution
      to provide high standards in radiotherapy services. MATERIAL AND METHODS: Data of
      189 radiotherapy units of the DEGRO survey 2000 complemented and corrected (Table
      1) are analyzed with simple and multiple linear regression (models in Table 2).
      RESULTS: In 21 private radiotherapy facilities actual numbers of physicians split
      up in 0.19 for every 1,000 megavoltage courses per year, 1.8 per megavoltage
      unit, 0.68 for every ten beds for inpatients minus 0.67 or plus 1.2 physicians
      per facility providing radiotherapy only or combined with other services,
      respectively. Radiotherapy units in hospitals were analyzed in two groups, i. e.
      radiotherapy only (n = 69) or in combination with other services (n = 59). In the
      latter, reported numbers of physicians split up in 3.2 for every 1,000
      megavoltage courses per year, minus 0.13 per megavoltage unit, 0.87 for every ten
      beds for inpatients, plus 2.2 per facility. Units providing radiotherapy only had
      0.86 physicians for every 1,000 megavoltage courses per year plus 1.0 per
      megavoltage unit plus 0.97 for every ten beds plus 1.0 per facility. In 36
      radiotherapy university clinics actual numbers of physicians split up in 2.4 for
      every 1,000 megavoltage courses per year, 1.7 per megavoltage unit, 0.86 for
      every ten beds for inpatients, plus 1.5 per clinic. For confidence limits see
      Table 3, for results of univariate analysis Figure 1 and 2. CONCLUSION: In German
      radiotherapy facilities, physician workload varies considerably. It exceeds that
      reported for the USA by a substantial margin.

PMID- 12491058
TI  - Radiation-induced changes of telomerase activity in a human Ewing xenograft
      tumor.
AB  - AIM: The effect of ionizing irradiation on telomerase activity and further
      associated biological factors was evaluated in a human Ewing tumor xenograft
      model on nude mice. MATERIAL AND METHODS: The human Ewing tumor cell line STA-ET
      1 was established in a nude mouse model. Initially, the dose-response
      relationship for the tumor model was established. For the radiation experiments
      two dose levels were chosen: 5 Gy and 30 Gy. After 5 Gy, there was no significant
      growth delay whereas after 30 Gy there was a marked growth delay without the
      induction of a complete remission. Tumors were examined 6, 12, 24, 48, 72, and 96
      hours post irradiation. After irradiation with 30 Gy further time points were 6,
      9, 12 and 15 days. For each dose and time group, three tumors were evaluated.
      RESULTS: There was a reduction of telomerase activity after 5 Gy to 50% (not
      statistically significant) after 3 days; however, after 30 Gy there was a
      reduction of telomerase activity to 23% of the initial value after 6 days (p =
      0.001). Telomerase activity correlated with the expression of human telomerase
      reverse transcriptase (hTERT), but not with the expression of telomerase
      associated protein (TP1) and human telomerase RNA (hTR). The maximal amounts of
      necrosis or apoptosis after 30 Gy were 19% and 6.9%, respectively. CONCLUSIONS:
      Ionizing radiation reduces telomerase activity and the expression of hTERT which
      cannot be explained by the induction of necrosis or apoptosis alone. The
      reduction of telomerase activity may contribute to delayed cell death after
      radiotherapy. The combined use of radiation and specific telomerase inhibitors
      may be a potentially synergistic treatment strategy.

PMID- 12491059
TI  - Ionizing radiation modulates cell surface integrin expression and adhesion of
      COLO-320 cells to collagen and fibronectin in vitro.
AB  - PURPOSE: Adhesion of tumor cells to endothelial cells and to the extracellular
      matrix is a key step in the initial phase of metastasis. Since radiotherapy of
      tumors can induce alterations of the cell surface, we investigated the effect of
      ionizing radiation on the expression of integrins in the colorectal tumor cell
      line COLO-320 and the modulation of adhesion capacity of irradiated cells to
      collagen and fibronectin. MATERIAL AND METHODS: The cell surface expression of a
      broad range of integrins on COLO-320 cells was determined by flow cytometry
      during 144 hours after X-irradiation. The functional significance of increased
      adhesion molecule expression was assessed by cell-matrix adhesion and receptor
      blocking experiments. RESULTS: Cell surface expression of the following integrin
      alpha and beta subunits was quantified: beta1 (CD29), alpha 2 (CD49b), alpha 5
      (CD49e) and alpha 6 (CD49f). The expression of alpha 1, alpha 2, alpha 5, and
      alpha 6 changes as a function of time after irradiation (5 Gy). For beta1 even a
      function of dose (1-5 Gy) could be shown. Adhesion experiments confirmed a time
      dependent increase in adhesion to both collagen and fibronectin. Radiation
      induced increase in adhesion was inhibited significantly by using a CD29
      antibody. CONCLUSIONS: Ionizing radiation modulates cell surface expression of
      integrins and cell-matrix interactions. The beta1-integrin subunit plays an
      important role in radiation-induced adhesion to both collagen and fibronectin.
      Possible consequences of these in-vitro results for radiotherapy of colorectal
      tumors in vivo are discussed.

PMID- 12491060
TI  - Simulator verification of the accuracy of patient repositioning after virtual
      simulation. Is physical simulation still needed?
AB  - PURPOSE: To evaluate the frequency and amount of displacements after
      repositioning a patient on the physical simulator following virtual simulation.
      MATERIAL AND METHODS: After laser marking at the CT scanner and virtual
      simulation, patients were repositioned on the simulator. The isocenter obtained
      from the calculated table movements was checked by fluoroscopically measuring the
      distances to standardized anatomic landmarks and comparing them to the treatment
      plan. RESULTS: In 86% of patients, displacements were < or = 0.5 cm. There was no
      significant difference between the supine and prone position, diagnosis
      categories or CT reconstruction indices. The use of immobilization devices and
      cranial versus body stem localization did make a significant difference. Rates of
      exact repositioning were high in brain and head and neck patients and
      comparatively low in abdominal tumors and breast cancer. CONCLUSIONS:
      Immobilization devices play an important role for the precision of radiotherapy.
      Whenever precise positioning is possible (e. g. with a head mask), virtual
      simulation alone might be sufficient. Patients with abdominal and breast tumors,
      were repositioning precision is often suboptimal, might profit from an additional
      physical simulation.

PMID- 12491061
TI  - Sparing of contralateral major salivary glands has a significant effect on oral
      health in patients treated with radical radiotherapy of head and neck tumors.
AB  - BACKGROUND: Has a conscious exclusion of the contralateral major salivary glands
      (parotid, submandibular, and sublingual glands) a significant impact on the
      milieu of the oral cavity (saliva flow, pH, buffer capacity, and colonisation
      with Streptococcus mutans) in patients with ENT tumors receiving radical
      radiotherapy? PATIENTS AND METHODS: 20 consecutive consenting patients with ENT
      tumors were evaluated once before, weekly during, and 6 weeks after the end of
      treatment in regard to saliva flow, ph, buffer capacity, and colonisation with
      Streptococcus mutans. In 13 patients the major salivary glands on both sides were
      included in the treated volume, in seven patients the treatment portals excluded
      consciously the contralateral major salivary glands. RESULTS: The stimulated
      saliva flow decreases already during the 1st week of radiotherapy, the decrease
      follows the dose exponentially; the saliva flow is further reduced in the weeks
      after the end of treatment. The effect is less pronounced in patients with
      sparing of contralateral major salivary glands. The majority of patients with
      unilateral sparing of the major salivary glands retain the baseline value of
      buffer capacity, whereas buffer capacity of all patients with inclusion of all
      major salivary glands is markedly reduced with 20 Gy already, without signs of
      recovery when treatment has stopped. With unilateral salivary gland sparing the
      pH always remains basic, in bilaterally irradiated patients the pH changes from a
      mean of 7.3 to 5.8 during treatment. The colonisation with Streptococcus mutans
      varies little in both groups during the radiotherapy; after the end of therapy,
      it is higher in bilaterally irradiated patients. CONCLUSIONS: The conscious
      arrangement of irradiation portals in order to spare contralateral major salivary
      glands in patients with radical radiotherapy of ENT tumors has a significant
      influence on the oral environment: the stimulated saliva flow is higher, the
      buffer capacity retains the baseline value, the saliva pH remains basic, and the
      colonisation with Streptococcus mutans is reduced.

PMID- 12491062
TI  - Oxygenation status of gynecologic tumors: what is the optimal hemoglobin level?
AB  - BACKGROUND: Tumor hypoxia has been linked to the development of treatment
      resistance, tumor progression, and poor prognosis. Since anemia is a major
      causative factor for the development of hypoxia, the association between blood
      hemoglobin concentration (cHb) and tumor oxygenation was examined in this study.
      PATIENTS AND METHODS: Pretreatment O(2) tension (pO(2)) measurements were
      performed in 59 primary carcinomas of the uterine cervix in which a stringent
      histopathologic examination of the electrode tracks was mandatory in order to
      exclude measurements in necrotic, stromal or normal cervical tissue. In addition,
      pO(2) readings in twelve primary cancers and 17 local recurrences of vulvar
      cancers were included in this study. cHb was determined at the time of pO(2)
      measurements. RESULTS: Data presented clearly show that an optimal Hb level with
      regard to the median pO(2) values of cervical and vulvar cancers should prevail
      at cHb values of between 12 and 14 g/dl (7.45-8.60 mmol/l). In anemic patients
      (cHb < 12 g/dl), the deterioration of the tumor oxygenation status can be
      explained by a reduced O(2) transport capacity. At cHb values > 14 g/dl, a
      worsening of the tumor oxygenation is apparent, most probably due to a drop in
      perfusion following a drastic increase in viscous resistance to flow. This
      pathogenetic mechanism is thought to counteract and finally to abrogate the high
      O(2) transport capacity in this cHb range. CONCLUSIONS: This study suggests that
      cHb values of between 12 and 14 g/dl are optimal with regard to the oxygenation
      status in the tumor entities investigated, a finding which may have far-reaching
      implications in the clinical setting.

PMID- 12491063
TI  - VERIDOS: a new tool for quality assurance for intensity modulated radiotherapy.
AB  - BACKGROUND: The use of intensity modulated radiation fields needs an extended
      quality assurance concept. This consists of a linac related part and a case
      related part. Case related means the verification of an individual treatment
      plan, optimized on a CT data set of an individual patient and prepared for the
      treatment of this patient. This part of the quality assurance work is usually
      time consuming, delivers only partially quantitative results and is uncomfortable
      without additional help. It will be shown in this paper how the software VERIDOS
      will improve the optimization of the case related part of the quality assurance
      work. MATERIAL AND METHODS: The main function of the software is the quantitative
      comparison of the calculated dose distribution from the treatment planning
      software with the measured dose distribution of an irradiated phantom. Several
      additional functions will be explained. Two self-developed phantoms made of RW3
      (solid water) and GAFCHROMIC films or Kodak EDR2 films for the measurement of the
      dose distributions were used. VERIDOS was tested with the treatment planning
      systems Helay-TMS and Brainscan. RESULTS: VERIDOS is a suitable tool for the
      import of calculated dose matrices from the treatment planning systems Helax-TMS
      and Brainscan and of measured dose matrices exported from the dosimetry software
      Mephysto (PTW). The import from other treatment planning systems and scanning
      software applications for film dosimetry is generally possible. In such case the
      import function has to be adapted to the special header of the import matrix. All
      other functions of this software tool like normalization (automatically,
      manually), working with corrections (ground substraction, factors),
      overlay/comparison of dose distributions, difference matrix, cutting function
      (profiles) and export functions work reliable. CONCLUSIONS: VERIDOS improves the
      optimization of the case related part of the quality assurance work for intensity
      modulated radiation therapy (IMRT). The diverse functions of the software offer
      the radiation physicist a wide base to verify the IMRT plan independent from the
      mode of its delivery (compensator technology or MLC technology).

PMID- 12491064
TI  - [Costs of long-term complications in type 2 diabetes patients in Germany. Results
      of the CODE-2 Study].
AB  - METHODS: In the German arm of CODE-2((R)) (Costs of Diabetes in Europe - Type 2),
      medical, demographic and economic data were collected retrospectively for a
      period of 1 year on the basis of medical files of 809 patients by personal
      interviews with 135 primary care physicians. The results were extrapolated to the
      German diabetes type 2 population. The influence of micro- and macrovascular
      complications on total costs was analyzed. Costs of three major complications
      (ulcer, amputation, and stroke/PRIND) were determined. Here, comorbidities with
      other major complications were excluded. RESULTS: About half of the patients with
      diabetes type 2 had severe diabetes-related comorbidity, 56.2% showing more than
      one. For patients with macro- or microvascular complications, the costs increase
      2.5 up to 4.1 times in comparison to the average health-insured patient. Costs
      for patients with ulcer of the lower extremities added to a mean total of EURO
      7,537.- (DM 14,742.-) in the year of complication occurring. For patients
      undergoing amputation, mean annual costs of EURO 10,796.- (DM 21,115.-) arose. In
      diabetes patients suffering from a stroke, costs in the respective year summed up
      to EURO 7,147.- (DM 13,987.-). Amputations therefore led to a more than sixfold
      increase in costs, ulcer and stroke to a more than fourfold increase compared to
      diabetes patients without complications. CONCLUSIONS: This analysis demonstrates
      the huge financial expenditure for managing specific diabetes-related
      complications and long-term effects. In order to reduce total costs, the focus
      should turn to early prevention of complications. Targeted intervention studies
      will have to prove that an initial increase in treatment costs due to preventive
      measures can be more than compensated by savings occurring from prevention of
      complications.

PMID- 12491065
TI  - [Rheumatoid arthritis - pathogenetic role of neuroendocrine axes and the
      peripheral nervous system].
AB  - BACKGROUND: Local innate and adaptive immune processes are of importance during
      the acute phase of rheumatoid arthritis (RA). In the advanced inflammatory phase
      alterations of systemic anti-inflammatory feedback mechanisms might be important
      features which may support chronic inflammation. ALTERATIONS: Similarly, like in
      other chronic inflammatory diseases, inadequately low cortisol and androgen serum
      levels can be detected in RA patients. In addition, there is a marked reduction
      of anti-inflammatory sympathetic nerve fibers in the inflamed joints paralleled
      by an enhanced number of pro-inflammatory sensory nerve fibers. Thus, an
      uncoupling of synergistically acting endocrine and neuronal, anti-inflammatory
      mechanisms (cortisol, dehydroepiandrosterone, androgens, sympathetic
      neurotransmitters) and a preponderance of pro-inflammatory mechanisms (estrogens,
      sensory neurotransmitters) may lead to chronic inflammatory disease. CONCLUSION:
      From this pathogenetic point of view new therapeutic strategies could be
      developed for the treatment of patients with RA.

PMID- 12491066
TI  - [Neuropsychiatric involvement in systemic lupus erythematosus. Part 1: clinical
      presentation and pathogenesis].
AB  - BACKGROUND: Central nervous system (CNS) involvement is a frequent complication
      of systemic lupus erythematosus (SLE) ranging from a subclinical to a severe
      disabling disease. Neuropsychiatric manifestations have been described in 18-67%
      of cases depending on the diagnostic criteria. The cerebral involvement may
      precede the full-blown picture of SLE or may develop in the course of disease,
      most frequently within the first 3 years. CLINICAL PRESENTATION: Neuropsychiatric
      manifestations in SLE comprise diffuse psychiatric symptoms, focal neurologic
      symptoms, and the involvement of the peripheral nervous system. Numerous CNS
      syndroms have been described: migraine, seizure, stroke, chorea, transverse
      myelopathy, psychosis, mood disorders, acute confusional state, and cognitive
      dysfunction. The diagnosis of cerebral involvement can be difficult and has to be
      differentiated from neurologic complications which may be, for instance, due to
      uremia, hypertension, drug toxicity, and infection. PATHOGENESIS: A large number
      of etiopathophysiologic processes are involved: antineuronal antibodies,
      antibodies against ribosimal P-protein, and cytokines have been implicated in the
      pathogenesis of diffuse neuropsychiatric symptoms. Focal neurologic symptoms are
      the consequence of vascular injury induced by circulating immune complex,
      occlusive vasculopathy as a result of endothelial cell activation induced by
      cytokines and complement activation, or macro- and microvascular thrombosis
      induced by antiphospholipid antibodies. In the later stages of disease,
      cerebrovascular manifestations are often related to accelerated atherosclerosis,
      which is entertained by increased intravascular complement turnover and
      antiphospholipid antibodies.

PMID- 12491067
TI  - [Apoptosis in disease].
AB  - BACKGROUND: Apoptosis, the death of a single cell according to an exactly defined
      intracellular program, is a key principle allowing embryonic development and
      later on tissue homeostasis in metazoans. MOLECULAR BASE: The molecular base is
      an evolutionary highly conserved intracellular signaling cascade, which is
      preserved from hematodes to mammals. Initiation of the program finally leads to
      the activation of caspases, a set of cysteinyl-specific proteases, which
      indicates the beginning of the end of a cell life. During evolutionary
      development, the role of central effectors did not change, but an enormous
      sophistication of necessary control mechanisms evolved. In recent years it became
      clear that subtle changes in the fine-tuned balance of life and death of single
      cells are the underlying cause of many diseases. AIMS AND CONCLUSION: Our review
      focuses on clinical aspects of apoptosis. In the first part the major proteins
      forming the deadly intracellular cascade will be discussed, while the second part
      relates to diseases which are characterized by a dysfunction of the apoptotic
      program.

PMID- 12491068
TI  - Gamma-aminobutyric acid modulation of acetylcholine-induced contractions of a
      smooth muscle from an echinoderm (Sclerodactyla briareus).
AB  - This study provides pharmacological evidence for the presence of GABAergic
      neurons innervating the longitudinal muscle of the body wall (LMBW) of
      holothurians. Gamma-aminobutyric acid (GABA) A and B receptor subtypes were both
      present in this system and regulated spontaneous contractions as well as
      responses to acetylcholine (ACh) that stimulated contraction of the LMBW. GABA
      dose-dependently relaxed the resting tone of the LMBW. GABA (10(-5) M) inhibited
      ACh-induced (10(-4) M) contractions by 20%. The GABA B agonist, baclofen, relaxed
      the LMBW, an effect potentiated by GABA. Pretreatment with baclofen (10(-4) M)
      inhibited ACh (10(-4) M) contractions of the LMBW by 50%. Phaclofen, a GABA
      receptor B antagonist, caused a dose-dependent increase in resting tension.
      Phaclofen-induced (10(-5) M) contractions were reversed by the addition of GABA
      or baclofen (10(-4) M) and potentiated by the addition of another GABA B receptor
      antagonist, 2-hydroxy-saclofen (10(-5) M). Pretreatment with phaclofen (10(-5) M)
      caused a marked potentiation of ACh-induced (10(-4) M) contractions by 101%. 2
      Hydroxy-saclofen (10(-5) M) had a toxic effect on the LMBW, rendering it
      completely unresponsive either to ACh or to a second exposure to GABA, and so
      exhibiting cross-desensitization. Muscimol, a GABA A receptor agonist, had no
      effect on the resting tension of the LMBW. Curiously, pretreatment of the muscle
      with muscimol (10(-5) M) potentiated ACh-evoked (10(-4) M) contractions by nearly
      20%. Bicuculline (10(-5) M), a GABA A receptor antagonist, generated large,
      sustained contractions and partially blocked GABA-induced (10(-4) M) relaxation.
      Like 2-hydroxy-saclofen, bicuculline (10(-5) M) had a profound cross
      desensitizing effect on the LMBW to subsequent exposures to GABA and ACh. ACh was
      unable to potentiate the sustained contractions induced by bicuculline.

PMID- 12491069
TI  - Nitric oxide: a vasodilatatory mediator in the cephalic aorta of Sepia
      officinalis (L.) (Cephalopoda).
AB  - Evidence is presented that nitric oxide (NO) may regulate blood pressure in
      cephalopod molluscs. In vitro tests performed on the cephalic aorta of Sepia
      officinalis (L.) (Cephalopoda) showed that the NO releasers (glyceroltrinitrate,
      sodium nitroprusside, 3-morpholinylsydnoneimine chloride and KNO(2)) induced
      concentration-dependent vasodilatation of vessel segments (without the tunica
      adventitia/periadventitia) precontracted by dopamine. These vasodilatatory
      actions could be totally blocked by oxadiazolo[4,3-a] quinoxalin-1-one, an
      inhibitor of the NO-sensitive guanylyl cyclase, and partially mimicked by the
      cyclic guanosine monophosphate (cGMP) analogue 8-bromo cGMP and by the
      phosphodiesterase inhibitor, zaprinast. The NO-precursor, L-arginine, showed
      vasodilatatory effects only on segments of the aorta in which the layers
      containing nerves (tunica adventitia/periadventitia) had been left intact,
      suggesting that NO synthase may be located within peripheral nerves.

PMID- 12491070
TI  - Effects of SEPYLRFamide on acetylcholine-induced currents of Helix aspersa
      neurones: role of ryanodine receptors.
AB  - The possible participation of ryanodine receptors in the modulatory effects of
      the endogenous Helix heptapeptide, SEPYLRFamide, on the acetylcholine-induced
      currents (ACh-currents) of Helix aspersa neurones was studied using the two
      electrode voltage clamp technique. SEPYLRFamide (bath application) caused a
      reduction of the ACh-currents of D1, D2, F1, F2, F76 and F77 neurones. Ryanodine
      (10 microM; bath application), which modifies ryanodine-controlled Ca(2+)
      channels, potentiated the inhibitory effect of SEPYLRFamide on the ACh-current.
      An antagonist of cyclic adenosine diphosphate ribose (cADPR) and ryanodine
      receptors, ruthenium red (1 mM; intracellular injection), reduced the inhibitory
      effects of SEPYLRFamide on the ACh-current. Ryanodine (10 microM) did not change
      the inhibitory effect of SEPYLRFamide on the ACh-current after intracellular
      injection of ruthenium red. An agonist of ryanodine receptors, caffeine (5 mM;
      bath application), reduced the ACh-current. Ryanodine (10 microM) did not change
      the reduction of ACh-currents induced by the first application of caffeine but
      decreased the reduction of ACh-currents induced by subsequent applications of
      caffeine. It is proposed that ryanodine receptors are involved in the inhibitory
      modulatory effects of SEPYLRFamide on somatic cholinergic receptors of Helix
      aspersa neurones.

PMID- 12491071
TI  - The A-like potassium current of a leech neuron increases with age in cell
      culture.
AB  - Single leech neurons isolated and maintained in culture sprout and form
      electrical and chemical synapses, as they do in vivo, retaining most of the
      electrical properties of the intact membrane. However, some cells, such as
      Retzius, Anterior Pagoda (AP) cells and motoneurons, exhibit consistent changes
      of biophysical characteristics, which mimic those induced by axotomy in vivo and
      are reversed after reconnection. To improve our understanding of the mechanisms
      involved in these alterations and of their physiological significance, we
      investigated the early changes in outward currents developed by cultured AP
      neurons, using the patch-clamp technique in the whole-cell recording
      configuration. Different currents were isolated and a differential sensitivity to
      the time spent in culture and to internal calcium was observed. Three potassium
      currents were dissected: an A-like current, a delayed rectifier and a third
      unidentified component. The A-like potassium current was significantly increased
      with neuronal age in cell culture and was a function of the internal Ca(2+)
      concentration, whereas the two other potassium currents remained unchanged.
      Intracellular recordings performed from axotomized neurons of cultured ganglia
      revealed clear-cut alterations in spike adaptation, which might be due to changes
      of the A-like current.

PMID- 12491072
TI  - Characterization of a putative pheromone biosynthesis-activating neuropeptide
      (PBAN) receptor from the pheromone gland of Heliothis peltigera.
AB  - The binding of [(3)H]tyrosyl-PBAN28-33NH(2) to pheromone gland membranes of the
      moth Heliothis peltigera was investigated. The study describes the development of
      a pheromone biosynthesis-activating neuropeptide (PBAN) radioreceptor assay and
      demonstrates the presence of a putative PBAN binding site on the pheromone gland.
      It also describes synthesis of a radioligand and optimization of binding
      conditions with respect to membrane preparation, number of gland equivalents,
      kinetics of ligand binding and composition of the binding solution. Binding was
      found to be optimal when membranes were freshly prepared from frozen glands,
      incubated at a concentration of one gland equivalent per reaction tube in the
      presence of 10 mM HCO(3)(-) ions. Equilibrium of ligand binding was obtained
      after 20 min. Presence of other components such as NaCl, KCl or SH reagents did
      not have any effect on binding. Binding was found to be saturable, with a K(d) of
      5.73 +/- 1.05 x 10(-6) M and a Bmax of 1.85 +/- 0.22 nmol/mg protein. Binding was
      effectively displaced by unlabeled PBAN1-33NH(2) and PBAN28-33NuEta(2) with a
      K(i) of 4.3 +/- 1.1 x 10(-6) M and 4.9 +/- 2.6 x 10(-6) M, respectively.

PMID- 12491073
TI  - Regulation of pharyngeal motility by FMRFamide and related peptides in the
      medicinal leech, Hirudo medicinalis.
AB  - The medicinal leech possesses FMRFamide-like immunoreactivity in neural processes
      and somata associated with the pharynx and pharyngeal ganglia. The pharynx
      possessed about 25 immunoreactive somata; about half of the approximately 20
      neurons of the pharyngeal ganglia were immunoreactive. We provide brief
      descriptions of several neurons located in the first neuromere of the
      subesophageal ganglion involved in controlling pharyngeal motility. Double
      labeling experiments indicate that one of these cells, named Swallow neuron 1
      (SW1), contains a FMRFamide-like peptide. Stimulation of SW1 caused the mouth to
      open and the pharynx to dilate. Upon termination of SW1 stimulation, the mouth
      closed, and a peristaltic wave progressed from the mouth down the length of the
      pharynx. Stimulation of SW1 did not produce 1:1 postsynaptic potentials in
      pharyngeal muscle cells. Thus, SW1 is apparently not a motor neuron. The pharynx
      responded to application of FMRFamide and related peptides by producing a series
      of 20- to 35-s phasic contractions superimposed upon an increase in basal tonus.
      The peptide-induced response was quantified by measuring increases in basal
      tonus, peak tension, and integrated area. Although there were some differences in
      the order of potency depending upon which parameter was considered, the
      approximate order of potency of RFamide peptides tested was: pQDPFLRFamide > or =
      FMRFamide approximately YGGFMRFamide > or = YMRFamide approximately FLRFamide
      approximately GGKYMRFamide approximately YLRFamide > leucomyosuppressin
      approximately perisulfakinin. Except for differences in potency, each of the
      RFamide peptides produced similar contractile waveforms. FMRFamide-induced
      responses were reduced by the protein kinase C inhibitor bisindolylmaleimide I
      (10 microM), the nonspecific protein kinase inhibitor H-7 (50 microM), and were
      increased by the protein phosphatase inhibitor okadaic acid (1 microM). However,
      the FMRFamide-induced response was unaffected by the protein kinase A inhibitor H
      89 (1 microM), the phosphodiesterase inhibitor theophylline (1 mM), the
      phospholipase A(2) inhibitor OBAA (0.1 microM) or the cation channel blocker
      amiloride (100 microM).

PMID- 12491075
TI  - Meeting report of the 74th Congress of the Japanese Gastric Cancer Association.

PMID- 12491074
TI  - Molecular cloning of a putative voltage- and cyclic nucleotide-gated ion channel
      present in the antennae and eyes of Drosophila melanogaster.
AB  - The amino acid sequence BCNG-1 (brain cyclic nucleotide gated 1, of the mouse),
      the first member of mamalian I(h) channels, was used to construct a set of
      polymerase chain reaction (PCR) primers from possibly conserved regions. Reverse
      transcription-PCR with Drosophila melanogaster mRNA yielded in a PCR product,
      which exhibited a high homology to BCNG-1. Using these PCR products to screen a
      D. melanogaster head cDNA library we isolated a cDNA encoding a member of a new
      class of putative voltage- and cyclic nucleotide-gated potassium channels from D.
      melanogaster. The most important features of the amino acid sequence predicted
      from the cDNA were a C-terminal cyclic nucleotide-binding region, an S4-voltage
      sensor and a putative potassium-selective pore-forming motif. The high homology
      of 51% to the sea urchin I(h) channel, which belongs to the same class of ion
      channels as BCNG-1, leads us to suggest that the Drosophila cDNA is the first
      insect member of a new class of hyperpolarization-activated and cyclic nucleotide
      gated channels. As shown by in situ hybridization, a pronounced mRNA expression
      was detected in neuronal tissue, including sensory tissue like the compound eyes,
      and the olfactory and the auditory organs.

PMID- 12491076
TI  - Lack of consistency in the associations of Helicobacter pylori seropositivity
      with Se and Le polymorphisms among Japanese.
AB  - BACKGROUND: In our previous study, a marked association between Helicobacter
      pylori seropositivity and functional polymorphisms of the secretor and Lewis
      genes (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.14-0.70 for se/se
      genotype relative to Se/Se genotype; and OR, 10.3; 95% CI, 3.16-33.8 for high
      risk group defined by the combination of Se and Le relative to low-risk group)
      had been observed for 239 non-cancer Japanese outpatients of the gastroenterology
      clinic (OGC) undergoing gastroscopy at Aichi Cancer Center Hospital. METHODS: The
      present study was a confirmatory study to examine the association for 679 first
      visit outpatients (FVO) of all clinics at the same cancer hospital and for 465
      health checkup examinees (HCE) in the same city. RESULTS: The associations
      between H. pylori seropositivity and the Se and Le genotypes were nonsignificant
      or even in the opposite direction among the FVO (OR, 1.52; 95% CI, 1.00-2.32 for
      se/se genotype relative to Se/Se genotype; and OR, 0.77; 95% CI, 0.43-1.40 for
      the high-risk group defined similarly to the previous study), and among the HCE
      (OR, 1.25; 95% CI, 0.75-2.07; and OR, 1.07; 95% CI, 0.50-2.26, respectively). The
      discrepancy between the previous and present results was not explained by the
      difference in the distributions of age, sex, smoking, and H. pylori
      seroprevalence. CONCLUSION: Even in the same ethnic group, different sources of
      subjects may demonstrate inconsistent findings due to an unidentified effect
      modification. Inconsistent findings have rarely been reported by the same
      research group, but they are very important to understand the whole picture of
      the association under study.

PMID- 12491077
TI  - Determining prognostic factors for gastric cancer using the regression tree
      method.
AB  - BACKGROUND: The regression tree method is a useful statistical technique that has
      been little used in the analysis of prognosis. METHODS: The prognostic factors of
      gastric cancer were investigated, using the regression tree method, in 555
      patients who had undergone curative resection for serosa-negative gastric cancer
      and who were enrolled in a randomized controlled trial of postoperative adjuvant
      chemotherapy (JCOG [Japan Clinical Oncology Group] 8801 study). RESULTS: By the
      regression tree method, the first divided prognostic factor (the most important
      factor) was lymph node metastasis; in particular, extent of lymphatic spread had
      the greatest impact on prognosis. In addition, age, tumor size, depth of
      invasion, and individual dose intensity were found to be significant prognostic
      factors, whereas sex, tumor location, macroscopic tumor type, and extent of lymph
      node dissection were not. The resulting tree structure consisted of nine terminal
      nodes with different prognostic factors, and four clusters were obtained by the
      merging of terminal nodes that showed a similar prognosis. The cluster which
      showed the best survival rate (5-year survival rate, 0.986) consisted of two
      terminal nodes: node 12, which contained N0T1 patients who were younger than 62
      years and had a tumor size of less than 7.5 cm, and node 14, which contained N1
      patients who were younger than 46 years. CONCLUSION: In serosa-negative gastric
      cancer, lymph node metastasis was the most important prognostic factor.
      Utilization of the regression tree method enabled visual interpretation of the
      results of statistical analyses through the graphic representation of prognostic
      factors. It allowed the identification of the optimal combination of these
      prognostic factors that defined several groups of patients with distinct
      prognoses and may serve as a useful reference for the individualization of
      treatment strategy.

PMID- 12491078
TI  - Effects of sex and racial/ethnic group on the pattern of gastric cancer
      localization.
AB  - BACKGROUND: In Western countries, the overall incidence of gastric cancer is
      declining, while the incidence of proximal gastric cancer is rising. We evaluated
      the effect of sex, racial/ethnic group, and age on the localization of gastric
      cancer. METHODS: The records of all gastric cancer patients who registered at The
      University of Texas M. D. Anderson Cancer Center from January 1, 1985, to May 31,
      1998, were reviewed. Tissue diagnosis and established tumor location were
      required. RESULTS: The case records of 1242 eligible patients, consisting of 821
      non-Hispanic white, 230 Hispanic, 125 African American, 63 Asian, and 3 Native
      American patients, were analyzed. Among the 459 women, racial/ethnic group did
      not have a significant impact on gastric cancer localization (P = 0.57). However,
      among the 783 men, proximal cancers were significantly more frequent in the non
      Hispanic white patients (57% vs 38% Hispanic, 41% African American, 17% Asian; P
      < 0.0001). Symptoms at diagnosis significantly varied for proximal vs non
      proximal cancers. CONCLUSION: Proximal gastric cancer localization was more
      frequent among non-Hispanic white men, while non-Hispanic white women had a
      localization pattern similar to those of other racial/ethnic groups. Proximal
      gastric cancer represents a distinct subtype of gastric cancer that may have
      different biology, risk factors, and clinical behavior.

PMID- 12491079
TI  - Delayed rise in incidence of gastric cancer in females results in unique sex
      ratio (M/F) pattern: etiologic hypothesis.
AB  - BACKGROUND: The age-standardized and cumulative incidence rates of gastric cancer
      (GCA) are twice as high in males as in females. METHODS: Based on age-group
      specific (5-year age groups) annual incidence data of GCA among males and females
      published by 18 cancer registries worldwide, and on a consecutive series of 938
      GCAs from Finland, we explored how the male predominance of GCA has changed over
      the decades and how this male predominance may possibly vary worldwide between
      populations with high and low gastric cancer incidence. RESULTS: It appeared that
      the age-group-specific male-to-female (M/F) ratio of the annual GCA incidence is
      not constant but increases with age, reaches a peak at age around 60, and
      decreases thereafter. This special form of the M/F curve is not seen in other
      gastrointestinal (GI) cancer types (colon, rectum, pancreas). This "low-high-low"
      form of the M/F curve is related to a 10- to 15-year delay in the appearance and
      onset of GCA of the intestinal type in females compared with males. The age-group
      specific M/F ratio rises as the GCA of the intestinal subtype prevails in males
      and is rare in females before age 60 and starts to decrease after age 60 as the
      GCA of the intestinal subtype begins to be common also in females. This special
      form of the M/F curve is globally consistent and similar in countries or
      populations of high and low GCA incidence. The data from the Finnish Cancer
      Registry indicate that the age group-specific M/F curve of the annual GCA
      incidence has, in addition, remained unchanged over the decades (from the 1950s)
      in spite of a decrease in the annual GCA incidence of more than 70%. In order to
      examine the role of gastritis-related diseases as a cause of the sex difference
      in GCA, 1700 consecutive endoscopied outpatients were studied in Finland. In this
      series, the age-group-specific prevalences of Helicobacter pylori gastritis,
      atrophic gastritis, or intestinal metaplasia were proportionally as common in
      males as in females in all age groups except for the youngest one (20-49 years),
      in which H. pylori nonatrophic gastritis was slightly more common in males than
      in females. CONCLUSION: The male predominance of GCA is a global phenomenon, and
      is similar in populations with high and low GCA incidence, and this predominance
      is related to a 10- to 15-year delay in the appearance and onset of GCA of the
      intestinal subtype in females compared with males. It is suggested that sex
      hormones (estrogens) protect women against GCA, and that GCA begins to be as
      prevalent in females as in males only after the menopausal age. Another
      possibility is that a later acquisition of H. pylori gastritis in females than in
      males causes the relative delay in the appearance and onset of new GCA cases in
      females compared with males.

PMID- 12491080
TI  - The expression of RCAS1 and tumor infiltrating lymphocytes in patients with T3
      gastric carcinoma.
AB  - BACKGROUND: This study aimed to assess the prognostic value of receptor binding
      cancer antigen expressed on SiSo cells (RCAS1) expression and host immune
      response in gastric carcinomas. METHODS: We investigated the relationship between
      RCAS1 expression, density of tumor-infiltrating lymphocytes (TIL), and
      clinicopathological findings in 129 patients with T3 gastric carcinoma who
      underwent curative surgery. RESULTS: RCAS1 immunoreactivity was detected in the
      membrane and cytoplasm of tumor cells. Positive immunoreactivity for RCAS1 was
      detected in 70 patients (54.3%) and high expression levels of RCAS1 were found in
      33 patients (25.6%). The expression of RCAS1 significantly correlated with the
      histological type of carcinoma and lymph node metastasis. Apoptotic rates in TILs
      showed marginally higher significance in patients with high RCAS1 expression than
      in those with low expression. The 5-year survival rates were 77.9% in patients
      with low RCAS1 expression and 48.4% in those with high RCAS1 expression. Although
      there was no significant difference in survival between the patients with marked
      and slight infiltration of TILs, frequent apoptosis in TILs indicated
      significantly worse prognosis. Patients with low RCAS1 expression survived
      significantly longer than those with high RCAS1 expression, as did those patients
      with a high rate of apoptosis in TILs. Multivariate analysis revealed that RCAS1
      expression, as well as tumor size and lymph node metastasis, was an independent
      prognostic factor. CONCLUSIONS: The expression of RCAS1 was significantly
      correlated with poor prognosis in patients with T3 gastric carcinoma. RCAS1
      protein may play an important role in the evasion of tumor cells from
      immunological defense mechanisms in human gastric carcinoma.

PMID- 12491081
TI  - Serum pepsinogen levels in gastric cancer patients and their relationship with
      Helicobacter pylori infection: a prospective study.
AB  - BACKGROUND: Our aim was to study the serum pepsinogen levels in gastric cancer
      patients in our population in relation to histology and the presence of
      Helicobacter pylori. METHODS: Forty-six patients with gastric cancer and 70
      controls were studied prospectively in a 1-year period. Serum levels of
      pepsinogen I (PG I), pepsinogen II (PG II), and gastrin were measured by
      radioimmunoassay. RESULTS: The mean PG I levels for cancer patients and controls
      were 83.5 microg/l and 60.9 microg/l, respectively (P = 0.03), the mean PG II
      levels were 27.2 microg/l and 12.1 microg/l respectively (P < 0.0001). The PG
      I/II ratio was significantly lower in cancer patients (P = 0.04) and in those
      with Helicobacter infection. Serum pepsinogen levels were not affected by any
      pathological characteristics. Histology showed that the prevalence of chronic
      gastritis, intestinal metaplasia, and gastric atrophy was 97%, 56%, and 15%,
      respectively. CONCLUSION: The prevalence of gastric atrophy is low in our
      population, and serum pepsinogen measurement is not useful as a screening tool
      for gastric cancer in this population.

PMID- 12491082
TI  - Effectiveness of doxifluridine (5'-DFUR)/docetaxel against advanced/recurrent
      gastric cancer showing resistance to various anticancer drug regimens.
AB  - A 58-year-old man was diagnosed as having type 3 gastric cancer (poorly
      differentiated adenocarcinoma). He underwent total gastrectomy with splenectomy,
      as well as D3 dissection, and received postoperative chemotherapy combining oral
      uracil and futrafur (UFT) with cisplatin (CDDP), but results showed recurrence of
      multiple abdominal lymph node metastases around the aorta. He therefore received
      various anticancer drug regimens (irinotecan [CPT-11]/CDDP; 1 M tegafur-0.4 M
      gimeracil-1 M oteracil potassium [TS-1], methotrexate (MTX)/5-fluorouracil);
      however, final results showed growth of lymph node metastasis and simultaneous
      worsening of his general condition. The patient then received combined
      administration of doxifluridine (5'-DFUR)/docetaxel (5'-DFUR, 1000 mg/body [666.7
      mg/m(2)], given by consecutive daily administration, orally, for days 1-14; and
      docetaxel, 80 mg/body [60 mg/m(2)], on day 8, by venous drip, every 3 weeks).
      Three courses of this regimen resulted in approximately 90% reduction of the
      abdominal lymph node size, disappearance of the right cervical lymph node
      metastasis, reductions of the levels of two tumor markers (carcinoembryonic
      antigen [CEA] and carbohydrate antigen [CA]19-9), and improvement of his general
      condition. In total, seven courses of the regimen were carried out. The patient
      died on day 298 after starting this combined regimen and showed a response period
      of 126 days. The primary toxicity identified was neutropenia (grade 4), as well
      as other low-grade (grade 1, 2) hematological and nonhematological toxicities. In
      the field of gastric cancer treatment, especially for patients showing multiple
      resistance to anticancer drugs, an effective therapy is critically needed.

PMID- 12491083
TI  - Primary gastric adenocarcinoma in a 2.5-year-old girl.
AB  - Primary gastric adenocarcinoma is extremely rare in children. Here, we report an
      additional case of primary adenocarcinoma, located at the lesser curvature in a
      girl at the age of 2.5 years. She had no family history and no apparent
      underlying cause for the tumor. She died 4 months after admission despite
      complete resection of the mass and chemotherapy.

PMID- 12491084
TI  - Gastric cancer in India.

PMID- 12491085
TI  - D2 gastrectomy course, The Royal College of Surgeons of England, February 13-15,
      2002.

PMID- 12491086
TI  - Disruption of the C7orf2/Lmbr1 genic region is associated with preaxial
      polydactyly in humans and mice.

PMID- 12491087
TI  - Bisphosphonate incadronate inhibits maturation of ectopic bone induced by
      recombinant human bone morphogenetic protein 2.
AB  - To determine the effects of a bisphosphonate on the quality of bone morphogenetic
      protein-(BMP-) induced bone, incadronate was administered to rats in which
      subcutaneous ectopic bones were induced by recombinant human BMP-2. Incadronate
      (1 microg/kg/day) was administered to rats carrying the BMP-induced bones three
      times per week, from the 3rd to 7th week after BMP implantation (incadronate
      group). Aliquots of phosphate-buffered saline were administered in the same
      protocol without incadronate to the control group. During the 3rd, 4th, 7th, or
      10th week, the BMP-induced bones were removed and observed by contact
      microradiography (CMR), H&E staining, enzyme histochemistry for tartrate
      resistant acid phosphatase (TRAP), and immunohistochemistry for cathepsin K. By 3
      weeks when administration of incadronate began, woven bones formed in the
      periphery of the BMP pellets and osteoclasts were attached to these bones. At 4
      weeks, in both the incadronate and control groups, bone formation advanced
      inward. However, in the incadronate group, poorly calcified areas, corresponding
      to the remaining BMP pellets, were found in the middle areas of bone formation,
      whereas osteoclasts decreased when compared with those of the control group.
      During the 10 weeks, bone marrow was formed and the characteristics of lamellar
      bones, in which the lacunae of small osteocytes were regularly arranged, were
      noted in the control group. In contrast, the poorly calcified areas were still
      present up to 10 weeks in incadronate group in which the osteoclasts were also
      scarcer than in the control group. These findings suggested that osteoclast
      mediated bone resorption was inhibited by incadronate administration, and that
      immature bones including the BMP pellets remained for a long time, indicating
      that the process of bone maturation was blocked. The possibility of using
      incadronate for the purpose of inhibiting osteoclastic bone resorption was
      confirmed, but further study is needed before clinical application.

PMID- 12491088
TI  - Does hysterectomy with ovarian conservation affect bone metabolism and density?
AB  - We evaluated whether hysterectomy with ovarian conservation (HYX) has an effect
      on bone metabolism and density in 176 healthy Caucasian postmenopausal women aged
      48-59 years. Bone properties of the hip, spine, radius, tibia, and calcaneus were
      measured using different bone assessment modalities. In addition, bone turnover
      was assessed using serum bone-specific alkaline phosphatase (BAP), osteocalcin
      (OC), and tartrate-resistant acid phosphatase (TRAP) 5b as biomarkers. Our
      results showed that women having HYX had a significantly lower level of OC ( P =
      0.017) and a marginally lower level of TRAP 5b ( P = 0.051) and higher bone
      mineral density (BMD) of the femoral neck ( P = 0.037) and lumbar spine ( P=
      0.001) than women with no history of HYX. In addition, the cortical BMD and bone
      strength index (I(polar)) of the tibia also showed higher values at different
      sections in women having HYX than women with no history of HYX ( P = 0.055 to P<
      0.005). These results suggest that the uterus may have a role in regulating bone
      metabolism that has not been detected previously.

PMID- 12491089
TI  - Relative contribution of lean and fat mass component to bone mineral density in
      males.
AB  - We investigated the relative contribution of lean body mass (LBM) and body fat
      mass to bone mineral density (BMD) in 93 healthy Japanese male volunteers (mean
      age, 33.1 +/- 6.9 years; range, 18-54 years). Age, height (Ht), weight (Wt), and
      body mass index (BMI, Wt/Ht(2)) were recorded. Body fat mass, percentage of body
      fat, body fat mass/Ht(2), LBM, LBM/Wt, LBM/Ht(2), and lumbar spine (L2-L4) and
      total body BMD (TBBMD) were measured by dual-energy X-ray absorptiometry. On the
      Pearson correlation test, LBM was positively correlated with L2-L4 BMD. LBM,
      LBM/Wt, and LBM/Ht(2) were positively correlated with TBBMD. However, body fat
      mass and body fat mass/Ht(2) were not correlated with lumbar spine and total body
      BMD. On the partial correlation test, LBM was still correlated with lumbar spine
      ( r = 0.307, P < 0.05) and total body BMD ( r = 0.545, P< 0.0001), irrespective
      of age and height, whereas body fat mass was not correlated with BMD of these
      sites ( r = -0.069 and -0.169, respectively). We concluded that, in males, LBM is
      one of the significant determinants of BMD whereas body fat mass is a negligible
      BMD determinant.

PMID- 12491090
TI  - Correlation between bone mineral density and intervertebral disk degeneration in
      pre- and postmenopausal women.
AB  - The purpose of this study was to investigate the relationship between
      intervertebral disk degeneration and bone mass. Magnetic resonance imaging was
      performed to evaluate lumbar disk degeneration according to Thompson's
      classification (grades 1 and 2, normal disk; grades 3, 4, and 5, degenerated
      disk), and bone mineral density (BMD) in the lumbar vertebrae, radius, and
      calcaneus was measured by dual-energy X-ray absorptiometry for 90 women (22-74
      years old). The relationship between the grade of intervertebral disk
      degeneration and the BMD ( Z score) was analyzed in pre- and postmenopausal
      women. In premenopausal women, BMD was significantly higher at all measured sites
      in the degenerated disk group judged at the L5-S1 level than in the normal disk
      group ( P < 0.05). In postmenopausal women, BMD was significantly higher at the
      anteroposterior L2-L4, lateral L3, and calcaneus in the degenerated disk group
      judged at the L2-L3 level than in the normal disk group ( P < 0.05). BMD at the
      anteroposterior L2-L4 and calcaneus was significantly higher in the degenerated
      disk group judged at the L3-L4 level than in the normal disk group ( P < 0.05).
      In conclusion, the BMD of not only the lumbar vertebrae but also the calcaneus
      and radius was mutually related to lumbar intervertebral disk degeneration from
      an early stage of degeneration.

PMID- 12491091
TI  - Calcium balance in young adults on a vegan and lactovegetarian diet.
AB  - For people in Western countries, the vegan diet has the advantage of low energy
      intake, but the calcium status of this strictly plant-based diet is still
      unclear. The aim of this study was to determine the calcium balance of
      individuals on a vegan diet in comparison with a lactovegetarian diet in a short
      term investigation. Seven women and one man, ranging in age from 19 to 24 years,
      received during the first 10 days a vegan diet based on plant foods and calcium
      rich mineral water and a lactovegetarian diet during the following 10 days.
      Portion size was adapted to the subjects' individual energy requirements. Calcium
      status was assessed by means of calcium intake in food and calcium output in
      feces and urine as measured by flame atomic absorption spectrophotometry. In
      addition, deoxypyridinoline was measured in urine as a marker of bone resorption.
      The results show a significantly smaller daily calcium intake with an average of
      843 +/- 140 mg in the vegan versus 1322 +/- 303 mg in the lactovegetarian diet.
      Apparent calcium absorption rates were calculated as 26% +/- 15% in the vegan and
      24% +/- 8% in the lactovegetarian group (NS). The calcium balance was positive
      both in the vegan diet (119 +/- 113 mg/day) and in the lactovegetarian diet (211
      +/- 136 mg/day) (NS). Deoxypyridinoline excretion showed no significant
      difference between the two diets (105 +/- 31 and 98 +/- 23 nmol/day). The present
      results indicate that calcium balance and a marker of bone turnover are not
      affected significantly when calcium is provided either solely by plant foods or
      by a diet including dairy products, despite the significantly different calcium
      intake levels in the diets. We conclude that a well-selected vegan diet maintains
      calcium status, at least for a short-term period.

PMID- 12491092
TI  - Polymorphisms of four bone mineral density candidate genes in Chinese populations
      and comparison with other populations of different ethnicity.
AB  - Studies on polymorphisms of candidate genes and their association with bone
      mineral density (BMD) have been reported in many populations, but few have been
      reported in Chinese populations. We investigated polymorphisms of the following
      five commonly used markers of four prominent BMD candidate genes with the purpose
      of identifying useful genetic markers for osteoporosis genetic research in
      Chinese: the Sp1 and RsaI polymorphisms of the collagen type 1 alpha l (Col1a1)
      gene, the -174G/C promoter polymorphism of the interleukin 6 (IL-6) gene, the
      Asn363Ser polymorphism of the glucocorticoid receptor (GR) gene, and the T --> C
      polymorphism in intron 5 of the transforming growth factor beta(1) (TGF-beta(1))
      gene. We evaluated these polymorphisms using PCR-RFLP in samples of at least 124
      random individuals. We compared the polymorphisms of these five markers with
      other populations using the chi(2) test and Fisher's exact two-tailed test. For
      the RsaI polymorphism, only three heterozygotes but no variant homozygote were
      identified. For the -174G/C polymorphic site, only one GC heterozygote and no CC
      homozygote were found. Alleles s, Ser, and A(1) at the Sp1, Asn363Ser, and T -->
      C marker sites that have been found to be polymorphic in other populations were
      not found in Chinese. Significant differences of allele and genotype frequency
      distributions were observed at these polymorphisms ( P < 0.001) after comparing
      with other populations. Our results suggest that variant alleles of the five
      markers are absent or too rare to be useful genetic makers in Chinese, despite
      the fact that they have been commonly used as polymorphic markers in osteoporosis
      genetic research in other populations.

PMID- 12491093
TI  - The relation between tooth loss and bone mass in postmenopausal osteoporotic
      women in Turkey: a multicenter study.
AB  - The purpose of this study was to investigate the associations of tooth loss with
      skeletal bone mass, years since menopause, educational level, current smoking
      status, dietary calcium intake, and number of pregnancies in postmenopausal
      osteoporotic women in Turkey. The study population consisted of 1171
      postmenopausal women aged 40-86 years (mean age, 61.19 +/- 7.28 years). A
      detailed history was obtained from all women, including relevant lifestyle
      parameters, risk factors, and measurements of weight and height. Women were
      separated into three groups according to the number of teeth remaining as group 1
      (edentulous, 457 women), group 2 (10 or fewer teeth, 232 women), and group 3
      (more than 10 teeth remaining, 482 women). There was no significant difference
      among the three groups in mean age and menopausal age ( P < 0.05). Body mass
      index of group 1 was significantly higher than that of group 2 ( P< 0.01).
      Educational level was significantly different between three groups: groups 1 and
      2 ( P< 0.001), groups 1 and 3 ( P< 0.0001), and groups 2 and 3 ( P< 0.001).
      Educational level was lowest in group 1 and highest in group 3. Despite a low
      ratio of cigarette smoking in general, a smoking habit was most prevalent in
      group 3 and least in group 2. The ratio of women receiving adequate calcium was
      significantly lower in group 1 than in other groups ( P< 0.001); mean calcium
      intake was similar in all groups. The number of pregnancies was significantly
      higher in group 1 than in other groups ( P< 0.001). Lumbar bone mineral density
      (BMD) of group 1 was significantly lower than that of groups 2 and 3 ( P< 0.001).
      Although no significant difference was found between groups 1 and 3, femoral neck
      BMD of group 2 was less than in others, and differences between groups 1 and 2
      and between groups 2 and 3 ( P< 0.001) were significant. Lumbar bone mineral
      content (BMC) of group 1 was significantly lower than that of groups 2 and 3 ( P<
      0.001), and lumbar BMC in group 2 was significantly higher than in group 3 ( P<
      0.05). Femoral neck BMC in group 1 was significantly higher than in groups 2 and
      3 ( P< 0.001). In conclusion, lumbar BMD and BMC in the edentulous group were
      significantly lower, whereas femoral neck BMD and BMC were significantly higher
      in edentulous group compared with the others. Our findings indicated that
      improvement in lifestyle factors and nutritional strategies for the treatment and
      prevention of osteoporosis may have additional benefit in reducing tooth loss.

PMID- 12491094
TI  - Structuring parameters for assessment of bone quality using a morphological
      filter and star volume analysis: structuring property in the cancellous bone of
      the human femoral head.
AB  - This study examines structuring parameters for the assessment of bone quality
      based on the relationship of bone strength to the trabecular structure or bone
      mineral density (BMD). Thirty-nine human cancellous bone blocks sampled from
      resected Ward's triangle area were investigated. The trabecular bone pattern of
      each bone block was binarized into its corresponding trabecular skeletal pattern
      using computed radiography with a morphological filter. Every binarized
      trabecular skeletal pattern was quantified to find the trabecular skeletal pixel
      percentage (SkP = volume parameter of trabecular skeletal signal component) and
      skeletal star volume (Vt = connection parameter of trabecular skeletal
      structure). After BMD and elasticity for each bone block was measured by dual X
      ray absorptiometry and the breaking test, the correlations to SkP and Vt were
      determined. In addition, an attempt was made to detect changes of the trabecular
      structure in the Ward's triangle area of the femoral head after patients had
      received treatment for osteoporosis. This evaluation used the structuring
      parameters SkP and Vt. The results showed that the larger the BMD value, the
      greater the elasticity, although some samples with similar BMD values had
      considerably different elasticities. With increased Vt values the trabecular
      skeletal pattern that had horizontal skeletal elements orientated perpendicular
      to the loading direction showed higher elasticity. No correlation between SkP and
      either elasticity or BMD was observed in either the subset (sequential images of
      morphological filter) or sumset images (combined with subset images). On the
      other hand, the correlation coefficient between Vt and elasticity was similar to
      that between BMD and elasticity for subset image ( n = 6). For sumset images (3-6
      and 4-7), the correlation coefficient of Vt was equal or higher than that of BMD
      and the connectivity of the trabecular skeletal structure was more closely linked
      to bone strength as compared to BMD. Therefore, it was concluded that because no
      high correlation could be detected between Vt and BMD, BMD and the connectivity
      of trabeculae are independently related to bone strength. In addition, this
      method was used to evaluate patients after treatment for osteoporosis, and
      noticeable changes were seen in the bone trabecular skeletal structure in the
      Ward's triangle area of the femoral head. In reference to these clinical images,
      variations in SkP and Vt were quantitatively assessed. These results suggest that
      the SkP and Vt obtained using computed radiography, morphological filter, and
      star volume analysis are useful structuring parameters for the assessment of bone
      quality.

PMID- 12491095
TI  - False-positive magnetic resonance imaging skeletal survey in a patient with
      sporadic hypophosphatemic osteomalacia.

PMID- 12491096
TI  - RNA-protein interactions in spherical viruses.
AB  - The three-dimensional structure of many non-enveloped spherical RNA viruses has
      been determined in great detail, mainly using X-ray crystallography. Great
      insight in the structure of the protein capsid has been obtained, but much less
      information is available about the secondary and tertiary structure of the RNA in
      situ, due to a number of methodological problems. In this paper the current
      knowledge about RNA-protein interactions and the folding of the RNA is reviewed,
      with a special emphasis on the plant virus Turnip yellow mosaic virus. A major
      characteristic of many spherical RNA viruses appears to be the positioning of A
      type double helical segments of 7-9 basepairs at icosahedral symmetry axes,
      probably interacting via its phosphates with basic amino acid residues of the
      coat protein in a sequence-independent manner. It is only in the case of the RNA
      bacteriophages that we know in atomic detail how an RNA hairpin interacts with
      the coat protein.

PMID- 12491097
TI  - Zantedeschia mosaic virus causing leaf mosaic symptom in calla lily is a new
      potyvirus.
AB  - Anovel virus, Zantedeschia mosaic virus (ZaMV-KR), causing mosaic and
      malformation symptoms was isolated from calla lily ( Zantedeschia spp.) in Korea
      and its biological and molecular properties were characterized. The virus was
      distinct from Dasheen mosaic virus, an Araceae-infecting potyvirus, by
      serological and sequence analyses. Multiple alignments of the CP amino acid
      sequence between the virus and other potyviruses showed 51.8 to 62.1% identity.
      Phylogenetic analyses of the CP revealed that the virus could be clustered with
      Plum pox virus and Turnip mosaic virus. Sequence comparison of the CP gene
      between the virus and three other ZaMV isolates from Taiwan showed over 93.9%
      identity, and most of amino acids changes occurred in the N-terminal region.
      Sequence comparison of 3' NTR revealed homology levels of 27.0 to 47.9% between
      the virus and other potyviruses. Our results support ZaMV as a distinct species
      of the genus Potyvirus.

PMID- 12491098
TI  - Detection of rice grassy stunt tenuivirus nonstructural proteins p2, p5 and p6
      from infected rice plants and from viruliferous brown planthoppers.
AB  - The genome of Rice grassy stunt virus (RGSV) consists of 6 ambisense RNA
      segments, among which RNAs 1, 2, 5 and 6 are equivalent to RNAs 1, 2, 3 and 4,
      respectively, of Rice stripe virus, the type species of the genus Tenuivirus. The
      RGSV 36-kDa nucleocapsid protein (N) is encoded on the complementary strand of
      RNA 5. Here, we studied accumulation of three nonstructural proteins, a 23-kDa p2
      protein encoded on vRNA 2 (virus genomic strand), a 22-kDa p5 protein encoded on
      vRNA 5, and a 21-kDa p6 protein encoded on vRNA 6, from RGSV-infected rice leaf
      tissues and from viruliferous vector insects (brown planthopper, Nilaparvata
      lugens) by Western blot analyses. p2, p5 and p6 were detected from RGSV-infected
      rice leaf homogenates; p2 was detected mostly in the cytoplasmic soluble fraction
      but also a small amount was detected in the cell-wall, organelle-enriched and
      crude membrane fractions; p5 and p6 were detected from the cytoplasmic soluble
      fraction in large amounts. Among individual nymphs of N. lugens raised on RGSV
      infected rice leaves, only 20% of insects were positive with the N protein. A
      large amount of p5 was detected from all the N-positive insects. Small amounts of
      p2 and p6 were detected only from a subset of the N- and p5-positive insects. p5
      may have an essential role in virus infection in both plant and insect hosts,
      whereas p2 may function in plants such as a cell-to-cell movement protein.

PMID- 12491099
TI  - Molecular studies of the synergistic interactions between plum pox virus HC-Pro
      protein and potato virus X.
AB  - Helper component proteinase (HC-Pro) is a multifunctional viral protein involved
      in vection and movement of potyvirus; suppression of host post-transcriptional
      gene silencing reaction; and synergism of potyvirus with other viruses, notably
      potexvirus. When the HC-Pro of plum pox potyvirus (PPV) was transiently expressed
      in N. benthamiana and N. clevelandii plants via potato virus X (PVX) vector, a
      highly synergistic response of leaf necrosis or plant death, was observed in
      PVXHC-infected plants. However, when mutations were introduced into the highly
      conserved "PTK" and "KITC" motifs of HC-Pro, known for their involvement in
      protein/protein interaction during aphid-mediated transmission of potyvirus, the
      resulting change of amino acid residue from lysine (K) to glutamic acid (E) in
      the "KITC" motif had no obvious influence.

PMID- 12491100
TI  - Genetic organisation of Iris yellow spot virus M RNA: indications for functional
      homology between the G(C) glycoproteins of tospoviruses and animal-infecting
      bunyaviruses.
AB  - The complete nucleotide sequence (4838 nucleotides) of Iris yellow spot virus
      (IYSV) M RNA indicates, typical for tospoviruses, the presence of two genes in
      ambisense arrangement. The vRNA ORF codes for the potential cell-to-cell movement
      (NSm) protein (34.8 kDa) and the vcRNA ORF for the viral glycoprotein (G1/G2)
      precursor (128.6 kDa). Multiple sequence alignment of the NSm and G1/G2 precursor
      proteins of IYSV with those of other tospoviruses, showed highest homologies to
      Peanut bud necrosis virus (PBNV) and Watermelon silver mottle virus (WSMV). The
      potential cell-to-cell movement protein of tospoviruses is highly conserved (40
      70% identity), with the exception of the first 60 N terminal amino acids, a
      domain that clearly diverged. For the G1 and G2 viral glycoproteins, blast
      searches revealed a significant homology between the C-terminally located
      tospoviral G1 (G(C)) protein with the counterpart of the animal-infecting
      bunyaviruses, suggesting a functional homology for these proteins.

PMID- 12491101
TI  - The primary neutralization epitope of porcine respiratory and reproductive
      syndrome virus strain VR-2332 is located in the middle of the GP5 ectodomain.
AB  - Pigs infected with porcine respiratory and reproductive syndrome virus (PRRSV)
      strain VR-2332 were found to generate high levels of antibodies (Abs) that bound
      in an indirect ELISA to synthetic peptides representing segments of the primary
      envelope glycoprotein (GP5) ectodomain of this virus. Use of overlapping GP5
      ectodomain peptides of various length indicated that the epitope recognized by
      the Abs was located in the middle of the ectodomain (amino acids 36-52), in the
      same relative segment that contains the single linear neutralization epitope of
      the closely related mouse arterivirus, lactate dehydrogenase-elevating virus
      (LDV). The VR-2332 GP5 segment exhibits 77% amino acid homology with the
      corresponding GP5 ectodomain segments of both the European PRRSV strain Lelystad
      virus (LV) and LDV. This explains some observed crossreaction between the pig Abs
      and neutralizing anti-LDV monoclonal Abs with peptides representing the GP5
      ectodomains of VR-2332, LV and LDV. The GP5 binding Abs of pigs seem to be the
      primary PRRSV neutralizing Abs, since the well timed appearance in sera of all VR
      2332 infected pigs of GP5 peptide binding Abs correlated 100% with the appearance
      of neutralizing Abs and earlier studies indicated that GP5 of PRRSV, like that of
      other arteriviruses, contains the main neutralization epitope of PRRSV. In
      addition, one neutralizing anti-LDV monoclonal Ab that is specific for the GP5
      ectodomain epitope of LDV also strongly neutralized both PRRSV strains, VR-2332
      and LV. The PRRSV GP5 epitope is associated with an N-glycan that is conserved in
      both PRRSV genotypes and all LDV isolates. This N-glycan may impede the humoral
      immune control of PRRSV in infected pigs and might be responsible for the low
      immunogenicity of PRRSV when injected into mice.

PMID- 12491102
TI  - Subcellular targeting domains of Abutilon mosaic geminivirus movement protein
      BC1.
AB  - Abutilon mosaic geminivirus (AbMV) encodes two movement proteins, BV1 and BC1,
      which mediate the intra- and intercellular transport of viral DNA in plants
      cooperatively. It has been shown previously that singly expressed BC1, fused to
      green fluorescent protein (GFP), accumulates preferentially either at the cell
      periphery or around the nucleus in separate plant cells. To define the BC1
      domains responsible for understanding the subcellular sorting, deletion mutants
      were fused to GFP and expressed transiently in epidermal cells of non-host
      (Allium cepa) as well as of host (Nicotiana benthamiana) plants with basically
      the same results in both species. BC1-mediated intracellular sorting was
      dependent on two protein domains, an "anchor domain" (amino acids 117 to 180)
      which is necessary and sufficient to fix GFP:BC1 at the cell periphery and the
      nuclear environment, and a "pilot domain" (amino acids 1 to 49) in the absence of
      which the fusion proteins were found at both sites in the same cell
      simultaneously.

PMID- 12491103
TI  - Amino acid substitutions within the Cys-rich domain of the tobacco etch potyvirus
      HC-Pro result in loss of transmissibility by aphids.
AB  - We examined the role of several amino acid residues located at the N-terminus of
      the tobacco etch potyvirus (TEV) helper component-proteinase (HC-Pro) in virus
      transmissibility by aphids. Site-directed mutagenesis resulted in changes
      affecting amino acids that appear highly conserved among a number of potyviruses.
      The TEV HC-Pro amino acid residues Gly343, Val345, Ala346, Ile348, Pro355,
      Lys358, and Ile359 were arranged within a Cys-rich domain in a region dispensable
      for TEV infectivity. Two HC-Pro mutants (TEV-P355R and -K358N) exhibited a
      drastically reduced rate of aphid transmission whereas other mutants (TEV-G343D, 
      V345E, -A346H, -I348D, and -P355L) were completely unable to be aphid
      transmitted. In contrast, the I359M mutation had no effect on aphid
      transmissibility of TEV. This lack of transmissibility did not appear to be due
      to large differences in the amounts of both coat protein (CP) and HC-Pro in
      infected tobacco plants. Our results indicated that these amino acid residues
      likely play a highly conserved role in aphid transmission among potyviruses.

PMID- 12491104
TI  - Visna/maedi virus Env protein expressed by a vaccinia virus recombinant induces
      cell-to-cell fusion in cells of different origins in the apparent absence of Env
      cleavage: role of glycosylation and of proteoglycans.
AB  - The in vivo productive infection by the ovine Visna/maedi lentivirus (VISNA) is
      restricted to cells of the monocyte/macrophage lineage. The basis for this
      restriction is not understood. Although the VISNA envelope (Env) glycoprotein is
      the main target for virus neutralization, studies on the role of this protein in
      virus infection are limited. A vaccinia virus recombinant (VV- env-MV) containing
      the entire VISNA env sequence was generated and shown to produce in infected
      cells a protein of about 165 kDa (referred to as gp150). During VV- env-MV
      infection, expression of env caused extensive cell-to-cell fusion in cell lines
      of different origins. Pulse-chase and Western blot analyses revealed that gp150
      is not cleaved in VV- env-MV infected cells. The glycoprotein gp150 formed
      oligomers held by disulfide bonding. Cell-to-cell fusion was prevented in the
      presence of the inhibitor of glycosilation, tunicamycin, but it was markedly
      enhanced by an inhibitor of proteoglycan synthesis, beta-D-xyloside. These
      findings showed that the receptor for VISNA Env is widely distributed within
      cells, that fusion-from-within of cells can occur in the apparent absence of
      proteolytic cleavage of gp150, and that fusion require a glycosylated Env but not
      the addition of proteoglycan chains at the cell surface. This recombinant virus
      could have utility as a potential vaccine against VISNA.

PMID- 12491105
TI  - Sequence analysis of an Australian isolate of sugarcane bacilliform badnavirus.
AB  - The genome of an Australian isolate of Sugarcane bacilliform virus (SCBV-IM) was
      cloned, sequenced and analysed. The genome consisted of 7687 nucleotides and
      contained three open reading frames which were similar in size and organisation
      to those of other badnaviruses. SCBV-IM was found to be most similar to the SCBV
      Morocco isolate with amino acid sequence similarity of 91.4 %, 83.8 % and 85.3 %
      in the ORF I, II and III coding regions, respectively. Phylogenetic analysis of
      the SCBV-IM ORF III deduced amino acid sequence showed that SCBV isolates were
      more closely related to each other than to other badnaviruses. Amplification of
      SCBV sequences from three different sugarcane varieties revealed considerable
      variability in the viral populations, both within single infected plants as well
      as between infected plants, suggesting that the SCBV isolates sequenced to date
      may not be representative of the range of virus variability.

PMID- 12491106
TI  - Expression of tegument protein pp65 of human cytomegalovirus (CMV) and its
      application to the analysis of viral-specific cellular immunity in CMV-infected
      individuals.
AB  - Investigations into human cytomegalovirus (CMV)-specific cellular immunity are
      important to better understand and manage CMV infections. CMV phosphoprotein pp65
      is thought to be a major antigen for CMV-specific cellular immunity. We newly
      synthesized protein pp65 with a baculovirus expression system and purified it via
      metal affinity chromatography in a soluble form. The recombinant protein pp65 was
      antigenic in an enzyme immuno-linked assay for pp65-specific IgG in sera from 196
      children. Traditional lymphoproliferation assays have shown that pp65 protein
      promotes specific lymphoproliferation in CMV-seropositive donors. Using an
      intracellular cytokine detection system, we showed that this recombinant protein
      stimulated CD4-positive T cells to express interferon-gamma. The results of these
      assays using protein pp65 were comparable with the use of CMV whole antigen. pp65
      and CMV-specific cellular immunity, and CMV DNA load were also compared in four
      recipients of unrelated cord blood transplantation. The delay in re-constitution
      in CMV-specific cellular immunity was associated with reactivation of CMV. These
      results indicated that the recombinant protein pp65 can be used to study specific
      immunity in CMV infections.

PMID- 12491107
TI  - Remarkable morphological diversity of viruses and virus-like particles in hot
      terrestrial environments.
AB  - Electron microscopic studies of the viruses in two hot springs (85 degrees C, pH
      1.5-2.0, and 75-93 degrees C, pH 6.5) in Yellowstone National Park revealed
      particles with twelve different morphotypes. This diversity encompassed known
      viruses of hyperthermophilic archaea, filamentous Lipothrixviridae, rod-shaped
      Rudiviridae, and spindle-shaped Fuselloviridae, and novel morphotypes previously
      not observed in nature. Two virus types resembled head-and-tail bacteriophages
      from the families Siphoviridae and Podoviridae, and constituted the first
      observation of these viruses in a hydrothermal environment. Viral hosts in the
      acidic spring were members of the hyperthermophilic archaeal genus Acidianus.

PMID- 12491108
TI  - The complete nucleotide sequence of Beet black scorch virus (BBSV), a new member
      of the genus Necrovirus.
AB  - The complete nucleotide sequence of Beet black scorch virus (BBSV) was
      determined. The BBSV genome is composed of 3641 nucleotides and has similar
      organization with Tobacco necrosis virus D of 61% nucleotide identity. The 5'
      proximal open reading frame (ORF) encodes a putative 23 kDa protein and a 82 kDa
      protein by reading-through of an amber termination codon. Three small ORFs
      located in the center of the genome may encode for a 4.2 kDa protein and two 7
      kDa proteins. The 3'-proximal ORF encodes a 24.5 kDa protein equivalent in mass
      to the viral coat protein. Considering biological and molecular similarities with
      TNV, it is concluded that BBSV is a new member of the genus Necrovirus.

PMID- 12491109
TI  - Maize dwarf mosaic disease in different regions of China is caused by Sugarcane
      mosaic virus.
AB  - Sugarcane mosaic virus (SCMV) was detected in all 62 maize samples collected from
      eight maize-growing provinces in China showing dwarf mosaic symptoms by
      immunocapture reverse-transcription polymerase chain reaction (RT-PCR). Maize
      dwarf mosaic virus (MDMV), Sorghum mosaic virus (SrMV) and Johnsongrass mosaic
      virus (JGMV), however, were not detected in any of the samples by RT-PCR. Eleven
      cDNA fragments of approximately 0.8 kilobases covering most of the coat protein
      (CP) gene of SCMV were sequenced and sequence analysis indicates that these
      eleven isolates share 98.1 to 100 % identity at the amino acid level. Sequence
      comparison and phylogenetic analysis of the CP genes from the eleven Chinese
      isolates as well as 21 SCMV subgroup virus isolates indicate that the eleven
      Chinese virus isolates were closely related to SCMV with 97.0 to 98.1 % sequence
      identity at the amino acid level, while relatively lower sequence identity was
      found with MDWV, SrMV or JGMV. The results indicate that the Chinese isolates are
      members of the SCMV species, and thus, SCMV can be considered as the most common
      and important potyvirus infecting maize in China.

PMID- 12491110
TI  - Poliovirus modulates Bcl-xl expression in the human U937 promonocytic cell line.
AB  - Poliovirus induces bcl-2-independent apoptosis in the human U937 promonocytic
      cell line [28]. Here we describe that this cell death, induced after viral
      infection, correlates with the modulation of the protooncoprotein Bcl-xl.
      Furthermore, poliovirus infection decreases the detected Bcl-xl in a U937 clone
      that overexpresses this protein (U937bcl-xl). Although in U937bcl-xl cells, Bcl
      xl was not as highly regulated as in parental U937 cells, correlation between Bcl
      xl modulation and the cleavage of poly(ADP-ribose)polymerase could be observed.
      Nevertheless, the induction of shutoff after infection of transfected control
      U937neo or U937bcl-xl clones was not significantly altered. Finally, production
      of new viral particles was slightly restricted in Bcl-xl-overexpressing U937
      cells. Taken together, these results suggest that Bcl-xl is modulated during the
      induction of apoptosis in the promonocytic cell line U937 after poliovirus
      infection, although modulation of this protooncogene was not sufficient to modify
      the course of infection.

PMID- 12491112
TI  - Improved clarity of meaning from the use of both formal species names and common
      (vernacular) virus names in virological literature.

PMID- 12491111
TI  - Prevention of transplacental infection of bovine foetus by bovine viral diarrhoea
      virus through vaccination.
AB  - Results are presented for an experimental validation of the efficacy of an EU
      licensed, inactivated bovine viral diarrhoea virus vaccine (Bovilis BVDV). This
      study was designed to assess the quality of efficacy 6 months after a single
      course of vaccination (two intramuscular doses a month apart). A natural
      challenge at about 87 days of gestation by 3 persistently infected carrier
      heifers rapidly infected all experimental heifers. This resulted in
      transplacental BVDV infection of all 7 unvaccinated dams whereas 11 immunised
      dams produced 9 live-born calves and 2 aborted foetuses from which no BVDV could
      be recovered.

PMID- 12491113
TI  - [Preface].

PMID- 12491114
TI  - [What can experimental research offer to rheumatology today--the viewpoint of
      molecular biology? Contribution of molecular biology to pathogenesis research in
      rheumatology using the example of rheumatoid arthritis].
AB  - Molecular biology plays an increasing role for the development of innovative
      approaches to analyze the pathogenesis of rheumatic diseases and to improve
      diagnosis and therapy of these disorders. Some of these approaches/techniques
      have recently yielded important results, e.g. the analysis of 1) chromosomal
      aberrations (numerical and, in part, structural aberrations in synovial
      fibroblasts/macrophages from chronic joint inflammation); 2) cell clonality
      (oligoclonal expansion of synovial T-cells, B-cells, but also fibroblasts); 3)
      the importance of genetic factors (genome-wide screening for arthritis
      susceptibility genes); 4) mutations in key genes of cell cycle and/or function
      (mutations in p53 and proto-oncogenes in the inflamed synovial membrane); and 5)
      gene expression patterns (e.g. by high-density microarrays, custom arrays, in
      situ hybridization, and real-time PCR). It can be expected that these analyses
      will result in central new findings concerning the understanding of the
      pathogenetic basis of chronic inflammatory rheumatic diseases, with the potential
      to develop differential diagnostic criteria for these hitherto extremely
      heterogeneous diseases, and to create the basis for individual-oriented therapy.

PMID- 12491115
TI  - [Diagnosis and therapy monitoring applying methods of molecular medicine].
AB  - New experimental approaches are presented which are implemented in rheumatology
      research. DNA microarray technology and proteome analysis are two new methods
      which are applied to gain a global survey over the gene expression at the RNA and
      protein level under various conditions. Based on these methods of molecular
      medicine important functional proteins in the pathogenesis of rheumatoid
      arthritis (RA) as well as clinical relevant genetic polymorphisms shall be
      identified. New insights are expected which will help in the differentiation of
      clinical entities and in the search for new therapeutic strategies in the
      treatment of RA.

PMID- 12491116
TI  - [Evidence-based guidelines--what is the present situation?].
AB  - Guidelines have proven to be an important tool for improving quality of health
      care. Evidence-based guidelines are particularly well accepted and have a high
      degree of credibility based on the transparent process of their development and
      the explicit use of clinical patient-oriented research, on which the
      recommendations are based. The goal of the guidelines "Management of early
      rheumatoid arthritis", currently developed by an interdisciplinary working group,
      is to minimize out existing deficiencies in the provision of health care.

PMID- 12491117
TI  - [Problems integrating research projects in routine medical practise].
AB  - Better integration of research projects into the rheumatologic private practises
      in Germany is of great interest both for the scientific project carriers and for
      the rheumatologists in practice themselves. The present restrictions in this area
      may be explained by the lack of resources of this group of rheumatologists needed
      for such an engagement, mainly for economic reasons. There would be the need to
      integrate surgery reserach into the practices, with sufficient additional space
      and man power. For this goal, the material and legal conditions would have to be
      created.

PMID- 12491118
TI  - [Therapy optimization studies torn between science and funding].
AB  - There is no doubt that clinical studies are valuable cornerstones in the
      development of rational diagnostics and therapy, for the patients' safety, for
      quality assurance as well as for the development of a body of evidence in
      medicine. Well recognized multicentric study groups are active in several medical
      disciplines in Germany. Public funding resources however are miserable as
      compared to other countries. For example in hematology and oncology funds are
      almost exclusively available by private foundations as the Deutsche Krebshilfe
      only. Additionally physicians and institutions who are actively promoting
      clinical studies have to pay charges for patients' insurance and for registration
      of studies by the authorities. Furthermore there are increasing difficulties
      obtaining reimbursement for patients' care in clinical studies. In this context
      outdated regulations of the German Sozialgesetzbuch V lawbook play an important
      role. In summary a pronounced reform deficit paired with bureocratic tendencies
      has become manifested. The most important demands are in this situation: a
      reliable and realistic regulatory basis for treatment-related clinical studies
      has to be created. Studies on treatment strategies with registered drugs have to
      be free from the obligatory patients' insurance which is required for study with
      non-registered drugs. It has to be clarified that in these studies some
      regulations of good clinical practice as obligatory external monitoring and
      source data verification are not feasible and will not be required. The
      Sozialgesetzbuch V has to be adapted and the actual ban of clinical studies in
      private practice has to be ended. Treatment related clinical studies have to be
      free from charges of ethical committees and regulatory authorities. Thereby the
      financial overload of clinical studies could be reduced and some motivation for
      further bureocratic proliferation is removed. Finally a longterm, reliable
      funding resource has to be created independently from the pharmaceutical
      industry. A possible model could be a foundation for treatment-related studies
      which is financed by public funds and by funds from the reimbursement companies.

PMID- 12491119
TI  - [Effectiveness of rehabilitation with musculoskeletal diseases].
AB  - Multidisciplinary treatment focusing on impairments, activities and participation
      are an important component within the therapeutic regimen in musculoskeletal
      conditions. In Germany, for more than 95% of the patients multidisciplinary
      treatment is provided as inpatient rehabilitation. According to the results of a
      study from the Netherlands, inpatient rehabilitation is superior to usual care in
      terms of decreasing disease activity and improving emotional well-being in
      rheumatoid arthritis. Another randomized, controlled study gives evidence that
      rehabilitation is more effective as compared to usual care in ankylosing
      spondylitis. In patients suffering from fibromyalgia, after inpatient
      rehabilitation, symptoms improve significantly and this is true even one year
      after discharge. The results of a quality management project financed by the
      German health insurance and including several thousand patients with
      musculoskeletal diseases show an improvement in physical and emotional dimensions
      of health status at discharge and after a six month follow-up. Recent studies
      comparing inpatient with outpatient rehabilitation in patients with
      musculoskeletal diseases provide information that both forms are equally
      effective. Taking into account the high number of inpatient rehabilitation
      procedures in Germany, more outcomes research is required urgently.

PMID- 12491120
TI  - [Current aspects of cost effectiveness of TNF-alpha blocking agents in patients
      with rheumatoid arthritis].
AB  - Facing increasing health-related costs and limited health care resources, the
      assessment of cost effectiveness (CE) of medical procedures is also gaining
      considerable importance in the field of rheumatology. Since high annual therapy
      costs of 17,000-21,000 Euro are related to the employment of TNF-alpha blocking
      agents such as etanercept and infliximab (compared to annual costs of 350-5000
      Euro of other disease modifying drugs (DMARDs) in the treatment of rheumatoid
      arthritis (RA)), their CE has become an important issue. The present
      investigation summarizes economic evaluations of cost and effectiveness of TNF
      alpha blocking agents and compares the results to those of traditional DMARD
      therapies in patients with RA. The implications of these economic results on the
      further use of TNF-alpha blocking drugs and methodological improvements of their
      economic evaluation are discussed. The current literature provides evidence for
      the CE of the combination therapy with methotrexate (MTX), hydroxychloroquine
      (HCQ), and sulfasalazine (SASP). In comparison to this finding, the use of
      etanercept and MTX yields much higher costs, although the highest rate of ACR20
      responses is achieved by this combination (additional costs of $42,000 per ACR20
      response compared to combination of MTX, HCQ, and SASP). Two recent studies show
      more promising results of about $12,000/QUALY and even cost savings per QUALY
      administering etanercept and infliximab, respectively. The wide range of the CE
      ratios is mainly explained by different methodological approaches. Whether the
      wider employment of TNF-alpha blocking drugs (comprising not only selected
      patients) proves to be economically effective, remains to be investigated by
      further economic analyses. In contrast to the initial disappointing results of
      the comparison of established DMARD therapies and TNF-alpha blocking drugs in
      terms of CE, recently published data renders evidence that the CE of the TNF
      alpha blocking drugs is comparable to other accepted therapies in internal
      medicine.

PMID- 12491121
TI  - [Diagnostics].
AB  - The round-table group "diagnostic" discussed the laboratory-based diagnosis of
      rheumatic diseases under the following three main questions: "What is
      necessary?"; "What is possible?" and "What has been achieved?".

PMID- 12491122
TI  - [Pharmacotherapy of rheumatoid arthritis].
AB  - The therapeutic goals in rheumatoid arthritis have been so far pain reduction,
      improvement of function and inhibition of disease progression. Nowadays
      therapeutic strategies must aim at the induction of remission. Long-term results
      clearly improve with an early start of DMARD therapy. Additional corticosteroid
      therapy can further reduce joint destruction. After an early start with DMARD
      therapy (methotrexate in most cases) corticosteroids should be additionally given
      in moderate and severe cases. Reconsideration of the therapeutic regime should be
      performed no later than three months after start of therapy. In the case of
      remission corticosteroids should be reduced. If there is no remission the DMARD
      therapy should be intensified, if necessary together with a combination therapy.
      After another three months a step-down concept can be applied if remission
      occurs. Otherwise therapy should again be intensified, if necessesary with the
      use of biologicals.

PMID- 12491123
TI  - [Round-table-talk on patient education in rheumatology].
AB  - Primarily the discussion group focused on obtaining current information about the
      existing patient education programs for different rheumatic diseases developed by
      a working group of the German Society of Rheumatology, about the institutions
      running the patient education courses, the train-the-trainer seminars, the costs
      and the problems of fund raising from the health insurance companies. As a
      successful example for running patient education courses in an outpatient
      setting, the cooperation between the Arthritis Center of Hannover and the League
      against Rheumatism in Lower Saxony was illustrated. Then the group defined three
      important future tasks: to reach a standard of funding patient education by every
      health insurance company in Germany, to increase the efforts to inform the public
      about patient education and to establish a nation-wide network of patient
      education centers. A meeting of all Collaborative Arthritis Centers in Germany
      was proposed to discuss the necessary steps to reach these aims.

PMID- 12491124
TI  - [Current aspects of examination in rheumatology].

PMID- 12491125
TI  - [Expert assessment of patients with rheumatoid arthritis].
AB  - Rheumatoid arthritis (RA) is the most common inflammatory disease of the
      locomotor system associated with early loss of function and joint destruction. A
      relevant number of patients with RA withdraw from employment within the first
      years. To give a medical opinion on patients with RA regarding ability for work
      requires thorough knowledge of the disease, its characteristic deformities and
      prognostic indicators as well as knowledge of the essential examinations and
      instruments for the estimation of functioning and disability.

PMID- 12491126
TI  - [Degenerative joint and spine diseases].
AB  - Degenerative joint and spine diseases account for more than 70% of all complaints
      and functional impairment in the human locomotor system. An expert assessor has
      to answer questions referring to loss of capability of earning a living and to
      the extent of an invalidity. He will often be confronted with questions whether
      or not the body damage is related to an accident. He therefore has to be familiar
      with accident mechanisms and typical injury patterns. Particular details of
      examination and imaging important for fulfilling the assessor's task are given.
      Special hints will be given referring to evaluation of rotator cuff lesions and
      spine syndromes.

PMID- 12491127
TI  - [Expert assessment of patients with seronegative spondyloarthropathies].
AB  - Besides rheumatoid arthritis, seronegative spondyloarthropathies are one of the
      most common inflammatory musculoskeletal diseases. The main clinical
      manifestations are spondylitis and sacroiliitis, but peripheral arthritis and
      involvement of other organ systems are known as well. The typical ankylosis of
      the spine is resulting in a marked loose of the functional capacity. During the
      course of disease, work disability is progressing and finally the patient may
      become permanent disabled. Patients with ankylosing spondylitis can be viewed by
      experts for several reasons. To guarantee an objective medical expert view, a
      detailed clinical examination and use of clinical indices are mandatory.

PMID- 12491128
TI  - [Guidelines for assessment of patients with connective tissue diseases].
AB  - Guidelines for assessments of connective tissue diseases in social jurisdiction
      and for insurance are not available in Germany. This article is a guideline
      reflecting published data, modern therapy and actual prognosis. In addition, help
      for interpretation and examples are given.

PMID- 12491129
TI  - [The expert assessment of fibromyalgia].
AB  - Research on fibromyalgia over the last ten years has focused on the broad variety
      of pathogenetic aspects of a pain amplification syndrome. This emphasizes pain as
      the leading symptom. The sociomedical implications are obvious and considerable,
      and therefore fibromyalgia has increasingly become the subject of expert
      assessments. The expert assessment should not discuss the existence or non
      existence of fibromyalgia, but evaluate the individual impairments, disabilities
      and handicaps which may lead to an individual degree of dysfunctioning.

PMID- 12491130
TI  - [Novel autoantibodies for the diagnosis of rheumatoid arthritis].
AB  - The diagnosis of rheumatoid arthritis has been hampered by the lack of a truly
      disease-specific serologic marker. Thus, despite its moderate specificity
      rheumatoid factor (RF) is still the only established marker antibody for RA and
      among the diagnostic criteria of the American College of Rheumatology the only
      serologic one. However, in recent years, several newly characterized
      autoantibodies have been described that may have the potential to become
      diagnostic indicators for RA. In particular, antibodies to citrullinated targets
      (anti-keratin or anti-filaggrin antibodies, respectively, antibodies to synthetic
      citrullinated peptides) appear to be highly specific for RA. Other potentially
      useful antibodies include anti-RA33 autoantibodies and antibodies to the stress
      protein BiP which seem to have higher specificity for RA than RF. Apart from
      being promising diagnostic markers these autoantibodies or the underlying
      cellular autoimmune reactions, respectively, may also play a role in the
      pathogenesis of RA.

PMID- 12491131
TI  - [Technique and diagnostic value of musculoskeletal ultrasonography in
      rheumatology. Part 6: ultrasonography of the wrist/hand].
AB  - Sonography of the hands is especially helpful in the diagnosis of early
      arthritis. Sonography allows for a very sensitive detection of small joint
      effusion, tenosynovitis and small erosive bone lesions earlier than conventional
      radiography. Musculoskeletal sonography is also helpful in morphological analysis
      of changes of the median nerve in patients with carpal tunnel syndrome. The
      following standard scans are suggested for the sonographic evaluation of the
      wrist: 1. dorsal longitudinal scan along the radio-carpal joint, 2) along the
      ulno-carpal joint, and 3) dorsal transverse scan along the wrist to detect joint
      fluid collection, synovitis, tenosynovitis, ganglia, irregularities of the bone
      surface in osteoarthritis, and erosions due to inflammatory disease, 4) volar
      longitudinal scan along the radio-carpal joint, and 5) along the ulno-carpal
      joint, and 6) volar transverse scan along the wrist to diagnose the same
      objective as the above mentioned scans and to evaluate the median nerve in cases
      of carpal tunnel syndrome. Optional scans are the following: 7) ulnar
      longitudinal 8) transverse scan along the ulnar joint space and the extensor
      carpi ulnaris muscle to detect tenosynovitis and caput ulnae syndrome, 9) radial
      longitudinal, and 10). transverse scan along the joint space to diagnose
      synovitis and tenosynovitis. The following standard scans are suggested for the
      sonographic evaluation of the fingers: 1) volar longitudinal, 2) volar transverse
      scan in extension along the finger joints to detect effusion and synovial
      proliferation, tenosynovitis, irregularities of the bone surface (osteophytes,
      erosions), 3) dorsal longitudinal scans in extension and flexion >70 degrees
      along the CMC I, MCP, PIP and DIP joints to evaluate effusion and synovial
      proliferation, tenosynovitis or tendinitis, irregularities of the bone surface
      (osteophytes, erosions), and 4) dorsal transverse scans along the finger joints
      to evaluate these structures in an additional dimension. Optional 5) scans
      include the following: medial longitudinal scan along the MCP I, II, PIP and DIP
      joints, and 6) lateral longitudinal scan along the MCP V, PIP and DIP joints to
      evaluate the erosive bone process and joint instability. A linear transducer with
      a frequency of between 7.5 and 12 MHz is recommendable. The anterior distance
      between the bone and the joint-capsule of the wrist is > or = 3 mm in probable
      and > or = 4 mm in definite synovitis or effusions. Synovitis or effusions are
      probable if the difference between right and left wrist is > or = 1 mm, and they
      are definite if the difference is > or = 2 mm. A carpal tunnel syndrome is
      probable with a cross-sectional area of the median nerve of > or = 12 mm(2).

PMID- 12491132
TI  - [The off-label-prescription of TNF-alpha blocking agents for
      spondyloarthropathies in the context of recent statement by a German federal
      court].
AB  - With the TNF alpha-blocking agents for the first time a very efficient and
      probably disease-modifying treatment for the spondyloarthropathies, especially
      ankylosing spondylitis and psoriatic arthritis, has become available. Because
      these drugs have not yet been approved for this indication in the European
      Community they are regarded as off-label-therapy in Germany. It is the purpose of
      this article to discuss a recently released statement by a German federal court
      whether the herein formulated conditions for the prescription of off-label
      therapies is met for TNF-blocker treatment for this indication.

PMID- 12491133
TI  - [Revised recommendations of the Deutsche Gesellschaft fur Rheumatologie on
      therapy with tumor necrosis factor-inhibiting active substances on inflammatory
      diseases].

PMID- 12491134
TI  - [Recommendations of the Deutschen Gesellschaft fur Rheumatologie on therapy of
      rheumatoid arthritis with the interleukin-1-receptor-antagonist Akakinra
      (KINERET)].

PMID- 12491135
TI  - [Topical non-steroidal antirheumatic substances].

PMID- 12491136
TI  - Prolactin and thyroid hormones in patients with systemic sclerosis: correlations
      with disease manifestations and activity.
AB  - OBJECTIVE: To determine serum levels of prolactin (PRL) and thyroid hormones and
      to investigate the correlation between these hormones and different disease
      manifestations in patients with systemic sclerosis (SSc). METHODS: Twenty four
      patients with SSc (23 women, mean age 37.7+/-12.7) were subjected to thyroid
      hormones assessment. Prolactin (PRL) was assessed in 23 female patients. The
      patients were evaluated regarding different disease manifestations. Fifteen
      normal female volunteers were involved as controls. RESULTS: Serum levels of PRL
      in all patients was significantly higher than controls (16.75+/-9.06 for patients
      vs. 11.6+/-4.5 for controls with p<0.001). Eight patients out of 23 (34.8%)
      showed hyperprolactinemia. In patients with diffuse SSc (dSSc), PRL levels showed
      significant correlation with the rate of skin tethering (r = +0.72, p<0.01) and
      abnormal left ventricular filling pattern (decreasing E/A ratio), i.e.,
      occurrence of diastolic dysfunction (r = +0.65, p<0.05). Hyperprolactinemia in
      all patients correlated significantly with disease duration (r = -0.42, p<0.05).
      Mean serum levels of free thyroxin (FT4) in all patients were significantly lower
      than the control group(7.46+/-2.7 for patients vs 10.47+/-2.5 with p<0.001).
      Eight out of all 24 patients (33.3%) showed hypothyroidism. In group A
      (duration<3 years); FT4 levels correlated significantly with Dlco% (r = +0.90,
      p<0.01). While in group B (duration>3 years), T4 hypothyroidism correlated
      significantly with hand joint restriction of motion (r = +0.66, p<0.01). Serum
      levels of triiodothironine (FT3) in all patients were nonsignificantly lower than
      the control group (4.8+/-2.3 for patients vs 5.3+/-1.9 for controls, P = NS).
      Three patients out of 24 (12.5%) showed T3 thyrotoxicosis. Serum levels of T3
      correlated significantly with liver enzyme elevations (r = +0.46, p<0.05) and ESR
      (r = +0.41, p<0.05). CONCLUSION: This study demonstrates the close association
      between PRL or thyroid hormones and some organ involvement in SSc.

PMID- 12491137
TI  - [Radiological changes in the cervical spine in rheumatoid arthritis -- prognostic
      factors obtained by a cross-sectional study].
AB  - OBJECTIVE: The involvement of the cervical spine is the most serious skeletal
      manifestation of rheumatoid arthritis (RA). Instabilities of the upper cervical
      spine can lead to neurological complications and signs of vertebrobasilar
      insufficiency. The study investigates the relationship between the course of the
      RA and the degree of radiological changes in the cervical spine and describes
      prognostic factors of cervical spine involvement. MATERIAL AND METHODS: Clinical
      data were gathered from 205 patients with RA. Standardized X-ray examination of
      the cervical spine was performed and arthritic changes were assessed by a
      semiquantitative score. The association of clinical symptoms with defined
      radiological changes was evaluated. RESULTS: Radiological changes in the cervical
      spine related to RA were found in 67.8% of the patients. Anterior atlantoaxial
      dislocations were detected in 25.4%, subaxial dislocations in 55.6% and a
      vertical displacement of the dens in 21.5% of the cases. The degree of
      radiological changes in the cervical spine was not directly correlated with
      neurological symptoms. Age above 55 years, disease duration of more than 10
      years, an onset of cervical pain later than 11 years after the diagnosis of RA,
      steroid therapy for more than 5 years, bilateral shoulder involvement and the
      presence of severe erosive changes in at least one peripheral joint were
      positively associated with the development of severe changes in the cervical
      spine. In patients with basilar impression, paraesthesia in the upper extremities
      was significantly more common. CONCLUSION: Prognostic factors are helpful for the
      assessment of risk of cervical spine involvement in RA. Since definite clinical
      hints for cervical involvement are absent, the cervical spine has to be included
      in the routine examination of patients with RA.

PMID- 12491138
TI  - IgVH-genes analysis from psoriatic arthritis shows involvement of antigen
      activated synovial B-lymphocytes.
AB  - The pathogenesis of psoriatic arthritis (PA), which occurs in 5-7% of patients
      with psoriasis vulgaris, is enigmatic. There are no molecular data about synovial
      B-cells of chronic synovitis of PA. In order to understand the B-cell response in
      PA, we analysed IgVH genes and specified replacement to silent mutation (R/S)
      ratios of the complementarity determining regions (CDR) and framework regions
      (FR) as well as VH families. To prove the existence of a common pattern we
      additionally analysed the IgVH genes at the amino-acid level. From 5 PA patients
      we took cryo-tissue sections with somatically mutated IgVH genes (sum R/sum S in
      the CDRs: 2.5-6.8), 62 of which were analysed. In one patient two cases of
      clonally related IgVH genes were observed. Identical amino-acid replacements in
      IgVH1 and IgVH4 were found at the same mutational "cold spot". These data
      indicate that antigen-activated B-cells participate in the formation of chronic
      synovitis of PA. Since, neither histopathologically nor immunohistochemically, no
      germinal centres could be detected, the clonally related IgVH genes may be
      interpreted as residues of a germinal centre reaction that occurred before
      synovectomy. The existence of identical amino-acid replacement mutations in IgVH1
      and IgVH4 genes suggests that a limited number of antigens are common to all PA
      patients analysed. The recombinant expression of the IgVH could help to define B
      cell specificities underlying the pathogenesis of chronic synovitis and
      dermatitis of PA.

PMID- 12491139
TI  - [The juxtaacetabular ganglion].
AB  - A juxtaarticular ganglion (JAG) is a rare tumor-like lesion of the acetabulum,
      causing chronic hip disability. Due to its location, a JAG is a special form of
      an intraosseous ganglion. There is a lack of histological criteria to
      differentiate a JAG from an osteoarthritic cyst. The clinical findings of a JAG
      are determined by its proximity to the joint gap and its extraarticular
      extension. In a case report the necessary diagnostics as well as the therapeutic
      consequences are discussed.

PMID- 12491141
TI  - [Erythema nodosum].

PMID- 12491140
TI  - [Essential cryoglobulinemic vasculitis with severe peripheral neuropathy and
      neurogenic muscular atrophy -- inducing remission by cascade filtration].
AB  - We report on a 60 year old patient with peripheral neuropathy, neurogenic
      muscular atrophy, skin ulcers, arthritis and weakness. Detection of cryoglobulins
      in association with typical clinical symptoms, exclusion of hepatitis C and any
      other disease led to a rare diagnosis: essential cryoglobulinemic vasculitis. The
      case demonstrates not only the difficult diagnostic process but also the problems
      of an adequate and effective therapy. Since the usual immunosuppressive
      treatments such as methotrexate, high dose corticosteroid and intermittent
      intravenous pulse cyclophosphamide therapy (Austin's scheme) failed, we performed
      plasmapheresis (cascade filtration), which brought about an immediate and long
      term remission. Besides discussing various types of plasmapheresis procedures and
      potential pathophysiological mechanisms, we point out that this therapy could
      find an early use in severe essential cryoglobulinemic vasculitis because of its
      excellent risk/benefit ratio.

PMID- 12491143
TI  - [Jacques E. Forestier (1890-1978) -- the versatile].

PMID- 12491145
TI  - Proceedings of the 10th International Conference on Neuroscience of HIV
      Infection: emerging issues.
AB  - The 10th International Conference on Neuroscience of HIV Infection was held
      conjointly with the 4th International Symposium on NeuroVirology. This review
      summarizes a number of important topics addressed at the conference including
      clinical aspects of HIV-1 associated dementia and peripheral nervous system
      pathology and their epidemiology in the era of highly active antiretroviral
      therapy. The neuropathogenesis was discussed with a special focus on different
      cellular compartments involved, viral and non-viral factors, immune activation,
      and alterations of the blood-brain barrier, animal models and their relevance for
      understanding HIV dementia. New aspects of antiretroviral therapy as well as
      immunization were covered. Neuroradiological approaches including new MR
      techniques and neuropsychological tests were presented. Viral opportunistic
      infections (e.g., JCV infection resulting in progressive multifocal
      leukoencephalopathy) as well as coinfection with hepatitis C represented a
      further topic.

PMID- 12491146
TI  - Molecular basis of prion diseases.

PMID- 12491147
TI  - Regulation of human immunodeficiency virus type 1 gene expression and
      pathogenesis by CCAAT/enhancer binding proteins in cells of the
      monocyte/macrophage lineage.
AB  - CCAAT/enhancer binding proteins (C/EBPs) are transcription factors that regulate
      a variety of cellular genes involved in broad range of physiological processes,
      including immune cell functions that involve cytokine expression and release as
      well as immune cell differentiation and inflammation. In addition, C/EBP factors
      regulate many viral promoters, including the human immunodeficiency virus type 1
      (HIV-1) long terminal repeat (LTR). The dependence of HIV-1 gene expression and
      replication on C/EBP factors in cells of myeloid origin positions these factors
      as important regulators of HIV-1 during the course of disease, because cells of
      monocyte/macrophage origin are critical components of viral pathogenesis in the
      peripheral blood and in other tissue compartments, including the central nervous
      system (CNS). Recent studies also indicate potentially important correlates
      between HIV-1 LTR C/EBP site sequence variation (which alters factor recruitment
      and activity), sequence compartmentalization, and the severity of HIV-1-induced
      immunologic dysfunction and neuropathogenesis. Cumulatively, studies of C/EBP
      factors and their roles in the regulation of host and viral gene expression
      indicate the importance of these factors in the progression of HIV-1-associated
      disease and, specifically, the genesis of CNS disease and HIV-1-associated
      dementia.

PMID- 12491148
TI  - Human immunodeficiency virus dementia: evidence of a subcortical process from
      studies of fine finger movements.
AB  - HIV-1 associated dementia is the major manifestation of HIV-1 within the central
      nervous system and a devastating disease which is characterized by cognitive,
      motor, and emotional deficits. HIV-1 associated minor motor deficits can manifest
      as psychomotor slowing and predict the later development of HIV-1 associated
      dementia, AIDS, and death. These minor motor deficits can be described, e.g., by
      electrophysiological assessment of basal ganglia motor function (frequency of
      most rapid alternating finger movements, reaction and contraction times of most
      rapid index finger extensions). Minor motor deficits quantified by contraction
      times can be subdivided into a more incipient and a more sustained type of
      deficit. Parallel examination of motor function and positron emission tomography,
      magnetic resonance spectroscopy of the basal ganglia, or SPECT helps to point to
      the basal ganglia as a pivotal point of HIV-1 associated CNS pathology.

PMID- 12491149
TI  - Selected peripheral neuropathies associated with human immunodeficiency virus
      infection and antiretroviral therapy.
AB  - A variety of peripheral neuropathies are associated with human immunodeficiency
      virus (HIV) infection. Although the incidence of certain forms of neuropathy is
      increased in HIV infection, in other cases, the association may be fortuitous.
      Different forms of peripheral neuropathy occur with increased frequency at
      particular stages of HIV disease. For example, inflammatory demyelinating
      neuropathy (IDP) is often the first manifestation of HIV disease, when CD4
      lymphocyte counts are relatively high. As immunosuppression progresses and HIV
      viral load becomes uncontrolled, the incidence of distal symmetrical
      polyneuropathy (DSP) increases. In advanced stages of HIV disease (CD4 count <50
      cells/mm(3)), patients may develop opportunistic cytomegalovirus (CMV) nerve
      infection, which can present as progressive polyradiculopathy (PP) or
      mononeuropathy multiplex (MM). In addition to the neuromuscular disorders caused
      by HIV and its concomitant immunosuppression, the use of antiretroviral (ARV)
      drugs and other therapeutic agents in HIV disease is frequently limited by
      neuromuscular side effects. This paper will review the symmetrical forms of
      polyneuropathy that occur in association with HIV infection and nucleoside
      analogue therapy. The clinical, electrophysiologic, and pathologic features of
      these disorders will be described along with a discussion of theories of
      pathogenesis and results of treatment to date.

PMID- 12491150
TI  - A novel simian immunodeficiency virus model that provides insight into mechanisms
      of human immunodeficiency virus central nervous system disease.
AB  - Although highly active antiretroviral therapy (HAART) has reduced the incidence
      of dementia, a significant proportion of HIV-infected individuals cease therapy
      because of unacceptable side effects. Further, HAART is not available to the
      majority of HIV-infected people worldwide. Thus, animal models remain an
      important means by which to investigate the pathogenesis of HIV-induced CNS
      disease, particularly events during acute infection. We have developed an
      accelerated, consistent SIV/macaque model of HIV infection in which over 90
      percent of inoculated macaques develop SIV encephalitis and behavioral changes by
      three months post-inoculation (p.i.). Viral load in the CSF during terminal
      infection and the ratio of MCP-1 in CSF:plasma are strong predictors of the
      severity of encephalitis at necropsy. The high incidence of CNS disease in this
      model provides an opportunity to correlate host and viral events in the CNS
      during acute infection with the later development of CNS disease. Using this
      model, we have demonstrated that viral DNA persists in the brain throughout
      asymptomatic infection despite significant suppression of active virus
      replication. We have further demonstrated that encephalitis is associated with
      the selective replication of macrophage-tropic, neurovirulent viral strains, and
      that recrudescence of virus replication during terminal infection occurs by
      reactivation of preexisting viral strains in the brain.

PMID- 12491151
TI  - Murine models for human immunodeficiency virus type 1-associated dementia: the
      development of new treatment testing paradigms.
AB  - The neuroimmune events leading to human immunodeficiency virus (HIV)-1-associated
      dementia (HAD) are linked to macrophage secretory neurotoxins (cellular and viral
      toxins). To study such events, we developed a murine model of HIV-1 encephalitis
      (HIVE), the pathological equivalent of HAD. Severe combined immunodeficient
      (SCID) mice injected with HIV-1-infected monocyte-derived macrophages (MDMs) into
      basal ganglia exhibited many of the pathological features of human HIVE.
      Moreover, behavioral and cognitive abnormalities in the HIVE mice were associated
      with neuronal dysfunction and decreased synaptic density. Thus, the rationale for
      testing novel therapeutic approaches (anti-inflammatory, antiretroviral, or
      neuroprotective) in the HIVE SCID mice is clear. Animals treated with anti
      inflammatory compounds (platelet-activating factor [PAF] antagonist and tumor
      necrosis factor [TNF]-alpha release inhibitor) showed a marked reduction in brain
      inflammation and a reduction in neuronal injury. Comparative analyses of highly
      active antiretroviral therapy (HAART) regimens provided direction for which one
      might be most efficient for reduction of viral load in infected brain tissue.
      Moreover, modifications of the HIVE model might serve as a vehicle for testing
      vaccine approaches. Reconstitution of immunodeficient animals with syngeneic T
      lymphocytes followed by injection of HIV-1-infected MDMs in the brain resulted in
      cytotoxic antivirus T lymphocyte (CTL) response. CD8-positive T cells migrated to
      the sites of human MDMs, leading to the cell-mediated destruction of HIV-1
      infected MDMs. These results, taken together, strongly support the use of HIVE
      SCID mouse model as a novel system for studies of the neuropathogenesis of HIV-1
      infection, as well as for testing novel therapeutic and vaccine interventions for
      human disease.

PMID- 12491152
TI  - The art of survival during viral persistence.
AB  - Central nervous system infection by the neurotropic JHM strain of mouse hepatitis
      virus (JHMV) results in chronic demyelination characterized by viral persistence
      in the absence of infectious virus. CD8(+) T cells inhibit acute viral
      replication via cell type-specific effector mechanisms. Perforin-mediated
      cytolysis controls virus in microglia/macrophages and astrocytes, whereas
      interferon (IFN)-gamma regulates viral replication in oligodendroglia. JHMV
      infection of antibody-deficient mice confirmed a primary role of cellular
      immunity and a redundant role for humoral immunity during acute infection.
      However, infectious virus reactivates in antibody-deficient mice following viral
      clearance. This observation suggests that virus-specific T cells in the central
      nervous system are unable to control viral persistence. Reactivation in antibody
      deficient mice is not associated with increased T-cell infiltration, but is
      prevented via transfer of neutralizing antibody. A vital role for humoral
      immunity during persistence is supported by the accumulation and retention of
      virus-specific antibody secreting cells following clearance of infectious virus.
      Thus, cell-mediated immune responses control acute infection, whereas humoral
      immunity maintains viral persistence. Therefore, although the central nervous
      system provides an environment for prolonged retention of both T cells and plasma
      cells, plasma cells are critical in maintaining persistent virus at undetectable
      levels. The low turnover of virus, T cells, and B cells constitute a unifying
      feature of persistent infection, illustrating the dichotomy between distinct
      immune effectors in regulating acute and persistent central nervous system
      infection.

PMID- 12491153
TI  - Overview of the cellular immunity against JC virus in progressive multifocal
      leukoencephalopathy.
AB  - The human polyomavirus JC (JCV) infects most healthy adults without causing any
      disease. In the setting of severe deficit of cell-mediated immunity, such as in
      acquired immunodeficiency syndrome (AIDS), malignancies or in organ transplant
      recipients, JCV can reactivate and cause progressive multifocal
      leukoencephalopathy (PML), a deadly demyelinating disease of the central nervous
      system. The humoral immune response, measured by the presence of virus-specific
      immunoglobulin G (IgG) in the blood or by intrathecal synthesis of IgG in the
      cerebrospinal fluid (CSF), is unable to contain the progression of PML. CD4+ T
      lymphocytes recognize extracellular viral proteins that have been degraded into
      peptides through the exogenous pathway and presented on major histocompatibility
      complex (MHC) class II molecules at the surface of antigen-presenting cells.
      Consistent with their underlying immunosuppression, the proliferative response of
      CD4+ T lymphocytes to mitogens or JCV antigens is reduced in PML patients. CD8+
      cytotoxic T lymphocytes recognize intracellularly synthesized viral proteins that
      have been degraded into peptides through the endogenous pathway, and presented on
      MHC class I molecules at the surface of virus-infected cells. One of such JCV
      peptide, the VP1(p100) ILMWEAVTL, has been characterized as a cytotoxic T
      lymphocyte (CTL) epitope in HLA-A *0201 + PML survivors. Staining with the
      corresponding A *0201/JCV VP1(p100) tetrameric complex showed that VP1(p100)
      stimulated peripheral blood mononuclear cells (PBMCs) of 5/7 (71%) PML survivors
      had JCV-specific CTL, versus none of 6 PML progressors (P = .02). This cellular
      immune response may therefore be crucial in the prevention of PML disease
      progression and the tetramer staining assay may be used as a prognostic marker in
      the clinical management of these patients.

PMID- 12491154
TI  - Pathogenesis of Semliki Forest virus encephalitis.
AB  - This article provides a review of the pathogenesis of Semliki Forest virus (SFV)
      encephalitis. In mice, outcome of infection varies according to age of the mouse
      and strain of the virus and can include acute encephalitis, subacute
      demyelinating meningoencephalomyelitis, and persistent subclinical central
      nervous system (CNS) infection. All strains of virus are virulent in mice
      infected <12 days of age. The L10 strain is also virulent in mice >14 days age,
      whereas the A7(74) strain is avirulent. The genetic difference between these
      strains maps to the nsp3 gene. For A7(74) virus, age-related virulence correlates
      with ability of CNS neurons to replicate virus and undergo apoptotic cell death.
      Immature developing neurons support complete virus replication but as neuronal
      populations and circuits mature in the postnatal brain, virus infection becomes
      progressively restricted and nonproductive. This restricted replication can be
      overcome by gold I compounds, which may function by inducing neuronal
      dedifferentiation to a state permissive for virus replication. Biochemical
      pathways associated with membrane biogenesis may be an important determinant of
      this effect. Infection of some developing neuronal populations results in
      apoptosis, whereas infection of mature neurons results in persistent infection.
      An active type-I interferon system prevents virus spread in extraneural tissues.
      An initial high-titer plasma viremia is controlled by immunoglobulin M (IgM)
      antibodies. Virus enters the brain across cerebral endothelial cells and
      initiates scattered foci of perivascular infection. The blood-brain barrier is
      disrupted. Neurons and oligodendrocytes are the cell types most frequently
      infected. Infectivity in the brain can be eliminated by IgG antibodies, though an
      active T-cell response is required for virus elimination. Lesions of inflammatory
      demyelination require the presence of CD8(+) T lymphocytes and probably result
      from destruction by these cells of virally infected oligodendrocytes.

PMID- 12491155
TI  - The protean manifestations of varicella-zoster virus vasculopathy.
AB  - Varicella-zoster virus (VZV) vasculopathy in the central nervous system (CNS)
      affects large and small cerebral vessels. Large-vessel disease is most common in
      immunocompetent individuals, whereas small-vessel disease usually develops in
      immunocompromised patients. In some patients, both large and small vessels are
      involved. Neurological features are protean. Neurological disease often occurs
      months after zoster and sometimes without any history of zoster rash. Magnetic
      resonance imaging (MRI) scanning, cerebral angiography, and examination of
      cerebrospinal fluid (CSF) with virological analysis are needed to confirm the
      diagnosis. VZV vasculopathy patients do not always have VZV DNA in CSF, but
      diagnosis can be confirmed by finding anti-VZV antibody in CSF, along with
      reduced serum/CSF ratios of VZV immunoglobulin G (IgG) compared to albumin or
      total IgG. When VZV vasculopathy develops months after zoster, antiviral
      treatment is often effective.

PMID- 12491156
TI  - Key issues in varicella-zoster virus latency.
AB  - The molecular mechanisms by which varicella-zoster virus (VZV) causes a latent
      infection in human trigeminal and spinal ganglia are not well understood. It is
      known that VZV establishes latency in ganglia following the primary infection
      causing varicella (chickenpox), and that the virus may reactivate after years of
      dormancy to produce herpes zoster (shingles). Two key issues have been the cell
      type localization of latent VZV in human ganglia, and the nature and extent of
      VZV gene expression during latency. Although the cell specificity of latent VZV
      has been controversial for almost a decade, it is now widely accepted that the
      virus is mainly latent in neuronal cells, with only a small proportion of non
      neuronal cells infected. All of the studies carried out so far have indicated
      that VZV gene expression is highly restricted during ganglionic latency. Although
      at least four VZV genes have been identified as being expressed, the possibility
      that latent gene expression is significantly greater than this cannot yet be
      excluded. There is also evidence for VZV gene-encoded proteins being expressed
      during latency, although the precise extent of this is unclear. Advances in this
      difficult field may be expected to arise from both newly developed molecular
      technology and more refined animal models of VZV latency.

PMID- 12491157
TI  - Approaches in the understanding of morbillivirus neurovirulence.
AB  - Certain members of the morbillivirus genus, canine distemper virus, phocine
      distemper virus, and the cetacean viruses of dolphins and porpoises exhibit high
      levels of central nervous system (CNS) infection in their natural hosts. CNS
      complications are rare for measles virus (MV) and are not associated with
      rinderpest virus (RPV) and peste des petits ruminants virus (PPRV) infection.
      However, both RPV and PPRV are neurovirulent in permissive murine strains. Human
      postmortem tissue, neural cell cultures, and animal models have been used to
      answer major questions concerning morbillivirus neurovirulence. Studies of the MV
      CNS complication subacute sclerosing panencephalitis (SSPE) indicate that virus
      could enter the CNS either by direct infection of endothelial cells or in
      infected leucocytes, followed by infection of predominately neurones and
      oligodendrocytes. It has been established that MV neurovirulence in mice is
      partially determined by the virus-receptor specificity. The two known MV
      receptors, CD46 and SLAM, have been examined in normal and SSPE brain tissue and
      the findings suggest that further receptors may be necessary to explain infection
      of the CNS with wild-type strains of MV. In both humans and mice (and in vitro),
      once infection of neurones has been established, virus spreads transneuronally.
      It is possible that all morbilliviruses transiently infect the CNS in their
      natural hosts, but development of disease is dependent on the efficiency of the
      immune response. Alternatively, for RPV and PPRV, virus entry may be restricted
      due either to absence of viral receptors or failure of virus to replicate or
      spread in the CNS.

PMID- 12491158
TI  - Tat-induced deregulation of neuronal differentiation and survival by nerve growth
      factor pathway.
AB  - HIV-1 enters the brain at the early stage of infection and resides primarily in a
      limited number of macrophages/microglia and astrocytes. Infection of these cells,
      however, may not explain the massive neuronal pathology which is seen in AIDS
      associated dementia, suggesting a role for factors released from HIV-1 infected
      cells that trigger a cascade of events leading to neurodegeneration. Our results
      indicate that Tat, the potent regulatory protein of HIV-1 which is secreted by
      infected cells and can affect neighboring uninfected cells by transcellular
      means, can influence multiple biological events that lead to neuronal injury.
      These findings demonstrate that treatment of neuronal cells with Tat affects
      MAPK/ERK1/2 activity, the downstream central component of the nerve growth factor
      (NGF) signaling pathway. Furthermore, our data indicate that treatment of cells
      with Tat severely decreases expression of p35, a neuron-specific activator of
      cdk5, a cyclin dependent kinase that phosphorylates several neuronal proteins
      including neurofilament, and plays an important role in neuronal differentiation
      and survival. In parallel, Tat can bind to the cellular protein, Puralpha, which
      associates with cdk5. Further, results from Puralpha knockout animals revealed a
      decrease in p35 activity, pointing to the importance of Puralpha association with
      cdk5 in the activity of cdk5:p35 complex. These data demonstrate the
      cooperativity between HIV-1 Tat and the Puralpha in deregulation of the NGF
      signal transduction pathway in neuronal cells.

PMID- 12491159
TI  - The latency-associated gene of herpes simplex virus type 1 (HSV-1) interferes
      with superinfection by HSV-1.
AB  - During herpes simplex virus type 1 (HSV-1) lifelong latency in human peripheral
      sensory ganglia (PSG), only the viral latency-associated transcript (LAT) gene is
      expressed. This raises the possibility that this gene is involved in
      establishment of latency of the virus, its maintenance, or reactivation. Here we
      present data that indicate yet another independent function of the LAT gene:
      interference with HSV-1 superinfection of latently infected neurons. Neuronal
      cells stably expressing the LATs are protected from infection with HSV-1, but not
      from infection by other RNA and DNA viruses, including HSV-2. These unexpected
      findings may explain the observation that human PSG are latently infected with
      just a single strain of HSV-1, despite repeated exposure during life to multiple
      viral strains. Thus, the LATs may protect the latent HSV-1 reservoir from
      cytopathic superinfections, and at the same time the host is protected at the
      viral entry site from HSV-1 insults that may eventually cause viral encephalitis.

PMID- 12491160
TI  - Regulation of caspase 8- and caspase 9-induced apoptosis by the herpes simplex
      virus type 1 latency-associated transcript.
AB  - The latency-associated transcript (LAT) is the only herpes simplex virus type 1
      (HSV-1) gene that is abundantly transcribed during latency. Plasmids expressing
      LAT inhibit apoptosis induced by etoposide and ceramide in transiently
      transfected cells. LAT also inhibits apoptosis in trigeminal ganglia of rabbits
      and promotes spontaneous reactivation, suggesting these events are coupled. In
      this study, we compared caspase cleavage (activation) in cells infected with
      dLAT2903 (LAT-null mutant) versus wild-type McKrae or the rescued LAT-null mutant
      (dLAT2903R). Neuro-2A cells (mouse neuroblastoma), but not NIH3T3 cells infected
      with dLAT2903, contained higher levels of cleaved caspase 9 compared to cells
      infected with McKrae. Cleaved caspase 9 was also readily detected in neuro-2A
      cells, but not NIH3T3 cells, after ultraviolet (UV) light treatment, suggesting
      that the ability of cells to process caspases and undergo apoptosis influences
      the antiapoptotic properties of LAT. HSV-1 expresses numerous genes in addition
      to LAT that can block apoptosis during productive infection of cultured cells.
      Because these genes may mask the effects of LAT on apoptosis, transient
      transfection assays were performed to test whether LAT can inhibit caspase 8- and
      caspase 9-induced apoptosis. A plasmid expressing nucleotides 1 to 4658 of LAT
      efficiently inhibited caspase 8- and caspase 9-induced apoptosis in transiently
      transfected neuro-2A cells. These studies indicate that LAT has the potential to
      inhibit the two major pathways of apoptosis in the absence of other viral genes.
      Furthermore, these studies support a role for the antiapoptotic properties of LAT
      in the latency-reactivation cycle.

PMID- 12491161
TI  - Neuropathogenesis of Japanese encephalitis virus.
AB  - In the central nervous system, the Japanese encephalitis virus can replicate only
      in neurons. The mechanism of the type of neurotropism was analyzed. The
      susceptibility to Japanese encephalitis virus infection in the rat brain was
      closely associated with neuronal immaturity. The initial specific binding of the
      virus to cells is one of the reasons for neurotropism of the Japanese
      encephalitis virus. The treatment of Japanese encephalitis virus infection with
      the neutralizing monoclonal antibody against the E protein did not inhibit the
      virus from binding to the cell surfaces, but strongly inhibited Japanese
      encephalitis virus-induced cell fusion and internalization of the virus into the
      host cells. One of the genome regions responsible for neuropathogenesis of the
      Japanese encephalitis virus was located on the E protein-coding region. The 138th
      amino acid of the E protein was important for neuropathogenesis expression of the
      Japanese encephalitis virus. The cell fusion activity of the E protein was
      closely correlated with neuropathogenesis of the virus.

PMID- 12491162
TI  - The epidemiology of human immunodeficiency virus-associated neurological disease
      in the era of highly active antiretroviral therapy.
AB  - Highly active antiretroviral therapy (HAART) is effective in suppressing systemic
      human immunodeficiency virus (HIV) viral load and has decreased mortality rates
      and the incidence of systemic opportunistic infections in patients with acquired
      immunodeficiency syndrome (AIDS). Multiple studies now suggest that the incidence
      rates of HIV-associated neurological disease and central nervous system (CNS)
      opportunistic infections also are decreasing. Since the introduction of HAART in
      1996, the incidence of HIV dementia has decreased by approximately 50%. The mean
      CD4 cell count for new cases of HIV dementia is increasing, but it remains as a
      complication of moderate-advanced immunosuppression. The incidence of HIV
      associated distal sensory polyneuropathy has decreased, although the incidence of
      antiretroviral drug-induced toxic neuropathy has increased. However, as patients
      with AIDS live longer as a result of HAART, the prevalence of peripheral
      neuropathy in HIV-seropositive patients may be increasing. The incidence rates of
      CNS opportunistic infections (cryptococcal meningitis, toxoplasmosis, progressive
      multifocal leukoencephalopathy) and primary CNS lymphoma have decreased since the
      introduction of HAART. As patients develop increasing resistance mutations to
      antiretroviral drugs and with subsequent decline in CD4 cell counts, in the near
      future, the incidence of HIV-associated neurological disease may begin to rise.

PMID- 12491163
TI  - Molecular studies of cerebrospinal fluid in human immunodeficiency virus type 1
      associated opportunistic central nervous system diseases--an update.
AB  - Although the incidence of opportunistic central nervous system (CNS) diseases has
      markedly declined in developed countries following the advent of highly active
      antiretroviral therapies (HAARTs), they still represent a major diagnostic and
      therapeutic challenge over the world. The application of nucleic acid
      amplification techniques to the study of cerebrospinal fluid (CSF) has
      contributed substantially to their diagnosis. The detection of specific microbial
      genomes in the CSF is now the preferred test for some CNS opportunistic diseases,
      such as progressive multifocal leukoencephalopathy or cytomegalovirus
      encephalitis. More recent developments of these techniques are the quantitative
      amplification techniques and postamplification studies. Quantification of nucleic
      acids in CSF is an important aid both at the time of diagnosis, for the
      interpretation of positive findings, and during patient follow-up.
      Postamplification analyses can provide important information with regard to
      clinical patient management, e.g., detection of genotypic resistance to
      antimicrobial drugs, and in the attempt to elucidate disease epidemiology and
      pathogenesis.

PMID- 12491164
TI  - Psychiatric complications in human immunodeficiency virus infection.
AB  - Human immunodeficiency virus (HIV) infection is associated with psychiatric
      complications, including cognitive impairment, affective disorders, and
      psychosis. These psychiatric complications impair quality of life, affect disease
      prognosis, and impede treatment by compromising medication adherence. They also
      increase the likelihood of HIV transmission, either directly or via their high
      prevalence rate among drug abusers. In this article, the authors provide a brief
      overview of the most common psychiatric complications associated with HIV
      infection and discuss the role of dopamine as a link between psychiatric
      manifestations and the progression of immunodeficiency infection.

PMID- 12491165
TI  - Conditional virus replication as an approach to a safe live attenuated human
      immunodeficiency virus vaccine.
AB  - Despite intensive efforts, no safe and effective vaccine has been developed for
      the prophylaxis of human immunodeficiency virus/acquired immunodeficiency
      syndrome (HIV/AIDS). Studies with the simian immunodeficiency virus (SIV)/macaque
      model demonstrated that live attenuated viruses are the most effective vaccines
      tested thus far. However, due to ongoing low-level replication of the attenuated
      virus and the error-prone replication machinery, the attenuated virus may regain
      replication capacity and become pathogenic. We therefore designed a novel vaccine
      strategy with an HIV-1 virus that replicates exclusively in the presence of the
      nontoxic effector doxycycline (dox). This was achieved by replacement of the
      viral TAR-Tat system for transcriptional activation by the Escherichia coli
      derived Tet system for inducible gene expression. This designer HIV-rtTA virus
      replicates in a strictly dox-dependent manner and may represent an improved
      vaccine strain because its replication can be turned on and off at will.
      Spontaneous virus evolution resulted in optimization of the components of the Tet
      system for their new function to support virus replication in human cells. The
      optimised Tet system may be of particular use in other applications such as
      inducible expression of gene therapy vectors in the brain.

PMID- 12491166
TI  - Insulin-like growth factor I receptor signaling system in JC virus T antigen
      induced primitive neuroectodermal tumors--medulloblastomas.
AB  - Medulloblastomas represent about 25% of all pediatric intracranial neoplasms.
      These highly malignant tumors arise from the cerebellum, affecting mainly
      children between ages 5 and 15. Although the etiology of medulloblastomas has not
      yet been elucidated, several reports suggest that both the cellular protein
      insulin-like growth factor I (IGF-I) and the early protein of the human
      polyomavirus JC (JCV T antigen) may contribute to the development of these
      tumors. The results of this study show a potential functional cooperation between
      these two proteins in the process of malignant transformation. Both
      medulloblastoma cell lines and medulloblastoma biopsies are characterized by the
      abundant presence of the IGF-I receptor (IGF-IR) and its major signaling
      molecule, insulin receptor substrate 1 (IRS-1). Importantly, IRS-1 is
      translocated to the nucleus in the presence of the JCV T antigen. Nuclear IRS-1
      was detected in T antigen-positive cell lines and in T antigen-positive biopsies
      from patients diagnosed with medulloblastoma. The IRS-1 domain responsible for a
      direct JCV T antigen binding was localized within the N-terminal portion of IRS-1
      molecule and the competition for IRS-1 T antigen binding by a dominant-negative
      mutant of IRS-1 inhibited growth and survival of JCV T antigen-transformed cells
      in anchorage-independent culture condition.

PMID- 12491167
TI  - Antiretroviral therapeutics.
AB  - Recent developments in antiretroviral therapeutics are summarized. The seven
      groups of antiretroviral drugs are briefly described, focussing on mechanism of
      action and new compounds. Updated recommendations of the International AIDS
      Society are reviewed.

PMID- 12491168
TI  - [On the prevalence and treatment needs for mental disorders in rehabilitation].

PMID- 12491169
TI  - [Etiology of mental disorders in chronic somatic illness].
AB  - There is a close association between psychological strain as well as
      psychological disorders and somatic diseases. Psychological impairments are
      embedded in a complex interacting model of somatic illnesses and psychological
      strain and not only a reaction due to physical disease. Comorbidity of depressive
      or anxiety disorders and medical diseases have been consistently reported in
      clinical studies whereas the association between substance abuse, somatoform
      disorders and eating disorders with chronic somatic disease has been examined
      less. This article describes relevant explanation models as well as risk factors,
      e. g. neurobiological, psychological and social factors, which have an impact on
      this association between mental disorders and chronic physical diseases.
      Moreover, etiological models for the comorbidity of oncological, cardiovascular
      and musculoskeletal diseases on the one hand and psychological disorders on the
      other hand are explained. Epidemiologic and family genetic investigation models
      will improve the knowledge about comorbidity in the future. Combining these
      approaches with neuroscientific and biopsychiatric models will enhance the
      knowledge about pathogenesis of comorbid disorders. Beside the scientific aim,
      the correct diagnosis and treatment of comorbid mental disorders is an important
      issue. Therefore improved diagnostics and treatment of psychological disorders
      has a substantial function in medical rehabilitation.

PMID- 12491170
TI  - [Epidemiology of comorbid mental disorders in rehabilitation patients with
      musculosceletal and cardiovascular diseases].
AB  - An association between mental disorders, musculoskeletal and cardiovascular
      diseases has been reported in many clinical studies with inpatients. However, no
      data exist about the prevalence of mental disorders in patients undergoing
      rehabilitation treatment for musculoskeletal and cardiovascular diseases. The
      present study investigates 4-week, 12-month and lifetime prevalence rates of
      comorbid mental disorders in more than 1700 patients out of 10 rehabilitation
      clinics. The patients were screened (GHQ-12, HADS) in the context of a two-stage
      epidemiological survey. In the second-stage examination a subsample of 369
      patients was interviewed with a standardized clinical interview (CIDI) in order
      to obtain DSM-IV and ICD-10 diagnoses of mental disorders. 43 % (musculoskeletal)
      and 36 % (cardiovascular) of the patients have high GHQ-scores (cut off > 4).
      Furthermore, up to 24 % of the musculoskeletal and cardiovascular patients have
      elevated scores on the HADS subscales depression and anxiety (cut off > 10). For
      the 4-week period, prevalence rates of mental disorders in the sample of patients
      with musculoskeletal diseases are 31 % and 20 % in the sample of patients with
      cardiovascular diseases. The most frequent current disorders are affective and
      anxiety disorders. The high psychosocial burden expressed by the patients and the
      prevalence of depressive and anxiety disorders emphasize the importance of (1)
      effective diagnostic strategies to recognize mental disorders, (2) specialized
      psychological services in rehabilitation clinics, which provide psychological
      support and effective interventions for patients with musculoskeletal and
      cardiovascular diseases.

PMID- 12491171
TI  - [Screening for mental disorders in cardiac and orthopaedic rehabilitation].
AB  - The detection of patients with comorbid mental disorders is of high clinical
      importance in cardiac and orthopaedic rehabilitation. To simplify detection of
      cases, screening instruments are recommended. This study investigated the
      discriminant validity of the General Health Questionnaire (GHQ-12) and the
      Hospital Anxiety and Depression Scale (HADS-D) to identify patients with comorbid
      mental disorders and specifically affective or anxiety disorders. 213 patients
      with cardiovascular diseases and 206 patients with musculoskeletal diseases
      participated in a two-stage survey. Patients were assessed with the GHQ-12 and
      the HADS-D; and they were examined for DSM-IV mental disorders by clinical
      standardized interview (CIDI). Validity of the two screenings regarding the
      detection of mental disorders was compared using ROC-analysis. In both patient
      groups the HADS-D performed better in nearly all analyses compared to the GHQ-12,
      especially in the detection of affective disorders (AUC in cardiac patients 0.78,
      in orthopaedic patients 0.79). Both screening instruments can be used for the
      detection of comorbid affective and anxiety disorders in patients with
      cardiovascular and musculoskeletal diseases. Limitations in performance of
      screening instruments are due to the different methodological approaches of tests
      as well as to difficulties in diagnosing mental disorders in patients with
      physical illness.

PMID- 12491172
TI  - [Documentation and treatment of mental impairment in somato-medical
      rehabilitation].
AB  - Using routine data collected in 2000 for the quality assurance programme of the
      German Pension Insurance subjective mental impairment and disorders documented in
      discharge letters of patients undergoing rehabilitation funded by the Federal
      Insurance Institute for Salaried Employees (BfA) (n = 19,272) were correlated
      with psychological treatment and inpatient somato-medical rehabilitation
      provided. The results show discrepancies between self-evaluation, original
      diagnosis and treatment received. The frequency of treatments varies between
      hospitals. The differences in treatment are attributed rather to a varying
      quality of implementation of the bio-psycho-social concept than to a lack of
      human resources.

PMID- 12491173
TI  - [Therapy goal setting in patients with psychological stress in orthopaedic and
      cardiac rehabilitation].
AB  - OBJECTIVES: To study goal-setting for patients with psychological stress in
      orthopaedic and cardiac rehabilitation centres. DESIGN: A questionnaire assessing
      patients' somatic, functional and psychosocial status ("IRES"-questionnaire) was
      administered to 3109 patients with musculoskeletal diseases and 1670 patients
      with cardiovascular diseases from a total of 26 rehabilitation centres at their
      admission and discharge. For all patients, physicians filled in the "Physician's
      Sheet" ("Arztbogen") that assesses patient-specific goals of therapy. RESULTS:
      Nearly 50 % of the patients suffered from psychological stress at their
      admission. Of the patients with high psychological stress (higher than in 90 % of
      the general population) only 11.1 % (musculoskeletal diseases) and 3.4 %
      (cardiovascular diseases) were diagnosed as having a mental disorder (ICD-10
      diagnosis in the range of F00 - F99). High psychological stress reported by
      patients themselves is associated with only a small increase of goal setting in
      psychological therapy documented in the "Physician's Sheet". The most important
      factors that influence the predefinition of psychological goals of therapy are
      high multimorbidity, an ICD-10 diagnosis in the range of F00 - F99, low age, high
      motivation for rehabilitation and being a woman. However, statistically
      significant differences between rehabilitation centres in the predefinition of
      psychological goals of therapy were detected. It can be assumed that differences
      in concepts of therapy are responsible for this finding. CONCLUSION: The results
      show that physicians use the patient's self-assessments of their psychological
      stress only to a small extent while planning psychosocial interventions and care.
      The predefinition of goals in a context of "forced" consideration of patients
      self-assessments leads to a higher degree of consistency between patients'
      judgements and goal settings. It also shows a slightly higher predictive power
      for rehabilitation effects than the predefinition of goals of therapy without
      noticing patients' self-assessments. This demonstrates the usefulness of a
      patient-centred screening instrument for psychological stress in orthopaedic and
      cardiac rehabilitation.

PMID- 12491174
TI  - [The emotional burden in caregiving relatives of stroke patients].
AB  - Sustained psychosocial burdens as a consequence of stroke not only affect the
      stroke victim but frequently their spouses and significant others as well. The
      present study analyses the extent of emotional burden in spouses of stroke
      patients (Beck Depression Inventory, BDI and Beck Anxiety Inventory, BAI),
      examining the relationships of emotional burden in spouses with the medical
      assessment regarding stroke severity (Barthel Index, BI) and with the spouses'
      own perceptions of the stroke patients' impairment (Patient Competency Rating,
      PCR) as well as determining the factors that were independently associated with
      emotional burden in spouses. 82 spouses of stroke patients are examined in our
      study. The questioning was realised on admission into inpatient or partially
      inpatient rehabilitation centres. Initial results indicated that relatives of
      stroke victims have higher scores for anxiety compared to the general population.
      The assessment of disability in the stroke victims by their spouses correlates
      directly with the psychosocial burden of the spouses. By using this methodology,
      a high-risk group of spouses could be identified. The predictors of emotional
      burden in spouses (Anxiety and Depression) are gender of spouse and the spouse's
      subjective perception of disability in the stroke victim. The age of spouses and
      medical assessment of the severity of stroke on the other hand have no predictive
      value for the extent of emotional burden in spouses.

PMID- 12491175
TI  - [Treatment recommendations in psychosomatic rehabilitation -- empirical analyses
      based on the pension insurers' standardized discharge report].
AB  - BACKGROUND: The recommendations for aftercare listed in discharge reports
      represent a core component of communication between inpatient psychosomatic
      rehabilitation and ambulatory follow-up care. The standardized discharge report
      used by the pension insurance institutes makes use of a generic category system
      for systematization and simplification of recommendations for aftercare. Neither
      the practice of making recommendations for aftercare as observed by therapists
      and physicians responsible for treatment in the inpatient setting nor the
      appropriateness and differentiation of the category system has previously been
      systematically examined. A randomized sample of discharge reports was analyzed
      for this purpose. METHODS: A sample of 500 discharge reports from an inpatient
      oriented psychosomatic rehabilitation setting were analyzed regarding the
      categories of recommended aftercare measures and their relationship with socio
      demographic variables, clinical diagnosis and sociomedical variables. RESULTS:
      Outpatient psychotherapy represents the most frequently recommended aftercare
      treatment, being suggested in nearly 70% of the patients. Further substantial
      percentages were found in recommendations for areas including occupational
      rehabilitation, somatic-medical recommendations, and recommendations for health
      behaviour and self-help groups. In approximately one quarter of the patients,
      recommendations for aftercare were given that were coded under the category of
      "other suggestions". In younger and socio-medically burdened patients,
      recommendations for the fields of occupational rehabilitation and psychotherapy
      were more frequently given. In patients with a somatic illness or a somatoform
      disorder as the primary diagnosis, recommendations within the field of outpatient
      psychotherapy were found less frequently, while recommendations in the somatic
      medical area were more commonly found. DISCUSSION: The results give some support
      for the clinical validity of the form of recommendations given for aftercare
      measures in an inpatient psychosomatic rehabilitation setting. At the same time,
      the analyses indicate excessive as well as insufficient differentiation in the
      generic category system for follow-up treatment recommendations, which could lead
      to a loss of valuable information at the interface between inpatient and
      outpatient treatments.

PMID- 12491178
TI  - Perforator flaps--the history of evolution.
AB  - This article reviews the recent evolution of perforator flaps. The tie between
      perforator flaps and skin flaps as well as perforator flaps and musculocutaneous
      flaps is explained. The paraumbilical perforator flap, the deep inferior
      epigastric artery flap (DIEP flap), the gluteal artery perforator flap (GAP flap)
      and various perforator flaps and perforator-based flaps are described in
      combination with the review of the relevant literature. As a prospect into the
      future, the technique of "supra-microsurgery" is presented.

PMID- 12491179
TI  - [Fasciocutaneous radial artery perforator vessels - an anatomic study].
AB  - PURPOSE/BACKGROUND: Distal and proximal pedicled forearm flaps that are nourished
      by radial perforator vessels have been described. These flaps spare the radial
      artery during flap harvest. The question is, whether it is possible to raise
      individual free fasciocutaneous radial perforator flaps. METHOD AND MATERIAL: The
      number, external vessel diameter, and distribution of fasciocutaneous radial
      perforator vessels were investigated on 20 fresh cadaver arms. All specimen were
      then treated with the Spalteholz technique to demonstrate the arborizing of the
      perforator vessels. RESULTS: There was an average of 12 (range 9 to 16)
      fasciocutaneous perforator vessels per radial artery. The most proximal
      perforator vessel had an external diameter of 0.8 (range 0.5 to 1.0) mm, the
      others were measured smaller then 0.5 mm. There was a rich network of anastomoses
      at the level of the fascia up to the level of the subdermal plexus. CONCLUSIONS:
      The anatomic basis of the proximally and distally based radial perforator flaps
      was confirmed. Free flaps based exclusively on fasciocutaneous radial perforators
      would require supra-microsurgical skills due to the small vessel diameter. For
      practical reason it seems to be advisable to include parts of the radial artery
      into such a flap design.

PMID- 12491180
TI  - [Individual perforator flaps of the upper extremity].
AB  - Perforator flaps allow an individual flap design on the basis of a preoperative
      ultrasound examination. Aim of the present study is a preliminary evaluation of
      results and technical pitfalls of this new technique in the use for flap coverage
      on the dorsum of the hand and the elbow region. Since 1999, seven individually
      designed pedicled perforator flaps were prepared on the upper extremity. In four
      cases, defects on the dorsum of the hand and in a further three defects in the
      elbow region were treated. In the latter cases the flaps were harvested in a
      mainly epifascial plane, without dissecting the perforating vessels down to their
      origin. Five flaps were based on perforating vessels of the interosseous
      arteries, a further two from the lateral collateral humeral artery. Three out of
      four pedicled perforator flaps used on the dorsum of the hand healed completely.
      One flap was lost because of venous insufficiency due to the lack of wrist
      immobilisation. In the elbow region, two out of three defects were successfully
      covered with an individual perforator flap. One flap was lost due to venous
      insufficiency, a further needed an additional split-skin graft with a partial
      flap loss. The main advantage of the presented technique remains the possibility
      of individual flap design. However, the donor-site defect is almost negligible
      since in most cases a primary closure of the donor site was possible. The main
      arteries remained untouched leaving the blood supply to the hand unchanged.
      Nevertheless, the mainly epifascial harvest of the perforating vessels in the
      elbow region has the disadvantage of a short pedicle together with a high degree
      of torsion which leads to an increased risk of flap loss due to venous
      insufficiency.

PMID- 12491181
TI  - [The thoracodorsal artery perforator flap].
AB  - This report presents our experience with the thoracodorsal artery perforator
      flap. Its use and pitfalls are critically highlighted, especially the application
      of this flap as an island flap. Only few publications on this recently described
      flap are available, possibly because of the high level of skill needed in its
      preparation. In our hospital, this flap was twice used as an island flap, both of
      which failed, and ten times as a free flap one of which was a failure. Harvesting
      of this flap is a delicate procedure involving transmuscular vessel preparation,
      additionally transposition as an island flap is limited in range. Based on our
      limited experience, we can recommend use of this flap only in carefully selected
      cases. This procedure has to be performed by experienced microsurgeons, after
      training on cadavers, and after preoperative color Doppler imaging for
      determining the precise location of the main perforators. Only in cases, where a
      long vascular pedicle for an appropriate free tissue transfer is necessary, and
      where aesthetic appearance as well as minimizing donor-site morbidity are more
      important than a potentially higher failure rate, utilizing this perforator flap
      is justified.

PMID- 12491182
TI  - Clinical experience of 1284 free anterolateral thigh flaps.
AB  - The past decade has witnessed yet another rebirth in reconstructive surgery with
      the introduction of the so-called "perforator flaps". The demonstration of safe
      harvest of skin flaps based on dissection of cutaneous pedicles regardless of the
      course taken (through muscle or septum) has been revolutionary in allowing much
      greater choice in donor sites. Based on our experience in 1284 cases, the
      anterolateral thigh (ALT) region has proven itself to be an ideal donor site with
      reliable vascularity, ease of harvest and tremendous versatility. Inclusive in
      this flap is a large cutaneous territory, multiple components (adipofascial,
      muscle, fascia and skin) and possibility of chimeric applications. Although
      particularly useful in the head and neck (911 cases), the ALT flap was applied to
      reconstruct defects throughout the body. Donor site morbidity is limited as well.
      In short, the anterolateral thigh flap represents one of the most useful soft
      tissue flaps for free tissue transplantation.

PMID- 12491183
TI  - [The free gracilis perforator flap for autologous breast reconstruction].
AB  - The free gracilis perforator flap is an alternative possibility for autologous
      breast reconstruction, if previous abdominal operations preclude this donor site,
      or if there is atypical distribution of fat tissue. The perforator flap is based
      on the main pedicle of the gracilis muscle. The muscle itself and its innervation
      can be completely preserved, if the angiosome of this vascular pedicle offers
      sufficient tissue. In skinny patients however it may be necessary to include the
      neighbouring angiosome of the second gracilis pedicle by means of the
      intramuscular anastomosis between both pedicles. In such a case a thin muscle
      strip with the joining vessel must be included in the flap. The bulk of the
      gracilis muscle and its motor nerve can, however, still be preserved. Breast
      reconstruction with this technique was successfully performed on six patients
      (two bilateral). It is a good alternative to a reconstruction with gluteal, or
      anteromedial, or lateral thigh perforator flaps.

PMID- 12491184
TI  - Perforator flaps in lower extremity reconstruction.
AB  - Perforator flaps are defined as skin flap without fascia or muscle and they are
      nourished by one or more perforating vessels perforating the fascia, muscle, or
      intermuscular septum. As early as 1985 in Japan, we proposed this concept over
      that of the fasciocutaneous flap, which was believed to be nourished by fascial
      plexus. The pedicle perforators are classified as septocutaneous, muscular
      (intermuscular), periosteal, and intertendinous perforators. As useful perforator
      flaps in the lower extremity, posterior tibial perforator island flaps, saphenous
      island flaps, peroneal island flaps, malleolar island perforator flaps, deep
      inferior epigastric perforator free flap (DIEP flap), anterolateral thigh free
      flap (ALT flap), and latissimus dorsi muscle free perforator flap (thoracodorsal
      artery perforator flap, T-DAP or TAP flap) were described. These flaps have the
      advantage of minimal donor-site morbidity, relatively rapid dissection and flap
      elevation, and reliable skin territory.

PMID- 12491185
TI  - [The superior gluteal artery perforator flap (S-GAP-Flap)].
AB  - Superior gluteal artery perforator flap for breast reconstruction with autologous
      tissue (S-GAP-flap): With the introduction of perforator flaps for breast
      reconstruction with autologous tissue the gluteal region became again
      investigated as a possible donor site. With the S-GAP-flap breast reconstruction
      from the gluteal region is possible utilising skin and fat without muscle
      sacrifice. 52 S-GAP-flaps for autologous breast reconstruction with a flap loss
      rate of 7.7 % were performed at the Department of Plastic and Hand surgery,
      Behandlungszentrum Vogtareuth, Germany from 1997 till 2002. Although there is an
      obvious learning curve also with this free tissue transfer, the S-GAP-flap is a
      reliable alternative in autologous breast reconstruction, when tissue from the
      lower abdomen is not available.

PMID- 12491186
TI  - [A comment on perforator flaps].

PMID- 12491187
TI  - [Christmas--a light deficiency disease?].

PMID- 12491188
TI  - [Rhythms of the heart--time of the music].

PMID- 12491189
TI  - [Poetic medicines. Drugs in literary works 800 bc to 1980 ad].

PMID- 12491190
TI  - [Sugar, condiments and chocolate--more than just delicious].

PMID- 12491191
TI  - [Does fat make you fat and low-fat make you thin?].

PMID- 12491192
TI  - [The "French Paradox"--effects of alcohol, wine and wine polyphenols on the
      heart].

PMID- 12491193
TI  - [Parasagittal meningioma in a skull dated 32500 years before present from
      southwestern Germany].
AB  - Summary. During excavation in 1931 by Riek in the cave of Vogelherd close to
      Stetten in the Lone Valley in southwestern Germany there was found an
      anatomically modern human skull (called: "Stetten 2") dated 32500 years before
      present. The skull was excavated without postcranial skeleton in the cave and
      showed no signs of burial. Paleopathological examinations of the calvarium
      reveals skeletal abnormalities that indicate parasagittal meningioma next to the
      bregma. Paracentral Meningiomas cause seizures and focal weakness, followed by
      headache. These observations are discussed in the context of modern medical
      knowledge. Our theory integrated archaeological, anthropological and
      paleopathological knowledge and helped to create the understanding of Paleolithic
      and earliest modern man knew regarding the "brain" and illness.

PMID- 12491194
TI  - Respiratory virus infections in adults with hematologic malignancies: a
      prospective study.
AB  - During a 2-year period, 157 consecutive episodes of respiratory virus infections
      that occurred in 130 patients with upper or lower respiratory tract infection
      were analyzed for respiratory viruses. A respiratory virus was identified in 75
      episodes (48%), and several viruses were found in 13 episodes: there were a total
      of 56 influenza A virus infections, 14 respiratory syncytial virus infections, 8
      adenovirus infections, 8 infections with parainfluenza virus types 1 or 3, and 7
      enterovirus infections. On multivariate analysis, the only variable that
      predicted progression to pneumonia in patients with an upper respiratory tract
      infection was the presence of respiratory syncytial virus, whereas
      lymphocytopenia had a nonsignificant trend. Also, among the 38 patients who had
      pneumonia at any time during the episode, both respiratory syncytial virus and
      lymphocytopenia were commonly found. For both epidemiological and therapeutic
      considerations, frequent screening for respiratory viruses should be incorporated
      into the routine diagnostic study of patients with hematologic malignancies.

PMID- 12491195
TI  - High rate of invasive fungal infections following nonmyeloablative allogeneic
      transplantation.
AB  - Nonmyeloablative allogeneic transplantation is an emerging therapy for
      hematologic and solid malignancies and potentially offers patients reduced
      transplant-related toxicity. Data regarding infectious complications of these
      protocols are limited, but early studies have demonstrated little infectious
      morbidity, particularly low rates of invasive fungal infections (IFIs). In the
      present study, 31 consecutive cases of nonmyeloablative transplantation were
      reviewed over a 2.5-year period, with a specific focus on infectious
      complications. Twenty-six patients (84%) had at least 1 significant infection
      during the year after transplantation, and infection-related mortality was 37%.
      Cytomegalovirus end-organ disease was diagnosed in 3 patients (10%). Ten patients
      (32%) were given the diagnosis of IFI; 7 (23%) met criteria for proven IFI.
      Fungal-related mortality was 80% within the group of patients with IFI and
      accounted for a significant portion of the overall mortality in the study. Severe
      graft-versus-host disease, high-dose corticosteroid use, recurrent neutropenia,
      and relapsed or refractory disease were factors associated with development of
      IFI.

PMID- 12491196
TI  - Improved detection of Mycobacterium tuberculosis in Peruvian children by use of a
      heminested IS6110 polymerase chain reaction assay.
AB  - A novel heminested IS6110 polymerase chain reaction (PCR) assay was evaluated as
      a tool for diagnosing tuberculosis in 222 children. In an analysis of 392
      specimens (gastric aspirates, nasopharyngeal aspirates, and sputum samples),
      results of PCR were compared with those of 3 culture methods, acid-fast bacillus
      (AFB) staining, and clinical assessment by the Stegen-Toledo score. The
      sensitivity of PCR (67%) was comparable to that of the 3-culture method (71%) and
      was significantly higher than that of Lowenstein-Jensen culture (54%) or AFB
      stain (42%) for children with highly probable tuberculosis. PCR detection rates
      for culture-positive specimens were 100% for smear-positive samples and 76.7% for
      smear-negative samples. The specificity of PCR was 100% in control children.
      Compared with culture, PCR demonstrated a sensitivity of 90.4%, a positive
      predictive value of 89%, a specificity of 94%, and a negative predictive value of
      95% (kappa=.85). With clinical assessment as the standard, PCR had a sensitivity
      of 71%, a positive predictive value of 92%, a specificity of 95%, and a negative
      predictive value of 79% (kappa=.67). PCR is a rapid and sensitive method for the
      early diagnosis of pediatric tuberculosis.

PMID- 12491197
TI  - Serum cytokine concentrations do not parallel Mycobacterium tuberculosis-induced
      cytokine production in patients with tuberculosis.
AB  - We measured serum cytokine concentrations and Mycobacterium tuberculosis
      stimulated cytokine production by peripheral blood mononuclear cells (PBMCs)
      obtained from persons infected with M. tuberculosis. Serum interferon-gamma (IFN
      gamma) and interleukin-10 (IL-10) concentrations were elevated in patients with
      tuberculosis compared with healthy persons who had reactions to tuberculin skin
      tests, but IL-18 concentrations were not. In contrast, M. tuberculosis-stimulated
      PBMCs from patients with tuberculosis produced less IFN-gamma and IL-18 but
      similar amounts of IL-10, compared with PBMCs from healthy subjects who had
      reactions to tuberculin skin tests. Pretreatment of PBMCs from healthy subjects
      with reaction to tuberculin with serum from patients with tuberculosis inhibited
      IFN-gamma production in response to M. tuberculosis, and inhibition was blocked
      by anti-IL-10. Thus, serum concentrations of IFN-gamma, IL-18, and IL-10 do not
      parallel M. tuberculosis-induced cytokine levels, and increased IL-10 serum
      levels in patients with tuberculosis inhibit IFN-gamma production in response to
      mycobacterial antigens.

PMID- 12491198
TI  - Cluster of cases of acute hepatitis associated with hepatitis E virus infection
      acquired in the Netherlands.
AB  - Increasing evidence suggests that hepatitis E virus (HEV) infection may occur in
      developed countries and that swine may act as a reservoir. We report a cluster of
      2 confirmed cases and 1 presumptive case of hepatitis associated with HEV. The
      typed strain from 1 case was related to HEV strains found in North America and
      Europe, and it was also related to a cluster of swine HEV strains found in The
      Netherlands. Our findings indicate that locally acquired HEV infections in
      industrialized countries may be overlooked. Routine testing for HEV infection in
      patients with acute hepatitis in The Netherlands should be considered before a
      diagnosis of autoimmune hepatitis is reached and steroid therapy is initiated.

PMID- 12491199
TI  - Population-based surveillance and a case-control study of risk factors for
      endemic lymphocutaneous sporotrichosis in Peru.
AB  - Population-based surveillance and a case-control study were conducted in Abancay,
      Peru, to estimate the burden of disease and to determine risk factors for
      sporadic lymphocutaneous sporotrichosis (LS). Laboratory records from local
      hospitals were reviewed for the years of 1997 and 1998, and prospective
      surveillance was conducted for the period of September 1998 through September
      1999. A case-control study was conducted with 2 matched control subjects per case
      patient. The mean annual incidence was 98 cases per 100,000 persons. Children had
      an incidence 3 times higher than that for adults and were more likely to have LS
      lesions on the face and neck. Identified risk factors included owning a cat,
      playing in crop fields, having a dirt floor in the house, working mainly
      outdoors, and having a ceiling made of raw wood or conditions associated with a
      lower socioeconomic status. Decreased environmental exposure, such wearing
      protective clothing during construction activities for adults or limiting contact
      with cats and soil for children, and improvements in living spaces may decrease
      the incidence of LS.

PMID- 12491200
TI  - Broad-range bacterial polymerase chain reaction for early detection of bacterial
      meningitis.
AB  - The diagnosis of bacterial meningitis often depends on isolation of bacteria on
      culture, which may take 24-48 h. DNA amplification techniques could provide rapid
      diagnosis, which would guide the clinician in antimicrobial therapy decisions.
      This study determined the clinical utility of polymerase chain reaction (PCR) for
      the diagnosis of meningitis with use of a broad range of bacterial primers.
      Seventy-four cerebrospinal fluid specimens obtained from 70 patients were
      subjected to PCR with use of primers derived from conserved regions of the
      bacterial 16S RNA gene. The test characteristics for the broad-range bacterial
      PCR were as follows: sensitivity, 100%; specificity, 98.2%; positive predictive
      value, 94.4%; and negative predictive value, 100%. Broad-range bacterial PCR may
      be useful for excluding the diagnosis of meningitis, and the results may
      influence the decision to initiate or discontinue antimicrobial therapy.

PMID- 12491201
TI  - Trends in risk profiles for and mortality associated with invasive aspergillosis
      among liver transplant recipients.
AB  - To discern whether the characteristics and outcome of invasive aspergillosis in
      liver transplant recipients have evolved during the past decade, 26 patients who
      underwent transplantation during 1990-1995 (known as "the earlier cohort") were
      compared with 20 patients who underwent transplantation during 1998-2001 (known
      as "the later cohort"). Twenty-three percent of the Aspergillus infections in the
      earlier cohort occurred > or =90 days after transplantation, compared with 55% of
      such infections in the later cohort (P=.026). The earlier cohort was
      significantly more likely to have disseminated infection (P=.034) and central
      nervous system (CNS) involvement (P=.0004) than was the later cohort. The
      mortality rate was significantly higher for the earlier cohort (92%) than for the
      later cohort (60%; P=.012). Only disseminated infection (not the year of
      transplantation) approached statistical significance as an independent predictor
      of outcome. In the current era, invasive aspergillosis occurs later in the
      posttransplantation period, is less likely to be associated with CNS infection,
      and is associated with a lower mortality rate, compared with invasive
      aspergillosis in the early 1990s.

PMID- 12491202
TI  - Comparison of mortality associated with methicillin-resistant and methicillin
      susceptible Staphylococcus aureus bacteremia: a meta-analysis.
AB  - A meta-analysis was performed to summarize the impact of methicillin-resistance
      on mortality in Staphylococcus aureus bacteremia. A search of the MEDLINE
      database for studies published during the period of 1 January 1980 through 31
      December 2000 and a bibliographic review identified English-language studies of
      S. aureus bacteremia. Studies were included if they contained the numbers of and
      mortality rates for patients with methicillin-resistant S. aureus (MRSA) and
      methicillin-susceptible S. aureus (MSSA) bacteremia. Data were extracted on
      demographic characteristics of the patients, adjustment for severity and comorbid
      illness, source of bacteremia, and crude and adjusted odds ratios (ORs) and 95%
      confidence intervals (CIs) for in-hospital mortality. When the results were
      pooled with a random-effects model, a significant increase in mortality
      associated with MRSA bacteremia was evident (OR, 1.93; 95% CI, 1.54-2.42;
      P<.001); significant heterogeneity was present. We explored the reasons for
      heterogeneity by means of subgroup analyses. MRSA bacteremia is associated with
      significantly higher mortality rate than is MSSA bacteremia.

PMID- 12491203
TI  - Management of rabies in humans.
AB  - Rabies is a fatal disease in humans, and, to date, the only survivors of the
      disease have received rabies vaccine before the onset of illness. The approach to
      management of the rabies normally should be palliative. In unusual circumstances,
      a decision may be made to use an aggressive approach to therapy for patients who
      present at an early stage of clinical disease. No single therapeutic agent is
      likely to be effective, but a combination of specific therapies could be
      considered, including rabies vaccine, rabies immunoglobulin, monoclonal
      antibodies, ribavirin, interferon-alpha, and ketamine. Corticosteroids should not
      be used. As research advances, new agents may become available in the future for
      the treatment of human rabies.

PMID- 12491204
TI  - Diagnosis of Legionella infection.
AB  - Legionellae, which are important causes of pneumonia in humans, continue to be
      incorrectly labeled as exotic pathogens. The ability to diagnose Legionella
      infection is limited by the nonspecific nature of clinical features and the
      shortcomings of diagnostic tests. Despite recent improvements, existing
      diagnostic tests for Legionella infection either lack sensitivity for detecting
      all clinically important legionellae or are unable to provide results within a
      clinically useful time frame. Understanding local Legionella epidemiology is
      important for making decisions about whether to test for Legionella infection and
      which diagnostic tests to use. In most situations, the use of both the urinary
      antigen test plus sputum culture is the best diagnostic combination. Polymerase
      chain reaction (PCR) is a promising tool, but standardized assays are not
      commercially available. Further work needs to focus on the development of urinary
      antigen tests assays that detect a wider range of pathogenic legionellae and on
      the development of standardized PCR assays.

PMID- 12491205
TI  - Pneumocystis carinii pneumonia in patients in the developing world who have
      acquired immunodeficiency syndrome.
AB  - We review Pneumocystis carinii pneumonia (PCP) in patients in the developing
      world (i.e., Africa, Asia, the Philippines, and Central and South America) who
      have acquired immunodeficiency disease (AIDS). During the first decade of the
      AIDS pandemic, PCP rarely occurred in African adults. More recent reports have
      noted that PCP comprises a significantly greater percentage of cases of pneumonia
      than it did in the past. This trend dramatically contrasts with that observed in
      industrialized nations, where a reduction in the number of cases of PCP has
      occurred as a result of the widespread use of primary P. carinii prophylaxis and
      highly active antiretroviral therapy. Throughout the developing world, the rate
      of coinfection with Mycobacterium tuberculosis and PCP is high, ranging from 25%
      to 80%. Initiation of treatment when PCP is in an advanced stage may account for
      the high mortality rates (20%-80%) associated with pediatric PCP in the
      developing world.

PMID- 12491206
TI  - Natural history of human immunodeficiency virus disease in southern India.
AB  - There are few reports of the natural history of human immunodeficiency virus
      (HIV) infection from Asia. In a retrospective analysis of 594 patients (72.9%
      male; baseline CD4 cell count, 216 cells/microL) receiving care at YRG Center for
      AIDS Research and Education, a tertiary HIV referral center in southern India,
      the mean duration of survival from serodiagnosis was 92 months. Ninety-three
      percent of the patients acquired infection through heterosexual contact. The most
      common acquired immune deficiency syndrome-defining illnesses were pulmonary
      tuberculosis (49%; median duration of survival, 45 months), Pneumocystis carinii
      pneumonia (6%; median duration of survival, 24 months), cryptococcal meningitis
      (5%; median duration of survival, 22 months), and central nervous system
      toxoplasmosis (3%; median duration of survival, 28 months). Persons with a CD4
      lymphocyte count of <200 cells/microL were 19 times (95% confidence interval
      [CI], 5.56-64.77) more likely to die than were those with CD4 cell count of >350
      cells/microL. Patients who had > or =1 opportunistic infection were 2.6 times
      more likely to die (95% CI, 0.95-7.09) than were those who did not have an
      opportunistic infection. Antiretroviral therapy for patients with low CD4
      lymphocyte counts improved the odds of survival (odds ratio, 5.37; 95% CI, 1.82
      15.83).

PMID- 12491207
TI  - Prevention of human immunodeficiency virus-related opportunistic infections in
      France: a cost-effectiveness analysis.
AB  - A simulation model of human immunodeficiency virus (HIV) disease, which
      incorporated French data on the progression of HIV disease in the absence of
      antiretroviral therapy and on cost, was used to determine the clinical impact and
      cost-effectiveness of different strategies for the prevention of opportunistic
      infections in French patients who receive highly active antiretroviral therapy
      (HAART). Compared with use of no prophylaxis, use of trimethoprim
      sulfamethoxazole (TMP-SMZ) increased per-person lifetime costs from euro 185,600
      to euro 187,900 and quality-adjusted life expectancy from 112.2 to 113.7 months,
      for an incremental cost-effectiveness ratio of euro 18,700 per quality-adjusted
      life-year (euro/QALY) gained. Compared with use of TMP-SMZ alone, use of TMP-SMZ
      plus azithromycin cost euro 23,900/QALY gained; adding fluconazole cost an
      additional euro 54,500/QALY gained. All strategies that included oral ganciclovir
      had cost-effectiveness ratios that exceeded euro 100,000/QALY gained. In the era
      of HAART, on the basis of French data, prophylaxis against Pneumocystis carinii
      pneumonia, toxoplasmic encephalitis, and Mycobacterium avium complex bacteremia
      is cost-effective. Prophylaxis against fungal and cytomegalovirus infections is
      less cost-effective than are other therapeutic options for HIV disease and should
      remain of lower priority.

PMID- 12491208
TI  - Hepatitis C virus and human immunodeficiency virus coinfection in an urban
      population: low eligibility for interferon treatment.
AB  - One hundred eighty human immunodeficiency virus (HIV)- and hepatitis C virus
      (HCV)-coinfected patients were prospectively evaluated for suitability for
      interferon and ribavirin therapy. Of the 149 patients with chronic HCV infection
      who completed the evaluation, 44 (30%) were eligible for treatment and 105 (70%)
      were ineligible, with the main barriers being missed clinic visits, active
      psychiatric illness, active drug or alcohol use, decompensated liver disease, or
      medical illness.

PMID- 12491209
TI  - Knowledge of genotypic resistance mutations among providers of care to patients
      with human immunodeficiency virus.
AB  - A questionnaire assessed clinician knowledge of genotypic resistance mutations in
      human immunodeficiency virus. Only 24% of respondents were able to identify at
      least 1 mutation for each of > or =4 drug groups listed, and 36% were unable to
      match any mutations with any of the drug groups. Knowledge was most deficient
      among providers caring for < or =50 patients (P=.001) but also was poor among the
      38 physicians caring for > or =100 patients (mean patient load, 211 patients).

PMID- 12491210
TI  - Recurrent Kawasaki disease-like syndrome in a patient with acquired
      immunodeficiency syndrome.
AB  - A review of Kawasaki disease (KD)-like syndromes (KDLS) in patients with human
      immunodeficiency virus (HIV) raised the question whether vasculitis in children
      and KDLS in immunocompromised adults might be etiologically related. We describe
      a 42-year-old white man with AIDS and Kaposi sarcoma who presented with KDLS,
      which was diagnosed on the basis of clinical criteria for KD. Analysis of a
      conjunctival tissue sample revealed endothelial cell damage with fibrin
      deposition and infiltration of immunoglobulin A-secreting plasma cells.

PMID- 12491211
TI  - Rapid diagnosis of acute Salmonella gastrointestinal infection.
AB  - Serologic tests for the detection of Salmonella serotype Enteritidis in children
      may become supplementary to stool culture examination. A total of 190 children
      were examined with a new 1-step, 2-minute test (TUBEX) that detects anti
      Salmonella immunoglobulin M antibodies, which was found to be 92.6% sensitive and
      94.8% specific (P<.0001).

PMID- 12491212
TI  - Minocycline-ethylenediaminetetraacetate lock solution for the prevention of
      implantable port infections in children with cancer.
AB  - In this prospective cohort study, minocycline-ethylenediaminetetraacetate (M
      EDTA) was used as a lock solution in indwelling ports inserted in 14 children
      with cancer. No port infections, thrombotic events, or other adverse events were
      observed, compared with 10 port infections that occurred in 48 control patients
      whose ports were flushed with heparin. M-EDTA is a promising lock solution in
      long-term catheters.

PMID- 12491213
TI  - Human herpesvirus 6B infection of the large intestine of patients with diarrhea.
AB  - Four patients had severe diarrhea after undergoing stem cell transplantation.
      Human herpesvirus 6B (HHV-6B) DNA was detected in large intestine tissue
      specimens and in peripheral blood mononuclear cells. In situ hybridization was
      positive for HHV-6B DNA in the nuclei of goblet cells and, sometimes, in the
      histiocytes in the submucous region of the large intestine, which suggests that
      HHV-6B may infect and reactivate in these cells.

PMID- 12491215
TI  - Linezolid to decrease length of stay in the hospital for patients with
      methicillin-resistant Staphylococcus aureus infection.

PMID- 12491216
TI  - Signs of meningeal irritation: what is their diagnostic accuracy?

PMID- 12491218
TI  - A regimen containing rifabutin for the treatment of tuberculosis in patients
      intolerant to rifampin.

PMID- 12491220
TI  - Association of TT virus primary infection with rhinitis in a newborn.

PMID- 12491221
TI  - Carotid artery dissection as a possible severe complication of pertussis in an
      adult: clinical case report and review.
AB  - Adults can experience typical symptoms of pertussis. Complications due to severe
      paroxysmal coughing have been reported in this age group. We report carotid
      artery dissection as a possible severe complication of pertussis in a previously
      healthy adult. Adult booster immunization against pertussis should be considered
      to protect adults themselves from this illness and its potential complications.

PMID- 12491222
TI  - Borderline tuberculoid leprosy: an immune reconstitution phenomenon in a human
      immunodeficiency virus-infected person.
AB  - Two months after starting highly active antiretroviral treatment (HAART), an
      individual with human immunodeficiency virus type 1 (HIV-1) infection and
      profound CD4+ T lymphocytopenia developed several erythematous plaques on his
      face, which were due to borderline tuberculoid leprosy with reversal reaction.
      The temporal association between the development of these lesions and changes in
      blood CD4+ lymphocyte count and plasma HIV-1 load observed during HAART strongly
      suggests that the presentation of leprosy resulted from immune reconstitution.

PMID- 12491223
TI  - A positive enzyme-linked immunoelectrotransfer blot assay result for a patient
      without evidence of cysticercosis.
AB  - The enzyme-linked immunoelectrotransfer blot (EITB) has been considered
      diagnostic of cysticercosis when the results are positive. We describe a patient
      with a single band at 50 kDa on EITB and neuroimaging abnormalities suggestive of
      neurocysticercosis but no evidence of exposure to Taenium solium. Autopsy
      findings excluded neurocysticercosis. We suggest that a single band at 50 kDa on
      an EITB be considered an equivocal finding rather than diagnostic of
      cysticercosis.

PMID- 12491224
TI  - Isolated splenic cat scratch disease in an immunocompetent adult woman.
AB  - We report a case of isolated splenic cat scratch disease in an immunocompetent
      woman. The clinical presentation of prolonged fever, night sweats, weakness, and
      intrasplenic lesions was highly suggestive of lymphoma. This is the second
      reported case of isolated splenic cat scratch disease in an adult and the first
      in a healthy adult.

PMID- 12491228
TI  - Pneumocystis carinii pneumonia in a previously healthy infant.

PMID- 12491225
TI  - Mental retardation and abnormal skeletal development (Dyggve-Melchior-Clausen
      dysplasia) due to mutations in a novel, evolutionarily conserved gene.
AB  - Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are
      similar, rare autosomal recessive osteochondrodysplasias. The radiographic
      features and cartilage histology in DMC and SMC are identical. However, patients
      with DMC exhibit significant developmental delay and mental retardation, the
      major features that distinguish the two conditions. Linkage studies localized the
      SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting
      that they are allelic disorders. Sequence analysis of the coding exons of the
      FLJ90130 gene, a highly evolutionarily conserved gene within the recombination
      interval defined in the linkage study, identified mutations in SMC and DMC
      patients. The affected individuals in two consanguinous DMC families were
      homozygous for a stop codon mutation and a frameshift mutation, respectively,
      demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm
      the hypothesis that SMC and DMC are allelic disorders and identify a gene
      necessary for normal skeletal development and brain function.

PMID- 12491229
TI  - The intracellular life of chlamydiae.
AB  - The ability to cause persistent infection is one of the major characteristics of
      all chlamydial species in their appropriate hosts. Persistent infection with
      Chlamydia trachomatis and Chlamydia pneumoniae has been implicated in the
      pathogenesis of many chronic diseases, some initially not thought to be
      infectious, including pelvic inflammatory disease, arthritis, asthma, and
      atherosclerosis. Chlamydiae have a unique developmental cycle with
      morphologically distinct infectious and reproductive forms: elementary (EB) and
      reticulate bodies (RB). Chlamydiae appear to circumvent the host endocytic
      pathway and inhabit a nonacidic vacuole that is dissociated from late endosomes
      and lysosomes. Chlamydiae also have been demonstrated to enter a persistent state
      after treatment with cytokines such as interferon-gamma (IFN-gamma), treatment
      with antibiotics, or restriction of certain nutrients, or to enter this state
      spontaneously under certain culture conditions. While the organism is in the
      persistent state, metabolic activity is reduced, and the organism is often
      refractory to antibiotic treatment. Ultrastructural analysis of IFN-gamma-treated
      C pneumoniae demonstrates atypical inclusions containing large reticulate-like
      aberrant bodies with no evidence of redifferentiation into EBs. Persistent C
      pneumoniae infection appears to be associated with continued expression of genes
      associated with DNA replication but not with those genes involved with bacterial
      cell division. The latter observation may explain the appearance of the large
      abnormal RBs seen in ultrastructural studies. Studies of the association of
      chlamydiae with chronic disease have been hampered by difficulties in diagnosing
      chronic, persistent infection with the organism, which, in turn, render
      determining the efficacy of antibiotic therapy very difficult.

PMID- 12491230
TI  - Ehrlichiosis in children.
AB  - Ehrlichia are obligate intracellular bacteria that belong to the family
      Rickettsiaceae. Human monocytic ehrlichiosis (HME) and human granulocytic
      ehrlichiosis (HGE) are the 2 ehrlichial diseases that are of greatest health
      concern in the United States. The agents causing HME and HGE are zoonotic
      pathogens requiring a mammalian reservoir and an arthropod vector. Differences in
      the geographic distribution of their tick vectors account for the concentration
      of HME in the South and southeastern United States and HGE in the Northeast and
      northern Midwest. Both infections have been reported in coastal regions from
      Rhode Island to Florida. HME and HGE are flulike illnesses that usually are self
      limited but may be fatal. Diagnosis is confirmed by identification of the
      microorganism on blood smear or polymerase chain reaction or by detection of anti
      ehrlichial antibody. Doxycycline is the antibiotic of choice for treatment of
      ehrlichiosis.

PMID- 12491231
TI  - Current laboratory diagnosis of Q fever.
AB  - Q fever is a worldwide zoonosis caused by the strictly intracellular bacterium
      Coxiella burnetii. Among symptomatic patients (one-half of patients remain
      asymptomatic), acute Q fever most frequently manifests as a self-limited febrile
      illness, pneumonia, or hepatitis. Endocarditis is the predominant form of chronic
      Q fever. All the classical techniques of bacteriology may be used for diagnosis
      of C burnetii infection. Nonetheless, because of the risk of contamination,
      isolation must be performed in biosafety level 3 laboratories. Moreover, to date
      no diagnostic tests for detection by polymerase chain reaction or specific
      antibodies for immunochemistry are available commercially. Hence, Q fever is
      diagnosed in most cases by serology. The most reliable technique appears to be
      micro-immunofluorescence, which exhibits both good sensitivity and specificity. A
      wider use of this serology in cases of blood culture-negative endocarditis,
      atypical pneumonia, unexplained fever, and hepatitis should lead to an increase
      of diagnosed cases.

PMID- 12491232
TI  - Latent tuberculosis: models, mechanisms, and novel prospects for eradication.
AB  - Latent tuberculosis (TB) infects one-third of the world. We present evidence for
      the existence of a latent state of TB in humans, cite new approaches to diagnosis
      and treatment, and identify several models that attempt to mimic the latent
      state. Persistent infection in mice and in vitro systems of microaerophilic
      and/or anaerobic growth and nutrient starvation have been the most productive
      models in yielding insights into the host and mycobacterial pathways involved in
      the latent state. These pathways may serve as targets for better diagnosis,
      treatment, and prevention of latent TB in man.

PMID- 12491233
TI  - Legionella pneumophila pathogenesis and immunity.
AB  - Legionella pneumophila is a ubiquitous intracellular bacterium found widely in
      the environment and is the cause of sporadic outbursts of opportunistic
      infection, mainly in immunocompromised individuals, including young children as
      well as aged persons. The host response to this organism is similar to responses
      to other opportunistic intracellular microbes and features both innate and
      adoptive immune mechanisms. Innate immunity includes the responses of a variety
      of host cells and cytokines, including those produced by macrophages stimulated
      by microbial antigens. Adoptive immunity consists of activated lymphocytes and
      the cytokines they produce, such as interferon and other cytokines that activate
      macrophages to restrict the growth and spread of intracellular bacteria. The role
      of cytokines specifically in resistance and immunity to Legionella is exemplified
      by studies concerning the nature and mechanism whereby interferon produced by
      activated T lymphocytes influences macrophages to resist infection by this
      bacterium, not only by restricting growth but also killing this bacterium. This
      cytokine is considered to have a key role in activating macrophages in adoptive
      immunity to Legionella and other intracellular bacteria. In particular,
      interferon is known to have a crucial role in activating macrophages to resist
      infection by L. pneumophila. This review also describes newer findings that
      demonstrate that various cytokines that define Th1 vs Th2 helper cell activity
      also are important in regulating resistance versus susceptibility to this
      ubiquitous microorganism.

PMID- 12491234
TI  - Current issues in the diagnosis and management of pediatric empyema.
AB  - Empyema is a rare but recognized complication of bacterial pneumonia in children.
      The incidence of empyema may be rising as vaccination practices and antibiotic
      prescribing practices promote the emergence of more virulent and resistant
      organisms. Diagnostic methods vary widely, from thoracentesis to plain
      radiographs to detailed computed tomography scans. Treatment practices also vary,
      with some practitioners preferring medical treatment, others employing chest tube
      drainage or fibrinolytic therapy, and still others aggressively pursuing surgical
      options. Further study is needed to define the ideal management of empyema. The
      authors review the current literature and propose an updated management algorithm
      that incorporates accepted practices as well as emerging trends in diagnosis and
      management of empyema.

PMID- 12491235
TI  - Robert Koch: Nobel laureate and controversial figure in tuberculin research.
AB  - Tuberculosis has been a major cause of death for centuries. Likewise, anthrax has
      posed a deadly threat to both farm animals and humans and today poses a threat as
      a weapon of biological warfare. Cholera, which wreaked havoc in the East and
      threatened to enter Europe, also posed a deadly threat. The causes of these
      diseases remained mysteries for centuries. Nobel laureate Robert Koch (1843
      1910), often called the founder of medical bacteriology, is credited with
      discovering the tubercle bacillus, Mycobacterium tuberculosis; with demonstrating
      for the first time in history the life cycle of the anthrax bacillus under
      controlled in vitro conditions; and with identifying Vibrio cholorae as the cause
      of cholera. In later life, he also was at the center of several controversies.
      This article provides a brief summary of Koch's exploration into bacteriology
      and, especially, his experience with tuberculosis and the controversies that
      developed in the latter part of his life, as well as his childhood and early
      adult years and the development of his now well-known "postulates."

PMID- 12491239
TI  - Molecular chaperones--cellular machines for protein folding.
AB  - Proteins are linear polymers synthesized by ribosomes from activated amino acids.
      The product of this biosynthetic process is a polypeptide chain, which has to
      adopt the unique three-dimensional structure required for its function in the
      cell. In 1972, Christian Anfinsen was awarded the Nobel Prize for Chemistry for
      showing that this folding process is autonomous in that it does not require any
      additional factors or input of energy. Based on in vitro experiments with
      purified proteins, it was suggested that the correct three-dimensional structure
      can form spontaneously in vivo once the newly synthesized protein leaves the
      ribosome. Furthermore, proteins were assumed to maintain their native
      conformation until they were degraded by specific enzymes. In the last decade
      this view of cellular protein folding has changed considerably. It has become
      clear that a complicated and sophisticated machinery of proteins exists which
      assists protein folding and allows the functional state of proteins to be
      maintained under conditions in which they would normally unfold and aggregate.
      These proteins are collectively called molecular chaperones, because, like their
      human counterparts, they prevent unwanted interactions between their immature
      clients. In this review, we discuss the principal features of this peculiar class
      of proteins, their structure-function relationships, and the underlying molecular
      mechanisms.

PMID- 12491241
TI  - Chirality of living systems: a helping hand from crystals and oligopeptides.
AB  - Left-right asymmetry is ubiquitous in nature. Recent studies reveal changes in
      the energy and growth rate of crystal surfaces to which D or L amino acids bind,
      with the binding itself being dictated by stereochemical matching. Likewise,
      oligomerization of amino acids appears to be a chiroselective process that
      enables the propagation of sequences with defined handedness.[[For a definition
      of chiroselective self-assembly, see: M. Bolli, R. Micura, A. Eschenmoser, Chem.
      Biol. 1997, 4, 309-320.]] These results, along with related findings on symmetry
      breaking and further amplification of asymmetry at a supramolecular level,
      constitute new insights into the origin of homochirality in living species.

PMID- 12491240
TI  - Bis(mu-oxo)dimetal "diamond" cores in copper and iron complexes relevant to
      biocatalysis.
AB  - Although quite a familiar feature in high-valent manganese chemistry, the M(2)(mu
      O)(2) diamond core motif has only recently been found in synthetic complexes for
      M=Cu or Fe. Structural and spectroscopic characterization of these more reactive
      Cu(2)(mu-O)(2) and Fe(2)(mu-O)(2) compounds has been possible through use of
      appropriately designed supporting ligands, low-temperature handling methods, and
      techniques such as electrospray ionization mass spectrometry and X-ray
      crystallography with area detector instrumentation for rapid data collection.
      Despite differences in electronic structures that have been revealed through
      experimental and theoretical studies, Cu(2)(mu-O)(2) and Fe(2)(mu-O)(2) cores
      exhibit analogously covalent metal-oxo bonding, remarkably congruent Raman and
      extended X-ray absorption fine structure (EXAFS) signatures, and similar
      tendencies to abstract hydrogen atoms from substrates. Core isomerization is
      another common reaction attribute, although different pathways are traversed; for
      Fe, bridge-to-terminal oxo migration has been discovered, while for Cu,
      reversible formation of an O-O bond to yield a peroxo isomer has been identified.
      Our understanding of biocatalysis has been enhanced significantly through the
      isolation and comprehensive characterization of the Cu(2)(mu-O)(2) and Fe(2)(mu
      O)(2) complexes. In particular, it has led to the development of new mechanistic
      notions about how non-heme multimetal enzymes, such as methane monooxygenases,
      fatty acid desaturase, and tyrosinase, may function in the activation of dioxygen
      to catalyze a diverse array of organic transformations.

PMID- 12491242
TI  - Electrocyclization of (Z)-1,2,4,6-heptatetraene and its heterosubstituted
      analogues: pericyclic or pseudopericyclic?

PMID- 12491244
TI  - Fabrication of a metal-coated three-dimensionally ordered macroporous film and
      its application as a refractive index sensor.

PMID- 12491245
TI  - A one-dimensional BaI2 chain with five- and six-coordination, formed within a
      single-walled carbon nanotube.

PMID- 12491246
TI  - Rational design of homochiral solids based on two-dimensional metal carboxylates.

PMID- 12491247
TI  - Inorganic chemistry goes protein size: a Mo368 nano-hedgehog initiating
      nanochemistry by symmetry breaking.

PMID- 12491248
TI  - Ligand-templated four-metal chains dimerize into a unique [Cu(II)(8)] cluster.

PMID- 12491249
TI  - Calixarene-type macrocycles by oxidation of phenols related to vitamin E.

PMID- 12491251
TI  - Selective direct synthesis of organofunctionalized dialkylgermanes from
      solvochemically activated germanium.

PMID- 12491252
TI  - Beltlike macrocycles with four and eight
      (cyclopentadienyl)(cyclobutadienyl)cobalt building blocks, formed by stepwise
      oligomerization of 1,6-cyclodecadiyne units.

PMID- 12491250
TI  - Natural product derived receptor tyrosine kinase inhibitors: identification of
      IGF1R, Tie-2, and VEGFR-3 inhibitors.

PMID- 12491253
TI  - A trans-platinum(II) complex as a single-molecule insulator.

PMID- 12491254
TI  - Intramolecular [3+2] cycloaddition of a nitrilium phosphane ylide complex to the
      P-phenyl group of a Wittig ylide.

PMID- 12491255
TI  - Self-assembly of ZnO: from nanodots to nanorods.

PMID- 12491256
TI  - The first "naked" primary phosphanide anion [ArPH](-).

PMID- 12491257
TI  - Cation-promoted hierarchical formation of supramolecular assemblies of self
      organized helical molecular components.

PMID- 12491258
TI  - The determination of the absolute configurations of diastereomers of (S)
      camphanoyl 3-hydroxy-5-oxohexanoic acid derivatives by X-ray crystallography.

PMID- 12491259
TI  - A new mononuclear iron(III) complex containing a peroxocarbonate ligand.

PMID- 12491260
TI  - Helical sense bias induced by point chirality in cage compounds.

PMID- 12491261
TI  - Alkene C-H activations at dinuclear complexes promoted by oxidation.

PMID- 12491262
TI  - Bis(1,2,3,4-eta4-anthracene)cobaltate(1-).

PMID- 12491263
TI  - Peptide-templated saccharide synthesis on a solid support.

PMID- 12491264
TI  - A new method for the synthesis of cycloheptenones by Rh(I)-catalyzed
      intramolecular hydroacylation of 4,6-dienals.

PMID- 12491265
TI  - Super-hydrophobic surface of aligned polyacrylonitrile nanofibers.

PMID- 12491266
TI  - A reactive intermediate in the synthesis of iron arsenates: synthesis of the
      first one-dimensional iron arsenate oxalate and its transformation into two- and
      three-dimensional iron arsenates.

PMID- 12491267
TI  - [Zn4(thf)(4)(MeZn)(4)(O(3)SiR)(4)] (R=2,6-iPr(2)C(6)H(3)N(SiMe3)), a compound
      containing trigonal-planar, tetrahedral, and trigonal-bipyramidal metal atoms: a
      new route to larger aggregates.

PMID- 12491268
TI  - The adrenaline test for enzymes.

PMID- 12491269
TI  - Cubane with a handle: [[In(3)As(4)Nb]-As](7-) in Cs(7)NbIn(3)As(5).

PMID- 12491270
TI  - Surface structure and crystal growth of zeolite Beta C.

PMID- 12491271
TI  - Pd-catalyzed decarbonylative olefination of aryl esters: towards a waste-free
      Heck reaction.

PMID- 12491272
TI  - Electron-hole pairs stabilized in Al-ZSM-5 zeolites.

PMID- 12491273
TI  - The phosphorylation site database--a valuable tool for biologists and
      biochemists?

PMID- 12491279
TI  - Palladium-catalyzed alpha-arylation of esters: ideal new methodology for
      discovery chemistry.

PMID- 12491278
TI  - Dynamic covalent chemistry.
AB  - Dynamic covalent chemistry relates to chemical reactions carried out reversibly
      under conditions of equilibrium control. The reversible nature of the reactions
      introduces the prospects of "error checking" and "proof-reading" into synthetic
      processes where dynamic covalent chemistry operates. Since the formation of
      products occurs under thermodynamic control, product distributions depend only on
      the relative stabilities of the final products. In kinetically controlled
      reactions, however, it is the free energy differences between the transition
      states leading to the products that determines their relative proportions.
      Supramolecular chemistry has had a huge impact on synthesis at two levels: one is
      noncovalent synthesis, or strict self-assembly, and the other is supramolecular
      assistance to molecular synthesis, also referred to as self-assembly followed by
      covalent modification. Noncovalent synthesis has given us access to finite
      supermolecules and infinite supramolecular arrays. Supramolecular assistance to
      covalent synthesis has been exploited in the construction of more-complex
      systems, such as interlocked molecular compounds (for example, catenanes and
      rotaxanes) as well as container molecules (molecular capsules). The appealing
      prospect of also synthesizing these types of compounds with complex molecular
      architectures using reversible covalent bond forming chemistry has led to the
      development of dynamic covalent chemistry. Historically, dynamic covalent
      chemistry has played a central role in the development of conformational analysis
      by opening up the possibility to be able to equilibrate configurational isomers,
      sometimes with base (for example, esters) and sometimes with acid (for example,
      acetals). These stereochemical "balancing acts" revealed another major advantage
      that dynamic covalent chemistry offers the chemist, which is not so easily
      accessible in the kinetically controlled regime: the ability to re-adjust the
      product distribution of a reaction, even once the initial products have been
      formed, by changing the reaction's environment (for example, concentration,
      temperature, presence or absence of a template). This highly transparent, yet
      tremendously subtle, characteristic of dynamic covalent chemistry has led to key
      discoveries in polymer chemistry. In this review, some recent examples where
      dynamic covalent chemistry has been demonstrated are shown to emphasise the basic
      concepts of this area of science.

PMID- 12491280
TI  - 1,1'-Ferrocenedi(amido) chelate ligands in titanium and zirconium complexes.

PMID- 12491281
TI  - Sensitized luminescence of trivalent europium by three-dimensionally arranged
      anatase nanocrystals in mesostructured titania thin films.

PMID- 12491282
TI  - Multiple emissions from 1,3-diphenyl-5-pyrenyl-2-pyrazoline nanoparticles:
      evolution from molecular to nanoscale to bulk materials.

PMID- 12491283
TI  - Template effects, asymmetry, and twinning in helical inclusion compounds.

PMID- 12491284
TI  - Structural analysis of C(60) trimers by direct observation with scanning
      tunneling microscopy.

PMID- 12491285
TI  - Computational prediction of the phase transformation of two as-synthesized
      oxyfluorinated compounds into the zeotype CHA forms.

PMID- 12491286
TI  - Assembly of a face-to-face tetranuclear copper(I) complex as a host for an
      anthracene guest.

PMID- 12491287
TI  - The mechanism of catalytic enantioselective fluorination: computational and
      experimental studies.

PMID- 12491288
TI  - Molecular dynamic computer simulations of phase behavior of non-ionic
      surfactants.

PMID- 12491289
TI  - A highly efficient catalyst for the telomerization of 1,3-dienes with alcohols:
      first synthesis of a monocarbenepalladium(0)-olefin complex.

PMID- 12491290
TI  - Simple synthesis of oligosilyl-alpha,omega-dipotassium compounds.

PMID- 12491291
TI  - Modulation of the reactivity profile of IBX by ligand complexation: ambient
      temperature dehydrogenation of aldehydes and ketones to alpha,beta-unsaturated
      carbonyl compounds.

PMID- 12491292
TI  - Oxidation of silyl enol ethers by using IBX and IBX.N-oxide complexes: a mild and
      selective reaction for the synthesis of enones.

PMID- 12491293
TI  - One-step preparation of block copolymer vesicles with preferentially segregated
      acidic and basic corona chains.

PMID- 12491294
TI  - A method to identify and screen libraries of guests that complex to a synthetic
      host.

PMID- 12491295
TI  - Aluminum-catalyzed asymmetric addition of TMSCN to aromatic and aliphatic ketones
      promoted by an easily accessible and recyclable peptide ligand.

PMID- 12491296
TI  - Unprecedented regiocontrol using an aldolase I antibody.

PMID- 12491297
TI  - Biocatalytic asymmetric hydrogen transfer.

PMID- 12491298
TI  - Compartmentalization of a gadolinium complex in the apoferritin cavity: a route
      to obtain high relaxivity contrast agents for magnetic resonance imaging.

PMID- 12491299
TI  - The asymmetric Meerwein-Schmidt-Ponndorf-Verley reduction of prochiral ketones
      with iPrOH catalyzed by Al catalysts.

PMID- 12491300
TI  - Highly efficient stereocontrolled total synthesis of the polyfunctional
      carotenoid peridinin.

PMID- 12491301
TI  - Dynamics and energetics of hole trapping in DNA by 7-deazaguanine.

PMID- 12491302
TI  - Hydroxylation of N-heterocycle ligands observed in two unusual mixed-valence
      Cu(I)/Cu(II) complexes.

PMID- 12491303
TI  - Diastereoselective asymmetric nitro-aldol reaction of alpha-amino aldehydes under
      high pressure without catalyst.

PMID- 12491305
TI  - Ultrastable and highly acidic, zeolite-coated mesoporous aluminosilicates.

PMID- 12491304
TI  - Sigmatropic shiftamers: fluxionality in broken ladderane polymers.

PMID- 12491306
TI  - Diffusion-limited, aggregation-based, mesoscopic assembly of surface-roughened
      shell-type bimetallic nanoparticles into fractal networks at the air-water
      interface [correction].

PMID- 12491307
TI  - The first water-soluble copper(I) calix[6]arene complex presenting a hydrophobic
      ligand binding pocket: a remarkable model for active sites in metalloenzymes.

PMID- 12491308
TI  - Self-complementary metal complexes containing a DNA base pair.

PMID- 12491309
TI  - Dearomatizing disrotatory electrocyclic ring closure of lithiated N
      benzoyloxazolidines.

PMID- 12491311
TI  - Highly enantioselective desymmetrization of anhydrides by carbon nucleophiles:
      reactions of Grignard reagents in the presence of (-)-sparteine.

PMID- 12491310
TI  - Click chemistry in situ: acetylcholinesterase as a reaction vessel for the
      selective assembly of a femtomolar inhibitor from an array of building blocks.

PMID- 12491312
TI  - A stereospecific ruthenium-catalyzed allylic alkylation.

PMID- 12491313
TI  - Enantioselective synthesis of kedarcidin chromophore aglycon in differentially
      protected form.

PMID- 12491319
TI  - Configurational stability and transfer of stereochemical information in the
      reactions of enantioenriched organolithium reagents.
AB  - The conversion of a prochiral methylene group into a stereogenic center by means
      of a lithiation/substitution sequence has emerged as a powerful synthetic
      transformation over the past 15 years. This reaction proceeds via a chiral
      organolithium intermediate, and the stereochemical fidelity of the overall
      reaction sequence is intimately dependent on the stereochemical behavior of the
      chiral organolithium as well as on the rate and stereochemical sense of the
      electrophilic substitution step. Chiral organolithium reagents were first
      reported by Letsinger, Curtin, and Applequist half a century ago. The lithiated
      intermediates in these early studies were not highly configurationally stable,
      and applications in stereoselective synthesis were not immediately forthcoming.
      The two decades that followed the 1980 report by Still and Sreekumar of a
      configurationally stable alpha-oxyorganolithium were marked by an increased
      interest in these reagents. As the synthetic applications of chiral organolithium
      reagents have grown, so have accompanying mechanistic studies of these
      intermediates which serve as the basis for this review.

PMID- 12491318
TI  - From self-organizing polymers to nanohybrid and biomaterials.
AB  - Block copolymers form a large number of superlattices with characteristic
      dimensions in the range of a few nanometers up to several micrometers by self
      organization. The interplay of supramolecular physics and chemistry opens up new
      approaches to the production of inorganic, organic, and biological structures and
      to their integration into functional units. Possible applications in the fields
      of materials science and molecular biology are being investigated. Block
      copolymers find numerous applications from the production of inorganic
      nanoparticles (metals, semiconductors, magnets) and mesoporous materials up to
      take-up/release systems in chemo- and gene therapy.

PMID- 12491320
TI  - Chemical transformations: translation and the periodic table in Japan.

PMID- 12491321
TI  - A new era in divalent organolanthanide chemistry?

PMID- 12491322
TI  - Catalytic, enantioselective syntheses of beta-lactones--versatile synthetic
      building blocks in organic chemistry.

PMID- 12491323
TI  - Introduction of bulky perfluoroalkyl groups at the periphery of zinc
      perfluorophthalocyanine: chemical, structural, electronic, and preliminary
      photophysical and biological effects.

PMID- 12491324
TI  - Synthesis and structure of a biconcave cobalt perfluorophthalocyanine and its
      catalysis of novel oxidative carbon-phosphorus bonds formation by using air.

PMID- 12491325
TI  - Observation of uniaxial negative thermal expansion in an organic crystal.

PMID- 12491326
TI  - Supramolecular templating of the double-cubane [(Cu3(Hpz(tBu))6(mu3-Cl)(mu3
      OH)3)2Cu]Cl6 (Hpz(tBu)=5-tert-butylpyrazole).

PMID- 12491327
TI  - Proof of principle in the selective treatment of cancer by antibody-directed
      enzyme prodrug therapy: the development of a highly potent prodrug.

PMID- 12491328
TI  - Magnetization of chiral monolayers of polypeptide: a possible source of magnetism
      in some biological membranes.

PMID- 12491329
TI  - A nanoporous metal-organic framework based on bulky phosphane ligands.

PMID- 12491330
TI  - A (6-4) photolyase model: repair of DNA (6-4) lesions requires a reduced and
      deprotonated flavin.

PMID- 12491331
TI  - Fapy.dA induces nucleotide misincorporation translesionally by a DNA polymerase.

PMID- 12491332
TI  - Direct screening for phosphatase activity by turnover-based capture of protein
      catalysts.

PMID- 12491333
TI  - The inhibiting influence of aromatic solvents on the activity of asymmetric
      hydrogenations.

PMID- 12491335
TI  - P2-ligand complexes as building blocks for the formation of one-dimensional
      polymers.

PMID- 12491334
TI  - The core structure of TMC-95A is a promising lead for reversible proteasome
      inhibition.

PMID- 12491336
TI  - Tetra- and pentacyclopropylcyclopentadiene-two new donor-substituted ligands for
      metal complexes.

PMID- 12491337
TI  - Spinel sialons.

PMID- 12491338
TI  - A highly active and air-stable ruthenium complex for olefin metathesis.

PMID- 12491339
TI  - Characterization and photochemistry of the gallium and indium subhydrides Ga2H2
      and In2H2.

PMID- 12491340
TI  - Carbonyltris(trifluoromethyl)borane, (CF3)3BCO, an unusual boron carbonyl.

PMID- 12491341
TI  - Unexpected carbonyl mobility in aminoketoses: the key to major Maillard
      crosslinks.

PMID- 12491342
TI  - A method for thermal generation of aryloxyl radicals at ambient temperatures:
      application to low-density lipoprotein (LDL) oxidation.

PMID- 12491343
TI  - A one-pot cross-metathesis/allylboration reaction: a three-component coupling for
      the synthesis of functionalized homoallylic alcohols.

PMID- 12491344
TI  - Electrodeposition of redox polymers and co-electrodeposition of enzymes by
      coordinative crosslinking.

PMID- 12491345
TI  - Formation of a nonaoxirane from A2E, a lipofuscin fluorophore related to macular
      degeneration, and evidence of singlet oxygen involvement.

PMID- 12491346
TI  - Reversible binding of C60 to an anthracene bearing a dendritic poly(amidoamine)
      substituent to give a water-soluble fullerodendrimer.

PMID- 12491347
TI  - Stereospecific interconversion between cis and trans 2,3-epoxysulfides.

PMID- 12491348
TI  - Asymmetric epoxidation of allyl alcohol on organic-inorganic hybrid chiral
      catalysts grafted onto the surface of silica and in the mesopores of MCM-41.

PMID- 12491349
TI  - Regiospecific inverse-electron-demand Diels-Alder reaction of simultaneously
      electrogenerated diene and dienophile: an expeditious route to polyfunctionalized
      1,4-benzoxazine derivatives.

PMID- 12491350
TI  - Voltage-driven changes in molecular dipoles yield negative differential
      resistance at room temperature.

PMID- 12491351
TI  - N,N-dialkylhydrazones as the imine component in the Staudinger-like [2+2]
      cycloaddition to benzyloxyketene.

PMID- 12491352
TI  - A novel regio- and stereoselective synthesis of sulfamidates from 1,2-diols using
      Burgess and related reagents: a facile entry into beta-amino alcohols.

PMID- 12491353
TI  - A supramolecular array of fullerenes by quadruple hydrogen bonding.

PMID- 12491354
TI  - Callipeltoside A: assignment of absolute and relative configuration by total
      synthesis.

PMID- 12491355
TI  - Gallium flux synthesis of Tb3-xC2Si8B(12)3: a novel quaternary boron-rich phase
      containing B12 icosahedra.

PMID- 12491356
TI  - Novel 1,4-diphosphanes with imidazolidin-2-one backbones as chiral ligands:
      highly enantioselective Rh-catalyzed hydrogenation of enamides.

PMID- 12491357
TI  - Mimicking metallophosphatases: revealing a role for an OH group with no libido.

PMID- 12491358
TI  - Sol-gel transcription of sugar-appended porphyrin assemblies into fibrous silica:
      unimolecular stacks versus helical bundles as templates.

PMID- 12491359
TI  - Intramolecular 1,8-hydrogen abstraction between glucopyranose units in a
      disaccharide model promoted by alkoxy radicals.

PMID- 12491360
TI  - A new catalyst for the selective oxidation of butane and propane.

PMID- 12491361
TI  - A dinuclear Zn catalyst for the asymmetric nitroaldol (Henry) reaction.

PMID- 12491369
TI  - Heparin-protein interactions.
AB  - Heparin, a sulfated polysaccharide belonging to the family of glycosaminoglycans,
      has numerous important biological activities, associated with its interaction
      with diverse proteins. Heparin is widely used as an anticoagulant drug based on
      its ability to accelerate the rate at which antithrombin inhibits serine
      proteases in the blood coagulation cascade. Heparin and the structurally related
      heparan sulfate are complex linear polymers comprised of a mixture of chains of
      different length, having variable sequences. Heparan sulfate is ubiquitously
      distributed on the surfaces of animal cells and in the extracellular matrix. It
      also mediates various physiologic and pathophysiologic processes. Difficulties in
      evaluating the role of heparin and heparan sulfate in vivo may be partly ascribed
      to ignorance of the detailed structure and sequence of these polysaccharides. In
      addition, the understanding of carbohydrate-protein interactions has lagged
      behind that of the more thoroughly studied protein-protein and protein-nucleic
      acid interactions. The recent extensive studies on the structural, kinetic, and
      thermodynamic aspects of the protein binding of heparin and heparan sulfate have
      led to an improved understanding of heparin-protein interactions. A high degree
      of specificity could be identified in many of these interactions. An
      understanding of these interactions at the molecular level is of fundamental
      importance in the design of new highly specific therapeutic agents. This review
      focuses on aspects of heparin structure and conformation, which are important for
      its interactions with proteins. It also describes the interaction of heparin and
      heparan sulfate with selected families of heparin-binding proteins.

PMID- 12491370
TI  - 10 years after rio-concepts on the contribution of chemistry to a sustainable
      development.
AB  - The principles of the United Nations Conference on Environment and Development
      (UNCED), held in June 1992 in Rio de Janeiro, and Agenda 21, the comprehensive
      plan of action for the 21st century, adopted 10 years ago by more than 170
      governments, address the pressing problems of today and also aim at preparing the
      world for the challenges of this century. The conservation and management of
      resources for development are the main focus of interest, to which the sciences
      will have to make a considerable contribution. Natural, economic, and social
      sciences will have to be integrated in order to achieve this aim. In their future
      programs, the associations of the chemical industries in Europe, Japan, and the
      USA have explicitly accepted their obligation to foster a sustainable
      development. In this review we investigate innovations in chemistry exemplarily
      for such a development with regard to their ecological, economical, and social
      dimensions from an integrated and interdisciplinary perspective. Since base
      chemicals are produced in large quantities and important product lines are
      synthesized from them, their resource-saving production is especially important
      for a sustainable development. This concept has been shown, amongst others, by
      the example of the syntheses of propylene oxide and adipic acid. In the long run,
      renewable resources that are catalytically processed could replace fossil raw
      materials. Separation methods existing today must be improved considerably to
      lower material and energy consumption. Chemistry might become the pioneer of an
      innovative energy technique. The design of chemical products should make possible
      a sustainable processing and recycling and should prevent their bio-accumulation.
      Methods and criteria to assess their contribution to a sustainable development
      are necessary. The time taken to introduce the new more sustainable processes and
      products has to be diminished by linking their development with operational
      innovation management and with efficient environmental-political control
      procedures.

PMID- 12491371
TI  - De novo structure determination from residual dipolar couplings by NMR
      spectroscopy.

PMID- 12491372
TI  - The uronium/guanidinium Peptide coupling reagents: finally the true uronium
      salts.

PMID- 12491374
TI  - Structure of Bis(pentafluorophenyl)xenon, Xe(C(6)F(5))(2).

PMID- 12491373
TI  - Capillary electrophoresis analysis of DNA adducts as biomarkers for
      carcinogenesis.

PMID- 12491375
TI  - As[P(NMe(2))(3)](2)(+) as simultaneous As(I) and P(I) source: synthesis and
      density function calculations of planar tetracoordinate arsonium and phosphonium
      ions.

PMID- 12491376
TI  - Gold-xenon complexes.

PMID- 12491377
TI  - Open-framework nickel succinate, [Ni(7)(C(4)H(4)O(4))(6)(OH)(2)(H(2)O)(2)].2
      H(2)O: a new hybrid material with three-dimensional Ni-O-Ni Connectivity.

PMID- 12491378
TI  - Icosahedral virus particles as addressable nanoscale building blocks.

PMID- 12491379
TI  - Octahedral arrangement of porphyrin moieties around hexarhenium(III) cluster
      cores: structure of (mu(3)-Selenido)hexa(5-(4-pyridyl)-10,15,20
      tritolylporphyrin)hexarhenium(III) (2+).

PMID- 12491380
TI  - Photochemical formation of tire-shaped molybdenum blues: topology of a defect
      anion, [Mo(142)O(432)H(28)(H(2)O)(58)](12-).

PMID- 12491381
TI  - Direct evidence for the nonrandom nature of Al substitution in zeolite ZSM-5: an
      investigation by (27)Al MAS and MQ MAS NMR.

PMID- 12491383
TI  - Hydrothermal synthesis of molecular sieve fibers: using microemulsions to control
      crystal morphology.

PMID- 12491382
TI  - A new approach to osmium-catalyzed asymmetric dihydroxylation and
      aminohydroxylation of olefins.

PMID- 12491384
TI  - Biomimetic NAD(+) models for tandem cofactor regeneration, horse liver alcohol
      dehydrogenase recognition of 1,4-NADH derivatives, and chiral synthesis.

PMID- 12491385
TI  - Transfer of chiral information through achiral ion recognition by a novel
      pseudocrown ether with a binaphthyl moiety.

PMID- 12491386
TI  - Alpha-lithiation of 1-aryl-3,3-dialkyltriazenes and intramolecular conversion to
      benzylamine and tetrahydrobenzotriazine derivatives.

PMID- 12491387
TI  - Fluorescent deazaflavin-oligonucleotide probes for selective detection of DNA.

PMID- 12491388
TI  - Iron-catalyzed polyethylene chain growth on zinc: linear alpha-olefins with a
      poisson distribution.

PMID- 12491389
TI  - Stereoselective prins cyclizations of delta, epsilon-unsaturated ketones to cis-3
      chlorocyclohexanols with TiCl(4).

PMID- 12491390
TI  - C-HtriplebondO hydrogen bond mediated chain reversal in a peptide containing a
      gamma-amino acid residue, determined directly from powder X-ray diffraction data.

PMID- 12491391
TI  - The shortest route to chiral ditosylmethylamine.

PMID- 12491392
TI  - The extended borinium cation: [(tBu(3)PN)(2)B](+).

PMID- 12491393
TI  - A nanoscale hybrid system based on gold nanoparticles and heteropolyanions.

PMID- 12491394
TI  - "Oscillating" metallocene catalysts: how do they oscillate?

PMID- 12491395
TI  - Total synthesis of the presumed amphidinolide A.

PMID- 12491396
TI  - The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: discovery of a
      new method to generate cis-propenyl amides.

PMID- 12491401
TI  - Recent advances in synthesis and applications of transition metal containing
      mesoporous molecular sieves.
AB  - Work in mesoporous silica-based materials began in the early 1990s with work by
      Mobil. These materials had pore sizes from 20-500 A and surface areas of up to
      1500 m(2) g(-1) and were synthesized by a novel liquid crystal templating
      approach. Researchers subsequently extended this strategy to the synthesis of
      mesoporous transition metal oxides, a class of materials useful in catalysis,
      electronic, and magnetic applications because of variable oxidation states, and
      populated d-bands-features not found in silicates. These materials are already
      showing promise in electronic and optical applications hinging on the
      semiconducting properties of transition metal oxides and their potential to act
      as electron acceptors, an important feature in the design of cathodic materials.
      This is the first general review of non-silicate mesoporous materials and will
      focus on recent advances in this area, emphasizing materials possessing unique
      electronic, magnetic, or optical properties. Also covered are advances in the
      synthesis and applications of mesostructured sulfides as well as a new class of
      template-synthesized platinum-based materials that show promise in heterogeneous
      catalysis.

PMID- 12491402
TI  - Glycosamino acids: building blocks for combinatorial synthesis-implications for
      drug discovery.
AB  - The unique functions of carbohydrates, including energy storage, transport,
      modulation of protein function, intercellular adhesion, signal transduction,
      malignant transformation, and viral and bacterial cell-surface recognition,
      underlie a significant pharmaceutical potential. The development of combinatorial
      carbohydrate libraries in this important arena has been slow, in contrast to the
      rapid development of combinatorial synthesis in the area of small-molecule
      libraries and biopolymers. This is largely as a result of the inherent
      difficulties presented by this class of polyfunctional compounds. Nevertheless,
      strategies to cope with these problems have been devised over the past seven
      years, and combinatorial carbohydrate libraries have appeared. The incorporation
      of an amino acid moiety into the carbohydrate scaffold generates glycosamino
      acids, which are attractive building blocks for the preparation of carbohydrate
      based libraries because of the well-established automated peptide synthesis.
      Derivatization as well as homo- and heterooligomerization of glycosamino acids
      can be used to create novel structures with unique properties. Glycosamino acids
      are hybrid structures of carbohydrates and amino acids which can be utilized to
      generate potential glycomimetics and peptidomimetics. The incorporation of
      glycosamino acids into peptides allows the engineering of carbohydrate-binding
      sites into synthetic polypeptides, which may also influence the pharmacokinetic
      and dynamic properties of the peptides. Furthermore, sugar-amino acid hybrids
      offer a tremendous structural and functional diversity, which is largely
      unexplored and requires combinatorial strategies for efficient exploitation. This
      article provides an overview of previous work on glycosamino acids and discusses
      their use in combinatorial synthesis and drug discovery. Supporting information
      for this article is available on the WWW under http://www.angewandte.com or from
      the author.

PMID- 12491403
TI  - The "Correctly Folded" state of proteins: is it a metastable state?

PMID- 12491404
TI  - Coordinative unsaturation in platinum(IV) chemistry: from proposed reaction
      intermediates to the first structurally characterized complexes.

PMID- 12491405
TI  - A novel concept of reversing neuromuscular block: chemical encapsulation of
      rocuronium bromide by a cyclodextrin-based synthetic host.

PMID- 12491406
TI  - A ring-in-ring complex.

PMID- 12491407
TI  - A cucurbituril-based gyroscane: a new supramolecular form.

PMID- 12491408
TI  - Design of a protein surface antagonist based on alpha-helix mimicry: inhibition
      of gp41 assembly and viral fusion.

PMID- 12491409
TI  - A breathing hybrid organic-inorganic solid with very large pores and high
      magnetic characteristics.

PMID- 12491410
TI  - Infinite secondary building units and forbidden catenation in metal-organic
      frameworks.

PMID- 12491412
TI  - Oligo(phenylenevinylene)s with terminal donor-acceptor substitution.

PMID- 12491411
TI  - Photoresponsive cyclic bis(cysteinyl)peptides as catalysts of oxidative protein
      folding.

PMID- 12491414
TI  - Synthesis and structures of silver-selenide cluster complexes
      [Ag(4)(SeiPr)(4)(dppm)(2)], [Ag(8)(SeEt)(8)(dppp)]( infinity ),
      [Ag(28)Se(6)(SenBu)(16)(dppp)(4)], and
      [Ag(124)Se(57)(SePtBu(2))(4)Cl(6)(tBu(2)P(CH(2))(3)PtBu(2))(12)].

PMID- 12491413
TI  - Crystal structure analysis of 1,1,4,4-tetrafluorobutadiene and experimental
      determination of the charge density of 1,1,4,4-tetrafluorobutatriene.

PMID- 12491415
TI  - Hybrid metallacoronates or one-dimensional oxo-bridged metal strings by self
      assembly-coordination number controlled product formation chelate complexes, Part
      20.

PMID- 12491417
TI  - Dinitroxide carbenes, a new class of carbenes with autoumpolung character:
      preparation in solution and stabilization in transition metal complexes.

PMID- 12491416
TI  - Natural products are biologically validated starting points in structural space
      for compound library development: solid-phase synthesis of dysidiolide-derived
      phosphatase inhibitors.

PMID- 12491418
TI  - Visualization of molecular recognition events on microstructured lipid-membrane
      compartments by in situ scanning force microscopy.

PMID- 12491420
TI  - Unprecedented ferromagnetic interaction in homobinuclear erbium and gadolinium
      complexes: structural and magnetic studies.

PMID- 12491419
TI  - The (2-Phenyl-2-trimethylsilyl)ethyl(PTMSEL) linker-A novel linker for the solid
      phase synthesis of protected peptides and glycopeptides cleavable with fluoride.

PMID- 12491421
TI  - Foldamers as dynamic receptors: probing the mechanism of molecular association
      between helical oligomers and rodlike ligands.

PMID- 12491422
TI  - Tuning the electrical conductivity and self-assembly of regioregular
      polythiophene by block copolymerization: nanowire morphologies in new di- and
      triblock copolymers.

PMID- 12491423
TI  - From surfactant-inorganic mesostructures to tungsten nanowires.

PMID- 12491424
TI  - Dynamic kinetic resolution and desymmetrization of enantiotopic groups by
      cyclodehydration of racemic or prochiral delta-oxoesters with (R)-phenylglycinol:
      enantioselective synthesis of piperidines.

PMID- 12491425
TI  - A highly enantioselective and general conjugate addition of thiols to cyclic
      enones with an organic catalyst.

PMID- 12491426
TI  - Directed ortho-metalation, a new insight into organosodium chemistry.

PMID- 12491428
TI  - IAN-amines: direct entry to a chiral C(2)-symmetric zirconium(IV) beta-diketimine
      complex.

PMID- 12491427
TI  - Palladium-catalyzed regio- and diastereoselective tandem silastannylation/allyl
      addition of allene aldehydes and allene ketones: synthesis of cis cyclopentanols
      and cyclohexanols.

PMID- 12491429
TI  - Synthetic studies on the sulfur-cross-linked core of antitumor marine alkaloid,
      discorhabdins: total synthesis of discorhabdin A.

PMID- 12491430
TI  - Preparation of new functionalized cyclopropylmagnesium reagents.

PMID- 12491431
TI  - Self-assembled, deterministic carbon nanotube wiring networks.

PMID- 12491433
TI  - Expanding divalent organolanthanide chemistry: the first organothulium(II)
      complex and the in situ organodysprosium(II) reduction of dinitrogen.

PMID- 12491432
TI  - Protein affinity labeling mediated by genetically encoded peptide tags.

PMID- 12491443
TI  - Halide effects in transition metal catalysis.
AB  - Among the most common ligands found on transition metal catalysts are halide
      ions. Of the commercially available catalysts or pre-catalysts, most are halo
      metal complexes. In recent years, manipulation of this metal-halide functionality
      has revealed that this can be used as a highly valuable method of tuning the
      reactivity of the complex. Variation of the halide ligand will usually not alter
      the nature of the system to the extent that it becomes unreactive but will impart
      sufficiently large changes that differences in reactivity or selectivity occur.
      These differences are a product of the steric and electronic properties of the
      halide ligand which has the ability to donate electron density to the metal
      occurs in a predictable manner. Despite the common perception in asymmetric
      catalysis that halide ligands are of secondary importance compared to chiral
      ligands, halide ligands have been found to exert dramatic effects on the
      enantioselectivity of asymmetric transformations. While the mechanism of action
      is known for relatively few of the cases, many intriguing and potentially
      synthetically useful trends are apparent. This review discusses the physical
      properties of the halides and their effects on stoichiometric and catalytic
      transition metal processes. The metal-halide moiety thus emerges as a tunable
      functionality on the transition metal catalyst that can be used in the
      development of new catalytic systems.

PMID- 12491444
TI  - The hydrogen bond in the solid state.
AB  - The hydrogen bond is the most important of all directional intermolecular
      interactions. It is operative in determining molecular conformation, molecular
      aggregation, and the function of a vast number of chemical systems ranging from
      inorganic to biological. Research into hydrogen bonds experienced a stagnant
      period in the 1980s, but re-opened around 1990, and has been in rapid development
      since then. In terms of modern concepts, the hydrogen bond is understood as a
      very broad phenomenon, and it is accepted that there are open borders to other
      effects. There are dozens of different types of X-H.A hydrogen bonds that occur
      commonly in the condensed phases, and in addition there are innumerable less
      common ones. Dissociation energies span more than two orders of magnitude (about
      0.2-40 kcal mol(-1)). Within this range, the nature of the interaction is not
      constant, but its electrostatic, covalent, and dispersion contributions vary in
      their relative weights. The hydrogen bond has broad transition regions that merge
      continuously with the covalent bond, the van der Waals interaction, the ionic
      interaction, and also the cation-pi interaction. All hydrogen bonds can be
      considered as incipient proton transfer reactions, and for strong hydrogen bonds,
      this reaction can be in a very advanced state. In this review, a coherent survey
      is given on all these matters.

PMID- 12491445
TI  - High-pressure syntheses of novel binary nitrogen compounds of main group
      elements.
AB  - The application of high-pressure methods in the search for novel materials
      usually requires additional effort compared to syntheses at ambient pressure.
      Depending on the desired p/T conditions different methods may be used. Special
      techniques and experimental apparatus such as shock waves, diamond anvil cells,
      and multianvil presses, which have been applied mainly by earth scientists and
      physicists in the past, are increasingly being applied by synthetic chemists and
      material scientists. A series of fascinating discoveries have been made recently
      as is demonstrated by three examples of binary nitrogen compounds: 1) Diazenides,
      compounds with N(2)(2-) ions, were obtained as single-phase products and
      structurally characterized for the first time. 2) At 11 GPa and 1800 K a
      phosphorus(V) nitride was prepared, which contains tetragonal PN(5) pyramids as a
      novel structural motif. 3) Macroscopic amounts of spinel silicon nitride were
      synthesized by shock-wave techniques, which allows the comprehensive
      characterization and possibly the implementation of this new hard material.

PMID- 12491446
TI  - Molecular gastronomy.

PMID- 12491447
TI  - DNA-templated synthesis: more versatile than expected.

PMID- 12491448
TI  - Kinetic studies of carbocation-carbanion combinations: key to a general concept
      of polar organic reactivity.

PMID- 12491449
TI  - Rate acceleration through dispersion interactions: effect of a hemicarcerand on
      the transition state of inner phase decompositions of diazirines.

PMID- 12491450
TI  - Supramolecular cluster catalysis: benzene hydrogenation catalyzed by a cationic
      triruthenium cluster under biphasic conditions.

PMID- 12491451
TI  - Immobilized highly charged colloidal crystals: a new route to three-dimensional
      mesoscale structured materials.

PMID- 12491452
TI  - The rational design of anion host compounds: an exercise in subtle energetics.

PMID- 12491453
TI  - Characterization of reactive intermediates by diffusion-ordered NMR spectroscopy:
      a snapshot of the reaction of (13)CO(2) with [Cp(2)Zr(Cl)H].

PMID- 12491454
TI  - The first highly efficient asymmetric synthesis of alpha-substituted methyl
      sulfonates.

PMID- 12491455
TI  - Protonated sulfuric acid: preparation of trihydroxyoxosulfonium
      hexafluoroantimonate H(3)SO(4)(+)SbF(6)(-).

PMID- 12491456
TI  - Direct observation of a cytosine analogue that forms five hydrogen bonds to
      guanosine: guanidino G-clamp.

PMID- 12491458
TI  - Cesiumauride ammonia (1/1), CsAu.NH(3): a crystalline analogue to alkali metals
      dissolved in ammonia?

PMID- 12491457
TI  - De novo protein surface design: use of cation-pi interactions to enhance binding
      between an alpha-helical peptide and a cationic molecule in 50 % aqueous
      solution.

PMID- 12491459
TI  - High-throughput screening of enantioselective catalysts by immunoassay.

PMID- 12491460
TI  - Ordered Langmuir-Blodgett films of amphiphilic beta-hairpin peptides imaged by
      atomic force microscopy.

PMID- 12491461
TI  - An unprecedented mixed-charged state in a supramolecular assembly of ligand-based
      mixed-valence redox isomers (ET(*+))(3)[Cr(III)(Cl(4)SQ)(2)(Cl(4)Cat)](
      )[Cr(III)(Cl(4)SQ)(Cl(4)Cat)(2)](2-).

PMID- 12491462
TI  - A pillared-layer coordination polymer network displaying hysteretic sorption:
      [Cu(2)(pzdc)(2)(dpyg)](n) (pzdc= pyrazine-2,3-dicarboxylate; dpyg=1,2-Di(4
      pyridyl)glycol).

PMID- 12491463
TI  - The first disulfur and diselenium complexes of platinum: syntheses and crystal
      structures.

PMID- 12491464
TI  - Synthesis and structure of the first stable phosphabismuthene.

PMID- 12491465
TI  - Erodible conducting polymers for potential biomedical applications.

PMID- 12491466
TI  - Characterization of C(2) (C(x)H(y)) intermediates from adsorption and
      decomposition of methane on supported metal catalysts by in situ INS vibrational
      spectroscopy.

PMID- 12491467
TI  - Real-time observation of the H/D exchange reaction between ethylene and hydrogen
      on Pt(111).

PMID- 12491468
TI  - Unusual peroxo intermediates in the reaction of dioxygen with carboxylate-bridged
      diiron(II,II) paddlewheel complexes.

PMID- 12491469
TI  - A boronic ester annulation strategy for diversity-oriented organic synthesis.

PMID- 12491470
TI  - Microporous supramolecular coordination compounds as chemosensory photonic
      lattices.

PMID- 12491471
TI  - Three-dimensional organically templated open-framework transition metal
      selenites.

PMID- 12491472
TI  - Sequential catalytic asymmetric allylic transfer reaction: enantioselective and
      diastereoselective construction of tetrahydropyran units.

PMID- 12491473
TI  - Efficient intramolecular oxidative amination of olefins through direct dioxygen
      coupled palladium catalysis.

PMID- 12491474
TI  - ZEKE photoelectron spectroscopy of the cis and trans isomers of formanilide.

PMID- 12491475
TI  - Ruthenium-catalyzed oxidative Heck reactions.

PMID- 12491476
TI  - Enantiopure double-helical alkynyl cyclophanes.

PMID- 12491477
TI  - 1,2-azaborolyls, isoelectronic analogues of the ubiquitous cyclopentadienyl
      ligand: synthesis of B-heteroatom-substituted 1,2-azaborolyl complexes and an
      assessment of their electronic features.

PMID- 12491478
TI  - Total synthesis of ambruticin.

PMID- 12491479
TI  - A convenient oxime-carbapalladacycle-catalyzed Suzuki cross-coupling of aryl
      chlorides in water.

PMID- 12491480
TI  - Highly efficient white organic electroluminescence from a double-layer device
      based on a boron hydroxyphenylpyridine complex.

PMID- 12491483
TI  - Overview of the summit meeting evaluating research in African-American women.
AB  - There is a disparity in the breast cancer survival rate among African-American
      women compared with the rate among white women. The summit meeting addressed the
      breast cancer crisis among African-American women by bringing together
      scientists, breast cancer advocates, and policy makers. The goal of the meeting
      was to develop a research agenda. For breast cancer research to advance, priority
      areas must be identified. The current article suggests questions and issues which
      are addressed in this cancer monograph.

PMID- 12491484
TI  - Existing data on breast cancer in African-American women: what we know and what
      we need to know.
AB  - BACKGROUND: Much of what is known about breast cancer in African-American (AA)
      women is based on existing cancer surveillance data. Thus, it is important to
      consider the accuracy of these resources in describing the impact of breast
      cancer in AA populations. METHODS: National cancer surveillance data bases are
      described, their most recent findings are presented, their limitations are
      outlined, and recommendations are made for improving their utility. RESULTS:
      Breast cancer characteristics have been studied well in urban (but not in rural)
      and Southern AA populations. The recent Surveillance, Epidemiology, and End
      Results (SEER) Program expansion and the continued improvement of state cancer
      registry operations will provide opportunities to study larger and more diverse
      AA subpopulations. Recommendations for improving the utility of surveillance data
      bases include adding new items to better describe correlates of advanced stage at
      diagnosis and reduced survival of AA women with breast cancer by linking
      surveillance data bases with other large data bases to provide area-level
      socioeconomic status, health insurance status, and retrieving new information
      about patient comorbidities and biomarkers from medical records; improving the
      completeness and accuracy of treatment and survival information already collected
      for all patients; working to improve the dissemination of appropriate cancer data
      to nonresearch consumer communities, including clinicians, patients, advocates,
      politicians, and health officials; and the development of new training programs
      for cancer registrars and researchers. CONCLUSIONS: The continued improvement of
      cancer surveillance systems should be considered important activities in this
      research agenda, because these data will play a far-reaching role in the
      prevention and control of breast cancer in AA women.

PMID- 12491485
TI  - Ethnicity-related variation in breast cancer risk factors.
AB  - BACKGROUND: A variety of factors are predictors of breast cancer risk. However,
      the studies conducted to establish these risk factors have rarely included
      African American women. The few studies with sufficient numbers of African
      American women suggest that risk factors for breast cancer among African-American
      women are similar to those of white women. Although risk factors may be similar
      for African-American and white women, differences in the prevalence of risk
      factors may explain the differences in patterns of incidence. METHODS: The
      authors reviewed the epidemiologic studies of breast cancer among African
      American women and identified resources with information regarding the prevalence
      of risk factors among African American and white women. RESULTS: Considerable
      variation exists in the studies of breast cancer risk factors among African
      American women. Because few studies have included sufficient numbers of African
      American women, no firm conclusions can be drawn regarding whether risk estimates
      for African American women differ from those of white women. Estimates of the
      prevalence of breast cancer risk factors indicate that African American and white
      women differ in terms of their ages at menarche, menstrual cycle patterns, birth
      rates, lactation histories, patterns of oral contraceptive use, levels of
      obesity, frequency of menopausal hormone use, physical activity patterns, and
      alcohol intake. CONCLUSIONS: The risk factor profile of African-American women
      appears to differ from that of white women. This may explain in part, the higher
      incidence rates for African Americans before age 45 years and the lower incidence
      rates at older ages. Discussions of these data at a workshop highlighted the need
      for future research on breast cancer risk among African Americans. This research
      should acknowledge the heterogeneous heritage, cultural beliefs, and cultural
      knowledge of African-American women. Studies conducted in collaboration with the
      African-American community of women and with the breast cancer advocacy community
      can benefit from assistance in the design of questionnaires and recruitment of
      participants.

PMID- 12491486
TI  - Breast cancer risk assessment models: applicability to African-American women.
AB  - BACKGROUND: Mortality rates are higher among African-American women with breast
      cancer than they are among white women. This population subset can benefit from
      available risk reduction strategies. Optimal public health gains from
      chemoprevention strategies depend on the ability to assess accurately the risk
      for the individual. However, it is not known if existing breast cancer prediction
      models are accurate predictors of the disease among African-American women.
      METHODS: Literature was reviewed for breast cancer risk prediction models and
      their validation studies. Reported data were also reviewed regarding the strength
      of established breast cancer risk factors for African-American women. RESULTS:
      The two currently accepted breast cancer risk assessment models, the Gail Model
      and the Claus Model, were designed primarily to provide risk assessments for
      white women. Neither model has been validated in African-American women. Reported
      data are inconsistent regarding the prevalence and strength of risk factors
      included in these models. CONCLUSIONS: Efforts should be made to validate
      existing risk assessment models in African-American women and future research
      should be directed at the identification of more reliable risk assessment
      features.

PMID- 12491487
TI  - Breast cancer genetics in African Americans.
AB  - BACKGROUND: An overview of the state of genetic testing for BRCA1 and BRCA2 genes
      was presented at the Summit Meeting on Breast Cancer Among African American
      women. METHODS: An exhaustive literature search was performed using PubMed and
      abstracts published from meetings of the American Association for Cancer
      Research, the American Society of Human Genetics, and the American Society of
      Clinical Oncology. The Breast Cancer Information Core was also searched for
      information regarding sequence variants in which the ethnicity of the individual
      tested was known. RESULTS: Of the 26 distinct BRCA1 pathogenic mutations (protein
      truncating, disease-associated missense, and splice variants) detected in
      Africans or African Americans, 15 (58%) have not been previously reported. In
      addition, 18 deleterious BRCA2 mutations have been identified and 10 (56%) of
      these are unique to the group. Only two pathogenic BRCA1 mutations (943ins10 and
      M1775R) have been detected in three or more unrelated families. However, seven
      additional BRCA1 or BRCA2 deleterious mutations have been reported in at least
      two unrelated families. Three of these recurrent BRCA1 mutations (943ins10,
      1832del5, and 5296del4) have been characterized by haplotype studies and each
      likely arose from a common ancestor, including one ancestor that could be traced
      to the Ivory Coast in West Africa. Although only a few African-American families
      have been tested for BRCA1 and BRCA2 mutations, the probability of finding a
      mutation is invariably dependent on the age of onset and the number of breast
      and/or ovarian cancer cases in the family. The psychosocial implications of
      genetic testing for African Americans have not been well studied, so that high
      risk African Americans may underestimate their risks of breast and ovarian
      cancer. CONCLUSIONS: Deleterious BRCA1 and BRCA2 mutations have been identified
      in African-American and African families. A number of unique mutations have been
      described, but recurrent mutations are widely dispersed and are not readily
      identifiable in the few families that have been tested. Access to genetic
      counseling and testing in a culturally sensitive research setting must remain a
      high priority before genetic testing can be disseminated in the community.

PMID- 12491488
TI  - Treatment choices and response rates in African-American women with breast
      carcinoma.
AB  - BACKGROUND: Breast cancer mortality rates are higher among African-American women
      compared with white American women, yet little is known regarding ethnicity
      related variation in patterns of primary surgical treatment, locoregional
      recurrence rates, and response to induction chemotherapy. METHODS: The available
      literature was reviewed to evaluate outcome from breast-conservation therapy in
      African-American women and response rates to systemic therapy. RESULTS: Breast
      conservation therapy appears to be underused among African-American women, a
      pattern that is noted also among white women with breast carcinoma. Higher rates
      of locoregional recurrence are seen among African-American women regardless of
      whether they receive breast-conserving treatment or undergo mastectomy, and this
      appears to be a function of primary tumor biology. Response rates to
      appropriately delivered systemic therapy are similar for African-American
      patients and white patients. CONCLUSIONS: Despite the apparent increased
      aggressiveness of disease seen in African-American women with breast carcinoma,
      patterns of response to local and systemic therapy are similar to the patterns
      seen in white women with breast carcinoma.

PMID- 12491489
TI  - Histopathology of breast cancer among African-American women.
AB  - Although the overall incidence of breast cancer in African-American women is
      lower than in white women, African-American women younger than 50 years old have
      a higher incidence of breast cancer than white women. African-American women with
      breast cancer have a poorer survival rate than white women and are more likely to
      die of breast cancer in almost every age group. To explain this disparity, we
      studied a substantial body of literature that reported a biologic difference in
      the tumors found in African-American and white women. Specifically, more
      aggressive histopathologic patterns have been described among African-American
      patients with breast cancer when compared with white women. In addition, there
      are data that support an ethnicity-related variation in the expression of breast
      tumor hormonal markers. The objective of this study was to critically evaluate
      the existing published data on the histologic features of breast cancer to
      determine whether breast cancer in African-American women is a histologically
      more aggressive disease than in white women. We conclude that the aggressive
      tumor histology reported in African-American women has not been analyzed
      carefully with respect to the age of the patient at the time of diagnosis and the
      stage of disease at presentation. Furthermore, there is a need for central
      pathology review using accepted, published criteria for diagnosis of uncommon and
      controversial histologic subtypes of breast cancer.

PMID- 12491490
TI  - Mammography screening in African American women: evaluating the research.
AB  - BACKGROUND: Notwithstanding some controversy regarding the benefits of screening
      mammography, it is generally assumed that the effects are the same for women of
      all race/ethnic groups. Yet evidence for its efficacy from clinical trial studies
      comes primarily from the study of white women. It is likely that mammography is
      equally efficacious in white and African American women when applied under
      relatively optimal clinical trial conditions, but in actual practice African
      Americans may not be receiving equal benefit, as reflected in their later stage
      at diagnosis and greater mortality. METHODS: Initial searches of Medline using
      search terms related to screening mammography, race, and other selected topics
      were supplemented with national data that are routinely published for cancer
      surveillance. Factors that potentially compromise the benefits of mammography as
      it is delivered in the current health care system to African American women were
      examined. RESULTS: While there have been significant improvements in mammography
      screening utilization, observational data suggest that African American women may
      still not be receiving the full benefit. Potential explanatory factors include
      low use of repeat screening, inadequate followup for abnormal exams, higher
      prevalence of obesity and, possibly, breast density, and other biologic factors
      that contribute to younger age at diagnosis. CONCLUSIONS: Further study of
      biologic factors that may contribute to limited mammography efficacy and poorer
      breast cancer outcomes in African American women is needed. In addition,
      strategies to increase repeat mammography screening and to ensure that women
      obtain needed followup of abnormal mammograms may increase early detection and
      improve survival among African Americans. Notwithstanding earlier age at
      diagnosis for African American women, mammography screening before age 40 years
      is not recommended, but screening of women aged 40-49 years is particularly
      critical.

PMID- 12491491
TI  - Breast cancer among young African-American women: a summary of data and
      literature and of issues discussed during the Summit Meeting on Breast Cancer
      Among African American Women, Washington, DC, September 8-10, 2000.
AB  - BACKGROUND: African-American women younger than age 45 years have a higher risk
      of incidence and mortality due to breast cancer than other women. The reason for
      this disparity in risk is not well understood. METHODS: This review summarizes
      the literature on the topic of breast cancer in young women and presents a
      summary of a discussion on this topic during a national forum on breast cancer
      among African-American women. RESULTS: The occurrence of breast cancer among
      African-American women younger than the age of 45 years has not been well
      studied. There is a clear and long-term pattern of higher incidence and mortality
      and poorer survival in this population subgroup. CONCLUSION: Research is needed
      to understand the reasons for these disparities and to reduce or eliminate them.
      Studies focused on hormonal factors, genetic factors, diet and obesity, and
      timely access to state-of-the-art prevention, information, screening, diagnosis,
      and treatment are likely to produce important new knowledge in this area.

PMID- 12491492
TI  - Breast cancer risk and lifestyle differences among premenopausal and
      postmenopausal African-American women and white women.
AB  - BACKGROUND: Very little is known about the role of lifestyle in breast cancer
      risk, and even less is known about whether differences in lifestyle contribute to
      the disparities in this risk between African-American women and white women. In
      this study, the authors examined differences in diet and physical activity
      between African-American women and white women and discuss the research that is
      needed regarding the role of lifestyle in breast cancer risk. METHODS: The
      authors used bivariate and multiple regression analyses to estimate the
      difference between African-American women and white women in body mass index
      (BMI), physical activity, the Healthy Eating Index, intake of selected nutrients,
      and serum levels of some micronutrients. Data were taken from the National Health
      and Nutrition Examination Survey III, 1988-1994. RESULTS: African-American women
      had a higher BMI, and older African-American women were less active physically
      compared with white women. African-American women of all ages had a poorer
      quality diet, and they consumed more protein and cholesterol but less dietary
      fiber, folate, and vitamin A. African-American women had lower predicted serum
      levels of folate and vitamin A but higher predicted serum levels of lutein.
      CONCLUSIONS: The current findings generally are consistent with the hypothesis
      that nutrition differences may contribute to the higher rate of breast cancer
      experienced by younger African-American women, although extensive research is
      needed. More longitudinal data and research on nutrition, genetics, and breast
      cancer among African-American women are needed. Studies should examine how to
      help African-American women make behavioral changes to reduce their risk of
      breast cancer.

PMID- 12491493
TI  - Environmental risk factors for breast cancer among African-American women.
AB  - There are few unequivocably established environmental carcinogens for breast
      cancer in women. Nevertheless, environmental factors are believed to explain much
      of the international variation in breast cancer risk and possibly differences
      among racial/ethnic groups. Along with lifestyle, some adverse exposures may be
      higher in minority racial/ethnic groups and in underserved populations that
      experience higher ambient contamination. Associations have been found between
      environmental agents and breast cancer in subgroups of women who can be
      identified by common susceptibility traits as well as by timing of exposures at
      certain milestones of reproductive life. Susceptibility can be defined by social,
      environmental, and genetic modalities-factors that may predominate in certain
      racial/ethnic groups but that also transcend racial/ethnic boundaries. For
      example, genes involved in transcription and estrogen metabolism have rapid
      variants that are more prevalent among African-Americans, yet risk accompanying
      metabolic changes from these genes will prevail in all racial/ethnic groups. Lack
      of reliable exposure assessment remains a principal obstacle to elucidating the
      role of environmental exposures in breast cancer. Resources must be identified
      and consolidated that will enable scientists to improve exposure assessment and
      to assemble studies of sufficient size to address questions regarding exposure,
      susceptibility, and vulnerability factors in breast cancer. Breast cancer studies
      should be expanded to examine combinations of chemicals as well as competing or
      complementary exposures such as endogenous hormones, dietary intake, and
      behavioral factors.

PMID- 12491494
TI  - Quality of life concerns in patients with breast cancer: evidence for disparity
      of outcomes and experiences in pain management and palliative care among African
      American women.
AB  - BACKGROUND: African-American women are at higher risk for breast cancer mortality
      compared with their white counterparts. Furthermore, African-American women
      present for diagnosis and treatment later in the disease process. It may be
      expected that this greater disease burden would impose more symptoms compared
      with women who present with earlier stage disease. However, the effect of breast
      cancer on the quality of life of African-American women largely has been
      unexplored. METHODS: A qualitative literature review was conducted to identify
      racial disparities in the palliative care of patients with cancer and their
      impact on quality of life for African-American women. A Medline search was done
      encompassing the years between 1985 and 2000 and included the following search
      terms: breast cancer, palliative care, pain management, quality of life, health
      care disparities, and African Americans. Relevant articles were read and
      summarized for inclusion in this review. RESULTS: Differences in treatment
      patterns, pain management, and the use of hospice care exist between African
      American women and women in other ethnic groups. Explanations for these
      differences have not been researched well. In addition, the emotional, social,
      and other aspects of quality of life for African-American women with breast
      cancer are not well understood, in part due to the absence of a standardized
      quality-of-life measure. CONCLUSIONS: Physicians and other health care providers
      must be educated better about pain management and hospice care and, in turn, must
      inform their patients better about these issues. Physicians' and researchers'
      considerations of the influence of race and ethnicity on quality of life are
      critical. Furthermore, future research should be focused on the establishment of
      a standardized measure for quality of life that better encompasses its social,
      spiritual, and emotional aspects. Quality-of-life measures should be incorporated
      into routine health surveillance mechanisms, with an increased emphasis on
      minority and other under-served populations.

PMID- 12491495
TI  - Barriers to breast cancer control for African-American women: the interdependence
      of culture and psychosocial issues.
AB  - BACKGROUND: This study evaluates the cultural context of the behaviors and
      beliefs of African-American women to determine the success or failure of breast
      cancer prevention and control interventions. Cultural and psychologic reactions,
      such as fear, distrust, fatalism, and other "historic rooted" factors, are major
      determinants to participation in these interventions by African-American women.
      METHODS: Psychosocial and cultural issues were delineated through a literature
      review in the areas of cancer prevention, breast cancer control, and African
      American women. Assessments were conducted to document key successful models and
      activities that increased the participation of African-American women in breast
      cancer prevention and control interventions. Current community-based intervention
      strategies and activities were assessed. RESULTS: Effective breast cancer
      prevention and control programs must address and develop cultural competent
      models that promote behavioral change in this population of women. CONCLUSIONS:
      Studying the relationship between culture and psychosocial issues is integral to
      our understanding of how African-American women participate and respond to cancer
      prevention and control interventions. Cultural competent models that reduce and
      eliminate cancer disparities in this population must be developed.

PMID- 12491496
TI  - The perspective of African-American breast cancer survivor-advocates.
AB  - BACKGROUND: This article discusses the sometimes unique presentation and course
      of breast cancer in African-American women and the impact these differences have
      on the perception of breast disease among African-American women. METHODS: The
      project described represents the thoughts of many African-American breast cancer
      survivors, as summarized by three breast cancer survivor-advocates who work
      through very different national organizations, each of whom has vast experience
      working directly with African-American breast cancer survivors and their
      families. RESULTS: In addition to discussions of compelling considerations that
      have an impact on survivor access, such as agency, culture, and class, other
      important access questions are raised for research scientists and clinicians that
      have an impact on the prevention, screening, and detection and treatment of
      breast cancer in African-American women as well as their accrual to clinical
      trials. CONCLUSIONS: To eradicate ethnicity-related disparities in breast cancer
      outcomes for African-American women, it is important for the medical community
      (clinicians and research scientists) to develop active partnerships with African
      American and other breast cancer survivor-advocates in order to establish
      effective breast health awareness and breast cancer treatment programs and to
      develop meaningful breast cancer research programs.

PMID- 12491497
TI  - Increasing the pool of academically oriented African-American medical and
      surgical oncologists.
AB  - BACKGROUND: In the United States, breast cancer mortality rates are significantly
      higher among African-American women than among women of other ethnic backgrounds.
      Research efforts to evaluate the socioeconomic, environmental, biologic, and
      genetic mechanisms explaining this disparity are needed. METHODS: Data regarding
      patterns in the ethnic distribution of physicians and oncologists were
      accumulated from a review of the literature and by contacting cancer-oriented
      professional societies. This information was evaluated by participants in a
      national meeting, "Summit Meeting Evaluating Research on Breast Cancer in African
      American Women." Results of the data collection and the conference discussion are
      summarized. RESULTS: Ethnic minority specialists are underrepresented in academic
      medicine in general, and in the field of oncology in particular. This fact is
      unfortunate because ethnic minority students are more likely to express a
      commitment to providing care to medically underserved communities and, thus, they
      need to be better represented in these professions. Correcting these patterns of
      underrepresentation may favorably influence the design and implementation of
      culturally and ethnically sensitive research. CONCLUSIONS: Efforts to improve the
      ethnic diversity of oncology specialists should begin at the level of recruiting
      an ethnically diverse premed and medical student population. These recruitment
      efforts should place an emphasis on the value of mentoring.

PMID- 12491498
TI  - Breast cancer research among African-American women: accurate racial categories?
AB  - This essay questions the appropriateness of racial categories in breast cancer
      research and recommends the discontinuation of "African-American" as a valid
      racial category in breast cancer research until better categories can be
      developed.

PMID- 12491499
TI  - Pathologic characteristics of breast parenchyma in patients with hereditary
      breast carcinoma, including BRCA1 and BRCA2 mutation carriers.
AB  - BACKGROUND: BRCA1 and BRCA2 alterations are associated with an increased risk of
      developing breast carcinoma. The authors hypothesized that the progression of
      breast neoplasia may differ between patients with hereditary disease and patients
      with nonhereditary disease and that this difference in progression may be
      visualized by studying the prevalence of precursor lesions and neoplastic
      lesions. METHODS: The authors developed two case cohorts of high-risk patients
      with a strong family history of breast carcinoma who underwent prophylactic
      mastectomy. The first cohort was comprised of women who underwent therapeutic
      mastectomy and contralateral prophylactic mastectomy, and the second cohort was
      comprised of women who underwent bilateral prophylactic mastectomy. Patients
      without a family history of breast carcinoma who underwent unilateral or
      bilateral prophylactic mastectomy were selected as a control group. DNA from
      peripheral blood leukocytes was screened for BRCA1 and BRCA2 mutations. The
      available pathologic materials were reviewed independently by two pathologists,
      and all neoplastic and precursor lesions were identified and classified.
      Proliferation activity was assessed using MIB-1 immunohistochemistry on all
      available lesions from the unilateral mastectomy cohort. RESULTS: The 28 women
      from the unilateral cohort with deleterious BRCA1/2 mutations had a lower
      prevalence of proliferative fibrocystic changes (PFC) (7%) compared with their
      matched control group (25%) (P = 0.075) and with patients who had a family
      history but no BRCA1/2 mutation (22-33%). None of the 11 deleterious mutation
      carriers from the bilateral cohort (0%) had PFC compared with 36% of women in the
      matched control group (P = 0.03). There was no major difference in the prevalence
      of other precursor lesions (including in situ carcinoma) in either cohort.
      Invasive carcinomas from the deleterious mutation carriers in the unilateral
      cohort were of higher grade compared with the control group (P = 0.003) and
      patients without a mutation (P < 0.0001) but were of similar grade compared with
      carriers of unclassified variant BRCA1/2 alterations (P = 0.20). Neoplastic
      lesions from the deleterious mutation carriers in the unilateral cohort had
      higher MIB-1 proliferation indices compared with other patients with and without
      a family history of breast carcinoma. CONCLUSIONS: The current data suggest that
      the progression rate of breast neoplasia is accelerated in women who carry
      BRCA1/2 deleterious mutations compared with other patients who have breast
      carcinoma with or without a family history. This increased progression rate
      should be taken into account when considering the surveillance of asymptomatic
      women.

PMID- 12491500
TI  - Selective modulation of postmenopausal women: cutting the Gordian knot of hormone
      replacement therapy with breast carcinoma.
AB  - BACKGROUND: Hormone replacement therapy (HRT) has proven and presumable benefits
      for women desiring postmenopausal health preservation. Among HRT-associated
      risks, the fear of breast carcinoma intimidates women and physicians
      contemplating hormonal treatment and limits long-term compliance. Identifying
      effective alternative medications that are not associated with breast carcinoma
      or that even may prevent its development would be a major advance. METHODS: This
      article discusses the clinical perspective of HRT and selective estrogen receptor
      modulators (SERMs) in light of the molecular and cellular mechanisms of estrogen
      and progesterone action on the breast. Emphasis is placed on the potential of
      selective receptor modulation as the future of postmenopausal treatment. RESULTS:
      Current epidemiologic evidence suggests that HRT is associated with a small but
      substantial increase in the risk of breast carcinoma, and combined estrogen
      progesterone regimens further increase this hazard. Ample biologic data support
      this clinical association and propose multiple molecular mechanisms for the
      effects of estrogen and progesterone on breast cells. SERMs are a novel class of
      drugs that demonstrate estrogen agonistic and antagonistic actions in a tissue
      specific manner. SERMs act by binding the estrogen receptor and selectively
      modulating its effect on gene transcription at target tissues. CONCLUSIONS: SERMs
      offer an alternative to HRT that can successfully circumvent the intimidating
      side-effect of breast carcinoma. Further insight into the molecular mechanisms of
      SERM action may enable the development of agents with improved target-tissue
      selectivity. Identifying selective modulators with unique pharmacologic
      properties would facilitate the creation of individualized treatment for the
      postmenopausal woman according to her particular predisposition for menopause
      related morbidities and her overall clinical profile.

PMID- 12491501
TI  - Adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil,
      vincristine, and prednisone compared with single-agent L-phenylalanine mustard
      for patients with operable breast carcinoma and positive axillary lymph nodes: 20
      year results of a Southwest Oncology Group study.
AB  - BACKGROUND: Adjuvant combination chemotherapy with cyclophosphamide,
      methotrexate, and 5-fluorouracil plus vincristine and prednisone (CMFVP) was
      compared with single-agent L-phenylalanine mustard (L-PAM) for the treatment of
      patients with axillary lymph node positive primary breast carcinoma over 20-years
      of follow-up. METHODS: Four hundred forty-one women with axillary lymph node
      positive breast carcinoma were randomized to receive either combination
      chemotherapy with cyclophosphamide (60 mg/m(2) orally every day for 1 year),
      fluorouracil (300 mg/m(2) intravenously [IV] weekly for 1 year), methotrexate (15
      mg/m(2) IV weekly for 1 year), vincristine (0.625 mg/m(2) IV for 10 weeks),
      prednisone (30 mg/m(2) orally on Days 1-14, 20 mg/m(2) on Days 15-28, and 10
      mg/m(2) on Days 29-42), or single-agent chemotherapy with L-PAM (5 mg/m(2) orally
      every day for 5 days every 6 weeks for 2 years) after undergoing surgery.
      Patients were stratified according to menopausal status and number of positive
      lymph nodes (1-3 positive lymph nodes or > 3 positive lymph nodes). Seventy-seven
      patients were ineligible. RESULTS: The maximum follow-up is 24 years, with a
      median follow-up of 21.5 years. Disease free survival and overall survival were
      superior with CMFVP (two-sided log-rank test; P = 0.0008 and P = 0.007,
      respectively). For all patients, the estimated 20-year survival rate of patients
      who received CMFVP was 40% compared with 27% for patients who received L-PAM.
      There was a substantial survival benefit for CMFVP compared with L-PAM in the
      subsets of premenopausal patients and patients with four or more positive lymph
      nodes. The estimated 20-year survival rate for premenopausal women who received
      CMFVP was 49% compared with 33% for premenopausal women who received L-PAM. Among
      women with > or = 4 positive lymph nodes, the estimated survival rate for
      patients who received CMFVP was 31% compared with 15% for patients who received L
      PAM. Both regimens were tolerated well. Toxicity was more severe and frequent
      among patients who received CMFVP. CONCLUSIONS: The authors conclude that, after
      20 years of follow-up, adjuvant chemotherapy with CMFVP remains superior to L-PAM
      for the treatment of patients with lymph node positive breast carcinoma.

PMID- 12491502
TI  - Long-term follow-up of a prospective policy of margin-directed radiation dose
      escalation in breast-conserving therapy.
AB  - BACKGROUND: A prospectively applied treatment policy for breast-conserving
      therapy used margin assessment as the exclusive guide to the intensity of
      radiation therapy directed at the tumor bed. METHODS: From 1982 to 1994, 498
      women with 509 Stage I/II breast carcinomas with a median follow-up of 121 months
      were treated. Final margin status (FMS) categories were defined as greater than 5
      mm, greater than 2-5 mm, greater than 0-2 mm, and positive. For margins less than
      or equal to 2 mm or indeterminate, reexcisions were performed if feasible. All
      patients received whole breast irradiation to 50.0-50.4 Gy. Final tumor bed
      boosts as a function of FMS were as follows: no residual on reexcision, no boost
      performed; FMS greater than 5 mm, boost of 10 Gy; FMS greater than 2-5 mm, boost
      of 14 Gy; FMS greater than 0-2 mm or positive, boost of 20 Gy. Cases were
      analyzed for local failure with respect to histology, age, tumor size, excision
      volume, reexcision, and total dose. RESULTS: FMS was positive, greater than 0-2
      mm, greater than 2-5 mm, and greater than 5 mm, and no residual tumor on
      reexcision in 21%, 20%, 17%, 14%, and 28% of cases, respectively. At 12 years,
      Kaplan-Meier local failure rates were 17% for FMS positive, 9% for FMS greater
      than 0-2 mm, 5% for FMS greater than 2-5 mm, 0% for FMS greater than 5 mm, and 6%
      for specimens without evidence of residuum on reexcision (P = 0.009). Patients 45
      years old and younger had a 12-year local failure rate of 15% whereas patients
      older than 45 years had a 12-year local failure rate of 6% (P = 0.01). On
      multivariate analysis, young age (P = 0.03) predicted increased local failure
      rate, whereas margins that were less than or equal to 2 mm or positive predicted
      late (> 5 years) but not early (< or = 5 years) recurrence (P = 0.003).
      CONCLUSIONS: Graded tumor bed dose escalation in response to FMS results in very
      low rates of local failure over the first 5 years for all FMS categories.
      However, tumors with close/positive margins have significantly increased local
      failure rates after 5 years of follow-up even with increased radiation boost
      dose. In addition, graded tumor bed dose escalation does not fully overcome the
      adverse influence of young age.

PMID- 12491503
TI  - Doxorubicin-paclitaxel: a safe regimen in terms of cardiac toxicity in metastatic
      breast carcinoma patients. Results from a European Organization for Research and
      Treatment of Cancer multicenter trial.
AB  - BACKGROUND: The potential cardiotoxicity of the doxorubicin-paclitaxel regimen,
      when paclitaxel is given shortly after the end of the anthracycline infusion, is
      an issue of concern, as suggested by small single institution Phase II studies.
      METHODS: In a large multicenter Phase III trial, 275 anthracycline naive
      metastatic breast carcinoma patients were randomized to receive either
      doxorubicin (60 mg/m(2)) followed 30 minutes later by paclitaxel (175 mg/m(2) 3
      hour infusion; AT) or a standard doxorubicin-cyclophosphamide regimen (AC; 60/600
      mg/m(2)). Both treatments were given once every 3 weeks for a maximum of six
      cycles. Close cardiac monitoring was implemented in the study design. RESULTS:
      Congestive heart failure (CHF) occurred in three patients in the AT arm and in
      one patient in the AC arm (P = 0.62). Decreases in left ventricular ejection
      fraction to below the limit of normal were documented in 33% AT and 19% AC
      patients and were not predictive of CHF development. CONCLUSIONS: AT is devoid of
      excessive cardiac risk among metastatic breast carcinoma patients, when the
      maximum planned cumulative dose of doxorubicin does not exceed 360 mg/m(2).

PMID- 12491504
TI  - Energy restriction early in life and colon carcinoma risk: results of The
      Netherlands Cohort Study after 7.3 years of follow-up.
AB  - BACKGROUND: This study evaluated the effects of severe undernutrition during
      adolescence and subsequent colon carcinoma risk. METHODS: The authors evaluated
      The Netherlands Cohort Study on Diet and Cancer (NLCS) among 62,573 women and
      58,279 men aged 55-69 years at baseline. Information on diet and risk factors was
      collected by questionnaire in 1986. Additional information was collected
      concerning residence during the hunger winter (1944-1945), the World War II years
      (1940-1944), and father's employment status during the economic depression of
      1932-1940, which were used as indicators of exposure. After 7.3 years of follow
      up, 807 colon carcinoma cases (388 females and 419 males) were available for
      analysis. RESULTS: Multivariate analysis showed that both men and women who had
      lived in a western city in 1944-1945 had a decreased colon carcinoma risk (men:
      relative risk [RR] = 0.85, 95% confidence interval [CI] = 0.62-1.16; women: RR =
      0.80, 95% CI = 0.59-1.09). No association between colon carcinoma risk and urban
      versus rural residence was found during the war years (1940-1944). Having an
      unemployed father during the economic depression (1932-1940) was also associated
      with a small decrease in colon carcinoma risk for men (RR = 0.90, 95% CI =0.62
      1.31) and women (RR = 0.75, 95% CI 0.49-1.14). In subgroup analyses, a decreased
      colon carcinoma risk for men and women who were in their adolescent growth spurt
      and living in a western city during the hunger winter of 1944-1945 was noted
      (men: RR = 0.72, 95% CI = 0.31-1.65; women: RR = 0.88, 95% CI = 0.40-1.96). No
      associations were statistically significant because of the limited study size.
      CONCLUSIONS: In the current study, a weak inverse relation was found between
      energy restriction early in life and subsequent colon carcinoma risk for men and
      women. However, these findings need replication in a larger study.

PMID- 12491505
TI  - Advanced age at diagnosis is an independent predictor of time to death from
      prostate carcinoma for patients undergoing external beam radiation therapy for
      clinically localized prostate carcinoma.
AB  - BACKGROUND: Whether age at diagnosis is predictive of time to prostate carcinoma
      specific death after external beam radiation therapy (RT) for patients who are
      diagnosed with clinically localized prostate carcinoma during the prostate
      specific antigen (PSA) era has not been investigated previously. METHODS: A
      multivariate Cox regression analysis was used to evaluate the ability of
      pretreatment risk group and age at diagnosis to predict time to all causes of
      death and time to death from prostate carcinoma for 381 patients who underwent RT
      for clinically localized prostate carcinoma. RESULTS: Age at diagnosis, as a
      continuous variable (P(continuous) = 0.04), and risk group (P(categorical) =
      0.02) were independent predictors of time to death from prostate carcinoma,
      whereas only age at diagnosis (P(continuous) = 0.01) was a predictor of time to
      all causes of death. When analyzed as a categorical variable, beginning at age 73
      years, age at diagnosis was an independent predictor (P(categorical) < 0.04) of
      time to death from prostate carcinoma. Upon further analysis, this finding was
      limited to high-risk patients. For example, age > or = 75 years at diagnosis
      predicted for a shorter median time to death from prostate carcinoma (6.3 years
      vs. 9.7 years; P = 0.002) in high-risk patients. CONCLUSIONS: Patients with
      clinically localized, high-risk prostate carcinoma who were diagnosed at age > or
      = 73 years and were treated with RT had a worse prognosis compared with patients
      who were diagnosed age < 73 years, raising the possibility that a more aggressive
      prostate carcinoma biology may develop during andropause.

PMID- 12491506
TI  - Trends in the incidence of testicular germ cell tumors in the United States.
AB  - BACKGROUND: Recent reports have suggested that the increasing rates of testicular
      germ cell tumors in some populations have begun to plateau. This study was
      conducted to examine whether rates among white men in the United States have
      begun to stabilize and whether rates among black men in the United States have
      remained low. METHODS: Testicular germ cell tumor incidence data from in the
      Surveillance, Epidemiology, and End Results Program were analyzed for the years
      1973-1998. Trends were examined separately for seminoma and nonseminoma. Using
      age-period-cohort analyses with 5-year age intervals and 5-year calendar-period
      intervals, changes in the slope of the trends in birth-cohort and calendar-period
      effects were examined. RESULTS: Among white men, rates of seminoma continued to
      increase, but the rate of increase steadily declined throughout the 26-year time
      span. Nonseminoma rates among whites increased more slowly during the first three
      time intervals, then plateaued in the final interval. Rates of both seminoma and
      nonseminoma in black men fluctuated throughout the first three time intervals. In
      the final interval, the rates of seminoma increased almost 100%, whereas the
      rates of nonseminoma increased more modestly. Age-period-cohort modeling of the
      incidence data in white men found that, whereas the dominant effect was that of
      birth cohort, there also was a period effect. CONCLUSIONS: Among white men in the
      United States, the incidence of testicular germ cell tumors varied by histology,
      with a continuing increase in risk only for seminoma. Among black men in the
      United States, the surprising increases seen between 1988 and 1998 were likely to
      be a calendar-period effect.

PMID- 12491507
TI  - Epirubicin and meglumine gamma-linolenic acid: a logical choice of combination
      therapy for patients with superficial bladder carcinoma.
AB  - BACKGROUND: Anthracyclines have been established as first-line drugs for
      intravesical use in the treatment of patients with superficial bladder carcinoma,
      although they result only in a modest reduction in tumor recurrence rates. The
      essential fatty acid gamma-linolenic acid (GLA) also is an effective cytotoxic
      agent against superficial bladder carcinoma when it is applied topically. The
      objective of this study was to assess the efficacy of combined epirubicin and GLA
      with the purpose of developing a suitable model for modification of existing
      intravesical regimens. METHODS: The human urothelial carcinoma cell lines MGH-U1
      and RT112 were used in standard cytotoxicity assays and were exposed to meglumine
      GLA (MeGLA) and epirubicin in two-dimensional concentration matrices. A thiozolyl
      blue (methyl-thiazoldiphenyl tetrazolium) assay was used to determine residual
      cell biomass. Drug interaction was quantified by median-effect analysis software
      (CalcuSyn), and the evaluation of drug uptake utilized fluorescence confocal
      microscopy (FCM) and flow cytometry. RESULTS: MeGLA caused a significant
      enhancement of anthracycline uptake, viewed by FCM, from 92 fluorescence units to
      222 fluorescence units (P < 0.001). Flow cytometry confirmed the increased drug
      uptake and showed that the mean epirubicin content per cell increased from 23 to
      57 units and from 8 to 24 units for MGH-U1 and RT112 cells, respectively (99%
      confidence interval < 0.3). This resulted in improved cytotoxicity, and it was
      shown that the drugs acted synergistically with all but the highest MeGLA
      concentrations. CONCLUSIONS: The efficacy of epirubicin was enhanced
      significantly when it was used in combination with most concentrations of MeGLA
      (< 300 microg/mL), and the two agents acted synergistically. There was a
      corresponding increase in epirubicin uptake by cells under these conditions. At
      high MeGLA concentrations, however, anthracycline solubility was compromised, and
      drug synergy was lost.

PMID- 12491508
TI  - Matrix metalloproteinase-26 is expressed in human endometrium but not in
      endometrial carcinoma.
AB  - BACKGROUND: The human matrix metalloproteinase (MMP)-26, also called matrilysin-2
      or endometase, has been isolated as a matrilysin (MMP-7) homolog. Matrix
      metalloproteinase-26 was expressed in tissue samples from the placenta and
      endometrial tumors and its expression may be related to the development of
      endometrial carcinomas. METHODS: Total RNAs were isolated from 5 endometrial
      carcinoma cell lines, 36 normal endometrial tissue samples, 4 hyperplasia tissue
      samples, and from 24 endometrial carcinoma tissue samples. Reverse transcription
      polymerase chain reation (RT-PCR) was performed to detect MMP-26 mRNA expression.
      To identify MMP-26 mRNA localization and protein expression, we performed in situ
      RT-PCR and immunohistochemistry, respectively. RESULTS: Reverse transcription
      polymerase chain reaction analysis revealed that MMP-26 mRNA was expressed in 24
      of 36 normal human endometrial tissue samples. However, MMP-26 mRNA expression
      was not detected in endometrial carcinoma cell lines nor in endometrial carcinoma
      tissue samples except for one case. Western blot analysis showed similar results.
      In situ RT-PCR analysis revealed that MMP-26 expression was localized in the
      epithelial glandular cells but faint expression was observed in the stromal
      cells. Subsequently, we separated endometrial tissues into epithelial glandular
      and stromal cells. Using RT-PCR, the purified epithelial glandular cells
      exhibited MMP-26 mRNA expression but the purified stromal cells did not.
      Immunohistochemical analyses revealed that MMP-26 protein expression is also
      limited to endometrial epithelial glandular cells but not to cancer cells.
      Therefore, MMP-26 expression is limited to normal epithelial glandular cells.
      CONCLUSIONS: We found a significant difference in MMP-26 expression in normal and
      malignant endometrial tissue samples, although its function is still unknown.
      These data suggest that MMP-26 may be a candidate for a new tumor marker for
      endometrial carcinomas.

PMID- 12491509
TI  - Diagnosis of neck recurrences in patients with differentiated thyroid carcinoma.
AB  - BACKGROUND: The follow-up of patients with differentiated thyroid carcinoma (DTC)
      is traditionally carried out with (131)I whole body scan ((131)I WBS) and serum
      thyroglobulin (Tg) measurement. Neck ultrasonography (US) is also used. METHODS:
      We compared the roles of Tg measurement (IRMA assay) after l-thyroxine (T4)
      withdrawal, (131)I WBS, and US in the diagnosis of DTC neck recurrences.
      Diagnosis of DTC neck recurrences was based on fine-needle aspiration biopsy
      (FNAB) or on histologic results. Four hundred ninety-four DTC patients (120
      males, 374 females; mean age, 49.3 years), submitted to total thyroidectomy and
      subsequent radioablative (131)I treatment, underwent serum Tg measurement off T4
      therapy, (131)I WBS, and neck US at our institution. Mean (+/- SD) follow-up time
      was 55.1 +/- 37.7 months. Neck DTC recurrences were detected in 51 (10.3%)
      patients (34 females, 17 males; mean age, 49.5 years). RESULTS: Neck recurrences
      occurred after 44.6 +/- 21.4 months from initial treatment. Serum Tg levels
      increased (> or = 2 ng/mL) off T4 therapy in 29 patients (sensitivity 56.8%),
      (131)I WBS showed neck uptake in 23 patients (sensitivity 45.1%) and coexisting
      distant metastases were detected in 9 of 23 patients, and US identified neck
      recurrence in 48 patients (sensitivity 94.1%). Of these 48 neck recurrences, 19
      were found in the laterocervical compartment and 29 in the central neck
      compartment. CONCLUSIONS: Traditional techniques for the surveillance of DTC
      patients are not as sensitive as US in the detection of neck recurrences. Neck US
      detects recurrences in patients with undetectable serum Tg levels and negative
      IWBS and should be performed as the first-line test in the follow-up of all DTC
      patients.

PMID- 12491510
TI  - Treatment of large cell lymphoma in elderly patients with a mitoxantrone,
      cyclophosphamide, etoposide, and prednisone regimen: long-term follow-up results.
AB  - BACKGROUND: Patients with aggressive non-Hodgkin lymphoma (NHL) require intensive
      and extensive therapy, which seems impracticable in elderly patients due to
      hematologic and extrahematologic toxicity. Consequent dose reduction and therapy
      attenuation can reduce treatment-related toxicity but also decreases therapeutic
      efficacy. Thus, age represents a fundamental prognostic factor that has a
      profound influence on both therapeutic decisions and patient outcome. METHODS:
      Between January, 1990 and June, 1997, 145 patients age > 64 years (median age,
      72.3 years) with a diagnosis of aggressive NHL were treated on a chemotherapy
      regimen that consisted of mitoxantrone, cyclophosphamide, etoposide, and
      prednisone. RESULTS: Ninety-one patients (63%) achieved complete remission, and
      48 patients (33%) achieved partial remission, for an overall response rate of
      96%. Six patients (4%) were resistant to therapy. The overall survival rate, with
      a median follow-up of 66 months, was 44%, and the failure free survival rate was
      42%. The disease free survival rate was 63.5%, with a median follow-up of 60
      months. Multivariate survival analysis showed that the achievement of complete
      remission was the single most important prognostic factor, which was associated
      significantly with longer survival (P < 0.0001). Toxicity was moderate, with 5
      deaths (3%) due to complications related to therapy. CONCLUSIONS: The current
      results confirm that a protocol devised specifically for elderly patients may
      reduce toxicity and allow longer overall survival in this particular subset of
      patients.

PMID- 12491511
TI  - Slower molecular response to treatment predicts poor outcome in patients with
      TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time
      quantitative reverse transcriptase-polymerase chain reaction study.
AB  - BACKGROUND: The translocation t(12;21)(p13;q22), which produces the TEL/AML1
      fusion gene, is the most frequent chromosomal abnormality in patients with
      childhood acute lymphoblastic leukemia (ALL) and generally is associated with a
      favorable prognosis. Furthermore, real-time quantitative-polymerase chain
      reaction (RQ-PCR)-based detection of TEL/AML1 represents an accurate technique
      for the reproducible assessment of minimal residual disease (MRD). METHODS: The
      authors employed RQ-reverse transcriptase-PCR (RQ-RT-PCR) technology to analyze
      MRD levels in 57 newly diagnosed patients with TEL/AML1 positive ALL in a
      prospective study. RESULTS: On Day + 33, a particularly important time point in
      terms of outcome prediction based on MRD monitoring, 75% of patients reached
      negativity, 13% of patients were positive at very low levels (< 10(-4); i.e., 1
      or more leukemic cell per 10(4) normal cells), and another 13% of patients were
      positive at the level of 10(-2) to 10(-4) cells. No patient showed MRD levels >
      or = 10(-2) cells at this time. The data demonstrate that patients with TEL/AML1
      positive ALL had a better response to induction chemotherapy on Day + 33 compared
      with a group of unselected patients with ALL (P = 0.0001). However, four patients
      with TEL/AML1 positive ALL developed relapse disease. Remarkably, these children
      were positive for MRD on Day + 33 at a level between 10(-2) cells and 10(-4) (n =
      3 patients) and at < 10(-4) (n = 1 patient). Kaplan-Meier analysis of disease
      free survival showed the statistical significance of this distribution (MRD
      positive vs. MRD negative; log-rank P = 0.0016). CONCLUSIONS: The authors
      conclude that, although the TEL/AML1 positive leukemias generally are associated
      with a favorable outcome, MRD positivity assessed by RQ-RT-PCR analysis at the
      end of induction therapy represents a significantly negative prognostic feature.

PMID- 12491512
TI  - Phase II study of cladribine and cyclophosphamide in patients with chronic
      lymphocytic leukemia and prolymphocytic leukemia.
AB  - BACKGROUND: One of the mechanisms of action of cladribine is the inhibition of
      DNA repair of damage caused by radiation, alkylating agents, or other drugs. To
      determine its antitumor activity in combination with cyclophosphamide, we
      initiated a Phase II trial of the two agents in patients with advanced chronic
      lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL). METHODS: Twenty-nine
      patients with refractory or recurrent CLL or PLL received cladribine 4
      mg/m(2)/day and cyclophosphamide 350 mg/m(2)/day (both administered
      intravenously) for 3 days every 4 weeks. RESULTS: Eleven patients (38%), nine
      with CLL and two with PLL, had a response. The median duration of response was 12
      months. Severe extrahematologic toxicity (National Cancer Institute Grade 3-4)
      occurred in two patients, consisting of skin rash in one patient and progressive
      multifocal leukoencephalopathy in the other. The most common form of hematologic
      toxicity was severe neutropenia, which developed after 25% of the 84 courses was
      administered. Severe thrombocytopenia and anemia developed after 12% and 7% of
      the courses, respectively, and five episodes of anemia were immunomediated. In
      addition, three major infections resulted in the death of one patient.
      CONCLUSIONS: Although inferior to the combination fludarabine plus
      cyclophosphamide, this regimen showed interesting activity in patients with
      advanced CLL or PLL. Myelosuppression was the major dose-limiting toxic effect.

PMID- 12491513
TI  - Temozolomide in combination with interferon alpha-2b in patients with metastatic
      melanoma: a phase I dose-escalation study.
AB  - BACKGROUND: Metastatic melanoma (MM) is associated with a high risk of central
      nervous system (CNS) metastases, and current chemotherapy does not adequately
      treat or protect patients with MM against CNS metastases. Therefore, the authors
      initiated a Phase I study to determine the pharmacokinetics and safety profile of
      temozolomide (TMZ), a novel oral alkylating agent known to cross the blood-brain
      barrier, in combination with interferon alpha-2b (IFN-alpha2b). METHODS: Twenty
      three patients with MM were enrolled in this single-center, open-label study.
      Patients with CNS metastasis were excluded. One cohort (n = 6 patients) received
      oral TMZ (200 mg/m(2) per day) for 5 days every 28-day cycle plus subcutaneous
      IFN-alpha2b (5 million International Units [MIU]/m(2) per day, 3 times per week).
      A second cohort (n = 17 patients) received TMZ 150 mg/m(2) per day on the same
      schedule plus escalating doses of IFN-alpha2b (5.0 MIU/m(2) per day, 7.5 MIU/m(2)
      per day, and 10 MIU/m(2) per day 3 times per week). RESULTS: The most common
      adverse events were fatigue, fever, nausea/emesis, anxiety, and diarrhea. Most
      toxicity was mild to moderate in severity. The primary dose-limiting toxicity was
      thrombocytopenia. The maximum tolerated dose was either TMZ 150 mg/m(2) plus IFN
      alpha2b 7.5 MIU/m(2) or TMZ 200 mg/m(2) plus IFN-alpha2b 5.0 MIU/m(2). Four
      patients (17%) had objective responses (one complete response and three partial
      responses), and four patients had stable disease. The median survival was 9
      months. The pharmacokinetics of TMZ were not affected by coadministration of IFN
      alpha2b. CONCLUSIONS: TMZ can be combined safely with IFN-alpha2b. This regimen
      demonstrated clinical activity in patients with MM and merits further
      investigation to define its effect on the incidence of brain metastases.

PMID- 12491514
TI  - Is whole-brain irradiation necessary for primary central nervous system lymphoma?
      Patterns of recurrence after partial-brain irradiation.
AB  - BACKGROUND: Neurotoxicity after whole-brain irradiation remains a major problem
      in the treatment of primary central nervous system lymphoma (PCNSL). To clarify
      whether whole-brain radiation is necessary for PCNSL, the authors retrospectively
      analyzed the outcome of patients treated with partial-brain irradiation. METHODS:
      A nationwide survey was performed regarding the treatment of PCNSL. Among 62
      institutions surveyed, 7 were identified in which whole-brain irradiation was not
      necessarily employed. Questionnaires were sent to these institutions and 43
      patients who had been treated using partial-brain fields since 1985 were
      collected. Thirty-two patients had solitary lesions and 11 had multiple lesions.
      Patterns of recurrence could be identified in 38 patients. RESULTS: The
      cumulative in-field and out-field recurrence rates at 5 years were 57% and 49%,
      respectively. Of 14 out-field recurrences, 2 occurred at the safety margin of the
      previous radiation field. The out-field recurrence rate was 45% in patients with
      a single lesion and 67% in those with multiple tumors (P = 0.79). The out-field
      recurrence rate was 22% for patients treated with safety margins of > or = 4 cm
      and 83% for those treated with safety margins of < 4 cm (P = 0.0079). The median
      survival time and the 5-year survival rate were 28.5 months and 20%,
      respectively, in the former group of patients and 15 months and 11%,
      respectively, in the latter group (P = 0.057). CONCLUSIONS: Focal radiotherapy
      with safety margins of < 4 cm appears to be associated with a very high rate of
      out-field recurrence, but the use of a radiation field with generous safety
      margins (> or = 4 cm) appears to be worth further investigation.

PMID- 12491515
TI  - Racial/ethnic variation in clinical presentation, treatment, and survival among
      breast cancer patients under age 35.
AB  - BACKGROUND: The age specific breast cancer incidence rate for African-American
      women under age 35 is more than twice the rate for white women of similar age,
      and the mortality rate is more than three times higher. To determine factors that
      may explain racial/ethnic variation in outcomes among young women diagnosed with
      breast cancer, the authors examined the clinical presentation, treatment, and
      survival of African-American, Hispanic, and white women under age 35 years.
      METHODS: Surveillance, Epidemiology, and End Results (SEER) Program data for 1990
      1998 and SEER Patterns of Care data for 1990, 1991, and 1995 were used for this
      analysis. Multivariate logistic regression analyses were performed to examine
      factors associated with the receipt of selected breast cancer treatments. Kaplan
      Meier survival analyses and Cox proportional hazards regression analyses were
      used to examine 5-year overall survival and disease-specific survival. RESULTS:
      The authors found racial/ethnic variation in clinical presentation, treatment,
      and survival. Both African-American and Hispanic women presented with higher
      disease stage and a higher prevalence of adverse prognostic indicators compared
      to white women. African-American and Hispanic women received cancer-directed
      surgery and radiation less frequently after undergoing breast-conserving surgery.
      Racial/ethnic differences in clinical presentation and treatment were associated
      with poorer overall survival in unadjusted analyses. African-American and
      Hispanic women also had poorer overall survival after controlling for clinical
      and demographic characteristics and type of treatment. CONCLUSIONS: Future
      research studies should further examine the factors that influence racial/ethnic
      differences in incidence, clinical presentation, and treatment differentials
      among young women diagnosed with breast cancer. A better understanding of these
      factors will facilitate the development of strategies to help eliminate this
      health disparity.

PMID- 12491517
TI  - Cancer chronotherapy: principles, applications, and perspectives.
AB  - BACKGROUND: Cell physiology is regulated along the 24-hour timescale by a
      circadian clock, which is comprised of interconnected molecular loops involving
      at least nine genes. The cellular clocks are coordinated by the suprachiasmatic
      nucleus, a hypothalamic pacemaker that also helps the organism adjust to
      environmental cycles. The rest-activity rhythm is a reliable marker of the
      circadian system function in both rodents and humans. This circadian organization
      is responsible for predictable changes in the tolerability and efficacy of
      anticancer agents, and possibly also may be involved in tumor promotion or
      growth. METHODS: Expected least toxic times of chemotherapy were extrapolated
      from experimental models to human subjects with reference to the rest-activity
      cycle. The clinical relevance of the chronotherapy principle (i.e., treatment
      administration as a function of rhythms) has been investigated previously in
      randomized multicenter trials. RESULTS: In the current study, chronotherapeutic
      schedules were used to safely document activity of the combination of
      oxaliplatin, 5-fluorouracil, and leucovorin against metastatic colorectal
      carcinoma and to establish new medicosurgical management for this disease, and
      were reported to result in unprecedented long-term survival. CONCLUSIONS:
      Chronotherapy concepts appear to offer further potential to improve current
      cancer treatment options as well as to optimize the development of new anticancer
      or supportive agents.

PMID- 12491516
TI  - A Phase I study of 9-nitrocamptothecin given concurrently with capecitabine in
      patients with refractory, metastatic solid tumors.
AB  - BACKGROUND: 9-Nitrocamptothecin (9-NC) is an orally available camptothecin analog
      with antineoplastic activity that results from the inhibition of DNA
      topoisomerase I. Previous studies have suggested that it has significant clinical
      efficacy. The primary toxicities of 9-NC include gastrointestinal upset,
      cystitis, and myelosuppression at the maximum tolerated dose (MTD) of 1.5 mg/m(2)
      per day. Capecitabine is a prodrug of 5-fluorouracil that is approved for use in
      patients with metastatic breast carcinoma and colorectal carcinoma, and it offers
      the convenience of oral administration. This trial examined the combination of
      these two oral agents in patients with metastatic solid tumors. METHODS:
      Capecitabine was administered twice daily at a total daily dose of 1300 mg/m(2)
      per day for 14 days followed by a 1-week break. 9-NC was taken daily 5 days per
      week for 2 weeks in a dose-escalation scheme. The starting dose was 0.5 mg/m(2)
      per day, and cohorts of 3 patients were enrolled until the dose level reached
      1.25 mg/m(2) per day. RESULTS: Twenty-one patients were evaluable for toxicity
      and response, and nausea and emesis were the dose-limiting toxicities. Despite
      antiemetic prophylaxis with 5-hydroxytryptamine-3 antagonists, 2 of 3 patients at
      the 1.0 mg/m(2) per day dose level had Grade 2-3 nausea; while at the MTD of 0.75
      mg/m(2) per day, 3 of 14 patients had Grade > or = 2 nausea. The incidence of
      hand-foot syndrome, stomatitis, diarrhea, and myelosuppression did not exceed
      that expected with capecitabine alone, suggesting that 9-NC does not exacerbate
      these side effects. No objective responses were seen. Stable disease was observed
      in 9 patients (43%) with a median duration of 11 weeks, including 3 patients with
      responses that lasted from 20 weeks to 40 weeks. CONCLUSIONS: The combination of
      9-NC and capecitabine with the current schedule was limited in dose by nausea and
      had minimal clinical efficacy in a group of patients with refractory solid
      tumors.

PMID- 12491518
TI  - Phase I trial of weekly docetaxel and gemcitabine in patients with refractory
      malignancies.
AB  - BACKGROUND: A Phase I study using weekly docetaxel and gemcitabine was conducted
      to investigate toxicity; to determine the maximum tolerated dose (MTD) of each
      agent; and, in a preliminary fashion, to determine the antitumor activity of the
      combination. METHODS: Docetaxel and gemcitabine were administered intravenously
      on Days 1, 8, and 15 every 28 days. The dose levels of docetaxel and gemcitabine
      were as follows: Level I, docetaxel 20 mg/m(2)and gemcitabine 400 mg/m(2); Level
      II, docetaxel 30 mg/m(2)and gemcitabine 400 mg/m(2); Level III, docetaxel 30
      mg/m(2)and gemcitabine 600 mg/m(2); Level IV, docetaxel 36 mg/m(2)and gemcitabine
      600 mg/m(2); and Level V, docetaxel 36 mg/m(2)and gemcitabine 800 mg/m(2).
      RESULTS: Thirty-three eligible patients were entered. The diagnoses were as
      follows: Eleven patients had nonsmall cell lung carcinoma, 3 patients had
      carcinoma of the bladder, 3 patients had renal carcinoma, 2 patients had adrenal
      carcinoma, 5 patients had unknown primary tumors, and 9 patients had
      miscellaneous malignancies. Fifty-nine percent of patients had received prior
      chemotherapy. The median age was 62 years (range, 27-77 years), and the median
      Eastern Cooperative Oncology Group performance status was 1 (range, 0-1). Five
      patients were treated at Dose Levels I and II, 6 patients were treated at Dose
      Levels III and V, and 11 patients were treated at Dose Level IV. Grade 3-4
      toxicities during Cycle I included neutropenia, thrombocytopenia, mucositis, and
      diarrhea. Dose-limiting toxicity, consisting of neutropenia and thrombocytopenia,
      occurred in three of six patients at Dose Level V. The combination of docetaxel
      36 mg/m(2) and gemcitabine 600 mg/m(2) (Dose Level IV) was determined as the MTD
      and was the recommended Phase II dose. Two patients had a partial response: one
      patient with bladder carcinoma (Dose Level II) and one patient with nonsmall cell
      lung carcinoma (Dose Level III). CONCLUSIONS: Overall, weekly docetaxel and
      gemcitabine were well tolerated. Further studies using this combination are
      planned, including a Phase II trial in patients with advanced nonsmall cell lung
      carcinoma.

PMID- 12491519
TI  - Long-term results of three-dimensional conformal radiation therapy for patients
      with rhabdomyosarcoma.
AB  - BACKGROUND: The authors evaluated the outcome of patients with rhabdomyosarcoma
      (RMS) who were treated with three-dimensional (3D) conformal radiation therapy
      (RT) at a single institution. METHODS: The records of all 69 patients with RMS
      who received 3D RT from 1989 to 2001 were reviewed. All patients received
      multiagent chemotherapy with or without surgical resection. Follow-up of
      surviving patients ranged from 1.0 year to 12.8 years (median, 4.3 years).
      RESULTS: The median patient age was 6 years (range, 1-29 years), and there was a
      male:female ratio of 1.5:1. Forty-eight patients had embryonal sarcomas, 14
      patients had alveolar sarcomas, and 7 patients had undifferentiated sarcomas. The
      parameningeal area (n = 22 patients) and the trunk (n = 21 patients) were the
      most common sites. Twelve percent of patients had Stage I disease, 10% of
      patients had Stage II disease, 51% of patients had Stage III disease, and 27% of
      patients had Stage V disease. Nine percent of patients were in clinical Group II,
      64% of patients were in Group III, and 27% of patients were in Group IV. Regional
      lymph nodes were involved in 33% of patients, and 77% of tumors measured > or = 5
      cm in greatest dimension. The actuarial 5-year local and regional control rates
      were 90% and 91%, respectively. No predictive factors for local failure were
      identified; however, alveolar histology was correlated with regional recurrence
      (29% compared with 4%; P = 0.02). The disease free and overall survival rates
      were 60% and 63% at 5 years, respectively. Disease stage was most predictive of 5
      year survival (76% of patients with Stage I-III disease compared with 24% of
      patients with Stage IV disease; P < 0.001). CONCLUSIONS: High rates of local
      control were achieved in patients with RMS using 3D RT. Regional lymph node
      failure was increased significantly among patients with alveolar histology.
      Control of metastatic disease remains a formidable problem for patients with
      Stage IV RMS.

PMID- 12491520
TI  - Granulocyte-macrophage-colony-stimulating factor added to a multipeptide vaccine
      for resected Stage II melanoma.
AB  - BACKGROUND: Forty-eight patients with resected Stages IIA and IIB melanoma were
      immunized with two tumor antigen epitope peptides derived from gp100(209-217)
      (210M) (IMDQVPSFV) and tyrosinase(368-376) (370D) (YMDGTMSQV) emulsified with
      incomplete Freund's adjuvant (IFA). Patients were assigned randomly to receive
      either peptides/IFA alone or with 250 microm of granulocyte-macrophage-colony
      stimulating factor (GM-CSF) subcutaneously daily for 5 days to evaluate the
      toxicities and immune responses in either arm. Time to recurrence and survival
      were secondary end points. METHODS: Immunizations were administered every 2 weeks
      x 4, then every 4 weeks x 3, and once 8 weeks later. A leukapheresis to obtain
      peripheral blood mononuclear cells for immune analyses and skin testing with
      peptides and recall reagents was performed before and after eight vaccinations.
      RESULTS: Local pain and granuloma formation, fever, and lethargy of Grade 1 or 2
      were observed. Transient vaccine-related Grade III and no Grade IV toxicity was
      observed. Seventeen of the 40 patients for whom posttreatment skin tests were
      performed developed a positive skin test response to the gp100 peptide, but only
      1 of the 40 patients developed a positive skin test response to tyrosinase.
      Immune responses were measured by release of interferon-gamma (IFN-gamma) in an
      enzyme-linked immunosorbent assay (ELISA) by effector cells in the presence of
      peptide-pulsed antigen-presenting cells, by cytokine release of IFN-gamma, GM
      CSF, and tumor necrosis factor-alpha in a Luminex assay, or by an antigen
      specific tetramer flow cytometry assay. Thirty-four of the 39 patients for whom
      the ELISA data were performed demonstrated an immune response after vaccination,
      as did 37 of 42 patients by tetramer assay. Enzyme-linked immunosorbent assay,
      Luminex, and tetramer responses in the GM-CSF/peptide/IFA group were higher than
      in the peptide/IFA group. Epitope spreading to the MART-1/MelanA 27-35 and 26-35
      (27L) epitopes was detected by tetramer assay in 10 patients. Seven of 48
      patients experienced disease recurrence with a median of 24 months of follow-up
      and 2 patients in this intermediate to high risk group have died. CONCLUSION:
      These data suggest a significant number of patients with resected melanoma mount
      an antigen-specific immune response against a peptide vaccine. There is a trend
      for GM-CSF to modestly increase the immune response and support further
      development of GM-CSF as a vaccine adjuvant.

PMID- 12491521
TI  - Circulating 92-kilodalton matrix metalloproteinase (MMP-9) activity is enhanced
      in the euglobulin plasma fraction of head and neck squamous cell carcinoma.

PMID- 12491523
TI  - Methyl-beta-cyclodextrin-enhanced solubilization and aerobic biodegradation of
      polychlorinated biphenyls in two aged-contaminated soils.
AB  - The bioremediation of aged polychlorinated biphenyl (PCB)-contaminated soils is
      adversely affected by the low bioavailability of the pollutants. Randomly
      methylated-beta-cyclodextrins (RAMEB) were tested as a potential PCB
      bioavailability-enhancing agent in the aerobic treatment of two aged-contaminated
      soils. The soils, contaminated by about 890 and 8500 mg/kg of Aroclor 1260 PCBs,
      were amended with biphenyl (4 g/kg), inorganic nutrients (to adjust their C:N
      ratio to 20:1), and variable amounts of RAMEB (0%, 0.5%, or 1.0% [w/w]) and
      treated in both aerobic 3-L solid-phase reactors and 1.5-L packed-bed loop
      reactors for 6 months. Notably, significant enhancement of the PCB biodegradation
      and dechlorination, along with a detectable depletion of the initial soil
      ecotoxicity, were generally observed in the RAMEB-treated reactors of both soils.
      RAMEB effects were different in the two soils, depending upon the treatment
      conditions employed, and generally increased proportionally with the
      concentration at which RAMEB was applied. RAMEB, which was slowly metabolized by
      the soil's aerobic microorganisms, was found to markedly enhance the occurrence
      of the indigenous aerobic, cultivable biphenyl-growing bacteria harboring genes
      homologous to those of two highly specialized PCB degraders (i.e., bphABC genes
      of Pseudomonas pseudoalcaligenes KF707 and bphA1A2A3A4BC1 genes of Rhodococcus
      globerulus P6) and chlorobenzoic acid-degrading bacteria as well as the
      occurrence of PCBs in the water phase of the soil reactors. These findings
      indicate that RAMEB enhanced the aerobic bioremediation of the two soils by
      increasing the bioavailability of PCBs and the occurrence of specialized bacteria
      in the soil reactors.

PMID- 12491524
TI  - A combinatorial biocatalysis approach to an array of cholic acid derivatives.
AB  - A 39-member library of bile acid derivatives was prepared starting from
      3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-oic acid methyl ester using a
      combinatorial biocatalytic approach. A regioselective oxidation step, catalyzed
      by hydroxysteroid dehydrogenases, followed by an acylation step with a series of
      different acyl donors catalyzed by Candida antarctica lipase B, led to the
      modification of the bile acid scaffold. Each member of the library was obtained
      in high purity and good yield.

PMID- 12491525
TI  - Enrichment of denitrifying glycogen-accumulating organisms in anaerobic/anoxic
      activated sludge system.
AB  - Denitrifying glycogen-accumulating organisms (DGAO) were successfully enriched in
      a lab-scale sequencing batch reactor (SBR) running with anaerobic/anoxic cycles
      and acetate feeding during the anaerobic period. Acetate was completely taken up
      anaerobically, which was accompanied by the consumption of glycogen and the
      production of poly-beta-hydroxy-alkanoates (PHA). In the subsequent anoxic stage,
      nitrate or nitrite was utilized as electron acceptor for the oxidation of PHA,
      resulting in glycogen replenishment and cell growth. The above phenotype showed
      by the enrichment culture demonstrates the existence of DGAO. Further, it was
      found that the anaerobic behavior of DGAO could be predicted well by the
      anaerobic GAO model of Filipe et al. (2001) and Zeng et al. (2002a). The final
      product of denitrification during anoxic stage was mainly nitrous oxide (N(2)O)
      rather than N(2). The data strongly suggests that N(2)O production may be caused
      by the inhibition of nitrous oxide reductase by an elevated level of nitrite
      accumulated during denitrification. The existence of these organisms is a concern
      in biological nutrient removal systems that typically have an
      anaerobic/anoxic/aerobic reactor sequence since they are potential competitors to
      the polyphosphate-accumulating organisms.

PMID- 12491526
TI  - Measurement of strain-dependent toxicity in the indene bioconversion using
      multiparameter flow cytometry.
AB  - The bionconversion of indene to cis-(1S,2R)-indandiol, a potential key
      intermediate in the synthesis of Merck's HIV protease inhibitor, CRIXIVAN trade
      mark, can be achieved using Rhodococcus, Pseudomonas putida, and Escherichia coli
      strains. This study reports on the application of multiparameter flow cytometry
      for the measurement of cytoplasmic membrane integrity and membrane depolarization
      as indicators of toxic effects of the substrate, product, and by-products using
      each of these strains. Measurements of oxygen uptake rate (OUR) and optical
      density (OD) as indicators of metabolic activity and biomass growth,
      respectively, were also made. Measurements of the cytoplasmic membrane potential,
      cell viability, and respiratory activity provided a sensitive set of parameters
      to assess toxicity in the indene bioconversion and provided the basis for process
      improvements and strain selection. The toxic concentrations of the substrate,
      product, and by-products for each strain have been determined. The results show
      that it is possible to accumulate cis-(1S,2R)-indandiol and cis-1-amino-2-indanol
      up to 20 g/L without significant negative effects on cell physiology using any of
      the strains tested. The Gram-negative P. putida (421-5 and GM 730) and E. coli
      strains were more resistant to indene and the isolated chemicals of the
      biotransformation than the Gram-positive Rhodoccoccus I24 strain, possibly due to
      the presence of the outer membrane and efflux pump mechanisms. P. putida GM 730
      and the E. coli TDO 123 strains responded similarly to toxic effects, and the E.
      coli TDO 123 strain was more resistant than the P. putida 421-5 strain. In
      addition to the recommendations for strain selection, the identified targets for
      bioprocess improvement include a combination of genetic as well as process
      engineering approaches.

PMID- 12491527
TI  - Bioimmobilization of keratinase using Bacillus subtilis and Escherichia coli
      systems.
AB  - Immobilized keratinase can improve stability while retaining its proteolytic and
      keratinolytic properties. Conventional purification followed by chemical
      immobilization is a laborious and costly process. A new genetic construct was
      developed to produce the keratinase-streptavidin fusion protein. Consequently,
      the purification and immobilization of the fusion protein onto a biotinylated
      matrix can be accomplished in a single step. The method was tested in both the
      Bacillus subtilis and Escherichia coli systems. In B. subtilis, the fusion
      protein was produced extracellularly and readily immobilized from the medium. In
      E. coli, the fusion protein was produced intracellularly in inclusion bodies;
      additional separation and renaturation processes were required prior to
      immobilization from the cell extract. The overall efficiencies were approximately
      the same, 24-28%, using both systems.

PMID- 12491528
TI  - Geminivirus vectors for high-level expression of foreign proteins in plant cells.
AB  - Bean yellow dwarf virus (BeYDV) is a monopartite geminivirus that can infect
      dicotyledonous plants. We have developed a high-level expression system that
      utilizes elements of the replication machinery of this single-stranded DNA virus.
      The replication initiator protein (Rep) mediates release and replication of a
      replicon from a DNA construct ("LSL vector") that contains an expression cassette
      for a gene of interest flanked by cis-acting elements of the virus. We used
      tobacco NT1 cells and biolistic delivery of plasmid DNA for evaluation of
      replication and expression of reporter genes contained within an LSL vector. By
      codelivery of a GUS reporter-LSL vector and a Rep-supplying vector, we obtained
      up to 40-fold increase in expression levels compared to delivery of the reporter
      LSL vectors alone. High-copy replication of the LSL vector was correlated with
      enhanced expression of GUS. Rep expression using a whole BeYDV clone, a
      cauliflower mosaic virus 35S promoter driving either genomic rep or an intron
      deleted rep gene, or 35S-rep contained in the LSL vector all achieved efficient
      replication and enhancement of GUS expression. We anticipate that this system can
      be adapted for use in transgenic plants or plant cell cultures with appropriately
      regulated expression of Rep, with the potential to greatly increase yield of
      recombinant proteins.

PMID- 12491529
TI  - Use of confocal microscopy to follow the development of penetrative hyphae during
      growth of Rhizopus oligosporus in an artificial solid-state fermentation system.
AB  - Two methods were compared for determining the concentration of penetrative
      biomass during growth of Rhizopus oligosporus on an artificial solid substrate
      consisting of an inert gel and starch as the sole source of carbon and energy.
      The first method was based on the use of a hand microtome to make sections of
      approximately 0.2- to 0.4-mm thickness parallel to the substrate surface and the
      determination of the glucosamine content in each slice. Use of glucosamine
      measurements to estimate biomass concentrations was shown to be problematic due
      to the large variations in glucosamine content with mycelial age. The second
      method was a novel method based on the use of confocal scanning laser microscopy
      to estimate the fractional volume occupied by the biomass. Although it is not
      simple to translate fractional volumes into dry weights of hyphae due to the lack
      of experimentally determined conversion factors, measurement of the fractional
      volumes in themselves is useful for characterizing fungal penetration into the
      substrate. Growth of penetrative biomass in the artificial model substrate showed
      two forms of growth with an indistinct mass in the region close to the substrate
      surface and a few hyphae penetrating perpendicularly to the surface in regions
      further away from the substrate surface. The biomass profiles against depth
      obtained from the confocal microscopy showed two linear regions on log-linear
      plots, which are possibly related to different oxygen availability at different
      depths within the substrate. Confocal microscopy has the potential to be a
      powerful tool in the investigation of fungal growth mechanisms in solid-state
      fermentation.

PMID- 12491530
TI  - Determination of in vivo oxygen uptake and carbon dioxide evolution rates from
      off-gas measurements under highly dynamic conditions.
AB  - In vivo kinetics of Saccharomyces cerevisiae are studied, in a time window of 150
      s, by analyzing the response of O(2) and CO(2) in the fermentor off-gas after
      perturbation of chemostat cultures by metabolite pulses. Here, a new mathematical
      method is presented for the estimation of the in vivo oxygen uptake rate (OUR)
      and carbon dioxide evolution rate (CER) directly from the off-gas data in such
      perturbation experiments. The mathematical construction allows effective
      elimination of delay and distortion in the off-gas measurement signal under
      highly dynamic conditions. A black box model for the fermentor off-gas system is
      first obtained by system identification, followed by the construction of an
      optimal linear filter, based on the identified off-gas model. The method is
      applied to glucose and ethanol pulses performed on chemostat cultures of S.
      cerevisiae. The estimated OUR is shown to be consistent with the independent
      dissolved oxygen measurement. The estimated in vivo OUR and CER provide valuable
      insights into the complex dynamic behavior of yeast and are essential for the
      establishment and validation of in vivo kinetic models of primary metabolism.

PMID- 12491531
TI  - A mechanistic model of photosynthesis in microalgae.
AB  - A dynamic model of photosynthesis is developed, accounting for factors such as
      photoadaptation, photoinhibition, and the "flashing light effect." The model is
      shown to explain the reported photosynthesis-irradiance responses observed under
      various conditions (constant low light, constant intense irradiance, flashing
      light, diurnal variation in irradiance). As significant distinguishing features,
      the model assumes: (1) The stored photochemical energy is consumed in an enzyme
      mediated process that obeys Michaelis-Menten kinetics; and (2) photoinhibition
      has a square-root dependence on irradiance. Earlier dynamic models of
      photosynthesis assumed a first-order dependence of photoinhibition on irradiance
      and different kinetics of consumption of the stored energy than used in this
      work. These earlier models could not explain the photosynthesis-irradiance
      behavior under the full range of irradiance scenarios-a shortcoming that is
      overcome in the model developed in this work.

PMID- 12491532
TI  - Maximization of hydrogen production ability in high-density suspension of
      Rhodovulum sulfidophilum cells using intracellular poly(3-hydroxybutyrate) as
      sole substrate.
AB  - Growth of and hydrogen production by wild-type (WT) Rhodovulum sulfidophilum were
      compared with those by one of its mutants lacking the poly(3-hydroxybutyrate)
      (PHB) biosynthesis ability (PNM2). During phototrophic growth under aerobic
      conditions with fixed illumination, changes in the extinction coefficient and PHB
      content of WT and PNM2 cells revealed interference of light penetration by PHB.
      WT cells synthesized PHB at an early stage of the cultivation. PHB degradation
      after exhaustion of acetate during the cultivation of WT resulted in a decrease
      of the extinction coefficient. The hydrogen production rate under anaerobic
      conditions with fixed illumination was examined in WT and PNM2 cell suspensions
      at different densities. The hydrogen production rate was determined not by the
      light penetration but by the kinds of hydrogen donors and the density of
      suspension. The highest value of the rate of hydrogen production from PHB, 33.0
      ml/l/h, was improved compared with 26.6 ml/l/h, which was the highest value in
      hydrogen production from succinate. Under the same illumination, conversion to
      hydrogen from PHB is more efficient than that from succinate, which is one of the
      best substrates for hydrogen production. These results suggest that the hydrogen
      production rate can be maximized in the hydrogen production system based on PHB
      degradation, which is achieved in high-density suspension under external
      substrate-depleted conditions after aerobic cultivation in the presence of an
      excess amount of acetate.

PMID- 12491533
TI  - Development of a novel titration and off-gas analysis (TOGA) sensor for study of
      biological processes in wastewater treatment systems.
AB  - The development of the new TOGA (titration and off-gas analysis) sensor for the
      detailed study of biological processes in wastewater treatment systems is
      outlined. The main innovation of the sensor is the amalgamation of titrimetric
      and off-gas measurement techniques. The resulting measured signals are: hydrogen
      ion production rate (HPR), oxygen transfer rate (OTR), nitrogen transfer rate
      (NTR), and carbon dioxide transfer rate (CTR). While OTR and NTR are applicable
      to aerobic and anoxic conditions, respectively, HPR and CTR are useful signals
      under all of the conditions found in biological wastewater treatment systems,
      namely, aerobic, anoxic and anaerobic. The sensor is therefore a powerful tool
      for studying the key biological processes under all these conditions. A major
      benefit from the integration of the titrimetric and off-gas analysis methods is
      that the acid/base buffering systems, in particular the bicarbonate system, are
      properly accounted for. Experimental data resulting from the TOGA sensor in
      aerobic, anoxic, and anaerobic conditions demonstrates the strength of the new
      sensor. In the aerobic environment, carbon oxidation (using acetate as an example
      carbon source) and nitrification are studied. Both the carbon and ammonia removal
      rates measured by the sensor compare very well with those obtained from off-line
      chemical analysis. Further, the aerobic acetate removal process is examined at a
      fundamental level using the metabolic pathway and stoichiometry established in
      the literature, whereby the rate of formation of storage products is identified.
      Under anoxic conditions, the denitrification process is monitored and, again, the
      measured rate of nitrogen gas transfer (NTR) matches well with the removal of the
      oxidised nitrogen compounds (measured chemically). In the anaerobic environment,
      the enhanced biological phosphorus process was investigated. In this case, the
      measured sensor signals (HPR and CTR) resulting from acetate uptake were used to
      determine the ratio of the rates of carbon dioxide production by competing groups
      of microorganisms, which consequently is a measure of the activity of these
      organisms. The sensor involves the use of expensive equipment such as a mass
      spectrometer and requires special gases to operate, thus incurring significant
      capital and operational costs. This makes the sensor more an advanced laboratory
      tool than an on-line sensor.

PMID- 12491534
TI  - Transfection of NS0 myeloma fusion partner cells with HSP70 gene results in
      higher hybridoma yield by improving cellular resistance to apoptosis.
AB  - Mouse myeloma NS0 cells widely used in hybridoma technology lack the expression
      of a major stress protein Hsp70 which is the principal component of the basic
      cellular defense mechanism. These cells rapidly undergo apoptosis at the late
      stationary phase of batch culture following nutrient exhaustion. Since Hsp70 was
      recently demonstrated to protect cells against numerous apoptotic stimuli, the
      aim of the present study was to examine the protective potential of the protein
      expression in engineered myeloma NS0 cells and in resulting hybridomas. Myeloma
      cells were transfected with the hsp70 gene under beta-actin gene promoter. To
      imitate harmful conditions that hybridoma or myeloma cells often experience when
      cultivated in large scale for an antibody production, NS0(wt) and NS0(hsp70) cell
      cultures were maintained without changing the medium for a few days, and the
      expression of apoptotic markers has been studied. It was found that long-term
      cultivation induced apoptosis in original cells manifested by typical nuclei
      fragmentation, DNA ladders and activation of caspase-3. In contrast, in
      transfected cells under the same conditions the outcome of apoptosis was
      postponed for 24 hours. Most relevant was that the fusion of transfected myeloma
      cells with immune splenocytes resulted in twofold hybridomas output compared with
      wild-type fusion partner. Almost half of the hybridomas continued to be hsp70
      positive and maintained higher robustness in culture. The level of monoclonal
      antibodies production by hybridoma cells obtained with the use of NS0(wt) and
      NS0(hsp70) was similar, however, the secreted product was better preserved in
      culture supernatants of Hsp70-positive cells. It is concluded that transfection
      of mouse myeloma cells with the hsp70 gene can be a novel means to increase
      hybridoma yield and reduce the sensitivity of myeloma and hybridoma cells to
      culture conditions insults accompanying monoclonal antibody production.

PMID- 12491536
TI  - Molecular determinants of glucagon receptor signaling.
AB  - A 29-amino acid polypeptide hormone, glucagon has been one of the most prolific
      models in the study of hormone action. The key biologic function of glucagon is
      to counterbalance the actions of insulin and maintain a normal level of serum
      glucose. Diabetes mellitus can thus be considered a bihormonal disorder with an
      excess of glucagon contributing to the hyperglycemic state. The effects of
      glucagon are mediated by the glucagon receptor, which is itself a prototypical
      member of a distinct category called family B receptors within the G protein
      coupled superfamily of seven-helical transmembrane receptors (GPCRs). At the
      structural level, the peptide ligands of family B receptors are highly
      homologous, in particular in the N-terminal region of the molecules. The
      mechanism by which highly homologous peptide ligands selectively recognize their
      receptors involves distinct molecular interactions that are gradually being
      elucidated. This review focuses on structural determinants of the glucagon
      receptor that are important for its activity with respect to interaction with its
      ligand and G proteins. Information about the glucagon receptor is presented
      within the context of what is known about other members of the family B GPCRs.

PMID- 12491537
TI  - Mode of action of membrane active antimicrobial peptides.
AB  - Water-membrane soluble protein and peptide toxins are used in the defense and
      offense systems of all organisms, including plants and humans. A major group
      includes antimicrobial peptides, which serve as a nonspecific defense system that
      complements the highly specific cell-mediated immune response. The increasing
      resistance of bacteria to conventional antibiotics stimulated the isolation and
      characterization of many antimicrobial peptides for potential use as new target
      antibiotics. The finding of thousands of antimicrobial peptides with variable
      lengths and sequences, all of which are active at similar concentrations,
      suggests a general mechanism for killing bacteria rather than a specific
      mechanism that requires preferred active structures. Such a mechanism is in
      agreement with the "carpet model" that does not require any specific structure or
      sequence. It seems that when there is an appropriate balance between
      hydrophobicity and a net positive charge the peptides are active on bacteria.
      However, selective activity depends also on other parameters, such as the volume
      of the molecule, its structure, and its oligomeric state in solution and
      membranes. Further, although many studies support that bacterial membrane damage
      is a lethal event for bacteria, other studies point to a multihit mechanism in
      which the peptide binds to several targets in the cytoplasmic region of the
      bacteria.

PMID- 12491538
TI  - Structure and function of membrane fusion peptides.
AB  - Membrane fusion peptides are highly conserved hydrophobic domains of fusion
      proteins that insert into membranes during membrane fusion. Recent success with
      solving the structures of the influenza hemagglutinin fusion peptide and some
      critical mutants of this peptide in membrane environments at high resolution has
      led to a new understanding of the mechanism of membrane fusion. This review
      highlights the structures that have been solved and summarizes recent
      thermodynamic and spectroscopic studies on the interactions of this interesting
      class of peptides with lipid bilayers.

PMID- 12491539
TI  - Chemistry and biology of the ramoplanin family of peptide antibiotics.
AB  - The peptide antibiotic ramoplanin factor A2 is a promising clinical candidate for
      treatment of Gram-positive bacterial infections that are resistant to antibiotics
      such as glycopeptides, macrolides, and penicillins. Since its discovery in 1984,
      no clinical or laboratory-generated resistance to this antibiotic has been
      reported. The mechanism of action of ramoplanin involves sequestration of
      peptidoglycan biosynthesis Lipid intermediates, thus physically occluding these
      substrates from proper utilization by the late-stage peptidoglycan biosynthesis
      enzymes MurG and the transglycosylases (TGases). Ramoplanin is structurally
      related to two cell wall active lipodepsipeptide antibiotics, janiemycin, and
      enduracidin, and is functionally related to members of the lantibiotic class of
      antimicrobial peptides (mersacidin, actagardine, nisin, and epidermin) and
      glycopeptide antibiotics (vancomycin and teicoplanin). Peptidomimetic
      chemotherapeutics derived from the ramoplanin sequence may find future use as
      antibiotics against vancomycin-resistant Enterococcus faecium (VRE), methicillin
      resistant Staphylococcus aureus (MRSA), and related pathogens. Here we review the
      chemistry and biology of the ramoplanins including its discovery, structure
      elucidation, biosynthesis, antimicrobial activity, mechanism of action, and total
      synthesis.

PMID- 12491540
TI  - Anaesthetic considerations for laparoscopic cholecystectomy.
AB  - Minimally invasive surgical procedures aim to minimize the trauma of the
      interventional process but still achieve a satisfactory therapeutic result.
      Tissue trauma is significantly less than that with conventional open procedures,
      offering the advantages of reduced post-operative pain, shorter hospital stay,
      more rapid return to normal activities and significant cost savings. Laparoscopic
      cholecystectomy is now a routinely performed procedure and has replaced
      conventional open cholecystectomy as the procedure of choice for symptomatic
      cholelithiasis. Public expectation and developments in instrumentation have
      fuelled this change. The physiological effects of intraperitoneal carbon dioxide
      insufflation combined with variations in patient positioning can have a major
      impact on cardiorespiratory function, particularly in elderly patients with co
      morbidities. Intra-operative complications may include traumatic injuries
      associated with blind trocar insertion, gas embolism, pneumothorax and surgical
      emphysema associated with extraperitoneal insufflation. Appropriate monitoring
      and a high index of suspicion can result in early diagnosis of, and treatment of,
      complications. Laparoscopic cholecystectomy has proven to be a major advance in
      the treatment of patients with symptomatic gallbladder disease.

PMID- 12491541
TI  - Anaesthesia for minimally invasive gastric and bowel surgery.
AB  - It is of great importance that anaesthetic regimens match surgical procedures in
      regard to surgical time, in reducing organ dysfunction elicited by the
      anaesthesia and surgical trauma and by providing optimal post-operative pain
      treatment, leaving the possibility of early mobilization. New, rapidly eliminated
      anaesthetic drugs are, by virtue of their pharmacodynamic and pharmacokinetic
      profiles, optimal for use; combined with continuous thoracic epidurals with local
      anaesthetics and low-dose opioids, these drugs may permit reduction of various
      post-operative complications. Minimally invasive surgical techniques (e.g.
      laparoscopy) lead to serious anaesthesiological considerations concerning changes
      in haemodynamic and pulmonary parameters and intra-abdominal blood flow changes
      caused by increased intra-abdominal pressures. Few studies have evaluated whether
      these changes affect surgical outcome and whether or not different anaesthetic
      regimens influence relevant morbidity parameters. In future documentation it is
      important that controlled, well-designed clinical studies evaluate how the
      advantages from multimodal anaesthetic techniques improve relevant surgical
      outcome.

PMID- 12491542
TI  - Anaesthetic considerations for hysteroscopic surgery.
AB  - Use of the hysteroscope in modern gynaecological practice continues to develop as
      a diagnostic and management tool for intrauterine disease. Operative hysteroscopy
      (OH) is now an accepted alternative to hysterectomy for women with menorrhagia.
      The advantages of OH are associated with its short operating time, rapid post
      operative recovery and low morbidity. However, there are concerns about the
      potential serious complications which can occur during and following OH, and it
      is important that both surgeons and anaesthetists are aware of these--especially
      as many procedures take place as day-cases. Much has been written in the
      urological literature concerning complications of endoscopic surgery. Information
      gathered from patients with post-transurethral resection of the prostate (TURP)
      syndrome has been useful in the treatment of gynaecology patients. However, the
      techniques used in TURP are not entirely comparable to hysteroscopic surgery as
      the uterus has a very thick wall, which requires higher distension pressures. The
      main complications of OH are fluid overload, hyponatraemia, hypo-osmolality,
      haemorrhage, uterine perforation and, rarely, gas or air embolism. Fluid overload
      with hyponatraemia and hypo-osmolality occurs in up to 6% of cases and it can be
      fatal. Therefore, all possible measures should be taken to prevent it or to
      detect it and treat it early. There are no controlled studies comparing different
      anaesthetic techniques for OH. Regional anaesthesia may offer an advantage over
      general anaesthesia because it enables early detection of fluid overload. Great
      care should be taken when positioning the patient to prevent peripheral
      neuropathy.

PMID- 12491543
TI  - Anaesthesia for thoracoscopic surgery.
AB  - The surgical requirement for thoracoscopy is a good view of the contents of the
      thorax. This is achieved by capitalizing on natural consequences and the skills
      of anaesthesiologists to produce a pneumothorax and collapse the ipsilateral lung
      -a process that is commonly enhanced by insufflating carbon dioxide. Insufflating
      CO2 to actively promote lung collapse creates the dynamics of a tension
      pneumothorax. Complications are clinically insignificant if CO2 is used
      judiciously. There is a body of experience using ordinary endotracheal tubes and
      two-lung ventilation. Techniques of one-lung ventilation are more widely
      reported. All the factors known to contribute to the significant increase in
      shunt fraction associated with one-lung ventilation apply. The manoeuvre of
      collapsing a lung is no longer regarded as benign. Chemical attempts to produce a
      reversible post-pneumonectomy pulmonary circulation have not been shown to be an
      improvement. Post-operative pain can be severe. The mechanism is not defined but
      it differs from that associated with thoracotomy. Epidural analgesia and opioids
      may be required. Chronic pain syndromes have been described as complications.

PMID- 12491544
TI  - Anaesthesia for minimally invasive cardiac surgery.
AB  - Minimally invasive cardiac surgery is used for both extracardiac and intracardiac
      procedures. Extracardiac procedures, such as coronary artery bypass grafting, are
      often performed on a beating heart. Intracardiac procedures are done with the aid
      of cardiopulmonary bypass. The surgery is performed via a minithoracotomy or a
      ministernotomy. Thoracoscopic video-assisted surgery, often with robotic
      assistance, necessitates prolonged one-lung ventilation to optimize exposure.
      Port-access surgery will require appropriate positioning of various catheters to
      establish cardiopulmonary bypass. Adequate flow during cardiopulmonary bypass may
      require suction augmentation of venous return and may increase the risk of air
      emboli. Limited exposure of the heart during surgery poses challenges with
      management of arrhythmia, haemostasis, myocardial protection and de-airing at the
      end of surgery. Patient selection is important to avoid intra-operative and post
      operative complications. Prolonged single-lung ventilation, incomplete
      revascularization in hybrid procedures, and limited access for rapid intervention
      pose challenges with patient management. Conversion to sternotomy that may be
      required occasionally and extension of portals over several dermatomal segments
      mandate a versatile analgesic technique.

PMID- 12491545
TI  - Anaesthesia for minimally invasive neurosurgery.
AB  - Technological advances in imaging, computing and surgical instrumentation have
      encouraged the application of minimally invasive surgical techniques to various
      neurosurgical disorders. This chapter discusses the wide application of
      neurosurgery and the implications for anaesthesia, focusing on the specific
      anaesthetic considerations for neuroendoscopy, stereotactic procedures and
      radiosurgery.

PMID- 12491546
TI  - Anaesthesia and endovascular surgery.
AB  - Anaesthetic requirements for endovascular surgery for aortic, carotid and
      peripheral vascular disease are reviewed. Peculiarities of the surgery which may
      impinge on anaesthetic management are discussed together with the pre-operative
      assessment issues of particular relevance to patients with generalized vascular
      disease. The detailed anaesthetic management for carotid and aortic endovascular
      repair is addressed. The lowered peri-operative stress and general morbidity
      levels which occur with endovascular surgery allow sicker patients with greater
      risk factors to present for this type of surgery, thus increasing the challenges
      facing anaesthetists.

PMID- 12491547
TI  - Anaesthesia for minimally invasive surgery in children.
AB  - There continues to be an increase in the applications of minimally invasive
      surgical techniques in infants and children. This increase includes their use for
      new surgical procedures as well as their application in younger patients
      including neonates. As with any new surgical procedure, specific modifications of
      the anaesthetic technique may be necessary. This chapter reviews (1) the pre
      operative evaluation of infants and children scheduled for minimally invasive
      surgery; (2) techniques for pre-medication and anaesthetic induction; (3) intra
      operative anaesthetic implications of laparoscopy, including the
      cardiorespiratory consequences of CO2 pneumoperitoneum; (4) intra-operative
      anaesthetic implications of thoracoscopy, including techniques for one-lung
      ventilation (OLV); and (5) post-operative issues, including pain management and
      monitoring of cardiorespiratory function as they apply to the patient of
      paediatric age.

PMID- 12491548
TI  - Anaesthesia, minimally invasive surgery and pregnancy.
AB  - Minimally invasive surgery is being performed more frequently in pregnant
      patients. Numerous published reports have documented the safety and advantages of
      laparoscopic cholecystectomy and laparoscopic appendectomy during pregnancy.
      Pregnancy is associated with a variety of changes in the respiratory and
      cardiovascular systems, which make the parturient undergoing laparoscopic surgery
      particularly susceptible to hypoxia, hypercarbia and hypotension. This chapter
      provides a review of those physiological changes of pregnancy of particular
      concern for anaesthesiologists, and of the physiological responses to intra
      abdominal carbon dioxide insufflation, not only in healthy patients, but also in
      the altered physiological state associated with pregnancy. We also describe our
      approach to anaesthetic management for minimally invasive surgery during
      pregnancy. With appropriate precautions, including vigilant monitoring and
      anticipation and treatment of the potential adverse effects of carbon dioxide
      pneumoperitoneum, anaesthesiologists may provide safe care for these patients,
      and pregnant women can benefit from the advantages of minimally invasive surgery.

PMID- 12491549
TI  - Outcome after regional anaesthesia in the ambulatory setting--is it really worth
      it?
AB  - Regional anaesthesia provides a continuum of perioperative care that includes
      perioperative pain management, decreased opioid requirements and decreased post
      operative nausea and vomiting. In addition to these benefits, a wide variety of
      perioperative outcomes can be enhanced by utilizing regional anaesthesia in the
      ambulatory setting. Regional anaesthesia has been shown to improve the
      cardiovascular, pulmonary, gastrointestinal, coagulative, immunological and
      cognitive functions and to be of benefit in an economic context. These
      improvements are particularly advantageous in caring for elderly and high-risk
      patient populations undergoing surgery. In addition, regional anaesthesia can
      facilitate early recovery with excellent post-operative analgesia and few side
      effects, which may decrease overall operative costs. This chapter identifies
      important perioperative outcomes that may be positively influenced by the use of
      regional anaesthesia in the ambulatory setting.

PMID- 12491550
TI  - Paediatric regional anaesthesia--what makes a difference?
AB  - Regional anaesthetic techniques are useful for providing post-operative pain
      control for ambulatory surgery in children. This chapter focuses on unique
      features of paediatric anatomy and physiology that allow successful performance
      of these techniques. An overview of the effective use of long-acting local
      anaesthetics in children is presented. Combinations of local anaesthetics and
      adjunct medications that prolong caudal blockade, the most commonly performed
      paediatric block, are reviewed, with a goal of providing prolonged analgesia with
      minimal side-effects. An overview of the use of peripheral nerve blockade and
      specific recommendations for the use of these blocks in children is also
      presented.

PMID- 12491551
TI  - Making an ambulatory surgery centre suitable for regional anaesthesia.
AB  - This chapter reviews a management strategy for transforming an outpatient surgery
      centre from that which exclusively uses general anaesthesia to one using regional
      anaesthesia with peripheral nerve blocks. Barriers presented by patients, nursing
      staff, surgeons and administrators can be notable; these might undermine the well
      intended efforts of highly-skilled regionalists. Clearly, understanding the
      process benefits from the time the patient enters the facility until discharge
      home is essential, especially when presenting requests for support from facility
      administrators. Using a team approach is a logical place to start, as is defining
      new quality indicators and tracking patient outcomes. The centerpiece of the
      anaesthesia care process remains pre-emptive multimodal analgesia, routine
      multimodal antiemetic prophylaxis and avoidance of general anaesthesia (GA) with
      volatile agents. The remainder of the care process relies on teamwork among all
      healthcare providers and meaningful administrative support.

PMID- 12491552
TI  - Spinal anaesthesia: local anaesthetics and adjuncts in the ambulatory setting.
AB  - Intrathecal lidocaine remains a popular choice for ambulatory spinal anaesthesia
      due to its reliability, rapid onset and predictable rapid recovery profile.
      However, concerns with transient neurological symptoms (TNS) and their
      significant association with lidocaine have generated interest in alternative
      local anaesthetic agents to provide adequate spinal anaesthesia with the briefest
      possible recovery period. This chapter updates current data on drug dose-response
      relationships for local anaesthetics and the increasing use of intrathecal
      adjuncts to improve the anaesthetic and recovery profile for ambulatory spinal
      anaesthesia. Newer spinal anaesthetic techniques for common ambulatory procedures
      highlight the success of combining subclinical doses of local anaesthetics and
      intrathecal adjuncts. Controversies regarding the possible lower risk of TNS with
      newer spinal anaesthetic techniques and new discharge criteria are reviewed. The
      final section provides technical pearls to optimize ambulatory spinal anaesthetic
      outcomes.

PMID- 12491553
TI  - Anaesthesia for shoulder surgery.
AB  - Early and efficient rehabilitation is necessary for improving outcome after
      shoulder surgery. Pain, which is severe to very severe in this condition, is the
      major factor which compromises early physical therapy. Interscalene block is a
      well recognized and efficient technique for controlling pain after major open
      shoulder surgery. Among the different approaches which have been described, the
      modified lateral technique is the safest to perform and the most suitable for
      insertion of an interscalene catheter. A number of different techniques have been
      tried to control pain after shoulder surgery. However, the application of a
      continuous infusion of local anaesthetics through an interscalene catheter is
      actually the best technique available to achieve pain relief at rest and on
      movement after this type of surgery. This chapter emphasizes the advantages of
      the modified lateral approach, the use of patient-controlled interscalene
      analgesia and the traps and tricks of the interscalene block. Thus, this chapter
      demonstrates why interscalene anaesthesia and analgesia are the most appropriate
      techniques for shoulder surgery.

PMID- 12491554
TI  - Anaesthesia for procedures of the hand and elbow.
AB  - The majority of upper extremity surgeries are performed on an ambulatory basis
      under intravenous regional anaesthesia or brachial plexus blockade. The former
      technique is easy to perform, has a rapid onset and a high success rate but
      provides limited post-operative analgesia. Brachial plexus blockade provides
      excellent intraoperative anaesthesia as well as post-operative analgesia,
      eliminates the need for post-operative opioids, resulting in a decrease in
      recovery time, shortened hospital stay, increased patient satisfaction and
      ultimately a decrease in perioperative costs when compared with general
      anaesthesia. This chapter reviews upper extremity surgical procedures performed
      below the shoulder, the anaesthetic options available, and techniques used to
      optimize post-operative pain control.

PMID- 12491555
TI  - Single-injection applications for foot and ankle surgery.
AB  - Foot or ankle surgery is often performed in an ambulatory care setting. The post
      operative pain that follows can be moderate to severe in intensity and difficult
      to control with oral analgesics. Regional anaesthetic techniques have been
      advocated for such procedures. Wound infiltration with long-acting local
      anaesthetic provides post-operative pain relief which, though efficient, lasts
      for too short a time. Intravenous regional anaesthesia (IVRA) is a safe
      anaesthetic technique for minor surgery of short duration. It is not indicated
      for painful and/or complex procedures. Ankle block is convenient for most
      procedures but is somewhat less reliable than popliteal sciatic nerve block.
      Associated with a saphenous or femoral nerve block, posterior popliteal sciatic
      nerve block is the technique of choice. Patients can be safely discharged even
      when long-acting local anaesthetics are used. In major surgery a continuous
      technique can be proposed. When the prone position is impossible the lateral
      approach is an efficient alternative.

PMID- 12491556
TI  - Anaesthesia for outpatient knee surgery.
AB  - Surgical procedures of the knee are increasingly common in outpatient centres.
      Advances in arthroscopy and other technologies allow more complex knee procedures
      to be performed on an outpatient basis. This chapter focuses on the application
      and advantages of peripheral nerve block regional anaesthesia in the anaesthetic
      management of knee surgery patients. Specific nerve blocks and local anaesthetics
      suitable for various knee procedures are discussed. The use of perineural
      catheters in the outpatient management of major knee surgery patients is also
      considered.

PMID- 12491557
TI  - Paravertebral anaesthesia/analgesia for ambulatory surgery.
AB  - For many years, paravertebral nerve blockade has been an established technique
      for providing analgesia to the chest and abdomen. The current emphasis on
      containment of health care costs has resulted in a rediscovery of anaesthetic
      techniques, such as paravertebral blocks, that facilitate outpatient surgical
      management and promote early discharge. Paravertebral nerve blocks (PVB) produce
      excellent surgical conditions for many procedures of the chest and abdomen while
      providing profound long-lasting analgesia with few undesirable side-effects that
      aids in the compassionate early discharge of the patient from the ambulatory
      setting. This chapter reviews the pertinent anatomy and techniques involved in
      the successful placement of PVB. Continuous paravertebral catheters,
      pharmacological agents used in PVB, and single versus multiple injection
      paravertebral block techniques are also covered. Specific clinical situations
      that are particularly well suited to the application of PVB as the primary
      anaesthetic in the ambulatory setting and other clinical situations where
      analgesia from PVB is efficacious are discussed.

PMID- 12491558
TI  - Major surgery in the ambulatory environment: continuous catheters and home
      infusions.
AB  - The ability to provide continuous peripheral nerve blocks to patients safely on
      an outpatient basis has been a major advance in ambulatory surgery over the past
      several years. The first reports of patients self-administering local anaesthetic
      via wound and perineural catheters were published in 1998. Such infusions have
      now become a necessary component for the success of various ambulatory
      procedures. The rapid development of these techniques has been based on advances
      in equipment manufacturing, drug development and the need to provide a greater
      degree of analgesia for patients in the ambulatory setting. Many of the concepts
      used to provide safe ambulatory infusion have been drawn from studies of patients
      receiving these types of therapies in a hospital setting. Few studies have
      actually examined these techniques is an outpatient environment. However, the
      advantages of these analgesic techniques over traditional oral narcotics for
      patients undergoing major surgery in the ambulatory environment have led to their
      rapid acceptance as a standard of care at many institutions.

PMID- 12491559
TI  - Continuous interscalene block for ambulatory shoulder surgery.
AB  - Management of acute post-operative pain due to shoulder surgery may be
      successfully and consistently achieved in ambulatory patients by using continuous
      interscalene block. This chapter outlines the anterior and posterior approaches
      to the proximal brachial plexus and describes a method of precisely placing a
      catheter along the brachial plexus by stimulating the plexus through the needle
      used for placing the catheter as well as through the catheter itself. A technique
      for securing the catheter by subcutaneous tunneling to prevent dislodgement is
      also described. Suggested drugs and dosages for initial boluses, continuous
      infusions and patient controlled interscalene analgesia are discussed. Sedation
      for block placement, and special precautions, are outlined.

PMID- 12491560
TI  - Outpatient lower extremity infusions.
AB  - The considerable development of ambulatory surgery has led to an increase in the
      number of lower extremity procedures performed in an outpatient setting. More
      recently, the availability of disposable pumps has allowed us to extend the
      indications of continuous nerve blocks for ambulatory post-operative pain
      management. Indications for lumbar plexus continuous blocks include anterior
      cruciate ligament (ACL) reconstruction and patella repairs as well as frozen
      knee, whereas continuous sciatic blocks are indicated for major foot and ankle
      surgery. Different modes of local anaesthetic administration have been applied,
      including the use of repeated bolus, continuous administration and, more
      recently, patient-controlled perineural infusions. This latter technique seems to
      be the preferred mode because it offers the advantage of tailoring the amount of
      local anaesthetics, mostly 0.2% ropivacaine, to the individual need and also
      maximizes the duration of infusion for a given volume of local anaesthetic.
      Although the preliminary reports indicate that lower extremity continuous blocks
      provide effective post-operative ambulatory analgesia and are safe, especially as
      a part of a multimodal approach, appropriate training in these techniques
      represents one of the most important limiting factors of the placement of
      perineural catheters. Additional research is required to determine the optimal
      conditions in which these techniques are indicated.

PMID- 12491561
TI  - Incisional and intra-articular infusions.
AB  - Incisional and intra-articular local anaesthetic techniques are simple, safe and
      inexpensive analgesic methods for the management of post-operative pain following
      a variety of surgical procedures. These techniques are capable of providing
      effective analgesia over a limited field and with minimal systemic effects. In
      the literature single-dose local anaesthetics have been administered in most of
      the studies; however, the duration of analgesia is short-lived. In recent years
      catheter techniques have been increasingly used as intermittent bolus or
      continuous infusion in the surgical wound or intra-articularly for long-lasting
      post-operative analgesia in both hospitalized and day-case patients. The
      incisional and intra-articular use of opioids and several non-opioids, either
      alone or in combination with local anaesthetics, has also been evaluated. This
      chapter reviews the current status of single dose and infusions of local
      anaesthetics and adjuvants for incisional and intra-articular analgesic
      techniques and also looks at future perspectives.

PMID- 12491562
TI  - The Holy Grail: long-acting local anaesthetics and liposomes.
AB  - The ability to provide an extended duration of analgesia of days following a
      single injection without the need for catheters, pumps and infusion systems would
      be a great benefit in acute and chronic pain. Exciting progress is being made in
      our ability to combine local anaesthetics with liposomes and polymer
      microspheres. These interesting formulations in animal models have allowed up to
      4 days of analgesia. Their use clinically will be a great advance which could
      possibly occur in the near future.

PMID- 12491563
TI  - [Significance of environmental medicine in modern medicine].

PMID- 12491564
TI  - [Psychiatric aspects of multiple chemical sensitivity (MCS)].
AB  - Patients with multiple chemical sensitivity (MCS) react to low levels of common
      environmental chemicals with various health complaints. The etiology and
      pathogenesis of MCS is not clear. Objective criteria for diagnosis are lacking.
      Usually there are no pathological somatic findings, while psychiatric morbidity
      is considerably high. Somatoform, mood and anxiety disorders are diagnosed most
      frequently. A subgroup of MCS patients may suffer from a special form of
      somatoform disorders related to the environment. Critics of a psychogenic model
      of MCS argue that psychiatric diagnoses are descriptive, and causality can not be
      derived from them. However, clinicians are expected to evaluate the most probable
      cause of the complaints and give therapeutic recommendations. There are promising
      therapeutic concepts for somatoform and other psychiatric disorders, but not for
      MCS. Double-blind challenge tests, but also therapy evaluation studies could
      contribute to a better understanding of the pathogenesis of MCS in the future.

PMID- 12491565
TI  - [Autologous chondrocyte transplantation--progress or misleading development in
      high-tech medicine?].
AB  - Autologous chondrocyte transplantation (ACT) is a recently developed procedure
      for repairing chondral defects of the knee. An analysis of the literature
      provides no evidence so far for regular regeneration of hyaline cartilage, and no
      randomized controlled studies are available showing a long-term efficacy.
      Therefore, controlled randomized studies are urgently needed. At present, ACT
      cannot be recommended for extended application in clinical practice.

PMID- 12491566
TI  - [Isolated traumatic meniscus rupture--is there progress?].
AB  - A review of the literature revealed that there are no new scientific data which
      can rule out the existence of an isolated traumatic meniscus tear. However, the
      large number of publications on the subject of meniscus pathology do suggest that
      the traumatic tear of a "healthy" meniscus without ligamental or osseous
      concomitant lesions is indeed very rare. In order to perform an individual
      medical examination, therefore, medical experts need every available information
      to assess such a case.

PMID- 12491567
TI  - [Seasonal variations in sudden death in sports clubs].
AB  - 2,825 cases of sudden deaths (2,669 men, 156 women) in sports-clubs between 1981
      and 1999 were evaluated retrospectively by means of the cosinor method in order
      to detect a circannual distribution of occurrence. Deaths due to cardiovascular
      and traumatic events were additionally studied with regard to seasonal
      differences of frequency. The number of sudden deaths per month during a period
      of 19 years could be significantly fitted to a cosine model with a maximum in
      June, the absolute maximum value being observed in May (n = 317). In particular,
      accidents were more frequently found in spring and summer.

PMID- 12491568
TI  - [So-called trauma criterium (a criterium of DSM-IV) in posttraumatic stress
      disorder and its significance for social and legal insurance (I)].
AB  - Since the diagnosis posttraumatic stress disorder (PTSD) was included in the
      American diagnosis system DSM-III in 1980, the ongoing scientific discussion has
      led to a shift in the definition of the so called A-criterion (trauma criterion)
      away from the general theory that the disease-causing event has to be outside
      normal human experience towards the point of view that it is more or less
      determined by the subjective experience of the individual. Without wishing to
      become involved in the discussion, in the publication the author tries to
      explain, on the basis of references to basic concepts found in insurance law
      (accident, initial damage, suitability of event, objectivity, epidemiological
      considerations), that in social insurance as well as in non-life insurance an
      objective insured event which has a severe emotional impact on the individual is
      a prerequisite for payment. The conclusions is that not every mental disorder
      which occurs after an insured event and which has quite rightly been classified
      as PTSD (or partial PTSD) on the basis of the symptoms involved in accordance
      with ICD-10/DSM-IV (criteria B-D) necessarily results in payment under insurance
      law.

PMID- 12491569
TI  - [Comment on A. Gandjour, K. W. Lauterbach: Medical ethics and economics in public
      health care: an irreconcilable conflict?].

PMID- 12491570
TI  - [Comment on E. Stresemann: An evil expert witness, a fallen angel?].

PMID- 12491571
TI  - [Comment on E. Stresemann: An evil expert witness, a fallen angel?].

PMID- 12491572
TI  - Chirality and drugs used to treat psychiatric disorders.

PMID- 12491574
TI  - Reboxetine: a preliminary report on its use through the Special Access Program.
AB  - OBJECTIVE: To describe the effectiveness and tolerability of reboxetine under
      Special Access Program conditions in Canada in a group of patients with
      refractory depressive disorders. DESIGN: Retrospective open-label study. SETTING:
      Six clinical academic settings in Canada, primarily tertiary institutional
      settings. PATIENTS: Twenty-six female and 19 male outpatients with depressive
      disorders, primarily unipolar depression. Most of the patients were treatment
      resistant. INTERVENTION: Reboxetine through the Special Access Program. OUTCOME
      MEASURE: Severity of depression before treatment with reboxetine was
      retrospectively assessed with the Clinical Global Impression (CGI) Global
      Severity Scale; change with treatment was evaluated with the CGI Global
      Improvement Scale. RESULTS: Before reboxetine treatment, 20 (44%) patients scored
      in the moderate CGI severity category, 11 (24%) in the marked category and 12
      (27%) in the severe category. The dose range for reboxetine was 2-16 mg, with 40
      (89%) patients in the 4-10 mg range. With reboxetine treatment, 25 (56%) patients
      were considered "very much improved" or "much improved"; 8 (18%) patients were
      "minimally improved"; 7 (16%) received ratings that reflected "no change" or
      minimal worsening, and 5 (11%) were rated as "much worse" or "very much worse."
      CONCLUSIONS: Reboxetine was effective at a clinically meaningful level in
      decreasing severity of depression in 56% of patients. Given the high rate of
      prior resistance to other antidepressant therapies, there is a definite role for
      this agent in the treatment of depressive disorders.

PMID- 12491575
TI  - Suicide in Israel: 1985-1997.
AB  - OBJECTIVE: To examine trends in suicide rates in Israel over a 13-year period.
      METHOD: All cases of autopsy-confirmed suicide in Israel from 1985 to 1997 were
      retrospectively reviewed. RESULTS: An overall annual increase in suicide rates,
      with rates in men 3 times higher than those in women, was observed. Suicide rates
      were highest in the second and third decades of life. Unlike Western countries
      where gunshot wounds are the most common method of suicide for men and poisoning
      is most common for women, asphyxiation by hanging was the most common method used
      by men in Israel, followed by firearm wounds and jumping from heights. In women,
      however, jumping from heights was the most common method, followed by hanging and
      poisoning. CONCLUSION: Increasing rates of suicide may be associated with waves
      of immigration to Israel, increased substance abuse and depression and the
      political and social climate. Further study to examine the precipitating factors
      is warranted.

PMID- 12491573
TI  - Drug-metabolizing cytochrome P450s in the brain.
AB  - Most CYP subfamilies have been identified in brain, but there is much more
      information available on the distribution and metabolic activity of CYP
      subfamilies in brain of rodents than in humans, and what we do know still lags
      far behind our knowledge of hepatic CYPs. With the constant acquisition of data
      on the genetics, molecular structure and metabolic capacity of brain CYPs, we are
      increasingly able to investigate their role in the brain and the possible
      consequences of altered local metabolism. However, at this stage, the
      contribution of brain CYPs to local metabolism of drugs, toxins and endogenous
      compounds is still speculative, as is the role for these CYPs in modulating brain
      function and in the development of brain diseases. Much investigative work
      remains to be done to firmly establish the links between the presence of CYPs in
      brain, their function in this highly heterogeneous and complex organ and the
      consequences on overall brain function and health.

PMID- 12491577
TI  - The 25th annual meeting of the Canadian College of Neuropsychopharmacology.
      Ottawa, Ontario, Canada, June 9-12, 2002.

PMID- 12491576
TI  - Effects of short-term administration of valproate on serotonin-1A and dopamine
      receptor function in healthy human subjects.
AB  - OBJECTIVE: To examine the effects of short-term valproate treatment on human
      brain serotonin and dopamine function by means of challenge tests with
      ipsapirone, a partial agonist at 5-HT1A receptors, and apomorphine, a dopamine
      receptor agonist. DESIGN: Experimental challenge-rechallenge, within-subjects
      repeated measures, before and at the end of 14 days of treatment with valproate
      at a dosage of 625 mg/d (reached gradually over the first 5 days). PARTICIPANTS:
      Eight healthy male volunteers (mean age 38 years) selected for good physical and
      mental health who were nonsmokers. OUTCOME MEASURES: Pharmacological probes were
      used to evaluate the effects of valproate. In the ipsapirone challenge, changes
      in adrenocorticotropic hormone (ACTH), cortisol and body temperature were
      measured, and in the apomorphine challenge, growth hormone (GH) and prolactin
      were the dependent variables. RESULTS: Valproate treatment did not significantly
      alter the ACTH, cortisol or body temperature responses to ipsapirone (20 mg by
      mouth), which reached equivalent plasma levels at each challenge. Similarly,
      valproate treatment did not alter the GH or prolactin responses to apomorphine (5
      micrograms/kg subcutaneously). CONCLUSIONS: These results suggest that short-term
      treatment with valproate at a dose of 625 mg/d does not alter hypothalamic or
      pituitary 5-HT1A or dopamine receptor responses to challenges with ipsapirone and
      apomorphine, respectively.

PMID- 12491579
TI  - [Brain hypothermia for ischemic brain damage].

PMID- 12491580
TI  - [Results of treatment for male prolactinomas].
AB  - We evaluated the results of medical treatment for male prolactinomas. We
      encountered eight patients with male prolactinomas. The age was 25 to 54 years
      old (mean 43 years) and the chief clinical symptoms were visual acuity/field
      defect in three patients, pituitary apoplexy in one patient, disturbance of
      ejection in one patient, generalized convulsion in one patient, headache in one
      patient and general fatigue in one patient. The serum prolactin level was 279 to
      7,360 ng/ml (mean 2,832 ng/ml). The tumors in all patients were large with a mean
      diameter of 34.9 mm (range, 21 to 43 mm). In only one patient, the operation was
      performed due to pituitary apoplexy. All the patients were treated by medication,
      with bromocriptine being used in seven patients and terguride in one. The follow
      up period was 0.8 to 13 years (mean 5.9 years) and, in all patients, the medical
      treatment was continued. The tumor decreased in size in all patients and the
      serum prolactin level at the last follow-up observation was 0.5 to 70.5 ng/ml
      (mean 26.9 ng/ml). All the neurological symptoms disappeared in the early stage
      of treatment. As for the complications of medical treatment; in one patient,
      orthostatic hypotension occurred during the initial administration of
      bromocriptine and one patient suffered CSF leakage two months after the
      administration of bromocriptine, so the repair of the sella floor by
      transsphenoidal surgery was necessary. The medical treatment for male
      prolactinomas is effective for a long term and should be the primary treatment
      for the male prolactinomas. In conclusion, patients can maintain a good quality
      of life for a long time by using dopamine agonists.

PMID- 12491581
TI  - [Clinical significance of posterior cerebral artery stenosis/occlusion in
      moyamoya disease].
AB  - PURPOSE: The present study was aimed at clarifying the clinical significance of
      posterior cerebral artery (PCA) stenosis/occlusion in pediatric and adult
      moyamoya disease. SUBJECTS AND METHODS: This study included a total of 132
      patients (52 children and 80 adults) who were diagnosed as by cerebral
      angiography having moyamoya disease. CT or MRI was performed to examine the
      location of cerebral infarction in all subjects. Cerebral blood flow and
      vasoreactivity to acetazolamide were measured in 80 patients before surgery,
      using single photon emission computed tomography (SPECT). Three-dimensional MR
      angiography (3D-MRA) was repeated in 32 pediatric patients after surgery in order
      to clarify the natural course of the PCA stenosis/occlusion. RESULTS: Of 264
      sides in 132 patients, PCA stenosis/occlusion was observed in 50 sides of 40
      patients (30.3%). Its incidence was significantly higher in ischemic-type
      patients than in hemorrhagic-type and asymptomatic patients, and was higher in
      patients in the advanced stage of the disease. The hemisphere ipsilateral to PCA
      stenosis/occlusion had higher incidence of ischemic symptoms, cerebral
      infarction, and impaired cerebral hemodynamics. TIA (hemianopsia) or cerebral
      infarction in the occipital lobe was noted in 4 (10%) of 40 patients during
      follow-up periods after bypass surgery for anterior circulation. Of 32 pediatric
      patients, none showed progression of PCA stenosis on 3D-MRA during follow-up
      periods. CONCLUSIONS: The present study showed that the involvement of PCA could
      increase the risk of TIA and/or cerebral infarction in both anterior and
      posterior circulation areas, suggesting that the PCA plays an important
      collateral role in moyamoya disease.

PMID- 12491582
TI  - [Restenosis after CEA: pathogenesis and treatment].
AB  - This study examined the incidence and mechanism of restenosis after carotid
      endarterectomy (CEA) in Japanese patients. To determine the optimal management
      for carotid restenosis, we retrospectively compared re-CEA with stent placement.
      One hundred and twenty-six patients who had received 135 CEA with primary suture
      were studied with angiography or duplex ultra-sonography as a follow-up study to
      detect restenosis (> 50% diameter reduction). Data was collected regarding
      demographics of the patients suffering restenosis, including age, sex, other risk
      factors. Recurrent carotid stenosis (more than 50% stenosis) developed in 9 CEA
      sites (6.7%) during a mean follow-up interval of 11.0 months (4.7-46.7 months).
      Recurrent carotid stenosis occurred to a significantly higher degree in women (p
      = 0.015). There was no significant difference in other risk factors. All patients
      who developed carotid restenosis were asymptomatic. Re-do CEA and carotid
      stenting were used to treat restenosis in 3 and 5 patients, respectively. No
      operative procedure was performed in the remaining one patient with milder
      restenosis (55%). The 30-day stroke morbidity-mortality rate was 33.3% in CEA and
      0% in stent placement. In only one of 4 early restenosis patients, there was a
      bright lesion in diffusion weighted MR images after stent placement. To treat
      restenosis after CEA, stent placement is indicated because of a lower risk of
      distal emboli and there being no need to dissect the previous wound. To prevent
      restenosis, through plaque removal is necessary and patch closure may be needed
      especially in females.

PMID- 12491583
TI  - [Primary intracerebral malignant fibrous histiocytoma: case report].
AB  - We report a rare case of a primary intracerebral malignant fibrous histiocytoma
      (MFH) with malignant progression from a premalignant stage. A 73-year-old male
      presented with mild hemiparesis on the right side of his body 4 months prior to
      admission. MR images showed a homogenously enhanced mass in the left parietal
      lobe. The patient underwent an uneventful extirpation of the solid mass.
      Microscopically, the solid tumor contained histiocytic cells and spindle-shaped
      fibroblastic cells arranged in a storiform pattern. The tumor cells were
      immunoreactive for vimentin, MAC 387 (macrophage marker) and alpha-1-antitrypsin.
      The MIB-1-positive rate was 1%. The histological diagnosis was fibrous
      histiocytoma. Postoperative MR images demonstrated no abnormally enhanced
      lesions. The patient's neurological symptoms and signs gradually improved. One
      year after surgery, he developed right hemiparesis. MR images showed a
      heterogeneously enhanced mass in the left sensorimotor area. This recurrent tumor
      was totally resected. Microscopically, the tumor was composed of atypical spindle
      shaped cells, forming a storiform pattern. Pleomorphism was prominent, and
      necrotic foci were also seen. The MIB-1 labeling index averaged 11%. The
      histological findings corresponded to those of MFH. Unfortunately, the patient
      died of interstitial pneumonia contracted during postoperative radiotherapy.
      Early detection and resection at a stage of low malignant potential, followed by
      radiochemotherapy, are crucial for the management of this mesenchymal tumor.

PMID- 12491584
TI  - [A case of primary cerebellar glioblastoma in childhood].
AB  - Primary cerebellar glioblastomas are exceedingly rare in childhood, with only 19
      cases having been reported. We treated a 7-year-old girl with primary cerebellar
      glioblastoma, who rapidly deteriorated due to cerebrospinal fluid dissemination.
      The 7-year-old girl was admitted to our hospital with a history of headache for
      one month. On admission, increased intracranial pressure and left cerebellar
      signs were observed. Magnetic resonance imaging (MRI) revealed a ring-enhanced
      mass in the left cerebellar hemisphere and a low intensity lesion in the pons.
      The tumor had compressed the fourth ventricle and caused obstructive
      hydrocephalus. Gross total resection of the left cerebellar tumor was performed.
      Histological examination revealed nuclear atypia, mitoses, and necrosis, which
      satisfied the World Health Organizations histological criteria for grade IV
      astrocytoma. The MIB-1 labeling index was more than 60%. She was treated with
      adjuvant therapies consisting of 60.2 Gy local irradiation to the posterior
      fossa, including the brain stem lesion, and chemotherapy using 1-(4-amino-2
      methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). However, the
      patient developed of anorexia and vomiting 4 months after surgery, and MRI
      disclosed local recurrence at the left middle cerebellar peduncle and diffuse
      dissemination along the lateral ventricle wall. The patient was treated with
      three-drug chemotherapy using ifosfamide, cisplatin, and etoposide and 39.2 Gy of
      whole-brain irradiation. However, her condition deteriorated gradually and she
      died 10 months after admission (6 months after the onset of tumor recurrence).
      Primary cerebellar glioblastomas in children carry a very poor prognosis and tend
      to cause cerebrospinal fluid dissemination.

PMID- 12491585
TI  - [Aseptic meningitis as a complication caused by an allergic reaction after
      microvascular decompression: two case reports].
AB  - We report here two cases of patients complicated with aseptic meningitis after
      microvascular decompression (MVD). The first case, a 56-year-old female
      complained of headache with high fever 18 days after the MVD for right trigeminal
      neuralgia. The amount of cells in cerebrospinal fluid (CSF) had so much increased
      that bacterial meningitis was suspected. However, there was no improvement after
      antibiotics therapy, so immune globulin was injected and the meningitis gradually
      improved. Eosinophilia remained in peripheral blood and the symptoms improved
      rapidly after the steroid therapy. Because of this, we suspected that meningitis
      was caused by an abnormal allergic reaction. The second case, a 30-year-old male
      complained of headache with mild fever 15 days after MVD for left hemifacial
      spasm. The amount of cells in CSF increased, so bacterial meningitis was
      suspected. Eosinophilia remained in peripheral blood and the steroid therapy
      proved very effective for the meningitis. Because of this, we suspected that
      meningitis was caused by an abnormal allergic reaction. We suspected that the two
      patients suffered from aseptic meningitis caused by allergic reaction, and the
      antigen for this abnormal allergic reaction was the foreign materials used for
      MVD. The materials were Dacron for prostesis, Goatex or Lyodula for dural plasty,
      fibrin glue for preventing CSF leakage. We ascertained that the abnormal allergic
      reaction was caused by human fibrinogen in the second case. It is important to be
      aware of such allergic reaction to fibrin glue in the post-operative stage after
      MVD.

PMID- 12491586
TI  - [Unilateral absence of the external carotid artery: three case reports].
AB  - We encountered three cases of unilateral absence of the external carotid artery.
      We were able to find only Franklin's case reported in the literature published to
      date. The absence of the external carotid artery has been explained as due to the
      fact that the development of the external carotid artery arising from the ventral
      aorta was disturbed by unknown factors in the early embryonic stage. In the
      process of embryonal development, the internal carotid artery and branchial
      arteries (that are to be components of the external carotid artery) have remained
      without connection and without development of the ECA trunk. The final result is
      that the branches of the external carotid artery originate directly from the
      carotid artery. The existence of dextrocardia in case 2 and an azygos anterior
      cerebral artery in case 3 suggests that the absence of the external carotid
      artery occurred during the early embryonal stage due to unknown factors.
      Angiography is essential to make a diagnosis of the absence of the external
      carotid artery. However this time ultrasound sonography was very helpful towards
      further delineation of ulceration and thickening of the intima-media complex that
      were not diagnosed by angiography. The ultrasound sonographic findings and
      operative findings revealed characteristic rudimentary findings of ECA aplasia.
      In particular, this ulceration has a shape like a broad-based volcano that is
      hollow inside.

PMID- 12491587
TI  - [Subarachnoid hemorrhage due to ruptured dissecting aneurysm of peripheral
      superior cerebellar artery].
AB  - The peripheral superior cerebellar artery (SCA) dissecting aneurysm (DA) is
      extremely rare, with only 4 cases (including our case) having been reported. Here
      we report a case of subarachnoid hemorrhage due to ruptured DA of peripheral SCA
      and summarize the 23 cases of the DA of peripheral arteries in the posterior
      fossa. A 64-year-old woman was found unconscious at home and was admitted to our
      hospital on December 12, 1998. A computed tomography scan revealed a diffuse
      subarachnoid hemorrhage (Fisher's classification Group 3), mainly in the
      prepontine cistern. Her neurological state on admission was Hunt and Kosnik grade
      III. A cerebral angiogram was performed on admission, and revealed a slightly
      enlarged lesion at the anterior pontine segment of the left SCA. The day after
      admission, a second angiogram was performed and revealed that the lesion was not
      well-defined. She was treated conservatively, with no change in condition. On the
      16th day after admission, a third angiogram was performed and revealed a saccular
      aneurysm-like lesion arising at that region with intra luminal pooling sign. She
      was treated, using the left subtemporal approach. In the operation, organized
      clots and hemosiderin were identified in the prepontine cistern. However,
      saccular aneurysm was not found at all and only the arterial wall was thin and
      discolored. These serial angiogram and operative findings revealed a DA of
      peripheral SCA. In this case, serial angiogram showed singular change of findings
      within a short period. We emphasize the need to repeat the angiogram taking due
      timing into account.

PMID- 12491588
TI  - [Demyelinating disease, no. 6 in series of articles: basic knowledge of
      neuropathology for neurosurgeons].

PMID- 12491589
TI  - [Problems and proposals from neurosurgical practice, no. 10 in series of
      articles: controversy and reform proposals concerning insured medical care in
      neurosurgery].

PMID- 12491590
TI  - [Clinical significance of fine-needle aspiration biopsy in major salivary gland
      tumors].
AB  - We compared preoperative evaluations of 93 fine-needle aspiration biopsies (FNAB)
      of major salivary gland tumors done over a 5 year period with pathologic
      diagnoses of surgically resected specimens. The overall accuracy was 88.5%. Eight
      of 15 aspirates from malignant tumors were correctly diagnosed by FNAB, for a
      sensitivity of 53.3%, while 69 of 72 aspirates from benign tumors were correctly
      diagnosed by FNAB, for a specificity of 95.8%. Five malignant tumors diagnosed as
      benign by FNAB were squamous cell carcinoma, carcinoma in pleiomorphic adenoma,
      malignant lymphoma, low-grade mucoepidermoid carcinoma, and acinic cell
      carcinoma. The false negatives in the first 2 cases appeared to be due to
      inaccurate placement of the aspiration site. The other 3 cases showed lack of
      atypia, leading to a benign diagnosis. Malignant lymphoma is difficult to
      diagnose as malignant, even in properly aspirated specimens, so we recommend open
      biopsy when malignant lymphoma is suspected from physical and radiological
      examinations. A case confirmed pathologically as benign myoepithelioma was
      diagnosed as adenoid cystic carcinoma preoperatively, based on the finding of a
      cribriform pattern containing mucin. It should be borne in mind that
      myoepithelioma and adenoid cystic carcinoma are difficult to distinguish by FNAB.
      Although FNAB is useful in diagnosing major salivary gland tumors, its low
      sensitivity (high percentage of false negatives) is undesirable. It may thus be
      helpful in intraoperative decision-making when combined with frozen sectioning.

PMID- 12491591
TI  - [A clinical study of sleep apnea syndrome].
AB  - Between December 1996 and June 2001 at Yamaguchi University Hospital overnight
      polysomnography (PSG) was conducted on 167 patients with snoring and sleep apnea.
      We treated obstructive sleep apnea syndrome (OSAS) patients with uvulo-palate
      pharyngoplasty (UPPP), and/or nasal surgery, nasal continuous positive airway
      pressure (nasal-CPAP), and prosthetic dental devices. We studied the effects of
      surgery and dental device use by follow-up PSG. Nasal-CPAP therapy was done for
      lower subsequent compliance. We discuss results with reference to the literature.

PMID- 12491592
TI  - [Changes in the F wave during recovery from peripheral facial paralysis].
AB  - OBJECTIVE: We studied normal F wave parameters and F wave changes in patients
      with longstanding facial paralysis. SUBJECTS: Controls were 11 healthy volunteers
      studied to estimate normal F wave parameters. Subjects were 8 patients with
      Hunt's syndrome and 12 with Bell's palsy available for F wave detection among
      outpatients at our department between April 1999 and March 2000. They had ENoG of
      0% within 2 weeks of paralytic onset. The test was repeated 68 times. DIAGNOSTIC
      INTERVENTION: Results of 68 tests were classified into 5 groups based on the
      course after paralysis developed and their F wave parameters were compared with
      controls. F wave parameters were minimal latency, maximum latency, mean latency,
      and frequency of F wave development. Stimulation was repeated 20 times in a test.
      RESULTS: No significant difference was noted in minimal latency in each group
      compared to controls. Maximum and mean latency were prolonged significantly in
      each group compared to controls. The frequency of F wave development was
      significantly reduced in groups in which examinations were done in less than 6
      months and for 6 months to 1 year. CONCLUSIONS: Nerve fibers with fast conduction
      were considered to have recovered with on 6 months. This suggested that nerve
      conduction velocity in facial paralysis patients does not recover the same as
      normal conduction velocity. The maximum and mean latency in each of the postpalsy
      group was significantly longer than that in the normal control group. We
      therefore concluded that regenerated nerve fibers include some with a conduction
      velocity significantly slower than normal. The frequency in groups A and B was
      significantly lower than that in controls, but after 1 year or more had elapsed
      after the onset of palsy, the frequency was approximately the same as that in
      controls.

PMID- 12491593
TI  - [Comparative studies of platinum concentrations in the neck tissues of rats
      between intraarterial and intravenous infusion of CDDP].
AB  - We studied the comparative pharmacokinetics of platinum between intraarterial and
      intravenous CDDP infusion in male rats. Platinum concentrations in cervical
      tissues, serum, and tongue tissues were measured by a single intraarterial
      infusion or an intravenous infusion at a CDDP dose of 10 mg/kg. Intraarterial
      infusion was conducted through the left common carotid artery and intravenous
      infusion through the left external cervical vein. Tissues and blood samples were
      collected from bilateral sides every 30 minute for 120 minutes after completion
      of CDDP infusion. Platinum levels in serum showed no significant difference
      between the 2 routes. Platinum levels in tongue tissue showed a significant
      difference between the 2 routes favoring of intraarterial administration 30
      minutes after infusion. Platinum levels in left cervical tissue following
      intraarterial administration peaked 90 minutes after infusion, significantly
      higher than that in right cervical tissue or that following intravenous
      administration. These findings suggest that CDDP transfers from target organs to
      neck tissues of the dosage side via the lymphatic duct, and that intraarterial
      infusion chemotherapy is effective at the target organ and at cervical lymph
      nodes or cervical tissues.

PMID- 12491594
TI  - [Angles between left and right vertical semicircular canals].
AB  - To clarify anatomical relationships between the left and right vertical
      semicircular canal (SCC), we measured angles between the left and right posterior
      SCCs, and angles between left and right anterior SCCs. Subjects were T2 images of
      axial magnetic resonance imaging (MRI) in 50 patients reporting headaches. The
      mean angle between the left and right posterior SCC was 92.6 degrees (S.D. =
      11.7) and that between the left and right anterior SCC was 76.1 degrees (S.D. =
      10.4). These results suggest that angles between the left and right vertical
      semicircular canals are not always 90 degrees, and interindividual differences in
      the relationship between canal planes are great, indicating a need for discretion
      in analyzing peripheral nystagmus.

PMID- 12491595
TI  - [A case of spinal epidural abscess associated with retropharyngeal abscess].
AB  - Spinal epidural abscesses are known to occur associated with retropharyngeal
      abscess, but such cases are few in the literature. We treated a 72-year-old woman
      who reported pain in the back of the neck. Computed tomography (CT) showed a
      retropharyngeal abscess extending to the upper neck through the carotid space on
      the left side and an magnetic resonance imaging (MRI) showed a spinal epidural
      abscess without cervical vertebral osteomyelitis. The abscess was assumed to
      reach the epidural space along the nerve root through the intervertebral foramen.
      Since tonsillitis appeared to cause the retropharyngeal abscess, we performed
      tonsillectomy, and then drained pus through the superior constrictor muscle,
      effecting a subsequent cure. Staphylococcus aureus was recovered from both the
      pus and tonsil, and Streptococcus constellatus, a member of the Streptococcus
      milleri group, from the tonsil. Based on a review of the literature, clinical
      courses of spinal epidural abscess associated with retropharyngeal abscess are
      not always simple, as 4 of the 7 cases found demonstrated poor prognosis. Spinal
      epidural abscess should be considered a critical complication of retropharyngeal
      abscess.

PMID- 12491596
TI  - [Cephalometric analysis in patients with obstructive sleep apnea syndrome:
      effectiveness of measuring skeletal morphology and soft tissue dimensions].
AB  - We assessed the surgical indication in obstructive sleep apnea syndrome (OSAS) by
      comparing cephalometry between a responder group of uvulopalatopharyngoplasty
      (UPPP) and a nonresponder group. Cephalometric studies were conducted on 43
      patients--42 men and one women--who required UPPP and underwent both pre- and
      postoperative polysomnography, and on 50 non-OSAS patients who formed the control
      group. Angles and distances were measured based on the Downs-Northwestern method
      as detailed in the reference cited. The comparison between the OSAS and control
      groups indicated anterior displacement of the maxilla, and anteroposterior
      discrepancies of the maxilla and the mandible in OSAS. Significant differences
      were seen in distance measurements for all values other than the distance from
      the sella to the nasion. We then compared the 3 groups--responders,
      nonresponders, and controls. From differences in the Y-axis angle, the Gonial
      angle, the ANB angle, the distance from the gonion to the menton, and the maximum
      thickness of the soft palate between responder and control groups, we concluded
      that the efficacy of UPPP is higher in OSAS patients who have several factors
      such as micrognathia, anteroposterior discrepancy in the maxillary and mandibular
      bases, and thick soft palate. We concluded that routinely conducting that
      cephalometric analysis would be useful for deciding on adopting UPPP.

PMID- 12491597
TI  - [Allergic fungal sinusitis].
AB  - Allergic fungal sinusitis (AFS) is considered an allergic inflammation against
      fungus, and has been reported to be refractory, with very high recurrence. In
      Europe and the United States, AFS incidence is reported from 4% to 7% in patients
      with chronic sinusitis undergoing endoscopic sinus surgery (ESS). In Japan,
      however, only 5 patients, including ours have been reported, making AFS very rare
      in Japan. We prospectively studied the incidence, pathogenesis and diagnosis of
      AFS in Japan among 102 patients with chronic sinusitis who underwent ESS. Four
      cases (3.9%) were diagnosed with AFS based on the criteria of Bent and Kuhn. This
      incidence is slightly lower than that reported in Europe and the United States.
      We report the diagnosis, treatment, and course in 4 AFS patients. Of these, an
      allergen provocation test against detected fungus was conducted in 2 from whom
      informed consent was obtained. In the immediate phase, positive reactions were
      observed. Immunoglobulin E (IgE) antibody-mediated type I allergy may be involved
      in the pathogenesis of AFS.

PMID- 12491598
TI  - [The relevance of a simultaneous measurement of WBC and CRP as a POCT(point of
      care testing) of the inflammatory markers running title: the POCT(point of care
      testing) of WBC and CRP].
AB  - The POCT(point of care testing) is not enough popular as the term in Japan, but
      many tests are actually performed as POCT. We have developed POCT analyzer to
      measure WBC and CRP simultaneously from whole blood, and one of its key
      technologies is Hct correction of CRP concentration from whole blood to plasma.
      After its launch, the users are discussing some findings, one of what is a
      transition phase of WBC and CRP found by frequent measurement of both. In case of
      acute infectious inflammation, the CRP peak follows the WBC peak after 1 or 2
      days. Needless to say, this finding makes haste to foresee a remission by both
      doctor and patient family. Thus, the POCT has a possibility to give additional
      and/or another advanced medical relevance even if it is alternative.

PMID- 12491599
TI  - [Coagulation monitoring in point of care testing--as global point of view].
AB  - Point Of Care Testing(POCT) facilitates obtaining TAT results for rapid decision
      making in Critical Care therapy, so that POCT has been in high demand in order to
      implement efficient diagnosis and therapy for Patients. Efficient therapy and
      diagnosis is highly needed to improve patient service, and reduction of total
      medical cost is under pressure. Measurements of essential parameters for critical
      care with small meters or devices are available as POCT. e.g. Coagulation
      parameters. Since Coagulation parameters are critical parameter, Coagulation
      Monitoring is done in the Emergency room, CCU, ICU and Operating room.
      Coagulation Self Monitoring has already been implemented in several European
      countries for patients receiving Anti Coagulation therapy, e.g. those who have
      undergone surgery for Artificial Heart Valve, because increasing numbers of
      patients requiring self monitoring is expected.

PMID- 12491600
TI  - [Microbiology--laboratory examinations for bacterias].
AB  - As it has been required to identify pathogenic microbes in shorter times, simple
      and rapid methods have been developed and used. Here, we summarized the present
      situation of rapid diagnostic testing in clinical microbiology in Japan, and also
      presented our results on PBP2' detection. The rapid test kits available in Japan
      for E. coli, Helicobacter pylori, Salmonella, Streptococcus and Staphylococcus
      aureus were described. Rapid examination methods are based mainly on immunologic
      reactions, which included slide agglutination using latex particle,
      immunochromatography and ELISA. Times required for the identification are 10 to
      15 minutes. Moreover, rapid test kits employing PCR are also marketed. Further,
      we evaluated MRSA-LA "Seiken" which is a rapid detection kit for PBP2' produced
      by MRSA. The test was shown to be highly sensitive and specific. For the rapid
      identification of pathogenic microbes, simple and rapid test kits described here
      will be used more in clinical diagnosis.

PMID- 12491601
TI  - [Rapid detection tests for viruses available in pediatric clinics].
AB  - Respiratory or gastrointestinal symptoms caused by common viral infections are
      self-limiting in most patients in pediatric clinics. However, it is also true
      that a small proportion of patients do develop serious conditions such as
      encephalitis and respiratory distress. Early diagnosis is indispensable for
      appropriate treatment. Rapid detection tests for influenza virus, respiratory
      syncytial virus, rotavirus and adenovirus are widely used in pediatric clinics.
      The sales of rapid detection tests for influenza virus have shown a remarkable
      increase in recent years after neuraminidase inhibitors became available for
      treatment. The methods utilized in these tests are enzyme immune assay,
      chromatographic immune assay, optical immune assay and others. Their sensitivity
      and specificity are reported to be sufficient for clinical use. According to the
      questionnaires sent out to the users of these tests, most users were satisfied
      with these rapid detection tests; however, some users requested greater accuracy,
      simplicity and longer shelf life. Clinicians should be aware that poor sampling
      may result in wrong results. Simple technique, quick reaction, clear results and
      low expense are required for these detection tests as point of care tests (POCT).
      The development of clinical laboratory medicine has made clinical laboratories
      more centralized and integrated than in the past decades. The development of POCT
      will bring clinical laboratories much closer to clinicians and patients than in
      the present.

PMID- 12491602
TI  - [Rapid diagnosis of infectious complications after transplantation].
AB  - Transplantation has become a standard therapy offering potential cures for a
      numbers of disorders. Patients undergoing transplantation are exposed to the risk
      of developing bacterial, viral and fungal infections due to underlying diseases,
      transplantation protocols, and treatment regimens. Severe infections are a major
      course of morbidity and mortality. Early diagnosis is essential for the prompt
      initiation of appropriate therapy and the management of such complications.
      Posttransplant microbiological surveillance is used for identifying patients at
      high risk and when infection is suspected. Microbiological examinations are also
      performed in some instances to monitor the patient's response to therapy.
      Molecular detection of microorganisms is a rapid diagnostic technique and becomes
      a useful tool for early recognition and treatment of viral and fungal infections.

PMID- 12491603
TI  - [Lung injury and serum markers].
AB  - The lung injury such as interstitial pneumonia and pulmonary fibrosis causes
      severe respiratory failure resulting in poor prognosis. Recently, SP-A and SP-D
      as well as KL-6 are known as serum markers for these lung injuries. SP-A and SP-D
      are the surfactant specific proteins and synthesized by alveolar type II
      epithelial cells. KL-6 is one of the membrane proteins of type II cells. As these
      proteins are highly specific to the lungs, they are used as serum markers for
      diagnosis, determination of the severity, follow up of the clinical course and
      prognosis of interstitial pneumonia. Although these markers are clinically
      useful, further information on the mechanisms why they are present in the serum
      and also on the relationships between these proteins needs to be accumulated.

PMID- 12491604
TI  - [Improvement for identification of Mycobacterium tuberculosis complex by
      immunochromatographic assay anti-MPB 64 monoclonal antibodies with "H2O2"
      addition trial on blood culture samples].
AB  - An improvement trial for identification of the Mycobacterium tuberculosis complex
      by immunochromatographic assay using anti-MPB 64 monoclonal antibodies (MPB 64
      ICA) is documented. The new MPB 64-ICA is very useful for simple and rapid
      identification of the Mycobacterium tuberculosis complex with specificity, but it
      is a little difficult to prove the Mycobacterium tuberculosis complex on the
      blood culture samples taken from the immunosuppressive or the AIDS patients,
      because the reactive bands are red or reddish-purple in both the control and
      positive zones of immunochromatographic assay, which are often indistinguishable
      from the background mixed with hemoglobin caused from the blood samples. We tried
      to remove the hemoglobin interference in the samples and was able to make clear
      the background with addition of hydrogen peroxide (H2O2). The results are
      followings; the optimum time and density of H2O2 are from 5 to 15 minutes and
      35%, respectively. Accordingly, the improvement trial for identification of the
      Mycobacterium tuberculosis complex by immunochromatographic assay using MPB64-ICA
      with H2O2 is useful to identify the positive reactive band from the interference
      by hemoglobin.

PMID- 12491605
TI  - [Revisited univariate delta check method for hematologic laboratories (I)-
      Usefulness for detection of specimen mix-up in patients with hematologic
      disorders].
AB  - We evaluated the delta check method for hematologic laboratories to detect
      specimen mix-up. We selected 271 patients with hematologic disorders and two
      types of investigation were conducted. The first investigation comprised
      statistical analysis, while the second involved evaluation of the procedure. From
      parameters of white blood cell, red blood cell, hemoglobin, hematocrit, mean
      corpuscular volume (MCV), mean corpuscular hemoglobin(MCH), mean corpuscular
      hemoglobin concentration (MCHC), and platelets, MCV was considered to represent
      the best single marker to detect artificial mix-up. About 98% of MCV delta values
      from one patient were within 3 fl. Conversely, 40% of MCV delta values in
      artificial mixups exceed 10 fl. No correlations between time interval and MCV
      delta values were detected. However, some cases were observed in which MCV delta
      values changed markedly over a short period of time even though the samples
      originated from one patient. In conclusion, we recommend investigation for
      specimen mix-up in cases where MCV delta values exceed 4 fl.

PMID- 12491606
TI  - [Revisited univariate delta check method for hematologic laboratories (II)-
      Causes of marked MCV change in identical patients with hematologic disorder].
AB  - We have identified causative factors contributing to marked mean corpuscular
      volume(MCV) change. We selected 38 patients who demonstrated changes in MCV of >
      or = 10 fl within less than 30 days. Of the 38 patients, 27 had received blood
      transfusions and 6 had undergone allogeneic bone marrow transplantation within
      the previous 2 months. No definitive cause was detected in 5 patients. In
      conclusion, blood transfusion and bone marrow transplantation can result in
      substantial MCV change in a short time and can represent confounding factors for
      the MCV delta check method.

PMID- 12491607
TI  - [DNA typing for determination of zygosity on multiple pregnancies using fragment
      analysis for microsatellite].
AB  - Zygosity on multiple pregnancies is important factor of prognosis in fetus and
      new bones. In the past, determination of zygosity has been made mainly on the
      basis of histological and microscopic observations. Such a morphological
      distinction, however is not sufficient. Fragment analysis based on capillary
      electrophoresis has been developed as a rapid and accurate technique for DNA
      typing. To elucidate the clinical availability of fragment analysis, we examined
      the zygosity of nine multiple pregnancies (three twins and six triplets) by
      fragment analysis of microsatellite DNAs and other common DNA tests (PCR-SSCP
      assay and VNTR analysis using agarose gel electrophoresis). Fragment analysis and
      PCR-SSCP identified the heterozygosity in two of three twins and all of six
      triplets including one presumable dizygotic triplet, while VNTR analysis failed
      to recognize one of two dizygotic twins and three of five trizygotic triplets.
      Although detection efficiency of PCR-SSCP seems to be similar to that of fragment
      analysis, PCR-SSCP could not separate the several microsatellite DNAs that
      fragment analysis showed to be heterozygous. Moreover, fragment analysis could
      detect a minor population possessing the different DNA types (> 5%) in the same
      cell suspension. The present results suggest that fragment analysis of
      microsatellite DNAs may be an excellent and beneficial method for clinical
      application of zygosity determination in multiple pregnancies.

PMID- 12491608
TI  - [Immunoelectron microscopic analysis of intraglomerular deposits in IgA-dominant
      immunotactoid glomerulopathy].
AB  - Immunotactoid glomerulopathy (ITG) demonstrates glomerular deposits that are
      characterized by highly organized ultrastructure. The deposits appear to be
      composed of immunoglobulin and complement that were negative for amyloid by Congo
      red stain. However, it has been difficult to distinguish the difference between
      ITG and fibrillary glomerulonephritis. In the present study, we performed an
      immunoelectron microscopic study to identify the factors that seemed to be
      associated with the glomerular deposits in a case of IgA-dominant ITG. IgA, light
      chain kappa and fibrinogen were colocalized in association with fibrillar
      deposits in the extracellular matrix of mesangial cells. Therefore, it is likely
      that the complex of IgA, light chain kappa and fibrinogen are associated with the
      formation of highly organized ultrastructural deposits in a case of IgA-dominant
      ITG.

PMID- 12491609
TI  - [Repeat prostate biopsy in patients with previous negative biopsies].
AB  - We retrospectively analyzed the results of 104 patients who underwent a second
      prostate needle biopsy. Between January 1993 and September 2000, 654 needle
      biopsies were performed and cancer was found in 239 patients. Among the other 415
      patients, 104 patients underwent a second biopsy. The average prostate specific
      antigen (PSA) value was 9.6 ng/ml (2.0-30.9) (Tandem R conversion value). Cancer
      was detected in 16 out of 104 cases (15%) at the second biopsy, 4 out of 39 (10%)
      at the third biopsy, and 3 out of 10 (30%) at the fourth biopsy. The age, PSA
      value, digital examination, echography, and magnetic resonance imaging (MRI) were
      not helpful in distinguishing the patients with prostate cancer and atypical
      histological findings at the previous biopsy were the most important information.
      Among the 9 patients who showed atypical findings at the previous biopsy, 6 (67%)
      had cancer.

PMID- 12491610
TI  - Efficacy of percutaneous transluminal angioplasty in the management of chronic
      hemodialysis patients.
AB  - Percutaneous transluminal angioplasty (PTA) has gained wide acceptance as an
      effective technique for the dilatation of stenoses in the arterial tree. We
      evaluated the long-term results of vascular access in a group undergoing
      hemodialysis, in particular the effects of PTA. Twenty-four percutaneous
      procedures were performed on 18 patients. Detection was based on physical
      examination, flow rate measurements, venous pressure, and analytical
      determinations performed at dialysis. The initial success rate was 87.5%, with 1
      , 6-, and 18-month patency rates of 82.6, 67.5, and 38.5%, respectively. There
      was no difference between primary and secondary patency rates. The assisted
      primary patency rates for PTA and surgical revision were not significantly
      different. Although neither surgical nor endovascular management resulted in long
      term function for the majority of shunts after stenosis or thrombosis,
      endovascular treatment can extend the life of dialysis shunts with results
      similar to surgical revision. Transluminal dilatation may be performed in
      appropriate cases to obviate the need for surgery.

PMID- 12491611
TI  - [Adult sacrococcygeal teratoma: a case report].
AB  - We report a case of adult sacrococcygeal teratoma resected by an abdominosacral
      approach. A cystic mass 13 cm in diameter in the pelvic cavity and left
      hydronephrosis were detected incidentally by abdominal computed tomographic (CT)
      scan in a 55-year-old man. The pelvic tumor extending from the presacral area to
      the coccyx was resected via a combined abdominal and transsacral approach. The
      resected specimen weighed 700 g and the pathological diagnosis was mature
      teratoma. While the sacrococcygeal area is the most frequent site of teratoma in
      infants, it is a rare site in adults. This is to our knowledge, the 30th case
      report of adult sacrococcygeal teratoma in Japan. At one month after the
      operation the patient had no bowel dysfunction and no dysbasia, but he had mild
      bladder dysfunction requiring self-catheterization twice a day at twelve months.
      The patient had no evidence of disease at twenty months after the operation.

PMID- 12491612
TI  - [A case of renal cell carcinoma with heterotopic bone formation].
AB  - We report a case of renal cell carcinoma with heterotopic bone formation in a 28
      year old woman. The patient was referred to our hospital with a complaint of left
      lumbargo. Laboratory data were within normal limits. Radiography (KUB) suggested
      a calcification in the left kidney and abdominal computed tomographic (CT) scan
      confirmed the presence of a renal mass which contained a calcification. Selective
      renal angiography revealed a hypervascular (microaneurysm-like change) tumor at
      the lower part of the kidney. Left nephrectomy was performed. Histopathological
      diagnosis was renal cell carcinoma with heterotopic bone formation (clear cell
      carcinoma, G1 > G2, pT1b). There has been neither metastasis nor any recurrence
      during the 7 months since her operation.

PMID- 12491613
TI  - [Sarcomatoid carcinoma of the urinary bladder with a spontaneous perforation: a
      case report].
AB  - A 65-year-old woman was referred to our clinic with gross hematuria. Cystoscopy
      revealed a non-papillary and non-pedunculated tumor on the left lateral wall of
      the bladder. A piece of necrotic tissue obtained from the bladder irrigation was
      histologically squamous cell carcinoma. A perforation at the left lateral wall of
      the bladder was found on the cystogram. Bone scintigraphy showed multiple
      metastases and computed tomography scans showed multiple lymph node metastases in
      the pelvic cavity. The clinical diagnosis was bladder carcinoma of T4N2M1 stage
      with an abscess due to a spontaneous perforation. Total cystectomy with bilateral
      ureterocutaneostomy was performed. She died due to sepsis 13 days after the
      operation. Histologically, the tumor was composed of carcinomatous and
      sarcomatous elements. The carcinomatous element was compatible with squamous cell
      carcinoma and the sarcomatous element was composed of undifferentiated malignant
      spindle cells. Immunohistochemical examination showed that the carcinomatous
      component was positive for keratin and human chorionic gonadotropin (HCG) and the
      spindle cell component positive for vimentin, desmin and HCG. Therefore, we
      diagnosed the tumor as sarcomatoid carcinoma. We reviewed 56 cases of
      carcinosarcoma of the bladder in Japan and discussed the clinicopathology of the
      disease.

PMID- 12491614
TI  - [A case of arteriovenous hemangioma of the undescended testis].
AB  - An 8-month-old boy was admitted to our hospital with the complaint of left
      inguinal pain during his follow-up of left cryptorchism. Computed tomography
      showed a solid mass with a low density area in the left inguinal region. Tumor
      markers, including alpha-fetoprotein and human gonadotropin-beta, were normal.
      Exploration of the left testis by an inguinal approach revealed a reddish mass
      occupying more than half of the testicular parenchyma and we performed left
      orchiectomy. The tumor was histopathologically diagnosed as arteriovenous
      hemangioma.

PMID- 12491615
TI  - [A case of acid burn of the penis].
AB  - A 27-year-old man presented to our hospital complaining of multiple mild injuries
      sustained in an attack of violence at the workplace. He had received chemical
      burns to the penis induced by hydrochloric acid and had developed severe
      phimosis. He complained of pain on erection and ballooning during urination. The
      foreskin was partially resected with foreskin grafting for the stricture. The
      postoperative outcome was favorable and his symptoms were relieved.

PMID- 12491616
TI  - [Clinical investigation of 6 cases of urachal carcinoma].
AB  - We have encountered 6 cases of urachal carcinoma in the past 7 years. They
      consisted of 4 females and 2 males, with the mean age of 48 years old. Of them, 2
      cases were identified as gestational complications. Bladder irritating symptoms
      and extracystic symptoms other than hematuria were not observed as initial
      symptoms, and urinary cytology was positive in 2 cases. Cystoscopy is essential
      for diagnosis, but the spread of the tumor was clearly visualized by sagittal
      section patterns on magnetic resonance imaging. A correlation between the tumor
      and clinical course was suggested immunohistochemically with, carcinoembronic
      antigen and carbohydrate antigen 19-9. Cases of gestation concurrent with urachal
      carcinoma are very rare, but are expected to increase in the future. Thus
      appropriate medical treatment must be given to the maternal body. For the
      treatment, appropriateness of advanced surgery more than partial resection of the
      bladder combined with total urachoumbilical resection was recommended. However,
      an effective adjuvant chemotherapy after the first surgical resection needs to be
      established to improve the patient's quality of life.

PMID- 12491617
TI  - [A case of focal xanthogranulomatous pyelonephritis difficult to differentiate
      from renal cell carcinoma].
AB  - A 34-year-old female with left flank pain persisting for 3 months consulted us on
      19 Feb, 2001. Ultrasonography (US), computerized tomography (CT), magnetic
      resonance imaging (MRI) and renal angiography revealed a cystic renal tumor in
      the upper pole of the left kidney invading the spleen, and paraaortic lymph node
      swelling. Left radical nephrectomy combined with splenectomy and partial
      diaphragmectomy was performed under a tentative diagnosis of renal cell
      carcinoma. However, histopathological findings revealed xanthogranulomatous
      pyelonephritis (XGP). XGP is a rare, severe, chronic inflammatory disease
      characterized by accumulation of lipid laden macrophages. XGP is classified as
      diffuse or focal type. Preoperative diagnosis of focal XGP is difficult because
      of radiological similarities to renal cell carcinoma. Our case was more difficult
      to diagnose because she showed few signs of inflammation and had no history of
      urinary tract infection or stones.

PMID- 12491618
TI  - [Inflammatory pseudotumor of the urinary bladder: a case report].
AB  - A 52-year-old man presented with gross hematuria. He had neither history of
      urinary tract infection nor trauma. Cystoscopy revealed a bladder tumor with
      ulcer on a left lateral wall. Computed tomography confirmed a round solid mass 3
      cm in diameter invading deeply into the muscle layer of the urinary bladder.
      Transurethral biopsy revealed an inflammatory pseudotumor of the urinary bladder.
      Partial cystectomy was performed. This is the 38th reported case of inflammatory
      pseudotumor of the urinary bladder in Japan. No local recurrence was seen 3
      months after surgery.

PMID- 12491619
TI  - [Inverted papilloma of the urinary bladder: three case reports].
AB  - We report three cases of inverted papilloma of the urinary bladder. Case 1. A 19
      year-old male complained of pollakisuria, gross hematuria and micturition pain.
      Cystoscopy revealed a smooth-surfaced tumor on a stalk at the bladder neck. The
      tumor was removed transurethrally. Histological diagnosis was inverted papilloma.
      As a safe guard, intravesical chemotherapy (Adriamycin) was performed, since
      pathological findings revealed a small region with mild atypical cells in the
      removed tumor. The patients has been subsequently followed up for ten years
      without any evidence of recurrence. Case 2. A 63-year-old male was admitted to
      our hospital because of a bladder tumor incidentally found by abdominal
      ultrasonography. The tumor was removed transurethrally. Histological diagnosis
      was inverted papilloma. The patient has been subsequently followed up for one
      year without any evidence of recurrence. Case 3. A 71-year-old male complained of
      pollakisuria, loss of urinary force and interruption of the urinary stream. A
      smooth-surfaced tumor found at the bladder neck was removed transurethrally.
      Histological diagnosis was inverted papilloma. Three months later, cystoscopy
      revealed two sessile papillary tumors on the left lateral wall of the urinary
      bladder. Pathological diagnosis was transitional cell carcinoma (G2, pTa).
      Although the inverted papilloma is a benign tumor, there is a possibility of
      recurrence or development of transitional cell carcinoma. Therefore, we advocate
      periodical follow-up examinations.

PMID- 12491620
TI  - [A case of eosinophilic cystitis].
AB  - A 67-year-old man presented with pollakisuria, and miction pain. The patient who
      had superficial bladder cancer was treated with transurethral resection and
      instillation of Pirarubicin hydrochloride. Urinalysis revealed a marked increase
      in eosinophilic cells. A cystoscopic examination revealed an ischemic lesion and
      hypervascular lesion throughout the bladder. Histological findings of biopsied
      bladder specimens showed eosinophilic cystitis. Bladder symptoms are improved
      with steroid administration.

PMID- 12491621
TI  - Solitary fibrous tumor in the retroperitoneum: a case with infiltrative growth.
AB  - Solitary fibrous retroperitoneal tumor is rare. We present a case with
      infiltrative growth in a 56-year-old female patient whose initial symptom was
      palpable tumor in the lower abdomen. Computed tomography and magnetic resonance
      imaging indicated a mass in the retroperitoneum under the left kidney with a
      poorly demarcated infiltrative growth. Surgical findings revealed a gelatinous
      tumor in the retroperitoneum, which had invaded up to the fatty tissue
      surrounding the Gerota's fascia and to the fatty tissue surrounding the
      descending colon. However, as there was no invasion into the Gerota's fascia, it
      was possible to preserve the left kidney. Pathohistological examination revealed
      increased cellularity in the tumor tissues as well as tissues with atypical
      nuclei of the tumor cells with some cell division. Due to these findings, it was
      diagnosed as malignant solitary fibrous tumor. Only surgical treatment was
      performed and the patient is alive without recurrence 2 years and 4 months after
      surgery.

PMID- 12491622
TI  - [Biochemical study on steroid sulphatase in the endometrioid adenocarcinoma].

PMID- 12491623
TI  - [Analysis of the imprinted domain in the vicinity of MEST at chromosomal 7q32].

PMID- 12491624
TI  - [A study on the screening of prenatal trisomy 21 using the fucosylated alpha
      fetoprotein ratio measured by a liquid-phase binding assay].

PMID- 12491625
TI  - [A study of interaction between keratinocytes and fibroblasts in keloid].

PMID- 12491626
TI  - [Histomorphometric analysis on interface between the three-dimensional fabric
      artificial intervertebral disc and the vertebral body in experimental disc
      replacement with a sheep model].

PMID- 12491627
TI  - [The effect of antiepileptic drugs for slow wave sleep of the patients with
      symptomatic localization-related epilepsy].

PMID- 12491628
TI  - [Clinical characteristics and antithrombotic therapy for stroke prevention in
      patients with atrial fibrillation].

PMID- 12491629
TI  - [Presensitization of donor splenic dendritic cells with the CD40/CD40L blockade
      induce long-term graft acceptance].

PMID- 12491631
TI  - [Endocrine tumors: at the crossroads of genetics and surgery].

PMID- 12491632
TI  - [Towards the end of abdominoperineal resection for cancer].

PMID- 12491633
TI  - [Multiple endocrine neoplasia type I or Werner syndrome. What is important to
      know about surgery of a rate disease].
AB  - Multiple endocrine neoplasia type 1 (MEN1) is a rare but misleading disease. The
      diagnosis is evocated when two main lesions are present (parathyroid, endocrine
      pancreas, pituary gland) but also when a family tree shows recurrent lesions.
      Other lesions must be taken into account (adrenal glands, neuroendocrine thymic
      or bronchic lesions, cutaneous lesions, lipomas, nervous central system tumors).
      Any surgical cure without knowing the MEN1 background leads to failure. Specific
      treatment of each lesion is reviewed. Genetic diagnosis is possible but the
      mutation is not found in all cases. Nevertheless, when the mutation is known in a
      family, a negative genetic test allows to exclude the disease. Prognosis is
      related to hepatic metastases and to thymic neuroendocrine tumors which are rare
      (2.1%) but aggressive. As a general rule, any apparently isolated endocrine
      lesion such hyperparathyroidism must prompt the surgeon to look for another
      endocrine lesion and to look for an abnormal family tree with recurent
      monoglandular or pluriglandular lesions.

PMID- 12491635
TI  - [Surgical treatment of acute pancreatitic with infected necrosis by necrosectomy
      pancreatostomy].
AB  - Technical modalities of surgical treatment of infected pancreatic necrosis
      remains controversial. The aim of this retrospective study was to assess the
      results of necrosectomy associated by pancreatostomy using active drainage
      according Mikulicz, which is currently an unusual technique. PATIENTS AND
      METHODS: From 1985 to 1997, 18 consecutive patients (median age = 63; range = 35
      88 years) were operated on through laparotomy for infected necrosis and treated
      by necrosectomy combined with Mikulicz drainage. Fourteen patients were referred
      from another center, including 9 who had previous surgery. Necrosectomy was
      performed after a median delay of 22 days (1-45) after onset of pancreatitis, in
      all patients because of severe sepsis (including 12 patients with persisting
      shock) and presence at CT scan of necrotic collections containing gas bubbles (n
      = 15) and/or infection proven by percutaneous aspiration (n = 3). RESULTS: After
      the first procedure, patients underwent between 2 and 25 (median: 5) additional
      necrosectomies through the pancreatostomy tract. Thirteen surgical complications
      were observed in 8 patients: digestive fistula (n = 7), intraabdominal bleeding
      (n = 3), gastrointestinal haemorrhage (n = 1), colic stenosis with colectasy (n =
      1). Five patients, all referred from another center, died (28%) between the 47th
      and the 140th day from multiorgan failure (n = 4) or gastrointestinal haemorrhage
      (n = 1). The median hospital stay was 109 days (26-265) including 51 in intensive
      care unit (1-134). The 13 surviving patients were followed during an average of 2
      years (4 months-7 years). All developed an incisional hernia of the
      pancreatostomy tract, which was surgically treated in 6 cases. CONCLUSIONS:
      Necrosectomy-pancreatostomy is an appropriate treatment of acute pancreatitis
      with infected necrosis, despite the usual need of additional but easy
      necrosectomies, and the frequent occurrence of incisional hernia. Results
      observed in patients referred to our center suggest that earlier diagnosis of
      necrosis infection using percutaneous aspiration could improve the prognosis.

PMID- 12491634
TI  - [Evaluation of povidone abdominal washing for prevention of peritoneal cancer
      cell seeding: experimental study in the rat].
AB  - GOAL: The aim of the study was to evaluate the in vitro cytototoxicity of diluted
      povidone iodine on colon cancer cells and its in vivo antitumoral effect in a
      model of peritoneal carcinomatosis in the rat. METHODS: Cell cytotoxicity of a
      povidone iodine diluted solution was assessed, in vitro, on rat colon cancer
      cells (DHD/K12/PROb) and human colon cancer cells (HT29). The antitumoral effect
      of diluted povidone iodine washing was measured in BDIX rats after the
      intraperitoneal inoculation of 10(6) DHD/K12/PROb cells. Results were compared to
      an abdominal washing within a 9 g/l salinel solution. In one experiment,
      peritoneal scars and a colocolic anastomosis were performed after the injection
      of cancer cells. RESULTS: A short 10 min incubation of human and rat colon cancer
      cells with diluted povidone iodine resulted in a complete cell killing. In
      animals, a peritoneal washing with 1% diluted povidone iodine completely
      inhibited the tumor growth in parietal peritoneum. However, development of
      peritoneal tumor nodules was not inhibited in the omentum, in scarified
      peritoneum or in intestinal anastomosis. CONCLUSIONS: Despite its high in vitro
      efficacy, diluted povidone iodine has an incomplete effect in the prevention of
      peritoneal carcinomatosis, with only a partial inhibition in scarred peritoneum
      epiploic area and intestinal anastomosis. In contrary, it procures a complete
      inhibition of tumor growth in normal peritoneum.

PMID- 12491636
TI  - [Prospective study of early predictive factors of permanent hypocalcemia after
      bilateral thyroidectomy].
AB  - AIM OF THE STUDY: The aim of this prospective cohort study was to identify the
      early criteria potentially predictive for outcome of permanent hypocalcemia after
      thyroidectomy. PATIENTS AND METHODS: Serum calcium (Ca) et phosphorus (Ph) were
      measured daily until discharge in 2035 consecutive patients undergoing bilateral
      thyroidectomy. In all patients experiencing postoperative hypocalcemia, defined
      as a Ca < 8.0 mg/dl on two consecutive days, parathyroid hormone was measured
      prior initiation of calcium therapy et discharge (early PTH), et blood sample was
      also obtained 7 to 14 days after discharge for Ca et Ph measurements (delayed Ca
      et Ph). These patients were then followed up until complete resolution of
      hypocalcemia or at least one year. Those still needing substitutive therapy to
      maintain normocalcemia one year after surgery were considered to have permanent
      hypocalcemia. Correlation of outcome with clinical characteristics, postoperative
      Ca et Ph levels, early PTH, et delayed Ca et Ph were examined with univariate
      analysis et multivariate logistic regression. RESULTS: Postoperative hypocalcemia
      occurred in 153 patients (7.5%) and spontaneously recovered in all but 7 patients
      (0.3%). Delayed Ca, and delayed Ph were found to be predictive for outcome of
      hypocalcemia by univariate analysis (p < 0.01). Relative risk to develop
      permanent hypocalcemia was 15 for patients with early PTH < 12 pg/ml, 52 when
      delayed Ph was > 4.0 mg/dl, and 121 when delayed Ca was < 8.0 mg/dl. None of the
      113 patients with delayed Ca > or = 8.0 mg/dl and delayed Ph < or = 4.0 mg/dl
      developed permanent hypocalcemia, in contrast to 1 out of 31 patients (3%) with
      delayed Ca > 8.0 mg/dl or delayed Ph > 4.0 mg/dl, and 6 out of 9 patients (66%)
      with delayed Ca < 8.0 mg/dl and delayed Ph > 4.0 mg/dl. Both delayed Ca and
      delayed Ph appeared as independent factors predicting outcome of hypocalcemia at
      one year with multivariate logistic regression analysis. CONCLUSION: Delayed
      serum calcium and phosphorus levels, when measured one week after starting
      calcium therapy but prior to administration of any vitamin D analogs, accurately
      predict outcome of hypocalcemia after thyroidectomy. Patients with delayed Ca
      under 8.0 mg/dl and/or delayed Ph above 4.0 mg/dl are at high risk to develop
      permanent hypocalcemia.

PMID- 12491637
TI  - [Male breast cancer: 19 case reports].
AB  - Breast cancer is rarely encountered in men. In developed countries, it accounts
      for less than 1% of cancers in men, whereas in women it represents about 23% of
      all cancers. A retrospective review was performed on 19 cases of men who
      underwent surgery for breast carcinoma between 1989 and 2000. The aim of this
      work was to analyse epidemiological and etiological aspects, circumstances of
      discovery, pathological characteristics, therapy modalities as well as prognostic
      factors. The mean age was 65.3 years. A high incidence of overweight, diabetes,
      hypertension and hypercholesterolemia was found. The most frequent clinical
      presentation was a firm subareolar lump, at a low stage (stage I 23% and stage II
      41%). The most common pathological type was an infiltrating ductal carcinoma
      (89%). Hormone receptors where most often positive (92% for oestrogen and 100%
      for progesterone receptors). 84% of patients underwent simple mastectomy and
      axillary dissection, 74% chest wall irradiation after surgery, 26% received
      chemotherapy and 42% hormonal therapy. Median follow-up was 52 months. The
      estimated 2-year overall survival (OS) and disease-free survival (DFS) was
      respectively 93% and 87.5% and the 5-year OS and DFS respectively 86% and 75%.
      The management of male and female breast carcinoma is identical, as well as their
      prognosis at equal stages. However male breast carcinoma is more often diagnosed
      at a more advanced stage, thus a breast screening in men would permit a sooner
      diagnosis and a better prognosis.

PMID- 12491638
TI  - [Three-luminal nasojejunal tube in digestive surgery: preliminary feasibility
      study].
AB  - STUDY AIM: The benefit of enteral nutrition is an established fact for severely
      burned or multiple injured patients with a reduction of septic morbidity. Enteral
      nutrition is now possible in upper gastrointestinal tract surgery with the
      development of nasojejunal triple lumen tube and we report a new application with
      an operative placement. The aim of the study was to evaluate the nasojejunal
      triple lumen tube in digestive surgery. MATERIAL AND METHODS: From November 1999
      to August 2001, a nasojejunal triple lumen tube was placed during surgery for
      high surgical risk patients (n = 17) or under radioscopic control for the
      treatment of post operative complications (n = 6). RESULTS: The surgical
      placement was possible in all cases. The radioscopic placement failed in two
      cases, one of which being solved with endoscopic procedure. There was no
      morbidity during the tube placement. Four patients were excluded because of early
      post operative death (n = 3) or premature removal of the tube by the patient (n =
      1). The enteral nutrition was early in 18 patients and its mean duration was 18.2
      days (range 3-75). Technical problems occurred in 9 patients and the replacement
      of the tube was necessary in 8 cases. CONCLUSION: The nasojejunal triple lumen
      tube is a feasible, safe and relatively well-tolerated procedure in upper
      gastrointestinal tract surgery.

PMID- 12491639
TI  - [Radial artery aneurysm: an unusual complication of radial artery
      catheterization].
AB  - Percutaneous arterial cannulation is systematically used in cardiac surgery and
      reanimation for hemodynamic monitoring. It was frequently used in coronarography.
      Risk factors for occurrence of radial aneurysm after catheterization may include
      advanced age, longer duration of catheterization, hospitalization duration, and
      general infection with Staphylococcus aureus. We report an uncommon case of
      radial artery aneurysm, after cardiac surgery. We operated the patient with a
      good result.

PMID- 12491640
TI  - [Mature cystic teratoma of the ovary with differentiated and secretive gastric
      mucosa].
AB  - Large teratomas with gastric mucosa are rare. We report a case of mature cystic
      teratoma in an ovary of a young woman. Tumor growth was large and rapid enough to
      displace abdominal organs. The cyst was aspirated (removing 101 of mucinoid
      liquid) and excised by medial hypogastric laparotomy. The histological
      examination revealed differentiated gastric fundal mucosa with no other tissue
      involvement.

PMID- 12491642
TI  - [Gastric duplication in the adult: a case report presenting as recurring acute
      edematous pancreatitis].
AB  - A duplication cyst of the gastric antrum was diagnosed in a 35-year man after
      recurring attacks of acute pancreatitis. The patient was operated on with the
      preoperative diagnosis of cystic dystrophy on aberrant pancreatic tissue of the
      antrum wall. Diagnosis of duplication was established on pathologic examination
      of antrectomy specimen. A review of the literature about gastric duplication is
      performed.

PMID- 12491641
TI  - [Intramural pseudodiverticulosis of the esophagus. A case report and review of
      the literature].
AB  - Oesophageal intramural pseudodiverticulosis is a very rare cause of dysphasia.
      This work reports the observation of a 42 year-man who presented with dysphasia;
      Diagnosis was established by baryum meal. The patient underwent an oesophagectomy
      because of failure of endoscopic dilatation. Pathologic examination revealed
      characteristic lesions of esophageal pseudodiverticulosis, with fissures between
      the lumen and sero-mucosal glands located in the oesophageal wall and containing
      Candida spores. By means of a review of the relevant literature,
      etiopathogenesis, diagnosis and treatment of oesophageal intramural
      pseudodiverticulosis are discussed.

PMID- 12491643
TI  - [Why did the invincible armada met her fate in Calais? Or the history of the
      founding of the University of Lille].

PMID- 12491644
TI  - [Pancreatic head resection (Frey technique) and Wirsungo-jejunal anastomosis in
      the treatment of chronic pancreatitis].
AB  - We report herein a modification of the standard wirsungojejunostomy in patients
      with chronic pancreatitis, which includes concomitant duodenum-preserving
      resection of the head of the pancreas as described by Frey. This technique is
      safe and seems to provide more effective long-term pain relief than standard
      wirsungo-jejunal anastomosis.

PMID- 12491645
TI  - [Endoscopic sphincterotomy for all cases of acute pancreatitis? Where is the
      scientific proof?].

PMID- 12491646
TI  - [Those who read medical articles are at risk of dying due to a typing error].

PMID- 12491647
TI  - [Discussion about Peschaud et al.'s article: surgical treatment of pancreatic
      metastasis from kidney cancer].

PMID- 12491648
TI  - Effects of acute and prolonged opiate abstinence on extinction behaviour in rats.
AB  - We examined the role of withdrawal in relapse to drug-seeking and drug-taking by
      testing the effects of opiate abstinence on extinction behaviour in rats trained
      to self-administer heroin. Male Long-Evans rats responded for IV heroin under a
      heterogeneous chain (VI 120 s; FR 1) schedule in which "seeking" responses
      preceded a "taking" response which produced a drug infusion. Responding was then
      measured in extinction during acute (6, 12, and 24 hr) and prolonged (3, 6, 12,
      and 25 day) abstinence. Sucrose consumption and somatic withdrawal were assessed
      at each testing period. During acute abstinence, responses on the "drug-seeking"
      manipulandum increased at 24 hr, whereas responses on the "drug-taking"
      manipulandum increased at 6 hr. Both responses were elevated during the 12-day
      abstinence test. Sucrose consumption was reduced and somatic withdrawal scores
      were increased in opiate-experienced rats at each test period. Results suggest
      that heroin abstinence has different effects on drug-seeking and drug-taking and
      that these effects do not temporally coincide with somatic measures of opioid
      withdrawal.

PMID- 12491650
TI  - Feeling-of-knowing for proper names.
AB  - The main objective of the presented study was to study feeling-of-knowing (FOK)
      in proper name retrieval. Many studies show that FOK can predict performance on a
      subsequent criterion test. Although feeling-of-knowing studies involve questions
      about proper names, none make this distinction between proper names and common
      names. Nevertheless, the specific character of proper names as a unique label
      referring to a person should allow participants to target precisely the desired
      verbal label. Our idea here was that the unique character of proper name
      information should result in more accurate FOK evaluations. In the experiment,
      participants evaluated feeling-of-knowing for proper and common name
      descriptions. The study demonstrates that FOK judgments are more accurate for
      proper names than for common names. The implications of the findings for proper
      names are briefly discussed in terms of feeling-of-knowing hypotheses.

PMID- 12491649
TI  - [Targets of the memorized position and visual contexts].
AB  - The goal of this study was to determine whether a sensorimotor or cognitive
      encoding is used to encode a target position and save it into iconic memory. The
      methodology consisted of disrupting a manual aiming movement to a memorized
      visual target by displacing the visual field containing the target. The nature of
      the encoding was inferred from the nature and the size of the errors relative to
      a control. The target was presented either centrally or in the right periphery.
      Participants moved their hand from the left to the right of fixation. Black and
      white vertical stripes covered the whole visual field. The visual field was
      either stationary throughout the trial or was displaced to the right or left at
      the extinction of the target or at the start of the hand movement. In the latter
      case, the displacement of the visual field obviously could only be taken into
      account by the participant during the gesture. In this condition, our hypothesis
      was that the aiming error would follow the direction of visual field
      displacement. Results showed three major effects: (1) Vision of the hand during
      the gesture improved the final accuracy; (2) visual field displacement produced
      an underestimation of the target distance only when the hand was not visible
      during the gesture and was always in the same direction displacement; and (3) the
      effect of the stationary structured visual field on aiming precision when the
      hand was not visible depended on the distance to the target. These results
      suggest that a stationary structured visual field is used to support the memory
      of the target position. The structured visual field is more critical when the
      hand is not visible and when the target appears in peripheral rather than central
      vision. This suggests that aiming depends on memory of the relative peripheral
      position of the target (allocentric reference). However, in the present task,
      cognitive encoding does not maintain the "position" of the target in memory
      without reference to the environment. The systematic effect of the visual field
      displacement on the manual aiming suggests that the role of environmental
      reference frames in memory for position is not well understood. Some studies, in
      particular those of Giesbrecht and Dixon (1999) and Glover and Dixon (2001),
      suggested differing roles of the environment in the retention of the target
      position and the control of aiming movements toward the target. The present
      observations contribute to understanding the mechanism involved in locating and
      grasping objects with the hand.

PMID- 12491651
TI  - Influence of probe-trial selection on the location negative priming effect.
AB  - Using the location variant of the typical negative priming procedure,
      participants were cued (100% reliable) before (Experiment 1) or after (Experiment
      2) the prime trial as to whether a distractor would or would not accompany the
      target on the probe trial. The crucial results were that on cued trials, the
      predictable absence, produced the removal of the negative priming effect
      (disengagement), and that this disengagement of the priming process, motivated by
      the predictable absence of a probe-trial distractor, could take place on-line.
      These findings demonstrated the "selection-state" dependency (probe trial) of the
      location negative priming process, supporting inhibition-based and episodic
      retrieval models in their contention that the ultimate function of this process
      is to enhance the efficiency of future distractor processing, and hence
      selection. The disengagement results revealed an adaptive feature of a process
      that can be detrimental or irrelevant to upcoming processing.

PMID- 12491652
TI  - Overcoming spontaneous patterns of coordination during the acquisition of a
      complex balancing task.
AB  - Learning in complex tasks is usually conceived as the problem of mastering the
      multiple and redundant degrees of freedom of the system. To reduce control
      requirements, two different strategies are conceivable. The first one consists of
      a "freezing-freeing" process for most articular joints to reduce the number of
      active biomechanical degrees of freedom to be managed. The second strategy
      consists of introducing rigid couplings between the oscillators building the
      system. In this case, learning implies the dissolution of initial couplings and
      the emergence of new, more task-specific couplings. The goal of our study was to
      analyze the spontaneous coordination of beginners and its development in a
      complex balancing task on a stabilometer, and to examine the emergence of these
      two strategies. Our results showed that beginners were characterized by strong
      couplings between the joints of the lower limbs. During learning, new and more
      task-specific couplings emerged that reflected a new organization of the trunk
      and a decoupling of some joints of the lower limbs that were initially coupled
      during the first few trials.

PMID- 12491653
TI  - Examining the role of the fixation cue in inhibition of return.
AB  - To clarify the role of the fixation cue in inhibition of return (IOR), the
      present study compared four conditions: fixation cue immediately after the
      peripheral cue, in the middle of the stimulus-onset asynchrony (SOA), immediately
      before the onset of the target, or no fixation cue. With a 200-ms SOA, less IOR
      was found when the fixation cue was either absent or occurred immediately after
      the peripheral cue. No differences between the four conditions were found with
      400-ms and 800-ms SOAs. These findings suggest that there is a brief period of
      time in which attention cannot be withdrawn from the peripherally cued location.
      Once attention has been withdrawn from the peripherally cued location, IOR can be
      found at short SOAs.

PMID- 12491654
TI  - Adults' representations of division facts: a consequence of learning history?
AB  - There has been a recent increase in the study of adults' performance on simple
      division problems. Researchers up to now have focused on the relationship between
      multiplication and division and have found that multiplication often has a
      mediating role in the solution of division problems (Campbell, 1997, 1999;
      LeFevre & Morris, 1999; Mauro, LeFevre, & Morris, 2002). In this study, division
      was exclusively examined to determine the strategies that are used to solve these
      problems and to identify factors relating to particular strategy use. Thirty-two
      participants were asked to solve two sets of 64 simple division problems (from 4
      divided by 2 to 81 divided by 9) and error, latency, and strategy report data
      were collected. Fewer errors were made on easy problems, which were also solved
      more quickly than difficult problems. Participants used retrieval,
      multiplication, and other strategies to solve the problems and tended to use
      retrieval more on easy than difficult problems and used multiplication more on
      difficult problems than easy problems. Unexpected age differences in strategy use
      were also found. Older participants tended to rely more heavily on retrieval than
      younger participants. These results suggest that older participants may have
      stronger representations for simple division problems than younger participants.

PMID- 12491655
TI  - Neighbourhood density effects in reading aloud: new insights from simulations
      with the DRC model.
AB  - A series of nine simulations with the Dual Route Cascaded (DRC) model (Coltheart,
      Rastle, Perry, Langdon, & Ziegler, 2001) investigated neighbourhood density (N)
      effects in nonword and word naming. Two main finding emerged from this work.
      First, when naming nonwords there are two loci for the effect of N in the model,
      contrary to Coltheart et al.'s single locus explanation of what the model is
      doing. The early N effect involves interactive activation between the
      orthographic lexicon and the letter units such that high N facilitates letter
      identification, which in turn affects the nonlexical route. The late N effect
      arises from activation in the orthographic lexicon that feeds forward to the
      phonological lexicon and primes phonemes in the phoneme system. Second, when
      naming words the presence/absence of an effect of N on the Letter Units through
      feedback from the lexical level depends on the parameter settings. Implications
      and suggestions for future directions are made.

PMID- 12491656
TI  - Balancing science, ethics and politics: stem cell research, a paradigm case.

PMID- 12491657
TI  - The role of the courts in health care rationing: the German model.

PMID- 12491658
TI  - Constitutional values and the ethics of health care: a comparison of the United
      States and Germany.

PMID- 12491659
TI  - The "R" word.

PMID- 12491660
TI  - The market ethos and the integrity of health care.

PMID- 12491661
TI  - Social ethics and organizational structures influencing the allocation of health
      care in Germany and the United States.

PMID- 12491662
TI  - The economic and ethical dimensions of health policy.

PMID- 12491664
TI  - Health records privacy and confidentiality: pending questions.

PMID- 12491663
TI  - German health care--towards universal access. An overview of the principles of
      access and benefits.

PMID- 12491665
TI  - Family health care based on the principle of solidarity.

PMID- 12491666
TI  - Budgeting and rationing in the German health care system.

PMID- 12491667
TI  - Managed care and undividing loyalties.

PMID- 12491668
TI  - [Problems of disinfectological biosafety provision].

PMID- 12491669
TI  - [Problems of providing medical care to residents in emergency situations
      connected with exposure to biological factors].

PMID- 12491670
TI  - [Threat of terrorism--a real stressogenic situation: new tasks for science and
      practice].

PMID- 12491671
TI  - [Resistance to psychoemotional stress as a biosafety problem].

PMID- 12491672
TI  - [Strategies for increasing the level of medical provision to residents of eastern
      regions of Russia].

PMID- 12491673
TI  - [Ecotoxicants and population health].

PMID- 12491674
TI  - [Life support in emergency situations in the Russian European north].

PMID- 12491675
TI  - [Hygienic basis for provision of biosafety to man].

PMID- 12491676
TI  - [Specific and nonspecific indication of microorganisms in the environment].

PMID- 12491677
TI  - [Resolution of the Eleventh (LXXIV) session of the general meeting of the Russian
      Academy of Medical Sciences "Medical Biosafety Problems"].

PMID- 12491678
TI  - [Modern pathophysiology and its development].

PMID- 12491679
TI  - [Features of population health and health care in Moscow].

PMID- 12491680
TI  - [Role of environmental pollution with lead and maintaining psychological
      development of preschool age children].

PMID- 12491681
TI  - Spinal cord injury and male infertility.
AB  - Spinal cord injury (SCI) commonly affects males in their reproductive years.
      After spinal cord injury, most men experience fertility related problems
      including erectile and ejaculatory dysfunction, impaired spermatogenesis,
      abnormal sperm viability, motility, and morphology, genitourinary infection and
      endocrine abnormalities. In this article we will review the pathophysiology,
      evaluation and management of infertility in spinal cord injury. The impact of
      spinal cord injury on seminal plasma and the contribution of seminal oxidative
      stress to the poor sperm quality of men with spinal cord injury will be
      presented. Success with sperm retrieval techniques and assisted reproductive
      technology in SCI men with spinal cord injury will be discussed.

PMID- 12491682
TI  - [Effects of 19-nortestosterone on sex accessory gland growth in hypogonadal
      mice].
AB  - OBJECTIVES: To evaluate the effects of 19-nortestosterone (NT) on the growth and
      development of the ventral prostate (VP), epididymis, and seminal vesicles (SV)
      in hypogonadal (hpg) mice. METHODS: The silastic tube filled with NT was
      implanted subdermally into mature hpg mice (n = 7) for five weeks. Similar
      silastic tubes without NT were implanted into both of hpg mouse control group (n
      = 7) and normal mouse group (n = 10) instead. The weights of sex accessory glands
      and the branch tip number of VP from all mice were evaluated. RESULTS: The
      weights of VP, SV, and epididymis in NT treated hpg group were significantly
      higher than those of hpg control group (P < 0.005); and the branching morphology
      of the VP showed a tendency to be normal and the development of prostate ductal
      tip was improved significantly. Especially, the weight of SV in NT treated hpg
      mice was equal to that of normal mice, while the weights of VP, epididymis and
      branching tip number in NT treated hpg group was still significantly lower than
      that of normal mice (P < 0.005). CONCLUSIONS: The NT treatment significantly
      stimulates the growth and development of the sex accessory gland in mature hpg
      mouse.

PMID- 12491683
TI  - [Effects of newborn bull serum and vitamins on cryopreservation of mouse
      seminiferous epithelial cells].
AB  - OBJECTIVES: To investigate the effects of newborn bull serum(NBS), vitamin C and
      vitamin E on cryopreservation of mouse seminiferous epithelial cells. METHODS:
      The seminiferous epithelial cells from 7-day-old mice were cryopreserved in
      different freezing solutions. The cell recoveries were examined by Trypan blue
      exclusive staining after thawing. The freezing solutions composed of DMEM, 10%
      dimethylsulphoxide(DMSO), and 0, 5%, 10%, or 20% NBS, respectively, or composed
      of DMEM, 10% DMSO, 10% NBS, and 150 micrograms/ml vitamin C or 50 micrograms/ml
      vitamin E, respectively. RESULTS: The cell recoveries in freezing solution
      containing 0, 5%, 10%, or 20% NBS were 83.4%, 84.7%, 85.7% and 83.6%,
      respectively. There were no significant differences between them. The cell
      recoveries in freezing solution containing vitamin C or vitamin E were 88.0% and
      82.9%, respectively. There was no significant differences compared with that in
      freezing solution containing 10% DMSO and 10% NBS. CONCLUSIONS: NBS, vitamin C
      and vitamin E have no significant protecting effects on mouse seminiferous
      epithelial cells, and can not significantly improve the cell recoveries.

PMID- 12491684
TI  - [Study on the relationship of balanced translocation t(1;12) with
      spermatogenesis].
AB  - OBJECTIVES: To investigate the relationship between chromosome balanced
      translocation t(1;12) (q24;q24) and spermatogenesis in infertile twin brothers.
      METHODS: For twin brothers, karotype were determined. The levels of testosterone,
      FSH and LH were detected. YRRM1, DAZ and DYS240 were analyzed. In younger brother
      a biopsy was taken from testis. RESULTS: Chromosome analysis for both twin
      brothers revealed a karotype of 46, XY, t(1;12) (q24;q24). Sperm count was less
      than 1.0 x 10(6)/ml. There was no deletion for YRRM1, DAZ and DYS240 gene on Y
      chromosome. Photomicrograph of seminiferous tubules showed the arrest of
      spermatogenesis. CONCLUSIONS: Chromosome balanced translocation t(1;12) (q24;q24)
      may be the cause of the spermatogenesis arrest in infertile twin brothers. Gene
      in the point of translocation may be related to spermatogenesis.

PMID- 12491685
TI  - [The expression of nitric oxide synthase in testes of male rat].
AB  - OBJECTIVES: To determine the expression of nitric oxide synthase (NOS) in testis
      and to investigate the effects of NO on the reproductive function of testis.
      METHODS: Testes of adult male Sprague-Dawley rats were fixed in 4%
      paraformaldehyde. The paraffin sections were made as routine. Immunohistochemical
      ABC method was used to observe the localization of NOS. RESULTS: Endothelia NOS
      (eNOS), neuronal NOS (nNOS) and inductive NOS (iNOS) were all expressed in Leydig
      cells. Only eNOS was expressed in peritubular myoid cells, endothelial and smooth
      muscle cells of blood vessel, while only nNOS expressed in tunica adventitia of
      testicular blood vessels. The reactive substance distributes in cytoplasm with
      negative nuclei. Immunoreactivity for eNOS, nNOS and iNOS in all spermatogenic
      cells was negative. CONCLUSIONS: Three kinds of NOS were all expressed in testis
      and the distribution of different NOS had a little difference.

PMID- 12491686
TI  - [Freezing effect on sperm DNA].
AB  - OBJECTIVES: To assess the effect of freezing on the sperm DNA. METHODS: To assess
      the sperm DNA preserved at -80 degrees C by using the single cell gel
      electrophoresis (SCGE). RESULTS: There was no statistical difference on the time
      factor by analysis of variance (ANOVA). CONCLUSIONS: Integrity of sperm DNA could
      not be devastated in frozen states.

PMID- 12491687
TI  - [The effect of antioxidant enzyme on germ cell apoptosis in cryptorchidism].
AB  - OBJECTIVES: To evaluate the effect of superoxide dismutase (SOD), catalase (CAT)
      and glutathione peroxidase (GSHPx) on germ cell apoptosis in cryptorchidism.
      METHODS: Forty-eight immature male Sprague-Dawley rats were divided into the
      cryptorchid and the control group randomly. Testes were harvested at 1, 3 and 7
      days after the operation. Germ cell apoptosis was determined by TUNEL technique,
      at the same time the activities of antioxidant enzymes and the level of malonic
      diethyl aldehyde (MDA) were detected with spectrophotometer. RESULTS: At the 7th
      day, as compared with the control, testicular weight, SOD activities, CAT
      activities and the ratio of SOD/(CAT + GSHPx) were reduced significantly(P <
      0.01), GSHPx activities had no apparent change(P > 0.05), while apoptosis index
      and the MDA level increased predominantly in cryptorchidism(P < 0.01).
      CONCLUSIONS: Germ cell apoptosis in cryptorchidism related closely to the
      decrease of antioxidant enzyme activity.

PMID- 12491688
TI  - [Sperm retrieval methods and pregnancy outcome of 100 azoospermia patients].
AB  - OBJECTIVES: To review the retrospective treatment results of the azoospermia
      patients during January 2001 to January 2002 in the fertility center. METHODS:
      One hundred males attempted intracytoplasmic sperm injection (ICSI) cycle for
      treatment of azoospermia. All patients were undergone sperm retrieval by
      percutaneous epididymal sperm aspiration (PESA) or testicular sperm extraction
      (TESE) while their wives received conventional ovarian hyperstimulation. The
      hormone levels, testicular histology, the rates of sperm retrieval,
      fertilization, implantation and pregnancy were analysed and evaluated. RESULTS:
      Sperm were retrieved by PESA in 76 of 100 (76%) and by TESE in 23 of 100 (23%)
      men of azoospermia. The fertilization rate, implantation rate and clinical
      pregnancy rate were 71.3%, 20.35% and 42.11% respectively in PESA group, and
      75.18%, 22.05% and 41.60% respectively in TESA group. Thirty-two clinical
      pregnancies were achieved with 15 ongoing pregnancies and subsequent live
      delivery for 15 cases in PESA group, and 2 cases of miscarriage, while 10
      clinical pregnancies were achieved with 6 ongoing pregnancies, 2 cases of live
      delivery and 2 cases of miscarriage in TESA group. One case failed to retrieve
      sperm by TESE and canceled. CONCLUSIONS: Hormonal levels and testicular histology
      are unable to predict which men with azoospermia will have sperm retrieved by
      PESA and TESE. PESA and TESE with ICSI are effective methods to treat
      azoospermia. There were no significant differences in fertilization, implantation
      and clinical pregnancy rate between two groups.

PMID- 12491689
TI  - [The relationships of PSA, FPSAR, clinical and pathological stage in patients
      with prostate cancer].
AB  - OBJECTIVES: To investigate the relationship between clinical and pathological
      stage, serum prostate specific antigen (PSA) concentration and free-to-total PSA
      ratio (FPSAR) in patients with prostate cancer. METHODS: Clinical and
      pathological stage were determined on the basis of pathological examination and
      clinic material in 42 prostate cancer patients treated by prostatectomy. PSA and
      FPSAR were measured before the operation. Spearman rank correlation was applied
      to evaluate the relationship between clinical and pathological stage, serum PSA
      concentration and FPSAR. RESULTS: Serum PSA concentration was significantly
      positively correlated with pathological stage(P < 0.05) but not correlated with
      clinical stage (P > 0.05) in prostate cancer patients. FPSAR was significantly
      correlated with pathological stage and negatively correlated with clinical stage
      in prostate cancer patients (P < 0.05). CONCLUSIONS: FPSAR is a more powerful
      predictor of clinical stage, pathological stage and prognosis than PSA.

PMID- 12491690
TI  - [Investigation of the mechanism of genitofemoral nerve in the contralateral
      testes damage of unilateral cryptorchid rats].
AB  - OBJECTIVES: To investigate the mechanism of genitofemoral nerve in the
      contralateral testes damage of unilateral cryptorchid rats. METHODS: After
      unilateral cryptorchid rat model (21-day) was made and the ipsilateral
      genitofemoral nerve was divided, the germ cells apoptosis and the concentrations
      of lactate of contralateral testes were detected and compared after 120 days.
      RESULTS: After the ipsilateral genitofemoral nerve was divided, the germ cells
      apoptosis and the lactate levels of the contralateral testes were all decreased
      from (17.28 +/- 1.36)% to (5.76 +/- 0.76)% and (2.19 +/- 0.24) mmol/L to (1.70 +/
      0.31) mmol/L, respectively. CONCLUSIONS: The damage pathway of the contralateral
      testes of unilateral cryptorchidism probably related to the apoptosis of the germ
      cells which caused by the reflex decrease of the contralateral testicular blood
      flow via the transmissions of genitofemoral nerve.

PMID- 12491691
TI  - [The establishment of testicular fibrosis model in Wistar rats].
AB  - OBJECTIVES: To establish the testicular fibrosis model in rats. METHODS: Wistar
      rats were divided into control group(n = 12) and model group(n = 40) randomly.
      Testicular fibrosis model was built with the classical method of establishing
      experimental autoimmune orchitis (EAO) combined with injecting Bacille Calmette
      Guerin (BCG) into left testis. RESULTS: The incidence rate of EAO and the rate of
      testicular fibrosis were 100%, 11.1% and 100%, 81.5% at 80, 140 days after the
      first infection, respectively. CONCLUSIONS: The model of rat testicular fibrosis
      was established successfully.

PMID- 12491692
TI  - [Effect of androgen on penile erection induced by L-arginine in paraventricular
      nucleus].
AB  - OBJECTIVES: To investigate the relationship between penile erection induced by L
      arginine in paraventricular nucleus (PVN) and androgen. METHODS: Twenty-four
      mature male rabbits were randomly divided into three groups which were castrate,
      castrate with testosterone propionate (T) replacement and pseudo-operation. One
      month later, the highest intracavernous pressure (ICP) and nitric oxide synthase
      (NOS) of each PVN tissue were measured after infusing L-arginine into the PVN.
      RESULTS: The mean ICPs of the highest values in castrate, castrate given T
      replacement and pseudo-operation groups were (22.640 +/- 4.747) mmHg, (38.146 +/-
      4.907) mmHg and (39.991 +/- 3.068) mmHg, respectively. The mean value of NOS
      activity of each group were (0.807 +/- 0.188) U/mg.prot, (1.457 +/- 0.293)
      U/mg.prot and (1.528 +/- 0.204) U/mg.prot, respectively. The ICP and NOS activity
      in castrate were different statistically from T replacement and pseudo-operation
      group (both P < 0.01). T replacement group had no statistical difference from
      pseudo-operation group(P > 0.05). CONCLUSIONS: Nitric oxide (NO) is one of the
      neurotransmitters in PVN particularly relevant for the control of penile
      erection. Penile erection induced by L-arginine in PVN depends on androgen.

PMID- 12491693
TI  - [Effects of fenvalerate exposure on the semen quality of occupational workers].
AB  - OBJECTIVES: To study the effects of fenvalerate exposure on the semen quality of
      occupational workers in order to find out the early effective biomarkers.
      METHODS: Thirty-two male workers who exposed to fenvalerate and 46 male
      administrators in the office in a pesticide factory were selected as the exposure
      group and internal control group, respectively, and 22 male administrators in a
      center for disease control were served as the external control group. In order to
      evaluate the exposed levels, the concentration of fenvalerate, toluene and xylene
      in the ambient air of working place in these three groups were monitored
      simultaneously for three consecutive days. After the semen were collected
      according to the standard method, the workers' semen qualities were analysed with
      University of California at Davis (UCDavis) method and the sperm motility were
      evaluated using computer assisted sperm analysis(CASA). RESULTS: In the exposure
      group, the concentrations of fenvalerate were significantly higher than those in
      the internal and external control group (P < 0.01), while no significant
      difference of the concentration on toluene or xylene was found (P > 0.05). Sperm
      motion parameters in the exposure group such as linearity(LIN),
      straightness(STR), and the sperm count were decreased significantly, and the
      abnormality rate of viscidity, coagulation and sperm count were increased
      significantly as compared with the internal and the external control groups(P <
      0.05). Furthermore, the sperm progression and beat cross frequency (BCF) in the
      exposure group were also lower significantly than those in the external control
      group(P < 0.05), while the abnormality rate of sperm progression was increased
      significantly. CONCLUSIONS: In such a low concentration, occupational exposure to
      fenvalerate can affect workers' semen quality, especially the sperm count and
      sperm movement ability.

PMID- 12491694
TI  - [Investigation of progesterone receptor on human sperm plasma membrane].
AB  - OBJECTIVES: To investigate the localization and positive percentage of
      progesterone receptor (PR) on the human sperm surface. METHODS: After in vitro
      capacitation, progesterone binding sites on the sperm were quantitatively
      analyzed by fluorescence microscopy and flow cytometry using fluorescein
      isothiocyanate-labeled bovine serum albumin-progesterone complex (P-BSA-FITC).
      RESULTS: The spermatozoa stained by P-BSA-FITC mainly showed two labeling
      patterns, with the green fluorescence on the whole acrosomal region or the
      equatorial acrosomal region only and the stainless postacrosomal and tail
      regions. The percentage of progesterone-binding sperm was (30.2 +/- 2.4)%.
      CONCLUSIONS: There is selective expression of PR on the human sperm acrosome
      surface.

PMID- 12491695
TI  - [Interventional therapy for the chronic seminal vesiculitis].
AB  - OBJECTIVES: To investigate the efficacy of transperineal seminal vesicle puncture
      under ultrasound guidance and continuous transcatheter antibiotic drugs
      instillation for the treatment of chronic seminal vesiculitis. METHODS: Forty-two
      patients with hemospermia were treated from April 1988 to January 2001. Of them
      35 patients with urogenital inflammation were treated by transperineal seminal
      vesicle puncture under ultrasound guidance and continuous transcatheter
      antibiotic drugs instillation. RESULTS: Transperineal seminal vesicle puncture
      and continuous transcatheter antibiotic drugs instillation therapy was adopted
      for 35 patients with urogenital inflammation and the cure rate was 91.43%.
      CONCLUSIONS: Transperineal seminal vesicle puncture under ultrasound guidance and
      continuous transcatheter antibiotic drugs instillation was an effective method
      for diagnosis and treatment of chronic seminal vesiculitis.

PMID- 12491696
TI  - [Ultrastructural observation of detrusor in BPH patients].
AB  - OBJECTIVES: To observe the detrusor ultrastructure in BPH patients and to
      investigate the relationship between detrusor instability and ultrastructure.
      METHODS: The patients were divided into groups of detrusor instability(DI) and
      detrusor stability(DS) according to urodynamics examination. The structure of the
      detrusor were observed by light microscopy and transmission electron
      microscopy(TEM). RESULTS: The intercellular intermediate junctions and
      cytoplasmic process junctions in DS were 11.34 +/- 3.23 and 4.26 +/- 1.78
      respectively. The intercellular intermediate junctions decreased obviously (3.12
      +/- 1.47, P < 0.01) instead of a large amount of cytoplasmic process junctions
      (26.37 +/- 7.14, P < 0.01) in DI. CONCLUSIONS: There is a close relevance between
      intercellular junctions and DI. The observation of the ultrastructure of the
      detrusor is helpful for the diagnosis of BPH with DI and for the clinical
      treatment.

PMID- 12491697
TI  - [The clinical efficacy of Naftopidil tablet in the treatment of benign prostatic
      hyperplasia].
AB  - OBJECTIVES: To evaluate the clinical efficacy and safety of Naftopidil tablet in
      treating benign prostatic hyperplasia. METHODS: Eighty BPH patients were divided
      into two groups randomly by double-blind, double-simulated and active control
      parallel study trials. Forty patients in treatment group were given Naftopidil
      tablet 25 mg, p.o., qn for 42 days, while 40 patients in control group were given
      Tamsulosin 0.2 mg, p.o., qn for 42 days. Statistical analysis was given from 77
      cases in the groups. Estimation of the efficacy was done by the change of major
      indexes include international prostate symptom score (IPSS), maximum flowrate
      (Qmax) and secondary indexes such as quality of life (QOL), residual urine (Ru)
      and volume of prostate (V). RESULTS: The changes of IPSS, Qmax, QOL had
      significant difference between two groups before and after treatment(P < 0.05).
      The change of Ru had no significant difference between two groups before and
      after treatment (P > 0.05) while there was significant difference between two
      groups after six-week treatment(P < 0.05). The change of V had no significant
      difference (P > 0.05). The adverse reactions in both groups were mild, and there
      was no significant difference between two groups(P > 0.05). CONCLUSIONS:
      Naftopidil tablet was safe and effective in treating benign prostatic
      hyperplasia.

PMID- 12491698
TI  - [The clinical value of PSA and ECT in diagnosis of prostate cancer bone
      metastasis].
AB  - OBJECTIVES: To evaluate the clinical significance of PSA and ECT bone scans in
      the diagnosis of bone metastasis in prostate cancer patients. METHODS: Sixty
      seven cases of prostate cancer were reviewed, bone metastasis (BM) occurred in 44
      cases, and 23 cases without BM (NBM). The relation between PSA, ECT and bone
      metastasis was analyzed. RESULTS: The sensitivity of BM with bone scan of ECT was
      91.67%. Single local density of radionuclide with bone scan was found in 6 cases,
      only 2 cases have BM. The value of PSA between BM and Non-BM group had
      significant difference (87.28 micrograms/L vs 25.37 micrograms/L, P < 0.01). PSA
      and the degree of bone metastasis was positively correlated. PSA < 10
      micrograms/L, the morbidity of BM was 0; PSA 10-20 micrograms/L, 7.69%; PSA 20-60
      micrograms/L, 53.33%; PSA 60-100 micrograms/L, 91.67%; and PSA > 100
      micrograms/L, 100%. CONCLUSIONS: ECT is a high sensitive method in diagnosis of
      bone metastasis of prostate cancer, but it is not specific in patients with
      single focus of BM. As for those patients of prostate cancer without any
      treatment, while PSA < 10 micrograms/L, the morbidity of BM is rare; while PSA >
      100 micrograms/L, BM is in high suspect.

PMID- 12491699
TI  - [Advances in eukaryotic expression systems].
AB  - The increasing popularity of eukaryotic expression systems can be attributed to
      their capability of performing many post-translational modifications. At present,
      There mainly are three expression systems including yeast expression system,
      insect cell expression system and mammalian cell expression system. The
      methylotropic yeast Pichia Pastoris usually utilizes alcohol oxidase promoter to
      drive the expression of foreign gene. Recently, a continuous fermentation has
      been developed in Pichia Pastoris with the glyceraldehyde-3-phosphate
      dehydrogenase (GAP) promoter. The baculovirus-mediated insect cell expression
      system is considered to be safe, powerful, but cell-lytic. Baculovirus-S2 system
      uses the popular and genetically well understood Drosphila S2 cells which do not
      appear to be lysed after infection. In mammalian cell expression system,
      recombinant adenovirus are attracting a great deal of attention as a highly
      efficient gene transfer vehicle. The frequency of Ad vector rescue by homologous
      recombination in E. coli and Cre-mediated site-specific recombination is
      significantly higher than by homologous recombination in vivo. Tetracycline
      regulatable system is a widely used mammalian cell inducible expression system
      due to its high efficiency and stringency.

PMID- 12491701
TI  - [Correlation of the factors on benign prostatic hyperplasia combined with
      obstruction].
AB  - Benign prostate obstruction(BPO) means bladder outlet obstruction (BOO) due to
      benign prostatic hyperplasia (BPH), which concerns BPH, and lower urinary tract
      symptoms(LUTS). To treat the BPO is the main purpose of therapy on BPH in clinic.
      This review includes recent advances in study of changes on urodynamics(UDS),
      morphology, prostatic composition, which occur in BPO.

PMID- 12491700
TI  - [Advances in sperm capacitation].
AB  - Sperm must be capacitated before sperm-ovum fusion. Capacitation was once
      considered as hyperactivation. But now many investigators thought that
      capacitation wasn't equal to hyperactivation, and that sperm hyperactivation
      might be a moiety of capacitation or the result of capacitation. In the present,
      the methods used to study sperm capacitation include fertilization in vitro,
      induction of sperm acrosome reaction, FITC-labeled chlortetracycline and plant
      hemoagglutinin. The studies on sperm capacitation in vitro mainly focused on the
      inductive substances of sperm capacitation and subsequent results analysis. It
      could lay foundation for the manifestation of molecular mechanism of sperm
      capacitation and destination of sperm capacitation in molecular levels.

PMID- 12491702
TI  - [The situation of sildenafil in the treatment of men with erectile dysfunction].
AB  - This review provides an overview of the pharmacology mechanism of sildenafil. The
      efficacy and safety of the medicine are briefly summarized. The special
      conclusion was made for the usage of sildenafil to the particular patients such
      as those with hypertension or those taking any antihypertensive agent, with
      cardiovascular disease, with diabetes, with spinal cord injury, after radical
      prostatectomy and on chronic dialysis. In general, sildenafil is effective and
      safe for various ED patients.

PMID- 12491703
TI  - Stabilization of the pre-arthritic trapeziometacarpal joint using ligament
      reconstruction.
AB  - INTRODUCTION: Trapeziometacarpal pre-arthrosis is a common condition with only
      limited therapeutic possibilities. Eaton and Littler designed a tendon
      stabilization. MATERIALS AND METHODS: A series of 21 thumbs with painful
      carpometacarpal joints, treated with a ligament reconstruction according to Eaton
      and Littler, is described. Three failed and further surgery was required. The
      outcome of 18 is evaluated. There were 11 women, 7 men with a mean age of 33.7
      years, all having stages I or II of osteoarthritis. Six (30%) had a traumatic
      event in their history. RESULTS: In the early stages of degenerative
      osteoarthritis, the overall outcome was good with a mean DASH score of 23.2. The
      carpometacarpal joint was stable but a 43% progression of radiographic
      osteoarthritic deterioration of the joint occurred. CONCLUSION: Stabilization of
      a painful pre-arthritic trapeziometacarpal joint is useful and reliable. A
      traumatic instability had worse results and probably is a contraindication to
      this technique.

PMID- 12491704
TI  - [Extensor tenodesis to the retinaculum extensorum: anatomic and biomechanical
      study].
AB  - INTRODUCTION: The extensor tenodesis is a direct dynamic tenodesis which is
      activated by wrist flexion due either to hand weight or flexor carpi radialis.
      This tenodesis is usually performed to the distal radius, but it is possible to
      fix EDC (extensor digitorum communis) to the retinaculum extensorum. MATERIAL AND
      METHODS: Biomechanical study concerned 12 anatomical subjects (24 wrists). The
      biometric and radiological analysis of retinaculum displacement distalwards was
      made under low (1 kg) and moderate (6 kg) pulling. Surgical clips were placed on
      the proximal and distal limits of the retinaculum in order to study their
      positions on roentgenograms. RESULTS: Average width of the retinaculum was 19 mm.
      Average movement under 1 kg drive was 6 mm and 8.6 mm under 6 kg drive. X-rays
      showed that the proximal border of the retinaculum was always located proximally
      to the wrist rotate centre, whatever the traction. DISCUSSION: We found the same
      anatomical features described by different authors, except for the width of the
      retinaculum. Our study suggests that the retinaculum is strong enough to support
      a surgical tenodesis.

PMID- 12491705
TI  - [The "candlestick" technique for the correction of certain types of congenital
      metacarpal synotosis].
AB  - Metacarpal synostosis is a rare congenital hand malformation requiring only
      occasionally a surgical correction. However in case of divergent epiphyses there
      is a progressive accentuation of the deformity. In the "Y" type of symmetrical
      synostosis, the authors propose a trapezoidal osteotomy with upside down
      relocation allowing realignement of the epiphyses without distant bone donor
      site.

PMID- 12491706
TI  - Monteggia fractures in adults. Review of 54 cases.
AB  - INTRODUCTION: We present a review of Monteggia fractures treated in our hospital
      between 1992 and 1998. PATIENTS AND METHODS: Fifty four patients with a Monteggia
      fracture were treated in our hospital with an average follow-up of 24 months (12
      48 months). The average age was 41 years (18-81 years). According to the
      classification of Bado, there were 24 type I, 20 type II, 6 type III and 4 type
      IV. The etiology was in 27 cases a motor-vehicle and motorcycle accident, five a
      pedestrian struck by a car, 21 by a causal fall and only one by a direct hit by
      an iron bar in an assault. In 56% of the patients, the lesions were associated
      with polytrauma. In all the cases, treatment consisted of open reduction and
      internal fixation of the ulnar fracture using different methods of osteosynthesis
      (3.5 mm DCP, 3.5 mm reconstruction plates, 6.5 mm cancellous screw, tension band
      technique with Kirschner wires, and one-third tubular plates). Initial treatment
      of the radial head dislocation was attempted by closed reduction and verification
      under fluoroscopy. Subsequent open reduction and osteosynthesis were performed in
      10 cases, and resection of radial head was necessary in three cases as the
      initial treatment. There were six open fractures with one case developing chronic
      infection. RESULTS: Results were evaluated according to the criteria of Anderson
      (union fracture, elbow and wrist flexion/extension). The results were excellent
      in nine patients (17%), satisfactory in 33 (61%), unsatisfactory in nine (17%)
      and failure in three (5%). Complications could be attributed to the severity of
      injury, type of fixation and errors in technique (four non-union, three failure
      of one-third tubular plates, one distal radioulnar instability) and to some
      features peculiar to this lesion (five nerve injuries, three redislocations of
      the radial head and four radioulnar synostosis). We needed to perform 14
      reoperations to resolve some of the above mentioned complications.

PMID- 12491707
TI  - Outcome study of arthroscopic suturing of ulnar avulsions of the triangular
      fibrocartilage complex of the wrist.
AB  - INTRODUCTION: Ulnar wrist pain due to a TFCC lesion is frequent. Based on studies
      of the vascularity, ulnar avulsion can be sutured. Arthroscopic techniques have
      been designed but results are sparsely published. MATERIALS AND METHODS: This is
      a retrospective study of 35 patients with an ulnar avulsion of the TFCC. All the
      patients were treated with an originally designed arthroscopical technique. The
      evaluation was focused on the subjective and functional ouome. A pain score and a
      DASH score were used. RESULTS: The general impression was positive with a mean
      DASH score of 15 points. Two-thirds of the patients had a DASH score totaling
      less than 20. Twenty-nine patients had a good outcome, six were fair or poor.
      CONCLUSION: Arthroscopical repair of the TFCC is a reliable and useful technique.

PMID- 12491708
TI  - Recurrent palmar dislocation of the distal radioulnar joint. A case report.
AB  - Recurrent palmar dislocation of the distal radioulnar joint is not a common
      injury. We report one case in a 73-year-old female. This injury was incorrectly
      diagnosed at the first presentation because there has been no distinct deformity
      at the wrist and extension-flexion was normal. The need for proper physical
      examination and accurate radiographic positioning is stressed. Distal diaphysis
      resection combined with distal radioulnar arthrodesis (modified Sauve-Kapandji
      procedure) was the preferred method of treatment in an old patient. Two years
      after the injury, the patient was asymptomatic.

PMID- 12491709
TI  - [Isolated dislocation of the carpal scaphoid. A case report with review of the
      literature].
AB  - Isolated dislocation of the carpal scaphoid is an extremely rare injury, which is
      usually accompanied by significant ligamento-capsular lesions. A review of the
      literature found only 21 reported cases. The aim of this report is to present a
      single case of isolated radio-palmar dislocation of the scaphoid treated
      conservatively, which provided a good functional result at 10 years follow up.

PMID- 12491710
TI  - [Total carpometacarpal dislocations. Two case reports].
AB  - We report two cases of carpometacarpal dislocation of the four long fingers. They
      were diagnosed in emergency and treated by open reduction and stabilization by
      intramedullary pinning. They were followed for an average of 30 months. The
      results were rated good, and the two patients had an excellent grip strength, no
      deformity, no instability, no disabling or limited prehension. Dislocation or
      fracture-dislocation of the carpometacarpal joints are uncommon injuries. The
      diagnosis can be easily missed. The authors recommend closed or open reduction
      and fixation by pins and immobilisation in a plaster cast. The results was good
      in the two cases without complications.

PMID- 12491711
TI  - ["Role of the medical expert". GEM Conference, Paris, December 2001].

PMID- 12491712
TI  - [Advice and client attitude in expert medical consultation].

PMID- 12491713
TI  - [The use of digital photographs for surgical and rehabilitation records. Methods
      and results].
AB  - Digital pictures are performed on patients in the pre and postoperative periods,
      and sometimes during surgery. Seven thousand fourty eight records have been
      recorded. This method is useful for a multidisciplinary responsibility,
      particularly for the hand therapist and the splint follow-up. It is also good for
      patient information, for Workman's compensation doctors and for experts. The
      pitfall is that one have to manage the records on a strict day by day base.

PMID- 12491714
TI  - Numerical simulation of the sedimentation of cylindrical pollutant particles in
      fluid.
AB  - The sedimentation of cylindrical pollutant particles which fall through a fluid
      is investigated. Differing from previous research work, particle oscillation and
      effect of particle on the fluid are considered, and the torque exerted on a
      particle when viscous fluid flow around a particle is got through experiment and
      included in the numerical simulation. The computational results showed that the
      sedimentation velocities of particle increase slowly with the increase of
      particle aspect ratio phi. For disk-like particle, when the motion direction of
      particle is parallel to axis of particle, particle falls more slowly than the
      case of perpendicular to axis of particle; while for rod-like particle, it is
      inverse. For sedimentation of a crowd of high-frequency oscillating cylindrical
      particles with arbitrary initial orientation, both vertical velocity and
      horizontal velocity oscillate dramatically, the degree of oscillation of the
      former is stronger than the later. A crowd of particles fall more quickly than an
      isolated particle. Particles tend to strongly align in the direction of gravity.
      The computational results agreed well with the experimental ones and helpful for
      controlling of pollutant particles.

PMID- 12491715
TI  - Speciation and fractionation of heavy metals in soil experimentally contaminated
      with Pb, Cd, Cu and Zn together and effects on soil negative surface charge.
AB  - Speciation and fractionation of heavy metals in soil subsamples experimentally
      loaded with Pb, Cd, Cu and Zn in orthogonal design was investigated by sequential
      extraction, and operationally defined as water-soluble and exchangeable(SE),
      weakly specific adsorbed(WSA), Fe and Mn oxides-bound(OX) and organic-bound(ORG).
      The results showed that fractions of heavy metals in the soil subsamples depended
      on their speciation. About 90% of Cd and 75% of Zn existed in soil subsamples in
      the SE fraction. Lead and Cu existed in soil subsamples as SE, WSA and OX
      fractions simultaneously, although SE was still the major fraction. Organic-bound
      heavy metals were not clearly apparent in all the soil subsamples. The
      concentration of some heavy metal fractions in soil subsamples showed the good
      correlation with ionic impulsion of soil, especially for the SE fraction.
      Continuous saturation of soil subsamples with 0.20 mol/L NH4Cl, which is the
      first step for determination of the negative surface charge of soil by the ion
      retention method, resulted in desorption of certain heavy metals from the soil.
      It was found that the percentage desorption of heavy metals from soil subsamples
      depended greatly on pH, the composition and original heavy metal content of the
      soil subsamples. However, most of the heavy metals in the soil subsamples were
      still be retained after multiple saturation. Compared with the parent soil, the
      negative surface charge of soil subsamples loaded with heavy metals did not show
      difference significantly from that of the parent one by statistical analysis.
      Heavy metals existed in the soil subsamples mainly as exchangeable and
      precipitated simultaneously.

PMID- 12491716
TI  - A reactor system combining reductive dechlorination with co-metabolic oxidation
      for complete degradation of tetrachloroentylene.
AB  - A laboratory sequential anaerobic-aerobic bioreactor system, which consisted of
      an anaerobic fixed film reactor and two aerobic chemostats, was set up to degrade
      tetrachloroethylene (PCE) without accumulating highly toxic degradation
      intermediates. A soil enrichment culture, which could reductively dechlorinate
      900 microM (ca. 150 mg/L) of PCE stoichiometrically into cis-1,2-dichloroethylene
      (cis-DCE), was attached to ceramic media in the anaerobic fixed film reactor. A
      phenol degrading strain, Alcaligenes sp. R5, which can efficiently degrade cis
      DCE by co-metabolic oxidation, was used as inoculum for the aerobic chemostats
      consisted of a transformation reactor and a growth reactor. The anaerobic fixed
      film bioreactor showed more than 99% of PCE transformation into cis-DCE in the
      range of influent PCE concentration from 5 microM to 35 microM at hydraulic
      retention time of 48 h. On the other hand, efficient degradation of the resultant
      cis-DCE by strain R5 in the following aerobic system could not be achieved due to
      oxygen limitation. However, 54% of the maximum cis-DCE degradation was obtained
      when 10 mumol of hydrogen peroxide (H2O2) was supplemented to the transformation
      reactor as an additional oxygen source. Further studies are needed to achieve
      more efficient co-metabolic degradation of cis-DCE in the aerobic reactor.

PMID- 12491717
TI  - Capture and separation of CO2 from flue gas by coupling free and immobilized
      amines.
AB  - A novel system was proposed for the capture and separation of CO2 from flue gas.
      In this method, a resin was employed to regenerate the amine capturing CO2 from
      flue gas at room temperature. The feasibility for the resin to regenerate amines
      such as MEA, MAE, TEA, and ammonia was demonstrated. It was also discovered that
      the resin could be regenerated by hot water.

PMID- 12491718
TI  - Thermodynamic study of adsorption of phenolic compounds onto Amberlite XAD-4
      polymeric adsorbents and its acetylized derivative MX-4.
AB  - Adsorption equilibrium isotherms of phenolic compounds, phenol, p-cresol, p
      chlorophenol and p-nitrophenol, from aqueous solutions by Amberlite XAD-4
      polymeric adsorbent and its acetylized derivative MX-4 within temperature range
      of 283-323K were obtained and fitted to the Freundlich isotherms. The capacities
      of equilibrium adsorption for all four phenolic compounds from their aqueous
      solutions increased around 20% on the acetylized resin, which may be contributed
      to the specific surface area and the partial polarity on the network. Estimations
      of the isosteric enthalpy, free energy, and entropy for the adsorption process
      were reported.

PMID- 12491719
TI  - Environmental chemical study on the marsh of Fatimid cemetery at Aswan City,
      Egypt.
AB  - Environmental chemical study were carried out on the Fatimid cemetery marsh at
      Aswan City(24 degrees 1'N and 32 degrees 9'E), Egypt, Marsh contents(warter,
      soil, sediment, metal and nonmetal-bearing salts, and emergent weed) were
      analysed to known the source of marsh water, speciation of the different elements
      between the marsh contents, and the toleration of emergent weed(Phargmites
      australies) for different metals and their bioaccumulation coefficients. Thus,
      metals(Ca, Mg, Na, K, Ni, Fe, Mn, Cu, Zn, Cd and Pb) and nonmetals(CO(3)2-, HCO3
      , Cl-, SO(4)2-, PO(4)3-, NO3-, SiO2, organic matter and pH value) were determined
      in the samples. According to the chemical analysis, and applying the base
      exchange equation(water type) and calculate the hydrochemical parameters for
      marsh water samples, we can indicate that the marsh water is ground water with Na
      SO4 type and deep meteoric genesis. Topsoil of marsh dry land characterized by
      CaCl as dominant salt, while NaCl is a dominant salt in subsoil. The elevated pH
      values of marsh contents minimized the metal solubilities in different samples.
      Phragmites australies showed a strong ability to accumulate Mn and Fe in the
      aerial part in opposite to Co, Ni and Cd.

PMID- 12491720
TI  - A two-stage anaerobic system for biodegrading wastewater containing terephthalic
      acid and high strength easily degradable pollutants.
AB  - The high strength easily biodegradable pollutants (represented by CODE) are
      strong inhibitors of terephthalic acid (TA) anaerobic biodegradation. At the same
      time, TA can inhibit easily biodegradable pollutants removal under anaerobic
      conditions to a limited extent. This mutual inhibition could happen and cause a
      low removal efficiency of both TA and CODE, when the effluent from TA workshops
      containing TA and easily biodegradable pollutants are treated by a single
      anaerobic reactor system. Based upon the treatment kinetics analysis of both TA
      degradation and CODE removal, a two-stage up-flow anaerobic sludge blanket and up
      flow fixed film reactor(UASB-UAFF) system for dealing with this kind of
      wastewater was developed and run successfully at laboratory scale. An UASB
      reactor with the methanogenic consortium as the first stage removes the easily
      biodegradable pollutants(CODE). An UAFF reactor as the second stage is mainly in
      charge of TA degradation. At a CODE loading of 15.3 g/(L.d) and a TA loading of
      1.4 g/(L.d), HRT 18.5 h, the CODE and TA removal rate of the system reached 89.2%
      and 71.6%, respectively.

PMID- 12491721
TI  - Abatement of waste gases and water during the processes of semiconductor
      fabrication.
AB  - The purpose of this article is to examine the methods and equipment for abating
      waste gases and water produced during the manufacture of semiconductor materials
      and devices. Three separating methods and equipment are used to control three
      different groups of electronic wastes. The first group includes arsine and
      phosphine emitted during the processes of semiconductor materials manufacture.
      The abatement procedure for this group of pollutants consists of adding iodates,
      cupric and manganese salts to a multiple shower tower (MST) structure. The second
      group includes pollutants containing arsenic, phosphorus, HF, HCl, NO2, and SO3
      emitted during the manufacture of semiconductor materials and devices. The
      abatement procedure involves mixing oxidants and bases in an oval column with a
      separator in the middle. The third group consists of the ions of As, P and heavy
      metals contained in the waste water. The abatement procedure includes adding
      CaCO3 and ferric salts in a flocculation-sedimentation compact device equipment.
      Test results showed that all waste gases and water after the abatement procedures
      presented in this article passed the discharge standards set by the State
      Environmental Protection Administration of China.

PMID- 12491722
TI  - In situ IR, pulse reaction and TPD-ITD study of catalytic performance of room
      temperature carbon monoxide oxidation on supported gold catalysts.
AB  - With in situ IR, two different CO adsorption bands were detected on various
      chemical state gold catalysts. One band is attributed to the linear CO on an
      oxidized gold catalyst(2100 cm-1), the other one is ascribed to the bridged CO on
      metallic gold (2085 cm-1), CO pulse reaction showed that Au/Fe2O3 catalyst had a
      room-temperature activity even in the presence of moisture. The produced CO2 was
      detained and more easily desorbed from supported gold catalyst than support
      oxide. TPD-IDT results indicated that the O2- superoxide ions are the possible
      active oxygen species.

PMID- 12491723
TI  - Ozonation of refractory chemicals in leachate with hydrogen peroxide.
AB  - Nearly 97% of organic chemicals in Hong Kong leachate could be effectively
      removed by the UASB(upflow anaerobic sludge blanket) process followed by the
      fenton coagulation. The COD of leachate was lowered from an average of 12,900
      mg/L to 1440 mg/L after the USAB treatment, and was further lowered to 394 mg/L
      after the fenton coagulation. The remaining refractory residues could be further
      removed by ozonation with the addition of H2O2. The ozonation for the supernatant
      of the fenton coagulation was most effective at pH 7-8, with the addition of 300
      mg/L of H2O2, and 30 min of reaction. The final effluent contained only 85 mg/L
      of COD and 10 mg/L of BOD5. On the other hand, direct ozonation of UASB effluent
      lowered the COD to 905 mg/L and BOD5 to 103 mg/L. Ozonation improved the
      biodegradability of the organic residues, and also converted part of organic-N in
      the leachate into NH3-N and NO3(-)-N.

PMID- 12491724
TI  - Determination and discussion hydraulic retention time in membrane bioreactor
      system.
AB  - Based on the microorganism kinetic model, the formula for computing hydraulic
      retention time in a membrane bioreactor system (MBR) is derived. With considering
      HRT as an evaluation index a combinational approach was used to discuss factors
      which have an effect on MBR. As a result, the influencing factors were listed in
      order from strength to weakness as: maximum specific removal rate K, saturation
      constant Ks, maintenance coefficient m, maximum specific growth rate mu m and
      observed yield coefficient Yobs. Moreover, the formula was simplified, whose
      parameters were experimentally determined in petrochemical wastewater treatment.
      The simplified formula is theta = 1.1(1/beta-1) (Ks + S)/KX0, for petrochemical
      wastewater treatment K and Ks equaled 0.185 and 154.2, respectively.

PMID- 12491725
TI  - Trophic attributes of the mudskipper, Periophthalmus barbarus (Gobiidae:
      Oxudercinae) in the mangrove swamps of Imo River Estuary, Nigeria.
AB  - Aspects of the trophic attributes of the mudskipper, Periophthalmus barbarus
      occurring in the mangrove swamps of Imo River Estuary, Nigeria, were investigated
      during a 12-month period (April, 1992-March, 1993). Feeding intensity increased
      with size, it was higher in the dry season(November-April) than in the wet
      season(May-October), monthly changes in the indices of feeding intensity were
      significantly correlated. Major food objects comprised detritus and benthic
      algae; crustaceans, insects, macrophyte matter and sand grains were minor food
      objects while fish, molluscs, Chilopoda, nematodes and fungi were unconsciously
      devoured objects. Diet varied seasonally; algae and sesarmid crabs were generally
      more in the dry season than during the rains whereas FPOM and fish increased in
      the wet over dry season. The mudskipper display a high degree of euryphagy and
      can be considered as a generalist and an omnivore. The lower trophic status of P.
      barbarus qualifies it as a good aquaculture candidate. Food richness was higher
      in big-sized class(BSC) than small-sized class(SSC). Size-based and seasonal
      variations were not apparent in food richness. Diet breadth was higher in the BSC
      than the SSC, there was dry season increase in diet breadth.

PMID- 12491726
TI  - Water pricing towards sustainability of water resources: a case study in Beijing.
AB  - The role of water pricing for managing water resources is widely recognized in
      many areas of the world because of the increasing scarcity of water resources, a
      high competition between water uses and environmental degradation. Based on the
      analysis of cost of water, this paper explores which types of cost should be
      reflected in the water pricing enhancing the sustainability of water resources.
      The principle of full cost pricing in which the cost should include supply cost,
      opportunity cost and externalities is proposed as a means to achieve the
      sustainability of water resources. In a case study of Beijing, low water price is
      analyzed as one reason for unsustainable water consumption. Thus water pricing
      justified is necessary and pressing. It is proposed to justify water price in
      phased manner and eventually towards full cost pricing. The assessment of impacts
      on water resources by raising water price shows water pricing could alleviate the
      conflict between water supply and demand. This paper concludes that water pricing
      can play an effective role in enhancing the sustainability of water resources in
      Beijing.

PMID- 12491727
TI  - Biodegradation of acetanilide herbicides acetochlor and butachlor in soil.
AB  - The biodegradation of two acetanilide herbicides, acetochlor and butachlor in
      soil after other environmental organic matter addition were measured during 35
      days laboratory incubations. The herbicides were applied to soil alone, soil-SDBS
      (sodium dodecylbenzene sulfonate) mixtures and soil-HA (humic acid) mixtures.
      Herbicide biodegradation kinetics were compared in the different treatment.
      Biodegradation products of herbicides in soil alone samples were identified by
      GC/MS at the end of incubation. Addition of SDBS and HA to soil decreased
      acetochlor biodegradation, but increased butachlor biodegradation. The
      biodegradation half-life of acetochlor and butachlor in soil alone, soil-SDBS
      mixtures and soil-HA mixtures were 4.6 d, 6.1 d and 5.4 d and 5.3 d, 4.9 d and
      5.3 d respectively. The biodegradation products were hydroxyacetochlor and 2
      methyl-6-ethylaniline for acetochlor, and hydroxybutachlor and 2,6-diethylaniline
      for butachlor.

PMID- 12491728
TI  - Effect of TiO2 surface properties on the SCR activity of NOx emission abatement
      catalyst.
AB  - NOx emission abatement catalysts V2O5 supported on various TiO2 including
      anatase, rutile and mixture of both were investigated with various physico
      chemical measurements such as BET, NH3-TPD, NARP, XRD and so on, and the effect
      of TiO2 surface properties on the SCR (selective catalytic reduction) activity of
      V2O5/TiO2 catalysts was studied. It was found that the TiO2 surface properties
      had strong effect on the SCR activity of V2O5/TiO2 catalysts. The stronger acidic
      property resulted in the higher exposure of active sites as well as the higher
      SCR activity.

PMID- 12491729
TI  - Population dynamics of Piscicola geometra (Hirudinea: Rhynchobdellida) on
      Oreochromis niloticus (Cichlidae) cultured in a rainforest fish pond, south
      eastern Nigeria.
AB  - The distribution, abundance and intensity of the annelid worm, Piscicola
      geometra(leeches) infecting Oreochromis niloticus cultured in a rainforest fish
      pond, South Eastern Nigeria was studied over a 12 months period. Three hundred
      fish were examined of which 48.3% were infected. Infection occurred throughout
      the year, with a peak in February. Female fish had a significantly higher
      intensity of infection(P < 0.05) than males. There was a clear seasonal
      periodicity in the degree of infection and the distribution of the parasite
      exhibited an aggregated or contagious model of dispersion. There was a
      significant positive correlation between the size of the fish and worm burden.

PMID- 12491730
TI  - Nitrogen and phosphorus removal under intermittent aeration conditions.
AB  - A practice wastewater treatment plant was operated using intermittent aeration
      activated sludge process to enhance biological nitrogen and phosphorus removal.
      When the influent concentrations of CODCr, BOD5, TN, TP, NH3-N, TKN, and SS
      varied in a range of 207.5-1640 mg/L, 61.8-637 mg/L, 28.5-75.6 mg/L, 4.38-20.2
      mg/L, 13.6-31.9 mg/L, 28.5-75.6 mg/L, and 111-1208 mg/L, the effluent means were
      less than 50 mg/L, 20 mg/L, 5 mg/L, 1.0 mg/L, 5 mg/L, 10 mg/L, and 20 mg/L,
      respectively. Based on a long time of operating results, this process is very
      suitable for nutrient biological removal for treating the municipal wastewater
      those water characteristics are similar as that of the Songjiang Municipal Waste
      Water Treatment Plant(SJMWTP).

PMID- 12491731
TI  - Variations of plant life form diversity along the Northeast China Transect and
      its direct gradient analysis.
AB  - Plant life form diversity and its direct gradient analysis on a larger scale
      climate change gradient were tested, based on the data from Northeast China
      Transect platform. The results showed that the species numbers, life form
      richness and life form diversity were relative higher at the eastern forests and
      the ecotone between typical vegetation, while those on the meadow grasslands and
      typical steppes were lower. Although plant life forms can reflect the climate
      variations, life form diversity is not consistent with the major global gradient
      along the NECT.

PMID- 12491732
TI  - Comparative study of four QSAR models of aromatic compounds to aquatic organisms.
AB  - Quantitative structure-activity relationships (QSARs) were developed for 43
      aromatic compounds toxicity to Photobacterium phosphoreum and Daphnia magna based
      on four methods: octanol/water partition coefficient, linear solvation energy
      relationship, molecular connectivity index and group contribution. Through the
      evaluation of four QSAR methods, LSER was proved to be the best. And it applied
      to the widest range of chemicals with the greatest accuracy.

PMID- 12491733
TI  - Freeliving marine nematodes as a pollution indicator of the Bohai Sea.
AB  - A hierarchical diversity index--taxonomic distinctness index delta+, which was
      first defined by Warwick and Clark in 1998, was employed to evaluate the
      pollution status of the Bohai Sea with freeliving marine nematodes. The result
      showed that the Bohai Bay and other coastal sampling sites might be affected by
      oil and gas production and other anthropogenic influences. In other words,
      anthropogenic disturbance was affecting this component of the benthos in these
      locations. And most offshore sampling sites in the middle of the Bohai Sea were
      clear and unpolluted.

PMID- 12491734
TI  - Leaf litter ecological fate in the Schelde Estuary in Belgium.
AB  - Two dominant species of Willow(Salix triandra) and Reed (Phragmites australis)
      along the Schelde Estuary(in Belgium) were selected in this research. The
      pigments of higher plant was used as biomarkers, the decomposition process of the
      two species were studied after they fall into the Schelde Estuary. After
      statistical analysis (Spearman rank order correlation, P < 0.05), the results has
      shown the decomposition dynamics pattern of the pigments, and the willow showed
      different pattern in comparing with the reed, e.g. Chlorophyll-a decomposition
      dynamics for willow is: y1 = 12196x2 - 175895x + 1E + 06 + k, R2 = 0.5706 while
      for reed is: y2 = -37878x2 + 229782x + 734282 + k, R2 = 0.9065. The precise time
      of the leaf litter spent in the water was also calculated as were less than 24
      days, 24-37 days, longer than 37 days(willow) and less than 24 days, longer than
      24 days(reed), the leaf litter fate of the two dominant species in the Schelde
      Estuary was also compared.

PMID- 12491735
TI  - Characteristics of regional climate change and pattern analysis on Ordos Plateau.
AB  - The characteristics of precipitation, temperature and their combination determine
      the special ecological environment pattern of Ordos Plateau. Analyzing its
      evolutionary trend attributes to understanding the succession process of the
      ecological environment of Ordos Plateau and has crucial instructional
      significance on the ecological restoration research being conducted in this
      region. Four time scales, arranging from ten days, one month, one season growing
      season contrasting to non-growing season) to one year were adopted to analyze the
      climate data which included nearly 30 years and were collected by eight weather
      stations on Ordos Plateau. The results indicated that the mean annual temperature
      and the mean monthly temperature of February, September and December, had
      increased significantly during the late 30 years. The annual precipitation did
      not show significant changes but its distribution pattern had changed obviously.
      The ratio of precipitation of major growing season (May-October) to annual
      precipitation had increased distinctively, and five counties' precipitation
      reached statistically significant level. And the ratio of precipitation of latter
      growing season (September) to one year decreased significantly while the ratio of
      non-growing season (November-next April) to one year changed insignificantly. The
      results showed that maybe the interaction of increased mean temperature and
      insignificant change of precipitation in non-growing season was one of the
      reasons why the desertification of the region was deteriorating in recent years.
      Using some factors closely relating to vegetation succession such as mean annual
      temperature, mean annual precipitation, distributive pattern of precipitation,
      mean temperature of the coldest month, mean temperature of the warmest month,
      precipitation of the warmest month, mean temperature of growing season,
      precipitation of growing season, potential evapotranspiration(PET) and radiative
      dryness index(RDI), to synthetically analyze the climate characteristics of Ordos
      Plateau. The regionalized Ordos Plateau to three synthetical climate types were
      recognized as follows: Type I, semi-humid and low evaporation(including Jungar
      Banner, Dongsheng City and Ejin Horo Banner), Type II, semi-arid, semi-humid and
      moderate evaporation(including Uxin Banner and Dalad Banner), Type III, arid and
      high evaporation(including Hanggin Banner, Otog Banner and Otog Qian Banner).

PMID- 12491736
TI  - Future challenges for anaesthesia departments. Introduction.

PMID- 12491737
TI  - The place of research and the role of academic anaesthetists in anaesthetic
      departments.
AB  - The specialty of anaesthesia developed because of its fundamental contribution to
      health care, including the prevention of pain from surgery, respiratory, and
      critical care medicine, cardiopulmonary resuscitation and pain medicine. Through
      these contributions anaesthesia became an important component of the medical
      profession. To continue our position in medicine, our intellectual foundation
      must be maintained and augmented mainly via research. No matter what role they
      play, all members of an anaesthetic department must contribute to the past
      intellectual development of anaesthesia as a basis for outlining the future
      approaches in research, including basic science, applied, transitional, clinical,
      educational and economic research. The challenges to the anaesthetist-scientist
      include evaluation, funding, conflicts of interest, legal and fraud. The future
      of the anaesthetic profession is mainly with its intellectual resources,
      especially research as the basis of improved patient care, and to have a major
      impact on the future of medicine overall.

PMID- 12491739
TI  - Undergraduate and postgraduate education.
AB  - Education is a core activity of academic departments but pressure from
      universities to maximize research income and research productivity, and from
      hospitals to deliver a more efficient clinical service, has pushed the importance
      of education into third place in many departments. Academic departments of
      anaesthesia can make significant contributions to undergraduate teaching.
      Students appreciate the one-to-one teaching which they receive from anaesthetists
      and the range of practical skills which they can learn. The main teaching burden
      of an academic department of anaesthesia relates to education of clinical
      trainees. National curriculum requirements must be delivered. Organization of a
      structured training programme, together with the appraisal and assessment systems
      which are necessary to ensure satisfactory progress of each trainee, require
      supervision by a number of academic staff, as well as administrative support.
      Higher postgraduate degrees may be gained by teaching or a combination of
      teaching and research. Teaching methods are changing, and there are opportunities
      to exploit e-learning on Intranet sites, and anaesthesia simulators, in both
      undergraduate and postgraduate education. Clinical governance issues and
      increasing scrutiny by authorities which fund teaching or set professional
      standards have resulted in demands for evidence that educational objectives are
      being met and that assessment systems are robust. There is a recognition that
      education has a cost, and resources are available from universities and hospitals
      to support the teaching activities of academic departments of anaesthesia.

PMID- 12491738
TI  - The strict separation of clinical and academic budgets: an analysis at a German
      medical university department of anaesthesia.
AB  - In the past, cross-funding between medical and academic budgets has been commonly
      practiced at university medical departments in Germany. Recent developments have
      however, generated pressures to enforce the separation of funding for both areas,
      as intended by law, and to distribute them on the basis of performance. A pilot
      project at Munster University Hospital, initiated by the German Federal Ministry
      for Research and Education in 1998, is described here. The main aim of the
      project was to find ways of distinguishing between research and teaching areas,
      on the one hand, and health care on the other, in terms of documenting
      performance and itemizing costs.

PMID- 12491740
TI  - Appraisal and reassessment of the specialist in anaesthesia.
AB  - Appraisal and reassessment of the physician is an integral part of ensuring that
      'quality of care' provided by the health care system is the best possible within
      the constraint of resources. Assessment tools used for initial certification at
      completion of medical school as a general physician and for initial certification
      as an anaesthesiologist are discussed. The expansion of core or general physician
      competencies to include behavioural, communication and evidence-based resource
      management skills in addition to knowledge and clinical skills is reviewed. With
      global workforce market expansion into the health care sector, equitable
      application of valid, reliable assessments of the physician will be increasingly
      important as international anaesthesiologists seek clinical licensure. Standards
      of care can be defined at several levels, including hospital, court, licensing
      body and government. Examples of each level are given. Re-certification of
      anaesthesiologists currently occurs in two distinct ways: by examination and
      through continuing medical education. Details of each approach are included.

PMID- 12491741
TI  - Anaesthetic team and the role of nurses--North American perspective.
AB  - Anaesthesia is an American invention but the development of anaesthesia practice
      took two paths at its inception. The American-based ether anaesthetic technique
      allowed for non-physician personnel to administer the drug. As nurses already
      played a role in assisting surgeons, it was logical for them to assist in the
      anaesthetic. This article discusses the historical events leading to the
      development of nurse anaesthesia practice in the USA. The current status of
      physician and nurse anaesthetist interactions--both harmonious and acrimonious-
      are presented.

PMID- 12491742
TI  - Anaesthetic team and the role of nurses--European perspective.
AB  - The only evidence in favour of the provision of assistance for anaesthesiologists
      seems to be that single-handed anaesthesiologists generate higher anaesthetic
      mortality than does a team system. In mainland Europe, the independent scope of
      the practice of nurse anaesthetists has been constrained while possible new roles
      for nurses have been suggested in the United Kingdom. In the USA, Anesthesiology
      Assistants are developing as an alternative to nurse anesthetists. The current
      fluidity will probably settle in Europe into a cadre of Assistant Anaesthetists,
      predominantly drawn from graduate nurses but with some graduates in biological or
      medical sciences, receiving a further 2-year specialist training. To attract
      people of this calibre, their role will have to offer some degree of clinical
      autonomy over the management of general anaesthesia. Considerations of safety
      will constrain this autonomy but the introduction of a monitor of anaesthetic
      depth and sophisticated communication systems will relieve anxiety about this
      development.

PMID- 12491743
TI  - The evolution of human resource needs in the USA.
AB  - The development of the specialty of anaesthesiology in the USA over the last half
      century has seen a significant growth in the number of anaesthesia departments
      and trainees. With no comprehensive national planning policy for physician human
      resources in existence, the number of anaesthesiologists has been determined by
      other things, such as market forces and capacities of the training programme. The
      American Society of Anesthesiologists has doubled in size in the past 15 years.
      The proliferation of anaesthesiologists has certainly been beneficial in terms of
      safety and access to anaesthesia care. However, the recent prospect of too many
      anaesthesiologists for the future has led to wide oscillations in the number of
      trainees and employment opportunities.

PMID- 12491744
TI  - The evolution of human resource needs in Europe.
AB  - The distribution of anaesthesia-related staff in Europe is characterized by a
      wide disparity between countries--and also within countries, between the rural
      regions and between large and small cities. The density of anaesthesiologists
      varies in different European areas--for example, 4.4 per 100,000 inhabitants in
      Ireland compared to 15.6 in Italy; conversely, trainee anaesthesiologists are
      more numerous in those countries in which the number of qualified specialists is
      low. These large differences may be explained by factors such as the management
      of training and assessment, the existence (or otherwise) of nurses, and the
      workload; mainly in Eastern European countries, the factors include economic
      conditions and health care policies. Most important are (i) the regulation of
      entrants into the specialty, and (ii) the range of the anaesthesiologist's duties
      -including (as well as anaesthesia) intensive care, emergency medicine and pain
      management. Important modifications could come from an increase in the workload,
      a decrease in the working time, and perhaps from the development of migratory
      flows when Eastern European countries join the European Union. The evolution of
      anaesthesiology in the future will depend on many unknown events: progress in
      pharmacology and techniques, the development of day-case anaesthesia, the
      behaviour of new consumers and, above all, future health policies.

PMID- 12491745
TI  - Evolution of the anaesthetic workload--the French experience.
AB  - The use of anaesthesia has shown major growth during the period 1975-1985.
      Increases safety in anaesthesia safety have permitted its use in surgery and in
      other exploratory procedures involving older patients and those with more severe
      clinical conditions. A survey, designed by the French Society of
      Anaesthesiologists, collected and analysed data relating to anaesthesia performed
      in France in 1996 from a representative sample collected in all French hospitals
      and clinics; the results of this survey were compared with an earlier survey
      performed in 1980. The participation rate of hospitals was 98%. The results of
      this survey showed that, between 1980 and 1996, the number of anaesthetic
      procedures had increased by 120% and the annual rate had increased from 6.6 to
      13.5 anaesthetic procedures per 100 population. The annual rate varied between
      5.4 per 100 in girls 5-14 years of age and 30.2 per 100 in men 75-84 years of
      age. The second important phenomenon which occurred between 1980 and 1996 was a
      marked increase in regional anaesthesia--from 4 to 23% of all cases. This
      represents a 14-fold increase in the number of cases involving regional
      anaesthesia. Anaesthesia for obstetric procedures represented 9% of all cases.
      Seventy-six per cent of all anaesthetics which were started between midnight and
      7.00 a.m. were related to obstetric activities. Changes that occurred in the
      practice of anaesthesia could be explained by changes in the types of procedure
      requiring anaesthesia: in 1980, 88% of anaesthetics were required for surgical
      procedures, while in 1996 surgery accounted for 71% of all cases, obstetrics for
      9%, and other procedures for the remaining 20%. The practice of epidural
      anaesthesia for deliveries has developed markedly in France during recent years,
      increasing from 1.5 to 51% of all deliveries between 1980 and 1996. This survey
      has offered an interesting overview of recent developments in anaesthesia--which
      are probably representative of the evolutionary trends in most industrialized
      countries. These changes can be summarized in three major points: (i) a global
      increase in the use of anaesthesia related to improvements in its safety; (ii) a
      significantly increased use of anaesthesia in elderly patients; and (iii) a
      marked increase in regional anaesthesia.

PMID- 12491746
TI  - Isotopic processes in atmospheric chemistry.
AB  - Trace gases are responsible for the atmospheric processes underlying air
      pollution and global change. Analysis of the distribution of stable isotopes in
      these gases is a way of gaining additional knowledge that may not otherwise be
      available. This approach requires knowledge of the isotopic signature of
      emissions sources and chemical reactions. This review focuses on the chemical
      physics of the processes underlying the distribution of stable isotopes in
      atmospheric gases.

PMID- 12491747
TI  - Hybrid systems through natural product leads: an approach towards new molecular
      entities.
AB  - Hybrid systems are constructs of different molecular entities, natural or
      unnatural, to generate functional molecules in which the characteristics of
      various components are modulated, amplified or give rise to entirely new
      properties. These hybrids can be designed from carefully selected components
      either through domain integration of key structural/functional features or via
      straightforward covalent linkages. Some of the recently reported hybrid systems
      based on steroid, carbohydrate, C60-fullerene platforms, amongst others, mainly
      crafted with the object of enhancement of the therapeutical spectrum, will be
      discussed.

PMID- 12491748
TI  - Fluorinated amino acids in protein design and engineering.
AB  - Selective incorporation of unnatural amino acids into proteins is a powerful tool
      for illuminating the principles of protein design. In particular, fluorinated
      amino acids have recently emerged as valuable building blocks for designing
      hyperstable protein folds, as well as directing highly specific protein-protein
      interactions. We review the collagen mimetic and coiled coil peptide systems that
      exemplify generalizable paradigms for future design. The unique electronic and
      phase properties of fluorocarbons are discussed, and protein synthesis using
      unnatural amino acids is briefly reviewed.

PMID- 12491749
TI  - Spontaneous resolution under supramolecular control.
AB  - The spontaneous resolution of enantiomers is an intriguing and important
      phenomenon in a number of research areas. Non-covalent interactions can play a
      key role in the process which can now be observed not only in crystals, but in
      liquid crystals, self-assembled monolayers, self-assembled fibres, and
      supramolecules self-assembled in solution. The evidence gathered in all of these
      areas is important for explaining the transfer of chirality from molecule to
      bulk, and in particular the spontaneous resolution of enantiomers.

PMID- 12491750
TI  - Homogeneous vanadium-based catalysts for the Ziegler-Natta polymerization of
      alpha-olefins.
AB  - Although their activity is often inferior to that of other systems, the use of
      vanadium-based catalysts in homogeneous Ziegler-Natta polymerizations allows the
      preparation of high-molecular-weight polymers with narrow molecular-weight
      distributions, ethene/alpha-olefin copolymers with high alpha-olefin
      incorporation, and syndiotactic polypropene. The main reason for the low activity
      of these catalysts is their deactivation during catalysis by reduction of active
      vanadium species to low-valent, less active or inactive species. We here present
      an up-to-date review of this area with particular emphasis on the attempts to
      improve catalyst performance and stability by the use of additives or ancillary
      ligands.

PMID- 12491751
TI  - Parallel kinetic resolution of racemic mixtures: a new strategy for the
      preparation of enantiopure compounds?
AB  - Kinetic resolution of racemic mixtures is a well-established methodology for the
      preparation of optically active compounds. However, excellent
      enantioselectivities are required to obtain them in enantiopure form, due to the
      decrease in ee when conversion values are close to 50%. To overcome this
      limitation, a parallel (asymmetric) reaction can remove the disfavored
      enantiomer. In this review, several examples of this strategy showing its wide
      range of applicability are described, as well as their mathematical treatment and
      some new applications in combinatorial chemistry.

PMID- 12491752
TI  - Well, color them latex free.

PMID- 12491753
TI  - Moving to centralized purchasing can promote savings. A will and away.

PMID- 12491754
TI  - Survey says. FDA researches number of hospitals reprocessing inhouse.

PMID- 12491755
TI  - Stats. A waxing worker shortage.

PMID- 12491756
TI  - New Joint Commission report warns: sentinel events most likely in the ED.
AB  - According to new data from the Joint Commission on Accreditation of Healthcare
      Organizations, most sentinel events resulting in death or permanent injury occur
      in the emergency department (ED). The most frequently missed diagnosis was
      meningitis, so surveyors will want to see policies for diagnosis, treatment, and
      adequate follow-up. Identify and monitor high-risk groups, including patients who
      leave without being seen. An effective system is needed to address abnormal
      findings that surface after the patient has left the ED.

PMID- 12491757
TI  - The new survey process will surprise you.
AB  - The Joint Commission on Accreditation of Healthcare Organizations will change its
      accreditation process as of 2004, and emergency department (ED) managers expect
      positive changes. Surveyors will focus on patient safety and error reporting. ED
      staff should be in serviced about what changes to expect. There will be a new
      emphasis on continuity of care.

PMID- 12491758
TI  - Are you ready to carry out smallpox vaccine plans?
AB  - New recommendations for smallpox vaccination have addressed key concerns of
      emergency department (ED) managers. The program would be voluntary. Vaccinated
      staff would not be quarantined. Fifteen or more ED staff members at each hospital
      would receive the vaccine as part of a total team of 40 or more, with the exact
      number varying according to individual needs.

PMID- 12491759
TI  - Are you losing $250,000 of revenue each year?
AB  - Common reasons for missed reimbursement include undervaluing the level of
      service, lost billing, exceeding time limits, and underpayments. A point-based
      system is recommended for documentation of nursing care. The facility level of
      service may be higher than the physician level of service. Don't miss payments
      for additional procedures performed in the emergency department.

PMID- 12491760
TI  - Growing ED liability crisis is spotlighted in survey.

PMID- 12491761
TI  - Mold contamination continued.

PMID- 12491762
TI  - Re: Sick building--sick patients.

PMID- 12491763
TI  - Transfer of patients from acute to long-term care: influence of patient
      characteristics on waiting period.
AB  - Hawaii's number of nursing home beds per capita is much lower than the national
      average, making it difficult to transfer some hospitalized patients to long-term
      care facilities. We prospectively followed patients wait-listed for nursing home
      placement in two Honolulu hospitals and found several patient characteristics
      that impeded transfer. These results could be used to help with long-term care
      planning.

PMID- 12491764
TI  - Surveillance for methicillin-resistant Staphylococcus aureus in Battambang,
      Cambodia.
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) and humanitarian missions are
      increasing worldwide. The prevalence of MRSA in the populations served may be
      unknown. A BRAVA (Blast Resuscitlation and Victim Assistance) mission was
      conducted at Battambang, Cambodia that included microbiology support. No MRSA was
      detected in our patients despite the reported increase in MRSA in Asia. Continued
      investigation is warranted for future missions.

PMID- 12491765
TI  - The informed consent process in cancer research studies.

PMID- 12491766
TI  - [Calcium signaling and brain functions].
AB  - Calcium signaling plays a critical role in various cell types by activation of
      receptors and Ca2+ channels in response to neurotransmitters, hormones, growth,
      factors etc. Although a variety of functions of intracellular Ca2+ are reported,
      Ca2+/calmodulin-dependent protein kinases (CaMK) are involved in their mediation.
      We have been studying on CaMK I, II, III, IV and K in the dynamic regulation in
      the cells in relation to functions. In this study, we elucidated the structures
      of the isoforms of CaMKII subunits with nuclear translocation signal (NTS). NTS
      is included in the variable domain following the regulatory domain with a
      sequence of KKRK. The isoforms of CaMK subunits such as alpha B, gamma A, gamma
      A.B, delta 3 and delta 7 contain NTS in the sequences of the structures.
      Transfection of the isoforms with NTS into NG108-15 cells stimulated the
      expression of brain-derived neurotrophic factor in the cytoplasm. Activation of
      CaMKII and IV and mitogen-activated protein kinase (MAPK) was observed during
      long-term potentiation (LTP) induction in the CA1 area of hippocampus. The
      activation of CaMKII was sustained for a long period, whereas that of CaMKIV and
      MAPK was transient. The results suggest that CaMKII is involved in LTP induction,
      while CaMKIV and MAPK are rather involved in LTP maintenance. We present and
      discuss our recent studies on regulation of CaMKs in neuronal functions.

PMID- 12491767
TI  - [IP3 receptor, a Ca2+ oscilator--role of IP3 receptor in development and neural
      plasticity].
AB  - IP3 is an important second messenger to release Ca2+ from internal store.
      IP3receptor (IP3R) works as an IP3 induced Ca2+ release channel and requires IP3
      and Ca2+ as coagoinist. We found IP3R is involved in fertilization, meiosis and
      mitosis by using a specific antibody. We further found that IICR is essential for
      determination of dorsoventral axis formation. Neuronal type 1 IP3R-deficient mice
      generated by a gene-targeting technique exhibit a significant reduction of birth
      rate and abnormal behavior (ataxia and seizure). Long-term depression of the
      cerebellum was blocked in the type 1 IP3R-deficient mice. Long-term potentiation
      (LTP) of CA1 hippocampus was enhanced but depotentiation and LTP suppression was
      reduced in IP3R1-deficient mice. These evidences suggest that IICR is involved in
      neuronal plasticity. The coupling mechanism between ER Ca2+ stores and plasma
      membrane store-operated channels is crucial to Ca2+ signaling. Recently we found
      that IP3R interacts with the TRP3 Ca2+ channel on the plasma membrane and
      functional coupling of IP3R to TRP3 channel is important for store operated Ca2+
      entry. Recently we found that IP3R is involved in determination of polarity and
      input specificity of activity-induced synaptic modification.

PMID- 12491768
TI  - ["Death and survival of neuronal cells exposed to Alzheimer's disease-relevant
      insults"].
AB  - The mechanism for neuronal cell death by familial Alzheimer's disease (FAD) genes
      turned out to consist of various elemental combinations by the different types of
      cytotoxicity. We therefore tried a new approach toward identifying novel anti-AD
      suppressors of neuronal death, termed disease-based death trap screening. The
      identified genes were classified into three categories. In the first category,
      there were known anti-cell death genes; in the second, there were known genes
      with unknown function; and in the third, there were novel genes. The cDNA that
      encodes a 24-residue peptide, termed HN, is in the third category. HN protects
      neuronal death caused not only by all known kinds of FAD genes (mutant APP, PS1
      and PS2), but also by anti-APP antibody and Abeta peptides, but not by long polyQ
      or SOD1 mutants. HN is a secretory peptide and exerts its protective function
      from the outside of the cell. The function of HN strictly depends on the
      structure. C8A-HN lost the activity and S14G-HN had approximately 1000 times
      increased potency of its action. Immunoblot analysis detected 3-kDa HN
      immunoreactive peptide in the testis and the colon in 3-week-old mice and only in
      the testis in 12-week-old mice. Notably, no HN immunoreactivity was detected in
      the brain. However, in an AD brain, not in an age-matched control, HN
      immunoreactivity was detected in neurons in the occipital lobe and in reactive
      glias in the hippocampal sections. The specific binding for HN exists on the
      neuronal cells and the rescue action of HN is specifically inhibited by genistein
      but not by wortmannin, suggesting that HN acts through the neuronal surface
      receptor linked to certain tyrosine kinases, but different from typical receptor
      tyrosine kinases. This study will provide a new insight into the research of AD.

PMID- 12491769
TI  - [Recent advances of strategy for the brain functions--a targeting for tiny
      presynaptic boutons].
AB  - Recent advances in our knowledge of synaptic transmission have been achieved
      using brain slice preparations. Since the complexes of neuronal networks often
      make multiple synaptic contacts to a single postsynaptic neuron, the electrical
      stimulation of presynaptic nerve bundle simultaneously activates not only plural
      presynaptic axons but also the collateral pathways. Accordingly, the mechanisms
      of transmitter release from a single presynaptic nerve terminal are poorly
      understood. Recently, a more simplified preparation of cultured neurons has been
      developed and the properties of transmitter release were clearly studied.
      However, little information exists as to whether the release properties and
      presynaptic modulation of single native terminals behave similarly to terminals
      formed in culture preparations. We have then develop a mechanical dissociation
      technique of single CNS neurons attaching functional native excitatory and
      inhibitory synaptic terminals (boutons). These dissociated neurons exhibit
      spontaneous synaptic activities, and their presynaptic modulation has been
      extensively studied. We further visualized single presynaptic boutons onto a
      synaptic bouton preparation and electrical stimulation was selectively given to
      one of the boutons. Here we show how such an electrophysiological approach allows
      us to understand the transmitter release in a single presynaptic element in the
      CNS. We discuss the pharmacological and physiological prospects.

PMID- 12491770
TI  - [Calcium regulation by troponin and its genetic disorder in striated muscle
      contraction].
AB  - Contraction of skeletal and cardiac muscles is regulated by Ca2+ through specific
      Ca(2+)-regulatory proteins, troponin and tropomyosin, located in the thin
      filament. Troponin is a Ca2+ receptive protein consisting of three differet
      components, troponins C, I, and T. The essential mechanisms of Ca(2+)-regulation
      are the inhibition of contractile interaction between myosin and actin by the
      inhibitory action of troponin I and the reversal of the inhibition by troponin I
      through the Ca(2+)-binding to troponin C. All three components of troponin are
      required for the Ca(2+)-regulation of contraction. This article reviews following
      aspects of troponin researches: 1) early studies on the structure and function of
      troponin, 2) molecular mechanisms of Ca(2+)-regulation, 3) principles of troponin
      exchange in skinned fibers and properties of troponin isoforms thereafter
      clarified under physiological conditions, 4) recent studies on the functional
      consequences of the mutations in human cardiac troponins T and I that cause
      genetic disorders, familial hypertrophic cardiomyopathy (HCM), and familial
      dilated cardiomyopathy (DCM).

PMID- 12491771
TI  - [Anti-dementia drugs for Alzheimer disease in present and future].
AB  - Alzheimer disease(AD) is characterized as neurodegenerative disease showing
      impairment of cognitive function, death of neuronal cells, numerous numbers of
      senile plaques and tangle of neurofilaments. There are two different hypotheses
      that neurotoxicity of aggregated amyloid beta protein(A beta) and
      hyperphosphorylation of tau protein are the causes of AD. The dysfunction of
      cholinergic neuronal system is observed in the early stage of AD. Therefore, the
      strategy to increase of acetylcholine (ACh) level in brain by using ACh esterase
      inhibitor is mainstream in the present. We have tacrine, donepezil, rivastigmine
      and galantamine. Tacrine, the first drug for AD, is replaced by other drugs,
      because of its hepatic toxicity. Galantamine binds allosteric sites of nicotine
      receptor and stimulates it in addition to its inhibitory effect on ACh esterase.
      Metamantine was approved in EU in 2002. It is non-competitive inhibitor of NMDA
      receptors, and dopamine releaser, which has neuroprotective effect. All of the
      above drugs improve cognitive function of patients, and they could delay
      hospitalization for 7 months or more. In the present anti-inflammatory drugs,
      anti-oxidative drugs and estrogen are under investigation. As anti-A beta
      therapy, inhibitors of beta -and gamma-secretase, A beta aggregation inhibitors,
      A beta degradation stimulators and A beta vaccination are possible strategies.
      The inhibitors of tau protein phosphorylation and activators of phosphates could
      be that of anti-tau protein phosphorylation. Additionally, it is expected to have
      the strategies such as neuroregeneration by neurotorophic factors and
      immunopyline ligands, and supply of neuronal cells by gene therapy and human ES
      cells.

PMID- 12491772
TI  - [The mechanism of A beta production and its inhibition as a therapeutic strategy
      for the prevention of Alzheimer's disease].
AB  - Deposition of amyloid beta peptide (A beta) as senile plaques or cerebrovascular
      amyloid characterizes the brains of patients with Alzheimer's disease (AD). A
      beta are composed of 40-42 amino acids that are proteolytically produced from its
      precursor beta APP. We have shown that the deposition of A beta ending at the
      42nd residue (A beta 42) is one of the earliest pathological changes in AD
      brains. Genetic and cell biological evidence strongly suggest that mutations in
      beta APP or presenilin (PS) 1 and 2 genes cause AD through increase in production
      of A beta 42. Recently, PS1 and PS2 are shown to be the catalytic subunits of
      gamma-secretase that cleaves the intramembrane segments of beta APP and Notch.
      beta-amyloid hypothesis that emphasizes the primacy of A beta in the pathogenesis
      of AD is currently being verified by the new experimental therapeutic approaches,
      e.g., A beta vaccine therapy or administration of inhibitors of beta- or gamma
      secretases. The mechanistic roles of newly identified co-factor proteins of PS
      (i.e., APH-1 and PEN-2) in gamma-secretase function, as well as recent advances
      in the development of gamma- or beta-secretase inhibitors will be discussed.

PMID- 12491773
TI  - [Progress in developing anti-Alzheimer drugs].
AB  - According to the amyloid hypothesis, accumulation of beta amyloid in the brain
      seems to be the primary influence driving Alzheimer's disease pathogenesis. From
      the studies of A beta production, aggregation, degradation and clearance, several
      strategies for preventing or delaying the disease onset and progression have been
      postulated. These are beta-secretase inhibitors, gamma-secretase inhibitors, A
      beta degrading enzymes, anti-cholesterol drugs, non-steroidal anti-inflammatory
      drugs, beta-sheet breakers, chelating agents, SAP competitors, beta-amyloid
      vaccination, agents for trapping peripheral A beta, and so on. Here I review
      recent progress in developing anti-Alzheimer drugs.

PMID- 12491774
TI  - [A systems-biological approach in drug discovery for circadian rhythm disorders].
AB  - A paradigm shift is occurring in all over the biological fields, from the
      molecular level to the system level. However, systematic and efficient method to
      dissect the complicated genetic network is still immature. To dissect such a
      complicated system, we took a systems-biological approach based on genomic,
      molecular and cell biological techniques and applied to mammalian circadian
      rhythms, one of the most complicated biological systems. We profiled
      suprachiasmatic nuclei (SCN) and liver genome-wide expression patterns under
      light/dark (LD) cycles and constant darkness (DD). We extensively determined
      transcription start sites (TSS) of human orthologues for newly identified cycling
      genes and then performed bioinformatical searches for relationships between time
      of-day specific expression and transcription factor response elements around TSS.
      Here we demonstrate the role of the Rev-ErbA/ROR response element in gene
      expression during circadian night, which is in phase with Bmal1 and antiphase to
      Per2 oscillations. This role was verified using a newly developed in vitro
      validation system, in which cultured fibroblasts transiently transfected with
      clock-controlled reporter vectors exhibited robust circadian bioluminescence. The
      systems-biological approach used here enhances accurate and comprehensive
      measurement of circadian dynamics, accelerates extensive identification of
      clockwork circuits, and leads to systems-level understanding of mammalian
      circadian clocks.

PMID- 12491775
TI  - [SNP database and establishment of personalized medicine].
AB  - We are aiming to identify susceptibility genes for common or otherwise clinically
      relevant diseases of metabolism such as diabetes, asthma, and hypertension, and
      analyze the molecular causality. Although genetic and environmental factors play
      equally crucial roles in the pathogenesis of the common diseases of civilization,
      genetic factor is directly involved in the causality and molecular mechanism. The
      elucidation of molecular etiology provides specific molecular targets for
      therapeutic drugs even at the individual level. Thus our priority is analysis of
      the molecular causality of the common metabolic disorders of civilization. We
      will identify individual and group polymorphisms (SNPs) in the genome relevant to
      the treatment of individual patients closely related to susceptibility to
      disease, prognosis of disease, and responses to drugs. To determine the genetic
      susceptibilities, we apply genetic approaches such as linkage studies with
      affected sib-pairs and association studies using SNPs database together with
      haplotype analysis.

PMID- 12491776
TI  - [Modeling of all genome and database].
AB  - We have developed the protein modeling software FAMS (Full automatic protein
      modeling system), and using the FAMS the proteins coded in the all the genes were
      modeled. And we developed web browsing software. We had participated in the
      CAFASP2 contest of the CASP4 which is the competition of the protein structure
      prediction. We won almost best server in the CAFASP2 which is the contest of full
      automatic protein modeling. Accordingly the database quality made by using the
      FAMS program will be very good. The FAMS modeling web service is available in
      http://physchem.pharm.kitasato-u.ac.jp/. FAMSBASE is seen in the web site of
      http://famsbase.bio.nagoya-u.ac.jp/.

PMID- 12491777
TI  - [Drug discovery based on microarray].
AB  - Gene regulatory networks developed from full genome expression libraries from
      gene perturbation variant cell lines can be used to quickly and efficiently
      identify the molecular mechanism of action of drugs or lead compound molecules.
      We developed an extensive yeast gene expression library consisting of full-genome
      cDNA array data for over 500 yeast strains each with a single gene disruption.
      Using this data, combined with dose and time course expression experiments with
      the oral antifungal agent, we used Boolean network discovery techniques to
      determine the genes whose expression was most profoundly affected by this drug.
      Our system identified the gene as the most significantly suppressed target
      molecule due to exposure to the antifungal agent. This process for network based
      drug discovery can significantly decrease the time and resources necessary to
      make rational drug targeting decisions.

PMID- 12491778
TI  - [Differentiation of neural stem cells into blood vessel cells and their
      modulators].
AB  - Multipotent stem cells that can generate neurons and glial cells exist in various
      regions of the vertebrate central nervous system (CNS) during development. The
      multipotent neural stem cells were isolated from rat embryonic day 14 (E14) or
      mouse E12 cortex and cultured by neurosphere formation in serum-free medium in
      the presence of basic fibroblast growth factor (bFGF). Differentiation was
      induced by the addition of 10% FBS to low density cultures (2.5 x 10(3)
      cells/cm2). Immunological analyses and RT-PCR indicated that neural stem cells
      gave rise to both endothelial cells and smooth muscle cells (SMCs). A
      reconstituted collagen gel fiber of NSC-derived SMCs caused contractions in
      response to typical contractile agonists (Oishi K. et al., J. Physiol., 540, 139
      152, 2002). Moreover, neural stem cells subcultured into a collagen gel formed
      endothelial tube-like structures (Kawakita E, et al., J Smooth Muscle Res 6, J
      33, 2002). These results arise one possibility that blood vessel cells in head
      are at least in part derived from NSCs.

PMID- 12491779
TI  - [Mechanism of improvement of spatial cognition with dietary docosahexaenoic
      acid].
AB  - We estimated the effects of dietary administration of docosahexaenoic acid (DHA,
      22:6n-3) on rat spatial cognition using young male Wistar rats. Chronic
      administration of DHA to rats increased the hippocampal levels of DHA. Six weeks
      after the start of the administration, the rats were for 5 weeks trained to
      acquire a reward at the end of each of 4 arms of an 8-arm radial maze. The
      retention test interposed with a delayed task (20-min interval after the first 2
      free choices) was then given to each rat to determine spatial working memory
      retention. On completion of the test, the Fos expression in the hippocampus was
      examined immunohistochemically. DHA administration reduced the number of working
      memory errors after the 20-min interval in the retention test. The number of Fos
      positive neurons in the CA1 hippocampus demonstrated a statistically significant
      negative correlation with the number of working memory errors, suggesting that
      the DHA-induced improvement in spatial cognition is associated with increased Fos
      expression in the CA1 hippocampus.

PMID- 12491780
TI  - [The improvement of memory retention and retrieval of a novel vasopressin
      fragment analog NC-1900].
AB  - The effects of a novel vasopressin (AVP) fragment analog NC-1900 (pGlu-Asn-Ser
      Pro-Arg-Gly-NH2 acetate) were studied on the performance of memory retention and
      retrieval in mice. NC-1900 of one time application of 1 hr after the acquired
      trial (electric shock) extended the latent period of passive avoidance task 21
      days after the acquired trial. Though the extended response was also recognized
      with AVP4-9, the potency was approx. 1/1000 of NC-1900. The potentiation wasn't
      recognized with vasopressin. NC-1900 showed a significantly high correct answer
      after 21 days after the last trial in the search task. While, V1 antagonist Pmp1
      Tyr (Me)2-AVP shortened the latent period of passive avoidance task. On the other
      hand, NC-1900 extended the reaction latency 21 days after the acquired trial by
      the application 1 hr before the retention trial. Though this improvement of
      memory retrieval was recognized with vasopressin and AVP4-9, the potency was
      1/100-1/1000. NC-1900 improved the retrieval 24 h after the CO2 exposure. V1
      antagonists Pmp1-Tyr-Me2-AVP or Deamino-Pen1, O-Me-Tyr2-AVP, and PMA had no
      effects on the retrieval 21 days after the acquired trial. These results suggest
      that NC-1900 may have the memory retention and retrieval potentiating action, and
      that phospholipase C-protein kinase C system may be involved in the former
      action, and the latter action not be involved.

PMID- 12491781
TI  - [Dopamine receptors and calcium channels regulating striatal inhibitory synaptic
      transmission].
AB  - A whole-cell patch-clamp study was performed to investigate the modulatory role
      of dopamine (DA), its ionic mechanisms and their developmental changes in the
      GABAergic synaptic transmission onto cholinergic interneurones in the rat
      striatal slices. Inhibitory postsynaptic currents (IPSCs) were evoked by focal
      stimulation. Bath application of DA inhibited the IPSCs in a concentration
      dependent manner with an IC50 value of 10 microM. Pharmacological studies with DA
      receptor agonists and antagonists suggest the involvement of D2-like receptors.
      DA reduced the frequency of miniature inhibitory postsynaptic currents without
      affecting their amplitude distribution. Analyses using selective blockers for N-,
      or P/Q type Ca2+ channels could estimate the contribution of each Ca2+ channel
      subtype to the GABAergic transmission. DA had no longer affected the IPSCs after
      the effect of an N-type channel blocker, omega-conotoxin (omega-CgTX) had reached
      its steady state. The inhibitory effects of omega-CgTX and DA or a D2-like
      receptor agonist decreased in parallel during postnatal 12-60 days. DA's action
      was occluded by omega-CgTX throughout these developmental stages. These results
      suggest that activation of presynaptic D2-like receptors selectively blocks N
      type Ca2+ channels, thereby inhibiting GABA release, and that contribution of N
      type channels and D2-like receptor-mediated presynaptic inhibition decrease in
      parallel with development.

PMID- 12491782
TI  - [A novel function of anti-fibrinolytic factor, PAI-1, in the central nervous
      system: a possible role as the neurotrophic factor].
AB  - Plasminogen activator inhibitor-1 (PAI-1) is a serpin that suppresses
      fibrinolysis by inhibiting the activity of plasminogen activator (PA). Together
      with PA, PAI-1 is expressed in the central nervous system and may play a role in
      the regulation of PA activity. Our present study has demonstrated that, in
      cultures of PC-12 neurons, depletion of PAI-1 from the culture medium induces
      disappearance of the cell's neurites and the cell death. Aprotinin and antipain,
      the inhibitors of PA, were not counterparts of PAI-1 in the protection of neurite
      disappearance. We also found that PAI-1 had the abilities to promote release of
      the survival factors of neurons, IL-6 and VEGF and activation of a survival
      serine/threonine kinase Akt. These results suggest that PAI-1 has physiological
      functions other than its role as PA inhibitor for the survival of neurons.

PMID- 12491783
TI  - [Synthesis of sphingomyelin analogues as a sphingomyelinase inhibitor and the
      application as a blocking agent of extracellular stress signaling].
AB  - Sphingomyelin (SM) pathway, where sphingomyelinase (SMase) hydrolyzes SM to
      produce ceramide, has recently been suggested to link to the signaling pathway
      that determines cell death. Therefore, elucidation of the mechanism by which
      SMase is activated and the regulation of SMase activity will be an important
      therapeutic strategy for various cytokine-related and ischemic diseases. We have
      synthesized nine difluoromethylene analogues of SM as SMase inhibitors and
      evaluated their inhibitory potencies. In this study, we show that the inhibitor
      suppresses ceramide production and cell death of PC-12 neurons that have been
      induced by deprivation of serum from the culture medium. The SMase inhibitor
      could also suppress neuronal cell death in a mouse model of brain ischemia. These
      results suggest a possibility that the prevention of various extracellular stress
      induced cell death signalings is accomplished by inhibiting the cell membrane
      SMase.

PMID- 12491784
TI  - [Modulation of sphingosine 1-phosphate, a new lipid mediator, on nitric oxide
      production by vascular smooth muscle cells].
AB  - The effects of sphingosine 1-phosphate (S1P) on nitric oxide (NO) production
      induced by interleukin (IL)-1 beta in cultured rat vascular smooth muscle cells
      (VSMCs) have been investigated. Rat VSMCs abundantly expressed mRNA of Edg-3 and
      Edg-5 receptor subtypes in both unstimulated and IL-1 beta-stimulated cells. S1P
      at higher than 0.1 microM inhibited the NO production induced by IL-1 beta in a
      concentration-dependent manner, in which S1P at 10 microM caused over 90%
      inhibition. S1P also inhibited inducible NO synthase (iNOS) protein and mRNA
      expressions induced by IL-1 beta in a concentration-dependent manner, which
      effects were smaller than that in the NO production. S1P also significantly
      inhibited GTP cyclohydrolase I (GTPCH) mRNA expression induced by IL-1 beta. PTX
      pretreatment partially prevented the inhibitory effects of S1P on the NO
      production and iNOS induction, while completely prevented the inhibitory effects
      on iNOS and GTPCH mRNA expressions. In PTX-pretreated VSMC, S1P showed a bell
      shaped enhancing and inhibitory effect on iNOS protein expression. These results
      suggest that S1P modulates IL-1 beta induction of NO production by rat VSMCs
      through multiple mechanisms, partially via Edg-3 and Edg-5 receptor subtypes
      coupled to PTX-sensitive G proteins.

PMID- 12491785
TI  - [Regulations and pathophysiological significance of the biosynthesis of
      tetrahydrobiopterin in human endothelial cells].
AB  - Tetrahydrobiopterin(BH4) serves as an essential cofactor for the biosynthesis of
      nitric oxide (NO). BH4 is de novo synthesized from GTP and GTP cyclohydrolase
      I(GCH I) is the rate-limiting enzyme in the biosynthesis of BH4. Under
      inflammatory conditions, it is reported that endothelial cells release large
      amount of BH4. In this study, we examined the regulation mechanism of the
      biosynthesis of BH4 in human umbilical vein endothelial cells(HUVEC).
      Prostacyclin and forskolin, reagents of stimulation of cAMP signaling cascade,
      reduced cytokine induced biosynthesis of BH4 through the inhibition of expression
      of GCH I mRNA. On the other hand, stimulations of NO-cGMP signaling pathway
      inhibited GCH I activities through the post translational modification of GCH I
      enzyme. Both two signaling cascade lead to vasodilation. It is suggested that the
      biosynthesis of BH4 can be regulated by negative feed back regulation systems
      between endothelium and smooth muscle cells to prevent over stimulated
      vasodilation.

PMID- 12491786
TI  - [Expression mechanisms of inducible type nitric oxide synthasegene via
      interleukin-1 receptor signaling].
AB  - The functional study on NF-kB bindings sites in transcription-regulatory region
      of rat inducible type nitric oxide synthase (iNOS) has been carried out by
      reporter assay to learn the signaling mechanisms of actions of interleukin-1 (IL
      1). By progressive excision of 5'-ends of the insert and introduction of
      mutagenesis of each NF-kB binding site, it has been shown that 3 kB sites are
      essential for IL-1-induced signaling pathway in a mutually dependent manner.

PMID- 12491787
TI  - [Pathophysiological role of endothelin-1 in the vascular remodeling process].
AB  - Endothelin (ET)-1, which had been discovered as the most potent vasoconstrictive
      peptide, plays active roles in the various biological responses. However, it is
      controversial how is ET-1 involved in the vascular remodeling process. Therefore,
      present experiments were performed to investigate the role of ET-1 for the
      initiation/progression of intimal hyperplasia. Intimal hyperplasia was caused
      with the time to peak of 4 to 6 weeks after endothelial removal of the rabbit
      carotid artery and accompanied by increased ET-1 content as well as ET receptor
      density within the hyperplastic vessel wall. ET-1 receptors could be classified
      into three subtypes of ETA, ETB and tentative nonETA/nonETB. TUNEL- and Ki-67
      positive cells were detectable with the time to peak of 1 to 2 weeks, whereas all
      positive cells disappeared within 6 weeks. ATZ1993 as a mixed type antagonist for
      ET-A, ET-B and nonETA/nonETB receptor subtypes inhibited the intimal hyperplasia,
      of which inhibition was accompanied by increased TUNEL- and p53-positive cells
      and decreased Bcl-2-positive cells. ET-1 accelerated the [3H]-thymidine
      incorporation by cultured vascular smooth muscle cells and, on the other hand,
      reduced TUNEL-positive cells, which was caused by the serum deprivation. The
      reduction of TUNEL-positive cells with ET-1 was blocked by ATZ1993 or BQ123 as an
      antagonist for ETA receptor, but unaffected by BQ788 as an antagonist for ETB
      receptor. These results strongly suggest that ET-1 plays crucial roles as a
      mitogen and an inhibitory factor of apoptosis in the vascular remodeling process
      after endothelial removal.

PMID- 12491788
TI  - [V-1, a catecholamine biosynthesis regulatory protein, enhances GTP
      cyclohydrolase I gene transcription in a cAMP-responsive element dependent
      manner].
AB  - V-1 is a 12 kDa protein containing 2.5 copies of the ankyrin repeat, which has
      been demonstrated to be required for protein-protein interactions. Recently we
      have for the first time reported that stable overexpression of V-1 enhances mRNA
      expression of catecholamine synthesizing enzymes in PC12D cells, and as a result,
      catecholamine production is upregulated. GTP cyclohydrolase I (GCH) is the enzyme
      in the first and rate-limiting step for the biosynthesis of tetrahydrobiopterin
      (BH4) which is an essential cofactor for tyrosine hydroxylase. In the present
      study, to examine further the function of V-1 in control of the BH4 biosynthesis,
      we assayed BH4 content and GCH enzyme activity in V-1-overexpressing PC12D cell
      clones. It was shown that both BH4 content and GCH enzyme activity were increased
      in V-1-verexpressing PC12D cell clones. It was also revealed that V-1
      overexpression caused augmentation of both the GCH protein and mRNA expression
      and the cAMP-responsive element (CRE) dependent transcription. Furthermore,
      promoter analysis showed an increased activity in the construct with 150 bp of
      promoter region of the human GCH gene in the V-1-overexpressing clones. These
      results suggest that V-1 promotes GCH gene expression via a CRE-dependent
      transcription to positively control the BH4 biosynthesis in catecholaminergic
      cells.

PMID- 12491789
TI  - [PAR (protease-activated receptor) as a novel target for development of gastric
      mucosal cytoprotective drugs].
AB  - Protease-activated receptor-2 (PAR-2), a G protein-coupled seven trans-membrane
      domain receptor, is distributed throughout the gastrointestinal tract, modulating
      various functions. In gastric mucosa, PAR-2 present in sensory neurons, upon
      activation, triggers mucus secretion by stimulating release of CGRP and
      tachykinins, resulting mucosal cytoprotection. PAR-2 activation also suppresses
      acid secretion and increase mucosal blood flow, contributing to the protective
      mechanisms. In contrast, PAR-2 is also present in chief cells, facilitating
      pepsinogen secretion. PAR-2 would thus appear to be primarily protective in
      gastric mucosa, but may also have an aggressive property in certain conditions.
      Finally, functions of PARs other than PAR-2 in gastric mucosa are also discussed.

PMID- 12491790
TI  - [Various mammalian tissues contain cell membrane-bound amine oxidase termed
      semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6)].
AB  - Recently it has been demonstrated a role of fat-cell SSAO on glucose transport
      and GLUT4 translocation to the cell surface. Many compounds have been identified
      as relatively selective SSAO inhibitors, but those currently available also
      inhibit monoamine oxidase (MAO, EC 1.4.3.4). In this study, inhibitory properties
      of a haloamine, 2-bromoethylamine (2-BEA), to guinea pig and rat lung-bound SSAO
      have been studied. 2-BEA could not inhibit both forms of MAO, but it
      competitively inhibited rat lung SSAO activity with a Ki value of 2.5 microM
      without preincubation and after preincubation, the mode of inhibition changed to
      be non-competitive. Dialysis and dilution experiments with 2-BEA-pretreated
      preparations resulted in no recovery of SSAO activity. A decreased rate of SSAO
      inhibition under N2 atmosphere to that obtained under O2 was produced after 2-BEA
      treatment, suggesting that oxidised intermediate was necessary for its
      inhibition. The plot of 1/k' vs 1/2-BEA intersected on the y-axis indicate that
      the inhibition by 2-BEA is not affinity-labeling agent, but a suicide inhibitor
      of SSAO.

PMID- 12491791
TI  - [Functional analysis of Na+/Ca2+ exchanger using novel drugs and genetically
      engineered mice].
AB  - The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in
      either Ca2+ efflux or Ca2+ influx mode, depending on the ion gradients across the
      plasma membrane and the membrane potential. In heart, smooth muscle cells,
      neurons, and nephron cells, this exchanger is thought to play an important role
      in the regulation of intracellular Ca2+ concentration. We aim at clarifying the
      function and pathologic state of the exchanger by developing NCX inhibitors and
      NCX-engineered mice as experimental tools, and finally establishing a novel
      therapeutic method using the exchanger as a molecular target. First, we present
      the pharmacological profiles and the molecular mechanism of NCX inhibitors (KB
      R7943, SEA0400, SN-6) recently developed. Our results suggest that these NCX
      inhibitors preferentially block the Ca2+ influx mode rather than the Ca2+ efflux
      mode. Further mutational analysis reveals that these NCX inhibitors have
      different interaction domains in the exchanger molecule. Secondly, we present
      that heterozygous NCX1-knockout mice are useful as a low NCX1-expressing animal
      model. From comparative experiments with heterozygous and wild-type mice and
      pharmacological experiments of the NCX inhibitors, we provided an evidence that
      NCX1 functionally contributes to maintaining the vascular tension.

PMID- 12491792
TI  - [Caspase-3-mediated alpha-smooth muscle actin cleavage during staurosporine
      induced myofibroblast apoptosis].
AB  - To examine the possibility that staurosporine is applicable for the treatment of
      abnormal scar formation such as hypertrophic scar and keloid, the cellular
      process during staurosporine-induced apoptosis was analyzed in myofibroblasts
      isolated from a rat granulation tissue pouch. Staurosporine induced myofibroblast
      apoptosis in a time- and a dose-dependent manner with typical morphological
      changes. Staurosporine activated caspase-3 up to 3.6-fold by cleaving pro-caspase
      3 to active forms. Alpha-smooth muscle actin was degraded during staurosporine
      induced apoptosis. The degradation of alpha-smooth muscle actin was detected at
      an early stage of staurosporine-induced apoptosis. Recombinant active caspase-3
      and staurosporine-stimulated caspase-3 both cleaved purified alpha-smooth muscle
      actin in vitro. These results suggested that alpha-smooth muscle actin is
      directly degraded by caspase-3 in response to apoptotic stimuli in
      myofibroblasts.

PMID- 12491793
TI  - [Physiological role of cyclic ADP-ribose as a novel endogenous agonist of
      ryanodine receptor in adrenal chromaffin cells].
AB  - Cyclic ADP-ribose (cADPR) is suggested to be a novel messenger of ryanodine
      receptors (RyR) in various cellular systems. However, the regulation of its
      synthesis in response to cell stimulation and its functional roles are still
      unclear. We examined the physiological relevance of cADPR to the messenger role
      in stimulation-secretion coupling in bovine adrenal chromaffin cells. In
      digitonin-permeabilized cells, cADPR-induced Ca2+ release but not caffeine-,
      ryanodine-, and IP3-induced Ca2+ release was inhibited by FK506 which bind to
      FKBP and dissociate it from the RyR. These evidence suggesting that cADPR may be
      the ligand for FKBP-RyR complex, resulting in a dynamic regulation of RyR
      mediated Ca2+ release. ACh causes biphasic [Ca2+]i rise, an initial transient
      rise followed by sustained rise, in intact cells. 8Br-cADPR, an antagonist of
      cADPR and FK506 specifically reduced the sustained phases of ACh-induced [Ca2+]i
      rise. Imperatoxin inhibitor (IpTxi) blocked the inhibitory effect of 8Br-cADPR
      and FK506, suggesting that cADPR contributes to sustained [Ca2+]i rise. 8Br
      cADPR, FK506, and IpTxi reduced CA release in response to ACh in chromaffin
      cells. These results provide evidence that the synthesis of cADPR is regulated by
      cell stimulation, and the cADPR/Ca(2+)-induced Ca2+ release pathway forms a
      positive feedback to stimulation-induced secretory response in the chromaffin
      cells.

PMID- 12491794
TI  - [Adrenomedullin in pregnancy].
AB  - In this study, we used the animal model of preeclampsia. The blood pressure in
      animals receiving L-NAME at 25 mg/day were significantly higher compared to that
      of rats receiving saline solution only. In addition, L-NAME treated rats showed a
      high fetal mortality as compared with intact rats. Also, we demonstrated infusion
      of AM reverse the hypertension and decrease in pup mortality induced by L-NAME
      during pregnancy. We showed that the AM mRNA levels predominantly exists in a
      high level in the placenta, uterus and ovary as compared with other tissues.
      These evidences suggest that AM may have a possible important role during
      pregnancy. In conclusion, the present study suggest that L-NAME-induced elevated
      blood pressure and increased fetal mortality can be reversed by low dose of AM.
      Thus AM may play an important role in the regulation of blood pressure, the blood
      supply to the utero-placental unit and fetal development.

PMID- 12491795
TI  - [Effects of sphingosine-1-phosphate, a lipid mediator, in cardiovascular
      tissues].
AB  - Effects of sphingosine-1-phosphate (S1P), a putative lipid mediator, was examined
      in vascular smooth muscle and endothelial cells by means of measuring
      intracellular Ca2+ concentration ([Ca2+]i), whole-cell membrane currents and
      tension. Application of S1P in a concentration range from 30 to 1000 nM to human
      umbilical vein endothelial cells (HUVECs) induced a slowly developing increase in
      [Ca2+]i. and concomitant non-selelctive cationic inward currents. Pretreatment of
      HUVECs with pertussis toxin (PTX) almost abolished the S1P-induced elevation of
      [Ca2+]i, suggesting that PTX sensitive edg1 receptors are involved in the S1P
      induced response in HUVECs. Moreover, treatment of HUVECs with S1P for 24 hrs
      caused cell-proliferation to 150% of the control. On the other hand, application
      of S1P had no effect on [Ca2+]i in rabbit, rat and mouse aortic myocytes. When
      S1P applied to rabbit aorta with endothelium, the muscle ring had small
      relaxation which disappeared in endothelium-denuded aorta. In contrast, rat
      cerebral arterial myocytes had increase in [Ca2+]i in the presence of S1P. These
      results suggest that responses of vascular tissues to S1P vary from cell to cell.
      To clarify physiological and pharmacological significance of S1P in
      cardiovascular system, comprehensive analyses are required.

PMID- 12491796
TI  - [Transactivation of the vascular endothelial growth factor receptor KDR/Flk-1 by
      the bradykinin B2 receptor induces an angiogenic phenotype in human cultured
      coronary endothelial cells].
AB  - BACKGROUND: Endothelial cells (ECs) are believed to be critical cellular elements
      responsible for postnatal angiogenesis. Vascular endothelial growth factor (VEGF)
      stimulates angiogenesis via the activation of KDR/Flk-1 receptor, which is mainly
      expressed in ECs. Transactivation of KDR/Flk-1 receptor by bradykinin (BK) B2
      receptor contributes to the activation of endothelial nitric-oxide (NO) synthase.
      Therefore, we examined whether transactivation by BK induced angiogenesis.
      METHODS AND RESULTS: We developed an in vitro model of human coronary artery ECs
      (HCECs) tube formation on a matrix gel. We demonstrated that BK dose-dependently
      induced tube formation. Although a lower concentration of BK did not induce tube
      formation, the combination of a lower concentration of BK and VEGF did. These
      effects blocked specific inhibitors of VEGF receptor tyrosine kinases (Tki) and
      NO synthase. In addition, BK induced the tyrosine phosphorylation of KDR/FlK-1
      receptor (transactivation), as did VEGF itself. This transactivation was also
      blocked by Tki. CONCLUSIONS: Transactivation of KDR/Flk-1 by BK through B2
      receptor is a potent signaling in angiogenic phenotype in HCECs.

PMID- 12491797
TI  - [BK channels play an important role as a negative feedback mechanism in the
      regulation of spontaneous rhythmic contraction of urinary bladder smooth
      muscles].
AB  - Smooth muscles of urinary bladder wall exhibit spontaneous rhythmic contraction
      which is myogenic in origin. Although the precise mechanism responsible for the
      generation of this mechanical activity remains to be established, it can be
      related closely to the action potential (AP) in urinary bladder smooth muscle
      (UBSM) cell, and may be the fundamental constituent to determine urinary bladder
      physiological functions to store and micturate urine. In the present study,
      possible roles of voltage-dependent and Ca(2+)-sensitive K+ (BK) channels, highly
      expressed in UBSM cells, were examined in the regulation of spontaneous UBSM
      contraction with reference to the generation of AP. Iberiotoxin (IbTx), a
      selective BK channel blocker, strongly increased mechanical activity and AP
      generation in guinea-pig UBSM. In contrast, BK channel openers (NS-1619, niflumic
      acid; estradiol, tamoxifen: BK channel alpha- and beta-subunit activators,
      respectively) significantly diminished AP generation and spontaneous mechanical
      activity. The present study indicates that BK channels play the primary role as a
      negative feedback element to limit extracellular Ca2+ influx through affecting AP
      configurations in the generation of UBSM contraction. BK channel openers
      including beta-subunit activators may be a potentially useful therapeutic remedy
      for the treatment of urinary bladder dysfunctions such as frequent urination.

PMID- 12491798
TI  - [Beta 3-adrenoceptor-mediated relaxation of guinea-pig gastric funds smooth
      muscle: cAMP-independent characteristics and a primary role of 4-aminopyridine
      sensitive voltage-dependent K+ (Kv) channels].
AB  - beta-Adrenoceptor subtypes which mediate relaxation of guinea-pig
      gastrointestinal smooth muscles in response to catecholamines ((-)-isoprenaline,
      (-)-noradrenaline and (-)-adrenaline) and beta 3-adrenoceptor agonists (BRL37344
      and (+/-)-CGP12177A) are predominantly beta 3-adrenoceptors. Although cAMP-PKA
      system is thought to play a substantial role in the smooth muscle relaxation
      mediated via beta 1- and beta 2-adrenoceptors, there is little information on the
      role of cAMP in beta 3-adrenoceptor-meidated relaxation. The present study was
      carried out to elucidate the role of cAMP in beta 3-adrenoceptor-meidated
      relaxation of guinea-pig gastric fundus smooth muscle. Furthermore, possible
      contribution of two types of K+ (voltage-dependent and Ca(2+)-activated K+, BKCa;
      voltage-dependent, Kv) channels was also examined pharmaco-mechanically. In
      gastric fundus smooth muscle, catecholamines and beta 3-adrenoceptor agonists
      elicited potent relaxations in the presence of beta 1- and beta 2-adrenoceptor
      antagonists. All of these relaxations were not diminished by an adenylate cyclase
      inhibitor, SQ-22,536 (100 microM), which indicates their characteristic of cAMP
      independency. SQ-22,536-resistant, beta 3-adrenoceptor-mediated relaxations were
      strongly attenuated by a Kv channel blocker, 4-aminopyridine (3 mM), but not by
      iberiotoxin (100 nM), a selective blocker of BKCa channel. The present results
      indicate that 4-aminopyridine-sensitive Kv channels play a primary role in cAMP
      independent relaxation of guinea-pig gastric fundus smooth muscle in response to
      the stimulations of beta 3-adrenoceptors.

PMID- 12491800
TI  - [Anti-osteopenic effect of taurine: possible involvement of activated MEK-ERK
      Cbfa1 signaling].
AB  - Previously we first noted that taurine (TR) has anti-osteopenic effect on low Ca
      diet-induced osteopenia in rats (1). Employing osteoblastic MC3T3-E1 cells, the
      mechanism of the anti-osteopenic effect was explored in vitro. TR (1 mM) was
      found to promote mineralization of extracellular matrices, without affecting
      alkaline phosphataase activity. Gel shift assay using 32P-labeled OSE2
      (osteoblast-specific cis-element 2: the consensus sequence for Cbfa1, refer to 2)
      indicated that TR (1 mM) increased the nuclear localization of Cbfa1, just as TPH
      (1-34) (3,4) and bisphosphonates did (5). In addition, TR was found to stimulate
      ERK phosphorylation. PD98059, a MEK inhibitor, suppressed effects of TR on both
      Cbfa1 transactivation and ERK activation. The results strongly suggest that TR
      first activates intracellular MEK-ERK-Cbfa1 signaling system thereby promoting
      mineralization and finally leading to its bone anabolic action.

PMID- 12491799
TI  - Structure-activity relationship studies of phenoxypropanolamine derivatives for
      beta 3-adrenergic activity.
AB  - In this study, some compounds of phenoxypropanolamine (SWR-0342SA) derivatives
      were found to possess beta 3-adrenoceptor (beta 3-AR) agonistic activity.
      Addition and deletion of the substituents on phenoxyacetate, chain length
      variation between two aromatic rings, conversion of phenoxypropanolamine to
      phenylethanolamine, insertion of double bonds and another ether group in the side
      chain between two phenyl rings in SWR-0342SA derivatives resulted in novel
      phenoxypropanolamine and phenylethanolamine compounds. This study was performed
      to evaluate the structural modification of the parent SWR-0342SA and their
      effects on the binding affinities as well as functional activities of these
      derivatives using COS-7 cells and CHO cells expressing human beta 1, beta 2, beta
      3-AR and only beta 3-AR respectively. Compounds SWR-0342SA, SWR-0339SA (S
      enantiomer with trans-ethylidene group), SWR-0315NA (non-isomeric with racemic
      ethylidene group and sodium salt), and SWR-0334NA (non-isomeric with trans
      ethylidene group and sodium salt), all belonging to phenoxypropanolamine group,
      were found to have high binding and functional activities and were supposed to be
      potent beta 3-AR agonists. Since many of the phenoxypropanolamine compounds acts
      as antagonists to beta 1- and beta 2-ARs, these derivatives have also been
      evaluated for their affinity to beta 1- and beta 2-ARs. The pKi values of these
      derivatives to beta-AR subtypes were also compared. These compounds show little
      selectivities towards beta 3-AR subtypes.

PMID- 12491801
TI  - [Isolation and determination of an antidote for botulinum neurotoxin from black
      tea extract].
AB  - The botulinum neurotoxin produced by Clostridium botulinum exhibits the strongest
      neurotoxicity, and causes botulism in mammals. We have found an inactivator for
      clostridial neurotoxins in black tea extract (thearubigin fraction) as a natural
      foodstuff. In this study, we have isolated and identified the inactivators. The
      activity against the neuromuscular blocking action of botulinus neurotoxin type A
      was examined in mouse phrenic nerve diaphram preparation. The purification
      procedure of the inactivators was as follows. Tea was extracted with aqueous
      acetone, and then filtrated and lyophilized. It was also extracted with n-hexane,
      chloroform, ethyl acetate, n-butylalchol and water, so the activity of the
      antidote was recognized to be in the n-butylalchol layer (named the thearubigin
      fraction). A two-step reversed phase HPLC was developed for the thearubigin
      fraction. Three flavonoids were found to have the major activity. The structural
      elucidation of the compounds by means of NMR spectrascopy revealed, kaempfenol-3
      O-[glc-(6-1)-rha-(3-1)-glc];keampfetrin, kaempferol-3-O-[glc-(6-1)
      rha];nicotiflorin and quercetin glycoside.

PMID- 12491802
TI  - [Intracellular Ca2+ mediating biodefense signal on CCl4-induced autoprotection].
AB  - To study a role of intracellular Ca2+ on protection effects in animals against
      intoxication, that is, autoprotection. When carbon tetrachloride (CCl4) of 0.2
      ml/kg was i.p. administered daily to male Donryu rats, the serum alanine
      aminotransferase (ALT) activity rose to a maximal level one day later, and then
      decreased to the control level within three days. Thus, the animals were not
      received any intoxication effect of CCl4 due to second, third and fourth
      administrations. Thus, animals have a sensitive and non-sensitive periods against
      intoxication of CCl4. In non-sense period, the animals were protective against
      the poison. Such protection is an autoprotection. To study a role of
      intracellular Ca2+ on CCl4-induced autoprotection, we measured the intracellular
      Ca2+ in hepatocytes isolated from rats after daily CCl4 i.p. administration.
      Then, the peaks of the intracellular Ca2+ centered on three days and twelve hours
      after the first CCl4 administration from the first to fourth administration.
      These results show that the peak of the intracellular Ca2+ is perfectly
      corresponding with the trough of the serum ALT; that is, the protective period in
      animals against intoxication. Therefore, this result means that intracellular
      Ca2+ can mediate biodefense signal caused by CCl4 intoxication.

PMID- 12491803
TI  - [COX inhibitor, suppression of polyposis, and chemoprevention].
AB  - Early experiments using carcinogen-induced rat intestinal tumor models
      demonstrated the inhibitory effects of non-steroidal anti-inflammatory drugs
      (NSAIDs) on intestinal tumorigenesis. Furthermore, epidemiological studies and
      clinical trials for familial adenomatous polyposis (FAP) patients supported the
      possibility that NSAIDs can be used as chemopreventive agents. The major target
      molecules of NSAIDs are cyclooxygenases (COX), which catalyze the rate-limiting
      step of prostaglandin biosynthesis. Two isoenzymes of COX have been identified:
      COX-1 and COX-2. Whereas COX-1 is expressed constitutively in most tissues and
      responsible for tissue homeostasis, COX-2 is inducible and plays an important
      role in inflammation and tumorigenesis. A genetic study using compound mutant
      mice of COX-2-/- and Apc delta 716, a model for human familial adenomatous
      polyposis (FAP), directly demonstrated that induction of COX-2 is critical for
      intestinal polyp formation. Numerous studies have also demonstrated that COX-2
      selective inhibitors suppress intestinal polyp formation in Apc gene-mutant mice
      and xenografted cancer cell growths. In addition, stimulation of angiogenesis is
      one of the major effects by COX-2 expression that is induced in the polyp stromal
      cells. These data from animal model studies should be helpful in understanding
      the in vivo mechanism(s) of tumor suppression by NSAIDs or COX-2 inhibitors.
      Here, we review the animal studies that reported the suppression of intestinal
      tumor growths by NSAIDs or COX-2 inhibitors.

PMID- 12491804
TI  - [Angiogenesis, anti-angiogenesis, and tumor suppression].
AB  - Recent studies have revealed that a number of gene products such as vascular
      endothelial growth factor and its receptors are deeply involved in the process of
      angiogenesis. Most of these genes were characterized not only by the
      biochemical/molecular biological approach but also by the genetical approach
      including the use of gene-targeted mice. Furthermore, some of these genes are
      strongly correlated with the formation of pathological blood vessels such as
      tumor angiogenesis, suggesting that these gene products are good candidates for
      screening anti-angiogenic materials. Inhibitors against VEGF and its receptors
      have been most extensively studied and developed, but inhibitors to other factors
      such as MMPs and angiopoietins may also be useful for developing anti-angiogenic
      materials. In addition to these molecules, unidentified gene products could be
      specifically involved in certain types of pathological angiogenesis.

PMID- 12491805
TI  - [Embryonic stem cell lines for regenerative therapy and pharmaceutical research].
AB  - The establishment of human embryonic stem (ES) cell lines has brought great
      potential and expectations for regenerative medicine and pharmaceutical research,
      because many types of human cells could be produced by their unlimited growth and
      differentiation in culture. Primate and human ES cell lines have been established
      from blastocysts of monkey and surplus human blastocysts from fertility clinics.
      They showed several differences compared to mouse ES cells, including a tendency
      to produce the trophectoderm lineage and a different expression pattern of
      surface antigens. This may reflect species-specific differences, or these primate
      ES cells could represent earlier stages of development than mouse ES cells. Also,
      they show no response to the LIF and gp130 signals, which are widely used to
      repress spontaneous differentiation of mouse ES cell colonies. We have
      established several ES cell lines from blastocysts of the cynomolgus monkey. They
      can be maintained in culture as stem cell colonies, and they produce several
      differentiated cell types in culture. When such ES cells were transplanted into
      SCID mice, they produced teratomas containing many differentiated tissues.

PMID- 12491806
TI  - [Mouse models for rheumatoid arthritis and their use in drug development].
AB  - Rheumatoid arthritis (RA) is a serious medical problem, with approximately 1% of
      the people in the world affected. The disease is autoimmune in nature and
      characterized by chronic inflammation of the synovial tissue in multiple joints,
      which leads to joint destruction, although the etiopathogenesis has not been
      elucidated completely. It is remarkable that expression of inflammatory cytokines
      is augmented in the joints. We previously reported on an inflammatory arthropathy
      resembling RA that develops in high incidence among transgenic (Tg) mice that
      carry the human T cell leukemia virus type I (HTLV-I) tax gene. Autoimmune
      pathogenesis was suggested in this RA model, and levels of cytokines including IL
      1 were elevated in the joints of these Tg mice. Depletion of IL-1 by gene
      targeting greatly reduced the incidence of the disease, indicating the importance
      of this cytokine in the development of arthritis. Furthermore, IL-1 receptor
      antagonist (IL-1Ra)-deficient mice develop autoimmunity and arthritis
      spontaneously. These observations suggest that excess IL-1 signaling causes
      autoimmunity. We show that IL-1 activates the immune system non-specifically by
      inducing CD40L and OX40 co-signaling molecules on T cells. In this review, the
      roles of IL-1 in the development of autoimmunity and arthritis will be discussed
      in correlation with the development of new drugs.

PMID- 12491807
TI  - [Pharmacology of monoamine neurotransmitter transporters].
AB  - Following exocytotic release, the biogenic amine neurotransmitters,
      norepinephrine, dopamine, and serotonin are removed from the synaptic cleft by
      the respective transporter, NET, DAT, and SERT, located on the plasma membrane
      and then re-stored into synaptic vesicles by vesicular monoamine transporter,
      VMAT. The molecular cloning of these transporters revealed that NET, DAT, and
      SERT are members of a sodium-dependent neurotransmitter transporter gene family,
      while VMATs arise from proton-dependent transporter gene family. Structural
      features common to NET, DAT, and SERT reveal a putative 12 transmembrane-spanning
      domain structure with cytosolic N- and C-terminal regions. Recent evidence
      suggest the regulation of the functional expression of these transporters via
      phosphorylation, which include direct phosphorylation of transporter proteins
      and/or of associated proteins that may control transporter function/expression.
      In addition, the substrates and inhibitors for these transporters appear capable
      of regulating transporter cell surface expression, thereby suggesting both
      activity-dependent and pharmacological regulatory mechanisms for transporter
      expression. Analyses of the genes provide new insight into their relation to
      neuronal diseases since NET, DAT and SERT are the molecular targets for many
      antidepressants as well as drugs of abuse such as cocaine and amphetamine. The
      availability of cDNAs of these and vesicular transporters has permitted detailed
      pharmacological studies in heterologous expression systems, and thus would
      promise the development of novel drugs with diverse chemical structures.

PMID- 12491808
TI  - [Neurotrophin-like low molecular weight compounds].
AB  - A large number of compounds have been reported to prevent ischemia-induced
      neuronal death, whereas there are few described to enhance recovery of brain
      functions. Since neurotrophins do not only prevent neuronal death but also
      protect neuronal circuits, they may be potential candidates. However, their poor
      penetration of the blood-brain-barrier hampers their development as therapeutic
      agents. In this context, low-molecular-weight compounds that possess neurite
      outgrowth- and neuronal survival-promoting activities may be alternative
      candidates. Neurite outgrowth-promoting prostaglandins, which were recently
      synthesized based on the chemical structure of anti-tumor cyclopentenone
      prostaglandin derivatives, have been characterized by their neurotrophic effects
      on neurons in the central nervous system. In this paper, we present a review of
      these compounds as therapeutic agents against several neurodegenerative diseases.

PMID- 12491809
TI  - [Recent findings on the dromotropic actions of the class III antiarrhythmic
      agents].
AB  - Class III antiarrhythmic agents have been considered to lengthen the myocardial
      effective refractory period (ERP) without any significant effects on the
      conduction velocity. However, recent investigations have clarified the positive
      or negative dromotropic effects of these agents. Amiodarone, a representative
      class III agent, exerts negative dromotropism by suppressing the fast sodium
      current responsible for conduction in acute administration (class I effects).
      Chronic amiodarone causes prolongation of ERP (class III effects), which is
      sometimes associated with negative dromotropism based on the alteration of
      passive or active membrane properties. Sotalol shows neither significant positive
      nor negative dromotropism under the normoxic condition, whereas this agent is
      reported to exert positive dromotropism mediated by the cAMP-dependent
      facilitation of gap junctional electrical coupling under the hypoxic condition.
      Some pure class III agents such as nifekalant are suspected to elicit 'apparent'
      positive dromotropism in the premature impulse propagation. This is explained by
      the right and upward shift of the strength-interval curve, which theoretically
      transforms the graded premature response to the all-or-none response. Although
      the clinical relevancy of these phenomena remains to be investigated, such
      variable dromotropism of the individual class III agent may contribute to the
      better understanding and development of antiarrhythmic agents.

PMID- 12491810
TI  - [Pharmacological profile and clinical effects of montelukast sodium (Singulair
      chewable tablet), an antiasthmatic agent].
AB  - Montelukast (Singulair) is an antiasthmatic agent that has the chemical structure
      of a quinoline. Montelukast has a high affinity for the CysLT1 receptor and a
      potency that is not influenced by human serum protein. Montelukast antagonizes
      contractions of guinea-pig trachea induced by LTD4 in a competitive manner.
      Intravenous montelukast inhibited bronchoconstriction induced by LTD4 in guinea
      pigs. Oral montelukast inhibited increased airway resistance induced by antigen
      in squirrel monkeys. Montelukast also inhibited both inflammatory and immunologic
      responses induced by either LTD4 or antigen in guinea pigs and rats. Plasma
      concentrations of montelukast after oral administration of 10 mg in humans were
      shown to be over the effective level for at least 24 h. These lines of evidence
      support the effectiveness of a regimen of 10 mg/day for asthmatic symptoms in
      humans. In a number of clinical experiments, montelukast not only improved
      asthmatic symptoms and respiratory indices, but also inhibited airway
      inflammation and exercise-induced bronchoconstriction. These effects persisted
      during extended treatment. Montelukast produced an additive effect to basic
      therapy with an inhaled steroid. There were no differences in the incidence and
      magnitude of adverse effects between montelukast and placebo groups in clinical
      experiments. Montelukast is expected to serve as a first line of asthmatic
      therapy because of its consistent efficacy and good safety profile and it is
      associated with good compliance in patients because of its simple regimen of one
      10 mg tablet/day.

PMID- 12491811
TI  - [Preclinical and clinical profile of Valsartan, a selective angiotensin II type-1
      receptor blocker].
AB  - Valsartan (Diovan) is a potent, orally active, specific, and highly selective
      blocker for the AT1-receptor subtype. The antihypertensive effects of oral
      treatment with valsartan were preclinically demonstrated in the sodium-depleted
      marmosets, renal hypertensive rats (2K1C), spontaneous hypertensive rats (SHR)
      and stroke-prone SHR. Moreover, valsartan had protective effects against
      hypertensive end-organ damage such as cardiac hypertrophy and renal disease. In
      an investigation of pharmacokinetics and pharmacodynamics in normotensive male
      volunteers, valsartan was rapidly absorbed with the maximal plasma concentration
      occurring 2-3 h after oral administration. The elimination half-life was about 4
      6 h, valsartan was poorly metabolized, and most of the drug was excreted via
      feces. Valsartan produced persistent reductions of blood pressure in patients
      with mild to moderate essential hypertension and had a good safety profile with a
      wide therapeutic window between the effective pharmacological doses and the toxic
      doses. Therefore, valsartan is expected to be a safe and effective
      antihypertensive agent for the treatment of essential and severe hypertension.

PMID- 12491812
TI  - Uniting the house of medicine: TMA & Medical Specialty Societies.

PMID- 12491813
TI  - Loss prevention case of the month. Failure to respond to panic laboratory values.

PMID- 12491814
TI  - Environmental investigations and children with elevated blood lead levels.

PMID- 12491815
TI  - Patient-delivered therapy: an additional means for addressing the Chlamydia
      trachomatis problem.

PMID- 12491816
TI  - Health care provider's liability for emotional distress.

PMID- 12491817
TI  - Simulations of airflow and substance concentration around a human body.
AB  - In order to predict airflow and suspended substance concentration around a human
      body, we developed a geometric model of the human form and generated grids around
      it for Computational Fluid Dynamics (CFD). According to a CFSV model proposed by
      us we made a domain that included a geometric human model and generated the grids
      within this domain. By using this model with the grids and the developed CFD
      program, it is possible to simulate the airflow and the transfer of a suspended
      substance around the body. The simulated airflow provided a different velocity
      profile for each region of the body due to the characteristics of the body shape.
      The simulated distribution of the suspended substance concentration demonstrates
      how usable the present model is for quantifying a substance in any exposed region
      of the body.

PMID- 12491818
TI  - Cardiovascular risk factors in a tourist town: association with job-related
      factors.
AB  - Previous studies have shown that mortality from cardiovascular diseases in
      fishing villages was lower than that in farming villages. In contrast, few
      reports on the population living in a tourist village have appeared. Then, we
      report here the characteristic features of a tourist town, and that in fishing
      and farming towns. The rural farming town in Gunma prefecture had a population of
      15,100. The population working in the primary industry was 17.1%, and the farming
      population was 17.0%. The fishing town in Shizuoka prefecture had a population of
      11,700. The population working in the primary industry was 11.0%, and the fishing
      population was 10.2%. The rural tourist town in Shizuoka prefecture had a
      population of 17,800. The population working in the tertiary industry was 60.2%,
      and the wholesaling or retailing population was 16.6%. Standardized mortality
      ratios of cardiovascular diseases in the tourist town reported by Shizuoka health
      officials were higher than the fishing town. The rate of participation at ages of
      50-59 years for the basic health examination in the tourist town was lower than
      the fishing and the farming towns. From the results of the health examination of
      residents at ages of 50-59 years, the high prevalence of obesity and hypertension
      in men and high prevalence of hypertension in women were found in the tourist
      town. In the tourist town, self-employed women at ages of 50-59 years had
      irregular time of meals and insufficient care of diet in comparison with employed
      women. Furthermore, the prevalence of hypertension in self-employed women was
      also higher than that of employed women. We could suggest that health status in
      communities might be associated with job-related factors.

PMID- 12491819
TI  - Effects of exercise practice on the maintenance of radius bone mineral density in
      postmenopausal women.
AB  - The effect of exercise practice on the radius bone mineral density (BMD) was
      investigated on 480 women at the age of perimenopause and later. The BMD at the
      1/3 distal site of the radius on a non-dominant hand was measured using the Dual
      Energy X-ray Absorptiometry method. The subjects were divided into group E with
      regular exercising and group C without regular exercising. The difference of mean
      radius BMD values was not statistically significant between groups E and C. Each
      of the groups E and C was further classified into a perimenopause group and
      groups with stratified postmenopausal years (postmenopausal years less than 5,
      less than 10 and more than 10). Then, the mean radius BMD value of the
      perimenopause subgroup was taken as 100% for each of the groups E and C, and the
      relative radius BMD values of subgroups were compared between groups E and C. The
      relative BMD values for the subgroup of postmenopausal years more than 10 were
      higher in E group than those in C group, while no difference was observed in
      below postmenopausal 10 years between the two groups. To clarify the BMD
      difference among exercise events, group E was further divided into the following
      three subgroups: the subgroup practising events which give high-impact to arm (HI
      group), such as tennis, ping-pong, golf and volleyball, the subgroup practising
      swimming (SW group), and the subgroup practising events which give low-impact to
      arm (LI group), such as walking, running, aerobic dance and light gymnastics. No
      significant differences were observed in BMD values among the above sports event
      stratified subgroups when postmenopausal years were less than 10 years, but the
      relative BMD values for the subgroup of postmenopausal years more than 10 were
      higher in HI and LI group than those in control group. These results suggest the
      possibility that exercise practice suppresses a postmenopausal decline in bone
      density for preventing osteoporosis from developing.

PMID- 12491820
TI  - Cyclooxygenase-2 inhibitor inhibits the fracture healing.
AB  - We investigated the effects of cyclooxigenase-2 (cox-2) on fracture healing.
      After closed non-displaced fractures were created at the middle of both femoral
      shafts in 12-week-old Wister rats, a cox-2 specific inhibitor, etodolac (20
      mg/day; intra-peritoneal) was administered every day for three weeks (E group).
      Bone union and callus formation were evaluated by weekly radiographs. Three weeks
      after surgery, the mechanical strength of the fractured femur was evaluated by a
      three-point-bending test. These results were compared with those of a vehicle
      control group (V group). The fracture healing score on radiographs in the E group
      three weeks after the surgery was 3.3 +/- 0.9, and in the V group it was 5.8 +/-
      1.5, indicating that fracture healing was significantly poorer in the E than the
      V group (p < 0.05). From the three point bending test, the ultimate strength and
      stiffness of etodolac-treated fractured femurs were shown to be significantly
      lower than those in vehicle control group (p < 0.05). Mechanically, femurs of
      etodolac treated rats were weaker than those of control rats. Thus, it was
      concluded that etodolac, a cox-2 specific inhibitor, inhibited fracture healing.

PMID- 12491821
TI  - Ventilatory and gas exchange responses under spontaneous and fixed breathing
      modes during arm exercise.
AB  - To evaluate the difference of ventilatory and gas exchange response differences
      between arm and leg exercise, six healthy young men underwent ramp exercise
      testing at a rate of 15 W.min-1 on a cycle ergometer separately under either
      spontaneous (SPNT) or fixed (FIX) breathing modes, respectively. Controlled
      breathing was defined as a breathing frequency (fb; 30 breaths.min-1) which was
      neither equal to, nor a multiple of, cranking frequency (50 rev.min-1) to prevent
      coupling of locomotion and respiratory movement, i.e., so-called locomotor
      respiratory coupling (LRC). Breath-by-breath oxygen uptake (VO2), ventilation
      (VE), CO2 output (VCO2), tidal volume (VT), fb and end-tidal PCO2 (PETCO2) were
      determined using a computerized metabolic cart. Arm exercise engendered a higher
      level of VO2 at each work rate than leg exercise under both FIX and SPNT
      conditions. However, FIX did not notably affect the VO2 response during either
      arm or leg exercise at each work rate compared to SPNT. During SPNT a
      significantly higher fb and lower PETCO2 during arm exercise was found compared
      with leg exercise up to a fb of 30 breaths.min-1 while VE and VT were nearly the
      same. During fixed breathing when fb was fixed at a higher rate than during SPNT,
      a significantly lower PETCO2 was observed during both exercise modes. These
      results suggest that: 1) FIX breathing does not affect the VO2 response during
      either arm or leg exercise even when non-synchronization between limb locomotion
      movement and breathing rate was adopted; 2) at a fb of 30 breaths.min-1 FIX
      breathing induced a hyperventilation resulting in a lower PETCO2 which was not
      associated with the metabolic rate during either arm or leg exercise, showing
      that VE during only leg exercise under the FIX condition was significantly higher
      than under the SPNT condition.

PMID- 12491822
TI  - The rate of phosphocreatine hydrolysis and resynthesis in exercising muscle in
      humans using 31P-MRS.
AB  - Time-resolved 31-phosphorus nuclear magnetic resonance spectroscopy (31P-MRS) of
      the biceps femoris muscles was performed during exercise and recovery in six
      healthy sedentary male subjects (maximal oxygen uptake; 46.6 +/- 1.7 (SEM) ml.kg
      1.min-1), 5 male sprinters (56.2 +/- 2.5), and 5 male long-distance runners (73.6
      +/- 2.2). Each performed 4 min of knee flexion exercises at absolute values of
      1.63 W and 4.90 W, followed by 5 min of recovery in a prone position in a 2.1 T
      superconducting magnet with a 67 cm bore. 31P-MRS spectra were recorded every
      12.8 s during the rest-exercise-recovery sequence. Computer-aided contour
      analysis and pixel imaging of phosphocreatine peaks (PCr) and inorganic phosphate
      (Pi) were performed. The work loads in the present study were selected as mild
      exercise (1.63 W) and heavy exercise (4.90 W), corresponding to 18-23% and 54-70%
      of maximal exercise intensity. Long-distance runners showed a significantly
      smaller decrement in PCr and less acidification at a given exercise intensity
      compared to those shown by sedentary subjects. The transient responses of PCr and
      Pi during recovery were characterized by first-order kinetics. After exercise,
      the recovery rates of PCr and Pi were significantly faster in long-distance
      runners than in sedentary subjects (P < 0.05). Since it is postulated that PCr
      resynthesis is controlled by aerobic metabolism and mitochondrial creatine
      kinase, it is suggested that the faster PCr and Pi recovery rates and decreased
      acidification seen in long-distance runners during and after exercise might be
      attributed to their greater capacity for aerobic metabolism.

PMID- 12491823
TI  - A relative high dose of vitamin E does not attenuate unweighting-induced
      oxidative stress and ubiquitination in rat skeletal muscle.
AB  - We previously reported that intragastric administration of cysteine could be
      beneficial to prevent unweighting-induced ubiquitination and degradation of
      muscle protein in association with redox regulation [Ikemoto et al., Biol. Chem.,
      383 (2002), 715-721]. In this study, we investigated whether vitamin E, another
      potent antioxidative nutrient, also had beneficial effects on the muscle protein
      catabolism. However, daily intragastric supplementation of 1.5 or 15 mg/rat of
      alpha-tocopherol did not prevent weight loss of hindlimb skeletal muscle in tail
      suspended rats. To elucidate the reason for the non-effectiveness of vitamin E,
      we further examined concentrations of oxidative stress markers, ubiquitination of
      muscle proteins and fragmentation of myosin heavy chain in gastrocnemius muscle
      of rats daily treated with 15 mg of alpha-tocopherol. Unexpectedly, vitamin E
      increased concentrations of glutathione disulfide and thiobarbituric acid
      reactive substance and decreased glutathione level in the muscle, compared with
      those of vehicle treatment, indicating that vitamin E enhanced unweighting
      induced oxidative stress in skeletal muscle. The vitamin E supplementation did
      not suppress the ubiquitination of muscle proteins and fragmentation of myosin
      heavy chain caused by tail-suspension. Our results suggest that supplementation
      of a relative high dose of vitamin E could not inhibit ubiquitin-dependent
      degradation of muscle protein in tail-suspended rats possibly due to its
      prooxidant action.

PMID- 12491824
TI  - [Update of authorship criteria in biomedical articles].
AB  - In the year 2000, a previous Editorial in this journal reviewed the criteria for
      authorship as defined by experienced authors and editors, discussed in selected
      references from the biomedical literature. An emphasis was given to the
      definition of authorship stated in the available 1997 version of the "Uniform
      Requirements for Manuscripts Submitted to Biomedical Journals". After that
      Editorial was published, an updated version of the "Uniform Requirements"
      established important changes in their criteria; e.g. Participation of each
      author in the work should permit them to take public responsibility for
      "appropriate portions of the content"; and acquisition of data was added as an
      acceptable alternative in the first requisite for authorship. These and other
      changes should be disused to prospective authors, particularly in multicentric
      studies usually leading to multi-authorship. This new Editorial and a translation
      into Spanish of the authorship criteria contained in an-updated (2001) version of
      the "Uniform Requirements" are included in this issue of Revista Medica de Chile
      with the purpose of stimulating authors and readers to think in their
      implications.

PMID- 12491825
TI  - [Hypercoagulability in atrial fibrillation and its relationship with risk factors
      for systemic embolism].
AB  - BACKGROUND: Atrial fibrillation is associated to a high risk of systemic embolism
      and to hypercoagulability. AIM: To evaluate the activation of the coagulation
      cascade through determinations of the thrombin-antithrombin complex in patients
      with atrial fibrillation and to correlate this data with the clinical and
      echocardiographic risk factors for systemic embolism. PATIENTS AND METHODS: In 53
      patients with atrial fibrillation plasma levels of the thrombin-antithrombin
      complex were determined on admission to a coronary care unit and 30 days later.
      Using a univariate and multiple regression analysis, the association basal
      thrombin-antithrombin with the duration of the arrhythmia, age over 70 years,
      previous use of antiplatelet agents, history of hypertension, mitral valve
      disease, diabetes, heart failure, previous systemic embolism, left atrial
      diameter and the presence of spontaneous contrast echo or thrombus in the left
      atrial appendage, was studied. RESULTS: Basal thrombin-antithrombin values were
      40.1 +/- 69 mg/L (Median 8.34 [3.0-47.5]) compared to 2.7 +/- 3.3 mg/L in healthy
      controls (p < 0.001). No significant correlation was found between activation of
      the coagulation cascade and risk factors for systemic embolism. There were no
      significant differences in thrombin-antithrombin values between patients with
      chronic or paroxysmal atrial fibrillation (29.5 +/- 43 mg/L and 49.4 +/- 83 mg/L
      respectively). Mean thrombin-antithrombin values in patients under antiplatelet
      agents were lower than in those without treatment (17.3 +/- 43 vs 66.8 +/- 127
      mg/L; p = 0.018). CONCLUSIONS: The activation of the coagulation cascade in
      patients with atrial fibrillation was confirmed. However, no association of this
      activation with well known clinical and echocardiographic risk factors for
      systemic embolism, was found. Previous antiplatelet treatment prevented a higher
      activation of the coagulation cascade.

PMID- 12491826
TI  - [Secular changes in anthropometrical variables at birth: a local perspective].
AB  - BACKGROUND: Anthropometrical measurements at birth are the result of the
      conditions during pregnancy, being an issue of current interest due to the
      reported relationship of birth weight with non communicable chronic diseases in
      adulthood. AIM: To study the change in anthropometrical measurements at birth,
      between the period 1974-1978 and the period 1995-1999, in two counties of
      Valparatso, Chile. MATERIAL AND METHODS: We collected information from the public
      health care system in a universe of 5,018 newborns of the two periods. RESULTS:
      When compared to 1974-1978, the period 1995-1999, showed 38% decrease in the
      number of deliveries, 0.7% decrease in parity, 1.4% decrease in pre-term
      deliveries and one year increase of mother's age. Likewise birth weight increased
      by 246 g in males and 210 g in females (p < 0.01). Birth length increased by 0.5
      cm in males and 0.4 cm in females (p < 0.01). Low birth weight was reduced from 9
      to 4.2% and length under -2 standard deviations from normal, also decreased from
      5.4 to 1.5% (p < 0.001). CONCLUSIONS: In the last 20 years, an improvement in
      anthropometrical measurements at birth was observed. Better conditions during
      pregnancy probably explain these changes.

PMID- 12491827
TI  - [Occupational stress and health in a sample of chilean executives].
AB  - BACKGROUND: Most individual and organizational costs related to job stress are
      due to preventable health problems. To study the impact of occupational stress in
      Chile, an instrument that evaluates the different variables involved in the
      stress process is required. AIM: To study the effects of work stressors and
      psychological variables on health among Chileans managers. To study reliability
      and validity of the Spanish version of the Occupational Stress Indicator (OSI-2).
      SUBJECTS AND METHODS: A translated version of the OSI-2 was applied to a sample
      of 264 white-collar managers. RESULTS: A high frequency of symptoms was reported
      by our sample. Back pain was the most frequently reported symptom in managers
      with high levels of stress. Regression analysis showed that, together, work
      stressors and psychological characteristics significantly explained self
      perceived mental (27.6%) and physical (22.9%) health variance. Responsibilities
      of the executive role were the stressors most highly associated with poor stress
      outcomes. The psychological variables most strongly correlated with mental and
      physical health were Problem-focused Coping and the subscale Impatience of Type A
      Behavior. The reliability and validity of the OSI-2, Spanish version, were
      reasonably high. CONCLUSIONS: The transactional model of work stress was
      confirmed in a sample of Chilean managers evaluated with the Spanish version of
      the OSI-2.

PMID- 12491828
TI  - [Frequency of the 185delAG mutation in the BRCA1 gene in Chilean healthy women
      with family history of breast cancer].
AB  - BACKGROUND: Breast cancer is the most common malignancy among women, and is the
      second cause of cancer mortality among Chilean women. Female mortality due to
      breast cancer in Chile has shown a steady increase from 9.5 deaths per 100.000
      women in 1985 to 12.8 deaths per 100.000 in 1995. A family history of breast
      cancer is one of the main risk factors for the development of the disease. BRCA1
      and BRCA2 are two major hereditary breast cancer susceptibility genes. Mutations
      in these genes are associated to inherited breast cancer; 664 predisposing
      mutations have been described, but in specific populations only some of them,
      such as 185delAG have been found to be associated with susceptibility to breast
      cancer. AIM: To establish the frequency of the 185delAG mutation in the BRCA1
      gene in Chilean healthy women with a family history of breast cancer. PATIENTS
      AND METHODS: The 185delAG mutation was studied by mismatch polymerase chain (PCR)
      reaction in 382 Chilean healthy women with at least two relatives affected with
      breast cancer. The PCR products were digested with the restriction enzyme HinfI.
      Digestion of the normal allele (170 pb fragment) produces a 150 pb fragment; the
      PCR product for the mutant allele does not contain a site for HinfI and therefore
      remains as a 170 bp fragment after digestion. RESULTS: One of the 382 healthy
      women presented the fragment of 170 pb after digestion with HinfI suggesting that
      she was heterozygous carrier for this mutation. The mutant patient had a
      mammography without suspicion of cancer. CONCLUSIONS: The frequency of the
      185delAG mutation in BRCA1 was 0.26% (1/382) in Chilean healthy women with a
      family history of breast cancer.

PMID- 12491829
TI  - [Early enteral nutrition in cancer patients subjected to a total gastrectomy].
AB  - BACKGROUND: Total parenteral nutrition has a high cost and frequency of
      complications. Enteral feeding is a feasible alternative that can be started
      early in the postoperative period. AIM: To assess digestive tolerance to early
      enteral feeding in cancer patients undergoing total gastrectomy and to compare
      early enteral feeding (EEF) with total parenteral nutrition plus enteral feeding
      (TPN + EF), initiated after overcoming postoperative ileus. PATIENTS AND METHODS:
      Subjects with a resectable gastric cancer were considered eligible for the study.
      During surgery a nasoenteral tube was placed and patients were prospectively
      randomized to EEF or TPN + EF. Digestive tolerance, effectiveness, complications
      and costs between both modalities of nutritional support were compared. RESULTS:
      Twenty eight patients (15 male, aged 63 +/- 14 years old) were studied. Fourteen
      patients were randomized to EEF and 14 to TPN + EF. Diarrhea occurred in 14 and
      29% of EEF and TPN + EF patients respectively, (p: NS). Patients with TPN + EF
      received an average of 28 Cal/kg/day and 1.1 g/kg/day proteins. Patients with EEF
      received an average of 29 Cal/kg/day and 0.8 g/kg/day proteins. At the eighth
      postoperative day, serum albumin was 3.9 +/- 0.7 and 3.2 +/- 0.5 g/dl in EEF and
      TPN + EF patients respectively (p < 0.05), serum prealbumin was 16.9 +/- 5 and
      12.3 +/- 4.3 mg/dl in EEF and TPN + EF patients respectively (p < 0.05) and
      nitrogen balance was +2.4 +/- 1.5 and -1.6 +/- 0.6 g/24 h in EEF and TPN + EF
      patients respectively (p < 0.05). Postoperative hyperglycemia was observed with a
      lower frequency and nutritional support costs and length of hospital stay were
      significantly lower in the EEF group. CONCLUSIONS: After total gastrectomy EEF is
      well tolerated, safe and effective, even during the early postoperative ileus.
      This therapeutic modality could be the first choice for nutritional support in
      these patients.

PMID- 12491830
TI  - [Prevalence of sexual dysfunction in climacteric women. Influence of menopause
      and hormone replace therapy].
AB  - BACKGROUND: Few trials have studied the prevalence of sexual dysfunction (SD) and
      related risk factors in postmenopausal women using the DSM-IV criteria. AIM: To
      evaluate the prevalence of SD in menopausal women and the impact of risk factors.
      PATIENTS AND METHODS: Five hundred thirty four healthy women, 40 to 64 years of
      age were interviewed using the Laumann test (DSM-IV). RESULTS: Mean age was 52.4
      +/- 5.7 years. Eighty three percent were peri or postmenopausal, 23% used
      hormonal substitution therapy and 79.2% were sexually active. Among sexually
      active women, the prevalence of SD increased along with age, from 22.2% at the 40
      44 years old range to 66.0% in the 60-64 years old group. Hormone users and
      healthy women had a low risk for SD (Odds ratio (OR): 0.1 IC: 0.0-0.1 and OR: 0.6
      IC: 0.3-0.9, respectively). The risk increased in menopausal women (OR: 3.3 IC:
      1.6-6.9), those older than 49 years (OR: 3.4 IC: 1.8-6.4), those subjected to
      hysterectomy (OR: 3.7 IC: 1.3-10.6) or those with an impotent sexual partner (OR:
      3.2 IC: 1.2-8.6). CONCLUSIONS: There is a high prevalence of SD among climacteric
      women. Estrogens, either endogenous or exogenous, have a positive influence on
      sexuality.

PMID- 12491831
TI  - [Invasive fungal infections in children with cancer, neutropenia and fever, in
      Chile].
AB  - BACKGROUND: Invasive fungal infections (IFI) cause prolonged hospitalizations and
      increase the possibility of death among patients with cancer and febrile
      neutropenia (FN). Up to 10% of febrile neutropenic episodes may be caused by IFI.
      AIM: To estimate the incidence of IFI among a large group of Chilean children
      with cancer and FN. PATIENTS AND METHODS: Clinical and laboratory information was
      collected from a data base provided by the "Programa Infantil Nacional de Drogas
      Antineoplasicas" (PINDA) that included 445 FN episodes occurring in five
      hospitals in Santiago, Chile. This information was used to identify children that
      presented with signs and symptoms compatible with an IFI. According to predefined
      criteria based on a literature review, IFI episodes were categorized as "proven",
      "probable" or "possible". RESULTS: A total of 41/445 episodes (9.2%) were
      compatible with an IFI of which 4 (0.9%) were proven, 23 (5.2%) probable, and 14
      (3.1%) possible. Hospitalization was longer (27 vs 8 days, p < .01), new
      infectious foci appeared with higher frequency (71 vs 38%, p < .01), and
      mortality was higher (10 vs 1.6%, p < .001) in children with IFI compatible
      episodes, when compared to children who did not have an IFI. CONCLUSIONS: The
      estimated incidence of IFI in Chilean children with cancer and FN ranged between
      6-9% depending on the stringency of criteria selection used for classification.
      This estimate is similar to that reported by other studies. The low detection
      yield of clinically compatible IFI underscores the need of improved diagnosis of
      fungal infections in this population.

PMID- 12491832
TI  - [Risk factors for permanent kidney damage in children with urinary tract
      infection].
AB  - BACKGROUND: In children, urinary tract infection (UTI) is a very common disease,
      and can cause permanent kidney damage. AIM: To determine risk factors for
      permanent kidney damage, in children with UTI. PATIENTS AND METHODS: In 337
      children with UTI (237 female, mean age 4.2 years) a static renal scintigraphy
      was performed to assess the presence of permanent kidney damage. The history of
      vesicoureteral reflux and number of episodes of UTI was obtained. RESULTS: One
      hundred three children had a history of one episode of infection and the rest had
      recurrent infections. Permanent kidney damage was observed in 161 children (48%).
      This damage was observed in 39% of children of less than one year of age, in 43%
      of children aged 1 to 5 years of age and in 58% of children older than 5 years (p
      = 0.02). Sixty three percent of 122 children with vesicoureteral reflux had
      permanent kidney damage, compared with 27% of children without this condition (p
      < 0.001). Likewise, damage was observed in 36% of children with one episode of
      infection and 47% of children with recurrent infections (p < 0.01). No gender
      differences were observed. CONCLUSIONS: Vesicoureteral reflux, recurrence of UTI
      and age are associated with permanent renal damage in children with UTI.

PMID- 12491833
TI  - [Mesenteric angina: infrequent cause of chronic pain in hemodialysis patient].
AB  - We report a 73 years old male undergoing chronic hemodialysis with a history of
      seven years of abdominal pain and weight loss. A mesenteric angiography disclosed
      a critical stenosis of the celiac artery and a partial stenosis of the superior
      mesenteric artery. Other causes of abdominal pain were excluded. The patient was
      subjected to a successful angioplasty with stent placement that resulted in a
      complete relief of the pain.

PMID- 12491834
TI  - [Intestinal necrosis as clinical presentation of Takayasu arteritis].
AB  - A 32 years old female was admitted to hospital due to acute abdominal pain,
      nausea, vomiting and liquid stools. Physical examination was normal except for
      pain on her left inferior abdominal quadrant without peritoneal irritation signs.
      An abdominal CAT-scan suggested thrombosis at celiac trunk, although the echo
      Doppler showed no alterations except for signs of ischemia in the distal branch
      of the superior mesenteric artery. An exploratory laparotomy was performed
      disclosing a necrosis of the distal ileum and cecum, diffuse peritonitis and
      thrombosis of the ileocecoapendiculocolic artery. No vasculitis lesions were
      found in the arteries of medium size examined. A history of intermittent
      claudication for the past 3 years as well as acrocyanosis, asymmetry of pulses
      and blood pressure in the superior extremities was ascertained after the surgery.
      A MRI angiogram showed multiple stenoses and irregularities at the celiac trunk,
      hepatic, superior mesenteric and fibular arteries. No abnormalities at the aortic
      arch and its main branches were documented. A sepsis due to Candida sp
      complicated her postoperative period. After recovery, prednisone 1 mg/kg/day was
      started and the anticoagulation continued. The abdominal pain, intermittent
      claudication and superior limb acrocyanosis disappeared. This is an unusual case
      of type IV Takayasu's arteritis with acute abdominal signs as the first
      manifestation.

PMID- 12491835
TI  - [Verrucous endocarditis secondary to Saccharomyces cerevisiae. A case report].
AB  - We report a preterm infant with 30 weeks of gestation, that received broad
      spectrum antimicrobials during the first days of life. At nine days of life, the
      infant appeared with abdominal distension and hematochezia. A systolic murmur
      with changing auscultatory features also appeared. An echocardiography showed an
      atrial vegetation. A yeast, that was identified as the emergent pathogen
      Saccharomyces cerevisiae appeared in two blood cultures. Treatment with
      amphotericin B was started, the dose was adjusted calculating the minimal
      inhibitory concentration of amphotericin B, and measuring plasma levels of the
      antimicrobial. Therefore the minimal effective dose was prescribed, avoiding its
      deleterious effects. After 14 days of antifungal therapy, a new echocardiography
      showed a reduction in the size of the atrial vegetation. At 35 days, it
      disappeared and amphotericin B was discontinued. On the outpatient follow up, the
      infant has shown a normal growth and a normal cardiac auscultation.

PMID- 12491836
TI  - [Malaria in Chile: 1913-2001].
AB  - BACKGROUND: Malaria was restricted to the I Region of Chile, being Anopheles
      pseudopunctipennis the only vector species. In 1936 the parasitosis affected more
      than 50% of the population and 62.4% of military recruits, proceeding from
      Southern regions became infected. From 1937 to 1947, an antimalaria campaign was
      carried out, stressing actions on the battle against the vector and the treatment
      of malaria infected individuals. Since April 1945 no autochthonous cases of
      malaria have been detected. AIM: To update the situation of malaria in Chile.
      METHODS: 1) Imported malaria: Analysis of occasional publications on the subject
      (1945-1988) and the annual reports of the Ministry of Health Department of
      Epidemiology (1990-2001). Annual reports on the Anopheles specimens collected-
      mostly larvae--in the provinces of Arica and Iquique and examined in the
      Parasitology Unit of the School of Medicine, University of Chile, during the
      period 1980-2001. RESULTS: 1) Imported malaria. A total of 24 cases were
      published in the period 1945-1988. In the 1980-2001 period, the Ministry of
      Health recorded 66 cases with 5 (8.8%) deaths. 2) Anophelines: Only in 1984,
      1985, 1998 and 2001 A. pseudopunctipennis foci were detected. Entomological
      surveillance was stressed and insecticides were applied on these focuses.
      CONCLUSIONS: Autochthonous malaria does not exist in Chile since 1945. The
      detection of malaria cases in countries where the parasitosis was eradicated, can
      be the result of tourism or migrations. In Chile, the Environmental Programs of
      Arica and Iquique perform periodical surveys in localities where mosquitoes
      exist. When A. pseudopunctipennis is found, the entomological vigilance is
      stressed and insecticide applications are reiterated until the situation is
      controlled.

PMID- 12491837
TI  - [Authorship criteria for scientific publication: a translation into Spanish from
      the 2001 updated version of the document Uniform Requirements for Manuscripts
      submitted to Biomedical Journals"].

PMID- 12491838
TI  - [Arturo Vivado Orsini and the renewal of psychiatric treatments].
AB  - During the first half of the twentieth century, new psychiatric treatments were
      discovered, such as malario therapy, insulin therapy, electroshock, penicillin
      therapy, and the anti-alcoholic aversive therapy. These treatments gave a new
      hope to mental patients, even in our country. It was precisely while Dr. Arturo
      Vivado, Full Professor of Psychiatry at the University of Chile, worked and
      taught, that these treatments were progressively applied in Chile. After an
      effortful career, Dr. Vivado was appointed Director of the Psychiatric Asylum in
      Santiago, in 1945. He was a skillful clinician and pragmatic with his
      psychological belief, equanimus and affectionate with people. His most important
      contributions to the specialty are described in this review.

PMID- 12491839
TI  - [Changes in the epidemiology of infectious disease in Chile: 1990-2000].

PMID- 12491840
TI  - [Changes in the epidemiology of infectious disease in Chile: 1990-2000].

PMID- 12491841
TI  - Juvenile crime: a renewed suggestion for prevention.

PMID- 12491842
TI  - Criminal psychological profiling of serial arson crimes.
AB  - The practice of criminal psychological profiling is frequently cited as being
      applicable to serial arson crimes. Despite this claim, there does not appear to
      be any empirical research that examines serial arson offence behaviors in the
      context of profiling. This study seeks to develop an empirical model of serial
      arsonist behaviors that can be systematically associated with probable offender
      characteristics. Analysis has produced a model of offence behaviors that identify
      four discrete behavior patterns, all of which share a constellation of common
      nondiscriminatory behaviors. The inherent behavioral themes of each of these
      patterns are explored with discussion of their broader implications for our
      understanding of serial arson and directions for future research.

PMID- 12491843
TI  - Shame and guilt in child sexual offenders.
AB  - In this article, the authors build on previous discussions of the possible role
      of shame and guilt in sexual offending. They review the general psychological
      literature on shame and guilt and conclude that the distinction between internal
      and external shame is an important one in considering sexual offenders. The
      effects of shame and guilt on victim empathy and relapse are discussed, and it is
      proposed that the phenomena of shame and guilt have implications for treatment
      beyond those identified in previous studies. Shame is a salient feature in the
      initial presentation of many sexual offenders against children. Furthermore,
      aspects of the treatment of sexual offenders can be characterized as a shift from
      shame toward guilt. Implications of shame and guilt for treatment of sexual
      offenders are described.

PMID- 12491844
TI  - Diagnosing sexual sadism in sexual offenders: reliability across diagnosticians.
AB  - On the basis of detailed accounts of offences committed by 12 dangerous sexual
      offenders and of descriptions of their life histories, their responses to various
      tests, self-reports of offenders' sexual interests and activities, and results of
      phallometric evaluations, 15 expert forensic psychiatrists diagnosed whether each
      offender met the criteria for sexual sadism. The psychiatrists also indicated
      their confidence in the diagnoses they made and rated the relevance to the
      diagnosis of sexual sadism for various features of the offence and the offender.
      Results revealed unsatisfactory levels of diagnostic agreement among the
      psychiatrists. On the other hand, they agreed quite well on the importance for
      the diagnosis of several of the offence features described. Suggestions are
      offered for clinical practice.

PMID- 12491845
TI  - A controlled, problem-solving, group-based intervention with vulnerable
      incarcerated young offenders.
AB  - Recent research has indicated that vulnerable incarcerated young offenders--such
      as those at risk of suicidal behaviour, those on formal protection due to their
      inability to assimilate into mainstream, and those who are bullied but remain in
      normal circulation--display impoverished problem-solving abilities. Furthermore,
      deficits in their problem-solving skills are significantly correlated with levels
      of anxiety, depression, and hopelessness. This study evaluated the effectiveness
      of a time-limited, group-based problem-solving training intervention compared
      with a no-treatment control for vulnerable, incarcerated young offenders. A total
      of 46 young offenders were equally allocated to intervention or control groups.
      Intervention participants experienced significant reductions in their levels of
      anxiety, depression, and hopelessness and improvement in their self-assessed
      social problem-solving abilities. Gains in aspects of self-assessed problem
      solving ability and mental health for the intervention group continued to be
      evident at 3-month follow-up. Methodological concerns in this study and
      directions for future research are discussed.

PMID- 12491846
TI  - Comparing inmate perceptions of two residential substance abuse treatment
      programs.
AB  - Drug and alcohol abuse by criminal offenders remains at an all time high.
      Residential substance abuse and treatment (RSAT) programs were developed to
      address the drug and alcohol treatment needs of inmates in prisons. Typically,
      such programs range in length from 6 to 12 months, have an Alcoholics Anonymous
      and/or Narcotics Anonymous component, and occur in a therapeutic community
      environment. Some programs also include a cognitive self-change component. Inmate
      participation in their programming is crucial to the success of a therapeutic
      community treatment environment, yet there is little research on the perceptions
      of RSAT inmates regarding their programming. In this research, the authors
      describe, compare, and contrast the perceptions of inmate clients of two RSAT
      programs in a rural mountain state.

PMID- 12491847
TI  - Alcohol and drug use among rural and urban incarcerated substance abusers.
AB  - A number of prisoners use drugs. Limited information is available about the
      extent to which urban and urban substance abusers differ in their drug use in
      criminal justice settings. In addition, many believe that rural areas are
      protected from drug use. However, findings from this study show only marginally
      statistical significant differences in drug use between incarcerated rural and
      urban drug users. It was expected that urban drug users would be more drug career
      involved with consistently higher levels of drug use and associated problems.
      Specifically, rural drug users in this study were older at age of first use of
      marijuana and cocaine; report fewer years of cocaine, hallucinogen, and heroin
      use; and report more alcohol and sedative use. Findings from this study suggest
      that rural and urban drug users are similar and that rural areas may be
      protective from some drug use but risky for other drug use.

PMID- 12491848
TI  - Child abuse: the fundamental issue in forensic clinical practice.

PMID- 12491849
TI  - Attitudes about electric and magnetic fields: do scientists and other risk
      experts perceive risk similarly?
AB  - Wherever there is electric power, 60-hertz (60-Hz) electric and magnetic fields
      (EMFs) are produced. Recently, conflicting reports have been published by
      government agencies about adverse health effects linked to EMFs. This paper seeks
      to identify the demographic and job-related factors that may explain differences
      among experts' perception of risk attributable to EMFs. Eighty-one participants
      at a bioelectromagnetics conference completed a survey on risk perceptions.
      Results indicated that education and employment sector were significant
      predictors of agreement with the statement that EMFs are not a problem. Future
      studies should look at the role of risk perception on environmental risk
      communication and determine the extent of message distortion, if any, based upon
      employment and demographic characteristics.

PMID- 12491850
TI  - Reflections on a career in public health: evolving foodborne pathogens,
      environmental health, and food safety programs.
AB  - Events affecting environmental health and food safety policy, programs and
      organization and emerging or identified foodborne diseases are reviewed by
      decade. The review starts with the impact of the 1940s war years on environmental
      sanitation, as it was called, and disease control. It continues with the
      intensifying disease surveillance and improvements in sanitation of the 1950s and
      the improvements in foodborne-disease surveillance and the reorganization of
      environmental programs of the 1960s. Many previously unknown foodborne pathogens
      were identified, and more changes in environmental policy came about in the
      1970s. Evaluation of foodborne-disease control measures were initiated. In the
      1980s, evaluation of major foodborne-disease problems came to the forefront. In
      the 1990s, the media and consumer groups became aware of foodborne-disease
      problems and concerned with the environment. The first decade of the 21st century
      will be faced with continuing dilemmas posed by emerging diseases and will need
      to provide solutions through the balancing of science, education, and politics.

PMID- 12491851
TI  - Risk communication and public response to industrial chemical contamination in
      Sydney, Nova Scotia: a case study.
AB  - The town of Sydney, located on the north coast of Nova Scotia, is Canada's most
      contaminated community. The local tidal estuary, called the tar ponds, was used
      as a receptacle for industrial waste from a century of coke production and steel
      making and is estimated to contain more than 700,000 metric tons of polycyclic
      aromatic hydrocarbons, 50,000 metric tons of polychlorinated biphenyls, and many
      other residuals including arsenic, naphthalene, and toluene. Many residents have
      expressed consternation over the potential for exposure and subsequent health
      effects from the ponds. Recent epidemiological studies estimate a 30 to 40
      percent increased incidence in several types of cancer within the community. This
      paper examines the claims and responses made by a variety of interested parties
      about the chemical contamination in Sydney. It also considers how those claims,
      in addition to a number of other mediating factors, may have influenced the local
      community in the mobilization of a response to the contamination.

PMID- 12491853
TI  - When falling in love falls out of bounds.

PMID- 12491852
TI  - Drug companies crying foul over Medicaid's formulary push.

PMID- 12491854
TI  - Combating the coming physician shortage.

PMID- 12491855
TI  - Should consumers be present on an HMO's board of directors?

PMID- 12491856
TI  - Formulary submission process catches on ... slowly.

PMID- 12491857
TI  - Applause, catcalls greet retainer medicine.

PMID- 12491858
TI  - Companies leaning on workers in battle against pharmacy costs.

PMID- 12491859
TI  - Measuring efficiency of physician practices using data envelopment analysis.
AB  - PURPOSE: Medical-group practices are becoming increasingly common-place, with
      more than a third of licensed physicians in the United States currently working
      in this mode. While previous studies have focused on physician practices, little
      attention has been focused specifically on the contribution of internal
      organizational factors to overall physician practice efficiency. This paper
      develops a model to help determine best practices of efficient physician offices
      while allowing for choices between inputs. Measuring how efficient practices
      provide services yields useful information to help improve performance of less
      efficient practices. DESIGN: Data for this study were obtained from the 1999
      Medical Group Management Association (MGMA) Cost Report. In this study, 115
      primary care physician practices are analyzed. Outputs are defined as gross
      charges; inputs include square footage and medical, technical, and administrative
      support personnel. METHODOLOGY: Data envelopment analysis (DEA) is used in this
      study to develop a model of practice outputs and inputs to help identify the most
      efficient medical groups. DEA is a linear programming technique that converts
      multiple input and output measures to a single comprehensive measure of
      efficiency. These practices are used as a reference set for comparisons with less
      efficient ones. CONCLUSION: The overall results indicate that size of physician
      practice does not increase efficiency. There does not appear to be extensive
      substitution among inputs. Compared to other practices, efficient practices seem
      to manage each input well.

PMID- 12491860
TI  - HIPAA modifications ease burdens, but don't take anything for granted.

PMID- 12491861
TI  - Managed care outlook: Biggest one-year premium jump.

PMID- 12491862
TI  - Transparency: a clear vision for the future.
AB  - It's imperative that long term care avoid the kind of mistakes that have damaged
      the credibility of the Catholic Church, Arthur Andersen, and the airline
      industry.

PMID- 12491863
TI  - Policies stress more freedom of choice for people with disabilities.

PMID- 12491864
TI  - Building on program parallels. A facility's corporate compliance structure may
      well provide the nucleus for a strong risk management program.

PMID- 12491865
TI  - Meeting the survey head-on.

PMID- 12491866
TI  - Direct marketing 'hits home'.

PMID- 12491867
TI  - Threats ... and then homicides and a suicide.

PMID- 12491868
TI  - Aspects of artwork applicable internationally.

PMID- 12491869
TI  - The magic of music.

PMID- 12491870
TI  - Selective serotonin reuptake inhibitor. Discontinuation syndrome.
AB  - Based on emerging research findings, nurses are urged to become more aware of
      SSRI discontinuation syndrome. To ameliorate or avoid the associated symptoms,
      client education is recommended, and dosage tapering is encouraged whenever
      possible. Although the symptoms associated with discontinuation syndrome usually
      are mild, they may pose particular safety concerns for clients with co-occurring
      conditions. In these situations, precautions should be taken to prevent
      exacerbation of existing problems.

PMID- 12491871
TI  - Threats on campus. Need for faculty response.
AB  - Be calm and decisive in all your actions. Threats are meant to intimidate and
      instill fear. Do not assume someone else will handle the situation. Report the
      threat immediately to your supervisors. Make a crime report to campus public
      safety officers and law enforcement officials in the appropriate jurisdiction.
      Follow up to determine the status of the investigation. Refer the student to
      campus and/or community mental health services. Document the student's behavior
      and threats. Don't spend time alone with students who exhibit warning signs that
      could result in violence. Arrange your office so you have easy access to an exit.
      Be sure that the desk and chair are not between you and the door. Save all
      written and electronic threats and provide them to law enforcement officials.
      There is a mechanism for determining the origin of e-mail threats. Obtain a
      restraining order if necessary.

PMID- 12491872
TI  - Cold case homicides. Investigative interviews of child witnesses.
AB  - Nurses interviewing child witnesses in cold case homicide investigations face
      unique challenges arising from the passage of time. 2.  Postevent influences must
      be evaluated carefully when examining children's descriptions about remote
      events. 3.  Interview strategies that incorporate various types of
      developmentally appropriate tasks offer highly traumatized children the
      opportunity to tell their stories.  4. Although years may have passed, some
      children are able to provide accurate and unique details about a homicide they
      witnessed.

PMID- 12491873
TI  - A theory of recovery.
AB  - 1. Mental illness generally involves a loss of self--the meaning and purpose that
      once defined life are gone. 2.  People respond to loss of self by asking "why." 
      3. Whether or not people find answers to "why" questions, they need to move on to
      asking, "How do I proceed?"  4. Action based on answers to "how" questions
      provides new meaning and purpose.

PMID- 12491874
TI  - Clinical management of "entitled" clients.
AB  - As this process occurs, the painful affects become toned down for the clients. By
      exploring the source of clients' painful affects, wounded self-esteem, fearful
      projections, and dysfunctional defenses, misguided entitlement can be undermined.
      Much of this work will occur in a formal psychotherapy process, but nurses can
      create healthy object relatedness. To do so, they must see beyond the provocative
      and offensive behaviors to the vulnerable individual within who desperately needs
      compassionate and intelligent nursing care.

PMID- 12491875
TI  - The dart man. Neurological impairment and social reactions.

PMID- 12491876
TI  - Cold-inducible promoters for heterologous protein expression.

PMID- 12491877
TI  - Dual-expression vectors for efficient protein expression in both E. coli and
      mammalian cells.

PMID- 12491878
TI  - A dual-expression vector allowing expression in E. coli and P. pastoris,
      including new modifications.

PMID- 12491879
TI  - Purification of recombinant proteins from E. coli by engineered inteins.

PMID- 12491880
TI  - Calmodulin as an affinity purification tag.

PMID- 12491881
TI  - Calmodulin-binding peptide as a removable affinity tag for protein purification.

PMID- 12491882
TI  - Maltose-binding protein as a solubility enhancer.

PMID- 12491883
TI  - Thioredoxin and related proteins as multifunctional fusion tags for soluble
      expression in E. coli.

PMID- 12491884
TI  - Discovery of new fusion protein systems designed to enhance solubility in E.
      coli.

PMID- 12491885
TI  - Assessment of protein folding/solubility in live cells.

PMID- 12491886
TI  - Improving heterologous protein folding via molecular chaperone and foldase co
      expression.

PMID- 12491887
TI  - High-throughput purification of polyHis-tagged recombinant fusion proteins.

PMID- 12491888
TI  - Co-expression of proteins in E. coli using dual expression vectors.

PMID- 12491889
TI  - Small-molecule affinity-based matrices for rapid protein purification.

PMID- 12491890
TI  - Use of tRNA-supplemented host strains for expression of heterologous genes in E.
      coli.

PMID- 12491892
TI  - Studying protein-protein interactions using a bacterial two-hybrid system.

PMID- 12491891
TI  - Screening peptide/protein libraries fused to the lambda repressor DNA-binding
      domain in E. coli cells.

PMID- 12491893
TI  - Using bio-panning of FLITRX peptide libraries displayed on E. coli cell surface
      to study protein-protein interactions.

PMID- 12491894
TI  - Use of inteins for the in vivo production of stable cyclic peptide libraries in
      E. coli.

PMID- 12491895
TI  - Hyperphage. Improving antibody presentation in phage display.

PMID- 12491896
TI  - Combinatorial biosynthesis of novel carotenoids in E. coli.

PMID- 12491897
TI  - Using transcriptional-based systems for in vivo enzyme screening.

PMID- 12491898
TI  - Identification of genes encoding secreted proteins using mini-OphoA mutagenesis.

PMID- 12491899
TI  - SNPs: why do we care?

PMID- 12491900
TI  - Denaturing high-performance liquid chromatography.

PMID- 12491901
TI  - SNP detection and allele frequency determination by SSCP.

PMID- 12491902
TI  - Conformation-sensitive gel electrophoresis.

PMID- 12491903
TI  - Detection of mutations in DNA by solid-phase chemical cleavage method. A
      simplified assay.

PMID- 12491904
TI  - SNP discovery by direct DNA sequencing.

PMID- 12491905
TI  - Computational SNP discovery in DNA sequence data.

PMID- 12491906
TI  - Genotyping SNPs with molecular beacons.

PMID- 12491907
TI  - SNP genotyping by the 5'-nuclease reaction.

PMID- 12491908
TI  - Genotyping SNPs by minisequencing primer extension using oligonucleotide
      microarrays.

PMID- 12491909
TI  - Quantitative analysis of SNPs in pooled DNA samples by solid-phase
      minisequencing.

PMID- 12491911
TI  - Pyrosequencing for SNP genotyping.

PMID- 12491910
TI  - Homogeneous primer extension assay with fluorescence polarization detection.

PMID- 12491912
TI  - Homogeneous allele-specific PCR in SNP genotyping.

PMID- 12491913
TI  - Oligonucleotide ligation assay.

PMID- 12491914
TI  - Invader assay for SNP genotyping.

PMID- 12491915
TI  - MALDI-TOF mass spectrometry-based SNP genotyping.

PMID- 12491916
TI  - Determination of gene dosage. Utilization of endogenous and exogenous internal
      standards.

PMID- 12491917
TI  - Semiquantitative PCR for the detection of exon rearrangements in the Parkin gene.

PMID- 12491918
TI  - Detection of FMR1 trinucleotide repeat expansion mutations using Southern blot
      and PCR methodologies.

PMID- 12491919
TI  - Extreme expansion detection in spinocerebellar ataxia type 2 and type 7.

PMID- 12491920
TI  - Repeat expansion detection (RED) and the RED cloning strategy.

PMID- 12491921
TI  - Repeat analysis pooled isolation and detection (RAPID) cloning of microsatellite
      expansions.

PMID- 12491922
TI  - DIRECT technologies for molecular cloning of genes containing expanded CAG
      repeats.

PMID- 12491923
TI  - Antibody-based detection of CAG repeat expansion containing genes.

PMID- 12491924
TI  - Detection of trinucleotide repeat containing genes by matrix-assisted laser
      desorption/ionization (MALDI) mass spectrometry.

PMID- 12491925
TI  - Fluorescence PCR and GeneScan analysis for the detection of CAG repeat expansions
      associated with Huntington's disease.

PMID- 12491926
TI  - Molecular detection of galactosemia mutations by PCR-ELISA.

PMID- 12491927
TI  - Denaturing high-performance liquid chromatography and sequence analyses for MECP2
      mutations in Rett syndrome.

PMID- 12491928
TI  - Multiplexed fluorescence analysis for mutations causing Tay-Sachs disease.

PMID- 12491929
TI  - Single-strand conformational polymorphism analysis (SSCP) and sequencing for ion
      channel gene mutations.

PMID- 12491930
TI  - Pulse field gel electrophoresis for the detection of facioscapulohumeral muscular
      dystrophy gene rearrangements.

PMID- 12491931
TI  - Denaturing gradient gel electrophoresis (DGGE) for mutation detection in Duchenne
      muscular dystrophy (DMD).

PMID- 12491932
TI  - Genetic diagnosis of Charcot-Marie-Tooth disease.

PMID- 12491933
TI  - Analysis of human mitochondrial DNA mutations.

PMID- 12491934
TI  - Detection of mitochondrial DNA mutations associated with leber hereditary optic
      neuropathy.

PMID- 12491935
TI  - PCR-based strategies for the diagnosis of Prader-Willi/Angelman syndromes.

PMID- 12491936
TI  - Fluorescence in situ hybridization (FISH) for identifying the genomic
      rearrangements associated with three myelinopathies. Charcot-Marie-Tooth disease,
      hereditary neuropathy with liability to pressure palsies, and Pelizaeus
      Merzbacher disease.

PMID- 12491937
TI  - Drosophila models of polyglutamine diseases.

PMID- 12491938
TI  - A comparative gene expression analysis of Emery-Dreifuss muscular dystrophy using
      a cDNA microarray.

PMID- 12491939
TI  - The COS-7 cell in vitro paradigm to study myelin proteolipid protein 1 gene
      mutations.

PMID- 12491940
TI  - In vitro expression systems for the Huntington protein.

PMID- 12491941
TI  - Heterologous expression of ion channels.

PMID- 12491942
TI  - An assay for characterizing in vitro the kinetics of polyglutamine aggregation.

PMID- 12491943
TI  - Characterization of prion proteins.

PMID- 12491944
TI  - Detection of NF1 mutations utilizing the protein truncation test (PTT).

PMID- 12491945
TI  - Application of the protein truncation test (PTT) for the detection of
      tuberculosis sclerosis complex type 1 and 2 (TSC1 and TSC2) mutations.

PMID- 12491946
TI  - Development and characterization of antibodies that immunoprecipitate the FMR1
      protein.

PMID- 12491947
TI  - Immunological methods for the analysis of protein expression in neuromuscular
      diseases.

PMID- 12491948
TI  - Filling the position of lead administrator in schools of allied health: the
      experience of search committees.
AB  - This study was conducted as the second phase of a larger study assessing
      leadership development in schools or units of member institutions of the
      Association of Schools of Allied Health Professions. A survey was mailed to the
      chairs of 21 search committees for the position of lead administrator (i.e., dean
      or director) of an allied health school or unit; 20 (95%) responded. Of the
      respondents, 55% reported that filling the dean/director position was very easy
      (15%) or moderately easy (40%). The mean number of viable candidates was 11.7,
      and the mean time to recruit a new dean/director was 6.9 months. Most (65%) new
      deans/directors had backgrounds in the health professions, with the greatest
      number being nursing (n = 3). The greatest proportion (30%) were
      assistant/associate deans before becoming dean/director. The actual experiences
      of search committees in this study showed a relatively adequate pool of
      applicants for dean/director of allied health positions.

PMID- 12491949
TI  - Serving a diverse population: the role of speech-language pathology professional
      preparation programs.
AB  - A national survey of 228 program directors was conducted to determine how
      master's level professional preparation programs are meeting the challenge of
      preparing speech-language pathologists to provide quality services to an
      increasingly diverse population. A total of 91 respondents provided information
      regarding their programs' efforts to address diversity by increasing the
      diversity of speech-language pathology professionals, preparing students in
      research for diverse populations, and providing students with the didactic
      knowledge and clinical experience required to serve diverse populations. Results
      indicated that professional preparation programs continue to lag in their
      enrollment of minority students, but there are efforts actively to recruit and
      retain students from diverse groups. Much variation in preparation in research
      was found across programs. Graduate students are being presented with information
      concerning diversity issues, but clinical experiences vary greatly according to
      the geographic location of the preparation program and individual practicum
      placements. Implications of these findings for speech-language pathology
      preparation programs and other allied health programs are discussed.

PMID- 12491950
TI  - The use of distance education for a bachelor's degree to master's degree
      transition program in physical therapy.
AB  - Distance education has been used in health professional education programs to
      provide continuing and advanced education. Distance education in physical therapy
      has been limited. This article describes the use of distance education methods to
      deliver a transitional bachelor's degree to master's degree program for a cohort
      of two classes of physical therapy students. The 6-month program allowed a total
      of 26 students to receive a master's degree while working full-time and residing
      off campus. Student feedback indicated that the program met goals of advancing
      their education, increasing their marketability, and being affordable. The use of
      a variety of media to deliver the program and student comments about the methods
      are described.

PMID- 12491951
TI  - Establishing a transdisciplinary research team in academia.
AB  - The establishment of a transdisciplinary research team, the Applied Developmental
      Neuroscience group, is described. The group, which initially included a physical
      therapist, occupational therapist, speech-language pathologist, and developmental
      pediatrician, is focused on linking theory and practice for intervention with
      children with disabilities. The group encountered challenges related to personal
      attributes such as trust, communication, time, and commitment; the task of
      finding a common theoretical perspective; and the autonomous academic
      environment. The strategies used to address these challenges and the benefits of
      a transdisciplinary model, such as cross-fertilization of theoretical
      perspectives and more powerful application and testing of theoretical frameworks
      in a research context, are described.

PMID- 12491952
TI  - Future trends in health care doctoral education.
AB  - A study designed to ascertain the future need for and focus of doctoral health
      education, particularly in relation to the importance of interdisciplinary
      instruction, research preparation, and program delivery modality, is presented.
      The results of a survey of 682 health and human service professionals and 659
      employers throughout the Midwest are discussed.

PMID- 12491953
TI  - Continuing competence in selected health care professions.
AB  - Health services professionals are confronting the challenge of maintaining and
      improving competence over the course of lengthy careers in diverse practice
      specialties. This article reviews the efforts of a selection of health care
      professions to ensure lifetime competence and reviews some of the challenges
      encountered in these efforts. Although each profession has its own issues,
      significant generic questions are common to all.

PMID- 12491954
TI  - Recruitment of African American adults as research participants for a language in
      aging study: example of a principled, creative, and culture-based approach.
AB  - Recruitment of African Americans as research participants continues as a major
      challenge for researchers studying health and human behavior. Numerous reasons
      for low participation by African Americans have been cited, most of which evolve
      around four primary factors: social injustice, education, economics, and cultural
      differences. To ensure adequate representation of the diversity within the U.S.
      population in research, the federal government mandates the inclusion of
      individuals from underrepresented groups as study participants. For African
      Americans, this number is approximately 12%. Controversy exists, however, as to
      whether published research studies reflect adequate representation of African
      Americans as study participants. This article reports a successful approach to
      the recruitment and retention of 80 African American adults who participated in a
      study investigating language comprehension in aging.

PMID- 12491955
TI  - A comparison of distance education instructional methods in occupational therapy.
AB  - The progression of technology is rapidly bringing new opportunities to students
      and academic institutions, resulting in a need for additional information to
      determine the most effective strategies for teaching distance learners. The
      purpose of this study was to compare the effectiveness of three instructional
      strategies (two-way interactive video and audio, chat rooms, and independent
      learning) and student preferences regarding instructional methods in a mental
      health programming distance learning course. Precourse and postcourse surveys
      were completed by 22 occupational therapy students enrolled in the course.
      Effectiveness of the teaching methods was determined based on the results of
      students' examinations. The findings indicated that there were no statistically
      significant differences in student performance on multiple-choice examinations
      using the three instructional methods. Of students, 77% indicated a preference
      for two-way interactive video and audio instruction. To provide effective
      education via distance learning methods, faculty members need to structure
      assignments that facilitate interaction and communication among learners. As
      distance education becomes more commonplace, it is important to identify the
      methods of instruction that are the most effective in delivering essential course
      content and the methods that provide the atmosphere most conducive to learning.

PMID- 12491956
TI  - Use of a computer tutorial on nutritional assessment by three different groups of
      health professions students.
AB  - A computer tutorial on nutritional assessment was developed and used with three
      different groups of health professions students. Complete data were available for
      45 nursing students, 36 physician assistant students, and 68 physical therapy
      students. Overall for the three groups there was a significant increase (p <
      0.0001) from pretest to posttest scores. This increase was not significantly
      different among the groups, suggesting that a single computer tutorial can be
      used effectively to teach basics of nutritional assessment to different groups of
      health professions students and allow sharing of cost for computer instruction
      among programs.

PMID- 12491957
TI  - Entering the small, small world of nanotechnology.

PMID- 12491958
TI  - The evolution of engineering management in Latin America and the Caribbean.

PMID- 12491959
TI  - Development of a program model to evaluate the potential for reuse of single-use
      medical devices: results of a pilot test study.
AB  - Single-use medical devices (SUDs, or disposables) have become a major expense in
      hospital budgets. The need for cost reduction and the availability of
      sterilization technologies other than the autoclave have prompted hospitals
      worldwide to begin reusing disposables, in many cases without proper assessment
      of the true costs (time, personnel, etc) and ease/difficulty of implementation of
      an institutional reuse program. Our group has developed a rigorous program model
      to evaluate SUDs for reuse. The program comprises 3 sequential protocols: (1)
      device audit, (2) laboratory evaluation, and (3) clinical evaluation. Use of this
      model can produce scientific and financial data sufficient for any institution
      interested in reuse to reach an initial decision about its feasibility. In
      addition to the testing outcomes, regulatory requirements, the position of
      manufacturers and third-party reprocessors, and legal and ethical concerns must
      be considered. A successful reuse program must include ongoing evaluations to
      ensure that the safety levels and cost savings established during the initial
      audit and evaluation phases continue. Herein, we give the rationale and details
      of our program model and discuss results of our pilot application of the "ideal"
      protocol in a real-world context.

PMID- 12491960
TI  - Developing an effective inspection and preventive maintenance program.

PMID- 12491961
TI  - In-house support of Medrad dye injectors.

PMID- 12491962
TI  - The fundamentals of ... image-guided surgery.

PMID- 12491963
TI  - The JIT-genius.

PMID- 12491964
TI  - Selection for aluminium tolerance in embryogenic lines of Citrus sinensis L. and
      C. aurantium L.
AB  - The Citrus cultivars 'Amargo' and 'Pineapple' produce embryogenic cultures on two
      types of sugars, galactose and lactose. Two percent lactose is optimal for both
      cultivars; embryogenic callus is produced 8-10 weeks after inoculation. Whereas
      2% galactose is optimal for 'Amargo', it is 3% for 'Pineapple'. Three types of
      embryos are recognized: whitish, greenish and heart shaped. In 8 to 10 week old
      cultures we do also observe a black spotted type of embryos. A high percentage of
      plant conversion for both cultivars is observed on a medium containing 30 mg/l of
      adenine and 2 mg/l of GA3 for 'Amargo'; for 'Pineapple' it is necessary to add
      BA. We tested two techniques for selection of Al-tolerant lines: one on stagnant
      liquid medium, and another on shaken liquid medium. The second technique gives a
      more serious selection pressure; there are almost no surviving calli. In 'Amargo'
      more calli survived than in 'Pineapple'. Selected calli had to be subcultured
      nine times to determine their stability. Four callus types of the two cultivars
      grew normally on selective media containing 0, 400, 1000 or 2000 mumol of
      aluminium.

PMID- 12491965
TI  - Identification of pummelo (Citrus grandis (L.) Osbeck) cultivars using isozyme
      electrophoresis.
AB  - One hundred and one pummelo plants representing eight different cultivars of
      pummelo were fingerprinted and evaluated for intra- and inter-varietal
      variability using five enzyme systems. Starch gel electrophoresis was used to
      analyse extracts from fresh young leaves collected from trees located in the
      provinces of Can Tho and Vinh Long. Isozymic analysis revealed that all cultivars
      are isozymically heterogeneous, and composed of two or more clones. A total of 26
      clones were discriminated from eight cultivars. Unique combinations of isozymic
      variants of the five enzymes assayed identified 18 (69%) of the 26 clones. The
      remaining eight clones could be separated into four additional groups. Our
      results have proven the potential use of isozymic variability for cultivar
      identification and assessment of the uniformity or purity of a variety.

PMID- 12491966
TI  - Leaf photosynthesis of 'Cat Hoa Loc' mango (Mangifera indica L.) and 'Nam Roi'
      pummelo (Citrus grandis (L.) Osbeck.) in the rainy season.
AB  - With an EARS--Plant photosynthesis meter we determined gross photosynthesis (P)
      of leaves of 'Cat Hoa Loc' mango on 4 years old trees planted in the Fruit Tree
      Experiment and Production Station, Campus 2, Department of Crop Science, College
      of Agriculture, Can Tho University in the rainy season of the year 2000. The same
      experiment was conducted on 'Nam Roi' pummelo on a farm located in the Binh Minh
      district, Vinh Long province. In the rainy season the calculated gross
      photosynthesis of 'Cat Hoa Loc' mango leaves at flowering stage was higher than
      that at the vegetative stage. However, the photosynthetically active radiation
      and quantum yield of 'Cat Hoa Loc' mango leaves in both stages did not reach the
      light saturation point when compared with values from estimated equation of
      photosynthetic light curve. The same holds true for 'Nam Roi' pummelo in the
      vegetative stage.

PMID- 12491967
TI  - Propagation of 'Nam Roi' pummelo (Citrus grandis (L.) Osbeck.) by cuttings.
AB  - 'Nam Roi' pummelo is a famous fruit tree in the Mekong Delta of Viet Nam.
      Therefore, in recent years, growers extended the cultured area because it
      guarantees a high income. As a consequence there is a high demand for planting
      material, and we studied the possibilities of vegetative propagation by cuttings
      during the period from March 1999 to February 2000. The results of our study
      showed that a rice husk substrate was better than sand, and that naphthalene
      acetic acid (NAA) 1000 ppm stimulated rooting (84% rooted). The type of cutting
      was also a factor affecting the success rate; we studied three types of cuttings.

PMID- 12491969
TI  - Arabidopsis thaliana mutants with an altered susceptibility to the root-knot
      nematode Meloidogyne incognita.
AB  - Sedentary endoparasitic nematodes of plants are obligate parasites of roots in
      which they complete their sophisticated life cycle. To study the plant/root-knot
      nematode interaction, a screening was performed for mutants of Arabidopsis
      thaliana that were less susceptible to nematode infection. Ethyl methanesulfonate
      mutagenized A. thaliana M2 seeds (13,000) were germinated and the seedlings were
      screened in vitro for nematode susceptibility. Another 5,000 plants were screened
      in a sand mixture under glasshouse conditions. Ten mutants that were at least a 2
      fold less susceptible than the wild-type were retained and analyzed in more
      detail in vitro as well as in the greenhouse. All mutants with a fairly normal
      morphology had only a slightly, but reproducibly, decreased susceptibility to
      nematodes. One mutant (AMi 2) with a 17-fold lower susceptibility to nematode
      infection and an aberrant phenotype could be rescued by tryptophan.

PMID- 12491968
TI  - Changes in the microbiology of activated sludge upon the addition of iron salts
      with or without nitrite or nitrate.
AB  - Iron salts are frequently used in activated sludge treatment as coagulants or to
      improve reactor performance. However, the effect of the iron salts on the
      microbiology has received little attention. Furthermore, the interaction of iron
      ions with nitrite or nitrate present in the sludge has not been considered. In
      this research, the influence of ferrous and ferric iron additions, and their
      possible interactions with nitrite or nitrate at levels of a few mM, on the
      activated sludge microbiology of semi-continuous bench-scale reactors were
      examined. Conventional as well as molecular techniques have been used to
      investigate the microbial communities. Microscopic investigations showed that
      repeated addition of ferric iron at 2 mM gave rise to breaking of the sludge
      flocs, resulting in massive growth of sessile-protozoa and lowering of the
      numbers of nitrifiers. Ferrous iron at the same dosage resulted in large coherent
      flocs. Nitrite hereby seemed to enhance the detrimental effect of the ferric iron
      on the floc structure, whereas nitrate had a neutralizing character. 16S rRNA
      gene analysis showed a clear impact of the different iron respectively nitrogen
      treatments on the composition of bacterial communities. Cloning the sludge
      samples revealed the increased presence of denitrifying Feoxidizing bacteria in
      both the Fe(II) and Fe(III) reactors, suggesting a redox-state cycling between
      Fe(II) and Fe(III) in the mixed liquor.

PMID- 12491971
TI  - [Thinking framework, vision and time framework].

PMID- 12491970
TI  - [Salmonella enteritis in dogs, not relevant?].
AB  - In order to shed some light on the different opinions regarding the importance of
      Salmonella infections in dogs, we gathered some data from our laboratory
      database. Of the 6589 faecal samples from diarrhoeic dogs examined, 69 (1%)
      yielded Salmonella spp. Another eleven isolates were cultured from materials
      other than faeces. If Salmonella spp. can be cultured directly from faeces, this
      should be interpreted as clinically significant; however, even if the organism is
      found only after enrichment it may still be a clinical case. Antibiotic therapy
      is indicated in all dogs that are severely ill or have systemic infection,
      fluoroquinolones or trimethoprim/sulphonamides being drugs of choice. Double
      blind placebo-controlled studies of humans with gastroenteritis have shown that
      the length of postconvalescent excretion of Salmonella is not affected by
      antimicrobials. For the elimination of the carrier state, however,
      fluoroquinolones are successful in human medicine. Salmonellae are zoonotic
      agents and transmission from dog to man has been reported. This should be taken
      into account when deciding on antimicrobial therapy. Of our isolates (n = 80),
      96% were susceptible to enrofloxacin, 94% to trimethoprim/sulphonamides, 94% to
      gentamicin, 86% to ampicillin and amoxicillin-clavulanic acid, 47% to cephalexin
      and 63% to tetracycline.

PMID- 12491972
TI  - [Quality relations for veterinarian pig husbandry takes shape. An interview by J.
      Hulsen with Jos Verheijden, president working group DV 2000].

PMID- 12491973
TI  - [Dead behind the door....].

PMID- 12491974
TI  - ["Help, the veterinarian is drowning!"].

PMID- 12491975
TI  - [Mycoplasma and PRDC. Seminar Working Group Medicine of the Pig in cooperation
      with Boehringer Ingelheim].

PMID- 12491976
TI  - [Use of carcinogenic veterinary drugs in the veterinary clinic, an unacceptable
      risk for people?].

PMID- 12491977
TI  - [Echinococcus multilocularis in foxes: preventive measurements necessary].

PMID- 12491978
TI  - [Swelling in the abdomen after sterilization of a cat].

PMID- 12491979
TI  - [In search of Ariadne's thread].
AB  - The article was presented on the opening of the jubilee 40th Polish Psychiatric
      Conference, where the main theme was "Integration in psychiatry" The author
      describes the present developmental tendencies in medicine and analyses the
      changes which took place in psychiatry in the recent years, beginning with a
      favourable manner of perceiving and treating psychiatric patients by their
      surroundings, through the strengthening of the patients' positions and control of
      their laws, formalized by appropriate legal regulations, all the way to
      unfavourable instances which formulate a barrier and endangerment of further
      advances in psychiatric treatment reforms.

PMID- 12491980
TI  - [The loss of close person and the cognitive functions of persons with Alzheimer
      type dementia].
AB  - AIM: The aim of the present investigations was qualification of influence of loss
      of near and dear persons on cognitive functions in persons with Alzheimer's
      disease. METHOD: The initial population consisted of all the people who in the
      period from 1/02 to 30/10/2000 were treated at one of the following psychiatric
      treatment institutions: psychiatric ward of the hospital, psychiatric regional
      outpatient clinic, psychiatric department. The qualifying criteria were:-
      patient's consent to the examinations;--possibility of obtaining an objective
      interview;--no psychic diseases in the interview;--recognition of dementia
      syndrome on the basis of DSM IV criteria. 59 persons have been qualified for the
      examinations. After qualifying the patient basic examination was being conducted
      and consisted of the following elements:--Mini Mental Scale Examination (MMSE);-
      Alzheimer's Disease Assessment Scale: AMDP scale--inventory 3--anamnesis was
      applied to obtain history data. RESULTS: The investigations showed a possible
      relationship between stress factors and degree of cognitive function.

PMID- 12491981
TI  - [The quality of life of chronic schizophrenic patients in their own and their
      family's assessment].
AB  - The aim of the research was to analyse the subjective quality of life of chronic,
      schizophrenic patients. The patients' quality of life was compared to the
      evaluation of their family. They evaluate the quality of life similarly. The
      differences concern the relationship between the quality of life and clinical
      characteristics.

PMID- 12491982
TI  - [Quality of life of schizophrenia patients and health related problem solving
      skills--comparison between the group of patient participated in social skills
      training and psychoeducation group].
AB  - AIM: The aim of this study was to obtain answers to the following questions: 1.
      Are there differences in the level of knowledge among the patients divided into
      two groups t. i. social skills training group (SSTG) and psychoeducation group
      (SG)? 2. Do the differences correlate with the level of subjective quality of
      life (SQOL)? 3. Does the participation at two groups influence SQOL and whether
      this correlates with two different methods of running of rehabilitation
      activities such as social skills training and psychoeducation? METHOD: The group
      of 47 patients diagnosed with schizophrenia by DSM-IV were tested. They were
      divided into two groups: SSTG (24 persons) and SG (23 persons). RESULTS: The
      increase of knowledge in coping with schizophrenia symptoms was significant in
      the whole tested group but it was significantly higher in the training group. The
      SQOL and the level of knowledge in schizophrenia do not correlate. The level of
      SQOL decreased after taking part in social skills training. CONCLUSIONS: 1) The
      participation at any of tested rehabilitation activities causes an increase in
      the knowledge of coping with the problems resulting from schizophrenia. 2) The
      level of knowledge in schizophrenia does not directly influence SQOL. The level
      of SQOL significantly decreased in SSTG. It suggests that clinicians should
      concentrate on the stage just after the training cycle in order to support the
      patients by giving positive reinforcement.

PMID- 12491983
TI  - [Processing of context and source of information monitoring in schizophrenia].
AB  - Recent research has suggested that deficit in the processing of context could be
      responsible for various impairments in cognitive functioning observed in
      schizophrenia. Source monitoring, an ability closely related to memory for
      context, seems to be one of the most important correlates of positive symptoms,
      especially auditory hallucinations and delusions of alien control.

PMID- 12491984
TI  - [Effectiveness of cognitive skills training in schizophrenia].
AB  - AIM: This study evaluated methods for improving cognitive skills of patients with
      schizophrenia. METHOD: Subjects in the experimental group received 12 sessions of
      practice with various cognitive tasks, while patients in the control group
      participated in sessions of psychoeducation. RESULTS: Cognitive assessment before
      and after the study phase showed that patients in the experimental group had made
      significantly more improvement than the control group. Both groups improved on
      the insight scores, however, reductions in the level of psychopathology were less
      tangible.

PMID- 12491985
TI  - [Sense of coherence, style of coping and adaptation after hysterectomy].
AB  - AIM: This article is devoted to analysis of factors favourable for adaptation
      after hysterectomy procedure. The consequence of expressing the hysterectomy as a
      stress situation is laying a great emphasis on analysis of coping with yourself
      and the factors affecting this process. We suggest the model where the sense of
      coherence affect indirectly thought the styles of coping on the level of health.
      METHOD: Overall we examine 71 woman, 35 of them 10 days after the operation and
      36 having this procedure 24-36 months earlier. The applied methods were: SOC-29,
      CISS, BDI, STAI and the Kuppermann Index. RESULTS: We obtain results that confirm
      significant impact of the sense of coherence and the style of coping to women's
      health. CONCLUSIONS: The results challenge proposed model as the only
      explanation. The sense of coherence influence the health not only thought the
      styles of coping. Discrepancies that were obtained thought the researches suggest
      the necessity of examining other possible relationships between those variables.

PMID- 12491986
TI  - [The trap of addiction--reflections on the substitute of happiness].
AB  - This essay is a set of concepts concerning human nature with its intrinsic move
      towards happiness and positive balance of feelings. One of the methods of
      obtaining pleasure is the use of psychoactive substances. This infallible method
      becomes a trap. The aim of our work was to present the reader how significant the
      positive emotions and the ways of obtaining them in our every day life are. In
      our world of mind and knowledge we often depreciate the role of positive
      emotions. Suddenly, being embedded in crisis, we seek the easiest way to get the
      positive state back. This paper presents various models of addiction with the
      emphasis of the psychosocial model. Self-sustaining vicious circle mechanisms
      disintegrate slowly every single sphere of ones personality. The social
      functioning of the individual is also influenced by the addiction. The authors
      emphasize the disadvantageous influence of social and civilization changes on the
      decrease in the amount of positive emotions experienced by the individuals
      accompanied by the simultaneous increase in "academic intelligence" in developed
      societies. To describe that phenomenon the authors propose the concept of
      "civilization cross".

PMID- 12491987
TI  - [Evaluation of q11-q13 locus of chromosome 15 aberrations and polymorphisms in
      the B3 subunit of the GABA-A receptor gene (GABRB3) in autistic patients].
AB  - The aim of the study was the evaluation of chromosomal aberrations, especially
      locus q11-q13 of chromosome 15 and polymorphisms in the g-aminobutyric acid
      receptor subunit B3 gene (GABRB3) and genetic aetiology of autistic disorder. We
      studied 20 probands (aged 4-27 years old) and their parents and siblings (73
      persons). Following cytogenetic methods were used: conventional GTG-banding
      analysis, study of fra(X), fluorescence in situ hybridisation, with two specific
      probes: SNRPN and UBE3A/D15S10. Dinucletide (CA)n repeat polymorphism at the
      GABRB3 gene was analysed using PCR-STR method. Chromosomal analysis revealed
      paracentomere inversion--46, XX, inv(9)(p11q13) in 1 patient, but this is
      frequently found in population chromosomal variation. FISH didn't reveal
      abnormalities in 15q11-q13 region. ETDT analysis didn't reveal connection between
      autistic disorder and studied marker. Lack of anomalies in 15q11-q13 region may
      be related to small number of probands, heterogenity of studied group and small
      number of studied locus and markers. So conclusions should be related only to
      this studied group, and not to all autistic patients.

PMID- 12491988
TI  - [Surgical treatment of mental disorders].
AB  - AIM: The surgical treatment of mental disorders--the authors present the
      neuroanatomical base of stereotactic operations on the limbic system in patients
      with the mental disorders. METHOD: Four main procedures are discussed: anterior
      cinguotomy, anterior capsulotomy, subcaudate tractotomy, limbic leucotomy.
      RESULTS: On the ground of available literature the authors present the results of
      these operations which are performed with the use of stereotactic equipment
      guided by MRI and CT. In this article the indications for different surgical
      procedures are presented and refer mainly to depression, obsessive-compulsive
      disorder and anxiety. The authors present the principles of qualification and the
      exclusion criteria of the patients in the countries in which these kinds of
      operations are performed.

PMID- 12491989
TI  - Report from ICAAC: new drugs and antiretroviral therapy for naive patients.

PMID- 12491990
TI  - International HIV Workshop on Management of Treatment-Experienced Patients.

PMID- 12491991
TI  - HIV notes from the 40th annual meeting of the Infectious Diseases Society of
      America.

PMID- 12491992
TI  - Report on adherence from the XIV International AIDS Conference in Barcelona.

PMID- 12491993
TI  - Women's health issues: news from the XIV International AIDS Conference in
      Barcelona.

PMID- 12491994
TI  - State of the HAART.

PMID- 12491995
TI  - Immunodeficiency. It's not getting easier to understand.

PMID- 12491996
TI  - A chimp off the old block.

PMID- 12491997
TI  - Preventing viral entry. Fusion inhibitors.

PMID- 12491998
TI  - Protease sparing regimens.

PMID- 12491999
TI  - Women & HIV.

PMID- 12492000
TI  - Can temporarily stopping therapy boost the immune system?

PMID- 12492001
TI  - Can I stop my PCP prophylaxis?

PMID- 12492002
TI  - Your benefits & you. Know which income is taxable and which is not.

PMID- 12492003
TI  - A back-to-work strategy can protect your benefits.

PMID- 12492004
TI  - Legal issues. 'No' isn't always the final word.

PMID- 12492005
TI  - Having sex? Here's how to stay out of jail. New statute spells out disclosure
      terms.

PMID- 12492006
TI  - Some progress in the pipeline reported at ICAAC.

PMID- 12492007
TI  - Study of Provir as diarrhea treatment for people with HIV continuing.

PMID- 12492009
TI  - Names surveillance bill veto may cost lives.

PMID- 12492008
TI  - Is drinking water sold in vending machines safe for people with HIV?

PMID- 12492010
TI  - Consider college.

PMID- 12492011
TI  - Viatical settlement may be a helpful option for many people with HIV.

PMID- 12492012
TI  - Among ourselves. An epidemic of violence.

PMID- 12492013
TI  - Straight talk from DuPont on Sustiva.

PMID- 12492014
TI  - A therapeutic touch. An interview with Jelka Jonker. Interview by Fiona Kyck.

PMID- 12492015
TI  - New testosterone therapy OK'd.

PMID- 12492016
TI  - Remune vaccine trial halted; study design flaws cited.

PMID- 12492017
TI  - BMS-232632, a new protease inhibitor, is taken once daily.

PMID- 12492018
TI  - Tenofovir DF trial announced by Gilead.

PMID- 12492019
TI  - Nutrition & HIV. It's the water.

PMID- 12492020
TI  - Your benefits & you. Pack this page with your luggage.

PMID- 12492021
TI  - Social Security's long memory may work to your disadvantage.

PMID- 12492022
TI  - Survey shows prevention concerns.

PMID- 12492024
TI  - Researchers explore prevention for positives.

PMID- 12492023
TI  - The Durban Declaration. More than 5,000 scientists worldwide affirm that HIV is
      the cause of AIDS.

PMID- 12492025
TI  - Women and children first.

PMID- 12492026
TI  - Fresh data on new anti-HIV drugs presented in Durban.

PMID- 12492027
TI  - Long-term treatment strategies explored.

PMID- 12492028
TI  - Lipodystrophy: no answers emerge in Durban.

PMID- 12492030
TI  - Your benefits & you. Rights of insured protected by State Supreme Court.

PMID- 12492029
TI  - Liver toxicities rising.

PMID- 12492031
TI  - A view from the prevention beat. In conversation with Dr. Pat Gay. Interview by
      Nancy Wongvipat.

PMID- 12492032
TI  - Stay on the lookout for problems with your eyes.

PMID- 12492033
TI  - Slim nutrition data from Durban whets the appetite for more research.

PMID- 12492034
TI  - Date labels on food. What do they mean?

PMID- 12492035
TI  - Your benefits & you. Accessing benefits while incarcerated.

PMID- 12492036
TI  - Legal issues & HIV. Using advance health care directives wisely.

PMID- 12492037
TI  - New guidelines on metabolic complications of HIV and antiretroviral treatment.

PMID- 12492038
TI  - Nevirapine patient assistance program: model for better administration?

PMID- 12492039
TI  - Heart-disease risk and C-reactive protein.

PMID- 12492040
TI  - Vaccine against three kinds of HIV begins human tests.

PMID- 12492042
TI  - U.S. AIDS research needs tissue donations.

PMID- 12492041
TI  - Prevention: new approach will test tenofovir for persons at high risk.

PMID- 12492043
TI  - Drug patents and developing countries: problems remain.

PMID- 12492044
TI  - Marijuana lung health report: less than meets the eye?

PMID- 12492045
TI  - Ziagen OK'd by FDA.

PMID- 12492046
TI  - Getting ready for adherence.

PMID- 12492048
TI  - Your benefits & you. Clearing up confusion on Contestable Clauses.

PMID- 12492047
TI  - Revealing data on infectiousness of HIV.

PMID- 12492050
TI  - Stress. Are you its victim?

PMID- 12492049
TI  - Using Agenerase. Nutritional considerations affect bioavailability of new P.I.

PMID- 12492051
TI  - Hypnosis AIDS project bridges the mind and body.

PMID- 12492052
TI  - Who's got the look?

PMID- 12492053
TI  - Adherence matters. Hospitalization may interrupt meds.

PMID- 12492054
TI  - Health insurance accessibility for employees of small groups.

PMID- 12492055
TI  - Putting your life and finances back together.

PMID- 12492056
TI  - Choosing cesarean? PCD may have no effect in blocking perinatal transmission of
      HIV.

PMID- 12492057
TI  - Crixivan, Norvir combination therapy studied.

PMID- 12492058
TI  - Adherence matters. Life lessons.

PMID- 12492059
TI  - Your benefits & you. Medicare buy-in programs may save money for you.

PMID- 12492060
TI  - Treating gynecological complications of HIV.

PMID- 12492061
TI  - Agenerase approved by FDA.

PMID- 12492062
TI  - Getting hip to hepatitis.

PMID- 12492063
TI  - Studies fail to find NGF benefit.

PMID- 12492064
TI  - Manufacturer agrees to cease unproved claims about Noni juice.

PMID- 12492065
TI  - Build a network of support to help you use meds wisely.

PMID- 12492066
TI  - Understanding the dynamics of addiction.

PMID- 12492067
TI  - Your benefits & you. Get hip to HIPP.

PMID- 12492068
TI  - Early detection is best protection against developing breast disorders.

PMID- 12492069
TI  - New guidelines provide greater flexibility in treating HIV.

PMID- 12492070
TI  - The other end of the stethoscope: an interview with Mark Katz, M.D. Interview by
      Glenn Gaylord.

PMID- 12492072
TI  - Anabolic steroid studies remain inconclusive.

PMID- 12492071
TI  - Cautions on using Viagra and P.I.s issued.

PMID- 12492073
TI  - Social Security disability. The route to getting a 'yes'.

PMID- 12492074
TI  - 'Rescue' therapies. Toronto conference sheds some light on options for
      experienced patients.

PMID- 12492075
TI  - Lipodystrophy & HIV. Abundant questions, scarce answers.

PMID- 12492076
TI  - New Norvir soft-gel capsule formulation approved by FDA.

PMID- 12492077
TI  - Pharmacy action fuels drug-marketing debate.

PMID- 12492078
TI  - New partnership calls for clinical testing of two fusion inhibitors.

PMID- 12492079
TI  - Hope emerges for controlling perinatal HIV transmission.

PMID- 12492080
TI  - Adherence matters. Try these tools to plan your meds.

PMID- 12492081
TI  - Gene therapy for head and neck cancer.
AB  - Head and neck cancer, because of its anatomic accessibility and poor overall
      survival rate, has become a frequent target of novel gene therapy intervention
      strategies. Viral and nonviral vectors have been used to transfer a variety of
      tumor suppressor genes, suicide genes, and immunologic genes into head and neck
      cancer cells in both the laboratory and clinical setting. Gene therapy as an
      isolated treatment modality will probably not replace standard treatment
      modalities in the management of head and neck cancer. It seems likely, however,
      that gene transfer will find its way into the multidisciplinary care of the head
      and neck cancer patient, where novel treatments are combined with standard
      therapies in order to maximize tumor response.

PMID- 12492082
TI  - [Digital substraction angiography using gadolinium as contrast medium for
      patients with renal failure. A study of 15 patients].
AB  - OBJECTIVES: To study the feasibility of IA-DSA for diagnostic or interventional
      purposes using gadolinium (Gd) as a contrast medium (CM) for patients with poor
      renal function. MATERIALS AND METHODS: This study is about 15 patients with renal
      insufficiency (creat. > 133 micromol/l) who needed IA-DSA for diagnostic or
      interventional purposes. Gd was used as a CM at a dose < or = 0.4 micromol/kg and
      a concentration > or = 75%. Serum creatinine level was evaluated before, at 24 h
      and 48 h after injection of Gd. An increase of creat. > or = 44 micromol/l was
      considered significant. Image quality was evaluated by two specialists. RESULTS:
      In 14/15 (93%) patients no significant elevation of the serum creat. level was
      noted. The images are of good to medium quality, the diagnostic or therapeutic
      purpose was however reached. Image quality depends on Gd concentration; the
      feasibility of the exam is limited by the quantity of Gd used and its dilution.
      The procedure is well tolerated without side effects. CONCLUSION: Gd allows
      arteriograms of adequate quality for diagnostic or therapeutic purposes without
      renal complications at doses used until now (0.4 micromol/kg). The procedure is
      easy to perform but only one region or organ can be studied in one procedure
      considering the relatively small volume of contrast allowed.

PMID- 12492083
TI  - Manipulability, force, and compliance analysis for planar continuum manipulators.
AB  - Continuum manipulators, inspired by the natural capabilities of elephant trunks
      and octopus tentacles, may find niche applications in areas like human-robot
      interaction, multiarm manipulation, and unknown environment exploration. However,
      their true capabilities will remain largely inaccessible without proper
      analytical tools to evaluate their unique properties. Ellipsoids have long served
      as one of the foremost analytical tools available to the robotics researcher, and
      the purpose of this paper is to first formulate, and then to examine, three types
      of ellipsoids for continuum robots: manipulability, force, and compliance.

PMID- 12492084
TI  - The role of the generalist obstetrician-gynecologist in the early detection of
      ovarian cancer.
AB  - The purpose of this Committee Opinion is to define the role of the generalist
      obstetrician-gynecologist in the early detection of ovarian cancer. Currently, it
      appears that the best way to detect early ovarian cancer is for both the patient
      and her clinician to have a high index of suspicion of the diagnosis in the
      symptomatic woman. In evaluating symptoms, physicians should perform a physical
      examination, including a pelvic examination. In premenopausal women with
      symptoms, a CA 125 measurement has not been shown to be useful in most
      circumstances. In postmenopausal women with a pelvic mass, a CA 125 measurement
      may be helpful in predicting a higher likelihood of a malignant tumor than a
      benign tumor, which may be useful in making consultation or referral decisions or
      both. A woman with a suspicious or persistent complex adnexal mass requires
      surgical evaluation by a physician trained to appropriately stage and debulk
      ovarian cancer. Data suggest that currently available screening tests do not
      appear to be beneficial for screening low-risk, asymptomatic women. An annual
      gynecologic examination with an annual pelvic examination is recommended for
      preventive health care.

PMID- 12492085
TI  - Beware of new drugs, study suggests.

PMID- 12492086
TI  - Medical errors, poor communication undermine quality of care, patient
      satisfaction.

PMID- 12492087
TI  - Preterm birth affects the intestinal response to parenteral and enteral nutrition
      in newborn pigs.
AB  - Maturation of gastrointestinal (GI) function in neonates is stimulated by enteral
      nutrition, whereas parenteral nutrition induces GI atrophy and malfunction. We
      investigated whether preterm birth alters the GI responses to parenteral and
      enteral nutrition. Pigs were delivered either preterm (107 d gestation) or at
      term (115 d gestation) and fed total parenteral nutrition (TPN) or enteral sow's
      milk (ENT) for 6 d after birth. Immaturity of the preterm pigs was documented by
      reduced blood pH, oxygen saturation and neutrophil granulocyte function, impaired
      intestinal immunoglobulin G uptake from colostrum, and altered relative weights
      of visceral organs (small intestine, liver, spleen, pancreas, and adrenals). For
      both ages at delivery, increases occurred in pancreatic weight (30-75%) and
      amylase activity (0.5- to 13-fold) after birth, but much more in ENT than in TPN
      pigs (P < 0.05). Six days of TPN feeding was associated with reduced intestinal
      weight for both delivery groups (60% of values in ENT, P < 0.001), but only in
      term TPN pigs was the weight lower than at birth (-20%, P < 0.05). Likewise, it
      was only in term TPN pigs that intestinal maltase activity increased, compared
      with ENT, and the absorption of glucose and proline decreased. Only in preterm
      pigs did TPN feeding increase lactase activity (+50% compared with ENT, P <
      0.05). For both delivery ages, the mRNA of lactase-phloridzin hydrolase and
      sodium-coupled glucose transporter 1 (SGLT-1) were increased in TPN, compared
      with ENT. In conclusion, the trophic effect of enteral vs. parenteral nutrition
      on the GI tract is also present after preterm birth, but the postnatal maturation
      of many GI functions is modified, compared with term birth. The effects of
      nutritional regimen on the maturation of the gut epithelium in neonates depend on
      gestational age at birth.

PMID- 12492088
TI  - Beyond patient advocacy.

PMID- 12492089
TI  - Protocol designed to identify often-overlooked problems in the elderly.

PMID- 12492090
TI  - New model out-performs glucose tolerance test in predicting risk of diabetes.

PMID- 12492091
TI  - John P. Peters Symposium. June 6, 1998.

PMID- 12492092
TI  - From the Centers for Disease Control and Prevention. Approval of a new rapid test
      for HIV antibody.

PMID- 12492094
TI  - From the Centers for Disease Control and Prevention. Primary and secondary
      syphilis--United States, 2000-2001.

PMID- 12492093
TI  - From the Centers for Disease Control and Prevention. Increases in fluoroquinolone
      resistant Neisseria gonorrhoeae--Hawaii and California, 2001.

PMID- 12492096
TI  - From the Centers for Disease Control and Prevention. Probable variant Creutzfeldt
      Jakob disease in a US Resident--Florida, 2002.

PMID- 12492095
TI  - The worldwide context of European architectural policy.

PMID- 12492097
TI  - From the Centers for Disease Control and Prevention. Update: fatal and severe
      liver injuries associated with rifampin and pyrazinamide treatment for latent
      tuberculosis infection.

PMID- 12492098
TI  - From the Centers for Disease Control and Prevention. Multistate outbreaks of
      Salmonella serotype Poona infections associated with eating cantaloupe from
      Mexico--United States and Canada, 2000-2002.

PMID- 12492099
TI  - Law. Bully booked.

PMID- 12492100
TI  - Imatinib mesylate for chronic myeloid leukemia: what do we really know?
AB  - Imatinib mesylate (GleevecTM) is a tyrosine kinase inhibitor, one of a new class
      of anticancer drugs called signal transduction inhibitors. A systematic review of
      case-series reports shows imatinib, when indirectly compared to conventional
      therapy, improves overall 12-month survival, but not surrogate outcomes, in
      individuals with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+
      CML) in myeloid-blast crisis, and accelerated phase. Surrogate outcomes, but not
      overall survival, were improved in chronic phase disease. Preliminary data from
      one randomized controlled trial suggest imatinib has a greater impact on
      surrogate outcomes compared to the combination of interferonalpha and cytarabine
      in patients undergoing treatment for chronic phase Ph+CML, however, it is not yet
      known whether it prolongs or improves quality of life.

PMID- 12492101
TI  - Potassium iodide for thyroid protection in a nuclear accident or attack.

PMID- 12492102
TI  - Bioavailability and bioequivalence requirements: abbreviated applications. Final
      Rule.
AB  - The Food and Drug Administration (FDA) is amending its regulations on
      bioavailability and bioequivalence and on the content and format of an
      abbreviated application to reflect current FDA policy and to correct certain
      typographical and inadvertent errors. This action is intended to improve the
      accuracy and clarity of the regulations.

PMID- 12492103
TI  - Stroke Society of Australasia Annual Scientific Meeting. Auckland, New Zealand, 6
      8 September 2001. Abstracts.

PMID- 12492104
TI  - Medical devices: reclassification and codification of the absorbable
      polydioxanone surgical suture. Final rule.
AB  - The Food and Drug Administration (FDA) is announcing that it has issued an order
      in the form of a letter to Ethicon, Inc., reclassifying the absorbable
      polydioxanone surgical (PDS) suture intended for use in soft tissue
      approximation, including use in pediatric cardiovascular tissue where growth is
      expected to occur and ophthalmic surgery, from class III (premarket approval) to
      class II (special controls). Elsewhere in this issue of the Federal Register, FDA
      is announcing the availability of the guidance document entitled "Class II
      Special Controls Guidance Document: Surgical Sutures; Guidance for Industry and
      FDA," which is immediately in effect as the special control for the PDS suture,
      but remains subject to public comment and possible future revision under the
      agency's good guidance practices. The agency is reclassifying this device into
      class II because new information supplied by the petitioner indicates that
      special controls, in addition to general controls, will provide reasonable
      assurance of the safety and effectiveness of the device, and there is sufficient
      information to establish special controls. Accordingly, the order is being
      codified in the Code of Federal Regulations. Any firm submitting a premarket
      notification (510(k)) for a new PDS suture will need to address the issues
      covered in the special control guidance. However, the firm need only show that
      its device meets the recommendations of the guidance or in some other way
      provides equivalent assurances of safety and effectiveness.

PMID- 12492106
TI  - Proceedings of the 11th International Workshop on Neonatal Nephrology and 6th
      Seminar on Pediatric Nephrology.

PMID- 12492105
TI  - How will we be surveyed on safety goals?

PMID- 12492107
TI  - Management of failed intubation in a septic parturient.

PMID- 12492108
TI  - Transforming growth factor beta mimetics: discovery of 7-[4-(4
      cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of
      histone deacetylase.
AB  - Transforming growth factor beta (TGF-beta) is a multifunctional protein that has
      been shown to possess potent growth-inhibitory activity. To identify small
      molecular weight compounds with TGF-beta-like activities, high throughput
      screening was performed using mink lung epithelial cells stably transfected with
      a TGF-beta-responsive plasminogen activator inhibitor 1 promoter/luciferase
      construct. Biaryl hydroxamate compounds were identified that demonstrated TGF
      beta-like activities. 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid (A
      161906) demonstrated complete TGF-beta-like agonist activity in the plasminogen
      activator inhibitor 1/luciferase construct. A-161906 inhibited the proliferation
      of multiple cell lines in a concentration-dependent manner. Cells were growth
      arrested at the G1-S checkpoint similar to TGF-beta. Consistent with the G1-S
      arrest, A-161906 induced the expression of the cyclin-dependent kinase inhibitor
      p21waf1/cip1. A-161906 produced many cellular effects similar to that of TGF-beta
      but did not displace labeled TGF-beta from its receptors. Cells with mutations in
      either of the TGF-beta receptors I or II were growth-arrested by A-161906.
      Therefore, the site of action of A-161906 appears to be distal to the receptors
      and possibly involved with the signaling events controlled by TGF-beta. The TGF
      beta mimetic effect of A-161906 can be partially, if not entirely, explained by
      its activity as a histone deacetylase (HDAC) inhibitor. A-161906 demonstrated
      potent HDAC-inhibitory activity (IC50 = 9 nM). A-161906 is a novel small
      molecular weight compound (< 400 MW) having TGF-beta mimetic activity as a result
      of its potent HDAC-inhibitory activity. These results and those of others
      demonstrate the importance of HDACs in regulation of the TGF-beta signaling
      pathway(s).

PMID- 12492109
TI  - Relationship of XIST expression and responses of ovarian cancer to chemotherapy.
AB  - Expression profiling to characterize cancer pharmacology has become a new
      approach to discover novel molecular targets for prognostic markers and cancer
      therapy. In a study to compare the global RNA expression profiles between primary
      and recurrent ovarian tumors from the same patient, we have identified XIST
      (inactive X chromosome-specific transcripts) as the most differentially expressed
      gene that was down-regulated in the recurrent tumor. XIST encodes a spliced
      noncoding polyadenylated transcript that is unique in being expressed exclusively
      from the inactive X chromosome and is involved in the X-inactivation process.
      Subsequent characterization of XIST expression in a panel of female cancer cell
      lines showed that the expression level of XIST correlates significantly with
      Taxol sensitivity. The clinical relevance of this observation is demonstrated by
      the strong association between XIST RNA levels and disease-free periods of
      ovarian cancer patients in a group of 21 ovarian cancer cases with Taxol in the
      therapeutic regiments. Cytogenetic studies on ovarian cancer cell lines indicated
      that loss of inactive X chromosome is one mechanism for the loss of XIST
      transcripts in the cell lines. Our data suggest that XIST expression may be a
      potential marker for chemotherapeutic responses in ovarian cancer.

PMID- 12492111
TI  - Effective strategy of dendritic cell-based immunotherapy for advanced tumor
      bearing hosts: the critical role of Th1-dominant immunity.
AB  - Although dendritic cell (DC)-based cancer-specific immunotherapy is a potent
      strategy for various types of carcinomas, few clinical studies have yielded
      optimal antitumor effects. Systemic immunodeficiency is observed in patients with
      advanced malignant disease. In this study, we explored the ability to induce
      antitumor immunity of the cultured monocyte-derived DCs from hosts with advanced
      malignant disease, using a mouse model. We found remarkable dysfunction of DCs
      from mice with advanced cancer, which exhibited T helper (Th)2-dominant immunity,
      and subsequent reduced antitumor immune response. On the other hand, we found
      dramatic restoration of the ability of DCs to induce optimal antitumor immune
      responses after systemic administration of streptococcal preparation OK-432 to
      the tumor-bearing mice, which induced Th1-dominant immunity. In therapeutic
      experiments, intratumoral injections of immature DCs from the OK-432-treated
      mice, designated OK-DCs, enhanced inhibition of tumor growth compared with
      injections of immature DCs from mice with advanced malignancies, designated T-DCs
      (P < 0.05), leading to significant prolongation in overall survival (P < 0.05).
      In analysis of cell surface antigens, antigen-presenting capability and
      interleukin 12 production, we showed functional skewing in T-DCs and significant
      restorations in OK-DCs. More CD8+ tumor-infiltrating lymphocytes were detected in
      the mice treated with OK-DCs; furthermore, CTL assays showed that intratumoral
      injection of OK-DCs induced tumor-specific immune response to spleen as great as
      those of N-DCs. These results suggested that Th1-dominant immunity might play a
      crucial role in the differentiation of DCs, and OK-432 might be useful for
      inducing optimal antitumor effects in DC-based immunotherapy in tumor-bearing
      hosts.

PMID- 12492110
TI  - Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on
      downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma.
AB  - Pancreatic cancer is the fifth leading cause of cancer death in North America.
      Gemcitabine improves the quality of life of patients but fails to significantly
      reduce mortality. Our laboratory has demonstrated previously that the
      phosphatidylinositol 3'-kinase inhibitor wortmannin promotes gemcitabine
      antitumor activity (S. S. W. Ng et al., Clin. Cancer Res., 7: 3269-3275, 2001).
      The present study examined the effects of the epidermal growth factor receptor
      (EGFR) inhibitor OSI-774 ("Tarceva") alone and in combination with wortmannin
      and/or gemcitabine on downstream signaling molecules, as well as apoptosis in
      primary pancreatic cancer xenografts implanted orthotopically in severely
      combined immunodeficient mice. Tumors established from two pancreatic cancer
      patients [Ontario Cancer Institute Pancreas number (OCIP#) 2 and OCIP#7] were
      treated with various combinations of the above three drugs and harvested for
      analyses of the following: the levels of phosphorylated and nonphosphorylated
      forms of EGFR, protein kinase B (PKB/Akt) and extracellular-regulated kinase
      (ERK1/2), and the extent of apoptosis using immunofluorescence image analysis and
      TUNEL assay, respectively. OSI-774 alone significantly inhibited phosphorylation
      of EGFR in both of the primary xenografts. Phosphorylation of pERK decreased in
      OCIP#2, but not in OCIP#7. No significant effects on pPKB because of OSI-774 were
      observed in either tumor type. The extent of apoptosis was significantly
      increased by 2-fold in OCIP#2 tumors treated with gemcitabine and wortmannin in
      combination; an additional 2-fold increase in apoptosis was evident in the
      presence of OSI-774. Although wortmannin failed to enhance gemcitabine-induced
      apoptosis in OCIP#7 tumors, the extent of apoptosis was significantly increased
      with the inclusion of OSI-774 in the combination. Taken together, these findings
      support the use of OSI-774 plus a phosphatidylinositol 3'-kinase inhibitor in
      combination with gemcitabine in the treatment of pancreatic cancer.

PMID- 12492113
TI  - Vasodilator-stimulated phosphoprotein (VASP) phosphorylation provides a biomarker
      for the action of exisulind and related agents that activate protein kinase G.
AB  - Recent studies provide evidence that exisulind and two potent derivatives, CP461
      and CP248, induce apoptosis in colon cancer cells by inhibiting cyclic GMP (cGMP)
      specific phosphodiesterases (phosphodiesterases 2 and 5). This causes an increase
      in intracellular levels of cGMP, thus activating the cGMP-dependent protein
      kinase G (PKG), which then activates pathways that lead to apoptosis. To further
      examine this mechanism and to provide a potential in vivo biomarker for
      activation of this pathway, we examined phosphorylation of the vasodilator
      stimulated phosphoprotein (VASP), a ubiquitously expressed endogenous substrate
      for PKG. We found that VASP was phosphorylated after treating SW480 colon cancer
      cells with exisulind, CP461, or CP248. CP248-induced VASP phosphorylation was
      inhibited by a specific PKG inhibitor but not by a protein kinase A inhibitor.
      The drug 3-(5'-hydroxymethyl-2'-furyl)-benzylindazole and nitric oxide donors
      that activate cellular guanylyl cyclase and thus increase cellular levels of cGMP
      also caused VASP phosphorylation. With all of these agents, the phosphorylation
      of VASP was associated with increased intracellular levels of cGMP and the
      induction of apoptosis. We also demonstrated direct in vivo phosphorylation of
      VASP with constitutively activated mutants of PKG. These results suggest that
      VASP phosphorylation can provide a useful endogenous cellular biomarker for
      anticancer agents that cause cGMP-mediated apoptosis.

PMID- 12492112
TI  - The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis.
AB  - Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent,
      has been shown to inhibit key components of the angiogenic process, including
      matrix metalloproteinases and vascular endothelial growth factor-mediated
      signaling events. In this study, we report the presence of a proapoptotic
      activity within this compound. Neovastat treatment of bovine aortic endothelial
      cells caused cell death with characteristics of apoptosis, including chromatin
      condensation and DNA fragmentation. Neovastat markedly induced caspase-3, caspase
      8, and caspase-9 activities, at similar levels to those measured in cells treated
      with tumor necrosis factor-alpha. Activation of caspases by Neovastat appears to
      be essential for its proapoptotic effects because all apoptotic features were
      blocked by zVAD-fmk, a broad-spectrum caspase inhibitor. The activation of
      caspases was correlated with the cleavage of the nuclear substrate poly(ADP
      ribose) polymerase, and by a concomitant release of cytochrome c from
      mitochondria to the cytoplasm. Neovastat-induced apoptosis appears to be specific
      to endothelial cells because treatment of other cell types such as U-87, COS-7,
      NIH-3T3, and SW1353 did not result in increased caspase-3 activity. These results
      demonstrate that Neovastat contains a proapoptotic factor that specifically
      induces the activation of caspases in endothelial cells and the resulting
      apoptosis of these cells.

PMID- 12492114
TI  - Mitogen-activated protein kinase routes as targets in the action of diaza
      anthracene compounds with a potent growth-inhibitory effect on cancer cells.
AB  - 1,8-Diaza-anthracene-tetraones are novel intermediates in the synthesis of the
      antifolate antibiotic diazaquinomycin A that was found before to have potent
      antitumor activity. Three of them (CV65, CV66, and CV70) were found to inhibit
      growth of a panel of several human tumor cell lines. The IC50s ranged from 0.05
      to 1.5 microM and are comparable with that of doxorubicin. Among the three drugs,
      CV70 showed the highest cytotoxic activity. The growth-inhibitory action of these
      compounds was unrelated to the p53 status of the cells. At micromolar
      concentrations, all three compounds induced apoptosis, CV70 being the most
      proapoptotic. The incubation of HeLa cells with CV65, CV66, and CV70, at
      concentrations between 10 and 20 microM, inhibited the activation of c-Jun NH2
      terminal kinase by various stimuli and prevented growth factor-induced
      extracellular signal-regulated kinase (ERK) 5 activation. At least one drug,
      CV65, also inhibited p38. This was surprising because proapoptotic antitumor
      drugs activate stress signaling pathways. Activation of ERK1/ 2 by growth factors
      or phorbol esters was unaffected by preincubation of cells with CV compounds. In
      vitro, CV compounds inhibit the enzyme quinone reductase but not c-Jun NH2
      terminal kinase or ERK5. Because doxorubicin also inhibits quinone reductase, we
      conclude that the inhibitory effect of CV compounds on stress signaling kinases
      is not a direct effect on the kinases and is likely attributable to upstream
      elements of the activation cascades.

PMID- 12492115
TI  - Cisplatin potentiates 1,25-dihydroxyvitamin D3-induced apoptosis in association
      with increased mitogen-activated protein kinase kinase kinase 1 (MEKK-1)
      expression.
AB  - 1,25-Dihydroxyvitamin D3 (1,25D3) exhibits potent antitumor activity in the
      murine squamous cell carcinoma (SCC) SCCVII/SF, and the combination of 1,25D3
      with cisplatin (1,25D3/cisplatin) demonstrates even greater activity. Because
      these agents possess different mechanisms of cytotoxicity, studies were initiated
      to define the mechanism by which the combination displays enhanced activity.
      Median dose-effect analysis demonstrates that 1,25D3 and cisplatin act
      synergistically to inhibit SCC growth. When SCC cells were treated with 1,25D3
      (10 nM) and/or cisplatin (0.5 microg/ml), greater caspase-3 activation was
      observed for the combination than for either agent alone. This suggests that the
      enhanced cytotoxicity is, at least in part, due to greater induction of
      apoptosis. No alterations in cellular platinum concentration or platinum-DNA
      adducts were observed for 1,25D3/cisplatin cotreatment compared with cisplatin
      treatment alone. Effects of the combination on cisplatin and 1,25D3 signaling
      pathways in adherent (nonapoptotic) and floating (apoptotic) cells were explored.
      Cisplatin induced p53 and its downstream targets, p21(Cip1) (p21) and Bax, in
      both cell populations. In contrast, 1,25D3 reduced p53, p21, and Bax to nearly
      undetectable levels in adherent cells. In the floating cells, 1,25D3 reduced
      levels of p53 and p21, but Bax expression was maintained at control levels.
      Expression of these proteins in cells treated with 1,25D3/cisplatin was similar
      to treatment with 1,25D3 alone. The two agents also had divergent effects on
      survival and stress signaling pathways. Phospho-extracellular signal-regulated
      kinase 1/2 and phospho-Jun levels increased after treatment with cisplatin but
      decreased after treatment with 1,25D3 and 1,25D3/cisplatin. Moreover, cisplatin
      decreased levels of mitogen-activated protein kinase kinase kinase (MEKK-1),
      whereas 1,25D3 up-regulated MEKK-1, and 1,25D3/cisplatin further up-regulated
      MEKK-1. We propose that the increased cytotoxicity for 1,25D3/cisplatin results
      from cisplatin enhancement of 1,25D3-induced apoptotic signaling through MEKK-1.

PMID- 12492116
TI  - Mifepristone pretreatment overcomes resistance of prostate cancer cells to tumor
      necrosis factor alpha-related apoptosis-inducing ligand (TRAIL).
AB  - Examination of the effects of TRAIL (tumor necrosis factor alpha-related
      apoptosis-inducing ligand) showed higher apoptotic response in LNCaP C4-2,
      whereas LNCaP were resistant. However, treatment of LNCaP with Mifepristone, an
      antiprogestin, before TRAIL induced significant apoptosis, similar to the levels
      observed in LNCaP C4-2. Experiments to determine the reasons for altered response
      of the cell lines showed no significant differences in death/decoy receptors and
      caspase-8 activity. However, treatment induced increased truncation of Bid and
      activation of caspases -9, -7, and -3 in LNCaP C4-2. Time course experiments
      showed that caspase-8 was activated before the involvement of mitochondrial
      pathway, and caspase-9 was responsible for activation of caspases -7 and -3. Use
      of specific caspase inhibitors demonstrated the presence of a short-loop feedback
      activation of Bid. Published reports suggested that increased phosphorylation of
      Akt was responsible for resistance of LNCaP to TRAIL. However, no significant
      differences were noticed in the levels of phosphorylated Akt in TRAIL-resistant
      LNCaP and TRAIL-sensitive LNCaP C4-2. On the basis of our results, it is
      suggested that the differences in response of the two cell lines to TRAIL is at
      the mitochondrial level.

PMID- 12492117
TI  - PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage
      in association with G2-M phase arrest and apoptosis.
AB  - Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and
      time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that
      coincided with the PS-341-induced G2-M phase arrest. The observed Bcl-2 cleavage
      paralleled the degree of PS-341-induced apoptosis but was detected to a similar
      extent with comparable concentrations of two other proteasome inhibitors (MG-132
      and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD
      and AC-YVAD did not induce BcI-2 phosphorylation and cleavage. Exposure to PS-341
      resulted in an additional Mr 25,000 cleavage fragment of Bcl-2, whereas only a Mr
      23,000 fragment was observed with other anticancer agents. The formation of the
      Mr 25,000 fragment was not prevented by caspase inhibitors unlike the Mr 23,000
      fragment, which suggests mediation by a caspase-independent pathway. Cell
      fractionation studies revealed that the Bcl-2 cleaved fragments localize within
      membrane structures and was an early event (at approximately 12 h,
      posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase
      (PARP), beta-catenin, and DNA fragmentation (at approximately 36 h
      posttreatment). The Mr 23,000 Bcl-2 cleavage product was inhibited by the pan
      caspase inhibitor and the inhibitors of capase-3, -8, -9; but the PARP cleavage
      was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests
      that the Mr 23,000 Bcl-2 cleavage occurred at both the initiation and execution
      stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341
      leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique
      proteolytic cleavage product, which are associated with G2-M phase arrest and the
      induction of apoptosis.

PMID- 12492118
TI  - Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone
      marrow microenvironment.
AB  - Multiple myeloma (MM) remains incurable with current therapies, and novel
      biologically based therapies are urgently needed. Thalidomide and its analogues,
      as well as proteasome inhibitors, are examples of such novel agents that target
      both the myeloma cell and its microenvironment and can overcome classical drug
      resistance. In this study we demonstrate that arsenic trioxide (As2O3) mediates
      anti-MM activity both directly on tumor cells and indirectly by inhibiting
      production of myeloma growth and survival factors in the bone marrow (BM)
      microenvironment. Specifically, As2O3 at clinically achievable levels (2-5
      microM) induces apoptosis even of drug-resistant MM cell lines and patient cells
      via caspase-9 activation, enhances the MM cell apoptosis induced by
      dexamethasone, and can overcome the antiapoptotic effects of interleukin 6. As2O3
      also acts in the BM microenvironment to decrease MM cell binding to BM stromal
      cells, inhibits interleukin 6 and vascular endothelial growth factor secretion
      induced by MM cell adhesion, and blocks proliferation of MM cells adherent to BM
      stromal cells. These studies provide the rationale for clinical trials of As2O3,
      either alone or together with dexamethasone, to overcome classical drug
      resistance and improve outcome in patients with MM.

PMID- 12492119
TI  - Regulation of p53 stabilization by DNA damage and protein kinase C.
AB  - We have demonstrated previously that the protein kinase C (PKC) signal
      transduction pathway acts upstream of caspases to regulate caspase activation and
      apoptosis induced by the DNA-damaging agent cisplatin (CP). In the present study,
      we have examined whether PKC influences p53 and, hence, cellular
      sensitivity/resistance to CP. The basal p53 level was low in HeLa cells but was
      elevated in CP-resistant HeLa (HeLa/CP) cells. CP had no effect on the p53
      content in HeLa cells, but it caused p53 accumulation in HeLa/CP cells.
      Rottlerin, a PKCdelta inhibitor that prevents CP-induced proteolytic activation
      of PKCdelta, caused an accumulation of p53 in HeLa cells when treated in
      conjunction with CP, but it had no additional effect in HeLa/CP cells. The
      ability of rottlerin to prevent proteolytic activation of PKCdelta or to induce
      accumulation of p53 by CP was compromised in HeLa/CP cells. PKC activator phorbol
      12, 13-dibutyrate attenuated constitutive p53 levels in both HeLa and HeLa/CP
      cells. Whereas the combination of rottlerin and CP increased the half-life of p53
      in HeLa cells, CP alone was sufficient to stabilize p53 in HeLa/CP cells. These
      results suggest that both DNA damage and inhibition of proteolytic activation of
      PKCdelta by CP were necessary for the stabilization of p53 in HeLa cells.
      Furthermore, an increase in p53 was not associated with enhanced sensitivity of
      HeLa cells to CP.

PMID- 12492120
TI  - Enterolactone inhibits the growth of 7,12-dimethylbenz(a)anthracene-induced
      mammary carcinomas in the rat.
AB  - The inverse association between a high enterolactone (ENL) concentration in both
      urine and serum, and the risk of breast cancer found in epidemiological studies
      suggests a chemopreventive action for ENL. However, no causal relationship has
      been established in clinical studies or in experimental models for breast cancer.
      In the present study, the potential chemopreventive action of p.o. administered
      ENL (1 or 10 mg/kg of body weight) was tested in 7,12-dimethylbenz(a)anthracene
      induced mammary cancers of the rat. Rats were maintained on a standard open
      formula chow diet. Daily p.o. administration of ENL at a dose of 10 mg/kg of body
      weight for 7 weeks significantly inhibited tumor growth. The growth-inhibitory
      effect of ENL was more pronounced on the new tumors, which developed during the
      treatment period, but ENL also inhibited the growth of those tumors established
      before the start of the lignan administration. The rat serum concentration of
      ENL, which illustrated a permanent positive effect on breast cancer growth, was
      0.4 microM, which is >10-fold as compared with the serum concentrations found in
      the general human population. The effect of ENL was not restricted to any
      specific histological tumor type. ENL was demonstrated to act as a weak aromatase
      inhibitor in vitro and to reduce the relative uterine weight of the 7,12
      dimethylbenz(a)anthracene-treated nonovariectomized rats. However, in a short
      term assay ENL had no effect on the uterine growth of the intact or
      androstenedione-treated immature rats. Thus, the mechanism of the ENL action and
      its minimum or optimal daily dose remains to be clarified.

PMID- 12492121
TI  - Combination with an antisense oligonucleotide synergistically improves the
      antileukemic efficacy of erucylphospho-N,N,N-trimethylpropylammonium in chronic
      myeloid leukemia cell lines.
AB  - The aim of this study was to enhance the antileukemic efficacy of the
      alkylphosphocholine erucylphospho-N,N,N-trimethylpropylammonium (ErPC3) in
      chronic myeloid leukemia (CML)-derived cell lines by a bcr-directed antisense
      oligonucleotide (ASO-bcr). The mechanism was substantiated by Western blotting of
      the BCR-ABL expression level of CML cells, and the efficacy was substantiated by
      inhibition of colony formation compared with normal hematopoietic cells. The
      clonogenicity of K-562 cells expressing high levels of p210(BCR-ABL) was
      inhibited significantly by the ASO-bcr (T/C%, 30; P < 0.05) but not by ErPC3
      (T/C%, 70). Combined sequential exposure to ErPC3 and the ASO-bcr, however,
      inhibited synergistically colony growth (T/C%, 3; P < 0.01). The colony growth of
      BV-173 cells expressing lower levels of p210(BCR-ABL) than K562 cells was
      inhibited to a greater extent by the ASO-bcr (T/C%, 15; P < 0.01). AR-230 cells
      that express high levels of p230(BCR-ABL) showed an intermediate decrease in
      colony formation in response to the ASO-bcr (T/C%, 20; P < 0.05). BCR-ABL levels
      of BV-173, CML-T1, and LAMA-84 cells were reduced in response to the ASO-bcr, as
      evidenced by Western blot. However, K-562 and AR-230 cells showed reduced BCR-ABL
      expression only after repeated treatment. ErPC3 and the ASO-bcr did not reduce
      colony formation (CFU-GM) of normal mouse bone marrow cells from long-term bone
      marrow cell cultures; instead, ErPC3 stimulated colony formation (P < 0.05) and
      did not induce chromosomal aberrations in mouse bone marrow. In conclusion, the
      combination of ErPC3 with a suitable antisense oligonucleotide inhibited
      synergistically colony formation of CML cell lines without damaging normal cells
      and thus might have a bearing on the purging of autologous hematopoietic
      transplants in CML patients.

PMID- 12492122
TI  - The ultrasonic stethoscope: the new instrument in cardiology?

PMID- 12492123
TI  - Quadricuspid aortic valves.
AB  - Quadricuspid aortic valves (QAV) are a rare but well recognized cause of
      significant aortic regurgitation. The first case was found reported in 1862.
      Since then there have been 110 reported cases of QAV and we report 4 more.
      Previously, these were diagnosed at the time of surgery or postmortem
      examination. With advances in echocardiography, including harmonic imaging, and
      also the advent of transesophageal echocardiography, more cases are being
      diagnosed prior to surgery. We describe four more cases, three diagnosed
      preoperatively and one at the time of surgery, and then review the previously
      reported cases. Of the 114 cases reported, 46 had the aortic valve replaced, most
      commonly in the 5th and 6th decade of life. Hurwitz and Roberts classified
      quadricuspid valves according to the size of the leaflets. It has previously been
      believed that QAVs with four equal sized leaflets were less likely to develop
      significant aortic regurgitation; however, on review of the available cases, this
      would not appear to be the case. The preoperative diagnosis of QAVs is important
      as they can be associated with abnormally placed coronary ostium. Of the 114
      cases reported, there are 10 reports of abnormally placed ostia. There has been
      at least one reported case of death occurring because of obstruction of an
      abnormally placed right coronary ostium by a prosthetic aortic valve.

PMID- 12492124
TI  - Electrocardiogram abnormalities predict angiographic coronary artery disease in
      women with chest pain: results from the NHLBI WISE Study.
AB  - BACKGROUND AND HYPOTHESIS: Noninvasive risk stratification for coronary artery
      disease (CAD) isless accurate in women than in men. Based on recent reports that
      gender-specific exercise electrocardiogram (ECG) parameters predict CAD, we
      evaluated the independent predictive value of the resting ECG for angiographic
      CAD in women with chest pain. METHODS: Women (n = 850, mean age 58 years) with
      chest pain in the NHLBI Women's Ischemia Syndrome Evaluation (WISE) underwent 12
      lead ECG testing and quantitative coronary angiography. RESULTS: Significant
      angiographic CAD (> or = 50% stenosis in > or = 1 coronary) was present in 39% of
      women. Q waves in < or = 2 contiguous ECG leads were present in 107 women (13%),
      including 49 of 657 (7%) without history of infarction. Among 585 women without
      prior infarction orrevascularization, 48% of those with Q waves in contiguous
      leads versus 26% of others, had significant CAD (p = 0.003; odds ratio [OR] =
      2.5, 95% confidence interval [CI] = 1.3-4.8). Women with Q waves in < or = 2
      inferior ECG leads were particularly likely to have CAD (63 vs. 26% of others, p
      < 0.001; OR = 4.6,95% CI = 2.0-10.8). Other ECG findings predictive of CAD were
      any ST-T abnormality (OR = 1.9,95% CI = 1.3-2.8) and T-wave inversion (OR = 2.4,
      95% CI = 1.3-4.2). In risk-adjusted analysis, inferior Q waves and T-wave
      inversion independently predicted significant CAD. When considered together with
      radionuclide perfusion test results, T-wave inversion on resting ECG added
      significant independent predictive value (OR = 2.8, 95% CI = 1.1-7.2, p = 0.03).
      CONCLUSIONS: Selected resting ECG parameters independently predict angiographic
      CAD in women with chest pain, including women who have also undergone
      radionuclide stress testing. Prospective studies should consider resting ECG
      parameters in diagnostic algorithms for CAD in women.

PMID- 12492125
TI  - Dobutamine stress echocardiography in the diagnosis of coronary artery disease in
      women with chest pain: comparison with different noninvasive tests.
AB  - BACKGROUND: Diagnosis of coronary artery disease(CAD) in women remains elusive.
      The classical diagnostic armamentarium has been found to be very limited.
      Dobutamine stress echocardiography has emerged as a powerful test in assessing
      CAD in the general population, but most studies failed to include women.
      HYPOTHESIS: The accuracy of dobutamine stress echocardiography in the diagnosis
      of CAD in women with chest pain is high and superior to dipyridamole
      echocardiography, exercise electrocardiography, and sestamibi single-photon
      emission tomography (MIBI-SPECT) scintigraphy. METHODS: We studied 99 consecutive
      women with chest pain and no previous history of CAD who underwent dobutamine
      echocardiography and coronary angiography. We also compared these results with
      those of dipyridamole echocardiography in 63 patients. exercise stress testing in
      83 (48 conclusive), and MIBI-SPECT scintigraphy during dobutamine infusion in 54.
      RESULTS: Significant CAD was found in 42 women. Sensitivity and specificity of
      dobutamine stress echocardiography were 69 and 89%, respectively. Dipyridamole
      echocardiography showed similar accuracy (sensitivity 72% and specificity 94%).
      Finally, sensitivity of exercise test and MIBI-SPECT was similar (76 and 88%,
      respectively) and specificity was lower (53 and 57%, respectively). After
      excluding patients known to have a high incidence of false positive results, MIBI
      SPECT specificity rose up to 80%. CONCLUSION: Dobutamine stress echocardiography
      and dipyridamole echocardiography bear a high diagnostic accuracy in women with
      chest pain. MIBI-SPECT is also a useful tool after excluding subgroups with a
      high incidence of false positive results.

PMID- 12492126
TI  - Limitation of infarct size and ventricular remodeling in patients with completely
      reperfused anterior acute myocardial infarction--the potential role of ischemia
      time.
AB  - BACKGROUND: Experimental studies suggest that coronary reperfusion does not
      result in appreciable myocardial salvage beyond 3 to 4 h. HYPOTHESIS: The present
      study was undertaken to examine the potential role of ischemia time as a
      determinant of infarct size and cardiac function in humans. METHODS: Ninety
      patients (69 men, 21 women, aged 61 +/- 1 years) presented within 24 h of onset
      of a first anterior infarct had ST-segment elevation on electrocardiogram. All
      patients underwent coronary intervention within 24 h of onset of symptoms and
      obtained complete reperfusion of the infarct-related artery. RESULTS: Infarct
      size expressed as a percentage of the area at risk (IS/RA) and left ventricular
      end-diastolic volume (LVEDV) were significantly (p < 0.017) smaller and left
      ventricula rejection fraction (LVEF) assessed by left ventriculography (35 +/- 4
      days) was significantly higher in patients treated within 4 h after onset
      (IS/RA:55 +/- 4%, LVEDV: 127 +/- 7 ml, LVEF: 62 +/- 2%) than in those treated 4
      to 12 h (97 +/- 2%, 140 +/- 13 ml, 52 +/- 3%) and 12 to 24 h (93 +/- 2%,163 +/-
      14 ml, 49 +/- 5%) after symptom onset. Left ventricular end-diastolic volume was
      significantly smaller in patients treated 4 to 12 h after onset than in those
      treated 12 to 24 h after onset. CONCLUSIONS: Patients with < 4 h of myocardial
      ischemia exhibited significant myocardial salvage and better left ventricular
      function and patients with 4 to 12 h of myocardial ischemia exhibited
      significantly smaller LVEDV than those with more prolonged ischemia, although
      there was no difference in final infarct size.

PMID- 12492127
TI  - Images in cardiology: (not quite) identical twins.

PMID- 12492128
TI  - Profiles in cardiology. Julius Friedrich Cohnheim.

PMID- 12492129
TI  - Inhibition of fibrin-induced neurogenic pulmonary edema by previous unilateral
      left-vagotomy correlates with increased levels of brain nitric oxide synthase in
      the nucleus tractus solitarii of rats.
AB  - In the course of investigations on mechanisms underlying development of
      neurogenic pulmonary edema (NPE), we have evaluated effects of nitric oxide (NO)
      in the central nervous system on incidence and severity in the fibrin-induced
      pulmonary edema model. Rats left-unilaterally vagotomized 1, 2 and 4 weeks before
      injections of fibrinogen and thrombin into the cisterna magna, after cutting the
      right vagus nerve, grouped as LVIW, LV2W or LV4W, respectively. The brain NO
      synthase (NOS) mRNA level in the left medulla oblongata was elevated in the LV2W
      group, compared to the control, but decreased in the LV4W rats. Incidences of
      pulmonary edema were 100% in the control group, decreasing to 78% in LV1W group,
      17% in LV2W group, and back to 72% in LV4W group. The lung water ratio, a
      parameter of severity, demonstrated a similar pattern of change as the incidence.
      The lowered incidence and severity obtained in the LV2W group were reversed by
      intracisternal injection of N-nitro-L-arginine methyl ester (L-NAME). From these
      results, we propose that an increase in nitric oxide, possibly in the nucleus
      tractus solitarius 2 weeks after left vagotomy, may have an inhibitory action on
      the development of neurogenic pulmonary edema in rats.

PMID- 12492130
TI  - Effects of botulinum toxin type A on the superior cervical ganglia in rabbits.
AB  - Sympathetic neurolysis is very important in treating chronic pain, especially
      sympathetically maintained pain. However, conventional neurolytic agents destroy
      nerve fibers nonselectively and may leave serious complications. Botulinum toxin
      type A (BTA) selectively acts on cholinergic nerves and inhibits the secretion of
      acetylcholines (Ach) at the involved nerve endings. Because cholinergic nerves
      also exist in autonomic ganglia, it is believed that BTA has pharmacological
      effects on sympathetic ganglia. In this study, after the administration of BTA
      into the superior cervical ganglion (SCG) in rabbits, the possible clinical use
      of BTA as a neurolytic agent was evaluated. In the normal saline-treated control
      group, miosis was not observed in all 12 rabbits. However, in the BTA-treated
      group, 15 cases of miosis were observed among 40 rabbits (37.5%). Furthermore,
      BTA induced miosis in a dose-dependent manner, though onset time and duration of
      miosis varied. Mean time of onset and duration were 1.8 days and 5.3 weeks,
      respectively. By eosin-hematoxylin (H&E) staining finding, no significant
      chronological and histological changes between the control and the experimental
      groups were observed. In conclusion, BTA was found to have a sympathetic ganglion
      blocking effect over a period of more than 1 month without causing considerable
      pathologic changes in the SCG, that is, this toxin may be used in the case of
      sympathetically maintained pain control as a sympatholytic.

PMID- 12492131
TI  - Vagal intraganglionic laminar endings and intramuscular arrays mature at
      different rates in pre-weanling rat stomach.
AB  - To assess whether vagal afferents in the gastrointestinal (GI) tract mature
      postnatally and differentiate at different rates, potentially reflecting the
      changing functional requirements of weaning and independence, the vagal afferent
      innervation of the stomach was inventoried in pre-weanling and adult rats.
      Wheatgerm agglutinin-horseradish peroxidase was injected into the nodose ganglia
      of 9-day-old and adult rats, and after tracer transport, the animals were
      sacrificed. Their stomachs were prepared as wholemounts and processed with
      tetramethylbenzidine. Inventories were obtained with a counting grid that was
      systematically positioned throughout the wholemounts by the use of a sampling
      template that was adjusted for stomach size and shape. Densities in the gastric
      antrum, corpus, and forestomach were determined for (1) afferent bundles, (2)
      individual fibers separated from the bundles and presumably located near their
      targets, (3) differentiated intraganglionic laminar endings (IGLEs) associated
      with myenteric ganglia, and (4) differentiated intramuscular arrays (IMAs)
      situated within the smooth muscle layers. In pre-weanling rats, which were 10
      days old at perfusion, the distributions of vagal bundles and fibers were similar
      to those of adults, suggesting that the basic vagal architecture develops early.
      Differentiated IGLEs were also distributed in a mature pattern in 10 day olds,
      whereas few IMAs had yet been distributed and differentiated in the forestomach
      of the pre-weanlings. The authors hypothesize that these different developmental
      patterns for the two types of vagal afferents are consistent with their putative
      functional roles as, respectively, mechanoreceptors (IGLEs) that coordinate
      rhythmic motor function needed early for the digestion of milk and stretch
      receptors (IMAs) needed later as the GI tract natures for the transition to solid
      food at weaning.

PMID- 12492132
TI  - Functional GABAB receptors are present in guinea pig nodose ganglion cell bodies
      but not in peripheral mechanosensitive endings.
AB  - The effects of the GABAB-selective agonist baclofen were studied on guinea pig
      nodose ganglion neurones using grease gap and intracellular recording techniques,
      and on peripheral mechanosensitive endings in the guinea pig oesophagus and
      stomach with extracellular recordings. GABA dose-dependently reduced the
      amplitude of the compound action potential of C-type neurones (C spikes, EC50 =
      30.9 microM), which was prevented by the GABAA antagonist bicuculline (10
      microM). The GABAB agonist baclofen (1-300 microM) did not produce any
      significant effect on the amplitude of C spikes. In microelectrode studies,
      baclofen (100 microM) evoked hyperpolarisation (by 2.53 +/- 0.51 mV, n = 6, N =
      5) in a subset of nodose neurones (6 out of 26, N = 18). In seven out of eight
      neurones (N = 8) with a slow after-hyperpolarisation following action potentials,
      baclofen significantly inhibited its amplitude by 19 +/- 4% (n = 7, p < 0.05).
      GABA (100 microM) evoked a depolarisation of 9.3 +/- 2.4 mV (10 nodose neurones,
      N = 9, p < 0.05) associated with a decrease in input impedance of 49 +/- 12% (N =
      4, p < 0.05). Baclofen (100-200 microM) did not affect either spontaneous or
      stretch-evoked firing of distension-sensitive vagal mechanoreceptors of the
      guinea pig oesophagus and stomach but did inhibit mechanoreceptors in the ferret
      oesophagus. Antibodies to GABAB receptor 1a splice variants labelled most of the
      neurones and numerous fibres in the guinea pig nodose ganglion while antibodies
      to GABAB receptor 1b splice variants stained only nerve cell bodies. There were
      numerous nerve fibres showing GABAB receptor 1a- and 1b-like immunoreactivity in
      the myenteric plexus in the guinea pig oesophagus and stomach but not in
      anterogradely labelled extrinsic vagal nerve fibres. The result indicates that
      most guinea pig C-type nodose ganglion neurones have GABAB receptors on their
      cell bodies but their density on distension-sensitive peripheral endings is too
      low to allow modulation of mechanotransduction. There is a significant species
      dependent difference in the expression of GABAB receptors on peripheral vagal
      mechanosensitive endings.

PMID- 12492133
TI  - Micturition-related electrophysiological properties in the substantia nigra pars
      compacta and the ventral tegmental area in cats.
AB  - Parkinson's disease patients are known to have not only motor but also urinary
      autonomic disorders, suggesting central dopaminergic pathways being involved in
      the micturition function. However, there is little evidence that the substantia
      nigra pars compacta (SNC) and the ventral tegmental area (VTA), the major
      dopamine-containing nuclei in the midbrain, should participate in regulating
      micturition. We investigated micturition-related electrophysiological properties
      in the SNC and VTA. In 20 male cats under ketamine anaesthesia, in which
      spontaneous isovolumetric micturition reflex was generated, we performed
      electrical stimulation and extracellular single-unit recording in the SNC and the
      VTA, and correlation analysis of the neuronal firings and antidromic stimulation
      between the SNC/VTA and the pontine storage centre (PSC). Electrical stimulations
      in the SNC elicited termination of the micturition reflex, whereas those in the
      VTA elicited both termination and facilitation of the reflex. Forty-nine neurons
      in the SNC/VTA showed firing in response to the bladder storage/micturition
      cycles. The major neurons were tonic storage (55%) and phasic storage neurons
      (22%), which were found diffusely in th e SNC/VTA. The rest were tonic
      micturition (16%) and phasic micturition neurons (6%), which were concentrated in
      the caudal part (A2-4 in the Horsley-Clarke coordinates). These neuronal types
      were further subclassified into augmenting, constant, binary and decrementing
      neurons according to their temporal discharge rate change. The decrementing
      neurons were concentrated in the caudal part (A2-4), whereas the augmenting
      neurons in the rostral part (A4-6). Some of the recorded neurons had preceding
      firing pattern, which was more frequently found in the tonic type than in the
      phasic-type neurons. Twenty-four of the neuronal firings in the SNC/VTA were
      recorded simultaneously with those in the PSC. However, there was no apparent
      time-correlation between both sets of neuronal firings. In 15 of the simultaneous
      recording sites, electrical stimulation was applied to one site to see if
      antidromic response might be evoked in another site. However, there was no
      orthodromic or antidromic response in either SNC/VTA or PSC. In conclusion, the
      present study indicates that neurons in the SNC and the VTA are involved in supra
      pontine control of micturition, particularly of urinary storage phase. It is also
      likely that the major role of the SNC is inhibition of the micturiton reflex,
      whereas that of the VTA is both facilitation and inhibition of the micturition
      reflex.

PMID- 12492134
TI  - Glucagon-like peptide-1 evokes action potentials and increases cytosolic Ca2+ in
      rat nodose ganglion neurons.
AB  - We previously reported that the intraportal appearance of glucagon-like peptide-1
      (GLP-1) facilitates the afferent activity (the spike discharge firing rate) of
      the rat hepatic vagus in a dose-dependent fashion. To examine whether GLP-1
      directly activates single neurons isolated from the rat nodose ganglion, GLP-1
      induced changes of the membrane potential and cytosolic-free Ca2+ concentration
      ([Ca2+]i) in the cells were measured using whole-cell patch-clamp and
      microfluorometric techniques, respectively. GLP-1 application (3 x 10(-12) - 3 x
      10(-9) M) induced a gradual depolarization from a mean resting membrane potential
      of - 55.0 +/- 3.1 mV and evoked a burst of action potentials with a time lag of
      7.5 +/- 4.5 min after its starting (n = 4). The burst of action potentials
      continued during the application and even up to 13 min or more after its
      cessation. GLP-1 at a concentration of 10(-12) - 10(-8) M induced an increase of
      [Ca2+]i. The GLP-1-induced [Ca2+]i responses were often oscillatory and lasted
      even up to 10 min or more after the washout of GLP-1. An adenylate cyclase
      activator, forskolin, mimicked the GLP-1-induced increase in [Ca2+]i. The present
      results indicate that GLP-1 activates nodose ganglion neurons as manifested by
      membrane depolarization, a burst of action potentials and [Ca2+]i increase,
      possibly via the cAMP pathway. Together with our previous observations, the
      results strongly suggest cellular mechanisms by which the postprandial humoral
      information, intraportal appearance of GLP-1, is uniquely converted to the neural
      information in the hepatoportal area.

PMID- 12492135
TI  - Responses of hepatic glucose output to noxious mechanical stimulation of the skin
      in anaesthetised rats.
AB  - Responses of hepatic glucose output (HGO) to noxious mechanical stimulation of
      different skin areas were investigated in anaesthetised rats with central nervous
      system intact or acutely spinalized at the thoracic 1-2 (T1-T2) level by focusing
      on the involvement of the sympathetic and parasympathetic nerves in the responses
      of HGO. We measured HGO with a microdialysis probe implanted into the left
      lateral lobe of the liver. Pinching was applied to bilateral skin areas of the
      abdomen and hindlimb for 10 min. Atropine was injected in order to block the
      action of the parasympathetic nerves, whereas phentolamine and propranolol were
      injected in order to block the action of the sympathetic nerves. The HGO started
      to increase immediately after the cessation of pinching of the abdomen and the
      hindlimb, and lasted for 30 min. The increase of HGO was observed during stimulus
      period in animals pretreated with atropine, and totally abolished in animals
      pretreated with phentolamine and propranolol. The responses of HGO to abdominal
      pinching, but not to hindlimb pinching, remained after spinal cord transection at
      the T1-T2 level. The present results suggest that HGO is regulated as a reflex
      response via both sympathetic and parasympathetic nerves by noxious mechanical
      stimulation of the skin. Furthermore, it was shown that relative contribution of
      the spinal and supraspinal organization to the somato-HGO responses was dependent
      on the skin areas stimulated.

PMID- 12492136
TI  - Human autonomic activity and its response to acute oxygen supplement after high
      altitude acclimatization.
AB  - It is well established that after acclimatization at high altitude, many
      sympathetic pathways are hyperactive yet heart rate (HR) remains unchanged. In
      this study, we attempted to determine if this unchanged heart rate is due to
      compensatory mechanisms such as changes in parasympathetic activity or levels of
      receptors for autonomic neurotransmitters. We also examined the role played by
      hypoxia in these autonomic adaptations to high altitude. Three experiments were
      carried out on five healthy lowlanders both at sea level (SL) and after 2 weeks
      of acclimatization at 3800 m (Post-Ac) with: (a) placebo (control); (b) acute
      beta-adrenergic receptor blockade by propranolol (PRO), or (c) acute
      parasympathetic receptor blockade by glycopyrrolate (GLY). Compared with SL
      control values, post-Ac venous norepinephrine (NE) and dopamine increased by 96%
      (p < 0.001) and 55% (p < 0.05), but epinephrine and HR did not change. PRO
      resulted in a smaller decrease in HR (bpm) Post-Ac than at SL (15 +/- 6 vs. 21 +/
      6, p < 0.05), while GLY caused a greater increase in HR Post-Ac than at SL (59
      +/- 8 vs. 45 +/- 6, p < 0.05). Breathing oxygen at SL concentration while at
      altitude did not decrease NE, or alter the effect of PRO on HR, but reduced the
      chronotropic effect of GLY by 14% (p < 0.05). These results suggest that after
      acclimatization to altitude, increased parasympathetic neurotransmitter release
      and decreased beta-adenoreceptor activity account for the unchanged HR despite
      enhanced sympathetic activity. Acute oxygen replacement rapidly counteracted the
      parasympathetic, but not sympathetic hyperactivity that occurs at high altitude.

PMID- 12492137
TI  - Effects of aldehyde dehydrogenase-2 genotype on cardiovascular and endocrine
      responses to alcohol in young Japanese subjects.
AB  - The present study was designed to investigate the effects of aldehyde
      dehydrogenase-2 (ALDH2) genotype on cardiovascular and endocrine responses to
      alcohol ingestion in young, healthy Japanese subjects. For this purpose, we
      monitored changes in the electrocardiogram (ECG), blood pressure (BP), finger
      blood flow (BF) and facial skin temperature (FST) during and after alcohol
      ingestion (0.4 ml/kg body weight). Spectral analyses of beat-to-beat variations
      of heart rate (HR), BP and BF were applied. Two major spectral components were
      examined at low frequency (LF: 0.04-0.15 Hz) and high frequency (HF: 0.15-10.4
      Hz) bands for HR and BP variability (BPV). Significant effects for ALDH2 genotype
      were observed in HR variability (HRV) analysis; HF power of HRV was markedly
      depressed and the LF/HF ratio was significantly higher with alcohol in ALDH2
      deficient (ND) subjects, while ALDH2-normal (NN) subjects did not display such
      changes. Analysis of BP variability showed increased LF and HF power after
      alcohol ingestion in the NN subjects, but there were no significant differences
      between genotypic groups. We also examined BF variability (BFV) in six major
      spectral components; power of the 0.8-2.2 Hz frequency band was significantly
      affected by genotype and higher power was observed in the ND subjects. Plasma
      concentrations of both epinephrine and norepinephrine increased after alcohol
      ingestion only in the ND subjects. Furthermore, plasma concentrations and urinary
      excretion of epinephrine, but not norepinephrine, were higher after alcohol
      ingestion in the ND than in the NN subjects. Blood acetaldehyde levels were about
      10-fold higher in the ND than in the NN subjects although blood alcohol levels
      similarly increased in the ND and NN subjects. Our results also indicated that
      alcohol ingestion increased secretion of pituitary-adrenal hormones including
      ACTH, beta-endorphin and cortisol in the ND subjects. The present results along
      with previous studies suggest that alcohol-induced tachycardia in the ND subjects
      was probably mediated by acetaldehyde-induced rise in epinephrine secretion from
      the adrenal medulla and/or changes in the autonomic nervous system. Alcohol
      induced relative predominance of cardiac sympathetic activity in the ND subjects
      might be ascribed partly to increased norepinephrine secretion from sympathetic
      nerve terminals. Effects of acetaldehyde on these cardiovascular and endocrine
      systems were discussed in terms of their effects on the central nervous system.

PMID- 12492138
TI  - Physiologic assessment of autonomic dysfunction in pallidopontonigral
      degeneration with N279K mutation in the tau gene on chromosome 17.
AB  - Autonomic function was investigated in five affected and five at-risk members of
      a single kinship of pallidopontonigral degeneration (PPND), which is a
      progressive syndrome of parkinsonism and frontotemporal dementia resulting from a
      mutation in the N279K tau gene on chromosome 17. Affected subjects reported
      symptoms including hyperhidrosis, sialorrhea, urinary frequency or incontinence,
      thermal intolerance, male sexual dysfunction, lacrimation, and dryness of the
      eyes or mouth. None had orthostatic hypotension. Autonomic testing revealed mild
      to-moderate abnormalities in all five affected subjects and minor abnormalities
      in the three oldest, asymptomatic, at-risk subjects. Findings in affected
      subjects consisted of preganglionic sudomotor dysfunction in all five, impaired
      cardiovagal function in three, and reduced or absent pupillary near responses in
      four. Tests of adrenergic function were normal in all subjects. The degree of
      autonomic dysfunction correlated significantly with disease duration and with
      indices of disease severity. In conclusion, there is evidence in PPND of a
      disturbance in the central autonomic network.

PMID- 12492139
TI  - Sympathetic sudomotor skin activity in human after complete spinal cord injury.
AB  - Spinal cord injury (SCI) causes serious disturbances in autonomic innervation and
      malfunction of the sympathetic nervous system that controls the pelvic organs,
      blood pressure, skin temperature and sweating. We studied sympathetic sudomotor
      pathways in 6 healthy subjects and 14 patients with sensory and motor complete
      SCI on cervical, thoracic and lumbar level. Sympathetic skin responses (SSRs)
      were provoked by auditory bursts and electrical stimulation of median, pudendal
      and tibial nerve and recorded from the palmar and plantar skin. The SSRs in
      healthy subjects occurred generally with the same pattern and with similar
      latencies suggesting a common sudomotor pathway mediating the SSR. Appearance or
      absence of the SSRs in SCI following stimulation above the lesion depend on the
      spinal level of lesion and on the location of stimulation. Lesions below T3 show
      palmar and lesions below T12 palmar and plantar SSR. Pudendal nerve stimulation
      evoked plantar SSRs in patients with complete cervical and thoracic SCI. No SSRs
      were obtained in patients with lesions at L1 and more caudal. SSRs following
      pudendal nerve stimulation in complete SCI above the level L1 are mediated by
      sacral somatic afferents and a sympathetic pathway originating at the upper
      lumbar level. The underlying sacro-lumbar reflex circuit is organized on spinal
      level and requires intact lumbar segments. Tibial nerve stimulation was not found
      to elicit SSRs below a SCI lesion and we suppose that this type of electrical
      stimulation cannot activate the spinal sudomotor reflex circuit.

PMID- 12492140
TI  - Denervation of vagal cardiopulmonary receptors by injection of kainic acid into
      the nodose ganglia in dogs.
AB  - We determined if kainic acid, a neuroexcitotoxin, could be used to denervate the
      cell bodies of cardiopulmonary vagal sensory neurons. Kainic acid (5 microg) was
      injected into the nodose ganglion of five dogs. Ten to fourteen days following
      this procedure, these kainic acid-injected dogs were anesthetized and tested for
      the extent of the deafferentation. Five additional dogs were used as the control
      group. Heart rate and mean arterial pressure were measured, and a Swan-Ganz
      catheter was advanced into a branch of the pulmonary artery to measure pulmonary
      capillary wedge pressure. We recorded renal sympathetic nerve activity from
      branches of the left renal nerves. Bilateral carotid occlusion increased heart
      rate and mean arterial pressure in only the denervated group, but sympathetic
      nerve activity increased significantly in both groups. This demonstrates that the
      carotid baroreflex is preserved after kainic acid is injected into the nodose
      ganglia. Volume expansion by use of warmed saline (15 ml kg(-1)) increased
      pulmonary capillary wedge pressure 5 mm Hg in control and 14 mm Hg in denervated
      dogs. In control dogs, sympathetic nerve activity decreased by 10% per mm Hg
      increase in pulmonary capillary wedge pressure while in denervated dogs, it
      decreased by 2% per mm Hg. This demonstrates that the vagal cardiopulmonary
      baroreflex is essentially abolished after injection of kainic acid into the
      nodose ganglia. After opening the chest, acetylstrophanthidin 100 microg was
      applied directly to the epicardial surface of the left ventricle to activate
      cardiac vagal afferents. Epicardial acetylstrophanthidin decreased sympathetic
      nerve activity by 28% in the control group, but resulted in no change in the
      kainic-acid-injected dogs. This demonstrates that vagal cardiac chemosensitive
      reflexes are abolished after bilateral injection of kainic acid into the nodose
      ganglia. At the end of these experiments, we removed the nodose ganglia for
      histological evaluation. The vast majority of cell bodies in the ganglia from the
      denervated group appeared injured compared to cell bodies in ganglia that had not
      been injected, suggesting that the destruction of cell bodies of vagal afferents
      was responsible for the functional denervation. Our findings are consistent with
      the interpretation that kainic acid treatment interrupts vagal afferents that
      meditate reflex responses to epicardial acetylstrophanthidin and to volume
      expansion.

PMID- 12492141
TI  - Testing putative hemichordate homologues of the chordate dorsal nervous system
      and endostyle: expression of NK2.1 (TTF-1) in the acorn worm Ptychodera flava
      (Hemichordata, Ptychoderidae).
AB  - Recent phylogenetic investigations have confirmed that hemichordates and
      echinoderms are sister taxa. However, hemichordates share several cardinal
      characterstics with chordates and are thus an important taxon for testing
      hypotheses of homology between key chordate characters and their putative
      hemichordate antecedents. The chordate dorsal nervous system (DNS) and endostyle
      are intriguing characters because both hemichordate larval and adult structures
      have been hypothesized as homologues. This study attempts to test these purported
      homologies through examination of the expression pattem of a Ptychodera flava NK2
      gene, PfNK2.1, because this gene is expressed both in the DNS and
      endostyle/thyroid in a wide range of chordate taxa. We found that PfNK2.1 is
      expressed in both neuronal and pharyngeal structures, but its expression pattem
      is broken up into distinct embryonic and juvenile phases. During embryogenesis,
      PfNK2.1 is expressed in the apical ectoderm, with transcripts later detected in
      presumable neuronal structures, including the apical organ and ciliated feeding
      band. In the developing juvenile we detected PfNK2.1 signal throughout the
      pharynx, including the stomochord, and later in the hindgut. We conclude that the
      similar utilization of NK2.1 in apical organ development and chordate DNS is
      probably due to a more general role for NK2.1 in neurogenesis and that
      hemichordates do not possess a homologue of the chordate DNS. In addition, we
      conclude that P. flava most likely does not possess a true endostyle; rather
      during the evolution of the endostyle NK2.1 was recruited from its more general
      role in pharynx development.

PMID- 12492142
TI  - An amphioxus nodal gene (AmphiNodal) with early symmetrical expression in the
      organizer and mesoderm and later asymmetrical expression associated with left
      right axis formation.
AB  - The full-length sequence and zygotic expression of an amphioxus nodal gene are
      described. Expression is first detected in the early gastrula just within the
      dorsal lip of the blastopore in a region of hypoblast that is probably comparable
      with the vertebrate Spemann's organizer. In the late gastrula and early neurula,
      expression remains bilaterally symmetrical, limited to paraxial mesoderm and
      immediately overlying regions of the neural plate. Later in the neurula stage,
      all neural expression disappears, and mesodermal expression disappears from the
      right side. All along the left side of the neurula, mesodermal expression spreads
      into the left side of the gut endoderm. Soon thereafter, all expression is down
      regulated except near the anterior and posterior ends of the animal, where
      transcripts are still found in the mesoderm and endoderm on the left side. At
      this time, expression also begins in the ectoderm on the left side of the head,
      in the region where the mouth later forms. These results suggest that amphioxus
      and vertebrate nodal genes play evolutionarily conserved roles in establishing
      Spemann's organizer, patterning the mesoderm rostrocaudally and setting up the
      asymmetrical left-right axis of the body.

PMID- 12492144
TI  - Time, pattern, and heterochrony: a study of hyperphalangy in the dolphin embryo
      flipper.
AB  - The forelimb of whales and dolphins is a flipper that shows hyperphalangy
      (numerous finger bones). Hyperphalangy is also present in marine reptiles,
      including ichthyosaurs and plesiosaurs. The developmental basis of hyper-phalangy
      is unclear. Kukenthal suggested that phalanx anlagen split into three pieces
      during cetacean development, thereby multiplying the ancestral number.
      Alternatively, Holder suggested that apical ectodermal ridge (AER)-directed limb
      outgrowth might be prolonged by a timing shift (heterochrony), leading to
      terminal addition of extra phalanges. We prepared a series of whole mounted and
      serially sectioned embryonic flipper buds of the spotted dolphin Stenella
      attenuata. This cetacean shows marked hyperphalangy on digits II and III. We
      confirm previous reports that the proximodistal laying down of phalanges is
      prolonged in digits II and III. Histology showed that the apical ectoderm was
      thickened into a cap. There was a weak ridge-like structure in some embryos. The
      cap or ridge formed part of a bud-like mass that persisted on digits II and III
      at stages when it had disappeared from other digits. Thus the dolphin differs
      from other mammals in showing a second period of limb outgrowth during which
      localized hyperphalangy develops. New phalanges only formed at the tip of the
      digits. These findings are consistent with a model in which heterochrony leads to
      the terminal addition of new phalanges. Our results are more easily reconciled
      with the progress zone model than one in which the AER is involved in the
      expansion of a prepattern. We suggest that patterning mechanisms with a temporal
      component (i.e., the "progress zone" mechanism) are potential targets for
      heterochrony during limb evolution.

PMID- 12492143
TI  - A novel amphioxus cadherin that localizes to epithelial adherens junctions has an
      unusual domain organization with implications for chordate phylogeny.
AB  - Although data are available from only vertebrates, urochordates, and three
      nonchordate animals, there are definite differences in the structures of classic
      cadherins between vertebrates plus urochordates and nonchordates. In this study
      we examined structural diversity of classic cadherins among bilaterian animals by
      obtaining new data from an amphioxus (Cephalochordata, Chordata), an acorn worm
      (Hemichordata), a sea star (Echinodermata), and an oyster (Mollusca). The
      structures of newly identified nonchordate cadherins are grouped together with
      those of the known sea urchin and Drosophila cadherins, whereas the structure of
      an amphioxus (Branchiostoma belcheri) cadherin, designated BbC, is differently
      categorized from those of other known chordate cadherins. BbC is identified as a
      cadherin by its cytoplasmic domain whose sequence is highly related to the
      cytoplasmic sequences of all known classic cadherins, but it lacks all of the
      five repeats constituting the extracellular homophilic-binding domain of other
      chordate cadherins. The ectodomains of BbC match the ectodomains found in
      nonchordate cadherins but not present in other chordate cadherins. We show that
      the BbC functions as a cell-cell adhesion molecule when expressed in Drosophila
      S2 cells and localizes to adherens junctions in the ectodermal epithelia in
      amphioxus embryos. We argue that BbC is the amphioxus homologue of the classic
      cadherins involved in the formation of epithelial adherens junctions. The
      structural relationships of the cadherin molecules allow us to propose a
      possibility that cephalochordates might be basal to the sister-groups vertebrates
      and urochordates.

PMID- 12492145
TI  - Limbs in whales and limblessness in other vertebrates: mechanisms of evolutionary
      and developmental transformation and loss.
AB  - We address the developmental and evolutionary mechanisms underlying fore- and
      hindlimb development and progressive hindlimb reduction and skeletal loss in
      whales and evaluate whether the genetic, developmental, and evolutionary
      mechanisms thought to be responsible for limb loss in snakes "explain" loss of
      the hindlimbs in whales. Limb loss and concurrent morphological and physiological
      changes associated with the transition from land to water are discussed within
      the context of the current whale phylogeny. Emphasis is placed on fore- and
      hindlimb development, how the forelimbs transformed into flippers, and how the
      hindlimbs regressed, leaving either no elements or vestigial skeletal elements.
      Hindlimbs likely began to regress only after the ancestors of whales entered the
      aquatic environment: Hindlimb function was co-opted by the undulatory vertical
      axial locomotion made possible by the newly evolved caudal flukes. Loss of the
      hindlimbs was associated with elongation of the body during the transition from
      land to water. Limblessness in most snakes is also associated with adoption of a
      new (burrowing) lifestyle and was driven by developmental changes associated with
      elongation of the body. Parallels between adaptation to burrowing or to the
      aquatic environment reflect structural and functional changes associated with the
      switch to axial locomotion. Because they are more fully studied and to determine
      whether hindlimb loss in lineages that are not closely related could result from
      similar genetically controlled developmental pathways, we discuss developmental
      (cellular and genetic) processes that may have driven limb loss in snakes and leg
      less lizards and compare these processes to the loss of hindlimbs in whales. In
      neither group does ontogenetic or phylogenetic limb reduction result from failure
      to initiate limb development. In both groups limb loss results from arrested
      development at the limb bud stage, as a result of inability to maintain necessary
      inductive tissue interactions and enhanced cell death over that seen in limbed
      tetrapods. An evolutionary change in Hox gene expression--as occurs in snakes--or
      in Hox gene regulation--as occurs in some limbless mutants--is unlikely to have
      initiated loss of the hindlimbs in cetaceans. Selective pressures acting on a
      wide range of developmental processes and adult traits other than the limbs are
      likely to have driven the loss of hindlimbs in whales.

PMID- 12492146
TI  - Hox genes and the evolution of the arthropod body plan.
AB  - In recent years researchers have analyzed the expression patterns of the Hox
      genes in a multitude of arthropod species, with the hope of understanding the
      mechanisms at work in the evolution of the arthropod body plan. Now, with Hox
      expression data representing all four major groups of arthropods (chelicerates,
      myriapods, crustaceans, and insects), it seems appropriate to summarize the
      results and take stock of what has been learned. In this review we summarize the
      expression and functional data regarding the 10 arthropod Hox genes: labial
      proboscipedia, Hox3/zen, Deformed, Sex combs reduced, fushi tarazu, Antennapedia,
      Ultrabithorax, abdominal-A, and Abdominal-B. In addition, we discuss mechanisms
      of developmental evolutionary change thought to be important for the emergence of
      novel morphological features within the arthropods.

PMID- 12492147
TI  - Site-specific lipophilic modification of interferon-alpha.
AB  - Interferon-alpha (IFNalpha), a cytokine with modulatory activities on many cell
      types, is useful for treating many types of cancer and infectious diseases. This
      study investigates whether modification of a protein, using IFNalpha as an
      example, with a lipophilic group can alter its distribution and kinetic
      properties in the body. Ser163 of IFNalpha2a was mutated to Cys to generate a
      free sulfhydryl group for site-specific chemical modification. IFNalpha2a(S163C)
      was conjugated by iodoacetamide derivatives of varying lengths, and the modified
      IFNalpha2a was purified by gel filtration chromatography. The biological
      activities of IFNalpha2a(S163C) and lipophilized IFNalpha2a(S163C) were similar
      to that of IFNalpha2a, as evidenced by their inhibitory effects on the growth of
      Daudi cells and on the replication of vesicular stomatitis virus in Madin-Darby
      bovine kidney cells. Lipophilized IFNalpha2a(S163C) bound to human serum albumin
      and cell membranes more readily than did IFNalpha2a. Future experiments will
      investigate whether lipophilized IFNalpha2a(S163C) has improved pharmacokinetic
      properties.

PMID- 12492148
TI  - Activation of dynamin II by POPC in giant unilamellar vesicles: a two-photon
      fluorescence microscopy study.
AB  - The interaction of dynamin II with giant unilamellar vesicles was studied using
      two-photon fluorescence microscopy. Dynamin II, labeled with fluorescein, was
      injected into a microscope chamber containing giant unilamellar vesicles, which
      were composed of either pure 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
      (POPC) or a mixture of POPC and phosphatidylinositol 4,5-bisphosphate
      (PI(4,5)P2). Binding of the fluorescent dynamin II to giant unilamellar vesicles,
      in the presence and absence of PI(4,5)P2, was directly observed using two-photon
      fluorescence microscopy. This binding was also visualized using the fluorescent N
      methylanthraniloyl guanosine 5'-[gamma-thio]triphosphate analogue. The membrane
      probe 6-dodecanoyl-2-dimethylamine-naphthalene was used to monitor the physical
      state of the lipid in the giant unilamellar vesicles in the absence and presence
      of dynamin. A surprising finding was the fact that dynamin II bound to vesicles
      in the absence of PI(4,5)P2. Activation of the GTPase activity of dynamin II by
      pure POPC was then shown.

PMID- 12492149
TI  - Evaluation by site-directed mutagenesis of active site amino acid residues of
      Anaerobiospirillum succiniciproducens phosphoenolpyruvate carboxykinase.
AB  - Anaerobiospirillum succiniciproducens phosphoenolpyruvate (PEP) carboxykinase
      catalyzes the reversible formation of oxaloacetate and adenosine triphosphate
      from PEP, adenosine diphosphate, and carbon dioxide, and uses Mn2+ as the
      activating metal ion. The enzyme is a monomer and presents 68% identity with
      Escherichia coli PEP carboxykinase. Comparison with the crystalline structure of
      homologous E. coli PEP carboxykinase [Tari, L. W., Matte, A., Goldie, H., and
      Delbaere, L. T. J. (1997). Nature Struct. Biol. 4, 990-994] suggests that His225,
      Asp262, Asp263, and Thr249 are located in the active site of the protein,
      interacting with manganese ions. In this work, these residues were individually
      changed to Gln (His225) or Asn. The mutated enzymes present 3-6 orders of
      magnitude lower values of Vmax/Km, indicating high catalytic relevance for these
      residues. The His225Gln mutant showed increased Km values for Mn2+ and PEP as
      compared with wild-type enzyme, suggesting a role of His225 in Mn2+ and PEP
      binding. From 1.5-1.6 Kcal/mol lower affinity for the 3'(2')-O-(N
      methylantraniloyl) derivative of adenosine diphosphate was observed for the
      His225Gln and Asp263Asn mutant A. succiniciproducens PEP carboxykinases, implying
      a role of His225 and Asp263 in nucleotide binding.

PMID- 12492150
TI  - Effect of a zwitterionic surfactant (HPS) on the conformation and hemolytic
      activity of St I and St II, two isotoxins purified from Stichodactyla helianthus.
AB  - N-hexadecyl-N-N'-dimethyl-3-ammonio-1-propane-sulfonate (BPS) is a zwitterionic
      surfactant that readily binds to sticholysins I and II, two sea toxins isolated
      from Stichodactyla helianthus. The binding constants, evaluated from changes in
      fluorescence intensities elicited by the surfactant, are approximately 0.5-0.7
      microM(-1). The binding of the surfactant changes the conformation of the
      tertiary protein, without significant changes in its secondary structure, as
      reported from far-ultraviolet circular dichroism spectra. The changes elicited by
      HPS lead to loss of the native conformation (as reported from near-ultraviolet
      circular dichroism spectra) and to a shift of the intrinsic protein fluorescence
      toward longer wavelengths, an increase in fluorescence intensities and lifetimes,
      and a faster quenching by acrylamide. All these changes are indicative of a more
      expanded tertiary conformation. Despite this, the toxins fully retain their
      hemolytic activities, indicating that spectroscopic changes can be poor
      predictors of toxin activity.

PMID- 12492151
TI  - Identification of phospholipase D from cabbage as N-terminally acetylated PLD2.
AB  - Recently, the genes of two isoenzymes of phospholipase D from white cabbage (PLD1
      and PLD2) with molecular masses of 91.7 and 91.9 kDa, respectively, have been
      sequenced and expressed in Escherichia coli [Schaffner, I., Rucknagel, K.-P.,
      Mansfeld, J., and Ulbrich-Hofmann, R. (2002). Eur. J. Lipid Sci. Technol. 104: 79
      87]. Both enzymes are highly homologous (91% identity) and behave very similarly.
      Phospholipase D purified from white cabbage leaves (PLDcab) is compared with the
      two recombinant enzymes in sodium dodecylsulfate and native polyacrylamide gel
      electrophoresis, isoelectric focusing, N-terminal sequencing, and mass
      spectrometry after tryptic digestion. As a result, PLDcab clearly can be assigned
      to PLD2. In contrast to recombinant PLD2, however, PLDcab is N-terminally
      acetylated.

PMID- 12492152
TI  - Purification and characterization of the fusion protein trypsin-streptavidin
      expressed in Escherichia coli.
AB  - Expression of fusion protein trypsin-streptavidin (TRYPSA) in Escherichia coli
      was evaluated and the protein purified. Protein expression was induced by 1 mM
      isopropylthio-beta-D-galactoside (IPTG), and the enzyme activity was measured by
      the hydrolysis rate of p-toluenesulfonyl-L-arginine methyl ester (TAME).
      Expression of the fusion protein in the cell-free extract decreased with
      increased induction time; correspondingly, that in the inclusion bodies
      increased. The total expression in Luria-Bertani broth (LB) and Terrific Broth
      (TB) media reached the highest levels in 2 hr at 30 degrees C. The optimum
      expression level was 35 and 48 U/L in LB and TB, respectively. Expression of the
      fusion protein was verified by Western Blot analysis using streptavidin
      antiserum, and the fusion protein was purified using a benzamidine Sepharose 6B
      affinity column at room temperature. The molecular size of the soluble purified
      fusion protein was determined by size-exclusion chromatography using Superose 12
      FPLC. A molecular weight of 39-40 kDa was obtained, indicating that the soluble
      protein exists as a monomer; thus, the presence of the trypsin domain must
      prevent the streptavidin domain from tetramer formation.

PMID- 12492153
TI  - Increased expression and secretion of recombinant alpha-amylase in Saccharomyces
      cerevisiae by using glycerol as the carbon source.
AB  - Saccharomyces cerevisiae transformed with plasmids containing the barley alpha
      amylase gene was cultured, and enzyme activity and cell density were monitored at
      various time intervals. Proteins in yeast extract and culture medium were
      analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).
      Western blots of intra- and extracellular proteins were sequentially probed with
      anti-amylase antibody and anti-rabbit horseradish peroxidase conjugate, followed
      by chemiluminescent detection. The enzyme activity of recombinant barley alpha
      amylase secreted by the yeast clone DY150[pYEX-Amyl] showed a significant
      increase when the culture medium included glycerol as the carbon source. The
      enhancement reached a 4.5-fold increase at 120 hr, and the effect was strain
      nonspecific. Intra- and extracellular proteins increased significantly with time
      in both the yeast clone and the control grown in YEPG (2% yeast extract, 1% bacto
      peptone, 2% glycerol). Proteins in YEPD (2% yeast extract,1% bacto-peptone, 2%
      glucose) and YEPG cultures showed very different band patterns, indicating that
      the metabolic pathway was altered. Western blot analysis indicated that the
      recombinant amylase accumulated inside yeast cells, at a relatively low level,
      compared with that in the culture medium. The transcript level of the alpha
      amylase gene was significantly increased in the clone cultured in YEPG. This
      investigation demonstrates that the use of glycerol as a carbon source for S.
      cerevisiae enhances the synthesis and secretion of the recombinant enzyme while
      suppressing cell growth.

PMID- 12492154
TI  - Aggregate formation and the structure of the aggregates of disulfide-reduced
      proteins.
AB  - Aggregate formation and the structure of the aggregates of disulfide-reduced
      proteins were investigated using alpha-lactalbumin and lysozyme as model
      proteins. First, reducing conditions were adjusted so that only one of the four
      disulfide bonds present in each native protein was cleaved. These three-disulfide
      (3SS) proteins are known to adopt almost native conformations, yet formed
      precipitates with a basic peptide, lactoferricin, and heparin and heparin
      fragment, respectively, at concentrations at which native proteins mixed with
      these compounds remained clear. The 3SS-lysozyme also formed precipitates in the
      absence of these ligands. Thus, subtle structural changes could lead to
      aggregation. Electron microscopy revealed fibrillar structures in the aggregates
      of extensively reduced proteins in the absence of ligands but not in their
      presence, which shows that the reduction of disulfide bonds suffices for fibril
      formation and that ligands inhibit fibril formation.

PMID- 12492155
TI  - Why particles?

PMID- 12492156
TI  - Chapter one: exposure measurements.
AB  - Determining human exposure to suspended particulate concentrations requires
      measurements that quantify different particle properties in microenvironments
      where people live, work, and play. Particle mass, size, and chemical composition
      are important exposure variables, and these are typically measured with time
      integrated samples on filters that are later submitted to laboratory analyses.
      This requires substantial sample handling, quality assurance, and data reduction.
      Newer technologies are being developed that allow in-situ, time-resolved
      measurements for mass, carbon, sulfate, nitrate, particle size, and other
      variables. These are large measurement systems that are more suitable for fixed
      monitoring sites than for personal applications. Human exposure studies need to
      be designed to accomplish specific objectives rather than to serve too many
      purposes. Resources need to be divided among study design, field sampling,
      laboratory analysis, quality assurance, data management, and data analysis
      phases. Many exposure projects allocated too little to the non-measurement
      activities.

PMID- 12492157
TI  - Chapter two: methodologies for characterisation of combustion sources and for
      quantification of their emissions.
AB  - Emissions from the combustion of biomass and fossil fuels result in generation of
      a large number of particle and gaseous products in outdoor and/or indoor air,
      which create health and environmental risks. Of particular importance are the
      very small particles that are emitted in large quantities from all the combustion
      sources, and that could be potentially more significant in terms of their impact
      on health and the environment than larger particles. It is important to quantify
      particle emissions from combustion sources for regulatory and control purposes in
      relation to air quality. This paper is a review of particle characteristics that
      are used as source signatures, their general advantages and limitations, as well
      as a review of source signatures of the most common combustion pollution sources
      including road transport, industrial facilities, small household combustion
      devices, environmental tobacco smoke, and vegetation burning. The current methods
      for measuring particle physical characteristics (mass and number concentrations)
      and principles of methodologies for measuring emission factors are discussed in
      the paper as well. Finally, the paper presents the recommendations for the future
      techniques for measurements of combustion products.

PMID- 12492158
TI  - Chapter three: methodology of exposure modeling.
AB  - In this chapter, the concept of exposure assessment and its evolution is
      introduced, and evaluated by critically appraising the pertinent literature as it
      applies to exposures to Particulate Matter (PM). Exposure measurement or
      estimation methodologies and models are reviewed. Three exposure/measurement
      methodologies are assessed. Estimation methods focus on source evaluation and
      attribution, sources include those outdoors and indoors as well as in
      occupational and in-transit environments. Fate and transport models and their
      inputs are addressed to estimate concentrations outdoors and indoors; source
      attribution techniques help focus on the contributing sources. Activity pattern
      techniques are also reviewed and their use in exposure models to estimate
      inhalation exposure to PM is presented. Deterministic, regression and other
      stochastic models of exposure to PM are reviewed and evaluated. Strengths,
      limitations, assumptions and affirmations of the use of exposure assessment as an
      integral component of risk assessment and risk management are discussed in the
      conclusions and discussions section of this work.

PMID- 12492159
TI  - Policy uses of particulate exposure estimates.
AB  - This paper reviews the uses of particulate exposure estimates for science and
      policy. We propose a set of normative factors to guide the selection and
      application of various approaches for exposure assessment. For exposure estimates
      intended for use in support of the development or air pollution regulations or
      selection of control strategies, the proposed criteria include--compatibility
      with policy scope and scale, cost-effectiveness, characterization of uncertainty,
      political and institutional feasibility, and sensitivity to framing. For exposure
      assessment in support of epidemiological research, key criteria are-compatability
      with the specific hypothesis being tested, and compatibility with the temporal
      and spatial scale of analysis. The various major approaches for estimation of
      exposure--direct and indirect measurement, empirical and physical modeling--are
      catalogued and compared with these proposed criteria.

PMID- 12492160
TI  - Designing monitoring networks to represent outdoor human exposure.
AB  - Measurements of outdoor human exposure to suspended particulate matter (PM) are
      always constrained by available resources. An effective network design requires
      tradeoffs between variables measured, the number of sampling locations, sample
      duration, and sampling frequency. Sampling sites are needed to represent
      neighborhood and urban spatial scales with minimal influences from nearby
      sources. Although most PM measurements for determining compliance with standards
      are taken over 24-h periods every third to sixth day, outdoor human exposure
      assessment requires measurements taken continuously throughout the day,
      preferably over durations of 1 h or less. More detailed particle size and
      chemistry data are also desirable, as smaller size fractions and specific
      chemicals may be better indicators of adverse health effects than total mass
      samples.

PMID- 12492161
TI  - Methods for collecting time/activity pattern information related to exposure to
      combustion products.
AB  - Focus groups, surveys and questionnaires, diaries and observations can be used to
      gather information about people's exposure to a wide range of combustion
      products. Information about locations and durations of exposure, and sources of
      exposure can be obtained with these instruments. The types of instruments used
      must be fine tuned to meet the design characteristics of the community in which
      the study will be conducted.

PMID- 12492162
TI  - Fine PM measurements: personal and indoor air monitoring.
AB  - This review compiles personal and indoor microenvironment particulate matter (PM)
      monitoring needs from recently set research objectives, most importantly the NRC
      published "Research Priorities for Airborne Particulate Matter (1998)".
      Techniques and equipment used to monitor PM personal exposures and
      microenvironment concentrations and the constituents of the sampled PM during the
      last 20 years are then reviewed. Development objectives are set and discussed for
      personal and microenvironment PM samplers and monitors, for filter materials, and
      analytical laboratory techniques for equipment calibration, filter weighing and
      laboratory climate control. The progress is leading towards smaller sample flows,
      lighter, silent, independent (battery powered) monitors with data logging
      capacity to store microenvironment or activity relevant sensor data, advanced
      flow controls and continuous recording of the concentration. The best filters are
      non-hygroscopic, chemically pure and inert, and physically robust against
      mechanical wear. Semiautomatic and primary standard equivalent positive
      displacement flow meters are replacing the less accurate methods in flow
      calibration, and also personal sampling flow rates should become mass flow
      controlled (with or without volumetric compensation for pressure and temperature
      changes). In the weighing laboratory the alternatives are climatic control (set
      temperature and relative humidity), and mechanically simpler thermostatic
      heating, air conditioning and dehumidification systems combined with numerical
      control of temperature, humidity and pressure effects on flow calibration and
      filter weighing.

PMID- 12492163
TI  - Monitoring of particulate matter outdoors.
AB  - Recent studies of the size and composition of atmospheric particulate matter (PM)
      have demonstrated the usefulness of separating atmospheric PM into its fine and
      coarse components. The need to measure the mass and composition of fine and
      coarse PM separately has been emphasized by research in exposure, epidemiology,
      and toxicology of atmospheric PM. This paper provides a background on the size
      distribution and properties of PM relevant to the differences between fine and
      coarse particles. Various decisions that must be made when deciding how to
      separate, collect, and measure PM are discussed. Techniques for monitoring fine
      and coarse particles, including the US Federal Reference Method for PM2.5 and
      several techniques for PM10-2.5, are presented. Problems encountered in
      collecting semivolatile PM and in weighing atmospheric PM collected on a filter
      are described. Continuous monitoring methods for PM mass and for PM components
      (carbon, nitrate, and sulfate) are described and brief descriptions are given of
      analytical techniques for the chemical characterization of collected PM. This
      information should be especially useful for environmental workers familiar with
      monitoring methods for total suspended particles or PM10 but who will need to
      measure PM2, and PM10-2.5 in the future.

PMID- 12492164
TI  - Combustion sources of particles. 1. Health relevance and source signatures.
AB  - Combustion processes result in generation of a large number of particle and
      gaseous products that create health and environmental risks. Of particular
      importance are the very small particles that are emitted in large quantities from
      all the combustion sources, and that have been shown to be potentially more
      significant in terms of their impact on health than larger particles. To control
      and mitigate the particles with a view of health and environmental risk
      reduction, a good understanding is necessary of the relative and absolute
      contribution from the emission sources to the airborne concentrations. This
      understanding could only be achieved by developing source signature libraries
      through direct emission measurements from the sources on one hand, and by
      measuring particle concentrations in the air, and apportioning them to the
      specific local and distant sources using the signatures, on the other hand. This
      paper is a review of particle characteristics that are used as source signatures
      as well as their general advantages and limitations. The second part of the paper
      reviews source signatures of the most common combustion pollution sources.

PMID- 12492165
TI  - Combustion sources of particles: 2. Emission factors and measurement methods.
AB  - Emissions from the combustion of biomass and fossil fuels are a significant
      source of particulate matter (PM) in ambient outdoor and/or indoor air. It is
      important to quantify PM emissions from combustion sources for regulatory and
      control purposes in relation to air quality. In this paper, we review emission
      factors for several types of important combustion sources: road transport,
      industrial facilities, small household combustion devices, environmental tobacco
      smoke, and vegetation burning. We also review current methods for measuring
      particle physical characteristics (mass and number concentrations) and principles
      of methodologies for measuring emission factors. The emission factors can be
      measured on a fuel-mass basis and/or a task basis. Fuel-mass based emission
      factors (e.g., g/kg of fuel) can be readily used for the development of emission
      inventories when the amount of fuels consumed are known. Task-based emission
      factors (g/mile driven, g/MJ generated) are more appropriate when used to conduct
      comparisons of air pollution potentials of different combustion devices. Finally,
      we discuss major shortcomings and limitations of current methods for measuring
      particle emissions and present recommendations for development of future
      measurement techniques.

PMID- 12492166
TI  - Exposure efficiency: an idea whose time has come?
AB  - Exposure efficiency, the fraction of material released from a source that is
      eventually inhaled or ingested, is arguably the simplest of all possible
      descriptions of the link between pollutant emissions and population exposures.
      This paper, prepared in late 1999 for the SGOMSEC Workshop, notes that several
      groups of researchers independently developed the concept of exposure efficiency
      in the late 1980s and early 1990s but argues that the potential importance of
      exposure efficiency in risk analysis and life cycle assessment has only recently
      been appreciated. The paper reviews the history of the concept; discusses and
      summarizes previous estimates of exposure efficiency for particulate matter and
      other air pollutants; presents new values for fine particulate matter emitted
      from power plants and mobile sources in the United States; and illustrates how
      preliminary estimates of exposure efficiency might be developed. The authors
      assert that in order for the concept of exposure efficiency to achieve its full
      potential exposure efficiency estimates for a wide variety of pollutants and
      sources must be developed and that both the results and methods must be made
      widely available and accessible to the community of risk assessors and life cycle
      analysts.

PMID- 12492168
TI  - Modeling exposure to particulate matter.
AB  - Exposure assessment, a component of risk assessment, links sources of pollution
      with health effects. Exposure models are scientific tools used to gain insights
      into the processes affecting exposure assessment. The purpose of this paper is to
      review the process and methodology of estimating inhalation exposure to
      particulate matter (PM) using various types of models. Three types of models are
      discussed in the paper. Indirect type of models are physical models that employ
      inventories of outdoor and indoor sources and their emission rates to identify
      major sources contributing to exposure to PM, and use fate and transport and
      indoor air quality models to estimate PM concentrations at receptor sites. PM
      concentrations and time spent by a subject at each receptor site are input
      variables to the conventional exposure model that estimates the desired exposure
      levels. Direct type models use measured exposure or exposure concentrations in
      conjunction with information obtained from questionnaires to formulate exposure
      regression models. Stochastic models use exposure measurements, estimates can
      also be used, to formulate exposure population distributions and investigate
      associated uncertainty and variability. Since models developed using databases
      from western countries are not necessarily applicable in developing countries,
      the difference in requirements among western and developing countries is
      highlighted in the paper. Employment of exposure modeling methods in developing
      countries requires development of local information. Such information includes
      local outdoor and indoor source inventories, local or regional meteorological
      conditions, adjustment of indoor models to reflect local building construction
      conditions, and use of questionnaires to obtain local time budget and activity
      patterns of the subject population.

PMID- 12492167
TI  - Receptor modeling application framework for particle source apportionment.
AB  - Receptor models infer contributions from particulate matter (PM) source types
      using multivariate measurements of particle chemical and physical properties.
      Receptor models complement source models that estimate concentrations from
      emissions inventories and transport meteorology. Enrichment factor, chemical mass
      balance, multiple linear regression, eigenvector. edge detection, neural network,
      aerosol evolution, and aerosol equilibrium models have all been used to solve
      particulate air quality problems, and more than 500 citations of their theory and
      application document these uses. While elements, ions, and carbons were often
      used to apportion TSP, PM10, and PM2.5 among many source types, many of these
      components have been reduced in source emissions such that more complex
      measurements of carbon fractions, specific organic compounds, single particle
      characteristics, and isotopic abundances now need to be measured in source and
      receptor samples. Compliance monitoring networks are not usually designed to
      obtain data for the observables, locations, and time periods that allow receptor
      models to be applied. Measurements from existing networks can be used to form
      conceptual models that allow the needed monitoring network to be optimized. The
      framework for using receptor models to solve air quality problems consists of:
      (1) formulating a conceptual model; (2) identifying potential sources; (3)
      characterizing source emissions; (4) obtaining and analyzing ambient PM samples
      for major components and source markers; (5) confirming source types with
      multivariate receptor models; (6) quantifying source contributions with the
      chemical mass balance; (7) estimating profile changes and the limiting precursor
      gases for secondary aerosols; and (8) reconciling receptor modeling results with
      source models, emissions inventories, and receptor data analyses.

PMID- 12492169
TI  - Accessible tools for classification of exposure to particles.
AB  - In this manuscript we describe various alternative tools to estimate exposure to
      particles. We stress methods that are cost effective and widely available to
      those throughout the world. The use of surrogate measures arises from the need to
      estimate exposures of large populations where individual measurements are not
      feasible, for predictive modeling or to assess exposures rapidly before personal
      monitoring campaigns can be implemented. In addition, an understanding of the
      relationship between exposures and surrogate variables can be useful in helping
      to identify mitigation strategies to reduce exposures. We have separated the
      various alternative exposure measures by the scales of impact, describing
      approaches to assess regional, urban and household indoor air quality. In
      particular, we emphasize scenarios that are relevant to particle exposures that
      may be experienced in developing countries as a result of domestic energy use for
      cooking and heating. In all cases the approaches we describe are applicable to
      large populations as the data collection techniques are relatively inexpensive
      and specifically applicable on a population basis for risk assessment,
      epidemiology or to evaluate determinants of exposure and health outcomes. The
      ultimate use of the assessed exposures will determine the relevance of potential
      surrogate measures.

PMID- 12492170
TI  - Evolution of particulate regulation in China--prospects and challenges of
      exposure-based control.
AB  - China's urban and rural populations face very serious health risks from
      combustion particles. Major sources of exposure to inhalable particulates include
      the burning solid fuels (biomass and coal) for household cooking and heating,
      coal-fired industrial and residential boilers, tobacco smoking, and diesel motor
      vehicles. China began to address particulate pollution problems over 25 years ago
      and has implemented a series of progressively more aggressive policies. This
      paper reviews the successes and limitations of past and existing policies for
      particulate controls, as well as the effects of China's economic reforms and
      energy policies on particulate exposure and pollution management. We examine the
      challenge of emissions reporting, required as part of both China's pollution levy
      system and emerging system for "total emissions control." Finally, we discuss
      practical steps toward exposure-based regulation of particulates, which would
      take advantage of the high cost-effectiveness for lifesaving of controlling
      particulate exposure from household and neighborhood sources relative to that of
      controlling exposure from industrial sources.

PMID- 12492171
TI  - Indian aerosols: present status.
AB  - This article presents the status of aerosols in India based on the research
      activities undertaken during last few decades in this region. Programs, like
      International Geophysical Year (IGY), Monsoon Experiment (MONEX), Indian Middle
      Atmospheric Program (IMAP) and recently conducted Indian Ocean Experiment
      (INDOEX), have thrown new lights on the role of aerosols in global change. INDOEX
      has proved that the effects of aerosols are no longer confined to the local
      levels but extend at regional as well as global scales due to occurrence of long
      range transportation of aerosols from source regions along with wind
      trajectories. The loading of aerosols in the atmosphere is on rising due to
      energy intensive activities for developmental processes and other anthropogenic
      activities. One of the significant observation of INDOEX is the presence of high
      concentrations of carbonaceous aerosols in the near persistent winter time haze
      layer over tropical Indian Ocean which have probably been emitted from the
      burning of fossil-fuels and biofuels in the source region. These have significant
      bearing on the radiative forcing in the region and, therefore, have potential to
      alter monsoon and hydrological cycles. In general, the SPM concentrations have
      been found to be on higher sides in ambient atmosphere in many Indian cities but
      the NOx concentrations have been found to be on lower side. Even in the haze
      layer over Indian Ocean and surrounding areas, the NOx concentrations have been
      reported to be low which is not conducive of O3 formation in the haze/smog layer.
      The acid rain problem does not seem to exist at the moment in India because of
      the presence of neutralizing soil dust in the atmosphere. But the high
      particulate concentrations in most of the cities' atmosphere in India are of
      concern as it can cause deteriorated health conditions.

PMID- 12492172
TI  - Rational selection of oral 5-aminosalicylate formulations and prodrugs for the
      treatment of ulcerative colitis.

PMID- 12492173
TI  - The variable stiffness colonoscope: a scope for all seasons?

PMID- 12492174
TI  - Predictors of turnover of lower gastrointestinal symptoms in diabetes mellitus.

PMID- 12492175
TI  - Meet Sarah--a vignette of autoimmune hepatitis and pregnancy.

PMID- 12492176
TI  - Management of peptic ulcer disease not related to Helicobacter pylori or NSAIDs.
AB  - Helicobacter pylori (H. pylori) infection is widely accepted as the most
      important factor in the pathogenesis of duodenal ulcer. However, in parallel with
      more effective eradication of H. pylori, the prevalence of H. pylori is changing,
      and H. pylori-negative peptic ulcer disease appears to be increasing. When making
      a diagnosis of H. pylori-negative peptic ulcer disease, it is essential to avoid
      misclassification because of inaccurate diagnosis. In addition, secondary causes
      may need to be excluded with appropriate investigations. In the absence of H.
      pylori, nonsteroidal anti-inflammatory drug usage is the most common cause of
      peptic ulcer; surreptitious nonsteroidal anti-inflammatory drug usage is a cause
      of unexplained ulcer disease in up to 60% of patients. Hypersecretory syndromes
      such as Zollinger-Ellison syndrome, although rare, need to be excluded. Once all
      known etiological factors are excluded, there remains a group of patients with so
      called "idiopathic ulcers." The interplay of etiological factors in the
      pathogenesis of idiopathic peptic ulcer disease is poorly defined but may include
      a genetic predisposition, altered acid secretion, rapid gastric emptying,
      defective mucosal defense mechanisms, psychological stress, and smoking. The
      management of idiopathic peptic ulcers is not defined; they appear to be more
      resistant to standard therapy, can be associated with more frequent
      complications, and those that relapse may require long-term maintenance therapy.

PMID- 12492177
TI  - Infliximab in the treatment of Crohn's disease: a user's guide for clinicians.
AB  - Induction therapy with infliximab is indicated for treatment of signs and
      symptoms, and induction and maintenance of remission in patients with moderate to
      severely active inflammatory Crohn's disease with an inadequate response to
      conventional therapy, and for reduction in the number of draining fistulas in
      patients with fistulizing Crohn's disease. Emerging indications for infliximab
      therapy in patients with Crohn's disease include maintenance of fistula
      improvement (reduction in the number of draining perianal or enterocutaneous
      fistulas) and complete fistula response (no draining fistulas) in patients with
      fistulizing Crohn's disease, steroid sparing in steroid-treated patients, early
      use in hospitalized patients who have not failed conventional medical therapy
      where there is either a severe clinical presentation or a rapid onset of action
      is desired, and in a variety of unusual and extra-intestinal manifestations of
      Crohn's disease. An infliximab dose of 5 mg/kg is recommended initally, but some
      patients who require maintenance dosing may benefit from increasing the
      infliximab dose over a range of 5-10 mg/kg. An induction regimen of 3 doses at 0,
      2, and 6 weeks is the preferred dosing strategy for inducing remission. The
      optimal dosing interval for patients who require retreatment appears to be every
      8 weeks for most patients. Concomitant immunosuppressive therapy with
      azathioprine, 6-mercaptopurine, or methotrexate may result in improved outcomes
      due to a reduction in the frequency of human anti-chimeric antibody formation,
      acute infusion reactions, and a reduced risk of delayed hypersensitivity-like
      reactions and formation of antinuclear antibodies. Pretreatment with
      diphenhydramine (and in selected cases of acetaminophen and, rarely,
      corticosteroids) is recommended in patients with a history of infusion reactions
      and patients at risk for delayed hypersensitivity-like reactions. Patients with
      evidence of active infection should not receive infliximab until the infection is
      adequately treated, and all patients should be screened for tuberculosis prior to
      initiating infliximab therapy.

PMID- 12492178
TI  - Portal Hypertensive gastropathy.
AB  - Portal hypertensive gastropathy (PHG), a term used to describe the endoscopic
      appearance of gastric mucosa with a characteristic mosaic-like pattern with or
      without red spots, is a common finding in patients with portal hypertension.
      Current classification systems that describe the severity of PHG have many
      limitations, but it appears that simple grading systems have better inter- and
      intraobserver agreement. The wide variation in the reported prevalence of PHG is
      probably related to selection bias, absence of uniform criteria and
      classification, and more importantly, the differences in inter- and intraobserver
      variation. Pathogenesis of PHG is not clearly defined, but there is a very close
      relationship between portal hypertension and development of PHG. GAVE is a
      separate entity from PHG, but patients with severe PHG may have a GAVE-like
      appearance in the gastric antrum. Acute bleeding from PHG, seen usually in the
      presence of severe PHG, is often mild and self-limiting. Currently, the only
      treatment that could be recommended for prophylaxis of bleeding from PHG is
      nonselective B-blockers.

PMID- 12492179
TI  - Prevalence of mabDAS-1 positivity in biopsy specimens from the esophagogastric
      junction.
AB  - OBJECTIVE: Intestinal metaplasia (IM) is a precursor for malignancies at the
      esophagogastric junction. A monoclonal antibody, mAbDAS-1, can probably identify
      cellular characteristics of IM before the appearance of goblet cells. The aim of
      this study was to examine the prevalence of mAbDAS-1 positivity in biopsies from
      the squamocolumnar junction (SCJ) and to correlate this positivity with the
      presence of IM and clinical findings. METHODS: In 559 patients, reflux symptoms
      were scored, and the presence of reflux esophagitis and hiatus hernia was
      evaluated during endoscopy. Two biopsy specimens were obtained from the SCJ. In a
      subset of patients (n = 99), biopsies from the endoscopically defined cardiac
      region (2 cm distal to proximal margin of gastric folds) were available. Biopsy
      specimens were stained with hematoxylin and eosin, Alcian Blue, modified Giemsa,
      and mAbDAS-1. RESULTS: mAbDAS-1 positivity was observed in the SCJ biopsies of
      201 of 486 (41.4%) patients without IM and in 64 of 73 (87.7%) patients with IM.
      Patients without IM but with antibody positivity showed similar histological
      characteristics as patients with IM at the SCJ. Biopsies of 123 of 559 patients
      (22%) revealed a columnar-cuboidal epithelium, which was found to be mAbDAS-1
      positive in 64.2% (77 of 123). Tissue specimens from the cardiac region without
      IM stained positive in 14.2% (13 of 91), 12 of those also stained at the SCJ.
      CONCLUSIONS: In patients without IM, a high prevalence of mAbDAS-1 positivity was
      observed. Biopsies of these patients showed similar histological characteristics
      as patients with IM. Although not all patients exhibiting this reactivity may
      develop IM, mAbDAS-1 reactivity may help in the understanding of the histogenesis
      of IM at the SCJ.

PMID- 12492180
TI  - Esophageal pneumatic dilation for postfundoplication dysphagia: safety, efficacy,
      and predictors of outcome.
AB  - OBJECTIVE: Persistent dysphagia occurs in 5-10% of patients after fundoplication.
      The cause is obscure in most cases, and the management has not been well
      established. The aim of this study is to evaluate the clinical outcomes and the
      predictors of success for esophageal pneumatic dilations in patients with
      dysphagia after fundoplication. METHODS: We retrospectively reviewed 14 patients
      who underwent pneumatic dilation for persistent postfundoplication dysphagia. All
      patients had esophageal manometry before dilations. RESULTS: There were nine
      responders to pneumatic dilations (30-40-mm balloons). The nadir lower esophageal
      sphincter (LES) relaxation pressure was the only significant predictor for
      successful dilation and was higher among the responders than nonresponders
      (median 10 mm Hg vs 5 mm Hg). All six of 14 patients with nadir LES pressure > or
      = 10 mm Hg had a good response. There was no significant difference in the LES
      basal pressure between the responders and nonresponders (median 20 mm Hg vs 12 mm
      Hg). The median distal peristaltic amplitude (74 mm Hg vs 69 mm Hg), percent of
      failed peristalsis (8% vs 45%), and ramp pressure (19 mm Hg vs 17 mm Hg) did not
      differ significantly between the responders and nonresponders. No perforations
      occurred. CONCLUSIONS: Pneumatic dilation is a reasonably safe and effective
      treatment for patients with postfundoplication dysphagia. Raised nadir LES
      relaxation pressure seems to be a useful predictor of successful outcome.

PMID- 12492181
TI  - Effect of Helicobacter pylori eradication on development of erosive esophagitis
      and gastroesophageal reflux disease symptoms: a post hoc analysis of eight double
      blind prospective studies.
AB  - OBJECTIVES: The aim of this study was to assess the development of erosive
      esophagitis, the development of gastroesophageal reflux disease (GERD) symptoms
      in patients without prior symptomatic or endoscopic GERD, and the worsening of
      GERD symptoms in patients with prior symptomatic GERD in a post hoc analysis of
      eight double-blind prospective trials of Helicobacter pylori (H. pylori) therapy
      in 1165 patients. METHODS: Patients with active or past duodenal ulcer and
      without baseline erosive esophagitis had end of study endoscopies 4-30 wk after
      completion of therapy. A total of 533 patients had heartburn and regurgitation
      scores assessed at baseline and 4 wk after end of therapy, and were divided into
      two groups: 1) no prior GERD symptoms (N = 127) and 2) prior GERD symptoms (N =
      406). H. pylori was assessed at baseline and > or = 4 wk after therapy by rapid
      urease test, histology, and culture. RESULTS: Erosive esophagitis developed in 24
      (4%) of 621 patients with cure versus 14 (3%) of 544 with persistent H. pylori
      (OR = 1.52, 95% CI = 0.78-2.97). In the longest study (28-30-wk follow-up),
      esophagitis developed in two (7%) of 28 patients with cure versus five (7%) of 76
      with persistent infection. New GERD symptoms developed in 13 (14%) of 92 patients
      with cure versus seven (20%) of 35 with persistent infection (OR = 0.66,95% CI =
      0.24-1.82). GERD worsened in 20 (7%) of 269 with cure vs 20 (15%) of 137 with
      persistent H. pylori (OR = 0.47, 95% CI = 0.24-0.91; p = 0.02). CONCLUSIONS: Our
      results do not support the hypothesis that H. pylori eradication in patients with
      duodenal ulcer disease leads to the development of erosive esophagitis, the
      development of new symptomatic GERD, or worsening of symptoms in patients with
      pre-existing GERD.

PMID- 12492182
TI  - Neodymium:yttrium-aluminum garnet contact laser ablation of Barrett's high grade
      dysplasia and early adenocarcinoma.
AB  - OBJECTIVES: We describe the efficacy and safety of neodymium:yttrium-aluminum
      garnet (Nd:YAG) contact laser ablation of Barrett's high grade dysplasia (HGD)
      and/or early adenocarcinoma. METHODS: Consecutive Barrett's patients in whom HGD
      or adenocarcinoma was detected were eligible. Radial array echoendosonography and
      high frequency catheter probe ultrasonography were performed. Patients were
      excluded if ultrasound revealed the presence of Barrett's cancer with regional
      lymph nodes or celiac trunk metastases or extension of the tumor into superficial
      submucosa (T1sm1) or greater. Nd:YAG laser used quartz contact probes, with all
      Barrett's epithelium targeted at each session. Complete ablation was confirmed
      with Lugol's iodine chromoendoscopy followed by surveillance biopsies of the
      neosquamous epithelium. Adverse events were ascertained by scheduled telephone
      contact interviews. RESULTS: A total of 36 patients with HGD/adenocarcinoma were
      evaluated at our center, 17 of whom met all inclusion criteria. Of the patients,
      14 have remained in the study, and all have had successful elimination of HGD and
      cancer. In addition, 11 patients (78.6%) achieved complete endoscopic and
      histological ablation of all Barrett's tissue. Two patients (14.3%) achieved 95%
      destruction of Barrett's with residual metaplastic columnar epithelium containing
      goblet cells without dysplasia. The remaining patient has obtained 75% ablation
      of Barrett's, with residual metaplastic columnar epithelium harboring Barrett's
      with low grade dysplasia. Major complications included two esophageal strictures
      (11.8%) and one mild upper GI bleed (5.9%). CONCLUSIONS: This preliminary
      experience with Nd:YAG contact laser for the treatment of Barrett's HGD and early
      superficial cancers seems promising. The need for additional controlled trials
      with larger numbers of patients with longer follow-up, as well as consideration
      of a head-to-head trial with Photofrin photodynamic therapy, is warranted.

PMID- 12492183
TI  - Helicobacter pylori test-and-treat intervention compared to usual care in primary
      care patients with suspected peptic ulcer disease in the United States.
AB  - OBJECTIVES: [corrected] The Helicobacter pylori (H. pylori) "test-and-treat"
      strategy in uninvestigated dyspepsia is an effective alternative to prompt
      endoscopy. Our aims were to determine whether the combination of an educational
      session and availability of office-based H. pylori testing (test-and-treat
      intervention [TTI]) increases use of the test-and-treat strategy by primary care
      practitioners and whether it improves patient outcomes. METHODS: We conducted a 1
      yr prospective trial of patients with suspected peptic ulcer disease in six
      primary care centers, three with TTI and three designated as usual care controls
      (UCC). RESULTS: H. pylori testing was performed in 81% of 54 TTI patients and in
      49% of 39 UCC patients (p = 0.004). TTI and UCC patients had similar
      gastroenterology referral rates (24% vs 33%, p = 0.33), endoscopy or upper GI
      radiography rates (30% vs 31%, p = 0.91), and primary care visits per patient
      (3.1 +/- 2.8 vs 3.1 +/- 2.6, p = 0.92). TTI patients were less likely than UCC
      patients to receive repeated antisecretory medication prescriptions (35% vs 66%,
      p = 0.003). Symptomatic status at 1 yr and satisfaction with medical care did not
      differ between groups. Median (and interquartile range) annualized disease
      related expenditures per patient were $454 ($162-932) for TTI and $576 ($327
      1,435) for UCC patients (p = 0.17). CONCLUSIONS: The combination of an
      educational session and availability of office-based H. pylori testing may
      increase acceptance of the test-and-treat strategy by primary care providers. It
      remains to be determined whether increased use of the test-and-treat strategy
      yields significant improvements in clinical and economic outcomes compared to
      usual care.

PMID- 12492184
TI  - Changing rates of Helicobacter pylori testing and treatment in patients with
      peptic ulcer disease.
AB  - OBJECTIVES: The aim of this study was to identify temporal trends in the rate of
      Helicobacter pylori (H. pylori) testing, prevalence, and treatment among patients
      with peptic ulcer disease in Olmsted County, MN, from 1984 through 1997. METHODS:
      All 3317 Olmsted County residents with a clinical diagnosis of peptic ulcer
      disease at the Mayo Clinic from 1984 through 1997 were identified. The complete
      medical records of an age-, sex-, and calendar year-stratified random sample were
      reviewed (n = 720); 298 patients (41%) had confirmed peptic ulcer disease.
      Changes in proportions of H. pylori testing, infection, and treatment over time
      were analyzed by logistic regression. RESULTS: Of the 298 patients with confirmed
      peptic ulcer disease, 32% were tested for H. pylori; 36% were positive for
      infection, of whom 66% received antibiotic therapy. The rate of testing for H.
      pylori increased from 0% in 1984 to 96% in 1997, but the prevalence of infection
      did not change (36.4% vs 36.5%). The rate of treatment of those infected
      increased from 0% to 95%. By logistic regression, calendar year was associated
      with H. pylori testing and treatment but not infection. Recent use of
      nonsteroidal anti-inflammatory drugs was reported by 58% of patients, and 44%
      presented with GI bleeding. CONCLUSIONS: Physicians' practice of testing and
      treating for H. pylori in patients with confirmed peptic ulcer disease has
      steadily increased over the past 14 yr. However, in our study, only 36% of these
      patients were infected with H. pylori, whereas the majority used nonsteroidal
      anti-inflammatory drugs (NSAIDs). Therefore, testing seems to be more appropriate
      than empiric treatment in patients with peptic ulcer disease.

PMID- 12492185
TI  - Topographic association of gastric epithelial expression of Ki-67, Bax, and Bcl-2
      with antralization in the gastric incisura, body, and fundus.
AB  - OBJECTIVES: Helicobacter pylori (H. pylon) infection seems to induce
      antralization (ie., gastric mucosal transformation from transitional or body type
      to antral type), which is strongly associated with gastric atrophy and intestinal
      metaplasia. The aim of this study was to determine the topographic associations
      of Ki-67 (a protein expressed in proliferative cells), Bax (a pro-apoptotic
      protein), and Bcl-2 (an antiapoptotic protein) expression with antralization.
      METHODS: In each of 104 patients, eight biopsy specimens were taken from the
      gastric antrum, incisura, body, and fundus for the determination of H. pylori
      infection, histological changes, and epithelial expression of Ki-67, Bax, and Bcl
      2. A labeling index (LI), i.e., the rate of positive cells over total cells
      counted, was used for Ki-67 and Bax expression. Bcl-2 overexpression was
      considered to be present if the rate of Bcl-2 positive cells over total cells
      counted was > or = 5%. RESULTS: H. pylori infection was present at the gastric
      antrum, incisura, body, and fundus in 50, 48, 51, and 49 patients, respectively.
      Ki-67 LI was greater in the presence vs absence) of H. pylori infection at the
      antrum (51 vs 40), incisura (47 vs 36), body (43 vs 30), and fundus (41 vs 31)
      (all p < 0.001). At the incisura, Ki-67 LI was greater (47 vs 32, p < 0.001), Bax
      LI was lower (22 vs 30, p < 0.05), and prevalence of Bcl-2 overexpression was
      higher (44% vs 18%, p < 0.001) in the presence (vs absence) of antralization.
      Compared with normal mucosa, gastric atrophy/intestinal metaplasia were
      associated with an increased Ki-67 LI and decreased Bax LI at the antrum (49 vs
      32 and 15 vs 23, respectively), incisura (47 vs 32 and 15 vs 26, respectively)
      (all p < 0.001). Bcl-2 overexpression was more frequent in gastric
      atrophy/intestinal metaplasia at the antrum (56% vs 11%, p < 0.001) and incisura
      (63% vs 19%, p < 0.001) compared with normal mucosa. CONCLUSIONS: Antralization
      at the incisura is topographically associated with increased cell proliferation,
      reduced Bax expression, and Bcl-2 overexpression, which implies that
      antralization may be an important histological marker for future cancer risk.

PMID- 12492186
TI  - Impaired host immunity contributes to Helicobacter pylori eradication failure.
AB  - OBJECTIVES: Effective eradication of Helicobacter pylori (H. pylori) infection
      has often proved more difficult than expected. Antimicrobial resistance
      incompletely explains eradication failure. This study tests the hypothesis that
      an impaired immune response may contribute to failed eradication after standard
      antibiotic therapy. METHODS: Parameters of host immunity were assessed as blood T
      lymphocyte production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4)
      being surrogate markers of mucosal Th1 and Th2 responses, respectively. The
      validity of using circulating T cell cytokines as surrogate markers of mucosal
      immunity was established (unstimulated lymphocyte IL-4 level correlation r2 =
      0.549, p < 0.001; antigen-stimulated lymphocyte correlation r2 = 0.62, p <
      0.001). RESULTS: A total of 52 dyspeptic patients and 11 patients with previous
      H. pylori eradication failure were recruited into the study. There was no
      significant difference in secretion of IFN-gamma from peripheral blood T cells,
      in either unstimulated or antigen-stimulated cultures, between clinical groups.
      There was, however, a significant reduction in secretion of IL-4 from blood T
      cells in subjects failing to eradicate H. pylori compared with those who
      successfully eradicated the infection in both unstimulated and stimulated
      cultures. A significant difference in IL-4 secretion was also detected in antigen
      stimulated cultures compared with that in H. pylori-positive subjects (p < 0.05).
      Low levels of IL-4 secretion were detected irrespective of the number of courses
      of antibiotic therapy. Lower levels of IgG anti-H. pylori antibody were detected
      in both serum and saliva of subjects with persistent H. pylori infection after
      use of antibiotics compared with untreated H. pylori-positive subjects
      (difference not statistically significant). CONCLUSIONS: These results support
      the hypothesis that impaired mucosal immunity, particularly involving the
      secretion of IL-4, may contribute to H. pylori eradication failure. Measurement
      of whole blood secretion of IL-4 may predict which patients are more likely to
      fail standard antibiotic therapy.

PMID- 12492187
TI  - Gastric motility in patients with presinusoidal portal hypertension.
AB  - OBJECTIVE: The aim of this study was to evaluate the consequences of portal
      hypertension (PH) for the motor functions of the human stomach. METHODS: The PH
      model used was the hepatosplenic form of mansonic schistosomiasis, as this is a
      condition characterized by PH but with considerably preserved hepatocellular
      function. The study included 15 patients with PH and 25 healthy volunteers who
      served as controls. The adaptive relaxation of the stomach was studied in 12
      patients with PH and in 10 controls by a manometric method during rapid
      insufflation (25-30 s) of 700 ml of air into the gastric fundus. The gastric
      emptying of a liquid solution (15 patients with PH and 20 controls) and of a
      solid-liquid meal (nine patients with PH and 12 controls) was determined by gamma
      scintigraphy. The thickness of the gastric antrum wall was measured by
      ultrasonography in 12 patients with PH and in 10 controls. RESULTS: Patients with
      PH showed the following: 1) reduction of the adaptive relaxation of the stomach
      (p < 0.0001); 2) acceleration of gastric emptying of the test solution (T 1/2, p
      = 0.0316), which became particularly expressive 25, 30, 40, and 50 min after
      ingestion (p = 0.0181, 0.0215, 0.0181, and 0.0215, respectively); 3) no
      alteration in gastric emptying of the solid-liquid meal as judged by T 1/2 values
      (p = 0.9170) or lag-phase values (p = 0.7544); and 4) a conspicuous increase in
      gastric wall thickness as determined by antrum wall measurements (p = 0.0008).
      CONCLUSIONS: The reduced gastric adaptive relaxation demonstrated in patients
      with PH and normal hepatocellular function leads us to consider this condition as
      a cause of diastolic dysfunction of the stomach. In this disease, the motor
      alteration may be explained as a consequence of the reduction of gastric wall
      compliance, probably resulting from edema and vascular ectasia, which were
      indirectly detected by the increase thickness of the gastric antrum wall. The
      discrete acceleration of liquid gastric may be also related to the reduced
      gastric wall compliance.

PMID- 12492188
TI  - A double blind, randomized, placebo-controlled trial of proton pump inhibitor
      therapy in patients with uninvestigated dyspepsia.
AB  - OBJECTIVES: In patients with uninvestigated dyspepsia, a common initial
      management strategy in primary care is to prescribe a course of empiric
      antisecretory therapy and to refer those patients who do not respond for
      endoscopy. The objective of this research was to evaluate the effects of an
      empiric course of antisecretory therapy on dyspepsia-related health in patients
      with uninvestigated dyspepsia. METHODS: We conducted a double blind, randomized,
      placebo-controlled trial in which patients with uninvestigated dyspepsia were
      randomized to a 6-wk course of omeprazole 20 mg p.o. b.id. versus placebo
      capsules p.o. bi.d. and followed over 1 yr. The patients were at least 18 yr old
      with at least a 1-wk history of dyspepsia without alarm features. Dyspepsia
      related health was measured using the Severity of Dyspepsia Assessment (SODA), a
      valid, reliable, disease-specific outcome measure. The primary outcome was
      treatment failure, defined by a SODA Pain Intensity score > or = 29 (scores, 2
      47) during follow-up. Patients who were treatment failures underwent endoscopy.
      RESULTS: We enrolled 140 patients. The mean age was 51 yr, and seven (5%) were
      women. At 2 wk there were fewer treatment failures in the omeprazole group: 12 of
      71 patients (17%) in the omeprazole group failed compared with 24 of 69 (35%) in
      the placebo group (p = 0.037, log rank test). Also, at 6 wk there were fewer
      failures in the omeprazole group: 21 of 71 patients (30%) in the omeprazole group
      failed compared with 31 of 69 (45%) in the placebo group in 0.067, log rank
      test). However, at the 1-yr follow-up, there was no significant difference in
      treatment failure rates in the two groups: 37 of 71 patients (52%) in the
      omeprazole group failed compared with 41 of 69 (59%) in the placebo group (p =
      0.28, log rank test). CONCLUSIONS: In patients with uninvestigated dyspepsia, as
      compared with a strategy that would entail prompt endoscopy for all patients, an
      initial 6-wk course of either placebo or omeprazole reduces the need for
      endoscopy over a 1-yr follow-up. Compared with placebo, an initial 6-wk course of
      omeprazole delays, but does not reduce, the need for endoscopy. For proton pump
      inhibitor therapy to reduce the need for endoscopy, it may need to be given
      continuously.

PMID- 12492189
TI  - Variable stiffness colonoscopes are associated with less pain during colonoscopy
      in unsedated patients.
AB  - OBJECTIVES: Application of a new variable stiffness colonoscope (VSC) is expected
      to control loop formation and to lessen patient discomfort. The aim of this
      prospective study was to compare the efficacy of VSC with a conventional
      colonoscope (CC) in unsedated colonoscopy, based on the experience of examiners.
      METHODS: Four-hundred sixty-seven patients were randomly assigned to undergo
      colonoscopy with either VSC or CC by an endoscopist, including experienced and
      less-experienced examiners. The percentages of completed procedure and time to
      cecal intubation were recorded. Patients were asked to rate pain on a 5-point
      pain score. RESULTS: The percentages of completed procedure with VSC and CC were
      98% and 95%, respectively, by less-experienced hands, and 99% and 98%,
      respectively, by experienced hands. Time for cecal intubation with VSC and CC was
      15.7 and 18.5 min, respectively, by less-experienced hands, and 9.8 and 10.6 min,
      respectively, by experienced hands. A significantly lower mean pain score was
      noted in VSC patients compared with CC patients, irrespective of experience of
      the examiner. The percent of patients rating the procedure as moderately or
      severely painful was significantly lower with VSC than with CC, both in less
      experienced (19% vs 40%; p < 0.01) and experienced hands (15% vs 26%; p < 0.05).
      CONCLUSIONS: Our results indicated that VSC allows favorable examination compared
      with CC regarding completeness, time to cecal intubation, and comfort of patients
      undergoing unsedated colonoscopy, irrespective of the examiner's experience.
      These features suggest VSC as the preferred colonoscope for patients undergoing
      unsedated colonoscopy.

PMID- 12492190
TI  - Procedure-related abdominal discomfort in patients undergoing colorectal cancer
      screening: a comparison of colonoscopy and flexible sigmoidoscopy.
AB  - OBJECTIVES: The aims of this study were to determine if there was a difference in
      procedure-related abdominal discomfort or willingness to return for subsequent
      screening examinations between patients undergoing colonoscopy and those
      undergoing flexible sigmoidoscopy. METHODS: Two groups were compared: patients
      referred for screening flexible sigmoidoscopy and patients referred for screening
      colonoscopy. All patients were asymptomatic for colorectal cancer. Four
      university-based gastroenterologists performed all procedures. Patients received
      conscious sedation for colonoscopy but not for flexible sigmoidoscopy. A research
      nurse blinded to the procedure performed and the study purpose administered a
      standardized telephone questionnaire assessing and quantifying peri-procedural
      discomfort. RESULTS: A cohort of 466 patients underwent screening examinations,
      and 87% were contacted subsequent to their examination. Procedure-related
      discomfort, postprocedural discomfort, or discomfort at either of these two times
      ("peri-procedural discomfort") occurred in 28% (68/243), 14% (34/243), and 36%
      (88/243) of patients undergoing colonoscopy, respectively. Procedure-related
      discomfort, postprocedural discomfort, or discomfort at either of these two times
      occurred in 58% (94/162), 16% (26/162), and 62% (100/162) of patients undergoing
      flexible sigmoidoscopy, respectively. Peri-procedural discomfort was
      significantly more common in patients undergoing flexible sigmoidoscopy than with
      colonoscopy (p < 0.0005). Patients undergoing screening colonoscopy were more
      willing to undergo the procedure again than those undergoing screening flexible
      sigmoidoscopy (p < 0.0005). CONCLUSIONS: Patients undergoing screening
      colonoscopy with conscious sedation are less likely to experience peri-procedural
      discomfort than those undergoing screening flexible sigmoidoscopy. Although most
      patients are willing to undergo subsequent screening examinations, patients
      undergoing screening colonoscopy are significantly more willing to undergo a
      subsequent examination than those undergoing screening flexible sigmoidoscopy.

PMID- 12492191
TI  - Challenging pancreatic cancer-prone pedigrees: a nosologic dilemma.
AB  - OBJECTIVES: Our objective is to describe 11 pancreatic cancer (PC)-prone
      families, none of which are consonant with known hereditary cancer syndromes, in
      an attempt to portray familial aggregations of this disease that might be
      encountered in a clinical practice setting. METHODS: We selected 11 families
      containing two or more first- and/or second-degree relatives affected with PC
      from a registry of 200 PC-prone kindreds. Each proband and/or key relative(s) was
      interviewed and completed a detailed family history questionnaire (after
      providing informed consent) that allowed us to extend the pedigree as far as
      possible with retrieval of primary medical and pathology documents, whenever
      available. RESULTS: All of the 11 families show PC features that merit clinical
      attention and raise questions as to whether this familial clustering could be due
      to "chance" alone, exposure to certain common environmental factors, such as
      cigarette smoking, and/or polygenic, multifactorial, or Mendelian inherited
      factors. CONCLUSIONS: It is estimated that about 5% of PC may have a primary
      hereditary etiology. Because of early death, reduced penetrance, and often
      profuse phenotypic and genotypic heterogeneity, particularly with respect to
      variable age of onset and association with diverse patterns of cancer at
      different anatomic sites, the pedigrees require extension for ultimate diagnosis.
      Physician knowledge about PC's natural history and syndrome delineation should
      ultimately foster earlier diagnoses and possibly prevention of this disease.
      These high-risk patients may provide a source of DNA for formal linkage analysis
      in the search for culprit cancer-prone susceptibility loci.

PMID- 12492192
TI  - Urinary excretion of N-methylhistamine as a marker of disease activity in
      inflammatory bowel disease.
AB  - OBJECTIVE: Mast cells are thought to participate in the pathogenesis of
      inflammatory bowel disease (IBD). In this study, urinary excretion of N
      methylhistamine (UMH), a stable metabolite of the mast cell mediator histamine,
      was evaluated as an indicator of disease activity in patients with IBD. METHODS:
      Urinary excretion of UMH (microg/mmol creatinine x m2 body surface area) was
      measured by radioimmunoassay in 55 controls, 56 patients with Crohn's disease,
      and in 36 patients with ulcerative colitis. Excretion rates were correlated with
      clinical, serological, and endoscopic disease activity, disease extent, and
      location. RESULTS: Urinary excretion of UMH was found to be significantly
      elevated in IBD. Patients with active Crohn's disease (7.1 +/- 4.2, p = 0.002 vs
      controls) and active ulcerative colitis (8.1 +/- 4.8, p = 0.02 vs controls) had
      higher rates of UMH excretion than patients in remission (6.3 +/- 3.8 and 5.2 +/-
      2.3, respectively) or controls (4.6 +/- 1.9). In Crohn's disease and ulcerative
      colitis, a significant correlation of UMH excretion with clinical disease
      activity was obtained (Crohn's Disease Activity Index r2 = 0.58, Clinical
      Activity Index r2 = 0.57, p < 0.0001). Serologically, orosomucoid showed the best
      positive correlation with disease activity (Crohn's Disease Activity Index r2
      0.80, Clinical Activity Index r2 = 0.86, p < 0.0001), but UMH excretion was found
      to reflect disease activity more accurately than C-reactive protein (Crohn's
      Disease Activity Index r2 = 0.46, Clinical Activity Index r2 = 0.42, p < 0.0001).
      No association between UMH excretion and disease type or localization could be
      found in Crohn's disease. However, UMH excretion correlated strongly with
      endoscopic severity of inflammation in Crohn's disease (Crohn's Disease
      Endoscopic Index of Severity r2 = 0.70, p < 0.0001) or disease extent in
      ulcerative colitis. CONCLUSIONS: Urinary excretion of the histamine metabolite
      UMH is enhanced in IBD. It appears to represent an integrative parameter to
      monitor clinical and endoscopic disease activity in IBD, which appears to be
      influenced most likely by mediators released from histamine-containing cells,
      such as intestinal mast cell subtypes.

PMID- 12492193
TI  - Balsalazide is superior to mesalamine in the time to improvement of signs and
      symptoms of acute mild-to-moderate ulcerative colitis.
AB  - OBJECTIVE: Balsalazide is a novel azo-bonded 5-aminosalicylic acid treatment for
      mild-to-moderate ulcerative colitis. The study objective was to compare
      symptomatic remission rates with balsalazide and mesalamine while controlling for
      extent of disease and time since diagnosis in patients with active, mild-to
      moderate ulcerative colitis. METHODS: A total of 173 patients with
      sigmoidoscopically verified ulcerative colitis were randomized to 8 wk of double
      blind treatment with balsalazide 6.75 g/day or mesalamine 2.4 g/day. Both
      treatments provided 2.4 g/day of oral 5-aminosalicylic acid. Patients maintained
      symptom diaries throughout the treatment period. RESULTS: Overall, 46% of
      balsalazide- and 44% of mesalamine-treated patients achieved symptomatic
      remission. Higher response rates were noted in newly diagnosed patients with < or
      = 40 cm of disease (68% vs 61%) than in recently relapsed patients with >40 cm of
      disease (36% vs 25%). The median time to symptomatic remission was 12 days
      shorter with balsalazide (25 days) than with mesalamine (37 days). Significantly
      more balsalazide patients showed sigmoidoscopic (p = 0.002), stool frequency (p =
      0.006), rectal bleeding (p = 0.006), and physician's global assessment score (p =
      0.013) improvement by 14 days than did mesalamine patients. Similar proportions
      of patients reported adverse events (54% vs 64%), which were most commonly
      related to the gastrointestinal and central and peripheral nervous systems.
      CONCLUSIONS: Balsalazide is an effective and safe treatment for mild-to-moderate
      ulcerative colitis. Improvement of symptoms occurs considerably earlier with
      balsalazide than with mesalamine.

PMID- 12492194
TI  - Predictors of turnover of lower gastrointestinal symptoms in diabetes mellitus.
AB  - BACKGROUND: Both the natural history of GI symptoms and factors influencing
      symptom turnover in diabetes mellitus are unknown. We aimed to determine the
      natural history of GI symptoms in diabetes mellitus over a 3-yr period. METHODS:
      Subjects with predominantly Type 2 diabetes on the mailing list of Diabetes
      Australia were recruited and completed a validated questionnaire (n = 892); of
      these, 64% completed the questionnaire again 3 yr later. Subjects were classified
      as never having GI symptoms (abdominal pain, constipation, diarrhea, fecal
      incontinence), fluctuating (only on one survey), or persistent symptoms. RESULTS:
      Symptoms more often fluctuated than persisted, but the prevalence at recruitment
      and 3 yr later was similar. Predictors of symptom turnover varied. In a
      multivariate model, abnormal sweating and diabetic foot problems predicted
      symptom turnover for abdominal pain (OR = 2.01, 95% CI = 1.07-3.76 and 2.54, 1.23
      5.24, respectively), and paresthesiae ("pins and needles") and foot problems
      predicted fecal incontinence (OR = 2.24, 1.06-4.75 and 2.38, 1.04-5.45,
      respectively), but not constipation or diarrhea. Symptom turnover in constipation
      was associated with depression (OR = 2.73, CI = 1.89-3.94) and neuroticism (OR =
      0.57, CI = 0.36-0.89), and depression was associated with abdominal pain (OR =
      1.56, CI = 1.02-2.38), but psychological factors were not related to the other
      symptoms. The odds for symptoms persisting were not generally related to type or
      duration of diabetes, or self-rated glycemic control. CONCLUSION: The natural
      history of GI symptoms in diabetes has been described for the first time;
      symptoms may either persist or fluctuate, but the prevalence is constant because
      symptom onset is balanced by disappearance. Glycemic control does not seem to
      predict symptom change.

PMID- 12492195
TI  - Variation at NOD2/CARD15 in familial and sporadic cases of Crohn's disease in the
      Ashkenazi Jewish population.
AB  - OBJECTIVE: Recent reports indicate that allelic variants in NOD2/CARD15 are
      associated with Crohn's disease (CD) susceptibility, and that homozygosity or
      compound heterozygosity at this locus for any of three recently defined sequence
      variants confers a greatly increased risk of CD. These sequence changes include
      two missense mutations, R702W and G908R, and a frameshift insertion, 1007insC.
      The aim of this study was to determine the frequency of these NOD2/CARD15
      variants in familial and sporadic CD patients in the Ashkenazi population and to
      determine their effects on disease susceptibility and age of disease onset (AOO).
      METHODS: Allele and genotype frequencies of these three variants were determined
      in 481 CD patients of Jewish descent and 110 Jewish controls; 169 patients had a
      family history of CD, and 312 were "sporadic" cases. Variants were detected by
      polymerase chain reaction using allele-specific primers labeled with fluorescent
      dye. RESULTS: Familial cases had a significantly higher frequency of the G908R
      variant than sporadic cases (0.127 vs 0.059, p = 0.0003) and correspondingly, a
      significantly higher proportion of homozygotes and compound heterozygotes (11.8%
      vs 4.5%, p = 0.0027). Homozygotes and compound heterozygotes had an OR for CD of
      14.6 for familial cases and 5.1 for sporadic cases. There was no increased risk
      of CD for simple heterozygotes. The AOO was significantly lower for CD patients
      who were homozygotes and compound heterozygotes for NOD2/CARD15 (17.5 vs 22.4 yr,
      p = 0.04), but only for familial cases. CONCLUSIONS: NOD2/CARD15 contributes more
      to CD susceptibility in familial cases than in sporadic cases, and to an earlier
      AOO. There is no increased risk of CD for individuals carrying only a single copy
      of these NOD2/ CARD15 variants, whereas individuals carrying two copies have a 5
      15-fold increased risk. The penetrance of the NOD2/CARD15 mutations was estimated
      at less than 1%.

PMID- 12492196
TI  - Colonoscopy accurately predicts the anatomical severity of colonic Crohn's
      disease attacks: correlation with findings from colectomy specimens.
AB  - OBJECTIVE: For the assessment of colonic Crohn's disease (CCD) attacks, no
      clinicobiological and/or morphological (endoscopic, radiological) criteria of
      severity have been validated in relation to anatomical criteria of severity (ACS)
      as a gold standard obtained from colectomy specimen examination. Our objective
      was to assess the accuracy of colonoscopy in predicting the anatomical severity
      grading of CCD. METHODS: Colectomy specimens from 78 consecutive patients
      operated between 1982 and 1996 for CCD resistant to medical treatment were
      analyzed and classified into two groups according to the presence (ACS+) or
      absence (ACS-) of ACS. These were defined as either deep ulcerations eroding the
      muscle layer, or mucosal detachments or ulcerations limited to the submucosa but
      extending to more than one third of one defined colonic segment (right,
      transverse, left colon). Three endoscopic criteria of severity (ECS) were then
      defined: 1) deep ulcerations eroding the muscle layer (ECS1), 2) deep ulcerations
      not eroding the muscle layer but involving more than one third of the mucosal
      area (ECS2), and 3) mucosal detachment on the edge of ulcerations (ECS3).
      RESULTS: According to colectomy specimen examination, 68 and 10 patients belonged
      to ACS+ and ACS- groups, respectively. ECS1, ECS2, and/or ECS3 were found in 70
      patients. Positive predictive values of ECS1, ECS2, and ECS3 for the presence of
      ACS were 90%, 98%, and 92%, respectively. Negative predictive values were 43%,
      72%, and 23% respectively. However, at least one ECS (ECS1, ECS2, or ECS3) was
      found in 95% of patients with ACS. The extent of ulcerations at colonoscopy was
      correlated to the results of colectomy specimen examination (p < 0.001). Taking
      into account only patients with ACS, 88% of those with at least one ECS were
      diagnosed through left side colonoscopy. Usual clinical and biological severity
      criteria were not different in ACS + and ACS- groups. Two cases of toxic
      megacolon and toxic shocks were observed after the colonoscopy. CONCLUSIONS: In
      experienced hands, colonoscopy can be useful in severe CCD attacks. When at least
      one ECS is found, colonoscopy predicts the anatomical severity of the colitis
      with a high probability. Conversely, when none of the three ECSs is found,
      colonoscopy can reasonably exclude the diagnosis of severe anatomical CCD.

PMID- 12492198
TI  - Assessment of predictors of response to neostigmine for acute colonic pseudo
      obstruction.
AB  - OBJECTIVE: Acute colonic pseudoobstruction (ACPO) most commonly develops after
      surgery, with narcotic administration, or in association with severe illness.
      Most cases resolve with conservative management. Colonoscopic decompression may
      be required in patients failing to respond to conservative treatment. Neostigmine
      has been proposed as an effective treatment for ACPO as an alternative to
      colonoscopic decompression. We sought to identify factors associated with
      spontaneous resolution of ACPO and to identify variables associated with a
      response to i.v. administration of neostigmine for the treatment of ACPO.
      METHODS: Retrospective analysis of Mayo Clinic's diagnostic index revealed all
      patients who developed ACPO between July, 1999 and September, 2001 at the Mayo
      Clinic Medical Center. We separately analyzed those patients who did not resolve
      ACPO with conservative management and to whom i.v. neostigmine was administered.
      Patient records were abstracted for demographic data, etiology of ACPO,
      management, and response to treatment. RESULTS: A total of 151 patients were
      identified with ACPO between July, 1999 and September, 2001; 117 patients (77%)
      had spontaneous resolution of symptoms. Of the 34 "nonresolvers," 18 patients
      received neostigmine, whereas 16 did not receive neostigmine. Of those 16
      patients, 11 required colonoscopic decompression, two underwent surgery, and
      three died of underlying illness. "Spontaneous resolvers" were less likely to be
      taking narcotics (59% vs 74%, p = 0.08). Of the 16 nonresolvers who did not
      receive neostigmine, only one had a contraindication to neostigmine use. Of the
      18 patients that who received neostigmine, 16 patients (89%) had prompt
      evacuation (<30 min) of flatus or stool. Sustained clinical response to
      neostigmine was noted in 11 of 18 (61%); the remaining seven patients (39%)
      required colonoscopic decompression or surgery for recurrent or persistent
      colonic dilation. Neostigmine-responders were more likely to be older (mean age,
      76 yr vs 54 yr, p = 0.03), than nonresponders. Preneostigmine cecal diameter did
      not differ significantly between responders (median, 12 cm) and nonresponders
      (median, 13 cm), p = 0.9. Median time to resolution of ACPO in spontaneous
      resolvers was 4 days compared to 2 days in patients responding to neostigmine; p
      = 0.038. CONCLUSIONS: Most patients with ACPO respond to conservative treatment.
      Female gender and older age are associated with a response to neostigmine in
      those patients who do not respond to conservative management. Neostigmine appears
      to be under-used in patients with ACPO who do not have a true contraindication to
      its use.

PMID- 12492197
TI  - Th1-mediated intestinal inflammation in Crohn's disease may be induced by
      activation of lamina propria lymphocytes through synergistic stimulation of
      interleukin-12 and interleukin-18 without T cell receptor engagement.
AB  - OBJECTIVE: The development of T helper type 1 (Th1) CD4+ T cells in the
      intestinal mucosa is driven by interleukin (IL)-12 produced from activated
      macrophages and IL-18 produced from activated macrophages and epithelial cells.
      Each of these two cytokines is important for the mucosal response during
      intestinal inflammation, but their synergistic effect is not fully understood. To
      characterize the synergistic effect of IL-12 and IL-18 with respect to human
      intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina
      propria lymphocytes from normal control subjects (LPL-NL) and patients with
      Crohn's disease (LPL-CD). METHODS: Expression of IL-12 receptor (IL-12R) beta1,
      beta2, and IL-18Ralpha in LPLs was analyzed by flow cytometry. The functional
      activity of IL- 12 and IL-18 was assessed by the effect of recombinant IL-12 and
      recombinant IL-18 on interferon-gamma production, the proliferative response, and
      the induction of IL-2R, IL-12R, and IL-18R of LPLs. RESULTS: IL-12Rbeta2
      expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL
      demonstrated a proliferative response and a significant increase in interferon
      gamma production and IL-2Ralpha expression when exposed to both IL- 12 and IL-
      18, but neither IL- 12 nor IL-18 were able to induce this response on their own.
      However, IL-12 and IL-18 produced this response in LPL-CD when administered
      alone. Moreover, a more pronounced synergistic effect of IL-12 and IL-18 was
      observed in LPL-CD. The response normally observed after administration of IL-12
      and IL-18 was significantly inhibited by anti-IL-2 and anti-IL-2Ralpha monoclonal
      antibody. Furthermore, IL-12 was observed to upregulate IL-18Ralpha expression in
      LPL-CD. CONCLUSIONS: These findings suggest that a combination of IL-12 and IL-18
      in the absence of T cell receptor engagement may serve as a potent regulatory
      factor for LPL and contribute to the maintenance and enhancement of chronic
      inflammation in CD.

PMID- 12492199
TI  - Small intestinal glucose absorption and duodenal motility in type 1 diabetes
      mellitus.
AB  - OBJECTIVE: Small intestinal glucose absorption is increased in animal models of
      diabetes mellitus, but little data are available in humans. Small intestinal
      motility is reported to be frequently abnormal in patients with diabetes and
      could potentially affect glucose absorption. Our aim was to evaluate small
      intestinal glucose absorption and duodenal motor responses to intraduodenal
      nutrients, in patients with type 1 diabetes and controls. METHODS: Eight type 1
      patients (two with autonomic neuropathy) and nine controls were studied during
      euglycemia. A manometric catheter was positioned across the pylorus, and nutrient
      infused intraduodenally (90 kcal over 30 min), followed by a bolus of 3-O
      methylglucose (3-OMG). Blood was sampled to measure glucose and 3-OMG
      concentrations. RESULTS: During nutrient infusion, the number of duodenal waves
      did not differ between patients and controls. After the infusion, patients with
      diabetes had more propagated duodenal wave sequences (p < 0.05). The area under
      the plasma 3-OMG curve did not differ between the groups but correlated with both
      the blood glucose concentration at the time of 3-OMG administration (r = 0.64, p
      < 0.005) and the number of duodenal waves (r = 0.52, p < 0.05) and antegrade
      propagated duodenal sequences (r = 0.51, p < 0.05) preceding the 3-OMG bolus.
      CONCLUSIONS: During euglycemia, duodenal motor responses to small intestinal
      nutrient are comparable in patients with relatively uncomplicated type 1 diabetes
      and healthy subjects, but duodenal motility after nutrient infusion is increased
      in patients. Small intestinal glucose absorption is similar in patients and
      controls, but may be dependent on the blood glucose concentration and duodenal
      motor activity.

PMID- 12492200
TI  - Is there a difference between abdominal pain and discomfort in moderate to severe
      IBS patients?
AB  - OBJECTIVES: The aims of this study were to: 1) determine the relative prevalence
      of self-reported pain-predominant and discomfort-predominant symptom patterns in
      irritable bowel syndrome (IBS) patients; and 2) test the hypotheses that pain
      predominant patients report higher GI symptom severity, show higher psychological
      symptom severity, show worse quality of life, and demonstrate higher health care
      use. METHODS: A total of 256 consecutive ROME I-positive IBS patients with
      moderate to severe symptoms were classified according to whether they rated their
      predominant IBS symptoms as pain (n = 52), or as nonpainful discomfort (n = 128)
      on the Irritable Bowel Syndrome Quality of Life questionnaire. The validity of
      this classification scheme was confirmed by interview in a subsample of 45
      patients. IBS-specific symptom patterns, psychometric assessment, and health
      related quality of life measures were obtained using validated survey
      instruments. RESULTS: Contrary to the generally accepted notion that pain is the
      most predominant symptom in IBS, twice as many patients self-classified their
      symptoms as abdominal discomfort rather than abdominal pain. The classifications
      based on questionnaire data were shown to be valid in a subsample of subjects (n
      = 45) who underwent classification based on an independent, blinded, clinical
      interview (r = 0.77, p < 0.05). Pain and discomfort subgroups were similar in
      age, gender, predominant bowel habit, and overall GI symptom severity. In
      addition, the subgroups reported similar degrees of psychological distress,
      impaired quality of life, and increased patterns of health care use. CONCLUSIONS:
      Subgroups of moderate to severe IBS patients do report their predominant GI
      symptoms in terms of pain or nonpainful discomfort, regardless of severity of
      their overall GI symptoms or psychological symptoms. These findings are most
      consistent with a cognitive labeling bias of visceral sensations as either pain
      or discomfort.

PMID- 12492201
TI  - Patient satisfaction with alosetron for the treatment of women with diarrhea
      predominant irritable bowel syndrome.
AB  - OBJECTIVE: The efficacy and tolerability of alosetron in women with diarrhea
      predominant irritable bowel syndrome (IBS) have been established in double-blind,
      placebo-controlled trials. However, the degree to which alosetron fulfills the
      needs of those suffering from IBS has not been thoroughly examined from the
      patient's perspective. This randomized, double-blind, placebo-controlled study
      conducted in women with diarrhea-predominant IBS evaluated patients' overall
      satisfaction with treatment as well as their satisfaction with respect to several
      specific medication attributes. METHODS: Patients randomized to receive either
      alosetron 1 mg b.id. (n = 532) or placebo (n = 269) were administered a
      questionnaire on which they rated on 7-point Likert scales their prestudy IBS
      treatment (at the screening visit) or study medication (on wk 12 or final study
      visit) with respect to overall satisfaction and 11 specific medication
      attributes. RESULTS: Whereas approximately 10% of patients were satisfied or very
      satisfied overall with prestudy IBS medication, 69% of patients were satisfied or
      very satisfied overall with alosetron and 46% with placebo (p < 0.001) at the end
      of 12 wk of therapy. The majority of alosetron-treated patients (61-87%) were
      satisfied or very satisfied with each of 11 specific medication attributes (p <
      0.001 vs placebo for each attribute). Favorable satisfaction ratings for
      alosetron were assigned to the five medication attributes that patients
      considered to be most important, including relief of urgency (68% alosetron vs
      41% placebo), speed of relief (71% vs 40%), time to return to normal activities
      (75% vs 49%), relief of abdominal pain (62% vs 44%), and prevention of return of
      urgency (68% vs 42%). CONCLUSIONS: Women with diarrhea-predominant IBS are
      satisfied with alosetron 1 mg b.i.d. treatment overall and also with respect to
      specific attributes of IBS medication they consider most important.

PMID- 12492202
TI  - Autonomic functioning during REM sleep differentiates IBS symptom subgroups.
AB  - OBJECTIVE: The aim of this study was to investigate autonomic activity by means
      of heart rate variability analysis in a sample of irritable bowel syndrome (IBS)
      patients, allowing stratification into IBS symptom subgroups. METHODS: Thirty
      three female IBS patients (mean age 37 yr) and 21 healthy female controls (mean
      age 38 yr) participated. Patients were stratified into 16 subjects with only
      lower bowel symptoms (IBS only) and 17 subjects with both lower bowel and
      dyspeptic symptoms (IBS+D). The protocol included standard polysomnography to
      assess stages of sleep with concomitant electrocardiographic measurement of beat
      to-beat intervals of the cardiac cycle. Fifteen-min segments were selected from
      presleep waking, stage 2 of non-rapid eye movement (REM), and REM sleep and
      analyzed by spectral analysis of heart rate variability to calculate the high
      frequency band, a measure of vagal tone, and the low-frequency/high-frequency
      ratio, an indicator of sympathovagal balance. RESULTS: The high-frequency band
      power during REM sleep was significantly lower, indicating substantial vagal
      withdrawal in IBS-only patients compared with IBS+D patients and controls. The
      low-frequency/high-frequency band ratio was significantly higher during REM sleep
      for IBS-only patients. CONCLUSIONS: IBS-only patients had greater sympathetic
      dominance, indicated by elevated low-frequency/high-frequency band ratio, during
      REM sleep because of vagal withdrawal. Autonomic functioning, unique to REM
      sleep, differentiates IBS symptom subgroups, suggesting that autonomic
      functioning during REM sleep may be a useful biological marker to identify IBS
      patient subgroups.

PMID- 12492203
TI  - Psychological state and quality of life in patients having behavioral treatment
      (biofeedback) for intractable constipation.
AB  - OBJECTIVE: Behavioral techniques, including biofeedback, improve symptoms in a
      majority of patients with intractable idiopathic constipation. However, it is
      unknown whether there is also improvement in patients' psychological well-being
      and quality of life (QOL). It is also unknown whether psychological or QOL
      factors can be used to predict the response to treatment. We aimed to assess
      these factors prospectively. METHODS: Thirty-one consecutive patients (median age
      36 yr) receiving biofeedback retraining for idiopathic constipation were studied.
      A bowel symptom record, the General Health Questionnaire-28 (GHQ-28) (n = 31) and
      Hospital Anxiety and Depression Scale (n = 20), both psychological measures, and
      the Short Form-36 (SF-36) (n = 22), a generic QOL measure, were recorded before
      and after treatment. RESULTS: Twenty-two of the patients felt subjectively
      symptomatically improved. When considering all patients, treatment resulted in
      decreased depression (p < 0.05), anxiety (p < 0.05), and somatic symptoms (p <
      0.01) (psychological measures: GHQ-28), and improved general health (p < 0.05)
      and vitality (p < 0.05) (QOL measures: SF-36). Patients who improved
      symptomatically showed significantly higher scores on the GHQ-28 and SF-36, in
      contrast to the unchanged scores in patients who did not symptomatically improve.
      Pretreatment GHQ-28 did not predict who would benefit from treatment, but
      patients in whom pain, emotional problems, or low vitality interfered with daily
      living (SF-36 pain subscales) were significantly (p < 0.05) less likely to
      respond to treatment. CONCLUSIONS: The symptomatic improvement produced by
      biofeedback in constipated patients is associated with improved psychological
      state and QOL. Some of the psychological morbidity in these patients is
      reversible. QOL parameters may be useful for predicting a likely response to
      treatment.

PMID- 12492204
TI  - Improvement of autoimmune hepatitis during pregnancy followed by flare-up after
      delivery.
AB  - OBJECTIVES: Pregnancy in autoimmune hepatitis has been a rare event, but it has
      become more frequent with improved therapy. The present study aimed to analyze
      the consequences for mother and child in patients with autoimmune hepatitis.
      METHODS: Fourteen pregnancies have been followed in five patients with autoimmune
      chronic hepatitis (AIH) and in one with autoimmune sclerosing cholangitis
      (overlap AIH-PSC). RESULTS: Features of AIH improved markedly from the second
      trimester of pregnancy onward, allowing a decrease in immunosuppressive therapy.
      After delivery (or stillbirth in one patient), the activity of the autoimmune
      disease flared up rapidly in 12 of 14 events. CONCLUSIONS: Pregnancy induces a
      state of immune tolerance with improvement of the liver tests in AIH. This could
      result from a transition of TH1 to TH2 predominance during pregnancy. A flare-up
      often occurs after delivery. Preemptive increase of the immunosuppressive therapy
      is therefore advocated consecutive to delivery. Azathioprine use seems to be safe
      during pregnancy.

PMID- 12492205
TI  - Telomerase expression and p53 status in hepatocellular carcinoma.
AB  - OBJECTIVES: [corrected] Genomic instability is a driving force for tumorigenesis.
      Telomerase and p53 play central roles in maintaining genomic integrity. The
      purpose of this study was to assess the role of telomerase expression and p53
      protein overexpression in hepatocellular carcinoma (HCC). METHODS: Telomerase
      activity and p53 overexpression were investigated in 63 patients undergoing
      hepatectomy for HCC by a telomeric repeat amplification protocol and
      immunohistochemistry, respectively. The associations among telomerase expression,
      p53 overexpression, and clinicopathological features were analyzed, and
      independent prognostic factors in the recurrence of HCC after hepatectomy were
      determined. RESULTS: Telomerase expression did not correlate with
      clinicopathological features except hepatitis virus status (p = 0.04) and was
      identified as a significant prognostic variable for HCC recurrence (p = 0.027)
      along with portal venous invasion (p = 0.001). In contrast, p53 overexpression
      strongly correlated with tumor differentiation (p < 0.0001) but did not reflect
      time to recurrence (p = 0.26). Telomerase expression did not correlate with p53
      overexpression (p = 0.35). CONCLUSIONS: The reactivation of telomerase was of
      significant value in predicting the recurrence of HCC after hepatectomy. However,
      p53 overexpression did not correlate with telomerase expression in HCC, nor did
      it reflect the time to recurrence.

PMID- 12492206
TI  - Video-assisted thoracoscopic surgery with talc pleurodesis in the management of
      symptomatic hepatic hydrothorax.
AB  - OBJECTIVES: Video-assisted thoracoscopic surgery with talc pleurodesis is a
      therapeutic option for patients with hepatic hydrothorax that is refractory to
      medical therapy. We report the outcomes of 15 patients who underwent this
      procedure for significantly symptomatic disease. METHODS: Data on 15 consecutive
      patients presenting to our institution between November, 1996, and June, 2000,
      with refractory hepatic hydrothorax was retrospectively collected. Baseline
      demographical and clinical characteristics and outcomes after the procedure were
      analyzed. RESULTS: The mean age of our cohort was 51.5 yr, and eight (53%) of the
      15 patients were male. The etiologies of liver disease were hepatitis C virus
      and/or alcohol (n = 12) and cryptogenic cirrhosis (n = 3). Nine patients were
      Child-Pugh class C and six class B. Success defined as control of symptomatic
      hydrothorax in the first 30 days after the procedure was achieved in 11 of 15
      patients (73%). Eight of these patients remained asymptomatic at a median follow
      up of 5.5 months after the procedure, but three patients experienced symptomatic
      fluid reaccumulation 45, 61, and 62 days after the initial procedure. After a
      second VATS procedure, control was achieved in two of these three patients.
      Complications included pain around the chest tube site, low grade fever with
      leukocytosis, pleurocutaneous fistula and empyema, all of which responded to
      medical therapy. Four patients did not respond to the procedure. There were no
      procedure-related deaths. Overall mortality and baseline clinical characteristics
      were similar between responders and nonresponders to VATS with pleurodesis.
      CONCLUSIONS: Symptomatic hepatic hydrothorax can be controlled with a single VATS
      with pleurodesis in as many as 53% of patients and with two procedures in 73%
      with no procedure-related mortality. The procedure may be considered as a
      palliative alternative in patients needing frequent thoracocentesis. It also
      provides an alternative to transjugular intrahepatic portosystemic shunts and is
      a bridge toward liver transplantation.

PMID- 12492207
TI  - Hypertransaminasemia in pediatric celiac disease patients and its prevalence as a
      diagnostic clue.
AB  - OBJECTIVES: The aims of this study were to evaluate the following: 1) the
      prevalence of hypertransaminasemia (HT) in a pediatric celiac disease (CD) and
      its relation with clinical parameters; 2) the frequency of HT as the only
      manifestation of pediatric CD; and 3) the evolution of HT after a gluten free
      diet. METHODS: A total of 114 consecutive pediatric CD patients were studied (60%
      with classical and 40% with atypical forms). Antiendomisyum antibodies and anti
      tissue transglutaminase antibodies were determined in patients with a clinical
      suspicion of CD (including unexplained chronic HT), in patients at risk, and in
      patients with preoperative increased ALT activity for minor surgery. CD was
      confirmed by duodenal biopsy. At baseline, the relationship between clinical
      factors and aminotransferase status was univariately and multivariately assessed.
      After starting a gluten free diet, patients were followed up, until serological
      markers cleared and serum aminotransferase normalized. RESULTS: HT occurred in
      32% of patients (37 of 114) at diagnosis. HT was the only manifestation of CD in
      five patients (4.3%). Patients with HT were younger (2.9 +/- 0.4 yr) than
      patients with normal aminotransferases (5.1 +/- 0.5 yr) (p = 0.007). A higher
      percentage of patients with classical CD tend to have abnormal aminotransferases
      (73%; 95% CI = 65-81%) than do patients with atypical CD (27%; 95% CI = 19-35%)
      (p = 0.068). Logistic regression analysis showed that only younger age was
      significantly associated with HT (p = 0.039; OR = 0.8; 95% CI = 0.71-0.99).
      Aminotransferases normalized with a gluten free diet in all 35 patients who were
      followed-up, either before (n = 18) or at the same time (n = 17) as serological
      markers cleared. CONCLUSIONS: HT is a frequent finding in pediatric CD patients
      and, in a substantial proportion, may be the only manifestation of CD. Thus,
      serological markers of CD should be introduced in the first step of the
      diagnostic workup of liver diseases in pediatric patients.

PMID- 12492208
TI  - Colonoscopic miss rates determined by direct comparison of colonoscopy with colon
      resection specimens.
AB  - OBJECTIVES: Colonoscopy is an effective method for discovery of adenomas and for
      colon cancer screening and prevention. Studies evaluating back-to-back
      colonoscopies have estimated significant miss rates but are limited by the lack
      of a definitive gold standard. Our study evaluated the sensitivity of colonoscopy
      compared with examination of surgically resected colon as a gold standard.
      METHODS: This was a retrospective analysis of patients who had a portion of colon
      surgically removed and had lower endoscopy within 5 months. The focus of the
      review was not for the particular lesion for which the surgery was indicated but,
      rather, for the synchronous lesions in the portions of bowel that were removed.
      Sensitivity was determined by counting the number of lesions detected at
      colonoscopy compared with those found in the surgically resected segment.
      RESULTS: A total of 73 synchronous lesions were present in the resected segments
      of 156 patients. Colonoscopy detected 56 of 73 the lesions (sensitivity 76.7%:
      95% CI = 67-86). Of the 17 missed lesions, 14 of 17 (82%, 95% CI = 64-100) were <
      1-cm polyps. Endoscopy overlooked one 1-cm adenoma in the ascending colon. Two
      cancers were missed, both in the same patient in whom endoscopy detected a
      sigmoid cancer but missed synchronous lesions in the cecal and ascending colon.
      CONCLUSIONS: Colonoscopy is an effective method of finding cancers and polyps,
      but it is associated with significant miss rates for polyps <1 cm. The entire
      bowel should be carefully evaluated to exclude synchronous tumors in patients
      with known colorectal cancer. Further improvement of colonoscopic techniques and
      technologies is warranted.

PMID- 12492209
TI  - A prospective, controlled assessment of factors influencing acceptance of
      screening colonoscopy.
AB  - OBJECTIVES: Medicare beneficiaries now have access to screening colonoscopy (SC).
      For colon cancer screening to be fruitful, SC must become more acceptable to a
      broad segment of this population. However, we currently lack knowledge of which
      aspects of SC have an impact on patient acceptance. The aims of this study were:
      1) to identify the features of SC that are most important in deterring
      participation, and 2) to prioritize and to compare the perceptions of never
      screened individuals with those of individuals previously screened for colon
      cancer. METHODS: Questionnaires were distributed to 300 outpatients at Mayo
      Clinic, Rochester (150 never-screened patients; 150 previously screened
      patients). The survey instrument addressed domains of the Health Belief Model and
      colon cancer risk perception. Patients ranked the three most important barriers
      to SC and answered general knowledge questions on colon cancer. RESULTS: Response
      rates of never-screened (84%) and screened (88%) patients were similar. Never
      screened patients were less likely to have a regular primary physician (80% vs
      95%, p = 0.0003) and were less likely to have undergone a prior screening
      mammography (87% vs 96% of women, p = 0.02) compared with screened patients. The
      four most reported deterrents to SC ("volume of bowel preparation," "adequate
      analgesia," "no recommendation from primary physician," and "embarrassment") were
      ranked similarly by both groups. Never-screened patients had less understanding
      of the incidence and treatment outcomes of colon cancer. CONCLUSION: Colon cancer
      screening behavior seems to be associated with having a regular primary
      physician, as well as other cancer screening behaviors. Knowledge of colon cancer
      is the most reliable discriminator of prior screening status. There does not seem
      to be any difference in the preferences expressed by never-screened and screened
      patients with respect to the aspects of colonoscopy that they find objectionable.

PMID- 12492210
TI  - Reflecting ophthalmoscope.

PMID- 12492211
TI  - Celiac disease-associated autoimmune cholangitis.
AB  - There is an association between celiac disease (CD) and primary biliary
      cirrhosis, but there is little information regarding the association between CD
      and autoimmune cholangitis (antimitochondrial antibody-negative primary biliary
      cirrhosis). We describe a case of a 60-yr-old woman with chronic serum liver
      biochemistry elevations, recent onset of pruritus, and unexplained iron
      deficiency anemia. Liver biopsy was suggestive of stage 1 primary biliary
      cirrhosis, but serum antimitochondrial antibody testing was negative. Subsequent
      evaluation revealed CD based on markedly elevated antiendomysial antibody titers
      and characteristic histological features on mucosal biopsies. Initiation of a
      gluten-free diet led to resolution of iron deficiency anemia, pruritus, and
      elevated serum liver biochemistries. This suggests that CD may play a direct role
      in the development of autoimmune cholangitis. Additionally, normalization of
      hepatic biochemistries may be achieved without the use of immunosuppressive
      agents in some patients. CD should be considered in all patients diagnosed with
      autoimmune cholangitis as a gluten-free diet may avoid the need for
      immunosuppressive therapy in affected patients.

PMID- 12492212
TI  - Cholangiocarcinoma: the "other" liver cancer on the rise.

PMID- 12492213
TI  - Interferon for postresection recurrence of hepatocellular carcinoma.

PMID- 12492214
TI  - Low-dose aspirin: protection from the panacea.

PMID- 12492215
TI  - Re: Groll et al.--Comparison of IBS-36 and IBS-QOL instruments.

PMID- 12492216
TI  - Endoscopic removal of heterotopic pancreas for the relief of symptoms.

PMID- 12492217
TI  - Retrieval of multiple colonic polyps remains to have problems.

PMID- 12492218
TI  - Abdominal wall pain will be missed until examinations change!

PMID- 12492219
TI  - A pilot study of brush cytology via unsedated esophagoscopy for screening of
      Barrett's esophagus.

PMID- 12492220
TI  - Exacerbation of Crohn's colitis with severe colonic hemorrhage in a patient on
      rofecoxib.

PMID- 12492221
TI  - Severe lower gastrointestinal bleeding in Crohn's disease: successful control
      with infliximab.

PMID- 12492222
TI  - Cecal volvulus after colonoscopy.

PMID- 12492223
TI  - Spirulina-associated hepatotoxicity.

PMID- 12492224
TI  - Sepsis: a frequent, life-threatening syndrome.
AB  - Innovative treatments have enhanced the understanding of the pathophysiology of
      sepsis. An understanding of the underlying nature of the disorder is necessary to
      develop new therapies and determine their roles in treating patients with sepsis.
      By studying and determining the interactions among the inflammatory, coagulation,
      and fibrinolytic pathways, investigators have discovered exciting new areas of
      research into the mechanisms of tissue injury in sepsis.

PMID- 12492225
TI  - Pharmacology, clinical efficacy, and safety of drotrecogin alfa (activated).
AB  - The protein C pathway, which plays an important role in maintaining normal
      hemostasis and is a critical link between the inflammatory and procoagulant host
      responses to infection, is involved in modulating the coagulation and
      inflammation associated with severe sepsis. Recombinant human activated protein C
      (APC), or drotrecogin alfa (activated), shares the intrinsic pharmacologic
      activity of endogenous APC. In the Recombinant Human Activated Protein C
      Worldwide Evaluation in Severe Sepsis (PROWESS) trial, drotrecogin alfa
      (activated) decreased absolute mortality by 6% and relative risk of mortality by
      19% compared with placebo. Drotrecogin alfa (activated) is an important
      advancement in the treatment of adult patients with severe sepsis.

PMID- 12492226
TI  - Pharmacokinetics and clinical use of drotrecogin alfa (activated) in patients
      with severe sepsis.
AB  - Drotrecogin alfa (activated) pharmacokinetics have been reported in healthy
      volunteers and in patients with severe sepsis. Clearance is rapid and appears to
      increase with weight; consequently, drotrecogin alfa (activated) is dosed on a
      weight basis. Drotrecogin alfa (activated) promotes fibrinolysis and inhibits
      thrombin production to produce an anticoagulant effect. The primary adverse
      events are related to its pharmacologic activity, with serious bleeding reported
      in 3.5% of patients receiving the drug in a multicenter phase III trial compared
      with 2.0% for patients receiving placebo. Monitoring parameters correspond with
      bleeding and should include international normalized ratio, platelet count,
      hematocrit, and overt signs of bleeding. Because of the protein nature of
      drotrecogin alfa (activated), pharmacists should be aware of the proper
      preparation and stability issues in order to afford efficient, cost-effective
      administration. As further data on drotrecogin alfa (activated) therapy become
      available, dosing and monitoring strategies may be altered to optimize the
      clinical benefits.

PMID- 12492227
TI  - Current issues regarding the use of drotrecogin alfa (activated).
AB  - The key issues clinicians are facing regarding drotrecogin alfa (activated)
      include questions concerning the pathophysiology and appropriate patient
      selection for administration of this drug. In the Recombinant Human Activated
      Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the efficacy of
      drotrecogin alfa (activated) was demonstrated in patients with severe sepsis.
      Because of this trial's strict inclusion and exclusion criteria, however, the
      applicability of the study criteria to different types of patients raises
      important issues. Coupling the data from the PROWESS trial with additional
      information being gained from expanding clinical experience, as well as
      additional studies, clinicians will be able to better understand and refine the
      use of activated protein C within their respective practices.

PMID- 12492228
TI  - Impact of drotrecogin alfa (activated) on resource use and implications for
      reimbursement.
AB  - Selecting therapies in health care requires rigorous review of clinical and
      economic data. The financial implications of new clinical treatment options are
      an important component. The preferred method for evaluating the costs and effects
      of therapies is cost-effectiveness analysis along with an estimation of utility
      associated with the life-years gained. Preliminary reports suggest patients
      receiving drotrecogin alfa (activated) for severe sepsis have a faster resolution
      of cardiovascular and pulmonary dysfunction with minimal additional financial
      burden despite additional survivors. Furthermore, the reported cost/quality
      adjusted life-year of $48,800 is consistent with many other common life-saving
      measures. Recently approved new technology payments for hospitals treating
      patients with drotrecogin alfa (activated) minimize financial impact. Clinicians
      and administrators should work collaboratively to optimize the therapy of
      patients with severe sepsis, minimize the financial impact on the health care
      system, and maximize the utility of drotrecogin alfa (activated).

PMID- 12492229
TI  - Strategies to optimize drotrecogin alfa (activated) use: guidelines and
      therapeutic controversies.
AB  - Drotrecogin alfa (activated) is a new agent that may substantially affect the
      treatment of patients with severe sepsis. Despite its therapeutic promise,
      treatment with drotrecogin alfa (activated) represents a new challenge for many
      clinicians and health care centers. Specifically, optimizing the appropriate role
      for drotrecogin alfa (activated) requires balancing numerous issues, including
      its efficacy in high-risk patients with its potential for indiscriminate
      administration. One common approach to minimizing indiscriminate administration
      of drotrecogin alfa (activated) and maximizing its efficacy while minimizing its
      toxicity is for hospitals to develop therapeutic guidelines that define how the
      agent should be used. We outline factors that should be considered when
      developing drotrecogin alfa (activated) therapy guidelines and address realistic
      questions that routinely arise in clinical practice regarding the implementation
      of such guidelines and the administration of this product. In general, the
      guidelines must facilitate optimization of drug therapy and not be viewed as
      hurdles to drug therapy Developing clear guidelines that are based on evidence,
      outlining a specific process to facilitate optimal therapy, and educating all
      parties involved are paramount to ensuring that the benefits of therapy are
      maximized.

PMID- 12492230
TI  - The S-state model: a work horse for HRTEM.
AB  - The S-state model describes the dynamical scattering of electrons in a specimen
      foil, consisting of atom columns parallel to the beam direction, such as a
      crystal or a particular crystal defect. In this model the electrons are
      considered to be trapped in the electrostatic potential of an atom column, in
      which it scatters dynamically. This picture allows physical insight, and it
      explains why a one-to-one correspondence is maintained between the exit wave and
      the projected structure, even in case of strong dynamical scattering. Furthermore
      the model can be parameterised in a simple closed analytical form. Apart from the
      computational advantages, the S-state model proves to be very useful to deduce
      the projected structure directly from the exit wave, so as to "invert" the
      dynamical scattering. In this paper the validity of the S-state model, is
      evaluated in much depth by a proper quantum mechanical treatment. The analytical
      parameterisation of the 1S eigenfunction and eigenenergy is discussed. It is
      shown that the method, even in case of small tilts, is valid for most
      thicknesses, currently used in HRTEM studies. Even for closely spaced atom
      columns, such as the dumbbells in Si [1 1 0], Sn [1 1 0] and GaN [1 1 0], the
      positions of the atom columns can be deduced with an accuracy of a few pm.

PMID- 12492231
TI  - Ferroelectric electron holography.
AB  - Ferroelectrics are increasingly important as materials in semiconductor
      technology, e.g. for building non-volatile memory chips. For optimisation of the
      properties of such devices, there is an urgent need for methods, which analyse
      the ferroelectric properties at nanometer scale. Furthermore, the basic
      understanding of the interaction of ferroelectrics with electrons in the
      transmission electron microscopy is still incomplete. It is shown that electron
      holography offers a promising way to understand and investigate ferroelectrics in
      the electron microscope.

PMID- 12492232
TI  - Synchrotron soft X-ray and field-emission electron sources: a comparison.
AB  - The soft X-ray spectral region and the useful range of electron energy-loss
      spectroscopy are very similar, both including the energy range 100-1000 eV.
      Moreover, well-developed monochromators and parallel detection devices with
      comparable resolution exist for both. Despite the differing interactions of
      electrons and photons, many complementary experiments in imaging, spectroscopy
      and diffraction have been performed using both techniques. We therefore compare
      the brightness, degeneracy, monochromaticity, beam size, source size, spatial and
      temporal coherence of field-emission electron beams and soft X-ray synchrotron
      radiation from typical undulators. Recent brightness values for nanotip field
      emitters and undulators, both measured and calculated, are provided with examples
      from the Advanced Light Source synchrotron-radiation facility at Berkeley USA.
      The quantum mechanical upper limit on source brightness, as well as relationships
      among beam brightness, coherence parameters, and degeneracy, are discussed.
      Factors which limit these parameters and methods of measurement are reviewed, and
      the implications for diffraction, imaging and spectroscopic experiments as well
      as radiation damage are briefly commented on.

PMID- 12492233
TI  - Imaging of the boron doping in silicon using low energy SEM.
AB  - Scanning electron imaging of plan views of boron-doped patterns in silicon is
      examined, together with the mechanism of formation of the electronic contrast in
      this kind of structures. Main to-date published results are critically reviewed
      and new data are presented concerning the secondary, backscattered and total
      emission electron contrasts, including their qualitative and quantitative
      behaviour, particularly in the low energy range achieved with the help of the
      cathode lens (the scanning low energy electron microscopy mode, SLEEM). Surface
      analysis of the structure by means of Auger electron spectrometer has been
      performed, too, both before and after ion beam bombardment. The scanning electron
      microscope micrographs, acquired after the oxide mask removal in HF, are examined
      in a variety of detection modes, aiming at identification of the signal component
      primarily bearing the contrast. The energy dependence of the contrasts is
      presented as well as its change owing to alteration in the vacuum conditions. The
      most important findings include an extremely high contrast obtained in the SLEEM
      mode and even more enhanced under medium vacuum conditions at which the
      carbonaceous layer of surface contamination plays its role. The observed
      phenomena are partly explained in the frame of the "flat band" model of a
      passivated surface. The increased contrast in the SLEEM mode is understood as
      connected with the above-surface electric field of the cathode lens, generating
      space charge layers inside the semiconductor. In addition, charge carriers,
      injected via the primary electron beam, are considered as influencing the
      contrast vs. energy dependence.

PMID- 12492234
TI  - Reminiscence on a long successful cooperation.

PMID- 12492235
TI  - Numerical calculation of electron optical aberrations.
AB  - A numerical method for the accurate calculation of aberration figures in systems
      with a straight optical axis is concisely outlined. The method involves computing
      a fundamental set of paraxial rays, and then directly ray-tracing a judiciously
      chosen set of deviations from these paraxial rays, that enable the direct
      plotting of aberration figures. This method avoids using complicated aberration
      integrals, and can directly handle the effects of high-order aberrations and
      asymmetry errors. A fast general predictor-corrector method for the numerical ray
      tracing is also presented.

PMID- 12492236
TI  - BEM simulation of Wien filters.
AB  - The boundary element method can provide accurate solutions to the electromagnetic
      problem in numerical simulations of electron optics devices. In this paper, we
      describe our approach, which applies a subsectional-bases method to generate a
      boundary division, representing the shape and behaviour of the Wien filter
      precisely. We investigate by direct ray tracing the origin of the second-order
      geometrical aberrations of this filter and propose new designs to reduce them.

PMID- 12492237
TI  - Accuracy of electrostatic lens computations with FOFEM.
AB  - The increased speed of personal computers enables fast computation of
      rotationally symmetric electrostatic lenses with the first-order finite element
      method in meshes with a large number of mesh points. In order to produce an
      estimate of accuracy of the computed potential, we propose a simple procedure
      based on doubling the number of mesh points in each coordinate. In this way, we
      can produce for the lower-density mesh at each point the information about error
      of the potential and visualize the sources of the computation errors.

PMID- 12492238
TI  - Simulation methods for multipole imaging systems and aberration correctors.
AB  - Two different methods have been derived and implemented for simulation of
      multipole imaging systems and aberration correctors. The first method uses an
      aberration theory for combinations of multipole lenses and deflectors, including
      primary and secondary aberrations up to the fifth order. A damped least-squares
      algorithm is used to minimise the dynamically correctable aberrations. This
      yields the appropriate signals for the dynamic correction elements, e.g.
      stigmators and dynamic focus lenses. The second method uses a direct ray-tracing
      approach. The numerically computed multipole lens and deflection fields are
      fitted with analytic functions through which trajectories are directly traced
      with a high degree of self-consistency. By computing the paths of many particles
      simultaneously, the combined effects of aberrations and discrete Coulomb
      interactions are accurately simulated. Furthermore, the effects of electrical and
      mechanical asymmetries on the multipole elements can readily be simulated with
      this approach.

PMID- 12492239
TI  - Theory of electron-optical achromats and apochromats.
AB  - A detailed theoretical formulation of the primary and secondary chromatic
      aberrations of electron-optical systems with a straight optic axis is outlined.
      To simplify the mathematical expenditure only systems composed of magnetic round
      lenses and magnetic and electrostatic quadrupoles are taken into account. By
      appropriately arranging these elements, it is possible to construct feasible
      electron-optical analogues of light-optical achromats and apochromats.

PMID- 12492240
TI  - Simplified computation of third-rank image aberrations of electron-optical
      systems with curved axis.
AB  - Using the classical perturbation theory only the image aberrations of second rank
      of an electron-optical system with a curved axis are easy to obtain. Analytical
      integral expressions of these second-rank aberrations were already published in
      German by Plies and Typke (Z. Naturforsch. 33a (1978) 1361, 35a (1980) 566). They
      employed the eikonal method in the case of arbitrary electrostatic and stationary
      magnetic fields without space charge and currents in the beam region. Their
      results are repeated briefly in English and a method is discussed of how a
      magnetic round lens field can be considered in the case of a system with a single
      section symmetry, i.e., an orthogonal system with no torsion of the curved optic
      axis. Then the important second-rank fundamental trajectories are introduced
      which are directly related to the integral expressions already given in Plies and
      Typke (1978). Then the secondary aberrations (obtained by the second step of the
      successive approximation method) and the complexity of the third-rank aberrations
      are discussed. After that two new methods are proposed for a simplified
      calculation of the third-rank image aberrations. Both proposals use the second
      rank fundamental trajectories and the second proposed method additionally uses
      the spatial potential and field achieved by using a three-dimensional field
      solver. Since these two simplified computation methods are still rather
      complicated an additional method based on ray tracing is discussed. For this
      purpose a trajectory equation with respect to the curved optic axis and well
      suited for numerical integration with high accuracy is derived. This offers the
      possibility of exact numerical ray tracing of selected and representative axial
      and field rays. After subtracting from such a ray the known first- and second
      rank ray with the same trajectory parameters (aperture, off-axial coordinate,
      energy deviation) one obtains the complete residual aberration.

PMID- 12492241
TI  - Low-energy foil aberration corrector.
AB  - A spherical and chromatic aberration corrector for electron microscopes is
      proposed, consisting of a thin foil sandwiched between two apertures. The
      electrons are retarded at the foil to almost zero energy, so that they can travel
      ballistically through the foil. It is shown that such a low-voltage corrector has
      a negative spherical aberration for not too large distances between aperture and
      foil, as well as a negative chromatic aberration. For various distances the third
      and fifth-order spherical aberration coefficients and the first- and second
      order chromatic aberration coefficients are calculated using ray tracing.
      Provided that the foils have sufficient electron transmission the corrector is
      able to correct the third-order spherical aberration and the first-order
      chromatic aberration of a typical low-voltage scanning electron microscope.
      Preliminary results show that the fifth-order spherical aberration and the second
      order chromatic aberration can be kept sufficiently low.

PMID- 12492242
TI  - Aberration characteristics of immersion lenses for LVSEM.
AB  - This paper investigates the on-axis aberration characteristics of various
      immersion objective lenses for low voltage scanning electron microscopy (LVSEM).
      A simple aperture lens model is used to generate smooth axial field
      distributions. The simulation results show that mixed field electric-magnetic
      immersion lenses are predicted to have between 1.5 and 2 times smaller aberration
      limited probe diameters than their pure-field counterparts. At a landing energy
      of 1 keV, mixed field immersion lenses operating at the vacuum electrical field
      breakdown limit are predicted to have on-axis aberration coefficients between 50
      and 60 microm, yielding an ultimate image resolution of below 1 nm. These
      aberrations lie in the same range as those for LVSEM systems that employ
      aberration correctors.

PMID- 12492243
TI  - Initial resolution measurements of miniaturized electrostatic lenses for LVSEM.
AB  - Theoretical and experimental investigations on miniaturized electrostatic lenses
      for high-resolution low-voltage scanning electron microscopical applications are
      presented. The electron optical column consists of a Schottky emitter including
      the extraction anode and a miniaturized three electrode lens consisting of
      conventional (electron microscopical) platinum apertures. The lens has been
      optimized with respect to resolution and a value of about 5 nm at a working
      distance of 1 mm and a beam energy of 1 keV is predicted by simulation. Details
      on the resolution measurements are presented. An initial experimental value
      amounts to 31 nm. Specific problems encountered during building and alignment of
      the lens and measuring the resolution are discussed as well.

PMID- 12492244
TI  - Electron-electron interactions in cathode objective lenses.
AB  - The impact of electron-electron interactions on the electron-optical performance
      of imaging cathode objective lenses is evaluated. Three types of cathode
      objectives are considered: decelerating and accelerating electrostatic, and
      combined magnetic lenses. The beam blur is calculated for field sizes ranging
      from 50 microm x 50 microm to 500 microm x 500 microm and total beam currents
      ranging from 200 nA to 20 microA. The functional dependence of the beam blur upon
      electron beam current and current density is elucidated in detail.

PMID- 12492245
TI  - Gait in children with juvenile chronic arthritis. Timing and force parameters.
AB  - OBJECTIVES: To examine gait in children with juvenile chronic arthritis (JCA)
      with reference to velocity, ground reaction forces and temporal parameters.
      METHODS: Fifteen children with JCA were assigned into two groups (uni- and
      bilateral involvement and classified as pauci- or polyarticular arthritis).
      Fourteen healthy children participated in the control group. Light-beams were
      used to determine walking velocity and the children with JCA rated their pain on
      a visual analogue scale. Two force plates registered the ground reaction forces
      and foot-switches were used to obtain temporal parameters. RESULTS: The mean
      velocity for the children with JCA was significantly less than for the healthy
      controls. Velocity normalized to height showed a tendency for the children with
      JCA to walk slower than controls. Differences between JCA children and healthy
      controls were observed for peak vertical forces during heel contact and push-off.
      No temporal differences were observed between the groups. CONCLUSIONS: Such
      kinetic and temporal information may provide the clinician with a sensitive tool
      for pre- and post assessment of intra-articular steroid injections and/or
      physical therapy.

PMID- 12492246
TI  - Patients' views of priority setting for new medicines. A qualitative study of
      patients with rheumatoid arthritis.
AB  - OBJECTIVE: To identify rheumatoid arthritis patients' perceptions about what
      should govern priority setting for the new class of high-cost anti-rheumatics,
      the TNF inhibitors. METHODS: Qualitative study employing semi-structured
      interviews of 22 patients diagnosed with rheumatoid arthritis at three hospitals
      in the region of Stockholm, Sweden. The interviews were conducted from December
      1999 to March 2000. RESULTS: Patients suggest that a basis for priority setting
      should be need, including priority to persons with severe and/or early disease,
      and to those not responding to other anti-rheumatics. Some patients believe that
      age and productivity have to be taken into account in priority setting, while
      others oppose this view. Some patients want the individual physician to carry out
      priority setting, while others consider this too arbitrary. Respondents often
      suggest criteria unfavourable to themselves. Alongside suggestions for priority
      setting criteria, there is also a notion that, ideally, priority setting should
      not have to take place at all. CONCLUSIONS: Patients' views of priority setting
      are not necessarily influenced by the patients' individual needs and may
      contribute to the development of priority guidelines. Knowledge of the patients'
      perceptions of priority setting for a specific treatment might also support
      patient-provider discussions on priority setting.

PMID- 12492247
TI  - Light and electron microscopic analysis of liver biopsy samples from rheumatoid
      arthritis patients receiving long-term methotrexate therapy.
AB  - OBJECTIVE: We study liver damage in forty-two patients with rheumatoid arthritis
      (RA) using light (LM) and electron microscopy (EM) and assess histological
      changes after four years of treatment with methotrexate (MTX). PATIENTS AND
      METHODS: liver biopsies (LB) were taken before and after four years of treatment.
      Patients received weekly doses of between 7.5-15 mg of MTX. RESULTS: Fourteen per
      cent of the baseline LB presented mild perisinusoidal fibrosis (Roenigk IIIA) and
      the rest a lower Roenigk grade; EM identified an increase in collagen fibers in
      the Disse spaces in 50% of baseline LB. Neither microscopy technique revealed
      histological progression in any of the sequential LB. Variables that correlated
      with histological abnormalities were patient's age, length of evolution of the
      disease, alcohol consumption and biochemical data (gammaglutamate transferase and
      albumin); the cumulative dose of MTX was not correlated with worse histological
      findings. Correlation between the two microscopy techniques was good, though EM
      was more sensitive than LM for the detection of fibrosis. CONCLUSIONS: RA
      patients present with liver damage before treatment with MTX. The alterations are
      mild. At low doses MTX treatment is safe. In addition to the recommendations of
      the American College of Rheumatology, other factors associated with liver
      impairment are patient's age and length of evolution of the RA.

PMID- 12492248
TI  - Comparison of low-dose rofecoxib versus 1000 mg naproxen in patients with
      osteoarthritis. Results of two randomized treatment trials of six weeks duration.
AB  - OBJECTIVE: To compare the efficacy and safety of rofecoxib 12.5 mg once daily to
      naproxen 500 mg twice daily in patients > or = 40 years of age with knee or hip
      osteoarthritis (OA). METHOD: Two identical 6-week, randomized, double-blind
      studies were conducted (1 in Africa, Australia, Europe, Canada, Mexico, & South
      America; 1 in Asia). Primary endpoints were pain walking on a flat surface,
      patient global assessment of response to therapy, and investigator global
      assessment of disease status. RESULTS: Overall, 944 patients participated. For
      all efficacy endpoints, treatment effects for rofecoxib and naproxen were
      comparable and seen at the first measures of efficacy. Both compounds were
      generally well-tolerated, with an improved gastrointestinal safety profile for
      rofecoxib versus naproxen. CONCLUSIONS In these studies, rofecoxib 12.5 mg once
      daily (the lowest indicated dose) and naproxen 500 mg twice daily showed similar
      treatment effects in OA patients. Rofecoxib and naproxen were generally well
      tolerated.

PMID- 12492249
TI  - Aerobic and neuromuscular performance capacity of physically active females with
      early or long-term rheumatoid arthritis compared to matched healthy women.
AB  - OBJECTIVE: To examine aerobic capacity and neuromuscular performance in
      physically active females with early or long-term rheumatoid arthritis (RA) and
      healthy women. METHODS: Twenty-three RA-patients (12 early RA patients (ERA). 11
      long-term RA (LRA) and 12 healthy controls (HC) performed maximal aerobic oxygen
      uptake (VO2max), muscle force production. walking and jump tests. RESULTS: The
      VO2max ranged between 23-27 ml x kg(-1) min(-1) and did not differ between the
      groups. Isometric grip strength was 25% (p = 0.017) and bilateral leg extension
      strength 19% (p = 0.031) lower in LRA patients compared to ERA. In LRA the
      explosive force (p = 0.023) and relaxation times (p = 0.025-0.032) of bilateral
      leg extension and vertical squat jump (p = 0.015) did not reach the level of HC
      or ERA. The trunk muscle forces did not differ between the groups. CONCLUSIONS:
      The physically active females even with LRA could maintain their aerobic fitness
      comparable to that of age matched healthy subjects. However, the neuromuscular
      profile suggests that especially explosive strength characteristics of the leg
      extensors cannot be maintained at the normal level with habitual physical
      activities.

PMID- 12492250
TI  - Leukocyte protein calprotectin and outcome in rheumatoid arthritis. A
      longitudinal study.
AB  - OBJECTIVE: To determine if calprotectin is predictive for outcome in patients
      with rheumatoid arthritis (RA). METHODS: Fifty six RA in-patients with variable
      disease duration were prospectively followed for five years. Clinical and
      laboratory data were collected to assess disease activity. Health Assessment
      Questionnaire (HAQ) and radiographic scores (of hands and wrists) as described by
      Larsen were used as outcome measures. Plasma calprotectin levels were determined
      with ELISA technique. RESULTS: Significant correlations (r) were found cross
      sectionally at follow-up between calprotectin concentration and other known
      parameters of disease activity and severity: CRP (r = 0.67). investigator's
      global assessment of disease activity (r = 0.57). Waaler titre (r = 0.50). HAQ
      score (r = 0.48) and number of swollen joints (r = 0.48). Calprotectin at
      baseline was not identified as an independent predictor for HAQ or radiographic
      progression in the multivariate analysis. CONCLUSION: The results confirm
      calprotectin as a good measure of disease activity and joint inflammation in RA.
      However, the level of calprotectin at baseline was not predictive for
      radiographic damage or functional impairment five years later.

PMID- 12492251
TI  - CD14 and TNfa promoter polymorphisms in patients with acute arthritis. Special
      reference to development of chronic spondyloarthropathy.
AB  - OBJECTIVE: To examine CD14 and TNFalpha gene polymorphisms in early arthritis in
      relation to clinical outcome. METHODS: We studied 141 Caucasians who had had
      early arthritis 10 to 38 years earlier. We analysed CD14 (-159) and TNFalpha (
      238, -308, -376) polymorphisms using a novel cycle minisequencing method. DNA
      pools from 370 Caucasian blood donors served as controls. RESULTS: CD14 (-159)C-
      >T allele frequencies were comparable among patients and controls (39% vs 40%).
      Fifty men and 42 women had recovered while 24 men and six women had chronic
      spondyloarthropathy (SpA). Mutant T allele frequency was higher in the chronic
      SpA group than in the recovered group in women (75% vs 32%, relative risk 1.3,
      95% confidence limit 1.1 to 1.6, P = 0.011), but not in men (38% vs 44%). All
      female patients with chronic SpA had CD14 (-159)T allele and none had a possibly
      protective TNFalpha (-308)G-->A allele. CONCLUSIONS: Possession of CD14 (-159)T
      allele does not increase risk of ReA but may increase susceptibility of female
      patients to development of chronic SpA.

PMID- 12492252
TI  - The significance of mannan-binding lectin gene alleles in patients with primary
      Sjogren's syndrome.
AB  - OBJECTIVE AND METHODS: To investigate the significance or mannan-binding lectin
      (MBL) gene alleles in patients with primary Sjogren's syndrome (pSS). Genotypes
      were determined in 65 pSS patients and 138 controls. RESULTS: No difference in
      MBL genotype or allele frequencies was detected between the pSS patients and
      controls. However, when the effect of MBL genotypes on the diagnostic findings in
      pSS patients was assessed, none of the eight patients with 52/w genotype
      fulfilled four (definite) Californian criteria (P = 0.007). Among these eight the
      Chisholm-Mason histological grade was > or = 3 in only three (P = 0.017).
      Furthermore, the MBL concentration was lower in patients with 52/w genotype
      compared to those with wild-type (w/w) genotype (P = 0.035). CONCLUSION: Our
      findings suggest that MBL structural gene polymorphisms do not influence on
      susceptibility to pSS. However, MBL may be associated with salivary gland
      destruction in pSS, and its concentration may be comparable with the intensity of
      inflammatory reaction. Further studies are warranted to clarify the possible
      mechanisms involved.

PMID- 12492253
TI  - Local treatment of tendinopathies: a comparison between tropisetron and depot
      corticosteroids combined with local anesthetics.
AB  - OBJECTIVE: To determine whether local injection of the 5-HT3-receptor antagonist,
      tropisetron. reduces pain in tendinopathies to the same degree as a local
      injection of corticosteroids in combination with local anesthetic. METHODS: Forty
      patients with tendinopathies were enrolled in this randomized, observer-blind
      study. An injection of either 5 mg tropisetron. or 10 mg dexamethasone combined
      with 60 mg lidocaine was administered around the affected tendon. The effect was
      measured with a visual analog pain scale before the injection, after 3 hours and
      on each of the following 7 days, in patients with good effects also 3 months
      after the injection. RESULTS: There were no significant differences between the
      tropisetron and the corticosteroid/anesthetic group in terms of pain at rest or
      on movement during the study. Both treatments were well tolerated. CONCLUSION:
      Local injection of tropisetron seems to be as safe and as effective as the
      combination of corticosteroids and local anesthetics in the treatment of painful
      tendinopathies.

PMID- 12492254
TI  - Purpura fulminans and anticardiolipin antibodies in a patient with Grave's
      disease.
AB  - We describe a patient with Grave's discase who developed purpura fulminans and
      who was found to have anticardiolipin antibodies after being started on
      propylthiouracil (PTU). We discuss the potential role of the antiphospholipid
      antibody in this woman's presentation, and its association to both PTU and
      autoimmune thyroid disease.

PMID- 12492255
TI  - A case of systemic lupus erythematosus that manifested in the course of
      schizophrenia.
AB  - A case of schizophrenia is presented in which SLE was diagnosed after 14-year
      duration. Antibodies to single and double-stranded DNAs, but not to histone. were
      detected. This case suggests that similar immunological abnormalities as SLE are
      associated with the pathogenesis of a group of schizophrenia and that class
      switch of anti-dsDNA antibodies are important in the pathogenesis of SLE.

PMID- 12492256
TI  - Subacute cutaneous lupus erythematosus in a patient with rheumatoid arthritis.
AB  - A 51-year woman with a seropositive rheumatoid arthritis (RA) developed
      antiLa/SSB antibodies and erythematosquamous lesions on her upper back. The
      histological diagnosis was subacute cutaneous lupus erythematosus (SCLE)
      (papulosquamous form). There was no indication or a drug-induced SCLE. The
      concurrence of RA and SCLE seems to be rare. We review the clinical, serologic
      and immunogenetic features in these patients with coexistent RA and SCLE.

PMID- 12492257
TI  - Modified Larsen score--a comment.

PMID- 12492258
TI  - Integrating social model principles into broad-based treatment: results of a
      program evaluation.
AB  - Although traditional social model recovery programs appear to be decreasing, some
      aspects of social model recovery continue to exert a strong influence in broad
      based, integrated programs. This article describes a four-week program that
      integrates licensed therapists, certified counselors, psychiatric consultation,
      and social model recovery principles into a broad-based treatment approach. The
      Social Model Philosophy Scale revealed a low overall rating on social model
      philosophy. However, social model principles that were heavily stressed included
      practicing 12-step recovery, the importance of getting a 12-step sponsor, staff
      client interactions outside a formal office, employing staff who are in recovery,
      and emphasizing a goal of abstinence. Three- and six-month follow-up revealed
      significant improvement in alcohol and drug use, heavy alcohol use, satisfaction
      with family relationships, 12-step involvement, illegal behaviors, arrests,
      unsafe sex, self-esteem, use of medical resources, and health status. Findings
      provide a rationale for larger, multi-site studies that assess the effectiveness
      of social model characteristics using multivariate techniques.

PMID- 12492259
TI  - Improving the organization, management, and outcomes of substance abuse treatment
      programs.
AB  - OBJECTIVE: This study presents an organizing framework for empirical analyses of
      substance abuse treatment program effectiveness, based on relevant theories of
      organization and public management and the body of substance abuse treatment
      studies, and is applied in analyses of treatment program data. METHOD: We use
      descriptive analyses of data from the National Treatment Improvement Evaluation
      Study that were collected from 519 substance abuse treatment service delivery
      units and 6593 patients to identify instruments of policy and management that
      might either frustrate or facilitate the implementation of "best practices" in
      substance abuse treatment. RESULTS: The analyses show statistically significant
      and substantively interesting relationships among measures of organizational
      structure and mission, financial management (e.g., revenues per patient and
      revenue sources), human resources management (e.g., staffing levels, the use of
      case managers, etc.), and measures of service technology (e.g., the provision of
      supportive services, counseling intensity, etc.). CONCLUSION: Researchers should
      strive to measure and account for the significant interactions among structural,
      management, and service technology variables in substance abuse treatment
      programs and the impact of these variables, mediated through patient
      characteristics and pre-treatment histories, on treatment outcomes.

PMID- 12492260
TI  - Arrestees' perceived needs for substance-specific treatment: exploring urban
      rural differences.
AB  - An interview study among a group of arrestees in seven county jails was conducted
      in the state of Ohio between June 1999 and September 2001, examining the
      prevalence of alcohol and drug dependence within the group and assessing the need
      for substance-abuse treatment. Four of the county jails where interviews were
      conducted are in urban areas, and three are in rural areas. The present study
      focused on demographic variables, situation-related factors, current drug
      dependence diagnoses, past treatment experience, and jail location-rural or
      urban. It sought to assess whether these factors predicted arrestees' perceived
      needs for substance-specific treatment (for alcohol, marijuana, cocaine, and/or
      opiate addiction); and, further, whether any predictors of a perceived need for
      treatment would be identical for arrestees housed in rural jails and those housed
      in urban jails. The results show that some of the factors assessed do exert
      differential effects on rural and urban arrestees' perceived needs for substance
      specific treatment. Future treatment policy within the criminal justice system
      should perhaps take into account inmates' individual characteristics and the
      rural or urban location of the jail initiating their processing. It may be
      possible, by paying attention to these variables, to enhance inmates' motivation
      to enter treatment programs, leading ultimately to drug-use cessation.

PMID- 12492261
TI  - Rates of psychiatric comorbidity among U.S. residents with lifetime cannabis
      dependence.
AB  - Cannabis is the most widely used illegal drug in the U.S. population. Surveys
      have estimated that the lifetime prevalence rate for cannabis dependence is
      approximately 4%. Though the presence of a psychiatric disorder increases the
      likelihood of developing substance dependence, the field lacks data regarding the
      association between mental disorders and cannabis dependence. The aim of this
      study is to describe the prevalence of psychiatric disorders among individuals
      with cannabis dependence. The National Comorbidity Survey was used to obtain
      these data. We found that 90% of respondents with cannabis dependence had a
      lifetime mental disorder, compared to 55% without cannabis dependence. Alcohol
      dependence, antisocial personality disorder, and conduct disorder had the
      strongest associations with cannabis dependence, followed by anxiety and mood
      disorders. A large proportion of respondents with internalizing disorders
      developed mood or anxiety disorders prior to onset of their first cannabis
      dependence symptom. Data regarding the prevalence of comorbid mental disorders
      underscore the importance of thorough and systematic evaluation of patients
      seeking treatment for cannabis dependence. The failure to identify comorbidity
      may lead to inadequate treatment, and a poorer prognosis.

PMID- 12492262
TI  - Computer detection of cognitive impairment and associated neuropsychiatric
      dimensions from the content analysis of verbal samples.
AB  - This is a report of a study testing the capacity of a computerized measure of the
      content analysis of five minute verbal samples to detect and measure cognitive
      impairment and comorbid neuropsychiatric dimensions in 117 drug-abusing
      inpatients. The cognitive impairment scores obtained from the computerized
      procedure correlated significantly with independent scores from the Trails B and
      Stroop Color and Word test as well as with ANAM (Automated Neuropsychiatric
      Assessment Metric) neuropsychological tests, including the Matching to Sample
      Efficiency and Accuracy, the Code Substitution Efficiency, the Continuous
      Performance Task Efficiency and Accuracy, the Code Substitution Delayed Recall
      Accuracy, and the Simple Reaction Time Efficiency. When the computerized verbal
      content-analysis-derived cognitive impairment scores were combined with scores of
      selected other ANAM measures, more and higher intercorrelations occurred with
      Trails A, Trails B, the Stroop Color and Word test, and the Wisconsin Card Sort
      test. In addition, validated measures of a broad range of associated
      neuropsychiatric dimensions can be obtained simultaneously from the same five
      minute verbal samples providing the cognitive impairment scores. No significant
      effects were found on the cognitive impairment scores of age, education, gender,
      race, and duration of drug-abuse abstinence.

PMID- 12492263
TI  - Nicotine intervention during detoxification and treatment for other substance
      use.
AB  - This preliminary study evaluated the efficacy of a brief smoking cessation
      intervention (30 controls, 34 intervention groups) on a smoke-free inpatient unit
      for substance use detoxification. Controls received usual care, including the
      transdermal nicotine patch and referral to an outpatient smoking program. The
      intervention group additionally received a structured motivational enhancement
      program. Biochemically confirmed smoking cessation rate and abstinence/reduction
      of alcohol or other drug use were the main outcome measures taken 6 months after
      treatment initiation. The smoking cessation intervention did not result in
      greater participation in formal outpatient smoking cessation treatment and was
      not associated with either enhanced smoking cessation (6 vs. 0%) or greater
      smoking reduction at follow-up. Both groups significantly reduced the number of
      cigarettes smoked per day (cpd) from about 24 at baseline to 10cpd. The groups
      did not differ on abstinence from nonnicotine addictive substances. Smoking
      cessation treatment in substance users undergoing detoxification resulted in
      little or no smoking cessation advantage.

PMID- 12492264
TI  - The RAFFT as a screening tool for adult substance use disorders.
AB  - The purpose of this study was to evaluate the specificity and sensitivity of the
      RAFFT, a brief screening tool, in adult patients with substance use disorders
      (SUD) when presenting to a psychiatric emergency room. A total of 215 patients
      were evaluated with the RAFFT, the CAGE, the Mini International Neuropsychiatric
      Interview, and urine drug screens. The RAFFT performed well in adults with SUD
      and was not influenced by factors such as gender, race, socioeconomic status, or
      the co-existence of psychiatric disorders. In alcohol use disorders, the CAGE
      performed better than the RAFFT, due to the lower specificity (or more false
      positive answers) of the latter.

PMID- 12492265
TI  - Drugs and substances: views from a Latino community.
AB  - The last three decades have seen an increase in the study of licit and illicit
      substance use and abuse. Very few studies, however, have been conducted to show
      the views of minority people on what substance abuse really is and how it affects
      their families and communities, although connections have often been made between
      crime and minority involvement in drug trafficking, use and abuse. This
      exploratory study presents an attempt to explore Latino or Hispanic people's
      perceptions and attitudes regarding the use and abuse of both licit and illicit
      substances, in a Texas City. Further, it is set up to examine individuals' views
      on drugs' definitions, their use in their community, and their effects on abusive
      and violent behavior in the family. The findings indicate that although
      individuals in this Hispanic community hold views on drugs similar to those in
      other communities, they nonetheless place most importance on the impact of the
      use of legal substances (alcohol and tobacco) on problem creation.

PMID- 12492266
TI  - Genetic segregation analysis of alcohol and other substance-use disorders in
      families with recurrent, early-onset major depression.
AB  - OBJECTIVE: The goal of this study was to conduct a complex segregation analysis
      of alcohol and other substance-use disorders in families identified by probands
      with recurrent, early-onset major depression (RE-MDD). METHOD: Eighty-one
      families were identified through probands over the age of 18, who met criteria
      for recurrent (> or = 2 episodes), early-onset (< or = 25 years), nonpsychotic,
      unipolar major depression (RE-MDD) and included 407 first-degree relatives and
      835 extended relatives. Psychiatric diagnoses for probands and their family
      members who provided blood samples were formulated from structured personal
      interviews, structured family history assessments, and available medical records.
      The remaining family members who participated and those who were deceased were
      evaluated through the family history method augmented by available medical
      records. Best estimate diagnoses were made during a consensus conference
      according to established diagnostic criteria. Segregation analyses were performed
      using the REGD routine in S.A.G.E. release 4.0. RESULTS: The best-fitting models
      for the transmission of "alcohol use disorders" or "alcohol/other substance use
      disorders" were sex-dependent Mendelian recessive models with significant
      residual spousal effects. Moreover, the parameter estimates for the models were
      very similar for these phenotypes. In contrast, the segregation analysis of
      "substance use disorder" supported a transmissible, but non-Mendelian, major
      effect. CONCLUSIONS: Our results suggest that a major locus contributes to the
      expression of alcohol use disorders or alcohol/other substance-use disorders
      within families identified by probands with RE-MDD. Due to the limitations of the
      segregation analysis model, our results cannot address whether the same major
      locus is segregating across families in our sample or whether multiple major loci
      are involved (genetic heterogeneity). Previous studies supported single gene
      transmission of recurrent major depression and major mood disorders in these
      families [Marazita et al. Am. J. Hum. Genet. 1997, 61, 1370-1378; Maher et al.
      Am. J. Med. Genet. (Neuropsychiatr. Genet.) 2002. 114 (2), 214-221]. Mounting
      evidence suggests that at.least some of this "comorbidity" may result from the
      effects of shared susceptibility genes or an overlap in the sets of genes that
      contribute to the vulnerability of developing these mental disorders [Zubenko,
      G.S. Mol. Psychiatry 2000, 5, 131-136].

PMID- 12492267
TI  - Environmental influences on alcohol consumption practices of alcoholic beverage
      servers.
AB  - Public drinking establishments have long been associated with heavy drinking
      among both their patrons and servers. Whether these environments represent
      locations where heavy drinking is learned (learning hypothesis) or simply places
      where already-heavy drinkers gather in a supportive environment (selection
      hypothesis) remains an important question. A sample of licensed alcoholic
      beverage servers in the state of Indiana, USA, was surveyed to better understand
      the drinking behaviors of servers within the alcohol service industry. Responses
      (N = 938) to a mailed questionnaire were analyzed to assess the relative
      influence of environmental and demographic factors on the drinking behavior of
      servers. Stepwise regression revealed "drinking on the job" as the most
      influential environmental factor on heavy drinking behaviors, followed by age and
      gender as influential demographic factors. Support was found for the selection
      hypothesis, but not for the learning hypothesis. Policy implications are
      discussed. factors on the drinking behavior of servers. Stepwise regression
      revealed "drinking on the job" as the most influential environmental factor on
      heavy drinking behaviors, followed by age and gender as influential demographic
      factors. Support was found for the selection hypothesis, but not for the learning
      hypothesis. Policy implications are discussed.

PMID- 12492268
TI  - Psychiatric illness in a clinical sample of children with prenatal alcohol
      exposure.
AB  - The purpose of this study was to describe psychiatric disorders exhibited by
      children with prenatal alcohol exposure. Twenty-three children between the ages
      of 5 and 13 years who were referred to the UCLA Fetal Alcohol and Related
      Disorders Clinic because of heavy exposure to alcohol in utero were evaluated.
      Children with intelligence quotients of 70 and above and their families were
      interviewed by the study child psychiatrist and psychologist and psychiatric
      diagnoses were based upon DSM-IV diagnostic criteria. Inter-observer reliability
      of diagnosis was established comparing clinical diagnoses with diagnoses made
      using the "best-estimate" procedure. For the best estimate method, items from the
      Child Behavior Checklist, the Fetal Alcohol Behavior Scale, the Child Symptom
      Inventory-4, the Conners' Rating Scale, as well as information from historical
      records were reviewed by two experienced clinicians who were blind to the
      diagnostic and alcohol exposure status of the children. Approximately 87% of the
      sample met criteria for a psychiatric disorder. The majority of the children
      (61%) were assigned a mood disorder diagnosis. Twenty-six percent were diagnosed
      with major depressive disorder or adjustment disorder with depressed mood and 35%
      met criteria for bipolar disorder. Psychiatric disorders are common in children
      with prenatal alcohol exposure. In particular, these children seem to be highly
      vulnerable to mood disorders. There is a need for training in how to recognize
      the physical and behavioral phenotypes of children with prenatal alcohol exposure
      so that appropriate treatment can be initiated early.

PMID- 12492269
TI  - Determining the resting position of the glenohumeral joint: a cadaver study.
AB  - STUDY DESIGN: Single-session repeated-measures design. OBJECTIVE: To define the
      resting position of the glenohumeral joint by investigating the magnitude of the
      anterior and posterior displacements of the humeral head and medial and lateral
      rotation ranges of motion (ROMs) of the glenohumeral joint at different abduction
      angles in cadaver specimens. BACKGROUND AND PURPOSE: The resting position of a
      joint is the position in the joint's ROM at which the joint capsule has its
      greatest laxity. It is frequently chosen as the position for assessing and
      treating joints with dysfunction. However, no study has been conducted to
      determine the resting position of the glenohumeral joint. METHODS: Seven freshly
      frozen cadaver shoulder specimens (age at time of death [mean +/- SD] was 66.9 +/
      2.5 years) were studied. Specimens were mounted on a system that uses computer
      controlled hydraulics and motors to induce and monitor translation and rotation
      movements of the glenohumeral joint. The magnitudes of total displacement
      (DTotal) of the head of the humerus and total ROM (RTotal) of the glenohumeral
      joint were measured in the plane of the scapula at 0 degrees (neutral), 30
      degrees, 40 degrees, 50 degrees, 60 degrees, and the end range of glenohumeral
      joint abduction. The resting position was determined as the midpoint of the
      shared range of the 95% to 99.9% confidence intervals of the predicted abduction
      position where the peaks of displacement and rotation occurred. RESULTS: The
      DTotal measurements (mean +/- SD) at 0 degrees, 30 degrees, 40 degrees, 50
      degrees, 60 degrees, and the end range of glenohumeral joint abduction were 30.53
      +/- 9.35, 44.87 +/- 7.34, 45.35 +/- 8.53, 43.99 +/- 10.02, 39.63 +/- 9.85, and
      23.80 +/- 10.42 mm, respectively. The RTotal measurements (mean +/- SD) for the
      same positions were 67.15 degrees +/- 15.87 degrees, 95.64 degrees +/- 24.26
      degrees, 98.88 degrees +/- 29.56 degrees, 97.08 degrees +/- 30.17 degrees, 90.91
      degrees +/- 28.73 degrees, and 63.48 degrees +/- 25.93 degrees, respectively. The
      resting position was located at 39.33 degrees +/- 4.37 degrees of glenohumeral
      abduction (45.13% +/- 7.58% of the available abduction ROM). The resting position
      (Y) varied linearly with the maximum available abduction ROM (X) (Y = 0.607X -
      13.120, R2 = 0.679, F = 10.61, P = 0.023). There was a main effect of joint
      position on both displacement (P<0.001) and rotation ROM (P<0.001). CONCLUSION:
      In the plane of the scapula, the resting position of the glenohumeral joint
      (angle measured between the scapula and humerus) occurred at 39 degrees of
      abduction (45% of the maximum available abduction ROM) and varied linearly with
      the amount of available abduction ROM. This finding suggests that in patients
      with glenohumeral joint hypomobility the resting position is located closer to
      neutral and that evaluation and treatment should be initiated accordingly at a
      smaller angle of abduction than the traditional resting position. Our data were
      derived from cadaver specimens, therefore, caution should be taken when
      generalizing the results of the present study to a patient population.

PMID- 12492270
TI  - Differential diagnosis of a sacral stress fracture.

PMID- 12492271
TI  - Ankle cryotherapy facilitates soleus function.
AB  - STUDY DESIGN: A 2-factor (group and time) experimental design with repeated
      measures on time. OBJECTIVES: To determine the effects of ankle cryotherapy on
      voluntary and resting motor function of the soleus over a 60-minute period. To
      determine if a relationship exists between changes in torque production and
      Hoffmann reflex (H-reflex) following ankle joint cryotherapy treatment.
      BACKGROUND: Controversy surrounds the use of cryotherapy prior to activity and
      rehabilitation. While cooling muscle may have a deleterious effect on motor
      function, cooling the joint may enhance motor function around the joint. The H
      reflex is a good resting measure of motoneuronal activity. However, its
      relationship to voluntary activity is unknown. METHODS AND MEASURES: Thirty
      subjects were pretested (baseline) for normalized H-reflex (defined as the ratio
      of maximum H-reflex [Hmax] to maximum direct motor response [Mmax]) and peak
      plantar flexion torque. A crushed ice bag was placed over the ankle of 15
      subjects for 30 minutes. H-reflex and torque measurements were collected
      immediately following the cryotherapy treatment at 30, 60, and 90 minutes.
      Surface temperatures were recorded from the ankle and electrode site with each
      measurement interval. RESULTS: Both peak H-reflex and plantar flexion torque at
      30, 60, and 90 minutes increased relative to baseline measurements. Each
      measurement was also greater than the corresponding control at 30, 60, and 90
      minutes. A weak correlation (r = 0.38; P = 0.036) existed between changes in H
      reflex and plantar flexion torque at 30 minutes. CONCLUSIONS: The soleus
      motoneuron pool is facilitated following a 30-minute crushed ice application to
      the ankle and over a 60-minute postcooling period. These data support the use of
      joint cooling prior to activity and rehabilitation.

PMID- 12492272
TI  - Effect of ankle taping and bracing on vertical ground reaction forces during drop
      landings before and after treadmill jogging.
AB  - STUDY DESIGN: Single-group repeated-measures experimental design. OBJECTIVES: The
      purpose of this study was to evaluate the effects of prophylactic ankle
      stabilization on vertical ground reaction forces before and after treadmill
      jogging. BACKGROUND: Previous research has demonstrated acute effects of ankle
      taping and bracing on ankle joint kinematics and vertical ground reaction forces
      during drop landings. Based on the number of investigations demonstrating
      increased range of motion of the braced or taped ankle following exercise, it may
      be plausible that the aforementioned landing alterations may return to normal
      following an exercise bout. METHODS AND MEASURES: Fourteen healthy recreational
      participants performed stiff and soft drop landings before and after a 20-minute
      treadmill exercise bout under 3 different ankle stabilizer conditions (no
      stabilizer, ankle brace, and ankle tape). A forceplate was used to collect ground
      reaction force data under the dominant foot. The first and second peak impact
      force, as well as the time to each of the 2 peak forces, were determined for each
      trial and used as dependent variables. RESULTS: The time to reach peak forces
      were significantly less under the ankle brace and tape conditions in comparison
      to the control (no-stabilizer) condition. CONCLUSIONS: It appears that ankle
      taping and bracing decrease the time to reach peak impact forces. These
      alterations indicate that during dynamic activity the musculoskeletal structures
      of the body may be subjected to loads within shorter time periods. Whether these
      effects are detrimental over time remains speculative at this point and requires
      further research.

PMID- 12492273
TI  - Electromyographic activity of the hyoepiglotticus muscle and control of
      epiglottis position in horses.
AB  - OBJECTIVE: To determine whether the hyoepiglotticus muscle has respiratory
      related electromyographic activity and whether electrical stimulation of this
      muscle changes the position and conformation of the epiglottis, thereby altering
      dimensions of the aditus laryngis. ANIMAL: 6 Standardbred horses. PROCEDURE:
      Horses were anesthetized, and a bipolar fine-wire electrode was placed in the
      hyoepiglotticus muscle of each horse. Endoscopic images of the nasopharynx and
      larynx were recorded during electrical stimulation of the hyoepiglotticus muscle
      in standing, unsedated horses. Dorsoventral length and area of the aditus
      laryngis were measured on images obtained before and during electrical
      stimulation. Electromyographic activity of the hyoepiglotticus muscle and
      nasopharyngeal pressures were measured while horses exercised on a treadmill at
      50, 75, 90, and 100% of the speed that produced maximum heart rate. RESULTS:
      Electrical stimulation of the hyoepiglotticus muscle changed the shape of the
      epiglottis, displaced it ventrally, and significantly increased the dorsoventral
      length and area of the aditus laryngis. The hyoepiglotticus muscle had
      inspiratory activity that increased significantly with treadmill speed as a
      result of an increase in phasic and tonic activity. Expiratory activity of the
      hyoepiglotticus muscle did not change with treadmill speed in 4 of 6 horses.
      CONCLUSIONS AND CLINICAL RELEVANCE: Findings reported here suggest that
      contraction of the hyoepiglotticus muscle increases dimensions of the airway in
      horses by depressing the epiglottis ventrally during intense breathing efforts.
      The hyoepiglotticus muscle may be an important muscle for dilating the airway in
      horses, and contraction of the hyoepiglotticus muscle may induce conformational
      changes in the epiglottis.

PMID- 12492274
TI  - Plasma pharmacokinetics and tissue fluid concentrations of meropenem after
      intravenous and subcutaneous administration in dogs.
AB  - OBJECTIVE: To estimate pharmacokinetic variables and measure tissue fluid
      concentrations of meropenem after IV and SC administration in dogs. ANIMALS: 6
      healthy adult dogs. PROCEDURE: Dogs were administered a single dose of meropenem
      (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of
      meropenem in dogs and to evaluate a unique tissue fluid collection method, an in
      vivo ultrafiltration device was used to collect interstitial fluid. Plasma,
      tissue fluid, and urine samples were analyzed by use of high-performance liquid
      chromatography. Protein binding was determined by use of an ultrafiltration
      device. RESULTS: Plasma data were analyzed by compartmental and noncompartmental
      pharmacokinetic methods. Mean +/- SD values for half-life, volume of
      distribution, and clearance after IV administration for plasma samples were 0.67
      +/- 0.07 hours, 0.372 +/- 0.053 L/kg, and 6.53 +/- 1.51 mL/min/kg, respectively,
      and half-life for tissue fluid samples was 1.15 +/- 0.57 hours. Half-life after
      SC administration was 0.98 +/- 0.21 and 1.31 +/- 0.54 hours for plasma and tissue
      fluid, respectively. Protein binding was 11.87%, and bioavailability after SC
      administration was 84%. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of our data
      revealed that tissue fluid and plasma (unbound fraction) concentrations were
      similar. Because of the kinetic similarity of meropenem in the extravascular and
      vascular spaces, tissue fluid concentrations can be predicted from plasma
      concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would
      achieve adequate tissue fluid and urine concentrations for susceptible bacteria
      with a minimum inhibitory concentration of 0.12 microg/mL.

PMID- 12492275
TI  - Short-term effect of therapeutic shoeing on severity of lameness in horses with
      chronic laminitis.
AB  - OBJECTIVE: To evaluate the short-term effects of 4 therapeutic shoeing systems on
      lameness and voluntary limb-load distribution in horses with chronic laminitis.
      ANIMALS: 10 horses with chronic laminitis. PROCEDURES: A clinical trial was
      conducted that used a concurrent control, crossover design to evaluate the
      relative effectiveness of a standard flat shoe, fullered egg-bar shoe, heart-bar
      shoe, and modified equine digital support system to alleviate chronic lameness in
      horses. Therapeutic success was assessed during a 7-day period by use of
      subjective (Obel grade and clinical score) and objective (force-plate data)
      evaluations. RESULTS: Comparison of pretreatment and intertreatment control data
      indicated that disease status of the horses did not change during the course of
      the study. None of the therapeutic shoeing treatments used resulted in a
      significant change in severity of lameness. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results were interpreted to imply that substantial clinical improvement should
      not be expected during the first 7 days after therapeutic shoeing for the
      specific shoes tested in this study. On the basis of our results, we hypothesize
      that when used as the lone indicator of therapeutic success, severity of lameness
      may not be a valid indicator.

PMID- 12492276
TI  - Isolation of immunogenic outer membrane proteins from Mannheimia haemolytica
      serotype 1 by use of selective extraction and immunoaffinity chromatography.
AB  - OBJECTIVE: To use antibodies produced by calves in response to infection with
      Mannheimia haemolytica in immunoaffinity chromatography for the identification
      and subsequent isolation of the dominant immunogenic antigens from bacteria grown
      in iron-deficient media. SAMPLE POPULATION: Serum from 10 calves actively
      infected with M haemolytica. PROCEDURE: An outer membrane protein fraction was
      obtained from sonicated salt-extracted M haemolytica cells by extraction with N
      lauroyl sarcosinate. The immunoglobulin fraction of serum from calves actively
      infected with M haemolytica was used to prepare an immunoaffinity column. The
      immunoaffinity column was used to isolate the dominant immunogenic proteins from
      the outer membrane protein fraction. The resultant immunogenic protein fraction
      was subjected to ELISA and immunoblot methods as well as carbohydrate
      quantification. Sequencing of the N-terminal was performed on the most prominent
      protein. RESULTS: 5 immunogenic proteins with molecular weights of 42, 30, 24,
      20, and 15 kd were isolated. The immunogenic protein fraction was found to
      contain 51% carbohydrate. The immunoaffinity column capacity was 1 microg of
      immunogenic protein/mL of gel. The N-terminal sequence of the 42-kd protein was
      Tyr-Gln-Thr-Tyr-Gln-Ser-X-Leu-Gln, where X could not be identified. CONCLUSIONS
      AND CLINICAL RELEVANCE: lmmunogenic proteins were isolated by use of
      immunoaffinity chromatography. A substantial amount of carbohydrates was co
      purified in the process. Additional experiments are needed to determine whether
      the carbohydrates would hinder or enhance development of vaccine preparations.
      This method could potentially allow a more rapid production of antigens for use
      in vaccines.

PMID- 12492277
TI  - Effects of feeding aspirin and supplemental vitamin E on plasma concentrations of
      3-methylindole, 3-methyleneindolenine-adduct concentrations in blood and
      pulmonary tissues, lung lesions, and growth performance in feedlot cattle.
AB  - OBJECTIVE: To evaluate the effect of feeding aspirin and supplemental vitamin E
      on growth performance, lung lesions, plasma concentrations of 3-methylindole
      (3MI), and 3-methyleneindolenine (3MEIN)-adduct concentrations in blood and
      pulmonary tissues of feedlot cattle. ANIMALS: 256 crossbred steers; 64 cattle
      were used in experiment 1 and 192 cattle were used in experiment 2. PROCEDURES: A
      2 X 2 factorial design was used for each experiment. Treatment factors were
      aspirin (0 or 3 g daily) and vitamin E (200 or 1,500 IU daily). Steers were
      housed in pens (8 steers/pen). Steers were slaughtered on days 59 and 138 for
      experiments 1 and 2, respectively. Lungs were grossly evaluated. 3MEIN-adduct
      concentrations were determined, and blood and pulmonary tissues. RESULTS:
      Treatment was not associated with improvement or adverse effects on weight gain,
      dry-matter intake, or feed efficiency in experiment 2. In experiment 1, 36 of 63
      (57.1%) steers had lung lesions. Lesions were not associated with treatment or
      concentrations of 3MI and 3MEIN-adduct. Plasma 3MI concentration and
      concentrations of 3MEIN-adduct in blood and pulmonary tissues were 3.11
      microg/mL, 0.51 U/microg of protein, and 0.49 U/microg of protein, respectively.
      Aspirin was associated with increased blood concentrations of 3MEIN-adduct for
      diets that did not contain supplemental vitamin E. CONCLUSIONS AND CLINICAL
      RELEVANCE: Differences n performance of feedlot steers were not associated with
      treatment diet. It is possible that concurrent exposure of feedlot cattle to
      other factors typically associated with development of respiratory tract disease
      would affect these findings.

PMID- 12492278
TI  - Plasma and synovial fluid endothelin-1 and nitric oxide concentrations in horses
      with and without joint disease.
AB  - OBJECTIVE: To compare plasma and synovial fluid endothelin-1 (ET-1) and nitric
      oxide (NO) concentrations in clinically normal horses and horses with joint
      disease. ANIMALS: 36 horses with joint disease, and 15 horses without joint
      disease. PROCEDURE: Horses with joint disease were assigned to 1 of the 3 groups
      (ie, synovitis, degenerative joint disease [DJD], or joint sepsis groups) on the
      basis of findings on clinical and radiographic examination and synovial fluid
      analysis. Endothelin-1 and NO concentrations were measured in plasma from blood
      samples, collected from the jugular vein and ipsilateral cephalic or saphenous
      vein of the limb with an affected or unaffected joint, as well as in synovial
      fluid samples obtained via arthrocentesis from the involved joint. RESULTS:
      Plasma ET-1 concentrations between affected and unaffected groups were not
      significantly different. Median concentration and concentration range of ET-1 in
      synovial fluid obtained from the joint sepsis group (35.830 pg/mL, 7926 to 86.614
      pg/mL; n = 7) were significantly greater than values from the synovitis (17.531
      pg/mL, 0.01 to 46.908 pg/mL; 18), DJD (22.858 pg/mL, 0.01 to 49.990 pg/mL; 10),
      and unaffected (10.547 pg/mL, 0.01 to 35.927 pg/mL; 10) groups. Plasma and
      synovial fluid NO concentrations between affected and unaffected groups were not
      significantly different. CONCLUSIONS AND CLINICAL RELEVANCE: Endothelin-1 is
      locally synthesized in the joints of horses with various types of joint disease.
      Synovial fluid concentrations of ET-1 varied among horses with joint disease,
      with concentrations significantly higher in the synovial fluid of horses with
      joint sepsis. These results indicate that ET-1 may play a role in the
      pathophysiologic mechanism of joint disease in horses.

PMID- 12492279
TI  - Comparison of the cardiopulmonary effects of anesthesia maintained by continuous
      infusion of romifidine, guaifenesin, and ketamine with anesthesia maintained by
      inhalation of halothane in horses.
AB  - OBJECTIVE: To compare cardiopulmonary responses during anesthesia maintained with
      halothane and responses during anesthesia maintained by use of a total
      intravenous anesthetic (TIVA) regimen in horses. ANIMALS: 7 healthy adult horses
      (1 female, 6 geldings). PROCEDURE: Each horse was anesthetized twice. Romifidine
      was administered IV, and anesthesia was induced by IV administration of ketamine.
      Anesthesia was maintained for 75 minutes by administration of halothane (HA) or
      IV infusion of romifidine, guaifenesin, and ketamine (TIVA). The order for TIVA
      or HA was randomized. Cardiopulmonary variables were measured 40, 60, and 75
      minutes after the start of HA orTIVA. RESULTS: Systolic, diastolic, and mean
      carotid arterial pressures, velocity time integral, and peak acceleration of
      aortic blood flow were greater, and systolic, diastolic, and mean pulmonary
      arterial pressure were lower at all time points for TIVA than for HA. Pre
      ejection period was shorter and ejection time was longer for TIVA than for HA.
      Heart rate was greater for HA at 60 minutes. Minute ventilation and alveolar
      ventilation were greater and inspiratory time was longer for TIVA than for HA at
      75 minutes. The PaCO2 was higher at 60 and 75 minutes for HA than forTIVA.
      CONCLUSIONS AND CLINICAL RELEVANCE: Horses receiving a constant-rate infusion of
      romifidine, guaifenesin, and ketamine maintained higher arterial blood pressures
      than when they were administered HA. There was some indication that left
      ventricular function may be better during TIVA, but influences of preload and
      afterload on measured variables could account for some of these differences.

PMID- 12492280
TI  - Comparison of sampling techniques for measuring the antimicrobial susceptibility
      of enteric Escherichia coli recovered from feedlot cattle.
AB  - OBJECTIVE: To evaluate the effectiveness of various sampling techniques for
      determining antimicrobial resistance patterns in Escherichia coli isolated from
      feces of feedlot cattle. SAMPLE POPULATION: Fecal samples obtained from 328 beef
      steers and 6 feedlot pens in which the cattle resided. PROCEDURE: Single fecal
      samples were collected from the rectum of each steer and from floors of pens in
      which the cattle resided. Fecal material from each single sample was combined
      into pools containing 5 and 10 samples. Five isolates of Escherichia coli from
      each single sample and each pooled sample were tested for susceptibility to 17
      antimicrobials. RESULTS: Patterns of antimicrobial resistance for fecal samples
      obtained from the rectum of cattle did not differ from fecal samples obtained
      from pen floors. Resistance patterns from pooled samples differed from patterns
      observed for single fecal samples. Little pen-to-pen variation in resistance
      prevalence was observed. Clustering of resistance phenotypes within samples was
      detected. CONCLUSIONS AND CLINICAL RELEVANCE: Studies of antimicrobial resistance
      in feedlot cattle can rely on fecal samples obtained from pen floors, thus
      avoiding the cost and effort of obtaining fecal samples from the rectum of
      cattle. Pooled fecal samples yielded resistance patterns that were consistent
      with those of single fecal samples when the prevalence of resistance to an
      antimicrobial was > 2%. Pooling may be a practical altemative when investigating
      patterns of resistance that are not rare. Apparent clustering of resistance
      phenotypes within samples argues for examining fewer isolates per fecal sample
      and more fecal samples per pen.

PMID- 12492281
TI  - Effects of medetomidine-midazolam, acepromazine-butorphanol, and midazolam
      butorphanol on induction dose of thiopental and propofol and on cardiopulmonary
      changes in dogs.
AB  - OBJECTIVE: To evaluate dose-sparing effects of medetomidine-midazolam (MM),
      acepromazine-butorphanol (AB), and midazolam-butorphanol (MB) on the induction
      dose of thiopental and propofol and to examine cardiopulmonary changes in dogs.
      ANIMALS: 23 healthy Beagles. PROCEDURE: Dogs were administered MM, AB, MB, or
      physiologic saline (0.9% NaCI) solution (PS) IM, and anesthesia was induced with
      thiopental or propofol. Cardiopulmonary measurements were obtained before and
      after administration of medication and 0, 5, 10, and 15 minutes after
      endotracheal intubation. RESULTS: Induction doses were reduced significantly by
      preanesthetic administration of MM, AB, and MB (thiopental, 20, 45, and 46% after
      administration of PS; propofol, 42, 58, and 74% after administration of PS,
      respectively). Recovery time in dogs administered MM-thiopental or MM-propofol
      and AB-propofol were significantly prolonged, compared with recovery time in dogs
      administered PS-thiopental or PS-propofol. Relatively large cardiovascular
      changes were induced by administration of MM, which were sustained even after the
      induction of anesthesia. Administration of AB and MB induced cardiovascular
      changes during and immediately after endotracheal intubation that were
      significantly decreased by induction with thiopental or propofol. However, mild
      hypotension developed with AB-propofol. Apnea was observed in dogs administered
      MM during induction of anesthesia, but most respiratory variables did not change
      significantly. CONCLUSIONS AND CLINICAL RELEVANCE: Preanesthetic medication with
      MM greatly reduced the anesthesia induction dose of thiopental and propofol but
      caused noticeable cardiopulmonary changes. Preanesthetic medication with AB and
      MB moderately reduced the induction dose of thiopental and propofol and amelio
      rated cardiovascular changes induced by these anesthetics, although AB caused
      mild hypotension.

PMID- 12492282
TI  - Kinetics of endotoxin concentration and tumor necrosis factor-alpha, interleukin
      1beta, and interleukin-6 activities in the systemic and portal circulation during
      small intestinal ischemia and reperfusion in dogs.
AB  - OBJECTIVE: To determine whether small intestinal ischemia and reperfusion induces
      bacterial translocation and proinflammatory cytokine response in either the
      systemic or portal circulation in dogs. ANIMALS: 17 healthy adult Beagles.
      PROCEDURE: The superior mesenteric artery (SMA) was occluded for 0 (group-3
      dogs), 30 (group-1 dogs), or 60 (group-2 dogs) minutes, followed by reperfusion
      for 180 minutes; serum lactate and endotoxin concentrations and tumor necrosis
      factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 activities in
      the systemic and portal circulation and intramucosal pH were measured at various
      time points. RESULTS: In group-2 dogs, TNFalpha activity was found to be
      significantly increased in the portal circulation, peaking at 60 minutes of
      reperfusion; TNF-alpha activity, in the systemic circulation, gradually increased
      from 60 minutes of reperfusion to the end of the experiment; however, the
      increase was not significant. In group-1 and -2 dogs, IL-6 activities
      significantly and gradually increased in the systemic and portal circulation
      during the reperfusion phase, and the magnitude of these increases was dependent
      on the duration of the ischemic phase. There were no significant changes in IL
      1beta activity or endotoxin concentration in any dog group. CONCLUSIONS AND
      CLINICAL RELEVANCE: Results of the our study indicate that intestinal ischemia
      and reperfusion leads to significant increases of the circulating TNF-alpha and
      IL-6 activities, depending on the duration of the ischemia phase, in the absence
      of detectable endotoxin in the circulation. This finding suggests that intestinal
      ischemia and reperfusion induces a systemic proinflammatory cytokine response in
      dogs.

PMID- 12492283
TI  - Spontaneous in vitro contractile activity of specimens from the abomasal wall of
      healthy cows and comparison among dairy breeds.
AB  - OBJECTIVE: To characterize and compare in vitro contractility patterns of
      sections of abomasal wall harvested from cattle of 3 dairy breeds. SAMPLE
      POPULATION: Longitudinal and circular smooth muscle preparations harvested from
      the antrum and body of the abomasum of 30 recently slaughtered Holstein-Friesian,
      Brown Swiss, and Simmental X Red Holstein cows. PROCEDURE: Spontaneous isometric
      contractions of specimens in tissue baths of modified Krebs solution were
      recorded during a 4-hour period. Maximal amplitude, frequency of contractions,
      and change of basal tension were used to characterize contractility. Statistical
      analyses were used to test for differences among time periods, among breeds,
      between specimen locations, and between fiber orientations. RESULTS: Myoactivity
      patterns of abomasal smooth muscle preparations are highly variable and differ on
      the basis of location and fiber orientation. Frequency of contractions differed
      significantly among time periods for longitudinally oriented specimens with
      decreasing frequencies of contractions over time. Maximal amplitude of the
      longitudinally oriented specimens from the antrum increased significantly,
      whereas maximal amplitude of the circularly oriented specimens from the antrum
      decreased significantly. Values did not differ significantly among breeds.
      CONCLUSIONS AND CLINICAL RELEVANCE: Patterns of spontaneous contractility of
      abomasal wall specimens are not homogeneous. During a 4-hour recording period,
      maximal amplitude and frequency of contractions of specimens varied significantly
      with respect to orientation and location; however, spontaneous contractile
      myoactivity did not differ significantly among breeds. Therefore, breed
      predisposition for displaced abomasum is not correlated with spontaneous activity
      of smooth muscle specimens.

PMID- 12492284
TI  - Cardiopulmonary effects of xylazine and acepromazine in pregnant cows in late
      gestation.
AB  - OBJECTIVE: To determine effects of sedation achieved by xylazine (XYL) or
      acepromazine (ACE) on cardiopulmonary function and uterine blood flow in cows in
      late gestation. ANIMALS: 8 cows between 219 and 241 days of gestation. PROCEDURE:
      Doses of ACE (0.02 mg/kg) or XYL (0.04 mg/kg) were administered IV. Measurements
      were obtained to determine cardiopulmonary effects and oxygen delivery to the
      uterus. RESULTS: Heart rate was not significantly affected by administration of
      ACE, but it decreased markedly after administration of XYL. Uterine artery flow
      was decreased at all times by XYL and was always less than for ACE. Xylazine
      increased uterine vascular resistance through 30 minutes and caused reduced PaO2
      and increased PaCO2 at all time periods. Acepromazine caused a 5% decrease in
      PaO2 only at 5 minutes. Xylazine reduced oxygen delivery by 59% at 5 minutes and
      32% at 45 minutes. In contrast, ACE caused a nonsignificant reduction of oxygen
      delivery by 16% at 15 minutes and a return to baseline values by 45 minutes
      CONCLUSIONS AND CLINICAL RELEVANCE: Xylazine markedly reduces flow and
      availability of oxygenated blood to the uterus, which may critically impair
      delivery of oxygen to the fetus at a stressful and important time of development
      or delivery. Acepromazine was associated with slight reductions of much shorter
      duration. When XYL is used to sedate pregnant cows, it could impose physiologic
      distress on the fetus and potentially increase fetal morbidity and mortality.
      When sedation of the dam is desirable, ACE could be an alternative to XYL.

PMID- 12492285
TI  - Effect of desmopressin acetate administration on primary hemostasis in Doberman
      Pinschers with type-1 von Willebrand disease as assessed by a point-of-care
      instrument.
AB  - OBJECTIVE: To evaluate primary hemostasis following administration of
      desmopressin acetate (DDAVP) to Doberman Pinschers with type-1 von Willebrand
      disease (vWD). ANIMALS: 16 nonanemic Doberman Pinschers with type-1 vWD.
      PROCEDURE: Closure time (CT), defined as time required for occlusion of an
      aperture by a platelet plug assessed within the point-of-care instrument, plasma
      von Willebrand factor (vWF) concentration, and buccal mucosal bleeding time
      (BMBT) were determined before and 1 hour after administration of DDAVP (1
      microg/kg, SC). RESULTS: Baseline closure times measured with adenosine
      diphosphate ([ADP-CT], 108 to > 300 seconds; reference range, 52 to 86 seconds)
      and epinephrine ([EPI-CT], 285 to > 300 seconds; 97 to 225 seconds) as platelet
      agonists were prolonged in all dogs. Following DDAVP administration, ADP-CT (59
      to 186 seconds) was significantly shortened from baseline, but there was no
      decrease in EPI-CT. Although mean plasma vWF concentration increased
      significantly after DDAVP administration, only 1 dog had an increase of > 35
      U/dL. There was no correlation between increase in plasma vWF concentration and
      shortening of the ADP-CT. Baseline BMBT was prolonged in 12 of 14 dogs, with
      significant shortening of BMBT after DDAVP administration in 6 of 7 dogs. In
      vitro replacement of vWF-deficient plasma with plasma from an unaffected dog
      shortened the ADP-CT whereas in vitro addition of DDAVP had no effect.
      CONCLUSIONS AND CLINICAL RELEVANCE: Administration of DDAVP to Doberman Pinschers
      with type-1 vWD resulted in improved hemostatic function, as assessed by the
      point-of-care instrument and shortening of BMBT, despite minimal increase in
      plasma vWF concentration.

PMID- 12492287
TI  - Epidemiologic investigation of seroprevalence of antibodies to Toxoplasma gondii
      in cats and rodents.
AB  - OBJECTIVE: To provide an epidemiologic investigation of the seroprevalence of
      antibodies to Toxoplasma gondii in populations of cats and wild rodents in Rhode
      Island and to address the possible epidemiologic role of wild rodents in the
      spread of toxoplasmosis. ANIMALS: 200 cats and 756 small wild rodents. PROCEDURE:
      Serum samples were obtained from 84 cats in animal shelters and 116 cats in
      veterinary hospitals. Serum samples were also obtained from 756 small wild
      rodents from multiple sites in Rhode Island. Sera from rodents and cats were
      assayed for antibodies to Tgondii by use of the modified agglutination test
      RESULTS: Overall, 42% (84/200) of cats had serum antibodies to Tgondii.
      Seroprevalence was not significantly different between stray (50%; 42/84) versus
      client-owned (36%; 42/116) cats, between male (43%; 40/94) versus female (42%;
      39/93) cats, or between indoor (26%; 7/27) versus outdoor (39%; 35/89) cats.
      Seroprevalence rate of trapped rodents was 0.8% (6/756). Six rodents captured in
      Washington County accounted for of the seropositive rodents. Four of 6 of the
      seropositive rodents were trapped at a single site in Washington County (an
      abandoned barn). Five stray cats, known to have resided at the same site in
      Washington County as 4 of the seropositive rodents, were also found to be
      seropositive for antibodies to T gondii. CONCLUSIONS AND CLINICAL RELEVANCE:
      Seroprevalence rate in rodents was not correlated with the seroprevalence rate in
      cats. Stray cats, especially those known to be feral, may be more likely to
      perpetuate the cat-mouse cycle of T gondii than client-owned cats.

PMID- 12492286
TI  - Sound signature for identification and quantification of upper airway disease in
      horses.
AB  - OBJECTIVE: To investigate whether upper airway sounds of horses exercising with
      laryngeal hemiplegia and alar fold paralysis have distinct sound characteristics,
      compared with unaffected horses. ANIMALS: 6 mature horses. PROCEDURE: Upper
      airway sounds were recorded in horses exercising on a high-speed treadmill at
      maximum heart rate (HR(MAX)) under 3 treatment conditions (ie, normal upper
      airway function [control condition], and after induction of left laryngeal
      hemiplegia or bilateral alar fold paralysis) in a randomized crossover design.
      Fundamental frequency, spectrograms using Gabor transform, and intensity
      characteristics of acquired sounds (peak sound level [sound(peak] and highest
      frequency of at least -25 dB sound intensity [F(25max)]) were evaluated. RESULTS:
      Evaluation of the fundamental frequency of the time domain signal was not useful.
      Sensitivity and specificity (83 and 75%, respectively) of spectrograms were
      greatest at maximal exercise, but the exact abnormal condition was identified in
      evaluation of only 12 of 18 spectrograms. Increased accuracy was obtained using
      sound(peak) and F(25max) as discriminating variables. The use of sound(peak)
      discriminated between control and laryngeal hemiplegia conditions and F(25max)
      between laryngeal hemiplegia and alar fold paralysis conditions. This increased
      the specificity of sound analysis to 92% (sensitivity 83%) and accurately
      classified the abnormal state in 92% of affected horses. CONCLUSIONS AND CLINICAL
      RELEVANCE: Sound analysis might be a useful adjunct to the diagnosis and
      evaluation of treatment of horses with upper airway obstruction, but would appear
      to require close attention to exercise intensity. Multiple measurements of
      recorded sounds might be needed to obtain sufficient accuracy for clinical use.

PMID- 12492288
TI  - Prevalence and importance of internal tandem duplications in exons 11 and 12 of c
      kit in mast cell tumors of dogs.
AB  - OBJECTIVE: To determine the prevalence of activating internal tandem duplications
      (ITDs) in exons 11 and 12 of c-kit in mast cell tumors (MCTs) of dogs and to
      correlate these mutations with prognosis. SAMPLE POPULATION: 157 formalin-fixed,
      paraffin-embedded MCTs from dogs in the pathology database of the Veterinary
      Medical Teaching Hospital at the University of California, Davis. PROCEDURE:
      Genomic DNA was isolated from tumor specimens and a polymerase chain reaction
      procedure was performed to determine whether there were ITDs in exons 11 and 12.
      RESULTS: We identified ITDs in 1 of 12 (8%) grade-I, 42 of 119 (35%) grade-lI,
      and 9 of 26 (35%) grade-ll tumors (overall prevalence, 52 of 157 [33%]). Logistic
      regression analysis revealed that the odds of grade-II and -III tumors possessing
      an ITD were approximately 5 times greater than that for grade-I tumors, although
      these odds did not differ significantly. Although MCTs possessing an ITD were
      twice as likely to recur after excision and twice as likely to result in
      metastasis as those without an ITD, these values also did not differ
      significantly. CONCLUSIONS AND CLINICAL RELEVANCE: These results provide evidence
      that ITDs in c-kit occur frequently in MCTs of dogs. The high prevalence of c-kit
      activating mutations in MCTs of dogs combined with the relative abundance of mast
      cell disease in dogs provide an ideal naturally developing tumor in which to test
      the safety and efficacy of novel small-molecule kinase inhibitors such as
      imatinib mesylate.

PMID- 12492289
TI  - Myoplasmic calcium regulation in myotubes from horses with recurrent exertional
      rhabdomyolysis.
AB  - OBJECTIVE: To determine whether alterations in myoplasmic calcium regulation can
      be identified in muscle cell cultures (myotubes) and intact muscle fiber bundles
      derived from Thoroughbreds affected with recurrent exertional rhabdomyolysis
      (RER). ANIMALS: 6 related Thoroughbreds with RER and 8 clinically normal
      (control) Thoroughbred or crossbred horses. PROCEDURES: Myotube cell cultures
      were grown from satellite cells obtained from muscle biopsy specimens of RER
      affected and control horses. Fura-2 fluorescence was used to measure resting
      myoplasmic calcium concentration as well as caffeine- and 4-chloro-m-cresol (4
      CMC)-induced increases in myoplasmic calcium. In addition, intact intercostal
      muscle fiber bundles were prepared from both types of horses, and their
      sensitivities to caffeine- and 4-CMC-induced contractures were determined.
      RESULTS: Myotubes of RER-affected and control horses had identical resting
      myoplasmic calcium concentrations. Myotubes from RER-affected horses had
      significantly higher myoplasmic calcium concentrations than myotubes from control
      horses following the addition of > or = 2mM caffeine; however, there was no
      difference in their response to 4-CMC (> or = 1 mM). Caffeine contracture
      thresholds for RER and control intact muscle cell bundles (2 vs 10mM,
      respectively) were significantly different, but 4-CMC contracture thresholds of
      muscle bundles from RER-affected and control horses (500 microM) did not differ.
      CONCLUSIONS AND CLINICAL RELEVANCE: An increase in caffeine sensitivity of muscle
      cells derived from a family of related RER-affected horses was detected in vitro
      by use of cell culture with calcium imaging and by use of fiber bundle
      contractility techniques. An alteration in muscle cell calcium regulation is a
      primary factor in the cause of this heritable myopathy.

PMID- 12492290
TI  - In vitro effects of oxytocin, acepromazine, detomidine, xylazine, butorphanol,
      terbutaline, isoproterenol, and dantrolene on smooth and skeletal muscles of the
      equine esophagus.
AB  - OBJECTIVE: To characterize the in vitro effects of oxytocin, acepromazine,
      xylazine, butorphanol, detomidine, dantrolene, isoproterenol, and terbutaline on
      skeletal and smooth muscle from the equine esophagus. ANIMALS: 14 adult horses
      without digestive tract disease. PROCEDURE: Circular and longitudinal strips from
      the skeletal and smooth muscle of the esophagus were suspended in tissue baths,
      connected to force-displacement transducers interfaced with a physiograph, and
      electrical field stimulation was applied. Cumulative concentration-response
      curves were generated for oxytocin, acepromazine, xylazine, detomidine,
      butorphanol, isoproterenol, terbutaline, and dantrolene. Mean maximum twitch
      amplitude for 3 contractions/min was recorded and compared with predrug-vehicle
      values for the skeletal muscle segments, and area under the curve (AUC) for 3
      contractions/min was compared with predrug-vehicle values for the smooth muscle
      segments. RESULTS: No drugs caused a significant change in skeletal muscle
      response. In smooth muscle, isoproterenol, terbutaline, and oxytocin
      significantly reduced AUC in a concentration-dependent manner. Maximum reduction
      in AUC was 69% at 10(-4) M for isoproterenol, 63% at 10(-6) M for terbutaline,
      and 64% at 10(-4) M for oxytocin. CONCLUSIONS AND CLINICAL RELEVANCE:
      Isoproterenol, terbutaline, and oxytocin cause relaxation of the smooth muscle
      portion of the esophagus. The clinical relaxant effects on the proximal portion
      of the esophagus reported of drugs such as oxytocin, detomidine, and acepromazine
      may be the result of centrally mediated mechanisms.

PMID- 12492291
TI  - Effects of treatment with oxytocin, xylazine butorphanol, guaifenesin,
      acepromazine, and detomidine on esophageal manometric pressure in conscious
      horses.
AB  - OBJECTIVE: To compare effects of oxytocin, acepromazine maleate, xylazine
      hydrochloride-butorphanol tartrate, guaifenesin, and detomidine hydrochloride on
      esophageal manometric pressure in horses. ANIMALS: 8 healthy adult horses.
      PROCEDURE: A nasogastric tube, modified with 3 polyethylene tubes that exited at
      the postpharyngeal area, thoracic inlet, and distal portion of the esophagus, was
      fitted for each horse. Amplitude, duration, and rate of propagation of pressure
      waveforms induced by swallows were measured at 5, 10, 20, 30, and 40 minutes
      after administration of oxytocin, detomidine, acepromazine, xylazine-butorphanol,
      guaifenesin, or saline (0.9% NaCI) solution. Number of spontaneous swallows,
      spontaneous events (contractions that occurred in the absence of a swallow
      stimulus), and high-pressure events (sustained increases in baseline pressure of
      > 10 mm Hg) were compared before and after drug adminision. RESULTS: At 5 minutes
      after administration, detomidine increased waveform amplitude and decreased
      waveform duration at the thoracic inlet. At 10 minutes after administration,
      detomidine increased waveform duration at the thoracic inlet. Acepromazine
      administration increased the number of spontaneous events at the thoracic inlet
      and distal portion of the esophagus. Acepromazine and detomidine administration
      increased the number of high-pressure events at the thoracic inlet. Guaifenesin
      administration increased the number of spontaneous events at the thoracic inlet.
      Xylazine-butorphanol, detomidine, acepromazine, and guaifenesin administration
      decreased the number of spontaneous swallows. CONCLUSIONS AND CLINICAL RELEVANCE:
      Detomidine, acepromazine, and a combination of xylazine butorphanol had the
      greatest effect on esophageal motility when evaluated manometrically. Reduction
      in spontaneous swallowing and changes in normal, coordinated peristaltic activity
      are the most clinically relevant effects.

PMID- 12492292
TI  - Establishment of an immortalized cell line and transplantable xenograft from a
      bronchioloalveolar lung carcinoma of a cat.
AB  - OBJECTIVE: To establish an immortalized cell line and transplantable xenograft of
      feline bronchioloalveolar lung carcinoma (BAC). SAMPLE POPULATION: Pleural
      effusion from a 12-year-old Persian male cat with BAC. PROCEDURE: Tumor cells
      from the pleural effusion were grown in monolayer cell culture and injected into
      severe combined immunodeficient (SCID) mice to establish an immortalized cell
      line as well as a transplantable xenograft. RESULTS: Both the primary lung
      carcinoma, the derived cell line, and the transplantable xenograft had evidence
      of a type-II pneumocyte origin expressing lamellar bodies ultrastructurally and
      thyroid transcription factor-1 and surfactant immunocytochemically. All 3 also
      expressed nuclear p53 immunoreactivity. A metaphase spread of the cell line
      (SPARKY) probed with fluorescein-labeled genomic feline DNA gave evidence of its
      feline origin. Flow cytometric studies indicated aneuploidy with a DNA index of
      1.6. An R-banded karyotype revealed a modal number of 66 including the feline Y
      chromosome. The cell line had a doubling time of 16 hours. The xenograft (SPARKY
      X) reached a diameter of 1 cm in 3 weeks in SCID mice. Deoxyribonucleic acid
      fingerprint analysis revealed that SPARKY and SPARKY-X were novel and strongly
      matched each other, except for the murine component found in SPARKY-X.
      Interestingly, SPARKY-X manifested the characteristic lepidic growth pattern of
      pulmonic BAC. CONCLUSIONS: Both the cell line and xenograft retained their
      autochthonous BAC phenotype, making them useful for the subsequent dissection of
      molecular abnormalities in feline BAC and in vitro screening of chemotherapeutic
      agents.

PMID- 12492293
TI  - Contextual and cued fear conditioning in C57BL/6J and DBA/2J mice: context
      discrimination and the effects of retention interval.
AB  - Context discrimination and time course studies of contextual fear conditioning
      revealed strain differences between C57BL/6J (B6) and DBA/2J (D2) mice. Both
      strains discriminated contexts, but D2 mice exhibited less freezing in a shock
      paired context. The strains did not differ immediately, or at 1 and 3 hr after
      contextual fear conditioning training. D2 mice showed less freezing at 15 min, 30
      min, and 24 hr after training. B6 mice exhibited exaggerated generalized freezing
      and poor discrimination between the context and altered context 7-30 days after
      training. The acoustic startle response in B6 mice was also enhanced at 14 days
      after training. D2 mice did not show this pattern of generalized freezing. B6,
      but not D2, mice retained contextual memories for at least 60 days.

PMID- 12492294
TI  - Locomotor activity responses to ethanol, other alcohols, and GABA-A acting
      compounds in forward- and reverse-selected FAST and SLOW mouse lines.
AB  - Mice selectively bred for high (FAST) or low (SLOW) locomotor stimulant response
      to ethanol have been found to differ in response to drugs with gamma-aminobutyric
      acid (GABA)-ergic actions. Reverse selection produced lines that are similar in
      sensitivity to ethanol stimulation (r-FAST and r-SLOW) and provided a unique
      model for testing hypotheses about shared genetic influence on sensitivity to
      ethanol and GABAergic drugs. FAST mice were more stimulated than SLOW mice by all
      drugs tested: ethanol, methanol, n-propanol, t-butanol, pentobarbital, diazepam,
      and allopregnanolone. In contrast, r-FAST and r-SLOW mice differed in sensitivity
      to only a few isolated drug doses. Locomotor responses of each reverse-selected
      line were significantly different from the responses of their respective forward
      selected line for all drugs. Results support an effect of selection for ethanol
      sensitivity on allosteric modulation of the GABA-A receptor.

PMID- 12492295
TI  - Medial preoptic lesions disrupt parental behavior in both male and female
      California mice (Peromyscus californicus).
AB  - California mice (Peromyscus californicus) are monogamous and naturally
      biparental, making them an ideal species in which to study the neural basis of
      paternal behavior. A male or female from each male-female pair was given an
      electrolytic or sham lesion in the medial preoptic area (MPOA), an area known to
      be critical for the expression of maternal behavior in rats, and retested for
      parental responsiveness. MPOA-lesioned males and females showed significantly
      longer latencies to show parental behavior and spent significantly less time near
      pups, sniffing pups, and licking pups than sham-lesioned mice. However, MPOA
      lesions did not reduce time spent hovering over pups. The results suggest that
      the neural mechanisms mediating paternal behavior are similar to those mediating
      maternal behavior in this species.

PMID- 12492296
TI  - Interhemispheric asymmetry of human sleep EEG in response to selective slow-wave
      sleep deprivation.
AB  - Recent evidence suggests that the human sleep electroencephalogram (EEG) shows
      regional differences over both the sagittal and coronal planes. In the present
      study, in a group of 10 right-handers, the authors investigated the presence of
      hemispheric asymmetries in the homeostatic regulation of human sleep EEG power
      during and after selective slow-wave sleep (SWS) deprivation. The SWS deprivation
      was slightly more effective over the right hemisphere, but the left hemisphere
      showed a markedly larger increase of EEG power in the 1.00-24.75 Hz range during
      recovery-night non-REM sleep, and a larger increase of EEG power during both
      deprivation-night and recovery-night REM sleep. These results support the greater
      need for sleep recuperative processes of the left hemisphere, suggesting that
      local sleep regulation processes may also act during REM sleep.

PMID- 12492297
TI  - Organizing and activating effects of sex hormones in homosexual transsexuals.
AB  - The cause of transsexualism remains unclear. The hypothesis that atypical
      prenatal hormone exposure could be a factor in the development of transsexualism
      was examined by establishing whether an atypical pattern of cognitive functioning
      was present in homosexual transsexuals. Possible activating effects of sex
      hormones as a result of cross-sex hormone treatment were also studied. Female-to
      male and male-to-female transsexuals were compared with female and male controls
      with respect to spatial ability before and after treatment. The data were
      consistent with an organizing effect, but there was no evidence of an activating
      effect. Homosexual transsexuals, who prior to hormone treatment scored in the
      direction of the opposite sex, may have reached a ceiling in performance and
      therefore do not benefit from activating hormonal effects.

PMID- 12492298
TI  - Estrogen improves response accuracy and attenuates the disruptive effects of
      delta9-THC in ovariectomized rats responding under a multiple schedule of
      repeated acquisition and performance.
AB  - Despite evidence of an interaction between cannabinoids and estrogen in the
      brain, little information is available regarding the consequences of this
      interaction on behavior. A within-subjects design was used to examine the effects
      of estrogen and delta9-tetrahydrocannabinol (delta9-THC) on learning and memory
      in ovariectomized rats responding under a multiple schedule of repeated
      acquisition and performance. Treatment with low physiological levels of estrogen,
      delivered in Silastic capsules, improved response accuracy without affecting
      response rate during acquisition. Estrogen also attenuated the ability of delta9
      THC (0.56- 3.2 mg/kg) to decrease response accuracy and rate during acquisition
      and response accuracy during performance. Results indicate that estrogen can
      improve accuracy during acquisition of a nonspatial operant task and can
      attenuate delta9-THC- induced behavioral deficits.

PMID- 12492299
TI  - Artificial rearing causes changes in maternal behavior and c-fos expression in
      juvenile female rats.
AB  - This study investigated the effects of early-rearing experiences on
      responsiveness to pups and on the pattern of c-fos activation in the brain of
      juvenile female rats. From Days 4 to 20, littermate females were reared with
      their mothers (MR) or artificially (AR). AR rats received minimal licking-like
      tactile stimulation (AR-min) or maximal stimulation (AR-max). On Day 20, rats
      were exposed to pups for 4 or 8 days, exposed to a playmate for 4 or 8 days, or
      left in isolation for 4 or 8 days. Compared with MR rats, pup-exposed AR rats
      engaged in less pup licking, and all AR rats showed significant reductions in c
      fos immunoreactivity in the medial preoptic area and the parietal and piriform
      cortices. The AR-min group showed the greatest difference in Fos-lir compared
      with the MR groups. Possible mechanisms that mediate the effects of rearing on
      the development of neural circuits underlying maternal behavior are discussed.

PMID- 12492300
TI  - Air-stepping in neonatal rats: A comparison of L-dopa injection and olfactory
      stimulation.
AB  - The kinematic parameters of air-stepping induced by 2 methods known to elicit
      locomotion (olfactory stimulation vs. L-dopa injection) were compared in 3-day
      old rats. In the 1st stage, suspended pups were induced to step with an olfactory
      stimulus of soiled shavings from the nest. In the 2nd stage, they received a
      subcutaneous injection of L-dopa. Their movements were faster, with a larger
      amplitude and a phase delay in ipsilateral coupling. Third, the olfactory
      stimulus was presented in conjunction with L-dopa. The characteristics of
      locomotion returned to the same level as with the olfactory stimulus alone. These
      results suggest that olfactory stimulation involves higher nerve centers able to
      modulate the dopaminergic pathways. They are discussed in relation to the neural
      structure involved in locomotion.

PMID- 12492301
TI  - Cognitive deficits in docosahexaenoic acid-deficient rats.
AB  - This study investigated the influence of brain docosahexaenoic acid (DHA)
      deficiency on simple and complex olfactory-based learning and memory in 2nd
      generation (F2) adult male rats. Rats raised and maintained on either an n-3
      adequate or an n-3-deficient diet were tested for acquisition of an olfactory
      learning set and an olfactory memory task, and for motivation to obtain a water
      reward. Despite a 76% decrease in brain DHA, n-3-deficient rats were able to
      acquire most simple 2-odor discrimination tasks but were deficient in the
      acquisition of a 20-problem olfactory learning set. This deficit could not be
      attributed to changes in sensory capacity but, instead, appeared to represent a
      deficit in higher order learning.

PMID- 12492302
TI  - Instrumental learning within the spinal cord: IV. Induction and retention of the
      behavioral deficit observed after noncontingent shock.
AB  - Spinalized rats given shock whenever 1 hind leg is extended learn to maintain
      that leg in a flexed position, a simple form of instrumental learning. Rats given
      shock independent of leg position do not exhibit an increase in flexion duration.
      Experiment 1 showed that 6 min of intermittent legshock can produce this deficit.
      Intermittent tailshock undermines learning (Experiments 2-3), and this effect
      lasts at least 2 days (Experiment 4). Exposure to continuous shock did not induce
      a deficit (Experiment 5) but did induce antinociception (Experiment 6).
      Intermittent shock did not induce antinociception (Experiment 6). Experiment 7
      addressed an alternative interpretation of the results, and Experiment 8 showed
      that presenting a continuous tailshock while intermittent legshock is applied can
      prevent the deficit.

PMID- 12492303
TI  - Reflex facilitation during eyeblink conditioning and subsequent interpositus
      nucleus inactivation in the rabbit (Oryctolagus cuniculus).
AB  - In eyeblink conditioning in the rabbit (Oryctolagus cuniculus), not only is a
      conditioned response (CR) acquired, but also the original reflex is modified as a
      function of training. In Experiment 1, by comparing unconditioned responses in
      unpaired and paired groups, 3 types of reflex facilitation were distinguished.
      One type was linked to exposure to the unconditioned stimuli (USs) and/or
      experimental setting. The 2nd type was related to the formation of the memory
      trace for conditioned eyeblink. The 3rd type was linked to the conditioned
      stimulus immediately preceding the US in the paired group. In Experiment 2,
      reversible inactivation of the interpositus nucleus (IPN) abolished the CR and
      reduced the CR-related reflex facilitation, indicating that the latter depends on
      the plasticity of the IPN.

PMID- 12492304
TI  - NMDA receptor antagonists impair memory for nonspatial, socially transmitted food
      preference.
AB  - Rats avoid unfamiliar foods and learn to prefer those that they smell on the
      breath of conspecifics. Hippocampal lesions produce rapid forgetting of this
      socially acquired memory. The authors report that NMDA receptor antagonists
      impair this memory. Rats given CPP were trained in the social transmission of
      food preference task. Normal rats showed robust memory 72 hr later. CPP-injected
      rats performed normally 24 hr, but randomly 72 hr, after training. Spatial
      context was irrelevant: Rats trained and tested in different rooms performed the
      same as rats trained and tested in 1 room. MK801 and intrahippocampal injections
      of APV produced amnestic effects similar to CPP. Thus, NMDA receptor activation
      is crucial for the persistence of socially acquired, hippocampus-dependent,
      nonspatial memory.

PMID- 12492305
TI  - Inhibition of protein kinase A activity interferes with long-term, but not short
      term, memory of conditioned taste aversions.
AB  - The present experiments examined whether inhibition of cyclic adenosine
      monophosphate (cAMP)-dependent protein kinase A (PKA) activity interferes with
      conditioned taste aversion (CTA) memories. Rats were centrally infused with the
      selective PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate
      triethylamine (Rp-cAMPS) before conditioning. Direct infusions of Rp-cAMPS into
      the amygdala showed no interference with short-term memory but did show
      significant attenuation of long-term memory and more rapid extinction. Results
      suggest that PKA activity is involved in the consolidation of long-term memory of
      CTAs, and that the amygdala may be 1 site that is important for this activity.

PMID- 12492306
TI  - Group II metabotropic glutamate receptors within the amygdala regulate fear as
      assessed with potentiated startle in rats.
AB  - The contribution to fear and fear learning of amygdala Group II metabotropic
      glutamate receptors was examined in rats. Pretest intra-amygdala infusions of the
      Group II receptor agonist LY354740 (0.3 or 1.0 microg/side) significantly
      disrupted fear-potentiated startle. The same rats were unimpaired when later
      tested without drug. The Group II receptor agonist (2R,4R)-4-aminopyrrolidine-2,4
      dicarboxylate (3.0 microg/side) mimicked the effect of LY354740, and
      coadministration of the Group II receptor antagonist LY341495 (0.3 microg/side)
      prevented it. Pretraining LY354740 (0.3 microg/side) infusions also blocked
      learning. The effects on learning and performance were significantly less
      pronounced in rats with misplaced cannulas. Thus, Group II metabotropic receptors
      within or very near the amygdala regulate fear and fear learning and are a
      potential target for anxiolytic compounds.

PMID- 12492307
TI  - High and low responders to novelty and mesolimbic noradrenaline: effects of
      noradrenergic agents on radial-maze performance.
AB  - The authors used high and low responders to novelty (HRs and LRs, respectively)
      to examine the effects of noradrenergic injections into the nucleus accumbens
      using a special radial-maze task. During the 5 successive test days, solvent
      treated HRs acquired this task faster than LRs. Isoproterenol (beta-agonist)
      combined with phenylephrine (alpha-agonist) improved acquisition in LRs but not
      in HRs; this effect was counteracted by propranolol (beta-antagonist) and
      phentolamine (alpha-antagonist). Propranolol combined with phentolamine, as well
      as phentolamine alone, disrupted acquisition in HRs but not in LRs. Data show
      that the effects of noradrenergic agents in HRs and LRs are due to differences in
      acquisition directed by type-specific differences in functional mesolimbic
      noradrenaline.

PMID- 12492308
TI  - TNF-alpha and psychologically stressful events in healthy subjects: potential
      relevance for multiple sclerosis relapse.
AB  - The authors conducted a prospective and descriptive pilot study in 14 healthy
      medical students, investigating whether a psychologically stressful event (final
      examination) may modify serum tumor necrosis factor alpha (TNF-alpha) levels.
      There was a dramatic and sustained decrease of phytohemagglutinin (PHA)-induced
      TNF-alpha several weeks before and the day of the examination, followed by a
      significant increase of TNF-alpha starting the next day. Examination-induced
      stress was confirmed by both elevated urinary cortisol concentration and
      significant increase in stress scale scores. Extending these results to patients
      suffering from multiple sclerosis (MS) leads to the hypothesis that psychological
      stress may influence the course of MS by substantially altering TNF-alpha levels,
      and suggests the need for further studies in MS patients exposed to stressful
      conditions.

PMID- 12492309
TI  - Effects of the dopamine antagonist PD 152255 on juvenile rats' responses to
      dorsal stimulation, the transport response, and related behaviors.
AB  - The authors gave 23- and 40-day-old rats doses of the dopamine D3 antagonist PD
      152255 and tested them on transport response intensity, vertical cling catalepsy
      duration, and dorsal immobility duration. Administration of PD 152255 resulted in
      dose-dependent increases in transport response intensity in 40-day-old rats but
      was without effect in 23-day-old rats. Administration of PD 152255 caused
      increases in dorsal immobility durations in both 23- and 40-day-old subjects. The
      drug was without effect on vertical cling catalepsy. Results are discussed with
      respect to the role of D3 receptors in the transport response and the nature of
      D2-D3 receptor interactions.

PMID- 12492310
TI  - Chemoenzymatic asymmetric total syntheses of antitumor agents (3R,9R,10R)- and
      (3S,9R,10R)-Panaxytriol and (R)- and (S)-Falcarinol from Panax ginseng using an
      enantioconvergent enzyme-triggered cascade reaction.
AB  - Total asymmetric synthesis of two components of Panax ginseng showing antitumor
      activity, i.e., (3R,9R,10R)- and (3S,9R,10R)-Panaxytriol and of both enantiomers
      of Falcarinol was accomplished. Due to the fact that the synthetic strategy was
      based on enantioconvergent biotransformations, the occurrence of any undesired
      stereoisomer was entirely avoided. The absolute configuration of naturally
      occurring Panaxytriol was confirmed to be (3R,9R,10R) on the basis of optical
      rotation values. It was shown that enzyme-triggered cascade reactions represent a
      valuable tool for the synthesis of natural products.

PMID- 12492311
TI  - Molecular triads composed of ferrocene, C60, and nitroaromatic entities:
      electrochemical, computational, and photochemical investigations.
AB  - Synthesis and physicochemical characterization of a series of molecular triads
      composed of ferrocene, C(60), and nitroaromatic entities are reported.
      Electrochemical studies revealed multiple redox processes involving all three
      redox active ferrocene, C(60), and nitrobenzene entities. Up to eight redox
      couples within the accessible potential window of o-dichlorobenzene containing
      0.1 M (TBA)ClO(4) are observed. A comparison between the measured redox
      potentials with those of the starting compounds revealed absence of any
      significant electronic interactions between the different redox entities. The
      geometric and electronic structure of the triads are elucidated by using ab
      initio B3LYP/3-21G methods. In the energy-optimized structures, as predicted by
      electrochemical studies, the first HOMO orbitals are found to be located on the
      ferrocene entity, while the first LUMO orbitals are mainly on the C(60) entity.
      The coefficients of the subsequent LUMO orbitals track the observed site of
      electrochemical reductions of the triads. The photochemical events of the triads
      are probed by both steady-state and time-resolved techniques. The steady-state
      emission intensities of the triads and the starting dyad, 2
      (ferrocenyl)fulleropyrrolidine, are found to be completely quenched compared to
      fulleropyrrolidine bearing no redox active substituents. The subpicosecond and
      nanosecond transient absorption spectral studies revealed efficient charge
      separation (and rapid charge recombination) in the triads, and this has been
      attributed to the close spacing of the redox entities of the triad to one
      another.

PMID- 12492312
TI  - Synthesis of novel phthalocyanine-tetrathiafulvalene hybrids; intramolecular
      fluorescence quenching related to molecular geometry.
AB  - A number of silicon phthalocyanine bis-esters have been synthesized and
      characterized, with axial ligands containing one or more tetrathiafulvalene
      groups. Variations in the substitution positions around a central aromatic
      "hinge" within the ligands lead to different molecular geometries, and the
      fluorescence of the macrocyclic core is subsequently quenched to varying degrees
      by the electron-rich tetrathiafulvalene moiety, the magnitude of this effect
      being dependent upon both the relative separation of the two units and the
      flexibility of the linking group. Pc derivative 24, with a highly flexible linker
      group, and pc derivative 28, with a dendritic axial ligand, have the intensity of
      the macrocycle emission reduced by 99% and 96%, respectively, relative to a
      similar silicon pc reference compound lacking the TTF moieties. Molecular
      modeling studies of a series of such hybrids allow the degree of this
      fluorescence quenching to be related to the intramolecular spacing. Additionally,
      the potential for rapid electrochemical switching of the phthalocyanine
      fluorescence by oxidation of the appended tetrathiafulvalene units is explored.

PMID- 12492313
TI  - Ab initio study of the (5R)- and (5S)-TT pyrimidine h5(6-4) pyrimidone
      photoproducts. Implications on the design of new biologically relevant analogues.
AB  - A computational study of a series of N(1)- and/or C(6)-alkyl-5,6-dihydrothymine
      diastereomers at theory levels up to MP4(SDTQ)/6-31G//HF/6-31G and MP2/6
      311G//HF/6-31G has demonstrated the respective importance of the substituents at
      positions 1, 5, and 6 on the energetically favored conformation of each isomer.
      Results obtained both in the gas and condensed phase indicate that unsubstitution
      of the N(1)-position favors a half-chair conformation with the C(5) -and C(6)
      substituents in the equatorial position. On the other hand, in the case of the
      (6S)-1,6-dimethyl-5,6-dihydrothymine, the C(6)-substituent adopts the axial
      position to minimize its van der Waals interactions with the N(1)-substituent.
      Furthermore, if the configuration at the C(5)-dihydrothymine position has no
      resultant influence on the total molecular free energy, when a pyrimidone
      substituent is introduced at the dihydrothymine C(6)-position, additional
      repulsive forces between the C(5)- and C(6)-substituents make the diaxially
      substituted half-chair conformation the most energetically favorable one. These
      results indicate that the observed C(6)-axially substituted conformation of the
      thymine-thymine pyrimidine h(5)(6-4) pyrimidone photoproducts is not necessarily
      induced by the macrocyclic structure. They also nicely explain the formation
      mechanism of these photoproduct derivatives, and allow the prediction of the
      conformation of new analogues.

PMID- 12492314
TI  - Novel antibacterial macrolides: synthesis of 15-membered diolides.
AB  - Novel 15-membered macrolides possessing the dilactone skeleton, diolides 13a and
      13b, have been synthesized in our research program aimed at finding new
      antibacterial macrolides. Key strategic elements of the approach include the ring
      expanding reaction of 13-membered dilactones, prepared from erythromycin A (Ery
      A), to 15-membered dilactones via intramolecular translactonization. The absolute
      configuration at the regenerated C-8 position of the new diolides was determined
      by chemical transformation, leading to the corresponding lactam analogues, whose
      stereochemistry is known in the literature. For further confirmation, X-ray
      analysis was performed. The X-ray structure determination of 13a revealed a
      backbone conformation similar to that of Ery-A. Novel 15-membered diolide 13a and
      the 11,12-diol 18 exhibited antibacterial activities comparable to that of Ery-A.

PMID- 12492315
TI  - [4+3] versus [4+2] mechanisms in the dimerization of 2-boryl-1,3-butadienes. A
      theoretical and experimental study.
AB  - The thermal dimerization of 2-boryl-1,3-butadienes and the scope of this reaction
      to prepare six-membered rings difficult to synthesize by other methodologies have
      been studied. In addition, the nature of this dimerization has been studied
      theoretically. It has been found that the reaction coordinate associated with the
      formation of the cycloadduct of lowest energy has significant [4+3] character.
      This behavior is caused by the favorable carbon-carbon overlap and the large
      values of the corresponding resonance integrals. However, beyond the transition
      structure, the [4+2] pathway becomes the preferred one thus leading to the
      exclusive formation of the [4+2] cycloadduct. Aside from this effect, donating
      groups at the boryl moiety favor the [4+2] mechanism.

PMID- 12492316
TI  - Diels-Alder Reaction of phosphaethene with 1,3-dienes: an ab initio study.
AB  - Computations on Diels-Alder (DA) reactions of phosphaethene with 1,3-butadiene
      and with isoprene reveal asynchronous transition structures. The DFT (B3LYP/6
      311+G) activation energies of these reactions, 12-14 kcal/mol, are much lower
      than that of the parent ethene-butadiene reaction, 28 kcal/mol, even though the
      exothermicities of all lie in the same range, from -29 to -33 kcal/mol. The
      transition states (TSs) for the phosphethene-butadiene or isoprene DA reactions
      are earlier than the TSs of the butadiene-ethene cycloaddition. Due to the
      weakness of the C=P pi bond compared to the C=C pi bonds, the energies required
      to reach the phosphaethene TSs are much less than the carbocyclic cases. The
      computed (1)H NMR chemical shifts and nucleus independent chemical shifts (NICS)
      quantify the aromatic character of the transition states. Regioselectivities of
      the neutral phosphaethene-isoprene DA reactions are modest, at best. However,
      computations on radical cation DA reactions of phosphaethene with isoprene, which
      proceed stepwise with open chain intermediates, can account for the high
      regioselectivities that have been observed in some cases.

PMID- 12492317
TI  - An acid-base switchable [2]rotaxane.
AB  - A chemically addressable, bistable [2]rotaxane, which incorporates a dumbbell
      shaped component containing both secondary dialkylammonium and 1,2
      bis(pyridinium)ethane recognition sites for its ring component, dibenzo[24]crown
      8 (DB24C8), has been assembled. (1)H NMR spectroscopy has demonstrated that
      deprotonation (and reprotonation) of the secondary dialkylammonium (dialkylamine)
      recognition site induces the DB24C8 ring to move away from this site to the 1,2
      bis(pyridinium)ethane one (and back again) in a discrete manner, particularly
      when the experiment is performed in CDCl(3) solution.

PMID- 12492318
TI  - Synthesis of substituted quinolines using the dianion addition of N-Boc-anilines
      and alpha-tolylsulfonyl-alpha,beta-unsaturated ketones.
AB  - A short and versatile synthesis of substituted quinolines is provided. Alkylation
      of sodium tolylsulfinate with bromomethyl- or chloromethyl ketones generates beta
      keto sulfones. Knoevenagel condensation of the beta-keto sulfones with an
      aldehyde provides alpha-tolylsulfonyl-alpha,beta-unsaturated ketones. Michael
      addition of the dianion of N-Boc-anilines in the presence of CuCN and LiCl with
      the unsaturated ketone generates a 1,4-adduct, which after deprotection of the
      Boc group and thermal elimination of the tolyl sulfone provides the quinoline.

PMID- 12492319
TI  - Diastereoselective reduction of a chiral N-Boc-protected delta-amino-alpha,beta
      unsaturated gamma-keto ester Phe-Gly dipeptidomimetic.
AB  - The readily available N-Boc-protected delta-amino alpha,beta-unsaturated gamma
      keto ester 1 was diastereoselectively reduced to the corresponding alcohols 2 and
      3, using boron- and aluminum-based reducing reagents. Reduction reactions were
      successful and resulted in anti/syn ratios of alcohols of >95:5 (80% yield),
      using LiAlH(O-t-Bu)(3) in EtOH at -78 degrees C under chelation control, and 5:95
      (98% yield), using NB-Enantride in THF at -78 degrees C under Felkin-Anh control.

PMID- 12492320
TI  - A highly stereoselective asymmetric synthesis of (--)-lobeline and (--)-sedamine.
AB  - A highly stereoselective asymmetric synthesis of (--)-sedamine and (--)-lobeline
      is described from benzaldehyde in 16 and 17 steps with an overall yield of 20%
      and 14%, respectively. The key intermediate syn-3,4-epoxyalcohol was prepared in
      a highly diastereomeric fashion (>99% ee, dr) and served as a common intermediate
      for both alkaloids.

PMID- 12492321
TI  - New flexible synthesis of pyrazoles with different, functionalized substituents
      at C3 and C5.
AB  - Syntheses of pyrazoles featuring a functionalized side chain attached to carbon 3
      and varying alkyl and aryl substituents attached to carbon 5 are presented.
      Installation of R = methyl, isopropyl, tert-butyl, adamantyl, or phenyl groups at
      C5 is reported here, starting by coupling protected alkynols with acid chlorides
      RCOCl, forming alkynyl ketones, which are reacted with hydrazine to form the
      pyrazole nucleus. Alcohol deprotection and conversion to a chloride gave 5
      substituted 3-(chloromethyl)- or 3-(2-chloroethyl)pyrazoles. This sequence can be
      done within 2 d on a 30 g scale in excellent overall yield. Through nucleophilic
      substitution reactions, the chlorides are useful precursors to other
      polyfunctional pyrazoles. In the work here, derivatives with side chains LCH(2)-
      and LCH(2)CH(2)- at C3 (L = thioether or phosphine) were made as ligands. The
      significance of the ligands made here is that by placing a ligating side chain on
      a ring carbon (C3), rather than on a ring nitrogen, the ring nitrogen not bound
      to the metal and its attached proton will be available for hydrogen bonding,
      depending on the steric environment created by R at C5.

PMID- 12492323
TI  - Inter- and intramolecular stereoselective protonation of enols(1,2).
AB  - Kinetic control of the stereoselectivity of protonation of enolates and other
      delocalized species commonly affords the less stable diastereomer as a
      consequence of the considerable exothermicity and resulting sp(2) transition
      state hybridization of the alpha-carbon. Protonation then is from the less
      hindered face of the enolate. The present study is aimed at reversing this
      phenomenon by intramolecular delivery of the proton. The approach employed
      required the synthesis of two enolate precursors, one with a 2-pyridyl group
      strategically close to the alpha-carbon and the other with a phenyl group in the
      same location. The synthesis required 15 steps and involved new methodology.
      Intramolecular proton transfer, reversing the usual stereoselectivity, was
      successful. The selectivity proved to depend on several factors including the exo
      versus endo configuration of the diastereomer reacting, the proton donor
      employed, and the concentration of the proton donor. A kinetic analysis permitted
      the determination of the relative reaction orders of the protonation on the two
      faces of the enolate.

PMID- 12492322
TI  - Diastereoselective synthesis of all stereoisomers of beta-methoxytyrosine, a
      component of papuamides.
AB  - beta-Methoxytyrosine (beta-OMeTyr) is a stereoundefined component of papuamides A
      and B, novel cyclodepsipeptides, with anti-HIV and cytotoxic activities. For
      structural determination and total synthesis of papuamides, all stereoisomers of
      beta-OMeTyr were stereoselectively prepared from (S)- and (R)-serine,
      respectively.

PMID- 12492324
TI  - Asymmetric synthesis of anti- and syn-beta-amino alcohols by reductive cross
      coupling of transition metal-coordinated planar chiral arylaldehydes with
      aldimines.
AB  - Samarium iodide-mediated cross-coupling of N-tosyl ferrocenylideneamine with
      planar chiral ferrocenecarboxaldehydes or benzaldehyde chromium complexes gave
      diastereoselectively the corresponding anti-beta-amino alcohol derivatives in
      good yields, while N-tosyl benzylideneamine produced syn-beta-amino alcohols by
      coupling with planar chiral arylaldehydes. Dynamic kinetic resolution of a
      configurationally equilibrated reactive species generated from achiral N-tosyl
      ferrocenilideneamine and benzylideneamine by reduction with samarium iodide was
      observed in the cross-coupling with planar chiral arylaldehydes giving both
      antipodes of beta-amino alcohols depending on the planar chirality. The obtained
      anti-beta-amino alcohol with the ferrocene ring was utilized as a chiral ligand
      for catalytic asymmetric reduction of acetophenone.

PMID- 12492325
TI  - Mono-N-methylation of primary amines with alkyl methyl carbonates over Y
      faujasites. 2. Kinetics and selectivity.
AB  - In the presence of a Na-exchanged Y faujasite, the reaction of primary aromatic
      amines 1 with 2-(2-methoxyethoxy)methylethyl carbonate
      [MeO(CH(2))(2)O(CH(2))(2)OCO(2)Me, 2a] yields the corresponding mono-N-methyl
      derivatives ArNHMe with selectivity up to 95%, at substantially quantitative
      conversions. At 130 degrees C, the reaction can be run under diffusion-free
      conditions and is strongly affected by the solvent polarity: for instance, in
      going from xylene (epsilon(r) = 2.40) to triglyme (epsilon(r) = 7.62) as the
      solvent, the pseudo-first-order rate constant for the aniline (1a) disappearance
      shows a 5-fold decrease. In DMF (epsilon(r) = 38.25), the same reaction does not
      occur at all. Competitive adsorption of the solvent and the substrate onto the
      catalytic sites accounts for this result. The behavior of alkyl-substituted
      anilines ZC(6)H(4)NH(2) [Z = p-Me, p-Et, p-Pr, p-(n-Bu) (1b-e); Z = 3,5-di-tert
      butyl- and 2,4,6-tri-tert-butylanilines (1f,g)] and p-alkoxyanilines p
      ZC(6)H(4)NH(2) [Z = OMe, OEt, OPr, O-n-Bu (1b'-e')] clearly indicates a steric
      effect of ring substituents: as diffusion of the amine into the catalytic pores
      is hindered, the reaction hardly proceeds and the mono-N-methyl selectivity
      (S(M/D)) drops as well. Moreover, the strength of adsorption of the amine onto
      the catalyst influences the rate and the selectivity as well: the reaction of p
      anisidine and p-toluidine-despite the higher nucleophilicity of these compounds
      is slower and even less selective with respect to aniline. From a mechanistic
      viewpoint, the intermediacy of carbamates ArN(Me)CO(2)R [R =
      MeO(CH(2))(2)O(CH(2))(2)] is suggested. At 90 degrees C, the reaction of
      benzylamine (7)-a model for aliphatic amines-with dimethyl carbonate shows that
      the reaction outcome can be improved by tuning the amphoteric properties of the
      catalyst: in going from CsY to the more acidic LiY zeolite, methylation is not
      only more selective (S(M/D) ratio increases from 77% to 84%) but even much faster
      (CsY, conversion of 36% after 22 h; LiY, conversion of 43% after 7 h).

PMID- 12492326
TI  - Studies toward the total synthesis of mumbaistatin, a highly potent glucose-6
      phosphate translocase inhibitor. Synthesis of a mumbaistatin analogue.
AB  - A strategy for the total synthesis of the highly potent glucose-6-phosphate
      translocase inhibitor mumbaistatin (1) and structural analogues was elaborated.
      Such compounds represent a lead structure in the development of potential new
      drugs for the treatment of diabetes. To evaluate the general strategy, the close
      mumbaistatin analogue 10 was synthesized in a convergent manner. The
      anthraquinone building block 20 was efficiently prepared via aryne/phthalide
      annulation. After conversion of 20 into the corresponding 9,10
      dimethoxyanthracene-1-carbaldehyde derivative (13), coupling with a lithiated
      arene (12) and subsequent multiple oxidation under Jones conditions yielded the
      mumbaistatin analogue 10. The preparation of the functionalized arene
      intermediates was achieved exploiting highly regioselective bromination and ortho
      lithiation reactions.

PMID- 12492327
TI  - Nitrogen inversion in cyclic amines and the bicyclic effect.
AB  - The hitherto unsolved problem of the origin of the unusually high nitrogen
      inversion-rotation (NIR) barriers in 7-azabicyclo[2.2.1]heptanes (the bicyclic
      effect) was examined using the natural bond orbital (NBO) approach.
      Reinvestigating the NIR barrier for tropane by DNMR, we found that NIR barriers
      increase smoothly on going from nitrogen-bridged bicyclic systems of a larger
      ring size to the smaller ring homologous systems. The experimental NIR barriers
      are reproduced with good accuracy using the MP2/6-31G level of theory. The NBO
      analysis for these and other azabicycles led to the conclusion that the height of
      these barriers is mostly determined by the energy of the sigma-orbitals of the
      C(alpha)(-)C(beta) bonds as well as the nitrogen lone pair. Thus, the bicyclic
      effect is actually an extreme case of a common C(alpha-)N-C(alpha) tripyramid
      geometry-NIR barrier dependence for N-bridged bicyclic amines. By establishing
      the rate-determining role of the C(alpha-)N-C(alpha) tripyramid fragment for NIR,
      we have derived the first sufficiently accurate quantitative correlations amine
      geometry-NIR barrier for monocyclic as well as bicyclic N-H and N-Me amines
      (i.e., for an amine set which also includes the bicyclic effect systems).

PMID- 12492328
TI  - Synthesis of 2,5-disubstituted thienosultines and their thermal reactions with
      dienophiles and nucleophiles.
AB  - The 2,5-disubstituted thienosultines (5,7-disubstituted 1,4-dihydro-1H-3lambda(4)
      thieno[3,4-d][2,3]oxathiin-3-oxides) 5a-d were prepared from the corresponding
      dichlorides 4a-d with the commercially available Rongalite (sodium formaldehyde
      sulfoxylate) in 17-60% yields. When heated in the presence of electron-poor
      dienophiles, sultines 5a-d underwent elimination of SO(2), and the resulting non
      Kekule biradicals 7a-d were intercepted as the 1:1 adducts 8-12 in good to
      excellent yields. The pyrolysis of sultines and sulfolenes with different
      concentrations of dienophiles revealed that either a preequilibrium between
      starting reagents and biradical species or Diels-Alder and retro-Diels-Alder
      reaction mechanisms may be involved; however, more work is necessary to establish
      the proposed mechanisms. Reaction of sultine 5b with nBuLi was found to undergo a
      nucleophilic ring-opening reaction to give sulfinyl alcohol 17 after H(2)O
      workup. When sultine 5a was heated in benzene in a sealed tube in the presence of
      methanol, methanol-d(4), or 2-mercaptoethanol, the respective 1:1 trapping
      adducts 19-21 as well as the rearranged sulfolene 6a were isolated in similar
      amounts. The isolation of adducts 19-21 may be explained by the involvement of
      either biradical or ionic intermediates during the pyrolysis.

PMID- 12492329
TI  - Carbopalladation of nitriles: synthesis of 2,3-diarylindenones and polycyclic
      aromatic ketones by the Pd-catalyzed annulation of alkynes and bicyclic alkenes
      by 2-iodoarenenitriles.
AB  - 2-iodobenzonitrile, its derivatives, and various heterocyclic analogues undergo
      palladium(0)-catalyzed annulation onto diarylacetylenes or bicyclic alkenes to
      afford 2,3-diarylindenones and polycyclic aromatic ketones in very good to
      excellent yields. This reaction represents one of the first examples of the
      addition of an organopalladium moiety to the carbon-nitrogen triple bond of a
      nitrile. The reaction is compatible with a number of functional groups. A
      reaction mechanism, as well as a model accounting for the electronic effects of
      substituents on the aromatic ring of the nitrile, is proposed.

PMID- 12492330
TI  - 3,5,7-trimethyl-1-azatricyclo[3.3.1.1(3,7)]decan-2-ylidene, an aminocarbene
      without pi conjugation.
AB  - 3,5,7-trimethyl-1 -azatricyclo[3.3.1.1(3,7)]decan-2-ylidene, an aminocarbene
      without pi conjugation, has been generated from the corresponding tosylhydrazone
      salt. Addition of the carbene to alkenes is stereospecifically cis, thus showing
      that the reacting state is singlet. Competition studies reveal that the carbene
      is somewhat nucleophilic, implying a measure of overlap between the lone pair on
      nitrogen and the empty orbital on carbon. In turn, such overlap implies a
      pyramidal structure for the divalent carbon.

PMID- 12492331
TI  - A quantitative approach to the recycling of alpha-tocopherol by coantioxidants.
AB  - A systematic investigation is reported on the regeneration of alpha-tocopherol
      (alpha-TOH) in homogeneous solution by coantioxidants in order to better
      understand the mechanism and the factors responsible for the effectiveness of
      this process. The current availability of thermochemical data concerning the
      reactants involved in the regeneration reactions, as well as a large number of
      the kinetic constants for the various reactions involved, allowed us to
      rationalize the experimental observations collected so far. Three limiting cases
      have been considered. The first case is that of a coantioxidant irreversibly
      regenerating alpha-TOH, where the effectiveness of the recycling process depends
      on the magnitude of the rate constant k(r). The second case is that of a
      coantioxidant reversibly recycling alpha-TOH, where regeneration can only be
      observed if the bond dissociation enthalpy value of the coantioxidant is lower or
      at least close to that of the O-H bond of alpha-tocopherol. The third case is
      that of a catechol derivative (chosen as a model compound for polyphenolic
      antioxidants), where recycling of alpha-TOH is feasible even though the BDE value
      is significantly higher than that of vitamin E. In this case, the driving force
      for the recycling process is the removal of the semiquinone radical from the
      catechol derivative by the alpha-tocopheroxyl radical, which makes the
      regeneration of alpha-TOH practically irreversible.

PMID- 12492332
TI  - Lewis acid-promoted oxidative addition of thioimidates to Pd0.
AB  - The isomeric S-methyldihydropyrrins 9-Z and 9-E exhibit markedly different
      behavior in Pd(0)-catalyzed cross-coupling reactions. Thioimidates 9-Z are
      readily converted to imines 10-Z employing Pd(0)/AlkZnI. Under identical
      conditions 9-E are inert. Oxidative addition to Pd(0) requires activation by Zn
      or other Lewis acids, which is sterically unfavorable with 9-E. Analogous results
      were obtained with the related thioimidates 11-E,Z as well as with
      methylthiopyridines 19alpha-gamma. In the case of both 11 and 19 oxidative
      addition to Pd(0) was greatly facilitated in the presence of BF(3) x Et(2)O. The
      importance of Lewis acid activation to Pd(0) oxidative addition in such
      substrates appears to be a general phenomenon not previously recognized.

PMID- 12492333
TI  - Asymmetric cyclization of omega-formyl-1,3-dienes catalyzed by a zerovalent
      nickel complex in the presence of silanes.
AB  - A nickel(0)-catalyzed asymmetric cyclization of omega-formyl-1,3-diene in the
      presence of silanes in which five- or six-membered carbocycles or pyrrolidine
      derivatives were afforded up to 86% ee by the use of (2R,5R)-2,5-dimethyl-1
      phenylphospholane as a monodentate chiral ligand was investigated. The reaction
      course of this asymmetric cyclization can be explained for by two possible
      mechanisms: one in which the cyclization proceeds via a pi-allylnickel
      intermediate to produce a cyclized product having an internal olefin in the side
      chain, and one in which the cyclization proceeds via a sigma bond metathesis of
      silane and the nickel-oxygen bond of oxanickelacycle to produce a cyclized
      compound having a terminal olefin and/or an internal olefin in the side chain. It
      was speculated that both of these mechanisms operate in this asymmetric
      cyclization depending upon the nature of silanes and the reaction conditions.

PMID- 12492334
TI  - Synthesis of beta- and gamma-carbolines by the palladium-catalyzed
      iminoannulation of alkynes.
AB  - A variety of substituted beta- and gamma-carbolines have been prepared in
      moderate to excellent yields by the palladium-catalyzed annulation of internal
      and terminal acetylenes by the tert-butylimines of N-substituted 3-iodoindole-2
      carboxaldehydes and 2-haloindole-3-carboxaldehydes, respectively. This annulation
      chemistry is effective for a wide range of alkynes, including aryl-, alkyl-,
      hydroxymethyl-, ethoxycarbonyl-, and trimethylsilyl-substituted alkynes. When an
      unsymmetrical internal alkyne is employed, this method generally gives two
      regioisomers. When a terminal alkyne is employed, only one regioisomer has been
      isolated. This palladium-catalyzed annulation chemistry has also been
      successfully applied to the synthesis of two biologically interesting beta
      carboline alkaloids, ZK93423 and abecarnil (ZK112119).

PMID- 12492335
TI  - Stereoselective synthesis of the 5'-hydroxy-5'-phosphonate derivatives of
      cytidine and cytosine arabinoside.
AB  - Both the (R)- and (S)-5'-hydroxy 5'-phosphonate derivatives of cytidine and
      cytosine arabinoside (ara-C) have been prepared via phosphite addition or a Lewis
      acid mediated hydrophosphonylation of appropriately protected 5'-nucleoside
      aldehydes. Phosphite addition to a cytosine aldehyde protected as the 2',3'
      acetonide gave predominately the 5'R isomer, while phosphite addition to the
      corresponding 2',3'-bis TBS derivative favored the 5'S stereochemistry. In
      contrast, phosphite addition to the 2',3'-bis TBS protected aldehyde derived from
      ara-C gave only the 5'R adduct. However, TiCl(4)-mediated hydrophosphonylation of
      the same ara-C aldehyde favored the 5'S stereoisomer by a 2:1 ratio. Once all
      four of the diastereomers were in hand, the stereochemistry of these compounds
      could be assigned based on their spectral data or that obtained from their O
      methyl mandelate derivatives. After hydrolysis of the phosphonate esters and
      various protecting groups, the four alpha-hydroxy phosphonic acids were tested
      for their ability to serve as substrates for the enzyme nucleoside monophosphate
      kinase and for their toxicity to K562 cells.

PMID- 12492336
TI  - Syntheses of 1-alkyl-1,2,4-triazoles and the formation of quaternary 1-alkyl-4
      polyfluoroalkyl-1,2,4-triazolium salts leading to ionic liquids.
AB  - 1,2,4-triazole was alkylated (alkyl = methyl, butyl, heptyl, decyl) at N-1 in
      >90% isolated yields. The resulting 1-alkyl triazoles were quaternized at N-4 in
      >98% isolated yields using fluorinated alkyl halides with >98% isolated yields,
      under neat reaction conditions at 100-120 degrees C to form N1-CH(3)-N4
      (CH(2))(2)C(m)F(2)(m)(+ 1)-triazolium (Taz) iodide (m = 1, 6), N1-C(4)H(9)-N4
      (CH(2))(2)C(m)F(2)(m)(+ 1)-Taz iodide (m = 1, 4, 6), N1-C(7)H(15)-N4
      (CH(2))(2)C(m)F(2)(m)(+ 1)-Taz iodide (m = 1, 4, 6), N1-C(10)H(21)-N4
      (CH(2))(2)C(m)F(2)(m)(+1)-Taz iodide (m = 1, 4), and N1-C(n)H(2)(n )(+ 1)-N4
      (CH(2))(2)F-Taz bromide (n = 4, 7, 10). Single-crystal X-ray analyses confirmed
      the structure of [1-CH(3)-4-CH(2)CH(2)CF(3)-Taz](+)I(-). It crystallized in the
      orthorhombic space group Pccn, and the unit cell dimensions were a = 13.8289(9)
      A, b = 17.3603(11) A, c = 9.0587(6) A (alpha = beta = gamma = 90 degrees ).
      Metathesis of these polyfluoroalkyl-substituted triazolium halides with other
      salts led to the formation of quaternary compounds, some of which comprise ionic
      liquids, namely, [R(R(f))-Taz](+)Y(-) (Y = NTf(2), BF(4), PF(6), and OTf), in
      good isolated yields without the need for further purification: N1-CH(3)-N4
      (CH(2))(2)C(m)F(2)(m)( +) (1)-Taz Y (m = 1, 6; Y = NTf(2)), N1-C(4)H(9)-N4
      (CH(2))(2)C(m)F(2)(m)(+ 1)-Taz Y (m = 1, 4, 6; Y = NTf(2)), N1- C(7)H(15)-N4
      (CH(2))(2)C(m)F(2)(m)(+ 1)-Taz Y (m = 1, 4, 6; Y = NTf(2)), N1-C(10)H(21)-N4
      (CH(2))(2)C(m)F(2)(m)(+1)-Taz Y (n = 1, 4; Y = NTf(2)), N1-C(n)H(2)(n )(+ 1)-N4
      (CH(2))(2)F-Taz Y (n = 7, 10; Y = NTf(2)), N1-C(10)H(21)-N4-(CH(2))(2)F-TazY (Y =
      OTf), N1-C(7)H(15)-N4-(CH(2))(2)F-TazY (Y = BF(4)), N1-C(4)H(9)-N4
      (CH(2))(2)C(m)F(2)(m) (+ 1)-Taz Y (m = 4, 6; Y = PF(6)), N1-C(7)H(15)-N4
      (CH(2))(2)C(4)F(9)-Taz Y (Y = PF(6)), N1-C(4)H(9)-N4-(CH(2))(2)C(m)F(2)(m)(+ 1)
      Taz Y (m = 4, 6; Y = OTf). All new compounds were characterized by (1)H, (19)F,
      and (13)C NMR and MS spectra and elemental analyses. T(g)s and T(m)s of ionic
      liquids were determined by DSC.

PMID- 12492337
TI  - A computational study on addition of Grignard reagents to carbonyl compounds.
AB  - The mechanism of stereoselective addition of Grignard reagents to carbonyl
      compounds has been investigated using B3LYP density functional theory
      calculations. The study of the reaction of methylmagnesium chloride and
      formaldehyde in dimethyl ether revealed a new reaction path involving carbonyl
      compound coordination to magnesium atoms in a dimeric Grignard reagent. The
      structure of the transition state for the addition step shows that an interaction
      between a vicinal-magnesium bonding alkyl group and C=O causes the C-C bond
      formation. The simplified mechanism shown by this model is in accord with the
      aggregation nature of Grignard reagents and their high reactivities toward
      carbonyl compounds. Concerted and four-centered formation of strong O-Mg and C-C
      bonds was suggested as a polar mechanism. When the alkyl group is bulky, C-C bond
      formation is blocked and the Mg-O bond formation takes precedence. A diradical is
      formed with the odd spins localized on the alkyl group and carbonyl moiety.
      Diradical formation and its recombination were suggested to be a single electron
      transfer (SET) process. The criteria for the concerted polar and stepwise SET
      processes were discussed in terms of precursor geometries and relative energies.

PMID- 12492338
TI  - Synthesis and conformational dynamics of tricyclic pyridones containing a fused
      seven-membered ring.
AB  - A new synthetic approach to tricyclic pyridones bearing a fused seven-membered
      ring is described. These compounds exhibit atropisomerism and exist in
      enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed the
      rates of racemization to be measured and hence the free energy barrier for
      flipping the seven-membered ring to be deduced. Introduction of a further element
      of planar chirality leads to diastereomeric atropisomerism. The rate of
      interconversion of the diastereomers has been quantified by 2D EXSY NMR
      spectroscopy allowing a full description of the conformational dynamics of the
      system.

PMID- 12492339
TI  - Photochemistry of racemic and resolved 2-iodooctane. Effect of solvent polarity
      and viscosity on the chemistry.
AB  - The photochemistry of racemic and resolved 2-iodooctane was examined in
      cyclopentane, methanol, and 2-methyl-2-propanol, media with differing polarities
      and viscosities. The photochemistry of racemic 2-iodooctane was also examined in
      the gas phase. The photochemistry of 2-deuterio- and 1,1,1-trideuterio-2
      iodooctane in cyclopentane and methanol was also studied. The photoreactions in
      cyclopentane, 2-methyl-2-propanol, and the gas phase occurred exclusively through
      homolytic reactions, while in methanol, they occurred predominantly (>53%)
      through heterolytic reactions. By comparing the disappearance of the optically
      active substrate with its loss of optical activity, F, the fraction of the
      initially formed radical pair (RP) or ion pair (IP) resulting in product was
      determined for the three solvents. Because F contains contributions of both
      escape of the partners in the RP or IP into the bulk of the solvent and reaction
      within the RP or IP to yield products other than the substrate, there was no
      correlation between F and solvent viscosity. The F values will be valuable in
      assessing the photochemistry of 2-iodooctane in the same media with circularly
      polarized light.

PMID- 12492340
TI  - Mechanistic organic chemistry in a microreactor. Zeolite-controlled
      photooxidations of organic sulfides.
AB  - The intrazeolite and solution photooxygenations of a series of sulfides have been
      compared. The unusual zeolite environment enhances the rates of reaction, it
      suppresses the Pummerer rearrangements, and it has a dramatic effect on the
      sulfoxide/sulfone ratio. A detailed kinetic study utilizing trapping experiments
      and intramolecular competition provides evidence for cation complexation to a
      persulfoxide intermediate as the underlying phenomenon for the unique
      intrazeolite behavior. For example, the enhanced rate of reaction is traced to
      the cation stabilization of the persulfoxide toward unproductive decomposition to
      substrate and triplet oxygen.

PMID- 12492341
TI  - Electrolytic partial fluorination of organic compounds. 64.(1) Anodic mono- and
      difluorination of thiazolyl sulfides.
AB  - The anodic fluorination of 2-thiazolyl methyl sulfide, 2-thiazolyl propargyl
      sulfide, and 2-thiazolyl acetonyl sulfide was successfully carried out to provide
      the corresponding 5-fluorothiazole and 2,5,5-trifluorothiazoline derivatives. The
      latter products were readily hydrolyzed to give isolable 5,5-difluoro-2
      hydroxythiazoline derivatives. On the other hand, anodic fluorination of 2
      thiazolyl cyanomethyl sulfide afforded 5-fluorothiazole and alpha-fluorinated
      thiazole derivatives. Thus, the product selectivity was found to be greatly
      changed by the electron-withdrawing ability of substituents at the side chain of
      the thiazole ring. This is the first report of a successful anodic fluorination
      of a thiazole ring.

PMID- 12492342
TI  - Structures and cytotoxic properties of sponge-derived bisannulated acridines.
AB  - A reinvestigation of sponge natural products from additional Indo-Pacific
      collections of Xestospongiacf. carbonaria and X. cf. exigua has provided further
      insights on the structures, biological activities, and biosynthetic origin of
      bisannulated acridines. These alkaloids include one known pyridoacridine,
      neoamphimedine (2), and three new analogues, 5-methoxyneoamphimedine (4),
      neoamphimedine Y (5), and neoamphimedine Z (6). A completely new acridine,
      alpkinidine (7), was also isolated. A disk diffusion soft agar assay, using a
      panel of five cancer cell lines (solid tumors and leukemias) and two normal
      cells, was used to evaluate the differential cytotoxicity (solid tumor
      selectivity) of the sponge semipure extracts and selected compounds including
      amphimedine (1), 2, 4, and 7. While all four compounds were solid tumor
      selective, 1 and 2 were the most potent and 4 was the most selective. The
      rationale used to characterize the new structures is outlined along with the
      related biosynthetic pathways envisioned to generate 2 and 7.

PMID- 12492343
TI  - Preparing functional bis(indole) pyrazine by stepwise cross-coupling reactions:
      an efficient method to construct the skeleton of dragmacidin D.
AB  - A direct approach for selective construction of properly substituted bis(indole)
      pyrazine, the skeleton of a marine alkaloid dragmacidin D, has been developed.
      The key steps involved the regioselective introduction of two indole units, using
      the palladium(0)-catalyzed Suzuki and the Stille cross-coupling reactions
      sequentially.

PMID- 12492344
TI  - Photochemical reactivity of 1-substituted-1-aza-1,4-dienes promoted by electron
      acceptor sensitizers. Di-pi-methane rearrangements and alternative reactions via
      radical-cation intermediates.
AB  - Irradiation of a series of beta,gamma-unsaturated imines, oxime acetates, and
      oxime methyl ethers, using 9,10-dicyanoanthrathene (DCA) or dicyanodurene (DCD)
      as electron acceptor sensitizers, affords the corresponding cyclopropanes
      resulting from 1-aza-di-pi-methane rearrangements via radical cations. In some
      cases, alternative reactions of these intermediates occur to yield nitriles,
      dihydroquinolines, dihydronaphthalene derivatives, and cycloaddition products.
      Some of these products result from reactions via alkene radical-cation
      intermediates while others arise by pathways involving imine radical-cation
      intermediates. The yields of products formed in these processes were
      significantly higher when DCD was used as electron-acceptor sensitizer instead of
      DCA.

PMID- 12492345
TI  - Thiolytic chemistry of alternative precursors to the major metabolite of the
      cancer chemopreventive oltipraz.
AB  - The compounds 7-methyl-6,8-bis(methyldisulfanyl)pyrrolo[1,2-a]pyrazine (5; "bis
      disulfide") and methanethiosulfonic acid S-((6-(methanesulfonylsulfanyl)-7
      methyl)pyrrolo[1,2-a]pyrazin-8-yl) ester (6; "bis methanesulfonic acid
      thioester") have been synthesized to serve as alternative precursors to the major
      metabolite, 4, of the cancer chemopreventive oltipraz, 1, to test whether they
      possess similar biological activities. In the present work the mechanisms by
      which these compounds react with glutathione have been investigated in order to
      validate the assumption that they would be chemically competent in the presence
      of the biological thiols to give the oltipraz metabolite. A kinetic and product
      study was carried out in mainly aqueous media, </=15% ethanol by volume, at 37
      degrees C. The kinetic analysis and identification of intermediates by
      electrospray HPLC/MS indicate that compound 5 decomposes in two sequential
      reactions via thiol-disulfide interchange involving removal of the two thiomethyl
      groups. In contrast, 6 decomposes in three sequential steps, the first entailing
      formation of the diglutathionyl adduct, followed by two subsequent thiol
      disulfide interchange reactions involving loss of the glutathionyl moieties. Both
      5 and 6, as well as oltipraz itself, give nearly quantitative yields of the
      metabolite 4 in reactions with glutathione. Analysis of the decay of 6 by EPR
      spin trapping methods indicates that less than 0.2% of the reaction flux proceeds
      through radicals more stable than the hydroxyl radical.

PMID- 12492346
TI  - Cyclic alkenenitriles: chemoselective oxonitrile cyclizations.
AB  - Potassium tert-butoxide triggers the chemoselective cyclization between nitrile
      anions and remote, enolizable carbonyl groups, despite the acidity difference
      favoring enolate formation and addition to the nitrile group. Domino
      deprotonation, cyclization, and dehydration efficiently transform a diverse array
      of omega-oxonitriles into carbocyclic and heterocyclic five- and six-membered
      alkenenitriles in a single synthetic operation.

PMID- 12492347
TI  - Tetrathiomolybdate assisted epoxide ring opening with masked thiolates and
      selenoates: multistep reactions in one pot.
AB  - Tetrathiomolybdate provides an easy access to beta-hydroxy disulfides, beta
      hydroxy sulfides, and selenides from epoxides in a tandem, multistep process in
      one pot. This strategy has been utilized effectively in the construction of
      thiabicylo[3.2.2]nonane derivative 24.

PMID- 12492348
TI  - 3,3-difluoro-1-iodocyclopropenes: a simple synthesis and their reactions.
AB  - The [1 + 2] cycloaddition reaction of 1-iodoalkynes with difluorocarbene,
      generated from the decomposition of FSO(2)CF(2)COOSiMe(3) in diglyme in the
      presence of 10 mol % NaF at 120 degrees C, gives 3,3-difluoro-1-iodocyclopropenes
      in good yields. These new iodides can be trifluoromethylated and functionalized
      via the Heck reaction. The unusual hydrolytic reactions of the iodides under
      acidic conditions was also investigated.

PMID- 12492349
TI  - Carbopalladation of nitriles: synthesis of benzocyclic ketones and
      cyclopentenones via Pd-catalyzed cyclization of omega-(2-iodoaryl)alkanenitriles
      and related compounds.
AB  - An efficient procedure for the synthesis of 2,2-disubstituted benzocyclic ketones
      by intramolecular carbopalladation of nitriles has been developed. The
      cyclization of substituted 3-(2-iodoaryl)propanenitriles affords indanones in
      high yields. The reaction is compatible with a wide variety of functional groups.
      This methodology has been extended to the synthesis of tetralones and
      cyclopentenones.

PMID- 12492350
TI  - Regioselective preparation of 2-substituted 3,4-diaryl pyrroles: a concise total
      synthesis of ningalin B.
AB  - Methylisocyanoacetate undergoes a 2 + 3 cycloaddition with alpha,beta-unsaturated
      nitriles to provide a regioselective synthesis of 2-substituted 3,4-diaryl
      pyrroles. The ease of preparation of alpha,beta-unsaturated nitriles allows the
      rapid synthesis of pyrroles with varied substituents. Using this method, a key
      intermediate (1) for the synthesis of the marine natural products lukianol A,
      lamellarin O, and lamellarin Q was prepared in two steps. A total synthesis of
      ningalin B (11) was also accomplished utilizing this methodology.

PMID- 12492351
TI  - Diastereoselective total synthesis of both enantiomers of epolactaene.
AB  - A stereocontrolled total synthesis of both the (+)- and (-)-epolactaene ((+)- and
      (-)-1) enantiomers from tetrahydropyran-2-ol is described. The following
      reactions in this synthesis are particularly noteworthy: (1) the stereoselective
      construction of the conjugated (E,E,E)-triene by a combination of kinetic
      deprotonation and thermodynamic equilibration, (2) the E-selective Knoevenagel
      condensation of beta-ketonitrile 33 with a chiral 2-alkoxyaldehyde, (3) a
      diastereoselective epoxidation achieved using a bulky nucleophile (TrOOLi) and an
      appropriate protecting group, (4) the mild hydrolysis of an alpha-epoxy nitrile
      by silica gel on TLC facilitated by hydroxyl-mediated, intramolecular assistance.

PMID- 12492352
TI  - Zn(II)-mediated alkynylation-cyclization of o-trifluoroacetyl anilines: one-pot
      synthesis of 4-trifluoromethyl-substituted quinoline derivatives.
AB  - A novel efficient route to 4-trifluoromethyl-substituted quinoline derivatives
      through the Zn(II)-mediated alkynylation-cyclization of o-trifluoroacetyl
      anilines is described.

PMID- 12492353
TI  - Polyglycerol as a high-loading support for boronic acids with application in
      solution-phase Suzuki cross-couplings.
AB  - In this paper, we describe the usage of a soluble high-loading polyglycerol
      support for functionalized boronic acids without further linker design. The
      quantitatively formed polyglycerol boron esters were subsequently employed in
      homogeneous Suzuki cross-coupling reactions to give high yields (84-91%) of
      functional biaryls with minimal amounts of the Pd catalyst (0.2 mol %). In situ
      precipitation and ultrafiltration were used as simple and effective purification
      protocols. Furthermore, the reaction conditions were optimized by the choice of
      the solvent and the catalyst.

PMID- 12492354
TI  - An epiisopicropodophyllin aza analogue via palladium-catalyzed pseudo-domino
      cyclization.
AB  - A new aza analogue of epiisopicropodophyllin (the C-3 epimer of podophyllotoxin)
      has been synthesized exploiting two original strategic steps. Rings A/B and E are
      entered at an early stage via a cationic benzhydrylation process. A palladium
      catalyzed pseudo-domino (Pd-PDOM) intramolecular process generates rings C/D in a
      single synthetic operation.

PMID- 12492355
TI  - Solid-phase synthesis of substituted alkynes using the Nicholas reaction.
AB  - The first example of a Nicholas reaction on solid phase is reported, involving
      the reaction of cobalt complexes of polymer-bound alkynols with different
      nucleophiles in the presence of a Lewis acid, to form carbon-oxygen or carbon
      carbon bonds.

PMID- 12492356
TI  - Facile and highly stereoselective synthesis of the tetracyclic erythrinane core.
AB  - A highly stereoselective synthesis of the tetracyclic core of the Erythrina
      alkaloids is reported through the application of a Meyers bicyclic lactam
      template.

PMID- 12492357
TI  - Synthesis of C-3' methyl taxotere (docetaxel).
AB  - Protected (3R,4S)-N-Boc-3-hydroxy-4-methyl-4-phenylazetidin-2-one has been
      synthesized stereoselectively and used to esterify protected 10-desacetylbaccatin
      III to give, following removal of the protecting groups, novel C-3' methyl
      taxotere (docetaxel).

PMID- 12492358
TI  - A new procedure for preparation of carboxylic acid hydrazides.
AB  - The standard method for preparing carboxylic acid hydrazides is hydrazinolysis of
      esters in alcoholic solutions. However, when applied to alpha,beta-unsaturated
      esters, the main product typically is the pyrazolidinone resulting from an
      undesired Michael-type cyclization. Other alternative methodologies reported for
      direct preparation of hydrazides from acids are inefficient. We developed an
      efficient and general process, involving preforming activated esters and/or
      amides followed by reaction with hydrazine, for the preparation of hydrazides
      including those of alpha,beta-unsaturated acids. This process gives the desired
      hydrazides in excellent yield and purity under mild conditions.

PMID- 12492359
TI  - Diels-Alder reactions of quinol lactones: a change of regioselectivity with
      stannic chloride catalysis.
AB  - Lewis acid-mediated Diels-Alder reactions of quinol lactone 2 gave
      regioselectivity opposite to that of the uncatalyzed reaction. Compound 12 is
      proposed as the reactive intermediate generated by the reaction of 2 with stannic
      chloride.

PMID- 12492360
TI  - Domino carbocationic rearrangement of aryl-2-(1-N-methyl/benzyl-3
      indolyl)cyclopropyl ketones: a serendipitous route to 1H-cyclopenta[c]carbazole
      framework.
AB  - Aryl-2-(N-methyl/benzyl-3-indolyl)cyclopropyl ketones 2a-m are shown to undergo a
      novel unexpected domino carbocationic rearrangement in the presence of
      SnCl(4)/CH(3)NO(2) yielding 2-aroyl-3-aryl-1H-cyclopenta[c]carbazoles 3a-m in
      good yields. The possible mechanistic pathway for this interesting transformation
      involves a series of cascade events, (a) electrophilic ring opening of
      cyclopropyl ketone, (b) intermolecular enol capture of the resulting zwitterionic
      intermediate, (c) electrophilic dimerization of indole moieties to give
      tetrahydrocarbazole intermediate and its subsequent aromatization by elimination
      of an indole moiety and dehydrogenation, and (d) intramolecular aldol
      condensation of the side chain to give a cyclopentene ring. The overall
      transformation involves formation of three carbon-carbon bonds along with a fused
      benzene and a substituted cyclopentene ring in one-pot operation from simple
      indole precursors.

PMID- 12492361
TI  - Asymmetric transformations of acyloxyphenyl ketones by enzyme-metal
      multicatalysis.
AB  - A multipathway process comprising several enzyme- and metal-catalyzed reactions
      has been explored for the asymmetric transformations of acyloxyphenyl ketones to
      optically active hydroxyphenyl alcohols in the ester forms. The process comprises
      nine component reactions in three pathways, all of which take place by the
      catalytic actions of only two catalysts, a lipase and a ruthenium complex. The
      synthetic reactions were carried out on 0.2-0.6 mmol scales for eight different
      substrates under an atmosphere of hydrogen (1 atm) in toluene at 70 degrees C for
      3 days. In most cases, the yields were high (92-96%) and the optical purities
      were excellent (96-98% ee), This work thus has demonstrated that enzyme-metal
      multicatalysis has great potential as a new methodology for asymmetric
      transformations.

PMID- 12492362
TI  - Phototransposition reactions of methyl-substituted benzotrifluorides: proof of
      the role of trifluoromethyl-substituted carbon.
AB  - Irradiation in acetonitrile of any one of the six isomers of
      dimethylbenzotrifluoride 8 resulted in efficient photoisomerization to the
      others. The dominant processes in these phototransposition reactions divides the
      isomers into two triads. The first consists of 8-2,6 (2,6
      dimethylbenzotrifluoride), 8-2,3, and 8-3,4; the second consists of 8-3,5, 8-2,4,
      and 8-2,5. Moreover, irradiation of 2,6-dideuterio-4-methylbenzotrifluoride 5
      d(2) resulted in formation of 5,6-dideuterio-3-methylbenzotrifluoride 6-d(2).
      These observations demonstrate that it is the trifluoromethyl-substituted carbon
      that is the migratory one in these reactions.

PMID- 12492363
TI  - Highly regioselective cleavages and iodinations of cyclic ethers utilizing SmI2.
AB  - Various functionalized cyclic ethers such as oxiranes, oxetanes, and
      tetrahydrofurans have been prepared, and the regiochemistry of their ring opening
      with samarium diiodide and acyl chloride or anhydride has been investigated.
      Alkyl-substituted oxetane 5 and tetrahydrofurans 1 and 2 show almost no
      regioselectivity. However, high regioselectivities from the branched cyclic
      ethers (3, 8, 9, and 10) containing ethereal or hydroxyl moieties have been
      observed. This is probably the result of the bidentate chelated species between
      samarium and oxygen.

PMID- 12492364
TI  - Cross sections for low-energy (1-100 eV) electron elastic and inelastic
      scattering in amorphous ice.
AB  - We report the integral cross sections per scatterer (i.e. elastic collision,
      phonon excitations, vibrational excitations, electronic excitations and
      ionization) for 1-100 eV electron scattering in an amorphous film of ice
      condensed at a temperature of 14 K. The integral cross sections are determined
      relative to the total from a two-stream multiple-scattering analysis of the
      electron energy distribution backscattered from the film. Their energy dependence
      is obtained from both the analysis of the elastic electron reflectivity as a
      function of the film thickness and the vibrational electron energy-loss spectra
      measured for several incident energies and large film thickness. The magnitude
      and various features found in the energy dependence of the cross sections are
      discussed, whenever possible, by comparison with data and with scattering
      mechanisms available in the gas phase. Microcospic effects, which are implicitly
      included in cross sections determined in this way, are discussed in terms of
      interference and coherent multiple-scattering contributions among the scattering
      sites as well as interactions of the scattering sites with their neighbors in the
      condensed phase.

PMID- 12492365
TI  - Alanine radicals, part 3: properties of the components contributing to the EPR
      spectrum of X-irradiated alanine dosimeters.
AB  - The amino acid l-alpha-alanine has attracted considerable interest for use in
      radiation dosimetry and has been formally accepted as a secondary standard for
      high-dose and transfer dosimetry. Recent results have shown that the alanine EPR
      spectrum consists of contributions from three different radicals. A set of
      benchmark spectra describing the essential spectral features of these three
      radical components was used for reconstructions of the experimental spectra. In
      the present work, these basis spectra have been used to investigate the
      differential effects of variations in radiation doses and microwave power, as
      well as the dependence upon temperature annealing and UV illumination. The
      results presented here, based solely on relatively low-energy (60-80 keV) X rays,
      indicate that the three components behave very similarly with respect to
      radiation dose at room temperature. However, with respect to the thermal
      annealing/fading behavior and microwave power saturation properties, the three
      species behave significantly differently. It is concluded that even if it is now
      realized that three different radicals contribute to the composite EPR alanine
      spectrum, this has a minor impact on the established protocols for present-day
      applications (high-dose) of EPR/alanine dosimetry. However, some care should be
      exercised when e.g. constructing calibration curves, since fading and power
      saturation behavior may vary over the dose range in question. New results from UV
      illumination experiments suggest a possible procedure for experimental spectral
      separation of the EPR signals due to the three radicals.

PMID- 12492366
TI  - Changes in DNA flexibility after irradiation with gamma rays and neutrons studied
      with the perturbed angular correlation method.
AB  - Neutron and gamma irradiation of buffered solutions of calf thymus DNA resulted
      in changes in the dynamics of the macromolecule. In the low-dose region (0.8-10
      cGy of 239Pu-Be neutrons and 0.34-3 Gy of 60Co gamma rays), the flexibility of
      DNA decreased as indicated by slower rotation of the molecules. Neutrons appeared
      to be approximately 35 times more effective than 60Co gamma rays. The rotational
      correlation time, tau C, was measured using the perturbed angular correlation
      (PAC) method. Its variation appears to follow a linear-exponential behavior. An
      attempt is made to formulate this behavior as a function of the energy deposited
      on the macromolecule (radiation dose), the average threshold energy (dose)
      required to form new lesions, and the available population of intact DNA sites.

PMID- 12492367
TI  - Transmissible and nontransmissible complex chromosome aberrations characterized
      by three-color and mFISH define a biomarker of exposure to high-LET alpha
      particles.
AB  - Insertions have been proposed as potential stable biomarkers of chronic high-LET
      radiation exposure. To examine this in vitro, we irradiated human peripheral
      blood lymphocytes in G(0) with either 50 cGy (238)Pu alpha particles (LET 121.4
      keV/microm) or 3 Gy 250 kV X rays and stimulated their long-term culture up to
      approximately 22 population doublings postirradiation. Mitotic cells were
      harvested at regular intervals throughout this culture period and were assayed
      for chromosome aberrations using the techniques of three-color and 24-color
      mFISH. We observed the stable persistence of transmissible-type complex
      rearrangements, all involving at least one insertion. This supports the
      hypothesis that insertions are relevant indicators of exposure to high-LET
      radiation. However, one practical caveat of insertions being effective biomarkers
      is that their frequency is low due to the complexity and cell lethality of the
      majority of alpha-particle-induced complexes. Therefore, we propose a "profile of
      damage" that relies on the presence of insertions, a low frequency of stable
      simple reciprocal translocations (2B), and, significantly, the complexity of the
      damage initially induced. We suggest that the complexity of first- and second
      division alpha-particle-induced nontransmissible complex aberrations reflects the
      structure of the alpha-particle track and as a consequence adds radiation-quality
      specificity to the biomarker, increasing the signal:noise ratio of the
      characteristic 2B:insertion ratio.

PMID- 12492368
TI  - Use of the comet-FISH assay to demonstrate repair of the TP53 gene region in two
      human bladder carcinoma cell lines.
AB  - The alkaline single-cell gel electrophoresis (comet) assay can be combined with
      fluorescence in situ hybridization (FISH) methodology to investigate the
      localization of specific gene domains within an individual cell. The position of
      the fluorescent hybridization spots in the comet head or tail indicates whether
      the sequence of interest lies within or in the vicinity of a damaged region of
      DNA. In this study, we used the comet-FISH assay to examine initial DNA damage
      and subsequent repair in the TP53 gene region of RT4 and RT112 bladder carcinoma
      cells after 5 Gy gamma irradiation. In addition to standard comet parameter
      measurements, the number and location of TP53 hybridization spots within each
      comet was recorded at each repair time. The results indicate that the rate of
      repair of the TP53 gene region was fastest during the first 15 min after damage
      in both cell lines. When compared to overall genomic repair, the repair of the
      TP53 gene region was observed to be significantly faster during the first 15 min
      and thereafter followed a rate similar to that for the overall genome. The data
      indicate that the TP53 domain in RT4 and RT112 cells is repaired rapidly after
      gamma irradiation. Furthermore, this repair may be preferential compared to the
      repair of overall genomic DNA, which gives a measure of the average DNA repair
      response of the whole genome. We suggest that the comet-FISH assay has
      considerable potential in the study of gene-specific repair after DNA damage.

PMID- 12492369
TI  - Sticky anaphase aberrations after G2-phase arrest of gamma-irradiated human skin
      fibroblasts: TP53 independence of formation and TP53 dependence of consequences.
AB  - We have studied the impact of TP53 status on the extent and nature of chromosome
      damage seen in human skin fibroblasts after gamma irradiation beyond the G1-phase
      checkpoint but prior to the G2-phase checkpoint. Mitotic cells were examined in
      the absence and presence of treatment with nocodazole and the yield of
      aberrations was scored as a function of time postirradiation. The results
      revealed substantially greater damage in the absence of nocodazole, indicating
      that damage was being masked in its presence. While metaphase aberrations were
      seen exclusively in the presence of nocodazole, anaphase aberrations were seen
      principally in its absence. Furthermore, these were mostly of an unseparated, or
      "sticky", type that showed separation of the chromatids in the centromeric
      region, indicating normal degradation of cohesin, with retention of adhesion
      further out on the chromatid arms. Using postirradiation BrdU labeling and the
      absence of nocodazole, we were able to identify mitotic figures up to the third
      postirradiation mitosis. Analysis of the data revealed that in cells wild-type
      for TP53 the aberrant anaphases were lost after the first postirradiation
      mitosis, although they were still found in gradually decreasing amounts into the
      second and third postirradiation mitoses in E6-expressing cells. The data
      indicate that the formation of these sticky anaphases is independent of TP53
      status, an observation that is consistent with the TP53 independence of transient
      G2-phase arrest. However, the consequences of the formation of these lesions
      appear to be very different. In the case of cells wild-type for TP53 this is
      chronic G1-phase arrest, while in E6 cells it is anaphase catastrophe.

PMID- 12492370
TI  - Complexity of the mechanisms of initiation and maintenance of DNA damage-induced
      G2-phase arrest and subsequent G1-phase arrest: TP53-dependent and TP53
      independent roles.
AB  - Through a detailed study of cell cycle progression, protein expression, and
      kinase activity in gamma-irradiated synchronized cultures of human skin
      fibroblasts, distinct mechanisms of initiation and maintenance of G2-phase and
      subsequent G1-phase arrests have been elucidated. Normal and E6-expressing
      fibroblasts were used to examine the role of TP53 in these processes. While G2
      arrest is correlated with decreased cyclin B1/CDC2 kinase activity, the
      mechanisms associated with initiation and maintenance of the arrest are quite
      different. Initiation of the transient arrest is TP53-independent and is due to
      inhibitory phosphorylation of CDC2 at Tyr15. Maintenance of the G2 arrest is
      dependent on TP53 and is due to decreased levels of cyclin B1 mRNA and a
      corresponding decline in cyclin B1 protein level. After transiently arresting in
      G2 phase, normal cells chronically arrest in the subsequent G1 phase while E6
      expressing cells continue to cycle. The initiation of this TP53-dependent G1
      phase arrest occurs despite the presence of substantial levels of cyclin D1/CDK4
      and cyclin E/CDK2 kinase activities, hyperphosphoryated RB, and active E2F1.
      CDKN1A (also known as p21(WAF1/CIP1)) levels remain elevated during this period.
      Furthermore, CDKN1A-dependent inhibition of PCNA activity does not appear to be
      the mechanism for this early G1 arrest. Thus the inhibition of entry of
      irradiated cells into S phase does not appear to be related to DNA-bound PCNA
      complexed to CDKN1A. The mechanism of chronic G1 arrest involves the down
      regulation of specific proteins with a resultant loss of cyclin E/CDK2 kinase
      activity.

PMID- 12492371
TI  - Influence of environmental pH on G2-phase arrest caused by ionizing radiation.
AB  - We investigated the effects of an acidic environment on the G2/M-phase arrest,
      apoptosis, clonogenic death, and changes in cyclin B1-CDC2 kinase activity caused
      by a 4-Gy irradiation in RKO.C human colorectal cancer cells in vitro. The time
      to reach peak G2/M-phase arrest after irradiation was delayed in pH 6.6 medium
      compared to that in pH 7.5 medium. Furthermore, the radiation-induced G2/M-phase
      arrest decayed more slowly in pH 6.6 medium than in pH 7.5 medium. Finally, there
      was less radiation-induced apoptosis and clonogenic cell death in pH 6.6 medium
      than in pH 7.5 medium. It appeared that the prolongation of G2-phase arrest after
      irradiation in the acidic environment allowed for greater repair of radiation
      induced DNA damage, thereby decreasing the radiation-induced cell death. The
      prolongation of G2-phase arrest after irradiation in the acidic pH environment
      appeared to be related at least in part to a prolongation of the phosphorylation
      of CDC2, which inhibited cyclin B1-CDC2 kinase activity.

PMID- 12492372
TI  - Similar radiation sensitivities of acutely and chronically hypoxic cells in HT
      1080 fibrosarcoma xenografts.
AB  - It has been suggested that chronically hypoxic tumor cells may be more
      radiosensitive than acutely hypoxic or even aerobic cells. In the present study
      we have used the fact that chronically, but not acutely, hypoxic cells that are
      transformed with a vector containing an enhanced green fluorescent protein (EGFP)
      driven by a hypoxia-responsive promoter become green (high EGFP) at low oxygen
      concentrations and can be viably sorted from transplanted tumors in vitro. We
      showed that the fluorescence of HT 1080 human fibrosarcoma cells stably
      transfected with this vector increases constantly with decreasing O2
      concentrations (<2%, longer than 1 h, half maximum approximately 0.2% for longer
      than 8 h), and that cells subjected to repeated cycles of hypoxia/reoxygenation
      (simulating acutely hypoxic cells) showed only background fluorescence. To test
      the radiosensitivity of acutely and chronically hypoxic cells in tumors, we
      isolated high-EGFP ("chronically hypoxic") and low-EGFP cells (containing both
      acutely hypoxic and aerobic cells) from HT 1080 xenograft tumors by fluorescence
      activated cell sorting (FACS), immediately after in situ treatment with 20 Gy
      (ambient or clamped), and plated the cells to determine clonogenic survival in
      vitro. We found that the survival of high-EGFP cells after irradiation was not
      affected by clamping, suggesting that all, or almost all, of these cells were
      fully (chronically) hypoxic. Also, the survival of the low-EGFP cells irradiated
      under clamped conditions (acutely hypoxic cells) was not significantly different
      from that of the high-EGFR cells (chronically hypoxic) cells irradiated under
      nonclamped (or clamped) conditions. We therefore conclude that, at least in this
      tumor model, the radiation sensitivity of chronically hypoxic cells is similar to
      that of the acutely hypoxic cells.

PMID- 12492373
TI  - Carcinogenesis in laboratory mice after low doses of ionizing radiation.
AB  - Experimental data on the incidence of solid tumors from various long-term mouse
      studies performed at the Casaccia laboratories over several years were
      reconsidered, limiting the analysis to the results available for doses equal to
      or less than 17 cGy of neutrons and 32 cGy of X rays since these dose limits are
      reasonably close to the generally accepted low-dose levels for high- and low-LET
      radiation (i.e. D(high-LET) < 5 cGy and D(low-LET) < 20 cGy, respectively). The
      following long-term experiments with BC3F1 mice were reviewed: (a) females
      treated with single doses of 1.5 MeV neutrons or 250 kVp X rays, (b) males
      treated with fractionated doses of fission neutrons, and (c) mice of both sexes
      irradiated in utero 17.5 days post coitus with single doses of fission neutrons
      or X rays. An experiment with CBA mice of both sexes treated with single doses of
      fission neutrons was also included in this study. Analysis was done on animals at
      risk; thus all incidences of tumor-bearing animals were expressed as the
      percentage excess incidence with respect to the controls. Ovarian tumors and
      other solid neoplasms were considered. The percentage frequencies and mean
      survival times of tumor-free mice were also recalculated. The results indicate
      the existence of a region at low doses where the final incidence of solid
      neoplasms is indistinguishable from the background incidence. These data
      reinforce the idea that at low doses the effectiveness of ionizing radiation in
      inducing solid neoplasms in laboratory mice is very low.

PMID- 12492374
TI  - Late effects of the Chernobyl radiation accident on T cell-mediated immunity in
      cleanup workers.
AB  - The main goal of this investigation was to evaluate the abnormal T-cell immunity
      in cleanup workers who took part in the cleanup after the Chernobyl accident in
      1986. Peripheral blood mononuclear cells (MNCs) of apparently healthy cleanup
      workers (n = 134) were used to analyze the phenotype and proliferative response
      to mitogens in vitro. Evaluation of the MNC phenotype of cleanup workers did not
      reveal a significant disturbance in the T-cell subpopulation content except for
      an increase in CD3+CD16+56+ (NKT) cells. Immunophenotyping of phytohemagglutinin
      (PHA)-activated MNCs demonstrated suppression of CD4+ T-cell propagation and
      augmentation of CD8+ T-cell propagation in vitro compared to control individuals.
      DNA synthesis in the MNCs of cleanup workers was markedly inhibited after
      activation for 3 days with suboptimal concentrations of PHA, pokeweed mitogen and
      PMA. In contrast to control individuals, the monocytes of cleanup workers were
      able to stimulate the proliferation of T cells from healthy individuals but
      inhibited the proliferation of T cells from cleanup workers. This study affords a
      better understanding of the response of MNCs to stimulation with suboptimal
      concentrations of PHA and provides an approach to a more accurate analysis of the
      immunological disorders found after exposure to radiation from Chernobyl-related
      activities.

PMID- 12492375
TI  - Somatic cell mutations at the glycophorin a locus in erythrocytes of radiation
      workers from the Sellafield nuclear facility.
AB  - The glycophorin A (GPA) somatic mutation assay for N0 and NN mutant erythrocytes
      was performed on 245 current and 48 retired workers who had been occupationally
      exposed to radiation at the British Nuclear Fuels plc facility at Sellafield. A
      positive association with increasing age was found for current workers for both
      N0 and NN frequencies of 0.14 +/- 0.05 x 10(-6) (P = 0.012) and 0.25 +/- 0.07 x
      10(-6) (P = 0.0003) per year, respectively. No association with age was found for
      the retired workers. In a comparison of ever-smokers with never-smokers, no
      difference was observed for N0 frequencies for current workers, but a
      significantly higher frequency was found for ever-smokers in the retired group (P
      = 0.001). NN mutant frequencies were slightly higher in ever-smokers than in
      never-smokers for both current and retired workers, but in neither case was the
      increase significant. In age-adjusted analyses for N0 mutant frequencies, a
      slight positive radiation dose response was found for current workers (1.6 +/-
      3.8 x 10(-6) per Sv), for retired workers (2.9 +/- 2.5 x 10(-6) per Sv), and in
      the combined analysis (2.6 +/- 2.2 x 10(-6) per Sv), but in no case did this
      reach significance. Similar analyses for NN mutant frequencies revealed a
      positive dose response for current workers (4.7 +/- 4.6 x 10(-6) per Sv) and a
      negative response for retired workers (-2.4 +/- 3.6 x 10(-6) per Sv) that was
      maintained in the combined analysis (-1.4 +/- 2.8 x 10(-6) per Sv), but none of
      these slopes was significantly different from zero. The results suggest that the
      GPA mutation assay is insufficiently sensitive to be used as a biological marker
      of low-dose chronic exposure and provide further evidence that, in contrast to
      high acute radiation exposure, protracted exposure is much less effective at
      inducing somatic mutations in vivo.

PMID- 12492376
TI  - Design of a cylindrical brachytherapy implant applicator for the irradiation of
      an intestinal segment in mice.
AB  - YingExperimental determination of the RBE of new isotopes for brachytherapy
      implants (e.g. iodine-125 and palladium-103) remains a very difficult problem,
      especially in small animals, where the seeds cannot be implanted easily in the
      planned geometry in a reproducible way. This technical note describes an original
      device that makes it possible to irradiate a segment of the intestine in mice for
      the purpose of determining the RBE for crypt regeneration. The device is a length
      of tube (3.4 mm and 7 mm internal and external diameter, respectively) whose
      external surface has been longitudinally grooved and into which the seeds can be
      squeezed (each groove holds either one or two seeds). The tube is composed of two
      sections. This seed container can be surgically positioned around an intestinal
      ansa while the mice are anesthetized. The mean dose rates in the intestine (for
      eight seeds) were found to be 86.3 +/- 5.9 and 79.0 +/- 5.4 cGy/h for 29.2 MBq (1
      U) iodine and 28.6 MBq (1 U) palladium seeds, respectively. So far, more than 100
      mice have been irradiated successfully. Full dose-effect relationships can be
      obtained using the same seeds and applying them successively in different groups
      of animals (which ensured the accuracy of the relative doses).

PMID- 12492377
TI  - Environmental objections to the PAVE PAWS radar system: a scientific review.
AB  - As part of our continental defense system, the United States Air Force has
      operated a radar system, known generally by the label PAVE PAWS, off of Cape Cod,
      MA since 1978. Some populated areas in the vicinity of the system are subject to
      a low level of background radiofrequency radiation from the system, and local
      citizens' groups have expressed concern that this radiofrequency radiation may
      affect their health. These concerns have been fueled by presentations and letters
      by Dr. R. A. Albanese, an applied mathematician at the Air Force Research
      Laboratory, who has proposed standards by which that PAVE PAWS radiofrequency
      radiation which is incident on populations should be judged. I discuss those
      standards that are sufficiently well defined to be subject to analysis and show
      that they are not based on sound quantitative reasoning.

PMID- 12492378
TI  - Comments on "Historical and current highlights in radiation biology: Has anything
      important been learned by irradiating cells?" by Joel s. Bedford and William C.
      Dewey (Radiat. Res. 158, 251-291, 2002).

PMID- 12492380
TI  - West Nile virus: is there a message for Australia?

PMID- 12492381
TI  - Disease and death in Papua New Guinea.

PMID- 12492382
TI  - Whither the World Health Organization?
AB  - The outgoing Director-General of the World Health Organization, Gro Harlem
      Brundtland, has successfully returned health issues to the international arena.
      The new Director-General will have to cope with reduced control over funding,
      debate over WHO's mandate, and the relationships between WHO and other
      organisations. Despite the broad role described in WHO's constitution, many
      groups see WHO's mandate as narrowly directed at disease eradication. The method
      of choice for funding health programs has become public-private partnerships.
      These have the advantages of bringing private money, management expertise and
      research knowledge to bear on health problems, but rarely consider the health
      system as a whole, focusing instead on specific diseases. This has the potential
      to distort resource allocation and priorities. The international community needs
      to work to strengthen WHO and maintain its broad mandate to achieve the highest
      possible level of health for all people.

PMID- 12492383
TI  - Working with funding agencies in the delivery of healthcare in the Asia Pacific
      region.
AB  - Australia is one of the healthiest countries in the world, although we have a
      long way to go before the health of Indigenous Australians matches that of the
      population as a whole. In 1999-2000, the Commonwealth Government spent 8.5% of
      GDP on healthcare, ranking our health spending among the highest in the world. By
      contrast, many people living in our region are burdened by emerging epidemics,
      such as HIV/AIDS, diseases associated with economic and industrial development,
      and problems of communicable disease and nutritional deficiencies. For decades,
      many Australians have been working towards improving health in these developing
      countries by providing their knowledge and expertise. While the financial
      resources for healthcare are largely the responsibility of individual national
      governments, the international system plays an important role in assisting
      developing countries to improve their health standards. From our own experiences
      of working with AusAID and the World Health Organization on two projects to
      eradicate iodine-deficiency disorders in China and Tibet, we illustrate how
      health professionals can work with international aid agencies to deliver
      healthcare and make a difference to the lives of people in developing countries.

PMID- 12492384
TI  - Health for all beyond 2000: the demise of the Alma-Ata Declaration and primary
      health care in developing countries.
AB  - Access to basic health services was affirmed as a fundamental human right in the
      Declaration of Alma-Ata in 1978. The model formally adopted for providing
      healthcare services was "primary health care" (PHC), which involved universal,
      community-based preventive and curative services, with substantial community
      involvement. PHC did not achieve its goals for several reasons, including the
      refusal of experts and politicians in developed countries to accept the principle
      that communities should plan and implement their own healthcare services. Changes
      in economic philosophy led to the replacement of PHC by "Health Sector Reform",
      based on market forces and the economic benefits of better health. It is time to
      abandon economic ideology and determine the methods that will provide access to
      basic healthcare services for all people.

PMID- 12492385
TI  - An evolving model for training and education in resource-poor settings: teaching
      health workers to fish.
AB  - Training and education of health workers remains an indispensable part of good
      health development in resource-poor settings. Many past training programs have
      failed to achieve significant gains in health outcomes because of poor selection
      of participants, inadequate methodology, and/or the influence of external factors
      in the health system or social environment. The solutions lie in better planning
      of "who" and "what" should be trained; effective methods based on adult learning
      principles; alternative methods that maximise learner input and locate training
      as close as possible to the workplace and its problems; appropriate inclusion of
      the community; and coordination with other health system interventions.

PMID- 12492386
TI  - Australian medical schools and colleges working with developing countries.

PMID- 12492387
TI  - The morning after the night before: campfires revisited.
AB  - Even eight hours after a campfire has been extinguished with sand, it retains
      sufficient heat to cause a full-thickness burn with contact of one second.
      Because extinguishing with sand disguises the danger, this is a particular hazard
      for children. The only safe way to extinguish a campfire is with water.

PMID- 12492388
TI  - First-aid management of minor burns in children: a prospective study of children
      presenting to the Children's Hospital at Westmead, Sydney.
AB  - OBJECTIVE: To identify the adequacy of first aid care following minor burns in
      children. DESIGN: Prospective case series. SETTING: Emergency Department and
      Acute Wound Clinic, the Children's Hospital at Westmead (CHW), Sydney.
      PARTICIPANTS: 109 children who presented with minor burns (10% body surface area
      or less) to CHW over the five months from 2 November 1998 to 23 March 1999. MAIN
      OUTCOME MEASURES: Comparison of the adequacy of first aid delivered by parents
      and carers, general practitioners, local hospitals, and CHW. RESULTS: Burns
      included scalds, contact, flame, chemical or electrical burns. Adequate initial
      first aid had been given by parents or carers in only 24 of 109 cases (22%). The
      85 children who presented to medical care after inadequate initial first aid was
      given by parents or carers included 14 of 14 (100%) who had presented to their
      general practitioner (GP), 22 of 31 (71%) who had presented to their local
      hospital, 22 of 38 (58%) who had presented to CHW, and 2 of 2 (100%) who had had
      first contact with other health professionals. CONCLUSIONS: This study shows that
      there is a need to educate parents and health professionals regarding appropriate
      first aid for burns.

PMID- 12492389
TI  - Jellyfish envenoming syndromes: unknown toxic mechanisms and unproven therapies.
AB  - Interest in envenoming syndromes caused by Australian jellyfish has been intense
      since the deaths in early 2002 of two tourists in Queensland, attributed to the
      Irukandji syndrome. We review current knowledge of these envenoming syndromes,
      mechanisms of venom action and therapy, focusing on the deadly box jellyfish,
      Chironex fleckeri, and the array of jellyfish thought to cause the Irukandji
      syndrome. Current understanding of jellyfish venom activity is very limited, and
      many treatments are unproven and based on anecdote.

PMID- 12492391
TI  - Ethics review and use of reminder letters in postal surveys: are current
      practices compromising an evidence-based approach?

PMID- 12492390
TI  - Severity of Irukandji syndrome and nematocyst identification from skin scrapings.
AB  - OBJECTIVES: (1) To identify the causative jellyfish species by examining skin
      scrapings in patients presenting to Cairns Base Hospital with marine stings, and
      (2) to describe clinical outcomes of those with Irukandji syndrome and those in
      whom nematocysts were identified from skin scrapings. DESIGN AND SETTING: (1) A
      retrospective case series of 128 patients, identified from Cairns Base Hospital
      emergency department records with discharge diagnoses of marine stings between 1
      July 2001 and 30 June 2002. (2) A prospective study of skin scrapings from 50
      patients presenting with marine stings from the same period. MAIN OUTCOME
      MEASURES: Number of patients with Irukandji syndrome, their opioid requirements
      and cardiac findings (where available); identification of causative species from
      nematocysts isolated from skin scrapings. RESULTS: 116 patients retrospectively
      identified with marine stings had Irukandji syndrome. Of 50 patients who had skin
      scrapings, 39 had nematocysts consistent with Carukia barnesi. Symptoms
      experienced ranged from local pain alone to severe Irukandji syndrome with
      elevated troponin I levels, changes on electrocardiogram, cardiac dysfunction on
      echocardiography, and high opioid dose requirements. One patient had an
      unidentified cnidome on his skin scraping. He developed severe Irukandji syndrome
      and subsequently died from its complications. CONCLUSION: This is the first
      published report of Carukia barnesi being successfully identified from skin
      scrapings. Most patients with identifiable cnidomes experiencing Irukandji
      syndrome were stung by Carukia barnesi, which we show causes a wide range of
      illness, including cardiac dysfunction. Our finding of a cnidome not consistent
      with Carukia barnesi in the setting of Irukandji syndrome makes it possible that
      other species of jellyfish may also cause this syndrome.

PMID- 12492392
TI  - Withdrawal of methylphenobarbitone.

PMID- 12492393
TI  - Prevalence of pain among nursing home residents in rural New South Wales.

PMID- 12492394
TI  - Pain management programs in residential aged care.

PMID- 12492395
TI  - Halting the growth in diagnostic testing.

PMID- 12492396
TI  - An interventional program for diagnostic testing in the emergency department.

PMID- 12492398
TI  - Measuring outcomes in patients with depression or anxiety: an essential part of
      clinical practice.

PMID- 12492399
TI  - Biosynthesis of heparan sulphate with diverse structures and functions: two
      alternatively spliced forms of human heparan sulphate 6-O-sulphotransferase-2
      having different expression patterns and properties.
AB  - Heparan sulphate 6- O -sulphotransferase (HS6ST) catalyses the transfer of
      sulphate from adenosine 3'-phosphate, 5'-phosphosulphate to the 6th position of
      the N -sulphoglucosamine residue in HS. We previously described the occurrence of
      three isoforms of mouse HS6ST, mHS6ST-1, -2, and -3 [Habuchi, Tanaka, Habuchi,
      Yoshida, Suzuki, Ban and Kimata (2000) J. Biol. Chem. 275, 2859-2868]. In the
      present study, we have characterized HS6ST-2 and HS6ST-1 human isologues,
      including their chromosomal localizations. In the process of their cDNA cloning,
      we found two forms of HS6ST-2: the original (hHS6ST-2) and a short form (hHS6ST
      2S) with 40 amino acids deleted. Both hHS6ST-2 and hHS6ST-2S catalysed the same
      sulphation reaction, but their preferences for sulphation sites in HS substrates
      were different. Dot-blot analysis of the two forms showed that the original form
      was exclusively expressed in adult and foetal brain tissues, whereas the short
      form was expressed preferentially in ovary, placenta and foetal kidney,
      suggesting that the expression of two forms of hHS6ST-2 is strictly regulated to
      yield tissue-dependent differences in the fine structure of HS. A refined
      analysis of their reaction products has led us to another finding, that HS6STs
      could also transfer sulphate to N -sulphoglucosamine residues located at the non
      reducing terminal of HS with high affinity.

PMID- 12492400
TI  - Low levels of glutathione peroxidase 1 activity in selenium-deficient mouse liver
      affect c-Jun N-terminal kinase activation and p53 phosphorylation on Ser-15 in
      pro-oxidant-induced aponecrosis.
AB  - Low levels of hepatic selenium (Se)-dependent glutathione peroxidase 1 (GPX1)
      activity have been shown to protect against oxidative liver injury in Se
      deficient mice. The objective of the present study was to determine if the GPX1
      protection was associated with phosphorylations of c-Jun N-terminal kinase (JNK)
      and p53 on Ser-15, two key signalling events in oxidative-stress-mediated cell
      death. Both Se-deficient GPX1 knockout (GPX1(-/-)) and wild-type (WT) mice ( n
      =64) were pretreated with an intraperitoneal injection of Se (as sodium selenite,
      50 microg/kg body weight) 6 h before an intraperitoneal injection of paraquat
      (12.5 mg/kg). Liver aponecrosis, a mixed form of cell death sharing apoptosis and
      necrosis, was induced by paraquat in both groups of mice. However, its appearance
      was remarkably delayed and the severity was decreased by the repletion of hepatic
      GPX1 activity to <4% of the normal level by the Se injection in the WT mice,
      compared with that in the GPX1(-/-) mice. Consistently, the WT mice had lower
      levels of hepatic phospho-JNK, p53 and phospho-p53 (Ser-15) when compared with
      the GPX1(-/-) mice at 1-10 h after paraquat injection. Incubating liver
      homogenates with antibodies raised against JNK or phospho-JNK resulted in co
      immunoprecipitation of phospho-p53 (Ser-15), and the amounts of the precipitated
      phospho-p53 were greater in the GPX1(-/-) mice when compared with that in the WT
      mice. The co-precipitated complex by the anti-phospho-JNK antibody was capable of
      phosphorylating intrinsic or extrinsic p53 on Ser-15. In conclusion, phospho-JNK
      may catalyse phosphorylation of p53 on Ser-15 in Se-deficient mouse liver under
      moderate oxidative stress, and attenuation of that cascade by low levels of GPX1
      activity is associated with its protection against the pro-oxidant-induced liver
      aponecrosis.

PMID- 12492402
TI  - Meeting review: the microevolution of development.

PMID- 12492401
TI  - Cell-cycle arrest in Jurkat leukaemic cells: a possible role for docosahexaenoic
      acid.
AB  - Docosahexaenoic acid (DHA) is known to have anti-cancer activities by mechanisms
      that are not well understood. In the present study, we test one possible pathway
      for DHA action in Jurkat leukaemic cells. Low doses of DHA (10 microM) are shown
      to induce cell-cycle arrest, whereas higher doses are cytotoxic. However, when
      cells that were pre-treated with 10 microM DHA are given an additional 10 microM
      DHA dose, cell viability rapidly decreases. Immunoblotting reveals that repeated
      low doses of DHA results in activation of caspase 3, implying induction of
      apoptosis. DHA (10 microM) is shown to increase ceramide levels after 6 h of
      incubation and, after 24 h, the cells appear to be arrested in S phase. With DHA,
      the amount of phosphorylated retinoblastoma protein (pRb) decreases
      significantly. Western blot analysis also shows that DHA greatly reduces the
      level of cyclin A, while increasing the level of p21 WAF1, a cellular inhibitor
      of cyclin A/cyclin-dependent kinase 2 (cdk2) activity. Furthermore, the observed
      DHA-induced doubling of the ratio of hypophosphorylated pRb (hypo-pRb) to total
      pRb is inhibited by tautomycin and phosphatidic acid (PA), known inhibitors of
      protein phosphatase 1 (PP1), and by the PP2 inhibitor okadaic acid. The present
      study demonstrates one possible connected pathway for DHA action. By this
      pathway, low doses of DHA increase ceramide levels, which leads to inhibition of
      cdk2 activity and stimulation of PP1 and PP2A. The net effect of cdk2 inhibition
      and protein phosphatase activation is an inhibition of pRb phosphorylation,
      consequently arresting Jurkat cell growth.

PMID- 12492403
TI  - Ecological developmental biology: preface to the symposium.

PMID- 12492404
TI  - Development and evolution of adaptive polyphenisms.
AB  - Phenotypic plasticity is the primitive character state for most if not all
      traits. Insofar as developmental and physiological processes obey the laws of
      chemistry and physics, they will be sensitive to such environmental variables as
      temperature, nutrient supply, ionic environment, and the availability of various
      macro- and micronutrients. Depending on the effect this phenotypic plasticity has
      on fitness, evolution may proceed to select either for mechanisms that buffer or
      canalize the phenotype against relevant environmental variation or for a modified
      plastic response in which some ranges of the phenotypic variation are adaptive to
      particular environments. Phenotypic plasticity can be continuous, in which case
      it is called a reaction norm, or discontinuous, in which case it is called a
      polyphenism. Although the morphological discontinuity of some polyphenisms is
      produced by discrete developmental switches, most polyphenisms are due to
      discontinuities in the environment that induce only portions of what is in
      reality a continuous reaction norm. In insect polyphenisms, the environmental
      variable that induces the alternative phenotype is a token stimulus that serves
      as a predictor of, but is not itself, the environment to which the polyphenism is
      an adaptation. In all cases studied so far, the environmental stimulus alters the
      endocrine mechanism of metamorphosis by altering either the pattern of hormone
      secretion or the pattern of hormone sensitivity in different tissues. Such
      changes in the patterns of endocrine interactions result in the execution of
      alternative developmental pathways. The spatial and temporal compartmentalization
      of endocrine interactions has produced a developmental mechanism that enables
      substantial localized changes in morphology that remain well integrated into the
      structure and function of the organism.

PMID- 12492405
TI  - Environmental and endogenous control of sexuality in a rotifer life cycle:
      developmental and population biology.
AB  - Induction of mictic females, and hence initiation of sexuality, in the life cycle
      of some Brachionus requires an environmental stimulus associated with crowding.
      The inducing stimulus appears to be a taxonomically specific chemical released
      into the environment by the rotifers. Oocytes are induced to develop into mictic
      females before they are oviposited by their amictic mothers and begin cleavage
      divisions. Thus, the inducer affects the oocyte in the maternal body cavity
      either directly or indirectly by altering the physiology of its mother. The level
      of sexual reproduction expressed in populations of a Florida strain of B.
      calyciflorus is controlled by two types of endogenous factors and by the degree
      of crowding. First, some fraction of genetically identical oocytes in a clonal
      population fails to respond to even extreme crowding conditions, thus ensuring
      some potential for continued population growth by female parthenogenesis. Second,
      the propensity of amictic females to produce mictic daughters is extremely low
      when they hatch from fertilized resting eggs and then gradually increases to an
      asymptote after about 12 parthenogenetic generations. This multigenerational
      parental effect likely is due to a cytoplasmic factor in fertilized eggs that
      inhibits expression of the mictic-female phenotype and that is gradually diluted
      in successive parthenogenetic generations. The effect may increase a clone's
      genetic contribution to the resting-egg bank by increasing its population size
      through parthenogenetic generations before mictic females are induced.

PMID- 12492406
TI  - Phenotypic plasticity in plants: a case study in ecological development.

PMID- 12492407
TI  - Sexual dimorphism in gender plasticity and its consequences for breeding system
      evolution.
AB  - Flowering plants are able to develop gametes throughout their lives. As a
      consequence, environmental conditions can impact this development and alter a
      plant's functional gender or the degree to which it achieves fitness through male
      or female function. Two dimorphic breeding systems are widespread among
      angiosperm families: gynodioecy (hermaphrodites and females) and dioecy (males
      and females). Gynodioecy can evolve into dioecy, via loss of female function on
      the hermaphrodites, or it can remain stable. Here I discuss how developmental
      plasticity of gender can impact the sex ratio of populations and thereby
      influence the transition of one breeding system into another. I review studies
      showing that greater plasticity of fruit production by hermaphrodites as compared
      with females causes sex ratios among populations to vary in response to
      environmental conditions, with higher female frequency expected in harsh or low
      quality sites. I also review how dioecy may evolve in dry sites to avoid
      inbreeding and any consequent inbreeding depression. Taken together, these
      studies show the importance of understanding how ecological development affects
      functional gender and consequently the evolutionary stability or malleability of
      dimorphic breeding systems.

PMID- 12492408
TI  - Ecology meets endocrinology: environmental sex determination in fishes.

PMID- 12492409
TI  - Sex determination: where environment and genetics meet.
AB  - In mammals and birds the genetic constitution established at the time of
      fertilization determines the type of gonad that develops, whereas in all
      crocodilians and many turtles it is the temperature experienced during the mid
      trimester of embryogenesis that initiates gonadal differentiation. Research with
      the red-eared slider suggests considerable conservation in the genetic cascades
      that underlie the sex determination process in vertebrates and, further, that the
      patterns of expression of these genes appear to reflect phylogenetic
      relationships, with turtles being more similar to mammals than they are to birds
      and crocodilians. After the determination and differentiation of an individual's
      gonadal sex, epigenetic forces shape those morphological, physiological, and
      behavioral traits that characterize each individual's unique sexuality. Research
      with the leopard gecko thus relates to the fundamental question of what factors
      determine individual variability, particularly as it relates to sexually
      dimorphic behaviors. Taken together, this research illustrates how sexuality
      depends on sex, but sex should not be confused with sexuality. That is, sex is
      merely a means of categorizing individuals or gonads, whereas sexuality serves as
      a descriptor of concordant traits each of which is typically sexually dimorphic
      in its expression.

PMID- 12492410
TI  - Embryonic motility: environmental influences and evolutionary innovation.

PMID- 12492411
TI  - Scrambled eggs: mechanical forces as ecological factors in early development.
AB  - Many ecological interactions involve, at some level, mechanical forces and the
      movements or structural deformations they produce. Although the most familiar
      examples involve the functional morphology of adult structures, all life history
      stages (not just the adults) are subject to the laws of physics. Moreover, the
      success of every lineage depends on the success of every life history stage
      (again, not just the adults). Therefore, insights gained by using mechanical
      engineering principles and techniques to study ecological interactions between
      gametes, embryos, larvae, and their environment are essential to a well-rounded
      understanding of development, ecology, and evolution. Here I draw on examples
      from the literature and my own research to illustrate ways in which mechanical
      forces in the environment shape development. These include mechanical forces
      acting as selective factors (e.g., when coral gamete size and shape interact with
      turbulent water flow to determine fertilization success) and as developmental
      cues (e.g., when plant growth responds to gravity or bone growth responds to
      mechanical loading). I also examine the opposite cause-and-effect relationship by
      considering examples in which the development of organisms impacts ecologically
      relevant mechanical forces. Finally, I discuss the potential for ecological
      pattern formation as a result of feedback loops created by such bidirectional
      interactions between developmental processes and mechanical forces in the
      environment.

PMID- 12492412
TI  - Mammalian development in a changing environment: exposure to endocrine disruptors
      reveals the developmental plasticity of steroid-hormone target organs.
AB  - Recent findings in the field of environmental endocrine disruption have revealed
      that developmental exposure to estrogenic chemicals induces morphological,
      functional, and behavioral anomalies associated with reproduction. The aim of the
      present study was to determine the effects of in utero exposure to low doses of
      the estrogenic chemical bisphenol A (BPA) on the development of the female
      reproductive tissues and mammary glands in CD-1 mice. Humans are exposed to BPA,
      which leaches from dental materials and plastic food and beverage containers.
      Here we report that prenatal exposure to BPA induces alterations in tissue
      organization within the ovaries and mammary glands and disrupts estrous cyclicity
      in adulthood. Because estrogen receptors are expressed developmentally in these
      estrogen-target organs, we propose that BPA may directly affect the expression of
      genes involved in their morphogenesis. In addition, alterations in the sexual
      differentiation of the brain, and thus the hypothalamic-pituitary-gonadal axis,
      may further contribute to the observed phenotype. The emerging field of endocrine
      disruptors promises to provide new insights into the mechanisms underlying the
      development of hormone-target organs and demonstrates that the environment plays
      important roles in the making of phenotypes.

PMID- 12492413
TI  - Avian thyroid development in chemically contaminated environments: is there
      evidence of alterations in thyroid function and development?
AB  - Poor reproductive success, developmental abnormalities, and behavioral
      alterations in fish-eating birds in some Great Lakes areas have led to more than
      35 years of toxicological studies and residue monitoring of herring gull (Larus
      argentatus) populations. Polyhalogenated aromatic hydrocarbons (PHAHs),
      especially polychlorinated biphenyls (PCBs), are widespread contaminants in the
      Great Lakes ecosystem. The introduction of regulations and elimination of point
      sources since the 1970s have resulted in decreased PHAHs in fish-eating bird eggs
      and tissues. PCB exposure is associated with thyroid disruption (hypothyroidism)
      in mammals, but much less is known of PCB effects on avian thyroid function. Our
      1998-2000 studies of herring gulls from the Great Lakes show that both pipping
      embryos and prefledglings from highly contaminated sites have marked depletion of
      thyroid gland hormone stores compared with similarly aged gulls at the reference
      sites. However, organismal hypothyroidism was not apparent in many embryo and
      chick collections where severe depletion of thyroid gland hormone was observed.
      Adults, sampled at two high PCB sites and a low PCB site in the Great Lakes and
      the maritime reference colony in 2001, showed no differences in organismal
      thyroid status across sites, but gulls from the high sites had enlarged thyroid
      glands and depressed thyroid gland hormone stores. Here we discuss the evidence
      that ecological exposure to PHAHs are responsible for thyroid deficiencies in
      gulls and that during development these deficiencies lead to developmental
      abnormalities in young gulls from highly contaminated Great Lakes sites.

PMID- 12492414
TI  - Protection of DNA during early development: adaptations and evolutionary
      consequences.
AB  - The rapidly dividing cleavage stages of embryos do not have the typical responses
      to cell damage, such as induction of the heat shock response, use of mitotic
      checkpoints, or use of apoptosis to eliminate severely damaged cells. This could
      create problems with integrity of DNA, but the solution in these embryos appears
      to be a "be prepared" approach, in which specific adaptations are used to
      minimize DNA damage during cleavage and the use of apoptosis at the mid-blastula
      transition to remove any cells that were nevertheless damaged. It has been
      assumed that this approach has evolved because of the advantage of rapid
      production of a motile larvae. Alternatively, this particular approach may have
      the selective advantage of increasing mutation rate when there are greater
      environmental stresses. This could provide more variants on which selective
      pressures could act and thus accelerate evolution during environmentally
      stressful periods.

PMID- 12492415
TI  - Amphibian defenses against ultraviolet-B radiation.
AB  - As part of an overall decline in biodiversity, amphibian populations throughout
      the world are disappearing. There are a number of potential causes for these
      declines, including those related to environmental changes such as increasing
      ultraviolet-B (UV-B) radiation due to stratospheric ozone depletion. UV-B
      radiation can kill amphibian embryos or can cause sublethal effects that can harm
      amphibians in later life stages. However, amphibians have defenses against UV-B
      damage that can limit damage or repair it after exposure to UV-B radiation. These
      include behavioral, physiological, and molecular defenses. These defenses differ
      interspecifically, with some species more able to cope with exposure to UV-B than
      others. Unfortunately, the defense mechanisms of many species may not be
      effective against increasing persistent levels of UV-B radiation that have only
      been present for the past several decades due to human-induced environmental
      damage. Moreover, we predict that persistent UV-B-induced mortality and sublethal
      damage in species without adequate defenses could lead to changes in community
      structure. In this article we review the effects of UV-B radiation on amphibians
      and the defenses they use to avoid solar radiation and make some predictions
      regarding community structure in light of interspecific differences in UV-B
      tolerance.

PMID- 12492416
TI  - Origins of differentiation via phenotypic plasticity.
AB  - How cell types of multicellular organisms came to be differentiated is still an
      open issue. Here I offer a model that posits that the origins of some cell
      differentiation patterns were originally passive outcomes of environmental
      effects. As cells' contact with the external environment was diminished, their
      patterns of gene expression were altered, due to changes in concentrations of
      externally supplied substances. Later, as multicellular growth continued, the
      relationships of cell layers to each other shifted, producing concentration
      gradients of signaling molecules. These gradients emanated both from the external
      cell layer toward the inside and from internal cell layers to adjacent layers. In
      this scenario then, differentiation arose initially as a by-product of the
      changing patterns of gene expression and of the complex mixtures and changing
      concentrations of substances passing among layers. Subsequent selection would
      operate to stabilize the expression patterns in those cell layers whose
      phenotypes provide a fitness advantage to the organism.

PMID- 12492417
TI  - Generalized norms of reaction for ecological developmental biology.
AB  - A standard norm of reaction (NoR) is a graphical depiction of the phenotypic
      value of some trait of an individual genotype in a population as a function an
      environmental parameter. NoRs thus depict the phenotypic plasticity of a trait.
      The topological properties of NoRs for sets of different genotypes can be used to
      infer the presence of (nonlinear) genotype-environment interactions. Although it
      is clear that many NoRs are adaptive, it is not yet settled whether their
      evolutionary etiology should be explained by selection on the mean phenotypic
      trait values in different environments or whether there are specific genes
      conferring plasticity. If the second alternative is true, the NoR is itself an
      object of selection. Generalized NoRs depict plasticity at the level of
      populations or subspecies within a species, species within a genus, or taxa at
      higher levels. Historically, generalized NoRs have routinely been drawn though
      rarely explicitly recognized as such. Such generalized NoRs can be used to make
      evolutionary inferences at higher taxonomic levels in a way analogous to how
      standard NoRs are used for microevolutionary inferences.

PMID- 12492418
TI  - The murine neurokinin NK1 receptor gene contributes to the adult hypoxic
      facilitation of ventilation.
AB  - Substance P and neurokinin-1 receptors (NK1) modulate the respiratory activity
      and are expressed early during development. We tested the hypothesis that NK1
      receptors are involved in prenatal development of the respiratory network by
      comparing the resting respiratory activity and the respiratory response to
      hypoxia of control mice and mutant mice lacking the NK1 receptor (NK1-/-). In
      vitro and in vivo experiments were conducted on neonatal, young and adult mice
      from wild-type and NK1-/- strains. In the wild strain, immunohistological,
      pharmacological and electrophysiological studies showed that NK1 receptors were
      expressed within medullary respiratory areas prior to birth and that their
      activation at birth modulated central respiratory activity and the membrane
      properties of phrenic motoneurons. Both the membrane properties of phrenic
      motoneurons and the respiratory activity generated in vitro by brainstem-spinal
      cord preparation from NK1-/- neonate mice were similar to that from the wild
      strain. In addition, in vivo ventilation recordings by plethysmography did not
      reveal interstrain differences in resting breathing parameters. The facilitation
      of ventilation by short-lasting hypoxia was similar in wild and NK1-/- neonates
      but was significantly weaker in adult NK1-/- mice. Results demonstrate that NK1
      receptors do appear to be necessary for a normal respiratory response to short
      lasting hypoxia in the adult. However, NK1 receptors are not obligatory for the
      prenatal development of the respiratory network, for the production of the
      rhythm, or for the regulation of breathing by short-lasting hypoxia in neonates.

PMID- 12492419
TI  - Saturation and self-inhibition of rat hippocampal GABA(A) receptors at high GABA
      concentrations.
AB  - Current responses to ultrafast gamma-aminobutyric acid (GABA) applications were
      recorded from excised patches in rat hippocampal neurons to study the gating
      properties of GABA(A) receptors at GABA concentrations close to saturating ones
      and higher. The amplitude of currents saturated at approximately 1 mm, while the
      onset rate of responses reached saturation at 4-6 mm GABA. At high GABA
      concentrations (> 10 mm), the amplitude of current responses was reduced in a
      dose-dependent manner with a half-blocking GABA concentration of approximately 50
      mm. The peak reduction at high GABA doses was accompanied by a tendency to
      increase the steady-state to peak ratio. At concentrations higher than 30 mm,
      this effect took the form of a rebound current, i.e. during the prolonged GABA
      applications, the current firstly declined due to desensitization onset and then,
      instead of decreasing towards a steady-state value, clearly increased. Both the
      self-inhibition of GABA(A) receptors by high GABA doses and rebound were clearly
      voltage dependent, being larger at positive holding potentials. The fast
      desensitization component accelerated with depolarization at all saturating
      [GABA] tested. The rebound phenomenon indicates that the self-block of GABAA
      receptors is state dependent, and suggests that the sojourn in the desensitized
      conformation provides a 'rescue' from the block. We propose that high GABA
      concentrations inhibit the receptors by direct occlusion of the channel pore
      having no effect on the receptor gating.

PMID- 12492420
TI  - Spatial reconfiguration of charge transfer effectiveness in active bistable
      dendritic arborizations.
AB  - The aim of this work was to explore the electrical spatial profile of the
      dendritic arborization during membrane potential oscillations of a bistable
      motoneuron. Computational simulations provided the spatial counterparts of the
      temporal dynamics of bistability and allowed simultaneous depiction the
      electrical states of any sites in the arborization. We assumed that the dendritic
      membrane had homogeneously distributed specific electrical properties and was
      equipped with a cocktail of passive extrasynaptic and NMDA synaptic conductances.
      The electrical conditions for evoking bistability in a single isopotential
      compartment and in a whole dendritic arborization were computed and showed
      differences, revealing a crucial effect of dendritic geometry. Snapshots of the
      whole arborization during bistability revealed the spatial distribution of the
      density of the transmembrane current generated at the synapses and the
      effectiveness of the current transfer from any dendritic site to the soma. These
      functional maps changed dynamically according to the phase of the oscillatory
      cycle. In the low depolarization state, the current density was low in the
      proximal dendrites and higher in the distal parts of the arborization while the
      transfer effectiveness varied in a narrow range with small differences between
      proximal and distal dendritic segments. When the neuron switched to high
      depolarization state, the current density was high in the proximal dendrites and
      low in the distal branches while a large domain of the dendritic field became
      electrically disconnected beyond 200 micro m from the soma with a null transfer
      efficiency. These spatial reconfigurations affected dynamically the size and
      shape of the functional dendritic field and were strongly geometry-dependent.

PMID- 12492421
TI  - Lithium exposure enhances survival of NT2N cells (hNT neurons) in the
      hemiparkinsonian rat.
AB  - Lithium (Li +) treatment of NTera2/D1 (or hNT Neurons) in culture increases
      tyrosine hydroxylase (TH) expression in this cell-line [Zigova et al., (1999)
      Exp. Neurol., 157, 251-258]. It is not known if these Li + treated cells maintain
      TH expression once transplanted into the striatum of the hemiparkinsonian rats.
      hNT neurons were either treated with 1 mm LiCl or left untreated and then
      transplanted into the striatum of Sprague-Dawley rats. Some cells were exposed to
      the lithium for 24 h in culture while others were exposed only briefly (2-3 h)
      just prior to transplantation. We also examined whether Li + treatment of the
      animal after transplantation (0.24% w/w lithium carbonate in chow) was effective
      in increasing neuronal survival. One week after transplantation, the animals were
      perfused with 4% paraformaldehyde and immunocytochemistry was performed on 30
      micro m sections through the transplant. Human nuclear matrix antigen
      immunostaining demonstrated that there was significantly better survival of cells
      in the group treated briefly with lithium compared to all other groups. Brief
      exposure to lithium resulted in a greater expression of TH in situ as well.
      Neuron specific enolase immunohistochemistry showed that there was extensive
      fibre outgrowth in all groups. These results suggest that brief Li + exposure may
      enhance survival to over 60% and increase TH expression of hNT Neurons
      transplanted in the hemiparkinsonian rat nearly three-fold.

PMID- 12492422
TI  - Cholinergic modulation of nucleus accumbens medium spiny neurons.
AB  - The rat nucleus accumbens contains acetylcholine-releasing interneurons, presumed
      to play a regulatory role in the electrical activity of medium spiny output
      neurons. In order to examine this issue in detail, we made electrophysiological
      recordings in rat nucleus accumbens slices. These experiments showed that gamma
      aminobutyric acid-mediated inhibition of the output neurons might be facilitated
      by activation of nicotinic acetylcholine receptors, in addition to being
      suppressed via activation of muscarinic acetylcholine receptors. In contrast,
      glutamatergic excitation of output neurons appeared to be inhibited by activation
      of muscarinic acetylcholine receptors and to be insensitive to activation of
      nicotinic acetylcholine receptors. The spontaneous firing frequency of
      cholinergic neurons appeared to be under control of both a muscarinic and a
      nicotinic pathway in a bi-directional manner. Finally, we made paired recordings
      in which the functional connection between cholinergic neurons and output neurons
      was monitored. Driving the cholinergic neurons at physiological firing
      frequencies stimulated gamma-aminobutyric acid-mediated inhibition of the output
      neurons, via activation of nicotinic acetylcholine receptors. The onset of this
      effect was slow and lacked a fixed delay. These data indicate that activation of
      nicotinic acetylcholine receptors in rat nucleus accumbens may mediate the
      facilitation of gamma-aminobutyric acid-mediated inhibition of medium spiny
      output neurons. Possible mechanisms of neurotransmission, mediating this
      cholinergic modulation are discussed.

PMID- 12492423
TI  - Mitochondrial oxidative metabolism in motor neuron degeneration (mnd) mouse
      central nervous system.
AB  - The mnd mouse spontaneously develops slowly evolving motoneuron pathology leading
      to progressive motor impairment. There is strong evidence that a complex
      interplay between oxidative stress, mitochondria abnormalities and alteration of
      glutamate neurotransmission plays an important role in the pathogenesis of motor
      neuron diseases. Therefore, we investigated the presence of mitochondrial
      dysfunction in frontal, central (comprising the motor area) and occipital regions
      of the cerebral cortex and in the spinal cord of 35-week-old mnd mice. Lipid
      peroxide derivatives reacting with thiobarbituric acid (TBARS) were measured in
      the cervical, thoracic and lumbar spinal cord. In addition biochemical and
      behavioural analyses were carried out in mnd mice chronically treated with l
      carnitine from the 11th to the 34th week of life (mndT mice). Slight but
      significant alterations of mitochondrial enzyme activities were seen in the mnd
      cortical regions. The central area was the most affected and both complex I, IV
      and citrate synthase were decreased with respect to controls. The rate of oxygen
      consumption (QO2) was markedly decreased in both the upper (cervical + upper
      portion of the thoracic region) and lower (lumbar + lower portion of the thoracic
      region) mnd spinal cord. The level of TBARS showed a rostro-caudal trend to
      increase, being 30% higher in the lumbar tract of mnd mice in comparison with
      controls. L-carnitine treatment increased the mitochondrial enzyme activities in
      cortical regions towards control value and was effective in enhancing QO2 and
      decreasing TBARS levels in the spinal cord of mndT. Behavioural testing showed
      that L-carnitine significantly delayed the onset of motor behaviour impairment.
      This beneficial effect was declining at 35 week of age, when the biochemical
      measurements were performed.

PMID- 12492425
TI  - Extracellular acid increases the open probability of transduction channels in
      spider mechanoreceptors.
AB  - Ion channels of the epithelial sodium channel, degenerin and acid-sensitive
      channel (ENaC/DEG/ASIC) family share a number of structural and functional
      homologies. Several members of this group have been linked to mechanoreception
      and nociception, but there is no direct evidence that these molecules cause the
      transduction of mechanical stimuli in any mechanoreceptor. The receptor channels
      of a spider mechanoreceptor, the VS-3 slit-sense organ of Cupiennius salei, show
      several similarities to ENaC/DEG/ASIC channels, including Na+ selectivity and
      amiloride blockade. We recorded the receptor current under voltage clamp in VS-3
      neurons at different extracellular pH values. Acid pH partially blocked the
      delayed rectifier K+ current and increased the receptor current in these cells.
      Noise analysis of the receptor current showed that low pH increased the open
      probability of the receptor channels. Therefore, acid sensitivity is a further
      similarity between these mechanoreceptor channels and the ENaC/DEG/ASIC family.

PMID- 12492424
TI  - BDNF up-regulates evoked GABAergic transmission in developing hippocampus by
      potentiating presynaptic N- and P/Q-type Ca2+ channels signalling.
AB  - Chronic application of brain-derived neurotrophic factor (BDNF) induces new
      selective synthesis of non-L-type Ca2+ channels (N, P/Q, R) at the soma of
      cultured hippocampal neurons. As N- and P/Q-channels support neurotransmitter
      release in the hippocampus, this suggests that BDNF-treatment may enhance
      synaptic transmission by increasing the expression of presynaptic Ca2+ channels
      as well. To address this issue we studied the long-term effects of BDNF on
      miniature and stimulus-evoked GABAergic transmission in rat embryo hippocampal
      neurons. We found that BDNF increased the frequency of miniature currents
      (mIPSCs) by approximately 40%, with little effects on their amplitude. BDNF
      nearly doubled the size of evoked postsynaptic currents (eIPSCs) with a marked
      increase of paired-pulse depression, which is indicative of a major increase in
      presynaptic activity. The potentiation of eIPSCs was more relevant during the
      first two weeks in culture, when GABAergic transmission is depolarizing. BDNF
      action was mediated by TrkB-receptors and had no effects on: (i) the amplitude
      and dose-response of GABA-evoked IPSCs and (ii) the number of GABA(A) receptor
      clusters and the total functioning synapses, suggesting that the neurotrophin
      unlikely acted postsynaptically. In line with this, BDNF affected the
      contribution of voltage-gated Ca2+ channels mediating evoked GABAergic
      transmission. BDNF drastically increased the fraction of evoked IPSCs supported
      by N- and P/Q-channels while it decreased the contribution associated with R- and
      L-types. This selective action resembles the previously observed up-regulatory
      effects of BDNF on somatic Ca2+ currents in developing hippocampus, suggesting
      that potentiation of presynaptic N- and P/Q-channel signalling belongs to a
      manifold mechanism by which BDNF increases the efficiency of stimulus-evoked
      GABAergic transmission.

PMID- 12492426
TI  - Selective ablation of olfactory receptor neurons without functional impairment of
      vomeronasal receptor neurons in OMP-ntr transgenic mice.
AB  - This study used transgenic mice, in which expression of a bacterial
      nitroreductase (ntr) gene was linked to the expression of olfactory marker
      protein (OMP). The nitroreductase enzyme is thus expressed in mature chemosensory
      neurons of these OMP-ntr transgenic mice, and converts the pro-drug CB1954 to a
      cytotoxic form, specifically killing these neurons. Systemic injections of the
      pro-drug led to the ablation of receptor neurons in both the main olfactory and
      vomeronasal epithelia. Due to the anatomical separation of the epithelia,
      however, when the pro-drug was administered by intranasal infusion only the
      receptors of the main olfactory epithelium were destroyed. This procedure
      resulted in a profound deficit in olfactory investigation and discrimination in a
      habituation-dishabituation test, whereas the pregnancy blocking effect of male
      pheromones, which is mediated via the vomeronasal system was unaffected. OMP-ntr
      mice receiving intranasal infusion of pro-drug had not recovered any significant
      main olfactory function at 24 days following treatment. This novel technique
      could potentially be applied to selectively ablate olfactory receptor neurons
      expressing a particular olfactory receptor by linking its expression to that of
      the nitroreductase enzyme.

PMID- 12492427
TI  - Vasopressin and oxytocin reverse adenosine-induced pituicyte stellation via
      calcium-dependent activation of Cdc42.
AB  - In view of the potential impact of pituicyte morphology on neurohypophysial
      hormone secretion, we have studied the mechanisms involved in the shape changes
      induced by vasopressin (AVP) and oxytocin (OXT) in cultured rat pituicytes.
      Pituicytes induced to become stellate in the presence of 10 micro m adenosine
      revert to their nonstellate shape approximately 20 min after application of AVP
      or OXT. The IC50 for this effect is 0.1 nm for AVP and 36 nm for OXT. Both
      agonists induce Ca2+ signals in pituicytes, comprised of a transient peak and a
      plateau phase that is dependent on the presence of extracellular Ca2+. The EC50
      values of AVP for the transient and sustained responses are 4.5 and 0.1 nm,
      respectively; corresponding values for OXT are 180 and 107 nm. We determined
      pharmacologically that these hormone-induced Ca2+ signals are mediated by the V1a
      subtype of vasopressin receptors, similar to what we previously observed for
      hormone-induced reversal of stellation. Removal of extracellular Ca2+ or
      chelation of intracellular Ca2+ partially prevented AVP from reversing
      stellation, suggesting a role for Ca2+ in this event. We previously established
      that adenosine-induced stellation of pituicytes occurs via RhoA inhibition.
      However, pharmacological experiments and pull-down assays presented here show
      that AVP-induced reversal of stellation does not involve RhoA activation. Rather,
      AVP was found to induce a time-dependent activation of Cdc42, another small
      GTPase involved in cytoskeletal plasticity. Activation of Cdc42 by AVP is
      sensitive to intra- and extracellular Ca2+ depletion, similar to AVP-induced
      reversal of stellation. Furthermore, AVP-induced reversal of stellation is
      blocked by expression of an NWASP fragment known to inhibit endogenous Cdc42.

PMID- 12492428
TI  - Characterization of the expression of PDZ-RhoGEF, LARG and G(alpha)12/G(alpha)13
      proteins in the murine nervous system.
AB  - Small GTPases of the Rho-family, like Rho, Rac and Cdc42, are involved in
      neuronal morphogenesis by regulating growth cone morphology or dendritic spine
      formation. G-proteins of the G12-family, G12 and G13, couple G-protein-coupled
      receptors (GPCRs) to the activation of RhoA. Recently, two novel Rho-specific
      guanine nucleotide exchange factors (RhoGEFs), PDZ-RhoGEF and LARG, have been
      identified to interact with the activated alpha-subunits of G12/G13 and are thus
      believed to mediate GPCR-induced Rho activation. Although studies in neuronal
      cell lines have shown that G12/G13 and PDZ-RhoGEF mediate GPCR-induced neurite
      retraction, the role, as well as the expression of this signalling pathway, in
      intact brain has not been adequately studied. In the present study, we have
      characterized systematically the expression of G(alpha)12, G(alpha)13, PDZ-RhoGEF
      and LARG in various murine tissues as well as their subcellular localization in
      the central and peripheral nervous systems. By performing immunohistochemistry,
      using polyclonal antibodies raised against the above proteins, we observed that
      G(alpha)12, G(alpha)13 and their RhoGEF-effectors are distributed widely in the
      mammalian nervous system. Moreover, these proteins localize to distinct
      morphological compartments within neurons. While LARG and G(alpha)12 were mainly
      found in somata of the neurons, PDZ-RhoGEF and G(alpha)13 were predominantly
      localized in the neuropil of central neurons. Interestingly, PDZ-RhoGEF is a
      neural-specific protein, whereas LARG is nearly ubiqoutous. Our data provide
      evidence that the G12/13-RhoGEF-mediated pathway is present throughout the adult
      brain and may be involved in regulation of neuronal morphogenesis and function
      via GPCRs.

PMID- 12492429
TI  - Expression of functional NR1/NR2B-type NMDA receptors in neuronally
      differentiated SK-N-SH human cell line.
AB  - The present study demonstrates that human SK-N-SH neuroblastoma cells,
      differentiated by retinoic acid (RA), express functional NMDA receptors and
      become vulnerable to glutamate toxicity. During exposure to RA, SK-N-SH cells
      switched from non-neuronal to neuronal phenotype by showing antigenic changes
      typical of postmitotic neurons together with markers specific for cholinergic
      cells. Neuronally differentiated cells displayed positive immunoreactivity to the
      vesicular acetylcholine transporter and active acetylcholine release in response
      to depolarizing stimuli. The differentiation correlated with the expression of
      NMDA receptors. RT-PCR and immunoblotting analysis identified NMDA receptor
      subunits NR1 and NR2B, in RA-differentiated cultures. The NR1 protein
      immunolocalized to the neuronal cell population and assembled with the NR2B
      subunit to form functional N-methyl-D-aspartate (NMDA) receptors. Glutamate or
      NMDA application, concentration-dependently increased the intracellular Ca2+
      levels and acetylcholine release in differentiated cultures, but not in
      undifferentiated SK-N-SH cells. Moreover, differentiated cultures became
      vulnerable to NMDA receptor-mediated excitotoxicity. The glutamate effects were
      enhanced by glycine application and were prevented by the NMDA receptor blocker
      MK 801, as well as by the NR2B selective antagonist ifenprodil. These data
      suggest that SK-N-SH cells differentiated by brief treatment with RA may
      represent an unlimited source of neuron-like cells suitable for studying
      molecular events associated with activation of human NR1/NR2B receptors.

PMID- 12492430
TI  - Intrastriatal sonic hedgehog injection increases Patched transcript levels in the
      adult rat subventricular zone.
AB  - The morphogen sonic hedgehog (Shh) is implicated in neural tissue patterning and
      the growth of brain structures during embryogenesis and postnatal development and
      is also present in the adult brain. Shh signals through interaction with the
      tumour suppressor Patched (Ptc). This receptor for Shh is associated with
      Smoothened (Smo), a protein with high homology to the G-protein coupled
      receptors. However, little is known about the transduction mechanisms implicated
      in Shh signalling in the adult brain. The study described here shows that
      injection of aminoterminal myristoylated Shh (myrShhN) into the adult rat
      striatum robustly increases the levels of Ptc transcripts in selective brain
      areas including the subventricular zone (SVZ). The adult SVZ contains cell
      progenitors, which can proliferate and differentiate into new neurons and glia.
      In the myrShhN injected animals, proliferation and differentiation of these SVZ
      precursor cells were not affected as demonstrated by BrdU incorporation and
      immunohistochemistry performed with specific antibodies for nestin (uncommitted
      neural progenitors), PSA-NCAM (migrating neuroblasts) or GFAP (astrocytes).
      Together with the presence of Smo expressing cells and amino-terminal Shh (ShhN)
      protein in SVZ area of untreated animals, the data presented here supports the
      hypothesis that the Shh pathway may be activated in the adult brain, and that a
      niche for Shh signalling exists within the adult SVZ.

PMID- 12492432
TI  - Locus coeruleus activation modulates firing rate and temporal organization of
      odour-induced single-cell responses in rat piriform cortex.
AB  - Piriform cortex (PCx) is the primary cortical projection region for olfactory
      information and has bidirectional monosynaptic connections with olfactory bulb
      and association cortices. PCx neurons display a complex receptive field,
      responding to odours rather than their molecular components, suggesting that
      these neurons are involved in higher order olfactory processing. Neuromodulators,
      especially noradrenaline (NA), have important influences on sensory processing in
      other cortical regions and might be responsible for the plasticity observed in
      PCx during learning. The present study is the first attempt to examine in vivo
      the actions of NA on sensory responses in the PCx. Stimulation of the
      noradrenergic nucleus locus coeruleus (LC) was used to induce release of NA in
      the forebrain in urethane-anaesthetized rats. Extracellular recording of single
      units was made simultaneously in anterior and posterior PCx. The responses to an
      odour stimulus were measured over 25 trials. Twenty-five subsequent odour
      presentations were preceded by stimulation of the ipsilateral LC through a
      bipolar electrode, previously placed in the LC under electrophysiological
      control. This priming stimulation modified the activity of 77 of the 135 recorded
      neurons. For most cells, LC stimulation enhanced cortical responses to odour in
      terms of both spike count and temporal organization, with some differential
      effects in anterior and posterior regions. These results are the first to show
      enhancement of sensory responses in the olfactory cortex by LC activation.
      Spontaneous activation of LC neurons such as occurs during learning could serve
      to enhance olfactory perception and promote learning.

PMID- 12492431
TI  - Patterns of cation-chloride cotransporter expression during embryonic rodent CNS
      development.
AB  - Intracellular Cl- plays a key role in cellular volume regulation, cell cycle
      control and shaping the polarity of inhibitory postsynaptic responses mediated by
      anion-permeable GABA and glycine receptors. In this study, we have investigated
      the expression patterns of members of the cation-chloride cotransporters (CCCs),
      including the K-Cl cotransporters KCC1-4 and the Na-K-2 Cl cotranporter NKCC1
      during rodent embryonic brain development. At the time of neurogenesis (embryonic
      days; E12.5-14.5), KCC1 was only detectable in the developing choroid plexus.
      KCC2 mRNA was detectable as early as E12.5 in the ventral part of the (cervical)
      spinal cord, and by E14.5, the expression had spread to TUJ1-positive
      differentiating regions of the rhombencephalon, diencephalon and olfactory bulb,
      in parallel with neuronal maturation. KCC3 mRNA was scarce in the cortical plate
      at E14.5, and slightly up-regulated at birth. In contrast, KCC4 mRNA was
      abundantly expressed in the ventricular zone and was down-regulated perinatally.
      At E14.5, NKCC1 was highly expressed in the vimentin-positive radial glia of the
      proliferative zone of the subcortical region. At later embryonic stages, during
      gliogenesis (E17-P0), there was a shift in NKCC1 expression to the neuron
      specific Class III beta-tubulin (betaIII) positive region of the cortical plate.
      These unique spatiotemporal expression patterns of distinct CCCs during embryonic
      development suggests that Cl- regulatory mechanisms are critically involved in
      the control of neuronal development.

PMID- 12492433
TI  - Thalamocortical oscillations in a genetic model of absence seizures.
AB  - We used field potential recordings in an in vitro thalamocortical slice
      preparation to compare the rhythmic oscillations generated by reciprocally
      connected networks of the thalamus and cerebral cortex obtained from epileptic (>
      160 days old) WAG/Rij and age-matched, nonepileptic control (NEC) rats. To
      increase neuronal excitability, and thus to elicit spontaneous field potential
      activity in vitro, we applied medium containing: (i) zero [Mg2+]; (ii) high [K+]
      (8.25 mm); or (iii) low concentrations of the K+ channel blocker 4-aminopyridine
      (4AP, 0.5-1 micro m). Of these procedures, only the last was effective in
      triggering oscillatory activity that depended on the type of tissue. Thus, during
      4AP application: (i) sequences of fast (intraburst frequency 9.5-16.1 Hz) and
      slower (5-8.9 Hz) field potential oscillations (FPOs) were recorded in WAG/Rij
      slices (n = 23), but (ii) only fast FPOs were seen in NEC slices (n = 7). Slower
      FPOs in WAG/Rij slices reflected a larger degree of thalamocortical
      synchronization than fast FPOs, and disappeared after surgical separation of
      cortex and thalamus (n = 5); under these conditions fast FPOs continued to occur
      in thalamus only. In addition, fast and slower FPOs disappeared in all areas of
      the WAG/Rij slice during thalamic application of the excitatory amino acid
      receptor antagonist kynurenic acid (n = 3), while fast FPOs continued to occur in
      thalamus when kynurenic acid was applied to the cortex (n = 4). Bath application
      of the N-methyl-D-aspartic acid (NMDA) receptor antagonist 3,3-(2
      carboxypiperazine-4-yl)-propyl-1-phosphonate (CPP) abolished slower FPOs in
      WAG/Rij cortex and thalamus (n = 6) without infuencing fast FPOs recorded in
      WAG/Rij (n = 6) or NEC slices (n = 4). Moreover, cortical application of CPP (n =
      6) abated slower FPOs although they persisted following CPP application to the
      thalamus (n = 7). Our data demonstrate that highly synchronized, slower FPOs can
      occur during 4AP application in WAG/Rij but not in NEC slices. This activity,
      which may represent an in vitro hallmark of thalamocortical epileptogenicity,
      requires the function of reciprocally connected thalamic and cortical networks
      and depends on cortical NMDA receptor-mediated mechanisms.

PMID- 12492434
TI  - The effect of bilateral deafness on excitatory and inhibitory synaptic strength
      in the inferior colliculus.
AB  - The consequences of deafness on the central auditory nervous system have been
      examined at many levels, from molecular to functional. However, there has never
      been a direct and selective measurement of excitatory synaptic function following
      total hearing loss. In the present study, gerbils were deafened at postnatal day
      9, an age at which there is no deafferentation-induced cell death of ventral
      cochlear nucleus neurons. One to five days after bilateral cochlear ablation, the
      amplitude of evoked excitatory postsynaptic currents (EPSC) was measured with
      whole-cell voltage-clamp recordings in an inferior colliculus (IC) brain slice
      preparation in response to electrical stimulation of the ipsilateral lateral
      lemniscus (LL) or the commissure of the inferior colliculus (CIC). Deafness
      resulted in larger LL- and CIC-evoked EPSC amplitudes and durations. This result
      was observed at a depolarized holding potential. In addition, deafness caused a
      decrease in excitatory neurotransmitter release at the LL pathway, as assessed
      with a paired-pulse stimulation protocol. In contrast to its effect on excitatory
      synapses, bilateral cochlear ablation reduced inhibitory synaptic strength in IC
      neurons. The effects included a postsynaptic decrease in IPSC conductance, a 25
      mV depolarization in the IPSC equilibrium potential and a decrease of
      neurotransmitter release. Thus normal innervation differentially affects
      excitatory and inhibitory synaptic strength in IC neurons, and these changes may
      contribute to alterations in auditory coding properties following sensory
      deprivation.

PMID- 12492435
TI  - Environmental conditions influence hippocampus-dependent behaviours and brain
      levels of amyloid precursor protein in rats.
AB  - Sprague-Dawley rats were reared in enriched (EC; group housing, exposure to
      stimulating objects, frequent handling) or restricted (RC; individual housing, no
      exposure to stimulating objects, minimal handling) environments starting on day
      23 of life. At six months of age, they underwent behavioural tests to assess
      'cognitive' and 'stimulus-response' memory, selective attention, and inflammatory
      pain processing. Alterations in synapses and cell survival may occur as a result
      of environment differences; therefore we assessed the brain levels of several
      proteins implicated in neurite outgrowth, synaptogenesis, and cell survival.
      Brains were dissected and analysed for amyloid precursor protein (APP) and other
      synaptic and cytoskeletal proteins using Western blotting. The performance of EC
      animals in a hidden platform water maze task, and in a test of selective
      attention (both of which are thought to involve the hippocampus) was superior to
      that of RC animals. In contrast, performance of RC animals on two stimulus
      response tasks, the visible platform water maze test and simple visual
      discrimination (both of which are thought to be hippocampal independent) was
      indistinguishable from that of EC animals. Male EC rats displayed a different
      behavioural response to formalin during the inflammatory phase of nociception-
      the phase affected by hippocampal processing; a similar trend was observed in
      females. Female but not male RC rats exhibited elevated plasma corticosterone
      levels; adrenal weights were unaffected by environmental conditions. Region
      specific increases in brain levels of APP, neurofilament-70 (NF-70), and platelet
      activating factor receptor (PAF-R) were found in EC rats. These data suggest that
      enriched animals manifest enhanced functioning of certain hippocampus-mediated
      behaviours when compared with that of their restricted counterparts; and that
      brain levels of various synaptic and structural proteins involved in neurite
      outgrowth, cell survival, and synaptogenesis, are affected by environmental
      factors.

PMID- 12492436
TI  - mGluR1 in cerebellar Purkinje cells is required for normal association of
      temporally contiguous stimuli in classical conditioning.
AB  - In metabotropic glutamate receptor-subtype 1 (mGluR1)-null (mGluR1-/-) mice,
      cerebellar long-term depression (LTD) and several forms of memory are impaired.
      However, because mGluR1 is expressed in various brain regions in wild-type mice,
      it has been difficult to identify which type of memory depends on mGluR1
      expressed in a given brain region. Furthermore, severe ataxia in mGluR1-/- mice
      complicated interpretation of the data from non-cerebellum-dependent tasks. We
      have generated mGluR1-rescue mice, which express mGluR1 only in Purkinje cells
      (PCs) of their cerebellum, by introducing the mGluR1alpha transgene into mGluR1-/
      mice under the control of a PC-specific promoter. The mGluR1-rescue mouse has
      normal LTD and displays no apparent ataxia. Therefore, this mouse is the first
      animal model in which effects of mGluR1 deficiency outside PCs can be studied
      without cerebellar dysfunction. We used three eyeblink conditioning paradigms
      with different temporal specificities between conditioned stimulus (CS) and
      unconditioned stimulus (US). Delay conditioning, in which CS and US coterminate,
      was impaired in mGluR1-/- mice but normal in mGluR1-rescue mice. However, both
      strains of mice displayed severe impairment in trace conditionings, in which a
      stimulus-free interval of 250 or 500 ms intervened between CS and US. We also
      examined social transmission of food-preference and novel-object-recognition
      memory tests. In these tasks, mGluR1-rescue mice showed normal short-term but
      impaired long-term memory. We conclude that mGluR1 in PCs is indispensable for
      normal learning of association of temporally contiguous stimuli in associative
      conditioning. In contrast, mGluR1 in other cell types is required for associating
      discontiguous stimuli and long-term memory formation in nonspatial hippocampus
      dependent learning.

PMID- 12492437
TI  - Lateral hypothalamic lesions impair flavour-nutrient and flavour-toxin trace
      learning in rats.
AB  - Food-restricted rats with ibotenic acid lesions of the lateral hypothalamus (LHx)
      learned to prefer a flavour paired with concurrent intragastric (i.g.) infusions
      of maltodextrin, although their preference was weaker than that displayed by sham
      controls. Unlike controls, the LHx rats failed to acquire a flavour preference
      when the i.g. maltodextrin infusion was delayed by 15 min. The same rats learned
      to avoid flavours paired with i.g. lactose or lithium chloride over short delays
      (15-30 min), but were impaired, relative to controls, at a long conditioned
      unconditioned stimuli delay (2 h). These data indicate that the LH is critical
      for the formation of flavour-postingestive consequence learning over a delay,
      particularly with nutrient reinforcement. Lateral hypothalamus lesions might
      specifically impair the processing of nutrient-generated unconditioned stimuli
      and, more generally, could interfere with the maintenance of flavour memories.

PMID- 12492438
TI  - Morphological alterations in the amygdala and hippocampus of mice during ageing.
AB  - Declines in memory function and behavioural dysfunction accompany normal ageing
      in mammals. However, the cellular and morphological basis of this decline remains
      largely unknown. It was assumed for a long time that cell losses in the
      hippocampus accompany ageing. However, recent stereological studies have
      questioned this finding. In addition, the effect of ageing is largely unknown in
      another key structure of the memory system, the amygdala. In the present study,
      we have estimated neuronal density and total neuronal numbers as well as density
      of fragments of degenerated axons in different hippocampal subfields and
      amygdaloid nuclei. Comparisons were made among aged (21-26 months old) mice and
      normal adult littermates (8 months old). No significant volume loss occurs in the
      hippocampus of aged mice. Small but insignificant reductions in total neuronal
      numbers were found in the hippocampus and in the amygdaloid nuclei. In contrast
      to the mild effects of ageing upon neuronal numbers, fragments of degenerated
      axons were increased in both hippocampus and amygdala of aged mice. These data
      suggest that ageing does not induce prominent cell loss in the hippocampus or
      amygdala, but leads to degeneration of axons that innervate these forebrain
      structures. Thus, mechanisms underlying age-related dysfunction depend on
      parameters other than neuronal numbers, at least in the hippocampal formation and
      the amygdala.

PMID- 12492439
TI  - Forced swim stress activates rat hippocampal serotonergic neurotransmission
      involving a corticotropin-releasing hormone receptor-dependent mechanism.
AB  - Serotonin is important for adequate coping with stress. Aberrant serotonin
      function is implicated in the aetiology of major depression and anxiety
      disorders. Dysregulation of the hypothalamic-pituitary-adrenocortical axis,
      involving elevated corticotropin-releasing hormone (CRH) activity, also plays a
      role in these stress-related illnesses. Here we studied the effects of stress on
      hippocampal serotonin and the role of the CRH system using in vivo microdialysis.
      First, rats were subjected to a forced swim stress, resulting in a dramatic
      increase in hippocampal serotonin (1500% of baseline), which was associated with
      the occurrence of diving behaviour. The diving-associated increase in serotonin
      depended on activation of CRH receptors, as it was antagonized by
      intracerebroventricular pretreatment with D-Phe-CRH12-41. Secondly, the effects
      of intracerebroventricular administration of CRH and urocortin (0.03-1.0 microg)
      were studied. Both CRH and urocortin caused a dose-dependent rise in hippocampal
      serotonin (maximally 350% of baseline) and 5-hydroxyindoleacetic acid levels,
      suggesting the involvement of CRH receptor type 1. Because the effects of
      urocortin were prolonged, CRH receptor type 2 could play a role in a later phase
      of the neurotransmitter response. Experiments using adrenalectomized rats showed
      that CRH-induced serotonin changes were adrenally independent. These data suggest
      that the raphe-hippocampal serotonin system is able to mount, CRH receptor
      dependent, responses to specific stressful situations that surpass the usually
      observed maximal increases of about 300% of baseline during stress and enhanced
      vigilance.

PMID- 12492440
TI  - Specific contributions of the basal forebrain corticopetal cholinergic system to
      electroencephalographic activity and sleep/waking behaviour.
AB  - The present study examined the role of the basal forebrain corticopetal
      cholinergic projection in the regulation of cortical electroencephalographic
      activity across sleep/wake states in rats. Selective lesions of this projection
      were effected by local intraparenchymal infusions of the immunotoxin 192 IgG
      saporin. Lesions spared the septo-hippocampal cholinergic system, as well as p75
      receptor-bearing noncholinergic neurons in the suprachiasmatic nucleus. Relative
      to sham-lesioned control animals, rats with lesions of basal forebrain
      cholinergic neurons displayed a significant reduction in high frequency EEG
      activity, characterized especially by a reduction in gamma EEG power. Lesions did
      not significantly alter the overall proportion of sleeping and waking states as
      defined behaviourally, but the attenuation of high frequency EEG activity was
      apparent across all stages, including REM-like periods. Results are consistent
      with the view that the basal forebrain corticopetal cholinergic system exerts a
      general activational effect on the cortical mantle. Although this system may not
      be essential for sleep/wake stage-switching, it does impact on the cortical
      states associated with those stages.

PMID- 12492441
TI  - Compartment-specific changes in striatal neuronal activity during expression of
      amphetamine sensitization are the result of drug hypersensitivity.
AB  - Repeated exposure to drugs of abuse induces behavioural sensitization, i.e. a
      persistent hypersensitivity to the psychomotor stimulant effects of these drugs.
      This may be the result of increased responsiveness, to drugs, of mesostriatal
      dopamine systems and their projections, but it has also been suggested that acute
      and sensitized behavioural responses to psychostimulant drugs involve activation
      of distinct neuronal circuits. In order to distinguish between these
      possibilities, we studied amphetamine-induced c-fos immunoreactivity in
      subregions of rat striatum (patch and matrix compartments of caudate-putamen and
      nucleus accumbens core and shell) in drug-naive rats, as well as during long-term
      expression of amphetamine sensitization. We found that, in sensitized animals,
      amphetamine (1.0 mg/kg) evoked an increase in the ratio of c-fos-immunopositive
      cells in striatal patch and matrix compartments, suggesting a preferential
      involvement of striatal patches in the sensitized response to amphetamine. In
      drug-naive rats, amphetamine (0.5-5.0 mg/kg) dose-dependently increased c-fos
      expression in all striatal subregions. Remarkably, the highest dose of
      amphetamine also evoked an increase in patch : matrix ratio of c-fos
      immunoreactivity. In nucleus accumbens core and shell of amphetamine- and saline
      pretreated animals, amphetamine (1.0 mg/kg) evoked comparable increases in c-fos
      expression. These data indicate that distinct striatal compartments display a
      differential sensitivity to amphetamine in both drug-naive and amphetamine
      sensitized animals. In addition, they suggest that the shift in amphetamine
      induced c-fos expression from striatal matrix to patches in sensitized animals is
      the consequence of a change in the sensitivity to amphetamine, rather than a long
      term circuitry reorganization that is exclusive to the sensitized state.

PMID- 12492442
TI  - Calbindin neurons in the hamster suprachiasmatic nucleus do not exhibit a
      circadian variation in spontaneous firing rate.
AB  - The role of the mammalian suprachiasmatic nuclei (SCN) in generating circadian
      rhythms in behaviours and other physiological processes is well established. A
      prominent feature of SCN neurons is the circadian oscillation in action potential
      firing frequency, with a peak near midday. A subset of calbindin-immunoreactive
      (CB+) neurons form a compact subnucleus (CBsn) in the hamster SCN. Restoration of
      rhythmicity using fetal SCN grafts in SCN-lesioned hamsters is critically
      dependent upon the presence of CB+ neurons within the transplanted grafts
      [LeSauter & Silver (1999) J. Neurosci., 5574-5585]. The aim of the current study
      was to determine whether CB+ neurons within the CBsn of the hamster SCN fire
      action potentials in a circadian pattern as part of their output signal. Using
      patch-clamp recording, we demonstrated that CB+ neurons in the CBsn do not
      express a circadian rhythm in spontaneous firing frequency under diurnal
      conditions in vitro. Furthermore, the percentage of silent CB- cells varies with
      zeitgeber time, whereas the percentage of silent CB+ cells does not.
      Immunohistochemical analysis revealed that the CBsn is a nonhomogeneous nucleus,
      containing many more CB- than CB+ cells. Our results reveal that CB+ neurons
      within the CBsn represent a functionally distinct neuronal subpopulation in which
      rhythmic action potential output may not be necessary for the restoration of
      behavioural circadian rhythmicity.

PMID- 12492443
TI  - Altering electrical connections in the nervous system of the pteropod mollusc
      Clione limacina by neuronal injections of gap junction mRNA.
AB  - Neurons can communicate with each other either via exchange of specific molecules
      at synapses or by direct electrical connections between the cytoplasm of either
      cell [for review see Bruzzone et al. (1996) Eur. J. Biochem., 238, 1-27].
      Although electrical connections are abundant in many nervous systems, little is
      known about the mechanisms which govern the specificity of their formation.
      Recent cloning of the innexins--gap junction proteins responsible for electrical
      coupling in invertebrates (Phelan et al. (1998) Trends Genet., 14, 348-349], has
      made it possible to study the molecular mechanisms of patterning of the
      electrical connections between individual neurons in model systems. Here we
      demonstrate that intracellular injection of mRNA encoding the molluscan innexin
      Panx1 (Panchin et al. 2000 Curr. Biol., 10, R473-R474) drastically alters the
      specificity of electrical coupling between identified neurons of the pteropod
      mollusc Clione limacina.

PMID- 12492446
TI  - Impact of genetic defects on coronary atherosclerosis in patients suspected of
      having familial hypercholesterolaemia.
AB  - BACKGROUND: In the present study we assessed whether the presence of genetic
      mutations typical of familial hypercholesterolaemia (FH) was associated with
      greater atherosclerosis in the coronary vessels in patients with severe
      hypercholesterolaemia and a family history of early cardiovascular disease.
      MATERIALS AND METHODS: Two hundred and thirty-five patients selected for having
      severe hypercholesterolaemia and a family history of cardiovascular disease were
      classified as FH (57 men and 38 women) or non-FH (84 men and 56 women) according
      to a genetic analysis of the LDL-R or ApoB genes. Coronary atherosclerosis was
      evaluated by performing a thoracic CT scan and exercise stress testing. RESULTS:
      Familial hypercholesterolaemia individuals had a significantly higher prevalence
      of coronary calcification than the non-FH patients from among both the men (OR =
      3.90; 95% CI 1.86-8.19; P < 0.001) and the women (OR = 2.34; 95% CI 1.01-5.48; P
      = 0.05). In exercise stress testing, ECG abnormalities suggestive of cardiac
      ischaemia were found with a higher prevalence in the FH patients than the non-FH
      patients from among both the men (OR 6.15; 95% CI 2.16-17.5; P < 0.001) and the
      women (OR 4.76; 95% CI 0.91-24.6; P = 0.06). All differences were statistically
      significant after adjusting for age and cholesterol and for most classical risk
      factors that differed between the FH and non-FH groups. CONCLUSION: Among
      patients with severe hypercholesterolaemia and a family history of early
      cardiovascular disease, the presence of a genetically ascertained FH is
      associated with a higher prevalence of coronary artery calcifications and a
      positive exercise stress test. These results suggest that despite a similar
      phenotype, patients carrying mutations suggestive of FH may have a greater
      cardiovascular risk than patients without these mutations.

PMID- 12492447
TI  - Effects of age on the cardiac and vascular limbs of the arterial baroreflex.
AB  - BACKGROUND: Healthy ageing has several effects on the autonomic control of the
      circulation. Several studies have shown that baroreflex-mediated vagal control of
      the heart deteriorates with age, but so far there is little information regarding
      the effect of ageing on sympathetically mediated baroreflex responses. The aim of
      this study was to assess the effects of ageing on baroreflex control of the heart
      and blood vessels. MATERIALS AND METHODS: In 40 healthy volunteers, aged 20-87
      years, we applied oscillatory neck suction at 0.1 Hz to assess the sympathetic
      modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of
      parasympathetic stimulation on the heart. Breathing was maintained at 0.25 Hz.
      Blood pressure, electrocardiographic RR intervals and respiration were recorded
      continuously. Spectral analysis was used to evaluate the magnitude of the low
      frequency (0.03-0.14 Hz) and high-frequency (0.15-0.50 Hz) oscillations in the RR
      interval and blood pressure. Responses to neck suction were assessed as the
      change in power of the RR interval and blood pressure fluctuations at the
      stimulation frequency from baseline values. RESULTS: Resting low- and high
      frequency powers of the RR interval decreased significantly with age (P < 0.01).
      However, the low-frequency power of systolic blood pressure did not correlate
      with age. Spontaneous baroreflex sensitivity (alpha-index) showed a significant
      inverse correlation with age (r = -0.46, P < 0.05). Responses of the RR interval
      and systolic blood pressure to 0.1 Hz neck suction stimulation were not related
      to age, however, the RR interval response to 0.2 Hz neck suction declined
      significantly with age (r = -0.61, P < 0.01). CONCLUSIONS: These results confirm
      an age-related decrease in cardiovagal baroreflex responses. However,
      sympathetically mediated baroreflex control of the blood vessels is preserved
      with age.

PMID- 12492448
TI  - S-adenosylhomocysteine and the ratio of S-adenosylmethionine to S
      adenosylhomocysteine are not related to folate, cobalamin and vitamin B6
      concentrations.
AB  - BACKGROUND: It is unclear whether homocysteine itself is causal in the
      pathogenesis of cardiovascular disease. Alternatively or additionally, the
      association between homocysteine and cardiovascular disease may be because of its
      metabolic precursor, S-adenosylhomocysteine, or of the ratio of S
      adenosylmethionine to S-adenosylhomocysteine. Therefore, it is relevant to know
      how these moieties are interrelated, and whether, as is the case for
      homocysteine, they are influenced by blood levels of folate, cobalamin or vitamin
      B6. DESIGN: We cross-sectionally studied a population-based cohort of 97
      Caucasian subjects aged 60-85 years. Concentrations of homocysteine, S
      adenosylhomocysteine, S-adenosylmethionine, folate, cobalamin and vitamin B6 were
      measured in fasting blood samples. RESULTS: In multiple regression analysis,
      homocysteine was associated with vitamin B12 (per 50 pmol L-1 increase of
      cobalamin, change in homocysteine, -0.70 mmol L-1; 95% CI, -1.30 to -0.10 mmol L
      1) and folate (per 100 nmol L-1 increase in erythrocyte folate, change in
      homocysteine, -0.68 mmol L-1; 95% CI -1.28 to -0.08 mmol L-1). S
      adenosylhomocysteine, S-adenosylmethionine and the ratio of S-adenosylmethionine
      to S-adenosylhomocysteine were not associated with serum folate, cobalamin or
      vitamin B6, nor with erythrocyte folate. Furthermore, plasma homocysteine showed
      a negative correlation with the ratio of S-adenosylmethionine to S
      adenosylhomocysteine in plasma (r = -0.27; P < 0.01) but not in erythrocytes.
      CONCLUSIONS: In contrast to homocysteine, the plasma concentrations of S
      adenosylhomocysteine and the ratio of S-adenosylmethionine to S
      adenosylhomocysteine were not associated with the folate, cobalamin and vitamin
      B6 concentrations in the present study. If these precursors in part explain why
      homocysteine is associated with cardiovascular disease, homocysteine-lowering
      treatment with B vitamins may be less effective than currently expected, at least
      in an elderly population.

PMID- 12492449
TI  - Early endothelial dysfunction following renal mass reduction in rats.
AB  - BACKGROUND: Endothelial dysfunction has been previously described in severely
      hypertensive rats with renal mass reduction (RMR) receiving large dietary Na
      loads. Because hypertension and Na loading reduce endothelium-dependent
      vasodilation, the effect of renal failure per se is unclear. METHODS: Responses
      to acetylcholine in noradrenaline-contracted isolated perfused mesenteric
      arteries were studied. Vessels were obtained from RMR rats kept on a normal diet,
      3 and 10 days after surgery, and the results were compared with those from sham
      operated rats (SN). The role of three putative mediators of endothelium-dependent
      vasodilation was assessed using: L-NAME (10(-4) mol L(-1)); indomethacin (INDO,
      10(-5) mol L(-1)); and a mixture of charybdotoxin and apamin (C/A, both 10(-7)
      mol L(-1)), inhibitors of Ca-activated K-channels to mediate the effects of
      endothelium-derived hyperpolarizing factor (EDHF). RESULTS: Response to
      acetylcholine but not that to nitroprusside (endothelium-independent) was
      decreased in RMR. L-NAME reduced further acetylcholine relaxations in SN but not
      in RMR. By contrary, INDO decreased acetylcholine vasodilation in RMR but had no
      effect in SN. C/A had similar effects in the SN and RMR rats. The levels of 6
      keto prostaglandin F1alpha were elevated in the urine of the RMR rats and were
      perfusate from the RMR vessels. CONCLUSION: Endothelial dysfunction occurs early
      after RMR, even when systolic blood pressure is only minimally elevated and Na
      intake is normal. This alteration may be because of decreased availability of
      nitric oxide, partially compensated by increased prostacyclin production.

PMID- 12492450
TI  - Influence of atherosclerosis on age-related changes in renal size and function.
AB  - BACKGROUND: Renal size and function reflect the health of the kidney. These
      parameters are associated with age, gender and body weight. The kidneys are also
      influenced by micro- and macrovascular diseases. Atherosclerotic markers and risk
      factors may influence the age-related changes of renal size and function.
      METHODS: Data of 1056 patients who entered the SMART-study (Second Manifestations
      of ARTerial disease) were used to assess the effect of atherosclerosis on the
      relationship between age and renal size and function and to study the effect of
      atherosclerosis on renal size and function. Patients who were newly referred to
      the hospital with manifestations of vascular disease were screened for
      asymptomatic atherosclerosis with noninvasive tests. The carotid intima-media
      thickness (IMT) and albuminuria were used as estimates for the atherosclerotic
      burden. Renal size was defined as the mean pole-to-pole length of both kidneys
      measured by ultrasonography. Renal function was represented by serum creatinine.
      RESULTS: Intima-media thickness was a significant effect modifier of the age
      renal size relationship (P = 0.041). The increase of serum creatinine with age
      was more pronounced in the highest tertile of IMT (P = 0.048). Renal size
      decreased equally with age in patients with and without hypertension or diabetes
      mellitus (DM). The same held true for the age-renal function relationship.
      Albuminuria and DM were independent predictors of renal size and function.
      CONCLUSION: Atherosclerosis accelerates the decrease of renal size and the
      increase of serum creatinine with age. Renal size and function are determined by
      albuminuria and DM.

PMID- 12492451
TI  - Dose-effect relations of loop- and thiazide-diuretics on calcium homeostasis: a
      randomized, double-blinded Latin-square multiple cross-over study in
      postmenopausal osteopenic women.
AB  - BACKGROUND: Thiazide diuretics (TDs) reduce whereas loop diuretics (LDs) increase
      urinary calcium. We studied the effects of different doses of a TD and LD on
      electrolytes, calcitropic hormones and biochemical bone markers. SUBJECTS AND
      METHODS: In a five-period crossover study, comparing four active doses with
      placebo, 40 postmenopausal women with osteopenia were treated with different
      doses of LD bumetanide (n = 20, 0.5-2.0 mg per day) or TD bendroflumethiazide (n
      = 20, 2.5-10 mg per day). Each treatment period lasted 1 week. RESULTS: Urinary
      calcium decreased dose-dependently in response to the bendroflumethiazide. The
      best hypocalciuric effect was achieved by 5 mg day-1 of bendroflumethiazide.
      Total plasma calcium levels increased, whereas ionised calcium at ambient pH
      values decreased because of increased pH-values in response to the
      bendroflumethiazide. Plasma PTH levels did not change, whereas a slight dose
      dependent increase occurred in plasma 1,25(OH)2D levels. As a marker of bone
      formation, plasma osteocalcin levels increased. Conversely, bumetanide dose
      dependently increased renal calcium losses with a concomitant increase in plasma
      PTH and 1,25(OH)2D levels. Plasma osteocalcin levels increased and bone-specific
      alkaline phosphatase levels decreased dose-dependently. CONCLUSION: Whether a LD
      or TD is chosen as diuretic therapy affects calcium homeostasis. The effects of
      LDs are potentially harmful to bone. Further studies are needed to evaluate
      whether long-term treatment with LDs causes osteoporosis. Until then, we suggest
      using, if possible, a TD rather than a LD as diuretic therapy in order not to
      risk deleterious effects on bone metabolism.

PMID- 12492452
TI  - In vitro and in vivo lipolysis of plasma triglycerides increases the resistance
      to oxidative modification of low-density lipoproteins.
AB  - BACKGROUND: The majority of studies on low-density lipoprotein (LDL) particle
      size and susceptibility to oxidative modification have been either descriptive or
      interventional, but there are few mechanistic studies. MATERIALS AND METHODS:
      Effects of exhaustive in vitro and in vivo lipolysis of serum and plasma
      triglycerides, respectively, by lipoprotein lipase (LPL) were investigated in
      healthy normotriglyceridemic men. The LDL end-product of lipolysis of very low
      density lipoprotein (VLDL) underwent compositional analysis, gradient gel
      electrophoresis and an assessment of resistance to copper-induced oxidative
      modification. RESULTS: The LDL particle contents of free fatty acid and alpha
      tocopherol increased, whereas the contents of free and esterified cholesterol,
      alpha-carotene and coenzyme Q10 decreased upon incubation of serum with LPL in
      vitro. The LDL particle size decreased and the resistance to the oxidative
      modification of LDL increased. Lipolysis of plasma triglycerides in vivo,
      achieved by intravenous injection of heparin, did not alter the LDL particle size
      but increased the resistance to the oxidative modification of LDL. This change
      was accompanied by an increase in the LDL particle content of alpha-tocopherol,
      whereas the free fatty acid content was unaltered. CONCLUSIONS: The results show
      that the increased resistance to oxidative modification of LDL after lipolysis of
      plasma triglycerides was concomitant with an increased LDL particle content of
      alpha-tocopherol, and that free fatty acids did not seem to contribute to the
      increased resistance to oxidative modification of LDL in vivo. Furthermore, our
      data indicate that the resistance of LDL to oxidative modification is not
      dependent on particle size.

PMID- 12492453
TI  - Lipopolysaccharide represses cholesterol 7-alpha hydroxylase and induces binding
      activity to the bile acid response element II.
AB  - BACKGROUND: Inflammatory states such as hepatitis and sepsis are frequently
      associated with alterations of bile acid synthesis. These conditions are mediated
      by bacterial wall products like lipopolysaccharide (LPS). Cholesterol 7-alpha
      hydroxylase is the rate-limiting enzyme of bile acid synthesis. Hydrophobic bile
      acids repress cholesterol 7-alpha hydroxylase transcription via binding to the
      farnesoid X receptor and interaction with the bile acid response element II in
      the cholesterol 7-alpha hydroxylase promoter. METHODS: We tested the effect of
      LPS on hepatic expression of cholesterol 7-alpha hydroxylase in C57BL/6 mice and
      Wistar rats. Further, we analyzed the binding activity of hepatic nuclear
      extracts to the bile acid response element II and the binding site for farnesoid
      X receptor heterodimers (ecdysone response element). RESULT: Lipopolysaccharide
      caused a 100-fold reduction of cholesterol 7-alpha hydroxylase mRNA levels in
      mice and a 10-fold reduction in rats. Protein levels of cholesterol 7-alpha
      hydroxylase also decreased in both species. These changes inversely correlated
      with the increased binding activity of nuclear proteins to the bile acid response
      element II and the ecdysone response element. CONCLUSION: Lipopolysaccharide
      induced repression of cholesterol 7-alpha hydroxylase occurs at the
      transcriptional level. The underlying mechanism involves an increased binding
      activity of nuclear proteins to the bile acid response element II and the
      ecdysone response element. In conclusion, the farnesoid and retinoid X receptors
      participate in LPS-induced cholesterol 7-alpha hydroxylase repression.

PMID- 12492454
TI  - Inhibition of endogenous pancreatic enzyme secretion by oral pancreatic enzyme
      treatment.
AB  - BACKGROUND: The existence of a feedback mechanism for exocrine pancreatic
      secretion in humans is controversial. Exclusion of proteases from the duodenum
      stimulates exocrine pancreatic secretion. Conversely, addition of exogenous
      enzymes could reduce the enzyme secretion. Further investigation of the feedback
      mechanism should be performed under the most physiological conditions. In the
      present study we investigated exocrine pancreatic function by measuring fecal
      enzyme output in healthy volunteers consuming a normal diet, before and during a
      time course of exogenous pancreatic enzyme supplementation. MATERIAL AND METHODS:
      Twenty-five healthy subjects (HS) were given two different doses (30 and 60 FIP
      proteases kg(-1) d(-1)) divided by the number of meals. In all subjects, fecal
      elastase-1 (E1) concentrations and chymotrypsin (ChT) activities were measured
      without and with enzyme supplements after 7 days of treatment. In eight subjects,
      E1 concentrations and ChT activities were measured daily for 10 consecutive days.
      The subjects were given a dose regimen of 100 FIP proteases kg(-1) d(-1)(divided
      by the number of meals) for the first 7 days. RESULTS: Oral pancreatic treatment
      dose-dependently inhibited endogenous pancreatic secretion measured with the use
      of E1 concentrations. In both regimen groups, the differences were statistically
      significant. The exogenous enzymes, which interfere with colorimetric method for
      ChT, dose-dependently increased ChT output. However, only the higher dose
      resulted in a statistically significant difference. In the subgroup of eight HS,
      time-dependent changes of fecal enzyme output occurred with a decrease of E1
      concentrations and an increase of ChT activity from the second up to eighth or
      ninth day of the experiment. CONCLUSION: Exogenous applied pancreatic enzymes,
      dose- and time-dependently inhibited endogenous pancreatic secretion. The
      obtained results strongly support the existence of a protease mediated feedback
      mechanism in humans.

PMID- 12492455
TI  - Lactose intolerance: analysis of underlying factors.
AB  - BACKGROUND: We studied the degree of lactose digestion and orocecal transit time
      (OCTT) as possible causes for the variability of symptoms of lactose intolerance
      (LI) in a sample of a population with genetically determined low lactase
      activity. METHODS: Lactose digestion index (LDI) was measured by the recently
      developed 13C-lactose/2H-glucose test. The OCTT was determined using the breath
      hydrogen test. Based on a 6-h symptom score (SSC) after a challenge dose of 25 g
      of lactose the subjects were divided into a tolerant group (T: n= 15; SSC = 0)
      and an intolerant group (IT: n= 28; SSC 1-40). The intolerant group was
      subdivided according to the severity of symptoms: group ITa (n = 17; mild
      symptoms without diarrhoea) and group ITb (n = 11; with diarrhoea). RESULTS: The
      LDI was lower in the intolerant group (0.34 +/- 0.14) (mean +/- SD) than in the
      tolerant group (0.47 +/- 0.14) (P = 0.008). The OCTT of group IT (60, 30-90 min)
      (median, quartiles) was significantly shorter than that of group T (105, 60-120
      min) (P = 0.003) and was positively correlated with the LDI (P = 0.050). In
      groups ITa and ITb the OCTT (60, 30-90 min; 60, 26-83 min) and LDI (0.30 +/-
      0.14; 0.39 +/- 0.14) were similar. CONCLUSIONS: Lactose digestion capacity, which
      is determined by small intestinal lactase activity as well as by OCTT, affects
      the occurrence of lactose intolerance. However, the major difference in
      intolerance symptoms is caused by differences in the colonic processing of
      maldigested lactose.

PMID- 12492456
TI  - Angiostatin prolongs the survival of mice with leptomeningeal metastases.
AB  - BACKGROUND: As a result of the more effective treatment of primary tumours, the
      incidence of leptomeningeal metastases (LM) is increasing. Current treatment
      modalities have little effect on the survival of patients with LM. We
      investigated whether antiangiogenic treatment inhibits the progression of
      leptomeningeal tumours. MATERIALS AND METHODS: To assess the role of angiogenesis
      in leptomeningeal tumours, we inoculated melanoma cells in the subarachnoid space
      in balb/c mice. At different stages, the mice were sacrificed and the microvessel
      density was determined. Human specimens of LM were compared with the mouse model.
      For the intervention studies, the mice were treated with the angiogenesis
      inhibitor angiostatin. Survival was the endpoint in these studies. RESULTS:
      Tumour seeding in the early disease stages was concentrated around the pre
      existent arachnoid vasculature. In the more advanced stages, the tumour masses
      covered larger areas of the leptomeninges. Arachnoidal microvessel density in
      this advanced stage was increased compared with control mice. Systemic treatment
      of the mice with LM with angiostatin (100 mg kg-1 day-1) resulted in prolonged
      survival compared with mice treated with vehicle and with approximately one-fifth
      of the long-term survivors of the angiostatin-treated group. CONCLUSIONS: This
      study shows that neovascularization is important in the growth of LM in mice.
      Systemic targeting of the vascular compartment may be a useful approach in novel
      therapeutic strategies for patients with LM.

PMID- 12492457
TI  - Differential expression of alpha- and beta-defensins in human peripheral blood.
AB  - BACKGROUND: Human defensin peptides with broad-spectrum antimicrobial activity
      have been implicated in the human defence response towards microbial invasion.
      Two families of defensins designated alpha- and beta-defensins, respectively,
      have been identified. Little is known about the expression of both defensin
      families in human peripheral blood. The purpose of this study was to examine the
      expression of alpha- and beta-defensin genes in human peripheral blood. MATERIAL
      AND METHODS: Fifty-one healthy blood donors were screened for defensin
      expression. Blood from defensin responders was stimulated by lipopolysaccharide
      or heat-inactivated Pseudomonas aeruginosa ex vivo. Levels of mRNA were assessed
      by semiquantitative RT-PCR. Southern blot analysis and sequencing were used to
      confirm the identity of defensin gene transcripts. Western blotting analysis was
      used to detect the expression of defensin peptides. RESULTS: beta-defensin was
      undetected in human peripheral blood without stimulation. Following stimulation
      by lipopolysaccharide or heat-inactivated bacterial cells, the majority (88.2%)
      of healthy individuals had a detectable expression for beta-defensin-1 gene and
      39.2% for beta-defensin-2 gene, compared with none for beta-defensin-3. beta
      defensin-1 and -2 mRNAs in the stimulated human peripheral blood of responders
      became detectable at 3 h and showed a maximum at 6 h following induction by 100
      ng mL-1 of lipopolysaccharide or bacterial cells. In contrast, human alpha
      defensins 1-3 mRNA are constitutively expressed in peripheral leukocytes but not
      up-regulated by lipopolysaccharide or bacterial cells. CONCLUSIONS: In human
      peripheral blood, beta-defensin-1 and -2 genes were transiently transcribed and
      translated following the induction of lipopolysaccharide or heat-inactivated
      bacterial cells, whereas alpha-defensins 1-3 genes were constitutively
      transcribed, and beta-defensin-3 gene was not expressed. The inducible expression
      of beta-defensin-1 and -2 genes showed interindividual variability.

PMID- 12492458
TI  - Treatment with atorvastatin alters the ratio of interleukin-12/interleukin-10
      gene expression [corrected].
AB  - BACKGROUND: Statins have been shown to have pleiotropic effects extending beyond
      their ability to lower cholesterol. MATERIAL AND METHODS: Seventeen patients with
      heterozygous familial hypercholesterolaemia participated in a single-blind
      placebo controlled study. The patients underwent three treatment regimens:
      placebo (4 weeks), atorvastatin 10 mg day(-1) (4 weeks) and atorvastatin 40 mg
      day(-1) (12 weeks). Following each treatment period, serum lipids and plasma
      mevalonic acid were measured, mononuclear leukocytes were isolated and total RNA
      was prepared. The content of mRNA for IL-12p35 and IL-10 was assayed, blinded, by
      real-time quantitative polymerase chain reactions. RESULTS: Treatment of the
      subjects with atorvastatin decreased the abundance of IL-12p35 mRNA in
      mononuclear cells, but did not alter that of IL-10, so that the ratio of the IL
      12p35 to IL-10 mRNA content was significantly reduced (P < 0.0026). The IL
      12p35/IL-10 ratio correlated significantly with plasma mevalonic acid
      concentrations but not with serum LDL concentrations. CONCLUSIONS: This study
      provides evidence that atorvastatin exerts an immunomodulatory effect in vivo,
      characterized by a decrease in the ratio of IL-12 mRNA to IL-10 mRNA in
      leukocytes. The immunomodulatory effect of statins, in addition to their
      cholesterol-lowering properties, may contribute to the rapid cardiovascular
      benefit observed during treatment with statins and reduced the rate of rejection
      in patients with solid organ transplantation.

PMID- 12492461
TI  - The application of computer touch-screen technology in screening for psychosocial
      distress in an ambulatory oncology setting.
AB  - The objective of the study was to evaluate the acceptability and feasibility of
      computer touch-screen technology as a method for patients to report psychosocial
      functioning in an ambulatory cancer clinic. Patients participating in a
      randomized trial evaluating the use of self-reported psychosocial information in
      the clinical encounter were surveyed. The patients completed the Cancer Needs
      Questionnaire (CNQ), European Organization for the Research and Treatment of
      Cancer quality of life questionnaire (EORTC QLQ-C30) and the Beck Depression
      Inventory - Short Form (BDI) using a touch-screen computer. The time taken to
      complete the questionnaires was recorded electronically. Patients completed a
      seven-item pen and paper survey to assess acceptability of the process. Of the
      450 patients, 244 (54%) were 60 years or older. Although over half the patients
      had no prior computer experience, nearly all found the touch screen easy to use
      and the instructions easy to understand. Each question was answered by at least
      447 (99.3%) patients. The average time to complete the CNQ was 9.1 min, EORTC QLQ
      C30 4.0 min and BDI 3.1 min. Factors influencing time to completion were prior
      use of computers, physical condition, education and overall level of needs. The
      study found that the use of computer touch-screen technology is an acceptable and
      efficient method for obtaining self-reported information on quality of life,
      cancer needs and psychological distress.

PMID- 12492462
TI  - A randomized controlled crossover study of manual lymphatic drainage therapy in
      women with breast cancer-related lymphoedema.
AB  - This paper describes a randomized controlled crossover study examining the
      effects of manual lymphatic drainage (MLD) in 31 women with breast cancer-related
      lymphoedema. MLD is a type of massage used in combination with skin care,
      support/compression therapy and exercise in the management of lymphoedema. A
      modified version of MLD, referred to as simple lymphatic drainage (SLD), is
      commonly taught as a self-help measure. There has been limited research into the
      efficacy of MLD and SLD. The study reported here explores the effects of MLD and
      SLD on a range of outcome measures. The findings demonstrate that MLD
      significantly reduces excess limb volume (difference, d=71, 95% CI=16-126,
      P=0.013) and reduced dermal thickness in the upper arm (d=0.15, 95% CI=0.12-0.29,
      P =0.03). Quality of life, in terms of emotional function (d=7.2, 95% CI=2.3
      12.1, P=0.006), dyspnoea (d=-4.6, 95% CI=-9.1 to -0.15, P=0.04) and sleep
      disturbance (d =-9.2, 95% CI=-17.4 to -1.0, P=0.03), and a number of altered
      sensations, such as pain and heaviness, were also significantly improved by MLD.
      The study provides evidence to support the use of MLD in women with breast cancer
      related lymphoedema. The limitations of the study are outlined and future areas
      for study are highlighted.

PMID- 12492463
TI  - Intervention development for enhanced lay palliative caregiver support - the use
      of focus groups.
AB  - Caring for a family member or friend dying of cancer can be extremely stressful.
      Past research identified that lay caregivers frequently report unmet needs
      related to guidance and support to assist them to provide care. This study sought
      to extend prior needs-based research towards the development of a new nursing
      intervention focused on the guidance and support provided to persons caring for a
      relative or friend dying of cancer. Focus groups were conducted with current lay
      caregivers, bereaved lay caregivers and palliative care nurses. The findings
      endorsed the applicability of previous caregiver need research to the Australian
      context. Participants revealed that caregivers were commonly unprepared for their
      role and desired much more guidance and support from health professionals.
      Importantly, the research provided the essential ingredients for the future
      development of a new intervention aimed at augmenting home lay palliative
      caregiver guidance and support.

PMID- 12492464
TI  - The Living with Cancer Education Programme. I. Development of an Australian
      education and support programme for cancer patients and their family and friends.
AB  - After a diagnosis of cancer, patients and their families and friends experience a
      significant need for information about the illness, treatment and prognosis, as
      well as support. Structured education and support group-based programmes play a
      major role in meeting these needs. Following a needs assessment in 1985, the Anti
      Cancer Council of Victoria (ACCV), Australia, initiated development of the Living
      With Cancer Education Programme (LWCEP), a structured 8-week group programme
      providing education and support for people with cancer and their families and
      friends. This paper provides an historical overview of the LWCEP, as well as an
      outline of the programme aims, structure, content and delivery. Recent
      developments and future directions are also discussed. These include adaptation
      of the programme for individuals with advanced or recurrent cancer, modification
      of the programme structure and revision of the evaluation methodology.

PMID- 12492465
TI  - The Living with Cancer Education Programme. II. Evaluation of an Australian
      education and support programme for cancer patients and their family and friends.
AB  - A diagnosis of cancer can have major adverse physical, psychosocial and economic
      consequences for both the individual diagnosed with cancer and their family and
      friends. The provision of adequate information and support to individuals
      affected by cancer plays a key role in facilitating better adjustment and coping.
      Psychoeducational group programmes are an effective way of meeting this need.
      This paper reports on the results of an evaluation of an Australian education and
      support programme for individuals with cancer and their family and friends - the
      Living with Cancer Education Programme (LWCEP). Data are presented based on the
      evaluation of 152 programmes involving 1460 participants conducted between 1994
      and 2000. Participant responses related to changes in self, general coping
      abilities and satisfaction with the programme are reported. Results showed high
      satisfaction with the programme and significant improvement in coping abilities,
      knowledge and communication and relationships with significant others and health
      professionals among both groups of participants. These findings highlight several
      important issues for professionals involved in the psychosocial care of cancer
      patients and their family and friends.

PMID- 12492466
TI  - Living with breast cancer - a challenge to expansive and creative forces.
AB  - The aim of this qualitative case study is to obtain a deeper and more profound
      understanding of the life world of women living with breast cancer focusing
      particularly on changes in life perspective. The study is based on a series of
      interviews carried out within the space of one year and involving four women with
      breast cancer; each woman was interviewed four times. The participants were
      between 42 and 54 years of age; three of the four interviewed were in an advanced
      stage, with metastasis or recurrent breast cancer. There was an increased
      awareness of the relationship between life and death, which constituted a
      disclosure rather than an actual change in life perspective. The four women were
      'opening up' to the beauty and the essentials in life and experienced an
      increased desire to live their life in accordance with their own values. Their
      revitalized view of life increased their desire for authenticity. When it proved
      impossible to live in accordance with new insights the women were particularly
      frustrated. From a caring perspective our findings suggest that an awareness of
      patients' increased openness to their own needs and desires is an important
      resource in the healing and rehabilitative process of breast cancer patients. The
      paradoxes and the struggles involved disguise a hidden potential for health.

PMID- 12492469
TI  - RE-1 silencing transcription factor (REST) regulates human synaptophysin gene
      transcription through an intronic sequence-specific DNA-binding site.
AB  - Synaptophysin, one of the major proteins on synaptic vesicles, is ubiquitously
      expressed throughout the brain. Synaptophysin and synapsin I, another synaptic
      vesicle protein, are also expressed by retinoic acid-induced neuronally
      differentiated P19 teratocarcinoma cells. Here, we show that inhibition of
      histone deacetylase activity in P19 cells is sufficient to activate transcription
      of the synaptophysin and synapsin I genes, indicating that neuronal
      differentiation and impairment of histone deacetylases results in a similar gene
      expression pattern. The transcription factor REST, a repressor of neuronal genes
      in non-neuronal tissues, has been shown to function via recruitment of histone
      deacetylases to the transcription unit, indicating that modulation of the
      chromatin structure via histone deacetylation is of major importance for REST
      function and neuron-specific gene transcription. Furthermore, REST has been shown
      to be the major regulator of neuronal expression of synapsin I. Here, we have
      identified a functional binding site for REST in the first intron of the human
      synaptophysin gene indicating that REST blocks human synaptophysin gene
      transcription through an intronic neuron-specific silencer element. The
      synaptophysin promoter is, however, devoid of neuron-specific genetic elements
      and directs transcription in both neuronal and non-neuronal cells. Using a
      dominant-negative approach we have identified the transcription factor Sp1 as one
      of the regulators responsible for constitutive transcription of the human
      synaptophysin gene.

PMID- 12492470
TI  - Properties of purified gut trypsin from Helicoverpa zea, adapted to proteinase
      inhibitors.
AB  - Pest insects such as Helicoverpa spp. frequently feed on plants expressing
      protease inhibitors. Apparently, their digestive system can adapt to the presence
      of protease inhibitors. To study this, a trypsin enzyme was purified from the gut
      of insects that were raised on an inhibitor-containing diet. The amino-acid
      sequence of this enzyme was analysed by tandem MS, which allowed assignment of
      66% of the mature protein amino acid sequence. This trypsin, called HzTrypsin-S,
      corresponded to a known cDNA sequence from Helicoverpa. The amino acid sequence
      is closely related (76% identical) to that of a trypsin, HzTrypsin-C, which was
      purified and identified in a similar way from insects raised on a diet without
      additional inhibitor. The digestive properties of HzTrypsin-S and HzTrypsin-C
      were compared. Both trypsins appeared to be equally efficient in degrading
      protein. Four typical plant inhibitors were tested in enzymatic measurements.
      HzTrypsin-S could not be inhibited by > 1000-fold molar excess of any of these.
      The same inhibitors inhibited HzTrypsin-C with apparent equilibrium dissociation
      constants ranging from 1 nm to 30 nm. Thus, HzTrypsin-S seems to allow the insect
      to overcome different defensive proteinase inhibitors in plants.

PMID- 12492471
TI  - Structure of the O polysaccharides and serological classification of Pseudomonas
      syringae pv. porri from genomospecies 4.
AB  - Strains of Pseudomonas syringae pv. porri are characterized by a number of
      pathovar-specific phenotypic and genomic characters and constitute a highly
      homogeneous group. Using monoclonal antibodies, they all were classified in a
      novel P. syringae serogroup O9. The O polysaccharides (OPS) isolated from the
      lipopolysaccharides (LPS) of P. syringae pv. porri NCPPB 3365 and NCPPB 3364T
      possess multiple oligosaccharide O repeats, some of which are linear and composed
      of l-rhamnose (l-Rha), whereas the major O repeats are branched with l-rhamnose
      in the main chain and GlcNAc in side chains (structures 1 and 2). Both branched O
      repeats, which differ in the position of substitution of one of the Rha residues
      and in the site of attachment of GlcNAc, were found in the two strains studied, O
      repeat 1 being major in strain NCPPB 3365 and 2 in strain NCPPB 3364T. [formula:
      see text]. The relationship between OPS chemotype and serotype on one hand and
      the genomic characters of P. syringae pv. porri and other pathovars delineated in
      genomospecies 4 on the other hand is discussed.

PMID- 12492472
TI  - Leishmania donovani methionine adenosyltransferase. Role of cysteine residues in
      the recombinant enzyme.
AB  - Methionine adenosyltransferase (MAT, EC 2.5.1.6)-mediated synthesis of S
      adenosylmethionine (AdoMet) is a two-step process consisting of the formation of
      AdoMet and the subsequent cleavage of the tripolyphosphate (PPPi) molecule, a
      reaction induced, in turn, by AdoMet. The fact that the two activities, AdoMet
      synthesis and tripolyphosphate hydrolysis, can be measured separately is
      particularly useful when the site-directed mutagenesis approach is used to
      determine the functional role of the amino acid residues involved in each. The
      present report describes the cloning and subsequent functional refolding, using a
      bacterial expression system, of the MAT gene (GenBank accession number AF179714)
      from Leishmania donovani, the etiological agent of visceral leishmaniasis. The
      absolute need to include a sulfhydryl-protection reagent in the refolding buffer
      for this protein, in conjunction with the rapid inactivation of the functionally
      refolded protein by N-ethylmaleimide, suggests the presence of crucial cysteine
      residues in the primary structure of the MAT protein. The seven cysteines in L.
      donovani MAT were mutated to their isosterical amino acid, serine. The C22S,
      C44S, C92S and C305S mutants showed a drastic loss of AdoMet synthesis activity
      compared to the wild type, and the C33S and C47S mutants retained a mere 12% of
      wild-type MAT activity. C106S mutant activity and kinetics remained unchanged
      with respect to the wild-type. Cysteine substitutions also modified PPPi cleavage
      and AdoMet induction. The C22S, C44S and C305S mutants lacked in
      tripolyphosphatase activity altogether, whereas C33S, C47S and C92S retained low
      but detectable activity. The behavior of the C92S mutant was notable: its
      inability to synthesize AdoMet combined with its retention of tripolyphosphatase
      activity appear to be indicative of the specific involvement of the respective
      residue in the first step of the MAT reaction.

PMID- 12492474
TI  - Microperoxidase 8 catalysed nitrogen oxides formation from oxidation of N
      hydroxyguanidines by hydrogen peroxide.
AB  - Nitric oxide (NO) is a potent intra- and intercellular messenger involved in the
      control of vascular tone, neuronal signalling and host response to infection. In
      mammals, NO is synthesized by oxidation of l-arginine catalysed by hemeproteins
      called NO-synthases with intermediate formation of Nomega-hydroxy-l-arginine
      (NOHA). NOHA and some hydroxyguanidines have been shown to be able to deliver
      nitrogen oxides including NO in the presence of various oxidative systems. In
      this study, NOHA and a model compound, N-(4-chlorophenyl)-N'-hydroxyguanidine,
      were tested for their ability to generate NO in the presence of a haemprotein
      model, microperoxidase 8 (MP8), and hydrogen peroxide. Nitrite and nitrate
      production along with selective formation of 4-chlorophenylcyanamide was observed
      from incubations of N-(4-chlorophenyl)-N'-hydroxyguanidine in the presence of MP8
      and hydrogen peroxide. In the case of NOHA, the corresponding cyanamide, Ndelta
      cyano-L-ornithine, was too unstable under the conditions used and l-citrulline
      was the only product identified. A NO-specific conversion of 2-(4-carboxyphenyl)
      4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide to 2-(4-carboxyphenyl)-4,4,5,5
      tetramethylimidazoline-1-oxyl and formation of MP8-Fe-NO complexes were observed
      by EPR spectroscopy and low-temperature UV/visible spectroscopy, respectively.
      These results clearly demonstrate the formation of nitrogen oxides including NO
      from the oxidation of exogenous hydroxyguanidines by hydrogen peroxide in the
      presence of a minienzyme such as MP8. The importance of the bioactivation of
      endogenous (NOHA) or exogenous N-hydroxyguanidines by peroxidases of
      physiological interest remains to be established in vivo.

PMID- 12492473
TI  - Signaling events mediating activation of brain ethanolamine plasmalogen
      hydrolysis by ceramide.
AB  - Ceramide is a lipid second messenger that acts on multiple-target enzymes, some
      of which are involved in other signal-transduction systems. We have previously
      demonstrated that endogenous ceramide modifies the metabolism of brain
      ethanolamine plasmalogens. The mechanism involved was studied. On the basis of
      measurements of breakdown products, specific inhibitor effects, and previous
      findings, we suggest that a plasmalogen-selective phospholipase A2 is the
      ceramide target. Arachidonate-rich pools of the diacylphosphatidylethanolamine
      subclass were also affected by ceramide, but the most affected were plasmalogens.
      Concomitantly with production of free arachidonate, increased 1-O-arachidonoyl
      ceramide formation was observed. Quinacrine (phospholipase A2 inhibitor) and 1-O
      octadecyl-2-O-methyl-rac-glycerol-3-phosphocholine (CoA-independent transacylase
      inhibitor) prevented all of these ceramide-elicited effects. Therefore,
      phospholipase and transacylase activities are tightly coupled. Okadaic acid
      (phosphatase 2A inhibitor) and PD 98059 (mitogen-activated protein kinase
      inhibitor) modified basal levels of ceramide and sphingomyelinase-induced
      accumulation of ceramide, respectively. Therefore, they provided no evidence to
      determine whether there is a sensitive enzyme downstream of ceramide. The
      evidence shows that there are serine-dependent and thiol-dependent enzymes
      downstream of ceramide generation. Furthermore, experiments with Ac-DEVD-CMK
      (caspase-3 specific inhibitor) have led us to conclude that caspase-3 is
      downstream of ceramide in activating the brain plasmalogen-selective
      phospholipase A2.

PMID- 12492475
TI  - Thermal behaviour of cubic phases rich in 1-monooleoyl-rac-glycerol in the
      ternary system. 1-monooleoyl-rac-glycerol/n-octyl-beta-D-glucoside/water.
AB  - Using synchrotron X-ray diffraction the thermal behaviour was studied of the
      cubic phases in the 1-monooleoyl-rac-glycerol (MO)/n-octyl-beta-d-glucopyranoside
      (OG)/2H2O system with 58 or 45 wt % MO concentration and varying OG/2H2O
      contents. These MO contents correspond to a Pn3m cubic single-phase or a Pn3m
      cubic phase in excess water on the binary MO/water axis of the ternary phase
      diagram. The cubic liquid crystalline phases are stable with small fractions of
      OG, while higher OG concentrations trigger a cubic-to-lamellar phase transition.
      Moreover, with increasing OG concentration the initial Pn3m structure is
      completely converted to an Ia3d structure prior to the Lalpha phase being formed.
      Upon heating this effect is reversed, resulting in an Ia3d-to-Pn3m phase
      transition. For some samples additional peaks were observed in the diffractograms
      upon heating, resulting from the metastability notoriously shown by bicontinuous
      cubic phases. This judgement is supported by the fact that upon cooling these
      peaks were absent. Remarkably, both the Ia3d and the Pn3m cubic structures could
      be in equilibrium with excess water in this ternary system. A comparison is made
      with previous results on n-dodecyl-beta-d-maltoside (DM), showing that cubic
      phases with OG have higher thermal and compositional stability than with DM.

PMID- 12492476
TI  - Bioenergetics of the formyl-methanofuran dehydrogenase and heterodisulfide
      reductase reactions in Methanothermobacter thermautotrophicus.
AB  - The synthesis of formyl-methanofuran and the reduction of the heterodisulfide
      (CoM-S-S-CoB) of coenzyme M (HS-CoM) and coenzyme B (HS-CoB) are two crucial, H2
      dependent reactions in the energy metabolism of methanogenic archaea. The
      bioenergetics of the reactions in vivo were studied in chemostat cultures and in
      cell suspensions of Methanothermobacter thermautotrophicus metabolizing at
      defined dissolved hydrogen partial pressures ( pH2). Formyl-methanofuran
      synthesis is an endergonic reaction (DeltaG degrees ' = +16 kJ.mol-1). By
      analyzing the concentration ratios between formyl-methanofuran and methanofuran
      in the cells, free energy changes under experimental conditions (DeltaG') were
      found to range between +10 and +35 kJ.mol-1 depending on the pH2 applied. The
      comparison with the sodium motive force indicated that the reaction should be
      driven by the import of a variable number of two to four sodium ions.
      Heterodisulfide reduction (DeltaG degrees ' = -40 kJ.mol-1) was associated with
      free energy changes as high as -55 to -80 kJ.mol-1. The values were determined by
      analyzing the concentrations of CoM-S-S-CoB, HS-CoM and HS-CoB in methane-forming
      cells operating under a variety of hydrogen partial pressures. Free energy
      changes were in equilibrium with the proton motive force to the extent that three
      to four protons could be translocated out of the cells per reaction. Remarkably,
      an apparent proton translocation stoichiometry of three held for cells that had
      been grown at pH2<0.12 bar, whilst the number was four for cells grown above that
      concentration. The shift occurred within a narrow pH2 span around 0.12 bar. The
      findings suggest that the methanogens regulate the bioenergetic machinery
      involved in CoM-S-S-CoB reduction and proton pumping in response to the
      environmental hydrogen concentrations.

PMID- 12492477
TI  - Mixed lineage kinase LZK and antioxidant protein-1 activate NF-kappaB
      synergistically.
AB  - Leucine zipper-bearing kinase (LZK) is a novel member of the mixed lineage kinase
      (MLK) family [Sakuma, H., Ikeda, A., Oka, S., Kozutsumi, Y., Zanetta, J. P., and
      Kawasaki, T. (1997) J. Biol. Chem.272, 28622-28629]. We have previously shown
      that LZK activates the c-Jun-NH2 terminal kinase (JNK) pathway, but not the
      extracellular signal-related kinase (ERK) pathway, by acting as a mitogen
      activated protein kinase kinase kinase (MAPKKK) [Ikeda, A., Hasegawa, K., Masaki,
      M., Moriguchi, T., Nishida, E., Kozutsumi, Y., Oka, S., and Kawasaki, T. (2001)
      J. Biochem.130, 773-781]. However, the mode of activation of LZK remains largely
      unknown. By means of a yeast two-hybrid screening system, we have identified a
      molecule localized to mitochondria, antioxidant protein-1 (AOP-1), that binds to
      LZK and which acts as a modulator of LZK activity. Recently, several MAPKKKs
      involved in the JNK pathway, such as MEKK1, TAK1 and MLK3, were shown, using over
      expression assay systems, to activate a transcription factor, NF-kappaB, through
      activation of the IKK complex. Using similar assay systems, we demonstrated that
      LZK activated NF-kappaB-dependent transcription through IKK activation only
      weakly, but this was reproducible, and that AOP-1 enhanced the LZK-induced NF
      kappaB activation. We also provided evidence that LZK was associated directly
      with the IKK complex through the kinase domain, and that AOP-1 was recruited to
      the IKK complex through the binding to LZK.

PMID- 12492478
TI  - Characterization of gamma-tocopherol methyltransferases from Capsicum annuum L
      and Arabidopsis thaliana.
AB  - Tocopherols are essential micronutrients in human and animal nutrition due to
      their function as lipophilic antioxidants. They are exclusively synthesized by
      photosynthetic organisms including higher plants. Despite the attributed
      beneficial health effects and many industrial applications, research on the
      tocopherol biosynthetic pathway and its regulation in plants is still limited. In
      the work presented here we performed a detailed biochemical characterization of a
      gamma-tocopherol methyltransferase (gamma-TMT) from Arabidopsis thaliana and of a
      gamma-TMT purified from Capsicum annuum fruits, a tissue with high accumulation
      of tocopherols. The biochemical characteristics of both enzyme preparations were
      remarkably similar including substrate specificities. Both enzymes converted
      delta- and gamma- into beta- and alpha-tocopherol, respectively, but beta
      tocopherol was not accepted as a substrate, pointing to a specific methylation at
      the C(5)-position of the tocopherol aromatic head group. A kinetic analysis
      performed with the Arabidopsis enzyme was consistent with an iso-ordered bi-bi
      type reaction mechanism. Our results emphasize the role of gamma-TMT in
      regulating the spectrum of accumulated tocopherols in plants.

PMID- 12492479
TI  - Role of CCP2 of the C4b-binding protein beta-chain in protein S binding evaluated
      by mutagenesis and monoclonal antibodies.
AB  - Complement regulator C4b-binding protein (C4BP) and the anticoagulant vitamin K
      dependent protein S form a high affinity complex in human plasma. C4BP is
      composed of seven alpha-chains and a unique beta-chain, each chain comprising
      repeating complement control protein (CCP) modules. The binding site for protein
      S mainly involves the first of the three beta-chain CCPs (CCP1). However,
      recently it has been suggested that CCP2 of the beta-chain also contributes to
      the binding of protein S. To elucidate the structural background for the
      involvement of CCP2 in the protein S binding, several recombinant beta-chain CCP1
      2 variants having mutations in CCP2 were expressed and tested for protein S
      binding. Mutations were chosen based on analysis of a homology model of the beta
      chain and included R60A/R101A, D66A, L105A, F114A/I116A and H108A. All mutant
      proteins bound equally well as recombinant wild type to protein S. Several
      monoclonal antibodies against the beta-chain CCP2 were raised and their influence
      on protein S binding characterized. Taken together, the results suggest that the
      role of CCP2 in protein S binding is to orient and stabilize CCP1 rather than to
      be directly part of the binding site.

PMID- 12492480
TI  - Endogenous mono-ADP-ribosylation mediates smooth muscle cell proliferation and
      migration via protein kinase N-dependent induction of c-fos expression.
AB  - ADP-ribosylation has been coupled to intracellular events associated with smooth
      muscle cell vasoreactivity, cytoskeletal integrity and free radical damage.
      Additionally, there is evidence that ADP-ribosylation is required for smooth
      muscle cell proliferation. Our investigation employed selective inhibitors to
      establish that mono-ADP-ribosylation and not poly(ADP-ribosyl)ation was necessary
      for the stimulation of DNA synthesis by mitogens. Mitogen treatment increased
      concomitantly the activity of both soluble and particulate mono-ADP
      ribosyltransferase, as well as the number of modified proteins. Inclusion of meta
      iodobenzylguanidine (MIBG), a selective decoy substrate of arginine-dependent
      mono-ADP-ribosylation, prevented the modification of these proteins. MIBG also
      blocked the stimulation of DNA and RNA synthesis, prevented smooth muscle cell
      migration and suppressed the induction of c-fos and c-myc gene expression. An
      examination of relevant signal transduction pathways showed that MIBG did not
      interfere with MAP kinase and phosphatidylinositol 3-kinase stimulation; however,
      it did inhibit phosphorylation of the Rho effector, PRK1/2. This novel
      observation suggests that mono-ADP-ribosylation participates in a Rho- dependent
      signalling pathway that is required for immediate early gene expression.

PMID- 12492481
TI  - Binding of activated Factor XII to endothelial cells affects its inactivation by
      the C1-esterase inhibitor.
AB  - It is well known that activated Factor XII (FXIIa) and kallikrein are rapidly
      inactivated in plasma as a result of reaction with endogenous inhibitors. The
      purpose of this may be to prevent uncontrolled deleterious spreading and
      activation of target zymogens. Both FXII and the complex plasma
      prekallikrein/high molecular mass kininogen become activated when they bind, in a
      Zn2+-dependent manner, to receptors on human umbilical vein endothelial cells
      (HUVEC). The C1-esterase inhibitor (C1-INH) is by far the most efficient
      inhibitor of FXIIa. In the present study it has been investigated whether binding
      of FXIIa to HUVEC might offer protection against inactivation by C1-INH. It
      appeared that the relative amidolytic activity of purified FXIIa bound to the
      surface of HUVEC decreased according to the concentration of C1-INH in medium;
      however, the decrease was smaller than that measured for inactivation of FXIIa in
      solution. The secondary rate constant for the inactivation was 3-10-fold lower
      for cell-bound than for soluble FXIIa. The inactivation was found to be caused by
      C1-INH binding to cell-bound FXIIa. Accordingly, the amidolytic activity of
      saturated amounts of cell-bound FXIIa was reduced in the presence of C1-INH and
      was theoretically nonexistent at physiological C1-INH concentrations. Amidolytic
      activity was, however, present on HUVEC incubated with plasma indicating that the
      endogenous C1-INH did not completely abolish the activity of FXIIa generated
      during the incubation period. This supports the hypothesis that binding to
      endothelial cells protects the activated FXII against inactivation by its major
      endogenous inhibitor. Hence, the function of FXII may be localized at cellular
      surfaces.

PMID- 12492482
TI  - Fluorescence and FTIR study of pressure-induced structural modifications of horse
      liver alcohol dehydrogenase (HLADH).
AB  - The process of pressure-induced modification of horse liver alcohol dehydrogenase
      (HLADH) was followed by measuring in situ catalytic activity (up to 250 MPa),
      intrinsic fluorescence (0.1-600 MPa) and modifications of FTIR spectra (up to
      1000 MPa). The tryptophan fluorescence measurements and the kinetic data
      indicated that the pressure-induced denaturation of HLADH was a process involving
      several transitions and that the observed transient states have characteristic
      properties of molten globules. Low pressure (< 100 MPa) induced no important
      modification in the catalytic efficiency of the enzyme and slight conformational
      changes, characterized by a small decrease in the centre of spectral mass of the
      enzyme's intrinsic fluorescence: a native-like state was assumed. Higher
      pressures (100-400 MPa) induced a strong decrease of HLADH catalytic efficiency
      and further conformational changes. At 400 MPa, a dimeric molten globule-like
      state was proposed. Further increase of pressure (400-600 MPa) seemed to induce
      the dissociation of the dimer leading to a transition from the first dimeric
      molten globule state to a second monomeric molten globule. The existence of two
      independent structural domains in HLADH was assumed to explain this transition:
      these domains were supposed to have different stabilities against high pressure
      induced denaturation. FTIR spectroscopy was used to follow the changes in HLADH
      secondary structures. This technique confirmed that the intermediate states have
      a low degree of unfolding and that no completely denatured form seemed to be
      reached, even up to 1000 MPa.

PMID- 12492483
TI  - Characterization of native and recombinant A4 glyceraldehyde 3-phosphate
      dehydrogenase. Kinetic evidence for confromation changes upon association with
      the small protein CP12.
AB  - A4 glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was purified from the green
      alga Chlamydomonas reinhardtii and was also overexpressed in Escherichia coli.
      Both purified A4 tetramers of recombinant and native GAPDH were characterized for
      the first time. The pH optimum for both native and recombinant enzymes was close
      to 7.8. The pKs of the residues involved in catalysis indicate that a cysteine
      and a histidine may take part in catalysis by chloroplast GAPDH, as is the case
      for glycolytic GAPDH. Native and recombinant GAPDH show Michaelis-Menten kinetics
      with respect to their cofactors, NADH and NADPH, with greater specificity for
      NADPH. The kinetic parameters are similar to those of the heterotetrameric A2B2
      spinach chloroplast GAPDH. Native C. reinhardtii and recombinant GAPDHs exhibit a
      cooperative behavior towards the substrate 1,3-bisphosphoglycerate (BPGA). This
      positive cooperativity is specific to the C. reinhardtii enzyme, as higher plant
      A2B2 GAPDHs show Michaelis-Menten kinetics. Native GAPDH has twofold lower
      catalytic constant and K0.5 for BPGA than recombinant GAPDH. Mass spectrometry
      analysis of native GAPDH shows that it is a complex of GAPDH and the small
      protein CP12. In vitro reconstitution assays indicate that the kinetic
      differences are the result conformation changes of GAPDH upon association with
      CP12.

PMID- 12492484
TI  - Molecular characterization of artemin and ferritin from Artemia franciscana.
AB  - Embryos of the brine shrimp, Artemia franciscana, exhibit remarkable resistance
      to physiological stress, which is temporally correlated with the presence of two
      proteins, one a small heat shock/alpha-crystallin protein termed p26 and the
      other called artemin, of unknown function. Artemin was sequenced previously by
      Edman degradation, and its relationship to ferritin, an iron storage protein,
      established. The isolation from an Artemia expressed sequence tag library of
      artemin and ferritin cDNAs extends this work. Artemin cDNA was found to contain
      an ORF of 693 nucleotides, and its deduced amino-acid sequence, except for the
      initiator methionine, was identical with that determined previously. Ferritin
      cDNA is 725 bp in length with an ORF of 516 nucleotides. Artemin amino-acid
      residues 32-185 are most similar to ferritin, but artemin is enriched in
      cysteines. The abundance of cysteines and their intramolecular spatial
      distribution suggest that artemin protects embryos against oxidative damage
      and/or that its function is redox regulated. The conserved regions in artemin and
      ferritin monomers are structurally similar to one another and both proteins
      assemble into oligomers. However, modeling of the quaternary structure indicated
      that artemin multimers lack the central space used for metal storage that
      characterizes ferritin oligomers, implying different roles for this protein.
      Probing of Northern blots revealed two artemin transcripts, one of 3.5 kb and
      another of 2.2 kb. These transcripts decreased in parallel and had almost
      disappeared by 16 h of development. The ferritin transcript of 0.8 kb increased
      slightly during reinitiation of development, then declined, and was almost
      completely gone by 16 h. Clearly, the loss of artemin and ferritin during embryo
      development is due to transcriptional regulation and proteolytic degradation of
      the proteins.

PMID- 12492485
TI  - A hydrophobic segment within the C-terminal domain is essential for both client
      binding and dimer formation of the HSP90-family molecular chaperone.
AB  - The alpha isoform of human 90-kDa heat shock protein (HSP90alpha) is composed of
      three domains: the N-terminal (residues 1-400); middle (residues 401-615) and C
      terminal (residues 621-732). The middle domain is simultaneously associated with
      the N- and C-terminal domains, and the interaction with the latter mediates the
      dimeric configuration of HSP90. Besides one in the N-terminal domain, an
      additional client-binding site exists in the C-terminal domain of HSP90. The aim
      of the present study is to elucidate the regions within the C-terminal domain
      responsible for the bindings to the middle domain and to a client protein, and to
      define the relationship between the two functions. A bacterial two-hybrid system
      revealed that residues 650-697 of HSP90alpha were essential for the binding to
      the middle domain. An almost identical region (residues 657-720) was required for
      the suppression of heat-induced aggregation of citrate synthase, a model client
      protein. Replacement of either Leu665-Leu666 or Leu671-Leu672 to Ser-Ser within
      the hydrophobic segment (residues 662-678) of the C-terminal domain caused the
      loss of bindings to both the middle domain and the client protein. The
      interaction between the middle and C-terminal domains was also found in human 94
      kDa glucose-regulated protein. Moreover, Escherichia coli HtpG, a bacterial HSP90
      homologue, formed heterodimeric complexes with HSP90alpha and the 94-kDa glucose
      regulated protein through their middle-C-terminal domains. Taken together, it is
      concluded that the identical region including the hydrophobic segment of the C
      terminal domain is essential for both the client binding and dimer formation of
      the HSP90-family molecular chaperone and that the dimeric configuration appears
      to be similar in the HSP90-family proteins.

PMID- 12492486
TI  - Thermoanaerobacterium thermosulfurigenes cyclodextrin glycosyltransferase.
AB  - Cyclodextrin glycosyltransferase (CGTase) uses an alpha-retaining double
      displacement mechanism to catalyze three distinct transglycosylation reactions.
      To investigate these reactions as catalyzed by the CGTase from
      Thermoanaerobacterium thermosulfurigenes the enzyme was overproduced (8 mg.L(-1)
      culture) using Bacillus subtilis as a host. Detailed analysis revealed that the
      three reactions proceed via different kinetic mechanisms. The cyclization
      reaction (cyclodextrin formation from starch) is a one-substrate reaction,
      whereas the other two transglycosylation reactions are two-substrate reactions,
      which obey substituted enzyme mechanism kinetics (disproportionation reaction) or
      ternary complex mechanism kinetics (coupling reaction). Analysis of the effects
      of acarbose and cyclodextrins on the disproportionation reaction revealed that
      cyclodextrins are competitive inhibitors, whereas acarbose is a mixed type of
      inhibitor. Our results show that one molecule of acarbose binds either in the
      active site of the free enzyme, or at a secondary site of the enzyme-substrate
      complex. The mixed inhibition thus indicates the existence of a secondary sugar
      binding site near the active site of T. thermosulfurigenes CGTase.

PMID- 12492487
TI  - The effect of ST2 gene product on anchorage-independent growth of a glioblastoma
      cell line, T98G.
AB  - The ST2 gene, which is specifically induced by growth stimulation in fibroblasts,
      encodes interleukin-1 receptor-related proteins and is widely expressed in
      hematopoietic, helper T, and various cancer cells. However, the physiological as
      well as pathological functions of the ST2 gene products are not yet fully
      understood. In this study, we analyzed the expression of the ST2 gene in human
      glioma cell lines and human brain tumor samples with real-time polymerase chain
      reaction method, the results of which revealed that the expression level of the
      ST2 gene in glioma cell lines and glioblastoma samples is significantly lower
      than that in a fibroblastic cell line, TM12, and benign brain tumors, suggesting
      the reverse relationship between malignancy and ST2 expression. As we could not
      detect the soluble ST2 protein in the culture fluid of the T98G glioblastic cell
      line by ELISA, we established stable transformants of T98G that continuously
      produce and secrete the ST2 protein, in order to study the effect of the ST2
      protein on malignancy. Although we could not detect a remarkable difference in
      proliferation between transformants and control cells in conventional tissue
      culture dishes, the efficiency of colony formation in soft agar was significantly
      decreased in the case of cells that continuously produce the ST2 protein.
      Furthermore, inhibition of colony formation in soft agar was observed in wild
      type T98G cells when purified soluble ST2 protein was added to the culture, in a
      dose-dependent manner. Taken together, the results suggest that the expression of
      ST2 suppressed the anchorage-independent growth and malignancy.

PMID- 12492488
TI  - Kininogen-derived peptides for investigating the putative vasoactive properties
      of human cathepsins K and L.
AB  - Macrophages at an inflammatory site release massive amounts of proteolytic
      enzymes, including lysosomal cysteine proteases, which colocalize with their
      circulating, tight-binding inhibitors (cystatins, kininogens), so modifying the
      protease/antiprotease equilibrium in favor of enhanced proteolysis. We have
      explored the ability of human cathepsins B, K and L to participate in the
      production of kinins, using kininogens and synthetic peptides that mimic the
      insertion sites of bradykinin on human kininogens. Although both cathepsins
      processed high-molecular weight kininogen under stoichiometric conditions, only
      cathepsin L generated significant amounts of immunoreactive kinins. Cathepsin L
      exhibited higher specificity constants (kcat/Km) than tissue kallikrein (hK1),
      and similar Michaelis constants towards kininogen-derived synthetic substrates. A
      20-mer peptide, whose sequence encompassed kininogen residues Ile376 to Ile393,
      released bradykinin (BK; 80%) and Lys-bradykinin (20%) when incubated with
      cathepsin L. By contrast, cathepsin K did not release any kinin, but a truncated
      kinin metabolite BK(5-9) [FSPFR(385-389)]. Accordingly cathepsin K rapidly
      produced BK(5-9) from bradykinin and Lys-bradykinin, and BK(5-8) from des-Arg9
      bradykinin, by cleaving the Gly384-Phe385 bond. Data suggest that extracellular
      cysteine proteases may participate in the regulation of kinin levels at
      inflammatory sites, and clearly support that cathepsin K may act as a potent
      kininase.

PMID- 12492489
TI  - It's not my fault, blame it on my microenvironment.

PMID- 12492490
TI  - Role of stroma in carcinogenesis of the prostate.
AB  - Prostatic development is induced by androgens acting via mesenchymal-epithelial
      interactions. Androgens elicit their morphogenetic effects by acting through
      androgen receptors (ARs) in urogenital sinus mesenchyme (UGM), which induces
      prostatic epithelial development. In adulthood reciprocal homeostatic stromal
      epithelial interactions maintain functional differentiation and growth
      quiescence. Testosterone plus estradiol (T+E2) have been shown to induce
      prostatic carcinogenesis in animal models. Thus, tissue recombinant studies were
      undertaken to explore the mechanisms of prostatic carcinogenesis in BPH-1 cells
      in which ARs and estrogen receptors (ERs) are undetectable. For this purpose, BPH
      1 cells were combined with UGM, and the UGM+BPH-1 recombinants were grafted to
      adult male hosts. Solid branched epithelial cords and ductal structures formed in
      untreated UGM+BPH-1 recombinants. Growth was modest, and tumors did not develop.
      UGM+BPH-1 recombinants treated with T+E2 formed invasive carcinomas. BPH-1 cells
      lack ARs and ERs, whereas rat UGM expresses both of these receptors. These data
      show that immortalized nontumorigenic human prostatic epithelial cells can
      undergo hormonal carcinogenesis in response to T+E2 stimulation via paracrine
      mechanisms and demonstrate that the stromal environment plays an important role
      in mediating hormonal carcinogenesis. During prostatic carcinogenesis the stroma
      undergoes progressive loss of smooth muscle with the appearance of carcinoma
      associated fibroblasts (CAF). This altered stroma was tested for its ability to
      promote carcinogenesis of nontumorigenic but immortalized human prostatic
      epithelial cells (BPH-1). CAF+BPH-1 tissue recombinants formed large carcinomas.
      In contrast, recombinants composed of normal prostatic stroma+BPH-1 cells
      exhibited minimal growth. This stroma-induced malignant transformation was
      associated with additional genetic alterations and changes in gene expression.
      Thus, alteration in the stromal microenvironment was sufficient to promote
      malignant transformation of human prostatic epithelial cells.

PMID- 12492491
TI  - Tumor-stroma interactions directing phenotype and progression of epithelial skin
      tumor cells.
AB  - Tumor-stroma interactions play a significant role in tumor development and
      progression. Alterations in the stromal microenvironment, including enhanced
      vasculature (angiogenesis), modified extracellular matrix composition,
      inflammatory cells, and dys-balanced protease activity, are essential regulatory
      factors of tumor growth and invasion. Differential modulation of stromal
      characteristics is induced by epithelial skin tumor cells depending on their
      transformation stage when grown as surface transplants in vivo. Tumor cells can
      regulate the development of a "tumor-stroma" via the aberrant expression of
      growth factors or induction of growth factor receptors in the stromal
      compartment. In this context, secretion of the hematopoietic growth factors G-CSF
      and GM-CSF, constituitively expressed in enhanced malignant tumors, may be good
      candidates for induction of a tumor stroma through their effect on inflammatory
      cells. Upon its induction, the tumor stroma will reciprocally influence the
      differentiation status of tumor cells resulting in a normalization of benign
      tumor epithelia and the maintenance of a malignant phenotype, respectively. In
      the HaCaT model for squamous cell carcinoma of the skin, stromal activation and
      angiogenesis are transient in pre-malignant transplants, however they remain
      persistent in malignant transplants where progressive angiogenesis is closely
      correlated with tumor invasion. While continued expression of VEGF and PDGF are
      associated with benign tumor phenotypes, activation of VEGFR-2 is a hallmark of
      malignant tumors and accompanies ongoing angiogenesis and tumor invasion. As a
      consequence the inhibition of ongoing angiogenesis by blocking VEGFR-2 signalling
      resulted in dramatically impaired malignant tumor expansion and invasion.
      Comparably, tumor vascularization and invasion was blocked by disturbing the
      balance of matrix protease activity caused by a lack of PAI-1 in the stromal
      cells of the knockout mouse hosts. A similar inhibition of tumor vascularization
      was caused by TSP-1 over-expression in skin carcinoma cells, which also blocked
      tumor invasion and expansion. On the other hand, when granulation tissue and
      angiogenesis were only transiently activated as a result of stable transfection
      of PDGF into non-tumorigenic HaCaT cells, the target cells formed benign, but not
      malignant, tumors. Collectively, these data show that tumor vascularization,
      providing intimate association of blood vessels with tumor cells, is a
      prerequisite for tumor invasion. A potential mechanism for this interrelationship
      may be the differential regulation of MMP-expression in tumors of different
      grades of malignancy. In vitro MMP expression did not discriminate between benign
      and malignant tumor cells unless they were co-cultured with stromal fibroblasts.
      However, in vivo regulation of MMP expression was clearly dependent on tumor
      phenotype. While MMP-1 and MMP-13 were down-regulated in benign transplants, they
      were persistently up-regulated in malignant ones. A tight balance between
      proteases and their inhibitors is crucial for both the formation and infiltration
      of blood vessels and for tumor cell invasion, thus again emphasizing the
      importance of the stromal compartment for the development and progression of
      carcinomas.

PMID- 12492492
TI  - The organ microenvironment and cancer metastasis.
AB  - Primary neoplasms are biologically heterogeneous and the process of metastasis
      consists of a series of sequential, selective steps that few cells can complete.
      The outcome of cancer metastasis depends on multiple interactions between
      metastatic cells and homeostatic mechanisms that are unique to one or another
      organ microenvironment. The specific organ microenvironment determines the extent
      of cancer cell proliferation, angiogenesis, invasion, and survival. Therapy of
      metastasis should therefore be targeted not only against tumor cells, but also
      against the host factors that contribute to and support the progressive growth
      and survival of metastatic cancer cells.

PMID- 12492493
TI  - Prostate tumor-stroma interaction: molecular mechanisms and opportunities for
      therapeutic targeting.
AB  - Maintenance of cell and tissue homeostasis is dependent upon the dynamic balance
      of cell proliferation, differentiation, and apoptosis through interactions
      between cells and their microenvironment. The unique prostatic cellular
      phenotypes are induced and maintained by interaction between epithelium and
      adjacent stroma through intimate intercellular signaling pathways. In this
      article, we summarize current advances in the tumor-stroma interaction and its
      biologic and therapeutic implications. We specifically emphasize current studies
      of the possible factors driving the "vicious cycle" between stroma and emerging
      prostate tumor epithelial cells that may be responsible for carcinogenesis and
      metastasis to bone. Stroma responds both genotypically and phenotypically to
      tumor epithelium upon co-culture under 3-D conditions. Likewise, the emerging
      carcinoma responds to stromal signals that drive progression to malignancy. A
      vicious cycle mediated by soluble and insoluble molecules secreted by tumor cells
      and stroma appear be the critical factors supporting and sustaining tumor
      colonization in bone. Co-targeting tumor and stroma with therapeutic agents has
      yielded promising results both in pre-clinical models of prostate cancer and bony
      metastasis and in clinical trials of patients treated with a dual tumor and
      stroma targeting strategies. In conclusion, understanding and targeting the
      interaction of the tumor and its stromal microenvironmant may improve the
      prognosis, reduce the suffering and increase the survival of patients with
      advanced cancer metastasis.

PMID- 12492494
TI  - Melanoma development and progression: a conspiracy between tumor and host.
AB  - While a genome-centric paradigm in human cancer development was useful for the
      understanding of some malignancies such as leukemias, causative molecular defects
      intrinsic to melanocytes have not been defined in the majority of human
      melanomas. Recent work, however, has shown that regulatory signals governing
      melanocytic cell growth and differentiation may originate from the surrounding
      host cells either directly through physical contact or indirectly through soluble
      factors and extracellular matrix molecules. In this review, we present
      experimental systems useful for dissecting melanoma-host interactions and
      highlight evidence that the tumor microenvironment contributes to the oncogenic
      process. Thus, melanomagenesis is not merely an act of a single outlaw but a
      conspiracy orchestrated by multiple partners in the neighborhood who come into
      play in a precise spatiotemporal order. Defining intercellular molecular
      dialogues in human skin promises to provide key information for the development
      of novel treatment strategies that target the functional unit of stroma and
      tumor.

PMID- 12492495
TI  - The organizing principle: microenvironmental influences in the normal and
      malignant breast.
AB  - The current paradigm for cancer initiation and progression rests on the
      groundbreaking discoveries of oncogenes and tumor suppressor genes. This
      framework has revealed much about the role of genetic alterations in the
      underlying signaling pathways central to normal cellular function and to tumor
      progression. However, it is clear that single gene theories or even sequential
      acquisition of mutations underestimate the nature of the genetic and epigenetic
      changes in tumors, and do not account for the observation that many cancer
      susceptibility genes (e.g. BRCA1, APC) show a high degree of tissue specificity
      in their association with neoplastic transformation. Therefore, the cellular and
      tissue context itself must confer additional and crucial information necessary
      for mutated genes to exert their influence. A considerable body of evidence now
      shows that cell-cell and cell-extracellular matrix (ECM) interactions are
      essential organizing principles that help define the nature of the tissue
      context, and play a crucial role in regulating homeostasis and tissue
      specificity. How this context determines functional integrity, and how its loss
      can lead to malignancy, appears to have much to do with tissue structure and
      polarity.

PMID- 12492496
TI  - Cancer as a disease of epithelial-mesenchymal interactions and extracellular
      matrix regulation.
AB  - Carcinogenesis - the process of cancer formation - is commonly discussed in terms
      of genetic alterations that lead to deregulation of cell growth. Recently, there
      has been a resurgence of interest in epigenetic factors and, in particular, the
      role of the stromal microenvironment and angiogenesis in tumor formation. In this
      article, cancer is presented as a disease of the developmental processes that
      govern how cells organize into tissues and tissues into organs. This histogenetic
      perspective raises the possibility that epithelial-mesenchymal interactions and
      the extracellular matrix (basement membrane) that is deposited through these
      interactions may actively contribute to the carcinogenic process. Experimental
      work is reviewed that confirms that extracellular matrix plays a key role in
      normal histodifferentiation during both epitheliogenesis and angiogenesis, and
      that epigenetic deregulation of cell-matrix interactions may actively promote
      tumor initiation and progression. The contributions of integrins, cytoskeleton,
      tensegrity and local variations in extracellular matrix mechanics to these
      processes are discussed, as are the implications of this work for future studies
      on cancer formation.

PMID- 12492497
TI  - Matrix metalloproteinases in tumor-host cell communication.
AB  - The microenvironment or stroma immediately surrounding tumor cells consists of a
      three-dimensional extracellular matrix (ECM) and stromal cells such as
      fibroblasts and inflammatory cells. The matrix metalloproteinases (MMPs)
      constitute a family of over 24 members, which collectively are capable of
      degrading virtually the entire ECM. Strict regulation of MMP expression is
      critical in order to maintain proper ECM homeostasis, but in disease states such
      as cancer there is often a high level of MMP activity at the tumor-stroma
      interface. Several studies have documented the importance of MMP-mediated ECM
      destruction in the successful dissemination of several tumor types, but it has
      become increasingly clear that they are also involved in earlier stages of
      tumorigenesis. MMPs are implicated in a wide variety of roles that can assist
      tumor initiation, growth, migration, angiogenesis, the selection of apoptosis
      resistant subpopulations, and in invasion and metastasis. Interestingly, the
      factors responsible for many of these effects are derived from the cell surfaces
      of the tumor or stromal cells or are embedded in the ECM. Therefore, the MMPs can
      no longer be thought of solely as ECM destructionists, but as part of an elegant
      communication system through which the tumor interacts with the stroma.

PMID- 12492498
TI  - The tumor microenvironment: a potential arbitrator of the tumor suppressive and
      promoting actions of TGFbeta.
AB  - Transforming growth factor beta (TGFbeta) members are secreted in biologically
      inactive complexes that must be activated in order to enable binding to their
      cell surface receptors. Interestingly, many of the proteins that can activate
      TGFbeta have been implicated in either suppressing or promoting tumorigenesis.
      Included among these are matrix proteins (thrombospondin-1), receptors (integrins
      alphanubeta6 and alphanubeta8) and proteases (matrix metalloproteases and
      plasmin). These proteins cannot only activate TGFbeta, but can also modulate cell
      responsiveness to TGFbeta. In this section, we review data highlighting the
      complexity and bidirectionality of TGFbeta matrix interactions within the tumor
      microenvironment, and propose that these dynamic interactions are a critical
      spatial and temporal determinant of the effects of TGFbeta on tumorigenesis.

PMID- 12492499
TI  - Altered expression of the catenin p120 in human cancer: implications for tumor
      progression.
AB  - Tumor progression in epithelial tissues is characterized by a series of genetic
      and epigenetic changes that lead ultimately to metastasis. Alterations in E
      cadherin and its cytoplasmic regulators, the catenins, have been implicated as
      central to this process. Here, we focus on p120-catenin and its rising incidence
      in the pathology literature as a molecule altered in human tumors. The data show
      that p120 is frequently altered and/or lost in tumors of the colon, bladder,
      stomach, breast, prostate, lung, and pancreas. Moreover, in some cases p120 loss
      appears to be an early event in tumor progression, possibly preceding loss of E
      cadherin. Potential roles of p120 as a tumor suppressor or metastasis promoter
      are discussed.

PMID- 12492500
TI  - Motility cues in the tumor microenvironment.
AB  - It is now increasingly recognized that the microenvironment plays a critical role
      in the progression of tumors. Perhaps less obvious is the concept that the
      microenvironment may share responsibility in determining the "malignant" traits
      of tumor cells, i.e. invasiveness and metastasis. If tumors are tissues, however
      unbalanced, rather than a collection of "malignant" cells recruiting local
      resources for the purpose of growth, then it is inevitable that tumor cells will
      respond to local stimuli. These stimuli include cues for motility and migration,
      which normally appear in tissues undergoing formation, remodeling or healing.
      Carcinoma cells are likely to be sensitive to the motility cues that normally
      regulate epithelial morphogenetic movements such as ingression, delamination,
      invagination, and tube or sheet migration. "Malignant" tumors, then, can be
      redefined as those in which these cues arise more frequently or act more
      effectively. Here, we expand on this view and propose that invasion and
      metastasis may be the outcome of tumor cell responses to microenvironmental
      motility cues. Understanding how such motility cues arise and act, both in normal
      and tumor tissue, should be a high priority in cancer research.

PMID- 12492501
TI  - A paradigm for therapy-induced microenvironmental changes in solid tumors leading
      to drug resistance.
AB  - Intrinsic alterations in the tumor microenvironment are known to contribute to
      various forms of drug resistance. For example, tumor hypoxia, due to abnormal or
      sluggish blood flow within areas of solid tumors, can result in both
      microenvironment-mediated radiation and chemotherapeutic drug resistance. In
      contrast, acquired resistance to chemotherapy is generally considered to be the
      result of the gradual selection of mutant subpopulations having genetic mutations
      and biochemical alterations responsible for the resistant phenotype. Here we
      present a paradigm for therapyinduced microenvironment-mediated acquired drug
      resistance. It is based on the results showing that tumor cells appear to be
      heterogeneous in their relative dependence on adjacent tumor-associated
      vasculature for survival. Some tumor cells are highly vessel dependent, whereas
      some are significantly less so, and thus can survive in more hypoxic regions of
      tumors, distal from such tumor vessels. Hence, it is possible that variant tumor
      cells that are less vessel dependent may therefore be selected for over time by
      successful antiangiogenic drug therapies. This results in loss of response or
      attenuated responses to the therapy. Preliminary evidence is summarized in
      support of this hypothesis, using paired human colon cancer (HCT116) cell lines
      that contain two copies of either the wild-type or the disrupted p53 tumor
      suppressor gene. The mutant cells were found to be less responsive to
      antiangiogenic therapy, compared to the wild-type cells, and could be
      progressively selected for in mixed cell populations. Because p53 inactivation
      can lead to resistance to hypoxia-mediated apoptosis, the results suggest that a
      protracted and successful antiangiogenic therapy may create more hypoxic tumor
      microenvironments, thereby creating the necessary conditions to accelerate the
      selection of mutant tumor cells that are more adept in surviving and growing in
      such environments. As such, consideration might be given to the combined use of
      bioreductive hypoxic cell cytotoxic drugs and angiogenesis inhibitors to prolong
      the efficacy of antiangiogenic therapeutics.

PMID- 12492502
TI  - Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their
      microenvironment.
AB  - Matrix metalloproteinases (MMPs) have long been thought of as critical factors
      regulating matrix degradation associated with cell invasion into ectopic tissue
      compartments during primary tumor growth and metastasis. One member of the MMP
      family historically linked to these invasive processes is MMP-9/gelatinase B. By
      studying a transgenic mouse model of de novo epithelial carcinogenesis, new roles
      for MMP-9 have emerged that broaden the view of its functional contribution to
      malignant progression. The combined implication of these studies suggest that MMP
      9 functionally contributes to cancer development; however, its major regulatory
      role may be in its ability to activate poorly diffusible and/or matrix
      sequestered growth factors that regulate epithelial and/or endothelial cell
      growth as opposed to regulating cellular invasion across basement membranes.

PMID- 12492503
TI  - Enforced expression of FGF-7 promotes epithelial hyperplasia whereas a dominant
      negative FGFR2iiib promotes the emergence of neuroendocrine phenotype in prostate
      glands of transgenic mice.
AB  - The minimal rat probasin (PB) promoter was used to target expression of human
      fibroblast growth factor-7 (FGF-7)/keratinocyte growth factor (KGF) directly to
      prostatic epithelium of transgenic mice, converting FGF-7 from a paracrine to an
      autocrine factor. Four independent lines were established that expressed the
      transgene (PKS) in the prostate. Upon histologic analysis, the prostatic
      epithelium of PKS mice was found to be hyperplastic. Many of the prostatic ducts
      were filled with secretory epithelial cells tightly associated with a highly
      enfolded basement membrane. Distortions of the ductal smooth muscle layer were
      also observed. Prostates from year-old PKS mice had significantly more abnormal
      ducts than their wild-type nontransgenic littermates. The minimal rat PB promoter
      was also used to target a truncated FGFR2iiib receptor to prostatic epithelium to
      functionally abrogate endogenous FGF-7 signaling. Three lines were established
      that expressed the transgene (KDNR) in the prostate. Upon dissection it was noted
      that all four lobes of the prostates of KDNR mice were present but smaller in
      size. Histologic analysis indicated that the epithelium in many of the prostatic
      ducts was disorganized and contained numerous rounded cytokeratin-positive cells
      that were not tightly associated with the basement membrane. The stroma was
      disorganized and did not form a tight layer of smooth muscle around the
      epithelial ducts. Surprisingly, abrogation of FGF signaling in KDNR mice
      correlated with the emergence of a neuroendocrine-like phenotype that was not
      observed as a consequence of enforced FGF-7 expression in the PKS mice.

PMID- 12492504
TI  - Dedifferentiation of stromal smooth muscle as a factor in prostate
      carcinogenesis.
AB  - We had earlier established an animal model of prostate carcinogenesis using a
      combination of testosterone (T) and 17beta-estradiol benzoate (E2) on Noble rats
      (Wang and Wong, 1998). In the present study we examined the changes in a number
      of smooth muscle differentiation markers including smooth muscle alpha-actin and
      myosin, vinculin, desmin, laminin and vimentin as well as changes in fine
      structure by electron microscopy. Our immunohistochemical (IHC) studies revealed
      that smooth muscle cells (SMCs) subjacent to dysplastic (precancerous) sites and
      carcinoma usually exhibited a preferential loss of myosin, desmin and laminin.
      However, the expression of alpha-actin and vinculin appeared to be more
      persistent in most dysplastic or neoplastic sites. The study reaffirmed our
      earlier observation that there was a concurrent dedifferentiation of surrounding
      SMCs during the development and progression of prostate carcinogenesis. The
      structural study revealed that SMC subjacent to epithelial dysplasia displayed a
      spectrum of derangements. These included the loosening of muscular layers with
      SMC characterized by their highly irregular external contours with numerous spine
      like cytoplasmic projections. There was also a reduction in density of
      myofilaments and presence of many enlarged caveolae in muscle cells.
      Additionally, focal discontinuity or disruptions of muscular layer were often
      observed together with an increase in abundance of fibrous connective tissue.
      Moreover, the amount of smooth muscle appeared to be inversely correlated with
      the histologic grade of prostate tumors. In most instances, SMCs were totally
      absent in the moderately or poorly differentiated tumors and in metastatic tumors
      in the lung and the small intestine. Stromal muscular deformity was associated
      with concurrent changes in epithelial cells. Dysplastic epithelial cells were
      characterized by a reduction in abundance of secretory organelles such as
      reduction in size of Golgi apparatus, paucity of granular endoplasmic reticulum
      and secretory vesicles. The nuclei showed typical deformity characterized by deep
      nuclear membrane foldings. The basal lamina of dysplastic or tumor cells was
      present although focal structural abnormalities such as reduplication, disruption
      and smearing were sometimes observed. The present data indicate that derangements
      of epithelial cells during prostate carcinogenesis are associated with a
      reduction or dedifferentiation of stromal SMCs. Our results lend support to the
      hypothesis that transformed epithelium is incapable of maintaining normal
      differentiation of adjacent muscle. In turn, abnormal stromal, resulting from
      dedifferentiation or reduction of SMC, may lead to loss of stromal control over
      epithelial proliferation and differentiation. Consequently, a loss of
      differentiation in both epithelium and stromal SMCs may be critically involved in
      hormone-induced prostate carcinogenesis.

PMID- 12492505
TI  - beta-Catenin in early development of the lancelet embryo indicates specific
      determination of embryonic polarity.
AB  - The lancelet (amphioxus) embryo develops from a miolecithal egg and starts
      gastrulation when it is approximately 400 cells in size, in a fashion similar to
      that of some non-chordate deuterostomes. Throughout this type of gastrulation,
      the embryo develops characteristics such as the notochord and hollow nerve cord
      that commonly appear in chordates. beta-Catenin is an important factor in
      initiating body patterning. The behavior and developmental pattern of this
      protein in early lancelet development was examined in this study. Cytoplasmic
      beta-catenin was localized to the animal pole after fertilization and then was
      incorporated asymmetrically into the blastomeres during the first cleavage.
      Asymmetric distribution was observed at least until the 32-cell stage. The first
      nuclear localization was at the 64-cell stage, and involved all of the cells. At
      the initial gastrula stage, however, concentrated beta-catenin was found on the
      dorsal side. LiCl treatment affected the asymmetric pattern of beta-catenin
      during the first cleavage. LiCl also changed distribution of nuclear beta-catenin
      at the initial gastrula stage: distribution extended to cells on the animal side.
      Apparently associated with this change, expression domains of goosecoid, lhx3 and
      otx also changed to a radially symmetric pattern centered at the animal pole.
      However, LiCl-treated embryos were able to establish embryonic polarity. The
      present study suggests that in the lancelet embryo, polarity determination is
      independent of dorsal morphogenesis.

PMID- 12492506
TI  - Larval antigen molecules recognized by adult immune cells of inbred Xenopus
      laevis: partial characterization and implication in metamorphosis.
AB  - It has been shown that larval skin (LS) grafts are rejected by an inbred strain
      of adult Xenopus, which suggests a mechanism of metamorphosis by which larval
      cells are recognized and attacked by the newly differentiating immune system,
      including T lymphocytes. In an attempt to define the larval antigenic molecules
      that are targeted by the adult immune system, anti-LS antibodies (IgY) were
      produced by immunizing adult frogs with syngeneic LS grafts. The antigen
      molecules that reacted specifically with this anti-LS antiserum were localized
      only in the larval epidermal cells. Of 53 and 59-60 kDa acidic proteins that were
      reactive with anti-LS antibodies, a protein of 59 kDa and with an isoelectric
      point of 4.5 was selected for determination of a 19 amino acid sequence (larval
      peptide). The rat antiserum raised against this peptide was specifically reactive
      with the 59 kDa molecules of LS lysates. Immunofluorescence studies using these
      antisera revealed that the larval-specific molecules were localized in both the
      tail and trunk epidermis of premetamorphic larvae, but were reduced in the trunk
      regions during metamorphosis, and at the climax stage of metamorphosis were
      detected only in the regressing tail epidermis. Culture of splenocytes from LS
      immunized adult frogs in the presence of larval peptide induced augmented
      proliferative responses. Cultures of larval tail pieces in T cell-enriched
      splenocytes from normal frogs or in natural killer (NK)-cell-enriched splenocytes
      from early thymectomized frogs both resulted in significant destruction of tail
      pieces. Tissue destruction in the latter was enhanced when anti-LS antiserum was
      added to the culture. These results indicate that degeneration of tail tissues
      during metamorphosis is induced by a mechanism such that the larval-specific
      antigen molecules expressed in the tail epidermis are recognized as foreign by
      the newly developing adult immune system, and destroyed by cytotoxic T
      lymphocytes and/or NK cells.

PMID- 12492507
TI  - Localization of gamma-tubulin and cyclin B during early cleavage in
      physiologically polyspermic newt eggs.
AB  - To understand the mechanism of the very slow block to polyspermy in
      physiologically polyspermic eggs of the newt Cynops pyrrhogaster, we used
      confocal laser microscopy to determine the distribution of gamma-tubulin and
      cyclin B1 in fertilized eggs. More gamma-tubulin was localized in the animal
      hemisphere than in the vegetal. The centrosomes of the principal sperm nucleus
      and the zygote nucleus had much accumulated gamma-tubulin, but little gamma
      tubulin was associated with the centrosomes of the accessory sperm nuclei. These
      results are consistent with observations that the largest sperm aster is
      associated with the principal sperm nucleus. More cyclin B1 appeared in the
      animal hemisphere than in the vegetal at the end of interphase. The zygote
      nucleus had much accumulated cyclin B1, but little cyclin B1 was associated with
      the accessory sperm nuclei. Cyclin B1 disappeared earlier around the zygote
      nucleus at metaphase than around the accessory sperm nuclei. These findings
      correspond well with the earlier entry and exit into metaphase in the zygote
      nucleus than in the accessory sperm nuclei in newt eggs, supporting our
      maturation-promoting factor (MPF) model that accounts for the mechanism of
      nuclear degeneration in physiologically polyspermic eggs. Cyclin B1 began to
      accumulate in the nucleus during interphase in synchronous cleavage, and its
      greatest expression was in the centrosomes and the nucleus at prometaphase.

PMID- 12492508
TI  - Involvement of the signal transduction pathway mediated by epidermal growth
      factor receptor in the differentiation of chicken glandular stomach.
AB  - During the development of the chicken proventriculus (glandular stomach), the
      initially undifferentiated epithelium differentiates into two distinct cell
      populations: the glandular epithelium, cells of which secrete embryonic chicken
      pepsinogen (ECPg), and luminal epithelial cells, which express the chicken
      spasmolytic polypeptide gene (cSP). Based on knowledge of the adult mouse
      stomach, the ligands of epidermal growth factor (EGF) receptor (EGFR) were
      expected to affect differentiation of the proventricular epithelium. When EGF was
      added to the medium in which proventriculi were cultured in vitro, gland
      formation was suppressed in a dose-dependent manner and the amount of ECPg mRNA
      decreased, whereas morphological differentiation of luminal epithelium was
      stimulated. Simultaneous treatment of the proventriculus with EGF and tyrphostin
      47 resulted in the attenuation of the effect of EGF, suggesting that EGF, or
      other ligands of EGFR, may actually be involved in the normal course of
      development of the proventricular epithelium.

PMID- 12492509
TI  - Expression of FTZ-F1alpha in transgenic Xenopus embryos and oocytes.
AB  - Fushi tarazu transcription factor-1 (FTZ-F1) was originally found as a regulator
      of fushi tarazu gene expression in Drosophila. The frog homologue (FTZ-F1alpha)
      and the 3.5 kb 5'-flanking region of the FTZ-F1alpha gene have been cloned, and
      it has been shown by reverse transcription-polymerase chain reaction that FTZ
      F1alpha expression begins in embryos at stage 11 and becomes stronger after that.
      By in situ hybridization analysis, the FTZ-F1alpha mRNA was also found in
      immature frog oocytes. In this study, immunohistology revealed that the product
      of FTZ-F1alpha was localized in the cytoplasm of the immature oocyte. To analyze
      the promoter activity of the Rana rugosa FTZ-F1alpha gene, transgenic Xenopus
      were produced carrying the fusion construct, consisting of truncated 5'-flanking
      regions (3.0, 1.8 and 0.3 kb) of the FTZ-F1alpha gene and the green fluorescent
      protein (GFP) open reading frame. The 0.3 kb 5'-flanking region could drive GFP
      expression in Xenopus embryos at stage 20 and in immature oocytes in the ovary 2
      months after metamorphosis. Gel mobility shift assay was used to test whether
      proteins in extracts from Xenopus embryos and ovaries bound to the 0.3 kb DNA.
      The extract from embryos at stage 11 formed one retarded band. The extract from
      ovaries formed a different retarded band. The results, taken together, indicate
      that production of transgenic Xenopus is very useful for the analysis of the
      promoter activity of genes in amphibians. The results also suggest that at least
      two proteins (one in the embryo and the other in the ovary of 2-month-old
      postmetamorphosing Xenopus) bind the 0.3 kb 5'-flanking region of the FTZ-F1alpha
      gene. These proteins may be involved in the regulation of FTZ-F1alpha gene
      expression in amphibians.

PMID- 12492510
TI  - Foot formation in hydra: commitment of the basal disk cells in the lower
      peduncle.
AB  - Foot regeneration in the freshwater hydra Pelmatohydra robusta was examined using
      a monoclonal antibody AE03 as a marker. This antibody specifically recognizes
      mucous-producing ectodermal epithelial cells in the basal disk, but not cells in
      the peduncle region located just above the basal disk in the foot. When the basal
      disk was removed by amputation at the upper or lower part of the peduncle, AE03
      positive (basal disk) cells always appeared at the regenerating tip of the
      footless polyp approximately 12-16 h later. When a small piece of tissue was cut
      out from the upper or lower peduncle region, the tissue invariably turned into a
      smooth spherical or oblong shape within a few hours. AE03 signal appeared in
      these spheres variably depending on their origin: when tissue pieces were derived
      from the lower peduncle, the signal appeared in nearly all pieces and often
      covered the entire surface of the pieces within 24 h. In contrast, the signal
      appeared in less than 10% of pieces derived from the upper peduncle. Furthermore,
      the signal seldom covered more than half of the surface of these pieces. When
      maintained for many days, pieces derived from the upper peduncle often
      regenerated tentacles, whereas those from the lower peduncle seldom did. These
      and other observations suggest that epithelial cells in the peduncle can rapidly
      differentiate into basal disk cells when the basal tissue is removed. However,
      cells in the upper peduncle are not irreversibly committed to differentiate into
      basal disk cells because, when cut out as small tissue pieces, they could remain
      AE03 negative and become tentacle cells. In contrast, the cells in the lower
      peduncle apparently are irreversibly committed to differentiate into basal disk
      cells, as they always turned rapidly into AE03-positive cells once they were
      physically separated from (and freed from the influence of) the basal disk
      itself, regardless of the separation methods used.

PMID- 12492511
TI  - Bidder's organ in the toad Bufo marinus: effects of orchidectomy on the
      morphology and expression of lamina-associated polypeptide 2.
AB  - The Bidder's organ is an undeveloped ovary located anterior to the testis in male
      true toads (Bufonidae). The presence of sperm and oocytes, derived from the
      primordial germ cells of the male toad, provides an exceptional condition for the
      study of germ cell differentiation in vertebrates. In this study, the effects of
      orchidectomy on morphology and on lamina-associated polypeptide 2 (LAP2)
      expression were investigated in the Bidder's organ of Bufo marinus. To
      characterize bidderian oocytes, oogenesis in the ovary was divided into six
      stages. It was found that ovarian and bidderian oocytes were morphologically
      identical. To determine the expression of LAP2 isoforms, oocytes from the ovary
      and the Bidder's organ were examined by sodium dodecylsulfate-polyacrylamide gel
      electrophoresis and immunoblotting. In amphibians, LAP2beta is expressed in
      somatic cells, whereas LAP2omega is expressed in oocytes. The Bidder's organ
      normally contained previtellogenic oocytes of less than 150 micro m in diameter
      that expressed LAP2beta. However, the organ in some male toads contained a few
      larger oocytes, resulting in the faint detection of LAP2omega. After
      orchidectomy, bidderian oocytes grew and strongly expressed LAP2omega. Moreover,
      as in the ovary, LAP2omega was upregulated in bidderian oocytes of 240 microm in
      diameter. This work represents the first demonstration of the molecular
      similarity between ovarian and bidderian oocytes.

PMID- 12492512
TI  - Knockdown of connexin43-mediated regulation of the zone of polarizing activity in
      the developing chick limb leads to digit truncation.
AB  - In the developing chick wing, the use of antisense oligodeoxynucleotides to
      transiently knock down the expression of the gap junction protein, connexin43
      (Cx43), results in limb patterning defects, including deletion of the anterior
      digits. To understand more about how such defects arise, the effects of transient
      Cx43 knockdown on the expression patterns of several genes known to play pivotal
      roles in limb formation were examined. Sonic hedgehog (Shh), which is normally
      expressed in the zone of polarizing activity (ZPA) and is required to maintain
      both the ZPA and the apical ectodermal ridge (AER), was found to be downregulated
      in treated limbs within 30 h. Bone morphogenetic protein-2 (Bmp-2), a gene
      downstream of Shh, was similarly downregulated. Fibroblast growth factor-8
      expression, however, was unaltered 30 h after treatment but was greatly reduced
      at 48 h post-treatment, when the AER begins to regress. Expressions of Bmp-4 and
      Muscle segment homeobox-like gene (Msx-1) were not affected at any of the time
      points examined. Cx43 expression is therefore involved in some, but not all
      patterning cascades, and appears to play a role in the regulation of ZPA
      activity.

PMID- 12492514
TI  - Quantification of DNA synthesis in multicellular organisms by a combined DAPI and
      BrdU technique.
AB  - The development of a novel method to detect and quantify mitotic activity in
      multicellular organisms is reported. The method is based on the combinatorial use
      of 4',6-diamidino-2-phenylindole (DAPI) as a dye for the specific staining of DNA
      and the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) as a marker for DNA
      synthesis. It is shown that on nitrocellulose filters, the amount of DNA can be
      determined by DAPI as a prerequisite for the subsequent quantification of mitotic
      activity by BrdU. As a model system to prove the applicability of this technique,
      the blood fluke Schistosoma mansoni has been used. It is demonstrated that the
      DNA synthesis rate is higher in adult female schistosomes than in adult males.
      Furthermore, dimethyl sulfoxide, a widely used solvent for many mitogens and
      inhibitors of mitosis, has no influence on mitotic activity in adult
      schistosomes.

PMID- 12492513
TI  - In vitro Cre/loxP system in cells from developing gonads: investigation of the
      Sry promoter.
AB  - There have been few studies on the regulatory elements of the Sry gene, mainly
      because no Sry-expressing cell lines have yet been established. This paper
      describes a useful tool for investigating the regulation and upstream region of
      Sry by means of the in vitro Cre/loxP system. Using plasmids containing the 9.9
      kb mouse genomic Sry previously shown to induce testis development in XX
      transgenic mice, we constructed a Sry/Cre fusion gene plasmid in which Cre
      expression is controlled by the 5' and 3' untranslated regions of mouse Sry. To
      distinguish between male and female gonads of 11.5 days post-coitus (d.p.c.)
      fetuses, double transgenic fetuses carrying both the CAG (cytomegalovirus
      enhancer and beta-actin promoter)/loxP/lacZ transgene on the autosome and the
      green fluorescent protein transgene ubiquitously expressed on the Y chromosome
      were produced by crossing between two transgenic mouse lines. When Sry/Cre
      plasmids were transfected into the cells that had been prepared from the gonads,
      brains and livers of double transgenic fetuses, only a small number of X-gal
      stained cells were detected among the primary cultured cells from male and female
      gonads, and none were detected among the cells from the other tissues. The X-gal
      positive cells were negative for alkaline phosphatase, indicating that these
      cells were somatic cells expressing Sry. The Sry/Cre plasmids with a 0.4 kb
      upstream region of Sry yielded a large number of X-gal-positive cells in the
      cells from gonads, including various tissues of 11.5 d.p.c. fetuses, indicating
      the loss of the tissue-specific expression of Sry. The Sry/Cre with a 1.4 kb
      upstream region maintained tissue-specific activity of Sry. The results indicate
      that the present in vitro Cre/loxP system using transgenic mice is a simple and
      useful system for investigating the regulatory element of sex determination
      related genes, including Sry.

PMID- 12492516
TI  - Contact sensitization from Compositae-containing herbal remedies and cosmetics.
AB  - The Compositae (Asteraceae) family of plants is currently an important cause of
      allergic plant contact dermatitis in Europe. The family comprises some of the
      oldest and most valued medicinal plants, and the increasing popularity of herbal
      medicine and cosmetics may theoretically result in a growing number of Compositae
      sensitizations from these sources. According to the literature at least 15
      species, including among others arnica (Arnica montana), German and Roman
      chamomile (Chamomilla recutita and Chamaemelum nobile), marigold (Calendula
      officinalis), Echinacea and elecampane (Inula helenium), have been suspected of
      sensitization or elicitation of Compositae dermatitis. Epidemiological data are
      available for 2 species only, arnica and German chamomile, the rest of the
      evidence being anecdotal. Based on this, sensitization seems to occur relatively
      frequently with a few species such as arnica and elecampane, and occurs rarely
      with the majority, especially the widely used German chamomile. Sesquiterpene
      lactones are the most important allergens, but there are a few cases of
      sensitization from a coumarin, a sesquiterpene alcohol and a thiophene. The risk
      of elicitation of dermatitis by using Compositae-containing products in
      Compositae-sensitive individuals is by-and-large unknown.

PMID- 12492517
TI  - Implementation of fatty acid carriers to skin irritation and the epidermal
      barrier.
AB  - Acute perturbations are followed by barrier repair and enhanced lipid synthesis,
      as well as cellular fatty acid trafficking, yet irritation of the skin may be
      induced by repeat disturbance of barrier function. Recently, new insights in
      cellular fatty acid transport and metabolism have evolved with respect to skin
      irritation and barrier disturbances: (1) Employing sodium dodecyl sulfate, skin
      irritation is accompanied by the induction of an epidermal (E) cytosolic fatty
      acid binding protein (FABP) associated with enhanced barrier repair. Whether E
      FABP contributes to the water barrier function in normal skin remains to be
      elucidated; (2) Cutaneous inflammation, as it occurs in irritant contact
      dermatitis, can be reduced by peroxisome proliferating activated receptor (PPAR)
      agonists, such as linoleic acid, with clinical effects comparable to that of
      glucocorticoids; (3) PPARalpha agonists accelerate barrier recovery and enhance
      lamellar body synthesis, neutral lipid synthesis, in particular that of ceramides
      and cholesterol; (4) PPARalpha agonists increase the minimal erythema dose in UVB
      irradiated human skin. This review provides a brief overview of the current
      understanding of mammalian fatty acid (FA) metabolism with respect to epidermal
      barrier abrogation and repair, including new insights into cellular FA transport
      and metabolism.

PMID- 12492518
TI  - Contact hypersensitivity in hand dermatitis.
AB  - Contact hypersensitivity (CHS) in hand dermatitis (HD) was studied by patch
      testing (PT) 105 consecutive adult HD patients and 361 cases of suspected non
      hand allergic contact dermatitis (NHD). The suspected offending agents were also
      investigated by a questionnaire. Age and sex distribution was no different
      between the 2 groups. The total positivity rate of PT in the HD group was much
      lower than in the control group (46.7% versus 63.2%, p < 0.01, chi2-test). The
      most common allergens in HD were rubber mix(17.1%), p-phenylenediamine (PPD)
      (14.3%), fragrance mix (9.5%), nickel (9.5%), colophonium (6.7%) and potassium
      dichromate (2.9%), while those in the control group, in sequence, were nickel
      (20.5%), rubber mix (16.9%), PPD (14.1%), fragrance mix (12.7%), potassium
      dichromate (5.5%) and colophonium (5.0%). The positivity rate to nickel was lower
      in the HD group (9.5% versus 20.5%, p < 0.05, chi2-test), while there was no
      significant difference for the other allergens. HD was divided arbitrarily into 5
      groups: (1) vesicular form, in which fine papules and vesicles can be detected.
      65.7% of the HD was vesicular form and 55.1% of them were PT positive; (2)
      fissured form, in which dry skin with fine fissures or desquamation is seen. 8.6%
      of the HD was fissured form and 30% of them were PT positive; (3) hyperkeratotic
      form, in which the lesions are thick, hyperkeratotic plaques - 6.7% of the HD was
      this form and no positive reaction was found; (4) hand and foot dermatitis (HFD) 
      12.4% of HD was HFD and 53.8% of them were PT positive; (5) pompholyx - 6.7% of
      the patients had pompholyx and one positive result to nickel was detected. The
      suspected offending agents were reported in only 13 (12.4%) patients. These
      results suggest that CHS is less common in HD than in NHD and that other factors,
      such as skin irritation, may play more of a role in HD. Nickel allergy is less
      common in HD than in NHD. CHS may play a role in more than 1/2 of vesicular form
      HD, HFD and in some fissured HD also, but is less common in hyperkeratotic HD and
      pompholyx. Only a small proportion of the HD patients could report the suspected
      offending agents and PT should be performed in all patients with chronic HD.

PMID- 12492519
TI  - Topical immunotherapy with contact sensitizers: a model to study the natural
      history of delayed hypersensitivity.
AB  - So-called 'topical immunotherapy' (TI) is a well-established treatment modality
      based on the use of potent contact sensitizers, such as squaric acid dibutylester
      (SADBE), that are not found in the general or occupational environment of man,
      and do not induce cross-sensitization to other substances. Thus, unlike patients
      with sensitivity to other more or less commonplace allergens, subjects submitted
      to this treatment modality might provide useful data for the study of the natural
      course of contact sensitivity. On the basis of these premises, we have
      retrospectively reviewed 40 patients who had consecutively received TI with SADBE
      for severe alopecia areata and viral warts in the period 1993-2001, and returned
      to visit after a 1-7-year period since the last therapeutic challenge with the
      sensitizer. The chronological profile of loss of contact sensitization of this
      case cohort has been evaluated and compared to that of other series available in
      the literature. Provided more standardized TI application procedures are
      established, aim-oriented studies of the outcome of this treatment modality may
      bring useful data to be employed in construction of predictive models of decay of
      contact sensitization under conditions of antigen avoidance.

PMID- 12492520
TI  - Anaphylaxis due to formaldehyde released from root-canal disinfectant.
AB  - A 50-year-old woman developed anaphylaxis 8 h after application of a
      paraformaldehyde-containing root canal disinfectant. Radioallergosorbent test
      showed that she had a high level of formaldehyde-specific IgE in her serum. Prick
      tests to formaldehyde and paraformaldehyde showed immediate-type responses to
      both. We reviewed the literature describing cases with anaphylaxis/angioedma
      caused by formaldehyde in root canal disinfectants and found that about 1/2 of
      the reported cases developed symptoms over 2 h after dental treatment. We
      speculated that the delay in the manifestation of her symptoms was possibly due
      to gradual formaldehyde release from paraformaldehyde and time lag of penetrating
      and diffusing of formaldehyde outside the dentin. Patch testing showed that she
      also had delayed-type allergy to formaldehyde, paraformaldehyde and eugenol.
      Physicians should pay attention to root canal disinfectants, even if anaphylaxis
      occurs several hours after dental treatment.

PMID- 12492521
TI  - Structure-activity relationships for selected fragrance allergens.
AB  - Fragrance substances represent a very diverse group of chemicals, a proportion of
      them providing not only desirable aroma characteristics, but also being
      associated with adverse effects, notably the ability to cause allergic reactions
      in the skin. However, efforts to find substitute materials are hampered by the
      need to undertake animal testing to evaluate both the presence and the degree of
      skin sensitization hazard. One potential route to avoid such testing is to
      understand the relationships between chemical structure and skin sensitization.
      In the present work we have evaluated two groups of fragrance chemicals,
      saturated aldehydes (aryl substituted and aliphatic aldehydes) and alpha,beta
      unsaturated aldehydes. Data on their skin sensitization potency defined using the
      local lymph node assay has been evaluated in relation to their physicochemical
      properties. The initial outcome has been consistent with the concept that
      alpha,beta-unsaturated aldehydes react largely via Michael addition, whilst the
      group of saturated aldehydes form Schiff bases with proteins. Simple models of
      chemical reactivity based on these mechanisms suggest that it may be possible to
      predict allergenic potency. Accordingly, the evaluation of an additional group of
      similar aldehydes is now underway to assess the robustness of these models, with
      some emphasis being based on ensuring a wider spread of chemical reactivity.

PMID- 12492522
TI  - What do trainee hairdressers know about hand dermatitis?
AB  - Hand dermatitis is an important cause of morbidity in hairdressers. We conducted
      a questionnaire survey of 121 trainee hairdressers from 2 hairdressing colleges
      in Burnley (UK). The questionnaire concerned the number and types of hairdressing
      procedures performed, previous and current medical history, awareness of risks to
      the skin from hairdressing, and knowledge of hand dermatitis prevention. 17% of
      the trainees suffered currently from hand dermatitis. This is likely to be due to
      the large amount of wet work done by apprentice hairdressers, particularly those
      who worked in salons. 2/3 of trainees were not aware that atopic eczema
      predisposed to hand dermatitis. Formal pre-school and pre-employment counselling
      was limited. Knowledge on hand care among trainees was not often translated into
      practice, with gloves being worn by only 9% when shampooing and 58% when perming.
      Prevention of hand dermatitis by education and pre-employment counselling is of
      fundamental importance.

PMID- 12492524
TI  - Re-patch testing patients with long-term contact dermatitis.

PMID- 12492525
TI  - Resorcinol monobenzoate: a potential sensitizer in a computer mouse.

PMID- 12492526
TI  - Chemical burn due to trifluoroacetic anhydride.

PMID- 12492527
TI  - Photocontact dermatitis due to dexketoprofen.

PMID- 12492528
TI  - Allergic contact dermatitis from N-acetylcysteine eyedrops.

PMID- 12492529
TI  - Occupational cobalt sensitivity in 2 hard-metal press operators.

PMID- 12492530
TI  - Fragrance sensitization caused by temporary henna tattoo.

PMID- 12492531
TI  - Benzoyl peroxide as a cause of airborne contact dermatitis in an orthopaedic
      technician.

PMID- 12492532
TI  - Tolerance to a group C corticosteroid systemically in a patient with delayed-type
      hypersensitivity to group A systemic corticosteroids.

PMID- 12492533
TI  - On-line internet facilities for contact allergy software: CDESK/PRO.

PMID- 12492534
TI  - Contact urticaria from runner bean (Phaseolus coccineus).

PMID- 12492535
TI  - Different patterns of cross-reactivity in non-immediate hypersensitivity to
      heparins: from localized to systemic reactions.

PMID- 12492536
TI  - Allergic contact dermatitis due to hydrophilized ceramide.

PMID- 12492537
TI  - Delayed-type allergy to oral nimodipine.

PMID- 12492538
TI  - Occupational contact dermatitis from canary-grass seed.

PMID- 12492539
TI  - Delayed diagnosis of occupational contact dermatitis from sodium pyrithione in a
      metalworking fluid.

PMID- 12492540
TI  - Allergic contact dermatitis from trimethylolpropane triacrylate and
      pentaerythritol triacrylate.

PMID- 12492542
TI  - Anaphylaxis following prick testing with natural rubber latex.

PMID- 12492541
TI  - Contact allergy to permanent colorants used for tattooing a nipple after breast
      reconstruction.

PMID- 12492543
TI  - Quantitative aspects of contact allergy to chromium and exposure to chrome-tanned
      leather.
AB  - The potential of trivalent and hexavalent chromium to induce and elicit allergic
      contact dermatitis and the degree of chromium exposure from leather products are
      reviewed. Chromium dermatitis is often due to exposure in the occupational
      environment, with cement being one of the most common chromium sources. However,
      consumer products such as chromium(III)-tanned leather products are also an
      important source of chromium exposure. Apart from Cr(III), which is used for
      tanning, leather often also contains trace amounts of Cr(VI), which is formed by
      oxidation of Cr(III) during the tanning process. In a recent study of the Cr(VI)
      content of leather products bought on the Danish market, 35% of such articles had
      a Cr(VI) content above the detection limit of 3 p.p.m., ranging from 3.6 p.p.m.
      to 14.7 p.p.m. Leachable Cr(III) was detected at levels of 430-980 p.p.m. An
      examination of available dose-response studies showed that exposure to occluded
      patch test concentrations of 7-45 p.p.m. Cr(VI) elicits a reaction in 10% of the
      chromium-sensitive patients. When reviewing repeated open exposure studies, it is
      seen that either exposure to 5 p.p.m. Cr(VI) in the presence of 1% sodium lauryl
      sulfate (SLS) or exposure to 10 p.p.m. Cr(VI) alone both elicit eczema in
      chromium-sensitive patients. The eliciting capacity of Cr(III) has not been
      systematically investigated but, compared to Cr(VI), much higher concentrations
      are needed to elicit eczema.

PMID- 12492544
TI  - Tetrazepam drug sensitivity -- usefulness of the patch test.
AB  - The muscle relaxant tetrazepam may cause severe cutaneous adverse effects. We
      report 4 cases of varying intensity: Stevens-Johnson syndrome, erythema
      multiforme-like exanthema, maculopapular and maculo-urticarial exanthema. Patch
      testing with tetrazepam (10% in petrolatum) was strongly positive in the 2
      patients with severe skin eruptions and weakly positive in the other 2. Oral
      rechallenge with tetrazepam was positive in 3 patients (1 not done). Diazepam,
      with a similar chemical structure to tetrazepam, was negative on patch testing
      and on oral challenge testing in 2 patients. Although the optimal patch test
      concentration of tetrazepam has still to be determined, it is a useful diagnostic
      tool to confirm sensitization, particularly in patients with severe bullous
      eruptions.

PMID- 12492545
TI  - Efficacy of stratum corneum lipid supplementation on human skin.
AB  - Recent studies suggest that supplementing intercellular lipids of the stratum
      corneum in ageing populations or in people with dry skin can stimulate the
      functioning of the skin. This work lends support to the reinforcement capacity of
      two different stratum corneum lipid mixtures (synthetic stratum corneum lipid
      mixtures, SSCL, and internal wool lipid extracts, IWL) formulated as liposomes on
      healthy skin of two differently aged groups of individuals. Protection of healthy
      skin against detergent-induced dermatitis was evaluated. Transepidermal water
      loss and capacitance were used to evaluate the effect of these formulations in in
      vivo long-term studies. Increase in water-holding capacity is obtained only when
      the formulations applied are structured as liposomes. This is slightly more
      pronounced for aged skin. Subsequent SLS exposure reflected the protection of
      healthy human skin against detergent-induced dermatitis. Slightly better results
      were obtained with IWL containing a mixture of natural ceramides than with SSCL
      with only one ceramide present in the formulation. All these results support the
      beneficial effects of skin lipid supplementation given their resemblance to the
      lipids in the stratum corneum both in composition and in the structuring of the
      formulation.

PMID- 12492546
TI  - Contact allergy to the monomers in p-tert-butylphenol-formaldehyde resin.
AB  - In many adhesive formulations p-tert-butylphenol-formaldehyde resin (PTBP-F-R) is
      used as a binder. Contact allergy to this resin is not rare. In patients
      hypersensitive to PTBP-F-R, and butylphenol derivatives therein, it is for
      diagnostic and preventive reasons necessary to know the nature of the primary
      sensitizing substances, as well as the cross-reaction patterns for these. The aim
      of this study was to investigate contact allergy to monomers in PTBP-F-R and
      potential cross-reacting substances. 12 patients hypersensitive to PTBP-F-R were
      patch tested with 2 monomers, the raw materials formaldehyde and p-tert
      butylphenol, and 3 closely related substances. High pressure liquid
      chromatography (HPLC) was used to investigate the purity of the test substances.
      It was shown that the monomers 2-methylol p-tert-butylphenol and 2,6-dimethylol p
      tert-butylphenol could elicit allergic reactions in humans hypersensitive to PTBP
      F-R. No simultaneous reactions or cross-reactions were shown to formaldehyde, p
      tert-butylphenol, p-tert-butylcatechol, 2(3)-tert-butyl-4-hydroxyanisole (BHA) or
      3,5-di-tert-butyl-4-hydroxytoluene (BHT). It was also shown that low amounts of
      contaminants in the test substances, if not taken into account, could influence
      the conclusions drawn from the test results obtained.

PMID- 12492547
TI  - Latex allergy among construction workers.
AB  - To assess the incidence of latex allergy in construction workers, we studied all
      the 230 construction workers who attended our clinic between 1996 and 2000. In
      the 54 (23.5%) patients who reported any kind of intolerance to rubber gloves or
      boots, we performed both patch testing with the TRUE Test standard series and a
      rubber series and prick testing for latex. Latex-specific IgE levels were
      measured when prick testing was positive. 16 patients (7.0%) had a positive prick
      test to latex, of whom 14 had allergic contact urticaria from latex (ACUL). All
      of these 14 patients (6.1%) showed 1 or more positive reactions to the True Test
      series, which included 1 or more rubber chemicals in 9 of them. The level of
      specific Ig E to latex was greater than 0.35 kU/L in 15 of the 16 patients. In
      conclusion, our data suggest that the incidence of latex allergic contact
      urticaria among construction workers may be as high as that among health care
      workers. Most of these construction workers with Type I latex hypersensitivity
      had a concurrent Type IV hypersensitivity to chromate or rubber chemicals,
      presenting as occupational allergic contact dermatitis, which could have
      facilitated sensitization to latex.

PMID- 12492548
TI  - Contact allergy to the Asteraceae plant Ambrosia artemisiifolia L (ragweed) in
      sesquiterpene lactone-sensitive patients in southern Sweden.
AB  - Ambrosia artemisiifolia L. a classical cause of ragweed dermatitis in North
      America, is also found in Europe. 17 patients with contact allergy to
      sesquiterpene lactone (SL) mix were recalled for patch testing with extracts of
      North American and Swedish ragweed, the latter harvested in summer and autumn.
      8/17 patients were test-positive to the American extract, 14/17 to the Swedish
      summer extract and 15/17 to the autumn extract. All patients except 1 were found
      to have a chronic hand eczema of the pompholyx type. 5/16 hand eczema patients
      had a flare-up of their pompholyx at patch testing. We concluded that patients
      with SL mix allergy are allergic to American as well as to Swedish ragweed.
      Pompholyx seems to be a frequent clinical picture in patients with SL mix
      allergy.

PMID- 12492549
TI  - Investigation of the skin sensitizing activity of linalool.
AB  - An increasing range of chemicals appears to be capable of causing skin
      sensitization as a result of their capacity to undergo air oxidation
      (autoxidation) with the consequent formation of reactive species such as epoxides
      and hydroperoxides. In this small investigation, the ability of linalool, a
      common fragrance ingredient, to cause such effects was quantified using the local
      lymph node assay before and after careful purification by vacuum distillation.
      The commercially available grade of linalool (97% purity) was shown to be a weak
      skin sensitizer. Various impurities, including linalool oxide, dihydrolinalool,
      epoxylinalool, 3-hexenyl butyrate and 3,7-dimethyl-1,7-octadiene-3,6-diol were
      identified and were completely removed (except for the dihydrolinalool remaining
      at 1.4%) and the re-purified linalool retested. Neither linalool or
      dihydrolinalool are protein-reactive compounds. The sensitization potency of the
      re-purified linalool sample was considerably reduced, but not entirely
      eliminated, suggesting either that an allergenic impurity could be very quickly
      reformed by mechanisms of activation or that certain potent undetectable
      allergens remained. Both possibilities are consistent with what is understood of
      the chemistry and composition of commercially available linalool.

PMID- 12492550
TI  - Severe adverse drug reactions due to pseudoephedrine from over-the-counter
      medications.

PMID- 12492551
TI  - Prognosis of occupational dermatosis.

PMID- 12492552
TI  - Patch testing in allergic contact dermatitis caused by topical Chinese herbal
      medicine.

PMID- 12492553
TI  - Allergic contact dermatitis from ethylhexylglycerin.

PMID- 12492554
TI  - Frequency of contact allergy to Compositae extracts in patients with atopic
      dermatitis.

PMID- 12492555
TI  - Contact dermatitis from a dry stick deodorant.

PMID- 12492556
TI  - Allergic contact dermatitis from medium-chain triglycerides in a moisturizing
      lotion.

PMID- 12492557
TI  - Triple sensitization in a child with chronic otitis externa.

PMID- 12492558
TI  - Allergic contact dermatitis on previous skin graft site.

PMID- 12492559
TI  - Lymphomatoid allergic contact dermatitis from para-phenylenediamine.

PMID- 12492560
TI  - Allergic contact dermatitis from topical diclofenac in Solaraze gel.

PMID- 12492561
TI  - Occupational allergic contact dermatitis from PEG-4 rapeseed amide in a massage
      oil.

PMID- 12492562
TI  - Baseball pitcher's friction dermatitis.

PMID- 12492563
TI  - Delayed-type hypersensitivity skin reactions to low molecular weight heparins in
      a pregnant woman.

PMID- 12492564
TI  - A new source of allergic contact dermatitis from UV-cured (meth)acrylate
      adhesive.

PMID- 12492565
TI  - Cosmetics patch tests: first report from Israel.

PMID- 12492566
TI  - Bingo-hall worker's occupational copper contact dermatitis from coins.

PMID- 12492568
TI  - Disseminated fusariosis in a patient with acute leukaemia.

PMID- 12492569
TI  - Bone marrow cryptococcosis in a human immunodeficiency virus-negative patient.

PMID- 12492570
TI  - Tumour-associated antigens in multiple myeloma.

PMID- 12492571
TI  - Novel therapies for multiple myeloma.

PMID- 12492572
TI  - Thalidomide in multiple myeloma: current status and future prospects.

PMID- 12492573
TI  - Therapeutic effects of idiotype vaccination can be enhanced by the combination of
      granulocyte-macrophage colony-stimulating factor and interleukin 2 in a myeloma
      model.
AB  - Idiotype (Id) vaccination provides an interesting immunotherapeutic strategy
      against B-cell lymphomas. In multiple myeloma (MM), however, the therapeutic
      efficacy of Id vaccination has been disappointing. In an attempt to improve the
      antitumoral potential, we added granulocyte-macrophage colony stimulating factor
      (GM-CSF) and interleukin 2 (IL-2) to the protocol. Balb/c mice were inoculated
      i.p. (d 2) with different doses (1-5 x 10(5)) of HOPC myeloma cells secreting the
      Ig(HOPC) Id protein. Two days later, animals were injected with 10,000 U GM-CSF
      i.p. for 6 d consecutively (d 0-5). On d 5 and 11, myeloma-specific
      immunoglobulin (Ig(HOPC)) was administered i.p. together with incomplete Freund
      adjuvans followed by IL-2 (2 x 10,000 U/d; i.p) for 10 d (d 5-14). In animals
      inoculated with 10(5) myeloma cells, treatment with IL-2 given as a single agent
      prolonged the median survival time (MST, 67 d) when compared with the tumour
      control group (MST 48 d), whereas GM-CSF did not elicit any survival benefit (MST
      49 d). Complete tumour rejection could be achieved in 27% (4/15) by the
      combination of Id vaccination and GM-CSF. Additional treatment with IL-2 further
      increased antimyeloma activity. In this case, 59% of the animals showed no signs
      of tumour recurrence. In mice with high tumour burden (5 x 10(5)), no treatment
      modality achieved long-term survivors. Both natural killer (NK) cells and CD8+ T
      cells may be involved in the anti-tumoural immune response. These data provide
      evidence for the combined use of GM-CSF and IL-2 to enhance the therapeutic
      effectiveness of clinical cancer vaccination protocols.

PMID- 12492574
TI  - Size variants of beta-2-microglobulin-free human leucocyte antigen class I heavy
      chain make different contributions to its serum increase in multiple myeloma.
AB  - We previously showed that serum beta-2-microglobulin (beta2m)-free human
      leucocyte antigen (HLA) class I heavy chain (FHC) levels were increased in MM and
      correlate with disease activity. The present investigation, carried out in 124
      multiple myeloma patients, studied the expression of the three size variants of
      FHC, namely the 42 kDa intact heavy chain (A variant, AV), released through a
      shedding process, and the truncated FHC (tFHC) 39 kDa (BV) and 36-35 kDa (CV)
      released by means of membrane-type metalloprotease activity. The increase in FHC
      correlated with a high expression percentage of BV (r = 0.32, P = 0.0002) and
      tFHC (r = 0.42, P < 0.0001), which could help to discriminate multiple myeloma
      from monoclonal gammopathy of undetermined significance (tFHC mean ratio = 3.2;
      Mann-Whitney U-test, P < 0.0001). tFHC levels highly correlated with other
      disease activity markers, namely haemoglobin (r = -0.35; Spearman's rank, P =
      0.0001), percentage of bone marrow plasma cells (r = 0.4, P < 0.0001) and beta2m
      levels (r = 0.36, P < 0.0001), while only the last barely correlated (r = 0.2, P
      = 0.03) with AV. Finally, the 0.4, 0.57 and 0.71 mg/l BV, tFHC and (to a lesser
      extent) FHC cut-off values divided patients into two groups with different
      survival curves (P = 0.0005, P = 0.0025 and P = 0.04 respectively). These data
      are in favour of a correlation between disease aggressiveness and cleavage of
      these variants by membrane-type metalloprotease enzymes.

PMID- 12492575
TI  - Prognostic impact of cytogenetic and interphase fluorescence in situ
      hybridization-defined chromosome 13 deletion in multiple myeloma: early results
      of total therapy II.
AB  - Cytogenetic abnormalities of chromosome 13 (CA 13) and those detected by
      fluorescence in situ hybridization (FISH 13) have both been associated with poor
      prognosis in multiple myeloma (MM) patients. The prognostic implications of CA,
      FISH 13 and other standard laboratory parameters were examined in the first 231
      patients enrolled in Total Therapy II, an intensive cytotoxic chemotherapy
      programme with tandem autotransplants. Three-year projections of event-free
      survival (EFS) and overall survival (OS) were 71% and 77% respectively. CA 13 was
      detected in 14% and significantly correlated with FISH 13 (present in 51%),
      tumour burden, proliferative activity and lactic dehydrogenase (LDH). Both EFS
      and OS were significantly shorter in patients with CA 13, FISH 13, LDH >or= 190
      U/l, beta2 microglobulin >or= 4 mg/l and C reactive protein >or= 4.0 mg/l; other
      CA was an additional risk factor for OS. Two-thirds of CA 13 patients were
      identified by FISH 13 and plasma-cell-labelling index (PCLI) >or= 0.4%; however,
      PCLI failed to identify additional risk groups in FISH subsets. Although present
      in considerably fewer patients, CA 13 imparted more rapid relapse (61% at 3
      years) and death (43% at 3 years) than FISH 13 (38% and 35%; P = 0.02 and 0.1
      respectively) and should be part of the initial work-up of patients with MM.

PMID- 12492576
TI  - Macrophage inflammatory protein-1 alpha is produced by human multiple myeloma
      (MM) cells and its expression correlates with bone lesions in patients with MM.
AB  - Macrophage inflammatory protein-1 alpha (MIP-1alpha) is a chemokine primarily
      associated with bone absorption. We examined whether MIP-1alpha was produced by
      purified fresh tumour cells isolated from bone marrow samples from 31 multiple
      myeloma (MM) patients. High levels of MIP-1alpha were found in supernatants of
      myeloma cell cultures. Immunohistochemical staining showed MIP-1alpha in the
      cytoplasm of myeloma cells. MIP-1alpha mRNA expression was detected in 18 of 31
      patients. Bone lesions were seen in 16 of the 18 MIP-1alpha-positive patients but
      only in six of the 13 MIP-1alpha-negative patients (P = 0.0097,chi2-test). The
      data indicate that MIP-1alpha is produced by myeloma cells and possibly plays a
      role in the pathogenesis of bone lesions in MM patients.

PMID- 12492577
TI  - Cytogenetic heterogeneity of acute myeloid leukaemia (AML) with trilineage
      dysplasia: Japan Adult Leukaemia Study Group-AML 92 study.
AB  - Acute myeloid leukaemia (AML) with trilineage dysplasia (AML/TLD) is de novo AML
      recognized by the morphological dysplasia of three mature cell lines in the
      presence of leukaemic blasts. We studied the karyotypes of AML/TLD of patients
      with de novo AML, except for those with the French-American-British
      classification M3, who were enrolled onto the Japan Adult Leukaemia Study Group
      (JALSG)-AML 92 trial. Morphological and cytogenetic analyses were performed in
      559 patients and TLD phenotype was found in 155 patients (27.7%). The 511
      patients with informative morphological and cytogenetic data were classified into
      three groups according to karyotype: favourable, intermediate and adverse risk
      groups (92, 375 and 44 patients respectively). Normal karyotype was the most
      frequent as a total, and among both the non-TLD and TLD patients (164 patients
      45.3% and 78 patients 52.7% respectively). All but one patient with AML/TLD was
      classified into the intermediate or adverse cytogenetic risk group. TLD phenotype
      was associated with lower remission rate and shorter overall survival but it did
      not influence disease-free survival. Although we did not find any specific
      cytogenetic abnormalities for AML/TLD, the rarity of favourable karyotypes among
      TLD patients indicates the biological difference between AML/TLD and AML/non-TLD.

PMID- 12492578
TI  - Phenotypic and functional deficiencies of leukaemic dendritic cells from patients
      with chronic myeloid leukaemia.
AB  - Chronic myeloid leukaemia (CML) dendritic cells (DC) are possible candidates for
      inducing antileukaemic immunity. This study aimed to investigate the frequency,
      phenotype and function of blood-derived leukaemic DC in comparison with DC from
      healthy donors using flow cytometric assays and mixed leucocyte reaction (MLR).
      Immature leukaemic DC displayed a reduced endocytotic capacity as compared with
      healthy controls. Moreover, in vitro maturation of leukaemic DC was found to be
      deficient. Expression of CD80, CD83, CD86, and major histocompatibility complex
      class I and class II antigens were reduced on lipopolysaccharide (LPS)-matured
      leukaemic DC but were enhanced by a mixture of interleukin 1beta (IL-1beta), IL
      6, tumour necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2). Upon
      stimulation with bacterial LPS, intracellular TNF-alpha and IL-8 production was
      diminished in maturing DC from CML patients. This distinct cytokine deficiency
      was overcome when leukaemic DC were stimulated with cytokines/PGE2. MLR showed
      fully functional leukaemic DC after TNF-alpha-induced maturation, but a reduced
      proliferative alloresponse of leukaemic peripheral blood mononuclear cells.
      Further, intracellular production of cytokines in CML-derived T cells was
      markedly reduced. These data indicated that, in CML, the maturation response of
      leukaemic monocyte-derived DC to a natural stimulus like LPS is abnormal and may
      be caused by an aberrant TNF-alpha response in these cells. Thus, TNF-alpha alone
      or in combination with pro-inflammatory and T-cell stimulatory cytokines should
      be considered as an adjuvant for DC-based immunotherapy in CML.

PMID- 12492579
TI  - Outcome prediction by immunophenotypic minimal residual disease detection in
      adult T-cell acute lymphoblastic leukaemia.
AB  - Flow-cytometric detection of minimal residual disease (MRD) identifies patients
      with high relapse risk in childhood acute lymphoblastic leukaemia (ALL). We
      studied the efficacy of this method in adult T-ALL treated with the Italian co
      operative GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) LAL0496
      protocol. Bone marrow samples from 53 patients were taken at fixed treatment time
      points and MRD was analysed using a leukaemia-specific immunophenotype
      (cytoplasmic-CD3/nuclear-terminal desoxynucleotidyl transferase). The median
      follow-up was 17 months (range 3-61) and a median of 4.5 analyses/patient was
      performed (range 3-12). Six out of 53 (11.3%) patients were refractory to
      treatment, 30/53 (56.6%) relapsed and 17/53 (32.1%) remain in continuous complete
      remission. The probability of relapse at 2 years for MRD-positive patients at
      preconsolidation was 81.5%vs 38.9% for MRD-negative patients (P = 0.00078). This
      risk was still 54.5% for MRD-positive vs 15.8% for MRD-negative patients pre
      third reinduction (P = 0.0098) and 50.0% for MRD-positive vs 16.4% for MRD
      negative patients pre-sixth reinduction (P = 0.032). The relapse-predicting value
      of MRD did not depend on features at diagnosis such as age, sex and leucocyte
      count. Our data suggest that immunophenotypic MRD monitoring in the first year of
      treatment is a useful outcome predictor for adult T-ALL patients.

PMID- 12492580
TI  - Mu class glutathione S-transferase mRNA isoform expression in acute lymphoblastic
      leukaemia.
AB  - Glutathione S-transferases (GSTs) are implicated in cytotoxic drug resistance in
      leukaemia. In a previous study, expression of mu class GST (GSTM) was associated
      with poor prognosis in childhood acute lymphoblastic leukaemia (ALL), however,
      that study did not differentiate between individual GSTM isoforms. This study,
      therefore, investigated individual GSTM isoform expression in ALL blasts at the
      mRNA level. Leukaemic blasts from 21 children with ALL were studied.
      Interindividual variation in the pattern of GSTM mRNA isoform expression was
      demonstrated. GSTM2 transcript was expressed in all patients in contradistinction
      to GSTM5, which was not detected in any sample. GSTM3 and GSTM4 expression varied
      between individuals, with GSTM3 expressed in 62% and GSTM4 in 24% of patients.
      Lymphoblast expression of GSTM3 was positively related to good prognosis whereas
      expression of GSTM4 was not related to clinical outcome in this small cohort. No
      relationship was demonstrated with established indicators of prognosis, including
      sex, age, immunophenotype and presenting white cell count. The results suggest
      that expression of GSTM3 may play a role in determining prognosis in childhood
      ALL and could provide more information for accurate stratification of treatment.
      Further studies are required to determine whether there is a causal relationship
      between GSTM3 expression and clinical outcome.

PMID- 12492581
TI  - FLT3 internal tandem duplication in childhood acute myeloid leukaemia:
      association with hyperleucocytosis in acute promyelocytic leukaemia.
AB  - We evaluated the incidence of FLT3/internal tandem duplication (ITD) mutation in
      childhood acute myeloid leukaemia (AML) diagnosed over 15 years. FLT3/ITD was
      found in 10 of 45 (22.2%) non-acute promyelocytic leukaemia (non-APL) patients.
      The 5-year event-free survival of non-APL patients was higher in FLT3/ITD
      negative versus -positive patients (48.9%, SE 8.9, vs 20.0%, SE 16.1, P = 0.03).
      In childhood APL, FLT3/ITD incidence was higher than in non-APL, although not
      statistically significant (10 out of 29 patients, 34.5%, P = 0.29). In APL
      patients, FLT3/ITD was strongly correlated to a higher white blood cell count at
      diagnosis and the M3 French-American-British subtype.

PMID- 12492582
TI  - Common expression of an unusual CD45 isoform on T cells from patients with large
      granular lymphocyte leukaemia and autoimmune lymphoproliferative syndrome.
AB  - Patients with T-cell large granular lymphocyte (T-LGL) leukaemia and autoimmune
      lymphoproliferative syndrome (ALPS) share many features, including autoimmunity
      and an expansion of (cytotoxic) T cells, which in ALPS patients express an
      unusual (B220) isoform of CD45, corresponding to an altered O-glycosylation
      profile. Here we showed that T-LGL leukaemia cells also expressed this B220
      isoform. We hypothesize that B220+ T cells constitute proliferating T cells that
      have become competent to undergo apoptosis, but that constitutive (ALPS) or
      functional (T-LGL) defects prevent this process. Altered O-glycosylation of the
      extracellular domains of CD45 may have consequences for this tyrosine phosphatase
      as a regulator of cell proliferation and survival.

PMID- 12492583
TI  - High frequency of t(11;18) in gastric mucosa-associated lymphoid tissue lymphomas
      in Taiwan, including one patient with high-grade transformation.
AB  - t(11;18)(q21;q21), the most frequent chromosomal aberration of mucosa-associated
      lymphoid tissue (MALT) lymphoma, occurs in 30% of gastric patients. Although the
      translocation is often associated with an 'aggressive' course, it has not been
      described in transformed MALT lymphomas. We screened 15 gastric MALT lymphomas
      [three with concurrent or subsequent high-grade transformation and 11 diffuse
      large B-cell lymphomas (DLBCLs)] in Chinese patients for t(11;18). t(11;18) was
      found in 9/15 (60%) MALT lymphomas, but not in any DLBCLs. One patient, with
      subsequent high-grade transformation, showed the translocation in low- and high
      grade lesions. t(11;18) was frequent in Chinese gastric MALT lymphomas and
      unusually one transformed lymphoma carried the translocation.

PMID- 12492584
TI  - Identification of simultaneous mutation of fibrinogen alpha chain and protein C
      genes in a Japanese kindred.
AB  - Afibrinogenaemia usually induces a bleeding tendency during infancy, whereas
      protein C deficiency increases susceptibility to thrombosis in children or
      adolescence. Mutations of these genes have been, therefore, established as
      independent risk factors for coagulation disorders. We describe the homozygous
      mutation of the fibrinogen alpha chain gene and additional heterozygous mutation
      of the protein C gene in a male infant who showed prolonged umbilical bleeding
      after birth. On examination, the plasma fibrinogen was undetectable, and the
      activity and antigen level of protein C were reduced. The patient showed no
      fibrinogen Aalpha chain as well as Bbeta and gamma chains by Western blotting.
      The sequencing analysis showed the homozygous deletion of 1238 bases from intron
      3 at position 2008 to intron 4 at position 3245 in the fibrinogen alpha chain
      gene. Both parents were heterozygous carriers of this mutation. In this patient,
      an additional mutation was also detected in the protein C gene: the heterozygous
      deletion of exon 7 at position 6161-6163 or 6164-6166, resulting the deletion of
      one amino acid (Lys150 or 151). His mother was also a carrier of this mutation.
      As the simultaneous mutation of the fibrinogen alpha chain and protein C genes
      has not been previously reported, the influence of the interaction between these
      two mutations on the clinical manifestations of this patient should be carefully
      monitored for a long period.

PMID- 12492585
TI  - Effect of tamoxifen on venous thrombosis risk factors in women without cancer:
      the Breast Cancer Prevention Trial.
AB  - Tamoxifen reduces breast cancer incidence among healthy women, but is associated
      with an increased risk of venous thrombosis. We studied the 6 month effects of
      tamoxifen on venous thrombosis risk factors in women without cancer. One hundred
      and eleven women at one centre who were participants in a multicentre breast
      cancer prevention trial were randomized, in double-blind fashion, to receive 20
      mg/d of tamoxifen or placebo. The activated protein C (APC) ratio and
      concentrations of antithrombin, protein C antigen, and total protein S were
      measured at baseline and 6 months of treatment. None of the factors changed over
      6 months in placebo-treated women. Among tamoxifen-treated women, antithrombin
      and protein S, but not protein C or APC ratio were reduced. Sequential
      antithrombin concentrations with tamoxifen were 114% and 104% (P = 0.001 compared
      with placebo). Sequential protein S concentrations with tamoxifen were 18.42 and
      17.30 micro g/ml (P = 0.02 compared with placebo). Reductions in antithrombin and
      protein S were greater in postmenopausal women, but did not differ by other risk
      factors for venous thrombosis, such as body mass index. Reductions of
      antithrombin and protein S, but not protein C or APC resistance, might relate to
      the increased risk of venous thrombosis associated with tamoxifen treatment.

PMID- 12492586
TI  - Acquired resistance to activated protein C in breast cancer patients.
AB  - In 56 women with a lymph-node-positive breast carcinoma and 28 matched healthy
      control subjects, the sensitivity to activated protein C (APC-sr) was determined
      with an APC resistance test that quantifies the effect of APC on thrombin
      generation initiated via the extrinsic coagulation pathway. Carriers of the
      Factor V Leiden mutation were excluded from the study. Significant resistance to
      APC was found in the breast cancer patients: median APC-sr 2.02 vs 1.03 in the
      healthy control subjects (P < 0.001). No difference in APC-sr was found between
      patients with metastases and without metastases. In patients with metastases,
      protein S levels were significantly elevated compared with patients without
      metastases and healthy control subjects: 108.0%vs 96.0% and 94.5% (P = 0.008 and
      P = 0.007). The APC-sr correlated with protein S in the control subjects and in
      patients without metastases but not in patients with metastases. The disturbance
      of the haemostatic balance probed by the tissue-factor-based APC resistance test
      might contribute to the cancer-related hypercoagulability.

PMID- 12492587
TI  - Thrombus precursor protein, endogenous thrombin potential, von-Willebrand factor
      and activated factor VII in suspected deep vein thrombosis: is there a place for
      new parameters?
AB  - Because of its high negative predictive value, D-Dimer is an important parameter
      in the exclusion of deep vein thrombosis (DVT) but it produces a high number of
      false-positive results. We therefore evaluated different blood parameters in 74
      consecutive patients with suspected DVT, whose final diagnosis was based on the
      results of Duplex ultrasound or venography. DVT was diagnosed in 52.7%. While D
      Dimer, thrombin-antithrombin complexes, prothrombin fragment 1+2, von-Willebrand
      factor and thrombus precursor protein were significantly increased in patients
      with DVT, there was no influence concerning endogenous thrombin potential and
      activated factor VII. There was no significant correlation between the thrombus
      extension or the duration of symptoms with any of these parameters. D-Dimer
      showed the best sensitivity (94.9%) to specificity (45.7%) ratio and neither the
      sole nor the additional evaluation of any other investigated parameter increased
      its diagnostic performance. We, therefore, conclude that the determination of D
      Dimer remains the 'gold standard' in the laboratory testing of patients with
      suspected DVT.

PMID- 12492588
TI  - Plasma from patients with thrombotic thrombocytopenic purpura induces activation
      of human monocytes and polymorphonuclear neutrophils.
AB  - Thrombotic thrombocytopenic purpura (TTP) is a rare but severe disorder
      characterized by microangiopathic haemolytic anaemia, consumptive
      thrombocytopenia, neurological involvement and formation of platelet thrombi in
      the small vessels. The aetiopathology of TTP and the mechanism behind the
      beneficial effect of plasma exchange with plasma infusion have not yet been fully
      elucidated. We have studied the effect of plasma from four patients with TTP on
      human blood phagocyte activation, as measured by reactive oxygen species (ROS)
      production and CD11b expression. TTP plasma obtained in the acute phase of the
      disease induced ROS production by human monocytes and enhanced CD11b expression
      on neutrophils. This activation effect remained in the cryosupernatant but not in
      the cryoprecipitate made from TTP plasma, and disappeared when a complete
      response was achieved by plasma exchange. These findings suggest that activated
      blood phagocytes may be involved in the pathophysiology of TTP.

PMID- 12492589
TI  - Fcgamma receptor IIa and IIIa polymorphisms in childhood immune thrombocytopenic
      purpura.
AB  - Fcgamma receptor-mediated destruction of autoantibody-sensitized platelets is
      central to the immune pathophysiology of childhood immune thrombocytopenic
      purpura (ITP). Allelic variants exist among the random population for some
      Fcgamma receptors. The variants represent single nucleotide polymorphisms,
      leading to functional differences in the ability to bind immunoglobulin (Ig)G or
      IgG subclasses. The genotypic frequencies for two Fcgamma receptor single
      nucleotide polymorphisms, FcgammaRIIa-131 arginine (R) versus histidine (H) and
      FcgammaRIIIa-158 valine (V) versus phenylalanine (F) were examined in 98 children
      diagnosed with childhood ITP. The genotype frequencies were compared with those
      of 130 healthy control subjects. Chi-square analysis was used to determine
      whether the allelic frequencies of the high-affinity receptor variants were
      associated with childhood ITP. Both the FcgammaRIIa-131H and the FcgammaRIIIa
      158V were significantly over-represented in children with ITP versus the control
      subjects (P-values 0.03). The same statistical difference was noted with the
      combined FcgammaRIIa-131H and FcgammaRIIIa-158V allelic gene frequencies. There
      was no statistical difference between children who later developed chronic ITP
      compared with children with acute ITP, suggesting that additional factors are
      responsible for the development of the chronic form of the disease. These
      observations underscore the importance of Fcgamma receptor-mediated cell
      clearance in childhood ITP.

PMID- 12492590
TI  - Phenotypic and genetic analysis of a compound heterozygote for dys- and
      hypoprothrombinaemia.
AB  - We studied a 2-year-old boy with a phenotype of combined hypo- and
      dysprothrombinaemia. Sequencing of polymerase-chain-reaction-amplified genomic
      DNA revealed three different mutations in heterozygosity, a G to A transition at
      position 7312, resulting in the replacement of arginine 271 by histidine, an A to
      G transition at position 20058, resulting in the replacement of histidine 562 by
      arginine, and a 2-bp deletion at 20062-20063, causing a frameshift and a
      premature stop codon in exon 14. The first two mutations are compatible with the
      dysprothrombinaemia phenotype, whereas the small deletion is thought to be the
      cause of hypoprothrombinaemia.

PMID- 12492591
TI  - Risk factors for adults with Philadelphia-chromosome-positive acute lymphoblastic
      leukaemia in remission treated with allogeneic bone marrow transplantation: the
      potential of real-time quantitative reverse-transcription polymerase chain
      reaction.
AB  - The aim of this study was to evaluate the outcomes for Philadelphia-chromosome
      positive acute lymphoblastic leukaemia (Ph+ ALL) patients in remission treated
      with allogeneic bone marrow transplantation (BMT). Twenty-three adults were
      entered onto this study. The 2-year probabilities of relapse and disease-free
      survival (DFS) were 39.4 +/- 11.6% and 43.5 +/- 10.3% respectively. The presence
      of chronic graft-versus-host disease (GVHD) was found to be an independent
      predictive factor affecting lower relapse and DFS. To monitor the BCR-ABL
      transcript, we also analysed 48 bone marrow samples of eight patients using real
      time quantitative reverse-transcription polymerase chain reaction (RT-PCR). The
      kinetics of the BCR-ABL transcript correlated well with the patients' clinical
      course. In six patients who were in continuous remission after BMT, a rapid
      decrease in BCR-ABL copy number to the PCR-negative status was observed after the
      development of chronic GVHD. Meanwhile, routine bone marrow examination of two
      patients showed PCR positivity with a 3 or 4-log increase of BCR-ABL copy number
      and subsequent haematological relapse, which occurred 2 and 4 months later
      respectively. Although our data should be interpreted cautiously, the presence of
      chronic GVHD may reduce the risk of relapse in Ph+ ALL. Real-time quantitative RT
      PCR appears to be a useful test for BCR-ABL transcript monitoring.

PMID- 12492592
TI  - Assessing diversity: immune reconstitution and T-cell receptor BV spectratype
      analysis following stem cell transplantation.
AB  - T-cell receptor (TCR) BV spectratyping provides information concerning immune
      reconstitution complementary to that derived from monoclonal antibody analysis of
      surface antigen expression. However, the most appropriate way to analyse and
      represent these data, the number of subfamilies that should be analysed, and the
      effects of CD4/8 ratio on observed diversity, remain unclear. A diversity scoring
      system was developed based on analysis of 11 cord blood (CB) and 12 normal adult
      BV spectratypes. CB subfamily spectratypes demonstrated minor deviations from a
      Gaussian pattern consistent with current knowledge about germline TCR
      rearrangements. Diversity scores were significantly lower in myeloma patients
      than normal adults (P < 0.001) and fell significantly following stem cell
      transplantation (P = 0.003). Subsequently increasing diversity was not detected
      by two previously described complexity scoring systems. The CD4/8 ratio was
      neither the major determinant of the absolute diversity score nor of the change
      in score for individual patients, suggesting that analysis of unselected
      mononuclear cells can provide information largely independent of CD4/8 ratios.
      There was a relatively low correlation between individual subfamily scores and
      overall diversity score. The novel and objective diversity scoring system
      described appears better able to document changes in spectratype patterns than
      previously described techniques and should aid the standardization of reporting.

PMID- 12492593
TI  - FGFR3 dysregulation and clinical outcome in myeloma.

PMID- 12492594
TI  - Plasma exchange as a source of protein C for acute-onset protein C pathway
      failure.

PMID- 12492595
TI  - Parvovirus B19 infection and acute lymphoblastic leukaemia.

PMID- 12492596
TI  - Mean platelet volume is an independent risk factor for myocardial infarction but
      not for coronary artery disease.

PMID- 12492597
TI  - t(4;14)(p16.3;q32) is strongly associated with a shorter survival in myeloma
      patients.

PMID- 12492598
TI  - Serum erythropoietin values and endogenous erythroid colony growth in
      erythrocytoses and essential thrombocythaemia.

PMID- 12492602
TI  - Assessment of venous capacitance. Radionuclide plethysmography: methodology and
      research applications.

PMID- 12492603
TI  - A systematic review of systematic reviews of homeopathy.
AB  - Homeopathy remains one of the most controversial subjects in therapeutics. This
      article is an attempt to clarify its effectiveness based on recent systematic
      reviews. Electronic databases were searched for systematic reviews/meta-analysis
      on the subject. Seventeen articles fulfilled the inclusion/exclusion criteria.
      Six of them related to re-analyses of one landmark meta-analysis. Collectively
      they implied that the overall positive result of this meta-analysis is not
      supported by a critical analysis of the data. Eleven independent systematic
      reviews were located. Collectively they failed to provide strong evidence in
      favour of homeopathy. In particular, there was no condition which responds
      convincingly better to homeopathic treatment than to placebo or other control
      interventions. Similarly, there was no homeopathic remedy that was demonstrated
      to yield clinical effects that are convincingly different from placebo. It is
      concluded that the best clinical evidence for homeopathy available to date does
      not warrant positive recommendations for its use in clinical practice.

PMID- 12492604
TI  - The pharmacokinetics of ketobemidone in critically ill patients.
AB  - AIMS: To study the pharmacokinetics of orally and intravenously administered
      ketobemidone in critically ill patients. METHODS: Seventeen patients were studied
      during their stay in the intensive care unit at Huddinge University Hospital.
      Nine patients received a single intravenous dose of ketobemidone (0.04 mg kg-1)
      and eight patients received a single oral dose of 5 mg. Plasma concentrations of
      ketobemidone were measured using liquid chromatography-mass spectrometry. The
      pharmacokinetic analysis was performed using WinNonlin trade mark software.
      RESULTS: There was a wide variation in the different pharmacokinetic parameters
      among patients. Mean clearance in patients treated intravenously was 74.5 (95% CI
      43.2, 128.3) and mean Vd was 2.4 l kg-1 (95% CI 2.0, 2.8). t1/2,z also varied
      widely with a mean value of 4.41 h (95% CI 2.7, 7.0). The corresponding values
      for MRT were 5.4 and 3.3, 8.8. Mean oral clearance (CL/F) was 102 l h-1 (95% CI
      82.7, 125.8), mean Vz/F was 11.2 l kg-1 (95% CI 9.7, 13.1) and mean t1/2,z was
      6.0 (95% CI 4.9, 7.3) in orally treated patients. Cmax showed a mean of 38 nmol l
      1 (95% CI of 31, 47). A significant correlation was observed between the
      glomerular filtration rate (GFR) and the half-life of ketobemidone (r = -0.72, P
      < 0.05). t1/2,z was generally longer and the variation larger in critically ill
      patients compared with healthy individuals. However, there was no correlation
      between the elimination of ketobemidone in critically ill patients and plasma C
      reactive protein, white blood count or plasma albumin concentrations.
      CONCLUSIONS: The disposition of ketobemidone is highly variable in critically ill
      patients. In order to ensure sufficient analgesia and avoid toxicity, therapeutic
      monitoring should be employed when using ketobemidone in this group of patients.

PMID- 12492605
TI  - Faster absorption of ethanol and higher peak concentration in women after gastric
      bypass surgery.
AB  - AIMS: To investigate the absorption, distribution and elimination of ethanol in
      women with abnormal gut as a result of gastric bypass surgery. Patients who
      undergo gastric bypass for morbid obesity complain of increased sensitivity to
      the effects of alcohol after the operation. METHODS: Twelve healthy women
      operated for morbid obesity at least 3 years earlier were recruited. Twelve other
      women closely matched in terms of age and body mass index (BMI) served as the
      control group. After an overnight fast each subject drank 95% v/v ethanol (0.30 g
      kg-1 body weight) as a bolus dose. The ethanol was diluted with orange juice to
      20% v/v and finished in 5 min. Specimens of venous blood were taken from an
      indwelling catheter before drinking started and every 10 min for up to 3.5 h post
      dosing. The blood alcohol concentration (BAC) was determined by headspace gas
      chromatography. RESULTS: The maximum blood-ethanol concentration (Cmax) was 0.741
      +/- 0.211 g l-1 (+/- s.d.) in the operated group compared with 0.577 +/- 0.112 g
      l-1 in the controls (mean difference 0.164 g l-1, 95% confidence interval (CI)
      0.021, 0.307). The median time to peak (tmax) was 10 min in the bypass patients
      compared with 30 min in controls (median difference -15 min (95% CI -10, -20
      min). At 10 and 20 min post-dosing the BAC was higher in the bypass patients (P <
      0.05) but not at 30 min and all later times (P > 0.05). Other pharmacokinetic
      parameters of ethanol were not significantly different between the two groups of
      women (P > 0.05). CONCLUSIONS: The higher sensitivity to ethanol after gastric
      bypass surgery probably reflects the more rapid absorption of ethanol leading to
      higher Cmax and earlier tmax. The marked reduction in body weight after the
      operation might also be a factor to consider if the same absolute quantity of
      ethanol is consumed.

PMID- 12492606
TI  - Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6
      glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after
      short-term infusion of morphine.
AB  - AIMS: Concentrations in the cerebrospinal fluid (CSF) are a useful approximation
      to the effect site for drugs like morphine. However, CSF samples, are available
      only in rare circumstances. If they can be obtained they may provide important
      insights into the pharmacokinetics/pharmacodynamics of opioids. METHODS: Nine
      neurological and neurosurgical patients (age 19-69 years) received 0.5 mg kg-1
      morphine sulphate pentahydrate as an intravenous infusion over 30 min. Plasma and
      CSF were collected for up to 48 h. Concentration time-course and interindividual
      variability of morphine (M), morphine-3-glucuronide (M3G) and morphine-6
      glucuronide (M6G) were analysed using population pharmacokinetic modelling.
      RESULTS: While morphine was rapidly cleared from plasma (total clearance = 1838
      ml min-1 (95% CI 1668, 2001 ml min-1)) the glucuronide metabolites were
      eliminated more slowly (clearance M3G = 44.5 ml min-1 (35.1, 53.9 ml min-1),
      clearance M6G = 42.1 ml min-1 (36.4, 47.7 ml min-1)) and their clearance could be
      described as a function of creatinine clearance. The central volumes of
      distribution were estimated to be 12.7 l (11.1, 14.3 l) for morphine. Transfer
      from the central compartment into the CSF was also rapid for M and considerably
      slower for both glucuronide metabolites. Maximum concentrations were achieved
      after 102 min (M), 417 min (M3G) and 443 min (M6G). A P-glycoprotein exon 26
      polymorphism previously found to be linked with transport activity could be
      involved in CSF accessibility, since the homozygous mutant genotype was
      associated (P < 0.001) with high maximum CSF concentrations of M but not M3G or
      M6G. CONCLUSIONS: From the population pharmacokinetic model presented, CSF
      concentration profiles can be derived for M, M3G and M6G on the basis of dosing
      information and creatinine clearance without collecting CSF samples. Such
      profiles may then serve as the link between dose regimen and effect measurements
      in future clinical effect studies.

PMID- 12492607
TI  - Quinine pharmacokinetics in chronic haemodialysis patients.
AB  - AIMS: Quinine is often used to prevent muscle cramps in patients with chronic
      renal failure. A standard dose of 300 mg at bedtime is usually recommended, but
      little is known about the pharmacokinetics of quinine in the presence of renal
      failure. METHODS: We studied the pharmacokinetics of quinine in eight normal
      subjects and eight patients with chronic renal failure on haemodialysis after a
      single oral dose of quinine sulphate (300 mg). RESULTS: The concentration of
      alpha1-acid glycoprotein (AAG), the major binding protein for quinine, was
      increased in haemodialysis patients compared with control subjects (1.52 g l-1 vs
      0.63 g l-1 [mean difference 1.033; 95% CI 0.735, 1.330]) whereas albumin levels
      were decreased (30 g l-1 vs 40 g l-1 [mean difference 9.5; 95% CI 3.048,
      15.952]). Accordingly, the free fraction of quinine was decreased (0.024 vs 0.063
      [mean difference 0.0380; 95% CI 0.0221, 0.0539]) and the apparent volume of
      distribution tended to decrease (0.95 l kg-1 vs 1.43 l kg-1 [mean difference
      0.480; 95% CI 0.193, 1.154]). The quinine binding ratio correlated with the
      plasma concentration of AAG but not that of albumin. The clearance of free
      (unbound) quinine was increased in haemodialysis patients compared with controls
      (67.9 ml min-1 kg-1 vs 41.1 ml min-1 kg-1 [mean difference -26.8; 95% CI, 
      56.994, 3.469]), and the area under the curve (AUC) of the two main metabolites,
      3-hydroxyquinine and 10,11-dihydroxydihydroquinine were increased. CONCLUSIONS:
      In patients with chronic renal failure, there is an increase in plasma protein
      binding and in the clearance of free drug, resulting in lower plasma
      concentration of free quinine.

PMID- 12492608
TI  - MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg
      digoxin in healthy white males.
AB  - AIMS: A noncoding single nucleotide polymorphism (SNP) in exon 26 3435C > T of
      the highly polymorphic MDR1 gene has been demonstrated to alter digoxin
      absorption after induction of the MDR1 gene product P-glycoprotein by rifampicin
      or after multiple oral dosing. The aim of the study was to investigate the
      effects of the major known MDR1 SNPs on the absorption of digoxin after a single
      oral dose in a large sample without drug pretreatment. METHODS: Fifty healthy
      white male subjects between the age of 18 and 40 years were enrolled. Following
      an overnight fast, all subjects received a single oral dose of 1 mg digoxin.
      Venous blood samples were taken at intervals up to 4 h post dose to obtain a
      pharmacokinetic profile. RESULTS: AUC(0,4 h), Cmax and tmax, used as indices of
      digoxin absorption, were not significantly different in any of the genotype
      groups tested. In particular, there was no significant difference between
      homozygous carriers of the C and T allele in exon 26 3435 (AUC(0,4 h) 9.24 and
      9.38 micro g l-1 h, Cmax 4.73 and 3.81 micro g l-1, tmax 0,83 and 01.14 h).
      CONCLUSIONS: This lack of effect of the major MDR1 SNPs on digoxin absorption
      might be explained by saturation of the maximum transport capacity of intestinal
      Pgp at the dose used.

PMID- 12492609
TI  - No effect on central or peripheral blood pressure of systemic urotensin II
      infusion in humans.
AB  - AIMS: In rodent and primate studies, urotensin II is an extremely potent
      vasoconstrictor peptide with effects in the central aortic and arterial
      vasculature as well as on cardiac function. The aim of the present study was to
      assess systemic haemodynamic responses to intravenous urotensin II infusion in
      humans. METHODS: In 10 healthy male volunteers, intravenous urotensin II (3, 30
      and 300 pmol min-1) and saline placebo were given on separate occasions in a
      single-blind randomized manner. Systemic haemodynamics and arterial stiffness
      were assessed by sphygmomanometry, transthoracic bioimpedance, and pulse wave
      analysis. Plasma urotensin II immuno-reactivity was measured by radio
      immunoassay. RESULTS: Intravenous urotensin II infusions were well tolerated with
      no adverse clinical effects and no electrocardiographic changes. Circulating
      plasma urotensin II immuno-reactivity increased from baseline of 16 +/- 1 to 1460
      +/- 82 pmol l-1 (mean +/- s.e. mean) during infusion of urotensin II at 300 pmol
      min-1 (P < 0.001). However, there were no significant placebo adjusted changes in
      heart rate (95% confidence intervals: -3.6, + 4.4 min-1), mean arterial pressure
      (-5.8, + 1.7 mmHg) or cardiac index (-0.1, + 0.4 l min-1 m-2). There were also no
      changes in augmentation index (-4.1, + 5.2%) or pulse wave velocity (-1.3, + 0.3
      m s-1). CONCLUSIONS: Intravenous urotensin II infusion did not affect systemic
      haemodynamics or arterial stiffness, despite achieving an approximately 100-fold
      increase in plasma immuno-reactivity. We conclude that urotensin II is unlikely
      to have a physiological role in the short term regulation of vascular tone or
      blood pressure in man. Further confirmatory studies with urotensin II receptor
      antagonists are required.

PMID- 12492610
TI  - Effect of candesartan, a type 1 angiotensin II receptor antagonist, on bronchial
      hyper-responsiveness to methacholine in patients with bronchial asthma.
AB  - AIMS: Angiotensin II is a putative mediator in bronchial asthma. There have been
      very few studies investigating the involvement of angiotensin II receptors in
      bronchial hyper-responsiveness in asthmatic patients. We examined the effect of
      candesartan cilexetil, a specific angiotensin II type 1 (AT1) receptor
      antagonist, on bronchial responsiveness to inhaled methacholine in patients with
      asthma. METHODS: Bronchial responsiveness to methacholine, assessed as the
      concentration of methacholine producing a 20% fall in FEV1 (PC20-FEV1), was
      measured on three occasions 2 weeks apart in 11 stable asthmatic patients.
      Candesartan cilexetil (8 mg once a day) or a placebo was orally administered for
      1 week before the methacholine provocation test in a double-blind, randomized,
      crossover manner. RESULTS: Although there were no significant differences between
      treatment periods in FEV1 values at baseline, the geometric mean (95% CI) PC20
      FEV1 values increased significantly (P = 0.041) from 0.691 (0.379, 1.259) mg ml-1
      with placebo to 0.837 (0.506, 1.384) mg ml-1 with candesartan. Candesartan
      decreased the mean (95% CI) arterial blood pressure (placebo: 95.6 (89.0, 102.2)
      mmHg, candesartan: 86.4 (79.8, 93.1) mmHg, P = 0.015). There was no correlation
      between the change in blood pressure and the change in PC20-FEV1. CONCLUSIONS: We
      conclude that AT1 receptors are involved in bronchial hyper-responsiveness in
      asthmatic patients.

PMID- 12492611
TI  - Quantification of heparin-induced TFPI release: a maximum release at low heparin
      dose.
AB  - AIMS: Heparin releases tissue factor pathway inhibitor (TFPI) from the
      endothelium and this release may decrease after repeated high dose heparin
      administration. The primary aim was to investigate and quantify this phenomenon
      during a short low dose heparin infusion. Also, the effects of heparin on tissue
      plasminogen activator (t-PA) were studied. METHODS: Nine healthy, nonsmoking,
      male volunteers (range 19-23 years) received a continuous heparin infusion (2000
      IU) over 40 min. The endothelial TFPI release rate was estimated from the total
      TFPI concentration profile using a pharmacokinetic model. RESULTS: Mean +/- s.d.
      total and free TFPI increased from 62.9 +/- 9.4/8.3 +/- 2.1 ng ml-1 at baseline
      to 237.2 +/- 40.9/111.0 +/- 19.9 ng ml-1 after 40 min infusion. The relationship
      between heparin concentration (anti-IIa activity) and TFPI concentration followed
      a maximum effect model and a clockwise loop (proteresis) was observed. The TFPI
      release rate rapidly increased to maximum of 200 +/- 45 micro g min-1 after 17.5
      min heparin infusion but did not increase further although heparin concentrations
      further doubled. In contrast to TFPI, t-PA antigen decreased from 5.6 +/- 1.0 at
      baseline to 4.5 +/- 1.0 ng ml-1 at the end of infusion (t = 40 min) (difference
      of 1.1 ng ml-1 (95% confidence interval; 0.9, 1.3). CONCLUSIONS: Our application
      of concentration-effect models and pharmacokinetic principles to these
      haemostatic variables showed that endothelial TFPI release has a maximum that is
      already reached at low heparin dose, corresponding with an anti-IIa activity of
      0.08 IU ml-1. The relationship between anti-IIa activity and TFPI release rate
      showed signs of acute tolerance (clockwise loop) indicating exhaustion of
      endothelial TFPI pools. These findings may be of importance for the heparin dose
      used in conditions such as unstable angina, in which the favourable effects of
      heparin have been ascribed to its ability to release TFPI.

PMID- 12492612
TI  - Phenytoin pharmacokinetics and clinical effects in African children following
      fosphenytoin and chloramphenicol coadministration.
AB  - AIMS: Some children with malaria and convulsions also have concurrent bacterial
      meningitis. Chloramphenicol is used to treat the latter whereas phenytoin is used
      for convulsions. Since chloramphenicol inhibits the metabolism of phenytoin in
      vivo, we studied the effects of chloramphenicol on phenytoin pharmacokinetics in
      children with malaria. METHODS: Multiple intravenous (i.v.) doses of
      chloramphenicol succinate (CAP) (25 mg kg-1 6 hourly for 72 h) and a single
      intramuscular (i.m.) seizure prophylactic dose of fosphenytoin (18 mg kg-1
      phenytoin sodium equivalents) were concomitantly administered to 15 African
      children with malaria. Control children (n = 13) with malaria received a similar
      dose of fosphenytoin and multiple i.v. doses (25 mg kg-1 8 hourly for 72 h) of
      cefotaxime (CEF). Blood pressure, heart rate, respiratory rate, oxygen
      saturation, level of consciousness and convulsion episodes were monitored.
      Cerebrospinal fluid (CSF) and plasma phenytoin concentrations were determined.
      RESULTS: The area under the plasma unbound phenytoin concentration-time curve
      (AUC(0, infinity ); means (CAP, CEF): 58.5, 47.6 micro g ml-1 h; 95% CI for
      difference between means: -35.0, 11.4), the peak unbound phenytoin concentrations
      (Cmax; medians: 1.12, 1.29 micro g ml-1; 95% CI: -0.5, 0.04), the times to Cmax
      (tmax; medians: 4.0, 4.0 h; 95% CI: -2.0, 3.7), the CSF:plasma phenytoin ratios
      (means: 0.21, 0.22; 95% CI: -0.8, 0.10), the fraction of phenytoin unbound
      (means: 0.06, 0.09; 95% CI: -0.01, 0.07) and the cardiovascular parameters were
      not significantly different between CAP and CEF groups. However, mean terminal
      elimination half-life (t1/2,z) was significantly longer (23.7, 15.5 h; 95% CI:
      1.71, 14.98) in the CAP group compared with the CEF group. Seventy per cent of
      the children had no convulsions during the study period. CONCLUSIONS: Concomitant
      administration of chloramphenicol and a single i.m. dose of fosphenytoin alters
      the t1/2,z but not the other pharmacokinetic parameters or clinical effects of
      phenytoin in African children with severe malaria. Moreover, a single i.m. dose
      of fosphenytoin provides anticonvulsant prophylaxis in the majority of the
      children over 72 h. However, a larger study would be needed to investigate the
      effect of concomitant administration of multiple doses of the two drugs in this
      population of patients.

PMID- 12492613
TI  - Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme
      CYP3A4?
AB  - AIMS: To evaluate the antimalarial agent quinine as a potential in vivo probe for
      hepatic cytochrome P450 (CYP) 3A4 activity. METHODS: Ten healthy adult volunteers
      received, by randomized crossover design, either a single oral dose of quinine
      sulphate (600 mg) alone, or quinine sulphate (600 mg) plus the CYP3A4 inhibitor
      troleandomycin (TAO; 500 mg every 8 h). Plasma and urine samples were collected
      before quinine administration, and up to 48 h thereafter, then analysed by
      h.p.l.c. for both quinine and its CYP3A4-generated metabolite, 3-hydroxyquinine.
      During both phases, the erythromycin breath test (ERMBT) was administered at
      specific times to assess hepatic CYP3A4 activity. RESULTS: Compared with control,
      TAO treatment significantly decreased the mean time-averaged ERMBT result by 77%
      (95% CI, 68, 85%), the mean apparent oral clearance of quinine (CL/F ) by 45%
      (95% CI, 39, 52%), and the mean apparent formation clearance of 3-hydroxyquinine
      (CL3-OH) by 81% (95% CI, 76, 87%). There was no correlation between the TAO
      mediated percent decrease in the time-averaged ERMBT result and the percent
      decrease in CL/F or in CL3-OH. When TAO and control treatments were analysed
      separately, there were no significant correlations between the time-averaged
      ERMBT result and CL/F, CL3-OH, or single plasma quinine concentration at 12, 24,
      and 48 h. CONCLUSIONS: Quinine may be a useful probe to detect inhibition of
      liver CYP3A4 activity within an individual. Further studies are needed to
      determine whether it can provide a quantitative measure of CYP3A4 activity
      suitable for intersubject comparison.

PMID- 12492614
TI  - Amoxicillin/clavulanic acid is ineffective at preventing otitis media in children
      with presumed viral upper respiratory infection: a randomized, double-blind
      equivalence, placebo-controlled trial.
AB  - AIMS: To assess the equivalence of amoxicillin/clavulanic acid and placebo in the
      prevention of acute otitis media in children at high risk of acute otitis media
      who develop upper respiratory tract infection. METHODS: This was a multicentre,
      equivalence, randomized, double-blind trial of two parallel groups comparing 5
      days of amoxicillin/clavulanic acid 75 mg kg-1 day-1 (i.e. 25 mg kg-1 every 8 h)
      and placebo. The main outcome measure was acute otitis media occurring within 8
      12 days of initiating treatment. RESULTS: Two hundred and three infants, aged 3
      months-3 years with upper respiratory tract infection over 36 h and a history of
      recurrent acute otitis media were included over 8.5 months. Two children were
      lost to follow-up. Patient characteristics were similar in both groups. In the
      intention to treat analysis the frequency of acute otitis media was 16.2% (16/99)
      in the placebo group and 9.6% (10/104) in the amoxicillin/clavulanic acid group
      (P = 0.288). The difference between acute otitis media rates was 6.6% (one-sided
      95% confidence interval of 14.3%). The occurrence of side-effects was similar in
      the amoxicillin/clavulanic acid and placebo groups. CONCLUSIONS: The difference
      in effectiveness between antibiotic and placebo was not greater than 14.3%, and
      we calculated that 94 children would need to be exposed to antibiotics to avoid
      six cases of acute otitis media. In view of the risk of development of resistance
      due to frequent exposure to antibiotics, our study supports the need for
      reduction in the administration of antibiotics in upper respiratory tract
      infection even in children at high risk of acute otitis media.

PMID- 12492615
TI  - The value of inpatient pharmaceutical counselling to elderly patients prior to
      discharge.
AB  - AIMS: The use of medication and information discharge summaries (MIDS) has become
      a standard procedure in many hospitals. We have evaluated if these summaries,
      together with in-patient pharmaceutical counselling backed up with a simple
      medicine reminder card, may help with the delivery of seamless pharmaceutical
      care. METHODS: Elderly patients prescribed more than four items discharged to
      their own home received the standard discharge policy including a recently
      introduced MIDS and medicine reminder card. Each patient's GP was sent a copy on
      discharge. Pre-discharge a pharmacist counselled study patients about their
      medicines and compliance. A research pharmacist visited patients in their home
      approximately 2-3 weeks and at 3 months post-discharge to determine their drug
      knowledge, compliance, home medicine stocks and any healthcare related events.
      RESULTS: Forty-three study and 40 control patients completed both visits. Their
      mean (s.d.) ages were 80.2 (5,7) and 81.1 (5,8) years and they were prescribed
      7.1 (1.8) and 7.1 (2.3) items, respectively. At visit 1 knowledge (P < 0.01) and
      compliance (P < 0.001) was better in the study group. At visit 2 compliance had
      improved in the study group (P < 0.001). Unplanned visits to the GP and
      readmission to hospital amongst the study group were 19 and 5, respectively,
      which were both significantly less (P < 0.05) than 27 and 13 in the control
      group. At visit 2 for the study group the 24 unplanned GP visits and three re
      admissions were significantly (P < 0.05) less than the respective 32 and 15 in
      the control group. At visit 1, two study group patients had altered their own
      medication compared with 10 control patients. At visit 2 these reduced to 0 and
      4, respectively. CONCLUSIONS: In-patient pharmaceutical counselling, linked to a
      medication and information discharge summary and a medicine reminder card,
      contributed to better drug knowledge and compliance together with reduced
      unplanned visits to the doctor and re-admissions. A pharmaceutical domiciliary
      visit consolidated the improved healthcare outcomes.

PMID- 12492616
TI  - Adverse drug reactions and off-label drug use in paediatric outpatients.
AB  - AIMS: To investigate the potential relationship between off-label drug use and
      increased risk of adverse drug reactions in paediatric outpatients. METHODS: A
      prospective pharmacovigilance survey of drug prescribing in office based
      paediatricians was carried out in Haute-Garonne County (south west of France).
      RESULTS: The study involved a sample of 1419 children under 16 years old. Forty
      two percent of patients were exposed to at least one off-label prescription. The
      incidence of adverse drug reactions was 1.41% (95% CI 0.79, 2.11). Off-label drug
      use was significantly associated with adverse drug reactions (relative risk 3.44;
      95% CI 1.26, 9.38), particularly when it was due to an indication different than
      that defined in the Summary Product Characteristics (relative risk 4.42; 95% CI
      1.60, 12.25). CONCLUSIONS: Our data suggest an increasing risk of adverse drug
      reactions related to off-label drug use. This risk would be acceptable if further
      studies prove the potential benefit of such a drug use.

PMID- 12492617
TI  - Association between the N-acetylation genetic polymorphism and bronchial asthma.
AB  - AIMS: Since polymorphic N-acetyltransferase 2 (NAT2) has been suggested as a
      susceptibility factor for atopic diseases, the study was undertaken to
      investigate whether an association exists between acetylation polymorphism and
      asthma patients with atopy. METHODS: The frequencies of NAT2 alleles and
      genotypes were determined by PCR/RFLP in a total of 210 asthma patients
      (extrinsic (n = 108) and intrinsic (n = 102) asthmatics) and 240 control
      subjects. Presence of the NAT2*4 (wild-type) allele defined a NAT2 genotype as
      rapid and combinations of mutant alleles NAT2*5 A, *5B, *5C, *6 A, and *7B as
      slow. RESULTS: Genotypes coding for slow acetylation were detected in 70.4, 58.4
      and 58.3% of extrinsic asthmatics, but intrinsic asthmatics and control subjects,
      respectively. The frequency of slow acetylators was higher among extrinsic
      asthmatics than intrinsic asthmatics, this difference did not reach statistical
      significance (odds ratio 1.02, 95% confidence interval 0.64, 1.63, P = 0.085).
      However, we found a relatively moderate, but significantly higher, increased
      frequency of slow acetylators among extrinsic asthma patients compared with
      control subjects (odds ratio 1.70, 95% confidence interval 1.04, 2.76, P =
      0.042). CONCLUSIONS: This study shows an association between acetylation
      polymorphism and susceptibility to extrinsic asthma, but not to intrinsic asthma,
      suggesting a minor role of the NAT2 polymorphism in the development of atopic
      asthma.

PMID- 12492618
TI  - Renal 131I-hippuran extraction in man: effects of dopamine.
AB  - AIMS: This study examined the 131I-hippuran extraction fraction during baseline
      renal blood flow rates and at high flow rates induced by dopamine. METHODS: In 12
      healthy subjects, arterial and renal venous sampling was used to measure the
      renal extraction of 131I-hippuran. Effective renal plasma flow values determined
      by the urinary clearance of 131I-hippuran were compared with renal plasma flow
      values corrected for incomplete extraction of 131I-hippuran. RESULTS: Dopamine (3
      micro g kg-1 min-1) decreased 131I-hippuran extraction from 75 +/- 4% at baseline
      to 62 +/- 6% (means +/- 95% confidence intervals, P < 0.001). Hence, the increase
      in renal plasma flow (85 +/- 23%) greatly exceeded the rise in effective renal
      plasma flow (51 +/- 15%, P < 0.002). CONCLUSIONS: Dopamine induced increases in
      renal blood flow are largely under-estimated when measurements are not corrected
      for incomplete extraction of 131I-hippuran.

PMID- 12492619
TI  - Limited adherence to safety instructions in drug leaflets.

PMID- 12492620
TI  - The effect of diltiazem, a calcium channel blocker, in asthmatic patients.

PMID- 12492621
TI  - Treatment functional GI disease: the complex pharmacology of serotonergic drugs.

PMID- 12492623
TI  - Effects of supratherapeutic doses of ebastine and terfenadine on the QT interval.

PMID- 12492624
TI  - Palm oil in human nutrition: recent advances.

PMID- 12492625
TI  - Dietary fat and heart health: in search of the ideal fat.

PMID- 12492626
TI  - Cholesterolaemic effect of palmitic acid in relation to other dietary fatty
      acids.
AB  - The effect of dietary intake of high palmitic acid levels in combination with
      other fatty acids in normal subjects was assessed. Palmitic acid (10% of energy)
      was fed in conjunction with decreasing levels of linoleic acid to determine if a
      threshold level of linoleic acid prevented palmitic acid from being
      hypercholesterolaemic. Healthy subjects received each of the diet treatments for
      21 days, followed by washout periods of 7 days. In a second experiment, the
      effect of exchanging palmitic acid for trans fatty acids on plasma lipoprotein
      cholesterol levels and on rates for endogenous synthesis of cholesterol in normal
      subjects was investigated. Diet treatment lasted for 30 days. On day 30 of each
      diet treatment, a priming dose of deuterium was consumed, followed by a
      subsequent blood sample at 24 h. Blood cholesterol fractions were isolated and
      analysed by isotope ratio mass spectrometry to measure cholesterol fractional
      synthetic rates. In the first experiment, total plasma cholesterol levels
      increased as the percentage of linoleic acid decreased. The data indicated that
      high levels of palmitic acid were not hypercholesterolaemic if intake of linoleic
      acid was greater than 4.5% of energy. When the diet contained trans fatty acids
      plasma total and low-density lipoprotein-cholesterol increased and cholesterol
      synthesis increased with a decrease in high-density lipoprotein-cholesterol.

PMID- 12492627
TI  - Effect of dietary cholesterol, trans and saturated fatty acids on serum
      lipoproteins in non-human primates.
AB  - Nine cynomolgus monkeys were rotated randomly through four dietary treatments
      with each treatment lasting 6 weeks. A wash-out period of 4 weeks was maintained
      between each dietary rotation. The animals were fed diets containing 32% energy
      fat derived from palm olein (POL), lauric-myristic-rich oil blend (LM), American
      Heart Association (AHA) rich oil blend and hydrogenated soybean oil blend
      (trans). Diets were fed with (phase 1) or without (phase 2) the addition of
      dietary cholesterol (0.1%). In phase 1, when animals were fed without dietary
      cholesterol, plasma total cholesterol (TC) and low-density lipoprotein
      cholesterol (LDL-C) was significantly raised and high-density lipoprotein
      cholesterol (HDL-C) was significantly depressed by the trans diets relative to
      all other dietary treatments. The resulting LDL-C/HDL-C ratio was also
      significantly increased. The LM diet increased TC significantly relative to the
      AHA diet while LDL-C was significantly increased compared to both POL and AHA.
      Apolipoprotein (apo) B was not affected significantly by these dietary
      treatments. Apo A1 was significantly increased by POL relative to all other
      dietary treatments. The trans diet reduced apo A1 and the resulting apo B/A1
      ratio was increased significantly by trans relative to all other dietary
      treatments. Addition of 0.1% dietary cholesterol to these diets almost doubled
      the plasma TC and LDL-C in all dietary treatments. However, HDL-C was only
      marginally higher with the addition of dietary cholesterol. The LM + C
      (cholesterol added) diet resulted in the highest TC and LDL-C that was
      significant compared to all other dietary treatments. Trans + C increased TC
      compared to POL + C and AHA + C diets while increases in the LDL-C did not attain
      significance. The addition of dietary cholesterol did not affect HDL-C between
      treatments whereas plasma triglycerides were significantly increased by the trans
      + C diet relative to all other treatments. Both the trans + C and LM + C diets
      increased apo B and decreased apo A1 relative to the POL + C and AHA + C diets.
      The resulting apo B/A1 ratio was similarly altered. These results affirm that the
      lauric + myristic acid combination, along with trans fatty acids, increased
      lipoprotein-associated coronary heart disease risk factors compared to either POL
      or AHA.

PMID- 12492628
TI  - Effect of palm olein oil in a moderate-fat diet on low-density lipoprotein
      composition in non-human primates.
AB  - Plasma low-density lipoprotein cholesterol (LDL-C) concentrations in vervet
      monkeys (Cercopithecus aethiops) can be modulated by the type and amount of fat
      in the diet. There is, however, a paucity of information on the effect of
      different types and quantity of dietary fat on the plasma LDL composition in
      vervets. The objective of this study was to determine the effect of different
      sources of dietary fat on the concentrations and composition of circulating
      plasma LDL in vervets consuming moderate-fat diets containing either animal fat,
      sunflower oil or palm olein. Fifty adult male vervets, never exposed to a Western
      type atherogenic diet, were randomly assigned to two groups. For 6 weeks 30
      vervets were fed a moderate-fat (28%E) moderate-cholesterol (26 mg
      cholesterol/1000 kJ) diet (MFD) with a polyunsaturated to saturated fatty acid
      ratio (P/S) of 0.4; 20 vervets were fed a high-fat (34%E) high-cholesterol (98 mg
      cholesterol/1000 kJ) diet (HFD) with a P/S ratio of 0.6. Fasting blood samples
      were collected from all 50 vervets for plasma lipid measurements. The 30 vervets
      receiving the MFD were stratified into three comparable experimental groups of 10
      each according to their LDL-C and high-density lipoprotein cholesterol (HDL-C)
      concentrations and bodyweight. One group continued with the MFD, in which 11%E
      was derived from lard (MFD-AF); in the other two groups the lard was substituted
      isocalorically with either sunflower oil (SO) (MFD-SO) or palm olein oil (PO)
      (MFD-PO). The three groups were fed the respective experimental diets for 24
      months and LDL component concentrations and composition were assessed at 6
      monthly intervals. In the long-term study the MFD-AF, MFD-SO and MFD-PO groups
      showed no significant time-specific group differences at 6, 12, 18 or 24 months
      with regard to the LDL component concentrations, composition, as well as the LDL
      molecular weight. As expected, after 6 weeks of dietary exposure the HFD group
      had significantly higher plasma and lipoprotein total cholesterol, LDL component
      and apolipoprotein AI concentrations, as well as a higher LDL-C : HDL-C ratio
      compared to the MFD group (P 0.0005). LDL particle size was not significantly
      different between the HFD and MFD groups, but the HFD group had significantly
      fewer triacylglycerol and significantly more unesterified cholesterol molecules
      per LDL particle compared to the MFD group (P 0.0018). PO in a MFD is no
      different from AF or SO in its effect on LDL component concentrations,
      composition or particle size. The increased LDL-C concentration seen with the HFD
      could be accounted for by a more than two-fold increase in the number of
      circulating LDL particles and not as a result of enrichment of particles with
      cholesterol.

PMID- 12492629
TI  - Effect of palm olein oil in a moderate-fat diet on plasma lipoprotein profile and
      aortic atherosclerosis in non-human primates.
AB  - Several studies have reported on the effect of palm olein oil (PO; palmitic acid
      content approximately 38%) incorporation into the diet on blood cholesterol
      concentration. Information on the effect of PO on atherosclerosis is, however,
      lacking. In vervet monkeys (Cercopithecus aethiops), low-density lipoprotein
      cholesterol (LDL-C) concen-trations can be modulated by the type and amount of
      fat in the diet. The vervet is a proven model for both the type and composition
      of human atherosclerotic lesions. The aim of this study was to determine the
      effect of PO in a moderate-fat moderate-cholesterol diet (MFD) on plasma
      lipoproteins and the progression of atherosclerosis in a non-human primate model
      after 25.5 months of dietary exposure. Thirty adult male vervets, never exposed
      to a Western-type atherogenic diet, were stabilised on a MFD (28%E fat; 26 mg
      cholesterol/1000 kJ) with a polyunsaturated to saturated fatty acid (P/S) ratio
      of 0.4 for six weeks. Baseline LDL-C, high-density lipoprotein (HDL)-C and
      bodyweight were used to stratify the vervets into three comparable groups of 10
      each. One group continued with the MFD in which 11.0%E was derived from lard
      (AF). In the other two groups, the AF was substituted isocalorically with either
      sunflower oil (SO) or PO. Plasma lipids were measured at 6-monthly intervals and
      atherosclerosis was assessed in the aorta and in five peripheral arteries after
      25.5 months of dietary exposure. The frequency of atherosclerosis in peripheral
      arteries and aortas was low. PO, relative to SO and AF, significantly reduced the
      risk for developing early lesions in peripheral arteries (P = 0.0277 and P =
      0.0038, respectively) and, relative to AF, in aortas (P = 0.0335). The
      cholesterolaemic effect of MFD-PO was not significantly different from MFD-SO and
      MFD-AF. However, at 24 months the plasma total cholesterol concentration with MFD
      AF was significantly higher than with MFD-SO (P = 0.0256). It is confirmed that a
      MFD with PO is no different from AF or SO in its cholesterolaemic effect. The
      anti-atherogenic efficacy of a MFD with PO, relative to SO and AF, was
      demonstrated in a non-human primate model of atherogenesis.

PMID- 12492630
TI  - Red palm oil in experimental atherosclerosis.

PMID- 12492631
TI  - Bioavailability and vitamin A value of carotenes from red palm oil assessed by an
      extrinsic isotope reference method.
AB  - Red palm oil (RPO) contains high concentrations of beta- and alpha-carotene, and
      is presumed to possess a higher vitamin A value than other foods. The objective
      was to determine the metabolic vitamin A and carotene values of refined red palm
      oil in healthy adult subjects, using a stable isotope reference method. Twelve
      healthy subjects were administered a small standardised meal containing 10 g RPO
      (2.4 mg beta-carotene and 1.8 mg alpha-carotene) in a blended juice-based drink
      also containing 2 mg tetradeuterated retinyl acetate (d4-RA) as a metabolic
      reference. At baseline and at several times after the test meal, the
      concentrations of carotenes and of d4- and d0-(unlabelled) retinyl esters, in the
      plasma chylomicron-rich (d < 1.006) fraction were determined by high high
      performance liquid chromatography and gas chromatography mass spectrometry,
      respectively. The masses of palm oil-derived vitamin A and carotenes absorbed
      ('yield') were calculated assuming 80% absorption of the d4-RA reference dose.
      The mean yield of retinol from the RPO was 0.41 mg, ranging from 0.17 mg to 0.86
      mg. The mean yields of beta- and alpha-carotene were 0.29 mg and 0.25 mg,
      respectively, suggesting that beta-carotene was more extensively metabolised than
      alpha-carotene. Subjects assimilated an average of 23% of the dose of carotenes,
      as the sum of retinol and unmetabolised carotenes. The vitamin A values of red
      palm oil obtained under these conditions, a mean of 0.17 mg retinol absorbed per
      mg beta-carotene consumed (beta-carotene : retinol equivalency of 5.7:1) is
      higher than that of all other vegetable sources we have evaluated to date.

PMID- 12492632
TI  - Vitamin E in cardiovascular disease: has the die been cast?
AB  - Cardiovascular disease, in particular coronary artery disease (CAD), remains the
      most important cause of morbidity and mortality in developed countries and, in
      the near future, more so in the developing world. Atherosclerotic plaque
      formation is the underlying basis for CAD. Growth of the plaque leads to coronary
      stenosis, causing a progressive decrease in blood flow that results in angina
      pectoris. Acute myocardial infarction and unstable angina were recently
      recognised as related to plaque rupture, not progressive coronary stenosis. Acute
      thrombus formation causes an abrupt coronary occlusion. The characteristics of
      the fibrin cap, contents of the plaque, rheological factors and active
      inflammation within the plaque contribute to plaque rupture. Oxidative processes
      are important in plaque formation. Oxidized low density lipoproteins (LDL) but
      not unoxidized LDL is engulfed by resident intimal macrophages, transforming them
      into foam cells which develop into fatty streaks, the precursors of the
      atherosclerotic plaque. Inflammation is important both in plaque formation and
      rupture. Animal studies have shown that antioxidants reduce plaque formation and
      lead to plaque stabilisation. In humans, high intakes of antioxidants are
      associated with lower incidence of CAD, despite high serum cholesterol levels.
      This observation suggests a role for inflammation in CAD and that reducing
      inflammation using antioxidants may ameliorate these processes. Men and women
      with high intakes of vitamin E were found to have less CAD. Vitamin E
      supplementation was associated with a significant reduction in myocardial
      infarction and cardiovascular events in the incidence of recurrent myocardial
      infarction. In the hierarchy of evidence in evidence-based medicine, data from
      large placebo-controlled clinical trials is considered necessary. Results from
      various mega-trials have not shown benefits (nor adverse effects) conferred by
      vitamin E supplementation, suggesting that vitamin E has no role in the treatment
      of CAD. These results do not seem to confirm, at the clinical level, the effect
      of antioxidants against active inflammation during plaque rupture. However, a
      closer examination of these studies showed a number of limitations, rendering
      them inconclusive in addressing the role of vitamin E in CAD prevention and
      treatment. Further studies that specifically address the issue of vitamin E in
      the pathogenesis of atherosclerosis and in the treatment of CAD need be
      performed. These studies should use the more potent antioxidant property of alpha
      tocotrienol vitamin E.

PMID- 12492633
TI  - Effect of vitamin E on plasma malondialdehyde, antioxidant enzyme levels and the
      rates of wound closures during wound healing in normal and diabetic rats.
AB  - Vitamin E is composed of various subfamilies that include tocopherols and
      tocotrienols. These compounds have antioxidant properties but differ in
      structure, dietary source and potency. In this study we evaluated the efficacy of
      alpha-tocopherol as an antioxidant and its role in wound closure in normal and
      streptozotocin-induced diabetic rats. The healing of 6 cm linear incisions
      created on the back of each male Sprague-Dawley rat (250-300 g) was monitored by
      measuring the length of the wounds daily. The rats were divided into two
      categories; normal and streptozotocin-induced diabetic rats. For each category,
      the animals were further divided into two groups; those untreated and those
      receiving 200 mg/kg bodyweight alpha-tocopherols daily by oral gavage. All rats
      were fed standard food and water ad libitum. Blood samples were taken at 0, 5 and
      10 days after the wounds were created for the determination of malondialdehyde
      levels and red cell superoxide dismutase, catalase and glutathione peroxidase
      activities. The results showed that alpha-tocopherol reduced plasma
      malondialdehyde levels, increased glutathione peroxidase activity and accelerated
      the rate of wound closure in treated rats.

PMID- 12492634
TI  - Role of GTP-binding proteins in reversing the antiproliferative effects of
      tocotrienols in preneoplastic mammary epithelial cells.
AB  - Tocotrienols are a subclass of vitamin E compounds that display potent anticancer
      activity. Determining the anticancer mechanism of action of tocotrienols will
      provide essential information necessary for understanding the potential health
      benefits of these compounds in reducing the risk of breast cancer in women.
      Epidermal growth factor (EGF) is a potent mitogen for normal and neoplastic
      mammary epithelial cells. Initial events in EGF-receptor (EGF-R) mitogenic
      signalling are G-protein activation, stimulation of adenylyl cyclase and cyclic
      AMP (cAMP) production. Studies were conducted to determine if the
      antiproliferative effects of tocotrienols are associated with reduced EGF-induced
      G-protein and cAMP-dependent mitogenic signalling. Preneoplastic CL-S1 mouse
      mammary epithelial cells were grown in culture and maintained on serum-free media
      containing 0-25 micro mol/L tocotrienol-rich fraction of palm oil and/or
      different doses of pharmacological agents that alter intracellular cAMP levels.
      Tocotrienol-induced effects on EGF-receptor levels of tyrosine kinase activity,
      as well as EGF-dependent mitogen-activated pathway kinase (MAPK) and Akt
      activation, were determined by western blot analysis. Results demonstrate that
      the antiproliferative effects of tocotrienols in preneoplastic mammary epithelial
      cells do not reflect a reduction in EGF-receptor mitogenic responsiveness, but
      rather, result from an inhibition in early post-receptor events involved in cAMP
      production upstream from EGF-dependent MAPK and phosphoinositide 3-kinase/Akt
      mitogenic signalling. In summary, these data further characterise the mechanism
      of action of tocotrienols in suppressing preneoplastic mammary epithelial cell
      proliferation, and advance the current understanding of the potential health
      benefits of these compounds in reducing the risk of breast cancer in women.

PMID- 12492635
TI  - 17Beta-estradiol epoxidation as the molecular basis for breast cancer initiation
      and prevention.
AB  - Epidemiological and animal studies have indicated that 17beta-estradiol (E2) is
      involved in breast cancer; however, the mechanism is unclear. We found that E2
      could be activated by epoxidation, resulting in its ability to inhibit nuclear
      DNA-dependent RNA synthesis, and to bind DNA, forming DNA adducts both in vitro
      and in vivo. Because epoxidation is required for the activation of many chemical
      carcinogens, including benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene and
      aflatoxins, we proposed previously that E2 epoxidation is the underlying
      mechanism for the initiation of breast cancer. The first part of this review is
      to present the experimental evidence obtained from this laboratory in support of
      this hypothesis. Based on these newly discovered insights on E2 epoxidation and
      its initiation role in breast cancer carcinogenesis, a method to screen
      chemopreventive agents against breast cancer has been developed. This constitutes
      the second part of the review. Two examples will be used to illustrate the
      utility of this screening technique. The effect of fat on breast cancer has been
      a longstanding but unresolved issue. Epidemiological studies provide conflicting
      results regarding the association of dietary fat and breast cancer. Because
      vegetable oils contain various amount of mono- and polyunsaturated fatty acids,
      they are potential antioxidants. Data are presented to show that commercial
      vegetable oils, independent of their mono- or polyunsaturated fatty acid content,
      are all able to prevent the formation of E2 epoxide, as measured by the loss of
      the ability of E2 to inhibit nuclear RNA synthesis in vitro. Tamoxifen (TAM), an
      anti-estrogen used for breast cancer treatment, has recently been found to have a
      strong breast cancer preventive effect. The mechanism for this is unknown. Using
      the same screening technique, we found that when incubated together with E2 for
      epoxidation, TAM was able to prevent the formation of E2 epoxide, as evidenced by
      both the loss of the ability of E2 to inhibit nuclear RNA synthesis and the
      reduced binding of [3H]-labelled E2 to nuclear DNA in a dose-dependent manner.
      These experimental results suggest that the breast cancer preventive effect of
      TAM is to prevent the formation of E2 epoxide through a competitive epoxidation
      mechanism with E2.

PMID- 12492636
TI  - Polyphenol-enriched extract of oil palm fronds (Elaeis guineensis) promotes
      vascular relaxation via endothelium-dependent mechanisms.
AB  - Plant-based polyphenolic compounds have been reported to possess cardiovascular
      health benefits. Several dietary sources, including herbs and spices, fruits and
      vegetables, and tea and wine, contain an array of biologically active compounds
      that have been shown to be effective in retarding oxidation of low-density
      lipoproteins (LDL) and promoting vascular relaxation. In the present study four
      different plant sources, both edible and non-edible, were evaluated for potential
      activity. Organic extracts enriched in polyphenols were prepared from palm fronds
      (Elaesis guineensis); lemongrass (Cymbopogon citrates); papaya shoots (Carica
      papaya) and green chilli (Capsicum frutescenes) and tested for their ability to
      prevent in vitro oxidation of LDL, and for potential vascular relaxation actions.
      Rings of rat thoracic aorta and isolated perfused mesenteric vascular beds were
      mounted in organ baths, contracted using a half-maximal dose of noradrenaline and
      exposed to cumulative additions of test extracts. Palm frond extract resulted in
      considerable relaxation (>75%) in both preparations and was found to be
      endothelium-dependent as removal of endothelium or inhibition of endogenous
      nitric oxide (NO) led to a total loss in relaxant activity. Lemongrass extract
      caused a greater relaxation action in the mesenteric preparation compared to
      aortic rings, and appears to be mediated via NO-independent and non-prostanoid
      mechanisms. Of the extracts tested, palm fronds also demonstrated the highest
      antioxidant capacity, as determined by the ferric reducing activity/potential
      assay, and resulted in a significant delay (P < 0.05) in the oxidation of LDL.
      Collectively, these preliminary findings lend further support to the potential
      cardiovascular actions of plant polyphenols and also identify oil palm fronds as
      containing constituents that promote vascular relaxation via endothelium
      dependent mechanisms.

PMID- 12492637
TI  - Potential of palm oil utilisation in aquaculture feeds.
AB  - One key ingredient used in the formulation of aquafeed is fish oil, which is
      produced from small marine pelagic fish and represents a finite fishery resource.
      At the present time, global fish oil production has reached a plateau and is not
      expected to increase beyond current levels. Recent estimates suggest that fish
      oils may be unable to meet demands from the rapidly growing aquaculture industry
      by as early as 2005. Therefore, there is currently great interest within the
      aquafeed industry in evaluating alternatives to fish oils. The ever-expanding oil
      palm cultivation in Malaysia and other tropical countries offers the possibility
      of an increased and constant availability of palm oil products for aquafeed
      formulation. Research into the use of palm oil in aquafeed begun around the mid
      1990s and this review examines some of the findings from these studies. The use
      of palm oil in fish diets has generally shown encouraging results. Improved
      growth, feed efficiency, protein utilisation, reproductive performance and higher
      concentrations of alpha-tocopherol in fish fillets have been reported. Recent
      evidence for the ability of palm oil to substitute for fish oil in catfish diets
      is reviewed. The potential of palm oil use in aquafeed and future experimental
      directions are suggested. The aquaculture feed industry offers a great avenue to
      increase and diversify the use of palm oil-based products.

PMID- 12492638
TI  - Nutrition for life's stages: the evidence base.

PMID- 12492639
TI  - Nutrition: the new world map.
AB  - The map of nutrition, evident in the structure of any course or textbook, derives
      from theses that framed a science begun in the 1840s, developed until the 1940s,
      and consolidated until now. Nutritionists now are as perplexed as the explorers
      of half a millennium ago, who continued to use maps that did not fit the wider
      world they found. Until the 1600s, alternatives to Ptolemaic cosmology remained
      unthinkable despite its obvious inadequacy, because it was of a universe with the
      earth, and man made in the divine image, at its centre. Nutritionists now are
      inhibited for similar reasons. Two determining principles of nutrition science,
      the identification of health with growth and the belief that animal food is
      superior to plant food, have a deep origin; they derive from the materialist
      ideology that asserts a manifest destiny of humans to exploit and consume the
      living and natural world. In response, a new nutrition is emerging, with a global
      perspective, whose ideology places humans within nature, and whose theses make a
      wider frame, able to fit the world as we can discern it now. The new nutrition
      gives equal value to personal, population and planetary health, with all that
      implies, including the concept that the world is best perceived as a whole. The
      Copernican revolution changed the meaning of movement on earth. The new nutrition
      can change the meaning of life on earth. Now is the time to draw its map.

PMID- 12492640
TI  - Nutrition: the new world disorder.
AB  - Scale up 'we are what we eat' and nutrition is revealed as an aspect of world
      governance. The quality and nature of food systems has always tended to determine
      not only the health and welfare but also the fate of nations. The independence of
      nations depends on their development of their own human and natural resources,
      including food systems, which, if resilient, are indigenous, traditional, or
      evolved over time to climate, terrain and culture. Rapid adoption of untested or
      foreign food systems is hazardous not only to health, but also to security and
      sovereignty. Immediate gain may cause permanent loss. Dietary guidelines that
      recommend strange foods are liable to disrupt previous established food cultures.
      Since the 1960s the 'green revolution' has increased crop yield, and has also
      accelerated the exodus of hundreds of millions of farmers and their families from
      the land into lives of misery in mega-cities. This is a root cause of increased
      global inequity, instability and violence. 'Free trade' of food, in which value
      is determined by price, is imposed by dominant governments in alliance with
      industry when they believe they can thereby control the markets. The World Trade
      Organization and other agencies coordinate the work of transnational corporations
      that are the modern equivalents of the East India companies. Scientists should
      consider the wider dimensions of their work, nutrition scientists not least,
      because of the key place of food systems in all societies.

PMID- 12492641
TI  - Discrepancies in nutritional recommendations: the need for evidence based
      nutrition.
AB  - The widespread acceptance that 'evidence-based medicine' should determine all
      aspects of clinical practice leads to a consideration as to whether 'evidence
      based nutrition' should be based on similar principles. Randomised controlled
      trials (RCT) are universally regarded as the gold standard by which to determine
      whether a drug is appropriate in a particular clinical situation. The evidence
      for some nutritional recommendations is indeed substantiated by RCT but in the
      case of some chronic diseases, notably cancers, where nutritional factors may
      operate as promoters or protectors many years before the onset of clinical
      disease, RCT may not be particularly appropriate. A range of experimental studies
      and descriptive epidemiological approaches may be regarded as sufficient to
      justify nutritional recommendations or dietary guidelines. Recommendations for
      the prevention and treatment of selected diseases will be considered in the
      context of their evidence-base.

PMID- 12492642
TI  - Will feeding mothers prevent the Asian metabolic syndrome epidemic?
AB  - Evolutionary pressures have probably amplified the mechanisms for minimizing the
      impact of environmental factors through compensatory maternal mechanisms.
      Nevertheless, experimentally there are clear long-term programming effects of
      manipulations to the maternal diet on the likelihood of neural-tube defects
      associated with folate deficiency The fat/lean ratios of the newborn, and
      subsequent development, seem to be linked to amino acid or folate supply. An
      altered balance in the hypothalamic-pituitary-adrenal axis, which experimentally
      has profound effects on brain development, is induced by low-protein maternal
      diets. Such diets are linked to a reduced pancreatic capacity for insulin
      production and to an altered hepatic architecture, with a change in the control
      of glucose metabolism. Human studies suggest that what happens in pregnancy is
      modified by the child's diet in the first months of life. Low birthweight is
      linked to early stunting, and predisposes to abdominal obesity and metabolic
      syndrome in later life. Metabolic syndrome amplifies the risks of diabetes,
      hypertension, coronary heart disease and probably some cancers. Mothers with
      gestational diabetes are themselves prone to early type 2 diabetes and produce
      heavier babies prone to childhood obesity and adolescent type 2 diabetes. There
      is increasing evidence of an intergenerational effect, with big babies being
      prone to excess weight gain, which then, in girls, predisposes them to diabetes
      in pregnancy, which, in turn, promotes an accelerating cycle of early diabetes in
      subsequent generations. Essential fatty acids and fat soluble vitamins are
      important, but we need early interventions and monitoring systems to justify
      coherent policies.

PMID- 12492643
TI  - Child and adolescent obesity in the 21st century: an Australian perspective.
AB  - The early 21st century has seen the development of a global epidemic of obesity
      in both developed and developing countries. In Australia at least one in five
      children and adolescents are overweight or obese, with rapid rises in prevalence
      apparently continuing. Similar trends are seen in other countries. Child and
      adolescent obesity is associated with both immediate and long-term medical and
      psychosocial problems, including a clustering of risk factors for the development
      of cardiovascular disease and diabetes. Thus, obesity poses a major health
      problem for the paediatric population. Major environmental and societal changes
      have led to a decrease in physical activity, a rise in sedentary behaviour and
      the consumption of high fat and high-energy foods, all in turn influencing the
      development of obesity. Effective management involves a multimodal approach with
      a developmentally aware approach, involvement of the family, a focus on healthy
      food choices, incorporation of physical activity and a decrease in sedentary
      behaviour all being important. Ultimately, however, the obesity epidemic requires
      a major focus on primary prevention. Australia has a national strategy for the
      prevention of overweight and obesity that depends upon intersectoral and
      intergovernmental cooperation, supported by adequate resourcing and significant
      community ownership.

PMID- 12492644
TI  - Nutrition before birth, programming and the perpetuation of social inequalities
      in health.
AB  - The need to explain social inequalities in health has led to the theory that
      chronic disease is due, in part, to a legacy of adverse experiences in early
      life. Epidemiological studies show consistently that individuals who are small at
      birth have an increased risk of cardiovascular disease in adulthood. There is
      growing consensus that this association reflects a causal relationship and is not
      simply the product of bias or confounding. The concept of programming is invoked
      as the biological mechanism; birth size is thus a proxy for fetal programming.
      Recent findings suggest that fetal programming interacts with the post-birth
      environment. The adverse exposures that are thought to underlie and potentiate
      programming cluster in socially patterned ways, thus creating substantial
      inequalities in health. Experiments in animals demonstrate that nutritional
      interventions before or during pregnancy can produce programming phenomena in the
      offspring, sometimes without an impact on birth size. However, the extent to
      which maternal nutrition contributes to programming in contemporary developed
      countries is uncertain.

PMID- 12492645
TI  - Nutrition and the early origins of adult disease.
AB  - There is now overwhelming evidence that much of our predisposition to adult
      illness is determined by the time of birth. These diseases appear to result from
      interactions between our genes, our intrauterine environment and our postnatal
      lifestyle. Those at greatest risk are individuals in communities making a rapid
      transition from lives of 'thrift' to a lives of 'plenty'. From a global
      perspective, such origins of diabetes, coronary heart disease and stroke, should
      render research in these fields as one of the highest priorities in human health
      care. Prevention will be enhanced by elucidation of the mechanisms by which the
      fetus is programmed by the mother for the life she expects it to live. At the
      present time, there is evidence that fetal nutrition and premature exposure to
      cortisol are effective intrauterine triggers, but a multitude of alternative
      pathways require investigation. It is also likely that programming extends across
      generations, and may involve the embryo and perhaps the oocyte. An oocyte that
      becomes an adult human develops in the uterus of its grandmother, so further
      research is required to describe the role of environments of grandmothers and
      mothers in predisposing offspring to health or illness in adult life.

PMID- 12492646
TI  - Risk of suboptimal iron and zinc nutriture among adolescent girls in Australia
      and New Zealand: causes, consequences, and solutions.
AB  - Surveys in Australia, New Zealand and other industrialised countries report that
      many adolescent girls have dietary intakes of iron and zinc that fail to meet
      their high physiological requirements for growing body tissues, expanding red
      cell mass, and onset of menarche. Such dietary inadequacies can be attributed to
      poor food selection patterns, and low energy intakes. Additional exacerbating non
      dietary factors may include high menstrual losses, strenuous exercise, pregnancy,
      low socioeconomic status and ethnicity. These findings are cause for concern
      because iron and zinc play essential roles in numerous metabolic functions and
      are required for optimal growth, immune and cognitive function, work capacity,
      sexual maturation, and bone mineralization. Moreover, if adolescents enter
      pregnancy with a compromised iron and zinc status, and continue to receive
      intakes of iron and zinc that do not meet their increased needs, their poor iron
      and zinc status could adversely affect the pregnancy outcome. Clearly,
      intervention strategies may be needed to improve the iron and zinc status of high
      risk adolescent subgroups in Australia and New Zealand. The recommended treatment
      for iron deficiency anaemia and moderate zinc deficiency is supplementation.
      Although dietary intervention is often recommended for treating non-anaemic iron
      deficiency and mild zinc deficiency, it is probably more effective and
      appropriate for prevention than for the treatment of suboptimal iron and zinc
      status. Many of the strategies for enhancing the content and bioavailability of
      dietary iron are also appropriate for zinc.

PMID- 12492647
TI  - Family food environments of 5-6-year-old-children: does socioeconomic status make
      a difference?

PMID- 12492648
TI  - Asian migration to Australia: food and health consequences.
AB  - Australia's food and health patterns are inextricably and increasingly linked
      with Asia. Indigenous Australians arrived in the continent via Asia and have
      linguistic connections with people who settled in south India; there was
      interaction and food trade between both South-East Asia and China and northern
      indigenous Australians over thousands of years. After European settlement in
      1788, there have been several and increasing (apart from the period of the
      infamous White Australian Policy following the Colonial period and Independence,
      with Federation, in 1901) waves of Asian migration, notably during the gold rush
      (Chinese), the building of the overland Telegraph (Afghans), the Colombo Plan and
      Asian student education in Australia from the 1950s onwards (South-Eeast Asians),
      and with refugees (Vietnamese and mainland Chinese), and business (late twentieth
      century) and progressive family reunion. Each wave has injected additional food
      cultural elements and caused a measure of health change for migrants and host
      citizens. Of principal advantage to Australia has been the progressive
      diversification of the food supply and associated health protection. This has
      increased food security and sustainability. The process of Australian eating
      patterns becoming Asianized is evident through market garden development (and the
      introduction of new foods), fresh food markets and groceries, restaurants and the
      development of household cooking skills (often taught by student boarders). Most
      of the diversification has been with grain (rice), legumes (soy), greens, root
      vegetables, and various 'exotic fruits'. Food acculturation with migration is
      generally bi-directional. Thus, for Asians in Australia, there has been a
      decrease in energy expenditure (and a lower plane of energy throughput), an
      increase in food energy density (through increased fat and sugary drink intakes),
      and a decrease in certain health protective foods (lentils, soy, greens) and
      beverages (tea). This sets the stage for 'eco-diseases'. In a population probably
      genetically programmed (but modifiably) in utero to abdominal obesity, diabetes
      (type II and gestational) and cardiovascular disease, these conditions may be
      rapidly acquired on migration, along with certain cancers (breast, colo-rectal
      and prostate). Thus, whilst Asian migration to Australia has provided health
      opportunities for host citizens, there have been threats to migrant citizens in
      regard to nutrition-related health.

PMID- 12492649
TI  - Morbidity mortality paradox of 1st generation Greek Australians.
AB  - There is evidence in Australia that 1st generation Greek Australians (GA),
      despite their high prevalence of cardiovascular disease (CVD) risk factors (e.g.
      obesity, diabetes, hyperlipidaemia, smoking, hypertension, sedentary lifestyles)
      continue to display more than 35% lower mortality from CVD and overall mortality
      compared with the Australian-born after at least 30 years in Australia. This has
      been called a 'morbidity mortality paradox' or 'Greek-migrant paradox'.
      Retrospective data from elderly Greek migrants participating in the International
      Union of Nutrition Sciences Food Habits in Later Life (FHILL) study suggests that
      diets changed on migration due to the: (i) lack of familiar foods in the new
      environment; (ii) abundant and cheap animal foods (iii) memories of hunger before
      migration; and (iv) status ascribed to energy dense foods (animal foods, white
      bread and sweets) and 'plumpness' as a sign of affluence and plant foods
      (legumes, vegetable dishes, grainy bread) and 'thinness' as a sign of poverty.
      This apparently resulted in traditional foods (e.g. olive oil) being replaced
      with 'new' foods (e.g. butter), 'traditional' plant dishes being made more energy
      dense, larger serves of animal foods, sweets and fats being consumed, and
      increased frequency of celebratory feasts. This shift in food pattern contributed
      to significant weight gain in GA. Despite these potentially adverse changes, data
      from Greece in the 1960s (seven countries study) and from Australia in the 1990s
      (FHILL study) has shown that Greek migrants have continued to eat large serves of
      putatively protective foods (leafy vegetables, onions, garlic, tomatoes,
      capsicum, lemon juice, herbs, legumes, fish) prepared according to Greek cuisine
      (e.g. vegetables stewed in oil). Furthermore, GA were found to return to the
      traditional Greek food pattern with advancing years. We suspect that these
      factors may explain why GA have recently been found to have over double the
      circulating concentrations of antioxidant carotenoids, especially lutein,
      compared with Australians of Anglo-Celtic ancestry. This in turn may have helped
      to make the CVD risk factors 'benign' and reduce the risk of death. This raises
      the question whether specific dietary guidelines need to be developed for recent
      migrants to Australia, encouraging them to retain the best of their traditional
      cultures and include the best of the mainstream culture.

PMID- 12492651
TI  - Nutrition knowledge and food consumption: can nutrition knowledge change food
      behaviour?
AB  - The status and explanatory role of nutrition knowledge is uncertain in public
      health nutrition. Much of the uncertainty about this area has been generated by
      conceptual confusion about the nature of knowledge and behaviours, and, nutrition
      knowledge and food behaviours in particular. So the paper describes several key
      concepts in some detail. The main argument is that 'nutrition knowledge' is a
      necessary but not sufficient factor for changes in consumers' food behaviours.
      Several classes of food behaviours and their causation are discussed. They are
      influenced by a number of environmental and intra-individual factors, including
      motivations. The interplay between motivational factors and information
      processing is important for nutrition promoters as is the distinction between
      declarative and procedural knowledge. Consideration of the domains of nutrition
      knowledge shows that their utility is likely to be related to consumers' and
      nutritionists' particular goals and viewpoints. A brief survey of the recent
      literature shows that the evidence for the influence of nutrition knowledge on
      food behaviours is mixed. Nevertheless, recent work suggests that nutrition
      knowledge may play a small but pivotal role in the adoption of healthier food
      habits. The implications of this overview for public health nutrition are: (i) We
      need to pay greater attention to the development of children's and adults'
      knowledge frameworks (schema building); (ii) There is a need for a renewed
      proactive role for the education sector; (iii) We need to take account of
      consumers' personal food goals and their acquisition of procedural knowledge
      which will enable them to attain their goals; (iv) Finally, much more research
      into the ways people learn and use food-related knowledge is required in the form
      of experimental interventions and longitudinal studies.

PMID- 12492650
TI  - Acculturation: Aboriginal and Torres Strait Islander nutrition.
AB  - The health status of Australia's indigenous people remains the worst of any
      subgroup within the population, and there is little evidence of any significant
      improvement over the past two decades, a situation unprecedented on a world
      scale. Compared with non-indigenous Australians, adult life expectancy is reduced
      by 15-20 years, with twice the rates of mortality from heart disease, 17 times
      the death rate from diabetes and 10 times the deaths from pneumonia. Despite
      improvements in perinatal mortality, they continue to represent a major cause of
      death, with infant deaths up to 2.5 times higher than the general population. The
      problems of educational disadvantage and unemployment are reflected in twice the
      rates of smoking and high obesity levels. Seven percent of indigenous families
      are homeless, with many more in inadequate and overcrowded housing, sometimes
      lacking water or sewerage. Economic disadvantage is real: 23% worry about going
      without food. Nutritional deficiencies in children have resulted in failure to
      thrive, contributing greatly to the problems of pneumonia and infectious
      diseases. The remoteness and isolation of many Aboriginal communities limit
      education and employment opportunities. It is important to consider the
      historical context of Aboriginal and Torres Strait Islander people, in order to
      gain an understanding of current health problems. The impact of past policies and
      practices and the 'introduced diet' are reflected in the poor health outcomes
      described above. This session will explore some of the underlying historical,
      cultural, structural and political factors that can be linked to the current
      problems.

PMID- 12492652
TI  - An innovative program for changing health behaviours.
AB  - Health-related behaviours affecting diet, weight control and physical activity
      are important for long-term cardiovascular health but behaviour change is
      difficult to initiate and even more difficult to maintain. We have developed a
      health promotion program, in which social support has a key role, to encourage a
      prudent diet, weight control and physical activity. Behaviour change is based on
      evaluating initial behaviour, weighing up costs and benefits, assessing barriers
      to change and goal-setting. We first evaluated the program in couples beginning
      to live together, a group chosen because of the risk of weight gain and decreased
      physical activity after marriage, readiness to change behaviour at that time in
      the life course and the opportunity to use partner's support in achieving
      behaviour change. In an initial short-term study with 39 couples, intake of fat
      and take-away foods decreased and consumption of fruit, vegetables and reduced
      fat foods increased. Physical activity increased and there was a 6% fall in blood
      cholesterol. Further evaluation in 137 couples included assessment after 12
      months. A decrease in fat intake and increase in physical activity and fitness
      seen at the end of the program persisted 1 year later. Lower cholesterol and a
      trend to lower weight gain and lower blood pressure were also maintained after 12
      months. We have modified the program aiming for weight loss, improved dietary
      habits and increased physical activity in overweight treated hypertensives,
      supported by their partners. Decreased intake of energy, total and saturated fat,
      and weight loss seen at the end of the 16 week program was significantly greater
      in the intervention group than with usual care. Blood pressure fell in the
      program group at the end of intervention and, in men, withdrawal of
      antihypertensive drugs was significantly associated with the intervention. Weight
      loss and a decrease in waist circumference were maintained in the program group
      up to 16 months after entering the study. This program has the potential for
      wider application in other at-risk groups.

PMID- 12492653
TI  - Sustaining dietary changes for preventing obesity and diabetes: lessons learned
      from the successes of other epidemic control programs.
AB  - A degree of success has been achieved in controlling several epidemics of
      infectious and non-infectious causes of death in countries, such as, Australia
      and New Zealand. Using the epidemiological triad (host, vector, environment) as a
      model, the key components of the control of these epidemics have been identified
      and compared to the current status of interventions to prevent obesity and its
      main disease consequence, type 2 diabetes. Reductions in mortality from tobacco,
      cardiovascular diseases, road crashes, cervical cancer and sudden infant death
      syndrome have been achieved by addressing all corners of the triad. Similarly,
      prevention programs have minimized the mortality from HIV AIDS and melanoma
      mortality rates are no longer rising. The main lessons learned from these
      prevention programs that could be applied to the obesity/diabetes epidemic are:
      taking a more comprehensive approach by increasing the environmental (mainly
      policy-based) initiatives; increasing the 'dose' of interventions through greater
      investment in programs; exploring opportunities to further influence the energy
      density of manufactured foods (one of the main vectors for increased energy
      intake); developing and communicating specific, action messages; and developing a
      stronger advocacy voice so that there is greater professional, public and
      political support for action. Successes in the other epidemics have been achieved
      in the face of substantial barriers within individuals, society, the private
      sector and government. The barriers for preventing obesity/diabetes are no less
      formidable, but the strategies for surmounting them have been well tested in
      other epidemics.

PMID- 12492654
TI  - Eating well: ageing gracefully!
AB  - The potential impact of dietary manipulation on the maintenance of physical and
      cognitive function between middle and old age has profound consequences for
      optimization of health, independence and well-being for the latter years. This
      review article considers four key areas: the role of diet and longevity;
      potential dietary measures to prevent sarcopenia; diet and cognitive function;
      and dietary interventions with regard to primary or secondary prevention of age
      related chronic disorders. Caloric restriction has been shown to slow ageing and
      maintain health status in both primates and rats. The evidence has limited
      applicability to humans, since it is unlikely that 30% reduced diets could be
      maintained long-term. The causes of sarcopenia, which manifests as loss of
      strength, disability and reduced quality of life, are multifactorial. However,
      resistance with ageing to regulatory amino acids known to modulate translation
      and initiation, particularly leucine, raise possibilities with regard to dietary
      intervention. The pattern of protein intake appears to be important in whole-body
      protein retention in older adults. A body of evidence is emerging that associates
      various dietary factors with a reduction in cognitive decline with age, or a
      delay in the progression of Alzheimer's disease, particularly with regard to
      intake of vitamin E and C-containing foods, as well as fish intake.
      Epidemiological evidence demonstrates a role for dietary intervention in the
      primary prevention of chronic diseases, even in old age. However, the potentially
      harmful effects of micronutrient supplementation in the secondary prevention of
      coronary heart disease raise concern regarding appropriate dietary messages for
      the elderly. The role of the antioxidants, lycopene, lutein and zeaxanthin, in
      the prevention of cataracts and age-related macular degeneration support the
      almost universal dietary guideline 'eat more fruit and vegetables'. In future
      dietary guidelines for the elderly need to be evidence-based and take into
      account protective food patterns, rather than target specific foods.

PMID- 12492655
TI  - Preventing cancer: dietary lifestyle or clinical intervention?
AB  - In Australia, colorectal, prostate and breast cancers are the most frequently
      occurring cancers in our society, a pattern that is quite different from that of
      underdeveloped countries. While diet is largely responsible for these
      differences, technological advances mean that the solutions can be viewed as
      systematic, financial, lifestyle or technological. They range from those that
      require self-discipline and care for personal well-being through to those that
      are seemingly a quick technological fix that will work in spite of an unhealthy
      lifestyle. There are three main approaches available for prevention of these
      cancers: dietary lifestyle, chemoprevention and screening. It has been estimated
      that the potential for prevention by a healthy dietary lifestyle is excellent and
      might reduce the burden of breast, prostate and colorectal cancer by 33-55%, 10
      20% and 66-75%, respectively. This should be safe and inexpensive and have
      collateral benefit such as reduced cardiovascular disease and osteoporosis. But,
      population compliance with more plant-based, less calorie dense foods is
      uncertain, the most healthy are likely to be the most compliant and evidence for
      effectiveness when interventional programs are undertaken is disappointing. It is
      not clear how dependable the dietary approach would be where inherited genetic
      factors determine risk for one of these cancers. Chemoprevention, the
      administration of natural or synthetic agents that delay, slow down or inhibit
      the process of tumorigenesis, are still under development and study. Hormone
      receptor modulators for breast and derivatives of non-steroidal anti-inflammatory
      drugs for colorectal cancers seem to have most promise and may reduce tumour
      incidence or death by as much as 50%. These agents are simpler to comply with
      than changing dietary lifestyle and they are more potent, hence they may be of
      particular value in high-risk settings. But they are likely to be more costly and
      run the risk of adverse effects with few collateral benefits. Screening, or the
      testing of an individual for a disease when that individual does not have any
      symptoms or signs suggesting that the disease is present, aims to prevent or
      delay the development of the cancer. Screening impacts on mortality more so than
      on incidence, reducing colorectal cancer mortality in the range 15-60% and breast
      cancer mortality by 23-37%. Screening has the advantage of being effective in
      high-risk as well as average-risk groups and is an 'easy' solution for the person
      who elects not to follow a healthy dietary lifestyle. Nonetheless, it is
      expensive, demanding on resources, provides no collateral benefits and does not
      have the same potential to reduce incidence of disease as does the dietary
      approach. With these Western cancers, we are fortunate that there are options for
      prevention. At least choices are available and some will suite certain
      circumstances and personalities more than others.

PMID- 12492656
TI  - Importance of preventing weight gain in adulthood.
AB  - In the last 20 years, there has been a dramatic upsurge in the average weight of
      Australian adults. In this period, on average, Australian women have gained 4.8
      kg, whilst Australian men have gained 3.6 kg. Consequently, the prevalence of
      obesity in men has increased from 8% to 19% and in women from 7% to 21%. This
      threatens to wipe away many recent health gains, as obesity has been associated
      with a wide range of chronic and debilitating illnesses, such as diabetes, heart
      disease, some cancers, sleep apnoea and osteoarthritis. Any weight gain in
      adulthood is usually as a result of an increase in fat stores, and the risk of
      ill-health from increasing weight actually begins at quite low BMI.
      Unfortunately, weight gain can be difficult or slow to reverse in the middle
      years because of physiological and behavioural changes that occur at this time of
      life. Adults should focus on preventing or minimizing weight gain over time by
      retaining physical activity within their daily living and by sensible dietary
      changes. Even if weight gain does occur with age, a regimen of regular exercise
      and a diet rich in fruit and vegetables and low in fat will provide some
      protection against a rapid decline in health.

PMID- 12492657
TI  - Can food variety add years to your life?
AB  - The traditional food habits of Greeks and Japanese differ widely, yet both
      populations have the longest life expectancies in the world. Food variety is one
      feature common to both food cultures. By eating a wide variety of foods, numerous
      chemicals that give rise to the diverse range of colours, tastes, textures and
      smells of different foods are consumed. Many of these naturally occurring
      chemicals are likely to play a role in health. Within the broad scope of foods
      available, foods for thought include fish, legumes and nuts. These foods are also
      likely to protect older adults against some of the diseases more prevalent with
      ageing such as coronary heart disease and cancer.

PMID- 12492658
TI  - Benefits of exercise and dietary measures to optimize shifts in body composition
      with age.
AB  - Ageing is associated with changes in body composition, including an increase and
      redistribution of adipose tissue and a decrease in muscle and bone mass,
      beginning as early as the fourth decade of life. These changes have significant
      implications for the health and functioning of the individual because of their
      associations with chronic disease expression and severity, as well as geriatric
      syndromes such as mobility impairment, falls, frailty and functional decline.
      Therefore, understanding the preventive and therapeutic options for optimizing
      body composition in old age is central to the care of patients in mid-life and
      beyond. Pharmacological interventions are currently available for maintaining or
      improving bone mass, and much current interest is focused on anabolic agents that
      will preserve or restore muscle mass, as well as those that can potentially limit
      adipose tissue deposition. However, in this brief review, non-pharmacological
      modulation of body composition through appropriate dietary intake and physical
      activity patterns, will be discussed. There is sufficient evidence currently to
      suggest that a substantial portion of what have been considered 'age-related'
      changes in muscle, fat and bone are in fact related either to excess energy
      consumption, decreased energy expenditure in physical activity, or both factors
      in combination. In addition, selective underconsumption of certain macro- or
      micronutrients contributes to losses of muscle and bone mass. Each of the three
      compartments will be considered in turn, with recommendations for optimizing the
      size of these body tissue stores in early adulthood, and minimizing undesirable
      changes typically seen in middle and old age.

PMID- 12492659
TI  - Ethical consequences for professionals from the globalization of food, nutrition
      and health.
AB  - Globalization is the process of increasing interconnections and linkages, within
      societies and across geography, due to improved communication and expanded world
      trade. It limits the differentiation wrought by human cultural evolution, and
      homogenizes health practices, diet and lifestyle. There are both beneficial and
      adverse consequences of the globalization process. Globalization also presents a
      challenge to the development of ethics for practice and advocacy by food and
      nutrition professionals. Among the related terms, 'morals', 'values' and
      'ethics', the latter connotes the basic rules of conduct for interactions within
      society and with the inanimate environment; rules based on recognized principles
      (ethical principles). The application of these principles is to resolve ethical
      dilemmas that arise when more than one interest is at play. Recognized ethical
      principles include autonomy, beneficence, non-maleficence, justice, utility and
      stewardship. These can be framed in the context of issues that arise during
      advocacy for material and behavioural changes to improve the nutritional health
      of populations. Clearly, at the global level, codes of good conduct and the
      construction of good food governance can be useful in institutionalizing ethical
      principles in matters of human diets and eating practices. Ethical dilemmas arise
      in the context of innate diversity among populations (some individuals benefit,
      whereas others suffer from the same exposures), and due to the polarity of human
      physiology and metabolism (practices that prevent some diseases will provoke
      other maladies). Moreover, the autonomy of one individual to exercise independent
      will in addressing personal health or treatment of the environment may compromise
      the health of the individual's neighbours. The challenges for the professional in
      pursuit of ethical advocacy in a globalized era are to learn the fundamentals of
      ethical principles; to bear in mind a respect for difference and differentiation
      that continues to exist, and which should exist, among individuals and societies;
      and to avoid a total homogenization of agriculture and food supplies.

PMID- 12492660
TI  - Consent for observational studies in critical care: time to open Pandora's Box.

PMID- 12492661
TI  - Getting there--by evolution, not revolution.

PMID- 12492662
TI  - Mechanisms contributing to the vaso-active effects of prilocaine in human skin.
AB  - We investigated the roles of the endothelial nitric oxide and cyclo-oxygenase
      pathways in mediating the vasoactivity of prilocaine in the skin. We injected
      prilocaine 1% intradermally into forearm skin of 10 healthy, male subjects.
      Nitric oxide synthesis was inhibited at a second site by co-injecting prilocaine
      with l-NAME 1%. We then repeated the injections while blocking the cyclo
      oxygenase pathway with aspirin (4 x 600 mg). We measured blood flow responses to
      the injections using laser Doppler imaging. We found that, after the traumatic
      effects of injection had subsided, l-NAME reduced the vascular response to
      prilocaine by a third (p = 0.012), indicating an influence specifically on the
      drug response. Aspirin had no effect on the response (p = 0.588). We conclude
      that the vasoactive effects of prilocaine in human skin are mediated partly
      through the release of endothelial nitric oxide and, although other mechanisms
      might also be involved, the cyclo-oxygenase pathway does not appear to play a
      role.

PMID- 12492663
TI  - Anaesthetists' attitudes towards awareness and depth-of-anaesthesia monitoring.
AB  - Advances in technology have resulted in the development of several depth-of
      anaesthesia monitors. Whether any of these monitors can reduce the incidence of
      awareness is an important issue for anaesthetists and their patients. We
      therefore surveyed a random selection of anaesthetists, asking for their opinions
      of awareness and depth-of-anaesthesia monitoring in current clinical practice.
      Approximately half (52%) of the anaesthetists surveyed had experienced a patient
      with awareness. Anaesthetists considered that they had a lower incidence of
      awareness in their own practice when compared with others, 1:5000 vs. 1:10 000 (p
      < 0.001). Anaesthetists rated awareness on an 11-point scale as only a moderate
      problem, median (interquartile range) 5 (2-7). Older anaesthetists were less
      likely to rate the importance of awareness highly (p = 0.009) and to use
      awareness monitoring (p = 0.001). Anaesthetists are prepared to use depth-of
      anaesthesia monitoring more widely if it can be shown to prevent most cases of
      awareness in routine practice.

PMID- 12492664
TI  - The neuroanaesthesia workforce in Great Britain and Ireland.
AB  - A survey of the 36 units that provide a neuroanaesthesia service in Great Britain
      and Ireland was conducted. It shows the variation in the type of hospital, the
      number of whole-time equivalent neuroanaesthetists, the number of operating
      sessions and the number of neurosurgical beds per million of the catchment
      population of each unit. On-call commitment and arrangements for managing long
      cases are described. Current problems pertaining to neuroanaesthetic practice are
      mentioned. This survey will provide a basis for the planning of future
      neuroanaesthetic services, as the potential of expansion of neurosurgery and
      neuroradiology is realised. However, it is difficult to make accurate projections
      and hence advise on future workforce requirements in a climate of changing
      service delivery. Attention should be given to a number of workforce issues
      highlighted in this survey if recruitment into neuroanaesthesia is to be
      encouraged.

PMID- 12492665
TI  - The effect of nitrous oxide on cerebral blood flow velocity in children
      anaesthetised with desflurane.
AB  - The aim of this study was to determine the effect of nitrous oxide on cerebral
      blood flow velocity in children anaesthetised with desflurane. Eighteen healthy
      children scheduled for elective surgery were enrolled into the study. Anaesthesia
      was induced using sevoflurane, and a caudal block was performed following
      tracheal intubation. Anaesthesia was maintained with 1 age-adjusted MAC
      desflurane. A transcranial Doppler probe was used to measure middle cerebral
      artery blood flow velocity. Each patient was randomised to receive a sequence of
      either air/nitrous oxide/air or nitrous oxide/air/nitrous oxide in 30% oxygen.
      Fifteen minutes after each change in the nitrous oxide concentration, three
      measurements of cerebral blood flow velocity, blood pressure and heart rate were
      recorded. Neither the addition nor removal of nitrous oxide caused any
      significant changes in middle cerebral artery blood flow velocity, heart rate or
      blood pressure. This may be due to a more potent cerebral vasodilatory effect of
      desflurane in children.

PMID- 12492666
TI  - The thienopyridine derivatives (platelet adenosine diphosphate receptor
      antagonists), pharmacology and clinical developments.
AB  - The thienopyridines, ticlopidine and clopidogrel, are antiplatelet drugs. They
      are prodrugs and are metabolised in the liver to active metabolites that are non
      competitive antagonists of the platelet adenosine diphosphate receptor, P2Y12.
      Inhibition of platelet aggregation by these drugs is delayed until 24-48 h after
      administration, with maximal inhibition achieved after 3-5 days. Recovery of
      platelet function after drug withdrawal is slow (7-14 days). Ticlopidine and
      clopidogrel are effective in preventing atherothrombotic events in
      cardiovascular, cerebrovascular and peripheral vascular disease. Gastrointestinal
      side effects and skin rashes are common. However, neutropenia and thrombotic
      thrombocytopenic purpura are significant and sometimes fatal adverse effects of
      ticlopidine. Clopidogrel appears to offer several advantages over ticlopidine: a
      more rapid onset of action and a lower incidence of neutropenia and thrombotic
      thrombocytopenic purpura.A combination of clopidogrel and aspirin has become
      standard for antithrombotic therapy in cardiovascular disease. The anaesthetic
      considerations of patients taking the thienopyridine compounds are discussed.

PMID- 12492667
TI  - A strange little book.

PMID- 12492668
TI  - A comparison of the laryngeal mask airway and PA(Xpress) for short surgical
      procedures.
AB  - Sixty adult patients undergoing minor peripheral surgery under general
      anaesthesia were randomly allocated to receive either the laryngeal mask airway
      (laryngeal mask airway; size 4 for females and size 5 for males) or the PAXpress
      (adult size), inserted by a single operator with experience of > 50 insertions of
      each device. The laryngeal mask airway was correctly placed on the first attempt
      in 27 patients (90%) compared with 20 patients (67%) when using the PAXpress (p <
      0.01). No patient required more than two attempts at insertion and there were no
      failures with the laryngeal mask airway, compared with four (13%) who needed
      three attempts and two failures (7%) with the PAXpress (p < 0.001 and p < 0.01,
      respectively). Mean (SD) total placement time was shorter with the laryngeal mask
      airway [24.6 (3.1) s] than with the PAXpress[35.4 (2.5) s; p < 0.01]. The most
      common complication was sore throat, which occurred less frequently with the
      laryngeal mask airway (8 patients; 26%) than with the PAXpress (15 patients;
      53.5%; p < 0.001).

PMID- 12492669
TI  - A comparison of simulated difficult intubation with multiple-use and single-use
      bougies in a manikin.
AB  - In a randomised cross-over study, 20 anaesthetists attempted to place a multiple-
      or single-use bougie in the trachea of a manikin, in which a grade 3 Cormack and
      Lehane laryngoscopic view was simulated. The anaesthetists made two attempts at
      placement with each bougie and were blinded to success (tracheal placement) or
      failure (oesophageal placement). The success rates for the first attempts with
      the multiple- and single-use bougies were 85 and 15%, respectively [mean (95% CI)
      difference between the two bougies 70% (40-84%); p < 0.001]. The success rates
      for the second attempts were similar to those for the first attempts with both
      bougies. There is an increased risk of failure to intubate the trachea when using
      a single-use bougie, and this must be weighed against the unquantified risk of
      cross-infection from prions when using a multiple-use bougie.

PMID- 12492670
TI  - Global performance measures in intensive care.

PMID- 12492671
TI  - Magnetic resonance compatible equipment: read the small print!

PMID- 12492672
TI  - Immediate postanaesthetic recovery.

PMID- 12492673
TI  - A case for 'doing it in theatre'.

PMID- 12492674
TI  - A new device to facilitate blind tracheal intubation.

PMID- 12492675
TI  - Wrong blood in theatre.

PMID- 12492676
TI  - Fibreoptic equipment and prion disease.

PMID- 12492677
TI  - Awareness and traumatic recall of cricoid pressure.

PMID- 12492678
TI  - Tension gastrothorax.

PMID- 12492679
TI  - 'Continuous saline flow technique' prevents air entrainment during intrapleural
      block.

PMID- 12492680
TI  - Glass particle contamination: is it here to stay?

PMID- 12492682
TI  - Injection cap with missing septum.

PMID- 12492681
TI  - Flash forward: the new flashback?

PMID- 12492683
TI  - Anaesthesia management in a patient with Aicardi's Syndrome.

PMID- 12492684
TI  - Isoflurane and coronary steal.

PMID- 12492685
TI  - Total intravenous anaesthesia without muscle relaxant for eye surgery in a
      patient with Kugelberg-Welander Syndrome.

PMID- 12492686
TI  - Carbon dioxide pneumothorax during laparoscopic fundoplication.

PMID- 12492687
TI  - Safety and effectiveness of epidurals.

PMID- 12492688
TI  - Recurrent positional ventricular tachycardia in a patient with carcinoma of the
      oesophagus.

PMID- 12492689
TI  - A postoperative respiratory arrest in a post poliomyelitis patient.

PMID- 12492690
TI  - Drug syringe labelling.

PMID- 12492691
TI  - Pain control in day-case surgery.

PMID- 12492692
TI  - Postoperative cough-induced recurrence of spinal anaesthesia in the parturient.

PMID- 12492693
TI  - Post dural puncture headache.

PMID- 12492694
TI  - Hypno-analgesia for a labouring parturient with contra-indications to central
      neuraxial block.

PMID- 12492695
TI  - Scary white stuff.

PMID- 12492696
TI  - 'Hold up' and the gum elastic bougie.

PMID- 12492697
TI  - Development of the 'gum-elastic bougie'.

PMID- 12492698
TI  - Gum elastic bougies.

PMID- 12492699
TI  - Remifentanil infusion rate calculation.

PMID- 12492700
TI  - An unusual problem with pulse oximetry.

PMID- 12492702
TI  - Transplantation of the intestine: is it truly different?

PMID- 12492703
TI  - Post-transplant renal tubulitis: the recruitment, differentiation and persistence
      of intra-epithelial T cells.
AB  - Tubulitis is used by the Banff protocol as a major criterion to grade acute renal
      allograft rejection. This review integrates results from in vitro and in vivo
      studies to develop a chronological model to explain the development and functions
      of tubular inflammation during the rejection process. Proteoglycan-immobilized
      chemokines are the primary motivators for the vectorial recruitment of specific
      immune cell populations from the blood, through the endothelium and interstitial
      tissues to the renal tubules. After penetration of the basement membrane, T cells
      encounter TGF-beta that can induce expression of the alphaEbeta7 integrin on
      proliferating cells. This allows adhesion to E-cadherin on the baso-lateral
      surfaces of tubular epithelial cells and provides an explanation for the
      epithelial-specific cytotoxicity observed during acute rejection. Tubular
      epithelium is also a rich source of IL-15 that can stimulate IL-15 receptor
      expressing intratubular CD8+ T cells. This anti-apoptotic microenvironment may
      explain the long-term persistence of cycling T cells within intact tubules after
      episodes of acute rejection. These memory-like T cells may have local
      immunoregulatory properties, including the production of additional TGF-beta, but
      could also modify normal tubular homeostasis resulting in epithelial to
      mesenchymal transdifferentiation, tubulointerstitial fibrosis and, ultimately,
      graft failure.

PMID- 12492704
TI  - HLA-G in transplantation: a relevant molecule for inhibition of graft rejection?
AB  - The human MHC class I molecule HLA-G has long been known as a molecule
      selectively expressed by cytotrophoblastic cells. By inhibiting the cytolytic
      function of decidual NK cells, HLA-G protects the HLA-A and -B negative
      semiallogeneic embryonic tissue against the mother's immune system. In the light
      of this immuno-suppressive function, the role of HLA-G in transplantation was
      investigated. We will review here recently published data on this topic, showing
      that expression of HLA-G affects the responsive capacity of the immune system,
      might directly participate in graft acceptation, and should be taken into account
      for the monitoring of transplantation patients.

PMID- 12492705
TI  - Molecular profiling of anemia in acute renal allograft rejection using DNA
      microarrays.
AB  - Compromised renal function after renal allograft transplantation often results in
      anemia in the recipient. Molecular mechanisms leading to anemia during acute
      rejection are not fully understood; inadequate erythropoietin production and iron
      deficiency have been reported to be the main contributors. To increase our
      understanding of the molecular events underlying anemia in acute rejection, we
      analyzed the gene expression profiles of peripheral blood lymphocytes (PBL) from
      four pediatric renal allograft recipients with acute rejection and concurrent
      anemia, using DNA microarrays containing 9000 human cDNA clones (representing
      7469 unique genes). In these anemic rejecting patients, an 'erythropoiesis
      cluster' of 11 down-regulated genes was identified, involved in hemoglobin
      transcription and synthesis, iron and folate binding and transport. Additionally,
      some alloimmune response genes were simultaneously down-regulated. An independent
      data set of 36 PBL samples, some with acute rejection and some with concurrence
      of acute rejection and anemia, were analyzed to support a possible association
      between acute rejection and anemia. In conclusion, analysis using DNA microarrays
      has identified a cluster of genes related to hemoglobin synthesis and/or
      erythropoeisis that was altered in kidneys with renal allograft rejection
      compared with normal kidneys. The possible relationship between alterations in
      the expression of this cluster, reduced renal function, the alloimmune process
      itself, and other influences on the renal transplant awaits further analysis.

PMID- 12492706
TI  - Further analysis of the T-cell subsets and pathways of murine cardiac allograft
      rejection.
AB  - The present study examined the role of CD4+ and CD8+ T cells in cardiac allograft
      rejection when either the direct or indirect pathway was eliminated for the CD4+
      portion of the response. To study the pathways in vivo, we used genetically
      altered mouse strains that lack class II antigens as either the donors or
      recipients for cardiac transplantation. In contrast to earlier published studies,
      which used different strain combinations, we found that either CD4- or CD8
      depletion prolonged cardiac allograft survival moderately, but not indefinitely,
      in an MHC-mismatched, minor-matched combination. When the CD4+ indirect pathway
      was eliminated, rapid graft rejection occurred when both T-cell subsets were
      present and when either CD4+ or CD8+ T cells were depleted. When the CD4+ direct
      pathway was eliminated, rapid graft rejection occurred when both T-cell subsets
      were present, there was slow rejection when CD4+ T cells were eliminated, and no
      rejection was seen for more than 100 days when CD8+ T cells were eliminated.
      However, the long-surviving allografts on the recipients with only CD4+ cells and
      an indirect pathway did show evidence of chronic vasculopathy. Thus, either CD4+
      or CD8+ T cells can mediate acute cardiac allograft rejection in these
      experiments when both pathways are available. In addition, CD4+ T cells can
      provide help for acute rejection through either the direct or indirect pathway.
      Finally, recipients who have only CD4+ cells and an indirect pathway do not
      demonstrate acute rejection, but do show evidence of chronic rejection.

PMID- 12492707
TI  - Effects of patient compliance, parental education and race on nephrologists'
      recommendations for kidney transplantation in children.
AB  - Transplantation is the treatment goal for youth with kidney failure. To assess
      the effects of compliance, parental education and race on nephrologists'
      recommendations for transplantation in children, we surveyed a national random
      sample of adult and pediatric nephrologists. We elicited transplant
      recommendations for case vignettes created from random combinations of patient
      age, gender, race, cause of renal failure, family structure, parental education
      and compliance. Of 519 eligible physicians, 316 (61%) responded. Nephrologists
      were more likely to recommend transplantation for children of college-educated
      parents than children of parents who did not finish high school, despite
      identical clinical and demographic characteristics (adjusted OR 1.48, 95% CI
      1.18, 1.86). Patient noncompliance negatively influenced transplant
      recommendations (adjusted OR 0.1, 95% CI 0.08, 0.13). Additionally, compliance
      had a different effect on transplant recommendations for white compared with
      black patients. The adjusted OR of a white, compliant patient being referred for
      transplantation were twice that of a black compliant patient (OR 2.06, 95% CI
      1.17, 3.6). Education and compliance with therapy independently influence
      nephrologists' recommendations for transplantation in youth with kidney failure.
      Among the most compliant candidates, referral for transplantation may vary with
      patient race.

PMID- 12492708
TI  - Pregnancy outcomes in female renal recipients: a comparison of systemic lupus
      erythematosus with other diagnoses.
AB  - This study compares pregnancy outcomes in systemic lupus erythematosus (SLE)
      patients post renal transplant with recipients with other primary diagnoses,
      utilizing data from the National Transplantation Pregnancy Registry,
      Philadelphia, PA. Recipients were referred from transplant centers nationwide. A
      retrospective analysis was performed using data from questionnaires, hospital
      records and telephone interviews. Outcomes of pregnancies post renal transplant
      secondary to lupus nephritis (SLE: n = 38; 60 pregnancies) were compared with the
      pregnancy outcomes of renal recipients with other diagnoses (non-SLE: n = 247;
      374 pregnancies). Drug-treated hypertension during pregnancy was less common in
      the SLE group than in the non-SLE group (45.0% vs. 62.5%, p = 0.015). There were
      fewer cesarean sections in the SLE group (30.2 vs. 53.2%, p = 0.008). There was
      no primary or gestational diabetes in the SLE group. There were no other
      statistical differences in maternal conditions or pregnancy outcomes between the
      SLE and non-SLE groups, or in the incidence of post pregnancy graft loss. Female
      recipients transplanted for renal failure secondary to lupus nephritis can
      successfully maintain pregnancy. Outcomes are comparable to renal recipients with
      other diagnoses. Newborns in both groups were often premature and had low
      birthweight. Overall childhood health was reported to be good; there were no
      apparent predominant structural malformations among the children.

PMID- 12492709
TI  - Mucosal vascular alterations in isolated small-bowel allografts: relationship to
      humoral sensitization.
AB  - Acute vascular rejection (AVR) in human small-bowel transplantation is an
      inadequately characterized entity whose frequency and severity is not well
      understood. As compared to severe AVR, changes identifying early, mild or
      evolving AVR are not known. We created a scoring system to evaluate subtle
      mucosal vascular changes and examined 188 biopsies from 21 patients obtained in
      the first 3 months post transplant. A majority of patients had a transient rise
      in vascular injury, often within 30 days of transplant. Small-vessel congestion
      and erythrocyte extravasation were the most common alterations. The vascular
      injury score was not related to acute cellular rejection, HLA type or HLA antigen
      disparities. However, the patients with the vascular changes had significantly
      higher peak panel reactive antibodies (PRA) and a higher incidence of positive T
      cell and B-cell crossmatch. Finally, graft survival was significantly lower in
      the patients demonstrating the early vascular lesions. These data suggest that
      the vascular injury is partially associated with humoral presensitization of the
      recipient and may be a form of acute vascular rejection. Since these vascular
      changes are frequent, we advocate early post-transplant monitoring to identify
      and manage potentially high-risk patients.

PMID- 12492710
TI  - Pharmacokinetic and pharmacodynamic studies of one or two doses of daclizumab in
      renal transplantation.
AB  - In phase III trials daclizumab was used in a five-dose regimen of 1 mg/kg at 2
      weekly intervals, resulting in saturation of IL-2Ralpha on circulating
      lymphocytes for up to 120 days after renal transplantation. The purpose of this
      study was to evaluate daclizumab blood concentrations and the saturation of the
      IL-2Ralpha on the circulating lymphocytes with a limited dosing regimen of
      daclizumab. Twelve patients undergoing primary cadaver or living donor
      transplantation were randomized to either receive one dose (2 mg/kg) or two doses
      (2nd dose, 1 mg/kg) of daclizumab in addition to maintenance immunosuppression
      therapy consisting of either tacrolimus or cyclosporine, mycophenolate mofetil
      and prednisone. Patients were followed for 6 months after the transplantation.
      Pharmacokinetic and pharmacodynamic studies were performed up to 20 weeks after
      the transplantation. In patients treated with a single dose of daclizumab, the
      blood concentrations of daclizumab declined to 1 micro g/mL at 43 +/- 7 days
      after the transplantation. In patients treated with two doses of daclizumab, the
      blood concentrations of daclizumab declined to 1 micro g/mL at 45 +/- 13 days
      after the second dose for a total of 59 +/- 13 days after the transplantation.
      Daclizumab levels of 1 micro g/mL or greater were associated with saturation of
      the IL-2Ralpha on the circulating lymphocytes. In the new era of effective
      maintenance immunosuppression, a limited dosing regimen of daclizumab may be
      desired, practical and economical.

PMID- 12492711
TI  - Improved islet yields from Macaca nemestrina and marginal human pancreata after
      two-layer method preservation and endogenous trypsin inhibition.
AB  - We tested whether two-layer method (TLM) pancreas preservation and trypsin
      inhibition (Pefabloc) during processing allows longer preservation while
      retaining or improving viable islet recovery. Non-marginal primate (Macaca
      nemestrina) and marginal human (ischemic or preservation-injured) pancreata were
      processed with a research-oriented pan technique (Seattle method). Organs were
      processed upon arrival (+/- Pefabloc), or after TLM or University of Wisconsin
      solution (UW) preservation (+ Pefabloc). Islet yield, viability, and function
      were assessed. Pefabloc increased M. nemestrina islet yields from 9696 +/- 1749
      IE/g to 15 822 +/- 1332 IE/g (p < 0.01). Two-layer method preservation (< 6 h)
      further increased yields, to 23 769 +/- 2773 IE/g (vs. + Pefabloc; p < 0.01).
      Similarly, Pefabloc increased marginal human islet yields from 2473 +/- 472 IE/g
      to 4723 +/- 1006 IE/g (p < 0.04). This increase was maintained after lengthy TLM
      preservation (> 30 h; 4801 +/- 1066 IE/g). We also tested the applicability of
      TLM preservation (23.5 +/- 3.2 h) to the processing of marginal human pancreata
      by the Edmonton/Immune Tolerance Network clinical protocol. Islet yield and
      function approached published results of pancreata processed 4.8 +/- 0.8 h after
      organ recovery (p = 0.06). Pefabloc, and TLM vs. UW preservation, prolonged the
      tolerable interval between organ recovery and islet isolation. Islet yield,
      viability, and functionality improved from both marginal and nonmarginal
      pancreata.

PMID- 12492712
TI  - Renal allograft survival in transplant recipients with focal segmental
      glomerulosclerosis.
AB  - Previous literature suggests that the recurrence of focal segmental
      glomerulosclerosis (FSGS) after renal transplantation is more common in
      recipients who have received an HLA-identical living-related (LRD) transplant. To
      address the question if FSGS patients can safely receive a 6-antigen match LRD
      kidney transplant, we analyzed death-censored renal allograft survival data of
      FSGS patients from the United States Renal Data System database (USRDS). Using
      the USRDS and the U.S. Scientific Renal Transplant Registry between the years
      1988-97, we found 19259 adult primary renal transplant recipients, of which 2414
      patients had FSGS as their primary diagnosis as compared to 16845 patients who
      had other types of glomerulonephritis (GN). A Cox proportional hazard model was
      used to estimate death-censored graft survival among FSGS patients with a zero
      mismatch LRD kidney transplant. The model included a triple interaction term
      comparing FSGS vs. GN vs. living donation (LD) vs. cadaveric donation (CAD) vs.
      zero mismatch (six antigen or HLA-identical) vs. mismatch. Annually adjusted
      death censored graft loss rates per 1000 patients (ADGL) were calculated. Focal
      segmental glomerulosclerosis patients receiving a zero mismatch LRD kidney
      transplant had the lowest ADGL rate, losing 10.5 grafts per 1000 patients per
      year. Not significantly different but higher (14.3) was the ADGL rate for LD,
      zero mismatch GN recipients. The ADGL rate was significantly higher in FSGS
      recipients who received a LD, mismatched transplant (36.5). Focal segmental
      glomerulosclerosis patients who received a CAD, zero mismatched graft (44.1), or
      CAD, mismatched graft (63.2), had significantly higher ADGL rates. Zero mismatch
      LRD kidney transplants are not a risk factor for graft loss in FSGS patients but
      are associated with significantly better death-censored graft survival as
      compared to CAD 6-antigen match or mismatched donations.

PMID- 12492713
TI  - Long-term use of mycophenolate mofetil is associated with a reduction in the
      incidence and risk of late rejection.
AB  - To evaluate the association of long-term continuous (minimum 1 year)
      mycophenolate mofetil (MMF) vs. azathioprine (AZA) therapy with the incidence of
      late acute rejection, we analyzed 47 693 primary renal allograft recipients
      reported to the United States Renal Data System between 1988 and 1998. The
      primary study endpoint was acute rejection beyond 1 year after transplantation.
      Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models
      were used to investigate the risk of reaching the study endpoints. All
      multivariate analyses were corrected for potential confounding covariates.
      Mycophenolate mofetil was associated with a 65% decreased risk of developing late
      acute rejection as compared to AZA (RR = 0.35, CI 0.27-0.45, p < 0.001). The
      incidence of acute rejection episodes at 2 and 3 years post-transplantation was
      significantly lower in the MMF group (0.9% at 2 years, 1.1% at 3 years) than the
      AZA group (6.1% at 2 years, 9.3% at 3 years). In the primary vs. repeat late
      rejection analysis, MMF patients exhibited a decreased late acute rejection risk
      of 72% (RR = 0.28, p < 0.001) and 60%, respectively (RR = 0.40, p < 0.001). In
      African Americans, the late acute rejection risk was 70% lower in MMF patients
      than AZA patients (RR = 0.30, p < 0.001). Further study is indicated to determine
      the optimal duration of MMF therapy after renal allograft transplantation.

PMID- 12492714
TI  - Acute humoral rejection in hepatitis C-infected renal transplant recipients
      receiving antiviral therapy.
AB  - The use of interferon-alpha (IFN) in hepatitis C (HCV)-infected renal recipients
      has been associated with acute rejection and graft loss. We reviewed our recent
      experience in HCV (+) renal recipients treated with antiviral therapy for biopsy
      proven chronic hepatitis C. Twelve HCV (+) recipients who recently received
      antiviral therapy were analyzed. Post-treatment sera were tested for donor
      specific human leukocyte antigen (HLA) antibodies (DSA). Within 6 months of
      initiating antiviral therapy, two of 12 patients (17%) developed acute rejection,
      which was characterized as acute humoral rejection (de novo DSA in serum and C4d
      deposits in peritubular capillaries). Both progressed to graft failure. Nine of
      the remaining 10 patients tested did not have DSA. The use of IFN was associated
      with severe acute humoral rejection (C4d +, DSA +). The recognition of IFN
      associated acute humoral rejection in this series may explain the high rate of
      graft loss reported previously in renal recipients receiving IFN.

PMID- 12492715
TI  - Determinants of cardiovascular mortality after renal transplantation: a role for
      cytomegalovirus?
AB  - Death with a functioning graft (DWF) is now the most common cause of late renal
      transplant failure, with cardiovascular disease its most frequent etiology. In
      some populations, infection with cytomegalovirus (CMV) increases risk of coronary
      disease. Few data exist regarding CMV and cardiovascular mortality after renal
      transplantation. We reviewed charts of 158 adult patients who died more than 90
      days after receiving renal allografts and a matched cohort of 143 (of 2398)
      surviving patients transplanted at the University of Alabama at Birmingham
      between 1990 and 1998. Only advancing donor and recipient age increased risk of
      DWF; CMV infection did not. However, of 50 patients who died of cardiovascular
      causes, 94% were seropositive for CMV, while only 74% of the other 108 deaths
      occurred in CMV-seropositive patients (p < 0.05). Risk of cardiovascular death
      was greatest (p < 0.05) in patients with diabetes, advancing age, and CMV
      seropositivity. In renal transplant recipients, infection with CMV increases risk
      of death as a result of cardiovascular causes.

PMID- 12492716
TI  - Endoscopic diagnosis of bleeding Meckel's diverticulum in a multivisceral
      transplant recipient.
AB  - Small bowel transplantation has become a life-saving procedure for patients with
      intestinal failure who fail conventional therapy. Meckel's diverticulum is a rare
      cause of occult gastrointestinal bleeding that has not been reported in patients
      receiving intestinal allografts. We report a case in which transplantation of an
      asymptomatic Meckel's diverticulum as part of a multivisceral allograft led to
      intestinal bleeding requiring surgical intervention. Endoscopy identified the
      actual bleeding diverticulum. Diverticulectomy at the time of transplant was not
      performed due to the difficult operative course, and the need for frequent
      surveillance ileoscopy, which would be performed across a fresh intestinal
      anastomosis. The patient underwent resection of the diverticulum, along with 40
      cm of ileum, and did not experience further bleeding.

PMID- 12492717
TI  - Successful PTA and stenting for acute iliac arterial injury following pancreas
      transplantation.
AB  - Iliac artery injuries may occur during solid organ transplantation. We describe
      an approach to an iliac artery clamp injury after pancreatic allotransplantation.
      The patient is a 48-year-old diabetic male who underwent successful cadaveric
      pancreatico-duodenal transplantation complicated by a left common iliac artery
      clamp injury. The injury resulted in both graft and lower leg ischemia. The
      injury was recognized promptly and diagnosed by magnetic resonance angiogram
      (MRA). The lesion was successfully treated with percutaneous transluminal
      angioplasty and stenting with resolution of both graft and leg ischemia. We
      propose this technique as a minimally invasive approach to an iliac injury that
      can be used to treat vascular injuries during solid organ transplantation.

PMID- 12492718
TI  - Intracranial tuberculoma in a liver transplant patient: first reported case and
      review of the literature.
AB  - A 66-year-old female who had undergone an orthotopic liver transplant two years
      before admission was admitted with fever and neurological symptoms of several
      days' duration. Following an extensive work-up, which revealed positive
      intracranial lesions on computed typography and magnetic resonance imaging, the
      patient was begun on broad spectrum antimicrobials including corticosteroids. The
      patient responded though the etiology of infection remained unclear. After a
      stereotactic biopsy was performed revealing granulomas and acid-fast bacilli, the
      patient was started on antituberculous medications. A review of the literature
      reveals that the rare occurrence of intracranial tuberculoma should be considered
      in an orthotopic liver transplant (OLT) patient with central nervous system
      pathology.

PMID- 12492719
TI  - Valacyclovir for the prevention of cytomegalovirus infection after kidney
      transplantation is associated with macrocytosis.

PMID- 12492720
TI  - Transient bone marrow edema in renal transplantation: a distinct post
      transplantation syndrome with a characteristic MRI appearance.

PMID- 12492722
TI  - Introduction. Expanding the anti-allergy therapeutic horizon.

PMID- 12492723
TI  - Introduction to nasal and pulmonary allergy cascade.
AB  - The early phase of an IgE-dependent allergic reaction is followed by the
      activation of a complex network of inflammatory phenomena - T lymphocytes,
      cytokines, mediators, and adhesion molecules - that mediate late and ongoing
      allergic symptoms. The kinetics of respiratory inflammation following allergen
      exposure involve the migration of inflammatory cells to the mucosa within about
      30 min, increased inflammatory infiltration over the following hours, and then
      slow subsidence. A relationship between asthma and allergic rhinitis is supported
      by epidemiological, histological, physiological, and immunopathological data, and
      by the response of asthma symptoms in rhinitic patients to intranasal
      corticosteroids and antihistamines. For example, there is no morphological
      difference between the bronchial inflammatory response following allergen
      specific challenge in patients suffering from asthma alone or rhinitis alone. It
      is the allergen dose that makes the difference in the airway response to allergen
      in allergic rhinitis and asthma. Recognition of the relationship between asthma
      and allergic rhinitis has led to the introduction of new diagnostic terminology
      and treatment recommendations: 1) patients with persistent rhinitis should be
      evaluated for asthma; 2) patients with persistent asthma should be evaluated for
      rhinitis; and 3) a strategy should combine the treatment of upper and lower
      airways in terms of efficacy and safety.

PMID- 12492724
TI  - Therapeutic points of intervention and clinical implications: role of
      desloratadine.
AB  - Desloratadine, a potent, once-daily, orally active, nonsedating, histamine H1
      receptor antagonist, inhibits the release of histamine and other inflammatory
      mediators. Once-daily desloratadine therapy rapidly reduces the symptoms of
      perennial allergic rhinitis and seasonal allergic rhinitis (SAR), reduces the use
      of inhaled albuterol by patients with SAR and concomitant asthma, and improves
      symptoms and quality of life in patients with chronic idiopathic urticaria. An
      open-label, observational study in SAR patients revealed that desloratadine
      therapy significantly reduced nasal, ocular, dermal, asthma, and total symptoms,
      and enabled half of the patients with concomitant asthma to reduce their use of
      asthma medications. Globally, more than 91% of patients and physicians judged
      desloratadine to have excellent or good efficacy, and more than 98% judged it to
      have excellent or good tolerability. Furthermore, desloratadine therapy improved
      quality of life, decreasing by more than 10-fold the percentage of patients whose
      daily activities and/or sleep were moderately or severely affected by SAR.
      Allergic rhinitis, a major chronic airway disease that is a risk factor for
      asthma, warrants extended diagnostic procedures and well-tolerated therapy that
      encompasses the entire airway, addresses multiple steps in the allergic
      inflammatory cascade, and is effective on nasal, ocular, dermal, asthma, and
      total symptoms.

PMID- 12492725
TI  - Chronic urticaria: impact of allergic inflammation.
AB  - Urticaria is defined by weals (hives), with or without angioedema, that appear
      and peak in minutes to hours, usually disappear within 24 h, and are accompanied
      by pruritus that worsens during the night. Urticaria is caused by cutaneous mast
      cell degranulation, attributed to immunological, nonimmunological, and idiopathic
      causes. Chronic idiopathic urticaria (CIU) is the diagnosis when the
      pathophysiological mechanism of persistent urticaria remains unclear; up to half
      of patients with CIU have functional autoantibodies directed against the high
      affinity receptor for IgE (FcepsilonRI) or against IgE itself, which appear to
      induce mast cell degranulation. Systemic histamine H1-receptor antagonists, such
      as desloratadine, are central to the management of CIU. The efficacy and safety
      of desloratadine, 5 mg once daily, was studied in a double-blind, randomized,
      placebo-controlled, multicentre trial that included 190 patients, ages 12 and
      above, with at least a 6-week history of CIU and experiencing a flare of at least
      moderate severity. Desloratadine was superior to placebo in controlling pruritus
      and total symptoms after the first dose, and its superiority was maintained
      throughout the full 6 weeks of the study. Measures of sleep, daily activity,
      therapeutic response, and global CIU status were also significantly improved with
      desloratadine after the first dose and maintained throughout the study.

PMID- 12492726
TI  - Impact and modulation of nasal obstruction.
AB  - Nasal obstruction, the leading symptom of allergic rhinitis, results from the
      combined activity of early- and late-phase allergic reactions. Desloratadine
      inhibits both early- and late-phase inflammatory mediators in vitro. Thus, double
      blind, placebo-controlled, randomized, crossover trials were conducted to assess
      the efficacy of desloratadine against nasal obstruction, measured objectively and
      subjectively, during controlled exposure of patients with seasonal allergic
      rhinitis to allergen. Positive results were obtained in three single-dose
      studies; desloratadine 5 mg resulted in a greater improvement from baseline than
      did placebo in the total symptom score and the nasal obstruction symptom score (P
      </= 0.02). Desloratadine was more effective than placebo in a multiple-dose
      study; desloratadine 5 mg was given once daily for 7 days, and a 6-h allergen
      challenge was administered at the end of treatment compared with placebo.
      Desloratadine treatment was associated with less deterioration from baseline in
      the mean nasal airflow (P < 0.05) and in the mean severity score for the symptom
      of nasal obstruction (P < 0.03). Desloratadine significantly reduces the severity
      of nasal obstruction in patients with seasonal allergic rhinitis.

PMID- 12492727
TI  - Advances in allergy management.
AB  - Our understanding of the pathophysiology of allergy has moved to the molecular
      level, while study of epidemiology and genetics has revealed risks of developing
      allergies based on environmental and genetic profiles, and pharmacoeconomic data
      have enabled accurate measurement of the immense burden of allergic disease.
      These advances in allergy research have affected its management, particularly the
      search for new antiallergy therapies. New therapies should intervene in the
      systemic allergy inflammatory cascade and provide clinical efficacy that extends
      to multiple allergic disease states. In addition, these new therapies should
      present no additional safety issues, offer improvements over existing therapies,
      and have an impact on disease-impaired quality of life. In vitro studies show
      that desloratadine, a new, once-daily, nonsedating, selective histamine H1
      receptor antagonist, blocks the systemic allergy cascade at multiple points.
      Desloratadine 5 mg once daily relieves the symptoms of chronic idiopathic
      urticaria and of both seasonal (SAR) and perennial allergic rhinitis. In patients
      with concomitant asthma and SAR, asthma symptoms are relieved and beta2-agonist
      medication use is decreased by desloratadine. Unlike many other second-generation
      histamine H1-receptor antagonists, desloratadine provides the added benefit of
      efficacy against nasal obstruction in SAR. Desloratadine improves quality of life
      by decreasing the impact of allergic symptoms on sleep and on daily activities.

PMID- 12492728
TI  - Review article: immunopathogenetic and therapeutic aspects of autoimmune
      hepatitis.
AB  - Autoimmune hepatitis is a chronic, progressive liver disease that responds well
      to immunosuppressive therapy, but has a poor prognosis if untreated. Possible
      triggering factors include viruses, other autoimmune disorders and drugs. The
      molecular mechanisms contributing to the pathogenesis include: reactions of
      autoantibodies against their corresponding autoantigens; aberrant expression of
      histocompatibility antigen class I and II molecules, cell adhesion molecules and
      cytokines; increased oxidative stress; and the occurrence of angiogenesis. The
      prevalence of the disease is highest in Caucasians, Europeans and women. The
      natural history of autoimmune hepatitis shows a poor prognosis, with frequent
      progression to cirrhosis and hepatic insufficiency in untreated patients. The
      occurrence of hepatocellular carcinoma is rare and is found only in long-standing
      cirrhosis. Corticosteroids as monotherapy or in combination with azathioprine are
      the treatments of choice; different therapeutic schedules and particularities of
      treatment for pregnant women and children have been established. To avoid
      treatment-associated adverse effects, alternative therapies have been proposed,
      including ciclosporin, budesonide, tacrolimus, mycophenolate mofetil,
      ursodeoxycholic acid, methotrexate, cyclophosphamide, mercaptopurine and free
      radical scavengers. Liver transplantation is indicated for patients refractory to
      or intolerant of immunosuppressive therapy.

PMID- 12492729
TI  - Review article: is there an optimal therapeutic regimen for antimitochondrial
      antibody-negative primary biliary cirrhosis (autoimmune cholangitis)?
AB  - Testing for antimitochondrial antibodies is the most useful laboratory procedure
      in the diagnosis of primary biliary cirrhosis; nevertheless, 5-10% of patients
      with typical features of primary biliary cirrhosis do not have detectable
      antimitochondrial antibodies, their condition being referred to as
      antimitochondrial antibody-negative primary biliary cirrhosis or "autoimmune
      cholangitis". Uncertainty exists whether antimitochondrial antibody-positive and 
      negative primary biliary cirrhosis represent distinct entities. We reviewed
      studies that compared: (i) the clinical, laboratory and histological
      characteristics of antimitochondrial antibody-positive and -negative primary
      biliary cirrhosis; (ii) the response to treatment of both conditions; and (iii)
      the response of autoimmune cholangitis to ursodeoxycholic acid and
      immunosuppressive therapy. Antimitochondrial antibody-positive and -negative
      primary biliary cirrhosis were characterized by similar clinical, laboratory and
      histological abnormalities, clinical course and survival. Antimitochondrial
      antibody status did not seem to affect the response to ursodeoxycholic acid. At
      present, the efficacy of therapies for autoimmune cholangitis has not been
      established in controlled trials. Of 52 patients with autoimmune cholangitis
      treated with ursodeoxycholic acid in 13 uncontrolled studies, 83% had serum
      biochemical improvement. Also, a favourable effect of immunosuppressive drugs
      occurred in 57% of 54 patients with autoimmune cholangitis in 17 uncontrolled
      studies. Each of these trials included very few patients and most evaluated the
      effects of treatment on surrogate markers of disease only. No marker that
      consistently distinguished patients who would respond favourably to
      ursodeoxycholic acid or immunosuppression was apparent. Consequently, treatment
      is, at present, empirical. However, ursodeoxycholic acid may be given when
      histology reveals bile duct lesions, whereas immunosuppressive therapy should
      probably be reserved for patients exhibiting interface hepatitis.

PMID- 12492730
TI  - Systematic review: the pharmacokinetic profiles of oral mesalazine formulations
      and mesalazine pro-drugs used in the management of ulcerative colitis.
AB  - AIM: : To quantify through systematic review the pharmacokinetic profiles of the
      oral delayed release and sustained release mesalazine (5-aminosalicylate, 5ASA)
      formulations (Asacol, Salofalk, Mesasal, Claversal, Pentasa) and pro-drugs
      (sulfasalazine, olsalazine, balsalazide) used in the management of ulcerative
      colitis. METHODS: : Selected articles had: (1) adult healthy volunteers or
      patients with ulcerative colitis and (2) quantification of pharmacokinetic data
      to include, at a minimum, urinary excretion of total 5ASA [5ASA plus N-Acetyl
      5ASA (N-Ac-5ASA)]. DATA COLLECTION AND ANALYSIS: : Pharmacokinetic data (Tmax,
      Cmax, AUC, urinary excretion, faecal excretion) of 5ASA, its major metabolite N
      Acetyl-5ASA, total 5ASA, and the parent pro-drug compounds was extracted. MAIN
      RESULTS: : The summary results for urinary excretion of total 5ASA over 24-96 h
      in all subjects (either mean or median) were: sulfasalazine mean 11-33% or median
      22%; olsalazine mean 14-31% or median 16-27%; balsalazide mean 12-35% or median
      20%; Asacol mean 10-35% or median 18-40%; Pentasa mean 15-53% or median 23-34%;
      Salofalk, Mesasal and Claversal mean 27-56% or median 31-44%. The summary results
      for faecal excretion of total 5ASA over 24-96 h in all subjects (either mean or
      median) were: sulfasalazine mean 23-75% or median 38%; olsalazine mean 47-50% or
      median 17-36%; balsalazide mean 46% or median 22%; Asacol mean 40-64% or median
      20-56%; Pentasa mean 12-51% or median 39-59%; Salofalk, Mesasal and Claversal
      mean 37-44% or median 23-35%. CONCLUSIONS: : The systemic exposure to 5ASA, as
      measured by urinary excretion of total 5ASA, and the faecal excretion of total
      5ASA is comparable for all oral mesalazine formulations and pro-drugs. Thus,
      selection of a mesalazine therapy for the treatment of ulcerative colitis should
      be based on other factors such as efficacy, dose-response, toxicity of the parent
      compound and its metabolites, compliance issues related to dose forms and dosing
      schedules, and costs.

PMID- 12492731
TI  - Systematic review: serotonergic modulators in the treatment of irritable bowel
      syndrome--influence on psychiatric and gastrointestinal symptoms.
AB  - BACKGROUND: Both central and peripheral serotonergic modulators are used in the
      treatment of irritable bowel syndrome. The majority of patients with irritable
      bowel syndrome presenting to a gastroenterologist demonstrate affective
      dysregulation. Serotonin may play a regulatory role in both gastrointestinal
      motility and sensitivity, as well as in affective dysregulation, in irritable
      bowel syndrome. AIM: To analyse, systematically, randomized controlled trials
      studying the influence of serotonergic modulators on both gastrointestinal and
      psychiatric symptoms in irritable bowel syndrome, in order to elucidate baseline
      irritable bowel syndrome symptomatology and possible differential effects of
      serotonergic modulation on this symptomatology. METHODS: A standardized
      qualitative analysis was performed of studies investigating the influence of
      serotonergic modulators on both gastrointestinal and psychiatric symptoms in
      irritable bowel syndrome using a blind review approach. The studies were ranked
      according to their total quality score (maximum 100 points). RESULTS: Eleven
      studies fulfilled the entry criteria, six of which scored above 55 points. An
      association between gastroenterological and psychiatric changes was present in
      five of the six studies. CONCLUSIONS: The results strengthen the serotonergic
      association between gastroenterological and psychiatric symptoms. Adjusted
      guidelines for combined gastrointestinal and psychiatric assessments are
      recommended in order to further elucidate the serotonergic interaction between
      gastrointestinal and psychiatric symptoms.

PMID- 12492732
TI  - Systematic review: terlipressin in acute oesophageal variceal haemorrhage.
AB  - BACKGROUND: Controversy exists surrounding pharmacological therapy in acute
      variceal bleeding. AIM: To determine the efficacy and safety of terlipressin.
      METHODS: Randomized trials were identified and duplicate, independent, review
      identified 20 randomized trials involving 1609 patients that compared
      terlipressin with placebo, balloon tamponade, endoscopic treatment, octreotide,
      somatostatin or vasopressin for treatment of acute oesophageal variceal
      haemorrhage. RESULTS: Meta-analysis showed that compared to placebo, terlipressin
      reduced mortality (relative risk 0.66, 95% CI 0.49-0.88), failure of haemostasis
      (relative risk 0.63, 95% CI 0.45-0.89) and the number of emergency procedures per
      patient required for uncontrolled bleeding or rebleeding (relative risk 0.72, 95%
      CI 0.55-0.93). When used as an adjuvant to endoscopic sclerotherapy, terlipressin
      reduced failure of haemostasis (relative risk 0.75, 95% CI 0.58-0.96), and had an
      effect on reducing mortality that approached statistical significance (relative
      risk 0.74, 95% CI 0.53-1.04). No significant difference was demonstrated between
      terlipressin and endoscopic sclerotherapy, balloon tamponade, somatostatin or
      vasopressin. Haemostasis was achieved more frequently with octreotide compared to
      terlipressin (relative risk 1.62, 95% CI 1.05-2.50), but this result was based on
      unblinded studies. Adverse events were similar between terlipressin and the other
      comparison groups except for vasopressin, which caused more withdrawals due to
      adverse events. CONCLUSIONS: Terlipressin is a safe and effective treatment for
      acute oesophageal variceal bleeding, with or without adjuvant endoscopic
      sclerotherapy. Terlipressin appears to reduce mortality in acute oesophageal
      variceal bleeding compared to placebo, and is the only pharmacological agent
      shown to do so. Future studies will be required to detect potential mortality
      differences between terlipressin and other therapeutic approaches.

PMID- 12492733
TI  - Thiopurine methyltransferase genotype distribution in patients with Crohn's
      disease.
AB  - BACKGROUND: Inter-individual response to azathioprine is partly due to inter
      individual variation in the thiopurine methyltransferase (TPMT) activity. The
      TPMT genotype, which reflects the TPMT activity, has previously been studied in
      healthy Caucasians, with the most common variant allele being TPMT*3A. TPMT
      genotyping in adult patients with Crohn's disease has never been performed
      systematically. AIM: To determine the TPMT genotype distribution in adult
      patients with Crohn's disease. METHODS: One hundred and twenty randomly selected
      Danish patients (64 females and 56 males) with azathioprine-dependent Crohn's
      disease were included, and a polymerase chain reaction assay was used for TPMT
      genotyping. The patients were genotyped for the low-level genotype G460-->A and
      A719-->G transitions. RESULTS: One hundred and nine patients (90.3%; 95%
      confidence interval, 84.1-95.3) had a wild-type/ wild-type genotype, whereas 10
      patients (8.3%; 95% confidence interval, 4.1-14.8) had one non-functional mutant
      allele and one patient (0.8%; 95% confidence interval, 0.02-4.6) had two non
      functional mutant alleles. Only the TPMT*3A variant allele was found.
      CONCLUSIONS: The study showed a TPMT genotype distribution amongst adult Danish
      patients with Crohn's disease which was similar to the distribution of TPMT
      variant alleles normally found in healthy Caucasians.

PMID- 12492734
TI  - Mercaptopurine metabolite results in clinical gastroenterology practice.
AB  - BACKGROUND: Azathioprine (AZA) and its active metabolite mercaptopurine (MP) are
      frequently used in the management of inflammatory bowel disease. Measurement of
      the AZA/MP metabolites, thioguanine (TG) and methylmercaptopurine (MMP), has been
      suggested as a means to optimize therapy with AZA/MP in inflammatory bowel
      disease. AIM: To evaluate the results of initial AZA/MP metabolite panels sent by
      gastroenterologists during the first year of its widespread availability.
      METHODS: Initial AZA/MP metabolite panels sent by gastroenterologists to a single
      laboratory were reviewed and the metabolite panels were interpreted. RESULTS:
      Initial metabolite levels were reviewed for 9187 patients. Noncompliance was
      detected in 263 patients (3%) and under-dosing in 4260 patients (46%). 534
      patients (6%) had levels that were consistent with preferential metabolism via
      the TPMT pathway. The therapeutic goal was achieved in 2444 patients (27%) and an
      additional 552 patients (6%) had appropriate TG levels but potential
      hepatotoxicity. 936 patients (10%) had potential TPMT deficiency, and 58 patients
      (1%) had potential TPMT absence and were at risk for leukopenia. 140 patients
      (2%) had too high a dose. CONCLUSIONS: Measurement of AZA/MP metabolites can be
      used by practising gastroenterologists to identify potential reasons for
      nonresponse to AZA or MP, and to identify patients at risk for certain drug
      related toxicities.

PMID- 12492735
TI  - Infusion reactions to infliximab in children and adolescents: frequency, outcome
      and a predictive model.
AB  - BACKGROUND: Crohn's disease commonly affects children and adolescents, however
      the majority of research into the safety and efficacy of therapies for
      inflammatory bowel disease, including infliximab, has occurred only in adults.
      AIM: To determine the rate of reactions in children following infliximab
      infusions, and to identify variables that might be predictive of those reactions.
      METHODS: We performed a retrospective review of all infliximab infusions
      performed at Columbus Children's Hospital from December 1998 through September
      2001. RESULTS: Fifty-seven children received 361 infusions. Three hundred and
      fifty-five of the 361 infusions (98.3%) were completed. Fifty children had 304
      repeat infusions. There were a total of 35 infusion related reactions. Female
      gender and the use of immunosuppressive medications for less than 4 months were
      risk factors for a reaction to infusion number 2. A reaction to infusion 2 and
      immunosuppressive use for less than 4 months were risk factors for infusion
      number 3. CONCLUSIONS: The rate of infusion reactions in children receiving
      infliximab is similar to that in adults. Female gender, immunosuppressive use for
      less than 4 months and prior infusion reactions may be risk factors for
      subsequent infusion reactions in children.

PMID- 12492736
TI  - Pharmacokinetics of budesonide controlled ileal release capsules in children and
      adults with active Crohn's disease.
AB  - BACKGROUND: Systemic glucocorticosteroid therapy is effective in Crohn's disease,
      but is associated with side-effects. Budesonide has high topical anti
      inflammatory activity, but considerably lower systemic activity than other oral
      glucocorticosteroids. AIM: To evaluate the systemic exposure to budesonide
      (controlled ileal release capsules) in children and adults with active Crohn's
      disease, and to assess the suppression of plasma cortisol. METHODS: In an open
      label study, patients (eight children and six adults) with active Crohn's disease
      received 9 mg budesonide (Entocort capsules) orally once daily for 7 days. Plasma
      concentrations were determined on the seventh day of administration, and
      pharmacokinetic parameters were calculated. For reference, 0.5 mg budesonide was
      given intravenously separately. Plasma cortisol levels were compared with the pre
      treatment baseline values. RESULTS: Systemic exposure to budesonide (AUC0-24 h)
      after 1 week of oral administration was 41 +/- 21 nmol/L x h (mean +/- s.d.) in
      children and 35 +/- 20 nmol/L x h in adults. The estimated systemic availability
      in children was 9 +/- 5% and in adults 11 +/- 7%. The mean plasma cortisol (AUC0
      24 h) decreased by 64 +/- 18% in children and by 50 +/- 27% in adults.
      CONCLUSIONS: The systemic exposure, systemic availability and cortisol
      suppression after oral administration of 9 mg budesonide were similar in children
      and adults with active Crohn's disease. Budesonide was well tolerated and no
      clinically important safety-related findings were identified.

PMID- 12492737
TI  - Rectal tissue, plasma and urine concentrations of mesalazine after single and
      multiple administrations of 500 mg suppositories to healthy volunteers and
      ulcerative proctitis patients.
AB  - OBJECTIVE: Patients with ulcerative proctitis may have rectal mucosal properties
      different from healthy volunteers. This project compared the pharmacokinetics of
      rectally administered mesalazine in these two populations. METHODS: In two
      separate studies, nine patients with ulcerative proctitis and 16 healthy
      volunteers received a single 500 mg mesalazine suppository and then 500 mg every
      8 h for 5 days. Blood samples were collected for 12 h in healthy volunteers and
      30 h in patients, and urine for 24 h in healthy volunteers and 30 h in patients.
      Rectal biopsies were performed 8 h after the last dose. RESULTS: After a single
      dose to patients, mean mesalazine half-life (s.d.) was 5.0 (3.6) h. At steady
      state, means (s.d.) were 89.1 (78.9) ng/mL for C(min), 361.1 (240.8) ng/mL for
      C(max), and 7.1 (7.3) h for half-life. Mean (range) rectal mesalazine
      concentrations were 167 (1.4-541.6) ng/mg tissue. After a single dose in healthy
      volunteers, mean (s.d.) half-life was 4.0 (4.7) h. At steady-state, means (s.d.)
      were 22.4 (61.6) ng/mL for C(min), 359.4 (166.3) ng/mL for C(max), and 0.9 (0.5)
      h for half-life. CONCLUSION: Mesalazine is released in the rectum of patients,
      with a bioavailability of about 40%. Tissue distribution is also appreciable.
      Both parameters appear higher than in healthy volunteers.

PMID- 12492738
TI  - Risk factors for failure of Helicobacter pylori therapy--results of an individual
      data analysis of 2751 patients.
AB  - AIM: To study risk factors for failure of Helicobacter pylori eradication
      treatment. METHODS: Individual data from 2751 patients included in 11 multicentre
      clinical trials carried out in France and using a triple therapy, were gathered
      in a unique database. The 27 treatment regimens were regrouped into four
      categories. RESULTS: The global failure rate was 25.8% [95% CI: 24-27]. There was
      a difference in failure rate between duodenal ulcer patients and non-ulcer
      dyspeptic patients, 21.9% and 33.7%, respectively (P < 10(-6)). In a random
      effect model, the risk factors identified for eradication failure in duodenal
      ulcer patients (n = 1400) were: to be a smoker, and to have received the group 4
      treatment, while to receive a 10 day treatment vs. 7 days protected from failure.
      In non-ulcer dyspeptic patients (n = 913), the group 2 treatment was associated
      with failure. In both groups, age over 60 was associated with successful H.
      pylori eradication. There were less strains resistant to clarithromycin in
      duodenal ulcer patients than in non-ulcer dyspeptic patients. Clarithromycin
      resistance predicted failure almost perfectly. CONCLUSION: Duodenal ulcer and non
      ulcer dyspeptic patients should be managed differently in medical practice and
      considered independently in eradication trials.

PMID- 12492739
TI  - Is eradication sufficient to heal gastric ulcers in patients infected with
      Helicobacter pylori? A randomized, controlled, prospective study.
AB  - BACKGROUND: In Helicobacter pylori infection, the effect of short-term triple
      therapy with proton pump inhibitor plus two antibiotics on gastric ulcer healing
      is not well known. AIM: To compare 1-week triple therapy with 8-week proton pump
      inhibitor therapy on gastric ulcer healing in infected patients. PATIENTS AND
      METHODS: We randomly assigned 120 patients with H. pylori and gastric ulcers to
      proton pump inhibitor plus amoxicillin and clarithromycin for 1 week (n = 61) or
      proton pump inhibitor alone for 8 weeks (n = 59), with endoscopic assessment of
      ulcer healing 8 weeks after the start of treatment. RESULTS: Triple therapy
      eradicated H. pylori in 51 patients [intention-to-treat, 84%; 95% confidence
      interval (CI), 75-93%]. At 8 weeks, gastric ulcers were healed in 30 patients
      given triple therapy (49%; 95% CI, 37-62%) and in 49 patients given proton pump
      inhibitor (83%; 95% CI, 73-93%, P < 0.001). Healing rates in the triple therapy
      and proton pump inhibitor-only groups were 89% and 100%, respectively, for ulcers
      of < 1.0 cm in diameter, 54% and 77% for ulcers of 1.0 to < 1.5 cm in diameter,
      and 5% and 77% (P < 0.001) for ulcers of > or = 1.5 cm in diameter. CONCLUSIONS:
      One-week triple therapy healed most ulcers of < 1.0 cm, but not ulcers of > or =
      1.5 cm. Short-term therapy is effective for gastric ulcers of < 1.0 cm, but, for
      larger ulcers, follow-up therapy to suppress acid is needed.

PMID- 12492741
TI  - Human recombinant lactoferrin is ineffective in the treatment of human
      Helicobacter pylori infection.
AB  - BACKGROUND: Lactoferrin, a multifunctional glycoprotein, is known to have anti
      microbial actions. Bovine lactoferrin and recombinant human lactoferrin have been
      shown to inhibit Helicobacter pylori, and more recently recombinant human
      lactoferrin was found to significantly increase the eradication rate of H. pylori
      when added to standard triple therapy. AIM: To determine the efficacy, safety and
      tolerability of recombinant human lactoferrin as a therapy in suppressing or
      eliminating H. pylori infection in subjects with minimal upper gastrointestinal
      symptoms who have not previously been treated. SUBJECTS AND METHODS: Nine healthy
      subjects with minimal upper gastrointestinal symptoms and a positive urea breath
      test were recruited. None of the volunteers had previously been treated for H.
      pylori. Subjects received 5 x 1.0 g human recombinant lactoferrin daily for 5 or
      14 days. Breath tests were repeated during therapy and shortly after to check for
      eradication. The safety and tolerability of the drug were assessed by physical
      examination, by monitoring adverse events, and clinical laboratory evaluation.
      RESULTS: No conversion of the urea breath test from positive to negative was
      observed and there was no consistent change in urea breath test count to indicate
      a possible suppression of H. pylori. CONCLUSION: Lactoferrin, given as a single
      agent, does not eradicate H. pylori infection.

PMID- 12492740
TI  - Efficacy of triple therapy comprising rabeprazole, amoxicillin and metronidazole
      for second-line Helicobacter pylori eradication in Japan, and the influence of
      metronidazole resistance.
AB  - BACKGROUND: The widespread use of eradication therapy for Helicobacter pylori in
      Japan has led to an increase in antibiotic-resistant strains and the problem of
      re-treatment in cases of eradication failure. AIM: To perform drug sensitivity
      testing for metronidazole in 92 H. pylori-positive patients who had failed
      eradication treatment with first-line triple therapy, consisting of a proton pump
      inhibitor, amoxicillin and clarithromycin, and were administered metronidazole
      containing second-line therapy. METHODS: Second-line eradication therapy,
      consisting of rabeprazole (20 mg b.d.), amoxicillin (750 mg b.d.) and
      metronidazole (250 mg b.d.), was administered for 1 week and the eradication
      rates and influence of metronidazole resistance were determined. RESULTS: The
      eradication rates for rabeprazole-amoxicillin-metronidazole were 88% (81/92)
      using intention-to-treat analysis and 91% (81/89) using per protocol analysis.
      The eradication rates were 97% (61/63) for metronidazole-sensitive strains and
      82% (18/22) for metronidazole-resistant strains. CONCLUSIONS: As second-line H.
      pylori eradication treatment in Japan, rabeprazole-amoxicillin-metronidazole
      triple therapy is effective, even with metronidazole-resistant strains.

PMID- 12492742
TI  - Once-daily, low-cost, highly effective Helicobacter pylori treatment to family
      members of gastric cancer patients.
AB  - BACKGROUND: Helicobacter pylori eradication in family members of gastric cancer
      patients is now widely accepted, although problems related to costs and
      compliance persist. AIM: To compare the efficacy, tolerability and long-term re
      infection rates of two once-daily regimens for the eradication of H. pylori in
      family members of gastric cancer patients. METHODS: 106 first-degree family
      members of gastric cancer patients were recruited and submitted to the 13C-urea
      breath test (UBT) to detect H. pylori. If positive, they were randomly allocated
      to receive a combination of lanzoprazole 30 mg, clarithromycin OD (extended
      release formulation) 500 mg and furazolidone 400 mg, once daily, in the morning,
      for 7 days (Group A) or the same regimen with only 200 mg furazolidone (Group B).
      Eradication was confirmed by urea breath test performed 6 weeks after treatment.
      13C-urea breath test was repeated at 944 (784-1258) days after treatment in
      successfully treated participants to look for re-infection. RESULTS: Twenty-five
      participants were H. pylori negative and two H. pylori-positive individuals
      refused to sign the informed consent and were excluded. Therefore, 79
      participants were studied. Forty participants were allocated to Group A and 39 to
      Group B. All participants completed treatment. Adverse effects, mostly mild, were
      observed in 18% of Group A and 18% of Group B (N.S.). The intention-to-treat
      eradication rate was 87.5% in Group A and 61.5% in Group B (P = 0.006). The mean
      annual re-infection rate was 3%. CONCLUSIONS: The combination of lanzoprazole 30
      mg, one tablet of clarithromycin OD (extended release formulation) 500 mg and
      furazolidone 400 mg, once daily for 7 days, constitutes an inexpensive, safe and
      effective alternative for anti-H. pylori therapy in family members of gastric
      cancer patients.

PMID- 12492743
TI  - Oral antioxidant supplementation for fatigue associated with primary biliary
      cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over
      trial.
AB  - BACKGROUND: We have previously reported, in an uncontrolled trial, an improvement
      in fatigue scores in patients with primary biliary cirrhosis given oral
      antioxidant supplementation. We now present data from a controlled trial.
      PATIENTS AND METHODS: Sixty-one patients with primary biliary cirrhosis
      associated fatigue were randomized into a double-blind, placebo-controlled, cross
      over trial. Participants received 12 weeks each of placebo and antioxidant
      supplementation (vitamins A, C and E, selenium, methionine and ubiquinone) in
      random order, separated by a 4-week washout period. The primary trial outcome
      (fatigue) was assessed using the Fisk scale. Other symptoms of primary biliary
      cirrhosis were measured using Likert and visual analogue scales. RESULTS: Forty
      four patients completed both arms of the trial. No significant changes in fatigue
      were recorded in the active phase of treatment (median improvement in Fisk score,
      1; P = 0.61). Small improvements in Fisk scores were recorded during placebo
      therapy (median improvement, 4; P = 0.03). Neither medication was associated with
      improvement in any other symptoms related to primary biliary cirrhosis. Adverse
      effects were more common during active therapy and were mild and self-limiting.
      One patient died from unrelated causes during active treatment. CONCLUSIONS:
      Although oral antioxidant supplementation appears to be safe, we could not find
      any evidence for a beneficial effect on fatigue or other liver-related symptoms.

PMID- 12492744
TI  - Hepatic venous pressure gradient measurements to assess response to primary
      prophylaxis in patients with cirrhosis: a decision analytical study.
AB  - BACKGROUND: The measurement of the hepatic venous pressure gradient may identify
      a suboptimal response to beta-blockers in patients with varices at risk for
      bleeding. However, the cost-effectiveness of routine hepatic venous pressure
      gradient measurements to guide primary prophylaxis has not been examined.
      METHODS: We used decision analysis to evaluate two hepatic venous pressure
      gradient measurement strategies relative to standard beta-blocker therapy in a
      hypothetical cohort of patients with high-risk varices: (i) hepatic venous
      pressure gradient measurement 4 weeks after the initiation of beta-blocker
      therapy; and (ii) hepatic venous pressure gradient measurement prior to and 4
      weeks after the initiation of beta-blocker therapy. The total expected costs,
      variceal bleeding episodes and deaths were calculated over a 1-year time horizon.
      RESULTS: Beta-blocker therapy was associated with total costs of $1464, seven
      variceal bleeding episodes, one variceal bleeding episode-related death and 15
      deaths. One hepatic venous pressure gradient measurement was associated with
      total costs of $5015, four variceal bleeding episodes, one variceal bleeding
      episode-related death and 15 deaths. Two hepatic venous pressure gradient
      measurements were associated with total costs of $8657, four episodes of variceal
      bleeding, one variceal bleeding episode-related death and 15 deaths. Compared
      with beta-blocker therapy alone, the incremental costs per variceal bleeding
      episode prevented and death averted were, respectively, $108 185 and $355 100
      (one hepatic venous pressure gradient measurement) and $202 796 and $719 300 (two
      hepatic venous pressure gradient measurements). The results were sensitive to the
      time horizon of the analysis, the probability of bleeding whilst on beta-blockers
      and the cost of hepatic venous pressure gradient measurement. CONCLUSION: Hepatic
      venous pressure gradient measurement to guide primary prophylaxis is an expensive
      strategy for reducing variceal bleeding or death, especially in patients with
      limited life expectancy, such as those with advanced, decompensated cirrhosis.

PMID- 12492745
TI  - Pantoprazole maintenance therapy prevents relapse of erosive oesophagitis.
AB  - OBJECTIVES: To compare the safety and efficacy of pantoprazole with ranitidine
      for the maintenance of endoscopically documented healed (grade 0 or 1) erosive
      oesophagitis. METHODS: Patients (371) were randomly assigned to receive
      pantoprazole 10, 20 or 40 mg or ranitidine 150 mg. Endoscopies were performed
      after 1, 3, 6 and 12 months or when symptoms suggesting relapse (grade = 2)
      developed. Gastric biopsies were obtained at baseline and on at least one
      postbaseline visit. Symptom-free days and Gelusil use were assessed. RESULTS:
      Pantoprazole was significantly (P < 0.001) more effective in maintaining erosive
      oesophagitis healing. After 12 months, 33%, 40%, 68% and 82% of patients remained
      healed for the ranitidine and pantoprazole 10, 20 and 40 mg groups, respectively.
      Daytime and night-time heartburn were eliminated in > 90% of days for the
      pantoprazole 40 mg group. Gelusil use was significantly lower with pantoprazole
      20 and 40 mg than with ranitidine (P < 0.02) during the first 9 months.
      CONCLUSIONS: Twelve months of maintenance therapy with pantoprazole (10-40 mg
      once daily) was superior to ranitidine (150 mg twice daily) in maintaining
      erosive oesophagitis healing. Pantoprazole 40 mg provided the most consistent
      efficacy and was well tolerated.

PMID- 12492746
TI  - Comparison of efficacy and safety of two doses of two different polyethylene
      glycol-based laxatives in the treatment of constipation.
AB  - AIM: To compare standard and maximum daily doses of polyethylene glycol 3350 plus
      electrolytes (Transipeg) and polyethylene glycol 4000 (Forlax) in a multicentre,
      double-blind, randomized, parallel-group study. METHODS: Ambulatory patients with
      idiopathic chronic constipation were randomized to receive Forlax (10 or 20 g) or
      Transipeg (5.9 or 11.8 g) for 1 month. The primary efficacy end-point was stool
      frequency. Secondary efficacy parameters included stool consistency, date of
      occurrence of first motion, straining on defecation, rectal evacuation, abdominal
      pain and distension. Adverse events were recorded. RESULTS: Stool frequency was
      significantly increased compared with baseline in all treatment groups (P =
      0.0001). Most patients (> or = 67.3%) had their first stool within 1 day of
      starting treatment. Stool consistency significantly improved compared with
      baseline in all treatment groups (P = 0.0001). The percentage of patients with
      normal stool consistency was significantly higher for standard-dose Transipeg vs.
      both maximum-dose treatments (P < 0.01). Other secondary parameters were also
      significantly improved compared with baseline in all treatment groups (P =
      0.0001). All medications were well tolerated. CONCLUSIONS: Standard-dose
      Transipeg (5.9 g) normalized stool consistency with less semi-liquid or liquid
      stools than maximum-dose Transipeg and Forlax, with a non-significant trend
      towards less semi-liquid or liquid stools than standard-dose Forlax.

PMID- 12492747
TI  - Leukopenia and remission during azathioprine treatment.

PMID- 12492748
TI  - Ethics matter: to authors, editors and those we serve.

PMID- 12492749
TI  - Networking editors in Quebec.

PMID- 12492750
TI  - A collaborative approach to working with families.

PMID- 12492751
TI  - Understanding polydrug use: review of heroin and cocaine co-use.
AB  - The use of cocaine by heroin-dependent individuals, or by patients in methadone
      or buprenorphine maintenance treatment, is substantial and has negative
      consequences on health, social adjustment and outcome of opioid-addiction
      treatment. The pharmacological reasons for cocaine use in opioid-dependent
      individuals, however, are poorly understood and little is known about the
      patterns of heroin and cocaine co-use. We reviewed anecdotal evidence suggesting
      that cocaine is co-used with opioid drugs in a variety of different patterns, to
      achieve different goals. Clinical and preclinical experimental evidence indicates
      that the simultaneous administration of cocaine and heroin (i.e. 'speedball')
      does not induce a novel set of subjective effects, nor is it more reinforcing
      than either drug alone, especially when the doses of heroin and cocaine are high.
      There is mixed evidence that the subjective effects of cocaine are enhanced in
      individuals dependent on opioids, although it is clear that cocaine can alleviate
      the severity of symptoms of withdrawal from opioids. We also reviewed preclinical
      studies investigating possible neurobiological interactions between opioids and
      cocaine, but the results of these studies have been difficult to interpret mainly
      because the neurochemical mechanisms mediating the motivational effects of
      cocaine are modified by dependence on, and withdrawal from, opioid drugs. Our
      analysis encourages further systematic investigation of cocaine use patterns
      among opioid-dependent individuals and in laboratory animals. Once clearly
      identified, pharmacological and neuroanatomical methods can be employed in self
      administering laboratory animals to uncover the neurobiological correlates of
      specific patterns of co-use.

PMID- 12492752
TI  - A meta-analysis of estimated genetic and environmental effects on smoking
      behavior in male and female adult twins.
AB  - BACKGROUND: Numerous twin studies on smoking behavior have shown that genetic and
      environmental factors play significant and approximately equal roles in the
      determination of smoking initiation (SI) and smoking persistence (SP). However,
      estimates of heritability (h2), shared (c2) and unique environmental effects (e2)
      from the literature display considerable variability for SI and SP, due most
      probably to differences in statistical analysis models, age, gender, sample size,
      origin of cohorts and measurement of smoking behavior. METHODS: A systematic
      literature search identified six studies for SI and 10 studies for SP. Data from
      these studies were obtained and re-analysed by meta-analytical techniques.
      RESULTS: For SI, our results indicate that the parameters h2, c2 and e2 are (mean
      +/- SEM): 0.37 +/- 0.04, 0.49 +/- 0.04 and 0.17 +/- 0.03 in male adults, and 0.55
      +/- 0.04, 0.24 +/- 0.06 and 0.16 +/- 0.01 in female adults, respectively. These
      values were weighted by a combination of original estimates of variance from
      studies reporting variances plus estimated variances from studies where variances
      were not reported (called the combined variance method). Using the same approach
      for SP, we found that the parameters h2, c2 and e2 weighted by the combined
      variance method for the phenotype are (mean +/- SEM): 0.59 +/- 0.02, 0.08 +/-
      0.04 and 0.37 +/- 0.03 in male adults, and 0.46 +/- 0.12, 0.28 +/- 0.08 and 0.24
      +/- 0.07 in female adults, respectively. CONCLUSIONS: Our results indicate that
      genetic factors play a more significant role for SI but a less significant role
      for SP in female adults compared to male adults. Significant gender difference
      was also detected in shared environmental factors for SI and SP. However, no
      significant gender difference was detected for e2 for either phenotype. These
      findings suggest that genetic and environmental factors may contribute
      differently to the determination of smoking initiation and persistence in male
      and female smokers.

PMID- 12492753
TI  - Aggression involving alcohol: relationship to drinking patterns and social
      context.
AB  - AIMS: The present study examines the relationships between: (1) alcohol
      involvement/perceived intoxication level of participants and aggression severity;
      (2) respondent drinking patterns and involvement in alcohol-related aggression;
      and (3) social context and alcohol-related aggression. DESIGN: Random digit
      dialing (RDD) with computer assisted telephone interviewing (CATI) was used to
      obtain a random sample of Ontario adults aged 18-60 (response rate of 67%).
      PARTICIPANTS: Respondents who reported that they had been involved personally in
      physical aggression in the past 12 months were the focus of the present study.
      MEASUREMENTS: Questions were asked regarding the most recent incident of physical
      aggression, including whether the respondent and opponent drank alcohol prior to
      aggression, perceived intoxication levels at the time, number of participants,
      relationship to opponent, social context of aggression, time of day and day of
      week. Three items were used to assess aggression severity: injury to respondent,
      use of threats by respondent or opponent and police involvement. FINDINGS: (1)
      Injury to respondent and threats by respondent were not associated with alcohol
      involvement per se, but were significantly related to perceived level of alcohol
      intoxication; (2) drinking pattern of respondent was significantly associated
      with alcohol-related aggression but unrelated to aggression that did not involve
      alcohol; and (3) a number of contextual factors (e.g. gender, number of
      participants, time of day) were found to be associated with alcohol involvement
      in aggression. CONCLUSIONS: The results suggest that both drinking pattern and
      contextual factors are important in distinguishing between alcohol-related
      aggression and non-alcohol-related aggression. As well, alcohol intoxication may
      be an important predictor of aggression severity.

PMID- 12492754
TI  - A randomized controlled trial of a brief intervention after alcohol-related
      facial injury.
AB  - AIM: To evaluate the effectiveness of a brief motivational intervention on
      alcohol consumption and misuse in young males with alcohol-related face injury.
      DESIGN: Randomized controlled trial. SETTING: Oral and maxillofacial surgery out
      patient clinic in an urban teaching hospital. PARTICIPANTS: One hundred and fifty
      one participants were randomized to motivational intervention and control
      conditions. INTERVENTIONS: Control was treatment as usual. The intervention was
      treatment as usual plus a one-session brief motivational intervention
      administered by a nurse. MEASUREMENTS: Three sets of measurements were taken at
      baseline, 3-month and 1-year follow-up. Collateral measurements were also taken
      at 1-year follow-up. Primary outcome measures were total alcohol consumption,
      typical weeks consumption and days abstinent in preceding 3 months. Other outcome
      measures included the Alcohol Use Disorders Identification Test, a short form of
      the Alcohol Problems Questionnaire, and a measure of satisfaction with social
      relationships. RESULTS: There was a significant decrease in 84-day total alcohol
      consumption across the year (P < 0.006) and further, a significant effect for the
      motivational intervention was demonstrated (P < 0.029). This pattern was repeated
      for days abstinent and alcohol consumption in a typical week as well as alcohol
      related problems. There was a significantly greater reduction in the percentage
      of hazardous drinkers in the motivational intervention group (from 60% to 27%, P
      < 0.009) compared to the control group (from 54% to 51%, NS). CONCLUSION: A
      proportion of young men change their alcohol consumption following alcohol
      related injury. A nurse-led psychological intervention adds significantly to the
      proportion and magnitude of response.

PMID- 12492755
TI  - Impaired control over gambling in gaming machine and off-course gamblers.
AB  - AIM: To investigate and compare subjectively reported impaired control in two
      forms of gambling: off-course Totalizator Agency Board (TAB) horse/dog racing and
      electronic gaming machines (EGMs). Additionally, gender differences in EGM play
      were investigated. DESIGN: A survey sample of 84 male TAB gamblers and 137 EGM
      players (73 females and 64 males) was recruited at gambling sites. SETTING:
      Hotels and clubs in Adelaide, South Australia, were used as recruiting venues.
      Interviews were either conducted on site if there was sufficient privacy, or
      relocated to nearby cafes. PARTICIPANTS: The inclusion criteria were gambling at
      least weekly and being over the age of 18. Female off-course gamblers were not
      approached given their scarcity. MEASUREMENTS: A general gambling involvement
      questionnaire was devised from pilot research. Impaired control was measured
      using a shortened version of The Scale of Gambling Choices. FINDINGS: Impaired
      control over gambling has a robust factor structure, with little difference
      between EGM and TAB gamblers. Concurrent validity for the impaired control
      measure was demonstrated against measures of gambling involvement. CONCLUSION:
      Impaired control appears to be, in the main, a generic process across these two
      forms of gambling and for both sexes. Further refinement and application of the
      concept of impaired control to excessive gambling seems warranted given its
      strong face, construct and concurrent validity.

PMID- 12492756
TI  - Attentional bias and addictive behaviour: automaticity in a gambling-specific
      modified Stroop task.
AB  - AIMS: This study examined the relationship between attention and gambling
      behaviour by measuring the level of Stroop interference towards gambling-related
      words in a group of regular poker machine players. DESIGN: A 3 x 2 repeated
      measures experimental design was employed. The type of word presented (neutral,
      drug or gambling) was the within-subjects factor and the level of impaired
      control (high or low) over gambling behaviour was the between-subjects factor.
      PARTICIPANTS: A sample of poker machine players (n = 60), varying in their
      frequency of play, were split into two groups based on their level of subjective
      impaired control over their gambling behaviour (high or low). MEASUREMENTS: A
      computerized gambling-specific modified version of the Stroop task was used to
      assess response latencies. The test comprised three word categories: gambling,
      drug and neutral. The Scale of Gambling Choices (SGC) was used to assess
      participants' level of impaired control over gambling behaviour. FINDINGS: It was
      found that the participants who had difficulty in controlling their gambling
      behaviour (the low control group) took significantly longer to name the colour of
      the words relating to poker machine gambling, whereas those who had good control
      over their gambling behaviour (the high control group) did not show any
      significant differences across the three word categories. CONCLUSIONS: Results
      support the previous finding that people with a problem behaviour or emotion take
      longer to colour-name words relating to the area of their concern. The current
      study extends previous work that has investigated the role of cognitive
      distortions and biases in the area of addictive behaviour. The current study
      confirms McCusker & Gettings's findings, but by avoiding the mental disorder
      conceptualization facilitates theoretical understanding of addictive behaviour.
      Implications for past models and theories of the Stroop as well as future
      research directions are discussed.

PMID- 12492757
TI  - Possible age-associated bias in reporting of clinical features of drug
      dependence: epidemiological evidence on adolescent-onset marijuana use.
AB  - AIMS: To probe recent evidence on apparent excess occurrence of marijuana
      dependence when marijuana smoking starts in adolescence. DESIGN AND PARTICIPANTS:
      A national sample of recent-onset marijuana users was identified within public
      data files of the National Household Survey on Drug Abuse (NHSDA), 1995-98 (1,866
      adolescents and 762 adults). MEASUREMENTS: Marijuana dependence was assessed via
      seven standardized questions about its clinical features, such as being unable to
      cut down. Multivariate response models (GLM/GEE and MIMIC) were used to evaluate
      adolescent excess risk and possible item biases. FINDINGS: Among people who had
      just started to use marijuana, clinical features of marijuana dependence occurred
      twice as often among adolescents compared to adults, even with statistical
      adjustment for other covariates (P < 0.01 from GLM/GEE). MIMIC analyses suggest
      that adolescent-onset users have somewhat higher levels of marijuana dependence,
      and they also provide evidence of age-associated response bias for some but not
      all clinical features of marijuana dependence. That is, even with level of
      marijuana dependence held constant, adolescent recent-onset users were more
      likely than adults to report being unable to cut down (P = 0.01) and tolerance (P
      = 0.029). CONCLUSION: Nosologic, methodological and substantive reasons for
      observed age-related excess in occurrence of marijuana dependence problems among
      early onset users deserve more attention in future research.

PMID- 12492758
TI  - Supply control and harm reduction: lessons from the Australian heroin 'drought'.
AB  - AIMS: To examine the effects of supply-side drug law enforcement on the dynamics
      of the Australian heroin market and the harms associated with heroin. SETTING:
      Around Christmas 2000, heroin users in Sydney and other large capital cities in
      Australia began reporting sudden and significant reductions in the availability
      of heroin. The changes, which appear to have been caused at least in part by drug
      law enforcement, provided a rare opportunity to examine the potential impact of
      such enforcement on the harm associated with heroin. DESIGN: Data were drawn from
      a survey of 165 heroin users in South-Western Sydney, Australia; from the Drug
      Use Monitoring in Australia (DUMA) project; from NSW Health records of heroin
      overdoses; and from the Computerized Operational Policing System (COPS) database.
      FINDINGS: Heroin price increased, while purity, consumption and expenditure on
      the drug decreased as a result of the shortage. The fall in overall heroin use
      was accompanied by a significant reduction in the rate of overdose in NSW.
      However, the health benefits associated with the fall in overdose may have been
      offset by an increase in the use of other drugs (mainly cocaine) since the onset
      of the heroin shortage. There does not appear to have been any enduring impact on
      crime rates as a result of the heroin 'drought'. CONCLUSION: Supply control has
      an important part to play in harm reduction; however, proponents of supply-side
      drug law enforcement need to be mindful of the unintended adverse consequences
      that might flow from successfully disrupting the market for a particular illegal
      drug.

PMID- 12492759
TI  - Decreased heroin availability in Sydney in early 2001.
AB  - AIM: To examine the veracity of reports of a substantial decrease in the
      availability of heroin in Sydney in January 2001. DESIGN: Cross-sectional survey.
      SETTING: Sydney, Australia. PARTICIPANTS: Forty-one injecting drug users (IDUs)
      and 10 key informants (KIs). FINDINGS: Almost all IDUs (93%) reported that heroin
      was harder to obtain at the time of interview (mid-February 2001) than it was
      before Christmas 2000 and KIs concurred. IDUs (83%) and KIs (70%) also reported
      that the price of heroin had increased since Christmas, and that the purity of
      heroin had decreased (IDUs 73%; KIs 80%). Almost all IDUs reported a reduction in
      their heroin use and a subsequent increase in other drug use, particularly
      cocaine, benzodiazepines and cannabis. Similar reports about IDUs came from nine
      of the 10 KIs. Over half the KIs reported an increase in both property and
      violent crime as a result of the heroin shortage. This crime was reportedly
      occurring mainly between heroin suppliers and/or IDUs. Reports from other
      Australian jurisdictions suggest that the shortage was not specific to Sydney.
      CONCLUSIONS: The reduction in the availability of heroin provides a unique
      opportunity to investigate the impact of supply reduction.

PMID- 12492760
TI  - Illicit drug-related harm during the Sydney 2000 Olympic Games: implications for
      public health surveillance and action.
AB  - AIMS: To describe presentations to emergency departments during the Sydney 2000
      Olympic Games for conditions related to the use of illicit drugs; to discuss the
      implications of such presentations for surveillance and public health action at
      similar events in the future. DESIGN: Identification of target presentations in
      sentinel emergency departments; entry of data into a purpose-built database; and
      daily electronic transfer of data for central collation and analysis. SETTING:
      Fifteen sentinel emergency departments in the greater Sydney metropolitan area
      for a 38-day period spanning the Sydney 2000 Olympic Games. PARTICIPANTS: Four
      hundred and twenty-four presentations to sentinel emergency departments with
      conditions related to illicit drug use. MEASUREMENTS: Patient's age, sex, country
      and region of residence, location of emergency department, types of illicit drugs
      involved and departure status. FINDINGS: The mean daily number of presentations
      for adverse events due to illicit drug use was significantly higher (13.3 versus
      8.8 presentations, t = 2.2, P = 0.04) in the 2-week Olympic Games period than in
      the lead-up to the Games, culminating in a large peak following the closing
      ceremony. There was also a significant increase (5.1 versus 1.7 presentations, t
      = 2.8, P = 0.007) in the mean daily number of presentations related to use of
      ecstasy or amphetamines, whereas no change was noted in presentations related to
      heroin use. Over half (52%) of presentations occurred at two emergency
      departments in areas known as being 'hot-spots' for illicit drug use.
      CONCLUSIONS: Enhanced surveillance of adverse events following illicit drug use,
      possibly targeting known 'hot-spots', should be considered for future mass
      events. Advance preparation of preventive strategies, such as 'party-safe'
      messages, will enable rapid response to unusual patterns of illicit drug-related
      harm during future mass events.

PMID- 12492761
TI  - Neonatal outcome following buprenorphine maintenance during conception and
      throughout pregnancy.
AB  - AIMS: To assess the effects of maternal buprenorphine treatment at conception and
      during pregnancy on neonates in terms of birth outcomes and neonatal abstinence
      syndrome (NAS). DESIGN AND SETTING: Prospective, open-label, out-patient
      maintenance, case report study, conducted at the drug addiction out-patient
      clinic at the University Hospital Vienna. PARTICIPANTS: Two buprenorphine
      maintained pregnant women who had conceived during buprenorphine treatment. Both
      patients had previously given birth to healthy neonates following induction on to
      buprenorphine maintenance therapy in the second trimester. MEASUREMENTS: Mothers:
      urinalysis. Neonates: gestational age at delivery, Apgar scores, birth weight,
      length and NAS (Finnegan Scale). FINDINGS: Urinalyses were negative for both
      women for 25 and 38 months, respectively, during the pregnancy period. There were
      no complications during the course of the pregnancy. The newborns delivered by
      both women were healthy, birth outcomes were within normal ranges and there were
      no NAS symptoms requiring treatment. CONCLUSIONS: To our knowledge this is the
      first report detailing the pregnancies of women treated with buprenorphine at the
      time of conception and investigated in a prospective study. The NAS noted in
      neonates born to buprenorphine-maintained mothers appears to be less severe than
      the NAS observed in neonates born to methadone-maintained mothers. These
      preliminary data indicate that, in our patient cohort, buprenorphine maintenance
      at the time of conception and during pregnancy did not seem to affect birth
      outcome measurements such as pregnancy complications, week of delivery, birth
      weight, length, umbilical pH or neurodevelopmental progress. Future prospective
      studies with larger study populations are warranted.

PMID- 12492762
TI  - An evaluation of the Dartmouth Assessment of Lifestyle Inventory and the Leeds
      Dependence Questionnaire for use among detained psychiatric inpatients.
AB  - AIM: To examine the psychometric properties of the Dartmouth Assessment of
      Lifestyle Inventory (DALI) as a substance use disorder screening instrument, and
      the Leeds Dependency Questionnaire (LDQ) as a measure of severity of dependence
      among inpatients with severe mental disorders detained in hospital. DESIGN:
      Comparison of DALI scores, LDQ scores and a clinical assessment of substance use
      disorder. Statistical analysis calculated Cronbach's alpha, receiver operator
      characteristics, anova and multivariate linear regression. SETTING: An English
      medium secure psychiatric hospital. PARTICIPANTS: A random sample of 60 adult
      inpatients with one or more diagnoses of schizophrenia, personality disorder and
      mild to moderate learning difficulty. MEASUREMENTS: All participants completed
      the LDQ, DALI and a clinical assessment of substance use disorder using ICD-10
      criteria. FINDINGS: The diagnostic accuracy of the DALI instrument was 74% for
      alcohol disorders and 83% for drug disorders. The reliability of the LDQ and
      concurrent validity with the DALI were good (a = 0.915, R2 = 0.439, F (2, 57) =
      22.3, P < 0.001). CONCLUSIONS: The DALI's overall accuracy for screening
      inpatients is good, but it under-diagnosed substance use disorders, probably
      because the hospital environment moderates substance use. The results suggest
      that the LDQ has very good psychometric properties and is useful as a measure of
      substance dependence in this population. Furthermore, the validity of the LDQ in
      this clinical population provides evidence to suggest the same cognitive and
      behavioural processes of addiction operate among those inpatients with severe
      mental disorders detained in psychiatric hospital as in the general population.

PMID- 12492763
TI  - General practice management of illicit drug users in Scotland: a national survey.
AB  - AIMS: To describe the level of involvement of general practitioners (GPs) in the
      management of illicit drug dependency; nature of current practice in the
      management of illicit drug dependency; influence of guidelines on practice; GP
      training experience and needs; and to consider the policy implications of the
      findings. DESIGN: A cross-sectional postal questionnaire survey. SETTING: General
      practice in Scotland. PARTICIPANTS: A 1 : 4 randomized sample (n = 926) of
      general practice principals, stratified according to age, gender and number of
      practice partners. MEASUREMENTS: A structured postal questionnaire. FINDINGS: A
      63% response rate was achieved after two reminders (n = 583). Sixty per cent of
      respondents treated drug users, 51.5% provided methadone maintenance but only 58%
      used doses in the recommended range. Maintenance prescribing of dihydrocodeine
      and benzodiazepines was provided by 24% and 44.8% of respondents, respectively.
      While 79.3% had received the national clinical guidelines only 22.5% believed
      this had influenced their practice. Only a third of respondents had received drug
      dependency training. Beliefs about whether prescribing for drug misusers is part
      of a GPs professional remit was split. CONCLUSIONS: There was relatively high
      involvement with drug users, with methadone maintenance being the most common
      treatment provided. Maintenance prescribing of dihydrocodeine and benzodiazepines
      were common despite a lack of clinical evidence supporting the effectiveness of
      these treatments. This may reflect the nature of the presenting drug problems and
      highlights the difficulties some GPs may face in managing multiple drug
      dependencies within current guidelines. Further local training to implement
      guidelines along with trials of alternative treatments currently outwith
      guidelines should be considered.

PMID- 12492767
TI  - How do you define remission?
AB  - OBJECTIVE: To underscore the need to attain remission in the treatment of
      depression, taking into consideration the appropriate definitions of response and
      remission, as well as the impact of residual symptomatology. METHOD: A review of
      research pertaining to successful response and remission of depression following
      antidepressant intervention, as identified by a comprehensive MEDLINE search.
      RESULTS: Complete remission is both critical and attainable with appropriate
      antidepressant therapy. CONCLUSION: While adequate response to antidepressant
      medication is desired, the ultimate goal of therapy is remission, the achievement
      of an asymptomatic state characterized by complete functional recovery.

PMID- 12492768
TI  - Achieving gains beyond response.
AB  - OBJECTIVE: To review adverse outcomes following response in treatment of
      depression. METHOD: Review of published literature with particular emphasis on
      key papers. RESULTS: Moderately high rates of relapse and recurrence are found in
      naturalistic follow-up studies of depressed patients receiving modern treatment.
      These are reduced but not abolished in controlled trials by continuation and
      maintenance treatment with antidepressants. Suicide rates in follow-up studies
      are much elevated compared with the general population. Social function is
      impaired and remits more slowly than depressive symptoms. A key outcome is the
      occurrence of incomplete remission with residual symptoms, which is associated
      with high relapse rates and impaired social function. CONCLUSION: It is important
      to achieve complete remission in depression. Elimination of residual symptoms is
      an important target for full treatment of the depressive episode, in order to
      avoid later adverse outcomes.

PMID- 12492769
TI  - Treatment strategies in achieving remission in major depressive disorder.
AB  - OBJECTIVE: This paper discusses strategies for achieving remission in major
      depressive disorder, summarizing the results of comparative studies of various
      antidepressants. METHOD: Antidepressant efficacy was determined as either
      response or remission, measured using the Hamilton Depression Rating Scale, the
      Clinical Global Impressions scale and other widely used instruments. RESULTS:
      Study results suggest an advantage to pharmacotherapy that interacts with more
      than one neurotransmitter system, either as single mixed-activity drugs (e.g.
      clomipramine, mirtazapine and venlafaxine extended-release) or combinations of
      medications that are individually specific for a single neurotransmitter system.
      CONCLUSION: Remission should be the goal of antidepressant therapy. Treatment
      strategies include increasing the dosage of the chosen antidepressant; switching
      to an antidepressant with a different mechanism of action; augmenting one
      antidepressant with another agent; or using combination therapy. A substantial
      body of data indicates that for a subset of depressed patients, activation of
      multiple neurotransmitter systems is beneficial in achieving remission.

PMID- 12492770
TI  - Achieving remission from depression with venlafaxine and venlafaxine extended
      release: a literature review of comparative studies with selective serotonin
      reuptake inhibitors.
AB  - OBJECTIVE: To evaluate data supporting the ability of venlafaxine, an
      antidepressant with a dual mechanism of action, to produce remission from
      depression. METHOD: Review of multicentre, double-blind, randomized studies
      comparing venlafaxine or venlafaxine extended release (XR) with a selective
      serotonin reuptake inhibitor (SSRI), using Hamilton Depression Rating Scale total
      scores in the range of < or = 7 and < 10 as the final outcome measure, to
      evaluate the ability of venlafaxine/venlafaxine XR to produce full remission from
      depression. RESULTS: Venlafaxine/venlafaxine XR demonstrated higher rates of
      remission than did the SSRIs and placebo. CONCLUSION: With full remission rather
      than response as the measure of outcome, venlafaxine/venlafaxine XR demonstrated
      more robust antidepressant efficacy than the SSRIs and placebo. This finding
      suggests that venlafaxine/venlafaxine XR are appropriate standard-of-care
      therapies for the treatment of patients with major depressive disorder.

PMID- 12492774
TI  - The paraventricular nucleus: an important component of the central neurocircuitry
      regulating sympathetic nerve outflow.
AB  - AIM: The sympathetic nervous system plays an important role in the regulation of
      physiological homeostasis under basal conditions and in response to acute and
      chronic stressors. It is known that multiple levels of the neuroaxis, including
      the paraventricular nucleus (PVN) of the hypothalamus, are involved in regulation
      of efferent sympathetic nerve discharge (SND). This review focuses on the role of
      the PVN in regulation of functional characteristics of efferent SND. RESULTS: The
      available experimental evidence indicates that the level of efferent sympathetic
      nerve activity is altered after microinjection of numerous substances into the
      PVN, including excitatory amino acids, gamma-aminobutyric acid (GABAA) receptor
      agonists and antagonists, and PVN nitric oxide synthase inhibitors. In addition,
      antagonism of PVN GABAA receptors changes the pattern of synchronized discharge
      bursts in efferent sympathetic nerves and enhances the frequency-domain coupling
      between low-frequency bursts in sympathetic nerve pairs. Finally, PVN
      microinjections of excitatory amino acids (L-glutamate, D,L-homocysteic acid)
      have been shown to produce non-uniform changes in the level of efferent
      sympathetic nerve activity. CONCLUSION: These findings support the concept that
      the PVN is an important component of the central neurocircuitry regulating
      functional characteristics (basal level of activity, bursting pattern, and
      relationships between discharges in nerves innervating different targets) of
      efferent sympathetic nerve outflow.

PMID- 12492775
TI  - Paraventricular nucleus of the hypothalamus and elevated sympathetic activity in
      heart failure: the altered inhibitory mechanisms.
AB  - AIM: There is a characteristic neurohumoral activation in heart failure (HF).
      However, few studies have been performed to examine the role of the central
      nervous system in the activation of sympathetic outflow during HF. In this paper
      we review some of our studies, with particular emphasis on examining the role of
      the paraventricular nucleus (PVN) in the exaggerated sympathetic outflow commonly
      observed in HF. RESULTS: Our studies have revealed that the inhibitory mechanisms
      regulating sympathetic outflow are mediated by nitric oxide (NO) and gamma
      aminobutyric acid (GABA) within the PVN and are attenuated in HF. These
      alterations are associated with elevated sympathetic activity. Furthermore, these
      studies have indicated that the interactions among excitatory (angiotensin II and
      glutamate) and inhibitory (NO and GABA) neurotransmitters/mediators within the
      PVN significantly influence sympathetic outflow. CONCLUSION: Reduced inhibitory
      actions of NO and/or GABA within the PVN may exaggerate an increase in the
      actions of excitatory neurotransmitters such as glutamate and angiotensin II
      within the PVN and this may contribute to the overall sympatho-excitation
      commonly observed in HF.

PMID- 12492776
TI  - Proposed role of the paraventricular nucleus in cardiovascular deconditioning.
AB  - AIM: Cardiovascular deconditioning occurs in individuals exposed to prolonged
      spaceflight or bedrest and is associated with the development of orthostatic
      intolerance. Although the precise mechanisms remain to be fully elucidated,
      astronauts returning from space or bedrest patients returning to normal upright
      posture present with decreases in plasma volume and alterations in autonomic
      function. The hindlimb unloaded (HU) rat has been a useful model to study the
      effects of cardiovascular deconditioning as it mimics many of the changes that
      occur after spaceflight and bedrest. RESULTS: Experiments performed in HU rats
      suggest that cardiovascular deconditioning attenuates baroreflex mediated
      sympathoexcitation and enhances cardiopulmonary receptor mediated
      sympathoinhibition. These alterations appear to be due to changes in the central
      nervous system and may contribute to the pre disposition towards orthostatic
      intolerance associated with cardiovascular deconditioning. The paraventricular
      nucleus (PVN) of the hypothalamus is important in basal and reflex control of
      sympathetic outflow. Recent evidence suggests that nitric oxide (NO) is an
      important inhibitory neurotransmitter in the PVN and that alterations in
      nitroxidergic transmission in the PVN may be involved in elevated sympathetic
      tone in certain disease states. CONCLUSION: Based on evidence from other
      laboratories and published and preliminary data from our own laboratories, this
      review proposes a role for the PVN in cardiovascular deconditioning. In
      particular, we discuss the hypothesis that increased NO in the PVN contributes to
      the altered cardiovascular reflexes observed following deconditioning and how
      these reflexes may be related to the orthostatic intolerance observed after
      prolonged spaceflight or bedrest.

PMID- 12492777
TI  - Nitric oxide: a local signalling molecule controlling the activity of pre
      autonomic neurones in the paraventricular nucleus of the hypothalamus.
AB  - AIM: The gas molecule nitric oxide (NO) has been shown to modulate autonomic
      function by acting both peripherally and centrally. Accumulating evidence
      indicates that the paraventricular nucleus (PVN) of the hypothalamus is an
      important locus mediating central NO actions on autonomic function, under both
      physiological and pathological conditions. However, the cellular targets and
      mechanisms mediating NO actions within the PVN are still poorly understood.
      RESULTS: By combining in vitro patch-clamp recordings with neuronal tract tracing
      techniques, we show that neuronal excitability of autonomic-related neurones in
      the PVN is tonically inhibited by an endogenous NO input. Furthermore,
      immunohistochemical studies show that approximately 25% of autonomic-related PVN
      neurones express neuronal nitric oxide synthase, suggesting that at least a
      proportion of them contribute to the cellular sources of NO within the PVN.
      CONCLUSION: In summary, this work suggests that NO modulation of the firing
      activity of autonomic-related PVN neurones constitutes an efficient mechanism
      mediated central NO regulation of autonomic function.

PMID- 12492778
TI  - Central osmotic regulation of sympathetic nerve activity.
AB  - AIM: In this review, we will focus on the central neural mechanisms that couple
      osmotic perturbations to changes in sympathetic nerve discharge, and the possible
      impact these actions have in cardiovascular diseases such as arterial
      hypertension and congestive heart failure. RESULTS: Changes in extracellular
      fluid osmolality lead to specific regulatory responses in defence of body fluid
      and cardiovascular homeostasis. Systemic hyperosmolality is well known to
      stimulate thirst and the release of antidiuretic hormone. These responses are
      largely due to osmosensing neurones in the forebrain lamina terminalis and
      hypothalamus and are critical elements in a control system that operates to
      restore body fluid osmolality. An equally important, but less characterized,
      target of central osmoregulatory processes is the sympathetic nervous system.
      CONCLUSION: Understanding the neurobiology of sympathetic responses to changes in
      osmolality has important implications for body fluid and cardiovascular
      physiology. By stabilizing osmolality, vascular volume is preserved and thereby
      relatively normal levels of cardiac output and arterial pressure are maintained.

PMID- 12492779
TI  - Modifications to central neural circuitry during heart failure.
AB  - AIM: During heart failure (HF), excess sodium retention is triggered by increased
      plasma renin-angiotensin-aldosterone activity and increased basal sympathetic
      nerve discharge (SND). Enhanced basal SND in the renal nerves plays a role in
      sodium retention. Therefore, as a hypothetical model for the central sympathetic
      control pathways that are dysregulated as a consequence of HF, the central neural
      pathways regulating the sympathetic motor output to the kidney are reviewed in
      the context of their role during HF. CONCLUSION: From these findings, a model of
      the neuroanatomical circuitry that may be affected during HF is constructed.

PMID- 12492780
TI  - Strength and power changes of the human plantar flexors and knee extensors in
      response to resistance training in old age.
AB  - AIM: The aim of the present study was to assess and compare the improvements of
      muscle strength and power induced by a 16-week resistive programme in a
      population of 16 older men aged 65-81 years. METHODS: Training was performed
      three times per week at an intensity of 80% of one repetition maximum (1RM) and
      consisted of both calf raise and leg press exercises. Before-, during- and after
      training, maximum isometric and isokinetic torques, maximum power, 1RM, muscle
      cross-sectional area (CSA) and electromyographic activity (EMG) of the plantar
      flexors (PF) and knee extensors (KE) were examined. RESULTS: For the KE and PF,
      respectively, training resulted in a 29.9 +/- 4.4% (mean +/- SE) and 21.6 +/-
      5.4% increase in 1RM (P < 0.001-0.01), a 19.4 +/- 4.3 and 12.4 +/- 4.7% (P <
      0.001-0.05) increase in maximum isometric torque, and a 24.1 +/- 6.3 and 33.1 +/-
      10.9% (P < 0.05) increase in maximum muscle power, calculated from torque-angular
      velocity curves. The large increase in torque and power was partly accounted by a
      significant increase in the CSA of the PF (5.0 +/- 0.7%) and KE (7.4 +/- 0.7%),
      while no significant changes in integrated EMG activity of vastus lateralis and
      soleus muscles, and in extrapolated maximum shortening velocity were found. After
      training, a significant increase in torque/CSA (10.3 +/- 4%, P < 0.05) was found
      for the KE but not for the PF. CONCLUSION: Hence, hypertrophy cannot alone
      justify the increase in torque, and other factors, such as an increase in
      individual fibre-specific tension (in the case of KE), a decrease in antagonist
      muscles' coactivation, an improved co-ordination and an increased neural drive of
      the other heads of quadriceps may have contributed to the increments in strength.
      The significant increase in muscle power seems particularly noteworthy with
      respect to daily activities involving the displacement of the body over time,
      namely, the generation of muscle power.

PMID- 12492781
TI  - Distribution of monocarboxylate transporter isoforms MCT1, MCT2 and MCT4 in
      porcine muscles.
AB  - AIM: Monocarboxylate transporters (MCT), which cotransport lactate anions and
      protons across cell membranes, are important for regulation of muscle pH. We
      measured amounts of MCT1, MCT2 and MCT4 by immunoblotting in five different
      porcine muscles, to study MCT-isoform distribution both in oxidative and highly
      glycolytic muscles. METHODS: Samples from the longissimus dorsi, gluteus
      superficialis, semimembranosus, infraspinatus and masseter were taken from 18
      slaughtered pigs. RESULTS: Oxidative capacity, estimated on the basis of the
      activities of lactate dehydrogenase (LDH), citrate synthase (CS) and 3-OH-acyl
      CoA dehydrogenase (HAD), was highest in the infraspinatus and masseter, and was
      very low in the gluteus, semimembranosus and longissimus dorsi. In all muscles,
      the amount of MCT1 was small but variable. The amount of MCT2 was more abundant
      in the glycolytic than in the oxidative muscles, while MCT4 was found in equal
      amounts in all muscles. MCT2, but not MCT4, correlated negatively with CS and
      HAD. CONCLUSIONS: The results together with measured concentrations of lactate
      suggest that MCT2 may function as the housekeeping lactate transporter,
      preventing acidification especially in highly glycolytic muscles in which the
      capacity to oxidize lactate is low. The results also support the view that, as in
      other species, MCT4 would be important at high lactate concentrations that occur
      during stress.

PMID- 12492782
TI  - Variable frequency trains enhance torque independent of stimulation amplitude.
AB  - AIM: Variable frequency trains have been reported to enhance force of fatigued
      human skeletal muscle. More rapid calcium turnover and/or enhanced stiffness may
      be responsible for the augmented torque-time integral during surface stimulation
      at moderate amplitude. In contrast, it has recently been suggested that variable
      frequency train enhancement occurs only at low forces as a result of preferential
      stimulation of fast fibres and/or altered motor unit recruitment. If correct,
      this would limit the practical benefit of variable frequency trains. Accordingly,
      we tested the hypothesis that torque augmentation by variable frequency trains in
      fatigued skeletal muscle was independent of stimulation amplitude. METHODS: The
      m. quadriceps femoris of six males was stimulated with constant frequency trains
      (six 200-micros square waves separated by 70 ms) or variable frequency trains
      (first interpulse interval 5 ms) at an amplitude that initially evoked
      approximately 25 or approximately 50% of maximal voluntary isometric torque.
      RESULTS: After 180 constant frequency trains (50% duty cycle), isometric peak
      torque decreased approximately 63%. In fatigued muscle, variable frequency trains
      enhanced the torque-time integral by approximately 23% over that for constant
      frequency trains and this effect was independent of stimulation amplitude. This
      was due to greater peak torque and less slowing of rise time. CONCLUSION: These
      responses show that the torque-time integral can be enhanced at both moderate and
      high stimulation amplitudes. As such, it is suggested that neither recruitment
      nor preferential activation of fast muscle is responsible for the "catch-like"
      property that can be demonstrated in fatigued human skeletal muscle.

PMID- 12492783
TI  - Role of prostaglandin cyclooxygenase and cytochrome P450 pathways in the
      mechanism of natriuresis which follows hypertonic saline infusion in the rat.
AB  - AIM: The prostaglandin cyclooxygenase (COX) and P450 cytochrome (CYP450) pathways
      of arachidonic acid metabolism are functionally interrelated and both engaged in
      control of sodium excretion; the study focused on their contribution to the
      natriuresis which follows hypertonic saline infusion in the rat. METHODS: In
      anaesthetized rats, clearance studies were conducted, supplemented with laser
      Doppler measurements of the cortical and medullary blood flow (CBF, MBF), and
      measurement of medullary tissue admittance (Y), an index of interstitial ion
      concentration. RESULTS: Indomethacin (Indo), 5 mg kg(-1) i.v. paradoxically
      enhanced the natriuresis secondary to intra-aortic suprarenal 5% saline load,
      further increasing sodium excretion by 385 +/- 73% (P < 0.01). After acute
      clotrimazole, 10 mg kg(-1) i.v. an inhibitor of CYP450 epoxygenase, the increase
      in natriuresis was smaller and did not differ from that observed after the drug's
      ethanol solvent. In rats pre-treated with clotrimazole for 3 days, hypertonic
      saline loading increased sodium excretion (U(Na)V) to 0.94 +/- 0.22 micromol min(
      1) , compared with a significantly greater (P < 0.05) increase to 2.76 +/- 0.48
      micromol min(-1) measured in untreated controls. Indo increased U(Na)V twofold,
      similarly in the clotrimazole and in the control group; in the absence or
      presence of clotrimazole treatment, COX blockade significantly decreased MBF and
      increased Y. CONCLUSION: The data indicate that blockade of the CYP450
      epoxygenase significantly impairs excretion of sodium in rats acutely loaded with
      hypertonic NaCl solution. The paradoxical post-Indo natriuresis is preserved in
      clotrimazole treated rats, which speaks against the role of CYP450 pathway in the
      response.

PMID- 12492784
TI  - Vascular dementia: galantamine (Reminyl) as an emerging therapeutic option.

PMID- 12492785
TI  - Defining dementia: clinical criteria for the diagnosis of vascular dementia.
AB  - The recognition of cerebrovascular disease (CVD) as a contributing factor and a
      cause of dementia has led to the development of clinical criteria for vascular
      dementia (VaD). Due to high specificity, the consensus criteria developed by the
      National Institute for Neurological and Communicative Disorders and Stroke
      (NINDS)-Association Internationale pour la Recherche et l'Enseignement en
      Neurosciences (AIREN) have been used in controlled clinical trials to select
      patients with pure VaD. VaD is predominantly a subcortical frontal form of
      dementia with prominent executive dysfunction. In contrast, the criteria of the
      NINCDS-Alzheimer's Disease and Related Disorders Association (ADRDA) emphasize
      memory loss as the main feature to distinguish Alzheimer's disease (AD) from VaD
      and from other forms of dementia. Moreover, CVD may precipitate the clinical
      expression of AD. Although no criteria have been created specifically for
      patients having AD with CVD, the ischemic score, the Informant Questionnaire on
      Cognitive Decline in the Elderly and a history of prestroke mild cognitive
      impairment (MCI) may be useful for identifying patients with this mixed form of
      dementia.

PMID- 12492786
TI  - The role of neuroimaging in the diagnosis of vascular dementia.
AB  - Vascular dementia (VaD) and Alzheimer's disease share many pathological and
      clinical characteristics. Whereas clinical criteria can help differentiate VaD
      from other types of dementia, neuroimaging is required for confirmation of
      vascular lesions. Neuroimaging also provides information about location and size
      of vascular lesions that can lead to a better understanding of symptoms and may
      help guide therapy.

PMID- 12492787
TI  - Cognitive decline and treatment options for patients with vascular dementia.
AB  - Cognitive impairment is the primary symptom of vascular dementia (VaD). Animal
      and human studies indicate that, as with Alzheimer's disease (AD), deficits in
      cholinergic transmission -- including nicotinic receptor binding abnormalities --
      may be responsible for the development of cognitive impairment associated with
      VaD. Therefore, studies of acetylcholinesterase inhibitors (AChEIs) have been
      initiated and have shown promising results to date. These agents have
      demonstrated cognitive and global benefits in patients with VaD. Additionally,
      functional and behavioral benefits have been reported with the dual-mechanism
      AChEI galantamine. These studies suggest a potential role for AChEIs in the
      management of cognitive impairment associated with VaD.

PMID- 12492788
TI  - Non-cognitive benefits of galantamine (Reminyl) treatment in vascular dementia.
AB  - Vascular dementia (VaD) is a condition that involves deterioration in cognitive
      and non-cognitive areas. Although cognitive impairment is the defining symptom
      evaluated during clinical trials, changes in non-cognitive areas such as
      behavior, global functioning and activities of daily living are assessed because
      they assist in determining quality of life and overall well-being. Therapy has
      focused traditionally on preventing and controlling risk factors, as no approved
      treatments are currently available for these patients. Acetylcholinesterase
      inhibitors (AChEIs), the treatment of choice in patients with Alzheimer's disease
      (AD), are a potential treatment option for patients with VaD. Galantamine, an
      AChEI with nicotinic receptor modulation, has demonstrated clinically relevant
      benefits (cognition, global functioning, functional ability, behavior) in
      patients with either AD with cerebrovascular disease (AD with CVD) or probable
      VaD in a 6-month, randomized, double-blind, placebo-controlled study.

PMID- 12492789
TI  - Spinal anaesthesia for inguinal hernia repair?

PMID- 12492790
TI  - Neurologic deficits and arachnoiditis following neuroaxial anesthesia.
AB  - Of late, regional anesthesia has enjoyed unprecedented popularity; this increase
      in cases has brought a higher frequency of instances of neurological deficit and
      arachnoiditis that may appear as transient nerve root irritation, cauda equina,
      and conus medullaris syndromes, and later as radiculitis, clumped nerve roots,
      fibrosis, scarring dural sac deformities, pachymeningitis, pseudomeningocele, and
      syringomyelia, etc., all associated with arachnoiditis. Arachnoiditis may be
      caused by infections, myelograms (mostly from oil-based dyes), blood in the
      intrathecal space, neuroirritant, neurotoxic and/or neurolytic substances,
      surgical interventions in the spine, intrathecal corticosteroids, and trauma.
      Regarding regional anesthesia in the neuroaxis, arachnoiditis has resulted from
      epidural abscesses, traumatic punctures (blood), local anesthetics, detergents,
      antiseptics or other substances unintentionally injected into the spinal canal.
      Direct trauma to nerve roots or the spinal cord may be manifested as paraesthesia
      that has not been considered an injurious event; however, it usually implies
      dural penetration, as there are no nerve roots in the epidural space posteriorly.
      Sudden severe headache while or shortly after an epidural block using the loss of
      resistance to air approach usually suggests pneumocephalus from an intradural
      injection of air. Burning severe pain in the lower back and lower extremities,
      dysesthesia and numbness not following the usual dermatome distribution, along
      with bladder, bowel and/or sexual dysfunction, are the most common symptoms of
      direct trauma to the spinal cord. Such patients should be subjected to a
      neurological examination followed by an MRI of the effected area. Further spinal
      procedures are best avoided and the prompt administration of IV corticosteroids
      and NSAIDs need to be considered in the hope of preventing the inflammatory
      response from evolving into the proliferative phase of arachnoiditis.

PMID- 12492791
TI  - Low-dose bupivacaine plus fentanyl for spinal anesthesia during ambulatory
      inguinal herniorrhaphy: a comparison between 6 mg and 7. 5 mg of bupivacaine.
AB  - BACKGROUND: Inguinal herniorrhaphy is commonly performed as an outpatient
      procedure. Spinal anesthesia offers some advantages over general anesthesia in
      this setting. METHODS: Forty patients were randomly divided into two groups
      according to a double-blind protocol: Group L had spinal anesthesia with
      bupivacaine 6.0 mg and Group H with bupivacaine 7.5 mg; in both groups, fentanyl
      25 micro g was added to the spinal anesthetic. The sensory block was measured by
      'pin-prick' and the motor block was evaluated by a modified Bromage scale.
      RESULTS: No differences were seen in the spread, duration and regression of
      sensory block between the groups on the operated side. A greater number of
      patients required analgesics during the operation in Group L (6) compared with
      Group H (1) (P<0.05). The return of the modified Bromage scale to grade 0 was
      earlier in Group L than in Group H (P<0.05) but the time to mobilization and
      discharge was similar. Seven patients (17%) needed to be catheterized and two had
      the catheter retained overnight. Times to home discharge (median) were 350 and
      445 min, respectively, in Groups L and H. Postoperatively and during the first
      week, visual analog pain scores, analgesic requirements and side-effects were
      similar between the groups. In Group H, 95% of the patients and in Group L 85%
      would have the same anesthetic again if operated upon for a similar procedure.
      CONCLUSIONS: Spinal anesthesia with bupivacaine 7.5 mg and fentanyl offers an
      alternative to general or local anesthesia for ambulatory inguinal herniorrhaphy.
      However, the long discharge times and risk for urinary retention restrict its
      routine use in all patients.

PMID- 12492792
TI  - Comparison of epidural, continuous femoral block and intraarticular analgesia
      after anterior cruciate ligament reconstruction.
AB  - BACKGROUND: The purpose of this study was to compare three locoregional
      techniques of pain management after arthroscopic anterior cruciate ligament
      reconstruction (ACLR). METHODS: Sixty ASA I-II subjects were enrolled after
      obtaining written informed consent. Patients were randomly allocated to three
      groups of 20 subjects. The first group (EPI) received epidural ropivacaine 0.2%
      plus sufentanil 0.2 micro g ml-1, at 5 ml h-1. Patients in the second group (CFB)
      were given a continuous infusion of the same analgesic mixture through a femoral
      catheter. The third group (IA) received a continuous intraarticular infusion of
      ropivacaine 0.2% plus sufentanil 0.2 micro g ml-1, at 5 ml h-1. All subjects were
      allowed PCA boluses of 5 ml of local anesthetic. Analgesia was assessed for 36 h
      after the end of surgery by means of a visual analog scale (VAS) and a verbal
      scale (VS), as well as the number of PCA boluses administered and the amount of
      supplementary i.v. ketorolac, if given. RESULTS: The VAS and VS scores were
      significantly higher in group IA during the 24 h following surgery. Ketorolac
      requirement was higher in group IA throughout the postoperative observation.
      Adverse effects were similar in all groups except for urinary retention, which
      was significantly more frequent in group EPI. CONCLUSIONS: We conclude that
      either epidural or continuous femoral nerve block provide adequate pain relief in
      patients who undergo ACLR, whereas intraarticular analgesia seems unable to cope
      satisfactorily with the analgesic requirements of this surgical procedure.

PMID- 12492793
TI  - Preoperative emotional states in patients with breast cancer and postoperative
      pain.
AB  - BACKGROUND: The present study examined the relationship between psychological
      variables, including anxiety, depression, and patient-controlled analgesia (PCA)
      use in patients who underwent radical mastectomy. METHODS: Ninety-nine ASA I-II
      women with breast cancer between 18 and 60 years scheduled for modified radical
      mastectomy completed the state scale of the state-trait anxiety inventory and the
      Beck depression inventory before the day of surgery. Standard general anesthesia,
      surgery, and IV-PCA therapy was conducted. Postoperative ratings of pain
      intensity, opioid consumption and satisfaction with PCA were recorded for the
      first 24 h on the ward. The degree of pain intensity was evaluated by a visual
      analog scale (VAS, 1-10). Satisfaction with pain control was reported using an
      five-point scale from 1 (very dissatisfied) to 5 (very satisfied). RESULTS: The
      pain intensity, total analgesic consumption and dose/demand ratio were
      significantly related to preoperative anxiety and depression (P<0.05). Degree of
      dissatisfaction with PCA was significantly correlated with preoperative anxiety
      and depression (P<0.01). CONCLUSION: Patients with higher anxiety and depression
      levels had higher postoperative pain and analgesic requirements in this study.

PMID- 12492794
TI  - Comparison of the catheter-technique psoas compartment block and the epidural
      block for analgesia in partial hip replacement surgery.
AB  - BACKGROUND: The aim of this study was to compare the intra- and postoperative
      analgesia provided by the catheter-technique psoas compartment block and the
      epidural block in hip-fractured patients. We also compared hemodynamic stability,
      motor blockade, ease of performing the technique, and complications. METHODS:
      Thirty patients who underwent partial hip replacement surgery were included in
      this prospective single-blind study. Subjects were randomly assigned to Group E
      (n=15; general anesthesia plus epidural block with 15 ml of 0.5% bupivacaine) or
      Group P (n=15; general anesthesia plus psoas compartment block with 30 ml of 0.5%
      bupivacaine). Hemodynamic parameters were recorded at 10-min intervals
      intraoperatively. Regional anesthesia procedure time, number of attempts at
      block, intraoperative blood loss, and need for supplemental fentanyl and/or
      ephedrine were noted. Postoperatively, a patient-controlled analgesia device
      delivered an infusion and boluses of bupivacaine/fentanyl. Pain, motor blockade,
      ambulation time, patient satisfaction with analgesia, and complications were
      recorded postsurgery. RESULTS: The epidural required significantly more attempts
      than the psoas block, thus procedure time was longer in this group. Group E also
      showed significantly greater drops in mean arterial blood pressure from baseline
      at 30, 40 and 50 min after the start of general anesthesia. Significantly more
      Group E patients required epinephrine supplementation. The groups were similar
      regarding pain scores (at rest and on movement) and patient satisfaction, but
      Group E had higher motor blockade scores, longer ambulation time, and
      significantly more complications. CONCLUSION: The continuous psoas compartment
      block provides excellent intraoperative and postoperative analgesia with a low
      incidence of complications for partial hip replacement surgery

PMID- 12492795
TI  - New mathematical model for the correct prediction of the exchangeable blood
      volume during acute normovolemic hemodilution.
AB  - BACKGROUND: The blood volume that has to be exchanged for crystalloids and/or
      colloids during acute normovolemic hemodilution (ANH) in order to reach a preset
      target hemoglobin concentration (hb) is usually predicted by the Bourke and Smith
      formula developed in 1974. This formula systematically overestimates the 'true'
      exchangeable blood volume (EBV), a fact that may potentially endanger patients
      because the target hb will be missed and the normovolemic anemia might turn out
      to be more severe than a priori intended. Our objective was to develop a more
      accurate mathematical model of hemodilution kinetics and to validate this new
      model in animals and in patients undergoing ANH. METHODS: Twenty-two anesthetized
      beagle dogs and 18 patients under balanced anesthesia underwent isovolemic
      hemodilution with hydroxyethyl starch (HAES 6%, 200 000) to a target hb of 7 g dl
      1 or 9 g dl-1, respectively. Exchangeable blood volume predicted by use of the
      different mathematical models was compared with the blood volume actually
      exchanged to meet the preset target hb. RESULTS: Calculation of EBV by the Bourke
      and Smith formula (EBVB + S) systematically overestimated the volume actually
      exchanged (overestimation: dogs 15%, patients 20%), whereas our new iterative
      model predicted EBV (EBViterative) more reliably (overestimation: dogs 1%,
      patients 8%). In both cases EBVB + S differed significantly from the
      EBViterative. CONCLUSION: Exchangeable blood volume is predicted more accurately
      by the new iterative model than by the Bourke and Smith formula. The iterative
      model leads to an improvement in patient safety and provides a physiologically
      adequate basis for future studies investigating the efficacy of ANH in reducing
      allogenic blood transfusions.

PMID- 12492796
TI  - Effects of acute normovolemic hemodilution on ventriculoarterial coupling in
      dogs.
AB  - BACKGROUND: Acute normovolemic hemodilution (ANH) causes a decrease in systemic
      vascular resistance. Similar to vasodilating drugs, ANH might modify
      ventriculoarterial coupling. Left ventricular elastance (Ees), effective arterial
      elastance (Ea), stroke work (SW), and pressure volume area (PVA) were used as
      indicators to examine the effects of ANH on this coupling. METHODS: After
      institutional approval eight dogs were anesthetized with isoflurane and subjected
      to measurements including aortic pressure, left ventricular (LV) pressure, and LV
      volume. Left ventricular volume was measured with a conductance catheter. Ees was
      determined as the slope of the end-systolic pressure-volume relationship. Ea was
      determined as the ratio of LV end-systolic pressure to stroke volume.
      Ventriculoarterial coupling was evaluated as the ratio of Ees to Ea. Mechanical
      efficiency, another criterion for ventriculoarterial coupling, was calculated as
      the ratio of SW to PVA. Data are expressed as mean+/-SD, and P<0.05 was
      considered significant. RESULTS: Normovolemic exchange of 50 ml kg-1 of blood for
      6% hydroxyethyl starch (ANH50) reduced hemoglobin concentration from 12.8+/-3.0 g
      dl-1 to 6.4+/-1.3 g dl-1. Acute normovolemic hemodilution 50 did not change Ees
      significantly although it significantly decreased Ea. Left ventricular
      elastance/Ea did not change after ANH (1.0+/-0.4 at baseline and 1.2+/-0.5 at
      ANH50). Acute normovolemic hemodilution 50 significantly increased SW and PVA,
      preventing SW/PVA from changing significantly after ANH (0.57+/-0.10 at baseline
      and 0.62+/-0.14 at ANH50). CONCLUSION: Before ANH, ventriculoarterial coupling
      was so matched as to maximize SW at the expense of the work efficiency. This
      relation was preserved at ANH50.

PMID- 12492797
TI  - Anti-thrombotic effect of milrinone is caused by inhibition of calcium release
      from the dense tubular system in human platelets.
AB  - AIM: Milrinone, a phosphodiesterase III inhibitor, exerts positive inotropic
      effects which induce an increase in the intracellular calcium concentration by
      raising the cyclic adenosine monophosphate level in cardiac muscle. Milrinone was
      also reported to inhibit platelet aggregation, however, its mechanism remains
      unknown. Therefore, we investigated the effects of milrinone on intracellular
      calcium mobilization when platelets were activated. METHODS: Washed platelets,
      obtained from six healthy volunteers, were preincubated with milrinone (0.9 micro
      M) for 1 min and then exposed to 0.015 i micro ml-1 thrombin for 5 min. The
      effect of milrinone on changes in the intracellular calcium level using a
      fluorescent dye, fura-2, was also observed. Calcium mobilizations via plasma
      membrane calcium channels and the dense tubular system were assessed
      differentially. RESULTS: Milrinone (0.9 micro M) significantly suppressed the
      aggregation ratios at 5 min compared with those in controls (86+/-5%) to 75+/-8%.
      The increase in the intracellular calcium concentration was also significantly
      suppressed (controls, 915+/-293 nM vs. 405+/-240 nM) when stimulated by thrombin.
      Milrinone also significantly inhibited the release of calcium from the dense
      tubular system (controls, 284+/-111 nM vs. 158+/-51 nM). Calcium influx through
      the plasma membrane was suppressed by milrinone 2.4 micro M. CONCLUSION:
      Milrinone (0.9 micro M) inhibited thrombin-induced platelet aggregation. This
      inhibitory effect was mainly mediated by suppressing calcium release from the
      dense tubular system.

PMID- 12492798
TI  - Comparison of forced-air warming systems with lower body blankets using a copper
      manikin of the human body.
AB  - BACKGROUND: Forced-air warming has gained high acceptance as a measure for the
      prevention of intraoperative hypothermia. However, data on heat transfer with
      lower body blankets are not yet available. This study was conducted to determine
      the heat transfer efficacy of six complete lower body warming systems. METHODS:
      Heat transfer of forced-air warmers can be described as
      follows:[1]Qdot;=h.DeltaT.A where Qdot; = heat transfer [W], h = heat exchange
      coefficient [W m-2 degrees C-1], DeltaT = temperature gradient between blanket
      and surface [ degrees C], A = covered area [m2]. We tested the following forced
      air warmers in a previously validated copper manikin of the human body: (1) Bair
      Hugger and lower body blanket (Augustine Medical Inc., Eden Prairie, MN); (2)
      Thermacare and lower body blanket (Gaymar Industries, Orchard Park, NY); (3)
      WarmAir and lower body blanket (Cincinnati Sub-Zero Products, Cincinnati, OH);
      (4) Warm-Gard(R) and lower body blanket (Luis Gibeck AB, Upplands Vasby, Sweden);
      (5) Warm-Gard and reusable lower body blanket (Luis Gibeck AB); and (6) WarmTouch
      and lower body blanket (Mallinckrodt Medical Inc., St. Luis, MO). Heat flux and
      surface temperature were measured with 16 calibrated heat flux transducers.
      Blanket temperature was measured using 16 thermocouples. DeltaT was varied
      between -10 and +10 degrees C and h was determined by a linear regression
      analysis as the slope of DeltaT vs. heat flux. Mean DeltaT was determined for
      surface temperatures between 36 and 38 degrees C, because similar mean skin
      temperatures have been found in volunteers. The area covered by the blankets was
      estimated to be 0.54 m2. RESULTS: Heat transfer from the blanket to the manikin
      was different for surface temperatures between 36 degrees C and 38 degrees C. At
      a surface temperature of 36 degrees C the heat transfer was higher (between 13.4
      W to 18.3 W) than at surface temperatures of 38 degrees C (8-11.5 W). The highest
      heat transfer was delivered by the Thermacare system (8.3-18.3 W), the lowest
      heat transfer was delivered by the Warm-Gard system with the single use blanket
      (8-13.4 W). The heat exchange coefficient varied between 12.5 W m-2 degrees C-1
      and 30.8 W m-2 degrees C-1, mean DeltaT varied between 1.04 degrees C and 2.48
      degrees C for surface temperatures of 36 degrees C and between 0.50 degrees C and
      1.63 degrees C for surface temperatures of 38 degrees C. CONCLUSION: No relevant
      differences in heat transfer of lower body blankets were found between the
      different forced-air warming systems tested. Heat transfer was lower than heat
      transfer by upper body blankets tested in a previous study. However, forced-air
      warming systems with lower body blankets are still more effective than forced-air
      warming systems with upper body blankets in the prevention of perioperative
      hypothermia, because they cover a larger area of the body surface.

PMID- 12492799
TI  - Remifentanil produces vasorelaxation in isolated rat thoracic aorta strips.
AB  - BACKGROUND: Remifentanil can cause transient instability in hemodynamic
      variables. However this change may not be solely the result of autonomic or
      central nervous system inhibition or of centrally mediated vagal stimulation. In
      this study, the aim was to examine the direct effects of remifentanil on isolated
      thoracic aorta strips in vitro. METHODS: Forty-five Wistar rat thoracic aorta
      rings were isolated, and contraction-relaxation responses were recorded. RESULTS:
      In aortic rings precontracted with phenylephrine or potassium chloride,
      remifentanil produced concentration-dependent relaxation in both endothelium
      intact and denuded rings (P<0.001). Remifentanil induced significantly greater
      relaxation in intact rings than in those denuded of endothelium, regardless of
      whether they were precontracted with phenylephrine hydrochloride or KCl
      (P<0.001). When the endothelium was present, remifentanil produced greater
      relaxation in KCl-contracted rings than in PE-contracted rings at lower
      concentrations (10-9 and 10-8), and similar relaxation at higher concentrations
      (10-7 and 10-6). However, when the endothelium was removed, relaxation was
      similar in both solutions, at all concentrations (10-9 to 10-6). In intact rings,
      pretreatment with L-NO-ARG or indomethacin reduced the degree of remifentanil
      induced relaxation. In Ca+ +/- free media, calcium-dependent KCl contractions
      were inhibited in a dose-dependent manner by remifentanil (P<0.001). CONCLUSION:
      Remifentanil vasodilates by an endothelium-dependent mechanism, involving
      prostacyclin and nitric oxide released from the endothelium. Its endothelium
      independent vasodilation probably occurs via the suppression of voltage-sensitive
      Ca++ channels.

PMID- 12492800
TI  - The effects of hydroxyethyl starch solutions on thromboelastography in
      preoperative male patients.
AB  - BACKGROUND: Hydroxyethyl starches (HES) have been shown to decrease clot strength
      and to increase coagulation times assessed by thromboelastography (TEG). HES with
      minimal anticoagulant side-effects is beneficial for plasma volume expansion in
      the perioperative setting. A comparison of the in vivo effects of high, middle
      and low molecular weight HES solutions on TEG variables has not been performed so
      far. METHODS: Blood was obtained before and after intravenous infusion (10 ml kg
      1) of either saline, HES 70/0.5/4 (molecular weight in kDa/degree of
      substitution/C2:C6 ratio), HES 130/0.4/9, HES 200/0.6/9.4, or HES 450/0.7/4.6 in
      50 otherwise healthy patients. Thromboelastography was performed in 360 micro l
      of 1% celite activated citrated whole blood after recalcification. RESULTS: HES
      450/0.7/4.6 prolonged reaction time indicating impairment of the plasmatic
      coagulation system. TEG parameters indicative for platelet function, including
      angle alpha, maximum amplitude and coagulation time, deteriorated after infusion
      of HES 450/0.7/4.6 and HES 70/0.5/4. HES 200/0.6/9.4 and HES 130/0.4/9 impaired
      platelet contribution to hemostasis only partially, decreasing two or one TEG
      platelet parameters, respectively. CONCLUSION: Infusion of HES 450/0.7/4.6
      compromises TEG parameters more than the other solutions tested, whereas HES
      130/0.4/9 has the smallest effect. Further outcome-related studies are needed in
      order to assess the clinical relevance of our findings.

PMID- 12492801
TI  - Clinical trial of esmolol-induced controlled hypotension with or without acute
      normovolemic hemodilution in spinal surgery.
AB  - BACKGROUND: Drug-induced controlled hypotension (CH) combined with acute
      normovolemic hemodilution (ANH) is being widely used for blood conservation in
      surgical patients. The purpose of this study was to investigate the efficacy and
      safety of esmolol-induced CH combined with ANH (hematocrit down to 28%). METHODS:
      Thirty patients who were scheduled to receive spinal surgery were randomly
      divided into two groups: an esmolol-induced CH alone group (esmolol group, n=15)
      and a CH-ANH combined group (E-ANH group, n=15). Controlled hypotension was
      induced with esmolol 500 micro g/kg, followed by a continuous infusion of 0-300
      micro g/kg/min to maintain mean arterial pressure at 55-65 mmHg. RESULTS: The
      mean infusion rate of esmolol in the esmolol-ANH group was 46+/-6 micro g/kg/min
      (mean+/-SD), which was significantly lower than the 77+/-9 micro g/kg/min used in
      the esmolol group (P<0.05). The number of units of homologous blood (packed RBC)
      transfused perioperatively was 2.2+/-0.6 units in the esmolol-ANH group, which
      was significantly less than 4.3+/-0.4 units used in the esmolol group (P<0.01).
      While O2 delivery decreased significantly during CH, O2 consumption remained
      unchanged in both groups. No complications resulted from CH or ANH in any of the
      groups. CONCLUSION: Our data suggest that ANH of moderate degree can be combined
      with esmolol-induced CH to improve blood conservation in surgical patients.

PMID- 12492802
TI  - Comparison of granisetron and granisetron plus dexamethasone for the prevention
      of postoperative nausea and vomiting after laparoscopic cholecystectomy.
AB  - BACKGROUND: Laparoscopic cholecystectomies are associated with an appreciably
      high rate of postoperative nausea and vomiting (PONV). This study was designed to
      compare the effectiveness of granisetron plus dexamethasone with granisetron
      alone for the prevention of postoperative nausea and vomiting in patients after
      laparoscopic cholecystectomy. METHODS: In a randomized, double-blind study, 120
      patients of both sexes received granisetron 40 micro g kg-1 alone or granisetron
      40 micro g kg-1 plus dexamethasone 8 mg (n=60 of each) intravenously immediately
      before induction of anesthesia. Perioperative anesthetic care was standardized in
      all patients. Patients were then observed for 24 h after administration of the
      study drug. RESULTS: A complete response (defined as no PONV and no need for
      another rescue antiemetic) was achieved in 83% of the patients given granisetron
      and in 95% of the patients given granisetron plus dexamethasone (P<0.05). The
      overall cumulative incidences (0-24 h) of PONV were 11 (18.3%) in the granisetron
      and three (5%) in the combination group. No difference in adverse events were
      observed in any of the groups. CONCLUSION: The combination (granisetron plus
      dexamethasone) further increases the chance of complete response than granisetron
      alone. Therefore, the combination might be considered clinically relevant in a
      high risk setting.

PMID- 12492803
TI  - Remifentanil-propofol vs. sufentanil-propofol: optimal combinations in clinical
      anesthesia.
AB  - BACKGROUND: Two opioid regimens, computer-simulated to provide optimal general
      anesthesia in combination with propofol, were compared using clinical criteria.
      METHODS: Fifty patients undergoing thyroid surgery were blindly, prospectively
      and randomly allocated to receive either (a) i.v. remifentanil (1.5 micro g kg-1,
      followed by 0.2 micro g kg-1 min-1) or (b) i.v. sufentanil (0.2 micro g kg-1
      followed by 0.2 micro g kg-1 h-1). Remifentanil infusion was stopped at the last
      skin suture. Sufentanil infusion was stopped 30 min before the end of surgery.
      Intravenous propofol was titrated to keep BIS at 50+/-5. Remifentanil and
      sufentanil groups were compared with regards to (a) propofol delivery, (b)
      hemodynamic and recovery variables, and (c) effect-site propofol levels during a
      steady-state period for effect-site remifentanil and sufentanil levels. P<0.05
      was significant. RESULTS: Groups were similar in demographic data; types and
      durations of surgery; total propofol consumption; and response, extubation and
      emergence times. During the steady-state period for the opioid delivery, the
      remifentanil and sufentanil effect-site levels were 5.3 ng ml-1 and 0.18 ng ml-1,
      respectively (potency ratio=30). In both opioid groups, in accordance with
      previous computer-simulations, the effect-site propofol concentrations remained
      (a) within a narrow range unaffected by surgical stimuli, (b) significantly
      smaller in the remifentanil group than in the sufentanil group, but (c) smaller
      than expected from previous computer-simulations. More patients required
      ephedrine following induction of anesthesia in the remifentanil compared with the
      sufentanil group. CONCLUSIONS: The present clinical trial conducted in thyroid
      surgery is consistent with previous computer-simulated opioid-propofol
      combinations with respect to intraoperative and recovery variables. Effect-site
      propofol ranges were, however, lower than expected.

PMID- 12492804
TI  - Oral clonidine premedication does not reduce postoperative vomiting in children
      undergoing strabismus surgery.
AB  - BACKGROUND: We evaluated the effect of oral clonidine on postoperative vomiting
      (POV) in children undergoing strabismus surgery. METHODS: Eighty ASA physical
      status I children aged 3-12 years were randomly assigned to one of two groups in
      a double-blinded manner. One hour before surgery, each patient in the clonidine
      group (n=40) received clonidine 4 micro g kg-1 in apple juice 0.2 ml kg-1, and
      each of the controls (n=40) received apple juice 0.2 ml kg-1 only. The protocol
      for general anesthesia was propofol-sevoflurane in N2O/O2. A paracetamol
      suppository was administered in each case to prevent postoperative pain. Patient
      responses during 0-48 h after anesthesia were recorded as complete (no POV, no
      antiemetic rescue required), retching, vomiting, or rescue antiemetic. RESULTS:
      There were no significant differences between the clonidine and control groups
      regarding the number of patients with complete response (21 vs. 18, respectively)
      retching (10 vs. 14, respectively), vomiting (19 vs. 22, respectively), or rescue
      antiemetic (9 vs. 12, respectively) during the first 48 h. CONCLUSION: Oral
      premedication with clonidine 4 micro g kg-1 did not reduce the rate of POV in the
      children undergoing strabismus surgery.

PMID- 12492805
TI  - Functional improvement after physiotherapy with a continuous infusion of local
      anaesthetics in patients with complex regional pain syndrome.
AB  - Three patients were referred to our pain clinic with evidence of complex regional
      pain syndrome in their extremities. Two presented at the atrophic stage with
      joint contractures. Multiple analgesics had been prescribed without long-lasting
      relief. Physiotherapy was required to improve physical activity but was severely
      limited by pain. We instituted local anaesthetic infusion with the possibility of
      self-supplementation to facilitate physiotherapy; two via brachial plexus
      catheters for hand pain and one via epidural catheter for knee pain. Although
      their resultant pain scores were variable after cessation of local anaesthetic
      infusion, all the affected joints exhibited marked improvement in range of
      movement. We propose that this technique is a useful option for patients in all
      stages of complex regional pain syndrome where the emphasis is now directed
      toward functional improvement.

PMID- 12492806
TI  - Decrease in the incidence of post-dural puncture headache: maintaining CSF
      volume.
AB  - The incidence of epidural needle-induced post-dural puncture headache (PDPH) in
      parturients following dural puncture with a large bore (18-gauge) needle has been
      reported to range 76-85%. We describe seven cases in which the performance of
      epidural anesthesia in parturients was complicated by an unintentional dural
      puncture with an 18-gauge epidural needle. In all seven cases, the unintentional
      dural puncture was followed by (i) injection of the CSF in the glass syringe back
      into the subarachnoid space through the epidural needle, (ii) insertion of a
      epidural catheter into the subarachnoid space (now referred to as an intrathecal
      catheter), (iii) injection of a small amount of preservative free saline (3-5 ml)
      into the subarachnoid space through the intrathecal catheter, (iv) administration
      of bolus and then continuous intrathecal labor analgesia through the intrathecal
      catheter and then (v) leaving the intrathecal catheter in-situ for a total of 12
      20 h. PDPH occurred in only one of these cases (14%).

PMID- 12492807
TI  - Fetal heart rate decelerations during ECT-induced seizures: is it important?
AB  - Electroconvulsive therapy (ECT) is sometimes indicated during pregnancy and may
      offer advantages over pharmacotherapy for the patient and the fetus (1,2).
      However, very little data is available on the impact of epileptic or ECT-induced
      seizures on the fetus. We report a case of brief fetal heart rate decelerations
      in a fetus associated with maternal ECT-induced convulsions.

PMID- 12492808
TI  - Cardiac arrest in an infant with congenital adrenal hyperplasia.
AB  - We report a 3-month-old boy who suffered an out-of-hospital cardiac arrest.
      During resuscitation, the medical team was informed that he was receiving
      hydrocortisone treatment. The possibility of adrenal insufficiency with
      hyperkalemic cardiac arrest prompted the administration of calcium, which
      resulted in the return of spontaneous circulation. The infant's diagnosis of
      congenital adrenal hyperplasia was not spontaneously mentioned by the parents.
      This case illustrates the importance of obtaining adequate parental information
      and considering hyperkalemia as a possible cause of cardiac arrest.

PMID- 12492809
TI  - Subarachnoid anesthesia in a patient with type I Gaucher disease.
AB  - Gaucher's disease is a rare genetic disorder characterized by lack or functional
      insufficiency of glucocerebrosidase, an enzyme accountable for intracellular
      hydrolysis of glucosyl ceramide and other glycosphingolipids, which results in
      macrophage storage in the mononuclear-macrophage system. The severity of
      Gaucher's disease is correlated with the extent to which the central nervous
      system is involved. It is associated with the so-called Gaucher's cells in the
      bone marrow, but is specifically diagnosed by showing enzyme acid beta
      glucosidase activity in a sample of blood leukocyte or cultured macrophages from
      skin biopsy. In the last 10 years, an enzyme replacement therapy (alglucerase)
      for the disease has been available, which has significantly changed approaches to
      its treatment. Here we report the case of a 56-year-old female patient with type
      I Gaucher's disease who underwent surgery for subcapital hip fracture with
      subarachnoid anesthesia. Type I Gaucher's disease clinical and pathophysiologic
      aspects relevant to anesthetic management are discussed. As very few similar
      cases have been reported in the anesthesiology literature, it is our belief that
      the present case may help to elucidate some controversial issues relating to the
      perioperative anesthetic management of patients with type I Gaucher's disease.

PMID- 12492810
TI  - The CD1 family and T cell recognition of lipid antigens.
AB  - For many years it was thought that T lymphocytes recognized only peptide antigens
      presented by MHC class I or class II molecules. Recently, it has become clear
      that a wide variety of lipids and glycolipids are also targets of the T cell
      response. This novel form of cell-mediated immune recognition is mediated by a
      family of lipid binding and presenting molecules known as CD1. The CD1 proteins
      represent a small to moderate sized family of beta2-microglobulin-associated
      transmembrane proteins that are distantly related to MHC class I and class II
      molecules. They are conserved in most or all mammals, and control the development
      and function of T cell populations that participate in innate and adaptive immune
      responses through the recognition of self and foreign lipid antigens. Here we
      review the current state of our understanding of the structure and function of
      CD1 proteins, and the role of CD1-restricted T cell responses in the immune
      system.

PMID- 12492811
TI  - A male genital tract-specific carbohydrate epitope on human CD52: implications
      for immunocontraception.
AB  - The identification of unique sperm surface epitopes that are not expressed or
      exposed in the female reproductive tract is a key element in the development of
      antibody-based contraceptives. Western blotting and immunohistochemistry were
      performed to define the tissue distribution of the S19 epitope, which has been
      proposed as a target for immunocontraception. S19 is an IgG1 murine monoclonal
      antibody (mAb) directed to an N-linked carbohydrate epitope on a 15-25 kDa
      glycoprotein, sperm agglutination antigen-1 (SAGA-1), containing a peptide core
      identical to that of the lymphocytic surface protein CD52. In this study, the S19
      epitope was shown to be absent from human lymphocytes, demonstrating a
      distinction between this epitope and the CAMPATH epitope that is recognized by an
      antibody against the terminal tripeptide and GPI-anchor of CD52. Further tissue
      specificity analysis identified the S19 epitope in the epithelium of the human
      epididymis and vas deferens, as well as on both epididymal and ejaculated
      spermatozoa. In contrast, the S19 epitope was absent in the five human female
      reproductive tract and 18 other somatic tissues tested. These results support the
      use of the S19 epitope as a contraceptive immunogen and the suitability of the
      S19 mAb as an intravaginal contraceptive. To test the agglutinating activity of
      the S19 mAb in a formulation designed for vaginal use, S19 mAb were bound to the
      surface of Novasomes, a multilamellar liposome delivery vehicle. S19-Novasome
      formulations agglutinated human spermatozoa and were as effective as unbound S19
      mAb, demonstrating the feasibility of spermistatic contraceptives targeted to the
      male reproductive tract specific carbohydrate epitope.

PMID- 12492812
TI  - A MAGE-A4 peptide presented by HLA-B37 is recognized on human tumors by cytolytic
      T lymphocytes.
AB  - 'Cancer-germline' genes such as those of the MAGE family are expressed in many
      tumors and in male germline cells, but are silent in normal tissues. They encode
      shared tumor-specific antigens, which have been used in therapeutic vaccination
      trials of cancer patients. MAGE-A4 is expressed in more than 50% of carcinomas of
      esophagus, head and neck, lung, and bladder. We report here the identification of
      a new MAGE-A4 encoded peptide, which is recognized by a cytolytic T lymphocyte
      (CTL) clone on HLA-B*3701. The sequence of the peptide is SESLKMIF. It
      corresponds to the MAGE-A4156-163 protein sequence. When tumor cells expressing
      MAGE-A4 were transfected with HLA-B*3701, they were recognized by the CTL clone,
      demonstrating that the peptide ought to be processed in tumor cells and could
      therefore serve as a target for therapeutic antitumoral vaccination.

PMID- 12492813
TI  - Class II transactivator-induced expression of HLA-DO(beta) in HeLa cells.
AB  - HLA-DO is an intracellular nonclassical MHC class II molecule expressed in the
      endocytic pathway of B lymphocytes. It shapes the repertoire of peptides bound to
      classical class II molecules such as HLA-DR by regulating the activity of HLA-DM.
      Using a peptide corresponding to the cytoplasmic tail of HLA-DO(beta), we have
      developed a mouse monoclonal antibody, HKC5. Immunofluorescence microscopy
      revealed that HKC5 recognizes HLA-DO molecules present in the endoplasmic
      reticulum as well as those in vesicular compartments of the endocytic pathway. In
      addition, the antibody detects the isolated beta chain on Western blots. Using
      mutants of the DO(beta) cytoplasmic tail fused to a reporter molecule and
      expressed in epithelial cells, we showed by flow cytometry that the antibody
      epitope includes one or both of the leucine residues forming the lysosomal
      sorting signal. Finally, we have used HKC5 to evaluate the presence of the HLA
      DO(beta) chain in HeLa cells expressing the class II transactivator protein
      CIITA. Our flow cytometry and confocal microscopy analyses showed a marked
      expression of DO(beta) suggesting that HLA-DO could accumulate under the
      influence of CIITA in non-B cells.

PMID- 12492814
TI  - Surface antigens of human mesangial cells: impact of growth surface or IL-1alpha.
AB  - The interactions of mesangial cells (MC) with their environment are important
      events in glomerular physiology and pathology, yet a detailed characterization of
      the MC-surface antigens mediating these interactions is still lacking. In this
      study, a comparative phenotype analysis of primary human MC in culture using 191
      monoclonal antibodies directed against 108 antigens was performed by flow
      cytometry. The MC were grown on three different surfaces (human matrix,
      fibronectin, polystyrene) and cultured in the presence or absence of IL-1alpha.
      Seventy-one antibodies recognizing 35 different antigens (integrins: CD29, 49b,
      49c, 49e, 51, 61; immunoglobulin gene family: CD54, 58, 90, 106, 146, 147, 166;
      growth factor receptors: CD105, 140b; apoptosis related: CD95; hemostatis
      related: CD141, 142; miscellaneous: CD44, 109, 138, 151, 157, 165, and 11
      nonclustered antigens) reacted with mesangial cells. CD58, 109, 146, 147, 151,
      157, 165, and 166 are reported for the first time to be present on human
      mesangial cells. In comparison to growth on polystyrene, CD44, 54, 95, 105, 109,
      140b, 146, 147, 157, 165 and 166, were up-regulated on fibronectin, and CD44, 54,
      90, 95, 105, 106, 109, 138, 140b, 141, 142, 146, 147, 151, 157, 165 and 166 were
      up-regulated on human matrix. The stimulation by IL-1alpha up-regulated CD44,
      49e, 51, 54, 61, 106 on MC on polystyrene; CD49e, 51, 61, 106, 146, 165 on MC on
      fibronectin, and CD49e, 51, 54 on MC grown on human matrix. This analysis of
      surface antigen expression provides new information to enable a better
      understanding of the role of mesangial cells in glomerular pathophysiology.

PMID- 12492815
TI  - Analysis of microsatellite polymorphism around the HLA-B locus in Iranian
      patients with Behcet's disease.
AB  - We have previously suggested that in a Japanese population the susceptible locus
      for Behcet's disease (BD) is HLA-B51 itself. To confirm this finding in another
      population, we performed HLA class I typing using the PCR-SSP method and analyzed
      eight polymorphic markers distributed within 1100 kb around the HLA-B gene using
      automated sequencer and subsequent automated fragment detection by fluorescent
      based technology with the DNA samples of 84 Iranian patients with BD and 87
      healthy ethnically matched controls. As a result, three microsatellite alleles
      (MICA-A6, MIB-348, C1-4-1-217) and HLA-B51 were found to be strongly associated
      with BD. Of these alleles HLA-B51 is the most strongly associated allele. There
      were no alleles that were increased in allele frequency at any microsatellite
      loci centromeric of MICA or telomeric of HLA-B51. Therefore, HLA-B51 was
      confirmed to be by far the most strongly associated gene with BD in an Iranian
      population.

PMID- 12492816
TI  - Immunogenetic study of a new HLA allele, B*2723.
AB  - A novel HLA-B*27 allele (B*2723) detected by irregular serological and PCR-SSP
      typing results was identified by nucleotide sequencing of exons 2 and 3. B*2723
      differs from B*27052 by nine nucleotides which encode seven amino acid changes at
      positions 63 (Glu to Asn), 67 (Cys to Phe), 69 (Ala to Thr), 70 (Lys to Asn), 71
      (Ala to Thr), 74 (Asp to Tyr) and 77 (Asp to Ser) in the alpha1 helix. All these
      substitutions are possessed by B*35 alleles suggesting that B*2723 was created by
      a gene conversion-like event involving B*27052 and a B*35 allele. Using the HLA
      A*26 and DRB1*12 alleles of the B*2723-bearing haplotype as 'markers', two
      further examples of B*2723 were found in 29,851 blood donors. Therefore, B*2723
      has a 'minimum' gene frequency of 0.000034 (phenotype frequency 0.0067%) in blood
      donors resident in Wales. In all three families, B*2723 was present on a
      haplotype with: A*26; Cw*0202; DRB1*1201/6/7; DRB3*02; DQA1*05; DQB1*0301. The
      B*2723 product failed to react with HLA-B27 antisera and reacted weakly or not at
      all with Bw4 antisera. Lack of the ECAKA motif at amino acid positions 63, 67, 69
      71 probably accounts for lack of the B27 specificity while the amino acid
      combination 74Y, 77S, 80T, 81L may cause aberrant Bw4 reactivity.

PMID- 12492817
TI  - Characterization of a novel HLA-C allele, Cw*0315.
AB  - The presence of an unusual HLA class I reactivity pattern was detected in a
      Caucasoid-Asian individual by PCR-sequence specific primer (PCR-SSP) typing.
      Exons 2 and 3 were characterized using PCR-sequence-based typing (PCR-SBT) and
      were found to contain a novel Cw*03 sequence, Cw*0315. In the region studied,
      Cw*0315 was comprised mainly of the Cw*0302 sequence, but at four positions it
      contained nucleotides normally only found in other HLA Cw locus alleles. These
      positions each resulted in an amino acid substitution.

PMID- 12492818
TI  - Nomenclature for factors of the HLA system, 2002.

PMID- 12492820
TI  - Health promotion practices of older adults: model testing.
AB  - The purpose of this study was to describe the primary and secondary health
      promotion activities of a group of older adults living independently in a
      continuing care retirement community. Primary and secondary health promotion
      activities were described and compared among the young old (ages 65-80), the old
      (ages 81-85), and the old-old (ages 86-101). Model testing of the factors that
      influence participation in health-promoting activities was also completed. This
      descriptive study included 206 of 210 residents who participated in a single face
      to-face interview. The majority of the participants were female (79%), white
      (99%), and cognitively intact. Those in the old-old age group were less likely
      than the old and young-old groups to have: (1) their stools checked for occult
      blood; (2) their skin checked for lesions; or (3) a recent mammogram, Pap test,
      or prostate exam. Model testing found that age, chronic illnesses, degree of
      physical and mental health, and cognitive status directly or indirectly
      influenced older adults' participation in primary and secondary health behaviors.

PMID- 12492821
TI  - The effectiveness of the around-the-clock in-home care system: did it prevent the
      institutionalization of frail elderly?
AB  - This study compares two communities in Japan from the perspective of community
      health care resources and their use by the elderly during 1992-98. In one
      community, programs of home care services for the elderly were reorganized to
      provide around-the-clock in-home nursing and home help services seven days a week
      (ACC). Official records were the major sources of data. Evidence from the
      analysis indicated that ACC might contribute to less use of institutionalization
      as an alternative to home care, even though, in some instances,
      institutionalization is the only appropriate alternative.

PMID- 12492822
TI  - Community-based senior health promotion program using a collaborative practice
      model: the Escalante Health Partnerships.
AB  - Recent research demonstrates that, although the risk of disease and disability
      clearly increases with age, poor health need not be an inevitable consequence of
      aging. A healthy lifestyle is more influential than genetic factors in assisting
      older adults avoid the decline and deterioration traditionally associated with
      aging. Many effective strategies for reducing disease and disability are widely
      underused. The Escalante Health Partnerships is a community-based, nurse-managed
      health promotion and chronic disease care management program for community
      residing older adults. The program base supports a multidisciplinary,
      collaborative practice model, which has responded to the health needs of members
      of a community at high risk of having or developing chronic conditions.
      Preliminary comparisons of the health status of program participants with
      national norms demonstrate that these seniors report better general health,
      performance of roles, and social functioning, with the strongest correlations
      occurring between general health and vitality and between general health and role
      physical. In addition, these participants have 4.2 doctor visits per year, in
      comparison with 7.1 office visits for a national comparison group and 1.6
      hospital days per year, in comparison with 2.1 hospital days in the same
      referenced population. This collaborative partnership is a model that can be
      replicated cost-effectively in other communities.

PMID- 12492823
TI  - Factors associated with adolescent pregnancy- a sample of Taiwanese female
      adolescents.
AB  - This study was designed to explore the factors that differentiate sexually
      experienced teenagers who become pregnant from those who do not. The study
      examined the differences between pregnant and never-pregnant female adolescents
      in personal background characteristics, family characteristics, substance use,
      contraceptive attitude, contraceptive knowledge, contraceptive self-efficacy,
      sexual history, and effective contraceptive use. Sexually experienced but never
      pregnant female adolescents were selected from two vocational high schools.
      Pregnant adolescents were recruited by convenience sampling from obstetric
      clinics and health stations in Tainan City, Taiwan. Multiple logistic regression
      analysis identified six factors associated with pregnancy: poor contraceptive
      knowledge, poor contraceptive self-efficacy, low socioeconomic status, low
      effective contraceptive use scores, more frequent sexual intercourse, and older
      age. The results of this study provide health professionals with information to
      develop more-effective prevention and intervention programs to reduce adolescent
      pregnancy. The results also could be used as a reference for related research and
      policy development in other countries.

PMID- 12492824
TI  - A public health nursing practice model: melding public health principles with the
      nursing process.
AB  - There has been a shift in emphasis in public health from the provision of
      personal health services for individuals to efforts targeted at improving the
      health of the whole community. Many in public health nursing (PHN) have welcomed
      this shift, recognizing the important role PHN can play in promoting health and
      preventing disease for all. There continues to be a need to redefine PHN roles
      and practice so that public health nurses can participate more effectively. Los
      Angeles County Department of Health Services Public Health Nursing (LAC PHN) has
      developed a practice model grounded in nationally recognized components: the
      public health team, PHN standards of practice, the 10 Essential Public Health
      Services, Healthy People 2010's 10 Leading Health Indicators and additional local
      indicators, and the Minnesota Public Health Nursing Interventions Model. The LAC
      PHN Practice Model provides a conceptual framework that assists in clarifying the
      role of the public health nurse and presents a guide for public health practice
      applicable to all public health disciplines.

PMID- 12492825
TI  - Definition and identification of child abuse by Finnish public health nurses.
AB  - The purpose of this study was to determine how public health nurses in Finland
      defined child abuse and how they assessed their capability to identify child
      abuse in the family. Public health nurses described child abuse as consisting of
      physical and emotional abuse. They described physical abuse as consisting of two
      categories, direct physical abuse towards children and other acts causing
      children physical harm. Emotional abuse included neglect, teasing the child,
      frightening the child, rejecting the child in the family, and forcing the child
      to assume an adult role. The nurses divided the identification of child abuse
      into two categories: tools for identifying child abuse and markers indicating
      child abuse. The tools for identifying abuse included knowledge acquisition and
      interactive skills, intuition, and the capacity of the nurse to handle
      problematic situations. Public health nurses identified child abuse in the
      child's behavior and appearance and in family behaviors. Public health nurses
      seem to be aware of child abuse, but further research is needed if they need more
      specific skills regarding how to apply their theoretical knowledge to nursing
      practice to provide nursing care for abused children and their families.

PMID- 12492826
TI  - Do we really help? Perspectives of abused women.
AB  - Findings are presented from focus group data collected during a larger study
      describing factors that inhibit, support, and sustain women's abilities to leave
      and stay out of abusive relationships. A subset (n = 24) of the larger study
      sample (N = 40) participated in one of four focus groups. Participants had left
      or were currently in abusive intimate relationships. Women reported diverse
      experiences and were in various stages of abusive relationships. Ages ranged from
      21 to 51; 67% were Caucasian, and 20% African American. Most women (71%) had at
      least a high school education and were employed (60%), but 83% reported annual
      incomes less than $20,000. NVIVO software facilitated content analysis of
      transcriptions. After initial synthesis of data, 20 women participated in one of
      two confirmatory focus groups. Four primary themes emerged from the content
      analysis: (1) Living an Unnatural Experience included maladaptive physical and
      emotional responses to chronic violence; (2) The Experience of Telling included
      multiple intrapersonal, interpersonal, and societal barriers to disclosure; (3)
      The Experience of Leaving included descriptions of acute and long-term
      experiences and difficulties; and (4) Reducing Barriers included participant
      ideas on ways to reduce barriers to assistance. Recommendations are made to
      improve community interventions and programs that will facilitate the choices and
      enhance the successes of women who have experienced domestic violence.

PMID- 12492827
TI  - Women's efficiency in decision making and their perception of their status in the
      family.
AB  - This study is descriptive in nature. Three hundred ten women who applied to the
      Maternal-Child Health and Family Planning Center in Erzurum, Turkey, between June
      1 and August 30, 2001 were included in this study. Data were collected through
      the inquiry form, which was prepared to determine women's efficiency in decision
      making, their perception of their status within the family, and their demographic
      characteristics. Women's decision-making rate was lower than that of men, except
      for selecting clothes. Couples' joint decision-making rate was high on personal
      matters but low on official matters. The women's educational level affected their
      decision making in the family. The majority of the women perceived themselves as
      wives sharing everything within the family. Women's perception of their positions
      in the family was related to their status and decision making. The results can be
      used in primary care practice for women's health promotion. The sample in this
      study reflects only one area of Turkey.

PMID- 12492828
TI  - Knowledge and attitudes of high school students about AIDS: a Turkish
      perspective.
AB  - This study was conducted with 705 high school students (360 ninth graders and 345
      11th graders; 305 female, 400 male) for the purpose of determining their
      knowledge and attitudes about HIV/AIDS. Data were obtained using a self-completed
      questionnaire. The questionnaire was divided into three sections. Section A
      included questions about descriptive characteristics of the students. Section B
      included questions about HIV/AIDS knowledge. Section C included questions about
      students' attitudes towards AIDS and their information sources. The percentage,
      correlation, and one-way analysis of variance were used for data analysis.
      Research findings showed moderate knowledge levels (59.15 +/- 14.22 out of 100
      points) in a sample group of 705 Turkish high school students on all AIDS-related
      questions. Students in private schools had higher scores than those in public
      schools; boys had higher scores than girls; 11th graders had higher scores than
      ninth graders, and the methods of transmission were better known than methods of
      nontransmission. Scores increased in parallel with student age. Knowledge scores
      of students were also positively correlated with a higher level of parent
      education and the ease with which sexuality-related subjects were discussed at
      home. About half of the students believed that people with HIV/AIDS should be
      able to attend school and should not have to stop working. Most of the students
      were informed about HIV/AIDS by media. To prevent the illness, the most important
      role of the nurses is to focus on education and information for individuals,
      families, and communities.

PMID- 12492830
TI  - Developmental events and shoot apical meristem gene expression patterns during
      shoot development in Arabidopsis thaliana.
AB  - Critical developmental and gene expression profiles were charted during the
      formation of shoots from root explants in Arabidopsis tissue culture. Shoot
      organogenesis is a two-step process involving pre-incubation on an auxin-rich
      callus induction medium (CIM) during which time root explants acquire competence
      to form shoots during subsequent incubation on a cytokinin-rich shoot induction
      medium (SIM). At a histological level, the organization of shoot apical meristems
      (SAMs) appears to occur during incubation on SIM about the time of shoot
      commitment, i.e. the transition from hormone-dependent to hormone-independent
      shoot development. Genes involved in SAM formation, such as SHOOTMERISTEMLESS
      (STM) and CLAVATA1 (CLV1), were upregulated at about the time of shoot
      commitment, while WUSCHEL (WUS) was upregulated somewhat earlier. Genes required
      for STM expression, such as CUP-SHAPED COTYLEDON 1 and 2 (CUC1 and 2) were
      upregulated prior to shoot commitment. Gene expression patterns were determined
      for two GFP enhancer trap lines with tissue-specific expression in the SAM,
      including one line reporting on CUC1 expression. CUC1 was generally expressed in
      callus tissue during early incubation on SIM, but later CUC1 was expressed more
      locally in presumptive sites of shoot formation. In contrast, the expression
      pattern of the enhancer trap lines during zygotic embryogenesis was more
      localized to the presumptive SAM even in early stages of embryogenesis.

PMID- 12492831
TI  - Sulfate reduction is increased in transgenic Arabidopsis thaliana expressing 5'
      adenylylsulfate reductase from Pseudomonas aeruginosa.
AB  - The two-electron reduction of sulfate to sulfite in plants is mediated by 5'
      adenylylsulfate (APS) reductase, an enzyme theorized to be a control point for
      cysteine synthesis. The hypothesis was tested by expression in Arabidopsis
      thaliana under transcriptional control of the CaMV 35S promoter of the APS
      reductase from Pseudomonas aeruginosa (PaAPR) fused with the rbcS transit peptide
      for localization of the protein to plastids. PaAPR was chosen for the experiment
      because it is a highly stable enzyme compared with the endogenous APS reductase
      of A. thaliana, and because PaAPR is catalytically active in combination with the
      plant thioredoxins m and f indicating that it would likely be catalytically
      active in plastids. The results indicate that sulfate reduction and O
      acetylserine (OAS) production together limit cysteine synthesis. Transgenic A.
      thaliana lines expressing PaAPR accumulated sulfite, thiosulfate, cysteine, gamma
      glutamylcysteine, and glutathione. Sulfite and thiosulfate increased more than
      did cysteine, gamma-glutamylcysteine and glutathione. Thiosulfate accumulation
      was most pronounced in flowers. Feeding of OAS to the PaAPR-expressing plants
      caused cysteine and glutathione to increase more rapidly than in comparably
      treated wild type. Both wild-type and transgenic plants accumulated sulfite and
      thiosulfate in response to OAS feeding. The PaAPR-expressing plants were slightly
      chlorotic and stunted compared with wild type. An attempt to uncover the source
      of thiosulfate, which is not thought to be an intermediate of sulfate reduction,
      revealed that purified beta-mercaptopyruvate sulfurtransferase is able to form
      thiosulfate from sulfite and beta-mercaptopyruvate, suggesting that this class of
      enzymes could form thiosulfate in vivo in the presence of excess sulfite.

PMID- 12492832
TI  - The impact of oxidative stress on Arabidopsis mitochondria.
AB  - Treatment of Arabidopsis cell culture for 16 h with H2O2, menadione or antimycin
      A induced an oxidative stress decreasing growth rate and increasing DCF
      fluorescence and lipid peroxidation products. Treated cells remained viable and
      maintained significant respiratory rates. Mitochondrial integrity was maintained,
      but accumulation of alternative oxidase and decreased abundance of lipoic acid
      containing components during several of the treatments indicated oxidative
      stress. Analysis of the treatments was undertaken by IEF/SDS-PAGE, comparison of
      protein spot abundances and tandem mass spectrometry. A set of 25 protein spots
      increased >3-fold in H2O2/menadione treatments, a subset of these increased in
      antimycin A-treated samples. A set of 10 protein spots decreased significantly
      during stress treatments. A specific set of mitochondrial proteins were degraded
      by stress treatments. These damaged components included subunits of ATP synthase,
      complex I, succinyl CoA ligase, aconitase, and pyruvate and 2-oxoglutarate
      dehydrogenase complexes. Nine increased proteins represented products of
      different genes not found in control mitochondria. One is directly involved in
      antioxidant defense, a mitochondrial thioredoxin-dependent peroxidase, while
      another, a thioredoxin reductase-dependent protein disulphide isomerase, is
      required for protein disulfide redox homeostasis. Several others are generally
      considered to be extramitochondrial but are clearly present in a highly purified
      mitochondrial fraction used in this study and are known to play roles in stress
      response. Using H2O2 as a model stress, further work revealed that this treatment
      induced a protease activity in isolated mitochondria, putatively responsible for
      the degradation of oxidatively damaged mitochondrial proteins and that O2
      consumption by mitochondria was significantly decreased by H2O2 treatment.

PMID- 12492833
TI  - Tomato tos1 mutation identifies a gene essential for osmotic tolerance and
      abscisic acid sensitivity.
AB  - Osmotic stress severely limits plant growth and agricultural productivity. We
      have used mutagenesis to identify plant genes that are required for osmotic
      stress tolerance in tomato. As a result, we have isolated a novel mutant in
      tomato (tos1) caused by a single recessive nuclear mutation that is
      hypersensitive to general osmotic stress. Growth measurements demonstrated that
      the tos1 mutant is less sensitive to intracellular abscisic acid (ABA) and this
      decreased ABA sensitivity of tos1 is a basic cellular trait expressed by the
      mutant at all developmental stages analysed. It is not caused by a deficiency in
      the synthesis of ABA because the tos1 seedlings accumulated more ABA than the
      wild type (WT) after osmotic stress. In contrast, the tss2 tomato mutant, which
      is also hypersensitive to osmotic stress, is hypersensitive to exogenous ABA.
      Comparative analysis of tos1 and tss2 indicates that appropriate ABA perception
      and signalling is essential for osmotic tolerance.

PMID- 12492834
TI  - Thylakoid membrane-bound ascorbate peroxidase is a limiting factor of
      antioxidative systems under photo-oxidative stress.
AB  - To evaluate the physiological importance of thylakoid membrane-bound ascorbate
      peroxidase (tAPX) in the active oxygen species-scavenging system of chloroplasts,
      the level of tAPX in tobacco plants was altered by expression of the tAPX cDNA in
      both sense and antisense orientation. The tobacco plants transformed with
      constructs of antisense tAPXs from spinach and tobacco could not be obtained,
      suggesting that the suppression of tAPX in higher plants had a severe effect on
      the growth even under normal conditions. In contrast, the transgenic tobacco
      plants (TpTAP-12) overexpressing tAPX, which had approximately 37-fold higher
      activity than that of the wild-type plants, were generated. The TpTAP-12 plants
      showed increased tolerance to oxidative stress caused by application of
      methylviologen (MV, 50 microm) under light intensity (300 and 1600 microE m(-2)
      sec(-1)) and by chilling stress with high light intensity (4 degrees C, 1000
      microE m(-2) sec(-1)). At 24 h after the MV treatment under illumination at 300
      microE m-2 sec-1, destruction of chlorophyll was observed in the wild-type
      plants, but not in the TpTAP-12 plants. The activities of thiol-modulated enzymes
      in the Calvin cycle, the level and redox status of ascorbate (AsA), and the
      activity of tAPX in the wild-type plants significantly decreased, while those in
      the TpTAP-12 plants were hardly changed. These observations suggest that tAPX is
      a limiting factor of antioxidative systems under photo-oxidative stress in
      chloroplasts, and that the enhanced activity of tAPX functions to maintain the
      AsA content and the redox status of AsA under stress conditions.

PMID- 12492835
TI  - The Arabidopsis eukaryotic initiation factor (iso)4E is dispensable for plant
      growth but required for susceptibility to potyviruses.
AB  - An Arabidopsis thaliana line bearing a transposon insertion in the gene coding
      for the isozyme form of the plant-specific cap-binding protein, eukaryotic
      initiation factor (iso) 4E (eIF (iso) 4E), has been isolated. This mutant line
      completely lacks both eIF(iso)4E mRNA and protein, but was found to have a
      phenotype and fertility indistinguishable from wild-type plants under standard
      laboratory conditions. In contrast, the amount of the related eIF4E protein was
      found to increase in seedling extracts. Furthermore, polysome analysis shows that
      the mRNA encoding eIF4E was being translated at increased levels. Given the known
      interaction between cap-binding proteins and potyviral genome-linked proteins
      (VPg), this plant line was challenged with two potyviruses, Turnip mosaic virus
      (TuMV) and Lettuce mosaic virus (LMV) and was found resistant to both, but not to
      the Nepovirus, Tomato black ring virus (TBRV) and the Cucumovirus, Cucumber
      mosaic virus (CMV). Together with previous data showing that the VPg-eIF4E
      interaction is necessary for virus infectivity and upregulates genome
      amplification, this shows that the eIF4E proteins are specifically recruited for
      the replication cycle of potyviruses.

PMID- 12492836
TI  - Evidence that the Arabidopsis nuclear gibberellin signalling protein GAI is not
      destabilised by gibberellin.
AB  - Plant growth is regulated by bioactive gibberellin (GA), although there is an
      unexplained diversity in the magnitude of the GA responses exhibited by different
      plant species. GA acts via a group of orthologous proteins known as the DELLA
      proteins. The Arabidopsis genome contains genes encoding five different DELLA
      proteins, the best known of which are GAI and RGA. The DELLA proteins are thought
      to act as repressors of GA-regulated processes, whilst GA is thought to act as a
      negative regulator of DELLA protein function. Recent experiments have shown that
      GA induces rapid disappearance of nuclear RGA, SLR1 and SLN1 (DELLA proteins from
      rice and barley), suggesting that GA signalling and degradation of DELLA proteins
      are coupled. However, RGL1, another Arabidopsis DELLA protein, does not disappear
      from the nucleus in response to GA treatment. Here, we present evidence
      suggesting that GAI, like RGL1, is stable in response to GA treatment, and show
      that transgenic Arabidopsis plants containing constructs that enable high-level
      expression of GAI exhibit a dwarf, GA non-responsive phenotype. Thus, GAI appears
      to be less affected by GA than RGA, SLR1 or SLN1. We also show that neither of
      the two putative nuclear localisation signals contained in DELLA proteins are
      individually necessary for nuclear localisation of GAI. The various DELLA
      proteins have different properties, and we suggest that this functional diversity
      may explain, at least in part, why plant species differ widely in their GA
      response magnitudes.

PMID- 12492837
TI  - The cellulose-deficient Arabidopsis mutant rsw3 is defective in a gene encoding a
      putative glucosidase II, an enzyme processing N-glycans during ER quality
      control.
AB  - rsw3 is a temperature-sensitive mutant of Arabidopsis thaliana showing radially
      swollen roots and a deficiency in cellulose. The rsw3 gene was identified by a
      map-based strategy, and shows high similarity to the catalytic alpha-subunits of
      glucosidase II from mouse, yeast and potato. These enzymes process N-linked
      glycans in the ER, so that they bind and then release chaperones as part of the
      quality control pathway, ensuring correct protein folding. Putative beta-subunits
      for the glucosidase II holoenzyme identified in the Arabidopsis and rice genomes
      share characteristic motifs (including an HDEL ER-retention signal) with beta
      subunits in mammals and yeast. The genes encoding the putative alpha- and beta
      subunits are single copy and, like the rsw3 phenotype, widely expressed. rsw3
      reduces cell number more strongly than cell size in stamen filaments and probably
      stems. Most features of the rsw3 phenotype are shared with other cellulose
      deficient mutants, but some--notably, production of multiple rosettes and a lack
      of secreted seed mucilage--are not and may reflect glucosidase II affecting
      processes other than cellulose synthesis. The rsw3 root phenotype develops more
      slowly than the rsw1 and rsw2 phenotypes when seedlings are transferred to the
      restrictive temperature. This is consistent with rsw3 reducing glycoprotein
      delivery from the ER to the plasma membrane whereas rsw1 and rsw2 act more
      rapidly by affecting the properties of already delivered enzymes.

PMID- 12492838
TI  - Arabidopsis is susceptible to the cereal ear blight fungal pathogens Fusarium
      graminearum and Fusarium culmorum.
AB  - The fungal pathogens Fusarium graminearum and F. culmorum cause ear blight
      disease on cereal crops worldwide. The disease lowers both grain quality and
      grain safety. Disease prevalence is increasing due to changes in cropping
      practices and the difficulties encountered by plant breeders when trying to
      introgress the polygene-based resistance. The molecular basis of resistance to
      Fusarium ear blight in cereal species is poorly understood. This is primarily due
      to the large size of cereal genomes and the expensive resources required to
      undertake gene function studies in cereals. We therefore explored the possibility
      of developing various model floral infection systems that would be more amenable
      to experimental manipulation and high-throughput gene function studies. The
      floral tissues of tobacco, tomato, soybean and Arabidopsis were inoculated with
      Fusarium conidia and this resulted in disease symptoms on anthers, anther
      filaments and petals in each plant species. However, only in Arabidopsis did this
      initial infection then spread into the developing siliques and seeds. A survey of
      236 Arabidopsis ecotypes failed to identify a single genotype that was extremely
      resistant or susceptible to Fusarium floral infections. Three Arabidopsis floral
      mutants that failed to develop anthers and/or functional pollen (i.e. agamous-1,
      apetala1-3 and dad1) were significantly less susceptible to Fusarium floral
      infection than wild type. Deoxynivalenol (DON) mycotoxin production was also
      detected in Fusarium-infected flowers at >1 ppm. This novel floral pathosystem
      for Arabidopsis appears to be highly representative of a serious cereal crop
      disease.

PMID- 12492839
TI  - Overexpression of a kinase-deficient form of the EDR1 gene enhances powdery
      mildew resistance and ethylene-induced senescence in Arabidopsis.
AB  - The EDR1 gene of Arabidopsis has previously been reported to encode a Raf-like
      mitogen-activated protein kinase kinase (MAPKK) kinase, and to function as a
      negative regulator of disease resistance. A phylogenetic analysis of plant and
      animal protein kinases revealed, however, that plant Raf-like kinases are more
      closely related to animal mixed lineage kinases (MLKs) than Raf-like kinases, and
      are deeply divergent from both classes of animal kinases, making inferences of
      substrate specificity questionable. We, therefore, assayed the kinase activity of
      recombinant EDR1 protein in vitro. The EDR1 kinase domain displayed
      autophosphorylation activity and phosphorylated the common MAP kinase substrate
      myelin basic protein. The EDR1 kinase domain also phosphorylated a kinase
      deficient EDR1 protein, indicating that EDR1 autophosphorylation can occur via an
      intermolecular mechanism. Overexpression of a kinase-deficient full-length EDR1
      gene (35S::dnEDR1) in wild-type Arabidopsis plants caused a dominant negative
      phenotype, conferring resistance to powdery mildew (Erysiphe cichoracearum) and
      enhancing ethylene-induced senescence. RNA-gel blot analyses showed that the
      35S::dnEDR1 transgene was highly transcribed in transgenic plants. Western blot
      analysis, however, revealed that neither the wild-type nor mutant EDR1 protein
      could be detected in these lines, indicating that the dominant negative phenotype
      may be caused by a translational inhibition mechanism rather than by a protein
      level effect. Overexpression of orthologous dnEDR1 constructs may provide a novel
      strategy for controlling powdery mildew disease in crops.

PMID- 12492840
TI  - Molecular analysis of the stylar-expressed Solanum chacoense small asparagine
      rich protein family related to the HT modifier of gametophytic self
      incompatibility in Nicotiana.
AB  - Gametophytic self-incompatibility (GSI) systems involving the expression of
      stylar ribonucleases have been described and extensively studied in many plant
      families including the Solanaceae, Rosaceae and Scrophulariaceae. Pollen
      recognition and rejection is governed in the style by specific ribonucleases
      called S-RNases, but in many self-incompatibility (SI) systems, modifier loci
      that can modulate the SI response have been described at the genetic level. Here,
      we present at the molecular level, the isolation and characterization of two
      Solanum chacoense homologues of the Nicotiana HT modifier that had been
      previously shown to be necessary for the SI reaction to occur in N. alata
      (McClure et al., 1999). HT homologues from other solanaceous species have also
      been isolated and a phylogenetic analysis reveals that the HT genes fall into two
      groups. In S. chacoense, these small proteins named ScHT-A and ScHT-B are
      expressed in the style and are developmentally regulated during anthesis
      identically to the S-RNases as well as following compatible and incompatible
      pollination. To elucidate the precise role of each HT isoform, antisense ScHT-A
      and RNAi ScHT-B lines were generated. Conversion from SI to self-compatibility
      (SC) was only observed in RNAi ScHT-B lines with reduced levels of ScHT-B mRNA.
      These results confirm the role of the HT modifier in solanaceous SI and indicate
      that only the HT-B isoform is directly involved in SI.

PMID- 12492841
TI  - Poplar potassium transporters capable of controlling K+ homeostasis and K+
      dependent xylogenesis.
AB  - The cambial K+ content of poplar increases during the growth period in a K+
      supply dependent manner. Upon K+ starvation or application of
      tetraethylammoniumchloride (TEA+), a K+ channel blocker, the average vessel lumen
      and expansion zone area were significantly reduced. In search for the molecular
      basis of potassium-dependent xylogenesis in poplar, K+ transporters homologous to
      those of known function in Arabidopis phloem- and xylem-physiology were isolated
      from a poplar wood EST library. The expression profile of three distinct K+
      channel types and one K+ transporter, Populus tremula K+ uptake transporter 1
      (PtKUP1), was analysed by quantitative RT-PCR. Thereby, we found P. tremula
      outward rectifying K+ channel (PTORK) and P. tremula K+ channel 2 (PTK2)
      correlated with the seasonal wood production. K+ transporter P. tremula 1 (KPT1)
      was predominantly found in guard cells. Following the heterologous expression in
      Xenopus oocytes the biophysical properties of the different channels were
      determined. PTORK, upon membrane de-polarization mediates potassium release. PTK2
      is almost voltage independent, carrying inward K+ flux at hyperpolarized
      potential and K+ release upon de-polarization. PtKUP1 was expressed in a K+
      uptake-deficient Escherichia coli strain, where this K+ transporter rescued K+
      dependent growth. In order to link the different K+ transporters to the cambial
      activity and wood production, we compared the expression profiles to seasonal
      changes in the K+ content of the bark as well as xylem vessel diameter. Thereby,
      we found PTORK and PTK2 transcripts to follow the annual K+ variations in poplar
      branches. PtKUP1 was expressed at a low level throughout the year, suggesting a
      housekeeping function. From these data, we conclude that K+ channels are involved
      in the regulation of K+-dependent wood production.

PMID- 12492842
TI  - The HAT2 gene, a member of the HD-Zip gene family, isolated as an auxin inducible
      gene by DNA microarray screening, affects auxin response in Arabidopsis.
AB  - The plant hormone, auxin, regulates many aspects of growth and development.
      Despite its importance, the molecular mechanisms underlying the action of auxin
      are largely unknown. To gain a more comprehensive understanding of the primary
      responses to auxin, we analyzed the expression of genes in Arabidopsis seedlings
      treated with indole-3-acetic acid (IAA) for 15 min. We identified a single gene
      that is downregulated early, and 29 genes that are upregulated early. Several
      types of typical transcription factors are identified as early upregulated genes,
      suggesting that auxin signals are mediated by a master set of diverse
      transcriptional regulators. Of the genes that responded to auxin, the expression
      of the homeobox gene, HAT2, was induced rapidly. Furthermore, we show that the
      expression of HAT2 is induced by auxin, but not by other phytohormones. To
      analyze the function of HAT2 in the plant's response to auxin, we generated
      35S::HAT2 transgenic plants. These produced long hypocotyls, epinastic
      cotyledons, long petioles, and small leaves, which are characteristic of the
      phenotypes of the auxin-overproducing mutants, superroot1 (sur1) and superroot2
      (sur2). On the other hand, 35S::HAT2 plants showed reduced lateral root
      elongation, and reduced auxin sensitivity compared to wild-type plants. Together
      with the results of RNA blotting and biochemical analyses, these findings suggest
      that HAT2 plays opposite roles in the shoot and root tissues in regulating auxin
      mediated morphogenesis.

PMID- 12492843
TI  - The stability of cortical microtubules depends on their orientation.
AB  - Auxin controls the orientation of cortical microtubules in maize coleoptile
      segments. We used tyrosinylated alpha-tubulin as a marker to assess auxin
      dependent changes in microtubule turnover. Auxin-induced tyrosinylated alpha
      tubulin, correlated with an elevated sensitivity of growth to antimicrotubular
      compounds such as ethyl-N-phenylcarbamate (EPC). We determined the affinity of
      alpha-tubulin to EPC and found that it was dramatically increased when the
      tubulin was de-tyrosinylated. By proteolytic cleavage of the carboxy terminal
      tyrosine, such an increased affinity could be induced in vitro. Thus, the auxin
      induced sensitivity of growth to EPC is not caused by an increased affinity for
      this inhibitor, but caused by a reduced microtubule turnover. Double
      visualization assays revealed that the transverse microtubules induced by auxin
      consist predominantly of tyrosinylated alpha-tubulin, whereas the longitudinal
      microtubules induced by auxin depletion contain de-tyrosinylated alpha-tubulin.
      The results are discussed in terms of direction-dependent differences in the
      lifetime of microtubules.

PMID- 12492844
TI  - A genomics approach to the early stages of triterpene saponin biosynthesis in
      Medicago truncatula.
AB  - The saponins of the model legume Medicago truncatula are glycosides of at least
      five different triterpene aglycones: soyasapogenol B, soyasapogenol E,
      medicagenic acid, hederagenin and bayogenin. These aglycones are most likely
      derived from beta-amyrin, a product of the cyclization of 2,3-oxidosqualene.
      Mining M. truncatula EST data sets led to the identification of sequences
      putatively encoding three early enzymes of triterpene aglycone formation:
      squalene synthase (SS), squalene epoxidase (SE), and beta-amyrin synthase (beta
      AS). SS was functionally characterized by expression in Escherichia coli, two
      forms of SE by complementation of the yeast erg1 mutant, and beta-AS by
      expression in yeast. Beta-amyrin was the sole product of the cyclization of
      squalene epoxide by the recombinant M. truncatulabeta-AS, as judged by GC-MS and
      NMR. Transcripts encoding beta-AS, SS and one form of SE were strongly and co
      ordinately induced, associated with accumulation of triterpenes, upon exposure of
      M. truncatula cell suspension cultures to methyl jasmonate. Sterol composition
      remained unaffected by jasmonate treatment. Molecular verification of induction
      of the triterpene pathway in a cell culture system provides a new tool for
      saponin pathway gene discovery by DNA array-based approaches.

PMID- 12492845
TI  - Identification of an essential component of the elicitation active site of the
      EIX protein elicitor.
AB  - Defense mechanisms of plants against pathogens often entail cell wall
      strengthening, ethylene biosynthesis, expression of pathogen-related proteins and
      hypersensitive responses (HR). Pathogen-derived elicitors trigger these defense
      responses. The Elicitor Ethylene-inducing Xylanase (EIX) elicits HR and other
      plant defense responses in some tobacco and tomato cultivars independently of its
      xylan degradation activity. The elicitation epitope on the EIX protein
      responsible for inducing the HR response has been elucidated. Through the
      generation of EIX-specific polyclonal antibodies and screening of combinatorial
      phage display peptide libraries an essential sequence of the EIX elicitation
      activity has been identified. This sequence consists of the pentapeptide TKLGE
      mapped to an exposed beta-strand of the EIX protein. Substitution of the
      pentapeptide TKLGE to VKGT inhibited the elicitation activity but not the beta-1
      4-endoxylanase activity of the EIX protein further demonstrating that elicitation
      and enzyme activity are independent properties. Elucidation of a peptide sequence
      that is essential for elicitation of HR creates the opportunity to understand the
      control and signaling of plant defense.

PMID- 12492846
TI  - Cell cycle progression during endosperm development in Zea mays depends on
      parental dosage effects.
AB  - Interploidy crosses in flowering plants often cause seed abortion. Studies in
      maize have shown that failure of kernel development results from dosage effects
      among products of imprinted but as-yet-unknown genes in the endosperm, and that
      the operative stoichiometry is established for a ratio of two maternal genomes to
      one paternal genome. In this study, we used flow cytometry to monitor cell cycle
      activities in developing endosperms obtained after reciprocal crosses between
      diploid and tetraploid maize individuals. Our data show that dosage effects alter
      critical events involved in the establishment of endoreduplication during maize
      endosperm development. Particularly, maternal genomic excess (4x x 2x crosses)
      forces endosperm cells to enter early into endoreduplication while paternal
      genomic excess (2x x 4x crosses) prevents its establishment. Our results also
      suggest that altering mechanisms depend on two different sets of cell cycle
      regulatory genes--one imprinted through the female that is required for mitotic
      arrest, and another responsible for re-entry into S phase that is imprinted
      through the male. Further, molecular and physiological analyses should provide
      insights into the interaction of parental imprinting action and cell cycle
      regulation during endosperm development.

PMID- 12492847
TI  - A natural recessive resistance gene against potato virus Y in pepper corresponds
      to the eukaryotic initiation factor 4E (eIF4E).
AB  - We show here that the pvr2 locus in pepper, conferring recessive resistance
      against strains of potato virus Y (PVY), corresponds to a eukaryotic initiation
      factor 4E (eIF4E) gene. RFLP analysis on the PVY-susceptible and resistant pepper
      cultivars, using an eIF4E cDNA from tobacco as probe, revealed perfect map co
      segregation between a polymorphism in the eIF4E gene and the pvr2 alleles,
      pvr2(1) (resistant to PVY-0) and pvr2(2) (resistant to PVY-0 and 1). The cloned
      pepper eIF4E cDNA encoded a 228 amino acid polypeptide with 70-86% nucleotide
      sequence identity with other plant eIF4Es. The sequences of eIF4E protein from
      two PVY-susceptible cultivars were identical and differed from the eIF4E
      sequences of the two PVY-resistant cultivars Yolo Y (YY) (pvr2(1)) and FloridaVR2
      (F) (pvr2(2)) at two amino acids, a mutation common to both resistant genotypes
      and a second mutation specific to each. Complementation experiments were used to
      show that the eIF4E gene corresponds to pvr2. Thus, potato virus X-mediated
      transient expression of eIF4E from susceptible cultivar Yolo Wonder (YW) in the
      resistant genotype YY resulted in loss of resistance to subsequent PVY-0
      inoculation and transient expression of eIF4E from YY (resistant to PVY-0;
      susceptible to PVY-1) rendered genotype F susceptible to PVY-1. Several lines of
      evidence indicate that interaction between the potyvirus genome-linked protein
      (VPg) and eIF4E are important for virus infectivity, suggesting that the
      recessive resistance could be due to incompatibility between the VPg and eIF4E in
      the resistant genotype.

PMID- 12492848
TI  - Controlling gene expression in plants using synthetic zinc finger transcription
      factors.
AB  - Synthetic zinc finger proteins can be fused to transcriptional regulatory domains
      to create artificial transcription factors that modulate the expression of a
      specific target gene. Recent studies have demonstrated that synthetic zinc finger
      domains can be constructed to bind DNA sequences with a high degree of
      specificity. To devise a general strategy for controlling plant gene expression
      with artificial transcription factors, a rapid transient assay was developed to
      test the regulatory activity of synthetic zinc finger transcription factors
      (effectors) on target plasmids (reporters) in plant cells. Effective activation
      was demonstrated with zinc finger proteins fused to a derivative of the VP16
      activation domain. The mSin3 interaction domain (SID) of the human MAD1 protein
      provided moderate repression of target reporters. Unlike many naturally occurring
      transcription factors, these synthetic effectors exhibit a strong dependence on
      binding site position. Reporter genes that are stably integrated into plant cells
      responded similarly to transiently transfected reporter plasmids, verifying that
      this assay accurately reflects the behavior of these transcription factors on an
      endogenous target within the context of chromosomal DNA. These results provide
      evidence that synthetic zinc finger proteins can be used to manipulate the
      expression of endogenous genes in plants.

PMID- 12492849
TI  - Structure and function of the Mur enzymes: development of novel inhibitors.
AB  - One of the biggest challenges for recent medical research is the continuous
      development of new antibiotics interacting with bacterial essential mechanisms.
      The machinery for peptidoglycan biosynthesis is a rich source of crucial targets
      for antibacterial chemotherapy. The cytoplasmic steps of the biosynthesis of
      peptidoglycan precursor, catalysed by a series of Mur enzymes, are excellent
      candidates for drug development. There has been growing interest in these
      bacterial enzymes over the last decade. Many studies attempted to understand the
      detailed mechanisms and structural features of the key enzymes MurA to MurF. Only
      MurA is inhibited by a known antibiotic, fosfomycin. Several attempts made to
      develop novel inhibitors of this pathway are discussed in this review. Three
      novel inhibitors of MurA were identified recently. 4-Thiazolidinone compounds
      were designed as MurB inhibitors. Many phosphinic acid derivatives and substrate
      analogues were identified as inhibitors of the MurC to MurF amino acid ligases.

PMID- 12492850
TI  - From pre-cells to Eukarya--a tale of two lipids.
AB  - A mechanistic hypothesis for the origin of the three domains of life is proposed.
      A population of evolving pre-cells is suggested to have had a membrane of a
      racemate of chiral lipids that continuously underwent spontaneous symmetry
      breaking by spatial phase segregation into two enantiomerically enriched membrane
      domains. By frequent pre-cell fusions and fissions these membrane domains became
      partitioned between two pre-cell subpopulations having predominantly one lipid
      enantiomer or the other. The origin of the Bacteria and Archaea is explained by
      divergence of first a population of proto-bacteria and later a population of
      proto-archaea from the evolving pre-cells, each by the emergence of an enantio
      selective lipid biosynthesis within the corresponding pre-cell subtype. The
      origin of the Eukarya is explained by symbiosis between a population of Bacteria
      and a subpopulation of pre-cells with a predominance of the bacteria-type lipid
      enantiomers.

PMID- 12492851
TI  - The expression level determines the surface distribution of the transferrin
      receptor in Trypanosoma brucei.
AB  - The transferrin receptor (TfR) of Trypanosoma brucei is a heterodimer attached to
      the surface membrane by a glycosylphosphatidylinositol (GPI) anchor. The TfR is
      restricted to the flagellar pocket, a deep invagination of the plasma membrane.
      The membrane of the flagellar pocket and the rest of the cell surface are
      continuous, and the mechanism that selectively retains the TfR in the pocket is
      unknown. Here, we report that the TfR is retained in the flagellar pocket by a
      specific and saturable mechanism. In bloodstream-form trypanosomes transfected
      with the TfR genes, TfR molecules escaped flagellar pocket retention and
      accumulated on the entire surface, even at modest (threefold) overproduction
      levels. Similar surface accumulation was observed when the TfR levels were
      physiologically upregulated threefold when trypanosomes were starved for
      transferrin. These results suggest that the TfR flagellar pocket retention
      mechanism is easily saturated and that control of the expression level is
      critical to maintain the restricted surface distribution of the receptor.

PMID- 12492852
TI  - Early targeting of Min proteins to the cell poles in germinated spores of
      Bacillus subtilis: evidence for division apparatus-independent recruitment of Min
      proteins to the division site.
AB  - The earliest event in bacterial cell division is the assembly of a tubulin-like
      protein, FtsZ, at mid-cell to form a ring. In rod-shaped bacteria, the Min system
      plays an important role in division site placement by inhibiting FtsZ ring
      formation specifically at the polar regions of the cell. The Min system comprises
      MinD and MinC, which form an inhibitor complex and, in Bacillus subtilis, DivIVA,
      which ensures that division is inhibited only in the polar regions. All three
      proteins localize to the division site at mid-cell and to cell poles. Their
      recruitment to the division site is dependent on localization of both 'early' and
      'late' division proteins. We have examined the temporal and spatial localization
      of DivIVA relative to that of FtsZ during the first and second cell division
      after germination and outgrowth of B. subtilis spores. We show that, although the
      FtsZ ring assembles at mid-cell about halfway through the cell cycle, DivIVA
      assembles at this site immediately before cell division and persists there during
      Z-ring constriction and completion of division. We also show that both DivIVA and
      MinD localize to the cell poles immediately upon spore germination, well before a
      Z ring forms at mid-cell. Furthermore, these proteins were found to be present in
      mature, dormant spores. These results suggest that targeting of Min proteins to
      division sites does not depend directly on the assembly of the division
      apparatus, as suggested previously, and that potential polar division sites are
      blocked at the earliest possible stage in the cell cycle in germinated spores as
      a mechanism to ensure that equal-sized daughter cells are produced upon cell
      division.

PMID- 12492853
TI  - Localization of Mycoplasma pneumoniae cytadherence-associated protein HMW2 by
      fusion with green fluorescent protein: implications for attachment organelle
      structure.
AB  - The terminal organelle of the cell wall-less pathogenic bacterium Mycoplasma
      pneumoniae is a complex structure involved in adherence, gliding motility and
      cell division. This membrane-bound extension of the mycoplasma cell possesses a
      characteristic electron-dense core. A number of proteins having direct or
      indirect roles in M. pneumoniae cytadherence have been previously localized to
      the terminal organelle. However, the cytadherence-accessory protein HMW2, which
      is required for the stabilization of several terminal organelle components, has
      been refractory to antibody-based approaches to subcellular localization. In the
      current study, we constructed a sandwich fusion of HMW2 and enhanced green
      fluorescent protein (EGFP) and expressed this fusion in wild-type M. pneumoniae
      and the hmw2- mutant I-2. The fusion protein was produced in both backgrounds at
      wild-type levels and supported stabilization of proteins HMW1, HMW3 and P65, and
      haemadsorption function in mutant I-2. Furthermore, the fusion protein was
      fluorescent and localized specifically to the terminal organelle. However, the
      EGFP moiety appeared to interfere partially with processes related to cell
      division, as transformant cells exhibited an increased incidence of bifurcated
      attachment organelles. These data together with structural predictions suggest
      that HMW2 is the defining component of the electron-dense core of the terminal
      organelle.

PMID- 12492854
TI  - Distribution and function of new bacterial intein-like protein domains.
AB  - Hint protein domains appear in inteins and in the C-terminal region of Hedgehog
      and Hedgehog-like animal developmental proteins. Intein Hint domains are
      responsible and sufficient for protein-splicing of their host-protein flanks. In
      Hedgehog proteins the Hint domain autocatalyses its cleavage from the N-terminal
      domain of the Hedgehog protein by attaching a cholesterol molecule to it. We
      identified two new types of Hint domains. Both types have active site sequence
      features of Hint domains but also possess distinguishing sequence features. The
      new domains appear in more than 50 different proteins from diverse bacteria,
      including pathogenic species of humans and plants, such as Neisseria meningitidis
      and Pseudomonas syringae. These new domains are termed bacterial intein-like
      (BIL) domains. Bacterial intein-like domains are present in variable protein
      regions and are typically flanked by domains that also appear in secreted
      proteins such as filamentous haemagglutinin and calcium binding RTX repeats.
      Phylogenetic and genomic analysis of BIL sequences suggests that they were
      positively selected for in different lineages. We cloned two BIL domains of
      different types and showed them to be active. One of the domains efficiently
      cleaved itself from its C-terminal flank and could also protein-splice its two
      flanks, in E. coli and in a cell free system. We discuss several possible
      biological roles for BIL domains including microevolution and post translational
      modification for generating protein variability.

PMID- 12492855
TI  - Ectopic RNase E sites promote bypass of 5'-end-dependent mRNA decay in
      Escherichia coli.
AB  - In Escherichia coli, 5'-terminal stem-loops form major impediments to mRNA decay,
      yet conditions that determine their effectiveness or the use of alternative decay
      pathway(s) are unclear. A synthetic 5'-terminal hairpin stabilizes the rpsT mRNA
      sixfold. This stabilization is dependent on efficient translational initiation
      and ribosome transit through at least two-thirds of the coding sequence past a
      major RNase E cleavage site in the rpsT mRNA. Insertion of a 12-15 residue
      'ectopic' RNase E cleavage site from either the rne leader or 9S pre-rRNA into
      the 5'-non-coding region of the rpsT mRNA significantly reduces the stabilizing
      effect of the terminal stem-loop, dependent on RNase E. A similar insertion into
      the rpsT coding sequence is partially destabilizing. These findings demonstrate
      that RNase E can bypass an interaction with the 5'-terminus, and exploit an
      alternative 'internal entry' pathway. We propose a model for degradation of the
      rpsT mRNA, which explains the hierarchy of protection afforded by different 5'
      termini, the use of internal entry for bypass of barriers to decay, 'ectopic
      sites' and the role of translating ribosomes.

PMID- 12492856
TI  - EFG1 is a major regulator of cell wall dynamics in Candida albicans as revealed
      by DNA microarrays.
AB  - Cell wall dynamics in Candida albicans, the most common fungal pathogen in man,
      underlie regulatory processes during the yeast-to-hyphae transition. To analyse
      this regulation at the transcriptional level, we have established a DNA
      microarray representing genes implicated in cell wall biogenesis. Using these
      microarrays, we were able to identify YWP1 and HWP2 that are specifically
      transcribed in the yeast or hyphal growth form respectively. Cluster analysis
      revealed at least two major clusters of genes: cluster I comprised genes that
      were upregulated under at least one hyphae-inducing condition. Three as yet not
      further characterized genes were attributed to cluster II. These genes were
      transcribed in the yeast form of C. albicans and were downregulated in an EFG1
      dependent manner under specific hyphae-inducing conditions. We show further that,
      in contrast to CPH1, EFG1 plays a major role in the transcriptional regulation of
      cell wall proteins under the conditions investigated. EFG1 was essential for the
      transcription of both hyphae-specific genes such as HWP1 and HWP2 as well as the
      yeast form-specific gene YWP1. Moreover, we found that, under various conditions,
      EFG1 also can act as a strong repressor for the transcription of RBE1, another
      not yet characterized cell wall protein. Overall, our data show that EFG1 plays a
      major role in the induction and repression of cell wall genes, not only in the
      hyphal form but also in the yeast form of C. albicans.

PMID- 12492857
TI  - Unravelling the biology of macrophage infection by gene expression profiling of
      intracellular Salmonella enterica.
AB  - For intracellular pathogens such as Salmonellae, Mycobacteriae and Brucellae,
      infection requires adaptation to the intracellular environment of the phagocytic
      cell. The transition from extracellular to intravacuolar environment has been
      expected to involve a global modulation of bacterial gene expression, but the
      precise events have been difficult to determine. We now report the complete
      transcriptional profile of intracellular Salmonella enterica sv. Typhimurium
      following macrophage infection. During replication in murine macrophage-like J774
      A.1 cells, 919 of 4451 S. Typhimurium genes showed significant changes in
      transcription. The expression profile identified alterations in numerous
      virulence and SOS response genes and revealed unexpected findings concerning the
      biology of the Salmonella-macrophage interaction. We observed that intracellular
      Salmonella are not starved for amino acids or iron (Fe2+), and that the
      intravacuolar environment is low in phosphate and magnesium but high in
      potassium. S. Typhimurium appears to be using the Entner-Douderoff pathway to use
      gluconate and related sugars as a carbon source within macrophages. Almost half
      the in vivo-regulated genes were of unknown function, suggesting that
      intracellular growth involves novel macrophage-associated functions. This is the
      first report that identifies the whole set of in vivo-regulated genes for any
      bacterial pathogen during infection of mammalian cells.

PMID- 12492858
TI  - Mss11p is a transcription factor regulating pseudohyphal differentiation,
      invasive growth and starch metabolism in Saccharomyces cerevisiae in response to
      nutrient availability.
AB  - In Saccharomyces cerevisiae, the cell surface protein, Muc1p, was shown to be
      critical for invasive growth and pseudohyphal differentiation. The transcription
      of MUC1 and of the co-regulated STA2 glucoamylase gene is controlled by the
      interplay of a multitude of regulators, including Ste12p, Tec1p, Flo8p, Msn1p and
      Mss11p. Genetic analysis suggests that Mss11p plays an essential role in this
      regulatory process and that it functions at the convergence of at least two
      signalling cascades, the filamentous growth MAPK cascade and the cAMP-PKA
      pathway. Despite this central role in the control of filamentous growth and
      starch metabolism, the exact molecular function of Mss11p is unknown. We
      subjected Mss11p to a detailed molecular analysis and report here on its role in
      transcriptional regulation, as well as on the identification of specific domains
      required to confer transcriptional activation in response to nutritional signals.
      We show that Mss11p contains two independent transactivation domains, one of
      which is a highly conserved sequence that is found in several proteins with
      unidentified function in mammalian and invertebrate organisms. We also identify
      conserved amino acids that are required for the activation function.

PMID- 12492859
TI  - The Neisseria meningitidis adhesion regulatory protein CrgA acts through
      oligomerization and interaction with RNA polymerase.
AB  - CrgA is a LysR-type transcriptional regulator involved in the intimate adhesion
      of Neisseria meningitidis to target human epithelial cells. It is negatively
      autoregulated, and its expression is transiently induced upon contact with target
      cells. We analysed the functional organization of CrgA using in frame deleted
      proteins. Four truncated proteins were constructed and purified. They were
      deleted between residues 20 and 40, 121 and 154, 111 and 181 and 268 and 291.
      Meningococcal mutants harbouring the corresponding deleted crgA alleles were also
      constructed. All mutants showed a reduced ability to adhere to epithelial cells.
      beta-Galactosidase activity assays using a crgA-lacZ transcriptional fusion
      showed that all the mutations except the 268-291 deletion resulted in loss of
      induction upon contact with target cells. Gel mobility shift assays and cross
      linking assays showed that the oligomerization of CrgA is required for DNA
      binding and that the N-terminal part of CrgA is directly involved in DNA binding
      through a helix-turn-helix motif. The C-terminal region is also involved in DNA
      binding, probably by permitting the oligomerization of CrgA. The C-terminal
      region also seemed to interact with RNA polymerase. Therefore, the binding of
      CrgA and its interaction with RNA polymerase may inhibit the clearance of
      meningococcal promoters that are repressed by CrgA during the intimate adhesion
      of N. meningitidis to target cells.

PMID- 12492860
TI  - Impact of large chromosomal inversions on the adaptation and evolution of
      Pseudomonas aeruginosa chronically colonizing cystic fibrosis lungs.
AB  - Pseudomonas aeruginosa chronically colonizing the lungs of cystic fibrosis (CF)
      patients undergoes fast evolution leading to clonal divergence. More than half of
      the genotypes of P. aeruginosa clone C isolates exclusively from CF lung
      infection exhibit large chromosomal inversions (LCIs). To analyse the impact of
      LCIs, as a novel mechanism of bacterial adaptation, the underlying molecular
      mechanism was examined. Analysis of inversion breakpoints suggested an IS6100
      induced coupled insertion-inversion mechanism. A selective advantage was created
      by insertion of IS6100 into wbpM, pilB and mutS which leads to common CF
      phenotypes such as O-antigen and type IV pili deficiency and hypermutability.
      Speciation in bacteria is accompanied by LCIs. Therefore adaptation by LCIs that
      allows persistence of P. aeruginosa in the CF lung and species diversification in
      that new ecological niche can serve as a model for bacterial genome evolution.

PMID- 12492861
TI  - A role for division-site-selection protein MinD in regulation of internucleoid
      jumping of Soj (ParA) protein in Bacillus subtilis.
AB  - The Bacillus subtilis soj-spo0J locus encodes two proteins belonging to a family
      of proteins (the ParAB proteins) with dual roles in plasmid or chromosome
      segregation and transcriptional regulation. Soj protein was previously shown to
      be capable of abrupt subcellular relocation. The movement was highly co-operative
      and at any moment, most of the Soj in any cell formed a single large 'patch'
      covering all or part of one nucleoid. Movement, and co-operativity, in the sense
      of formation of a single patch, was dependent on Spo0J. Movement, but not co
      operativity, was also shown to be dependent, directly or indirectly, on FtsZ
      protein. We now report that the ftsZ effect arises because jumping onto a
      nucleoid is promoted by proximity to a cell pole. Studies of other mutants
      affected in cell division suggest that the attraction to the cell pole is
      mediated by the division-site-selection protein, MinD (which localizes at the
      cell poles). It does not require MinC, the main effector of the division site
      selection system. A mutant form of Soj, putatively locked in the ATP form of the
      protein, interacts with the cell pole (dependent on MinD) but not with the
      nucleoid. These results identify a novel function for MinD and demonstrate an
      intriguing link between proteins involved in the cell division and chromosome
      segregation machineries.

PMID- 12492862
TI  - Modulation of phage Mu repressor DNA binding and degradation by distinct
      determinants in its C-terminal domain.
AB  - Rapid degradation of the bacteriophage Mu immunity repressor can be induced in
      trans by mutant, protease-hypersensitive repressors (Vir) with an altered C
      terminal domain (CTD). Genetic and biochemical analysis established that distinct
      yet overlapping determinants in the wild-type repressor CTD modulate Vir-induced
      degradation by Escherichia coli ClpXP protease and DNA binding by the N-terminal
      DNA-binding domain (DBD). Although deletions of the repressor C-terminus resulted
      in both resistance to ClpXP protease and suppression of a temperature-sensitive
      DBD mutation (cts62), some cysteine-replacement mutations in the CTD elicited
      only one of the two phenotypes. Some CTD mutations prevented degradation induced
      by Vir and resulted in the loss of intrinsic ClpXP protease sensitivity,
      characteristic of wild-type repressor, and at least two mutant repressors
      protected Vir from proteolysis. One protease-resistant mutant became susceptible
      to Vir-induced degradation when it also contained the cts62 mutation, which
      weakens DNA binding but apparently facilitates conversion to a protease-sensitive
      conformation. Conversely, this CTD mutation was able to suppress temperature
      sensitivity of DNA binding by the cts62 repressor. The results suggest that
      determinants in the CTD not only provide a cryptic ClpX recognition motif but
      also direct CTD movement that exposes the motif and modulates DNA binding.

PMID- 12492863
TI  - Two different modes of transcription repression of the Escherichia coli acetate
      operon by IclR.
AB  - IclR is a repressor for the Escherichia coli aceBAK operon, which encodes
      isocitrate lyase (aceB), malate synthase (aceA) and isocitrate dehydroge-nase
      kinase/phosphorylase (aceK) in the glyoxylate bypass. IclR also represses the
      expression of iclR in an autogenous manner. DNase I footprinting and in vitro
      transcription assays indicated that IclR binds to an IclR box (-21 to +14), which
      overlaps the iclR promoter and thus competes with the RNA polymerase for DNA
      binding, leading to transcription repression. In the case of the aceBAK operon,
      IclR binds to IclR box II between -52 and -19 of the aceB promoter and interferes
      with binding of the RNA polymerase to this promoter. A secondary IclR binding
      site (IclR box I) was identified between -125 and -99 of the aceB promoter. IclR
      binds to this IclR box I even after formation of the aceB promoter open complex
      and, moreover, induces disassembly of the open complex, leading to repression of
      aceB transcription. In parallel, the location of the C-terminal domain of the RNA
      polymerase alpha subunit (alphaCTD) on DNA is shifted close to the IclR box I,
      indicating that direct interaction between the alphaCTD and the IclR box I
      associated IclR caused the repression.

PMID- 12492864
TI  - Siderophore-mediated cell signalling in Pseudomonas aeruginosa: divergent
      pathways regulate virulence factor production and siderophore receptor synthesis.
AB  - Under iron-limiting conditions, Pseudomonas aeruginosa produces a siderophore
      called pyoverdine. Pyoverdine is secreted into the extracellular environment
      where it chelates iron, and the resulting ferri-pyoverdine complexes are
      transported back into the bacteria by a cell surface receptor protein FpvA.
      Pyoverdine also acts as a signalling molecule inducing the production of three
      secreted virulence factors. Binding of ferri-pyoverdine to FpvA transduces a
      signal to the periplasmic part of the membrane-spanning antisigma factor FpvR.
      The signal is transmitted to the cytoplasmic part of FpvR, which controls the
      activity of an extracytoplasmic family (ECF) sigma factor protein PvdS. This
      results in the production of the virulence factors pyoverdine, exotoxin A and
      PrpL endoprotease. Here, we show that a second divergent branch of this
      signalling pathway regulates the production of the FpvA protein. FpvR negatively
      regulates the activity of a second ECF sigma factor, FpvI, which is required for
      the synthesis of FpvA, and the presence of ferri-pyoverdine greatly increases the
      activity of FpvI so that production of FpvA is induced. To the best of our
      knowledge, this is the first example of a branched signalling system of this sort
      and the first example of an antisigma factor protein (FpvR) that directly
      regulates the activities of two different ECF sigma factor proteins (PvdS and
      FpvI).

PMID- 12492865
TI  - CesT is a bivalent enteropathogenic Escherichia coli chaperone required for
      translocation of both Tir and Map.
AB  - Map is an enteropathogenic Escherichia coli (EPEC) protein that is translocated
      into eukaryotic cells by a type III secretion system. Although not required for
      the induction of attaching and effacing (A/E) lesion formation characteristic of
      EPEC infection, translocated Map is suggested to disrupt mitochondrial membrane
      potential, which may impact upon subsequent functions of the organelle such as
      control of cell death. Before secretion, many effector proteins are maintained in
      the bacterial cytosol by association with a specific chaperone. In EPEC,
      chaperones have been identified for the effector proteins translocated intimin
      receptor (Tir) and EspF, and for the translocator proteins EspB and EspD. In this
      study, we present evidence that the Tir-specific chaperone, CesT, also performs a
      chaperone function for Map. Using a combination of biochemical approaches, we
      demonstrate specific interaction between CesT and Map. Similar to other chaperone
      effector pairings, binding is apparent at the amino-terminus of Map and is
      indicated to proceed by a similar mechanism to CesT:Tir interaction. Map
      secretion from a cesT mutant strain (SE884) is shown to be reduced and,
      importantly, its translocation from this strain after infection of HEp-2 cells is
      almost totally abrogated. Although other chaperones are reported to have a
      bivalent binding specificity, CesT is the first member of its family that
      chaperones more than one protein for translocation.

PMID- 12492866
TI  - Amiodarone induces a caffeine-inhibited, MID1-depedent rise in free cytoplasmic
      calcium in Saccharomyces cerevisiae.
AB  - Calcium signalling is involved in myriad cellular processes such as mating
      morphogenesis. Mating in yeast induces changes in cell morphology with a
      concomitant increase in calcium uptake that is dependent on the MID1 and CCH1
      genes. Mid1p and Cch1p are believed to function in a capacitive calcium entry
      (CCE)-like process. Amiodarone alters mammalian calcium channel activity but,
      despite its clinical importance, its molecular mechanisms are not clearly
      defined. We have shown previously that amiodarone has fungicidal activity against
      a broad array of fungi. We show here that amiodarone causes a dramatic increase
      in cytoplasmic calcium ([Ca2+]cyt) in Saccharomyces cerevisiae. The majority of
      this increase is dependent on extracellular Ca2+ nonetheless, a significant
      increase in [Ca2+]cyt is still induced by amiodarone when no uptake of
      extracellular Ca2+ can occur. The influx of extracellular Ca2+ may be a direct
      effect of amiodarone on a membrane transporter or may be by a CCE mechanism.
      Uptake of the extracellular Ca2+ is inhibited by caffeine and reduced in strains
      deleted for the mid1 gene, but not in cells deleted for cch1. Our data are the
      first demonstrating control of yeast calcium channels by amiodarone and caffeine.

PMID- 12492867
TI  - A novel repressor of nif and glnA expression in the methanogenic archaeon
      Methanococcus maripaludis.
AB  - Nitrogen assimilation in the methanogenic archaeon Methanococcus maripaludis is
      regulated by transcriptional repression involving a palindromic 'nitrogen
      operator' repressor binding sequence. Here we report the isolation of the
      nitrogen repressor, NrpR, from M. maripaludis using DNA affinity purification.
      Deletion of the nrpR gene resulted in loss of nitrogen operator binding activity
      in cell extracts and loss of repression of nif (nitrogen-fixation) and glnA
      (glutamine synthetase) gene expression in vivo. Genetic complementation of the
      nrpR mutation restored all functions. NrpR contained a putative N-terminal winged
      helix-turn-helix motif followed by two mutually homologous domains of unknown
      function. Comparison of the migration of NrpR in gel-filtration chromatography
      with its subunit molecular weight (60 kDa) suggested that NrpR was a tetramer.
      Several lines of evidence suggested that the level of NrpR itself is not
      regulated, and the binding affinity of NrpR to the nitrogen operator is
      controlled by an unknown mechanism. Homologues of NrpR were found only in certain
      species in the kingdom Euryarchaeota. Full length homologues were found in
      Methanocaldococcus jannaschii and Methanothermobacter thermoautotrophicus, and
      homologues lacking one or more of the three polypeptide domains were found in
      Archaeoglobus fulgidus, Methanopyrus kandleri, Methanosarcina acetivorans, and
      Methanosarcina mazei. NrpR represents a new family of regulators unique to the
      Euryarchaeota.

PMID- 12492868
TI  - Penicillin-binding proteins in Streptococcus agalactiae: a novel mechanism for
      evasion of immune clearance.
AB  - Group B streptococci (GBS) remain the most significant bacterial pathogen causing
      neonatal sepsis, pneumonia and meningitis in the USA despite CDC-recommended
      chemoprophylaxis strategies for preventing infection. To cause infection
      pathogens such as GBS must evade recognition and clearance by the host's immune
      system. Strategies for avoidance of opsonization and phagocytic killing include
      elaboration of antiopsonophagocytic capsules and surface proteins. During
      screening for mutants of GBS that were attenuated for virulence in a neonatal rat
      sepsis model, we identified a mutant with a transposon insertion in the ponA
      gene. ponA encodes an extra-cytoplasmic penicillin-binding protein PBP1a, a newly
      identified virulence trait for GBS that promotes resistance to phagocytic killing
      independent of capsular polysaccharide. Complementation analysis in vivo and in
      vitro confirmed that the altered phenotypes observed in the mutant were due to
      the transposon insertion in ponA. Deletion of PBP1a does not affect C3 deposition
      on GBS suggesting that mechanism by which PBP1a protects GBS from phagocytic
      killing is distinct from the antiopsonic activity of capsular polysaccharide.
      This is the first report describing expression of an antiphagocytic surface
      protein by GBS and represents a novel mechanism for evasion of immune recognition
      and clearance that may explain the decreased virulence observed in Gram-positive
      bacterial species for penicillin-binding protein mutants.

PMID- 12492869
TI  - Class V chitin synthase determines pathogenesis in the vascular wilt fungus
      Fusarium oxysporum and mediates resistance to plant defence compounds.
AB  - Chitin, a beta-1,4-linked polysaccharide of N-acetylglucosamine, is a major
      structural component of fungal cell walls. Fungi have multiple classes of chitin
      synthases that catalyse N-acetylglucosamine polymerization. Here, we demonstrate
      the requirement for a class V chitin synthase during host infection by the
      vascular wilt pathogen Fusarium oxysporum. The chsV gene was identified in an
      insertional mutagenesis screen for pathogenicity mutants. ChsV has a putative
      myosin motor and a chitin synthase domain characteristic of class V chitin
      synthases. The chsV insertional mutant and a gene replacement mutant of F.
      oxysporum display morphological abnormalities such as hyphal swellings that are
      indicative of alterations in cell wall structure and can be partially restored by
      osmotic stabilizer. The mutants are unable to infect and colonize tomato plants
      or to grow invasively on tomato fruit tissue. They are also hypersensitive to
      plant antimicrobial defence compounds such as the tomato phytoanticipin alpha
      tomatine or H2O2. Reintroduction of a functional chsV copy into the mutant
      restored the growth phenotype of the wild-type strain. These data suggest that F.
      oxysporum requires a specific class V chitin synthase for pathogenesis, most
      probably to protect itself against plant defence mechanisms.

PMID- 12492870
TI  - The essential role of the invariant GGQ motif in the function and stability in
      vivo of bacterial release factors RF1 and RF2.
AB  - Release factors RF1 and RF2 are required in bacteria for the cleavage of peptidyl
      tRNA. A single sequence motif, GGQ, is conserved in all eubacterial,
      archaebacterial and eukaryotic release factors and may mimic the CCA end of tRNA,
      although the position of the motif in the crystal structures of human eRF1 and
      Escherichia coli RF2 is strikingly different. Mutations have been introduced at
      each of the three conserved positions. Changing the Gln residue to Ala or Glu
      allowed the factors to retain about 22% of tetrapeptide release activity in
      vitro, but these mutants could not complement thermosensitive RF mutants in vivo.
      None of several mutants with altered Gly residues retained activity in vivo or in
      vitro. Many GGQ mutants were poorly expressed and are presumably unstable; many
      were also toxic to the cell. The toxic mutant factors or their degradation
      products may bind to ribosomes inhibiting the action of the normal factor. These
      data are consistent with a common role for the GGQ motif in bacterial and
      eukaryotic release factors, despite strong divergence in primary, secondary and
      tertiary structure, but are difficult to reconcile with the hypothesis that the
      amide nitrogen of the Gln plays a vital role in peptidyl-tRNA hydrolysis.

PMID- 12492873
TI  - Phylogeography and conservation genetics of Eld's deer (Cervus eldi).
AB  - Eld's deer (Cervus eldi) is a highly endangered cervid, distributed historically
      throughout much of South Asia and Indochina. We analysed variation in the
      mitochondrial DNA (mtDNA) control region for representatives of all three Eld's
      deer subspecies to gain a better understanding of the genetic population
      structure and evolutionary history of this species. A phylogeny of mtDNA
      haplotypes indicates that the critically endangered and ecologically divergent C.
      eldi eldi is related more closely to C. e. thamin than to C. e. siamensis, a
      result that is consistent with biogeographic considerations. The results also
      suggest a strong degree of phylogeographic structure both between subspecies and
      among populations within subspecies, suggesting that dispersal of individuals
      between populations has been very limited historically. Haplotype diversity was
      relatively high for two of the three subspecies (thamin and siamensis),
      indicating that recent population declines have not yet substantially eroded
      genetic diversity. In contrast, we found no haplotype variation within C. eldi
      eldi or the Hainan Island population of C. eldi siamensis, two populations which
      are known to have suffered severe population bottlenecks. We also compared levels
      of haplotype and nucleotide diversity in an unmanaged captive population, a
      managed captive population and a relatively healthy wild population. Diversity
      indices were higher in the latter two, suggesting the efficacy of well-designed
      breeding programmes for maintaining genetic diversity in captivity. Based on
      significant genetic differentiation among Eld's deer subspecies, we recommend the
      continued management of this species in three distinct evolutionarily significant
      units (ESUs). Where possible, it may be advisable to translocate individuals
      between isolated populations within a subspecies to maintain levels of genetic
      variation in remaining Eld's deer populations.

PMID- 12492874
TI  - Landscape scale genetic effects of habitat fragmentation on a high gene flow
      species: Speyeria idalia (Nymphalidae).
AB  - Detection of the genetic effects of recent habitat fragmentation in natural
      populations can be a difficult task, especially for high gene flow species.
      Previous analyses of mitochondrial DNA data from across the current range of
      Speyeria idalia indicated that the species exhibited high levels of gene flow
      among populations, with the exception of an isolated population in the eastern
      portion of its range. However, some populations are found on isolated habitat
      patches, which were recently separated from one another by large expanses of
      uninhabitable terrain, in the form of row crop agriculture. The goal of this
      study was to compare levels of genetic differentiation and diversity among
      populations found in relatively continuous habitat to populations in both
      recently and historically isolated habitat. Four microsatellite loci were used to
      genotype over 300 individuals from five populations in continuous habitat, five
      populations in recently fragmented habitat, and one historically isolated
      population. Results from the historically isolated population were concordant
      with previous analyses and suggest significant differentiation. Also,
      microsatellite data were consistent with the genetic effects of habitat
      fragmentation for the recently isolated populations, in the form of increased
      differentiation and decreased genetic diversity when compared to nonfragmented
      populations. These results suggest that given the appropriate control
      populations, microsatellite markers can be used to detect the effects of recent
      habitat fragmentation in natural populations, even at a large geographical scale
      in high gene flow species.

PMID- 12492875
TI  - Migration and genetic structure of the grain aphid (Sitobion avenae) in Britain
      related to climate and clonal fluctuation as revealed using microsatellites.
AB  - Genetic structuring of populations reflects the interaction of genetic drift,
      mutation, migration and selection, with influences from life history. Aphids are
      interesting in this regard as they have the potential for unusually high levels
      of dispersal and natural selection, which typically counter each other. In the
      present study, winged grain aphids Sitobion avenae (F.) were collected in four
      12.2-m high suction traps along a north-south transect in Britain in order to
      eliminate sampling bias from plant hosts (cereals and grasses; Poaceae), it being
      known that these insects show host adaptation demonstrable using molecular
      markers. Samples were analysed at four polymorphic microsatellite loci over two
      consecutive years. Population allele frequencies were similar nationally during
      the two years, although clonal diversity varied greatly between sites and years.
      In the first sampling year following a harsh winter, diversity was found to
      display a latitudinal clinal trend: the proportion of unique clones (genotypes)
      increased with latitude. However, this pattern was less apparent the following
      year, after a milder winter. Nonetheless, overall FST analysis showed that there
      was little spatial genetic structuring in either sampling year. These data
      support the view that the insect is highly migratory and also support a
      theoretical model and previous data suggesting that the reproductive mode is
      clinal in S. avenae. This appears to be because natural selection (reduced
      reproductive success of asexual genotypes under cold conditions) is sufficiently
      powerful to overcome the homogenizing effects of strong migration. There was no
      clear evidence for isolation by distance for the genetic data obtained. The data
      are compared with similar data from other aphid species and other insects. Only
      by the collection of such data sets can an accurate picture be built up relating
      genetic variability to flight behaviour, including migratory ambit in this group
      of insects since, due to their small size and rapid dilution in the air, other
      marking approaches are impracticable over large geographical distances.

PMID- 12492876
TI  - Demographic and genetic estimates of effective population size (Ne) reveals
      genetic compensation in steelhead trout.
AB  - Estimates of effective population size (Ne) are required to predict the impacts
      of genetic drift and inbreeding on the evolutionary dynamics of populations. How
      the ratio of Ne to the number of sexually mature adults (N) varies in natural
      vertebrate populations has not been addressed. We examined the sensitivity of
      Ne/N to fluctuations of N and determined the major variables responsible for
      changing the ratio over a period of 17 years in a population of steelhead trout
      (Oncorhynchus mykiss) from Washington State. Demographic and genetic methods were
      used to estimate Ne. Genetic estimates of Ne were gained via temporal and linkage
      disequilibrium methods using data from eight microsatellite loci. DNA for genetic
      analysis was amplified from archived smolt scales. The Ne/N from 1977 to 1994,
      estimated using the temporal method, was 0.73 and the comprehensive demographic
      estimate of Ne/N over the same time period was 0.53. Demographic estimates of Ne
      indicated that variance in reproductive success had the most substantial impact
      on reducing Ne in this population, followed by fluctuations in population size.
      We found increased Ne/N ratios at low N, which we identified as genetic
      compensation. Combining the information from the demographic and genetic methods
      of estimating Ne allowed us to determine that a reduction in variance in
      reproductive success must be responsible for this compensation effect.
      Understanding genetic compensation in natural populations will be valuable for
      predicting the effects of changes in N (i.e. periods of high population density
      and bottlenecks) on the fitness and genetic variation of natural populations.

PMID- 12492877
TI  - Conservation genetics of the fisher (Martes pennanti) based on mitochondrial DNA
      sequencing.
AB  - Translocation of animals to re-establish extirpated populations or to maintain
      declining ones has often been carried out without genetic information on source
      or target populations, or adequate consideration of the potential effects of
      mixing genetic stocks. We consider the conservation status of the fisher (Martes
      pennanti) and evaluate the potential genetic consequences of past and future
      translocations on this medium-sized carnivore by examining population variation
      in mitochondrial control-region sequences. We sampled populations throughout the
      fisher's range in North America including five populations unaffected by
      translocations and two western populations that had received long-distance
      translocations. Twelve haplotypes showed little sequence divergence. Haplotype
      frequencies differed significantly among subspecies and between populations
      within subspecies. Analysis of molecular variance (amova) and neighbour-joining
      analyses of haplotype relationships revealed population subdivision similar to
      current subspecies designations, but which may reflect an isolation-by-distance
      pattern. Populations in Oregon and in Montana and Idaho received several
      translocations and each showed greater similarity to the populations where
      translocations originated than to adjacent populations. Additional sequences
      obtained from museum specimens collected prior to any translocations suggest
      historical gene flow among populations in British Columbia, Washington, Oregon,
      and California. Anthropogenic impacts in that region have greatly reduced and
      isolated extant populations in Oregon and California. Future translocations may
      be necessary to recover populations in Washington and portions of Oregon and
      California; our results indicate that British Columbia would be the most
      appropriate source population.

PMID- 12492878
TI  - Natural selection and the genetic differentiation of coastal and Arctic
      populations of the Atlantic cod in northern Norway: a test involving nucleotide
      sequence variation at the pantophysin (PanI) locus.
AB  - To examine the role of contemporary selection in maintaining significant allele
      frequency differences at the pantophysin (PanI) locus among populations of the
      Atlantic cod, Gadus morhua, in northern Norway, we sequenced 127 PanIA alleles
      sampled from six coastal and two Barents Sea populations. The distributions of
      variable sites segregating within the PanIA allelic class were then compared
      among the populations. Significant differences were detected in the overall
      frequencies of PanIA alleles among populations within coastal and Arctic regions
      that was similar in magnitude to heterogeneity in the distributions of
      polymorphic sites segregating within the PanIA allelic class. The differentiation
      observed at silent sites in the PanIA allelic class contradicts the predicted
      effects of widescale gene flow and suggests that postsettlement selection acting
      on cohorts cannot be responsible for the genetic differences described between
      coastal and Arctic populations. Our results suggest that the marked differences
      observed between coastal and Arctic populations of G. morhua in northern Norway
      at the PanI locus reflect the action of recent diversifying selection and that
      populations throughout the region may be more independent than suggested by
      previous studies.

PMID- 12492879
TI  - Phylogeny, taxonomy, genetics and global heritage ranks of an imperilled,
      freshwater snail genus Lithasia (Pleuroceridae).
AB  - Numerous aquatic species are threatened with extinction from habitat elimination
      or modification. One particularly imperilled group is the freshwater gastropod
      family Pleuroceridae. Pleurocerids reach their greatest diversity in the
      southeastern United States, and many species are currently considered extinct,
      endangered or threatened. One issue hindering efforts to implement conservation
      management plans for imperilled pleurocerid species is that the taxonomy is in an
      abysmal state. The taxonomy of pleurocerids is currently based on late 19th- and
      early 20th-century studies, which used a typological or morphospecies concept.
      Most biologists today doubt the validity of many of the currently recognized
      species; however, this does not stop them from assigning conservation ranks in an
      attempt to determine which species are imperilled or currently stable. We
      conducted a phylogenetic analysis of the pleurocerid genus Lithasia using
      morphological and mitochondrial DNA sequence (mtDNA) data in an attempt to
      delimit species boundaries and test previous taxonomic schemes. We found that the
      current taxonomy of Lithasia does not reflect species diversity adequately within
      the genus, with two new undescribed species being discovered. The conservation
      status ranks of the new, undescribed species are imperilled and would have been
      overlooked had we relied on the conventional taxonomy. Additionally, the
      undescribed species' conservation ranks that were previously apparently secure
      became vulnerable due to being inappropriately assigned as members of formerly
      widely distributed species instead of the imperilled status they warrant and vice
      versa, as some taxa that were considered imperilled are now thought to be
      modestly stable. Our study suggests that conservation ranks should be considered
      suspect at best in taxonomically poorly known groups until the taxa are reviewed
      using modern systematic methods.

PMID- 12492880
TI  - American marten (Martes americana) in the Pacific Northwest: population
      differentiation across a landscape fragmented in time and space.
AB  - American marten (Martes americana) have a close association with mature temperate
      forests, a habitat that expanded throughout the Pacific Northwest as glaciers
      receded at the end of the Pleistocene. Similar to several other forest-associated
      mammals in North America (e.g. black bear), genetic analysis of the marten shows
      a deep phylogeographical subdivision that reflects populations with distinctive
      evolutionary histories. Using a suite of 14 microsatellite markers, we explored
      the genetic structure of marten populations in two reciprocally monophyletic
      clades in the Pacific Northwest identified previously as M. caurina and M.
      americana by mitochondrial haplotypes and morphology. Microsatellite
      phylogeographical patterns were congruent with mitochondrial analyses. These
      independent data sets shed light upon hybridization patterns, population
      structure and evolutionary histories. Hybridization between M. caurina and M.
      americana individuals was documented in two regions of sympatry (Kuiu Island in
      southeastern Alaska and southern Montana). Northern insular populations of M.
      caurina exhibited higher differentiation and lower variability relative to
      northern populations of M. americana. Greater divergence among M. caurina
      populations may reflect longer isolation and persistence in coastal forest
      habitat that was fragmented by rising sea level in the early Holocene. Lower
      differentiation among northern M. americana populations and close relationship to
      other continental M. americana populations may reflect more recent expansion into
      the Pacific Northwest and/or continued gene flow among populations.
      Differentiation among M. caurina populations was attributed to habitat
      fragmentation (i.e. rising sea level), as opposed to isolation-by-distance;
      oceanic straits pose significant barriers to gene flow among M. caurina
      populations and between populations of M. caurina and M. americana.

PMID- 12492881
TI  - Evidences for multiple maternal lineages of Caryocar brasiliense populations in
      the Brazilian Cerrado based on the analysis of chloroplast DNA sequences and
      microsatellite haplotype variation.
AB  - In this work we report on the phylogeography of the endangered tree species
      Caryocar brasiliense based on variability in two classes of maternally inherited
      chloroplast DNA sequences with different rates of molecular evolution. Eleven
      sequence haplotypes of a noncoding region between the genes trnT and trnF and 21
      distinct 10-locus microsatellite haplotypes could be identified in a total of 160
      individuals, collected in 10 widespread populations of C. brasiliense. An amova
      indicated that most of the variation can be attributed to differences among
      populations, both for DNA sequence (87.51%) and microsatellites (84.38%).
      Phylogeography based on a median-joining network analysis of the noncoding region
      showed a sharp difference from the analysis of microsatellite haplotypes.
      Nevertheless, both analyses indicated that multiple lineages may have contributed
      to the origin of C. brasiliense populations in Brazilian Cerrado. Incongruences
      in the microsatellite haplotypes network suggest that homoplasy, which emerged
      from recurrent and independent mutations, greatly influenced the evolution of the
      C. brasiliense chloroplast genome. We hypothesize that our results may show the
      outcome of the restriction of ancient relic populations to moist refugias during
      extended droughts coinciding with glaciation in the northern hemisphere. The
      subsequent spread to favourable areas throughout Central Brazil may have caused
      contact between different lineages during the interglacial periods. The
      extinction of megafauna dispersers in the last glaciation may have caused a
      restriction in seed movement and currently, gene flow has been occurring mainly
      by pollen movement.

PMID- 12492882
TI  - Phylogeny, paraphyly and ecological adaptation of the colour and pattern in the
      Anolis roquet complex on Martinique.
AB  - Martinique is an environmentally heterogeneous island with a complex geological
      history. It is occupied by a solitary anole, Anolis roquet, showing marked
      geographical variation in colour and other features. Phylogenetic analysis of a
      segment (1 kb) of the mitochondrial cytochrome b gene across the Anolis roquet
      series in the southern Lesser Antilles and at 63 localities of Anolis roquet in
      Martinique indicate that A. roquet is paraphyletic as A. extremus (Barbados) is
      nested within the Martinique populations. Moreover, divergent phylogenetic
      lineages exist within Martinique (max. 10.6% uncorrected pairwise), and these
      lineages are closely associated with the geological history of this complex
      island. However, objective quantification of the spectroradiometric analysis of
      hue by delta analysis, together with analysis of the colour pattern, indicate
      that they are primarily determined by adaptation to environmental conditions,
      irrespective of these phylogenetic lineages. There is remarkable convergence in
      hue and pattern in both extreme xeric (dark chevrons on a dull, generally
      grey/brown, background), and montane conditions (black reticulation and non-UV
      white spots on a bright, saturated green background). Moreover, parallel trends
      occur between Martinique and other Lesser Antillean anoles, which further argues
      for adaptation (increase in green saturation in montane areas and higher levels
      of UV on the dewlap of some Atlantic forms). As an exception, there are two
      specific situations where anoles from different lineages look different. These
      are (i). in the low-altitude regions of the northwest where the northwestern and
      central lineages make contact, and (ii). in the far south of the island where the
      southern and central lineages meet.

PMID- 12492883
TI  - Phylogeography of the invasive cyanobacterium Cylindrospermopsis raciborskii.
AB  - Cylindrospermopsis raciborskii is a planktonic freshwater cyanobacterium that has
      become increasingly prevalent in tropical and temperate water bodies world-wide.
      This species is of concern from a water-quality perspective because of its known
      ability to produce toxins that can affect the health of humans and other animals.
      This study investigates genetic variation between strains of C. raciborskii
      isolated from freshwater rivers and reservoirs in Australia, Brazil, Germany,
      Hungary, Portugal and the USA. Strains were first characterized by analysis of
      their 16S rRNA gene nucleotide sequences and were found to have a sequence
      divergence of 99.1%. A phylogenetic tree, constructed using the 16S rRNA gene
      sequences showed that strains grouped into Australian, European and North/South
      American phylotypes. To investigate further the observed separation of strains
      into geographically distinct groups, we applied a cyanobacterium-specific short
      tandem repeat sequence technique, HIP1. An electrophoretic comparison of the HIP1
      polymerase chain reaction products showed clear distinctions between the C.
      raciborskii strains. A phylogenetic tree, based on the repeat element banding
      patterns, also revealed three distinct groups of C. raciborskii strains. The
      first group consisted of strains from the USA and Brazil; the second comprised
      European strains from Germany, Hungary and Portugal; and the third were strains
      from Australia. In general, between-country variation was greater than within
      country variation, indicating that this fingerprinting technique can successfully
      distinguish C. raciborskii strains taken from different global locations. The
      relationship between toxicity and the observed HIP1 polymerase chain reaction
      fingerprint profiles was less clear, although it is interesting to note that of
      the strains analysed in this study, only Australian strains are known to produce
      cylindrospermopsin and only Brazilian strains have been reported to produce
      paralytic shellfish poisoning toxins.

PMID- 12492884
TI  - Phylogeny and ecological radiation of New World thistles (Cirsium, Cardueae -
      Compositae) based on ITS and ETS rDNA sequence data.
AB  - Sequence data from a portion of the external transcribed spacer (ETS) and
      internal transcribed spacers (ITS-1 and ITS-2) of 18S-26S nuclear ribosomal DNA
      were used to resolve historical biogeography and ecology of true thistles
      (Cirsium, Cardueae, Compositae) in the New World. The 650 base-pair, 3' portion
      of the ETS examined here showed a level of variation across taxa similar to that
      of the ITS sequences included. A maximum-likelihood tree based on combined ETS
      and ITS sequences leads us to suggest that the New World species of true thistles
      constitute a major lineage, which in turn comprises several smaller lineages. A
      western North American lineage shows weak quartet-puzzling support, but includes
      a well-supported lineage of species endemic to the California Floristic Province.
      Comparisons of this Californian lineage with other neoendemic angiosperm groups
      of the region show that the Californian Cirsium lineage exhibits unusually high
      ecological diversity for a group displaying such low levels of rDNA sequence
      divergence across taxa. Similarly low levels of sequence divergence were found
      throughout the New World Cirsium lineage. These results indicate either that
      Cirsium underwent a rapid ecological radiation in North America, or that rDNA
      evolution in North American Cirsium has been highly conservative.

PMID- 12492885
TI  - Mitochondrial DNA phylogeography and population history of Meladema diving
      beetles on the Atlantic Islands and in the Mediterranean basin (Coleoptera,
      Dytiscidae).
AB  - The phylogeny and population history of Meladema diving beetles (Coleoptera,
      Dytiscidae) were examined using mitochondrial DNA sequence from 16S ribosomal RNA
      and cytochrome oxidase I genes in 51 individuals from 22 populations of the three
      extant species (M. imbricata endemic to the western Canary Islands, M. lanio
      endemic to Madeira and M. coriacea widespread in the Western Mediterranean and on
      the western Canaries), using a combination of phylogenetic and nested clade
      analyses. Four main lineages are observed within Meladema, representing the three
      recognized species plus Corsican populations of M. coriacea. Phylogenetic
      analyses demonstrate the sister relationship of the two Atlantic Island taxa, and
      suggest the possible paraphyly of M. coriacea. A molecular clock approach reveals
      that speciation within the genus occurred in the Early Pleistocene, indicating
      that the Atlantic Island endemics are not Tertiary relict taxa as had been
      proposed previously. Our results point to past population bottlenecks in all four
      lineages, with recent (Late-Middle Pleistocene) range expansion in non-Corsican
      M. coriacea and M. imbricata. Within the Canary Islands, M. imbricata seems to
      have independently colonized La Gomera and La Palma from Tenerife (although a
      colonization of La Palma from La Gomera cannot be discarded), and M. coriacea has
      independently colonized Tenerife and Gran Canaria from separate mainland
      lineages. In the Mediterranean basin this species apparently colonized Corsica on
      a single occasion, relatively early in its evolutionary history (Early
      Pleistocene), and has colonized Mallorca recently on multiple occasions. On the
      only island where M. coriacea and M. imbricata are broadly sympatric (Tenerife),
      we report evidence of bidirectional hybridization between the two species.

PMID- 12492886
TI  - Dispersal barriers and isolation among deep-sea mussel populations (Mytilidae:
      Bathymodiolus) from eastern Pacific hydrothermal vents.
AB  - Deep-sea hydrothermal vent species are widely dispersed among habitat islands
      found along the global mid-ocean ridge system. We examine factors that affect
      population structure, gene flow and isolation in vent-endemic mussels of the
      genus Bathymodiolus from the eastern Pacific Ocean. Mussels were sampled from
      localities including the Galapagos Rift (GAR, 0 degrees 48' N; 86 degrees 10' W)
      and the East Pacific Rise (EPR, 13 degrees N to 32 degrees S latitude) across a
      maximum distance of 4900 km. The sampled range crossed a series of topographical
      features that interrupt linear aspects of the ridge system, and it encompassed
      regions of strong cross-axis currents that could impede along-axis dispersal of
      mussel larvae. Examinations of mitochondrial DNA sequences and allozyme variation
      revealed significant barriers to gene flow along the ridge axis. All populations
      from the GAR and EPR from 13 degrees N to 11 degrees S were homogeneous
      genetically and appeared to experience unimpeded high levels of interpopulational
      gene flow. In contrast, mussels from north and south of the Easter Microplate
      were highly divergent (4.4%), possibly comprising sister-species that diverged
      after formation of the microplate approximately 4.5 Ma. Strong cross-axis
      currents associated with inflated bathymetry of the microplate region may
      reinforce isolation across this region.

PMID- 12492887
TI  - Palaeoclimatic changes explain Anatolian mountain frog evolution: a test for
      alternating vicariance and dispersal events.
AB  - Holarctic biodiversity has been influenced by climatic fluctuations since the
      Pliocene. Asia Minor was one of the major corridors for postglacial invasions in
      the Palearctic. Today this area is characterized by an extraordinarily rich fauna
      with close affiliation to European, Asian and Indo-African biota. However, exact
      scenarios of range expansion and contraction are lacking. Using a
      phylogeographical approach we (i). identify monophyletic lineages among Anatolian
      mountain frogs and (ii). derive a spatio-temporal hypothesis for the invasion
      process in Anatolia. We sequenced 540 bp of the mitochondrial 16S rRNA gene from
      40 populations of mountain frogs from Anatolia, the Elburz Mountains and the
      Caucasus. Our samples comprise all known species and subspecies: Rana macrocnemis
      macrocnemis, R. m. tavasensis, R. m. pseudodalmatina, R. camerani and R. holtzi.
      They include the type localities of four of these taxa. We used a nested clade
      analysis (NCA) to infer historical and recurrent events that account for the
      observed geographical distribution of haplotypes. None of the extant species is
      monophyletic. Based on a molecular clock calibration using homologous sequences
      of Western Palearctic water frogs of the same genus, we estimated that a basic
      radiation into three lineages c. 2 Mya was followed by several dispersal and
      fragmentation events. The geographical distribution of resident and widespread
      haplotypes allows us to infer and date scenarios of range expansion and
      fragmentation that are aligned with dramatic climatic oscillations that have
      occurred during the last 600000 years. Consequently, Pliocene and Pleistocene
      climatic oscillations triggered the evolution of Anatolian mountain frogs through
      an interplay of vicariance and dispersal events.

PMID- 12492888
TI  - Postglacial recolonization and cpDNA variation of silver birch, Betula pendula.
AB  - Chloroplast PCR-RFLP markers were used to reconstruct the history of the silver
      birch, Betula pendula Roth, in Europe since the last glacial maximum (LGM). In
      birch, fossil pollen maps do not reveal a clear chronological sequence of
      postglacial spread. If anything, the pollen record suggests that most of Europe
      was recolonized by birches as early as 10000 bp, probably from populations that
      remained close to the ice sheets during the LGM. The geographical distribution of
      haplotypes supports a scenario of early colonization. Two of the 13 haplotypes
      that were observed are common, representing 35% and 49% of the total sample,
      respectively. Although one of the common haplotypes is predominant in the NW and
      the other in the SE, both are present throughout most of the investigated
      geographical area. Rare haplotypes are geographically restricted. The
      distribution of the haplotypes reveals five genetic boundaries between groups of
      haplotypes and allows us to infer patterns of postglacial recolonization. Europe
      was re-occupied by two main waves of recolonization: one eastern and one western,
      with origins at intermediate latitudes. Populations in the Iberian Peninsula and
      in Italy did not take part in the postglacial recolonization of Europe.

PMID- 12492889
TI  - Condition-dependent sex allocation in a lek-breeding wader, the ruff (Philomachus
      pugnax).
AB  - Sex allocation theory predicts that females should bias the production of
      offspring towards the sex that will maximize maternal fitness. Here we
      demonstrate evidence for nonrandom sex allocation by female ruffs (Philomachus
      pugnax), at both the individual and population level in relation to female
      condition. At the population level, female condition varies significantly across
      3 years and is mirrored by population sex ratio, such that in years when females
      are in poor condition the population offspring sex ratio is female-biased, while
      in years when females are in better condition there was little or no bias. In the
      year when females were in overall poor condition, females in better condition
      produced more daughters. The same relationship is also revealed by comparing the
      sex ratios of individual females breeding in two consecutive years in different
      condition. As the condition of an individual female improves (across years) she
      tends to produce more female offspring. Although we have shown that, as in other
      birds, female condition is an important determinant of sex allocation, our
      results also suggest that such nonrandom allocation does not occur in every year,
      being particularly strong in a year when females, on average, are in poorer
      condition. We suggest that our results are consistent with the idea that skewing
      the sex ratio is likely to carry a cost to females and that it is adaptive only
      when the fitness differential between sons and daughters is sufficient to
      outweigh probable costs.

PMID- 12492890
TI  - Genetic mating system and the significance of harem associations in the bat
      Saccopteryx bilineata.
AB  - We analysed the polygynous mating system of the bat Saccopteryx bilineata using
      behaviour observations and genetic data on 11 microsatellite DNA loci. Basic
      social units in S. bilineata are harem groups that consist of single males and up
      to eight females. Colonies comprise several harem groups, and the composition of
      colonies and harems is often stable over several reproductive seasons. The
      combination of parentage exclusion and likelihood-based parentage assignment in
      this study produced detailed parentage information for a large colony of S.
      bilineata. Reproduction occurred mostly within the colony (17% extra-colony
      paternity), but social associations in harems within the colony did not represent
      reproductive units (70% extra-harem paternity). The latter finding was consistent
      over three reproductive seasons. Spatial association of the roosting sites of
      males and females could not explain parentage patterns in the colony. Even though
      intra-harem paternity was less frequent than expected, it contributed
      significantly to reproduction of harem males. On average, the number of offspring
      sired by a male with females in his harem territory increased significantly with
      harem size, which corresponds to the higher energetic investment that is related
      to the maintenance of large harems. However, extra-harem paternity was not
      correlated with a male's harem size or intra-harem reproductive success. This
      suggests that individual preferences of females rather than male traits
      associated with the ability to defend large harems are most likely to cause the
      detected differences between social association and genetic mating system.

PMID- 12492891
TI  - A molecular genetic analysis of the communal nesting of the ostrich (Struthio
      camelus).
AB  - The ostrich breeding system is complex and unique; communal clutches are laid by
      several females, although only one female, the major female, and the resident
      territorial male provide parental care. More eggs are laid in the nest than can
      be incubated and the major female ejects surplus eggs from the incubated central
      clutch. Microsatellite markers were used to analyse the parentage of communal
      nests in Nairobi National Park. This revealed that major females contributed a
      disproportionate number of fertile eggs to the central, incubated clutch and that
      multiple paternity and maternity within a nest were common; 68.9% of all
      incubated eggs on a nest were not parented by both the resident territorial male
      and the major female of that nest. All the males fertilized eggs on the clutches
      of neighbouring males. Unexpectedly, every major female with her own nest was
      also simultaneously a minor female with incubated eggs on neighbouring clutches.
      The relatedness between females laying in the same nest was not significantly
      different from the population average and significantly less than that between
      chicks hatched from the same nest.

PMID- 12492892
TI  - Associations between mycophagous Drosophila and their Howardula nematode
      parasites: a worldwide phylogenetic shuffle.
AB  - Little is known about what determines patterns of host association of
      horizontally transmitted parasites over evolutionary timescales. We examine the
      evolution of associations between mushroom-feeding Drosophila flies (Diptera:
      Drosophilidae), particularly in the quinaria and testacea species groups, and
      their horizontally transmitted Howardula nematode parasites (Tylenchida:
      Allantonematidae). Howardula species were identified by molecular
      characterization of nematodes collected from wild-caught flies. In addition, DNA
      sequence data is used to infer the phylogenetic relationships of both host
      Drosophila (mtDNA: COI, II, III) and their Howardula parasites (rDNA: 18S, ITS1;
      mtDNA: COI). Host and parasite phylogenies are not congruent, with patterns of
      host association resulting from frequent and sometimes rapid host colonizations.
      Drosophila-parasitic Howardula are not monophyletic, and host switches have
      occurred between Drosophila and distantly related mycophagous sphaerocerid flies.
      There is evidence for some phylogenetic association between parasites and hosts,
      with some nematode clades associated with certain host lineages. Overall, these
      host associations are highly dynamic, and appear to be driven by a combination of
      repeated opportunities for host colonization due to shared breeding sites and
      large potential host ranges of the nematodes.

PMID- 12492893
TI  - Bacterial diversity in maize rhizospheres: conclusions on the use of genetic
      profiles based on PCR-amplified partial small subunit rRNA genes in ecological
      studies.
AB  - A cultivation-independent approach based on polymerase chain reaction (PCR)
      amplified partial small subunit rRNA genes and genetic profiling by single-strand
      conformation polymorphism (SSCP) was used to characterize the bacterial diversity
      inhabiting the rhizosphere of maize plants grown on an agricultural field. The
      community structures of two cultivars, a genetically engineered and a
      nonengineered variety, different herbicide regimes and soil tillage were compared
      with each other at two sampling dates. SSCP-profiles were generated with DNA from
      bacterial cell consortia with primers hybridizing to evolutionarily highly
      conserved rRNA gene regions. On silver-stained gels, each profile consisted of
      approx. 50 distinguishable bands. Similarity analyses of patterns recorded by
      digital image analyses could not detect any difference between cultivars or
      treatments that was greater than the variability between replicates. A total of
      54 sequences recovered from different bands were identified and grouped into
      operational taxonomical units (OTUs). Surprisingly, only five of 40 OTUs
      contained sequences of both samplings. Three different bands from a profile were
      selected to test whether this small overlap was due to an incomplete recovery of
      sequences. From a faint band, two different OTUs were found when 12 clones were
      analysed, and from two strong bands 24 and 22 OTUs were detected from a total of
      26 and 36 clones, respectively. The OTUs belonged to phylogenetically different
      groups of bacteria. Gene probes that were developed to target different bands of
      the profiles, however, indicated in Southern blot analyses that patterns between
      treatments, replicates and samplings, and even from two different growing seasons
      were highly conserved. Our study demonstrates that community profiles can consist
      of more sequences than detectable by staining and that gene probes in Southern
      blot can be a useful control to investigate the composition of microbial
      communities by genetic profiles.

PMID- 12492894
TI  - Polymorphism of a complex resistance gene candidate family in wild populations of
      common bean (Phaseolus vulgaris) in Argentina: comparison with phenotypic
      resistance polymorphism.
AB  - Fifteen populations of wild bean (Phaseolus vulgaris), located in three provinces
      in Argentina, were analysed for their polymorphism for a complex resistance gene
      candidate (RGC) family clustered on the genome and for resistance phenotypes to
      strains of Colletotrichum lindemuthianum. Results indicate that RGC polymorphism
      is high. Population structure obtained for markers related to resistance was
      compared to population structure obtained for RAPD markers in order to infer the
      evolutionary forces driving polymorphism for resistance in wild populations at
      both molecular and phenotypic levels. Hierarchical analysis of differentiation
      showed that, within provinces, populations were differentiated for RAPD as well
      as for molecular and phenotypic markers of resistance. In contrast, provinces
      were differentiated only for RAPD and RGC markers and not for resistance
      phenotypes. The discrepancies found between diversity structures for molecular
      markers (RAPD and RGCs) and for resistance phenotypes suggest an effect of
      selection and indicate that diversity for resistance may not be driven by the
      same selective forces at the molecular and phenotypic levels. We further discuss
      whether specific selective forces are exerted on RGC markers and underline the
      importance of spatial scale of analysis for demonstrating an impact of selection.

PMID- 12492895
TI  - Similar estimates of population genetic composition and sex ratio derived from
      carcasses and faeces of Eurasian otter Lutra lutra.
AB  - Collecting faeces is viewed as a potentially efficient way to sample elusive
      animals. Nonetheless, any biases in estimates of population composition
      associated with such sampling remain uncharacterized. The goal of this study was
      to compare estimates of genetic composition and sex ratio derived from Eurasian
      otter Lutra lutra spraints (faeces) with estimates derived from carcasses. Twenty
      per cent of 426 wild-collected spraints from SW England yielded composite
      genotypes for 7-9 microsatellites and the SRY gene. The expected number of
      incorrect spraint genotypes was negligible, given the proportions of allele
      dropout and false allele detection estimated using paired blood and spraint
      samples of three captive otters. Fifty-two different spraint genotypes were
      detected and compared with genotypes of 70 otter carcasses from the same area.
      Carcass and spraint genotypes did not differ significantly in mean number of
      alleles, mean unbiased heterozygosity or sex ratio, although statistical power to
      detect all but large differences in sex ratio was low. The genetic compositions
      of carcass and spraint genotypes were very similar according to confidence
      intervals of theta and two methods for assigning composite genotypes to groups. A
      distinct group of approximately 11 carcass and spraint genotypes was detected
      using the latter methods. The results suggest that spraints can yield unbiased
      estimates of population genetic composition and sex ratio.

PMID- 12492896
TI  - Y chromosome conserved anchored tagged sequences (YCATS) for the analysis of
      mammalian male-specific DNA.
AB  - Y chromosome haplotyping based on microsatellites or single nucleotide
      polymorphisms has recently proven to be a powerful approach for evolutionary
      studies of human populations, and also holds great promise for the studies of
      wild species. However, the use of the approach is hampered in most natural
      populations by the lack of Y chromosome markers and sequence information. Here,
      we report the large-scale development of Y chromosome conserved anchor tagged
      sequence (YCATS) markers in mammals by a polymerase chain reaction screening
      approach. Exonic primers flanking 48 different introns of Y-linked genes were
      developed based on human and mouse sequences, and screened on a set of 20
      different mammals. On average about 10 introns were amplified for each species
      and a total of 100 kb of Y chromosome sequence were obtained. Intron size in
      humans was a reasonable predictor of intron size in other mammals (r2 = 0.45) and
      there was a negative correlation between human fragment size and amplification
      success. We discuss a number of factors affecting the possibility of developing
      conserved Y chromosome markers, including fast evolution of Y chromosome
      sequences due to male-biased mutation and adaptive evolution of male-specific
      genes, dynamic evolution of the Y chromosome due to being a nonrecombining unit,
      and homology with X chromosome sequences.

PMID- 12492897
TI  - Mitochondrial haplotype distribution, seed dispersal and patterns of postglacial
      expansion of ponderosa pine.
AB  - Maternally inherited mtDNA in a secondary contact zone of ponderosa pine revealed
      a cline less than 10 km wide - much narrower than previously described. A survey
      of 76 populations gave no evidence either of intermixing or of a mosaic contact
      zone. Such sharp contact zones are consistent with diffusive range expansion,
      rather than long distance colonization. However, evidence for long distance seed
      dispersal events was found in two populations where haplotypes were observed far
      from their main area of occurrence. The results suggest a small number of long
      distance colonists with diffusive dispersal from these centres.

PMID- 12492898
TI  - Peptides corresponding to the N- and C-terminal parts of PEBP are well-structured
      in solution: new insights into their possible interaction with partners in vivo.
AB  - Recently, it has been shown that mammalian PEBPs are implicated in several
      signalling pathways controlling the cellular cycle. In particular, during brain
      development, the N-terminal part of mammalian PEBP is specifically cleaved and
      the resulting 11 amino acid peptide stimulates the growth and activity of
      acetylcholinergic neurons. The crystallographic structure of bovine and human
      PEBPs has revealed that their N- and C-terminal parts are accessible and exposed
      to the solvent suggesting that they may be involved in specific interactions with
      cellular partners. We have chemically synthetized the two peptides corresponding
      to these terminal parts and studied their structure in solution by circular
      dichroism and NMR spectroscopies: both of them are well-structured. The N
      terminal peptide is composed of a series of turns, leading to a hook
      conformation. The C-terminal peptide displays a globally helical conformation
      similar to that observed in the whole protein; it is characterized by an
      amphipatic feature with a hydrophobic cluster located on one side. These
      structural features enlighten previous fluorescence and monolayer experiments and
      give new insights on the roles of both PEBP termini.

PMID- 12492899
TI  - Synthesis and evaluation of potential affinity labels derived from endomorphin-2.
AB  - In an attempt to identify potential peptide-based affinity labels for opioid
      receptors, endomorphin-2 (Tyr-Pro-Phe-PheNH2), a potent and selective endogenous
      ligand for mu-opioid receptors, was chosen as the parent peptide for
      modification. The tetrapeptide analogs were prepared using standard Fmoc-solid
      phase peptide synthesis in conjunction with incorporation of Fmoc-Phe(p-NHAlloc)
      and modification of the p-amino group. The electrophilic groups isothiocyanate
      and bromoacetamide were introduced into the para position on either Phe3 or Phe4;
      the corresponding free amine-containing peptides were also prepared for
      comparison. The peptides bearing an affinity label group and their free amine
      analogs were evaluated in a radioligand-binding assay using Chinese hamster ovary
      (CHO) cells expressing mu- and delta-opioid receptors. Modification on Phe4 was
      better tolerated than on Phe3 for mu-receptor binding. Among the analogs tested,
      [Phe(p-NH2)4]endomorphin-2 showed the highest affinity (IC50 = 37 nm) for mu
      receptors. The Phe(p-NHCOCH2Br)4 analog displayed the highest mu-receptor
      affinity (IC50 = 158 nm) among the peptides containing an affinity label group.
      Most of the compounds exhibited negligible binding affinity for delta-receptors,
      similar to the parent peptide.

PMID- 12492900
TI  - Studies on the aggregation and possible channel formation in membranes of a
      cyclic hexapeptide, cyclo (D-Ala-L-Pro-L-Ala)2.
AB  - The interaction of zwitterionic lipid DMPC and DPPC with cyclic hexapeptide,
      cyclo (D-Ala-L-Pro-L-Ala)2 was studied using circular dichroism (CD) and
      differential scanning calorimetry (DSC). Preliminary membrane conductance results
      showed that the peptide has a tendency to form channels inside the lipid bilayer.
      CD studies indicated that as the lipid/peptide (L/P) ratio (DMPC/peptide) was
      increased, the magnitude of the negative CD band having a lambda(max) around 200
      nm decreased. At a L/P ratio of 210:1, this band disappeared completely,
      indicating dramatic conformational changes in the peptide on interaction with the
      lipid bilayer. Reduction of the phase transition temperature and the maximum heat
      capacity of the lipid bilayer (DPPC) for gel-to-liquid crystalline phase
      transition indicates a strong interaction of the peptide with the lipid bilayer.

PMID- 12492901
TI  - pH dependence of the relative hydrophobicity and lipophilicity of amino acids and
      peptides measured by aqueous two-phase and octanol-buffer partitioning.
AB  - Partitioning of a series of free amino acids, their derivatives, and homo
      oligopeptides in aqueous dextran-PEG two-phase systems and octanol buffer systems
      was examined at pH values from 2.0 up to 12.5. The pH-dependent partition
      behavior of free amino acids and peptides in the two-phase systems was compared
      with that of monofunctional drug-like compounds and found to be clearly
      different. The differences observed indicate that the information provided by the
      techniques of partitioning in octanol buffer (log(D)(pH)) and in aqueous two
      phase systems, N(CH2), is different. It is suggested that the combination of the
      two descriptors, log(D) (lipophilicity) and N(CH2) (relative hydrophobicity), may
      be useful for QSAR analysis of the biological activities involving distribution
      and/or transport of chemical compounds in biological systems.

PMID- 12492902
TI  - Structural characterization of peptide fragments from hCD81-LEL.
AB  - The solution conformation of two peptides [1: PSGSNIISNLFKED; 2:
      GSSTLTALTTSVLKNNL] from human CD81 (hCD81) large extra-cellular loop (LEL) with
      known importance in the hepatitis C virus glycoprotein E2 (HCV-E2) binding
      interaction was characterized using circular dichroism spectroscopy. In addition,
      the solution structure of peptide 1 that contains a phenylalanine residue (F186
      in hCD81) known to be critical in the binding interaction with HCV-E2 was
      determined using 1D and 2D 1H NMR spectroscopy. Both peptides are unstructured in
      water but begin forming significant helical conformation following the addition
      of 20% or more trifluoroethanol (v/v), a result consistent with their alpha
      helical conformation found in the native protein. The CD data recorded as a
      function of pH and NaCl concentration are consistent with stabilization of the
      helical structure from electrostatic forces for both peptides. Peptide 1 is able
      to block the binding interaction of recombinant HCV-E2 (rHCV-E2) to hCD81
      expressed on Molt-4 T cells at high concentrations (3.5 mM), a low affinity that
      we attributed to the random coil structure in water.

PMID- 12492903
TI  - Safety and clinical effects of topical histatin gels in humans with experimental
      gingivitis.
AB  - BACKGROUND: Our research group has recently reported that exogenously applied
      histatins can inhibit plaque accumulation and gingival inflammation in a
      preclinical canine model (Paquette et al. 1997). OBJECTIVES: The aims of the
      present double-blinded, randomized, controlled clinical trial were to evaluate
      the safety and toxicity of three histatin (P-113) concentrations in gel
      formulations, and to assess potential clinical benefit on the development of
      gingivitis (partial mouth design). MATERIAL AND METHODS: One hundred and six
      healthy subjects were recruited and brought to optimal gingival health (GI < 0.5)
      prior to treatment initiation. At baseline, eligible subjects were randomized for
      one of the following treatments: (1) placebo; (2) 0.0625% P-113; (3) 0.125% P
      113; and (4) 0.375% P-113. Patients self-applied gels twice daily for 29 days to
      the maxillary right quadrant with the use of customized stents. In addition,
      patients deferred all oral hygiene procedures within this quadrant for the
      duration of the treatment period. Safety was assessed in terms of physical and
      oral examinations, clinical laboratory testing and recording of adverse events.
      Clinical indices were measured weekly and included gingival index (GI), plaque
      index (PI) and %BOP. RESULTS: All study formulations were well tolerated by
      patients, and no differences in adverse event occurrences were noted among
      treatment groups, including taste alteration or staining. For the intent-to-treat
      population, significantly smaller %BOP changes were noted in subjects treated
      with 0.0625, 0.125 and 0.375% P-113 gels (17.4, 18.18 and 17.9%, respectively)
      versus placebo (28.0%) (p < 0.05) at day 29. When groups were compared in terms
      of per cent responders (change in %BOP < 15 or < 20%), P-113 treatment groups
      exhibited a higher frequency of response, especially for the 0.0625 and 0.125% P
      113 formulations (p < 0.05). Although no statistically significant intergroup
      differences were noted for changes in GI or PI among all subjects (intent-to
      treat population), significantly smaller changes in PI at day 22 were observed
      among compliant individuals (defined as subjects using > 60% of the target gel
      mass) administering P-113 gels as compared with compliant placebo subjects (p <
      0.05). CONCLUSIONS: These data indicate safety and tolerance of P-113 gels for
      topical oral use in human subjects. These data also suggest that P-113 gels
      administered twice daily may reduce experimental gingivitis as measured with
      bleeding on probing in humans.

PMID- 12492904
TI  - Effect of triclosan dentifrices on mouth volatile sulphur compounds and dental
      plaque trypsin-like activity during experimental gingivitis development.
AB  - BACKGROUND: The objective of this study was to evaluate the effect of three
      commercial anti-plaque dentifrices containing 0.3% triclosan + 2% pvm/ma (Colgate
      Total), 0.3% triclosan + 0.75% Zn (Signal Global) and 0.3% triclosan + 5% PPi
      (Crest Complete) in comparison with an experimental dentifrice (0.3% triclosan +
      2% pvm/ma + 0.75% Zn + 4% PPi) and a control dentifrice without anti-plaque
      agents on trypsin-like activity in dental plaque (detected by the hydrolysis of
      [Na-Benzoyl-DL-Anginine p-Nitroanilide (BAPNA)] and volatile sulphur compounds
      (VSCs) in mouth air during experimental gingivitis development. METHOD: A 5-step
      double blind, crossover experimental gingivitis study was conducted on 19
      volunteers during a 21-day period. The volunteers refrained from brushing an
      experimental quadrant of teeth. The dentifrices were applied to those teeth via
      toothshield three times per day; simultaneously they brushed the other teeth with
      the same dentifrice. After each period, VSCs in mouth air and BAPNA hydrolysis by
      dental plaque accumulated in the experimental quadrant were determined. RESULTS:
      There was an increase (p < 0.05) in VSCs in mouth air when experimental
      gingivitis was induced in only one quadrant of teeth. None of the dentifrices was
      able to avoid the increase of VSCs during the experimental gingivitis
      development. The majority of the antiplaque dentifrices evaluated reduced the
      increase of VSC formation in comparison with the control (p < 0.05). There was no
      relationship between the ability of the dentifrices in reducing VSC formation and
      the inhibition of trypsin-like activity in dental plaque. CONCLUSIONS: Anti
      plaque dentifrices reduce the increase of VSCs that occurs during the development
      of experimental gingivitis.

PMID- 12492905
TI  - Quantitative assessment of apoptotic and proliferative gingival keratinocytes in
      oral and sulcular epithelium in patients with gingivitis and periodontitis.
AB  - BACKGROUND: Periodontal disease is caused by a chronic infection inducing an
      inflammatory reaction that leads to a breakdown of tooth-supporting tissue. The
      maintenance of an equilibrium between the host defence and microorganisms in the
      sulcus is essential to preserve health. All multicellular organisms have
      mechanisms for killing their own cells, and use physiological cell death for
      defence, development, homeostasis and ageing. Apoptosis and proliferation are
      very important phenomena in regulating this and a disturbance is often associated
      with disease e.g. cancer, AIDS, Alzheimer's disease, rheumatoid arthritis.
      OBJECTIVE: The aim of this study was to determine whether the number of apoptotic
      and proliferative gingival keratinocytes differed between patients with
      gingivitis and those with periodontitis. MATERIAL AND METHODS: The distribution
      of neutrophil elastase, PCNA/cyclin, DNA fragmentation (apoptosis) and p53 was
      determined with immunocytochemical techniques. We used paraffin-embedded sections
      from gingival biopsies and did quantitative analyses. RESULTS AND CONCLUSION:
      These showed that 5-12% of the keratinocytes in the basal layers of the
      epithelium proliferated in the two groups. Fewer apoptotic cells were seen in the
      oral epithelium than in the sulcus in all subjects in both groups. Only in the
      most apical part of the sulcus, close to the junctional epithelium, did the
      number of apoptotic keratinocytes exceed the proliferative ones in patients with
      periodontitis.

PMID- 12492906
TI  - A comparison of the plaque-inhibitory properties of stannous fluoride and low
      concentration chlorhexidine mouthrinses.
AB  - BACKGROUND: Plaque inhibition by chlorhexidine (CHX) rinses is dose related with
      a relatively flat dose-response curve above 5-6 mg twice daily. Low dose regimens
      could therefore reduce local side effects but maintain reasonable efficacy. AIMS:
      To compare the plaque inhibitory properties of two low-dose CHX rinse products
      with more conventional levels delivered from proprietary rinses. A secondary
      outcome was a comparison with a stannous fluoride/amine fluoride (SFAF) rinse
      product. METHODS: The study was a five-treatments, negative controlled,
      randomised, single blind crossover design balanced for residual effects,
      involving 20 healthy subjects in a 24-h plaque re-growth model. On day 1 of each
      study period, subjects were rendered plaque free, suspended tooth cleaning and
      followed the appropriate rinse regimen. On day 2, subjects were scored for plaque
      by index and area. The rinse codes and rinsing regimens were: (A) 15 mg CHX 2 x
      daily for 30 s (0.1% CHX), (B) 9 mg CHX 2 x daily for 60 s (0.06% CHX), (C) 10 ml
      SFAF rinse 1 x daily for 30 s, (D) 15 ml placebo 2 x daily for 60 s, and (E) 6 mg
      CHX 2 x daily for 30 s (0.06% CHX). RESULTS: Average mouth plaque indices and
      areas were highly significantly different between rinsing regimens. All test
      rinses were significantly more effective than the placebo rinse. There was a mean
      dose-response pattern for the CHX rinses, but there were no statistically
      significant differences between any of the test rinses. CONCLUSIONS: Lower doses
      of chlorhexidine in rinses can be used to exert plaque inhibition comparable with
      products used at higher doses and equivalent to benchmark products such as the
      SFAF rinse. However, the availability of chlorhexidine from formulations has to
      be considered as in part explaining the results.

PMID- 12492907
TI  - A study of triclosan and its solubilizers as inhibitors of oral malodour.
AB  - BACKGROUND: It is known that the detergents or organic solvents used to
      solubilize lipid-soluble triclosan can affect the biological activities exhibited
      by this molecule, such as its antibacterial, antiplaque, and anti-inflammatory
      effects. OBJECTIVE: To examine whether solubilizing agents influence the effect
      of triclosan against formation of volatile sulphur compounds (VSC), as these are
      known to be a major component of oral malodour. MATERIAL AND METHODS: Part A: one
      ml of human whole saliva (n = 10) was incubated for 24 h at 37 degrees C in a
      closed test tube with addition of 10 micro l triclosan solubilized in alcohol.
      Part B: in a clinical experiment, VSC formation enhanced by mouth-rinses with
      cysteine was followed by subjects (n = 9) rinsing with triclosan solubilized in
      different detergents and organic solvents. The amount and nature of VSC in the
      saliva headspace and in the mouth air of the test subjects were determined by gas
      chromatography. RESULTS: Triclosan had a marked dose-dependent effect against VSC
      in vitro when solubilized in alcohol, independent of the alcohol per se. In vivo,
      triclosan lost its anti-VSC effect when solubilized in oil, in an uncharged
      detergent or in a chromophor, whereas it maintained its effect when solubilized
      in a combination of sodium lauryl sulphate, propylene glycol and water.
      CONCLUSION: The solubilizing agent influences the anti-VSC effect of triclosan.

PMID- 12492908
TI  - Evidence for the early onset of gingival inflammation following short-term plaque
      accumulation.
AB  - AIM: A study was undertaken to examine cytokine markers in gingival crevicular
      fluid (GCF) during the early stages of plaque accumulation. METHODS: A panel of
      five subjects with good oral hygiene went without brushing for 1 or 3 days, after
      which GCF samples were taken by placing paper strips into the gingival margins of
      the maxillary premolars and first molar for 30 s. GCF flow rates were determined
      with a Periotron instrument (Oraflow, Inc., Plainview, New York), and neutrophils
      (polymorphonuclear leukocytes) were determined as myeloperoxidase activity.
      Interleukin-1b (IL-1b) and IL-8 were eluted from the paper strips and assayed
      with enzyme-linked immunosorbent assay (ELISA) systems. RESULTS: The plaque index
      rose to 2.7 +/- 0.2 (mean +/- SE) after 3 days without brushing, and the GCF flow
      rate increased to 146.8% of baseline. PMN and IL-8 concentrations fell but, when
      corrected for dilution as a result of increased GCF flow, were not statistically
      different from baseline. IL-1b was slightly elevated after 1 day, and increased
      to 223.8 +/- 54.3% (from 6.8 +/- 1.7 to 13.8 +/- 3.6 pg/30 s; p = 0.04) after 3
      days of plaque accumulation. Resumption of tooth brushing led to a return of IL
      1b to baseline (109.1% after 2 days of brushing). When subjects rinsed with 0.12%
      chlorhexidine during the 3-day no-brushing period, the increases in plaque index,
      GCF flow rates and IL-1b release rates did not occur. CONCLUSIONS: The results
      indicate that IL-1b release rates increase in the GCF after 3 days of plaque
      accumulation, before any clinical signs of inflammation appear.

PMID- 12492909
TI  - The effect of a SCN-/H2O2 toothpaste compared to a commercially available
      triclosan-containing toothpaste on oral hygiene and gingival health -- a 6-month
      home-use study.
AB  - OBJECTIVES: The aim of the study was to compare the gingival health benefits of a
      thiocyanate/carbamide peroxide toothpaste to that of a triclosan toothpaste in
      home use. MATERIALS AND METHODS: The study was a two-centre, randomised, double
      blind, parallel-group clinical trial, and consisted of a 2-week pre-experimental
      phase, followed by an experimental period of 6 months. A total of 140 healthy
      male and female volunteers (70 per group) who had at least 20 natural teeth with
      no probing depths greater than 5 mm and a mean gingival index (GI) of 1 or more
      at screening were admitted to the study. The two products were the test
      toothpaste (RCP) containing 0.5% SCN- (rhodanide), carbamide peroxide (equivalent
      0.1% H2O2), and 1450 p.p.m. fluoride, and a control toothpaste (Colgate Total)
      containing 0.3% triclosan, 2.0% polyvinyl methyl ether maleic acid (PVM/MA), and
      1450 p.p.m. fluoride (Triclosan). In the pre-experimental phase, all subjects
      used a fluoride toothpaste. Plaque (Turesky et al. 1970) and gingivitis (Loe &
      Silness 1963) were scored prior to beginning the pre-experimental phase, at
      baseline, and after 6 weeks and 3 and 6 months. RESULTS: In both the RCP and the
      Triclosan group, gingival health improved significantly between baseline and the
      following examinations. Plaque scores decreased significantly between baseline
      and 6 months in both groups. There were, however, no significant differences
      between the groups for either gingival index or plaque index. CONCLUSION: To
      conclude, this study seems to verify that in normal home use, a toothpaste
      containing a combination of thiocyanate and carbamide peroxide is as effective in
      reducing gingival inflammation and supragingival plaque formation as a benchmark
      control product.

PMID- 12492910
TI  - Tooth loss and pocket probing depths in compliant periodontally treated patients:
      a retrospective analysis.
AB  - BACKGROUND/AIMS: This retrospective study determined the treatment outcomes of
      142 compliant periodontal patients observed for at least 10 years at the
      University of Kiel. All patients had been treated for moderate to advanced
      periodontitis and regularly received supportive periodontal therapy (SPT).
      METHODS: Patient- and tooth-related variables [tooth loss and pocket probing
      depth (PPD)] were analysed. RESULTS: Of a total of 3353 teeth, 167 were extracted
      during active treatment and 99 during SPT, mainly for periodontal reasons. Forty
      five per cent of the patients did not lose any teeth during 11.7 years of
      observation. Thirty-seven per cent underwent extractions during active treatment
      or SPT, 18% both during active periodontal therapy and SPT. Mean tooth loss per
      patient was 0.07 teeth/year during SPT. Mobility, furcation involvement, smoking,
      and prescription antibiotics had a negative impact on prognosis. Intraindividual
      differences in PPD were significant between single- and multirooted teeth with
      initial PPD > or = 4 mm at baseline, following active treatment and at the end of
      SPT, and between firm and mobile teeth at baseline. Interindividual differences
      in mean PPD were only significant between smokers and non-smokers at the end of
      the observation period. CONCLUSIONS: Long-term maintenance of our patients was
      effective. Periodontal disease represented the major cause of tooth loss in a
      minority of the population.

PMID- 12492911
TI  - Periodontal treatment practices of Finnish dentists.
AB  - OBJECTIVES: To evaluate the treatment practices of Finnish general practitioners
      (GPs) and dental teachers (DTs) regarding periodontal treatment modalities, and
      their knowledge of possible contraindications for periodontal surgery. MATERIAL
      AND METHODS: A questionnaire on two periodontal cases was mailed to 400 GPs,
      selected by stratified randomization from the public and private sector, and to
      47 DTs. The response rate was 77%. Respondents were asked to choose the optimal
      treatment for a patient with a bleeding, 8-mm-deep periodontal pocket and to
      consider the influence on their treatment decision of the six possible
      contraindications for periodontal surgery presented, two of which were absolute
      (inadequate oral hygiene and poorly controlled diabetes) and four of which were
      relative contraindications. The respondents' treatment decisions were compared
      with recommendations from textbooks and the Consensus Report from the 1996 World
      Workshop of Periodontology. RESULTS: The majority of public (65%) and private
      (70%) dentists and almost all of the DTs chose treatment in agreement with
      recommendations. Correct answers from dentists were associated with a greater
      number of days in continuing education (OR = 1.5; p= 0.005). The two absolute
      contraindications were known by 38% of public and 31% of private sector dentists,
      and by 29% of DTs. The respective figures for relative contraindications were 40,
      58 and 53%. CONCLUSION: The majority of Finnish dentists followed the
      recommendations, but elaboration of international guidelines for good clinical
      practice is still needed to help clinicians to make optimal treatment decisions.

PMID- 12492912
TI  - Correlation and examiner agreement between a new method of plaque scoring and a
      popular established plaque index, modelled in vitro.
AB  - BACKGROUND, AIMS: Scoring of supragingival plaque is common to epidemiological
      studies, oral hygiene assessments and clinical trials of oral hygiene products.
      These clinical practices utilize indices such as the Turesky et al. (1970,
      Journal of Periodontology 41, pp. 41-43) modification [Turesky Plaque Index
      (TPI)] of the Quigley & Hein (1962, Journal of the American Dental Association
      65, pp. 26-29) plaque index for evaluating plaque extension. Whilst this index is
      in common use by clinicians, there is potential for ambiguity in the
      interpretation of scores by different examiners. The aims of this study were to
      compare examiner agreement between a new method of plaque scoring (NMPS) and TPI,
      and to determine if there was a correlation between the two indices. METHODS:
      Simulated plaque was scored from eight study casts, each consisting of 14 teeth.
      The two indices were both scored twice from the study casts by eight examiners
      experienced in plaque scoring. The first readings obtained were analysed for a
      correlation between the indices and between-examiner variability. Within-examiner
      variability was assessed using both first and second readings of each index.
      RESULTS: A positive correlation was found between the two indices (r = 0.717).
      The NMPS was found to have better inter- and intra-examiner agreement than TPI.
      CONCLUSION: The NMPS was found to have less variability within and between
      examiners than TPI: evaluation of NMPS in a clinical setting would now appear
      warranted.

PMID- 12492913
TI  - Randomised controlled trials and publication trends in periodontal research
      during 1980-2000.
AB  - OBJECTIVES: To study publication trends, as well as the number and proportion of
      randomised controlled trials covering different areas of periodontal research
      (RCT-Ps). MATERIAL AND METHODS: The study was based on Medline searches (MeSH
      terms) for the period 1980- 2000. The RCT-Ps (n = 675) were examined for
      relevance for different areas of periodontal research, journals of publication,
      and the countries of origin. RESULTS: In periodontal research the annual number
      of publications had increased from 162 in 1980 to 440 in 2000. Moreover, clinical
      trials in periodontal research (CT-Ps) had increased more than 10-fold, and RCT
      Ps more than 15-fold. More than 4 out of 10 RCT-Ps covered the areas 'periodontal
      surgery' and 'gingivitis and plaque treatment or prevention'. More than 6 out of
      10 RCT-Ps in total and more than 8 out of 10 RCT-Ps about 'periodontal surgery',
      were published in two different journals. U.S.A was the most common country of
      origin of RCT-Ps, contributing to almost 4 out of 10 RCT-Ps during 1988-2000.
      CONCLUSION: The annual number of RCT-Ps increased substantially during 1980-2000,
      and a few clinical research areas predominated. Future research should give
      priority to areas where clinical evidence is scarce and where high-quality RCT-Ps
      are most needed.

PMID- 12492914
TI  - Analysis of two common alpha 1-antitrypsin deficiency alleles (PI*Z and PI*S) in
      subjects with periodontitis.
AB  - BACKGROUND: pi alpha 1-Antitrypsin deficiency is a genetically determined
      condition resulting in predisposition to certain inflammatory diseases due to a
      protease: antiprotease imbalance that is exacerbated by tobacco smoking. Limited
      evidence suggests that there may be a significant enrichment of mild alpha 1
      antitrypsin deficiency phenotypes in subjects with chronic inflammatory
      periodontal disease. OBJECTIVE: To examine the prevalence of two common alpha1
      antitrypsin deficiency alleles (PI*Z and PI*S) in a UK population of subjects
      with periodontitis. SUBJECTS AND METHODS: The prevalence of PI*M, PI*S and PI*Z
      allele combinations was determined in 31 subjects with periodontitis and compared
      with 31 healthy control subjects matched for smoking status, ethnicity, age and
      gender. alpha 1-Antitrypsin genotyping was performed by multiplex real-time
      fluorescence polymerase chain reaction (PCR) using DNA extracted from whole
      blood. RESULTS: There was no difference in the proportion of any alpha 1
      antitrypsin genotype found in the diseased and control populations. CONCLUSIONS:
      We did not find evidence to support an association between mutant PI* alleles and
      periodontitis in a small, controlled study. Larger studies will be required to
      clarify the relationship between alpha1-antitrypsin genotype and susceptibility
      to inflammatory periodontal disease.

PMID- 12492915
TI  - Lateral ridge augmentation by the use of grafts comprised of autologous bone or a
      biomaterial. An experiment in the dog.
AB  - OBJECTIVE: The present investigation was performed to determine if a block of Bio
      Oss used as an onlay graft can be used as a scaffold for new bone formation.
      MATERIAL AND METHODS: Five mongrel dogs were used. The mandibular premolars were
      extracted. On both sides of the mandible, the buccal bone plate was resected and
      defects, about 25 mm long, 8 mm high and 5 mm wide, were produced After 3 months
      of healing, a second surgical procedure was performed. In the left side, a block
      of Bio-Oss was adjusted to the buccal bone wall. The graft had the shape of a
      cylinder and was retained with a miniscrew and covered with a collagen membrane.
      In the contra-lateral side of the mandible, a block biopsy was first obtained
      from the ascending ramus. This bone graft had the shape of a cylinder that was 8
      mm in diameter and 3 mm thick. The graft was transferred to the experimental
      site, adjusted to the buccal wall, retained with a miniscrew, and covered with a
      membrane. The flaps were repositioned and closed with sutures to ensure a
      complete coverage of the experimental sites. After 6 months of healing, the dogs
      were sacrificed and the experimental sites dissected. The biopsies were processed
      for ground sectioning. The sections were stained in toluidine blue, examined in
      the microscope, and a number of histo- and morphometric assessments made.
      RESULTS: The study demonstrated that cortical bone used as an onlay graft in the
      lateral aspect of the alveolar ridge, during a 6-month period of healing
      integrated with the host bone but underwent marked peripheral resorption. Thus,
      close to 30% of the height and 50% of the length of the graft was replaced with
      connective tissue. It was further observed that while the dimensions of a graft
      which contained a scaffold of cancellous bovine bone mineral remained unchanged,
      only moderate amounts of new bone formed at the base of this graft. CONCLUSION:
      Grafts of autologous cortical bone, placed on the surface of a one-wall defect,
      may undergo marked resorption during healing. A similar graft of Bio-Oss may
      retain its dimension, and limited amounts of new bone will form within the
      biomaterial.

PMID- 12492918
TI  - Efficacy of antimicrobial filter treatments on microbial colonization of air
      panel filters.
AB  - AIMS: To assess the activity of biostatic agents on the microbial colonization of
      panel filters. METHODS AND RESULTS: Microfibre glass acrylic filters, both used
      and unused, were examined for the presence of microorganisms. Test strains were
      used to verify microbial colonization of filter media. Antimicrobial agents were
      applied to the filter media and tested for their ability to reduce microbial
      colonization. The integrity of the panel filters and the antimicrobial activity
      trends of the filter media treated with antimicrobials were verified. A
      filtration efficiency test was carried out on the treated filters to evaluate
      filtration performance. Filters treated with antimicrobials demonstrated markedly
      less microbial colonization (density and varieties of species), higher filtration
      efficiency and delayed deterioration of the filter. CONCLUSIONS: The most
      important results of this study are the demonstration of preservation of the
      integrity of the filters and the lower release of microorganisms from treated
      filters. SIGNIFICANCE AND IMPACT OF THE STUDY: These results contribute to the
      resolution of problems concerning the microbial contamination of panel filters in
      the heating, ventilating and air-conditioning systems commonly used in the
      electronic industry, pharmaceutical industry, hospitals and other environments
      where the absence of contaminating particles and microorganisms is required.

PMID- 12492919
TI  - The incidence of antimicrobial-resistant Salmonella spp on freshly processed
      poultry from US Midwestern processing plants.
AB  - AIMS: To determine the incidence of antimicrobial-resistant Salmonella spp. on
      processed poultry (turkey) at Midwestern poultry plants. METHODS AND RESULTS: Two
      participating plants were visited at monthly intervals for a period of 1 year.
      Surface swabs were obtained from carcasses at two selected points on the
      production line, pre- and post-chill. In addition, samples of the chill water
      from chill tanks were also examined. Isolation and detection of Salmonella spp.
      from carcass swabs and chill water was carried out using standard enrichment
      techniques. Immunomagnetic separation was used to enhance the recovery of the
      pathogen. Salmonella isolates recovered were identified, serotyped and their
      antimicrobial resistance profiles determined using the National Antimicrobial
      Resistance Monitoring System. Results from the study indicated that the overall
      incidence of Salmonella was approx. 16.7%, with a greater incidence of the
      pathogen observed on pre-chill than post-chill carcasses. Salmonella isolates
      recovered displayed resistance to an average of four different antimicrobials.
      Approximately 15 different serotypes of Salmonella spp. were recovered, with
      Salmonella serotype Agona, Salmonella serotype Hadar, Salmonella serotype
      Heidelberg and Salmonella serotype Senftenberg being the most common.
      CONCLUSIONS: The incidence of Salmonella spp. was relatively low and isolates
      recovered showed significant degrees of antimicrobial resistance. Factors such as
      the processing plant examined, the season and farms that were presenting animals
      for processing influenced the incidence of the pathogen. SIGNIFICANCE AND IMPACT
      OF THE STUDY: Differences were observed in the serotypes of Salmonella recovered
      and the types of antimicrobial resistance found at the two plants. The study
      suggests that the use of antimicrobials at the farm level influences the creation
      of an environment that promotes the selection of antimicrobial-resistant
      Salmonella spp. The incidence, isolation and detection of Salmonella spp. on
      processed poultry are discussed.

PMID- 12492920
TI  - Identification of aerobic mesophilic bacilli isolated from board and paper
      products containing recycled fibres.
AB  - AIMS: To identify aerobic mesophilic bacteria isolated from coreboard, kitchen
      roll paper and food packaging boards containing recycled fibres and to create a
      rapid fingerprint-based database for their identification. METHODS AND RESULTS: A
      total of 197 isolates and 20 relevant type strains were characterized by
      automated ribotyping and as far as possible identified by the similarities of
      their riboprints to the relevant type strains. One strain from each unidentified
      ribotype, a total of 87 strains, was subjected to partial 16S rDNA sequencing and
      in most cases also to fatty acid analysis and physiological tests. From the
      isolates 113 and seven different ribotypes were generated belonging to the genera
      Bacillus and Paenibacillus, respectively. The dominating species, or closest
      related to them, were B. simplex (22.8% of isolates), B. licheniformis (18.3%)
      and B. amyloliquefaciens (12.7%); 5.1% of the isolates were identified as B.
      cereus, a potential food-borne pathogen. In particular, this species was present
      in one food packaging board (26.3% of isolates). Based on these results, 40.1% of
      the isolates and 45.0% of ribotypes were so different from the relevant type
      strains that they may represent novel species. CONCLUSIONS: All isolates were
      aerobic spore-formers, indicating that all non-spore-formers were eliminated
      during the drying stage of the processes. Although many isolates could be
      affiliated to described species of Bacillus or Paenibacillus, a significant
      proportion of the isolates could not be identified unambiguously as members of a
      described species. SIGNIFICANCE AND IMPACT OF THE STUDY: A RiboPrint
      identification database, composed of 120 composite patters, was established for
      bacteria originating from the pulp and paper industry. Considering the
      discrimination power of ribotyping, this database will be extremely useful in
      future for the reliable and rapid identification of bacteria isolated from pulp
      and paper industrial sources.

PMID- 12492921
TI  - Using event trees to quantify pathogen levels on root crops from land application
      of treated sewage sludge.
AB  - AIMS: To quantify the incremental exposure of root crops, at point of harvest, to
      enteric pathogens from sewage sludge applied to agricultural land according to
      current regulations and guidance (Safe Sludge Matrix). METHODS AND RESULTS: A
      quantitative risk assessment based on the Source-Pathway-Receptor approach is
      developed for Cryptosporidium and salmonellas. Event trees are constructed to
      model the partitioning of pathogens present in raw sewage into sludge at the
      sewage treatment works and to model to the pathways by which root crops may be
      exposed to those pathogens after treatment and land application of the sludge.
      The main barriers are sewage sludge treatment, and decay and dilution of the
      pathogens in the soil. The exposures are expressed in terms of the arithmetic
      mean. This represents the total loading and accommodates fluctuations not only in
      the levels of pathogens present in sewage but also in the removal efficiencies by
      the various barriers. One source of uncertainty is the degree of by-pass of
      sludge treatment at operational scale. CONCLUSIONS: The models predict that land
      application of sewage sludge treated by conventional processes (achieving 2-log
      removal) increases the exposures of root crops to salmonellas and Cryptosporidium
      oocysts by counts of 0.070 and 0.033 kg(-1), respectively. These predictions are
      based on decay periods in the soil of 5 and 12 weeks, respectively, and are
      therefore worst case in not allowing for the full extent of no harvesting
      periods. A Monte Carlo simulation predicts that 0.01% of 1-kg batches contained >
      50 salmonellas and demonstrates that, for risk assessment, it is acceptable to
      use the arithmetic mean exposure directly in the dose-response curve.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The predicted numbers of pathogens on root
      crops at point of harvest provide a basis for modelling the excess risks to
      humans consuming such crops. The approach underpins scientifically the Safe
      Sludge Matrix.

PMID- 12492922
TI  - Cold and carbon dioxide used as multi-hurdle preservation do not induce
      appearance of viable but non-culturable Listeria monocytogenes.
AB  - AIMS: To study whether the exposure to cold (4 degrees C) and carbon dioxide
      which results in the elongation of Listeria cells, induces a viable but
      nonculturable (VBNC) state. METHODS AND RESULTS: When cold and CO2 stressed L.
      monocytogenes were observed under a fluorescence microscope, using the LIVE/DEAD
      BacLight bacteria viability kit (Molecular Probes, Eugene, OR, USA), the healthy,
      mildly injured, and the putative VBNC cells accounted for 31.0% of the stressed
      cell population. By using the selective plate count, 31.4% of the same stressed
      cell population was found to be healthy and mildly injured (putative VBNC cells
      not included). If there were VBNC state cells present, we should have observed a
      significant difference between the above two numbers. In fact, there was no
      significant difference between the results obtained from those two methods.
      CONCLUSIONS: There were no VBNC state cells observed in the stressed cell
      population. We conclude that cold and CO2 do not induce L. monocytogenes to enter
      a VBNC state. SIGNIFICANCE AND IMPACT OF THE STUDY: Cold and modified atmospheres
      are widely used in fresh muscle food and fruit preservation. Whether they would
      induce L. monocytogenes into a VBNC state is of a great concern for microbial
      food safety.

PMID- 12492923
TI  - Low pressure ultraviolet studies for inactivation of Giardia muris cysts.
AB  - AIMS: The research was initiated to confirm earlier ultraviolet (u.v.) light
      inactivation studies performed on Giardia cysts using excystation as the
      viability indicator. Following this, a comparison of in vitro excystation and
      animal infectivity was performed for assessing cyst viability after exposure to
      low-pressure u.v. irradiation. METHODS AND RESULTS: Cysts of Giardia muris were
      inactivated using a low-pressure u.v. light source. Giardia muris was employed as
      a surrogate for the human pathogen Giardia lamblia. Cyst viability was determined
      by both in vitro excystation and animal infectivity. Cyst doses were counted
      using a flow cytometer for the animal infectivity experiments. Using in vitro
      excystation as the viability indicator, fluences as high as approximately 200 mJ
      cm(-2) did not prevent some cysts from excysting, thus verifying earlier work.
      Using animal infectivity, u.v. fluences of 1.4, 1.9 and 2.3 mJ cm(-2) yielded
      log10 reductions ranging from 0.3 to >or= 4.4. CONCLUSIONS: Results indicate that
      in vitro excystation is not a reliable indicator of G. muris cyst viability after
      u.v. disinfection. Very low doses of u.v. light rendered G. muris cysts non
      infective in the mouse model employed. SIGNIFICANCE AND IMPACT OF THE STUDY: Data
      presented represent the only complete u.v. inactivation curve for G. muris. This
      research provides evidence that u.v. can be an effective barrier against Giardia
      spp. in the treatment of drinking water supplies.

PMID- 12492924
TI  - Properties of Bacillus thuringiensis isolated from bank voles.
AB  - AIMS: To assess the properties of B. thuringiensis naturally occurring in the
      intestines of bank voles. METHODS AND RESULTS: Seventeen Bacillus thuringiensis
      strains, exhibiting typical growth on selective medium for the B. cereus group
      and characterized by the ability to produce parasporal crystals, were isolated
      from bank voles trapped in the Lomza Landscape Park of the Narew River Valley
      (north-east Poland). All isolates were characterized by pulsed field gel
      electrophoresis (PFGE) of chromosomal DNA and SDS polyacrylamide gel
      electrophoresis (SDS-PAGE) of whole-cell proteins. Six pulsotypes were found with
      PFGE typing, using SmaI or NotI as restriction enzymes. Significant differences
      in chromosome size, ranging from 2.4 to 4.2 Mb for the B. thuringiensis strains
      studied, were noted. Strain heterogeneity in pulsotypes was also reflected by the
      similarity of whole-cell protein profiles of the strains. Environmental isolates
      and reference strains grouped at 71% similarity according to SDS-PAGE data and at
      84% on the basis of biochemical tests. CONCLUSIONS: B. thuringiensis from
      intestines of bank voles demonstrated an important level of heterogeneity. The
      comparison of PFGE profiles and SDS-PAGE of whole-cell protein patterns may be
      useful to evaluate the relationship between B. thuringiensis isolates.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The results presented in this paper may
      help to explain the diversity of B. thuringiensis.

PMID- 12492925
TI  - Comparison of phenotypic and genotypic markers for characterization of an
      outbreak of Salmonella serotype Havana in captive raptors.
AB  - AIMS: To establish a typing method for tracing the epidemic relationship of 16
      strains of Salmonella serotype Havana isolated from captive raptors showing no
      symptomatology and residing in a wildlife hospital in Spain. METHODS AND RESULTS:
      Antimicrobial susceptibility testing, ribotyping, pulsed field gel
      electrophoresis (PFGE) and amplified fragment length polymorphism (AFLP)
      methodology were applied. Ten unrelated strains of serotype Havana were included
      as a control group to provide a basis of for the efficiency of the different
      markers used. All outbreak-related strains were resistant to nalidixic acid and
      streptomycin and showed the same ripotype, pulsotype and AFLP pattern.
      CONCLUSIONS: This is the first time that AFLP analysis has been tested with
      serotype Havana isolates and it has demonstrated to be the most useful
      epidemiological tool for discriminating between unrelated and outbreak-related
      strains of this serotype. The results obtained suggest that all the Salmonella
      serotype Havana isolates represented a common outbreak strain whose origin of
      contamination could not be established although it is thought that it was the
      poultry meat used for raptors'diet. SIGNIFICANCE AND IMPACT OF THE STUDY: Our
      study suggests the importance of microbiological analysis of these products in
      order to prevent contamination and dissemination of Salmonellae in this kind of
      Hospital.

PMID- 12492926
TI  - Effect of subtherapeutic concentrations of tylosin on the inhibitory stringency
      of a mixed anaerobe continuous-flow culture of chicken microflora against
      Escherichia coli O157:H7.
AB  - AIMS: The aim of this study was twofold: first to determine the effect of
      subtherapeutic concentrations of tylosin, a macrolide antibiotic used for growth
      promotion, on a mixed anaerobic continuous-flow fermentation culture of chicken
      gastrointestinal microorganisms (CCF) and secondly, to determine if these
      concentrations would allow persistence of Escherichia coli O157:H7 in CCF.
      METHODS AND RESULTS: CCF was treated with tylosin at 10.0, 20.0 and 40.0 microg
      ml(-1). Tylosin treatment resulted in a significant (P < 0.0001) decrease in
      total volatile fatty acids (VFAs) from a mean concentration of 101 +/- 10.8
      micromol ml(-1) in control cultures to 32.0 +/- 6.3 and 40.2 +/- 9.6 micromol ml(
      1) in 10 and 40 microg ml(-1) treated cultures, respectively. Untreated CCF
      challenged with E. coli O157:H7 cleared the challenge microorganism in 7 days at
      a rate of 0.96 log10 CFU ml(-1) day(-1). In contrast, E. coli O157:H7 persisted
      in all tylosin treated cultures. CONCLUSIONS: In the presence of tylosin, E. coli
      O157:H7 was able to persist in the CCF culture. The significant decrease in the
      production of VFAs may have been a contributing factor. SIGNIFICANCE AND IMPACT
      OF THE STUDY: The use of low-level, growth-promoting antimicrobials may
      compromise the ability of normal microflora that serve as a natural host defence
      against infection.

PMID- 12492927
TI  - Identification of lactic acid bacteria from spoilage associations of cooked and
      brined shrimps stored under modified atmosphere between 0 degrees C and 25
      degrees C.
AB  - AIMS: To evaluate spoilage and identify lactic acid bacteria (LAB) from spoilage
      associations of cooked and brined shrimps stored under modified atmosphere
      packaging (MAP) at 0, 5, 8, 15 and 25 degrees C. METHODS AND RESULTS: Bacterial
      isolates (102) from spoilage associations of cooked and brined MAP shrimps were
      characterized by phenotypic tests and identified as lactic acid bacteria (78
      isolates), other Gram-positive bacteria (13 isolates) and Gram-negative bacteria
      (11 isolates). A selection of 48 LAB isolates were further characterized and
      identified by phenotypic tests and SDS-PAGE electrophoresis of whole cell
      proteins. Selected clusters of LAB isolates were analysed by plasmid profiling,
      pulsed field gel electrophoresis and 16S rRNA gene sequencing. Enterococcus
      faecalis was identified in spoilage associations at 15 degrees C and 25 degrees
      C, and its metabolic activity corresponded to chemical changes in spoiled
      products. Carnobacterium divergens, a non-motile Carnobacterium sp. nov. and
      Lactobacillus curvatus were the LAB species observed in spoilage associations of
      products stored at 0 degrees C, 5 degrees C and 8 degrees C. CONCLUSIONS:
      Enterococcus spp. and Carnobacterium spp. were the dominant parts of spoilage
      associations of cooked and brined MAP shrimps stored at high and low
      temperatures, respectively. SIGNIFICANCE AND IMPACT OF THE STUDY: The SDS-PAGE
      technique and simple biochemical keys allowed the majority of LAB isolates from
      spoilage associations of cooked and brined MAP shrimps to be identified at the
      species level.

PMID- 12492928
TI  - Detection and recovery of sublethally-injured enterotoxigenic Staphylococcus
      aureus.
AB  - AIMS: To determine whether sublethally-injured (acid- or heat-shocked)
      Staphylococcus aureus cells are recoverable using selective agar overlays.
      METHODS AND RESULTS: Brain Heart Infusion (BHI) Agar overlaid with either Baird
      Parker Agar (BPA) or Gram-Positive Agar (GPA) was compared in the ability to
      resuscitate heat- and acid-shocked enterotoxigenic Staph. aureus. BHI/BPA
      overlays allowed for greater recovery of both heat- and acid-shocked cells than
      BHI/GPA, although the former was not selective and allowed growth of bacteria
      other than Staph. aureus. No significant difference existed in percent recovery
      of heat- and acid-shocked cells between the two overlay approaches. Significant
      differences were noted in counts on BHI/GPA plates and straight selective GPA/GPA
      plates, however. Viability of heat- and acid-shocked Staph. aureus was also
      examined using fluorescence microscopy, the relative counts of which correlated
      well to the calculated percent recovery on selective agar overlays. CONCLUSIONS:
      This work has shown that an improved agar overlay technique increases the
      sensitivity of the standard plate count while enumerating sublethally-injured
      enterotoxigenic Staph. aureus compared with direct plating onto selective media.
      SIGNIFICANCE AND IMPACT OF THE STUDY: These data emphasize the need to develop
      practical and cost-effective methods that reliably detect and enumerate
      sublethally-injured pathogens such as Staph. aureus.

PMID- 12492929
TI  - Cell-cell interactions influence resistance and survival of Salmonella serotype
      Typhimurium to environmental stress.
AB  - AIMS: The aim of this work was to study the effects of prolonged nutrient stress
      on survival, cell interactions and resistance to inimical processes in Salmonella
      serotype Typhimurium. METHODS AND RESULTS: Salmonella Typhimurium cells were
      subjected to prolonged incubation in the stationary phase of growth and the
      properties of starved cells (old) were investigated with reference to those of
      exponentially-growing cells (young). Competition experiments between old and
      young cells revealed cell-cell interactions that influenced stationary phase
      survival and response of the bacterium to heat stress. During prolonged
      incubation of cells, cycles of resistance and sensitivity to heat stress were
      identified. Competition experiments between old and young cells revealed that the
      resistance of young cells to heat increased to levels more like those of
      stationary phase cells than growing cells. The presence of old cells influenced
      the phenotype of young cells, possibly by means of cell-cell interactions. There
      was no evidence for the involvement of any extracellularly-produced factors in
      this phenomenon, but a requirement that the old competitor cells be viable could
      be demonstrated. CONCLUSIONS: It is proposed that the complex interactions within
      stationary phase cultures of Salm. Typhimurium may be due to cycles of mutation
      in concert with an as yet undefined interaction between old cells and growing
      ones. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides evidence for
      active and diverse responses to nutrient stress within populations of Salm.
      Typhimurium that promote survival and that may be important for the success of
      this bacterium as a pathogen.

PMID- 12492930
TI  - Variability and functional role of chromosomal sequences in 16SrI-B subgroup
      phytoplasmas including aster yellows and related strains.
AB  - AIMS: Partial genetic characterization of several chromosomal regions on 35 16SrI
      B phytoplasma strains maintained in periwinkle and collected in different
      geographical areas from plants of diverse species. METHODS AND RESULTS: Genes
      coding for ribosomal protein rpL22, elongation factor EF-Tu and random cloned
      sequences amplified with primers AY19p/m, G35p/m and BB88F1/R1 after RFLP
      analyses showed a high degree of polymorphism among the strains studied. The
      ribosomal protein (rp) subgroups B and K, and an undescribed subgroup designated
      N, were identified. Amplicons obtained with primers AY19p/m and BB88F1/R1,
      revealed a high and a low degree of polymorphism, respectively. CONCLUSIONS: A
      probable spacer role could be attributed to the AY19p/m sequence and a possible
      coding function to the BB88F1/R1 sequence. No relationship was found among
      genetic polymorphisms, identified by statistical analyses, and epidemiological or
      biological parameters. SIGNIFICANCE AND IMPACT OF THE STUDY: The analyses of five
      different genomic sequences of the 35 strains belonging to subgroup 16SrI-B
      allowed a finer distinction among them, confirming that the polymorphism level of
      16S rDNA is too low to be adopted as unique parameter for classification.

PMID- 12492931
TI  - Resistance to quinolones in Campylobacter jejuni and Campylobacter coli from
      Danish broilers at farm level.
AB  - AIMS: To investigate the prevalence of quinolone resistance among Campylobacter
      jejuni and Camp. coli isolates from Danish poultry at the farm level, as well as
      for the whole country. METHODS AND RESULTS: Data and isolates were collected from
      a national surveillance of Campylobacter in poultry. Quinolone resistance was
      investigated by determination of minimum inhibitory concentration (MIC) to
      nalidixic acid and enrofloxacin. Among Camp. jejuni and Camp. coli combined, 7.5%
      were resistant to nalidixic acid. Quinolone resistance varied considerably from
      farm to farm, with 0% on some farms and almost 100% on others, but the resistance
      was evenly distributed geographically. With respect to isolates from farms where
      resistance was detected, quinolone resistance was higher among Camp. coli (28.7%)
      than among Camp. jejuni (11.3%). PFGE typing of quinolone-resistant and quinolone
      susceptible isolates from four farms indicated that certain resistant isolates
      belonged to specific clones that were able to persist on the farms during several
      rotations, even in the absence of selective pressure. Some clones were present
      and repeatedly isolated in both a quinolone-susceptible and quinolone-resistant
      variant. CONCLUSIONS: Overall, quinolone resistance among Campylobacter isolates
      from Danish broilers was 7.5% in 1998 and 1999; it was higher among Camp. coli
      than Camp. jejuni. Genetic diversity among resistant isolates was lower than
      among susceptible isolates, and certain clones existed in both a resistant and a
      susceptible variant. Some resistant clones appeared to persist on the farms and
      were repeatedly isolated from poultry flocks. SIGNIFICANCE AND IMPACT OF THE
      STUDY: The study is important for the understanding of persistence and dynamics
      of Campylobacter in broiler houses. It also highlights the extent, farm-to-farm
      variation and persistence of quinolone-resistant Campylobacter in broiler houses.

PMID- 12492932
TI  - Optimization of submerged culture process for the production of mycelial biomass
      and exo-polysaccharides by Cordyceps militaris C738.
AB  - AIMS: The objective of the present study was to determine the optimal culture
      conditions for mycelial biomass and exo-polysaccharide (EPS) by Cordyceps
      militaris C738 in submerged culture. METHODS AND RESULTS: The optimal
      temperatures for mycelial biomass and EPS production were 20 degrees C and 25
      degrees C, respectively, and corresponding optimal initial pHs were found to be 9
      and 6, respectively. The suggested medium composition for EPS production was as
      follows: 6% (w/v) sucrose, 1% (w/v) polypeptone, and 0.05% (w/v) K2HPO4. The
      influence of pH on the fermentation broth rheology, morphology and EPS production
      of C. militaris C738 was carried out in a 5-l stirred-tank fermenter. The
      morphological properties were comparatively characterized by pellet roughness and
      compactness by use of image analyser between the culture conditions with and
      without pH control. The roughness and compactness of the pellets indicated higher
      values at pH-stat culture (pH 6.0), suggesting that larger and more compact
      pellets were desirable for polysaccharide production (0.91 g g(-1) cell d(-1).
      CONCLUSIONS: Under the optimized culture conditions (with pH control at 6), the
      maximum concentration of biomass and EPS were 12.7 g l(-1) and 7.3 g l(-1),
      respectively, in a 5-l stirred-tank fermenter. SIGNIFICANCE AND IMPACT OF THE
      STUDY: The critical effect of pH on fungal morphology and rheology presented in
      this study can be widely applied to other mushroom fermentation processes.

PMID- 12492933
TI  - Microbiological aspects of biowaste during composting in a monitored compost bin.
AB  - AIMS: To determine the microbial succession of the dominating taxa and functional
      groups of microorganisms and the total microbial activity during the composting
      of biowaste in a monitored process. METHODS AND RESULTS: Biowaste (vegetable,
      fruit and garden waste) was composted in a monitored composting bin system.
      During the process, taxonomic and functional subpopulations of microorganisms
      were enumerated, and dominating colonies were isolated and identified. All counts
      decreased during the thermophilic phase of the composting, but increased again
      when the temperature declined. Total microbial activity, measured with an enzyme
      activity assay, decreased during the thermophilic phase, increased substantially
      thereafter, and decreased again during maturation. Bacteria dominated during the
      thermophilic phase while fungi, streptomycetes and yeasts were below the
      detection limit. Different bacterial populations were found in the thermophilic
      and mesophilic phases. In fresh wastes and during the peak-heating phase, all
      bacterial isolates were bacilli. During the cooling and maturation phase the
      bacterial diversity increased, including also other Gram-positive and Gram
      negative bacteria. Among the fungi, Aspergillus spp. and Mucor spp. were
      predominant after the thermophilic phase. CONCLUSIONS: The microbial abundance,
      composition and activity changed substantially during composting and compost
      maturity was correlated with high microbial diversity and low activity.
      SIGNIFICANCE AND IMPACT OF THE STUDY: A more complete overview of the whole
      composting process of biowaste, based on microbial counts, species diversity and
      functional groups and abiotic parameters is presented, and the potential of a
      simple enzyme assay to measure total microbial activity was demonstrated.

PMID- 12492934
TI  - Conjugated linoleic acid biosynthesis by human-derived Bifidobacterium species.
AB  - AIMS: To assess strains of Lactobacillus, Lactococcus, Pediococcus and
      Bifidobacterium for their ability to produce the health-promoting fatty acid
      conjugated linoleic acid (CLA) from free linoleic acid. METHODS AND RESULTS: In
      this study, strains of Lactobacillus, Lactococcus, Pediococcus and
      Bifidobacterium were grown in medium containing free linoleic acid. Growth of the
      bacteria in linoleic acid and conversion of the linoleic acid to CLA was
      assessed. Of the bacteria assessed, nine strains of Bifidobacterium produced the
      c9, t11 CLA isomer from free linoleic acid. The t9, t11 CLA isomer was also
      produced by some strains, but at much lower concentrations. CONCLUSIONS: The
      production of CLA by bifidobacteria exhibited considerable interspecies
      variation. Bifidobacterium breve and B. dentium were the most efficient CLA
      producers among the range of strains tested, with B. breve converting up to 65%
      linoleic acid to c9, t11 CLA when grown in 0.55 mg ml(-1) linoleic acid. Strains
      also varied considerably with respect to their sensitivity to linoleic acid.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The production of CLA by probiotic
      bifidobacteria offers a possible mechanism for some health-enhancing properties
      of bifidobacteria and provides novel opportunities for the development of
      functional foods.

PMID- 12492935
TI  - Modelling the combined effect of temperature, pH and aw on the growth rate of
      Monascus ruber, a heat-resistant fungus isolated from green table olives.
AB  - AIMS: Growth modes predicting the effect of pH (3.5-5.0), NaCl (2-10%), i.e. aw
      (0.937-0.970) and temperature (20-40 degrees C) on the colony growth rate of
      Monascus ruber, a fungus isolated from thermally-processed olives of the
      Conservolea variety, were developed on a solid culture medium. METHODS AND
      RESULTS: Fungal growth was measured as colony diameter on a daily basis. The
      primary predictive model of Baranyi was used to fit the growth data and estimate
      the maximum specific growth rates. Combined secondary predictive models were
      developed and comparatively evaluated based on polynomial, Davey, gamma concept
      and Rosso equations. The data-set was fitted successfully in all models. However,
      models with biological interpretable parameters (gamma concept and Rosso
      equation) were highly rated compared with the polynomial equation and Davey model
      and gave realistic cardinal pHs, temperatures and aw. CONCLUSIONS: The combined
      effect of temperature, pH and aw on growth responses of M. ruber could be
      satisfactorily predicted under the current experimental conditions, and the
      models examined could serve as tools for this purpose. SIGNIFICANCE AND IMPACT OF
      THE STUDY: The results can be successfully employed by the industry to predict
      the extent of fungal growth on table olives.

PMID- 12492938
TI  - Female genital mutilation is a human rights issue of concern to all women and
      men.

PMID- 12492940
TI  - We have a part to play in changing the world: a conversation with Dr Vivien
      DeBack.

PMID- 12492941
TI  - Inside view: the time is now for strong, sustained WHO nursing leadership.

PMID- 12492942
TI  - Nursing shortages and evidence-based interventions: a case study from Scotland.
AB  - In this report, key aspects of change in the labour market for nurses in Scotland
      are examined, and an integrated policy framework intended to improve nurse
      recruitment, retention and utilization is outlined. The purpose of this article
      is to provide an overview of the dynamics of the nursing labour market in
      Scotland and to draw some more general messages from the evidence base on the
      effectiveness of interventions to improve recruitment and retention of nursing
      staff. The paper has three main elements: it provides a backdrop of key trends in
      the Scottish nursing labour market; it summarizes issues related to planning and
      nursing shortages, including an assessment of the utility of current indicators
      of recruitment and retention difficulties; and it reviews the main potential
      interventions to address nurse recruitment and retention difficulties, drawing
      from key research/evidence from UK and other English language sources. Five main
      interventions are examined: integrating the planning of the healthcare workforce;
      improving recruitment; incentives to improve retention; improving staff
      deployment; and improving utilization/skill mix.

PMID- 12492943
TI  - Patient involvement in education for enhanced quality of care.
AB  - Government policies in the UK are promoting health care practitioners working in
      partnership with patients and clients as an important constituent of quality in
      health care delivery. However, for practitioners to work in this way requires
      experience of such partnerships in the educational preparation. The involvement
      of patients and clients (i.e. service users) and their carers in the curriculum
      has been encouraged and supported in England since the early 1990s. From 1998,
      the comprehensive involvement in all phases of programme provision has been a
      requirement, ensuring that service users have a real 'voice' in influencing the
      direction of programmes. Examples of good practice are provided, demonstrating a
      range of approaches in the different stages of the educational process. Issues to
      be considered for successful implementation are included. Benefits to education
      and patient/client care are identified on the basis of literature and recent
      experience. They are strongly associated with enhanced quality of care. The
      article argues for a need to continue to broaden implementation for the major
      benefits of influencing the attitudes and approaches of students, and empowering
      users, with the end result of enhancing the quality of care. A strategic approach
      is needed to make user involvement an effective and workable reality. The need
      for systematic evaluation of the outcomes and for publications is highlighted.
      The principle of service user involvement in educational preparation is deemed to
      be equally relevant in other countries.

PMID- 12492945
TI  - International field test results of the Observable Indicators of Nursing Home
      Care Quality instrument.
AB  - Researchers at the University of Missouri-Columbia developed the Observable
      Indicators of Nursing Home Care Quality instrument to measure the dimensions of
      nursing home care quality during a brief on-site visit to a nursing home. The
      instrument has been translated for use in Iceland and used in Canada. Results of
      the validity and reliability studies using the instrument in 12 nursing homes in
      Reykjavik, in a large Veterans Home in Ontario with 14 units tested separately,
      and in 20 nursing homes in Missouri, are promising. High-content validity was
      observed in all countries, together with excellent inter-rater reliability and
      coefficient alpha. Test-retest reliabilities in Iceland and Missouri were good.
      Results of the international field test of the Observable Indicators of Nursing
      Home Care Quality instrument points to the usefulness of such an instrument in
      measuring nursing home care quality following a quick on-site observation in a
      nursing facility. The instrument should be used as a facility-wide assessment of
      quality, rather than for individual units within a facility. We strongly
      recommend its use by practising nurses in nursing homes to assess quality of care
      and guide efforts to improve care. We recommend its use by researchers and
      consumers and further testing of the use of the instrument with regulators.

PMID- 12492946
TI  - Using cost-analysis techniques to measure the value of nurse practitioner care.
AB  - Nurse practitioners are in a unique position to deliver high-quality care to a
      variety of populations and are being utilized in many countries worldwide.
      Although certain aspects of the nurse practitioner role may differ from country
      to country, limited financial support and competition for access to patients make
      it incumbent on nurse practitioners to document the cost-effectiveness of their
      care. Cost analysis, a business tool that can be used by any practitioner in any
      health care system, was used to examine business practices of an academic-based
      nurse-managed centre. In order for this tool to be effective, nurse practitioners
      must become comfortable with using cost-analysis techniques in their practices.
      Linking outcome data with cost data was found to be one method for explicating
      the value of nurse practitioner practice. Nurse practitioners must also recognize
      that they are competing with primary-care physician practices and other primary
      health-care practices. It is vital for nurse practitioners to document both the
      quality and the costs of their care in order to compete with physicians and other
      health care providers, in order to influence policy and other health-care
      decision makers.

PMID- 12492944
TI  - The telling and knowing of dying: philosophical bases for hospice care in Japan.
AB  - This article describes the historical and cultural factors that led to the modern
      definition of hospice in the United States and Japan. It also raises questions
      about the import of western hospice philosophy into Japan by examining some
      traditional values and cultural norms of behaviour surrounding dying in that
      country. The ethics of disclosure and open discussion, as a prerequisite to and
      foundational value in western hospice care, differs in Japan. If traditional
      Japanese values remain strong, expectations regarding hospice care based on this
      western ethics may be misplaced. This report ends with a suggestion of replacing
      the western imported hospice philosophy with an (as yet not explicated) Japanese
      philosophical ethic of the good.

PMID- 12492948
TI  - Clinical features of renal cell carcinoma less than 25 millimeters in diameter.
AB  - BACKGROUND: We retrospectively investigated the clinicopathological features and
      prognosis of patients who underwent surgical treatment at our department for
      renal cell carcinoma (RCC) less than 25 mm in diameter. METHODS: Of the 158
      patients who underwent surgical treatment between April 1975 and April 1998, 16
      (17 kidney, 10.1%) were included in this study. The study included 11 men and 5
      women (ratio: 2.2). The age range was 35-76 years (average: age 53). The right
      kidney was involved in 9, left kidney in 6 and bilateral kidneys in 1 patient.
      The follow-up period was 26-157 months (mean: 86 months). RESULTS: Thirteen
      tumors (81.2%) were incidental carcinomas. No patients had a tumor of rapid
      growing type. Radical nephrectomy was performed for 12 kidneys (70.6%), simple
      nephrectomy for 2 (11.8%) and partial nephrectomy for 3 (17.8%). Seven patients
      (43.7%) received interferon-alpha as postoperative adjuvant therapy. All tumors
      were pathologically classified as expansive type; 11 (64.8%) as clear cell
      carcinoma; 3 (17.6%) cyst-associated, and 3 (17.6%) papillary. Nine (52.9%)
      tumors were grade 1, and 8 (47.1%) were grade 2. Fourteen patients were pNo and
      V(-). The 5- and 10-year survival rates were excellent (100%). CONCLUSION: The
      features of small RCCs less than 25 mm were as follows: many tumors were
      incidental to clear cell carcinomas; all tumors were low grade, low stage and
      expansive type; no tumors showed acute phase reactants; and few tumors were of
      the solid type. Thus, the prognosis seemed to be excellent.

PMID- 12492949
TI  - Ultrasonographic changes of the female bladder neck during development.
AB  - BACKGROUND: Our previous study showed that the anteroposterior vesical wall angle
      (APVA) at the bladder neck on transabdominal ultrasonography varied widely
      between women. The present study examines whether the APVA changes during
      development in girls with a normal bladder. METHODS: Seventy-four females aged 0
      29 years with normal bladders were examined by transabdominal ultrasonography.
      They were divided into six age groups and their APVA was measured in the supine
      position by sagittal ultrasonography. Intravenous urography was conducted to
      examine bladder neck descent and bladder neck opening. RESULTS: The APVA ranged
      from 85 to 200 degrees. The mean APVA in girls aged 0-4 years was 129 +/- 30
      degrees (+/-SD) and the mean APVA in girls aged 5-9 years was 135 +/- 25 degrees.
      The mean APVA at ages 10-14 years was 161 +/- 26 degrees; at 15-19 years, 164 +/-
      33 degrees; at 20-24 years, 164 +/- 18 degrees; and at 25-29 years, 163 +/- 16
      degrees. The APVA values of these four groups were significantly larger (P <
      0.05) than those of the two younger groups. No bladder abnormalities were found
      on intravenous urography. CONCLUSION: The APVA was small in some girls under 10
      years of age, but the APVA of girls aged over 10 years was similar to that in
      young adults. The APVA may reflect bladder base plate tone and be partially
      related to hormonal changes in females during development.

PMID- 12492950
TI  - Treatment of monosymptomatic nocturnal enuresis by acupuncture: A preliminary
      study.
AB  - OBJECTIVES: This study was designed to clarify the clinical usefulness of
      acupuncture as a treatment option for monosymptomatic nocturnal enuresis, and
      evaluate the mechanisms of its effect. METHODS: Subjects comprised 15 patients
      (10 males, 5 females) with monosymptomatic nocturnal enuresis who were treated by
      acupuncture using a disposable stainless steel needle (0.3 mm in diameter, 60 mm
      in length) inserted into bilateral BL-33 (Zhongliao) points on the skin of the
      third posterior sacral foramina and rotated manually for 10 min reciprocally.
      Bladder capacities and number of wet nights per week were compared before and
      after treatment. Patients in whom wet nights decreased 50% or more compared with
      the baseline were considered responders. RESULTS: Nocturnal enuresis improvement
      rates following acupuncture treatment were 40% (6/15) just after treatment and
      47% (7/15) 2 months after. In 6 responders, just after treatment the nocturnal
      bladder capacity (NBC) increased significantly, from 201 mL to 334 mL (P < 0.05).
      No side-effects were recognized throughout the treatment period. CONCLUSION:
      Acupuncture may be beneficial in the treatment of nocturnal enuresis by
      increasing NBC, and provide a promising alternative to conventional therapies for
      monosymptomatic nocturnal enuresis.

PMID- 12492951
TI  - Clinical outcome of bacillus Calmette-Guerin perfusion therapy for carcinoma in
      situ of the upper urinary tract.
AB  - BACKGROUND: The objective of this study was to evaluate the efficacy of
      intrarenal bacillus Calmette-Guerin (BCG) instillation for the treatment of
      carcinoma in situ (CIS) of the upper urinary tract. METHODS: Sixteen patients who
      were diagnosed as having CIS of the upper urinary tract were treated with
      intrarenal BCG instillation. BCG (80 mg) in normal saline was administered once
      weekly, 6 times in total as one course through a percutaneous nephrostomy tube in
      5 patients, and a retrograde ureteric catheterization using a Single-J or Double
      J stent in 2 and 9 patients, respectively. RESULTS: During the median follow-up
      period of 30 months (range: 9-90 months), no patients died, and 13 patients
      remained cytologically negative in urine collected from the upper urinary tract
      after BCG treatment was completed. However, one of these 13 patients had CIS in
      the bladder and prostatic urethra 34 months after the BCG therapy and had to
      undergo radical cystectomy. The remaining 3 patients experienced recurrence in
      the upper urinary tract 4, 8, and 11 months after treatment, despite a favorable
      response to the initial BCG instillation. Of these 3 patients, one patient
      received an additional course of BCG therapy, while the remaining 2 underwent
      nephroureterectomy. Bladder irritability or a fever higher than 38 degrees C was
      observed in 12 or 9 patients, respectively; however, such side-effects were not
      clinically significant, and no patient received antitubercular treatment.
      CONCLUSION: Intrarenal instillation of BCG appears to be effective and safe for
      treatment of CIS of the upper urinary tract; however, further experience and
      longer follow-up studies of this treatment are required.

PMID- 12492952
TI  - Changes in serum and prostatic zinc concentrations in rats after intraprostatic
      injection of zinc: Comparison of two forms of zinc delivery.
AB  - BACKGROUND: We investigated changes in zinc concentrations in serum and prostatic
      tissue after an intraprostatic injection of zinc, and compared two forms of zinc
      delivery: solution and liposome. METHODS: Ninety-six male Wistar rats were used
      in the study (24 controls, 72 test rats). The test animals were randomly divided
      into two groups and were injected intraprostatically with 2 mL of 0.04 mol/L zinc
      sulfate according to the form of zinc delivery. Nine rats in each test group were
      sacrificed 1 day, 7, 14 and 28 days after injection, and 24 normal rats were
      injected intraprostatically with 2 mL of distilled water as controls. Serum and
      prostatic zinc concentrations of each group were measured by inductively coupled
      plasma atomic emission spectrometry. Blood chemistries, routine urinalysis, urine
      culture and histopathologic examination were also performed. RESULTS: Serum zinc
      concentrations did not change significantly after the intraprostatic injection of
      zinc. Prostatic zinc concentrations were found to be significantly greater (P <
      0.05) in zinc-injected groups than in the control group. The intraprostatic
      injection of zinc solution and zinc liposome increased zinc levels in both
      ventral and dorsolateral lobes significantly. Prostatic zinc levels increased
      progressively following injection, reaching a peak level in 7 days and
      maintaining a high value throughout the experimental period. The prostatic zinc
      level of the 1-day zinc liposome group was higher than that of the 1-day zinc
      solution group, while no significant difference was observed between the solution
      and liposome group in 7, 14, 28 days. No abnormal findings were observed in any
      of the laboratory and histopathologic examinations; however, an acute
      inflammatory response was observed in the 1-day groups. CONCLUSION: These
      findings suggest that an intraprostatic injection of zinc in normal rats
      increases and maintains the prostatic zinc level for at least 4 weeks without
      causing any systemic or local toxicities. These findings suggest the potentially
      important clinical applicability of local zinc to the treatment of chronic
      prostatitis.

PMID- 12492953
TI  - Changes in serum and prostatic zinc concentrations in rats after intraprostatic
      injection of zinc: Comparison of two forms of zinc delivery.

PMID- 12492954
TI  - Muscarinic M2 receptors inhibit Ca2+-activated K+ channels in rat bladder smooth
      muscle.
AB  - PURPOSE: To clarify the functional relationship between M2 muscarinic receptor
      and Ca2+-activated K+ channel, we investigated the effect of carbachol (CCh) on
      the membrane current of rat bladder smooth muscle cells. METHODS: Rat bladder
      single smooth muscle cells were patch clamped with whole-cell configuration.
      RESULTS: CCh (10 micro mol/L) transiently induced an outward current in the
      presence of K+ in the pipette solution. A high Ca2+ concentration in the pipette
      solution persistently induced an outward current, which was inhibited by CCh. In
      the presence of M2 inhibitor, AFDX-384, CCh induced the outward current
      persistently, indicating that M2 was involved in the current inhibition. In
      pertussis toxin pretreated cells, CCh did not apparently inhibit the outward
      current. The CCh-induced outward current was inhibited by iberiotoxin, a
      selective inhibitor of large-conductance Ca2+-activated K+ channels (BKCa).
      CONCLUSION: CCh induces BKCa, which is inhibited by M2- and Gi-mediated signal
      transduction pathway. This M2-mediated pathway may enhance contraction which is
      initiated by M3-stimulation in rat bladder smooth muscle.

PMID- 12492955
TI  - Histologically benign but telomerase positive adrenal pheochromocytoma.
AB  - Adrenalectomy was performed on a 37-year-old woman with right adrenal
      pheochromocytoma. Although the histological diagnosis was benign, telomerase
      repeat amplification protocol (TRAP) demonstrated positive telomerase activity.
      Thirty-five months after adrenalectomy, a recurrent tumor was found. Forty-seven
      months after adrenalectomy, bone metastases also appeared. Malignant
      pheochromocytoma was clinically diagnosed. Our experience suggests that
      telomerase-positive tumor cells are highly likely to repeat cell proliferation
      when they are left in the patient's body, and lead to recurrence. Therefore,
      telomerase-positive tumors should be clinically treated as malignant even if they
      have been histologically diagnosed as benign.

PMID- 12492956
TI  - Incidentally discovered pheochromocytoma in long-term hemodialysis patients.
AB  - Two cases of pheochromocytoma incidentally discovered in long-term hemodialysis
      patients are reported. Case 1 was a 47-year-old-man who had been receiving
      hemodialysis for 18 years. Case 2 was a 33-year-old woman who had been receiving
      hemodialysis for 12 years. Both cases were normotensive, and no specific symptoms
      suggesting pheochromocytoma were seen. Plasma norepinephrine (NE) levels were not
      elevated in both cases; however, the level of epinephrine (E) was double the
      normal range in Case 2. After surgery, plasma E level returned to the normal
      range in Case 2; however, the level of NE remained almost the same as the
      preoperative value in both cases. Plasma catecolamine levels in long-term
      hemodialysis patients with pheochromocytoma are reviewed in the present report,
      and the efficacy of imaging methods in the diagnosis of pheochromocytoma are
      discussed.

PMID- 12492957
TI  - Retroperitoneoscopic nephrectomy for juxtaglomerular cell tumor.
AB  - We present a case of juxtaglomerular cell tumor (JGCT) in a 20-year-old woman.
      She presented with hypertension and elevated plasma renin activity. Computed
      tomography without enhancement by contrast medium detected a tumor at the center
      of the left kidney. Retroperitoneoscopic left nephrectomy was performed and
      postoperatively her blood pressure and plasma renin activity returned to normal.
      This is the first report of retroperitoneoscopic nephrectomy performed for a
      JGCT.

PMID- 12492958
TI  - Ureteroenteric fistula after retrograde balloon dilatation of ureteral stricture.
AB  - Advances in endourology have made transluminal balloon dilatation a safe and
      effective procedure for the treatment of ureteral strictures. Bilateral ureteral
      stricture was treated with retrograde balloon dilatation and ureteral stenting in
      a 59-year-old-woman. The patient had previously undergone abdominoperineal
      resection and adjuvant radiotherapy due to rectosigmoid adenocarcinoma.
      Subsequently, unilateral ureteroenteric fistula was detected on follow-up
      retrograde ureteropyelography. To our knowledge, this is the first case of
      ureteroenteric fistula after balloon dilatation for ureteral stricture in a
      patient with predisposing factors for compromised vascularity of the ureter.

PMID- 12492959
TI  - Endoscopic management of post-traumatic prostatic and supraprostatic strictures
      using Neodymium-YAG laser.
AB  - We assessed the feasibility, efficacy and long-term results of endoscopic
      management using Neodymium-YAG (Nd-YAG) laser as a day care procedure in patients
      with post-traumatic supraprostatic and prostatic strictures. Three patients with
      post-traumatic prostatic and supraprostatic obliterative strictures underwent Nd
      YAG laser core through urethrotomy as a day care procedure. Patient age ranged
      between 12 and 14 years. Mean duration of injury was 16 months. The length of
      stricture was assessed by bi-directional endoscopy prior to the procedure in all
      cases. Core through procedure was carried out using Nd-YAG laser under the
      guidance of a cystoscope placed antegradely. Patients were discharged on the same
      day with urethral catheter. Foley catheters were removed at 6 weeks. Nd-YAG laser
      core through procedure was carried out successfully in all cases with negligible
      blood loss in a mean time of 48 min. There were no intraoperative or
      postoperative complications. Patients were discharged on the same day. Follow-up
      cystogram was conducted at 6 weeks and urethroscopy at months. At a mean follow
      up of 23 months, patients were asymptomatic and voiding well. Nd-YAG laser core
      through urethrotomy is a safe and effective procedure. It is a less invasive
      alternative to more complex urethroplasty procedures for patients with post
      traumatic prostatic and supraprostatic strictures. It can be carried out as a day
      care procedure in carefully selected patients and has no complications.

PMID- 12492960
TI  - Collecting duct carcinoma of the kidney.

PMID- 12492962
TI  - Endoscopic removal of intravesical thermometer using a rigid nephroscope and
      forceps.
AB  - Intravesical thermometers are occasionally encountered in urologic practice. In
      the present paper, we describe the removal of a thermometer from the bladder of a
      woman who presented with irritable bladder symptoms. The thermometer was removed
      intact transurethrally using a rigid nephroscope and forceps, even though both
      ends of the thermometer were embedded in the bladder wall. Our retrieval
      technique may be of general use in such cases, and it should be attempted before
      resorting to open surgery.

PMID- 12492964
TI  - Advances in the management of psoriasis: monoclonal antibody therapies.
AB  - Psoriasis is a common skin disorder characterized by erythematous, scaling
      plaques. Until recently, therapies for this disease have been aimed at reducing
      keratinocyte proliferation. We have learned that psoriasis is not primarily a
      disorder of keratinocyte hyperproliferation, but is an inflammatory disease. This
      knowledge, especially our current understanding of the role of activated T cells
      in psoriasis, has led to new therapeutic options and new areas of research.
      Immunosuppressive agents such as cyclosporine have proven very useful in the
      treatment of psoriasis, but their use is limited by toxicity. Monoclonal
      antibodies directed against key components of the inflammatory process have been
      studied in an attempt to produce safer, more selective immunosuppressive agents.
      This review summarizes much of the available literature describing the use of
      monoclonal antibodies in the treatment of psoriasis.

PMID- 12492965
TI  - Modulation in vitro of keratinocyte integrins by interferon-alpha and interferon
      gamma.
AB  - BACKGROUND: Interferon-alpha and -gamma are glycoproteins with antiviral and
      immunoregulatory properties. In vitro studies have shown a role for these
      cytokines in the regulation of epidermal keratinocyte growth and differentiation.
      In the same way, integrins are adhesion molecules which regulate keratinocyte
      proliferation and differentiation. AIM: To determine whether the regulatory
      activity of interferons on keratinocyte proliferation and differentiation is
      related to a modulation of keratinocyte integrins. METHODS: Two different methods
      were used: monolayers and reconstituted skin, incubated either with 1,200 U/mL
      interferon-alpha or 500 U/mL interferon-gamma or control medium for 48 h. The
      integrin expression was assessed by flow cytometry and immunohistochemistry.
      RESULTS: In monolayers, only the alpha3 subunit was significantly inhibited by
      interferon-gamma. In reconstituted skin, where keratinocytes are differentiated,
      both interferons had an inductive effect on beta1 expression and interferon-alpha
      had an inhibitory effect on alpha6 expression. CONCLUSION: Interferon-alpha and 
      gamma induce a modulatory effect on alpha3, alpha6 and beta1 which appears to be
      related to the state of differentiation. Moreover, the decreased expression of
      alpha6 and alpha3 could be one of the mechanisms involved in the formation of
      bullous lesions during long-term interferon therapy.

PMID- 12492966
TI  - Skin manifestations of arsenicosis in two villages in Bangladesh.
AB  - BACKGROUND: Arsenic contamination in groundwater affects 35 million people in
      Bangladesh, but the prevalence of arsenic contamination in local communities
      remains to be clarified. As skin manifestations are sensitive markers of
      arsenicosis, we examined the skin of adults and adolescents in two villages to
      elucidate the severity of arsenicosis. METHODS: Five hundred and sixty-one
      villagers were randomly selected for the evaluation of their skin. Three
      indicators, i.e. keratosis on the soles, keratosis on the palms, and melanosis
      and hypopigmentation on the trunk, were quantified for analysis. RESULTS: More
      than 50% of the villagers showed some skin manifestations due to arsenicosis.
      Keratosis on the soles was the most sensitive marker for the detection of
      arsenicosis at an early stage. Interestingly, the skin manifestations were more
      severe in males than in females. There was no correlation between the age and the
      severity of skin manifestations. CONCLUSIONS: The prevalence of arsenicosis was
      quite high and males were more vulnerable to arsenic contamination. Using skin
      manifestations, especially keratosis on the soles, as useful markers to detect
      and evaluate arsenicosis, it is clear that there is an urgent need to assess the
      exact prevalence and severity of arsenicosis in the population of Bangladesh in
      order to take measures to treat and control this problem.

PMID- 12492967
TI  - Necrotizing gangrene of the genitalia and perineum.
AB  - BACKGROUND: Necrotizing gangrene of the genitalia and perineum is a fulminant,
      life-threatening condition. This infection is usually polymicrobial and may be
      idiopathic or secondary to local trauma or surgery. Histologically, it is
      characterized by obliterative endarteritis and thrombosis of the subcutaneous
      vessels, fascial necrosis, and leukocytic infiltration. Mortality rates of 25-75%
      have been reported. Most cases of necrotizing gangrene begin insidiously, with
      scrotal discomfort and malaise. Later, erythema, increasing pain, and swelling,
      associated with fever and chills, develop. A biopsy is useful to confirm the
      clinical diagnosis and to obtain culture samples. Ultrasound imaging may reveal
      gas or testicular involvement and may help to distinguish this infection from
      other causes of scrotal pathology. MATERIALS AND METHODS: Fifteen patients with
      necrotizing gangrene of the genitalia and perineum, seen at the Dermatology and
      Plastic Surgery Sections of our Institutions between 1994 and 1999, are
      described. RESULTS: This series included 11 men (73%) and four women (27%), aged
      39-68 years (mean, 51 years). In our series, Clostridium perfingens,
      Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, Streptococcus
      viridans, Acinetobacter baumani, Escherichia coli, and Candida albicans were
      isolated. Hemodynamic stabilization and monitoring were performed in all
      patients. Intravenous antimicrobial therapy was promptly instituted. In most
      cases, two or more drugs were used. Concurrent surgical debridement of all
      necrotic areas was always required. When needed, split-thickness skin grafts were
      used to cover the penile shaft. Expanded mesh grafts were used to reconstruct the
      vulva and other denuded beds. The survival rate in this series was 87%.
      CONCLUSIONS: Necrotizing gangrene of the genitalia and perineum continues to be a
      diagnostic and therapeutic challenge. The usual polymicrobial infection with
      vascular involvement demands hemodynamic stabilization, systemic antimicrobial
      therapy, and surgical debridement. In some patients, genital, perineal, and
      abdominal wall reconstruction is also required.

PMID- 12492968
TI  - Cutaneous findings associated with chronic natural killer cell lymphocytosis.
AB  - BACKGROUND: Chronic Natural Killer Cell Lymphocytosis (CNKL) is a recently
      described rare proliferative disorder. We noted an association of cutaneous
      disorders with CNKL in our clinical experience. METHODS: We reviewed the medical
      records of all known patients with CNKL at our institution. RESULTS: Five of 14
      patients (36%) with CNKL had associated chronic cutaneous disease: two had
      livedoid vasculopathy; one, urticarial vasculitis; one, peripheral T-cell
      lymphoma; and one had complex recurrent aphthous stomatitis. In each case, except
      the one with lymphoma, the cutaneous disease was present before CNKL was
      diagnosed and CNKL persisted for the duration of the cutaneous disease. All five
      patients had increased numbers of large granular lymphocytes on a peripheral
      blood smear and three or four in the bone marrow (one patient did not undergo
      bone marrow biopsy). CONCLUSIONS: Although CNKL and the reported skin diseases
      have occurred in the same patients, a causal link cannot yet be established. With
      CNKL, dermatologists must recognize associated cutaneous diseases, monitor
      patients for systemic disorders and cytopenias, and appropriately refer patients
      to a hematologist.

PMID- 12492969
TI  - False positive VDRL (BFP-STS) and systemic lupus erythematosus; new data in
      clinico-laboratory associations.
AB  - AIM: To investigate the relationships between clinical features and serological
      parameters in systemic lupus erythematosus (SLE) patients with false positive
      venereal disease research laboratory (VDRL) test (BFP-STS) and those without.
      METHODS: The records of 74 patients with SLE were reviewed. These were divided on
      the basis of the presence of a biologically false positive serological test (BFP
      STS) (n = 18) or its absence (n = 56). The clinical features and serological
      parameters were subsequently evaluated in each group. RESULTS: A biologically
      false positive serological test was found in 18 patients (24.5%). Clinically,
      they had a significantly higher frequency of malar rash (P < 0.02), hemolytic
      anaemia (P < 0.02) and SLE-related antiphospholipid (APL) syndrome (P < 0.02).
      Neuropsychiatric lupus was more frequent in the group without BFP-STS. Moreover,
      subacute cutaneous LE (SCLE), Raynaud's phenomenon, livedo reticularis (LR) and
      cardiopulmonary complications were present only in the latter group. There was no
      significant association between BFP-STS and other autoantibodies including
      Extractable nuclear antigen (ENAs), however, there was a significant association
      with C3 hypocomplementemia (P < 0.05). Half of the patients with BFP-STS were
      positive for anticardiolipin antibodies (aCL Abs) vs. 28% in the negative group
      (P = NS). CONCLUSIONS: The study suggests that the clinical and serological
      relevance of BFP-STS in lupus patients may vary from those described in relation
      to other antiphospholipid determinants. Our patients appeared to have sparing of
      certain major organ systems, yet there was a greater tendency to developing
      Antiphospholipid (APL) syndrome and hemolytic anaemia.

PMID- 12492970
TI  - Polymerase chain reaction in cutaneous tuberculosis: is it a reliable diagnostic
      method in paraffin-embedded tissues?
AB  - BACKGROUND: Most cutaneous tuberculosis lesions contain few bacilli, so
      identification of Mycobacterium tuberculosis in conventional laboratory tests is
      difficult. In vitro amplification of specific DNA sequences using polymerase
      chain reaction (PCR) has become a valuable tool in the rapid detection of slow
      growing organisms like M. tuberculosis. AIM: To investigate the presence of M.
      tuberculosis DNA in cutaneous tuberculosis. METHODS: Twenty-two archival biopsy
      specimens diagnosed as cutaneous tuberculosis were investigated for the presence
      of M. tuberculosis DNA by PCR. Normal skin samples of 29 healthy patients were
      used as a control. RESULTS: Amplification of the M. tuberculosis DNA was observed
      in one of the cutaneous tuberculosis specimens and in a healthy control.
      CONCLUSION: Although PCR is a rapid diagnostic method, fixation procedures may
      decrease its sensitivity.

PMID- 12492971
TI  - Perception of men with androgenetic alopecia by women and nonbalding men in
      Korea: how the nonbald regard the bald.
AB  - BACKGROUND: Baldness has significant negative psychosocial effects. It has been
      asserted that the negative effects of baldness are often trivialized by the
      nonbald. Most studies concerning the perception of baldness have focused on the
      perceptions of the bald by themselves. In this study, we assessed the perception
      of baldness by the nonbald in Korea. METHOD: A questionnaire on the perception of
      balding men was answered by 130 women (age range 15-58 years), 90 nonbalding men
      (age range 18-72 years) and 30 balding men (age range 20-63 years). RESULTS:
      Balding men were perceived as being older and less attractive by over 90% of
      respondents. A perception that balding men are less confident, duller, and less
      potent was reported by less than half of respondents. A perception that balding
      men are less attractive was significantly more common among women than among
      nonbalding men (P < 0.05). A perception that balding men appear less confident
      was significantly more common among balding men than among nonbalding men (P <
      0.05). CONCLUSION: In this study of Koreans, the perception of balding men by
      others was similar to the perception of balding men by themselves. It is likely
      that androgenetic alopecia adversely influences social interactions of those who
      are subject to it.

PMID- 12492972
TI  - Demographic features and seasonal variations in patients with acne vulgaris in
      Saudi Arabia: a hospital-based study.
AB  - AIM: To review the demographic features and seasonal variations of acne vulgaris
      in patients diagnosed at the Dermatology Outpatient Clinic, King Fahad Hospital
      of the University (KFHU), Al-Khobar, Saudi Arabia. METHODS: Two hundred and
      twenty cases (142 females, 78 males; mean age, 14.8 and 16.3 years, respectively)
      seen between January 1, 1999 and December 31, 2000 were studied. RESULTS:
      Patients suffering from acne vulgaris made up 19.6% of the new cases seen at the
      clinic. The male to female ratio was 1 : 1.8. The mean age of onset was 16.3 +/-
      2.1 years for males and 14.8 +/- 3.9 years for females (P = 0.003). The largest
      numbers of patients were seen during the cold months of the year (November to
      February). CONCLUSIONS: Acne vulgaris constituted nearly one fifth of all visits
      to the dermatologist with female predominance. It appears nearly one and a half
      years earlier in females than in males. Seasonal variations were observed in acne
      as the condition exacerbates in winter, while if often improves during the summer
      months.

PMID- 12492974
TI  - Post-kala-azar dermal leishmanasis occurring after 10 years of treated kala azar.
AB  - Post-kala-azar dermal leishmaniasis (PKDL) as the name suggests, develops usually
      after 1-2 years of treated kala azar (KA).1 Infrequently, cases may be seen later
      than 2 years. A case of PKDL occurring after 10 years of treated KA is herein
      reported. Such a long disease-free interval may be forgotten by the patient, and
      if not carefully elicited in the history, the diagnosis of PKDL may be missed.

PMID- 12492973
TI  - Leg ulcers and hydroxyurea: report of three cases with essential thrombocythemia.
AB  - CASE 1: A 65-year-old woman with essential thrombocythemia (ET) had been taking
      oral hydroxyurea (HU), 1,000 mg daily, for 7 years. Six months ago, she developed
      an ulcer on the outer part of her left ankle, which healed spontaneously within 2
      months. She presented with a new, tender, shallow ulcer, 2 cm x 2 cm in size, at
      the same site. Doppler examination revealed thrombosis of the left common femoral
      vein and a calcified atheroma plaque of the left common femoral artery. The
      dosage of HU was decreased to 500 mg daily when the platelet counts were found to
      be within normal levels. The ulcer completely healed within 2 months with
      occlusive wound dressings, and has not recurred within the follow-up period of 1
      year. CASE 2: A 56-year-old women presented with multiple, painful, leg ulcers of
      1 year duration. She had been diagnosed as having ET and had been on HU therapy,
      1,500 mg/day, for the past 5 years. Interferon-alpha-2b was started 3 months ago,
      in addition to HU, which was tapered to 1,000 mg daily. She had suffered from
      hypertension for 20 years treated with nifedipine and enalapril, and had recently
      been diagnosed with diabetes mellitus which was controlled by diet. Examination
      revealed three ulcers located on the lateral aspects of both ankles and right
      distal toe. Arterial and venous Doppler examinations were within normal limits.
      Histopathology of the ulcer revealed nonspecific changes with a mixed
      inflammatory cell infiltrate around dermal vessels. The ulcers completely healed
      within 10 weeks with topical hydrocolloid dressings. After healing, she was lost
      to follow-up. A year later, it was learned that she had developed a new ulcer at
      her right heel, 3 months after her last visit (by phone call). This ulcer
      persisted for 8 months until HU was withdrawn. CASE 3: A 64-year-old woman with
      ET presented with a painful leg ulcer of 6 months' duration. She had been taking
      oral HU for 5 years. She had a 20-year history of hypertension treated with
      lisinopril. Examination revealed a punched-out ulcer of 2 cm x 2 cm over the
      right lateral malleolus. Doppler examination of the veins revealed insufficiency
      of the right greater saphenous and femoral veins. Angiography showed multiple
      stenoses of the right popliteal and femoral arteries. As her platelet count
      remained high, HU was continued. During the follow-up period of 13 months, the
      ulcer showed only partial improvement with local wound care.

PMID- 12492975
TI  - Larvicidal effects of mineral turpentine, low aromatic white spirits, aqueous
      extracts of Cassia alata, and aqueous extracts, ethanolic extracts and essential
      oil of betel leaf (Piper betle) on Chrysomya megacephala.
AB  - BACKGROUND: Many methods have been employed, with variable success, in the
      treatment of cutaneous myiasis caused by Chrysomya species. AIMS: Experiment 1:
      to assess the larvicidal effect of mineral turpentine (MT) and the main
      ingredient of MT, low aromatic white spirits (LAWS), on Chrysomya megacephala
      larvae in vitro. Experiment 2: to assess the larvicidal effects of aqueous
      extracts of winged senna (Cassia alata), and aqueous extracts, ethanolic extracts
      and essential oil of betel leaf (Piper betle). METHODS: In experiment 1, two
      samples of LAWS were obtained from two industrialists (samples 1 and 2). Adult
      flies of C. megacephala were bred in the insectory of the Department of
      Parasitology, Faculty of Medicine, University of Colombo. Petri dishes were
      prepared with pads of cotton wool. These cotton pads were soaked separately in
      MT, LAWS samples 1 and 2, and normal saline as a control. Ten larvae were placed
      in each Petri dish. The activity of the larvae was observed and recorded half
      hourly. MT and the two samples of LAWS were analyzed by chromatography. In
      experiment 2, volatile essential oil of betel was prepared using a standard steam
      distillation process. An ethanolic extract of betel was obtained after boiling
      the crushed leaf with water, and mixing the stock with ethanol. Betel oil
      dilutions of 1-4% were prepared using 1% Tween 80 (v/v aq) as a solvent, with
      0.05 g/100 mL sodium lauryl sulphate (as stabilizer) and 0.01 g/100 mL methyl
      paraben (as a preservative). Cotton wool swabs soaked in 1, 2, 3 and 4% essential
      oil of betel in 1% Tween 80 (v/v aq) prepared as above, 1, 2, 3 and 4% ethanolic
      extract of betel, 50 and 25% aqueous extract of C. alata, and 50 and 25% aqueous
      extract of betel were placed in separate Petri dishes. Ten larvae were placed in
      each Petri dish. 1% Tween 80 solvent with the stabilizer and the preservative,
      but without betel essential oil, was used as a negative control and MT was used
      as a positive control. Larval motility was assessed as before. RESULTS: MT and
      the two LAWS samples killed the larvae in vitro within 4 h. Chromatography showed
      more unidentified constituents in MT than in pure LAWS, indicating additional
      substances in MT. The 4 and 3% preparations of the essential oil of betel were
      effective in killing 100% of the larvae of Chrysomya within 3 h 30 min. The 2%
      extract of betel essential oil killed 96.7% of larvae in 4 h. Ethanolic and
      aqueous extracts of betel, the aqueous extract of C. alata, normal saline and the
      Tween 80 solvent were not larvicidal. CONCLUSIONS: MT and LAWS, the main
      ingredient of MT, were effective in killing Chrysomya larvae. Essential oil
      obtained from betel leaves also showed a dose-dependent larvicidal effect on
      Chrysomya larvae. This natural product may be effective in the treatment of wound
      myiasis.

PMID- 12492977
TI  - Cutaneous extramedullary hematopoiesis in idiopathic myelofibrosis.

PMID- 12492976
TI  - Paracoccidioidomycosis: unusual clinical presentation and utility of computerized
      tomography scanning for diagnosis.

PMID- 12492978
TI  - Dermatomyositis-like reaction induced by chemotherapeutical agents.

PMID- 12492979
TI  - Extranodal Rosai-Dorfman disease with cutaneous, ophthalmic and laryngeal
      involvement: report of a case treated with isotretinoin.

PMID- 12492980
TI  - Multiple pilomatricoma with perforation.

PMID- 12492981
TI  - Milia en plaque in a renal transplant patient: a rare presentation.

PMID- 12492982
TI  - Late onset phaeomycotic cyst in a renal transplant recipient.

PMID- 12492983
TI  - Granuloma faciale associated with adenocarcinoma of the prostate.

PMID- 12492984
TI  - Multinodular keratoacanthoma: a rare but definite entity.

PMID- 12492985
TI  - Chronic palmar ulcer: a case of epithelioid sarcoma.

PMID- 12492986
TI  - Xanthoma disseminatum.

PMID- 12492987
TI  - Unusual case of cutaneous tuberculosis associated with rheumatoid arthritis: a
      case report and literature review.

PMID- 12492988
TI  - Pyoderma gangrenosum of the scalp treated with cyclosporine A.

PMID- 12492989
TI  - Extranodal NK/T-cell lymphoma with extensive subcutaneous involvement, mimicking
      subcutaneous panniculitis-like T cell lymphoma.

PMID- 12492990
TI  - Leukoderma punctatum following systemic PUVA therapy.

PMID- 12492991
TI  - Cardio-facio-cutaneous syndrome: a case report.
AB  - Cardio-facio-cutaneous syndrome is a genetic disorder with a characteristic
      facies, abnormal skin and hair, mental retardation and congenital heart disease.
      It may be confused with Noonan's syndrome, which has a familial pattern and does
      not present hyperkeratotic skin lesions and abnormal hair, and there are few
      cases reported in the literature. We describe the first case of typical cardio
      facio-cutaneous syndrome observed in Brazil.

PMID- 12492992
TI  - A case of basal cell carcinoma arising in epidermal nevus.

PMID- 12492993
TI  - Sweet's syndrome in an infant--report of a rare case.

PMID- 12492994
TI  - Ig M class anticardiolipin antibody and anti-Ro/SS-A positivity in urticarial
      vasculitis associated with hepatitis C virus infection.

PMID- 12492995
TI  - A case of adult colloid milium with chronic sun exposure.

PMID- 12492996
TI  - Papillon-Lefevre syndrome: the response to acitretin.
AB  - Papillon-Lefevre syndrome is a rare autosomal recessive disease comprising
      palmoplantar keratoderma and periodontitis. Palmoplantar keratoderma can be
      severe, necessitating systemic treatment. Different systemic retinoids were found
      to be highly efficacious. We describe the successful use of acitretin in one
      patient who had severe palmoplantar keratoderma, with maintenance of the
      improvement using topical treatment.

PMID- 12492997
TI  - Topical prostaglandin analog (PGE2) in vitiligo--a preliminary study.
AB  - BACKGROUND: Several therapeutic options are available for the treatment of
      vitiligo, but none is uniformly effective. Prostaglandin has been shown to play a
      role in melanocyte proliferation and melanogenesis. Topical application of
      prostaglandin E2 (PGE2) over mice skin has been shown to increase melanocyte
      density. AIM: To evaluate the role of topical PGE2 in the treatment of vitiligo.
      METHODS: We enrolled 27 patients with limited vitiligo lesions in this study.
      Patients were instructed to apply a translucent gel containing 0.5 mg/3 g (166.6
      micro g/g) PGE2 to depigmented skin. RESULTS: Twenty-four patients were evaluated
      at the end of 6 months, as three patients withdrew for reasons unrelated to the
      study. At the end of treatment, 15 patients showed marked to complete
      repigmentation and three patients showed moderate repigmentation. The remaining
      six patients showed none to minimal repigmentation. CONCLUSIONS: Marginal
      repigmentation with hyperpigmented borders was seen in the majority of lesions.
      Our results are encouraging and offer a new and potentially efficacious treatment
      for this pigmentation disorder.

PMID- 12492998
TI  - Shortness of breath: an uncommon side-effect of cyproterone acetate in the
      treatment of androgenetic alopecia.
AB  - Cyproterone acetate is indicated for treatment of acne, hirsutism, seborrhea, and
      androgenetic alopecia in females. In general this medication is well tolerated in
      standard doses. Shortness of breath has been previously reported in men with
      prostatic carcinoma, receiving high-dose (200 mg/day) treatment with cyproterone
      acetate. We report a 66-year-old lady taking 50 mg/day of cyproterone acetate for
      biopsy proven androgenetic alopecia, who developed this unusual complication of
      shortness of breath. To our knowledge it has not been previously reported in
      women undergoing treatment for androgenization.

PMID- 12492999
TI  - Teicoplanin-induced skin eruption.

PMID- 12493000
TI  - A case of bullous morphea reported in mainland China.

PMID- 12493002
TI  - Genetic diversity and genomics of the immune response.

PMID- 12493003
TI  - Single nucleotide polymorphisms in innate immunity genes: abundant variation and
      potential role in complex human disease.
AB  - Under selective pressure from infectious microorganisms, multicellular organisms
      have evolved immunological defense mechanisms, broadly categorized as innate or
      adaptive. Recent insights into the complex mechanisms of human innate immunity
      suggest that genetic variability in genes encoding its components may play a role
      in the development of asthma and related diseases. As part of a systematic
      assessment of genetic variability in innate immunity genes, we have thus far have
      examined 16 genes by resequencing 93 unrelated subjects from three ethnic samples
      (European American, African American and Hispanic American) and a sample of
      European American asthmatics. Approaches to discovering and understanding
      variation and the subsequent implementation of disease association studies are
      described and illustrated. Although highly conserved across a wide range of
      species, the innate immune genes we have sequenced demonstrate substantial
      interindividual variability predominantly in the form of single nucleotide
      polymorphisms (SNPs). Genetic variation in these genes may play a role in
      determining susceptibility to a range of common, chronic human diseases which
      have an inflammatory component. Differences in population history have produced
      distinctive patterns of SNP allele frequencies, linkage disequilibrium and
      haplotypes when ethnic groups are compared. These and other factors must be taken
      into account in the design and analysis of disease association studies.

PMID- 12493004
TI  - Sequence variation in the human T-cell receptor loci.
AB  - Identifying common sequence variations known as single nucleotide polymorphisms
      (SNPs) in human populations is one of the current objectives of the human genome
      project. Nearly 3 million SNPs have been identified. Analysis of the relative
      allele frequency of these markers in human populations and the genetic
      associations between these markers, known as linkage disequilibrium, is now
      underway to generate a high-density genetic map. Because of the central role T
      cells play in immune reactivity, the T-cell receptor (TCR) loci have long been
      considered important candidates for common disease susceptibility within the
      immune system (e.g., asthma, atopy and autoimmunity). Over the past two decades,
      hundreds of SNPs in the TCR loci have been identified. Most studies have focused
      on defining SNPs in the variable gene segments which are involved in antigenic
      recognition. On average, the coding sequence of each TCR variable gene segment
      contains two SNPs, with many more found in the 5', 3' and intronic sequences of
      these segments. Therefore, a potentially large repertoire of functional variants
      exists in these loci. Association between SNPs (linkage disequilibrium) extends
      approximately 30 kb in the TCR loci, although a few larger regions of
      disequilibrium have been identified. Therefore, the SNPs found in one variable
      gene segment may or may not be associated with SNPs in other surrounding variable
      gene segments. This suggests that meaningful association studies in the TCR loci
      will require the analysis and typing of large marker sets to fully evaluate the
      role of TCR loci in common disease susceptibility in human populations.

PMID- 12493005
TI  - The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order,
      haplotypes and allelic polymorphism.
AB  - Recent genetic studies have established that the killer cell immunoglobulin-like
      receptor (KIR) genomic region displays extensive diversity through variation in
      gene content and allelic polymorphism within individual KIR genes. It is
      demonstrated by family segregation analysis, genomic sequencing, and gene order
      determination that genomic diversity by gene content alone gives rise to more
      than 20 different KIR haplotypes and at least 40-50 KIR genotypes. In the most
      reductionist format, KIR haplotypes can be accommodated within one of 10
      different prototypes, each with multiple permutations. Our haplotype model
      considers the KIR haplotype as two separate halves: the centromeric half bordered
      upstream by KIR3DL3 and downstream by 2DL4, and the telomeric half bordered
      upstream by 2DL4 and downstream by 3DL2. There are rare KIR haplotypes that do
      not fit into this model. Recombination, gene duplication, and inversion can
      however, readily explain these haplotypes. Additional allelic polymorphism
      imposes extensive individual variability. Accordingly, this segment of the human
      genome displays a level of diversity similar to the one observed for the human
      major histocompatibility complex. Recent application of immunogenetic analysis of
      KIR genes in patient populations implicates these genes as important genetic
      disease susceptibility factors.

PMID- 12493006
TI  - Genetic diversity of the human immunoglobulin heavy chain VH region.
AB  - The human immunoglobulin heavy chain VH region is one of the most complex regions
      in the human genome. The high level of diversity of this region has been shown by
      a number of studies. However, because of the limitations of the conventional
      experimental methods, it has been difficult to learn the extent of the diversity
      and the underlying mechanisms. This review describes a number of new genetic
      approaches developed in the authors' laboratory. By using these approaches,
      significant progress has been made in assigning different VH sequences to their
      respective loci, in learning the diversity of gene segment number and composition
      among the VH haplotypes, and in learning VH gene segment organization in
      individual haplotypes. Information obtained toward this direction could help in
      understanding the mechanisms underlying VH region diversity and the biological
      impact of the VH region diversity.

PMID- 12493007
TI  - Genetics of the immune response: identifying immune variation within the MHC and
      throughout the genome.
AB  - With the advent of modern genomic sequencing technology the ability to obtain new
      sequence data and to acquire allelic polymorphism data from a broad range of
      samples has become routine. In this regard, our investigations have started with
      the most polymorphic of genetic regions fundamental to the immune response in the
      major histocompatibility complex (MHC). Starting with the completed human MHC
      genomic sequence, we have developed a resource of methods and information that
      provide ready access to a large portion of human and nonhuman primate MHCs. This
      resource consists of a set of primer pairs or amplicons that can be used to
      isolate about 15% of the 4.0 Mb MHC. Essentially similar studies are now being
      carried out on a set of immune response loci to broaden the usefulness of the
      data and tools developed. A panel of 100 genes involved in the immune response
      have been targeted for single nucleotide polymorphism (SNP) discovery efforts
      that will analyze 120 Mb of sequence data for the presence of immune-related
      SNPs. The SNP data provided from the MHC and from the immune response panel has
      been adapted for use in studies of evolution, MHC disease associations, and
      clinical transplantation.

PMID- 12493008
TI  - The immunogenomics of minor histocompatibility antigens.
AB  - Minor histocompatibility (H) antigens are a diverse assemblage of major
      histocompatibility complex (MHC)-bound peptides with the unifying property of
      acting as alloantigens that induce allogeneic tissue rejection. They are a
      consequence of any form of accumulated genetic variation that translates to
      differential MHC-presented peptide epitopes, the most common form of which is
      simple sequence polymorphisms. The universe of potential minor H antigens is
      large when transplantation is performed between genetically unrelated, MHC
      matched individuals, especially considering the remarkable discriminative
      sensitivity of T cells. However, the phenomenon of immunodominance greatly
      simplifies immune responses that ensue. One mouse minor H antigen, H60, stands
      out in that the preponderance of the CD8 T cell response elicited in a complex
      alloantigenic setting is directed against this single minor H antigen epitope.
      Its immunodominance is because mice lacking H60 develop an unusually robust T
      cell repertoire dedicated to this single minor H antigen. The now well
      characterized mouse minor H antigen system should provide a vehicle to assess the
      degree to which immunodominant alloantigens contribute to transplant rejection.

PMID- 12493009
TI  - Comparative genomic analysis of the MHC: the evolution of class I duplication
      blocks, diversity and complexity from shark to man.
AB  - The major histocompatibility complex (MHC) genomic region is composed of a group
      of linked genes involved functionally with the adaptive and innate immune
      systems. The class I and class II genes are intrinsic features of the MHC and
      have been found in all the jawed vertebrates studied so far. The MHC genomic
      regions of the human and the chicken (B locus) have been fully sequenced and
      mapped, and the mouse MHC sequence is almost finished. Information on the MHC
      genomic structures (size, complexity, genic and intergenic composition and
      organization, gene order and number) of other vertebrates is largely limited or
      nonexistent. Therefore, we are mapping, sequencing and analyzing the MHC genomic
      regions of different human haplotypes and at least eight nonhuman species. Here,
      we review our progress with these sequences and compare the human MHC structure
      with that of the nonhuman primates (chimpanzee and rhesus macaque), other mammals
      (pigs, mice and rats) and nonmammalian vertebrates such as birds (chicken and
      quail), bony fish (medaka, pufferfish and zebrafish) and cartilaginous fish
      (nurse shark). This comparison reveals a complex MHC structure for mammals and a
      relatively simpler design for nonmammalian animals with a hypothetical prototypic
      structure for the shark. In the mammalian MHC, there are two to five different
      class I duplication blocks embedded within a framework of conserved nonclass I
      and/or nonclass II genes. With a few exceptions, the class I framework genes are
      absent from the MHC of birds, bony fish and sharks. Comparative genomics of the
      MHC reveal a highly plastic region with major structural differences between the
      mammalian and nonmammalian vertebrates. Additional genomic data are needed on
      animals of the reptilia, crocodilia and marsupial classes to find the origins of
      the class I framework genes and examples of structures that may be intermediate
      between the simple and complex MHC organizations of birds and mammals,
      respectively.

PMID- 12493010
TI  - Fc receptor homologs: newest members of a remarkably diverse Fc receptor gene
      family.
AB  - Newfound relatives of the classical Fc receptors (FcR) have been provisionally
      named the Fc receptor homologs (FcRH). The recent identification of eight human
      and six mouse FcRH genes substantially increases the size and functional
      potential of the FcR family. The extended family of FcR and FcRH genes spans
      approximately 15 Mb of the human chromosome 1q21-23 region, whereas in mice this
      family is split between chromosomes 1 and 3. The FcRH genes encode molecules with
      variable combinations of five subtypes of immunoglobulin (Ig) domains. The
      presence of a conserved sequence motif in one Ig domain subtype implies Ig Fc
      binding capability for many FcRH family members that are preferentially expressed
      by B lineage cells. In addition, most FcRH family members have consensus tyrosine
      based activating and inhibitory motifs in their cytoplasmic domains, while the
      others lack features typical of transmembrane receptors. The FcRH family members,
      like the classical FcRs, come in multiple isoforms and allelic variations. The
      unique individual and polymorphic properties of the FcR/FcRH members indicate a
      remarkably diverse Fc receptor gene family with immunoregulatory function.

PMID- 12493011
TI  - Genomics-based approaches to gene discovery in innate immunity.
AB  - The completion of draft sequences of the human and mouse genomes offers many
      opportunities for gene discovery in the field of immunology through the
      application of the methods of computational genomics. One arm of the innate
      immune system includes the antimicrobial peptides that protect multicellular
      organisms from a diverse spectrum of microorganisms. The beta-defensins comprise
      an important family of mammalian antimicrobial peptides. To better define the
      beta-defensin gene family, we developed an approach to search genomic databases
      for conserved motifs present in the beta-defensin family using HMMER, a
      computational search tool based on hidden Markov models (HMMs), in combination
      with the basic local alignment search tool. The approach was first used to
      identify candidate second-exon coding regions, and later applied to finding
      associated first exons. This strategy discovered 28 new human and 43 new mouse
      beta-defensin genes in five syntenic chromosomal regions. Within each syntenic
      cluster, the gene sequences and organization were similar, suggesting that each
      cluster pair arose from a common ancestor and was retained because of conserved
      functions. These findings demonstrate an important proof-of-principle for a
      genome-wide search strategy to identify genes with conserved structural motifs.
      Such an approach may be readily adopted to address other questions of relevance
      to immunology.

PMID- 12493012
TI  - Genomics-based identification of self-ligands with T cell receptor-specific
      biological activity.
AB  - Self-peptide/major histocompatibility complex (MHC) complexes profoundly
      influence the biology of T lymphocytes. They promote the selection of the T cell
      receptor (TCR) repertoire in the thymus, maintain the homeostasis of peripheral T
      cells prior to encounter with antigen, and modify the responsiveness of T cells
      to foreign antigens. In addition, they can serve as antigens for autoaggressive T
      cells that induce autoimmune diseases. The complete sequencing of the genomes of
      human, mouse, and many pathogenic organisms now provides us with a comprehensive
      list of all possible proteins that may be the source of foreign antigenic and
      self-peptides. A computational approach using profile-based similarity searches
      on potential self-MHC-binding peptides can be used to efficiently predict self
      peptides with biological activities. The common feature of the identified
      peptides is similarity to antigen. Thus, self-peptides may form 'hazy' images of
      the universe of antigens that are used as templates to create and maintain the
      TCR repertoire.

PMID- 12493013
TI  - Natural selection and the diversification of vertebrate immune effectors.
AB  - The molecules of the vertebrate immune system provide some of the best documented
      examples of natural selection acting at the molecular level. The major
      histocompatibility complex (MHC) molecules are a family of highly polymorphic
      loci whose products present peptides to T cells. Four distinct lines of evidence
      support the hypothesis that the natural selection acts to maintain MHC
      polymorphism: (1) evidence from the unusual allelic frequency distribution seen
      at MHC loci; (2) evidence from the pattern of nucleotide substitution at MHC
      loci, which shows an enhanced rate of nonsynonymous (amino acid-altering)
      substitution in the codons encoding the peptide-binding region of the molecules;
      (3) the existence of long-lasting polymorphisms at certain MHC loci; and (4) the
      fact that introns at MHC loci are homogenized by recombination and subsequent
      genetic drift. Certain other immune system gene families provide evidence that
      natural selection has acted to create diversity among family members. Examples
      include molecules of the specific immune system (such as immunoglobulin V region
      genes) and molecules of the innate immune system (such as defensins).

PMID- 12493014
TI  - Variations in immune response genes and their associations with multifactorial
      immune disorders.
AB  - There are three genetic methods often used for detecting genes contributing to
      susceptibility or resistance to multifactorial diseases: nonparametric linkage
      analysis, case-control association analysis, and transmission disequilibrium
      test. In this review, we present the theoretical basis that the case-control
      association study has the highest power of detecting disease genes if there is no
      population stratification between patients and controls. Taking advantage of the
      high power, we have carried out extensive case-control association analyses of
      candidate genes for the search of susceptibility genes to rheumatic diseases in
      the Japanese as well as in some other populations. Several new associations have
      been disclosed, including those of TNFR2, FCGR2B, and CD19 gene polymorphisms
      with systemic lupus erythematosus, in addition to some unexpected findings such
      as the common occurrence of NKG2-C null allele in the healthy population. Genome
      wide association studies using single nucleotide polymorphisms (SNPs) or
      microsatellite polymorphisms have become realistic, and development of new high
      throughput and cost-effective SNP typing technologies is urgently needed. At the
      same time, our observations may indicate that the 'classical' candidate gene
      approach will remain a strong alternative, even in the age of 'post genome
      sequence'.

PMID- 12493015
TI  - Mapping genes for autoimmunity in humans: type 1 diabetes as a model.
AB  - Type 1 diabetes (T1D) arises from autoimmune destruction of the beta cells of the
      pancreas leading to a complete dependence on exogenous insulin for survival. Like
      many autoimmune disorders, the etiology of T1D is complex, resulting from the
      action of multiple genes and environmental factors. Identification of genes that
      contribute to T1D susceptibility should improve disease prediction and contribute
      to the understanding of the underlying pathology of the disorder. Two regions of
      the human genome, the human leukocyte antigen (HLA) region and the insulin gene
      region are generally thought to contain susceptibility loci for T1D. Although
      additional putative T1D loci have been reported, the supporting evidence has
      often been of modest significance and findings have displayed poor
      reproducibility across multiple studies. This review summarizes the current state
      of genetic linkage and association studies in T1D and suggests future directions.
      We argue that much of the difficulty in mapping T1D susceptibility loci has
      resulted from inadequate sample sizes and we illustrate the substantial gains in
      power that can be achieved by pooling data across studies. These findings suggest
      that substantial progress toward the identification of susceptibility genes in
      T1D and other genetically complex disorders may be achieved through increased
      collaboration and consortium mapping efforts.

PMID- 12493016
TI  - Genetics and genomics of asthma and allergic diseases.
AB  - Asthma and eczema (atopic dermatitis) are characterized by a number of
      unexplained phenomena: the familial aggregation of disease, the initiation of
      disease by apparently trivial exposure to allergens, the preferential
      transmission of disease from affected mothers and the large increase in
      prevalence of disease in Westernized societies in the last century. A number of
      genes and chromosomal regions have been identified that consistently show linkage
      to asthma and its related phenotypes. Known loci modify the strength of the
      atopic response, nonspecific inflammation, the ability to respond to particular
      allergens and nonspecific airway reactivity. Eczema has been shown to be due to a
      different set of genetic loci that are shared with other skin diseases such as
      psoriasis and leprosy. Genetic and genomic studies both provide evidence that
      epithelial surfaces are active in the induction of allergic disease.

PMID- 12493019
TI  - Histopathology of portal hypertension: a practical guideline.

PMID- 12493020
TI  - Focal nodular hyperplasia-like areas in cirrhosis.
AB  - AIMS: Focal nodular hyperplasia-like lesions have rarely been described in
      cirrhotic livers. We describe five cases of such lesions. METHODS AND RESULTS:
      Between 1998 and 2001, 146 liver transplants were performed at the Royal Free
      Hospital for cirrhosis of the liver. Nodular lesions identified in the livers
      removed at transplantation were defined histologically according to the
      International Working Party classification (Hepatology 1995; 22; 983). They were
      present in 63 of these livers, as follows: 36 dysplastic nodules, 121
      macroregenerative nodules, and 71 hepatocellular carcinomas. In five patients, an
      additional 12 nodules (size range 4-23 mm, median 10.5 mm) showed histological
      features suggestive of focal nodular hyperplasia including mildly inflamed
      vascular fibrous septa, and ductular proliferation. Pre-transplantation imaging
      showed features suspicious for hepatocellular carcinoma, in three of these
      lesions (12, 23 and 23 mm diameter) from two different patients. These lesions
      were histologically indistinguishable from focal nodular hyperplasia occurring in
      non-cirrhotic livers, with fibrous scars and septa which contained vascular and
      ductular structures. CONCLUSIONS: It is important to recognize that these lesions
      may occur in the context of cirrhosis and that they should be considered in the
      differential diagnosis with hepatocellular carcinoma, dysplastic nodules and
      macroregenerative nodules.

PMID- 12493021
TI  - Fibrinogen storage disease without hypofibrinogenaemia associated with acute
      infection.
AB  - AIMS: The presence of ground glass hepatocytes in a liver biopsy may be related
      to different conditions, including fibrinogen storage disease. Three types of
      fibrinogen storage disease have been described, namely types I, II and III. Type
      I is an hereditary hypofibrinogenaemia genetically characterized by a mutant
      variant of the fibrinogen molecule designated as fibrinogen Brescia, consistent
      with a gamma284 Gly-->Arg mutation. Only rare cases of types II and III
      fibrinogen storage disease have been described. The purpose of the present paper
      is to describe two cases of fibrinogen storage disease without associated
      hypofibrinogenaemia, which appeared during acute infectious diseases. METHODS AND
      RESULTS: Both patients were female, aged 77 and 73 years, who developed high
      transaminases during an infectious disease. In each case blood coagulation tests
      were within the normal range, and despite clinical and laboratory investigations
      no possible cause for liver disease could be found. Liver biopsies were
      performed; in both cases weakly eosinophilic cytoplasmic inclusions were
      observed. Using immunohistochemistry the inclusions were found to be due to
      fibrinogen accumulation. At ultrastructural level features corresponding to type
      II inclusions were observed. Molecular studies, performed in case 2, excluded the
      mutation typical of type I fibrinogen storage disease. Both patients also
      presented features of chronic hepatitis. In case 1, giant cell granulomas were
      additionally present. No close relatives of the patients presented any clinical
      or laboratory features of liver disease. In both patients altered liver function
      test values gradually, spontaneously, returned to within normal ranges after
      infectious disease was resolved. CONCLUSIONS: These cases suggest that, on rare
      occasions, hepatocytes may accumulate fibrinogen during an infectious disease.

PMID- 12493022
TI  - Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in mucinous carcinoma of the
      breast: comparison with invasive ductal carcinoma.
AB  - AIMS: Mucinous carcinoma of the breast usually shows less frequent lymph node
      metastasis and more favourable outcome compared with invasive ductal carcinoma.
      The aim of this study is to compare the expression profiles of several mucins in
      mucinous carcinomas and invasive ductal carcinomas to gain insight into the
      relationship between the less aggressive biological nature of mucinous carcinoma
      and the role of mucins. METHODS AND RESULTS: We examined the expression profiles
      of MUC1 (membrane-bound mucin) of different glycoforms (from non-glycosylated
      form to fully glycosylated form), MUC2 (intestinal type secretory mucin), MUC5AC
      (gastric surface type secretory mucin) and MUC6 (gastric pyloric gland type
      secretory mucin) in 17 mucinous carcinomas and 46 invasive ductal carcinomas
      using immunohistochemistry. Various glycoforms of MUC1 were expressed frequently
      in both mucinous carcinomas (65-100%) and invasive ductal carcinomas (92-100%),
      although non-glycosylated MUC1 (MUC1/CORE) and fully glycosylated MUC1 (MUC1/HMFG
      1) showed significantly lower expression rates in mucinous carcinomas compared
      with those in invasive ductal carcinomas. The expression rates of MUC2 (94%) and
      MUC6 (71%) in mucinous carcinomas were significantly higher than those of MUC2
      (15%) and MUC6 (15%) in invasive ductal carcinomas. There was no significant
      difference in the expression rate of MUC5AC in mucinous carcinomas (12%) and that
      in invasive ductal carcinomas (4%). CONCLUSIONS: The expression rate of MUC1/CORE
      and MUC1/HMFG-1, which is related to poor prognosis in the gastric and colorectal
      cancers, is low in mucinous carcinomas. The high expression rate of gel-forming
      secretory mucins (MUC2 and MUC6) in mucinous carcinoma suggests that high
      production of these types of mucins may act as a barrier to cancerous extension
      resulting in their less aggressive biological behaviour.

PMID- 12493023
TI  - Association of maspin expression with the high histological grade and lymphocyte
      rich stroma in early-stage breast cancer.
AB  - AIMS: Maspin is a recently described member of the serpin family or protease
      inhibitors that is known to be a tumour suppressor gene product. Loss of maspin
      expression has been found in most breast cancer cases and is correlated with cell
      motility and tumour invasiveness. However, its precise role in human breast
      cancer remains to be discovered. We aimed to evaluate the role of maspin in early
      stage breast cancer. METHODS AND RESULTS: We analysed the expression of maspin in
      192 stage I and II primary breast cancers by immunohistochemistry. Of these
      cases, 34.4% showed maspin expression. Maspin expression was more frequently
      found in invasive ductal carcinoma (36.4%) than in invasive lobular carcinoma
      (7.1%). High maspin expression was demonstrated in breast cancers showing high
      histological grade or lymphocyte-rich stroma (P < 0.05). Maspin expression was
      not associated with overall and disease-free survival rate of breast cancer.
      CONCLUSIONS: The results indicate that different biological mechanisms may be
      responsible for maspin expression in histologically distinct types of breast
      cancer. Our survey suggests that maspin expression in breast cancer might have a
      compensatory role rather than prognostic one.

PMID- 12493024
TI  - Changes in the distribution pattern of gelatin-binding protein of 28 kDa
      (adiponectin) in myocardial remodelling after ischaemic injury.
AB  - AIMS: Gelatin-binding protein of 28 kDa (GBP28) is a collagen-like plasma protein
      having a binding capacity with collagens. We investigated GBP28 role on
      myocardial remodelling as well as the diagnostic significance of GBP28
      immunostaining in myocardial infarction. METHODS AND RESULTS: Myocardial tissues
      obtained from 47 autopsied hearts with infarction were immunostained with
      antibodies against GBP28, fibronectin, type III and IV collagens, and prolyl 4
      hydroxylase. GBP28 was distributed in interstitium of infarcted lesions at an
      early stage. GBP28 was linearly found both along the border with vital myocardium
      and at the periphery of surviving cardiomyocyte around the lesion at granulative
      stage. However, it was not observed in the scar. GBP28 distribution patterns were
      similar to those of fibronectin in infarcted lesions and those of type IV
      collagen at the periphery of cardiomyocyte. Type III collagen was not recognized
      in the early-stage lesion but increased along with scar maturation. Prolyl 4
      hydroxylase was found in surviving cardiomyocytes around the lesion during all
      stages and in interstitial cells appeared in granulation tissue. CONCLUSION:
      GBP28 plays a role as a scaffold of newly formed collagen in myocardial
      remodelling after ischaemic injury, and GBP28 immunostaining may assist in a
      diagnosis of healing stage.

PMID- 12493025
TI  - Philadelphia chromosome and/or bcr-abl mRNA-positive primary thrombocytosis:
      morphometric evidence for the transition from essential thrombocythaemia to
      chronic myeloid leukaemia type of myeloproliferation.
AB  - AIMS: The incidence, bone marrow morphology and genetic features of bcr+
      essential thrombocythaemia were investigated. METHODS AND RESULTS: Sixty-four
      consecutive patients meeting the criteria of essential thrombocythaemia have been
      investigated for bcr-abl rearrangement and chimera mRNA expression. Reverse
      transcriptase-polymerase chain reaction indicated bcr-abl expression in six
      patients, in two of whom large fraction of the blood and bone marrow cells proved
      to be positive for Philadelphia chromosome (Ph) by fluorescent in-situ
      hybridization (FISH) and conventional cytogenetic analysis. In the remaining four
      patients FISH analysis could not detect Ph+ cells among the blood cells, but in
      one of these four patients conventional cytogenetic analysis indicated a very
      small fraction (2%) of Ph+ mitoses in the bone marrow (bcr+ essential
      thrombocythaemia patients). In three of these four patients, X-chromosome-linked
      clonality assay showed that the disease is of uncommitted stem cell origin.
      During an average of 57 month long follow-up no transformation to chronic myeloid
      leukaemia type of disease or acceleration/blastic crisis could be observed in the
      four bcr+ essential thrombocythaemia patients. They did not differ significantly
      from typical essential thrombocythaemia patients in quantitative indices of bone
      marrow cellularity or the size of megakaryocytes. In these two parameters as well
      as in the total nucleolus organizer region area per nucleus, however, significant
      differences could be detected between these four as well as typical chronic
      myeloid leukaemia patients. Statistical analysis of the morphometric data
      obtained from all six Ph+ and bcr+ essential thrombocythaemia patients combined
      indicated a shift of the bone marrow morphology towards the chronic myeloid
      leukaemia type of myeloproliferation. CONCLUSIONS: These investigations indicate
      that bcr+ essential thrombocythaemia is infrequent among essential
      thrombocythaemia patients, and this condition resembles essential
      thrombocythaemia more than chronic myeloid leukaemia. Various expansions of the
      Ph+ clone appear to lead to either essential thrombocythaemia or, rather, chronic
      myeloid leukaemia type of myeloproliferation; however, data in the present study
      do not indicate that bcr+ essential thrombocythaemia would be a form fruste
      variant of chronic myeloid leukaemia.

PMID- 12493026
TI  - Paget's disease of the oesophagus associated with mucous gland carcinoma of the
      lower oesophagus.
AB  - AIM: To report a rare case of oesophageal Paget's disease and its rarer
      combination with submucosal gland carcinoma of the lower oesophagus. METHODS AND
      RESULTS: A 74-year-old Saudi female was admitted with the complaint of dysphagia.
      Endoscopic examination showed an ulcerated tumour at the gastro-oesophageal
      junction. Initial biopsy showed an undifferentiated carcinoma with pagetoid
      spread in the oesophageal stratified squamous epithelium. Oesophago-gastrectomy
      specimen showed a lobulated, poorly differentiated mucous gland carcinoma at the
      gastro-oesophageal junction. The tumour showed focal acinar differentiation and
      obvious cancerization of the submucosal glands, somewhat similar to the breast
      lobular carcinoma in situ. One of the isolated and cancerized submucosal glands
      also showed carcinoma in situ of its duct. Oesophageal surface epithelium showed
      extensive pagetoid spread, both over and away from the main tumour. The pagetoid
      tumour cells showed selective positivity for cytokeratin 7, cytokeratin Cam 5.2,
      BerEP4 and to a lesser extent for CEA. CONCLUSIONS: As far as we know, this is
      the fifth case report of oesophageal Paget's disease and the first report of its
      association with the underlying mucous gland carcinoma.

PMID- 12493027
TI  - Cyclin E immunoexpression in gastric cancer does not correlate with
      clinicopathological parameters.
AB  - AIMS: To ascertain whether cyclin E immunoexpression relates to
      clinicopathological characteristics of gastric cancer and is of possible routine
      use. METHODS AND RESULTS: One hundred and twenty-four gastrectomy specimens were
      assessed for age, gender, histological subtype, lymph node status and
      Helicobacter pylori infection. Immunohistochemistry using a commercially
      available antibody to cyclin E was then applied to the cases. The
      immunohistochemical staining was correlated with clinicopathological features.
      Fifty-three of 124 cases were cyclin E-positive, with 28 of these cases showing
      >50% of the tumour cells staining. However, no statistical significance was
      obtained between cyclin E immunostaining and any clinicopathological parameter,
      especially lymph node spread. CONCLUSIONS: We have not demonstrated any
      significant relationship between cyclin E immunopositivity and any of the usual
      clinicopathological parameters (especially lymph node involvement) and therefore
      cyclin E immunohistochemistry alone does not appear to have a role in the
      assessment of gastric cancer currently.

PMID- 12493028
TI  - Biopsy of a biopsy: validation of immunoprofiling in gastric cancer biopsy tissue
      microarrays.
AB  - AIMS: Tissue microarrays offer an efficient way of examining a large number of
      tumour cases on a single glass slide. A major concern, however, is tumour
      heterogeneity. Also, the use of tissue microarrays in biopsy material is
      unexplored. The purpose of the present study was to assess the possibility and
      validity of arraying three 0.6-mm cores per case in endoscopic gastric cancer
      biopsies for immunophenotyping. METHODS AND RESULTS: Thirty-eight cases were
      studied with immunohistochemical staining for p53, CD44v6 and vascular
      endothelial growth factor. Full tissue sections were compared with triple core
      tissue microarrays. Thirty-six cases contained three cores with tumour, one case
      contained two cores with tumour and one case contained only a single core with
      viable tumour and was excluded. Three further cores had been lost from three
      separate cases on the sections for immunohistochemistry. kappa values for whole
      sections versus tissue microarrays ranged between 0.77 and 0.94. p53
      immunohistochemical staining (interpretation as + or -) yielded the best result
      with only 1/37 mismatches, whereas CD44v6 (graded both for intensity and extent)
      showed 3/37 mismatches. The small depth of tissue in cores from biopsies
      necessitates all cores being arrayed flush with the face of the recipient wax
      block for maximizing the number of sections available. Compared with the first
      section over 30 additional 4- micro m sections were available before the first
      case (with one core left) had to be excluded and 80 sections before half the
      tissue cores were lost. CONCLUSIONS: It is impracticable to array more than 120
      150 cores per block. Tissue microarray with three cores per case is feasible and
      valid for studying biopsy material.

PMID- 12493029
TI  - Endometrioid adenocarcinoma of the uterus with a minimal deviation invasive
      pattern.
AB  - AIMS: Minimal deviation adenocarcinoma of endometrioid type is a rare
      pathological entity. We describe a variant of typical endometrioid adenocarcinoma
      associated with minimal deviation adenocarcinoma of endometrioid type. METHODS
      AND RESULTS: One 'pilot' case of minimal deviation adenocarcinoma of endometrioid
      type associated with typical endometrioid adenocarcinoma was encountered at our
      institution in 2001. A second case of same type was received in consultation. We
      reviewed 168 consecutive hysterectomy specimens diagnosed with 'endometrioid
      adenocarcinoma' specifically to identify areas of minimal deviation
      adenocarcinoma of endometrioid type. Immunohistochemistry was done with the
      following antibodies: MIB1, p53, oestrogen receptor (ER), progesterone receptor
      (PR), cytokeratin 7 (CK7), cytokeratin 20 (CK20), carcinoembryonic antigen (CEA),
      and vimentin (VIM). Four additional cases of minimal deviation adenocarcinoma of
      endometrioid type were identified. All six cases of minimal deviation
      adenocarcinoma of endometrioid type were associated with superficial endometrioid
      adenocarcinoma. In two cases with a large amount of minimal deviation
      adenocarcinoma of endometrioid type, the cervix was involved. The immunoprofile
      of two representative cases was ER+, PR+, CK7+, CK20-, CEA-, VIM+. MIB1
      immunostaining of four cases revealed little proliferative activity of the
      minimal deviation adenocarcinoma of endometrioid type glandular cells (0-1%)
      compared with the associated 'typical' endometrioid adenocarcinoma (20-30%). The
      same four cases showed no p53 immunostaining in minimal deviation adenocarcinoma
      of endometrioid type compared with a range of positive staining in the associated
      endometrioid adenocarcinoma. CONCLUSIONS: Minimal deviation adenocarcinoma of
      endometrioid type more often develops as a result of differentiation from typical
      endometrioid adenocarcinoma than de novo. Due to its deceptively benign
      microscopic appearance, minimal deviation adenocarcinoma of endometrioid type may
      be overlooked and may lead to incorrect assessment of tumour depth and
      pathological stage. There was a tendency for tumour with a large amount of
      minimal deviation adenocarcinoma of endometrioid type to invade the cervix.

PMID- 12493030
TI  - p53 expression in normal paraffin-embedded tissue using different antibodies and
      antigen retrieval buffer systems.
AB  - AIMS: The study was undertaken to demonstrate wild-type p53 in normal paraffin
      embedded tissues using two widely used antibodies, DO7 and 1801 and two different
      antigen retrieval buffer systems. METHODS AND RESULTS: Formalin-fixed paraffin
      embedded normal tissue samples were obtained from the archives of the John
      Radcliffe Hospital, Oxford. Antigen retrieval was performed by microwaving using
      two different buffer systems: (i) the commercially available Dako target
      retrieval solution (Cat. no. 1699) (pH 9.8-9.9), (ii) freshly prepared buffer
      consisting of 0.1 m EDTA with 0.1% Tween pH 6.0, and (iii) freshly prepared
      buffer consisting of 0.1 m EDTA with 0.1% Tween pH 8.0. Staining was performed
      with DO7 and 1801 antibodies using the Dako Envision kit (peroxidase/DAB). DO7
      antibody elicited strong nuclear staining in the mucosal cells of the small and
      large intestine, lymphoid cells, decidua, neurones such as Purkinje cells of the
      cerebellum, glandular epithelial cells and stromal cells of the prostate, cardiac
      myocytes and bronchial epithelial cells. Cytoplasmic staining was noted in
      Purkinje cells, glandular epithelium of prostate, exocrine pancreas and renal
      tubular epithelium. The 1801 antibody did not produce staining in any of these
      tissues. CONCLUSIONS: Our study demonstrates the presence of p53 in normal
      paraffin-embedded tissue with nuclear and/or cytoplasmic localization in some
      instances. In our view, DO7 appears to be better suited for such detection.

PMID- 12493031
TI  - Bizarre stromal cells in the oesophagus.

PMID- 12493032
TI  - Histiocyte and T-cell-rich B-cell lymphoma with Langhans giant cells.

PMID- 12493033
TI  - p63 expression in sarcomatoid/metaplastic carcinomas of the breast.

PMID- 12493034
TI  - Sex hormone receptor immunohistochemistry staining in Barrett's oesophagus and
      adenocarcinoma.

PMID- 12493035
TI  - Granulomatous cryptococcal lymphadenitis in immunocompetent individuals: report
      of two cases.

PMID- 12493036
TI  - Secretory IgA in the endolymphatic sac tumour.

PMID- 12493038
TI  - Interventional fetal cardiac therapy -- possible perspectives and current
      shortcomings.

PMID- 12493039
TI  - Routine uterine artery Doppler screening in twin pregnancies?

PMID- 12493040
TI  - Screening for pre-eclampsia and fetal growth restriction in twin pregnancies at
      23 weeks of gestation by transvaginal uterine artery Doppler.
AB  - OBJECTIVE: To assess the value of transvaginal uterine artery Doppler at 23 weeks
      of gestation in predicting the development of adverse perinatal outcomes in twin
      pregnancies. PATIENTS AND METHODS: Women with twin pregnancies attending for
      routine ultrasound examination at 23 weeks in any one of seven hospitals
      underwent Doppler assessment of the uterine arteries. The right and left uterine
      arteries were identified using color flow mapping and velocity waveforms were
      obtained using pulsed Doppler. The mean pulsatility index (PI) of the two
      arteries was determined and the presence of uterine artery notching noted.
      Results were compared between monochorionic and dichorionic twins, and with our
      previously reported data from singleton pregnancies. Screening characteristics in
      the prediction of pre-eclampsia, fetal growth restriction (FGR), placental
      abruption, fetal death and early preterm delivery were calculated. RESULTS:
      Uterine artery Doppler at 22-24 weeks of gestation was performed in 360 twin
      pregnancies, including 324 dichorionic and 36 monochorionic diamniotic twins.
      Complete outcome data were available in 351 (97.5%). The mean uterine artery PI
      did not change significantly with gestation and there was no significant
      difference in mean PI between the dichorionic and monochorionic groups. However,
      the mean PI was significantly lower in twin pregnancies than in singletons. The
      pregnancy was complicated by pre-eclampsia in 6.0% of cases, FGR below the 5th
      centile of both twins in 8.8%, abruption in 0.9%, intrauterine fetal death in
      1.7% and early preterm delivery at less than 32 completed weeks of gestation in
      5.7% of cases. The respective sensitivities of uterine artery mean PI above the
      95th centile for these complications were 33.3%, 9.7%, 66.6%, 33.3% and 18.6%.
      CONCLUSIONS: In twin pregnancies PI in the uterine arteries is lower than that in
      singleton pregnancies, but there is no significant difference between dichorionic
      and monochorionic twins. Doppler assessment of the uterine arteries at 23 weeks
      identifies a large proportion of twin pregnancies destined to develop adverse
      outcomes related to uteroplacental insufficiency.

PMID- 12493041
TI  - Doppler assessment of the uterine circulation in the second trimester in twin
      pregnancies: prediction of pre-eclampsia, fetal growth restriction and birth
      weight discordance.
AB  - OBJECTIVE: To compare singleton nomograms of the uterine circulation with
      previously established twin nomograms in the prediction of pre-eclampsia, fetal
      growth restriction (FGR), and birth weight discordance > or = 20% in twin
      gestations. METHODS: This was a retrospective analysis of maternal and perinatal
      data obtained from 256 dichorionic twin pregnancies. The mean uterine artery
      resistance index was calculated from both sides and the presence and absence of
      notching was recorded. Cut-off levels for abnormal flow parameters were the 95th
      centile of reference ranges of either singleton or twin nomograms. RESULTS:
      According to twin reference values, 14.0% of patients were screen positive,
      compared to only 3.1% when singleton reference values were used. The sensitivity
      of abnormal uterine artery Doppler results defined by twin nomograms vs.
      singleton nomograms was 36.4% vs. 18.2% for pre-eclampsia, 26.7% vs. 9.7% for
      FGR, 28.9% vs. 7.9% for birth weight discordance > or = 20%, and 26.5% vs. 10.3%
      for any adverse outcome, respectively. CONCLUSION: Despite using specially
      constructed twin nomograms, uterine artery Doppler studies in twin gestations had
      an overall low sensitivity in predicting adverse obstetric outcome. Negative
      predictive values of uterine Doppler studies in twin gestations are lower
      compared to those reported in unselected singleton pregnancies, i.e. maternal and
      fetal complications occur more frequently despite normal uterine artery
      waveforms. This suggests that there is an additional pathomechanism, causing pre
      eclampsia and FGR in twin gestations, that is unrelated to uteroplacental
      insufficiency.

PMID- 12493042
TI  - Absent or hypoplastic thymus on ultrasound: a marker for deletion 22q11.2 in
      fetal cardiac defects.
AB  - OBJECTIVE: Congenital heart defects (CHD), particularly conotruncal anomalies,
      may be associated with deletion of chromosome 22q11.2. Thymic aplasia or
      hypoplasia is known to be a typical feature in this condition. We aimed to
      establish (i) the prevalence of del22q11.2 in fetal CHD and (ii) whether
      ultrasound assessment of an absent or hypoplastic fetal thymus helps in
      preselection of a group who are at high risk for this deletion. STUDY DESIGN: In
      fetuses (> 16 weeks) with CHD, karyotyping and fluorescence in situ hybridization
      for 22q11.2 were offered and the fetal thymus was evaluated sonographically.
      RESULTS: One hundred and forty-nine fetuses with CHD and normal karyotype were
      analyzed. Seventy-six fetuses had conotruncal anomalies. 22q11.2 deletion was
      present in 10 cases (6.7%), all of which had conotruncal anomalies (13.1%).
      Thymic hypoplasia or absence was suspected in 11 cases with conotruncal anomaly.
      Nine of these 11 had the deletion; two cases were false positive. One fetus with
      a normal-sized thymus had deletion of 22q11.2 (sensitivity 90%, specificity
      98.5%, positive predictive value 81.8%, and negative predictive value 99.2%). By
      subtype of cardiac anomaly, there was deletion in four of six fetuses with
      interruption of the aortic arch, two of four with absent pulmonary valve
      syndrome, three of nine with truncus arteriosus and one of 11 cases of tetralogy
      of Fallot. Pulmonary atresia with ventricular septal defect (n = 7), right-sided
      aortic arch (n = 4), transposition of the great arteries (n = 14), double outlet
      right ventricle (n = 13) and other complex malpositions of the great vessels (n =
      8) were not associated with the deletion. CONCLUSION: Thymic hypoplasia or
      aplasia may reliably be diagnosed during fetal echocardiography. The technique
      allows identification of a group at high risk for 22q11.2 deletion and is more
      specific and sensitive than by subtype of cardiac anomaly alone.

PMID- 12493043
TI  - Anomalies of the fetal aortic arch: a novel sonographic approach to in-utero
      diagnosis.
AB  - OBJECTIVE: To describe a novel, sonographic approach for in-utero evaluation of
      normal and abnormal aortic arch. METHODS: Aortic arch was evaluated by imaging of
      the axial view of the upper fetal mediastinum. The normal left aortic arch was
      defined by the V-shaped appearance of the junction between the ductus arteriosus
      and aortic arch, with the trachea situated posteriorly. Right and double aortic
      arches were diagnosed when the great vessels appeared U-shaped, with intermediate
      location of the trachea. RESULTS: Between 1997 and 1999, 18 347 women were
      scanned in three prenatal centers, and pathological findings were prospectively
      recorded. In a retrospective analysis of the records, we identified 19 fetuses
      (0.1%) with atypical, U-shaped appearance, and no other structural abnormalities
      present. With the exception of one fetus with a ventricular septal defect, no
      congenital cardiac defects were present. Right aortic arch was found in 18 cases,
      while color Doppler made it possible to diagnose one case with double aortic
      arch, and one fetus was demonstrated as having Kommerell's diverticulum. In all
      18 cases, a left descending aorta and left ductus arteriosus were present, the
      latter coursing to the left of the trachea, forming a loose partial vascular
      ring. All were asymptomatic at birth and early infancy. The fetus with double
      aortic arch that had a true vascular ring underwent early infantile correction.
      CONCLUSIONS: It is possible to diagnose right and double fetal aortic arch using
      prenatal ultrasound. The use of color Doppler facilitated in-utero evaluation of
      possible complications, such as true vascular ring.

PMID- 12493044
TI  - Mid-trimester ultrasound prediction of gestational age: advantages and systematic
      errors.
AB  - OBJECTIVE: To detect possible sources of bias in ultrasound prediction of
      gestational age. SUBJECTS AND METHODS: Using the Swedish Medical Birth Registry,
      571 617 women were identified who were delivered between 1990 and 1997 and who
      had obtainable information on last menstrual period and expected date of delivery
      according to ultrasound. RESULTS: Male fetuses were more likely than females to
      be judged older than the last menstrual period date suggested at early fetometry.
      The estimated magnitude of the systematic error by infant gender corresponded to
      1.5 days. Similarly, the fetuses of young women, multiparous women, smokers and
      women with low educational level were at increased risk of being smaller than
      expected at ultrasound examination in early pregnancy. A strong association was
      seen between adjustments of expected date of delivery -7 days or more and small
      for-gestational age according to ultrasound at birth. Compared to singleton
      pregnancies, twin pregnancies were more likely to be judged more progressed at
      ultrasound fetometry than the last menstrual period date suggested. CONCLUSIONS:
      Compared to last menstrual period estimates, routine ultrasound measurements to
      predict date of delivery are comparatively reliable but systematic errors are
      inherent in the method. The erroneous adjusted dates may be due to incorrect
      measurements or systematic bias (e.g. gender), but they are also likely to
      reflect early growth restriction (e.g. in the case of maternal smoking and small
      for-gestational age). Further studies are needed to investigate whether the
      systematic errors in ultrasound prediction of gestational age could lead to
      suboptimal obstetric management in adjusted pregnancies.

PMID- 12493045
TI  - Fetal transabdominal biometry at 11-14 weeks of gestation.
AB  - OBJECTIVE: To establish comprehensive transabdominal ultrasonographic reference
      ranges for viable normal singleton human fetuses at 11-14 weeks' gestation.
      METHODS: Single transabdominal ultrasound measurements were taken once per
      pregnancy at a gestational age of between 11+0 and 14+0 weeks (crown-rump length,
      45-84 mm), in viable singleton fetuses with nuchal translucency < or = 3 mm and
      without detectable structural anomalies, using four standard planes: (i)
      biparietal diameter (BPD) and fronto-occipital diameter (FOD) resulting in head
      circumference (HC), anterior horn (Va), posterior horn (Vp), and hemisphere
      (HEM); (ii) transcerebellar diameter (TCD) and cisterna magna (CM); (iii)
      abdominal anteroposterior (AAP) and abdominal transverse diameter (ATD) resulting
      in abdominal circumference (AC); and (iv) femur length (FL). The respective
      ratios Va/HEM, Vp/HEM, HC/AC, BPD/FL, BPD/FOD, FL/CRL, FL/BPD and FL/AC and the
      estimated weight were derived. Reference ranges were constructed and the mean and
      5th and 95th centiles were plotted against gestation. RESULTS: There was a
      general increase in biometric parameters with gestation. The ratios for the
      ventricles vs. hemisphere and BPD/FL ratio decreased while the BPD/FOD and HC/AC
      ratios remained constant. Analysis of the reference range for BPD/FL was
      performed in both 167 and 664 fetuses and the results showed almost the identical
      type of equation, indicating a high degree of accuracy for the growth charts.
      CONCLUSIONS: We have established comprehensive reference ranges for first
      trimester fetal biometry by transabdominal sonography. These charts may have a
      role in the diagnosis of early onset symmetrical or asymmetrical growth
      restriction and in the interpretation of measurements in chromosomally abnormal
      fetuses, and they may help in the detection of skeletal dysplasias or
      acrania/anencephaly.

PMID- 12493046
TI  - Measuring cervical length with ultrasound: evaluation of the procedures and
      duration of a learning method.
AB  - OBJECTIVE: To evaluate the learning curve and principal learning steps for a
      novice ultrasound operator to master the technique for measuring cervical length
      by transvaginal ultrasound. SUBJECTS AND METHODS: The study involved asymptomatic
      patients with a singleton pregnancy between 21 and 38 weeks attending for a
      routine ultrasound scan. Two operators new to cervical ultrasound including one
      with experience in transvaginal gynecological ultrasound were assessed during
      their training. After an initial lecture session on the technique of cervical
      measurement, the trainees had one or two supervised practice sessions, validated
      by two interobserver agreement studies with 30 patients at a time; these compared
      the level of agreement between trainer and trainee throughout. Five examinations
      were performed in the first practice session; a second session was planned if the
      trainee could not perform all five examinations alone satisfactorily, in
      agreement with four quality criteria predefined for good cervical measurements.
      The second session lasted until five consecutive examinations could be performed
      adequately without the trainer's aid. Agreement between the two operators was
      assessed by intraclass correlation coefficient (ICC). The ICCs were compared with
      Fisher's Z transformation. RESULTS: Of the 150 patients included, 2.7% gave birth
      before term. The trainee with no experience in transvaginal ultrasound required
      two practice sessions; none of the five ultrasound scans performed in the first
      session was correct. In the second session, 18 consecutive ultrasound
      examinations were necessary to obtain five consecutive adequate results. During
      interobserver studies with the trainer, the ICC progressed from 0.43 in the first
      study to 0.64 in the second and 0.77 in the third (P = 0.049 between the first
      and third studies). The trainee with experience in transvaginal ultrasound
      required only one practice session. The ICC increased from 0.73 to 0.85 in the
      two interobserver studies with the trainer. CONCLUSIONS: Measurement of cervical
      length by transvaginal ultrasound examination is a technique that can be learnt
      rapidly. While roughly 23 supervised ultrasound scans appear necessary for an
      operator with no experience in transvaginal ultrasound, substantially fewer are
      required for an operator already familiar with this approach for other
      indications.

PMID- 12493047
TI  - Umbilical vein blood volume flow rate and umbilical artery pulsatility as 'venous
      arterial index' in the prediction of neonatal compromise.
AB  - OBJECTIVE: To assess the diagnostic power of the umbilical venous-arterial index
      (VAI) for the prediction of poor fetal outcome. SUBJECTS AND METHODS: This was a
      retrospective, cross-sectional clinical study in which normalized umbilical vein
      blood volume flow rate (nUV) (mL/min/kg estimated body weight), umbilical artery
      pulsatility index (UAPI), the newly developed VAI (nUV/UAPI), and the uterine
      artery resistance index (UTRI) were determined in 85 fetuses once (17-41
      gestational weeks) during pregnancy using standard ultrasound Doppler equipment.
      A risk score based on umbilical blood pH, 1-min Apgar score, birth weight,
      duration of gestation, type of respiratory support, and referral to the pediatric
      department was constructed, and fetuses were assigned to a control or a
      pathological group accordingly. Logistic regression and analysis of fitted
      receiver-operating characteristics curves were performed to evaluate the
      diagnostic power of nUV, UAPI, UTRI, and VAI. RESULTS: The incidence of
      compromised neonates was 17.6%. The area under the receiver-operating
      characteristics curve was larger for VAI than for UTRI or for UAPI (P < 0.002).
      At a cut-off value of 100 mL/min/kg, the sensitivity of VAI to predict poor
      neonatal outcome was 85% with a 15% false-positive rate. CONCLUSION:
      Determination of the VAI has a greater diagnostic power to predict poor fetal
      outcome than the pulsatility index in the umbilical artery or the resistance
      index in the uterine artery.

PMID- 12493048
TI  - Color Doppler and gray-scale ultrasound evaluation of the postpartum uterus.
AB  - OBJECTIVES: To evaluate the color Doppler and gray-scale sonographic appearance
      of the uterus after pregnancy, with special attention to the occurrence of areas
      of enhanced vascularity and placental remnants. PATIENTS AND METHODS: Cross
      sectional observational study involving 385 consecutive women presenting at their
      first visit after pregnancy. The uterus was evaluated using ultrasound with color
      Doppler. In the presence of placental remnants, blood was sampled for measurement
      of beta human chorionic gonadotropin (beta hCG), hemoglobin (Hb) and infectious
      parameters. If indicated, a dilatation and curettage was performed. RESULTS: In
      8.3% of women, areas of enhanced vascularity were detected with color Doppler
      examination. Most cases (68.9%) were focal areas of one or more vessels. In 2.6%
      of patients abnormal vascularity extended over a large area of the whole
      myometrium. In 6.75% of cases, placental remnants were detected. In 46% of these,
      blood sampling revealed beta hCG levels below 30 mIU/mL; serological infection
      parameters and Hb concentration were within the normal range. CONCLUSIONS: Areas
      of enhanced vascularity of the uterus, ranging from a focal vascular pedicle to a
      larger area of the myometrium, are relatively common after pregnancy. They are
      predominantly seen in the presence of placental remnants, in the early postpartum
      period and after instrumental or manual delivery of the placenta. There are no
      clear risk factors for retained placental tissue, besides the history of blood
      transfusion in the early postpartum, and perhaps multigravidity. Serology is of
      little help in the diagnosis of retained gestational products. The knowledge of
      the ultrasound and color Doppler features of the uterus after pregnancy may prove
      of practical value for the management of abnormal uterine bleeding in the
      postpartum period.

PMID- 12493049
TI  - Utility of color Doppler indices of dominant follicular blood flow for prediction
      of clinical factors in in vitro fertilization-embryo transfer cycles.
AB  - OBJECTIVE: To investigate the relationship between color Doppler indices of
      dominant follicular blood flow and clinical factors in in vitro fertilization
      embryo transfer cycles. SUBJECTS AND METHODS: This was a prospective study
      involving 26 patients completing a total of 33 in vitro fertilization cycles.
      Dominant follicular blood flow indices, peak systolic velocities, the resistance
      index and the pulsatility index were evaluated using transvaginal color Doppler.
      The indices were compared to the clinical outcomes of in vitro fertilization
      embryo transfer. RESULTS: There was a significant correlation between dominant
      follicular peak systolic velocities and the number of oocytes retrieved, as well
      as the number of mature oocytes obtained. There was no significant correlation
      between dominant follicular resistance index or pulsatility index and the number
      of follicles > 10 mm in diameter, the number of oocytes retrieved or the number
      of mature oocytes. There were no significant differences between dominant
      follicular peak systolic velocities, resistance index or pulsatility index, and
      fertilization rate or the ratio of good quality embryos. However, significant
      differences were found between the number of oocytes retrieved, as well as the
      number of mature oocytes for those patients in which the peak systolic velocity
      was below 25 cm/s. CONCLUSIONS: Doppler assessment of dominant follicle blood
      flow alone is useful for predicting the number of retrievable oocytes. However,
      morphological quality of the embryo produced or the pregnancy rate cannot be
      predicted by this method.

PMID- 12493050
TI  - Color Doppler energy prediction of malignancy in adnexal masses using logistic
      regression models.
AB  - OBJECTIVE: The aim of this study was to assess the usefulness of color Doppler
      energy in the preoperative diagnosis of ovarian malignancy using multivariate
      logistic regression analysis. METHODS: One hundred and thirty adnexal masses were
      studied with transvaginal B-mode, color energy, and pulsed Doppler
      ultrasonography before surgery in order to develop a model that could be used to
      determine malignancy. Each ultrasonographic variable (tumor size, wall thickness,
      septal structure, echogenicity, papillary projection, density (solid or not)) was
      included individually or combined together as part of the Sassone ultrasound
      score. Intratumoral blood flow velocity waveforms were obtained to determine
      pulsatility index and resistance index and a more subjective parameter, location
      of tumor vascularity, was also assessed. Menopausal status and serum CA 125
      levels were also entered as categorical variables. Sonographic parameters were
      entered alone, then associated with menopausal status and CA 125 serum levels,
      and finally with Doppler energy measurements. Our model was then validated in a
      group of 68 adnexal masses and compared to the model of Alcazar. RESULTS:
      Eighteen adnexal masses (13.8%) were malignant or of low malignant potential.
      Multivariate analysis showed that papillary projection of the tumor wall, cyst
      with solid parts, resistance index with a cut-off value of 0.53, CA 125, and
      central blood flow location, were the only factors to be independent predictors
      of malignancy. Menopausal status was not an independent factor. For the final
      model including the Doppler energy parameter the best sensitivity and specificity
      were 83% and 93%, respectively, at a cut-off value of 10% probability of
      malignancy compared to 83% and 87% for the morphological variables alone.
      Validation of the model showed its diagnostic performance to be as good as that
      reported in the original population and better than the model of Alcazar.
      CONCLUSION: Sonographic analysis of adnexal masses including color Doppler energy
      shows the best predictive properties according to histological diagnosis, and
      improves preoperative diagnosis of malignancy.

PMID- 12493051
TI  - Limitations of transvaginal sonography for the diagnosis of adenomyosis, with
      histopathological correlation.
AB  - OBJECTIVES: To evaluate the accuracy of transabdominal sonography (TAS) and
      transvaginal sonography (TVS) for the diagnosis of adenomyosis, and to determine
      the diagnostic relevance of various sonographic criteria. SUBJECTS AND METHODS: A
      total of 129 women scheduled for hysterectomy were enrolled into this prospective
      study. Group 1 (n = 23) consisted of patients with menometrorrhagia who were free
      of myoma and endometrial disorders on TAS. Group 2 consisted of all the other
      patients (n = 106). TAS and TVS findings were compared to histopathological
      results. RESULTS: The prevalence of adenomyosis in Groups 1 and 2 was 91.3% and
      24.5%, respectively. TAS had limited value for the diagnosis of adenomyosis in
      both groups. The sensitivity, specificity, and positive and negative predictive
      values of TVS in Groups 1 and 2 were 80.9% and 38.4%, 100% and 97.5%, 100% and
      83.3%, and 40% and 82.9%, respectively. The accuracy of combined TAS and TVS in
      Groups 1 and 2 was 91.3% and 83%, respectively. The presence of myometrial cysts
      was the most specific ultrasound diagnostic criterion for adenomyosis. Hypoechoic
      linear myometrial striations related to the presence of myometrial hypertrophy
      correlated to hormonal status with a sensitivity of 66.6% and a specificity of
      100% in Group 1. CONCLUSIONS: Our results show that TAS has a limited diagnostic
      capacity for adenomyosis but also that TVS alone was poor in patients with an
      enlarged uterus. In these cases a combination of TVS and TAS should be used.

PMID- 12493052
TI  - First-trimester features of Fowler syndrome (hydrocephaly-hydranencephaly
      proliferative vasculopathy).
AB  - We describe the features of Fowler syndrome (proliferative vasculopathy and
      hydrocephaly-hydranencephaly) diagnosed in the first trimester. The pregnancy
      with no significant family history was referred for karyotyping and ultrasound
      examination after a cystic hygroma was seen at 12 weeks. At 13 weeks, ultrasound
      examination revealed hydrocephaly-hydranencephaly, fetal akinesia, and
      arthrogryposis associated with increased nuchal translucency. The parents opted
      for termination of pregnancy and the diagnosis of Fowler syndrome was confirmed
      by pathological examination of the fetus. Calcified necrotic lesions and
      proliferative vasculopathy were observed in the entire central nervous system
      including the brainstem and spinal cord. Cases previously reported in siblings
      suggest an autosomal recessive transmission but specific genetic antenatal
      diagnosis is not yet available. The diagnosis of proliferative vasculopathy and
      hydrocephaly-hydranencephaly (Fowler syndrome) should be considered whenever
      hydrocephaly-hydranencephaly associated with a fetal akinetic sequence are
      encountered at the end of the first trimester. Genetic counseling is recommended.

PMID- 12493053
TI  - Prenatal diagnosis of hypoplasia of the corpus callosum in association with non
      ketotic hyperglycinemia.
AB  - Abnormalities of the corpus callosum are often associated with a poor prognosis
      due to the anatomical defect itself and associated anomalies that include
      malformations and inherited metabolic disorders. We report a case of the prenatal
      diagnosis of hypoplasia of the corpus callosum that was associated with non
      ketotic hyperglycinemia. Metabolic disorders are a known association with corpus
      callosum abnormalities and carry a dismal prognosis. A diagnosis of non-ketotic
      hyperglycinemia should be considered when a fetus presents with an abnormality of
      the corpus callosum. A literature search reviews other inherited diseases
      associated with hypoplasia of the corpus callosum.

PMID- 12493054
TI  - Clinically significant persistence and enlargement of an antenatally diagnosed
      isolated choroid plexus cyst.
AB  - Isolated choroid plexus cysts are usually diagnosed at the time of screening
      ultrasonography during the second trimester. While they raise the question of
      underlying chromosomal abnormalities, their clinical course is almost invariably
      benign with complete resolution often by the third trimester. We report the
      highly unusual case of a choroid plexus cyst diagnosed at 14 weeks of gestational
      age with subsequent further enlargement of the cyst, necessitating postpartum
      neurosurgical intervention.

PMID- 12493055
TI  - Antenatal diagnosis and management of a vallecular cyst.
AB  - Vallecular cysts are rare. It is important to be aware of their presence as they
      can cause upper airway obstruction. We describe a case of congenital vallecular
      cyst diagnosed at 28 weeks of gestation. This early diagnosis enabled us to plan
      careful perinatal management. We believe that, in cases of suspected
      oropharyngeal tumors, elective delivery should be carried out in a tertiary
      referral center in which emergency ventilation and tracheostomy are possible.

PMID- 12493056
TI  - Prenatal diagnosis of congenital epulis: a case report.
AB  - Congenital epulis or congenital granular cell tumor, is a benign tumor that has
      rarely been diagnosed prenatally. We report a case of a large congenital epulis
      diagnosed at 26 weeks of gestation that increased in size during gestation. Color
      and power Doppler ultrasound examination showed marked blood flow in the tumor.
      The tumor could be resected completely following Cesarean section and
      histologically examined. We discuss the prenatal diagnosis and histogenesis of
      congenital epulis.

PMID- 12493057
TI  - A systematic review of the accuracy of ultrasound in the diagnosis of
      endometriosis.
AB  - OBJECTIVE: To evaluate transvaginal and transabdominal ultrasound scanning, with
      or without Doppler, as a diagnostic test for the accurate diagnosis of pelvic
      endometriosis. METHODS: The MEDLINE (1966-2001) and EMBASE (1980-2001) databases
      were searched for relevant studies, published in English. Only studies fulfilling
      predefined criteria were selected. An assessment of quality was made for each
      study, and data were then reanalyzed using likelihood ratios to determine the
      usefulness of the test. RESULTS: In total, 67 papers were identified using the
      search strategy, of which 17 described relevant studies. Of these, seven
      fulfilled the inclusion criteria. All seven related to the use of transvaginal
      gray-scale imaging in the diagnosis of ovarian endometriomata specifically,
      rather than endometriosis. The positive likelihood ratios ranged from 7.6 to
      29.8, and the negative likelihood ratios ranged from 0.1 to 0.4. Confidence
      intervals were wide. One paper addressed the use of conventional color Doppler
      with ultrasound: the positive likelihood ratio was 1.2, with a negative
      likelihood ratio of 0.4. One paper assessed the use of color Doppler energy
      imaging, and showed a positive likelihood ratio of 33.5 and a negative likelihood
      ratio of 0.1. CONCLUSIONS: Transvaginal ultrasound appears to be a useful test
      both to make and to exclude the diagnosis of an ovarian endometrioma.

PMID- 12493058
TI  - First-trimester prenatal diagnosis of omphalocele using three-dimensional
      ultrasonography.

PMID- 12493059
TI  - Prenatal visualization of the vasculature of fetal sacrococcygeal teratoma by
      three-dimensional color power angiography.

PMID- 12493060
TI  - Fetoscopic demonstration of perimortem feto-fetal hemorrhage in twin-twin
      transfusion syndrome.

PMID- 12493064
TI  - The International Sepsis Forum's controversies in sepsis: how will sepsis be
      treated in 2051?

PMID- 12493063
TI  - Influence of flow on mucosal-to-arterial carbon dioxide difference.

PMID- 12493065
TI  - Recently published papers: of head injuries, high frequencies and haemodynamic
      optimization.

PMID- 12493066
TI  - Understanding the roles of the transcription factors nuclear factor-kappaB and
      hypoxia-inducible factor-1alpha in lung injury.

PMID- 12493068
TI  - ICUs worldwide: critical care in India.

PMID- 12493067
TI  - Ethics roundtable: Using new, expensive drugs.

PMID- 12493069
TI  - Science review: Redox and oxygen-sensitive transcription factors in the
      regulation of oxidant-mediated lung injury: role for nuclear factor-kappaB.
AB  - The primary role of pulmonary airways is to conduct air to the alveolar
      epithelium, where gas exchange can efficiently occur. Injuries to airways
      resulting from inhalation of airborne pollutants and parenteral exposure to
      ingested pollutants that cause oxidative stress have the potential to interfere
      with this process. A progressive rise of oxidative stress due to altered
      reduction-oxidation (redox) homeostasis appears to be one of the hallmarks of the
      processes that regulate gene transcription in lung physiology and
      pathophysiology. Reactive metabolites serve as signaling messengers for the
      evolution and perpetuation of the inflammatory process that is often associated
      with cell death and degeneration. Redox-sensitive transcription factors are often
      associated with the development and progression of many human disease states and
      inflammatory-related injury, particularly of the lung. The present review
      elaborates on the role of the redox-sensitive and oxygen-sensitive transcription
      factor NF-kappaB in mediating lung injury. Changes in the pattern of gene
      expression through regulatory transcription factors are crucial components of the
      machinery that determines cellular responses to oxidative and redox
      perturbations. Additionally, the discussion of the possible therapeutic
      approaches of antioxidants, thiol-related compounds and phosphodiesterase
      inhibitors as anti-inflammatory agents will thereby help understand the
      oxidant/redox-mediated lung injury mechanisms.

PMID- 12493070
TI  - Bench-to-bedside review: Cytopathic hypoxia.
AB  - The rate of oxygen consumption by certain tissues is impaired when mice or rats
      are injected with lipopolysaccharide. A similar change in the rate of oxygen
      consumption is observed when Caco-2 human enterocyte-like cells are incubated in
      vitro with cytomix, a cocktail of cytokines containing tumor necrosis factor, IL
      1beta, and IFN-gamma. The decrease in the rate of oxygen consumption is not due
      to a change in oxygen delivery (e.g. on the basis of diminished microvascular
      perfusion), but rather to an acquired intrinsic defect in cellular respiration, a
      phenomenon that we have termed 'cytopathic hypoxia'. A number of different
      biochemical mechanisms have been postulated to account for cytopathic hypoxia in
      sepsis, including reversible inhibition of cytochrome a,a3 by nitric oxide, and
      irreversible inhibition of one or more mitochondrial respiratory complexes by
      peroxynitrite. Recently, however, our laboratory has obtained data to suggest
      that the most important mechanism underlying the development of cytopathic
      hypoxia is depletion of cellular stores of nicotinamide adenine dinucleotide
      (NAD+/NADH) as a result of activation of the enzyme, poly(ADP-ribose) polymerase
      1. If cytopathic hypoxia is important in the pathophysiology of established
      sepsis and multiorgan dysfunction syndrome, then efforts in the future will need
      to focus on pharmacological interventions designed to preserve normal
      mitochondrial function and energy production in sepsis.

PMID- 12493072
TI  - Statistics review 6: Nonparametric methods.
AB  - The present review introduces nonparametric methods. Three of the more common
      nonparametric methods are described in detail, and the advantages and
      disadvantages of nonparametric versus parametric methods in general are
      discussed.

PMID- 12493071
TI  - Clinical review: Myocardial depression in sepsis and septic shock.
AB  - Myocardial dysfunction frequently accompanies severe sepsis and septic shock.
      Whereas myocardial depression was previously considered a preterminal event, it
      is now clear that cardiac dysfunction as evidenced by biventricular dilatation
      and reduced ejection fraction is present in most patients with severe sepsis and
      septic shock. Myocardial depression exists despite a fluid resuscitation
      dependent hyperdynamic state that typically persists in septic shock patients
      until death or recovery. Cardiac function usually recovers within 7-10 days in
      survivors. Myocardial dysfunction does not appear to be due to myocardial
      hypoperfusion but due to circulating depressant factors, including the cytokines
      tumor necrosis factor alpha and IL-1beta. At a cellular level, reduced myocardial
      contractility seems to be induced by both nitric oxide-dependent and nitric oxide
      independent mechanisms. The present paper reviews both the clinical
      manifestations and the molecular/cellular mechanisms of sepsis-induced myocardial
      depression.

PMID- 12493073
TI  - Intramucosal-arterial PCO2 gap fails to reflect intestinal dysoxia in hypoxic
      hypoxia.
AB  - INTRODUCTION: An elevation in intramucosal-arterial PCO2 gradient (DeltaPCO2)
      could be determined either by tissue hypoxia or by reduced blood flow. Our
      hypothesis was that in hypoxic hypoxia with preserved blood flow, DeltaPCO2
      should not be altered. METHODS: In 17 anesthetized and mechanically ventilated
      sheep, oxygen delivery was reduced by decreasing flow (ischemic hypoxia, IH) or
      arterial oxygen saturation (hypoxic hypoxia, HH), or no intervention was made
      (sham). In the IH group (n = 6), blood flow was lowered by stepwise hemorrhage;
      in the HH group (n = 6), hydrochloric acid was instilled intratracheally. We
      measured cardiac output, superior mesenteric blood flow, gases, hemoglobin, and
      oxygen saturations in arterial blood, mixed venous blood, and mesenteric venous
      blood, and ileal intramucosal PCO2 by tonometry. Systemic and intestinal oxygen
      transport and consumption were calculated, as was DeltaPCO2. After basal
      measurements, measurements were repeated at 30, 60, and 90 minutes. RESULTS: Both
      progressive bleeding and hydrochloric acid aspiration provoked critical
      reductions in systemic and intestinal oxygen delivery and consumption. No changes
      occurred in the sham group. DeltaPCO2 increased in the IH group (12 +/- 10 [mean
      +/- SD] versus 40 +/- 13 mmHg; P < 0.001), but remained unchanged in HH and in
      the sham group (13 +/- 6 versus 10 +/- 13 mmHg and 8 +/- 5 versus 9 +/- 6 mmHg;
      not significant). DISCUSSION: In this experimental model of hypoxic hypoxia with
      preserved blood flow, DeltaPCO2 was not modified during dependence of oxygen
      uptake on oxygen transport. These results suggest that DeltaPCO2 might be
      determined primarily by blood flow.

PMID- 12493074
TI  - Association of lipid peroxidation with hepatocellular injury in preterm infants.
AB  - INTRODUCTION: We wished to determine whether cholestasis induced by total
      parenteral nutrition (TPN) in preterm newborn infants is associated with
      increased oxidative stress secondary to increased reactive oxygen intermediates.
      We hypothesized that elevated urinary thiobarbituric-acid-reacting substances
      (TBARS), a marker of oxidative stress, would be associated with hepatocellular
      injury as measured by serum alanine transaminase (ALT) and aspartate transaminase
      (AST) levels. MATERIALS AND METHODS: Preterm infants (<35 weeks' gestation)
      admitted to the neonatal intensive care unit were enrolled (with their parents'
      informed consent) in either the 'cholestasis' group (if their direct bilirubin
      was >2 mg/dl [34.2 micromol/l] and duration of TPN was > or = 10 days [n = 27])
      or in the control group. Urine samples for measurement of TBARS (proportionate to
      lipid peroxidation) and blood specimens for analysis of serum bilirubin, ALT,
      AST, and alkaline phosphatase were obtained within 24 hours of enrollment.
      RESULTS: The cholestasis and control groups were comparable with respect to
      gestational age, birth weight, Apgar score, maximum FiO2, and duration of
      supplemental oxygen administration. Median serum direct bilirubin concentrations
      in the cholestasis and control groups were, respectively, 3.3 mg/dl (56.4
      micromol/l) and 1.7 mg/dl (29.1 micromol/l) (P < 0.001). Serum ALT and AST levels
      were also elevated in the cholestasis group, but alkaline phosphatase levels did
      not differ significantly between the groups. Urinary levels of TBARS in all the
      infants were correlated with ALT and AST but did not differ significantly between
      cholestatic and control infants. DISCUSSION: Our findings suggest that oxidant
      stress is associated with hepatocellular injury in preterm infants. This effect
      is not correlated with the degree of cholestasis.

PMID- 12493075
TI  - Stress ulcer prophylaxis in trauma patients.
AB  - INTRODUCTION: A number of issues concerning stress ulcer prophylaxis remain
      unresolved despite numerous randomized, controlled trials and several meta
      analyses. The role of stress ulcer prophylaxis, particularly in trauma patients,
      is further complicated by the lack of trials utilizing clinically important
      bleeding as an endpoint. Given the lack of consensus regarding stress ulcer
      prophylaxis in trauma patients, prescribing practices at Level I trauma centers
      in the United States were assessed. MATERIALS AND METHODS: A survey was developed
      that contained questions related to institutional prescribing and evaluation of
      stress ulcer prophylaxis. The survey was intended to delineate these practices at
      the 188 Level I trauma centers (at the time of the present survey) in the United
      States. RESULTS: One hundred and nineteen surveys were returned, yielding a
      response rate of 63%. Eighty-six percent stated that medications for stress ulcer
      prophylaxis are used in a vast majority of trauma patients admitted to the
      intensive care unit. Sixty-five percent stated that there is one preferred
      medication. For these institutions, histamine-2-blockers were the most popular at
      71%. Thirty-nine percent stated that greater than 50% of patients remain on
      stress ulcer prophylaxis following discharge from the intensive care unit.
      CONCLUSION: The lack of consensus with regards to appropriate stress ulcer
      prophylaxis is apparent in this survey of Level I trauma centers. For those
      institutions with a preferred agent, histamine-2-blockers were most common.

PMID- 12493076
TI  - Cricothyroidotomy for elective airway management in critically ill trauma
      patients with technically challenging neck anatomy.
AB  - INTRODUCTION: To assess the value of elective cricothyroidotomy for airway
      management in critically ill trauma patients with technically challenging neck
      anatomy. MATERIALS AND METHODS: A retrospective chart review of patients admitted
      to the Trauma Service at a Level I Trauma Center who underwent cricothyroidotomy
      for elective airway management over a 40-month period from January 1997 to April
      2000. Comparison was made with a cohort of Trauma Service patients who received a
      tracheostomy. RESULTS: Eighteen patients met study criteria, and an unpaired t
      test revealed significance (P < 0.05) for age only. There was no difference with
      Injury Severity Score, number of days in the intensive care unit, number of days
      requiring ventilation post procedure or number of days intubated prior to
      procedure. The major difference was the more technically challenging neck anatomy
      in the patients undergoing cricothyroidotomy. Five out of 18 patients undergoing
      cricothyroidotomy died prior to discharge and two out of 18 died after discharge
      from complications unrelated to their airway. Two out of 18 patients undergoing
      tracheostomy died prior to discharge from complications unrelated to their
      airway. For a period of 1 week-15 months (average, 5.5 months), notes in
      subsequent clinic appointments were reviewed for subjective assessment of wound
      healing, breathing and swallowing difficulties, and voice changes. One patient
      with a cricothyroidotomy required silver nitrate to treat some granulation
      tissue. Otherwise, no complications were identified. Telephone interviews were
      conducted with eight of the 11 surviving cricothyroidotomy patients and nine of
      the 16 surviving tracheostomy patients. One tracheostomy patient required
      surgical closure 3 months after discharge; otherwise, the only noted change was
      minor voice changes in three patients in each group. All six of these patients
      denied that this compromised them in any way. CONCLUSION: Elective
      cricothyroidotomy has a low complication rate and is a reasonable, technically
      less demanding option in critically ill patients with challenging neck anatomy
      requiring a surgical airway.

PMID- 12493077
TI  - Bovine colostrum in oral treatment of enterogenic endotoxaemia in rats.
AB  - INTRODUCTION: Under conditions of shock, bacteria and endotoxins in the
      intestines can traverse the mucosal barrier by translocation and enter the blood
      and lymphatic system. Immunoglobulins and lactoferrin have been reported to
      neutralize endotoxins and bacteria. We studied the essential therapeutic factors
      of colostrum products in an animal experiment. METHOD: We simulated endotoxaemia
      by per-oral administration of a suspension of Escherichia coli and antibiotics
      into the duodenum of anaesthetized rats after giving intraperitoneal carrageenan.
      At the same time, pure bovine colostrum or lactoferrin-enriched bovine colostrum
      was given. Therapeutic effects were studied by examining plasma endotoxin
      activity and bacterial contamination of mesenterial lymph nodes and peritoneal
      lavages. Albumin was used in a control group. RESULTS: The most effective bovine
      colostrum was able to reduce the maximum plasma endotoxin value by 67% as
      compared with the albumin group. The combination of this colostrum with
      lactoferrin brought about a reduction by 80%. The reduction in bacterial
      contamination of lymph nodes and peritoneal lavages was also evident. CONCLUSION:
      Both gammaglobulin and lactoferrin may help to eliminate endotoxins when bovine
      colostrum is administered into the gut in conditions of septic shock.

PMID- 12493078
TI  - Brachial plexopathy after prone positioning.
AB  - Two cases of brachial plexus injury after prone position in the intensive care
      unit are described. Mechanisms of brachial plexus injury are described, as are
      methods for prevention of this unusual complication.

PMID- 12493079
TI  - Effects of Anethum graveolens L. seed extracts on experimental gastric irritation
      models in mice.
AB  - BACKGROUND: As a folk remedy, Anethum graveolens seed (dill) is used for some
      gastrointestinal ailments. We aimed to evaluate aqueous and ethanolic extracts of
      anti-ulcer and acute toxicity effects of the Anethum graveolens in mice. RESULTS:
      Gastric mucosal lesions were induced by oral administration of HCl (1 N) and
      absolute ethanol in mice. The acidity and total acid content of gastric juice
      were measured in pylorus-ligated mice. LD50 values of the aqueous and ethanolic
      extracts were 3.04 g/kg, i.p., (1.5, 6.16) and 6.98 g/kg, i.p., (5.69, 8.56),
      respectively. The efficacy of high dose of extracts (p.o.) was similar to
      sucralfate. The acidity and total acid content were reduced by the orally or
      intraperitoneally administration of the extracts. CONCLUSIONS: The results
      suggest that A. graveolens seed extracts have significant mucosal protective and
      antisecretory effects of the gastric mucosa in mice.

PMID- 12493080
TI  - ORFer--retrieval of protein sequences and open reading frames from GenBank and
      storage into relational databases or text files.
AB  - BACKGROUND: Functional genomics involves the parallel experimentation with large
      sets of proteins. This requires management of large sets of open reading frames
      as a prerequisite of the cloning and recombinant expression of these proteins.
      RESULTS: A Java program was developed for retrieval of protein and nucleic acid
      sequences and annotations from NCBI GenBank, using the XML sequence format.
      Annotations retrieved by ORFer include sequence name, organism and also the
      completeness of the sequence. The program has a graphical user interface,
      although it can be used in a non-interactive mode. For protein sequences, the
      program also extracts the open reading frame sequence, if available, and checks
      its correct translation. ORFer accepts user input in the form of single or lists
      of GenBank GI identifiers or accession numbers. It can be used to extract
      complete sets of open reading frames and protein sequences from any kind of
      GenBank sequence entry, including complete genomes or chromosomes. Sequences are
      either stored with their features in a relational database or can be exported as
      text files in Fasta or tabulator delimited format. The ORFer program is freely
      available at http://www.proteinstrukturfabrik.de/orfer. CONCLUSION: The ORFer
      program allows for fast retrieval of DNA sequences, protein sequences and their
      open reading frames and sequence annotations from GenBank. Furthermore, storage
      of sequences and features in a relational database is supported. Such a database
      can supplement a laboratory information system (LIMS) with appropriate sequence
      information.

PMID- 12493081
TI  - The biological action of saponins in animal systems: a review.
AB  - Saponins are steroid or triterpenoid glycosides, common in a large number of
      plants and plant products that are important in human and animal nutrition.
      Several biological effects have been ascribed to saponins. Extensive research has
      been carried out into the membrane-permeabilising, immunostimulant,
      hypocholesterolaemic and anticarcinogenic properties of saponins and they have
      also been found to significantly affect growth, feed intake and reproduction in
      animals. These structurally diverse compounds have also been observed to kill
      protozoans and molluscs, to be antioxidants, to impair the digestion of protein
      and the uptake of vitamins and minerals in the gut, to cause hypoglycaemia, and
      to act as antifungal and antiviral agents. These compounds can thus affect
      animals in a host of different ways both positive and negative.

PMID- 12493082
TI  - Nutritional regulation of glucose-6-phosphatase gene expression in liver of the
      gilthead sea bream (Sparus aurata).
AB  - To examine the role of glucose-6-phosphatase (G6Pase) in glucose homeostasis in
      the diabetes-like experimental model of carnivorous fish, we analysed
      postprandial variations and the effect of starvation, ration size and diet
      composition on the regulation of G6Pase expression at the enzyme activity and
      mRNA level in the liver of gilthead sea bream (Sparus aurata). G6Pase expression
      increased in long-term starved or energy-restricted fish. In contrast to data
      reported for other fish species, short-term regulation of G6Pase expression was
      found in regularly fed S. aurata. G6Pase mRNA levels were lowest between 4 and 15
      h after food intake, whereas minimal enzyme activity was observed 10-15 h
      postprandially. Alterations of plasma glucose levels affect G6Pase in mammals.
      However, the carbohydrate content of the diet did not affect hepatic expression
      of G6Pase in S. aurata, suggesting that a different molecular mechanism is
      involved in the control of G6Pase expression in fish. Although G6Pase was
      unaffected, high-carbohydrate low-protein diets increased glucokinase (GK)
      expression and thus allowed a metabolic adaptation favouring glycolysis over
      gluconeogenesis. Interestingly, only the nutritional conditions that promoted
      variations in the blood glucose levels resulted in changes in the hepatic
      expression of G6Pase. These findings indicate a concerted regulation of G6Pase
      and GK expression and suggest that the direction and rate of the glucose-glucose
      6-phosphate substrate cycle flux is finely regulated in the liver of S. aurata,
      challenging the role attributed to deficient regulation of G6Pase or GK
      expression in the low ability of carnivorous fish to metabolize glucose.

PMID- 12493083
TI  - Effect of acute ingestion of fresh and stored lettuce (Lactuca sativa) on plasma
      total antioxidant capacity and antioxidant levels in human subjects.
AB  - The present study investigated whether storage under modified-atmosphere
      packaging (MAP) affected the antioxidant properties of fresh lettuce (Lactuca
      sativa). Eleven healthy volunteers (six men, five women) consumed 250 g fresh
      lettuce, and blood was sampled before (0 h) and 2, 3 and 6 h after consumption.
      The protocol was repeated 3 d later with the same lettuce stored at 5 degrees C
      under MAP conditions (O2-N2 (5:95, v/v)). Results showed that after ingestion of
      fresh lettuce, plasma total radical-trapping antioxidant potential (TRAP),
      measured as area under the curve, was significantly higher (1.3 (sem 0.3) mmol/l
      per 6 h; P<0.05) than the value obtained with MAP-stored lettuce (0.1 (sem 0.2)
      mmol/l per 6 h). Plasma TRAP, quercetin and p-coumaric acid were significantly
      different from baseline values (P<or=0.05) 2 and 3 h after fresh lettuce
      ingestion. Caffeic acid increased significantly at 3 h (P<0.05). Plasma beta
      carotene levels increased significantly at 6 h (P<0.05). Vitamin C concentrations
      (mg/l) rose from 10.9 (sem 2.0) to 12.7 (sem 3.0) (P<0.001), 12.7 (sem 2.0)
      (P<0.01) and 12.9 (sem 3.0) (P<0.05) at 0, 2, 3 and 6 h respectively. No changes
      were observed after ingestion of MAP-stored lettuce for all the measured markers.
      Our present results showed that ingestion of MAP-stored lettuce does not modify
      plasma redox status in healthy subjects. Further research is needed to develop
      post-harvesting techniques able to preserve the bioactive molecule content of
      plant food.

PMID- 12493084
TI  - Effects of dietary fat and conjugated linoleic acid on plasma metabolite
      concentrations and metabolic responses to homeostatic signals in pigs.
AB  - Sixteen female cross-bred (Large White x Landrace) pigs (initial weight 65 kg)
      with venous catheters were randomly allocated to four treatment groups in a
      factorial design. The respective factors were dietary fat (25 or 100 g/kg) and
      dietary conjugated linoleic acid (CLA; 0 or 10 g CLA-55/kg). Pigs were fed every
      3 h (close to ad libitum digestible energy intake) for 8 d and were bled
      frequently. Plasma glucose and non-esterified fatty acid (NEFA) responses to
      insulin and adrenaline challenges were determined on day 8. Plasma concentrations
      of NEFA were significantly increased (10.5 and 5.4 % for low- and high-fat diets
      respectively, P=0.015) throughout the experiment, suggesting that there was a
      possible increase in fat mobilisation. The increase in lipolysis, an indicator of
      ss-adrenergic stimulated lipolysis, was also evident in the NEFA response to
      adrenaline. However, the increase in plasma triacylglycerol (11.0 and 7.1 % for
      low- and high-fat diets respectively, P=0.008) indicated that CLA could have
      reduced fat accretion via decreased adipose tissue triacylglycerol synthesis from
      preformed fatty acids, possibly through reduced lipoprotein lipase activity.
      Plasma glucose, the primary substrate for de novo lipid synthesis, and plasma
      insulin levels were unaffected by dietary CLA suggesting that de novo lipid
      synthesis was largely unaffected (P=0.24 and P=0.30 respectively). In addition,
      the dietary CLA had no effect upon the ability of insulin to stimulate glucose
      removal.

PMID- 12493085
TI  - Acute effects of meal fatty acid composition on insulin sensitivity in healthy
      post-menopausal women.
AB  - Postprandial plasma insulin concentrations after a single high-fat meal may be
      modified by the presence of specific fatty acids although the effects of
      sequential meal ingestion are unknown. The aim of the present study was to
      examine the effects of altering the fatty acid composition in a single mixed fat
      carbohydrate meal on glucose metabolism and insulin sensitivity of a second meal
      eaten 5 h later. Insulin sensitivity was assessed using a minimal model approach.
      Ten healthy post-menopausal women underwent four two-meal studies in random
      order. A high-fat breakfast (40 g fat) where the fatty acid composition was
      predominantly saturated fatty acids (SFA), n-6 polyunsaturated fatty acids
      (PUFA), long-chain n-3 PUFA or monounsaturated fatty acids (MUFA) was followed 5
      h later by a low-fat, high-carbohydrate lunch (5.7 g fat), which was identical in
      all four studies. The plasma insulin response was significantly higher following
      the SFA meal than the other meals after both breakfast and lunch (P<0.006)
      although there was no effect of breakfast fatty acid composition on plasma
      glucose concentrations. Postprandial insulin sensitivity (SI(Oral)) was assessed
      for 180 min after each meal. SI(Oral) was significantly lower after lunch than
      after breakfast for all four test meals (P=0.019) following the same rank order
      (SFA < n-6 PUFA < n-3 PUFA < MUFA) for each meal. The present study demonstrates
      that a single meal rich in SFA reduces postprandial insulin sensitivity with
      'carry-over' effects for the next meal.

PMID- 12493086
TI  - Pre- and postprandial changes in plasma hormone and metabolite levels and hepatic
      deiodinase activities in meal-fed broiler chickens.
AB  - The present study aimed to study the effects of food deprivation and subsequent
      postprandial changes in plasma somatotrophic and thyrotrophic hormone levels and
      focused on the inter-relationships between these hormonal axes and representative
      metabolites of the intermediary metabolism of meal-fed broiler chickens. Male
      broiler chickens (2 weeks old) were fed a meal of 40-45 g/bird per d for two
      consecutive weeks (food-restricted (FR) treatment). The daily allowance was
      consumed in about 30 min. At 4 weeks of age, FR chickens were killed at several
      time intervals (ten per sampling time) in relation to the daily food allowance:
      before feeding (about 23.5 h of food deprivation), and at 10, 20, 30 (end of
      feeding), 40, 50, 60, 90, 120 and 200 min after initiation of feeding. Birds fed
      ad libitum served as controls (ad-libitum (AL) treatment). Liver tissue was
      collected for deiodinase type I and type III activity measurements and blood
      samples for analysis of growth hormone (GH), insulin-like growth factor (IGF)-I,
      thyroxine (T4), 3,3',5-triiodothyronine (T3), glucose, non-esterified fatty acids
      (NEFA), uric acid, triacylglycerol (TG) and lactate levels. Food deprivation
      caused a shift from lipogenesis to lipolysis and increased fatty acid turnover, a
      reduction in protein anabolism and reduced metabolic rate. Food intake was
      followed immediately by a pronounced increase in metabolic rate, initially mainly
      based on anaerobic mechanisms. Refeeding gradually reversed the fasting-induced
      alterations in plasma hormone and metabolite levels, but the time course of
      changes differed between metabolites, which clearly preceded those of the
      hormones investigated. The order of responsiveness after food provision were
      glucose>uric acid>or=NEFA>lactate>TG for the plasma metabolites and for hormones.
      Based on these different postprandial time courses, several functional
      relationships are proposed. Glucose is believed to be the primary trigger for the
      normalisation of the effects of fasting on these plasma variables by restoring
      hepatic GH receptor capacity, as well as decreasing deiodinase type III activity.

PMID- 12493087
TI  - Dietary interrelationships among arginine, methionine, and lysine in young
      broiler chicks.
AB  - Since excess dietary lysine (Lys) can increase the chick's arginine (Arg)
      requirement and excess Arg can increase the chick's methionine (Met) requirement,
      experiments were conducted to test the hypothesis that responses to dietary Lys
      and Met are also interrelated. Day-old Ross x Ross chicks were fed a maize
      soyabean meal-based diet supplemented with four levels of L-Arg (0, 5, 10 or 20
      g/kg), factorially arranged with four levels of supplemental DL-Met (0, 1, 2 or 3
      g/kg). Three replicate pens of ten chicks each were randomly assigned to each
      treatment and fed for 14 d. An increase in Arg in the diet caused growth and feed
      intake depression (P=0.0001), but increasing Met in the diet enhanced growth and
      feed intake (P=0.0001). Arg toxicity was dependent on the Met level of the diet
      (Arg x Met interaction; P=0.0153). Experiment 2 was conducted to study
      interrelationships among Arg, Met, and Lys. Eight treatments were factorially
      combined: two levels of supplemental L-Arg (0 or 10 g/kg), two levels of
      supplemental DL-Met (0 or 2 g/kg), and two levels of supplemental L-Lys (0 or 6
      g/kg). Six replicate pens of eight chicks per treatment were used. A three-way
      interaction among Arg, Met, and Lys was observed for body-weight gain and feed
      intake (P<0.023). As expected, kidney arginase activity increased as dietary Lys
      increased (P=0.0004). No interactions were found for kidney arginase activity.
      Muscle creatine increased when chicks were fed the higher Arg (25.2 g/kg) diet
      (P=0.0047). A three-way interaction among Arg, Met, and Lys was found for muscle
      creatine (P=0.0075). Excess dietary Lys depressed muscle creatinine
      concentration, but only in the presence of the lower concentrations of Arg and
      Met. To conclude, an interrelationship among Arg, Met, and Lys was demonstrated,
      and it was probably related to creatine biosynthesis.

PMID- 12493088
TI  - Acute-on-chronic effects of fatty acids on intestinal triacylglycerol-rich
      lipoprotein metabolism.
AB  - Postprandial triacylglycerol (TAG) metabolism is an important metabolic state
      that has been associated with cardiovascular disease. The magnitude of the
      postprandial TAG response is determined by dietary fat composition, which alters
      intestinal and hepatic TAG-rich lipoprotein (TRL) metabolism. Caco-2 cell
      monolayers are morphologically and physiologically similar to the human
      intestinal enterocytes, hence they are a good model to study intestinal
      lipoprotein metabolism. To date only the acute effect of fatty acid composition
      on intestinal TRL metabolism in Caco-2 cells has been investigated. Little is
      known of the effect of habitual, or chronic, dietary fat composition on
      intestinal TRL metabolism. Using the Caco-2 cell model, the present study
      investigated the acute-on-chronic effect of fatty acid composition on TRL
      metabolism. Caco-2 cells were grown in the presence of 0.05 mm-palmitic acid (PA;
      16 : 0), -oleic acid (OA; 18 : 1n-9),-eicosapentaenoic acid (EPA; 20 : 5n-3) or
      no fatty acid (control) for 19 d, then one of four acute treatments (control
      (bovine serum albumin (BSA; 5 g/l)) or BSA (5 g/l) plus 0.5 mm-PA, -OA or -EPA)
      were administered for 22 h. Significant acutexchronic interactions for the effect
      of fatty acid composition on cellular TAG:secreted de novo TAG, and cellular de
      novo TAG:de novo phospholipid were observed. Thus the effect of a fatty acid was
      determined by the duration of exposure to the fatty acid intervention. Acute PA
      treatment increased de novo TAG synthesis, but chronic PA supplementation did
      not. Acute and chronic OA treatments increased de novo TAG secretion. For EPA,
      chronic supplementation had the greatest effect on TAG synthesis and secretion.
      The acute-on-chronic effects of fatty acids on apolipoprotein B metabolism were
      relatively minor compared with the changes noted for TRL lipid composition. The
      present study shows that the Caco-2 cell model is valuable for studying
      intestinal TRL metabolism and that fatty acids modulate this process, the nature
      of which can be determined by the length of exposure of the cell to the fatty
      acid.

PMID- 12493089
TI  - Modulation of ovomucoid-specific oral tolerance in mice fed plant extracts
      containing lectins.
AB  - We investigated the effect of feeding extracts of four different legumes (red
      kidney bean (Phaseolus vulgaris), peanut (Arachis hypogaea), soyabean (Glycine
      max) and pea (Pisum sativum) on the specific immune response against a food
      protein. Mice were fed ovomucoid and the specific immune response was evaluated.
      Ovomucoid fed alone resulted in oral tolerance induction measured as both a
      reduced ovomucoid-specific spleen cell proliferation and antibody response.
      Feeding kidney-bean extract prevented induction of oral tolerance to ovomucoid
      measured as spleen cell proliferation in vitro. Pure kidney-bean lectin also
      prevented oral tolerance induction, suggesting that lectin in the kidney-bean
      extract caused inhibition of oral tolerance. Parenteral administration
      (intravenous and intraperitoneal) of pure kidney-bean lectin had no significant
      influence on oral tolerance induction. Soyabean extract also influenced the
      immune response against ovomucoid; however, this was not as pronounced as for
      kidney bean and was only significant (P<0.001) for the antibody response. No
      effect was observed when pea extract was fed and peanut extract had a non
      significant effect on induction of oral tolerance and on the general immune
      response. Plasma antibodies against kidney-bean lectin, but not against the three
      other legume lectins, were detected. Our current findings show that other dietary
      components can influence the specific immune response against food proteins.
      Various dietary components may thus contribute to the onset of adverse
      immunological responses.

PMID- 12493090
TI  - The effect of different cooking methods on folate retention in various foods that
      are amongst the major contributors to folate intake in the UK diet.
AB  - Folate intake is strongly influenced by various methods of cooking that can
      degrade the natural forms of the vitamin in foods. The aim of the present study
      was to determine the effect of different cooking methods on folate retention in
      various foods that contribute to folate intake in the UK diet. Typical purchasing
      and cooking practices of representative food folate sources were determined from
      a questionnaire survey of local shoppers (n 100). Total folate was determined by
      microbiological assay (Lactobacillus casei NCIMB 10463) following thermal
      extraction and tri-enzyme (alpha-amylase, protease and conjugase) treatment in
      raw foods and after typical methods of cooking. Boiling for typical time periods
      resulted in only 49 % retention of folate in spinach (191.8 and 94.4 microg/100 g
      for raw and boiled spinach respectively; P<0.005), and only 44 % in broccoli
      (177.1 and 77.0 microg/100 g for raw and boiled broccoli respectively, P<0.0001).
      Steaming of spinach or broccoli, in contrast, resulted in no significant decrease
      in folate content, even for the maximum steaming periods of 4.5 min (spinach) and
      15.0 min (broccoli). Prolonged grilling of beef for the maximum period of 16.0
      min did not result in a significant decrease in folate content (54.3 and 51.5
      microg/100 g for raw and grilled beef respectively). Compared with raw values,
      boiling of whole potatoes (skin and flesh) for 60.0 min did not result in a
      significant change in folate content (125.1 and 102.8 microg/100 g for raw and
      boiled potato respectively), nor was there any effect on folate retention whether
      or not skin was retained during boiling. These current results show that the
      retention of folate in various foods is highly dependent both on the food in
      question and the method of cooking. Thus, public health efforts to increase
      folate intake in order to improve folate status should incorporate practical
      advice on cooking.

PMID- 12493091
TI  - Evidence that glutamine modulates respiratory burst in stressed rat
      polymorphonuclear cells through its metabolism into arginine.
AB  - Glutamine (GLN) and arginine (ARG) are recognized for their ability to modulate
      immune cell function. However, the metabolic pathways involved in their action
      remain unclear. It was recently shown that GLN- or ARG-enriched diets increased
      radical oxygen species (ROS) production by neutrophils from stressed rats. Since
      these two amino acids have a tied metabolism, we hypothesized that conversion
      between GLN and ARG (and its active metabolites NO* and polyamines) might be
      involved. To test this hypothesis male Sprague-Dawley rats (n 117) were
      randomized into thirteen groups: rats in eleven groups were rendered catabolic by
      dexamethasone injection (1.5 mg/kg per d for 5 d) and 6.8 mmol either GLN, ARG or
      non-essential amino acids (NEAA; glycine, alanine and histidine)/kg per d were
      given by the enteral route; one group was pair-fed to the treated groups. The
      regimens of all the groups were rendered isonitrogenous by the addition of NEAA.
      The last group was not treated and was fed ad libitum. For each supplementation
      three subgroups were formed, each of which received a specific inhibitor:
      methionine sulfoximine (inhibitor of GLN synthase; 100 mg/kg per d), S
      methylthiourea (inhibitor of inducible NO* synthase (iNOS); 50 mg/kg per d) and
      difluoromethylornithine (inhibitor of ornithine decarboxylase (ODC); 50 mg/kg per
      d). Oxidative metabolism, intracellular H2O2, and extracellular O2*- production
      were measured in unstimulated and phorbol myristate acetate-stimulated
      polymorphonuclear neutrophils. GLN- and ARG-enriched diets increased respiratory
      burst by neutrophils (oxidative metabolism of 152 (sem 24) and 138 (sem 45) v. 57
      (sem 18) mV for GLN-, ARG- and NEAA-enriched diets respectively, P<0.05). In vivo
      inhibition of iNOS or ODC decreased ROS production induced by GLN and ARG. In
      vivo inhibition of GLN synthase did not modify the effect of ARG on ROS
      production. In conclusion, GLN and ARG modulate ROS production in neutrophils
      from stressed rats by the same pathway involving polyamine and NO* synthesis.

PMID- 12493092
TI  - Effects of dietary fat source and breed on the carcass composition, n-3
      polyunsaturated fatty acid and conjugated linoleic acid content of sheep meat and
      adipose tissue.
AB  - Seventy-two 8-week-old ram lambs from three breeds, Suffolk, Soay and Friesland,
      were offered one of four diets based on dried grass and formulated to have a
      similar fatty acid content (60 g/kg DM) and containing: Megalac (high in 16 : 0,
      control; Volac Ltd, Royston, Herts., UK), whole linseed (18 : 3n-3), fish oil (20
      : 5n-3 and 22 : 6n-3) or whole linseed plus fish oil. The lambs were slaughtered
      at approximately half of their mature live weight (43, 21 and 43 kg for Suffolk,
      Soay and Friesland lambs, respectively). Fish oil reduced DM intake and lamb live
      weight gain (P<0.001), while DM intake, live-weight gain and subcutaneous fat
      content were highest in Suffolk and lowest in Soay lambs. Linseed feeding doubled
      the proportion (x100) of 18 : 3n-3 in the longissimus dorsi from 1.4 to 3.1 and
      in the subcutaneous adipose tissue from 1.2 to 2.6 (P<0.001). Suffolk and
      particularly Soay lambs contained higher proportions of 18 : 3n-3 than Friesland
      lambs in the longissimus dorsi, while in the adipose tissue, Suffolk lambs had
      the highest level. Feeding fish oil increased the muscle proportion (x100) of 20
      : 5n-3 from 0.7 to 2.3 and 22 : 6n-3 from 0.3 to 0.8 (P<0.001). By contrast, the
      proportions of the longer-chain n-3 polyunsaturated fatty acids were similar
      across all three breeds. All three lipid supplements containing n-3
      polyunsaturated fatty acids increased the content of muscle trans-18 : 1 relative
      to the control values, but conjugated linoleic acid (cis-9,trans-11-18 : 2) only
      increased in the muscle of lambs fed linseed. Feeding linseed or fish oil lowered
      the n-6 : n-3 ratio in sheep meat, but neither diet nor breed had much effect on
      the polyunsaturated fatty acid: saturated fatty acid ratio.

PMID- 12493093
TI  - Food and macronutrient intake of male adolescent Kalenjin runners in Kenya.
AB  - A nutritional survey based on twelve adolescent male Kalenjin runners in Kenya
      during a 2-week field study was carried out in order to determine the composition
      of their diet and make a comparison with macronutrient recommendations for
      athletes. Food samples were collected for analysis of macronutrient distribution
      and energy content from main meals and the macronutrient distribution and energy
      content of additional food intake were based on the information of a 24 h recall
      interview and estimated from food tables. The diet of the Kalenjin runners was
      very high in carbohydrate (71 % 8.7 g/kg body weight per d) and very low in fat
      (15 %). Intake of total protein (13 %; 1.6 g/kg body weight per d) was above the
      daily intake recommended by the Food and Agriculture Organization/World Health
      Organization/United Nations University (FAO/WHO/UNU), while essential amino acid
      intake was estimated to be in the borderline-to-low range based on FAO/WHO/UNU
      recommendations for children <12 years and adults. The energy intake was mainly
      derived from vegetable sources (90 %) with maize and kidney beans as the staple
      food (81 %). The diet of the Kalenjin runners met recommendations for endurance
      athletes for total protein and most essential amino acid intake as well as
      carbohydrate intake even though it was based on a small range of food items.

PMID- 12493094
TI  - Unhealthy eating habits, physical exercise and macronutrient intakes are
      predictors of anthropometric indicators in the Women's Health Trial: Feasibility
      Study in Minority Populations.
AB  - The increasing prevalence of obesity in the USA, especially among minority
      populations, is a serious public health concern. This present study analysed
      repeated measurements at baseline and at 6 and 12 months on 351 women in the
      control group and 575 women in the intervention group of the Women's Health
      Trial: Feasibility Study in Minority Populations. Dynamic random effects models
      were estimated using the three repeated observations to explain the effects of
      energy and macronutrient intakes, physical exercise, unhealthy eating habits and
      socio-economic characteristics on the subjects' body weights and waist and hip
      circumferences. In both the control and intervention groups, physical exercise
      was negatively associated with body weight and with waist and hip circumferences,
      while an index of unhealthy eating habits was positively associated (P<0.05). The
      proportion of energy derived from carbohydrate and from saturated and
      monounsaturated fat were often significant predictors of body weight and of waist
      and hip circumferences in the two groups. The results indicated that nutrition
      education programmes for improving eating habits and increasing physical exercise
      can reduce obesity prevalence in the USA.

PMID- 12493095
TI  - The mobile bag technique as a method for determining the degradation of four
      botanically diverse fibrous feedstuffs in the small intestine and total digestive
      tract of ponies.
AB  - An in sacco mobile bag technique was used to determine the rate and extent of
      disappearance of unmolassed sugar-beet pulp, soyabean hulls, hay cubes and an oat
      hull-naked oats mixture (67:33, w/w) in the foregut and total digestive tract of
      ponies. Ponies were administered naso-gastrically polyester mesh bags containing
      350 mg feed, in a Latin square design. Bags were collected at the ileo-caecal
      junction (small intestine bag, SIB) and in the faeces (faecal bag, FB) and their
      residues analysed for proximate constituents and NSP composition and content. DM
      disappearances from individual bags were fitted to degradation profiles (Orskov &
      McDonald, 1979) and effective degradability values determined. Significant
      differences (P<0.05) in DM, organic matter and crude protein losses from SIB were
      noted between feeds with hay cubes and oat hulls-naked oats > sugar-beet pulp and
      soyabean hulls. Acid-detergent fibre, neutral-detergent fibre and NSP
      disappearances were small and varied little between feeds. In contrast, FB losses
      showed significant (P<0.05) differences for all constituents measured with sugar
      beet pulp > soyabean hulls > hay cubes > oat hulls-naked oats. Crude protein
      losses from sugar-beet pulp and soyabean hulls in FB were significantly higher
      (P<0.05) than from SIB. FB degradation curves showed degradation to be affected
      by bag residence time with sugar-beet pulp > soyabean hulls and the effective
      degradability showed that significantly more (P<0.05) sugar-beet pulp was lost at
      40.0 and 60.0 h than for the other three feeds. These results show that sugar
      beet pulp and soyabean hulls are rapidly degraded by ponies and could be used as
      alternatives to hay in equid rations. However, the foregut availability of crude
      protein from sugar-beet pulp is poor, so a readily digestible source of crude
      protein should be offered to animals with high protein demands when diets are
      based on sugar-beet pulp.

PMID- 12493096
TI  - Approaches to health via lowering of postprandial glycaemia.

PMID- 12493097
TI  - The genesis of neurosurgery and the evolution of the neurosurgical operative
      environment: part I-prehistory to 2003.
AB  - Despite its singular importance, little attention has been given to the
      neurosurgical operative environment in the scientific and medical literature.
      This article focuses attention on the development of neurosurgery and the
      parallel emergence of its operative setting. The operative environment has, to a
      large extent, defined the "state of the art and science" of neurosurgery, which
      is now undergoing rapid reinvention. During the course of its initial invention,
      major milestones in the development of neurosurgery have included the definition
      of anatomy, consolidation of a scientific basis, and incorporation of the
      practicalities of anesthesia and antisepsis and later operative technical
      adjuvants for further refinement of action and minimalism. The progress,
      previously long and laborious in emergence, is currently undergoing rapid
      evolution. Throughout its evolution, the discipline has assimilated the most
      effective tools of modernity into the operative environment, leading eventually
      to the entity known as the operating room. In the decades leading to the present,
      progressive minimalization of manipulation and the emergence of more refined
      operative definition with increasing precision are evident, with concurrent
      miniaturization of attendant computerized support systems, sensors, robotic
      interfaces, and imaging devices. These developments over time have led to the
      invention of neurosurgery and the establishment of the current state-of-the-art
      neurosurgical operating room as we understand it, and indeed, to a broader
      definition of the entity itself. To remain current, each neurosurgeon should
      periodically reconsider his or her personal operative environment and its
      functional design with reference to modernity of practice as currently defined.

PMID- 12493098
TI  - The genesis of neurosurgery and the evolution of the neurosurgical operative
      environment: part II--concepts for future development, 2003 and beyond.
AB  - The future development of the neurosurgical operative environment is driven
      principally by concurrent development in science and technology. In the new
      millennium, these developments are taking on a Jules Verne quality, with the
      ability to construct and manipulate the human organism and its surroundings at
      the level of atoms and molecules seemingly at hand. Thus, an examination of
      currents in technology advancement from the neurosurgical perspective can provide
      insight into the evolution of the neurosurgical operative environment. In the
      future, the optimal design solution for the operative environment requirements of
      specialized neurosurgery may take the form of composites of venues that are
      currently mutually distinct. Advances in microfabrication technology and laser
      optical manipulators are expanding the scope and role of robotics, with novel
      opportunities for bionic integration. Assimilation of biosensor technology into
      the operative environment promises to provide neurosurgeons of the future with a
      vastly expanded set of physiological data, which will require concurrent
      simplification and optimization of analysis and presentation schemes to
      facilitate practical usefulness. Nanotechnology derivatives are shattering the
      maximum limits of resolution and magnification allowed by conventional
      microscopes. Furthermore, quantum computing and molecular electronics promise to
      greatly enhance computational power, allowing the emerging reality of simulation
      and virtual neurosurgery for rehearsal and training purposes. Progressive
      minimalism is evident throughout, leading ultimately to a paradigm shift as the
      nanoscale is approached. At the interface between the old and new technological
      paradigms, issues related to integration may dictate the ultimate emergence of
      the products of the new paradigm. Once initiated, however, history suggests that
      the process of change will proceed rapidly and dramatically, with the ultimate
      neurosurgical operative environment of the future being far more complex in
      functional capacity but strikingly simple in apparent form.

PMID- 12493099
TI  - Evidence-based neurosurgery.
AB  - OBJECTIVE: The evidence-based medicine movement is gaining influence in many
      medical specialties. Although many think that clinical medicine always has been
      based on evidence, the discipline of evidence-based medicine places particular
      emphasis on a defined set of principles of critical analysis of individual
      research reports, methodologically rigorous synthesis of multiple reports, and
      the collection and dissemination of evidence repositories that allow rapid
      application of evidence in practice. This article provides a selective
      introduction to the discipline of evidence-based medicine as it applies to
      neurological surgery. METHODS: The vast literature on evidence-based medicine has
      been reviewed selectively to identify resources that are readable, accessible,
      and relevant to neurosurgery. RESULTS: The history, concepts, and techniques of
      evidence-based medicine are presented in brief, and educational and
      methodological resources, as well as evidence repositories, are introduced.
      CONCLUSION: The techniques of evidence-based medicine are relevant to
      neurological surgery. There is a relatively large repository of critically
      analyzed and summarized evidence that is useful to the neurosurgical
      practitioner. Familiarity with these techniques and repositories can help the
      neurosurgeon bring the best available evidence to bear on the care of individual
      patients.

PMID- 12493100
TI  - The impact of provider volume on mortality after intracranial tumor resection.
AB  - OBJECTIVE: Policies of regionalization and selective referral for a number of
      "high-risk" surgical procedures are being explored and implemented as a result of
      significant variation in postoperative mortality between high- and low-volume
      providers. The effect of provider volume on outcomes after intracranial tumor
      resection is unknown and warrants investigation. METHODS: By use of the
      Nationwide Inpatient Sample for 1996 and 1997, patients (older than 19 yr) who
      had a diagnosis of a malignant central nervous system neoplasm and underwent
      craniotomy or craniectomy were included. Hospital volume and surgeon volume were
      categorized by quartiles (very low, low, high, or very high volume). Unadjusted
      and case mix-adjusted analyses were performed with regard to postoperative in
      hospital mortality. RESULTS: The crude in-hospital mortality was 2.8% for a total
      of 7547 patients. The mean patient age was 55.8 years (66.5% <65; 33.5% >/=65).
      Mortality for very low- to very high-volume hospitals was as follows: 3.8, 3.2,
      2.4, and 1.8% (P < 0.001). Mortality for very low- to very high-volume surgeons
      was as follows: 4.1, 3.9, 3.1, and 1.4% (P = 0.003). Predictors of mortality in a
      logistic regression model were emergent admission (odds ratio [OR], 2.97; 95%
      confidence interval [CI], 2.02-4.38; P < 0.001), and age 65 years or greater (OR,
      1.63; 95% CI, 1.16-2.30; P = 0.005). The risk of mortality was reduced for very
      high-volume hospitals (OR, 0.58; 95% CI, 0.35-0.97; P = 0.038) and very high
      volume surgeons (OR, 0.42; 95% CI, 0.22-0.84; P = 0.012). CONCLUSION: Higher
      volume providers have superior outcomes after surgical resection of malignant
      intracranial tumors. This reduction was maintained despite adjustment for case
      mix. As the regionalization of high-risk surgery moves forward, it is important
      for neurosurgeons to maintain leadership roles in the development of specialty
      specific data collection and health policy initiatives that improve and reduce
      variation in outcomes.

PMID- 12493101
TI  - Natural history of petroclival meningiomas.
AB  - OBJECTIVE: For evaluation of the natural history of petroclival meningiomas, a
      cooperative retrospective study of 21 conservatively treated patients is
      reported. METHODS: All patients had petroclival meningiomas that were observed
      for at least 4 years, with regular clinical and radiological control
      examinations. The follow-up periods ranged from 48 to 120 months (mean, 82 mo;
      median, 85 mo). Functional evaluations were performed by using the Karnofsky
      index. Individual growth curves and rates were defined. RESULTS: Age and sex
      distributions and presenting symptoms were comparable to those of other studies.
      During follow-up monitoring, radiological tumor growth was observed in 76% of the
      cases. With 63% of the growing tumors, there was functional deterioration. We
      performed statistical analyses of demographic features, radiological findings,
      and functional deterioration. Severe functional deterioration was observed to be
      statistically significantly associated with infratentorial growth and increased
      growth rates. A change in the growth pattern often preceded functional
      deterioration. CONCLUSION: This study provides a better understanding of the
      natural course of petroclival meningiomas. The growth patterns of these tumors
      are unpredictable and variable. The exact factors influencing growth remain
      unclear. This study can contribute to the optimization of individual management
      of these tumors.

PMID- 12493102
TI  - Ventricular diverticula in obstructive hydrocephalus secondary to tumor growth.
AB  - OBJECTIVE: The association of ventricular diverticula with intra- and
      paraventricular tumors causing obstructive hydrocephalus has rarely been
      reported. METHODS: Records and imaging findings for 57 patients with obstructive
      hydrocephalus caused by tumors who were treated at our institution were reviewed
      for the presence of ventricular diverticula. For the anatomic study of
      ventricular diverticula, data were collected from five cadaveric heads. RESULTS:
      Ventricular diverticula were identified on magnetic resonance imaging scans in
      five cases. Diverticula were similarly located in the quadrigeminal cistern but
      originated from the medial wall of the atrium of the lateral ventricle in three
      cases and from the superior portion of the fourth ventricle in two cases.
      Regression of diverticula occurred in all cases after either insertion of a shunt
      or removal of the obstructing tumor. The cadaveric study suggested that the
      choroidal fissure and the rostral portion of the superior medullary velum might
      be the origins of diverticula from the atrium and from the superior portion of
      the fourth ventricle, respectively. CONCLUSION: Ventricular diverticula should be
      distinguished from other cystic lesions in the quadrigeminal region. Detection of
      an ostium of a diverticulum or communication between the cyst and the ventricular
      system is important for diagnosis.

PMID- 12493103
TI  - Craniocervical tuberculosis: protocol of surgical management.
AB  - OBJECTIVE: Craniovertebral junction tuberculosis (CVJ-TB) is rare and occurs in
      only 0.3 to 1% of patients with tuberculous spondylitis. In the available
      literature, the treatment options offered for this entity have ranged from a
      purely conservative approach to radical surgery without well-defined guidelines.
      In this study, we attempt to establish the most effective strategy for the
      management of this condition. METHODS: Twenty-five patients with CVJ-TB were
      treated during the past 8 years. Severe neck pain, restricted neck movement, and
      myelopathy were the predominant symptoms. The patients were graded according to
      their disability as follows: Grade I (n = 7), only neck pain with no pyramidal
      tract involvement; Grade II (n = 8), independent with minor disability; Grade III
      (n = 1), partially dependent on others for assistance with activities of daily
      living; and Grade IV (n = 9), completely dependent on others for assistance with
      all activities of daily living. Nine patients in Grade IV also had severe
      respiratory compromise. In all patients, lateral radiographs of the CVJ in
      flexion and extension were used to determine the presence of atlantoaxial
      dislocation (AAD). Bony destruction, paraspinal abscess, and thecal compression
      were seen on intrathecal contrast computed tomographic scans (n = 9) and magnetic
      resonance imaging studies (n = 22). Under the cover of antituberculous therapy
      (ATT) administered for 18 months, the patients were placed under a management
      protocol that took into account the patient's preoperative grade, the presence of
      mobile or fixed AAD, bony destruction and retropharyngeal abscess formation at
      the CVJ, and the clinicoradiological response to ATT within 3 months. Thus, 14
      patients were kept on conservative management, with their neck movements
      stabilized with an external orthosis; 4 patients underwent a single-stage
      transoral decompression and posterior fusion procedure; and 7 patients underwent
      direct posterior fusion. RESULTS: In a follow-up period that ranged from 6 months
      to 7 years (mean, 2.5 yr), the patients in Grades I and II maintained their
      neurological status. The single patient in Grade III improved to Grade II. Seven
      of the nine patients in Grade IV returned to normal, and one improved to Grade
      II. Neck pain improved in all patients. The only death in the series occurred as
      a result of aspiration pneumonitis leading to septicemia in a child in Grade IV
      with poor respiratory status and multilevel tuberculous involvement who had
      undergone transoral decompression and posterior fusion for fixed AAD. CONCLUSION:
      This study discusses the clinicoradiological presentation as well as the
      management of CVJ-TB, in which ATT is administered for 18 months. In the patients
      with minor deficits (Grades I and II), conservative neck stabilization is
      adopted; in the patients with severe deficits (Grades III and IV) due to
      significant cervicomedullary compression caused by fixed AAD or bone destruction
      and granulation, anterior decompression and posterior fusion are performed.
      Patients with persistent reducible AAD undergo direct posterior fusion. A
      significant improvement is possible even in poor-grade patients with judicious
      use of the surgical options and ATT.

PMID- 12493104
TI  - Stratification of outcome for surgically treated unruptured intracranial
      aneurysms.
AB  - OBJECT: The combination of low anticipated rupture rates for many unruptured
      aneurysms, better delineation of treatment risks, and the availability of
      alternative modalities of treatment have led to heightened scrutiny of the
      surgical management of unruptured intracranial aneurysms. Most reports to date
      have provided aggregate data concerning surgical treatment risks. This study was
      performed to better delineate risk estimates for the surgical treatment of
      patients with unruptured intracranial aneurysms according to a patient's risk
      profile with regard to age, aneurysm location, and aneurysm size. METHODS: We
      studied 493 patients who were treated with surgical clipping of 604 unruptured
      saccular aneurysms. Information regarding aneurysm size, location, patient age,
      and 6-month or greater outcome were gathered prospectively from 1992 to 1999.
      Multivariate analysis was performed to identify independent risk factors for
      outcome. On the basis of the model, risk stratification curves were generated.
      RESULTS: In our series, the mean patient age was 53 years, and the mean lesion
      size was 8.8 mm. Lesion locations included the internal carotid artery (n = 259,
      43%), the middle cerebral artery (n = 174, 28%), the anterior cerebral artery (n
      = 99, 17%), and the vertebrobasilar artery (n = 67, 11%). Multivariate analysis
      revealed that aneurysm size (beta = 0.122, P < 0.001), patient age (beta =
      0.0308, P < 0.05), and vertebrobasilar location (beta = 1.37, P = 0.0080) were
      independently associated with high risk of poor outcome or death. CONCLUSION:
      Small aneurysms in the anterior circulation in young patients carry a very low
      treatment risk (approximately 1%), and treatment in elderly individuals (ages 70
      years and older) with large lesions (greater than 10 mm), carries a significant
      risk of poor outcome (5% in the anterior circulation, 15% in the posterior
      circulation). The nomograms generated by this study should be particularly useful
      in discussing with patients the risks and benefits of surgical treatment of
      unruptured aneurysms.

PMID- 12493105
TI  - Analysis of complications of radiofrequency pallidotomy.
AB  - OBJECTIVE: To systematically report the complications of pallidotomy and to
      tentatively determine the incidences of complications of pallidotomy, possible
      influencing factors, and the acceptability of symptomatic hemorrhage rates for
      microelectrode-guided pallidotomy. METHODS: Clinical events were analyzed for
      1116 patients with Parkinson's disease who underwent microelectrode-guided
      pallidotomies at our center. Complications included visual field deficits,
      weakness, fatigue, hypersomnia, drooling, dysphagia, speech disorders, hiccups,
      hemorrhage, seizures, apraxia, coma, infection, mental confusion, and impaired
      memory. Complication rates for bilateral pallidotomy and double-lesion groups
      were compared with those for unilateral pallidotomy and single-lesion groups,
      respectively. RESULTS: Among the total of 1116 patients, the incidences of visual
      field deficits, weakness, fatigue, hypersomnia, drooling, dysphagia, and speech
      disorders were 0.4, 4.2, 19.9, 12.4, 7.0, 3.7, and 11.9%, respectively.
      Symptomatic hemorrhage was observed for 17 patients, apraxia for 3 patients, coma
      for 2 patients, mental confusion for 24 patients, and impaired memory for 18 of
      the 1116 patients. The incidences of fatigue, speech disorders, drooling,
      dysphagia, and hypersomnia were 18.1, 10.3, 5.2, 2.4, and 11.6%, respectively, in
      the unilateral pallidotomy group and 34.9, 25.5, 22.6, 14.2, and 17.0%,
      respectively, in the staged pallidotomy group. Of the three patients who
      underwent simultaneous bilateral pallidotomies (all <50 yr of age), all developed
      severe fatigue and two exhibited drooling and dysphagia. The incidences of
      weakness, fatigue, speech disorders, drooling, dysphagia, and hypersomnia were
      8.7, 30.4, 18.8, 7.2, 2.9, and 20.3%, respectively, in the double-lesion group
      and 3.2, 17.2, 9.7, 5.0, 2.3, and 11.5%, respectively, in the single-lesion
      group. CONCLUSION: Staged bilateral pallidotomy should be carefully evaluated
      before decision-making, whereas simultaneous bilateral pallidotomy is
      undesirable. Our study suggests that the size of the final lesion should be
      limited, to minimize the risks of complications. The incidence of symptomatic
      hemorrhage in microelectrode-guided pallidotomy is low and acceptable, because of
      the benefits of microelectrode-guided pallidotomy.

PMID- 12493106
TI  - Optimal temperature for the management of severe traumatic brain injury: effect
      of hypothermia on intracranial pressure, systemic and intracranial hemodynamics,
      and metabolism.
AB  - OBJECTIVE: We studied the effect of hypothermia on intracranial pressure,
      systemic and intracranial hemodynamics, and metabolism in patients with severe
      traumatic brain injury to clarify the optimal temperature for hypothermia, with a
      view toward establishing the proper management techniques for such patients.
      METHODS: The study was performed in 31 patients with severe head injury (Glasgow
      Coma Scale score as high as 5). All patients were sedated, paralyzed, ventilated,
      and cooled to 33 degrees C. Brain temperature, core temperature, intracranial
      pressure, cerebral perfusion pressure, jugular venous oxygen saturation, mixed
      venous oxygen saturation, cardiac output, oxygen delivery, oxygen consumption,
      and resting energy expenditure were monitored continuously. RESULTS: Intracranial
      pressure decreased significantly at brain temperatures below 37 degrees C and
      decreased more sharply at temperatures 35 to 36 degrees C, but no differences
      were observed at temperatures below 35 degrees C. Cerebral perfusion pressure
      peaked at 35.0 to 35.9 degrees C and decreased with further decreases in
      temperature. Jugular venous oxygen saturation and mixed venous oxygen saturation
      remained in the normal range during hypothermia. Resting energy expenditure and
      cardiac output decreased progressively with hypothermia. Oxygen delivery and
      oxygen consumption decreased to abnormally low levels at rectal temperatures
      below 35 degrees C, and the correlation between them became less significant at
      less than 35 degrees C than that when temperatures were 35 degrees C or higher.
      Brain temperature was consistently higher than rectal temperature by 0.5 +/- 0.3
      degrees C. CONCLUSION: These results suggest that, after traumatic brain injury,
      decreasing body temperature to 35 to 35.5 degrees C can reduce intracranial
      hypertension while maintaining sufficient cerebral perfusion pressure without
      cardiac dysfunction or oxygen debt. Thus, 35 to 35.5 degrees C seems to be the
      optimal temperature at which to treat patients with severe traumatic brain
      injury.

PMID- 12493107
TI  - Quality of life assessment with the medical outcomes study short form-36 among
      patients with cervical spondylotic myelopathy.
AB  - OBJECTIVE: Cervical spondylotic myelopathy (CSM) is a chronic degenerative
      condition of the cervical spine that produces narrowing of the spinal canal and
      disruption of spinal cord function. We used Medical Outcomes Study Short Form-36
      (SF-36), a generic quality of life outcome-assessment instrument, to assess the
      quality of life among patients with CSM. METHODS: A cohort of 88 Veterans
      Administration neurosurgery clinic patients with CSM underwent structured
      interviews for collection of data on demographic features, symptoms, operations,
      and comorbid diseases. Patients also completed the SF-36. Symptoms and
      examination findings were used to assign each patient scores on the Nurick,
      Cooper, and Harsh myelopathy scales and a Western modification of the Japanese
      Orthopaedic Association scale. SF-36 scores were compared with age-adjusted
      Veterans Administration population normative values by using Student's t test
      with unequal variances. Cuzick's nonparametric test for trend was used to explore
      the relationship between the SF-36 physical component summary scores and the
      myelopathy scale scores. RESULTS: Patients with CSM exhibited decreased quality
      of life in all eight SF-36 domains, as well as with the physical and mental
      component summary scores, compared with Veterans Administration population
      normative values (for all, P </= 0.003). Lower physical component summary scores
      were associated with worse myelopathy scores on the Nurick scale (P < 0.001),
      Cooper leg subscale (P = 0.012), and Harsh scale (P < 0.001). CONCLUSION:
      Patients with CSM exhibit decreased quality of life in all health domains
      assessed with the SF-36, a generic health outcome-measurement instrument. The
      impairments of patients with CSM extend beyond the motor, sensory, and bladder
      dysfunctions recorded with myelopathy scales, into the realms of emotional and
      mental health.

PMID- 12493108
TI  - Cervical spondylotic myelopathy: surgical results and factors affecting outcome
      with special reference to age differences.
AB  - OBJECTIVE: A variety of factors may affect the surgical outcome in patients with
      cervical spondylotic myelopathy. The aim of this study is to analyze the
      prognostic factors by comparing younger and elderly patient groups on the basis
      of preoperative radiological and clinical data. METHODS: To assess the prognostic
      factors after surgery had been performed, the clinical and radiological data of
      64 patients who underwent expansive laminoplasty were reviewed. Patients were
      classified into two groups, a younger patient group (<65 yr of age; n = 29) and
      an elderly patient group (>/=65 yr of age; n = 35). The neurological status of
      the patients was assessed by use of the Japanese Orthopaedic Association scale.
      Radiological features were examined with computed tomographic myelography and
      magnetic resonance imaging. The effects of the clinical and radiological findings
      on neurological outcome were investigated. RESULTS: The preoperative and
      postoperative mean Japanese Orthopaedic Association scores in elderly patients
      were significantly lower than those in younger patients. For elderly patients,
      the transverse area of the spinal cord at the level of maximum compression and
      symptom duration were the factors that predicted an excellent recovery. In
      contrast, the transverse area was the only predictor of excellent recovery in
      younger patients. Age, preoperative Japanese Orthopaedic Association score, canal
      diameter, and an intensity change on the spinal cord were not predictive in
      either age range. CONCLUSION: The transverse area of the spinal cord may be a
      reliable predictor of excellent recovery in both younger and elderly patient
      groups. Shorter symptom duration was an important factor in the excellent
      recovery of elderly patients.

PMID- 12493109
TI  - Palmar hyperhidrosis: intraoperative monitoring with laser Doppler blood flow as
      a guide for success after endoscopic thoracic sympathectomy.
AB  - OBJECTIVE: Video-assisted endoscopic thoracic sympathectomy is an effective
      surgical procedure for treating patients with palmar hyperhidrosis. An increase
      by more than 1 degrees C in palmar temperature has been observed to be predictive
      of good outcome. In this study, we investigated the use of palmar laser Doppler
      flowmetry as an intraoperative assessment of the efficacy of the operation.
      METHODS: One hundred sixty-six patients underwent a total of 330 endoscopic
      thoracic sympathectomy procedures from March 1996 to June 2001. We studied 17
      patients (15 men, 2 women) who underwent a total of 33 procedures. The patients'
      mean age was 27.07 +/- 7.92 years, and the mean hospital stay was 2.23 +/- 0.66
      days. RESULTS: Mean baseline laser Doppler blood flow was 2.63 +/- 2.56
      ml/min/100 g. After the procedure, mean blood flow increased significantly to
      7.24 +/- 5.88 ml/min/100 g (r = 0.768, P < 0.000, 95% confidence limit, -6.1060, 
      3.0946), a 232.18 +/- 219.12% increase. Mean palmar temperature increased to 1.44
      +/- 1.44 degrees C. All patients experienced relief after the operation.
      Compensatory hyperhidrosis occurred in 10 (58.8%) of 17 patients. CONCLUSION:
      Monitoring of palmar laser Doppler blood flow changes is a useful adjunct during
      endoscopic thoracic sympathectomy surgery, and, when coupled with the established
      methods of endoscopic visualization and palmar temperature, it can predict the
      success of the procedure accurately.

PMID- 12493110
TI  - Near-infrared indocyanine green video angiography: a new method for
      intraoperative assessment of vascular flow.
AB  - OBJECTIVE: We report our initial clinical experience with a new method for
      intraoperative blood flow assessment. The purposes of the study were to assess
      the use of indocyanine green (ICG) video angiography in neurovascular cases, to
      assess the handling and image quality, to compare the findings with postoperative
      angiographic results, and to evaluate the clinical value of the method in a
      preliminary feasibility study. METHODS: Fourteen patients with aneurysms (n = 12)
      or spinal (n = 1) or intracranial (n = 1) dural fistulae were included. Before
      and/or after aneurysm or dural fistula occlusion, ICG (25 mg) was injected
      intravenously. A near-infrared laser excitation light source (lambda = 780 nm)
      illuminated the operating field. The intravascular fluorescence of ICG (maximal
      lambda = 835 nm) was recorded by a nonintensified video camera, with optical
      filtering to block ambient and laser light for collection of only ICG-induced
      fluorescence. RESULTS: A total of 21 investigations were performed for 14
      patients. For the 17 successful ICG video angiographic investigations, image
      quality and resolution were excellent, allowing intraoperative real-time
      assessment of the cerebral circulation. ICG angiographic results could be divided
      into arterial, capillary, and venous phases, comparable to those observed with
      digital subtraction angiography. In all cases, the postoperative angiographic
      results corresponded to the intraoperative ICG video angiographic findings. In
      three cases, the information provided by intraoperative ICG angiography
      significantly changed the surgical procedure. CONCLUSION: ICG video angiography
      is simple and provides real-time information on the patency of arterial and
      venous vessels of all relevant diameters, including small and perforating
      arteries (<0.5 mm), and the visible aneurysm sac. It may be a useful adjunct to
      improve the quality of neurovascular procedures and to document the
      intraoperative vascular flow.

PMID- 12493111
TI  - An analysis of the accuracy of the CyberKnife: a robotic frameless stereotactic
      radiosurgical system.
AB  - OBJECTIVE: The use of stereotactic radiosurgical systems to treat intracranial
      and extracranial tumors and other lesions requires a high degree of accuracy in
      target identification and localization. The purpose of this study was to evaluate
      the total system accuracy of the CyberKnife (Accuray, Inc., Sunnyvale, CA), a
      frameless, image-guided, stereotactic radiosurgery system. METHODS: Clinically
      relevant accuracy or application accuracy of the CyberKnife radiosurgery system
      is based on 1) the beam delivery accuracy, which combines the robot and the
      camera image tracking system, and 2) target localization accuracy, which combines
      computed tomographic (CT) imaging and treatment planning. Clinically relevant
      accuracy can be measured by delivering a radiation dose to phantoms, in which the
      target is defined on a set of CT images using all components of the CyberKnife
      system, including the treatment planning software, the robot, the camera tracking
      system, and the linear accelerator. Clinically relevant accuracy was measured in
      head phantoms loaded with packs of radiochromic film. The accuracy measured is
      the displacement of the dose contours from the treatment plan to that measured in
      the radiosurgically exposed phantom. RESULTS: Measurements of mean errors of the
      second-generation CyberKnife system at Stanford University Medical Center,
      installed in 2001, ranged from 0.7 mm for a CT slice thickness of 0.625 mm to
      1.97 mm for a CT slice thickness of 3.75 mm. CONCLUSION: The frameless, image
      guided, second-generation CyberKnife radiosurgery system has a clinically
      relevant accuracy of 1.1 +/- 0.3 mm when CT slice thicknesses of 1.25 mm are
      used. CyberKnife precision is comparable to published localization errors in
      current frame-based radiosurgical systems.

PMID- 12493112
TI  - Intracranial hypotension after intraoperative lumbar cerebrospinal fluid
      drainage.
AB  - OBJECTIVE: Intraoperative lumbar cerebrospinal fluid drainage is frequently
      performed in a variety of neurosurgical procedures. A retrospective review is
      presented of the complications of lumbar cerebrospinal fluid drainage. METHODS:
      The records from 75 consecutive operations requiring intraoperative lumbar
      cerebrospinal drainage during a 1-year period at the Hospital of the University
      of Pennsylvania were reviewed to assess the types of complications attributable
      to spinal drainage and their rates of occurrence. The operations were categorized
      into 46 aneurysm clippings, 21 craniotomies for tumors, and 8 other cranial base
      procedures. RESULTS: Two patients developed transient postoperative neurological
      complications as a result of intracranial hypotension that resolved after
      epidural blood patching, with a reexploration craniotomy to drain an epidural
      collection performed in one patient. A third patient in the study developed a
      persistent deficit when intracranial hypotension led to intraoperative
      transtentorial herniation, which resulted in an unusual constellation of multiple
      brainstem infarcts that caused cranial neuropathy. CONCLUSION: Complications of
      intraoperative lumbar cerebrospinal fluid drainage resulting in transient (2 of
      75 patients, 3%) or persistent (1 of 75 patients, 1%) neurological deficits
      caused by intracranial hypotension occur infrequently and may be related to
      preexisting conditions such as hydrocephalus.

PMID- 12493113
TI  - Water jet dissection in neurosurgery: experimental results in the porcine
      cadaveric brain.
AB  - OBJECTIVE: Water jet dissection is currently under investigation as a new tool
      for use in neurosurgical procedures. The safety of this instrument has already
      been demonstrated. However, precise data demonstrating highly accurate tissue
      dissection in the brain in combination with vessel preservation are still
      missing. METHODS: In this study, 50 porcine cadaveric brains were dissected with
      the use of several nozzle types (80-150 in microm diameter, coherent straight or
      helically turned jet) and several levels of water jet pressure (1-40 bars). The
      dissection characteristics in various brain regions and the basilar artery were
      evaluated morphologically. RESULTS: The best results regarding reliable function,
      dissection accuracy, and the correlation of water jet pressure with dissection
      depth were obtained with the 120-microm Helix Hydro-Jet nozzle. An almost linear
      relationship of pressure increase with dissection depth was demonstrated. The
      dissection depth varied significantly up to threefold, depending on the area
      investigated (greatest resistance was in the brainstem, followed by hemispheres
      and then the cerebellum). Vessels including the basilar artery resisted pressure
      up to 15 bars in most cases, whereas the basilar artery was dissected
      significantly more often with higher pressure. CONCLUSION: The results indicate
      that 1) use of the water jet enables very precise and reliable brain parenchyma
      dissection with vessel preservation under conditions corresponding to the
      clinical situation, and 2) the nozzle type and water jet pressure must be
      selected carefully according to the brain area and tissue targeted. This study
      provides the morphological basis for further research with the use of the water
      jet technique in the brain. The water jet's characteristics may make this device
      a useful addition to the neurosurgical armamentarium.

PMID- 12493114
TI  - Lumbar disc herniation: microsurgical approach.
AB  - Lumbar microdiscectomy IS an effective and time-tested neurosurgical procedure.
      Appropriate patient selection is as important as surgical technique in ensuring
      good outcome. As with any operation, mastery of the relevant anatomy is
      paramount. We offer the following illustrations to help surgeons appreciate this
      anatomy: specifically, the relationship between the interspace, the nerve root,
      and the pedicle as seen during a microdiscectomy.

PMID- 12493115
TI  - Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate,
      neuronal death, cerebral blood flow, and perfusion pressure in three different
      rat models.
AB  - OBJECTIVE: To investigate which of three subarachnoid hemorrhage (SAH) models is
      the most suitable for studies of pathological and pathophysiological processes
      after SAH. METHODS: SAH was induced in rats via intracranial endovascular
      perforation (perforation model), blood injection into the cisterna magna (300
      microl), or blood injection into the prechiasmatic cistern (200 microl). The
      subarachnoid blood volume was quantitatively measured. Cerebral blood flow (CBF)
      (as assessed with laser Doppler flowmetry), intracranial pressure, and mean
      arterial blood pressure were recorded for 90 minutes after SAH. Mortality was
      recorded, and neuronal death was assessed in animals that survived 7 days after
      SAH. RESULTS: The subarachnoid blood volume was close to the injected amount
      after prechiasmatic SAH. In the other models, the volume varied between 40 and
      480 microl. The mortality rates were 44% in the perforation SAH group, 25% in the
      prechiasmatic SAH group, and 0% in the cisterna magna SAH group; the
      corresponding values for neuronal death were 11, 44, and 28%. Cerebral perfusion
      pressure approached baseline values within 5 minutes after SAH in all three
      models. CBF decreased to approximately 35% of baseline values immediately after
      SAH in all groups; it gradually increased to normal values 15 minutes after SAH
      in the cisterna magna SAH group and to 60 and 89% of baseline values 90 minutes
      post-SAH in the perforation and prechiasmatic SAH groups. CBF was significantly
      correlated with the subarachnoid blood volume. CONCLUSION: The prechiasmatic SAH
      model seems to be the most suitable for study of the sequelae after SAH; it
      produces a significant decrease in CBF, an acceptable mortality rate, and
      substantial pathological lesions, with high reproducibility. The CBF reduction is
      predominantly dependent on the amount of subarachnoid blood.

PMID- 12493116
TI  - IS20I, a specific alphavbeta3 integrin inhibitor, reduces glioma growth in vivo.
AB  - OBJECTIVE: The biological features of malignant gliomas include high cell
      proliferation, extensive local infiltration of tumor cells into normal brain, and
      marked neovascularization. alphavbeta3 integrin is highly expressed in malignant
      gliomas and plays a role in glioma growth. This article investigates the in vitro
      and in vivo effects of a synthetic alphavbeta3 integrin inhibitor called IS20I on
      human malignant gliomas. METHODS: The in vitro effects of IS20I were studied by
      performing adhesion assays, competition studies, semi-in vivo angiogenic assays,
      and migration and proliferation assays. For the in vivo experiments, IS20I was
      administered systemically in nude mouse intracranial and subcutaneous malignant
      glioma models. RESULTS: IS20I reacted selectively to alphavbeta3 integrin in
      glioma cells and tissues. In vitro, IS20I strongly inhibited angiogenesis and
      simultaneously exhibited potent antimitotic and antimigratory effects on numerous
      tumor and endothelial cell lines. In addition, at high concentrations, IS20I
      induced endothelial and tumor cell apoptosis. In vivo, when IS20I was
      administered intraperitoneally in subcutaneous and intracranial nude mouse glioma
      models, it potently reduced malignant glioma growth. Inhibition levels of 76 and
      82% were observed at concentrations of 1 and 5 mg/kg, respectively, in the U87
      intracranial model. The suppression of tumor growth is associated with a decrease
      in tumor vascularity, an increase in apoptosis, and a decrease in tumor cell
      proliferation. CONCLUSION: This work expands the understanding of the effects of
      anti-alphavbeta3 integrin inhibitors on malignant gliomas. In addition to direct
      proapoptotic and antiangiogenic effects, IS20I inhibits tumor and endothelial
      cell proliferation and migration, resulting in a potent inhibition of glioma
      growth in vivo.

PMID- 12493117
TI  - Anti-invasive effect of an anti-matrix metalloproteinase agent in a murine brain
      slice model using the serial monitoring of green fluorescent protein-labeled
      glioma cells.
AB  - OBJECTIVE: We aimed to analyze the anti-invasive effect of the anti-matrix
      metalloproteinase (anti-MMP) agent SI-27 by quantitative tracking of enhanced
      green fluorescent protein (EGFP)-labeled human malignant glioma cell lines in a
      brain slice model. METHODS: Persistent expression of EGFP in human malignant
      glioma cell clones (U87MG, U251MG, and U373MG) was established with the use of
      the pEGFP-C1 vector. Tumor spheroid in 1 microl Matrigel was implanted into the
      caudate nucleus-putamen of a severe combined immunodeficient mouse brain slice.
      To allow the quantitative assessment of tumor cell invasion, the invasion area
      index was measured on Days 1, 3, 5, and 7 with a fluorescence stereomicroscope
      and an image analyzer in the presence of various concentrations of SI-27 (0, 1,
      10, 50, or 100 microg/ml). RESULTS: In the control group (0 microg/ml), all
      glioma cell lines invaded in a fingerlike fashion and reached the contralateral
      hemisphere through the corpus callosum. SI-27 at concentrations of 10, 50, and
      100 microg/ml significantly suppressed the invasion area index on Days 5 and 7 in
      a dose-dependent manner, whereas 1 microg/ml had no effect. Transmission electron
      microscopy and laser confocal microscopy indicated that the tumor cells had
      penetrated the brain slice and that the normal structural integrity of the brain
      was maintained until Day 7. CONCLUSION: This model enabled unequivocal periodic
      tracking of individual invading tumor cells in normal brain. The significant
      suppression of glioma cell invasion by noncytotoxic concentrations of SI-27
      indicates that anti-MMP treatment may represent an important future therapeutic
      strategy for malignant cerebral neoplasms.

PMID- 12493118
TI  - Harvey Cushing's Canadian connections.
AB  - During his surgical career between 1896 and 1934, Harvey Cushing made eight
      visits to Canada. He had a broad impact on Canadian medicine and neurosurgery.
      Cushing's students Wilder Penfield and Kenneth McKenzie became outstanding
      leaders of the two major centers in Canada for neurosurgical treatment and
      training. On his first trip to Canada, shortly after completing his surgical
      internship in August 1896, Cushing traveled with members of his family through
      the Maritime Provinces and visited hospitals in Quebec and Montreal. Eight years
      later, in February 1904, as a successful young neurosurgeon at the Johns Hopkins
      Hospital, he reported to the Montreal Medico-Chirurgical Society on his surgical
      experience in 20 cases of removal of the trigeminal ganglion for neuralgia. In
      1922, as the Charles Mickle Lecturer at the University of Toronto, Cushing
      assigned his honorarium of $1000 to support a neurosurgical fellowship at
      Harvard. This was awarded to McKenzie, then a general practitioner, for a year's
      training with Cushing in 1922-1923. McKenzie returned to initiate the
      neurosurgical services at the Toronto General Hospital, where he developed into a
      master surgeon and teacher. On Cushing's second visit to McGill University in
      October 1922, he and Sir Charles Sherrington inaugurated the new Biology Building
      of McGill's Medical School, marking the first stage of a Rockefeller-McGill
      program of modernization. In May 1929, Cushing attended the dedication of the
      Osler Library at McGill. In September 1934, responding to the invitation of
      Penfield, Cushing presented a Foundation Lecture-one of his finest addresses on
      the philosophy of neurosurgery-at the opening of the Montreal Neurological
      Institute. On that same trip, Cushing's revisit to McGill's Osler Library
      convinced him to turn over his own treasure of historical books to Yale
      University.

PMID- 12493119
TI  - Pathogenesis and diagnostic pitfalls of ventricular diverticula: case report and
      review of the literature.
AB  - OBJECTIVE AND IMPORTANCE: Ventricular diverticula are local herniations of the
      ventricular system occurring in association with severe, long-standing
      hydrocephalus. Variability in the extent and location of these ventricular
      pouches may produce misleading radiological conformations and raise diagnostic
      challenges. In this report, we discuss the pathogenesis and differential
      diagnosis of ventricular diverticula on the basis of a case illustration.
      CLINICAL PRESENTATION: We report the case of a 38-year-old woman presenting with
      hydrocephalus secondary to an obstructive lesion of the third ventricle. A large,
      dilated structure compressing the brainstem was present in the posterior fossa.
      INTERVENTION: The posterior fossa lesion was identified as an atrial diverticulum
      by injection of contrast medium into the right lateral ventricle, which led to
      immediate enhancement of the infratentorial cavity. Ventricular drainage and
      removal of the third ventricular lesion, a colloid cyst, allowed progressive
      collapse of the diverticulum and symptom resolution. CONCLUSION: This report
      discusses the pathogenesis of ventricular diverticula and demonstrates that
      ventriculography can be used to differentiate atrial diverticula from other
      posterior fossa lesions when time-consuming multiplanar magnetic resonance
      imaging cannot be afforded on an emergency basis.

PMID- 12493120
TI  - Transient choroid plexus cysts and benign asymmetrical ventricles: a case
      suggesting a possible link: case report.
AB  - OBJECTIVE AND IMPORTANCE: Brain magnetic resonance imaging scans occasionally
      reveal asymmetrical ventricles with no identifiable cause. A case is presented
      that highlights a possible connection between transient choroid plexus cysts and
      benign asymmetrical ventricles. CLINICAL PRESENTATION: The patient was a 2.5-week
      old asymptomatic boy. Transcranial ultrasound and magnetic resonance imaging
      revealed the infant to have a left frontal horn choroid plexus cyst and a mildly
      dilated left lateral ventricle. Head circumference was at 90% of the norm for
      age. The neurological examination revealed nothing abnormal. Four months later,
      follow-up magnetic resonance imaging revealed complete resolution of the cyst
      with persistent ventricular asymmetry. INTERVENTION: No surgical intervention was
      undertaken. The lesion was assessed via x-ray. CONCLUSION: Spontaneously
      resolving choroid plexus cysts of infancy causing outflow obstruction of the
      lateral ventricle may be one of the underlying causes of benign asymmetrical
      ventricles.

PMID- 12493121
TI  - Posterior fossa decompression for life-threatening tonsillar herniation in
      patients with gliomatosis cerebri: report of three cases.
AB  - OBJECTIVE AND IMPORTANCE: Gliomatosis cerebri (GC) is a rare type of primary
      brain tumor that diffusely infiltrates more than two lobes of the brain while the
      normal cerebral architecture is maintained. To the best of our knowledge, the
      association between an acquired tonsillar herniation and GC has never been
      reported. In this article, we describe three patients with progressive
      gliomatosis of the cerebellar hemispheres who subsequently showed signs and
      symptoms secondary to tonsillar herniation. Early recognition of this potentially
      life-threatening complication allowed us to recommend prompt surgical
      intervention. CLINICAL PRESENTATION: One patient with primary, or Type I, GC
      presented with suboccipital headaches, and two patients with secondary, or Type
      II, GC presented with the signs and symptoms of progressive myelopathy. Serial
      imaging studies demonstrated progressive involvement of the cerebellum, descent
      of the cerebellar tonsils through the foramen magnum, and cervicomedullary spinal
      cord compression. INTERVENTION: Once the tonsillar herniation was recognized, all
      three patients underwent posterior fossa decompression, a cervical laminectomy to
      the lowest level of the tonsillar herniation, and duraplasty. All three patients
      experienced immediate improvement in their conditions. CONCLUSION: Early
      recognition of tonsillar herniation, a possibly overlooked cause of death in
      patients with GC, allows for early surgical intervention as a potentially
      lifesaving procedure and significant improvement in the patient's condition.

PMID- 12493122
TI  - Diencephalic syndrome of emaciation in an adult associated with a third ventricle
      intrinsic craniopharyngioma: case report.
AB  - OBJECTIVE AND IMPORTANCE: Diencephalic syndrome of emaciation (DS) is seen almost
      exclusively in infants and young children, and only two cases of DS in adults
      have been reported previously. We describe a case of DS associated with a third
      ventricle intrinsic craniopharyngioma in an adult patient. CLINICAL PRESENTATION:
      A 54-year-old man presented with profound emaciation, disorientation, memory
      loss, and psychological disorders. Computed tomographic scanning and magnetic
      resonance imaging of his brain disclosed a tumor within the third ventricle. The
      preoperative endocrinological examination indicated an elevated growth hormone
      level and a decreased somatomedin C level. INTERVENTION: The patient underwent
      partial resection of the tumor, which was adherent to the floor of the third
      ventricle but not to the ventricle wall, by an interhemispheric-transcallosal
      approach. The histological examination revealed a squamous papillary-type
      craniopharyngioma. The patient received 50 Gy of radiotherapy, which resulted in
      90 to 95% reduction of the tumor size within 6 months, as indicated by the
      magnetic resonance images presented. The psychological disorders, memory
      disturbance, and severe emaciation improved gradually thereafter. CONCLUSION:
      Although extremely rare, DS can occur in an adult harboring a tumor in the
      anterior hypothalamus.

PMID- 12493123
TI  - Symptomatic de novo arteriovenous malformation appearing 17 years after the
      resection of two other arteriovenous malformations in childhood: case report.
AB  - OBJECTIVE AND IMPORTANCE: This report describes the first case of symptomatic de
      novo arteriovenous malformation (AVM) appearing ectopically after total resection
      of other AVMs. We discuss the growth phenomenon and the nature of AVMs. CLINICAL
      PRESENTATION: A 27-year-old woman with sudden headache and right-sided numbness
      was admitted to our hospital. Computed tomographic scans revealed a hemorrhage of
      the corpus callosum and the bilateral lateral ventricles. A cerebral angiogram
      demonstrated an AVM that was fed by the bilateral pericallosal arteries and
      drained into the inferior sagittal sinus. Seventeen years earlier, at the age of
      10 years, the patient had undergone resection of two other AVMs. At that time,
      the newly presented AVM was not detected. This AVM had grown markedly and caused
      hemorrhage after 17 years. INTERVENTION: The AVM, which was located in the
      bilateral cingulate gyrus and the corpus callosum, was totally removed through a
      right frontal craniotomy. The patient was discharged without neurological
      deficits. CONCLUSION: Our findings suggest that patients who undergo complete
      resection of AVMs may sustain other de novo AVMs some years later. The growth of
      an AVM seems to be related to the patient's age at onset and the duration of the
      posttreatment period. We emphasize the importance of long-term follow-up in
      patients with cerebral AVMs treated during childhood.

PMID- 12493124
TI  - Reversal of blindness after transvenous embolization of a carotid-cavernous
      fistula: case report.
AB  - OBJECTIVE AND IMPORTANCE: Reversal of blindness after the endovascular treatment
      of a carotid-cavernous fistula (CCF) is exceedingly rare. It has been reported
      only once in a patient with a direct CCF. We report the first such case in a
      patient with an indirect CCF. Defining patients whose vision may recover is
      critical in coordinating the timing of therapy. Mechanisms of reversible visual
      loss in CCFs are discussed with the intent of elucidating the patients who
      compose this subgroup. CLINICAL PRESENTATION: A 65-year-old man had a 1-week
      history of blindness, chemosis, and proptosis of the right eye. Ophthalmoscopy
      was compromised by diffuse choroidal effusion and corneal edema that obscured
      visualization of the patient's retina. INTERVENTION: Transvenous embolization
      through retrograde catheterization of the superior ophthalmic vein allowed
      complete coil occlusion of the lesion. The patient's visual loss improved
      rapidly, returning to normal within 50 days. CONCLUSION: Although CCFs frequently
      are associated with permanent visual loss, a subset of patients demonstrates
      reversible ocular findings. If the retina of a patient with a CCF seems normal or
      is obscured, the potential for visual recovery, even from blindness, should
      prompt emergent treatment.

PMID- 12493125
TI  - Early carotid endarterectomy after ischemic stroke improves diffusion/perfusion
      mismatch on magnetic resonance imaging: report of two cases.
AB  - OBJECTIVE AND IMPORTANCE: The functional magnetic resonance imaging techniques of
      diffusion-weighted imaging and perfusion-weighted imaging allow for ultra-early
      detection of brain infarction and concomitant identification of blood flow
      abnormalities in surrounding regions, which may represent brain "at risk."
      CLINICAL PRESENTATION: We report two patients with acute ischemic stroke
      associated with ipsilateral high-grade carotid stenosis. The first patient, a 64
      year-old woman with a remote history of ischemic stroke and a vertebral artery
      aneurysm, presented with worsening of her preexisting right hemiparesis. The
      second patient, another 64-year-old woman with known multiple intracranial
      aneurysms and bilateral high-grade internal carotid artery stenosis, was admitted
      for the elective microsurgical clipping of an enlarging giant left carotid
      ophthalmic artery aneurysm. Postoperatively, she developed right hemiparesis and
      mild aphasia. Both patients showed progressive worsening of their neurological
      deficits in the setting of small or undetected diffusion-weighted imaging
      abnormalities and large perfusion-weighted imaging defects. INTERVENTION: After
      prompt carotid endarterectomy, symptoms in both patients resolved or improved.
      Follow-up magnetic resonance imaging scans demonstrated resolution or significant
      improvement in the perfusion abnormalities in both patients. CONCLUSION: Carotid
      endarterectomy in the setting of diffusion-weighted/perfusion-weighted imaging
      mismatch can lead to improvement in cerebral perfusion as evidenced by resolution
      of the perfusion-weighted imaging lesion. Diffusion/perfusion magnetic resonance
      imaging may be useful in identifying patients with severe neurological deficits
      but without large territories of infarction who may safely undergo early surgical
      revascularization.

PMID- 12493126
TI  - Intramedullary neurenteric cyst with a false mural nodule: case report.
AB  - OBJECTIVE AND IMPORTANCE: Spinal neurenteric cysts are rare congenital lesions
      that may occur either alone or in the context of a complex malformative disorder
      including typical vertebral and cutaneous abnormalities. The interest of the case
      of a spinal neurenteric cyst described here lies in its rare intramedullary
      location and in the false mural nodule image on the preoperative magnetic
      resonance imaging scan. A further distinctive feature is the association with a
      cleft spinal cord. CLINICAL PRESENTATION: A 28-year-old woman presented with a 2
      year history of progressive paraparesis and urinary retention. A magnetic
      resonance imaging study disclosed a T8-T9 intramedullary cystic lesion with a
      mural nodulelike formation on the posterior face. INTERVENTION: A posterior
      midline myelotomy exposed a cystic lesion that had translucent walls and
      contained a milky fluid. No mural nodules were found. Once the cyst had been
      emptied, a collateral finding was a cleft that was clearly observed in the
      anterior spinal cord. The histological diagnosis was a neurenteric cyst.
      Retrospectively, the nodular lesion found on the preoperative scan was attributed
      to mucinous clots deposited at the bottom of the cyst. CONCLUSION: This case
      report demonstrates that neurenteric cysts can vary widely in radiological
      appearance, depending on the contents of the cyst. These differences become
      especially important if the associated stigmata are lacking and the preoperative
      diagnosis rests on magnetic resonance imaging scan appearance alone.

PMID- 12493127
TI  - Navigated transoral approach to the cranial base and the craniocervical junction:
      technical note.
AB  - OBJECTIVE: The transoral approach is an elegant reliable surgical procedure that
      provides anterior exposure of the cranial base and the craniocervical junction.
      Our objective was to demonstrate the advantages of neuronavigation in planning
      and performing the transoral approach. METHODS: Three patients with chordomas and
      one patient with rheumatoid atlantoaxial subluxation were considered for a
      neuronavigated transoral procedure. For image guidance, the Stryker navigation
      system (Stryker Instruments, Kalamazoo, MI) was used. Registration was performed
      with individually constructed occlusal splints with four markers. RESULTS: The
      transoral approach was successfully used for two patients with chordomas
      involving the cranial base and the upper spine and for one patient with
      dislocation of the dens and medullary compression. In one case, preoperative
      simulation of the approach and trajectory planning demonstrated that adequate
      resection could not be achieved via the transoral route, and a paracondylar
      suboccipital approach was used. The registration accuracy achieved with the
      occlusal splint was less than 1 mm. CONCLUSION: Neuronavigation is a useful tool
      for planning and performing a transoral approach. It optimizes preoperative
      planning, clarifies and secures resection limits, and reduces overall surgical
      morbidity. Registration with an occlusal splint with four markers proved to be an
      attractive alternative to conventional systems.

PMID- 12493128
TI  - Irregular wide complex tachycardia.

PMID- 12493129
TI  - Image in Cardiology. Takayasu arteritis.

PMID- 12493130
TI  - Women do benefit from lipid lowering: latest clinical trial data.
AB  - Cardiovascular disease is the leading cause of morbidity and mortality among
      women in industrialized nations. Optimizing cardiovascular risk reduction is
      therefore of paramount importance, particularly among postmenopausal women, in
      whom the incidence of cardiovascular disease is highest. Accumulated data from a
      series of landmark trials unequivocally demonstrate the efficacy of statin
      therapy in the primary and secondary prevention of cardiovascular outcomes in
      both men and women. Moreover, the recently released Heart Protection Study
      provides substantive evidence that lowering low-density lipoprotein cholesterol
      below levels currently defined as optimal by National Cholesterol Educational
      Program guidelines is strongly associated with further cardiovascular risk
      reduction, and that this benefit accrues in all subgroups of patients, including
      women and the elderly. Despite the ability of hormone replacement therapy to
      improve serum lipid profiles, randomized trials of hormone therapy have
      demonstrated no benefit in reducing coronary outcomes among postmenopausal women.
      In contrast, data from over 8,000 women enrolled in the statin trials demonstrate
      that lipid lowering with statins is as effective at reducing cardiovascular
      outcomes in women as it is in men and suggest that statins should be considered
      standard of care for the prevention of adverse cardiovascular events in women at
      risk for coronary heart disease.

PMID- 12493131
TI  - Facilitated primary percutaneous transluminal coronary angioplasty for acute ST
      segment elevation myocardial infarction: rationale for reuniting pharmacologic
      and mechanical revascularization strategies.
AB  - The primary goal of therapy for acute ST segment elevation myocardial infarction
      is to preserve left ventricular systolic function and to decrease mortality by
      achieving rapid, complete, and sustained restoration of blood flow in the infarct
      related artery. Early studies assessing the safety and efficacy of combining full
      dose thrombolytic therapy with primary percutaneous transluminal coronary
      angioplasty (PTCA) were disappointing due to an increased incidence of abrupt
      closure, reinfarction, emergent coronary bypass surgery, and mortality. The
      observation that the presence of normal coronary blood flow at the time of
      primary PTCA is an independent predictor of survival coupled with interest in the
      patency of the downstream microvasculature has prompted investigators to revisit
      the concept of combining pharmacologic and mechanical strategies. The adjunctive
      use of pharmacologic therapy with mechanical reperfusion has been coined
      facilitated primary PTCA and involves the use of reduced-dose thrombolytics,
      platelet glycoprotein IIb/IIIa inhibitors, or both. The primary goal is to
      achieve pharmacologic reperfusion before performing definitive mechanical
      reperfusion. While the preliminary data presented is promising, we must await the
      results of ongoing large, randomized trials that have been specifically designed
      to address this question.

PMID- 12493132
TI  - Physical activity and coronary heart disease: prevention and effect on risk
      factors.
AB  - The general public recommendation to accumulate 30 minutes of daily physical
      activity on most, preferably all, days of the week was recently modified by the
      National Academy of Science Institute of Medicine to at least 60 minutes of
      cumulative daily physical activity to maintain cardiovascular health at a maximal
      level. Data suggest that regular physical activity, even as little as 30 minutes
      daily, can positively impact cardiovascular health by improving many of the major
      risk factors associated with coronary heart disease, including hypertension,
      dyslipidemia, obesity, insulin resistance, and endothelial function. With the
      recent and rapid rise in the rate of obesity in the United States, a doubling of
      the dose of physical activity daily may help offset the trend of increased
      caloric intake that has contributed to this epidemic. We briefly review the
      evidence regarding the amount and intensity of physical activity necessary to
      alter these cardiovascular risk factors with the goal of reducing coronary
      events.

PMID- 12493133
TI  - Saphenous vein graft aneurysm: case report and review.
AB  - The authors present a case of a large, saphenous vein graft aneurysm, and present
      a detailed review of the disease.

PMID- 12493134
TI  - Oral treatments for type II diabetes in patients with cardiovascular disease.
AB  - The incidence of type II diabetes mellitus is rising rapidly, both in the United
      States and worldwide. Often, the disease is first diagnosed by cardiologists
      during an evaluation for coronary or peripheral vascular disease. It is therefore
      important to understand the basic pathophysiology of insulin resistance, its role
      in the development of type II diabetes, and its association with accelerated
      atherosclerosis. An appreciation of when to begin testing for diabetes, how to
      make the diagnosis, and what treatment strategy to choose is imperative. While
      there are as yet little randomized data to guide hypoglycemic therapy as it
      pertains to reducing cardiovascular risk, evidence is accumulating that treatment
      of diabetes will have an impact on cardiovascular outcomes.

PMID- 12493135
TI  - Left hemiparesis from atrial myxoma emboli.
AB  - Atrial Myxomas are benign primary tumors of the heart, arising mainly from the
      left atrium. Clinical signs and symptoms produced by atrial myxomas may be non
      specific or result in mechanical obstruction of cardiac function, arrhythmias,
      and embolization. The authors present a case of a 60-year-old woman who developed
      total left hemiparesis resulting from left atrial myxoma embolization causing
      complete occlusion of the right middle cerebral artery.

PMID- 12493136
TI  - Focal parvovirus B19 myocarditis in a patient with Brugada syndrome.
AB  - The Brugada syndrome is characterized by a distinct ECG pattern consisting of ST
      segment elevation in the right precordial leads and right bundle branch block, a
      propensity for life-threatening arrhythmias, and an apparently structurally
      normal heart. The authors describe the case of a patient with an aborted sudden
      cardiac death and the typical ECG signs of Brugada syndrome. Nevertheless,
      magnetic resonance imaging displayed signal enhancement in the left ventricular
      myocardium. Additionally, histologic examination, in-situ hybridization, and PCR
      revealed evidence of a locally restricted inflammation due to parvovirus B19.
      Brugada syndrome is regarded as a primary electrical disease due to dysfunction
      of distinctive ion channels, but focal myocarditis may serve as a trigger for
      ventricular arrhythmias in this patient. Further morphologic studies will be
      helpful to establish the possible role of structural changes in the
      pathophysiology of this syndrome.

PMID- 12493137
TI  - Fusiform coronary aneurysm in the left circumflex artery with recurrent
      myocardial infarction and idiopathic thrombopenia.
AB  - The authors describe the rare case of a patient with fusiform coronary aneurysm
      with myocardial infarction in the left circumflex artery complicated by
      idiopathic thrombopenia. Medical treatment with a combination of warfarin and
      aspirin could not prevent recurrence of angina pectoris and myocardial
      infarction, but surgical ligation of the proximal site of the fusiform aneurysm
      and coronary bypass to the distal site of the fusiform aneurysm prevented further
      myocardial infarction and angina pectoris.

PMID- 12493139
TI  - Dietary counselling for dyslipidemia in primary care: results of a randomized
      trial.
AB  - This study compared the effectiveness of physician advice versus dietitian advice
      for a fat-reduced diet, and of dietitian advice for a fat-reduced diet versus a
      soluble fibre-enhanced diet in patients with moderate dyslipidemia. A total of
      111 men and women took part in this 26-week, three-group, randomized, clinical
      trial. The physician advice fat-reduced diet group (n = 38) and the dietitian
      advice fat-reduced diet group (n = 35) received dietary advice based on the
      American Heart Association (AHA) Step II guidelines. The dietitian advice soluble
      fibre-enhanced diet group (n = 38) consumed one-third cup per day of psyllium
      containing cereal and was advised to increase soluble fibre intake to over 10
      grams a day. LDL-C, TC/HDL-C ratio and body weight reductions over six months
      were -5.3%, -4.6%, and -1.9%, respectively, regardless of whether a physician or
      a dietitian provided advice, or whether advice was focused on a fat-reduced diet
      or a soluble fibre-enhanced diet. Both dietitians and physicians can help
      moderately dyslipidemic patients make clinically meaningful changes in blood
      lipid levels. Soluble fibre enhancement of the usual diet leads to similar
      reductions in LDL-C and TC/HDL-C ratio compared to interventions focused on fat
      reduction.

PMID- 12493140
TI  - Dietary reference intakes: a comparison with the Nova Scotia Nutrition Survey.
AB  - The purpose of this study was to compare the newly released dietary reference
      intakes with the 1990 Nova Scotia Nutrition Survey and identify characteristics
      that influence compatibility with these new recommendations. For each of 17
      nutrient recommendations, we calculated the proportion of participants who
      consumed intakes within the recommended range. We constructed a score reflecting
      overall compatibility between the new recommendations and the Nova Scotia
      Nutrition Survey data. Using this score as the dependent variable, we conducted
      multivariate regression analysis to evaluate the importance of demographic and
      behavioural factors for compatibility with the dietary reference intakes. Results
      indicate that compatibility with the dietary reference intakes was poor among
      Nova Scotians, particularly for magnesium, vitamins C and E, and macronutrients.
      Compatibility was lower among females than among males, and differed
      independently by age, body mass index, socioeconomic factors, smoking status, and
      alcohol consumption. Dietary intervention is needed in Nova Scotia. Reduced fat
      intake and increased intake of specific vitamins should be promoted. We recommend
      that nutrition education campaigns coinciding with the introduction of the
      dietary reference intakes in Nova Scotia target younger people, those of lower
      socioeconomic background, smokers, and those who are obese.

PMID- 12493141
TI  - Estimated absorbable iron intakes in quebec adults.
AB  - In the last 30 years, the prevalence of low dietary iron intake has increased,
      partly because North Americans have been encouraged to choose lower fat foods,
      including leaner meats. As a result, there has been a decrease in red meat
      consumption. The objective of this study was to estimate absorbable iron intakes
      of a representative sample of the Quebec adult population and to compare these
      results with the new North American recommendations for iron. Dietary intakes
      were obtained by 24-hour recall and absorbable iron intakes were estimated using
      Monsen & coworker's model. While 18.9 % and 2.5% of women and men respectively
      had an iron intake below the estimated average requirement (EAR), 66.2 % and
      25.6% had an estimated available iron intake below the recommended level for
      absorbed iron. Beef consumption had the strongest association with estimated
      absorbable iron, followed by vegetables. Subjects with a high education level
      consumed significantly less meat, beef and heme iron than subjects whose
      education level was low or moderate. These results indicate that there is a need
      for improving iron intake in the Quebec adult population.

PMID- 12493142
TI  - Dietary adequacy of the rotary diversified diet as a treatment for "Environmental
      Illness".
AB  - The rotary diversified diet, used in the management of environmental illness,
      consists of eliminating prohibited foods from the diet and rotating remaining non
      prohibited foods and their "food families" within a regular cycle. We assessed
      the adequacy of nutrient intakes in 22 women prescribed the diet, described the
      nature of supplement use, and assessed the relationship between adherence and
      nutrient intake levels. Except for calcium and folacin intakes, mean nutrient
      intakes met or exceeded recommended levels. No subjects had calcium intakes above
      the adequate intake for calcium; 72.7% had folate intakes below the estimated
      average requirement. Intakes of other nutrients, except thiamin and magnesium,
      were below the estimated average requirement in less than 25% of the sample;
      31.8% and 45.5% of subjects, respectively, had thiamin and magnesium intakes at
      this level. Those who adhered more closely to the rotary diversified diet had
      higher intakes of vitamin C, vitamin B6, folate, and fibre than did those who
      followed the diet less closely. Supplements conferred some nutritional benefits;
      however, supplemental niacin and magnesium intakes exceeded tolerable upper
      intake levels. Those prescribed the rotary diversified diet require nutrition
      counselling from dietitians to cope with the complexity and restrictiveness of
      the diet.

PMID- 12493143
TI  - A nutrition and behaviour change group for patients with anorexia nervosa.
AB  - A pilot outpatient group for patients with anorexia nervosa was developed and co
      led by a dietitian and a psychologist on a general hospital eating disorders
      team. The main goal of the short-term nutrition and behaviour change group was
      weight gain through normalization of eating. The first three groups conducted in
      the clinic were evaluated by monitoring group members' weights, collecting pre
      treatment and post-treatment scores on the Eating Attitudes Test-26, and
      comparing earlier and later food records. The mean (+/- standard deviation)
      patient weight gain per eight-week group cycle was 1.6 (+/- 1.9) kg (p<0.05) and
      the Eating Attitudes Test-26 score change was -17.1 (+/- 11.5) points (p<0.01).
      Statistically significant changes were found in consumption of calories (p<0.01),
      fat (p<0.005), and protein (p<0.02). This treatment approach warrants further
      refinement and investigation.

PMID- 12493144
TI  - Is there a role for aggressive surgical cytoreduction in patients with known
      metastatic cancer?

PMID- 12493145
TI  - Neoplastic meningitis: a unique disease process or a 'test tube' for evaluating
      cancer treatments?
AB  - Improved treatment of systemic cancers has prolonged the lives of many patients
      but has also led to increased incidence of neoplastic meningitis. The prognosis
      for patients who develop neoplastic meningitis or leptomeningeal dissemination of
      cancer cells remains poor. This paper reviews the pathologic reasons for this
      poor prognosis, describes recent research in animal models that explores new
      therapies, and discusses the potential of these new treatment possibilities for
      clinical use in the context of the associated biology and pathology. The author
      provides an overview of the accompanying articles for the Neuro-Oncology section,
      which explore the mechanisms leading to neoplastic meningitis, the role of
      radiotherapy and chemotherapy in this disease process, and the toxicities of
      treatment.

PMID- 12493146
TI  - The pathogenesis of neoplastic meningitis.
AB  - Neoplastic meningitis (NM) is a dreaded metastatic complication occurring in 5%
      to 10% of cancer patients. Survival is limited, usually ranging from 4 to 16
      weeks. The pathogenesis of NM has not been extensively investigated but can be
      considered from the anatomic and molecular biologic standpoints. Malignant cells
      reach the cerebrospinal fluid (CSF) and meninges by direct invasion from tumors
      located near or within the central nervous system (CNS), or via the bloodstream
      or other pathways that contact the CNS. Symptoms of NM are caused by malignant
      cells invading and damaging nervous tissue, obstructing the vascular supply to
      nervous tissue, or obstructing CSF pathways. The molecular changes responsible
      for the development of NM are not well delineated, but it is likely that they
      involve changes in molecules responsible for tumor cell adhesion, migration, and
      proliferation. An understanding of the pathogenesis of NM will allow for its
      earliest possible diagnosis and ultimately lead to therapies targeted at the
      underlying molecular causes of this devastating condition.

PMID- 12493147
TI  - Standard and novel radiotherapeutic approaches to neoplastic meningitis.
AB  - Neoplastic meningitis usually occurs late in the natural history of cancer.
      Adequate staging and assessment of the patient's overall reserves and prognosis
      are crucial in determining whether aggressive treatment is justified. Although
      radiotherapy remains the single most effective treatment, it is considered
      palliative for epithelial cancers and is generally directed to sites of bulky
      disease that obstruct the flow of cerebrospinal fluid or cause neurologic
      dysfunction. Such diseases as leukemia, medulloblastoma, and germinoma are
      exceptions that can be treated definitively with craniospinal irradiation.
      Innovations in conformal therapy may help to reduce the significant amount of
      myelosuppression associated with spinal irradiation. The main long-term toxicity
      associated with whole-brain irradiation (WBI) is dementia resulting from
      leukoencephalopathy, which may be exacerbated when WBI is given in combination
      with chemotherapy. A case report highlighting the use of radiotherapy for
      palliation in a patient with neoplastic meningitis is presented at the end of
      this article.

PMID- 12493148
TI  - Systemic chemotherapy, intrathecal chemotherapy, and symptom management in the
      treatment of leptomeningeal metastasis.
AB  - Metastasis to the leptomeninges occurs in many common cancers, including
      leukemia; lung, breast, and gastrointestinal cancers; and tumors of the brain. By
      way of the flow of cerebrospinal fluid, leptomeningeal metastasis spreads
      throughout the neuraxis. Consequently, therapy for leptomeningeal metastasis must
      be directed to the entire central nervous system (CNS). Treatment often consists
      of involved-field radiotherapy, systemic chemotherapy, and intrathecal
      chemotherapy. However, because meningeal spread occurs most often in advanced
      disease, treatment is mainly palliative, except in childhood leukemia, where
      durable remission has been reported. This article outlines the role of systemic
      and intrathecal chemotherapy in patients with leptomeningeal metastases.
      Strategies for symptom management in these patients are also described.

PMID- 12493149
TI  - Toxicity of treatment for neoplastic meningitis.
AB  - Neoplastic seeding of the leptomeninges often signifies limited life expectancy.
      Still, patients are frequently offered aggressive multimodality therapies to
      palliate symptoms, and, one hopes, to prolong survival. Treatment modalities
      directed at the central nervous system (CNS) include radiotherapy, intra
      cerebrospinal fluid (CSF) chemotherapy, standard systemic chemotherapy, and
      systemic high-dose chemotherapy. Because many of these modalities are used in
      combination, it is often difficult to discern which mode is the predominant cause
      of either acute or delayed complications. This review summarizes the incidence,
      clinical manifestations, laboratory findings, and pathology related to acute and
      delayed toxicity of treatment. It describes complications associated with
      radiotherapy, the use of an intraventricular implanted device (ie, Ommaya
      device), adverse effects of intra-CSF chemotherapy, and neurotoxicity, either
      associated with high-dose chemotherapy or manifested as delayed and chronic
      complications of combined therapies. All CNS-directed therapies are associated
      with a high rate of complications. The adverse effects of therapy profoundly
      affect the patient's quality of life, both at the acute phase of treatment and in
      late and chronic complications after therapy is completed. Intra-CSF chemotherapy
      is associated with a high rate of acute, reversible adverse effects that
      sometimes evolve into life-threatening medical conditions. Devastating delayed
      complications, mainly described as leukoencephalopathy, develop in more than 50%
      of patients who survive for extended periods and often lead to progressive loss
      of cognitive capacities. Careful assessment of the benefits and potential adverse
      reactions to a particular therapy regimen is mandated.

PMID- 12493150
TI  - Osteoporosis in women with breast cancer.
AB  - Osteoporosis is a disease that causes substantial morbidity and mortality for
      which preventive therapy is available. Women with breast cancer are at increased
      risk for osteoporosis for several reasons, including premature ovarian failure as
      a result of treatment, direct effects of chemotherapy, and effects of the breast
      cancer itself. As the incidence of breast cancer continues to increase and
      survival rates continue to improve, the importance of appropriate screening for
      and management of osteoporosis becomes more apparent. This article reviews the
      evidence supporting an increased risk for development of osteoporosis in women
      with breast cancer and summarizes strategies for prevention and treatment of
      osteoporosis in this population.

PMID- 12493151
TI  - The role of nuclear medicine in breast cancer detection: a focus on Technetium-99
      Sestamibi scintimammography.
AB  - Screening mammography in women aged over 50 years reduces breast cancer death by
      30%. However, because mammography cannot accurately differentiate benign from
      malignant lesions, many mammography-directed breast biopsies are benign. In the
      past decade, methods of "functional breast imaging," including magnetic resonance
      imaging, scintimammography using single photon emission tomography, and positron
      emission tomography, have improved the sensitivity and specificity rates of
      conventional mammography for the detection of breast cancer. The higher
      specificity of scintimammography is feeding current enthusiasm for the study of
      its role in early breast cancer detection, as a complement to mammography in the
      evaluation of indeterminate lesions, and for use in noninvasive axillary staging.
      This article reviews the applications of radionuclide technology in breast cancer
      diagnosis and surveillance.

PMID- 12493152
TI  - Ductal lavage, nipple aspiration, and ductoscopy for breast cancer diagnosis.
AB  - The intraductal approach to breast cancer has been invigorated this year by a
      series of papers exploring ductal-based screening through nipple aspiration and
      lavage and ductal exploration through endoscopy. The merging of these efforts to
      define the earliest biologic changes in the progression toward breast cancer is
      opening new fields for both bench-translational and clinical research. These
      techniques have already begun to show value in defining the presence and extent
      of proliferative disease in high-risk patients, allowing for more informed
      therapeutic decision making.

PMID- 12493153
TI  - Adjuvant therapy approaches to breast cancer: should taxanes be incorporated?
AB  - The triplet of docetaxel, doxorubicin, and cyclophosphamide (TAC) has emerged as
      an alternative chemotherapy regimen for adjuvant management of node-positive
      breast cancer. Based on recently reported 3-year data from the Breast Cancer
      International Research Group (BCIRG) 001, disease-free survival was significantly
      higher in patients who underwent adjuvant chemotherapy with TAC rather than the
      established regimen of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC).
      TAC reduced the risk of disease recurrence in estrogen receptor-positive and 
      negative patients. Whereas overall survival was not significantly different
      between the two groups, TAC led to a significant reduction in mortality in the
      subset of patients with one to three involved axillary lymph nodes. Overall,
      these interim BCIRG 001 results, coupled with those from Cancer and Leukemia
      Group B-9344 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28
      (phase III trials of sequential adjuvant chemotherapy with doxorubicin and
      cyclophosphamide followed by paclitaxel), suggest that taxanes are a valuable
      component of adjuvant chemotherapy for patients with node-positive breast cancer,
      including those with estrogen receptor positivity and/or extensive lymph node
      involvement. Accumulating data in the neoadjuvant setting lend further support to
      the view that the taxanes confer clinically meaningful benefits in the management
      of early-stage breast cancer. Such ongoing studies as NSABP B-30 will be
      instrumental in establishing the relative merits of sequential versus concurrent
      taxane-anthracycline adjuvant regimens for patients with node-positive breast
      cancer.

PMID- 12493154
TI  - Adjuvant systemic therapy for lymph node-negative breast cancer less than or
      equal to 1 cm.
AB  - Routine screening mammography has increased the incidence of stage I breast
      cancers. Many more women are being diagnosed with lymph node-negative tumors that
      are less than or equal to 1 cm in greatest diameter. The National Surgical
      Adjuvant Breast and Bowel Project recently performed a retrospective analysis of
      10,302 women participating in one of five clinical trials, including women with
      lymph node-negative breast cancer. Of these women, 1259 had tumors less than or
      equal to 1 cm. The analysis of the women with tumors less than or equal to 1 cm
      revealed an improved relapse-free survival (RFS) if tamoxifen was given after
      surgery, compared with surgery alone, for women with estrogen receptor (ER)
      positive tumors; and for women with ER-negative tumors, RFS was improved by
      delivering chemotherapy after surgery. The authors suggested that adjuvant
      systemic therapy should be considered for anyone with an invasive breast cancer,
      regardless of the size of the tumor. This paper reviews the data presented in
      that important, historic article, and discusses their conclusions. Also reviewed
      are the most recent recommendations for treatment of primary breast cancer from
      the International Consensus Panel that convened at the Seventh International
      Conference on Adjuvant Therapy of Primary Breast Cancer in St. Gallen,
      Switzerland. That panel also addressed the issue of adjuvant systemic therapy in
      women considered to have a minimal or low risk of developing recurrent disease.

PMID- 12493155
TI  - The importance of being a platelet.

PMID- 12493156
TI  - Pharmacologic radionuclide myocardial perfusion imaging.
AB  - Pharmacologic stress testing with myocardial perfusion imaging has enabled
      patients who cannot complete adequate exercise to undergo diagnostic and
      prognostic evaluation for coronary artery disease. Pharmacologic stress agents
      belong to two groups: vasodilators (such as adenosine and dipyridamole), and
      inotropes (such as dobutamine). All have similar sensitivity (89%-91%) and
      specificity (78%-86%) for the diagnosis of coronary disease. For risk
      stratification, the risk of future cardiac events is related to the extent and
      severity of perfusion abnormalities. Pharmacologic stress testing permits risk
      stratification as early as 1 to 4 days following an acute myocardial infarction,
      and is superior to exercise stress testing in this regard. Similarly, it
      identifies patients at high risk for perioperative cardiac events prior to
      noncardiac surgery. This review summarizes the current evidence available
      regarding the diagnostic and prognostic use of pharmacologic stress testing.

PMID- 12493157
TI  - Use of radionuclide imaging in acute coronary syndromes.
AB  - The triage of patients presenting to the emergency department (ED) with acute
      chest pain is a diagnostic challenge. Radionuclide myocardial perfusion imaging
      has been shown to have favorable diagnostic and prognostic value in this setting,
      with an excellent early sensitivity to detect acute myocardial infarction (MI)
      not achieved by other testing modalities. A normal resting perfusion imaging
      study has been shown to have a negative predictive value of over 99% to exclude
      MI. Observational and randomized trials of both rest and stress imaging in the ED
      evaluation of patients with chest pain have demonstrated reductions in
      unnecessary hospitalizations and cost savings compared with routine care.
      Perfusion imaging has also been used in risk stratification after MI, and for
      measurement of infarct size to evaluate reperfusion therapies. Novel "hot spot"
      imaging radiopharmaceuticals that visualize infarction or ischemia are currently
      undergoing evaluation and hold promise for future imaging of acute coronary
      syndromes.

PMID- 12493159
TI  - Imaging cell injury and death.
AB  - Although there has been much emphasis on detecting myocardial viability over the
      past decade, there is a growing interest in finding a marker for myocyte injury
      and death. There has been limited clinical utility for infarct-avid imaging with
      (99m)Technetium ((99m)Tc) pyrophosphate and (111)Indium antimyosin, but recent
      experience with (99m)Tc-labeled annexin V and contrast-enhanced magnetic
      resonance imaging has stimulated cell death detection. In the effort to image
      myocyte damage, it is crucial to understand the pathologic finding and cell
      signals that can be used as critical in vivo markers for the transition from
      viable to dead tissue. It may not be possible to capture an image at the precise
      moment when a myocyte dies, but we need to know the different processes that can
      occur. Specifically, it is important to understand that oncosis and apoptosis are
      two distinctly different methods of cell death, and both ultimately result in
      myocyte necrosis. As we approach the more complex problems of myocyte injury
      during inflammation, cardiomyopathy, ischemia, reperfusion, and transplant
      rejection, we realize that more specific markers of real-time tissue injury are
      needed. This review focuses on the pathophysiology of myocyte injury necrosis and
      repair as a method to guide newer developments in myocardial imaging.

PMID- 12493158
TI  - Single photon emission computed tomography perfusion imaging for assessment of
      myocardial viability and management of heart failure.
AB  - In the setting of coronary artery disease, some areas of dysfunctional myocardium
      may realize significant improvement in function as a consequence of
      revascularization. These areas represent viable myocardium, encompassing a
      spectrum of pathophysiology ranging from chronic stunning, in which resting blood
      flow is preserved, to hibernating myocardium, in which resting blood flow is
      decreased. The accurate preoperative evaluation of viable myocardium helps
      identify those patients with left ventricular dysfunction who will most benefit
      from coronary revascularization. Of the various modalities available for
      viability assessment, the nuclear medicine techniques (201)Thallium and
      (18)Fluorodeoxyglucose positron emission tomography have emerged as the most
      sensitive. It has been consistently shown that in patients with a significant
      amount of viable myocardium, there is a substantial survival benefit in
      revascularization versus medical therapy. The likelihood of affecting a
      significant improvement decreases with time to revascularization, however,
      particularly in the setting of an enlarged left ventricle secondary to
      ventricular remodeling.

PMID- 12493160
TI  - Measurement of ventricular function with radionuclide techniques.
AB  - The noninvasive assessment of resting left ventricular performance has become an
      integral part of the evaluation of patients with known or suspected cardiac
      disease, having important diagnostic, therapeutic, and prognostic significance.
      This article details the wide range of clinical diagnostic possibilities
      available by dynamic imaging of myocardial function using scintigraphic
      techniques, including gated planar and tomographic blood pool imaging, first-pass
      radionuclide angiography, and gated tomographic perfusion imaging. The clinical
      and technical aspects described should be useful to the cardiologist intent upon
      supervising the performance of these tests, as well as providing their
      interpretation.

PMID- 12493161
TI  - Magnetic resonance coronary angiography.
AB  - Magnetic resonance coronary angiography (MRCA) has witnessed tremendous technical
      advances over the past decade. Although high-quality images of the coronary
      arteries have been demonstrated, this imaging modality is not performed routinely
      today. The fundamental properties of the coronary arteries deterring noninvasive
      imaging are well known. This article provides an overview of the developmental
      efforts to overcome these challenges, and highlights key technical and clinical
      advances. The future prospect of MRCA depends on clinical implementation of the
      technique. In order to meet this challenge, the following issues must be
      addressed: contrast- and signal-to-noise ratio, temporal and spatial resolution,
      and scan protocol.

PMID- 12493162
TI  - Myocardial perfusion imaging by magnetic resonance imaging.
AB  - In the diagnosis and treatment of patients with suspected or known coronary
      artery disease, noninvasive methodologies for assessing myocardial perfusion have
      been invaluable. Clinically, nuclear techniques such as single photon emission
      tomography thallium and sestamibi have predominated. They are limited, however,
      by the radiation burden, relatively poor spatial resolution, and attenuation
      artifact caused by soft tissue. In contrast, magnetic resonance imaging (MRI) is
      notable for its anatomic detail, sharp tissue contrast, excellent spatial and
      temporal resolution, versatility, and lack of ionizing radiation. It is therefore
      a potentially attractive alternative to nuclear imaging for the assessment of
      myocardial perfusion. This review summarizes the principles of MRI myocardial
      perfusion measurement, discusses recent clinical applications, and highlights
      future developments in the field.

PMID- 12493163
TI  - Magnetic resonance imaging assessment of cardiac function.
AB  - Measurements of left ventricular function at rest and during stress are useful
      for identifying myocardial ischemia, injury, and the risk of subsequent
      myocardial infarction. Without ionizing radiation or intravascular contrast
      administration, magnetic resonance imaging techniques can be used to acquire
      precise measurements of left ventricular function. This relatively new
      development may enhance a physician's ability to provide care to patients with
      cardiovascular disease.

PMID- 12493164
TI  - Cardiac magnetic resonance spectroscopy.
AB  - This review describes recent advances in cardiac magnetic resonance spectroscopy
      (MRS). MRS allows noninvasive characterization of the metabolic state of cardiac
      muscle, in both animal and human models. Recent experimental MRS studies have
      allowed new insights into the essential role of energetics in heart failure.
      Various new studies suggest a rapidly growing role of MRS for phenotyping new
      genetically modified mouse models, and recent methodologic advances include
      development of absolute quantification of high-energy phosphates, measurement of
      ATP turnover rates and thermodynamic parameters (such as free ADP and free energy
      change of ATP hydrolysis), and improved acquisition sequences. New patient
      studies demonstrate the potential value of MRS as a clinical diagnostic tool in
      patients with ischemic heart disease, heart failure, cardiac transplantation,
      valve disease, and genetic cardiomyopathy.

PMID- 12493165
TI  - Future prospects in cardiac magnetic resonance imaging.
AB  - To appreciate the impact that key developments will have on the future of
      cardiovascular magnetic resonance (CMR) imaging, it is instructive to consider
      its present status. CMR has passed the threshold of being used primarily by
      innovators, and is now in the early adopter stage. To reach this threshold has
      taken many years, but its adoption by early majority users is expected to
      accelerate the growth of CMR. A number of factors govern its natural growth
      potential, including physician education and credentialing, scanner availability,
      technology, and reimbursement policies. The intrinsic dimensional accuracy of
      CMR, coupled with its high level of reproducibility, make it ideal for inclusion
      in trials, potentially with dramatic reductions in trial duration and the number
      of subjects required. Clinically, there are a number of applications for which
      CMR is widely regarded as being the diagnostic test of choice. Software and
      hardware developments that speed up the basic CMR procedure are being
      incorporated into scanners, extending the functionality of routine applications
      such as flow imaging and tag visualization. Exciting areas that are close to
      routine application include coronary artery imaging, and evaluation of myocardial
      perfusion and viability status.

PMID- 12493166
TI  - Microbiology of newer fluoroquinolones: focus on respiratory pathogens.
AB  - Community-acquired pneumonia, acute exacerbations of chronic bronchitis, and
      acute sinusitis are among the most common bacterial infections encountered in
      clinical practice. Pathogens frequently associated with these infections include
      Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis, Chlamydia
      pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. Unfortunately,
      resistance to antimicrobials commonly used for the treatment of these infections
      is increasing, limiting the clinical efficacy of these agents. Fluoroquinolones
      offer several advantages over other classes of antimicrobials used for the
      treatment of community-acquired respiratory tract infections. In general,
      fluoroquinolones have excellent in vitro activity against common respiratory
      pathogens, including some drug-resistant strains of S. pneumoniae. Microbial
      resistance to the newer fluoroquinolones is relatively uncommon, currently
      occurring in approximately 1% of clinical isolates in North America.
      Fluoroquinolones currently in clinical development may offer additional benefits
      over the marketed agents because they maintain good potency against isolates of
      S. pneumoniae displaying resistance to older quinolones (i.e., ofloxacin or
      ciprofloxacin) and may have a lower potential to engender resistance. This
      article reviews the in vitro activity of several newer fluoroquinolones,
      including agents currently in clinical development, against common respiratory
      pathogens, including antimicrobial-resistant strains. The mechanisms and
      prevalence of resistance of beta-lactam antimicrobials, macrolides, and
      fluoroquinolones also are reviewed.

PMID- 12493167
TI  - A DNA probe specific for Aeromonas colonies.
AB  - Members of the genus Aeromonas are important enteropathogens. Commercial
      identification systems are often unable to correctly identify Aeromonas strains
      and misidentification as Vibrio spp. is common. A digoxigenin-DNA probe based on
      a 237 bp of the glycerophospholipid-cholesterol acyltransferase gene has been
      tested in a colony hybridization assay. The probe hybridized with all Aeromonas
      species tested (n = 16) but not with strains of other enteropathogenic bacteria
      (n = 20). The probe allowed the unequivocal identification of Aeromonas in
      primary isolation media within 36 h.

PMID- 12493168
TI  - Surveillance of bacterial pathogens of diarrhea disease in Indonesia.
AB  - Emerging or reemerging infections due to bacterial disease may be a local,
      regional or global problem. Bacterial acute gastroenteritis is a potential cause
      of substantial morbidity in travelers and deployed U.S. military personnel. A
      surveillance study was conducted over a two-year period in Indonesia among 6760
      patients with debilitating diarrheal diseases. Of the 6,760 patients, 587 (9%) of
      the patient stools were positive for bacteria. The proportions of bacteria
      isolated from the 587 patients were: Shigella flexneri (39%), Salmonella spp.
      (26%), Vibrio spp. (17%), S. sonnei (7%), Campylobacter jejuni (4.4%), Salmonella
      typhi (3%) and S. dysenteriae (2.3%). Shigella flexneri was the most prevalent
      pathogen isolated, over Vibrio spp. No V. cholerae was isolated in the cities of
      Pontianak, Padang or Batam in Indonesia. Shigella dysenteriae reemergence was
      noted in Bali, Kalimantan, Batam and Jakarta after an absence of 15 years.
      Isolation of a high proportion of S. flexneri, and Vibrio spp. occurred during
      the rainy months. All bacterial isolates were susceptible to quinolones, with the
      exception of C. jejuni and Salmonella spp., which were resistant to
      ciprofloxacin, norfloxacin and nalidixic acid. Our findings highlight the decline
      of V. cholerae, the rise of S. flexneri and the reemergence of S. dysenteriae in
      Indonesia. The study also documents the emergence of quinolone-resistant
      Campylobacter spp. in the Indonesia archipelago.

PMID- 12493169
TI  - Use of simulated blood cultures for time to detection comparison between
      BacT/ALERT and BACTEC 9240 blood culture systems.
AB  - In order to avoid the influence of pre-analytical steps, the following study was
      performed by using sterile blood spiked with defined loads of microorganisms as
      inoculum. Time-to-Detection (TTD) was evaluated for the most frequently
      encountered bacteria and fungi in septicemia, comparing two commercially
      available blood culture systems, BACTEC 9240 (Becton Dickinson) and BacT/ALERT
      (Organon Teknika). A specific medium, Bactec Mycosis IC/F (Becton Dickinson), was
      compared with the Bactec Plus Aerobic (Becton Dickinson) and FAN Aerobic (Organon
      Teknika) media for recovery of fungi in general and in case of mixed
      bacterial/fungal septicemia. The results show that the BACTEC system detects
      nearly all enrolled microorganisms significantly faster than the BacT/ALERT; the
      anaerobic vial contributes to the detection of anaerobes and facultative
      anaerobes and, in the case of BACTEC, shortens TTD; the Bactec Mycosis IC/F
      bottle shortens TTD of fungi.

PMID- 12493170
TI  - Evaluation of Brucella dipstick assay for the diagnosis of acute brucellosis.
AB  - The diagnostic value of the dipstick assay was evaluated by comparison with Rose
      Bengal (RB), serum aglutination tests (SAT) and 2 mercaptoethanol test (2-ME) on
      consecutive serum samples submitted because of suspicion of brucellosis. Serum
      samples of 232 patients with suspected brucellosis that were submitted for
      laboratory confirmation were included in the study. Twelve out of 232 serum
      samples were detected as positive with the dipstick assay. All of these 12
      patients had positive RB and SAT results. In 16 RB positive samples dipstick test
      was negative. Fifteen of these samples had insignificant (titer<1/160) or
      borderline (titer 1/160) SAT results and the clinical symptoms of these patients
      were consistent with chronic brucellosis rather than acute or recent-onset
      brucellosis. Dipstick assay is an easy-to-perform assay that can be used for the
      diagnosis of acute brucellosis especially in rural areas where brucellosis is
      widespread and in settings where well-equipped laboratories are not available.

PMID- 12493171
TI  - Characterization of rpoB mutations in rifampin-resistant clinical Mycobacterium
      tuberculosis isolates from Kuwait and Dubai.
AB  - Mutations conferring resistance to rifampin in rifampin-resistant clinical
      Mycobacterium tuberculosis isolates occur mostly in the 81 bp rifampin-resistance
      determining region (RRDR) of the rpoB gene. In this study, 29 rifampin-resistant
      and 12 -susceptible clinical M. tuberculosis isolates were tested for
      characterization of mutations in the rpoB gene by line probe (INNO-LiPA Rif. TB)
      assay and the results were confirmed and extended by DNA sequencing of the PCR
      amplified target DNA. The line probe assay identified all 12 susceptible strains
      as rifampin-sensitive and the DNA sequence of RRDR in the amplified rpoB gene
      from two isolates matched perfectly with the wild-type sequence. The line probe
      assay identified 28 resistant isolates as rifampin-resistant with specific
      detection of mutation in 22 isolates including one isolate that exhibited hetro
      resistance containing both the wild-type pattern as well as a specific mutation
      within RRDR while one of the rifampin-resistant strain was identified as rifampin
      susceptible. DNA sequencing confirmed these results and, in addition, led to the
      specific detection of mutations in 5 rifampin-resistant isolates in which
      specific base changes within RRDR could not be determined by the line probe
      assay. These analyses identified 8 different mutations within RRDR of the rpoB
      gene including one novel mutation (S522W) that has not been reported so far. The
      genotyping performed on the isolates carrying similar mutations showed that
      majority of these isolates were unique as they exhibited varying DNA banding
      patterns. Correlating the ethnic origin of the infected TB patients with the
      occurrence of specific mutations at three main codon positions (516, 526 and 531)
      in the rpoB gene showed that most patients (11 of 15) from South Asian region
      contained mutations at codon 526 while majority of isolates from patients (6 of
      11) of Middle Eastern origin contained mutations at codon 531.

PMID- 12493172
TI  - Multicenter comparison of Fungitest for susceptibility testing of Candida
      species.
AB  - In four laboratories the reproducibility of Fungitest, a colorimetric breakpoint
      method for antifungal susceptibility testing, was examined. The interlaboratory
      agreement of test results from 50 Candida strains was dependent on the antifungal
      agents and ranged from 56% to 100%. Itraconazole showed the poorest, amphotericin
      B and flucytosine (100% and 96%, respectively) the highest concordance. When
      minor discrepancies were disregarded the agreement increased to 94% to 100% for
      all agents. In total, major discrepancies were only seen in 2.7%. The overall
      agreement between concordant results and the NCCLS standard method was high,
      ranging between 96.4% and 100%. Generally, sensitive strains showed a better
      agreement with Fungitest. Since the concordance in multisite studies with
      Fungitest will always depend on the isolates chosen, further studies with this
      test are necessary.

PMID- 12493173
TI  - Synergy of colistin with rifampin and trimethoprim/sulfamethoxazole on multidrug
      resistant Stenotrophomonas maltophilia.
AB  - Stenotrophomonas maltophilia is characterized by intrinsic resistance to a
      variety of antimicrobials. Therapeutic options are often limited particularly
      after the emergence of isolates resistant to trimethoprim/sulfamethoxazole. The
      application of colistin for infections caused by multidrug-resistant Gram
      negative pathogens is limited due to its toxicity. In order to evaluate the
      activity of the interaction of colistin with rifampin or
      trimethoprim/sulfamethoxazole on S. maltophilia, 24 different isolates resistant
      to trimethoprim/sulfamethoxazole were in vitro exposed over-time to the
      combination of 1x and 4 x MIC of colistin with 2 microg/ml of rifampin or 2/38
      microg/ml of trimethoprim/sulfamethoxazole. The applied concentrations for
      rifampin and trimethoprim/sulfamethoxazole reflect their mean serum levels.
      Synergy of colistin and rifampin was documented after the first two hours of
      bacterial growth for approximately 60% of isolates and it occurred with both
      applied concentrations of colistin. The interaction of colistin and rifampin
      prevented regrowth observed when single colistin was applied. Synergy of colistin
      and trimethoprim/sulfamethoxazole was mainly found when colistin was applied at a
      concentration of 4 x MIC involving 41.7% of isolates after 24 h of growth. In the
      presence of trimethoprim/sulfamethoxazole bacterial regrowth, observed when
      single colistin was applied, was prevented. It is concluded that growth of
      multidrug-resistant S. maltophilia is significantly inhibited by the interaction
      of colistin and rifampin and to a lesser extent of colistin and
      trimethoprim/sulfamethoxazole. These results merit further study in both the
      animal model and the clinical setting.

PMID- 12493174
TI  - Microbiologic effectiveness of time- or concentration-based dosing strategies in
      Streptococcus pneumoniae.
AB  - This in vitro study evaluated the pharmacodynamic performance of levofloxacin
      using different dosing strategies against both a levofloxacin-sensitive (MIC = 1
      mg/liter) and -resistant (MIC = 16 mg/liter) strain of Streptococcus pneumoniae.
      The strain was genotypically characterized by a mutation in gyrA and two
      mutations in parE; resistance was shown not to be efflux-mediated. The purpose of
      this study was to determine if simulated levofloxacin dosing strategies focused
      either on time or concentration would affect microbiologic outcome. Differing
      peak concentration/MIC ratios (1,2, and 10), T>MIC (3.6,9.6,15.6, and 24 h
      corresponding to 15, 40, 65, and 100% of the 24-h dosing interval), and AUC/MIC
      ratios (13-180) were generated by varying dosing strategies. Initial bacterial
      inocula were decreased by 99.9% in each experiment conducted. Despite the wide
      variation in exposure levels, in terms of AUC/MIC, Cp-max/MIC, and T>MIC, the
      kill portions of the bacterial density curves were super-imposable between all
      permutations of antibiotic exposure. However, there appeared to be an AUC/MIC
      breakpoint (35-40) defining bacterial regrowth. Over a 10-fold concentration
      range, levofloxacin appeared to kill S. pneumoniae in a concentration-independent
      fashion. When given in concentrations suitable to achieve specified
      pharmacodynamic endpoints (AUC/MIC >/=35), levofloxacin demonstrated the ability
      to eradicate both a levofloxacin-resistant and levofloxacin-sensitive strain of
      S. pneumoniae in the in vitro model.

PMID- 12493175
TI  - Four-year evaluation of frequency of occurrence and antimicrobial susceptibility
      patterns of bacteria from bloodstream infections in Latin American medical
      centers.
AB  - As part of the Latin American arm of the SENTRY Antimicrobial Surveillance
      Program, 7,207 bacterial isolates collected consecutively from bloodstream
      infections (BSI) during the period of January 1997 through December 2000 were
      analyzed. Ten Latin American laboratories located in six countries participated
      in the study during each year. Antimicrobial susceptibility testing was performed
      using the reference NCCLS broth microdilution method. The most frequently
      isolated species were (n/%): Staphylococcus aureus (1,532/21.3%), Escherichia
      coli (1,239/17.2%), coagulase-negative Staphylococcus (1,002/13.9%), Klebsiella
      pneumoniae (664/9.2%), and Pseudomonas aeruginosa (470/6.5%). The prevalence of
      S. aureus as a cause of BSI increased from 20.5% in 1997 to 23.3% in 2000 (p =
      0.011), but oxacillin-resistance rates remained relatively stable during this
      period (around 30%). Enterococci (216 isolates) showed low rates of resistance to
      both vancomycin (2.4%) and ampicillin (7.9%) and 72.7% of 289 Streptococcus
      pneumoniae isolates evaluated were susceptible to penicillin (MIC </=0.06
      microg/mL). Resistance rates among Gram-negative bacilli were much higher than
      those reported in other regions evaluated in the SENTRY Program. The main
      antimicrobial resistance problems among these pathogens were the high prevalences
      of ESBL-producing E. coli (6.7%) and K. pneumoniae (47.3%), and carbapenem
      resistance among P. aeruginosa (around 12%) and Acinetobacter spp. (around 10%).
      P. aeruginosa resistance rates to meropenem, piperacillin/tazobactam, amikacin,
      and ciprofloxacin showed a significant increase during the 4-year period
      evaluated. Resistance rates varied according to the country for several pathogen
      antimicrobial combinations. In summary, resistance to most antimicrobial agents
      for a number of species implicated in bacteremia, especially among Gram-negative
      rods, has reached worrisome levels and continues to increase.

PMID- 12493176
TI  - Skin and soft tissue infections in Latin American medical centers: four-year
      assessment of the pathogen frequency and antimicrobial susceptibility patterns.
AB  - We report the results of pathogen frequency and antimicrobial susceptibility of
      isolates collected from skin and soft tissue infections (SSTIs) in Latin American
      medical centers during the first 4 years (1997-2000) of the SENTRY Antimicrobial
      Surveillance Program. Ten laboratories participated each year distributed among
      nine cities in six countries. A total of 1,789 bacterial isolates were
      susceptibility tested by reference broth microdilution at the coordinating
      central laboratory. Results from isolates collected during the year 2000 were
      compared with those from isolates collected during the prior three years.
      Selected carbapenem-resistant Pseudomonas aeruginosa were genotyped by automated
      ribotyping to evaluate the occurrence of clonal, epidemic dissemination. The five
      most frequently isolated species were (n/%): Staphylococcus aureus (584/32.8%),
      Escherichia coli (233/13.1%), P. aeruginosa (211/11.9%), Enterococcus spp.
      (137/7.7%), and Klebsiella spp. (127/5.8%). The most problematic antimicrobial
      resistances were related to the high prevalence of multi-drug resistant (MDR)
      Gram-negative bacilli. Carbapenem resistance among non-fermentative Gram-negative
      bacilli was much higher than that reported in other regions evaluated in the
      SENTRY Program. Only 74.9% of P. aeruginosa and 84.9% of Acinetobacter spp. were
      considered susceptible to imipenem. The antimicrobial susceptibility rates of P.
      aeruginosa decreased during the study period for most antimicrobial agents
      evaluated. More than 40% of K. pneumoniae and nearly 10% of E. coli showed an
      extended spectrum beta-lactamase phenotype. Only 73.4% of E. coli and 76.0% of
      Enterobacter spp. were susceptible to ciprofloxacin. The molecular typing of
      carbapenem-resistant P. aeruginosa demonstrated clonal dissemination in two
      institutions. These reported results indicate that rates of resistance among
      isolates causing SSTI continue to raise in Latin America, with specific concerns
      for the high prevalence of MDR Gram-negative bacilli. National and international
      surveillance programs as a guide to focusing intervention strategies should
      assist in the control of escalating antimicrobial resistance in this geographic
      area.

PMID- 12493177
TI  - Urinary tract infection trends in Latin American hospitals: report from the
      SENTRY antimicrobial surveillance program (1997-2000).
AB  - Urinary tract infections (UTI) are one of the most common infectious diseases
      diagnosed in outpatients as well as in hospitalized patients. The objective of
      this study was to report the frequency of occurrence and antimicrobial
      susceptibility of uropathogens collected in Latin America between 1997 to 2000
      through the SENTRY Antimicrobial Surveillance Program. Antimicrobial
      susceptibility testing was performed and results interpreted using reference
      broth microdilution methods. In the 4 year period, a total of 1961 urine isolates
      from hospitalized patients were included. The patients' mean age was 51.3 years
      and most of the infections occurred among women (65.6%). Esherichia coli was the
      most frequent pathogen isolated followed by Klebsiella spp., Pseudomonas
      aeruginosa, and Proteus mirabilis. Among the E. coli isolates,
      piperacillin/tazobactam, aztreonam, extended-spectrum cephalosporins, carbapenems
      and amikacin constitute reasonable therapeutic options for treatment of serious
      UTI in Latin America (91.0-100.0% susceptible). High resistance rates to
      fluoroquinolones (17.5-18.9%) and trimethoprim/sulfamethoxazole (>45.0%) were
      observed among the E. coli. In contrast, nitrofurantoin displayed susceptibility
      rate of > 87.0%. Against Klebsiella spp. infections, the only effective
      therapeutic option would be the carbapenems due to the high number of isolates
      (>30.0%) producing extended-spectrum beta-lactamases (ESBL). Even the new
      fluoroquinolones showed limited activity against Klebsiella spp. (72.1-88.6%
      susceptible) and the P. aeruginosa isolates showed high resistance rates to most
      antimicrobial agents tested. The results of this survey endorse the importance of
      Enterobacteriaceae as cause of UTI in Latin America. Our results also demonstrate
      that the uropathogens isolated in the Latin American medical centers exhibit high
      resistance to various classes of antimicrobial agents. Carbapenem-resistant P.
      aeruginosa, ciprofloxacin-resistant E. coli, ESBL-producing K. pneumoniae
      constitute serious problem in this geographic region.

PMID- 12493178
TI  - Respiratory tract pathogens isolated from patients hospitalized with suspected
      pneumonia in Latin America: frequency of occurrence and antimicrobial
      susceptibility profile: results from the SENTRY Antimicrobial Surveillance
      Program (1997-2000).
AB  - In spite of the recent medical advances, lower respiratory tract infections are
      still the most frequent infectious causes of mortality worldwide. The objective
      of this study was to determine the frequency of occurrence and antimicrobial
      susceptibility of bacterial isolates collected from hospitalized patients with
      pneumonia in Latin American medical centers during the first four years of the
      SENTRY Program. The five most frequently isolated species were (n/%): Pseudomonas
      aeruginosa (659/26.3%), Staphylococcus aureus (582/23.3%), Klebsiella pneumoniae
      (255/10.2%), Acinetobacter spp. (239/9.6%), and Enterobacter spp. (134/5.4%). P.
      aeruginosa demonstrated high rates of resistance to most of the antimicrobials
      tested. Against P. aeruginosa, the most active agents were meropenem (MIC(50), 1
      microg/ml; 71.6% susceptible), amikacin (MIC(50), 4 microg/ml; 71.0%
      susceptible), and piperacillin/tazobactam (MIC(50), 16 microg/ml; 70.4%
      susceptible). Imipenem (MIC(50), 1 microg/ml; 84.1% susceptible) and meropenem
      (MIC(50), 2 microg/ml; 84.9% susceptible) were the most active agents against
      Acinetobacter spp. followed by tetracycline (MIC(50), </=4 microg/ml; 52.3%
      susceptible). Although the broad-spectrum cephalosporins had demonstrated
      excellent in vitro activity against Klebsiella pneumoniae isolates (MIC(50)s
      range, </= 0.12 to 0.25 microg/ml), elevated rates of resistance (46.3%-58.5%)
      were observed. Approximately 44.0% and 29.0% of K. pneumoniae and E. coli
      isolates were considered ESBL producers based on NCCLS criteria, respectively.
      Overall, the prevalence of methicillin-resistant S. aureus was 46.2%. The most
      active drugs against this pathogen were vancomycin, teicoplanin, linezolid and
      quinupristin/dalfopristin. In summary, the SENTRY Antimicrobial Surveillance
      Program has detected a high prevalence of methicillin-resistant S. aureus and
      multidrug resistant non-fermentative Gram-negative bacilli isolated from
      respiratory tract specimens of hospitalized patients with pneumonia in Latin
      America. Our results emphasize the importance of local surveillance programs in
      correctly guiding empiric therapy and local intervention programs in attempt to
      reduce antimicrobial resistance.

PMID- 12493179
TI  - Salmonella spp. isolates causing bloodstream infections in Latin America: report
      of antimicrobial activity from the SENTRY Antimicrobial Surveillance Program
      (1997-2000).
AB  - Recent years have seen a dramatic rise in the incidence and severity of cases of
      human salmonellosis. In addition, multidrug resistant strains have arisen. The
      objective of this study was to characterize the antimicrobial susceptibility
      profile of Salmonella spp. clinical isolates collected from Latin American
      medical centers as part of the SENTRY Antimicrobial Surveillance System. A total
      of 144 bloodstream Salmonella spp. isolates were collected between 1997 and 2000.
      The susceptibility to diverse antimicrobial agents was tested by broth
      microdilution techniques according to the NCCLS recommendations. The Salmonella
      spp. strains were more frequently collected from adult patients (67.0%; 21-60
      years) and isolated from Chile (28.5%) > Brazil (25.0%) > Mexico (18.8%) >
      Colombia (11.8%). Ampicillin (MIC(50), 1 microg/ml) showed good in vitro activity
      (92.4% susceptibility). Meropenem (MIC(50), 0.06 microg/ml) and gatifloxacin
      (MIC(50), 0.03 microg/ml) were the most potent compounds against the Salmonella
      spp. isolates (100.0% susceptible) followed by piperacillin/tazobactam (99.3%),
      ceftazidime (98.6%), ceftriaxone (98.6%), and amoxicillin/clavulanic acid
      (94.4%). The lowest susceptibility rates were observed for tetracycline (87.5%)
      and trimethoprim/sulfamethoxazole (91.7%). Four of 144 (2.8%) Salmonella spp.
      isolates demonstrated an ESBL phenotype; however, only two (1.4%) were confirmed
      as an inhibitable ESBL producer. The results of this study show that multidrug
      resistance, especially fluoroquinolone resistance, does not represent a serious
      problem among Salmonella isolates collected from the Latin American medical
      centers as monitored by the SENTRY Program.

PMID- 12493180
TI  - Occurrence and removal of organic pollutants in sewages and landfill leachates.
AB  - Sewages of different composition and the effluents of four sewage treatment
      plants (STPs), plus sewage sludges were analysed for semivolatile organic
      priority pollutants. Furthermore, 11 landfill leachates were analysed to evaluate
      their contribution to sewage pollutants when co-treated. Bis(2-ethylhexyl)
      phthalate (DEHP) was the pollutant occurring at highest concentrations (up to 122
      microg/l) and it was present in all sewages and leachates; concentrations of
      other phthalates were usually below 17 microg/l. Some polycyclic aromatic
      hydrocarbons (PAH) (<1 microg/l) and 2,6-dinitrotoluene (< or =5.9 microg/l) were
      also present in many of the sewages and leachates. Phthalates were present in STP
      effluents in low concentrations (<8 microg/l), while PAHs were usually not
      present. DEHP concentrations were at the same level in the sewage consisting of
      household wastewater and stormwater runoff and the sewages also including
      industrial discharges and landfill leachates, while PAHs were present in sewages
      containing industrial discharges. Leachate contribution to the total pollutant
      load to the STP was less than 1%. Sorption of DEHP to different particle size
      fractions in sewage was studied by serial membrane filtration. Most of the DEHP
      (71-84%) was attached to the particles 0.1-41 microm in size, and approximately
      10-27% of the DEHP was sorbed on particles larger than 41 microm. Less than 6% of
      the DEHP was in the fraction below 0.1 microm and readily available for microbial
      degradation.

PMID- 12493181
TI  - The effect of heavy metals on nitrogen and oxygen demand removal in constructed
      wetlands.
AB  - The objective of this study is to investigate the respective effects of Zn, Pb
      and Cd as well as the combined effect of Zn, Pb, Cd and Cu on the removal of
      nitrogen and oxygen demand in constructed wetlands. Four laboratory-scale gravel
      filled subsurface-flow constructed wetland units planted with cattails (Typha
      latifolia) were operated outdoors and fed with primary-treated domestic
      wastewater at a constant flow rate of 25 ml/min. After 6 months, three of the
      wetland units were fed with the same type of wastewater spiked with Zn(II),
      Pb(II) and Cd(II), respectively, at 20, 5 and 1 mg/l for a further 9 months. The
      remaining unit was fed with the same type of wastewater spiked with a combination
      of Zn(II), Pb(II), Cd(II) and Cu(II) at concentrations of 10, 2.5, 0.5 and 5
      mg/l, respectively, over the same period. The chemical oxygen demand (COD) and
      ammoniacal nitrogen (AN) concentrations were monitored at the inlet, outlet and
      three additional locations along the length of the wetland units to assess the
      performance of the wetland units at various metal loadings. At the end of the
      study, all cattail plants were harvested for the determination of total Kjeldahl
      nitrogen and metal concentrations. The results showed that the COD removal
      efficiency was practically independent of increasing metal loading or a
      combination of metal loadings during the duration of the study. In contrast, the
      AN removal efficiency deteriorated progressively with increasing metal loading.
      The relative effect of the heavy metals was found to increase in the order:
      Zn<Pb<Cd and the synergistic effect of metals was not observed. The metals seem
      to exhibit some inhibitory effect on nitrogen uptake by cattail plants as
      indicated by lower nitrogen uptake rates in comparison to rates recorded in
      wetland systems treating domestic wastewater only.

PMID- 12493182
TI  - Releases from copper smelters and refineries and zinc plants in Canada: human
      health exposure and risk characterization.
AB  - In these assessments of releases from copper smelters and refineries and from
      zinc plants as Priority Substances under the Canadian Environmental Protection
      Act (CEPA), available data were critically evaluated to determine if
      environmental exposure to selected components of these releases poses a risk to
      human health. The data on airborne levels of a variety of toxic substances near
      these facilities in Canada were obtained from the companies or provinces and
      systematically analyzed. Monitoring of ambient air near the Canadian copper
      smelters and refineries and zinc plants indicates that releases from these
      facilities result in increased potential for inhalation exposure of local human
      populations to several components of releases (As, Cd, Cr, Ni, Pb, SO(2) and
      PM(10)). Airborne levels in the vicinity of these metal-processing operations
      overlap those associated with cardiorespiratory effects for PM(10), and exceed
      health-based guidelines for SO(2) and, near some facilities, Pb. In addition, the
      margin between levels of As, Cd, Cr and Ni near these facilities in Canada and
      carcinogenic potency for each of these metals is relatively small near copper
      smelters, larger near copper refineries, and intermediate near zinc plants. On
      this basis, the risk to human health from environmental exposure to releases from
      these facilities is considered to be high compared with other Priority Substances
      assessed under CEPA, especially for facilities where copper is smelted.

PMID- 12493183
TI  - Influence of amalgam fillings on Hg levels and total antioxidant activity in
      plasma of healthy donors.
AB  - In order to evaluate the influence of specific factors on mercury (P-Hg) levels
      and antioxidant power (P-FRAP) in human plasma, 26 healthy donors were examined
      by a dentist, their plasma analyzed for Hg by atomic absorption spectrometry and
      for total antioxidant activity by FRAP method. Hg plasma concentration was found
      to be correlated with the number of amalgam fillings, suggesting that Hg released
      from fillings is a source of Hg in non-occupational exposed subjects. P-FRAP
      correlated negatively with P-Hg suggesting a pro-oxidant role of the Hg released
      from amalgam fillings. Though age by itself was not significantly correlated with
      P-FRAP, when considered together with P-Hg in multivariate analysis, it was found
      to be a major related cofactor. Multivariate analysis showed no influence of fish
      consumption or cigarette smoking on P-FRAP.

PMID- 12493184
TI  - Serum sample levels of selenium and copper in healthy volunteers living in Rio de
      Janeiro city.
AB  - The objective of this study was to analyze the serum sample levels of selenium
      and copper in healthy volunteers living in the city Rio de Janeiro. Thirty
      individuals were submitted for nutritional assessment, electrocardiogram,
      echocardiogram, and serum selenium and copper analysis through hydride generation
      and flame atomic absorption spectrometry, respectively. The accuracy and
      precision of these methods were evaluated using certified reference materials.
      None of the studied individuals was undernourished; 53% were overweight and 13.3%
      were slightly obese. The mean serum selenium level was 73.18+/-9.9 microg/l
      (56.50-94.50 microg/l). Among women it was 76.28+/-8.7 microg/l and in men
      72.23+/-10.24 microg/l (P=0.35). Among non-white individuals the mean was 73.12+/
      12.57 microg/l and in the white individuals it was 73.20+/-9.11 microg/l
      (P=0.98). The mean serum level of copper was 1.09+/-0.39 mg/l (0.56-1.80 mg/l).
      The mean found in women was 0.99+/-0.22 mg/l and in the men 1.13+/-0.43 mg/l
      (P=0.42). In non-white individuals it was 1.36+/-0.48 mg/l and in white
      individuals was 1.00+/-0.31 mg/l (P=0.02). The authors concluded that selenium
      and copper serum levels observed in this study were similar to those found in
      other cities.

PMID- 12493185
TI  - Variations in heavy metal concentrations in the moss species Abietinella abietina
      (Hedw.) Fleisch. according to sampling time, within site variability and increase
      in biomass.
AB  - Concentrations of Al, As, Cd, Co, Cr, Cu, Fe, Hg, Mo, Ni, Pb, V and Zn were
      analysed in the moss Abietinella abietina (Hedw.) Fleisch. to estimate
      atmospheric heavy metal depositions. Samples were taken at five comparable sites
      within a radius of 25 m four times during the year 2000 (July 3rd, August 3rd,
      September 7th, October 3rd). The samples were taken by means of a PVC-tube (r=10
      cm) and could therefore be related to aboveground growth and aerial deposition.
      The investigation showed significant differences between the various sampling
      times for concentrations of all heavy metals in total but not between
      concentrations of a single metal. For Cu, Hg, Mo, Pb and Zn temporal variation
      (=variation between the four times of sampling) was larger than spatial variation
      (=variation of concentrations between sub-samples at a single sampling time).
      Growth rates of the mosses differed significantly between sampling times, which
      reflects the low precipitation at the beginning of the season. Biomass increase,
      dust and precipitation influenced the metal concentrations. The calculation of
      deposition rates, which takes growth rates into account, showed significant
      differences between the various sampling times for Al, Cd, Cr, Cu and Ni, which
      is controversial to the results obtained from concentrations of these elements.
      Additionally, the calculation of atmospheric deposition rates showed a constant
      increase of metal depositions throughout the investigated period, which can not
      be seen by considering the concentrations only.

PMID- 12493186
TI  - Uptake of arsenic by New Zealand watercress (Lepidium sativum).
AB  - Watercress (Lepidium sativum) is consumed as a vegetable, especially by the
      indigenous community in New Zealand. An investigation was carried out on the
      accumulation of arsenic by watercress, following earlier reports of inordinate
      arsenic concentrations in some aquatic macrophytes collected from the Waikato
      River, North Island, New Zealand. The Waikato River and some other aquatic
      systems in Taupo Volcanic Zone, New Zealand have elevated arsenic concentrations
      due to geothermal activity. Watercress, river water and sediment samples were
      collected from 27 sites along the Waikato river and analysed for arsenic.
      Greenhouse trials with watercress grown in beakers containing added arsenic were
      conducted to confirm the ability of this species to accumulate arsenic. At a
      number of sites, the concentration of arsenic in both the water and the
      watercress samples exceeded the World Health Organisation (WHO) limit for
      drinking water (0.01 mg l(-1)) and foodstuffs (2 mg kg(-1) on a fresh weight
      basis). The average leaf and stem arsenic concentrations were, respectively, 29.0
      and 15.9 mg kg(-1) on a fresh weight basis. Plants grown in solutions of >0.4 mg
      l(-1) arsenic concentration had fresh weight arsenic concentrations above the WHO
      limit. Despite these higher concentrations, arsenic levels in plants grown under
      greenhouse conditions were approximately fivefold lower than in plants growing in
      the Waikato River, possibly because under natural conditions, the watercress is
      rooted in sediment containing on average approximately 35 mg kg(-1) arsenic. It
      is recommended that watercress from the Waikato River, or other areas with
      elevated water arsenic concentrations, should not be consumed.

PMID- 12493187
TI  - Blood lead levels and risk factors for lead poisoning among children in Jakarta,
      Indonesia.
AB  - The phase-out of leaded gasoline began in Jakarta, Indonesia on July 1, 2001. We
      evaluated mean blood lead levels (BLLs) and the prevalence of elevated BLLs of
      Jakarta school children and assessed risk factors for lead exposure in these
      children before the beginning of the phase-out activities. The study involved a
      population-based, cross-sectional blood lead survey that included capillary blood
      lead sampling and a brief questionnaire on risk factors for lead poisoning. A
      cluster survey design was used. Forty clusters, defined as primary schools in
      Jakarta, and 15 2nd- and 3rd-grade children in each cluster were randomly
      selected for participation in the study. The average age of children in this
      study was 8.6 years (range 6-12) and the geometric mean BLL of the children was
      8.6 microg/dl (median: 8.6 microg/dl; range: 2.6-24.1 microg/dl) (n=397). Thirty
      five percent of children had BLLs > or =10 microg/dl and 2.4% had BLLs > or =20
      microg/dl. Approximately one-fourth of children had BLLs 10-14.9 microg/dl. In
      multivariate models, level of education of the child's primary caregiver, water
      collection method, home varnishing and occupational recycling of metals, other
      than lead, by a family member were predictors of log BLLs after adjustment for
      age and sex. BLLs of children who lived near a highway or major intersection were
      significantly higher than those of children who lived near a street with little
      or no traffic when level of education was not included in the model. Water
      collection method was a significant predictor of BLLs > or =10 microg/dl after
      adjustment for age and sex. BLLs in children in this study were moderately high
      and consistent with BLLs of children in other countries where leaded gasoline is
      used. With the phase-out of leaded gasoline, BLLs of children in Jakarta are
      expected to rapidly decline as they have in other countries that have phased lead
      out of gasoline.

PMID- 12493188
TI  - The potential for oestrogenic effects of pesticides in headwater streams in the
      UK.
AB  - Twenty-six pesticidal compounds and samples of stormwater from two different
      agricultural catchments were screened for oestrogenic activity using an in vitro
      recombinant yeast-based assay. Only six fungicides showed an oestrogenic response
      with low comparative biological activity of 5000 to 2.5 million times less potent
      than 17beta-estradiol (E2), a natural steroidal oestrogen. Concentrations of
      biological activity expressed as E(2) equivalents for the headwater stream
      stormwater samples ranged from <0.01 to 0.11 ng E2/l. These values are at least
      one order of magnitude below levels that have been documented to produce
      oestrogenic effects in fish and are therefore considered to represent a low risk
      to associated headwater stream communities. The potential sources of the
      oestrogenic activity measured in the headwater streams are discussed.

PMID- 12493189
TI  - Bone cadmium and lead in prehistoric inhabitants and domestic animals from Gran
      Canaria.
AB  - Both lead and cadmium exposures derive from natural sources and also from
      industrialisation and certain habits, such as cigarette smoking in the case of
      cadmium. Some of these sources only affect human beings. The aim of this study
      was to determine the levels of lead and cadmium in bone samples of 16 prehispanic
      inhabitants of Gran Canaria, 24 prehispanic domestic animals (sheep, goat and
      pigs) from this island, 8 modern individuals, and 13 modern domestic animals. We
      found that modern individuals showed higher bone Cd values (mean=516.7+/-352.49
      microg/kg, range=167.20-1125 microg/kg) than prehistoric ones (mean=85.13+/
      128.96 microcg/kg, range=2.97-433 microg/kg). Values of prehistoric individuals
      did not differ from those of the prehistoric animals (mean=70.54+/-46.86
      microg/kg, range=11.06-216.50 microg/kg), but were higher than those of the
      modern animals (mean=7.31+/-10.35 microg/kg, range=0-35.62 microg/kg). In the
      same way, modern individuals and modern animals showed approximately 7-fold
      higher bone Pb than ancient individuals and ancient animals, respectively.
      Ancient animals showed significantly lower Pb values than all the other groups,
      whereas modern animals showed Pb values comparable to those of the ancient
      individuals. A significant correlation was observed between bone Pb and Cd
      (r=0.61, P<0.001). Since bone cadmium accumulation leads to osteoporosis, we have
      also tested the relationship between histomorphometrically assessed trabecular
      bone mass and bone cadmium both in modern and ancient individuals. No significant
      relationship was found between these two parameters.

PMID- 12493190
TI  - Bile metabolites of polycyclic aromatic hydrocarbons (PAHs) in European eels
      Anguilla anguilla from United Kingdom estuaries.
AB  - A total of 94 European eels (Anguilla anguilla) were collected from five
      estuaries in the UK. The deconjugated metabolites of polycyclic aromatic
      hydrocarbons (PAHs) in the bile of the eels were separated using HPLC. Six PAH
      metabolites were identified: 1-hydroxy (1-OH) metabolites of phenanthrene, pyrene
      and chrysene; and the 1-OH, 3-OH and 7,8 dihydrodiol metabolites of
      benzo[a]pyrene (BaP). The mean concentration of the six metabolites was greatest
      in eels from the Tyne (49 microM) followed by the Wear (33 microM), Tees (19
      microM), Thames (4 microM) and Severn (2 microM) estuaries. Although 1-OH pyrene
      was always the dominant compound, there were significant differences (P<0.05)
      between sites and between estuaries for some metabolites. Normalising the molar
      concentration of the bile metabolites to the bile biliverdin absorbance reduced
      sample variation. When the metabolites identified were each expressed as a
      percentage of the total detected, the metabolite profile was characteristic for
      each estuary.

PMID- 12493191
TI  - Heavy metal contamination in the Taimyr Peninsula, Siberian Arctic.
AB  - The Taimyr Peninsula is directly north of the world's largest heavy metal
      smelting complex (Norilsk, Russia). Despite this proximity, there has been little
      research to examine the extent of contamination of the Taimyr Peninsula. We
      analyzed heavy metal concentrations in lichen (Cetraria cucullata), moss
      (Hylocomium splendens), soils, lake sediment, freshwater fish (Salvelinus
      alpinus, Lota lota and Coregonus spp.) and collared lemming (Dicrostonyx
      torquatus) from 13 sites between 30 and 300 km from Norilsk. Element
      concentrations were low in both C. cucullata and H. splendens, although
      concentrations of Al, Fe, Cu, Ni and Pb were significantly higher than those in
      Arctic Alaska, probably due to natural differences in the geochemical
      environments. Inorganic surface soils had significantly higher concentrations of
      Cd, Zn, Pb and Mg than inorganic soils at depth, although a lake sediment core
      from the eastern Taimyr Peninsula indicated no recent enrichment by
      atmospherically transported elements. Tissue concentrations of heavy metals in
      fish and lemming were not elevated relative to other Arctic sites. Our results
      show that the impact of the Norilsk smelting complex is primarily localized
      rather than regional, and does not extend northward beyond 100 km.

PMID- 12493192
TI  - Evaluation of the genotoxic and teratogenic potential of a municipal sludge and
      sludge-amended soil using the amphibian Xenopus laevis and the tobacco: Nicotiana
      tabacum L. var. xanthi Dulieu.
AB  - The toxic, genotoxic and teratogenic potential of a municipal sewage sludge was
      assessed using the micronucleus assay on the larvae of the amphibian Xenopus
      laevis and with the tobacco somatic mutation test using the yellow-green xanthi
      Dulieu mutant a(1)(+)/a(1) a(2)(+)/a(2). The teratogenic potential was assessed
      by means of the Frog Embryo Teratogenesis Assay-Xenopus (FETAX). Various doses of
      the pasty sludge added to a crop soil were tested using the three bioassays. The
      test systems were performed either directly with sludge or sludge-amended soil
      samples (plant model) or with aqueous extracts (aquatic animal model). Using the
      tobacco model, we found no mutagenic impact of the soil amended with the sludge,
      perhaps because the clay-like nature of the soil, with its high adsorption
      capacity, may have prevented the contaminants from reaching the target. All
      leachates of amended soils produced a significant size reduction in Xenopus
      embryos. Depending on the soil/sludge ratio, some leachates were found to be
      genotoxic but were never teratogenic. This battery of in vivo test systems
      enabled us to estimate the global long-term effects under agricultural conditions
      with various genetic endpoints on ecologically relevant organisms characteristic
      of the aquatic and terrestrial compartments.

PMID- 12493193
TI  - Metallothionein concentrations in a population of Patella aspera: variation with
      size.
AB  - The determination of metallothionein (MT) concentrations in species with
      different feeding habits is important from the ecotoxicological point of view
      because it provides a better understanding of the role of these proteins in metal
      uptake pathways. The main objective was study the variation of MT and metal (Cd,
      Cu and Zn) concentrations with size and weight in the limpets Patella aspera. In
      addition investigate the relationship between MT and metal concentrations in
      limpets from different metal load environments of the south coast of Portugal
      with the aim to use MT in P. aspera as a biomarker of metal exposure. MT
      concentrations in the whole soft tissues of P. aspera increased with size and
      weight while metals decrease with size and weight. MT concentrations showed no
      significant relationship with Cd or Cu concentrations in the limpets from the
      South Portuguese Coast. However, a negative exponential relationship detected
      between MT and Zn concentrations suggest that Zn bound to MT might be displaced
      by Cd or Cu ions. The ability of limpets to store both Cd and Cu bound to MT may
      be responsible for the tolerance of this species to contaminated environments.
      The relationship between MT concentrations and Zn indicates that MT seems to play
      a minor role in binding Zn in Patella species.

PMID- 12493194
TI  - Contaminants in Svalbard polar bear samples archived since 1967 and possible
      population level effects.
AB  - Blood plasma samples were collected in 1967 from 32 polar bears (Ursus maritimus)
      in eastern Svalbard. These samples were stored frozen until 2001 and then
      analyzed for 33 polychlorinated biphenyls (PCB), two toxaphene congeners, DDTs,
      chlordanes (CHL), hexachlorobenzene, hexachlorocyclohexanes (HCHs), and
      polybrominated flame retardants (biphenyls and diphenyl ethers). The 1967
      pollutant levels were compared with values from 1993 to 1994 for adult females
      and adult males to obtain insights into the historical development of pollution
      in the Norwegian Arctic. Differences in the OC levels measured between 1967 and
      1993-1994 ranged from a decrease (PCB 187 and p,p-DDE) to unchanged in both sexes
      (PCBs 105, 118, 209, and HCH) to an increase in females (PCBs 99, 128, and CHL),
      to increases in both sexes (PCBs 138, 153, 156, 157, 170, 180, 194, and 206). The
      maximum change was a nine-fold increase in PCB 157 in adult females. Changes from
      1967 to 1993-1994 in contaminant pattern expressed relative to PCB 153 could be
      explained by a combination of selective metabolism and accumulation of
      organochlorines in polar bears and temporal changes in the contaminant mixture
      being transported to the Arctic. Harvest of polar bears in Svalbard ended in 1973
      and it appears that most pollutant levels were increasing at the same time that
      the population was expected to recover from over-harvest. The mean age of adult
      females in the Svalbard population was similar to other populations where
      pollution levels are lower but harvest is intense. Females with cubs-of-the-year
      > or =16 years old are uncommon in the population for unknown reasons. The
      impacts of contaminants on the Svalbard polar bear population are inconclusive
      but there are suggestions of contaminant-related population level effects that
      could have resulted from reproductive impairment of females, lower survival rates
      of cubs, or increased mortality of reproductive females.

PMID- 12493195
TI  - Volcanogenic fluorine in rainwater around active degassing volcanoes: Mt. Etna
      and Stromboli Island, Italy.
AB  - Many studies have assessed the strong influence of volcanic activity on the
      surrounding environment. This is particularly true for strong gas emitters such
      as Mt. Etna and Stromboli volcanoes. Among volcanic gases, fluorine compounds are
      potentially very harmful. Fluorine cycling through rainwater in the above
      volcanic areas was studied analysing more than 400 monthly bulk samples. Data
      indicate that only approximately 1% of fluorine emission through the plume is
      deposited on the two volcanic areas by meteoric precipitations. Although measured
      bulk rainwater fluorine fluxes are comparable to and sometimes higher than in
      heavily polluted areas, their influence on the surrounding vegetation is limited.
      Only annual crops, in fact, show some damage that could be an effect of fluorine
      deposition, indicating that long-living endemic plant species or varieties have
      developed some kind of resistance.

PMID- 12493196
TI  - Heavy metals in the vicinity of a chlor-alkali factory in the Upper Negro River
      ecosystem, Northern Patagonia, Argentina.
AB  - A study on heavy metal contents was performed in sediments and biota of the Upper
      Negro River (Alto Valle) aquatic system, Northern Patagonia, Argentina. The
      irrigation system of the Neuquen and Negro Rivers runs alongside these rivers for
      150 km, supporting intensive agricultural and economical activities, mainly
      related to fruit production. A mercury cell chlor-alkali factory operated between
      1951 and 1995. Close attention was given to the surroundings of the plant,
      located next to the Main Irrigation Channel, and to the PII drainage channel
      which received the plant's effluents between 1951 and 1979. From 1979 until its
      closure, the effluents were pumped above a ravine to a series of evaporation and
      decantation pools. Mercury and other heavy metals and metalloids (Ag, As, Ba, Co,
      Cr, Cs, Ni, Sb, Se, U and Zn) contents were measured for bottom sediments of the
      river and irrigation and drainage channels, for two widespread species of
      macrophytes (Potamogeton pectinatus and Myriophyllum brasiliensi), and for liver
      and muscle of native fish Odontesthes microlepidotus. River bed sediments show no
      evidence of heavy metal accumulation, however, biota might indicate that
      contaminants are entering the rivers. Mercury was the only element accumulated in
      the Main Irrigation channel sediments, the highest contents occurring in the
      surroundings of the nowadays shut-down chlor-alkali plant, returning to
      background values approximately 40 km downstream the plant. At the plant site,
      sediments from the center of the channel showed a decrease in Hg content in the
      upper 10 cm layer, ranging from 0.8 to 3.4 microg g(-1), and from 2.8 to 13.7
      microg g(-1) in the next 10 cm lower layer. Conversely, the PII drainage channel
      sediments showed accumulation of Hg (2-4 microg g(-1)), distributed uniformly at
      different depths and along the channel, until its mouth at Negro river. Mercury
      contents of macrophytes downstream the chlor-alkali plant are higher than the
      baseline for the area, and macrophytes and fish liver from the PII drainage
      channel present the highest content in this element. The drainage channel system
      showed different degrees of impact, those channels flowing through densely
      populated areas being the most affected.

PMID- 12493197
TI  - Clover as a tool for bioindication of phytotoxic ozone--5 years of experience
      from southern Sweden--consequences for the short-term critical levels.
AB  - Critical levels (CLs) for ozone effects on plants in Europe have been defined
      within the UN-ECE Convention on Long-Range Transboundary Air Pollution, CLRTAP.
      The purpose of the short-term CLs is to ensure protection of all crops to acute
      ozone injury. The currently used CLs are based on the ozone exposure of the
      plants during daylight hours expressed as AOT40 (Accumulated exposure Over the
      Threshold 40 nmol mol(-1) ozone). The aims of this study were: to test the
      performance of the current short-term CLs, to test alternative ozone exposure
      indices and to test if changes in the ozone cut-off concentration, the inclusion
      of a lag-period (LP) between exposure and identification of visible ozone injury
      or the duration of the ozone integration period improved the performance of the
      exposure index. The analysis was based on 38 different datasets from experiments
      with subterranean clover, Trifolium subterraneum in southern Sweden. AOT indices
      generally performed better than averaged ozone concentrations or SUM (Sum of
      ozone concentrations when a threshold is exceeded) indices. Regression analysis
      showed that the current short-term CL, AOT40 with a VPD (water vapour pressure
      deficit) threshold of 1.5 kPa, explained 56% of the variation in visible injury.
      A longer exposure period and the introduction of a LP, admitting visible ozone
      injury time to develop after exposure, improved the performance of the exposure
      index. AOT30 accumulated over 10 days before harvest, excluding a LP of 3 days
      before injury observation, performed best and explained 88% of the variation in
      visible injury. AOT40 indices left a rather large amount of visible injury
      unexplained indicating that a lower cut-off concentration for ozone is
      preferable. The results of the investigation indicated that a visible injury
      threshold of 10% improved the distinction between harmful and less harmful
      exposure.

PMID- 12493198
TI  - Estimation of adsorbed amounts of volatile chlorinated organic compounds to wet
      soil based on the properties of the compounds and soils.
AB  - The adsorption equilibriums of 7 volatile organic chlorinated compounds to 10 wet
      soils were investigated by continuous flow adsorption experiments. The adsorption
      equilibriums for the wet soils could be expressed by the Henry equation. The most
      part of the adsorbed amount existed on the organic substances in the soil, and
      the soil-water adsorption equilibrium constant could be estimated from the
      organic carbon content of the soil. The adsorption coefficient to the organic
      carbon of the chloroethylenes and chloroethanes could be expressed by the
      functions of the n-octanol/water partition coefficient, respectively. The
      adsorbed amounts could be estimated using equations relating the organic content
      and the water content of each soil, and the n-octanol/water partition coefficient
      and the Henry constant for the gas-water equilibrium of each compound. The
      estimated results agreed well with the measured data.

PMID- 12493199
TI  - Testing of a foodchain model using Chernobyl 137Cs fallout data and considering
      the effect of countermeasures.
AB  - Chernobyl 137Cs fallout data obtained during the period 1986-1996 from the most
      contaminated area in Russia were used within the IAEA BIOMASS programme to test
      the reliability of radiological assessment models. This model-testing scenario
      included information and data on countermeasures that were applied in the test
      area after the accident. This paper presents the predictions of the terrestrial
      foodchain model SPADE that was used in this model-testing exercise. SPADE
      predictions compared reasonably well with test data except for pigs and wild
      berries where differences were up to a factor of 50 and 200, respectively.
      Estimated intake of 137Cs and ingestion dose by adult men and women living in the
      test area compared favourably with the test data. Overall, SPADE proved to be
      capable of simulating agricultural countermeasures and their effectiveness.
      Modelling of countermeasures was found to be a complex process with large
      uncertainties regarding their 'real' implementation and effectiveness. The
      lessons learned from this exercise will be valuable in making future dose
      assessments/reconstructions involving countermeasures with improved results.

PMID- 12493200
TI  - Solubility of metals in an anoxic sediment during prolonged aeration.
AB  - This work was conducted to study the evolution of the solubility of selected
      metals during the aeration of an anoxic sediment. Batch experiments were carried
      out for 76 days with a metal-polluted dredged sediment. The pH, Eh and
      concentration of Al, Cu, Fe, Hg, Pb and Zn were periodically recorded. Results
      showed that during the early stages of aeration, the solubility of metals
      increased rapidly but was then followed by fast re-adsorption. As a consequence,
      after 14 days most of the metals excepted Cu and Zn were present at low or
      undetectable concentrations in solution. Re-adsorption of Zn was observed to be
      much slower during the first two weeks, whereas solubilisation of Cu increased
      gradually during months after land disposal. According to speciation
      calculations, Cu solubilisation was in part due to complexation in solution by
      carbonates. In the case of Hg, although complexation by dissolved organic matter
      (DOM) could be expected, re-adsorption was the dominant process. However, more
      knowledge about the behaviour of the DOM present in anoxic sediments is needed in
      order to make more quantitative statements about the mobility of heavy metals
      contained in dredged material.

PMID- 12493201
TI  - Chromium availability in ultramafic soils from New Caledonia.
AB  - The sources and potential availability of chromium (Cr) on soils formed on
      ultramafic rocks were investigated with mineralogical studies and selective
      chemical extractions. Soil solutions were collected in the field (i) along a soil
      toposequence under natural vegetation with ceramic cups; (ii) under grass in a
      mandarin trees plantation with tension-free tube lysimeters. On selected soil
      solutions, the Cr(VI) was determined colorimetrically with the s
      diphenylcarbazide method and total Cr by ICP-AES and speciation of Cr(VI) was
      performed with the MINEQL+ V 4.5 software. The main mineralogical sources of Cr
      were Cr-substituted goethite and chromite. Up to 90 mg kg(-1) of Cr was extracted
      by KH(2)PO(4), whereas KCl extractable Cr was very low, indicating that
      exchangeable Cr was mainly in the highly toxic Cr(VI) form in these soils. Under
      natural vegetation, the Cr concentrations in the soil solutions remained
      relatively low (<20 microg l(-1)) due to the high retention of the Cr(VI) anions
      by Fe-oxides. The Cr concentrations were larger in well aerated colluvial soils,
      where high levels of Mn-oxides are able to oxidize Cr(III) to Cr(VI), than in
      piedmont soil where the Mn-oxide content is lower, or in alluvial soils from the
      lowlands, where waterlogging occurs. Cr concentrations reached 700 microg l(-1)
      in the field that was fertilized with high amount of phosphorus, due to the
      exchange of Cr(VI) with phosphate. In such conditions, toxicity phenomena for
      crops can be expected.

PMID- 12493202
TI  - Synthesis, characterization and thermal studies of 2-oxo-1,3,5-trinitro-1,3,5
      triazacyclohexane (Keto-RDX or K-6).
AB  - 2-Oxo-1,3,5-trinitro-1,3,5-triazacyclohexane (Keto-RDX or K-6), the most powerful
      energetic material among nitrourea explosives, has been prepared and scaled up at
      laboratory level. The identity and purity of the product are tested by elemental
      analysis, IR, NMR, mass and HPLC techniques. Thermal response and sensitivity
      experiments on K-6 are also described. The data on sensitivity shows that K-6 can
      be utilised practically only in phlegmatized form.

PMID- 12493203
TI  - Influence of heat transport mechanisms on transport classification by SADT
      measurement as measured by the Dewar-method.
AB  - The self-accelerating decomposition temperature (SADT) is according to the United
      Nations Recommendations on the Transport of Dangerous Goods needed for transport
      classification of goods as class 4.1 (self-reactive). One of the methods
      recommended to determine the SADT is the Dewar-method.The method is well suited
      to assess the transport stability of liquids, whereas for solids the assessment
      errs on the unsafe side. The differences in heat transfer between solids and
      liquids are explained using cooling curves and classifying them by their Biot and
      Fourier-numbers and by applying the theories of Semenov and Frank-Kamenetskii for
      the critical heat release rates.

PMID- 12493204
TI  - Assessment of the effectiveness of downward water sprays for mitigating gaseous
      chlorine releases in partially confined spaces.
AB  - Water sprays are sometimes used as a means of mitigating accidental releases of
      chlorine gas. This paper gives results of a series of small-scale experimental
      field tests on the mitigation of chlorine gaseous releases (about 1kg/min) by
      various downward water sprays. The releases were from a cylinder of liquefied
      chlorine located in a storage shed. The shed could be configured to simulate
      confined and semi-confined installations used at public swimming pools. The water
      sprays were located in the shed. During these tests, different types of spray
      nozzles and storage configurations were tested under various atmospheric
      conditions, in order to select the best water spray. It was shown that the best
      chlorine downstream concentration reduction (factor 3-5 at 10m) was achieved with
      a flat fan water spray for the semi-confined configuration. Poor absorption in
      water was observed (<1%). The highest absorption (roughly 5%) was obtained with a
      fog water spray for the confined configuration. This is expected since chlorine
      is a low soluble gas. It has been evidenced for the confined configuration, that
      even if reduction of concentration has been observed (factor 2), downstream
      concentration remains very high (>10,000ppm), and above critical level of
      toxicity. Consequently, the use of water sprays in this case without additives to
      promote absorption seems to be inefficient.

PMID- 12493205
TI  - Electrokinetic remediation of clayey soils containing copper(II)-oxinate using
      humic acid as a surfactant.
AB  - The utility of humic acid (HA) as a surfactant for use in the electrokinetic
      remediation (ER) of the clayey soils containing copper(II)-oxinate (Cu(OX)(2))
      was examined. A small simulator of ER was devised, which consisted of three types
      of artificial soils on the basis of the commercial kaolin: kaolin, kaolin + HA
      and kaolin + Cu(OX)(2). The layers of kaolin containing HA and Cu(OX)(2) were
      sandwiched between two kaolin layers. In all experiments, a constant dc voltage
      gradient of 2.2V/cm was applied through the soil for 30h, and the pH of the
      solution in the anodic chamber was maintained at 7.0. Generally, HA has a
      negative charge at a neutral pH. However, the HA was mainly transferred to the
      cathodic chamber. This shows that the driving force of the HA in the system used
      herein is predominantly due to electroosmotic flow. Moreover, the amount of
      Cu(OX)(2) removed from the clayey soils in the presence of HA was three times
      larger than those in the absence of HA. This can be attributed to the fact that
      the water solubility of Cu(OX)(2) is enhanced by the presence of HA. Thus, we
      conclude that HA has a potential for use as an amendment for the ER of
      hydrophobic chemicals, such as Cu(OX)(2).

PMID- 12493206
TI  - Purification of storage brines from the preservation of table olives.
AB  - The chemical oxidation of the wastewaters generated during storage of table
      olives in NaCl brines, prior to their manufacturing process, was studied. Ozone
      alone produced COD removals in the range 14-23%, and a higher average removal of
      73% of the aromatic compounds. The additional presence of hydrogen peroxide and
      UV radiation increased these values to 39% for COD and 86% for aromatics.
      However, UV radiation alone only gave a removal of 9% for COD and 27% for
      aromatics, and the additional presence of 0.5M H(2)O(2) led to 13% for COD and
      38% for aromatics, respectively. The Fenton's reagent oxidation achieved a COD
      removal of 24% for the higher concentrations of Fe(2+) and H(2)O(2). The most
      effective process was the combination O(3)/UV/H(2)O(2) with total removals of 65
      and 92% for the COD and aromatics, respectively. The aerobic treatment of these
      effluents gave a 66% removal regardless of the initial biomass concentration
      used, and a rate constant of 0.19 per day was obtained for the process by using
      the Contois model. Finally, the aerobic treatment of the wastewaters previously
      ozonated alone, and ozonated with UV radiation, gave increases in the COD removal
      and a final rate constant of 0.44 per day. The enhancements were due to the
      chemical oxidations, these procedures being suitable technologies as pre
      treatments to subsequent biological processes for the purification of these
      residues.

PMID- 12493207
TI  - Model of spills and fires from LNG and oil tankers.
AB  - A comprehensive model for predicting the dynamics of spills from LNG and oil
      product tankers is constructed from fluid mechanics principles and empirical
      properties of oil and LNG spills on water. The analysis utilizes the significant
      tanker hold and discharge flow area dimensions to specify the cargo liquid
      outflow history and the ensuing pool characteristics, including the establishment
      of a pool fire. The pool fire area, duration, and heat release rate are
      determined as functions of the tanker cargo variables. Examples of an LNG and
      gasoline spill show that for likely discharge flow areas these spills may be
      regarded as instantaneous, simplifying the evaluation of risk consequences.

PMID- 12493208
TI  - Experimental evaluation of LPG tank explosion hazards.
AB  - Liquefied-pressure gases (LPG) are transported and stored in the liquid phase in
      closed tanks under sufficiently high pressure. In the case of an accident, an
      abrupt tank unsealing may release enormous quantity of evaporating gas and energy
      that has a destructive effect on the tank and its surroundings. In this paper,
      experiments with explosions of small LPG tanks are described. The data
      acquisition equipment applied in the tests provided a chance to learn dynamics of
      the process and determine hazard factors. The tests enabled a determination of
      temperature and pressure at which tanks containing LPG disrupt. The results
      enable a reconstruction of consecutive phases of the explosion and identification
      of hazards resulting from damage of the tanks. An explanation of the tank
      unsealing process with fluid parameters above critical point is given.

PMID- 12493209
TI  - Possible applications for municipal solid waste fly ash.
AB  - The present study focuses on existing practices related to the reuse of Municipal
      Solid Waste (MSW) fly ash and identifies new potential uses. Nine possible
      applications were identified and grouped into four main categories: construction
      materials (cement, concrete, ceramics, glass and glass-ceramics); geotechnical
      applications (road pavement, embankments); "agriculture" (soil amendment); and,
      miscellaneous (sorbent, sludge conditioning). Each application is analysed in
      detail, including final-product technical characteristics, with a special
      emphasis on environmental impacts. A comparative analysis of the different
      options is performed, stressing the advantages but also the weaknesses of each
      option. This information is systemized in order to provide a framework for the
      selection of best technology and final products. The results presented here show
      new possibilities for this waste reuse in a short-term, in a wide range of
      fields, resulting in great advantages in waste minimization as well as resources
      conservation.

PMID- 12493210
TI  - A study on major inorganic ion composition of atmospheric aerosols at Tirupati.
AB  - Atmospheric aerosol samples were collected from an urbanized area (Tirupati,
      South India) during the period April to September 2001 and were analyzed for
      major inorganic ions-F, Cl, NO(3,) SO(4), Na, K, Mg, Ca and NH(4) by employing
      the ion chromatograph. The average mass of the aerosol was found to be 55.64
      microgram(-3) with a total water-soluble load (total anion+total cation) of 5.74
      microgram(-3). Seasonal distribution of the aerosol mass and temporal variations
      of the ion concentrations present a clear trend of lowering atmospheric levels
      during the rainy season due to washout effect. Composition of the aerosols showed
      higher concentration of SO(4) followed by NO(3) and NH(4) and found to be
      influenced by local terrestrial sources. The presence of SO(4) and NO(3) may be
      due to re-suspension of soil particles (formation by heterogeneous oxidation).
      Ca, Mg and Cl are mainly soil derived ones. The presence of NH(4) may be
      attributed to the reaction of NH(3) vapors with acidic gases such as H(2)SO(4),
      HNO(3) and HCl or ammonia vapor may react or condense on an acidic particle
      surface of anthropogenic origin. Equivalent ratios of NH(4)/(NO(3)+SO(4)) varied
      between 0.62 and 0.74. It shows the aerosol to be slightly acidic due to the
      neutralization of basicity by SO(2) and NO(x).

PMID- 12493211
TI  - Environmental assessment of waste matrices contaminated with arsenic.
AB  - The use of equilibrium-based and mass transfer-based leaching tests has been
      proposed to provide an integrated assessment of leaching processes from solid
      wastes. The objectives of the research presented here are to (i) validate this
      assessment approach for contaminated soils and cement-based matrices, (ii)
      evaluate the use of diffusion and coupled dissolution-diffusion models for
      estimating constituent release, and (iii) evaluate model parameterization using
      results from batch equilibrium leaching tests and physical characterization. The
      test matrices consisted of (i) a soil contaminated with arsenic from a pesticide
      production facility, (ii) the same soil subsequently treated by a Portland cement
      stabilization/solidification (S/S) process, and (iii) a synthetic cement-based
      matrix spiked with arsenic(III) oxide. Results indicated that a good assessment
      of contaminant release from contaminated soils and cement-based S/S treated
      wastes can be obtained by the integrated use of equilibrium-based and mass
      transfer-based leaching tests in conjunction with the appropriate release model.
      During the time scale of laboratory testing, the release of arsenic from the
      contaminated soil matrix was governed by diffusion and the solubility of arsenic
      in the pore solution while the release of arsenic from the cement-based matrices
      was mainly controlled by solubilization at the interface between the matrix and
      the bulk leaching solution. In addition, results indicated that (i) estimation of
      the activity coefficient within the matrix pore water is necessary for accurate
      prediction of constituent release rates and (ii) inaccurate representation of the
      factors controlling release during laboratory testing can result in significant
      errors in release estimates.

PMID- 12493213
TI  - Optimisation of Fenton's reagent usage as a pre-treatment for fermentation
      brines.
AB  - Pre-treatment of fermentation brines from green olives has been carried out by
      the Fe(II)/Fe(III)/H(2)O(2) system. Reagent concentration exerted a positive
      influence on chemical oxygen demand (COD) removal. Hydrogen peroxide uptake
      showed values in the range 0.3-1.6mol of COD eliminated per mol of H(2)O(2)
      consumed depending on operating conditions. The optimum working pH was found to
      be in the interval 2.0-3.5. Reaction temperature increased the COD degradation
      rate, although similar COD conversion values were obtained after 5h of treatment
      regardless of the value of this parameter. An analysis of the biodegradability of
      this type of effluent demonstrated the beneficial effect of the chemical pre
      oxidation. According to the experimental results, it is suggested that there is
      an inhibitory effect of the wastewater due to its COD content and nature rather
      than attributable to the presence of high amounts of sodium chloride.
      Biodegradation efficiency increased as temperature was raised up to 30 degrees C.
      A further increase of this parameter up to 40 degrees C resulted in the death of
      the microorganisms.

PMID- 12493212
TI  - Treatment of brines by combined Fenton's reagent-aerobic biodegradation. II.
      Process modelling.
AB  - Process modelling of the integrated Fenton's reagent-aerobic biodegradation
      system has been carried out by considering a detailed reaction mechanism for the
      chemical oxidation step and the generalised Monod equation for the biological
      treatment. Chemical oxygen demand has been contemplated as a pseudo-component for
      simulation purposes. The proposed mechanism takes into consideration different
      features experimentally found. Thus, the inefficient hydrogen peroxide
      decomposition into oxygen and water, the influence of temperature and other
      operating variables and the role of oxygen have been considered. The aerobic
      biodegradation of the effluent after the chemical oxidation has taken place has
      been well simulated by Monod equation with no inhibitory terms. Dependency on
      temperature has been correlated by Arrhenius expression.

PMID- 12493214
TI  - Simultaneous nitrification-denitrification in slow sand filters.
AB  - While the ability of slow sand filters to remove total suspended solids (SS),
      turbidity, and organics from wastewaters is well known, this study has
      demonstrated that they can also achieve simultaneous nitrification
      denitrification, producing effluent total Kjedahl nitrogen (TKN) and total
      nitrogen (TN) concentrations as low as 0.6 and 1.5mg/l, respectively, utilizing
      particulate and slowly biodegradable COD in the process. The impact of filtration
      rates in the range of 0.15-0.38m/h, filter depth of 0.5-1.5m, and sand size 0.3
      0.5mm on nitrogen removal processes at temperatures of 10-39 degrees C was
      assessed. Nitrification efficiency, denitrification efficiency, and total
      nitrogen removal efficiency correlated well with filtration rate and sand size
      only, with all three parameters inversely proportional to the square root of the
      aforementioned two process variables. Nitrification exhibited the most
      sensitivity to filtration rate and sand size. The filters produced effluent with
      turbidities of 0.1-0.5 NTU, SS concentrations of 3-6mg/l in the fine sand and 6
      9mg/l in the coarse sand. Effluent BOD(5) and COD concentrations were mostly in
      the 0.8-2.6 and 15-34mg/l range, respectively.

PMID- 12493215
TI  - Hydrogen peroxide lifetime as an indicator of the efficiency of 3-chlorophenol
      Fenton's and Fenton-like oxidation in soils.
AB  - In this work the possibility of using the hydrogen peroxide lifetime as indicator
      of the oxidation efficiency of Fenton's and Fenton-like processes for soil
      treatment was explored. A reactivity scale, in terms of the oxidizing power in
      the different tested operating conditions (pH, iron sulfate concentration and
      stabilizer concentration) was built for each soil as a function of the hydrogen
      peroxide lifetime. Its validity was then confirmed through 3-chlorophenol
      Fenton's and Fenton-like slurry-phase oxidation experiments. The proposed
      reactivity scale proved to be effective for comparing the different operating
      conditions for the same soil, but failed when used to compare the oxidation
      performances for different soils, since the different adsorptive behavior of the
      tested soils may have influenced the contaminant removal rate.

PMID- 12493216
TI  - Microbial stability evaluation of cement-based waste forms at different waste to
      cement ratio.
AB  - An evaluation of the effect of differences in chromium nitrate to cement ratio on
      the microbial stability of a chromium nitrate/cement waste form, as reflected in
      the leaching of chromium, calcium, magnesium and aluminum; was carried out in
      this study. An increase in the proportion of chromium in the waste form from 4.8
      to 8.7% had no noticeable effect on microbial stability, with the total chromium
      leached essentially unchanged. Further increases in the proportion of chromium in
      the waste form from 8.7 to 10.7%, and from 10.7 to 15.9% resulted in a
      substantial decrease in microbial stability, with 3-fold and 1.3-fold increase in
      the total chromium leached, respectively, observed. For calcium, increases in the
      chromium proportion were accompanied with increases in the total calcium leached
      even though the increases were not in direct proportion to the increases in
      chromium proportion. For magnesium and aluminum, increases in the proportion of
      chromium within the range 4.8-10.7% were accompanied with increases in the total
      respective metals leached, with minor variation for each metal. On the whole, the
      maximum percentage chromium leached from the different waste forms was
      substantially lower than those of the other metals.

PMID- 12493221
TI  - Regioselective sulfonylation of 6,1',6'-tri-O-tritylsucrose through
      dibutylstannylation: synthesis of 4'-O-sulfonyl derivatives of sucrose.
AB  - 3-O-Mesyl-1,6-di-O-trityl-beta-D-fructofuranosyl-(2-->1)-6-O-trityl-alpha-D
      glucopyranoside (3) was synthesized via stannylation of 6,1',6'-tri-O
      tritylsucrose with dibutyltin oxide in benzene, followed by treatment of the
      crude product with methanesulfonyl chloride in the presence of triethylamine in
      dichloromethane at 0 degrees C. A similar treatment of the tri-tritylsucrose in
      toluene, instead of benzene, yielded 4-O-mesyl-1,6-di-O-trityl-beta-D
      fructofuranosyl-(2-->1)-6-O-trityl-alpha-D-glucopyranoside (4) as the major
      product. The X-ray crystal structure of the corresponding acetyl derivative, 3-O
      acetyl-4-O-mesyl-1,6-di-O-trityl-beta-D-fructofuranosyl-(2-->1)-2,3,4-tri-O
      acetyl-6-O-trityl-alpha-D-glucopyranoside (5), confirms the position and
      stereochemistry of the methanesulfonyl group at C-4 of the fructofuranosyl ring.

PMID- 12493222
TI  - Synthesis of two isomeric pentasaccharides, the possible repeating unit of the
      beta-glucan from the micro fungus Epicoccum nigrum Ehrenb. ex Schlecht.
AB  - Two isomeric pentasaccharides, beta-D-Glcp-(1-->3)-[beta-D-Glcp-(1-->6)]-beta-D
      Glcp-(1-->3)-[beta-D-Glcp-(1-->6)]-beta-D-Glcp (I) and beta-D-Glcp-(1-->6)-beta-D
      Glcp-(1-->3)-[beta-D-Glcp-(1-->3)-beta-D-Glcp-(1-->6)]-beta-D-Glcp (II), the
      possible repeating unit of the beta-glucan from the micro fungus Epicoccum nigrum
      Ehrenb. ex Schlecht, were synthesized as their 4-methoxyphenyl glycosides in a
      regio- and stereoselective manner. The pentasaccharide I was obtained from 3-O
      selective glycosylation of 4-methoxyphenyl 4,6-O-benzylidene-beta-D
      glucopyranoside (12) with 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranosyl-(1-->3)
      [2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranosyl-(1-->6)]-2,4-di-O-acetyl-alpha-D
      glucopyranosyl trichloroacetimidate (6) followed by acetylation,
      debenzylidenation, and 6-O-selective glucosylation with 2,3,4,6-tetra-O-benzoyl
      beta-D-glucopyranosyl trichloroacetimidate (1), and then by deprotection. The
      pentasaccharide II was obtained from 3-O-selective coupling of 12 with 2,3,4,6
      tetra-O-benzoyl-beta-D-glucopyranosyl-(1-->6)-2,4-di-O-acetyl-3-O-allyl-alpha-D
      glucopyranosyl trichloroacetimidate (10) followed by acetylation,
      debenzylidenation, and 6-O-selective glycosylation with 2,3,4,6-tetra-O-benzoyl
      beta-D-glucopyranosyl-(1-->3)-2,4,6-tri-O-acetyl-alpha-D-glucopyranosyl
      trichloroacetimidate (11), and finally by deprotection.

PMID- 12493223
TI  - Facile preparation of mono-2-O-modified eicosa-O-methylcyclomaltoheptaoses (-beta
      cyclodextrins).
AB  - Mono-2-O-benzylated eicosa-O-methylcyclomaltoheptaose (-beta-cyclodextrin) was
      prepared in one pot from cyclomaltoheptaose (beta-cyclodextrin) in 33% isolated
      yield and quantitatively converted to mono-2-OH-free eicosa-O
      methylcyclomaltoheptaose, which is the key compound for further modification.
      Transformation of this 2-OH group successfully gave several mono-2-O-modified
      eicosa-O-methylcyclomaltoheptaoses such as the acetate, the N,N
      dimethylcarbamate, the N-n-butylcarbamate, the methanesulfonate, and the S
      methyldithiocarbonate.

PMID- 12493224
TI  - Sulfonate protecting groups. Regioselective sulfonylation of myo-inositol
      orthoesters-improved synthesis of precursors of D- and L-myo-inositol 1,3,4,5
      tetrakisphosphate, myo-inositol 1,3,4,5,6-pentakisphosphate and related
      derivatives.
AB  - The regioselectivity of sulfonylation of myo-inositol orthoesters was controlled
      by the use of different bases to obtain the desired sulfonate. Monosulfonylation
      of myo-inositol orthoesters in the presence of one equivalent of sodium hydride
      or triethylamine resulted in the sulfonylation of the 4-hydroxyl group. The use
      of pyridine as a base for the same reaction resulted in sulfonylation of the 2
      hydroxyl group. Disulfonylation of these orthoesters in the presence of excess
      sodium hydride yielded the 4,6-di-O-sulfonylated orthoesters. However, the use of
      triethylamine or pyridine instead of sodium hydride yielded the 2,4-di-O
      sulfonylated orthoester. Sulfonylated derivatives of myo-inositol orthoesters
      were stable to conditions of O-alkylation but were cleaved using
      magnesium/methanol or sodium methoxide in methanol to regenerate the
      corresponding myo-inositol orthoester derivative. These new methods of protection
      deprotection have been used: (i) for the efficient synthesis of enantiomers of
      2,4-di-O-benzyl-myo-inositol, which are precursors for the synthesis of D- and L
      myo-inositol 1,3,4,5-tetrakisphosphate; (ii) for the preparation of 2-O-benzyl
      myo-inositol which is a precursor for the preparation of myo-inositol 1,3,4,5,6
      pentakisphosphate.

PMID- 12493225
TI  - Novel amphiphilic fluoroalkylated derivatives of xylitol, D-glucose and D
      galactose for medical applications: hemocompatibility and co-emulsifying
      properties.
AB  - 1-O-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl)xylitol 6 was synthesized as a
      novel standard compound for the assessment of hemocompatibility and co
      emulsifying properties in microemulsions for biomedical uses. 3-O
      (1,1,2,4,4,5,7,7,8,8,9,9,9-Tridecafluoro-5-trifluoro-methyl-3,6-dioxanonyl)-D
      glucose 9 and 6-O-(1,1,2,4,4,5,7,7,8,8,9,9,9-tridecafluoro-5-trifluoromethyl-3,6
      dioxanonyl)-D-galactose 12 were synthesized by nucleophilic addition of protected
      carbohydrates to perfluorinated vinyl oligoether. Biological tests revealed very
      good hemocompatibility and co-emulsifying properties for the amphiphiles 6, 9 and
      12.

PMID- 12493226
TI  - Synthesis, high-resolution NMR spectroscopic analysis, and single-crystal X-ray
      diffraction of isoxazoline tetracycles.
AB  - Three isoxazoline tetracycles were obtained enantiomerically pure by
      intramolecular 1,3-dipolar cycloaddition. The characterization of the new
      compounds was performed by high-resolution 1H and 13C NMR spectroscopy. The
      relative configuration of the new chiral centers was determined by NOESY
      experiments and confirmed by single-crystal X-ray structural analysis.

PMID- 12493227
TI  - Synthesis of acarbose analogues by transglycosylation reactions of Leuconostoc
      mesenteroides B-512FMC and B-742CB dextransucrases.
AB  - Two new acarbose analogues were synthesized by the reaction of acarbose with
      sucrose and dextransucrases from Leuconostoc mesenteroides B-512FMC and B-742CB.
      The major products for each reaction were subjected to yeast fermentation, and
      then separated and purified by Bio-Gel P2 gel permeation chromatography and
      descending paper chromatography. The structures of the products were determined
      by one- and two-dimensional 1H and 13C NMR spectroscopy and by matrix-assisted
      laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). B
      512FMC-dextransucrase produced one major acarbose product, 2(I)-alpha-D
      glucopyranosylacarbose and B-742CB-dextransucrase produced two major acarbose
      products, 2(I)-alpha-D-glucopyranosylacarbose and 3(IV)-alpha-D
      glucopyranosylacarbose.

PMID- 12493228
TI  - The binding of synthetic analogs of the upstream, terminal residue of the O
      polysaccharides (O-PS) of Vibrio cholerae O:1 serotypes Ogawa and Inaba to two
      murine monoclonal antibodies (MAbs) specific for the Ogawa lipopolysaccharide
      (LPS).
AB  - The binding of nineteen analogues of the upstream, terminal, monosaccharide
      residue of each of the O-polysaccharide (O-PS) of Vibrio cholerae O:1, serotype
      Ogawa and Inaba, with two murine monoclonal IgG antibodies both specific for the
      Ogawa LPS were measured using fluorescence spectroscopy. The use of the deoxy and
      the deoxyfluoro analogs allowed further refinement of the hydrogen-bonding
      pattern involved in the binding. Based on the binding characteristics observed
      for some of the ligands in the Inaba series, the binding of the monosaccharide
      that represents the upstream, terminal unit of the O-PS of V. cholerae O:1
      serotype Inaba was redefined. We show for the first time that the upstream,
      terminal monosaccharide of the Inaba O-PS shows weak binding with these two anti
      Ogawa antibodies. The results obtained allow further rationalization of the
      structural basis for the binding of V. cholerae O:1 antigens to their homologous
      antibodies.

PMID- 12493230
TI  - Preparation and characterisation of chitosans with oligosaccharide branches.
AB  - The trimer 2-acetamido-2-deoxy-D-glucopyranosyl-beta-(1-->4)-2-acetamido-2-deoxy
      D-glucopyranosyl-beta-(1-->4)-2,5-anhydro-D-mannofuranose (A-A-M) was reductively
      N-alkylated onto a fully de-N-acetylated chitosan (F(A)<0.001, DP(n)=25) to
      obtain branched chitosans with degree of substitution (DS) of 0.070, 0.23 and
      0.40, as determined by 1H NMR spectroscopy. The apparent pK(a) values of the
      primary and secondary amines of the chitosans substituted with the trimer A-A-M
      were determined by monitoring the chemical shift of the H-2 of GlcN, and were
      determined as 6.5-6.9 for the primary (unsubstituted) amines and as 5.0-5.2 for
      the secondary (substituted) amines. The intrinsic pK(a) values (pK(int)) were
      found to be 7.3-7.4 for the substituted and 8.7 for the unsubstituted amines. The
      chitosan branched with A-A-M (DS 0.40) was found to be soluble in aqueous
      solution over the entire pH range. SEC-MALLS (size-exclusion chromatography with
      a multi-angle laser light scattering detector) further showed that addition of
      branches did not affect the molar hydrodynamic volume of the chitosan.

PMID- 12493229
TI  - Sulfated and pyruvylated disaccharide alditols obtained from a red seaweed
      galactan: ESIMS and NMR approaches.
AB  - The water-soluble acid agaran isolated from Acanthophora spicifera (Rhodophyta)
      was submitted to alkaline treatment for the complete cyclization of alpha-L-Galp
      6-sulfate to 3,6-An-alpha-L-Galp units. The modified agaran was then partially
      depolymerized using partial reductive hydrolysis. The resulting oligosaccharide
      mixture was fractionated by adsorption and ion-exchange chromatography. Fractions
      were purified by gel-filtration chromatography and studied by ESIMS and NMR
      spectroscopy, including 1D 1H, 13C, DEPT and 2D 1H, 1H COSY, TOCSY and 1H, 13C
      HMQC procedures. The following neutral, pyruvylated, sulfated and
      sulfated/pyruvylated disaccharide alditols were obtained: beta-D-Galp-(1-->4)-3,6
      An-L-GalOH; 4,6-O-(1-carboxyethylidene)-beta-D-Galp-(1-->4)-3,6-An-L-GalOH; beta
      D-Galp 2-sulfate-(1-->4)-3,6-An-L-GalOH and 4,6-O-(1-carboxyethylidene)-beta-D
      Galp 2-sulfate-(1-->4)-3,6-An-L-GalOH.

PMID- 12493232
TI  - Extracellular polysaccharides of Erwinia futululu, a bacterium associated with a
      fungal canker disease of Eucalyptus spp.
AB  - Extracellular polysaccharides (EPSs) produced by an Erwinia spp. associated with
      a fungal canker disease of Eucalyptus were fractionated into two polysaccharides,
      one that was identified with that produced by Erwinia stewartii. The other has a
      similar structure, but with one terminal Glc residue replaced by pyruvic acid to
      give 4,6-O-[(R)-1-carboxyethylidene)-Galp. Their structures were determined using
      a combination of chemical and physical techniques including methylation analysis,
      periodate oxidation, low-pressure gel filtration and anion-exchange
      chromatographies, high-pH anion-exchange chromatography, mass spectrometry and 1D
      and 2D 1H NMR spectroscopy. The new polysaccharides, identified as EPS Futululu
      FF-1 and FF-2, have the following structures:The molecular weights of the
      polysaccharides range from 1.3-2.1x10(6) and their hydrodynamic properties are
      those of polydisperse, polyanionic biopolymers with pseudoplastic, non
      thixotropic flow characteristics in aqueous solutions.

PMID- 12493231
TI  - Structure of the O-specific polysaccharide of Proteus vulgaris O15 containing a
      novel regioisomer of N-acetylmuramic acid, 2-acetamido-4-O-[(R)-1-carboxyethyl]-2
      deoxy-D-glucose.
AB  - An acidic O-specific polysaccharide was obtained by mild acid degradation of the
      lipopolysaccharide of Proteus vulgaris O15 and studied by sugar and methylation
      analyses along with 1H and 13C NMR spectroscopy, including 2D COSY, TOCSY, ROESY,
      and H-detected 1H,(13)C HMQC experiments. The polysaccharide was found to contain
      an ether of GlcNAc with lactic acid, and the following structure of the repeating
      unit was established:-->3)-alpha-D-GlcpNAc4(R-Lac)6Ac-(1-->2)-beta-D-GlcpA-(1-
      >3)-alpha-L-6dTalp2Ac-(1-->3)-beta-D-GlcpNAc-(1-->where L-6dTal and D-GlcNAc4(R
      Lac) are 6-deoxy-L-talose and 2-acetamido-4-O-[(R)-1-carboxyethyl]-2-deoxy-D
      glucose, respectively. The latter sugar, which to our knowledge has not been
      hitherto found in nature, was isolated from the polysaccharide by solvolysis with
      anhydrous triflic acid and identified by comparison with the authentic synthetic
      compound. Serological studies with the Smith-degraded polysaccharide showed an
      importance of 2-substituted GlcA for manifesting of the immunospecificity of P.
      vulgaris O15.

PMID- 12493233
TI  - High-performance liquid chromatographic separation and on-line mass spectrometric
      detection of saturated and unsaturated oligogalacturonic acids.
AB  - A method for the simultaneous determination of saturated and unsaturated
      oligogalacturonic acids up to degree of polymerization (dp) of 7 by high
      performance liquid chromatography (HPLC) is presented. For this purpose, a
      Cyclobond I 2000 column and a volatile mobile phase consisting of ammonium
      formate and methanol were used, allowing direct coupling of HPLC to a mass
      spectrometer via an electrospray interface (ESI-MS) without additional desalting.
      The analytical system was used for the characterization of digests obtained by
      incubation of polygalacturonic acid with commercial enzyme preparations.

PMID- 12493234
TI  - Crystal structure of beta-cyclodextrin-dimethylsulfoxide inclusion complex.
AB  - beta-Cyclodextrin (beta-CD) crystallizes from 27% DMSO-water as beta
      CD.0.5DMSO.7.35H(2)O in the monoclinic space group P2(1) with unit cell
      constants: a=15.155(1), b=10.285(1), c=20.906(1) A, beta=109.86(1) degrees.
      Anisotropic refinement of 888 atomic parameters against 9,127 X-ray diffraction
      data converged at an R-factor of 0.055. The beta-CD macrocycle adopts a 'round'
      conformation stabilized by intramolecular, interglucose O-3(n) triplebond O
      2(n+1) hydrogen bonds. In the beta-CD cavity, DMSO, water sites W-1, W-3
      (occupancies 0.5, 0.25, 0.75) are not located concurrently with the water site W
      2 because the interatomic distances to W-2 are too short (1.56-1.75 A). DMSO is
      placed in the beta-CD cavity such that its S-atom is shifted from the O-4 plane
      center to the beta-CD O-6-side ca. 0.9 A and the C-S bond which is inclined 13.6
      degrees to the beta-CD molecular axis. It is maintained in position by hydrogen
      bonding to water site W-3 and the O-31-H group. 7.35 water molecules are
      extensively disordered in 13 positions both inside (W-1-W-4) and outside (W-5-W
      13) the beta-CD cavity. They act as hydrogen bonding mediators contributing
      significantly to the stability of the crystal structure.

PMID- 12493235
TI  - Preparation and investigation of antibacterial carbohydrate-based surfaces.
AB  - Surfaces bearing carbohydrate units have been modified in a two-step process to
      incorporate functionalities (lipophilic with polycationic units) that bear
      antibacterial activity. The effectiveness of these modified surfaces for
      antibacterial action against a series of seven Gram-positive and Gram-negative
      bacteria are reported.

PMID- 12493236
TI  - Inclusion of carvone enantiomers in cyclomaltoheptaose (beta-cyclodextrin):
      thermal behaviour and H-->D and D-->H exchange.
AB  - The inclusion compounds of carvone enantiomers in cylcomaltoheptaose (beta
      cyclodextrin, betaCD) are studied at defined temperatures above room temperature
      and in relation to H-->D and D-->H exchanges. Loss of water molecules and release
      of carvone molecules from the betaCD cavity are caused by increase of temperature
      above room temperature and are measured by the integrated intensities of the O-H
      and C-H Raman stretching bands, respectively. In turn, H-->D and D-->H exchanges
      are monitored by the integrated intensities of the O-H and O-D Raman stretching
      bands, respectively. All of these processes were followed in real time with a
      Raman spectrometer equipped with CCD detection. The results indicate that
      distinct carvone enantiomers lead to the formation of different betaCD inclusion
      hydrates that have different water content and hydration structures. In
      particular, the results suggest that SCarv-betaCD has a greater water content,
      dehydrates strongly for temperatures above room temperature, and exchanges
      protons faster than the RCarv-betaCD complex.

PMID- 12493237
TI  - Structure of the oligomers obtained by enzymatic hydrolysis of the glucomannan
      produced by the plant Amorphophallus konjac.
AB  - Dimers and trimers obtained by enzymatic hydrolysis of the glucomannan produced
      by the plant Amorphophallus konjac were analysed in order to obtain information
      on the saccharidic sequences present in the polymer. The polysaccharide was
      digested with cellulase and beta-mannanase and the oligomers produced were
      isolated by means of size-exclusion chromatography. They were structurally
      characterised using electrospray mass spectrometry, capillary electrophoresis,
      and NMR. The investigation revealed that many possible sequences were present in
      the polymer backbone suggesting a Bernoulli-type chain.

PMID- 12493240
TI  - Vertebrate evolution: doubling and shuffling with a full deck.
AB  - The number and role of whole-genome duplications in vertebrate evolution has
      intrigued evolutionary biologists since Ohno first proposed genome duplication as
      the force driving the 'big leap' in vertebrate morphological innovation. Attempts
      to resolve these issues have been thwarted by small and noisy datasets, and by
      lack of computational accuracy and statistical rigor. Recently, Ken Wolfe and
      colleagues presented a genome-scale, statistically rigorous analysis of evidence
      based on the spatial organization of duplicated genes, as well as estimates of
      duplication times. Their results provide the strongest evidence to date of large
      scale duplication throughout the vertebrate genome, consistent with at least one
      whole-genome duplication.

PMID- 12493241
TI  - The genes of the Green Revolution.
AB  - The spectacular increases in wheat and rice yields during the 'Green Revolution',
      were enabled by the introduction of dwarfing traits into the plants. Now,
      identification of the genes responsible for these traits shows that they
      interfere with the action or production of the gibberellin (GA) plant hormones.
      We knew that the wheat Rht genes encode growth repressors that are normally
      suppressed by GA, and recent work shows that the rice sd1 gene encodes a
      defective enzyme in the GA-biosynthetic pathway.

PMID- 12493242
TI  - Mammalian RNAi for the masses.
AB  - Just a couple of years ago, only biologists working with plants or Caenorhabditis
      elegans could use RNA-mediated interference (RNAi) technology to gain insight
      into gene function. However, the recent groundbreaking discovery that in vitro
      synthesized, 21- to 23-nucleotide, double-stranded RNAs can act as small
      interfering RNAs (siRNAs) to elicit gene-specific inhibition in mammalian cells
      has made RNAi possible in mammalian systems too. Reported only a year ago,
      mammalian RNAi is already changing our way of studying gene function in higher
      eukaryotes. And, a recent exciting advance allows delivery of siRNAs into
      mammalian cells by a DNA vector. In addition to providing a low-cost alternative
      to the chemically synthesized siRNAs, this DNA-vector-based strategy is capable
      of mediating stable target gene inhibition, thus allowing gene function analysis
      over an extended period of time.

PMID- 12493243
TI  - Macro effects of microRNAs in plants.
AB  - MicroRNAs (miRNAs) are 20- to 22-nucleotide fragments that regulate expression of
      mRNAs that have complementary sequences. They are numerous and widespread among
      eukaryotes, being conserved throughout evolution. The few miRNAs that have been
      fully characterized were found in Caenorhabditis elegans and are required for
      development. Recently, a study of miRNAs isolated from Arabidopsis showed that
      here also developmental genes are putative regulatory targets. A role for miRNAs
      have in plant development is supported by the developmental phenotypes of
      mutations in the genes required for miRNA processing.

PMID- 12493244
TI  - H19 and Igf2--enhancing the confusion?
AB  - Genomic imprinting, whereby certain genes are expressed dependent on whether they
      are maternally or paternally inherited, is restricted to mammals and angiosperm
      plants. This unusual mode of gene regulation results from the complex interplay
      between cis-regulatory elements, leading to parent-of-origin-dependent epigenetic
      modifications and tissue-specific patterns of imprinted gene expression. Many
      studies of imprinting and imprinted genes have focused on epigenetic effects,
      such as DNA methylation and chromatin structure. However, it is equally important
      to explore the interconnected role of regulatory elements at imprinted domains by
      genetic experiments, including the use of transgenes and deletions.

PMID- 12493245
TI  - Wild mice: an ever-increasing contribution to a popular mammalian model.
AB  - Classical laboratory inbred strains of mice have been extremely helpful for
      research in immunology and oncology, and more generally, for the analysis of
      complex traits. Unfortunately, because they all derive from a relatively small
      pool of ancestors, their genetic polymorphism is rather limited. However,
      recently strains belonging to different species of Mus have been established from
      wild progenitors. These are an interesting addition to the arsenal of mouse
      geneticists, because they can be crossed with classical laboratory strains to
      produce viable and fertile offspring with a large number of polymorphisms of
      natural origin. These strains are helpful for making genome annotations because
      they permit highly refined genotype-phenotype correlations. They also allow the
      interpretation of molecular variation within a clear evolutionary framework. In
      this article, we provide examples with the aim of promoting the use of these new
      strains.

PMID- 12493246
TI  - Hitchhiking mapping--functional genomics from the population genetics
      perspective.
AB  - Several statistical tests based on population genetic theory are used to identify
      genes that have recently acquired a beneficial mutation. Here, I describe the
      extension of these tests to a multilocus approach for a genome-wide survey for
      genes that have been under recent positive selection. As this strategy could
      potentially identify genes with weak phenotypic effects, it will be very useful
      in population genetic approaches aimed at understanding adaptation processes in
      natural populations. Furthermore, this 'hitchhiking mapping' could also help in
      the functional characterization of genomes.

PMID- 12493247
TI  - RNA interference: traveling in the cell and gaining functions?
AB  - Double-stranded RNA can induce the degradation of homologous RNAs in organisms as
      diverse as protozoa, animals, plants and fungi, resulting in post-transcriptional
      gene silencing. But in some species, RNA-mediated processes can also lead to
      translational repression, DNA methylation, heterochromatin formation or DNA
      elimination. In some situations, amplification of the 'trigger' double-stranded
      RNA seems to be required for efficient silencing. These findings imply that RNA
      mediated mechanisms can control gene expression at both the transcriptional and
      the post-transcriptional level, and that they can operate in the nuclear and the
      cytoplasmic compartments.

PMID- 12493249
TI  - Who is responsible for the care of refugees?

PMID- 12493248
TI  - Chloroplast research in the genomic age.
AB  - Chloroplast research takes significant advantage of genomics and genome
      sequencing, and a new picture is emerging of how the chloroplast functions and
      communicates with other cellular compartments. In terms of evolution, it is now
      known that only a fraction of the many proteins of cyanobacterial origin were
      rerouted to higher plant plastids. Reverse genetics and novel mutant screens are
      providing a growing catalogue of chloroplast protein-function relationships, and
      the characterization of plastid-to-nucleus signalling mutants reveals cell
      organelle interactions. Recent advances in transcriptomics and proteomics of the
      chloroplast make this organelle one of the best understood of all plant cell
      compartments.

PMID- 12493250
TI  - The P2X7 receptor of CLL lymphocytes-a molecule with a split personality.

PMID- 12493251
TI  - Thyroid-hormone suppressive therapy in benign thyroid nodules--is it effective?

PMID- 12493252
TI  - Foundation hospitals.

PMID- 12493253
TI  - Resilience or panic? The public and terrorist attack.

PMID- 12493254
TI  - Cholera and climate--the evidence grows.

PMID- 12493255
TI  - Age-specific relevance of usual blood pressure to vascular mortality: a meta
      analysis of individual data for one million adults in 61 prospective studies.
AB  - BACKGROUND: The age-specific relevance of blood pressure to cause-specific
      mortality is best assessed by collaborative meta-analysis of individual
      participant data from the separate prospective studies. METHODS: Information was
      obtained on each of one million adults with no previous vascular disease recorded
      at baseline in 61 prospective observational studies of blood pressure and
      mortality. During 12.7 million person-years at risk, there were about 56000
      vascular deaths (12000 stroke, 34000 ischaemic heart disease [IHD], 10000 other
      vascular) and 66000 other deaths at ages 40-89 years. Meta-analyses, involving
      "time-dependent" correction for regression dilution, related mortality during
      each decade of age at death to the estimated usual blood pressure at the start of
      that decade. FINDINGS: Within each decade of age at death, the proportional
      difference in the risk of vascular death associated with a given absolute
      difference in usual blood pressure is about the same down to at least 115 mm Hg
      usual systolic blood pressure (SBP) and 75 mm Hg usual diastolic blood pressure
      (DBP), below which there is little evidence. At ages 40-69 years, each difference
      of 20 mm Hg usual SBP (or, approximately equivalently, 10 mm Hg usual DBP) is
      associated with more than a twofold difference in the stroke death rate, and with
      twofold differences in the death rates from IHD and from other vascular causes.
      All of these proportional differences in vascular mortality are about half as
      extreme at ages 80-89 years as at ages 40-49 years, but the annual absolute
      differences in risk are greater in old age. The age-specific associations are
      similar for men and women, and for cerebral haemorrhage and cerebral ischaemia.
      For predicting vascular mortality from a single blood pressure measurement, the
      average of SBP and DBP is slightly more informative than either alone, and pulse
      pressure is much less informative. INTERPRETATION: Throughout middle and old age,
      usual blood pressure is strongly and directly related to vascular (and overall)
      mortality, without any evidence of a threshold down to at least 115/75 mm Hg.

PMID- 12493256
TI  - Brugada syndrome.

PMID- 12493257
TI  - Diagnostic strategy for patients with suspected pulmonary embolism: a prospective
      multicentre outcome study.
AB  - BACKGROUND: We designed a prospective multicentre outcome study to evaluate a
      diagnostic strategy based on clinical probability, spiral CT, and venous
      compression ultrasonography of the legs in patients with suspected pulmonary
      embolism (PE). The main aim was to assess the safety of withholding anticoagulant
      treatment in patients with low or intermediate clinical probability of PE and
      negative findings on spiral CT and ultrasonography. METHODS: 1041 consecutive
      inpatients and outpatients with suspected PE were included. Patients with
      negative spiral CT and ultrasonography and clinically assessed as having a low or
      intermediate clinical probability were left untreated. Those with high clinical
      probability underwent lung scanning, pulmonary angiography, or both. All patients
      were followed up for 3 months. FINDINGS: PE was diagnosed in 360 (34.6%)
      patients; 55 had positive ultrasonography despite negative spiral CT. Of 601
      patients with negative spiral CT and ultrasonography, 76 were clinically assessed
      as having a high probability of PE; lung scanning or angiography showed PE in
      four (5.3% [95% CI 1.5-13.1]). The remaining 525 patients were assessed as having
      low or intermediate clinical probability, and 507 of them were not treated. Of
      these patients, nine experienced venous thromboembolism during follow-up (1.8%
      [0.8-3.3]). The diagnostic strategy proved inconclusive in 95 (9.1%) patients,
      and pulmonary angiography was done in 74 (7.1%). INTERPRETATION: Withholding of
      anticoagulant therapy is safe when the clinical probability of PE is assessed as
      low or intermediate and spiral CT and ultrasonography are negative.

PMID- 12493258
TI  - HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter
      Cohort Study (MACS).
AB  - BACKGROUND: Although coinfection with HIV-1 and hepatitis B virus (HBV) is
      common, few long-term studies on liver-disease mortality in coinfected people
      have been undertaken. Our aim was to examine liver-related mortality among people
      at risk for HIV-1 and HBV infections. METHODS: We used data from a multicentre,
      prospective cohort study to classify 5293 men who had sex with men, according to
      their HIV-1 antibody status, ascertained semiannually, and their hepatitis-B
      surface antigen status (HBsAg), which we ascertained at baseline. Mortality rates
      were estimated in terms of person-years and Poisson regression methods were used
      to test for significance of relative risks. FINDINGS: 326 (6%) men were HBsAg
      positive, of whom 213 (65%) were HIV-1 positive. Of the 4967 HBsAg negative men,
      2346 (47%) were infected with HIV-1. The liver-related mortality rate was
      1.1/1000 person years, and was higher in men with HIV-1 and HBsAg (14.2/1000)
      than in those with only HIV-1 infection (1.7/1000, p<0.001) or only HBsAg
      (0.8/1000, p<0.001). In coinfected individuals, the liver-related mortality rate
      was highest with lower nadir CD4+ cell counts and was twice as high after 1996,
      when highly active antiretroviral therapy (HAART) was introduced. INTERPRETATION:
      Individuals coinfected with HIV-1 and HBV, especially those with low CD4+ nadir
      counts, are at increased risk for liver-related mortality, underscoring the
      importance of prevention, identification, and comprehensive management of
      hepatitis B in people infected with HIV-1.

PMID- 12493259
TI  - Health programmes and policies associated with decreased mortality in displaced
      people in postemergency phase camps: a retrospective study.
AB  - BACKGROUND: An estimated 35 million people have been displaced by complex
      humanitarian emergencies. International humanitarian organisations define
      policies and provide basic health and nutrition programmes to displaced people in
      postemergency phase camps. However, many policies and programmes are not based on
      supporting data. We aimed to identify associations between age-specific mortality
      and health indicators in displaced people in postemergency phase camps and to
      define the programme and policy implications of these data. METHODS: In 1998
      2000, we obtained and analysed retrospective mortality data for the previous 3
      months in 51 postemergency phase camps in seven countries. We did multivariate
      regression with 18 independent variables that affect crude mortality rates (CMRs)
      and mortality rates in children younger than 5 years (<5 MRs) in complex
      emergencies. We compared these results with recommended emergency phase minimum
      indicators. FINDINGS: Recently established camps had higher CMRs and <5 MRs and
      fewer local health workers per person than did camps that had been established
      earlier. Camps that were close to the border or region of conflict or had longer
      travel times to referral hospitals had higher CMRs than did those located further
      away or with shorter travel times, and camps with less water per person and high
      rates of diarrhoea had higher <5 MRs than did those with more water and lower
      rates of diarrhoea. Distance to border or area of conflict, water quantity, and
      the number of local health workers per person exceeded the minimum indicators
      recommended in the emergency phase. INTERPRETATION: Health and nutrition policies
      and programmes for displaced people in postemergency phase camps should be
      evidence-based. Programmes in complex emergencies should focus on indicators
      proven to be associated with mortality. Minimum indicators should be developed
      for programmes targeting displaced people in postemergency phase camps.

PMID- 12493260
TI  - Conjoined spinal cords in pygopagus twins.

PMID- 12493261
TI  - Polymorphism in the P2X7 receptor gene and survival in chronic lymphocytic
      leukaemia.
AB  - BACKGROUND: The P2X7 receptor is a ligand-gated cation channel that mediates ATP
      induced apoptotic death in haemopoietic and chronic lymphocytic leukaemia (CLL)
      cells. We aimed to investigate the clinical effect of a single nucleotide
      polymorphism in the P2X7 receptor gene (1513A-->C) and correlate findings with
      the immunoglobulin heavy chain variable (V(H)) gene mutation status, a prognostic
      marker in CLL. METHODS: We investigated tumour DNA in 170 patients with CLL using
      PCR-RFLP analysis with HhaI restriction enzyme cleavage to screen for the
      polymorphism in the P2X7 receptor gene. The VH gene mutation status was assessed
      in 165 patients by PCR amplification and nucleotide sequencing. We correlated the
      findings of the P2X7 receptor genotype with the V(H) gene mutation data and
      overall survival and screened for the P2X7 receptor polymorphism in 200 healthy
      controls. FINDINGS: Of the 170 patients, 35 (21%) were heterozygous and one (1%)
      homozygous for the 1513C allele; whereas 134 (79%) had the 1513A/A genotype of
      the P2X7 receptor gene. Overall survival was significantly longer for patients
      with CLL heterozygous for the 1513C allele than those with the 1513A/A genotype.
      Median survival for heterozygous patients was 104 months (range 33-467) and 72
      months (1-190) for homozygous patients (p=0.009). Of the 165 patients with CLL in
      whom we assessed the V(H) gene mutation status, the V(H) genes were mutated in 71
      (43%) patients and unmutated in 94; 18 (25%) of the 71 patients with mutated
      genes had 1513C allele compared with 17 (18%) of 94 who had unmutated genes. In
      patients with mutated VH genes, those with CLL who were 1513C positive had 53
      months' longer median survival than did those with the 1513A/A genotype (151 vs
      98 months, p=0.011). INTERPRETATION: The P2X7 polymorphism could affect clinical
      outcome in CLL, especially in patients with mutated V(H) genes. Studies are
      necessary to elucidate the biological role of the P2X7 polymorphism in CLL in
      vivo.

PMID- 12493262
TI  - Chronic facial crusts.

PMID- 12493263
TI  - Fosmidomycin for malaria.
AB  - Safe and effective antimalarial drugs with new methods of action are urgently
      needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium
      falciparum, and suppresses the growth of multidrug-resistant strains in vitro.
      Our aim was to assess the efficacy and tolerability of fosmidomycin in adults
      with malaria in Gabon. We administered the drug for 5, 4, or 3 days (1.2 g every
      8 h), in nine, eight, and ten evaluable patients, respectively. All treatment
      regimens were well tolerated. Cure rates by day 14 were 89% (eight of nine), 88%
      (seven of eight), and 60% (six of ten), for treatment durations of 5, 4, and 3
      days, respectively. These data suggest that fosmidomycin is a safe and effective
      treatment for uncomplicated malaria if given for 4 days or more.

PMID- 12493265
TI  - Europe moves to loosen restriction on GM foods.

PMID- 12493264
TI  - Risk factors for recurrence of primary sclerosing cholangitis of liver allograft.
AB  - Primary sclerosing cholangitis (PSC) is a disease of unknown cause that effects
      the biliary tree and is closely associated with inflammatory bowel disease. We
      did a retrospective analysis of the risk factors associated with recurrence of
      PSC in an allograft after liver transplantation. Recurrence of disease, assessed
      by liver histology or imaging the biliary tree, occurred in 56 of 152 patients
      (37%) at a median of 36 months (range 1.4-120 months). Multivariate analysis
      showed that being male (relative risk 1.2, 95% CI 0.73-2.15) and an intact colon
      before transplantation (8.7, 1.19-64.48) were associated with recurrence. These
      observations could help elucidate the pathogenesis of the disease.

PMID- 12493270
TI  - India sees parallel rise in malnutrition and obesity.

PMID- 12493271
TI  - A fresh look at UK health inequalities.

PMID- 12493272
TI  - Hong Kong experts help tackle mainland China's growing HIV/AIDS problem.

PMID- 12493273
TI  - Poverty linked to access to water, says new water league table.

PMID- 12493274
TI  - US government report released on deceptive drug advertisements.

PMID- 12493275
TI  - No agreement reached in talks on access to cheap drugs.

PMID- 12493276
TI  - Ethiopia openly appeals for help with looming famine.

PMID- 12493277
TI  - Management of acute optic neuritis.
AB  - Optic neuritis is a common condition that causes reversible loss of vision. It
      can be clinically isolated or can arise as one of the manifestations of multiple
      sclerosis. Occasional cases are due to other causes, and in these instances
      management can differ radically. The treatment of optic neuritis has been
      investigated in several trials, the results of which have shown that
      corticosteroids speed up the recovery of vision without affecting the final
      visual outcome. Other aspects of management, however, are controversial, and
      there is uncertainty about when to investigate and when to treat the condition.
      Here we review the diagnostic features of optic neuritis, its differential
      diagnosis, and give practical guidance about management of patients. The
      condition's association with multiple sclerosis will be considered in the light
      of studies that define the risk for development of multiple sclerosis and with
      respect to results of trials of disease-modifying drugs in these individuals.

PMID- 12493278
TI  - Mild cognitive impairment in older people.
AB  - CONTEXT: As public awareness of Alzheimer's disease increases, more people are
      asking for help and advice about memory problems. Memory complaints may be
      secondary to psychiatric, psychological, and physical conditions and is an almost
      universal early symptom of dementia. The concept of amnestic mild cognitive
      impairment attempts to describe those people in whom memory loss is not of such
      severity to merit a diagnosis of dementia. The importance of this group of people
      is not just the need to develop interventions which ameliorate individual
      suffering but that they represent a population at high risk of developing
      dementia, especially Alzheimer's disease, and are an appropriate target for
      dementia prevention strategies. STARTING POINT: K Kantarci and colleagues (Dement
      Geriatr Cogn Disord 2002; 14: 198-207) looked at the diagnostic accuracy of
      magnetic-resonance hippocampal volumetry and spectroscopy in patients with mild
      cognitive impairment, in normal older people, and in patients with Alzheimer's
      disease. Hippocampal volumes and N-acetyl aspartate/creatine spectroscopy were
      the most sensitive assessments discriminating people with mild cognitive
      impairment from Alzheimer's disease. Combination assessments were better at
      discriminating these two groups from normal controls. The histological
      underpinning of cognitive symptoms in older people has been demonstrated by the
      Cognitive Function and Ageing study (Lancet 2001; 357: 169-75), which showed that
      a third of people with no clinical evidence of dementia had histopathological
      hallmarks of Alzheimer's disease. WHERE NEXT? 25 million people across the world
      have dementia. Mild cognitive impairment, if a validated concept, represents an
      opportunity for preventing dementia. As more information becomes available about
      the cause of Alzheimer's disease and prospects emerge for prevention,
      identification of predementia states offers considerable scope to reduce the
      individual and societal cost of the illness. Continued validation of the criteria
      for mild cognitive impairment and studies of intervention should be a priority.
      As more evidence becomes available highlighting the relatively arbitrary nature
      of dementia diagnosis (based largely on interference with activities) and
      interventions become available for the prevention of dementia, mild cognitive
      impairment and related conditions will become more important.

PMID- 12493279
TI  - Prophylaxis against Pneumocystis carinii pneumonia for HIV-exposed infants in
      Africa.

PMID- 12493280
TI  - Effects of corticosteroid use on treatment of solid tumours.

PMID- 12493281
TI  - Keeping scientific advice non-partisan.

PMID- 12493282
TI  - The RITA 3 trial.

PMID- 12493283
TI  - The RITA 3 trial.

PMID- 12493284
TI  - The RITA 3 trial.

PMID- 12493285
TI  - The RITA 3 trial.

PMID- 12493286
TI  - The RITA 3 trial.

PMID- 12493288
TI  - The RITA 3 trial.

PMID- 12493289
TI  - Mother-to-child transmission of HIV-1 infection.

PMID- 12493290
TI  - Stress and burnout in doctors.

PMID- 12493292
TI  - Performance-based partnership agreements in Afghanistan.

PMID- 12493293
TI  - Antibody response to Staphylococcal slime and lipoteichoic acid.

PMID- 12493294
TI  - Antibody response to Staphylococcal slime and lipoteichoic acid.

PMID- 12493295
TI  - Goosebumps and the insula.

PMID- 12493296
TI  - Glucose homoeostasis in young adults without diagnosis of diabetes mellitus.

PMID- 12493297
TI  - Glucose homoeostatis in young adults without diagnosis of diabetes mellitus.

PMID- 12493298
TI  - Nicorandil-associated anal ulceration.

PMID- 12493299
TI  - Tobacco money: up in smoke?

PMID- 12493300
TI  - Tobacco money: up in smoke?

PMID- 12493301
TI  - Tobacco money: up in smoke?

PMID- 12493303
TI  - 1873 Kussmaul citation.

PMID- 12493304
TI  - Appropriateness of Singapore's HIV/AIDS control programme.

PMID- 12493306
TI  - Antitoxin approach to malaria.

PMID- 12493307
TI  - Pulmonary tumour embolism.

PMID- 12493308
TI  - Fire-and-forget in prevention of coronary heart disease.

PMID- 12493310
TI  - Death during surgery in Japan.

PMID- 12493311
TI  - Safety and usefulness of autologous cryopreserved platelets.

PMID- 12493312
TI  - Safety and usefulness of autologous cryopreserved platelets.

PMID- 12493314
TI  - Intercountry adoption, climate, and psychiatric disorders.

PMID- 12493315
TI  - Androgen suppression and irradiation for locally advanced prostate cancer.

PMID- 12493316
TI  - Androgen suppression and irradiation for locally advanced prostate cancer.

PMID- 12493318
TI  - Disarming Africa.

PMID- 12493319
TI  - Radiotherapy in soft-tissue sarcoma.

PMID- 12493321
TI  - Neonatal resuscitation for small for gestational age babies.

PMID- 12493322
TI  - Radiotherapy in soft-tissue sarcoma.

PMID- 12493323
TI  - Off-pump coronary artery bypass grafting in low-risk patients.

PMID- 12493324
TI  - Divine intervention.

PMID- 12493333
TI  - Inhaled corticosteroids (budesonide): the cornerstone of asthma therapy--what are
      the options?
AB  - The clinical value of corticosteroids in treating asthma has long been
      recognised. Major advances in the use of these drugs came with the introduction
      of inhaled corticosteroids (ICS) and the recognition that even mild asthma has an
      inflammatory component. ICS are now considered as first-line therapy in all
      asthma treatment guidelines. Over the past decade there has been clarification of
      the dose-response relationship with ICS and confirmation of the general long-term
      efficacy and safety of these drugs in both adults and children. Recent work has
      focused on simplifying dosing regimens and investigating flexibility of dosing.
      Moreover, ICS can be used in combination with other agents such as long-acting
      inhaled beta(2)-agonists to provide effective asthma control in patients with
      persistent asthma not adequately controlled on ICS alone. Thus, ICS remain the
      cornerstone of modern asthma therapy.

PMID- 12493334
TI  - Managing a variable disease.
AB  - Asthma varies in severity over time; consequently, treatment regimens must be
      sufficiently flexible to be adjusted when necessary. At present, inhaled
      corticosteroids (ICS) remain the cornerstone of asthma therapy and optimal
      treatment strategies must consider total daily dose and dosing frequency. The
      dose responsiveness to ICS varies for different indices of asthma. Symptoms and
      lung function respond readily to low-dose ICS and the dose-response curve is
      relatively flat. In contrast, the prevention of asthma exacerbations displays a
      more pronounced dose-response relationship. In mild asthma, once-daily dosing
      with budesonide is as effective as twice-daily dosing. However, in moderate-to
      severe asthma, four-times daily dosing is better than twice-daily dosing for
      obtaining maximal benefit with minimal side effects. A flexible treatment
      regimen, consisting of low-dose maintenance treatment combined with high dose and
      frequently dosed ICS at the earliest sign of an exacerbation, has been shown to
      be effective. This could be achieved using a single inhaler combination product
      if the beta(2)-agonist moiety allows for the same flexibility in dosing.
      Formoterol, with its wide dose range, rapid onset and long duration of effect,
      has the pharmacological features that permit this versatile, flexible dosing. As
      a result, Symbicort would seem to offer the flexibility required in a single
      inhaler for maintenance and reliever purposes in the management of this variable
      disease.

PMID- 12493335
TI  - Living with a variable disease.
AB  - Asthma is a variable disease which, when not fully controlled, may leave the
      patient with a sense of bewilderment, fear, anger and a loss of many 'normal'
      activities of daily living. The reasons for these fears range from the concern of
      having an asthma attack to concerns about taking medications, perhaps especially
      steroids. Complex treatment regimens and a lack of understanding by the patient
      of their asthma may lead to denial and a reduction in adherence to medication
      resulting in poor treatment outcomes. Patients' lack of understanding may
      originate from poor communication between patient and physician. Improved
      communication and ensuring that all of the patient's questions are answered, as
      well as simpler treatment regimens may improve asthma control. Detailed, written
      personal asthma action plans should act as a foundation for building good
      relationships between doctor and patient and enhance adherence. Simplifying
      treatment regimens, such as having an inhaled corticosteroid and a long-acting,
      beta(2)-agonist in a single inhaler, used in conjunction with these personal
      asthma action plans, should provide a therapy that enables patients to be in
      control of their asthma without having to live in fear of their illness.

PMID- 12493336
TI  - The long and short of beta2-agonists.
AB  - For patients whose asthma is not adequately controlled with inhaled
      corticosteroid (ICS) therapy alone, increasing the dose of ICS or the addition of
      a long-acting beta(2)-agonist is recommended. Greater improvements in lung
      function are achieved with the addition of a long-acting beta(2)-agonist to ICS
      therapy, rather than doubling the dose of ICS. Formoterol and salmeterol have a
      similarly long duration of effect (up to 12 h). However, as a result of their
      different chemical structures, there are marked pharmacological differences in
      the mechanism of action which affect their speeds of onset. These differences
      amount to a more rapid onset of effect for formoterol compared with salmeterol.
      Long-acting beta(2)-agonists appear to be well tolerated at elevated doses. These
      two features (tolerability at high doses and rapid onset of effect) support the
      use of formoterol as a reliever medication in addition to use in maintenance
      therapy. The long-acting beta(2)-agonists can be considered as beneficial
      additions to ICS therapy for the management of moderate-to-severe asthma.

PMID- 12493337
TI  - Innervation of equine airways.
AB  - Equine obstructive pulmonary disease (COPD), or heaves or recurrent airway
      obstruction, is a common equine pulmonary disease similar to human asthma and/or
      CODP. Since bronchospasm and inflammation are the key features in heaves, the
      purpose of this paper is to review the contribution of neural mechanism that may
      be relevant to this disease. Equine airway receive cholinergic and adrenergic
      innervation, as well as observed in many species. It was suggested that the
      autonomic neural control in asthma might be defective with an imbalance between
      excitatory and inhibitory pathways, resulting in excessively twitchy airways.
      Moreover, the recognition that, in addition to classical adrenergic and
      cholinergic pathway there are non-adrenergic-non-cholinergic inhibitory (iNANC)
      and excitatory (eNANC) innervation and many mediators, which have potent effects
      on airway function, has revived interest in neural control of airway.

PMID- 12493338
TI  - A widely available method for the assessment of aerosol delivery in cystic
      fibrosis.
AB  - Whilst nebulisers are commonly used in the treatment of cystic fibrosis (CF),
      nebulised aerosol lung deposition in individual patients is not routinely
      assessed in clinical practice. The present study was designed to evaluate whether
      a comparative measurement of aerosol lung deposition from nebulisers using a
      widely available scintigraphic method could be employed to assist the selection
      of the best system for individual patients. Lung deposition of the radiolabelled
      aerosol from the Pari LC Plus (Pari Medical Ltd) nebuliser and the HaloLite
      Adaptive Aerosol Delivery (AAD) system (Profile Therapeutics Ltd) was measured
      using planar scintigraphy in 10 healthy volunteers and 6 CF patients. The
      HaloLite AAD delivered on average 2.1 times (P=0.003) as much aerosol to the
      lungs compared with Pari LC Plus. Only two subjects had higher lung deposition
      from Pari LC Plus than HaloLite AAD system. There was marked inter-individual
      variation in the deposition pattern in CF patients. The aerosol deposition from
      HaloLite AAD had higher central distribution than that obtained with the Pari LC
      Plus. The overall intersubject variability of the delivered dose was 56% with
      Pari LC Plus and 24% with HaloLite AAD (P<0.05). The measurement of aerosol
      deposition from nebulisers can be performed using a simple and widely available
      methodology, and may improve nebuliser selection in CF patients.

PMID- 12493340
TI  - Chemical analysis of freshly prepared and stored capsaicin solutions:
      implications for tussigenic challenges.
AB  - The purpose of this study was to assess the stability of stored capsaicin
      solutions and the actual concentrations of prepared solutions. Capsaicin
      solutions ranging in concentration from 0.5 to 128 microM were mixed and analyzed
      using high performance liquid chromatography. Samples of varying concentrations
      were then stored under 4 environmental conditions: 4 degrees C and protected from
      light, room temperature (RT) exposed to light, RT protected from light, and -20
      degrees C and protected from light. The concentrations were measured every other
      month for 1 year. Actual concentrations of freshly prepared solutions were on
      average 88.3% of predicted. For solutions stored at 4 degrees C, there was a
      decrease only in the lower concentrations (0.5, 1, and 2 microM) after 2 months
      (P=0.003). Solutions stored at RT exposed to light decreased in concentration
      after 6 months (P=0.020), and solutions stored at RT protected from light
      decreased in concentration after 4 months (P=0.026). The group stored at -20
      degrees C decreased in concentration after 1 year (P=0.033). We conclude that the
      actual concentration of capsaicin solution is less than predicted, and solutions
      of 4 microM or higher concentration are stable for 1 year if stored at 4 degrees
      C protected from light.

PMID- 12493339
TI  - Cilomilast (Ariflo) does not potentiate the cardiovascular effects of inhaled
      salbutamol.
AB  - We investigated the safety and potential pharmacodynamic interactions arising
      from the co-administration of inhaled beta(2)-agonist salbutamol and cilomilast
      (Ariflo), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic
      obstructive pulmonary disease and asthma. This was a randomised, double-blind,
      placebo-controlled, multiple-dose, three-period crossover study involving non
      smoking volunteers between the ages of 18 and 50 years. Volunteers were randomly
      assigned to receive cilomilast plus nebulised salbutamol, cilomilast plus
      nebulised placebo or placebo plus nebulised salbutamol. Each volunteer received
      cilomilast (10 mg twice daily) or placebo for 5 days. On day 5, the morning dose
      of cilomilast or placebo was followed 1 h later with a single dose of nebulised
      salbutamol (2.5 mg) or placebo. Primary variables were average change from pre-
      to 1.5 h post-salbutamol or placebo inhalation in blood pressure, pulse rate, 12
      lead ECG and total number of heartbeats measured by 4-h Holter ECG. Thirteen
      volunteers completed the study. There was no evidence of a clinically important
      pharmacodynamic interaction between cilomilast and salbutamol in healthy
      volunteers. Both agents were well tolerated. In conclusion, the pharmacodynamic
      effects associated with salbutamol inhalation were unaffected by co
      administration of cilomilast.

PMID- 12493341
TI  - Overview consensus statement.

PMID- 12493342
TI  - Definition and epidemiology of overactive bladder.
AB  - The Standardisation Subcommittee of the International Continence Society (ICS)
      now recognizes overactive bladder (OAB) as a "symptom syndrome suggestive of
      lower urinary tract dysfunction." It is specifically defined as "urgency, with or
      without urge incontinence, usually with frequency and nocturia." The ICS
      definition was not formulated until January 2001 and was not formally approved
      until September 2001. Therefore, collection and discussion of the epidemiologic
      characteristics of OAB are somewhat hampered by the different definitions of this
      condition used by different investigators. Most communications that appeared
      before 2000 more often described characteristics of incontinence rather than OAB,
      and the estimates of OAB prevalence within those studies varied significantly.
      Until recently, little definite epidemiologic information was available on the
      prevalence and comorbidities of OAB. An important challenge in treating OAB is to
      increase awareness of this significant problem worldwide and to impress on other
      specialists and primary care physicians the importance of identifying this
      clinical problem and managing it in a way that will maximize quality-of-life
      improvement while minimizing morbidity.

PMID- 12493344
TI  - Pharmacologic perspective on the physiology of the lower urinary tract.
AB  - Myogenic activity, distention of the detrusor, and signals from the urothelium
      may initiate voiding. In the bladder, afferent nerves have been identified not
      only in the detrusor, but also suburothelially, where they form a plexus that
      lies immediately beneath the epithelial lining. Extracellular adenosine
      triphosphate (ATP) has been found to mediate excitation of small-diameter sensory
      neurons via P2X3 receptors, and it has been shown that bladder distention causes
      release of ATP from the urothelium. In turn, ATP can activate P2X3 receptors on
      suburothelial afferent nerve terminals to evoke a neural discharge. However, most
      probably, not only ATP but also a cascade of inhibitory and stimulatory
      transmitters and mediators are involved in the transduction mechanisms underlying
      the activation of afferent fibers during bladder filling. These mechanisms may be
      targets for future drugs. The central nervous control of micturition involves
      many transmitter systems, which may be suitable targets for pharmacologic
      intervention. gamma-Aminobutyric acid, dopamine, enkephalin, serotonin, and
      noradrenaline receptors and mechanisms are known to influence micturition, and
      potentially, drugs that affect these systems could be developed for clinical use.
      However, a selective action on the lower urinary tract may be difficult to
      obtain. Most drugs currently used for treatment of detrusor overactivity have a
      peripheral site of action, mainly the efferent (cholinergic) neurotransmission
      and/or the detrusor muscle itself. In the normal bladder, muscarinic receptor
      stimulation produces the main part of detrusor contraction, but evidence is
      accumulating that in disease states, such as neurogenic bladders, outflow
      obstruction, idiopathic detrusor instability, and interstitial cystitis, as well
      as in the aging bladder, a noncholinergic activation via purinergic receptors may
      occur. If this component of activation is responsible not only for part of the
      bladder contractions, but also for the symptoms of the overactive bladder, it
      should be considered an important target for therapeutic interventions.

PMID- 12493346
TI  - Pathophysiology: the varieties of bladder overactivity.
AB  - Overactive bladder (OAB) is the most common term currently used in clinical
      medicine to describe a complex of lower urinary tract symptoms (LUTS) with or
      without incontinence. The symptoms usually include urgency, frequency, nocturia,
      troublesome or incomplete emptying, and, occasionally, pain. Causes of bladder
      overactivity include neurologic illness or injury, bladder outlet obstruction,
      urethral weakness, detrusor hyperactivity and impaired contractility in elderly
      patients, emergence of new voiding reflexes, and so-called idiopathic bladder
      overactivity. Most clinicians agree that effective treatment for OAB symptoms
      should be guided by a basic assessment of patients for these contributing
      factors. However, it is not at all certain that outcomes are significantly
      improved by diagnostic precision. This is in part because of the ubiquity of LUTS
      in the setting of the various common lower urinary tract disorders: stress
      incontinence, outlet obstruction, and neurologic illness or injury. The ubiquity
      of LUTS would imply that they are caused by common mechanisms and, theoretically
      at least, would be amenable to a single form of effective therapy. Conversely,
      the limited kinds and number of LUTS and the limited representation of lower
      urinary tract structures in the central nervous system may mean that several
      different causes produce similar symptoms, but these are not amenable to a single
      form of effective therapy. Future research directions should keep each possible
      explanation in mind as new knowledge about lower urinary tract function and
      possible intervention continues to emerge.

PMID- 12493348
TI  - Nocturnal polyuria versus overactive bladder in nocturia.
AB  - The purpose of this article is to review the current state of knowledge on
      contributions of nocturnal urine overproduction and overactive bladder to the
      syndrome of nocturia. We review the recent literature and current state of the
      art in differential diagnosis, pathophysiology, and classification of nocturia.
      We found that multiple pathologic factors may result in nocturia, including
      cardiovascular disease, diabetes mellitus or insipidus, third spacing of fluid,
      sleep apnea, lower urinary tract obstruction, primary sleep disorders, and
      behavioral and environmental factors. Thus, nocturia may be attributed to
      nocturnal polyuria (nocturnal urine overproduction), diminished nocturnal bladder
      capacity, or both. Distinction between these conditions is made by a simple
      arithmetic analysis of the 24-hour voiding diary. Understanding the manifold
      origins of nocturia will lead to rational treatment of specific contributing
      pathophysiologic factors.

PMID- 12493350
TI  - Role of cystometry in evaluating patients with overactive bladder.
AB  - Overactive bladder (OAB) can be caused by a variety of conditions. We believe
      that cystometrography (CMG) is an essential part of the diagnostic evaluation,
      both in defining underlying pathophysiology and directing treatment. Essential to
      the diagnosis of OAB syndrome is some combination of urinary frequency, urgency,
      urge incontinence, and pain. CMG can be thought of simply as a provocative test
      to determine whether bladder filling, involuntary detrusor contractions, or low
      bladder compliance in fact reproduces any of these symptoms, and whether the
      symptoms abate when the bladder is empty or when the pressure decreases. At
      another level, the CMG has been likened to "the reflex hammer" of the lower
      urinary tract and, as such, provides important neurologic information. Finally,
      the voiding phase of the CMG is an essential component of the detrusor
      pressure/uroflow study, which is the only accurate method of diagnosing urethral
      obstruction and impaired detrusor contractility. Both of these conditions can
      coexist with detrusor overactivity. The treatment of OAB depends on the
      underlying cause. We believe that only by understanding the particular
      cystometric characteristics of patients with OAB can we determine the appropriate
      treatment. Urodynamic testing should serve as an essential part of therapy and
      guide future research in diagnosis and management.

PMID- 12493352
TI  - Special considerations of the overactive bladder in children.
AB  - The overactive bladder (OAB) in children is defined as both involuntary detrusor
      contractions and urethral instability. The development of urinary control plays a
      key role in its incidence and in our understanding of its pathogenesis. It is
      seen in a number of conditions but by far is most common among patients with
      dysfunctional voiding. Urinary infection can be both a cause and an effect of
      OAB. In some instances, vesicoureteral reflux may result from detrusor
      overactivity because its successful resolution has been shown to depend on
      abolition of the hyperactivity. Early diagnosis and appropriate treatment can
      affect upper urinary tract function and drainage and ultimate bladder function.
      Recognition is noted via a thorough history and careful physical examination.
      Urodynamic assessment is indicated in neurologically normal children >5 years old
      and is combined with a voiding cystourethrogram in boys and a radionuclide
      cystogram in girls who have a history of recurrent urinary infection. Treatment
      consists of prophylactic use of anticholinergic agents in patients with
      neurologic dysfunction, as an early adjunctive measure in boys after ablation of
      posterior urethral valves, and in children with vesicoureteral reflux. The dose
      must be carefully titrated in children with cerebral palsy to prevent the
      appearance of elevated residual urine. Behavioral therapy and biofeedback
      techniques are effective alternatives to anticholinergic agents for children with
      dysfunctional voiding.

PMID- 12493354
TI  - Geriatric considerations in the diagnosis and management of overactive bladder.
AB  - Numerous considerations affect the diagnosis and management of overactive bladder
      (OAB) in older patients, including neurologic and cardiovascular disorders,
      musculoskeletal conditions, diabetes, and psychiatric disorders. Older patients
      are commonly prescribed multiple medications, and many medications can contribute
      to OAB symptoms and/or interact with drug treatment for OAB. In addition to
      chronic illnesses and related medications, several factors outside the lower
      urinary tract can play an important part in managing OAB in older patients. These
      factors include mobility disorders, cognitive impairment, bowel habits, and fluid
      intake. Moreover, OAB often does not occur in isolation in the geriatric
      population. Estrogen deficiency and sphincter weakness in women, prostatic
      enlargement and obstruction in men, and impaired bladder contractility in both
      sexes are common and can have prominent effects on management. The diagnostic
      evaluation of geriatric patients with OAB can usually be accomplished with a
      basic assessment, without more invasive and expensive procedures. Treatment
      depends on numerous factors, ranging from comorbidities and functional status to
      transportation, finances, and patient and caregiver preferences. Adverse effects
      of bladder-relaxant medications can be bothersome and exacerbate existing
      conditions common in older patients (eg, constipation, glaucoma, gastroesophageal
      reflux, and dementia). Setting realistic goals for treatment and communicating
      them clearly to older patients and their caregivers are crucial for patient
      satisfaction. There are myriad opportunities for research designed to improve the
      management of OAB in the geriatric population.

PMID- 12493356
TI  - Overactive bladder in men: special considerations for evaluation and management.
AB  - Lower urinary tract symptoms (LUTS) in men may arise from a variety of underlying
      causes, including benign prostatic hyperplasia. LUTS may have a significant
      component of storage symptoms (urgency, frequency, urge incontinence) at
      presentation; however, the absence of overactive bladder (OAB) symptoms does not
      necessarily imply pure outlet obstruction nor does their presence indicate the
      lack thereof. Symptomatic correlates to urodynamic findings are high when
      considering isolated OAB symptoms. However, mixed presentations or more overtly
      obstructive scenarios have less correlation with baseline symptom appraisal
      instruments. The ideal approach for diagnosis and management is predicated on a
      graded approach, with more invasive evaluation withheld for those men in whom
      presumptive therapy fails or who present with associated complex symptoms and in
      whom a higher level of intervention is being considered. The increasing incidence
      of LUTS with age implies a partial detrusor contribution, which must be
      considered in the overall management schema.

PMID- 12493358
TI  - Special considerations in premenopausal and postmenopausal women with symptoms of
      overactive bladder.
AB  - The term overactive bladder (OAB) is used to describe the symptoms of urinary
      frequency and urgency with or without urge incontinence. Commonly reported
      symptoms are nocturia, urgency, frequency, and urge incontinence. However, some
      of these symptoms may be because of other lower urinary tract conditions or may
      simply represent a variant of normal physiologic function. Consequently, special
      considerations need to be made when diagnosing OAB in women. In women of all
      ages, lower urinary tract infection is the most common cause of irritative
      urinary symptoms, and midstream urine microscopy and culture should be performed.
      A chronic urinary residual secondary to voiding difficulties may also result in
      symptoms of frequency and overflow incontinence and may be diagnosed using a
      postmicturition ultrasound scan. In premenopausal women, pregnancy should also be
      excluded. In postmenopausal women, urogenital atrophy can cause irritative
      symptoms that may be improved with hormone replacement therapy. Vaginal
      administration has been shown to be most effective and may be used to supplement
      systemic replacement therapy. In addition, estrogen replacement may be beneficial
      in the management of OAB as an adjunct to anticholinergic therapy. When
      investigating elderly women with OAB, special consideration should be given to
      comorbidities, such as constipation and fecal impaction, mobility problems, and
      the loss of independence. Concomitant medication, such as diuretics and alpha
      adrenergic blockers, should also be noted and the need for therapy reviewed. In
      conclusion, OAB is a subjective diagnosis that should only be made when other
      lower urinary tract conditions have been excluded.

PMID- 12493360
TI  - Influence of behavior modification on overactive bladder.
AB  - Behavioral interventions have been used for decades to treat urge incontinence
      and other symptoms of overactive bladder. Perhaps the earliest form of treatment
      was the bladder drill, an intensive intervention designed to increase the
      interval between voids to establish a normal frequency of urination and
      normalization of bladder function. Bladder training is a modification of bladder
      drill that is conducted more gradually on an outpatient basis and has resulted in
      significant reduction of incontinence in older, community-dwelling women.
      Multicomponent behavioral training is another form of behavioral treatment that
      includes pelvic floor muscle training and exercise. This intervention focuses
      less on voiding habits and more on altering the physiologic responses of the
      bladder and pelvic floor muscles. Using biofeedback or other teaching methods,
      patients learn strategies to inhibit bladder contraction using pelvic floor
      muscle contraction and other urge suppression strategies. Although behavioral and
      drug therapies are known to be highly effective for reducing urge incontinence,
      few patients are cured with either treatment alone. Thus, future research should
      explore ways to enhance the effectiveness of these conservative therapies.
      Although the mechanisms by which behavioral treatments work have not been
      established, there is some evidence that behavioral and drug interventions may
      operate by different mechanisms, suggesting that they may have additive effects
      and that combining them may result in better outcomes. Future research needs to
      examine the mechanisms by which these therapies reduce incontinence and whether
      combining behavioral and drug treatment will result in better outcomes than
      either therapy alone.

PMID- 12493362
TI  - New perspectives on the overactive bladder: pharmacokinetics and bioavailability.
AB  - In the United States alone, approximately 17 million men and women have symptoms
      of overactive bladder (OAB). For many years, oxybutynin was the drug of choice
      for treating OAB. Although it provided effective treatment, multiple daily doses
      were required, and adverse events, such as dry mouth and constipation, were
      decided drawbacks. Controlled drug delivery systems seen in commercially
      available OAB formulations alter the pharmacokinetics of antimuscarinic
      medications in ways that maintain efficacy and allow once-daily dosing and
      reduction of adverse events. In the future, OAB medications will not only
      incorporate new chemical entities, such as the S-enantiomer of oxybutynin, but
      will also use novel drug delivery technologies, including transdermal patches and
      bladder implants.

PMID- 12493364
TI  - Muscarinic receptor subtypes and management of the overactive bladder.
AB  - Anticholinergic agents are the most widely used therapy for urge incontinence
      despite exerting adverse effects, such as constipation, tachycardia, and dry
      mouth, that limit their use. These adverse effects result from a lack of
      selectivity for the bladder over other organs. Although M2-muscarinic receptors
      are the predominant cholinoreceptor present in urinary bladder, the smaller
      population of M3-receptors appears to be the most functionally important and
      mediates direct contraction of the detrusor muscle. M2-receptors modulate
      detrusor contraction by several mechanisms and may contribute more to contraction
      of the bladder in pathologic states, such as bladder denervation or spinal cord
      injury. Prejunctional inhibitory M2-receptors or M4-receptors and prejunctional
      facilitatory M1-muscarinic receptors in the bladder have also been reported, but
      their relevance to the clinical effectiveness of muscarinic antagonists is
      unknown. In clinical studies, tolterodine, a nonselective muscarinic antagonist,
      has been reported to be equally effective to oxybutynin but to induce less dry
      mouth. Controlled-release and intravesical, intravaginal, and rectal
      administrations of oxybutynin have all been reported to cause fewer adverse
      effects. Conversely, darifenacin, a new M3-selective antagonist, has been
      reported to have selectivity for the bladder over the salivary gland in vivo.
      Whether M3-selective or nonselective muscarinic antagonists will be the most
      clinically effective for the overactive bladder-preserving the best balance
      between efficacy and tolerability-has yet to be established, and comparative
      clinical trials between compounds, such as darifenacin (M3 selective) and
      tolterodine (nonselective) will be required.

PMID- 12493366
TI  - Future studies of overactive bladder: the need for standardization.
AB  - Clinicians and researchers agree that pharmacologic studies of the overactive
      bladder (OAB) require precise planning, strict adherence to study design, and
      meticulous attention to study conduct and statistical methods. In addition, there
      should be straightforward and highly directed formulation of the conclusions
      derived expressly from data that have been collected. The exact methods to
      achieve these ends, however, are often debated among statisticians and experts in
      study design and by physicians who interpret the clinical implications of the
      findings. For these reasons, the conclusions of clinical research in OAB are
      commonly criticized on the basis of study objectives, study design, statistical
      methods, or conclusions. However, a subtler, but possibly more critical problem
      exists: the method of defining the population and the methods for collecting the
      data for the efficacy outcome parameters, including frequency, urgency, and urge
      incontinence.

PMID- 12493367
TI  - Rene Kuss: fifty years of retroperitoneal placement of renal transplants.

PMID- 12493368
TI  - The organ shortage: a social paradox to be reversed.

PMID- 12493369
TI  - Influence of race on cognitive and affective reactions to organ donation
      messages.

PMID- 12493370
TI  - Support for organ procurement: national, professional, and religious correlates
      among medical personnel in Austria and the Kingdom of Saudi Arabia.

PMID- 12493371
TI  - Chain exchange transplantation: could the pool of organs be expanded through
      donation by transplanted living cases?

PMID- 12493372
TI  - Effect of sirolimus on ischemia/reperfusion injury in transgenic hypertensive
      rat.

PMID- 12493373
TI  - Influence of hepatic ischemia-reperfusion injury on tacrolimus acute renal
      toxicity in pigs.

PMID- 12493374
TI  - Importance of selenium for the influence of ischemia-reperfusion syndrome after
      kidney transplantation from a non-heart beating donor in a pig model.

PMID- 12493375
TI  - Plasma and tissue levels of free oxygen radicals in recipients of kidneys from
      non-heart-beating donors: does recipient pretreatment with antioxidant drugs make
      sense? An experimental study in pigs.

PMID- 12493376
TI  - Amelioration of hepatic ischemia/reperfusion injury using indolepropionic acid.

PMID- 12493377
TI  - The different patterns of response to plasmapheresis of recurrent focal and
      segmental glomerulosclerosis.

PMID- 12493378
TI  - Five-year experience with the new Eurotransplant Kidney Allocation System, 1996
      to 2001.

PMID- 12493379
TI  - The histocompatibility profile of the Puerto Rican population.

PMID- 12493380
TI  - Left ventricular ejection fraction less than 40% is a useful predictor for poor
      patient survival in kidney transplant recipients over age 50 years.

PMID- 12493381
TI  - Influence of pretransplant panel reactive antibodies on the posttransplant
      sensitization status.

PMID- 12493382
TI  - Single-time kidney transplantation and monolateral nephrectomy for hypertension
      and antihypertensive therapy in renal transplant recipients.

PMID- 12493383
TI  - Antibodies to hepatitis C virus in patients with chronic renal disease in Sri
      Lanka.

PMID- 12493384
TI  - One or two marginal organs for kidney transplantation?

PMID- 12493385
TI  - Outcomes of pediatric living donor renal transplant after laparoscopic versus
      open donor nephrectomy.

PMID- 12493386
TI  - Laparoscopic donor nephrectomy in Germany.

PMID- 12493387
TI  - Expansion of the organ donor pool by the reuse of a previously transplanted
      kidney--is this ethically and scientifically valid?

PMID- 12493388
TI  - Living unrelated renal transplants in Cyprus.

PMID- 12493389
TI  - Auxiliary liver and combined kidney transplantation prevents hyperacute kidney
      rejection in highly sensitized patients.

PMID- 12493390
TI  - Factors influencing the glomerular filtration rate increase after cadaveric renal
      transplantation: a multivariate analysis.

PMID- 12493391
TI  - Even severe renal artery fibromuscular dysplasia is no contraindication for
      living donor renal transplantation: report of two successful cases with venous
      grafting of the donor renal artery.

PMID- 12493392
TI  - Recurrent immunoglobulin A nephropathy complicated with de novo membranous
      glomerulonephritis in renal allografts.

PMID- 12493393
TI  - Rates of acute rejection by recipient race and type of calcineurin inhibitor with
      mycophenolate mofetil.

PMID- 12493394
TI  - Recurrent focal segmental glomerulosclerosis after renal transplantation: is
      early recurrent proteinuria always a surrogate marker for recurrence of the
      disease?

PMID- 12493395
TI  - Relative contribution of HLA disparity to chronic allograft nephropathy.

PMID- 12493396
TI  - Renal production of hepatocyte growth factor increases after unilateral
      nephrectomy in man.

PMID- 12493397
TI  - Histopathological findings of 10-year protocol biopsy in pediatric kidney
      transplant recipients.

PMID- 12493398
TI  - Intracellular cytokine production in chronic renal allograft rejection.

PMID- 12493399
TI  - Expression of vascular endothelial growth factor mRNA and protein in human
      chronic renal allograft rejection.

PMID- 12493400
TI  - The correlation between FcgammaRIIA polymorphism and renal allograft survival.

PMID- 12493401
TI  - Evaluation of posttransplant RhD sensitization in RhD-negative renal recipients.

PMID- 12493402
TI  - Intravenous fluid therapy in renal transplant recipients: results of a US survey.

PMID- 12493403
TI  - Emerging challenges in transplantation in developing countries.

PMID- 12493404
TI  - Long-term consequences of the switch from sandimmune to neoral.

PMID- 12493405
TI  - Impact of cyclosporine dosing frequency on graft function and survival after the
      conversion from sandimmun to neoral in stable kidney transplanted patients.

PMID- 12493406
TI  - Basiliximab-sirolimus-prednisone induction regimen followed by delayed low-dose
      cyclosporine in renal transplant recipients of living donors.

PMID- 12493407
TI  - No long-term benefit of low-dose OKT3 induction therapy in non to moderately
      immunized renal allograft recipients.

PMID- 12493408
TI  - Evaluation of different sampling times for best prediction of cyclosporine area
      under the curve in renal transplant recipients.

PMID- 12493409
TI  - Pretransplant pharmacokinetics: does it predict the dose of tacrolimus after
      renal transplantation?

PMID- 12493410
TI  - The roles of C4 and AUC0-4 in monitoring of tacrolimus in stable kidney
      transplant patients.

PMID- 12493411
TI  - Quantitative gene expression of TGF-beta1, TNF-alpha, IL-1beta, and IL-6 in the
      renal artery wall of chronically rejected human renal allografts.

PMID- 12493412
TI  - Immune suppression-related T-cell subset interrelationships and specific regimen
      related factor analysis of cell surface differentiation and activation markers in
      renal allograft recipients.

PMID- 12493413
TI  - Low-dose prednisone accounts for a transient reduction on CD4+ and CD8+ T cells
      in renal transplant patients under triple therapy.

PMID- 12493414
TI  - Sirolimus rescue treatment in calcineurin-inhibitor nephrotoxicity after kidney
      transplantation.

PMID- 12493415
TI  - Tacrolimus-induced neurotoxicity in kidney transplant recipients.

PMID- 12493416
TI  - Postrenal transplant erythrocytosis: risk factors and effectiveness of
      angiotensin receptor antagonists.

PMID- 12493417
TI  - Magnetic resonance in renal transplantation: evaluation of post-surgery
      complications.

PMID- 12493418
TI  - Renal transplantation and prostate cancer: guidelines for screening and
      treatment.

PMID- 12493419
TI  - Case report: hepatic leiomyoma in a renal transplant recipient.

PMID- 12493420
TI  - Wilms tumor in a pediatric renal transplant recipient with unexpected Denys-Drash
      syndrome.

PMID- 12493422
TI  - Transfusion-transmitted virus infection in renal transplant recipients.

PMID- 12493421
TI  - Immune status in renal transplant recipients with hepatitis C virus infection.

PMID- 12493424
TI  - Polyomavirus (BK type) infection after renal transplantation detected by previous
      tissue biopsy section in paraffin.

PMID- 12493423
TI  - Parvovirus B19 infection and IGF system components in relation to erythropoiesis
      in dialyzed patients and kidney transplant recipients.

PMID- 12493425
TI  - Use of mycophenolate mofetil in kidney transplant recipients with viral hepatitis
      infection: is it justified?

PMID- 12493426
TI  - Prevalence of diabetes mellitus in renal transplant patients with hepatitis B or
      C virus infection.

PMID- 12493427
TI  - Effects of angiotensin converting enzyme inhibitor and angiotensin II receptor
      antagonist therapy in hypertensive renal transplant recipients.

PMID- 12493428
TI  - Clinical predictors of outcome in patients with heart failure and neurohormonal
      blockade: referral for transplantation from heart failure units without heart
      transplantation programs.

PMID- 12493429
TI  - Phosphorous-31 magnetic resonance spectroscopy assessment of phosphocreatine to
      inorganic phosphate ratio in donor hearts as a criterion for the decision to
      transplant.

PMID- 12493430
TI  - Bradyarrhythmias and cardiac pacing after orthotopic heart transplantation in a
      Chinese population.

PMID- 12493431
TI  - Prevalence and significance of renal artery stenosis and abdominal aortic
      atherosclerosis early after heart transplantation.

PMID- 12493432
TI  - Apoptosis and expression of heme oxygenase-1 in heart transplant recipients
      during acute rejection episodes.

PMID- 12493433
TI  - Is atropine infusion necessary to achieve the target heart rate in heart
      transplant patients during dobutamine stress echocardiography?

PMID- 12493434
TI  - IL-15R alpha-chain expression during anti-CD25 treatment of cardiac allograft
      recipients.

PMID- 12493435
TI  - C(2) monitoring of cyclosporine in stable heart transplant patients after two
      daily and three daily doses.

PMID- 12493436
TI  - Echocardiographic evaluation of cardiac remodeling after oversized heart
      transplantation in children.

PMID- 12493437
TI  - Cryptococcus neoformans infection as scleral abscess in a cardiac allograft
      recipient 6 months after heart transplantation.

PMID- 12493438
TI  - Methotrexate rescue therapy in lung transplantation.

PMID- 12493439
TI  - Improved survival after lung transplantation in patients treated with
      tacrolimus/mycophenolate mofetil as compared with cyclosporine/azathioprine.

PMID- 12493440
TI  - Efficacy of controlled reperfusion by using low pressure after myocardial
      ischemia in rats.

PMID- 12493441
TI  - Beneficial hemodynamic effects of autologous bone marrow cell transplantation in
      rats with heart failure.

PMID- 12493442
TI  - Protection of the ischemic heart during reperfusion: role of the low flow to
      avoid calcium overload into the myocardium in a pig model.

PMID- 12493443
TI  - Study of the effect of indoleamine 2,3-dioxygenase on murine mixed lymphocyte
      reactions and skin allograft rejection.

PMID- 12493444
TI  - Donor cardiac allografts from p53 knockout mice exhibit apoptosis-independent
      prolongation of survival.

PMID- 12493445
TI  - Vaccinia virus complement control protein ameliorates hyperacute xenorejection by
      inhibiting xenoantibody binding.

PMID- 12493446
TI  - Prevalence of depressive symptoms in patients being evaluated for liver
      transplantation.

PMID- 12493447
TI  - Living donor liver transplantation for fulminant hepatic failure.

PMID- 12493448
TI  - Can patients awaiting liver transplantation elicit an immune response to the
      hepatitis A vaccine?

PMID- 12493449
TI  - Psychosocial stress of living donors after living donor liver transplantation.

PMID- 12493450
TI  - Correlation of blood-free graft weight and volumetric graft volume by an analysis
      of blood content in living donor liver grafts.

PMID- 12493451
TI  - Impact of donor age on graft survival among liver transplant recipients: analysis
      of the United Network for Organ Sharing database.

PMID- 12493452
TI  - Evidence of psychosocial influences on acute rejection after liver
      transplantation.

PMID- 12493453
TI  - DQA1 and DQB1 genes polymorphism on acute rejection development in liver
      transplantation.

PMID- 12493454
TI  - Clinical use of c2 monitoring in long-term liver transplant recipients.

PMID- 12493455
TI  - Combined liver and kidney transplantation: a single-center experience.

PMID- 12493456
TI  - Autoimmune hepatitis following liver transplantation: relationship to recurrent
      disease and steroid weaning.

PMID- 12493457
TI  - Liver transplantation in three family members after Amanita phalloides mushroom
      poisoning.

PMID- 12493459
TI  - Hepatitis C treatment outcomes of African Americans following liver
      transplantation.

PMID- 12493458
TI  - Predictors of late kidney dysfunction post-liver transplantation.

PMID- 12493460
TI  - Seroconversion in patients with acute hepatitis B reinfection after liver
      transplantation with a combined treatment of lamivudine and hepatitis B immune
      globulin.

PMID- 12493461
TI  - Overseas liver transplantation for hepatitis C in Japanese patients: a comparison
      with patients from Australia/New Zealand.

PMID- 12493462
TI  - Anticoagulant therapy against hepatic artery thrombosis in living donor liver
      transplantation.

PMID- 12493463
TI  - Optimal venous drainage for right lobe living donor liver grafts.

PMID- 12493464
TI  - Cavoportal hemitransposition: patient selection criteria and outcome.

PMID- 12493465
TI  - Immediate tracheal extubation of the liver transplant recipients in the operating
      room.

PMID- 12493466
TI  - Ascites after liver transplantation and inferior vena cava reconstruction in the
      piggyback technique.

PMID- 12493467
TI  - Paratrend sensor as a novel method for continuous monitoring of hepatic
      microperfusion.

PMID- 12493468
TI  - Transgenic T cells persist in an adoptive transfer model of mouse liver
      transplantation tolerance.

PMID- 12493469
TI  - Future trends in clinical islet transplantation.

PMID- 12493470
TI  - Survival of pancreatic islet xenografts in NOD mice with the theracyte device.

PMID- 12493471
TI  - In vivo pancreatic-specific hypothermia: retrograde ductal perfusion experimental
      studies.

PMID- 12493472
TI  - Immunosuppression with sirolimus/tacrolimus combination in pancreas
      transplantation: 1-year results.

PMID- 12493473
TI  - Stapler duodenojejunostomy reduces intraabdominal infection after combined
      pancreas kidney transplantation as compared with hand-sawn anastomosis.

PMID- 12493474
TI  - Clinical outcome and etiology of chronic non-malignant intestinal failure: a
      pediatric series.

PMID- 12493475
TI  - Survival of small bowel transplants in canine mixed hematopoietic chimeras:
      preliminary results.

PMID- 12493476
TI  - Non-myeloablative stem cell transplantation for induction of host-versus-graft
      tolerance for adoptive immunotherapy of malignant and nonmalignant diseases and
      towards transplantation of organ allografts.

PMID- 12493477
TI  - Late-onset idiopathic thrombocytopenic purpura correlates with rapid B-cell
      recovery after allogeneic T-cell-depleted peripheral blood progenitor cell
      transplantation in children.

PMID- 12493478
TI  - Autologous hematopoietic stem cell transplantation for high-risk Hodgkin's
      disease: a single-center experience with the first 100 patients.

PMID- 12493479
TI  - Comparative gastrointestinal effects of mycophenolate mofetil capsules and
      enteric-coated tablets of sodium-mycophenolic acid in beagle dogs.

PMID- 12493480
TI  - Interaction of immunosuppressive agents rapamycin and its analogue SDZ-RAD with
      endothelial P-gp.

PMID- 12493481
TI  - Murine heart transgenic Fas ligand expression protects against allograft
      rejection.

PMID- 12493482
TI  - Early monitoring of lymphocyte subsets in patients with hand allotransplantation.

PMID- 12493483
TI  - Dynamic observation of serum cytokines in the patients with hand transplantation.

PMID- 12493484
TI  - MHC matching improves corneal allograft survival in mice with Th2-immune bias.

PMID- 12493485
TI  - Early cytokine production in response to cryopreserved heart valve implantation
      in pediatric recipients.

PMID- 12493486
TI  - Determination of pretransplant viability of Leydig cells by MTT colorimetric
      assay.

PMID- 12493488
TI  - Pretreatment of recipients with mitomycin-C-treated dendritic cells induces
      significant prolongation of cardiac allograft survival in mice.

PMID- 12493489
TI  - A multiplex PCR for simultaneous detection and differentiation of North American
      serotypes of bluetongue and epizootic hemorrhagic disease viruses.
AB  - In the present study, a multiplex RT-PCR-based assay for simultaneous detection
      and differentiation of North American serotypes of bluetongue (BT) virus (BTV)
      and epizootic hemorrhagic disease (EHD) virus (EHDV) in cell culture and clinical
      samples was developed. Two pairs of primers (B1 and B4) and (E1 and E4) were
      designed to hybridize to non-structural protein 1 (NS1) genomes of (BTV-11) and
      (EHDV-1), respectively. The multiplex PCR-based assay utilized a single tube-PCR
      amplification in which EHDV and BTV primers were used simultaneously in a
      multiplex format. The BTV primers generated a 790 base pair (bp) specific PCR
      product from RNA samples of North American BTV serotypes 2, 10, 11, 13 and 17;
      whereas EHDV serotypes 1 and 2 or total nucleic acid extract from non-infected
      baby hamster kidney (BHK) cells failed to demonstrate the 790bp specific BTV PCR
      product. Likewise, the EHDV primers produced a 387bp specific PCR product from
      RNA samples of EHDV serotypes 1 and 2, but not from BTV serotypes 2, 10, 11, 13,
      17 or from total nucleic acid extract of BHK cell controls. Two pairs of nested
      primers (B2 and B3) and (E2 and E3), internal to the annealing sites of primers
      (B1and B4) and primers (E1 and E4), produced a 520bp specific BTV and a 224bp
      specific EHDV PCR product from BTV and EHDV first amplification products,
      respectively. These nested amplifications increased the sensitivity of the PCR
      assay and confirmed the specificity of the first amplified EHDV or BTV PCR
      products. The described multiplex RT-PCR-based assay could be used to facilitate
      rapid detection and differentiation of North American BTV and EHDV serotypes and
      to provide a valuable tool to study the epidemiology of these orbivirus
      infections in susceptible animal populations.

PMID- 12493490
TI  - Natural bovine lentiviral type 1 infection in Holstein dairy cattle. I. Clinical,
      serological, and pathological observations.
AB  - Clinical, serological, and pathological abnormalities observed in Holstein cows
      naturally infected with bovine lentivirus 1 bovine immunodeficiency virus (BIV)
      and other infections were progressive and most commonly associated with weight
      loss, lymphoid system deficiency, and behavioral changes. Clinical evidence of
      meningoencephalitis was dullness, stupor, and occasional head or nose pressing
      postures. The polymerase chain reactions associated the BIV provirus with the
      lesions in the central nervous system and lymphoid tissues. Multiple concurrent
      infections developed in retrovirally infected cows undergoing normal stresses
      associated with parturition and lactation. A major functional correlate of the
      lymphoreticular alterations was the development of multiple secondary infections
      which failed to resolve after appropriate antibacterial therapy. The chronic
      disease syndrome in dairy cows associated with BIV may be useful as a model
      system for investigation of the pathogenesis of the nervous system lesions and
      lymphoid organ changes that occur in humans with lentiviral infection.

PMID- 12493491
TI  - Evidence for modulated immune response to Anaplasma phagocytophila sensu lato in
      cats with FIV-induced immunosuppression.
AB  - Human granulocytic ehrlichiosis (HGE) is an emerging infectious disease in which
      some patients experience unusual opportunistic infections. In this study, cats
      infected with the HGE agent, Anaplasma phagocytophila s.l., had clinical
      granulocytic ehrlichiosis (GE), anti-nuclear antibodies and increased IFN-gamma
      mRNA. In FIV-immunosuppressed cats with GE, there was upregulated IL-10
      transcription but not IFN-gamma. Cats with FIV had poor response to vaccines,
      regardless of GE status. This preliminary report demonstrates that cats with FIV
      infection make a good model of ehrlichiosis in an immunocompromised host, and
      that viral immunosuppression may not increase the severity of ehrlichiosis but
      may attenuate immune responses to the pathogen.

PMID- 12493492
TI  - Expression of hepatitis C virus core protein associated with malignant lymphoma
      in transgenic mice.
AB  - Hepatitis C virus (HCV) is a major causative agent for chronic liver diseases
      leading to hepatocellular carcinoma (HCC) and has also been suggested to be a
      possible etiologic factor for different lymphoproliferative diseases, including
      mixed cryoglobulinemia (MC) and B-cell non-Hodgkin's lymphoma (NHL). To
      understand the roles of HCV core protein in the pathogenesis of HCV related
      diseases, we produced two lines of the transgenic mice (HC82310 and HC9053) that
      express the HCV core transgene. One of the lines, HC9053, developed malignant
      lymphoma (ML, follicular center cell type) with a high frequency (80%) at the
      ages over 20 months. Hepatocellular adenoma was also observed in this line of
      transgenic mouse. We demonstrated expression of HCV core protein and mRNA in the
      liver of transgenic mice, and also detected the core mRNA in the enlarged lymph
      nodes of the transgenic mice which developed ML. These results suggest that the
      core protein may play an important role in the development of ML, and that the
      HC9053 transgenic mice provide suitable models for understanding the mechanism of
      HCV-related lymphoproliferative diseases.

PMID- 12493493
TI  - Pathological and serological evidence of Brucella-infection in baleen whales
      (Mysticeti) in the western North Pacific.
AB  - Abnormal testes and uterus were observed in 13 males (33%) and one female (3%)
      out of 40 common minke whales (Balaenoptera acutorostrata) in the western North
      Pacific. Similar lesions were found in testis and ovary, respectively, in one
      male (2%) and female (2%) out of 43 Bryde's whales (Balaenoptera edeni) in the
      western North Pacific. Grossly, granular lesions with caseation and calcification
      were main pathological signs, and they were restricted to reproductive organs of
      mature whales. Chronic purulent or granulomatous orchitis was observed by
      microscopic analysis. Antibodies to Brucella species were detected in the serum
      samples of 15/40 (38%) of common minke whales and 4/43 (9%) of Bryde's whales.
      Neither pathological nor serological change was found in the examined sperm
      whales (Physeter macrocephalus) in the western North Pacific and Antarctic minke
      whales (Balaenoptera bonaerensis). These results strongly suggest that Brucella
      infection was involved in two species of baleen whales (Mysticeti) in the North
      Pacific.

PMID- 12493494
TI  - Reactions of peripheral blood mononuclear cells (PBMC) of camels with monoclonal
      antibodies against ruminant leukocytes.
AB  - The particular immune system of the camel has been but little investigated. In
      this work circulating camel peripheral blood mononuclear cells (PBMC) were
      studied by flow cytometry. Monoclonal antibodies (mAbs) raised against ruminant
      leukocytes were used for the detection of cell surface antigens. Monoclonals to T
      cell markers, CD4 (CACT138A) and CD8 (CACT80C), exhibited no reactivity towards
      camel PBMC in contrast to their reactivity to PBMC of other ruminant species and
      those of cattle in particular. A relatively high percentage (29.1+/-8.9%) of
      camel PBMC reacted with a non-immunoglobulin cell surface marker, B-B2,
      comparable to the reactivity of bovine PBMC. The B-B7 cell marker revealed 22.4+/
      10.0% of reactive camel PBMC while the CD45 leukocyte common antigen was
      identified only on 19.4+/-3.1% of camel PBMC as compared to 74.7+/-4.9% for
      bovine PBMC. IgM (PIg45A) was detected on 9.1+/-1.4% of camel PBMC and on 46.6+/
      19.5% of the bovine PBMC. Double fluorescent labeling with two B-cell markers and
      an anti-ruminant lambda light-chain mAb revealed 7-9% of cells bearing both B and
      lambda L-chain markers. Light chain reactivity was also assessed using an anti
      goat F(ab')(2) antiserum. The values obtained, 14.3+/-5.8% for the camel and
      47.8+/-2.7% for the cattle, are close to the values observed for surface IgM.
      These data suggest that camels, like other ruminants, possess L-chain bearing
      cells of the B-cell lineage. However, in the camel, Igs are different in that in
      addition to regular four chain Igs, about 65% of them possess two heavy chain Igs
      devoid of light chains. Because different sets of V(H) gene segments are used by
      four and two chain Igs, it is possible that there might be two lineages of B
      cells each secreting a different form of antibodies.

PMID- 12493495
TI  - Clinicopathological investigation of 20 cases of primary tracheal cancer.
AB  - OBJECTIVE: Primary tracheal cancer is considered to be relatively rare. Its
      epidemiology, therapeutic strategy and prognosis are not well understood.
      METHODS: We retrospectively investigated the clinicopathological aspects of 20
      patients with primary tracheal cancer. RESULTS: Patients included 11 men and nine
      women with a mean age of 57.3 years. There were 12 squamous cell carcinomas and
      eight adenoid cystic carcinomas. Four patients received only palliative therapy.
      Sixteen patients underwent surgical treatment such as segmental tracheal,
      laryngotracheal, or carinal resection. One patient with squamous cell carcinoma
      died of postoperative mediastinitis. Although resected specimens from five
      patients had tumor positive margins, only one of those patients died after local
      recurrence and only three patients had postoperative treatment. The 5-year
      survival rate for patients who underwent surgery was 72.3%. CONCLUSIONS: Surgical
      treatment is the first choice therapeutic modality for primary tracheal cancer in
      consideration of its prognosis. While performing the operation, safety of the
      anastomosis should take precedence over completeness of resection.

PMID- 12493496
TI  - Topical vascular endothelial growth factor in rabbit tracheal surgery:
      comparative effect on healing using various reconstruction materials and
      intraluminal stents.
AB  - OBJECTIVES: The effect of topical vascular endothelial growth factor (VEGF) on
      post-surgical tracheal healing using various reconstruction materials was
      studied, with particular regard to prevention of granulation tissue or fibrosis.
      METHODS: Twenty-four New Zealand White rabbits underwent survival surgery using
      autograft patches (n=6), xenopericardium patches (n=6), intraluminal Palmaz wire
      stents (n=6), and controls (n=6). Autograft and pericardial half-patches were
      soaked in topical VEGF (5 microg/ml over 30 min) and saline before
      reimplantation. Stents and controls received circumferential injections of VEGF
      and saline in the tracheal wall. At 1-4 months postoperatively, specimens of
      sacrificed animals were stained with anti-VEGF antibody, followed by
      morphological and immunohistochemical examination. RESULTS: Rabbits with
      autografts and controls fared well until planned sacrifice. After xenopericardium
      repair, obstructive intraluminal granulation tissue led to early sacrifice in
      three rabbits. Stent insertion led to earlier death from airway obstruction in
      all six rabbits. Topical VEGF reduced granulation tissue after pericardial repair
      and fibrosis in all repairs except in stents. Remarkably, VEGF-pretreated half
      patches and saline half-patches stained similarly high for VEGF, suggesting also
      local production of VEGF, probably in plasmacells, and in submucosal glands.
      CONCLUSIONS: Autograft repair induces the least granulation tissue and fibrosis,
      and the best healing pattern. Stents rapidly induced critical airway obstruction,
      unhindered by VEGF, leading to premature death. Tracheal pretreatment with
      topical VEGF reduces postoperative fibrosis after autograft and pericardial patch
      repairs, and reduces granulation tissue after xenopericardium repair. In time,
      VEGF is probably locally produced, although its potential role in tracheal
      healing remains to be established.

PMID- 12493497
TI  - Heterotopic transplantation of cryopreserved tracheae in a rat model.
AB  - INTRODUCTION: The successful use of cryopreserved tracheal allografts in canine
      models suggests their use in humans. The grade of genetic difference, the
      mechanism of revascularisation and the method of cryopreservation are not clearly
      defined. The purpose of our study was to investigate the rejection of tracheal
      transplants in a standardised heterotopic rat model using different forms of
      cryopreservation. METHODS: Tracheae from Brown Norway rats were implanted into
      the omentum from Brown Norway rats or Lewis rats. We transplanted fresh isografts
      or allografts and pretreated isografts or allografts. Cryopreservation was
      performed in a medium containing 10% dimethyl sulphoxide at -80 degrees C for 28
      days (I) or -196 degrees C for 84 days (II) or without medium at -80 degrees C
      for 28 days (III). The transplants were excised after 7 and 21 days,
      respectively. RESULTS: Histological examinations revealed normal structure and
      function of isografts after 21 days. In the cryopreserved isograft, the
      epithelium had disappeared and the tracheal lumen was partially obstructed by a
      non-compact fibrous tissue. In the fresh allografts, the epithelium was replaced
      by aggressive fibrous tissue, infiltrating the membranous part of the trachea and
      occluding the tracheal lumen. The cartilage was vital without any sign of
      rejection. In the cryopreserved allografts, the tracheal lumen was obstructed by
      dense fibrous tissue with an inflammatory reaction. The cartilage of
      cryopreserved allografts (II) and (III) had lost the nuclei corresponding to non
      vital tissue. Only in the cryopreserved allografts (I) did we find nodular
      regeneration at the edges of the cartilaginous bow. CONCLUSIONS: The heterotopic
      transplantation model allows the study of the mechanisms leading to tracheal
      obstruction. Cryopreservation was found to have no clear advantage in reducing
      transplant immunogenicity. Cryopreservation leads to significant damage to the
      cartilage, the intensity of which is dependent on the mode of cryopreservation.

PMID- 12493498
TI  - Surgical results of stage I non-small cell lung cancer: comparison between
      elderly and younger patients.
AB  - OBJECTIVE: The aim of this study was to evaluate the overall cancer-related
      survival in younger and elderly (over 70 years old) patients with stage I non
      small cell lung cancer (NSCLC) together with prognostic factors in the elderly.
      METHODS: The patient records of 797 patients who underwent surgery for stage I
      NSCLC were analyzed retrospectively. A total of 132 patients were over 70 years
      old. The clinical variables and overall cancer-related survival were compared
      between two groups. An analysis was performed to determine the risk factors that
      influenced the survival of elderly patients. Variables analyzed included sex,
      presence of symptoms, operative procedure, histopathology, size of tumor and
      tumor classification. RESULTS: Between the two groups, the nature of the
      operation performed (pneumonectomy or not) and the presence of symptoms reached
      statistical significance (P<0.001). Overall 5- and 10-year survival rates were
      64.5% and 53.68% in younger patients and 58.23% and 52.24% in the elderly. There
      was no significant difference in survival between the groups (P=0.35). The only
      significant prognostic factor in the elderly patients was the size of the tumor
      in the multivariate analysis (P=0.0442, relative risk 2.28 (1.02-5.10 95% CI)).
      CONCLUSIONS: Surgical resection for stage I NSCLC in elderly patients over the
      age of 70 years results in a comparable overall cancer-related survival to that
      evident in younger patients. The size of the tumor is the only significant factor
      to influence the survival of elderly patients. Continued careful selection of
      elderly patients for surgical resection is important for acceptable operative
      results.

PMID- 12493499
TI  - Factors associated with perioperative complications and long-term results after
      pulmonary resection for primary carcinoma of the lung.
AB  - OBJECTIVE: The aim of this study was to describe perioperative morbidity and
      mortality of patients presenting with resectable lung cancer and to investigate
      the long-term survival. METHODS: We reviewed the records of 344 patients who
      underwent lung resection for bronchogenic carcinoma. Follow-up information was
      obtained from visits to the outpatient clinic. RESULTS: Between January 1991 and
      December 1995 there were 263 males and 81 females included with a mean age of
      65.7 years. One hundred and eight (31%) patients underwent a pneumonectomy, 159
      (46%) a lobectomy, 43 (13%) a bilobectomy, four (1%) a segmental resection and 30
      (9%) an explorative thoracotomy. A total of 341 complications occurred. The 30
      day mortality rate was 7.9% (27 patients). Patients with a low FEV1% and older
      patients have a higher risk of mortality within 30 days. Postoperative myocardial
      infarction and pneumonia were associated with an increase in 30 day mortality.
      The median survival was 3.6 years for stage I, 1.9 years for stage II, 1.0 years
      for stage IIIa, 0.9 years for stage IIIb and 0.9 years for stage IV. Prognostic
      factors for the long-term survival included stage, pneumonectomy, percentage FEV1
      <70, and large cell carcinoma. CONCLUSIONS: Pulmonary resection can be performed
      at an acceptable risk. Critical reviewing of our results made it possible to make
      recommendations for improvements.

PMID- 12493500
TI  - Validation of the Charlson comorbidity index in patients with operated primary
      non-small cell lung cancer.
AB  - OBJECTIVE: To validate the influence of the Charlson comorbidity index (CCI) in
      patients with operated primary non-small cell lung cancer. METHODS: From January
      1996 to December 2001, 205 consecutive resections for non-small cell lung cancer
      were performed at the Erasmus Medical Center Rotterdam. The patients ranged in
      age from 29 to 82 years, with a mean age of 64 years. In a retrospective study,
      each patient was scaled according to the CCI and the complications of surgery
      were determined. RESULTS: The hospital mortality was 2.4% (5/205). Of the 205
      patients 167 (32.7%) experienced minor complications and 32 (15.6%) major
      complications. In univariate analysis, gender, grades 3-4 of the CCI, any prior
      tumor treated in the last 5 years and chronic pulmonary disease were significant
      predictors of adverse outcome. Multivariate analysis showed that only grades 3-4
      of the CCI was predictive (odds ratio=9.8; 95% confidence interval=2.1-45.9).
      Although only comorbidity grades 3-4 was a significant predictor, for every
      increase of the comorbidity grade the relative risk of adverse outcome showed a
      slight increase. CONCLUSION: The CCI is strongly correlated with higher risk of
      surgery in primary non-small cell lung cancer patients and is a better predictor
      than individual risk factors.

PMID- 12493501
TI  - A comparison of three scoring systems for predicting complications after major
      lung resection.
AB  - OBJECTIVES: Although complications occur frequently after major lung resection,
      current predictive models are not entirely satisfactory. We devised a new
      predictive scoring system and compared it to two existing systems. METHODS: We
      performed an initial retrospective review of 400 patients who underwent major
      resection for lung cancer from 1980 to 1995. Predictive covariates (age,
      spirometry, diffusing capacity) associated with three or more complication groups
      were used to develop a scoring system. This system (EVAD) was then evaluated
      against the Physiological and Operative Severity Score for Enumeration of
      Mortality and Morbidity (POSSUM) and Cardiopulmonary Risk Index (CPRI) systems
      for patients operated between 1996 and 2001. RESULTS: Major resection for lung
      cancer included lobectomy (188) and pneumonectomy (30). Complication categories
      were: pulmonary (23; 10.5%); cardiovascular (24; 11.0%); infectious (8; 3.6%);
      other (29; 13.2%); nonfatal (45; 20.6%); and any (53; 24.2%). Death occurred in
      ten patients (4.6%). Mean EVAD scores were significantly different between groups
      with and without complications in all categories except infectious complications
      and death, whereas mean CPRI scores differed only for pulmonary complications,
      nonfatal complications, and death, and mean POSSUM scores did not appropriately
      differ for any complications. EVAD predicted incremental risk in all complication
      categories except cardiovascular, infectious, and death, whereas CPRI predicted
      incremental risk only for nonfatal and possibly any complications, and POSSUM did
      not predict incremental risk for any complication category. Receiver operating
      characteristic analysis demonstrated the EVAD system to be equivalent to or
      better than CPRI and POSSUM for all complication categories. CONCLUSIONS: A
      simple scoring system (EVAD) that utilizes pulmonary function test data and
      patient age predicts the likelihood of complications after major lung resection.
      It is easier to use and at least as accurate as other scoring systems currently
      in use.

PMID- 12493502
TI  - Primary traumatic pulmonary pseudocysts: a rare entity.
AB  - OBJECTIVE: Pulmonary contusion is the usual manifestation of lung parenchymal
      injury after blunt chest trauma. With deceleration these parenchymal lacerations
      can result in cavities known as primary traumatic pulmonary pseudocysts (TPPC).
      We present our experience in treating this rare entity. MATERIAL: From 1989
      trough 1999, 14 young patients, 11 male and three female ranging in age between
      13 and 24 years were treated for primary TPPC in our department. Blunt chest
      injuries resulting from traffic accidents were the causes in all our cases. The
      main symptoms were pain, hemoptysis and dyspnea not associated with severe
      hypoxemia. The cavitary lesion was apparent in chest radiographs, but the imaging
      modality of choice was the computed tomography. RESULTS: Multisystem injury was
      present in 7 of them. Two of our patients required ICU facilities but none needed
      mechanical ventilation. Hemopneumothorax was present in two cases, whereas
      pneumothorax in four drained by tube thoracostomy. The hospital stay ranged
      between 9 and 23 days. Contraction and complete radiological resolution of the
      PPC needed a follow up of 6-11 weeks. CONCLUSIONS: (1) Primary traumatic
      pulmonary pseudocysts are benign lesions secondary to blunt chest trauma needing
      only conservative treatment unless complications arise, such as hemo- or
      pneumothorax or infection of the cavitary lesion. (2) Computed tomography is a
      really sensitive method for early detection of the lesion while plain
      roentgenograms are sufficient for the follow up.

PMID- 12493503
TI  - Surgery of chronic traumatic aneurysm of the aortic isthmus: benefit of direct
      suture.
AB  - OBJECTIVE: Retrospective evaluation of long term results after direct suture
      repair of chronic traumatic aneurysm of the aortic isthmus. METHODS: From March
      1979 to June 1998, a total of 19 patients with chronic traumatic aneurysm of the
      aortic isthmus were operated on, among whom 12 (63%) underwent direct suture.
      These 12 patients (age ranging from 19 to 68 years; mean 34.2 years) constitute
      the subject of this study. All but one suffered traffic accidents. Mean delay
      between trauma and surgery was 4 years (range 3 months to 12 years). All patients
      underwent a left posterolateral thoracotomy through the fourth intercostal space.
      Extracorporeal circulation for spinal cord protection was installed in six
      patients (five ilio-iliac shunts, one atrio-iliac shunt). Aortic rupture was
      partial in five and circumferential in seven patients. The mean clamping time was
      25 min. The absence of loss of aortic substance and a careful mobilization of the
      aorta made the repair by direct suture easier; this technique could thus be
      achieved in 63.2% of all 19 patients operated on of chronic traumatic aneurysm
      within the same period. RESULTS: There was no in-hospital death and no
      postoperative paraplegia. With a median follow-up of 15 years 3 months (ranging
      from 22 to 10 years), there were no late complications. Chest X-ray was normal in
      all patients; eight of them underwent a control angiography between 18 and 72
      postoperative months; all these angiographies but one (20% stenosis without
      gradient) demonstrated a normal appearance of aortic isthmus. CONCLUSION: Direct
      suture for repair of chronic traumatic thoracic aneurysm is a safe procedure:
      long-term outcome was excellent and the complications observed with prosthetic
      grafts or with aortic endoprosthetic stent-grafts were avoided.

PMID- 12493504
TI  - Does off-pump coronary artery bypass (OPCAB) surgery improve the outcome in high
      risk patients?: a comparative study of 1398 high-risk patients.
AB  - OBJECTIVE: Although there has been some evidence supporting the theoretical and
      practical advantages of off-pump coronary artery bypass (OPCAB) over the
      conventional coronary artery bypass grafting (CABG) with cardiopulmonary bypass
      (CPB), it has not yet been determined which group of patients would benefit most
      from it. It has been advocated recently that high-risk patients could benefit
      most from avoidance of CPB. The aim of this retrospective study is to assess the
      efficacy of the OPCAB technique in multi-vessel myocardial revascularization in a
      large series of high-risk patients. METHODS: The records of 1398 consecutive high
      risk patients who underwent primary isolated CABG at Harefield Hospital between
      August 1996 and December 2001 were reviewed retrospectively. Patients were
      considered as high-risk and included in the study if they had a preoperative
      EuroSCORE of > or =5. Two hundred and eighty-six patients were operated on using
      the OPCAB technique while 1112 patients were operated on using the conventional
      CABG technique with CPB. The OPCAB patients were significantly older than the CPB
      patients (68.1+/-8.3 vs. 63.7+/-9.9 years, respectively, P<0.001). The OPCAB
      group included significantly more patients with poor left ventricular (LV)
      function (ejection fraction (EF) < or =30%) (P<0.001) and more patients with
      renal problems (P<0.001). RESULTS: There was no significant difference in the
      number of grafts between the groups. The CPB patients received 2.8+/-1.2 grafts
      per patient while OPCAB patients received 2.8+/-0.5 grafts per patient (P=1).
      Twenty-one (7.3%) OPCAB patients had one or more major complications, while 158
      (14.2%) CPB patients (P=0.008) developed major complications. Thirty-eight (3.4%)
      CPB patients developed peri-operative myocardial infarction (MI) while only two
      (0.7%) OPCAB patients developed peri-operative MI (P=0.024). The intensive
      therapy unit (ITU) stay for OPCAB patients was 29.3+/-15.4 h while for CPB
      patients it was 63.6+/-167.1 h (P<0.001). There were ten (3.5%) deaths in the
      OPCAB patients compared to 78 (7%) deaths in the CPB patients (P=0.041) within 30
      days postoperatively. CONCLUSIONS: This retrospective study shows that using the
      OPCAB technique for multi-vessel myocardial revascularization in high-risk
      patients significantly reduces the incidence of peri-operative MI and other major
      complications, ITU stay and mortality. Even though the OPCAB group included a
      significantly higher proportion of older patients with poor LV function (EF < or
      =30%) and renal problems, the beneficial effect of OPCAB was evident.

PMID- 12493505
TI  - Internal thoracic artery flow competition: studies in a canine H-graft model.
AB  - OBJECTIVE: Internal thoracic artery (ITA) flow competition is a diversion of
      graft flow through intact ITA branches with a net decrease in perfusion to the
      grafted coronary. Although a widely acknowledged phenomenon, the conditions under
      which flow competition occurs have not been established. This is examined in a
      canine H-graft model. METHODS: Eight dogs had a right ITA segment interposed (H
      graft) between their in situ left ITA (LITA) and the snared left anterior
      descending (LAD) coronary artery. Proximal LITA and H-graft flows were measured
      at baseline and during pacing-induced tachycardia, phenylephrine-induced
      hypertension, and nitroprusside-induced hypotension. Flows were measured with the
      distal LITA open and occluded. Two additional animals were subjected to eight
      separate 2-min periods of LAD ischemia, after which post-ischemic H-graft flow
      measurements were obtained with and without distal LIMA occlusion. RESULTS:
      During baseline conditions, proximal LITA flow was greater when the distal LITA
      was open rather than occluded (46+/-15 versus 35+/-12 ml/min, respectively;
      P=0.002), but H-graft flow did not change significantly (32+/-18 versus 35+/-18
      ml/min, respectively; P=0.21). Similarly, occlusion of the distal LITA had no
      impact on H-graft flow during tachycardia, hypertension, or hypotension. Only in
      animals subjected to transient LAD ischemia did H-graft flow increase with distal
      LITA occlusion, albeit marginally (65+/-7-70+/-9 ml/min, occluded versus open,
      respectively; P=0.04). CONCLUSIONS: Mild diversion of flow from the LAD was
      demonstrated during immediate post-ischemic coronary reperfusion only, and could
      not be elicited under any other physiologic condition. These data suggest that
      flow competition is unlikely to constitute a clinically significant limitation to
      the use of H-grafts or other modalities that leave ITA branches patent.

PMID- 12493506
TI  - The effect of aprotinin on ischemia-reperfusion injury in an in situ normothermic
      ischemic lung model.
AB  - OBJECTIVES: In the context of the physiopathology of damage due to ischemic
      preservation and reperfusion injury following preservation, we aimed to
      demonstrate the positive effects of the addition of aprotinin, a serine protease
      inhibitor, to low potassium dextran (LPD), used as a single-flush solution in
      normothermic ischemic animal models, on lung protection and the prevention of
      reperfusion injury. METHODS: In the study, 21 New Zealand white rabbits were used
      as experimental subjects. The subjects were ventilated with the assistance of a
      manual mechanical ventilator at 30 breaths/min and 10 ml/kg tidal volume. Lung
      protection solution was supplied to the pulmonary artery via a catheter. After
      applying the solution, ischemia was carried out for 120 min. At the end of this
      period, reperfusion was carried out for 90 min. The subjects were divided into
      three groups of seven subjects each. In the control group, pulmonary perfusion
      solution was not employed, whereas in the second group LPD was employed, and in
      the third group LPD and aprotinin (LPD+A) were perfused. Blood gas analysis,
      bronchoalveolar lavage (BAL) fluid examination, tissue malondialdehyde (MDA)
      level analysis and morphological examinations were performed. RESULTS: The LPD+A
      group showed the significantly highest levels of oxygenation at the 15th and 60th
      minutes of reperfusion (297+/-76.7 and 327+/-97.4 mmHg) in comparison to the LPD
      (157+/-20.6 and 170+/-53.6 mmHg) and control (64+/-8.4 and 59+/-7.2 mmHg) groups
      (P<0.001). The LPD+A group showed the significantly lowest levels of alveolar
      arterial oxygen difference at the 60th minute of reperfusion (389+/-15 mmHg) in
      comparison to the LPD (478+/-19 mmHg) and control (542+/-23) groups (P<0.001).
      The BAL fluid neutrophil percentage was significantly lower in the LPD+A group
      (22+/-2.4%) compared to the LPD (31+/-6.1%) and control (38+/-2.4%) groups. MDA
      levels were significantly lower in the LPD+A group (119.8+/-5.3 nmol MDA/g) when
      compared to the LPD (145.06+/-9.5 nmol MDA/g) and control (147.3+/-3.9 nmol
      MDA/g) groups (P<0.05). Morphological examinations revealed pathological lesions
      and alveolar hemorrhaging in all samples, with the LPD+A group having
      statistically more significant levels than the LPD and control groups (P<0.005).
      The LPD+A group had a significantly lower percentage of pathological lesions and
      alveolar hemorrhage grade values than the LPD and control groups (P<0.005).
      CONCLUSIONS: It was observed that the addition of aprotinin to LPD solution as a
      pulmonary flush solution in an in situ normothermic ischemic lung model prevents
      reperfusion injury by means of various mechanisms and also protects the
      morphological, functional and biochemical integrity of the lung. In our view,
      therefore, the addition of aprotinin to lung protection solution will provide
      positive results in lung transplantation protocols.

PMID- 12493507
TI  - Electromechanical impairment of human auricle and rat myocardial strip subjected
      to exogenous oxidative stress.
AB  - OBJECTIVE: Animal myocardial dysfunction induced by remote ischemia-reperfusion
      (IR) was shown to be partly accomplished via a direct effect of the pro-oxidant
      xanthine oxidase (XO). This direct remote effect was not tested in humans. We now
      assessed the performance of human auricles in the presence of solutions
      containing XO and/or allopurinol and compared them to those of rat myocardial
      strips. METHODS: Human and rat specimens (n=64) were separately exposed for 2h to
      Krebs-Henseleit solution that either (1) exited from rat livers that were earlier
      perfused for 2h (control-human or control-rat), (2) exited from livers that were
      earlier made ischemic for 2h (IR-human, IR-rat), (3) contained xanthine (X) 3.8
      microM + XO 3 mU ml(-1) (X+XO-human, X+XO-rat), or (4) exited from post 2h
      ischemic livers and contained 100 microM allopurinol (human or rat IR +
      allopurinol groups). RESULTS: Unlike the unchanged electromechanical performance
      in the control and IR+allopurinol auricles and strips, the rates of contraction,
      maximal force of contraction and working index of either preparation were reduced
      by 75-98% (P<0.01) when exposed to the IR reperfusate or to the X+XO-enriched
      Krebs. The basal amplitudes of contraction in these four latter groups increased
      twofold (P<0.01). XO activity was similarly low in the control and in the
      IR+allopurinol groups, but four- to 45-fold (P<0.001) higher in the IR and the
      X+XO groups, both in the rat and human organs. The reduced glutathione was
      reduced by approximately 50% (P<0.01) in either preparation in the IR and the
      X+XO groups compared to the control and IR+allopurinol groups. CONCLUSIONS:
      Remotely and exogenously originated oxidative burst directly induces
      electromechanical dysfunction and disrupts oxidant/antioxidant balance in human
      auricles as it does in the rat myocardial strip.

PMID- 12493508
TI  - Transmyocardial laser revascularization combined with vascular endothelial growth
      factor 121 (VEGF121) gene therapy for chronic myocardial ischemia--do the effects
      really add up?
AB  - OBJECTIVE: Different therapy strategies for coronary disease in conventionally
      untreatable patients have been developed, among them transmyocardial laser
      revascularization (TMLR) and the application of growth factors. The objective of
      our study was to determine whether a combined therapy of TMLR with a vascular
      endothelial growth factor(121) (VEGF(121)) plasmid is able to stimulate the
      development of sufficient collateral circulation and hereby to preserve cardiac
      function. MATERIALS AND METHODS: A severe stenosis of the left anterior
      descending artery was created in healthy pigs. After 1 week, perfusion and
      regional contractility were assessed at baseline. Afterwards, the ischemic area
      was treated with TMLR (n=8), intramyocardial injection of naked plasmid DNA
      encoding VEGF(121) (n=7), or both (n=7). Control animals were left untreated
      (n=8). After 3 months, the animals were re-examined and underwent
      immunohistological analysis. RESULTS: The number of capillaries increased only
      after injection of VEGF(121) plasmid alone compared to untreated ischemia and to
      the other therapy groups, whereas the number of arterioles was higher following
      TMLR treatment alone or in combination with VEGF(121) than it was in the case in
      untreated ischemic animals. However, only combined VEGF(121)+TLMR therapy
      resulted in an improvement in regional myocardial blood flow in comparison with 1
      week ischemia, indicating the efficient development of collateral circulation. In
      contrast, better regional contractility compared to the 1-week baseline, as well
      as restoration of the pre-ischemic values, were achieved by both VEGF(121) and
      combined VEGF(121)+TLMR therapies. CONCLUSIONS: This study of chronic myocardial
      ischemia with a porcine model indicates a synergistic action of TMLR and
      VEGF(121) gene therapy. Combined treatment alone achieved an increase of regional
      myocardial perfusion, which accompanied arteriogenesis and corresponded with the
      restoration of regional function.

PMID- 12493509
TI  - Maintained benefits and improved survival of dynamic cardiomyoplasty by activity
      rest stimulation: 5-year results of the Italian trial on "demand" dynamic
      cardiomyoplasty.
AB  - OBJECTIVE: Latissimus dorsi (LD) muscular degeneration caused by continuous
      electrical stimulation has been the main cause of the poor results of dynamic
      cardiomyoplasty (DCMP) and its exclusion from the recent international guidelines
      on heart failure. To avoid full transformation of the LD and to improve results,
      a new stimulation protocol was developed; fewer impulses per day are delivered,
      providing the LD wrap with daily periods of rest ("demand" stimulation), based on
      a heart rate cut-off. The aim of this work is to report the results at 5 years of
      follow-up of the Italian Trial of Demand Dynamic Cardiomyoplasty and to discuss
      their impact on the destiny of this type of cardiac assistance. METHODS: Twelve
      patients with dilated myocardiopathy (M/F=11/1, mean age 58.2+/-5.8 years, sinus
      rhythm/atrial fibrillation=11/1) were submitted during the period 1993-1996 to
      DCMP and at different intervals to demand protocol. Clinical, echocardiographic,
      mechanographic and cardiac invasive assessments were scheduled before initiating
      the demand protocol and during the follow-up at 0, 6 and every 12 months.
      RESULTS: The mean duration of follow-up was 40.2+/-13.8 months (range 18-64).
      There were no perioperative deaths. The demand stimulation protocol showed a
      decrease in 5 years in New York Health Association (NYHA) class (3.17+/-0.38
      1.67+/-0.77, P=0.0001), an improvement of left ventricular ejection fraction
      (22.6+/-4.38-32.0+/-7.0, P<0.001), a 5-year actuarial survival of 83.3% (one
      patient was switched to heart transplantation programme due to clinical worsening
      and another one died of massive pulmonary embolism). CONCLUSIONS: Demand DCMP
      maintains over time LD muscular properties, enhances clinical benefits and
      improves survival of DCMP, thus reopening the debate whether this type of
      treatment should be considered in patients with end-stage heart failure.

PMID- 12493510
TI  - Sorin Bicarbon bileaflet valve: a 10-year experience.
AB  - OBJECTIVE: To present a large 10 year experience of a collaborative evaluation of
      the Sorin Bicarbon (SB) mechanical prosthesis carried out in 14 centers in eight
      Western European countries. METHODS: Between 4/90 and 12/96, 2078 SB valves were
      implanted in 1875 patients aged 4-84 years (mean 58), 1108 males and 767 females.
      The valves inserted were 1026 aortic valve replacement (AVR), 656 mitral valve
      replacement (MVR) and 203 double valve replacement (DVR), additional procedures
      performed in 467 patients (282 coronary artery bypass grafting). RESULTS: Early
      mortality was 97 (5%), overall survival at 8 years was 71.8% AVR, 69.4% MVR,
      81.4% DVR. Total late valve-related deaths were 55; overall freedom from valve
      related death at 8 years was 95%. New York Heart Association (NYHA) status after
      surgery: 78% improved and 17% unchanged. Twenty-two valve thrombosis were
      observed, one fatal; overall freedom from thrombosis at 8 years was 98.5%.
      Embolism occurred in 95 patients, 77 cerebral events (16 deaths), overall freedom
      from embolism was 90.7% at 8 years. Six hemolytic events and 26 non-structural
      dysfunction (all periprosthetic leaks) were reported. Major bleeding occurred in
      66, with mortality rate of 32% mainly when intracerebral. Overall freedom from
      bleeding was 90.8% at 8 years. Endocarditis occurred in 31 patients, 29% were
      fatal; overall freedom from endocarditis was 97.8% at 8 years. Reoperation was
      performed in 49 cases--periprosthetic leak 20, infective endocarditis 14,
      thrombosed valve 13 (and non-valve related-2). Mortality (early and late)
      occurred in three reoperated patients. CONCLUSIONS: This is a durable and
      effective mechanical valve substitute with low morbidity and mortality and good
      functional results.

PMID- 12493511
TI  - Impact of high intensity transient signals on the choice of mechanical aortic
      valve substitutes.
AB  - OBJECTIVE: High intensity transient signals (HITS) observed during extracorporeal
      circulation and following mechanical valve replacement are suspected of causing
      cognitive dysfunction (deterioration of episodic and working memory). This study
      evaluates the role played by valve design (bileaflet versus tilting disc) and
      other parameters in the incidence of HITS. METHODS: Thirty patients were selected
      for the study as follows: 18 males, 58-78 years of age; ten St. Jude Medical, ten
      CarboMedics, ten Medtronic Hall (MH); all size 23, in optimum orientation (Ann
      Thorac Surg 68 (1999) 1069); all in sinus rhythm; no coronary or carotid artery
      disease; all in sinus rhythm, international normalized ratio greater than 2.5 and
      all at least 9 months postoperative. All patients had bilateral HITS measurement
      in both middle cerebral arteries via transcranial doppler for 30 min. If five
      HITS or more were observed during the initial 10 min, patients were subjected to
      100% oxygen breathing followed by 10 min of normal air breathing. Simultaneously,
      HITS were measured in the right radial and femoral arteries. RESULTS: Patients
      with bileaflet valve substitutes revealed HITS rates varying from 32 to 108
      counts/h. There was only one HITS observed in the MH valve group during the 5h
      observation period (0.2 HITS/h). There were no HITS detected in either the radial
      or the femoral arteries in any patient. After breathing 100% oxygen, HITS
      significantly decreased or completely disappeared (0-30 HITS/h). When normal air
      breathing was resumed HITS reappeared or increased. With an intravenous infusion
      of 100 mg of lysine acetylsalicylate (Aspisol, Bayer Leverkusen, Germany), HITS
      decreased by 16 to 41%. CONCLUSIONS: We conclude that bileaflet mechanical valve
      prostheses produce HITS even in their optimum orientation. HITS following
      bileaflet valve replacement have an unstable nature and might be composed of
      nitrogen and platelets. Tilting disc valves in their optimum orientation provide
      almost physiological conditions with HITS measured in the same range as
      bioprosthesis.

PMID- 12493512
TI  - Prevalence of 90-days postoperative wound infections after cardiac surgery.
AB  - OBJECTIVE: Postoperative wound infections generally cause considerable extra
      morbidity, mortality and costs. As nowadays length of hospitalization shortens,
      post-discharge surveillance is important to get reliable information on the
      prevalence of postoperative wound infections. In this study, the prevalences of
      sternal wound (SWI) and donor site infections (DSI) during hospitalization as
      well as, 30 and 90 days after cardiac surgery were studied paying special
      attention to the contribution of post-discharge surveillance. METHODS: A total of
      1885 patients who underwent cardiac surgery were included in the study and were
      followed for the prevalence of SWI or DSI up to 90 days postoperatively.
      Infection data during hospitalization were collected using medical records,
      bacteriological results and systematic observations of infection control nurses.
      After discharge from the hospital, data were collected with the help of the out
      patient clinic and the family physician. RESULTS: After cardiac surgery, SWI and
      DSI were diagnosed in 4.7 and 1.5% of patients during hospitalization, in 6.8 and
      4.6% at 30 days postoperatively, and in 9.0 and 7.3% of patients at 90 days
      postoperatively. Of the 90-days postoperative infections rates almost half of SWI
      and 80% of DSI were diagnosed post-discharge, a result predominantly achieved by
      the active participation of the family physicians. CONCLUSIONS: After 30 and 90
      days follow-up of patients after cardiac surgery, additional sternal wound and
      donor site infections were diagnosed compared with the in-hospital infection
      rate. Post-discharge surveillance is essential for a reliable assessment of
      surgical wound infections.

PMID- 12493513
TI  - Ischemic non-septal interventricular communication.

PMID- 12493514
TI  - Compression of the central airways by a bronchogenic cyst.

PMID- 12493515
TI  - Malignant melanocytic schwannoma, a rare tumor of the posterior mediastinum.

PMID- 12493516
TI  - Three-dimensional CT imaging and virtual endoscopy for the placement of self
      expandable stents in oesophageal and tracheobronchial neoplastic stenoses.
AB  - We examined the value of multislice computed tomography (CT) with three
      dimensional (3D) reconstruction of the images as a pre-treatment examination in
      order to plan endoluminal stenting in 14 patients with large tumours involving
      the oesophagus and/or the tracheobronchial tree. The measurement of the stenosis
      obtained during 3D reconstruction of the CT images corresponded to that obtained
      by endoscopy and to the prosthesis chosen in all cases, with the exception of one
      patient undergoing double stenting due to inadequate gaseous distension of the
      oesophageal lumen. 3D CT may add information with respect to axial imaging, and
      be helpful to better plan and perform stenting of the oesophagus and airways
      without burdening the preoperative work-up.

PMID- 12493517
TI  - A repair of funnel chest without sternal dissection in aortic root replacement.
AB  - A 46-year-old man with Marfan syndrome was admitted for repair of annuloaortic
      etasia and funnel chest. Before median sternotomy, seven transverse skin
      incisions were made for resection of deformed ribs. The convex portions at the
      costochondral junctions of the right 4 approximately 7th and left 5 approximately
      7th ribs were removed. Thereafter, the conventional median sternotomy was safely
      performed. Aortic root was replaced. After weaning from the cardiopulmonary
      bypass, the redundant distal end of the sternum was resected, fractured sites of
      the concave sternum were straightened and secured with wire fixation, and the
      split sternum was sutured with wires in an ordinary fashion.

PMID- 12493518
TI  - Bifid proximal anastomosis technique of radial artery.
AB  - We have modified proximal anastomosis of radial artery to reduce technical
      problems due to wall thickness disparity between radial artery and ascending
      aorta. Bifid proximal anastomosis of both radial arteries is done just after
      cannulation without cardiopulmonary bypass initiation. Proximal sides of two
      radial arteries are spatulated with thin incisions. Closer sides of radial
      arteries are sutured with 8/0 polypropylene suture. Then side clamp is applied on
      the ascending aorta. The proximal anastomosis is performed directly onto a 5-mm
      punched opening in the ascending aorta with continuous 6/0 polypropylene. Thus we
      create a graft with bifid proximal anastomosis.

PMID- 12493519
TI  - True aneurysm of an internal thoracic artery patch used for repair of a
      coarctation of the aorta.
AB  - This report describes the formation of a true aneurysm 15 years after an internal
      mammary artery patch aortoplasty of an aortic coarctation. A true aneurysm was
      confirmed on histology. To our knowledge, this is the first report of a case with
      such a complication.

PMID- 12493520
TI  - Management of aortobronchial fistula following coarctation repair.
AB  - Aortobronchial fistula is a rare complication following thoracic aortic
      operations and is invariably fatal if not promptly diagnosed and repaired. Direct
      prosthetic repair carries a risk of graft repair sepsis and fistula recurrence.
      We describe two cases presenting with aortobronchial fistula following
      coarctation repair which were successfully treated by different surgical
      approaches.

PMID- 12493521
TI  - Intimo-intimal intussusception: a rare clinical form of aortic dissection.
AB  - A 33-year-old hypertensive man presented with epigastric pain radiating to the
      back. Transoesophageal echocardiography (TOE) revealed an intimal flap on the
      aortic arch and descending aorta. No intimal flap of the ascending aorta was
      detected on TOE or CT. The diagnosis was made on opening the ascending aorta:
      complete circumferential dissection of the ascending aorta flush with the
      coronary ostia, with no residual intimal flap, and intimo-intimal glove-finger
      intussusception of the internal channel into the descending thoracic aorta.
      Aortic intussusception is a very rare form of Type I dissection, and the absence
      of intimal tear in the ascending aorta can be misleading and delay the diagnosis.

PMID- 12493522
TI  - Aneurysm of the right ventricular outflow following bovine valved venous conduit
      insertion.
AB  - A case of aneurysm of the right ventricular outflow tract is described after
      repair of tetralogy of Fallot using a Contegra supported conduit. Angiograms
      revealed that the aneurysm was located between the ventricular anastomosis and
      the proximal ring of the conduit confirming echocardiographic data. Because the
      conduit between the rings was not dilated, the valve was perfectly functioning.
      Pulmonary anastomosis was severely stenosed explaining the dilatation seen below.
      Conduit replacement with resection of the aneurysmal part of the failing conduit
      was performed. Supported conduits do not eliminate the risk of secondary
      dilatation below the artificial ring but preserve valvular function.

PMID- 12493523
TI  - Vertebral osteomyelitis combined streptococcal viridans endocarditis.
AB  - Endocarditis may be difficult to diagnose in patients with osteomyelitis in an
      early stage because they usually are treated for fever, bone pain and stiffness
      in the outpatient department. Herein we report an uncommon patient who developed
      severe lower back pain sustained for 2 months, and streptococcal viridans
      infected vertebral osteomyelitis combined endocarditis were diagnosed and cured.

PMID- 12493524
TI  - Esophagobronchial fistula caused by traction esophageal diverticulum.
AB  - Fistulization is a rare and not often described complication of esophageal
      diverticula. We present the case of a patient treated surgically in our service
      who had a history of diverticulum of the third distal of the esophagus, and was
      diagnosed for irritative post-ingestive cough with associated regurgitation and
      vomiting of undigested food.

PMID- 12493525
TI  - Pneumopericardium due to intrapericardial perforation of a gastric ulcer.
AB  - A 88-year-old male patient presented with fever, singultus and retrosternal pain.
      After 8 days of antibiotic therapy not resulting in clinical improvement, he
      suddenly developed a pneumopericardium. Contrast swallow and endoscopy showed
      intrapericardial perforation of a benign gastric ulcer. Excision of the ulcer and
      suturing of both the stomach and the diaphragm as well as lavage of the
      pericardium were done over a left thoracotomy. The patient recovered
      uneventfully.

PMID- 12493526
TI  - Recurrence of stage I thymoma in sternum, 13 years after "complete" excision.
AB  - Recurrence after complete excision of non-invasive thymoma is infrequent. We
      report a case of recurrent thymoma in the sternum in a 76-year-old man 13 years
      after complete surgical resection of stage I thymoma.

PMID- 12493527
TI  - DORV with non-committed VSD and Taussig-Bing hearts. Controversial anatomic
      entities.

PMID- 12493529
TI  - Bilateral harvesting of internal thoracic artery for coronary bypass: augmenting
      the risk for postoperative airway obstruction?

PMID- 12493532
TI  - Iatrogenic left main and proximal right coronary artery stenoses after aortic
      valve replacement.

PMID- 12493533
TI  - Role of palmitoylation/depalmitoylation reactions in G-protein-coupled receptor
      function.
AB  - G-protein-coupled receptors (GPCRs) constitute one of the largest protein
      families in the human genome. They are subject to numerous post-translational
      modifications, including palmitoylation. This review highlights the dynamic
      nature of palmitoylation and its role in GPCR expression and function. The
      palmitoylation of other proteins involved in GPCR signaling, such as G-proteins,
      regulators of G-protein signaling, and G-protein-coupled receptor kinases, is
      also discussed.

PMID- 12493534
TI  - Stress proteins and glial functions: possible therapeutic targets for
      neurodegenerative disorders.
AB  - Recent findings suggest that unfolded or misfolded proteins participate in the
      pathology of several neurodegenerative disorders, such as Alzheimer's disease and
      Parkinson's disease. Usually, several stress proteins and glial cells act as
      intracellular molecular chaperones and show chaperoning neuronal function,
      respectively. In the brains of patients with neurodegenerative disorders,
      however, stress proteins are expressed and frequently associated with protein
      aggregates, and glial cells are activated around degenerative regions. In
      addition, several stress proteins and glial cells may also regulate neuronal cell
      death and loss. Therefore, some types of stress proteins and glial cells are
      considered to be neuroprotective targets. We summarize the current findings
      regarding the neuroprotective effects of stress proteins and glial cells, and
      discuss the possibility of using this knowledge to develop new therapeutic
      strategies to treat neurodegeneration.

PMID- 12493535
TI  - The N-methyl-D-aspartate receptor subunit NR2B: localization, functional
      properties, regulation, and clinical implications.
AB  - The N-methyl-D-aspartate (NMDA) receptor is an example of a heteromeric ligand
      gated ion channel that interacts with multiple intracellular proteins by way of
      different subunits. NMDA receptors are composed of seven known subunits (NR1,
      NR2A-D, NR3A-B). The present review focuses on the NR2B subunit of the receptor.
      Over the last several years, an increasing number of reports have demonstrated
      the importance of the NR2B subunit in a variety of synaptic signaling events and
      protein-protein interactions. The NR2B subunit has been implicated in modulating
      functions such as learning, memory processing, pain perception, and feeding
      behaviors, as well as being involved in a number of human disorders. The
      following review provides a summary of recent findings regarding the structural
      features, localization, functional properties, and regulation of the NR2B
      subunit. The review concludes with a section discussing the role of NR2B in human
      diseases.

PMID- 12493536
TI  - Therapy of chronic obstructive pulmonary disease.
AB  - Chronic obstructive pulmonary disease is one of the commonest causes of morbidity
      and mortality in the world, and is increasing in prevalence. Current therapies
      are not very effective, and no current treatment prevents the relentless
      progression of airflow limitation that characterizes this disease. Smoking
      cessation is the only strategy that reduces this decline in lung function, and
      although bupropion is the most effective aid to quitting, more effective
      treatments of nicotine addiction are needed. The mainstay of treatment is
      bronchodilators for symptom relief, and inhaled anticholinergics and beta(2)
      agonists are useful by reducing hyperinflation of the lungs. A new once-daily
      inhaled anticholinergic is the most effective bronchodilator, but long-acting
      inhaled beta(2)-agonists are also useful. Theophylline is used as an additional
      bronchodilator in more severe patients, and may have some anti-inflammatory
      action. In contrast, inhaled corticosteroids are poorly effective and do not
      reduce disease progression, although recent studies with combination inhalers
      (corticosteroid + long-acting beta(2)-agonist) have shown better effects. Long
      term oxygen therapy is needed by patients with pulmonary hypertension and right
      heart failure. There is a pressing need to develop new classes of therapy, and
      several new drugs are current in development, including interleukin-8
      antagonists, phosphodiesterase-4 inhibitors, protease inhibitors, and
      antioxidants.

PMID- 12493537
TI  - Direct electrophilic radiofluorination of a cyclic RGD peptide for in vivo
      alpha(v)beta3 integrin related tumor imaging.
AB  - The association of the alpha(v)beta(3) integrin with tumor metastasis and tumor
      related angiogenesis has been suggested. Therefore, by imaging the
      alpha(v)beta(3) receptor with PET, information concerning the tumor status could
      be obtained. Cyclic peptides including the RGD sequence, were radiolabeled by
      direct electrophilic fluorination with [(18)F]AcOF. In tumor-bearing mice, the
      labeled peptides accumulated at the tumor with a high tumor to blood ratio. These
      findings suggest that an assessment of tumor characteristics may be obtained by
      using these (18)F-labeled peptides.

PMID- 12493538
TI  - Fluoro-, bromo-, and iodopaclitaxel derivatives: synthesis and biological
      evaluation.
AB  - Paclitaxel (Taxol) is a clinically important chemotherapeutic agent. We describe
      the synthesis of fluoro-, bromo-, and iodopaclitaxel and their [(18)F]fluoro-,
      [(76)Br]bromo-, and [(124)I]iodo- analogues. [(18)F]Fluoropaclitaxel shows high
      uptake and rapid clearance from tissues in rats. Preadministration of paclitaxel
      in normal rats significantly increases (p < 0.005) retention of
      [(18)F]fluoropaclitaxel and [(76)Br]bromopaclitaxel in blood (33.0%), heart
      (32.0%), lung (37.6%) kidney (142.4%); and blood (33.4%), lung (42.3%), kidney
      (62.4%), respectively. [(18)F]Fluoropaclitaxel uptake in the brain of mdr1a/1b(-/
      ) mice is increased 1400% (p < 1.3e-07) relative to wild-type controls.
      Preadministration of paclitaxel or XR9576, a modulator, had little effect on the
      biodistribution in these mdr1a/1b(-/-) mice. As a result, [(18)F]fluoropaclitaxel
      will be a useful radiopharmaceutical for the study of multidrug resistant tumors.

PMID- 12493539
TI  - Imaging [18F]FAU [1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) uracil] in dogs.
AB  - We have studied the biodistribution of [(18)F]FAU [(1-(2'-deoxy-2'-fluoro-beta-D
      arabinofuranosyl)uracil], which previous work has shown is incorporated into DNA
      and functions as an inhibitor of DNA synthesis. It is being tested as a potential
      antineoplastic agent and imaging agent for PET. We have produced [(18)F]FAU and
      injected the tracer into 3 normal dogs and imaged them for up to 4 hours and
      removed tissues along with blood and urine samples for HPLC and activity
      analysis. The results showed that [(18)F]FAU evenly distributed to most of
      organs. In sharp contrast to our prior experience with thymidine and its analogs,
      marrow had less retention of [(18)F]FAU than the non-proliferating tissues.

PMID- 12493540
TI  - Characterization of 3-[125I]iodo-alpha-methyl-L-tyrosine transport via human L
      type amino acid transporter 1.
AB  - We examined transport of 3-[(125)I]iodo-alpha-methyl-L-tyrosine ([(125)I]IMT) in
      Xenopus laevis oocytes co-expressing human L-type amino acid transporter 1 (a
      component of system L) and human 4F2hc. Human LAT1 mediated transport of
      [(125)I]IMT. [(125)I]IMT uptake was decreased by the presence of L-isomers of
      Cys, Leu, Ileu, Phe, Met, Tyr, His, Trp and Val and D-isomers of Leu, Phe and
      Met. Human LAT1-mediated [(125)I]IMT uptake was highly stereoselective for the L
      isomers of Tyr, His, Trp, Val and Ileu. To examine the effects of 3-iodination
      and alpha-methylation on IMT transport, kinetic parameters of IMT were compared
      with those of mother Tyr and 3-[(125)I]iodo-L-tyrosine (3-I-Tyr). Uptake of Tyr,
      3-I-Tyr and [(125)I]IMT followed Michaelis-Menten kinetics, with K(m) values of
      29.0 +/- 5.1, 12.6 +/- 6.1 and 22.6 +/- 4.1 microM, respectively. Neither the
      alpha-methyl group nor the size of the 3-iodinated Tyr residue was an obstacle to
      transport via hLAT1. Furthermore, affinity of IMT for hLAT1 is higher than that
      of the natural parent tyrosine. The level of efflux mediated by hLAT1 was highly
      stimulated by extracellularly applied L-Leu, suggesting exchange of [(125)I]IMT
      and L-Leu via hLAT1.

PMID- 12493541
TI  - Synthesis of no-carrier-added C-11 labeled D- and L-enantiomers of phenylalanine
      and tyrosine for comparative PET Studies.
AB  - The natural amino acids tyrosine (Tyr) and phenylalanine (Phe) were labeled with
      carbon-11 via a modified Bucherer-Strecker synthesis. A rapid reaction of the
      sodium bisulfite adduct of the aldehyde precursor with ammonia provided the
      precursor for radiosynthesis. [(11)C]Cyanide displacement followed by base
      hydrolysis afforded the corresponding (11)C-labeled amino acids. The purification
      and chiral separation were simply achieved by using a combination of solid-phase
      extraction and chiral HPLC to afford individual enantiomers of each amino acid.
      The decay corrected radiochemical yields for each of the enantiomers were 12-16%
      with respect to the [(11)C]cyanide after 40-45 min of radiosynthesis.
      Radiochemical purity of the products was >97% (typically >99%), enantiomeric
      excess was >98% with the specific radioactivity 2-3 Ci/micromol at the end of
      bombardment. Because of its simplicity and wide applicability, the described
      procedure could be the method of choice to produce [(11)C]amino acids for PET
      studies.

PMID- 12493542
TI  - Comparison of 99mTc-mercaptoacetyltriglycine and [131I]-o-iodohippurate
      elimination in perfused rat kidney.
AB  - Renal elimination of two renal radiodiagnostic agents, (99m)Tc
      mercaptoacetyltriglycine ((99m)Tc-MAG3) and [(131)I]-o-iodohippurate (OIH) has
      been studied using the method of the perfused rat kidney. The experiments showed
      significant differences between renal handling of (99m)Tc-MAG3 and OIH in the
      perfused rat kidney. While the renal clearance for (99m)Tc-MAG3 was relatively
      stable, the renal clearance values of OIH rapidly decreased after the OIH
      administration in a bolus dose. The infusion administration of OIH resulted in
      stable clearance values during the perfusion. The OIH/(99m)Tc-MAG3 renal
      clearance ratio was 2.47. Both compounds were bound to proteins in the perfusate
      to a considerable extent. An analysis of renal handling showed that contribution
      of tubular secretion to the total excretion was 95% for OIH, and 97% for (99m)Tc
      MAG3.

PMID- 12493543
TI  - Synthesis and evaluation of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4
      piperidyl]-3-[11C]ethyl-1,3-dihydro-2H-benzimidazol-2-one as a brain ORL1
      receptor imaging agent for positron emission tomography.
AB  - 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-[(11)C]ethyl-1,3
      dihydro-2H-benzimidazol-2-one ([(11)C]CPEB) was synthesized by [(11)C]N
      ethylation and evaluated as a potential brain ORL1 receptor imaging agent by
      positron emission tomography. The uptake of [(11)C]CPEB in the mouse brain was
      1.9% dose/g, 2 min post-injection, and gradually decreased with time. Receptor
      specific binding was observed, however, the contribution of other receptors was
      observed and the non-specific binding of [(11)C]CPEB was too high for imaging
      receptors in vivo. Therefore, [(11)C]CPEB is not a suitable tracer for in vivo
      ORL1 receptor imaging.

PMID- 12493544
TI  - Evaluation of DNA aptamers directed to thrombin as potential thrombus imaging
      agents.
AB  - Two DNA aptamers directed against two separate exosites on human alpha-thrombin
      were evaluated for thrombus-imaging potential. Aptamer ODN 1 is directed to the
      thrombin substrate binding site (exosite 1). Our finding that ODN 1 competes with
      fibrin for binding to exosite 1 on thrombin suggests that ODN 1 will not be
      useful for thrombus imaging. Aptamer ODN 2 is directed against the thrombin
      heparin binding site (exosite 2). ODN 2 bound to model thrombi that were formed
      either by clotting purified fibrinogen with thrombin, or by recalcifying citrated
      plasma. As the thrombin content of thrombi was increased the rate of ODN 2 uptake
      into preformed thrombi increased, whereas the rate of release of ODN 2 out of
      preformed thrombi decreased. This in vitro data suggested that ODN 2 might be
      useful for thrombus imaging because it can bind to exosite 2 on fibrin-bound
      thrombin. However, in a rabbit jugular vein model using thrombus supplemented
      with human thrombin, ODN 2 uptake was equal to the ovalbumin control, and did not
      reflect thrombin content. While the in vitro results with ODN 2 were consistent
      with thrombus imaging, the rapid clearance of ODN 2 from circulation, combined
      with slow mass transfer in the clot, seem to work against in vivo thrombin
      dependent imaging or washout analysis.

PMID- 12493545
TI  - The automated radiosynthesis of [18F]FP-TZTP.
AB  - [(18)F]FP-TZTP (3-(3-(3-[(18)F]fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6
      tetrahydro-1-methylpyridine) is a muscarinic ligand that displays in vivo
      selectivity for the M2 subtype. We have developed a one-step radiosynthesis of
      [(18)F]FP-TZTP that can be conducted with an automated synthesis unit. A number
      of hardware and software modifications to a Nuclear Interface C-11 Methylation
      System provided the equipment for the automated radiosynthesis. The manual
      synthesis produced [(18)F]FP-TZTP in a radiochemical yield of 23.4% +/- 4.3%
      (EOS, n = 69) with a specific activity of 4377 +/- 2011 mCi/micromol (EOB, n =
      100). The automated synthesis unit provided the product in a radiochemical yield
      of 18.8% +/- 2.4% (EOS, n = 25) with a specific activity of 4112 +/- 2572
      mCi/micromol (EOB, n = 25).

PMID- 12493546
TI  - Preparation of [11C] radioligands with high specific radioactivity on a
      commercial PET tracer synthesizer.
AB  - High specific radioactivity is required for receptor studies with PET. Hereby we
      wish to report our experience using Nuclear Interface PET Tracer Synthesizer for
      preparation of Carbon-11 radioligands and module's modifications, which allowed
      to achieve high specific radioactivity.

PMID- 12493547
TI  - Neuron loss in key cholinergic and aminergic nuclei in Alzheimer disease: a meta
      analysis.
AB  - Cell counts in the cholinergic nucleus basalis (NB), noradrenergic locus
      coeruleus (LC), dopaminergic substantia nigra (SN), and the serotonergic dorsal
      raphe nucleus (DRN) were assessed from primary-level reports in patients with
      Alzheimer disease (AD) and in controls. Sixty-seven studies that covered about 20
      years were included in the meta-analysis. Effect sizes were computed as a
      standardized mean difference (d) in cell counts between AD and controls. Effect
      sizes were largest in magnitude for the NB (mean d=2.48, 33 studies, N=585), and
      the LC (d=2.28, 24 studies, N=545), then the DRN (d=1.79, 11 studies, N=234), and
      were smallest for the SN (d=0.61, 14 studies, N=440). In general, the overall
      effect size estimates for the four cell areas were reliable. Using effect size
      magnitude in the SN as a referent, cell loss was about three times greater in the
      DRN and four times greater in the NB and LC. Symptomatic drug treatment for AD
      might be beneficially directed toward ameliorating multiple neurotransmitter
      deficiencies, particularly cholinergic and noradrenergic.

PMID- 12493548
TI  - Effects of aging on force variability, single motor unit discharge patterns, and
      the structure of 10, 20, and 40 Hz EMG activity.
AB  - The purpose of this investigation was to examine the discharge properties of
      single motor units and the structure of the rectified 10, 20, and 40 Hz
      electromyographic (EMG) activity to determine a physiological correlate for the
      greater force variability with aging. Young (n=10; mean: 22+/-1 years), old
      (n=10; mean: 67+/-2 years), and older-old (n=10; mean: 82+/-5 years) adult humans
      produced isometric second finger abduction force in both constant and sine-wave
      tasks at 5, 10, 20, and 40% of their maximal voluntary contraction. Force and
      fine-wire intramuscular electromyography were recorded from the first dorsal
      interosseous muscle. The amount and time-dependent structure of the discharge
      rate variability of single motor units and Fourier analysis of the rectified
      intramuscular EMG was performed. Force output variability increased across the
      young, old, and older-old groups. The amount and time-dependent structure of the
      discharge rate variability of single motor units did not differ between the young
      and aging groups. There was a progressive decrease in the relative power of
      approximately 40 Hz EMG activity from the young>old>older-old subjects across the
      5, 10, 20, and 40% maximum voluntary contraction (MVC) force levels. There was
      also a progressive increase in the relative power of the approximately 10 Hz EMG
      activity from young<old<older-old subjects at each target force level. The
      findings showed that a shift in the relative contribution of approximately 40 Hz
      to approximately 10 Hz neural activity is related to the reduced capacity of
      older adults to maintain optimal force control.

PMID- 12493549
TI  - Age-related deficits as working memory load increases: relationships with growth
      factors.
AB  - Young and aged female rats were tested on a water radial-arm maze designed to
      measure performance as working memory load increased, followed by brain-derived
      neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 3 (NT3)
      protein assessments in hippocampus and frontal cortex. Aged rats showed
      deficiencies in both working and reference memory. There were also profound age
      related working memory load effects. Aged rats made more errors as working memory
      load increased and showed learning only during early trials when memory load was
      low, while young rats exhibited learning over all trials. Neurotrophin assessment
      showed that frontal cortex NGF and BDNF levels were positively, and hippocampal
      NT3 negatively, correlated with number of errors made during specific trials in
      aged animals. Comparison to untested rats showed that testing increased NT3, but
      not BDNF or NGF, protein levels in both age groups. Findings suggest that young
      rats learn to handle a higher working memory load as testing progresses, while
      aged rats do not, and that frontal cortex and hippocampal neurotrophin levels may
      relate to working memory proficiency in aged female rats.

PMID- 12493550
TI  - A reliable MR measurement of medial temporal lobe width from the Sunnybrook
      Dementia Study.
AB  - We studied the hippocampal angle and spatial relationships of medial temporal
      lobe (MTL) structures, using midbrain colliculi and inter-collicular sulcus (ICS)
      as landmarks, and measured MTL width on axial 3D-T1-weighted MRI at ICS level in
      41 normal, aged participants. Mean hippocampal angle was 29 degrees (range 17-42
      degrees ) caudal to the anterior-posterior commissure (AC-PC) line. The slice at
      the ICS, parallel to the long axis of the hippocampus, best revealed a
      longitudinal view of hippocampus and parahippocampal gyrus in 76% of
      participants, compared to only 7% when slices were 20 degrees caudal to
      orbitomeatal line (OML), an accepted technique used to examine MTL width in
      previous CT studies. The MTL width measured midway and at its thinnest between
      the anterior-posterior borders of the midbrain was highly reproducible
      (intraclass correlation coefficients >0.98) using these new methods. These simple
      decision rules, individualized orientation along the hippocampus and using a
      standardized landmark like the ICS, make these measures more comparable across
      subjects, and hence more useful in detecting and monitoring MTL atrophy in
      dementia.

PMID- 12493551
TI  - Oxidative stress-mediated DHEA formation in Alzheimer's disease pathology.
AB  - An alternative pathway for dehydroepiandrosterone (DHEA) synthesis has been
      suggested by treating rat and human brain cells with ferrous sulfate and beta
      amyloid (Abeta). To determine if this pathway exists in human brain, levels of
      DHEA in hippocampus, hypothalamus and frontal cortex from Alzheimer's disease
      (AD) patients and age-matched controls were measured. DHEA is significantly
      higher in AD brain than control, and was highest in AD hippocampi. Cytochrome
      p450 17alpha-hydroxylase, responsible for peripheral DHEA synthesis, is not
      present in hippocampus. DHEA levels in AD cerebrospinal fluid (CSF) were
      significantly higher than age-matched controls. AD serum DHEA levels are lower
      than CSF, and not significantly different from controls. Treatment of control
      hippocampus, hypothalamus and serum with FeSO(4) increases DHEA, suggesting that
      levels of precursor are higher in control that in AD brain. This suggests that
      (i). an alternative precursor is present in control brain, (ii). AD brain DHEA is
      formed by oxidative stress metabolism of precursor, and (iii). CSF DHEA levels
      and serum DHEA formation in response to FeSO(4) may serve as an indicator of AD
      pathology.

PMID- 12493552
TI  - Effect of fenfluramine on caloric intake and macronutrient selection in Lou/c
      rats during aging.
AB  - Previous studies have shown a shift of preferences from carbohydrate to fat and a
      decrease in protein intake in self-selected Lou/c rats with advancing age. This
      study investigated a potential neurochemical mechanism underlying age-related
      modifications by evaluating the effects of fenfluramine (dl-F), a drug that
      enhances 5-HT release and blocks its re-uptake by presynaptic terminals, on
      macronutrient selection. The drug dl-F (1.5 and 3mg/kg s.c.) induces a dose
      related hypophagia with the oldest animals being the most sensitive. The main
      decrease is in fat consumption with minor changes in carbohydrate and protein
      consumptions. Young, but not old animals, compensate during the day the nocturnal
      intake decrease induced by dl-F. The plasma concentration of dexfenfluramine (d
      F) was higher as the rats aged. The icv administrations of dl-F induced a caloric
      intake decrease in the oldest groups and a differential effect on protein intake
      between old and young rats. Metergoline induced a partial reversion of dl-F
      effect on food intake but this effect was not age related. These data suggest a
      possible implication of serotoninergic system in modifications of food behavior
      during aging. However, further studies are needed.

PMID- 12493553
TI  - Telomere shortening in T cells correlates with Alzheimer's disease status.
AB  - Telomeres, the repeated sequences that cap chromosome ends, undergo shortening
      with each cell division, and therefore serve as markers of a cell's replicative
      history. In vivo, clonal expansion of T cells during immune responses to both
      foreign and autoantigens is associated with telomere shortening. To investigate
      possible immune alterations in Alzheimer's disease (AD) that might impact current
      vaccine-based therapeutic strategies, we analyzed telomere lengths in immune cell
      populations from AD patients. Our data show a significant telomere shortening in
      PBMC from AD versus controls (P=0.04). Importantly, telomere length of T cells,
      but not of B cells or monocytes, correlated with AD disease status, measured by
      Mini Mental Status Exam (MMSE) scores (P=0.025). T cell telomere length also
      inversely correlated with serum levels of the proinflammatory cytokine TNFalpha
      (a clinical marker of disease status), with the proportion of CD8+ T cells
      lacking expression of the CD28 costimulatory molecule, and with apoptosis. These
      findings suggest an immune involvement in AD pathogenesis.

PMID- 12493554
TI  - Regional pattern of hippocampus and corpus callosum atrophy in Alzheimer's
      disease in relation to dementia severity: evidence for early neocortical
      degeneration.
AB  - We used volumetric MRI and analysis of areas under receiver operating
      characteristic (ROC) curves to directly compare the extent of hippocampus
      amygdala formation (HAF) and corpus callosum atrophy in patients with Alzheimer's
      disease (AD) in different clinical stages of dementia. Based on neuropathological
      studies, we hypothesized that HAF atrophy, representing allocortical neuronal
      degeneration, would precede atrophy of corpus callosum, representing loss of
      neocortical association neurons, in early AD. HAF and corpus callosum sizes were
      significantly reduced in 27 AD patients (37% and 16%, respectively) compared to
      28 healthy controls. In mildly- and moderately-demented AD patients, the ROC
      derived index of atrophy was greater for HAF volume than for total corpus
      callosum area. The index of atrophy of posterior corpus callosum was not
      significantly different from HAF at mild, moderate or severe stages of dementia.
      In conclusion, these findings suggest a characteristic regional pattern of
      allocortical and neocortical neurodegeneraton in AD. Our data indicate that
      neuronal loss in parietotemporal cortex (represented by atrophy of corpus
      callosum splenium) may occur simultaneously with allocortical neurodegeneration
      in mild AD. Moreover, ROC analysis may provide a statistical framework to
      determine atrophy patterns of different brain structures in neurodegenerative
      diseases in vivo.

PMID- 12493555
TI  - The MRI pattern of frontal and temporal brain atrophy in fronto-temporal
      dementia.
AB  - OBJECTIVE: To compare patterns of brain atrophy in fronto-temporal dementia (FTD)
      and Alzheimer's disease (AD) since atrophy in individual areas may not be
      sufficiently specific as diagnostic marker. METHODS: Frontal, temporal and
      hippocampal atrophy was measured from MRI of 10 FTD patients, 27 AD, and 27
      controls. Corrected atrophy and asymmetry were computed (W-scores). RESULTS: FTD
      had mild atrophy in the hippocampus (average W-score=-1.3), severe in the frontal
      (W-score=-2.4) and very severe in the temporal lobes (W-score=-2.9). AD had
      moderate atrophy in the hippocampus and temporal lobes (W-score=-1.8 and -1.9,
      respectively), and very mild frontal atrophy (W-score=-0.9). Atrophy was more
      asymmetrical in FTD (left more atrophic) than in AD patients, particularly in the
      temporal lobes. A discriminant function including the asymmetry values of frontal
      and temporal regions could separate FTD from AD with 90% sensitivity and 93%
      specificity. CONCLUSIONS: FTD is characterized by a specific pattern of atrophy,
      more useful than atrophy of single regions in the differential diagnosis.

PMID- 12493556
TI  - Integrin alphav and NCAM mediate the effects of GDNF on DA neuron survival,
      outgrowth, DA turnover and motor activity in rats.
AB  - Glial cell line-derived neurotrophic factor (GDNF) is a specific neurotrophic
      factor for midbrain dopamine (DA) neurons, but the mechanism underlying the
      neurotrophic action of GDNF is not well known. The cell adhesion molecules
      integrin and Neural cell adhesion molecule (NCAM) play important roles in neurite
      outgrowth and fasciculation. In the present study, we found that subchronic GDNF
      administration to the pars compacta of substantia nigra in rats increased the
      expression of integrin alphav and NCAM. Immunostaining results demonstrated the
      wide distribution of integrin alphav and NCAM in all mesencephalic neurons. The
      results also demonstrated the co-expression of TH with integrin alphav and NCAM
      in the same neurons of mesencephalic culture. Further, GDNF significantly
      increased integrin alphav expression in single TH-positive neurons. Function
      blocking anti-integrin alphav and anti-NCAM antibodies antagonized the effects of
      GDNF on DA neuron survival, outgrowth, DA turnover, and locomotor activity in
      rats. These results demonstrate that integrin alphav and NCAM mediate the effects
      of GDNF on DA neuron survival and outgrowth during development and on DA turnover
      and motor function during adulthood.

PMID- 12493558
TI  - Impairment in abstraction and set shifting in aged rhesus monkeys.
AB  - Understanding the nature of changes in cognition with aging has increased in
      importance as the number of individuals over the age of 65 years grows. To date,
      studies have demonstrated that age-related changes occur most extensively in the
      cognitive domains of memory and executive function. Whereas a large number of
      studies have been conducted about the effects of aging on memory, far less have
      explored the effects of aging on the so called "executive function" which include
      abilities essential for successful performance of higher level activities of
      daily living. As part of our ongoing effort to better characterize these changes,
      we assessed executive function in a non-human primate model of normal human aging
      using the Conceptual Set Shifting Task (CSST). This recently developed task
      assesses abstraction, concept formation and set shifting in the monkey in a way
      analogous to the Wisconsin Card Sorting Test (WCST) in humans. Relative to young
      adult monkeys, aged monkeys evidenced significant difficulty in both acquisition
      and performance on this task, and moreover, demonstrated a high degree of
      perseverative responding. The pattern of performance displayed by the aged
      monkeys suggests an age-related decline in prefrontal cortex (PFC) functioning.

PMID- 12493557
TI  - Effects of caloric restriction on gene expression in the arcuate nucleus.
AB  - Neuroendocrine alterations that repress energy-costly physiologic processes such
      as reproduction and growth and induce stress responses, might underlie the
      antiaging effect of caloric restriction (CR). Neurons in the arcuate nucleus of
      the hypothalamus (ARH) might have a pivotal role in these neuroendocrine
      alterations. We investigated the effects of CR on gene expression of neuropeptide
      Y (NPY), proopiomelanocortin (POMC), growth hormone-releasing hormone (GHRH),
      somatostatin (SRIH), and cyclophilin (CP) in the ARH in male F344 rats at 6
      months of age. Rats were fed ad libitum or a 30% caloric restricted diet with a
      modified alternate-days feeding regimen from 6 weeks of age. Reverse
      transcription-polymerase chain reaction (RT-PCR) methods were used to quantify
      mRNA levels over multiple time points during the 12-h/12-h dark/light cycle over
      a 2-days feeding cycle. The present study demonstrated that CR increased NPY-mRNA
      levels, but decreased POMC, GHRH, and CP mRNA levels differentially over the
      feeding cycle. The SRIH level was not significantly affected by CR. The present
      results support the neuroendocrine hypothesis of CR.

PMID- 12493559
TI  - Neurofilament expression in the rat brain after cerebral infarction: effect of
      age.
AB  - In this study the role of neurofilaments (NFs) in brain plasticity after cerebral
      infarction in young and middle aged rats was evaluated. Focal cerebral ischemia
      was produced by reversible occlusion of the right middle cerebral artery in 3-
      and 20-month-old male Sprague-Dawley rats. After 1 week, brains were removed and
      in situ hybridization and immunostaining was performed for NF-68 kDa, 160 kDa and
      200 kDa in different phosphorylation states. After focal cerebral ischemia the
      levels of gene and protein expression of neurofilament proteins were increased in
      the border zone of the infarcted area compared with the unaffected contralateral
      site. Furthermore, the level of gene expression was significant lower in aged as
      in young animals. Focal cerebral ischemia resulted in a clearly increased number
      of immunostained axons in the penumbral region in both young and aged rats. On
      the other hand the immunostained apical dendrites became thicker and
      vacuolization appeared. Our results suggest that that neurofilament proteins are
      involved in response of brain to focal ischemia.

PMID- 12493561
TI  - Preservation of hippocampal neuron numbers in aged rhesus monkeys.
AB  - To investigate whether or not aging of nonhuman primates is accompanied by a
      region-specific neuron loss in the hippocampal formation, we used the optical
      fractionator technique to obtain stereological estimates of unilateral neuron
      numbers of the hippocampi of eight young (0-4 years) and five aged (18-31 years)
      male rhesus monkeys (Macaca mulatta). Our results show a preservation of neurons
      (mean x 10 (3)+/-S.D.x10(3)) in the subiculum (young=588+/-124, aged=612+/-207),
      CA1 (young=1051+/-249, aged=1318+/-311), CA2 (young=100+/-18, aged=113+/-12), CA3
      (young=478+/-125, aged=509+/-139), hilus (young=337+/-115, aged=394+/-90), and
      dentate gyrus (young=5550+/-1725, aged=7799+/-2087) of the hippocampal formation.
      These results confirm a previous stereological study in rhesus monkeys, but are
      in conflict with data for humans, showing age-dependent region-specific
      alterations in the hippocampal formation.

PMID- 12493560
TI  - Serum cholesterol, precursors and metabolites and cognitive performance in an
      aging population.
AB  - The present study investigated if a causal relation exists between serum
      concentrations of precursors and metabolites of cholesterol and cognitive
      performance in a healthy aging population. Cognitive function addressing four
      domains of 144 individuals (30-80 years) was tested at baseline and after 6 years
      of follow-up. Serum concentrations of different sterols related to cholesterol
      were measured. Serum levels of lathosterol and lanosterol correlated negatively
      with cognitive performance on the Word Learning tests for verbal learning and
      memory. This was observed at baseline and follow-up and was independent of age,
      sex and educational level. Furthermore, the levels of lathosterol and lanosterol
      at baseline correlated with performance on the Stroop test and Word Learning
      tests over the 6-year follow-up period. Serum levels of 27-hydroxycholesterol and
      24S-hydroxycholesterol showed inconsistent correlations, while cholesterol,
      desmosterol, sitosterol and campesterol were not related to cognitive
      performance.Thus, relative high serum ratios of the cholesterol precursors
      lanosterol and lathosterol, indicative for a high rate of endogenous cholesterol
      synthesis, are associated with relatively low memory performance in this aging
      population.

PMID- 12493562
TI  - The inherent, age-dependent loss of retinal ganglion cells is related to the
      lifespan of the species.
AB  - Retinal ganglion cells are neurons that transmit visual information from the
      retina to the brain. With age, there is an inherent loss of retinal ganglion
      cells that we have quantitated by retrograde labeling of these neurons. In adult
      mice, the loss of retinal ganglion cells is approximately 2.3% per month; in
      adult rats, the loss of retinal ganglion cells is approximately 1.5% per month.
      The total losses of these neurons over the average lifespans of mice and rats are
      similar to those which have been reported in monkeys and humans. Furthermore,
      caloric restriction, which extends the lifespans of mice and rats, slows the
      temporal age-related loss of retinal ganglion cells. Thus, the total age
      dependent losses of these neurons appear to be approximately the same over the
      lifespans of these mammalian species.

PMID- 12493563
TI  - Immunohistochemical characterization of clathrin assembly protein AP180 and
      synaptophysin in human brain.
AB  - Neurons rely on clathrin-mediated endocytosis for retrieving synaptic vesicles
      (SVs) at the presynaptic compartment after the release of neurotransmitters. The
      clathrin assembly protein AP180 is shown to be a regulator for this clathrin
      dependent SV recycling pathway. AP180 is efficient in facilitating the formation
      of clathrin-coated vesicles and regulating their size, but its exact location in
      synapse is not clear. In this study, we compared the expression of AP180 with
      synaptophysin in the aged human brain using confocal immunofluorescence
      microscopy. Synaptophysin is well characterized for its association with SVs and
      therefore a commonly used presynaptic marker. We achieved satisfactory
      immunofluorescent labeling by using an autofluorescence blocker Sudan Black B and
      more photostable Alexa Fluor dyes. Although we found that AP180 had an overall
      expression similar to synaptophysin, the immunoreactivity for the two proteins
      did not always co-localize.

PMID- 12493564
TI  - beta-Amyloid (1-40)-induced apoptosis of cultured cortical neurones involves
      calpain-mediated cleavage of poly-ADP-ribose polymerase.
AB  - beta-Amyloid((1-40))-induced apoptosis of cultured cortical neurones involves
      calpain-mediated cleavage of poly-ADP-ribose polymerase. beta-Amyloid protein is
      thought to contribute to the pathophysiology of Alzheimer's disease by inducing
      neuronal apoptosis. Our previous work has demonstrated that beta-amyloid
      activates voltage-dependent Ca(2+) channels in the cortex, resulting in an
      increase in intracellular Ca(2+) concentration. Calpain is a Ca(2+)-dependent
      neutral protease which becomes activated following alterations in intracellular
      Ca(2+) homeostasis. In this study we have demonstrated that beta-amyloid
      increases calpain activity in cultured cortical neurones in a time-dependent
      manner. Use of the cell-permeable calpain inhibitor, MDL 28170, has identified
      cleavage of the DNA-repair enzyme, poly-ADP-ribose polymerase, and DNA
      fragmentation as downstream consequences of calpain activation. Thus, we propose
      that the stimulatory effect of beta-amyloid on Ca(2+) influx triggers calpain
      mediated DNA fragmentation in cultured cortical neurones.

PMID- 12493566
TI  - Biological markers in Alzheimer disease.

PMID- 12493565
TI  - Alteration of nitric oxide synthase activity in young and aged apolipoprotein E
      deficient mice.
AB  - Impairments in cognitive performance have been observed in aged apolipoprotein E
      (apoE)-deficient mice, and apoE epsilon 4 allele is a risk factor in Alzheimer's
      disease (AD). The absence of apoE correlates with diminished antioxidative
      capacity in animals, and elevated cerebral oxidative stress has been observed in
      AD individuals carrying the epsilon 4 alleles. Nitric oxide (NO) is a
      neurosignaling molecule that has significant roles in cognition. NO has also been
      implicated in neurodegenerative diseases due to its oxidative properties. The
      current study examined the possible relationship between apoE and nitric oxide
      synthase (NOS) by comparing hippocampal and cortical NOS activities in wild-type
      and apoE-knockout mice. Our results showed that apoE deficiency had no effect on
      NOS activity in these animals; however, aged animals uniformly exhibited
      significantly higher NOS activity levels. These findings suggest that increased
      NOS activity may contribute to cognitive impairments in aged wild-type and apoE
      knockout mice due to excess accumulation of oxidative damages in areas involved
      in learning and memory.

PMID- 12493567
TI  - Effects of nighttime low frequency noise on the cortisol response to awakening
      and subjective sleep quality.
AB  - The effects of night-time exposure to traffic noise (TN) or low frequency noise
      (LFN) on the cortisol awakening response and subjective sleep quality were
      determined. Twelve male subjects slept for five consecutive nights in a noise
      sleep laboratory. After one night of acclimatisation and one reference night,
      subjects were exposed to either TN (35dB L(Aeq), 50dB L(Amax)) or LFN (40dB
      L(Aeq)) on alternating nights (with an additional reference night in between).
      Salivary free cortisol concentration was determined in saliva samples taken
      immediately at awakening and at three 15-minute intervals after awakening. The
      subjects completed questionnaires on mood and sleep quality. The awakening
      cortisol response on the reference nights showed a normal cortisol pattern. A
      significant interaction between night time exposure and time was found for the
      cortisol response upon awakening. The awakening cortisol response following
      exposure to LFN was attenuated at 30 minutes after awakening. Subjects took
      longer to fall asleep during exposure to LFN. Exposure to TN induced greater
      irritation. Cortisol levels at 30 minutes after awakening were related to
      "activity" and "pleasantness" in the morning after exposure to LFN. Cortisol
      levels 30 minutes after awakening were related to sleep quality after exposure to
      TN. This study thus showed that night time exposure to LFN may affect the
      cortisol response upon wake up and that lower cortisol levels after awakening
      were associated with subjective reports of lower sleep quality and mood.

PMID- 12493568
TI  - The effect of endogenous estradiol metabolites on the proliferation of human
      breast cancer cells.
AB  - Evidence is accumulating that estradiol metabolites may be involved in
      carcinogenesis as some metabolites exert proliferative and others anti
      proliferative properties on human cancer cells. The present study is the first to
      investigate the effect of 14 endogenous estradiol metabolites on the
      proliferation of the human breast cancer cell line, MCF-7, in comparison with the
      effect of the parent substance 17beta-estradiol with special concern on high
      pharmacological concentrations. The steroids were tested in the range from 10(-8)
      to 10(-5) M on MCF-7 cells which were incubated for nine days. Estradiol and
      almost all A-ring metabolites displayed biphasic reactions on cell proliferation,
      i.e. stimulatory at low concentrations and inhibitory at the highest
      concentration, 10(-5) M. The D-ring metabolites did not show such clear biphasic
      patterns, in most of them the stimulatory effect prevailed at the highest dosage
      used. The strongest inhibitory effect was seen for the A-ring metabolite 2
      methoxyestradiol at the concentrations of 10(-6) and 10(-5) M and the strongest
      stimulatory effect was noted for the D-ring metabolite estriol at the same
      concentrations. The results indicate that some A-ring metabolites might be
      suitable for breast cancer treatment when used in high dosages. This is of
      special interest, since many of these metabolites have very weak estrogenic
      activity.

PMID- 12493569
TI  - Effect of nimesulide on gastric acid secretion in the mouse stomach in vitro.
AB  - Nimesulide, a selective inhibitor of cyclooxygenase-2, has been reported to cause
      less gastric damage, compared to other NSAIDs. We investigated the effect of
      nimesulide on basal gastric acid secretion, a contributing factor in NSAID
      induced gastric damage, and histamine, pentagastrin, 5-methylfurmethide, isobutyl
      methylxanthine or high K(+) stimulated acid secretion in the isolated mouse
      stomach. The stomachs, removed from mice, were transferred into an organ bath and
      continuously perfused. Changes in pH following the addition of secretagogues were
      measured by a pH electrode system. The effects of nimesulide on basal and
      secretagogues-stimulated acid secretion were compared to those of indomethacin.
      Nimesulide (1 microM to 100 microM) produced a rightward concentration-dependent
      shift and reduction of maximum acid secretion of all the agonist-stimulated acid
      secretion curves. Indomethacin was only effective at the higher concentration of
      100 microM. Compared to their effects singly, nimesulide (20 microM) and
      famotidine (0.15 microM) together caused a further shift without further
      reduction in maximum acid output of the histamine-stimulated curve, suggesting
      that nimesulide was not acting at the histamine H(2)-receptor. Nimesulide
      concentration-dependent reduction of stimulated acid secretion in the isolated
      mouse stomach was not by antagonism of the histamine H(2) receptor and is
      probably beyond the level of adenylate cyclase stimulation. A direct effect on
      the calcium channel is demonstrated.

PMID- 12493570
TI  - Tonic pain response in mice: effects of sex, season and time of day.
AB  - Seasonal and diurnal variations in tonic pain reactions were examined in female
      and male CBA/J mice maintained in a 12/12 dark/light cycle, at controlled
      temperature and humidity conditions. Animals were injected into the dorsum of one
      hindpaw with a dilute (20 microl, 1%) formalin solution. Pain-related behaviors
      were quantified as the time spent licking the injected paw and the number of
      flinching episodes. The experiments were performed during the first part of the
      light phase (Light: from 7 to 10 a.m.) or during the first part of the dark phase
      of the diurnal cycle (Dark: from 7 to 10 p.m.), in two different periods of the
      year: Spring (March-June) and Winter (November-January). Considering all data,
      females showed a slightly enhanced licking response, as well as an increase in
      the time spent in self-grooming, in comparison with males. In Spring, the licking
      and flinching responses were higher during the Dark phase than during the Light
      phase. This held for both sexes and for both phases of the behavioral response to
      formalin injection. By contrast, no significant diurnal variation in pain
      reactions was found in Winter. These seasonal and diurnal differences were not
      due to nonspecific changes in motor behavior, inasmuch as locomotor activity and
      self-grooming showed a different pattern: during the second phase after formalin,
      self-grooming was higher in the Light period in the experiments performed in
      Spring, whereas locomotor activity showed no significant seasonal changes. These
      results show that the behavioral reactions to prolonged noxious input, integrated
      both at spinal and supraspinal sites, undergo similar seasonal and diurnal
      variations in both sexes, strengthening the importance of chronobiological
      factors in the modulation of nociception.

PMID- 12493571
TI  - Palladium and platinum ions interfere with the measurement of erythrocyte
      vesiculation by inhibiting the acetylcholinesterase activity of the released
      spectrin-depleted microvesicles.
AB  - Palladium (Pd(2+)) and platinum (Pt(2+)) ions were found to inhibit erythrocyte
      membrane-bound acetylcholinesterase (AChE) with Ki values of 6.0 and 6.5
      microg/ml, respectively. Lineweaver-Burke plots revealed that the inhibition of
      erythrocyte AChE by both metal ions was competitive in nature. Binding studies
      using alkaline phosphatase as a reporting enzyme confirmed that both metal ions
      indeed did bind to the enzyme molecules. In the process of red cell vesiculation,
      membrane-bound AChE is shed along with vesicles. The measurement of AChE
      activities in the medium containing vesiculated RBC could potentially be served
      as an index of vesiculation. Inhibition of AChE activities by both metal ions can
      thus constitute a potential source of error in vesiculation measurement. To
      illustrate these effects, a simulated vesiculation system, using green tea
      polyphenol in the presence (25 microg/ml) or absence of Pd(2+) ion was
      simultaneously examined by the electronmicrography and the AChE method. We
      observed vesiculation under the experimental condition in Pd(2+)-free controls
      that was associated with a time-dependent increase in AChE activity were barely
      detected in the Pd(2+)-spiked specimen because of the masking effect exerted by
      the metal ions themselves.

PMID- 12493572
TI  - Estrogen modulates neuromedin B effects on thyrotropin and prolactin release in
      vitro.
AB  - Neuromedin B(NB), a bombesin-like peptide, has been shown to inhibit thyrotropin
      (TSH) release in pituitary explants of male rats and to stimulate Prolactin (PRL)
      release in male pituitary cell cultures. We investigated the effect of estrogen
      status of female rats on the response of thyrotrophs and lactotrophs to
      neuromedin B (NB) in vitro. Ovariectomized rats were treated with near
      physiological or high doses of 17beta estradiol benzoate (0.7 or 14 EB microg/100
      gBW/daily, 10 days) or with vehicle (OVX). EB treatment induced a dose-dependent
      increase in serum prolactin and an increase in pituitary NB content, measured by
      specific RIA, that was similar in both EB groups (P < 0.05). TSH release from
      isolated hemipituitaries of OVX rats was significantly reduced (P < 0.05) in the
      presence of 10(-7) M NB. OVX + EB0.7 glands responded to NB with a not
      statistically significant dose-dependent decrease in TSH release. However, glands
      from hyperestrogenized rats (OVX + EB14) required a higher dose (10(-5) M) of NB
      to inhibit TSH release (P < 0.05). PRL release was highly increased (p < 0.001)
      by the presence of 10(-5) M NB only in glands of hyperestrogenized rats, while no
      effect of NB was observed in the other groups. In conclusion, estrogen status of
      female rats modulates the inhibitory effect of NB on TSH release in vitro and
      hyperestrogenism is required for stimulatory effect of NB on PRL release in
      vitro. It is suggested that the induction of PRL release by neuromedin B is a
      pharmacological rather than a physiological effect, but neuromedin B may
      contribute to the increased release of PRL associated with hyperestrogenism.

PMID- 12493573
TI  - Effect of polysaccharides from Angelica sinensis on gastric ulcer healing.
AB  - Our previous study showed that a crude extract from Angelica sinensis (ASCE),
      which mainly consisted of polysaccharides, significantly promoted migration and
      proliferation of normal gastric epithelial cells. These results strongly suggest
      that ASCE has a direct wound healing effect on gastric mucosa. However, there is
      no report concerning the effect of ASCE on gastric ulcer healing in animal
      models. In this study, we found that ASCE promoted ulcer healing. The area of the
      ulcer was reduced. This was accompanied with a significant increase in mucus
      synthesis when compared with the control. Angiogenesis was inhibited by the
      treatment of ASCE. Cell proliferation, ODC and EGFR protein expression was not
      affected in this process. Thus, the mechanism of how ASCE accelerates ulcer
      healing in addition to its effect on mucus synthesis remains to be investigated.

PMID- 12493574
TI  - Inhibition of the oligosaccharides extracted from Morinda officinalis, a Chinese
      traditional herbal medicine, on the corticosterone induced apoptosis in PC12
      cells.
AB  - The mechanisms of the antidepressant action of the oligosaccharides (P(6))
      extracted from Morinda Officinalis were studied. By flow cytometry analysis,
      treatment of PC12 cells with corticosterone (Cort) induced apoptosis in a
      concentration and time dependent manner. The highest percentage of apoptotic
      cells accumulated to 27.85 +/- 9.2% following pretreatment with Cort 10 microM
      for 5 d. In agarose gel electrophoresis of DNA, the sample obtained from PC12
      cells pretreated with Cort 10 microM for 5 d showed a typical ladder pattern
      suggesting that Cort increased the DNA fragmentation significantly. Furthermore,
      the ultrastructure of Cort-treated cells displayed typical apoptosis-like
      morphological changes including fragmented chromatin accumulation to the inside
      of nucleolus membrane with a shape like crescent moon or ring, nuclear
      fragmentation or apoptotic body. In the presence of P(6), or tricyclic
      antidepressant desipramine (DIM), the apoptosis induced by Cort in the three
      measurements above was significantly inhibited. These results indicate that DIM
      or P(6) antagonize the apoptosis induced by Cort in PC12 cells, which may be one
      of the cellular mechanisms of their antidepressant effects.

PMID- 12493575
TI  - Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis
      with increased matrix metalloproteinases (MMPs) of Kupffer cells.
AB  - The aim of this study was to investigate whether matrix metalloproteinases (MMP
      13, 9) of Kupffer cells induced by gadolinium chloride (GdCl(3)) treatment can
      reverse dimethylnitrosamine (DMN)-induced liver fibrosis (in vivo) and the effect
      of GdCl(3) on MAP kinase activity (in vitro). Male Wistar rats 6 weeks of age
      received DMN (10 mg/kg) three successive days a week for 4 weeks. Then two groups
      of rats (n = 6 each) were treated twice weekly with either GdCl(3) (7 mg/kg) or
      saline solution intravenously for the next 4 weeks. Animals were sacrificed to
      estimate the degree of liver fibrosis. Isolated Kuppfer cells were treated with
      GdCl(3) and the expressions of MMPs, MAP kinase activity (ERK, SAPK/JNK, P38) as
      well as apoptosis were also examined. Rats that received DMN for 4 weeks followed
      by GdCl(3) injection for 4 weeks showed an reduced liver hydroxyproline content
      compared to rats treated with DEN followed by saline (277 +/- 22 VS 348 +/- 34
      microg/g, n = 6 each, P < 0.01). There were significantly increased MMP-13 mRNA
      levels in GdCl(3)-treated rats. However, no significant change was observed in
      procollagen type I mRNA levels. Isolated Kuppfer cells treated with GdCl(3)
      showed increased MAP kinase activity, especially P38 pathway as well as MMP-13, 9
      mRNA and type I collagen-degrading activity leading to apoptosis. SB203580,
      inhibitor of P38 pathway diminished these activation and prevented apoptosis.
      These results suggest that Kuppfer cells can reverse liver fibrosis via the
      expression of MMPs mainly through P38 pathway.

PMID- 12493576
TI  - Molecular cloning and identification of a putative PKC epsilon cDNA from Limulus
      polyphemus brain.
AB  - The protein kinase C (PKC) family of enzymes is broadly distributed and has been
      implicated in a diverse array of cellular functions. Recent evidence supporting
      PKC involvement in the regulation of the Limulus choline cotransporter prompted
      us to clone PKC from a Limulus central nervous system (CNS) cDNA library. An
      Aplysia californica calcium independent PKC (Apl II) cDNA probe was used to
      screen the library and 5' RACE SMART PCR was used to obtain the full-length
      sequence. The resulting cDNA, which included 5' and 3' nontranslation regions,
      was 4675 bp. Analysis of the encoded peptide sequence using the Swiss-prot
      database revealed at least 58% identity to PKC epsilon. A commercial polyclonal
      antibody against PKC epsilon was used in Western blots to positively label a 30
      kDa protein from Limulus CNS and the expressed fusion protein of the encoded
      sequence. These data support the presence of a newly identified PKC-like homolog
      in Limulus which likely represents a PKC epsilon equivalent.

PMID- 12493577
TI  - Drug and chemical metabolites in clinical toxicology investigations: the
      importance of ethylene glycol, methanol and cannabinoid metabolite analyses.
AB  - Metabolic pathways in humans have been elucidated for most therapeutic drugs,
      drugs of abuse, and various chemical/solvents. In most drug overdose cases and
      chemical exposures, laboratory analysis is directed toward identification and
      quantitation of the unchanged drug or chemical in a biologic fluid such as serum
      or whole blood. Specifically, most clinical laboratories routinely screen and
      quantitate unchanged methanol and/or ethylene glycol in suspected poisonings
      without toxic metabolite analysis. Martin-Amat established in 1978 that methanol
      associated toxicity to the optic nerve in human poisonings was due to the toxic
      metabolite formic acid found in methanol poisonings and not due to the direct
      action by unchanged methanol. Jacobsen reported in 1981 that ethylene glycol
      central nervous system and renal toxicity were primarily due to one acidic
      metabolite (glycolic acid) and not due to unchanged ethylene glycol. The first
      objective of this review is to describe clinical experience with formic acid and
      glycolic acid analysis in methanol and ethylene glycol human poisonings. Drug
      metabolite analysis also provides useful information in the assessment and
      monitoring of drug use in psychiatry and substance abusing populations. Drug
      analysis in substance abuse monitoring is focused on urine analysis of one or
      more major metabolites, and less frequently on the unchanged drug(s). Serial
      monitoring of the major urinary cannabinoid metabolite (delta(9)-THC-COOH) to
      creatinine ratios in paired urine specimens (collected at least 24 h apart) could
      differentiate new marijuana or hashish use from residual cannabinoid metabolite
      excretion in urine after drug use according to Huestis. The second objective is
      to demonstrate that creatinine corrected urine specimens positive for
      cannabinoids may help differentiate new marijuana use from the excretion of
      residual delta(9) -THC-COOH in chronic users of marijuana or hashish. Analysis of
      toxic chemical metabolites are helpful in the assessment and treatment of
      chemical poisoning whereas serial monitoring of urinary cannabinoid metabolites
      are predictive of illicit drug use in the substance abusing population.

PMID- 12493578
TI  - A new series of 13 buprenorphine-related deaths.
AB  - OBJECTIVES: Buprenorphine at high dosage became available in France in 1996, as a
      substitution treatment for heroin addicts. Since this date, numerous deaths were
      attributed to this drug. This paper reports a new series of 13 fatalities
      involving buprenorphine observed at the Institute of Legal Medicine of
      Strasbourg, between August 2000 to October 2001. DESIGN AND METHODS: During the
      mentioned period, about 800 forensic cases were screened at the laboratory.
      Buprenorphine and its primary metabolite norbuprenophine were assayed in
      postmortem specimens by HPLC/MS. From these 13 subjects, 11 were male. Blood
      levels ranged from 0.3 to 7.7 ng/mL (mean 3.5 ng/mL) and 0.3 to 16.2 ng/mL (mean
      2.9 ng/mL) for buprenorphine and norbuprenorphine, respectively. The mean values
      appear to be within the therapeutic range. CONCLUSIONS: IV injection of crushed
      tablets, a concomitant intake of psychotropics (especially benzodiazepines and
      neuroleptics) and the high dosage of the buprenorphine formulation available in
      France appear as the major risk factors for such fatalities.

PMID- 12493579
TI  - Analytical and clinical validation of a radioimmunoassay for the measurement of
      1,25 dihydroxy vitamin D.
AB  - OBJECTIVES: The analytical and clinical validation of the DiaSorin 1,25
      dihydroxyvitamin D RIA is described. DESIGN AND METHODS: The analytical
      parameters assessed included analytical sensitivity, dilution linearity, intra-
      and inter-assay precision, recovery, specificity, and interference studies. Where
      appropriate, assessments were performed according to NCCLS guidelines. The
      clinical validation assessed normal individuals and end-stage renal disease
      patients. RESULTS: The analytical sensitivity of the assay is < 2.0 pg/mL or <
      4.8 pM. The assay is specific for both 1,25 dihydroxyvitamin D2 and D3. Recovery
      ranged from 97% to 108% for spiked samples. Intra-assay precision, as %CV, ranged
      from 7% to 11%, while inter-assay precision was 12% to 15%. No interference was
      observed from bilirubin, cholesterol, hemoglobin, or triglycerides. Clinical
      validation demonstrated complete discrimination between normal and ESRD
      populations. CONCLUSIONS: These data demonstrate that the DiaSorin 1,25 (OH)(2)
      vitamin D RIA is a robust, accurate, and precise tool for the assessment of 1,25
      (OH)(2) vitamin D.

PMID- 12493580
TI  - Relation between iron content of serum ferritin and clinical status factors
      extracted by factor analysis in patients with hyperferritinemia.
AB  - OBJECTIVES: The aims of this study were to develop a new technique for
      determination of iron content of serum ferritin (ICF, micromol Fe/mg protein) and
      to investigate relations between ICF and clinical status in patients with
      hyperferritinemia. METHODS: ICF values were determined by a combination of
      immunoprecipitation of ferritin and direct colorimetric iron assay. One hundred
      fifty patients with hyperferritinemia were screened. Factor analysis of the
      results of 11 laboratory tests was applied to extract factors representing the
      clinical status of patients. Relations between the extracted factors and the ICF
      values or serum ferritin concentrations were assessed. RESULTS: Within-run
      coefficients of variation (CVs) of the ICF assay were <==5.7%. The mean ICF value
      of 150 patients was 0.423 micromol/mg (SD, 0.211 micromol/mg). Three factors
      representing clinical status were identified: inflammation, tissue cell damage,
      and body iron status. Serum ferritin level correlated with all three factors. In
      contrast, ICF correlated significantly only with the factor representing tissue
      cell damage (r = 0.293, p = 0.001), and this correlation was independent of
      inflammation and iron status (p = 0.008). CONCLUSIONS: ICF changes in response to
      tissue cell damage independent of inflammatory and body iron statuses, whereas
      serum ferritin changes in response to all three pathologic statuses.

PMID- 12493581
TI  - Pregnancy associated plasma protein-A: ultrasensitive immunoassay and
      determination in coronary heart disease.
AB  - OBJECTIVES: Markers of myocardial injury have been vital in the assessment of
      patients with coronary heart disease. Pregnancy associated plasma protein A
      (PAPP)-A is an insulin-like growth factor (IGF) binding protein (IGFBP)-4
      protease and a potential early indicator of unstable angina. We developed an
      ultrasensitive enzyme-linked immunosorbent assay (ELISA) for PAPP-A and measured
      serum PAPP-A in patients with biochemical evidence of acute coronary syndrome.
      DESIGN AND METHODS: Method development was based on pair-wise evaluation of a
      panel of antibodies and determination of PAPP-A specificity and sensitivity
      relative to those of a conventional method. Association of PAPP-A with myocardial
      damage was assessed in serum samples classified based on serum creatine kinase
      (CK)-MB or cardiac troponin-T levels. RESULTS: Serum PAPP-A was significantly
      higher in samples with elevated CK-MB or troponin-T than in samples with normal
      CK-MB (p < 0.001). Marker-association studies showed strong correlation between
      PAPP-A and troponin-T (r = 0.59, p < 0.001) in a subset of troponin-T positive
      samples. Indications for both parallel as well as divergence in the expression of
      PAPP-A and troponin-T was also evident when serial timed samples available from a
      number of patients were analyzed. CONCLUSIONS: The data are consistent with the
      conclusion that expression of PAPP-A is enhanced in patients with biochemical
      evidence of acute coronary syndrome and suggest strongly that demonstration of
      PAPP-A association with other cardiac markers might be influenced by their
      relative release dynamics (timing and duration). The availability of the
      ultrasensitive PAPP-A ELISA should facilitate systematic investigations of PAPP-A
      expression in this and other pathophysiological conditions that might involve
      altered expression of the IGF/PAPP-A system.

PMID- 12493582
TI  - Dialyzable free cortisol after stimulation with Synacthen.
AB  - OBJECTIVES: To compare the changes in free vs. total serum cortisol
      concentrations after acute stimulation of the adrenal cortex. DESIGN AND METHODS:
      Paired serum samples of ten individuals taken immediately before and 1 h after
      stimulation with 250 microg ACTH (1-24) (Synacthen) given i.v. were analyzed.
      Total cortisol was quantified using liquid chromatography tandem-mass
      spectrometry with an online sample extraction system and tri-deuterated cortisol
      as the internal standard. Free cortisol was measured with the same method after
      equilibrium dialysis. Concentrations of the corticosteroid-binding globulin (CBG)
      were determined by radioimmuno assay. RESULTS: Total cortisol increased by a mean
      of 106% (mean basal cortisol 312 nmol/L (SD 140 nmol/L), stimulated 686 nmol/L
      (SD 163 nmol/L); p < 0.001, paired t-test for differences); no significant change
      of CBG concentrations was found (874 nmol/L (SD 179 nmol/L) before stimulation,
      869 nmol/L (SD 225 nmol/L) after stimulation). The mean increase of free cortisol
      was 263% (mean basal free cortisol 20.3 nmol/L (SD 13.2 nmol/L), stimulated 73.8
      nmol/L (SD 26.7 nmol/L); p < 0.001) and thus substantially more pronounced
      compared to the increase of total cortisol (p < 0.01). The ratio of free to total
      serum cortisol was significantly increased after stimulation (6.1% (SD 1.7%)
      before stimulation, 10.6% (SD 1.9%) after stimulation; p < 0.001). CONCLUSIONS:
      After acute neuroendocrine stimulation of the adrenal cortex the relative
      increase of free bioactive cortisol concentrations is substantially more
      pronounced than the increase of total cortisol concentrations.

PMID- 12493583
TI  - Idiopathic hypoalbuminemia explained by reduced synthesis rate and an increased
      catabolic rate.
AB  - OBJECTIVE: To determine the contribution of albumin synthetic and catabolic rates
      to steady state levels in a patient with idiopathic hypoalbuminemia. METHODS:
      Using L-[1-(13)C] valine, both FSR (fractional synthesis rate) as well as FCR
      (fractional catabolic rate) were studied. Human albumin cDNA analysis and
      determination of the exact albumin mass by electrospray mass spectrometry were
      performed. RESULTS: Compared with controls, plasma albumin concentration in the
      patient was reduced (6.7 vs. 37.0 +/- 2.6 g/L). Albumin FSR (= FCR in steady
      state) was increased compared to controls. The ASR (absolute synthesis rate) of
      albumin was decreased based on the enrichment in plasma valine and KIV, but
      estimated to be normal based on VLDL apoB100 at plateau compared to controls.
      Direct estimation of albumin FCR rejected the latter. No mutation was found in
      the transcribed region of albumin gene. The exact mass of albumin (66.493 Da) was
      not different from controls. CONCLUSION: The hypoalbuminemia was a result of
      accelerated clearance of albumin from plasma in addition to defective albumin
      synthesis. This study also shows that the chosen method of the precursor pool
      could lead to misinterpretation of data in hepatic protein synthesis.

PMID- 12493584
TI  - Correlation between polyamines and apoptosis among Egyptian breast cancer
      patients.
AB  - OBJECTIVES: The polyamines putrescine, spermidine, and spermine, play an
      important role in cell proliferation, differentiation, and transformation. The
      aim of this study is to correlate the polyamines with apoptosis and clinico
      pathologic events in Egyptian breast cancer patients. METHODS: PUT, SPD, and SPN
      were investigated using thin layer chromatography (TLC) and apoptosis in fresh
      frozen tissue specimens obtained from 40 patients suffering from breast cancer,
      as well as 20 patients with benign breast lesions. RESULTS: The levels of PUT,
      SPD, and SPN were higher in breast cancer tissues than in benign breast lesions
      (p < 0.001). Polyamines were correlated well with apoptosis. Moreover, PUT was an
      independent prognostic factor for relapse. Also, SPD and SPN correlated
      significantly with early tumor grades. ROC curves were used to choose the best
      cut-off values for polyamines (70, 135, and 290 mmol/g tissue) for PUT, SPD, and
      SPN, respectively. At these cut-off values, the sensitivities were (75%, 60%, and
      70%), and the specificities were (80%, 95%, and 95%) for PUT, SPD, and SPN,
      respectively. CONCLUSION: Polyamines may be used as additional markers for
      detection of malignant transformation in breast tissue. Moreover, because of
      their ability to induce apoptosis in malignant tissues, polyamines are suitable
      targets for therapeutic intervention that is specifically directed to induce
      apoptosis.

PMID- 12493585
TI  - Plasma 5'-nucleotidase activities increase in women with hyperemesis gravidarum.
AB  - OBJECTIVES: To investigate plasma activities of 5'-nucleotidase, a key enzyme in
      the production of adenosine and evaluate the relationship between changes in 5'
      nucleotidase activities and pregnancy-related hormones, estrogen, progesterone
      and human chorionic gonadotropin (hCG) in women with hyperemesis gravidarum.
      DESIGN AND METHODS: Plasma 5'-nucleotidase activities and estradiol, progesterone
      and hCG levels were measured in 21 women with hyperemesis gravidarum and normal
      pregnancies, matched for age, parity and gestational week. RESULTS: In women with
      hyperemesis gravidarum, plasma 5'-nucleotidase activities averaged 8.1 +/- 0.6
      IU/L, which were significantly increased compared to those in normal pregnant
      women (5.5 +/- 0.5 IU/L)(p < 0.05). The increases in plasma 5'-nucleotidase
      activities were accompanied by elevations of plasma estradiol, progesterone and
      hCG levels. CONCLUSIONS: The increase of plasma 5'-nucleotidase activities may be
      at least partly attributed to elevations of pregnancy-related hormones,
      suggesting changes in purine metabolism in women with hyperemesis gravidarum.

PMID- 12493586
TI  - Urinary free light chain analysis by the Freelite immunoassay: a preliminary
      study in multiple myeloma.
AB  - Evaluate the Freelite free light chain immunoassay for urine analysis in myeloma.
      Urine specimens from 20 patients were analyzed by Freelite (The Binding Site) and
      SDS-agarose gel electrophoresis (Hydragel proteinurie, Sebia). Using the
      kappa/lambda ratio, Freelite was more sensitive than electrophoresis to detect
      free light chains, but concentration was overestimated in 75% of cases. Despite
      high sensitivity and full automation, Freelite inaccurately measures monoclonal
      free light chains in urine.

PMID- 12493587
TI  - Oxidative stress and antioxidant capacity in patients with inflammatory bowel
      disease.
AB  - OBJECTIVES: In this study we aimed to determine the levels of Glutathione
      peroxidase (GSH-Px) and Malondialdehyde (MDA) in patients with inflammatory bowel
      disease (IBD) to investigate their contribution to tissue injury in inflammatory
      bowel disease. DESIGN AND METHODS: Forty-seven GSH-Px patients (35 with
      ulcerative colitis and 12 with Crohn's disease) and 30 healthy controls were
      included in the study. Their plasma and MDA levels were compared using
      nonparametric statistical methods. RESULTS: Plasma GSH-Px levels of the patients
      group were significantly higher than the control group (p < 0.001). There was no
      significant difference between patients and controls in view of plasma levels of
      MDA. CONCLUSIONS: High levels of GSH-Px, which is response against oxidative
      stress, indicates the increase of free radicals in IBD, while normal plasma MDA
      levels suggest the clearance of free radicals without leading to lipid
      peroxidation. Our result reveals that there is an existing antioxidant capacity
      despite oxidative stress in patients with IBD.

PMID- 12493588
TI  - Anticipatory postural adjustments and the latency of compensatory stepping
      reactions in humans.
AB  - A compensatory stepping response is a commonly used strategy in recovering
      balance control after a postural perturbation. Unlike gait initiation, the
      compensatory stepping often occurs without an anticipatory postural adjustment
      (APA), in which body weight is shifted to the swing leg first and then back to
      the stance leg prior to foot lifting. In postural perturbation studies using a
      moving platforms stepping responses without an APA were found to have shorter
      latency to foot lifting than trials with an APA. We studied stepping responses of
      healthy young adults under postural perturbation of a pulling force impulse on
      the subject's waist. In contrast to previous studies, the latency of foot lifting
      was found in the current study to be shorter in the trials with an APA than
      trials without an APA. Furthermore, greater amplitude of an APA was associated
      with a shorter latency of foot lifting. Response with an APA of large amplitude
      may indicate high level of determinant for foot lifting. A pause as to whether or
      not to initiate/complete a stepping response is suggested to be partially the
      cause of delayed foot lifting in trials without an APA or with small amplitude of
      the APA.

PMID- 12493589
TI  - Hypothermia attenuates cerebral dopamine overloading and gliosis in rats with
      heatstroke.
AB  - The present study attempted to ascertain whether hypothermia attenuated the heat
      stroke-induced dopamine overload and gliosis in rat brain. Urethane-anesthetized
      rats were exposed to water blanket temperature (T(blanket)) of 42 degrees C until
      mean arterial pressure (MAP) began to decrease from their peak levels, which was
      arbitrarily defined as the onset of heat stroke. Extracellular concentrations of
      dopamine in brain were assessed by microdialysis methods. Hypothermia was
      accomplished by decreasing T(blanket) from 42 to 16 degrees C. The animals
      exposed to T(blanket) of 26 degrees C served as the normothermic controls. The
      values of MAP in heat stroke rats without hypothermia were all significantly
      lower than those in normothermic controls. However, the extracellular levels of
      dopamine and the number of glial fibrillary acidic protein-reactive cells in
      brain were greater. Hypothermia immediately after the onset of heat stroke
      reduced the heat stroke-induced circulatory shock as well as dopamine overload
      and gliosis in brain. The data demonstrate that hypothermia attenuates both
      dopamine overload and gliosis in rat brain associated with heatstroke.

PMID- 12493590
TI  - Rapid effects of neurotrophic factors on calcium homeostasis in rat visceral
      afferent neurons.
AB  - Neurotrophic factors maintain and modulate neuron function in adults. We tested
      the hypothesis that neurotrophic factors rapidly alter intracellular calcium
      concentrations, thereby affecting neuron excitability. The majority of rat nodose
      neurons express TrkA, TrkB and TrkC receptor after 1 day in culture. Addition of
      nerve growth factor, brain derived neurotrophic factor or glial derived
      neurotrophic factor increased cytosolic calcium in about one third of the neurons
      within less than 10 min. This increase was due to calcium release from
      intracellular stores and could be blocked by the tyrosine kinase inhibitor K252a.
      The rapid effect of neurotrophic factors suggests a role of these molecules in
      the early response after inflammation as potential mediators for sensitization of
      afferent neurons.

PMID- 12493591
TI  - Attenuated induction of heme oxygenase after intrathecal exposure to lysed blood
      in mice overexpressing superoxide dismutase.
AB  - Induction of heme oxygenase-1 (HO-1) in the spinal cord was studied in adult
      wildtype and transgenic mice overexpressing the antioxidant copper, zinc
      superoxide dismutase (CuZn SOD) 24 h after intrathecal infusion of heterologous
      lysed blood. Double immunolabeling techniques were used to determine the extent
      to which HO-1 was induced in astrocytes and microglia/macrophages. HO-1 was
      induced in both astrocytes and microglia/macrophages in the dorsal horns near the
      site of infusion of lysed blood in all mice. However, the number of HO-1 labeled
      cells was significantly less in the transgenic as compared to the wildtype
      animals. Together, these findings suggest that lysed blood preferentially induces
      HO-1 in glia and macrophages through the generation of oxidative stress.

PMID- 12493592
TI  - Inhibitory effect of caffeine on C-fibre-evoked excitation in the rat spinal
      dorsal horn recorded under Ca2+-free condition: an interaction with halothane.
AB  - Effect of caffeine on C-fibre-evoked excitation in the superficial dorsal horn of
      rat spinal cord slices was investigated in Ca(2+)-free medium using the optical
      imaging technique. Perfusing slices with Ca(2+)-free solution reversibly
      suppressed the late phase of dorsal-root stimulus-induced excitation, leaving
      short-lasting optical responses that primarily represent the excitation of
      presynaptic elements. Under the Ca(2+)-free condition, 0.1-10 mM caffeine
      depressed the peak optical amplitude in a concentration-dependent and reversible
      manner (IC(50) 4.5 mM, I(max) 84%). The volatile anaesthetic halothane at a
      clinical concentration (0.6 mM) also depressed the peak optical amplitude.
      Pretreatment with caffeine augmented the inhibitory effect of halothane. These
      results suggest that caffeine and halothane may interact presynaptically to cause
      synergistic inhibition of C-fibre-induced excitation in the dorsal horn.

PMID- 12493593
TI  - Relationship between electroencephalogram slow-wave magnitude and heart rate
      variability during sleep in rats.
AB  - To explore whether depth of sleep is related to changes in autonomic control in
      rats, continuous power-spectral analysis of electroencephalogram (EEG) and heart
      rate variability (HRV) was performed in unanesthetized rats during normal daytime
      sleep. Quiet sleep (QS) was associated with an increase in high-frequency power
      of HRV (0.6-2.4 Hz, HF) but a decrease in low-frequency power (0.06-0.6 Hz) to HF
      ratio (LF/HF) compared with awakening. During QS, LF/HF was significantly and
      negatively correlated with delta power of EEG (0.5-4.0 Hz), whereas mean R-R
      interval and HF were not. As in humans, cardiac sympathetic regulation in rats is
      negatively related to the depth of sleep during QS, although vagal regulation is
      not. Our methodology offers a parallel way of studying the interaction between
      cerebral cortical and autonomic functions in rats.

PMID- 12493594
TI  - Dynamics of the learning of a morphokinetic movement sequence in humans.
AB  - We studied the dynamics of the process through which subjects build a visuomotor
      representation in memory as they learn a morphokinetic movement sequence
      presented on videotape. It was hypothesized that recall accuracy is closely tied
      to the dynamics of the movement-representation process. When analyzed in the form
      of time series, recall performance should exhibit a deterministic inter-trial
      relationship reflecting the memorization activity. Twelve subjects divided into
      two groups recalled a sequence of arm movements 60 times. The model was presented
      to Group 1 (G1) on all 60 trials, whereas Group 2 only saw the model on the first
      30 trials. During these first 30 trials, the analysis of accuracy time series
      pointed out the short-term historicity of the deterministic inter-trials
      relationship. For the last 30 trials, this deterministic relationship disappeared
      in both experimental conditions, except for two subjects of G1, and was replaced
      by a white-noise process suggesting that a stable representation of the sequence
      has been built in long-term memory.

PMID- 12493595
TI  - New splicing variants for human Tyrosine Hydroxylase gene with possible
      implications for the detection of minimal residual disease in patients with
      neuroblastoma.
AB  - Expression of Tyrosine Hydroxylase (TH) is frequently seen in neuroblastomas, the
      most common extracranial tumor in children, and TH mRNA detection is used for the
      analysis of microcirculating or micrometastatic disease in this neoplasia. TH is
      known to have at least seven isoforms produced by alternative splicing of the N
      terminal region (exons 1-4), although no other splicing variants have been
      described downstream. TH expression was analyzed in six samples of neuroblastoma
      by RT-PCR using highly restrictive conditions and primers between exons 5 and 12,
      a region of the gene previously considered to be constant. In the analyzed
      samples we found two novel TH mRNAs, one lacking exon 8, and another lacking
      exons 8+9. These new splicing variants are described in a region of TH previously
      reported to be conserved, and that has been used for the design of reverse
      transcriptase-polymerase chain-reaction assays for the detection of minimal
      residual disease [Eur. J. Cancer, 27 (1991) 762]. The splicing pattern
      characteristic of every tumor could allow the monitoring of the minimal residual
      disease in a tumor-specific manner.

PMID- 12493596
TI  - Scale-invariant fluctuations of the dynamical synchronization in human brain
      electrical activity.
AB  - The dynamical properties of large-scale, long-term phase synchronization behavior
      in the alpha range of electroencephalographic signals were investigated. We
      observed dynamical phase synchronization and presented evidence of an underlying
      spatiotemporal ordering. Fluctuations in the duration of episodes of intermittent
      synchrony are scale-invariant. Moreover, the exponent used to describe this
      behavior is stable across different normal subjects. The results provide a new
      feature of self-organization in human brain activity and constitute a
      quantitative basis for modeling its dynamics.

PMID- 12493598
TI  - Magnesium attenuates persistent functional deficits following diffuse traumatic
      brain injury in rats.
AB  - Although a number of studies have demonstrated that magnesium improves acute
      motor and cognitive outcome after traumatic brain injury, others have failed to
      show positive effects on cognitive outcome and none have examined persistent
      functional deficits. The present study shows that severe impact-acceleration
      induced, diffuse traumatic brain injury in rats produced profound motor and
      cognitive deficits that persisted for at least 4 weeks after trauma. Intravenous
      administration of magnesium sulfate (250 micromoles/kg) at 30 min after injury
      significantly improved rotarod (sensorimotor) and open field (stress/anxiety)
      performance, and led to a faster rate of recovery in the Barnes maze (learning).
      We conclude that posttraumatic magnesium administration attenuates long-term
      motor and cognitive deficits after traumatic brain injury, and that this
      improvement may include some reduction of post-traumatic stress and anxiety.

PMID- 12493597
TI  - Galantamine blocks delayed rectifier, but not transient outward potassium current
      in rat dissociated hippocampal pyramidal neurons.
AB  - Galantamine is an acetylcholinesterase inhibitor in Alzheimer's disease therapy.
      In the present study, we investigated the effects of galantamine on delayed
      rectifier potassium current (I(K(DR))) and transient outward potassium current
      (I(K(A))) in acutely dissociated rat hippocampal pyramidal neurons by using whole
      cell patch clamp technique. I(K(DR)) was inhibited by galantamine in a
      concentration-dependent manner, while I(K(A)) remained unaffected. The IC(50)
      value for the blocking action of galantamine on I(K(DR)) was calculated as 2.0
      microM. At the concentration of 10 microM, galantamine inhibited I(K(DR)) by
      40.2% at +40 mV when depolarized from -50 mV, and shifted the activation curve
      and inactivation curve of I(K(DR)) to negative potential by -3.8 mV and -11.0 mV,
      respectively. In conclusion, galantamine potently inhibits I(K(DR)) but not
      I(K(A)) in rat hippocampal pyramidal neurons.

PMID- 12493599
TI  - 3D analysis of posturo-kinetic coordination associated with a climbing task in
      children and teenagers.
AB  - The aim of this study was to characterize the modifications of the posturo
      kinetic coordination during a climbing task as a function of postural and/or
      movement constraints in children (8-10 years) and adolescents (10-15 years). A 3D
      analysis of forces was recorded for different movement amplitudes and types of
      holds. The results show the involvement of horizontal and vertical forces to
      maintain equilibrium during the steady state changes for different experimental
      groups. The contribution of horizontal and vertical forces changes in the course
      of movement realization. The vertical momentum (Iz) is mainly involved in the
      movement initiation: this role is mostly meaning for children. The horizontal
      momentum (Ih) is mainly involved in controlling equilibrium: this role is mostly
      meaning for adolescents.

PMID- 12493600
TI  - Orthography effect on brain activities in the working memory process for
      phonologically ambiguous syllables: a functional magnetic resonance imaging study
      using Japanese speakers.
AB  - English /l/ and /r/ sounds are not distinctive for Japanese speakers and they are
      loosely associated with corresponding graphemes. The purpose of this study was to
      investigate the brain activities in the memory process for the graphemes
      containing 'l' and 'r' in Japanese speakers. Two functional magnetic resonance
      imaging (at 1.5 T) experiments was conducted using syllable working memory tasks.
      The task using 'l' and 'r' syllables was coupled with either task using 'b' and
      'n' syllables (l/r versus b/n block-designed experiment), or 'd' and 'n'
      syllables (l/r versus d/n block-designed experiment). The results revealed that
      the l/r working memory tasks induced augmented activation specifically in the
      right middle frontal gyrus (BA9, 46) and the right superior parietal lobule
      (BA7), compared with the b/n or d/n tasks. The results indicate that a visually
      biased memory process (i.e. excessive visual rehearsal or monitoring) was
      executed for phonologically ambiguous syllables. Significant activation in the
      left inferior frontal gyrus was not observed only in the b/n task, probably
      because articulatory contrast between /b/ and /n/ sounds was highly clear for
      Japanese speakers.

PMID- 12493601
TI  - Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in
      cultured rat primary neurons and astrocytes.
AB  - The amyloid precursor protein (APP) and its proteolytic cleavage products, the
      amyloid beta peptides, have been implicated as a cause of Alzheimer's disease.
      Peptide nucleic acids (PNA), the DNA mimics, have been shown to block the
      expression of specific proteins at both transcriptional and translational levels.
      Generally, the cellular uptake of PNA is low. However, recent studies have
      indicated that the effect of unmodified antisense PNA uptake is more pronounced
      in nervous tissue. In this study we have shown that biotinylated PNA directed to
      the initiator codon region of the APP mRNA (-4 - +11) was taken up into the
      cytoplasm of primary rat cerebellar granule cells and cortical astrocytes, using
      fluorescence and confocal microscopy studies. Uptake of PNA was faster in neurons
      than in astrocytes. Western blotting analysis showed that APP was strongly down
      regulated in both neurons and astrocytes. Thus, unmodified PNA can be used for
      studies on the function of APP in neurons and astrocytes.

PMID- 12493602
TI  - Correlations between brain electrical activities of two spatially separated human
      subjects.
AB  - Six channels electroencephalogram (EEG) were recorded simultaneously from pairs
      of separated human subjects in two acoustically and electromagnetically shielded
      rooms. While brain electric responses to visual pattern-reversal stimuli were
      elicited in one subject, the other subject relaxed without stimulation. EEGs of
      both subjects were averaged at times of stimulus onset, effective voltage of the
      averaged signals was computed within a running window, and expressed as ratio (Q)
      to the effective voltage of averaged EEG signal from non-stimulation periods.
      These ratios in non-stimulated subjects at the latency of the maximum response in
      stimulated subjects were analysed. Significant departures of Q ratios from
      reference distributions, based on baseline EEG in non-stimulation periods, were
      found in most non-stimulated subjects. The results indicate that correlations
      between brain activities of two separated subjects may occur, although no
      biophysical mechanism is known.

PMID- 12493603
TI  - Effects of temporal and/or spatial instructions on the speed-accuracy trade-off
      of pointing movements in children.
AB  - The present experiment examined in a visuo-manual task the effects of verbal
      instructions on the speed/accuracy trade-off across children aged 6, 8 and 10
      years and adults. Three different verbal instructions (speed, accuracy and speed
      accuracy) had to be respected to perform a pointing task. Analysis of reaction
      time (RT), movement time (MT) and percentage of targets reach showed that: (1)
      whatever the age, children were able to comply with the verbal instructions to
      adapt the velocity and/or the precision of their response (initiation and
      movement execution); (2) the main age-related difference of the speed-accuracy
      trade-off concerned the temporal (MT) but not the accuracy (targets reach)
      characteristics of the pointing movements; and (3) in the older children and even
      more precisely in adults, a temporal deficit was observed when the accuracy of
      aiming was required. This deficit increased as accuracy increased. These results
      were discussed within the theoretical frameworks of the developmental speed
      processing model proposed by Kail [Psychol. Bull., 109(3) (1991) 490-501] for RT
      data, and the speed-accuracy trade-off model proposed by Pachella [Pachella,
      R.G., The interpretation of reaction time in information-processing research, in,
      Kantowitz, B. (ed) Human Information Processing: Tutorial in Performance and
      Recognition, Erlbaum, (1974) 41-82] for MT and targets reach data.

PMID- 12493604
TI  - Alpha synuclein promoter and risk of Parkinson's disease: microsatellite and
      allelic size variability.
AB  - Polymorphism of the alpha synuclein promoter region (non-amyloid component of
      plaques (NACP)-Rep1) is associated with an increased risk of Parkinson's disease
      (PD) in three separate studies. We studied NACP-Rep1 polymorphism in two
      independent case control studies in our population. In study one, 104 PD and 104
      age, gender and race matched controls; and in study two, 102 PD and 102 age,
      gender and race matched controls were examined separately. The results of both
      studies were analyzed independent of one another. We found three polymorphic
      alleles (designated 0, 1, 2). In study one, the frequency of allele 2 was
      significantly higher in PD patients as compared to healthy controls (0.37 versus
      0.23, P=0.01, X(2)=9.98). In study two, the frequency of allele 2 was similar
      between PD and controls (0.31 versus 0.33, P=1.00, X(2)=0.30). There was a non
      significant higher allele 2 frequency in PD when both studies were analyzed
      together (0.34 versus 0.28, P=0.20, X(2)=3.4). No significant differences of the
      various genotypes between PD and controls were found. However there were
      differences of the mixed dinucleotide repeats sequences for similar homozygous
      genotypes. Variability of the microsatellite region and potential interacting
      factors that could affect alpha synuclein gene transcription should be further
      examined.

PMID- 12493606
TI  - Role of primary afferents in spinal cord stimulation-induced vasodilation:
      characterization of fiber types.
AB  - Selected patients with peripheral vascular disease can be treated with spinal
      cord stimulation (SCS) to improve blood flow in the limbs. However, the
      mechanisms producing these effects remain unclear. The present study was designed
      to investigate if SCS produces cutaneous vasodilation via antidromic activation
      of the unmyelinated C-fibers and/or the small myelinated fibers. SCS was applied
      to anesthetized rats with a ball electrode at the L2-L3 spinal level. In Protocol
      1, effects of capsaicin were examined. Blood flow changes in the hindpaw induced
      by SCS were measured in the footpad with laser Doppler flowmeters. Topical
      application of capsaicin (1%) on the tibial nerve did not affect SCS-induced
      vasodilation at 30 and 60% of motor threshold (MT). However, the duration of
      vasodilation induced by SCS at 90% MT and at 10 times MT was significantly
      reduced after capsaicin application on the tibial nerve. In Protocol 2,
      antidromic compound action potentials (CAPs) of the tibial nerve were recorded in
      response to SCS. CAPs of the large and the small myelinated afferent fibers were
      observed in response to SCS at all intensities. However, even with SCS at ten
      times MT, CAPs of C-fibers could not be detected in the tibial nerve. In Protocol
      3, antidromic CAPs of the dorsal root were measured in response to SCS.
      Antidromic CAPs of C-fibers in dorsal roots were evoked by SCS at >or=90% of MT.
      It is concluded that SCS-induced vasodilation at <or=60% of MT may be mediated
      via only the myelinated fibers, whereas vasodilation at >or=90% of MT may also
      involve antidromic activation of some unmyelinated C-fibers.

PMID- 12493605
TI  - Effects of intrathecal administration of a cell permeant caspase inhibitor, boc-D
      fluoromethylketone (BDFMK), on behavioral deficits following spinal cord
      ischemia: a dose-response analysis.
AB  - Caspase inhibition has been proposed as a target to attenuate ischemia-induced
      neurodegeneration and behavioral dysfunction. The present study evaluated the
      pharmacological effects of a single dose of an irreversible cell permeant general
      (nonselective) caspase inhibitor, Boc-D-fluoromethylketone (BDFMK) administered
      intrathecally (i.t.) in a reversible spinal cord ischemia model (RSCIM). Quantal
      analysis indicated that the P(50) (represents the duration of ischemia that
      produces permanent paraplegia in 50% of the animals in a group) of the control
      group was 25.08+/-4.71 min. Using the RSCIM, neuroprotection is observed if a
      drug significantly prolongs the P(50) compared to the control group. The P(50)
      values for the BDFMK-treated groups were 27.21+/-2.62, 27.28+/-3.29 and 28.98+/
      2.32 min, for the three dose groups studied. There were no statistically
      significant changes when measured 18 or 48 h following ischemia. Biochemical
      analysis of cell extracts from the caudal lumbar spinal cord indicated that there
      was increased production of the 120-kDa fragment of fodrin suggesting enhanced
      caspase-3 activity, an increase that was reduced by i.t. BDFMK administration.
      Moreover, in caudal lumbar spinal cord extracts from a set of paraplegic rabbits
      (25-50 min occlusion), we measured a 32-42% decrease of caspase-3 activity in
      BDFMK-treated rabbits. The present study shows that i.t. administration of BDFMK
      reduced caspase-3 activity, but the inhibition did not translate into a
      significant behavioral improvement. Our results suggest that administration of a
      single dose of the caspase inhibitor BDFMK is insufficient to attenuate ischemia
      induced behavioral deficits following aortic occlusion.

PMID- 12493607
TI  - Bioelectrical behaviour of hypoxic human neocortical tissue under the influence
      of nimodipine and dimethyl sulfoxide.
AB  - Nimodipine and dimethyl sulfoxide (DMSO) have been shown to affect
      electrophysiological responses in rodent brain tissue in an vitro model of
      hypoxia. In the present study, the same agents were now examined for their
      effects on human neocortical brain slices under repeated hypoxic conditions. DMSO
      (0.4%), with and without addition of nimodipine (40 micromol/l), did not increase
      the latency of anoxic depolarization (AD). This finding is not in line with our
      previous observations of DMSO effects, with and without nimodipine, on brain
      slices of guinea pigs. AD latency was significantly longer in human neocortical
      brain slices compared with hippocampal slices of rodents even without any
      pharmacological influence. A possible acute effect of DMSO-nimodipine may
      therefore be masked by an interspecies difference of hypoxia resistance.

PMID- 12493608
TI  - The effect of the 'classic' ketogenic diet on animal seizure models.
AB  - Bough et al. have recently demonstrated anticonvulsant effects of the 'classic'
      ketogenic diet (KD) in the pentylenetetrazol infusion model in rats.
      Proconvulsant effects were seen, however, when the 'classic' diet was tested
      against maximal electroshock (MES) seizures. These differing results may reflect
      the fact that the two models involve different kinds of epileptogenic stimulus,
      or, as Bough et al. note that the two tests involve different stimulation
      paradigms. The pentylenetetrazol infusion paradigm is a threshold test, whereas
      the MES test employs a stimulus which is well above threshold. The present
      experiments were designed to test the effects of the 'classic' KD against
      seizures triggered in rats by both threshold and suprathreshold levels of
      electricity and pentylenetetrazol. The threshold tests employed were the
      pentylenetetrazol infusion test, and the threshold electroconvulsive shock (ECS)
      test. The subcutaneous pentylenetetrazol (scMET) test was also included, since it
      is sometimes considered to be a 'threshold' test. The suprathreshold tests
      employed were the maximal pentylenetetrazol test (MMT) and the maximal
      electroshock test (MES). The KD failed to suppress seizures in either of the
      tests involving suprathreshold stimulation (MMT and MES), although there was a
      significant increase in latency in the MMT test. Small but significant threshold
      elevations (15-20%) were seen, however, in both the pentylenetetrazol infusion
      test and the ECS threshold test. No seizure suppression was seen in the scMET
      test, which actually employs a suprasthreshold stimulus. These data indicate that
      the KD has significant anticonvulsant effects against both chemically and
      electrically triggered seizures, but that they consist of small elevations in
      threshold which will be seen only when threshold measures are used.

PMID- 12493609
TI  - Seasonal changes in neurosteroid concentrations in the amphibian brain and
      environmental factors regulating their changes.
AB  - Up to now the regulatory mechanisms, which govern the concentrations of
      neurosteroids in the brain, are unclear. Seasonal breeders may serve as excellent
      models to understand physiological changes in neurosteroid levels and their
      regulatory mechanisms. The present study first investigated immunohistochemically
      the localization of cytochrome p450 side-chain cleavage enzyme (p450scc) and
      3beta-hydroxysteroid dehydrogenase/delta(5)-delta(4)-isomerase (3betaHSD) in the
      brain of the newt Cynops pyrrhogaster, a seasonally breeding amphibian. Both
      p450scc- and 3betaHSD-like immunoreactive cells were restricted to the preoptic
      area. Seasonal changes in neurosteroid concentrations were then examined using
      adult males. Pregnenolone concentrations in the brain showed marked changes
      during annual breeding cycle and a maximal level in August, independent of the
      plasma steroid levels which were all low throughout the year. Progesterone
      concentrations in the brain, which were lower than pregnenolone levels, also
      showed peaks in April and August. In contrast, the pregnenolone sulfate level was
      low and its change was less pronounced. To clarify environmental factors that
      induce seasonal changes in neurosteroid levels, adult males were further
      subjected to different photoperiods and ambient temperatures for 5 weeks. Both
      pregnenolone and progesterone concentrations in the brain were significantly
      higher in the long day (LD) group than in the short day (SD) group, whereas no
      significant effects of different ambient temperatures on neurosteroid levels were
      detected. These results suggest that the newt brain possesses steroidogenic
      enzymes p450scc and 3betaHSD and exhibits seasonal changes in the pregnenolone
      and progesterone concentrations. Photoperiod may be a more important
      environmental factor than temperature for the regulation of neurosteroid levels
      in the brain.

PMID- 12493610
TI  - Transport of 5-aminolevulinic acid between blood and brain.
AB  - Little is known about the movement of 5-aminolevulinic acid (delta-aminolevulinic
      acid; ALA) between blood and brain. This is despite the fact that increases in
      brain ALA may be involved in generating the neuropsychiatric symptoms in
      porphyrias and that systemic administration of ALA is currently being used to
      delineate the borders of malignant gliomas. The current study examines the
      mechanisms involved in the movement of [(14)C]ALA across the blood-brain and
      blood-CSF barriers in the rat. In the adult rat, the influx rate constant (K(i))
      for [(14)C]ALA movement into brain was low ( approximately 0.2 microl/g per min),
      was unaffected by increasing plasma concentrations of non-radioactive ALA or
      probenecid (an organic anion transport inhibitor) and, therefore, appears to be a
      diffusional process. The K(i) for [(14)C]ALA was 3-fold less than that for
      [(14)C]mannitol, a molecule of similar size. This difference appears to result
      from a lower lipid solubility rather than saturable [(14)C]ALA transport from
      brain to blood. The K(i) for [(14)C]ALA for uptake into the neonatal brain was 7
      fold higher than in the adult. However, again, this was unaffected by increasing
      plasma ALA concentrations suggesting a diffusional process. In contrast, at the
      blood-CSF barrier, there was evidence of carrier-mediated [(14)C]ALA transport
      from blood to choroid plexus and blood to CSF. Both processes were inhibited by
      administration of non-radioactive ALA and probenecid. However, experiments in
      choroid plexus epithelial cell primary cultures indicated that transport in these
      cells was polarized with [(14)C]ALA uptake from the apical (CSF) side being about
      7-fold greater than uptake from the basolateral (blood) side. In total, these
      results suggest that the brain is normally fairly well protected from changes in
      plasma ALA concentration by the very low blood-brain barrier permeability of this
      compound and by a saturable efflux mechanism present at the choroid plexus.

PMID- 12493611
TI  - Expression of Nav1.8 sodium channels perturbs the firing patterns of cerebellar
      Purkinje cells.
AB  - The sensory neuron specific sodium channel Na(v)1.8/SNS exhibits depolarized
      voltage-dependence of inactivation, slow inactivation and rapid repriming, which
      differentiate it from other voltage-gated sodium channels. Na(v)1.8 is normally
      selectively expressed at high levels in sensory ganglion neurons, but not within
      the CNS. However, expression of Na(v)1.8 mRNA and protein are upregulated within
      cerebellar Purkinje cells in animal models of multiple sclerosis (MS), and in
      human MS. To examine the effect of expression of Na(v)1.8 on the activity pattern
      of Purkinje cells, we biolistically introduced Na(v)1.8 cDNA into these cells in
      vitro. We report here that Na(v)1.8 can be functionally expressed at
      physiological levels (similar to the levels in DRG neurons where Na(v)1.8 is
      normally expressed) within Purkinje cells, and that its expression alters the
      activity of these neurons in three ways: first, by increasing the amplitude and
      duration of action potentials; second, by decreasing the proportion of action
      potentials that are conglomerate and the number of spikes per conglomerate action
      potential; and third, by contributing to the production of sustained, pacemaker
      like impulse trains in response to depolarization. These results provide support
      for the hypothesis that the expression of Na(v)1.8 channels within Purkinje
      cells, which occurs in MS, may perturb their function.

PMID- 12493612
TI  - The selective A2A receptor antagonist SCH 58261 reduces striatal transmitter
      outflow, turning behavior and ischemic brain damage induced by permanent focal
      ischemia in the rat.
AB  - Adenosine A(2A) receptor antagonists have been proved protective in different
      ischemia models. In this study we verified if the protective effect of the
      selective A(2A) antagonist, SCH 58261, could be attributed to the reduction of
      the excitatory amino acid outflow induced by cerebral focal ischemia. A vertical
      microdialysis probe was inserted into the striatum of male Wistar rats and, after
      24 h, permanent right intraluminal middle cerebral artery occlusion (MCAo) was
      induced. Soon after waking, rats showed a definite contralateral turning
      behavior, which persisted up to 7 h after MCAo. During 4 h after MCAo, glutamate,
      aspartate, GABA, adenosine and taurine outflow increased. SCH 58261 (0.01 mg/kg,
      i.p.), administered 5 min after MCAo, suppressed turning behavior and
      significantly reduced the outflow of glutamate, aspartate, GABA and adenosine. At
      24 h after MCAo, the rats showed severe sensorimotor deficit and damage in both
      the striatum and cortex. SCH 58261 significantly reduced cortical damage but did
      not protect against the sensorimotor deficit. The protective effect of SCH 58261
      against turning behavior and increased outflow of excitatory amino acids in the
      first hours after MCAo suggests the potential utility of selective adenosine
      A(2A) antagonists when administered in the first hours after ischemia.
      Furthermore, this study, for the first time, proposes that turning behavior after
      permanent intraluminal MCAo, be used as a precocious index of neurological
      deficit and neuronal damage.

PMID- 12493613
TI  - Receptor subtype-specific modulation by dopamine of glutamatergic responses in
      striatal medium spiny neurons.
AB  - The output of GABAergic medium-sized spiny neurons in the dorsal striatum is
      controlled in part by glutamatergic input from the neocortex and the thalamus,
      and dopaminergic input from ventral midbrain. We acutely isolated these neurons
      from juvenile (P14-24) rats to study the consequences of the interaction between
      glutamate and dopamine for neuronal excitability. Single-cell RT-PCR analysis was
      used to identify the expression patterns of dopamine receptors. D1 and D2
      dopamine receptor mRNA was detected in 11/22 and 3/22 of isolated neurons,
      respectively. Receptor mRNA co-expression was detected in 1/22 cells tested.
      Whole-cell voltage clamp recording (V(h)=-70 mV) was combined with local or bath
      application of dopaminergic and glutamatergic agonists to explore dopamine
      receptor modulation of glutamatergic excitation. Glutamate-evoked inward currents
      (5 microM, Mg(2+)-free, 1 microM glycine) were attenuated by dopamine (5 microM)
      to 83.2+/-3.6% (n=31). NMDA-evoked (20 microM), APV-sensitive currents were
      attenuated by dopamine to 80.9+/-4.5% (n=24). NMDA-induced responses were also
      attenuated by the D1 receptor agonist SKF 38393 (1 microM; n=28), while the D2/3
      receptor agonist quinpirole (10 microM) had no effect. The currents evoked by
      application of AMPA (5 microM) displayed a steady rundown. Application of
      dopamine abolished or significantly reduced the rundown in the cells tested
      (n=17). A similar effect was observed after the application of SKF 38393 (1
      microM), while quinpirole (10 microM) had no significant effect. Our results
      provide direct evidence for modulation by dopamine of glutamatergic responses of
      striatal medium spiny neurons, and demonstrate that the effects of this
      neuromodulator are receptor subtype specific. Disruption of this modulatory
      effect is likely to contribute to movement disorders associated with Parkinson's
      disease.

PMID- 12493614
TI  - Sex differences in the distribution of the steroid receptor coactivator SRC-1 in
      the song control nuclei of male and female canaries.
AB  - The steroid receptor coactivator SRC-1 modulates ligand-dependent transactivation
      of several nuclear receptors, including the receptors for sex steroid hormones.
      The distribution of SRC-1 transcripts was analyzed here by in situ hybridization
      in coronal sections through the brain of male and female canaries. A broad but
      heterogeneous distribution of SRC-1 transcripts was observed with high numbers of
      densely labeled cells being present in many steroid-sensitive areas including the
      medial preoptic nucleus, several hypothalamic nuclei, five song control nuclei
      (HVc, the lateral and medial portion of the magnocellular nucleus of the anterior
      neostriatum, area X and the nucleus uvaeformis) and several catecholaminergic
      areas (area ventralis of Tsai, substantia nigra, locus coeruleus). The volume of
      two song control nuclei, HVc and area X were reconstructed based on the
      boundaries of the cell groups exhibiting a denser SRC-1 expression as compared to
      the surrounding areas. Sex differences in the expression of SRC-1 were also
      detected in several song control nuclei. In particular, the volume of HVc based
      on the high density of SRC-1 expression was significantly larger in males than in
      females. The effect of steroids on the song control system could be, at least in
      part, indirect and result from a modulation by steroids of the catecholaminergic
      inputs to the song control nuclei. The presence of the steroid receptor
      coactivator SRC-1 in the telencephalic song control nuclei and in the
      catecholaminergic cell groups that innervate the song system supports the idea
      that SRC-1 expression could play an active role in the control of singing
      behavior by modulating estrogen and androgen receptor action at both locations.

PMID- 12493615
TI  - Anti-nociceptive effect induced by intrathecal injection of ATPA, an effect
      enhanced and prolonged by concanavalin A.
AB  - The present study investigated the effect of intrathecal injection of (RS)-2
      alpha-amino-3-(3-hydroxy-5-tbutylisoxazol-4-yl) propanoic acid (ATPA), a
      selective agonist to kainate receptor, on nociception in rats. Intrathecal
      administration of 1, 4 and 10 nmol of ATPA induced dose-dependent increases in
      the hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in
      rats. Pretreatment with intrathecal injection of 300 microg of concanavalin A
      (ConA) to block the desensitization of kainate receptors enhanced and prolonged
      the anti-nociceptive effect induced by intrathecal injection of ATPA. The results
      suggest that the pre-synaptic kainate receptor in the primary afferent terminals
      is involved in the transmission of nociceptive information in dorsal horn of the
      spinal cord in rats. Furthermore, blocking the desensitization of kainate
      receptor enhanced and prolonged the ATPA-induced anti-nociceptive effects.

PMID- 12493616
TI  - Acute neuropharmacologic action of chloroquine on cortical neurons in vitro.
AB  - Chloroquine, a common quinolone derivative used in the treatment of malaria, has
      been associated with neurologic side-effects including depression, psychosis and
      delirium. The neuropharmacologic effects of chloroquine were examined on cultured
      cortical neurons using microelectrode array (MEA) recording and the whole-cell
      patch clamp technique. Whole-cell patch clamp records under current-clamp mode
      also showed a chloroquine-induced depression of the firing rate of spontaneous
      action potentials by approximately 40%, consistent with the observations with the
      MEA recording, although no changes in either the baseline membrane potential or
      input resistance were observed. Voltage clamp recordings of spontaneous post
      synaptic currents, recorded in the presence of tetrodotoxin, revealed no obvious
      changes in either the amplitude or rate of occurrence of inward currents with
      application of chloroquine at 10 microM, suggesting that the fundamental
      molecular mechanisms underlying spontaneous synaptic transmission may not be
      affected by acute application of the drug. In contrast, a concentration-dependent
      inhibition of whole-cell calcium current was observed in the presence of
      chloroquine. These acute neuropharmacologic changes were not accompanied by
      cytotoxic actions of the compound, even after exposure of up to 500 microM
      chloroquine for 7 h. These data suggest that chloroquine can depress in vitro
      neuronal activity, perhaps through inhibition of membrane calcium channels.

PMID- 12493617
TI  - Heterogeneous synaptic inputs from the ventrolateral periaqueductal gray matter
      to neurons responding to somatosensory stimuli in the rostral ventromedial
      medulla of rats.
AB  - The ventrolateral cell column of the midbrain periaqueductal gray matter (vl-PAG)
      plays a major role in the attenuation of pain behaviour. It is established that
      this effect is exerted via modulation of neuronal activities in the rostral
      ventromedial medulla (RVM). Until recently it has been generally accepted that
      the vl-PAG exerts its modulatory effects upon RVM neurons through a direct
      monosynaptic pathway. However, recent data suggest that an additional indirect,
      di- or polysynaptic pathway may also exist. Using in vivo intracellular
      recordings we tested this hypothesis, by studying synaptic responses of
      somatosensory receptive RVM neurons evoked by electric stimulation of the vl-PAG
      in rats. RVM neurons were regarded as somatosensory receptive if they responded
      to electrical stimulation of the sciatic nerve. Most of the recorded RVM cells
      were excited by vl-PAG stimulation. Some of them responded with a short onset
      latency (3.6+/-0.9 ms) corresponding to monosynaptic excitation. All of these
      neurons were also excited by sciatic nerve stimulation at nociceptive
      intensities. In contrast to this, another proportion of the recorded RVM neurons
      responded with a four times longer (14.8+/-3 ms) onset latency to the vl-PAG
      stimulation, corresponding to polysynaptic modulation. All of these neurons were
      inhibited by sciatic nerve stimulation. The findings show that RVM neurons
      receive heterogeneous monosynaptic and polysynaptic inputs from the vl-PAG. The
      results also suggest that the monosynaptic and polysynaptic pathways modulate the
      activity of functionally distinct groups of RVM neurons.

PMID- 12493618
TI  - GABA(A) and GABA(B) receptors mediated inhibition affect the pattern adaptation
      of relay cells in the dorsal lateral geniculate nucleus (LGNd) of cats.
AB  - Pattern adaptation is very important for visual function, while the mechanisms
      that mediate pattern adaptation, especially in the dorsal lateral geniculate
      nucleus (LGNd), are still unclear. Iontophoresis of the antagonists and agonists
      of GABA receptors were employed to separately investigate the contribution of
      GABA(A) and GABA(B) receptors to pattern adaptation of LGNd cells. When GABA(A)
      receptors were blocked by bicuculline both the response amplitude of LGNd cells
      and the degree of adaptation increased significantly. Many neurons showing no
      pattern adaptation under the normal condition became adapted to a prolonged
      stimulus. Moreover, the proportion of cells showing adaptation doubled (from 40
      to 88%). The mean adaptation index (AI, adapted response amplitude/original
      response amplitude) was 0.82 during bicuculline application, compared with 0.92
      under the control condition. In additional, iontophoresis of baclofen, a
      selective GABA(B) receptor agonist, decreased the mean response amplitude to
      grating stimuli to 53% of normal. Nearly half of the neurons increased their
      adaptation index following baclofen administration and the mean AI increased from
      0.89 to 1.01. Iontophoresis of GABA(B) receptor antagonist (CGP35348) could
      abolish this effect, though it had no significant effect on visual response
      amplitude and pattern adaptation itself. Iontophoresis of another GABA(B)
      receptor antagonist, 2-OH-saclofen, also had no significant effect on visual
      response amplitude and pattern adaptation. These results suggest that both
      GABA(A) receptors and GABA(B) receptors modulate the pattern adaptation of LGNd
      cells and are involved in synaptic plasticity.

PMID- 12493619
TI  - EEG related neuronal activity in the pedunculopontine tegmental nucleus of
      urethane anaesthetized rats.
AB  - Cholinergic pathways ascending from the brainstem are considered as a decisive
      part of the reticular activating system. We recorded unit activity from the
      cholinergic pedunculopontine tegmental nucleus with extracellular microelectrodes
      in urethane-anesthetized rats and monitored cortical electroencephalogram (EEG)
      to examine the possible role of the nucleus in cortical activation. We found two
      types of cells showing EEG-correlated firing patterns. In one group, firing rate
      increased during cortical activation (F cell), while in another, higher rate was
      accompanied by cortical slow waves (S cell). Phasic changes in the firing rate of
      pedunculopontine neurons and in the cortical EEG were also analyzed. Changes of
      single unit activity in F cells always occurred before short periods of low
      voltage fast activity appeared in the cortical EEG. The S cells were more
      variable with respect to the temporal relation. In some of the S cells, changes
      in firing rate preceded changes in the EEG patterns, while in others they
      occurred after a certain delay. Our results indicate that F-cells in the PPT
      might be involved in the initiation of tonic and phasic changes in cortical
      activation.

PMID- 12493620
TI  - Pressor effects of L-glutamate injected into the diagonal band of Broca of
      unanesthetized rats.
AB  - The diagonal band of Broca (dbB) is involved in central cardiovascular control.
      In the present study we compared the effects of microinjections of L-glutamate
      into the dbB of unanesthetized rats with those observed after the injection of L
      glutamate into the same area in urethane-anesthetized rats. The microinjection of
      L-glutamate (10, 30, 100 or 200 nmol/200 nl) into the dbB of urethane
      anesthetized rats caused dose-related short-lasting depressor responses The
      depressor responses to L-glutamate were accompanied by dose-related heart rate
      reduction. The cardiovascular response to the injection of L-glutamate (10, 30 or
      100 nmol/200 nl) into the dbB of unanesthetized rats was characterized as a long
      lasting pressor response without consistent heart rate changes. The pressor
      response was dose-related and presented an ED(50) of approximately 30 nmol/200
      nl. The fact that the chemical stimulation of the dbB with L-glutamate caused
      only dose-related pressor responses in unanesthetized rats suggests that under
      normal conditions the dbB is predominantly a pressor area. After the
      characterization of the pressor response to L-glutamate microinjected into the
      dbB of unanesthetized rats we studied the mechanisms involved in the mediation of
      these responses. The pressor response to L-glutamate (30 nmol/200 nl) into the
      dbB was blocked by intravenous pretreatment with the vasopressin antagonist
      dTyr(CH(2))(5)(Me)AVP (50 microg/kg), suggesting the involvement of circulating
      vasopressin in this response. Further evidence of the involvement of the
      endocrine vasopressin system in the pressor response to L-glutamate injected into
      the dbB was provided by hypophysectomy since L-glutamate (30 nmol/200 nl)
      microinjection into the dbB of hypophysectomized rats caused only depressor
      responses. We presently report that chemical stimulation of the dbB with L
      glutamate caused only pressor responses in unanesthetized rats that were mediated
      by vasopressin release into the systemic circulation. Additionally, the results
      confirmed the existence of an L-glutamate-sensitive depressor system in the dbB,
      which is predominant in urethane-anesthetized rats or may be evidenced in
      unanesthetized hypophysectomized rats.

PMID- 12493621
TI  - High frequency oscillations in the dentate gyrus of rat hippocampal slices
      induced by tetanic stimulation.
AB  - Tetanic stimulation induces high-frequency network oscillations in area CA1 and
      in the subiculum of rat hippocampal slices. Here, we describe the effects of
      similar tetanic stimulation in the molecular layer of the dentate gyrus. We found
      field potential oscillations in the dentate granule cell layer which shared
      several properties with tetanically induced oscillations in CA1, including
      delayed onset, duration, progressive slowing of frequency within the oscillations
      and sensitivity to blockers of GABA(A) receptors, NMDA receptors and metabotropic
      glutamate receptors. However, the mean frequency of the oscillations in the
      dentate is approximately 100 Hz, much higher than tetanic oscillations in CA1
      and, in contrast to CA1, dentate high-frequency oscillations are sensitive to
      antagonists of AMPA-receptors. Oscillation frequency was decreased by
      metabotropic glutamate receptor antagonists and increased by antagonists of AMPA
      receptors as well as the gap junction blocker carbenoxolone. The oscillations can
      be observed in the whole dentate gyrus-CA3-network and are tightly correlated
      between the dentate gyrus and area CA3. Thus, tetanic stimulation in the dentate
      elicits a new pattern of network oscillations with coherence in the dentate-CA3
      network which may affect the processing of afferent information in the
      hippocampus.

PMID- 12493622
TI  - Prostaglandin E2 rescues cortical neurons from amyloid beta protein-induced
      apoptosis.
AB  - Cerebrospinal fluid prostaglandin E(2) (PGE(2)) levels are elevated in patients
      with Alzheimer's disease (AD), suggesting an involvement of PGE(2) in the
      neurodegeneration. AD is characterized by deposits of amyloid beta protein
      (Abeta) in various regions of the brain, e.g. the cerebral cortex. In the present
      study, we investigated the effects of PGE(2) on neuronal survival in primary
      cultures of rat cortical neurons. PGE(2) had no effect on neuronal cell viability
      or its morphology. Therefore, we examined the synergistic effects of PGE(2) with
      Abeta, a neurotoxin. Abeta caused neuronal cell death via apoptosis. PGE(2)
      significantly suppressed Abeta neurotoxicity, but did not promote the
      neurotoxicity. Furthermore, PGE(2) ameliorated Abeta-induced apoptotic features
      such as the condensation of chromatin and the fragmentation of DNA. Abeta
      increased the influx of Ca(2+) into neurons before cell death. Nimodipine, an
      inhibitor of the L-type voltage-sensitive calcium channel (L-VSCC), significantly
      reduced Abeta-potentiated Ca(2+) uptake. On the other hand, there was no effect
      on the Abeta-induced Ca(2+) influx by an N-VSCC blocker or P/Q-VSCC blockers.
      Moreover, the inhibitor of L-VSCC suppressed Abeta-induced neuronal cell death,
      whereas neither an N-VSCC blocker nor P/Q-VSCC blockers affected the
      neurotoxicity of Abeta. PGE(2) also suppressed the Abeta-induced Ca(2+) influx in
      a concentration-dependent manner. This study demonstrated that PGE(2) rescues
      cortical neurons from Abeta-induced apoptosis by reducing Ca(2+) influx in the
      primary culture. Furthermore, the present study suggested that the inhibition of
      L-VSCC contributes to the neuroprotective effect of PGE(2).

PMID- 12493623
TI  - Dual innervation of the lamprey retina by GABAergic and glutamatergic retinopetal
      fibers. A quantitative EM immunogold study.
AB  - A quantitative electron microscopic analysis of glutamate and GABA
      immunocytochemistry, using the postembedding immunogold technique, was undertaken
      in the lamprey retina to determine the proportion of glutamate-immunoreactive
      (GLU-ir) centrifugal visual terminals which were identified by anterograde axonal
      transport after an iontophoretic deposit of HRP in the sectioned optic nerve.
      Single immunogold labeling carried out with two different GABA and GLU antibodies
      showed that about 45% of the retinopetal axon terminals were GABAergic, and that
      two types of GLU-ir terminals (GLU-ir/1 and GLU-ir/2) were observed in the inner
      plexiform layer. The former type showed a high density of gold particles
      (Neosystem: 19.38+/-0.74; Sigma: 106.26+/-5.70) which statistically differed from
      the GLU-ir/2 (Neosystem: 3.23+/-0.31; Sigma: 31.73+/-5.61). Subcellular estimates
      showed that gold particles were concentrated over the vesicular pool in the GLU
      ir/1 terminals and over mitochondria in the second terminal type. Consecutive
      sections alternately processed for GABA and GLU revealed that the GABA
      immunonegative terminals corresponded to the GLU-ir/1, whereas the GABA-ir
      terminals only contained few GLU-ir particles, mostly concentrated in
      mitochondria. The occurrence of GABAergic and glutamatergic retinopetal terminals
      in the adult lamprey retina is discussed in functional terms of their
      differential inhibitory and excitatory effects on ganglion cell activity and the
      possible role of the centrifugal visual system in visually-guided behavior.

PMID- 12493624
TI  - Affective analgesia following the administration of morphine into the amygdala of
      rats.
AB  - The amygdala processes stimuli that threaten the individual and organizes the
      execution of affective behaviors that permit the individual to cope with the
      threat. The prototypical threat to an individual is exposure to a noxious
      stimulus. The present study evaluated the contribution of the amygdala in
      modulating the affective response of rats to noxious stimulation. Vocalization
      afterdischarges (VADs) are a validated model of the affective response of rats to
      noxious tailshock. The antinociceptive action of morphine microinjected into the
      amygdala on VAD thresholds was compared to its effect on the thresholds of other
      tailshock-elicited responses (vocalizations during shock, VDS and spinal motor
      reflexes, SMRs). Whereas VADs are organized within the forebrain, VDSs and SMRs
      are organized at medullary and spinal levels of the neuraxis, respectively. The
      bilateral administration of morphine into the basolateral complex of the amygdala
      (BLC) produced dose-dependent increases in VAD and VDS thresholds, although
      increases in VAD thresholds were significantly greater than increases in VDS
      thresholds. Administration of morphine into BLC was ineffective in elevating SMR
      thresholds. Morphine-induced increases in vocalization thresholds were reversed
      in a dose-dependent manner by microinjection of the opiate receptor antagonist
      methylnaloxonium into BLC. Microinjection of morphine in the vicinity to the BLC
      did not alter vocalization thresholds. The present results provide further
      evidence for the preferential involvement of the amygdala in modulation of the
      affective component of the pain experience.

PMID- 12493625
TI  - A demonstration of within-subjects latent inhibition in the human: limitations
      and advantages.
AB  - The magnitude of latent inhibition (LI) (a retardation of associative learning
      due to prior exposure to the conditioning stimulus) was measured in healthy
      volunteers using both a within- and a between-subjects version of the task.
      Reliable LI was demonstrated for the within-subjects paradigm (using a design
      that fully counter-balanced stimulus of pre-exposure) but the magnitude of the
      effect was smaller than for the between-subjects version. Measures of schizotypal
      personality were found to be associated with reduced LI for the between-subjects
      task, but not for the within-subjects task. We hypothesised that for the within
      subjects task learning about the first stimulus-consequence association (usually
      that for the not pre-exposed (NPE) stimulus) primes learning about the second
      stimulus, thus reducing the effect of pre-exposure and restricting the range of
      LI scores. In turn, this restricted range of LI scores does not allow subtle
      differences on schizotypal personality dimensions to reveal their effect using
      this within-subjects paradigm. In conclusion, a within-subjects LI task has been
      developed which is not open to explanation in terms of differences in stimulus
      salience. However, the limited range of pre-exposure scores in the current within
      subject paradigm may severely limit it is use as an indicator of subtle
      performance changes.

PMID- 12493626
TI  - Characteristics of changes in cholinergic function and impairment of learning and
      memory-related behavior induced by olfactory bulbectomy.
AB  - Memory function after olfactory bulbectomy (OBX) was examined in two tasks,
      namely, step-through passive avoidance task and elevated plus-maze task. OBX mice
      showed a significant impairment of learning and memory-related behavior on the
      7th and 14th day, as measured by passive avoidance task but not elevated plus
      maze task. The impairment of learning and memory-related behavior on the 14th day
      was improved by administration of the cholinesterase inhibitor physostigmine (0.1
      mg/kg, i.p.), the non-selective muscarinic agonist oxotremorine (0.1 mg/kg, i.p.)
      or the selective muscarinic M(1) agonist McN-A-343 (10 microg/mouse, i.c.v.). In
      contrast, administration of the nicotinic agonist lobeline (5-9.8 mg/kg, i.p.) or
      the selective muscarinic M(2) antagonist methoctramine (2.25-18 microg/mouse,
      i.c.v.) has no effect on the impairment of learning and memory-related behavior
      induced by OBX. In addition, we have demonstrated that the intensity of choline
      acetyltransferase (ChAT) fluorescence is significantly decreased in the cortex,
      hippocampus and amygdala on the 14th day after OBX. These results suggest that
      the impairment of learning and memory-related behavior induced by OBX may be
      caused by degeneration of cholinergic neurons and muscarinic M(1) receptors play
      an important role in the improvement process.

PMID- 12493627
TI  - Predatory hunting and exposure to a live predator induce opposite patterns of Fos
      immunoreactivity in the PAG.
AB  - Considering the periaqueductal gray's (PAG) general roles in mediating
      motivational responses, in the present study, we compared the Fos expression
      pattern in the PAG induced by innate behaviors underlain by opposite motivational
      drivers, in rats, namely, insect predation and defensive behavior evoked by the
      confrontation with a live predator (a cat). Exposure to the predator was
      associated with a striking Fos expression in the PAG, where, at rostral levels,
      an intense Fos expression was found largely distributed in the dorsomedial and
      dorsolateral regions, whereas, at caudal levels, Fos-labeled cells tended to be
      mostly found in the lateral and ventrolateral columns, as well as in the dorsal
      raphe nucleus. Quite the opposite, insect predation was associated with increased
      Fos expression predominantly in the rostral two thirds of the lateral PAG, where
      the majority of the Fos-immunoreactive cells were found at the oculomotor nucleus
      levels. Remarkably, both exposure to the cat and insect predation upregulated Fos
      expression in the supraoculomotor region and the laterodorsal tegmental nucleus.
      Overall, the present results clearly suggest that the PAG activation pattern
      appears to reflect, at least partly, the animal's motivational status. It is well
      established that the PAG is critical for the expression of defensive responses,
      and, considering the present findings, it will be important to investigate how
      the PAG contributes to the expression of the predatory behavior, as well.

PMID- 12493628
TI  - Conditional discrimination learning and negative patterning in rats with neonatal
      hippocampal lesion induced by ionizing radiation.
AB  - This study was undertaken to investigate the associative process underlying
      serial feature positive conditional discrimination learning (X-->A+/A-) and the
      role of the hippocampus in the solution of tasks demanding a configural
      association strategy such as the negative patterning discrimination (XA-/X+/A+).
      It has been suggested that the hippocampus is essential for the learning of
      complex tasks, so, it is expected that hippocampal lesions would prove equally
      detrimental to performance in both tasks, but would not interfere with simple
      discrimination learning. Hippocampal lesions were made with X-radiation exposure
      to neonate rats after completion of a parametric study 'J. Neurosci. Methods 75
      (1997) 41' that established the best radiation parameters to selectively lesion
      the hippocampal dentate gyrus. When adults, rats were submitted to a serial
      feature positive conditional discrimination task with the trials 'House
      light/Tone: water (H-->T+)', 'Tone: no water (T-)', and two simple discrimination
      with the trials 'Clicker: water (C+)' and 'Noise: no water (N-)' in Experiment I.
      In Experiment II, adult rats, irradiated and control, were submitted to the
      negative patterning task with the trials 'House light/Tone: no water (HT-)',
      'House light: water (H+)', 'Tone: water (T+)', and to the non-conditional
      discrimination with the trial Noise: no water (N-)'. In contrast to the
      expectation of impaired performance in these tasks by lesioned rats, animals with
      damage to the hippocampal dentate gyrus learned the complex and the simple tasks
      as well as control subjects. These results suggest that the dentate gyrus does
      not participate directly in the modulation of acquisition of tasks demanding a
      complex strategy of occasion setting in procedures of serial conditional
      discrimination or a configural strategy, important for the negative patterning
      discrimination solution.

PMID- 12493629
TI  - When visuo-motor incongruence aids motor performance: the effect of perceiving
      motion structures during transformed visual feedback on bimanual coordination.
AB  - Two experiments are reported in which bimanual coordination tasks were performed
      under correct and transformed visual feedback conditions. Participants were to
      generate cyclical line-drawing patterns, with varying degrees of coordinative
      stability, while perceiving correct or transformed visual information of the
      trajectories on a screen. Visuo-motor transformations that dissociated the
      perceived movement direction from the actually generated direction, were applied
      to one or both limbs, resulting in varying degrees of perceptual grouping power.
      The transformed feedback did not influence the most stable coordination patterns
      (in-phase) whereas the accuracy and/or stability of the less stable coordination
      patterns (anti-phase and particularly orthogonal) benefited from particular
      visual feedback manipulations, i.e. when coherently grouped visual motion
      structures emerged, the quality of coordination improved significantly. These
      findings indicate that perceptual transformations aid the production of more
      complex coordination patterns, thereby underscoring the importance of perception
      action coupling in bimanual coordination.

PMID- 12493630
TI  - Sulpiride alleviates the attentional impairments of rats with medial prefrontal
      cortex lesions.
AB  - Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair
      performance on a number of rodent tests of attention. Although this evidence
      clearly suggests a role for the rat mPFC in attentional functions, it is unclear
      whether subcortical changes associated with mPFC lesions might also be relevant
      to the neuropsychological deficits observed. Given the ample evidence suggesting
      increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we
      investigated the effects of dopamine receptor agonists and antagonists on the
      attentional deficits associated with mPFC lesions. Rats trained on a five-choice
      reaction time task received either complete mPFC lesions or lesions restricted to
      its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared
      with sham-operated rats, animals in both the lesioned groups were impaired at
      responding correctly to the visual targets, although this deficit was more marked
      in mPFC-lesioned rats. In addition, both lesions were associated with increased
      perseverative responding. The accuracy deficits of rats with mPFC lesions were
      alleviated by systemic administration of the dopamine D2 receptor antagonist
      sulpiride. In contrast, rats with PRL-IL damage were not affected and control
      rats were impaired by sulpiride. Administration of either the dopamine D1
      receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had
      similar, albeit non-significant effects. Higher doses of any of these drugs non
      specifically impaired performance. These results extend previous findings of
      attentional impairments in rats with mPFC lesions and are compatible with recent
      hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis
      of schizophrenia.

PMID- 12493632
TI  - Role of the neocortex in the water maze task in the rat: a detailed behavioral
      and Golgi-Cox analysis.
AB  - The role of the neocortex in acquisition of the water maze task was investigated
      with both detailed behavioral and anatomical analyses. The neocortical areas
      examined were: (1). primary visual and posterior parietal areas Oc1 and Oc2M,
      (2). parietal area Par1, and (3). prefrontal areas Cg1, Cg3, IL, and part of Fr2
      of Zilles, 1985. In Experiment 1, the effects of lesions in these areas were
      examined separately in different groups of naive male hooded rats. Additional
      rats were given water maze strategy pretraining before receiving a lesion.
      Strategy pretraining was used to separate water maze strategy learning from
      spatial learning to evaluate the contribution of the neocortical areas to these
      two components of task acquisition. All groups of naive lesioned rats were
      impaired in the task. In contrast, corresponding groups of pretrained lesioned
      rats performed as well as controls on all behavioral measures. In Experiment 2,
      the same neocortical areas lesioned in Experiment 1 were examined with the Golgi
      Cox method to determine whether water maze training was associated with changes
      in the dendritic arborization of neocortical pyramidal cells. Contrary to
      expectations, no anatomical changes that could be ascribed to the behavioral
      training were seen in the areas and cortical layers examined. The data suggest
      that (1). these areas contribute to water maze strategy learning in naive rats,
      (2). none of the areas are crucially required for spatial learning provided rats
      are familiar with the general behavioral strategies required in the task before
      the lesion is made, and (3). any changes in neuronal morphology that occur as a
      consequence of the training may be subtle and widely distributed.

PMID- 12493631
TI  - Transgenic mice expressing the PS1-A246E mutation: effects on spatial learning,
      exploration, anxiety, and motor coordination.
AB  - The functional consequence of the PS1-A246E mutation was assessed in transgenic
      mice on a background lacking the endogenous PS1 gene. These mice have elevated
      concentrations of A-beta protein (Abeta(42)) in the absence of plaque formation.
      By comparison to a mixed background strain (50% B6, 25% SJl, 25% 129Sv)
      controlled for age and gender, PS1-A246E transgenic mice displayed disinhibitory
      tendencies, as indicated by increased entries and duration in the open arms of
      the elevated plus-maze. Despite normal spontaneous alternation rates in a T-maze,
      latencies before responding were higher in PS1-A246E transgenic mice than
      controls. Moreover, the PS1-A246E transgenic mice fell more often from two
      stationary beams, but not from the coat-hanger and the rotorod. By contrast,
      ambulation in an automated photocell chamber and in an open-field was not
      affected. Nor was acquisition of place learning in the Morris water maze task.
      These results indicate that elevated Abeta(42) levels were insufficient for
      causing spatial defects but caused disinhibition, psychomotor slowing, and loss
      of motor skills in this model of familial Alzheimer's disease.

PMID- 12493633
TI  - Dose-addition of individual odorants in the odor detection of binary mixtures.
AB  - In a series of experiments, we have explored the rules of olfactory detection
      agonism between the odorants butyl acetate and toluene. First, we obtained the
      concentration-detection function for the odor of the individual compounds.
      Second, we selected the concentrations of the two substances producing three
      levels of detectability (low, medium, and high) and, for each level, tested the
      comparative detectability of the two single chemicals and three mixtures of
      varying proportions. In each case, the mixtures were prepared in such a way that,
      if a rule of complete dose addition were to hold, all five stimuli (two single,
      three mixtures) should be equally detected. The outcome revealed complete dose
      addition at relatively low detectability levels but fell short of dose addition
      at medium and high levels. A recent analogous study on trigeminal chemosensory
      detection via nasal pungency and eye irritation of these same stimuli have shown
      a similar trend but showed a less dramatic loss of dose additivity with increased
      detectability. These results on detection of mixtures suggest a more selective
      window of chemical tuning (i.e. less dose addition) in olfaction than in
      trigeminal chemoreception.

PMID- 12493634
TI  - State-dependent columnar organization of dorsal hippocampal activity in the
      freely-behaving cat.
AB  - We examined reflected light images from the dorsal hippocampus in freely-behaving
      cats to assess the topographical organization of neural activity expressed during
      sleep-waking states. Reflectance patterns, organized as columns along the CA3-CA1
      axis which appeared during rapid eye movement sleep (REM) and waking states, were
      compared to baseline periods collected during quiet sleep (QS). The columns were
      not static across states or behaviors within a state, but showed inversion in
      activation/inactivation patterns, and narrowed or widened over time. A
      correlation between state-dependence and reflectance patterns emerged, with
      transitions to active waking and REM most likely exhibiting enhanced columnar
      patterning, relative to QS. No columnar patterns appeared in overlying
      neocortical areas or in control media. The columnar patterns suggest a highly
      structured functional state-dependent organization in the dorsal hippocampus, as
      has been previously predicted by anatomical studies.

PMID- 12493635
TI  - Toward a better understanding of the perception of self-produced speech.
AB  - The subject of how humans hear their own voices while speaking has received
      sporadic attention. Previous investigations suggest that the voice is heard
      substantially via bone conduction, implying a different transfer function to the
      ear--perhaps a low-pass filter--than for purely air-conducted vocalizations.
      Determining the characteristics of the transfer function of self-produced speech
      might contribute to a better understanding of self-perception. Such information
      may have important implications for treating articulation disorders. The efficacy
      of training discrimination during the remediation of articulation disorders
      remains unclear, perhaps because clients are asked to discriminate either speech
      of others or recorded self-speech samples not readily recognized as their own.
      This study was conducted to determine preference for filtered self-monitored
      speech in a delayed feedback paradigm. Participants made immediate comparisons of
      their real-time speech to delayed-recorded filtered self-speech samples.
      Participants demonstrated a clear preference for low-pass filtered speech,
      supporting earlier findings, but we were unable to determine the transfer
      function itself. LEARNING OUTCOMES: As a result of this activity, the learner
      will be able to describe some reasons why an individual's tape recorded speech
      typically sounds different to him/her from his/her own, live speech. As a result
      of this activity, the learner will be able to describe some potential
      applications for an accurately-characterized transfer function for self-produced
      speech.

PMID- 12493636
TI  - A prospective cross-sectional study of speech in patients with the 22q11 deletion
      syndrome.
AB  - The purpose of this study was to investigate a consecutive series of 65
      participants between 3 and 33 years of age (median age of 9 years and 4 months)
      with a confirmed 22q11.2 deletion, in order to ascertain the frequency and
      severity of articulation difficulties, velopharyngeal impairment (VPI), and the
      level of intelligibility. The majority had velopharyngeal impairment; over half
      of them to such a degree that surgery had been performed or was considered
      necessary. A high level of correct place and manner of consonants was only found
      in children with the 22q11 deletion syndrome from age 6. The most misarticulated
      consonants were stops and fricatives. Glottal articulation assessed in words and
      sentences was less frequent than expected according to earlier studies. A high
      prevalence of reduced intelligibility at different ages indicates an obvious
      communication limitation in younger children, and for some individuals even as
      teenagers and adults. EDUCATIONAL OBJECTIVES: As a result of this activity, the
      participant will have knowledge about the frequency and severity of: (1)
      articulation difficulties; (2) velopharyngeal impairment; and (3) the level of
      intelligibility in patients with a 22q11.2 deletion.

PMID- 12493637
TI  - The influence of listener experience and academic training on ratings of
      nasality.
AB  - This study assessed listener agreement levels for nasality ratings, and the
      strength of relationship between nasality ratings and nasalance scores on one
      hand, and listener clinical experience and formal academic training in cleft
      palate speech on the other. The listeners were 12 adults who represented four
      levels of clinical experience and academic training in cleft palate speech. Three
      listeners were teachers with no clinical experience and no academic training
      (TR), three were graduate students in speech-language pathology (GS) with
      academic training but no clinical experience, three were craniofacial surgeons
      (MD) with extensive experience listening to cleft palate speech but with no
      academic training in speech disorders, and three were certified speech-language
      pathologists (SLP) with both extensive academic training and clinical experience.
      The speech samples were audio recordings from 20 persons representing a range of
      nasality from normal to severely hypernasal. Nasalance scores were obtained
      simultaneously with the audio recordings. Results revealed that agreement levels
      for nasality ratings were highest for the SLPs, followed by the MDs. Thus, the
      more experienced groups tended to be more reliable. Mean nasality ratings
      obtained for each of the rater groups revealed an inverse relationship with
      experience. That is, the two groups with clinical experience (SLP and MD) tended
      to rate nasality lower than the two groups without experience (GS and TR).
      Correlation coefficients between nasalance scores and nasality judgments were low
      to moderate for all groups and did not follow a pattern. EDUCATIONAL OUTCOMES: As
      a result of this activity, the reader will be able to (1) describe the influence
      of listener experience and academic training in cleft palate speech on perceptual
      ratings of nasality. (2) describe the influence of experience and training on the
      nasality/nasalance relationship and, (3) compare the present findings to previous
      findings reported in the literature.

PMID- 12493639
TI  - The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions.
AB  - Members of the Bcl-2 family are crucial integrators of survival and death signals
      in higher eukaryotes. Although recent studies have provided novel and quite
      unexpected insights into the mechanisms by which these proteins might issue life
      permits or death sentences in cells, we are still on the way to fully understand
      their modes of action. This review provides a snapshot on where we are on this
      journey and how we may exploit our knowledge on this family of proteins to unveil
      the mysteries of immune regulation.

PMID- 12493638
TI  - Second formant transitions in fluent speech of persistent and recovered preschool
      children who stutter.
AB  - This study investigated frequency change and duration of the second formant (F2)
      transitions in perceptually fluent speech samples recorded close to stuttering
      onset in preschool age children. Comparisons were made among 10 children known to
      eventually persist in stuttering, 10 who eventually recovered from stuttering,
      and 10 normally fluent controls. All were enrolled in the longitudinal Stuttering
      Research Project at the University of Illinois. Subjects fluently repeated
      standard experimental sentences. The same 36 perceptually fluent target segments
      (syllables embedded in words) from each subject's repeated sentences were
      analyzed. The syllables were divided into three phonetic categories based on
      their initial consonant: bilabial, alveolar, and velar placement. The frequency
      change and duration of F2 transitions were analyzed for each of the target CV
      segments. F2 transition onset and offset frequencies and their interval
      (duration) were measured for each utterance. Data indicate that near stuttering
      onset, children whose stuttering eventually persisted demonstrated significantly
      smaller frequency change than that of the recovered group. It is suggested that
      the F2 transitions should continue to be investigated as a possible predictor of
      stuttering pathways. LEARNING OUTCOMES: (1) Readers will learn about studies
      regarding second formant transition related to stuttering. (2) Readers will learn
      about differences between children who persist in stuttering and those who
      recover from stuttering. (3) Readers will learn about research concerned with
      early identification of risk criteria in persistent stuttering.

PMID- 12493640
TI  - Regulation of B lymphocytes in health and disease. Meeting review.
AB  - Signal transduction by the B cell receptor (BCR) is an absolute requirement for
      the selection and development of B lymphocytes at multiple checkpoints. Binding
      to antigen via the BCR is complemented by a co-stimulus delivered through
      accessory and co-stimulatory cell surface molecules that regulate the signalling
      threshold. In addition, identification of genes associated with immunodeficiency
      syndromes has highlighted the importance of genetic regulation, particularly in
      immunoglobulin class-switching and somatic hypermutation. A 1-day symposium
      organised by the Biochemical Society considered some of the recent advances in
      our understanding of the molecules and regulatory pathways involved in B
      lymphocyte activation, differentiation and survival and the health consequences
      when threshold settings malfunction.

PMID- 12493641
TI  - Functional characterization of the lectin pathway of complement in human serum.
AB  - Mannan-binding lectin (MBL) is a major initiator of the lectin pathway (LP) of
      complement. Polymorphisms in exon 1 of the MBL gene are associated with impaired
      MBL function and infections. Functional assays to assess the activity of the
      classical pathway (CP) and the alternative pathway (AP) of complement in serum
      are broadly used in patient diagnostics. We have now developed a functional LP
      assay that enables the specific quantification of autologous MBL-dependent
      complement activation in human serum. Complement activation was assessed by ELISA
      using coated mannan to assess the LP and coated IgM to assess the CP. Normal
      human serum (NHS) contains IgG, IgA and IgM antibodies against mannan, as shown
      by ELISA. These antibodies are likely to induce CP activation. Using C1q-blocking
      and MBL-blocking mAb, it was confirmed that both the LP and the CP contribute to
      complement activation by mannan. In order to quantify LP activity without
      interference of the CP, LP activity was measured in serum in the presence of C1q
      blocking Ab. Activation of serum on coated IgM via the CP resulted in a dose
      dependent deposition of C1q, C4, C3, and C5b-9. This activation and subsequent
      complement deposition was completely inhibited by the C1q-blocking mAb 2204 and
      by polyclonal Fab anti-C1q Ab. Evaluation of the LP in the presence of mAb 2204
      showed a strong dose-dependent deposition of C4, C3, and C5b-9 using serum from
      MBL-wildtype (AA) but not MBL-mutant donors (AB or BB genotype), indicating that
      complement activation under these conditions is MBL-dependent and C1q
      independent. Donors with different MBL genotypes were identified using a newly
      developed oligonucleotide ligation assay (OLA) for detection of MBL exon 1
      polymorphisms. We describe a novel functional assay that enables quantification
      of autologous complement activation via the LP in full human serum up to the
      formation of the membrane attack complex. This assay offers novel possibilities
      for patient diagnostics as well as for the study of disease association with the
      LP.

PMID- 12493642
TI  - The endothelium as physiological source of properdin: role of wall shear stress.
AB  - Properdin is a positive regulator of the alternative pathway of complement
      activation. It can be released by peripheral blood cells but is not synthesized
      in the liver and the physiological source of properdin in plasma is unknown. The
      endothelium is an extra-hepatic source for several complement components and
      shear stress can modulate their expression. The aim of this study was to analyze
      shear stress-exposed endothelial cells (EC) as physiological source for plasma
      properdin. Human umbilical vein EC (HUVEC) and human cardiac microvascular EC
      (HCMEC) were exposed to shear stress using a cone-and-plate apparatus and
      properdin expression was analyzed by RT-PCR, Northern, and Western blot. mRNA for
      properdin is barely detectable in untreated EC but strongly induced by laminar
      shear stress exposure (6 dyn/cm(2); 24 h). Properdin is induced also at the
      protein level and is released in the extracellular compartment. Properdin up
      regulation requires a shear stress of 2-3 dyn/cm(2), is not transient, and is
      reversible by restoration of static conditions. Turbulent flow exposure results
      in two times higher induction of properdin than laminar flow exposure. The
      ability of endothelial cells exposed to shear stress to synthesize properdin
      proposes the endothelium as physiological source for plasma properdin and
      suggests a link between flow conditions and the modulation of the alternative
      pathway. Furthermore, the stronger properdin induction by turbulent flow may
      suggest an involvement in the pathology of atherosclerosis.

PMID- 12493643
TI  - The IRF-2 DNA binding domain facilitates the activation of the class II
      transactivator (CIITA) type IV promoter by IRF-1.
AB  - IFN-gamma induced transcription of class II transactivator (CIITA), a major
      regulator of MHC class II gene expression, is directed by the CIITA type IV
      promoter. The IFN-gamma activation of the CIITA type IV promoter is mediated by
      STAT1 and IRF-1, which bind to the GAS and IRF-E of the promoter, respectively.
      We and others have determined that IRF-2, another member of the IRF family, also
      activates the CIITA type IV promoter, by binding to the IRF-E. Also, IRF-2
      cooperates with IRF-1 to activate the promoter. DNA binding analyses determined
      that IRF-1 and IRF-2 can co-occupy the IRF-E of the CIITA type IV promoter. To
      further understand the mechanism of IRF-1 and IRF-2 cooperativity in the
      activation of CIITA type IV promoter, we characterized the binding of IRF-1 and
      IRF-2 to the CIITA IRF-E and mapped the domains of IRF-2 required for the
      cooperative transactivation. Off-rate experiments revealed that the IRF-2/IRF-E
      complex was more stable than the IRF-1/IRF-E complex and that the affinity of IRF
      1 for the IRF-E was increased when IRF-1 co-occupied the IRF-E with IRF-2.
      Deletion analysis of functional domains of IRF-2 revealed that a previously
      described latent activation domain of IRF-2 was essential for IRF-2
      transactivation and participated in cooperative activation of the CIITA promoter
      by IRF-1 and IRF-2. However, the DNA binding domain of IRF-2 was sufficient for
      cooperativity with IRF-1 in the activation of the CIITA type IV promoter. DNA
      binding assay demonstrated that, like the full-length IRF-2, the IRF-2 DNA
      binding domain could co-occupy the CIITA IRF-E with IRF-1.

PMID- 12493644
TI  - Sigh in supine and prone position during acute respiratory distress syndrome.
AB  - Interventions aimed at recruiting the lung of patients with acute respiratory
      distress syndrome (ARDS) are not uniformly effective. Because the prone position
      increases homogeneity of inflation of the lung, we reasoned that it might enhance
      its potential for recruitment. We ventilated 10 patients with early ARDS
      (PaO2/FIO2, 121 +/- 46 mm Hg; positive end-expiratory pressure, 14 +/- 3 cm H2O)
      in supine and prone, with and without the addition of three consecutive "sighs"
      per minute to recruit the lung. Inspired oxygen fraction, positive end-expiratory
      pressure, and minute ventilation were kept constant. Sighs increased PaO2 in both
      supine and prone (p < 0.01). The highest values of PaO2 (192 +/- 41 mm Hg) and
      end-expiratory lung volume (1840 +/- 790 ml) occurred with the addition of sighs
      in prone and remained significantly elevated 1 hour after discontinuation of the
      sighs. The increase in PaO2 associated with the sighs, both in supine and prone,
      correlated linearly with the respective increase of end-expiratory lung volume (r
      = 0.82, p < 0.001). We conclude that adding a recruitment maneuver such as
      cyclical sighs during ventilation in the prone position may provide optimal lung
      recruitment in the early stage of ARDS.

PMID- 12493645
TI  - Mitochondrial electron transport chain function is enhanced in inspiratory
      muscles of patients with chronic obstructive pulmonary disease.
AB  - In chronic obstructive pulmonary disease, inspiratory muscles face increased
      resistive and elastic workloads and therefore increased energy requirements. The
      adaptive response of these muscles to this higher energy demand includes
      increased oxidative enzymes and changes in contractile protein expression but the
      consequences on mitochondrial function and energy metabolism have not been
      assessed so far. We investigated the in situ properties of the mitochondria of
      costal diaphragm and external intercostal muscles using the skinned fiber
      technique in 9 emphysematous and 11 age-matched control patients. Biopsies
      obtained during thoracic surgery were placed in an oxygraphic chamber to measure
      maximal oxygen uptake. We observed that the maximal oxidative capacity of
      diaphragm and external intercostal muscles increased significantly in the
      emphysematous group compared with the control group (+135 and +37%,
      respectively). Significant correlations were found between the maximal oxidative
      capacity and patients' pulmonary indexes of obstruction (diaphragm: r = -0.637,
      intercostal: r = -0.667, p < 0.005) and hyperinflation (diaphragm: r = 0.639, p <
      0.003, intercostal: r = 0.634, p < 0.01). Slow myosin heavy chain isoform
      increased in the diaphragm of the emphysematous group, with significant
      relationships between indexes of obstruction and hyperinflation and activities of
      biochemical mitochondrial markers. Thus, severe emphysema was associated with
      increased mitochondrial capacity and efficiency in the inspiratory muscles,
      supporting an endurance training-like effect.

PMID- 12493646
TI  - Pulmonary function and health-related quality of life in survivors of acute
      respiratory distress syndrome.
AB  - Although survival rates for acute respiratory distress syndrome have increased,
      there is only limited information regarding the quality of life and the
      relationship between quality of life and pulmonary function after survival. We
      prospectively measured pulmonary function, emotional function, and health-related
      quality of life in a cohort of acute respiratory distress syndrome survivors
      recruited from patients who were enrolled in a randomized clinical trial of high
      versus low tidal volume mechanical ventilation at 1 year after their recovery. No
      significant differences were found between the patients treated with high and low
      tidal volumes on any pulmonary function measure. Approximately 80% of the
      patients in both groups demonstrated reduced diffusing capacity; 20% had airflow
      obstruction, and 20% had chest restriction. Scores on measures of depression and
      anxiety were within the normal ranges, suggesting that they did not have
      significant affective symptoms. However, both groups reported decreased health
      related quality of life in physical functioning, physical ability to maintain
      their roles (role-physical), bodily pain, general health, and vitality (energy)
      on the Medical Outcome Study Short Form Health Survey with similar physical
      limitations reported on the Sickness Impact Profile questionnaire. The pulmonary
      function abnormalities correlated with decreased health-related quality of life
      for domains reflecting physical function. Acute respiratory distress syndrome
      survivors treated with high and low tidal volumes have abnormal pulmonary
      function that was related to decreased health-related quality of life 1 year
      after hospital discharge.

PMID- 12493647
TI  - TA-19, a novel protein antigen of Trichosporon asahii, in summer-type
      hypersensitivity pneumonitis.
AB  - The most common form of hypersensitivity pneumonitis in Japan is summer-type
      hypersensitivity pneumonitis (SHP), which is caused by the inhalation of
      Trichosporon asahii or Trichosporon mucoides. To seek protein antigens relevant
      to the immunopathogenesis of SHP, we constructed a cDNA expression library of T.
      asahii, a major causative yeast species of SHP. Using the immunoscreening method,
      we identified and cloned a novel gene encoding a 19-kD protein, named TA-19,
      which proved to be specifically recognized in the bronchoalveolar lavage (BAL)
      fluids and sera of patients with SHP. IgG, IgA, and IgM antibodies to the
      recombinant TA-19 protein were significantly elevated in the sera as well as in
      the BAL fluids from SHP patients compared with those from non-SHP groups. This
      protein also induced SHP-specific proliferation of the mononuclear cells from
      both the peripheral blood and BAL. These results reveal that TA-19 derived from
      T. asahii may play a relevant role in specific cellular and humoral immune
      responses in patients with SHP.

PMID- 12493648
TI  - Comparison of nasal and oral inhalation during exhaled breath condensate
      collection.
AB  - Analysis of exhaled breath condensate is a method for noninvasive assessment of
      the lung. Condensate can be collected with a nose clip (subjects inhale and
      exhale via the mouth) or without it (subjects inhale via the nose and exhale via
      the mouth), but the mode of inhalation may influence condensate volume and
      mediator levels. We compared condensate volume and adenosine, ammonia, and
      thromboxane B2 levels in young healthy volunteers (n = 25) in samples collected
      for 10 minutes from subjects with or without a nose clip. Patients with allergic
      rhinitis (n = 8) were also studied to assess the effect of upper airway
      inflammation on mediator levels. Adenosine, ammonia, and thromboxane B2 levels
      were determined by HPLC, spectrophotometry, and radioimmunoassay, respectively.
      Volume of condensate was significantly higher without nose clip than that with
      nose clip (mean +/- SD, 2321 +/- 736 microl and 1746 +/- 400 microl,
      respectively; p = 0.0001). We found no significant difference in any mediator
      levels between these two collection modes in healthy volunteers, but adenosine
      showed a tendency to differ between oral and nasal inhalation in patients with
      allergic rhinitis. Our data indicate that whereas a greater volume of condensate
      can be obtained when subjects inhale through their noses, the mode of inhalation
      does not influence mediator levels in young healthy volunteers, but may affect
      these levels in patients with allergic rhinitis.

PMID- 12493649
TI  - How political should a general medical journal be?

PMID- 12493650
TI  - Spend (slightly) less on health and more on the arts.

PMID- 12493651
TI  - Time to move beyond the mind-body split.

PMID- 12493652
TI  - Spirituality and clinical care.

PMID- 12493653
TI  - The joy of banning.

PMID- 12493654
TI  - Data dredging, bias, or confounding.

PMID- 12493655
TI  - Admissions for myocardial infarction and World Cup football: database survey.
AB  - OBJECTIVES: To examine hospital admissions for a range of diagnoses on days
      surrounding England's 1998 World Cup football matches. DESIGN: Analysis of
      hospital admissions obtained from English hospital episode statistics. SETTING:
      England. PARTICIPANTS: Population aged 15-64 years. MAIN OUTCOME MEASURES: Ratio
      of number of admissions for acute myocardial infarction, stroke, deliberate self
      harm, and road traffic injuries on the day of and five days after England's World
      Cup matches, compared with admissions at the same time in previous and following
      years and in the month preceding the tournament. RESULTS: Risk of admission for
      acute myocardial infarction increased by 25% on 30 June 1998 (the day England
      lost to Argentina in a penalty shoot-out) and the following two days. No excess
      admissions occurred for other diagnoses or on the days of the other England
      matches. The effect was the same when only the two days after the match were
      treated as the exposed condition. Individual analyses of the day of and the two
      days after the Argentina match showed 55 extra admissions for myocardial
      infarctions compared with the number expected. CONCLUSION: The increase in
      admissions suggests that myocardial infarction can be triggered by emotional
      upset, such as watching your football team lose an important match.

PMID- 12493656
TI  - Scared to death?

PMID- 12493657
TI  - Controlled prospective study of faecal occult blood screening for colorectal
      cancer in Bury, black pudding capital of the world.

PMID- 12493658
TI  - Ice cream evoked headaches (ICE-H) study: randomised trial of accelerated versus
      cautious ice cream eating regimen.

PMID- 12493659
TI  - Sex--can you get it right?

PMID- 12493660
TI  - Shapely centrefolds? Temporal change in body measures: trend analysis.

PMID- 12493661
TI  - What should we say to patients with symptoms unexplained by disease? The "number
      needed to offend".

PMID- 12493662
TI  - A paradigm shift in the medical literature.

PMID- 12493663
TI  - Readability of British and American medical prose at the start of the 21st
      century.

PMID- 12493664
TI  - A tale of two citations: counting on numeracy in the digital divide.

PMID- 12493665
TI  - Can medical education be fun as well as educational?

PMID- 12493666
TI  - Revalidation: the real life OSCE.

PMID- 12493667
TI  - A seasonal cost effectiveness analysis: the last Noel?

PMID- 12493668
TI  - Empty arms: the effect of the arms trade on mothers and children.

PMID- 12493669
TI  - How healthy is the world?

PMID- 12493670
TI  - Time and tide wait for no man.

PMID- 12493671
TI  - Identity and genetic ancestry tracing.

PMID- 12493672
TI  - Four futures for scientific and medical publishing.

PMID- 12493673
TI  - Is that it? How online articles have changed over the past five years.

PMID- 12493674
TI  - Papyrus to PowerPoint (P 2 P): metamorphosis of scientific communication.

PMID- 12493675
TI  - The mummy's curse: historical cohort study.
AB  - OBJECTIVE: To examine survival of individuals exposed to the "mummy's curse"
      reputedly associated with the opening of the tomb of Tutankhamen in Luxor, Egypt,
      between February 1923 and November 1926. DESIGN: Retrospective cohort study.
      PARTICIPANTS: 44 Westerners identified by Howard Carter as present in Egypt at
      the specified dates, 25 of whom were potentially exposed to the curse. MAIN
      OUTCOME MEASURES: Length of survival after date of potential exposure. RESULTS:
      In the 25 people exposed to the curse the mean age at death was 70 years (SD 12)
      compared with 75 (13) in those not exposed (P=0.87 for difference). Survival
      after the date of exposure was 20.8 (15.2) v 28.9 (13.6) years respectively
      (P=0.95 for difference). Female sex was a predictor for survival (P=0.02).
      CONCLUSIONS: There was no significant association between exposure to the mummy's
      curse and survival and thus no evidence to support the existence of a mummy's
      curse.

PMID- 12493676
TI  - Forgotten transfusion history: John Leacock of Barbados.

PMID- 12493677
TI  - The Soviet "Doctors' Plot"-50 years on.

PMID- 12493679
TI  - The case of the missing data.

PMID- 12493680
TI  - Are ethical principles relative to time and place? A Star Wars perspective on the
      Alder Hey affair.

PMID- 12493681
TI  - EBM: unmasking the ugly truth.

PMID- 12493682
TI  - Visible signs of illness from the 14th to the 20th century: systematic review of
      portraits.
AB  - OBJECTIVES: To see whether a collection of portraits depicting inhabitants of a
      defined geographical region and covering several centuries is a useful source for
      studying the sociocultural significance and epidemiology of particular visible
      diseases, such as goitre, which is known to have been common in this region.
      DESIGN: Systematic review of portraits and description of visible signs of
      illness. SETTING: The Burgerbibliothek (archives of the burghers' community) in
      Berne, Switzerland. DATA SOURCES: 3615 portraits; 2989 of individuals whose
      identity is known and 626 of individuals whose identity is unknown. MAIN OUTCOME
      MEASURES: Visible signs of illness evaluated by means of a standardised visual
      assessment. RESULTS: Visible signs of illness in portraits were common and
      appeared in up to 82% (451/553) of paintings from the 17th and 18th centuries.
      The most common findings were signs of goitre in women and overweight in men. In
      only the portraits where the neck region could be evaluated, 41% of women with
      known identities (139/343) had goitre compared with 24% of men with known
      identities (21/86). The prevalence of goitre was even higher in sitters whose
      identities were unknown: 63% in men (5/8) and 68% in women (82/121). Overweight
      in people with known identities was more common in men than in women (30%,
      346/1145 v 44%, 811/1844). Overweight was most common in sitters aged >40 than in
      those aged 40 or younger. Other conditions, such as missing teeth, amputated
      limbs, or osteoarthritic deformations were surprisingly rare in the portraits
      under evaluation. CONCLUSIONS: Goitre and other diseases are under-represented in
      the people depicted in these portraits. Artistic idealisation is a likely
      explanation for this observation: what was reproduced depended on what was
      considered pathological or shameful at the time, and therefore depended on age
      and sex. Stigmatising details may have been omitted. Further, artistic skills and
      contemporary fashion may have influenced the way in which people were reproduced.
      People depicted are possibly not representative of the general Bernese population
      as they constituted a socioeconomically advantaged group.

PMID- 12493683
TI  - Poverty and painting: representations in 19th century Europe.

PMID- 12493684
TI  - Doctors versus artists: Gustav Klimt's Medicine.

PMID- 12493685
TI  - Working as a healing practitioner and a general practitioner.

PMID- 12493687
TI  - My experience as the spouse of an overseas doctor.

PMID- 12493688
TI  - Cell adhesion and fertilization: steps in oocyte transport, sperm-zona pellucida
      interactions, and sperm-egg fusion.
AB  - Fertilization in mammals requires the successful completion of many steps,
      starting with the transport of gametes in the reproductive tract and ending with
      sperm-egg membrane fusion. In this minireview, we focus on three adhesion steps
      in this multistep process. The first is oocyte "pick-up," in which the degree of
      adhesion between the extracellular matrix of the cumulus cells and oviductal
      epithelial cells controls the successful pick-up of the oocyte-cumulus complex
      and its subsequent transfer into the oviduct. The second part of this review is
      concerned with the interaction between the sperm and the zona pellucida of the
      egg. Evidence is discussed that a plasma membrane form of galactosyltransferase
      on the surface of mouse sperm binds to ZP3 in the zona pellucida and initiates an
      acrosome reaction. Additional evidence raises the possibility that initial sperm
      binding to the zona pellucida is independent of ZP3. Last, we address the
      relationship between sperm adhesion to the egg plasma membrane and membrane
      fusion, especially the role of ADAM family proteins on the sperm surface and egg
      integrins.

PMID- 12493689
TI  - Nonhuman primate models of menopause workshop.
AB  - The Nonhuman Primate Models of Menopause Workshop was held on the National
      Institutes of Health campus in January 2001. The purpose of this workshop,
      sponsored by the National Institute on Aging, was to review what is known about
      the female reproductive aging process in various species of monkeys (particularly
      rhesus, baboons, cynomolgus, and chimpanzees), including hormone profiles during
      the menopausal transition, occurrence of hot flashes, extent of age-related and
      menopause-associated changes in hormone levels on metabolism, bone loss, and
      impaired cardiovascular and cognitive function. Many aspects of the female
      reproductive aging process appear to be concordant between humans and these
      monkey species, but several important features may be species-specific. Those
      features that appear to parallel human menopause and aging include general
      similarity of hormone profiles across the menopausal transition, progression to
      cycle termination through irregular cycles, declining fertility with age, age
      related gains in weight and percentage body fat content (with tendencies toward
      insulin resistance and glucose intolerance), increased low-density lipoprotein
      cholesterol and decreased high-density lipoprotein cholesterol, declines in serum
      dehydroepiandrosterone, similarities in temperature-regulation systems,
      protective responses to estrogen replacement following ovariectomy in terms of
      bone metabolism, lipid profiles, and cognitive changes. Important differences
      include relatively short postmenopausal life span, timing in menopause-related
      changes in hormone secretion, and seasonal menstrual cycles. In addition, the
      question of whether ovariectomy in young adults is an appropriate model for the
      consequences of natural or surgical menopause in middle-aged and older adults is
      unresolved, and the numbers of older female animals available for research on
      menopause are very limited. The use of animal models is seen by workshop
      participants to be crucial for a mechanistic understanding of the human
      menopausal process and its connections to postmenopausal health problems;
      however, extensive in-depth and broad-based research is required to determine if
      nonhuman primates are appropriate models of human menopause.

PMID- 12493690
TI  - Simple and efficient in vitro fertilization with cryopreserved C57BL/6J mouse
      sperm.
AB  - Archiving of mouse stocks by cryopreservation of sperm has great potential,
      because it is simple, rapid, and cheap. However, for some of the most commonly
      used inbred strains, including C57BL/6J, the postthaw fertility of the sperm (0%
      12%) is too low to be useful without recourse to zona nicking or intracytoplasmic
      sperm injection to aid penetration of the zona pellucida. In the present study,
      nonmotile sperm and cell debris were removed from thawed suspensions of C57BL/6J
      mouse sperm, and the remaining, largely progressively motile sperm were used for
      in vitro fertilization. These sperm fertilized 38%-88% of denuded, zona-intact
      eggs, and when 2-cell embryos were transferred to pseudopregnant recipient mice,
      40%-63% produced live-born young. The production of 2-cell embryos and the birth
      of live pups at these rates indicate that cryopreservation of sperm is a
      practical way to archive the haploid genome of genetically altered C57BL/6J mice.

PMID- 12493691
TI  - Regulation of insulin-like growth factor binding protein-1 promoter activity by
      FKHR and HOXA10 in primate endometrial cells.
AB  - Insulin-like growth factor binding protein-1 (IGFBP-1) is abundantly expressed in
      the liver and decidualized endometrium. FKHR, a FOXO forkhead transcription
      factor, stimulates IGFBP-1 promoter activity in liver cells through the insulin
      response sequences (IRSs). HOXA10, a homeobox transcription factor, is important
      in the decidualization process. Here we show that FKHR and HOXA10 are expressed
      in baboon endometrium during the menstrual cycle and pregnancy. Levels are lowest
      during the follicular phase and highest in pregnancy. Reporter gene studies
      reveal that FKHR stimulates both baboon and human IGFBP-1 promoter activity,
      whereas HOXA10 alone has a relatively weak effect. When FKHR and HOXA10 are
      expressed together, promoter activity is markedly up-regulated, which is
      indicative of cooperativity. A DNA binding-deficient FKHR mutant fails to
      stimulate promoter activity, even in the presence of HOXA10, and deletion or
      mutation of IRSs also disrupts the effect of FKHR and cooperativity with HOXA10.
      Conversely, the IRS region placed upstream of the 31 base pair IGFBP-1 minimal
      promoter is sufficient to mediate effects of FKHR and cooperativity with HOXA10.
      Pull-down studies reveal physical association between GST-FKHR and (35)S-HOXA10.
      These studies show that FKHR and HOXA10 interact directly and can function
      cooperatively to stimulate IGFBP-1 promoter activity in endometrial cells and
      perhaps in other settings.

PMID- 12493692
TI  - Gene expression in mouse oocytes and preimplantation embryos: use of suppression
      subtractive hybridization to identify oocyte- and embryo-specific genes.
AB  - The paucity of biological material has inhibited identifying genes that are
      differentially expressed during mammalian oogenesis and preimplantation
      development. We report here the linear amplification of mRNA from small numbers
      of mouse oocytes and preimplantation embryos to generate amounts of sense RNA
      that are sufficient for suppression subtractive hybridization. The resulting
      oocyte-specific and 8-cell-specific cDNA libraries were partially characterized,
      and the known oocyte-specific ZP1, ZP2, GDF-9, BMP15, and H1(oo) genes were found
      in the oocyte-specific cDNA library but not in the 8-cell-specific library.
      Further characterization of the subtracted oocyte and 8-cell embryo cDNA
      libraries should furnish a trove of information regarding temporal changes in
      gene expression during oogenesis and preimplantation development in the mouse.

PMID- 12493693
TI  - Structure and regulation of the murine Mash2 gene.
AB  - Transcription factors of the basic helix-loop-helix family such as Mash2 are
      essential for adequate differentiation of the trophoblast. Disruption of the
      Mash2 gene leads to early intrauterine death caused by placental insufficiency
      with an absent spongiotrophoblast and an underdeveloped chorion. The aim of the
      present study was to analyze the structure of the murine Mash2 gene, to screen a
      broad spectrum of organs for its expression, and to investigate placental Mash2
      expression at different gestational ages. The RNase protection assay identified,
      in addition to the postulated Mash2 mRNA, two unexpected Mash2 transcripts that
      could be confirmed by a 5' rapid amplification of cDNA ends. However, all three
      transcripts were detectable exclusively in murine placenta and not in other
      organs, such as the ovary, uterus, skin, lung, femur, skeletal muscle, kidney,
      skull, adrenal gland, tongue, stomach, spleen, skin, testis, or pancreas.
      Sequence analysis disclosed an additional transcription start site upstream of
      exon 2. Placental Mash2 mRNA is measurable at all investigated stages of
      gestation. After its initial detection on Day 8.5 postcoitum (p.c.; set to 100%;
      100.0% +/- 28.4%), the Mash2 mRNA concentration increases significantly and
      reaches a maximum of 812.0% +/- 69.7% on Day 12.5 p.c. The second half of
      gestation is marked by a more than 8-fold Mash2 decrease by Day 18.5 p.c. (77.0%
      +/- 28.4%). A 36.9% +/- 4.7% level of placental Mash2 mRNA is measurable at term.

PMID- 12493694
TI  - Effect of nutrition of oocyte donor on the outcomes of somatic cell nuclear
      transfer in the sheep.
AB  - The purpose of this study was to determine if the nutrition of the oocyte donor
      ewe influenced the success of somatic cell cloning. Merino ewes were fed at
      either a high- or a low-nutrition level for 3-5 mo before superovulation
      treatments. Freshly ovulated oocytes were enucleated and fused with serum-starved
      adult granulosa cells, and resulting reconstructed embryos were cultured for 6
      days in modified synthetic oviduct fluid. Embryo cleavage and development to
      blastocysts were recorded, and good-quality embryos were transferred to
      synchronized recipient ewes either fresh or, on a few occasions, after
      vitrification. Pregnancies were monitored by ultrasonography from Day 40 of
      pregnancy, and offspring were delivered by either cesarean section or vaginal
      delivery. No differences occurred in the numbers of follicles aspirated, of
      oocytes recovered, or of oocytes utilizable for cloning between the high and low
      groups. Neither were there treatment differences in development to the blastocyst
      stage. However, transfer of embryos from the high group led to significantly more
      pregnancies and implanted fetuses. Also, more of the established pregnancies from
      the high group were carried to term, although this difference was not
      statistically significant. Lamb mortality was high, with half the live-born
      perishing soon after birth and more succumbing to various infections within days
      or weeks of birth, but no clear association between the offspring fate and the
      treatment group could be established. These results suggest that more research
      into the effect of nutrition on oocyte quality and its subsequent effect on
      cloning is warranted.

PMID- 12493695
TI  - Regulated expression and ultrastructural localization of galectin-1, a
      proapoptotic beta-galactoside-binding lectin, during spermatogenesis in rat
      testis.
AB  - Galectin-1, a highly conserved beta-galactoside-binding protein, induces
      apoptosis of activated T cells and suppresses the development of autoimmunity and
      chronic inflammation. To gain insight regarding the potential role of galectin-1
      as a novel mechanism of immune privilege, we investigated expression and
      ultrastructural localization of galectin-1 in rat testis. Galectin-1 expression
      was assessed by Western blot analysis and immunocytochemical localization in
      testes obtained from rats aged from 9 to 60 days. Expression of this carbohydrate
      binding protein was developmentally regulated, and its immunolabeling exhibited a
      stage-specific pattern throughout the spermatogenic process. Immunogold staining
      using the anti-galectin-1 antibody revealed the typical Sertoli cell profile in
      the seminiferous epithelium, mainly at stages X-II. During spermiation (stages VI
      VIII), a strong labeling was observed at the luminal pole of seminiferous
      epithelium, localized on apical stalks of Sertoli cells, on heads of mature
      spermatids, and on bodies of residual cytoplasm. Moreover, spermatozoa released
      into the lumen showed a strong immunostaining. Following spermiation (stage
      VIII), galectin-1 expression was restored at the basal portion of Sertoli cells
      and progressively spread out through the whole cells as differentiation of
      germinal cells proceeded. Immunoelectron microscopy confirmed distribution of
      galectin-1 in nuclei and cytoplasmic projections of Sertoli cells and on heads
      and tails of late spermatids and residual bodies. Surface localization of
      galectin-1 was evidenced in spermatozoa from caput epididymis. Thus, the
      regulated expression of galectin-1 during the spermatogenic cycle suggests a
      novel role for this immunosuppressive lectin in reproductive biology.

PMID- 12493696
TI  - Developmental regulation of hyaluronan-binding protein (RHAMM/IHABP) expression
      in early bovine embryos.
AB  - Hyaluronan or hyaluronic acid (HA) is a normal component of mammalian follicular,
      oviduct, and uterine fluids. Granulosa and expanding cumulus cells secrete large
      amounts of HA, and when HA is added in maturation and culture media, it improves
      the developmental potential of oocytes and embryos. HA regulates gene expression,
      signaling, proliferation, motility, adhesion, and morphogenesis. Many of these
      biological activities of HA are mediated through binding to the receptor for HA
      mediated motility/intracellular HA-binding protein (RHAMM/IHABP). We evaluated
      the presence and dynamics of RHAMM/IHABP mRNA and protein expression in different
      stages of in vitro-produced bovine embryos using quantitative reverse
      transcriptase-real time-polymerase chain reaction and immunohistochemistry. We
      also analyzed the effects of different culture systems on the relative abundance
      of RHAMM/IHABP transcripts. RHAMM/IHABP mRNA levels decreased from the 2-cell to
      the 16-cell stage, increased again at the morula stage, and reached their highest
      level at the expanded blastocyst stage. RHAMM/IHABP mRNA abundance was
      significantly (P < 0.05) lower in embryos recovered in serum-containing medium
      than in embryos from serum-free media. Immunohistochemistry revealed the presence
      of RHAMM/IHABP first in 8-cell stages. Whereas RHAMM staining in 8-cell and
      morula stages was intense, it was weaker in blastocysts. Embryonic secretion of
      HA increased from the 2-cell stage until the 8-cell stage and then decreased in
      16-cell embryos. After this, HA secretion increased in expanded and hatched
      blastocyst stages. These data suggest that the positive effects of HA on in vitro
      produced bovine embryos may be mediated at least in part by RHAMM/IHABP.

PMID- 12493697
TI  - Developmental association of the synaptic activity-regulated protein arc with the
      mouse acrosomal organelle and the sperm tail.
AB  - In neurons, arc (activity regulated, cytoskeleton associated) is an immediate
      early gene (IEG) that is rapidly and transiently induced by excitatory
      stimulation. It is believed to mediate rapid strengthening of signaling
      structures at activated synaptic sites. Unlike most IEGs, arc does not encode
      nuclear transcription factor, but an effector molecule that associates with the
      actin cytoskeleton. Cytoskeletal rearrangements of microtubule- and actin-based
      networks that occur at activated synapses also take place in similar fashion
      during the formation of the acrosome, the site of regulated exocytosis at
      fertilization. In this paper, arc is reported to be highly expressed both at the
      RNA and protein levels in postmeiotic germ cells in the testis of adult mice.
      Immunofluorescence studies reveal that arc is first present in the perinuclear
      region of round, elongating, and elongate spermatids, where it colocalizes with
      the developing acrosome. In isolated mature sperm, arc is present in the
      acrosomal region of the sperm head, the centriole region of the neck, and the
      principal piece of the tail. Arc is lost to varying degrees during sperm
      capacitation and in acrosome-reacted sperm. Phalloidin staining of mature sperm
      cells reveals an overlapping pattern of filamentous-actin and arc expression.
      These results support a role for arc and the actin cytoskeleton in the acrosome
      formation, the sperm acrosome reaction, and in sperm cell motility.

PMID- 12493698
TI  - Pregnancy-associated plasma protein-A is involved in insulin-like growth factor
      binding protein-2 (IGFBP-2) proteolytic degradation in bovine and porcine
      preovulatory follicles: identification of cleavage site and characterization of
      IGFBP-2 degradation.
AB  - In mammalian ovaries, terminal follicular growth is accompanied by a decrease in
      levels of intrafollicular insulin-like growth factor binding protein-2 (IGFBP-2)
      and IGFBP-4. The decrease in IGFBP-4 is essentially due to an increase in
      proteolytic degradation by intrafollicular pregnancy-associated plasma protein-A
      (PAPP-A) in growing healthy follicles. In contrast, the decrease in IGFBP-2 is
      partly due to a decrease in mRNA expression by follicular cells and also to an
      increase in IGFBP-2 proteolytic degradation, as previously shown in ewes and
      sows. In the present work we show that bovine and porcine preovulatory follicular
      fluid contains a proteolytic activity that degrades IGFBP-2. Bovine and porcine
      preovulatory follicular fluids contain undetectable levels of native IGFBP-2 as
      assessed by Western ligand blotting in comparison with the corresponding serum.
      In contrast, much higher levels of 23- and 12-kDa proteolytic fragments were
      found by immunoblotting in bovine and porcine preovulatory follicular fluid than
      in the corresponding serum. Moreover, bovine and porcine preovulatory follicular
      fluids were able to induce proteolytic degradation of exogenous IGFBP-2, and this
      degradation was enhanced by insulin-like growth factors. Intrafollicular IGFBP-2
      proteolytic activity was surprisingly immunoneutralized in both species by a
      polyclonal antibody raised against human PAPP-A. In addition, recombinant human
      PAPP-A (rhPAPP-A) was able to cleave IGFBP-2 between Gln165 and Met166 in vitro,
      generating 23- and 12-kDa proteolytic fragments. IGFBP-2 was shown to be less
      sensitive than IGFBP-4 to cleavage by rhPAPP-A in vitro. As in follicular fluid,
      cleavage of IGFBP-2 by rhPAPP-A was dose-dependently enhanced by IGFs and
      inhibited by a peptide derived from the heparin-binding domain of IGFBP-5 (P5).
      Finally, Biacore analysis showed that P5 peptide-induced inhibition of IGFBP-2
      cleavage was due to a direct interaction of P5 with PAPP-A rather than with IGFBP
      2. Overall, these data show that in bovine and porcine preovulatory follicles,
      PAPP-A is responsible for IGF-dependent IGFBP-2 degradation. During follicular
      growth, the increase in IGFBP-2 cleavage by PAPP-A, as well as the decrease in
      IGFBP-2 expression, are responsible for the decrease in intact IGFBP-2 levels and
      the increase in IGF bioavailability. In atretic follicles, the increase and
      decrease in IGFBP-2 and PAPP-A mRNA expression, respectively, as well as the
      inhibition of PAPP-A activity by heparin-binding domains present in IGFBP-5 or
      other proteins, might participate in higher IGFBP-2 levels and a decrease in IGF
      bioavailability.

PMID- 12493699
TI  - Artificial expression of aquaporin-3 improves the survival of mouse oocytes after
      cryopreservation.
AB  - Successful cryopreservation of mammalian cells requires rapid transport of water
      and cryoprotective solutes across the plasma membrane. Aquaporin-3 is known as a
      water/solute channel that can transport water and neutral solutes such as
      glycerol. In this study we examined whether artificial expression of aquaporin-3
      in mouse oocytes can improve water and glycerol permeability and oocyte survival
      after cryopreservation. Immature mouse oocytes were injected with aquaporin-3
      cRNA and were cultured for 12 h. Then the hydraulic conductivity (L(P)) and
      glycerol permeability (P(GLY)) of matured oocytes were determined from the
      relative volume changes in 10% glycerol in PB1 medium at 25 degrees C. Mean +/-
      SD values of L(P) and P(GLY) of cRNA-injected oocytes (3.09 +/- 1.22 micro m min(
      1) atm(-1) and 3.69 +/- 1.47 x 10(-3) cm/min, respectively; numbers of oocytes =
      25) were significantly higher than those of noninjected oocytes (0.83 +/- 0.02
      micro m min(-1) atm(-1) and 0.07 +/- 0.02 x 10(-3) cm/min, respectively; n = 13)
      and water-injected oocytes (0.87 +/- 0.10 micro m min(-1) atm(-1) and 0.08 +/-
      0.02 x 10(-3) cm/min, respectively; n = 20). After cryopreservation in a glycerol
      based solution, 74% of cRNA-injected oocytes (n = 27) survived as assessed by
      their morphological appearance, whereas none of the water-injected oocytes
      survived (n = 10). When cRNA-injected oocytes that survived cryopreservation were
      inseminated in vitro, the penetration rate was 40% (n = 48) and the cleavage rate
      was 31% (n = 70), showing that oocytes retain their ability to be fertilized.
      This is the first report to show that artificial expression of a water/solute
      channel in a cell improves its survival after cryopreservation. This approach may
      enable cryopreservation of cells that have been difficult to cryopreserve.

PMID- 12493700
TI  - Expression of antimicrobial defensins in the male reproductive tract of rats,
      mice, and humans.
AB  - Defensins are antimicrobial peptides that play a major role in innate immunity.
      Using reverse transcriptase-polymerase chain reaction, immunochemistry, or both,
      we performed a search of all presently known defensins in rat testis, epididymis,
      and isolated testicular cells; in mouse testis and epididymis; and in human
      testis and ejaculates. In the rat, all alpha- and beta-defensins except RNP-4
      were expressed within the testis, whereas alpha-defensins RNP1-2, RNP-4, and beta
      defensins RBD-1 and RBD-2 were present within the epididymis. In the mouse, the
      cryptdin transcripts CRS1C, mBD-1, and mBD-2 were detected in the testis and
      epididymis, whereas mBD-3 and mBD-4 were expressed only in the epididymis, and
      CRS4C was absent in both organs. In the human testis, transcripts for four known
      defensins were expressed with the consistent exception of HBD-2 and HBD-3. In rat
      interstitial tissue, resident macrophages expressed most of the defensins
      studied, whereas Leydig cells produced only RBD-2. In contrast, all studied
      defensins except RNP-4 were present in the seminiferous tubules. Within these
      tubules, peritubular and Sertoli cells expressed most of the studied alpha- and
      beta-defensins, whereas spermatogonia displayed only alpha-defensins, but at
      relatively high levels. Meiotic pachytene spermatocytes expressed only beta
      defensins, whereas postmeiotic spermatids and their cytoplasmic lobes displayed
      both types. In humans, the HBD-1 peptide was expressed mainly in the germ line
      from pachytene spermatocytes to late spermatids. The peptide was also present in
      ejaculated spermatozoa and seminal plasma, where multiple soluble forms were
      present. Finally, high salt concentration or dithiothreitol-sensitive cationic
      extracts from human seminal plasma were indeed found to display antimicrobial
      activity. We conclude that the male reproductive tract produces defensins that
      most probably assume an important, innate organ defense system against pathogens.

PMID- 12493701
TI  - Efficacy of porcine gonadotropins for repeated stimulation of ovarian activity
      for oocyte retrieval and in vitro embryo production and cryopreservation in
      Siberian tigers (Panthera tigris altaica).
AB  - A comparison of the amino acid sequences demonstrated that Siberian tiger
      gonadotropins are more homologous with those of porcine than any other
      commercially available preparation. The present study measured the efficacy of
      repeated ovarian stimulation with purified porcine gonadotropins on the
      follicular, hormonal, and immunogenic responses in Siberian tigers as well as on
      the ability of oocytes retrieved by laparoscopic follicular aspiration to
      fertilize and cleave in vitro. Controlled rate and vitrification cryopreservation
      methods were also compared for their ability to support ongoing cleavage
      following thawing of presumptive 2- to 4-cell tiger embryos generated in vitro.
      Vitrification supported continued embryonic cleavage in vitro while controlled
      rate freezing did not. Stereological microscopy indicated an excellent ovarian
      response with the recovery of quality cumulus-oocyte complexes that apparently
      fertilized and cleaved in vitro. However, ultrastructural and physiological
      examination revealed abnormal and unnatural responses such as the failure of some
      cumulus-oocyte complexes to reach maturity and progestagen levels to approach
      normalcy. At the same time, analyses of blood for antibodies failed to detect an
      immune reaction to these foreign gonadotropins in an assay that tested positive
      for the chorionic gonadotropin-stimulated domestic cat. Together, these
      observations suggest that porcine gonadotropins may be effective for the ovarian
      stimulation of tigers but that some modifications to administration protocols are
      needed to produce a more natural response.

PMID- 12493702
TI  - Differential regulation of steroid hormone biosynthesis in R2C and MA-10 Leydig
      tumor cells: role of SR-B1-mediated selective cholesteryl ester transport.
AB  - The rat R2C Leydig tumor cell line is constitutively steroidogenic in nature,
      while the mouse MA-10 Leydig tumor cell line synthesizes large amounts of
      steroids only in response to hormonal stimulation. Earlier studies showed
      abundant cAMP-independent steroid production and constitutive expression of
      steroidogenic acute regulatory (StAR) protein in R2C cells. The objective of the
      current study was to identify possible genetic alterations in the R2C cell line
      responsible for rendering it a constitutively steroidogenic cell line, especially
      those that might have altered its cholesterol homeostatic mechanisms. Measurement
      of the levels of cholesterol esters and free cholesterol, precursors for
      steroidogenesis, indicated that R2C mitochondria were fourfold enriched in free
      cholesterol content compared with MA-10 mitochondria. In addition to the
      previously demonstrated increased expression of StAR protein, we show that R2C
      cells possess marginally enhanced protein kinase A activity, exhibit higher
      capacity to take up extracellular cholesterol esters, and express much higher
      levels of scavenger receptor-type B class 1 (SR-B1) and hormone sensitive lipase
      (HSL). These observations suggest that the high level of steroid biosynthesis in
      R2C cells is a result of the constitutive expression of the components involved
      in the uptake of cholesterol esters (SR-B1), their conversion to free cholesterol
      (HSL), and its mobilization to the inner mitochondrial membrane (StAR).

PMID- 12493703
TI  - Expression pattern and role of a 60-kilodalton progesterone binding protein in
      regulating granulosa cell apoptosis: involvement of the mitogen-activated protein
      kinase cascade.
AB  - Progesterone (P4) inhibits both granulosa cells and spontaneously immortalized
      granulosa cells (SIGCs) from undergoing apoptosis. P4 does so through a plasma
      membrane-initiated event. It appears that P4's membrane-initiated actions are
      mediated by a 60-kDa P4 binding protein (P4BP), which is detected by an antibody
      directed against the ligand binding domain of the nuclear P4 receptor (i.e., C
      262). Immunohistochemical analysis revealed that a C-262-detectable protein was
      first observed in the periphery of a few granulosa cells within early antral
      stage follicles. In nonatretic antral follicles, this protein was detected at the
      periphery of virtually all granulosa cells. In contrast, granulosa cells of
      atretic follicles lost the distinct peripheral localization of this C-262
      detectable protein. This reduction in the membrane localization was also observed
      by Western blot analysis. To assess the temporal changes in this 60-kDa P4BP
      during apoptosis, studies were conducted using SIGCs. That this 60-kDa protein is
      important in mediating P4's action was confirmed by the observation that C-262
      but not IgG attenuated P4's antiapoptotic action. Interestingly, the membrane
      localization of this 60-kDa P4BP was maintained but the ability of P4 to prevent
      apoptosis was lost within 20 min of initiating the apoptotic cascade. In
      addition, Erk-1 and -2 phosphorylation (i.e., activity) increased within 20 min
      of P4 withdrawal. Further, P4 suppressed the increase in the Erk-1
      phosphorylation if administered within 5 but not 20 min of initiating the
      apoptotic cascade. Moreover, the mitogen-activated protein kinase kinase (MEK)
      inhibitor, PD98059, reduced the percentage of SIGCs undergoing apoptosis in the
      absence of P4. Because MEK phosphorylates Erk, these observations suggests that
      1) the increase in Erk-1 activity is an important part of the apoptotic cascade,
      2) P4 promotes granulosa cell viability by modulating the activity of Erk-1, and
      3) P4 becomes "uncoupled" from its antiapoptotic signal transduction mechanism
      within 20 min of initiating apoptosis, even though the membrane localization of
      the 60-kDa P4BP is maintained.

PMID- 12493704
TI  - Concerted changes in the YB2/RYB-a protein and protamine 2 messenger RNA in the
      mouse testis under heat stress.
AB  - Translation of a number of mRNAs is under strict regulation via RNA-binding
      proteins in the spermatogenic cells of testes. A family of Y-box binding proteins
      represents promising candidates for these presently uncharacterized RNA-binding
      proteins. The effects of heat stress on the expression of a Y-box binding
      protein, YB2/RYB-a, and mouse protamine 2 (mP2) were investigated in cultured
      spermatogenic cells and mouse testes by immunoblot and Northern blot analyses.
      Localization and alterations in the expression of the YB2/RYB-a protein and the
      mP2 mRNA in heat-stressed testes were examined by immunohistochemistry and in
      situ hybridization, respectively. Levels of the YB2/RYB-a protein in
      spermatogenic cells decreased rapidly as the result of exposure to higher
      temperature, 37 degrees C or 43 degrees C, compared with the scrotal temperature,
      32.5 degrees C, under the culture conditions used. In experimental
      cryptorchidism, levels of the YB2/RYB-a protein were decreased after Day 10,
      while the mRNA levels were affected only slightly. The levels of the mP2 mRNA
      were also decreased and about comparable with those of the YB2/RYB-a protein.
      Exposure of the lower abdomen to a high temperature, 43 degrees C for 15 min,
      also damaged the testis and led to a decrease in YB2/RYB-a protein and the mP2
      mRNA levels in a coordinated manner. Because YB2/RYB-a is proposed to function as
      a stabilizer of mP2 mRNA, the perturbation of YB2/RYB-a by heat stress could
      account for the decline of the mP2 mRNA in elongated spermatids.

PMID- 12493705
TI  - Effect of pH value of freeze-drying solution on the chromosome integrity and
      developmental ability of mouse spermatozoa.
AB  - The nuclei of freeze-dried mouse spermatozoa are able to retain their chromosome
      integrity and developmental potential. To optimize the conditions of freeze
      drying, we examined whether pH values of the freeze-drying solution affect the
      chromosome integrity and developmental potential of sperm nuclei. The sperm
      freeze-drying solution we used contained a high concentration (50 mM) of calcium
      chelating EGTA. Sperm chromosomes were examined at the metaphase of the first
      mitosis after injection of freeze-dried spermatozoa into matured oocytes. The
      developmental potential of sperm nuclei was assessed by examining the development
      of fetuses in midgestation. The results showed that both sperm chromosomes and
      sperm developmental potential are maintained better when the freeze-drying
      solution was slightly alkaline (pH 8.0) rather than near neutral or acidic (pH
      7.4-6.0). The data indicated that the chromosome integrity and developmental
      ability of mouse spermatozoa are affected by the pH value of freeze-drying
      solution.

PMID- 12493706
TI  - Sertoli cells in the boar testis: changes during development and compensatory
      hypertrophy after hemicastration at different ages.
AB  - Changes in Sertoli cell numbers and testicular structure during normal
      development and compensatory hypertrophy were assessed in crossbred Meishan x
      White Composite males. Boars were assigned at birth to unilateral castration at
      1, 10, 56, or 112 days or to remain as intact controls through 220 days. The
      first testes removed were compared to assess testicular development. At 220 days,
      testicular structure was evaluated in boars representing the 25% with the largest
      (Lg) testis and the 25% with the smallest (Sm) testis in each treatment group.
      The number of Sertoli cells per testis reached a maximum by Day 56 in Sm testis
      but not until Day 112 in Lg testis boars, indicating a longer duration of Sertoli
      cell proliferation in Lg testis boars. Unilateral castration of Lg testis boars
      on Days 1, 10, 56, and 112 caused the weight of the remaining testis to
      hypertrophy by 149%, 135%, 119%, and 120%, respectively, and total sperm
      production to increase to 127%, 128%, 97%, and 106%, respectively. However,
      Sertoli cell numbers changed little in hemicastrate boars. In Lg testis boars,
      compensatory hypertrophy primarily involved proliferation of Leydig cells and
      expansion of existing Sertoli cells with little increase in Sertoli cell numbers,
      but in Sm testis boars, it involved expansion of existing Leydig and Sertoli
      cells without increase in cell numbers. These results indicate that Lg and Sm
      testis boars display intriguing differences during both development and
      compensatory hypertrophy, and they identify a unique animal model for further
      studies of factors that program and control Sertoli cell proliferation.

PMID- 12493707
TI  - Progesterone promotes survival of the rat corpus luteum in the absence of cognate
      receptors.
AB  - Progesterone production by the corpus luteum (CL) is essential for preparation of
      the endometrium for implantation and for the maintenance of gestation.
      Progesterone modulates its own production and opposes functional luteal
      regression induced by exogenous agents, such as prostaglandin F(2alpha). In the
      present study, we evaluated whether progesterone is also capable of interfering
      with the process of structural luteal regression, which is characterized by a
      decrease in weight and size of the gland because of programmed cell death (i.e.,
      apoptosis). We have found that a low number of luteal cells undergo apoptosis
      throughout gestation. On the day of parturition, but following the initial
      decline in endogenous progesterone production, a small increase in the number of
      luteal cells undergoing cell death was observed. This increase in apoptotic cells
      continued postpartum, reaching dramatic levels by Day 4 postpartum, and was
      accompanied by a marked decrease in average luteal weight. We have established
      that the exogenous administration of progesterone significantly reduces the
      decline in luteal weight observed during structural luteal regression postpartum.
      This effect was associated with a decrease in the number of cells undergoing
      apoptosis and with enhanced circulating levels of androstenedione. Furthermore,
      in vivo administration of progesterone delayed the occurrence of DNA
      fragmentation in postpartum CL incubated in serum-free conditions. Finally, we
      have shown that neither the CL of gestation nor the newly formed CL after
      postpartum ovulation express the classic progesterone-receptor mRNA. In summary,
      the present results support a protective action of progesterone on the function
      and survival of the CL through inhibition of apoptosis and stimulation of
      androstenedione production. Furthermore, this effect is carried out in the
      absence of classic progesterone receptors.

PMID- 12493708
TI  - Heteroplasmy in bovine fetuses produced by intra- and inter-subspecific somatic
      cell nuclear transfer: neutral segregation of nuclear donor mitochondrial DNA in
      various tissues and evidence for recipient cow mitochondria in fetal blood.
AB  - Varying degrees of mitochondrial DNA (mtDNA) heteroplasmy have been observed in
      nuclear transfer embryos, fetuses, and offspring, but the mechanisms leading to
      this condition are unknown. We have generated a clone of 12 bovine somatic cell
      nuclear transfer fetuses, using nuclear donor cells, recipient oocytes, and
      recipient heifers with defined mtDNA genotypes, to study nuclear-mitochondrial
      interactions and the origins of mtDNA heteroplasmy. Embryos were reconstructed
      from granulosa cells with Bos taurus mtDNA type A and recipient oocytes collected
      from three different maternal lineages with B. taurus mtDNA type B, B. taurus
      mtDNA type C, or B. indicus mtDNA. Sequence differences in the control region
      (CR) of B. taurus mtDNAs ranged from 6 to 11 nucleotides and differences between
      B. taurus and B. indicus CRs from 45 to 50 nucleotides. Fetuses were recovered
      from recipient heifers with B. taurus mtDNA type B on Day 80 after nuclear
      transfer (eight B. taurus A/B, two B. taurus A/C, and two B. taurus A/B.
      indicus). Agarose gel analysis of the CR by polymerase chain reaction-based
      restriction fragment length polymorphism failed to detect nuclear donor mtDNA in
      11 investigated tissues of 10 viable fetuses and in DNA samples of two fetuses in
      resorption (one B. taurus A/B and one B. taurus A/C). A more sensitive analysis
      of 1801 plasmid clones with CR inserts derived from tissues of a B. taurus A/B.
      indicus fetus detected no or very low levels of heteroplasmy (0.5-0.7%). However,
      the analyses detected considerable amounts ( approximately 2.5% and 5%) of
      recipient heifer mtDNA in blood samples from two fetuses. Our data do not suggest
      a replicative advantage of somatic nuclear donor cell mtDNA in bovine
      transmitochondrial clones produced with oocytes from domestic forms of the same
      or a different aurochs (B. primigenius) subspecies. Detection of mtDNA from the
      recipient animal in the circulation of two fetuses points to leakage of the
      placental barrier, mimicking heteroplasmy.

PMID- 12493709
TI  - Allogeneic offspring produced by male germ line stem cell transplantation into
      infertile mouse testis.
AB  - The testis is one of several immune-privileged organs and is known for its unique
      ability to support allogeneic or xenogeneic tissue transplants. We investigated
      the possibility of deriving offspring from mice that underwent transplantation
      with allogeneic male germ line stem cells in the testis. Although mature adult
      mice rejected allogeneic germ cells and were infertile, offspring were obtained
      by intracytoplasmic germ cell injection using partially differentiated donor
      cells. In contrast, complete spermatogenesis occurred when allogeneic germ cells
      were transplanted into immature pup testes. Tolerance induction by monoclonal
      antibody administration allowed the pup transplant recipients to produce
      allogeneic offspring by natural mating, whereas no spermatozoa were found in the
      epididymis of untreated recipients. Thus, these results indicate that a
      histoincompatible recipient can serve as a "surrogate father" to propagate the
      genetic information of heterologous male donors.

PMID- 12493710
TI  - Prostaglandin D2 synthase secreted in the caput epididymidis displays spatial and
      temporal delay between messenger RNA and protein expression during postnatal
      development.
AB  - Highly regionalized protein secretory activity is established progressively
      throughout the epididymal tubule during postnatal development. Prostaglandin D(2)
      synthase (PGDS) is a major protein in the ovine epididymis, the secretion of
      which is restricted to the proximal part of the epididymis. We investigated the
      mRNA and protein expression of PGDS during ontogenesis. PGDS mRNA was present in
      the testis and epididymis in the 50-day-old sheep fetus and persisted until 4 mo
      of age (2 mo before puberty) without mRNA translation in the epididymis. At 4.5
      mo, mRNA was present in all of the epididymis, but translation occurred in only
      the proximal caput. The secreted protein present in the lumen from the caput to
      the cauda had the same molecular mass and isoelectric point (pI) characteristics
      as the testicular form. At 5.5 mo, both mRNA and protein expression were
      restricted to the proximal caput. The protein secreted accumulated in the cauda
      but was not processed after secretion as it is in the adult animal; no changes in
      molecular mass or pI were observed. Our results show that for at least one gene
      (PGDS), transcriptional and posttranscriptional regulation during postnatal
      development is linked to the presence of unidentified translation factors present
      in testicular fluid.

PMID- 12493711
TI  - Mitochondrial DNA content of human spermatozoa.
AB  - Sperm mitochondria play an important role in spermatozoa because of the high ATP
      demand of these cells. Different mitochondrial DNA (mtDNA) mutations and
      haplogroups influence sperm function. The mtDNA dose also contributes to genetic
      variability and pathology in different tissues and organs, but nothing is known
      about its relevance in the performance of spermatozoa. We estimated the
      variability in mtDNA content within a population of men. Different mtDNA:nuclear
      DNA ratios were characteristic of progressive and nonprogressive spermatozoa,
      confirming the influence of mtDNA content on sperm functionality. We also
      estimated that the absolute content of mtDNA was 700 and 1200 mtDNA copies per
      cell in progressive and nonprogressive human spermatozoa, respectively. These
      results suggest that a marked increase of mtDNA copy number per cell volume takes
      place during spermatogenesis.

PMID- 12493712
TI  - In vitro parthenogenetic development of mouse oocytes following reciprocal
      transfer of the chromosome spindle between in vivo-matured oocytes and in vitro
      matured oocytes.
AB  - Mouse follicles grown in vitro from preantral to mature stages yield oocytes that
      can be fertilized in vitro, but embryonic development is poor. To investigate
      whether this poor development is due to a nuclear or a cytoplasmatic factor, we
      designed an experiment in which the MII chromosome spindle was exchanged between
      in vitro-matured oocytes and in vivo-matured oocytes by electrofusion. Subsequent
      embryo development was evaluated by blastocyst formation rate and blastocyst cell
      number after parthenogenetic activation. Electrofusion was successful in 62-78%
      of the oocytes. Transfer of the spindle apparatus from in vitro-matured oocytes
      to the in vivo MII cytoplasmic environment resulted in a high rate of blastocyst
      development, whereas in the reverse situation (transfer of the nucleus from in
      vivo-matured oocytes into in vitro-matured MII cytoplasm) poor quality embryos
      and a low rate of blastocyst formation was observed. These results indicate that
      the low developmental competence of in vitro-matured oocytes from mouse preantral
      follicles after activation is caused by the cytoplasmic component rather than the
      nuclear component.

PMID- 12493713
TI  - NYD-SP16, a novel gene associated with spermatogenesis of human testis.
AB  - By hybridizing human adult testis cDNA microarrays with human adult and embryo
      testis cDNA probes, a novel human testis gene NYD-SP16 was identified. NYD-SP16
      expression was 6.44-fold higher in adult testis than in fetal testis. NYD-SP16
      contains 1595 base pairs (bp) and a 762-bp open reading frame encoding a 254
      amino acid protein with 73% amino acid sequence identity with the mouse testis
      homologous protein. The NYD-SP16 gene was localized to human chromosome 5q14. The
      deduced structure of the NYD-SP16 protein contains one transmembrane domain,
      which was confirmed by GFP/NYD-SP16 fusion protein expression in the cytomembrane
      of the transfected human choriocarcinoma JAR cells, suggesting that it is a
      transmembrane protein. Multiple tissue distribution indicated that NYD-SP16 mRNA
      is highly expressed in the testes and pancreas, with little or no expression
      elsewhere. Further analysis of abnormal expression in infertile male patients
      revealed complete absence of NYD-SP16 in the testes of patients with Sertoli-cell
      only syndrome and variable expression in patients with spermatogenic arrest.
      Homologous gene expression in mouse testis was confirmed in spermatogenic cells
      by in situ hybridization. The results of cDNA microarray, in situ hybridization,
      and semiquantitative polymerase chain reaction in mouse testis of different
      stages indicated that NYD-SP16 expression is developmentally regulated. These
      results suggest that the putative NYD-SP16 protein may play an important role in
      testicular development/spermatogenesis and may be an important factor in male
      infertility.

PMID- 12493714
TI  - Characterization of rat follistatin-related gene: effects of estrous cycle stage
      and pregnancy on its messenger RNA expression in rat reproductive tissues.
AB  - Follistatin-related gene (FLRG) was first identified as a target of a chromosomal
      translocation in a human B-cell leukemia. Because FLRG protein binds to activins
      and bone morphogenetic proteins, FLRG is postulated to be a regulator of these
      growth factors. However, physiological aspects of FLRG are unclear. To elucidate
      the physiology of FLRG, we examined expression of FLRG in reproductive tissues of
      the rat. FLRG mRNA was abundantly expressed in the placenta. FLRG mRNA was also
      expressed in the ovary, uterus, testis, lung, adrenal gland, pituitary, kidney,
      small intestine, and heart. During the second half of pregnancy, expression of
      FLRG in the placenta continuously increased, whereas follistatin mRNA levels
      decreased from Day 12 to Day 14 and remained low thereafter. FLRG was also
      expressed in decidua. Levels of decidual FLRG mRNA remained low from Day 12 to
      Day 16 and then noticeably increased until Day 20. In contrast, follistatin mRNA
      was highly expressed in the decidua on Day 12, continuously decreased until Day
      16, and then remained at relatively low levels thereafter. During the rat estrous
      cycle, levels of ovarian FLRG mRNA fluctuated diurnally, with highest levels
      during daytime, and did not change relative to the day of the estrous cycle. The
      present results suggest that FLRG may play a role in the regulation of
      reproductive events.

PMID- 12493715
TI  - Porcine sperm capacitation and tyrosine kinase activity are dependent on
      bicarbonate and calcium but protein tyrosine phosphorylation is only associated
      with calcium.
AB  - Mammalian sperm undergo capacitation in the female reproductive tract or under
      defined conditions in vitro. Although capacitation is now considered to be
      mediated by intracellular signaling events, including protein phosphorylation,
      the regulation of the transduction mechanisms is poorly understood. The objective
      of the present study was to evaluate the importance of medium components on
      capacitation of porcine sperm, the appearance of an M(r) 32 000 sperm protein
      (p32), and activity of a tyrosine kinase (TK-32). As determined by the ability of
      the sperm to undergo the A23187-induced acrosome reaction, pig sperm require
      bicarbonate and calcium but not BSA for capacitation in vitro. The appearance of
      p32 was assessed by immunoblotting SDS-extracted and separated sperm proteins
      using an anti-phosphotyrosine antibody. The appearance of p32 requires calcium,
      although p32 appears even in the absence of bicarbonate in the incubation medium,
      demonstrating that the appearance of this tyrosine phosphoprotein is not a final
      end point of pig sperm capacitation. An in-gel tyrosine kinase renaturation assay
      showed that TK-32 activity depends on calcium and bicarbonate in the incubation
      medium. Immunoprecipitation experiments using an anti-phosphotyrosine antibody
      and inhibitor demonstrated that p32 and TK-32 are different proteins. These data
      indicate that the signal transduction mechanisms of capacitation in pig sperm are
      different from those in other mammals, suggesting that certain species
      specificity may exist with respect to this phenomenon.

PMID- 12493716
TI  - Localization and expression of tissue inhibitor of metalloproteinase-4 in the
      immature gonadotropin-stimulated and adult rat ovary.
AB  - The tissue inhibitors of metalloproteinases (TIMPs) are important regulators of
      the matrix metalloproteinases (MMPs), proteolytic enzymes essential for
      controlling the coordinated tissue remodeling that takes place in the ovary. In
      the present study, we characterized the ovarian expression pattern of TIMP-4. The
      localization of TIMP-4 mRNA was determined by in situ hybridization in adult
      cycling rats. TIMP-4 mRNA on the day of estrus was expressed in a punctate
      pattern in stroma and in corpora lutea (CL) from previous cycles but not in newly
      formed CL or follicles. At metestrus, TIMP-4 mRNA was present in certain CL from
      the current and previous cycles and continued to exhibit a punctate pattern of
      expression in the stroma. By diestrus, TIMP-4 mRNA was detected in the thecal
      layer surrounding follicles, and a relatively high level of expression was
      observed in a punctate pattern within new and previous CL and in the stroma. TIMP
      4 mRNA was also observed in the thecal layer at proestrus, but the punctate
      pattern within CL and stroma was absent. To correlate the changes in cellular
      localization with changes in overall TIMP-4 levels, ovarian mRNA and protein
      levels were examined in adult cycling rats and in gonadotropin-stimulated
      immature rats. In cycling rats, there was no change in mRNA or protein levels
      across the cycle, although there was a trend towards higher levels during estrus
      (P = 0.08). In gonadotropin-treated rats, there was an increase in TIMP-4 mRNA 48
      h after eCG administration with a corresponding doubling of TIMP-4 protein.
      Although TIMP-4 mRNA and protein tended to decline after hCG treatment, this
      trend was not significant (P = 0.08). These findings indicate that TIMP-4 could
      play an important role in regulating MMPs in a localized manner in follicles and
      CL throughout the cycle.

PMID- 12493717
TI  - Rapid loss of Oct-4 and pluripotency in cultured rodent blastocysts and
      derivative cell lines.
AB  - The POU transcription factor Oct-4 is essential for the pluripotent character of
      the mouse inner cell mass (ICM) and derivative embryonic stem (ES) cells. We
      analyzed the expression of Oct-4 during culture and establishment of cell lines
      from mouse and rat preimplantation embryos. Oct-4 was rapidly lost in primary
      outgrowths of the majority of cultured embryos prior to any evidence of
      morphological differentiation. Oct-4 persisted in only a minority of strain 129
      cultures, which can go on to give ES cells. We used transgenic rats in which the
      dual reporter/selection marker beta-geo is under control of Oct-4 regulatory
      elements to investigate the effect of direct selection for Oct-4 expressing
      cells. Ablation of all cells occurred, consistent with complete downregulation of
      Oct-4. Without selection, in contrast, continuous cultures of morphologically
      undifferentiated cells could be derived readily from rat blastocysts and ICMs.
      However, these cells did not express significant Oct-4 and, although capable of
      differentiating into extraembryonic cell types, appeared incapable of producing
      fetal germ layer derivatives. Downregulation of Oct-4 appears to be a limiting
      factor in attempts to derive pluripotent cell lines from preimplantation embryos.

PMID- 12493718
TI  - Immunolocalization of inhibin and activin alpha and betaB subunits and expression
      of corresponding messenger RNAs in the human adult testis.
AB  - Inhibin B is a testicular peptide hormone that regulates FSH secretion in a
      negative feedback loop. Inhibin B is a dimer of an alpha and a beta(B) subunit.
      In adult testes, the cellular site of production is still controversial, and it
      was hypothesized that germ cells contribute to inhibin B production. To determine
      which cell types in the testes may produce inhibin B, the immunohistochemical
      localization of the two subunits of inhibin B were examined in adult testicular
      biopsies with normal spermatogenesis, spermatogenic arrest, or Sertoli cell only
      (SCO) tubules. Moreover, using in situ hybridization with mRNA probes, the mRNA
      expression patterns of inhibin alpha and inhibin/activin beta(B) subunits have
      been investigated. In all testes, Sertoli cells and Leydig cells showed positive
      immunostaining for inhibin alpha subunit and expressed inhibin alpha subunit
      mRNA. Using inhibin beta(B) subunit immunoserum on testes with normal
      spermatogenesis and with spermatogenic arrest, intense labeling was located in
      germ cells from pachytene spermatocytes to round spermatids but not in Sertoli
      cells. Inhibin beta(B) subunit mRNA expression was intense in germ cells from
      spermatogonia to round spermatids and in Sertoli cells in these testes. In testes
      with SCO, high inhibin beta(B) subunit mRNA labeling density was observed in both
      Sertoli cells and Leydig cells, whereas beta(B) subunit immunostaining was
      negative for Sertoli cells and faintly positive for Leydig cells. These results
      agree with the recent opinion that inhibin B in adult men is possibly a joint
      product of Sertoli cells and germ cells.

PMID- 12493719
TI  - Bovine embryo culture in the presence or absence of serum: implications for
      blastocyst development, cryotolerance, and messenger RNA expression.
AB  - We have previously shown that, while the intrinsic quality of the oocyte is the
      main factor affecting blastocyst yield during bovine embryo development in vitro,
      the main factor affecting the quality of the blastocyst is the postfertilization
      culture conditions. Therefore, any improvement in the quality of blastocysts
      produced in vitro is likely to derive from the modification of the
      postfertilization culture conditions. The objective of this study was to examine
      the effect of the presence or absence of serum and the concentration of BSA
      during the period of embryo culture in vitro on 1) cleavage rate, 2) the kinetics
      of embryo development, 3) blastocyst yield, and 4) blastocyst quality, as
      assessed by cryotolerance and gene expression patterns. The quantification of all
      gene transcripts was carried out by real-time quantitative reverse transcription
      polymerase chain reaction. Bovine blastocysts from four sources were used: 1) in
      vitro culture in synthetic oviduct fluid (SOF) supplemented with 3 mg/ml BSA and
      10% fetal calf serum (FCS), 2) in vitro culture in SOF + 3 mg/ml BSA in the
      absence of serum, 3) in vitro culture in SOF + 16 mg/ml BSA in the absence of
      serum, and 4) in vivo blastocysts. There was no difference in overall blastocyst
      yield at Day 9 between the groups. However, significantly more blastocysts were
      present by Day 6 in the presence of 10% serum (20.0%) compared with 3 mg/ml BSA
      (4.6%, P < 0.001) or 16 mg/ml BSA (11.6%, P < 0.01). By Day 7, however, this
      difference had disappeared. Following vitrification, there was no difference in
      survival between blastocysts produced in the presence of 16 mg/ml BSA or those
      produced in the presence of 10% FCS; the survival of both groups was
      significantly lower than the in vivo controls at all time points and in terms of
      hatching rate. In contrast, survival of blastocysts produced in SOF + 3 mg/ml BSA
      in the absence of serum was intermediate, with no difference remaining at 72 h
      when compared with in vivo embryos. Differences in relative mRNA abundance among
      the two groups of blastocysts analyzed were found for genes related to apoptosis
      (Bax), oxidative stress (MnSOD, CuZnSOD, and SOX), communication through gap
      junctions (Cx31 and Cx43), maternal recognition of pregnancy (IFN-tau), and
      differentiation and implantation (LIF and LR-beta). The presence of serum during
      the culture period resulted in a significant increase in the level of expression
      of MnSOD, SOX, Bax, LIF, and LR-beta. The level of expression of Cx31 and
      Cu/ZnSOD also tended to be increased, although the difference was not
      significant. In contrast, the level of expression of Cx43 and IFN-tau was
      decreased in the presence of serum. In conclusion, using a combination of
      measures of developmental competence (cleavage and blastocyst rates) and
      qualitative measures such as cryotolerance and relative mRNA abundance to give a
      more complete picture of the consequences of modifying medium composition on the
      embryo, we have shown that conditions of postfertilization culture, in
      particular, the presence of serum in the medium, can affect the speed of embryo
      development and the quality of the resulting blastocysts. The reduced
      cryotolerance of blastocysts generated in the presence of serum is accompanied by
      deviations in the relative abundance of developmentally important gene
      transcripts. Omission of serum during the postfertilization culture period can
      significantly improve the cryotolerance of the blastocysts to a level
      intermediate between serum-generated blastocysts and those derived in vivo. The
      challenge now is to try and bridge this gap.

PMID- 12493720
TI  - Exogenous steroid substrate modifies the effect of 2,3,7,8-tetrachlorodibenzo-p
      dioxin on estradiol production of human luteinized granulosa cells in vitro.
AB  - The in vitro effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on steroid
      metabolism in human luteinized granulosa cells (hLGC) have been summarized as a
      decreased estradiol (E(2)) production without altering either E(2) metabolism or
      cytochrome P450 aromatase activity. In the present study, hLGC were used to
      analyze the fate of different substrates for cytochrome P450 17alpha
      hydroxylase/17,20-lyase (P450(c17)) in the presence or absence of TCDD. Human
      LGCs were plated directly on plastic culture dishes in medium supplemented with 2
      IU/ml of hCG. TCDD (10 nM) or its solvent was added directly to the cells at the
      time of medium change, every 48 h for 8 days. The objective of the experiment was
      to test the hypothesis that exogenous steroid, substrate for P450(c17), would
      reduce the TCDD effects on E(2) synthesis. With dehydroepiandrosterone (DHEA) (a
      P450(c17) product), a dose-related increase in E(2) production was observed and
      the effect of TCDD on lowering E(2) production disappeared. In contrast, with
      increasing doses, up to 10 micro M, of pregnenolone (P(5)), no change in E(2)
      production was observed. However, 17alpha-hydroxypregnenolone (17P(5)) at 10
      micro M produced a modest but significant increase in the E(2) production.
      Treatments with P(5) and 17P(5) did not alter the effect of TCDD on E(2)
      production. Radiolabeled substrate utilization by hLGC suggests that the
      principal metabolic pathway for Delta5 substrates is the conversion to a Delta4
      product probably by a very active 3beta-hydroxysteroid dehydrogenase. We conclude
      that estrogen production by hLGC is limited at the level of lyase activity. Thus,
      these data suggest that the most likely target for the TCDD-induced inhibition of
      estrogen synthesis by hLGC is the 17,20-lyase activity of the P450(c17) enzyme
      complex.

PMID- 12493721
TI  - Use of heterologous complementary DNA array screening to analyze bovine oocyte
      transcriptome and its evolution during in vitro maturation.
AB  - We have analyzed gene expression in bovine oocytes before and after in vitro
      maturation (IVM) using heterologous hybridization onto cDNA array. Total RNA was
      purified from pools of over 200 oocytes either immediately after aspiration from
      follicles at the surface of slaughterhouse cow ovaries or following in vitro
      maturation. Radiolabeled cDNA probes were generated by reverse-transcription
      followed by linear PCR amplification and were hybridized to Atlas human cDNA
      arrays. To our knowledge, this is the first report of gene expression profiling
      by this technology in the mammalian female germ cell. Our results demonstrate
      that cDNA array screening is a suitable method for analyzing the transcription
      pattern in oocytes. About 300 identified genes were reproducibly shown to be
      expressed in the bovine oocyte, the largest profile available so far in this
      model. The relative abundance of most messenger RNAs appeared stable during IVM.
      However, 70 transcripts underwent a significant differential regulation (by a
      factor of at least two). Their potential role in the context of oocyte maturation
      is discussed. Together they constitute a molecular signature of the degree of
      oocyte cytoplasmic maturation achieved in vitro.

PMID- 12493722
TI  - Cloning and functional characterization of a gonadal luteinizing hormone receptor
      complementary DNA from the African catfish (Clarias gariepinus).
AB  - A cDNA encoding a putative African catfish (Clarias gariepinus) gonadal LH
      receptor (cfLH-R) has been cloned. Multiple sequence alignment of the deduced
      amino acid sequence revealed that the cfLH-R had the highest identity with
      vertebrate LH receptors (>50%). Overall sequence identity between the cfLH-R and
      the African catfish FSH receptor (cfFSH-R) is 47%. Sequence analysis of part of
      the cfLH-R gene revealed the presence of an intron typically found in other
      vertebrate LH-R genes. Abundant cfLH-R mRNA expression was detected in ovary and
      testis as well as in head-kidney (the adrenal homologue in fish). Other tissues,
      such as muscle, brain, cerebellum, stomach, heart, and seminal vesicles, also
      contained detectable cfLH-R mRNA. Transient expression of the cfLH-R in HEK-T 293
      cells resulted in significantly increased basal cAMP levels in the absence of
      gonadotropic hormone. The cAMP levels could be further elevated in response to
      catfish LH, salmon LH, human LH, human choriogonadotropin, and human FSH. Salmon
      FSH and human TSH, however, were inactive. We conclude that we have cloned a cDNA
      encoding the LH-R of the African catfish. This receptor displays constitutive
      activity but is still responsive to additional ligand-induced activation.

PMID- 12493723
TI  - Proliferation and differentiation of bovine type A spermatogonia during long-term
      culture.
AB  - The present study was aimed at developing a method for long-term culture of
      bovine type A spermatogonia. Testes from 5-mo-old calves were used, and pure
      populations of type A spermatogonia were isolated. Cells were cultured in minimal
      essential medium (MEM) or KSOM (potassium-rich medium prepared according to the
      simplex optimization method) and different concentrations of fetal calf serum
      (FCS) for 2-4 wk at 32 degrees C or 37 degrees C. Culture in MEM resulted in more
      viable cells and more proliferation than culture in KSOM, and better results were
      obtained at 37 degrees C than at 32 degrees C. After 1 wk of culture in the
      absence of serum, only 20% of the cells were alive. However, in the presence of
      2.5% FCS, approximately 80% of cells were alive and proliferating. Higher
      concentrations of FCS only enhanced numbers of somatic cells. In long-term
      culture, spermatogonia continued to proliferate, and eventually, type A
      spermatogonial colonies were formed. The majority of colonies consisted mostly of
      groups of cells connected by intercellular bridges. Most of the cells in these
      colonies underwent differentiation because they were c-kit positive, and
      ultimately, cells with morphological and molecular characteristics of
      spermatocytes and spermatids were formed. Occasionally, large round colonies
      consisting of single, c-kit-negative, type A spermatogonia (presumably
      spermatogonial stem cells) were observed. For the first time to our knowledge, a
      method has been developed to allow proliferation and differentiation of highly
      purified type A spermatogonia, including spermatogonial stem cells during long
      term culture.

PMID- 12493724
TI  - Expression of the orphan nuclear receptor, germ cell nuclear factor, in mouse
      gonads and preimplantation embryos.
AB  - Germ cell nuclear factor (GCNF, NR6A1) is an orphan member of the nuclear
      receptor superfamily and functions as a repressor of gene transcription. GCNF
      mRNA is expressed in postgastrulation mouse embryos and is required for normal
      mouse embryonic development. In adult mice, GCNF transcripts are predominantly
      expressed in spermatogenic cells and growing oocytes of the gonads. To extend
      this observation to the protein level, we generated and characterized a specific
      antibody against GCNF. Using this antibody we found that GCNF protein was
      exclusively present in postmeiotic spermatogenic cells of the testis in 21- and
      56-day-old mice. In the ovary, GCNF protein was present in the cytoplasm of
      oocytes from primary to preovulatory follicles. GCNF protein was also present in
      unfertilized oocytes and preimplantation embryos. The presence of GCNF protein in
      adult mouse gonads indicates that GCNF may play a role during gametogenesis. Our
      results also show that GCNF in early embryos is a maternal protein and could be
      involved in the regulation of zygotic gene expression and preimplantation
      embryonic development.

PMID- 12493725
TI  - Cloning and characterization of a novel sperm-associated isoantigen (E-3) with
      defensin- and lectin-like motifs expressed in rat epididymis.
AB  - In the present study we report the identification of a novel epididymis-specific
      secretory glycoprotein, E-3, which is a sperm-associated isoantigen containing
      defensin- and lectin-like motifs. E-3 was detected in rat epididymal fluid and in
      sperm extracts by two-dimensional (2-D) Western blotting using rat hyperimmune
      sera raised against rat sperm. The immunoreactive spot of approximately 28 kDa
      with an isoelectric point (pI) of 3.5 was cored from silver-stained gels.
      Microsequencing by tandem mass spectrometry and database searches revealed
      several peptides to be novel sequences. Degenerate deoxyinosine-containing
      primers corresponding to the novel peptides were used in rapid amplification of
      cDNA ends and polymerase chain reaction to clone E-3 from a rat epididymal cDNA
      library. A 449-base pair nucleotide sequence was subsequently obtained consisting
      of a complete open reading frame (ORF) of 111 amino acids, which showed
      similarity to the defensin and lectin families. The first 21 amino acids
      constituted a putative signal peptide, suggesting that E-3 is a secretory
      protein. Mature E-3 protein corresponding to amino acids 22-111 was expressed in
      E. coli, and chickens were immunized with recombinant E-3 (rE-3). The resulting
      anti-rE-3 antisera recognized the recombinant immunogen as well as a "native"
      protein of 28 kDa, pI 2.5-3.5 in both epididymal fluid and in sperm extracts on 2
      D Western blots. Northern hybridization indicated that E-3 mRNA was present in
      the epididymis but not in testis or other tissues, and that E-3 mRNA was
      predominantly expressed in the corpus and cauda of the epididymis, but not in the
      initial segment or caput. Similarly, Western blots detected the E-3 protein only
      in the epididymal fluid and sperm from the corpus and caudal regions. Finally,
      indirect immunofluorescence localized E-3 on the entire tail, and with less
      intensity on the head of the sperm. These observations indicate that E-3 is a
      secreted epididymal protein that becomes associated with the sperm as it transits
      through the corpus and cauda. The presence of a defensin-like motif suggests that
      E-3 may play a role in protecting the sperm from microbial infections in the
      epididymis and in the female reproductive tract.

PMID- 12493726
TI  - Expression, immunolocalization, and functional activity of Na+/H+ exchanger
      isoforms in mouse endometrial epithelium.
AB  - The luminal fluid microenvironment of the uterus is important for sperm
      capacitation and embryo development. In an attempt to understand the possible
      role of Na(+)/H(+) exchangers (NHEs) in uterine function, the mRNAs of different
      NHE isoforms as well as their subcellular localization (apical versus
      basolateral) and functional activity were investigated in mouse endometrial
      epithelial cells using reverse transcriptase-polymerase chain reaction (RT-PCR),
      immunohistochemistry, and intracellular pH (pH(i)) measurement techniques. The
      presence of NHE1, NHE2, and NHE4, but not NHE3 mRNAs were revealed by RT-PCR.
      Immunostaining showed that NHE1, NHE2, and NHE4 were present in both apical and
      basolateral membranes. The pH(i) recovery from intracellular acidification was
      Na(+)-dependent; however, the rate of pH(i) recovery depending on basolateral
      Na(+) was 12.4 times faster than that depending on apical Na(+). The Na(+)
      dependent rate of pH(i) recovery was also inhibited by amiloride, indicating H(+)
      extrusion through NHEs; however, the amiloride sensitivity of the apical membrane
      was less than that of the basolateral membrane, suggesting the involvement of
      different types of NHEs in the two membranes. The results indicate that the
      basolaterally located NHE1, NHE2, and NHE4, in addition to participating in the
      homeostatic control of intracellular pH, may play a role in H(+) extrusion in
      order to achieve transepithelial HCO(3)(-) secretion. The apically located NHEs
      may be involved in mediating Na(+) absorption as alternatives of or complementary
      to epithelial Na(+) channels.

PMID- 12493727
TI  - Adenosine triphosphate activates mitogen-activated protein kinase in pre
      neoplastic and neoplastic ovarian surface epithelial cells.
AB  - To investigate the role of ATP in ovarian tumorigenesis, the present study
      examined the expression of the P2U purinoceptor (P2U-R) and effect of ATP on
      growth stimulation in pre-neoplastic and neoplastic ovarian surface epithelial
      (OSE) cells. The immortalized OSE (IOSE) cell lines, including IOSE-29 (pre
      neoplastic), IOSE-29EC (neoplastic), and OVCAR-3 (ovarian adenocarcinoma cell
      line) were used. Our results indicated that P2U-R mRNA was expressed and that ATP
      exerted a growth-stimulatory effect in IOSE-29, IOSE-29EC, and OVCAR-3. To
      investigate the mechanism of the growth-stimulatory effect, the activation of
      mitogen-activated protein kinases (MAPKs) by ATP was examined. Treatment with ATP
      resulted in MAPK activation in IOSE-29 and IOSE-29EC cells, whereas the
      stimulatory effect of ATP in cellular proliferation and MAPK activation was
      completely abolished in the presence of PD98059 (an MAPK/ERK kinase inhibitor)
      and staurosporin (a protein kinase C inhibitor), suggesting that the growth
      stimulatory effect of ATP is mediated via protein kinase C-dependent MAPK
      activation in pre-neoplastic and neoplastic OSE cells. In a time-dependent study,
      ATP significantly increased MAPK activity at 5-20 min in IOSE-29 cells. Activated
      MAPK declined to control levels after 20 min in these cells. Treatment with ATP
      significantly induced MAPK activation after 5 min and was sustained for 60 min in
      IOSE-29EC cells. In addition, treatment with ATP resulted in substantial
      phosphorylation of Elk-1, the Ets family transcriptional factor, confirming that
      ATP action is mediated by activation of MAPK. In conclusion, we have demonstrated
      that P2U-R was expressed and that ATP induced growth stimulation in IOSE and
      OVCAR-3 cells. Furthermore, treatment with ATP resulted in the activation of an
      MAPK cascade and phosphorylation of Elk-1 in IOSE-29 and IOSE-29EC cells. These
      results suggest that the MAPK cascade may be involved in growth stimulation in
      response to ATP in pre-neoplastic and neoplastic OSE cells.

PMID- 12493728
TI  - Expansion of murine spermatogonial stem cells through serial transplantation.
AB  - Mammalian male germ cells might be generally thought to have infinite
      proliferative potential based on their life-long production of huge numbers of
      sperm. However, there has been little substantial evidence that supports this
      assumption. In the present study, we performed serial transplantation of
      spermatogonial stem cells to investigate if they expand by self-renewing division
      following transplantation. The transgenic mouse carrying the Green fluorescent
      protein gene was used as the donor cell source that facilitated identification
      and recollection of colonized donor germ cells in the recipient testes. The
      established colonies of germ cells in the recipient testes were collected and
      transplanted to new recipients. This serial transplantation of spermatogonial
      stem cells repopulated the recipient testes, which were successfully performed
      sequentially up to four times from one recipient to the next. The incubation
      periods between two sequential transplantations ranged from 55 to 373 days.
      During these passages, the spermatogonial stem cells showed constant activity to
      form spermatogenic colonies in the recipient testis. They continued to increase
      in number for more than a year following transplantation. Colonization efficiency
      of spermatogonial stem cells was determined to be 4.25% by using Sl/Sl(d) mice as
      recipients that propagated only undifferentiated type A spermatogonia in their
      testes. Based on the colonization efficiency, one colony-forming activity was
      assessed to equate to about 20 spermatogonial stem cells. The spermatogonial stem
      cells were estimated to expand over 50-fold in 100 days in this experiment.

PMID- 12493729
TI  - Maintenance of sexual immaturity in male mice and bucks by immunization against N
      terminal peptides of the follicle-stimulating hormone receptor.
AB  - The follicle-stimulating hormone is one of the two pituitary hormones that
      control fertility in both sexes. In the male, receptors for FSH (FSHR) are only
      expressed on testicular Sertoli cells. FSH plays different roles during the male
      life; it functions as a growth factor during development and sustains
      spermatogenesis in adults. However, the exact role of this hormone as an
      initiator of male fertility is not fully understood and few data are available
      concerning its involvement during the peripubertal period. We recently produced
      filamentous phages displaying FSHR fragments overlapping residues 18-38, which,
      if injected in animals, induced anti-FSH receptor immunity capable of inhibiting
      hormone binding. We employed this strategy to transiently inhibit FSH activity in
      male mice and male goats of the Saanen and the Mongolian Alpas Cashmere breeds at
      the prepubertal stage. Anti-FSHR peptide immunization from the age of 3 wk
      delayed the acquisition of fecundity in male mice by up to 1 wk. Once fertile,
      progeny sizes produced by mating immunized males and untreated females were found
      to be reduced by up to 60%. In two different breeds of goats, FSHR peptide
      vaccines were able to maintain circulating testosterone at low prepubertal levels
      for several months despite no alteration in LH levels, reflecting their ability
      to delay the onset of puberty. These results support the conclusion that FSH may
      play a central role in the male at puberty through the control of testosterone
      production.

PMID- 12493730
TI  - Localization and secretion of inhibins in the equine fetal ovaries.
AB  - To clarify the source of inhibins in equine female fetuses, concentrations of
      immunoreactive (ir-) inhibin, inhibin pro-alphaC, and inhibin A in both fetal and
      maternal circulation and in fetal ovaries were measured. In addition, the
      localization of inhibin alpha and inhibin/activin beta(A), and beta(B) subunits
      and the expression of inhibin alpha(A) and inhibin/activin beta(A) subunit mRNA
      in fetal ovaries were investigated using immunohistochemistry and in situ
      hybridization. Concentrations of circulating ir-inhibin, inhibin pro-alphaC, and
      inhibin A were remarkably more elevated in the fetal than in the maternal
      circulation between Days 100 and 250 of gestation. Fetal ovaries contained large
      amounts of ir-inhibin, inhibin pro-alphaC, and inhibin A. In contrast, these
      inhibin forms were undetectable in both the maternal ovaries and placenta. The
      inhibin alpha and inhibin/activin beta(A) and beta(B) subunit proteins were
      localized to enlarged interstitial cells of the equine fetal ovary. Expression of
      inhibin alpha and inhibin/activin beta(A) subunit mRNAs were also observed in the
      interstitial cells. We conclude that the main source of large amounts of inhibins
      in fetal circulation is interstitial cells of fetal ovary and is not of maternal
      origin. Furthermore, these inhibins may play some important physiological roles
      in the development of gonads in the equine fetus.

PMID- 12493731
TI  - Familial Alzheimer disease-linked presenilin 1 variants enhance production of
      both Abeta 1-40 and Abeta 1-42 peptides that are only partially sensitive to a
      potent aspartyl protease transition state inhibitor of "gamma-secretase".
AB  - Presenilin 1 (PS1) plays an essential role in intramembranous "gamma-secretase"
      processing of several type I membrane proteins, including the beta-amyloid
      precursor proteins (APP) and Notch1. In this report, we examine the activity of
      two familial Alzheimer's disease-linked PS1 variants on the production of
      secreted Abeta peptides and the effects of L-685,458, a potent gamma-secretase
      inhibitor, on inhibition of Abeta peptides from cells expressing these PS1
      variants. We now report that PS1 variants enhance the production and secretion of
      both Abeta1-42 and Abeta1-40 peptides. More surprisingly, whereas the IC(50) for
      inhibition of Abeta1-40 peptide production from cells expressing wild-type PS1 is
      approximately 1.5 microm, cells expressing the PS1deltaE9 mutant PS1 exhibit an
      IC(50) of approximately 4 microm. Immunoprecipitation and matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry reveal that the levels of
      Abeta1-43 peptides are elevated in medium of PS1deltaE9 cells treated with higher
      concentrations of inhibitor. The differential effects of wild-type and mutant PS1
      on gamma-secretase production of Abeta peptides and the disparity in sensitivity
      of these peptides to a potent gamma-secretase suggest that PS may be necessary,
      but not sufficient, to catalyze hydrolysis at the scissile bonds that generate
      the termini of Abeta1-40 and Abeta1-42 peptides.

PMID- 12493732
TI  - Roles of cytosolic Hsp70 and Hsp40 molecular chaperones in post-translational
      translocation of presecretory proteins into the endoplasmic reticulum.
AB  - Hsp70 molecular chaperones and their co-chaperones work together in various
      cellular compartments to guide the folding of proteins and to aid the
      translocation of proteins across membranes. Hsp70s stimulate protein folding by
      binding exposed hydrophobic sequences thereby preventing irreversible
      aggregation. Hsp40s stimulate the ATPase activity of Hsp70s and target unfolded
      proteins to Hsp70s. Genetic and biochemical evidence supports a role for
      cytosolic Hsp70s and Hsp40s in the post-translational translocation of precursor
      proteins into endoplasmic reticulum and mitochondria. To gain mechanistic
      insight, we measured the effects of Saccharomyces cerevisiae Ssa1p (Hsp70) and
      Ydj1p (Hsp40) on the translocation of histidine-tagged prepro-alpha-factor
      (ppalphaF6H) into microsomes. Radiolabeled ppalphaF6H was affinity purified from
      wheat germ translation reactions (or Escherichia coli) to remove endogenous
      chaperones. We demonstrated that either Ssa1p or Ydj1p stimulates post
      translational translocation by preventing ppalphaF6H aggregation. The binding
      and/or hydrolysis of ATP by Ssa1p were required to maintain the translocation
      competence of ppalphaF6H. To clarify the contributions of membrane-bound and
      cytosolic Ydj1p, we compared the efficiency of chaperone-dependent translocation
      into wild-type and Ydj1p-deficient microsomes. Neither soluble nor membrane-bound
      Ydj1p was essential for post-translational protein translocation. The ability of
      Ssa1p, Ydj1p, or both chaperones to restore the translocation competence of
      aggregated ppalphaF6H was negligible.

PMID- 12493733
TI  - Structure of the C-terminal domains of merozoite surface protein-1 from
      Plasmodium knowlesi reveals a novel histidine binding site.
AB  - The protozoan parasite Plasmodium causes malaria, with hundreds of millions of
      cases recorded annually. Protection against malaria infection can be conferred by
      antibodies against merozoite surface protein (MSP)-1, making it an attractive
      vaccine candidate. Here we present the structure of the C-terminal domains of MSP
      1 (known as MSP-1(19)) from Plasmodium knowlesi. The structure reveals two
      tightly packed epidermal growth factor-like domains oriented head to tail. In
      domain 1, the molecule displays a histidine binding site formed primarily by a
      highly conserved tryptophan. The protein carries a pronounced overall negative
      charge primarily due to the large number of acidic groups in domain 2. To map
      protein binding surfaces on MSP-1(19), we have analyzed the crystal contacts in
      five different crystal environments, revealing that domain 1 is highly preferred
      in protein-protein interactions. A comparison of MSP-1(19) structures from P.
      knowlesi, P. cynomolgi, and P. falciparum shows that, although the overall
      protein folds are similar, the molecules show significant differences in charge
      distribution. We propose the histidine binding site in domain 1 as a target for
      inhibitors of protein binding to MSP-1, which might prevent invasion of the
      merozoite into red blood cells.

PMID- 12493734
TI  - Mechanism of the reductive half-reaction in cellobiose dehydrogenase.
AB  - The extracellular flavocytochrome cellobiose dehydrogenase (CDH; EC )
      participates in lignocellulose degradation by white-rot fungi with a proposed
      role in the early events of wood degradation. The complete hemoflavoenzyme
      consists of a catalytically active dehydrogenase fragment (DH(cdh)) connected to
      a b-type cytochrome domain via a linker peptide. In the reductive half-reaction,
      DH(cdh) catalyzes the oxidation of cellobiose to yield cellobiono-1,5-lactone.
      The active site of DH(cdh) is structurally similar to that of glucose oxidase and
      cholesterol oxidase, with a conserved histidine residue positioned at the re face
      of the flavin ring close to the N5 atom. The mechanisms of oxidation in glucose
      oxidase and cholesterol oxidase are still poorly understood, partly because of
      lack of experimental structure data or difficulties in interpreting existing data
      for enzyme-ligand complexes. Here we report the crystal structure of the
      Phanerochaete chrysosporium DH(cdh) with a bound inhibitor, cellobiono-1,5
      lactam, at 1.8-A resolution. The distance between the lactam C1 and the flavin N5
      is only 2.9 A, implying that in an approximately planar transition state, the
      maximum distance for the axial 1-hydrogen to travel for covalent addition to N5
      is 0.8-0.9 A. The lactam O1 interacts intimately with the side chains of His-689
      and Asn-732. Our data lend substantial structural support to a reaction mechanism
      where His-689 acts as a general base by abstracting the O1 hydroxyl proton in
      concert with transfer of the C1 hydrogen as hydride to the re face of the flavin
      N5.

PMID- 12493735
TI  - A thyroid hormone response unit formed between the promoter and first intron of
      the carnitine palmitoyltransferase-Ialpha gene mediates the liver-specific
      induction by thyroid hormone.
AB  - Carnitine palmitoyltransferase-I (CPT-I) catalyzes the rate-controlling step of
      fatty acid oxidation. CPT-I converts long-chain fatty acyl-CoAs to acylcarnitines
      for translocation across the mitochondrial membrane. The mRNA levels and enzyme
      activity of the liver isoform, CPT-Ialpha, are greatly increased in the liver of
      hyperthyroid animals. Thyroid hormone (T3) stimulates CPT-Ialpha transcription
      far more robustly in the liver than in non-hepatic tissues. We have shown that
      the thyroid hormone receptor (TR) binds to a thyroid hormone response element
      (TRE) located in the CPT-Ialpha promoter. In addition, elements in the first
      intron participate in the T3 induction of CPT-Ialpha gene expression, but the CPT
      Ialpha intron alone cannot confer a T3 response. We found that deletion of
      sequences in the first intron between +653 and +744 decreased the T3 induction of
      CPT-Ialpha. Upstream stimulatory factor (USF) and CCAAT enhancer binding proteins
      (C/EBPs) bind to elements within this region, and these factors are required for
      the T3 response. The binding of TR and C/EBP to the CPT-Ialpha gene in vivo was
      shown by the chromatin immunoprecipitation assay. We determined that TR can
      physically interact with USF-1, USF-2, and C/EBPalpha. Transgenic mice were
      created that carry CPT-Ialpha-luciferase transgenes with or without the first
      intron of the CPT-Ialpha gene. In these mouse lines, the first intron is required
      for T3 induction as well as high levels of hepatic expression. Our data indicate
      that the T3 stimulates CPT-Ialpha gene expression in the liver through a T3
      response unit consisting of the TRE in the promoter and additional factors, C/EBP
      and USF, bound in the first intron.

PMID- 12493736
TI  - Determinants of Rab5 interaction with the N terminus of early endosome antigen 1.
AB  - The Rab5 effector early endosome antigen 1 (EEA1) is a parallel coiled coil
      homodimer with an N-terminal C(2)H(2) Zn(2+) finger and a C-terminal FYVE domain.
      Rab5 binds to independent sites at the N and C terminus of EEA1. To gain further
      insight into the structural determinants for endosome tethering and fusion, we
      have characterized the interaction of Rab5C with truncation and site-specific
      mutants of EEA1 using quantitative binding measurements. The results demonstrate
      that the C(2)H(2) Zn(2+) finger is both essential and sufficient for the N
      terminal interaction with Rab5. Although the heptad repeat C-terminal to the
      C(2)H(2) Zn(2+) finger provides the driving force for stable homodimerization, it
      does not influence either the affinity or stoichiometry of Rab5 binding.
      Hydrophobic residues predicted to cluster on a common face of the C(2)H(2) Zn(2+)
      finger play a critical role in the interaction with Rab5. Although the homologous
      C(2)H(2) Zn(2+) finger of the Rab5 effector Rabenosyn binds to Rab5 with
      comparable affinity, the analogous C(2)H(2) Zn(2+) finger of the yeast homologue
      Vac1 shows no detectable interaction with Rab5, reflecting non-conservative
      substitutions of critical residues. Large changes in the intrinsic tryptophan
      fluorescence of Rab5 accompany binding to the C(2)H(2) Zn(2+) finger of EEA1.
      These observations can be explained by a mode of interaction in which a partially
      exposed tryptophan residue located at the interface between the switch I and II
      regions of Rab5 lies within a hydrophobic interface with a cluster of non-polar
      residues in the C(2)H(2) Zn(2+) finger of EEA1.

PMID- 12493737
TI  - Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's
      disease with non-cored plaques and no neuritic dystrophy.
AB  - The mutation L271V in exon 8 of the presenilin-1 (PS-1) gene was detected in an
      Alzheimer's disease pedigree. Neuropathological examination of affected
      individuals identified variant, large, non-cored plaques without neuritic
      dystrophy, reminiscent of cotton wool plaques. Biochemical analysis of L271V
      mutation showed that it increased secretion of the 42-amino acid amyloid-beta
      peptide, suggesting a pathogenic mutation. Analysis of PS-1 transcripts from the
      brains of two mutation carriers revealed a 17-50% increase in PS-1 transcripts
      with deletion of exon 8 (PS-1deltaexon8) compared with unrelated Alzheimer's
      disease brains. Exon trapping analysis confirmed that L271V mutation enhanced the
      deletion of exon 8. Western blots of brain lysates indicated that PS-1deltaexon8
      was overexpressed in an affected individual. Biochemical analysis of PS
      1deltaexon8 in COS and BD8 cells indicate the splice isoform is not intrinsically
      active but interacts with wild-type PS-1 to generate amyloid-beta. Western blots
      of cell lysates immunoprecipitated with anti-Tau or anti-GSK-3beta antibodies
      indicated that PS-1deltaexon8, unlike wild-type PS-1, does not interact directly
      with Tau or GSK-3beta, potential modifiers of neuritic dystrophy. We postulate
      that variant plaques observed in this family are due in part to the effects of PS
      1deltaexon8 and that interaction between PS-1 and various protein complexes are
      necessary for neuritic plaque formation.

PMID- 12493738
TI  - Basic helix-loop-helix transcription factor epicardin/capsulin/Pod-1 suppresses
      differentiation by negative regulation of transcription.
AB  - Epicardin/capsulin/Pod-1, expressed in skeletal myoblasts within brachial arches
      and in the condensing mesenchyme, is a member of the basic helix-loop-helix
      (bHLH) transcription factor family that is involved in various cell
      differentiation processes. In this study, we examined the functional properties
      of epicardin/capsulin/Pod-1 in differentiation. The yeast and mammalian two
      hybrid systems showed physical associations between epicardin/capsulin/Pod-1 and
      E2A, both of which were present in the nuclei. The bHLH domains mediated this
      association. Ectopic expression of epicardin/capsulin/Pod-1 inhibited E2A
      dependent activation of the exogenous and endogenous expression of the cyclin
      dependent kinase inhibitor, p21(WAF1/Cip1) gene, and the muscle creatine kinase
      gene that encodes the predominant creatine kinase isoform expressed in mammalian
      skeletal muscle. Transfection with epicardin/capsulin/Pod-1 small interfering RNA
      abolished the epicardin/capsulin/Pod-1-mediated suppression of E12-dependent
      activation of the p21 promoter. Chromatin immunoprecipitation assay showed that
      epicardin/capsulin/Pod-1 was physically associated with the muscle creatine
      kinase promoter in vivo. Moreover, terminal differentiation of C2C12 myoblasts
      was inhibited by exogenous introduction of epicardin/capsulin/Pod-1. These
      inhibitory functions of epicardin/capsulin/Pod-1 closely resemble those of the
      bHLH inhibitor Twist protein. These results indicate that epicardin/capsulin/Pod
      1 functions as a negative regulator of differentiation of myoblasts through
      transcription in at least two distinct steps, cell growth arrest and lineage
      specific differentiation.

PMID- 12493739
TI  - cAMP-induced Interleukin-10 promoter activation depends on CCAAT/enhancer-binding
      protein expression and monocytic differentiation.
AB  - The molecular mechanisms underlying the regulation of interleukin (IL)-10
      transcription in monocytic cells by various stimuli during inflammation and the
      stress reaction are not fully understood. Recently, we provided evidence that
      stress-induced IL-10 promoter activation in monocytic cells is mediated by
      catecholamines via a cAMP-dependent signaling pathway including CREB/ATF (cAMP
      responsive element binding protein/activating transcription factor) binding to
      two CRE motifs. However, the mutation of these sites diminished cAMP
      responsiveness by only 50%, suggesting a role for additional transcription
      factors and elements in the cAMP-dependent regulation of the human IL-10
      promoter. Here, we analyze the functional role of one such factor, C/EBP, in two
      cell lines of myelomonocytic origin, THP-1 and HL-60, which are known to differ
      in their differentiation status and C/EBP protein content. We show that the level
      of basal as well as cAMP-stimulated IL-10 transcription depends on the expression
      of C/EBP alpha and beta and their binding to three motifs in the
      promoter/enhancer region. The C/EBP5 motif, which is located between the TATA-box
      and the translation start point, is essential for the C/EBP-mediated constitutive
      and most of the cAMP-stimulated expression as its mutation nearly abolished IL-10
      promoter activity. Our results suggest a dominant role of C/EBP transcription
      factors relative to CREB/ATF in tissue-specific and differentiation-dependent IL
      10 transcription.

PMID- 12493740
TI  - Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)
      phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association
      of IRS-1/IRS-2 with the insulin receptor.
AB  - Grb10 has been proposed to inhibit or activate insulin signaling, depending on
      cellular context. We have investigated the mechanism by which full-length
      hGrb10gamma inhibits signaling through the insulin receptor substrate (IRS)
      proteins. Overexpression of hGrb10gamma in CHO/IR cells and in differentiated
      adipocytes significantly reduced insulin-stimulated tyrosine phosphorylation of
      IRS-1 and IRS-2. Inhibition occurred rapidly and was sustained for 60 min during
      insulin stimulation. In agreement with inhibited signaling through the IRS/PI 3
      kinase pathway, we found hGrb10gamma to both delay and reduce phosphorylation of
      Akt at Thr(308) and Ser(473) in response to insulin stimulation. Decreased
      phosphorylation of IRS-1/2 may arise from impaired catalytic activity of the
      receptor, since hGrb10gamma directly associates with the IR kinase regulatory
      loop. However, yeast tri-hybrid studies indicated that full-length Grb10 blocks
      association between IRS proteins and IR, and that this requires the SH2 domain of
      Grb10. In cells, hGrb10gamma inhibited insulin-stimulated IRS-1 tyrosine
      phosphorylation in a dose-dependent manner, but did not affect IR catalytic
      activity toward Tyr(972) in the juxtamembrane region and Tyr(1158/1162/1163) in
      the regulatory domain. We conclude that binding of hGrb10gamma to IR decreases
      signaling through the IRS/PI 3-kinase/AKT pathway by physically blocking IRS
      access to IR.

PMID- 12493741
TI  - Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to
      increased signaling by altering either activation or secretion of the mutant
      protein.
AB  - Transforming growth factor-beta1 (TGF-beta1) is secreted as a latent precursor,
      consisting of a homodimer of the latency-associated peptide and the mature
      peptide. TGFbeta-1 can only exert its many functions after going from this latent
      to an active state, in which the binding site of the mature peptide for its
      receptor is no longer shielded by the latency-associated peptide. We and others
      reported that mutations in TGFB1 cause Camurati-Engelmann disease, a rare bone
      disorder. Until now, seven mutations have been published. In this study, we
      investigate the effect of the LLL12-13ins, Y81H, R218C, H222D, and C225R
      mutations on the functioning of TGF-beta1 in vitro. A luciferase reporter assay
      specific for TGF-beta-induced transcriptional response with wild type and mutant
      TGF-beta1 constructs showed a positive effect of all mutations on TGF-beta1
      activity. By way of enzyme-linked immunosorbent assay, we found that in the
      R218C, H222D, and C225R mutant constructs, this effect is caused by an increase
      in active TGF-beta1 in the medium of transfected cells. The LLL12-13ins and Y81H
      mutations on the contrary have a profound effect on secretion; a decreased amount
      of TGF-beta1 is secreted, but the increased luciferase activity shows that the
      intracellular accumulation of (aberrant) TGF-beta1 can initiate an enhanced
      transcriptional response, suggesting the existence of an alternative signaling
      pathway. Our data indicate that the mutations in the signal peptide and latency
      associated peptide facilitate TGF-beta1 signaling, thus causing Camurati
      Engelmann disease.

PMID- 12493742
TI  - Inhibin is an antagonist of bone morphogenetic protein signaling.
AB  - Inhibins are endogenous antagonists of activin signaling, long recognized as
      important regulators of gonadal function and pituitary FSH release. Inhibin, in
      concert with its co-receptor, betaglycan, can compete with activin for binding to
      type II activin receptors and, thus, prevent activin signaling. Because bone
      morphogenetic proteins (BMPs) also utilize type II activin receptors, we
      hypothesized that BMP signaling might also be sensitive to inhibin blockade. Here
      we show that inhibin blocks cellular responses to diverse BMP family members in a
      variety of BMP-responsive cell types. Inhibin abrogates BMP-induced Smad
      signaling and transcription responses. Inhibin competes with BMPs for type II
      activin receptors, and this competition is facilitated by betaglycan. Betaglycan
      also enables inhibin to bind to and compete with BMPs for binding to the BMP
      specific type II receptor BMPRII, which does not bind inhibin in the absence of
      betaglycan. Betaglycan can confer inhibin responsiveness on cells that are
      otherwise insensitive to inhibin. These findings demonstrate that inhibin, acting
      through betaglycan, can function as an antagonist of BMP responses, suggesting a
      broader role for inhibin and betaglycan in restricting and refining a wide
      spectrum of transforming growth factor beta superfamily signals.

PMID- 12493743
TI  - Redundancy of radioresistant signaling pathways originating from insulin-like
      growth factor I receptor.
AB  - The insulin-like growth factor I receptor (IGF-IR) has the ability to confer
      clonogenic radioresistance following ionizing irradiation. We attempted to
      determine the downstream pathways involved in IGF-IR-mediated radioresistance and
      used mouse embryo fibroblasts deficient in endogenous IGF-IR (R-) as recipients
      for a number of mutant IGF-IRs. Mutational analysis revealed that the tyrosine at
      residue 950 (Tyr-950) of IGF-IR, as well as the C-terminal domain, are required
      for radioresistance and that both domains must be mutated to abrogate the
      phenotype. Furthermore, the contribution of downstream pathways was analyzed by
      combining the use of wild-type or Tyr-950 and C-terminal mutants with specific
      inhibitors of phosphatidylinositol 3'-kinase (PI3-K) or mitogen-activated protein
      extracellular signal-regulated kinase (ERK) kinase (MEK). Radioresistance could
      be induced by IGF-IR as long as the ability of the receptor to stimulate the
      MEK/ERK pathway was retained. This was confirmed by the expression of
      constitutively active MEK in R- cells. The ability to stimulate the PI3-K pathway
      alone was not sufficient, but PI3-K activation coupled with MEK/ERK pathway
      independent signals from the C terminus was able to induce radioresistance. Taken
      together, these results indicate that the IGF-IR-mediated radioresistant
      signaling mechanism progresses through redundant downstream pathways.

PMID- 12493744
TI  - Trafficking of the Ca2+-activated K+ channel, hIK1, is dependent upon a C
      terminal leucine zipper.
AB  - We demonstrate that the C-terminal truncation of hIK1 results in a loss of
      functional channels. This could be caused by either (i) a failure of the channel
      to traffic to the plasma membrane or (ii) the expression of non-functional
      channels. To delineate among these possibilities, a hemagglutinin epitope was
      inserted into the extracellular loop between transmembrane domains S3 and S4.
      Surface expression and channel function were measured by immunofluorescence, cell
      surface immunoprecipitation, and whole-cell patch clamp techniques. Although
      deletion of the last 14 amino acids of hIK1 (L414STOP) had no effect on plasma
      membrane expression and function, deletion of the last 26 amino acids (K402STOP)
      resulted in a complete loss of membrane expression. Mutation of the leucine
      heptad repeat ending at Leu(406) (L399A/L406A) completely abrogated membrane
      localization. Additional mutations within the heptad repeat (L385A/L392A,
      L392A/L406A) or of the a positions (I396A/L403A) resulted in a near-complete loss
      of membrane-localized channel. In contrast, mutating individual leucines did not
      compromise channel trafficking or function. Both membrane localization and
      function of L399A/L406A could be partially restored by incubation at 27 degrees
      C. Co-immunoprecipitation studies demonstrated that leucine zipper mutations do
      not compromise multimer formation. In contrast, we demonstrated that the leucine
      zipper region of hIK1 is capable of co-assembly and that this is dependent upon
      an intact leucine zipper. Finally, this leucine zipper is conserved in another
      member of the gene family, SK3. However, mutation of the leucine zipper in SK3
      had no effect on plasma membrane localization or function. In conclusion, we
      demonstrate that the C-terminal leucine zipper is critical to facilitate correct
      folding and plasma membrane trafficking of hIK1, whereas this function is not
      conserved in other gene family members.

PMID- 12493745
TI  - Impact of genetic background and ablation of insulin receptor substrate (IRS)-3
      on IRS-2 knock-out mice.
AB  - Although we and others have generated IRS-2 knock-out (IRS-2(-/-)) mice,
      significant differences were seen between the two lines of IRS-2(-/-) mice in the
      severity of diabetes and alterations of beta-cell mass. It has been reported that
      although IRS-1 and IRS-3 knock-out mice showed normal blood glucose levels, IRS
      1/IRS-3 double knock-out mice exhibited marked hyperglycemia. Thus, IRS-1 and IRS
      3 compensate each other's functions in maintaining glucose homeostasis. To assess
      the effect of genetic background and also ablation of IRS-3 on IRS-2(-/-), we
      generated IRS-2/IRS-3 double knock-out (IRS-2(-/-)IRS-3(-/-)) mice by crossing
      IRS-3(-/-) mice (129/Sv and C57Bl/6 background) with our IRS-2(-/-) mice (CBA and
      C57Bl/6 background). Intercrosses of IRS-2(+/-)IRS-3(+/-) mice yielded nine
      genotypes, and all of them including IRS-2(-/-)IRS-3(-/-) mice were apparently
      healthy and showed normal growth. However, at 10-20 weeks of age, 20-30% mice
      carrying a null mutation for the IRS-2 gene, irrespective of the IRS-3 genotype,
      developed diabetes. When mice with diabetes were excluded from the analysis of
      glucose and insulin tolerance test, IRS-2(-/-)IRS-3(-/-) showed a degree of
      glucose intolerance and insulin resistance similar to those of IRS-2(-/-) mice.
      Both IRS-2(-/-) and IRS-2(-/-)IRS-3(-/-) mice had moderately reduced beta-cell
      mass despite having insulin resistance. Insulin-positive beta-cells were
      decreased to nearly zero in IRS-2(-/-) mice with diabetes. Although Pdx1 and
      glucose transporter 2 expressions were essentially unaltered in islets from IRS
      2(-/-) mice without diabetes, they were dramatically decreased in IRS-2(-/-) mice
      with diabetes. Taken together, these observations indicate that IRS-3 does not
      play a role compensating for the loss of IRS-2 in maintaining glucose homeostasis
      and that the severity of diabetes in IRS-2(-/-) mice depends upon genetic
      background, suggesting the existence of modifier gene(s) for diabetes in mice of
      the 129/Sv genetic strain.

PMID- 12493746
TI  - Differentiation status-dependent regulation of cyclooxygenase-2 expression and
      prostaglandin E2 production by epidermal growth factor via mitogen-activated
      protein kinase in articular chondrocytes.
AB  - Although large amounts of epidermal growth factor (EGF) are found in the synovial
      fluids of arthritic cartilage, the role of EGF in arthritis is not clearly
      understood. This study investigated the effect of EGF on differentiation and on
      inflammatory responses such as cyclooxygenase-2 (COX-2) expression and
      prostaglandin E(2) (PGE(2)) production in articular chondrocytes. EGF caused a
      loss of differentiated chondrocyte phenotype as demonstrated by inhibition of
      type II collagen expression and proteoglycan synthesis. EGF also induced COX-2
      expression and PGE(2) production. EGF-induced dedifferentiation was caused by EGF
      receptor-mediated activation of extracellular signal-regulated protein kinases 1
      and 2 (ERK1/2) but not p38 kinase, whereas the activation of both ERK1/2 and p38
      kinase was necessary for COX-2 expression and PGE(2) production. Neither the
      inhibition of COX-2 expression and PGE(2) production nor the addition of
      exogenous PGE(2) affected EGF-induced dedifferentiation. However, COX-2
      expression and PGE(2) production were significantly enhanced in chondrocytes that
      were dedifferentiated by serial subculture, and EGF also potentiated COX-2
      expression and PGE(2) production, although these cells were less sensitive to
      EGF. Dedifferentiation-induced COX-2 expression and PGE(2) production were
      mediated by ERK1/2 and p38 kinase signaling. Our results indicate that EGF in
      articular chondrocytes stimulates COX-2 expression and PGE(2) production via ERK
      and p38 kinase signaling in association with differentiation status.

PMID- 12493747
TI  - Treatment of human T cells with bisperoxovanadium phosphotyrosyl phosphatase
      inhibitors leads to activation of cyclooxygenase-2 gene.
AB  - Protein-tyrosine phosphatase (PTP) inhibitors are potent activators of T
      lymphocytes, most likely by affecting the early steps of T cell receptor (TCR)
      signaling. We have analyzed the effect of the PTP inhibitor bisperoxovanadium
      (bpV) on expression of the human cyclooxygenase 2 (COX-2) gene, which is induced
      following TCR triggering. Here we show that COX-2 promoter activity is markedly
      up-regulated following exposure of Jurkat T cells to bpV(pic). Interestingly
      enough, treatment of Jurkat cells with cyclic AMP-elevating agents such as
      forskolin, in combination with bpV, resulted in a more important COX-2
      transcriptional activation. Such activation is inhibited by the immunosuppressive
      drugs FK506 and cyclosporin A. The two nuclear factor of activated T cells (NFAT)
      binding sites located within the COX-2 promoter region are involved in bpV
      mediated positive effect on COX-2 promoter. Electromobility shift assays showed
      that NFAT1 and activator protein-1 are both translocated to the nucleus following
      bpV treatment. The active participation of p56(lck), ZAP-70, p36(LAT), and
      calcium in the bpV-dependent signaling cascade leading to COX-2 transcriptional
      activation was demonstrated using deficient cell lines and specific inhibitors.
      Although several PTPs are most likely targeted by bpV, our data suggest that the
      bpV-mediated signaling cascade is initiated by inhibition of SHP-1, which leads
      to phosphorylation of p56(lck) and ZAP-70 and, ultimately, to NFAT and activator
      protein-1 nuclear translocation. These results suggest that PTP inhibitors can
      activate COX-2 gene expression in a manner very similar to the stimulation
      induced by TCR triggering.

PMID- 12493748
TI  - Happily at work.

PMID- 12493749
TI  - Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP
      signaling.

PMID- 12493750
TI  - Discovery of an alpha 2,9-PolyNeu5Ac glycoprotein in C-1300 murine neuroblastoma
      (clone NB41A3).
AB  - alpha2,8-PolyNeu5Ac is expressed on neural cell adhesion molecules during
      embryogenesis and also re-expressed on certain tumors. PolyNeu5Ac is therefore an
      oncodevelopmental antigen, has important regulatory effects on the adhesive and
      migratory behavior of neural cells, and is thus crucial to synaptic plasticity.
      Until now, alpha2,9-polyNeu5Ac, a linkage isomer of alpha2,8-polyNeu5Ac, has long
      been thought to occur only in capsules of neuroinvasive Neisseria meningitidis
      group C bacteria. Here we report the unexpected discovery of alpha2,9-polyNeu5Ac
      in a new cell adhesion-related glycoprotein on the membrane of C-1300 murine
      neuroblastoma cells (clone NB41A3). We also report the expression of alpha2,9
      polyNeu5Ac was affected by cell growth and retinoic acid-induced differentiation.
      Occurrence of the linkage isomer of alpha2,8-polyNeu5Ac has been left
      unrecognized by conventional methods using biological diagnostic probes for
      alpha2,8-polyNeu5Ac. Thus, our discovery may change contemporary views of biology
      and pathology of polysialic acid and open new avenues for the development of anti
      neural tumor drugs.

PMID- 12493751
TI  - Crystal structure of GRIP1 PDZ6-peptide complex reveals the structural basis for
      class II PDZ target recognition and PDZ domain-mediated multimerization.
AB  - PDZ domains bind to short segments within target proteins in a sequence-specific
      fashion. Glutamate receptor-interacting protein (GRIP)/ABP family proteins
      contain six to seven PDZ domains and interact via the sixth PDZ domain (class II)
      with the C termini of various proteins including liprin-alpha. In addition the
      PDZ456 domain mediates the formation of homo- and heteromultimers of GRIP
      proteins. To better understand the structural basis of peptide recognition by a
      class II PDZ domain and PDZ-mediated multimerization, we determined the crystal
      structures of the GRIP1 PDZ6 domain alone and in complex with a synthetic C
      terminal octapeptide of human liprin-alpha at resolutions of 1.5 and 1.8 A,
      respectively. Remarkably, unlike other class II PDZ domains, Ile-736 at alphaB5
      rather than conserved Leu-732 at alphaB1 makes a direct hydrophobic contact with
      the side chain of the Tyr at the -2 position of the ligand. Moreover, the peptide
      bound structure of PDZ6 shows a slight reorientation of helix alphaB, indicating
      that the second hydrophobic pocket undergoes a conformational adaptation to
      accommodate the bulkiness of the Tyr side chain, and forms an antiparallel dimer
      through an interface located at a site distal to the peptide-binding groove. This
      configuration may enable formation of GRIP multimers and efficient clustering of
      GRIP-binding proteins.

PMID- 12493752
TI  - Delineation of the hydroxyapatite-nucleating domains of bone sialoprotein.
AB  - Bone sialoprotein (BSP) is a highly modified, anionic phosphoprotein that is
      expressed almost exclusively in mineralizing connective tissues and has been
      shown to be a potent nucleator of hydroxyapatite (HA). Two polyglutamic acid
      (poly[E]) regions, predicted to be in an alpha-helical conformation and located
      in the amino-terminal half of the molecule, are believed to be responsible for
      this activity. Using a prokaryotic expression system, full-length rat BSP was
      expressed and tested for HA nucleating activity in a steady-state agarose gel
      system. The unmodified protein is less potent than native bone BSP, indicating a
      role for the post-translational modifications in HA nucleation. Site-directed
      mutagenesis of the poly[E] regions in full-length BSP was performed, replacing
      the poly[E] with either polyaspartic acid (poly[D]) or polyalanine (poly[A]) to
      examine role of charge and conformation, respectively, in HA nucleation.
      Replacement of single domains with either poly[A] or poly[D] did not alter
      nucleating activity nor did replacement of both domains with poly[D]. Replacement
      of both domains with poly[A], however, significantly decreased nucleating
      activity. In addition, two recombinant peptides, each encompassing one of the two
      poly[E] domains, were expressed and tested for nucleating activity. Whereas the
      peptide encompassing the second poly[E] domain was capable of nucleating HA, the
      first domain peptide showed no activity. The conformation of the wild-type and
      mutated proteins and peptides were studied by circular dichroism and small angle
      x-ray scattering, and no secondary structure was evident. These results
      demonstrate that a sequence of at least eight contiguous glutamic acid residues
      is required for the nucleation of HA by BSP and that this nucleating "site" is
      not alpha-helical in conformation.

PMID- 12493753
TI  - Three-dimensional models of proteases involved in patterning of the Drosophila
      Embryo. Crucial role of predicted cation binding sites.
AB  - Three-dimensional models of the catalytic domains of Nudel (Ndl), Gastrulation
      Defective (Gd), Snake (Snk), and Easter (Ea), and their complexes with substrate
      suggest a possible organization of the enzyme cascade controlling the
      dorsoventral fate of the fruit fly embryo. The models predict that Gd activates
      Snk, which in turn activates Ea. Gd can be activated either autoproteolytically
      or by Ndl. The three-dimensional models of each enzyme-substrate complex in the
      cascade rationalize existing mutagenesis data and the associated phenotypes. The
      models also predict unanticipated features like a Ca(2+) binding site in Ea and a
      Na(+) binding site in Ndl and Gd. These binding sites are likely to play a
      crucial role in vivo as suggested by mutant enzymes introduced into embryos as
      mRNAs. The mutations in Gd that eliminate Na(+) binding cause an apparent
      increase in activity, whereas mutations in Ea that abrogate Ca(2+) binding result
      in complete loss of activity. A mutation in Ea predicted to introduce Na(+)
      binding results in apparently increased activity with ventralization of the
      embryo, an effect not observed with wild-type Ea mRNA.

PMID- 12493755
TI  - The main role of human thymine-DNA glycosylase is removal of thymine produced by
      deamination of 5-methylcytosine and not removal of ethenocytosine.
AB  - Metabolites of vinyl chloride react with cytosine in DNA to form 3,N(4)
      ethenocytosine. Recent studies suggest that ethenocytosine is repaired by the
      base excision repair pathway with the ethenobase being removed by thymine-DNA
      glycosylase. Here single turnover kinetics have been used to compare the excision
      of ethenocytosine by thymine-DNA glycosylase with the excision of thymine. The
      effect of flanking DNA sequence on the excision of ethenocytosine was also
      investigated. The 34-bp duplexes studied here fall into three categories.
      Ethenocytosine base-paired with guanine within a CpG site (i.e. CpG.(epsilon)C
      DNA) was by far the best substrate having a specificity constant (k(2)/K(d)) of
      25.1 x 10(6) m(-1) s(-1). The next best substrates were DNA duplexes containing
      TpG.(epsilon)C, GpG.(epsilon)C, and CpG.T. These had specificity constants 45-130
      times smaller than CpG.(epsilon)C-DNA. The worst substrates were DNA duplexes
      containing ApG.(epsilon)C and TpG.T, which had specificity constants,
      respectively, 1,600 and 7,400 times lower than CpG.(epsilon)C-DNA. DNA containing
      ethenocytosine was bound much more tightly than DNA containing a G.T mismatch.
      This is probably because thymine-DNA glycosylase can flip out ethenocytosine from
      a G.(epsilon)C base pair more easily than it can flip out thymine from a G.T
      mismatch. Because thymine-DNA glycosylase has a larger specificity constant for
      the removal of ethenocytosine, it has been suggested its primary purpose is to
      deal with ethenocytosine. However, these results showing that thymine-DNA
      glycosylase has a strong sequence preference for CpG sites in the excision of
      both thymine and ethenocytosine suggest that the main role of thymine-DNA
      glycosylase in vivo is the removal of thymine produced by deamination of 5
      methylcytosine at CpG sites.

PMID- 12493754
TI  - Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the
      midbody.
AB  - Chk2 is a protein kinase intermediary in DNA damage checkpoint pathways. DNA
      damage induces phosphorylation of Chk2 at multiple sites concomitant with
      activation. Chk2 phosphorylated at Thr-68 is found in nuclear foci at sites of
      DNA damage (1). We report here that Chk2 phosphorylated at Thr-68 and Thr-26 or
      Ser-28 is localized to centrosomes and midbodies in the absence of DNA damage. In
      a search for interactions between Chk2 and proteins with similar subcellular
      localization patterns, we found that Chk2 coimmunoprecipitates with Polo-like
      kinase 1, a regulator of chromosome segregation, mitotic entry, and mitotic exit.
      Plk1 overexpression enhances phosphorylation of Chk2 at Thr-68. Plk1
      phosphorylates recombinant Chk2 in vitro. Indirect immunofluorescence (IF)
      microscopy revealed the co-localization of Chk2 and Plk1 to centrosomes in early
      mitosis and to the midbody in late mitosis. These findings suggest lateral
      communication between the DNA damage and mitotic checkpoints.

PMID- 12493756
TI  - Genes modulated by expression of GD3 synthase in Chinese hamster ovary cells.
      Evidence that the Tis21 gene is involved in the induction of GD3 9-O-acetylation.
AB  - 9-O-Acetylation is a common sialic acid modification, expressed in a
      developmentally regulated and tissue/cell type-specific manner. The relevant 9-O
      acetyltransferase(s) have not been isolated or cloned; nor have mechanisms for
      their regulation been elucidated. We previously showed that transfection of the
      GD3 synthase (ST8Sia-I) gene into Chinese hamster ovary (CHO)-K1 cells gave
      expression of not only the disialoganglioside GD3 but also 9-O-acetyl-GD3. We now
      use differential display PCR between wild type CHO-K1 cells and clones stably
      expressing GD3 synthase (CHO-GD3 cells) to detect any increased expression of
      other genes and explore the possible induction of a 9-O-acetyltransferase. The
      four CHO mRNAs showing major up-regulation were homologous to VCAM-1, Tis21, the
      KC-protein-like protein, and a functionally unknown type II transmembrane
      protein. A moderate increase in expression of the FxC1 and SPR-1 genes was also
      seen. Interestingly, these are different from genes observed by others to be up
      regulated after transfection of GD3 synthase into a neuroblastoma cell line. We
      also isolated a CHO-GD3 mutant lacking 9-O-acetyl-GD3 following chemical
      mutagenesis (CHO-GD3-OAc(-)). Analysis of the above differential display PCR
      derived genes in these cells showed that expression of Tis21 was selectively
      reduced. Transfection of a mouse Tis21 cDNA into the CHO-GD3-OAc(-) mutant cells
      restored 9-O-acetyl-GD3 expression. Since the only major gangliosides expressed
      by CHO-GD3 cells are GD3 and 9-O-acetyl-GD3 (in addition to GM3, the predominant
      ganglioside type in wild-type CHO-K1 cells), we conclude that GD3 enhances its
      own 9-O-acetylation via induction of Tis21. This is the first known nuclear
      inducible factor for 9-O-acetylation and also the first proof that 9-O
      acetylation can be directly regulated by GD3 synthase. Finally, transfection of
      CHO-GD3-OAc(-) mutant cells with ST6Gal-I induced 9-O-acetylation specifically on
      sialylated N-glycans, in a manner similar to wild-type cells. This indicates
      separate machineries for 9-O-acetylation on alpha2-8-linked sialic acids of
      gangliosides and on alpha2-6-linked sialic acids on N-glycans.

PMID- 12493757
TI  - Mammalian translation initiation factor eIF1 functions with eIF1A and eIF3 in the
      formation of a stable 40 S preinitiation complex.
AB  - We have examined the role of the mammalian initiation factor eIF1 in the
      formation of the 40 S preinitiation complex using in vitro binding of initiator
      Met-tRNA (as Met-tRNA(i).eIF2.GTP ternary complex) to 40 S ribosomal subunits in
      the absence of mRNA. We observed that, although both eIF1A and eIF3 are essential
      to generate a stable 40 S preinitiation complex, quantitative binding of the
      ternary complex to 40 S subunits also required eIF1. The 40 S preinitiation
      complex contained, in addition to eIF3, both eIF1 and eIF1A in a 1:1
      stoichiometry with respect to the bound Met-tRNA(i). These three initiation
      factors also bind to free 40 S subunits, and the resulting complex can act as an
      acceptor of the ternary complex to form the 40 S preinitiation complex (40
      S.eIF3.eIF1.eIF1A.Met-tRNA(i).eIF2.GTP). The stable association of eIF1 with 40 S
      subunits required the presence of eIF3. In contrast, the binding of eIF1A to free
      40 S ribosomes as well as to the 40 S preinitiation complex was stabilized by the
      presence of both eIF1 and eIF3. These studies suggest that it is possible for
      eIF1 and eIF1A to bind the 40 S preinitiation complex prior to mRNA binding.

PMID- 12493758
TI  - Structure-based rational design of streptavidin mutants with pseudo-catalytic
      activity.
AB  - Introduction of enzymatic activity into proteins or other types of polymers by
      rational design is a major objective in the life sciences. To date, relatively
      low levels of enzymatic activity could be introduced into antibodies by using
      transition-state analogues of haptens. In the present study, we identify the
      structural elements that contribute to the observed hydrolytic activity in egg
      white avidin, which promote the cleavage of active biotin esters (notably
      biotinyl p-nitrophenyl ester). The latter elements were then incorporated into
      bacterial streptavidin via genetic engineering. The streptavidin molecule was
      thus converted from a protector to an enhancer of hydrolysis of biotin esters.
      The conversion was accomplished by the combined replacement of a "lid-like loop"
      (L3,4) and a leucine-to-arginine point mutation in streptavidin. Interestingly,
      neither of these elements play a direct role in the hydrolytic reaction. The
      latter features were thus shown to be responsible for enhanced substrate
      hydrolysis. This work indicates that structural and non-catalytic elements of a
      protein can be modified to promote the induced fit of a substrate for subsequent
      interaction with either a catalytic residue or water molecules. This approach
      complements the conventional design of active sites that involves direct
      modifications of catalytic residues.

PMID- 12493759
TI  - Down-regulation of Rac-1 GTPase by Estrogen.
AB  - Rac1 GTPase is essential for the activation of the NAD(P)H oxidase complex and,
      thereby, regulates the release of reactive oxygen species (ROS) in the vessel
      wall. 17 beta-estradiol (E2) inhibits vascular ROS production. To elucidate the
      underlying molecular mechanisms we investigated the potential regulation of Rac1
      by E2 in vascular smooth muscle cells. Treatment of vascular smooth muscle cells
      with angiotensin II as well as overexpression of the constitutively active mutant
      RacL61 increased ROS release as assessed by dichlorofluorescein fluorescence,
      whereas inhibition of Rac1 by Clostridium sordellii lethal toxin or
      overexpression of dominant-negative RacN17 inhibited ROS production. Treatment
      with E2 (100 nm) completely prevented angiotensin II-induced NAD(P)H oxidase
      activity and ROS production. E2 time and concentration dependently decreased
      angiotensin II-induced and basal Rac1 mRNA and protein expression as well as Rac1
      activity. Down-regulation of Rac1 expression by E2 was mediated by inhibition of
      gene transcription (nuclear run-on assays), but E2 had no effect on Rac1 mRNA
      stability. Regulation of Rac1 was mediated by estrogen receptors since co
      incubation with ICI 182.780 prevented down-regulation of Rac1. To test these
      observations in vivo, ovariectomized spontaneously hypertensive rats were treated
      with E2 or vehicle. Real-time PCR and Western blotting showed reduction of aortic
      Rac1 mRNA and protein by 32 and 58%, respectively. Furthermore, down-regulation
      of Rac1 by E2 was observed in human mononuclear cells of women with elevated E2
      levels after controlled ovarian hyperstimulation. Rac1 GTPase gene-transcription
      and activity is regulated by 17 beta-estradiol, which may be an important
      molecular mechanism contributing to the cardiovascular effects of estrogens.

PMID- 12493760
TI  - Importance of Cys, Gln, and Tyr from the transmembrane domain of human alpha 3/4
      fucosyltransferase III for its localization and sorting in the Golgi of baby
      hamster kidney cells.
AB  - Human fucosyltransferase III (EC ) (FT3wt) is localized in the Golgi of baby
      hamster kidney cells and synthesizes Lewis determinants associated with cell
      adhesion events. Replacement of the amino acid residues from the transmembrane
      domain (TM) Cys-16, Gln-23, Cys-29, and Tyr-33 by Leu (FT3np) caused a shift in
      enzyme localization to the plasma membrane. The mislocalization caused a dramatic
      decrease in the amount of biosynthetic products of FT3wt, the Lewis determinants.
      Determination of the expression levels on the surface with mutants of the enzyme,
      where one, two, or three of these residues were replaced by Leu, suggested that
      Cys from the TM was required for the localization of FT3 in the Golgi.
      Furthermore, Cys-23 and Cys-29 mediated the formation of disulfide-bonded dimers
      but not higher molecular weight oligomers. In vitro reconstitution of intra-Golgi
      transport showed that FT3wt was incorporated into coatomer protein (COP) I
      vesicles, contrary to FT3np. These data suggested that Cys, Gln, and Tyr residues
      are important for FT3wt sorting into the transport vesicles possibly due to
      interactions with other membrane proteins.

PMID- 12493761
TI  - Functional interactions between yeast translation eukaryotic elongation factor
      (eEF) 1A and eEF3.
AB  - The translation elongation machinery in fungi differs from other eukaryotes in
      its dependence upon eukaryotic elongation factor 3 (eEF3). eEF3 is essential in
      vivo and required for each cycle of the translation elongation process in vitro.
      Models predict eEF3 affects the delivery of cognate aminoacyl-tRNA, a function
      performed by eEF1A, by removing deacylated tRNA from the ribosomal Exit site. To
      dissect eEF3 function and its link to the A-site activities of eEF1A, we have
      identified a temperature-sensitive allele of the YEF3 gene. The F650S
      substitution, located between the two ATP binding cassettes, reduces both
      ribosome-dependent and intrinsic ATPase activities. In vivo this mutation
      increases sensitivity to aminoglycosidic drugs, causes a 50% reduction of total
      protein synthesis at permissive temperatures, slows run-off of polyribosomes, and
      reduces binding to eEF1A. Reciprocally, excess eEF3 confers synthetic slow
      growth, increased drug sensitivity, and reduced translation in an allele specific
      fashion with an E122K mutation in the GTP binding domain of eEF1A. In addition,
      this mutant form of eEF1A shows reduced binding of eEF3. Thus, optimal in vivo
      interactions between eEF3 and eEF1A are critical for protein synthesis.

PMID- 12493762
TI  - The acetylase activity of p300 is dispensable for MDM2 stabilization.
AB  - It has been shown that p300 binds to MDM2 and leads to down-regulation of the p53
      function. However, it remains unclear whether the acetylase activity of p300 is
      necessary for regulating MDM2 stability. In this study, we address this issue.
      First, p300 did not acetylate MDM2 in solution and in cells. Second,
      overexpression of p300 in cells increased the level of the MDM2 protein but not
      its mRNA. Similarly, the acetylase-defective p300 AT2 mutant stabilized the MDM2
      protein as well. Consistently, the deacetylase inhibitor, trichostatin A, did not
      significantly affect the half-life of the endogenous MDM2 protein, whereas p300
      enhanced the half-life of MDM2. Finally, both wild type and acetylase-defective
      mutant p300 proteins associated with MDM2 in nuclear body-like structures where
      MDM2 might be protected from proteasomal degradation. Thus, these results suggest
      that p300 appears to stabilize MDM2 by retaining this protein in a specific
      nuclear structure rather than by acetylating it.

PMID- 12493763
TI  - A candidate X-linked mental retardation gene is a component of a new family of
      histone deacetylase-containing complexes.
AB  - Eukaryotic genes are under the control of regulatory complexes acting through
      chromatin structure to control gene expression. Here we report the identification
      of a family of multiprotein corepressor complexes that function through modifying
      chromatin structure to keep genes silent. The polypeptide composition of these
      complexes has in common a core of two subunits, HDAC1,2 and BHC110, an FAD
      binding protein. A candidate X-linked mental retardation gene and the
      transcription initiation factor II-I (TFII-I) are components of a novel member of
      this family of complexes. Other subunits of these complexes include polypeptides
      associated with cancer causing chromosomal translocations. These findings not
      only delineate a novel class of multiprotein complexes involved in
      transcriptional repression but also reveal an unanticipated role for TFII-I in
      transcriptional repression.

PMID- 12493764
TI  - Thrombin stimulation of vascular adhesion molecule-1 in endothelial cells is
      mediated by protein kinase C (PKC)-delta-NF-kappa B and PKC-zeta-GATA signaling
      pathways.
AB  - We recently demonstrated that thrombin induces the expression of vascular
      adhesion molecule-1 (VCAM-1) in endothelial cells by an NF-kappaB- and GATA
      dependent mechanism. In the present study, we describe the signaling pathways
      that mediate this response. Thrombin stimulation of the VCAM-1 gene and promoter
      in human umbilical vein endothelial cells was inhibited by preincubation with the
      phosphatidylinositol 3-kinase inhibitor, LY294002, the protein kinase C (PKC)
      delta inhibitor, rottlerin, a PKC-zeta peptide inhibitor, or by overexpression of
      dominant negative (DN)-PKC-zeta. In electrophoretic mobility shift assays,
      thrombin-mediated induction of NF-kappaB p65 binding to two NF-kappaB motifs in
      the upstream promoter region of VCAM-1 was blocked by LY294002 and rottlerin,
      whereas the inducible binding of GATA-2 to a tandem GATA motif was inhibited by
      LY294002 and the PKC-zeta peptide inhibitor. In co-transfection assays, thrombin
      stimulation of a minimal promoter containing multimerized VCAM-1 NF-kappaB sites
      was inhibited by DN-PKC-delta but not DN-PKC-zeta. In contrast, thrombin-mediated
      transactivation of a minimal promoter containing tandem VCAM-1 GATA motifs was
      inhibited by DN-PKC-zeta but not DN-PKC-delta. Finally, thrombin failed to induce
      VCAM-1 expression in vascular smooth muscle cells. Taken together, these data
      suggest that the endothelial cell-specific effect of thrombin on VCAM-1
      expression involves the coordinate activity of PKC-delta-NF-kappaB and PKC-zeta
      GATA signaling pathways.

PMID- 12493765
TI  - Transcriptional repressor germ cell-less (GCL) and barrier to autointegration
      factor (BAF) compete for binding to emerin in vitro.
AB  - Emerin belongs to the "LEM domain" family of nuclear proteins, which contain a
      characteristic approximately 40-residue LEM motif. The LEM domain mediates direct
      binding to barrier to autointegration factor (BAF), a conserved 10-kDa chromatin
      protein essential for embryogenesis in Caenorhabditis elegans. In mammalian
      cells, BAF recruits emerin to chromatin during nuclear assembly. BAF also
      mediates chromatin decondensation during nuclear assembly. The LEM domain and
      central region of emerin are essential for binding to BAF and lamin A,
      respectively. However, two other conserved regions of emerin lacked ascribed
      functions, suggesting that emerin could have additional partners. We discovered
      that these "unascribed" domains of emerin mediate direct binding to a
      transcriptional repressor, germ cell-less (GCL). GCL co-immunoprecipitates with
      emerin from HeLa cells. We determined the binding affinities of emerin for GCL,
      BAF, and lamin A and analyzed their oligomeric interactions. We showed that
      emerin forms stable complexes with either lamin A plus GCL or lamin A plus BAF.
      Importantly, BAF competed with GCL for binding to emerin in vitro, predicting
      that emerin can form at least two distinct types of complexes in vivo. Loss of
      emerin causes Emery-Dreifuss muscular dystrophy, a tissue-specific inherited
      disease that affects skeletal muscles, major tendons, and the cardiac conduction
      system. Although GCL alone cannot explain the disease mechanism, our results
      strongly support gene expression models for Emery-Dreifuss muscular dystrophy by
      showing that emerin binds directly to a transcriptional repressor, GCL, and by
      suggesting that emerin-repressor complexes might be regulated by BAF. Biochemical
      roles for emerin in gene expression are discussed.

PMID- 12493766
TI  - Syndecan-4 associates with alpha-actinin.
AB  - Cell adhesion to the extracellular matrix influences many cellular functions. The
      integrin family of matrix receptors plays major roles in the formation of
      adhesions, but other proteins modulate integrin signaling. Syndecan-4, a
      transmembrane proteoglycan, cooperatively signals with integrins during the
      formation of focal adhesions. To date, a direct link between syndecan-4 and the
      cytoskeleton has remained elusive. We now demonstrate by Triton X-100 extraction
      immunoprecipitation and in vitro binding assays that the focal adhesion component
      alpha-actinin interacts with syndecan-4 in a beta-integrin-independent manner.

PMID- 12493767
TI  - Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for
      mitochondrial DNA depletion myopathy.
AB  - Thymidine kinase 2 (TK2) is a mitochondrial (mt) pyrimidine deoxynucleoside
      salvage enzyme involved in mtDNA precursor synthesis. The full-length human TK2
      cDNA was cloned and sequenced. A discrepancy at amino acid 37 within the mt
      leader sequence in the DNA compared with the determined peptide sequence was
      found. Two mutations in the human TK2 gene, His-121 to Asn and Ile-212 to Asn,
      were recently described in patients with severe mtDNA depletion myopathy (Saada,
      A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., and Elpeleg, O. (2001) Nat.
      Genet. 29, 342-344). The same mutations in TK2 were introduced, and the mutant
      enzymes, prepared in recombinant form, were shown to have similar subunit
      structure to wild type TK2. The I212N mutant showed less than 1% activity as
      compared with wild type TK2 with all deoxynucleosides. The H121N mutant enzyme
      had normal K(m) values for thymidine (dThd) and deoxycytidine (dCyd), 6 and 11
      microm, respectively, but 2- and 3-fold lower V(max) values as compared with wild
      type TK2 and markedly increased K(m) values for ATP, leading to decreased enzyme
      efficiency. Competition experiments revealed that dCyd and dThd interacted
      differently with the H121N mutant as compared with the wild type enzyme. The
      consequences of the two point mutations of TK2 and the role of TK2 in mt
      disorders are discussed.

PMID- 12493769
TI  - Developmental regulation of apolipoprotein B mRNA editing is an autonomous
      function of small intestine involving homeobox gene Cdx1.
AB  - Apolipoprotein B mRNA editing is developmentally regulated in the human and
      rodent small intestine, changing from <1% at day 14 to approximately 90% by day
      20 in the rat fetus. This regulation is coincident with the developmental
      formation of the crypt-to-villus axis functional unit, a continuous and rapidly
      renewing system involving cell generation, migration, and differentiation.
      Utilizing small intestine isografts implanted into the subcutaneous tissue of
      adult recipients, apolipoprotein B mRNA editing was developmentally up-regulated,
      parallel to that seen with an intact control. In contrast, apoB mRNA expression
      remains nearly constant in the isograft, unlike the normal intact small
      intestine. Immunohistochemical analyses demonstrated that apoB-48 protein existed
      predominantly in well differentiated enterocytes along the villus surface whereas
      apoB-100 was in the lamina propria and crypts. ApoB mRNA editing levels were very
      low in the crypt-like rat intestinal cell line, IEC-6 ( approximately 0.3%), but
      very high in well differentiated enterocytes ( approximately 91.5%). The
      expression of homeobox gene Cdx1 increased 18-fold in small intestine in vivo
      during the same time course when apoB mRNA editing increased from approximately 2
      to approximately 90%. The overexpression of Cdx1 in IEC-6 cells increased apoB
      mRNA editing over 10-fold compared with the vector control. This increase was
      associated with a significant increase of activating factor ACF, a component of
      the apoB mRNA editing complex. Taken together, these data suggest that the
      developmental regulation of apoB mRNA editing is an autonomous
      cytodifferentiation function of small intestine for which homeobox gene Cdx1 may
      play an important role.

PMID- 12493768
TI  - Follicle-stimulating hormone activates extracellular signal-regulated kinase but
      not extracellular signal-regulated kinase kinase through a 100-kDa
      phosphotyrosine phosphatase.
AB  - In this report we sought to elucidate the mechanism by which the follicle
      stimulating hormone (FSH) receptor signals to promote activation of the p42/p44
      extracellular signal-regulated protein kinases (ERKs) in granulosa cells. Results
      show that the ERK kinase MEK and upstream intermediates Raf-1, Ras, Src, and L
      type Ca(2+) channels are already partially activated in vehicle-treated cells and
      that FSH does not further activate them. This tonic stimulatory pathway appears
      to be restrained at the level of ERK by a 100-kDa phosphotyrosine phosphatase
      that associates with ERK in vehicle-treated cells and promotes dephosphorylation
      of its regulatory Tyr residue, resulting in ERK inactivation. FSH promotes the
      phosphorylation of this phosphotyrosine phosphatase and its dissociation from
      ERK, relieving ERK from inhibition and resulting in its activation by the tonic
      stimulatory pathway and consequent translocation to the nucleus. Consistent with
      this premise, FSH-stimulated ERK activation is inhibited by the cell-permeable
      protein kinase A-specific inhibitor peptide Myr-PKI as well as by inhibitors of
      MEK, Src, a Ca(2+) channel blocker, and chelation of extracellular Ca(2+). These
      results suggest that FSH stimulates ERK activity in immature granulosa cells by
      relieving an inhibition imposed by a 100-kDa phosphotyrosine phosphatase.

PMID- 12493770
TI  - RasGRP4 regulates the expression of prostaglandin D2 in human and rat mast cell
      lines.
AB  - Mast cells (MCs) are a major source of prostaglandin (PG) D(2) in connective
      tissues, and the expression of this eicosanoid has been linked to asthma and
      other inflammatory disorders. While it is known that the surface receptor c-kit
      controls PGD(2) expression in MCs by regulating the levels of a synthase that
      converts PGH(2) to PGD(2), the intracellular signaling proteins that act
      downstream of c-kit in this cyclooxygenase pathway have not been identified. We
      recently cloned a new cation-dependent, guanine nucleotide exchange
      factor/phorbol ester receptor (designated RasGRP4) that is required for the
      efficient expression of granule proteases in the human MC line HMC-1. GeneChip
      analysis of approximately 12,600 transcripts in RasGRP4(-) and RasGRP4(+) HMC-1
      cells revealed a >100-fold difference in the levels of hematopoietic PGD(2)
      synthase mRNA. No other transcript in the eicosanoid pathway was influenced by
      RasGRP4 in a comparable manner. As assessed by SDS-PAGE immunoblot analysis,
      RasGRP4(+) HMC-1 cells contained substantial amounts of PGD(2) synthase protein.
      RasGRP4(+) MCs also produced approximately 15-fold more PGD(2) than did RasGRP4(
      ) MCs when both cell populations were activated by calcium ionophore. The induced
      transcript is therefore translated, and substantial amounts of functional PGD(2)
      synthase accumulate in RasGRP4(+) MCs. In support of the conclusion that RasGRP4
      controls PGD(2) expression in MCs, inhibition of RasGRP4 expression in the rat MC
      line RBL-2H3 using a siRNA approach resulted in low levels of PGD(2) synthase
      protein.

PMID- 12493771
TI  - Processing of an antibacterial peptide from hemocyanin of the freshwater crayfish
      Pacifastacus leniusculus.
AB  - An antibacterial peptide with 16 amino acid residues was found in plasma of the
      freshwater crayfish, Pacifastacus leniusculus. This peptide, designated astacidin
      1, was purified by cation-exchange column chromatography and reverse-phase high
      performance liquid chromatography. Astacidin 1 has a broad range of antibacterial
      activity, and it inhibits growth of both Gram-positive and Gram-negative
      bacteria. The primary sequence of astacidin 1 was FKVQNQHGQVVKIFHH-COOH. The
      molecular mass was 1945.2 Da, and no carbohydrate-linked amino acid residues
      could be found by mass spectrometry. A synthetic astacidin 1 resulted in similar
      activity as the authentic astacidin 1 against Gram-positive bacteria, whereas it
      had less or no activity against Gram-negative bacteria. Three amino-terminal
      truncated synthetic peptides were made; they all showed low activity, suggesting
      that the amino-terminal part of astacidin 1 contributes to the antibacterial
      activity. The structure of astacidin 1 based on the CD results showed that it has
      a beta-sheet structure in citric acid buffer at pH 4, 6, and 8. Cloning of
      astacidin 1 shows that it is the carboxyl-terminal part of crayfish hemocyanin
      and that astacidin 1 is produced by a proteolytic cleavage from hemocyanin under
      acidic conditions. The processing and release of astacidin 1 from hemocyanin is
      enhanced when crayfish are injected with lipopolysaccharide or glucan.

PMID- 12493772
TI  - Lcb4p is a key regulator of ceramide synthesis from exogenous long chain
      sphingoid base in Saccharomyces cerevisiae.
AB  - Long chain sphingoid bases (LCBs) and their phosphates (LCBPs) are not only
      important intermediates in ceramide biosynthesis but also signaling molecules in
      the yeast, Saccharomyces cerevisiae. Their cellular levels, which control
      multiple cellular events in response to external and intrinsic signals, are
      tightly regulated by coordinated action of metabolic enzymes such as LCB kinase
      and LCBP phosphatase. However, little is known about the mechanisms by which the
      two enzymes generate biosynthetic or signaling outputs. It has been shown that
      the LCBP phosphatase, Lcb3p, is required for efficient ceramide synthesis from
      exogenous LCB. Here we present direct evidence that the major LCB kinase, Lcb4p,
      but not the minor kinase, Lcb5p, regulates synthesis of ceramide from exogenously
      added LCB. Surprisingly, our biochemical evidence suggests that the LCBP used for
      ceramide synthesis must be generated on the membrane. Our data show that Lcb4p is
      tightly associated with membranes and is localized to the endoplasmic reticulum
      where it can work in concert with Lcb3p. These results raise the conceptually
      attractive possibility that membrane-associated and cytosolic Lcb4p play distinct
      roles to differentially generate biosynthetic and signaling pools of LCBP.

PMID- 12493773
TI  - Global profiling of the cell surface proteome of cancer cells uncovers an
      abundance of proteins with chaperone function.
AB  - There is currently limited data available pertaining to the global
      characterization of the cell surface proteome. We have implemented a strategy for
      the comprehensive profiling and identification of surface membrane proteins. This
      strategy has been applied to cancer cells, including the SH-SY5Y neuroblastoma,
      the A549 lung adenocarcinoma, the LoVo colon adenocarcinoma, and the Sup-B15
      acute lymphoblastic leukemia (B cell) cell lines and ovarian tumor cells. Surface
      membrane proteins of viable, intact cells were subjected to biotinylation then
      affinity-captured and purified on monomeric avidin columns. The biotinylated
      proteins were eluted from the monomeric avidin columns as intact proteins and
      were subsequently separated by two-dimensional PAGE, transferred to
      polyvinylidene difluoride membranes, and visualized by hybridization with
      streptavidin-horseradish peroxidase. Highly reproducible, but distinct, two
      dimensional patterns consisting of several hundred biotinylated proteins were
      obtained for the different cell populations analyzed. Identification of a subset
      of biotinylated proteins among the different cell populations analyzed using
      matrix-assisted laser desorption ionization and tandem mass spectrometry
      uncovered proteins with a restricted expression pattern in some cell line(s),
      such as CD87 and the activin receptor type IIB. We also identified more widely
      expressed proteins, such as CD98, and a sushi repeat-containing protein, a member
      of the selectin family. Remarkably, a set of proteins identified as chaperone
      proteins were found to be highly abundant on the cell surface, including GRP78,
      GRP75, HSP70, HSP60, HSP54, HSP27, and protein disulfide isomerase. Comprehensive
      profiling of the cell surface proteome provides an effective approach for the
      identification of commonly occurring proteins as well as proteins with restricted
      expression patterns in this compartment.

PMID- 12493774
TI  - Nep98p is a component of the yeast spindle pole body and essential for nuclear
      division and fusion.
AB  - During the mating of yeast Saccharomyces cerevisiae, two haploid nuclei fuse to
      produce a diploid nucleus. This process requires the functions of BiP/Kar2p, a
      member of the Hsp70 family in the endoplasmic reticulum, and its partner protein,
      Jem1p. To investigate further the role of BiP and Jem1p in nuclear fusion, we
      screened for partner proteins for Jem1p by the yeast two-hybrid system and
      identified Nep98p. Nep98p is an essential integral membrane protein of the
      nuclear envelope and is enriched in the spindle pole body (SPB), the sole
      microtubule-organizing center in yeast. Temperature-sensitive nep98 mutant cells
      contain abnormal SPBs lacking the half-bridge, suggesting the essential role of
      Nep98p in the organization of the normal SPB. Additionally, nep98 mutant cells
      show defects in mitotic nuclear division and nuclear fusion during mating.
      Because Jem1p is not required for nuclear division, Nep98p probably has dual
      functions in Jem1p-dependent karyogamy and in Jem1p-independent nuclear division.

PMID- 12493775
TI  - Prefusion rearrangements resulting in fusion Peptide exposure in Semliki forest
      virus.
AB  - Semliki Forest virus (SFV), like many enveloped viruses, takes advantage of the
      low pH in the endosome to convert into a fusion-competent configuration and
      complete infection by fusion with the endosomal membrane. Unlike influenza virus,
      carrying an N-terminal fusion peptide, SFV represents a less-well understood
      fusion principle involving an endosequence fusion peptide. To explore the series
      of events leading to a fusogenic configuration of the SFV, we exposed the virus
      to successive acidification, mimicking endosomal conditions, and followed
      structural rearrangements at probed sensor surfaces. Thus revealed, the initial
      phase involves a transient appearance of a non-linear neutralizing antibody
      epitope in the fusion protein, E1. Concurrent with the disappearance of this
      epitope, a set of masked sequences in proteins E1 and E2 became exposed. When pH
      reached 6.0-5.9 the virion transformed into a configuration of enlarged diameter
      with the fusion peptide optimally exposed. Simultaneously, a partly hidden
      sequence close to the receptor binding site in E2 became fully uncovered. At this
      presumably fusogenic stage, maximally 80 fusion peptide-identifying antibody Fab
      fragments could be bound per virion, i.e. one ligand per three copies of the
      fusion protein. The phenomena observed are discussed in terms of alphavirus
      structure and reported functional domains.

PMID- 12493776
TI  - SW13 cells can transition between two distinct subtypes by switching expression
      of BRG1 and Brm genes at the post-transcriptional level.
AB  - The human adrenal carcinoma cell line, SW13, has been reported to be deficient in
      both BRG1 and Brm expression and therefore is considered to lack a functional
      SWI/SNF complex. We found that the original cell line of SW13 is composed of two
      subtypes, one that expresses neither BRG1 nor Brm (SW13(vim-)) and the another,
      which does express both (SW13(vim+)). The presence of BRG1 and Brm in SW13
      correlates completely with the cellular ability to express such genes as
      vimentin, collagenase, c-met, and CD44 that were under the control of a
      transcription factor, AP-1, which was shown previously to require a functional
      SWI/SNF complex for its transactivating activity. Transient treatment with
      inhibitors of histone deacetylase induced a stable transition of SW13(vim-) to a
      cell type indistinguishable from SW13(vim+), suggesting that these two subtypes
      are epigenetically different. Run-on analysis indicated that, unlike these four
      genes driven by AP-1, transcription of the BRG1 and Brm genes in SW13(vim-) are
      initiated at a frequency comparable with SW13(vim+). In both SW13(vim-) and
      SW13(vim+) cells, the BRG1 and Brm genes were transcribed through the entire gene
      at a similar efficiency, indicating that their expression was completely
      suppressed at the post-transcriptional level in SW13(vim-) cells. We would like
      to propose that SW13 can spontaneously transition between two subtypes by
      switching expression of BRG1 and Brm at the post-transcriptional level.

PMID- 12493777
TI  - Mechanism of Ca2+-mediated regulation of NDR protein kinase through
      autophosphorylation and phosphorylation by an upstream kinase.
AB  - NDR1 (nuclear Dbf2-related) is a serine/threonine protein kinase belonging to
      subfamily of kinases implicated in the regulation of cell division and
      morphology. Previously, we demonstrated that the activity of NDR1 is controlled
      by phosphorylation of two regulatory residues, Ser-281 and Thr-444. Moreover, we
      found that NDR1 becomes activated through a direct interaction with EF-hand
      Ca(2+)-binding proteins of the S100 family. In this work, we characterize this
      regulatory mechanism in detail. We found that NDR1 autophosphorylates in vitro
      predominantly on Ser-281 and to a lesser extent on Thr-74 and Thr-444. All of
      these residues proved to be crucial also for NDR1 activity in vivo; however, in
      contrast to Ser-281 and Thr-444, Thr-74 seems to be involved only in binding to
      S100B rather than directly regulating NDR1 activity per se. When we added
      Ca(2+)/S100B, we observed an increased autophosphorylation on Ser-281 and Thr
      444, resulting in stimulation of NDR1 activity in vitro. Using phosphospecific
      antibodies, we found that Ser-281 also becomes autophosphorylated in vivo,
      whereas Thr-444 is targeted predominantly by an as yet unidentified upstream
      kinase. Significantly, the Ca(2+)-chelating agent BAPTA-AM suppressed the
      activity and phosphorylation of NDR1 on both Ser-281 and Thr-444, and
      specifically, these effects were reversed when we added the sarcoplasmic
      endoplasmic reticulum Ca(2+) ATPase pump inhibitor thapsigargin.

PMID- 12493778
TI  - MEKK1 is required for inducible urokinase-type plasminogen activator expression.
AB  - Urokinase-type plasminogen activator (uPA) regulates the remodeling of
      extracellular matrix and controls reparative processes such as wound healing and
      liver regeneration. Here we show inducible uPA expression is controlled by MEKK1,
      a MAPK kinase kinase that regulates the ERK1/2 and JNK pathways. MEKK1 is
      activated in response to growth factors and cytoskeletal changes. We have found
      MEKK1 to be necessary for uPA up-regulation in response to treatment with phorbol
      12-myristate 13-acetate or basic fibroblast growth factor. We demonstrate that
      growth factor-treated MEKK1-deficient fibroblasts display greatly reduced uPA
      expression and activity compared with control fibroblasts. Further, we show that
      growth factor-induced uPA expression requires MEKK1-dependent MKK1 and JNK
      activity and that transfection of MEKK1 into knockout cells restores inducible
      uPA expression and activity. Importantly, disrupted expression of MEKK2, a
      related MAPK kinase kinase, had no effect on uPA activity. Therefore, we conclude
      that MEKK1 expression is required for PMA- or FGF-2-induced signals to control
      uPA expression and function.

PMID- 12493779
TI  - Immune reconstitution with antiretroviral therapies in chronic HIV-1 infection.

PMID- 12493780
TI  - Non-specific immunotherapy of HIV-1 infection: potential use of the synthetic
      immunodulator murabutide.

PMID- 12493781
TI  - The importance of efflux pumps in bacterial antibiotic resistance.

PMID- 12493782
TI  - A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus.
AB  - GG918, a synthetic inhibitor of P-glycoprotein-mediated mammalian tumour
      multidrug resistance, was found to be equipotent to reserpine in enhancing the in
      vitro activity of norfloxacin and ciprofloxacin against strains of Staphylococcus
      aureus expressing distinct efflux-related multidrug resistance pumps. Four- to
      eight-fold reductions in MICs of these fluoroquinolones were observed for SA
      1199B, a strain that overexpresses NorA (the major S. aureus multidrug
      transporter), and SA-K2068, which possesses a multidrug efflux-related pump
      distinct from NorA. Neither inhibitor potentiated the activity of newer
      fluoroquinolones such as levofloxacin or moxifloxacin by more than two-fold, and
      this effect was observed only in SA-1199B and SA-K2068. GG918 and reserpine
      exposure resulted in two- to four-fold reductions in norfloxacin and
      ciprofloxacin MICs in a fluoroquinolone-susceptible control strain and in strains
      expressing the MsrA and TetK proteins, which mediate efflux-related resistance to
      macrolides and tetracyclines, respectively, suggesting inhibition of as yet
      uncharacterized pumps for which norfloxacin and ciprofloxacin are substrates. In
      the MsrA- and TetK-expressing strains no more than a two-fold augmentation of
      erythromycin or tetracycline activity was observed with either inhibitor,
      suggesting minimal, if any, inhibitory activity against these efflux proteins.
      Using GG918 as a lead compound, a structure-activity evaluation may reveal a more
      potent and broader spectrum inhibitor of S. aureus antibiotic efflux pumps.

PMID- 12493783
TI  - Fluoroquinolone resistance in Campylobacter species from man and animals:
      detection of mutations in topoisomerase genes.
AB  - Consecutive isolates of quinolone-resistant campylobacter isolated over a 5 year
      period (1990-1995) from the faeces of patients with enteritis in Plymouth, UK,
      were examined for the epidemiology of mutations in gyrA (n = 127). In addition,
      clinical isolates and poultry isolates from Germany, The Netherlands and other
      regions of the UK collected before 1995 were examined for mutations in the
      quinolone resistance-determining region of gyrA by single-stranded conformational
      polymorphism analysis and direct sequencing of a 270 bp fragment of PCR-generated
      DNA. The majority of isolates (173/208) carried a mutation at codon 86 in gyrA
      resulting in substitution of Ile for Thr; all of these were resistant to
      ciprofloxacin (MIC > or = 2 mg/L). One isolate of Campylobacter jejuni had a
      mutation at Asp-90, and another had a double mutation at Thr-86 and Pro-104. Only
      two resistant isolates showed no mutation in gyrA. A novel gyrA sequence was
      amplified from two Campylobacter lari and one C. jejuni, which exhibited a valine
      at codon 86. Only 8/192 isolates had changes in gyrB; all were shown to relate to
      silent mutations in gyrB and presumably reflect natural polymorphisms in the
      gene.

PMID- 12493784
TI  - Identification of a cell envelope protein (MtrF) involved in hydrophobic
      antimicrobial resistance in Neisseria gonorrhoeae.
AB  - The mtrCDE-encoded efflux pump of Neisseria gonorrhoeae provides gonococci with a
      mechanism to resist structurally diverse antimicrobial hydrophobic agents (HAs).
      Strains of N. gonorrhoeae that display hypersusceptibility to HAs often contain
      mutations in the efflux pump genes, mtrCDE. Such strains frequently contain a
      phenotypically suppressed mutation in mtrR, a gene that encodes a repressor
      (MtrR) of mtrCDE gene expression, and one that would normally result in HA
      resistance. We have recently examined HA-hypersusceptible clinical isolates of
      gonococci that contain such phenotypically suppressed mtrR mutations, in order to
      determine whether genes other than mtrCDE are involved in HA resistance. These
      studies led to the discovery of a gene that we have designated mtrF, located
      downstream of the mtrR gene, that is predicted to encode a 56.1 kDa cytoplasmic
      membrane protein containing 12 transmembrane domains. Expression of mtrF was
      enhanced in a strain deficient in MtrR production, indicating that this gene,
      together with the closely linked mtrCDE operon, is subject to MtrR-dependent
      transcriptional control. Orthologues of mtrF were identified in a number of
      diverse bacteria. Except for the AbgT protein of Escherichia coli, their products
      have been identified as hypothetical proteins with unknown function(s). Genetic
      evidence is presented that MtrF is important in the expression of high-level
      detergent resistance by gonococci. We propose that MtrF acts in conjunction with
      the MtrC-MtrD-MtrE efflux pump, to confer on gonococci high-level resistance to
      certain HAs.

PMID- 12493785
TI  - Effect of extended-spectrum beta-lactamases on the susceptibility of Haemophilus
      influenzae to cephalosporins.
AB  - The extended-spectrum beta-lactamases (ESBLs) TEM-3, TEM-4 and TEM-5 were cloned
      into Haemophilus influenzae. These recombinant strains exhibited cefotaxime MICs
      of 0.5, 0.25 and 0.12 mg/L for TEM-3, -4 and -5, respectively, and the MIC of
      cefaclor was 4.0 mg/L. These MICs are higher than those of beta-lactamase
      negative strains, or those producing simple wild-type TEM-1 beta-lactamase, but
      not high enough to be categorized as resistant according to the breakpoints of
      the NCCLS. The clones were also categorized as susceptible using NCCLS disc
      diffusion methodology and interpretive criteria. This study shows that current
      NCCLS susceptibility testing methods may have difficulty in detecting ESBLs if
      they were to occur in H. influenzae.

PMID- 12493786
TI  - In vitro susceptibilities of zygomycetes to conventional and new antifungals.
AB  - In vitro susceptibilities of 36 zygomycete isolates, belonging to six genera, to
      itraconazole, posaconazole, voriconazole, terbinafine, amphotericin B and 5
      fluorocytosine were determined by using a broth microdilution adaptation of the
      National Committee for Clinical Laboratory Standards M-38P reference method. The
      influence of incubation time on MIC values, and the performance of a
      spectrophotometric method for MIC determination in comparison with the visual
      reference method, were also evaluated. Amphotericin B was active against most of
      the isolates. All the isolates were highly resistant to 5-fluorocytosine (MICs >
      256 mg/L). Voriconazole was significantly less active than the other drugs with
      an overall MIC(90) (MIC at which 90% of the isolates were inhibited) of 32 mg/L.
      In contrast, posaconazole showed good activity (MIC(90) 1 mg/L). A wide range of
      MICs, from 0.03 to > or =32 mg/L, was obtained for itraconazole and terbinafine.
      Differences in susceptibility between and within genera were noted. Rhizopus spp.
      were significantly less susceptible to itraconazole, posaconazole, terbinafine
      and amphotericin B than Absidia spp., and less susceptible than Mucor spp. to
      amphotericin B. Terbinafine appeared to be more active against Rhizopus
      microsporus than against Rhizopus oryzae (geometric mean MIC of 0.15 and 64 mg/L,
      respectively). The activity of the drugs was dependent on the incubation period.
      A significant increase in MICs was noted between 24 and 48 h of incubation. On
      the other hand, the two methods used for MIC determination (visual and
      spectrophotometric readings) showed good agreement. These results suggest that
      the zygomycetes are a heterogeneous group for antifungal susceptibility. Some of
      the conventional and new antifungals are effective in vitro; their efficacies in
      vivo remain to be determined. The spectrophotometric method appears to be a
      valuable alternative to the visual method for MIC determination for zygomycetes.

PMID- 12493787
TI  - Phenotypes of macrolide resistance of group A streptococci isolated from
      outpatients in Bavaria and susceptibility to 16 antibiotics.
AB  - The purpose of the present study was to determine the antimicrobial resistance
      among Streptococcus pyogenes in Bavaria, Germany. Five hundred and forty isolates
      of S. pyogenes were collected from patients with tonsillopharyngitis. Of these,
      425 isolates were obtained from children and 115 from adult patients. All
      isolates were tested for susceptibility to macrolides, clindamycin, penicillin
      and 10 other commonly prescribed antimicrobial agents, using broth microdilution
      tests. All isolates were fully susceptible to penicillin, amoxicillin and
      cephalosporins; 16.1% of the isolates were resistant to tetracycline. MIC(90)
      values of erythromycin, clarithromycin, azithromycin and josamycin were 16, 4, 16
      and 0.5 mg/L. The overall resistance rate of S. pyogenes to erythromycin,
      clarithromycin and azithromycin was 13.3%. All isolates resistant to erythromycin
      were also resistant to clarithromycin and azithromycin, and vice versa.
      Erythromycin resistance rates were higher in adult patients (19.1%) than in
      children (11.8%). The resistance rate to josamycin was only 1.5%, a value similar
      to that of clindamycin (1.1%). Among the 72 erythromycin-resistant isolates the M
      phenotype of macrolide resistance predominated (78%), while percentages of
      cMLS(B) (8%) and iMLS(B) (14%) phenotypes were low. Of the iMLS(B) strains (n =
      10), the majority were of the subtype C (n = 8). The M phenotype was associated
      with a low, and the iMLS(B)-C phenotype with a high, rate of resistance to
      tetracycline. Conclusively, present data point to rising macrolide resistance
      among S. pyogenes in Bavaria.

PMID- 12493788
TI  - Multicentre surveillance of antimicrobial resistance in enterococci and
      staphylococci from Colombian hospitals, 2001-2002.
AB  - Invasive isolates of staphylococci and enterococci were collected from 15
      tertiary care centres in five Colombian cities from 2001 to 2002. A total of 597
      isolates were available for analysis. Identification was confirmed by both
      automated methods and multiplex PCR assays in a central laboratory.
      Staphylococcus aureus and coagulase-negative staphylococci (CoNS) corresponded to
      49.6% and 29.6% of isolates, respectively, and 20.8% were identified as
      enterococci. MICs of ampicillin, ciprofloxacin, chloramphenicol, erythromycin,
      gentamicin, linezolid, oxacillin, rifampicin, teicoplanin, tetracycline,
      trimethoprim/sulfamethoxazole (SXT) and vancomycin were determined using an agar
      dilution method as appropriate. Screening for vancomycin-resistant S. aureus was
      also carried out on brain-heart infusion agar plates supplemented with
      vancomycin. The presence of mecA and van genes was investigated in methicillin
      resistant staphylococci and glycopeptide-resistant enterococci (GRE),
      respectively. All staphylococci were susceptible to vancomycin, teicoplanin and
      linezolid. No VISA isolates were found. In S. aureus and CoNS, the lowest rates
      of resistance were found for SXT (7.4%) and chloramphenicol (10.7%),
      respectively. Resistance to oxacillin in S. aureus and CoNS was 52% and 73%,
      respectively. The mecA gene was detected in 97.5% of methicillin-resistant S.
      aureus isolates. In enterococci, resistance to glycopeptides was 9.7%: vanA
      (58.3%) and vanB (41.7%) genes were found. Pulsed-field gel electrophoresis
      indicated that the GRE isolates were closely related. Rates of resistance to
      ampicillin, ciprofloxacin, chloramphenicol, rifampicin and high levels of
      gentamicin and streptomycin were 9.7%, 27.4%, 8.9%, 43%, 17% and 28.2%,
      respectively. All enterococci were susceptible to linezolid.

PMID- 12493789
TI  - An international survey of the antimicrobial susceptibility of pathogens from
      uncomplicated urinary tract infections: the ECO.SENS Project.
AB  - The ECO.SENS study is the first international survey to investigate the
      prevalence and susceptibility of pathogens causing community-acquired acute
      uncomplicated urinary tract infections (UTIs). Midstream urine samples were taken
      for culture and for testing for the presence of leucocytes from 4734 women not
      older than 65 years presenting with symptoms of acute UTI at 252 community health
      care centres in 17 countries. Recognized urinary tract pathogens were identified
      and the susceptibility to 12 antimicrobials determined. Pathogens were present in
      3278 (69.2%) patients, Escherichia coli accounting for 77.0% of isolates. In E.
      coli, 42% of the isolates were resistant to one or more of the 12 antimicrobial
      drugs investigated. Resistance was most common to ampicillin (29.8%) and
      sulfamethoxazole (29.1%), followed by trimethoprim (14.8%),
      trimethoprim/sulfamethoxazole (14.1%) and nalidixic acid (5.4%). Resistance in E.
      coli to co-amoxiclav, mecillinam, cefadroxil, nitrofurantoin, fosfomycin,
      gentamicin and ciprofloxacin was <3%. However, co-amoxiclav resistance was
      apparent in Portugal (9.3%) as was resistance to the quinolones, nalidixic acid
      and ciprofloxacin, in Portugal (11.6% and 5.8%, respectively) and Spain (26.7%
      and 14.7%, respectively). Overall, Proteus mirabilis were less resistant to
      ampicillin (16.1%) and more resistant to trimethoprim (25.5%) than E. coli,
      whereas Klebsiella spp. were more resistant to ampicillin (83.5%) and fosfomycin
      (56.7%). 'Other Enterobacteriaceae' were more resistant to the broad spectrum
      beta-lactams (ampicillin 45.9%, co-amoxiclav 21.3% and cefadroxil 24.6%),
      nitrofurantoin (40.2%) and fosfomycin (15.6%). In Staphylococcus saprophyticus
      resistance development was rare. Overall, antimicrobial resistance was lowest in
      the Nordic countries and Austria and highest in Portugal and Spain.

PMID- 12493790
TI  - A comparison of antibiotic regimens in the treatment of acute melioidosis in a
      mouse model.
AB  - Melioidosis is caused by the Gram-negative bacillus Burkholderia pseudomallei.
      Most clinical reports of disease are from south-east Asia and northern Australia.
      The organism is intrinsically resistant to most commonly available antibiotics.
      Standard therapy includes ceftazidime either alone or in combination with co
      trimoxazole. The clinical advantage in adding co-trimoxazole has never been
      determined; nor has the activity of newer, fourth-generation cephalosporins, such
      as cefepime, been studied in the treatment of this condition. BALB/c mice have
      been shown to represent an animal model of melioidosis. This animal model was
      used in this study to compare the efficacy of ceftazidime and cefepime alone or
      with co-trimoxazole, in the therapy of melioidosis. Antibiotic levels in the mice
      were determined by HPLC, and dosing was modified to keep plasma antibiotic levels
      at or above the MIC for the organism-antibiotic combination for a significant
      part of a 12 h period. Bacterial load, as determined by splenic counts, showed
      that ceftazidime in combination with co-trimoxazole was the most effective
      therapeutic option. The animal model described in this study can be used as a
      preliminary evaluation of therapeutic options for melioidosis.

PMID- 12493791
TI  - Efficacy of liposome-encapsulated ciprofloxacin compared with ciprofloxacin and
      ceftriaxone in a rat model of pneumococcal pneumonia.
AB  - Encapsulation of ciprofloxacin in sterically stabilized liposomes results in a
      prolonged circulation time and improved pharmacokinetics. Liposome-encapsulated
      ciprofloxacin was compared with conventional ciprofloxacin and ceftriaxone in a
      rat model of pneumococcal pneumonia. Male Sprague-Dawley rats were infected
      transtracheally with type 3 Streptococcus pneumoniae and then treated with
      intravenous ceftriaxone (100 mg/kg), ciprofloxacin (40 or 80 mg/kg) or liposomal
      ciprofloxacin (40 or 80 mg/kg) administered once or twice daily for 3 days. White
      blood counts, development of bacteraemia and mortality were measured for 10 days.
      Antibiotic concentrations in serum, lung lavage fluid and white blood cells
      recovered from lung lavage fluid were determined. Liposomal ciprofloxacin
      concentrations were significantly higher in serum and lavage fluid compared with
      conventional ciprofloxacin, resulting in greater area under the serum
      concentration-time curve and maximum serum concentration. Despite these higher
      concentrations, survival rates were similar between groups treated with
      equivalent doses of liposomal ciprofloxacin versus ciprofloxacin. When
      antibiotics were given once daily, ceftriaxone was more effective than either
      form of ciprofloxacin.

PMID- 12493792
TI  - Absorption, pharmacokinetics and excretion of levovirin in rats, dogs and
      cynomolgus monkeys.
AB  - The absorption, pharmacokinetics and excretion of levovirin were studied in
      Sprague-Dawley rats (30 mg/kg) and Beagle dogs (30 mg/kg) following intravenous
      (iv) and oral administration of [(3)H]levovirin, and in Cynomolgus monkeys
      following iv and oral administration of [(14)C]levovirin. Oral absorption was
      31.3% in rats, 67.3% in dogs and 17.5% in monkeys, and the bioavailability was
      29.3% in rats, 51.3% in dogs and 18.4% in monkeys. After iv administration, the
      elimination half-life (t(1/2)) was 1.47 h in rats, 3.70 h in dogs and 3.50 h in
      monkeys. The total body clearance was 8.24, 2.96 and 2.58 mL/min per kg,
      respectively, in rats, dogs and monkeys and the apparent volume of distribution
      was 0.79, 0.95 and 0.65 L/kg. No metabolite was detected in plasma or urine of
      rats, dogs or monkeys, indicating negligible metabolism of levovirin in these
      animals. Excretion of total radioactivity in urine after oral dosing accounted
      for 15.4% of the administered dose in rats, 49.9% in dogs and 21.4% in monkeys.
      Biliary excretion did not play a significant role in the elimination of
      levovirin.

PMID- 12493793
TI  - Pharmacokinetic aspects of levofloxacin 500 mg once daily during sequential
      intravenous/oral therapy in patients with lower respiratory tract infections.
AB  - Levofloxacin is considered an effective antibiotic in the treatment of community
      acquired lower respiratory tract infections (LRTIs). A study was carried out on
      17 in-patients to assess the pharmacokinetics of a 500 mg once-daily switch
      intravenous (i.v.)/oral regimen of levofloxacin in the treatment of LRTI
      patients. Blood samples were collected under steady-state conditions at
      appropriate intervals. Levofloxacin plasma concentrations were analysed by means
      of HPLC and pharmacokinetic parameters were estimated using the WinNonlin
      pharmacokinetic software package. A lower clearance of levofloxacin (<2
      mL/min/kg), conditioning both a longer elimination half-life (approximately 9 h)
      and a larger AUC(0-tau) (approximately 80 mg/L x h), was observed for both routes
      in our patients than in healthy volunteers. These differences may be explained
      considering that levofloxacin is excreted mainly as unchanged drug by the renal
      route, and most of our patients (71%) were very elderly subjects whose renal
      function physiologically declines with age. The almost complete (> or =99%)
      absolute oral bioavailability suggests that a comparable exposure to the iv
      regimen may be achieved after oral administration. The overall clinical success
      rate was 94.1%.

PMID- 12493794
TI  - Emergence of penicillin resistance among Fusobacterium nucleatum populations of
      commensal oral flora during early childhood.
AB  - Penicillin resistance due to beta-lactamase production is surprisingly common
      among oral bacteria in childhood. Fusobacterium nucleatum, a Gram-negative
      anaerobic bacillus, is a member of the developing oral commensal flora. As part
      of the investigation on the emergence of oral bacterial resistance, the aim of
      the present study was to examine longitudinally the penicillin resistance among
      salivary F. nucleatum populations as related to age, day care attendance and
      sibling history, and exposure to antimicrobial agents. Altogether 1492 F.
      nucleatum isolates from saliva of 44 healthy infants followed at a study clinic
      at 2, 6, 12, 18 and 24 months of age were tested for beta-lactamase production.
      Furthermore, the 276 beta-lactamase-positive isolates were examined for their in
      vitro susceptibility to penicillin G by the NCCLS-approved agar dilution method.
      Statistical analysis of the associations between penicillin-resistant isolates
      and infants' age, day care attendance, number of siblings and their ear
      infections, and exposure to antimicrobial agents was performed by SPSS Windows
      Version 10. The prevalence of infants harbouring beta-lactamase-producing F.
      nucleatum strains increased from 2% to 49% during the follow-up time. In nearly
      all cases beta-lactamase-producing F. nucleatum isolates were found
      simultaneously with beta-lactamase-negative isolates. Most beta-lactamase
      producing isolates (80%) showed an MIC of > or =8 mg/L. In conclusion, the
      prevalence of infants harbouring penicillin-resistant F. nucleatum due to beta
      lactamase production increased with age and usage of antimicrobial agents during
      the first year of life.

PMID- 12493795
TI  - Antibacterial effect of beta-thujaplicin on staphylococci isolated from atopic
      dermatitis: relationship between changes in the number of viable bacterial cells
      and clinical improvement in an eczematous lesion of atopic dermatitis.
AB  - Beta-thujaplicin (hinokitiol) is a tropolone-related compound purified from the
      wood of Chamaecyparis obtusa, SIEB: et Zucc. and Thuja plicata D. Don. All
      Staphylococcus aureus isolates were inhibited by beta-thujaplicin with MICs of
      1.56-3.13 mg/L. However, a paradoxical zone phenomenon occurred, with each
      isolate producing regrowth at higher beta-thujaplicin concentrations. Other
      antimicrobial agents showed a wide range of MICs. The combination of beta
      thujaplicin and zinc oxide inhibited the paradoxical zone phenomenon, and
      enhanced killing activity against clinically isolated staphylococci. Large
      numbers of viable bacterial cells, especially S. aureus cells, were detected in
      the skin surface of atopic dermatitis, in comparison with those in healthy
      volunteers. The number of cells increased as the severity of the skin condition
      worsened. Topical application of beta-thujaplicin resulted in a reduction in the
      number of bacterial cells on the skin surface, and an improvement in skin
      condition after treatment. The results of this study suggest that the degree of
      reduction in the number of viable bacterial cells in an eczematous lesion of
      atopic dermatitis is related to the degree of improvement in skin condition.

PMID- 12493796
TI  - Early administration of oral oseltamivir increases the benefits of influenza
      treatment.
AB  - Our objective was to evaluate the benefit of early treatment of influenza illness
      using oral oseltamivir. This open-label, multicentre international study
      investigated the relationship between the interval from illness onset to first
      dose (time-to-treatment) and illness duration in the intent-to-treat infected
      population using accelerated failure time (AFT) modelling. A total of 1426
      patients (12-70 years) presenting within 48 h of the onset of influenza symptoms
      were treated with oseltamivir 75 mg twice a day for 5 days during the 1999-2000
      influenza season; 958 (67%) had laboratory-confirmed influenza virus infection.
      Earlier intervention was associated with shorter illness duration (P < 0.0001).
      Initiation of therapy within the first 12 h after fever onset reduced the total
      median illness duration by 74.6 h (3.1 days; 41%) more than intervention at 48 h.
      Intermediate interventions reduced the illness proportionately compared with 48
      h. In addition, the earlier administration of oseltamivir further reduced the
      duration of fever, severity of symptoms and the times to return to baseline
      activity and health scores. Oseltamivir was well tolerated. The most common
      adverse events were nausea and vomiting, which were transient and generally
      occurred only with first dosing. When oseltamivir was taken with food, the
      tolerability was enhanced. The overall discontinuation rate was low (1.8%). In
      conclusion, the IMPACT study demonstrated that earlier initiation of oral
      oseltamivir therapy increased its therapeutic effects, which were seen at every
      time point of intervention and were progressive. Thus, early presentation,
      diagnosis and treatment of patients with influenza maximized the benefits of
      oseltamivir therapy.

PMID- 12493797
TI  - Acquired macrolide resistance genes and the 1 bp deletion in the mtrR promoter in
      Neisseria gonorrhoeae.
AB  - The presence of macrolide-lincosamide-streptogramin B resistance genes erm(B),
      erm(C) and erm(F), the macrolide resistance mef(A) gene, and the DNA sequence of
      a 13 bp repeat in the promoter region of the mtrR gene, were determined in 62
      Neisseria gonorrhoeae isolates collected between 1992 and 1999 in Seattle,
      Washington, USA. Eleven isolates with erythromycin and azithromycin MICs of < or
      =0.06 mg/L, had no acquired genes or deletions in the 13 bp repeat region. Among
      44 isolates with erythromycin MICs 1.0-16.0 mg/L, and azithromycin MICs 0.06-4.0
      mg/L, 16 carried the 1 bp deletion in the mtrR promoter region alone, nine
      carried one or more of the four acquired macrolide resistance genes alone, and 14
      carried both acquired macrolide resistance genes plus the 1 bp deletion in the
      mtrR promoter region. Three isolates with erythromycin MICs > or = 8 mg/L, and
      azithromycin MICs of 4.0 mg/L, carried only erm genes. Five isolates with MICs of
      1-2 mg/L did not carry the 1 bp deletion, or any of the acquired resistance genes
      examined. Our data suggest that the 1 bp deletion in the mtrR promoter region is
      not found in all erythromycin-resistant (MIC > or = 1.0 mg/L) N. gonorrhoeae.

PMID- 12493798
TI  - Comparison of levels of HIV-1 resistance to protease inhibitors by recombinant
      versus conventional virus phenotypic assay and two genotypic interpretation
      procedures in treatment-naive and HAART-experienced HIV-infected patients.
AB  - OBJECTIVES: To compare genotypic and phenotypic HIV-1 drug resistance assays.
      METHODS: Protease inhibitor (PI) susceptibility was phenotypically analysed in
      HIV-1 isolates and recombinant viruses expressing proteases from viral isolates.
      Two genotypic interpretation methods were carried out in parallel. RESULTS:
      Entirely concordant resistance levels were shown in 5/10 (50%) highly active anti
      retroviral therapy (HAART)-experienced patients, whereas minor discrepancies were
      observed in the remaining five patients. CONCLUSIONS: The four assays provide
      comparable results. The recombinant virus phenotypic assay may provide the most
      accurate evaluation of resistance; however, genotypic interpretation procedures
      are helpful for daily therapeutic decisions.

PMID- 12493799
TI  - Characteristics of clinical Helicobacter pylori strains from Ecuador.
AB  - In Ecuador, Helicobacter pylori infections are highly prevalent. A total of 42 H.
      pylori clinical isolates from 86 patients attending the outpatient clinic of the
      gastroenterology department of the university hospital of Guayaquil in Ecuador
      were characterized. Their susceptibility, and cagA and vacA status were
      determined. Resistance to metronidazole and clarithromycin was found in 80.9% and
      9.5% of strains, respectively. Neither amoxicillin- nor tetracycline-resistant
      strains were found. The most prevalent genotype was the cagA(+), vacA s1b,m1
      type. This genotype was associated with gastric cancer and peptic ulcer. Typing
      by random amplified polymorphic DNA showed no genetic relationship among the
      strains.

PMID- 12493800
TI  - Activities of 13 quinolones by three susceptibility testing methods against a
      collection of Haemophilus influenzae isolates with different levels of
      susceptibility to ciprofloxacin: evidence for cross-resistance.
AB  - The activities of nalidixic acid, ciprofloxacin, norfloxacin, ofloxacin,
      pefloxacin, flerofloxacin, sparfloxacin, grepafloxacin, gatifloxacin,
      moxifloxacin, trovafloxacin, levofloxacin and clinafloxacin against a panel of
      Haemophilus influenzae strains were assessed by three susceptibility testing
      methods: Etest, agar dilution and the reference broth microdilution method using
      Haemophilus test medium (HTM) in all cases. The panel included 62 clinical and
      two reference H. influenzae strains; 32 had decreased susceptibility to
      ciprofloxacin (MIC > or = 0.12 mg/L) and 30 were susceptible to this antibiotic
      (MIC < or = 0.06 mg/L). Both Etest and HTM agar dilution results (r = 0.96;
      86.61% and 82.1% of MICs within + one log(2), respectively) correlated well with
      the reference microdilution method. The MIC(90) of ciprofloxacin was 4.0 mg/L
      (range 0.007-32.0 mg/L). Trovafloxacin activity was similar to that of
      ciprofloxacin but sparfloxacin, grepafloxacin, ofloxacin, pefloxacin and
      flerofloxacin activities were higher (with MIC values one log(2) dilution lower
      than ciprofloxacin). The least active were norfloxacin (MIC(90) 16 mg/L) and
      nalidixic acid (MIC(90) 128 mg/L). Levofloxacin and moxifloxacin were more active
      than ciprofloxacin (MIC(90) 2 mg/L); clinafloxacin and gatifloxacin were the most
      active with an MIC(90) of 0.25 mg/L. Cross-susceptibility among all quinolones
      was observed (r > 0.9). Resistance to ciprofloxacin was associated with a similar
      magnitude of activity loss to other new and old quinolones. Ciprofloxacin MIC
      determination should be sufficient to detect the decreased susceptibility to the
      whole group of quinolones.

PMID- 12493801
TI  - Antibiotic resistance of Neisseria gonorrhoeae in Spain: trends over the last two
      decades.
AB  - In vitro activities of six antimicrobial agents against 2966 strains of Neisseria
      gonorrhoeae, isolated in Spain between 1983 and 2001, were determined. The
      percentages of intermediately susceptible and resistant isolates to penicillin
      (MIC > or = 0.12 mg/L) and tetracycline (MIC > or = 0.5 mg/L) were very high over
      the period of study. Strains intermediately susceptible to cefoxitin were
      identified at a variable percentage during the study. All N. gonorrhoeae isolates
      were susceptible to spectinomycin and ceftriaxone. Recently, resistance to
      ciprofloxacin has emerged.

PMID- 12493802
TI  - Comparative spectrum and activity of NVP-PDF386 (VRC4887), a new peptide
      deformylase inhibitor.
AB  - The antibacterial activity of NVP-PDF386 (VRC4887), a novel peptide deformylase
      (PDF) inhibitor, was tested against over 1000 recent clinical isolates collected
      during 2001 and 2002. The MIC(50/90) (mg/L) results for NVP-PDF386 (VRC4887)
      were: Staphylococcus aureus (SA) 0.5/1, coagulase-negative staphylococci (CoNS)
      0.5/1, Streptococcus pneumoniae 0.25/0.5, other streptococci 0.25/0.5,
      enterococci 1/2, Moraxella catarrhalis 0.25/0.25, Haemophilus influenzae 8/32 and
      Enterobacteriaceae or non-fermentative Gram-negative bacilli >32/>32 mg/L. No
      differences in NVP-PDF386/(VRC4887) MIC distributions were observed between
      methicillin-resistant (MR) S. aureus and methicillin-susceptible (MS) S. aureus,
      MR-CoNS and MS-CoNS, penicillin-susceptible and non-susceptible streptococci, and
      macrolide-susceptible and -resistant strains. The potency of NVP-PDF386 (VRC4887)
      compared favourably with those of control compounds, including glycopeptides,
      oxazolidinones, a streptogramin combination and other agents with activity
      focused against Gram-positive cocci.

PMID- 12493803
TI  - Antifungal activity of the echinocandin anidulafungin (VER002, LY-303366) against
      yeast pathogens: a comparative study with M27-A microdilution method.
AB  - This study further evaluated the in vitro activity of anidulafungin (VER002,
      Versicor Inc.) (LY303366) against 460 clinical yeast isolates. MICs of
      anidulafungin, fluconazole and itraconazole were determined by following the
      NCCLS M27-A guidelines. Minimum fungicidal concentrations (MFCs) of anidulafungin
      were determined for 230 isolates of Candida spp. The activity of anidulafungin in
      vitro was significantly superior (P < 0.05) to those of itraconazole and
      fluconazole against Candida albicans, Candida tropicalis, Candida glabrata and
      Candida krusei, but anidulafungin was less active for Candida famata and Candida
      parapsilosis. The differences were not significant for the other species
      evaluated.

PMID- 12493804
TI  - In vitro and in vivo anticryptococcal activities of a new pyrazolo-isothiazole
      derivative.
AB  - We investigated the activity of a pyrazolo-isothiazole derivative (G8) against
      Cryptococcus neoformans. A first screening test showed that G8 at 10 mg/L
      inhibited the growth of 14 of 15 clinical isolates tested. Killing experiments
      showed that fungicidal activity was achieved after 8 h of treatment with G8 at
      concentrations > or =10 mg/L. In a murine model of systemic cryptococcosis, G8
      was effective at prolonging survival compared with the controls. Our data
      indicate that this new derivative has a potential therapeutic role in infections
      caused by C. neoformans.

PMID- 12493806
TI  - Identification of class 1 integrons-associated gene cassettes in Escherichia coli
      isolated from Varanus spp. in Indonesia.

PMID- 12493807
TI  - Mutations in gyrA and parC associated with resistance to fluoroquinolones in
      epidemiologically defined clinical strains of Acinetobacter baumannii.

PMID- 12493805
TI  - Immunovirological outcomes in 70 HIV-1-infected patients who switched to
      lopinavir/ritonavir after failing at least one protease inhibitor-containing
      regimen: a retrospective cohort study.
AB  - The immunovirological outcome of lopinavir/ritonavir was evaluated in 70
      antiretroviral-experienced HIV patients; at baseline, median CD4+ cell count was
      218 cells/mm(3) and median plasma viraemia 4.58 log(10) copies/mL. After 12
      months, we observed an increase in CD4+ cell count to 322 cells/mm(3) (P =
      0.0001) and a decrease in plasma viraemia to 2.35 log(10) copies/mL (P = 0.0001).
      Four patients discontinued lopinavir/ritonavir during observation. Among
      metabolic parameters, only triglyceride concentrations increased during treatment
      (P = 0.02). Twenty-six patients had a genotypic resistance test at baseline; four
      had > or =6 mutations known to reduce susceptibility to lopinavir/ritonavir.
      Undetectable plasma viraemia was obtained only in patients with < or =5 mutations
      (61.9%).

PMID- 12493808
TI  - Resistance phenotypes and genotypes of multiresistant Salmonella enterica subsp.
      enterica serovar Typhimurium var. Copenhagen isolates from animal sources.

PMID- 12493809
TI  - Adding 2% glucose to culture media does not influence the activity of caspofungin
      against Candida species.

PMID- 12493810
TI  - The presence of ermB in Streptococcus pneumoniae has no influence on AZD2563 MIC
      values.

PMID- 12493811
TI  - Susceptibility of MRSA to triclosan.

PMID- 12493812
TI  - Linezolid resistance in clinical isolates of Staphylococcus aureus.

PMID- 12493813
TI  - Activity of gemifloxacin against invasive and multi-resistant Streptococcus
      pneumoniae isolates collected in the UK.

PMID- 12493814
TI  - Emergence of gonococcal strains with resistance to azithromycin in Spain.

PMID- 12493815
TI  - Antimicrobial resistance of Neisseria gonorrhoeae in the municipality of Moron,
      Cuba: emergence of isolates with intermediate resistance to fluoroquinolones.

PMID- 12493816
TI  - Antimicrobial resistance among uropathogens that cause community-acquired urinary
      tract infections in Bangui, Central African Republic.

PMID- 12493817
TI  - An outbreak of a CTX-M-type beta-lactamase-producing Klebsiella pneumoniae: the
      importance of using cefpodoxime to detect extended-spectrum beta-lactamases.

PMID- 12493818
TI  - Activity of faropenem, a new furanem, against European respiratory pathogens
      collected during 2000-2001: a comparison with other beta-lactam agents.

PMID- 12493819
TI  - Impact of AUC/MIC ratios on the pharmacodynamics of the des-F(6) quinolone
      garenoxacin (BMS-284756) is similar to other fluoroquinolones.

PMID- 12493820
TI  - Disseminated oxacillin-resistant Staphylococcus aureus infection responsive to
      vancomycin and quinupristin-dalfopristin combination therapy.

PMID- 12493821
TI  - Production of alpha 1,3-galactosyltransferase-deficient pigs.
AB  - The enzyme alpha1,3-galactosyltransferase (alpha1,3GT or GGTA1) synthesizes
      alpha1,3-galactose (alpha1,3Gal) epitopes (Galalpha1,3Galbeta1,4GlcNAc-R), which
      are the major xenoantigens causing hyperacute rejection in pig-to-human
      xenotransplantation. Complete removal of alpha1,3Gal from pig organs is the
      critical step toward the success of xenotransplantation. We reported earlier the
      targeted disruption of one allele of the alpha1,3GT gene in cloned pigs. A
      selection procedure based on a bacterial toxin was used to select for cells in
      which the second allele of the gene was knocked out. Sequencing analysis
      demonstrated that knockout of the second allele of the alpha1,3GT gene was caused
      by a T-to-G single point mutation at the second base of exon 9, which resulted in
      inactivation of the alpha1,3GT protein. Four healthy alpha1,3GT double-knockout
      female piglets were produced by three consecutive rounds of cloning. The piglets
      carrying a point mutation in the alpha1,3GT gene hold significant value, as they
      would allow production of alpha1,3Gal-deficient pigs free of antibiotic
      resistance genes and thus have the potential to make a safer product for human
      use.

PMID- 12493822
TI  - RacA, a bacterial protein that anchors chromosomes to the cell poles.
AB  - Eukaryotic chromosomes are anchored to a spindle apparatus during mitosis, but no
      such structure is known during chromosome segregation in bacteria. When sister
      chromosomes are segregated during sporulation in Bacillus subtilis, the
      replication origin regions migrate to opposite poles of the cell. If and how
      origin regions are fastened at the poles has not been determined. Here we
      describe a developmental protein, RacA, that acts as a bridge between the origin
      region and the cell poles. We propose that RacA assembles into an adhesive patch
      at a centromere-like element near the origin, causing chromosomes to stick at the
      poles.

PMID- 12493823
TI  - Weak alignment offers new NMR opportunities to study protein structure and
      dynamics.
AB  - Protein solution nuclear magnetic resonance (NMR) can be conducted in a slightly
      anisotropic environment, where the orientational distribution of the proteins is
      no longer random. In such an environment, the large one-bond internuclear dipolar
      interactions no longer average to zero and report on the average orientation of
      the corresponding vectors relative to the magnetic field. The desired very weak
      ordering, on the order of 10(-3), can be induced conveniently by the use of
      aqueous nematic liquid crystalline suspensions or by anisotropically compressed
      hydrogels. The resulting residual dipolar interactions are scaled down by three
      orders of magnitude relative to their static values, but nevertheless can be
      measured at high accuracy. They are very precise reporters on the average
      orientation of bonds relative to the molecular alignment frame, and they can be
      used in a variety of ways to enrich our understanding of protein structure and
      function. Applications to date have focused primarily on validation of
      structures, determined by NMR, X-ray crystallography, or homology modeling, and
      on refinement of structures determined by conventional NMR approaches. Although
      de novo structure determination on the basis of dipolar couplings suffers from a
      severe multiple minimum problem, related to the degeneracy of dipolar coupling
      relative to inversion of the internuclear vector, a number of approaches can
      address this problem and potentially can accelerate the NMR structure
      determination process considerably. In favorable cases, where large numbers of
      dipolar couplings can be measured, inconsistency between measured values can
      report on internal motions.

PMID- 12493824
TI  - The topomer search model: A simple, quantitative theory of two-state protein
      folding kinetics.
AB  - Most small, single-domain proteins fold with the uncomplicated, single
      exponential kinetics expected for diffusion on a smooth energy landscape. Despite
      this energetic smoothness, the folding rates of these two-state proteins span a
      remarkable million-fold range. Here, we review the evidence in favor of a simple,
      mechanistic description, the topomer search model, which quantitatively accounts
      for the broad scope of observed two-state folding rates. The model, which
      stipulates that the search for those unfolded conformations with a grossly
      correct topology is the rate-limiting step in folding, fits observed rates with a
      correlation coefficient of approximately 0.9 using just two free parameters. The
      fitted values of these parameters, the pre-exponential attempt frequency and a
      measure of the difficulty of ordering an unfolded chain, are consistent with
      previously reported experimental constraints. These results suggest that the
      topomer search process may dominate the relative barrier heights of two-state
      protein-folding reactions.

PMID- 12493825
TI  - A structural basis for the mechanism of aspartate-beta-semialdehyde dehydrogenase
      from Vibrio cholerae.
AB  - L-Aspartate-beta-semialdehyde dehydrogenase (ASADH) catalyzes the reductive
      dephosphorylation of beta-aspartyl phosphate to L-aspartate-beta-semialdehyde in
      the aspartate biosynthetic pathway of plants and micro-organisms. The aspartate
      pathway produces fully one-quarter of the naturally occurring amino acids, but is
      not found in humans or other eukaryotic organisms, making ASADH an attractive
      target for the development of new antibacterial, fungicidal, or herbicidal
      compounds. We have determined the structure of ASADH from Vibrio cholerae in two
      states; the apoenzyme and a complex with NADP, and a covalently bound active site
      inhibitor, S-methyl-L-cysteine sulfoxide. Upon binding the inhibitor undergoes an
      enzyme-catalyzed reductive demethylation leading to a covalently bound cysteine
      that is observed in the complex structure. The enzyme is a functional homodimer,
      with extensive intersubunit contacts and a symmetrical 4-amino acid bridge
      linking the active site residues in adjacent subunits that could serve as a
      communication channel. The active site is essentially preformed, with minimal
      differences in active site conformation in the apoenzyme relative to the ternary
      inhibitor complex. The conformational changes that do occur result primarily from
      NADP binding, and are localized to the repositioning of two surface loops located
      on the rim at opposite sides of the NADP cleft.

PMID- 12493826
TI  - Homology modeling and molecular dynamics simulations of the N-terminal domain of
      wheat high molecular weight glutenin subunit 10.
AB  - High molecular weight glutenin subunits (HMW-GS) are of a particular interest
      because of their biomechanical properties, which are important in many food
      systems such as breadmaking. Using fold-recognition techniques, we identified a
      fold compatible with the N-terminal domain of HMW-GS Dy10. This fold corresponds
      to the one adopted by proteins belonging to the cereal inhibitor family. Starting
      from three known protein structures of this family as templates, we built three
      models for the N-terminal domain of HMW-GS Dy10. We analyzed these models, and we
      propose a number of hypotheses regarding the N-terminal domain properties that
      can be tested experimentally. In particular, we discuss two possible ways of
      interaction between the N-terminal domains of the y-type HMW glutenin subunits.
      The first way consists in the creation of interchain disulfide bridges. According
      to our models, we propose two plausible scenarios: (1) the existence of an
      intrachain disulfide bridge between cysteines 22 and 44, leaving the three other
      cysteines free of engaging in intermolecular bonds; and (2) the creation of two
      intrachain disulfide bridges (involving cysteines 22-44 and cysteines 10-55),
      leaving a single cysteine (45) for creating an intermolecular disulfide bridge.
      We discuss these scenarios in relation to contradictory experimental results. The
      second way, although less likely, is nevertheless worth considering. There might
      exist a possibility for the N-terminal domain of Dy10, Nt-Dy10, to create
      oligomers, because homologous cereal inhibitor proteins are known to exist as
      monomers, homodimers, and heterooligomers. We also discuss, in relation to the
      function of the cereal inhibitor proteins, the possibility that this N-terminal
      domain has retained similar inhibitory functions.

PMID- 12493828
TI  - NMR detection of multiple transitions to low-populated states in azurin.
AB  - Transitions to conformational states with very low populations were detected for
      the reduced blue copper protein azurin from Pseudomonas aeruginosa by applying
      constant relaxation time CPMG measurements to the backbone (15)N nuclei at three
      magnetic fields (11.7, 14.1, and 18.8 T) and three temperatures (25.7, 35.4, and
      44.8 degrees C). Two exchange processes with different rate constants could be
      discriminated despite populations of the excited states below 1% and spatial
      neighborhood of the two processes. The group of (15)N nuclei involved in the
      faster process exhibits at 44.8 degrees C a forward rate constant of 11.7+/-2.4
      s(-1) and a population of the exited state of 0.39+/-0.07%. They surround the
      aromatic ring of histidine 35 whose protonation state is coupled to the flipping
      of a neighboring peptide plane. For the slower process, the forward rate constant
      and population of the exited state at 44.8 degrees C are 4.1+/-0.1 s(-1) and
      0.45+/-0.02%, respectively. The residues involved cluster nearby the copper ion,
      which is separated from the protonation site of histidine 35 by about 8 A,
      indicating conformational rearrangements involving the copper coordinating loops.
      The dependence of the equilibrium constant on the temperature is consistent with
      an enthalpy-dominated transition around the copper, but an entropy-controlled
      transition near histidine 35. The detection by nuclear magnetic resonance of
      millisecond to second conformational transitions near the copper ion suggests a
      low energy-cost rearrangement of the copper-binding site that may be necessary
      for efficient electron transfer.

PMID- 12493829
TI  - Pressure-induced unfolding of the molten globule of all-Ala alpha-lactalbumin.
AB  - Pressure-induced unfolding of a molten globule (MG) was studied in a residue
      specific manner with (1)H-(15)N two-dimensional NMR spectroscopy using a variant
      of human alpha-lactalbumin (alpha-LA), in which all eight cysteines had been
      replaced with alanines (all-Ala alpha-LA). The NMR spectrum underwent a series of
      changes from 30 to 2000 bar at 20 degrees C and from -18 degrees C to 36 degrees
      C at 2000 bar, showing a highly heterogeneous unfolding pattern according to the
      secondary structural elements of the native structure. Unfolding began in the
      loop part of the beta-domain, and then extended to the remainder of the beta
      domain, after which the alpha-domain began to unfold. Within the alpha-domain,
      the pressure stability decreased in the order: D-helix approximately 3(10)-helix
      > C-helix approximately B-helix > A-helix. The D-helix, C-terminal 3(10)-helix
      and a large part of B- and C-helices did not unfold at 2000 bar, even at 36
      degrees C or at -18 degrees C. The results verify that the MG state consists of a
      mixture of variously unfolded conformers from the mostly folded to the nearly
      totally unfolded that differ in stability and partial molar volume. Not only heat
      but also cold denaturation was observed, supporting the view that the MG state is
      stabilized by hydrophobic interactions.

PMID- 12493827
TI  - Electrostatic interactions in the reconstitution of an SH2 domain from
      constituent peptide fragments.
AB  - Fragment complementation has been used to delineate the essential recognition
      elements for stable folding in Src homology 2 (SH2) domains by using NMR
      spectroscopy, alanine scanning, and surface plasmon resonance. The unfolded 9-kD
      and 5-kD peptide fragments formed by limited proteolytic digestion of the N
      terminal SH2 domain from the p85alpha subunit of phosphatidylinositol 3'-kinase
      fold into an active native-like structure on interaction with one another. The
      corresponding 5-kD fragment of the homologous Src protein, however, was not
      capable of structurally complementing the p85 9-kD fragment, indicating that
      fragment complementation among these SH2 domains is sensitive to the sequence
      differences between the Src and p85 domains. Partial complementation and folding
      activity could be recovered with hybrid sequences of these SH2 domains. Complete
      alanine scanning of the 5-kD p85 fragment was used to identify the sequence
      recognition elements required for complex formation. The alanine substitutions in
      the p85 5-kD fragment that abolished binding affinity with the cognate 9-kD
      fragment correlate well with highly conserved residues among SH2 domains that are
      either integrally involved in core packing or found at the interface between
      fragments. Surprisingly, however, mutation of a nonconserved surface-exposed
      aspartic acid to alanine was found to have a significant effect on
      complementation. A single additional mutation of arginine to aspartic acid
      allowed for recovery of native structure and increased the thermal stability of
      the designed Src-p85 chimera by 18 degrees C. This modification appears to
      relieve an unfavorable surface electrostatic interaction, demonstrating the
      importance of surface charge interactions in protein stability.

PMID- 12493830
TI  - Position-dependent interactions between cysteine residues and the helix dipole.
AB  - A protein model was developed for studying the interaction between cysteine
      residues and the helix dipole. Site-directed mutagenesis was used to introduce
      cysteine residues at the N-terminus of helix H in recombinant sperm whale
      myoglobin. Based on the difference in thiol pK(a) between folded proteins and an
      unfolded peptide, the energy of interaction between the thiolate and the helix
      dipole was determined. Thiolates at the N1 and N2 positions of the helix were
      stabilized by 0.3 kcal/mole and 0.7 kcal/mole, respectively. A thiolate at the
      Ncap position was stabilized by 2.8 kcal/mole, and may involve a hydrogen bond.
      In context with other studies, an experimentally observed helix dipole effect may
      be defined in terms of two distinct components. A charge-dipole component
      involves electrostatic interactions with peptide bond dipoles in the first two
      turns of the helix and affects residues at all positions of the terminus; a
      hydrogen bond component involves one or more backbone amide groups and is only
      possible at the capping position due to conformational restraints elsewhere. The
      nature and magnitude of the helix dipole effect is, therefore, position
      dependent. Results from this model system were used to interpret cysteine
      reactivity in rodent hemoglobins and the thioredoxin family.

PMID- 12493831
TI  - Comparison of beta-lactamases of classes A and D: 1.5-A crystallographic
      structure of the class D OXA-1 oxacillinase.
AB  - The crystallographic structure of the Escherichia coli OXA-1 beta-lactamase has
      been established at 1.5-A resolution and refined to R = 0.18. The 28.2-kD
      oxacillinase is a class D serine beta-lactamase that is especially active against
      the penicillin-type beta-lactams oxacillin and cloxacillin. In contrast to the
      structures of OXA-2, OXA-10, and OXA-13 belonging to other subclasses, the OXA-1
      molecule is monomeric rather than dimeric and represents the subclass
      characterized by an enlarged Omega loop near the beta-lactam binding site. The 6
      residue hydrophilic insertion in this loop cannot interact directly with
      substrates and, instead, projects into solvent. In this structure at pH 7.5,
      carboxylation of the conserved Lys 70 in the catalytic site is observed. One
      oxygen atom of the carboxylate group is hydrogen bonded to Ser 120 and Trp 160.
      The other oxygen atom is more exposed and hydrogen bonded to the Ogamma of the
      reactive Ser 67. In the overlay of the class D and class A binding sites, the
      carboxylate group is displaced ca. 2.6 A from the carboxylate group of Glu 166 of
      class A enzymes. However, each group is equidistant from the site of the water
      molecule expected to function in hydrolysis, and which could be activated by the
      carboxylate group of Lys 70. In this ligand-free OXA-1 structure, no water
      molecule is seen in this site, so the water molecule must enter after formation
      of the acyl-Ser 67 intermediate.

PMID- 12493832
TI  - Stably folded de novo proteins from a designed combinatorial library.
AB  - Binary patterning of polar and nonpolar amino acids has been used as the key
      design feature for constructing large combinatorial libraries of de novo
      proteins. Each position in a binary patterned sequence is designed explicitly to
      be either polar or nonpolar; however, the precise identities of these amino acids
      are varied extensively. The combinatorial underpinnings of the "binary code"
      strategy preclude explicit design of particular side chains at specified
      positions. Therefore, packing interactions cannot be specified a priori. To
      assess whether the binary code strategy can nonetheless produce well-folded de
      novo proteins, we constructed a second-generation library based upon a new
      structural scaffold designed to fold into 102-residue four-helix bundles.
      Characterization of five proteins chosen arbitrarily from this new library
      revealed that (1) all are alpha-helical and quite stable; (2) four of the five
      contain an abundance of tertiary interactions indicative of well-ordered
      structures; and (3) one protein forms a well-folded structure with native-like
      features. The proteins from this new 102-residue library are substantially more
      stable and dramatically more native-like than those from an earlier binary
      patterned library of 74-residue sequences. These findings demonstrate that chain
      length is a crucial determinant of structural order in libraries of de novo four
      helix bundles. Moreover, these results show that the binary code strategy--if
      applied to an appropriately designed structural scaffold--can generate large
      collections of stably folded and/or native-like proteins.

PMID- 12493833
TI  - Induced fit in guanidino kinases--comparison of substrate-free and transition
      state analog structures of arginine kinase.
AB  - Arginine kinase (AK) is a member of the guanidino kinase family that plays an
      important role in buffering ATP concentration in cells with high and fluctuating
      energy demands. The AK specifically catalyzes the reversible phosphoryl transfer
      between ATP and arginine. We have determined the crystal structure of AK from the
      horseshoe crab (Limulus polyphemus) in its open (substrate-free) form. The final
      model has been refined at 2.35 A with a final R of 22.3% (R(free) = 23.7%). The
      structure of the open form is compared to the previously determined structure of
      the transition state analog complex in the closed form. Classically, the protein
      would be considered two domain, but dynamic domain (DynDom) analysis shows that
      most of the differences between the two structures can be considered as the
      motion between four rigid groups of nonsequential residues. ATP binds near a
      cluster of positively charged residues of a fixed dynamic domain. The other three
      dynamic domains close the active site with separate hinge rotations relative to
      the fixed domain. Several residues of key importance for the induced motion are
      conserved within the phosphagen kinase family, including creatine kinase.
      Substantial conformational changes are induced in different parts of the enzyme
      as intimate interactions are formed with both substrates. Thus, although induced
      fit occurs in a number of phosphoryl transfer enzymes, the conformational changes
      in phosphagen kinases appear to be more complicated than in prior examples.

PMID- 12493834
TI  - Single-stranded DNA binding of the cold-shock protein CspB from Bacillus
      subtilis: NMR mapping and mutational characterization.
AB  - Cold-shock proteins (CSPs) bind to single-stranded nucleic acids, thereby acting
      as a "RNA chaperone." To gain deeper insights into the rather unspecific nature
      of ssDNA/RNA binding, we characterized the binding interface of CspB from
      Bacillus subtilis to a 25-mer of ssDNA (Y-Box25) using heteronuclear 2D NMR
      spectroscopy. Seventeen residues, including eight out of nine aromatic amino
      acids, are directly involved in the Y-Box25 interaction and were identified by
      extreme line broadening of their cross-peaks. Eight residues belong to the
      earlier proposed RNP binding motifs. A second set of seven backbone amides
      becomes evident by major chemical shift perturbations reporting remote
      conformational rearrangements upon binding. These residues are located in loop
      beta3-beta4 and loopbeta4-beta5, and include Ile18. The individual contributions
      of the so-identified residues were examined by fluorescence titration experiments
      of 15 CspB variants. Phenylalanine substitutions in- and outside the RNP motifs
      significantly reduce the binding affinity. Unrestricted possible backbone
      conformations of loop beta3-beta4 also markedly contribute to binding. Stopped
      flow fluorescence kinetics revealed that the different binding affinities of CspB
      variants are determined by the dissociation rate, whereas the association rate
      remains unchanged. This might be of importance for the "RNA chaperone" activity
      of CspB.

PMID- 12493835
TI  - Screening for functional expression and overexpression of a family of diiron
      containing interfacial membrane proteins using the univector recombination
      system.
AB  - The large number of uncharacterized genes emerging from genome sequencing
      projects has resulted in a need for quick and reliable screening methods for
      protein expression parameters. We have utilized the univector plasmid
      recombination system (as previously reported) to develop a series of vectors for
      rapid screening for expression in Escherichia coli. A high level of recombinant
      protein expression is a requirement for purification of protein for structural
      determination and other purposes. In other applications, successful
      complementation of a missing enzyme activity in E. coli, as well as directed
      evolution studies and metabolic engineering, often require a much lower level of
      protein expression. In this report we describe the construction of a number of
      new pHOST vectors that can be screened for both low- and high-level expression.
      We isolated a mutant vector for MBP fusions that exhibited a more optimal level
      of expression for complementation of aerobic respiration in hemA(-) E. coli, our
      functional assay for the alternative oxidase. We then demonstrated the use of our
      system to rapidly screen for both optimal functional expression and optimal
      overexpression of the alternative oxidase as well as two other members of a
      family of membrane-bound diiron carboxylate proteins, the plastid terminal
      oxidase and 5-demethoxyquinone hydroxylase.

PMID- 12493836
TI  - Structural energetics of protein-carbohydrate interactions: Insights derived from
      the study of lysozyme binding to its natural saccharide inhibitors.
AB  - High-sensitivity isothermal titration calorimetry was used to characterize the
      binding of the glycohydrolitic enzyme hen egg-white lysozyme to its natural
      saccharide inhibitors, chitobiose and chitrotriose. Measurements were done at a
      pH of 4.7, in the 15 degrees C -45 degrees C temperature range. Using a
      structural-energetic parameterization derived previously for lectin-carbohydrate
      associations, both binding enthalpies and entropies for the present systems and
      for the complex of chitobiose with turkey egg-white lysozyme from the literature
      were correctly accounted for. These observations suggest that both lysozymes and
      lectins follow the same structural-energetic behavior in the binding to their
      ligands. From the analysis of lysozyme data in conjunction with other binding
      data reported in the literature, an ad hoc parameterization of DeltaCp for
      protein-carbohydrate complexes was derived for the first time. The novel
      parameters for both polar and apolar surface areas differed significantly from
      correlations obtained previously from model compounds and protein-folding data.
      As DeltaCp is extremely sensitive to changes in solvent structure, this finding
      indicates that protein-carbohydrate complexes have distinctive hydration
      properties. According to our analysis, the dehydration of polar groups is the
      major cause for the observed decrease in DeltaCp, which implies that these groups
      behave hydrophobically. The contribution of apolar surface areas was found of the
      expected sign, but their specific weight is much smaller than those obtained in
      other correlations. This small contribution to DeltaCp is consistent with
      Lemieux's hypothesis of a low degree of hydration of apolar surfaces on
      carbohydrates.

PMID- 12493837
TI  - Isolation and biochemical characterization of LEAP-2, a novel blood peptide
      expressed in the liver.
AB  - The human genome contains numerous genes whose protein products are unknown in
      terms of structure, interaction partner, expression, and function. To unravel the
      function of these orphan genes, it is of particular value to isolate native forms
      of protein and peptide products derived from these genes. From human blood
      ultrafiltrate, we characterized a novel gene-encoded, cysteine-rich, and cationic
      peptide that we termed liver-expressed antimicrobial peptide 2 (LEAP-2). We
      identified several circulating forms of LEAP-2 differing in their amino-terminal
      length, all containing a core structure with two disulfide bonds formed by
      cysteine residues in relative 1-3 and 2-4 positions. Molecular cloning of the
      cDNA showed that LEAP-2 is synthesized as a 77-residue precursor, which is
      predominantly expressed in the liver and highly conserved among mammals. This
      makes it a unique peptide that does not exhibit similarity with any known human
      peptide regarding its primary structure, disulfide motif, and expression.
      Analysis of the LEAP-2 gene resulted in the identification of an alternative
      promoter and at least four different splicing variants, with the two dominating
      transcripts being tissue-specifically expressed. The largest native LEAP-2 form
      of 40 amino acid residues is generated from the precursor at a putative cleavage
      site for a furin-like endoprotease. In contrast to smaller LEAP-2 variants, this
      peptide exhibited dose-dependent antimicrobial activity against selected
      microbial model organisms. LEAP-2 shares some characteristic properties with
      classic peptide hormones and it is expected that the isolation of this novel
      peptide will help to unravel its physiological role.

PMID- 12493838
TI  - Protein hydrogen exchange mechanism: local fluctuations.
AB  - Experiments were done to study the dynamic structural motions that determine
      protein hydrogen exchange (HX) behavior. The replacement of a solvent-exposed
      lysine residue with glycine (Lys8Gly) in a helix of recombinant cytochrome c does
      not perturb the native structure, but it entropically potentiates main-chain
      flexibility and thus can promote local distortional motions and large-scale
      unfolding. The mutation accelerates amide hydrogen exchange of the mutated
      residue by about 50-fold, neighboring residues in the same helix by less, and
      residues elsewhere in the protein not at all, except for Leu98, which registers
      the change in global stability. The pattern of HX changes shows that the coupled
      structural distortions that dominate exchange can be several residues in extent,
      but they expose to exchange only one amide NH at a time. This "local fluctuation"
      mode of hydrogen exchange may be generally recognized by disparate near-neighbor
      rates and a low dependence on destabilants (denaturant, temperature, pressure).
      In contrast, concerted unfolding reactions expose multiple neighboring amide NHs
      with very similar computed protection factors, and they show marked destabilant
      sensitivity. In both modes, ionic hydrogen exchange catalysts attack from the
      bulk solvent without diffusing through the protein matrix.

PMID- 12493839
TI  - Leucine 145 of the ribotoxin alpha-sarcin plays a key role for determining the
      specificity of the ribosome-inactivating activity of the protein.
AB  - Secreted fungal RNases, represented by RNase T1, constitute a family of
      structurally related proteins that includes ribotoxins such as alpha-sarcin. The
      active site residues of RNase T1 are conserved in all fungal RNases, except for
      Phe 100 that is not present in the ribotoxins, in which Leu 145 occupies the
      equivalent position. The mutant Leu145Phe of alpha-sarcin has been recombinantly
      produced and characterized by spectroscopic methods (circular dichroism,
      fluorescence spectroscopy, and NMR). These analyses have revealed that the mutant
      protein retained the overall conformation of the wild-type alpha-sarcin.
      According to the analyses performed, Leu 145 was shown to be essential to
      preserve the electrostatic environment of the active site that is required to
      maintain the anomalous low pKa value reported for the catalytic His 137 of alpha
      sarcin. Enzymatic characterization of the mutant protein has revealed that Leu
      145 is crucial for the specific activity of alpha-sarcin on ribosomes.

PMID- 12493840
TI  - Structural characterization of transglutaminase-catalyzed cross-linking between
      glyceraldehyde 3-phosphate dehydrogenase and polyglutamine repeats.
AB  - The accumulation of abnormal polyglutamine-containing protein aggregates within
      the cytosol and nuclei of affected neurons is a hallmark of the progressive
      neurodegenerative disorders caused by an elongated (CAG)(n) repeat in the genome.
      The polyglutamine domains are excellent substrates for the enzyme
      transglutaminase type 2 (tissue), resulting in the formation of cross-links with
      polypeptides containing lysyl groups. Enzymatic activity toward the Q(n) domains
      increases greatly upon lengthening of such Q(n) stretches (n > 40). Among the
      possible amine donors, the glycolytic enzyme glyceraldehyde-3-phosphate
      dehydrogenase was shown to tightly bind several proteins involved in
      polyglutamine expansion diseases. Recently, the authors have shown that K191,
      K268, and K331, out of the 26 lysines present in glyceraldehyde-3-phosphate
      dehydrogenase, are the reactive amine-donor sites forming cross-links with
      substance P, which bears the simplest Q(n) domain (n = 2). The present study
      reports that synthetic peptides of both pathological and nonpathological length
      (n = 43 and 17, respectively) form cross-links with the same K residues located
      in the C-terminal region of glyceraldehyde-3-phosphate-dehydrogenase. In
      addition, it is shown that extra K residues present in the C termini of
      glyceraldehyde-3-phosphate-dehydrogenase are susceptible to cross-linking in the
      presence of transglutaminase. The present results indicate a possible modulating
      effect of Q(n) stretches on tissue transglutaminase substrate specificity and
      mechanism of recognition.

PMID- 12493841
TI  - Calretinin and calbindin D28k have different domain organizations.
AB  - The domain organization of calretinin (CR) was predicted to involve all six EF
      hand motifs (labeled I to VI) condensed into a single domain, as characterized
      for calbindin D28k (Calb), the closest homolog of calretinin. Unperturbed
      (1)H,(15)N HSQC NMR spectra of a (15)N-labeled calretinin fragment (CR III-VI,
      residues 100-271) in the presence of the unlabeled complimentary fragment (CR I
      II, residues 1-100) show that these fragments do not interact. Size exclusion
      chromatography and affinity chromatography data support this conclusion. The HSQC
      spectrum of (15)N-labeled CR is similar to the overlaid spectra of individual
      (15)N-labeled CR fragments (CR I-II and CR III-VI), also suggesting that these
      regions do not interact within intact CR. In contrast to these observations, but
      in accordance with the Calb studies, we observed interactions between other CR
      fragments: CR I (1-60) with CR II-VI (61-271), and CR I-III (1-142) with CR IV-VI
      (145-271). We conclude that CR is formed from at least two independent domains
      consisting of CR I-II and CR III-VI. The differences in domain organization of
      Calb and CR may explain the specific target interaction of Calb with caspase-3.
      Most importantly, the comparison of CR and Calb domain organizations questions
      the value of homologous modeling of EF-hand proteins, and perhaps of other
      protein families.

PMID- 12493842
TI  - Partial NMR assignments and secondary structure mapping of the isolated alpha
      subunit of Escherichia coli tryptophan synthase, a 29-kD TIM barrel protein.
AB  - The alpha subunit of tryptophan synthase (alphaTS) from S. typhimurium belongs to
      the triosephosphate isomerase (TIM) or the (beta/alpha)(8) barrel fold, one of
      the most common structures in biology. To test the conservation of the global
      fold in the isolated Escherichia coli homolog, we have obtained a majority of the
      backbone assignments for the 29-kD alphaTS by using standard heteronuclear
      multidimensional NMR methods on uniformly (15)N- and (15)N/(13)C-labeled protein
      and on protein selectively (15)N-labeled at key hydrophobic residues. The
      secondary structure mapped by chemical shift index, nuclear Overhauser
      enhancements (NOEs), and hydrogen-deuterium (H-D) exchange, and several abnormal
      chemical shifts are consistent with the conservation of the global TIM barrel
      fold of the isolated E. coli alphaTS. Because most of the amide protons that are
      slow to exchange with solvent correspond to the beta-sheet residues, the beta
      barrel is likely to play an important role in stabilizing the previously detected
      folding intermediates for E. coli alphaTS. A similar combination of uniform and
      selective labeling can be extended to other TIM barrel proteins to obtain insight
      into the role of the motif in stabilizing what appear to be common partially
      folded forms.

PMID- 12493844
TI  - Warmer paleotemperatures for terrestrial ecosystems.
AB  - Floras of predominantly wet-soil environments show a greater than expected
      proportion of toothed leaves, affecting the outcome of leaf physiognomically
      based temperature estimates. New analyses of foliar physiognomy of plants growing
      in predominantly wet soils in modern forests suggest that current methods of
      inferring paleotemperatures from fossil floras yield underestimates of 2.5-10
      degrees C. The changes we propose bring terrestrial paleotemperature estimates
      into agreement with temperatures inferred from other biological and geological
      proxies and strengthen the use of leaf physiognomy as a method for climate
      reconstruction.

PMID- 12493845
TI  - Plant culture: thirteen seasonal pieces. January--bark, the skin of a tree.

PMID- 12493843
TI  - A pervasive mechanism for analgesia: activation of GIRK2 channels.
AB  - G protein-coupled inwardly rectifying potassium channels (GIRKs) provide a common
      link between numerous neurotransmitter receptors and the regulation of synaptic
      transmission. We asked whether GIRKs specify a single behavioral action that is
      produced by drugs acting on the diverse receptors coupled with GIRKs. By using
      GIRK2-null mutant mice, we found marked reduction or complete elimination of the
      antinociceptive (hot plate test) effects of ethanol, oxotremorine, nicotine,
      baclofen, clonidine, and the cannabinoid receptor agonist WIN 55,212. However,
      ketamine analgesia remained intact. For most drugs, there was a sex difference in
      antinociceptive action, and the impact of deletion of the GIRK2 channel was less
      in female mice. The deletion of the GIRK2 channel blocks the opioid-dependent
      component of stress-induced analgesia (SIA), whereas nonopioid SIA was not
      changed. We propose that opioid, alpha adrenergic, muscarinic cholinergic, gamma
      aminobutyric acid-B, and cannabinoid receptors are coupled with postsynaptic
      GIRK2 channels in vivo. Furthermore, this pathway accounts for essentially all of
      the antinociceptive effects in males, although females appear to recruit
      additional signal transduction mechanisms for some analgesic drugs.

PMID- 12493846
TI  - Molecular evolution and genetic engineering of C4 photosynthetic enzymes.
AB  - The majority of terrestrial plants, including many important crops such as rice,
      wheat, soybean, and potato, are classified as C(3) plants that assimilate
      atmospheric CO(2) directly through the C(3) photosynthetic pathway. C(4) plants,
      such as maize and sugarcane, evolved from C(3) plants, acquiring the C(4)
      photosynthetic pathway in addition to the C(3) pathway to achieve high
      photosynthetic performance and high water- and nitrogen-use efficiencies.
      Consequently, the transfer of C(4) traits to C(3) plants is one strategy being
      adopted for improving the photosynthetic performance of C(3) plants. The recent
      application of recombinant DNA technology has made considerable progress in the
      molecular engineering of photosynthetic genes in the past ten years. It has
      deepened understanding of the evolutionary scenario of the C(4) photosynthetic
      genes. The strategy, based on the evolutionary scenario, has enabled enzymes
      involved in the C(4) pathway to be expressed at high levels and in desired
      locations in the leaves of C(3) plants. Although overproduction of a single C(4)
      enzyme can alter the carbon metabolism of C(3) plants, it does not show any
      positive effects on photosynthesis. Transgenic C(3) plants overproducing multiple
      enzymes are now being produced for improving the photosynthetic performance of
      C(3) plants.

PMID- 12493847
TI  - Molecular characterization of XVSAP1, a stress-responsive gene from the
      resurrection plant Xerophyta viscosa Baker.
AB  - The strategy of 'complementation by functional sufficiency' was used to isolate a
      cDNA designated XVSAP1 from a cDNA library constructed from dehydrated Xerophyta
      viscosa Baker leaves. Analysis of the cDNA sequence indicated a highly
      hydrophobic protein with six transmembrane regions. Southern blot analysis
      revealed that there are at least two copies of XVSAP1 in X. viscosa. The deduced
      amino acid sequence showed 49% identity to WCOR413, a low-temperature-regulated
      protein from wheat. The protein also showed between 25% to 56% identity to
      WCOR413-like proteins from Arabidopsis thaliana. Expression of XVSAP1 in
      Escherichia coli (srl::Tn10) conferred osmotic stress tolerance when the cells
      were grown in 1 M sorbitol. Analysis of gene expression using semi-quantitative
      RT-PCR indicated that XVSAP1 is induced by dehydration, salt stress (100 mM),
      both low (4 degrees C) and high temperature (42 degrees C) and high light
      treatment (1500 micromol m(-2) s(-1)). These results suggest that XVSAP1 may have
      a significant role to play in the response of X. viscosa to abiotic stresses.

PMID- 12493848
TI  - Effect of pmt gene overexpression on tropane alkaloid production in transformed
      root cultures of Datura metel and Hyoscyamus muticus.
AB  - In order to increase the production of the pharmaceuticals hyoscyamine and
      scopolamine in hairy root cultures, a binary vector system was developed to
      introduce the T-DNA of the Ri plasmid together with the tobacco pmt gene under
      the control of CaMV 35S promoter, into the genome of Datura metel and Hyoscyamus
      muticus. This gene codes for putrescine:SAM N-methyltransferase (PMT; EC.
      2.1.1.53), which catalyses the first committed step in the tropane alkaloid
      pathway. Hairy root cultures overexpressing the pmt gene aged faster and
      accumulated higher amounts of tropane alkaloids than control hairy roots. Both
      hyoscyamine and scopolamine production were improved in hairy root cultures of D.
      metel, whereas in H. muticus only hyoscyamine contents were increased by pmt gene
      overexpression. These roots have a high capacity to synthesize hyoscyamine, but
      their ability to convert it into scopolamine is very limited. The results
      indicate that the same biosynthetic pathway in two related plant species can be
      differently regulated, and overexpression of a given gene does not necessarily
      lead to a similar accumulation pattern of secondary metabolites.

PMID- 12493849
TI  - Seed germination is blocked in Arabidopsis putative vacuolar sorting receptor
      (atbp80) antisense transformants.
AB  - The membrane receptor protein from pea, peabp80, has been shown to function by in
      vitro binding studies, and in vivo in yeast mutant, as a vacuolar sorting
      receptor (VSR). Families of proteins with homology to peabp80 have been
      identified in many plants including Arabidopsis: The family of membrane
      receptors, atbp80a-f (Arabidopsis thaliana binding protein 80 kDa) is highly
      homologous to peabp80 and may also function as vacuolar sorting receptors.
      Interactions with vacuolar sorting determinants have been shown only in vitro for
      atbp80b. In this paper, atbp80b was over- and under-expressed in Arabidopsis.
      Transgenic plants that over-expressed atbp80b showed no visible phenotype.
      However, antisense transformants were defective in germination. In non
      germinating antisense transformants the embryo appeared to be normal, but, using
      several methods, it was not possible to rescue the non-germinating seeds,
      indicating that the mechanisms were probably independent of a seed-coat-imposed
      inhibition. To make a correlation between the lack of germination and gene
      expression, transcription analysis of all atbp80 genes was performed in the non
      germinating antisense seeds indicating that all the normally transcribed genes
      were not detected. Then, a gene expression study of atbp80s genes was carried-out
      following seed imbibition and in various organs during wild-type plant
      development showing that all the genes from the family were transcribed and
      differentially expressed.

PMID- 12493850
TI  - Expression of a cyanobacterial sucrose-phosphate synthase from Synechocystis sp.
      PCC 6803 in transgenic plants.
AB  - Sucrose-phosphate synthase (SPS) from the cyanobacterium Synechocystis sp. PCC
      6803 lacks all of the Ser residues known to be involved in the regulation of
      higher plant SPS by protein phosphorylation. The Synechocystis SPS is also not
      allosterically regulated by glucose 6-phosphate or orthophosphate. To investigate
      the effects of expressing a potentially unregulated SPS in plants, the
      Synechocystis sps gene was introduced into tobacco, rice and tomato under the
      control of constitutive promoters. The Synechocystis SPS protein was expressed at
      a high level in the plants, which should have been sufficient to increase overall
      SPS activity 2-8-fold in the leaves. However, SPS activities and carbon
      partitioning in leaves from transgenic and wild-type plants were not
      significantly different. The maximal light-saturated rates of photosynthesis in
      leaves from tomato plants expressing the Synechocystis SPS were the same as those
      from wild-type plants. Tomato plants expressing the maize SPS showed 2-3-fold
      increases in SPS activity, increased partitioning of photoassimilate to sucrose
      and up to 58% higher maximal rates of photosynthesis. To investigate the apparent
      inactivity of the Synechocystis SPS the enzyme was purified from transgenic
      tobacco and rice plants. Surprisingly, the purified enzyme was found to have full
      catalytic activity. It is proposed that some other protein in plant cells binds
      to the Synechocystis SPS resulting in inhibition of the enzyme.

PMID- 12493851
TI  - Sn, a maize bHLH gene, modulates anthocyanin and condensed tannin pathways in
      Lotus corniculatus.
AB  - Anthocyanins and condensed tannins are major flavonoid end-products in higher
      plants. While the transactivation of anthocyanins by basic helix-loop-helix
      (bHLH) transcription factors is well documented, very little is known about the
      transregulation of the pathway to condensed tannins. The present study analyses
      the effect of over-expressing an Sn transgene in Lotus corniculatus, a model
      legume, with the aim of studying the regulation of anthocyanin and tannin end
      products. Contrary to expectation, effects on anthocyanin accumulation were
      subtle and restricted to the leaf midrib, leaf base and petiole tissues. However,
      the accumulation of condensed tannin polymers was dramatically enhanced in the
      leaf blade and this increase was accompanied by a 50-fold increase in the number
      of tannin-containing cells in this tissue. A detailed analysis of selected lines
      indicated that this transactivational phenotype correlated with high steady-state
      transcript levels of the introduced transgene and the introduction of a single
      copy of the CaMV35S-Sn construct into these clonal genotypes. While the levels of
      condensed tannins in leaves were increased by up to 1% of the dry weight, other
      major secondary end-products (flavonols, lignins and inducible phytoalexins) were
      unaltered in transactivated lines. These results give an initial insight into the
      developmental and higher-order regulation of polyphenolic metabolism in Lotus and
      other higher plant species.

PMID- 12493852
TI  - Redox regulation and storage processes during maturation in kernels of Triticum
      durum.
AB  - Metabolic changes during the development and maturation of Triticum durum Desf.
      (L.) kernels were studied, with particular emphasis on changes in the redox state
      of ascorbate and glutathione, as well as in the activities of the enzymes
      responsible for the recycling of their oxidized forms (ascorbic free radical
      reductase, EC 1.6.5.4; dehydroascorbate reductase, EC 1.8.5.1; glutathione
      reductase, EC 1.6.4.2) and for detoxification or utilization of hydrogen peroxide
      (ascorbate peroxidase, EC 1.11.1.11; catalase, EC 1.11.1.6). In parallel with
      this analysis, the production and storage of reserve compounds was studied, in
      particular, soluble carbohydrates (mono- di-saccharides and fructans) and the
      transition from sulphydryl groups to disulphide bridges into proteins. The
      results indicate that both the activities of the ascorbate and glutathione redox
      enzymes and that of catalase are high before the start of drying maturation,
      after which they decrease. Moreover, analysis of the redox state of ascorbate and
      glutathione pairs and the sulphydryl to disulphide transition into proteins
      suggests that these three parameters are tightly related during kernel
      maturation, thus confirming the involvement of the two redox pairs in protein
      maturation as well as in protection against reactive oxygen species. The
      physiological implications of the changes in cellular redox state and in soluble
      carbohydrates for the acquisition of desiccation tolerance and reaching the
      resting phase in orthodox seeds are also discussed.

PMID- 12493853
TI  - Biochemical and physiological studies of Arabidopsis thaliana transgenic lines
      with repressed expression of the mitochondrial pyruvate dehydrogenase kinase.
AB  - Pyruvate dehydrogenase kinase (PDHK), a negative regulator of the mitochondrial
      pyruvate dehydrogenase complex (mtPDC), plays a pivotal role in controlling mtPDC
      activity, and hence, the TCA cycle and cell respiration. Previously, the cloning
      of a PDHK cDNA from Arabidopsis thaliana and the effects of constitutively down
      regulating its expression on plant growth and development has been reported. The
      first detailed analyses of the biochemical and physiological effects of partial
      silencing of the mtPDHK in A. thaliana using antisense constructs driven by both
      constitutive and seed-specific promoters are reported here. The studies revealed
      an increased level of respiration in leaves of the constitutive antisense PDHK
      transgenics; an increase in respiration was also found in developing seeds of the
      seed-specific antisense transgenics. Both constitutive and seed-specific partial
      silencing of the mtPDHK resulted in increased seed oil content and seed weight at
      maturity. Feeding 3-(14)C pyruvate to bolted stems containing siliques
      (constitutive transgenics), or to isolated siliques or immature seeds (seed
      specific transgenics) confirmed a higher rate of incorporation of radiolabel into
      all seed lipid species, particularly triacylglycerols. Neither constitutive nor
      seed-specific partial silencing of PDHK negatively affected overall silique and
      seed development. Instead, oil and seed yield, and overall plant productivity
      were improved. These findings suggest that a partial reduction of the repression
      of the mtPDC by antisense PDHK expression can alter carbon flux and, in
      particular, the contribution of carbon moieties from pyruvate to fatty acid
      biosynthesis and storage lipid accumulation in developing seeds, implicating a
      role for mtPDC in fatty acid biosynthesis in seeds.

PMID- 12493854
TI  - Isolation and promoter analysis of two genes encoding different endo-beta-1,4
      glucanases in the non-climacteric strawberry.
AB  - Two endo-beta-1,4-glucanase (EGase; EC 3.2.1.4.) genes, highly expressed during
      ripening of the non-climacteric strawberries (Fragariaxananassa Duch. cv.
      Chandler), were isolated. Serial promoter deletions of both genes (i.e. FaEG1 and
      FaEG3) fused to GUS were transiently assayed in strawberry fruits by using a
      technique recently developed in this laboratory. Although differences were
      observed with the short fragments, GUS activity became comparable with the
      largest fragments of both promoters. The apparently similar strength of the two
      largest promoter fragments was in contrast with previous results of Northern
      analyses which demonstrated different transcripts amounts for the two genes. The
      inclusion of the 3' flanking region of both genes in the transient assays showed
      that, in the case of FaEG3, the 3' region had a down-regulating effect on the
      expression of GUS, and this might account for the lower amount of FaEG3 mRNA
      usually observed in ripe fruits compared to that of FaEG1. Downstream instability
      elements might be involved in such down-regulation.

PMID- 12493855
TI  - Isolation of GUS marker lines for genes expressed in Arabidopsis endosperm,
      embryo and maternal tissues.
AB  - In order to identify marker lines expressing GUS in various endosperm
      compartments and at different developmental stages, a collection of Arabidopsis
      thaliana (L.) Heynh. promoter trap lines were screened. The screen identified 16
      lines displaying GUS-reporter gene expression in the endosperm, embryo and other
      seed organs. The distinctive patterns of GUS expression in these lines provide
      molecular markers for most cell compartments in the endosperm of Arabidopsis
      seeds at all developmental stages, and represent a valuable research tool for
      characterizing present and future Arabidopsis seed mutants. GUS expression
      patterns of these 16 lines are presented here. One line showed chalazal endosperm
      specific GUS activity at the heart stage of embryo development. In six lines
      embryo-specific GUS activity was detected. Six lines exhibited GUS activity
      predominantly in the endosperm and embryo while two lines showed strong GUS
      activity in all seed organs. In one line GUS activity was detected in integuments
      and syncytial endosperm, while the GUS activity at the cotyledonary stage of the
      embryo was seed coat-specific. In addition, two funiculus markers and two silique
      markers expressed in the abscission zone and the guard cells are also presented.

PMID- 12493856
TI  - Early steps in the oxidative burst induced by cadmium in cultured tobacco cells
      (BY-2 line).
AB  - The rapid generation of H(2)O(2) by Cd(2+)-treated plant cells was investigated
      in cultured tobacco (Nicotiana tabacum L.) BY-2 cells. The starting point for the
      generation of H(2)O(2) has been located at the cell plasma membrane using
      cytochemical methods. Treatment of the cells with diphenyleneiodonium (DPI) and
      imidazol, both inhibitors of the neutrophil NADPH oxidase, prevented the
      generation of H(2)O(2) induced by Cd(2+). These data suggest the involvement of
      an NADPH oxidase-like enzyme leading to H(2)O(2) production through O(2)(*-)
      dismutation by superoxide dismutase enzymes. To investigate the implication of
      Ca(2+) channels in a Cd(2+)-induced oxidative burst, different inhibitors of
      Ca(2+) channels were used. Only La(3+) totally inhibited the generation of
      H(2)O(2) induced by Cd(2+). However, verapamil and nifedipine, inhibitors of
      Ca(2+) channels, were not effective. Calmodulin or a Ca(2+)-dependent protein
      kinase is also implicated in the signal transduction sequence, based on the
      results obtained with two types of calmodulin antagonists, fluphenazine and N-(-6
      amino-hexyl)-5-chloro-1-naphthalenesulphonamide (W-7) and staurosporine, an
      inhibitor of protein kinases. However, neomycin, an inhibitor of the
      phosphoinositide cycle, did not inhibit the generation of H(2)O(2) induced by
      Cd(2+), suggesting mainly an induction of the oxidative burst mediated by
      calmodulin and/or calmodulin-dependent proteins.

PMID- 12493857
TI  - Isolation, characterization and expression of cyclin and cyclin-dependent kinase
      genes in Jerusalem artichoke (Helianthus tuberosus L.).
AB  - Tuber explants of Jerusalem artichoke (Helianthus tuberosus L.) are a model
      system for cell-cycle re-entry from a quiescent state, involving the activation
      of division of tuber parenchyma cells in response to exogenous auxin. To enable
      molecular studies of this system, two cyclin (Heltu;CYCD1;1 and Heltu; CYCD3;1)
      and two cyclin-dependent kinase (Heltu; CDKA;1 and Heltu;CDKB1;1) genes have been
      isolated from a Jerusalem artichoke cDNA library and their expression
      demonstrated during the activation of cell division. It was found that CDKA;1
      transcripts are present in quiescent tubers, whereas CYCD1;1, CYCD3;1 and CDKB1;1
      transcripts are induced during cell-cycle re-entry as well as during bud growth
      of whole tubers. Both CYCD1;1 and CYCD3;1 transcripts appear shortly before, or
      coincident with, the onset of S phase.

PMID- 12493858
TI  - Malate synthase gene expression during fruit ripening of Cavendish banana (Musa
      acuminata cv. Williams).
AB  - Malate synthase (MS) is a key enzyme responsible for malic acid synthesis in the
      glyoxylate cycle, which functions to convert stored lipids to carbohydrates, by
      catalysing the glyoxylate condensation reaction with acetyl-CoA in the
      peroxisome. In this study, the cloning of an MS cDNA, designated MaMS-1, from the
      banana fruit is reported. MaMS-1 was 1801 bp in length encoding a single
      polypeptide of 556 amino acid residues. Sequence analysis revealed that MaMS-1
      possessed the conserved catalytic domain and a putative peroxisomal targeting
      signal SK(I/L) at the carboxyl terminal. MaMS-1 also shared an extensive sequence
      homology (79-81.3%) with other plant MS homologues. Southern analysis indicated
      that MS might be present as multiple members in the banana genome. In Northern
      analysis, MaMS-1 was expressed specifically in ripening fruit tissue and
      transcripts were not detected in other organs such as roots, pseudostem, leaves,
      ovary, male flower, and in fruit at different stages of development. However, the
      transcript abundance in fruit was affected by stage of ripening, during which
      transcript was barely detectable at the early stage of ripening (FG and TY), but
      the level increased markedly in MG and in other fruits at advanced ripening
      stages. Furthermore, MaMS-1 expression in FG fruit could be stimulated by
      treatment with 1 microl l(-1) exogenous ethylene, but the stimulatory effect was
      abolished by the application of an ethylene inhibitor, norbornadiene. Results of
      this study clearly show that MS expression in banana fruit is temporally
      regulated during ripening and is ethylene-inducible.

PMID- 12493859
TI  - Distribution of xylem hydraulic resistance in fruiting truss of tomato influenced
      by water stress.
AB  - In this study xylem hydraulic resistances of peduncles (truss stalk), pedicels
      (fruit stalk) and the future abscission zone (AZ) halfway along the pedicel of
      tomato (Lycopersicon esculentum L.) plants were directly measured at different
      stages of fruit development, in plants grown under two levels of water
      availability in the root environment. The xylem hydraulic connection between
      shoot and fruits has previously been investigated, but contradictory conclusions
      were drawn about the presence of a flow resistance barrier in the pedicel. These
      conclusions were all based on indirect functional measurements and anatomical
      observations of water-conducting tissue in the pedicel. In the present study, by
      far the largest resistances were measured in the AZ where most individual vessels
      ended. Plants grown at low water availability in the root environment had xylem
      with higher hydraulic resistances in the peduncle and pedicel segments on both
      sides of the AZ, while the largest increase in hydraulic resistance was measured
      in the AZ. During fruit development hydraulic resistances in peduncle and pedicel
      segments decreased on both sides of the AZ, but tended to increase in the AZ. The
      overall xylem hydraulic resistance between the shoot and fruit tended to increase
      with fruit development because of the dominating role of the hydraulic resistance
      in the AZ. It is discussed whether the xylem hydraulic resistance in the AZ of
      tomato pedicels in response to water stress and during fruit development
      contributes to the hydraulic isolation of fruits from diurnal cycles of water
      stress in the shoot.

PMID- 12493860
TI  - Biosensor reporting of root exudation from Hordeum vulgare in relation to shoot
      nitrate concentration.
AB  - The aim of this study was to determine the relationship between shoot nitrate
      concentration, mediated by nitrate supply to roots, and root exudation from
      Hordeum vulgare. Plants were grown for 14 d in C-free sand microcosms, supplied
      with nutrient solution containing 2 mM nitrate. After this period, three
      treatments were applied for a further 14 d: (A) continued supply with 2 mM
      nitrate (zero boost), (B) supply with 10 mM nitrate (low boost), and (C) supply
      with 20 mM nitrate (high boost). At the end of the treatment period, a bacterial
      biosensor (Pseudomonas fluorescens 10586 pUCD607, marked with the lux CDABE genes
      for bioluminescence) was applied to the microcosms to report on C-substrate
      availability, as a consequence of root exudation. The nitrate boost treatments
      significantly affected shoot nitrate concentrations, in the order C>B>A. In
      treatments receiving a nitrate boost (B, C), increased shoot nitrate
      concentration was correlated with increased plant biomass, reduced root length,
      reduced number of root tips, and increased mean root diameter, relative to the no
      boost treatment (A). Imaging of biosensor bioluminescence (proportional to
      metabolic activity in response to availability of root exudates) indicated that
      root exudation increased with decreasing shoot nitrate concentration. Biosensor
      reporting of root C-flow indicated that exudation was greater from root tip
      regions than from the whole root, but that specific exudation rates for all sites
      were unaffected by treatments. Total root exudation across treatments was found
      to be closely correlated with total root length, indicating that increased root
      exudation, per unit root biomass, with decreasing nitrate supply was associated
      with altered root morphology, as a consequence of systemic plant responses to
      internal N-status.

PMID- 12493861
TI  - Xyloglucan endotransglucosylase action is high in the root elongation zone and in
      the trichoblasts of all vascular plants from Selaginella to Zea mays.
AB  - The endotransglucosylase action of the enzyme xyloglucan
      endotransglucosylase/hydrolase (XTH) was localized in the roots of diverse
      vascular plants: club-mosses (lycopodiophytes), ferns, gymnosperms, monocots, and
      dicots. High action was always found in the epidermis cell wall of the elongation
      zone and in trichoblasts in the differentiation zone. Clearly XTH and its action
      in root development evolved before the evolutionary divergence of ferns and seed
      plants and also of the lycopodiophytes and euphyllophytes.

PMID- 12493862
TI  - Vascular connections between the receptacle and empty achenes in sunflower
      (Helianthus annuus L.).
AB  - Empty achenes in sunflower, particularly in the centre of the capitulum, may be
      caused by poor vascularization. This hypothesis was tested by microscopic
      examination and translocation experiments. Phloem and xylem were identified by
      fluorescence of aniline-blue-stained callose and autofluorescence, respectively.
      Vascular strands that extended from the receptacle into empty achenes were
      regularly found in longitudinal sections. The phloem-mobile probe,
      carboxyfluorescein, was translocated from the receptacle to the pericarp and the
      testa of empty achenes. Similarly, (14)CO(2)-derived (14)C-photoassimilates moved
      into empty achenes. The observations suggest that empty achenes are both
      structurally and functionally connected with the vascular system of the
      receptacle. Hence, deficient vascular connections do not prevent seed filling in
      sunflower.

PMID- 12493863
TI  - The uptake and partitioning of cadmium in two cultivars of potato (Solanum
      tuberosum L.).
AB  - The uptake and distribution of Cd in potatoes over the course of a growing season
      was investigated in two cultivars of potatoes that differed in tuber Cd
      concentration. Plants were grown in soil with supplemental Cd. The concentrations
      of Cd in different tissues varied greatly in the order roots>shoots>> tubers.
      After the initiation of tuber bulking, shoot growth ceased and the increase in
      total plant Cd was mostly due to accumulation in the tubers. The constancy of the
      Cd concentration in shoots suggested that import of Cd via the xylem must be
      matched by export in the phloem, which implied that Cd must have significant
      phloem mobility. It was found that the differences in tuber Cd between cultivars
      Wilwash and Kennebec were not due to differences in total uptake or growth, but
      to differences in Cd partitioning within the plant. This partitioning was
      specific to Cd and was not observed for a range of nutrient elements. Most of the
      differences in tuber Cd concentration between the cultivars could be accounted
      for by a 3-fold higher retention of Cd in the roots of cv. Wilwash. The
      involvement of root sequestration, and xylem and phloem pathways in the loading
      of Cd into tubers is considered.

PMID- 12493864
TI  - Spermidine and related-metabolic inhibitors modulate sugar and amino acid levels
      in Vitis vinifera L.: possible relationships with initial fruitlet abscission.
AB  - The relationships between free polyamines (PAs), sugar and amino acid status were
      investigated in cuttings from two cultivars of Vitis vinifera L., Pinot noir
      (PN), a low abscising cultivar and Merlot (MRT), a high abscising one. In both
      cultivars free PAs decreased in inflorescences, but more drastically in MRT
      plants. Upon anthesis, this was associated with a decreased sugar content,
      especially sucrose, and an increase in total free amino acids. Thereafter,
      sucrose and amino acids showed opposite trends. In addition, darkening the PN
      plants at full flowering resulted in a dramatic decrease of PAs and sugars in
      inflorescences, but an increase in amino acid content, followed by high
      abscission. The concept that initial fruitlet abscission might be regulated by
      free PAs through changes in primary metabolites was hypothesized. Hence, the
      application of exogenous spermidine (Spd), but not putrescine (Put), prior to
      flowering markedly inhibits abscission. The Spd treatment also increased soluble
      sugar content but reduced amino acids in both leaves and inflorescences, while
      Put had no significant effect. By contrast, cyclohexylamine and beta
      hydroxyethylhydrazine, as potent inhibitors of Spd synthase and PA-oxidases,
      respectively, exerted inverse effects on sugar, amino acid and abscission levels.
      Sucrose and free proline seemed to be highly sensitive to these treatments. This
      study suggests that Spd could regulate fruitlet abscission in grapevine by
      modulating, in a reverse way, the levels of sugars and amino acids in
      inflorescences.

PMID- 12493865
TI  - Increased growth of young citrus trees under reduced radiation load in a semi
      arid climate.
AB  - This study investigated the effects of radiation heat-load reduction by shading
      on the growth and development of citrus trees in a warm subtropical region. The
      experiment was conducted from mid-June until late October when daily maximal air
      temperature averaged 29.3 degrees C. Two-year-old de-fruited Murcott tangor
      (Citrus reticulata BlancoxCitrus sinensis (L.) Osb.) trees were grown under 30%
      or 60% shade tunnels, or 60% flat shade (providing midday shade only), using
      highly reflective aluminized nets. Non-shaded trees were used as the control.
      Shading reduced direct more than diffuse radiation. Daily radiation was reduced
      by 35% for the 30% Tunnel and 60% Flat treatments, and by 55% for the 60% Tunnel.
      Two days of intensive measurement showed that shading increased average sunlit
      leaf conductance by 44% and photosynthesis by 29%. Shading did not significantly
      influence root and stem dry weight growth, but it increased the increment in leaf
      dry weight during the three month period by an average of 28% relative to the
      control, while final tree height in the 30% Tunnel treatment exceeded the control
      by 35%. Shoot to root and shoot mass ratios increased and root mass ratio
      decreased due to shading because of the increase in leaf dry weight. Shading
      increased starch concentration in leaves while the shadiest treatment, 60%
      Tunnel, decreased starch concentration in the roots. Carbon isotope ratio
      (delta(13)C) of exposed leaves that developed under shading was significantly
      reduced by 1.9 per thousand in the 60% Tunnel, indicating that shading increased
      CO(2) concentrations at the chloroplasts (C(c)), as would be expected from
      increased conductance. Substomatal CO(2) concentrations, C(i), computed from leaf
      net CO(2) assimilation rate and conductance values, also indicate that shading
      increases internal CO(2) concentrations. Based on tree dry mass, tree height, and
      total carbohydrates fractions, the 30% Tunnel and the 60% Flat were the optimal
      shade treatments.

PMID- 12493866
TI  - The abundance of minor chlorophyll a/b-binding proteins CP29 and LHCI of barley
      (Hordeum vulgare L.) during leaf senescence is controlled by light.
AB  - The abundance of the minor light-harvesting complexes CP29 and LHCI generally
      declines during the senescence of barley leaves. When light intensity declined
      due to clouding during the senescence of flag leaves from barley plants grown
      under field conditions, the levels of both light-harvesting complexes temporarily
      increased in parallel with photosystem II-efficiency [F(v)/F(m)]. A sudden shift
      from high light conditions to low light conditions during the growth of barley
      plants in a growth chamber also resulted in an increase in the abundance of minor
      light-harvesting complexes and a parallel increase in F(v)/F(m) as well as in the
      chlorophyll a+b-content of senescing primary foliage leaves. Northern blot
      analyses with a cDNA probe specific for the barley Lhcb4 gene encoding CP29
      showed that the light-dependent changes in the abundance of CP29 during
      senescence are paralleled by corresponding changes in the transcript level. The
      results indicate that adjustments of the levels of minor light-harvesting
      complexes during senescence under high light conditions may serve in the
      prevention of photo-oxidative damage to the photosynthetic reaction centres and
      under low light in ensuring efficient photosynthesis of the residual
      photosynthetic reaction centres.

PMID- 12493867
TI  - Xanthophyll cycle pool size and composition in relation to the nitrogen content
      of apple leaves.
AB  - The objective of this study was to determine xanthophyll cycle pool size and
      composition in response to N status and their relationships to non-photochemical
      quenching in apple leaves. Bench-grafted Fuji/M.26 trees were fertilized with
      different N concentrations (0-20 mM) in a modified Hoagland's solution for 6
      weeks to create a wide range of leaf N status (1-4.4 g m(-2)). Chlorophyll
      content, xanthophyll cycle pool size, lutein, total carotene, and neoxanthin on a
      leaf area basis all increased linearly with increasing leaf N. However, only the
      ratios of the xanthophyll cycle pool and of lutein to chlorophyll were higher in
      low N leaves than in high N leaves. Under high light at midday, both zeaxanthin
      (Z), expressed on a chlorophyll basis, and the percentage of the xanthophyll
      cycle pool present as Z, increased as leaf N decreased. Thermal dissipation of
      excitation energy, measured as non-photochemical quenching of chlorophyll
      fluorescence, was positively related to, whereas efficiency of excitation
      transfer and photosystem II quantum efficiency were negatively related to, Z,
      expressed on a chlorophyll basis or on a xanthophyll cycle pool basis. It is
      concluded that both xanthophyll cycle pool size (on a chlorophyll basis) and
      conversion of violaxanthin to zeaxanthin are enhanced in response to N limitation
      to dissipate excessive absorbed light under high irradiance.

PMID- 12493868
TI  - Evaluation of the growth response of six invasive species to past, present and
      future atmospheric carbon dioxide.
AB  - The response of plant species to future atmospheric carbon dioxide concentrations
      [CO(2)] has been determined for hundreds of crop and tree species. However, no
      data are currently available regarding the response of invasive weedy species to
      past or future atmospheric [CO(2)]. In the current study, the growth of six
      species which are widely recognized as among the most invasive weeds in the
      continental United States, Canada thistle (Cirsium arvense (L.) Scop.), field
      bindweed (Convolvulus arvensis L.), leafy spurge (Euphorbia esula L.), perennial
      sowthistle (Sonchus arvensis L.), spotted knapweed (Centaurea maculosa Lam.), and
      yellow star thistle (Centaurea solstitialis L.) were grown from seed at either
      284, 380 or 719 micromol mol(-1) [CO(2)] until the onset of sexual reproduction
      (i.e. the vegetative period). The CO(2) concentrations corresponded roughly to
      the CO(2) concentrations which existed at the beginning of the 20th century, the
      current [CO(2)], and the future [CO(2)] projected for the end of the 21st
      century, respectively. The average stimulation of plant biomass among invasive
      species from current to future [CO(2)] averaged 46%, with the largest response
      (+72%) observed for Canada thistle. However, the growth response among these
      species to the recent [CO(2)] increase during the 20th century was significantly
      higher, averaging 110%, with Canada thistle again (+180%) showing the largest
      response. Overall, the CO(2)-induced stimulation of growth for these species
      during the 20th century (285-382 micromol mol(-1)) was about 3x greater than for
      any species examined previously. Although additional data are needed, the current
      study suggests the possibility that recent increases in atmospheric CO(2) during
      the 20th century may have been a factor in the selection of these species.

PMID- 12493869
TI  - Reversibility of cold- and light-stress tolerance and accompanying changes of
      metabolite and antioxidant levels in the two high mountain plant species
      Soldanella alpina and Ranunculus glacialis.
AB  - Two high mountain plants Soldanella alpina (L.) and Ranunculus glacialis (L.)
      were transferred from their natural environment to two different growth
      conditions (22 degrees C and 6 degrees C) at low elevation in order to
      investigate the possibility of de-acclimation to light and cold and the
      importance of antioxidants and metabolite levels. The results were compared with
      the lowland crop plant Pisum sativum (L.) as a control. Leaves of R. glacialis
      grown for 3 weeks at 22 degrees C were more sensitive to light-stress (defined as
      damage to photosynthesis, reduction of catalase activity (EC 1.11.1.6) and
      bleaching of chlorophyll) than leaves collected in high mountains or grown at 6
      degrees C. Light-stress tolerance of S. alpina leaves was not markedly changed.
      Therefore, acclimation is reversible in R. glacialis leaves, but constitutive or
      long-lasting in S. alpina leaves. The different growth conditions induced
      significant changes in non-photochemical fluorescence quenching (qN) and the
      contents of antioxidants and xanthophyll cycle pigments. These changes did not
      correlate with light-stress tolerance, questioning their role for light- and cold
      acclimation of both alpine species. However, ascorbate contents remained very
      high in leaves of S. alpina under all growth conditions (12-19% of total soluble
      carbon). In cold-acclimated leaves of R. glacialis, malate represented one of the
      most abundant compounds of total soluble carbon (22%). Malate contents declined
      significantly in de-acclimated leaves, suggesting a possible involvement of
      malate, or malate metabolism, in light-stress tolerance. Leaves of the lowland
      plant P. sativum were more sensitive to light-stress than the alpine species, and
      contained only low amounts of malate and ascorbate.

PMID- 12493870
TI  - Interactive effects of water stress and xylem-limited bacterial infection on the
      water relations of a host vine.
AB  - Xylella fastidiosa, a xylem-limited bacterial pathogen that causes bacterial leaf
      scorch in its hosts, has a diverse and extensive host range among plant species
      worldwide. Previous work has shown that water stress enhances leaf scorch symptom
      severity and progression along the stem in Parthenocissus quinquefolia infected
      by X. fastidiosa. The objective here was to investigate the mechanisms underlying
      the interaction of water stress and infection by X. fastidiosa. Using the eastern
      deciduous forest vine, P. quinquefolia, infection and water availability were
      manipulated while measuring leaf water potentials (psi(L)), stomatal conductance
      (g(s)), whole shoot hydraulic conductance (K(h)), per cent xylem embolism, and
      xylem vessel dimensions. No significant differences in any of the physiological
      measurements were found between control and infected plants prior to drought.
      Drought treatment significantly reduced psi(L) and g(s) at all leaf positions
      throughout the day in late summer in both years of the study. In addition,
      infection significantly reduced psi(L) and g(s) in the most basal leaf positions
      in late summer in both years. Whole shoot hydraulic conductance was reduced by
      both low water and infection treatments. However, per cent embolized vessels and
      mean vessel diameter were affected by drought treatment only. These results imply
      that the major effect of infection by X. fastidiosa occurs due to reduced
      hydraulic conductance caused by clogging of the vessels, and not increased
      cavitation and embolism of xylem elements. The reduced K(h) caused by X.
      fastidiosa infection acts additively with the water limitation imposed by Drought
      stress.

PMID- 12493871
TI  - Diurnal variation in uptake and xylem contents of inorganic and assimilated N
      under continuous and interrupted N supply to Phleum pratense and Festuca
      pratensis.
AB  - Compensation by dark-period uptake of NH(4)(+) and NO(3)(-) in the grasses Phleum
      pratense L. and Festuca pratensis Huds. following N deprivation during the
      preceding light period was investigated in flowing solution culture under an
      artificial 10/14 h light/dark cycle. N was supplied as either NO(3)(-), NH(4)(+)
      or NH(4)NO(3) at 20+/-5 mmol m(-3), available continuously or only during the
      dark period, for 5-10 d. Intermittent N supply did not affect total daily N
      uptake, growth rate or net partitioning of dry matter. Net uptake and influx of
      NO(3)(-) varied similarly throughout the diurnal cycle when NO(3)(-) was supplied
      continuously, with a marginal contribution by NO(3)(-) efflux. Influx was
      significantly higher and efflux slightly higher following interruption of NO(3)(
      ) supply during the light period. Nitrate accounted for 80% of N in xylem exudate
      except between hours 6-9 of the light period when the amino acid concentration
      increased 3-fold, primarily as glutamine. Diurnal variation in relative NO(3)(-)
      uptake exhibited five phases of constant acceleration/deceleration, described
      reasonably well assuming NO(3)(-) influx was subject to metabolic co-regulation
      by NO(3)(-) and amino acid levels in the cytoplasmic compartment of the roots.
      Accordingly, influx is determined by variation in root NO(3)(-) levels throughout
      the dark period and the first half of the light period, but is down-regulated by
      increased amino acid levels during the second half of the light period. The sharp
      light/dark transitions affect transpiration rate and hence xylem N flux which, in
      turn, affect NO(3)(-) levels in the cytoplasmic compartment of the roots and the
      rate of NO(3)(-) assimilation in the shoot.

PMID- 12493872
TI  - Mutant alleles at the rugosus loci in pea affect seed moisture sorption isotherms
      and the relations between seed longevity and moisture content.
AB  - Pea (Pisum sativum L.) mutant near-isogenic lines (RRrbrb, rrRbRb, rrrbrb) with
      lower starch but higher lipid contents, brought about by lesions in the starch
      biosynthetic pathway, had seed moisture sorption isotherms displaced below that
      of the wild type (RRRbRb). The negative logarithmic relationship between seed
      longevity and seed storage moisture content (%, f.wt basis), determined in
      hermetic storage at 65 degrees C, also differed: longevity in the mutant near
      isogenic lines was poorer and less sensitive to moisture content than in the wild
      type (i.e. C(W) was lower). The low-moisture-content limit (m(c)) to this
      relation also differed, being lower in the mutant near-isogenic lines (5.4-5.9%)
      than in the wild type (6.1%). In contrast, all four near-isogenic lines showed no
      difference (P >0.25) in the negative semi-logarithmic relationship between
      equilibrium relative humidity (ERH) and seed longevity. It is concluded that the
      effect of these alleles at the r and rb loci on seed longevity was largely
      indirect; a consequence of their effect on seed composition and hence on moisture
      sorption isotherms. However, this explanation could not be invoked at moisture
      contents below m(c) where differences in longevity remained substantial (RRRbRb
      double that of rrrbrb). Hence, these mutant alleles affected seed longevity
      directly at very low moisture contents.

PMID- 12493873
TI  - Is schizophrenia linked to chromosome 1q?

PMID- 12493874
TI  - Breakthrough of the year.

PMID- 12493875
TI  - Breakthrough of the year. Small RNAs make big splash.

PMID- 12493876
TI  - Breakthrough of the year. The runners-up.

PMID- 12493877
TI  - Breakthrough of the year. Areas to watch in 2003.

PMID- 12493878
TI  - Breakthrough of the year. Scorecard 2002.

PMID- 12493879
TI  - Breakthrough of the year. Bioterrorism: the calm after the storm.

PMID- 12493880
TI  - Breakthrough of the year. Breakdown of the year: physics fraud.

PMID- 12493881
TI  - Biological agents. New U.S. rules set the stage for tighter security, oversight.

PMID- 12493882
TI  - California budget. Latest cuts send universities reeling.

PMID- 12493883
TI  - Science and security. Academy asks to ease visas for scholars.

PMID- 12493884
TI  - Stem cell medicine. Stanford gets gift for new institute.

PMID- 12493885
TI  - 2004 budget. No holiday cheer for NIH, NSF.

PMID- 12493886
TI  - Research funding. Italian researchers facing lean times.

PMID- 12493887
TI  - High-energy physics. CERN council chooses ITER's head as chief.

PMID- 12493888
TI  - Astronomy. Europe's telescope builders aim high.

PMID- 12493889
TI  - Public health. Rough-and-tumble behind Bush's smallpox policy.

PMID- 12493890
TI  - Public health. Treating vaccine reactions: two lifelines, but no guarantees.

PMID- 12493891
TI  - Public health. Looking for vaccines that pack a wallop without the side effects.

PMID- 12493892
TI  - Transgenic crops. China takes a bumpy road from the lab to the field.

PMID- 12493893
TI  - Archaeology. Armenia uncovers a Bronze Age treasure trove.

PMID- 12493894
TI  - Animal models. Can a mouse be standardized?

PMID- 12493895
TI  - Animal models. To build a better mouse cage.

PMID- 12493896
TI  - Nanotechnology. Biology offers nanotechs a helping hand.

PMID- 12493897
TI  - Portraits of science. A Polish, Jewish scientist in 19th-century Prussia.

PMID- 12493898
TI  - Public health. Strengthening the FDA.

PMID- 12493899
TI  - Oscillating systems. On emerging coherence.

PMID- 12493900
TI  - Structural biology. LDL receptor's beta-propeller displaces LDL.

PMID- 12493901
TI  - Circadian rhythms. Carbon monoxide and clocks.

PMID- 12493902
TI  - Geology. Earth's early atmosphere.

PMID- 12493903
TI  - Human genetics. Mapping human history.

PMID- 12493904
TI  - Climate change. Ups and downs of CO2 uptake.

PMID- 12493906
TI  - Neoarchean biomineralization by benthic cyanobacteria.

PMID- 12493905
TI  - Finding genes that underlie complex traits.
AB  - Phenotypic variation among organisms is central to evolutionary adaptations
      underlying natural and artificial selection, and also determines individual
      susceptibility to common diseases. These types of complex traits pose special
      challenges for genetic analysis because of gene-gene and gene-environment
      interactions, genetic heterogeneity, low penetrance, and limited statistical
      power. Emerging genome resources and technologies are enabling systematic
      identification of genes underlying these complex traits. We propose standards for
      proof of gene discovery in complex traits and evaluate the nature of the genes
      identified to date. These proof-of-concept studies demonstrate the insights that
      can be expected from the accelerating pace of gene discovery in this field.

PMID- 12493907
TI  - Formation of a one-dimensional array of oxygen in a microporous metal-organic
      solid.
AB  - We report the direct observation of dioxygen molecules physisorbed in the
      nanochannels of a microporous copper coordination polymer by the MEM (maximum
      entropy method)/Rietveld method, using in situ high-resolution synchrotron x-ray
      powder diffraction measurements. The obtained MEM electron density revealed that
      van der Waals dimers of physisorbed O2 locate in the middle of nanochannels and
      form a one-dimensional ladder structure aligned to the host channel structure.
      The observed O-O stretching Raman band and magnetic susceptibilities are
      characteristic of the confined O2 molecules in one-dimensional nanochannels of
      CPL-1 (coordination polymer 1 with pillared layer structure).

PMID- 12493908
TI  - Microporous and photoluminescent chalcogenide zeolite analogs.
AB  - Crystalline semiconducting sulfide and selenide zeolite analogs were synthesized
      that possess four-connected, three-dimensional tetrahedral networks built from
      tetravalent (M4+ = Ge4+ or Sn4+, where M = meta) and trivalent (M3+ = Ga3+ or
      In3+) cations. Microporous materials were obtained in all four combinations of
      M4+ and M3+, and some of them were thermally stable up to at least 380 degrees C.
      These materials exhibit framework topologies with pore size ranging from 12 to 24
      tetrahedral atoms, high surface area, high framework charge density and ion
      exchange capacity, and tunable electronic and optical properties.

PMID- 12493909
TI  - Mass-independent sulfur of inclusions in diamond and sulfur recycling on early
      Earth.
AB  - Populations of sulfide inclusions in diamonds from the Orapa kimberlite pipe in
      the Kaapvaal-Zimbabwe craton, Botswana, preserve mass-independent sulfur isotope
      fractionations. The data indicate that material was transferred from the
      atmosphere to the mantle in the Archean. The data also imply that sulfur is not
      well mixed in the diamond source regions, allowing for reconstruction of the
      Archean sulfur cycle and possibly offering insight into the nature of mantle
      convection through time.

PMID- 12493910
TI  - Calibration of sulfate levels in the archean ocean.
AB  - The size of the marine sulfate reservoir has grown through Earth's history,
      reflecting the accumulation of oxygen into the atmosphere. Sulfur isotope
      fractionation experiments on marine and freshwater sulfate reducers, together
      with the isotope record, imply that oceanic Archean sulfate concentrations were
      <200 microM, which is less than one-hundredth of present marine sulfate levels
      and one-fifth of what was previously thought. Such low sulfate concentrations
      were maintained by volcanic outgassing of SO2 gas, and severely suppressed
      sulfate reduction rates allowed for a carbon cycle dominated by methanogenesis.

PMID- 12493911
TI  - Interannual variability in the North Atlantic Ocean carbon sink.
AB  - The North Atlantic is believed to represent the largest ocean sink for
      atmospheric carbon dioxide in the Northern Hemisphere, yet little is known about
      its temporal variability. We report an 18-year time series of upper-ocean
      inorganic carbon observations from the northwestern subtropical North Atlantic
      near Bermuda that indicates substantial variability in this sink. We deduce that
      the carbon variability at this site is largely driven by variations in winter
      mixed-layer depths and by sea surface temperature anomalies. Because these
      variations tend to occur in a basinwide coordinated pattern associated with the
      North Atlantic Oscillation, it is plausible that the entire North Atlantic Ocean
      may vary in concert, resulting in a variability of the strength of the North
      Atlantic carbon sink of about +/-0.3 petagrams of carbon per year (1 petagram =
      10(15) grams) or nearly +/-50%. This extrapolation is supported by basin-wide
      estimates from atmospheric carbon dioxide inversions.

PMID- 12493912
TI  - Control of facial muscle development by MyoR and capsulin.
AB  - Members of the MyoD family of basic helix-loop-helix (bHLH) transcription factors
      control the formation of all skeletal muscles in vertebrates, but little is known
      of the molecules or mechanisms that confer unique identities to different types
      of skeletal muscles. MyoR and capsulin are related bHLH transcription factors
      expressed in specific facial muscle precursors. We show that specific facial
      muscles are missing in mice lacking both MyoR and capsulin, reflecting the
      absence of MyoD family gene expression and ablation of the corresponding myogenic
      lineages. These findings identify MyoR and capsulin as unique transcription
      factors for the development of specific head muscles.

PMID- 12493913
TI  - Genetic structure of human populations.
AB  - We studied human population structure using genotypes at 377 autosomal
      microsatellite loci in 1056 individuals from 52 populations. Within-population
      differences among individuals account for 93 to 95% of genetic variation;
      differences among major groups constitute only 3 to 5%. Nevertheless, without
      using prior information about the origins of individuals, we identified six main
      genetic clusters, five of which correspond to major geographic regions, and
      subclusters that often correspond to individual populations. General agreement of
      genetic and predefined populations suggests that self-reported ancestry can
      facilitate assessments of epidemiological risks but does not obviate the need to
      use genetic information in genetic association studies.

PMID- 12493914
TI  - CREM-dependent transcription in male germ cells controlled by a kinesin.
AB  - ACT is a LIM-only protein expressed exclusively in round spermatids, where it
      cooperates with transcriptional activator CREM in regulating various postmeiotic
      genes. Targeted inactivation of CREM leads to a complete block of mouse
      spermiogenesis. We sought to identify the regulatory steps controlling the
      functional interplay between CREM and ACT. We found that ACT selectively
      associates with KIF17b, a kinesin highly expressed in male germ cells. The ACT
      KIF17b interaction is restricted to specific stages of spermatogenesis and
      directly determines the intracellular localization of ACT. Sensitivity to
      leptomycin B indicates that KIF17b can be actively exported from the nucleus
      through the Crm1 receptor. Thus, a kinesin directly controls the activity of a
      transcriptional coactivator by a tight regulation of its intracellular
      localization.

PMID- 12493915
TI  - Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active
      lysine.
AB  - Acetyl-coenzyme A (CoA) synthetase (Acs) is an enzyme central to metabolism in
      prokaryotes and eukaryotes. Acs synthesizes acetyl CoA from acetate, adenosine
      triphosphate, and CoA through an acetyl-adenosine monophosphate (AMP)
      intermediate. Immunoblotting and mass spectrometry analysis showed that
      Salmonella enterica Acs enzyme activity is posttranslationally regulated by
      acetylation of lysine-609. Acetylation blocks synthesis of the adenylate
      intermediate but does not affect the thioester-forming activity of the enzyme.
      Activation of the acetylated enzyme requires the nicotinamide adenine
      dinucleotide-dependent protein deacetylase activity of the CobB Sir2 protein from
      S. enterica. We propose that acetylation modulates the activity of all the AMP
      forming family of enzymes, including nonribosomal peptide synthetases,
      luciferase, and aryl- and acyl-CoA synthetases. These findings extend our
      knowledge of the roles of Sir2 proteins in gene silencing, chromosome stability,
      and cell aging and imply that lysine acetylation is a common regulatory mechanism
      in eukaryotes and prokaryotes.

PMID- 12493916
TI  - A distinct signaling pathway used by the IgG-containing B cell antigen receptor.
AB  - The immunoglobulin G (IgG)-containing B lymphocyte antigen receptor (IgG-BCR)
      transmits a signal distinct from that of IgM-BCR or IgD-BCR, although all three
      use the same signal-transducing component, Igalpha/Igbeta. Here we demonstrate
      that the inhibitory coreceptor CD22 down-modulates signaling through IgM-BCR and
      IgD-BCR, but not that through IgG-BCR, because of the IgG cytoplasmic tail, which
      prevents CD22 phosphorylation. These results suggest that the cytoplasmic tail of
      IgG specifically enhances IgG-BCR signaling by preventing CD22-mediated signal
      inhibition. Enhanced signaling through IgG-BCR may be involved in efficient IgG
      production, which is crucial for immunity to pathogens.

PMID- 12493917
TI  - Photosynthetic light harvesting by carotenoids: detection of an intermediate
      excited state.
AB  - We present the first direct evidence of the presence of an intermediate singlet
      excited state (Sx) mediating the internal conversion from S2 to S1 in
      carotenoids. The S2 to Sx transition is extremely fast and is completed within
      approximately 50 femtoseconds. These results require a reassessment of the energy
      transfer pathways from carotenoids to chlorophylls in the primary step of
      photosynthesis.

PMID- 12493918
TI  - Coordinated nonvectorial folding in a newly synthesized multidomain protein.
AB  - The low-density lipoprotein receptor (LDL-R) is a typical example of a
      multidomain protein, for which in vivo folding is assumed to occur vectorially
      from the amino terminus to the carboxyl terminus. Using a pulse-chase approach in
      intact cells, we found instead that newly synthesized LDL-R molecules folded by
      way of "collapsed" intermediates that contained non-native disulfide bonds
      between distant cysteines. The most amino-terminal domain acquired its native
      conformation late in folding instead of during synthesis. Thus, productive LDL-R
      folding in a cell is not vectorial but is mostly posttranslational, and involves
      transient long-range non-native disulfide bonds that are isomerized into native
      short-range cysteine pairs.

PMID- 12493919
TI  - Tech.Sight. Bioelectronics. Biomaterials for sensors, fuel cells, and circuitry.

PMID- 12493920
TI  - Are comprehensive orthopaedic societies needed or relevant in the face of
      increasing sub-specialisation in orthopaedics and traumatology?

PMID- 12493921
TI  - Severe necrotising soft tissue infections in orthopaedic surgery.
AB  - PURPOSE: To review all cases of necrotising infection managed in the Department
      of Orthopaedic Surgery of Dunedin Hospital in New Zealand between 1989 and 1998.
      METHODS: Hospital records were analysed for predisposing factors, clinical
      features, diagnostic results, treatment strategies, and outcomes. RESULTS: 13
      cases (9 males and 4 females) of necrotising infection were identified. The mean
      age was 48 years (range, 8-76 years). Presenting symptoms included painful
      swelling, erythema, and necrosis. Most patients had predisposing factors and had
      received nonsteroidal anti-inflammatory drugs before presentation. 12 patients
      underwent surgical debridement including a total of 4 amputations. Septic shock
      developed in 9 patients who required dialysis for renal failure. Four patients
      died. The most common organisms identified were group A beta-haemolytic
      streptococci. CONCLUSION: Severe necrotising infections require a high index of
      suspicion and rapid medical and surgical intervention to reduce the mortality and
      morbidity.

PMID- 12493922
TI  - Laser doppler flow imaging of open lower leg fractures in an animal experimental
      model.
AB  - PURPOSE: Open lower leg fractures are frequently associated with severe soft
      tissue damage, followed by osteomyelitis. Using an animal experimental model, we
      investigated the effect of timing of coverage of a tibial fracture with a local
      muscle flap. METHODS: 80 rabbits had a tibial fracture induced in a standardised
      fashion, which was stabilised by screw osteosynthesis. After 3 (group A; n=40)
      and 7 days (group B; n=40), respectively, the tissue defect was covered by a
      local gastrocnemius flap. In increasing intervals from 1 to 2, 4, 8, and 16
      weeks, the rabbits from each group were killed and the bone fracture was analysed
      histomorphologically. Cortical microcirculation was measured by 2-channel laser
      doppler flowmetry. RESULTS: Muscle flaps after 3 days improved perfusion
      significantly as compared with 7 days (24 Flux [standard error, 5 Flux] versus 10
      Flux [3 Flux]; baseline, 1.4 Flux). Group A animals also displayed a lower rate
      of necrosis (0 versus 38). The incidence of osteomyelitis was higher in group B
      than in group A (24% versus 0%). CONCLUSION: Laser doppler flowmetry was proven
      to be a reliable, minimally invasive means for identifying avital tissue, leading
      to reduction in the loss of vital bone tissue in experimental settings.

PMID- 12493923
TI  - Giant cell tumour of bone with late presentation: review of treatment and
      outcome.
AB  - PURPOSE: To review cases of giant cell tumour of bone or osteoclastoma managed at
      the University Malaya Medical Center, University of Malaya, Kuala Lumpur, from
      January 1990 to December 1999. METHODS: Medical records of all patients with
      musculoskeletal tumours were reviewed. Demographic data, clinical presentation,
      surgical management, and clinical outcomes were reviewed retrospectively.
      RESULTS: Most of the 31 patients who were treated for giant cell tumour of bone
      presented late on the basis of the duration of their symptoms and radiological
      features. Five of the patients had been referred for local recurrences. 26
      patients were treated for primary tumours: 18 needed wide excision, 7 curettage,
      and one amputation. The joint could not be preserved and arthrodesis was
      performed for 11 patients. Three (12%) of the 26 patients had local recurrence
      during a mean follow-up of 60 months, including one (6%) who had recurrence after
      wide excision and 2 (29%) after curettage. Pulmonary metastasis was noted in 4
      cases, 2 of which were confirmed histologically. CONCLUSION: Even in an advanced
      stage of disease, good clinical outcomes can be achieved with adequate excision
      and appropriate reconstruction. For lesions around the knee, autologous
      rotational grafting is a good alternative method of reconstruction.

PMID- 12493924
TI  - Traumatic cervical cord injury at C3-4 without radiographic abnormalities:
      correlation of magnetic resonance findings with clinical features and outcome.
AB  - PURPOSE: Clinical features and outcomes of 43 patients at the Department of
      Orthopaedic Surgery, Okayama Rosai Hospital, Okayama, were studied prospectively.
      These patients were not found to have radiographic abnormalities but magnetic
      resonance images showed acute cervical spinal cord trauma at the C3-4 disc level.
      METHODS: Magnetic resonance images were analysed at presentation (immediately
      after the injury) and subsequent follow-up visits (at subacute and chronic
      stages, respectively) in an attempt to correlate imaging findings to clinical
      features and outcomes, respectively. RESULTS: The injury mechanism was usually a
      hyperextension of the cervical spine. The level of neurological involvement was
      assessed in 9 patients with complete tetraplegia: the motor level was C5 in 6
      patients and C4 in 3, whereas the sensory level was C5 in 7 patients, C4 in one,
      and C3 in one. Respiratory dysfunction in patients with severe paralysis, or numb
      and clumsy hands in patients with incomplete paralysis were the characteristic
      clinical features of cervical spinal cord injury at these lesions. Three patterns
      of signal change on magnetic resonance images were observed in patients with
      spinal cord injury at C3-4. A low-intensity area on T2-weighted images in the
      acute stage indicated a poor prognosis, while a high-intensity area at 2 to 3
      weeks after injury indicated some degree of permanent paralysis. CONCLUSION: The
      serial signal changes of magnetic resonance images and the clinical severity or
      outcome seemed to be well correlated.

PMID- 12493925
TI  - Postoperative outcome of lumbar spinal canal stenosis after fenestration:
      correlation with changes in intradural and extradural tube on magnetic resonance
      imaging.
AB  - PURPOSE: To evaluate the serial changes in clinical results and the intradural
      and extradural spaces on magnetic resonance imaging (MRI) after bilateral
      fenestration in 48 patients with lumbar spinal canal stenosis (LSCS). METHODS: A
      prospective interventional study was performed to study the clinical results,
      magnetic resonance imaging scans among patients who were followed up for more
      than 3 years. RESULTS: All patients showed improvement in clinical symptoms after
      operation, but clinical results deteriorated in 9 (19%) patients. Postoperative
      MRI scans showed that poor dural tube expansion, grouping of the cauda equina,
      and decrease in the cross-sectional area of the dural tube were factors
      associated with poor outcomes. The cross-sectional area of the dural tube and
      images of the cauda equina observed by MRI, before and after fenestration and
      during follow-up, reflected changes in clinical symptoms involving decompressed
      segments. CONCLUSION: Serial changes in the cross-sectional area of the dural
      tube and images of the cauda equina observed preoperatively, postoperatively, and
      on follow-up by MRI may be useful when evaluating patients' condition before and
      after operation. It is also useful for predicting outcomes.

PMID- 12493926
TI  - Spinal fusion and instrumentation for paediatric neuromuscular scoliosis:
      retrospective review.
AB  - PURPOSE: A retrospective study was conducted to review the surgical results among
      24 patients with neuromuscular scoliosis, who were treated with spinal
      instrumentation and fusion at the Department of Orthopaedic Surgery, National
      University Hospital, Singapore between March 1993 and December 1998. METHODS: We
      examined complete hospital records of patients who had scoliosis due to
      aetiologies such as spinal muscular atrophy, cerebral palsy, Duchenne muscular
      dystrophy, and congenital myopathies. The mean age of patients was 10.6 years
      (range, 6-14 years) and the mean follow-up duration was 5.5 years. RESULTS: 18
      patients had posterior surgery alone, whereas 4 had an anterior release with
      posterior instrumentation, and 2 had an anterior fusion with instrumentation. The
      mean length of stay in the intensive care unit was 2 days and the mean duration
      of hospital stay was 11 days. The mean correction in scoliosis angle ranged from
      75.6 degrees to 25.7 degrees. All patients could at least sit without support
      postoperatively. The one-second forced expiratory volume and forced vital
      capacity were, in general, maintained throughout the follow-up. There were 2
      major complications and 2 minor ones; these were pseudarthrosis with rod breakage
      requiring revision, deep infection necessitating hardware removal, superficial
      infection that responded to antibiotics, and urinary tract infection requiring 3
      weeks of antibiotic treatment. There were no deaths or any neurological
      complications after instrumentation. CONCLUSION: Spinal stabilisation and fusion
      in children with neuromuscular scoliosis is a safe and effective treatment
      modality. The effect of surgery on long-term pulmonary function, however, remains
      controversial and needs to be addressed.

PMID- 12493927
TI  - Early experience of endoscopy-assisted anterior spinal surgery.
AB  - PURPOSE: Endoscopy-assisted anterior spinal surgery is less invasive, resulting
      in less tissue trauma. It has a shorter recovery period, leads to less morbidity,
      and is more cost efficient than conventional surgery. We report our early
      experience of endoscopic anterior spinal surgery in Thailand, which was performed
      with a basic laparoscopic instrument set and self-developed instruments for
      spinal surgery. METHODS: All patients who underwent endoscopic anterior spinal
      surgery from July 2000 to May 2001 at the Orthopaedic Department, Nakhonpathom
      Hospital, Nakhonpathom were prospectively documented. The two-portal technique
      was applied on these patients: the first portal, a 4-cm skin incision, was made
      as the portal for the surgical instruments; the second portal, a one-cm skin
      incision, was made as the portal for the endoscope. RESULTS: Nine patients
      underwent anterior spinal surgery with the minimally invasive technique. The mean
      patient age was 51.5 years (range, 17-72 years); 3 patients were females and 6
      were males. The procedures included thoracoscopy, retroperitoneoscopy,
      diaphragmatic crus detachment, discectomy, corpectomy, fusion, and
      instrumentation. The mean operating time was one hour 58 minutes, and the mean
      estimated blood loss was 372 ml; there were no serious complications. CONCLUSION:
      Endoscopy-assisted anterior spinal surgery can be performed without spending a
      high budget; the procedure is not difficult if the surgeon can develop some
      instruments and has experiences with arthroscopic surgery and anterior spinal
      surgery.

PMID- 12493928
TI  - Brooks' posterior stabilisation surgery for atlantoaxial instability: review of
      54 cases.
AB  - PURPOSE: To assess the effectiveness of Brooks' posterior stabilisation and
      fusion for the unstable atlantoaxial joint due to congenital dysplastic dens and
      trauma. METHODS: We retrospectively studied records of 54 patients (36 males and
      18 females; age range, 3-58 years) who underwent Brooks' posterior stabilisation
      procedure between March 1975 and December 1999, at the Catholic University of
      Korea Medical Center and Dong-Shin General Hospital, Seoul. A single-stranded
      Kirschner wire was used to stabilise the first 19 cases (thin wires in 12 cases
      and thick wires in 7), and double-stranded wires were used in the next 35 cases
      (thin wires in 4 cases and thick wires in 31). After surgery, patients were
      immobilised in bed with light Halter traction of the head, followed by cervical
      bracing. RESULTS: Fusion was observed by X-ray postoperatively at 15 weeks in 48
      patients. Reduction was achieved in 3 luxation cases (including the single case
      of rotatory fixation). Brooks' fusion failed in 4 patients with dens fractures
      and 2 with dens anomaly. Four dens fractures in cases of successful Brooks'
      fusion in Brooks' fusion did not unite. Wire failure occurred in 4 cases of thin
      single-stranded wire fixation, namely, 2 cases of dens fractures and 2 of dens
      anomaly. CONCLUSION: Brooks' procedure is safe and has a high fusion rate when
      double-stranded strong wire fixation of the atlantoaxial joint is combined with
      meticulous bone grafting and subsequent cervical bracing.

PMID- 12493929
TI  - Salvaging unstable or recurrent dislocating total hip arthroplasty with the
      constrained acetabular component.
AB  - PURPOSE: To review cases of implantation of constraining acetabular components
      for unstable or recurrent dislocating total hip arthroplasty at the Department of
      Orthopaedics, Concord Hospital, Sydney. METHODS: A retrospective analysis was
      performed on prospectively collected data of 13 consecutively enrolled patients.
      RESULTS: From 1989 to 2000, 13 constraining acetabular components were implanted
      into 13 patients as a revision procedure. The surgical approach for the
      implantation of the constrained liner was posterolateral in 11 cases; a modified
      Hardinge approach was applied in 2 cases. The mean clinical follow-up duration
      was 43 months (range, 14-121 months) and the mean age at the time of surgery was
      73 years (range, 52-84 years). No patients were lost to follow-up. Indications
      for using the constrained acetabular component were recurrent dislocation in
      revision hip replacements (n=8), and intra-operative instability (n=5). There
      were no episodes of dislocation of the constrained arthroplasty. In 7 cases, the
      constrained component was implanted into a previously well-fixed shell.
      CONCLUSION: We recommend the judicious use of the constrained component in cases
      of hip instability during or after total hip arthroplasty when other methods are
      not successful.

PMID- 12493930
TI  - Chondrocyte damage following osteochondral grafting using metal and plastic
      punches: comparative study in an animal model.
AB  - PURPOSE: Osteochondral impaction grafting to manage isolated chondral defects in
      femoral condyles usually uses a metal punch to impact the grafts into predrilled
      cavities. Damage to the chondrocytes during impaction is a concern, however, and
      new methods are being sought to minimise the damage. We studied if impaction with
      a plastic punch instead of a metal punch reduces the extent of chondrocyte damage
      in an animal model. METHODS: 32 osteochondral plugs were prepared from knees of
      10 freshly slaughtered sheep knees; the contralateral condyles were then prepared
      to receive the osteochondral grafts. 20 plugs were impacted into predrilled
      holes: 10 using a metal punch and 10 using a plastic punch. The 12 remaining
      plugs were used as controls. The plugs were recovered, incubated for 24 hours in
      calf serum, and stained with 3-[4,5-dimethylthiazol]-2,5-diphenyltetrazolium to
      measure the content of viable cells. Digital photographs of the stained cartilage
      were then analysed on a 0-to-255 grey-scale. RESULTS: We found no significant
      difference in the extent of chondrocyte damage caused by impaction using metal
      and plastic punches. The content of viable cells in plugs impacted by metal and
      plastic punches, however, was significantly lower than that in the control plugs,
      as reflected by higher means of light intensity of 52.9 (p<0.001) and 32.4
      (p=0.005), respectively. CONCLUSION: Impaction grafting clearly damages
      chondrocytes of the osteochondral plug. The use of a plastic punch does not
      reduce the extent of chondrocyte damage during the impaction grafting procedure.

PMID- 12493931
TI  - Bone and soft tissue tumours of the foot: review of 83 cases.
AB  - PURPOSE: To review cases of bone and soft tissue tumours of the feet managed at
      the Hyogo College of Medicine, Nishinomiya and Takarazuka Municipal Hospital,
      Takarazuka, Japan. METHODS: Retrospective analysis of 83 patient records treated
      for bone and soft tissue tumours of the feet between 1974 and 2000. RESULTS:
      There were 33 benign bone tumours, one primary malignant bone tumour, and 2
      metastatic bone cancer. Marginal resection was performed in cases of
      osteochondroma and curettage in cases of other benign bone tumour. Despite below
      knee amputation in the case of chondrosarcoma, the patient died because of
      pulmonary metastasis. Two patients with metastatic cancer also died, and 2 cases
      of osteochondroma and one of benign chondroblastoma recurred. There were 47 cases
      of soft tissue tumour. Treatment for benign soft tissue tumours was marginal
      resection; no cases recurred. In contrast, all patients with soft tissue sarcoma
      died after surgery. The majority of bone tumours were located in the toe and
      hindfoot areas, in the first and second decades of life, whereas soft tissue
      tumours occurred mainly in the midfoot area and in patients aged between 20 and
      50 years. The sex distribution was almost even for bone tumours (male: female
      ratio, 19:17), whereas about half as many males as females had soft tissue
      tumours (14:33). CONCLUSION: Bone and soft tissue tumours of the feet are
      uncommon. Most bone tumours are chondrogenic, but differential diagnosis of
      malignant from benign disease is difficult and prognosis is poor. Management of
      benign tumours by marginal resection has good prognosis, whereas prognosis of
      soft tissue sarcomas is very poor.

PMID- 12493932
TI  - Local osteopenia associated with management of intra-articular distal radial
      fractures by insertion of external fixation pins in the distal fragment:
      prospective study.
AB  - PURPOSE: To assess the restoration of the bone mass of the distal radius
      following the use of implants in the distal radial fragment. Highly comminuted
      Frykman type 7 and 8 fractures were studied to determine whether the use of
      fixation pins in the comminuted distal radial fragment leads to osteopenia in the
      distal radial fragment after healing of the fracture. METHODS: As part of a
      clinical trial, 30 patients with comminuted intra-articular fractures of the
      distal radius were treated with closed reduction, external non-bridging fixation,
      and early postoperative mobilisation. To detect local osteopenia, bone density
      measurements were taken at the distal metaphysis and mid-diaphysis following
      healing of the fractured radius and the contralateral unaffected radius in 12
      patients. RESULT: The mean age of the 12 patients for whom bone density
      measurements were recorded was 52.5 years (range, 39-87 years). There were 9
      females and 3 males included in the study. Seven patients had a Frykman type 8
      fracture and 5 patients had a Frykman type 7 fracture. Significant osteopenia was
      absent despite the use of four 2.5-mm fixation pins in the distal fragments of
      the healed distal radial fracture. The median value of the maximal step was 2.8
      mm (range, 0-9.1 mm). The median value of the intra-articular interfragmentary
      gap was 1.8 mm (range, 0-13.4mm). CONCLUSION: The findings of this study do not
      suggest long-term osteopenia following the use of four 2.5-mm pins in the distal
      fragments. The non-bridging fixator, by allowing early physical activity,
      possibly led to satisfactory functional and structural results.

PMID- 12493933
TI  - Use of reconstruction nails to manage ipsilateral displaced femoral neck-shaft
      fractures: assessment of a new approach.
AB  - PURPOSE: Owing to unpredictable femoral neck reduction, reconstruction nails are
      not suitable for fixation of group 3 ipsilateral femoral neck-shaft fractures. We
      developed a new one-step fixation technique to overcome this problem. This study
      aims to assess this new technique at the Orthopaedic Department, Chi-Mei
      Foundation Medical Center, Tainan. METHODS: Of 31 consecutive patients with
      femoral fractures treated by reconstruction nails, five patients had group 3
      ipsilateral femoral neck-shaft fractures, 4 of whom were treated by a new
      surgical technique. Two 5.0-mm drills were firstly inserted to tether the
      trochanter fragment, and distal locking screws were secondly applied to
      immobilise the shaft fracture. The neck-shaft angle was then restored in a closed
      fashion and proximal cephalomedullary screws were attached. Patients were
      followed up by post-operative radiography. RESULTS: All 5 cases of group 3
      ipsilateral femoral neck-shaft fracture obtained radiographic union without
      significant surgical sequelae. Three of the patients had implants removed. No
      patients presented with osteonecrosis at the 3-year follow-up. CONCLUSION: The
      new approach to manage ipsilateral femoral neck-shaft fractures by using
      reconstruction nails obtains relatively good clinical results.

PMID- 12493934
TI  - Review article: knee flexion after total knee arthroplasty.
AB  - Many factors affect or predict the flexion range achieved after total knee
      arthroplasty. While the knees that have good preoperative flexion have better
      final flexion, knees with good preoperative flexion do lose some flexion whereas
      those with poor preoperative flexion can gain flexion. Although studies of
      different prosthetic designs have produced conflicting results, recent studies
      appear to favour posterior cruciate ligament (PCL)--substituting over PCL
      retaining prostheses. Several factors related to surgical techniques have been
      found to be important. These include the tightness of the retained posterior
      cruciate ligament, the elevation of the joint line, increased patellar thickness,
      and a trapezoidal flexion gap. Vigorous rehabilitation after surgery appears
      useful, while continuous passive motion has not been found to be effective.
      Obesity and previous surgery are poor prognostic factors; certain cultural
      factors, such as the Japanese style of sitting, offer 'unintentional' passive
      flexion and result in patients with better range. If the flexion after surgery is
      unsatisfactory, manipulation under anaesthesia within 3 months of the total knee
      arthroplasty can be beneficial.

PMID- 12493935
TI  - Using a custom mega prosthesis to treat hydatidosis of bone: a report of 3 cases.
AB  - Three cases of hydatidosis of bone with pathological fracture were treated by
      wide resection, custom mega prosthesis replacement, and chemotherapy. Two
      patients were females and one was male, with a mean age of 47 years (range, 38-55
      years). Two of them had a pathological fracture of the proximal femur, and one
      had a pathological fracture of the distal femur. All patients were treated
      postoperatively with albendazole 400 mg, twice daily, for 12 weeks. During the
      mean follow-up period of 4.5 years, no recurrence of Echinococcal infection was
      noticed. The use of the custom mega prosthesis technique has not been reported
      elsewhere, and hydatid disease of the bone can now be considered an extended
      indication for custom mega prosthesis in addition to its application in surgery
      for tumours and massive trauma.

PMID- 12493936
TI  - Reconstruction of a scalp and skull defect with free latissimus dorsi
      myocutaneous flap following dermatofibrosarcoma protuberans.
AB  - A 53-year-old male underwent more than 10 surgical treatments over 14 years,
      including a simple excision and local flap transfer, after recurrences of
      dermatofibrosarcoma protuberans of the head. Clinical results indicated that
      simple excision of dermatofibrosarcoma protuberans should not be performed as
      initial treatment. Instead, free flap transplantation, which permits a wide
      excision and complete reconstruction, should be the first treatment option.

PMID- 12493937
TI  - Repetition of an unusual stress fracture in an anorexic man: a case report.
AB  - Stress fractures of the fibula commonly occur distally in runners, whereas stress
      fractures of the proximal fibula are uncommon and typically occur in jumpers.
      Furthermore, it is rare for a stress fracture to be repeated in the same bone. We
      report a case of a repeated stress fracture of the proximal fibula in a male
      runner with abnormal gait that primarily involved excessive pronation. Unusual
      risk factors in this case were anorexia nervosa and use of an inhaled
      corticosteroid. The patient was treated conservatively, and healing of the
      fracture was completed at 12 weeks.

PMID- 12493944
TI  - Hear ye, hear ye: prevent hearing loss.

PMID- 12493945
TI  - What makes NPs politically active?

PMID- 12493946
TI  - Diagnose and treat mild to moderate Alzheimer's disease.
AB  - Early diagnosis and treatment of Alzheimer's disease, a chronic, debilitating
      disease, can delay cognitive, functional, and behavioral declines in afflicted
      patients. Here, learn how to diagnose and manage the disease with the latest
      pharmacologic approaches. Early diagnosis and treatment, coupled with caregiver
      support, can delay nursing home placement, improving patient well-being.

PMID- 12493947
TI  - How to help older adults quit smoking.
AB  - With the demographic trend toward an aging society, helping older smokers break a
      long-term nicotine addiction needs more attention. Clinicians should consider the
      subtle differences in the smoking patterns and the psychological meanings of
      smoking among older smokers when prescribing a successful smoking cessation
      modality. This article discusses the essential components of a smoking cessation
      program designed for these individuals.

PMID- 12493948
TI  - A look at asthma care in a university setting.
AB  - Is campus-based asthma care meeting students' needs? In this study, we examined
      asthma severity, impact, and quality of care in a sample of university students.
      Our research highlights the importance of designing university asthma programs
      specific to the needs of young adults that follow national asthma guidelines.

PMID- 12493949
TI  - Identifying the etiology of sleep problems in children.

PMID- 12493950
TI  - Why don't we receive equal reimbursement?

PMID- 12493951
TI  - Three-dimensional localization of sentinel lymph nodes using combined emission
      and transmission SPECT data.
AB  - PURPOSE: With conventional planar imaging, preoperative anatomic localization of
      a sentinel lymph node is possible in only two dimensions. To improve spatial
      localization of sentinel lymph nodes, a dual-head camera equipped with a
      transmission source was used to create combined transmission-emission SPECT
      images in a patient with a malignant melanoma of the left forearm. METHODS: Lymph
      node scintigraphy was performed after injection of Tc-99m-labeled nanocolloid
      around the tumor site 1 day before operation. SPECT was performed using a gamma
      camera equipped with a transmission collimator system originally designed to
      correct attenuation. Transmission and emission images were created
      simultaneously, matched, and displayed in three dimensions. RESULTS: In the
      combined emission-transmission images, the sentinel lymph node was clearly
      located in the left axilla. The lymph nodes could be identified during operation
      at the same location as that detected by SPECT. Based on preoperative
      information, the sentinel lymph node was identified rapidly and the extent and
      duration of the operation were minimized. CONCLUSIONS: This method provides
      better anatomic information, especially in deep structures such as the axilla or
      pelvis. With accurate three-dimensional preoperative information, intraoperative
      access is quicker and less invasive for the patient.

PMID- 12493952
TI  - Octreotide imaging plus bone scintigrams to optimally localize
      gastroenteropancreatic neuroendocrine tumors.
AB  - PURPOSE: In-111 pentetreotide (Octreotide) is highly sensitive for detecting
      gastroenteropancreatic neuroendocrine tumors and their metastases. However, a
      lack of landmarks makes it difficult to localize them anatomically. To overcome
      this difficulty, the authors simultaneously obtained Octreotide and bone
      tomoscintigrams, in addition to standard planar images. They used a bicolor scale
      to display pairs of scintigrams to easily identify the distribution of both
      tracers. METHODS: Twenty-one hours after Octreotide injection, Tc-99m MDP was
      also administered to the patients. Three hours later, dual-energy planar and
      tomographic data were acquired simultaneously. The latter were reconstructed
      using a filtered back-projection algorithm using a Metz filter. Both sets of data
      were displayed simultaneously using a bicolor scale, such that Octreotide data
      appear in green and bone data in red. RESULTS: Planar, tomographic, and three
      dimensional data were obtained. With this approach, foci of abnormal uptake are
      localized more precisely. Hard data can be transmitted easily to referring
      physicians, who appreciate this compact and efficient means to locate foci of
      abnormal uptake, especially during surgery planning. However, this method is not
      well suited to the visualization of small lesions with low Octreotide uptake
      because the intensity range is drastically reduced. Such lesions are better seen
      on Octreotide planar images and standard tomoscintigrams. CONCLUSIONS: This
      approach, which involves only standard image processing, provides landmarks to
      easily localize significant Octreotide uptake. It can be implemented readily in
      most nuclear medicine workstations. It complements but does not replace the usual
      method to display Octreotide data.

PMID- 12493953
TI  - Avascular necrosis of the talus.
AB  - Persistent pain in the ankle after relatively minor trauma is common and usually
      resolves spontaneously. Two cases of persistent pain after minor trauma are
      presented that involved unusual characteristics of scintigraphic and magnetic
      resonance imaging, compatible with avascular necrosis of the talar body. This is
      a rare finding in the absence of steroid use or significant trauma to the foot.
      The unusual vascular anatomy of the talus is considered in the possible mechanism
      of injury.

PMID- 12493954
TI  - Protocol for the combined diagnostic and therapeutic use of recombinant human
      thyroid-stimulating hormone.
AB  - Patients may be prepared for radioiodine diagnostic imaging by withdrawal of all
      thyroid medication or by the administration of extrinsic thyroid-stimulating
      hormone (TSH). Although purified human and bovine TSHs were used in the past,
      they are no longer recommended because of their adverse effects. Recently, a new
      extrinsic TSH called recombinant human TSH (rhTSH) was developed and is
      commercially available. It is a highly purified, recombinant form of the
      naturally occurring human TSH. It was introduced to decrease complications
      associated with temporary hypothyroid states required at times in the follow-up
      evaluation of patients with thyroid cancer. Although rhTSH is currently used for
      patient preparation in diagnosis only, its use in preparations for subsequent
      radioiodine therapy may be helpful in some clinical circumstances. The authors
      describe a patient with papillary thyroid cancer in whom a 2-day rhTSH protocol
      was used for diagnosis and extended for therapeutic purposes. The protocol was
      useful to obtain the diagnostic information needed to determine whether to treat,
      and it allowed rapid progress to therapy without further patient preparation.
      Until rhTSH is fully approved for both diagnostic and therapeutic uses, this
      modified 2-day protocol would allow patients with special clinical circumstances
      to be evaluated and treated rapidly.

PMID- 12493955
TI  - Unique contraction pattern in patients after coronary bypass graft surgery by
      gated SPECT myocardial perfusion imaging.
AB  - PURPOSE: Although left ventricular systolic function seems to be accurately
      represented on gated SPECT myocardial perfusion imaging, specific patterns of
      wall motion (WM) and thickening after coronary bypass graft surgery (CABG),
      demonstrated by other imaging methods, have not been characterized for gated
      SPECT myocardial perfusion imaging. METHODS: Gated SPECT myocardial perfusion
      imaging was studied in 30 consecutive patients after CABG (group 1) and 40 non
      CABG patients-30 with normal stress perfusion studies (group 2) and 10 with known
      previous anterior wall infarction (group 3). Two expert readers evaluated
      epicardial and endocardial systolic WM. Regional WM and the thickening percentage
      were obtained using CEQUAL 20 segment bull's eye analysis and compiled into
      regional values. RESULTS: Qualitatively, the post-CABG patients had hypokinetic
      septum, a hyperdynamic lateral wall, and preservation of anterior WM. In 25 of 30
      (83.3%) patients, an anterior systolic epicardial "swing" was evident and was
      different from the inward endocardial and epicardial motion seen in groups 2 and
      3. Septal WM was decreased in group 1 compared with group 2 (2.9 vs. 6.0 mm, <
      0.001), with no significant difference in septal thickening. This was not
      different from the reduced septal motion seen in group 3 (4.1 mm), which was
      accompanied by both reduced thickening and abnormalities of anterior WM. Lateral
      WM was increased in group 1 compared with group 2 (9.9 vs. 8.2, < 0.001), with no
      significant difference in lateral wall thickening (34.6% vs. 39%). CONCLUSIONS:
      There is a characteristic contraction pattern on gated SPECT myocardial perfusion
      imaging in post-CABG patients distinguished by apparent septal hypokinesis with
      preservation of septal wall thickening, apparent increase in endocardial lateral
      WM, and an anterior epicardial "swing," different from the contraction pattern
      seen in normal patients and those with previous anterior wall infarction. The
      related perfusion pattern aids in evaluation of the mechanism of these findings.

PMID- 12493956
TI  - Intense Ga-67 accumulation in pure primary mediastinal seminomas.
AB  - The authors examined three patients with pure primary mediastinal seminomas, all
      of whom had marked Ga-67 uptake on scintigraphy. The unusual presentation of
      sclerotic bone metastases with remarkable extraosseous soft tissue involvement
      was observed in one patient. Another had a seminoma associated with a
      multiloculated thymic cyst, which is a rare lesion.

PMID- 12493957
TI  - Tc-99m MIBI uptake and its relation to the proliferative potential of brain
      tumors.
AB  - PURPOSE: Many studies have shown that the S-phase fraction is a reflection of the
      proliferation potential of tumors, and DNA aneuploidy is more common in malignant
      tumors. In this preliminary study, the authors assessed the Tc-99m MIBI uptake of
      brain tumors and its relation to tumor grade and DNA content of the tumor cells.
      METHODS: Ten patients (eight male, two female; mean age, 53.2 +/- 6.11 years)
      with untreated brain tumors were included in the study. SPECT imaging was
      performed 20 minutes after injection of 740 MBq (20 mCi) Tc-99m MIBI. A single
      detector camera with a low-energy high-resolution collimator was used for image
      acquisition. A region of interest was drawn in the tumor area under magnetic
      resonance guidance. A Tc-99m MIBI uptake index was computed as the mean tumor-to
      background ratio. Flow cytometric analysis of fresh tumor tissue specimens was
      performed immediately. The percentages of cells in the G0/G1, S, and G2/M phases
      were determined for each patient. RESULTS: DNA aneuploidy was found in 4 (49%)
      patients, whereas diploidy was found in 6 (60%) patients. There was a significant
      positive correlation between the Tc-99m MIBI uptake and the percentage of the S
      phase fraction of the cell cycle ( = 0.000, r = 0.95). The Tc-99m MIBI index was
      significantly greater in aneuploid tumors than in diploid tumors ( < 0.01).
      CONCLUSIONS: High-grade brain tumors have increased Tc-99m MIBI uptake compared
      with that of low-grade tumors. Tc-99m MIBI uptake is correlated with the
      percentage of the S-phase fraction of the cell and the aneuploidy level of the
      brain tumor. This preliminary report suggests that Tc-99m MIBI imaging may be
      useful in the evaluation of the biologic characteristics of brain tumors.

PMID- 12493958
TI  - Massive pulmonary embolism presenting as complete unilateral absence of lung
      perfusion on pulmonary scintigraphy: correlative imaging with angiography and
      computed tomography.

PMID- 12493959
TI  - Aortic dissection causing a unilateral perfusion defect on lung scintigraphy.

PMID- 12493960
TI  - Splenosis detected by heat-denaturated Tc-99m red blood cell scintigraphy.

PMID- 12493961
TI  - An incidental pelvic spleen and splenule appearance on liver-spleen imaging.

PMID- 12493962
TI  - The incidental discovery of follicular thyroid cancer with in-111 pentetreotide
      scintigraphy in a patient with carcinoid tumor of the lung.

PMID- 12493963
TI  - Scintigraphic and computed tomographic imaging of isolated peripancreatic nodal
      gastrinomas.

PMID- 12493964
TI  - Bilateral stress fracture of the proximal fibula in a young soccer player on bone
      scanning.

PMID- 12493965
TI  - Langerhans cell histiocytosis of the lumbar spine.

PMID- 12493966
TI  - Osteopetrosis: a potential mimic of osteomyelitis on three-phase bone
      scintigraphy.

PMID- 12493967
TI  - Ollier's disease: characteristic Tc-99m MDP scan features.

PMID- 12493968
TI  - Accessory findings on F-18 FDG positron emission tomography in bronchogenic
      carcinoma.

PMID- 12493969
TI  - Positron emission tomography in intussusception of colon cancer, where computed
      tomography failed.

PMID- 12493970
TI  - Tc-99m HMPAO brain SPECT imaging for the diagnosis of gray matter heterotopia.

PMID- 12493971
TI  - Dynamic and static cerebral perfusion scintigraphy of cerebral arteriovenous
      malformations.

PMID- 12493972
TI  - Resting and acetazolamide-activated Tc-99m HMPAO brain SPECT for congenital
      bilateral absence of the internal carotid arteries.

PMID- 12493973
TI  - Renal abscess: filling in with Tc-99m ciprofloxacin of defects seen on Tc-99m
      DMSA SPECT.

PMID- 12493974
TI  - Peritoneal scintigraphy in the diagnosis of complications associated with
      continuous ambulatory peritoneal dialysis.

PMID- 12493975
TI  - Osseous localization of non-Hodgkin lymphoma shown on Tc-99m HMPAO-labeled
      leukocyte scintigraphy.

PMID- 12493976
TI  - Presacral mass evaluated with computed tomography and whole-body Tc-99m white
      blood cell imaging.

PMID- 12493977
TI  - Esophageal cancer detected by Tl-201 chest SPECT.

PMID- 12493978
TI  - Evolution of hyperostosis frontalis interna butterfly sign demonstrated by bone
      scan.

PMID- 12493979
TI  - Detecting vulvar cancer with inguinal lymph node metastases by dual-phase Tl-201
      scan.

PMID- 12493980
TI  - A guest editorial: stump the professor.

PMID- 12493981
TI  - Advances in endometrial ablation.
AB  - The evolution of the surgical treatment of dysfunctional uterine bleeding has
      resulted in the design and manufacture of instrumentation that is minimally
      invasive, has a low risk profile, and is technically simple to operate. Whereas
      hysterectomy was the only definitive surgical option before 1981, operative
      hysteroscopy with transcervical resection of the endometrium and rollerball
      ablation of the endometrium gained favor in the mid-1980s and 1990s. During the
      past 10 years, devices dedicated entirely to the ablation (or destruction) of the
      endometrium have been designed, modeled, tested, and approved for clinical use in
      the United States. This review describes the methods by which the technologies
      are evaluated and approved for clinical use by the Food and Drug Administration.
      In addition, the reported efficacy of each approved device is reviewed. The
      complications associated with the devices, as well as the potential long-term
      risks of endometrial ablation, also are reported. Finally, the cost for device
      disposables and nondisposables is presented. TARGET AUDIENCE: Obstetricians &
      Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this
      article, the reader will be able to list the various FDA-approved uterine
      ablation devices, compare the effectiveness of the various uterine ablation
      devices, and summarize the various adverse events associated with the use of the
      uterine ablation devices.

PMID- 12493982
TI  - Asymptomatic postmenopausal simple ovarian cyst.
AB  - High-resolution transvaginal ultrasound frequently reveals incidental, simple
      ovarian cysts in asymptomatic postmenopausal women. Traditionally oophorectomy
      has been recommended for these women. However, evidence is emerging that most
      postmenopausal simple ovarian cysts are benign, allowing conservative management.
      Furthermore, many of these cysts will resolve spontaneously. Cancer antigen 125
      (CA-125) and color Doppler may help differentiate benign from malignant cysts.
      When oophorectomy is favored, the laparoscopic approach may be considered,
      depending on the clinical situation. Nonoperative management of simple ovarian
      cysts in asymptomatic women is reasonable; regular follow-up with sonography
      should be performed. Because sonography is an operator-dependent test, it is
      imperative that the sonographer have expertise in ovarian imaging. Monitoring of
      CA-125 levels may be useful. Indications for removal during follow-up are
      increasing size, development of solid components, abnormal Doppler flow, CA-125
      elevation, patient desire for removal of the cyst, and noncompliance with
      sonographic follow-up. TARGET AUDIENCE: Obstetricians & Gynecologists, Family
      Physicians LEARNING OBJECTIVES: After completion of this article, the reader will
      be able to estimate the prevalence of benign simple ovarian cysts in a
      postmenopausal population of women, to describe the natural history of a simple
      ovarian cyst, and outline the features consistent with a benign ovarian cyst on
      ultrasound.

PMID- 12493983
TI  - Factors affecting early surgical intervention after uterine artery embolization.
AB  - Uterine artery embolization (UAE) is an effective technique for the management of
      uterine myoma. However, complications of this procedure can be serious, including
      uterine infection and bowel necrosis in conjunction with necrosis of subserous or
      pedunculated myomas. Treatment failure is more likely to occur in the presence of
      submucosal myoma associated with a uterine infection or a large myoma of more
      than 8 cm. Accordingly, patients whose primary symptoms include submucosal myoma
      and menorrhagia are best treated with a hysteroscopic myomectomy or hysterectomy.
      The role of the gynecologist is crucial for most effective management and safe
      use of uterine artery embolization. TARGET AUDIENCE: Obstetricians &
      Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this
      article, the reader will be able to list the complications of uterine artery
      embolization for fibroids, to describe postembolization syndrome, and identify
      the myomas that are more likely to fail uterine artery embolization.

PMID- 12493984
TI  - Jems on the move.

PMID- 12493985
TI  - Learn from history.

PMID- 12493986
TI  - A call to action.

PMID- 12493987
TI  - Cardiac alert: Aurora Fire Department advances cardiac care through cardiac cath
      lab field activation.

PMID- 12493988
TI  - Hydrofluoric acid exposures: preparing personnel for the care of patients
      involved in HF acid incidents.

PMID- 12493989
TI  - The sterile blade: hospital emergency department partners with EMS on
      laryngoscope disinfection process.

PMID- 12493990
TI  - AIDS update: occupational exposure & post-exposure treatment of HIV/AIDS.
AB  - HCPs in the United States have many benefits that work in their favor to help
      reduce the risk for disease transmission. The United States has laws and
      regulations regarding the implementation of needlesafe devices to reduce
      needlestick injuries. PEP is readily available when needed, and AIDS cases
      continue to decline nationwide. Personal protective equipment is readily
      available. Case numbers for occupational transmission of HIV infection to HCPs
      remain low. The United States also has set a national goal to cut new HIV
      infections in half by the year 2005. Federal law requires every EMS department to
      establish a designated infection control officer. Infection control officers must
      review and evaluate exposure incidents and ensure prompt, proper medical follow
      up.

PMID- 12493991
TI  - Use your 12-lead's full potential.

PMID- 12493992
TI  - One and, two and, three and... Ever wanted a better way to perform chest
      compressions? The AutoPulse might be the key.

PMID- 12493993
TI  - Acute coronary syndromes revisited.

PMID- 12493994
TI  - Tie-downs. Use of restraints, part 1.

PMID- 12493995
TI  - Data security. Are you headed for a data disaster?

PMID- 12493997
TI  - Boneheads kill appetites for knowledge.

PMID- 12493998
TI  - FirstWatch: bioterrorism alert system for EMS.

PMID- 12493999
TI  - Up close and personal.

PMID- 12494000
TI  - Long-term care nurses' knowledge of end-of-life care.
AB  - Long-term care (LTC) facilities usually contract with hospice agencies to provide
      palliative (comfort) care to their terminally ill residents, yet only 1% of
      nursing home residents enroll in hospice care. Integrating hospice services with
      nursing home services presents many challenges. One of the most critical
      challenges is the lack of education in palliative care among physicians, licensed
      nurses, and certified nursing assistants in LTC settings. A study of 164 licensed
      nurses from 24 LTC facilities in north central Texas found deficiencies in their
      knowledge of palliative care. The mean score on the Palliative Care Quiz for
      Nursing was 12.3 of a possible 20 (62%, SD = 2.7). Implications for practice
      include a critical need for in-service education on end-of-life content for
      practicing LTC nurses and integration of such content in all curricula for future
      nurses.

PMID- 12494001
TI  - The nurse's role in end-of-life decision-making for patients and families.
AB  - This article discusses some of the cultural changes required for organizations to
      build systems that move beyond mere completion of the advance directive to
      advance care planning that affects end-of-life decision-making. It specifically
      describes one organization's educational approach to clarifying the role of the
      nurse as patient advocate within these cultural changes and suggests strategies
      to help the nurse gain necessary competence in end-of-life decision-making.

PMID- 12494003
TI  - Implementing a do-not-resuscitate order in an adult day center.
AB  - Participants in adult day centers may indicate that they do not want to be
      resuscitated if they have a life-threatening health crisis. To comply with their
      wishes the adult day center needs to have policies procedures in place to
      professionally legally safeguard the institution. These authors describe the
      process for developing implementing the do-not-resuscitate policy.

PMID- 12494004
TI  - A family assessment tool for hospitalized elders.
AB  - This article describes the development of the FAMILY card, a family assessment
      instrument used in the Nursing Care Quality Initiative (NCQI) to assess the
      involvement and needs of family members of hospitalized elders. Through the NCQI
      project, particular attention has been paid to integrating both clinical
      expertise in geriatric nursing care and the principles of family-centered care
      into the nursing care provided by staff on the NCQI study units. Two case studies
      illustrating use of the SPICES geriatric assessment instrument and the newly
      developed FAMILY assessment card are included as exemplars.

PMID- 12494005
TI  - Warmed blankets: an intervention to promote comfort for elderly hospitalized
      patients.
AB  - A common complaint among hospitalized elderly patients is discomfort related to
      the cool environment. The purpose of this pilot study was to examine the effect
      of the application of a warmed blanket on the level of comfort in elderly
      hospitalized patients. A sample of 49 older adults who complained of feeling
      uncomfortable (in pain, being cold, or feeling anxious) were measured on their
      level of discomfort before and 1 hour after the application of a warm blanket.
      The level of discomfort after receiving the blanket was significantly less (P
      <.001).

PMID- 12494006
TI  - Issues of attraction, retention, and affective states for geriatric nurse
      practitioners in long-term care.
AB  - Limited research exists on self-reported geriatric nurse practitioner (GNP)
      perceptions. Thirty-six GNPs completed a survey for level of importance rather
      than rank-order. Subjects also completed the Profile of Mood States. Through the
      use of Pearson correlation techniques, results indicate that the number of years
      in nursing was related to appreciation from patients, one of the factors keeping
      GNPs satisfied with long-term care (r =.503). Results indicate that these GNPs
      had a higher overall affect compared with college norms.

PMID- 12494008
TI  - The Memorial Meal Mates: a program to improve nutrition in hospitalized older
      adults.
AB  - A common problem among older hospitalized patients is inadequate nutritional
      intake. The Memorial Meal Mates project was developed to address this problem.
      College-aged volunteers were provided a 3-hour in-service taught by an
      interdisciplinary team. During a 2-month period, the Memorial Meal Mates fed 34
      patients, who were compared with 34 other patients fed by nursing staff. The mean
      intake of the Meal Mates group was 58.88%, compared with the mean intake of the
      control group of 32.45%. Patients fed by the volunteers nearly doubled their
      intake over those fed by nursing staff.

PMID- 12494010
TI  - [Is it real to replace angiotensin converting enzyme inhibitors as basic remedy
      in the treatment of chronic heart failure?].

PMID- 12494009
TI  - 2002 Mosby Geriatric Nurse Manager awards: John Roske and Barbara Kremer-Schmitt.

PMID- 12494011
TI  - [Modification of clinical classification of heart failure with quantitative
      evaluation of functional state].
AB  - Definite dissociation exists between severity of clinical symptoms of heart
      failure and degree of cardiac dysfunction. Comparative analysis of existing heart
      failure classifications reveals low degree of congruence in evaluation of
      patient's state by different experts. This disagreement is mainly caused by
      limited number of gradations in NYHA classification and descriptive character of
      information. That is why supplementation of current classification with
      quantitative assessment of functional state by means of introduction of precise
      and easily obtainable statements is required. A modification of 6 min walk test
      is suggested for this purpose. The paper contains methodology of the test and
      calculations necessary for assessment of working capacity (in joules) and
      intensity of work (in watts). Possibility of evaluation of results of
      cardiovascular surgery is especially stressed.

PMID- 12494012
TI  - [Treadmill stress-echocardiography in diagnosis of coronary artery involvement in
      patients with various probability of ischemic heart disease].
AB  - Results of treadmill stress-echocardiography were compared with those of coronary
      angiography in 153 patients (133 men, 20 women, mean age 55.7-/+8.5 years) with
      various initial probability of ischemic heart disease (IHD) which was determined
      for each patient basing on sex, age and status of angina. Probabilities of IHD >
      or = 75% and >10% but <7 5% were considered high and intermediate, respectively.
      According to coronary angiography 40 patients had no significant coronary artery
      stenoses while 32, 36 and 45 patients had hemodynamically significant single,
      double and triple vessel stenoses, respectively. The use of echocardiographic
      criteria of myocardial ischemia allowed to increase sensitivity of treadmill test
      in patients with high IHD probability from 74 to 91% (p<0.01) and its specificity
      in patients with intermediate IHD probability from 45 to 83% (p<0.001). Value of
      stress-echocardiography for diagnosis of the presence of stenotic lesions in
      coronary arteries depended on initial probability of IHD.

PMID- 12494013
TI  - [Synchronous antihypertensive and antiischemic action of lacidipine in elderly
      patients with hypertension and ischemic heart disease].

PMID- 12494014
TI  - [Changes of autologous coronary vessels and aortocoronary grafts in patients with
      ischemic heart disease after coronary artery bypass grafting].
AB  - AIM: 1) to assess effect of coronary lesion morphology on changes of grafts
      during first year after surgery; 2) to study the state of native coronary
      vascular bed during first year after surgery; 3) to elucidate special features of
      atherosclerosis in grafts and coronary arteries in remote period after surgery.
      MATERIAL AND METHODS: One hundred eighty seven patients with 3-vessel coronary
      artery disease subjected to aorto-coronary or mammary-coronary grafting. RESULTS
      AND CONCLUSION: Proportions of closed venous grafts were 24,2% among grafts to
      arteries with 50-75% stenoses, 13.1% among grafts to occluded arteries (p=0.023),
      and 20.1% among grafts to arteries with 75-99% stenoses. Among venous grafts to
      arteries with lumen diameter <1.5 mm 30.4% were occluded what was significantly
      more than among grafts to vessels with 1.5-2.5 mm (15.5%, p=0.003) and >2.5 mm
      (14.5%, p=0.004) diameter. Morphological risk factors of venous graft closure in
      immediate postoperative period were 50-75% stenosis and lumen diameter <1.5 mm.
      All mammary-coronary anastomoses were patent in 1 year, 99% of them remained
      patent 5 years after surgery. No relationship was found between patency of venous
      grafts after 5 years of follow-up and morphological characteristics (lumen
      diameter and percent stenosis) of bypassed arteries. During first year there was
      no significant differences between patients with patent and occluded grafts both
      in incidences of novel atherosclerotic lesions (10.4 and 10.3%, respectively,
      p=0.943) and proportion of closures of initially stenotic arteries (9.6 and
      10.3%, respectively, p=0.085). After 5 years novel atherosclerotic lesions were
      found in 31.9 and 33.6% of patients with patent and occluded grafts, respectively
      (p=0.910). Complete occlusions of stenosed vessels proximal to anastomosis
      occurred more often among patients with patent than with occluded grafts (28.6
      and 15.9%, respectively, p=0.047). Thus in remote postoperative period
      development of atherosclerosis in proximal segments of arteries with patent
      grafts was more 'aggressive' than in arteries with occluded grafts.

PMID- 12494015
TI  - [Antihypertensive efficacy and tolerability of nebivolol].
AB  - Nebivolol was given to 59 patients with hypertension for 8 weeks. This was
      accompanied by augmentation of amplitude of photoplethysmogram in all and
      normalization of blood pressure in 67% of patients. Nebivolol did not cause
      orthostatic hypotension or bronchial spasm.

PMID- 12494016
TI  - [Simvastatin (40 mg/day) in patients with hereditary hypercholesterolemia: effect
      on high density lipoprotein cholesterol].
AB  - AIM: To study effect of simvastatin of the level of high density lipoprotein
      (HDL) cholesterol (CH). MATERIAL AND METHODS: Simvastatin (40 mg/day) was given
      for 3 months to 15 patients (3 men, 12 women, mean age 56-/+10.3 years) with
      hereditary type II hypercholesterolemia after washout from lipid lowering
      therapy. Initial level of HDL CH was below and above 1.0 mmol/l in 7 and 8
      patients, respectively. Blood lipids, activity of liver enzymes and creatine
      kinase were determined after 1 and 3 months of therapy with simvastatin. Safety
      and tolerability of simvastatin were also studied. RESULTS: Simvastatin was well
      tolerated. In 1 patient the drug was stopped because of pain in the liver and
      nausea. In patients with initially low HDL CH levels of total and low density
      lipoprotein (LDL) CH significantly decreased by 29.6 and 36.8%, respectively,
      after 3 months, while level of HDL CH increased by 20% after 1 month of therapy.
      In patients with initially normal HDL CH levels of total and LDL CH significantly
      decreased by 31.1 and 32.6%, respectively, while those of triglycerides and HDL
      CH did not change. CONCLUSION: In patients with hereditary hypercholesterolemia
      40 mg/day of simvastatin besides pronounced lowering of LDL CH level caused
      significant increase of HDL CH (up to 20% in 1 month) in patients with initially
      low level of this parameter.

PMID- 12494017
TI  - [Prolonged pulmonary artery pressure monitoring in patients with pulmonary
      hypertension].
AB  - Pulmonary artery pressure (PAP) was monitored for 24-48 hours in 10 and 8
      patients with primary and secondary pulmonary hypertension, respectively. The
      data obtained were compared with results of prolonged PAP monitoring in 2 healthy
      volunteers. Variability of mean PAP was 7.43-/+3.1, 5.78-/+1.64, and 3.4-/+0.63
      mm Hg, coefficient of variability - 10.39-/+3.68, 13.04-/+6.01 and 22.73-/+8.03%
      in patients with primary and secondary pulmonary hypertension and healthy
      subjects, respectively. After surgery in patients with secondary pulmonary
      hypertension coefficient of variability rose from 13.04-/+6.01 to 16.7-/+12.8%,
      while variability decreased from 5.78-/+1.64 to 4.3-/+1.65 mm Hg. Level of
      spontaneous fluctuations of PAP was the highest in healthy subjects (71.4%) and
      the lowest - in patients with primary pulmonary hypertension (34.9%). Thus PAP
      variability is a widespread phenomenon which should be taken into consideration
      during right heart catheterization and acute pharmacological tests.

PMID- 12494018
TI  - [Decreased ATP-synthesis ability of liver mitochondria in spontaneously
      hypertensive rats (SHR): role of calcium overload of the mitochondria].
AB  - It has been shown previously, that a decrease of ATP amount and changed balance
      of the other macroergic phosphates are observed in different tissues of
      spontaneously hypertensive rats (SHR) compared with the normotensive controls
      (WKY). The aim of the present study was to assess the ability of SHR liver
      isolated mitochondria to synthesize ATP and to clarify its dependence on
      extramitochondrial calcium concentration. Macroergic phosphate concentrations
      were measured by high performance liquid chromatography (HPLC). The present work
      shows for the first time, that SHR liver mitochondria initially differ from WKY
      ones by decreased (by 30%) ATP synthesis rate. Respiratory control coefficient
      and phosphorylation rate in SHR and WKY mitochondria change in different manner
      when extramitochondrial calcium concentration increases from 0 to 50 microM. When
      calcium concentration is increased up to 50 microM both parameters in WKY
      mitochondria are about one half compared with the condition when the medium does
      not contain calcium. In the conditions, when the medium contains 50 microM of
      calcium, complete uncoupling of oxidation and phosphorylation in SHR mitochondria
      is observed. Thus the decrease of ATP synthesis rate in SHR mitochondria in
      conjunction with reduced tolerance to calcium overload (by respiratory control
      coefficient and phosphorylation rate) in comparison with WKY may be considered as
      the main cause of cell energy deficiency, observed in experimental variant of
      primary arterial hypertension.

PMID- 12494019
TI  - [The protective action of ubiquinone at ischemia and reperfusion].
AB  - Effects of prolonged consumption of ubiquinone on myocardial injury caused by
      ischemia and reperfusion were studied in reperfused rat hearts. Wistar rats
      received lipophylic or hydrophilic forms of ubiquinone for 6-8 weeks with chow or
      water, respectively. Isolated isovolumic hearts with a constant volume latex
      balloon in the left ventricular cavity were subjected to total normothermic
      ischemia (25 min) and subsequent reperfusion (50 min). Time course of ischemic
      contracture and its level in both groups of ubiquinone treated animals were
      similar to those in controls. However recovery of left ventricular developed
      pressure after reperfusion was significantly better in both ubiquinone groups (54
      /+9, 65-/+7, and 24-/+4 mm Hg in animals treated with lipophylic and hydrophylic
      ubiquinone and controls, respectively, p<0.01). As a result the developed
      pressure and heart rate product reflecting maximal aerobic capacity of the heart
      was also better restored. Both ubiquinone groups demonstrated absence of
      increased coronary tone that was characteristic for control animals. Mitochondria
      isolated from reperfused hearts of ubiquinone treated rats showed better
      preservation of structure and respiratory control. Rate of succinate-dependent
      generation of superoxide radicals determined with a spin trap TIRON in
      mitochondria from hearts of rats treated with hydrophylic ubiquinone (35-/+8 mmol
      O(2) /min/g) was approximately twice lower (p<0.05) than in control group (74
      /+12 mmol O(2) /min/g) while the value in lipophylic ubiquinone group (48-/+9
      mmol O(2) /min/g) did not differ significantly from the control. The results
      evidence that prolonged consumption of water-soluble ubiquinone increases
      resistance of rat myocardium to injuring action of reperfusion.

PMID- 12494020
TI  - [Fungal myocarditis in deep visceral candidiasis].
AB  - Morphological and functional changes of the myocardium were studied in 40
      patients with candidiasis and attempt to establish morphological criteria of
      fungal myocarditis was undertaken. Retrospective analysis of autopsy material
      showed that myocardial involvement in candidiasis was possible and was not as
      rare as it had been accepted. Clinical symptomatology was not always similar to
      that of classical infectious-allergic myocarditis. However immunological
      parameters were characteristic of inflammatory process. Complex echocardiographic
      study gave important information for assessment of the state of the myocardium.

PMID- 12494022
TI  - [Phenotypic characteristics of patients with primary disorders of cardiac
      conduction].

PMID- 12494021
TI  - [Interrelationship between derangements of autonomic regulation of cardiac
      rhythm, severity of coronary atherosclerosis, and left ventricular contractility
      in patients with myocardial infarction].

PMID- 12494023
TI  - [Etio-pathogenetic mechanisms of recurrences of atrial fibrillation of toxic
      alcoholic origin].
AB  - The following conditions in patients with alcoholic cardiac involvement
      predispose to recurrences of atrial fibrillation: atrial dilatation, shortening
      of refractory period, slowing of atrial conduction, increased vulnerability to
      extra stimuli, appearance of fragmented electrical activity i.e. late atrial
      potentials on high resolution ECG, autonomic influences on the heart, hypokalemia
      and hypomagnesemia.

PMID- 12494024
TI  - [News from the conference of arterial hypertension, Praga, 2002].

PMID- 12494025
TI  - [Third generation of calcium antagonists: focus on lacidipine].
AB  - Similarities and dissimilarities of 3 third generation calcium antagonist
      (amlodipine, lacidipine and lercanidipine) are presented. Lacidipine is
      characterized by prolonged antihypertensive action despite its plasma half life
      is just about 14 hours. Duration of lacidipine effect can be explained by
      accumulation in lipid bilayer of cellular membranes where it interacts with
      calcium channels. Pharmacodynamics of lacidipine is discussed in detail as well
      as experience of its use in hypertension including data of ELSA study which has
      demonstrated ability of lacidipine to inhibit progression of carotid artery
      atherosclerosis.

PMID- 12494026
TI  - [Metabolic syndrome from the point of view of a cardiologist: diagnosis, non drug
      and drug treatment].
AB  - Timely diagnosis and treatment of metabolic syndrome is important because of high
      prevalence of this pathology in population. For the elaboration of approaches to
      complex treatment of this syndrome it is necessary to understand pathogenetic
      mechanisms of development of hypertension and metabolic changes as well as
      acquire an array of non drug and drug methods of influence on elevated blood
      pressure and disordered carbohydrate, lipid and purine metabolism.
      Phenylalkylamine calcium antagonists should be used as drugs of choice for
      treatment of hypertension. These agents exert slowing of heart rate,
      coronarolytic and antiatherogenic effects, the latter being especially important
      in this group of patients. Resistance of hypertension to treatment developing on
      the background of insulin resistance of peripheral tissues dictates necessity of
      the use of combinations of antihypertensive drugs with consideration of their
      metabolic effects. For correction of metabolic changes metformin is used in
      addition to non drug methods which include diet and exercise. Treatment with
      metformin allows to decrease insulin resistance and thus severity of derangements
      of metabolism.

PMID- 12494027
TI  - [The role of mast cell population in aortic intima in development of human
      atherosclerosis].
AB  - AIM: To assess the role of mast cells in development of human atherosclerosis.
      MATERIAL: Autopsy material (transverse cross-sections of the aorta and membranous
      preparations of intima) from 53 persons who died of accidental causes. Original
      method of the study of aortic cellular populations on membranous preparations of
      intima allowed to analyze character of accumulation of lipids in fatty streaks,
      as well as changes of mast cells and relative amount of various cellular
      populations in intact intima and during development of early atherosclerotic
      lesions. RESULTS: In intact intima mast cells are consistently found, their
      quantity depends on age and degree of intimal hyperplasia. Density of mast cell
      population in age groups 17-29 and 30-49 years was 5.8 and 9.6 cells/mm2,
      respectively. Ratio of mast cells to total amount of lymphocytes and monocytes
      was 1:6. Two types of fatty streaks ('early' and 'transitional') can be
      distinguished depending on structure of lipid inclusions and cellular
      composition. Compared with intact intima 'early' fatty streaks have increased
      content of lymphocytes and monocytes. Average density of mast cells in early
      streaks is 12.2 cells/mm2 with ratio of mast cells to total amount of lymphocytes
      and monocytes 1:11. Development of 'transitional' fatty streaks preceding plaque
      formation is characterized by signs of inflammation with multifold increase of
      content of lymphocytes and monocytes and ratio of amount of mast cells to that of
      mononuclear cells 1:20. Density of mast cells including their degranulating forms
      is the highest (18.1 cells/mm2) on periphery of 'transitional' fatty streaks
      while substantially smaller amount of mast cells (3.2 cells/mm2) can be found in
      central areas of these streaks. CONCLUSION: Mast cells actively participate in
      atherogenesis, development and progression of atherosclerotic lesions. Formation
      of fatty streaks in human aorta is associated with signs of immune inflammation
      (lymphocytic-monocytic reaction and increased amount of mast cells).

PMID- 12494028
TI  - [Prognostic significance of treadmill stress-echocardiography in patients with
      ischemic heart disease].
AB  - Prognostic value of treadmill echocardiography was studied in 146 patients (125
      men, 21 women, age 58,6-/+9 years) with overt or suspected ischemic heart
      disease. During 35-/+6 months of follow-up there were 26 cardiac events (11
      cardiovascular deaths, 6 myocardial infarctions and 9 revascularization
      procedures). Independent predictors of events were presence of angina, maximal
      heart rate, and result of a stress test. Both exercise tolerance and
      echocardiographical signs of ischemia were related to development of events
      however the latter had better predictive power. Among patients with exercise
      tolerance below 7 METS with and without ischemia rates of events were 33 and 11%,
      respectively. Among patients with exercise tolerance above 7 METS with and
      without ischemia event rates were 23 and 6.8%, respectively.

PMID- 12494029
TI  - [Significance of trimetazidine for out of hospital physical rehabilitation after
      myocardial infarction].

PMID- 12494030
TI  - [Postinfarction angina in elderly patients: results of surgical and drug
      treatment].
AB  - Clinical and angiographical characteristics and results of surgical treatment and
      drug therapy were assessed in 49 men with postinfarction angina (mean age 64.1
      /+3.5 years) and 112 patients with progressing and stable angina (mean age 63.8
      /+3.0 years). Of 49 patients with postinfarction angina 30 were subjected to
      coronary artery bypass grafting (CABG) while 19 were treated with drugs only.
      Remote results were known in 17 and 19 patients of surgical and conservative
      groups, respectively. Average duration of follow-up was 66-/+20 months. Compared
      with patients with progressing and stable angina those with postinfarction angina
      had similar amplitude of ST-segment deviation during stress tests, ejection
      fraction, average number of involved coronary vessels, and profile of concomitant
      diseases, but higher prevalence of left main stenoses (23.6 and 40.8%,
      respectively, p=0.05). Among patients with postinfarction angina available for
      follow-up long-term survival of those treated with CABG was higher compared with
      patients treated conservatively (p=0.02). Nonfatal myocardial infarction
      developed in 17.7 and 31.6%, symptomatic improvement was registered in 76.5 and
      5.3% of patients in surgical and conservative groups, respectively. In patients
      with postinfarction angina aged >or=60 years CABG surgery compared with drug
      therapy was associated with better survival and improved symptomatic status.

PMID- 12494031
TI  - [Doppler echocardiographic assessment of hemodynamic parameters on patients with
      tetralogy of Fallot].
AB  - Continuous Doppler echocardiography was used for the study of hemodynamic
      parameters on various stages of treatment of 61 children (mean age 12.4 months)
      with tetralogy of Fallot. Twenty five patients were studied before surgery during
      spells of cyanosis and hyperpnea. Thirty six patients were treated with systemic 
      pulmonary arterial anastomosis and in 25 patients total correction was carried
      out. Doppler echocardiographic study was repeated in 2 weeks and 1 year after
      surgery. Attack of cyanosis and hyperpnea was associated with reduction of
      pulmonary blood flow and increase of venoaortic shunting. Comparison of
      hemodynamic parameters before and after creation of aorta-to-pulmonary artery
      anastomosis allowed to establish Doppler echocardiographic criteria of assessment
      of the anastomosis functional state. Repetitive Doppler echocardiographic studies
      showed that hemodynamic results of total correction depended on the type of
      repair of right ventricular outflow tract. Severity of pulmonary artery valve
      insufficiency also depended on the type and extent of surgical intervention.

PMID- 12494032
TI  - [Stability of diurnal blood pressure rhythm during 48-hour ambulatory blood
      pressure monitoring].
AB  - Evaluation of nocturnal blood pressure (BP) fall is important for prognosis and
      selection of antihypertensive therapy. We assessed stability of BP diurnal rhythm
      in 56 hospitalized hypertensive patients by means of 48-hour ambulatory BP
      monitoring. According to the degree of congruence of BP fall during two nights of
      monitoring the following groups of patients were distinguished: with similar
      diurnal BP rhythm in both nights (72% of all patients, including 42% with
      sufficient and 30% with insufficient nocturnal BP decline), with different
      diurnal BP rhythms - with sufficient fall of BP in one night and insufficient in
      another (28% of all patients). BP variability in all patients did not change and
      could be considered very stable. Thus when insufficient nocturnal BP fall is
      detected its stability should be confirmed by repeat BP monitoring.

PMID- 12494033
TI  - [Pathogenetic role of moxonidine in the treatment of hypertension in
      postmenopausal women].
AB  - AIM: To assess efficacy of monotherapy with moxonidine in female patients with
      hypertension and climacteric syndrome. METHOD: Twenty-four hour blood pressure
      monitoring was carried out in 32 women (mean age 52.3-/+5.2 years) before and
      after 28 days of monotherapy with moxonidine (0.2-0.4 mg). RESULTS: In 4 weeks
      the following significant changes were registered: lowering of systolic and
      diastolic blood pressures, decrease of blood pressure variability and rate of its
      morning rise, increase of 24-hour blood pressure index. This was accompanied by
      significant decrease of vascular peripheral resistance without changes of
      myocardial contractility. There were no significant changes of parameters of
      carbohydrate, lipid and purine metabolism. CONCLUSION: Moxonidine in women with
      hypertension and climacteric syndrome caused blood pressure lowering at the
      account of decreased total peripheral resistance and restoration of physiological
      blood pressure rhythm.

PMID- 12494034
TI  - [Assessment of safety and antihypertensive efficacy of a cardioselective beta
      blocker nebivolol in patients with hypertension and concomitant chronic
      obstructive bronchitis].
AB  - Safety, tolerability and antihypertensive efficacy of a cardioselective beta
      blocker nebivolol was studied in 30 patients with mild and moderate hypertension
      and concomitant stage I chronic obstructive bronchitis. Nebivolol (5 mg/day) was
      given for 1 month; in 5 patients complementary hydrochlorothiazide (12.5 mg/day)
      was required for sufficient antihypertensive effect. Nebivolol was well tolerated
      (only 1 patient complained of head ache), did not cause worsening of bronchitis
      and spirometric parameters, exerted no cardiodepressive action, and did not
      induce apparent disturbances of metabolism.

PMID- 12494035
TI  - [Moxomidine effectiveness in women with arterial hypertension associated with
      metabolic syndrome in initially high heart rate].

PMID- 12494036
TI  - [Angiotensin-converting enzyme gene polymorphism in patients with primary
      disturbances of cardiac conduction].
AB  - Increased frequencies of angiotensin-converting enzyme (ACE) D-allele and ID
      genotype among patients with idiopathic atrioventricular blocks and I allele and
      II genotype among patients with idiopathic intraventricular blocks allow to
      consider these genotypes risk factors of corresponding disturbances of cardiac
      conduction. Decreased frequency of ACE I allele and II genotype among patients
      with idiopathic atrioventricular blocks is indicative of a possible protective
      role of II genotype against development of this type of cardiac conduction
      defect. Low frequency of D allele and genotype D prevents derangements of
      conduction in His-Purkinje system.

PMID- 12494037
TI  - [Angiotensin converting enzyme inhibitor enalapril in the treatment of
      endomyocardial fibrosis in patients with lymphogranulomatosis subjected to radio-
      and chemotherapy].
AB  - Echocardiography was used in the study of 40 patients with stage IIA-IVB
      lymphogranulomatosis. In 2-6 years before the study all patients had been treated
      with combination radio- (36-44 Gy) and chemotherapy. Echocardiography revealed
      endomyocardial fibrosis and signs of cardiac remodeling (reduced left ventricular
      dimensions and volumes, decreased myocardial mass and impaired diastolic
      function). The patients were divided into 2 groups. Patients of group 1 were
      given enalapril (5-10 mg/day), of group 2 - potassium and magnesium aspartate and
      inosine. In 2 months 68% of patients in group 1 demonstrated improvement of
      structural and functional state of the heart, no such changes occurred in group
      2.

PMID- 12494038
TI  - [Myocardial mass and geometry in population study of women in Tallinn
      (echocardiography data)].
AB  - In a framework of a population study in Tallinn triple blood pressure
      measurements, electro- and echocardiography were carried out in 398 women (82.6%
      of all participants) aged 35-59. Left ventricular hypertrophy (left ventricular
      mass >or=198 g, left ventricular mass/height ratio >or=121 g/m, left ventricular
      mass/body surface area ratio >or=120 g/m2) was found in 43% of these women.
      Distribution of variants of left ventricular remodeling was as follows:
      concentric hypertrophy - 9.1%, eccentric hypertrophy - 33.9%, concentric
      remodeling - 9.5%, normal myocardial geometry - 47.5%. Only concentric
      hypertrophy was associated with elevated blood pressure and obesity frequency of
      both of which increased with age.

PMID- 12494040
TI  - [Echocardiographic assessment of cardiac remodeling in patients with aneurisms
      after myocardial infarction].

PMID- 12494039
TI  - [Isoproterenol induced changes of protein expression and myocardial
      ultrastructure].
AB  - AIM: To elucidate alterations in myocardial ultrastructure and protein expression
      caused by isoproterenol. METHODS: Biochemical, immunohistochemical and electron
      microscopic studies of rat myocardium were carried out 2 hours and 3 weeks after
      single injections of isoproterenol (50 and 10 mg/kg). Relative content of
      myospecific proteins (KRP - kinase-related protein, desmin), cytoskeletal
      proteins (tubulin, vinculin, and myosin light chain kinase - MLCK) and
      extracellular matrix protein, fibronectin, was determined by immunoblotting.
      RESULTS: In 2 hours after injection of 50 mg/kg of isoproterenol destruction of
      some cardiomyocytes, contracture of myofibrils, and mild edema of intercellular
      space occurred; the content of KRP decreased by l6%, and that of tubulin,
      vinculin and fibronectin - by 27-29%. Reduced level of these proteins and also of
      MLCK persisted until 3 weeks after injection and was associated with altered
      cardiomyocyte ultrastructure. Glycogen granules were sparse, mitochondria
      contained arrow-like inclusions characteristic for calcium overload, huge
      mitochondria connected by specialized intermitochondrial contacts were present.
      Enlarged intercellular space contained areas of fibrosis with increased amount of
      type I and II collagens and fibronectin. Lower dose of isoproterenol (10 mg/kg)
      did not cause noticeable damaging action in the acute period, but in 3 weeks
      thickening of extracellular matrix occurred accompanied by increases of KRP and
      tubulin contents (by 26-32% compared with control level). Similar rise in
      expression of these proteins, and also of MLCK was observed after addition of
      isoproterenol to culture of chicken cardiomyocytes. CONCLUSION: These results
      indicate that even single injection of isoproterenol causes long lasting
      structural alterations in cardiac muscle accompanied by increased expression of
      extracellular matrix proteins as well as sarcoplasmic proteins apparently
      involved in the hypertrophic response of the cardiomyocytes.

PMID- 12494041
TI  - [Ambulatory observation - a model of organization of secondary prevention of
      chronic heart failure].

PMID- 12494042
TI  - [Invasive cardiology: focus on restenosis. Part II].
AB  - In-stent restenosis represents a pathological process which histology is
      different from that of restenosis after balloon angioplasty. In-stent restenosis
      is mainly caused by neointima proliferation. This part of review deals with
      technologies of prevention of in-stent restenosis including novel stent designs
      and coatings aimed at suppression of neointima proliferation.

PMID- 12494043
TI  - [The role of nitrous oxide and oxygen free radicals in development of
      hypertensive disease].

PMID- 12494044
TI  - [Syndrome of obstructive sleep apnea and related cardiovascular disorders].

PMID- 12494045
TI  - [Significance of electrocardiographical symptoms in myocardial infarction].

PMID- 12494046
TI  - [Clinical and electrocardiographical features of the Brugada syndrome and
      literature review].

PMID- 12494047
TI  - [Lethal outcome in a patient with pulmonary hypertension and liver cirrhosis on
      the 12-th week of pregnancy].
AB  - A patient with pulmonary hypertension and focal liver cirrhosis was hospitalized
      on the 12-th week of pregnancy because of threatened abortion and died after 2
      days of hospital stay during which symptoms of portal and pulmonary hypertension
      progressed, decompensation of pulmonary heart and hepatic cellular insufficiency
      ensued and syndrome of disseminated intravascular coagulation developed.

PMID- 12494048
TI  - [Coronary angioplasty with direct stenting: assessment of primary results and
      some economical aspects].
AB  - Comparison of immediate angiographical and clinical results of direct coronary
      stenting and stenting after predilation was carried out in 68 patients. Groups of
      patients subjected to direct stenting and stenting with predilation had similar
      clinical and angiographical characteristics. Direct stenting was successful in
      100%, stenting with predilation--in 97.2% of patients with residual stenosis 5.1
      and 4.9%, respectively. There were no cases of stent loss, death or emergent
      bypass grafting during neither the procedure nor period of hospitalization. There
      was 1 Q-wave myocardial infarction (2.8%) and 2 non-Q wave myocardial infarctions
      (1 in each group). Compared with stenting with predilation procedure of direct
      stenting was associated with significantly shorter procedure duration (39-/+7.1
      min, 60-/+12.5 min, respectively), radiation exposure time (7.9-/+6.3 and 13.5
      /+8.9 min, respectively), lower workload of the laboratory (4.9-/+3.5 and 6.1
      /+2.0 patients/day, respectively), decreased consumption of contrast medium (200
      /+71 and 275-/+75.9 ml, respectively), and thus lower overall cost of the
      procedure. CONCLUSION: Direct coronary stenting is a convenient, safe and
      economically justified method of stent implantation.

PMID- 12494049
TI  - [Postoperative spasm of mammary-coronary grafts and possibilities of its
      correction by dihydropyridine calcium antagonists nifedipine and amlodipine].
AB  - AIM: To assess efficacy of dihydropyridine calcium antagonists nifedipine and
      amlodipine for prevention of spasm of internal mammary artery after mammary
      coronary bypass grafting. MATERIAL AND METHODS: Eighty eight men (age 56,5-/+7.2
      years) subjected to mammary-coronary grafting were randomized to 3 groups.
      Patients of group 1 (n=35) received nifedipine (10 mg t.i.d.), patients of group
      2 (n=30) received amlodipine (5 mg o.d.) and patients of group 3 (n=23) did not
      receive calcium antagonists. The following parameters were studied: mean linear
      and volume velocity of blood flow, graft lumen diameter, systolic-diastolic
      index. Dynamics of flow was assessed during 2 weeks after surgery. RESULTS: In
      nifedipine treated patients blood flow through grafts to posterior
      interventricular, anterior interventricular, anterior interventricular and
      diagonal branches rose by 61.2, 37.4, and 102.9%, respectively. In amlodipine
      treated patients these figures were 103.4, 113.1 and 147.1%, respectively.
      Treatment with nifedipine was associated with decrease of graft systolic
      diastolic index by 20.2, 20.7, 19.9%, respectively, treatment with amlodipine--by
      27.3, 20.6, 32.9%, respectively. Lumen diameter of grafts to posterior
      interventricular, anterior interventricular, anterior interventricular and
      diagonal branches in nifedipine treated patients increased by 9.5, 17.6, and
      7.7%, respectively, in amlodipine treated patients--by 20, 22.7, and 25.9%,
      respectively. Moreover amlodipine was better tolerated. CONCLUSION: The first
      dose of nifedipine and amlodipine increased diameter of mammary-coronary grafts
      and blood flow through them. Augmentation of these effects which occurred during
      further use of nifedipine and amlodipine for 2 weeks was milder and more gradual
      in amlodipine treated patients.

PMID- 12494050
TI  - [Left ventricular hypertrophy does not affect diagnostic accuracy of treadmill
      stress echocardiography in patients with normal left ventricular contractility at
      rest].
AB  - Results of exercise echocardiography (treadmill) and of coronary angiography were
      compared in 119 subjects (mean age 54.9-/+7.9 years) with normal left ventricular
      contractility at rest. Forty two patients had no pronounced lesions in coronary
      arteries, while 77 had >50% stenoses in main coronary arteries. Sensitivity and
      specificity of stress echocardiography were similar in patients with (n=48) and
      without (n=71) left ventricular hypertrophy (76 and 78%, 75 and 74%,
      respectively). Specificity and diagnostic accuracy of stress echocardiography
      were substantially higher than those of ECG during treadmill test especially in
      patients with left ventricular hypertrophy.

PMID- 12494051
TI  - [Use of trimetazidine in the combined therapy of myocardial infarction with left
      ventricular dysfunction].

PMID- 12494052
TI  - [Use of selective long-acting beta-blocker with vasodilating activity celiprolol
      in patients with essential hypertension].
AB  - Effects of 8 weeks therapy with long-acting selective b-blocker celiprolol (200
      mg o.d.) on 24-hour blood pressure, central hemodynamics (oscillometry) and
      microcirculation (laser doppler flowmetry) were studied in 30 patients (17 women
      and 13 men, mean age 51.9 years), with stage I-II essential hypertension.
      Celiprolol lowered both systolic and diastolic blood pressure (BP) during all
      periods of 24-hour BP monitoring and improved BP circadian rhythm. Treatment with
      celiprolol was not associated with considerable heart rate decrease or changes of
      stroke volume and cardiac output. 24 hour monitoring of parameters of central
      hemodynamics during treatment with celiprolol revealed existence of significant
      direct correlation between mean BP and total peripheral vascular resistance.
      Thus, hypotensive effect of celiprolol was mostly attributed to its vasodilatory
      action. This activity of celiprolol was confirmed by its beneficial influence on
      parameters of microcirculation. After therapy normalization of peripheral blood
      flow was observed in 50%, and tendency to its improvement--in 83,3 % of patients.

PMID- 12494053
TI  - [Effect of nebivolol on remodeling of the heart and vessels and the state of
      hemodynamics in patients with hypertension].
AB  - Echocardiography, doppler echocardiography and venous occlusion plethysmography
      were used for the study of effects of monotherapy with nebivolol (2.5-10, mean
      5.1 mg/day for 24 weeks) on remodeling of cardiovascular system and the state of
      hemodynamics in 25 patients with stage II hypertension and chronic heart failure
      (NYHA class I-II). Treatment with nebivolol was associated with lowering of
      systolic and diastolic blood pressure (by 22% and 26%, respectively), significant
      reduction of left ventricular mass index, improvement of parameters of systolic
      and diastolic left ventricular function and lowering of NYHA class of heart
      failure. Favorable changes of remodeling of peripheral vessels and of endothelium
      dependent vasodilatation also occurred.

PMID- 12494054
TI  - [Hypertension--main risk factor of stroke. Results of a three years register in
      Krasnodar].
AB  - Incidence of first stroke and stroke mortality in Krasnodar in 1997-2000 were
      higher compared with data of similar registers in Moskva and Novosibirsk.
      Hospitalization rate of patients with stroke especially of those with severe
      stroke was low with high 28 days and 1 year mortality. Main risk factor of stroke
      was hypertension which in about 2 thirds of patients was classified as mild. Half
      of the patients with hypertension had history of hypertensive crises. Despite
      high level of awareness about presence of hypertension only every tenth patient
      received regular antihypertensive therapy which however in most cases was
      ineffective. One half of the patients received no antihypertensive treatment at
      all. Even after stroke most of the patients did not take antihypertensive drugs
      and antiaggregants. Results of the register show that there exists a great deal
      of resource for implementation of standard measures aimed at primary and
      secondary stroke prevention and lowering of mortality of patients with stroke.

PMID- 12494055
TI  - [The role of depressive disorders in hypertensive disease and possibilities of
      their correction: assessment of the effect of tianeptine].

PMID- 12494056
TI  - [Effect of eprosartan on left ventricular diastolic function and cerebral
      hemodynamics in patients with hypertension].
AB  - Eprosartan (600-1200 mg/day) was given for 4 weeks to 28 patients aged 32-62
      years with stage II-III hypertension (WHO, 1999). Left ventricular diastolic
      function and cerebral blood flow were assessed by echocardiography and ultrasound
      dopplerography. Treatment with eprosartan was associated with improvements of
      impaired left ventricular diastolic function, structural and functional state of
      the heart, venous outflow from cerebral vessels, and restoration of unpaired
      autoregulation of cerebral blood flow. All these phenomena could potentially lead
      to normalization of cerebral tissue perfusion and stabilization of cerebral blood
      flow.

PMID- 12494057
TI  - [Prevalence of excessive body mass and its relation to mortality from
      cardiovascular and main chronic noninfectious diseases among urban male
      population of geographical different regions in Russia].
AB  - The paper contains data on prevalence of low, normal, excessive body mass and
      obesity among urban male populations aged 20-54 years in different regions.
      Relative risk of death associated with body mass was estimated on the basis of a
      twenty years prospective study of sample populations in Moskva and St-Peterburg
      and level of attributed risk was used for assessment of contribution of body mass
      to cardiovascular mortality and mortality from other chronic diseases. Levels of
      main risk factors, smoking intensity and alcohol consumption were studied in
      deciles of body mass index distribution.

PMID- 12494058
TI  - [High-resolution ECG in assessment of myocardial functional state in patients
      with ischemic heart disease and resultant cardiac dilatation].
AB  - High resolution signal-averaged ECG (SAECG), echocardiography and 24-hour Holter
      ECG monitoring were used in the study of 30 patients (mean age 56-/+2 years) with
      coronary heart disease and stable class II-IV angina (group 1) and 66 patients
      (mean age 45-/+1 years) with dilated cardiomyopathy of ischemic origin (group
      II). SAECG was used for detection of late ventricular potentials and calculation
      of time-voltage and velocity parameters of P-waves. Disturbances of myocardial de
      and repolarization indicative of pronounced hemodynamic left atrial overload
      associated with elevated left ventricular end diastolic pressure were revealed.
      These disturbances were more pronounced in patients of group II. Late ventricular
      potentials and arrhythmias were more frequent in patients with more severe
      cardiac failure. Sensitivity of SAECG for detection of arrhythmogenic substrate
      in the myocardium was 70 and 90% in groups I and II, respectively. Positive
      predictive power of ventricular late potentials for occurrence of ventricular
      arrhythmias in these groups was 86 and 91%, respectively.

PMID- 12494059
TI  - [24-hour blood pressure rhythm: clinical and predictive value].
AB  - Clinical and predictive value of 24-hour blood pressure rhythm is reviewed.
      Insufficient nocturnal blood pressure lowering induces augmented pressure load on
      target organs. On the other hand it reflects dysregulatory changes due to target
      organ involvement. Lack of adequate nocturnal blood pressure lowering is
      considered by some investigators as independent risk factor of target-organ
      damage. This dictates necessity of registration of parameters of 24-hour blood
      pressure profile in evaluation of patients with hypertension.

PMID- 12494060
TI  - [Clinical hypertensiology: analysis of trials completed in 2001-2002].

PMID- 12494061
TI  - [Practical application of Holter ECG monitoring. III. Diagnosis of ischemic
      changes of the myocardium].

PMID- 12494062
TI  - [Ischemic remodeling of the left ventricle (definition, pathogenesis, diagnosis,
      medical and surgical correction)].

PMID- 12494063
TI  - [Clinical presentations of aneurysms and dissections of the aorta].

PMID- 12494064
TI  - [Carcinoid syndrome as a cause of right ventricular failure. Diagnosis with x-ray
      computed tomography and magnetic resonance imaging].

PMID- 12494065
TI  - [Activity of blood platelets and functional state of endothelium in patients with
      unstable angina with favorable and unfavorable outcome (prospective study)].
AB  - Functional activity of platelets (aggregation and plasma levels of soluble P
      selectin) and functional state of endothelium (antiaggregatory activity of vessel
      wall - AAVW, cuff occasion test, and plasma content of von Willebrand factor)
      were assessed in patients with unstable (n=41) and stable (n=19) angina and
      healthy donors (n=20). According to results of follow up for 1 year patients with
      unstable angina (UA) were divided into 2 groups - with (n=21) and without (n=20)
      events (coronary death, nonfatal myocardial infarction). In patients with UA and
      events parameters of spontaneous and ADP-induced platelet aggregation, contents
      of P-selectin and von Willebrand factor were higher while AAVW lower than in UA
      patients without events, patients with stable angina and healthy subjects.
      Correlations between AAVW and platelet aggregation, between AAVW and level of von
      Willebrand factor were negative in patients with UA, and positive in patients
      with stable angina and healthy subjects. These results of correlation analysis
      were interpreted as a reflection of impairment of antithrombotic endothelial
      function in patients with UA.

PMID- 12494066
TI  - [Proinflammatory cytokines and soluble intercellular adhesion molecule-1 in
      ischemic heart disease].
AB  - Blood serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta
      (IL-1beta) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured
      by ELISA in patients with stable and unstable angina. Levels of cytokines and
      sICAM-1 were elevated in patients with stable and were even higher in patients
      with unstable angina. Among patients with stable angina those with more severe
      symptoms had higher serum activity of TNF-alpha and IL-1beta. Increased
      expression of sICAM-1 was associated with augmented systemic secretion of
      cytokines. This association was more pronounced in patients with unstable angina.
      Patients with stable angina and hyperlipidemia compared with those with normal
      lipids had higher levels of sICAM-1. Levels of both cytokines were similar in
      patients with and without hyperlipidemia. However levels of total and low density
      lipoprotein cholesterol increased while level of high density lipoprotein
      cholesterol decreased with elevation of TNF-alpha from the lowest to the highest
      tertile.

PMID- 12494067
TI  - [Relationship between parameters of heart rate variability, angiographical
      severity of coronary atherosclerosis and functional class of angina in patients
      with ischemic heart disease].
AB  - AIM: To elucidate relationship between heart rate variability and severity of
      coronary atherosclerosis. MATERIAL: Seventy five patients with class I-IV angina
      subjected to coronary angiography and 23 apparently healthy subjects of the same
      age without overt coronary heart disease. METHODS: Analysis of parameters of
      variational pulsometry and heart rate entropy at rest and during test with
      controlled breathing (6 breaths/min). RESULTS AND CONCLUSION: Heart rate
      variability decreased with increase of functional class of angina and severity of
      coronary artery atherosclerosis. Within same functional class heart rate
      variability was lower in patients with more severe coronary atherosclerosis.

PMID- 12494069
TI  - [Comparison of efficacy of bolus injection and drop infusion of streptokinase in
      patients with myocardial infarction].

PMID- 12494068
TI  - [Atenolol induced bradycardia in patients with stable angina: effects on exercise
      tolerance, myocardial perfusion and left ventricular contractility].
AB  - AIM: To assess effects of atenolol-induced heart rate decrease on myocardial
      perfusion, left ventricular contractility and tolerance to exercise in patients
      with chronic coronary artery disease. MATERIAL AND METHODS: Twenty eight men
      (mean age 54,5-/+9,2 years) with stable class I-III angina and positive
      reproducible result of bicycle exercise test underwent rest/stress 99mTc-MIIBI
      gated single-photon emission computed tomography (SPECT) before and after 10 days
      of administration of atenolol (20 patients) or placebo (8 patients). Dose of
      atenolol was titrated to achieve at least 15% decrease of heart rate from
      baseline. RESULTS: After 10 days of treatment with atenolol heart rate decreased
      from 78-/+3.1 to 59-/+1.1 bpm (p=0.01), whereas in placebo group there were no
      significant changes. Compared with placebo, treatment with atenolol was
      associated with significant decreases in extent and severity of perfusion
      defects, ischemic score and number of ischemic segments. No significant changes
      of parameters of left ventricular contractility occurred. Treatment with atenolol
      was associated with symptomatic improvement and increase of the total exercise
      time. CONCLUSION: Heart rate lowering during monotherapy with atenolol was
      associated with improvement of myocardial perfusion and tolerance to exercise.

PMID- 12494070
TI  - [Dynamics of left ventricular remodeling in patients with acute myocardial
      infarction].
AB  - Dynamics of structural and functional left ventricular parameters was
      investigated in 51 patients with acute anterior myocardial infarction by means of
      serial (on days 1, 2, 3, 5, 7, 10 and 21 of infarction) echocardiographical
      study. Increase of end-diastolic volume index relative to initial values became
      significant on 5th-7th days and continued to progress until 3rd week of
      infarction. Left ventricular cavity became dilated and attained more occurred
      shape predominantly at the account of increased transverse diameters.
      Abnormalities of left ventricular contractile and pump functions were most
      pronounced during first 3 days of the disease. Between 5th and 10th days
      improvement and stabilization of myocardial functional state took place
      accompanied by progression of left ventricular dilation and increase of its
      sphericity with lessening of degree of myocardial asynergy.

PMID- 12494071
TI  - [Peculiarities of blood pressure rhythms and blood pressure variability in
      adolescents with hypertension (in accordance with twenty-four monitoring of blood
      pressure)].
AB  - Registration of 24-hour blood pressure in adolescents with and without
      hypertension revealed active participation of sympathetic nervous system in
      genesis of juvenile hypertension. Hypertension in adolescents was mainly
      systolic, blood pressure elevation as a rule was accompanied by accelerated heart
      rate and increased pulse pressure. Episodes of blood pressure elevations occurred
      mostly during day time. Desynchronization of 24-hour rhythms due to excessive
      nocturnal blood pressure lowering was found to be typical for this age group.
      More than two thirds of adolescents with episodes of blood pressure elevation had
      also 'white coat hypertension'.

PMID- 12494072
TI  - [Clinical effectiveness of beta-adrenoblockers and their effects on copulative
      function in patients with hypertension].
AB  - Twenty four hour blood pressure and ECG monitoring, assessment of sexual function
      (questionnaires, penile artery Doppler flowmetry) were carried out in male
      hypertensives treated with atenolol, metoprolol, or bisoprolol. Compared with
      atenolol and metoprolol bisoprolol was found to be more effective and safe. The
      use of bisoprolol was associated with no negative changes and even with
      improvement of some parameters of sexual function. Sildenafil could be used for
      correction of male sexual dysfunction occurring during treatment with other beta
      blockers.

PMID- 12494073
TI  - [The use of combination therapy with lacidipine and beta-adrenoblockers in
      patients with hypertension].

PMID- 12494074
TI  - [Clinical assessment of efficacy and safety of noliprel in patients with
      hypertension].

PMID- 12494075
TI  - [Effect of nebivolol on dynamics of microalbuminuria, renal blood flow and 24
      hour blood pressure profile in patients with hypertension].

PMID- 12494076
TI  - [Prevalence of electrocardiographic signs of pulmonary hypertension in a sample
      of male population of Novosibirsk].
AB  - Prevalence of ECG signs of right ventricular hypertrophy and pulmonary
      hypertension was assessed in a representative sample (n=715) of nonorganized male
      population (age 25-64 years) of Novosibirsk studied within a framework of WHO
      MONICA project. Other methods of investigation included Rose questionnaire,
      anthropometry, ECG interpreted with Minnesota code, and echocardiography.
      Echocardiography data were used as reference for determination of sensitivity and
      specificity of ECG-criteria of pulmonary hypertension.

PMID- 12494077
TI  - [Effect of adriamycin on expression and content of myocardial structural and
      regulatory proteins].
AB  - The biochemical and morphological study of the cytoskeleton and extracellular
      matrix of rat heart was carried out after single injection of adriamycin (2.2 or
      0.44 mg/kg). Hearts were taken for the study after 2 hours and 3 weeks after
      injection. The light and electronic microscopy, immunohistochemical determination
      of type I, III and IV collagens and fibronectin using specific antibodies were
      implied for morphological study; electrophoresis and immunoblotting were implied
      for the determination of the content of some proteins of cardiomyocytes (KRP or
      telokin, desmin, tubulin and vinculin), and extracellular matrix (fibronectin)
      and vascular smooth muscle cells (MLCK, myosin light chain kinase). Adriamycin
      injection in the dose 2.2 mg/kg which is close to therapeutic and known to alter
      intracellular membranes approximately in the half of cardiomyocytes, did not
      influence the relative volume and structure of collagen network but distinctly
      reduced the density of fibronectin-distribution. The content of tubulin,
      fibronectin, MLCK and KRP was significantly decreased by 18-24%, while contents
      of desmin and vinculin were changed insignificantly. After 3 weeks, an increased
      density and extension of collagen network indicating the development of diffuse
      fibrosis were observed. Contents of tubulin and KRP were increased above control
      level by 50 and 20%, respectively. Similar hyperrestitution of tubulin,
      fibronectin and KRP content by 15-25% was determined after smaller dose of
      adriamycin (0.44 mg/kg). Only content of MLCK out of proteins studied remained at
      lower level in both groups by 25-34%. Isolated chick embryo cardiomyocytes
      subjected to adriamycin responded by increased level of KRP expression by 20% in
      4 days while the level of tubulin expression remained unchanged. Results showed
      that damage of cardiomyocytes and extracellular matrix after single injection of
      adriamycin in the dose close to therapeutic was followed by increased expression
      of some proteins of cytoskeleton and extracellular matrix. KRP seems to play
      active role in this reparative response while the steadily reduced level of MLCK
      expression may disturb the control of coronary vessels.

PMID- 12494079
TI  - [Hypertension in obese patients: the role of leptin].

PMID- 12494078
TI  - [Antihypertensive therapy and thyroid function: effect of prazosin and its
      combination with beta-blockers].

PMID- 12494080
TI  - [Angiotensin converting enzyme inhibitors in renal diseases].
AB  - Chronic diffuse renal diseases, involvement of the kidney in systemic and
      metabolic disorders are characterized by steady progression of renal pathology
      with loss of functional nephrons, lowering of renal functions and gradual
      development of chronic and eventually terminal renal failure. Basic mechanism of
      progression of chronic renal failure is activation of local renin-angiotensin
      system with intrarenal formation of a potent vasoconstrictor and growth factor -
      angiotensin II. Potentially nephroprotective effect can be achieved by
      pharmacological block of angiotensin II by angiotensin converting enzyme
      inhibitors. It has been shown in some prospective studies (AIPRI, REIN, ACEi-1
      Trial, MICRO-HOPE) that the use of these drugs is associated with slowing of
      progression of renal pathology irrespective of its etiology and delayed
      development of terminal renal failure in patients with preexisting chronic renal
      insufficiency. Data available indicate that angiotensin converting enzyme
      inhibitors should be first line agents in the treatment of patients with chronic
      diffuse renal diseases of various etiology and diabetic nephropathy.

PMID- 12494081
TI  - [Syndrome of ventricular preexcitation].

PMID- 12494082
TI  - [Long QT interval syndrome].
AB  - Long QT interval syndrome is a cardiac disorder associated with fatal ventricular
      arrhythmias (torsade de pointes and ventricular fibrillation). Timely diagnosis
      and adequate treatment may decrease mortality due this syndrome. The present
      review summarizes results of recent studies of etiology, pathogenesis, clinical
      picture, diagnosis and treatment of the long QT syndrome.

PMID- 12494083
TI  - [Body mass of coronary patients: disputable problems].

PMID- 12494084
TI  - [Defibrillator as an obligatory component of on-board medical equipment in
      airplanes].

PMID- 12494085
TI  - [Relationship between myocardial viability and ventricular late potentials in
      patients with history of myocardial infarction].
AB  - AIM: To study relationship between presence and volume of viable myocardium and
      registration of late ventricular potentials in patients with history of
      myocardial infarction. MATERIAL AND METHODS: High resolution ECG, dobutamine
      stress echocardiography and Holter ECG monitoring were carried out 34 patients
      (mean age 54.1-/+3.1 years) with history of documented myocardial infarction.
      RESULTS: According to data of dobutamine stress echo patients were divided into 2
      groups: with irreversible myocardial dysfunction (n=16, group 1) and with
      hibernating myocardium (n=18, group 2). Ventricular late potentials were
      registered in 3 (18.7%) and 11 (61,1%) patients in groups 1 and 2, respectively.
      Group 2 patients more often had high-grade ventricular arrhythmias. There was no
      association between presence of ventricular late potentials and Lown grade of
      ventricular arrhythmias on Holter ECG. Duration of filtered QRS (QRSt) complex
      correlated directly with index of regional wall motion abnormality, end-diastolic
      volume, and negatively - with total ejection fraction. CONCLUSION: Among
      myocardial infarction survivors patients in whom dobutamine stress echo detects
      viable myocardium significantly more often have ventricular late potentials and
      high grade ventricular arrhythmias compared with patients with myocardial scars
      without viable myocardium.

PMID- 12494086
TI  - [Complex of factors affecting heart rate dispersion in survivors of myocardial
      infarction].
AB  - AIM: To establish complex of independent variables related to parameters of heart
      rate variability in patients with postinfarction cardiosclerosis. MATERIAL:
      Seventy four patients (age 49-/+0.8 years) were studied in 6 months or later
      after myocardial infarction. Temporal and spectral characteristics of heart rate
      variability from 5 min ECG strips were sequentially included in a multiple linear
      regression model as dependent variables while data of clinical and instrumental
      investigation were considered as independent parameters. RESULTS AND CONCLUSION:
      Depression of heart rate variability in survivors of myocardial infarction was
      linked to age, late postinfarction remodeling of the heart, development of
      systolic and diastolic left ventricular dysfunction and clinical severity of
      heart failure.

PMID- 12494087
TI  - [The use of zopiclone for correction of elevated blood pressure in elderly
      patients with essential hypertension and insomnia].

PMID- 12494088
TI  - [Psychological traits and quality of life of patients with hypertension and
      metabolic risk factors].
AB  - Psychological status and quality of life were assessed in 75 patients with mild
      and moderate hypertension and metabolic disturbances. Patients with hypertension
      and metabolic risk factors compared with patients without these factors were
      characterized by higher frequency of neurotic disorders, worse quality of life
      and mood, lower activity. It is suggested that psychic disorders which are rather
      frequent in patients with hypertension affect negatively clinical course of
      underlying disease, complicate clinical picture of hypertension, and cause
      patient's denial of continuous antihypertensive therapy.

PMID- 12494089
TI  - [Experience of the use of nebivolol in the treatment of hypertension in
      postmenopausal women].
AB  - Nebivolol was given to 30 hypertensive postmenopausal women as monotherapy (5-10
      mg/day) or in combination with hydrochlorothiazide. Clinical effect was achieved
      in 76.6 and 86.7% of women on mono- and combination therapy, respectively.
      Hypotensive effect was confirmed by 24-hour blood pressure monitoring. Blood
      pressure lowering was associated with decrease of total peripheral resistance and
      regression of left ventricular hypertrophy. Nebivolol appeared to be
      metabolically neutral and only sporadic adverse effects were registered.

PMID- 12494090
TI  - [Effect of amiodarone on autonomic status and its efficacy in the treatment of
      different variants of paroxysmal atrial fibrillation].
AB  - Association of autonomic status and efficacy of therapy with amiodarone was
      studied in 90 patients with paroxysmal atrial fibrillation of ischemic (n=45,
      mean age 62 years) and nonischemic (n=45, mean age 38 years) origin. Autonomic
      status was assessed by measurement of heart rate variability.
      Electrophysiological and echocardiographical studies were also conducted before
      and after 4 weeks of amiodarone therapy. Treatment with amiodarone was
      accompanied by substantial lowering of the tone of autonomic nervous system in
      patients with adrenergic type of paroxysmal atrial fibrillation while there was
      no dynamics of parasympathetic tone in patients with vagal or mixed types.
      Positive association between amiodarone therapy and decrease of left atrial
      dimension and improvement of left ventricular contractility was also observed. It
      was concluded that the use of amiodarone was justified in adrenergic but not in
      vagal or mixed variants of paroxysmal atrial fibrillation.

PMID- 12494091
TI  - [Clinical signs of homozygous familial hypercholesterolemia].
AB  - During 15 years 12 patients with clinically verified diagnosis homozygous
      familial hypercholesterolemia were treated in the A.L. Myasnikov Institute of
      Clinical Cardiology. The paper presents description of main phenotypic
      manifestations of the condition (xanthomas, levels of lipids, the state of
      cardiovascular system) based on results of investigation of these patients.

PMID- 12494092
TI  - [Nitric oxide activates Ca2+ activated potassium current in rat tail artery
      smooth muscle cells via cGMP-dependent mechanism].
AB  - Mechanisms of nitric oxide (NO) action on K(Ca) channels were investigated using
      patch-clamp technique and freshly isolated smooth muscle cells from rat tail
      artery. In whole-cell experiments, the outward current was increased 6,64-/+0,72
      fold (n=10) by 100 microM sodium nitroprusside (SNP), which was significantly
      different compared with 1,07-/+0,03-fold (n=8) increase of the outward current by
      addition of experimental bath solution. In the presence of 300 nM iberiotoxin,
      the specific blocker of K(Ca) channels, the outward current was not altered by
      100 microM SNP. In addition, in the presence of 1 microM Rp-8-Br-PET-CGWS, the
      specific protein kinase G-inhibitor, the outward current was not affected by 100
      microM SNP. These results suggest that NO released from NO-donors stimulates
      K(Ca) current in rat tail artery smooth muscle cells by activating protein kinase
      G and not by direct effect on the channel 1.

PMID- 12494093
TI  - [Cardiological aspects of the antiphospholipid syndrome. Part I. Valvular lesions
      in the primary and secondary antiphospholipid syndrome and systemic lupus
      erythematosus].
AB  - AIM: To assess prevalence of cardiac valvular lesions in patients with primary
      (P) antiphospholipid syndrome (APLS) and systemic lupus erythematosus (SLE) with
      and without secondary APLS. MATERIAL AND METHODS: Patients with PAPLS (n=56, 15
      men and 41 women), SLE and APLS (n=88, 23 men, 65 women) and SLE without APLS
      (n=51, 19 men, 32 women) were followed up for 9 years. Serological markers of
      APLS were anticardiolipin antibodies and lupus anticoagulant. RESULTS: Prevalence
      of various heart defects was the highest in PAPLS (43%) compared with SLE with
      APLS (c2=5.6, p=0.001) and SLE without APLS (c2=9.3, p=0.0002). In secondary APLS
      prevalence of valvular involvement was 27% what was substantially more than in
      SLE without APLS (4%) (c2=7.2, p=0.0007). Changes of mitral valve cusps and
      mitral regurgitation were found in 33, 41 and 50% of patients with SLE, SLE with
      APLS and PAPLS, respectively. Pronounced mitral regurgitation and valve defects
      were significantly more frequent in patients with any APLS compared with those
      with SLE without APLS. Thickening of aortic cusps was significantly more frequent
      in patients with PAPLS compared with patients with SLE (with and without APLS).
      Changes of tricuspid valve were significantly more frequent in patients with any
      APLS. Progression of valvular pathology was observed in 2 patients with SLE and
      APLS after 4 and 5 years of follow up. During 9 years thrombotic complications
      developed in 8 patients with APLS and valvular lesions (6 strokes, 2 retinal
      thromboses). CONCLUSION: An association exists between presence of APLS and
      various cardiac valvular lesions. Lesions of aortic valve are associated with
      PAPLS: Development of valvular pathology in patients with SLE and PAPLS during
      follow up dictates the necessity to monitor echocardiographical parameters and
      titers of anticardiolipin antibodies.

PMID- 12494095
TI  - [Long term results of treatment of hypertrophic cardiomyopathy by permanent dual
      chamber cardiac pacing].

PMID- 12494094
TI  - [Comparative effects of amiodarone, diltiazem, and atenolol on results of
      electrical cardioversion in patients with chronic atrial fibrillation].

PMID- 12494096
TI  - [QT prolongation as risk factor of arrhythmias in patients treated with chronic
      hemodialysis].

PMID- 12494097
TI  - [Invasive cardiology--focus on restenosis. Part I].
AB  - In-stent restenosis is mainly caused by neointima proliferation and represents a
      pathological process which histology is different from that of restenosis after
      balloon angioplasty. Frequency of in-stent restenoses increases parallel with
      progressively increasing number of procedures of coronary stenting. The review
      summarizes results of research devoted to restenosis pathology and pathogenesis
      including animal studies, presents methods of mechanical treatment of in-stent
      restenoses (balloon inflation, direct and rotational atherectomy), as well as
      techniques of beta and gamma irradiation aimed at prevention of restenosis
      development.

PMID- 12494098
TI  - [Brain natriuretic peptide and heart failure].

PMID- 12494099
TI  - [Psychosomatic aspects of ischemic heart disease].

PMID- 12494100
TI  - [Mitral valve prolapse].

PMID- 12494101
TI  - [Practical application of Holter ECG monitoring. Part II. Cardiac rhythm in
      healthy subjects. Disorders of cardiac rhythm: supraventricular and ventricular
      arrhythmias].

PMID- 12494102
TI  - [Possibilities of stress-echocardiography in diagnostics of pathology of aortic
      valve. Part I].

PMID- 12494103
TI  - [Thrombosed atherosclerotic aneurisms of the right coronary artery].

PMID- 12494104
TI  - [Comparative assessment of persistent and paroxysmal atrial fibrillation as
      causes of cardiocerebral embolism].
AB  - In 66 patients with embolic stroke of cardiac origin (33 with persistent and 33
      with paroxysmal atrial fibrillation) transthoracic and transesophageal (21
      patients, 31.2%) echocardiography was used for detection of atrial thrombosis.
      Lone atrial fibrillation was significantly more frequent among patients with
      paroxysmal atrial fibrillation. Frequency of thrombosis of left atrial appendage
      was similar in patients with nonrheumatic persistent and paroxysmal atrial
      fibrillation.

PMID- 12494105
TI  - [Identification of slow anterograde conduction of excitation in patients with
      paroxysmal reciprocal atrioventricular nodal tachycardia].
AB  - Basing on results of examination of a cohort of patients with typical paroxysmal
      reciprocal atrioventricular tachycardia a group of patients with continuous curve
      of anterograde conduction was distinguished. The use of incremental doses of
      adenosine triphosphate (ATP) during transesophageal atrial pacing allowed in some
      cases to identify slow conduction through atrioventricular node and to initiate
      paroxysmal nodal tachycardia. The dose of ATP causing conduction block over fast
      pathway depended on the duration of effective refractory period.

PMID- 12494106
TI  - [Dynamics of parameters of heart rate variability in patients with ischemic heart
      disease after direct myocardial revascularization].
AB  - AIM: To study dynamics of parameters of heart rate variability (HRV) in patients
      with ischemic heart disease after direct myocardial revascularization. MATERIAL
      AND METHODS: Electrocardiography (ECG), 24 hour Holter ECG with spectral and
      temporal analysis of 24-hour HRV, as well as echocardiography (Echo) and stress
      Echo were carried out in 24 patients with ischemic heart disease before, in 2-4
      weeks and 2 months after surgery. Healthy persons of the same age (n=20) were
      used as controls. RESULTS: Prior to operation HRV in all patients was lower than
      in controls. In 2-4 weeks after coronary artery bypass grafting (CABG) further
      lowering of HRV parameters occurred. In 2 months after CABG HRV parameters in
      patients without complications were similar to preoperative values but remained
      lower than in controls.

PMID- 12494107
TI  - [Heart rate variability before and after coronary artery bypass surgery in
      patients with ischemic heart disease].
AB  - Short term heart rate variability (HRV) was studied in 44 patients before, in 2
      weeks and 2 months after coronary artery bypass grafting (CABG). Prior to surgery
      the patients were divided into 2 groups: with normal and substantially lowered
      HRV parameters. In 2 weeks after CABG lowering of HRV was registered in all
      patients. In 2 months parameters of HRV returned to preoperative level almost in
      all patients but did not exceed it despite restoration of coronary blood flow and
      improvement of myocardial contractility. Intergroup differences of
      characteristics of HRV remained the same as before CABG.

PMID- 12494108
TI  - [Influenza virus infection in progressing atherosclerosis].
AB  - AIM: To study relationship between influenza virus infection and activity of
      clinical presentations of atherosclerosis. METHODS AND RESULTS: Average blood
      level of IgG to influenza A virus was significantly higher in patients with
      progressing forms of ischemic heart disease then in patients without objective
      signs of exacerbation of atherosclerotic process. Mean titles of antibodies to
      parainfluenza virus and adenoviruses were similar in both groups of patients.
      Direct detection of viral DNA by polymerase chain reaction was carried out in
      samples of aortic wall taken during coronary artery bypass surgery with the use
      of primers for hemagglutinin of H1N1, H3N2 viruses. RNA of influenza virus was
      found in these samples. CONCLUSION: The presence of viral RNA in vascular
      atherosclerotic lesions could be indicative of possible pathogenetic role of
      influenza infection in progression of clinical course of atherosclerosis.

PMID- 12494109
TI  - [Tolerability and efficacy of retard form of indapamide in the treatment of
      hypertension in elderly patients (results of multicenter open non-comparative
      trial in Russian program ARGUS)].
AB  - Open noncomparative multicenter study of tolerability and efficacy of a retard
      form of indapamide (1.5 mg o.d. for 3 months) in patients older then 55 years was
      conducted in 14 centers in Russia. Numbers of patients included into was analysis
      of safety and tolerability were 1277 and 1121, respectively. After 3 months
      systolic, diastolic and pulse blood pressure (BP) decreased by 20.2, 13.2, 27.5%
      (supine) and by 19.4, 11.8, 26.9% (standing), respectively. There were no
      significant changes of heart rate. Effect of treatment was considered positive in
      92.4% of patients. Normalization of blood pressure occurred in 51.8% of patients
      (in 46.2% and 53.4% among men and women, respectively, p=0.0252; in 55.7% and 48%
      among patients aged <65 and >65 years, respectively). In patients with type II
      diabetes rates of positive effect and achievement of target BP <130/85 mm Hg were
      60.8% and 31.4%, respectively. Hypokaliemia (3.0-3.5 mmol/l) was registered in 43
      patients (3.4%), age of 27 of these patients was 65 years. There were no
      pronounced changes of blood serum levels of creatinine, glucose and uric acid.
      Significant lowering of atherogeneity cholesterol index occurred in the whole
      group while both this index and total cholesterol significantly decreased in
      patients with baseline hypercholesterolemia. Thus in patients older that 55 years
      monotherapy with retard form of indapamide was demonstrated to be safe and
      effective antihypertensive intervention.

PMID- 12494110
TI  - [The state of microcirculation in hypertensive disease (essential hypertension)].
AB  - Skin microcirculation was studied by laser doppler flowmetry in 149 patients with
      essential hypertension (92 men, 67 women; mean age 50.1+/-4.9 years) and in 25
      normotensive controls. In patients with hypertension prevailed pathological
      hemodynamic types of microcirculation. Hyperemic, spastic and congestive types
      were found in 20.1, 23.5 and 40.3% of patients, respectively, while only 16.1% of
      patients had normal hemodynamic type. Moreover presence and severity of
      microcirculatory disorders depended on stage of hypertension and level of blood
      pressure. Thus, patients with essential hypertension had pronounced impairment of
      microcirculation caused by structural and functional changes of microcirculatory
      vascular bed.

PMID- 12494111
TI  - [The use of enalaprilat for the treatment of uncomplicated hypertensive crises in
      patients with hypertensive disease (essential hypertension)].
AB  - When used for the treatment of hypertensive crises enalaprilat produced
      pronounced lowering of both systolic and diastolic blood pressures. Lowering of
      blood pressure was accompanied by regression of clinical symptoms. There were no
      episodes of excessive blood pressure drop. The use of enalaprilat was associated
      with normalization of parameters of central and cerebral hemodynamics, lessening
      of degree of strain of regulatory systems of the body. Diminishment of left
      atrial dilatation and augmentation of left ventricular ejection fraction occurred
      in patients with initially dilated left atrium.

PMID- 12494112
TI  - [Blood pressure profile in patients with hyper- and hypotension: effect of
      physiological stresses].
AB  - Responses to physiological stresses, relationship between character and severity
      of these reactions and parameters of 24-hour blood pressure (BP) profile were
      studied in patients with arterial hyper- and hypotension. Disturbed regulation of
      BP in hyper-, and hypotension was associated not only with pronounced spontaneous
      BP variability but also with hyper- and hypotensive responses of BP to natural
      and modeled orthostatic, psychoemotional, physical and nutritional stresses.
      Frequency of hypotensive episodes in patients with hypertension was similar to
      that of hypertensive episodes in patients with hypotension. The use of stress
      tests facilitated assessment of BP responses to various loads, determination of
      clinical value of hemodynamic changes and possibilities of correction of detected
      disturbances.

PMID- 12494113
TI  - [Effect of hormone replacement therapy on blood serum lipids in postmenopausal
      women with type 2 diabetes].
AB  - There are limited data concerning influence of hormone replacement therapy (HRT)
      on lipid profile in women with type 2 diabetes. Aim of the study was to compare
      changes of blood lipids during HRT in postmenopausal women with and without type
      2 diabetes. Seventy seven women included in the study were assigned to 1 of 4
      groups, basing on being diabetic or nondiabetic, and further subdivided into
      users of estrogen alone (ERT), and of estrogen plus progestin (EPRT). Effect of 6
      month ERT (oral estradiol valerate 2 mg/day) and EPRT (oral estradiol valerate 2
      mg/day sequentially combined with cyproterone acetate 1 mg/day) on total
      cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density
      lipoprotein cholesterol (HDL-C), triglycerides and lipoprotein (a) [Lp(a)] was
      separately assessed. EPRT and ERT caused decrease in LDL-C by 15% and 12%, and
      increase in HDL-C by 12% and 13%, respectively, in patients with diabetes (p<0.05
      in all cases). LDL-C decreased by 11% and 15%, respectively, in women without
      diabetes (p<0.05 in all cases). Lp(a) was also reduced 25% with EPRT (p<0.01) and
      ERT (p<0.05). HDL-C increased 10% (p<0.05) with ERT but remained unchanged with
      EPRT. In conclusion, changes in all lipid parameters except Lp(a) caused by ERT
      and EPRT were comparable in postmenopausal women with and without type 2
      diabetes.

PMID- 12494115
TI  - [Current problems in diagnosis and treatment of cardiological patients (data from
      the XXIIIrd Congress of the European Society of Cardiology)].

PMID- 12494114
TI  - [C-reactive protein--marker of inflammation in atherosclerosis (new data)].
AB  - According to contemporary conceptions two interrelated processes underlie
      development and progression of atherosclerosis: changes of metabolism and
      transport of lipids inflammation of vessel wall. Vascular inflammation plays
      fundamental role in destabilization of atherosclerotic plaque and thus in
      development of vascular (atherothrombotic) complications. Within wide spectrum of
      biological and immunological markers (and mediators) of inflammation special
      meaning is attributed to C-reactive protein (CRP) which belongs to a family of
      'acute phase' proteins. Measurement of CRP concentration by recently developed
      well standardized high sensitivity methods is informative complementary test for
      assessment of risk of vascular complications (and possibly their severity) of
      atherosclerosis.

PMID- 12494116
TI  - [Interaction of angiotensin converting enzyme inhibitors with nonsteroidal
      antiinflammatory drugs].
AB  - Analysis of results of randomized controlled studies revealed pronounced
      attenuation of vasodilating, natriuretic, and cardioprotective effects of
      angiotensin converting enzyme inhibitors (ACEI) by concomitant use with of
      indomethacin and aspirin in patients with hypertension, chronic heart failure,
      and acute myocardial infarction. In some studies beneficial effects of ACEI were
      shown to be weakened by concomitant use with of other nonsteroidal
      antiinflammatory drugs, including selective inhibitors of cyclooxygenase-2.

PMID- 12494117
TI  - [Is effective struggle against smoking tobacco feasible?].

PMID- 12494118
TI  - [Multidisciplinary approach to the treatment of chronic heart failure: principles
      of organization and practical application].

PMID- 12494119
TI  - [Pravastatin: pharmacological action, pleiotropic effects and efficacy in
      prevention of atherosclerosis].
AB  - This literature review presents data on pharmacological action of pravastatin,
      its lipid lowering activity, and influence on main mechanisms of atherogenesis.
      Beneficial pleiotropic (nonlipid) effects of pravastatin: normalization of
      endothelial function, antiinflammatory action, antiischemic- and antithrombotic
      effects are also described. These effects represent possible mechanisms of
      participation of pravastatin in stabilization of prone to rupture atheromatous
      plaques. Early and pronounced clinical efficacy of pravastatin demonstrated in
      trials with clinical endpoints is discussed and value of the drug for primary and
      secondary prevention of atherosclerosis stressed.

PMID- 12494120
TI  - [Antiarrhythmic drug allapinin: review of results of clinical investigation].
AB  - Antiarrhythmic drug allapinin has been used in clinical practice for a long time
      but data of investigation of its effects and mechanism of action are scanty. The
      aim of this review is to summarize results of clinical studies of allapinin
      supplementing them with personal unpublished data. The review embraces
      pharmacokinetics and pharmacodynamics of the drug, its efficacy in the treatment
      of various cardiac rhythm disturbances and side effects. The conclusion is made
      that clinical application of allapinin as class 1C antiarrhythmic drug according
      to Vaughan-Williams classification should be guided by general recommendations
      concerning indications and contraindications for this class of antiarrhythmic
      drugs. Special feature of allapinin is its high efficacy for prevention of
      attacks of paroxysmal atrial fibrillation.

PMID- 12494121
TI  - [Development of a false aneurysm of the heart after myocardial infarction].

PMID- 12494123
TI  - [The use of a beta-blocker esmolol in patients with acute myocardial infarction
      treated with streptokinase].
AB  - Infusion of esmolol (50-300 mcg/kg/min, mean 119-/+75.5 mcg/kg/min, average
      duration 3.2-/+1.22 h)) was carried out in 49 streptokinase treated patients
      within 6 hours of myocardial infarction. Infusion was associated with slowing of
      heart rate and lowering of mean dynamic systolic blood pressure (by 22%). No
      changes of stroke volume and index occurred. Complications requiring either
      cessation of infusion or decrease of its rate developed in 14.3% of patients
      (lowering of systolic blood pressure below 100 mm Hg in 5, complete atrio
      ventricular block in 2) as a rule in the beginning of the infusion.

PMID- 12494124
TI  - [Pharmacodynamics, safety, and clinical effects of a novel glycoprotein IIb/IIIa
      antagonist framon during high risk coronary angioplasty].
AB  - Preparation framon [F(ab')2 fragments of the anti-glycoprotein (GP) IIb/IIIa
      monoclonal antibody (FRaMon)] blocks fibrinogen binding to GP IIb/IIIa and
      platelet aggregation. Dynamics of platelet aggregation inhibition, safety, and
      clinical effects of framon were studied in high-risk coronary angioplasty. Twenty
      seven patients underwent angioplasty with framon, 29 - with abciximab and 28 -
      with no GP IIb/IIIa antagonists. Framon at 0.2 mg/kg (n=16) and 0.25 mg/kg (n=11)
      bolus administration inhibited platelet aggregation induced by 20 mcM ADP by more
      than 90%, 80%, 60% and 30% in comparison with the predrug level 1, 12, 24 and 72
      h after injection, respectively. Almost the same dynamics of aggregation
      inhibition was observed upon abciximab administration at 0.25 mg/kg bolus + 0.125
      mcg/kg/min infusion for 12 h. No signs of individual intolerance and side effects
      including allergic reactions and bleedings were detected in patients treated with
      framon. Slight decrease of platelet count (15-20%) was observed on the first day
      after framon administration. Antibodies against framon were detected in 1 out of
      22 tested patients. Free (nonbound to platelets) framon was completely removed
      from the circulation 12 h after injection. The number of endpoints (death,
      myocardial infarction and indications for repeat revascularization) within 1 year
      after angioplasty was approximately the same in the groups with framon and
      abciximab - 7 of 25 (28%) and 7 of 28 (25%), respectively, and more than 1.5 fold
      higher in the group without GP IIb/IIIa blockers - 12 of 27 (44,4%).

PMID- 12494125
TI  - [Heart fatty acid binding protein in patients with ST-elevation acute coronary
      syndrome hospitalized within 6 hours after onset of pain].
AB  - AIM: To compare diagnostic value of a novel marker of myocardial necrosis heart
      fatty acid binding protein (FABP) with that of troponin I (TnI) and total
      creatine kinase (CK) in patients admitted early after onset of ST-elevation acute
      coronary syndrome. MATERIAL: Fifty seven patients with ST-segment elevations
      justifying thrombolytic therapy admitted within 6 hours (29/57 within 3 and 12/57
      - 2 hours) after onset of chest pain. In all patients myocardial infarction (MI)
      was eventually confirmed by development of Q waves and/or diagnostic increase of
      CK. METHODS: Samples of blood were taken at admission to coronary care unit. Cut
      off values for an elevated level of FABP was 12 ng/ml, TnI - 1.2 and 0.4 ng/ml,
      CK - 400 IU/l. RESULTS: Overall FABP was elevated in 47 (83%), TnI - in 16
      (28.1%), CK in 7 (12.3%) patients. Among patients admitted within first 3 and 2
      hours FABP was elevated in 23/29 (79.3%) and 11/12 (91%), TnI - in 9/29 (31%) and
      5/12 (41.7%), CK in 3/29 (10.3%) and 1/12 (8.3%) patients, respectively. The use
      of lower cut-off of abnormality (0.4 ng/ml) increased proportion of patients with
      elevated TnI up to 56.1% in the group as a whole, to 48.3% and 50% among patients
      admitted within first 3 and 2 hours, respectively. Nevertheless proportion of
      patients with elevated FABP remained higher with difference being significant for
      the whole group and patients admitted within first 3 hours (p=0.004 and 0.016,
      respectively). CONCLUSION: Most patients with ST-elevation acute coronary
      syndrome hospitalized within 2-6 hours after onset of pain had elevated levels of
      heart FABP.

PMID- 12494126
TI  - [Trimetazidine in pectoris patients older than 65 years with stable angina].
AB  - AIM: To study efficacy of trimetazidine including action on quality of life in
      patients over 65 years of age with stable angina pectoris. MATERIAL: Seventy two
      patients (75% men, age 65-80 years) with stable class II-III angina not
      completely controlled by baseline conventional combined antianginal therapy
      (nitrates, beta-blockers, and calcium antagonists). METHODS: Trimetazidine (60
      mg/day) was added to baseline therapy for 12 weeks. Clinical evaluation before
      and after trimetazidine included registration of symptoms, analysis of parameters
      of treadmill exercise tests (Bruce protocol) including characteristics of post
      test recovery and assessment of quality of life (Seattle Angina Questionnaire).
      RESULTS: Sixty nine patients concluded the protocol. The use of trimetazidine was
      associated with significant (p<0.0001) improvement of quality of life,
      significant prolongation of exercise time before 1 mm ST depression (p<0.0005),
      exercise time before appearance of angina (p<0.0001), time before angina
      cessation after end of exercise (p<0.01), significant reduction of number of
      anginal attacks (p<0.01), and diminishment of consumption of short acting
      nitrates (p<0.01). CONCLUSION: Addition of trimetazidine to conventional
      antianginal therapy in elderly patients was associated with improved quality of
      life, increased exercise tolerance and decreased clinical signs of stable angina.

PMID- 12494127
TI  - [Blood lipids in offsprings of patients with ischemic heart disease].
AB  - AIM: To elucidate correlations between characteristics of lipid metabolism in
      patients with ischemic heart disease and their offsprings. MATERIAL: Patients
      with overt ischemic heart disease (probands, n=24, mean age 53-/+1.9 years),
      their first (n=25, mean age 25.7-/+1.8 years) and second generation (n=20, mean
      age 13.5-/+1.3 years) offsprings. METHODS: The following parameters were studied:
      levels of lipids, lipoproteins, native and modified serum apolipoproteins,
      composition of phospholipids and fatty acids in blood erythrocytes, content of
      intracellular cholesterol in human aortic intima smooth muscle cells in vitro.
      RESULTS AND CONCLUSION: Members of a family had similar characteristics of lipid
      metabolism. According to levels of lipids, characteristics of composition of
      phospholipids and fatty acids in erythrocytes, presence of atherogenic factors in
      blood serum three variants of family traits of disturbances of lipid metabolism
      were distinguished.

PMID- 12494128
TI  - [Assessment of right ventricular function in patients with congenital heart
      defects with pulmonary hypertension. The role of some parameters of
      hemodynamics].
AB  - Intracardiac hemodynamics was studied in 46 patients with intraventricular septal
      defect and 32 patients with incomplete atrioventricular canal. The study
      confirmed practical value of assessment of contractility of right ventricular
      myocardium basing on information obtained during prolonged catheterization of the
      right cardiac chambers, construction of right ventricular function curves and
      analysis of pressure-volume loops. Compared with conventional hemodynamic
      monitoring this approach to analysis of intracardiac hemodynamics provided real
      time assessment of cardiac function, facilitated elucidation of causes of
      lowering of cardiac output and elaboration of optimal pathways of regulation of
      the myocardial contractile state.

PMID- 12494129
TI  - [Prevalence of detection of autoantibodies to beta-1 adrenoreceptors in patients
      with myocarditides and cardiomyopathies].
AB  - BACKGROUND: Autoantibodies to the second extracellular loop of a cardiac beta1
      adrenoreceptors has been detected in some patients with cardiomyopathies and
      myocarditides. In animal experiments these autoantibodies have been shown to
      cause reduction of myocardial contractility. AIM: To estimate prevalence of
      detection of autoantibodies to beta1-adrenoreceptors in patients with
      myocarditides and cardiomyopathies. MATERIAL: Forty three patients including 18
      with dilated cardiomyopathy (DCM), 14 with ischemic heart disease (IHD), 3 with
      myocarditides, 1 with alcoholic cardiomyopathy and 7 after cardiac
      transplantation. METHOD: Autoantibodies to beta1-adrenoreceptor were determined
      in patient's blood serum by direct immunoassay. Synthetic fragment containing 26
      amino acids of the beta1-adrenoreceptor second loop was used as antigen. RESULTS:
      Ten patients had obviously elevated content of autoantibodies. Three of these
      patients had IHD, 3 - DCM, 1 was studied 6 moths after myocarditis and 3 - 6-9
      years after cardiac transplantation. Tests were repeated with intervals from 6
      months to 1 year and levels of autoantibodies remained elevated in all these
      patients. Detection of antibodies did not depend on the etiology of systolic
      cardiac failure (IHD, DCM), severity of hemodynamic impairment, presence of
      disorders of cardiac rhythm or conduction.

PMID- 12494130
TI  - [Clinical characteristics of hypertensive disease in patients with alexithymia].
AB  - AIM: To study hemodynamics and metabolism in patients with hypertensive disease
      and various severity of alexithymia. MATERIAL AND METHODS: Psychological testing
      was included into complex examination of 202 patients with stage II hypertensive
      disease. RESULTS: Patients with alexithymia had longer duration of hypertensive
      load, higher frequency of target organs damage, intensified processes of lipid
      peroxidation and depressed activity of antioxidant defense, derangements of lipid
      metabolism. Twenty four hour blood pressure index characterizing day-night
      pressure gradient depended on the psychological status of patients. Nocturnal
      hypertension or insufficient nocturnal lowering of blood pressure were more
      frequent in patients with alexithymia. CONCLUSION: The presence of alexithymic
      personality traits was associated with more severe clinical presentation of
      hypertensive disease.

PMID- 12494131
TI  - [Does "pulmogenic hypertension" exist?].
AB  - Validity of criteria of so called "pulmogenic hypertension" in chronic
      obstructive pulmonary diseases was assessed with the use of a questionnaire and
      simultaneous 24 hour monitoring of blood pressure and peak expiratory rate in 80
      and 28 patients, respectively. This method of bifunctional monitoring allowed to
      study relationship between blood pressure level and degree of bronchial
      obstruction. The results did not confirm the presence of "pulmogenic
      hypertension" as a special form of arterial hypertension.

PMID- 12494132
TI  - [Changes of erythrocyte membrane structure in patients with myocardial
      infarction].

PMID- 12494133
TI  - [Efficacy and safety of the use of lisinopril in the treatment of patients with
      hypertension].

PMID- 12494134
TI  - [Federal targeted program 'Prevention and Management of Arterial Hypertension in
      Russian Federation'].

PMID- 12494135
TI  - [Contemporary approaches to diagnosis and management of chronic heart failure
      (summary of the American College of Cardiology/American Heart Association
      Guidelines)].
AB  - ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in
      the Adult are summarized in detail. According to statements of these Guidelines
      most patients with chronic heart failure as a rule should receive combination of
      representatives of 4 different drug classes - diuretic, angiotensin converting
      enzyme inhibitor, beta-adrenoblocker and usually digoxin. Special indications
      have been formulated for inclusion in complex therapy of aldosterone receptor
      blockers (first of all spironolactone), angiotensin1 receptor blockers and direct
      vasodilators (hydralazine, isosorbide dinitrate).

PMID- 12494136
TI  - [Preventing of stroke by antihypertensive drugs: potential and limitations].
AB  - Analysis of controlled randomized studies of efficacy of antihypertensive drugs
      in primary and secondary prevention of stroke is presented. Basing on this
      analysis a conclusion is made that in patients with hypertension representatives
      of all 4 main classes of antihypertensive drugs prevent stroke with similar
      efficacy. Magnitude of reduction of risk of both first and recurrent stroke is
      determined not by the class of a drug but by degree of blood pressure lowering.
      Special emphasis is made on necessity of careful approach to blood pressure
      lowering in elderly patients.

PMID- 12494137
TI  - [Clinical sequelae of tissue angiotensin converting enzyme inhibition:
      practicability of use in ischemic heart disease].
AB  - Harmonic combination of efficacy and safety allowed angiotensin converting enzyme
      inhibitors (ACEI) to conquer popularity among physicians in the treatment of
      hypertension, heart failure, myocardial infarction, diabetic and non-diabetic
      nephropathy. This multiprofile application is determined by their action not only
      on systemic but also on tissue renin-angiotensin systems which augmented activity
      plays important role in genesis of various pathological states. One of novel and
      most promising directions of use of ACEI especially of those with inherent high
      tissue specificity and vascular selectivity (quinapril, perindopril, ramipril,
      trandolapril) is the treatment of atherosclerosis. Antiatherosclerotic effects of
      ACEI were studied in a variety of clinical trials with assessment of their effect
      on long term outcome. These trials demonstrated positive action of ACEI on the
      clinical course of cardiovascular and cerebrovascular diseases. Expediency of
      prescription of ACEI to patients with atherosclerosis of coronary vessels and
      other vascular beds irrespective of the presence of hypertension and heart
      failure becomes now obvious.

PMID- 12494138
TI  - [Apheresis of immunoglobulins - new approach to the treatment of severe dilated
      cardiomyopathy].
AB  - Two courses of immunoadsorption with 'Ig Adsopak' were used in the treatment of a
      patient with dilated cardiomyopathy (DCM) during which all class G and partially
      class M and A immunoglobulins were removed. Every course consisted of 5 daily
      procedures and resulted in removal of 98% of immunoglobulins. This was associated
      with complete removal of autoantibodies to beta1-adrenoreceptor. After the end of
      a course loss of immunoglobulins was replenished by intravenous infusion of
      Pentaglobin and Oktagam. Echocardiographic study carried out before, during and
      after second course of apheresis revealed reduction of left and right ventricular
      and atrial volumes and dimensions, improvement of contractility of anterior part
      of interventricular septum and of anterolateral left ventricular wall. As
      efficacy of drug therapy of dilated cardiomyopathy is low and facilities of
      cardiac transplantation are limited the method of therapeutic apheresis reveals
      novel perspectives of the treatment of dilated cardiomyopathies.

PMID- 12494139
TI  - [Lipoprotein (a) and ischemic heart disease in patients with hypertensive
      disease].
AB  - Relationship between level of lipoprotein (a) and presence of ischemic heart
      disease (IHD) was studied in 191 patients with hypertensive disease (essential
      hypertension) (112 men, 79 women, age 56.9-/+10.6 years) and 33 patients with
      normal blood pressure (23 men, 10 women, age 50.8-/+11.0 years). Concentration of
      lipoprotein (a) in men with hypertension and IHD (n=62) was significantly higher
      than in men with hypertension without IHD (n=50) (median 19 and 9 mg/dl,
      respectively, p=0.02). Women with hypertension and with (n=23) and without (n=56)
      IHD had similar blood levels of lipoprotein (a) (median 13 and 15 mg/dl,
      respectively, p=0.89). Difference in lipoprotein (a) levels between patients with
      hypertensive disease and those with normal blood pressure was not significant
      (median 14 and 10 mg/dl, respectively, p=0.50).

PMID- 12494140
TI  - [Dynamics of rates of fatal and nonfatal complications of hypertension in a
      population of workers subjected to occupational vibration (15-year follow-up)].
AB  - Prospective monitoring of fatal and nonfatal myocardial infarctions and strokes
      was carried out in a population of workers with professional exposure to
      vibration. Duration of monitoring was 15 years. In the end of this period
      implementation of a program of preventive intervention was associated with
      lowering of rates of cerebral and coronary events (3.0 vs. 5.2% among
      nonparticipants in this program). In 5 years after cessation of the program an
      increase of risk of cardiovascular complications especially that of strokes
      occurred. Changes of rates of events in a group of workers not subjected to
      special intervention were less pronounced. Negative dynamics of event rates in
      the group of active prevention could be attributed to continuing action of
      unfavorable occupational factor.

PMID- 12494141
TI  - [Effects of nebivolol on microcirculation, platelet aggregation and blood
      viscosity in patients with essential hypertension].
AB  - AIM: To assess effects of a selective beta1-adrenoreceptor blocker acting in part
      via nitric oxide nebivolol on microcirculation, platelet aggregation and blood
      viscosity. MATERIAL: Thirty patients with mild-to-moderate essential hypertension
      (mean age 54,1-/+9,3 years). METHODS: Ambulatory blood pressure monitoring, laser
      doppler flowmetry, registration of spontaneous and ADP-induced platelet
      aggregation. Nebivolol (5 mg/day) or its combination with hydrochlorothiazide
      (12,5 mg/day) were given for 3 months. RESULTS: Treatment with nebivolol caused
      significant reduction of systolic and diastolic blood pressures. Spontaneous and
      low dose ADP-induced platelet aggregation significantly decreased during
      treatment while blood viscosity did not change. In patients with hyperemic and
      spastic-hyperemic hemodynamic type of microcirculation improvement of
      microcirculation occurred due to changes of myogenic tone of arterioles and
      precapillary sphincters and 'damping' properties of resistance arterioles.
      CONCLUSION: In patients with essential hypertension hypotensive action of
      nebivolol was associated with antiaggregation effect and improvement of blood
      flow in microvascular networks.

PMID- 12494142
TI  - [Changes of distensibility of the aorta in elderly patients during long-term
      therapy with various classes of hypotensive drugs (magnetic resonance tomography
      data)].

PMID- 12494143
TI  - [Prevalence of hypertension among young people and efficacy of its treatment with
      enalapril].

PMID- 12494144
TI  - [Factors affecting pulmonary circulation after pulmonary artery thromboembolism].

PMID- 12494145
TI  - [Gender differences in the state of the system of hemostasis in patients with
      ischemic heart disease].
AB  - Levels of fibrinogen, von Willebrand factor, d-dimer, antithrombin III, protein
      C, plasminogen, and plasminogen activator inhibitor were measured in 62 men and
      37 women with ischemic heart disease before and after 20-min venous occlusion.
      Women compared with men had higher baseline levels of fibrinogen (4.046-/+0.1785
      and 3.584-/+0.1591 g/l, respectively, p=0.021), von Willebrand factor (122.1
      /+9.31 and 99.5-/+6.16%, respectively, p=0.035), plasminogen activator inhibitor
      (4.8-/+0.31 and 2.9-/+0.27 IU/l, respectively, p=0.009). Levels of antithrombin
      III, protein C, and plasminogen in women were higher than in men both at baseline
      (108.5-/+1.65 and 100.7-/+1.60 %, p=0.001; 129.1-/+2.91 and 107.2-/+3.79%,
      p=0.001; 113.6-/+2.13 and 104.1-/+1.89%; p=0.001, respectively) and after venous
      occlusion. There were no gender differences in dynamics of parameters of
      hemostasis during venous occlusion. Multifactorial regression analysis showed
      that gender was independently (of age, duration of hypertension, smoking, body
      mass index, and total cholesterol level) related to only antithrombin III and
      protein C levels.

PMID- 12494146
TI  - [Prospective analysis of conservative treatment of acute coronary syndrome].
AB  - The in-hospital and intermediate outcomes in 341 patients with acute coronary
      syndrome treated with conservative (non-invasive) interventions were analysed.
      The coronary reperfusion was achieved in 59% patients with acute myocardial
      infarction (MI) treated with thrombolysis, but in 27% patients with MI treated
      only heparin and aspirin. In-hospital survival was 91% in 93 patients with MI
      treated with thrombolysis and 82% in 71 patients with MI without thrombolysis. On
      6 month survival was 86% in patients with MI treated with thrombolysis, 70% in
      patients with MI without thrombolysis, 79% in patients with non-Q-wave MI and 88%
      in patients with unstable angina.

PMID- 12494147
TI  - [Effect of perindopril on left ventricular structural and functional parameters
      in patients with preserved systolic function after myocardial infarction.
      Relation to polymorphism of angiotensin converting enzyme gene].

PMID- 12494148
TI  - [Results of stenting and surgical treatment in patients with ischemic heart
      disease and multivessel coronary artery involvement].
AB  - Efficacy of surgical and endovascular (with the use of stents) methods of
      treatment was assessed in 56 patients with ischemic heart disease and double and
      triple vessel involvement. Coronary artery bypass grafting (CABG) was carried out
      in 31, implantation of stents - in 25 patients. Clinical factors used for
      assessment of efficacy of treatment were development of events (deaths,
      myocardial infarctions), presence of angina, changes of exercise capacity. In
      immediate postoperative period there were 2 myocardial infarctions (1 in each
      group, i.e. 4 and 3.2% after stenting and CABG, respectively) and no deaths.
      Absence of clinical effect (persistence of angina) more often occurred after
      stenting (12%) that after CABG (6.5%). Length of hospital stay was shorter after
      stenting (13-/+8 days) than after CABG (24-/+10 days). Increment of exercise
      tolerance was higher after stenting than after CABG (62-/+10 and 54-/+8 W,
      respectively). During 1 year of follow-up 1 myocardial infarction developed
      (after stenting). In a year after procedure angina recurred in 24 and 12.9% of
      patients subjected to stenting and CABG, respectively; increments of exercise
      tolerance were 53-/+8 and 49-/+7 W after stenting and CABG, respectively. These
      results are indicative of high efficacy of surgical and endovascular (with
      implantation of stents) treatment of multivessel coronary artery disease.

PMID- 12494149
TI  - [Dynamics of structural and functional parameters of cardiovascular system in
      patients with ischemic heart disease during one year after coronary artery bypass
      grafting].

PMID- 12494150
TI  - [Myocardial blood flow in different regions of the heart in patients with
      ischemic heart disease before and after revascularization].
AB  - Laser doppler flowmetry was used for the intraoperative study of myocardial blood
      flow before and after revascularization in 116 patients with 2-3 vessel coronary
      artery disease and class II-IV angina. In patients without myocardial infarction,
      with microfocal myocardial infarction, or operated early after myocardial
      infarction revascularization caused no significant increase of myocardial blood
      flow. In patients with macrofocal infarction surgery was associated with
      significant increase of myocardial blood flow. Efficacy of revascularization
      could be assessed by lowering of flow gradients between various regions of the
      myocardium.

PMID- 12494151
TI  - [Effect of therapeutic education of patients with chronic heart failure on
      quality of life and requirement of rehospitalizations. Results of 12-months
      randomized study].

PMID- 12494152
TI  - [Antihypertensive drugs and malignant neoplasia].
AB  - Analysis of epidemiological, cohort and randomized studies of antihypertensive
      drugs containing reports of development of malignant neoplasms shows that long
      term use of some antihypertensive drugs while preventing cardiovascular
      complications has been associated with increased risk of malignancies. Most
      convincing evidence exists for association between the use of diuretics and renal
      cancer. Association between the use of reserpine and breast cancer in women,
      between atenolol and some types of cancer in elderly men also can not be ruled
      out. There is no proof of existence of either negative or positive correlation
      between malignant neoplasia and long-term use of calcium antagonists, angiotensin
      converting enzyme inhibitors or angiotensin receptor blockers.

PMID- 12494153
TI  - [The no-reflow phenomenon and its clinical significance].
AB  - The no-reflow phenomenon is characterized by inadequate myocardial perfusion
      without angiographic manifestations of mechanical vascular occlusion. The
      phenomenon occurs after coronary vascular interventions (coronary angiography,
      percutaneous coronary angioplasty, stenting, coronary artery bypass surgery). The
      development of the no-reflow phenomenon significantly worsens clinical evolution
      of disease increasing the number of cases of congestive heart failure and
      hospital mortality. Changes of endothelial function and morphology, changes of
      blood rheology and microvascular autoregulation are important for pathogenesis of
      the phenomenon. The treatment include intracoronary introduction of verapamil,
      adenosine, intravenous introduction of activators of KATP channels (nicorandil),
      inhibitors of glycoprotein IIb/IIIa receptors. The reasons for early preventive
      use of intracoronary introduction of verapamil and other drugs in the presence of
      risk of development of no-reflow phenomenon are presented. The interrelationship
      between no-reflow phenomenon and syndrome X is also stressed.

PMID- 12494154
TI  - [Emerging problems of medical ethics in Russia: medical practice and research].
AB  - The problem of maintenance of integrity of medical profession is rarely discussed
      in Russia. Meanwhile the following pressing challenges emerge within the medical
      community in this country: tolerant attitude to violations of ethical principles
      and falsification in research, incompetence and deceit in practical work, wide
      penetration of alternative medicine and witchery into everyday medical practice,
      involvement of physicians in advertising and marketing of drugs, even direct
      selling of them by medical doctors. Medical community should urgently respond to
      these challenges and develop mechanisms of internal control. This can be
      accomplished within the framework of associations of physicians and medical
      professional groups. Without solution of the above problems Russian medicine
      would never occupy appropriate high position in the society.

PMID- 12494155
TI  - [Practical application of Holter ECG monitoring. Part I. Basic principles of the
      equipment of Holter ECG monitoring system. Indications for Holter monitoring].

PMID- 12494156
TI  - [Assessment of quality of life of patients with cardiovascular diseases].

PMID- 12494157
TI  - [Congenital (hereditary) long QT syndrome: possible factors predisposing to
      development of ventricular tachyarrhythmias. Part II].
AB  - In 3 close relatives (mother, son, mother's first cousin) with long Q-T syndrome
      syncopal attacks were preceded by lowering of ionized calcium in peripheral
      blood. This mechanism is supposed to be a trigger of ventricular tachycardia in
      long Q-T syndrome.

PMID- 12494158
TI  - [Cardiomyopathies with predominant right ventricular involvement].

PMID- 12494159
TI  - [Feasibility of implementation of guidelines for the management of acute coronary
      syndrome in cardiac unit of a community hospital].
AB  - AIM: To assess feasibility of implementation of Guidelines of Russian Society of
      Cardiology (RSC) on the management of non ST elevation acute coronary syndrome
      (adaptation of Guidelines of the European Society of Cardiology) in an ordinary
      noninvasive community hospital. METHODS: Retrospective analysis of inhospital
      management of 266 consecutive patients with acute coronary syndromes without
      persistent ST elevation admitted to coronary unit of a community hospital in
      January-July, 2001. MATERIAL AND RESULTS: Main characteristics of the group: mean
      age 69 years (34% >75 years), men - 56%, history of myocardial infarction - 38%,
      hypertension - 67%, diabetes - 23%, pain at rest as an index event - 98%,
      symptoms duration exceeding 20 min - 61%, ECG changes - 87% (42% ST deviation),
      signs of left ventricular failure - 14%. Myocardial infarction as index event was
      diagnosed in 32% of pts by serial measurement of total CK activity. There were no
      angiographies or revascularizations during hospital stay (20-/+6 days) because of
      absence of catheterization facilities. Medical treatment: antiplatelet agents -
      99% (98% - aspirin) of patients; proportion of patients treated with heparins -
      83% (low molecular weight heparins - 18,5%). Most of the patients received b
      blockers (79%) and nitrates (78%). Use of calcium channel blockers was relatively
      low (15%). Few patients (20%) received statins. Inhospital rate of death and
      nonfatal myocardial infarction was 3,5% i 3%, respectively. Rate of chest pain
      recurrence was high (38% overall, 26% with ischemic ST-T ECG changes) and at
      least partially could be explained by the lack of invasive interventions.
      CONCLUSION: Management of patients with non ST elevation ACS in coronary unit of
      a community hospital during the period surveyed in this study was in line with
      corresponding RSC guidelines (as related to noninvasive treatment) except
      duration of hospitalization. This was associated with acceptable rate of death
      or/and myocardial infarction (6,5%) in a group of relatively high risk pts. High
      rate of angina recurrences during rather long hospital stay reflected absence of
      invasive treatment.

PMID- 12494160
TI  - [Thrombolytic therapy of acute myocardial infarction in elderly patients.
      Immediate and long-term remote prognosis].
AB  - AIM: To study effects of thrombolytic therapy in elderly patients. MATERIAL AND
      METHODS: One hundred twenty three patients with acute myocardial infarction were
      admitted within first 12 hours of myocardial infarction, 66 of them were
      subjected to thrombolytic therapy with streptokinase (group 1) while 57 were not
      because of contraindications (group 2). In group 1 age of 49 patients was 66-75
      years, and that of 17 patients exceeded 75 years. RESULTS: In 24.2% of patients
      pain ceased during thrombolysis. This effect occurred less often in patients over
      75 years of age. Reperfusion arrhythmias were registered in 15.1% of older
      patients. Patients of group 2 more often had acute left ventricular failure
      (47.4% vs. 18.2% in group 1, p=0.003). Rate of development of acute heart failure
      was higher in patients aged over 75 years (by 8% compared with younger patients
      in both groups). Chronic heart failure developed in 36.8% and 13.6% of patients
      in group 2 and 1, respectively (p=0.001). Rate of chronic heart failure in group
      1 was lower than among total population of patients, subjected to thrombolytic
      therapy (13.6 and 26.5%, respectively, p=0.040). Rate of early angina and
      reinfarction was higher in group 1 than in group 2 (by 4 and 3%, respectively).
      In 12 months rate of angina was higher in group 1 compared with group 2 (83.3 and
      52.6%, respectively, p=0.088). Among patients with heart failure in group 1
      prevailed those with class I-II (p=0.175) while in group 2 there were more
      patients with class III-IV than class I-II heart failure. Rate of chronic heart
      failure among patients older than 75 years was by 13 and 22.8% higher, than in
      younger patients of groups 1 and 2, respectively. One year mortality was 9.1% in
      group 1 and 22.8% (p=0.019) in group 2. Mortality among patients over 75 years of
      age was higher in both groups especially in group 1 (by 13.5%).

PMID- 12494161
TI  - [Prognostic value of cardiac troponin I in patients with non-ST elevation acute
      coronary syndrome].
AB  - AIM: To elucidate relationship between initial blood levels of troponin I and
      occurrence of such events as death, myocardial infarction, coronary artery bypass
      surgery, and angioplasty in patients with non-ST elevation acute coronary
      syndrome. MATERIAL: One hundred one patients aged 32-78 years admitted to
      coronary care unit within 24 hours after onset of pain including 69 (68.3%) with
      unstable angina and 32 (31.7%) with non-ST elevation myocardial infarction.
      METHOD: Troponin I was determined by immunoassay, values below 0.4 ng/ml were
      considered normal. RESULTS. During 30 days of hospitalization there were 16
      (35.5%) and 5 events (8.9%) events (p=0.001) among 45 patients who had elevated
      level of troponin I (group 1) and 56 patients with normal troponin I (group 2),
      respectively. By 6 months events occurred in 19 (42.2%) and 6 (10.7%) patients in
      groups 1 and 2, respectively (p=0.0004). CONCLUSION: Thus elevated blood level of
      troponin I in patients with non-ST elevation acute coronary syndrome has
      important value for prognosis.

PMID- 12494162
TI  - [Fatal and nonfatal cardiovascular complications in patients with essential
      hypertension (hypertensive disease) during follow-up for many years].
AB  - Fatal and nonfatal complications (stroke, myocardial infarction, chronic heart
      failure, sudden coronary death, chronic renal insufficiency) were registered
      during long term follow-up of 529 patients with hypertensive disease and results
      were analyzed retrospectively. Duration of ambulatory treatment in two thirds of
      patients exceeded 15 years. There were 243 deaths in 1993-1999. Mean age of those
      who died was 75 years. Main fatal complications were strokes and myocardial
      infarctions. Their rates were similar. Strokes comprised one third of all deaths
      irrespective of age. There were no significant differences between rates of
      ischemic and hemorrhagic strokes. Among causes of death proportion of sudden
      death was the highest in patients younger than 60 years while that of chronic
      heart failure rose with age. There were no cases of chronic renal failure.
      Atherosclerotic lesions in coronary and cerebral vessels were found at autopsies
      irrespective of cause of death.

PMID- 12494163
TI  - [Effect of therapy with lisinopril on the state of cerebral blood flow in women
      with hypertension in peri- and postmenopause].
AB  - Blood flow in extra and intracranial arteries was assessed by doppler ultrasound
      in 26 hypertensive women without history of stroke. Studies were performed before
      treatment, after acute test with lisinopril and in 1 month of therapy with
      lisinopril. Baseline investigation revealed changes of velocity characteristics
      of blood flow and resistance indexes indicative of impaired cerebral hemodynamics
      both at extra- and intracranial level. After treatment with lisinopril signs of
      improvement of blood flow in extra- and intracranial arteries were found. Most
      important finding was normalization of ability of extracranial arteries to spasm
      and dilation presumably associated with restoration of hemodynamic reserve of
      cerebral vessels.

PMID- 12494164
TI  - [Long term use of a non-selective beta-blocker with vasodilating properties
      carvedilol in patients with severe heart failure].
AB  - Results of drug treatment of 51 patients (41 men, 10 women) aged 35-86 years
      (mean age 62 years) included into COPERNICUS trial are presented. All patients
      had compensated NYHA class IV chronic heart failure and left ventricular ejection
      fraction less than 25%. For at least 2 months the patients received therapy with
      diuretics and angiotensin converting enzyme inhibitors (84%) or angiotensin
      receptor blockers (16%) and then were randomized to either carvedilol or placebo.
      Average duration of follow-up was 17 months. Carvedilol was well tolerated both
      during dose titration and during maintenance therapy. Addition of carvedilol to
      standard therapy of patients with severe heart failure was associated with
      increase of average ejection fraction from 21.7 to 30.3%. Rates of cardiovascular
      and sudden deaths, risk of hospitalization among carvedilol treated patients were
      25, 33 and 57% less than among patients subjected only to standard therapy.

PMID- 12494165
TI  - [Comparative analysis of results of two techniques of ablation for typical atrial
      flutter].
AB  - AIM: To compare efficacy of two techniques of ablation for typical atrial
      flutter: 'old' which end point was impossibility of arrhythmia reinduction and
      'novel' aimed at change of sequence of right atrial excitation during coronary
      sinus ostium pacing for verification of isthmus block after ablation of the
      inferior vena cava-tricuspid valve isthmus. METHOD: Retrospective analysis of
      results of 122 procedures of catheter ablation for common atrial flutter.
      RESULTS: Efficacy of both methods was similar but the use of the 'novel'
      technique was associated with shorter overall duration of a procedure and
      fluoroscopy time, lesser number of applications required for successful ablation,
      and lower rates of induction of atrial fibrillation and of atrial flutter
      recurrences.

PMID- 12494166
TI  - ['Uninterrupted' anterograde atrioventricular excitation conduction in patients
      with paroxysmal reciprocal atrioventricular nodal tachycardias].
AB  - Different variants of anterograde atrioventricular conduction of excitation were
      distinguished basing on data obtained from 150 patients with paroxysmal
      reciprocal atrioventricular nodal tachycardias. Excitation conduction during
      programmed and accelerating atrial transesophageal pacing allowed to assess
      characteristics of excitation conduction along fast and slow conduction pathways
      in atrioventricular node. Some parameters were suggested that allowed to predict
      possibility of detection of different variants of anterograde atrioventricular
      conduction of excitation. Electrophysiological mechanisms of detection of various
      types of atrioventricular conduction curves are discussed.

PMID- 12494167
TI  - [Assessment of the use of various cardiac pacing modes for selection of
      antiarrhythmic therapy for prevention of recurrent attacks of atrial fibrillation
      and flutter].
AB  - AIM: To determine optimal mode of transesophageal pacing for selection of
      appropriate antiarrhythmic therapy for prevention of attacks of atrial
      fibrillation and flutter in patients with ischemic heart disease. MATERIAL AND
      METHODS: Two hundred eighteen patients with ischemic heart disease and attacks of
      atrial fibrillation or flutter. Selection of antiarrhythmic drugs was carried out
      with the use of competitive, rapid, salvos of ultra rapid, and slowly
      accelerating ultra rapid modes of pacing. Results. Most effective and
      reproducible method for induction of attacks of atrial flutter and fibrillation
      was slowly accelerating ultra rapid mode of pacing. Average duration of positive
      clinical effect of preventive antiarrhythmic therapy selected basing on the
      results of this mode in patients with ischemic heart disease was 3.1-/+0.3 years.
      Unfavorable prognostic sign decreasing preventive effect of antiarrhythmic
      therapy was left atrial dilatation. CONCLUSION: Slowly accelerating mode of
      transesophageal pacing was most effective tool for selection of antiarrhythmic
      therapy aimed at prevention of attacks of atrial fibrillation and flutter in
      patients with ischemic heart disease.

PMID- 12494168
TI  - [Comparative assessment of different types of adaptational protection of the
      myocardium during stress].
AB  - AIM: To study in rats effects of 3 types of adaptation on structural
      rearrangement of myocardium during stress. METHOD: Corrosion preparations of
      coronary vessels, morphometry of focal lesions of cardiomyocytes and correlation
      analysis of relationships between data obtained by these methods. RESULTS AND
      CONCLUSIONS: Preliminary adaptation to mild stress exerted maximal protection of
      myocardial cells against severe stress at minimal expansion of coronary vascular
      bed. Correlation analysis showed that vascular factor played modest role in
      realization of this cardioprotection (Pearson coefficient 0.31, p<0.05). On the
      contrary adaptation to hypoxia exerted minimal protective effect on myocardium
      against stress despite maximal expansion of vascular bed. The latter factor
      played rather important role in realization of this type of cardioprotection
      (correlation coefficient -0.89, p<0.001). Adaptation to physical effort occupied
      intermediate position according to the parameters studied.

PMID- 12494169
TI  - [To the problem of efficacy of beta-adrenoblockers in patients with various
      pathogenetic variants of hypertension].

PMID- 12494170
TI  - [Efficacy of physical factors according to the state of hormonal homeostasis in
      myocardial infarction].

PMID- 12494171
TI  - [Synthesis of nitric oxide and development of atherosclerosis].
AB  - The paper reviews data on the possible role of malfunction of nitric oxide (NO)
      synthesis in pathogenesis of atherosclerosis. The singularities of NO synthesis,
      types of enzymes catalyzing this reaction (a set of NO-synthases), and some
      possible aspects of regulation of their activity are briefly surveyed. Available
      data concerning effect of derangements of NO synthesis on development of
      endothelial dysfunction and atherosclerosis are discussed. Possible mechanisms of
      abnormalities of NO synthesis caused by the influence of atherogenic risk factors
      (hypercholesterolemia, oxidized LDL, diabetes, inflammation etc.) as well as
      probable clinical consequences of these abnormalities are presented. Genetic
      aspects of NO synthesis are considered and probable role of NO-synthase genes in
      inheritance of predisposition to the majority of cardiovascular diseases is
      stressed. A conclusion is made that available knowledge is not sufficient for
      unequivocal formulation of the role of NO in development of atherosclerosis, that
      further studies are necessary.

PMID- 12494172
TI  - [Cardiovascular complications of type 2 diabetes].
AB  - Cardiovascular complications due to micro- and microangiopathy are main causes of
      death of patients with type 2 diabetes. Principal role in development of these
      complications belong to hyperglycemia which triggers such pathological processes
      as endothelial dysfunction, oxidative stress, impairment of hemostasis and blood
      rheology. Therefore glucose lowering therapy is pathogenetic not only for
      diabetes but also for its cardiovascular complications. Glucose lowering drugs
      should be maximally effective and safe for the cardiovascular system. These
      requirements gliclaside which in addition to pronounced glucose lowering effect
      also acts on all links of the pathogenesis of micro- and macroangiopathies. While
      selecting cardiovascular drugs one should take into consideration their effect on
      carbohydrate metabolism and cardioprotective properties. Angiotensin converting
      enzyme inhibitors are leaders in this field.

PMID- 12494173
TI  - [Assessment of efficacy of treatment of patients with chronic ischemic heart
      disease].
AB  - The lecture summarizes data on approaches to organization of studies in which
      evidence based data on efficacy and safety of therapy of patients with ischemic
      heart disease can be obtained. Some novel approaches to improvement of quality of
      assessment of benefits of treatment are suggested. It is stressed that results of
      studies of a drug can not be transferred to another one even belonging to the
      same group. Indications to various methods of estimation of antiischemic action
      of drugs and their limitations are also described.

PMID- 12494174
TI  - [Beta-adrenoblockers: evidence based principles of therapy].

PMID- 12494175
TI  - [Depression--a novel risk factor of ischemic heart disease and predictor of
      coronary death].
AB  - According to results of recent prospective studies depression is an independent
      risk factor of ischemic heart disease and should be considered together with such
      acknowledged risk factors as dyslipidemia, hypertension and smoking. Possible
      pathophysiological mechanisms of relationship between depression and ischemic
      heart disease are lowered heart rate variability and defects of physiological
      characteristics of platelets, depression also influences compliance to treatment
      and physicians recommendations. Depression negatively affects prognosis:
      mortality after myocardial infarction of patients with depression is 3-6 time
      higher than of those without depression. Incidence of depression is rather high
      and special investigation reveals its clinically significant symptoms in every
      fifth patient. Depression worsens clinical course of ischemic heart disease.
      Timely detection of depression is very important.

PMID- 12494176
TI  - [Aspirin in primary prevention of ischemic heart disease].
AB  - High efficacy of aspirin in secondary prevention after myocardial infarction and
      stroke is well established. However the place of aspirin in primary prevention of
      coronary heart disease and other cardiovascular diseases remains questionable.
      Analysis of results of large controlled studies of efficacy and safety of aspirin
      in high risk subjects shows that low doses of aspirin should be used in men with
      high risk of coronary heart disease but without main risk factors of stroke.

PMID- 12494177
TI  - [Some results and perspectives of heart failure research].
AB  - Heart failure is a frequent often in the practice of a cardiologist but data on
      its actual incidence are inconsistent. This can be explained by variations in
      methodological approaches. Screening studies require simple easily obtainable and
      safe techniques capable to characterize activity of a patient. Their results
      should be compatible with widely accepted NYHA classification. Six minute walking
      test is one of possible solutions. Its results agree with NYHA classes, peak
      oxygen consumption and prognosis of survival. For improvement of accuracy of
      estimation of physical working capacity it is important to consider body mass.
      This can be achieved by a simple portable device constructed by the authors. To
      assess sufficiency of circulation during testing it is advisable to determine the
      load at which decorreleation between dynamics of effort and that of physiological
      parameters is revealed. Basing on the above considerations the authors suggest to
      define heart failure as a condition when decorrelation of physiological functions
      causes deterioration of perfusion and worsening of quality of life.

PMID- 12494178
TI  - [Effect of long-term myocardial unloading with beta1-adrenoblocker atenolol on
      the state of the left ventricle in patients with moderate ischemic dysfunction of
      the heart as shown by doppler echocardiography].
AB  - Effects of 12-month therapy with a beta1-adrenoblocker atenolol on the process of
      late postinfarction remodeling of the heart and parameters of intracardiac
      hemodynamics were assessed in an open noncomparative study on 55 survivors of
      macrofocal myocardial infarction. Therapy with atenolol was associated with: (1)
      reduction of myocardial hypertrophy in patients with increased left ventricular
      myocardial mass without effect on its volume, cavity geometry and global systolic
      function; (2) normalization of initially 'hypertrophic' type of transmitral blood
      flow. Affecting mainly the demand component of the myocardial oxygen
      supply/demand ratio atenolol promoted inclusion of hibernating cardiomyocytes
      into active contraction.

PMID- 12494179
TI  - [Trimetazidine in correction of chronic heart failure in patients with ischemic
      heart disease].
AB  - Twenty patients with NYHA class II-IV heart failure and ejection fraction below
      40% received standard therapy (control period) or standard therapy plus open
      trimetazidine (20 mg t.i.d.) for 3 months in a cross-over design. Therapy with
      trimetazidine was associated with attenuation of clinical signs of heart failure
      (average NYHA class 2.90-/+0.10, 2.27-/+0.20 and 2.88-/+0.13, p<0.05, at
      baseline, after trimetazidine and control period, respectively), improvement of
      results of 6-minute walk test (average distance 321-/+19, 375-/+20 m, p<0.02, and
      303-/+17 m at baseline, after trimetazidine and control period, respectively),
      increase of left ventricular ejection fraction (from 34.1-/+2.0 to 38.1-/+1.8%,
      p<0.05) and improvement of quality of life. Thus in patients with heart failure
      addition of trimetazidine to standard therapy for 3 months produced positive
      effect on clinical and hemodynamic status, exercise tolerance and quality of
      life.

PMID- 12494180
TI  - [Coronary stenting in acute myocardial infarction complicated with cardiogenic
      shock].
AB  - AIM: To assess immediate and long-term results of urgent coronary stenting in
      patients with cardiogenic shock. MATERIAL AND METHODS: Twenty three patients (15
      men, 8 women mean age 58-/+12 years) with myocardial infarction and cardiogenic
      shock treated with vasopressors and intraaortic balloon pumping (IABP). Culprit
      lesions were localized in left anterior descending and right coronary arteries in
      16 and 7 cases, respectively. Prior to stenting 18 and 5 patients had TIMI grade
      0 and 1 flow, respectively. RESULTS: Stents (n=26, Seaquence and Ephesos, length
      12-28 mm, diameter 2-3.5 mm) were successfully implanted in all patients after
      balloon predilation. After stenting TIMI grade 3 flow was achieved in 15
      patients, 8 patients had TIMI-2 flow without angiographic signs of dissection or
      residual stenosis. There were 4 inhospital deaths and 19 patients (83%) were
      discharged. One angioplasty and 2 coronary artery bypass grafting procedures
      because of restenosis and reocclusion were successfully performed during first 4
      months of follow-up. CONCLUSION: Urgent stenting combined with IABP was effective
      method of treatment of cardiogenic shock with 83% inhospital survival and 61%
      freedom from repeat revascularization.

PMID- 12494181
TI  - [Stratification of patients with hypertension and selection of antihypertensive
      therapy].
AB  - Patients with hypertension (78 men, 113 women aged 20-73 years) were stratified
      according to risk of development of cardiovascular complications. In low and
      moderate risk patients (n=31) with borderline hypertension, dyslipidemia and
      pronounced obesity mainly non-drug measures were employed directed at lowering of
      excess body mass. Medium risk patients (n=25) with isolated hypertension group
      were treated with angiotensin converting enzyme inhibitors and phenylalkylamine
      calcium antagonists. High risk patients (n=55) with metabolic syndrome received
      same antihypertensive drugs as medium risk patients. In very high risk patients
      (n=79) with diabetes, excessive body mass, dyslipidemia and proteinuria complex
      therapy consisting of antihypertensive and hypoglycemic drugs and non-drug
      interventions was used. This risk stratification based management of patients
      with hypertension on turned out to be highly effective and resulted not only in
      normalization of blood pressure but also in improvement of carbohydrate and lipid
      metabolism, lowering of resistance to insulin and excessive body mass, and
      improvement of renal function.

PMID- 12494182
TI  - [Effect of mexidol on oxidative stress in cerebral variant of hypertensive
      crisis].
AB  - Parameters of oxidative stress were studied in 44 patients with grade II-III
      essential hypertension and cerebral variant of hypertensive crisis. All patients
      received antihypertensive treatment. Mexidol was administered intravenously (300
      mg o.d.) for 7 days starting with the second day of a hypertensive crisis.
      Control group consisted of 27 patients who were not treated with mexidol. The
      level of lipid peroxidation products and parameters of antioxidative system were
      used for assessment of the state of oxidative stress. Significant increases of
      the coefficient of oxidative stress were registered at all study points in
      patients who were not treated with mexidol. Treatment with antioxidant mexidol
      was associated with decreased coefficient of oxidative stress throughout the
      whole study period (up to 14-th day).

PMID- 12494183
TI  - [NOS3 gene polymorphism and left ventricular hypertrophy in patients with
      essential hypertension].
AB  - One hundred nine patients with essential hypertension were studied (50 male and
      59 female, mean age - 62,6-/+1,08 years). Seventy six patients had left
      ventricular hypertrophy measured by echocardiography. NOS3 polymorphisms
      (Glu298Asp and ecNOS4a/4b) were studied by PCR. In patients without left
      ventricular hypertrophy (LVH) genotypes frequencies of NOS3 (Glu298Asp) were:
      Glu/Glu - 34.4%; Glu/Asp - 62,5%; Asp/Asp - 3,1%. In patients with LVH - Glu/Glu 
      55.3%; Glu/Asp - 40.8%; Asp/Asp - 3.9%; p=0,117. Percent of Glu/Glu genotype was
      significantly higher in LVH group (p=0,047). Genotypes frequencies of ecNOS4a/4b
      were: in patients without LVH - 4b/4b - 37,5%; 4a/4b - 62,5%; 4a/4a - 0; in
      patients with LVH - 4b/4b - 21.1%; 4a/4b - 76.3%; 4a/4a - 2,6%;. p=0,151.
      Patients with 4a allele had higher Amax than 4b/4b patients (76,3+2,11 m/s and
      67,9+4,72 m/s; p=0,040). Therefore, we show associations between Glu allele of
      NOS3 (Glu298Asp) and left ventricular hypertrophy and between 4a allele
      (ecNOS4a/4b) and diastolic dysfunction in patients with essential hypertension.

PMID- 12494184
TI  - [Metabolic effects of angiotensin-II receptor blockers].

PMID- 12494185
TI  - [Correction of elevated blood pressure in morning hours by angiotensin converting
      enzyme inhibitors].

PMID- 12494186
TI  - [Effect of therapy with clopidogrel on walking tolerance and parameters of
      hemostasis in patients with atherosclerosis of lower extremities and intermittent
      claudication].

PMID- 12494187
TI  - [Endogenous opioid system and resistance of the heart against arrhythmogenic
      influences].

PMID- 12494188
TI  - [Efficacy of orlistat in the treatment of constitutional-alimentary obesity in
      patients with high risk of cardiovascular complications].

PMID- 12494189
TI  - [Effect of calcium antagonists on long-term prognosis of patients with myocardial
      infarction].

PMID- 12494190
TI  - [Efficacy of trimetazidine in stable angina pectoris refractory to traditional
      treatment].

PMID- 12494191
TI  - [Electrophysiological effects of prostaglandin E2 in dysfunction of sinus node].

PMID- 12494192
TI  - [Use of myocardial tissue Doppler imaging in cardiology].
AB  - Tissue Doppler imaging is a new promising method of non-invasive assessment of
      cardiac function. This method has heralded a renaissance of interest in
      longitudinal ventricular function. There is evidence that long-axis function is a
      more sensitive index of myocardial contractility than conventional
      echocardiographic parameters, and that therefore, this technique could contribute
      to early diagnosis of systolic dysfunction. Tissue Doppler imaging can be
      successfully applied in the assessment of regional myocardial function. It has
      been proven that myocardial velocities truly reflect structural myocardial
      changes (the degree of myocardial fibrosis) and beta-adrenoreceptor density. The
      use of tissue Doppler imaging in concert with stress echocardiography is also
      extremely encouraging and is considered as the most likely solution to the
      problem of quantitative analysis of stress echocardiography. The method
      additionally opens new horizons in non-invasive assessment of diastolic function
      of the heart. Myocardial velocities have been shown to have important advantages
      over conventional Doppler indices of left ventricular diastolic filling.
      Frustration among cardiologists caused by unreliability of the traditional
      approach in the assessment of diastolic properties of the heart seems to have
      been overcome. Tissue Doppler imaging allows the examination of right ventricular
      systolic and diastolic function, the differentiation between constrictive
      pericarditis and restrictive cardiomyopathy and the estimation of pressures in
      cardiac chambers and in the pulmonary artery. It can also establish the presence
      of accessory conduction pathways, the diagnosis of rejection of transplanted
      hearts and can be used for identification of indications for biventricular
      pacing. Although many clinicians believe that tissue Doppler imaging is still an
      experimental technique, it can now be introduced into the routine practice of
      echocardiographic laboratories. The wider use of the method will help to develop
      its benefits and better understand and overcome limitations.

PMID- 12494193
TI  - [Osteoporosis and cardiovascular diseases].

PMID- 12494194
TI  - [Vascular remodeling and apoptosis in health and disease].

PMID- 12494195
TI  - [Adverse effects of angiotensin II type 1 receptor blockers ].
AB  - Angiotensin II type 1 receptor blockers belong to a novel class of cardiovascular
      agents that is characterized by excellent tolerance. The overall rate of their
      side effects is similar to that of placebo. Specific nonproductive cough is much
      less common during treatment with angiotensin II blockers compared with
      angiotensin converting enzyme inhibitors. Nevertheless serious side effects very
      rarely occur with angiotensin II blockers and include cough, angioneurotic edema,
      anemia, liver damage, renal failure, aggravation of angina and migraine. The data
      of current literature concerning adverse effects of angiotensin II in different
      clinical situations are extensively reviewed. Angiotensin II type 1 receptor
      blockers are not considered to be safe in pregnancy, bilateral renal artery
      stenosis and severe renal or hepatic impairment.

PMID- 12494196
TI  - [Reflected wave and isolated systolic hypertension: problems of pathogenesis and
      therapy].
AB  - The value of reflected (tidal) wave amplitude in the pathogenesis of isolated
      systolic hypertension (ISH) is discussed and main characteristics of elastic
      properties of arteries (compliance, distensibility, rigidity, pulse wave
      velocity, and amplitude of reflected wave) are considered. In ISH systolic and
      pulse blood pressures are associated with augmentation of the reflected wave
      amplitude. Increased pulse wave velocity characteristic of ISH leads to
      displacement of reflected wave from diastole to systole. Summation of two waves
      (primary and reflected) causes elevation of systolic blood pressure. Choice of
      antihypertensive drugs for the treatment of ISH is determined by their action on
      pulse wave velocity, delay of reflected wave and arterial compliance. Preferable
      agents are angiotensin converting enzyme inhibitors, calcium antagonists,
      diuretics and beta-blockers with vasodilating properties. In bradycardia with
      high stroke volume normalization of heart rate can be achieved by M
      anticholinergic drugs and theophylline.

PMID- 12494197
TI  - [Some new data concerning effectiveness of amlodipine, atorvastatine and
      quinaprile for heart diseases].

PMID- 12494199
TI  - [Immediate results of direct coronary artery stenting].
AB  - Stent implantation is as a rule preceded by balloon angioplasty (predilation).
      This increases duration and cost of the procedure. Low profile stents with
      improved design allow to perform direct (i.e. without predilation) stenting.
      Immediate results of our series of direct coronary artery stenting procedures
      evidence for high efficacy and safety of the technique.

PMID- 12494198
TI  - [Clinical and angiographical results of the use of the EPHESOS stent in patients
      with coronary artery atherosclerosis].
AB  - The Ephesos is a new balloon-expandable, stainless steel, tubular stent with
      multicellular design. This open nonrandomized study assesses the immediate and
      long-term clinical and angiographic outcomes after Ephesos implantation in
      patients with native coronary artery disease. The Ephesos was implanted in 168
      patients with 198 de novo lesions. Most patients (56%) had unstable angina, and
      38% of lesions were type B2-C. The mean lesion length was 12.5-/+7.2 mm, and 29%
      of lesions were >15 mm in length. No stent deployment failure occurred, as well
      as acute or subacute stent thrombosis. In-hospital non-Q-wave myocardial
      infarction occurred in 2 patients. The 6-month event-free survival was 83.9%. Two
      patients with no restenosis in the target vessel died of fatal infarction due to
      abrupt closure of a nontarget vessel. The 6-month angiographic follow-up was
      obtained in 164 patients (98%) (192 lesions). The loss index was 0.27-/+0.25.
      Angiographic restenosis rate was 12%. Twenty patients with restenosis had repeat
      target lesion revascularization. The results of this study indicate a potential
      benefit of EPHESOS for the prevention of stent thrombosis and restenosis in these
      relatively high-risk patients.

PMID- 12494200
TI  - [C-reactive protein as possible early prognostic marker of restenosis development
      in coronary artery stents].
AB  - AIM: To study possible link between inflammatory response of the body to stent
      implantation and development of instent restenosis. METHODS: C-reactive protein
      (CRP) was determined in 24 patients subjected to coronary stenting. Coronary
      angiography was repeated in 7.1-/+0.68 months after initial procedure. RESULTS:
      At repeat angiography positive results of stenting persisted in 18 while
      restenosis developed in 6 patients. All patients had increased CRP levels on days
      2-3 after stenting. Day 2 CRP levels were higher in patients with than without
      restenosis (28-/+4.22 mg/l and 14.17-/+2.14 mg/l, respectively, p<0.05). CRP
      levels tended to normalize by day 5. CONCLUSION: Coronary artery stenting in
      patients with angina pectoris is associated with transitory elevation of CRP
      level. Day 2 CRP >or=24 mg/l with high degree of probability predicts restenosis
      in remote period.

PMID- 12494201
TI  - [Changes of parameters of the functional state of the organism and oxidative
      stress in patients after surgical revascularization at early stage of restorative
      treatment].
AB  - Early complex restorative treatment with individualized aerobic physical exercise
      in 2-4 weeks after surgical myocardial revascularization significantly increased
      physical working capacity and cardiorespiratory reserve of the body. Pronounced
      oxidative stress which had been present after myocardial revascularization
      decreased under the action of restorative therapy. Most pronounced increases of
      total physical capacity and cardiorespiratory reserve and lowering of oxidative
      stress occurred in patients with lowest initial parameters of the functional
      state of the organism.

PMID- 12494202
TI  - [Comparative analysis of parameters of corrected and uncorrected QT-interval
      dispersion of magneto-, electrocardiography and isomagnetic maps in patients with
      ischemic heart disease].
AB  - AIM: To compare possibilities of magnetocardiography (MCG) and
      electrocardiography for assessment of regional dispersion of ventricular recovery
      time using parameters of corrected and uncorrected QT-interval dispersion (DQTs
      and DQT). MATERIAL: Twenty three patients with class II angina pectoris including
      11 patients with history of myocardial infarction (MI) and 13 practically healthy
      subjects. RESULTS: Mean DQT and DQTc were significantly higher (p<0.005) in
      patients than in healthy subjects according to both techniques. Values of DQT and
      DQTc obtained by MCG were higher in patients with history of MI compared with
      those without MI (p=0.006 and 0.02, respectively). There was a significant
      positive correlation between age and DQT and DQTc determined by
      electrocardiography. Mean number of T-wave dipoles was significantly higher in
      patients than in healthy subjects. Substantial positive correlation was found
      between number of T-wave dipoles on isomagnetic maps and age in both patients and
      healthy people. CONCLUSION: The method of MCG gave supplementary information on
      the state of ventricular depolarization in patients with ischemic heart disease.

PMID- 12494203
TI  - [Assessment of efficacy and safety of nebivolol in patients with stable effort
      angina].
AB  - AIM: To study efficacy and safety of nebivolol in patients with stable angina
      pectoris. MATERIAL: Twenty patients with stable effort angina pectoris and
      positive exercise test without contraindications to beta-blockers, signs of NYHA
      class III-IV heart failure, and obstructive lung disease. After 5-7 days of
      control period all patients were given nebivolol (starting dose 5 mg/day) for 8
      weeks. Graded exercise tests on treadmill and patient's diaries were used for
      assessment of treatment efficacy. RESULTS: Treatment with nebivolol (5-10 mg o.d.
      ) was associated with significant slowing of heart rate, lowering of blood
      pressure, and increase of exercise duration until appearance of angina or 1 mm ST
      segment depression. Nebivolol did not affect left ventricular ejection fraction,
      bronchial conductance, or results of biochemical tests (including lipid profile).
      Adverse reaction (dizziness which disappeared after lowering of a dose) was
      registered in 1 patient. CONCLUSION: Nebivolol is an effective drug for the
      treatment of patients with stable angina.

PMID- 12494204
TI  - [Antiischemic efficacy of trimetazidine in patients with ischemic heart disease,
      stable angina pectoris and disturbances of carbohydrate metabolism].
AB  - AIM: To compare antiischemic effects of trimetazidine in patients with stable
      angina pectoris with and without disturbances of carbohydrate metabolism.
      MATERIAL: Patients with ischemic heart disease, stable class II-III angina
      pectoris and reproducible positive results of on-treatment exercise tests (n=40,
      mean age 56.7-/+1.95 years, 37 men) with normal carbohydrate metabolism (group 1,
      n=20) and with disturbances of carbohydrate metabolism (group 2, n=20). METHODS:
      All patients in addition to individually selected antianginal therapy were given
      trimetazidine (60 mg/day) for 2 months. Bicycle exercise tests were repeated
      after 1 and 2 months. Patient's diaries were used for registration of anginal
      attacks and nitroglycerine consumption. RESULTS: Addition of trimetazidine was
      associated with significant (p<0.005) prolongation of exercise duration until 1
      mm-ST depression in both groups. Exercise duration was 553-/+10.5 and 555-/+10.2
      s (p>0.05) at baseline, 657-/+15.3 and 695-/+10.1 s (p<0.05) after 2 months in
      groups 1 and 2, respectively. Other effects of trimetazidine in groups 1 and 2
      included increases of total work performed during exercise test (by 14 and 22%,
      respectively), decreases in numbers of patients with ST depression (by 40,
      p<0.05, and 50%, p<0.05, respectively), numbers of anginal attacks (by 30,
      p<0.001, and 43%, p<0.001, respectively) and nitroglycerine pills (by 13%,
      p<0.001 and 51%, p<0.001, respectively). The decrease in supplemental
      nitroglycerine consumption was significantly more pronounced in group 2
      (p<0.0001). There was no significant increment in double product in both groups.
      CONCLUSION: Antiischemic effect of trimetazidine was greater in patients with
      angina pectoris and disturbances of carbohydrate metabolism than in similar
      patients without such disturbances. KEY WORDS. trimetazidine; diabetes, type II,
      ischemic heart disease; angina pectoris.

PMID- 12494205
TI  - [The role of heredity and environment in formation of 24-hour blood pressure
      profile in patients with hypertension (a study of twins)].
AB  - Twenty four hour blood pressure monitoring was carried out in 64 sex concordant
      pairs of monozygotic and dizygotic hypertensive twins (mean age 52.7-/+3.2
      years). Clinico-genetic analysis of quantitative parameters showed that during
      day awake time systolic, diastolic, and mean blood pressures were mainly
      determined by environmental factors while pulse pressure and heart rate were
      predominantly affected by genetic factors. Formation of parameters of variability
      of blood pressure and its biphasic rhythm were under the influence of random
      (intrafamily) environmental factors.

PMID- 12494206
TI  - [Effect of long term therapy with captopril on dopplerographic parameters of
      intrarenal blood flow and renal function in patients with hypertension and
      diabetes].
AB  - Effect of 9-12 month treatment with captopril on dopplerographic parameters of
      intrarenal blood flow and renal function was studied in 30 hypertensive diabetics
      without clinical signs of nephroangiopathy. There was an interrelationship
      between strict blood pressure (BP) control (average 24-hour BP below 135/83) and
      improvement of parameters of intrarenal hemodynamics. BP normalization and most
      pronounced positive changes of renal perfusion during therapy with captopril were
      achieved in patients with mild hypertension and initially high intrarenal
      resistance yet at the stage of normo- or microalbuminuria. In moderate
      hypertension with microalbuminuria treatment with captopril was associated with
      stabilization of parameters of renal blood flow and rate of 24-hour albumin
      excretion at their initial level despite less strict control of BP and
      unsatisfactory compensation of diabetes. BP response to captopril in patients
      with hypertension and diabetes was related to initial state of intrarenal
      hemodynamics. In patients with mild hypertension indexes of resistance of renal
      and intrarenal arteries could be used for prediction of sensitivity to
      antihypertensive action of captopril.

PMID- 12494207
TI  - [Angiotensin II receptor blocker telmisartan: effect on 24-hour blood pressure
      profile and left ventricular hypertrophy in patients with hypertension].
AB  - AIM: To study antihypertensive efficacy of monotherapy with telmisartan and its
      action on left ventricular myocardium remodeling in patients with hypertension.
      MATERIAL AND METHODS: Telmisartan (40-80 mg/day) was given for 24 weeks to 24
      patients aged 37-69 years with I-II degree of blood pressure (BP) elevation and
      hypertrophy of left ventricular myocardium. Antihypertensive action of
      telmisartan was assessed by 24-hour BP monitoring. Left ventricular myocardial
      mass was estimated by echocardiography before and after 24 weeks of therapy.
      RESULTS: Telmisartan equally decreased both diurnal and nocturnal systolic and
      diastolic BP (by10.4-11.7%), lowered maximal BP during morning hours, and
      restored initially disturbed 24-hour BP rhythm. Target BP levels were achieved in
      16 patients (70%). Therapy with telmisartan was associated with significant 10.9%
      reduction of left ventricular myocardial mass index (from 151.6-/+5.4 to 135.1
      /+5.9 g/m2, p=0,02) at the account of decreased thickness of left ventricular
      wall. CONCLUSION: These results give reason for the use of telmisartan for the
      treatment of patients with hypertensive disease and left ventricular hypertrophy.

PMID- 12494208
TI  - [Clinical assessment of prolonged therapy of patients with hypertension and
      diabetes with imidazoline receptor agonist moxonidine].

PMID- 12494209
TI  - [Recovery of left atrial function after cardioversion of atrial fibrillation: the
      role of some clinical and echocardiographical factors].
AB  - Sinus rhythm was restored in 102 patients with atrial fibrillation. Cardioversion
      was spontaneous (n=6), pharmacological (n=35), and electrical - early (n=46) or
      postponed because of necessity of full anticoagulation (n=15). Irrespective of
      method of cardioversion all patients had signs of atrial stunning. Doppler
      echocardiography performed within 24 hours and in 3, 7 and 14 days after
      cardioversion showed that rate of recovery of mechanical left atrial function had
      pronounced individual variations. In patients with spontaneous termination of
      atrial fibrillation normalization of left atrial contractile activity occurred in
      about 3 days, after pharmacological cardioversion - in 1 week (in 91.4% of
      cases). After early and postponed electrical cardioversion mechanical left atrial
      function recovered in 2 weeks in 97.8 and 73.3% of patients, respectively. Most
      important impact on this process produced duration of the last attack of atrial
      fibrillation and left atrial dimensions.

PMID- 12494210
TI  - [Effects of ryanodine receptors block on spontaneous initiation of atrial
      fibrillation in the intact canine heart].
AB  - To study the possible role of intracellular Ca2+ overload in initiation of
      cholinergic-dependent atrial fibrillation (AF), we tested the effects of
      ryanodine in canine models of AF. In anesthetized open-chest dogs (n=10) AF was
      induced by two methods: (I) perfusion (9 ml/min) with normal Tyrode solution
      containing acetylcholine (ACh) into the sinus node artery (SNA) and (II)
      stimulation of the right vagal nerve (VS, 5 sec train). AF was induced in all
      dogs: by perfusion with ACh (3.7-/+1.5 mcM) into the SNA in 97-/+3% of attempts
      and by VS in 78-/+6% of attempts. Intravenous infusion of ryanodine (5 mg/kg) did
      not prevent induction of AF during ACh perfusion (84-/+5%, NS) but completely
      prevented the induction of AF by VS (4-/+3%, p<0.001). Atrial activation mapping
      (112 unipolar electrodes) did not show any significant differences between the
      beginning of ACh-dependent AF in control and after ryanodine treatment. Ryanodine
      significantly reduced both systolic and diastolic arterial pressures but had no
      effect on heart rate, atrial effective refractory period (AERP) and conduction
      velocity for one hour after infusion. Ryanodine, itself, did not exert antivagal
      activity, so after ryanodine treatment in the presence of VS (8 Hz) the reduction
      of AERP and the deceleration of heart rate were similar to that in control. These
      data suggest that ryanodine can suppress the initiation of AF induced by VS but
      not AF induced by ACh perfusion. We can conclude that the initiation of AF during
      ACh perfusion unlikely relates to triggering activity induced by intracellular
      Ca2+ overload. In addition, we suggest that besides ACh some 'unclear' ryanodine
      sensitive factor(s) contribute to the initiation of AF induced by VS.

PMID- 12494211
TI  - [Prevalence of ischemic heart disease and mortality among kaunas population aged
      35-64 years in the prospective study].
AB  - MONICA (MONItoring trends and determinants of CArdiovascular diseases) study was
      carried out in Kaunas in 1983-1993 in three random samples of population aged 35
      64 (overall 2694 men and 2801 women). The prevalence of previous MI among men was
      higher than among women in the first and in the third surveys (2,2 and 1,1%, p
      <0,05 and 4,4 and 1,2%, p <0,001, respectively). The prevalence of angina
      pectoris among men and among women did not reveal statistically significant
      difference in all three surveys. The prevalence of silent myocardial ischemia was
      higher among women than among men in the two surveys. The prevalence of all forms
      of IHD was higher among women than among men in the first and in the second
      surveys (16,2 and 10,2%, p <0,001 and 16,4 and 10,9%, p <0,001, respectively).
      Total mortality, mortality from CVD and from IHD among men with IHD was higher
      than among men without IHD. Total mortality and mortality from CVD among women
      with silent myocardial ischemia and IHD was higher than in control group. The
      differences in mortality among women with different forms of IHD were not
      significant from those without IHD.

PMID- 12494212
TI  - [Prognostic value of duration and variability of QT and RR intervals in general
      population of Novosibirsk].
AB  - Increased duration and dispersion of QT interval and lowered variability of RR
      interval are considered to be probable precursors of dangerous ventricular
      arrhythmias and sudden death. Standard epidemiological methods were used for the
      study of a representative sample of nonorganized male population (age 25-64
      years) in Novosibirsk in a framework of the MONICA project. Database of the total
      mortality register was used for verification of deaths. Resting ECGs were
      analyzed using the Minnesota code criteria blindly relative to other data of the
      study. Duration and dispersion of QT and QTc intervals as well as temporal
      parameters of RR variability were determined manually. Assessment of significance
      of these factors for prognosis was made with the use of methods of survival
      analysis. Among all characteristics of QTc interval maximal duration and
      dispersion of QTc were the strongest predictors of death from any cause and
      cardiovascular death being independent of age, mean blood pressure, ischemic
      heart disease, body mass index and smoking. Predictive power of these QTc
      interval parameters was similar in total male population and in subpopulation of
      patients with cardiovascular diseases. In men without cardiovascular diseases
      parameters of RR variability on ECG at rest were predictors of cardiovascular
      death independent of age, mean blood pressure, body mass index, total cholesterol
      and smoking.

PMID- 12494213
TI  - [Statin is indicated to all patients with high risk of complications of coronary
      heart disease irrespective of the level of low density lipoprotein cholesterol.
      Results of HPS].

PMID- 12494214
TI  - [One more (conclusive?) confirmation of ineffectiveness of antioxidant vitamins
      for prevention of coronary heart disease].

PMID- 12494215
TI  - [Hypertensive crises: classification and current management].
AB  - Data of current literature concerning with hypertensive emergencys and urgencies
      is presented. Hypertensive emergencys is a heterogeneous group of clinical
      states, caused or complicated by arterial hypertension, that require prompt blood
      pressure lowering to reduce morbidity and preserve life. The currently available
      choices for parenteral therapy of hypertensive emergencies and for oral therapy
      of hypertensive urgencies in selected groups of patients are extensively
      reviewed.

PMID- 12494216
TI  - [Hypertension and anxiety states].

PMID- 12494218
TI  - [Effect of atorvastatin on endothelial function in patients with familial
      hypercholesterolemia].
AB  - AIM: To study the influence of treatment with HMG-CoA reductase inhibitor
      atorvastatin on endothelial function in patients with familial
      hypercholesterolemia type IIa. MATERIALS AND METHODS: Sixteen patients (5m/11w,
      51-/+3 years) with familial hypercholesterolemia were studied before and after 3
      months of therapy with atorvastatin 20 mg/day. EDRF release test (D.Celermajer,
      1992) was used to assess flow-mediated endothelium-dependent vasodilatation (FMD)
      of the brachial artery in response to reactive hyperemia. Plasma nitrite/nitrate
      (NOx) levels were measured as an indirect index of nitric oxide (NO) production
      in vivo using HPLC. RESULTS: Atorvastatin treatment resulted in a 32% reduction
      in total serum cholesterol (CH), 41% reduction in low density lipoprotein (LDL)
      CH, 16% reduction in triglycerides and a 21% increase in high density lipoprotein
      CH. Flow mediated dilatation (FMD) was impaired at baseline (5.8-/+0.9%) and
      significantly improved up to 9.5-/+0.9% after 3 month atorvastatin therapy
      (p<0.002). Change in FMD inversely correlated with baseline FMD (r = -0.58,
      p<0.05). There was no significant correlation between FMD and neither total serum
      CH nor LDL CH levels at baseline. During atorvastatin therapy significant
      reduction of plasma NOx levels occurred from 53.4-/+5.1 mcmol/l at baseline
      (range 42.6-86.2 mcmol/l) to 35.5-/+5.1 mcmol/l (18.4-46.0 mcmol/l) after
      treatment (p<0.02, n=7). CONCLUSION: In patients with familial
      hypercholesterolemia atorvastatin produced beneficial effect on endothelial
      function (increase in flow-mediated dilatation, decrease in NOx).

PMID- 12494219
TI  - [Atherosclerosis in victims of cancer].
AB  - Atherosclerotic changes in aortas and coronary arteries of victims of cancer were
      investigated within framework of 2 epidemiological studies of men aged 20-59
      years in Malmo, Prague, Riga, Tallin, Yalta and of women aged 40-59 years in
      Malmo, Riga and Yalta conducted in 1963-1966 (first study) and 1985-1989 (second
      study) years. The first study included 763 men and 419 women and the second - 744
      men and 293 women with malignancies. Control group comprised practically healthy
      victims of accidents. Extent of atherosclerosis depended on localization of
      cancer. Compared with controls men with lung and stomach cancer had greater area
      of raised lesions in aorta and coronary arteries, those with bowel cancer - in
      coronary arteries. In women with lung cancer area of raised lesions exceeded that
      of controls only in aorta. Proportion of lung cancer among all tumors was higher
      in the second compared with the first study (in men 32.7 and 23.2%, in women 10.6
      and 4.8%, respectively). Among victims of lung cancer extent of atherosclerosis
      was greater in smokers compared with nonsmokers.

PMID- 12494220
TI  - [Correction of atherogenic exogenously-induced postprandial hyperlipidemia with
      pravastatin].
AB  - Effect of an HMG-CoA reductase inhibitor pravastatin on atherogenic changes in
      the lipid transport system during postprandial hyperlipidemia immediately after
      ingestion of fatty meal was studied in patients with coronary heart disease and
      fasting hyperlipidemia. Treatment with pravastatin (20-40 mg/day for 3 months)
      resulted in normalization of fasting levels of blood lipids and decreased
      postprandial hyperlipidemia due to of enhanced removal of triglyceride-rich
      atherogenic lipoproteins from blood and their diminished secretion in response to
      fat load. Moreover pravastatin increased tolerance of the lipid-transport system
      to exogenous saturated fats. KEY WORDS. coronary heart disease; postprandial
      hyperlipidemia; pravastatin; lipoproteins, metabolism.

PMID- 12494221
TI  - [Simvastatin in management of patients with primary hypercholesterolemia:
      tolerability and efficacy of daily doses 10-80 mg].
AB  - AIM: To analyze retrospectively data on lipid lowering efficacy, tolerability and
      safety of different doses of simvastatin in patients with primary hyperlipidemia.
      MATERIAL AND METHODS: Thirty five patients (mean age 54.9-/+8.5 years, 15 men, 20
      women) received simvastatin for 3-6 months in doses 10 (n=12), 20 (n=8), 40
      (n=10) and 80 (n=5) mg/day. Average lowering of low density lipoprotein
      cholesterol was 28.9, 37.6, 39.7, and 46.2% on doses 10, 20, 40 and 80 mg/day,
      respectively. Elevation of activity of transaminases (AST and ALT) above 3 upper
      limits of normal (ULN) accompanied by right upper quadrant pain occurred in 1
      patient and the drug (10 mg/day) was stopped. Symptomless elevation of AST and
      ALT activities above 2 ULN was registered in 2 other patients receiving 10 and 20
      mg/day. The dose of 80 mg/day was well tolerated - none of 5 patients had
      symptoms of myopathy or elevated creatinekinase activity.

PMID- 12494222
TI  - [Biochemical and morphological characteristics of atherosclerosis of major
      arteries in Tashkent male population].

PMID- 12494223
TI  - [Stress-ultrasound study of hemodynamic reserve of aortic compression chamber in
      atherosclerosis: effect on coronary blood flow].
AB  - AIM: To study the role of hemodynamic reserve of aortic compression chamber (ACC)
      in compensation of coronary blood flow during stress. MATERIAL: Ninety three
      subjects (78 men and 15 women) including 74 patients with chronic ischemic heart
      disease (mean age 50-/+7 years) and 19 healthy volunteers (mean age 45-/+5
      years). METHODS: Hemodynamic reserve of ACC was defined as volume of blood
      deposited in walls of ascending aorta at the end of systole. M-mode cross-section
      of ascending aorta was obtained during transesophageal pacing with long-axis view
      from parasternal approach. Antegrade and retrograde blood flow in the ascending
      aorta was registered through suprasternal approach with wave-impulse doppler.
      Movements of left ventricular walls were assessed via apical approach with the
      use of 12-segment model. The following factors were directly determined or
      calculated: morphometrical parameters, elasticity and rigidity of aorta, temporal
      and amplitudal characteristics of antegrade and retrograde flow in ascending
      aorta, stroke volume, cardiac output, coronary fraction of stroke volume,
      coronary blood flow. Results. During transesophageal pacing in healthy subjects
      elastic ACC despite increasing limit of diastole duration accumulated energy,
      pressure and part of volume of moving blood, providing sufficient flow in the
      coronary circulation. In patients with ischemic heart disease rigid ACC
      functioned as hydrodynamically inert tube being the cause of progressive
      diminishment of coronary flow. CONCLUSION: Decreased capacitance and functional
      reserves of ACC in atherosclerosis constituted the first hemodynamic barrier
      determining deficit of coronary blood flow during stress.

PMID- 12494224
TI  - [Heart rate variability in unstable angina during 'day-to-day' monitoring].
AB  - Spectral analysis of heart rate variability was used for assessment of background
      autonomic activity in patients with unstable angina pectoris. There were weak
      linear and strong nonlinear links between autonomic activity and frequency of
      angina pectoris during 'day-to-day' monitoring.

PMID- 12494225
TI  - [FLAG--a program of achievability of target blood pressure levels during
      treatment of patients with hypertension with fosinopril].
AB  - The Program FLAG was initiated by the Scientific Society of Arterial Hypertension
      in order to assess achievability of WHO/ISH target blood pressure (BP) levels in
      conventional ambulatory practice. Overall 2829 patients (mean age 53.1 years, 65%
      women) were enrolled in 17 cities of 5 regions in Russia. Nineteen, 68, 10 and 3%
      of patients had 1-st, 2-nd, 3-rd degree of blood pressure elevation and isolated
      systolic hypertension, respectively. During treatment with angiotensin converting
      enzyme inhibitor fosinopril (10-20 mg/day) -/+ hydrochlorothiazide BP level
      140/90 mm Hg or 'positive effect' (BP lowering et least by 10%) were achieved in
      62.1 and 88.8% of cases, respectively. Average BP level decreased from 162.8/98.7
      to 134.2/82.5 mm Hg and lowering of systolic and diastolic BP was 17 and 16%,
      respectively. The regimen of antihypertensive therapy used in the program was
      well tolerated and safe (adverse effects were registered in 8.3% of patients, in
      5.2% of patients these effects lead to withdrawal of fosinopril). The therapy was
      equally effective in men and women irrespective of age. The results allow to
      recommend the treatment scheme tested in the FLAG program for use in multiple
      patients with hypertension.

PMID- 12494226
TI  - [The value of blood pressure self-measurement by patients with hypertension].
AB  - Blood pressure (BP) self-measurement (SM) is a promising method of investigation
      of patients with hypertension capable to provide information unobtainable neither
      with traditional office measurements nor with 24-hour BP monitoring. Advantages
      of BPSM are as follows: accessibility, low effect of anxiety on results of BP
      measurement; possibility of long-term monitoring of BP. Conditions which should
      be satisfied in order to realize these advantages include availability of
      individually selected measurement device, correct fulfillment of measurements,
      sufficient frequency of measurements, exact reporting of results to a physician.
      Besides inherent possibility of incorrect measurements BPSM has some other
      limitations - tendency to underestimation of real BP level and relatively low
      sensitivity in diagnosis of hypertension. At present BPSM can be used both for
      diagnosis of hypertension and for assessment of efficacy of antihypertensive
      therapy. Comparative value of BPSM and 24-hour blood pressure monitoring for
      clinical pharmacology deserves special investigation. In some difficult cases
      ('white coat hypertension', 'pseudoresistance to therapy') BPSM should apparently
      precede 24-hour BP monitoring.

PMID- 12494227
TI  - [Possibility of the outpatient use of lacidipine in elderly patients with
      hypertension].

PMID- 12494228
TI  - [Diagnostic value of ventricular late potentials, heart rate variability and QT
      dispersion in patients with acute myocardial infarction].
AB  - Late ventricular potentials (LVP), heart rate variability (HRV) and dispersion of
      QT interval (QTd) were studied in 91 patients with myocardial infarction with
      various ventricular arrhythmias. Patients with episodes of sustained ventricular
      tachycardia (group 4) had the following characteristics: prevalence of LVP 73.7%,
      QTd 82.5 ms, standard deviation of RR intervals (SD) 26.5 ms; spectral analysis
      of HRV revealed preponderance of sympathetic influences and lowered vagal
      activity. Frequency of LVP detection, QTd and SD in patients with ventricular
      extrasystoles (Lown classes 3-5) (group 3) were 33.3%, 72.8 ms, and 42.8 ms,
      respectively. Patients of group 3 also had augmented sympathetic and lowered
      parasympathetic influences. These data significantly differed from those obtained
      in patients with Lown class 1-2 ventricular extrasystoles (group 2) and patients
      without extrasystoles (group 1). Groups 3 and 4 had significantly different
      prevalences of LVP and values of some HRV parameters but similar QTd. There was
      close correlation between presence of severe ventricular arrhythmias and some
      parameters of HRV and signal averaged ECG. Stepwise regression analysis showed
      that the following group of parameters was related to the presence of malignant
      ventricular rhythm disturbances: heart rate, SD and total QRS duration (p<0.05).
      Thus patients with life threatening ventricular arrhythmias were characterized by
      the presence of LVP and changes of some parameters of HRV and QTd. Registration
      of these parameters can apparently be used for prediction of potentially fatal
      ventricular arrhythmias in patients with myocardial infarction.

PMID- 12494229
TI  - [The use of a program of medical and psychological support after coronary artery
      bypass surgery in patients with ischemic heart disease].
AB  - The paper contains analysis of results of restorative treatment in a sanatorium
      and subsequent ambulatory care for 1 year of 167 patients after coronary artery
      bypass surgery. All patients received similar curative and preventive aid, 127
      patients in addition participated in a special program of medical and
      psychological support while 40 patients comprised control group. The program was
      carried out in a sanatorium and consisted of several sessions of various types of
      group psychotherapy. Participation in this program allowed to achieve
      sufficiently high level of motivation to comply with recommendations of a
      physician and to implement self-psychoregulation and self-control of the
      functions of own body. Program participants had better quality of life and more
      frequently returned to work.

PMID- 12494230
TI  - [The use of positron emission tomography for noninvasive diagnosis of
      mitochondrial dysfunction and assessment of myocardial compensatory reserve in
      children with cardiomyopathies].
AB  - BACKGROUND: Recent experimental and clinical studies have shown that
      cardiomyopathy (CMP) can be associated with disorders of oxidative metabolism in
      cardiomyocyte mitochondria. These disorders are connected with deficit of enzymes
      and complexes of electron transfer chain, and can constitute pathogenetic base of
      the disease. AIM. To study myocardial metabolism in children with
      cardiomyopathies using positron emission tomography (PET). METHODS: PET studies
      were carried out in 17 patients (pts.) aged 3-13 years (mean age 7,5-/+3,1) with
      CMP: hypertrophic (HCMP, n=4), dilated (DCMP, n=9), after radical correction of
      tetralogy of Fallot (TF, n=4). The dynamic study with [1-11C]-acetate was
      performed for evaluation of Krebs cycle activity. Rate constant (kmono) and [11C]
      activity elimination half-time (T1/2) were calculated using myocardial time
      activity curve. Myocardial perfusion was assessed with [13N]-ammonia, glucose
      metabolism - with [18F]-fluorodeoxyglucose. RESULTS: Patients with HCMP: left
      ventricular (LV) perfusion was normal, Krebs cycle activity - decreased; glucose
      utilization was increased in comparison with normal level in 2, and was normal in
      2 other children. Patients with DCMP: LV perfusion was normal; Krebs cycle
      activity in LV was decreased in 6 and normal - in 3 pts. Overall 2 pts. with CMP
      had focal perfusion defects. More pronounced decrease of Krebs cycle activity in
      these regions compared with other LV parts implied development of ischemic
      injuries. Decrease of glucose utilization in these fields indicated that the
      injuries were irreversible. Patients with TF: 3 pts. had normal perfusion and
      Krebs cycle activity; 1 patient with severe hemodynamic disorders had decreased
      perfusion, glycolysis and Krebs cycle activity in both ventricles indicative of
      the presence of myocardial dystrophic changes. CONCLUSION: Despite normal
      perfusion children with cardiomyopathy had decreased Krebs cycle activity
      (mitochondrial dysfunction). Decrease in oxidative metabolism could be
      compensated by increased glycolysis.

PMID- 12494231
TI  - [The value of transesophageal echocardiography for determination of tactics of
      cardioversion of atrial fibrillation].
AB  - Transesophageal echocardiography was carried out in 110 patients before
      cardioversion of nonvalvular atrial fibrillation which duration exceeded 2 days.
      Twenty thrombi were found in 18 patients (16.4%). Anticoagulant phenindione was
      given to these patients for 3 weeks. Patients without thrombus received
      intravenously amiodarone followed with procainamide. Sinus rhythm was restored in
      39.3% of these cases. In 5.5% of patients atrial fibrillation terminated
      spontaneously. Control transesophageal echocardiography showed that after 3 weeks
      there remained 11 atrial thrombi but all of them lost motility. Electrical
      cardioversion was successful in 90.7% of patients receiving short term and in 80%
      of patients receiving 3-week anticoagulant therapy (p>0.05). All patients
      received phenindione for 4 weeks after cardioversion. There were no
      thromboembolic or hemorrhagic complications. Ability of transesophageal
      echocardiography to detect atrial thrombi allows to carry out early cardioversion
      and to identify patients with high risk of embolism.

PMID- 12494232
TI  - [Effect of angiotensin converting enzyme inhibitor spirapril on dimensions of
      experimental myocardial infarction, development of ischemic tachyarrhythmias, and
      ischemic adaptation of the heart].

PMID- 12494233
TI  - [Effect of bicycle training with free choice of physical load on sexual disorders
      in patients with myocardial infarction].

PMID- 12494234
TI  - [Special features of dynamics and measurement of QT-interval on holter ECG
      recordings].

PMID- 12494235
TI  - [Transmyocardial laser myocardial revascularization as a method of surgical
      treatment of patients with ischemic heart disease].

PMID- 12494237
TI  - Neuroscience in the post-genome era.

PMID- 12494238
TI  - Cortical responses to visual motion in alert and anesthetized monkeys.

PMID- 12494240
TI  - An astrocyte bridge from synapse to blood flow.

PMID- 12494241
TI  - Look at the big picture (details will follow).

PMID- 12494242
TI  - Activity-dependent synapse development: changing the rules.

PMID- 12494243
TI  - Hide, remember, seek.

PMID- 12494247
TI  - Moderators of placebo response to antipsychotic treatment in patients with
      schizophrenia: a meta-regression.
AB  - RATIONALE: Variation in placebo response within and among clinical trials
      involving patients with schizophrenia can substantially affect conclusions about
      the efficacy of new antipsychotic medications. Therefore, it is of great
      importance to identify factors that moderate response to placebo in such trials.
      OBJECTIVE: The objective of this meta-regression analysis was to estimate the
      effect of potential moderators of placebo response in randomized, short-term
      clinical trials involving patients with schizophrenia, schizoaffective disorder
      or schizophreniform disorder. METHODS: Mean placebo response and potential
      moderators were extracted from 35 placebo-controlled, randomized trials of
      antipsychotic medications in patients with schizophrenia. Placebo response was
      defined as the absolute change in the Brief Psychiatric Rating Scale total score.
      Fixed-effects meta-regression was used to investigate between-trial variation in
      placebo response. RESULTS: Trial duration accounted for a substantial proportion
      of the between-trial variation in response (27%), with greater improvement on
      placebo observed in shorter trials. Other variables showed insufficient variation
      across trials to permit any inferences regarding their relationships with placebo
      response. CONCLUSIONS: Placebo-controlled trials of short duration (<6-8 weeks)
      are vulnerable to substantial placebo response. Recruiting patients with more
      severe pathology to mitigate placebo response does not appear to offer benefits
      and may even be counterproductive. Meta-analyses based on individual patient data
      offer the potential for much more detailed and inferentially sound exploration of
      factors affecting placebo response and are highly recommended.

PMID- 12494248
TI  - Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison
      of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase
      activities with in vitro chemosensitivity to 5-FU.
AB  - BACKGROUND: In tumor cells, the enzyme orotate phosphoribosyl transferase (OPRT)
      contributes to 5-fluorouracil (5-FU) phosphorylation and another enzyme,
      dihydropyrimidine dehydrogenase (DPD), is associated with 5-FU catabolic action.
      We measured OPRT and DPD activities and, to determine whether their levels might
      serve as indicators of 5-FU sensitivity, simultaneously assayed in vitro
      chemosensitivity to 5-FU. METHODS: Tissue specimens were obtained from colorectal
      cancer patients and in vitro chemosensitivity was tested using fluorescein
      diacetate assay (FDA) or histoculture drug response assay (HDRA). DPD and OPRT
      activities were measured by radioassay. RESULTS: The chemosensitivity assay was
      performed on 62 colorectal cancer specimens. Results were evaluable in 29 of 30
      cases (96.7%) for FDA and 30 of 32 cases (98.3%) for HDRA. The positive
      sensitivity rate was 37.9% by FDA assay and 30% by HDRA assay. In positive
      specimens, the mean DPD activity was 44.9 +/- 32.6 pmol/min per mg protein, and
      in negative specimens, it was 53.8 +/- 33.7 pmol/min per mg protein ( P= 0.875).
      In contrast, the mean OPRT value was significantly higher in positive specimens
      (0.418 +/- 0.180 nmol/min per mg protein) than in negative specimens (0.325 +/-
      0.153 nmol/min per mg protein; P < 0.05). The chemosensitivity test proved
      positive in 60% of the specimens with ORPT activity of 0.413 or above and 50% of
      those with DPD activity of 30 or below. Of the patient specimens showing OPRT
      activity of 0.413 or above and DPD activity of 30 or below, 88.9% were positive
      for 5-FU sensitivity, suggesting the possibility that the combination of these
      two levels may be predictive of 5-FU positive sensitivity. CONCLUSION: DPD and
      OPRT activities within cancer cells may predict positive sensitivity to 5-FU.

PMID- 12494249
TI  - Thermoradiotherapy for local control of chest wall invasion in patients with
      advanced non-small cell lung cancer.
AB  - BACKGROUND: We tested the feasibility of hyperthermia combined with concurrent
      radiotherapy (thermoradiotherapy) for pain relief and local control of non-small
      cell lung cancer (NSCLC) invading to the chest wall. METHODS: Thirteen patients
      with advanced NSCLC (eight stage IIIB and five stage IV) and severe pain caused
      by chest wall invasion of tumor were treated with thermoradiotherapy. During the
      conventional fractionated radiotherapy period, 8-MHz radiofrequency capacitive
      hyperthermia was administered once or twice per week for a total of three to nine
      treatment sessions. Pain relief, objective tumor response, thermometry, and
      toxicity were evaluated. RESULTS: Twelve of the 13 patients (92%) experienced
      satisfactory pain relief, and objective tumor shrinkage was observed in 11 of the
      13 patients (85%), including complete regression in two. The thermometry
      parameters of minimum and maximum intratumor temperatures, mean of all intratumor
      temperatures, and rate of the time during which intratumor temperature was 41
      degrees C or higher were 37.6 +/- 0.8 degrees C, 42.4 +/- 0.7 degrees C, 40.3 +/-
      0.3 degrees C, and 80.1 +/- 8.6%, respectively. Adverse reactions included local
      transient skin pain in three patients, but no major toxicity was observed.
      CONCLUSION: Concurrent thermoradiotherapy for chest wall invasion by advanced
      NSCLC was feasible, with tolerable toxicity, and it may be effective for pain
      relief and local tumor control. Further studies comparing thermoradiotherapy and
      radiotherapy alone for such patient populations are warranted.

PMID- 12494250
TI  - Relationship between postoperative recurrence and expression of cyclin E, p27,
      and Ki-67 in non-small cell lung cancer without lymph node metastases.
AB  - BACKGROUND: Cyclin E and p27 play pivotal roles in cancer development and
      progression. We investigated whether the prognosis in cases of non-small cell
      lung cancer without lymph node metastases that underwent complete resection could
      be associated with tissue expression of cyclin E, p27, and Ki-67. METHODS: Tumors
      from 62 patients at least 5 years after surgery were assessed by
      immunohistochemistry for expression of cyclin E, p27, and Ki-67. Disease-free
      survival (DFS) after surgery was used to evaluate disease prognosis. We also
      investigated the relationship between expression of these factors and
      postoperative recurrence. RESULTS: In non-small cell lung cancer, p27-negative
      expression and pT factor were significantly unfavorable prognostic factors in
      multivariate analysis. The DFS rate in cyclin E-positive expression was
      significantly lower than in cyclin E-negative expression. Similarly, p27-negative
      expression and high Ki-67 expression correlated with a shortened DFS rate. In
      combinations of expression of cyclin E and p27, the cyclin E-negative/p27
      positive group had a significantly higher DFS rate than did the other groups.
      According to histological type, there were correlations between the risk of
      postoperative recurrence and expression of these three biological factors,
      especially in adenocarcinoma. CONCLUSION: By analyzing the expression of cyclin
      E, p27, and Ki-67 of tumor cells, it was possible to extract the patient group
      for whom closer follow-up and postoperative treatment is necessary to improve
      survival rate.

PMID- 12494251
TI  - Combination chemotherapy with paclitaxel and intraperitoneal cisplatin for
      ovarian cancer with disseminated lesions in the peritoneum and the diaphragm.
AB  - BACKGROUND: In ovarian cancer, the management of micrometastases disseminated in
      the peritoneal cavity is extremely important. We performed intravenous paclitaxel
      (PAC) infusion combined with cisplatin (CDDP) intraperitoneal infusion for
      progressive ovarian cancer. METHODS: Twelve patients with progressive epithelial
      ovarian cancer (FIGO IIIc), which was resected using an optimal method at primary
      surgery, except for disseminated lesions in the peritoneum and the diaphragm,
      were studied. At primary surgery, a reservoir was placed in the peritoneal
      cavity. If metastases were identified in the diaphragm, then another reservoir
      was also placed in the subdiaphragm (double reservoirs). The basic regimen was
      set at 175 mg/m(2) with divided doses of PAC and 75 mg/m(2) CDDP by
      intraperitoneal injection. When a double reservoir was used, 30 mg/m(2) of
      subdiaphragmatic CDDP and 45 mg/m(2) of intraperitoneal CDDP were administered.
      The patients received five courses of this regimen. The response to the therapy
      was evaluated with tumor markers, and by using cytodiagnoses on the peritoneal
      washing fluid collected from the reservoirs. RESULTS: After five courses of the
      chemotherapy, the tumor marker levels and cytodiagnoses of all patients became
      negative. With reference to adverse effects, grade 3-4 neutropenia was detected
      in 2 patients (16.6%), peripheral neuropathy was detected in 4 patients (33.3%),
      and alopecia was detected in 11 patients (91.6%). The median follow-up period was
      29.2 months and median progression-free survival was 25.6 months. CONCLUSION: The
      combination chemotherapy with intravenous PAC and intraperitoneal CDDP was
      effective on ovarian cancer with disseminated lesions in the peritoneum and the
      diaphragm, having only mild adverse effects.

PMID- 12494252
TI  - Dihydropyrimidine dehydrogenase levels in nonsmall-cell lung cancer tissues.
AB  - BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) activity in tumor tissues is
      thought to play an important role in the antitumor effect of 5-fluorouracil (FU).
      In order to define 5-FU-resistant nonsmall-cell lung cancer, we assessed the DPD
      level in tumor tissues with an enzyme immunoassay. METHODS: Using a sandwich
      enzyme immunoassay, the DPD level in lung cancer tissues was quantitatively
      measured in 52 patients with primary lung cancer who had undergone a pulmonary
      lobectomy. RESULTS: The mean DPD level in tumor tissues was significantly higher
      than that in normal lung tissues (194 units/mg protein vs 53 units/mg protein; P
      < 0.001). The DPD level in tumor tissues correlated with neither sex nor age.
      Although there was no difference in the DPD level according to the grade of
      differentiation, squamous cell carcinoma exhibited a significantly lower level of
      DPD than adenocarcinoma. However, the DPD level in tumor tissues did not
      correlate with the advance of disease. CONCLUSION: Compared with adenocarcinoma,
      squamous cell carcinoma might be a favorable target for 5-FU-based chemotherapy
      in the treatment of nonsmall-cell lung cancer.

PMID- 12494253
TI  - Anaphylaxis to cisplatin following nine previous uncomplicated cycles.
AB  - Anaphylaxis to cisplatin is an infrequent life-threatening complication which may
      occur even in patients who have received prior treatment with cisplatin. We
      report here a patient with carcinoma of the cervix with recurrent abdominal and
      thoracic disease who was previously treated with concurrent cisplatin and
      radiation for local control of pelvic disease. After nine previous uncomplicated
      cycles she developed severe anaphylaxis to cisplatin. The anaphylactic reaction
      was managed successfully with corticosteroids, nebulization with beta(2)
      agonists, and isotonic fluid support. With the extensive use of platinum-based
      chemotherapy regimens, either alone or in combination with radiation therapy in
      the management of gynecological malignancies, this uncommon complication should
      be kept in mind for early detection and successful management.

PMID- 12494254
TI  - Isolated internal mammary sentinel lymph node metastasis in two breast cancer
      patients.
AB  - Lymphatic mapping with sentinel node biopsy may lead to more accurate staging of
      breast cancer patients. Two patients with sentinel nodes in the internal mammary
      node chain are described. These nodes were visualized on lymphoscintigraphy
      images and harvested by the surgeon. They were shown to contain tumor cells in
      the absence of axillary involvement. This led to upstaging and to a change in the
      subsequent management.

PMID- 12494255
TI  - Locoregional adoptive immunotherapy resulted in regression in distant metastases
      of a recurrent esophageal cancer.
AB  - Esophageal cancer is one of the most common malignant diseases. However,
      postoperative recurrences are still resistant to currently available
      radiochemotherapy. We recently reported a study on the initial clinical efficacy
      of locoregional adoptive immunotherapy for advanced esophageal cancer. We report
      here our clinical experience of remarked responses in distant metastatic lesions
      in a patient with recurrent cancer after receiving this immunotherapy. A male
      patient underwent curative surgery, and presented with multiple recurrent
      metastases in the supraclavicular lymph nodes (LNs), liver, and abdominal aortic
      LNs. Autologous tumor-activated lymphocytes (AuTLs) generated ex vivo were
      regionally injected into supraclavicular LNs every 2 weeks 13 times. Mean numbers
      of the administrated cells were 0.8 x 10(9) cells/injection. AuTLs established
      from peripheral blood lymphocytes stimulated by autologous tumor cells with
      interleukin-2 were tested for their cytotoxicity before every treatment. During
      immunotherapy, Grade 2 diarrhea and fever were observed. The clinical partial
      responses were obtained in all lesions and were sustained for 11 months. Because
      clinical toxicity was tolerable, this immunotherapy might be useful for patients
      with far-advanced esophageal cancers.

PMID- 12494256
TI  - Osteoclast-like giant cell tumor of the pancreas.
AB  - A rare case of osteoclast-like giant cell tumor of the pancreas is reported. A 45
      year-old woman presented with upper abdominal pain and weight loss. Examination
      revealed a tumor in the tail of pancreas, and distal pancreatectomy with
      splenectomy was performed. Pathological findings showed the tumor was composed of
      two cell types: atypical mononuclear round cells and abundant osteoclast-like
      multinucleated giant cells with central nucleoli. Immunohistochemical study
      showed that the atypical cells were strongly reactive for vimentin and negative
      for CD68, while the giant cells were immunoreactive for CD68, but negative for
      vimentin. The tumor was diagnosed as osteoclast-like giant cell tumor of the
      pancreas. We report this case and review 31 cases previously described in the
      literature.

PMID- 12494257
TI  - Introduction of pneumococcal vaccine to standard immunisation programmes in
      Europe: what are we waiting for?

PMID- 12494258
TI  - Safety and efficacy of the seven-valent pneumococcal conjugate vaccine: evidence
      from Northern California.
AB  - Pneumococcal disease remains a significant cause of morbidity among young
      children. A large-scale efficacy trial in the Northern California Kaiser
      Permanente system (the KP trial) demonstrated that a seven-valent conjugate
      vaccine (PCV) is safe and immunogenic in young children and effective in
      preventing both invasive pneumococcal disease caused by vaccine serotypes (97.4%
      efficacy) and episodes of otitis media (7.0% efficacy). Since the publication of
      the results of the KP trial in 2000, we have performed an additional analysis on
      the safety, immunogenicity, and efficacy of the vaccine in low birth weight (LBW)
      and preterm (PT) infants, and have examined the efficacy of the vaccine during 1
      year of wide-scale post-licensure use. The vaccine was at least as immunogenic in
      LBW and PT infants as in normal-weight, full-term infants and was 100% effective,
      although the LBW and PT infants had higher rates of adverse events such as
      redness and swelling. LBW and PT infants receiving pneumococcal vaccine also had
      higher rates of adverse events, such as hives, than those receiving control
      meningococcal vaccine, but these reactions were not severe. When the PCV was used
      in the general population, the efficacy remained high and there was no
      corresponding increase in disease caused by nonvaccine serotypes. There was also
      evidence that vaccine administration led to herd immunity. Febrile illness was
      the only adverse event seen more frequently after vaccine administration than
      during a control period. CONCLUSION: the seven-valent conjugate vaccine is safe
      and effective for use in the general population.

PMID- 12494259
TI  - Time to recommend pneumococcal vaccination for all children in Europe: experience
      in France.
AB  - The French decision-making processes for recommendation and introduction of
      infant vaccination with Prevenar reflect a public health-based dialogue between
      the Direction Generale de la Sante and Wyeth (Paris-La Defense, France) nurtured
      by open and ongoing exchanges. Three surveillance programmes are being discussed:
      (1) to ascertain the future impact of large-scale Prevenar vaccination on
      invasive pneumococcal disease incidence, (2) to follow the evolution and carriage
      of pneumococcus and (3) to look at the possibilities to establish an
      epidemiological surveillance and active "vaccinovigilance" in France (to estimate
      the number of adverse events that might be expected among the population targeted
      by the vaccination recommendation). CONCLUSION: in this way, the Direction
      Generale de la Sante and Wyeth are working towards the implementation of a broad
      scale vaccine introduction.

PMID- 12494260
TI  - Invasive pneumococcal disease in children: geographic and temporal variations in
      incidence and serotype distribution.
AB  - We examined published studies from the United States, Europe, and Latin America
      to better understand geographic and temporal variability in the epidemiology of
      invasive pneumococcal disease (IPD) in young children. A comparison of IPD
      incidence levels reported for children <5 years of age within the United States
      (CDC) surveillance system over the past 5 years revealed little variation over
      that time period. Within the Danish national surveillance system, a 3-4 fold
      increase in bacteremic IPD in that age group was reported over the past 15 years.
      Nonetheless, the United States IPD incidence remains 4-8 fold higher than that
      reported for Denmark or other Western European countries. A retrospective
      analysis at one North American hospital spanning 40 years indicated that the
      seven serogroups represented in the licensed pneumococcal conjugate vaccine (4,
      6, 9, 14, 18, 19, 23) consistently comprised 80%-90% of all serogroups causing
      IPD in young children. More recent retrospective comparisons in Spain, the United
      Kingdom, France, Belgium, and Denmark suggest modest increases in vaccine
      serogroup coverage over the past 10-20 years. However, in European children
      vaccine serogroups consistently account for 10%-20% less of the overall IPD
      burden as compared to North American children. CONCLUSION: factors that likely
      underlie a significant proportion of these apparent temporal and geographic
      differences include variability in blood culturing rates, in antibiotic
      resistance levels, and in the precise age distributions of the populations
      studied.

PMID- 12494261
TI  - Will the 7-valent pneumococcal vaccine have a similar impact on all invasive
      pneumococcal infections in children in Germany as in the Kaiser Permanente Trial?
AB  - A 7-valent pneumococcal conjugate (7-vPc) vaccine was shown to be highly
      effective in California preventing 89.1% of all invasive pneumococcal infections
      (IPI) regardless of serotype. There is concern whether a similar effectiveness
      will be attained in Germany where 52% of all IPI in children <16 years were
      caused by the serotypes in the vaccine. The study was based on prospective,
      active surveillance of IPI in German children aged <16 years during 1997 to 2000.
      Coverage by the 7-vPc vaccine (with and without 6A) in unvaccinated children in
      the Kaiser Permanente Trial (KPT) was compared to the coverage in German children
      in the same age period as in the KPT. The proportion of potentially preventable
      cases was estimated both for unvaccinated children in the KPT and for Germany by
      multiplication of the coverage rates with the vaccine efficacy estimate from the
      KPT (intention to treat analysis). Successful serotyping could be attained for
      38.3% of the 1,743 German IPI cases. In the age period from 7 to 43 months
      concerned in the KPT, the proportion of cases with serotypes covered by the 7-vPc
      vaccine (+6A) was 91% (95% CI 80%-97%) in the unvaccinated children in the KPT
      compared to 76% (95% CI 71%-80%) in Germany. The respective estimates for the
      number of potentially preventable IPI cases were 85% (95% CI 75%-91%) in the KPT
      compared to 71% (95% CI 67%-75%) in Germany. CONCLUSION: Age specific serotype
      coverage rates have to be considered for extrapolation of the Kaiser Permanente
      Trial to the German situation. Although 14% lower than in the Kaiser Permanente
      Trial, 71% of potentially preventable cases of invasive pneumococcal infection
      still predict an excellent effectiveness for the 7-valent pneumococcal conjugate
      vaccine in Germany.

PMID- 12494262
TI  - Arteriogenesis - is this terminology necessary?
AB  - The role of the collateral circulation has been controversially discussed over
      many decades. With the availability of purified growth factors such as the
      fibroblast growth factors several studies provided data, that the growth of
      collateral arteries, termed arteriogenesis, is not limited to its natural
      timecourse. When applied in experimental models FGF in particular led to a
      significant increase in collateral conductance upon arterial occlusion. Thus the
      proliferation of preexisting bypassing arterioles could be enhanced
      therapeutically. The purpose of this review is to discuss the physiological
      importance of different kinds of vascular growth (e.g. vasculogenesis,
      angiogenesis, arteriogenesis) to enhance blood flow to ischemic limbs or the
      heart. It is outlined that large conductance arteries rather than capillary
      networks are needed to compensate for perfusion deficits due to atherosclerotic
      stenosis or occlusion.

PMID- 12494263
TI  - Editorial comment on Arteriogenesis - is this terminology necessary?

PMID- 12494264
TI  - Prostacyclin inhibits adhesion of polymorphonuclear leukocytes to human vascular
      endothelial cells due to adhesion molecule independent regulatory mechanisms.
AB  - Prostacyclin is an important endothelial mediator involved in the interaction of
      neutrophils (PMN) with the vessel wall. Many studies have shown the beneficial
      effects of prostacyclin in ischemia and reperfusion. However, no previous study
      has investigated the direct effects of the prostacyclin analogs iloprost (ILO)
      and alprostadil (PGE(1)) on the endothelial part of the adhesion process. Human
      umbilical vein endothelial cells (HUVECs) were grown to confluence, stimulated
      with 300 U/ml TNF-alpha and treated with increasing concentrations of ILO and
      PGE(1). The cells were washed to remove TNF and the inhibitors and adhesion of
      fluorescence-green labeled PMN was determined microscopically. ICAM-1, VCAM-1 and
      E-selectin expression were measured by a cell-surface ELISA. The chemoattractant
      activity of the endothelial cell releasate was tested in a Boyden chamber.ILO and
      PGE(1) reduced PMN-adhesion in a concentration-dependent manner (ILO: -54 +/- 9 %
      at 0.5 microM, PGE1: -46 +/- 10 % at 10 microM). However, the surface expression
      of ICAM-1, VCAM-1 and E-selectin remained unaltered. When the supernatant of
      iloprost/PGE(1)-treated cells was transferred onto cells that were activated, but
      not treated with ILO or PGE(1), the reduction of PMN adhesion remains sustained.
      These data indicate that the inhibitory effect of ILO/ PGE(1) treatment is
      achieved by a reduced chemoattractant potential. PAF-antagonists were able to
      block neutrophil adhesion and mimicked the effect of ILO, while exogenous PAF
      diminished the inhibitory effect of ILO concentration-dependently. This study
      demonstrates the beneficial effects of ILO and PGE(1) on inflammatorily activated
      endothelial cells. These prostacyclin analogs inhibit PMN-adhesion despite
      maximal adhesion molecule expression by regulating the balance of - yet to be
      determined - endothelial-derived mediators.

PMID- 12494265
TI  - Effect of atrial dilatation on electrophysiologic properties and inducibility of
      atrial fibrillation.
AB  - INTRODUCTION: Atrial dilatation may play an important role in the occurrence of
      atrial fibrillation (AF) in clinical situations. However, the electrophysiologic
      characteristics of dilated atria are still unclear. METHODS AND RESULTS: In 18
      isolated Langendorff-perfused canine hearts (14.6 +/- 2.2 kg), we measured atrial
      effective refractory periods (ERPs) at four different sites, conduction velocity
      and percentage of slow conduction on the right atrium (using a high-density
      electrode plaque), and assessed the inducibility of AF at the baseline (0 cm
      H(2)O) and high (15 cm H(2)O) atrial pressure. The atrial ERPs did not change
      significantly, but the dispersion of ERP increased significantly (40 +/- 18 vs 25
      +/- 9 vs ms, p = 0.01) during high atrial pressure. The percentage of slow
      conduction (< 25 cm/s) over the mapping area, and the inducibility of AF
      increased during high atrial pressure (23.7 +/- 10.2 % vs 32.1 +/- 12.5 %, p =
      0.02). The AF inducibility significantly correlated with the ERP dispersion (R =
      0.75, p < 0.001) and maximal percentage of slow conduction (R = 0.88, p < 0.001).
      Furthermore, ERPs were significantly shorter in the induced AF group than those
      without induced AF (68 +/- 17 vs 84 +/- 16 ms, P < 0.05). CONCLUSIONS: The
      increased inhomogenity in atrial electrophysiological properties during atrial
      dilatation contributed to the inducibility of AF.

PMID- 12494266
TI  - Prolonged action potential durations, increased dispersion of repolarization, and
      polymorphic ventricular tachycardia in a mouse model of proarrhythmia.
AB  - INTRODUCTION: In the congenital long QT syndrome, inhomogeneously prolonged
      action potentials, bradycardia, and hypokalemia can cause afterdepolarizations
      and torsade de pointes. Other genetic factors may contribute to similar forms of
      ventricular tachycardias in hypertrophied or failing hearts, especially if the
      outward current I(Kr) is blocked pharmacologically. We sought to develop a mouse
      heart model for such arrhythmias in order to identify the proarrhythmic potential
      in transgenic animals. METHODS AND RESULTS: Hearts of adult wild-type (CD1) mice
      were isolated and the aorta was retrogradely perfused. Three monophasic action
      potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10(
      5)M and 2 x 10(-5)M) prolonged action potential duration (APD) in a concentration
      dependent and reverse frequency-dependent fashion (from 34 +/- 1 to 48 +/- 2 ms
      at 100 ms basic cycle length (BCL), from 38 +/- 2 to 54 +/- 3 ms at 180 ms BCL
      for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness
      and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular
      bradycardia and doubled dispersion of APD (APD70max-min: 11 +/- 1 vs. 4 +/- 1 ms,
      APD90max-min: 12 +/- 1 vs. 5 +/- 1 ms, p < 0.05). If combined with hypokalemia,
      afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8
      hearts at K(+) =3.0 mM and in 10 of 12 hearts at K(+) = 2.0 mM. Prior to
      polymorphic ventricular tachycardia, dispersion of APD further increased
      (APD70max-min: 17 +/- 3 ms; APD90max-min: 25 +/- 3 ms; p < 0.05). CONCLUSIONS:
      This isolated beating mouse heart model can be used to study drug-induced action
      potential prolongation and repolarization-related ventricular arrhythmias
      provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic
      predisposition to ventricular arrhythmias that may only become apparent under
      such proarrhythmic conditions.

PMID- 12494267
TI  - Angiotensin II effects on STAT3 phosphorylation in cardiomyocytes: evidence for
      Erk-dependent Tyr705 dephosphorylation.
AB  - Experiments were performed to define the basis for negative regulation of STAT3
      activation (i.e., Tyr705 phosphorylation) by angiotensin II in cardiomyocytes.
      Treatment of cardiomyocytes with angiotensin II resulted in rapid and sustained
      phosphorylation of STAT3 on Ser727; in contrast, STAT3 Tyr705 phosphorylation was
      decreased, with dephosphorylation being most pronounced at 30 minutes.
      Angiotensin II-induced STAT3 Tyr705 dephosphorylation was not prevented by
      inhibiting protein synthesis, but was blocked by vanadate or the MEK inhibitor
      PD98059. PD98059 was found to inhibit angiotensin II-induced Erk activation and
      STAT3 Ser727 phosphorylation. Angiotensin II also attenuated LIF-induced STAT3
      Tyr705 phosphorylation, and this effect could be blocked with PD89059. These
      results are consistent with Erk-mediated STAT3 Ser727 phosphorylation leading to
      STAT3 Tyr705 dephosphorylation, and accounting for angiotensin II-mediated STAT3
      inhibition in cardiomyocytes. We propose that Erk serves as a scaffolding protein
      in recruiting either a protein tyrosine or MAP kinase phosphatase to STAT3.

PMID- 12494268
TI  - Direct injection and expression in vivo of full-length cDNA of the cardiac
      isoform of alpha-2 macroglobulin induces cardiac hypertrophy in the rat heart.
AB  - Earlier studies from this laboratory have shown that the serum protein of
      molecular weight of 182 kDa, which plays an indispensable role in the development
      of cardiac hypertrophy, may be a cardiac isoform of alpha-2 macroglobulin
      belonging to macroglobulin family (36). Furthermore, reports on the stable
      expression in vivo of several reporter genes injected directly into the
      myocardium of rat and the approach of direct gene transfer into adult mammalian
      heart to characterize the activity of a cellular gene and to modulate overall
      cardiac function in vivo prompted us to evaluate the hypertrophy inducing
      potential of a full-length cDNA for the 182 kDa protein upon direct injection.
      The full-length cDNA of the cardiac isoform of alpha-2 M obtained from
      hypertrophied rat heart mRNA and cloned in an eukaryotic expression vector namely
      pcDNA 3.1(-) was injected directly into the rat heart; the protein whose
      expression was constitutively triggered by the cytomegaloviral promoter could be
      detected in the serum of the injected animals and it could exert its function of
      inducing the hypertrophy, by a highly plausible way, by which the cardiac
      specific 182 kDa protein may bind to many growth modulating factors in the serum,
      and then be targeted to cardiomyocytes by a receptor mediated mechanism (36). The
      development of cardiac hypertrophy was monitored by determining the heart weight
      body weight ratio. This ratio along with Northern blot analysis of muscle
      specific marker genes such as beta-MHC, MLC-2 and ANF, and the induction of
      promoter activity of beta-MHC and c-fos genes monitored using chloramphenicol
      acetyl transferase as a reporter gene confirmed the induction of cardiac
      hypertrophy upon direct injection of the full-length cDNA of 182 kDa protein.

PMID- 12494269
TI  - Mitochondrial KATP channel-dependent and -independent phases of ischemic
      preconditioning against myocardial infarction in the rat.
AB  - To obtain insight into the role of the mitochondrial ATP-sensitive K(+)
      (mitoK(ATP)) channel in ischemic preconditioning (PC), we aimed to clarify the
      mitoK(ATP) channel-dependent phase of PC in two PC protocols with different
      intervals between PC ischemia and an index ischemia. The possible contribution of
      mitoK(ATP) channel opening to protein kinase C activation in PC was also examined
      by Western blotting. Myocardial infarction was induced by 30-min coronary
      occlusion/2-h reperfusion in rat hearts in situ, and infarct size was expressed
      as a percentage of the area at risk (% IS/AR). PC was performed with 2 episodes
      of 5-min ischemia, and each heart was subjected to 30-min ischemia either 5 min
      or 20 min after PC. At 5 min after PC, both PKC-delta and -epsilon were
      translocated and the myocardium was protected against infarction (% IS/AR = 28.3
      +/- 2.7 % vs. 72.7 +/- 2.2 in controls p < 0.05). Pretreatment with a selective
      mitoK(ATP) channel blocker, 5-hydroxydecanoate (5-HD, 10 mg/kg), abolished the
      cardioprotection but not PKC translocation by PC. At 20 min after PC, PKC
      translocation remained at the same level as that 5 min after PC, but the anti
      infarct tolerance was attenuated (%IS/AR = 43.5 +/- 4.7 %). Injection of 5-HD
      after PC did not affect anti-infarct tolerance at 5 min after PC but abolished
      the protection at 20 min after PC without any effects on PKC. These results
      suggest that the mitoK(ATP) channel plays a role in triggering of PC in a PKC
      independent manner and that the role of the mitoK(ATP) channel as a mediator of
      protection is detectable after, but not before, the PC effect starts to decay
      without a change in the level of PKC translocation in the rat heart.

PMID- 12494270
TI  - Ginkgo biloba extract EGb 761 attenuates myocardial stunning in the pig heart.
AB  - Myocardial stunning, a transient contractile dysfunction that appears following a
      brief period of ischemia, is at least partly due to the production of oxygen
      derived free radicals. The objective of the present study was to determine
      whether the Ginkgo biloba extract EGb761, which has antioxidant properties in
      vitro, can attenuate myocardial stunning in vivo. Forty-seven anesthetized open
      chest farm pigs underwent 10 min of occlusion of the left anterior descending
      coronary artery (LAD), followed by 3 hours of reperfusion. They were pretreated
      with either physiological saline, 100 mg or 300 mg of EGb 761 (Protocol I) or 3
      mg or 9 mg of ginkgolide B (GkB) (Protocol II). Contractile function was assessed
      by sonomicrometry. Both doses of EGb 761 significantly improved recovery of
      contractile function in the reperfused myocardium with segment shortening
      averaging 23 +/- 5 % of baseline values at 3 hours post-reflow in controls versus
      81 +/- 10 % and 57 +/- 12 % in the EGb100 and EGb300 groups, respectively (p <
      0.05 vs control in both cases). In contrast, neither dose of GkB improved
      functional recovery during reperfusion. ESR experiments revealed that EGb761
      resulted in a 59 % decrease in myocardial spin-adduct release during reperfusion
      (p < 0.05 versus control and GkB groups). A significant 28 % decrease (p < 0.05
      vs control group) was also obtained in GkB-treated animals. These results
      indicate that EGb 761 can attenuate myocardial stunning following a brief
      ischemic insult in the in situ pig heart by an effect that involves a decrease in
      the formation of free radicals. As the effect of EGb 761 on functional recovery
      cannot be explained by the presence of GkB, the beneficial action of the extract
      on myocardial stunning likely involves complementary effects of both its non
      ginkgolide and ginkgolide constituents.

PMID- 12494271
TI  - A case of Sjogren's syndrome or multiple sclerosis? A diagnostic and therapeutic
      dilemma.
AB  - BACKGROUND: Primary Sjogren's syndrome (SS) with central nervous system
      involvement and antiphospholipid syndrome have been reported to mimic multiple
      sclerosis (MS). SS has also been found in patients diagnosed with definite MS.
      PATIENTS AND METHODS: A Chinese lady developed multiple relapsing neurological
      events involving the brain and spinal cord from the age of 40 years. Magnetic
      resonance imaging of the brain and spinal cord during acute relapses showed
      increased T2 signals and spinal cord edema. She later developed positive anti
      nuclear antibody and anti-Ro autoantibody followed by sicca symptoms, confirming
      the diagnosis of SS. She died from aspiration pneumonia following pseudobulbar
      palsy shortly after SS was diagnosed. CONCLUSIONS: Patients with MS-like disease
      and autoantibodies should be carefully evaluated for other systemic autoimmune
      diseases as the treatment and prognosis differ from MS. In particular, sicca
      symptoms should be sought as they often go unnoticed by patients. This is
      especially important in Orientals in whom MS is relatively uncommon.

PMID- 12494273
TI  - Prevalence of erectile dysfunction: a systematic review of population-based
      studies.
AB  - A systematic review was conducted on the prevalence of erectile dysfunction (ED)
      in the general population. Studies were retrieved which reported prevalence rates
      of ED in the general population. Using a specially developed criteria list, the
      methodological quality of these studies was assessed and data on prevalence rates
      were extracted. We identified 23 studies from Europe (15), USA (5), Asia (2) and
      Australia (1). On our 12-item criteria list, the methodological quality ranged
      from 5 to 12. The prevalence of ED ranged from 2% in men younger than 40 y to 86%
      in men 80 y and older. Comparison between prevalence data is hampered by major
      methodological differences between studies, particularly in the use of various
      questionnaires and different definitions of ED. We stress the importance of
      providing all necessary information when reporting on the prevalence of ED.
      Moreover, international studies should be conducted to establish the true
      prevalence of ED across countries.

PMID- 12494274
TI  - The neuropathy of erectile dysfunction.
AB  - These studies were intended to explore the relationship between autonomic
      neuropathy and erectile dysfunction (ED). Sensory thresholds reflecting the
      integrity of both large diameter, myelinated neurons (ie pressure, touch,
      vibration) and small diameter axons (ie hot and cold thermal sensation) were
      determined on the penis and finger. Data were compared across subjects with and
      without ED, controlling for age, hypertension and diabetes. The correlation of
      specific thresholds scores and IIEF values were also examined. Seventy-three
      patients who visited the academic urology clinics at Montefiore hospital were
      evaluated. All patients were required to complete the erectile function domain of
      the International Index of Erectile Function (IIEF) questionnaire: 20 subjects
      had no complaints of ED and scored within the 'normal' range on the IIEF.
      Patients were subsequently tested on their index finger and glans penis for
      vibration (Biothesiometer), pressure (Semmes-Weinstein monofilaments), spatial
      perception (Tactile Circumferential Discriminator), and warm and cold thermal
      thresholds (Physitemp NTE-2). Sensation of the glans penis, as defined by the
      examined sensory thresholds, was significantly diminished in patients with ED and
      these differences remained significant when controlling for age, diabetes and
      hypertension. In contrast, thresholds on the index finger were equivalent in the
      ED and non-ED groups. Threshold and IIEF scores were highly correlated,
      consistent with an association between diminished sensation and decreasing IIEF
      score (worse erectile functioning). These relations also remained significant
      when controlling for age, diabetes and hypertension. The findings demonstrate
      dysfunction of large and small diameter nerve fibers in patients with ED of all
      etiologies. Further, the neurophysiologic measures validate the use of the IIEF
      as an index of ED, as objective findings of sensory neuropathy were highly
      correlated with worse IIEF scores. The sensory threshold methods utilized
      represent novel, non-invasive and relatively simple procedures, which can be used
      in a longitudinal fashion to assess a patient's neurological response to
      therapies.

PMID- 12494275
TI  - Malaysian cultural differences in knowledge, attitudes and practices related to
      erectile dysfunction: focus group discussions.
AB  - This qualitative study aimed to examine cultural differences in knowledge,
      attitudes and practices related to erectile dysfunction (ED) utilizing focus
      group discussion. Six focus groups consisting of 66 men, 45-70-y-old were
      conducted-two Malay groups (n=18), two Chinese groups (n=25) and two Indian
      groups (n=23). Participants were purposely recruited from the general public on a
      voluntary basis with informed consent. Transcripts were analyzed using
      qualitative data analysis software ATLASti. The Malay and Chinese traditional
      remedies for preventing or treating ED are commonly recognized among all races.
      Many have a negative perception of someone with ED. Malay and Chinese men tended
      to blame their wife for their problem and thought that the problem might lead to
      extra-marital affairs, unlike the Indian men who attributed their condition to
      fate. Malays would prefer traditional medicine for the problem. The Chinese felt
      they would be more comfortable with a male doctor whilst this is not so with the
      Malays or Indians. Almost all prefer the doctor to initiate discussion on sexual
      issues related to their medical condition. There is a need for doctors to
      consider cultural perspectives in a multicultural society as a lack of
      understanding of this often contributes to an inadequate consultation.

PMID- 12494276
TI  - Expression of functional prostaglandin D (DP) receptors in human corpus
      cavernosum smooth muscle.
AB  - Prostaglandin D(2) (PGD(2)) binds to specific G-protein coupled receptors (DP)
      and induces smooth muscle relaxation by stimulating the synthesis of
      intracellular cAMP. In this study, we examined the role of PGD(2) and DP
      receptors in regulating human penile smooth muscle contractility. We determined
      that human corpus cavernosum tissue and smooth muscle cells in culture expressed
      functional DP receptor and lipocalin-like prostaglandin D synthase by reverse
      transcribed polymerase chain reaction (RT-PCR). Functional PGD synthase activity
      was confirmed by the synthesis of PGD(2) in human corpus cavernosum smooth muscle
      cells upon addition of exogenous arachidonic acid. Organ bath preparations of
      human corpus cavernosum tissue strips, contracted with phenylephrine, relaxed in
      a dose-dependent fashion to either PGD(2) or the DP selective agonist BW245C.
      Cultures of human corpus cavernosum smooth muscle cells treated with BW245C
      showed a two-fold increase in cAMP synthesis. These data are consistent with the
      expression of functional DP receptors in human corpus cavernosum. This suggests
      the presence of an intact prostanoid autocrine system that may play a role in
      regulating penile erectile function.

PMID- 12494277
TI  - A novel compound JPM8: in vivo penile activity promotion in rats, effect on the
      relaxation and cGMP/cAMP accumulation in isolated rabbit corpora cavernosa.
AB  - JPM8 is a novel sildenafil-like PDE5 inhibitor. Its efficacy was tested in vivo
      by the oral administration of drugs to a rat model and recording penile activity
      changes. Effect on the relaxation of the rabbit cavernosa was tested in vitro
      using an organ bath were drugs are added to the tissue media and relaxation was
      recorded using a transducer connected to a chart recorder. The accumulation of
      cGMP and cAMP was measured by incubation of cavernosa strips and then extracting
      the produced cGMP and cAMP in the incubation mixture, then quantitating it using
      ELISA. JPM8 showed increased and promoted sexual and penile activity in rats in a
      similar but slightly higher trend than the positive control sildenafil. JPM8 was
      more efficient in relaxing the rabbit corpora cavernosa than sildenafil. The cGMP
      and cAMP accumulation showed a similar trend for both drugs. We concluded that
      JPM8 was very effective in promoting sexual activity in rats, relaxing the
      corpora cavernosa and promoting cGMP accumulation in rabbits.

PMID- 12494278
TI  - Is sildenafil failure in men after radical retropubic prostatectomy (RRP) due to
      arterial disease? Penile duplex Doppler findings in 174 men after RRP.
AB  - Sildenafil is frequently the first-line treatment for post-radical retropubic
      prostatectomy (RRP) erectile dysfunction (ED) with maximum treatment satisfaction
      rates of 43%-80%. The etiology of erectile dysfunction after RRP has been
      attributed to psychogenic, vascular, veno- occlusive or nerve injury causes. The
      purpose of this study was to gain insight into the penile duplex Doppler arterial
      parameters in men with ED after RRP who failed sildenafil. The purpose was to
      assess whether sildenafil failure after RRP is associated with underlying
      corporal arterial disease. A total of 174 consecutive men presenting with
      sildenafil refractory ED after nerve-sparing RRP underwent color duplex penile
      Doppler evaluation with vasoactive injection. Mean age was 59.6 y and mean time
      from surgery was 11.6 months. Some 81% (141/174) of the men had no pre-operative
      ED (PED). Significant differences in penile duplex Doppler parameters for
      arterial disease were seen between men with and without PED. In men without PED,
      19% (27/141) manifested arterial insufficiency. However, in men with PED, 50%
      (16/33) demonstrated arterial disease. Nerve sparing status did not affect the
      presence of arterial disease. Sildenafil refractory erectile dysfunction after
      RRP in men without PED is not predominantly associated with penile Doppler
      parameters consistent with arterial insufficiency.

PMID- 12494279
TI  - Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in
      patients with diabetes mellitus.
AB  - Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has become a first-line
      therapy for diabetic patients with erectile dysfunction (ED). The efficacy in
      this subgroup, based on the Global Efficacy Question, is 56% vs 84% in a selected
      group of non-diabetic men with ED. Two novel PDE5 inhibitors, tadalafil (Lilly
      ICOS) and vardenafil (Bayer), have recently completed efficacy and safety
      clinical trials in 'general' and diabetic study populations and are now
      candidates for US FDA approval. A summary analysis of the phase three clinical
      trials of sildenafil, tadalafil and vardenafil in both study populations is
      presented to provide a foundation on which the evaluation of the role of the
      individual PDE5 inhibitors for the treatment of patients with ED and DM can be
      built.

PMID- 12494280
TI  - Role of rho-kinase activity in angiotensin II-induced contraction of rabbit
      clitoral cavernosum smooth muscle.
AB  - Isometric tension measurement using a selective Rho-kinase inhibitor (+)- (R)
      trans4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y-27632) and a
      selective myosin light chain kinase (MLCK) inhibitor 1-(5-iodonaphthalene-1
      sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML7) were used in rabbit
      clitoral cavernosum smooth muscle (CSM). N(G)-nitro-L-arginine methyl ester (L
      NAME) was used to evaluate the relationship between NO release and Rho-kinase. Y
      27632 significantly attenuated contractions induced by ANG II, dose-dependently.
      However, ML7 did not affect the contractile response to ANG II except in the high
      concentrations of ML7. Y-27632 inhibited contraction with phenylephrine (PhE),
      but ML7 did not inhibit contraction with PhE. Nitric oxide synthase inhibitor
      (NAME) did not affect the Y-27632-induced relaxation in the pre-contracted strip
      with PhE. The present study demonstrates that G-protein-coupled increase in
      myofilament Ca(2+) sensitivity mediated through the RhoA/Rho-kinase signal
      pathway is involved in the control by ANG II of the clitoral CSM tone. RhoA/Rho
      kinase pathway acts in the ANG II-induced contraction independently of the NO
      pathway.

PMID- 12494281
TI  - Treatment of erectile dysfunction in patients with Peyronie's disease using
      sildenafil citrate.
AB  - Erectile dysfunction (ED) has frequently been associated with Peyronie's Disease
      (PD) and may further compromise coitus. This is a retrospective analysis of ED in
      patients with PD since the release of sildenafil citrate (SC) focusing
      specifically on our patients' responses to SC. One-hundred seventy six patients
      with PD were evaluated between April 1998 and May 2001. All patients received a
      complete medical and sexual history, physical exam, penile duplex ultrasound
      (PDU, with 30-90 mg of papaverine) to assess penile vascular integrity, plaque
      dimensions, and erect penile deformity. Based on these findings, appropriate
      treatment options were offered for their PD and their ED including SC, which was
      offered to 73 men. Patient response to SC was specifically assessed during
      patient office interview and via a mailed EDITS (Erectile Dysfunction Inventory
      of Treatment Satisfaction) questionnaire. Seventy (39.8%) and 104 (59.1%)
      patients complained of decreased erectile capacity (ie rigidity) occurring before
      and after the onset of PD, respectively. Only two patients reported no change of
      erectile capacity. In all, 103 (58.5%) patients complained of significant
      reduction in sexual function due to diminished rigidity and sought treatment for
      their ED. Of the ED treatment options available, 73 (70.9%) patients were given a
      prescription for SC. Forty-eight (75.0%) patients returned the EDITS
      questionnaire while four of 73 (5.5%) patients did not fill their prescription
      and five of 73 (6.8%) did not engage in sexual activity following an initial
      trial of SC due to side effects (flushing, headaches). Based upon the EDITS
      response, 34 of 48 (70.8%) patients reported that they were either very satisfied
      or somewhat satisfied, five of 48 (10.4%) patients were neither satisfied nor
      dissatisfied, and nine of 48 (18.8%) patients were somewhat dissatisfied or very
      dissatisfied with the effectiveness of SC in enhancing their erectile response.
      No patient reported worsening of PD deformity or an increase in penile pain. The
      30 patients who were not prescribed SC chose the following options to enhance
      rigidity: eight (7.8%) underwent prosthesis placement, four (3.9%) opted for
      vacuum constriction device (VCD), four (3.9%) chose intracorporal injections, and
      14 (13.6%) used no adjunctive therapy. Erectile dysfunction is a problem
      associated with PD and all typical treatment options are acceptable. However, to
      our knowledge, there is no published study reviewing the efficacy of SC in
      patients with ED associated with PD. There appears to be no contraindication to
      using SC as being the least invasive and most convenient treatment option for ED
      with PD. Although the potential risk of coital trauma to the erect penis with PD
      is present, there is no evidence from this study that erections and coitus
      enhanced specifically by SC resulted in worsening deformity or progression of the
      PD. EDITS questionnaire results reveal that SC is an agent that allowed
      successful coitus in 70.8% of males with PD.

PMID- 12494282
TI  - Acceptance, efficacy and preference of Sildenafil in patients on long term auto
      intracavernosal therapy: a study with follow-up at one year.
AB  - PURPOSE: To assess the acceptance, long term efficacy and preference of
      Sildenafil in impotent patients previously on auto-intracavernosal therapy.
      MATERIALS AND METHODS: The patients were the 107 men (mean age 58.4 y) on auto
      intracavernosal therapy (auto-IC) for more than 6 months (mean duration 32.7
      months >12 months in 100) who were consecutively seen within 6 months of the
      launch of Sildenafil in France. If there was no contra-indications to Sildenafil
      they were proposed a trial of Sildenafil at home. Following this trial they were
      given the possibility to change their therapy and were followed for 1 y at 3
      months intervals. RESULTS: Three patients had contra-indications to Sildenafil.
      Of the remaining 104, 45 (43%) refused the trial, mainly because they were afraid
      of possible cardiac risks (n=21, including 51% of the psychogenic and mixed
      patients compared to 8% of the predominantly organic ones). Among the 59 who
      tried it, Sildenafil gave good results in 46 (78%), including 100% of the
      predominantly psychogenic and 61.5% of the predominantly organic ones) with
      minimum effective doses of 25 mg in 7, 50 mg in 18 and 100 mg in 21. It failed in
      9 (15%) and gave average results in 4 (penetration with a non fully satisfying
      erection). There was a clear relationship between the sensitivity to Sildenafil
      and that to Alprostadil, the vasoactive agent predominantly used for the auto
      ICIs. Every 46 patients with good result of Sildenafil elected to continue with
      this drug, including 3 who used both Sildenafil and auto-ICIs in alternance.
      Every 4 patients with average results elected to continue with auto-ICI including
      1 who also used Sildenafil in alternance. Five of the 50 patients with good or
      average results were lost to follow-up within 6 months. At the 1 y follow-up
      visit, 43 of the 45 others were still using Sildenafil, in alternance with auto
      ICI in 1. No one reported a decrease in efficacy with time. The 2 patients with
      average results still in the study were on auto-ICIs. CONCLUSION: Sildenafil is
      highly effective in the impotent men previously treated with auto-ICI and its
      efficacy is maintained at least for 1 y. When tried and effective it is preferred
      by most men but almost half of our patients refused trying it.

PMID- 12494283
TI  - Sexual disabilities are not singularities.
AB  - This report is based on a survey (performed 1996) of sex life in a nationally
      representative sample of Swedish women (n=1335) and men (n=1475) aged 18-74 y.
      From that survey we have previously reported on prevalence of sexual disabilities
      and problems caused by them (1). The main object of this article is to describe
      intra- and inter-gender concurrence of sexual disabilities and problems in
      sexually active subjects. Furthermore, the relative risk of low level of sexual
      well-being as predicted by sexual disabilities and distress is addressed.
      Respondents (59% of target sample) participated in an investigation which
      combined structured interviews with questionnaires/checklists. Main results are
      that within and across genders sexual disabilities concur to significant degrees.
      Of the women 48 and 26% reported at least one own and partner sexual disability
      or distress caused by them, respectively. For the men the corresponding
      proportions were 26 and 17%, respectively. Odds ratios showed that for the women
      low sexual interest, difficulties in obtaining orgasm and partner's early
      ejaculation were significant predictors of low level of sexual well-being. For
      the men low level of interest and partner's difficulties in obtaining orgasm were
      the only, but equally powerful, predictors. It is concluded that in clinical
      practice and for those who have a partner, sexual disabilities and distress
      caused by them should be regarded from the partner relationship perspective.

PMID- 12494284
TI  - Captopril treatment reverses erectile dysfunction in male stroke prone
      spontaneously hypertensive rats.
AB  - The involvement of antihypertensive therapy in the pathology of hypertension
      associated male erectile dysfunction is unclear. Stroke prone spontaneously
      hypertensive rats (SHRSP) were treated chronically with the angiotensin
      converting enzyme (ACE) inhibitor captopril or placebo, normotensive rats served
      as controls. Mean arterial and intracavernosal pressure were measured during the
      induction of erection by autonomic ganglion stimulation. SHRSP-placebo treated
      rats were hypertensive and had a blunted erectile response. Captopril treatment
      returned both the blood pressure and erectile response to control levels.
      Therefore, ACE inhibitor therapy may not be responsible for the erectile
      dysfunction observed in treated hypertensive subjects.

PMID- 12494285
TI  - Comparison of a needle-free high-pressure injection system with needle-tipped
      injection of intracavernosal alprostadil for erectile dysfunction.
AB  - Patients identified from hospital records as using alprostadil injections for
      erectile dysfunction were invited to take part in this open crossover study. On
      alternate weeks eight patients were given intracavernosal needle injections and
      transdermal needle-free injection of alprostadil in a randomized order. Efficacy
      of injection and associated pain were assessed and compared for the two methods.
      Pain produced during injection was significantly greater with the needle-free
      system than with the needle-tipped injection whilst efficacy was significantly
      less. Bruising was reported in all except one patient following needle-free
      injection only. Patient ratings of the needle-free injector were significantly
      lower than ratings for needle-tipped alprostadil delivery and when asked to
      express a preference, every patient chose the needle-tipped injection over the
      needle-free device.

PMID- 12494286
TI  - The efficacy of citalopram in the treatment of premature ejaculation: a placebo
      controlled study.
AB  - BACKGROUND: Despite the limited number of available study comparing of their
      efficacy, selective serotonin re-uptake inhibitors (SSRI) have been thought to
      have beneficial effects for the patients with premature ejaculation. In the
      present study, we decided to examine the efficacy of citalopram, an SSRI, in the
      treatment of premature ejaculation. METHOD: The study was consisted of 26 married
      patients diagnosed with premature ejaculation according to Diagnostic and
      Statistical Manual of Mental Disorders Third Revised Version (DSM-III-R). The
      patients were randomly assigned to two groups, citalopram (group I) and placebo
      (group II), each consisting of 13 patients. The effects of drug on the
      ejaculatory function were assessed by the intravaginal ejaculation latency time.
      Additionally, all patients were screened by using Clinical Global Impression
      Improvement Scale (CGI-I) and Yonsei Sexual Function Inventory-II (YSFI-II).
      RESULTS: The increase in the intravaginal ejaculation latency time in the
      citalopram group was statistically significant than that of placebo group. In
      addition, with respect to the subscales of the YSFI-II scale, similar overall
      significant improvements were seen in the patients given citalopram compared to
      those given placebo. Of group I patients, five (38.5%) were considered as 'very
      much improved' and four (30.8%) 'much improved' by CGI-I and only one of group II
      patients (7.7%) showed 'much improved'. CONCLUSION: The patients treated with
      citalopram showed significantly greater improvement compared to the patients
      receiving placebo.

PMID- 12494287
TI  - FK506 binding protein 12 is expressed in rat penile innervation and upregulated
      after cavernous nerve injury.
AB  - To evaluate whether FK506 and other immunophilin ligands may have potential
      therapeutic efficacy for erectile function preservation after penile nerve
      injury, we demonstrated localizations of the immunophilin FK506 binding protein
      12 (FKBP 12) in intact and injured rat penile nerves and correlated these
      findings with localizations of neuronal nitric oxide synthase (nNOS), which
      neuronally forms nitric oxide for mediation of penile erection, in response to
      systemically administered FK506. Adult male Sprague-Dawley rats were subjected to
      unilateral right cavernous nerve forceps crush injury and administered FK506 (1
      mg/kg i.p.) or saline at the same time and daily up to 7 days. At 1, 3 and 7 days
      after injury, bilateral cavernous nerves and major pelvic ganglia were collected
      for nNOS immunohistochemistry, FKBP 12 immunohistochemistry, and FKBP 12 in situ
      hybridisation. Protein expressions of nNOS and FKBP 12 were observed in major
      pelvic ganglion, cavernous nerve and nerve terminals within the rat penis as well
      as mRNA expression of FKBP 12 observed in the rat major pelvic ganglion neuronal
      cell bodies to a minimal extent at baseline conditions. After cavernous nerve
      injury, nNOS immunoreactivity was observed to be slightly diminished in
      ipsilateral penile nerve structures at only one day following injury while both
      FKBP 12 protein and mRNA expressions were observed to be increased at each
      interval of study. FK506 treatment did not affect staining of intact or injured
      nerves. Our demonstration that FKBP 12 is localized to penile innervation in the
      rat and becomes upregulated following cavernous nerve crush injury, independent
      of FK506 treatment, suggests that this immunophilin mediates a neurotrophic
      mechanism. Whether FK506 affords neuroprotection that preserves penile erection
      through FKBP 12 upregulation is unclear.

PMID- 12494288
TI  - Bicycle saddle shape affects penile blood flow.
AB  - The purpose of this study was to evaluate the effect of bicycle saddle shape on
      penile blood flow during cycling. Penile blood flow was measured using a laser
      Doppler flowmeter in 20 potent male volunteers. In a counterbalanced, crossover
      design, measurements were taken in the standing and sitting positions, on either
      a narrow unpadded or wide unpadded saddle, before and after cycling for 5 min.
      Before cycling, penile blood flow (ml/min/100 g tissue) was significantly
      decreased from 1.6+/-0.7 to 1.5+/-0.7 (P=0.010) on the wide saddle and from 1.7+/
      0.6 to 1.0+/-0.5 (P<0.001) on the narrow saddle. After 5 min of cycling, the
      changes in penile blood flow on the wide and narrow saddles were 0.34+/-0.49 and 
      0.38+/-0.49, respectively (P<0.001). The narrow saddle is associated with more
      significant reductions in penile blood flow and could be a source of blunt
      perineal trauma, potentially leading to erectile dysfunction.

PMID- 12494289
TI  - Selegiline enhances erectile activity induced by dopamine injection in the
      paraventricular nucleus of the hypothalamus in anesthetized rats.
AB  - Apomorphine delivered in the paraventricular nucleus of the hypothalamus (PVN)
      induces penile erection in rats, suggesting a role of dopaminergic projection to
      the PVN in the control of penile erection. We assessed whether the selective
      inhibitor of monoamine oxidase B, selegiline, could enhance the erectile activity
      induced by dopamine delivery in the PVN. Intracavernous and blood pressure (ICP
      and BP) were monitored in anesthetized rats to quantify ICP rises (number and
      percentage of ICP maximum/mean BP (ICPmax/BP x 100)) elicited by 10 micro g
      dopamine injection in the PVN after saline or 3 mg/kg i.v. selegiline (8 rats per
      group). The number of ICP rises (mean+/-s.d.: 4.5+/-2.9 vs 1.4+/-1.9; P=0.017)
      and their ICPmax/BP x 100 (49+/-8% vs 34+/-9%; P=0.015) were significantly
      greater upon dopamine injection in the PVN than upon vehicle. Compared to saline
      i.v., 3 mg/kg selegiline pretreatment significantly increased the number of ICP
      rises induced by dopamine injection in the PVN (9.4+/-2.6 vs 4.5+/-2.9; P<0.001),
      without affecting their amplitude. This suggests that drugs potentiating
      dopaminergic responses in the central nervous system might enhance proerectile
      commands of supraspinal origin.

PMID- 12494290
TI  - Enhanced relaxation of diabetic rabbit cavernosal smooth muscle in response to
      nitric oxide: potential relevance to erectile dysfunction.
AB  - New Zealand white rabbit cavernosal smooth muscle strips (n=6) were mounted in
      organ baths. Relaxations to nitric oxide (10(-7)-10(-4) mol/l) were measured and
      the same procedure was repeated on strips from rabbits 6 months after alloxan
      induced diabetes (n=6). Transverse cavernosal sections were obtained from the
      same penises. Low and high resolution autoradiographs were prepared using [(3)H]
      L-N(G)-nitroarginine (an index of nitric oxide binding sites) and analysed
      densitometrically. Histochemical analysis was performed on adjacent sections
      using NADPH diaphorase (an index of nitric oxide synthase activity). Nitric oxide
      relaxed control rabbit cavernosal smooth muscle strips in a concentration
      dependent manner. Diabetic rabbit cavernosal smooth muscle strips were
      significantly (P<0.03) more sensitive to nitric oxide (mean IC(50)=3.9 x 10(-6)
      mol/l). Nitric oxide synthase binding sites were localised to the cavernosal
      endothelium and smooth muscle. Nitric oxide synthase activity was increased in 6
      month diabetic cavernosal smooth muscle. These findings suggest impairments in
      the L-arginine-nitric oxide pathway may play a role in the pathophysiology of
      diabetic erectile dysfunction.

PMID- 12494291
TI  - High dose sildenafil citrate as a salvage therapy for severe erectile
      dysfunction.
AB  - The objectives of this study were to evaluate the efficacy and tolerability of
      high dose sildenafil as a salvage therapy for patients refractory to the maximum
      recommended dose of sildenafil. Fifty four fully evaluated patients with chronic
      erectile failure (ED) who had previously failed to respond to a home trial of
      sildenafil (100 mg) with erections suitable for sexual intercourse were studied.
      Each man was treated at home with sildenafil at escalating doses of up to 200 mg
      until either maximal response or intolerable adverse effects occurred. Erectile
      function was quantified using the erectile function domain of the International
      Index of Erectile Function (IIEF) before treatment, with sildenafil 100 mg and
      with maximal dose of sildenafil and a global efficacy question after 4 weeks of
      treatment. The mean age of the study group was 59.6+/-11.2 y. 13/54 (24%) had
      arteriogenic ED, 16/54 (30%) had mixed vasculogenic ED, 9/54 (17%) had cavernosal
      veno-occlusive dysfunction, 11/54 (20%) had post radical retropubic prostatectomy
      ED and 5/54 (9%) had psychogenic ED. 13/54 (24.1%) responded to sildenafil at a
      median maximal dose of 200 mg, 4/13 required 150 mg and 9/13 required 200 mg.
      41/54 (76%) failed to respond to sildenafil. Mean IIEF question 3 and 4 scores
      were 1.5 and 1.4 at baseline, 2.2 and 1.9 with sildenafil 100 mg, 2.8 and 2.5
      with sildenafil 150 mg and 3.0 and 2.9 with sildenafil 200 mg, respectively.
      After 4 weeks, treatment was regarded as having improved their erections by 37%,
      46.3% and 68% of patients with sildenafil 100 mg, 150 mg and 200 mg,
      respectively. 34/54 (63%) reported adverse effects with maximal dose sildenafil
      comprising headache (19), facial flushing (32), dyspepsia (14), nasal congestion
      (11), dizziness (5) and visual disturbances (5). 4/13 (31%) responders refused to
      continue treatment due to adverse effects.In conclusion, sildenafil at doses of
      up to 200 mg is an effective salvage therapy for 24.1% of previous sildenafil non
      responders but is limited by a significantly higher incidence of adverse effects
      and a 31% treatment discontinuation rate.

PMID- 12494293
TI  - Hypervascularity of the glans penis diagnosed with cutaneous temperature
      measurements.
AB  - Hypervascularity of the penis is a complication that has been described after
      deep dorsal vein arterialization. We present a patient with hypervascularity of
      the penis which was diagnosed with cutaneous temperature measurements of the
      penis. Our patient underwent both pre- and post-operative cutaneous temperature
      measurements taken at seven locations along the shaft and glans of the penis with
      the Physitemp BTE-2A Thermal Sensitivity Tester. After deep dorsal vein
      arterialization our patient's cutaneous temperature at the glans increased 4.2
      degrees C. After ligation of the distal deep dorsal vein for hypervascularity,
      the cutaneous temperature at the glans decreased 1.3 degrees C. We present a
      novel technique using cutaneous tempewrature measurements which may be used as a
      test for the efficacy of arterial revascularization and its potential
      complications.

PMID- 12494292
TI  - Sexual dysfunction in male patients on hemodialysis: assessment with the
      International Index of Erectile Function (IIEF).
AB  - In this study we determine the sexual problems and the prevalence of erectile
      dysfunction (ED) in male hemodialysis patients by means of the International
      Index of Erectile Function (IIEF). A total of 187 male patients were included in
      the study. All of the patients who underwent hemodialysis were asked to complete
      the IIEF questionnaire. The IIEF domain scores were calculated and erectile
      dysfunction grading was determined on erectile function domain. Patients were
      also asked to report whether they had disclosed their sexual problems to
      physicians or not.The mean age was 49.3+/-13.2 y and the duration of hemodialysis
      was 38.1+/-8.4 months. By means of the IIEF, the prevalence of erectile
      dysfunction of any degree was 80.7%. The prevalence of any ED for the patients
      <50 y and >or=50 y was 74.5% and 86.6%, respectively. The prevalence and the
      severity of ED was significantly higher in patients >or=50 y. The frequency of
      intercourse attempts during the last four weeks was 1-2 in 130 (69.5%) of
      patients. Only 1% of patients disclosed their erectile problems and sought
      medical assistance prior to our study.Erectile dysfunction is highly prevalent in
      hemodialysis patients. The prevalence and the severity of ED increased with age.
      Evaluations for ED should be included in routine assessment of hemodialysis
      patients.

PMID- 12494294
TI  - Implantation of penile prosthesis in a patient with severe corporeal fibrosis
      induced by cavernosal injection therapy.
AB  - Implantation of a penile prosthesis in men with complicated fibrosis of corpus
      cavernosum is very difficult and even impossible. Cavernosal dilation requires
      sharp intracavernosal dissection to implant prosthesis, however complete removal
      of the fibrotic tissue is often impossible. We introduce a new technique using
      electric resection and electrovaporization of fibrotic tissue for implantation of
      penile prosthesis in a patient with severe corporeal fibrosis.

PMID- 12494295
TI  - Sildenafil use in patients with olanzapine-induced erectile dysfunction.
AB  - In the present study, we aimed to examine the efficacy of sildenafil in patients
      with an antipsychotic (olanzapine)-induced erectile dysfunction (ED). The study
      group comprised 10 patients who experienced ED associated with the use of
      olanzapine. The patients initially received 50 mg sildenafil at baseline. If
      clinically indicated, titration up to 100 mg was permitted. All patients were
      assessed by Clinical Global Impression-Improvement (CGI-I) and International
      Index of Erectile Dysfunction (IIEF) scales at baseline and weeks 2 and 4. At
      final assessment, three patients were considered 'very much improved' and four
      'much improved' according to CGI-I. Our results suggest that sildenafil use is
      effective and well-tolerated in patients with olanzapine-induced ED.

PMID- 12494299
TI  - Effects of dietary yoghurt on immunological and clinical parameters of
      rhinopathic patients.
AB  - OBJECTIVES: To examine the immunological and clinical influence of 4 months'
      feeding with either yoghurt or partially skimmed milk or nothing, on 20
      volunteers. SUBJECTS: Thirteen subjects had a demonstrated allergic rhinopathy
      and seven were healthy subjects and participated as controls. RESEARCH DESIGN:
      Either a group of seven or a group of six rhinopathic patients were fed either
      450 g yoghurt or 450 g partially skimmed milk, respectively, for 4 months between
      March and October 1999. All subjects maintained their usual diet throughout the
      study. Peripheral blood mononuclear cells (PBMC) were isolated before and after
      the experimental period and cultured for periods of 40 and 64 h. Proliferation
      index assay and release of IFNgamma and IL-4 without and with PHA stimulation
      were assessed. Allergic rhinopathy was evaluated before and after the 4 months
      period by performing the nasal functionality tests (Active Anterior
      Rhinomanometry, Acoustic Rhinometry), the prick test, the nasal specific
      provocation test (NPT), the dosage of specific IgE blood levels, the evaluation
      of the symptomatological score and the nasal mucociliary transport test. RESULTS:
      No significant change of the proliferation index was noted among the three
      groups. Cultured PBMC of the group fed with yoghurt released more IFNgamma and
      less IL-4. Cytokine plasma levels were at and remained at basal levels. Prick
      test, specific serum IgEs and NPT remained immodified. Muco-ciliary transport
      time (MCTt) and symptomatological score showed a definitive improvement after
      yoghurt feeding. CONCLUSION: Yoghurt feeding appears to improve or prevent
      allergic recurrences in rhinopatic patients.

PMID- 12494300
TI  - Changes in the intake of vitamins and minerals by men and women with
      hyperlipidemia and overweight during dietetic treatment.
AB  - OBJECTIVES: To assess the influence of a low-fat, low-energy diet on the intake
      of vitamins and minerals in patients with overweight and hyperlipidemia. SETTING:
      Outpatient clinic for hyperlipidemia treatment. SUBJECTS: A total of 134 subjects
      chosen from patients attending Outpatient Clinic of Metabolic Diseases.
      INTERVENTIONS: Patients were assigned to a hypolipidemic, low-energy diet of 4.18
      6.27 MJ/day (1000 or 1500 kcal/day), where fat provided less than 30% of energy,
      saturated fatty acids less than 10% of energy and daily supply of cholesterol was
      below 300 mg. Dietary assessment with the use of 3 days dietary records were
      performed at baseline and after 8 weeks of the diet. RESULTS: The implementation
      of a low-fat, low-energy diet resulted in a decrease of the intake of nutrients
      assessed, statistically significant for phosphorus, magnesium, iron and vitamin
      B(1), B(2) and niacin in men and for iron in women. No marked and statistically
      significant reduction in the percentage of the RDA was found, except magnesium,
      thiamin and riboflavin in men and iron in women. Nutritional density was
      statistically improved for phosphorus, potassium, magnesium and vitamins E, C and
      B(6) in men and for all nutrients assessed in women. CONCLUSIONS: In comparison
      with a habitual diet, the low-fat, low-energy diet did not cause any marked and
      statistically significant decrease in the intake of minerals and vitamins or in
      the adherence to the RDA, with the exception of magnesium, thiamin and riboflavin
      in men and iron in women.

PMID- 12494301
TI  - Mild iodine deficiency in a sample of New Zealand schoolchildren.
AB  - OBJECTIVE: To assess the iodine status of New Zealand schoolchildren. DESIGN: A
      proportionate to population size school-based cluster survey was used to randomly
      select children from two cities. The indicators used to assess iodine status were
      urinary iodine, as determined in a casual urine sample, and thyroid volume, as
      measured by ultrasonography. A qualitative food frequency questionnaire designed
      to ascertain frequency of consumption over the previous 3 months of foods or food
      groups that are good sources of dietary iodine, including iodized salt, was
      administered to each child. SETTING: Dunedin and Wellington, New Zealand.
      PARTICIPANTS: Three-hundred children aged 8-10 y from 30 schools. RESULTS: The
      median urinary iodine concentration of the children was 6.6 micro g/dl
      (interquartile range, 4.5-9.1). The percentage of children who had urinary iodine
      levels less than 5 micro g/dl was 31.4 (95% confidence interval (CI), 24.2-38.6).
      Comparison of thyroid volume with 2001 World Health Organization age/sex-specific
      and age/BSA-specific cut-off values resulted in a goitre prevalence of 11.3% (95%
      CI, 7.6-15.1) and 12.0% (95% CI, 7.9-16.1), respectively. Almost 30% of the
      children's caregivers did not use iodized salt in cooking and 51% of the children
      did not use iodized salt at the table. CONCLUSIONS: Mild iodine deficiency was
      found in this sample of children. Iodized table salt may no longer be making a
      significant contribution to the iodine intakes of New Zealand children.

PMID- 12494302
TI  - Efficacy of a multi-micronutrient dietary intervention based on haemoglobin, hair
      zinc concentrations, and selected functional outcomes in rural Malawian children.
AB  - OBJECTIVE: To investigate the efficacy of enhancing the content and
      bioavailability of micronutrients in diets of stunted rural Malawian children on
      their growth and body composition, morbidity, anaemia and hair zinc
      concentrations. DESIGN: A quasi-experimental design with non-equivalent control
      group involving 410 intervention and 220 control children aged 30-90 months.
      SETTING AND SUBJECTS: Children from two intervention and two control villages in
      Mangochi District, Southern Malawi participated in a 6 month dietary
      intervention. Anthropometry, malarial screening, haemoglobin, and hair zinc were
      measured at baseline and after 12 months, as well as socio-economic status at
      baseline, and common infections monthly post-intervention. RESULTS: Groups were
      comparable at baseline. Post-intervention children had greater Z-scores for lean
      body mass (mid-upper arm circumference -0.75 vs -1.05; arm muscle area: 0.63 vs 
      1.03, P<0.001) than controls but Z-scores for weight-for-height and height-for
      age were similar. After controlling for baseline variables, mean haemoglobin was
      higher (107 vs 102 g/l, P<0.01), whereas the incidence of both anaemia (62 vs
      80%) and common infections (based on a median overall illness score for fever,
      diarrhoea, upper and lower respiratory infections) were lower in intervention
      compared to controls, with no change in hair zinc concentrations or malaria
      status post-intervention. CONCLUSION: Improvements in the micronutrient adequacy
      of diets of post-intervention children were associated with a favourable increase
      in indices of lean body mass and reductions in the incidence of anaemia and
      common infections in these rural Malawian stunted children.

PMID- 12494303
TI  - The relation between single/double or repeated tea catechin ingestions and plasma
      antioxidant activity in humans.
AB  - OBJECTIVE: The purpose of this study was to investigate the effects of
      single/double or repeated intake of a normal amount of tea catechin on plasma
      catechin concentrations and antioxidant activity in young women. DESIGN: First,
      after an overnight fast, five healthy subjects were given water or single/double
      dose(s) of tea polyphenol extract (164 mg tea catechins containing 61%
      epigallocatechin gallate in 190 ml water). Blood samples were taken before and
      30, 60 and 180 min after the ingestion. Second, 16 healthy subjects ingested the
      tea polyphenol extract three times a day at mealtimes for 7 days followed by
      withdrawal of tea polyphenol extract for 7 days. Blood samples were taken before
      and after ingestion, and 7 days after the withdrawal of tea catechin. Subjects
      were prohibited from drinking any beverages containing polyphenols or antioxidant
      supplements during the study period. Catechin and other antioxidant
      concentrations in the plasma were measured, and changes in antioxidant activity
      were evaluated by ferric reducing ability of plasma assay. RESULTS: Single/double
      ingestion of tea polyphenol extract did not cause an increase in the antioxidant
      activity. There was no also change in antioxidant activity after the ingestion of
      tea polyphenol extract for 7 days. Plasma-free epigallocatechin gallate
      concentration remained at the pre-study level; however, the plasma FRAP value
      decreased significantly at 7 days after the withdrawal of tea polyphenol extract.
      Decreases in endogenous antioxidants in the plasma, including vitamin C and
      bilirubin, were also observed 7 days after withdrawal of tea polyphenol.
      CONCLUSIONS: The results suggest that continuous daily intake of tea catechins
      affects the concentrations of endogenous antioxidants in the plasma and has the
      potential to maintain total antioxidant activity.

PMID- 12494304
TI  - A chart to link child centiles of body mass index, weight and height.
AB  - BACKGROUND: Weight for height in children is often assessed by comparing the
      child's weight-for-age centile with their height-for-age centile. However, this
      assessment has not been validated statistically, and it differs from the body
      mass index (BMI) centile. OBJECTIVE: To study indices of weight-for-height based
      on weight centile-for-age adjusted for height centile-for-age, and to see how
      they relate to the BMI centile-for-age. DESIGN: Cross-sectional survey of data
      for 40 536 boys and girls aged 0-18 y from the 1980 Nationwide Dutch Growth
      Survey, using the British 1990 and US CDC 2000 growth references. OUTCOME
      MEASURES: Two measures of weight for height: (a) the difference between weight
      centile and height centile, and (b) BMI centile, with the centiles analysed as SD
      scores (SDS). RESULTS: BMI centile is correlated strongly with weight centile
      (r=0.77) but weakly with height centile (r=0.1). By contrast the difference
      between weight centile and height centile is correlated only weakly with weight
      centile (r=0.3) and strongly negatively with height centile (r=-0.5). BMI centile
      is predicted to high accuracy by the multiple regression on weight centile and
      height centile (93-97% of variance explained, s.e.e. 0.2 units). CONCLUSIONS: A
      child's BMI centile can be calculated to high accuracy from their weight and
      height centiles as read off the weight and height charts. This avoids the need to
      calculate BMI or to plot it on the BMI chart. A chart is provided to simplify
      this calculation, which works throughout the spectrum of nutritional status. It
      can also be used to monitor individuals' weight, height and BMI centiles
      simultaneously as they change over time. However the simpler procedure of
      comparing weight and height centiles (eg a difference of two or three channel
      widths) is a poor measure of weight-for-height and should not be used.

PMID- 12494305
TI  - Protein restriction, glomerular filtration rate and albuminuria in patients with
      type 2 diabetes mellitus: a randomized trial.
AB  - OBJECTIVE: Protein restriction delays the progression of non-diabetic and type 1
      diabetic renal disorders. This study assessed whether protein restriction delays
      the onset or early progression of renal disorders in type 2 diabetes. DESIGN:
      Randomized controlled trial. Outcomes were albuminuria (mg/24 h) and, as an
      estimate of the glomerular filtration rate, cimetidine-influenced creatinine
      clearance. SETTING: Primary care. SUBJECTS: Patients with type 2 diabetes and
      microalbuminuria or at least detectable albuminuria, or a diabetes duration >5 y.
      INTERVENTIONS: The experimental group received dietary counselling on protein
      restriction (n=63); a control group (n=68) received the usual dietary advice. The
      duration of intervention and follow-up was 28+/-7 months. RESULTS: After 6
      months, protein intake differed only by 0.08 g/kg/day between the study groups.
      Subsequently, this difference decreased and eventually disappeared. An initial
      effect of protein restriction on albuminuria in favor of the experimental group
      was not sustained, and the glomerular filtration rate decreased in the
      experimental group at a 1.6+/-2.2 ml/min/1.73 m(2) y lower rate than in the
      control group (P=0.5). Comparison of patients in the experimental group with a
      decrease in protein intake of at least 0.20 g/kg/day, with controls with no
      decrease, indicated a similarly small and insignificant effect on glomerular
      filtration rate. CONCLUSIONS: It is concluded that, in the longer term prevention
      or delay of renal damage in patients with type 2 diabetes, protein restriction is
      neither feasible nor efficacious.

PMID- 12494306
TI  - Anthropometric measurements in both sides of the body in the assessment of
      nutritional status in prepubertal children.
AB  - OBJECTIVE: To analyze the impact of choosing the left or the right side of the
      body on the anthropometric measurements and derived nutritional indices, in
      prepubertal children. DESIGN: Cross-sectional pilot nutrition survey. SETTING:
      General prepubertal school-age population. SUBJECTS: One-hundred and sixty-four
      children (97 boys and 67 girls) aged 7-9 y. INTERVENTIONS: None. RESULTS: The
      agreement between anthropometric measurements in both sides of the body showed
      that in males and in females, suprailiac skinfold thickness and arm circumference
      were significantly higher in the left than in the right side of the body. The
      agreement between body composition assessed by anthropometric measurements in
      both sides of the body showed that only in males was arm muscle area
      significantly higher in the left than in the right side, and arm fat percentage
      was higher in the right than in the left side of the body. Total body fat
      percentage calculated from skinfold thickness did not show statistically
      significant differences when skinfolds were obtained in the both sides of the
      body, either in boys and in girls. CONCLUSIONS: Our results show that differences
      between the sides of the body were lower than the technical error of measurement
      of the anthropometric measurements obtained and seem not to be biologically
      significant in this age group. It is necessary to standardize the method of
      anthropometric assessment of the nutritional status in terms of body side.

PMID- 12494307
TI  - Cooking of meat and fish in Europe--results from the European Prospective
      Investigation into Cancer and Nutrition (EPIC).
AB  - OBJECTIVES: There is epidemiologic evidence that the consumption of fried,
      grilled or barbecued meat and fish that are well-done or browned may be
      associated with an increased cancer risk. These high-temperature cooking methods
      are thought to be surrogates for mutagens and carcinogens produced in meat and
      fish, eg heterocyclic amines or polycyclic hydrocarbons. Since data on food
      cooking methods are scarce, the aim of this study was to describe the variation
      in meat and fish cooking methods in different parts of Europe. DESIGN: Using a
      standardized 24 h recall from a sub-sample of the EPIC cohort (35 644 persons, 35
      75 y old), mean daily intake of meat and fish prepared by different cooking
      methods and the relative contribution of the cooking methods to the overall
      cooking of meat and fish was calculated. RESULTS: Whereas frying was more often
      noted in northern Europe, roasting and stir frying were more often used in the
      south. Concerning high-temperature cooking methods, their frequency of
      application varies between 15% in the EPIC cohort of North-Italy and 49% in the
      cohort of The Netherlands. Average consumption of fried, grilled and barbecued
      meat and fish ranges from a low of 12 g/day in the centres in southern Spain to a
      high of 91 g/day in northern Spain. CONCLUSION: High variation in both the kind
      of meat/fish consumed as well as its cooking methods is observed within EPIC. In
      order to use this variation for the evaluation of the impact of cooking methods
      on cancer risk, a questionnaire on meat and fish cooking methods is being
      developed and could be applied in the whole EPIC cohort.

PMID- 12494308
TI  - Determinants of growth failure in 12-24-month-old children in a high-density
      urban slum community in East London, South Africa.
AB  - OBJECTIVE: The study's main objectives were the identification of determinants of
      growth failure in 12-24-month-old children from an urban slum community attending
      a day hospital as well as the identification of focus areas for intervention.
      DESIGN: The research was executed as a case-control study with a one-to-two
      design. A hypothetical causal model was developed for the undernutrition
      situation in Duncan Village. A questionnaire to assess the direct and underlying
      causes of growth failure in the study population was developed from this model.
      SUBJECTS: One-hundred and fifty children were selected for the study, with 100
      children in the control group and 50 children in the growth-failure group. Each
      child in the growth-failure group was matched with two children in the control
      group based on age and sex. The children were chosen according to anthropometric
      indices and p-albumin levels. SETTING: The research was conducted at a primary
      health care centre in Duncan Village, an overpopulated urban slum area in East
      London, a small city on the east coast of South Africa. RESULTS: No significant
      differences were found between the two groups for the occurrence of disease and
      infection. Dietary intake seemed to be generally poor in all the children. No
      significant differences were found between the two groups for the indicators of
      household food security, health service utilization and environmental conditions.
      The most important underlying determinants of growth failure that were identified
      in the study population seem to be related to the caring capacity, and the
      resultant caring behaviours of mothers. The risk for growth failure is increased
      when a child has a mother who is not the head of the household (relative risk)
      (RR=4.3), who is not involved with the discipline of her children (RR=2.2), who
      is not the guardian of the child (RR=8), who was not born in Duncan Village or in
      a city (RR=2.16), who is not able to write (RR=2.7) or read Xhosa (RR=2.53), who
      has a school education of <or=grade 9 (RR=2.9), who did not receive nutrition
      education (RR=2.2), who smokes (RR=10) and drinks beer regularly (RR=10), who has
      a BMI <25 (RR=2.7), who was subjectively judged to show little interest in her
      child (RR=4) as well as an inadequate caring attitude towards her child
      (RR=3.61), and whose clothing was dirty (RR=2.7) and not tidy (RR=2.9). Further
      determinants included the following: a child who weighed <2500 g at birth
      (RR=4.96), who had not received supplemental milk while still breast-fed
      (RR=2.00), who did not receive baby cereal as first food (RR=2.6), whose clothes
      (RR=2.7) were dirty and whose hands were infrequently washed (RR=10).
      CONCLUSIONS: The results of this research suggest that initiatives to address the
      problem of growth failure in 12-24-month-old children attending the Duncan
      Village Day Hospital should focus mainly on improving the caring capacity of
      mothers in the study area.

PMID- 12494309
TI  - Fatty acid and sn-2 fatty acid composition in human milk from Granada (Spain) and
      in infant formulas.
AB  - OBJECTIVE: To investigate differences in fatty acid and sn-2 fatty acid
      composition in colostrum, transitional and mature human milk, and in term infant
      formulas. SETTING: Departament de Nutricio i Bromatologia, University of
      Barcelona, Spain and University Hospital of Granada, Spain. SUBJECTS: One-hundred
      and twenty mothers and 11 available types of infant formulas for term infants.
      DESIGN: We analysed the fatty acid composition of colostrum (n=40), transitional
      milk (n=40), mature milk (n=40) and 11 infant formulas. We also analysed the
      fatty acid composition at sn-2 position in colostrum (n=12), transitional milk
      (n=12), mature milk (n=12), and the 11 infant formulas. RESULTS: Human milk in
      Spain had low saturated fatty acids, high monounsaturated fatty acids and high
      linolenic acid. Infant formulas and mature human milk had similar fatty acid
      composition. In mature milk, palmitic acid was preferentially esterified at the
      sn-2 position (86.25%), and oleic and linoleic acids were predominantly
      esterified at the sn-1,3 positions (12.22 and 22.27%, respectively, in the sn-2
      position). In infant formulas, palmitic acid was preferentially esterified at the
      sn-1,3 positions and oleic and linoleic acids had higher percentages at the sn-2
      position than they do in human milk. CONCLUSION: Fatty acid composition of human
      milk in Spain seems to reflect the Mediterranean dietary habits of mothers.
      Infant formulas resemble the fatty acid profile of human milk, but the
      distribution of fatty acids at the sn-2 position is markedly different.

PMID- 12494312
TI  - Dietary and lifestyle interventions in the management of the metabolic syndrome:
      present status and future perspective.
AB  - OBJECTIVE: To review the mechanisms underlying the metabolic syndrome, or
      syndrome X, in humans, and to delineate dietary and environmental strategies for
      its prevention. DESIGN: Review of selected papers of the literature. RESULTS:
      Hyperinsulinemia and insulin resistance play a key role in the development of the
      metabolic syndrome. Strategies aimed at reducing insulin resistance may be
      effective in improving the metabolic syndrome. They include low saturated fat
      intake, consumption of low-glycemic-index foods, physical exercise and prevention
      of obesity. CONCLUSIONS: Future research, in particular the genetic basis of the
      metabolic syndrome and the interorgan interactions responsible for insulin
      resistance, is needed to improve therapeutic strategies for the metabolic
      syndrome.

PMID- 12494313
TI  - A brief review of the archaeological evidence for Palaeolithic and Neolithic
      subsistence.
AB  - Knowledge of our ancestor's diets is becoming increasingly important in
      evolutionary medicine, as researchers have argued that we have evolved to
      specific type of 'Palaeolithic' diet, and many modern nutritional disorders
      relate to the mismatch between the diet to which we have evolved, and the
      relatively newer agricultural-based 'Neolithic' diets. However, what is the
      archaeological evidence for pre-agricultural diets and how have they changed over
      the four million years of hominid evolution? This paper briefly introduces the
      three lines of evidence we have for Palaeolithic and Neolithic diets;
      morphological changes, archaeological material evidence, and direct measurement
      of diet from bone chemistry. The morphological changes, increasing gracilization
      of the mandible and increasing brain size have been interpreted (based on
      analogies with living primates) as the move from plants to higher-quality, more
      digestible, animal meat, although this is debated. The archaeological evidence is
      especially weak, as many organic materials, especially plants, do not survive
      well, and are therefore invisible in the archaeological record. Artefacts, such
      as stone tools which are likely to be used for hunting and animal bones with
      evidence of human processing and butchering do indicate that hunting did occur at
      many times in the past, but it is impossible to judge the frequency. Direct
      evidence from bone chemistry, such as the measurement of the stable isotopes of
      carbon and nitrogen, do provide direct evidence of past diet, and limited studies
      on five Neanderthals from three sites, as well as a number of modern Palaeolithic
      and Mesolithic humans indicates the importance of animal protein in diets. There
      is a significant change in the archaeological record associated with the
      introduction of agriculture worldwide, and an associated general decline in
      health in some areas. However, there is an rapid increase in population
      associated with domestication of plants, so although in some regions individual
      health suffers after the Neolithic revolution, as a species humans have greatly
      expanded their population worldwide.

PMID- 12494314
TI  - Sphincterotomy and the treatment of detrusor-sphincter dyssynergia: current
      status, future prospects.
AB  - STUDY DESIGN: Literature review of current treatment options for detrusor
      sphincter dyssynergia (DSD) in spinal cord injury. OBJECTIVES: To review the
      outcomes and complications associated with external sphincterotomy and to
      summarise the results and complications of alternative treatment options for
      detrusor-sphincter dyssynergia in spinal cord injury. In addition, we propose a
      potential alternative future drug treatment for external sphincter dyssynergia
      based upon recent research on the neuropharmacology of the external urethral
      sphincter. SETTING: The National Spinal Injuries Centre, Stoke Mandeville
      Hospital, Aylesbury, UK. METHODS: Medline search from 1966 to 2002 using the
      words 'external sphincterotomy', 'detrusor-sphincter dyssynergia' and 'neurogenic
      bladder combined with surgery'. RESULTS: While external sphincterotomy is an
      effective treatment for DSD, a significant number of men following this procedure
      continue to have high intrarenal pressures, recurrent urinary infection or
      troublesome autonomic dysreflexia and a worryingly high proportion demonstrate
      persistently raised leak point pressures, putting them at subsequent risk of
      renal damage. Alternative treatments for external sphincter dyssynergia include
      urethral stents and balloon dilatation, both of which are effective. However,
      over the long term stents can undergo encrustation and there remains a definite
      risk of stent migration necessitating stent removal or replacement. Balloon
      dilatation of the external sphincter is associated with a risk of subsequent
      stricture formation. Intraurethral Botulinum A toxin seems to be effective though
      there have been no large randomised studies comparing it against placebo.
      However, it is not a durable treatment option and it has not found a common place
      in the treatment of DSD. There is now a considerable amount of experimental data
      from both animal and human studies to suggest that nitric oxide (NO) is an
      important physiological inhibitory neurotransmitter in the urethral sphincter,
      mediating relaxation of the external urethral sphincter. The potential role of
      sphincter NO augmentation for treatment of DSD is discussed. CONCLUSION: External
      sphincterotomy remains the mainstay of treatment for urodynamically significant
      detrusor-sphincter dyssynergia, but in recent years a number of effective,
      alternative treatment options have become available. While at present there is no
      effective systemic drug treatment, recent research into external sphincter
      neuropharmacology suggests that systemic or topical augmentation of external
      sphincter NO may provide an effective method for lowering sphincter pressure.

PMID- 12494315
TI  - Effect of the trauma mechanism on the bladder-sphincteric behavior after spinal
      cord injury.
AB  - STUDY DESIGN: Retrospective study. OBJECTIVE: To determine if spinal cord
      injuries due to gunshot wounds (GW) are associated with different bladder and
      sphincteric behavior compared to other trauma mechanisms. SETTING: Spinal injury
      center, Brazilian university hospital. METHODS: We retrospectively evaluated the
      records and urodynamic studies of 71 patients with spinal cord injury (SCI)
      referred to the Brazilian National Spinal Cord Injury Center over the year 2000,
      and compared the bladder-sphincteric pattern of patients with injuries caused by
      GW with those caused by other trauma mechanisms. RESULTS: The causes of SCI were
      (1) gunshot wounds (31 patients: 43.7%); (2) motor vehicle accidents (16
      patients: 22.5%); (3) falls (16 patients: 22.5%) and (4) diving (three patients:
      4.2%). In five patients (7.1%) the causes were unusual trauma mechanisms like
      stab wound (one patient) and direct trauma in vigorous sports (two patients) or
      fights (two patients). The levels of the injuries were cervical in 22 patients
      (31.0%), thoracic in 39 (54.9%) and lumbar in 10 (14.1%). Detrusor hyperreflexia
      with detrusor-sphincter dyssynergia was present in 65% of the patients overall
      and in 76% of the thoracic gunshot wounded. Areflexia occurred in 20% of the
      patients and in 16% of thoracic injured patients with gunshots. Detrusor
      hyperreflexia with detrusor-sphincter dyssynergia was the pattern encountered in
      50% of the individuals suffering from SCI because of other mechanisms and
      areflexia was present in 35.8%. There was no statistical difference between GW
      patients and other mechanisms according to bladder and sphincter functions.
      CONCLUSIONS: There was a substantial overlap of bladder and sphincteric behaviors
      between patients with different levels of spinal injuries, but the trauma
      mechanism was not important to determine the bladder and sphincteric functions.

PMID- 12494316
TI  - The effect of ketamine/xylazine anesthesia on sensory and motor evoked potentials
      in the rat.
AB  - STUDY DESIGN: Experimental laboratory investigation of the effect of anesthesia
      on evoked potentials in rats. OBJECTIVES: To define the optimal ketamine/xylazine
      anesthesia levels for the recording of different evoked potentials. SETTING:
      BioSurgery Preclinical Department, Baxter BioScience, Vienna, Austria. METHODS:
      Rats were implanted with cranial screws that allow stimulation and recording of
      evoked potentials. Somatosensory evoked potentials (SEPs), brainstem-derived
      motor evoked potentials (BMEPs) and corticomotor evoked potential (CMEPs) were
      recorded under different levels of anesthesia. The recorded signals were
      evaluated by measuring their latencies and amplitudes. The level of anesthesia
      was assessed by scoring the hind limb withdrawal reflex. RESULTS: All three
      signals showed a strong dependency on the level of anesthesia. The observed
      effects, however, differed between the three signals. SEP amplitudes and
      latencies declined as animals slowly transgressed from deep to light anesthesia.
      In contrast, BMEP amplitudes were larger and latencies shorter in light
      anesthesia than in deep anesthesia. CMEPs finally were hard to record under deep
      anesthesia, but were easily recorded in light anesthesia. BMEPs that were
      recorded during light anesthesia also showed a significant change in
      configuration that was coupled with a notable increase in the variability of its
      amplitudes. CONCLUSIONS: The level of ketamine/xylazine anesthesia affects evoked
      potentials and thus should be controlled during electrophysiological recording.
      Our results suggest that SEPs should be best recorded during deep anesthesia,
      while BMEPs and CMEPs are best recorded during intermediate and light anesthesia.

PMID- 12494317
TI  - Effects of testosterone replacement therapy on skeletal muscle after spinal cord
      injury.
AB  - STUDY DESIGN: Randomized control. OBJECTIVE: To examine the effects of
      testosterone replacement therapy (TRT) on skeletal muscle 11 weeks after complete
      SCI. SETTING: Athens, Georgia USA. METHODS: Soleus (SOL), gastrocnemius (GA),
      tibialis anterior (TA), vastus lateralis (VL) and triceps brachii (TRI) muscles
      were taken from twelve young male Charles River rats 11 weeks after complete SCI
      (T-9 transection, n=8) or sham surgery (n=4). Rats received either TRT (two 5 cm
      capsules, n=4) or empty capsules (n=8) implanted at surgery. Muscle samples were
      sectioned and fibers analyzed qualitatively for myosin ATPase and quantitatively
      for succinate dehydrogenase (SDH), alpha-glycerol-phosphate dehydrogenase (GPDH)
      and actomyosin ATPase (qATPase) activities using standard techniques. RESULTS:
      SCI decreased average fiber size (49+/-4%) in affected muscles and the percentage
      of slow fibers in SOL (93+/-3% to 17+/-2%). In addition, there was a decrease in
      SDH and an increase in GPDH and qATPase activities across the four hind-limb
      muscles of the SCI animals. Fiber size in the TRI was increased (31+/-2%) by SCI
      while enzyme activities were not altered. Average fiber size across the four hind
      limb muscles was decreased by only 30% in TRT SCI animals and their SOL contained
      39+/-2% slow fibers. TRT also attenuated changes in enzyme activities. There was
      no effect of TRT on the TRI relative to SCI. CONCLUSIONS: TRT was effective in
      attenuating alterations in myofibrillar proteins during 11 weeks of SCI in
      affected skelatal muscles. SPONSORSHIP: Supported by a grant from The National
      Institutes of Health (HD-33738) and HD-37645 to KV, and HD-39676 to GAD.

PMID- 12494318
TI  - Endoprosthesis in paraplegics with periarticular ossification of the hip.
AB  - STUDY DESIGN: Clinical study. OBJECTIVES: To evaluate indications of hip
      endoprosthesis in periarticular ossifications. SETTING: A Spinal Cord Injury
      Centre in Germany. METHODS: Clinical examination, X-ray control. RESULTS: Surgery
      of periarticular ossification (paraosteoarthropathy, POA) either involves simple
      resection of the ossification or removal of the hip. The latter has an impact on
      the sitting posture with concomitant increased pressure sore risk. Nevertheless
      the hip is biomechanically important in paraplegics. We are investigating the
      outcome of total hip replacement (THR) in patients with ankylosis due to
      periarticular ossification. Six hip replacement cases seen in follow-up of up to
      24 months showed no loosening, with good mobility of the joint. We follow a
      strict perioperative POA prophylaxis, which resulted in each case reporting only
      a slight recurrence (Brooker 1-2) without any loss of functional mobility.
      CONCLUSION: In ankylotic hips with mobility/social/hygenic problems we favour a
      hip replacement in cases with osteoarthritis or high risk of osteoporotic
      fracture. A replacement of the joint should be preferred to a Girdlestone
      operation.

PMID- 12494319
TI  - Long-term exercise training in persons with spinal cord injury: effects on
      strength, arm ergometry performance and psychological well-being.
AB  - STUDY DESIGN: Randomized controlled trial of exercise training in persons with
      spinal cord injury. OBJECTIVE: The purpose of this study was to examine the
      effects of 9 months of twice-weekly exercise training on strength, arm ergometry
      performance, and indices of psychological well-being and quality of life.
      SETTING: Centre for Health Promotion and Rehabilitation, McMaster University,
      Hamilton, Ontario, Canada. METHODS: Thirty-four men and women (aged 19-65 years)
      with traumatic spinal cord injury (C4-L1; ASIA A-D) of 1-24 years duration
      volunteered to participate, and were randomized into exercise (EX; n=21) and
      control (CON; n=13) groups. Twenty-three subjects (11 EX; 12 CON) successfully
      completed the 9-month study. Subjects were assessed for one repetition maximum
      (1RM) strength, arm ergometry performance, and several indices of quality of life
      and psychological well-being at baseline, 3, 6, and 9 months. RESULTS: At
      baseline, there were no significant differences between groups in age, submaximal
      arm ergometry performance, muscle strength, or psychological well-being.
      Following training, the EX group had significant increases in submaximal arm
      ergometry power output (81%; P<0.05), and significant increases in upper body
      muscle strength (19-34%; P<0.05); no significant changes occurred in CON.
      Participants in EX reported significantly less pain, stress and depression after
      training, and scored higher than CON in indices of satisfaction with physical
      function, level of perceived health and overall quality of life (P<0.05).
      Exercise adherence (per cent of prescribed sessions attended) in those subjects
      who completed the 9 months of training was 82.5%. CONCLUSIONS: These results
      demonstrate that long-term twice-weekly exercise training in this population is
      feasible, and results in significant gains in both physical and psychological
      well-being.

PMID- 12494320
TI  - Comparative analysis of goal achievement during rehabilitation for older and
      younger adults with spinal cord injury.
AB  - OBJECTIVE: To evaluate rehabilitation outcome in a representative sample of older
      and younger SCI patients. DESIGN: Case series, consecutive sample, survey.
      SETTING: Tertiary care, spinal cord injury unit (National Spinal Injuries
      Centre), Stoke Mandeville Hospital. PARTICIPANTS: One hundred and forty-seven
      male and 45 female newly injured in-patients (consisting of 152 younger adults,
      age range=16 to 54, and 40 older adults, age range=55 to 85) admitted between
      1995 and 1999. INTERVENTION: All patients were actively participating in a
      comprehensive, multidisciplinary Goal Planning and Needs Assessment
      rehabilitation programme. MAIN OUTCOME MEASURE: The Needs Assessment Checklist.
      Specifically designed and developed for the spinal cord injured population, this
      clinical assessment tool provides a way of assessing and ensuring that
      rehabilitation programmes are geared toward each patient's individual needs,
      providing the patient with the skills appropriate to their level of lesion. As
      part of ongoing psychometric analyses of the Needs Assessment Checklist, internal
      consistency reliability coefficients are reported for this measure. RESULTS: The
      type and cause of injury for the older adult group in this study was comparable
      with previous research. Older adults' rehabilitation gains were comparable to
      those of the younger age group. Younger adults were more mobile initially after
      their injury. However, when the two groups were matched for injury
      characteristics etc. the only differences in final outcome between older and
      younger adults were in skin management ability. Both groups showed significant
      improvements in all areas of need in the period between mobilisation and entering
      the pre-discharge ward. CONCLUSION: These results highlight important
      considerations for the rehabilitation of older adults and emphasise the need for
      active, individually tailored rehabilitation programmes. There are specific areas
      of need (i.e. skin management) where older adults do not achieve comparable
      levels of independence. Special attention needs to be paid to the problems
      presented by SCI older adults and efforts should be made to better prepare
      rehabilitation professionals to adapt to age specific differences.

PMID- 12494321
TI  - Sudden onset of paraparesis caused by hypertrophy of the thoracic posterior
      longitudinal ligament.
AB  - STUDY DESIGN: Case report of a rare form of hypertrophy of the thoracic posterior
      longitudinal ligament (HPLL), causing paraparesis. OBJECTIVE: To describe this
      very rare pathological condition in the thoracic spine and the results of
      surgical intervention. SETTING: A department of orthopaedic surgery in Japan.
      METHODS: A 61-year-old man presented with acute paraparesis associated with HPLL
      in the thoracic region. A radiographic and pathological review of the case was
      conducted. Anterior decompression was performed, and he was followed for 3 years
      after the operation. RESULTS: Pathologic examination of the surgical specimen
      revealed proliferation of fibrocartilage and calcification. The patient's
      paraparesis ameliorated after the operation. CONCLUSION: For this case of
      myelopathy due to HPLL in the thoracic spine, urgent decompression gave excellent
      results. Clinical awareness of HPLL may aid correct diagnosis and prompt therapy.

PMID- 12494328
TI  - Inhibition of cytochrome P450 3A4 by extracts and kavalactones of Piper
      methysticum (Kava-Kava).
AB  - Inhibitors of cytochrome P450 3A4 (CYP3A4) were identified in crude extracts from
      the rhizomes of Piper methysticum G. Forst. (Kava-Kava) using bioassay-guided
      fractionation. After preliminary purification of an ethyl acetate extract with
      solid phase extraction, the eluate was further fractionated by means of HPLC and
      fractions were tested for inhibitory potency using cDNA expressed CYP3A4.
      Positive fractions were analysed with LC/MS using electrospray ionisation and
      kavapyrones could be identified as the main CYP3A4 inhibitory components of Piper
      methysticum.

PMID- 12494329
TI  - Structure-activity relationships of flavonoids, isolated from Scutellaria
      baicalensis, binding to benzodiazepine site of GABA(A) receptor complex.
AB  - Twenty-six flavonoids were isolated from Scutellaria baicalensis. Their
      affinities for the benzodiazepine (BDZ) binding site of GABA A receptor have been
      studied using [ 3H]flunitrazepam binding to rat cortical membranes in vitro. The
      structure-activity relationships suggested that 2'-OH flavones exhibited the most
      potent binding affinity, which could lead to the design and discovery of new BDZ
      receptor ligands.

PMID- 12494330
TI  - Inhibition of VHR dual-specificity protein tyrosine phosphatase activity by
      flavonoids isolated from Scutellaria baicalensis: structure-activity
      relationships.
AB  - Three flavonoids: norwogonin, dihydronorwogonin and baicalein, were isolated from
      the roots of Scutellaria baicalensis, as potential inhibitors of VHR dual
      specificity protein tyrosine phosphatase (DS-PTPase). Norwogonin (IC 50 = 1.1
      microM), dihydronorwogonin (IC 50 = 2.9 microM) and baicalein (IC 50 = 2.4
      microM) showed potent inhibitory activity toward VHR, but had no inhibitory
      activity against T-cell protein tyrosine phosphatase or serine/threonine protein
      phosphatase 1. From comparisons to the inhibitory activities of other similar
      flavonoids, it could be suggested that the presence of a hydroxy group in the B
      ring of flavonoids interferes with the inhibitory activity toward VHR DS-PTPase.

PMID- 12494331
TI  - In vitro inhibition of [3H]-angiotensin II binding on the human AT1 receptor by
      proanthocyanidins from Guazuma ulmifolia bark.
AB  - A bioassay-guided fractionation of the 70% acetone extract of the bark of Guazuma
      ulmifolia Lam. on the inhibition of angiotensin II binding to the AT 1 receptor
      led to the isolation and identification of bioactive oligomeric and polymeric
      proanthocyanidins consisting mainly of (-)-epicatechin units. The displacement of
      [3H]-angiotensin II binding was dose-dependent and correlated with the degree of
      polymerization of the different fractions containing proanthocyanidins. A strong
      displacement was seen for the residual fraction suggesting that the most active
      substances corresponding to the highly polymerized proanthocyanidins. Angiotensin
      II AT 1 receptor binding might be considered as a potentially interesting
      biological activity of proanthocyanidins contributing to the very broad spectrum
      of biological activities of the condensed tannins.

PMID- 12494332
TI  - Yam (Dioscorea batatas) tuber mucilage exhibited antioxidant activities in vitro.
AB  - The yam (Dioscorea batatas Decne) tuber mucilage (YTM) was extracted and
      partially purified by SDS and heating treatments. This purified YTM exhibited
      antioxidant activities in a series of in vitro tests, including 1,1-diphenyl-2
      picrylhydrazyl (DPPH) radical (half-inhibition concentration, IC 50, was 0.86
      mg/mL) and hydroxyl radical (IC 50 was 22 microg/mL) scavenging activity assays,
      reducing power test, anti-lipid peroxidation and anti-human low density
      lipoprotein peroxidation tests (IC 50 was 145.46 microg/mL) using butylated
      hydroxytoluene (BHT), reduced glutathione, or ascorbic acid for comparisons. With
      electron paramagnetic resonance (EPR) spectrometry for DPPH radical detection,
      the intensities of the EPR signals were decreased by the increased amounts of YTM
      added (IC 50 was 1.62 mg/mL). These results suggest that mucilage of yam tuber
      might play roles as antiradicals and antioxidants.

PMID- 12494333
TI  - Dihydroisotanshinone I protects against menadione-induced toxicity in a primary
      culture of rat hepatocytes.
AB  - Dihydroisotanshinone I is a phenanthrenequinone derivative isolated from the
      roots of Salvia trijuga Diels. The present study demonstrated the
      hepatoprotective effect of dihydroisotanshinone I against menadione-induced
      cytotoxicity in a primary culture of rat hepatocytes. Pretreating the cells with
      dihydroisotanshinone I at concentrations ranging from 2.5 microM to 20 microM for
      24 hours caused dose-dependent protection against hepatotoxicity induced by
      menadione. Intracellular glutathione level and activity of DT-diaphorase have
      been suggested to play important roles in menadione-induced cytotoxicity.
      However, treating the hepatocytes with 20 microM dihydroisotanshinone I for 24
      hours did not cause a significant change in glutathione level and DT-diaphorase
      activity. On the contrary, adding dihydroisotanshinone I to freshly isolated
      hepatocytes at concentrations between 50 nM to 200 nM inhibited NADH-induced
      superoxide production dose-dependently as indicated by the decrease of lucigenin
      amplified chemiluminescence. In addition, dihydroisotanshinone I at
      concentrations ranging from 5 microM to 20 microM inhibited tert-butyl
      hydroperoxide-induced lipid peroxidation dose-dependently in isolated hepatocytes
      as indicated by the level of malondialdehyde. These results suggest that the
      protective action of dihydroisotanshinone I against menadione-induced
      hepatotoxicity is attributed to its antioxidant properties including the free
      radical scavenging activity and inhibition of lipid peroxidation. Abbreviations.
      DTD:DT-diaphorase GSH:glutathione LDH:lactate dehydrogenase MDA:malondialdehyde
      MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide TBHP: tert-butyl
      hydroperoxide

PMID- 12494334
TI  - Antimicrobial activity of the essential oil and some isolated sulfur-rich
      compounds from Scorodophloeus zenkeri.
AB  - The essential oil and several pure sulfur compounds isolated from Scorodophloeus
      zenkeri were tested for their antibacterial and antifungal activity using a paper
      disc method, the poisoned food technique, a microatmosphere method and the
      measurement of cellular ATP content. The essential oil completely inhibited the
      growth of all fungi tested including yeasts, with the exception of Aspergillus
      flavus, and was active against the Gram-positive bacteria studied, but not the
      Gram-negative organisms. 2,4,5,7-Tetrathiaoctane, 2,4,5,6,8-pentathianonane,
      2,3,4,6,8-pentathianonane, 2,3,5,6,8,10-hexathiaundecane, 2,3,5-trithiahexane 5
      oxide, 2,4,5,7-tetrathiaoctane 2-oxide, 2,3,5,7-tetrathiaoctane 3,3-dioxide and
      2,3,5-trithiahexane 3,3-dioxide differed in their effects on the strains studied
      with respect to both growth and synthesis of cellular ATP. 2,3,5-Trithiahexane,
      2,3,4,6-tetrathiaheptane, methyl methanethiosulfonate and bis-methyl
      sulfonylmethane exhibited no antimicrobial activity.

PMID- 12494335
TI  - Antimalarial agents from plants. III. Trichothecenes from Ficus fistulosa and
      Rhaphidophora decursiva.
AB  - Bioassay-directed fractionation of an extract prepared from the dried leaves and
      stem barks of Ficus fistulosa Reinw. ex Blume (Moraceae) led to the isolation of
      verrucarin L acetate (1), together with 3alpha-hydroxyisohop-22(29)-en-24-oic
      acid, 3beta-gluco-sitosterol, 3,4-dihydro-6,7-dimethoxyisocarbostyril, 3,4,5
      trimethoxybenzyl alcohol, alpha-methyl-3,4,5-trimethoxybenzyl alcohol, indole-3
      carboxaldehyde, palmanine, and aurantiamide acetate. Roridin E (2) was identified
      in a subfraction from the dried leaves and stems of Rhaphidophora decursiva
      Schott (Araceae). Verrucarin L acetate and roridin E were characterized as
      macrocyclic trichothecene sesquiterpenoids and found to inhibit the growth of
      Plasmodium falciparum with IC 50 values below 1 ng/ml.

PMID- 12494336
TI  - Kavalactones and dihydrokavain modulate GABAergic activity in a rat gastric
      brainstem preparation.
AB  - Using an in vitro neonatal rat gastric-brainstem preparation, the activity of
      majority neurons recorded in the nucleus tractus solitarius (NTS) of the
      brainstem were significantly inhibited by GABA A receptor agonist, muscimol (30
      microM), and this inhibition was reversed by selective GABA A receptor
      antagonist, bicuculline (10 microM). Application of kavalactones (300 microg/ml)
      and dihydrokavain (300 microM) into the brainstem compartment of the preparation
      also significantly reduced the discharge rate of these NTS neurons (39 % and 32
      %, respectively, compared to the control level), and this reduction was partially
      reversed by bicuculline (10 microM). Kavalactones or dihydrokavain induced
      inhibitory effects were not reduced after co-application of saclofen (10 microM;
      a selective GABA B receptor antagonist) or naloxone (100 nM; an opioid receptor
      antagonist). Pretreatment with kavalactones (300 microg/ml) or dihydrokavain (300
      microM) significantly decreased the NTS inhibitory effects induced by muscimol
      (30 microM), approximately from 51 % to 36 %. Our results demonstrated modulation
      of brainstem GABAergic mechanism by kavalactones and dihydrokavain, and suggested
      that these compounds may play an important role in regulation of GABAergic
      neurotransmission.

PMID- 12494337
TI  - Cardiovascular effects of the essential oil of Alpinia zerumbet leaves and its
      main constituent, Terpinen-4-ol, in rats: role of the autonomic nervous system.
AB  - Cardiovascular effects of intravenous ( i. v.) treatment with the essential oil
      of Alpinia zerumbet (EOAZ) were investigated in rats. Additionally this study
      examined (I) whether the autonomic nervous system is involved in the mediation of
      EOAZ-induced changes in mean aortic pressure (MAP) and heart rate (HR), and (II)
      whether these changes could be, at least in part, attributed to the actions of
      terpinen-4-ol (Trp-4-ol), the major constituent of EOAZ. In both pentobarbitone
      anaesthetised and conscious rats, i. v. bolus injections of EOAZ (1 to 20 mg/kg)
      elicited immediate and dose-dependent decreases in MAP. In anaesthetised rats,
      EOAZ decreased HR only at higher doses (10 and 20 mg/kg), while changes of this
      parameter were not uniform in conscious rats. Hypotensive responses to EOAZ were
      of the same order of magnitude or duration, irrespective of whether the animal
      was under general anaesthesia. Pretreatment of anaesthetised rats with bilateral
      vagotomy did not modify significantly the hypotensive and bradycardic responses
      to EOAZ. In conscious rats, i. v. injections of bolus doses (1 to 10 mg/kg) of
      Trp-4-ol also elicited immediate and dose-dependent decreases in MAP. However,
      these hypotensive effects were significantly greater than those evoked by the
      same doses of EOAZ (1 to 10 mg/kg). Intravenous pretreatment of conscious rats
      with either methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) had no
      significant effects on the EOAZ-induced hypotension. These data show that i. v.
      treatment with the EOAZ in either anaesthetised or conscious rats induced an
      immediate and significant hypotension, an effect that could be partially
      attributed to the actions of Trp-4-ol. The hypotension appears independent of the
      presence of an operational sympathetic nervous system, suggesting that the EOAZ
      may be a direct vasorelaxant agent.

PMID- 12494338
TI  - Effects of tanshinone VI on the hypertrophy of cardiac myocytes and fibrosis of
      cardiac fibroblasts of neonatal rats.
AB  - The possible effects of tanshinone VI (tsh), a diterpene from the root of Tan
      Shen (Salvia miltiorrhiza, Bunge (Labiatae)) on hypertrophy and fibrosis in
      cultured neonatal rat cardiac myocytes and fibroblasts were examined. Tsh had no
      significant effect on protein synthesis, which was evaluated by [3H]-leucine
      incorporation into the acid insoluble fraction in the cells, in the absence of
      stimulatory factors in cardiac myocytes. The amount of protein produced in
      cardiac myocytes was increased by 10(-8) M endothelin-1 (ET-1), 10(-6) M
      phenylephrine (PE), or 10(-8) M insulin-like growth factor-1 (IGF-1), suggesting
      that hypertrophy of cardiac myocytes in vitro was induced by these factors. The
      ET-1-, PE-, or IGF-1-induced increase in protein synthesis was attenuated by
      treatment with 10(-5) M tsh. Treatment with 10(-5) M tsh significantly decreased
      the synthesis of collagen by cardiac fibroblasts, which was evaluated by [3H]
      proline incorpolation into acid-insoluble fraction of the fiblobrasts, in the
      absence of stimulatory factors for the production. Fetal bovine serum (FBS) or
      IGF-1 increased collagen synthesis in a concentration-dependent manner. The
      increase at 5% FBS or 10(-8) M IGF-1 was inhibited by 10(-5) M tsh. Fibroblast
      conditioned medium (FB-CM) increased protein synthesis in cardiac myocytes in a
      concentration-dependent manner (10; - 100 %). Tsh attenuated the FB-CM-induced
      increase in protein synthesis by cardiac myocytes. These results show that tsh
      may attenuate the humoral factor-induced hypertrophy of cardiac myocytes and
      fibrosis of cardiac fibroblasts. The findings suggest that tsh may improve the
      development of cardiac remodeling under pathophysiological conditions.
      Abbreviations. ANP:atrial natriuretic peptide DMEM:Dulbecco-modified Eagle's
      medium ET-1:endothelin-1 FB-CM:fibroblast-conditioned medium FBS:fetal bovine
      serum IGF-1:insulin-like growth factor-1 PE:phenylephrine tsh:tanshinone VI

PMID- 12494339
TI  - An in vitro and hydroponic growing system for hypericin, pseudohypericin, and
      hyperforin production of St. John's wort (Hypericum perforatum CV new stem).
AB  - While the interest in medicinal plants continues to grow, there is a lack of
      basic information with respect to efficient protocols for plant production.
      Recently, in vitro regeneration protocols have been developed to provide masses
      of sterile, consistent St. John's wort. The current study assessed the potential
      for acclimatization of in vitro grown St. John's wort plantlets to a nutrient
      film technique (NFT) hydroponic system in a controlled environment greenhouse.
      Quantitative analyses of hypericin, hyperforin and pseudohypericin in flower
      tissues were used as the parameters to assess the quality of the greenhouse-grown
      plants. The three bioactive compounds were found to be present in similar or
      higher amounts than previously reported values for field-grown plants. These data
      provide evidence that greenhouse hydroponic systems can be effectively used for
      the efficient production of St. John's wort and other medicinal plants.

PMID- 12494340
TI  - Biotransformation of 2alpha,5alpha,10beta,14beta-tetraacetoxy-4(20),11-taxadiene
      by cell suspension cultures of Catharanthus roseus.
AB  - Catharanthus roseus cell suspension cultures were employed for the
      biotransformation of 2alpha,5alpha,10beta,14beta-tetraacetoxy-4(20),11-taxadiene
      ( 1), and four metabolites were obtained. Based on their physical and chemical
      data, the structures of the four metabolites were respectively elucidated as
      10beta-hydroxy-2alpha,5alpha,14beta-triacetoxy-4(20),11-taxadiene (2), 5alpha
      hydroxy-2alpha,10beta, 14beta-triacetoxy-4(20),11-taxadiene (3), 6alpha,10beta
      dihydroxy-2alpha,5alpha,14beta-triacetoxy-4(20),11-taxadiene (4), and
      6alpha,9alpha,10beta-trihydroxy-2alpha,5alpha,14beta-triacetoxy-4(20),11
      taxadiene (5), among which 3 and 5 were characterized as new taxoids. The effects
      of the stages of substrate addition on the biotransformation were also
      investigated. The results revealed that the biotransformation rate for 1 reached
      85.3 % and the yield of 2 70 % when 1 was administered during the mid-linear
      phase (9 - 12 th day) of the cell growth cycle. On the other hand, the yield for
      4 reached the highest level of 11.8 % when 1 was added in the early linear phase
      (6 th day).

PMID- 12494341
TI  - Differentiation between the complement modulating effects of an arabinogalactan
      protein from Echinacea purpurea and heparin.
AB  - Due to the important physiological role of the complement system, complement
      modulation, either inhibition or stimulation, is an interesting target for drug
      development. Several plant polysaccharides are known to exhibit complement
      modulating activities. Sometimes these effects are described as complement
      inhibition, although the basic mechanism is a stimulation of the complement
      activation. This misinterpretation is due to the observed reduced haemolysis in
      the widely used haemolytic complement assay, which does not allow to
      differentiate between complement activators and inhibitors, when it is performed
      in the classical manner. The aim of the presented study was to demonstrate that
      by simple modifications of the classical procedure this assay becomes an
      efficient tool to distinguish between real complement inhibitors and complement
      activating compounds without performing expensive, molecular mechanistic
      investigations. As practical examples heparin with proven complement inhibiting
      activity and AGP, a new arabinogalacatan-protein type II isolated from pressed
      juice of the aerial parts of Echinacea purpurea, as a potential complement
      activating compound were included in the study. By means of varying the
      preincubation time of the test compound with complement, AGP was clearly
      identified as a stimulator of both the classical and alternative pathway of
      complement activation. These findings correspond to the results of molecular
      mechanistic investigations. Selective removal of the arabinose side chains of AGP
      resulted in considerably reduced activity. Therefore, the three-dimensional
      structure of the polysaccharide, i. e., a backbone branched by side chains, is
      supposed to be important for the interactions with the complement system. The
      complement activating effects of AGP may contribute to the well-established
      immunostimulating effects of the pressed juice from Echinacea purpurea.
      Abbreviations. AGP:arabinogalactan-protein AGP-hydr.:hydrolysed arabinogalactan
      protein AP-CA:haemolytic complement assay for the alternative pathway CP
      CA:haemolytic complement assay for the classical pathway EGTA-VB:veronal buffered
      saline containing EGTA and Mg 2+HPS:human pooled serum RT:room temperature
      LPS:lipopolysaccharide RaE:rabbit erythrocytes RT:room temperature
      ShE(A):(sensitised) sheep erythrocytes VB:veronal buffered saline containing Ca
      2+ and Mg 2+

PMID- 12494342
TI  - Activity-guided fractionation of the seeds of Ziziphus jujuba using a
      cyclooxygenase-2 inhibitory assay.
AB  - Bioactivity-guided fractionation of petroleum ether- and EtOAc-soluble extracts
      of the seeds of Ziziphus jujuba using a cyclooxygenase-2 assay as a monitor
      indicated that the triglyceride, 1,3-di-O-[9(Z)-octadecenoyl]-2-O-[9(Z),12(Z)
      octadecadienoyl]glycerol (3), and a fatty acid mixture of linoleic, oleic and
      stearic acids, were the major active components. A new pentacyclic lupane-type
      triterpene derivative, 3-O-[9(Z)-octadecenoyl]betulinic acid (1), and betulinic
      acid (2) were also isolated and identified. All isolates as well as pure
      linoleic, oleic and stearic acids were evaluated for their inhibitory effects
      against both cyclooxygenases-1 (COX-1) and -2 (COX-2).

PMID- 12494343
TI  - Diayangambin exerts immunosuppressive and anti-inflammatory effects in vitro and
      in vivo.
AB  - In this study, the furofuran lignan (+)-diayangambin [tetrahydro-1,4-bis(3,4,5
      trimethoxyphenyl)-(1 R)-1alpha,3abeta,4alpha,6abeta-1 H,3 H-furo [3,4- c]furan]
      was evaluated in vitro and in vivo for its immunomodulatory and anti-inflammatory
      efficacy. Human mononuclear cell proliferation was inhibited by diayangambin with
      an IC 50 value of 1.5 (0.5 - 2.8) microM. In addition, the compound reduced for
      40.8 % prostaglandin E 2 generation in stimulated RAW 264.7 macrophage cell line
      at 10 microM. In vivo, a clear reduction of ear swelling was observed when
      diayangambin (40 mg/kg) was administered orally to 2,4-dinitrofluorobenzene
      treated mice. The inhibition of swelling was associated with a reduction of
      leukocyte infiltration determined as myeloperoxidase activity. In the carrageenan
      mouse paw edema model, diayangambin significantly suppressed inflamed paw volume
      and prostaglandin E 2 levels. Our findings indicate the potential interest of
      diayangambin in the treatment of immune and inflammatory responses.

PMID- 12494344
TI  - Quinolone alkaloids, diacylglycerol acyltransferase inhibitors from the fruits of
      Evodia rutaecarpa.
AB  - From the diacylglycerol acyltransferase (DGAT) activity-guided fractionation, a
      new quinolone alkaloid, 1-methyl-2-tetradecyl-4(1H)-quinolone (1) was isolated
      from the fruits of Evodia rutaecarpa together with three known quinolone
      alkaloids, evocarpine (2), 1-methyl-2-[(4 Z,7 Z)-4,7-decadienyl]-4(1H)-quinolone
      (3) and 1-methyl-2-[(6 Z,9 Z)-6,9-pentadecadienyl]-4(1 H)-quinolone (4). They
      showed a dose-dependent DGAT inhibition with IC 50 values of 69.5 microM ( 1),
      23.8 microM (2), 20.1 microM (3) and 13.5 mu (4).

PMID- 12494345
TI  - In vitro inhibitory effect of rubraxanthone isolated from Garcinia parvifolia on
      platelet-activating factor receptor binding.
AB  - Rubraxanthone and isocowanol isolated from Garcinia parvifolia Miq. were
      investigated for their inhibitory effects on platelet-activating factor (PAF)
      binding to rabbit platelets using 3H-PAF as a ligand. Rubraxanthone showed a
      strong inhibition with IC 50 value of 18.2 microM. The IC 50 values of
      macluraxanthone, 6-deoxyjacareubin, 2-(3-methylbut-2-enyl)-1,3,5
      trihydroxyxanthone, 2-(3-methylbut-2-enyl)-1,3,5,6-tetrahydroxyxanthone and 1,3,5
      trihydroxy-6,6'-dimethylpyrano(2',3':6,7)-4-(1,1-dimethylprop-2-enyl)-xanthone
      were also determined for comparison. In the course of our study on structure
      activity relationship of xanthones, the results revealed that a geranyl group
      substituted at C-8 was beneficial to the binding while a hydroxylated prenyl
      group at C-4 resulted in a significant loss in binding to the PAF receptor.

PMID- 12494346
TI  - Microtubule-interacting activity and cytotoxicity of the prenylated coumarin
      ferulenol.
AB  - In this study we investigated biological activity of ferulenol, a prenylated 4
      hydroxycoumarin from Ferula communis. Ferulenol stimulates tubulin polymerization
      in vitro, and inhibits the binding of radiolabeled colchicine to tubulin. It
      rearranges cellular microtubule network into short fibres, and alters nuclear
      morphology. Remarkably, ferulenol exerts a dose-dependent cytotoxic activity
      against various human tumor cell lines. Abbreviations. DAPI:4,6-diamidino-2
      phenylindole DMEM:Dulbecco's modified Eagle's medium
      EGTA:ethylenebis(oxyethylenenitrilo)tetraacetic acid FBS:fetal bovine serum
      FITC:fluoresceine isothiocyanate GTP:guanosine 5'-triphosphate MES:2-[N
      morpholino]ethane-sulfonic acid MTP:microtubule protein SDS:sodium dodecyl
      sulfate

PMID- 12494347
TI  - Antibacterial activity of a stearic acid derivative from Stemodia foliosa.
AB  - From the hexane-soluble fraction of an ethanol extract from leaves and stems of
      Stemodia foliosa (Scrophulariaceae), the new stearic acid 4-[(n
      pentoxy)phenethyl] ester (1) was isolated. This compound exhibited antibacterial
      properties at 10 microg/mL concentration by using disc diffusion method against
      Gram-positive bacteria Bacillus cereus and Bacillus subtilis and fast-acid
      bacterium Mycobacterium fortuitum. The structure of the new compound was
      elucidated by spectroscopic methods and by chemical conversion.

PMID- 12494348
TI  - Two flavonols from Artemisa annua which potentiate the activity of berberine and
      norfloxacin against a resistant strain of Staphylococcus aureus.
AB  - Bioassay-guided fractionation of an extract of Artemisia annua L. (Asteraceae)
      was conducted in order to assess the possible presence in the plant material of
      inhibitors of bacterial multidrug resistance pumps. Fractions were tested for
      Staphylococcus aureus growth inhibition in the presence of a subinhibitory dose
      of the weak antibacterial alkaloid berberine. Active fractions yielded the
      flavones chrysosplenol-D and chrysoplenetin, which themselves had very weak
      growth inhibitory action, but which made a potent combination with berberine. In
      comparison with work on other flavonols, it is likely that potentiation is due to
      the inhibition of an S. aureus multidrug resistance (MDR) pump. These same two
      flavonols were earlier reported to potentiate the activity of artemisinin against
      Plasmodium falciparum.

PMID- 12494349
TI  - Oral administration of a soy extract improves endothelial dysfunction in
      ovariectomized rats.
AB  - Effects of oral administration for 4 weeks of a soy fraction with mainly
      isoflavones (Glycine max, Leguminosae) (SOYPH; 5 mg/kg) on vascular dysfunction
      induced by bilateral ovariectomy (OVX) in rats were studied. We evaluated
      vascular reactivity of aortic rings after acetylcholine (ACh 10 nM-10 microM),
      sodium nitroprussiate (SN 15 - 30 nM) and NG-L-arginine (L-NMA; 10 - 100 microM).
      Uterine weight and nitric oxide synthase (NOS) activity were also investigated.
      The same parameters were observed after 4 weeks treatment with 17beta-estradiol.
      In OVX rats endothelial-dependent vascular responses were changed: reduction of
      induced contraction ( L-NMA 100 mM: sham OVX 2.1 +/- 0.2 g/mg tissue; OVX 1.7 +/-
      0.4 g/mg tissue). Ovariectomy produced a reduction of constitutive NOS activity.
      Uterine weight was increased in animals treated with 17beta-estradiol but not
      with SOYPH. Either SOYPH or 17beta-estradiol produced a similar improvement of
      endothelial dysfunction and increased NOS activity. Our data suggest that soy
      isoflavones produce an improvement of endothelial dysfunction induced by
      ovariectomy so as 17beta-estradiol, but probably without changes in reproductive
      system.

PMID- 12494350
TI  - Accumulation of hydrolyzable tannins by Aleurites fordii callus culture.
AB  - A callus culture of Aleurites fordii Hemsley (Euphorbiaceae) producing five
      galloylglucoses and an ellagitannin, geraniin, was established. The production of
      pentagalloylglucose was remarkably enhanced under light irradiation compared with
      that in the dark. Cell growth and tannin production were also greatly affected by
      changing the concentrations and composition of nitrogen sources.

PMID- 12494351
TI  - Two norditerpenoid ester alkaloids from Aconitum bulleyanum.
AB  - Two new norditerpenoid alkaloids, 8-acetyl-14-p-methoxybenzoate of talatisamine
      (1) and 14-p-methoxybenzoate of talatisamine (2), were isolated from Aconitum
      bulleyanum Diels. The structures were elucidated on the basis of spectroscopic
      and chemical studies.

PMID- 12494352
TI  - Two new triterpenoids from the fresh leaves of Psidium guajava.
AB  - Two new triterpenoids, guajavolide (2 alpha,3 beta,6 beta,23-tetrahydroxyurs-12
      en-28,20 beta-olide; 1) and guavenoic acid (2 alpha,3 beta,6 beta,23
      tetrahydroxyurs-12,20(30)-dien-28-oic acid; 2) along with one known triterpene
      oleanolic acid (3) were isolated from the fresh leaves of Psidium guajava. Their
      structure elucidation and stereochemistry were determined by spectroscopic
      experiments, including 2D-NMR techniques.

PMID- 12494353
TI  - Endoscopic endonasal transsphenoidal approach: outcome analysis of 100
      consecutive procedures.
AB  - The endoscopic endonasal transsphenoidal approach has been proposed in the past
      decade as a minimally invasive surgical technique for the removal of pituitary
      tumors. From January 1997 to November 1999, 100 consecutive patients with
      pituitary tumors underwent endoscopic endonasal surgery, according to Jho's
      technique. We employed 0 degrees, 30 degrees, 45 degrees, and 70 degrees rigid
      endoscopes, 18 - 30 cm in length, 4 mm in diameter with an outer sleeve for
      irrigation and secured to a holder. Among the 87 pituitary adenomas, tumor
      removal was total in 51, subtotal (> 80 %) in 20 and partial in 16 cases. Four
      craniopharyngiomas were totally removed and an intra-suprasellar arachnoid cyst
      was emptied; a biopsy was performed in the two patients with a clivus chordoma.
      The two cases of sphenoid sinusitis were cured by surgery, the three patients
      with spontaneous CSF rhinorrhea were successfully treated and the residual nasal
      meningocele was removed. The endoscopic endonasal transsphenoidal approach
      appeared to be less traumatic than the traditional microsurgical approach, was
      very effective, and was characterized by a reduced number of complications.
      However, the relatively small series together with the short follow-up do not
      allow us to draw definitive conclusions. The post-operative reduction in hospital
      stay (two days in 40 of 100), significantly reduced the cost of patient's
      management.

PMID- 12494354
TI  - Stereotactic guided laser-induced interstitial thermotherapy (SLITT) in gliomas
      with intraoperative morphologic monitoring in an open MR: clinical expierence.
AB  - Stereotactic guided laser-induced interstitial thermotherapy (SLITT) is a minimal
      invasive method to produce thermonecrosis in cerebral tumour tissue. Clinical
      data are sparse due to its limited application until now and the value of this
      approach for tumour control and survival time remain to be defined. Twenty-four
      patients (7 low-grade gliomas, 11 anaplastic gliomas, 6 glioblastomas) with brain
      tumours, most recurrences, were treated with SLITT, in total 30 laser procedures
      were performed. Under local anaesthesia a 600 micro m laser-fiber was inserted by
      the stereotactic-guided technique. In open low-field MR the denaturation of the
      tumour by a Nd-YAG-laser (1064 nm) was monitored using T 1 -weighted 3-D turbo
      FLASH sequences. The ablation procedure had to be stopped twice because of
      neurological deficit, one major infection occurred. In two cases neurological
      improvement was observed. Mean survival times for low grade astrocytomas,
      anaplastic gliomas and glioblastomas were 144 months, 39 months, 17 months,
      respectively. Mean survival times after SLITT were 34 months, 30 months and 9
      months, respectively. Mean times to progression after SLITT for the 3
      histological subgroups were 16 months, 10 months and 4 months, respectively. Five
      patients with low grade astrocytoma and a KI greater or equal 70 maintained a
      high quality functional status for 11, 20, 21, 33 and 43 months. In anaplastic
      tumours patients maintained a KI of 70 for a median time of 15 months and for
      those with glioblastoma the respective high quality duration was 7.5 months after
      SLITT. SLITT for selected patients with glioma could have a clinical value in a
      multimodality treatment schedule maintaining quality of live. Due to the minimal
      invasive technique, the method is a therapy of choice and may be favoured to
      reoperation. Major indications of this treatment are small tumours, in eloquent
      regions and deep seated, as well as in older patients or patients in poor
      functional status.

PMID- 12494355
TI  - Flexible endoscope-assisted endonasal transsphenoidal surgery for pituitary
      tumors.
AB  - We have performed rigid endoscope-assisted endonasal transsphenoidal
      microsurgeries for pituitary tumors in 230 patients. Recently, we further
      introduced the use of a flexible endoscope to inspect the tumor bed and
      suprasellar structures more extensively. We report our experience with the
      flexible endoscope in endonasal transsphenoidal surgery for pituitary tumors. The
      endoscopes were used to complement the microscope in visualization. The flexible
      endoscopes were used in 34 recent cases with suprasellar and/or lateral tumor
      extension. During or after removal of the main tumor bulk, the flexible endoscope
      together with a rigid endoscope was used to inspect the tumor cavity, especially
      at the blind spot of the microscope. Despite limited resolving power, in all the
      34 cases the flexible endoscope was a highly efficient tool permitting extensive
      visualization of almost the whole surgical area, even in narrow surgical fields
      and spaces not visible with an operating microscope or a rigid endoscope, and
      allowing continuous change of viewing angle. The residual tumor situated
      laterally or in the suprasellar areas that could not be reached and was
      impossible to remove by a rigid endoscope could be dissected and extirpated under
      a flexible endoscope using grasping forceps in 5 patients with pituitary adenoma
      and all the craniopharyngioma cases. The flexible endoscope may be more efficient
      in the lateral and suprasellar areas than the rigid endoscope in compensating for
      the narrow surgical field in endonasal pituitary surgery, despite its limited
      resolving power. Surgeons should make the best use of the advantages of each
      instrument.

PMID- 12494356
TI  - Gamma knife radiosurgery in the management of arteriovenous malformations of the
      Basal Ganglia region of the brain.
AB  - OBJECTIVES: The authors report the results of gamma knife (GK) radiosurgery on a
      clinical series of selected patients with basal ganglia arteriovenous
      malformations (BGAVMs) in the brain. Clinical, epidemiological, anatomical and
      functional characteristics of BGAVMs and of supratentorial cortical AVMs are
      comparatively analyzed, and their influence on radiosurgical outcome is
      discussed. METHODS: At our Department, 33 BGAVMs (21 with FU > 2 years) and 209
      cortical AVMs (110 with FU > 2 years) with a radiosurgical volume </= 10 cc were
      treated with GK between February 1993 and July 2001. Mean age, male/female ratio
      (M/F), and incidence of haemorrhagic onset in the two subgroups of patients were
      as follows: 25.5 years (5 - 62 years), 16 M/17 F, and 30/33 (91%) in BGAVMs; 34.4
      years (8 - 74 years), 124 M/85 F, and 107/209 (51%) in cortical AVMs. Statistical
      analysis performed using the contingency table method and deviance analysis
      according to generalized linear models showed that the differences in age and
      incidence of haemorrhagic onset were highly significant. RESULTS: The rates of
      complete obliteration, permanent morbidity, bleeding/rebleeding during the
      latency period, and unsuccessful embolisation attempts in the two subgroups of
      patients were as follows: 81%, 4%, 8%, and 41.7%, respectively, in BGAVMs; 85.5%,
      2%, 2%, and 2% in cortical AVMs. Statistical analysis did not show any
      significant difference between the two subgroups of patients in the rates of
      complete obliteration, permanent morbidity, or latency period
      bleeding/rebleeding, while difference in failed embolization rates resulted to be
      highly significant (P = 0.00003). CONCLUSIONS: In our experience, the different
      clinical, epidemiological and anatomico-functional characteristics of BGAVMs and
      cortical AVMs do not seem to influence the radiosurgical outcome, since complete
      obliteration and permanent neurological sequelae rates were very similar in these
      two subgroups of patients. GK may be considered the first choice treatment
      modality for BGAVMs with < 10 cc volume, since it offers a very high cure rate,
      very low permanent morbidity, and zero mortality. Although haemorrhagic onset is
      much more frequent in BGAVMs than in cortical AVMs, the difference between the
      bleeding/rebleeding rates in the two subgroups of patients during the latency
      period is not statistically significant, and seems to be limited to the first
      year after GK.

PMID- 12494357
TI  - Postoperative radiotherapy for ganglioglioma; report of three cases and review of
      the literature.
AB  - Gangliogliomas are rare tumors of the central nervous system. The definite role
      of postoperative radiotherapy has not been established. In studying three cases
      who underwent radiotherapy after subtotal resection, we evaluated the clinical,
      pathological, radiological features with follow-up of mean 8.1 years. All of
      three patients were male, and mean age was 22.3 years. All of the cases have
      temporal lobe lesions and, except for one, they all have seizures. Radiotherapy
      was given to all patients after surgery. Parallely opposed local fields were
      used. A total of 54 Gy in 5.5 weeks was given to the mid-plane using a Co-60 tele
      therapy device. No recurrence, no new symptoms, and no new neurological
      deficiency were detected during follow-up.

PMID- 12494358
TI  - Comparing open surgery with endoscopic releasing in the treatment of carpal
      tunnel syndrome.
AB  - AIM: The aim of this study is to retrospectively assess the complications and
      result of cases that underwent open surgery or endoscopic releasing for carpel
      tunnel syndrome. METHOD: A total of 50 cases of carpel tunnel syndrome, 30 of
      whom underwent endoscopic release using the biportal extrabursal technique
      described by Chow, and the other 20 that underwent open surgery were included in
      the study. Average age of the cases was 41 (24 - 62), 44 of them were females and
      6 males. RESULTS: Follow-up examinations of the patients at the first and third
      month after operation revealed no limitation of activity in 40 (80 %) cases,
      minimal limitation in 4 (8 %), moderate limitation in 5 (10 %) and significant
      limitation in 1 (2 %). Among the group that underwent endoscopic release, as a
      major complication, the median nerve was almost totally cut in a patient
      undergoing endoscopic release. During the same operation setting perifascicular
      neurorrhaphy was done. Fourth and fifth digital nerve lesions occurred in three
      cases. Among the group that underwent open surgery fourth and fifth digital nerve
      injury occurred in one case, and in another case severe inflammation requiring
      reoperation occurred. CONCLUSION: Before intervention, cases of carpal tunnel
      syndrome should be examined well as regards which technique to use. Experience of
      the surgeon with the technique to be used should also be taken into
      consideration. Endoscopic carpal tunnel releasing, though a relatively easier
      procedure, leads to neurovascular injuries more frequently than open surgery;
      thus open surgery appears to be safer.

PMID- 12494359
TI  - Treatment of Chiari malformation, syringomyelia and hydrocephalus by
      neuroendoscopic third ventriculostomy.
AB  - This short paper illustrates a case with cervical myelomeningocoele, a Chiari
      malformation (CM), hydrocephalus (HC) and cervical syringomyelia treated by
      neuroendoscopic third ventriculostomy (NTV) with resolution of both the
      hydrocephalus and the syrinx. Two similar cases are discussed. The technique is
      advocated for the treatment of such complex dysraphic conditions.

PMID- 12494360
TI  - Treatments of hamartoma with neuroendoscopic surgery and stereotactic
      radiosurgery: a case report.
AB  - Hypothalamic hamartoma is a non-neoplastic tumor manifesting as gelastic seizure,
      precocious puberty, and abnormal behavior. Treatment of it is very complicated
      due to its location. We report a case of hypothalamic hamartoma treated by
      neuroendoscopic surgery and stereotactic radiosurgery. A 5-year-old girl
      presented with violent behavior, precocious puberty, gelastic seizure and atonic
      seizure. She was diagnosed with hypothalamic hamartoma by CT and magnetic
      resonance imaging at 11 months of age. Tumor size did not change, but tumor
      intensity had changed on the MR image at 5 years of age. Magnetic resonance
      spectroscopy revealed decreased N-acetylaspartate and increased choline and
      creatine in the tumor. After neuroendoscopic biopsy, she underwent linear
      accelerator stereotactic radiosurgery. But her symptoms remained unchanged for 6
      months. She then underwent partial resection and laser coagulation of the tumor
      by a neuroendoscopic approach. After the procedure, the frequency of her seizures
      was remarkably decreased, and her violent behavior improved. The transventricular
      neuroendoscopic approach to the hypothalamus is less invasive than the radical
      surgery. Neuroendoscopic surgery can be one of the treatments of choice for
      hypothalamic hamartoma.

PMID- 12494361
TI  - "True" aneurysm of the posterior communicating artery as a possible effect of
      collateral circulation in a patient with occlusion of the internal carotid
      artery. A case study and literature review.
AB  - "True" posterior communicating artery (PCoA) aneurysms are extremely rare. A case
      of a 63-year-old patient with a ruptured "true" aneurysm of the right PCoA
      associated with the occlusion of the right internal carotid artery is presented.
      For nine years before he suffered from subarachnoid hemorrhage, the patient had
      developed symptoms of transient ischemic attack (TIA) due to the occlusion of the
      right internal carotid artery. The left vertebral angiogram demonstrated a "true"
      right PCoA aneurysm and collateral flow from the right posterior communicating
      artery to the right internal carotid artery. The right internal carotid system
      was also fed by collateral circulation from the left carotid artery through the
      anterior communicating artery. Transcranial colour-coded real-time sonography
      (TCCS) demonstrated increased velocity and turbulent blood flow in both
      communicating arteries. The patient was operated on and the aneurysm was clipped
      successfully. This case report suggests that the blood flow disturbances
      resulting from the collateral circulation through the PCoA could be a conductive
      factor in the formation and development of the aneurysm. This is the first
      described case of a "true" aneurysm of the PCoA coexistent with the occlusion of
      the internal carotid artery.

PMID- 12494362
TI  - Successful obliteration of a ruptured partially thrombosed giant m1 fusiform
      aneurysm with coil embolization at distal m1 after extracranial-intracranial
      bypass.
AB  - Proximal occlusion or trapping combined with EC-IC bypass is usually employed as
      a definite treatment for a giant fusiform aneurysm in cases where it is
      impossible to apply clips and do vascular reconstruction. Endovascular treatment
      is very important as an alternative or combined technique if direct surgery is
      impossible. The authors report a young male who presented with a 2 nd episode of
      intracranial bleeding in basal ganglion and subarachnoid hemorrhage with mild
      right hemiparesis. His 3D-CT scan revealed left ruptured partially thrombosed
      giant M1 fusiform aneurysm and left unruptured C3 saccular aneurysm. He underwent
      STA-MCA bypass with attempted M1 reconstruction and a week later attempted total
      occlusion of the M1 aneurysm with coils. But only a ruptured point at the distal
      M1 was occluded which, however, resulted in temporary mild right hemiparesis and
      aphasia. A month later when he was supposed to have his 2 nd coiling procedure
      his angiogram demonstrated spontaneous and complete obliteration of both the M1
      and C3 aneurysms without any new neurological deficit, so no further endovascular
      procedure was attempted. The discussion is based on this case and previous
      reports regarding difficult giant M1 fusiform aneurysms, its treatment and
      spontaneous thrombosis of aneurysmal sac after bypass and distal occlusion.
      Conclusions are drawn that 1) spontaneous thrombosis of M1 and C3 aneurysms
      should be the result of hemodynamic alteration in both aneurysms due to a lower
      flow velocity induced by distal bypass and distal occlusion of M1, 2) combined
      distal bypass and endovascular obliteration of the aneurysmal sac with coils is a
      good alternative if vascular reconstruction is difficult or impossible.

PMID- 12494363
TI  - Combined minimally invasive approach using microsurgery and thoracoscopic surgery
      for resecting a dumbbell-type thoracic schwannoma.
AB  - We present a case of a thoracic schwannoma with an intravertebral component, a so
      called "dumbbell-type" tumor, that was resected with a combined minimally
      invasive approach using microsurgery and thoracoscopic surgery simultaneously. A
      31-year-old man was admitted to our hospital for treatment of a thoracic
      schwannoma 45 mm in maximal diameter at the level of the third thoracic vertebra.
      After the tumor was separated from intravertebral structures by using a
      microsurgical technique via the posterior approach with a hemilaminectomy and
      minimal unilateral facetectomy, the mass was removed completely by using video
      thoracoscopy. We stress that this approach should be the most useful and less
      invasive technique for treating the dumbbell-type of thoracic neurogenic tumor
      compared with a single or combination technique involving thoracotomy, multi
      level laminectomy and costotransversectomy. Below, we make some notes on this
      technique from the neurosurgeon's standpoint.

PMID- 12494364
TI  - An endoscopic curved Kerrison rongeur for spinal stenosis surgery.
AB  - OBJECTIVE: Adequate neural decompression with minimal structural alteration is
      the goal of lumbar stenosis surgery. Often because of limited visualization
      significant parts of the facet joints are removed enhancing the potential for
      developing instability. To overcome this problem we have developed a small curved
      Kerrison rongeur that contains a 10 000-pixel endoscope. This instrument allows
      one to visualize and decompress structures within the lateral recess that may
      have required more extensive removal of portions of the facet joints. METHODS:
      Ten patients with symptomatic lumbar spinal stenosis were decompressed using the
      endoscopic rongeur. RESULTS: Compression of the lateral dura and nerve root by
      the facet and ligamentum could easily be identified. In all cases the ligament
      could be easily removed and the facet joint was undercut only enough to
      decompress the nerve. CONCLUSION: This instrument has the potential for less
      invasive decompression of spinal stenosis and further study of its utility is
      planned.

PMID- 12494365
TI  - [On German-American relations in ophthalmology (address by F. C. Blodi on 4
      December 1990 in Leipzig)].

PMID- 12494366
TI  - [The role of protein kinase C in the pathophysiology of diabetic retinopathy].
AB  - Hyperglycemic control in diabetes mellitus is a major key to prevent the
      development and progression of diabetic retinopathy. One important pathomechanism
      in the development of diabetic complications is the activation of protein kinase
      C (PKC) induced by high glucose due to an increased diacylglycerol (DAG) level.
      Resulting vascular dysfunctions are increased vascular permeability and
      contractility, increased production of extracellular matrix and cell
      proliferation. The PKC isoenzyme family plays a fundamental role in the cellular
      signal transduction via phosphorylation and modification of enzymes, receptors,
      transcription factors and kinases. The PKC activation influences the gene
      transcription and ion transport. Different PKC isoenzymes function as mediators
      but also as inhibitors of the insulin effects. The hyperglycemia induced DAG
      production seems to predominantly activate PKC-beta in retinal vascular
      endothelial cells. The development of selective PKC-beta inhibitors enables new
      pharmacological therapeutical approaches for treatment of diabetic retinopathy.
      Ongoing clinical studies investigate if the treatment with specific PKC-beta
      inhibitors can prevent the progression of diabetic retinopathy and diabetic
      macular edema.

PMID- 12494367
TI  - [Epidemiology of diabetes-induced blindness -- a review].
AB  - BACKGROUND: In the declaration of St. Vincent of 1989 the World Health
      Organization (WHO) and the International Diabetes Federation (IDF) aimed at a
      reduction of diabetes-induced blindness in Europe by one third within five years.
      Despite that, proliferative diabetic vitreoretinopathy (PDVR) and diabetic
      macular edema (DME) continue to be the leading causes for diabetes-induced
      legally defined blindness in working-age adults in western industrialized
      nations. MATERIAL AND METHODS: An analysis of literature of recent years is
      performed to give an overview over prevalence and incidence of diabetic blindness
      in Western industrialised countries. Data from literature is compared to new data
      collected in the German State of Hessen. RESULTS: Both our own data and data from
      literature show a constant to slightly decreasing prevalence and incidence of
      diabetes-related blindness. CONCLUSIONS: The aims of the St. Vincent declaration
      of 1989 have not been attained so far. Diabetes-related ocular diseases continue
      to be treated only after onset of symptoms. Effective screening programs for
      prevention, which would entail tremendous saving of Public Health expenditure,
      are an exception.

PMID- 12494368
TI  - [Comparison of precision of the TonoPenXL with the Goldmann and Draeger
      applanation tonometer in a sitting and recumbent position of the patients -- a
      clinical study on 251 eyes].
AB  - PURPOSE: Comparison of precise intraocular pressure (IOP) measurement with
      TonoPenXL, Goldmann and Draeger applanation tonometer in a sitting and recumbent
      position. MATERIAL AND METHODS: The IOP of 251 eyes of 127 consecutive patients
      (SFB 539) was measured prospectively in a sitting position (1 x Goldmann, 3 x
      TonoPenXL) and in recumbent position (1 x Draeger, 3 x TonoPen). The mean of
      three TonoPenXL measurements was only accepted in a 5 % interval. Additionally,
      corneal ultrasonic pachymetry (Tomey, AL-2000), central corneal power, refractive
      error, gender and age were registered. RESULTS: The IOP measured with the
      TonoPenXL was in 92 % in a range of 2 mm Hg from the Goldmann standard. In a
      vertical position, the IOP TonoPenXL (16.7 +/- 4.5 mm Hg) was 0.2 mm Hg lower
      than the IOP Goldmann (16.9 +/- 5.1 mm Hg; regression analysis: IOP TonoPenXL =
      1.78 + 0.88 IOP Goldmann). In a horizontal position, the IOP TonoPenXL (17.5 +/-
      5.0 mm Hg) was 0.5 mm Hg higher as the IOP Draeger (17.0 +/- 5.3 mm Hg;
      regression analysis: IOP TonoPen = 0.34 + 1.016 IOP Draeger). Using the
      TonoPenXL, the IOP was 0.8 mm Hg higher in recumbent position than in a sitting
      position (regression analysis: IOP TonoPen recumbent position = - 2.27 + 1.19 IOP
      TonoPen sitting position). We found no relationship found between central corneal
      power, central corneal thickness and IOD measured with the TonoPenXL.
      CONCLUSIONS: The TonoPenXL is useful for IOP measurement in a sitting and
      recumbent position. The results are reproducible in 92% with the Goldmann
      applanation tonometer. The ophthalmologist has a comfortable measurement and
      screening tool for consultations or IOP investigation under general anaesthesia.

PMID- 12494370
TI  - [Evidence of silicone oil deposits via high resolution ultrasound].
AB  - BACKGROUND: Using biomicroscopy the evidence of deposits of silicone oil in the
      anterior segment after vitrectomy is limited. We examined the anterior segment by
      high resolution ultrasound to verify the possibility to identify silicone oil.
      MATERIALS AND METHODS: Ten patients treated by vitrectomy with instillation of
      silicone oil were examined by high resolution ultrasound before and after the
      removal of silicone oil. The duration of silicone oil tamponade was at least 5
      months. A 20-MHz-sectorscanner was used for examination. We compared the findings
      of ultrasound and biomicroscopy with groups of patients with or without
      pharmacological mydriasis, blue or brown colour of the iris. RESULTS: The
      patients treated by vitrectomy and instillation of silicone oil showed small high
      reflective structures at the endothelium, the anterior front of the iris and in
      the angle. These highly reflective structures were found more often before, less
      often after operative extraction of silicone oil and could not be shown in the
      control groups. Using biomicroscopy we could not see an equivalent to all of the
      highly reflective structures. CONCLUSIONS: The highly reflective structures we
      found by ultrasound are probably inclusions in endothelial cells, silicone oil
      induced calcifications or free particles of silicone oil. High resolution
      ultrasound with a 20-MHz-sectorscanner can be used for identifying indication and
      localising of silicone oil in the anterior segment even if biomicroscopic signs
      are absent.

PMID- 12494369
TI  - [Pigment epithelial detachments in age-related macular degeneration --
      classification, differentiation and prognosis].
AB  - BACKGROUND: A pigment epithelial detachment (PED) is an exudative manifestation
      of late age-related macular degeneration (AMD). Its long-term unfavourable
      prognosis is influenced by the association of a neovascular membrane. Seemingly
      identical PEDs in ophthalmoscopy can be further differentiated by fluorescein and
      indocyanine green angiography. The purpose of this prospective follow-up study
      was to determine the most reliable angiographic classification to distinguish
      PEDs in AMD and to evaluate their outcome. MATERIAL AND METHODS: 73 eyes of 68
      patients with a PED in AMD were examined with simultaneous angiography with
      fluorescein and indocyanine green. 34 eyes were additionally scanned by
      retinatomography. Fluorescein angiographic classification comprises 4 types: 1.
      early hyperfluorescent type, 2. late hyperfluorescent type, 3. drusen type, 4.
      irregular fluorescent type. Indocyanine green angiographic classification
      consists of the following three groups: 1. angiographically no vascularisation,
      2. associated choroidal neovascularisation, 3. associated polypoidal choroidal
      vasculopathy. RESULTS: Both classifications show statistically significant
      correlation with visual acuity (fluorescein classification: P = 0.0112, ICG
      classification: P = 0.0004) and area of the PEDs (fluorescein classification: P =
      0.0002, ICG-classification: P < 0.0001). ICG-classification additionally is
      significantly associated with the volume (P = 0.0008). Both classifications
      correlate (P = 0.0001). Factors influencing visual acuity are: age (P = 0.0044),
      associated neovascular membrane (P = 0.0004), area (P < 0.0001), volume (P =
      0.0077) and height (P < 0.0001). CONCLUSIONS: PEDs in AMD can best be classified
      by indocyanine green angiography on the basis of an associated prognostically
      important neovascular membrane, which can only be further distinguished into
      choroidal neovascularisation or polypoidal choroidal vasculopathy by indocyanine
      green angiography. Statistical analysis shows qualitatively and quantitatively
      more significant results for the indocyanine green angiographic classification.

PMID- 12494371
TI  - [Morning glory syndrome -- a clinical study of two cases].
AB  - BACKGROUND: Handmann was the first to describe the morning glory syndrome in 6
      cases in 1929. In 1970 Kindler published some cases with an "unusual congenital
      anomaly of the optic disc". Since then, several authors have come to the
      conclusion that both authors described the same disease. PATIENTS AND METHODS: In
      January 2000, morning glory syndrome was diagnosed in two patients, mother and
      daughter. Ophthalmological and electrophysiological examinations, further brain
      scan and magnetic resonance imaging (MRI) of the orbit were performed. RESULTS:
      Malformation of the optic disc was bilateral in both cases. Optic disc
      abnormality was accompanied by no other anomalies or malformations. Ultrasound
      examination and MRI of the orbit did not detect posterior staphyloma in our
      cases. Thus, our two patients are the first to be described in the literature,
      where the anomaly of the optic disc occurred in isolation. DISCUSSION: Our cases
      are different from those described in the literature as far as the characteristic
      anomaly of the optic disc was bilateral and the occurrence was genetical. It is
      also noteworthy that no other ophthalmological or general malformations could be
      detected in our patients besides the anomaly of the optic disc. Morning glory
      syndrome occurred in isolation, which makes our cases unique.

PMID- 12494372
TI  - [Hydrophobic AcrySof lenses or heparin-modified PMMA lenses in combined
      vitrectomy surgery -- results of a four-year study].
AB  - BACKGROUND: Combining pars plana vitrectomy with phacoemulsification and
      implantation of an intracapsular IOL provides many advantages and is performed as
      a routine operation. MATERIALS AND METHODS: Over a period of 3 years we compared
      foldable acrylic lenses AcrySof (Alcon) to heparin-modified PMMA lenses
      (Pharmacia) in a prospective study. The last implanted lenses had a follow-up
      period of at least 1 year. Out of 396 eyes from 329 patients we implanted 182
      AcrySof lenses and 214 heparin-modified lenses. RESULTS: Both a smaller scleral
      tunnel incision and a lower rate of secondary cataract are advantages of foldable
      AcrySof lenses. Higher vulnerability of an AcrySof lens and a less stable lens
      iris-diaphragm are of disadvantage. Heparin-modified PMMA lenses do not show
      these disadvantages, however, in consequence of using them you have to accept the
      wider scleral tunnel incision and a higher adhesion to cells. Furthermore, we
      found slightly more posterior synechiae with these lenses. CONCLUSIONS: In all,
      both types of intraocular lenses are suitable for combined surgery. We recommend
      using heparin-modified PMMA lenses in case of pre-existent instability of the
      lens-iris diaphragm or of patients' inability to maintain the prone position.

PMID- 12494373
TI  - [Subhyaloid hemorrhage in association with an atypical central vein occlusion].
AB  - BACKGROUND: Subhyaloid macular bleeding is a rather rare complication caused by
      central or branch retinal vein occlusions, by vascular malformations, Terson's
      syndrome, trauma or valsalva's manoeuver. We report on a young and otherwise
      healthy patient with a large subhyaloid macular hemorrhage associated with an
      atypical central vein occlusion. HISTORY AND SIGNS: A 25-year old female was
      evaluated for an acute and dramatic drop of visual acuity of the right eye. The
      ophthalmological findings included an extensive subhyoidal macular bleeding,
      congested, tortuous retinal veins and some flame-shaped preretinal haemorrhages
      along a couple of veins. Furthermore, a slight edema in the area of an inferiorly
      of the macular region localized cilioretinal artery was visible. The general
      history of the patient was unremarkable with the exception of smoking.
      Anamnestically, Valsalva's manoeuver could not be excluded by the patient.
      CONCLUSION: Atypical central vein occlusions can be the rare cause of a
      subhyaloid macular hemorrhage. A Valsalva's manoeuver could have caused in our
      patient the subhyaloid macular and the preretinal bleedings. The temporarily
      raised venous pressure could have been responsible for the central vein
      occlusion, secondarily causing the occlusion of a cilioretinal paramacular
      artery.

PMID- 12494374
TI  - [General metastases in squamous cell carcinoma of the conjunctiva].
AB  - BACKGROUND: Squamous cell carcinoma of the conjunctiva is rare. Together with
      epithelial dysplasia of the conjunctiva the incidence is reported to be 1.9 per
      100,000 population and year. After adequate therapy total cure is often achieved.
      Generalised metastases are however extremely rare. PATIENT AND METHOD: The case
      of a 71-year old white male patient is presented. Because of a recurrent
      conjunctival tumour in his right eye local resections had to be performed. The
      histopathological diagnosis was epithelial dysplasia. After a 3-year history a
      squamous cell carcinoma developed. In spite of multiple operations total excision
      of the tumour could not be achieved. Exenteration was refused by the patient.
      After radiotherapy of the orbit a temporary improvement was observed. However, 9
      years later the patient died of general metastases to the long bones, the spine,
      and the ribs. RESULTS: Histological examination of material obtained during
      hemilaminectomy of the vertebrate bodies 8 and 9 confirmed the diagnosis of
      metastases of a squamous cell carcinoma. CONCLUSION: Although extremely rare,
      general metastases after squamous cell carcinoma of the conjunctiva must be kept
      in mind. This has to be considered when obtaining informed consent of the
      patient, planning adequate therapy and follow-up.

PMID- 12494375
TI  - [IV: Significance tests -- when to apply which one?].
AB  - Standard statistics software packages offer a variety of significance tests. The
      major problem, however, is the correct choice of an appropriate significance test
      for the underlying data and design setting. In general, the choice of
      significance tests should decide between two sample versus one sample (i.e.
      interindividual versus intraindividual) analyses; a further determinant is the
      clinical endpoint's scale level (mainly continuous or categorical). Two sample
      comparisons can be performed using the Wilcoxon test for continuous endpoints and
      the exact Fisher test for binary endpoints. Intraindividual comparisons become
      feasible using the sign test for continuous and the McNemar test for binary
      endpoints. Time to event data can be analysed using the log rank test. If one
      measurement series has to be compared to a single reference value, the sign test
      can be applied for continuous data, the binomial test for binary data.

PMID- 12494377
TI  - [Entrapment neuropathies - quality requirements for neurological and
      neurophysiological diagnosis].
AB  - In some entrapment neuropathies, the diagnosis is easily established on clinical
      grounds. The best example is the carpal tunnel syndrome, the most frequently
      diagnosed entrapment neuropathy. Other entrapment neuropathies are not clear-cut:
      There is doubt that the syndrome exists at all or its limits are poorly defined,
      or the frequency is rather variable from one medical center to another. In this
      situation, a clarification of the diagnostic criteria may be necessary,
      especially with regard to the most common and the most disputed nerve
      entrapments.

PMID- 12494378
TI  - [Invited commentary on the article of M Stohr: entrapment neuropathies - quality
      requirements for neurological and neurophysiological diagnosis].

PMID- 12494379
TI  - [Standardized management of subtotal and total amputation injuries at the lower
      leg level - the "Integrated Treatment Concept"].

PMID- 12494380
TI  - [Fibronectin-chemotaxis and collagen-gel contraction of the palmar aponeurosis in
      morbus dupuytren].
AB  - Causes for Morbus Dupuytren (MD) on the cellular level are largely unknown. We
      have studied chemotaxis and collagen-gel contraction of cultivated cells from
      nodules and cords of Morbus Dupuytren patients and normal palmar aponeurosis. The
      cells of the seized tissue showed an increased chemotaxis in gradients of the
      chemo-attractant fibronectin. Furthermore embedded into collagen-gels cells from
      MD patients especially from the region of cords to the skin had an enhanced
      ability to contract a three-dimensional collagen network compared to those
      originating from the center of the nodules and control palmar aponeurosis. One
      reason for the increase of chemotactic motion and the ability to contract gels
      could be a surplus of receptors for extracellular matrix proteins (integrins) on
      the surface of cells from seized tissues. Flow cytometry of cells
      fluorimetrically stained for beta 1 -, alpha 2 - and alpha 3 -integrins displayed
      no differences in the quantity of these main cell surface receptors.

PMID- 12494381
TI  - [Therapy of the peromelic form of symbrachydactyly by double second-toe
      transplantation].
AB  - From 1989 to 2001 eleven children with the peromelic type of symbrachydactyly
      underwent a staged double second toes transplantation for restoration of two
      finger rays. The second toe of the feet were transplanted first to the small
      finger position and in the second step to the thumb position. One failure
      occurred in the first toe transplantation and another developed a venous
      thrombosis with partial necrosis and eventually a useless ray. Eight children
      were reviewed retrospectively in a mean follow-up of 5.3 years. The ability to
      pinch was restored in four children. In all patients without complications the
      function of the hand improved and the sensitivity was good.

PMID- 12494382
TI  - [Dystrophic epidermolysis bullosa: surgical treatment of advanced hand
      deformities].
AB  - Dystrophic epidermolysis bullosa (Hallopeau-Siemens, recessive dystrophic
      epidermolysis bullosa) is a rare inherited disorder of the skin and mucosa,
      characterized by blistering in response to the slightest mechanical trauma.
      Healing is associated with scarring and the formation of contractures and milia.
      Following repetitive trauma (friction), this process leads to severe hand
      deformities with digits contracted in flexion, the thumb contracted in adduction
      and pseudo-syndactyly. In advanced cases (as described here), the hands show a
      mitten-like deformity and digits are encased in an epidermal "cocoon". This
      results in complete loss of function with major consequences for both the
      patient's (children's) daily life and their psychosocial development. We
      demonstrate the advantages of the (simplified) surgical procedure including "de
      cocooning"/degloving, syndactyly-release, release of the thumb and the digital
      joint contractures and Kirschner-wire stabilization. Spontaneous
      epithelialisation of skin defects proved to be unproblematic and advantageous
      compared to skin transplantations, flaps, keratinocyte transplantations and other
      more ambitious procedures. Reviewing the published long-term results of other
      methods, we favour the procedure described because it simplifies and accelerates
      the overall treatment. From 1998 to 2001, we treated three children with
      recessive dystrophic epidermolysis bullosa and five hands were operated. A total
      number of 23 interventions was necessary (21 x using face masks, 2 x oral
      intubation). Pseudo-syndactyly (digits II - V, partially or totally) occurred in
      four hands after six to ten months. Flexion contractures of the digits occurred
      in two hands after eight to ten months. Limitating adduction contracture of the
      thumb occurred in two hands after eight to twelve months. Digital function (pinch
      and grasp) was actually preserved in two hands for 15 to 30 months. An active
      surgical approach is justified by the gain in functional improvement of the hand 
      even if only temporary - and, consecutively, by the positive effect on the
      child's development.

PMID- 12494383
TI  - [Late results following avulsion injuries of the thumb].
AB  - Out of the 127 amputated thumbs replanted at our unit during the last 15 years,
      there were 27 avulsion injuries. The average age of the 24 male patients was 33
      years, that of the three female patients was 34 years. 70 % of the injuries were
      occupational accidents. Among the 27 patients, 21 had a complete and six an
      incomplete avulsion of the thumb. The level of avulsion-amputation was at the MP
      joint ten times, between MP and IP joint ten times and at the IP-joint seven
      times. The healing rate of the subtotally avulsed thumbs was 100 %, that of the
      completely amputated thumbs 36 %. The most important post-operative complications
      observed were venous and secondary arterial thrombosis, whereby most of them
      occurred within the first 24 hours after replantation. The duration of ischaemia
      had a significant influence on the healing rate. In 80 % of the cases
      reconstruction of nerves have been carried out secondarily. A two-point
      discrimination was achieved in two cases only. The osteosynthesis was done almost
      exclusively with K-wires. Ten of 19 patients had to change their profession,
      while nine of them were able to return to their previous jobs, which in these
      cases were pre-dominantly white collar jobs. Another patient went for early
      retirement (he was a painter). All 19 patients followed-up had a range of
      movement of their saddle joints which was sufficient for the needs of most of the
      activities of daily life. Stiffness of the MP and IP joints was a common finding
      but had little functional impact, as it has been reported by other authors
      previously. We conclude from the results presented that in cases of avulsion
      injury of the thumb replantation is a procedure with significant chances of
      success.

PMID- 12494384
TI  - [Arthrolysis of the elbow joint in patients with heterotopic calcifications after
      burn injuries].

PMID- 12494385
TI  - [Narrowing of the third extensor tendon compartment in minimal displaced distal
      radius fractures with impending rupture of the EPL tendon].
AB  - Delayed ruptures of the extensor pollicis longus tendon (EPL) occur in about 0.7
      percent following undisplaced distal radius fractures. Two possible mechanisms
      are mainly discussed in the literature: A mechanical irritation of the tendon
      caused by a sharp edge of the fractured bone and a direct microvascular
      compromise of the poorly vascularized tendon. In undisplaced fractures, however,
      a mechanical irritation seems less likely. In the cases here described we were
      able to demonstrate a fragment displacement in the area of Lister's tubercle
      suspected by the native X-ray and further evaluated by a CT scan. The use of CT
      scans even in minor displaced distal radius fractures involving Lister's tubercle
      may demonstrate a direct contact of the EPL tendon with a sharp edge of this
      fractured bone and make adequate surgery possible.

PMID- 12494386
TI  - [Treatment of metacarpal fractures].
AB  - Conservative treatment of metacarpal fractures is recommended if there is no
      joint displacement, malrotation, displacement of over 30 degrees ad axim and
      shortening of over 5 mm. Surgery should be performed in open fractures and serial
      fractures of metacarpal bone. Early functional treatment should be carried out in
      stable, not displaced fractures. A cast can be used for a short period in full
      extended position of fingers and flexion in metacarpo-phalangeal joint in 60 - 90
      degrees. Twin-tape fixation allows functional treatment after soft-tissue
      swelling has disappeared. Closed reduction of displaced fractures of the fifth
      metacarpal bone (boxer's fracture) is not successful. Cases with displacement of
      over 30 degrees may be treated surgically by intramedullary stabilisation.

PMID- 12494387
TI  - [Invited commentary on the article of R Merk, J Rudigier: denervation of finger
      joints as an alternative procedure to arthrodesis or endoprosthesis].

PMID- 12494390
TI  - [Circumscribed median nerve compression caused by a leiomyoma. Preoperative
      localization with spiral CT].
AB  - Dysfunction of the median nerve is quite common and mostly observed related to
      carpal tunnel and pronator syndromes. We report a rare case of median nerve
      compression caused by a leiomyoma in the distal forearm. Spiral CT with MPR
      (multiplanar reconstruction) clearly located the lesion preoperatively.

PMID- 12494398
TI  - Fimbrial control of bidirectional synaptic plasticity of medial perforant path
      dentate transmission.
AB  - Lesions of the fimbria-fornix (FF) tract cause profound impairments of cognitive
      ability in animals. Our previous study showed that spatial performance correlates
      with long-term potentiation (LTP) of the dentate gyrus (DG), but not of the CA1
      region, in rats with bilateral FF lesions, suggesting that FF lesions selectively
      inhibited LTP in the DG. The cortical input to the DG is anatomically and
      physiologically divided into two types of afferents, i.e., the medial perforant
      path (MPP) and the lateral perforant path (LPP), which show distinct synaptic
      properties. To elucidate the difference in the FF modulation of these two inputs,
      field responses were recorded from MPP- or LPP-DG synapses in anesthetized rats.
      MPP-DG synapses of rats with FF lesions displayed neither LTP in response to
      theta-burst stimulation nor long-term depression (LTD) in response to low
      frequency burst stimulation. In contrast to the MPP, LPP-DG synapses showed
      normal LTP in rats with FF lesions. The low-frequency burst stimulation could not
      induce LTD at LPP-DG synapses in either intact or FF-lesioned rats. These results
      suggest that the FF pathway selectively supports the mechanisms of bidirectional
      synaptic plasticity at MPP-DG synapses. This study provides new insights into
      external control of information processing in the hippocampus.

PMID- 12494399
TI  - Regional infusions of serotonin into the striatum and memory consolidation.
AB  - Lesions, temporal inactivation, electrical stimulation and administration of
      drugs that antagonize synaptic activity of the striatum lead to significant
      deficits of memory. Also, it has been shown that interruption of dopaminergic,
      GABAergic, or cholinergic activity in discrete areas of this structure is
      sufficient to disrupt cognitive functions. In spite of the known interactions
      among dopamine, GABA, acetylcholine, and serotonin, there is a notable scarcity
      of data germane to the participation of striatal serotonin in learning and
      memory. It was important, therefore, to investigate the possible involvement of
      serotonin in cognition. In light of the differential distribution of serotonergic
      elements within the striatum, a prediction was made that focal injections of
      serotonin into distinctive regions would produce dissimilar effects on memory.
      Rats were trained in a one-trial step-through inhibitory avoidance task and a
      retention test was carried out 24 h later. Posttraining injections of serotonin
      into the dorsal and ventral aspects of the posterior region produced strong
      amnesia compared to similar injections into the dorsal and ventral aspects of the
      anterior region. The present findings support the hypothesis that striatal
      serotonergic activity is involved in memory functions and also provide further
      evidence of neurochemical heterogeneity within the striatum regarding memory
      consolidation.

PMID- 12494400
TI  - Increased dopamine D3 receptor expression accompanying behavioral sensitization
      to nicotine in rats.
AB  - Behavioral sensitization to nicotine, which appears following repeated nicotine
      administration, has been suggested to take part in the development of smoking
      habit in humans. The mesolimbic dopaminergic system plays a role in this process
      and a hypersensitivity of postsynaptic neurons of the nucleus accumbens as been
      proposed as a mechanism, but changes in dopamine D(1) or D(2) receptors have not
      been demonstrated to date. A challenge administration of nicotine (0.5 mg/kg
      s.c.) produced a strong increase in locomotor activity in rats repeatedly
      pretreated with nicotine (0.5 mg/kg s.c.), but not saline, once a day for 5 days.
      This behavioral sensitization was accompanied by an increase in D(3) receptor
      binding and mRNA in the shell of nucleus accumbens. D(3) receptor expression was
      unchanged in the core of nucleus accumbens and dorsal striatum, as it was in the
      shell of nucleus accumbens after an acute administration of nicotine to naive
      rats. In contrast, no changes were noticed in D(1) and D(2) receptor expressions
      in any brain region examined after chronic or acute treatment with nicotine. In
      addition, nicotine challenge decreased preprodynorphin and preprotachykinin mRNA
      levels in naive rats, but only preprotachykinin mRNA levels in rats pretreated
      with nicotine. These biochemical changes resemble those occurring during
      behavioral sensitization to levodopa of dopamine-denervated rats, which had been
      causally related to the induction of D(3) receptor expression. We propose that a
      similar mechanism is responsible for behavioral sensitization to nicotine.

PMID- 12494401
TI  - Presynaptic quantal plasticity: Katz's original hypothesis revisited.
AB  - Changes in the amplitudes of signals conveyed at synaptic contacts between
      neurons underlie many brain functions and pathologies. Here we review the
      possible determinants of the amplitude and plasticity of the elementary
      postsynaptic signal, the miniature. In the absence of a definite understanding of
      the molecular mechanism releasing transmitters, we investigated a possible
      alternative interpretation. Classically, both the quantal theory and the vesicle
      theory predict that the amount of transmitter producing a miniature is determined
      presynaptically prior to release and that rapid changes in miniature amplitude
      reflect essentially postsynaptic alterations. However, recent data indicates that
      short-term and long-lasting changes in miniature amplitude are in large part due
      to changes in the amount of transmitter in individual released packets that show
      no evidence of preformation. Current representations of transmitter release
      derive from basic properties of neuromuscular transmission and endocrine
      secretion. Reexamination of overlooked properties of these two systems indicate
      that the amplitude of miniatures may depend as much, if not more, on the Ca(2+)
      signals in the presynaptic terminal than on the number of postsynaptic receptors
      available or on vesicle's contents. Rapid recycling of transmitter and its
      possible adsorption at plasma and vesicle lumenal membrane surfaces suggest that
      exocytosis may reflect membrane traffic rather than actual transmitter release.
      This led us to reconsider the disregarded hypothesis introduced by Fatt and Katz
      (1952; J Physiol 117:109-128) that the excitability of the release site may
      account for the "quantal effect" in fast synaptic transmission. In this case,
      changes in excitability of release sites would contribute to the presynaptic
      quantal plasticity that is often recorded.

PMID- 12494402
TI  - Visualization of alpha5 subunit of GABAA/benzodiazepine receptor by 11C Ro15-4513
      using positron emission tomography.
AB  - Although [(11)C]Ro15-4513 and [(11)C]flumazenil both bind to the central
      benzodiazepine (BZ) receptors, the distributions of the two ligands are not
      identical in vivo. Moreover, the in vivo pharmacological properties of
      [(11)C]Ro15-4513 have not been thoroughly examined. In the present study, we
      examined the pharmacological profile of [(11)C]Ro15-4513 binding in the monkey
      brain using positron emission tomography (PET). [(11)C]Ro15-4513 showed
      relatively high accumulation in the anterior cingulate cortex, hippocampus, and
      insular cortex, with the lowest uptake being observed in the pons. Accumulation
      in the cerebral cortex was significantly diminished by the BZ antagonist
      flumazenil (0.1 mg/kg, i.v.), but not that in the pons. Using the pons as a
      reference region, the specific binding of [(11)C]Ro15-4513 in most of the
      cerebral cortex including the limbic regions clearly revealed two different
      affinity sites. On the other hand, specific binding in the occipital cortex and
      cerebellum showed only a low affinity site. Zolpidem with affinity for alpha1,
      alpha2, and alpha3 subunits of GABA(A)/BZ receptor fully inhibited [(11)C]Ro15
      4513 binding in the occipital cortex and cerebellum, while only about 23% of the
      binding was blocked in the anterior cingulate cortex. Diazepam with affinity for
      alpha1, alpha2, alpha3, and alpha5 subunits inhibited the binding in all brain
      regions. Since Ro15-4513 has relatively high affinity for the alpha5 subunit in
      vitro, these in vivo bindings of [(11)C]Ro15-4513 can be interpreted as the
      relatively high accumulation in the fronto-temporal limbic regions representing
      binding to the GABA(A)/BZ receptor alpha5 subunit.

PMID- 12494403
TI  - Effect of isolation rearing on pre- and post-synaptic serotonergic function in
      the rat dorsal hippocampus.
AB  - Several behavioural, neurochemical, and structural alterations found in isolation
      reared rats are similar to those in human schizophrenia. This study investigated
      changes in cholinergic and serotonergic function in the hippocampus following
      isolation rearing. Rats were reared in social isolation from weaning for 6 weeks
      before study and compared to group-reared rats. An in vitro electrophysiological
      study investigated the effect of isolation rearing on postsynaptic 5-HT(1A)
      function on CA1 hippocampal neurones activated with the muscarinic agonist
      carbachol and found no change in the sensitivity of these postsynaptic receptors
      between the groups. However, a change in presynaptic function was identified, as
      there was a significant reduction in the time taken for neuronal firing to
      recover to 50% of the original rate following 5-HT (10 microM) application, in
      isolation compared to group-reared rats. These data suggest a possible change in
      reuptake following isolation. Uptake studies using (3)[H]5-HT, however, found no
      change in the inhibition of uptake produced by either fluoxetine or paroxetine in
      isolation compared to group-reared rats. The selective 5-HT(1B) antagonist CP
      294253 (1 microM), increased endogenous 5-HT release from hippocampal slices in
      vitro and this effect was greater (P < 0.001) in group compared to isolation
      reared rats. These results indicate that the change in presynaptic 5-HT neuronal
      function was due to impaired autoreceptor responsiveness. Carbachol (1 microM)
      increased the firing rate of all neurones recorded but only a proportion of these
      showed a concentration-related increase. Isolation rearing increased the
      sensitivity of neurones, showing a concentration-related increase in firing in
      response to carbachol, but had no effect on the other neurones. In summary, the
      present study showed that isolation rearing alters presynaptic 5-HT(1B) but not
      postsynaptic 5-HT(1A) receptor activity in the hippocampus. Isolation rearing in
      the rat results in hippocampal dysfunction, including reduced serotonergic and
      enhanced muscarinic activity of some neurones. These effects may in part underlie
      the behavioural consequences of isolation relevant to human developmental
      disorders.

PMID- 12494404
TI  - Creation, expression, and characterization of a constitutively active mutant of
      the human serotonin 5-HT6 receptor.
AB  - The serotonin 5-HT(6) receptor, a G-protein-coupled receptor, displays high
      affinity for antipsychotic, antidepressant, and psychotropic drugs. We created a
      constitutively active form of the human 5-HT(6) receptor in order to probe the
      molecular domains of receptor activation and to determine if inverse agonist
      activities of antipsychotic drugs contribute to their clinical profile. Previous
      studies from our laboratory support a critical role for the c-terminal region of
      the third intracellular loop (il3) in the activation of G(q)-coupled serotonin
      receptors. In the present study, PCR-based mutagenesis was used to mutate serine
      267 (S6.34) in the c-terminal region of il3 to lysine (S267K). The native and
      S267K 5-HT(6) receptors were expressed in COS-7 cells to study the functional
      effects of the mutation. The S267K receptor shows 10-fold higher affinity for
      serotonin than the native receptor and demonstrates agonist-independent activity.
      Clozapine decreased the basal activity of the S267K receptor to vector control
      levels. Therefore, we can conclude that the S267K mutation renders the 5-HT(6)
      receptor constitutively active and that clozapine is an inverse agonist at the
      mutant 5-HT(6) receptor. These results indicate that the c-terminal region of il3
      of the G(s)-coupled 5-HT(6) receptor is a key domain for G-protein coupling,
      similar to the G(q)-coupled 5-HT receptors. The inverse agonist action of
      clozapine indicates that drugs displaying competitive antagonist activity at
      native 5-HT(6) receptors may display inverse agonist activity at the
      constitutively activated form of the receptor.

PMID- 12494405
TI  - Regional differences in sympathetic purinergic transmission along the length of
      the mouse vas deferens.
AB  - Contraction of the smooth muscle in the mouse vas deferens is elicited by
      sympathetic nerves releasing at least two neurotransmitters, adenosine
      triphosphate (ATP) and noradrenaline (NA). Several studies have indicated the
      presence of regional variation in the purinergic and noradrenergic contributions
      to sympathetic nerve-evoked contractions in rodent vasa deferentia. We examined
      the relative contribution of ATP and NA to neurotransmission and contraction at
      the prostatic and epididymal ends of the mouse vas deferens. The success rate of
      recording excitatory junction currents (EJCs, extracellular indication of ATP
      release) from varicosities at the prostatic end of the vas deferens was eight
      times greater than for varicosities located at the epididymal end. Both regions
      of the vas deferens responded similarly to focal application of NA and ATP.
      Furthermore, the relative density and distribution of P2X(1)-receptor mRNA and
      anti-P2X(1) immunostaining did not differ between the two regions. Our results
      suggest that most varicosities located at the epididymal end of the vas deferens
      are releasing an insufficient amount of ATP to evoke detectable EJCs.

PMID- 12494406
TI  - D-tubocurarine reduces GABA responses in rat substantia nigra dopamine neurons.

PMID- 12494407
TI  - The mGluR5 antagonist MPEP reduces the conditioned rewarding effects of cocaine
      but not other drugs of abuse.
AB  - We examined the ability of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a
      selective antagonist of the type 5 metabotropic glutamate receptor (mGluR5), to
      reduce the rewarding effects of various drugs of abuse in the conditioned place
      preference (CPP) paradigm. Mice were treated with MPEP (1, 5, and 20 mg/kg i.p.)
      10 min prior to cocaine (15 mg/kg i.p.), D-amphetamine (2 mg/kg i.p.), nicotine
      (0.5 mg/kg i.p.), morphine (5 mg/kg i.p.), or ethanol (2 g/kg i.p.) on 3
      successive days of CPP conditioning trials. MPEP pretreatment dose-dependently
      reduced the development of CPP for cocaine only. When tested alone at the doses
      effective in reducing CPP, MPEP produced neither a place preference nor aversion.
      These data provide further support for a role of the mGluR5 receptor in the
      rewarding effects of cocaine.

PMID- 12494408
TI  - Direct adsorption of low-density lipoprotein and lipoprotein(a) from whole blood:
      results of the first clinical long-term multicenter study using DALI apheresis.
AB  - Direct adsorption of lipoproteins (DALI) is the first low-density lipoprotein
      (LDL)-apheresis technique by which atherogenic LDL and lipoprotein(a) (Lp(a)) can
      be selectively removed from whole blood without plasma separation. The present
      study was performed to evaluate the efficacy, selectivity and safety of long-term
      DALI apheresis. Sixty-three hypercholesterolemic coronary patients were treated
      by weekly DALI sessions. Initial LDL-cholesterol (C) plasma levels averaged 238
      +/- 87 mg/dl (range 130-681 mg/dl). On average, 34 sessions (1-45) were performed
      processing 1.5 patient blood volumes. The primary aim was to acutely reduce LDL-C
      by >or=60% per session. To this end, three different adsorber sizes could be
      employed, i.e., DALI 500, 750, and 1000, which were used in 4, 73, and 23% of the
      2156 sessions, respectively. On average, 7387 ml of blood were processed in 116
      min per session. This resulted in the following mean acute changes: LDL-C 198 -->
      63 mg/dl (-69%), Lp(a) 86 --> 32 mg/dl (-64%), triglycerides 185 --> 136 mg/dl (
      27%). HDL-C (-11%) and fibrinogen (-15%) were not significantly influenced. The
      mean long-term reduction of LDL-C was 42% compared to baseline while HDL-C
      slightly increased in the long run (+4%). The selectivity of LDL removal was good
      as recoveries of albumin, immunoglobulins, and other proteins exceeded 85%.
      Ninety-five percent of 2156 sessions were completely uneventful. The most
      frequent adverse effects were hypotension (1.2% of sessions) and paresthesia
      (1.1%), which were probably due to citrate anticoagulation. Access problems had
      to be overcome in 1.5%, adsorber and hardware problems in 0.5% of the sessions.
      In this multicenter long-term study, DALI apheresis proved to be an efficient,
      safe, and easy procedure for extracorporeal LDL and Lp(a) elimination.

PMID- 12494409
TI  - A randomized comparison of plateletpheresis with the same donors using four blood
      separators at a single blood center.
AB  - At one blood center, each of 20 donors underwent plateletpheresis on four blood
      cell separators in random order. We compared the CS3000+, Amicus V 2.41, MCS
      Plus, and Spectra LRS V 7 Turbo regarding platelet (PLT) yield, pre- and post
      procedure PLT counts, percent fall in donor PLT count, process time, efficiency,
      PLT product and donor PLT volume (MPV). Using >or= 150 x 10(9) PLTs/L pre
      donation counts, a goal was set of 4.5 x 10(11) PLTs unit in up to 100 minutes
      processing time. Results were (mean values) PLT yields of Amicus, Spectra,
      CS3000+, and MCS Plus: 4.3, 4.6, 4.3, 4.0 x 10(11) PLTS, respectively; percent
      donor PLT fall: 24, 32, 30, 29%, respectively; processing times: 50, 74, 87, 101
      minutes, respectively; relative efficiency (RE): 2.2, 1.6, 1.2,1.0, respectively
      (based on the MCS Plus performance with RE of 1 = 4 x 10(9) PLTS/min); PLT
      product MPV: 6.7, 7.4, 6.8,7.1 fL, respectively; pre-procedure donor MPV: 7.7,
      7.3, 7.6 and 7.6 fL, respectively; and percent donor MPV change: -5.2, 0, -6.6,
      and -10%, respectively. Significant changes in the donor MPV were noted (P <
      0.05) but could not be related to product MPV. Spectra seemed to collect larger
      PLTs (higher MPV); the significance remains unknown for both donors and
      recipients. Importantly, all four separators gave acceptable and comparable PLT
      yields (P < 0.05) with Spectra trending higher. The short process time and high
      RE together indicate highly efficient collections particularly by Amicus and
      Spectra.

PMID- 12494410
TI  - Extracorporeal photopheresis reduces the number of mononuclear cells that produce
      pro-inflammatory cytokines, when tested ex-vivo.
AB  - Extracorporeal photopheresis (ECP) has been shown to be clinically effective in
      the treatment of many T cell-mediated conditions. ECP's mechanism of action
      includes the induction of apoptosis and the release of pro-inflammatory
      cytokines. Recently, we have observed early lymphoid apoptosis, detectable
      immediately post ECP. We were interested to determine what influence ECP has on
      pro-inflammatory cytokine secretion at this early pre-infusion stage. Samples
      from 6 cutaneous T cell lymphoma (CTCL) and 5 graft versus host disease (GvHD)
      patients were taken pre ECP and immediately post ECP, prior to re-infusion.
      Following separation, the PBMCs were added to a cell culture medium and
      stimulated with PMA, Ionomycin, and Brefeldin A for 6 hours. Using flow
      cytometry, intracellular cytokine expression of IFNgamma and TNFalpha was
      determined in the T cell population. The monocytes were evaluated for IL6,
      IFNgamma, IL12, and TNFalpha. For both patient groups, the number of IFNgamma
      expressing T cells fell significantly at re-infusion, whilst both T cell- and
      monocyte-expressing TNFalpha levels were reduced at re-infusion. All other
      cytokines tested showed no significant change post ECP. For GvHD, pro
      inflammatory cytokines have a pathological role. Their down-regulation may have a
      direct clinical benefit. However, the reduction in the number of IFNgamma- and
      TNFalpha-expressing mononuclear cells means, at this early stage, it is unlikely
      that these cytokines assist in the removal of the malignant Th2 cells present in
      CTCL.

PMID- 12494411
TI  - Development of an in vitro miniature model to simulate immunoadsorption in
      patients with systemic lupus erythematosus.
AB  - In SLE, immunoadsorption is used as an adjuvant therapy; however, adsorption
      profiles and binding mechanisms have not yet been completely investigated. Using
      a minicolumn filled with the sorbent IMPH with or without the ligand
      phenylalanine, we developed a model simulating clinical conditions in a reduced
      scale with a constant ratio of plasma to column volume and a constant plasma flow
      at room temperature. By desorbing the column, the adsorption efficacy for
      different antibodies could be measured directly. We demonstrate that the
      adsorption rate can be increased by a low plasma flow and by covering the column
      surface. Double perfusion of the same column did not increase the amount of
      adsorbed antibodies. We further demonstrate that the carrier material without a
      ligand is unable to bind antibodies or protein. In the IMPH sorbent anti-dsDNA
      antibodies were significantly better adsorbed than total IgG or total protein.
      After a single perfusion of 21 samples, we estimated a mean anti-dsDNA antibody
      adsorption rate of 22.5% (+/-13.6). A group of ten responders with a medium
      adsorption rate of 35.4% (+/-6.5) clearly differed from a second group of eleven
      nonresponders (10.9% +/- 4.2). Anti-cardiolipin antibodies (ACA) were adsorbed in
      a wide range (IgG type, 2.5-52.7%, IgM type, 1.1-37.8%) while anti-Ro (SSA)
      antibody adsorption was negligible. This in vitro minimodel provides a precise
      simulation of therapeutic immunoadsorption and helps to analyze the binding
      characteristics of the sorbent IMPH and shows its effectiveness in several
      antibody subsets of different patients.

PMID- 12494412
TI  - Maximal flow rates and sieving coefficients in different plasmafilters: effects
      of increased membrane surfaces and effective length under standardized in vitro
      conditions.
AB  - In Europe, capillary membrane filters are the favored method for plasmapheresis
      and detoxification systems including a plasma separation unit. Using capillary
      membrane filters clearance depends on the filtration rate and the sieving
      coefficient (Qs) for the plasma substrates. We investigated whether the increase
      of the effective membrane surface of plasmafilters enables higher clearance rates
      than a small plasmafilter. Heparinized porcine blood (5 I.U./l) of healthy pigs
      was used for an in vitro circuit. Filter types used were from GAMBRO: n = 5
      PF1000N (effective membrane surface: 0.15 m(2)), n = 4 PF2000N (0.35) and from
      ASAHI: n = 4 PLASMAFLO OP-05W (L) (0.5). Spontaneous hemolysis was chosen to
      indicate the individual threshold limit for maximal flow rates. Sieving
      coefficient was determined for ten parameters at lowest and highest blood flow
      (Qb) and filtration rates (Qf). PF1000N enabled maximal flow rates as high as
      PF2000N and PLASMAFLO (Qb/Qf in ml/min: 200/40). Qs for most substrates were
      similar between the filter types and the flow rates. Compared to PLASMAFLO, the
      filter type with the largest membrane surface, the PF1000N provided significantly
      better Qs for triglycerides and albumin and a trend for a better elimination of
      cholesterol, GGT, and LDH. The sieving properties of the PF2000N ranged between
      PF1000N and PLASMAFLO. Under standardized in vitro conditions, the larger
      plasmafilters tested did not improve the overall performance of the
      plasmapheresis procedure. Thus, enlargement of the membrane surface such as
      provided by two commercially available and clinically well-established
      plasmafilters could not be proven to enable higher clearance rates.

PMID- 12494413
TI  - Fuji surge technique and continuous in-line filtration to improve the quality of
      single donor platelet concentrates.
AB  - White blood cell (WBC)-reduced single donor platelet concentrates (SDPs) can be
      collected by most cell separators. WBC reduction can be achieved directly during
      plateletpheresis or by filtration. Continuous filtration with low filtration
      rates provides SDPs of good purity. To compensate the platelet (PLT) loss due to
      filtration, the PLT yield in the unfiltered primary product should be optimal.
      Fifty donors underwent plateletpheresis with the MCS+ blood cell separator
      (Haemonetics) with the new Fuji surge technique and continuous WBC filtration.
      Twelve SDPs were analysed for PLT yield, red blood cells (RBC), WBC, and pH after
      collection (Day 0) and at the end of storage (Day 5). Thereafter, further 38 SDPs
      were measured for PLT and WBC content in routine production at Day 0. PLT were
      determined electronically, RBC and WBC were counted manually (Neubauer and
      Nageotte chamber, respectively). For pH measurement, a pH-meter was used. Mean
      blood volume processed was 2621 +/- 112 ml in a donation time of 76 +/- 10 min.
      An average PLT yield of 3.45 +/- 0.88 x 10(11) was collected in a product volume
      of 325 +/- 77 ml. The collection efficiency was 60.0 +/- 5.5%. WBC contamination
      of all units tested was 0.046 +/- 0.059 x 10(6) and the RBC content of the SDPs
      analysed at Day 0 was 0.014 +/- 0.003 x 10(9). The pH was well maintained over
      the storage period of 5 days. The data indicate that Fuji surge technique and
      continuous in-line leukocyte filtration allow for the collection of SDPs with
      high platelet yield and low leukocyte contamination, meeting the Council of
      Europe quality standards.

PMID- 12494414
TI  - First two patients with ulcerative colitis who developed classical thrombotic
      thrombocytopenic purpura successfully treated with medical therapy and plasma
      exchange.
AB  - The association of ulcerative colitis (UC) and thrombotic thrombocytopenic
      purpura (TTP) is rare. Only one prior patient with these two syndromes has been
      reported in the literature. In that case, splenectomy and proctectomy were
      performed to control the symptoms of TTP. We present two patients with UC who
      developed TTP and were successfully treated with multiple plasma exchanges (PEXs)
      in conjunction with medical therapy without the necessity for surgical
      intervention. Acquired TTP may be another extraintestinal autoimmune feature of
      UC. TTP in association with UC may be refractory to high-dose steroids and PEX,
      possibly requiring vincristine and splenectomy, as in the one previously reported
      case, to achieve remission.

PMID- 12494415
TI  - Plasma exchange: why we do what we do.

PMID- 12494416
TI  - Studies of carcinogenicity of bitumen fume in humans.

PMID- 12494417
TI  - Estimating exposures in the asphalt industry for an international epidemiological
      cohort study of cancer risk.
AB  - BACKGROUND: An exposure matrix (EM) for known and suspected carcinogens was
      required for a multicenter international cohort study of cancer risk and bitumen
      among asphalt workers. METHODS: Production characteristics in companies enrolled
      in the study were ascertained through use of a company questionnaire (CQ).
      Exposures to coal tar, bitumen fume, organic vapor, polycyclic aromatic
      hydrocarbons, diesel fume, silica, and asbestos were assessed semi-quantitatively
      using information from CQs, expert judgment, and statistical models. Exposures of
      road paving workers to bitumen fume, organic vapor, and benzo(a)pyrene were
      estimated quantitatively by applying regression models, based on monitoring data,
      to exposure scenarios identified by the CQs. RESULTS: Exposures estimates were
      derived for 217 companies enrolled in the cohort, plus the Swedish asphalt paving
      industry in general. Most companies were engaged in road paving and asphalt
      mixing, but some also participated in general construction and roofing. Coal tar
      use was most common in Denmark and The Netherlands, but the practice is now
      obsolete. Quantitative estimates of exposure to bitumen fume, organic vapor, and
      benzo(a)pyrene for pavers, and semi-quantitative estimates of exposure to these
      agents among all subjects were strongly correlated. Semi-quantitative estimates
      of exposure to bitumen fume and coal tar exposures were only moderately
      correlated. EM assessed non-monotonic historical decrease in exposures to all
      agents assessed except silica and diesel exhaust. CONCLUSIONS: We produced a data
      driven EM using methodology that can be adapted for other multicenter studies.

PMID- 12494418
TI  - Cancer mortality among European asphalt workers: an international epidemiological
      study. I. Results of the analysis based on job titles.
AB  - BACKGROUND: Inhalation of bitumen fumes is potentially carcinogenic to humans.
      METHODS: We conducted a study of 29,820 male workers exposed to bitumen in road
      paving, asphalt mixing and roofing, 32,245 ground and building construction
      workers unexposed to bitumen, and 17,757 workers not classifiable as bitumen
      workers, from Denmark, Finland, France, Germany, Israel, the Netherlands, Norway,
      and Sweden, with mortality follow-up during 1953-2000. We calculated standardized
      mortality ratios (SMRs) and 95% confidence intervals (CIs) based on national
      mortality rates. Poisson regression analyses compared mortality of bitumen
      workers to that of building or ground construction workers. RESULTS: The overall
      mortality was below expectation in the total cohort (SMR 0.92, 95% CI 0.90-0.94)
      and in each group of workers. The SMR of lung cancer was higher among bitumen
      workers (1.17, 95% CI 1.04-1.30) than among workers in ground and building
      construction (SMR 1.01, 95% CI 0.89-1.15). In the internal comparison, the
      relative risk (RR) of lung cancer mortality among bitumen workers was 1.09 (95%
      CI 0.89-1.34). The results of cancer of the head and neck were similar to those
      of lung cancer, based on a smaller number of deaths. There was no suggestion of
      an association between employment in bitumen jobs and other cancers. CONCLUSIONS:
      European workers employed in road paving, asphalt mixing and other jobs entailing
      exposure to bitumen fume might have experienced a small increase in lung cancer
      mortality risk, compared to workers in ground and building construction. However,
      exposure assessment was limited and confounding from exposure to carcinogens in
      other industries, tobacco smoking, and other lifestyle factors cannot be ruled
      out.

PMID- 12494419
TI  - Cancer mortality among European asphalt workers: an international epidemiological
      study. II. Exposure to bitumen fume and other agents.
AB  - BACKGROUND: An increased risk of lung cancers among asphalt workers has been
      suggested in epidemiological studies based on large scale statistical analyses.
      METHODS: In a multi-country study of 29,820 male workers employed in road paving,
      asphalt mixing and roofing, 32,245 ground and building construction workers and
      17,757 other workers from Denmark, Finland, France, Germany, Israel, the
      Netherlands, Norway, and Sweden, with mortality that was documented from 1953
      2000. Exposures to bitumen fume, coal tar, 4-6 ring polycyclic aromatic
      hydrocarbons, organic vapor, diesel exhaust, asbestos, and silica dust were
      assessed via a job-exposure matrix. Standardized mortality ratios (SMRs) and 95%
      confidence intervals (CIs) based on national mortality rates, as well as relative
      risks (RRs) based on Poisson regression models were calculated. RESULTS: The SMR
      of lung cancer among workers exposed to bitumen fume (1.08, 95% CI 0.99-1.18) was
      comparable to that of non-exposed workers (SMR 1.05, 95% CI 0.92-1.19). In a sub
      cohort of bitumen-exposed workers without exposure to coal tar, the SMR of lung
      cancer was 1.23 (95% CI 1.02-1.48). The analysis based on the semi-quantitative,
      matrix-based exposures in the whole cohort did not suggest an increased lung
      cancer risk following exposure to bitumen fume. However, in an analysis
      restricted to road pavers, based on quantitative estimate of bitumen fume
      exposure, a dose-response was suggested for average level of exposure, applying a
      15-year lag, which was marginally reduced after adjustment for co-exposure to
      coal tar. The results for cancer of the head and neck were similar to those of
      lung cancer, although they were based on a smaller number of deaths. There was no
      clear suggestion of an association with bitumen fume for any other neoplasm.
      CONCLUSIONS: The results of the analysis by bitumen fume exposure do not allow us
      to conclude on the presence or absence of a causal link between exposure to
      bitumen fume and risk of cancer of the lung and the head and neck.

PMID- 12494420
TI  - Performance of different exposure assessment approaches in a study of bitumen
      fume exposure and lung cancer mortality.
AB  - BACKGROUND: We compared performance of different exposure assessment approaches
      in a cohort study of cancer risk among European asphalt workers. METHODS: Three
      bitumen fume exposure indices (duration of exposure (years), average exposure
      (mg/m3) and cumulative exposure (mg/m3*years)) and two latency models (with and
      without a 15 year lag) were considered for an association between lung cancer
      mortality and bitumen fume. RESULTS: There was no association between lung cancer
      risk and either duration or cumulative exposure. However, there was the
      suggestion of an increase in lung cancer risk accompanying rise in average
      exposure. Only models with average bitumen fume exposure (with or without lag)
      improved model fit, albeit to the same extent. CONCLUSIONS: Constructing
      quantitative indices of exposure intensity was justified because they produced
      the greatest improvement in fit of models that explored possible relationship
      between bitumen fume exposure and lung cancer risk. The identified associations
      require further investigation.

PMID- 12494421
TI  - Mortality and cancer incidence of workers in Finnish road paving companies.
AB  - BACKGROUND: This study, a component of the International Agency for Research on
      Cancer (IARC) Multicentric Study on Cancer Risk Among European Asphalt Workers,
      aimed at identifying major mortality risks among workers in Finnish road paving
      companies. METHODS: The Finnish cohort was comprised of 9,643 men and women from
      six road paving companies. The mortality of men employed during at least one
      season (5,676) was followed up from 1964 until end of 1994; an average of 17
      years. Standardized mortality ratios (SMR) and relative risks (RR), the latter
      based on multivariate Poisson regression models were estimated by occupational
      group and by various metrics of occupational exposures. RESULTS: All-cause
      mortality was elevated (SMR 1.11, 95% confidence interval, CI 1.03-1.20), mainly
      due to excesses in accidents, poisonings, and violence (1.29; CI 1.12-1.49), and
      lung cancer (1.38; 1.03-1.81). Workers exposed to bitumen fumes had a slightly
      elevated mortality from lung cancer (1.16; 0.69-1.83). Multivariate Poisson
      regression models with 15-year lag period suggested trends by cumulative exposure
      to coal tar, organic vapors, silica dust, diesel exhaust, and bitumen fume.
      CONCLUSIONS: The elevated mortality from external causes among Finnish
      building/ground construction workers was probably due to living conditions and
      related lifestyles. Some evidence was found for a risk of lung cancer due to
      occupational exposure, but the confirmation of these findings would require a
      longer follow-up and improved control for confounding.

PMID- 12494422
TI  - Cohort mortality study among French asphalt workers.
AB  - BACKGROUND: In conjunction with the European cohort study among asphalt workers
      coordinated by the International Agency for Research on Cancer (IARC), we studied
      the mortality of 15,011 French men who were followed for 17 years for a total of
      175,062 persons-years. This group contained 2,506 subjects who had ever been
      employed as asphalt workers: they contributed 30,692 person-years of risk. A
      reference group was composed of 6,675 subjects (i.e., 61,856 persons-years) who
      had been employed only in building or ground construction. METHODS: Mortality
      ratios standardized for age and period were computed with their 95% confidence
      intervals (CI) from the age and period mortality rates of all French men for the
      years covered by the study (1979-1996). We also compared the mortality of exposed
      workers and the reference group with Poisson regression models after adjustment
      for age, calendar period, and either duration of employment or length of follow
      up. RESULTS: Mortality from lung cancer was equivalent to the expected rate [SMR
      = 1.01 95% CI (0.6-1.6)], but was 40% greater than among the non-exposed
      reference group [RR = 1.4 95% CI (0.7-2.8)]. We also found an excess of
      gastrointestinal cancers, especially of the esophagus [SMR = 1.94, 95% CI (0.9
      3.6)] and stomach [SMR = 2.2, 95% CI (0.8-4.7)]. Comparison with the internal
      reference group confirmed these findings, especially for stomach cancer [RR =
      2.8, 95% CI (0.7-11.4)]. CONCLUSIONS: Although our results are not statistically
      significant, they suggest that road-paving workers may have a slightly higher
      rate of lung cancer and a moderately higher rate of stomach cancer than their non
      exposed counterparts. The excess of lung cancer may be due to potential
      confounding factors, including the occupational risk factor of coal tar exposure
      and the lifestyle risk factor of smoking. A nested case-control study is under
      way that will make it possible to control for smoking and other potential
      carcinogenic exposures; this is necessary before any definitive conclusions can
      be drawn.

PMID- 12494423
TI  - Epidemiologic study of cancer mortality among Israeli asphalt workers.
AB  - BACKGROUND: We describe the results of a cancer mortality study among asphalt
      workers in Israel. METHODS: Personal identifiers and employment histories of
      2,176 workers were extracted from company records. RESULTS: Mortality from all
      malignant neoplasms was significantly reduced in the whole cohort (SMR 0.68, 95%
      confidence interval (CI) 0.56-0.83). SMR for lung cancer was elevated in workers
      exposed to bitumen (SMR 1.05, 95% CI 0.62-1.66). No significant elevation or
      reduction in mortality was observed in relation to a specific site. SMRs for lung
      cancer was higher among ever exposed to bitumen than among unexposed. There was
      no association between lung cancer risk and estimated exposure to bitumen fume,
      and no dose-response was apparent. CONCLUSIONS: While the results of this cohort
      study indicate a slightly increased SMR for lung cancer, it did not produce
      evidence of a causal link between lung cancer and exposure to bitumen fume.

PMID- 12494424
TI  - Lung cancer mortality in a Dutch cohort of asphalt workers: evaluation of
      possible confounding by smoking.
AB  - BACKGROUND: Using data from a Dutch cohort of workers in road construction and
      asphalt mixing companies, this article describes possible confounding of the
      association between exposure to bitumen fume and lung cancer mortality by
      smoking. METHODS: A retrospective cohort of 3,714 workers with at least one
      season of employment was identified. Semi-quantitative exposure to bitumen fume
      was assessed by a job-exposure matrix. Information on smoking habits was
      available for a sub-cohort of 1,138 workers, who underwent medical examinations
      by the occupational health services in the past. RESULTS: Smoking habits differed
      between occupational title groups and there was a positive association between
      cumulative exposure and smoking. Internal analyses using the non-exposed subjects
      as reference category, showed a positive association between semi-quantitative
      bitumen fume exposure and lung cancer risk. After adjusting for differences in
      smoking habits, all relative risks were reduced, but a weak positive association
      could still be observed. CONCLUSION: Confounding by smoking on the association
      between exposure to bitumen fume and lung cancer mortality is possible, although
      the positive trend (not statistically significant) for lung cancer mortality
      remained. Only a nested case-control study may allow proper treatment of
      potential (residual) confounding by smoking in this population.

PMID- 12494425
TI  - Cancer incidence among male Norwegian asphalt workers.
AB  - BACKGROUND: The main objective of the present study was to investigate whether
      exposure to bitumen fumes could enhance the risk of cancer in asphalt workers.
      METHODS: A historical prospective cohort study was performed including 8,763 male
      asphalt workers from all main asphalt companies in Norway. Name, date of birth,
      and unique personal identification number, address, job type, and start and stop
      of employment in specific jobs was obtained for the workers. Information was
      complied from payroll and personnel records in the companies. The cohort was then
      linked to the Cancer Registry of Norway, which has complete records of individual
      cases of cancer in the Norwegian population since 1953. Follow-up was from 1
      January 1970 to 31 December 1997. The 5-year age and period adjusted general male
      population in Norway served as reference population. RESULTS: Lung cancer was
      found elevated with standardized incidence ratio (SIR) = 1.3 (95% confidence
      intervals (CI) = 1.1, 1.7) in the overall analysis. Lung cancer was found more
      elevated in workers first exposed in the 1950s and 1960s and in mastic asphalt
      workers (SIR = 4.2, 95% CI = 1.2, 10, based on four cases) and pavers (SIR = 1.4,
      95% CI = 1.0, 1.9). There was a deficiency in the incidence of malignant melanoma
      with 13 cases versus 26 expected. CONCLUSIONS: Risk of lung cancer was found
      enhanced among the asphalt workers. Some of the enhanced risk could probably be
      explained by the smoking habits of the workers. Exposure to coal tar may also
      have contributed to the enhanced risk.

PMID- 12494426
TI  - Mortality from non-malignant diseases among male Norwegian asphalt workers.
AB  - BACKGROUND: The possible associations between asphalt work and mortality from non
      malignant diseases in a cohort of male Norwegian asphalt workers that formed part
      of the European asphalt worker mortality study are examined. METHODS: The
      mortality experience among 8,610 male workers ever employed in asphalt work was
      observed from 01.01.1970 until 12.31.1996, yielding 127,636 person years of
      observation. The cause-specific deaths observed in the study cohort were compared
      with the expected figures calculated from 5-year period- and age-specific
      national death rates. A study-specific job exposure matrix was used for
      individual-individual exposure estimates. RESULTS: Eight hundred and three
      workers died during the observation period (SMR = 0.92, 95% confidence intervals
      (CI) = 0.58, 1.40). The mortality from non-malignant respiratory diseases was
      elevated (SMR = 1.25, 95%CI = 0.97, 1.58) and was associated with years since
      first employment in the asphalt industry. Mortality from respiratory diseases was
      highest among the workers first employed in the 1960s. Among the different job
      types held by the workers the pavers and mastic asphalt workers had the highest
      mortality from respiratory diseases. A weak dose-response was found with
      cumulative exposure to PAH and bitumen fume and mortality from non-malignant
      respiratory diseases in analyses employing the job-exposure matrix. Overall
      mortality, the mortality from circulatory diseases (SMR = 0.93, 95%CI = 0.83,
      1.03) and external causes (SMR = 0.90, 95%CI = 0.72, 1.11) was lower than
      expected. CONCLUSIONS: Mortality from respiratory diseases was found somewhat
      elevated among the asphalt workers. There was some evidence of exposure-response
      with both bitumen fume and PAH exposure. PAH from coal tar contributes to the PAH
      exposure.

PMID- 12494427
TI  - Cancer morbidity in Swedish asphalt workers.
AB  - BACKGROUND: Some studies have indicated an increased risk of lung cancer among
      asphalt workers. This study investigates the risk of lung cancer in Swedish
      asphalt workers. METHODS: A cohort of 6,150 asphalt workers, mainly employed in
      road construction, was compared to the general population, and to a reference
      group of construction workers not exposed to asphalt fumes. The exposure to
      polyaromatic hydrocarbons (PAH) at paving in Sweden during the 1980s and 1990s
      were estimated to be in the order of one or a few micrograms per cubic meter, but
      must have been higher in earlier years. RESULTS: Thirty-two lung cancer cases
      were observed among asphalt workers. The relative risk (SIR) and 95% confidence
      intervals were 0.98 (0.67-1.39). The corresponding relative risk, as compared to
      a group of construction workers and adjusted for smoking habits, was 1.03 (0.70
      1.45). We found no increased risk for other cancers investigated or death in
      other lung diseases. CONCLUSIONS: Asphalt workers do not have any increased lung
      cancer risk from exposure to fumes and gases from asphalt at the exposure levels
      that occurred in Sweden during the 1960s and 1970s.

PMID- 12494428
TI  - Donepezil for the treatment of language deficits in adults with Down syndrome: a
      preliminary 24-week open trial.
AB  - At present, there is no proven pharmacologic treatment for cognitive or language
      impairments in Down syndrome (DS). Cholinergic deficits have been documented in
      DS and linked to cognitive deficits. This study is a 24-week open-label clinical
      trial of donepezil hydrochloride for the treatment of language deficits in adults
      with DS. To our knowledge, this is the first prospective study to evaluate
      systematically the effects of donepezil, a cholinesterase inhibitor, on specific
      language domains in DS. The main finding that emerged was an improvement in
      expressive language performance following donepezil therapy. Despite the multiple
      methodological limitations, the results raise important questions regarding the
      role of the cholinergic system in language function and the specific effect of
      cholinergic therapy in the treatment of language impairment in DS. The results
      support the need for large-scale controlled studies of the effects of donepezil
      treatment on language and on other cognitive domains in DS.

PMID- 12494429
TI  - Genetic testing for hereditary colorectal cancer in children: long-term
      psychological effects.
AB  - Children who carry a gene mutation for familial adenomatous polyposis are
      virtually certain to develop colorectal cancer without annual endoscopic
      screening and a colectomy when polyps appear. Predictive genetic testing can
      identify children who need regular surveillance. While the medical benefits of
      genetic testing are clear, the psychological effects have not been well studied.
      We evaluated the long-term psychological effects of genetic testing in 48
      children and their parents. In each family, one parent was a known APC gene
      mutation carrier. Before genetic testing, and three times afterward, participants
      completed measures of psychological functioning, which, for children, included
      depression and anxiety symptoms, and behavior problems and competencies. Parents
      completed a measure of depression symptoms. Data were collected at 3-, 12-, and
      23-55 months after disclosure. Twenty-two children tested positive; 26 children
      tested negative. Mean length of follow-up was 38 months. There were no clinically
      significant changes in mean psychological test scores in children or parents,
      regardless of the children's test results or the sex of the affected parent.
      However, the group of children who tested positive and had a mutation-positive
      sibling showed significant, but subclinical, increases in depression symptoms.
      Furthermore, several individual mutation-negative children with a positive
      sibling had clinical elevations in anxiety symptoms at one or more follow-up.
      Behavior problems declined for all groups, and behavior competence scores
      remained unchanged. We conclude that most children do not suffer clinically
      significant psychological distress after testing. However, because some children
      showed clinically significant anxiety symptoms, long-term psychological support
      should be available to those families with both mutation-positive and mutation
      negative children, and with multiple mutation-positive children. Our findings
      should call for a multidisciplinary approach to genetic testing for children.

PMID- 12494430
TI  - Chromosome 22q11.2 deletion and phenotypic features in 30 patients with
      conotruncal heart defects.
AB  - This report describes the dysmorphic features and frequency of 22q11.2 deletion
      (del22q11) in 30 Turkish patients with conotruncal heart defects (CTHDs).
      Fluorescence in situ hybridization (FISH) analysis revealed deletions in the
      22q11.2 region in nine (30%) individuals. The CTHDs in this group were tetralogy
      of Fallot (four cases), double-outlet right ventricle (DORV) (two cases),
      transposition of great arteries (two cases), and ventricular septal defect (VSD)
      associated with other CTHDs (one case). The frequency of del22q11 in the study
      group was relatively high because many of the patients with dysmorphic findings
      also had cardiac anomalies involving the pulmonary artery, ductus arteriosus, or
      the aortic arch and its main branches. Twenty of the 30 patients exhibited
      several dysmorphic findings. Two of the nine patients with del22q11 exhibited no
      apparent dysmorphic features other than sacral dimple. Interestingly, one of the
      patients with del22q11 had a phenotypic appearance similar to that seen in oculo
      auriculo-vertebral spectrum (OAVS). This individual had left microtia, atresia of
      the external meatus, mandibular asymmetry, and peripheral facial nerve paralysis.
      His mental development was normal and there were no abnormalities on
      ophthalmological examination. The CTHDs in this patient were situs inversus
      dextrocardia, DORV, pulmonary stenosis, and VSD. Radiographs of this patient
      showed platybasia, complete fusion of C2-C3, and posterior fusion of the T1-T2
      vertebrae. This particular case indicates that the phenotypic features of
      del22q11 and OAVS may overlap.

PMID- 12494431
TI  - Risk perception of participants in a family-based genetic screening program on
      familial hypercholesterolemia.
AB  - The aim of this article is threefold. First, we describe the accuracy of people's
      risk perception who have been screened on familial hypercholesterolemia (FH) in a
      family-based screening program. Second, we identify factors that modify risk
      perception. Finally, we show the influence of risk perception on subsequent
      preventive behavior. The risk perception of 556 screenees (677 participants,
      overall response = 82%) was measured by postal questionnaires on three occasions:
      at screening and 3 days and 7 months after the test result was reported to the
      patient. Presentation of the risk was precategorized and given both as numerical
      (1 in x) and as verbal probability. In addition, medication use and attitudes
      toward gene therapy were determined 7 months after screening. On average, the
      screenees underestimated their numeric risk of having FH and getting a myocardial
      infarction (MI). Furthermore, FH-positive screenees perceived that they were at
      greater risk of MI than FH negatives, and screenees with the highest actual risk
      used medication more, perceived a greater risk, and opted more often for future
      gene therapy. Risk perception of having FH was influenced by cholesterol level,
      while MI risk perception was affected by age, education, cholesterol level, and
      cardiovascular disease (CVD) in the family. We conclude that FH-positive
      screenees correctly perceive a higher risk of getting a heart attack than do FH
      negative screenees. Screenees did not believe that MI was inevitable, and risk
      perception was associated with both medication use and the intention to opt for
      gene therapy, but not with other preventive measures. Thus, genetic risk
      notification seems to be acceptable and does not lead to aversion to preventive
      behavior.

PMID- 12494432
TI  - Trisomy 8 mosaicism: selective growth advantage of normal cells vs. growth
      disadvantage of trisomy 8 cells.
AB  - A fetus with trisomy 8 mosaicism was identified prenatally due to an abnormal
      maternal serum triple screen. Tissue samples were taken at birth to determine the
      level of trisomy 8 mosaicism found within embryonic and extra-embryonic tissues,
      rates of cell division for the two cell lines, and the effect of mosaicism on the
      phenotype. The level of trisomy 8 cells in blood and fibroblasts was higher than
      in placental tissue. Cell cycle kinetics, by incorporation of bromodeoxyuridine
      for 48 hr, was not significantly different between the trisomy 8 and normal cells
      for blood or amnion. Fluorescent in situ hybridization (FISH) using centromeric
      probe for chromosome 8 showed significantly more trisomy 8 in interphase vs.
      metaphase in lymphoblasts, umbilical cord fibroblasts, and chorion. The loss of
      trisomy 8 cells is not due to anaphase lag, as determined by micronuclei
      analysis. The similarity of cell cycle kinetics between trisomy 8 cells and
      normal diploid cells suggests some trisomy 8 cells are exiting the cell cycle
      prematurely. This growth disadvantage of trisomy 8 cells results in the
      appearance of growth advantage for diploid cells.

PMID- 12494433
TI  - Poor outcome in Down syndrome fetuses with cardiac anomalies or growth
      retardation.
AB  - The outcome of Down syndrome fetuses presenting with sonographic abnormalities in
      the second or third trimester is unclear. Therefore, we studied 55 pregnancies
      referred because of sonographically suspected fetal structural anomalies or
      growth retardation due to trisomy 21. A detailed ultrasound scan was performed in
      all cases to delineate the structural anomalies. Congenital heart malformations
      (CHMs) were diagnosed pre- and postnatally in 29 out of 55 Down fetuses (53%),
      with complete or incomplete atrioventricular septal defects (AVSDs) and
      ventricular septal defects (VSDs) being the most frequent anomalies. The most
      frequent noncardiac findings were a short femur (45%) and a small-for-gestational
      age (SGA) fetus (27%). Termination of pregnancy was carried out in 25 out of 55
      pregnancies (45%). Of the 30 continued pregnancies, 10 ended with intrauterine
      death. The remaining 20 pregnancies resulted in the delivery of a live-born
      infant whose prognosis was poor, with a 1-year survival of only 60%. Combining
      intrauterine death and death in the first year indicated that the overall
      survival rate was only 40%. Fatal outcome was noted in 68% (13/19) in the
      presence of CHM, in 83% (10/12) in SGA fetuses, in 86% (6/7) in combined CHM and
      SGA, but only in 17% (1/6) in the absence of CHM and SGA. This study indictes
      that second- and third-trimester in utero diagnosis of Down syndrome has a poor
      outcome when associated with CHM and/or SGA. This is important in the genetic
      counseling of the parents.

PMID- 12494434
TI  - Lack of association between Y chromosome haplogroups and male infertility in
      Japanese men.
AB  - The Y chromosome carries several genes involved in spermatogenesis, which are
      distributed in three regions in the euchromatic part of the long arm, called AZFa
      (azoospermia factor a), AZFb, and AZFc. Microdeletions in these regions have been
      seen in 10-15% of sterile males with azoospermia or severe oligozoospermia. The
      relatively high de novo occurrence of these microdeletion events might be due to
      particular chromosome arrangements associated with certain Y chromosome
      haplogroups. To test whether there is any association between Y chromosome types
      and male infertility, we studied a sample of 84 Japanese oligozoospermic or
      azoospermic males. The patients were analyzed for the presence of Yq
      microdeletions and also typed with a battery of unique event polymorphisms (UEPs)
      to define their Y haplogroups. Six of the infertile patients presented likely
      pathological microdeletions detectable with the sequence tagged sites (STS)
      markers used. There was no significant association between Y chromosome
      haplogroups and the microdeletions. We also compared the Y haplogroup frequencies
      in our subset sample of 51 idiopathic azoospermia patients with 57 fertile
      control Japanese males, and did not observe any significant differences. Contrary
      to previous reports, our data suggest that Y microdeletions and other molecular
      events causally associated with male infertility in Japan occur independently of
      the Y chromosome background.

PMID- 12494435
TI  - Mosaicism in a patient with Down syndrome reveals post-fertilization formation of
      a Robertsonian translocation and isochromosome.
AB  - It has been estimated that a few hundred children are born each year in the
      United States with translocation Down syndrome. About 5% of the cases with Down
      syndrome carry a Robertsonian translocation involving chromosome 21. The case
      described here is a patient with Down syndrome who showed mosaicism for two cell
      lines. Each cell line contains a different, de novo acrocentric rearrangement. We
      constructed somatic cell hybrids from the patient's cells and determined the
      parental origins of the rearrangements by molecular and fluorescence in situ
      hybridization (FISH) analyses. The analysis showed that the rob(14q21q) formed
      between a paternally inherited chromosome 21 and a maternally inherited
      chromosome 14, indicating that this rearrangement formed post-zygotically.
      Further molecular analysis also determined that the rea(21q21q) is an
      isochromosome of paternal origin. The cell line containing the isochromosome is
      unbalanced, resulting in trisomy 21. Because the same paternal chromosome 21 was
      involved in both the isochromosome and the Robertsonian translocation, we
      speculate that an unstable chromosome 21 was stabilized either through formation
      of a rob(14q21q) or through formation of an isochromosome. The mechanism proposed
      for the formation of the rob(14q21q) in this case is different from that for most
      de novo rob(14q21q), but similar to a previously reported mosaic case of Down
      syndrome.

PMID- 12494436
TI  - Postnatal growth failure, microcephaly, mental retardation, cataracts, large
      joint contractures, osteoporosis, cortical dysplasia, and cerebellar atrophy.
AB  - We describe two sibs with postnatal-onset growth deficiency, microcephaly,
      cataract, prominent supraorbital ridge, large joint contractures, severe
      osteoporosis, cortical dysplasia, cerebellar atrophy, and mental retardation. The
      combination appears to constitute a previously undescribed syndrome inherited in
      an autosomal recessive pattern.

PMID- 12494437
TI  - Scimitar vein anomaly with multiple cardiac malformations, craniofacial, and
      central nervous system abnormalities in a brother and sister: familial scimitar
      anomaly or new syndrome?
AB  - The scimitar vein "syndrome" is an anomaly of lobar aplasia or hypoplasia and
      total or partial anomalous venous drainage of one lung. We report a brother and
      sister born to nonconsanguineous Italian parents with a fatal infantile form of
      scimitar vein anomaly associated to multiple cardiac anomalies. The infants had
      major craniofacial anomalies. In addition, the boy had iris coloboma and enlarged
      cisterna magna; both sibs showed poor brain myelination at neuroimaging confirmed
      by histopathology in the girl. The cardiovascular system in the family members
      was fully investigated and all results were completely normal. The association of
      the above craniofacial anomalies has been occasionally mentioned in syndromes
      with anomalous venous return. The familial occurrence of isolated total anomalous
      pulmonary venous return has been documented in sibs, first cousins, and through
      consecutive generations. Familial pulmonary hypoplasia, as an isolated finding,
      has been observed in siblings and twins. To the best of our knowledge, even
      though five familial cases of scimitar "syndrome" have been described thus far,
      the constellation of anomalies shown by these two sibs has not been reported
      previously. It appears that scimitar vein "syndrome" is not a "syndrome" per se:
      it is most likely an anomaly of heterogeneous etiology. This family may represent
      its own novel syndrome of multiple congenital anomalies of which scimitar vein is
      a component.

PMID- 12494438
TI  - Concurrence of fragile X syndrome and 47, XYY in an individual with a Prader
      Willi-like phenotype.
AB  - We report on a 34-year-old developmentally disabled man referred to our clinic
      for evaluation of possible Prader-Willi syndrome on the basis of obesity and
      voracious appetite. Cytogenetic and molecular analysis revealed a 47, XYY
      karyotype and the presence of a trinucleotide repeat expansion resulting in
      fragile X syndrome. To our knowledge, this is the first report of concurrence of
      XYY and fragile X syndrome in the medical literature. Review of sex chromosome
      abnormalities associated with fragile X syndrome and phenotypic considerations
      are presented.

PMID- 12494439
TI  - Documentation of anomalies not previously described in Fryns syndrome.
AB  - We report on a case of Fryns syndrome with microcephaly, multiple facial
      anomalies, hypoplasia of distal phalanges, diaphragmatic defect with a thin,
      translucent diaphragm, microphthalmia (right), anophthalmia (left), and multiple
      midline developmental defects including gastroschisis, central nervous system
      defects including left arrhinencephaly and cerebellar hypoplasia, midline cleft
      of the upper lip, alveolar ridge and maxillary bone, and cleft nose with
      bilateral choanal atresia. These defects add to our knowledge of the phenotype of
      Fryns syndrome.

PMID- 12494441
TI  - Child with overgrowth, pigmentary streaks, polydactyly, and intestinal
      lymphangiectasia: macrocephaly-cutis marmorata telangiectatica congenita syndrome
      or new disorder?
AB  - We report a male patient with increased birth weight and growth, cutis marmorata,
      macrocephaly, large hands and feet, thick subcutaneous tissues, postaxial
      polydactyly, linear skin hyperpigmentation following the lines of Blaschko, and
      intestinal lymphangiectasia. Although the findings resemble the recently defined
      macrocephaly cutis marmorata syndrome, some findings suggest that this might be a
      new disorder. Differential diagnosis are discussed, with a review of the
      literature.

PMID- 12494442
TI  - Further delineation of the Toriello-Carey syndrome: a report of two siblings.
AB  - Toriello-Carey is a rare multiple malformation/mental retardation syndrome
      characterized by dysmorphic features, including telecanthus/hypertelorism, short
      palpebral fissures, a small nose with anteverted nares, malformed ears, and a
      Pierre Robin sequence. Affected patients also show several other important signs
      of midline field disruption: agenesis of the corpus callosum, laryngeal
      anomalies, and congenital heart defects. Hypotonia and developmental delay are
      present in most reported cases. Autosomal recessive inheritance was proposed, but
      an X-linked or sex-influenced gene disorder was also suspected. We report on two
      siblings, a brother and sister, supporting further an autosomal recessive type of
      inheritance. Both patients had severe clinical presentation with death in early
      infancy. Besides clinical findings typical for this condition, they showed
      additional traits, expanding further the phenotypic spectrum. A specific
      malformation pattern observed in the patients presented and, in the previously
      reported cases, suggests an early midline developmental field disruption,
      presumably caused by a developmental regulatory gene mutation.

PMID- 12494443
TI  - 18q-syndrome and ectodermal dysplasia syndrome: description of a child and his
      family.
AB  - The 18q- syndrome [MIM #601808] is a terminal deletion of the long arm of
      chromosome 18. The most common deletion extends from region q21 to qter. We
      report here a nine-year-old boy possessing a simple 18q- deletion who had
      abnormalities of the brain, skull, face, tooth, hair, bone, and skin, plus joint
      laxity, tongue palsy, subtle sensoneural deafness, mental and speech delay,
      attention deficit hyperactivity disorder (ADHD), tic, and restless legs
      syndromes. His karyotype was 46, XY, del (18)(q21.31-qter). The size of the
      deletion was approximately 45 cM. Most of these abnormalities were not explained
      by the 18q- deletion. The family pedigree suggested the presence of a subtle
      involvement of ectodermal and/or mesodermal structures. Karyotypes of the other
      family members were normal.

PMID- 12494444
TI  - Novel CNS syndrome and ectodermal dysplasia.

PMID- 12494445
TI  - Unique case of deletion and duplication in the long arm of the Y chromosome in an
      individual with ambiguous genitalia.

PMID- 12494446
TI  - Del 22Q11.2 and hemophagocytic lymphohistiocytosis: a non-random association.

PMID- 12494447
TI  - Cardio-facio-cutaneous syndrome: first presentation in a 52-year-old woman.

PMID- 12494448
TI  - Cyclin T: three forms for different roles in physiological and pathological
      functions.
AB  - Cyclins are members of family of proteins involved in the cell cycle regulation.
      They are regulatory subunits of complexes with proteins called cyclin-dependent
      kinases (CDKs). There are three forms of cyclin T: cyclin T1, cyclin T2a, and
      T2b. All cyclin T contain an N-terminal "cyclin homology box," the most conserved
      region among different members of the cyclin family that serves to bind CDK9. In
      addition to the N-terminal cyclin domain, cyclin T contains a putative coiled
      coil motif, a His-rich motif, and a C-terminal PEST sequence. The CDK9/cyclin T
      complex is able to activate gene expression in a catalytic-dependent manner,
      phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II. In
      addition, only cyclin T1 supports interactions between Tat and TAR. The
      interaction of Tat with cyclin T1 alters the conformation of Tat to enhance the
      affinity and specificity of the Tat:TAR interaction. On the other hand,
      CDK9/cyclin T2 complexes are involved in the regulation of terminal
      differentiation in muscle cells.

PMID- 12494449
TI  - Role of the IGF-I receptor in the regulation of cell-cell adhesion: implications
      in cancer development and progression.
AB  - The insulin-like growth factor-I receptor (IGF-IR) is a ubiquitous
      multifunctional tyrosine kinase that has an important role in normal cell growth
      and development. However, abnormal stimulation of IGF-IR signaling has been
      implicated in the development of different types of tumors. The strong
      antiapoptotic activity of IGF-IR has been recognized as critical in IGF-I
      dependent tumorigenesis, however, the impact of other IGF-IR functions, such as
      regulation of cell-cell and cell-matrix adhesion are also increasingly
      acknowledged. Here, on the model of breast cancer cells, we discuss how IGF-IR
      dependent regulation of intercellular adhesion may affect cell survival,
      resistance to antiestrogens, and invasion.

PMID- 12494450
TI  - Molecular cloning of Drosophila HCF reveals proteolytic processing and self
      association of the encoded protein.
AB  - HCF-1 functions as a coactivator for herpes simplex virus VP16 and a number of
      mammalian transcription factors. Mature HCF-1 is composed of two subunits
      generated by proteolytic cleavage of a larger precursor at six centrally-located
      HCF(PRO) repeats. The resulting N- and C-terminal subunits remain tightly
      associated via two complementary pairs of self-association domains: termed SAS1N
      SAS1C and SAS2N-SAS2C. Additional HCF proteins have been identified in mammals
      (HCF-2) and Caenorhabditis elegans (CeHCF). Both contain well-conserved SAS1
      domains but do not undergo proteolytic processing. Thus, the significance of the
      cleavage and self-association of HCF-1 remains enigmatic. Here, we describe the
      isolation of the Drosophila HCF homologue (dHCF) using a genetic screen based on
      conservation of the SAS1 interaction. The N-terminal beta-propeller domain of
      dHCF supports VP16-induced complex formation and is more similar to mammalian HCF
      1 than other homologues. We show that full-length dHCF expressed in Drosophila
      cells undergoes proteolytic cleavage giving rise to tightly associated N- and C
      terminal subunits. As with HCF-1, the SAS1N and SAS1C elements of dHCF are
      separated by a large central region, however, this sequence lacks obvious
      homology to the HCF(PRO) repeats required for HCF-1 cleavage. The conservation of
      HCF processing in insect cells argues that formation of separate N- and C
      terminal subunits is important for HCF function.

PMID- 12494451
TI  - Galphaq signaling is required for Rho-dependent transcriptional activation of the
      cyclooxygenase-2 promoter in fibroblasts.
AB  - Previously, we demonstrated that the gastrin releasing peptide (GRP) induces
      cyclooxygenase-2 (COX-2) expression through a Rho-dependent, protein kinase C
      (PKC)-independent signaling pathway in fibroblasts (Slice et al., 1999, J Biol
      Chem 274:27562-27566). However, the specific role of heterotrimeric guanine
      nucleotide binding regulatory proteins (G-proteins) that are coupled to the GRP
      receptor in Rho-dependent COX-2 expression has not been elucidated. In this
      report, we utilize embryonic fibroblasts from transgenic mice containing double
      gene knock-outs (DKO) for Galpha(q/11) and Galpha(12/13) to demonstrate that COX
      2 promoter activation by GRP requires Galpha(q). Furthermore, we show that GRP
      dependent COX-2 gene expression, as assessed by a COX-2 reporter luciferase
      assay, was induced in cells lacking Galpha(12/13) but was blocked in cells that
      did not express Galpha(q/11). GRP-dependent COX-2 promoter induction in
      Galpha(q/11) deficient cells was rescued by expression of wild type Galpha(q) but
      blocked by inhibition of calcium signaling in calcium-free media or in cells
      treated with 2-aminoethoxydiphenylborate (2-APB). Co-stimulation of transfected
      Galpha(q/11) deficient cells with GRP and thapsigargin (TG) induced the COX-2
      promoter. Activation of endogenous Rho by expression of Onco-lbc or expression of
      Rho A Q63L resulted in COX-2 promoter activation in Galpha(q/11) deficient cells.
      Inhibition of Rho by Clostridium botulinum C3 toxin blocked COX-2 promoter
      induction. Expression of Galpha(q) Q209L in the well-characterized fibroblast
      cell line, NIH3T3, induced the COX-2 promoter which was blocked by expression of
      C3 toxin. These results demonstrate that calcium signaling mediated by Galpha(q)
      and Rho play critical roles in GRP-dependent COX-2 expression in fibroblasts.

PMID- 12494452
TI  - Epidermal growth factor induces intracellular Ca2+ oscillations in microvascular
      endothelial cells.
AB  - An increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) may play a role
      in the proliferative effect of several growth factors. In this study, the changes
      in [Ca(2+)](i) elicited by epidermal growth factor (EGF) in rat cardiac
      microvascular endothelial cells (CMEC) have been investigated by using fura-2
      conventional and confocal microscopy. A large heterogeneity in the latency and in
      the pattern of the Ca(2+) response was found at each dose of EGF (2.5-100 ng/ml),
      whereas some cells displayed a non-oscillatory behavior and others exhibited a
      variable number of Ca(2+) oscillations. On average, the fraction of responsive
      cells, the total number of oscillations and the duration of the Ca(2+) signal
      were higher at around 10 ng/ml EGF, while there was no dose-dependence in the lag
      time and in the amplitude of the [Ca(2+)](i) increase. EGF-induced Ca(2+) spikes
      were abolished by the tyrosine kinase inhibitor genistein, but not by its
      inactive analogue daidzein, and by the phospholipase C blocker NCDC. Only 1-2
      transients could be elicited in Ca(2+)-free solution, while re-addition of
      extracellular Ca(2+) recovered the spiking activity. The oscillatory signal was
      prevented by the SERCA inhibitor thapsigargin and abolished by the calcium entry
      blockers Ni(2+) and La(3+). Moreover, EGF-induced Ca(2+) transients were
      abolished by the InsP(3) receptor blocker caffeine, while ryanodine was without
      effect. Confocal imaging microscopy showed that the Ca(2+) response to EGF was
      localized both in the cytoplasm and in the nucleus. We suggest that EGF-induced
      [Ca(2+)](i) increase may play a role in the proliferative action of EGF on
      endothelial cells.

PMID- 12494453
TI  - Analysis of hormone-stimulated phosphatidylinositol synthesis.
AB  - Agonist-stimulated phosphoinositide turnover is accompanied by compensatory
      resynthesis of these lipids. Several lines of evidence suggest that resynthesis
      of phosphatidylinositol (PtdIns) involves phosphorylation of diacylglycerol (DG)
      (salvage pathway) rather than acylation of glycerol phosphate (de novo pathway),
      although a contribution from the de novo pathway has not been ruled out. To
      determine the relative contribution of the de novo and salvage pathways in
      stimulated PtdIns resynthesis, an inhibitor of de novo synthesis (Triacsin C) was
      incubated simultaneously with the hormone agonist. Results indicate that at early
      times (90 min), hormone-stimulated PtdIns synthesis proceeds predominantly via
      the salvage pathway, although some de novo synthesis is also taking place. At
      later times (24 h), stimulated synthesis is solely via the de novo pathway.
      Increasing cellular DG content by either adding exogenous DG or treating cells
      with bacterial phospholipase C (bPLC) results in deacylation of the DG rather
      than phosphorylation; however, inhibition of this deacylation fails to stimulate
      phosphorylation by DG kinase (DGK), suggesting channeling of the DG substrate
      between PLC and DG kinase. Receptor activation is not required for activation of
      DGK, since treatment with a calcium ionophore induces the same Triacsin C
      insensitive PtdIns synthesis. Depletion of the polyphosphoinositide pools by
      treatment with wortmannin prevents both hormone and A23187-induced
      polyphosphoinositide hydrolysis; however, A23187 is still able to induce
      hydrolysis of PtdIns and subsequent compensatory resynthesis. The inability of
      R59949 to inhibit either hormone-induced or ionophore-induced PtdIns resynthesis
      suggests that the alpha isoform is not involved; however, its possible that the
      channeling phenomenon prevents the inhibitor from gaining access to the
      diacylglycerol kinase enzyme. Further study will be required to determine which
      isoform catalyzes hormone-induced resynthesis of PtdIns.

PMID- 12494454
TI  - Retinoic acid-induced AP-1 transcriptional activity regulates B16 mouse melanoma
      growth inhibition and differentiation.
AB  - Retinoic acid (RA) inhibits growth and induces differentiation of B16 mouse
      melanoma cells. These effects are accompanied by a large increase in PKCalpha
      mRNA and protein levels and surprisingly an increase in activating protein-1 (AP
      1) transcriptional activity. To further investigate the RA-induced AP-1 activity
      we established clones of B16 cells stably expressing an AP-1-luciferase reporter
      gene. Treatment of these clones with phorbol dibutyrate increased AP-1 activity
      which peaked at 2-4 h and returned to baseline level by 24 h. In contrast, RA
      treatment resulted in a slow increase in AP-1 activity that reached a maximum
      level at 48 h and was maintained for the duration of the treatment. We tested the
      importance of the RA-induced AP-1 activity by establishing clones which stably
      express a dominant negative fos gene (A-fos) and have greatly diminished AP-1
      activity. Growth rates of untreated A-fos expressing cells were similar to wt B16
      and clones not expressing A-fos. However, clones expressing the dominant-negative
      fos had a markedly decreased sensitivity to RA-induced inhibition of anchorage
      dependent and -independent growth. Treatment of wt B16 cells for 48 h with RA
      increased melanin production by two to fourfold, but this effect was completely
      lost in the A-fos clones. The ability of RA to induce RARbeta and PKCalpha
      expression was retained in A-fos clones, suggesting that A-fos was not
      interfering with RAR transcription activation functions. We tested whether the RA
      induced AP-1 activity might be mediated by the ERK1/2 MAPK pathway. Inhibition of
      ERK1/2 phosphorylation stimulated AP-1 activity, which was not additive to that
      induced by RA. This finding raises the possibility that this MAPK pathway may be
      a target of retinoid action. Our observations suggest that AP-1 transcriptional
      activity induced by RA likely plays an important role in the biological changes
      mediated by this retinoid in B16 melanoma cells.

PMID- 12494455
TI  - Differential levels of soluble endoglin (CD105) in myeloid malignancies.
AB  - Angiogenesis contributes to disease progression in solid and hematopoietic
      malignancies, and endoglin (CD105), a component of the transforming growth factor
      (TGF)-beta receptor complex, is a powerful marker of neovascularization. Elevated
      amounts of soluble CD105 (sCD105) have been recently identified in selected solid
      tumors but no data are available on sCD105 in hematopoietic malignancies.
      Therefore, levels of sCD105 were investigated in sera of patients with acute
      myeloid leukemia (AML) (n = 10) or chronic myeloproliferative disorders (CMD) (n
      = 28), and correlated with those of soluble TGF-beta(1) (sTGF-beta(1)). Dot blot
      assay detected higher amounts of sCD105 (P < 0.05) both in AML (4.34 +/- 2.62
      OD/mm(2)) and in CMD (3.71 +/- 2.09 OD/mm(2)) patients than in healthy subjects
      (n = 14, 2.38 +/- 1.18 OD/mm(2)). Instead, enzyme-linked immunosorbent assay
      (ELISA) identified (P < 0.05) lower and higher levels of sTGF-beta(1) in AML
      (32,017 +/- 1,900 pg/ml) and CMD (60,700 +/- 19,200 pg/ml) patients,
      respectively, compared to healthy individuals (n = 11, 47,173 +/- 5,443 pg/ml).
      In essential thrombocythemia (ET) patients with thrombotic episodes, levels of
      sCD105 were lower (P < 0.05) compared to patients without thrombotic
      complications, and inversely correlated with those of sTGF-beta(1) (r = 0.94).
      Conversely, amounts of sCD105 directly correlated with levels of sTGF-beta(1) (r
      = 0.74) in ET patients without thrombotic events. Our results show that high
      levels of sCD105 are present in myeloid malignancies that are characterized by a
      high cellular proliferation rate, and suggest that an altered balance between
      sCD105 and sTGF-beta(1) might favor disease progression and clinical
      complications.

PMID- 12494456
TI  - Peri-epithelial origin of prostanoids in the human colon.
AB  - The biology of prostanoids in the normal human colon is only beginning to be
      understood. We used in situ and in vitro techniques to define the lineage,
      number, per cell enzyme content, and epithelial functional effect of
      prostaglandin-generating cells, identified by the presence of cyclooxygenase 1
      (COX 1). Immunohistochemical results were quantitated densitometrically, and cell
      surface staining in situ was verified by flow cytometry of isolated cells and by
      Western blotting. Three populations of COX 1(+) mucosal cells were identified,
      based on their morphology and local distribution in human mucosa; these were in
      the intra-epithelial, crypt apical, and lamina propria regions, with each
      containing a similar amount of COX 1 protein on a per cell basis. The most
      numerous were COX 1(+) mononuclear cells in the lamina propria, identified as
      CD3(+) T lymphocytes, both in situ and ex vivo. In toto, 21% of lamina propria
      mononuclear cells were COX 1(+), and over 50% of these cells were CD3(+) T cells.
      Findings were similar in the colon with mild-moderate inflammation due to
      ulcerative colitis. Using established surface markers, intra-epithelial and crypt
      apical COX 1(+) cells were non-lymphoid CD45(+) leukocytes; neither IgA (B
      lymphocytes) nor alpha-smooth muscle actin (myelofibroblasts) was co-expressed on
      these COX 1(+) cells. Examining the effect of a major product of COX 1 in an in
      vitro system of human colonic epithelial monolayers, prostaglandin E(2) (PGE(2))
      in low concentration (10(-6) M) enhanced epithelial barrier function and
      partially protected epithelia from the barrier-disruptive consequences of a pro
      inflammatory cytokine, IFN-gamma. We conclude that the human colon contains three
      tiers of cell types for local synthesis of prostanoids, distinguishable by their
      location, morphology, and cell lineage. Further, maintenance of the barrier
      function of colonic epithelium may be added to other cell functions in mucosa
      regulated, in part, by prostanoids.

PMID- 12494457
TI  - Quantitative and qualitative adaptation of skeletal muscle mitochondria to
      increased physical activity.
AB  - Endurance capacity rely on high muscle oxidative capacity but should also involve
      a tighter coupling between energy production and utilization within the myocyte.
      The present study examined the responses of muscle oxidative capacity and the
      regulation of oxidative phosphorylation by phosphate acceptors in locomotor
      muscles of voluntary running rats (n = 8), using saponin permeabilized fibers of
      the deep and superficial parts of plantaris muscle (dPLA and sPLA, respectively).
      Non-ADP stimulated respiration of skinned fibers increased by 33% (P < 0.05) and
      100% (P < 0.001) in sPLA and dPLA, respectively. The maximal ADP-stimulated
      respiration was 57% (P < 0.001) and 32% (P < 0.01) higher in active rats than in
      sedentary rats (n = 8), in sPLA and dPLA, respectively. This finding was
      consistent with a 72% increase in the CS activity in plantaris muscle of
      exercising rats (P < 0.01). Voluntary running induced a 334% increase in the
      apparent Km for ADP in sPLA (P < 0.001), and a 61% increase in dPLA (P < 0.05),
      showing a lower affinity for cytosolic ADP of mitochondria present in both,
      predominantly glycolytic, and oxidative fibers. There was an increase in the
      creatine kinase efficacy in both sPLA and dPLA (131%, 75%, P < 0.001,
      respectively), consistent with an increase in the activity of the mitochondrial
      isoform of creatine kinase (106%, P < 0.01). It is concluded that, in addition to
      the well-known increased oxidative capacity, voluntary running is associated with
      changes in the regulation of oxidative phosphorylation by phosphate acceptors, in
      both glycolytic and oxidative fibers, in the direction of increased coupling
      between energy production and energy utilization.

PMID- 12494458
TI  - Fluid shear stress inhibits TNF-alpha-induced apoptosis in osteoblasts: a role
      for fluid shear stress-induced activation of PI3-kinase and inhibition of caspase
      3.
AB  - In bone, a large proportion of osteoblasts, the cells responsible for deposition
      of new bone, normally undergo programmed cell death (apoptosis). Because
      mechanical loading of bone increases the rate of new bone formation, we
      hypothesized that mechanical stimulation of osteoblasts might increase their
      survival. To test this hypothesis, we investigated the effects of fluid shear
      stress (FSS) on osteoblast apoptosis using three osteoblast cell types: primary
      rat calvarial osteoblasts (RCOB), MC3T3-E1 osteoblastic cells, and UMR106
      osteosarcoma cells. Cells were treated with TNF-alpha in the presence of
      cyclohexamide (CHX) to rapidly induce apoptosis. Osteoblasts showed significant
      signs of apoptosis within 4-6 h of exposure to TNF-alpha and CHX, and application
      of FSS (12 dyne/cm(2)) significantly attenuated this TNF-alpha-induced apoptosis.
      FSS activated PI3-kinase signaling, induced phosphorylation of Akt, and inhibited
      TNF-alpha-induced activation of caspase-3. Inhibition of PI3-kinase, using
      LY294002, blocked the ability of FSS to rescue osteoblasts from TNF-alpha-induced
      apoptosis and blocked FSS-induced inhibition of caspase-3 activation in
      osteoblasts treated with TNF-alpha. LY294002 did not, however, prevent FSS
      induced phosphorylation of Akt suggesting that activation of Akt alone is not
      sufficient to rescue cells from apoptosis. This result also suggests that FSS can
      activate Akt via a PI3-kinase-independent pathway. These studies demonstrate for
      the first time that application of FSS to osteoblasts in vitro results in
      inhibition of TNF-alpha-induced apoptosis through a mechanism involving
      activation of PI3-kinase signaling and inhibition of caspases. FSS-induced
      activation of PI3-kinase may promote cell survival through a mechanism that is
      distinct from the Akt-mediated survival pathway.

PMID- 12494459
TI  - SNARE protein degradation upon platelet activation: calpain cleaves SNAP-23.
AB  - In order to better understand the molecular mechanisms of platelet granule
      secretion, we evaluated the effect of activation-induced degranulation on three
      functional platelet SNARE proteins, SNAP-23, VAMP-3, and syntaxin 4. Initial
      studies showed that SNAP-23 is lost upon SFLLRN-induced platelet activation.
      Experiments with permeabilized platelets demonstrated that proteolysis of SNAP-23
      was Ca(2+)-dependent. Ca(2+)-dependent proteolysis of SNAP-23 was inhibited by
      the cell-permeable calpain inhibitors, calpeptin and E-64d, as well as by the
      naturally occurring calpain inhibitor, calpastatin. In addition, purified calpain
      cleaved SNAP-23 in permeabilized platelets in a dose-dependent manner. In intact
      platelets, calpeptin prevented SFLLRN-induced degradation of SNAP-23. In
      contrast, calpeptin did not prevent SFLLRN-induced degradation of VAMP-3 and
      syntaxin 4 did not undergo substantial proteolysis following platelet activation.
      Calpain-induced cleavage of SNAP-23 was a late event occurring between 2.5 and 5
      min following exposure of permeabilized platelets to Ca(2+). Experiments
      evaluating platelet alpha-granule secretion demonstrated that incubation of
      permeabilized platelets with 10 microM Ca(2+) prior to exposure to ATP inhibited
      ATP-dependent alpha-granule secretion from permeabilized platelets. SNAP-23 was
      cleaved under these conditions. Incubation of permeabilized platelets with either
      calpeptin or calpastatin prevented Ca(2+)-mediated degradation of SNAP-23 and
      reversed Ca(2+)-mediated inhibition of ATP-dependent alpha-granule secretion.
      Thus, activation of calpain prior to secretion results in loss of SNAP-23 and
      inhibits alpha-granule secretion. These studies suggest a mechanism whereby
      calpain activation serves to localize platelet secretion to areas of thrombus
      formation.

PMID- 12494460
TI  - Potential role of apoptotic macrophages in pulmonary inflammation and fibrosis.
AB  - Induction of apoptosis has been associated with a variety of exposures which
      result in inflammatory and fibrotic lung disorders. Macrophages are key
      regulatory cells in the lung; however, the role of apoptotic macrophages in those
      pulmonary disorders is not well characterized. In the present investigation,
      apoptotic macrophages were instilled into the lungs of rats to study directly the
      pulmonary responses to apoptotic cells. The effects of apoptotic macrophages on
      lung inflammation and fibrosis, as well as associated protein expression of TNF
      alpha, TGF-beta, and matrix metalloproteinases (MMPs) were examined. Induction of
      macrophage apoptosis was carried out in vitro using a variety of known apoptosis
      inducers. Intratracheal administration of apoptotic macrophages (5 x 10(6)
      cells/rat) into the lung of rats caused an increase in pulmonary infiltration of
      macrophages and lung cell apoptosis 4 weeks after the treatment as indicated by
      terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)
      assay. In contrast, pulmonary instillation of saline or normal control
      macrophages had no effect. Histological analysis of lung sections showed collagen
      deposition and fibrotic lesions after apoptotic cell treatment but not in control
      groups. Immunohistochemical studies revealed increased expression of TNF-alpha,
      TGF-beta, MMP2, and MMP9 in the treatment group 4 weeks after the treatment.
      These results suggest a role for macrophage apoptosis in the initiation of these
      lung disorders. This study provides direct evidence that apoptotic macrophages
      can induce lung inflammation and fibrosis and that this induction may be
      associated with increased expression of TNF-alpha, TGF-beta, MMP2, and MMP9.
      Published 2002 Wiley-Liss, Inc.

PMID- 12494461
TI  - HOX gene network is involved in the transcriptional regulation of in vivo human
      adipogenesis.
AB  - Adipogenesis is regulated by the sequential activation of a series of
      transcription factors: the C/EBP proteins of type beta and delta trigger the
      process while PPARgamma and C/EBPalpha induce the differentiation from pre
      adipocyte to adipocyte, followed by adipo-specific gene expression. A number of
      observations suggest the involvement of genes controlling embryonal development
      in adipogenesis. In human thyroid follicular carcinoma, it has been recently
      identified an oncogenetic fusion protein resulting from the interaction between
      the isoform PPARgamma1 of PPARgamma and the homeoprotein encoded by the PAX-8
      gene. Recent observations have pointed out that gene expression associated with
      adipocyte differentiation in vivo and in vitro, although partially overlapping,
      is actually different. HOX genes make up a network of transcription factors
      (homeoproteins) controlling embryonal development as well as crucial functions of
      adult eukaryotic cells. The molecular organization of this network of 39 genes
      appears to be unique in the genome and probably acts regulating phenotypic cell
      identity. In the present study we have analyzed the expression of the complete
      HOX gene network, in vivo, in different deposits of human white adipose tissue
      and in embryonal brown adipose tissues. Most of the genes in the HOX network are
      active in white as well as brown adipose tissue. Furthermore HOX genes display a
      deposit-specific expression in white adipose tissue. Moreover, expression of the
      paralogous group 4 genes (HOX A4, HOX B4, HOX C4, and HOX D4), together with that
      of isolated genes in the network, appears to discriminate between white and brown
      adipose tissue. This data allows us to postulate the involvement of the HOX
      network in transcriptional regulation of human adipogenesis and to hypothesize on
      the molecular mechanisms that could be implicated.

PMID- 12494462
TI  - Breast cancer revisited using DNA array-based gene expression profiling.
AB  - Breast cancer is a complex genetic disease characterized by the accumulation of
      multiple molecular alterations. The resulting clinical heterogeneity makes
      current diagnostic and therapeutic strategies less than perfectly adapted to each
      patient. Pathological and clinical factors are insufficient to capture the
      complex cascade of events that drive the clinical behavior of tumors. High
      throughput molecular technologies provide novel tools to tackle this complexity.
      In particular, DNA arrays allow the simultaneous and quantitative analysis of the
      mRNA expression levels of thousands of genes in a single assay. Potential
      applications are multiple in the cancer field and the first research results are
      promising; comprehensive gene expression profiles of breast tumors are providing
      insights into mammary oncogenesis and are revealing new tumor subgroups
      previously indistinguishable. Significant advances will be the identification of
      new diagnostic, prognostic and predictive biomarkers as well as the discovery of
      new potential therapeutic targets. This review presents recent applications of
      DNA arrays in breast cancer research and discusses some issues to address in the
      near future to allow the technology to reach its full potential.

PMID- 12494463
TI  - Histone deacetylase inhibitor trichostatin A induces cell-cycle arrest/apoptosis
      and hepatocyte differentiation in human hepatoma cells.
AB  - Remodeling of the chromatin template by inhibition of HDAC activities represents
      a potential transcriptional therapy for neoplastic disease. A number of HDAC
      inhibitors that modulate in vitro cell growth and differentiation have been
      developed. We analyzed the effects of TSA, a specific and potent HDAC inhibitor,
      on the human hepatoma cell lines HepG2 and Huh-7. TSA increased levels of
      acetylated histones H3 and H4 in both HepG2 and Huh-7. It inhibited cell
      proliferation in vitro and induced G(0)/G(1) arrest in HepG2 and apoptosis in Huh
      7. Gene expression of liver-specific functions and liver-enriched transcription
      factors was upregulated by TSA. TSA upregulated the ammonia removal rate and the
      albumin synthesis rate of HepG2 and Huh-7. Our results indicate that TSA can
      induce cell-cycle arrest/apoptosis and hepatocyte differentiation in human liver
      cancer cell lines.

PMID- 12494464
TI  - Insulin-like growth factor binding protein-3 is overexpressed in endothelial
      cells of mouse breast tumor vessels.
AB  - Angiogenesis is a key process in a variety of human diseases, including cancer.
      The ability to target selectively the tumor vasculature is potentially useful for
      the diagnosis and treatment of cancer. Still, little information is available
      regarding markers that are restricted to the ECs of tumor vessels. cDNA array
      technology allows simultaneous analysis of relative expression levels of a broad
      spectrum of genes in 2 related cell populations. We used this technology with the
      aim of identifying markers specific for TECs. TECs were isolated by CD31-mediated
      immunomagnetic separation from tumors induced by s.c. injection of NF9006 breast
      carcinoma cells into syngeneic mice. NECs were isolated from lactating mammary
      glands. The endothelial nature of isolated cells was confirmed by RT-PCR using
      CD31-specific primers and by uptake of DiI-Ac-LDL. Macrophage contamination in
      the EC isolations could be reasonably ruled out by assessing the expression of
      the macrophage marker c-fms. (32)P-labeled cDNA probes generated by reverse
      transcription from total RNA were hybridized to mouse-specific gene arrays.
      Several genes consistently showed differential expression between TECs and NECs.
      However, expression of only 1 of these genes, IGFBP-3, was restricted exclusively
      to ECs. Semiquantitative RT-PCR revealed 22- to 33-fold differential expression
      of IGFBP-3 in the TEC fraction. IGFBP-3 was overexpressed by a factor of 5 in an
      additional mouse model of breast carcinoma induced by 4T1.2 tumor cells. These
      results indicate that IGFBP-3 is a potential novel marker of angiogenesis.
      Elucidation of its role in tumor neovascularization may open the possibility of
      IGFBP-3 as a therapeutic target for antiangiogenesis.

PMID- 12494465
TI  - Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of
      resistance to polyglutamylation-dependent novel antifolates in multiple human
      leukemia sublines.
AB  - We have studied the molecular basis of drug resistance in human CCRF-CEM leukemia
      cells exposed to high dose intermittent pulses of novel polyglutamatable
      antifolates that target various folate-dependent enzymes. These include the
      dihydrofolate reductase (DHFR) inhibitors edatrexate, methotrexate and
      aminopterin, the thymidylate synthase (TS) inhibitors ZD1694 and GW1843, the
      glycinamide ribonucleotide formyltransferase (GARTF) inhibitor DDATHF as well as
      the multitargeted antifolate LY231514 inhibiting both TS, DHFR and GARTF.
      Fourteen antifolate-resistant sublines were isolated, 11 of which displayed a
      drug resistance phenotype that was based on impaired folylpoly-gamma-glutamate
      synthetase (FPGS) activity as these cell lines: 1) typically lost 90-99% of
      parental FPGS activity; 2) expressed 1.4-3.3-fold less FPGS mRNA (only 4 cell
      lines); 3) displayed up to 10(5)-fold resistance to polyglutamylation-dependent
      antifolates including ZD1694 and MTA; 4) retained sensitivity to
      polyglutamylation-independent antifolates including ZD9331 and PT523; 5) were up
      to 19-fold hypersensitive to the lipid-soluble antifolates trimetrexate and
      AG377; 6) had a normal or a small decrease in [(3)H]MTX transport; and 7) had a
      2.1-8.3-fold decreased cellular folate pools and a consequently increased folate
      growth requirement. The remaining 3 antifolate-resistant sublines lost 94-97% of
      parental [(3)H]MTX transport and thus displayed a high level resistance to all
      hydrophilic antifolates. To screen for mutations in the hFPGS gene, we devised an
      RT-PCR single strand conformational polymorphism (SSCP) assay. RT-PCR-SSCP
      analysis and DNA sequencing showed that only a single FPGS-deficient subline
      harbored an FPGS mutation (Cys346Phe). Three-dimensional modeling of the human
      FPGS based on the crystal structure of Lactobacillus casei FPGS suggested that
      this mutation maps to the active site and interferes with the catalytic activity
      of the enzyme due to a putative bulky clash between the mutant Phe346 and a
      native Phe350 within alpha-helix A10 in a highly conserved C-terminal hydrophobic
      core. This was consistent with a 23-fold decreased affinity of the mutant
      Cys346Phe FPGS for L-glutamate. We conclude that decreased FPGS activity is a
      dominant mechanism of resistance to polyglutamylation-dependent novel antifolates
      upon a high-dose intermittent exposure schedule. The finding that cells may
      exhibit 5 orders of magnitude of resistance to polyglutamylation-dependent
      antifolates but in the same time retain parental sensitivity or hypersensitivity
      to polyglutamylation-independent antifolates or lipophilic antifolates offers a
      potentially promising treatment strategy in the overcoming of FPGS-based
      anticancer drug resistance.

PMID- 12494466
TI  - Prostaglandin J2 metabolites inhibit aromatase activity by redox-sensitive
      mechanisms: potential implications for breast cancer therapy.
AB  - The mechanisms by which prostaglandin (PG)J(2) metabolites inhibit tumorigenicity
      are poorly understood but may involve thiol reactivity or peroxisome proliferator
      activated receptor (PPAR)-dependent pathways. Because aromatase is an important
      therapeutic target in breast cancer treatment, we have investigated the effect of
      PGJ(2) metabolites on aromatase activity and evaluated a potential role for redox
      status during PGJ(2) metabolite action. 15-deoxy-Delta(12,14)PGJ(2) (15d-PGJ(2))
      and 9-deoxy-Delta(9,12)13,14-dihydroPGD(2) (Delta(12)PGJ(2)) caused dose
      dependent inhibition of both pre-induced aromatase activity in human breast
      fibroblasts and MDA MB 231 breast cancer cells and of constitutive aromatase
      activity in JEG-3 choriocarcinoma cells. Structure-activity studies showed that
      this inhibition was mimicked by 4-cyclopentene-1,3-dione but not by the PPARgamma
      agonist troglitazone nor the eicosanoids PGE(2) or arachidonic acid. The thiol
      oxidants diamide and H(2)O(2) simulated the inhibitory action of 15d-PGJ(2) on
      aromatase activity, whereas the glutathione (GSH) repletor and antioxidant N
      acetyl-cysteine (NAC) reversed these actions of 15d-PGJ(2) and H(2)O(2) on
      aromatase. 15d-PGJ(2) also caused a direct dose-dependent inhibition of aromatase
      activity in JEG-3 cell sonicates, which was also reversed in the presence of GSH.
      Kinetic analysis of this 15d-PGJ(2)-induced inhibition of cell-free aromatase
      indicated the involvement of a non-competitive mechanism possibly resulting from
      direct thiol-targeted alkylation of the enzyme. These redox-sensitive, PPARgamma
      independent actions of 15d-PGJ(2) on aromatase activity demonstrate a novel
      therapeutic potential for such cyclopentenone PGs in breast cancer treatment.

PMID- 12494467
TI  - Direct interaction with and activation of p53 by SMAR1 retards cell-cycle
      progression at G2/M phase and delays tumor growth in mice.
AB  - The tumor-suppressor p53 is a multifunctional protein mainly responsible for
      maintaining genomic integrity. p53 induces its tumor-suppressor activity by
      either causing cell-cycle arrest (G(1)/S or G(2)/M) or inducing cells to undergo
      apoptosis. This function of wild-type p53 as "guardian of the genome" is
      presumably achieved by forming molecular complexes with different DNA targets as
      well as by interacting with a number of cellular proteins, e.g., Mdm2, Gadd45,
      p21, 14-3-3sigma, Bax and Apaf-1. Upon activation, p53 activates p21, which in
      turn controls the cell cycle by regulating G(1) or G(2) checkpoints. Here, we
      report SMAR1 as one such p53-interacting protein that is involved in delaying
      tumor progression in vivo as well as in regulating the cell cycle. SMAR1 is a
      newly identified MARBP involved in chromatin-mediated gene regulation. The SMAR1
      gene encodes at least 2 alternatively spliced variants: SMAR1(L) (the full-length
      form) and SMAR1(S) (the shorter form). We report that expression of SMAR1(S), but
      not of SMAR1(L), mRNA was decreased in most of the human cell lines examined,
      suggesting selective silencing of SMAR1(S). Overexpression of SMAR1(S) in mouse
      melanoma cells (B16F1) and their subsequent injection in C57BL/6 mice delays
      tumor growth. Exogenous SMAR1(S) causes significant retardation of B16F1 cells in
      the G(2)/M phase of the cell cycle compared to SMAR1(L). SMAR1(S) activates p53
      mediated reporter gene expression in mouse melanoma cells, breast cancer cells
      (MCF-7) and p53 null cells (K562), followed by activation of its downstream
      effector, p21. We further demonstrate that SMAR1 physically interacts and
      colocalizes with p53. These data together suggest that SMAR1 is the only known
      MARBP that delays tumor progression via direct activation and interaction with
      tumor-suppressor p53.

PMID- 12494468
TI  - Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous
      tumors.
AB  - Deletions and structural rearrangements of the long arm of chromosome 13 are
      frequently observed in benign and low-malignant lipomatous tumors, but nothing is
      known about their molecular genetic consequences. We assessed the karyotypes of
      40 new and 22 previously published cases (35 ordinary lipomas, 15 spindle
      cell/pleomorphic lipomas, 2 myxolipomas, 1 angiomyxolipoma and 9 atypical
      lipomatous tumors) with chromosome 13-abnormalities, and found bands 13q12-22 to
      be frequently affected. Twenty-seven cases with structural abnormalities within
      this region were selected for breakpoint and deletion mapping by metaphase
      fluorescence in situ hybridization (FISH), using a set of 20 probes. Deletions
      were found in 23 of 27 cases. The remaining 4 cases had seemingly balanced
      rearrangements. The breakpoints were scattered but clustered to band 13q14, and
      in all cases with unbalanced abnormalities, a limited region within band 13q14
      was partially or completely deleted. A deletion within band 13q14 was found
      together with a breakpoint on the other homologue in 5 cases, 4 of which could be
      tested further with regard to the status of the retinoblastoma (RB1)-gene. In all
      4 cases, only 1 copy of the gene was deleted. In addition to the breaks and
      deletions in the vicinity of the RB1-locus, several other regions of 13q were
      recurrently affected, e.g., in the vicinity of the hereditary breast cancer
      (BRCA2; 13q12)- and lipoma HMGIC fusion partner (LHFP; 13q13)- genes. Our
      findings strongly indicate that deletion of a limited region (approximately 2.5
      Mbp) within 13q14, distal to the RB1-locus, is of importance in the development
      of a subset of lipomatous tumors.

PMID- 12494469
TI  - Analysis of the human APC mutation spectrum in a saccharomyces cerevisiae strain
      with a mismatch repair defect.
AB  - Somatic APC mutations in colorectal tumors with an RER phenotype reflect
      excessive frameshift mutations, especially in simple repetition tracts within the
      coding sequence. Because this type of mutation is characteristic of cells with a
      deficient DNA MMR system, the APC mutation signature of RER tumors may be
      attributable to a defect in the MMR system. However, there is little experimental
      evidence to prove that the spectrum of mutations and the APC gene distribution
      are directly influenced by MMR system defects. We therefore examined the mutation
      spectrum of the MCR of the APC gene after transfection into both MMR-proficient
      and MMR-deficient yeast strains and compared it with a previously reported human
      APC mutation database. Small insertions or deletions in mono- or dinucleotide
      repeats were more common in the MMR-deficient than in the MMR-proficient strain
      (91.2% vs. 38.1%, Fisher's exact test p < 0.0001). Furthermore, the 2 mutation
      hot spots, 4385-4394(AG)(5) and 4661-4666(A)(6), found in the yeast system
      corresponded with those in human tumors. Combining our data with those from human
      tumors, there appears to be hypermutable mutations in specific simple repetitive
      sequences within the MCR, which are more prevalent in MMR-deficient cells and RER
      tumors than in MMR-proficient cells and non-RER tumors. We therefore consider
      that the differences in the spectra of RER and non-RER tumors are attributable at
      least in part to the MMR system of the host cells.

PMID- 12494470
TI  - CDKN2A region polymorphism and genetic susceptibility to melanoma in the melim
      swine model of familial melanoma.
AB  - Some herds of miniature swine are genetically predisposed to cutaneous melanoma.
      To test if swine melanoma susceptibility could be linked to the CDKN2A gene,
      which is involved in a proportion of 9p21-linked human familial melanoma, we
      performed a genetic analysis of miniature pigs of the MeLiM strain. F(1) and
      backcross animals were generated by crossing 1 MeLiM boar with healthy Duroc
      sows. We isolated the swine CDKN2A gene and characterized a linked informative
      microsatellite marker, the S0644 marker. Using this marker and 2 flanking
      markers, we analyzed the segregation of the CDKN2A gene in a 3-generation
      pedigree. Allelic association, linkage analysis and haplotype analysis of these
      data led to exclusion of the CDKN2A gene as a candidate for melanoma
      susceptibility. Nonetheless, this analysis suggests an association with the swine
      1q25 chromosomal region, which is homologous to the human 9p21 region.

PMID- 12494471
TI  - Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic
      deletions in MSH2 and MLH1 genes.
AB  - Hereditary nonpolyposis colorectal cancer (HNPCC) is often caused by a deficiency
      in DNA mismatch repair. By using conventional methods of mutation analysis, point
      mutations in the DNA mismatch repair genes MSH2 and MLH1 have been detected in up
      to 64% of patients suspected of HNPCC. However, large genomic deletions cannot be
      detected by these methods. In our study, we applied a semiquantitative multiplex
      PCR to detect the proportion of large deletions in patients meeting the Bethesda
      criteria whose tumours exhibited microsatellite instability (MSI). Of 368
      unrelated patients, 180 exhibited MSI. In these patients, 68 disease-causing
      point mutations (38%) had previously been detected in the MSH2 and MLH1 genes by
      SSCP, heteroduplex analysis or DHPLC followed by direct sequencing. The remaining
      112 patients (including 24 patients with rare missense or other unclarified
      variants) were examined for large deletions. We identified deletions in 19
      patients (10.6%); 11/19 (58%) deletions were located in MSH2 and 8/19 (42%) in
      MLH1, respectively. The size of deletions ranged from 1 exon to a deletion of a
      whole gene. Five breakpoints of deletions were sequenced; Alu-repetitive elements
      were involved in all of them. In patients meeting the Amsterdam criteria the
      proportion of large deletions was 12.6%. A similar proportion of deletions was
      found in the group of patients with a positive family history for colorectal
      cancer and MSI tumours, not meeting the Amsterdam criteria. The results of our
      study suggest that large genomic deletions in both MSH2 and MLH1 genes play a
      considerable role in the pathogenesis of HNPCC and should be part of the routine
      HNPCC mutation detection protocols.

PMID- 12494472
TI  - Circulating interleukin-6 predicts survival in patients with metastatic breast
      cancer.
AB  - Interleukin-6 (IL-6) is a multifunctional cytokine produced by macrophages, T
      cells, B cells, endothelial cells and tumour cells. Interleukin-6 is able to
      promote tumour growth by upregulating anti-apoptotic and angiogenic proteins in
      tumour cells. In murine models it has been demonstrated that antibodies against
      IL-6 diminish tumour growth. Several reports have highlighted the prognostic
      importance of IL-6 in e.g., prostate and colon cancer. We addressed prospectively
      the prognostic significance of serum IL-6 (sIL-6), measured at diagnosis of
      metastasis, in 96 unselected and consecutive patients with progressive metastatic
      breast cancer before the initiation of systemic therapy. The median sIL-6 value
      for the breast cancer population was 6.6 +/- 2.1 pg/ml. Patients with 2 or more
      metastatic sites had higher sIL-6 values compared to those with only 1 metastatic
      site (respectively 8.15 +/- 1.7 pg/ml and 3.06 +/- 6.6 pg/ml; p < 0.001).
      Patients with liver metastasis (8.3 +/- 2.4 pg/ml), with pleural effusions (10.65
      +/- 9.9 pg/ml) and with dominant visceral disease (8.15 +/- 3.3 pg/ml) had
      significantly higher values compared to those without liver metastases (4.5 +/-
      3.4 pg/ml; p = 0.001), without pleural effusions (5.45 +/- 1.5 pg/ml; p = 0.0077)
      and with dominant bone disease (4.5 +/- 1.4 pg/ml; p = 0.007) respectively. No
      correlation between sIL-6 and age, menopausal status, performance status, tumour
      grade, body-mass index, histology and hormone receptor status was found.
      Multivariate analysis showed that high levels of serum IL-6 have independent
      prognostic value. We conclude that circulating IL-6 is associated with worse
      survival in patients with metastatic breast cancer and is correlated with the
      extent of disease.

PMID- 12494473
TI  - Prognostic impact of matrix metalloproteinase-9 in operable non-small cell lung
      cancer.
AB  - We assessed the clinical impact of MMP-9 expression on long-term survival in
      patients with operable non-small cell lung cancer (NSCLC). Primary tumors of 143
      consecutive patients with NSCLC resected completely and without overt distant
      metastases (pT1-4, pN0-2, M0, R0) were examined for MMP-9 expression using
      immunohistochemistry with a polyclonal, affinity-purified rabbit antibody that
      recognizes both latent and active MMP-9. Immunohistochemical staining of tumor
      cells was evaluated in comparison to normal bronchiolar epithelium that served as
      an internal positive control. MMP-9 expression was categorized into negative,
      <or=5% tumor cells stained; heterogeneous, >5% and <95% tumor cells stained; and
      homogeneous, >or=95% tumor cells stained at least as intensively as bronchiolar
      epithelium. The median follow-up period was 72 months (range = 12-144 months).
      Homogeneous expression of MMP-9 was observed in 26 of 143 patients (18.2%) and
      did not correlate with clinicopathological parameters. Relapse defined as
      diagnosis of distant metastasis or local recurrence was observed in 78 of the 130
      (60%) patients eligible for clinical follow up analysis. Relapse led to cancer
      related death in all of the 78 patients within the observation period. Kaplan
      Meier analysis showed a significant association between homogeneous MMP-9
      expression and shortened cancer-related survival (log-rank p = 0.016).
      Multivariate regression analysis including pT-status, pN-status, tumor histology
      and tumor grading showed an independence of this prognostic impact of homogeneous
      MMP-9 expression (p = 0.045). Thus, immunohistochemical evaluation of MMP-9
      expression may provide a basis for the preselection of patients to be included in
      trials investigating specific protease inhibitor therapy after surgical resection
      of NSCLC.

PMID- 12494474
TI  - Tissue microarray-based analysis shows phospho-beta-catenin expression in
      malignant melanoma is associated with poor outcome.
AB  - Beyond depth of invasion, there are very few prognostic markers to predict
      outcome in melanoma. It has been shown recently that the beta-catenin oncogene is
      mutated or shows altered subcellular localization suggesting that activation of
      beta-catenin mediated signaling plays a role in oncogenesis. We hypothesize that
      assessment of activated beta-catenin, as detected by a phospho-specific antibody,
      may be useful to predict outcome in melanoma. We use immuno-histochemical
      analysis of beta-catenin and phospho-beta-catenin, first to verify the
      specificity of the phospho-beta-catenin antibody and then to assay expression in
      a tissue microarray-based study. The subcellular localization of beta-catenin is
      membranous in some cases and cytoplasmic and nuclear in others. We validate the
      specificity of a ser33/37/thr41 phospho-beta-catenin antibody in transfected
      cells and show that the expression is almost exclusively localized to the nucleus
      in both cultured cells and human tissue. Evaluation of both total and phospho
      beta-catenin antibodies showed that cytoplasmic/nuclear staining was more common
      in primary lesions, whereas nuclear phospho-beta-catenin was more common in
      metastatic lesions. High levels of nuclear phospho-beta-catenin are associated
      with significantly worse overall survival (51% vs. 25% overall survival at 5
      years, p = 0.046). These results suggest that phospho-specific antibodies to beta
      catenin define a unique subset of cases and that monitoring of phospho-beta
      catenin expression may be useful for assessing prognosis in malignant melanoma.

PMID- 12494475
TI  - EphA2 overexpression correlates with poor prognosis in esophageal squamous cell
      carcinoma.
AB  - EphA2 is a member of the Eph family of receptor tyrosine kinases, which interact
      with cell-bound ligands known as ephrins. EphA2 expression was investigated by
      immunohistochemistry with an anti-EphA2 monoclonal antibody in 80 patients with
      esophageal squamous cell carcinoma (ESCC) who had undergone surgery. EphA2
      overexpression was positive in 40 of the 80 patients (50%). A significant
      correlation was observed between EphA2 expression and regional lymph node
      metastasis (p=0.023), number of lymph node metastases (p=0.011) and poor degree
      of tumor differentiation (p=0.004). The survival rates of EphA2-positive patients
      were poorer than those of EphA2-negative patients (p=0.014). The 5-year survival
      rate of patients without EphA2 overexpression was 68%, whereas that of patients
      with EphA2 overexpression was 29%. EphA2 expression was also investigated in 7
      ESCC cell lines (TE-1, -2, -8, -13, -15, TT and TTn) and 1 immortalized human
      esophageal keratinocyte cell line (CHEK-1). Western blotting revealed different
      levels of EphA2 expression in the 8 cell lines. EphA2 was expressed at a high
      level in the ESCC cell lines compared to CHEK-1. EphA2 phosphorylation was
      demonstrated in all cell lines. Northern blot analysis showed that EphA2 mRNA
      expression in TE-1 was greater than that in the other ESCC cell lines. The
      observation of small gaps on Western blot analysis of the ESCC cell lines
      suggests that there may be a mechanism for EphA2 regulation at the point of
      translation. In conclusion, EphA2 overexpression appears to be related to poor
      degree of tumor differentiation and lymph node metastasis in ESCC. Consequently,
      patients with EphA2 overexpression have a poorer prognosis than those without.
      EphA2 is a potential target to prevent ESCC cells spreading into the lymphatic
      drainage.

PMID- 12494476
TI  - Serum selenium and risk of prostate cancer in U.S. blacks and whites.
AB  - Prostate cancer is the fourth most common cancer in men worldwide and the most
      common cancer in men in the United States, with reported incidence rates for U.S.
      blacks being the highest in the world. The etiology of prostate cancer and an
      explanation for the racial disparity in incidence in the United States remain
      elusive. Epidemiologic studies suggest that selenium, an essential trace element,
      may protect against the disease. To further explore this hypothesis, we measured
      serum selenium in 212 cases and 233 controls participating in a multicenter,
      population-based case-control study that included comparable numbers of U.S.
      black and white men aged 40-79 years. Serum selenium was inversely associated
      with risk of prostate cancer (comparing highest to lowest quartiles, OR = 0.71,
      95% CI 0.39-1.28; p for trend = 0.11), with similar patterns seen in both blacks
      and whites. Cubic regression spline analysis of continuous serum selenium
      indicated a reduced risk of prostate cancer above concentrations of 0.135
      microg/ml (median among controls) compared to a reference value set at the median
      of the lowest selenium quartile. Because both the selenoenzyme GPX and vitamin E
      can function as antioxidants, we also explored their joint effect. Consistent
      with other studies, the inverse association with selenium was strongest among men
      with low serum alpha-tocopherol concentrations. In conclusion, our results
      suggest a moderately reduced risk of prostate cancer at higher serum selenium
      concentrations, a finding that can now be extended to include U.S. blacks. Since
      selenium exposure varies widely throughout the world, further research on optimal
      concentrations for cancer prevention is justified.

PMID- 12494477
TI  - Single nucleotide polymorphisms in the XPG gene: determination of role in DNA
      repair and breast cancer risk.
AB  - In this study we determined the effect of single nucleotide polymorphisms in the
      XPG gene on DNA repair and breast cancer susceptibility. Ninety individuals, with
      previously studied DNA repair rate at 24 hr of 2 types of UV-specific cyclobutane
      pyrimidines dimers (CPDs) in skin were genotyped for XPG polymorphism at codon
      1104 (exon 15 G>C; Asp > His). The repair rate of TT=C dimer was similar in both
      wild-type GG homozygotes and GC heterozygotes, whereas, for TT=T, dimer repair
      was non-significantly (Student's t-test, p = 0.34) lower in GC heterozygotes than
      wild-type GG homozygotes. Genotyping of 220 breast cancer cases and 308 controls
      for the same single nucleotide polymorphism in exon 15 of the XPG gene exhibited
      marginally significant increased frequency of the variant allele (chi(2) 3.84, p
      = 0.05; OR 1.33, 95% CI 1.0-1.8) in cases (C-allele 0.29) compared to controls (C
      allele 0.24). Combined heterozygote and variant homozygote genotype frequency was
      also higher in cases than controls (chi(2) 4.79, p = 0.03; OR 1.50, 95%CI 1.04
      2.16).

PMID- 12494478
TI  - Abortions and breast cancer: record-based case-control study.
AB  - It has been suggested that abortions leave the breast epithelium in a
      proliferative state with an increased susceptibility to carcinogenesis. Results
      from previous studies of induced or spontaneous abortions and risk of subsequent
      breast cancer are contradictory, probably due to methodological considerations.
      We investigated the relationship between abortions and subsequent breast cancer
      risk in a case-control study using prospectively recorded exposure information.
      The study population comprised women recorded in the population-based Swedish
      Medical Birth Register between 1973-91. Cases were defined by linkage of the
      birth register to the Swedish Cancer Register and controls were randomly selected
      from the birth register. From the subjects' antenatal care records we abstracted
      prospectively collected information on induced and spontaneous abortions, as well
      as a number of potential confounding factors. Relative risk of breast cancer was
      estimated by odds ratios (OR) with 95% confidence intervals (95% CI). A reduced
      risk of breast cancer was observed for women with a history of at least 1
      compared to no abortions (adjusted OR = 0.84, 95% CI = 0.72-0.99). The adjusted
      OR decreases step-wise with number of abortions to 0.59 (95% CI = 0.34-1.03) for
      3 or more compared to no abortions. The patterns are similar for induced and
      spontaneous abortions. In conclusion, neither a history of induced nor
      spontaneous abortions is associated with an increased risk of breast cancer. Our
      data suggest a protective effect of pregnancies regardless of outcome.

PMID- 12494479
TI  - Changing epidemiology of nasopharyngeal carcinoma in Hong Kong over a 20-year
      period (1980-99): an encouraging reduction in both incidence and mortality.
AB  - Epidemiological data from the Hong Kong Cancer Registry for the period 1980-99
      were analyzed. Altogether 21,768 new cases of nasopharyngeal carcinoma (NPC) and
      8,664 related deaths were registered. In both genders, the peak incidence
      occurred in the 50-59 years age group, and this age distribution pattern remained
      similar throughout. The age-standardized incidence rate steadily decreased from
      28.5 in 1980-84 to 20.2 in 1995-99 per 100,000 males, and from 11.2-7.8 per
      100,000 females, resulting in a total decrease of 29% for males and 30% for
      females over this 20-year period. The magnitude of total decrease in NPC
      mortality amounted to 43% and 50%, respectively, as the age-standardized
      mortality rate steadily decreased from 13.7 in 1980-84 to 7.8 in 1995-99 per
      100,000 males, and from 4.5-2.2 per 100,000 females. The age-standardized
      mortality/incidence ratio also decreased from the peak of 0.48 in 1980-84 to 0.39
      in 1995-99 for males, and from 0.40-0.29 for females. Females had significantly
      lower age-standardized incidence (male/female ratio 2.5-2.6, p < 0.01) and
      mortality (male/female ratio 3.0-3.5, p< 0.01) throughout the whole period.
      Furthermore, females had consistently lower mortality/incidence ratio: 0.29 vs.
      0.39 in 1995-99. These data are highly suggestive of significant improvement in
      prevention and control of NPC in Hong Kong. Closer scrutiny of the differences in
      intrinsic and extrinsic factors between the genders might help to show important
      factors affecting oncogenesis and prognosis. Possible ways for further reduction
      of incidence and mortality are discussed.

PMID- 12494480
TI  - Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4
      carboxamide-bischloroethylnitrosourea combination therapy in patients with
      advanced breast cancer.
AB  - We assessed whether split dosing with the methylating agent DTIC is an effective
      strategy for inactivating the DNA repair protein O6-alkylguanine DNA-ATase in
      order to decrease tumour resistance to BCNU. ATase levels in PBMCs were used as a
      surrogate for tumour ATase depletion to determine whether this correlated with
      either the pharmacokinetics of DTIC and its major metabolite AIC or other
      clinical sequelae. Two 1 hr infusions of DTIC (400 mg/m(2)) 4 hr apart followed
      another 4 hr later by BCNU (75 mg/m(2)) were administered every 6 weeks in 7
      patients with heavily pretreated advanced breast cancer. The extent and kinetics
      of ATase depletion and recovery in PBMCs varied not only between patients but
      also between cycles in the same patient. Serial FNAs showed heterogeneity in
      tumour ATase expression but no clear pattern of change in ATase activity. DTIC
      and AIC exhibited biphasic clearance from the blood, consistent with a 2
      compartment pharmacokinetic model. The AUC of AIC was strongly correlated with
      the percentage decrease in PBMC ATase levels. There were no clinical responses,
      and toxicity in neutrophils and platelets was marked. Split-dose DTIC therefore
      does not appear to be a clinically effective approach to overcome O(6)-alkylating
      agent resistance in advanced breast cancer.

PMID- 12494481
TI  - Experimental photodynamic therapy with MESO-tetrakisphenylporphyrin (TPP) in
      liposomes leads to disintegration of human amelanotic melanoma implanted to nude
      mice.
AB  - Liposomal meso-tetrakis-phenylporphyrin (TPP) was tested for photodynamic therapy
      (PDT) of human amelanotic melanomas implanted in nude mice. After intratumoural
      TPP application (15 mg x kg(-1)) followed by PDT lamp irradiation (600-700 nm,
      635 nm peak), tumours retained their original volume up to the 23rd day post-PDT,
      whereas volumes increased 6 times in controls. PDT with intravenously (i.v.)
      administered liposomal (3.2 mg x kg(-1)) TPP mostly disintegrated tumours to zero
      volumes. Melanoma remissions were accompanied by tumour surface necroses and were
      documented by the appearance of nontumourous cells with nonpycnotic nuclei.
      Spatial arrangement of capillaries in remissing tumour was the same as in healthy
      surrounding tissue. Lower TPP doses (1, 0.3 and 0.1 mg x kg(-1)) were more or
      equally efficient than hydrophilic TPPS(4) (3.2 mg x kg(-1), i.e., sulfonated
      TPP), i.v. administered also in liposomes. Liposomal TPPS(4) only delayed the
      onset of subsequent tumour growth. Commercial Photosan 3 disintegrated tumours
      only in doses of approx. 7.5 mg x kg(-1); in lower doses it was less efficient
      than TPPS(4). The second PDT cycle (3.2 mg x kg(-1) TPP or 7.5 mg x kg(-1)
      Photosan 3), performed in a few unsuccessfully cured mice, predominantly led
      again to tumour remissions. Since the measured TPP and TPPS(4) content in
      melanomas was similar, these results demonstrate the advantage of PDT with a
      hydrophobic photosensitizer such as TPP. Photophysical properties of TPP and
      TPPS(4) are equal, but TPP has probably more favorable intracellular
      distribution, as documented by our studies, which leads to more efficient PDT.
      Consequently, liposomal TPP is suggested as a potentially suitable efficient
      preparation for PDT.

PMID- 12494484
TI  - Functional morphology and physiology of pulmonary rapidly adapting receptors
      (RARs).
AB  - Rapidly adapting receptors (RARs) in the airway mucosa are found from the
      nasopharynx to the bronchi. They have thin (Adelta) vagal afferent fibres and lie
      in and under the epithelium, but their morphology has not been defined. They are
      very sensitive to mechanical stimuli, and have a rapidly adapting irregular
      discharge. However, with in vitro preparations they are rather insensitive to
      chemical stimuli, apart from acid and nonisosmolar solutions. Their pattern of
      response varies with site. RARs in the nasopharynx, larynx, and trachea usually
      respond only during the onset of stimuli, while those in the trachea often have
      an off-response as well. Those in the bronchi are less rapidly adapting and more
      chemosensitive. Their membranes have mechanosensitive and acid-sensitive ion
      channels, but no vanilloid receptors. In vivo RARs are sensitive to a wide range
      of chemical irritants and mediators, and presumably are excited secondarily to
      mechanical changes in the mucosa and airway smooth muscle. In the central nervous
      system (CNS) they interact with other vagal afferent pathways. The reflexes they
      cause vary with site (inspiratory efforts from the nasopharynx, cough or
      expiratory efforts from the larynx and trachea, and deep breaths or tachypnoea
      from the bronchi). Pathways from RARs and other vagal reflexes show plasticity at
      the peripheral, ganglionic, and CNS levels.

PMID- 12494485
TI  - Functional morphology and physiology of slowly adapting pulmonary stretch
      receptors.
AB  - Since the original work by Hering and Breuer (1868) on slowly adapting pulmonary
      stretch receptors (SARs), numerous studies have demonstrated that these receptors
      are the lung vagal afferents responsible for eliciting the reflexes evoked by
      moderate lung inflation. SARs play a role in controlling breathing pattern,
      airway smooth muscle tone, systemic vascular resistance, and heart rate. Both
      anatomical and physiological studies support the contention that SARs, by their
      close association with airway smooth muscle, continuously sense the tension
      within the myoelastic components of the airways caused by lung inflation, smooth
      muscle contraction, and/or tethering of small intrapulmonary airways to the lung
      parenchyma. As a result, the receptor field location within the tracheobronchial
      tree of a SAR plays an important role in its discharge pattern, with variations
      in airway transluminal pressure and airway smooth muscle orientation being
      important modulating factors. The disruption of airway myoelastic components in
      various pulmonary diseases would be expected to alter the discharge pattern of
      SARs, and contribute to changes in breathing pattern and airway smooth muscle
      tone.

PMID- 12494486
TI  - Functional morphology and physiological properties of bronchopulmonary C-fiber
      afferents.
AB  - Nonmyelinated (C-) fibers represent the majority of vagal afferents innervating
      the airways and lung, and play an important role in regulating the respiratory
      and cardiovascular functions under both normal and abnormal physiologic
      conditions. Studies of the relationship between the conduction velocities of the
      vagal afferents and their sensitivities to capsaicin and other chemical irritants
      reveal that C-fibers are the primary type of chemosensitive afferents in the rat
      lung. Furthermore, a distinct sensitivity to capsaicin and a weak response to
      lung inflation are the defining characteristics of these afferents. In cultured
      rat nodose and jugular ganglion neurons, capsaicin-sensitive cells were
      identified by measurement of the capsaicin-evoked calcium transients using the
      Fura-2-based ratiometric imaging technique. The percentage of capsaicin-sensitive
      neurons gradually decreases as the cell diameter increases. However, the
      capsaicin-sensitive neurons cannot be precisely identified solely on the basis of
      the cell size. Anandamide, an endogenous cannabinoid released from leukocytes and
      epithelial cells, consistently evokes a stimulatory effect on pulmonary C-fiber
      endings by activating vanilloid receptor type 1 (VR1). The discharge pattern of
      pulmonary C-fibers evoked by anandamide closely resembles that produced by a much
      lower ( approximately 1/600) dose of capsaicin in the same fibers. Whether
      anandamide acts as a potential endogenous ligand to VR1 at the C-fiber terminals
      is unclear, and the physiological role of VR1 in modulating the transduction
      properties of these afferents also remains to be determined.

PMID- 12494487
TI  - Functional morphology of pulmonary neuroepithelial bodies: extremely complex
      airway receptors.
AB  - Innervated groups of neuroendocrine cells, called neuroepithelial bodies (NEBs),
      are diffusely spread in the epithelium of intrapulmonary airways in many species.
      Our present understanding of the morphology of NEBs in mammalian lungs is
      comprehensive, but none of the proposed functional hypotheses have been proven
      conclusively. In recent reviews on airway innervation, NEBs have been added to
      the list of presumed physiological lung receptors. Microscopic data on the
      innervation of NEBs, however, have given rise to conflicting interpretations.
      Using neuronal tracing, denervation, and immunostaining, we recently demonstrated
      that the innervation of NEBs is much more complex than the almost unique vagal
      nodose sensory innervation suggested by other authors. The aim of the present
      work is to summarize our present understanding about the origin and chemical
      coding of the profuse nerve terminals that selectively contact pulmonary NEBs. A
      thorough knowledge of the complex interactions between the neuroendocrine cells
      and at least five different nerve fiber populations is essential for defining the
      position(s) of NEBs among the many pulmonary receptors characterized by lung
      physiologists.

PMID- 12494488
TI  - Acute oxygen sensing in cellular models: relevance to the physiology of pulmonary
      neuroepithelial and carotid bodies.
AB  - The combination of studies in native tissues and immortalised model systems
      during the last decade has made possible a deeper understanding of the physiology
      and functional morphology of arterial and airway oxygen sensors. Complementary
      and overlapping information from these earlier studies has allowed a detailed
      description of the cellular events that link decreased environmental oxygen to
      the release of physiologically important vasoactive transmitters. Since these
      basic pathways have now been defined functionally, what remains to be determined
      is the molecular identity of the specific proteins involved in the signal
      transduction pathways, and how these proteins interact to produce a full
      physiological response. With these goals clearly in sight, we have embarked upon
      a strategy that is a novel combination of proteomics and functional genomics. It
      is hoped this strategy will enable us to develop and refine the initial models in
      order to understand more completely the process of oxygen sensing in health and
      disease.

PMID- 12494489
TI  - Receptor-mediated effects of nicotine and its nitrosated derivative NNK on
      pulmonary neuroendocrine cells.
AB  - Pulmonary neuroendocrine cells (PNECs) have been implicated in the development of
      small cell lung carcinoma (SCLC) and pediatric asthma, and smoking is a risk
      factor for both diseases. We as well as others have shown that the alpha(7)
      nicotinic acetylcholine receptor (alpha(7) nAChR) regulates the release of 5
      hydroxytryptamine (5-HT, serotonin) in PNECs and SCLC. Serotonin is an autocrine
      growth factor for PNECs and SCLC and acts as broncho-constrictor. We found that
      nicotine and its nitrosated carcinogenic derivative 4-(methylnitrosamino)-1-(3
      pyridyl)-1-butanone (NNK) bind to the alpha(7) nAChR in SCLC and PNECs, resulting
      in the influx of Ca(2+), release of 5-HT, and activation of a mitogenic pathway
      mediated by protein kinase C (PKC), Raf-1, mitogen activated protein kinase
      (MAPK) and c-myc. Exposure to 10% CO(2) acted synergistically. Unstimulated SCLC
      cells from smokers demonstrated high base levels of 5-HT release and of
      individual downstream signaling components in comparison to PNECs. Subchronic
      exposure of PNECs to NNK up-regulated the alpha(7) nAChR and its associated
      serotonergic mitogenic pathway in PNECs, an effect that may contribute to the
      development of SCLC in smokers and pediatric asthma in children of mothers who
      smoke.

PMID- 12494490
TI  - Morphometric analysis of the uterine endometrium of swine on days 12 and 16
      postestrus.
AB  - The uterine endometrium of swine is comprised of luminal epithelial, glandular
      epithelial, and stromal cells that secrete the luteolysin, prostaglandin
      F(2alpha) (PGF(2alpha)), during late diestrus. However, which of these cells
      contribute the most to luteolytic PGF(2alpha) secretion is unknown because the
      cellular composition of the endometrium has not been quantified. Therefore, this
      study quantified the cellular composition of the endometrium on days 12 and 16
      postestrus by histologic and morphometric analyses. On day 12, the endometrium
      consisted predominantly of stromal cells (47% of total cell quantity) and
      glandular epithelial cells (37%), whereas luminal epithelial cells represented
      only 16% of the total of the three cell types. The number of glandular epithelial
      cells tended to increase (P < 0.10) between days 12 and 16, such that they
      comprised 45% of the endometrium by day 16, while the number of stromal and
      luminal cells did not change and accounted for 45% and 10% of the cells,
      respectively. Luminal epithelial cells had a 58% greater cross-sectional area (P
      < 0.001) than glandular epithelial cells, whereas glandular epithelial cells had
      a 22% greater area (P < 0.001) than stromal cells. Glandular epithelial cells
      decreased (P < 0.001) in cross-sectional area between days 12 and 16, whereas the
      area of luminal epithelial and stromal cells remained unchanged. These results
      indicate that the porcine endometrium is comprised predominantly of stromal and
      glandular epithelial cells that are likely to contribute substantially to
      endometrial PGF(2alpha) secretion during luteolysis. The contribution of
      glandular epithelium to luteolytic PGF(2alpha) secretion probably increases
      during diestrus as the number of these cells increases.

PMID- 12494491
TI  - Mechanically altered embryonic chicken endothelial cells change their phenotype
      to an epithelioid phenotype.
AB  - Monolayers of retracted endothelial cells exhibiting wounds or zones denuded of
      cells were obtained from aortic explants from 10- to 12-day-old chicken embryos.
      Using time-lapse videomicroscopy, we investigated the sequence of events that
      occurred both during and after closure of the monolayer wounds. Such wound
      closure (re-endothelialization process) occurred 4-12 hr after removing the
      explants, depending on wound width and presence of serum. The cells from along
      the wound edges appeared to move toward one another. We suggest an important role
      for bFGF and TGFbeta-2 and -3 during this process. Twenty-five hours after
      removal there were still some areas of retracted cells, and many of the cells
      displayed a weak von Willebrand's Factor (vWf) immunoreactivity. Surprisingly,
      after 63-65 hr many of the endothelial cells had become epithelioid in shape and
      the vWf immunoreactivity appeared increased. This epithelioid phenotype is
      currently considered typical of cultured vascular non-muscle-like cells and
      intimal thickening cells. By 5-7 days, the vast majority of cells in the
      monolayer had acquired an epithelioid morphology, showing a cobblestone
      appearance. These cells were significantly smaller than polygonal cells. Most
      importantly, they showed strong vWf immunoreactivity. At the edge of the
      monolayers we found that the majority of the cells had become epithelioid. Some
      of them detached from their neighbors and became round in shape and acquired
      mesenchymal characteristics, some expressing smooth muscle alpha-actin (SM alpha
      actin). These findings demonstrate not only that embryonic endothelial cells that
      are transiently mechanically altered may change their phenotype to an epithelioid
      phenotype, but also that these cells may eventually transdifferentiate into
      mesenchymal cells expressing SM alpha-actin. Since some aspects of endothelial
      cell behavior have been shown to be regulated by locally released growth factors
      such as TGFbeta and FGF, we also investigated TGFbeta-2 and -3 and bFGF
      expression. Presence of TGFbeta-2 and -3 and bFGF-immunoreactive epithelioid and
      mesenchymal cells indicates that these growth factors may be involved in the
      changes described.

PMID- 12494492
TI  - Postnatal maturation of the dog stria vascularis-- an immunohistochemical study.
AB  - The lateral wall of the dog cochlear duct was investigated by classical staining
      and immunohistochemistry for NaK/ATPase beta2 isoform, cytokeratins (Cks),
      vimentin, nestin, and S100A6 during the postnatal cochlear maturation, i.e., from
      birth to postnatal day 110. The dog stria vascularis was immature at birth. Fine
      melanin granules were evident in the stria from the second week of life, and
      melanin concentration increased drastically beyond the first month. The marginal
      cells were NaK/ATPase- and Ck-positive; intermediate cells were either nestin-
      and S100A6-positive or vimentin-positive; the basal cells were vimentin-positive;
      the capillary endothelium showed vimentin and nestin labeling; the cell layer
      underlying the stria was nestin-positive. The fibrocytes of the spiral ligament
      and spiral prominence expressed nestin and vimentin. The epithelial cells
      overlaying the spiral prominence and the external sulcus were Ck-positive, and
      transiently nestin- and vimentin-positive. Double immunolabeling, for S100A6 and
      either nestin, vimentin, or NaK/ATPase, and for nestin and vimentin suggested the
      presence of two distinct intermediate cell types. The results enabled us to
      differentiate the cell types forming the lateral wall of the dog cochlear duct,
      and to follow their postnatal maturation. This study may form a basis for future
      investigations about spontaneous cochleosaccular degeneration in dogs. This
      species is an important companion animal, and a possible model for the study of
      comparable diseases in humans.

PMID- 12494494
TI  - Ibritumomab tiuxetan (Zevalin) for non-Hodgkin's lymphoma.

PMID- 12494495
TI  - [The world of stem cells].
AB  - Since its beginning, at the turn of the 19th century, biology has been mostly--if
      not exclusively--analytical. Reductionism has progressively unveiled a series of
      structures buried into one another like Russian dolls. The study of the genome,
      the deepest structure of organisms, represents the triumph of reductionism. With
      the deciphering of the genome and the birth of what is called the 'proteome'-
      i.e. the study of the proteins and of their interactions--, a new stage appears.
      To the disorganisation that characterised two centuries of biology, a phase of
      reconstruction of living organisms is substituted. This is concerned first with
      interactions of proteins and of cells. In addition, one of the most remarkable
      tools for this latter research has been provided by embryonic stem cells.

PMID- 12494496
TI  - Source and nature of embryonic stem cells.
AB  - The originally described method of isolation of mouse ES cells was from
      implantationally-delayed blastocysts that were subsequently explanted into tissue
      culture. The cell colony arising from the ICM proliferation was disaggregated and
      cultures established on mitotically inactivated fibroblast feeder layers. The use
      of delayed blastocysts is advantageous, but not essential, and ES cells have been
      similarly derived by explantation of cleavage-stage embryos and also early
      embryonic epiblast. ES cells are probably not homologous to ICM cells, but may
      better match five-day epiblast.

PMID- 12494497
TI  - Human embryonic stem cell lines: socio-legal concerns and therapeutic promise.
AB  - Stem cell lines would be very valuable for the repair of diseased or damaged
      organs. Stem cells derived from adult tissues raise few ethical problems, and
      would not be rejected if derived from the patient. They show considerable
      plasticity and might be appropriate for some clinical conditions, but they tend
      not to grow well in culture. Stem cells derived from the early human embryo
      proliferate indefinitely in culture and can give rise to many different tissues,
      but their derivation requires destruction of the embryo, which is not ethically
      acceptable in some countries. Other countries allow strictly regulated
      destructive research on human embryos, usually those that have been produced for
      infertile couples in infertility clinics. Embryos that are no longer required for
      the couple's own reproductive project could be donated for research rather than
      just discarded. Different approaches are being developed to avoid immunological
      rejection of embryonic stem cells used for therapy. Derivation of embryonic stem
      cell lines by somatic cell nuclear transfer ('cloning') from the patients
      themselves might be one possible approach, but is unlikely to be used in routine
      clinical practice if more cost-effective methods are available.

PMID- 12494498
TI  - Hemangioblasts and hemopoietic stem cells during ontogeny.
AB  - This review focuses on the emergence of hemopoietic stem cells (HSC) in the
      embryonic aorta, which was analysed in the avian model. Intraaortic clusters, a
      characteristic vertebrate anatomical feature, were shown to derive from the
      splanchnopleural (ventral) mesoderm, which has the potential to give rise to both
      angioblasts and hemopoietic cells. In contrast, the somitic mesoderm was shown to
      give rise to angioblasts only. The derivation of hemopoietic progenitors from
      endothelial cells in the floor of the aorta was followed by means of in vivo
      labelling experiments. Finally, the expression of gene-encoding transcription
      factors involved in the emergence of HSC was restricted to the floor of the aorta
      immediately prior to and during the appearance of intraaortic clusters.

PMID- 12494499
TI  - Emergence of hematopoietic stem cells in the human embryo.
AB  - We have previously identified a novel site of hematopoietic cell production
      within the human embryo, which is localised in the ventral wall of the dorsal
      aorta and vitelline artery. Cells emerging in that territory between 27 and 40
      days of gestation exhibit the expected phenotypic, molecular, and functional
      properties of hematopoietic stem cells and are the first multipotent, lympho
      myeloid progenitors that appear in human ontogeny. We have next demonstrated that
      vascular endothelial cells sorted stringently, by flow cytometry, from the human
      yolk sac and embryonic aorta exhibit dramatic blood-forming potential in culture.
      These results suggest a filiation between vascular endothelium and hematopoietic
      cells in the course of early human ontogeny. More preliminary data indicate that
      a subpopulation of vascular endothelial cells in the bone marrow may retain this
      hematogenous potential until adult stages.

PMID- 12494500
TI  - Reprogramming of bone marrow mesenchymal stem cells into cardiomyocytes.
AB  - We have isolated a cardiomyogenic cell line (CMG cell) from murine bone marrow
      mesenchymal stem cells. The cells showed a fibroblast-like morphology, but the
      morphology changed after 5-azacytidine exposure. They began spontaneous beating
      after 2 weeks, and expressed ANP and BNP. Electron microscopy revealed a
      cardiomyocyte-like ultrastructure. These cells had several types of action
      potentials: sinus-node-like and ventricular-cell-like action potentials. The
      isoform of contractile protein genes indicated that their muscle phenotype was
      similar to fetal ventricular cardiomyocytes. They expressed alpha 1A, alpha 1B,
      alpha 1D, beta 1, and beta 2 adrenergic and M1 and M2 muscarinic receptors.
      Stimulation with phenylephrine, isoproterenol and carbachol increased ERK
      phosphorylation and second messengers. Isoproterenol increased the beating rate,
      which was blocked with CGP20712A (beta 1-selective blocker). These findings
      indicated that cell transplantation therapy for the patients with heart failure
      might possibly be achieved using the regenerated cardiomyocytes from autologous
      bone marrow cells in the near future.

PMID- 12494501
TI  - New principles of cell plasticity.
AB  - Recent discoveries demonstrating surprising cell plasticity in animals and humans
      call into question many long held assumptions regarding differentiative potential
      of adult cells. These assumptions reflect a classical paradigm of cell lineage
      development projected onto both prenatal development and post-natal maintenance
      and repair of tissues. The classical paradigm describes unidirectional,
      hierarchical lineages proceedings step-wise from totipotent or pluripotent stem
      cells through intermediate, ever more restricted progenitor cells, leading
      finally to 'terminally differentiated' cells. However, in light of both the
      recent discoveries and older clinical or experimental findings, we have suggested
      principles comprising a new paradigm of cell plasticity, summarized here.

PMID- 12494502
TI  - International stem cell research considerations.
AB  - Legislative bodies in the international arena and in individual countries are
      actively engaged in developing policies regarding the establishment, distribution
      and use of human embryonic stem cells. Present and anticipated policies
      concerning research on human adult and embryonic stem cells of possible medical
      importance reflect the wide spectrum of popular views that range from complete
      rejection to enthusiastic support. Since the public debate concerning the use of
      human gametes or embryos for research purposes is not likely to abate anytime
      soon, all the more urgent becomes the quest for alternative approaches toward
      generating stem cells that are not embryonic and yet are pluripotent.

PMID- 12494503
TI  - Stem cell therapy: medical advance or moral challenge?
AB  - My professional lifetime has seen progress in the biomedical sciences that
      beggars belief. This has lead to astonishing advances in the ability to prevent
      and treat disease and, in the developed world at least, people live longer and
      healthier lives than ever before. Paradoxically, this has gone hand in hand with
      the growth of a vocal and influential anti-science lobby that not only rejects
      much modern science but is also deeply suspicious of new medical interventions.
      The prospect of cell therapy in the near or middle future is their current target
      especially where the use of embryonic stem cells or of cell nuclear transfer
      techniques is concerned. The prospect of cell therapy is welcomed with enthusiasm
      by patients with genetic and degenerative diseases who hope to benefit from them.
      On the other hand the whole idea is regarded as repugnant by the anti-science
      lobby. While some of this opposition is essentially luddite in nature, there are
      some more persuasive arguments raised particularly to any research than uses
      embryonic or foetal materials. These arguments will be examined critically. The
      moral problems of denying the sick the hope of effective treatments have to be
      weighed against those seen in the development of such treatments. (This article
      is closely based on an already published paper. P. Lachmann, Stem cell research:
      why is it regarded as a threat? An investigation of the economic and ethical
      arguments made against research with human embryonic stem cells.

PMID- 12494504
TI  - Medical perspectives of adults and embryonic stem cells.
AB  - In the last 30 years, allogeneic bone marrow transplantation has become the
      treatment of choice for many hematologic malignancies or inherited disorders and
      a number of changes have been registered in terms of long-term survival rate of
      transplanted patients as well as of available sources of hematopoietic stem cell
      (HSC). In parallel to the publication of better results in HSC transplantation,
      several recent discoveries have opened a scientific and ethical debate on the
      therapeutical potential of stem cells isolated from adult or embryonic tissues.
      One of the major discoveries in this field is the capacity of bone marrow-derived
      stem cells to treat a genetic liver disease in a mouse model, thus justifying the
      concept of transdifferentiation of adult stem cell and raising hopes on its
      possible therapeutical applications. We have tried here to summarise the advances
      in this field and to discuss the limits of these biological data.

PMID- 12494505
TI  - [Stem cells and cell therapy. Contribution to the ethical debate].
AB  - Divergent and sometimes conflicting positions with respect to human stem cells
      and cell therapy do not merely reflect disagreement among scientists and
      conflicts of interest. They attest the ethical tension resulting from recent
      progress in understanding the earliest stages of development of the human being
      that can be observed in vitro. Can the extremely potent notion of the human
      person starting with conception apply to the very first stage of artificial in
      vitro fertilisation and disregard the fact that to be a real substitute for
      natural conception, implantation in the uterus that enables the oocyte to nest
      and a new human being to develop must also be included? Several arguments are
      presented that plead in favour of making a clear distinction between the status
      of in vitro cells obtained by artificial fertilisation and that of the embryo,
      which becomes a developing human being from the moment it implants in the
      endometrium of the uterus. This subject could have remained in the sphere of the
      individual conscience, but it has now become a theme for social debate! The
      revision of the French 1994 so-called Bioethics Laws, which was recently approved
      on first reading on 22 January 2002, authorizes research on spare embroys from in
      vitro fertilisation under certain conditions. However, for the sole reason that
      there is a risk of opening the door wide to reproductive cloning, which is
      unanimously rejected and condemned, all research on stem cells deriving from the
      nuclear transfer of a somatic cell is prohibited, irrespective of the distinction
      between cloning for therapeutic purposes and reproductive cloning. It is
      undeniable that if the efficacy of somatic stem cells could be demonstrated, they
      would offer a far more preferable solution, for several reasons, than those
      involving stem cells obtained from spare embryos from IVF or nuclear transfer.
      Nevertheless, how will a comparison of the two methods be possible if one of them
      is prohibited a priori? At present, many fear that French researchers will be
      prevented from doing essential research that, even if it has far to go, is
      indispensable if we wish to attempt to control the failures of natural
      procreation and open the way towards the new regenerative medicine that so many
      look forward to.

PMID- 12494506
TI  - [Stem cell colloquy: conclusion].
AB  - The stem cell data presented and discussed during the symposium raise the hope
      that important medical progress can be made in several fields: neuro-degenerative
      diseases, those linked to cellular deficit, some aspects of aging linked to
      cellular degeneration, and the treatment of cancers that may harm normal tissues
      at risk of being infiltrated by malignant cells. Three main types of stem cells
      are available. (i) Those present in normal adult tissue: contrary to what was
      believed, some data suggest that certain adult stem cells have a great plasticity
      (they can differentiate into cells different from those in tissues from which
      they were taken) and can proliferate in vitro without losing their properties.
      Nevertheless, their use faces several obstacles: in ill or elderly subjects, then
      these cells can be limited in number or not multiply well in vitro. In this case,
      auto-grafting of the cells cannot be used. They must be sought in another
      subject, and allo-grafting causes difficult and sometimes insoluble problems of
      immunological tolerance. (ii) Embryonic stem cells from surplus human embryos,
      obtained by in vitro fertilisation, which the parents decide not to use: these
      cells have a great potential for proliferation and differentiation, but can also
      encounter problems of immunological intolerance. (iii) Cells obtained from cell
      nuclear transfer in oocytes: these cells are well tolerated, since they are
      genetically and immunologically identical to those of the host. All types of stem
      cells can be obtained with them. However, they do present problems. For obtaining
      them, female oocytes are needed, which could lead to their commercialization.
      Moreover, the first steps for obtaining these cells are identical to those used
      in reproductive cloning. It therefore appears that each type of cell raises
      difficult scientific and practical problems. More research is needed to overcome
      these obstacles and to determine which type of stem cell constitutes the best
      solution for each type of disease and each patient. There are three main ethical
      problems: (a) to avoid the commercialization of stem cells and oocytes (this can
      be managed through strict regulations and the supervision of authorized
      laboratories); (b) to avoid that human embryos be considered as a mere means to
      an end (they should only be used after obtaining the informed consent of the
      parents; the conditions of their use must be well defined and research programs
      must be authorized); (c) to avoid that research on stem cell therapy using cell
      nuclear replacement opens the way to reproductive cloning (not only should
      reproductive cloning be firmly forbidden but authorization for cell nuclear
      transfer should be limited to a small number of laboratories). Overall, it
      appears that solutions can be found for administrative and ethical problems.
      Harmonisation of international regulations would be desirable in this respect, in
      allowing at the same time each country to be responsible for its regulations. A
      last ethical rule should be implemented, not to give patients and their families
      false hopes. The scientific and medical problems are many, and the solutions will
      be long and difficult to find. Regenerative medicine opens important avenues for
      research, but medical progress will be slow.

PMID- 12494507
TI  - [Management of tuberculosis during pregnancy and puerperium].
AB  - We reported 22 cases with tuberculosis in pregnancy and puerperium, who were
      treated in our hospital from 1993 to 2001. Nine out of 22 cases were foreign
      women and the onset of tuberculosis was not clear and the diagnosis tended to be
      delayed in most cases. In the reports from industrial countries, most of those
      patients are foreign bone and the delay in diagnosis is common because symptoms
      are apt to be mixed up those for pregnancy and puerperium. In 10 of 22 cases,
      extrapulmonary lesions were noted. Most of our cases were treated with INH, RFP
      and EB, and in some severer cases PZA was added. WHO and BTS recommend standard
      therapy with PZA but ATS recommends INH, RFP and EB without PZA. Generally SM is
      contraindicated because of adverse effect of hearing loss for all pregnant
      periods, and the data for PZA and other second line drugs are insufficient. Our
      cases and their neonates showed normal course and no malformation nor congenital
      tuberculosis. 2 cases could not keep adherence for drugs and 2 babies got active
      tuberculosis. Precaution for infection is one of most important problem to deal
      with cases with tuberculosis during pregnancy and postpartum in the hospital. If
      she is still infectious on delivery, we should consider prevention for
      transmission and manage her in isolated manner. CDC recommends not to treat for
      latent tuberculosis during pregnancy because of high frequency of hepatic damage
      due to INH. It is the best way to check and treat latent tuberculosis before
      gestation if she is at high risk with tuberculosis.

PMID- 12494508
TI  - [A clinical study of deceased cases of pulmonary M. Avium complex (MAC) disease-
      : in contrast with survived cases followed-up for 5 years or longer].
AB  - We performed a clinical study of pulmonary M. avium complex (MAC) disease
      comparing decreased cases and survived cases followed-up for 5 years or longer.
      The results were as follows: 1. At the time of starting the initial medical
      treatment for pulmonary MAC disease, the deceased cases were older than the
      survived cases, and the deceased cases were severe than the survived cases in
      clinical conditions. The spread of the lesions was more extensive and cavities
      were more frequently observed in the deceased cases than in the survived cases.
      2. We classified the clinical pattern of pulmonary MAC disease into a primary
      infection type and a secondary infection type. Then, we subclassified the primary
      infection type into a localized type, which contained a tuberculosis-like type
      and middle, lingular or other lobar pneumonia type, and a diffuse type. The
      secondary infection type was more frequent in the deceased cases than in the
      survived cases, and any middle, lingular or other lobar pneumonia type was not
      observed in the deceased cases. 3. We classified the mode of progression of
      pulmonary MAC disease in the deceased cases into a tuberculosis-like progression
      and a diffuse progression. The tuberculosis-like type and the secondary infection
      type frequently showed the tuberculosis-like progression and the diffuse type
      frequently showed the diffuse progression. The patients who showed the
      tuberculosis-like progression were frequently sputum culture positive for MAC,
      while all patients showing the diffuse progression were culture negative at the
      time of death. An interval from the estimated onset of the disease to death was
      shorter in the tuberculosis-like progression type than in the diffuse progression
      type.

PMID- 12494509
TI  - [Pulmonary Mycobacterium avium complex disease showing nodular bronchiectasis--:
      pathological findings in two cases].
AB  - Histopathological examinations were carried out on 2 cases of Mycobacterium avium
      complex (MAC) disease of nodular bronchiectasis (NB) type on radiograms. The
      removed lung specimens revealed histological findings of granulomatous
      bronchiolopneumonia, consisting of epithelioid cell granulomas with lymphocytic
      infiltrations without exudation in the alveolar areas surrounding the respiratory
      bronchiole. The central bronchiolar walls were also affected by epithelioid cell
      granulomas with lymphocytic infiltration, occasionally showing polypoid
      protrusion into the bronchiolar lumen accompanying emphysema in the peripheral
      alveolar area. Bronchial lesions seemed to progress from peripheral to central
      airway with consequent atrophy and disappearance of intramural smooth muscles,
      resulted in bronchioloectasis. These histological findings well correspond to
      radiographical 'nodular bronchiectasis'. Large histiocytic granulomas without
      caseous necrosis developed in some area, which are not usually found in
      tuberculosis lesions. Epithelioid cell granulomas were occasionally found in the
      hilar lymph nodes as well as in the walls of lymphatic vessel in the pulmonary
      interlobular tissues, indicating intrapulmonary lymphatic spread of the
      mycobacteria.

PMID- 12494510
TI  - [A case of Mycobacterium avium pulmonary disease accompanied with pleural
      effusion].
AB  - Nontuberculous mycobacterial infection is seldom complicated with pleural
      involvement. We report a very rare case of M. avium pulmonary disease accompanied
      with pleural effusion. A 76-year-old man was admitted to our hospital because of
      cough and low-grade fever. A chest radiograph and computed tomograph showed
      centrilobular nodules in the right middle lobe and left lingula, and right
      pleural effusion. The patient had had a right spontaneous pneumothorax 50 days
      before his admission. The sputum smear was negative for acid fast bacilli. The
      smear of pleural effusion was positive for acid fast bacilli, the level of
      adenosine deaminase in the effusion was markedly elevated, and pleural effusion
      was positive for M. avium as assessed by polymerase chain reaction (PCR). The
      pleural biopsy specimen showed fibrous change without granuloma, while the
      transbronchial biopsy specimen showed noncaseous epithelioid granulomas. We
      considered that the pneumothorax was caused by the spread of pulmonary M. avium
      infection to the visceral pleura with its perforation.

PMID- 12494511
TI  - [A case of multidrug-resistant tuberculosis (MDR-TB) in young female complicated
      with acute respiratory distress syndrome and developing multiple giant cysts and
      pneumothorax in both lung].
AB  - A 20-year-old woman was admitted to our hospital because of cough and dyspnea in
      April 2001. On admission, laboratory data showed positive inflammatory signs. A
      chest roentogenogram revealed infiltrated shadow in the bilateral lung fields.
      Sputum smear examination showed acid-fast bacilli identified as Mycobacterium
      tuberculosis by DNA-DNA PCR method. Four days after admission, she had an acute
      respiratory distress syndrome (ARDS) and serious liver dysfunction. Moreover,
      drug sensitivity test revealed that this case was multidrug-resistant
      tuberculosis (MDR-TB), and she was treated with sensitive anti-tuberculous drugs
      (PZA, SM, LVFX). Three months later, her sputa converted to negative for tubercle
      bacillis, however, a chest computed tomogram (CT) revealed multiple giant cysts
      in the bilateral lung fields, which developed during treatment. Pneumothorax of
      both sides was repeatedly observed, and it was difficult to treat. At present (1
      year after admission), multiple giant cysts stopped its progression and treatment
      for tuberculosis is being continued.

PMID- 12494512
TI  - Current problems of drug-resistant tuberculosis and its control.
AB  - Drug resistance emerges wherever and whenever the microbial environment favors
      the selective growth of drug-resistant mutants. The programmatic errors that lead
      to the development of drug resistance are inappropriate regimens, non-adherence
      to therapy by the patients, the sale and availability of over-the-counter drugs,
      an interruption in the drug supply, and the unavailability of free diagnosis and
      treatment. As a result, drug-resistant organisms are spread in the community,
      generating secondary cases with primary drug resistance, which in turn can spread
      and generate further cases. The uninterrupted cycle of creation and spreading is
      responsible for increases in DR. According to global data on anti-tuberculosis
      drug resistance appearing in the WHO monographs, drug resistance is so ubiquitous
      as to be encountered in every country. Anti-TB DR among previously treated cases
      was found to be very high in some countries, while it remained relatively low in
      others. The median of at least one drug resistance among four major drugs tested,
      was 25.2% (ranging from 8.3 to 68.5%), and the median MDR-TB was 8.7% (ranging
      from 0 to 48.2%) among those previously treated patients. Drug resistance among
      new cases infected with drug-resistant organisms from patients with acquired or
      primary drug resistance was found to be higher in some areas than in others. The
      median of at least one drug resistance was 10.9% (ranging from 1.7 to 40.6%) and
      MDR-TB of 1.1% (ranging from 0 to 14.1%). Twelve geographic areas had levels of
      3% or more of MDR-TB among new cases. The majority of MDR-TB cases end up as
      incurable and spread these deadly organisms in the community, as indicated by
      several outbreaks in certain areas. Increased MDR-TB will seriously threaten TB
      control programs in the future. We must therefore exert our best efforts to
      prevent the further generation of such cases by improving the cure rate of newly
      diagnosed cases, and by aggressively intervening to identify and remove MDR-TB
      cases as soon as possible.

PMID- 12494513
TI  - [Molecular epidemiology of Mycobacterium tuberculosis: its accomplishment and
      future perspective].
AB  - In the traditional study of tuberculosis epidemiology, information about social
      contact of persons and patient's illness history used to be an only relevant
      basis for elucidating transmission of tuberculosis infection. Therefore, it was
      very difficult to give a clear conclusion of whether isolates from different
      patients derived from a common source of infection or not. Recently, the
      subspecies typing of M. tuberculosis strains has become possible, based on the
      visualization of multiple loci of an insertion sequence (IS6110) that is a
      relatively stable gene fragment existing in a specific region of the genome. The
      variability of the number of copies and locations of this IS6110 in a genome is
      the basis that enables this technique to be used for the above purpose, which is
      a unique tool applicable to the analysis of M. tuberculosis. Generally, this
      technique, i.e., restriction fragment length polymorphism (RFLP) analysis,
      depends on the diversity of pattern of any polymorphic marker found in a genome
      of a strain. Among various markers so far developed and examined, IS6110 has been
      proved most appropriate for the purpose of typing strains of M. tuberculosis
      complex, especially in such circumstances as in Japan where isolated strains'
      RFLP patterns are similar each with others so that finer subtyping is needed. In
      this lecture, I would like to review the following topics based on the world
      literature of molecular epidemiology and the findings of our own that we have
      achieved during 1992 through 2001 in our Institute; 1) typing of the isolates for
      the identification of the infection source, 2) pathogenesis of tuberculosis under
      low incidence situation, 3) predominance of certain genotypes endemic in an area,
      4) cross-contamination of isolates in the laboratory, 5) the stability of IS6110
      patterns, 6) phylogeny of M. tuberculosis complex, and 7) differentiation between
      M. tuberculosis and M. bovis BCG.

PMID- 12494514
TI  - [Tuberculosis control and technology assessment in Japan with special reference
      to cancer control].
AB  - Tuberculosis morbidity and mortality statistics show that tuberculosis control
      efforts in Japan have recently borne little fruit. Almost a similar situation has
      occurred in cancer control efforts in Japan. To overcome these difficulties, we
      should introduce the principles of evidence-based healthcare into control
      activities and each activity of tuberculosis control and cancer control should be
      evaluated strictly by technology assessment. The most important issue to be
      discussed is that screening programs for tuberculosis and various cancers have
      been eagerly conducted in Japan as a public health policy since 1951 and 1961 and
      there has been no change of "Early diagnosis/early treatment is best" policy
      although many changes have occurred around the diseases and the society since
      then. From the viewpoint of a cancer epidemiologist, the significance of
      screening tests for tuberculosis, the completeness of tuberculosis registries,
      the significance of tuberculosis registries as a monitoring system for
      tuberculosis treatment and the role of health centers in the new programs of
      tuberculosis control are discussed.

PMID- 12494515
TI  - [Treatment for tuberculosis in difficult situations].

PMID- 12494516
TI  - [Retroperitoneoscopic hand-assisted nephrectomy for live donor: Akita University
      experience].
AB  - PURPOSE: Laparoscopic nephrectomy is being employed in renal transplantation
      because of its minimal invasiveness, and several modifications in surgical
      procedures have been proposed. We devised a new technique of retroperitoneoscopic
      hand-assisted nephrectomy (RHAN) for live donor. We report the early experiences
      with this technique in 5 cases of live renal graft donor. TECHNIQUES AND
      SUBJECTS: The donors are placed in a modified decubitus position under general
      anesthesia, and all the laparoscopic surgical procedures were performed
      retroperitoneally using 3 port sites and a sealing device (LAP DISC) under a
      pressure of 10 mmHg. The LAP DISC is placed through a para-rectus abdominal skin
      incision of approximately 8 cm in length into the retroperitoneal cavity and used
      as a rout for instrumental as well as hand-assisted manipulations during the
      surgery. The hand-assistance through the LAP DISC made the surgical manipulation
      considerably easier and allowed the immediate removal of the graft after the
      interruption of the renal blood flow. This procedure was applied to 5 subjects, 4
      in the left and one in the right kidney. RESULTS: The operating data were 264-359
      min for operating time, 0.9-3.9 min for warm ischemic time and 40-755 ml for
      intra-operative blood loss, respectively. The serum creatinine level of the
      recipients at day 7 was 0.9-2.7 mg/dl. These values, except for operating time,
      were at the same range as those of the open live donor nephrectomy in our clinic.
      The 5 donors discharged 7-9 days after RHAN without any surgical complications.
      CONCLUSION: Our technique of RHAN will be a minimal invasive one in terms of both
      for the donors and the grafts, and be widely acceptable for donor nephrectomy on
      either side.

PMID- 12494518
TI  - [Economic evaluation of treatment for benign prostatic hyperplasia--transurethral
      resection vs thermotherapy vs laser vaporization].
AB  - OBJECTIVE: Cost containment has become an important issue in medical practice
      because of recent bad economic conditions. We analyzed the cost of benign
      prostatic hypertrophy (BPH) patients and cost-effective analysis was carried out
      comparing transurethral resection of prostate (TURP), visual laser ablation of
      the prostate (VLAP) and transurethral microwave thermotherapy (TUMT). MATERIALS &
      METHODS: Our series consists of 95 BPH patients treated with TURP, VLAP and TUMT
      between January 1, 1994 and March 31, 1997. The cost for each patient was
      calculated (46 were treated with TURP, 31 with VLAP and 28 with TUMT).
      Considering the clinical outcome, cost-effectiveness was compared in 3 groups
      retrospectively. RESULTS: The median level of total charges (insurance points)
      was 59,395 points for the TURP group, 66,784 points for the VLAP group and 14,927
      points for the TUMT group. The median follow-up period was 12.4 months, 46.7
      months and 14.4 months, respectively. Several patients needed medication after
      operation in the VLAP group. In the TUMT group, 3 patients needed re-operation
      and 5 other needed an alternative surgical method (TURP or transurethral needle
      ablation) and 1 needed both methods. DISCUSSION: TUMT is the most cost-effective
      method, however the recurent rate is highest in the follow-up period among the
      three groups. The costs of recurent cases were most expensive. We should select
      surgical treatment for BPH very carefully.

PMID- 12494517
TI  - [Combination chemotherapy with ifosfamide, 5-fuluorouracil, etoposide and
      cisplatin for advanced urothelial cancer: the treatment results and significance
      of tumor marker evaluation in response assessment of chemotherapy].
AB  - PURPOSE: We investigated treatment results of IFEPchemotherapy in patients with
      advanced urothelial cancer (N2-3, M1) and the usefulness of measuring serum CEA,
      CA19-9 and SCC to evaluate the treatment response of chemotherapy. PATIENTS AND
      METHODS: From March 1994 to May 2000, we treated 41 patients with IFEP therapy
      consisting of ifosfamide (2 g/m2), 5-fluorouracil (750 mg/m2), etoposide (100
      mg/m2) and cisplatin (20 mg/m2), all of which were given daily for 3 consecutive
      days every 3 weeks. Before initiating the chemotherapy, serum CEA, CA19-9 and SCC
      were measured. And in patients with high pretreatment serum concentration, they
      were serially evaluated and compared with the tumor response assessed by imaging
      studies and the patients' clinical course. RESULTS: The response rate of the
      chemotherapy was 53.7% (CR + PR), with a median survival period being 10.8 months
      and a median duration of response for the 22 responders being 7.5 months. One and
      three-year survival rates of all the patients were 59.3% and 16.5%. Response
      rates of primary tumors and metastatic lesions to the lymph node, bone, lung and
      liver were in 54% and 57%, 56%, 50% and 40%, respectively. Bone marrow toxicity
      was significant with 1 drug-related death. Before chemotherapy, tumor marker was
      elevated in 19 patients: CEA in 7, CA19-9 in 13 and SCC in 10. Serum levels of
      the tumor markers were related neither to the primary and metastatic tumor sites
      nor to patient's survival time. However, decline of serum tumor markers after
      chemotherapy was well related to response of the tumor assessed by imaging
      studies. CONCLUSION: IFEP chemotherapy appears to be active in the treatment of
      advanced urothelial tumor and serial measurement of serum CEA, CA19-9 and SCC may
      be useful in judgement of tumor response to the chemotherapy.

PMID- 12494519
TI  - [The analysis of thymidine phosphorylase examined by ELISA in bladder cancer].
AB  - PURPOSE: Some reports suggest that the high level expression of thymidine
      phosphorylase (TP), which is known as one of angiogenic factors, is related to
      high malignancy and also poor prognosis in the field of gastrointestinal cancer.
      So the authors investigated the expression of TP in bladder cancer. MATERIALS AND
      METHODS: The expression of TP in cancer tissues and normal tissues, which were
      obtained during transurethral resection of the tumor of 66 patients with initial
      primary bladder cancer, was examined by enzyme-linked immunosorbent assay
      (ELISA). And relationship of the TP expression and clinicopathologic factors was
      investigated. RESULTS: The level of TP expression was significantly high in
      cancer tissues compared with normal tissues (P < 0.0001). About the level of TP
      expression of cancer tissues, there was a significant difference between G1 and
      G3 in grade (P = 0.0099), Ta and T2 or greater (P = 0.0059), Ta, T1 and T2 or
      greater (P = 0.0157) in T stage, papillary and non-papillary in surface form (P =
      0.0056), pedunculated and sessile in tumor shape (P = 0.0458), and 1 cm or under
      and 3 cm or greater in size (P = 0.0267). The level was higher in latter,
      respectively. About the level of TP expression of normal tissues, the level was
      significantly higher in the cases with sessile tumor than the cases with
      pedunculated tumor (P = 0.0078). CONCLUSION: There is correlation between the
      level of TP expression of cancer tissues and their grade of malignancy, so we can
      expect that the level of TP expression of cancer tissues will be a prognostic
      factor. And what does it mean in the fact that the level of TP expression of
      normal tissues in patients with sessile tumor is higher? It should be clear after
      accumulation of the cases and collecting the episodes in the follow-up period.

PMID- 12494520
TI  - [Clinical study of influential factors on renal scarring after ESWL monotherapy
      for renal stone disease].
AB  - OBJECTIVE: ESWL is now widely used for the treatment of renal stone disease.
      Although ESWL has many advantages for patients' quality of life, few reports have
      demonstrated the long-term outcomes of the alterations of renal morphology after
      ESWL. We reported renal scarring after ESWL monotherapy in patients with renal
      calyceal stones. In this study, we evaluated a large series of patients' cohort
      treated at our institution, and assessed the causal effect of ESWL on the late
      occurrence of renal scar formation. PATIENTS AND METHODS: ESWL was performed with
      EDAP (LT-01,02) that generates shock wave energy by piezoelectric discharge. We
      analyzed the records of 285 kidneys treated between Dec. 1986 and Nov. 1998.
      Renal scarring was noted in 44 kidneys and not in 241 kidneys with periodical
      ultrasonography. We compared the backgrounds of the two groups using chi-square
      or non-parametric analysis. The Kaplan-Meier method and Cox regression model
      determined the analysis of renal scar formation. RESULTS: Univariate and multiple
      regression analysis revealed that the total amount of ESWL emission and
      hyperuricemia independently affected the probability of renal scar formation.
      CONCLUSIONS: Over-emission of ESWL (over 10,000 shots) must be care for the
      prevention of renal scarring in patients with renal calyceal calculi, especially
      when associated with hyperuricemia. After ESWL, periodical checkups with
      ultrasonography will provide useful information for the clinical diagnosis of
      renal scarring.

PMID- 12494521
TI  - [A case of gas gangrene caused by colon diverticulitis with perforation into the
      retroperitoneal space].
AB  - We report a case of retroperitoneal gas gangrene, which was caused by cecal
      diverticulitis with perforation. A-57-year-old male was admitted to the Sado
      General Hospital with the chief complaint of right lateral abdominal pain.
      Roentogenogram and Computelized Tomography (CT) showed gas accumulation in the
      retroperitoneal space behind the ascending colon. Based on the clinical,
      labolatory, and instrumental examination findings gas gangrene was diagnosed.
      Since urolithiasis or urinary tract infection was suspected to be the cause of
      the lesion at that time, the patient was transferred to our department
      immediately. CT scan done on day 3 at our inpatient department provided data
      suspicious for the cecal perforation into retroperitoneal space due to
      appendicitis or diverticulitis. We performed an acute drainage of the abscess and
      intensive care including continuous hemodiafiltration (CHDF), oxygen under high
      pressure (OHP), and chemotherapy with antibiotics was carried out. However, in
      spite of the above mentioned measures, the patient's condition deteriorated and
      he died due to progression of gangrene and multiple organ failure in 23 days. The
      autopsy revealed that the cause of perforation was cecal diverticulitis.
      Retroperitoneal gas gangrene is an uncommon entity and has been rarely reported.
      It is supposed that laparotomy with diagnostic and therapeutic purpose should
      have been performed in this case.

PMID- 12494522
TI  - [Aspects of conscious and responsible fertility].

PMID- 12494523
TI  - [Care of infants with congenital hip dislocation].

PMID- 12494524
TI  - [Risks in ophthalmology: ocular AIDS].

PMID- 12494525
TI  - [Training needs of nurses newly assigned to an Oncological Center].

PMID- 12494526
TI  - [Adverse reactions of blood donation].

PMID- 12494527
TI  - [Hospitalization of the aged: an approach focused on preventive aspects].

PMID- 12494528
TI  - [Diseases and nutrition: a primordial challenge in Public Health].

PMID- 12494530
TI  - [Glucides in the nutrition of obese patients].

PMID- 12494529
TI  - [Glucides in the nutrition of diabetics].

PMID- 12494531
TI  - [Destigmatication of mental disease].

PMID- 12494532
TI  - [Today's society: nursing and holistic view of the person].

PMID- 12494533
TI  - [Polyunsaturated fatty acids: omega-3 in child development].
AB  - The understanding of the role of lipids has made major advances following the
      identification, by George and Mildred Burr, of so-called "essential fatty acids",
      i.e. linoleic acid (LA) and alpha-linolenic acid (ALA). LA is supplied by animal
      and vegetal fats, while ALA reaches higher levels in breastmilk, fish, and olive
      oil. For both LA and ALA, the human body depends exclusively on the dietary
      supply. These lipids play a major role as structural components of cell
      membranes, in particular of neurons, nerves, myelinated sheath, retina, vessels,
      heart, and blood cells; moreover, they act as precursors of several short-life
      compounds with hormone-like action: prostaglandins, prostacylins, thromboxanes,
      leukotriens, all with a regulatory effect on several cell functions, and on
      cholesterol pathway. It has been suggested a "health programming" role for food,
      due to the impact of the type of feeding on the subsequent neuromotor
      development, learning abilities, behavior, metabolism, blood pressure, bone
      mineralization, and degenrative diseases. This is the consequence of changes of
      the genomic expression, with a guided clone selection. This is in line with the
      "imprinting hypothesis" proposed by K. Lorenz (1973 Nobel Prize for Physiology
      and Medicine), who suggested that stimulations at a particular age may drive
      animal behavior for the rest of their life.

PMID- 12494534
TI  - [Bioethics, deontology, and law in neonatal intensive care].
AB  - Neonatal intensive care has greatly improved the survival chances but, at the
      same time, it has also given rise to serious ethical problems. Different contexts
      influence both physicians attitude and end-of-life practices in neonatology. The
      clinicians can not ever follow the principles of bioethics, as they are sometimes
      in conflict. Also, the strategies or guidelines proposed as approaches to
      neonatal decision-making are difficult to practise. Probably a neonatologist
      makes his decision even on the basis of his interior conviction and it is well
      known that in Italy the debate on bioethics is the subject of confrontation
      between Roman Catholic and secular viewpoint, expressing two positions: the so
      called sanctity and the quality of life. However, a clinician has also an
      obligation to follow the Code of Professional Medical Ethics which cautions
      against therapeutic aggressiveness; but this document has not legal status. In
      addition, Italian law is strongly protective of infant life and any
      discrimination on the basis of malformation or poor prognosis violates
      constitutional law; moreover, the resuscitation of a preterm infant is mandatory
      even when the birth is the result of induced late abortion. The author concludes
      emphasizing the importance, in decision making, of accepting difference as
      opposed to the logic of the absoluteness of normality, because many handicaps may
      be accepted and a society expresses its moral richness also by the solidarity
      reserved to its weakest sons.

PMID- 12494535
TI  - [Kawasaki disease: clinical characteristics and cardiovascular involvement in a
      cohort of 121 patients].
AB  - Kawasaki disease is an acute generalized self-limiting vasculitis of small and
      medium size arteries of unknown ethiology, mostly affecting children younger then
      5 years of age. Coronary arteries may be involved with aneurysms lesions,
      thrombotic occlusion, acute coronary syndrome and sudden death. The mortality
      rate has been significantly reduced by combined therapy of intravenous
      immunoglobuline (IVIG) and acetil salicylic acid (ASA) from 3% to 0.2%. From
      February 1986 to November 2001, 121 children, 76 male and 45 females with
      Kawasaki disease, have been observed at the Paediatric Department, University of
      Florence. Coronary changes (i.e. coronary ectasia and coronary aneurysms) have
      been observed in 22.3%. In only one 3-months old child, giant aneurysms of
      coronary arteries and myocardial necrosis have been detected. In 26 of 27
      children at 2D echo a remodelling of the coronary changes within 12 months from
      the onset of the illness was observed. The mean follow-up has been five years
      (range 6-138 months) and in no patient further cardiac manifestations have been
      observed; however, as little is known about the progression of vascular damage, a
      more protracted follow-up is needed.

PMID- 12494536
TI  - [Latent celiac disease in subjects with serum anti-endomysial antibodies and
      normal intestinal biopsy].
AB  - OBJECTIVES: Data on the follow-up of a group of subjects with serum
      antiendomysial antibodies (EMA) and normal mucosal architecture at the intestinal
      biopsy are reported. Clinical problems concerning possible evolution of potential
      celiac disease (CD) towards gluten-induced histological damage are discussed.
      METHODS: Eleven patients belonging to high-risk groups for CD (5 with type-1
      diabetes, 2 with familiarity for CD and 4 with symptoms suggesting CD) who had a
      normal intestinal biopsy, despite positive antiendomysial test, were followed-up.
      Antigliadin and antitransglutaminase antibodies (anti-tTG) and HLA genotyping
      were also assessed. According to clinical and serological data a second biopsy
      was performed in six of them. RESULTS: At the time of the first normal biopsy,
      all patients were positive for EMA and 5/8 for anti-tTG. Five of 6 subjects
      genotyped were HLA-DQ2+ or DQ8+. Six patients were rebiopsed after 1 to 4 years.
      Three had mucosal atrophy, 1 had mild increase of intraepithelial lymphocytes and
      2 were morphologically normal. CONCLUSIONS: Subjects with antiendomysial
      antibodies and normal intestinal biopsy deserve clinical and serological follow
      up to reduce the time of possible latency of CD. Although good predictors of
      progression of the disease are not still available, antiendomysial antibodies
      assessment and HLA genotyping may help to suggest individuals at higher risk to
      develop gluten-induced enteropathy. This study confirms that subjects with
      persistent signs of gluten sensitivity and normal biopsy should be re-examined.

PMID- 12494537
TI  - [Urodynamic evaluation in children with enuresis].
AB  - We performed an urodynamic study in enuretic children to evaluate the
      relationship between urodinamic findings and symptoms. We studied 175 patients,
      with age from 5 to 12 years, who presented with nocturnal enuresis: 45
      monosymptomatic and 130 polysymptomatic (in association with urinary urgency,
      urge incontinence, etc.). Despite differences in symptoms, in 151 patients (86%)
      abnormal urodynamic findings were identified. Bladder instability was the most
      common disorder. However, mild abnormalities were found in the monosymptomatic
      patients. In treated patients urodinamic findings and clinical improvement were
      correlated. This study confirmed that most patients with nocturnal enuresis have
      cystometric abnormalities. Although possible etiologies of nocturnal enuresis are
      various, bladder dysfunction may be an underlying cause.

PMID- 12494538
TI  - [Values of white blood cell count in the diagnosis of acute appendicitis].
AB  - BACKGROUND: The diagnosis of acute appendicitis remains a critical challenge for
      paediatric surgeons. White Blood Cell (WBC) count, once considered a basic exam,
      is still routinely performed in most institutions, despite its lack of accuracy.
      Aim of this study is to assess the additional value of WBC count in the diagnosis
      of acute appendicitis. METHODS: We retrospectively reviewed the charts of
      children who underwent appendectomy for acute appendicitis in the last two years
      at our institution. In the patients treated in 1999 (Group A), WBC count was
      assessed routinely after admission. The surgeons relied on leukocytosis as well
      as on clinical findings and on ultrasound abdominal scan for the diagnosis of
      acute appendicitis. In the patients treated in 2000 (Group B), blood cell count
      was not tested or deliberately ignored by the surgeons. RESULTS: There were 65
      children in Group A and 70 in Group B; the two groups of patients were similar in
      terms of gender (p = 0.989) and age (p = 0.758). Criteria for operation were
      similar in the two groups (p = 0.222). No differences were found in the number of
      perforated (p = 0.989) and normal (p = 0.217) appendixes in the two groups as
      well as in the duration of hospital stay after surgery (p = 0.849). CONCLUSIONS:
      WBC count at admission has no proven additional value in the diagnosis of acute
      appendicitis and can be omitted without modifying diagnostic pathway and without
      affecting diagnostic accuracy.

PMID- 12494539
TI  - [Small bowel overgrowth: a frequent complication after abdominal surgery in
      newborns].
AB  - BACKGROUND/PURPOSE: Surgery for congenital or acquired gastroenterological
      disorders, and particularly that associated with short bowel, is not infrequently
      complicated by Small Bowel Bacterial Over growth (SBBO). Aim of this study is to
      evaluate the clinical course of children undergoing bowel surgery in the newborn
      period, assessing the development of SBBO and the response to intensive treatment
      with a "bowel cocktail" of gentamycin, metronidazole and cholestyramine. METHODS:
      17 children with various conditions were studied clinically and by Breath
      Hydrogen Test (fasting and after glucose). 14 children underwent more than one
      procedure. All children were treated with overall "bowel cocktail" of gentamycin,
      metronidazole and cholestyramine. RESULTS: 5 children recovered after one course
      of treatment and 11 children relapsed at least once and required further courses
      of therapy. One child died from TPN related liver failure and another following a
      liver and small bowel transplant for short bowel syndrome. A third child required
      total intestinal tube splinting according to Sauer and another one required a
      tapering of the preatretic enlarged jejunal loop. CONCLUSIONS: Our study suggests
      that children undergoing bowel surgery in the neonatal period and those having
      more than one procedure are at greater risk of developing small bowel bacterial
      overgrowth postoperatively. Interestingly, loss of the ileocecal valve was not
      associated with an increased risk of bacterial overgrowth.

PMID- 12494540
TI  - [The role of skin expansion: giant nevi of the hand].
AB  - The Authors, after considering the epidemic and evolution of giant nevi, present
      their surgical protocol for giant melanocitic nevi of the hand. Their experience
      is based on 2 cases, but the rarity of these lesions of the hand, the
      reconstructive technique used and the results obtained justify the report in
      detail. The Authors used in both cases an expanded groin flap to repair the
      postexcisional wound. Skin expansion allowed both to obtain flaps, which were
      wide and reliable, and to close primarily the donor areas. The definitive
      resorption of the subcutaneous fat caused by the expansion allowed to obtain thin
      and adaptable flaps, which ensured excellent results also in areas of primary
      functional value, such as the hand. In both cases, the expanded going flap was
      used to repair the dorsum of the hand. In one case the lateral and medial parts
      of the fingers were repaired with skin grafts.

PMID- 12494541
TI  - Graves-Basedow's disease in children and adolescents: total vs subtotal
      thyroidectomy.
AB  - "Graves' disease" is an autoimmune pathology and is the most important cause of
      hyperthyroidism in children and adolescents. The treatment for this disease is
      controversial; there are three different options: synthetic antithyroid drugs,
      ablation of the thyroid gland with I 131 or surgery. Our study reports the
      clinical and therapeutic aspects and long-term results of 27 patients (< = 18
      years old) treated with total thyroidectomy or "near-total" thyroidectomy from
      1975 to August 2001. Antithyroid drugs represent the preliminary treatment of
      choice. For a long time in the past therapy with radioactive iodine was not
      recommended; now it represents an efficiently therapy with low morbility.
      Surgical treatment is suitable when a young patient presents a considerable
      enlargement of the thyroid gland or when antithyroid medical treatment does not
      achieve a good control of the disease, or when rapid control of hyperthyroidism
      is necessary. The surgical treatment can be a total thyroidectomy or a "near
      total" thyroidectomy. The first is the best choice for us, because it has a low
      risk of relapse and a major efficacy in the ophthalmopathy.

PMID- 12494542
TI  - [Urethral duplication in pediatric age. A case report].
AB  - Urethral duplication is a rare congenital anomaly, resulting from a wide range of
      malformations of the urogenital sinus. Generally, the duplication develops on the
      sagittal plane; the accessory urethra may run dorsally or ventrally to the
      orthotopic one. The duplication is defined as epispadic in the first case, and
      hypospadic in the second. In the medical literature approximately 150 cases have
      been reported. Relatively more frequent among males, it is often associated with
      other malformations of the urogenital tract or other organs. The authors present
      a case of a 4 year old child with a complete epispadic duplication, that is, two
      external meatus, one of which the dorsal aspect of the glans, and the other
      orthotopic. Clinically, duplication and weakening of the stream, urinary
      incontinence and UTI were present. US examination documented the normality of the
      upper urinary tract and of the bladder. Retrograde urethrocystography showed a
      completely permeable urethral duplication, with two external meatus. The excision
      of the accessory urethra was carried out together with the reconstruction of the
      hypospadic meatus with an "overlap anastomosis". The post-operatory period was
      uneventful, and one year after surgery the patient is asymptomatic, with normal
      uroflowmetric readings and echographically documented complete bladder emptying.
      In the opinion of the authors, the treatment is indicated in symptomatic forms
      and the surgical options varies, depending on the type and grade of malformation,
      its clinical manifestations and the presence of associated anomalies. Antibiotic
      treatment is not effective and other treatments, such as diathermocoagulation or
      the injection of caustic substances into the accessory duct have been abandoned.

PMID- 12494543
TI  - Case report: Salmonella panama osteomyelitis in a Ghanaian child with sickle cell
      disease.
AB  - Sickle cell disease is a rare condition in italian patients and even rarer are
      its complications, in particular Salmonella osteomyelitis. We describe a case of
      a Ghanaian child with sickle cell disease who developed osteomyelitis due to
      Salmonella panama, treated successfully with surgical debridement, followed by a
      prolonged period of specific antibiotic therapy.

PMID- 12494544
TI  - Infantile cerebellar thrombosis: a case of lupus anticoagulants?
AB  - Lupus Anticoagulants (LA) pathology is a disease frequently associated with
      venous and/or arterial thrombosis. The authors describe a 6 year-old boy
      complaining cephalea and emesis, followed by lethargy, in whom antiphospholipids
      antibodies were detected. Brain magnetic resonance scans showed lesions of the
      cerebellum. The characteristics of LA disease are discussed.

PMID- 12494545
TI  - Fetal monolateral urinoma and neonatal renal function outcome in posterior
      urethral valves obstruction: the pop-off mechanism.
AB  - The "fetal urinoma" is a clinical and diagnostic entity due to urinary
      extravasation, early diagnosed in fetal and/or neonatal period. Both urinoma and
      urinary ascites, whose pathogenesis is not clear, are recognized associations of
      uterero-pelvic junction obstruction (UPJO) and neonatal posterior urethral valves
      (PUV) related with a protected fetal and neonatal renal function. Clinical and
      experimental studies have demonstrated that fetal urinary tract obstruction
      results in severe renal parenchymal injury. The so called "pop-off" valve
      mechanism has been advocated to justify the upper tract function preservation.
      Protective "pop-off" mechanisms, such as a unilateral reflux and dysplasia,
      urinary extravasation and congenital bladder diverticula are present in about 30%
      of patients with PUV. Their presence correlates with better overall long-term
      renal function. This mechanism has been justified as a sort of self derivation,
      to explain the renal function preservation in fetal and neonatal period. In the
      last two years we observed three cases of fetal monolateral urinoma, prenatally
      detected in fetuses with diagnosis of PUV. All three cases did well for that
      concerning renal function despite some current opinions suggesting the necessity
      of a bilateral urinary extravasation in order to preserve upper urinary tract
      function.

PMID- 12494546
TI  - A new technique for the surgical management of deformities in the growing spine.
AB  - The Luque procedure was developed to correct the deformity without the need of
      bracing and maintaining that correction with growth. However many authors are
      disappointed by their results and the complications which appear in the
      management of infantile scoliosis with Luque trolley alone. Besides failed
      implants, pseudarthrosis, modest spinal growth and protuberant rods and wires,
      the major problem of the Luque systems is the high incidence of loss of
      correction by postoperative rotation. Therefore a new application technique is
      recommended. A standard posterior extraperiostal approach is chosen. Sublaminar
      titanium cables are passed at each level except the caudal lamina. Then the rods
      are precontoured in shape of the planed curve correction. We use a low profile
      titanium instrumentation with 5.0 mm diameter rods and 4.2 mm pedicle screws. In
      contrast to the conventional use of two antiparallel "L"-rods we recommend the
      use of one reversed "U"-rod securing the laminae with sublaminar titanium cables
      of the upper end vertebrae. For fixation of the lower spine a dual-opening
      pedicle screw system is used. Using a holding forceps the distal rods are
      introduced and fixed into the side opening of the screws then secured by
      sublaminar wires. In addition both single rods are stabilized by a low profile
      cross link bar. This technique allows to correct pelvic obliquity and a stable
      anchorage of two screws reduces risk of postoperatively rotation or caudal rod
      slippage due to gravity forces.

PMID- 12494547
TI  - [Physiological loading of the mandibular osteosynthesis: development of an
      improved mandibular load simulator].
AB  - Loading conditions physiologically approximating those acting on the normal
      masticatory system were incorporated into a new mandibular load simulator.
      Separate tension wires attached to each ramus of the mandible simulated the
      resultant force vectors of the masticatory musculature. The muscle insertion
      points were chosen in accordance with the anatomical situation, and the maximum
      in vivo forces acting on the joint. In a first application, the stability of a
      2.4 mm LC-WDCP was compared with that of a 2.7 mm EDCP in plastic mandible
      models. It was found that under largely physiological loading, the 2.4 mm LC-EDCP
      exerted a stabilizing effect similar to that of a 2.7 mm EDCP. Although of
      smaller dimensions, the 2.4 mm LC-EDCP appears to enable an osteosynthesis of
      similar stability in the treatment of fractures of the mandibular angle.

PMID- 12494548
TI  - [Personal emergency call system based on human vital and system technical
      parameters in a Smart Home environment].
AB  - Progress in microtechnology and radio transmission technology has enabled the
      development of highly reliable emergency-call systems. The present article
      describes systems that have been specially designed to improve the safety and
      independence of handicapped and elderly persons living at home. For such persons
      immediate help in an emergency situation is of crucial importance. The technical
      state of the art of emergency-call systems specially developed for use by the
      elderly, is briefly discussed, in particular the well-known radio emergency-call
      button, with the aid of which an alarm can be activated manually. This system,
      however, does not offer adequate safety in all emergency situations. Alternative
      or complementary systems designed to automatically trigger an alarm on the basis
      of the recording and evaluation of so-called vital parameters, are therefore
      proposed. In addition, in a smart-home environment with networked devices,
      further parameters--so-called environment parameters can be used. It is found
      that the identification of an emergency situation becomes more reliable as the
      number of parameters employed increases.

PMID- 12494549
TI  - [Detailed evaluation of the agarose diffusion test in biocompatibility study with
      a microscopic image analysis system. Effect of plasma sterilization on
      biocompatible of an improved photoset polymer].
AB  - In addition to sterilizability, biocompatibility is a further necessary property
      of biomaterials. The agarose diffusion test is an established standard in vitro
      procedure for investigating this property. The usual method of evaluating the
      agarose diffusion test, based on macroscopic determination of the size of the
      zone of decoloration, and microscopic assessment of cell lysis, limits the power
      of the test. To obtain more information on the impact of plasma sterilization on
      the biocompatibility of a new polymer, a high-resolution computer-aided
      morphometric image analysis system for the quantification of the agarose
      diffusion test at the cellular level has been developed. This was able to detect
      statistically significant differences in the cell lysis rate of plasma sterilized
      polymer specimens before and after 4 weeks of incubation in a physiological
      solution. The new method provides highly detailed information on the interaction
      of soluble material elements and cells. In addition to cell damage by potentially
      toxic elements, the sensitivity of the L929 fibroblasts used in the agarose
      diffusion test to mechanical stress also needs to be considered and verified by
      further investigations.

PMID- 12494550
TI  - [A new method of testing the effectiveness of sterile packaging in general
      practice].
AB  - The aim of our study was to develop a practical test for assessing the
      effectiveness of the microbial barrier of packaging materials for sterile
      products. The suitability of the test was verified in the exemplary case of
      double-wrapped sterilized trays. During testing, the bacterial count of the
      ambient air was 35 and 440 colony-forming units/cubic metre. The test is based on
      the co-sterilization in the sterile packing of petri dishes containing CASO agar,
      which at the end of the test were investigated for re-contamination. The petri
      dishes covered the sterilizing sieves as completely as possible. After
      sterilization, the packaging was loaded 300 to 900 times at a pressure of 1 kg
      (5x/min). This was followed by incubation for 48 hours at 37 degrees C, and
      evaluation (No. of colonies). The ability of the agar to culture colonies of
      bacteria was preserved unchanged for a period of at least 3 weeks after
      sterilization. For double-wrapped trays it was shown that re-contamination
      increases with intensity of mechanical loading and the atmospheric bacterial
      count. Since the package was breached only for the analysis, confounding factors
      due to removal of contents for examination, were effectively excluded. This test
      procedure is characterised by simplicity in handling and high specificity. As a
      final pack test it effectively closes a gap in the quality assurance chain for
      sterile materials.

PMID- 12494551
TI  - [Detection of myocardial ischemia by epicardial detection of potassium ion
      activity].
AB  - Early detection of myocardial ischaemia is a central problem in cardiological and
      cardiosurgical intensive care. A new approach is the use of ion-selective
      electrodes implanted directly on the myocardium, enabling detection of increased
      potassium activity as an indication of general hypoxia. After a comprehensive
      study of the electrode parameters, an animal experiment was carried out, in which
      it was found that respiration-induced hypoxia resulted in an increase in
      epicardial potassium activity (p < 0.01). Blood gas analysis performed
      simultaneously revealed reduced arterial pO2, but no acidosis. Haemodynamic data
      evidenced hypoxic depression of circulatory parameters. Histological examinations
      of the myocardium beneath the electrodes revealed typical lymphocytic
      infiltration. Electron microscopy demonstrated crystolysis in the mitochondria as
      an early sign of hypoxia, thus confirming the sensitivity of these electrodes.
      This underscores the potential of ion-selective electrodes for the detection of
      myocardial ischaemia, and they should now be investigated in the clinical
      setting.

PMID- 12494552
TI  - [BSE/TSE--the present epidemiologic and diagnostic situation].
AB  - In 1992, 1994 and 1997, first BSE cases were diagnosed among imported cattle. The
      first domestic BSE case in Germany was confirmed on 26 November 2000. Altogether
      192 cases (7 cases in 2000, 125 cases in 2001 and 60 cases in 2002) were reported
      (at the date: 7. August 2002). Comparing the BSE situation in Germany with other
      European countries under consideration of the surveillance schemes applied,
      Germany has a similar BSE incidence based on 100,000 adult cattle as France and
      Spain but a higher incidence than neighboring countries like The Netherlands,
      Austria and Denmark. At present, on average 2,3 cases per week are confirmed in
      Germany. With respect to the age distribution of the BSE cases, about 84% of all
      domestic cases confirmed originated out of the years 1995 and 1996 with a
      accumulation in 1996 (about 53% of all cases). Single BSE cases with the years of
      birth 1990, 1991 and 1993 demonstrate, that the BSE agent is circulating among
      the German cattle population at least since the beginning of the nineties.
      Between 1985 und 7 August 2002, scrapie was diagnosed in 26 sheep flocks in
      Germany, but alone during the year 2002 (until 7 August 2002) 11 scrapie affected
      sheep flocks were discovered.

PMID- 12494553
TI  - [Selection for disease resistance in domestic ruminants and swine by indicator
      traits as well as marker and causal genes--a review. Part 1: Short introduction
      to immunogenetics of MHC and non-MHC genes and special immunogenetics of cattle
      and swine].
AB  - The introduction deals with immunogenetic investigations on the field of life
      stock. The main chapter is outlined as a tabular overview of current
      opportunities of the application of indicator traits as well as marker and causal
      genes in breeding for disease resistance in cattle, sheep, goats and swine. In
      the discussion of the second part, emphasis was layed on diseases of small
      ruminants in central and western Europe. Indicator traits are discussed with
      respect of their advantages and disadvantages. The rigorous selection of specific
      traits is connected with an increase of the number of homozygotes. In contrary,
      pathogens do undergo mutations, thus escaping the host's immune system. Out of
      this point of view it is advisable, to set on selection very cautiously. The role
      of technologies of modern immunogenetics is pointed out in respect of
      constructing disease resistant animals.

PMID- 12494554
TI  - The effect of Alkanna tinctoria Tausch on burn wound healing in rabbits.
AB  - Eighteen adult male New Zealand White rabbits were used in the treatment of
      partial thickness, severe and olive oil burns. Both right and left sides of the
      animals were burned to make partial thickness, severe and hot olive oil burn
      wounds. The solution of A. tinctoria TAUSCH in 16% prepared in medical olive oil
      in weight basis, were applied to the left, and right side served as control. It
      was topically applied twice a day by gently rubbing against the burn area. While
      complete healing of partial thickness and olive oil burn wounds occurred in 7 to
      10, and 26 days, respectively, with well formed dermal-epidermal junctions in
      both groups, severely burned wounds appeared to be nonresponsive to A. tinctoria.

PMID- 12494555
TI  - Ovine progressive pneumonia (Maedi-Visna): an emerging respiratory disease of
      sheep in Ethiopia.
AB  - A serological study was done to assess the role of Maedi-Visna (MV) infection in
      sheep from flocks with high respiratory tract disease morbidity in Ethiopia. Of
      105 sheep examined from central Ethiopia 78 (74%) were positive for MV-infection.
      However, antibodies to the virus were not detected in 48 sheep and 70 goats from
      elsewhere in Ethiopia. The infection was detected in all breeds of sheep examined
      (Awassi, Hampshire, Corriedale, indigenous Menz breeds and their crosses) but
      with a significant breed difference (chi 2 = 20, p < 0.001) varying from 48% in
      imported Awassi sheep to 92% in the indigenous Menz sheep. This suggests that
      Menz sheep are more susceptible to infection, which may support the observation
      of a higher incidence of clinical disease in these sheep compared to exotic
      breeds and their crosses. It also supports recent studies indicating that MV is
      becoming one of the most important respiratory tract diseases in sheep in central
      Ethiopia. Our findings indicate that MV was introduced into Ethiopia via sheep
      imported into the central highlands and that it now constitutes an important
      emerging disease is discussed. Measures to control the disease are suggested.

PMID- 12494556
TI  - Multiple oxytocin application increases the predictability of prostaglandin
      induced farrowing in swine.
AB  - In a large Croatian commercial unit, 1204 of parity 2-7 late pregnant sows were
      from January till Mai 2002 randomly assigned to four farrowing groups and treated
      as follows: Group one (n = 302 sows) received a single perivulvar injection of
      175 g cloprostenol at day 113 of pregnancy. The remaining animals have received a
      treatment as group one and were additionally treated with 10 IU of oxytocin
      intramuscularly 6 hours after prostaglandin application (Group two, n = 311), or
      with 10 IU of oxytocin 6 and 12 hours later (Group three, n = 291), or 10 IU of
      oxytocin 6, 12 and 18 hours later (Group four, n = 300). Onset of farrowing,
      duration of parturition, total born litter size and stillbirth rate were
      evaluated. Except total born litter size, combined oxytocin + cloprostenol
      treated sows revealed significantly (p < 0.01) better results as the only with
      cloprostenol treated ones. Multiple oxytocin application increased the
      predictability of farrowing. The application of multiple oxytocin injections
      following prostaglandin partusinduction are recommended for batch farrowing of
      sows in large production units.

PMID- 12494557
TI  - A clinical overview of removable prostheses: 2. Impression making for partial
      dentures.
AB  - This, the second article in a series on the prescription of removable partial
      dentures, will deal with the issue of primary impression and primary casts for
      partial dentures. The principles of definitive impressions and master cast
      planning will be described.

PMID- 12494558
TI  - Magnetic retention in prosthetic dentistry.
AB  - Magnets are a popular method of attaching removable prostheses to either retained
      roots or osseointegrated implants. This paper reviews the development of magnets
      in dentistry and describes the different types of magnetic attachments that are
      available. The clinical applications of magnets in prosthetic dentistry are
      illustrated and future technological advancements indicated. Whilst different
      magnetic materials that mirrored the developing technology have been used, the
      main drawback to their use is the potential of corrosion of the magnetic material
      in the mouth. However, newly emerging technologies may provide a solution to this
      problem, allowing the continued use of magnets in prosthetic dentistry.

PMID- 12494559
TI  - The timing of orthodontic treatment.
AB  - The time at which orthodontic treatment should be started remains a matter of
      conjecture. Anomalies of dental development and functional problems tend to be
      addressed in the mixed dentition, while definitive treatment tends to be delayed
      until the late mixed dentition to maximize growth potential and patient
      compliance. However, some clinicians advocate starting treatment earlier in
      certain types of malocclusion. In this article, the current concepts of early
      treatment, both physiological and psychological, will be explored and the
      relevant indications and contraindications discussed.

PMID- 12494560
TI  - Oral lichenoid drug eruptions: their recognition and management.
AB  - Lichen planus is a relatively common, often clinically distinctive, mucocutaneous
      condition with an uncertain aetiology. One variant of lichen planus is the so
      called 'lichenoid drug eruption'. In contrast to idiopathic lichen planus,
      lichenoid drug eruptions, where practicable, may be managed by substitution of
      the offending drug. The dental clinician is in a prime position to identify these
      lesions and liaise with medical colleagues regarding their management. This
      article reviews oral lichenoid drug eruptions, emphasizing those aspects of
      relevance to the general dental practitioner.

PMID- 12494561
TI  - Assessing the anxious patient.
AB  - Dental anxiety is a problem for many adults and children and for many patients
      anxiety acts as a barrier to treatment: avoidance of treatment, irregular
      attendance or attendance for emergency treatment only being typical ways of
      dealing with the problem. For the dental team a patient's anxiety poses major
      management problems, as an anxious patient may require more time for treatment,
      is very likely to miss appointments and may have raised pain thresholds. A major
      cause of stress for clinicians is the management of anxiety in their patients.

PMID- 12494562
TI  - Implant complications and failures: the fixed prosthesis.
AB  - The implant-retained fixed prosthesis has been advocated as an effective
      restoration offering significant benefits over conventional prosthetics. The
      success of treatment depends on careful pre-surgical planning and prosthesis
      design. This paper outlines some common complications encountered during the
      planning, fabrication and maintenance of both large and small fixed prostheses
      and suggests how these complications can be minimized.

PMID- 12494563
TI  - Quadhelix appliance therapy resulting in pyogenic granuloma of the tongue.
AB  - This paper describes the examination, diagnosis and treatment of a rapidly
      enlarging tongue mass presenting in a healthy 12-year-old girl. This mass caused
      distress to both the patient and her parents and diagnostic uncertainty for her
      general medical and dental practitioners. The lesion was in fact caused by an
      orthodontic quadhelix appliance and responded to simple treatment.

PMID- 12494564
TI  - [Current problems of legal regulation and organization of relations in health
      protection of citizens and public health care in the Russian Federation].

PMID- 12494566
TI  - [Health status of fertile-age women after surgery on reproductive organs].

PMID- 12494565
TI  - [Quality of life in psychosomatic diseases].
AB  - To study life quality (LQ) in psychosomatic diseases, 104 patients (58 females
      and 46 males) with these diseases were examined. Among them there were 35
      patients with coronary heart disease (CHD), 28 with arterial hypertension (AH),
      21 with type 2 diabetes mellitus (DM), 20 with duodenal peptic ulcer (PU). A
      matched group comprised 26 patients with acute pneumonia (AP). Low LQ was
      determined according to all 3 components: somatic, mental, and social. The lowest
      LQ was noted in patients with CHD, AH, and DM, indicating severity of these
      diseases accompanying marked changes in all spheres of life. PU was characterized
      by higher values that showed a fair LQ and that were due to a more favorable
      course of the disease. Patients with AP had a high LQ, which suggests that this
      acute disease does not lower LQ or accompany pronounced changes in human life. By
      and large, paychosomatic patients' LQ depended on age, severity, stage, and
      duration of a disease, disability.

PMID- 12494567
TI  - [Attitude of rural residents to healthy life styles].

PMID- 12494568
TI  - [Mental disorders in hospitalized children].
AB  - The authors made a statistical analysis of 1491 case histories in children aged 4
      14 years treated for various psychotic disorders at a mental hospital in 1992
      2001. The proportion of these children remained to be relatively stable and
      averaged 14.2% of the total number of inpatients. Throughout the 10-year follow
      up, among children with psychoses, boys were prevalent: an average ratio of boys
      to girls being 3.4:1. In Saint Petersburg, there has been recently a steady
      reduction in the number of children with psychosis admitted to hospitals, the
      number patients treated in the outpatient setting being on the increase. At the
      same time the rates of rehospitalizations are also on the rise of patients mainly
      with severest psychoses. In the past 10 years, Saint Petersburg has been a town
      of a steady rise in the number of disabled individuals due to mental diseases
      among children with schizophrenia and dementia admitted to the hospital.

PMID- 12494569
TI  - [Alcohol and cardiovascular disease mortality].

PMID- 12494571
TI  - [Current problems of coordination and interaction in public health management].
AB  - Coordination and interaction in public health management are analyzed. It is
      concluded that it is necessary to develop an effective interdepartmental
      coordination system regulated by federal legal and normative order documents.

PMID- 12494570
TI  - [Morbidity with temporal disability in workers of the Astrakhan gas refining
      plant].
AB  - Morbidity and temporary disability in 1987 to 2000 were analyzed in workers and
      employees of the Astrakhan gas-refining plant. There is a stable trend of the
      incidence and mean duration of disability in such groups of diseases as
      hypertensive disease and cerebrovascular lesions; gastroduodenal ulcer, diseases
      of the liver, gallbladder, and pancreas; those of the kidney, and urinary tract,
      infections of the skin and subcutaneous fat, diseases of the osteomuscular system
      and connective tissue. The average annual rate of increase in the mean duration
      of a case of ischemic heart disease decreased from 17.2 to 1.4%. There was a
      change in the trend of the mean duration of a case of acute respiratory infection
      on the average from +11.9 to -10.7% a year.

PMID- 12494572
TI  - [Methodological and organizational approaches to the development of socio
      hygienic monitoring of the health status of the population].
AB  - Sociohygienic monitoring is regarded as a tool of active observation and
      justified intervention to correct health formation by means of a number of
      specific components of the monitoring system. It is suggested that the capacities
      of some monitoring components sufficient for a research and experimental base to
      promote health, be extensively introduced into practice of the public health
      system. Emphasis is laid on an important role of the elaboration of
      sociopsychological measures to work with some groups of the population and their
      informed consent for collaboration while implementing the preventive programs of
      the public health system.

PMID- 12494574
TI  - [Evaluation of the efficiency of use of the bed fund of a central district
      hospital].
AB  - The paper deals with a complex sociohygienic study of the basic indices of
      resource provision of the public health system in the Tver Region and with an
      analysis of the scope of inpatient care to the population of the Torzhok
      District, Tver Region. Based on an in-depth examination, the efficiency of the
      use of the bed fund of the central district hospital (CDH) was evaluated and
      economic losses from inadequate use of beds and economic effects of work of daily
      CDH-based hospitals were calculated.

PMID- 12494573
TI  - [Methodological approaches to developing programs on children's health
      management].
AB  - The development of specific plants of action to manage the health of different
      population groups should be based on the results of pilot studies whose purpose
      is to obtain information that is useful and understandable for decision makers.
      To improve the health of children living in the town of Gai, Orenburg Region,
      which is one of the most pressing problems for the town, 100 potential risk
      factors of frequent diseases among preschool children were analyzed. It has been
      shown that the frequent occurrence of diseases may be due to the influence of a
      complex of biomedical and sociohygienic factors. The use of multifactorial
      analysis permits one not only to assess a role of each factor, but to predict the
      effectiveness of different preventive measures. The findings yielded a
      scientifically grounded interdepartmental program for children's health
      improvement.

PMID- 12494575
TI  - [Economic efficiency of medical care in the preparation of young men for military
      service].
AB  - The paper considers topical problems of medical examination of young men to
      define the category of their fitness for military service and organizational
      aspects of three-stage implementation in this area under the present conditions.
      Appropriate methods for evaluating economic efficiency have been developed and
      tested. They make it possible to deduce in situ an integral to assess activities
      in medical providing the preparation of young men for military service in the
      context of years, some nosological entities, and medical facilities.

PMID- 12494576
TI  - [Assessment of the quality of dental surgical services rendered by voluntary
      health insurance programs].

PMID- 12494577
TI  - [Chief physicians' views on problems in the organization and reforming of public
      health care].

PMID- 12494578
TI  - [The term "rural public health"].

PMID- 12494579
TI  - [Estimation of the use of diagnostic resources in an obstetric hospital].

PMID- 12494580
TI  - [Organizational aspects of extracorporeal blood correction service].

PMID- 12494581
TI  - [Public and charitable aid to children in Russia in the First World War years].

PMID- 12494582
TI  - [The eminent scientist-hygienist I. P. Skvortsov].

PMID- 12494583
TI  - [V.V. Veresaev and his "Physician's Sketch Book"].

PMID- 12494584
TI  - [History of training in midwifery art in the Vyatka Province in the 19th-20th
      centuries].

PMID- 12494585
TI  - [Medical dynasties and their implication in the development of scientific and
      practical medicine in Siberia].

PMID- 12494586
TI  - [Nikolai Alekseevich Bogoiavlenskii (1896-1973)].

PMID- 12494587
TI  - [Memorable dates and anniversaries in the history of medicine and public health
      in 2002].

PMID- 12494588
TI  - [Every tenth child is a "cuckoo child". Looks quite like the father!... Or
      perhaps not...?].

PMID- 12494589
TI  - [Sex and fun -- and with the child comes the mistrust].

PMID- 12494591
TI  - [Hazardous pleasant odors. Scented substances cause asthma in asthma patients].

PMID- 12494590
TI  - [After diagnosis 11 more years remain. COPD alarm in Europe!].

PMID- 12494592
TI  - [Sex hormones as risk factor? More asthma in cases of irregular menstrual
      periods].

PMID- 12494593
TI  - [50% of "cleaned" equipment contaminated by fecal germs. Infection caused by the
      endoscope? (Interview)].

PMID- 12494594
TI  - [Question of a Colleague. Can I still give advice to my wife about hormone
      replacement?].

PMID- 12494595
TI  - [Rhinosinusitis. Current diagnostic and therapeutic aspects].
AB  - Over the past years, the incidence of acute and chronic forms of rhinosinusitis
      has been increasing, and between 10 and 15% of the population of Central Europe
      are affected annually. Accordingly, the economic significance of rhinosinusitis
      is considerable. This makes the need for appropriate diagnostic and therapeutic
      strategies all the more urgent. In addition to case history and a physical
      examination, a helpful diagnostic strategy also includes rhinoendoscopy and--in
      particular in preparation for surgery--a CT scan. A plain radiograph does not
      suffice to confirm chronic sinusitis. The major therapeutic pillar in the
      treatment of acute rhinosinusitis is medication in conformity with accepted
      guidelines (proof of efficacy!). In the majority of cases chronic courses can be
      managed by minimally invasive surgery.

PMID- 12494596
TI  - [Complications of rhinosinusitis].
AB  - Rhinogenous complications may manifest in the region of the orbits, bone or soft
      parts of the wall of the frontal sinus, or endocranially. With regard to orbital
      complications, a differentiation is made between edema, periostitis,
      subperiosteal abscess and phlegmon--depending on severity and extent. A possible
      sequela of frontal sinusitis may be osteomyelitis. If the frontal bone is
      involved, there is a danger that the infection may spread to the endocranium via
      medullary spaces and blood vessels. The diagnostic basis for deciding appropriate
      treatment is CT or MRI. While orbital edema and periostitis usually respond to
      conservative treatment, subperiosteal abscess, orbital phlegmon and abscess of
      the brain require immediate operative treatment under antibiotic cover. The
      treatment of choice for osteomyelitis of the frontal bone is the liberal removal
      of affected bone, also under antibiotic cover.

PMID- 12494597
TI  - [Ophthalmological emergencies. 1. The acute red eye].

PMID- 12494598
TI  - [Weeks of pain, vertebral body fractures during sleep, invalidism. Save your
      osteoporosis patients from this fate].
AB  - In terms of their clinical impact, bone fractures as late sequelae of
      osteoporosis are still largely ignored in Germany. Up to 80-90% of patients with
      treatment-requiring osteoporosis are not receiving specific treatment. The
      consequences for the patient are enormous: weeks of severe pain, subsequent
      fractures that occur for ever more banal reasons, increasing restriction of daily
      activities, invalidism and an increasing need for nursing care. All this despite
      the availability of powerful medications. In concert with an appropriate early
      diagnosis, not only could the majority of patients be spared such a fate, but
      also the costs incurred as a direct consequence of such fractures could be
      drastically lowered.

PMID- 12494599
TI  - [Sudden confusion. Not always caused by blood supply!].

PMID- 12494600
TI  - [Shortly before the influenza season. Even risk patients are often not
      protected].

PMID- 12494601
TI  - [ACE inhibitors for diabetic patients. passed the test on the heart and kidneys].

PMID- 12494602
TI  - [Muscular pain and fatigue: is fibromyalgia sticking behind? These points bring
      it to light].

PMID- 12494603
TI  - [Changed guidelines of the German High Blood Pressure League. AT(1) blocker in
      the first league now].

PMID- 12494604
TI  - [Combination of beta-1 agonist and corticosteroid is advantageous not only in
      asthma. COPD patients spared exacerbations].

PMID- 12494605
TI  - [5-alpha reductase inhibitors or alpha blockers? The combination brakes best
      prostatic hyperplasia].

PMID- 12494606
TI  - [Heart failure studies are transferrable to everyday practice. No fear of beta
      blockers!].

PMID- 12494607
TI  - [Exhibition on the 100th anniversary of the death of Rudolf Virchow. Every day a
      new pathological preparation].

PMID- 12494608
TI  - Fever and Brugada syndrome.

PMID- 12494609
TI  - Impact of fusion avoidance on performance of the automatic threshold tracking
      feature in dual chamber pacemakers: a multicenter prospective randomized study.
AB  - The Autocapture algorithm enables automatic capture verification on a beat-by
      beat basis by recognizing the evoked response signal following each pacemaker
      stimulus. The algorithm intends to increase patient safety while decreasing
      energy consumption. However, the occurrence of fusion beats, particularly during
      dual chamber pacing, may limit the energy saving effect of Autocapture. The aim
      of this multicenter, prospective, randomized study was to evaluate the impact of
      the Fusion Avoidance (FA) algorithm on the incidence of fusion beats. Thirty
      eight patients (mean age 69 +/- 13 years) with intrinsic AV conduction who were
      implanted with an Affinity DR were studied. After programming a PV/AV delay of
      120/190 ms, patients were randomized to FA On or Off. Each group was further
      randomized with respect to activation of the AutoIntrinsic Conduction Search
      (AICS) algorithm. The total number of beats, ventricular paced beats, fusion
      beats, backup pulses, and threshold searches were analyzed from 24-hour Holter
      recordings. The number of total beats was comparable in both FA groups. The
      number of total ventricular paced beats, fusion beats, backup pulses, and
      threshold searches were significantly reduced in the FA On group (% reduction:
      68% P < 0.001, 75% P < 0.01, 95% P < 0.01, and 94% P < 0.05, respectively). The
      number of ventricular paced beats with full capture was significantly reduced
      when AICS was activated (P < 0.05). In conclusion, the FA algorithm substantially
      reduces the amount of ventricular paced beats, fusion beats, unnecessary backup
      pulses and threshold searches, and therefore, provides added benefits in energy
      saving obtained by Autocapture.

PMID- 12494610
TI  - P wave duration and morphology predict atrial fibrillation recurrence in patients
      with sinus node dysfunction and atrial-based pacemaker.
AB  - P wave duration and morphology have never been systematically evaluated as
      markers of AF in patients with a conventional indication to pacing. This study
      correlated sinus P wave duration and morphology and the incidence of AF in
      patients with sinus node dysfunction (SND), previous history of AF before
      implant, and atrial-based pacemaker. Included were 140 patients (86 men, 54
      women; mean age 71.8 +/- 10.4 years) with recurrent paroxysmal AF and who
      received a DDD (128 patients) or AAI (12 patients) pacemaker for SND. Forty-nine
      patients had structural heart disease. Sinus P wave duration and morphology was
      evaluated in leads II, III. Twenty-two patients had an abnormal P wave
      morphology, diphasic (+/-) in 5 and notched (+/+) in 17. The basic pacemaker rate
      was programmed between 60 and 70 beats/min. Rate responsive function was
      activated in 65 patients. During a follow-up of 27.6 +/- 17.8 months, AF was
      documented in 87 patients. Forty-four patients developed permanent AF, following
      at least one episode of paroxysmal AF in 26 cases. Statistical analysis used Cox
      model regression. Univariate predictors of AF (P < 0.10) were drugs (mean: 2 +/-
      1.4) and DC shock before pacing (16/140 patients), P wave duration (mean 112.5 +/
      24.6 ms), basic pacemaker rate (mean 68 +/- 5 beats/min), and drugs in the
      follow-up (mean 1.2 +/- 0.94). Multivariate analysis showed that P wave duration
      (b = 0.013, s.e. = 0.004; P = 0.003), and drugs before pacing (b = 0.2; s.e. =
      0.08; P < 0.01) resulted in a significant independent predictor of AF. Actuarial
      incidence of patients free of AF at 30 months was 35%: 56% in patients with a P
      wave < 120 ms, and 13% in those with P wave > or = 120 ms (P < 0.01 by Score
      test). Univariate predictors of permanent AF were drugs and DC shock before
      pacing, left atrial size (mean 39 +/- 6 mm), P wave duration, abnormal P wave
      morphology (22/140 patients), and drugs in the follow-up. Multivariate analysis
      showed that P wave morphology was the most important predictor of permanent AF (b
      = -0.56, s.e. = 0.2; P = 0.008). Incidence of patients free of permanent AF at 30
      months was 69%: 74% in patients with normal P wave, compared to 28% in the case
      of abnormal P wave morphology (P < 0.01). P wave duration and morphology are good
      markers of postpacing AF recurrence in patients with SND and an atrial-based
      pacemaker. This observation suggests that intra- and interatrial conduction
      disturbances be extensively evaluated before implantation, and the indication for
      atrial resynchronization procedures be reevaluated.

PMID- 12494611
TI  - Primary radiofrequency ablation for incessant idiopathic ventricular tachycardia.
AB  - Fascicular VT and RVOT tachycardia are sometimes difficult to induce by
      programmed electrical stimulation (PES), despite pharmacologic provocation. In
      such instances, catheter mapping is hampered and efficacy of catheter ablation is
      difficult to judge. The study included nine patients who presented with incessant
      idiopathic VT and were directly taken to the electrophysiological laboratory for
      RF ablation. During the same period, elective ablation was performed on 108
      patients with idiopathic VT. The success rate, procedural and fluoroscopy times
      number of energies, and the peak temperature were evaluated and compared. Of the
      nine patients, seven had incessant fascicular VT and two had RVOT tachycardia.
      The mean VT cycle length was 356 +/- 32 ms and the earliest endocardial
      activation time during VT was 23.6 +/- 6 ms relative to surface QRS complexes. A
      fascicular potential was not seen in three of the seven patients with fascicular
      VT. The mean procedural time was 71 +/- 32 minutes and 144 +/- 40 minutes (P =
      0.023) while the fluoroscopy time was 14.6 +/- 4.6 minutes and 30 +/- 16 minutes
      (P < 0.001), respectively, in the primary ablation and elective groups. The total
      number of RF energies delivered was 2.0 +/- 1.3 versus 7.4 +/- 5.6 (P = 0.07),
      respectively. The significantly increased procedural time during elective
      ablation was largely due to time spent in fascicular VT induction. All patients
      in the primary ablation group were successfully ablated and none had a
      recurrence. Primary ablation is a safe and effective option in patients with
      incessant idiopathic VT. Moreover, in fascicular VT, it is superior to elective
      ablation in terms of success, fluoroscopy and procedural times.

PMID- 12494612
TI  - Identification of ventricular tachycardia of epicardial origin from unipolar
      potentials obtained at the endocardial surface: is it feasible?
AB  - VT late after myocardial infarction usually originates from the endocardial
      surface; subepicardial substrates are also possible. The identification of these
      atypical locations with endocardial mapping remains unresolved even with new
      mapping technologies. This study compared isopotential maps, signal morphology,
      and activation patterns around left endocardial breakthroughs recorded in VTs
      originating from the subepicardium or subendocardium after remote myocardial
      infarction. These results were extracted from a database of 111 tachycardias
      obtained at surgery in 34 patients. Mapping was performed with a 128-unipolar
      electrode system using an epicardial mesh and a left ventricular endocardial
      balloon. Subepicardial (n = 7) and subendocardial VTs (n = 10) were defined as
      complete superficial reentry and/or as tachycardias with a > or = 25-ms delay
      between the earliest activity and the breakthrough of activation on the opposite
      surface. A positive potential distribution covering the area of initial
      endocardial activity was observed in a single subepicardial VT but in none of the
      subendocardial ones (P = NS). R waves were observed on the earliest endocardial
      unipolar signals in two subepicardial VTs and five subendocardial VTs (P = NS).
      The area covered by the first 5-ms or 10-ms isochrone at the endocardial level
      was larger in subepicardial VTs than in subendocardial VTs but the difference was
      not significant. In conclusion, despite a wider endocardial area of early
      activity in VTs of subepicardial origin, no reliable criteria can be proposed to
      identify these tachycardias from mapping data restricted to the endocardial
      surface. This is probably due to highly nonuniform anisotropic propagation around
      the scarred tissue.

PMID- 12494613
TI  - Efficacy of metoprolol and sotalol in the prevention of recurrences of sustained
      ventricular tachyarrhythmias in patients with an implantable cardioverter
      defibrillator.
AB  - ICDs provide protection against sudden cardiac death in patients with life
      threatening ventricular arrhythmias. Nevertheless, most ICD recipients receive
      adjunctive antiarrhythmic drug therapy to reduce the number of recurrent episodes
      and ICD discharges. The aim of the study was to compare the efficacy of
      metoprolol and d,l-sotalol in preventing VT/VF recurrences in patients with an
      ICD in a prospective, randomized trial. One hundred patients (83 men, 17 women;
      mean age 59 years, SD +/- 11 years) were randomized to receive metoprolol or
      sotalol after implantation of an ICD. There were no significant differences
      between the two groups with regard to age, sex, underlying cardiac disease, left
      ventricular ejection fraction, NYHA class assessment and clinical arrhythmia. The
      median follow-up was 728 days (25th percentile: 530 days, 75th percentile: 943
      days) in the metoprolol group and 727 days (25th percentile: 472 days, 75th
      percentile: 1,223 days) in the sotalol group (P = 0.52). Thirty-three patients
      treated with metoprolol and 30 patients receiving sotalol had at least one
      episode during the follow-up. Event-free survival curves were generated for the
      two treatment arms using the Kaplan-Meier method and showed no significant
      difference (P = 0.68). Eight patients treated with metoprolol and six patients
      treated with sotalol died during follow-up. Total mortality was not significantly
      different between the two study groups (P = 0.43). Metoprolol is as efficacious
      as sotalol in preventing VT/VF recurrences in patients with an ICD.

PMID- 12494614
TI  - 1-year performance of a defibrillation lead with a small electrode surface for
      high impedance pacing: a randomized, controlled study.
AB  - A small electrode surface reduces pacing current drain and can extend generator
      longevity. The study evaluated the performance of a tined, quadripolar
      defibrillation lead (model 6944) that has a small-surfaced, steroid-eluting
      electrode tip for high impedance pacing. In a prospective, controlled study, 34
      patients with conventional ICD indications were randomized one to one to receive
      the high impedance model 6944 or a tined defibrillation lead with a conventional
      sized, steroid-eluting electrode tip model 6942. Lead performance was evaluated
      at implant, prior to hospital discharge, and 1, 3, 6, and 12 months thereafter.
      Baseline characteristics did not differ significantly between patients implanted
      with lead model 6942 (n = 16) or model 6944 (n = 17). One patient randomized to
      receive the model 6942 was excluded from the study and was implanted with an
      active-fixation lead after stable lead positioning was neither possible with the
      6942 nor with the 6944 electrode. No other lead related adverse events were
      observed. At implant, there were no significant differences between pacing
      thresholds, sensing performance, defibrillation impedances, and defibrillation
      thresholds in both groups, but pacing impedance of the model 6944 (988.6 +/-
      217.7 omega) was approximately twice as high as high as in the model 6942 (431.7
      +/- 83.7 omega; P < 0.0001). This difference remained highly significant
      throughout the observation period of 12 months, while R wave amplitudes and
      pacing thresholds remained equal in both lead models. The use of a tined
      defibrillation lead with a small, steroid-eluting electrode tip appears safe and
      results in a high pacing impedance without compromising system performance.

PMID- 12494615
TI  - Transesophageal echocardiographic evaluation of tricuspid valve regurgitation
      during pacemaker and implantable cardioverter defibrillator lead extraction.
AB  - Chronically implanted ventricular pacing and defibrillator (ICD) leads can adhere
      to the tricuspid valve. This study examined the effect of lead extraction, and
      laser sheath extraction in particular, on tricuspid valve regurgitation. Lead
      extraction was first tried with traction using limited force followed by a laser
      sheath if not successful. Tricuspid valve regurgitation before and after
      extraction was evaluated with transesophageal echocardiography and graded from 0
      (none) to 4 (severe). A change in regurgitation was considered clinically
      relevant if it increased with two grades or more and resulted in at least grade 3
      regurgitation. Fifty ventricular leads were extracted in 43 consecutive patients,
      including 14 ICD leads. In 20 patients (group I) leads were removed without a
      (laser) sheath crossing the tricuspid valve, in 23 patients (group II) leads were
      extracted with lasing across the valve. The mean time from implant was 43 +/- 43
      months and 99 +/- 78 months, respectively, (P = 0.007). Tricuspid regurgitation
      increased in five (12%) patients. In group I only in one patient the laser failed
      proximal of the valve and forceful traction was subsequently used, and in group
      II this occurred in four (17%) patients. This difference did not reach
      statistical significance even excluding the patient from group I (P = 0.111). The
      increase of tricuspid regurgitation cautions against indiscriminate extraction of
      superfluous leads. There is a trend that when tools like a laser sheath are
      necessary the chance of tricuspid valve damage increases.

PMID- 12494616
TI  - Frequent and prolonged asymptomatic episodes of paroxysmal atrial fibrillation
      revealed by automatic long-term event recorders in patients with a negative 24
      hour Holter.
AB  - The presence, frequency, and duration of episodes of paroxysmal atrial
      fibrillation (PAF) is difficult to establish. This is caused by the limited
      duration of standard Holter recordings and to the unsatisfactory yield of patient
      triggered event recorders, because of asymptomatic events and of an inconsistent
      use of the patient dependent triggering function. A prospective cohort of 65
      consecutive patients with recurrent palpitations and a negative 24-hour ECG
      Holter was investigated by means of a cardiac event recorder bearing continuous
      automatic arrhythmia analysis and storage. Over a mean duration of 77 +/- 36
      hours, episodes of PAF were diagnosed in 20 (31%) patients, who had a total of 37
      episodes; mean duration of PAF episodes was 7 hours 50 minutes +/- 8/hours 45
      minutes (minimum 45 minutes, maximum 28 hours). Eleven (55%) of these 20 patients
      were asymptomatic and would have remained undiagnosed without the automatic mode
      of the event recorder. Asymptomatic PAF episodes were longer than symptomatic
      ones (10 hours 30 minutes +/- 6 hours 30 minutes vs 4 hours 50 minutes +/- 4
      hours, P < 0.05). In addition, episodes of sustained paroxysmal supraventricular
      tachycardia (PSVT) were diagnosed in 39 (57%) patients, of whom 34 (87%) were
      symptomatic. In this prospective cohort, a second standard 24-hour monitoring
      would have missed 44% of the patients with PAF or PSVT and a classical patient
      triggered event recorder 13%. In patients still complaining of palpitations after
      one negative 24-hour Holter, numerous, prolonged, and often asymptomatic episodes
      of PAF can be revealed by long-term automatic event recorders. These devices
      should help clarify the clinical consequences of such episodes.

PMID- 12494617
TI  - Chronic threshold testing of implantable cardioverter defibrillators does not
      increase coagulation activity or platelet activation.
AB  - It is unknown if the brief periods of circulatory statis occurring with induction
      of VF during DFT testing in patients with an ICD activate blood coagulation
      processes. To address this question, coagulation activity and platelet activation
      were measured in peripheral venous blood samples obtained from 12 patients
      undergoing DFT testing under general anesthesia, 3 (n = 11) or 6 months (n = 1)
      after ICD implantation for recurrent ventricular arrhythmias. Five patients were
      anticoagulated with warfarin and two to six episodes of VF (median five) were
      induced per patient. Blood samples were drawn at baseline, after each DFT test
      and on the following morning. Coagulation activity was assessed by measuring
      prothrombin fragment 1 + 2 (F1 + 2) (a marker of thrombin generation), soluble
      fibrin (a marker of fibrin production), and D-dimer (a breakdown product of cross
      linked fibrin). Platelet activation was evaluated by measuring the expression P
      selectin on the platelet surface using flow cytometry. No significant changes in
      F1 + 2, soluble fibrin, D-dimer, or P-selectin expression occurred during DFT
      testing, or between baseline and morning after samples. Moreover, results were
      unaffected by warfarin. These findings suggest that chronic threshold testing of
      implantable cardioverter defibrillators is not associated with activation of
      blood coagulation processes.

PMID- 12494618
TI  - Automatic discrimination between supraventricular and ventricular tachycardia
      using a multilayer perceptron in implantable cardioverter defibrillators.
AB  - The morphological analysis of implantable cardioverter defibrillator (ICD) stored
      electrograms (EGM) using a multilayer perceptron (MLP) has been proposed for
      discrimination between supraventricular and ventricular arrhythmias. However, a
      reliable estimation of the accuracy of MLP methods is lacking. The aim of the
      study was to compare the morphology and spectrum-based MLP with more conventional
      morphology-based algorithms in a large series of ICD-stored episodes of
      arrhythmia. One set of ICD-stored electrograms was used for control and training
      purposes and a second one, consisting of spontaneous episodes in patients with
      dual chamber ICDs, for validation of the MLP performance. The correlation
      waveform analysis (CWA) and the EGM width criterion were compared with MLP
      methods. Bootstrap resampling techniques were used to extract the relevant
      information in the MLP training. The morphology-based MLP achieved better
      discrimination than any other method, with areas under the receiver operating
      characteristic (ROC) curve (tolerance intervals): 0.96 (0.81, 0.96) for MLP, 0.91
      (0.77, 0.94) for CWA, and 0.68 (0.49, 0.78) for EGM width in the validation set.
      A specificity of 73.0% was obtained at 95% sensitivity, compared with 38.1% and
      55.1% using CWA and EGM width criteria, respectively. In contrast, the
      generalization capabilities of spectral-based MLP methods are poor, showing a
      lower area under the ROC curve in the validation set. Time-domain MLP techniques
      may be useful for the morphological analysis of the intracardiac EGM signal
      stored by ICD devices. When properly trained and validated, these methods perform
      better than other commonly used morphological criteria for discrimination between
      supraventricular and ventricular arrhythmias.

PMID- 12494619
TI  - The incidence and risk factors for venous obstruction after implantation of
      transvenous pacing leads.
AB  - Several investigators have shown that the incidence of venous obstruction after
      pacemaker implantation was observed in 31-50% of pacemaker patients. However,
      these previous reports did not investigate the venous system prior to
      implantation. The aim of this study was to determine the incidence and risk
      factors for venous obstruction in patients with transvenous pacing leads. The
      study included 131 consecutive patients (64 men, 67 women; mean age 71.3 +/- 9.8
      years) who were investigated using intravenous digital subtraction angiography
      (DSA) before and after permanent pacemaker implantation. Follow-up DSA was
      performed for a mean interval of 44 +/- 6 months after pacemaker lead
      implantation in 79 of 131 patients. A diameter narrowing > 60% was defined as an
      obstruction. Prior to implantation of pacing leads, venous obstruction was
      present in 18 (13.7%) of 131 patients. In 15 of these 18 patients, the
      obstruction was present at the site of the left innominate vein. Follow-up DSA,
      after implantation of pacing leads, showed that venous obstruction was observed
      in 26 (32.9%) of 79 patients. There were no significant differences between
      obstruction and nonobstruction groups in terms of age, sex, cardiothoracic ratio,
      left atrial dimension, left ventricular ejection fraction, baseline heart
      diseases for indication of pacemaker implantation, or number and body size of
      pacing leads. Neither clinical symptoms nor abnormal physical findings were
      observed in any patients. In conclusion, the incidence of venous obstruction
      after pacing lead implantation is less than that of previous reports, which might
      be related to the incidence of venous obstruction before pacing leads
      implantation.

PMID- 12494620
TI  - What is the minimal pacing rate that prevents torsades de pointes? Insights from
      patients with permanent pacemakers.
AB  - In the acquired long QT syndrome, torsades de pointes (TP) is invariably preceded
      by pauses or bradycardia. Thus, it has been proposed that out-of-hospital
      initiation of drugs that prolong repolarization should be safe in patients with
      permanent pacemakers. However, a minimal protective pacing rate has not been
      identified. The authors reviewed published reports of acquired TP in patients
      with permanent pacing. Those providing documentation of tachycardia onset and
      pacemaker programming were included in the analysis. Events occurring < or = 1
      month after AV nodal ablation were excluded. Eighteen cases were identified (age
      74 +/- 5; 10 women). QT prolonging drugs were present in 15 patients (quinidine
      5, sotalol 3, disopyramide 3, amytriptiline, chloroquine, cisapride +
      haloperidol, and monopride + flecainide 1 each). Hypokalemia was present in eight
      patients. At the time of TP, the programmed lower rate was 63 +/- 13 beats/min.
      However, the effective pacing rate was lower (55 +/- 11 beats/min) due to
      invocation of pause-promoting features (hysteresis [4 patients]; + PVARP
      extension on PVC [1 patient]) or ventricular oversensing (2 patients). No patient
      developed TP with an effective pacing rate > 70 beats/min. TP is possible in the
      presence of a functional permanent pacemaker. Programmed lower rates < or = 70
      beats/min are not protective. At programmed lower rates > 70 beats/min, TP may
      occur only when facilitated by programmable pause-promoting features or
      oversensing. It remains to be seen if rate smoothing algorithms can prevent TP
      when the baseline rate is programmed < or = 70 beats/min.

PMID- 12494621
TI  - Temporal changes in the endocardial ST segment during the evolution of myocardial
      infarction in dogs.
AB  - Acute coronary occlusion causes ST-segment elevation on the body surface ECG and
      on the epicardial electrogram in the territory supplied by that artery. The
      occurrence and significance of endocardial ST changes have not been studied. The
      NOGA electromechanical mapping was performed on eight anesthetized dogs at
      baseline, immediately after occlusion of the LAD, and again at 5 hours to assess
      regional changes in the ST segment. At 3 days and 4 weeks the ventricles were
      remapped for comparison. Regional unipolar ST-segment elevation was measured for
      each zone from NOGA maps at 0, 80, and 120 ms after the J point. ST segments rose
      immediately in the infarct zones, as demarcated by echocardiography, compared to
      remote zones, but by 3 days had dropped below, and at 4 weeks returned to
      baseline values. Immediately postocclusion, ST elevation at 120 ms best
      differentiated between normal versus abnormal echo scores (concordance = 0.80),
      probably by correcting for pressure induced ST elevation. In conclusion, acute
      endocardial ST-segment changes occur in the infarct zone in the dog, showing a
      distinctive temporal evolution.

PMID- 12494622
TI  - Compatibility of automatic threshold tracking pacemakers with previously
      implanted pacing leads in children.
AB  - The Autocapture function controls and optimizes the amplitude of the pacing pulse
      and saves energy. The manufacturer recommends using a special low polarization,
      low threshold bipolar Pacesetter lead for the Autocapture function. The purpose
      of this study was to evaluate the compatibility of Autocapture with previously
      implanted pacing leads. The study included 15 patients (mean age 13.6 +/- 3.4
      years) who needed pulse generator replacement and received the VVIR pacemaker
      Regency SR+ or the DDDR pacemakers Affinity DR or Integrity DR with the
      Autocapture function. The new pulse generators connected to previously implanted
      ventricular leads. At the time of implantation the pacing threshold was 1.0 +/-
      0.35 V at 0.5 ms, the lead impedance was 580 +/- 80 omega, and the spontaneous R
      wave amplitude was 7.89 +/- 4.89 mV. The polarization signal (PS) was 3.8 +/-
      3.04 mV, and evoked response (ER) was 8.15 +/- 4.57 mV at the predischarge
      testing. Follow-up telemetry was done at months 1, 3, 6, 12, and 18. The follow
      up duration was 9.4 +/- 5 months (range 1-18 months). If the results of PS and ER
      measurements were acceptable for autocapture, it turned on at the 1-month visit.
      In six (40%) patients the results were found acceptable for autocapture function.
      Age, lead impedance, pacing threshold, intrinsic R wave measurement, lead age,
      fixation mechanism, and ER measurements were not statistically different in
      Autocapture suitable and not suitable groups. The main reason not to activate
      Autocapture had been increased PS. Any significant fluctuations were not observed
      in pacing threshold, lead impedance, ER, and PS during follow-up. In conclusion,
      previously implanted pacing leads may be compatible with the Autocapture
      function.

PMID- 12494623
TI  - Percutaneous treatment for pacemaker-associated superior vena cava syndrome.
AB  - Superior vena cava (SVC) obstruction is an uncommon but serious complication
      associated with permanent pacemaker implantation. The mechanical stress
      associated with pacemaker wires may lead to vessel wall inflammation, fibrosis,
      and thrombus formation, and ultimately to venous stenosis and occlusion. The
      surgical treatment of pacemaker related SVC syndrome requires thoracotomy and
      carries significant morbidity. This article illustrates the authors' initial
      experience with a "one-step" percutaneous approach for this problem, consisting
      of percutaneous retrieval of a pacemaker system, followed by venous
      revascularization with angioplasty and stenting, and installation of a new
      pacemaker device.

PMID- 12494624
TI  - The Brugada syndrome: is an implantable cardioverter defibrillator the only
      therapeutic option?

PMID- 12494625
TI  - Supraventricular tachycardia immediately following abolition of preexcitation
      during RF delivery: AVRT or not?

PMID- 12494626
TI  - Fever unmasking the Brugada syndrome.
AB  - This case report describes a 66-year-old woman with severe polymorphic
      ventricular tachycardia and syncope during a febrile state. The electrocardiogram
      revealed a right bundle branch block and pattern of elevated ST segment in the
      anterior and inferior leads similar to the Brugada syndrome. These
      electrocardiographic anomalies disappeared when the temperature returned to
      normal. The administration of procainamide reproduced the electrocardiographic
      changes. An electrophysiological study using two extrastimuli induced ventricular
      tachycardia. An automatic defibrillator was implanted.

PMID- 12494627
TI  - Induction of ventricular fibrillation in Brugada syndrome by site-specific right
      ventricular premature depolarization.
AB  - This patient was a 50-year-old man. Oral pilsicainide unmasked a Brugada-type ECG
      abnormality and self-terminating polymorphic VT was repetitively induced. The
      polymorphic VT always developed following a specific ventricular premature
      complex showing a left bundle branch block pattern suggesting a limited origin in
      the right ventricle.

PMID- 12494628
TI  - Migration and infection of a pace-sense lead from an abdominal defibrillator
      system.
AB  - A 47-year-old man had an ICD system with epicardial and endocardial components
      and an abdominal generator placed in 1990 following a cardiac arrest. Ten years
      later his BT10 lead was amputated due to an insulation defect, and he received a
      new pectoral generator with transvenous leads. A few months later he developed
      fevers, chills, and bacteremia. Evaluation demonstrated migration of the entire
      BT10 lead into the right atrium. Complete surgical explantation was required and
      the bacteremia resolved. This case illustrates the importance of solid anchoring
      of distal lead components following generator removal and the potential
      complication of intravascular lead migration.

PMID- 12494629
TI  - Implantable cardioverter defibrillator proarrhythmia due to an interaction with
      "noncompetitive atrial pacing": an algorithm to prevent atrial arrhythmias.
AB  - An episode of device related proarrhythmia observed with a dual chamber ICD is
      reported. Ventricular tachycardia was induced due to an inappropriate interaction
      of programmed device settings with automatic algorithms, including noncompetitive
      atrial pacing (NCAP), an algorithm used to prevent atrial tachyarrhythmias.

PMID- 12494630
TI  - Brugada syndrome unmasked by febrile illness.
AB  - The ionic mechanisms responsible for the electrocardiographic phenotype of the
      Brugada syndrome are temperature dependent. This report describes a healthy young
      man with ECG changes typical of Brugada syndrome that were unmasked during a
      febrile illness.

PMID- 12494631
TI  - A view from down under: laparoscopic look at a subrectus pacemaker.
AB  - This article describes an infant with multiple congenital anomalies who underwent
      laparoscopic insertion of a gastrostomy tube. Prior repair of congenital heart
      defects had resulted in complete heart block necessitating the implantation of an
      epicardial pacemaker. A photograph taken within the peritoneal cavity provides a
      unique view of the patient's subrectus pulse generator.

PMID- 12494632
TI  - Polymerase chain reaction. Basic principles and routine practice.

PMID- 12494634
TI  - Single-step PCR optimization using touchdown and stepdown PCR programming.

PMID- 12494633
TI  - Computer programs for PCR primer design and analysis.

PMID- 12494635
TI  - XL PCR amplification of long targets from genomic DNA.

PMID- 12494636
TI  - Coupled one-step reverse transcription and polymerase chain reaction procedure
      for cloning large cDNA fragments.

PMID- 12494637
TI  - Long distance reverse-transcription PCR.

PMID- 12494638
TI  - Increasing PCR sensitivity for amplification from paraffin-embedded tissues.

PMID- 12494639
TI  - GC-rich template amplification by inverse PCR. DNA polymerase and solvent
      effects.

PMID- 12494640
TI  - PCR procedure for the isolation of trinucleotide repeats.

PMID- 12494641
TI  - Methylation-specific PCR.

PMID- 12494642
TI  - Direct cloning of full-length cell differentially expressed genes by multiple
      rounds of subtractive hybridization based on long-distance PCR and magnetic
      beads.

PMID- 12494643
TI  - Cloning PCR products. An overview.

PMID- 12494644
TI  - Using T4 DNA polymerase to generate clonable PCR products.

PMID- 12494645
TI  - Enzyme-free cloning of PCR products and fusion protein expression.

PMID- 12494646
TI  - Directional restriction site-free insertion of PCR products into vectors.

PMID- 12494647
TI  - Autosticky PCR. Directional cloning of PCR products with performed 5' overhangs.

PMID- 12494648
TI  - A rapid and simple procedure for direct cloning of PCR products into
      baculoviruses.

PMID- 12494649
TI  - PCR approaches to DNA mutagenesis and recombination. An overview.

PMID- 12494650
TI  - In-frame cloning of synthetic genes using PCR inserts.

PMID- 12494651
TI  - Megaprimer PCR.

PMID- 12494652
TI  - PCR method for generating multiple mutations at adjacent sites.

PMID- 12494653
TI  - A fast polymerase chain reaction-mediated strategy for introducing repeat
      expansions into CAG-repeat containing genes.

PMID- 12494654
TI  - PCR screening in signature-tagged mutagenesis of essential genes.

PMID- 12494655
TI  - Staggered extension process (StEP) in vitro recombination.

PMID- 12494656
TI  - Random mutagenesis by whole-plasmid PCR amplification.

PMID- 12494657
TI  - PCR-based strategies to clone unknown DNA regions from known foreign integrants.
      An overview.

PMID- 12494658
TI  - Long distance vectorette PCR (LDV PCR).

PMID- 12494659
TI  - Nonspecific, nested suppression PCR method for isolation of unknown flanking DNA
      ("cold-start method").

PMID- 12494660
TI  - Inverse PCR. cDNA cloning.

PMID- 12494661
TI  - Inverse PCR. Genomic DNA cloning.

PMID- 12494662
TI  - Gene cloning and expression profiling by rapid amplification of gene inserts with
      universal vector primers.

PMID- 12494663
TI  - The isolation of DNA sequences flanking Tn5 transposon insertions by inverse PCR.

PMID- 12494664
TI  - Rapid amplification of genomic DNA sequences tagged by insertional mutagenesis.

PMID- 12494665
TI  - Isolation of large-terminal sequences of BAC inserts based on double-restriction
      enzyme digestion followed by anchored PCR.

PMID- 12494666
TI  - A "step down" PCR-based technique for walking into and the subsequent direct
      sequence analysis of flanking genomic DNA.

PMID- 12494667
TI  - Use of PCR in library screening. An overview.

PMID- 12494668
TI  - Cloning of homologous genes by gene-capture PCR.

PMID- 12494669
TI  - Rapid and nonradioactive screening of recombinant libraries by PCR.

PMID- 12494670
TI  - Rapid cDNA cloning by PCR screening (RC-PCR).

PMID- 12494671
TI  - Generation and PCR screening of bacteriophage lambda sublibraries enriched for
      rare clones (the "sublibrary method").

PMID- 12494672
TI  - PCR-based screening for bacterial artificial chromosome libraries.

PMID- 12494673
TI  - A 384-well microtiter-plate-based template preparation and sequencing method.

PMID- 12494674
TI  - A microtiter-plate-based high throughput PCR product purification method.

PMID- 12494675
TI  - Scientific review of the Welfare Food Scheme.
AB  - INTRODUCTION: The COMA Panel on Maternal and Child Nutrition has undertaken the
      first scientific review of the Welfare Food Scheme since its inception in 1940.
      It has: reviewed current dietary recommendations, identified from national data,
      population groups vulnerable to adverse nutritional outcomes, evaluated the
      contribution of the current scheme to prevention of these vulnerabilities and
      identified further information needs and highlighted improvements likely to be
      cost neutral. HISTORY AND ENTITLEMENT: Originally the Scheme incorporated
      universal provision. Subsequently it was targeted at the most socio-economically
      vulnerable. Today, a quarter of children under five are beneficiaries by virtue
      of their family's income. The Scheme has two principal beneficiary groups:
      pregnant women, mothers and young chidren in families eligible for certain social
      security benefits. With the exception of children under one year of age, all are
      entitled to a pint of milk a day (using redeemable milk tokens) and free vitamin
      supplements (available from designated clinics). Infant formula instead of milk
      is available for infants who are not breastfed. children under five years
      attending Scheme-registered day care facilities can receive one third of a pint
      of milk a day. Children aged 5-16 years not registered at school by virtue of
      mental or physical disability are entitled to a pint of milk a day. CURRENT DIET
      AND VULNERABLE GROUPS: The following adverse nutritional outcomes were
      considered: pregnant women and mothers low uptake of periconceptional folic acid
      supplements low dietary intake during pregnancy vitamin D deficiency.

PMID- 12494676
TI  - The short story of HLA and its methods.
AB  - BACKGROUND: During the past 40 years, typing for the human leukocyte antigens
      (HLA) was done using serological techniques. Several improvements were achieved
      as to the efficiency and reliability of these techniques. One of the major
      drawbacks of serology, however, is the need of viable cells. Especially blood
      cells drawn from deceased donors, as are the usual source for typing of corneal
      donors, may have a grossly impaired viability and a reduced expression of
      antigens on their cell surface. This makes serological typing difficult and
      liable to errors. In the mid-1980s, molecular typing was first introduced in many
      laboratories. This first period dealt with the so-called restriction fragment
      length polymorphism method, a tedious method not suited for prospective typing.
      Only with the introduction of the polymerase chain reaction was the suitability
      of molecular techniques with respect to perspective typing achieved. METHODS:
      International workshops and the effort of many laboratories led to a
      standardization of the methods. External proficiency testing exercises on
      transplantation relevant procedures in the laboratories affiliated to
      transplantation centers and the introduction of an accreditation system in the
      USA and in Europe increased significantly the reliability of all relevant
      immunogenetical testing. RESULTS: To date, patients and prospective organ and
      tissue donors are typed in addition to serology also with molecular methods.
      Using these techniques, the reliability and reproducibility of HLA typing have
      reached levels of more than 98%. Even 8-day-old peripheral blood samples can now
      be typed routinely with these methods, formerly impossible by serology.
      CONCLUSION: The laboratories affiliated to the transplantation centers are ready
      for high reliability testing of all HLA markers required by the clinic according
      to the results of controlled clinical long-term follow-up studies.

PMID- 12494677
TI  - Degree of compatibility for HLA-A and -B affects outcome in high-risk corneal
      transplantation.
AB  - BACKGROUND: HLA-A/-B matching on a split typing level is more laborious, more
      expensive and offers less chances for a well-fitting match than does matching on
      the conventional broad typing level. It is important, therefore, to investigate
      whether or not split matching offers advantages and would, therefore, be
      advisable. METHODS: 303 high-risk patients out of 2,471 keratoplasty patients
      from 1982 through 1996, whose histories were all followed prospectively, could be
      re-evaluated retrospectively according to their broad or split matching levels
      ('good' vs. 'moderate'). RESULTS: Only a 'good' split level matching was
      significantly better than a 'moderate' one in the long run (up to 12 years). For
      the broad level matching this was only true for the first few years after
      keratoplasty. CONCLUSION: If only HLA-A/-B are matched and if only results longer
      than 3-4 years (up to 12 years) are taken into consideration, then split level
      matching offers clear-cut advantages over broad level matching.

PMID- 12494678
TI  - Histocompatibility and corneal transplantation.
AB  - BACKGROUND: HLA typing and matching have been poorly implemented in corneal
      transplantation, mainly because of inconclusive or contradictory analytical
      results. Consequently, we studied the immune response of corneal transplant
      recipients to HLA histoincompatibilities in a large homogeneous study. METHODS:
      All corneal transplantations were performed by a single surgeon in a single
      center between 1976 and 1996. Population genetic and other statistical analyses
      were performed. Simulation studies assessed the effects of HLA-DR mistypings on
      analytical results. RESULTS: Mono- and multivariate analyses identified
      retransplantation, degree of vascularization, HLA-AB and -DR match grades,
      endothelial cell count, graft size, recipient gender, storage method and panel
      reactive antibodies as significantly influencing the survival of corneal
      transplants. Simulation studies showed that the beneficial effect of HLA-DR
      matching is abrogated by HLA-DR mistypings. CONCLUSIONS: Corneal transplant
      recipients have a normal immune response to HLA incompatibilities. Demonstration
      of that fact requires accurate HLA typings.

PMID- 12494679
TI  - HLA class I and II matching improves prognosis in penetrating normal-risk
      keratoplasty.
AB  - BACKGROUND: HLA matching in penetrating keratoplasty is still neglected in most
      eye clinics. This is due to contradictory results of studies performed in the
      past. Different surgical techniques in multicenter studies, missing risk
      differentiation in high-risk situations and faulty HLA typing can be identified
      as the main reasons for these contradictory results. In this monocenter study,
      the value of HLA class I and II matching (A, B, DR loci) was examined in a
      homogenous group of 398 normal-risk keratoplasty patients using modern typing
      techniques. METHODS: Penetrating normal-risk keratoplasty was performed in two
      groups of patients (group I with 0-2, group II with 3-6 mismatches in the A/B/DR
      loci). Surgery was done by 3 experienced surgeons according to a standardized
      scheme. Also, postoperative therapy and controls were standardized. There were no
      statistically significant differences between the two study groups as regards
      number of AB0 or H-Y compatibilities, patient age, patient gender, ratio of
      previous intraocular surgery, ratio of triple procedures, indication for surgery,
      follow-up period, donor age, donor gender, post-mortem time of the graft and
      endothelial cell density of the graft at the end of organ culture. HLA typing was
      performed in a quality-controlled laboratory, serologically for HLA class I (A
      and B loci) and moleculargenetically for HLA class II (DR locus). RESULTS: Four
      years postoperatively, the ratio of clear and rejection-free graft survival was
      91% in group I and 67% in group II (Kaplan-Meier estimation, log rank test, p =
      0.03). Monovariate analysis in the Cox model gave no influence of solitary HLA
      class I or II matching, but only an influence of combined HLA class I and II
      matching (p = 0.03). CONCLUSIONS: In this monocenter study with proper typing
      techniques the beneficial effect of HLA class I plus II matching on clear and
      rejection-free graft survival could be demonstrated in a homogenous group of
      normal-risk keratoplasty patients.

PMID- 12494680
TI  - Individual analysis of expected time on the waiting list for HLA-matched corneal
      grafts.
AB  - OBJECTIVE: Recent studies report the beneficial effect of HLA matching for long
      term prognosis of penetrating keratoplasty (kp). This improvement of prognosis,
      however, has to be weighed against the additional time on the waiting list due to
      the search for a HLA-compatible graft. Reliable estimation of this additional
      waiting period is a prerequisite for informed consent on the waiting policy.
      METHODS: A mathematical model based on survival analysis and HLA haplotype
      frequencies was used to estimate time on the waiting list for each of 1,400 HLA
      typed patients registered at the Lions Cornea Bank NRW. Additionally, the waiting
      period of each patient was retrospectively determined. Both values were tested
      for correlation. This analysis was performed for acceptance of up to two
      mismatches on HLA-A, -B and -DR. RESULTS: When accepting two, one and zero
      mismatches, median predicted waiting period was 1 +/- 6, 7 +/- 49 and 17 +/- 159
      months respectively. Median waiting period in retrospective simulation was 1 +/-
      3, 5 +/- 9 and 15 +/- 14 months. Correlation of values from the predictive
      formula and simulation was statistically significant (p < 0.0001). CONCLUSION:
      Predicted time on the waiting list is a valuable tool for management of HLA
      matching in kp.

PMID- 12494681
TI  - Shortage in the face of plenty: improving the allocation of corneas for
      transplantation.
AB  - BACKGROUND: As there are plenty of potential corneal donors, theoretically there
      should be no shortage of corneal grafts. Practically, however, shortages have
      been a problem, especially with HLA-matched corneas, which are increasingly
      requested. This increase requires evaluation and proper adaptation to meet all
      requests in the future. METHODS: BIS' allocation data for corneal transplants
      were analyzed for the years 1998 through 2001. RESULTS: Allocation of matched
      corneas almost doubled in 2000. The waiting list for matched grafts could be
      reduced by one third. CONCLUSIONS: A steep increase in demand for matched grafts
      could be noted by the year 2000. This signifies that the results of positive
      matching studies have ultimately been taken notice of by the ophthalmic surgeons
      with consequent adaptation of their graft orders. BIS has mostly been able to
      cope with these rapidly changing and increasing demands, but more efforts are
      continuously needed to supply those typed and matched corneas within short time.
      Our next step will be to offer HLA-DR matching routinely in addition to the
      current HLA-A/-B matching. We are looking forward with great interest to the
      introduction of even more specified matching algorithms in the not too far
      distant future, and are prepared to meet all the requirements which might be
      associated with such challenges.

PMID- 12494682
TI  - Future HLA matching strategies in clinical transplantation.
AB  - BACKGROUND: HLA matching has shown to be beneficial in clinical transplantation.
      Due to the enormous polymorphism of the HLA system, however, it is not feasible
      to select a completely HLA-matched donor for every potential recipient. Only for
      patients with frequently occurring HLA phenotypes is it realistic to expect a
      well-matched donor within a reasonable waiting time. The majority of patients
      will be transplanted with a partially mismatched donor. In order to select the
      optimal donor for this category of patients, it is important to take advantage of
      the differential immunogenicity and thus differential importance of mismatched
      HLA antigens. METHODS: Based on retrospective analyses of graft survival data and
      in vitro tests measuring T-cell alloreactivity, the relative importance of
      different mismatches was evaluated. RESULTS: It has been possible to define
      acceptable or permissible mismatches with a low immunogenicity, which are
      associated with a good graft survival, versus taboo mismatches with a high
      immunogenicity and a poor graft survival. CONCLUSIONS: Further developing this
      new line of permissible versus taboo mismatches, a new strategy will emerge for
      future HLA matching, which will not only suit a rare number of patients with
      frequent haplotypes but a great percentage of all patients. This principle of
      different immunogenicity of different mismatches can not only be applied to T
      cell alloreactivity as shown here, but also to B-cell alloreactivity, where a
      recently developed computer algorithm (HLA matchmaker) can be instrumental in
      selecting donors with HLA mismatches, which do not lead to alloantibody
      formation.

PMID- 12494683
TI  - The role of minor histocompatibility alloantigens in penetrating keratoplasty.
AB  - BACKGROUND/AIMS: To review the experimental evidence that implicates minor
      histocompatibility (H) antigens in the vulnerability of orthotopic corneal
      transplants to rejection, and to speculate on the possible role of minor H
      antigens in penetrating keratoplasty in humans. METHODS: Orthotopic corneal
      transplantations have been conducted in numerous inbred strains of mice and rats,
      and the fate of these grafts, as well as the immune responses mounted by
      recipients, have been examined in vivo and in vitro. RESULTS: Minor H antigens
      have been found to be more important barriers to the success of orthotopic
      corneal transplants in rodents than have grafts disparate at the major
      histocompatibility complex (MHC). The reasons for this reversal of the
      immunogenetic rules of transplantation reflect unique features of the cornea with
      respect to (a) expression of MHC-encoded molecules, (b) content of class II MHC
      bearing antigen presenting cells, (c) vulnerability to rejection by direct
      alloreactive T cells, and (d) existence of ocular immune privilege. CONCLUSION:
      Since minor H antigens are the major barriers to acceptance of orthotopic corneal
      allografts in rodents, minor H antigens should be considered as important targets
      of rejection in failed penetrating keratoplasty in humans.

PMID- 12494684
TI  - A clinician's outlook on HLA matching for keratoplasty.
AB  - BACKGROUND: A clinician's view of HLA matching for keratoplasty (kp) must
      basically be a rather pragmatic one: as immunosuppressives are getting more and
      more potent with acceptable toxicity, what advantage does HLA matching offer in
      addition to or supplementing immunosuppressives? Also, one wants to know what can
      be expected of further fundamental progress in this field in the future. METHODS:
      The author tries to answer these questions based on three sources: (1) the papers
      in this volume, all written by highly experienced and leading specialists in
      their field; (2) the international kp literature, and (3) the author's own kp
      experiences of 30 years' duration with many clinical studies derived therefrom.
      RESULTS: There is no doubt that HLA matching has a great potential in kp and
      works already well on a statistical basis in high-risk as well as in normal-risk
      patients. In the individual kp patient, however, a decision as to what extent
      current HLA matching would be useful and advisable is a question far less easy to
      answer. This is exemplified by clinical examples. CONCLUSIONS: HLA matching, as
      it is practically feasible now, is recommended as an adjunctive
      immunoprophylactic measure for every patient for whom the calculable waiting time
      is tolerable. Matching should, whenever possible, comprise HLA-A/-B as well as 
      DR matching and should, if possible, be performed on solid molecular grounds. In
      the future, the new 'weighted' concept of permissible versus taboo mismatches
      will become more and more operative and will substitute the current still simple
      matching criteria which can nothing more than respect unweighted numbers of
      fitting alleles. It seems probable that sometime later still more refined systems
      (e.g. 'minors') will supplement or even partially substitute current HLA typing.
      In whichever direction typing and matching will continue to develop in the
      future, it seems clear by now that a systematic start into typing and matching in
      keratoplasty is inevitable for all those surgeons and cornea bankers who want to
      keep on with progress in this field.

PMID- 12494685
TI  - [Shock--2: Therapy of shock: Fluids are necessary].

PMID- 12494686
TI  - [Synchronized cardioversion: baton for harmonic symphony of the heart].

PMID- 12494687
TI  - [Nursing care in cardiac pacemaker therapy: new multiplicity].

PMID- 12494688
TI  - [Nursing care of patients after PTCA: more patient education--less anxiety].

PMID- 12494689
TI  - [Nursing care of patients with heart assist devices: the bridge back into
      (almost) normal life].

PMID- 12494690
TI  - [Nursing care of patients with intra-aortic balloon counter pulsation (IABP):
      recognizing complications early].

PMID- 12494691
TI  - [Terminal phase of life: "We must not become slaves to heroic measures"].

PMID- 12494692
TI  - [Learning in nursing care: matters of the heart].

PMID- 12494693
TI  - [Active management of change in nursing care: using admittation to find nursing
      practice solutions].

PMID- 12494694
TI  - [The Nurnberg Prevention and Education Program: healthy nutrition can be
      learned].

PMID- 12494695
TI  - [Graduate education in patient education and counseling: chronically ill patients
      need help with self-care].

PMID- 12494696
TI  - [Therapy limits and discontinuation from the nursing viewpoint: human dignity
      must be respected].

PMID- 12494697
TI  - [Experiences during an overseas semester of learning in South Africa: black and
      white close-ups].

PMID- 12494698
TI  - [System of nursing education in South Africa: land of contrasts].

PMID- 12494699
TI  - [Students manage a nursing station: rehearsals for reality].

PMID- 12494700
TI  - [Correlation of "self-controlled individual learning responsibility" and
      "practice of manual skills" educational goals exemplified by "skin and physical
      health" class in the nursing curriculum].

PMID- 12494701
TI  - [Non plaque-related gingivitis].
AB  - Gingivitis is a symptom revealing an underlying pathology, mostly due to a
      bacterial accumulation. This explains why for dentists gingivitis is often
      synonymous of a plaque-related gingivitis. This is a dangerous simplification
      since it can be due to very different etiologies, which evidently imply very
      different treatments. This paper illustrates the most frequent causes, not only
      encountered by the periodontologist, but also by the general practitioner, such
      as erosive lichen planus, herpes, Candida and radiotherapy.

PMID- 12494702
TI  - [Clinical relevance of surface characteristics on the formation of plaque on
      teeth and implants].
AB  - The mouth is, from an ecologic point of view, an 'open growth system' with a
      continuous transport of micro-organisms. To cause infection (caries or
      periodontitis) or even to survive in the oral cavity, micro-organisms need to
      attach to one of the available surfaces, otherwise they will be removed by a
      continuous flow of saliva. The mouth, with his ideal growth conditions for micro
      organisms, has many places, called niches, that can be colonised with micro
      organisms. It is not surprising that the mouth is being colonised with more then
      400 different species. This article discusses successively colonisation of the
      oral cavity, bacterial adhesion, plaque growth from a clinical point of view, the
      influence of surface properties on the initial plaque adhesion and maturation,
      and finally important factors influencing the plaque formation on oral implants.

PMID- 12494703
TI  - [The role of periodontal diseases in bad breath].
AB  - The majority of bad breath originates within the oral cavity. However, it is also
      possible that it is caused by other extra-oral sources. Ear-nose-and-throat
      causes and systemic diseases, such as diabetes mellitus, uremia, liver failure,
      pulmonary carcinoma, bronchiectasis, are the most frequent problems. In 65-85% of
      the cases of bad breath, we find the cause in the parodontium and/or tongue.
      Components from tongue coating and periodontal pockets circulate through the
      saliva in the whole oral cavity and also reach the tonsils.

PMID- 12494704
TI  - [Full mouth one stage disinfection of the oropharynx. A new treatment strategy
      for periodontitis].
AB  - Most periodontal pathogens colonise different niches such as the oral mucosa,
      tongue, saliva, periodontal pockets, all hard intra-oral surfaces and the
      tonsils. Since intra-oral translocation of these pathogens between these niches
      is possible, a 'one stage' disinfection of the whole mouth in one or two
      consecutive days as treatment strategy for periodontal infections must be
      considered. A one stage full-mouth disinfection is achieved by a scaling and root
      planing of all periodontal pockets within 24 hours, in combination with a
      chlorhexidine application in all niches (subgingival irrigation, mouth wash,
      brushing of the tongue, and spray for the pharynx). As such, reinfection by
      bacteria of recently instrumented sites is inhibited. This approach results in
      significant additional clinical and microbiological results compared to the
      classical approach (scaling and rootplaning per quadrant with several days or
      weeks between each session).

PMID- 12494705
TI  - [Guided bone augmentation in edentulous areas].
AB  - The use of autogenous onlay blocks placed together with self-tapping implants can
      achieve an excellent long-term success rate of individual implants. Autogenous
      bone chips or deproteinized bovine bone can be used to deal with fenestration and
      dehiscence defects when used in combination with e-PTFE membranes. The role of
      DFDBA as space maintainer under barrier membranes cannot be ignored. In most
      cases PTFE membranes are used because they offer reliable results. The use of a
      collagen membrane when supported by a bone substitute to maintain space gives
      good results, although long-term research is required. The future will be however
      tissue engineering. The principle is that a matrix, carrying stem cells and
      biological mediators like growth factors, is used. More research involves the use
      of human stem cells responsible for regeneration of different human tissues.

PMID- 12494706
TI  - [Are antibiotics effective in the treatment of periodontitis?].
AB  - Antibiotics are promoted for the treatment of periodontitis as an adjunct to
      mechanical debridement. Numerous studies have shown that some topically and
      systemically administered antibiotics provide an improved short-term clinical
      effect if used as an adjunct to scaling and rootplaning. However, the few long
      term studies (> 5 years) question the clinical relevance.

PMID- 12494707
TI  - [How threatening is periodontitis? Effects of periodontitis on the human body].
AB  - Periodontitis is a chronic inflammatory process which is not only threatening for
      the dentition. Bacteriae and their substances can enter the bloodstream by
      eating, toothcleaning or dental treatment and harm the body. Known are heart
      valve infections by S. sanguis, but also pneumonia is seen more in patients with
      periodontitis. Recently it appears that periodontitis is probably the main course
      of preterm low birthweight babies. It has also been shown that there exists a
      close association between periodontitis and cardiovascular diseases.
      Investigations even suggest that this might be a causal relation.

PMID- 12494708
TI  - [Preoperative radiological planning for oral implants].
AB  - For patients who lost one or more teeth, oral osseointegrating implants can offer
      a natural and solid solution. In order to rehabilitate (partially) edentulous
      patients with oral implants, a surgical intervention is inevitable. It is
      therefore of utmost importance that both esthetical and biomechanical demands are
      met in as few interventions and as little time as possible, which makes a
      thorough preoperative examination of the edentulous region mandatory. Radiographs
      of different kinds offer the possibility to evaluate bone volume and--to a lesser
      extent--quality of the area to be rehabilitated. It should however be kept in
      mind that radiography necessarily brings about a certain amount of possible
      detrimental radiation burden. Selection of the appropriate radiographic technique
      should therefore be based on a well thought-out balance between diagnostic value
      and risk level of the intervention on the one hand and radiation burden on the
      other.

PMID- 12494709
TI  - [Plastic periodontal surgery].
AB  - In this article some indications and procedures of mucogingival and plastic
      periodontal surgery are reviewed. Frenectomy, vestibulary extension and free
      gingival graft, which all are widely used among periodontitsts, are described. In
      the second part of this review different surgical methods for covering recession
      like periodontal defects are discussed. The clinical results of coronally
      advanced flap, connective tissue graft, and guided tissue regeneration are
      compared. The preference of the Nijmegen periodontal clinic to use coronally
      advanced flap--with or without connective tissue graft--is explained.

PMID- 12494710
TI  - [Acute myeloid leukemia].

PMID- 12494711
TI  - Undergraduate training in the atraumatic restorative treatment (ART) approach--an
      activity report.
AB  - The Division of Public Oral Health at the University of the Witwatersrand
      conducted a 2-week ART training course for 5th year dental students in the School
      of Oral Health Sciences. Students were taught both theoretical knowledge and
      clinical skills in ART. Course evaluation showed that the course achieved its
      aims and objectives and was considered a worthwhile experience by students.
      However, there were some limitations to the format of the programme. We recommend
      that ART should be integrated as part of clinical student training in the BDS
      curriculum.

PMID- 12494712
TI  - Microscope observations of ART excavated cavities and restorations.
AB  - This in vitro light and scanning electron microscope study examined 39 extracted
      tooth specimens, hand excavated and restored according to atraumatic restorative
      treatment (ART), using 'press finger', by 'skilled' and 'novice' operators.
      Surface features of five excavated cavities, 12 restoration surfaces and the
      tooth restoration relationships of 22 bisected restored tooth crowns were
      examined to better understand the clinical effect of the technique. Hand
      excavated cavity surfaces were rough with a complex surface arrangement of
      grooves, crevices, ridges, furrows and overhangs. Enamel and dentine were covered
      with debris except where surface fractures exposed enamel prisms and occluded
      dentinal tubules. Ten of the 22 bisected restored specimens had large voids (1-3
      mm in length) within the glass-ionomer cement (GIC) restoration or at the tooth
      restoration interface. Smaller bubbles (< 50 microns) and irregular shaped
      inclusions were common in all restorations. Adaptation of the GIC to the cavity
      margin was extremely variable and easily distinguished from the effects of
      dehydration shrinkage. It is thought that cavity surface irregularities could
      cause placement problems making it difficult to adapt the GIC to cavity
      peripheries. While 'press finger' enabled excellent penetration of GIC into
      fissures, the technique left restoration surfaces rough. At low magnification,
      surfaces were irregular; at magnifications higher than X500 scratches, pits,
      porosities, chipping and voids were evident. However, the 'press finger'
      technique was able to merge the GIC to a fine edge on the occlusal surface so
      that the restoration margin was not obvious. No apparent difference was found
      between the restorations placed by the 'skilled' and 'novice' operators. Tooth
      restoration relationships in the ART approach are entirely different to those of
      traditional restorative techniques. The ART approach requires skill, diligence
      and comprehension to be undertaken correctly.

PMID- 12494714
TI  - Allergic reactions caused by dental restorative products.

PMID- 12494713
TI  - One-year evaluation of atraumatic restorative treatment and minimum intervention
      techniques on primary teeth.
AB  - Atraumatic restorative treatment (ART) and minimal intervention treatment (MIT)
      techniques were evaluated under field conditions in 5 regions of the Western Cape
      Province of South Africa, where caries prevalence exceeds 60% and remains mostly
      untreated. The purpose of the study was to compare and evaluate results of ART
      and MIT techniques in the primary dentition of 6-9 year-old schoolchildren using
      glass-ionomer (GI) (Fuji IX) and compomer (Dyract AP) materials. At baseline 401
      children were treated, and 1,119 restorations placed by 5 calibrated dentists,
      53% with ART (using hand instruments only) and 47% with MIT (minimal use of slow
      hand-piece) techniques. Evaluations were done with a CPI periodontal probe to
      measure marginal defects and to detect decay. A pain assessment for the
      restoration procedures indicated that 80% of subjects experienced no pain, 18%
      discomfort and slight pain, and 2% required local anaesthetic. After one year
      90.5% of subjects and 80% of restorations were followed up (11.1% lost as a
      result of exfoliation); of these restorations 86% were clinically acceptable
      (84.1% of the ART and 88% of the MIT). With the art technique 82.7% of GI
      restorations and 85.6%, of compomer restorations were acceptable. With the MIT
      technique 86.5% of GI restorations and 89.9% of compomer restorations were
      acceptable. Success of restorations per region varied significantly: regions 1
      and 2-90%, region 3-80%, region 4-70% and region 5-95%. There were no significant
      statistical differences in respect of materials or methods employed. ART and MIT
      techniques were well accepted as complementary caries approaches by operators.
      One-year results show that ART and MIT techniques were successful, substantiating
      its use for the primary dentition in areas with high caries prevalence. Longer
      term assessments are required.

PMID- 12494715
TI  - General practitioner's radiology case 5. Supragingival calculus.

PMID- 12494716
TI  - There is a time for every purpose under heaven....

PMID- 12494717
TI  - Consumer drop-in centers: operations, services, and consumer involvement.
AB  - Interest in involvement of consumers in mental health and psychiatric
      rehabilitation services delivery has expanded in recent years, encompassing self
      help approaches, consumers employed as providers in formal agencies, and
      consumers operating their own services. This study reports results from in-depth
      phone surveys conducted with 32 consumer drop-in centers in Michigan. Results
      indicate that centers operate in many ways like other human services businesses,
      albeit with much smaller budgets. Funding levels, salaries, and services showed
      great heterogeneity among the centers and in comparison with reports in the
      literature. Centers autonomously run by consumers and centers with consumer
      involvement (operated by a non-consumer agency) were found to differ
      significantly on several variables, including consumer control, funding and
      service levels, and challenges. Implications for the growth and increased use of
      consumer drop-in centers are discussed.

PMID- 12494718
TI  - Tracking change in psychological distress among homeless adults: an examination
      of the effect of housing status.
AB  - Although research has documented the endemic nature of psychological distress
      among homeless people, little is known about the variation of and change in
      distress when psychiatric disabilities and housing status are considered. Using
      longitudinal data from a homeless sample, the author examined the pattern of
      distress across three groups--people with serious mental illness (SMI), people
      with drug or alcohol problem, and people with neither diagnosis. Distress
      symptoms were most pervasive and persistent among people with SMI. The effect of
      housing status on distress differed across the three groups and was statistically
      significant for people with no psychiatric diagnosis.

PMID- 12494719
TI  - Social work in restructuring hospitals: program management five years later.
AB  - Hospital restructuring in North America has involved re-engineering, downsizing,
      reorganizing, and remodeling of traditional hierarchical functional organizations
      into multisite programmatic conglomerates. The implications for professional
      disciplines have been dramatic in that departments such as social work have been
      dismantled and social work practice has come under the domain of program managers
      representing multiple disciplines. In this study 12 hospitals in Ontario, Canada,
      that were studied in the early stages of restructuring in 1995 expanded to 22
      sites by 1999. The effect of the mergers and moves to program management on the
      social work profession was examined. The key findings are that social work line
      positions were not lost, but accountability and recruitment were no longer in the
      hands of the discipline. These findings suggest that it is more critical now than
      ever for social workers to champion their contributions to health.

PMID- 12494720
TI  - Parenting adolescents with attention deficit hyperactivity disorder: analysis of
      the literature for social work practice.
AB  - Parenting an adolescent with ADHD presents a number of unique challenges and
      stressors. Social workers can play an important role in providing psychosocial
      therapies for clients with ADHD and their families. However, practice with this
      population has not been well-addressed in the social work literature. This
      article analyzes theories of parenting stress; stress, appraisal, and coping
      theory; and the research literature about parenting and ADHD, with a focus on
      relevance for social work practice.

PMID- 12494721
TI  - Predictors of psychological well-being among assisted-living residents.
AB  - Assisted-living facilities are a rapidly growing source of supportive housing for
      frail elderly people. This study examined the psychological well-being of elderly
      assisted-living residents and factors associated with well-being. Participants
      were nondemented elderly residents of an assisted-living community in the urban
      southeast. Depression, life satisfaction, and demographic, health, and social
      support variables were measured through face-to-face interviews. A sizeable
      minority of the residents reported high levels of depressive symptoms and low
      life satisfaction. Female gender, self-reported health, functional impairment,
      perceived social support, and participation in activities were significantly
      associated with well-being. The predictive value of gender and health variables
      were reduced when social support was introduced. Implications for policy and
      social work practice are discussed.

PMID- 12494722
TI  - Medication Assistance Program: University of Missouri Health Care Department of
      Social Services.

PMID- 12494723
TI  - Crisis in caregiving: a call to action.

PMID- 12494724
TI  - Long-term care for people with developmental disabilities.

PMID- 12494725
TI  - Ethical issues in the social worker's role in physician-assisted suicide.

PMID- 12494726
TI  - Loratadine is viable in patients with geriatric rhinitis.

PMID- 12494727
TI  - HRT: getting a perspective on the WHI and what women need.

PMID- 12494728
TI  - Pruritic, blistering eruption. Lesions on the elbows, knees, and lower back not
      caused by allergens.

PMID- 12494730
TI  - Pain perception in the older patient. Using the pain hologram to understand neck
      and shoulder pain.
AB  - Pain is a common complaint and its perception is a complex issue. The older
      person with neck and shoulder pain may have contributions to that pain from
      multiple and diverse sources. These can range from nociceptive stimulation,
      neurologic sensitization, emotional issues, socio-cultural biases, cognitive
      interpretation and meanings of the pain to that person, concurrent medical and
      psychiatric illnesses, and memory (both pain and non-pain related memories). The
      affective dimension of pain can be more influential on a person's ultimate pain
      experience than the sensory-discriminative component, and both must be understood
      for each patient, in terms of it's relative weight in each pain. Neck and
      shoulder pain can represent eudynia and maldynia, or concurrent existence of
      both. To properly treat patients with this complaint, physicians must understand
      what comprises each individual's pain hologram and direct treatment at as many
      component parts as possible.

PMID- 12494731
TI  - Substance abuse in older adults. An overview.
AB  - Substance abuse among older adults, including abuse of alcohol and prescription
      and over-the-counter drugs, has been called an invisible epidemic. Signs and
      symptoms of abuse in older adults vary from those presented in younger persons
      and this variation can complicate the diagnosis. Validated screening tools, such
      as CAGE and MAST-G, can aid diagnosis, but primary care physicians also need to
      be alert to suspicious medical conditions often associated with substance use
      disorders. Treatment goal is almost always abstinence; although efficacy remains
      uncertain, brief interventions by primary care physicians are recommended when
      patients are identified as at-risk. Pharmacotherapies may be used, but caution is
      advised due to associated side effects. Physicians may even be able to prevent
      the development of benzodiazepine dependence by prescribing alternative
      treatments for anxiety and depression in this population.

PMID- 12494732
TI  - Depression in late life. An historic account demonstrates the importance of
      making the diagnosis.
AB  - Depression in older patients is common and responds well to treatment, yet the
      diagnosis is often missed. Not only has this conclusion been confirmed by recent
      research, it also was suggested years ago in the famous case of Ebenezer Scrooge.

PMID- 12494733
TI  - [Negotiation in the geriatric evaluation, trap or reality?].

PMID- 12494734
TI  - [Evaluation of residents' and families' satisfaction, a quality improvement
      tool].

PMID- 12494735
TI  - [Respecting sleep rhythms, a health promotion program for the elderly].

PMID- 12494736
TI  - [Quality care, nurses' hope].

PMID- 12494737
TI  - [Dealing with Alzheimer's disease. 1/6--communication].

PMID- 12494738
TI  - [Working in geriatrics: challenged ethics?].

PMID- 12494739
TI  - [Aggression in institutions for the elderly].

PMID- 12494740
TI  - [Risk of contagious epidemics in geriatric institutions].

PMID- 12494741
TI  - Bioterrorism preparedness for local health departments.
AB  - Bioterrorism preparedness has not traditionally been an everyday concern of local
      public health departments. The likely first responders to a biological
      bioterrorism event will be local public health personnel. The events of September
      11, 2001, and the anthrax crisis that followed tested the capabilities of the
      public health system and demonstrated its fragility. Little federal funding has
      trickled down to local health departments, and they have not been included in
      planning or training for bioterrorism preparedness. Now local health departments
      must develop detailed bioterrorism response plans. Effective plans will involve
      internal assessment of strengths and weaknesses and strategizing with other local
      community agencies. Our health department is a suburban county agency that serves
      a population of over 250,000. We have started this self-assessment and planning
      process. This bioterrorism guide has provided some structure for us and may be
      helpful for other local health departments as they begin this process.

PMID- 12494742
TI  - A comparison of chronic pain between an urban and rural population.
AB  - Residents of rural and urban areas of North Dakota were surveyed regarding
      chronic pain. Participants (N = 188) responded to questions pertaining to the
      prevalence and characteristics of chronic pain, quality of life, and social
      support. Overall, 58% of the participants reported chronic pain, with arthritis
      as the leading cause, the lower back as the main location, and oral medication as
      the most common treatment. Individuals from rural and urban locations differed
      significantly in the rate of chronic pain reported. Participants with chronic
      pain reported a significantly lower quality of life than individuals without
      chronic pain.

PMID- 12494743
TI  - Challenges in home care practice: a decision-making perspective.
AB  - A qualitative approach using an ethnographic design was used to investigate the
      nature of clinical decision making in home care practice from home care nurses'
      perspective. In-depth interviews were conducted with experienced home care nurses
      (N = 16) in addition to observations of nurses during meetings and client visits.
      The findings indicate that the decision-making challenges involved in home care
      practice consisted of the following 4 major categories: (a) challenges that arise
      in the development of client-centered care plans, (b) challenges that arise from
      the home care practice environment, (c) challenges related to developing
      confidence in clinical decision making, and (d) challenges in ethical decision
      making. Education and practice recommendations for enhancing clinical decision
      making are also discussed.

PMID- 12494744
TI  - Why rural elders drive against advice.
AB  - The purpose of this study was to describe the reasons rural elders continue to
      drive against the advice of health professionals, family, or friends. Interviews
      were conducted with a convenience sample of 45 older adults living in isolated
      communities with populations ranging from 225 to 8,700 residents. Findings
      suggest that declining health was the primary reason the participants were
      advised to stop driving. They refused to do so because they did not believe they
      were unsafe, valued their independence, and feared isolation if they could not
      drive. Significant reassurance that they would not be forgotten would be required
      for them to stop driving.

PMID- 12494745
TI  - Psychosocial determinants of cigarette smoking among college students.
AB  - Although the prevalence of cigarette smoking among adolescents and adults
      consistently declined in the past decade, smoking among college students rose
      sharply. To reduce the morbidity and premature mortality caused by smoking,
      antismoking interventions need to target this vulnerable population. Anonymous
      self-report data were collected from a convenience sample of 224 college students
      who voluntarily completed a Web-based survey developed to assess the relation of
      risk-taking tendency, depression, social normative beliefs, and smoking
      resistance self-efficacy to cigarette smoking behavior. Employing structural
      analysis using LISREL (Joreskog & Sorbom, 1996), all 4 factors were confirmed as
      determinants of smoking. Resistance self-efficacy, the only direct antecedent,
      mediated the link to risk-taking tendency, depression, and social normative
      beliefs. Antismoking interventions that focus on enhancing refusal skills and are
      delivered to homogeneous groups are proposed as an effective approach to reducing
      cigarette smoking among college students.

PMID- 12494746
TI  - 1H-NMR assay of papaverine hydrochloride and formulations.
AB  - A precise and specific 1H-NMR method has been developed for the assay of
      papaverine hydrochloride (1) as a bulk drug, as well as in tablet and injection
      dosage forms. The assay depends upon the integration of the 12 protons of the
      four methoxy groups of 1 relative to that of the three methyl protons of
      acetanilide (internal standard). In addition to the accurate quantitative
      determination of 1, the method provides a specific means of identifying 1 as well
      as detecting other alkaloids or impurities.

PMID- 12494747
TI  - Identification of triterpene saponins in Quercus robur L. and Q. petraea Liebl.
      Heartwood by LC-ESI/MS and NMR.
AB  - A detailed structural study of the major acidic triterpene saponins from European
      oak heartwood, Quercus robur L. and Q. petraea Liebl., revealed the presence of 2
      alpha,3 beta,19 alpha-trihydroxyolean-12-ene-24,28-dioic acid (1), 2 alpha,3
      beta,19 alpha-23-tetrahydroxyolean-12-ene-24,28-dioic acid (2), and their
      corresponding glycosides, 28-beta-D-glucopyranosyl-2 alpha,3 beta,19 alpha
      trihydroxyolean-12-ene-24,28-dioic acid (3), and 28-beta-D-glucopyranosyl-2
      alpha,3 beta,19 alpha,23-tetrahydroxyolean-12-ene-24,28-dioic acid (4). Compounds
      were isolated and purified by successive flash chromatography and semi
      preparative HPLC, and structurally determined by NMR and LC-ESI/MS in the
      negative ion mode. Compounds 2 and 4 have been identified for the first time in
      Quercus species and are new compounds.

PMID- 12494748
TI  - Solid-phase extraction and reversed-phase high-performance liquid chromatography
      of the five major alkaloids in Narcissus confusus.
AB  - A novel, fast and precise method, combining solid-phase extraction and reversed
      phase high-performance liquid chromatography is described for the quantitative
      determination of five alkaloids (galanthamine, N-formylnorgalanthamine,
      haemanthamine, homolycorine and tazettine/pretazettine) from bulbs of wild
      Narcissus confusus, a high galanthamine-containing plant species growing in the
      Iberian Peninsula.

PMID- 12494749
TI  - Identification of isomeric dicaffeoylquinic acids from Eleutherococcus senticosus
      using HPLC-ESI/TOF/MS and 1H-NMR methods.
AB  - Liquid chromatography-electrospray time-of-flight mass spectrometry (HPLC
      ESI/TOF/MS) and a novel NMR technique, developed to maximise the sensitivity
      obtained from the standard NMR spectrometer, have been applied to the
      identification of the phenolic constituents of Eleutherococcus senticosus. In
      addition, molecular modelling and dihedral bond angle calculations based on the
      vicinal 3JHH-coupling constants have been used in the unambiguous assignment of
      signals in the 1H-NMR spectra. 5'-O-Caffeoylquinic acid and three isomeric
      compounds, 1',5'-O-dicaffeoylquinic acid, 3',5'-O-dicaffeoylquinic acid and 4',5'
      O-dicaffeoylquinic acid, have been isolated and identified from a sample. The
      isolation and structure determination of the latter two compounds are reported
      for the first time from this plant.

PMID- 12494750
TI  - Stereochemical assignment of naturally occurring 2,3-epoxy-2-methylbutanoate
      esters.
AB  - A method to determine the absolute configuration of 2,3-epoxy-2-methylbutanoate
      ester residues in natural products is presented, based on (i) the reduction of
      the ester function to yield a 2-methyl-1,2-butanediol, (ii) esterification of the
      obtained primary alcohol with either (R)-(+)- or (S)-(-)-Mosher's acid to afford
      the corresponding Mosher's ester, and (iii) 1H-NMR spectral comparison of the
      final product with that of the Mosher's esters prepared from 2-methyl-1,2
      butanediols of known stereochemistry.

PMID- 12494751
TI  - An HPLC method for the direct assay of the serotonin precursor, 5-hydroxytrophan,
      in seeds of Griffonia simplicifolia.
AB  - 5-Hydroxytryptophan (1) is a naturally occurring amino acid found in significant
      levels in seeds of Griffonia simplicifolia and used in the treatment of the
      numerous effects of serotonin deficiency syndrome. An HPLC method has been
      developed for the direct assay of 1 in seeds of G. simplicifolia which overcomes
      the problems associated with previous techniques. By optimising the solvent
      extraction procedures and the HPLC conditions, levels of 1 could be estimated
      following a single-step seed extraction. The chromatographic conditions, solvent
      system and the extraction technique developed make this method relatively simple,
      fast and efficient. Using the described methods, the highest ever levels of 1
      (namely, 20.83% on a fresh weight basis) have been determined in seeds of G.
      simplicifolia obtained in Ghana.

PMID- 12494752
TI  - Capillary zone electrophoresis of syringyl and guaiacyl monomers resulting from
      lignin thioacidolysis.
AB  - A capillary zone electrophoretic method has been developed for the quantitative
      determination of syringyl (S) and guaiacyl (G) monomers resulting from lignin
      thioacidolysis. The effects on the separation of altering a number of parameters
      have been investigated, resulting in an efficient and rapid separation. Analysis
      times were about 10 min instead of 50 min for the conventional GC methods, with
      no requirement for a derivatisation step prior to analysis. Relative standard
      deviations ranged between 8 and 12% for the absolute determination of S and G
      monomers, and between 1.4 and 3.5% for the S/G ratio.

PMID- 12494753
TI  - Analysis and quantitative determination of group B saponins in processed soybean
      products.
AB  - Pure analytical standards for the major saponins present in processed soy
      products, the group B saponins (soyasaponins I, II, III and IV), were isolated in
      mg quantities by a combination of processing, precipitation/re-solubilisation,
      TLC and preparative HPLC. These standards were determined to be pure by LC-ESI/MS
      analysis and NMR. The standards were used to perfect a facile analytical HPLC
      method using spectrometric detection to determine the percent composition of the
      group B soyasaponins in various products from processing of soybean.

PMID- 12494754
TI  - Application of centrifugal force to the extraction and separation of
      parasorboside and gerberin from Gerbera hybrida.
AB  - A method for the separation of parasorboside and gerberin from the ornamental
      plant Gerbera hybrida (Asteraceae) has been developed. The two closely related
      glucosides were extracted using an Extrachrom instrument, a prototype multi
      functional separation tool equipped with an extraction chamber. The rotation
      planar extraction procedure was compared with that of a medium pressure solid
      liquid extraction system. The resulting extracts were pre-purified using rotation
      planar chromatography and the results compared with those obtained using medium
      pressure liquid chromatography with silica gel as the stationary phase and a
      mobile phase of methanol:ethyl acetate:tetrahydrofuran at selectivity point Ps =
      111 with 1% formic acid as modifier. The title compounds were isolated from the
      purified extracts by TLC and their structures confirmed by 1H- and 13C-NMR
      spectroscopy.

PMID- 12494755
TI  - Anthocyanin composition of the fruit of Coriaria myrtifolia L.
AB  - The anthocyanin composition of the fruit of Coriaria myrtifolia L. and the
      changes which occur during ripening were studied using HPLC-PAD and LC-MS. Ten
      anthocyanins were detected and identified by their absorption and mass spectra as
      the 3-glucoside and 3-galactoside derivatives of delphinidin, cyanidin,
      petunidin, peonidin and malvidin. Fruit ripening was accompanied by substantial
      changes in the anthocyanin profile, with methoxylated anthocyanins, i.e. malvidin
      and peonidin, predominating in the final stages of ripening, and the
      trihydroxylated anthocyanin, delphinidin, during the earlier stages. Furthermore,
      galactoside derivatives were more abundant than glucosides in the ripe fruit. At
      full maturity, the fruits of C. myrtifolia were very rich in anthocyanins with a
      content of 10.7% (on a dry weight basis), a level which is higher than that found
      in most fruits usually considered to be anthocyanin-rich. The ability to grow C.
      myrtifolia in damaged and nitrogen poor soils, together with the possibility of
      using this plant for the extraction of anthocyanin, makes it ideal for
      consolidating soils and repopulating semi-desert or fire-damaged areas.

PMID- 12494756
TI  - Extraction of phyllanthusols A and B from Phyllanthus acidus and analysis by
      capillary electrophoresis.
AB  - Extracts of roots Phyllanthus acidus were examined by free zone capillary
      electrophoresis, micellar electrokinetic chromatography (MEKC), and MEKC using
      the sweeping technique which involves application of a negative potential to the
      inlet end of the capillary and very much longer than conventional injection
      times. The latter technique, using a buffer of 50 mM sodium dihydrogen phosphate
      (pH 2) containing 80 mM sodium dodecylsulphate and 30% methanol was found to
      allow complete resolution of the active constituents of P. acidus, phyllanthusols
      A and B, from each other and from other extracted components in under 30 min.
      Several other components could be detected when hydrodynamic injection times of
      500 s were used. The separation, combined with an appropriate extraction
      procedure and using an internal standard of proguanil, permitted quantification
      of both phyllanthusols. Calibrations were linear over the range 2-8 micrograms/mL
      for phyllanthusol A, and 1-4 micrograms/mL for phyllanthusol B. Within-day and
      day-to-day repeatability RSDs were below 10%, and the precision of extraction RSD
      was around 14%. The limits of quantification and detection were 0.55 and 0.24
      microgram/mL, respectively.

PMID- 12494757
TI  - Direct determination of alkaloid contents in Fumaria species by GC-MS.
AB  - The isoquinoline alkaloids protopine, cryptopine, sinactine, stylopine,
      bicuculline, adlumine, parfumine, fumariline, fumarophycine, fumaritine,
      dihydrofumariline, parfumidine and dihydrosanguinarine have been determined and
      identified by gas chromatography-mass spectrometry in Fumaria agraria, F.
      bastardii, F. capreolata, F. sepium, F. densiflora, F. faurei, F. officinalis
      subsp. officinalis, F. parviflora, F. petteri subsp. calcarata and F.
      macrosepala. The chemotaxonomic significance of the results is discussed.

PMID- 12494758
TI  - Determination of the diterpenoid, kaurenoic acid, in Annona glabra by HPLC.
AB  - The isolation of ent-kaur-16-en-19-oic acid (1) from the leaves and bark of
      Annona glabra and its determination by reversed-phase HPLC with a photodiode
      array detector is described. The results indicate that 1 accumulates in the bark
      of the plant with only very low concentrations in the leaves. Levels of 1 varied
      throughout the year being highest for bark and leaves in the autumn (5.29 +/-
      0.23 and 0.27 +/- 0.01 mg/g dry weight, respectively) and lowest in the spring
      for bark and in the winter for leaves (4.00 +/- 0.25 and 0.11 +/- 0.01 mg/g dry
      weight, respectively).

PMID- 12494759
TI  - NMR shift data of neo-clerodane diterpenes from the genus Ajuga.
AB  - The complete assignment of the NMR spectra of ajugarin I and ajugareptansin, as
      models for other neo-clerodane diterpenoids isolated from the genus Ajuga, is
      reported in order to improve their usefulness as reference compounds. Conflicting
      NMR shift data for some members of this group are discussed, and plausible
      reassignments are proposed [i.e. the identity of ajugacumbin C and ajugamarin A2;
      the revision of ajugacumbin D as 12-hydroxyajugacumbin A, and of ajugacumbin E as
      12-hydroxy-1-(3-hydroxy-2-methylenebutanoyloxy)ajugarin I] in order to provide a
      unified basis for future use.

PMID- 12494760
TI  - Biology of aging.

PMID- 12494761
TI  - Prediction and statistical analysis of alternatively spliced exons.

PMID- 12494762
TI  - Multiple roles of the SR protein family in splicing regulation.

PMID- 12494763
TI  - Heterogeneous nuclear ribonucleoprotein particle A/B proteins and the control of
      alternative splicing of the mammalian heterogeneous nuclear ribonucleoprotein
      particle A1 pre-mRNA.

PMID- 12494764
TI  - Phosphorylation-dependent control of the pre-mRNA splicing machinery.

PMID- 12494765
TI  - Splicing regulation in Drosophila sex determination.

PMID- 12494766
TI  - Alternative pre-mRNA splicing and regulation of programmed cell death.

PMID- 12494767
TI  - Alternative pre-mRNA splicing and neuronal function.

PMID- 12494769
TI  - Critical alarms and patient safety. ECRI's guide to developing effective alarm
      strategies and responding to JCAHO's alarm-safety goal.
AB  - Alarm-safety issues are nothing new in healthcare. ECRI, for example, has
      emphasized the importance of alarm safety for many years. Yet patients continue
      to be injured or killed because of ineffective alarm coverage, inappropriate
      alarm use, and failure to hear alarms. And countless "near miss" incidents occur
      that are never reported. In July of this year, the U.S. Joint Commission on
      Accreditation of Healthcare Organizations (JCAHO) intensified the focus on this
      topic in U.S. hospitals by making alarm safety one of its National Patient Safety
      Goals for 2003. Hospitals addressing JCAHO's recommendations for meeting this
      goal need to know what to do and what not to do. This special Guidance Article
      provides advice on just what JCAHO expects, how U.S. hospitals should respond to
      its initiative, and how much in the way of time and resources will be required.
      In addition, we detail our broad-based recommendations on improving alarm safety,
      which cover issues that are common to healthcare institutions around the world.

PMID- 12494768
TI  - Modulation of alternative splicing by antisense oligonucleotides.

PMID- 12494770
TI  - Lost arrhythmia detection on Datascope PatientNet central station during leads
      off condition is not evident at bedside.

PMID- 12494771
TI  - Maintaining public access AEDs.

PMID- 12494772
TI  - Broken standoffs in Control Desk of Stockert SIII heart-lung machine may delay
      oxygenated blood flow to patients.

PMID- 12494773
TI  - Embrittled catheters in some Allegiance Pharmaseal Thoracentesis Trays may break
      or crumble inside the patient.

PMID- 12494774
TI  - [What is the role of polyclinical medical university in the hospital-university
      affiliation?].

PMID- 12494775
TI  - [Medical research in general medicine: activities of the Lausanne General
      Medicine Division].
AB  - Primary care research activities conducted by the General Medicine Division of
      Lausanne are described here in the light of three studies: practitioners use of
      ultra-sonographic examinations, early detection of vitamin B12 deficiency and
      interaction between iron deficiency and fatigue by young women. Primary care
      research interest as well as its limits and difficulties are discussed.

PMID- 12494776
TI  - [Hypertension -- therapeutic observation: the medical impression of telemetry].

PMID- 12494777
TI  - [Quality aspects of digestive system endoscopy].

PMID- 12494778
TI  - [Of what value is an antitubercular dispensary in our age?].
AB  - The TB Dispensary of Lausanne, included in the University Medical Policlinic, is
      a specialized unit dealing with TB, mainly among underserved population. Several
      studies have been conducted on the clinical and epidemiologial aspects of TB and
      about the management of the disease in risk groups, mainly migrants.

PMID- 12494779
TI  - [Malaria.02: research for a world-wide exposition].
AB  - To reduce malaria-attributable mortality, there is a need to improve the
      diagnosis, to develop new drugs and vaccines, and to promote evidence-based case
      management. Following a case/control study aimed at identifying clinical and
      laboratory predictors of malaria, we made a systematic review on fever in
      returning travelers. We then developed evidence-based guidelines for these
      febrile patients. The next step is to assess the feasibility and safety of these
      web-based guidelines in the context of primary care. As far as the prevention is
      concerned, the Medical Outpatient Clinic (MOC) is collaborating to the pre
      clinical and clinical development of several malaria vaccines: one of them
      (Combination B), including three proteins of the asexual blood stage (MSP1, MSP2,
      RESA), has already shown a remarkable efficacy to reduce parasite density in
      Papua New Guinean children: The MOC is thus heavily involved in research for the
      health of travelers, as well as the one of populations living in poor countries.
      Prevention and treatment of defavorised populations represents indeed one of the
      specific mission of the Medical Outpatient Clinic.

PMID- 12494780
TI  - [General cardiology: an extinct path?].

PMID- 12494781
TI  - [Dyslipidemias and cardiovascular diseases: towards a new perspective].
AB  - During the last decades, new developments in the detection and therapy of
      dyslipidemia provided a firm conviction for the efficacy and the safety of lipid
      lowering therapies in primary and secondary prevention of cardiovascular
      diseases. To be cost-effective in primary prevention, the statin-therapy needs to
      select high risk patients. According to the guidelines, the global assessment of
      cardiovascular risk is based on traditional risk factors (RF-CV). The emergence
      of new RF-CV is helpful. However, at every level of risk factor exposure, there
      is a substantial variation of atherosclerosis. Thus, subclinical disease
      measurements, representing the end result of risk exposure may be useful for
      improving cardiovascular risk prediction. Using the high resolution B-mode
      ultrasound to detect plaques both on femoral and carotid arteries in asymptomatic
      patients, our results show the advantages and limits of a non invasive method to
      improve the selection of eligible patients requiring a more aggressive lipid
      lowering therapy.

PMID- 12494782
TI  - [Dental medicine and medicine].
AB  - The objective of "oral medicine" is to integrate medical knowledge and dental
      knowledge. This article emphasizes the importance of such integration in the
      management of medically compromised patients by the dentist. The aging population
      and the increasing number of medically compromised patients result in a situation
      where the dentist must adapt the diagnosis ant the treatment of oral lesions to
      both the patient general history and the patient medication history. The main
      systemic diseases affecting oral health are reviewed, emphasizing the care
      required by this category of patients, the importance of links between medicine
      and dentistry and the requirements for graduate and postgraduate education in
      comprehensive medicine.

PMID- 12494783
TI  - [Management of tuberculosis in an region where it is not enedemic: what lessons
      have been learned from the Valais experience?].

PMID- 12494784
TI  - [Hepatitis C].

PMID- 12494785
TI  - [Production, society and management of addiction: some lessons from a quarter
      century of public health].

PMID- 12494786
TI  - [Pharmaceutical chemistry of "dipines"].
AB  - The paper gives an overview on the pharmaceutical chemistry of of dihydropyridine
      Ca-antagonists through the chapters of history and preparation, structure and
      properties, metabolism, therapeutical use and analysis. In the author's concept
      the paper represents a model for postgraduate education. Consequently, after
      proper volume-cutting, it covers the complete material for undergraduate courses.

PMID- 12494788
TI  - [The background of acid-base interactions in nonaqueous solvents--an analytical
      approach].
AB  - The acid-base determination of different substances by non-aqueous titrations is
      highly preferred in pharmaceutical analyses since the method is quantitative,
      exact and well reproducible. The modern interpretation of the reactions in
      nonaqueous solvents started in the past century, but several inconsistencies and
      unsolved problems can still be found in the literature. The acid-base theories of
      Bronsted-Lowry and Lewis as well as the so-called solvent theory are outlined
      first, then the promoting (and levelling) and the differentiating effects are
      discussed on the basis of the hydrogen bond concept.

PMID- 12494787
TI  - [Adsorption of neutral polymers on liposomes: investigation of the correlation
      between liposomes and polymers].
AB  - The characteristics of the adsorption process of neutral polymers: poly(vinyl
      alcohol), poly(vinyl pyrrolidone), and dextrane onto liposomes with three
      different lipid compositions were investigated as follows. 1 determination of the
      amount of polymers adsorbed on the surface of liposomes, 2 detection of the
      changes in the membrane structure brought by the adsorption of polymers with a
      high precision densimeter, 3 test dye release experiments with membrane diffusion
      cells after remote loading of liposomes with acridine orange (AO). The amount of
      polymers adsorbed on the surface of liposomes was expressed with adsorption
      isotherms at 25 +/- 1 degrees C. Connections were found between the lipid
      composition influencing the fluidity of liposome membrane, the surface charge
      density of liposomes, the physical-chemical properties of the polymers and the
      quantitative adsorption properties of the polymers. Decreasing of the molar
      excess volume values counted from the results of the high precision densimetric
      measurements revealed the compression of the membrane structure caused by polymer
      adsorption. We were able to influence the test dye (AO) release properties of the
      soy lecithin phospholipid (SLPL)/cholesterol (Chol)/dicethyl phosphate (DCP) =
      25:3:2 (mol/mol) liposomes by the changing of the amount of PVA or DEX added to
      their dispersions.

PMID- 12494789
TI  - [Study of the acid buffering capacity of dietary components regarding food-drug
      interactions].
AB  - Food intake is known to exert numerous effects on drug pharmacokinetics through a
      variety of mechanisms, and for some medicinal compounds, food-drug interaction
      could prove of crucial clinical importance. As for acid-labile drugs,
      bioavailability studies performed in both fasting and fed states are considered
      essential. A simple and fast in vitro procedure using the USP Dissolution
      Apparatus II (paddle method) was applied to study acid buffering capacity of food
      components under simulated in vivo environment. As expected, carbohydrates
      (starch, sugars) and fat (oil emulsions) failed to show considerable acid
      buffering capacities, while protein-containing components (milk powder, gelatine)
      showed significant acid buffering capacity. The results of an in vitro model
      applying the so-called "standard meal" were in correlation with data obtained
      from studies performed in healthy volunteers. Nevertheless, in vitro models
      simulating both the fed and the fasting states in the GIT help explore factors
      related to food effect on drug dissolution; and consequently, achieve better
      insight into postprandial drug behaviour.

PMID- 12494790
TI  - [Determination of morphine and its derivatives by means of luminescence
      analysis].
AB  - A survey is provided on the physical and chemical bases of luminescence and its
      applications in analytical chemistry. Practical uses of fluorescence and
      phosphorescence, these highly sensitive analytical methods are assessed.
      Luminescence-based analysis methods are summarised on the parent compounds and
      their analytical derivatives focussing on morphine and related compounds,
      including metabolites. Hyphenated techniques, analyses of chemical and biological
      samples are also discussed.

PMID- 12494791
TI  - [Investigation of the sorption properties and pharmaceutical application of
      alpha1-acid glycoprotein by liquid chromatography].
AB  - The separation and quantitation of the enantiomers and also the determination of
      the enantiomeric purity are all current and indispensable tasks for the
      pharmaceutical analysis. The aim of this work was to study the sorption
      properties of the alpha 1-acid glycoprotein (AGP) based stationary phase, which
      may have crucial importance for the enantioselectivity. New binding data are
      presented for the mechanism of the chromatographic separation, which has not
      clarified in the literature yet. On the basis of these new findings the
      composition of the mobile phase for a given analytical separation can be
      designed, including the preparative separation, as well. Binding data for
      dioxane, known as a solvent with low dielectric constant, are determined at first
      time. It was found that the sorption of both acetonitrile and dioxane is pH
      dependent: as at pH 7.2 the binding can be characterized by a saturation curve,
      while at pH 4.0 by a twostep, monotone curve. The pH-dependence of the adsorption
      has been explained by conformational changes of the selector, which were
      confirmed by CD-spectroscopic and fluorescence quenching study of the native AGP.
      In accordance with the binding study by increasing the acetonitrile percentage at
      pH 4.0 a tipical alpha-helical peak was observed in the CD-spectrum. Opposite
      that at pH 7.2 the increase in the acetonitrile content does not result in any
      changes in the spectra. Effective dynamic quenching constants of AGP have been
      determined at given acetonitrile concentrations using 2,2,2-trichloroethanol as
      fluorescence quencher. In agreement with the results of the CD measurements at pH
      4.0 it was found that the degree of quenching enhanced by increasing the amount
      of the acetonitrile, that can be explained by enhanced exposure of the buried
      tryptophan residues. Taking these results into account, new optimized and
      validated HPLC methods have been developed for compendial control in testing the
      enantiomeric purity of an acidic (ibuprophen), a basic (propranolol) and a
      neutral (norgestrel) drug molecule.

PMID- 12494792
TI  - 401(k) plan asset allocation, account balances, and loan activity in 2000.

PMID- 12494793
TI  - Build it and they will come.

PMID- 12494794
TI  - What makes a good nurse?

PMID- 12494795
TI  - Inside the mind of today's consumer.

PMID- 12494796
TI  - Private matters.

PMID- 12494797
TI  - Physician-based brand strategies.

PMID- 12494798
TI  - How far have we come? A look back at 25 years of healthcare marketing. Interview
      by Richard K. Thomas.

PMID- 12494799
TI  - Bringing centers of excellence online. Consumer Web sites provide support for
      strategic goals.

PMID- 12494800
TI  - [Regional anesthesia for eye surgery and brainstem anesthesia: "zero risk" still
      does not exist].

PMID- 12494801
TI  - [Use of midazolam in postoperative sedation of patients with multiple organ
      failure treated with hemodiafiltration. Clinical study and pharmacokinetics].
AB  - OBJECTIVES: Evaluate the risk of accumulation of midazolam and conjugated 1
      hydroxy-midazolam in high-risk ICU patients treated by continuous veno-venous
      haemofiltration. STUDY DESIGN: A prospective pharmocokinetic and clinical
      evaluation in 11 patients, with hepatic and renal failure. METHODS: Midazolam and
      metabolites were dosed in plasma and ultratiltration liquid by chromatography.
      Sedation was assessed by a simplified Ramsay score (EDS) with 4 levels. RESULTS:
      The mean duration of continuous infusion was 11 +/- 6 days. Peak plasma levels
      were over 150 ng ml-1 during the first 3 days, but normalized after that, only by
      drug adjustment based on scoring and clinical observation. There was no
      progressive accumulation of OH-midazolam, in spite of high levels (> 1000 ng ml
      1). The Sieving coefficient (S) was 0.11 +/- 0.10 and 0.44 +/- 0.15 for midazolam
      and conjugated OH-midazolam respectively. A significant clearance (9.6 +/- 1.9 ml
      min-1) was observed for the conjugated products. T 1/2 beta was 11 h and was
      correlated with the mean time of recovery. A significant correlation was found
      between sedation score and both midazolam (r = 0.47) and OH-midazolam (r = 0.32).
      CONCLUSION: OH-midazolam risk of accumulation and significant clearance by
      haemodiafiltration should be taken into account in the drug adjustment in
      patients treated by continuous veno-venous haemofiltration.

PMID- 12494802
TI  - [Training for adult subclavian venous catheterization: use of real-time
      echography].
AB  - OBJECTIVE: To assess the training in adult subclavian venous catheterization of
      an inexperienced operator, with two different procedures: ultrasound guidance vs
      anatomic landmark technique. STUDY DESIGN: Prospective, comparative study.
      PATIENTS AND METHODS: After informed consent, 50 adults were divided in two
      groups, with an original method of inclusion, designed to assess the training of
      the operator, which alternated ultrasound guidance (n = 25) and Aubaniac's
      landmark technique (n = 25). RESULTS: All the catheterizations have been
      completed. The success rate at first attempt was higher in ultrasound group than
      in landmark group, without reaching significance (76 vs 56%). Two arterial
      punctures were reported in landmark group. With ultrasound guidance, there were
      21 puncture sites at the external third and 4 at the medial third of the
      clavicle. Average access time (skin to vein) was 15 +/- 8 seconds in ultrasound
      group and 63 +/- 78 seconds in landmark group (p < 0.01), with a significant
      relation between access time and patient rank in landmark group (r2 = 0.42, p <
      0.01). CONCLUSION: Ultrasound guidance makes the training in adult subclavian
      venous catheterization easier, and allows inexperimented operator to be rapidly
      efficient. The use of ultrasound would decrease the incidence of complications by
      a real time visualization of anatomical structures, and by a more external
      approach of the vein than in the Aubaniac's technique.

PMID- 12494803
TI  - [Comparative efficiency of nebulized adrenaline and salbutamol in severe acute
      asthma. A randomized, controlled prospective study].
AB  - OBJECTIVE: To compare nebulized salbutamol and nebulized adrenaline in acute
      severe asthma (ASA). STUDY DESIGN: Prospective controlled study. PATIENTS AND
      METHODS: October 1998 at May 99, 44 patients (31 women and 13 men, 35 +/- 11 yrs)
      with ASA (defined as peak expiratory flow rate (PEF) < 150 l min-1 and normo- or
      hypercapnia) were randomized to receive either nebulized salbutamol (n = 22), 10
      mg/h-1 during 2 h then 5 mg every 4 h or nebulized adrenaline (n = 22), 6 mg/h-1
      during 2 h then 3 mg every 4 h. The efficacy was assessed by PEF, forced
      expiratory volume in one second (FEV1) and Fischl's score during eight hours and
      by arterial blood gases during the first hour. Side-effects were evaluated by
      heart rate, systolic blood pressure, serum potassium and blood glucose.
      Statistical tests: Wilcoxon, Fischer exact, ANOVA and Scheffe's test. RESULTS:
      Both groups were similar with respect to age, sex, severity, duration of asthma
      and length of crisis. With the two treatments, PEF increased significantly but no
      statistical difference were observed between the two groups during the eight
      hours: 117.7 +/- 41.6 l min-1 to 203.3 +/- 56.9 l min-1 in the salbutamol group;
      116.4 +/- 36.8 l min-1 to 217.3 +/- 188.8 l min-1 in the adrenaline group; p =
      0.77. FEV1, Fischl's score and arterial blood gases did not differ significantly
      between treatments at every time interval. There were no significant difference
      between the two groups in terms of side-effects. The intravenous way was
      necessary at 3 cases of the salbutamol group and 4 cases of adrenaline group
      (NS). CONCLUSION: The results suggest that nebulized adrenaline is as effective
      as nebulized salbutamol in the ASA without significant side-effects. The
      nebulization could reduce systemic effects of adrenaline.

PMID- 12494804
TI  - [Bilateral ilioinguinal nerve block for ambulatory varicocele surgery].
AB  - OBJECTIVE: The aim of this study was to evaluate the effectiveness of bilateral
      ilioinguinal-iliohypogastric nerve blocks for pain relief following ambulatory
      bilateral varicocelectomy. STUDY DESIGN: Prospective and randomised. PATIENTS AND
      METHODS: Sixty adult men scheduled for bilateral varicocelectomy were included in
      this prospective study. All patients had a standardised general anesthesia. After
      surgical procedures, patients were randomized into two groups: patients in group
      I received a bilateral ilioinguinal nerve block with 15 ml x 2 of 0.25%
      bupivacaine; patients in group II received subcutaneously 1 mg kg-1 of tramadol.
      Visual analogue pain scores at rest and during mobilisation were recorded at 5
      min and 1, 3, 5 postoperative hours. The side effects of analgesia and amounts of
      rescue analgesics were recorded. RESULTS: Pain scores at rest and during
      mobilisation, the incidence of postoperative nausea and vomiting and additional
      analgesics requirement were significantly reduced in group I. There was no
      complication. CONCLUSION: Ilioinguinal nerve block is effective in controlling
      pain after bilateral varicocelectomy in ambulatory surgery.

PMID- 12494806
TI  - [Brainstem anesthesia after peribulbar anesthesia].
AB  - We report a case of pupilloplasty under peribulbar anaesthesia complicated by a
      brainstem anaesthesia requiring tracheal intubation and mechanical ventilation.
      Immediate outcome was good. We discuss the different mechanisms of this
      complication. The subarachnoidal (intrathecal) injection of local anaesthesic
      seems to be the most probable cause. The use of short needles should
      theoretically decrease the risk. Despite all these precautions, peribulbar
      anaesthesia should not be considered as an ordinary procedure.

PMID- 12494805
TI  - [Use of ropivacaine for peridural postoperative analgesia].
AB  - OBJECTIVES: To describe pharmacology and toxicology of ropivacaine. To assess the
      clinical efficacy of ropivacaine when used for postoperative epidural analgesia
      and to provide recommendations for clinical practice. DATA SOURCES: Search in the
      Medline data base of original articles in French and English published since
      1995, using the following key words: ropivacaine, postoperative analgesia,
      epidural, caudal block. STUDY SELECTION: Prospective randomised studies in adults
      and children were selected. Letters to editors and editorials were excluded. DATA
      EXTRACTION: Articles have been analyzed: to determine the dose of ropivacaine
      required for postoperative epidural analgesia, to assess the benefits of
      combination of epidural ropivacaine and additives (opioids or other), to compare
      epidural ropivacaine and bupivacaine and to assess the use of ropivacaine via
      caudal route for paediatric postoperative analgesia. DATA SYNTHESIS: 20 mg h-1 of
      ropivacaine is required to provide effective analgesia. This dose produces a
      motor block in a significant number of patients. Combination with an opioid
      allows for a reduction in ropivacaine requirement and subsequently in the
      incidence of motor blockade. In adults, equipotency ratio of ropivacaine and
      bupivacaine varies between 1.5/1 and 1/1 depending upon the concentration used.
      At equipotent doses, early postoperative mobilisation is facilitated with
      ropivacaine. In case of paediatric caudal analgesia, this ratio is close to 1.
      CONCLUSIONS: Epidural ropivacaine combined with opioid provide good postoperative
      pain relief. Reduction in the incidence of motor blockade and safe toxicological
      profile make this local anaesthetic a suitable alternative of bupivacaine for
      postoperative epidural analgesia.

PMID- 12494807
TI  - [Severe complications after a translaryngeal tracheotomy].
AB  - We report the case of a 71-year-old man receiving anticoagulant treatment because
      of a mechanical aortic valve. Because of an unsuccessful weaning after abdominal
      surgery, a translaryngeal tracheostomy was realised without incident. The patient
      died few days later after a hypoxic cardiac arrest due to a severe haemorrhage
      after the first recannulation. This case illustrates a severe complication
      because of the recannulation after a translaryngeal tracheostomy and how cautions
      one should be before realizing a percutaneous tracheostomy in a patient under
      anticoagulant treatment.

PMID- 12494808
TI  - [Tension pneumopericardium: a rare complication after thoracic stab wound].
AB  - The authors report a case involving a patient with thoracic stab wound. The
      patient developed tension pneumopericardium with acute cardiac tamponade. The
      clinical and radiological features of tension pneumopericardium and its treatment
      are discussed.

PMID- 12494809
TI  - [Idiopathic brachial neuralgia after cesarean section].
AB  - We report a case of idiopathic brachial nevralgia of the right shoulder in a 30
      year-old female, after caesarean section, under spinal anaesthesia. Two days
      after surgery, intense cervical pain appeared on the second day, associated with
      rapid collapse of muscular shoulder belt. Full recovery occurred in four months.

PMID- 12494810
TI  - [Intravenous beta-2-adrenergic agonists for tocolytic therapy in pre-eclampsia:
      two cases of acute pulmonary edema].
AB  - Two cases of pulmonary oedema during beta 2-adrenergic agonist therapy in pre
      eclampsia pregnant patients are reported. In our first case, the pulmonary oedema
      was exceptionally severe, because the patient (twins at 26 SA) had to be
      intubated and ventilated, but the caesarean section was performed only 6 weeks
      later. These two clinical observations underline the fact that B2 adrenergic
      agonist are not indicated for the treatment of preeclampsy. Furthermore they
      suggest that such patients should be rapidly admitted to intensive care units.

PMID- 12494811
TI  - [Myocardial infarction in AIDS].
AB  - We report two cases of myocardial infarction, in young HIV positive patients seen
      in the Emergency Department. These patients were under treatments: for one, an
      association of nucleosidic inhibitors, and for the other one, the combination of
      nucleosic analogue inhibitor with a non nucleosic analogue; in the last case, the
      patient underwent, few months before, a treatment containing a protease
      inhibitor. In both cases, the pain wasn't typical and didn't refer to a coronary
      heart disease. Lipid tests were normal. The diagnosis has been made quickly and
      allows a coronary angioplasty with a favourable issue. Authors are arguing the
      characteristics of this cardiac pathology, recently discovered in HIV positive
      patients, and do insist on the need to think at a coronary heart disease in front
      of any chest pain symptom even unusual.

PMID- 12494812
TI  - [Amniotic fluid embolism during labor].
AB  - Amniotic fluid embolism is an unpredictable but dramatical complication of
      pregnancy that occurs when amniotic fluid enter into the maternal circulation.
      The classical clinical feature is acute respiratory distress, circulatory
      distress, seizures and coagulopathy. However there is no routine laboratory
      diagnosis, so that is a diagnosis of exclusion. We report here the case of a
      patient, on labor with an epidural analgesia who suddenly suffered from seizures,
      circulatory arrest, and haemorrhage. A symptomatic management was instituted and
      a caesarean section was performed. An haemostatic hysterectomy was required. The
      patient survived without any sequelae. Neurological outcome of the child is still
      reserved.

PMID- 12494813
TI  - [Early rupture of a cryopreserved arterial allograft].
AB  - Cryopreserved arterial allografts are used in vascular surgery to treat infected
      arterial prosthesis. This treatment reduces mortality and morbidity compared to
      conventional surgery. We observed a case of early rupture of the allograft with
      the death of the patient due to a misdiagnosis. Recent findings show that cases
      of rupture have been described, and that current cryopreservation protocols may
      be the cause of degeneration. To avoid a sudden death for the patient, this
      complication must be known to diagnose quickly and treat surgically before a
      final haemorrhagic shock.

PMID- 12494814
TI  - [Pneumothorax: an unusual complication following gastrointestinal endoscopy].

PMID- 12494815
TI  - [Periumbilical analgesia: paraumbilical block or rectus sheath block?].

PMID- 12494816
TI  - [One diagnosis can be blocked by another one].

PMID- 12494817
TI  - [Persistence of spirometry in the absence of the patient: dysfunction of several
      Julian ventilators (Drager)].

PMID- 12494818
TI  - [Transfusion without consent in emergency cases: recent developments].

PMID- 12494819
TI  - [Use in practice of general intravenous anesthesia in renal insufficiency].

PMID- 12494820
TI  - [Meeting report of the Anesthesia-Resuscitation in ORL Club (Carorl)].

PMID- 12494821
TI  - Group practice provides fee-based messaging for patients.

PMID- 12494822
TI  - Good content alone won't bring them back.
AB  - Good content is important, but it won't make your site unique. The challenge for
      medical Webmasters is to find ways to encourage users to go directly to their
      site rather than to a general search engine. That requires knowing your
      audiences, and providing features that meet their needs.

PMID- 12494823
TI  - Why health quality organizations can't consolidate.

PMID- 12494824
TI  - Getting the most out of interactivity.

PMID- 12494825
TI  - Streamlining the Web effort.
AB  - How one organization is using content management software, a good set of links,
      and connections to back-end applications to create a first-rate Web site that
      requires limited maintenance resources.

PMID- 12494826
TI  - Gastrointestinal outbreaks associated with Norwalk virus in restaurants in
      Vancouver, British Columbia.

PMID- 12494827
TI  - Using a soft silicone-coated net dressing to manage skin tears.
AB  - Traditional management of skin tears can cause new damage and slow down healing.
      This paper discusses how to categorise these acute wounds and the significance of
      a study that used a soft silicone-coated net dressing on patients in a Belgian
      hospital.

PMID- 12494828
TI  - A sharp debridement procedure devised by specialist nurses.
AB  - In the clinical governance era, self-education is not adequate training for
      nurses to carry out sharp debridement, which is a risky process. Specialist
      nurses in south-east London drew up a workable procedure for training and
      practice.

PMID- 12494829
TI  - Measuring the incidence of lower limb ulceration in the Chinese population in
      Hong Kong.
AB  - OBJECTIVE: This retrospective study set out to examine the incidence, patient
      characteristics and current practice among patients with ulcers on the lower leg
      and foot who were under the care of the community nursing service of a regional
      hospital in Hong Kong. There is no clear differentiation between leg ulcers and
      foot ulcers in local practice in Hong Kong. METHOD: The nursing records of 819
      subjects receiving treatment at home from the regional hospital's community
      nursing service were reviewed. All were active cases on 31 October 2000. RESULTS:
      The patients' median age was 76 (range: 36-100); 86% were aged over 65. Seventy
      five percent of the patients had dressings changed daily, with 28 types of
      dressing being used. Nurses changed dressings in the patients' homes or in
      residential homes. Of the 94 patients with ulcers on the lower leg and foot, 75%
      had their dressings changed daily and only six less than three times a week.
      Fifty-four percent received regular podiatry clinic follow-up. CONCLUSION: Care
      of patients with ulcers on the lower limb represents a considerable workload for
      community nurses in Hong Kong, where little attention has been paid to the
      problem and current treatments. The number of patients with these ulcers cared
      for by community nurses in Hong Kong was high, with wide variations in
      management. Further investigation into evidence-based practice is needed to
      develop clinical guidelines and protocols that will achieve quality care.
      Research is now required in a clinical setting and for comparison with existing
      wound-care products.

PMID- 12494830
TI  - How a discipline came of age: a history of wound care.

PMID- 12494831
TI  - Healing venous ulcers with cycloidal multidirectional vibration therapy.
AB  - OBJECTIVE: This preliminary study combined compression bandaging with cycloidal
      vibration to determine whether this would enhance the rate of healing of venous
      leg ulceration. METHOD: Twenty-one patients with venous ulceration were enrolled
      into a 12-week trial. The vibration device was used three times daily for 30
      minutes on each occasion, along with compression bandaging. RESULTS: Ulcers of 13
      patients (62%) healed within 12 weeks. The remaining eight patients completed the
      12-week study with a 31-90% reduction in ulcer size. A reduction in pain was
      observed in 17 out of 21 patients (81%). Ultrasound measurements showed reduced
      fluid content in the upper dermis in patients whose ulcers had healed and in
      others whose ulcers were improving. CONCLUSION: This preliminary study shows that
      gentle cycloid vibration, combined with standard compression bandaging, enhances
      the healing rate of venous ulcers and helps to relieve pain.

PMID- 12494832
TI  - Evaluating the effectiveness of a compression sleeve in managing secondary
      lymphoedema.
AB  - Compression gradient wrap sleeves are an alternative to bandages in controlling
      lymphoedema, but there is very little data on the effectiveness of these
      products. This small study examined their effect on compliance and patient
      outcomes.

PMID- 12494833
TI  - Larvae therapy and venous leg ulcers: reducing the 'yuk factor'.
AB  - When a podiatrist modified a nylon maggot therapy containment bag used to dress a
      wound, debridement was slower but the maggots could be more easily observed and
      were easier to remove. It is also more user friendly for patients and
      practitioners.

PMID- 12494834
TI  - Deadly virus.

PMID- 12494835
TI  - A brief guide to anthrax.
AB  - Anthrax is an acute infectious disease caused by Bacillus anthracis. The organism
      is found in soil and is directly transmissible to humans via skin abrasions or by
      inhalation or ingestion of airborne spores. This article provides an overview of
      the history, microbiology and epidemiology of anthrax, and the various types of
      the disease. The article also discusses diagnosis and treatment as well as
      vaccination and infection control issues. In light of recent publicity over the
      use of anthrax as a form of bioterrorism, all health care workers should develop
      sufficient knowledge of anthrax, including how it is spread and the risk to the
      general public, in order to be able to provide appropriate information if
      necessary.

PMID- 12494836
TI  - What you need to know about.... meningitis.

PMID- 12494837
TI  - Behaviour problems and assessment in dementia.
AB  - People with dementia develop behaviour problems, the causes of which are often
      complex. Such behaviour often challenges the ability to provide care. Patient
      dignity must always be considered when attempting to reduce antisocial behaviour.
      Medication may be necessary but should not be seen as a first resort. Cognitive
      testing, rating scales, physical examination, biochemical tests and brain scans
      are used to confirm a diagnosis of dementia.

PMID- 12494838
TI  - Medication management for people with a diagnosis of schizophrenia.
AB  - Failure to keep up their antipsychotic medication is a major cause of relapse in
      people with psychosis. Compliance therapy, a pragmatic intervention based on
      motivational interviewing and cognitive behavioural therapy, is effective in
      enhancing concordance and reducing the risk of relapse. There is emerging
      evidence that after training in medication management, mental health nurses are
      able to deliver compliance therapy to people with a diagnosis of schizophrenia.

PMID- 12494839
TI  - Empowering patients.

PMID- 12494840
TI  - A fine balance.

PMID- 12494841
TI  - Beyond the call.

PMID- 12494843
TI  - Exchange rates.

PMID- 12494842
TI  - Where the grass is greener.

PMID- 12494845
TI  - Dishing the dirt in the office.

PMID- 12494844
TI  - Why nurses need a big pay rise now.

PMID- 12494846
TI  - Sharing grief.

PMID- 12494847
TI  - Setting up a nurse practitioner service.
AB  - In this article the authors argue that nurse practitioners must undergo a formal
      course of education that teaches them to be politically and professionally aware,
      clinically competent, develops their interpersonal skills and enables them to
      attain the confidence to express their views and needs. This, together with their
      skills of assessment and diagnosis, makes nurse practitioners marketable members
      of the healthcare team.

PMID- 12494849
TI  - Chronic obstructive pulmonary disease.
AB  - Chronic obstructive airways disease is a chronic, progressive disorder
      characterised by airways obstruction. The author discusses the management of
      patients with this condition, and examines the use of bronchodilator therapy,
      inhaled steroids, smoking cessation and pulmonary rehabilitation.

PMID- 12494848
TI  - Self-management plans in childhood asthma.
AB  - Current literature supports the use of self-management plans in childhood asthma.
      The aim of this article is to describe the purpose of such plans. It gives step
      by-step advice on how to prepare an individualized management plan and discusses
      important considerations on how they can best be implemented in clinical
      practice.

PMID- 12494850
TI  - Make the most of your team.

PMID- 12494851
TI  - Patient fact sheet for nurse prescribers. Nicotine replacement therapy.
AB  - Clinical trials show that NRT doubles the chance of success for those who try to
      stop smoking. NRT reduces withdrawal symptoms like irritability, depression and
      craving. Very few people become addicted to NRT. Some ex-smokers continue to use
      it for a year or more but this is mainly to prevent a return to smoking. For the
      best results, NRT should be used in sufficient quantities and for long enough.
      Smokers should follow the instructions in the package and seek advice from their
      nurse, pharmacist or GP if they need more information.

PMID- 12494852
TI  - Glorification of suffering.

PMID- 12494853
TI  - The Tuskegee syphilis study.

PMID- 12494854
TI  - Advertising genetic testing.

PMID- 12494855
TI  - Just your roots are showing.

PMID- 12494856
TI  - Red light, green light: the California cloning and stem cell laws.

PMID- 12494857
TI  - Protecting posthumous children.

PMID- 12494858
TI  - Covert video surveillance in pediatric care.

PMID- 12494859
TI  - Whose advice? Expert committees get a makeover.

PMID- 12494860
TI  - "How can they act like that?" Clinicians and patients as characters in each
      other's stories.

PMID- 12494861
TI  - You always were a bastard.

PMID- 12494862
TI  - What child is this?

PMID- 12494863
TI  - Nursing home to emergency room? The troubling last transfer.

PMID- 12494864
TI  - A novel plasmin-inhibitor inhibits the growth of human tumor xenografts and
      decreases metastasis number.
AB  - The novel plasmin inhibitor YO-2, which also exerts an apoptosis-inducing effect
      on various human tumor cell cultures, was examined regarding its tumor growth
      inhibitory and antimetastatic action. The tumor growth inhibitory effect of YO-2
      was studied using HT-29 human colon carcinoma, HT-18 human melanoma and HT-58
      human B cell lymphoma inoculated as xenografts into immuno-deprived mice.
      Antimetastatic activity was tested on the B16 mouse melanoma muscle-lung model.
      YO-2 inhibited the growth of all xenografts in the range of 40-50%, when
      administered s.c. at a dose of 2.0 mg/kg (HT-29, HT-58) or orally at a dose of
      0.4 mg/kg (HT-18). YO-2 decreased the number of lung metastasis found in mice
      inoculated i.m. with B16 melanoma, 4 mg/kg being the most effective. Since YO-2
      is the only plasmin inhibitor having antihemorrhagic and also antitumor effect,
      this compound could be rationally used in combination therapy of neoplastic
      disease, especially when hemorrhage aggravates the course of the disease.

PMID- 12494865
TI  - Effects of cyclophosphamide and soluble tumor-associated antigens on lymphoid
      infiltration, proliferative activity and rate of apoptosis in chemically-induced
      rat mammary tumors.
AB  - The aim of this study was to analyze the roles of proliferative activity,
      lymphoid infiltration and apoptotic rate in the cellular mechanism underlying the
      promotion effects of soluble tumor-associated antigens (sTAA) in mammary cancer
      in rats treated with the anticancer drug cyclophosphamide (CPA). Studies were
      performed on the following groups of rats: i) control tumor-bearing rats, ii)
      tumor-bearing rats treated with sTAA, iii) tumor-bearing rats treated with CPA,
      iv) tumor-bearing rats treated with CPA and sTAA. Mammary gland cancer was
      induced with dimethylbenz(a)anthracene (DMBA), and the rate of lymphoid
      infiltration, T cell content (CD4+ and CD8+ cells), and mitotic and apoptotic
      indices in tumors were evaluated. In control tumor-bearing rats, high lymphoid
      proliferation, as well as a high number of CD8+ cells, was found in tumors.
      Treatment with sTAA further significantly increased the total number of lymphoid
      cells and the number of CD8+ lymphocytes. CPA sharply decreased the production of
      all lymphoid cells studied, especially of CD4+ lymphocytes. The combined
      treatment of CPA and sTAA increased the number of lymphoid cells, although they
      did not reach control levels. The mitotic index significantly decreased as a
      result of the treatment with CPA alone and especially after the combined
      treatment with CPA and sTAA. The results of our experiments demonstrate that
      vaccination with sTAA actively promotes the generation of the host's antitumor
      immune response. This is manifested in inhibited proliferative activity of tumor
      cells, stimulated production of T lymphocytes and increased rate of apoptosis
      among tumor cells.

PMID- 12494866
TI  - Short-term effects of TNP-470 in combination with cisplatin in the rat model of
      bladder cancer.
AB  - PURPOSE: To investigate the short-term effects of TNP-470 in combination with
      cisplatin in a rat model of bladder cancer. MATERIALS AND METHODS: Following
      treatment of TNP-470 with or without cisplatin for 7 days, the states of
      angiogenesis, apoptosis and cell proliferation were evaluated in rat bladder
      cancer induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. RESULTS: In comparison
      with untreated tumors, we noted a significantly decreased microvessel density
      (MVD) in the rat bladder cancer treated by TNP-470, and a significantly increased
      apoptotic index (AI) when treated by cisplatin. In TNP-470 plus cisplatin-treated
      tumors, both significantly decreased MVD and increased AI were observed in non
      invasive and invasive rat bladder cancers in addition to a significantly
      decreased proliferation index (PI) in invasive cancer. CONCLUSION: The
      combination therapy of TNP-470 with cisplatin may act through both the inhibition
      of angiogenesis and induction of apoptosis, and invasive tumor cells may be much
      more sensitive to this combined therapy in rat bladder cancer.

PMID- 12494867
TI  - Immunohistochemical HLA-DR antigen expression with lymphocyte subsets and
      proliferative activity in pterygium.
AB  - The immunohistochemical expression of HLA-DR antigen, CD8, CD4, CD68, S1OO, PCNA
      and Ki-67 was performed in order to investigate the role of immune mechanisms in
      pterygium, in correlation with proliferative activity. A series of 98 surgically
      excised pterygia, 18 pingueculae and 20 normal conjunctivae, was studied by the
      avidin-biotin method, on formalin-fixed, paraffin-embedded tissue. HLA-DR antigen
      was abundantly expressed in pterygium epithelial cells, whereas almost no
      expression was found in pinguecula and normal conjunctiva. A high value of Ki-67
      and PCNA expression coexisted in the same areas with HLA-DR antigen expression in
      pterygium and a statistically significant positive correlation resulted between
      them (p = 0.002). Aberrant infiltration of inflammatory cells (CD4, CD8, CD68,
      S100) was detected in pterygium, while lower densities were found in pinguecula
      and conjunctiva. The data suggest that immunopathological mechanisms may
      contribute in the pathogenesis of pterygium. In addition, the aberrant HLA-DR
      antigen expression seems to be correlated with the growth fraction of the lesion.

PMID- 12494868
TI  - Effect of cisplatin treatment on early activation of oncogenes in vivo.
AB  - The aim of the study was to monitor the early effect of cytostatics containing
      platinum on oncogenes in inbred CBA/Ca mice. In human head-neck tumors after
      treatment with the Cisplatin supplemented BVM (Bleomycin, Vincristine,
      Methotrexate) protocol, further surgeries are often necessary due to regional
      recurrence. Body weight equivalent amounts of human dose of Cisplatin were
      administered intraperitoneally to 6-8-week-old, inbred, female CBA/Ca mice.
      Twenty four 48 and 72 hours after the treatment RNA was isolated from the target
      organs and the quantitative expression of c-myc, Ha-ras and p53 genes was
      examined by dot-blotting in potential target tissues. Significant overexpression
      of Ha-ras and p53 genes was measured in the bone marrow. Regarding the expression
      of Ha-ras gene, a significant increase was also found in the lymph nodes after 48
      hours. The p53 expression in the lungs was down-regulated compared to the control
      group. In the "short-term" in vivo test, 24-hour examination of gene expression
      and amplification is suitable for detecting the early effects of carcinogenetic
      exposure. Cisplatin-induced gene expression alterations call attention to its
      possible role in the development of regional recurrence in patients treated with
      cisplatin-containing regimens.

PMID- 12494869
TI  - Kikuchi-Fujimoto disease in Greece. A study of four cases and review of the
      literature.
AB  - Kikuchi-Fujimoto disease is a rare disease first described in 1972 by Kikuchi and
      Fujimoto et al. (1,2). Clinically the disease presents with lymphadenitis usually
      in the cervical region. Most reported cases of Kikuchi-Fujimoto disease have been
      of Asian origin. The cause is unknown and the condition is self-limiting. Some
      kind of viral or postviral etiology has been implicated. Bacterial and protozoal
      organisms as well as various other antigens, chemical, physical and neoplastic,
      have also been postulated. An association with systemic lupus erythematosus has
      also been shown. Lymphadenitis, hepatomegaly and splenomegaly as well as
      leukopenia, elevated erythrocyte sedimentation rate and hepatic abnormalities are
      common findings. Fever, malaise, fatigue, headache, night sweats, nausea,
      vomiting, weight loss, cutaneous manifestations, and even neurological symptoms
      are other complaints. Histologically the lymph nodes show partial involvement
      with patchy irregular areas of necrosis in the paracortical area with absence of
      neutrophils. We describe four cases of Kikuchi-Fujimoto disease observed in
      Greece. Their characteristics are discussed, whilst a review of the literature is
      attempted.

PMID- 12494870
TI  - Relationship between DNA mismatch repair genes expression, Ku-genes expression
      and ploidy-related parameters in the progression of pigmented lesions of the
      skin.
AB  - Defects of DNA repair systems in cutaneous tumours are related to DNA mismatch
      repair genes (MLH1, MSH2, PMS1, PMS2) and Ku70/80 genes involved in double-
      strand repair. In this study we investigated the statistical relationship between
      these systems and DNA-ploidy-related parameters in 19 naevus cell naevi, 23
      lentigos maligna, 76 primary melanomas and 31 melanoma metastases, applying the
      correlation coefficient according to Spearman. In naevi significant correlations
      were found between Ku70/80 gene expression and some ploidy-related parameters. In
      lentigos, additionally, some significant correlations between the expression of
      DNA mismatch repair genes were found. Similar results were demonstrated for
      primary melanomas. In metastases no one significant correlation between DNA
      mismatch repair genes and Ku-genes was present. We postulate that DNA mismatch
      repair genes and Ku70/80 genes are functionally independent and that some of them
      are able to influence ploidy-related parameters.

PMID- 12494871
TI  - Flow cytometric analysis of DMBA-induced early in vivo ras expression.
AB  - According to recent publications 7,12-dimethylbenz[a]anthracene (DMBA) induces
      not only mammary cancer but also leukemia in Long-Evans (LE) rats. After
      treatment with DMBA, trisomy of the chromosome bearing N-ras and mutations in the
      codon 61 of different ras family genes are frequent. These alterations are
      already visible within 48 hours. Since there are very few data on ras genes'
      expression in the early stages of leukemogenesis, in our investigations LE rats
      were treated with DMBA and the expression of ras genes was measured within two
      days. DMBA was administered to outbred Long-Evans rats and the fluorescence
      intensity of the antibody recognizing the ras gene family was measured in femoral
      bone marrow cells 24 and 48 hours after the treatment. One of the bone marrow
      cell populations, separated by FSC and SSC, showed elevated ras gene expression
      at both 24 and 48 hours after the administration of the carcinogen. These results
      suggest that, besides the specific chromosomal aberrations and gene mutations,
      elevated ras gene expression could also be the marker of DMBA exposure.

PMID- 12494872
TI  - Cytotoxic and radical scavenging activity of blended herbal extracts.
AB  - Chinese medicines have been applied to a variety of diseases producing various
      favorable effects, possibly due to the interactions between individual
      components. Establishment of an evaluation method for such interactions may
      facilitate the production of new natural medicines. We investigated here the
      interaction of the hot water extract of Aconiti Tuber (one of the most prominent
      Chinese medicines) and that of Scutellariae Radix, Coptidis Rhizoma, Glycyrrhizae
      Radix, Atractylodesi, Lanceae Rhizoma or Poria, by measuring the superoxide anion
      (O2-), hydroxyl radical (OH) and nitric oxide (NO) scavenging activity, using ESR
      spectroscopy. We found that a 1:1 mixture of the hot water extract of one herb
      and that of another herb (referred to as a combined formula) showed a higher
      radical scavenging activity and cytotoxic activity than the hot water extract of
      a 1:1 mixture of two herbs (referred to as a blended formula). Both formulae
      showed higher cytotoxic activity against human oral tumor cell lines than against
      normal cells. These data further confirm the medicinal usefulness of combinations
      of empirical Chinese medicines.

PMID- 12494873
TI  - Apelin expression in normal human tissues.
AB  - Apelin is an endogenous ligand of the human orphan receptor APJ (orphan G protein
      coupled receptor). This peptide is produced through processing from the C
      terminal portion in the pre-proprotein consisting of 77 amino acid residues and
      exists in multiple molecular forms. Although the main physiological functions of
      apelin have not been clarified yet, it has been demonstrated that apelin
      partially suppresses cytokine production from mouse spleen and, specifically,
      induces the promotion of extracellular acidification and inhibition of cAMP
      production in Chinese hamster ovary cells. Moreover, it is involved in the
      regulation of blood pressure and blood flow. In this study we have analyzed, by
      immunohistochemistry, apelin distribution in several human tissues, demonstrating
      that apelin has a widespread pattern of expression. These results seem to confirm
      that apelin functions widely in various tissues interacting with its specific
      receptor APJ.

PMID- 12494874
TI  - Immunohistochemical study of apelin, the natural ligand of receptor APJ, in a
      case of AIDS-related cachexia.
AB  - Apelin, a peptide first isolated from bovine stomach extracts, was discovered as
      an endogenous ligand for the APJ receptor. APJ has been shown to be a co-receptor
      for human and simian immunodeficiency virus (HIV and SIV). Apelin specifically
      inhibited the entry of primary T-tropic and dualtropic HIV-1 isolated from
      different clones expressing antiviral CD4 and APJ. On the basis of these results,
      we decided to compare the apelin expression level between normal and AIDS
      infected tissues by immunohistochemistry. We found that apelin expression was
      less intense in AIDS-infected tissues compared to normal tissues, in particular
      in the pancreas, kidney, adrenal glands and lymphoid organs. These results
      suggest an involvement of this peptide in immunodeficiency and in the immune
      response to AIDS.

PMID- 12494875
TI  - The in vivo DNA aneuploidization during expansion of conventional renal cell
      carcinoma.
AB  - Although numerous studies on the prognostic value of DNA aneuploidy in RCC have
      been reported, the in vivo DNA aneuploidization during RCC expansion has not been
      revealed. The present study was undertaken to observe the DNA aneuploidization
      during RCC expansion. We studied prospectively 67 consecutive conventional RCCs.
      The ploidy status was determined by analyzing five fresh tumor tissues from
      different areas by flow cytometry. The diploid, heterogeneous aneuploid tumors
      and homogeneous aneuploid tumors could be detected, respectively, in 44.8%, 23.9%
      and 31.3% of cases. The diploid tumors decreased significantly and aneuploid
      tumors increased significantly as the tumor expanded. The similar DNA content
      distribution was found between the heterogeneous aneuploid tumors and homogeneous
      aneuploid tumors. The hypertriploid clone was the most frequent in aneuploid
      tumors. The tumors of multiple aneuploid clones (16.4%) were mainly found in
      large-sized tumors. These results suggested that some RCCs underwent DNA
      aneuploidization during the tumor expansion and that a major route of
      aneuploidiztion (hypertriploidization) and several pathways existed. Our results
      also supported the idea that the progressive chromosomal instability was
      associated with continued tumor growth of RCC. The molecular mechanism and the
      clinical significance of aneuploidy phenotypes need to be further investigated.

PMID- 12494876
TI  - Drug combinations in the therapy of low response to phosphodiesterase 5
      inhibitors in patients with erectile dysfunction.
AB  - Combinatorial drugs utilising a clinically-proven single agent approach in
      erectile dysfunction (ED) have led to the search for additional compounds to
      improve therapy and the safety profile. Selective inhibitors of Phosphodiesterase
      type 5, such as Sildenafil, demonstrate a defined failure rate in ED. The
      therapeutic concept to increase blood influx and or to decrease blood efflux in
      patients with ED under therapy encountered severe drawbacks. It appeared
      impossible to decrease the NO-content in the corpora cavernosa and associated
      organs followed by synchronized increase of NO by a second drug. One has to
      metabolically activate cAMP by the first acting compound followed by cGMP
      stimulation. The pharmacology of the counteractive drugs was investigated
      clinically and a combination of 50 mg sildenafil with 5 mg dihydro-ergotamine
      (DHE) was identified as of practical use in patients with low response to
      Sildenafil. The safety profile appeared to be improved by this combination
      therapy. The present study is a clinical follow-up of patients treated with
      different therapeutical regimens to document the effectiveness of Sildenafil in
      combination with DHE.

PMID- 12494877
TI  - Mutant ICR mouse, kuru2, manifests hearing impairment and abnormal behavior.
AB  - BACKGROUND: Establishment of mutant animals presents valuable information on
      corresponding human diseases. We established a mutant mouse, kuru2, from the
      previously reported Ascites ICR Mouse. MATERIALS AND METHODS: Epileptic
      individuals of Ascites ICR Mouse were mated and maintained with sibling mating.
      This mouse was characterized by hearing impairment and abnormal behavior such as
      ataxic gait, disturbance of positional sense, hyperirritability, head-tossing and
      circling movement. RESULTS: No detectable auditory brain stem response was evoked
      from an early stage of life. Abnormal behavior started from 4 to 12 weeks of age.
      Microscopic examination revealed no major abnormalities in the central nervous
      system. In the inner ear, the vestibule and cochlea were well developed, however
      degeneration of the spiral ganglions was observed at a late age. The genetic mode
      was autosomal recessive. DISCUSSION: Since this mouse has a distinctive
      phenotype, the animal may provide an understanding of hereditary hearing
      impairment and abnormal behavior.

PMID- 12494878
TI  - Safety and efficacy of the new bisphosphonate ibandronate in the management of
      bone metastasis following rapid infusion.
AB  - BACKGROUND: We evaluated the safety and efficacy of the new BP ibandronate, given
      as a rapid infusion. PATIENTS AND METHODS: We administered 4 mg of ibandronate as
      an intravenous infusion over 30 minutes. Thirty patients (16 breast cancers, 4
      prostate cancers, 10 multiple myelomas) with bone metastases received 4 mg of
      ibandronate injected intravenously over 30 minutes in normal saline 0.9%, 250cc
      every 3 or 4 weeks. The patients were followed-up over 2 hours after infusion. A
      total of 198 infusions were administered over a period of 24 months and the
      patients were followed-up for long-term ibandronate-related side-effects, as well
      as for any potential clinical benefit. RESULTS: Following the first
      administration of ibantronate, serum levels of calcium, phosphate and alkaline
      phosphatase were significantly decreased and the difference was statistically
      significant (p < 0.001) for all three parameters examined. The reduced time of
      infusion (30 minutes vs 2 hours) did not correlate with any side-effects during
      or post-administration. Serum levels of creatinine and urea nitrogen did not
      increase significantly, while changes in temperature and blood pressure were not
      detected in the patients examined. With regard to efficacy, all the patients,
      after repeated administrations, reduced the doses of analgesics needed; 26 out of
      30 patients had stable disease in the bones while 1 out of 30 patients had
      significant improvement of bone lesions in consecutive bone scans. CONCLUSION:
      Infusional administration of ibandronate is efficient in the management of
      hypercalcaemia of malignancy and it results in a reduced need for analgesics. The
      rapid infusion over 30 minutes is safe and could be given in the setting of a day
      care unit.

PMID- 12494879
TI  - Growth factors, cytokines, chemokines and neuropeptides in the modeling of T
      cells.
AB  - The T lymphocyte lineage, from initial stem cells to peripheral mature T-cells,
      are members of a highly reactive cell system engaged in the control of internal
      homoeostasis and body intactness. It fulfills its commitments in close
      communication with the cellular and non-cellular microenvironment and with
      neuroendocrine regulatory mechanisms. Tools of such communication are various
      substances and compounds identified as cytokines, chemokines, hormones, growth
      factors and neuropeptides. Any pathogenetical model of functional aberration and
      disease development in the T-cell system must take into account the delicate
      network control exerted by the above mechanisms. In the following we describe the
      major players in the network regulation of T-cell development and function as a
      basis for a computational modeling study.

PMID- 12494880
TI  - Papillary pneumocytoma of the lung simulating a pleomorphic adenoma.
AB  - A rare case of papillary pneumocytoma of the lung is reported. The
      immunohistochemical positivities for EMA, cytokeratin and TTF-l strongly support
      the hypothesis that the neoplastic cells are originated from type 2 pneumocytes.
      The tumour also presented areas displaying stroma of non-specific mixoid
      appearance, simulating a benign tumour of the salivary gland type. We propose
      that these mixoid areas constitute structures of metaplastic origin.

PMID- 12494881
TI  - Recent progress in understanding the relationships among aging, replicative
      senescence, cell turnover and cancer.
AB  - The link between aging and cancer is more than just the increasing accumulation
      of mutations with time. Recent research provides evidence that senescent cells
      are not merely passive bystanders, but may promote cancer through degradation of
      the tissue microenvironment. Another critical factor in the relationship between
      aging and cancer is p53 function; its activity level is apparently finely tuned
      to suppress cancer while regulating both apoptosis and the replacement of damaged
      cells through stem cell proliferation. The deacetylase activity of the sir2 gene
      product plays a role in longevity regulation in invertebrates, and also regulates
      p53 function in mammals, implying yet another link between aging and cancer in
      mammals.

PMID- 12494882
TI  - Potential molecular targets of tea polyphenols in human tumor cells: significance
      in cancer prevention.
AB  - Next to water, tea is the most popular beverage in the world, and the cancer
      preventive effects of this beverage have been suggested. Epidemiological studies
      have shown decreased cancer occurrence in those individuals who drink green tea
      regularly. A wealth of research suggests numerous mechanisms of action to explain
      these observations. The most abundant and popular compound studied in tea
      research is (-)-epigallocatechin-3-gallate (EGCG), which acts as a powerful
      antioxidant and can inhibit a number of tumor cell proliferation- and survival
      related proteins. Tea polyphenols are known to inhibit the large multi-catalytic
      protease (the proteasome) and metaloproteionases, involved in tumor survival and
      metastasis, respectively. Additionally, tea polyphenols inhibit the activities of
      many tumor-associated protein kinases, including epidermal growth factor
      receptor, vascular endothelial growth factor receptor, platelet-derived growth
      factor receptor, mitogen-activated protein kinase, and IkB kinase. Tea
      polyphenols have also been found to inhibit some cancer-related proteins that
      regulate DNA replication and transformation. At present, it is not known which of
      these activities of tea polyphenols are required for its cancer-preventive
      effects. However, by understanding the in vivo concentrations of tea polyphenols
      required to inhibit each of these activities, we may start to sort out in the
      future the mechanisms responsible for the cancer-preventive effects of tea.

PMID- 12494883
TI  - Vaccines for immunotherapy of breast cancer and prostate cancer: new developments
      and comparative aspects.
AB  - This review summarizes the most recent findings and the newest approaches in the
      design of vaccines for breast cancer and prostate cancer. The antigens associated
      with breast cancer and prostate cancer and their use in vaccine development are
      discussed. We consider the comparative aspects in the new vaccines and focus on
      their clinical potential. The future directions in designing cancer vaccines are
      discussed.

PMID- 12494884
TI  - Racial differences in childhood tumors.
AB  - The purpose of this brief review is to inform the reader of the appearance of
      childhood neoplasms along racial and ethnic lines. The Lag time, general aspects
      and specific tumors, such as astrocytomas, medulloblastomas and those of the
      skin, including cases affecting the face and mouth, are discussed. Other tumors
      discussed are melanomas, those of the nasopharynx, liver, bone, Hodgkin's disease
      and especially leukemias as primary forms. Special emphasis was put on the racial
      and other variabilities producing various combinations and specific responses to
      treatment.

PMID- 12494885
TI  - Metastatic potential of human neoplasms.
AB  - Primary human neoplasms are heterogeneous for a large number of properties that
      include invasion and metastasis. The process of metastasis consists of multiple
      selective steps. The outcome of metastasis is determined by the continuous
      interaction of metastatic cells with host homeostatic mechanisms. Since the
      outcome of metastasis is influenced by both the intrinsic properties of the tumor
      cell and host factors, the successful metastatic cell must be viewed as a cell
      able to manipulate its new microenvironment. For many years, our efforts to treat
      cancer have concentrated on the destruction of tumor cells. Strategies to treat
      tumor cells and to modulate the host organ microenvironment should provide an
      additional approach for cancer treatment. Recent advancements in our
      understanding of the biological basis of cancer metastasis present unprecedented
      possibilities for translating basic research to the clinical reality of cancer
      treatment.

PMID- 12494886
TI  - Ultrasound guided, pre-radiation oxygen measurements using polarographic oxygen
      needle electrodes in spontaneous canine soft tissue sarcomas.
AB  - BACKGROUND: Poor tumour oxygenation is associated with radiation resistance. The
      recording of pre-treatment oxygenation status has been shown to be of prognostic
      relevance. MATERIAL AND METHODS: Eleven dogs with spontaneously arising soft
      tissue sarcomas were included in this study. Oxygen partial pressure measurements
      (pO2) were performed with the Eppendorf method. RESULTS: The mean of median pO2
      was 9.6 mmHg (range: 0.1-30 mmHg). Four of the nine dogs included in the
      statistical analysis showed a median pO2 < or = 2.5 mmHg. The natural logarithm
      of the hypoxic subvolume correlated with the hypoxic fraction < or = 2.5 mmHg (p
      = 0.0712) and < or 5 mmHg (p = 0.0988). Mean corpuscular hemoglobin (MCH) and
      mean corpuscular volume (MCV) correlated significantly to several oxygen
      parameters. CONCLUSION: Hypoxia exists in spontaneous canine soft tissue sarcomas
      and the dog can be used as a reliable model for repeated oxygenation
      measurements. Ultrasonography assures reliability of needle placement.

PMID- 12494887
TI  - Modulation of human NK cell lines by vascular endothelial growth factor and
      receptor VEGFR-1 (FLT-1).
AB  - Our laboratory has previously reported that natural killer (NK) cells bind to
      angiogenic microvessels in established cancer metastases. Vascular endothelial
      growth factor (VEGF) plays an important role in solid tumor angiogenesis by
      enhancing new blood vessel formation to transport nutrients and oxygen into
      tumors. Here we report that the human natural killer cell lines, NK-92 and YT,
      express the mRNA message and protein product for VEGF-B and its receptor, VEGFR
      1/Flt-1. While stimulation of these cells by the potent angiogenic factor VEGF
      A165, which also binds to VEGFR-1, does not alter the proliferation of the cells,
      it does increase adhesion to a model basement membrane-like extracellular matrix,
      Matrigel. VEGF-A165 also induces NK cell binding to human microvascular
      endothelial cells in newly forming but not established microvessels in vitro.
      These results suggest that human NK cells produce an angiogenic factor which may
      be involved in autocrine and paracrine regulations of angiogenesis. VEGF-A165
      appears to stimulate NK cell adhesion to the microvasculature within established
      cancer metastases.

PMID- 12494888
TI  - Clinical characteristics and gB genotype of cytomegalovirus infection in Japan.
AB  - To investigate the role of cytomegalovirus (CMV) gB genotypes, we examined the
      relationship between gB genotypes and clinical features in 19 patients with CMV
      infection. We analyzed 9 immunocompetent patients (1A) and 5 patients (1B) with
      various basic disorders in the symptomatic group. Five patients were enrolled in
      the asymptomatic group (2). To investigate gB genotypes, PCR was performed with
      oligonucleotide primers using clinical specimens and PCR products were digested
      with HinfI and RsaI We determined the PCR genotype by using restriction fragment
      length polymorphism (RFLP) analysis patterns. In the symptomatic group (1A and
      1B), all clinical specimens were identified as gB genotype 1. In the asymptomatic
      group (2), only 2 specimens were identified as gB genotype 3. The distribution of
      CMV gB genotypes in clinical specimens was as follows: gB 1-17 out of 19 (89.5%)
      and gB 3-2 out of 19 (10.5%). Our data revealed that gB genotype 3 CMV did not
      show symptomatic infection.

PMID- 12494889
TI  - Combined chemo/anti-angiogenic cancer therapy against Lewis lung carcinoma (3LL)
      pulmonary metastases.
AB  - A6 is an eight amino acid peptide derived from the non-receptor binding region of
      urokinase plasminogen activator (uPA), which interferes with the uPA/uPA receptor
      system. A6 has been synthesized as a potential anti-angiogenic, anti-cancer
      agent. The current study has investigated the potential therapeutic activity of
      A6 in the Lewis lung carcinoma (3LL) model of pulmonary metastasis. A6 was found
      to have direct anti-tumor activity against established 3LL pulmonary metastases
      at a low tumor burden (10-20 colonies per lung) and was therapeutic in
      combination with cyclophosphamide at high tumor burdens (> 100 colonies per
      lung). Mechanistic studies have revealed that A6 directly inhibits the invasion
      of 3LL cells through a Matrigel model basement membrane by 40-45%. Moreover,
      treatment with either A6 or doxorubicin resulted in thicker tubes in endothelial
      tube formation studies. Our results suggest that A6, by virtue of its anti
      invasive and anti-angiogenic properties, might work additively or synergistically
      with chemotherapeutic agents and thereby contribute to enhanced therapy of
      established 3LL cancer metastases.

PMID- 12494890
TI  - Inhibition of receptor tyrosine kinase-based signal transduction as specific
      target for cancer treatment.
AB  - Every cell in a multicellular organism receives signals from the extracellular
      matrix and neighboring cells. These signals are transmitted, via transmembrane
      receptors and cascade proteins of the intracellular message system, inside the
      cell and often to the nucleus, regulating almost every physiological function of
      the cell. Protein tyrosine kinases constitute a family of receptors that regulate
      major cellular events, such as cell proliferation, differentiation, cell adhesion
      and apoptosis. Mutant tyrosine kinases and/or their aberrant activity are
      associated with human cancer and other hyper-proliferative diseases. Strategies
      for inhibition of aberrant tyrosine kinase activity, such as antisense
      oligonucleotides, antigenic stimulation and small molecular inhibitors have been
      developed. STI571, a phenylaminopyrimidine derivative, is considered to be the
      pioneer of the small molecular inhibitors available to date. It is a successful
      tyrosine kinase inhibitor, which is currently approved and used for the treatment
      of chronic myelogenous leukemia and gastrointestinal tumors. In this article we
      review the mechanisms of cell signaling, the signal transduction pathways related
      to tyrosine kinases, their relationship with cancer, and the strategies developed
      to inhibit the aberrant tyrosine kinase receptor-based signal transduction. Drug
      resistance and future perspectives for combination therapies are also discussed.

PMID- 12494891
TI  - Monocyte/macrophage recruitment, activation and differentiation modulate
      interleukin-8 production: a paracrine role of tumor-associated macrophages in
      tumor angiogenesis.
AB  - Tumor-associated macrophages (TAM) have been shown to play an important role in
      tumor angiogenesis. The purpose of this study was to determine whether monocyte
      recruitment, activation and differentiation mediated by monocyte chemotactic
      protein-1 (MCP-1) and macrophage colony stimulating factor (M-CSF) modulate the
      expression of the angiogenic factor, Interleukin (IL)-8. Isolated human
      peripheral blood monocytes secreted low basal levels of IL-8. Incubation of
      monocytes with M-CSF or MCP-1 resulted in an up-regulation of IL-8 mRNA and
      protein expression. The differential expression of IL-8 by monocytes following
      MCP-1 and M-CSF treatments involved activation of the NFkB transcription factor.
      Further activation with lipopolysaccharide (LPS) caused an increase in IL-8
      secretion in monocytes but not in monocyte-derived macrophages (MDM). MDM
      conditioned media significantly up-regulated IL-8 expression in human malignant
      melanoma cells in vitro. In summary, we demonstrated that MCP-1 and M-CSF,
      critical for monocyte recruitment, activation and differentiation, differentially
      regulate IL-8 expression and may play an important role in monocyte/macrophage
      mediated tumor angiogenesis.

PMID- 12494892
TI  - Vascular stroma-derived endothelial colony forming progenitor cells adapt to
      tumour growth.
AB  - Under appropriate nutrient agar culture conditions, primary or xenografted human
      and animal tumour biopsy-derived cell suspensions will form two types of colony.
      The first type, consisting of tight colonies of round cells which form tumours
      when introduced into nude mice, is of neoplastic origin. The second type of
      colony, the cells of which fail to form tumours on injection into nude mice,
      consists of loose colonies of larger, inter-connecting elongated bi- or tripolar
      cells and is thought to originate from vascular stroma-derived endothelial colony
      forming progenitor cells (V-ECPC). The likely importance of V-ECPC to tumour
      growth is emphasised by a positive correlation between the VECPC-derived
      endothelial cell colonies and both tumour vascularity and growth rate. A high
      cloning efficiency obtained from tumours of particularly intense vascular nature
      indicates that this cell is of importance in vascular adaptation and therefore
      tumour growth. In contrast, avascular, fibrotic tumour tissue yielded very low
      numbers of stromal vascular endothelial cell colonies. The results suggest that
      stromal vascular endothelial cell colonies do not arise from the mature
      fibroblastic elements of the tumour stroma, but rather from cells within actively
      growing regions. Tritiated thymidine uptake studies show that the vascular stroma
      derived endothelial colony forming progenitor cells cell are cycling. Cell
      separation studies have characterized the as yet morphologically unidentified V
      ECPC as having a sedimentation rate of 4.7 mm./hr and a mean density of 1.068
      g/cm3 and hence a calculated volume of 450 microns 3.

PMID- 12494893
TI  - Polyamine involvement in breast cancer phenotype.
AB  - In this review, we will summarize current evidence implicating the polyamine
      pathway in two critical aspects of breast cancer biology, e.g. mammary
      carcinogenesis and tumor progression. We believe that the findings reported here
      provide a strong rationale for further exploring the role of anti-polyamine
      therapy in the adjuvant setting and in breast cancer chemoprevention.

PMID- 12494894
TI  - COX-2, NSAIDs and human neoplasia. Part I: Colorectal neoplasms.
AB  - Cyclooxygenase-2 (COX-2), the inducible cyclooxygenase isozyme involved in the
      conversion of arachidonic acid (AA) to biologically active prostanoids, has
      become the subject of intense interest during the last few years. The recent
      surge of interest stems from seminal studies that correlated elevated expression
      of COX-2 with tumor induction and progression, and epidemiological studies that
      correlated reduced risk of developing certain types of cancers with chronic use
      of non-steroidal anti-inflammatory agents (NSAIDs). Although these observations
      were first reported with colorectal cancer (CRC), similar findings have
      subsequently been made with other types of cancers. A wide spectrum of studies
      continue to be undertaken in both laboratory and clinical settings to elucidate
      the mechanisms underlying these anti-tumor effects of COX-2 for potential
      translation into cancer chemoprevention and therapy. The aim of this article is
      to present a review of COX genes, the prostaglandin-cyclooxygenase relationship,
      the role of COX-2 in carcinogenesis and the rationale for targeting COX-2 with
      NSAIDs for cancer chemoprevention. Special emphasis is given to the role of COX-2
      expression in the genesis and progression of colorectal neoplasia, and its
      correlation with other pathological characteristics of CRC. Preliminary
      observations on COX-2 expression in inflammatory bowel disease (IBD)-related
      colorectal neoplasia are also presented.

PMID- 12494895
TI  - Antiidiotypic antibodies carrying the "internal image" of peptide YIGSR inhibit
      spontaneous metastasis of Lewis lung carcinoma in mice.
AB  - BACKGROUND: It has been reported that the laminin derivative synthetic peptide
      YIGSR can bind to a metastasis-associated laminin receptor and inhibit
      experimental metastasis. Several antiidiotypic antibody (anti-Id) vaccines have
      been used in clinical trials with promising results. We used an anti-Id vaccine
      based on peptide YIGSR for the inhibition of spontaneous metastasis in Lewis Lung
      carcinoma-bearing mice. MATERIALS AND METHODS: High titer anti-YIGSR serum from
      immunized rabbits was used to immunize sixteen Lewis Lung Carcinoma (LLC)-bearing
      mice. Another group of sixteen mice (controls) inoculated with LLC was immunized
      with control rabbit serum. After 24 days of tumor growth, the volume of the tumor
      was estimated, a blood sample was collected and the lungs were examined
      macroscopically and microscopically for metastasis. The presence of anti-Id
      antibodies was detected by Western blotting, ELISA and inhibition of cell
      attachment assays. RESULTS: Tumor growth was limited and metastasis was inhibited
      in the mice that received the anti-Id YIGSR vaccine as compared to controls. Both
      groups of mice developed anti-rabbit antibodies as indicated by Western blotting.
      However only the serum of mice immunized with high titer anti-YIGSR rabbit serum
      (anti-Id YIGSR vaccine) could inhibit the binding of the anti-YIGSR rabbit serum
      to the peptide YIGSR in ELISA assays. In addition the serum of mice that received
      the anti-Id YIGSR vaccine but not the controls inhibited cell attachment to the
      peptide on solid face assays. CONCLUSION: An anti-Id antimetastatic vaccine may
      be developed based on YIGSR.

PMID- 12494896
TI  - How to analyze ex vivo T-cell responses in cancer patients.
AB  - Tumor-associated antigens are present in several malignancies and represent
      promising targets for immunotherapeutic approaches. Antigen-specific CD8+ T-cells
      are an important component of immunosurveillance in malignant diseases as they
      recognize, target, and kill tumor cells. The induction of T-cells reactive
      against epitopes of tumor-associated antigens is the major immunological aim of
      several cancer vaccination trials. In recent years, significant progress has been
      made in developing methods to detect and characterize these antigen-specific T
      cells. Here, we review and compare the most important techniques for specific T
      cell analyses including cytokine-based functional assays, HLA class I/epitope
      tetrameric complexes, and PCR-based methods. We emphasize single cell methods and
      underline the importance of ex vivo methods without prior culturing.

PMID- 12494897
TI  - Carcinogenic effects of low-level ionizing radiation: problems and prospects.
AB  - For public health purposes, the overall risks of cancer are assumed to increase
      in proportion to the dose of ionizing radiation, without a threshold. Assessment
      of the risks that may be attributable to doses below the range in which empirical
      data are available, however, entails the use of models, the credibility of which
      depends on the extent to which the models are consistent with what is known about
      the occurrence and mechanisms of the effects in question. Although the weight of
      existing evidence is consistent with the hypothesis that the risks of genetic and
      carcinogenic effects of ionizing radiation increase as linear-nonthreshold
      functions of the dose, this concept is challenged by some observers in view of
      growing evidence that low doses of radiation may elicit adaptive responses that
      enhance the repair of DNA damage and protect in other ways as well. Further
      research is needed to resolve the issue.

PMID- 12494898
TI  - Sustained release of growth factors.
AB  - With the identification, characterization and cloning of specific growth factors,
      recombinant proteins are now widely used in the clinic. The use of recombinant
      hematopoietic growth factors has, for example, allowed the clinical manipulation
      of the hematopoietic system. Recombinant human granulocyte colony-stimulating
      factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are
      now widely used to mobilize hematopoietic stem cells (HSC) thereby providing a
      source of HSC for autologous or allogeneic transplantation, in addition to
      treating congenic, iatrogenic and disease-related neutropenia. However, one
      disadvantage associated with the use of most recombinant molecules is their rapid
      clearance. Clearance mechanisms include glomerular filtration, receptor binding
      and/or enzymatic degradation. Because of the rapid clearance, of recombinant
      molecules they require repeated administration to achieve biological efficacy.
      Initially, continuous infusion (CI) was used to address this pharmacological
      deficiency. CI has the advantage of delivering drugs in a controlled manner and
      is particularly appropriate when it is important to maintain constant plasma drug
      concentrations. However, the requirement for continuous venous access and the use
      of ambulatory pumps limits its use. Thus other approaches have been developed to
      improve the pharmacokinetic and pharmacodynamic properties of recombinant
      proteins in vivo. These have included the addition of polyethylene glycol (PEG)
      to the recombinant molecules (PEGylation) and the use of sustained release
      delivery matrices and liposomes. One goal of these approaches is to achieve
      clinical efficacy with significantly fewer, possibly single injections, thereby
      increasing patient compliance. In addition to improving the pharmacokinetic and
      pharmacodynamic profile of recombinant molecules, sustained release may also
      increase the biological activity of the molecules.

PMID- 12494899
TI  - Enhanced in vitro and in vivo cytotoxicity of umbilical cord blood cells against
      human breast cancer following activation with IL-15 and colony stimulating
      factors.
AB  - BACKGROUND: Cord blood mononuclear cells (MNC) are a rich source of precursor
      cytotoxic effector cells. Earlier we have shown that interleukin-2 (IL-2)
      activated MNC from cord blood have significant cytotoxic activity against human
      leukemia and breast cancer cells in vitro and in vivo, compared to MNC from
      peripheral blood. MATERIALS AND METHODS: In order to further improve the
      antitumor cytotoxic ability of cord blood MNC, IL-2 was combined with IL-15 and
      colony stimulating factors GMCSF, G-CSF and M-CSF for the activation. The
      activated cells were examined for their cytotoxic effects in vitro against human
      breast cancer cell lines MDA-231, MDA453 and SKB43 and in vivo against MDA-231
      grown in SCID mice. Phenotypes of these activated cells were determined using
      flow cytometry. The expression of immune response related genes in activated
      cells was measured using RT-PCR techniques. RESULTS: There was a significant
      increase in cytotoxicity of the effector cells activated with IL-2, IL-15 and
      some colony stimulating factors compared to cells activated with each of these
      cytokines alone or other combinations. Our results demonstrated the increase in
      cytotoxicity appears to be due to: 1) increase in CD56-positive cytotoxic cells;
      2) cytokine/cytotoxic factors produced by the effector cells, such as Interferon
      7 and Perforin; 3) stimulation by accessory cells, such as dendritic cells. In
      vivo administration of in vitro-activated cord blood cells into SCID mice bearing
      MDA-231 tumors reduced the number of metastases and increased survival compared
      to untreated tumor bearing controls. CONCLUSION: The combination of IL-2 with IL
      15 and CSF is better for the activation of cord blood effector cells than to IL-2
      alone.

PMID- 12494900
TI  - Bacteria-related spontaneous and therapeutic remission of human malignancies.
AB  - The development of specific immunotherapeutic approaches to cancer treatment is
      making progress. However, a crucial clinical break-through in cancer vaccination
      is still missing. Spontaneous clinical remissions of malignancies are a rare
      phenomenon. The mechanisms are not clear but there are remissions described in
      correlation with bacterial infections. The use of bacteria or bacterial
      components might be a promising path for non-specific immunotherapy of tumors and
      might be a helpful adjuvant for specific immunotherapy. Here, we briefly review
      spontaneous remissions of various malignancies in humans, the impact of bacterial
      infection on tumor regression and the utilization of bacterial components in
      clinical trials.

PMID- 12494901
TI  - Preneoplastic lesions of the prostate-clinical, pathological and molecular
      biological aspects.
AB  - Needle biopsy is the mainstay of definitive diagnosis of prostate cancer (PCA).
      While prostate-specific antigen (PSA) screening has facilitated early diagnosis
      of PCA, it has also resulted in an increase in the proportion of prostate
      biopsies showing various preneoplastic lesions (PNLs). At times such lesions are
      the sole finding in the limited amount of tissue available for assessment in an
      individual biopsy. Hence accurate identification of these lesions is important to
      avoid errors in the diagnosis of prostatic malignancy and in patient management.
      Furthermore, some interesting observations have been made regarding the molecular
      biological aspects of various PNLs during the last decade. In parallel with
      anatomic and physiological differences in various human races, racial differences
      have also been observed regarding the incidence of prostatic intra-epithelial
      neoplasia. This review focuses on prostatic intraepithelial neoplasia (PIN),
      atypical adenomatous hyperplasia (AAH) and atypical prostatic glands or atypical
      small acinar proliferation (ASAP) as putative preneoplastic lesions of the
      prostate. These lesions are reviewed with reference to their overall incidence,
      histopathological findings, histological differential diagnosis, clinical
      significance and molecular biological aspects.

PMID- 12494902
TI  - T cell kinetics and apoptosis in immune organs and mammary tumors of rats treated
      with cyclophosphamide and soluble tumor-associated antigens.
AB  - The aim of this review was to analyze the role of cell kinetics and apoptosis in
      the cellular mechanism underlying the effects of soluble tumor-associated
      antigens (sTAA) on chemically-induced mammary cancer in rats treated with the
      anticancer drug cyclophosphamide (CPA). Mammary gland cancer was induced with
      dimethylbenz(a)anthracene (DMBA), and tumors, the spleen, thymus, bone marrow and
      lymph nodes were studied by morphometric and immunohistochemical methods. We
      suggest that inhibition of the functional activity of the immune system is one of
      the main reasons for the toxic effects of CPA, and that the tumor-suppressive
      antitoxic effects of sTAA result from their activation of T-lymphocyte production
      in this system, particularly in the spleen and lymph nodes. The results of our
      experiments have shown that vaccination with sTAA actively promotes generation of
      the host's antitumor immune response. This is manifested in inhibited
      proliferative activity of the tumor cells, stimulated production of T lymphocytes
      and an increased rate of apoptosis among tumor cells.

PMID- 12494903
TI  - The therapeutic efficacy of angiostatin against weakly- and highly-immunogenic
      3LL tumors.
AB  - BACKGROUND: Antiagiogenesis represents a promising approach to cancer therapy. We
      have previously demonstrated that the antitumor effects of endostatin, one of the
      most potent angiostatic agents, could be enhanced when combined with
      immunotherapy. Our current study evaluated whether anti-tumor immune response
      could also potentiate the therapuetic efficacy of another antiangiogenic drug,
      angiostatin. METHODS AND RESULTS: Using Matrigel assay, we showed that our
      preparation of recombinant angiostatin possessed potent anti-angiogenic activity
      in vivo. The antitumor effects of recombinant angiostatin were tested against
      weakly-immunogenic 3LL Lewis lung carcinoma versus its highly immunogenic variant
      3LL-C75. We showed that angiostatin inhibited the growth of 3LL-C75 more potently
      than that of 3LL tumor, suggesting that the host's immune response potentiates
      the antitumor effects of angiostatin. This conclusion was further supported by
      the finding that the antitumor activity of angiostatin against 3LL-C75 tumor was
      lower in immunodeficient nude mice in comparison with immunocompetent mice.
      Immunization of C57BL/6 mice with 3LL-C75 cells stimulated the antitumor immunity
      and inhibited the growth of parental 3LL tumor. Angiostatin treatment of
      immunized mice further enhanced the antitumor effect of tumor vaccination.
      CONCLUSION: Antitumor immune response could complement the therapeutic efficacy
      of angiostatin.

PMID- 12494904
TI  - MAGE-1, a cancer/testis-antigen, expression in childhood astrocytomas as an
      indicator of tumor progression.
AB  - During the last decade, the aberrant expression of normal testicular proteins in
      neoplastically transformed cells became common knowledge. Cancer/testis-antigens
      (CTAs) represent a novel family of immunogenic proteins. The MAGE genes were
      initially analyzed from melanomas and turned out to have an almost exclusively
      neoplasm-specific expression pattern. This expression pattern might contribute to
      the genetic instability of neoplastically transformed cells. In normal adult
      tissues, most 23 human MAGE genes are expressed only in the testis, but only in
      the mitotic spermatogonia (germ cells) and in the primary spermatocytes. The
      immunocytochemistry was carried out on routine, formalin-fixed, paraffin-wax
      embedded 3 to 4 mm thick astrocytoma (ASTR) tissue sections. A four step,
      indirect, biotin-streptavidin based method was employed with alkaline phosphatase
      enzyme conjugation. Immunocytochemical presence and cellular localization of the
      MAGE-1 CT-antigen, employing anti-MAGE-1 MoAB was observed only in anaplastic,
      high-grade ASTRs (100%), certainly including glioblastomas, in this study. The
      immunoreactivity was always heterogeneous, showing a cytoplasmic pattern and
      loosely grouped cells with similar staining characteristics being detected within
      the cellular and hormonal microenvironment of the ASTRs. We never identified MAGE
      1, CT-antigen expression in the lowest grade, pilocytic ASTRs. The MAGE-1 CTA
      expression levels may also be used to evaluate the malignant and
      dedifferentiation tendencies of low-grade ASTRs and predict the likelihood of
      mutations of the genome and further dedifferentiation towards even more malignant
      anaplastic ASTR and glioblastoma multiforme IPs.

PMID- 12494905
TI  - Expression of proline-directed protein kinase, (p34cdc2/p58cyclin A), a novel
      cell proliferation marker in childhood brain tumors.
AB  - The presence of two proteins of the proline-directed protein kinase (PDPK), the
      catalytic subunit p34cdc2 and the regulatory subunit p58cyclin A was determined
      in seven primitive neuroectodermal tumors (PNETs), three choroid plexus neoplasms
      and eleven astroglial tumors. The highest expression was registered in the
      cellularly undifferentiated PNETs and glioblastoma multiforme from the astroglial
      malignant group. Rabbit immunoantiserum against the two subunits of PDPK, a cell
      proliferation marker, was employed to detect proliferation activity in childhood
      brain tumors. The PDPK activity was present from Gl- to M-phases in 21 childhood
      brain tumors with different central nervous system (CNS) localization and
      cellular atypia. Immunocytochemical analysis employed an indirect, alkaline
      phosphatase conjugated biotin-streptavidin antigen detection technique on frozen
      and routine, formalin-fixed and paraffin-wax-embedded tissue sections of brain
      tumors. We compared the proliferation activity in the cells of normal,
      morphologically changed and neoplastically transformed choroid plexus. The
      average proliferation activity was low in comparison with other tissues. The
      results in normal and neoplastically transformed choroid plexus were very
      similar. The lowest proliferation activity in the astroglial group belonged to
      pilocytic ASTRs. The use of cell differentiation as a prognostic factor in
      primary brain tumors has already been established and is strongly suggested by
      our research group. Further systematic neoplasm studies and regular employment of
      these two polyclonal antibodies for immunocytochemical screening experiments are
      necessary to determine their true diagnostic and prognostic significance.

PMID- 12494906
TI  - T-20: a model for novel anti-HIV drugs in development.

PMID- 12494907
TI  - Pneumocystis carinii pneumonia in an untreated HIV-infected patient.

PMID- 12494908
TI  - Recent research in HIV infection: Part I.

PMID- 12494909
TI  - MMP inhibition and the development of cerebrovascular atherosclerosis: The road
      ahead.

PMID- 12494910
TI  - [Epidemiology of profound neurosensory deafness in Lebanese children].
AB  - The prevalence of profound sensorineural deafness in childhood is about 1/1000.
      274 children attending seven specialized Lebanese institutions were examined. The
      aim of this study is to evaluate the distribution of the different etiologies of
      this type of deafness in Lebanon: 51.82% are of genetic causes (25.2% due to
      consanguinity); 32.84% of acquired causes, the most frequent etiologies were
      rubella and perinatal meningitis; 15.32% of unknown etiologies. The new
      acquisitions in term of genetic counseling are discussed.

PMID- 12494911
TI  - [Endoscopic evaluation of chronic human immunodeficiency virus-related diarrhea].
AB  - Chronic diarrhea is an important clinical problem in patients infected with HIV.
      Data assessing the diagnostic yield of upper and lower endoscopy are limited. We
      reported 10 cases of HIV-infected patient referred to our hospital for chronic
      diarrhea from March 1995 to June 1999. 60% of the pathogens were identified
      obviously by stool studies. Cryptosporidium and Mycobacterium avium
      intracellulare (MAI) were the most common organisms. In this study, endoscopy
      identified 2 additional cases of MAI and one of 5 cryptosporidia detected in
      stool. Immunologic test identified a CMV infection in one case. Stool tests and
      endoscopy identified obviously 80% of the pathogens. Most investigators and us
      agree that stool studies should be the first diagnostic test. In patients with
      negative stool studies, lower endoscopy is more cost-effective than upper
      endoscopy and indicated as an initial exam.

PMID- 12494912
TI  - [Profile of skin diseases observed in a department of dermatology (1995-2000)].
AB  - OBJECTIVE: The aim of this retrospective study was to determine the nature and
      frequency of skin diseases observed at the Dermatology Department (Hotel-Dieu de
      France University Hospital) between January 1st, 1995 and December 31, 1999, and
      to compare them according to age and sex. PATIENTS AND METHODS: All the patients
      who presented to the consultation were enclosed in the study. Their file included
      sex, age, one or several diagnoses, the number of visits for each disease. Only
      new diagnoses were taken into account. Data were handled by Epilnfo program.
      RESULTS: 6822 patients (59.01% women, 40.99% men, average age 31 years) were seen
      with 8552 diagnoses. Fungal infections represent the most frequent disease
      (14.6%), followed by acne (14.1%), eczema (8.56%), viral infections (7.9%) and
      skin tumors (7.28%). Women consulted more often than men for acne, rosacea,
      eczema, hair loss, melasma and stretch marks; whereas men consulted more often
      for fungal and viral infections, and alopecia areata. DISCUSSION: The most
      frequent skin diseases (all ages merged), were fungal infections, acne and
      eczema. The same three diagnoses were found before as the most frequent in a
      previous Lebanese study. The profile of skin diseases in Lebanon turns out very
      close to observations made in developed countries, but it differs from the
      Western profile on two fundamental points: absence of leg ulcers and rarity of
      skin tumors. This profile seems, besides, very remote from the Middle-Eastern and
      Arabic context especially because of the absence of some endemic diseases such as
      tinea capitis, leprosy and leishmaniosis.

PMID- 12494913
TI  - [Endocrinologic recovery after treatment of an intrasellar aneurysm].
AB  - OBJECTIVE: Cavernous intrasellar aneurysms are rare, but may be clinically
      mistaken for an hypophyseal tumor, thus the need for a preoperative diagnosis.
      CLINICAL PRESENTATION: We report on a 60-year-old woman suffering from
      retroorbital headache, diplopia and decreased visual acuity, along with
      hyperprolactinemia and both gonadotropic and thyreotropic deficencies. Computed
      tomography revealed a sellar mass with superior extension, but MR raised the
      possibility of a cavernous aneurysm, that was confirmed by arteriography,
      avoiding a disastrous transsphenoidal surgery. DISCUSSION: Intracavernous
      aneurysms are known having a benign course, but serious meningeal hemorrhage can
      occur in 1.4% of cases and carotid-cavernous fistulae in 8% of patients,
      warranting treatment. Medial development is rare and may be responsible for
      endocrinologic manifestations. Neurosurgical approach remains hazardous, and
      endovascular occlusion represents the method of choice. CONCLUSION:
      Intracavernous aneurysm must be taken into consideration in the differential
      diagnosis of pituitary masses because it has a completely different management.

PMID- 12494914
TI  - [Brief history of ORL and its development in Lebanon ].

PMID- 12494915
TI  - Inhibition of contact activation by a kininogen peptide (HKH20) derived from
      domain 5.
AB  - Contact activation can be initiated by interaction of Factor XII, prekallikrein
      (PK) and high molecular weight kininogen (HK) with inorganic negatively charged
      biologic macromolecules, or upon cell surfaces, or interaction with membrane
      protein derivatives such as aggregated beta amyloid. The latter two examples are
      zinc-dependent. The interaction with cells is dependent on peptides derived from
      HK domains 3 and 5 termed LDC27 and HKH20, respectively. We have tested the
      ability of each of these peptides to inhibit HK-dependent contact activation.
      HKH20 inhibited activation of prekallikrein when a mixture containing HK,
      prekallikrein and Factor XII was incubated with dextran sulfate, gC1qR, amyloid
      beta or endothelial cells. Comparable quantities of LDC27 had no effect. The
      binding of biotinylated HK or biotinylated Factor XII was inhibited in a dose
      response fashion by increasing concentrations of HKH20 while LDC27, again had no
      effect. The N-terminal region of HKH20 (amino acids 475-485) is of particular
      importance for binding and histidine 485 prominently enhances the reaction as
      assessed employing overlapping and deleted peptides. Since there is a role for HK
      heavy chain in binding to endothelial cells and LDC27 can be employed as an
      affinity ligand to isolate the binding proteins, we increased the LDC27
      concentration from 10-fold to 250-fold to determine whether it is functional.
      Inhibition of endothelial cell-dependent prekallikrein activation required 100
      fold greater concentration of LDC27 when compared to HKH20 to achieve significant
      inhibition. We conclude that the interactions of the light chain of HK via HKH20
      is of particular importance for activation of the bradykinin forming cascade in
      zinc-dependent or independent reactions and is true for all "surface" initiators
      tested thus far.

PMID- 12494916
TI  - The lateral enamel lamina--component of tooth primordia in selected mammalian
      species.
AB  - The lateral enamel lamina (LEL) is a part of the enamel organ, which is probably
      not involved in tooth formation. It represents, besides the "stalk" of the tooth
      primordium, a second interconnection between enamel organ and oral epithelium or
      vestibular lamina. We detected the LEL in the sheep (Ovis aries), the dolphin
      (Stenella attenuata), and the vole (Microtus agrestis) by light microscopy and
      computer-aided three-dimensional reconstruction. The LEL could be found in cap to
      bell stage tooth primordia, most clearly in slowly developing tooth germs. LEL
      like structures have been furthermore described or depicted in tooth germs of the
      mouse, the elk (Alces alces), the dugong (Dugong dugong), the elephant (Loxodonta
      africana), and the human. Probably it is a part of all mammalian tooth primordia
      that undergoes regression during morphogenesis of the enamel organ. As a reducing
      structure, it should be considered in studies of tooth development.

PMID- 12494917
TI  - The invertebrate colonization during decomposition of Eichhornia azurea Kunth in
      a lateral lake in the mouth zone of Paranapanema River into Jurumirim reservoir
      (Sao Paulo, Brazil).
AB  - The invertebrate colonization during decomposition of Eichhornia azurea was
      observed in a lateral lake in the mouth zone of Paranapanema River into Jurumirim
      Reservoir in two periods of the year. The litter bags method was used for
      measuring the decomposition rate as well as to evaluate the invertebrates
      colonization. Forty-two litter bags, measuring 15 x 20 cm in size and 2 mm mesh
      net, were incubated "in situ". Six litter bags (three for colonization and three
      for decomposition measurements) were removed after the 1st, 3rd, 7th, 14th, 28th,
      56th and 72nd days of incubation. After each day, the material was carefully
      cleaned for detritus removal and invertebrate sampling. The biological material
      was fixed with 4% formaline and then sorted and identified. The remaining plant
      material was dried in an oven (at 60 degrees C) and weighed. A fast material loss
      occurred during the first 24 hours and the decomposition rate was higher during
      the rainy season than in the dry season. A peak on invertebrate density (110
      ind.g.DW-1) on the remaining detritus of Eichhornia azurea was recorded in the
      56th day of dry season, when the polyphenol concentration of plant detritus was
      0.57 UDO.g.DW-1. In the rainy season, higher density was found in the 28th day of
      incubation, when the polyphenol concentration was 4.36 UDO.g.DW-1. Apparently,
      the reduction in the polyphenol concentration was followed by an increase in
      invertebrate densities. The majority of the species observed in the detritus
      belongs to the collector group that was dominant after the 7th and 14th days in
      the rainy and dry seasons, respectively.

PMID- 12494918
TI  - Pluralistic evaluation of a rapid access gynaecology clinic.

PMID- 12494919
TI  - An evaluation of an innovative interprofessional masters degree.

PMID- 12494920
TI  - Isolation, characterisation and identification of lactic acid bacteria from
      bushera: a Ugandan traditional fermented beverage.
AB  - One hundred and thirteen strains of lactic acid bacteria (LAB) were selected from
      351 isolates from 15 samples of traditionally fermented household bushera from
      Uganda and also from laboratory-prepared bushera. Isolates were phenotypically
      characterised by their ability to ferment 49 carbohydrates using API 50 CHL kits
      and additional biochemical tests. Coliforms, yeasts and LAB were enumerated in
      bushera. The pH, volatile organic compounds and organic acids were also
      determined. The LAB counts in household bushera varied between 7.1 and 9.4 log
      cfu ml(-1). The coliform counts varied between < 1 and 5.2 log cfu ml(-1). The pH
      of bushera ranged from 3.7 to 4.5. Ethanol (max, 0.27%) was the major volatile
      organic compound while lactic acid (max, 0.52%) was identified as the dominant
      organic acid in household bushera. The initial numbers of LAB and coliforms in
      laboratory-fermented bushera were similar; however, the LAB numbers increased
      faster during the first 24 h. LAB counts increased from 5.5 to 9.0 log cfu ml(-1)
      during the laboratory fermentation. Coliform counts increased from 5.9 to 7.8 log
      cfu ml(-1) at 24 h, but after 48 h, counts were less 4 log cfu ml(-1). Yeasts
      increased from 4.3 to 7.7 log cfu ml(-1) at 48 h, but thereafter decreased
      slightly. The pH declined from 7.0 to around 4.0. Lactic acid and ethanol
      increased from zero to 0.75% and 0.20%, respectively. Lactic acid bacteria
      isolated from household bushera belonged to Lactobacillus, Streptococcus and
      Enterococcus genera. Tentatively, Lactobacillus isolates were identified as
      Lactobacillus plantarum, L. paracasei subsp. paracasei, L. fermentum, L. brevis
      and L. delbrueckii subsp. delbrueckii. Streptococcus thermophilus strains were
      also identified in household bushera. LAB isolated from bushera produced in the
      laboratory belonged to five genera (Lactococcus, Leuconostoc, Lactobacillus,
      Weissella and Enterococcus. Eight isolates were able to produce acid from starch
      and were identified as Lactococcus lactis subsp. lactis (four strains),
      Leuconostoc mesenteroides subsp. mesenteroides (one strain), Leuconostoc
      mesenteroides subsp. dextranicum (one strain), Weissella confusa (one strain) and
      L. plantarum (one strain).

PMID- 12494921
TI  - HIV type 1 subtypes circulating in eastern and northeastern regions of India.
AB  - Genetic subtyping has been a powerful tool in tracking the global spread of HIV.
      To determine the HIV-1 subtypes circulating in eastern and northeastern regions
      of India blood samples were collected from female sex workers in Calcutta and
      intravenous drug users (IDUs) in Manipur. Fifty-four samples from Calcutta and 25
      samples from Manipur were analyzed for HIV-1 subtyping by heteroduplex mobility
      assay (HMA). Twenty-six samples from these regions were sequenced. HMA and
      sequencing of the samples from these regions revealed subtype C as the major
      subtype, circulating within both eastern and northeastern regions. In Manipur,
      subtype ThaiB was also detected as the second major subtype. Some of the IDUs
      from Manipur were found to be dual infected with subtype C and ThaiB.

PMID- 12494922
TI  - Determination of genetic subtypes of HIV type 1 isolated from Korean AIDS
      patients.
AB  - To determine HIV-1 subtypes in Korean patients, we analyzed the nucleotide
      sequences of the HIV-1 env gene isolated from 19 Korean patients. DNA was
      extracted from cultured lymphocytes and the proviral V3 env gene was amplified by
      nested polymerase chain reaction. DNA sequences were determined using a cycle
      sequencer with fluorescence-labeled dye terminators, and aligned using a set of
      reference sequences. The phylogenetic tree was constructed by the neighbor
      joining method. Most of the enrolled patients were in the advanced stage of AIDS
      with CD4+ lymphocyte counts ranging from 10 to 560 (median 50) per mm3. Eighteen
      of the nineteen patients' sequences fall into subtype B (95%) and one was subtype
      A (5%). The tetrameric motifs at the tip of the V3 loop were comprised of GPGR
      (10 cases, 53%), GPGS (5 cases, 26%), and GPGQ, GPGG, GQGR, and APGS (one case
      each, 5%). Subtype B was found to be the most predominant clade of HIV-1 in our
      AIDS patients.

PMID- 12494923
TI  - Heterosexually acquired CRF01_AE/B recombinant HIV type 1 found in Thailand.
AB  - CRF01_AE and subtype B are circulating in Thailand and the strains have become
      intermixed in some high-risk groups, establishing the possibility of intersubtype
      recombination. The first such recombinant, mostly B with gp120 from CRF01_AE, was
      recently identified. Here we report a heterosexually acquired recombinant of
      different structure, with most of the genome from CRF01_AE but almost the entire
      envelope from subtype B. Surveillance by V3 serotype and genotype in multiple
      regions, followed by full-genome sequencing, was used to identify this strain.
      Pending vaccine trials in Thailand require knowledge of the presence of such
      strains in the population, and these recombinants provide valuable reagents for
      the laboratory evaluation of cross-subtype immunity. Studies are underway to
      determine whether either recombinant is circulating widely.

PMID- 12494924
TI  - A cross-comparison of retrospective notes extraction and combined notes
      extraction and patient interview in the completion of a comorbidity index (ACE
      27) in a cohort of United Kingdom patients with head and neck cancer.
AB  - Co-existent comorbidity is a major determinant of treatment outcome in head and
      neck cancer. Most of the work pertaining to this topic has been done in the
      United States, where the standard practice is for trained cancer registrars to
      grade comorbidity using validated indexes by retrospective notes review. The
      adult comorbidity evaluation-27 index (ACE-27) is a validated instrument that has
      been widely used in head and neck cancer. Although the required clinical data may
      be available in the notes, a significant amount of historical information is
      required to grade comorbidity. The aim of this study was to assess the accuracy
      and inter-rater reliability of the retrospective notes review process, in a
      typical setting in the United Kingdom (UK), by comparing the information obtained
      on notes review alone by a physician to that available after a structured patient
      interview. The study concludes that the retrospective notes review is an accurate
      and reliable technique for grading comorbidity whose completeness can be improved
      by the use of patient questionnaire as part of a structured interview.

PMID- 12494925
TI  - [Anesthetic management of pediatric video-assisted thoracoscopic surgery with
      Fogarty catheter].

PMID- 12494926
TI  - Current awareness in human psychopharmacology.

PMID- 12494927
TI  - World status of monitoring iodine deficiency disorders control programs.
AB  - Monitoring and evaluation are the last phases of a national iodine deficiency
      disorders (IDD) control program but among the most important. This paper
      summarizes the latest recommendations by the World Health Organization (WHO), the
      United Nations Children's Fund (UNICEF), and the International Council for
      Control of Iodine Deficiency Disorders (ICCIDD) about indicators and their
      normative values for monitoring the progress of IDD elimination and illustrates
      the successful monitoring programs in Switzerland and in China. Salt is the usual
      vehicle for iodine supplementation and quality control for iodine content can be
      assessed quantitatively by titration and qualitatively by simple test kits that
      can be used in the field. The most useful indicator of iodine nutrition is the
      median urinary iodine concentration. Thyroid size, especially by ultrasound, and
      neonatal thyrotropin (TSH) are also valuable. In Switzerland, access to iodized
      salt on a voluntary basis started in 1922. The initial level of iodization, 1.9
      3.75 ppm iodine as potassium iodide (KI), was slowly increased to 15 ppm, and
      recently to 20 ppm, after careful epidemiologic and biologic monitoring.
      Elimination of IDD has been highly successful. The program costs US dollars 0.07
      per year per person. In China, a national program of iodized salt (10-30 ppm)
      started in 1960 under the authority of the central government and rapidly
      expanded. National monitoring surveys have taken place every 2 years since 1993.
      Median urinary iodine, initially low, increased to 165 microg/L in 1995 and to
      306 microg/L in 1999, prompting a decrease in the amount of iodine added to salt.
      The total goiter rate decreased to 20.4% in 1995 and to 8.8% in 1999. IDD can
      presently be considered as eliminated in China. Review of monitoring in the 128
      other major countries affected by IDD shows extremely variable achievements, with
      evidence of IDD elimination in at least 18 additional countries. Some countries
      that were severely iodine deficient in the past are now exposed to iodine excess
      and risk its effects. Sustainable elimination of IDD is within reach and would
      constitute an unprecedented global success story in the field of noncommunicable
      diseases, but continuing vigorous action is required to attain this goal.

PMID- 12494928
TI  - Ethics watch. Public perceptions and regulatory policy.

PMID- 12494929
TI  - Planning is just the first step.

PMID- 12494930
TI  - Poor photos compromise report.

PMID- 12494931
TI  - Friction and chatter.

PMID- 12494932
TI  - Comparing bond strengths.

PMID- 12494933
TI  - Early treatment symposium.

PMID- 12494934
TI  - Where are we headed?

PMID- 12494935
TI  - New strains of bacteria and exacerbations of COPD.

PMID- 12494936
TI  - New strains of bacteria and exacerbations of COPD.

PMID- 12494937
TI  - Voriconazole versus amphotericin B for invasive aspergillosis.

PMID- 12494938
TI  - Paternal inheritance of mitochondrial DNA.

PMID- 12494939
TI  - Nurses' and social workers' experience with patients who requested assistance
      with suicide.

PMID- 12494940
TI  - Polymyalgia rheumatica and giant-cell arteritis.

PMID- 12494941
TI  - Polymyalgia rheumatica and giant-cell arteritis.

PMID- 12494942
TI  - Polymyalgia rheumatica and giant-cell arteritis.

PMID- 12494943
TI  - Re-exploration for bleeding after coronary artery bypass grafting: what is the
      acceptable range of re-exploration rate?

PMID- 12494944
TI  - Urinary tract infection in iNOS-deficient mice with focus on bacterial
      sensitivity to nitric oxide.
AB  - Inducible nitric oxide synthase (iNOS)-deficient mice were used to examine the
      role of iNOS in Escherichia coli-induced urinary tract infection (UTI). The
      toxicity of nitric oxide (NO)/peroxynitrite to bacteria and host was also
      investigated. The nitrite levels in urine of iNOS+/+ but not iNOS/ mice increased
      after infection. No differences in bacterial clearance or persistence were noted
      between the genotypes. In vitro, the uropathogenic E. coli 1177 was sensitive to
      3-morpholinosydnonimine, whereas the avirulent E. coli HB101 was sensitive to
      both NO and 3-morpholinosydnonimine. E. coli HB101 was statistically (P < 0.05)
      more sensitive to peroxynitrite than E. coli 1177. Nitrotyrosine immunoreactivity
      was observed in infected bladders of both genotypes and in infected kidneys of
      iNOS+/+ mice. Myeloperoxidase, neuronal (n)NOS, and endothelial (e)NOS
      immunoreactivity was observed in inflammatory cells of both genotypes. Our
      results indicate that iNOS/ and iNOS+/+ mice are equally susceptible to E. coli
      induced UTI and that the toxicity of NO to E. coli depends on bacterial
      virulence. Furthermore, myeloperoxidase and nNOS/eNOS may contribute to
      nitrotyrosine formation in the absence of iNOS.

PMID- 12494945
TI  - Is schizophrenia linked to chromosome 1q?

PMID- 12494946
TI  - Discontinuation of cefixime tablets--United States.

PMID- 12494947
TI  - Model-driven brain shift compensation.
AB  - Surgical navigation systems provide the surgeon with a display of preoperative
      and intraoperative data in the same coordinate system. However, the systems
      currently in use in neurosurgery are subject to inaccuracy caused by
      intraoperative brain deformation (brain shift), since they typically assume that
      the intracranial structures are rigid. Experiments show brain shift of up to 1
      cm, making it the dominant error in the system. We propose a biomechanical-model
      based approach for brain shift compensation. Two models are presented: a damped
      spring-mass model and a model based on continuum mechanics. Both models are
      guided by limited intraoperative (exposed brain) surface data, with the aim to
      recover the deformation in the full volume. The two models are compared and their
      advantages and disadvantages discussed. A partial validation using intraoperative
      MR image sequences indicates that the approach reduces the error caused by brain
      shift.

PMID- 12494948
TI  - Commentary: Gilding the global lily.

PMID- 12494949
TI  - Estimation of the partial volume effect in MRI.
AB  - The partial volume effect (PVE) arises in volumetric images when more than one
      tissue type occurs in a voxel. In such cases, the voxel intensity depends not
      only on the imaging sequence and tissue properties, but also on the proportions
      of each tissue type present in the voxel. We have demonstrated in previous work
      that ignoring this effect by establishing binary voxel-based segmentations
      introduces significant errors in quantitative measurements, such as estimations
      of the volumes of brain structures. In this paper, we provide a statistical
      estimation framework to quantify PVE and to propagate voxel-based estimates in
      order to compute global magnitudes, such as volume, with associated estimates of
      uncertainty. Validation is performed on ground truth synthetic images and MRI
      phantoms, and a clinical study is reported. Results show that the method allows
      for robust morphometric studies and provides resolution unattainable to date.

PMID- 12494950
TI  - Computerized detection of pulmonary nodules in chest radiographs based on
      morphological features and wavelet snake model.
AB  - We have developed a new computer-aided diagnosis scheme for automated detection
      of lung nodules in digital chest radiographs based on a combination of
      morphological features and the wavelet snake. In our scheme, two processes were
      applied in parallel to reduce the false-positive detections after initial nodule
      candidates were selected. One process consisted of adaptive filtering for
      enhancement of nodules and suppression of normal lung structures, followed by
      extraction of conventional morphological features. The other process consisted of
      a novel approach for elimination of false positives called the edge-guided
      wavelet snake model. In the latter process, multiscale edges of the candidate
      nodules were extracted to yield parts of the nodule boundaries. A wavelet snake
      was then used for fitting of these multiscale edges for approximation of the true
      boundaries of nodules. A boundary feature called the weighted overlap between the
      snake and the multiscale edges was calculated and used for elimination of false
      positives. Finally, the weighted overlap and the morphological features were
      combined by use of an artificial neural network for efficient reduction of false
      positives. Our scheme was applied to a publicly available database of digital
      chest images for pulmonary nodules. Receiver operating characteristic analysis
      was employed for evaluation of the performance of each process in the scheme. The
      combined features yielded a large reduction of false positives, and thus achieved
      a high performance in discriminating between true and false positives. These
      results show that our new method, in particular the false-positive reduction
      method based on the wavelet snake, is effective in improving the performance of a
      computerized scheme for detection of pulmonary nodules in chest radiographs.

PMID- 12494951
TI  - Causal structures for evaluating statin class effects.

PMID- 12494952
TI  - Need for better interactions between physicians and pharmaceutical sales
      representatives.

PMID- 12494953
TI  - Antibiotic-associated maculopapular reaction.

PMID- 12494954
TI  - Law, medicine, and trust.

PMID- 12494955
TI  - Reinventing the double helix: a novel and nonobvious reconceptualization of the
      biotechnology patent.

PMID- 12494956
TI  - The doctors' big squeeze: huge increases in medical malpractice insurance rates
      are driving doctors out of business. What's the answer?

PMID- 12494957
TI  - Changing renal allocation: is there a long-term price for short-term gain?

PMID- 12494958
TI  - Lorraine Eiler: saving indigenous culture.

PMID- 12494959
TI  - Veterinarians test the waters of fish medicine.

PMID- 12494960
TI  - Stretch your bovine practice potential--use technicians to the max.

PMID- 12494961
TI  - Studies offer scientific appraisal of tail docking effects in dairy cattle.

PMID- 12494962
TI  - Air, water, land, light: all affect cattle.

PMID- 12494963
TI  - Our oath of kindness.

PMID- 12494964
TI  - Curriculum reform revisited.

PMID- 12494965
TI  - What is your diagnosis? A large mass in the mid-portion of the abdomen with a
      tubular component extending into the caudal portion of the abdomen.

PMID- 12494966
TI  - Rabies surveillance in the United States during 2001.
AB  - During 2001, 49 states and Puerto Rico reported 7,437 cases of rabies in nonhuman
      animals and 1 case in a human being to the Centers for Disease Control and
      Prevention, an increase of < 1% from 7,364 cases in nonhuman animals and 5 human
      cases reported in 2000. More than 93% (6,939 cases) were in wild animals, whereas
      6.7% (497 cases) were in domestic species (compared with 93.0% in wild animals
      and 6.9% in domestic species in 2000). The number of cases reported in 2001
      increased among bats, cats, skunks, rodents/lagomorphs, and swine and decreased
      among dogs, cattle, foxes, horses/mules, raccoons, and sheep/goats. The relative
      contributions of the major groups of animals were as follows: raccoons (37.2%;
      2,767 cases), skunks (30.7%; 2,282), bats (17.2%; 1,281), foxes (5.9%; 437), cats
      (3.6%; 270), dogs (1.2%; 89), and cattle (1.1%; 82). Nine of the 19 states where
      the raccoon-associated variant of the rabies virus has been enzootic reported
      decreases in the numbers of rabid raccoons during 2001. Among states with
      extensive wildlife rabies control programs, Ohio reported (other than rabies in
      bats) 1 case of rabies in a raccoon that was associated with the epizootic of
      rabies in raccoons and 1 case in a bovid that was infected with a bat variant of
      the rabies virus, compared with no cases reported in any terrestrial animals
      during 2000. Texas reported 1 case associated with the dog/coyote variant of the
      rabies virus (compared with no cases in 2000) and 20 cases associated with the
      gray fox variant of the virus (a decrease of 50% from reported cases in 2000).
      Reports of rabid skunks in Massachusetts and Rhode Island, states with enzootic
      raccoon rabies, exceeded reports of rabid raccoons for the fifth consecutive
      year. A similar situation may soon exist in the state of Maine (32 rabid skunks
      and 34 rabid raccoons during 2001). Nationally, the number of rabies cases in
      skunks during 2001 increased by 2.7% over those reported in 2000. Texas reported
      the greatest number of rabid skunks ever documented during a single year by any
      state, as well as the greatest numerical increase in rabid skunks (778 cases in
      2001, compared with 550 in 2000; an increase of 228 cases, or 41.5%) and the
      largest overall state total of rabies cases (1,043) during 2001. Arizona reported
      the greatest percentage increase in rabid skunks (247.1%), representing an
      increase from 17 rabid skunks in 2000 to 59 in 2001. Nineteen of these cases were
      infected with a bat variant of the rabies virus, documenting a spillover event
      followed by unprecedented detection of temporal enzootic transmission of a bat
      variant in a terrestrial species. The number of cases of rabies reported in bats
      during 2001 (1,281 cases) increased 3.3% and surpassed the previous year's record
      (1,240 cases) as the largest number of reported cases ever recorded for this
      group of mammals. Cases of rabies reported in dogs (89) and cattle (82) decreased
      by 21.9 and 1.2%, respectively; these are the lowest numbers reported for rabid
      cattle and dogs since the dawn of national rabies record keeping (ca 1938). Cases
      in cats (270) increased by 8.4% over those reported in 2000, whereas rabies among
      sheep and goats declined 70%, from 10 cases in 2000 to 3 cases (goats only) in
      2001. Rabies among horses and mules declined 1.9% (52 cases in 2000 to 51 cases
      in 2001). Reported cases of rabies in mongooses in Puerto Rico increased 18.6%,
      compared with the previous year (70 cases in 2001 from 59 cases in 2000), whereas
      cases of rabies in dogs declined 15.3% (15 to 13). One case of rabies in a human
      being reported by California during 2001 was the result of infection with a
      canine variant of the rabies virus acquired outside the United States.

PMID- 12494967
TI  - Psittacosis/avian chlamydiosis.
AB  - Considerable progress continues to be made in understanding chlamydial organisms,
      their host species, diagnosis, and treatment. (1-3) Thus, national guidelines are
      updated annually to provide a standardized approach to handling infections in
      humans and birds. (2-3) Prior to development of these guidelines, considerable
      variation in approach by state agencies has been documented. (39) A more recent
      national assessment of state regulations and procedures has not been conducted.
      Decreasing imports of birds and increasing education may contribute to a
      reduction in human risk from avian infections. Keeping new birds separate from
      old birds in aviaries and poultry production facilities may reduce the incidence
      of avian chlamydiosis. Although wide-scale testing of birds may not be cost
      effective, (28) focal testing and treatment may help reduce human risk. The
      recent loss of a major source for pelleted feed for small birds, such as
      budgerigars, was a severe setback for veterinarians and local agencies in
      managing this disease. However, new medication formulas under development may
      help to address this problem. (2-3)

PMID- 12494968
TI  - Oral bleeding associated with pancreatic enzyme supplementation in three dogs
      with exocrine pancreatic insufficiency.
AB  - Three dogs with exocrine pancreatic insufficiency developed oral bleeding during
      treatment with pancreatic enzyme supplements. According to the owners of the
      dogs, bleeding from the oral cavity developed during or shortly after consumption
      of meals containing the pancreatic enzyme supplement. Oral bleeding stopped in
      all dogs when owners reduced the dose of the pancreatic enzyme supplement. In 2
      dogs, the decrease in the dose of the pancreatic enzyme supplement did not affect
      fecal consistency. However, in the third dog, the decrease in dose led to a
      recurrence of clinical signs. Findings in these dogs suggest that high doses of
      pancreatic enzyme supplements can cause oral bleeding in dogs with pancreatic
      insufficiency, but that oral bleeding can be successfully managed by dose
      reduction in most dogs.

PMID- 12494969
TI  - Use of intraluminal nitinol stents in the treatment of tracheal collapse in a
      dog.
AB  - Tracheal collapse is a common problem that is typically observed in middle-aged
      and older small-breed dogs. It is a structural, obstructive airway disease with a
      dynamic component that can affect the intra- and extrathoracic portions of the
      trachea and mainstem bronchi. Many methods of treatment have been suggested,
      including medical management and provision of extraluminal and intraluminal
      support. All techniques used to treat intrathoracic and mainstem bronchial
      collapse have been associated with major complications or limitations. This
      report describes the implantation of intraluminal nitinol stents to successfully
      treat intrathoracic as well as extrathoracic tracheal collapse in a dog. The
      stents are composed of material that has characteristics similar to those of the
      trachea; nitinol stents may provide a method of supporting intrathoracic tracheal
      and mainstem bronchial collapse in dogs.

PMID- 12494970
TI  - Ultrasonographic findings in cats with clinical, gross pathologic, and histologic
      evidence of acute pancreatic necrosis: 20 cases (1994-2001).
AB  - OBJECTIVE: To determine ultrasonographic findings in cats with clinical, gross
      pathologic, and histologic evidence of acute pancreatic necrosis. DESIGN:
      Retrospective study. ANIMALS: 20 cats. PROCEDURE: Ultrasound reports and
      permanent ultrasonographic images were reviewed, and ultrasonographic findings
      were recorded. Thoracic and abdominal radiographs were also reviewed, when
      available. Anatomic localization of pancreatic necrosis was determined from the
      gross pathology report; duration and severity of pancreatic necrosis were
      determined by reviewing histologic specimens. The presence of concurrent disease
      was recorded from the final pathology report. RESULTS: The pancreas was
      considered ultrasonographically normal in 10 cats and was not observed in 3.
      Ultrasonographic findings were considered compatible with pancreatitis in the
      remaining 7 cats. Gross pathologic findings indicated that pancreatitis was
      multifocal in all 7 of these cats; histologically, pancreatitis was acute or
      subacute in 5 and associated with severe or moderate necrosis in 6. In the
      remaining 13 cats, gross pathologic findings indicated that pancreatitis was
      multifocal (n = 8) or focal (2), or gross pathologic findings were normal (3).
      Histologically, pancreatitis was peracute or acute in 11 of these 13 cats and
      associated with severe or moderate necrosis in 8. Thoracic and abdominal
      radiographic findings were nonspecific. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results of ultrasonography were consistent with a diagnosis of pancreatitis in
      only 7 of 20 cats with acute pancreatic necrosis in the present study. This
      suggests that new diagnostic criteria must be established if abdominal
      ultrasonography is to be an effective tool in the diagnosis of pancreatitis in
      cats.

PMID- 12494971
TI  - Spontaneous femoral capital physeal fractures in adult cats: 26 cases (1996
      2001).
AB  - OBJECTIVE: To determine clinical, radiographic, and histologic abnormalities in
      adult cats > 1 year old with spontaneous (ie, nontraumatic) femoral capital
      physeal fractures. DESIGN: Retrospective study. ANIMALS: 26 cats. PROCEDURE:
      Medical records of cats > 1 year old with femoral capital physeal fractures and
      no history of trauma were examined. RESULTS: Mean +/- SD age of the cats was 22.5
      +/- 6.5 months. Twenty-five cats were neutered males. Mean weight of the cats was
      significantly greater than mean weight of a group of age- and sex-matched control
      cats. Of 16 cats for which age at the time of neutering was known, 14 had been
      neutered before 6 months of age. Nine cats had bilateral fractures. Severity of
      femoral neck osteolysis and sclerosis increased with increased duration of
      clinical signs. The contralateral femoral capital physis, distal femoral physes,
      and proximal tibial physes were radiographically open in 13 of 18,19 of 24, and
      24 of 24 cats, respectively. Histologically, the epiphysis contained normal
      articular cartilage and bone, but attached growth plate cartilage lacked the
      normal columnar arrangement of chondrocytes. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results suggested that adult cats with spontaneous femoral capital physeal
      fractures were most likely to be heavier, neutered males with delayed physeal
      closure.

PMID- 12494972
TI  - Laparoscopic repair of ruptured urinary bladder in a stallion.
AB  - A 12-year-old stallion was evaluated because of pollakiuria; endoscopy of the
      urinary tract during general anesthesia revealed that the urinary bladder was
      intact. After recovery, the stallion developed clinical and biochemical signs of
      bladder rupture, which was confirmed by endoscopy. Cystoplasty in adult stallions
      represents a unique surgical dilemma; the large distance between the incision
      site and the bladder necessitates the repair be accomplished under maximum
      tension with minimal exposure. Because traditional surgical approaches through
      ventral midline or paramedian incisions provide limited access and viewing,
      laparoscopy was used to provide a definitive diagnosis, good viewing, easy
      access, tension-free dissection, and a secure repair. Lack of surgical
      complications and postoperative discomfort, rapid and uncomplicated healing, and
      patient-client satisfaction make laparoscopic cystoplasty the preferred method
      for surgical repair of ruptured urinary bladder in adult stallions.

PMID- 12494973
TI  - Risk of abortion associated with Neospora caninum during different lactations and
      evidence of congenital transmission in dairy cows.
AB  - OBJECTIVE: To examine the relationship between exposure to Neospora caninum and
      abortion in dairy cows during their first, second, third, and fourth or later
      lactations and to establish the main mode of transmission in female calves from
      birth until their first pregnancy was terminated by abortion or parturition.
      DESIGN: Prospective observational study. ANIMALS: 460 Holstein cows and 79 female
      calves. PROCEDURE: Cows were classified as seropositive or seronegative to N
      caninum within 7 days after calving; incidence of abortion was compared between
      groups during different lactations. Blood samples were collected from female
      calves before ingestion of colostrum and every 6 months until their first
      pregnancy was terminated by abortion or parturition; number of seropositive
      calves was compared between seropositive and seronegative dams. RESULTS: During
      the first pregnancy of their second lactation, risk of abortion for seropositive
      cows was 2.8 times that of seronegative cows. Among 10 calves born to
      seropositive cows, 4 were classified as seropositive at birth and thereafter.
      Among 69 calves born to seronegative cows, all were classified as seronegative at
      birth; 67 calves remained seronegative thereafter. CONCLUSIONS AND CLINICAL
      RELEVANCE: Exposure to N caninum alone was not significantly associated with
      abortion in cows during the first, third, and fourth or later lactations.
      Seropositive cows that have aborted previously may have subsequent abortions
      attributable to N caninum. Congenital infection was the main mode of N caninum
      transmission in a cohort of female calves.

PMID- 12494974
TI  - Ultrasound in obstetrics and gynecology: is this hot technology too hot?

PMID- 12494975
TI  - Acoustic output upper limits proposition: should upper limits be retained?

PMID- 12494976
TI  - Arrhythmias in rat hearts exposed to pulsed ultrasound after intravenous
      injection of a contrast agent.
AB  - OBJECTIVE: To develop an animal model suitable for characterizing
      electrocardiographic arrhythmias in hearts exposed to ultrasound after injection
      of a microbubble contrast agent. METHODS: Conduction complex and heart lesion
      data were recorded from 20 rats that received intravenous injections of 0.25 mL
      of a contrast agent and were exposed to pulsed ultrasound (frequency, 3.1 MHz;
      pulse duration, 1.3 microseconds; pulse repetition frequency, 1700 Hz; and in
      situ peak rarefactional pressure, 15.9 MPa). The volume of the contrast agent
      based on body weight and the mechanical index (ultrasonic pressure) exceeded
      those used in echocardiography by 14 to 345 and 3 to 29 times, respectively.
      RESULTS: Premature atrial complexes, premature ventricular complexes, or
      polymorphic ventricular tachycardia occurred in 10 rats. When ultrasound exposure
      was halted, arrhythmias ceased but reoccurred in 4 of the 10 rats when exposure
      resumed. Myocardial degeneration identified by histochemical staining
      (hematoxylin-basic fuchsinpicric acid) was observed in 16 rats; however, only 10
      rats had arrhythmias. There was no significant difference in the amount of
      histochemical staining in hearts from rats with arrhythmias when compared with
      rats without arrhythmias. CONCLUSIONS: An animal model suitable for
      characterizing electrocardiographic arrhythmias in rat hearts exposed to
      ultrasound after injection of a microbubble contrast agent was developed. Because
      arrhythmias were induced principally when the contrast agent interacted with
      ultrasound during exposure, the presence of myocardial degeneration alone was not
      a sufficient explanation for ectopic electrical activity. Under these extreme
      exposure conditions, the data suggest that pulsed ultrasound through its
      biomechanical interactions with contrast agents has the potential to induce
      arrhythmias.

PMID- 12494977
TI  - Diagnostic ultrasound treatment increases the bone fracture-healing rate in an
      internally fixed rat femoral osteotomy model.
AB  - OBJECTIVE: To investigate the healing effects of diagnostic ultrasound in a
      standardized rat femur fracture model. METHODS: Thirty-two male rats aged 14
      weeks were used, and each rat's right femur was osteotomized and stabilized under
      anesthesia. The rats were then divided into 4 groups. Five days after surgery,
      ultrasound was applied every fifth day with diagnostic sonographic equipment and
      a probe with a 7.5-MHz frequency and 11.8-mW/cm2 total output intensity for 10
      minutes in each session. Ultrasound was applied 8 times in group A, 3 times in
      group B, and only once in group C. Ultrasound was not applied to sham-operated
      group D. Healing and callus formation of the rats' femur fractures were evaluated
      by radiography and dual-energy x-ray absorptiometry. RESULTS: Dual-energy x-ray
      absorptiometric and radiographic results showed that the ultrasound therapy
      accelerated the fracture healing. Radiographically, groups A and B showed better
      fracture healing than groups C and D. Ultrasound exposure increased both the
      whole-bone mineral density and the density at the fracture region, increasing in
      parallel with the exposure period. CONCLUSIONS: This study confirms the
      previously shown efficacy of low-intensity ultrasonic stimulation in acceleration
      of the normal fracture repair process even when performed with a diagnostic
      sonographic device.

PMID- 12494978
TI  - Clinical experience with upper extremity venous sonography in a high-risk cancer
      population.
AB  - OBJECTIVE: To determine the frequency of sonographically evident upper extremity
      venous thrombosis in symptomatic cancer patients with and without central venous
      catheters. METHODS: Retrospective review of 573 consecutive upper extremity
      venous sonographic reports from a 26-month period was performed. Findings
      including distribution of venous thrombosis, the presence of a central line,
      cancer type, and miscellaneous findings were recorded. RESULTS: Overall, 514
      studies (90%) had satisfactory visualization of all upper extremity vessels; 53
      (9%) had limited visualization of 1 or more vessels; and 6 (1%) were
      inconclusive. Venous thrombosis was present in 227 (40%) of 573 studies. Of the
      studies with positive findings, there were 186 acute, 13 chronic, 19 fibrin
      sheath versus nonocclusive, and 9 superficial thromboses. Central venous
      catheters were present in 325 (57%) of 573 studies. Sonographically evident
      thrombosis was present in 157 (48%) of 325 studies with central catheters versus
      70 (28%) of 248 studies without central venous catheters (P = .001) CONCLUSIONS:
      Upper extremity venous thrombosis is common (40%) in symptomatic cancer patients
      and is nearly twice as frequent in cancer patients with indwelling central venous
      catheters.

PMID- 12494979
TI  - A detailed analysis of equivocal duplex findings in patients with suspected deep
      venous thrombosis.
AB  - OBJECTIVE: To analyze equivocal duplex findings in patients with clinically
      suspected deep venous thrombosis and thus to increase the diagnostic utility of
      color duplex sonography in this category of patients. METHODS: Phlebography was
      requested in a series of 102 consecutive patients with inconclusive duplex
      findings. These patients were, according to the duplex findings only, subdivided
      into having low, intermediate, and high probability of deep venous thrombosis.
      RESULTS: Phlebographywas attempted in 71 cases and successfully performed in 49.
      The remaining 53 patients were prospectively followed clinically for 6 months.
      Phlebography showed deep venous thrombosis in 1 of 63 patients in the group with
      low probability, 3 of 31 in the intermediate group, and all of the 8 patients
      with high probability. Twenty-two (31%) of the 71 attempted phlebographic
      examinations were nondiagnostic. None of the patients in the follow-up group had
      any thromboembolic complications. CONCLUSIONS: Even if a duplex examination is
      equivocal, it is still possible to extract clinically useful information by
      categorizing the duplex results into subgroups with low, intermediate, and high
      probability of deep venous thrombosis. This can have implications for the
      diagnostic or therapeutic handling of these patients and thus can increase the
      utility of sonography in patients with inconclusive duplex findings.

PMID- 12494980
TI  - Offset of the fetal tricuspid septal leaflet.

PMID- 12494981
TI  - Fetal nose bone length: a marker for Down syndrome in the second trimester.
AB  - OBJECTIVE: To evaluate the significance of nasal bone length in relation to the
      detection of Down syndrome in the second trimester. METHODS: We evaluated
      consecutive fetuses referred to our facility between 15 and 20 weeks' gestation
      for sonography and amniocentesis because of an increased risk of aneuploidy. A
      detailed structural survey, biometric measurements, and measurement of the nasal
      bone were obtained at the time of amniocentesis and subsequently compared with
      karyotype. The characteristics of the fetuses with Down syndrome were compared
      with those of the euploid fetuses. RESULTS: A total of 239 fetuses were
      evaluated. Sixteen fetuses (7%) had Down syndrome, and 223 were euploid. In
      fetuses with Down syndrome, 6 (37%) of 16 did not have detectable nose bones,
      compared with 1 (0.5%) of 223 control fetuses, yielding a likelihood ratio of 83.
      Detectable nasal bones were seen in 10 fetuses with Down syndrome and 222 euploid
      fetuses. A receiver operating characteristic curve for the biparietal diameter
      nasal bone length ratio showed that a value of 9 or greater detected 100% of
      fetuses with Down syndrome and 22% of euploid fetuses. If the ratio were 10 or
      greater, then 81 % fetuses with Down syndrome and 11 % of euploid fetuses would
      have been identified. If the ratio were 11 or greater, 69% of fetuses with Down
      syndrome would be identified, compared with 5% of euploid fetuses. CONCLUSIONS:
      The absence of a nasal bone is a powerful marker for Down syndrome. A short nasal
      bone is associated with an increased likelihood for fetal Down syndrome in a high
      risk population.

PMID- 12494982
TI  - Quantification of the wall inhomogeneity in B-mode sonographic images of the
      carotid artery.
AB  - OBJECTIVE: The process of atherosclerosis has been assessed increasingly by
      sonography in B-mode images of the carotid arteries. Carotid artery
      atherosclerosis is thought to be associated with major atherosclerotic diseases
      in other regions of the arterial bed, especially the coronary arteries. In
      addition to the intima-media thickening as an established surrogate parameter of
      the atherosclerotic wall process, changes of the sonographic morphologic pattern
      of the intima-media layer might reflect this process. METHODS: After automatic
      identification of the intimal and adventitial boundaries of the distal common
      carotid artery wall, the gray level inhomogeneity of the circumscribed intima
      media area was quantified. Older subjects without cardiovascular disease (mean +/
      SD, 66.2 +/- 3.8 years; n = 43) were compared with young subjects without
      cardiovascular disease (24.4 +/- 5.3 years; n = 34) and patients with manifest
      coronary artery disease (65.0 +/- 9.2 years; n = 69). RESULTS: Patients with
      coronary artery disease had a significantly higher intima-media thickness (0.92
      +/- 0.21 mm; P < .05) and wall inhomogeneity (4.56 +/- 0.97; P < .001) than the
      old group (0.86 +/- 0.15 mm and 3.83 +/- 0.62). Both parameters were lowest in
      the young group (0.56 +/- 0.05 mm and 2.53 +/- 0.76; P < .05 for both parameters
      and groups). CONCLUSIONS: Measurement of gray level wall inhomogeneity of the
      intima-media layer of the common carotid artery may help discriminate between
      subjects with high and low atherosclerotic burden and may show age-related
      changes of the intima-media layer. This new quantitative parameter is thought to
      reflect the atherosclerotic wall process in addition to the intima-media
      thickness measurement.

PMID- 12494983
TI  - A new angle-independent Doppler ultrasonic device for assessment of blood flow
      volume in the extracranial internal carotid artery.
AB  - OBJECTIVE: To evaluate a new angle-independent ultrasonic device for assessment
      of blood flow volume in the internal carotid artery. METHODS: In vitro, a
      pulsatile pump was set to provide an outflow of physiological fluid at 500 mL/min
      through an 8-mm-diameter tube. Flow volume rates were measured 10 times by 10
      different operators and compared with time-collected flow volume rates. In vivo,
      internal and common carotid artery blood flow volumes were measured in 28
      volunteers by 2 operators using a FlowGuard device (Biosonix Ltd). Internal and
      common carotid artery diameters and blood flow volumes were also assessed by
      Duplex sonography and compared with FlowGuard measurements. In 10 volunteers,
      internal carotid artery blood flow volume changes in response to monitored breath
      manipulations were recorded. RESULTS: In vitro, intraoperator variability was
      4.04% (range, 2%-5.7%). The mean error rate +/- SD was 3.54% +/- 0.8% (range,
      2.7%-5.2%). In vivo, the mean common carotid artery blood flow volume was 456 +/-
      39 mL/min (range, 417-583 mL/min) with a mean diameter of 6.7 +/- 0.7 mm (range,
      5.8-8.7 mm). The mean internal carotid artery blood flow volume was 277 +/- 25
      mL/min (range, 239-338 mL/min) with a mean diameter of 5 +/- 0.5 mm (range, 4.1
      6.1 mm). No significant difference was found between operators. Internal carotid
      artery diameter and blood flow volume measured by the FlowGuard were closely
      correlated with the results of Duplex sonography. Repeated shifts of end-tidal
      CO2 induced reproducible changes in internal carotid artery flow volume: 187.5 +/
      18.1 mL/min at 26.8 +/- 1.9 mm Hg and 382.1 +/- 18.2 mL/min at 47 +/- 2.2 mm Hg.
      CONCLUSIONS: The FlowGuard showed that volume flow studies in the internal
      carotid artery could be easily performed, with results compatible with those of
      previous clinical reports. Duplex comparative results and breath-induced changes
      in internal carotid artery flow volume justify further evaluation of the system.

PMID- 12494984
TI  - Sonographically guided antegrade common femoral artery access.
AB  - OBJECTIVE: To evaluate the feasibility of sonographically guided antegrade common
      femoral artery puncture and superficial femoral artery access. METHODS: Fifty
      antegrade common femoral artery punctures and superficial femoral artery access
      procedures were performed under sonographic guidance alone in 30 consecutive
      patients (24 male and 6 female; mean age, 55.1 +/- 25.7 years; range, 13-85
      years). The indications were (1) insertion of a vascular sheath for balloon
      angioplasty in 42 attempts (24 patients with lower leg ischemia) and (2)
      insertion of an angiographic catheter for 1-shot intra-arterial chemoinfusion
      therapy in 8 attempts (6 patients with distal femoral osteosarcomas). RESULTS:
      Technical success was achieved in 28 of 30 patients or 48 (96%) of 50 procedures
      (95% confidence interval, 80.39-98.32). The average procedure time +/- SD
      (excluding the failures) was 3 +/- 1 minutes (range, 2-6 minutes). In the 2
      failures (2 [4%] of 50) in which common femoral artery punctures were
      accomplished, further superficial femoral artery cannulations were completed
      under fluoroscopic road map angiographic guidance. A small groin hematoma was
      noted in 1 patient. No arteriovenous fistula or pseudoaneurysm was encountered.
      CONCLUSIONS: Sonographically guided antegrade common femoral artery puncture and
      selective cannulation of the superficial femoral artery are feasible and safe.
      They may be used as adjunctive modalities in difficult cases of common femoral
      artery access.

PMID- 12494985
TI  - Sonographic detection of gallbladder duplication: two cases discovered in utero.
AB  - OBJECTIVE: To report the in utero diagnosis of a duplicated gallbladder. METHODS:
      Obstetric sonography was performed at 2 separate referral centers. A
      comprehensive level 11 examination was performed at each center. RESULTS: In both
      cases, a duplicated gallbladder was detected in utero without the presence of
      other anatomic abnormalities. CONCLUSIONS: Gallbladder duplication, although
      uncommon, should be considered when an additional cystic structure is seen in the
      right upper quadrant. Recognition of the presence of a duplicated gallbladder, a
      relatively benign condition, prevents invoking a more serious diagnosis, such as
      a choledochal or duodenal duplication cyst.

PMID- 12494986
TI  - Prenatal diagnosis of severe hypospadias with two- and three-dimensional
      sonography.

PMID- 12494987
TI  - Prenatal sonographic features of penoscrotal transposition.

PMID- 12494988
TI  - Pseudoaneurysm of the uterine artery after cesarean delivery: sonographic
      diagnosis and treatment.

PMID- 12494989
TI  - A cognitive behaviorist approach to the study of animal behavior.
AB  - Traditional psychological approaches to animal learning and behavior have
      involved either the atheoretical behaviorist approach proposed by B. F. Skinner
      (1938), in which input-output relations are described in response to
      environmental manipulations, or the theoretical behaviorist approach offered by
      C. L Hull (1943), in which associations mediated by several hypothetical
      constructs and intervening variables are formed between stimuli and responses.
      Recently, the application of a cognitive behaviorist approach to animal learning
      and behavior has been found to have considerable value as a research tool. This
      perspective has grown out of E. C. Tolman's cognitive approach to learning in
      which behavior is mediated by mechanisms that are not directly observable but can
      be inferred from the results of critical experiments. In the present article, the
      author presents several examples of the successful application of the cognitive
      behaviorist approach. In each case, the experiments have been designed to
      distinguish between more traditional mechanisms and those mediated by
      hypothesized internal representations. These examples were selected because the
      evidence suggests that some form of active cognitive organization is needed to
      account for the behavioral results.

PMID- 12494990
TI  - Common processes may contribute to extinction and habituation.
AB  - Psychologists routinely attribute the characteristics of conditioned behavior to
      complicated cognitive processes. For example, many of the characteristics of
      behavior undergoing extinction have been attributed to retrieval from memory. The
      authors argue that these characteristics may result from the simpler process of
      habituation. In particular, conditioned responding may decrease during extinction
      partially because habituation occurs to the stimuli that control responding when
      those stimuli are presented repeatedly or for a prolonged time (e.g., the
      experimental context, the conditioned stimulus in classical conditioning). This
      idea is parsimonious, has face validity, and evokes only processes that are well
      established by other evidence. In addition, behavior undergoing extinction shows
      12 of the fundamental properties of behavior undergoing habituation. However,
      this model probably cannot provide a complete theory of extinction. It provides
      no obvious explanation for some of the other characteristics of extinguished
      behavior.

PMID- 12494991
TI  - Behavioral and motivational effects of immune-system activation.
AB  - Immune-system activity induces changes in animal behavior such as decreased food
      intake, decreased exploratory behavior, increased sleep, and impaired cognitive
      functioning. These changes are mediated by proinflammatory cytokines, and the
      administration of cytokines produces the same profile of behavior change as do
      infection and inflammation. Results demonstrating differential effects of immune
      system activation depending on environmental contingencies and physiological
      states support the hypothesis that the behavioral effects of immune activity may
      be mediated by motivation. In this article, the author outlines the behavioral
      changes induced by immune-system activation and discusses evidence for a
      motivational analysis of immune-induced behavior change and the potential
      involvement of motivation in human sickness behavior.

PMID- 12494992
TI  - Two tests of the stuck-in-time hypothesis.
AB  - The authors report 2 experiments that test the stuck-in-time hypothesis, which
      argues that animals cannot time-date events and thus do not remember when events
      occurred and do not anticipate future events. In Experiment 1, rats in the
      experimental condition could earn a large reward by reentering the 1st arm that
      they visited on a radial maze. They did not learn to reenter this arm early and
      did no better than did a control group that was not given a large reward for
      reentering the first arm. In Experiment 2, rats in the experimental group could
      earn a large reward by delaying entry into a distinctive arm. These rats did not
      learn to delay entry into the distinctive arm, and they performed no better than
      did the control-group rats, which did not receive a large reward for delayed
      entry. These experiments provide further evidence in support of the stuck-in-time
      hypothesis.

PMID- 12494993
TI  - Shock-duration reduction on the basis of interresponse times: the effect of the
      interresponse time limit.
AB  - Rats were trained on a free-operant procedure in which the duration of randomly
      occurring shocks depended on the interresponse times of lever presses. Shocks of
      1.6-mA intensity were delivered at random intervals with an average density of 10
      shocks per min. Each shock that was delivered lasted 0.3 s as long as the
      interresponse times were within a preset limit. Whenever the interresponse time
      exceeded the limit, the shocks that were delivered lasted 1 s until the
      occurrence of a response that met the limit. The limit was reduced in 3-s steps
      from 15 s to either 6 s or 3 s, at which point 3 of the animals were exposed to
      an ascending series. The avoidance of long-duration shocks was highly efficient
      at the 15-s and 12-s limits, and it decreased at the 9-s limit. With the
      exception of one animal, performance was substantially worse at the 6-s limit and
      it deteriorated for all the animals that were exposed to the 3-s limit. The data
      suggest that shock-duration reduction is quite effective as negative
      reinforcement for avoidance but is perhaps less effective than shock-intensity
      reduction.

PMID- 12494994
TI  - Up or down: the influence of upcoming reinforcement on consummatory and operant
      behavior.
AB  - Research has shown that animal subjects that are given a chance to consume a low
      valued substance will consume less of it if a high-valued substance will soon be
      available than they would if the low-valued substance were to remain available
      (negative consummatory contrast). Research has also shown that subjects that
      lever press for a low-valued reinforcer will press the lever more often for that
      reinforcer if they will soon be able to lever press for a high-valued reinforcer
      than they would if they continue to press for the low-valued reinforcer (positive
      induction). The present study investigated these different changes in behavior
      across 3 experiments. The results suggest that the occurrence of contrast or
      induction does not depend on the type of substances that are used. We argue that
      further investigation of the contrast vs. induction issue is warranted because it
      has empirical, theoretical, and applied implications.

PMID- 12494995
TI  - Induction of Oct-3/4 expression in somatic cells by gap junction-mediated cAMP
      signaling from blastomeres.
AB  - We report the induction of embryonic gene expression in epithelial HC-11 cells
      upon communication with blastomeres in compacting mouse embryos. In contrast to
      NIH3T3 fibroblasts, HC-11 epithelial cells form gap junctions with blastomeres
      after injection into cleavage-stage embryos, as shown by targeting of
      phosphorylated connexin43 (pCx43) to areas of cell-to-blastomere contact and dye
      coupling. This was accompanied by expression of the embrvo-specific transcription
      factor, Oct-3/4, in the HC-11 cells. Dye coupling and Oct-3/4 expression were
      abolished with heptanol and 18beta- glycyrrhetinic acid, two gap junction
      blockers. Oleamide, which blocks gap junction-mediated communication but not
      electrical conductance, also inhibited Oct-3/4 expression in HC-11 cells,
      suggesting that Oct-3/4 induction results from transfer of molecules of < 1 kDa
      through gap junctions. Inhibition of cAMP signaling in blastomeres abolishes Oct
      3/4 expression in somatic cells despite gap junction formation. In addition,
      reprogramming of NIH3T3 fibroblasts in an extract of HC-11 cells enabled assembly
      of pCx43 and Oct-3/4 expression after contact of the reprogrammed cells with
      blastomeres. We propose that gap junction-mediated cAMP signaling between
      blastomeres and somatic cells results in changes in somatic cell gene expression.

PMID- 12494996
TI  - Loss of desmoglein 2 suggests essential functions for early embryonic development
      and proliferation of embryonal stem cells.
AB  - Desmoglein 2 (Dsg2) is a Ca(2+)-dependent adhesion molecule of desmosomes and is
      synthesized in all desmosome-bearing tissues from their earliest appearance
      onward. To examine the function of Dsg2, its gene was inactivated by homologous
      recombination in embryonal stem (ES) cells for the generation of knockout mice.
      DSG2 -/- mice and a considerable number of DSG2 +/- mice died at or shortly after
      implantation. On the other hand, DSG2 -/- blastocysts developed an apparently
      normal trophectoderm layer, the first tissue known to produce desmosomes, and
      hatched properly. Immunofluorescence analyses of these blastocysts showed,
      however, that the distribution of the desmosomal plaque protein desmoplakin was
      disturbed, whereas the adherens junction proteins E-cadherin and beta-catenin
      appeared to be unaffected. Unexpectedly, we found that Dsg2 seems to be essential
      for the inner cell mass and the ES cell population derived there from. We present
      evidence that Dsg2, which is located in desmoplakin-negative wild-type ES cells
      in non-desmosomal junctions, is needed for normal ES cell proliferation. Our
      observations thus reveal that important Dsg2 functions are desmosome-independent
      during early development and are needed for ES cell and early embryo survival.

PMID- 12494997
TI  - The human melanoma associated protein melanotransferrin promotes endothelial cell
      migration and angiogenesis in vivo.
AB  - Melanotransferrin is a member of the transferrin family, which is comprised of
      serum transferrin, lactoferrin and ovotransferrin, and is highly expressed on
      melanoma cells compared to normal melanocytes. Since melanoma is an highly
      vascularized tumour that expresses melanotransferrin at high levels, we tested
      purified recombinant melanotransferrin for its capability to induce angiogenesis
      in the chick chorioallantoic membrane. Macroscopic and microscopic evaluation of
      the vascular density demonstrated that melanotransferrin exerts an angiogenic
      response quantitatively similar to that elicited by fibroblast growth factor-2.
      Overexpression of vascular endothelial growth factor-receptor-2 was observed in
      newly formed vessels, suggesting that the angiogenic activity of
      melanotransferrin may depend on activation of endogenous vascular endothelial
      growth factor. In addition, when antibodies against vascular endothelial growth
      factor were included in the assay, the angiogenic response was inhibited by 50%.
      In a Boyden chamber assay purified recombinant melanotransferrin induced
      chemotactic migration of vascular cells, which was decreased in the the presence
      of anti-vascular endothelial growth factor antibodies suggesting an involvement
      of vascular endothelial growth factor present in endothelial cells also in this
      assay. However, melanotransferrin was found not to directly bind to integrin
      alphavbeta3 or the vascular endothelial growth factor-receptor-2 as assessed in a
      BlAcore assay. A possible correlation between vascularization occurring during
      melanoma progression and the expression of melanotransferrin and vascular
      endothelial growth factor was established by immunolocalization of the two
      factors in sections of melanoma at different clinical steps of melanoma
      progression. These latter data strongly imply that melanotransferrin may
      participate in the vascularization of solid tumours and that inhibition of
      melanotransferrin could form the basis for intervention in tumours which use this
      pathway.

PMID- 12494998
TI  - Characterisation of the lumenal domain of TGN38 and effects of elevated
      expression of TGN38 on glycoprotein secretion.
AB  - The TGN-localised, type I integral membrane protein TGN38 has previously been
      suggested to play a role as a cargo transporter within mammalian cells. We have
      undertaken a series of experiments designed to address this hypothesis, and, in
      so doing, have partially characterised the glycosylation status of the lumenal
      domain of TGN38. We find that elevated expression of different regions of the
      lumenal domain of TGN38 has no reproducible effect on secretion from stably
      transfected NRK cells expressing the different lumenal domain constructs; neither
      does it affect the gross morphology of organelles of the secretory and endocytic
      pathways. However, we observed that, whilst elevated expression of full-length
      TGN38 in stably transfected NRK cells does not have any significant effect on the
      morphology of organelles of the secretory and endocytic pathways, it does lead to
      a change in the pattern of protein secretion from these cells. In particular,
      elevated expression of full-length TGN38 led to increased secretion of a 48-kDa
      glycoprotein identified as plasminogen activator inhibitor-1.

PMID- 12494999
TI  - Concentration of Ran on chromatin induces decondensation, nuclear envelope
      formation and nuclear pore complex assembly.
AB  - Nuclear envelope (NE) formation can be studied in a cell-free system made from
      Xenopus eggs. In this system, NE formation involves the small GTPase Ran. Ran
      associates with chromatin early in nuclear assembly and concentration of Ran on
      inert beads is sufficient to induce NE formation. Here, we show that Ran binds to
      chromatin prior to NE formation and recruits RCC1, the nucleotide exchange factor
      that generates Ran-GTP. In extracts prepared by high-speed centrifugation,
      increased concentrations of Ran are sufficient to induce chromatin decondensation
      and NE assembly. Using field emission in-lens scanning electron microscopy
      (FEISEM), we show that Ran promotes the formation of smoothed membranes and the
      assembly of nuclear pore complexes (NPCs). In contrast, RanT24N, a mutant that
      fails to bind GTP and inhibits RCC1, does not support efficient NE assembly,
      whereas RanQ69L, a mutant locked in a GTP-bound state, permits some membrane
      vesicle recruitment to chromatin, but inhibits vesicle fusion and NPC assembly.
      Thus, binding of Ran to chromatin, followed by local generation of Ran-GTP and
      GTP hydrolysis by Ran, induces chromatin decondensation, membrane vesicle
      recruitment, membrane formation and NPC assembly. We propose that the biological
      activity of Ran is determined by its targeting to structures such as chromatin as
      well as its guanine nucleotide bound state.

PMID- 12495000
TI  - Determination of the occurrence of Arcobacter butzleri in beef and dairy cattle
      from Texas by various isolation methods.
AB  - Arcobacter butzleri is a pathogenic bacterium that has been found in dairy
      cattle, pigs, poultry, and humans. As of this writing, there are no data on the
      incidence of A. butzleri in beef cattle. Given the differences in rearing
      practices used for feedlot cattle and those used for dairy cattle, differences in
      the incidences of this organism in various types of cattle may also exist.
      Numerous culture methods have been used to isolate A. butzleri, but there are few
      data on the comparative efficacies of these methods. The objectives of this study
      were to determine the incidence of A. butzleri in cattle from Texas and to
      compare the effectiveness levels of the Johnson-Murano (JM) method (consisting of
      enrichment in JM broth followed by plating on JM agar) and the Collins method
      (consisting of enrichment in EMJH-P80 broth followed by plating on Cephalothin,
      Vancomycin, and Amphotericin B [CVA] agar) in the isolation of this organism.
      Fifty cattle each from two feedlots, a dairy, and a stocker yard were sampled.
      Fecal swabs were obtained from cattle, and each sample was cultured by the JM
      method, the Collins method, and combinations of the two methods with the broth of
      one method being used with the agar of the other. Polymerase chain reaction was
      used to identify the isolates for confirmation of A. butzleri. Samples from 18 of
      200 cattle tested positive for A. butzleri. This organism was detected by the JM
      method in 4.5% of the samples and by the Collins method in 2.5% of the samples.
      An incidence of 4.0% was found when JM broth was used with CVA agar, while no
      samples tested positive for A. butzleri when EMJH-P80 broth was used with JM
      agar.

PMID- 12495001
TI  - Fate of Escherichia coli O157:H7 during silage fermentation.
AB  - The survival characteristics of Escherichia coli O157:H7 in silage derived from
      contaminated grass were investigated. The survival of other enteric bacteria was
      also investigated to determine if E. coli O157:H7 demonstrates enhanced acid
      tolerance in comparison. Samples of chopped grass were treated as follows: (i) no
      additive (control); (ii) inoculation with E. coli O157:H7 to a final
      concentration of log10 4.0 CFU g(-1); (iii) addition of an 85% solution of formic
      acid at 3.0 ml kg(-1) grass; and (iv) addition of both E. coli O157:H7 and formic
      acid, at the above concentrations. Treated 6-kg grass samples were packed into
      laboratory silos, sealed, and stored at 15 degrees C for up to 180 days.
      Individual replicate silos were removed from storage periodically and subjected
      to microbiological and chemical analyses. Chemical analyses of the silage samples
      indicated that lactic acid-dominant fermentations, with a rapid drop in pH,
      occurred. Numbers of enteric bacteria decreased from log10 7.0 to 8.0 CFU g(-1)
      to undetectable levels within 19 days' storage. E. coli O157:H7 did not survive
      the silage fermentation process, with numbers declining from approximately log10
      4.0 CFU g(-1) to undetectable levels within 19 days of ensiling. The pattern of
      decline in numbers of E. coli O157:H7 was the same as that for the enteric
      bacteria, indicating that under the conditions tested, the acid tolerance of E.
      coli O157:H7 was not significantly different from the acid tolerance of other
      enteric bacteria. This study found that E. coli O157:H7 did not survive a good
      silage fermentation process, indicating that properly ensiled grass that is
      correctly stored is unlikely to be a vector for the transmission of the pathogen
      among cattle.

PMID- 12495002
TI  - Distribution of Salmonella in swine production ecosystems.
AB  - The objective of this 2-year field survey was to sample multiple ecological
      compartments within swine production systems to identify potential sources of
      Salmonella infection for swine. Twelve single-site production systems within
      Illinois were identified by slaughter sampling to have detectable Salmonella in
      swine and therefore selected for study. There were four visits to each farm
      during a 5-month period. Fecal samples were obtained from swine and other wild
      and domestic mammals. Arthropods and environmental samples of feed, water, pen
      floors, boots, and bird feces were also collected. All 8,066 samples obtained
      were cultured to detect Salmonella. Salmonella was detected on 11 of the 12
      farms. There were 206 positive cultures, including samples from swine (83), pen
      floors (54), boots (32), flies (16), mice (9), cats (3), and birds (3). Swine
      shedding Salmonella in feces were detected on 9 of the 12 farms. The more
      Salmonella-abundant ecological compartments were cats (12% of samples positive),
      boots (11%), bird feces (8%), flies (6%), and mice (5%); 2.1% of 4,024 swine
      samples were positive. All 221 feed samples were negative for Salmonella. There
      was a correlation between a farm having a high prevalence of shedding Salmonella
      in pigs and a high abundance on pen floors, flies, and boots. The most common
      serotypes detected were Derby, Agona, Worthington, and Uganda, which were
      distributed throughout the ecosystem, suggesting widespread transmission across
      ecological compartments. The ubiquitous distribution of Salmonella suggests that
      an effective control strategy must target multiple compartments of the swine
      production ecosystem.

PMID- 12495003
TI  - Prevalence of Salmonella in two Botswana abattoir environments.
AB  - A 1-year study was carried out to investigate the prevalence of Salmonella in two
      abattoir environments coded "A" and "B" in Gaborone, Botswana. The total number
      of environmental samples collected from abattoirs A and B was 250 and 300,
      respectively. The samples were taken from soils in the corrals, knife blades, saw
      blades, cattle-drinking water, cattle feces, and feed. Preenrichment, enrichment,
      and selective/differential media, which enabled the favorable growth of
      Salmonella, were used in the study. Salmonellae were present in all sampled
      environments. The most common serotypes found in the environment at abattoir A
      were E1, C1, C2, and B. Serotypes B, C1, C2, C3, and E1 were common in abattoir
      B. Antigenic characterization of the salmonellae isolates showed that Salmonella
      Anatum, Salmonella Azteca, Salmonella Saintpaul, Salmonella Cerro, and Salmonella
      Westhampton were predominant in abattoir A, whereas Salmonella Anatum, Salmonella
      Mbandaka, Salmonella Molade, Salmonella Reading, and Salmonella Oranienburg were
      dominant in abattoir B. Implementing hazard analysis critical control point
      principles in work procedures would definitely reduce the gross contamination
      taking place in abattoirs.

PMID- 12495004
TI  - Density of total and pathogenic (tdh+) Vibrio parahaemolyticus in Atlantic and
      Gulf coast molluscan shellfish at harvest.
AB  - The densities of total and pathogenic Vibrio parahaemolyticus in 671 samples of
      molluscan shellfish harvested in 1999 and 2000 from 14 sites in seven Gulf and
      Atlantic coast states were determined at 2-week intervals over a period of 12 to
      16 months in each state. Changes in V. parahaemolyticus densities in shellfish
      between harvest and sample analysis were minimized with time and temperature
      controls. Densities were measured by direct plating techniques, and gene probes
      were used for identification. Total and pathogenic V. parahaemolyticus organisms
      were identified with probes for the thermolabile direct hemolysin (tlh) gene and
      the thermostable direct hemolysin (tdh) gene, respectively. An enrichment
      procedure involving 25 g of shellfish was also used for the recovery of
      pathogenic V. parahaemolyticus. The densities of V. parahaemolyticus in shellfish
      from all harvest sites were positively correlated with water temperature.
      Shellfish from the Gulf Coast typically had higher densities of V.
      parahaemolyticus than did shellfish harvested from the North Atlantic or mid
      Atlantic coast. Vibrio parahaemolyticus counts exceeded 1,000 CFU/g for only 5%
      of all samples. Pathogenic (tdh+) V. parahaemolyticus was detected in
      approximately 6% of all samples by both procedures, and 61.5% of populations in
      the positive samples from the direct plating procedure were at the lower limit of
      detection (10 CFU/g). The frequency of detection of pathogenic V.
      parahaemolyticus was significantly related to water temperature and to the
      density of total V. parahaemolyticus. The failure to detect pathogenic V.
      parahaemolyticus in shellfish more frequently was attributed to the low numbers
      and uneven distribution of the organism.

PMID- 12495005
TI  - Bacterial contamination of cucumber fruit through adhesion.
AB  - In this study, the adhesion of bacteria to fresh cucumber surfaces in aqueous
      suspension was shown to be dependent on time of incubation, inoculum species and
      concentration, and temperature. The adhesion of bacteria to the fruit in wash
      water was less extensive at lower temperatures and shorter exposure times.
      Various species of bacteria were adsorbed to cucumber surfaces in the following
      relative order: Salmonella Typhimurium > Staphylococcus aureus > Lactobacillus
      plantarum > Listeria monocytogenes. Cells were adsorbed at all temperatures
      tested (5, 15, 25, and 35 degrees C) at levels that depended on incubation time,
      but the numbers of cells adsorbed were larger at higher incubation temperatures.
      Levels of adhesion of bacteria to dewaxed fruit were higher for L. monocytogenes
      and lower for Salmonella Typhimurium, L. plantarum, and S. aureus than were
      levels of adhesion to waxed fruit.

PMID- 12495006
TI  - Incidence and susceptibility to antimicrobial agents of Listeria spp. and
      Listeria monocytogenes isolated from poultry carcasses in Porto, Portugal.
AB  - The occurrence of Listeria spp. and Listeria monocytogenes in 63 samples of
      Portuguese poultry carcasses obtained from two local butcher shops and one
      canteen in the city of Porto, Portugal, and the susceptibility of these bacteria
      to antimicrobial agents allowed for use in human or animal therapeutics were
      evaluated. All poultry samples were contaminated with Listeria spp., and L.
      monocytogenes was isolated from 41% (26 of 63) of the samples. Other Listeria
      species, including L. innocua, L. welshimeri, and L. seeligeri, were also
      isolated from poultry samples. A multiplex polymerase chain reaction method was
      used for the identification of all of the Listeria isolates; this method showed
      total conformity with the conventional method of biochemical identification and
      proved to be more reliable, faster, and less arduous. In addition, high
      percentages of Listeria spp. (84%) and L. monocytogenes (73%) isolates were found
      to be resistant to one or more antimicrobial agents of different groups, and 12
      different resistance profiles were recorded. The frequency of the resistance of
      L. monocytogenes isolates to enrofloxacin and clindamycin is notable. The results
      of this study suggest a high incidence of L. monocytogenes on Portuguese poultry
      products available for consumers and indicate that poultry could be a potential
      vehicle of foodborne infections due to strains of L. monocytogenes that are
      resistant to antimicrobial agents.

PMID- 12495007
TI  - Distribution patterns of Escherichia coli O157:H7 in ground beef produced by a
      laboratory-scale grinder.
AB  - This study determined the distribution patterns of Escherichia coli O157:1H7 in
      ground beef when a contaminated beef trim was introduced into a batch of
      uncontaminated beef trims prior to grinding in a small-scale laboratory grinder.
      A beef trim (15.3 +/- 2 g) was inoculated with a rifampicin-resistant strain of
      E. coli O157:H7 (E. coli O157:H7rif) and introduced into a stream of
      noncontaminated beef (322 +/- 33 g) prior to grinding. Seven inoculum levels (6,
      5, and 4 total log CFU [high]; and 3, 2, 1, and 0 total log CFU [low]) were
      studied in triplicate. E. coli O157:H7rif was not detected in 3.1 to 43% of the
      ground beef inoculated with the high levels or in 3.4 to 96.9% of the ground beef
      inoculated with the low levels. For all inoculum levels studied, the five ground
      beef fractions (each 7.8 +/- 0.6 g) with the highest pathogen levels accounted
      for 59 to 100% of the total pathogens detected. For all inoculum levels, there
      was a linear relationship between the quantity of ground beef containing E. coli
      O157:H7rif and the inoculum level. The quantity of E. coli O157:H7rif in the beef
      remaining in the grinder was proportional to the inoculum level and was related
      to the location in the grinder. Different components of the grinder accumulated
      E. coli O157:H7rif in different quantities, with the most significant
      accumulation being in the nut (collar) that attaches the die to the blade. This
      study determined specific distribution patterns of E. coli O157:H7rif after the
      grinding of a contaminated beef trim along with uncontaminated trims, and the
      results indicate that the grinding operation should be regarded as a means of
      distribution of microbial contamination in risk analyses of ground beef
      operations.

PMID- 12495008
TI  - Composition and physiological profiling of sprout-associated microbial
      communities.
AB  - The native microfloras of various types of sprouts (alfalfa, clover, sunflower,
      mung bean, and broccoli sprouts) were examined to assess the relative effects of
      sprout type and inoculum factors (i.e., sprout-growing facility, seed lot, and
      inoculation with sprout-derived inocula) on the microbial community structure of
      sprouts. Sprouts were sonicated for 7 min or hand shaken with glass beads for 2
      min to recover native microfloras from the surface, and the resulting suspensions
      were diluted and plated. The culturable fraction was characterized by the density
      (log CFU/g), richness (e.g., number of types of bacteria), and diversity (e.g.,
      microbial richness and evenness) of colonies on tryptic soy agar plates incubated
      for 48 h at 30 degrees C. The relative similarity between sprout-associated
      microbial communities was assessed with the use of community-level physiological
      profiles (CLPPs) based on patterns of utilization of 95 separate carbon sources.
      Aerobic plate counts of 7.96 +/- 0.91 log CFU/g of sprout tissue (fresh weight)
      were observed, with no statistically significant differences in microbial cell
      density, richness, or diversity due to sprout type, sprout-growing facility, or
      seed lot. CLPP analyses revealed that the microbial communities associated with
      alfalfa and clover sprouts are more similar than those associated with the other
      sprout types tested. Variability among sprout types was more extensive than any
      differences between microbial communities associated with alfalfa and clover
      sprouts from different sprout-growing facilities and seed lots. These results
      indicate that the subsequent testing of biocontrol agents should focus on similar
      organisms for alfalfa and clover, but alternative types may be most suitable for
      the other sprout types tested. The inoculation of alfalfa sprouts with
      communities derived from various sprout types had a significant, source
      independent effect on microbial community structure, indicating that the process
      of inoculation alters the dynamics of community development regardless of the
      types of organisms involved.

PMID- 12495009
TI  - Microbial antagonists of foodborne pathogens on fresh, minimally processed
      vegetables.
AB  - On many types of raw or minimally processed foods, the bacterial microbiota is
      often composed of mixed species. The activities of one bacterial species may
      influence the growth and activities of others that are present. The objective of
      this project was to evaluate the microbial composition of fresh and minimally
      processed vegetables to determine if naturally occurring bacteria on produce are
      competitive with or antagonistic to potentially encountered pathogens. Naturally
      occurring bacteria were obtained from ready-to-eat salad vegetables on four
      occasions to allow for seasonal variation. Minimally processed vegetables were
      sampled at various stages in their processing from raw vegetables to packaged
      products. Some portions were analyzed microbiologically within 24 h, while other
      portions were stored refrigerated and analyzed after 72 h. Microbiological
      analysis was conducted for bacterial enumeration and to obtain isolates. An agar
      spot method was used to screen isolates for antimicrobial activity against
      Staphylococcus aureus ATCC 27664, Escherichia coli O157:H7 E009, Listeria
      monocytogenes LCDC 81-861, and Salmonella Montevideo. Of the 1,180 isolates
      screened for inhibitory activity, 37 (3.22%) were found to have various degrees
      of inhibitory activity against at least one test pathogen. Many isolates showed
      inhibitory activity against all four pathogens. The isolates with the most
      extensive inhibition were removed from finished lettuce piece shreds. Of the 37
      inhibitory isolates, 34 (91.9%) were gram negative. All isolates with inhibitory
      activity are able to multiply at both 4 and 10 degrees C.

PMID- 12495010
TI  - Lytic and nonlytic mechanism of inactivation of gram-positive bacteria by
      lysozyme under atmospheric and high hydrostatic pressure.
AB  - A different behavior was observed in three gram-positive bacteria exposed to hen
      egg white lysozyme by plate counts and phase-contrast microscopy. The
      inactivation of Lactobacillus johnsonii was accompanied by spheroplast formation,
      which is an indication of peptidoglycan hydrolysis. Staphylococcus aureus was
      resistant to lysozyme and showed no signs of peptidoglycan hydrolysis, and
      Listeria innocua was inactivated and showed indications of cell leakage but not
      of peptidoglycan hydrolysis. Under high hydrostatic pressure, S. aureus also
      became sensitive to lysozyme but did not form spheroplasts and was not lysed.
      These results suggested the existence of a nonlytic mechanism of bactericidal
      action of lysozyme on the latter two bacteria, and this mechanism was further
      studied in L. innocua. Elimination of the enzymic activity of lysozyme by heat
      denaturation or reduction with beta-mercaptoethanol eliminated this bactericidal
      mechanism. By means of a LIVE/DEAD viability stain based on a membrane-impermeant
      fluorescent dye, the nonlytic mechanism was shown to involve membrane
      perturbation. In the absence of lysozyme, high-pressure treatment was shown to
      induce autolytic activity in S. aureus and L. innocua.

PMID- 12495011
TI  - Effect of dissolved carbon dioxide on thermal inactivation of microorganisms in
      milk.
AB  - Postpasteurization addition of CO2 inhibits growth of certain microorganisms in
      dairy products, but few workers have investigated the effect of CO2 on the
      thermal inactivation of microorganisms during pasteurization. Concentrations of
      CO2 ranging from 44 to 58 mM added to raw whole milk significantly (P < 0.05)
      reduced the number of surviving standard plate count (SPC) organisms in milk
      heated over the range of 67 to 93 degrees C. A decrease in thermal survival rates
      (D-values) for Pseudomonas fluorescens R1-232 and Bacillus cereus ATCC 14579
      spores in milk was positively correlated with CO2 concentrations (1 to 36 mM).
      D(50 degrees C)-values for P. fluorescens significantly decreased (P < 0.05) in a
      linear fashion from 14.4 to 7.2 min. D(89 degrees C)-values for B. cereus spores
      were significantly (P < 0.05) decreased from 5.56 min in control milk to 5.29 min
      in milk containing 33 mM CO2. The Weibull function was used as a model to
      describe the thermal inactivation of P. fluorescens, B. cereus spores, and SPC
      organisms in raw milk. Nonlinear parameters for the Weibull function were
      estimated, and survival data fitted to this model had higher R2 values than when
      fitted to the linear model, further providing support that the thermal
      inactivation of bacteria does not always follow first-order reaction rate
      kinetics. These results suggest that CO2 could be used as a processing aid to
      enhance microbial inactivation during pasteurization.

PMID- 12495012
TI  - Altered ability of Bacillus cereus spores to grow under unfavorable conditions
      (presence of nisin, low temperature, acidic pH, presence of NaCl) following heat
      treatment during sporulation.
AB  - The effect of thermal treatment on the heat resistance of Bacillus cereus spores
      and their ability to germinate and grow under more or less adverse conditions
      during sporulation was investigated. Spores produced by sporulating cells
      subjected to a mild heat treatment (at a temperature 15 degrees C higher than the
      growth temperature) were more resistant to heat than were spores produced by
      untreated cells. Spore germination and growth (the lag time, the maximal growth
      rate, and the occurrence of a decrease in population) may be greatly affected by
      adverse environmental conditions brought about by the addition of nisin, low
      temperatures, acidic pHs, and, to a lesser extent, the addition of NaCl.
      Furthermore, heat treatments applied to sporulating cells or to mature spores
      induced a modification of the lag time (interaction of both treatments).
      Therefore, mild heat treatments applied during sporulation may affect the heat
      resistance of spores and the ability of these spores to germinate under adverse
      conditions and may thus increase the risk associated with the presence of spores
      in lightly processed foods.

PMID- 12495013
TI  - Factors affecting patulin production by Penicillium expansum.
AB  - Patulin, a mycotoxin produced by Penicillium spp. during fruit spoilage, is a
      major concern with regard to human health because exposure can result in severe
      acute and chronic toxicity, including carcinogenic, mutagenic, and teratogenic
      effects. In this study, we investigated the effects of Penicillium expansum
      isolate, apple cultivar, storage temperature and time, and pH on the production
      of patulin. Patulin was analyzed by a previously developed micellar
      electrokinetic capillary electrophoresis method. P. expansum isolates originating
      from across Ontario produced widely differing levels of patulin, ranging from 0
      to >6 mg/g by dry mycelial weight. The highest patulin levels were those for
      isolates displaying aggressive growth (characterized by rapidly increasing
      acidity) accompanied by profuse mycelial development. Distinct patterns in fungal
      growth rates and patulin production were evident among isolates grown in
      McIntosh, Empire, and Mutsu ciders. Extensive fungal growth and higher patulin
      levels (538 to 1,822 microg/ml on day 14) in apple ciders were associated with
      incubation at room temperature (25 degrees C), although potentially toxic patulin
      levels (75 to 396 microg/ml on day 24) were also found in refrigerated ciders (4
      degrees C) inoculated with P. expansum.

PMID- 12495014
TI  - Utilization of fluorogenic assay for rapid detection of Escherichia coli in
      acidic fruit juice.
AB  - This study was undertaken to investigate interference by acids commonly found in
      fruit juice in Escherichia coli assays involving the use of 4-methylumbelliferyl
      beta-D-glucuronide (MUG) as a fluorogenic substrate for enzyme reaction.
      Fluorescence intensity was negatively correlated (P < 0.001) with the volume of
      fresh citrus juice tested by the lauryl tryptose broth (LST)-MUG assay, and the
      permissible sample sizes were limited to 0.3 and 0.5 ml for fresh citrus juices
      with pHs of 3.3 and 3.9, respectively. In addition, false-negative results were
      visually observed under UV light when the E*Colite assay was used to test large
      volumes (5 to 10 ml per test) of fresh citrus juice or when the test broth used
      for the LST-MUG assay was supplemented with citric, malic, or tartaric acid at 2
      to 4 g/liter. These results suggest that the size and pH of acidic samples should
      be controlled in MUG-based fluorogenic assays. The inhibitory effect on
      fluorescence was due to high acidity, which reduces fluorescence from 4
      methylumbelliferone. Buffering improved the assays. When sodium bicarbonate was
      incorporated in the enrichment broth at 10 g/liter, the permissible sample sizes
      for fresh grapefruit juice (pH 3.1) increased from 0.3 to 1 ml for the LST-MUG
      (with 9.9 ml of broth) assay and from 3 to 10 ml for the E*Colite (with 99 ml of
      broth) assay.

PMID- 12495015
TI  - Optimizing enrichment culture conditions for detecting Helicobacter pylori in
      foods.
AB  - The survival and growth of Helicobacter pylori under enrichment conditions in
      fresh, autoclaved and irradiated ground beef were determined. H. pylori grew in
      autoclaved ground beef at 37 degrees C under microaerobic conditions in brain
      heart infusion broth with 7% horse serum at pH 7.3 after 3 to 7 days of lag time
      but did not grow within 7 days in irradiated (10 kGy) ground beef under the same
      enrichment conditions. Adjustment of the enrichment broth to pH 5.5 enabled the
      growth (ca. 2 log10 CFU/ml) of H. pylori within 7 days in the presence of
      irradiated ground beef and the prolific growth (ca. 3 to 4 log10 CFU/ml) of H.
      pylori within 3 days in the presence of autoclaved beef. H. pylori in fresh
      ground beef could not be isolated from enrichment media with antibiotics;
      however. H. pylori ureA could be detected by polymerase chain reaction (PCR) in
      such enrichment media after 1 to 3 days of incubation at 37 degrees C. The
      addition of supplements, i.e., 0.3% mucin, 0.05% ferrous sulfate, and 0.05%
      sodium pyruvate or 0.008 M urea, or the adjustment of the enrichment broth pH to
      5.5 or 4.5 enabled the detection of H. pylori ureA in enrichment media incubated
      for 1, 2, 3, and/or 7 days at 37 degrees C. H. pylori in sterile milk
      refrigerated at 4 degrees C at an initial level of 10(6) CFU/ml was inactivated
      to an undetectable level within 6 days; however, H. pylori was not detected
      either by a PCR assay or by the plating of enrichment cultures of 120 raw bovine
      milk samples.

PMID- 12495016
TI  - Multiplex polymerase chain reaction assay for the differential detection of
      trichothecene- and fumonisin-producing species of Fusarium in cornmeal.
AB  - The genus Fusarium comprises a diverse group of fungi including several species
      that produce mycotoxins in food commodities. In this study, a multiplex
      polymerase chain reaction (PCR) assay was developed for the group-specific
      detection of fumonisin-producing and trichothecene-producing species of Fusarium.
      Primers for genus-level recognition of Fusarium spp. were designed from the
      internal transcribed spacer regions (ITS1 and ITS2) of rDNA. Primers for group
      specific detection were designed from the TRI6 gene involved in trichothecene
      biosynthesis and the FUM5 gene involved in fumonisin biosynthesis. Primer
      specificity was determined by testing for cross-reactivity against purified
      genomic DNA from 43 fungal species representing 14 genera, including 9
      Aspergillus spp., 9 Fusarium spp., and 10 Penicillium spp. With purified genomic
      DNA as a template, genus-specific recognition was observed at 10 pg per reaction;
      group-specific recognition occurred at 100 pg of template per reaction for the
      trichothecene producer Fusarium graminearum and at 1 ng of template per reaction
      for the fumonisin producer Fusarium verticillioides. For the application of the
      PCR assay, a protocol was developed to isolate fungal DNA from cornmeal. The
      detection of F. graminearum and its differentiation from F. verticillioides were
      accomplished prior to visible fungal growth at <10(5) CFU/g of cornmeal. This
      level of detection is comparable to those of other methods such as enzyme-linked
      immunosorbent assay, and the assay described here can be used in the food
      industry's effort to monitor quality and safety.

PMID- 12495017
TI  - Modified concentration method for the detection of enteric viruses on fruits and
      vegetables by reverse transcriptase-polymerase chain reaction or cell culture.
AB  - Fruits and vegetables may act as a vehicle of human enteric virus if they are
      irrigated with sewage-contaminated water or prepared by infected food handlers.
      An elution-concentration method was modified to efficiently detect, by reverse
      transcriptase-polymerase chain reaction (RT-PCR) or by cell culture,
      contamination by poliovirus, hepatitis A virus (HAV), and Norwalk-like virus
      (NLV) of various fresh and frozen berries and fresh vegetables. The protocol
      included washing the fruit or vegetable surface with 100 mM Tris-HCl, 50 mM
      glycine, and 3% beef extract, pH 9.5 buffer, which favors viral elution from acid
      releasing berries, supplemented with 50 mM MgCl2 to reduce the decrease in viral
      infectivity during the process. The viral concentration method was based on
      polyethylene glycol precipitation. Copurified RT-PCR inhibitors and cytotoxic
      compounds were removed from viral concentrates by chloroform-butanol extraction.
      Viruses from 100 g of vegetal products could be recovered in volumes of 3 to 5
      ml. Viral RNAs were isolated by a spin column method before molecular detection
      or concentrates were filtered (0.22-microm porosity) and inoculated on cell
      culture for infectious virus detection. About 15% of infectious poliovirus and
      20% of infectious HAV were recovered from frozen raspberry surfaces. The
      percentage of viral RNA recovery was estimated by RT-PCR to be about 13% for NLV,
      17% for HAV, and 45 to 100% for poliovirus. By this method, poliovirus and HAV
      RNA were detected on products inoculated with a titer of about 5 x 10(1) 50%
      tissue culture infectious dose per 100 g. NLV RNA was detected at an initial
      inoculum of 1.2 x 10(3) RT-PCR amplifiable units. This method would be useful for
      the viral analysis of fruits or vegetables during an epidemiological
      investigation of foodborne diseases.

PMID- 12495018
TI  - Evidence for Escherichia coli O157:H7 attachment to water distribution pipe
      materials by scanning electron microscopy.
AB  - Scanning electron microscopy observation was used to investigate the adhesion of
      Escherichia coli O157:H7 on water distribution pipe surfaces such as copper and
      polyethylene plastic at different contact times and storage temperatures. Our
      results indicated that E. coli cells could easily attach to both surface types
      after exposures as short as 1 or 4 h at ambient (20 degrees C) and refrigeration
      temperatures (4 degrees C). Also, we found that copper surfaces have a higher
      number of attached E. coli cells than plastic surfaces. The number of cells
      attached to each type of material depended on the nature of the water
      distribution pipe surfaces and the length of contact time. In addition, the
      surface energy value of each surface estimated by contact angle measurements
      using water, alpha-bromonaphthalene, and dimethyl sulfoxide as wetting agents
      showed that both copper (41.2 megajoules [MJ] m(-2)) and plastic (45.8 MJ x m(
      2)) have a low energy surface. In no cases could evidence of extracellular
      material be observed on surfaces with either exposure condition.

PMID- 12495019
TI  - Death of Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes in
      garlic butter as affected by storage temperature.
AB  - Garlic is known to have antimicrobial activity against several spoilage and
      pathogenic bacteria. However, the fate of Salmonella, Escherichia coli O157:H7,
      and Listeria monocytogenes in garlic butter has not been reported. This study was
      undertaken to determine the viability of these organisms in garlic butter as
      affected by the type of raw minced garlic added to the butter, storage
      temperature, and storage time. Unsalted butter at 40 degrees C was combined with
      raw minced jumbo, elephant, or small-cloved garlic at a 4:1 butter/garlic ratio
      (wt/wt), inoculated with mixed-strain suspensions of Salmonella, E. coli O157:H7,
      or L monocytogenes, and stored at 4.4, 21, or 37 degrees C for up to 48 h. All
      pathogens retained their viability at 4.4 degrees C, regardless of the presence
      of garlic. The addition of garlic to butter enhanced the rates of inactivation of
      all three pathogens at 21 and 37 degrees C. The most rapid decline in pathogen
      populations was observed at 37 degrees C. The inactivation of L. monocytogenes
      occurred more slowly than did that of Salmonella or E. coli O157:H7. The
      inactivation of Salmonella and L. monocytogenes was more rapid in jumbo garlic
      butter than in elephant or small-cloved garlic butter. It is concluded that
      Salmonella, E. coli O157:H7, and L. monocytogenes did not grow in unsalted
      butter, with or without garlic added (20%, wt/wt), when inoculated products were
      stored at 4.4, 21, and 37 degrees C for up to 48 h.

PMID- 12495020
TI  - Use of vacuum-steam-vacuum and ionizing radiation to eliminate Listeria innocua
      from ham.
AB  - Listeria spp. are a frequent postprocess contaminant of ready-to-eat (RTE) meat
      products, including ham. Vacuum-steam-vacuum (VSV) technology has been used
      successfully to eliminate Listeria innocua from hot dogs. Ionizing radiation can
      eliminate Listeria spp. from RTE meats. However, the excessive application of
      either technology can cause changes in product quality, including structural
      changes, changes in cure color (redness), and lipid oxidation. In this study, two
      cycles of VSV were combined with 2.0 kGy of ionizing radiation to obtain 4.40-
      and 4.85-log10 reductions of L. innocua on ham meat and skin, respectively. The
      use of both treatments resulted in an additive, as opposed to synergistic,
      reduction of L. innocua on ham. The combination treatment did not cause
      statistically significant changes in product structure, color (redness), or lipid
      oxidation.

PMID- 12495021
TI  - No effect of soybean lipoxygenase on aflatoxin production in Aspergillus flavus
      inoculated seeds.
AB  - Soybean lines lacking lipoxygenase (LOX) activity were compared with soybean
      lines having LOX activity for the ability to support growth and aflatoxin B1
      production by the fungal seed pathogen Aspergillus flavus. Whole seeds, broken
      seeds, and heat-treated (autoclaved) whole seeds were compared. Broken seeds,
      irrespective of LOX presence, supported excellent fungal growth and the highest
      aflatoxin levels. Autoclaved whole seeds, with or without LOX, produced good
      fungal growth and aflatoxin levels approaching those of broken seeds. Whole
      soybean seeds supported sparse fungal growth and relatively low aflatoxin levels.
      There was no significant difference in aflatoxin production between whole soybean
      seeds either with or without LOX, although there did seem to be differences among
      the cultivars tested. The heat treatment eliminated LOX activity (in LOX+ lines),
      yet aflatoxin levels did not change substantially from the broken seed treatment.
      Broken soybean seeds possessed LOX activity (in LOX+ lines) and yet yielded the
      highest aflatoxin levels. The presence of active LOX did not seem to play the
      determinant role in the susceptibility of soybean seeds to fungal pathogens. Seed
      coat integrity and seed viability seem to be more important characteristics in
      soybean seed resistance to aflatoxin contamination. Soybean seeds lacking LOX
      seem safe from the threat of increased seed pathogen susceptibility.

PMID- 12495022
TI  - Relative immunogenicity of commonly allergenic foods versus rarely allergenic and
      nonallergenic foods in mice.
AB  - Food allergies affect 6 to 8% of children and 2% of adults in the United States.
      For reasons that are not clear, eight types of food account for a vast majority
      (approximately 90%) of food-induced hypersensitivity reactions. In this study,
      C57Bl/6 mice were used to test the hypothesis that commonly allergenic foods are
      intrinsically more immunogenic than rarely allergenic or nonallergenic foods in
      allergy-susceptible hosts. Groups of mice (n = 4 to 5) were injected
      intraperitoneally with the protein extracts (plus alum as an adjuvant) from
      chicken eggs, peanuts, almonds, filberts-hazelnuts, walnuts, soybeans, and wheat
      (commonly allergenic foods) and coffee, sweet potatoes, carrots, white potatoes,
      cherries, lettuce, and spinach (rarely allergenic and nonallergenic foods).
      Primary and secondary immune responses (as measured by specific IgG1 antibody
      serum levels) were measured by an enzyme-linked immunosorbent assay. Proteins
      from peanuts, almonds, filberts, sweet potatoes, cherries, and spinach elicited
      robust primary and/or secondary immune responses. Proteins from eggs, walnuts,
      and lettuce elicited poor primary responses but significant secondary responses.
      In contrast, wheat, soybeans, coffee, carrots, and white potatoes elicited barely
      detectable to poor primary and secondary immune responses. The order of the
      immunogenicity levels of these foods in mice is as follows: almonds = filberts >
      spinach (Rubisco) > peanuts > or = sweet potatoes > cherries > lettuce > walnuts
      > chicken eggs > carrots > or = white potatoes > wheat = coffee = soybeans. In
      summary, these data demonstrate for the first time that: (i) foods vary widely
      with regard to their relative immunogenicity in allergy-susceptible hosts and
      (ii) intrinsic immunogenicity in mice does not distinguish commonly allergenic
      foods from rarely allergenic or nonallergenic foods.

PMID- 12495023
TI  - Platelet aggregation inhibitory activity of bovine, ovine, and caprine kappa
      casein macropeptides and their tryptic hydrolysates.
AB  - Kappa-casein macropeptide (CMP) is one of the components of whey and is obtained
      as a by-product in cheesemaking. There has been increasing interest in research
      to find new uses of cheese industry by-products in order to improve their value
      and promote their use. Human platelet aggregation inhibitory activities of
      bovine, ovine, and caprine CMPs and their tryptic hydrolysates were studied. CMPs
      from the three species exhibited in vitro antithrombotic properties similar to
      the activity of the gamma-fibrinogen 400-411 peptide. Inhibitory activities
      increased following hydrolysis with trypsin. Active sequences were identified
      among the tryptic peptides by reversed-phase high-performance liquid
      chromatography with on-line mass spectrometry.

PMID- 12495024
TI  - Esterolytic and lipolytic activities of lactic acid bacteria isolated from ewe's
      milk and cheese.
AB  - In the present work, we report on the esterase and lipase activities of lactic
      acid bacteria representing the genera Lactococcus, Leuconostoc, Lactobacillus,
      and Enterococcus isolated from ewe's milk and cheeses. Esterase activity was
      studied using alpha- and beta-naphthyl derivatives of 2 to 12 carbon atoms and
      postelectrophoretic detection. The lactic acid bacteria evaluated had
      intracellular esterase activities, which preferentially degraded the alpha- and
      beta-naphthyl derivatives of 2 to 6 carbon atoms. By studying postelectrophoretic
      patterns, it was found that some strains presented more than one esterase.
      Lactobacillus plantarum O236 showed four enzymes that hydrolyze carboxyl ester
      linkages with different specificity. Lipase activity was studied in intracellular
      and extracellular fractions using tributyrin, tricaprylin, triolein, and milk fat
      as substrates. The intracellular and extracellular fractions of Leuconostoc
      mesenteroides O257, Lactobacillus plantarum O236, and Lactobacillus acidophilus
      O177 were able to hydrolyze tributyrin. L. plantarum O186, L. acidophilus O252,
      Enterococcus faecium O174 and O426, and Enterococcus faecalis Ov409 showed lipase
      activity associated with the intracellular fraction on tributyrin. Lactococcus
      lactis O233, L. plantarum O155, and Lactobacillus casei O190 did not hydrolyze
      triglycerides. Not all strains that showed esterase activity exhibited high
      activity on triglycerides. Esterase and lipase activities were species- and
      strain-specific. Wide variations in activity between strains highlight the need
      for selecting appropriate starters to produce enzyme-modified cheese as well as
      accelerated ripened cheese.

PMID- 12495025
TI  - Solution structure of the coiled-coil trimerization domain from lung surfactant
      protein D.
AB  - Surfactant protein D (SP-D) is one of four known protein components of the
      pulmonary surfactant lining the lung alveoli. It is involved in immune and
      allergic responses. SP-D occurs as a tetramer of trimers. Trimerization is
      thought to be initiated by a coiled coil domain. We have determined the solution
      structure of a 64-residue peptide encompassing the coiled coil domain of human SP
      D. As predicted, the domain forms a triple-helical parallel coiled coil. As with
      all symmetric oligomers, the structure calculation was complicated by the
      symmetry degeneracy in the NMR spectra. We used the symmetry-ADR (ambiguous
      distance restraint) structure calculation method to solve the structure. The
      results demonstrate that the leucine zipper region of SP-D is an autonomously
      folded domain. The structure is very similar to the independently determined X
      ray crystal structure, differing mainly at a single residue, Tyr248. This residue
      is completely symmetric in the solution structure, and markedly asymmetric in the
      crystalline phase. This difference may be functionally important, as it affects
      the orientation of the antigenic surface presented by SP-D.

PMID- 12495026
TI  - NMR solution structure and dynamics of motilin in isotropic phospholipid bicellar
      solution.
AB  - The structure and dynamics of the gastrointestinal peptide hormone motilin,
      consisting of 22 amino acid residues, have been studied in the presence of
      isotropic q = 0.5 phospholipid bicelles. The NMR solution structure of the
      peptide in acidic bicelle solution was determined from 203 NOE-derived distance
      constraints and six backbone torsion angle constraints. Dynamic properties for
      the 13Calpha-1H vector in Leu10 were determined for motilin specifically labeled
      with 13C at this position by analysis of multiple-field relaxation data. The
      structure reveals an ordered alpha-helical conformation between Glu9 and Lys20.
      The N-terminus is also well structured with a turn resembling that of a classical
      beta-turn. The 13C dynamics clearly show that motilin tumbles slowly in solution,
      with a correlation time characteristic of a large object. It was also found that
      motilin has a large degree of local flexibility as compared with what has
      previously been reported in SDS micelles. The results show that motilin interacts
      with the bicelle, displaying motional properties of a peptide bound to a
      membrane. In comparison, motilin in neutral bicelles seems less structured and
      more flexible. This study shows that the small isotropic bicelles are well suited
      for use as membrane-mimetic for structural as well as dynamical investigations of
      membrane-bound peptides by high-resolution NMR.

PMID- 12495027
TI  - SPINS: standardized protein NMR storage. A data dictionary and object-oriented
      relational database for archiving protein NMR spectra.
AB  - Modern protein NMR spectroscopy laboratories have a rapidly growing need for an
      easily queried local archival system of raw experimental NMR datasets. SPINS
      (Standardized ProteIn Nmr Storage) is an object-oriented relational database that
      provides facilities for high-volume NMR data archival, organization of analyses,
      and dissemination of results to the public domain by automatic preparation of the
      header files required for submission of data to the BioMagResBank (BMRB). The
      current version of SPINS coordinates the process from data collection to BMRB
      deposition of raw NMR data by standardizing and integrating the storage and
      retrieval of these data in a local laboratory file system. Additional facilities
      include a data mining query tool, graphical database administration tools, and a
      NMRStar v2. 1.1 file generator. SPINS also includes a user-friendly internet
      based graphical user interface, which is optionally integrated with Varian VNMR
      NMR data collection software. This paper provides an overview of the data model
      underlying the SPINS database system, a description of its implementation in
      Oracle, and an outline of future plans for the SPINS project.

PMID- 12495028
TI  - Principal component method for assessing structural heterogeneity across multiple
      alignment media.
AB  - The recent availability of residual dipolar coupling measurements in a variety of
      different alignment media raises the question to what extent biomolecular
      structure and dynamics are differentially affected by their presence. A
      computational method is presented that allows the sensitive assessment of such
      changes using dipolar couplings measured in six or more alignment media. The
      method is based on a principal component analysis of the covariance matrix of the
      dipolar couplings. It does not require a priori structural or dynamic information
      nor knowledge of the alignment tensors and their orientations. In the absence of
      experimental errors, the covariance matrix has at most five nonzero eigenvalues
      if the structure and dynamics of the biomolecule is the same in all media. In
      contrast, differential structural and dynamic changes lead to additional nonzero
      eigenvalues. Characteristic features of the eigenvalue distribution in the
      absence and presence of noise are discussed using dipolar coupling data
      calculated from conformational ensembles taken from a molecular dynamics
      trajectory of native ubiquitin.

PMID- 12495029
TI  - Observation of H-bond mediated 3hJH2H3 coupling constants across Watson-Crick AU
      base pairs in RNA.
AB  - 3hJH2H3 trans-hydrogen bond scalar coupling constants have been observed for the
      first time in Watson-Crick AU base pairs in uniformly 15N-labeled RNA
      oligonucleotides using a new 2hJNN-HNN-E. COSY experiment. The experiment
      utilizes adenosine H2 (AH2) for original polarization and detection, while
      employing 2hJNN couplings for coherence transfer across the hydrogen bonds (H
      bonds). The H3 protons of uracil bases are unperturbed throughout the experiment
      so that these protons appear as passive spins in E. COSY patterns. 3hJH2H3
      coupling constants can therefore be accurately measured in the acquisition
      dimension from the displacement of the E. COSY multiplet components, which are
      separated by the relatively large 1JH3N3 coupling constants in the indirect
      dimension of the two-dimensional experiment. The 3hJH2H3 scalar coupling
      constants determined for AU base pairs in the two RNA hairpins examined here have
      been found to be positive and range in magnitude up to 1.8 Hz. Using a molecular
      fragment representation of an AU base pair, density functional theory/finite
      field perturbation theory (DFT/FPT) methods have been applied to attempt to
      predict the relative contributions of H-bond length and angular geometry to the
      magnitude of 3hJH2H3 coupling constants. Although the DFT/FPT calculations did
      not reproduce the full range of magnitude observed experimentally for the 3hJH2H3
      coupling constants, the calculations do predict the correct sign and general
      trends in variation in size of these coupling constants. The calculations suggest
      that the magnitude of the coupling constants depends largely on H-bond length,
      but can also vary with differences in base pair geometry. The dependency of the
      3hJH2H3 coupling constant on H-bond strength and geometry makes it a new probe
      for defining base pairs in NMR studies of nucleic acids.

PMID- 12495030
TI  - Breaking symmetry in the structure determination of (large) symmetric protein
      dimers.
AB  - We demonstrate a novel methodology to disrupt the symmetry in the NMR spectra of
      homodimers. A paramagnetic probe is introduced sub-stoichiometrically to create
      an asymmetric system with the paramagnetic probe residing on only one monomer
      within the dimer. This creates sufficient magnetic anisotropy for resolution of
      symmetry-related overlapped resonances and, consequently, detection of
      pseudocontact shifts and residual dipolar couplings specific to each monomeric
      component. These pseudocontact shifts can be readily incorporated into existing
      structure refinement calculations and enable determination of monomer orientation
      within the dimeric protein. This methodology can be widely used for solution
      structure determination of symmetric dimers.

PMID- 12495031
TI  - A software tool for the prediction of Xaa-Pro peptide bond conformations in
      proteins based on 13C chemical shift statistics.
AB  - The chemical shift difference (delta[13C(beta)]-delta[13C(gamma)]) is a reference
      independent indicator of the Xaa-Pro peptide bond conformation. Based on a
      statistical analysis of the 13C chemical shifts of 1,033 prolines from 304
      proteins deposited in the BioMagRes database, a software tool was created to
      predict the probabilities for cis or trans conformations of Xaa-Pro peptide
      bonds. Using this approach, the conformation at a given Xaa-Pro bond can be
      identified in a simple NOE-independent way immediately after obtaining its NMR
      resonance assignments. This will allow subsequent structure calculations to be
      initiated using the correct polypeptide chain conformation.

PMID- 12495032
TI  - A 3D doubly sensitivity enhanced X-filtered TOCSY-TOCSY experiment.
AB  - We present a 3D double sensitivity enhanced X-filtered homonuclear TOCSY-TOCSY
      experiment for the assignment of unlabeled molecules complexed to labeled protein
      or nucleic acid-domains. The resulting spectrum is clean, can be measured in a
      reasonable amount of time and allows for increased resolution of overlapping
      resonances when compared to 2D methods. The 3D X-filtered TOCSY-TOCSY allows for
      assignment in cases where the size or the composition of the unlabeled molecule
      results in a high degree of overlap.

PMID- 12495033
TI  - 1H, 13C and 15N resonance assignments of Gads C-terminal SH3 domain in complex
      with an RXXK motif-containing peptide derived from SLP-76.

PMID- 12495034
TI  - 1H, 15N and 13C resonance assignments of the SH2 domain of Bruton's tyrosine
      kinase.

PMID- 12495035
TI  - Backbone resonance assignment of the 298 amino acid catalytic domain of protein
      tyrosine phosphatase 1B (PTP1B).

PMID- 12495036
TI  - 1H, 15N and 13C backbone assignment of MJ1267, an ATP-binding cassette.

PMID- 12495037
TI  - 1H, 13C and 15N resonance assignments of the human phosphatase PRL-3.

PMID- 12495038
TI  - Fifty years of anticoccidial vaccines for poultry (1952-2002).
AB  - Although earlier investigators experimented with anticoccidial vaccines, the
      world's first commercially successful product was developed by Prof S. A. Edgar
      of Auburn University, Auburn, AL. This product contained live, nonattenuated
      Eimeria tenella oocysts and was first marketed by Dorn and Mitchell, Inc., in
      1952. Under the trade names of DM Cecal Coccidiosis Vaccine, Coxine, NObiCOX, and
      CocciVac, it went through several formulations containing various Eimeria species
      that parasitize chickens, and a further product containing turkey Eimeria species
      was also developed. After many product and company changes, one turkey and two
      chicken formulations of CocciVac are still marketed worldwide by Schering-Plough
      Animal Health, Inc. Chicken and turkey formulations of Immucox, a similar type of
      vaccine, were developed by Dr. E.-H. Lee and first marketed in 1985 in Canada by
      Vetech Laboratories, Inc. In 1974, Dr. T. K. Jeffers of Hess and Clark, Inc.,
      Ashland, OH, published his discovery of precocious lines of coccidia, which
      facilitated the development of the first attenuated anticoccidial vaccine. For
      commercial reasons, Jeffers was unable to do this himself, but this first
      attenuated vaccine was designed by Dr. M. W. Shirley and colleagues at the
      Houghton Poultry Research Station (HPRS) in the United Kingdom. The vaccine was
      commercially developed under license in the United Kingdom by Glaxo Animal Health
      Ltd. and then Pitman-Moore, Inc., and launched in The Netherlands during 1989
      under the trade name Paracox. After further changes in company ownership, two
      formulations for chickens are now marketed worldwide by Schering-Plough Animal
      Health, Inc. Attenuation of coccidia by embryo adaptation was reported in 1972 in
      the United Kingdom by Dr. P. L. Long, who originally worked at the HPRS and later
      became a professor at the University of Georgia, Athens, GA. An embryo-adapted
      line of E. tenella was included with precocious lines of other species in a
      series of three attenuated vaccines for chickens under the trade name Livacox,
      developed by Dr. P. Bedrnik and launched in the Czech Republic in 1992 by
      Biopharm. The formulations of all other commercially available live anticoccidial
      vaccines for poultry are currently based upon the scientific principles
      established for the CocciVac, Paracox or Livacox vaccines.

PMID- 12495039
TI  - Evaluation of the immune response and detection of infectious bursal disease
      viruses by reverse transcriptase-polymerase chain reaction and enzyme-linked
      immunosorbent assay after in ovo vaccination of commercial broilers.
AB  - Maternal immunity can interfere with infectious bursal disease virus (IBDV)
      vaccine efficacy. The effect of maternal antibody (MacAb) on the immune response
      and detection of two vaccine viruses, an IBDV immune complex (cx) and IBDV-2512,
      was investigated. Vaccines were administered in ovo at 100 mean embryo infectious
      dose to commerical broiler embryos derived from young (29 wk) or old (63 wk)
      flocks. Chickens with low MatAb were challenged with an antigenic standard IBDV
      strain at 21 and 35 days post in ovo vaccination (PIOV). At 28 and 42 days PIOV,
      birds were euthanatized and bursa weight: body weight ratios were determined.
      MatAb of progeny from the 29-wk-old flock was higher (P < 0.05) than that from
      progeny of the 63-wk-old flock. Progeny titers declined by day 21 PIOV. Birds
      with MatAb vaccinated with either the IBDV-2512 or IBDV-Icx vaccine did not mount
      an antibody response by 21 days PIOV. The IBDV-Icx vaccination protected chickens
      against bursal atrophy when they were challenged at 21 and 35 days PIOV (83% and
      77%, respectively). Resistance to challenge in the absence of antibody implies
      that cellular immunity plays a role in IBDV protection. The IBDV-2512 vaccine
      caused atrophy of the bursae, and, therefore, we could not examine its protection
      by these criteria. Neither vaccine could be detected by antigen-capture
      chemiluminescent enzyme-linked immunosorbent assay. Therefore, total RNA was
      extracted and reverse transcription (RT)-polymerase chain reaction (PCR) and
      nested PCR were conducted to amplify the VP2 (hypervariable) region on viral RNA
      collected at 3, 6, 9, 15, and 21 days PIOV. Nested PCR detected the VP2 region of
      both IBDV vaccine viruses at day 3 PIOV. Only IBDV-2512 RNA was detected on day 6
      PIOV. However, the IBDV-Icx RNA was detected on days 9 and 15 PIOV but not on day
      21 PIOV. The IBDV-Icx RNA was evident in tissues and could induce protection
      against challenge. This work gives further insight into the mechanism of the IBDV
      Icx vaccine.

PMID- 12495040
TI  - Immunosuppression in specific-pathogen-free broilers administered infectious
      bursal disease virus vaccines by in ovo route.
AB  - The effect of two infectious bursal disease virus (IBDV) vaccines (IBDV-immune
      complex [Icx] and IBDV-2512), administered in ovo, on the cell-mediated immunity
      of specific-pathogen-free (SPF) broilers was examined. A decrease (P < 0.05) in
      the T-cell mitogenic response occurred in birds vaccinated with both vaccines on
      days 9 and 21 post in ovo vaccination (PIOV), but an increase (P < 0.05) occurred
      on day 15 PIOV. The T cells from birds given the IBDV-2512 were less responsive.
      There were no significant differences in proportions of lymphocytes expressing
      CT4+CT8 and CT8+CT4- except on day 21 PIOV, where an increase (P < 0.05) in IBDV
      2512-vaccinated birds and a decrease (P < 0.05) in percentage of CT4+CT8- in IBDV
      Icx-vaccinated birds was observed. There was an increase (P < 0.05) in percentage
      of CT8+CT4- T cells on day 21 PIOV in both vaccinated groups. A decrease (P <
      0.05) in B-cell percentage was observed on day 21 PIOV in birds given both
      vaccines. Results indicated that although humoral immunosuppression is associated
      with destruction of B cells (bursal atrophy), cell-mediated immunosuppression
      induced by these two IBDV vaccines in SPF birds was not associated with altered
      helper (CT4+CT8-) or cytotoxic (CT8+CT4-) subpopulations of T lymphocytes.

PMID- 12495041
TI  - Cloning and analysis of the gene for a major surface antigen of Mycoplasma
      gallisepticum.
AB  - Myplasma gallisepticum infects a wide variety of gallineaceous birds including
      chickens, turkeys, and pheasants. Infection occurs both horizontally and
      vertically. Thus, control of the spread of M. gallisepticum to noninfected flocks
      is difficult. Continual monitoring is necessary to identify infected flocks even
      under the most stringent infectious control practices. Monitoring, however, is
      usually performed by measuring hemagglutination activity (HA) in serum, an
      insensitive and variable test. Variability in the HA test arises differences in
      agglutination antigen, changes in antigenic profiles of the M. gallisepticum
      strain, and variability in reading the agglutination reaction. Enzyme-linked
      immunosorbent assays (ELISAs) are the preferred method of testing because of the
      ease in obtaining sera and the sensitivity and reproducibility of the assays, but
      the ELISA suffers from a lack of standardization in the test antigen. The ELISA
      test will be more easily accepted once the test antigen has been standardized. To
      this end, we have identified, cloned, and characterized the gene for an antigen
      that has potential as a species-specific antigen for M. gallisepticum The gene
      codes for a 75-kD protein, P75, that is recognized during natural infections.
      Recombinant P75 is not recognized in immunoblots by convalescent sera produced in
      chickens infected with Mycoplasma synoviae, Mycoplasma gallinarum, and Mycoplasma
      gallinaceum or in turkeys infected with Mycoplasma meleagridis.

PMID- 12495042
TI  - The in vitro efficacy of a quaternary ammonia disinfectant and/or
      ethylenediaminetetraacetic acid-tris against commercial broiler hatchery isolates
      of Pseudomonas aeruginosa.
AB  - Studies have indicated variations in the degree of efficacy of certain commercial
      disinfectants used in poultry production facilities. We used an adequate method
      of in vitro testing to compare the efficacy of disinfectants while testing them
      in conditions similar to those of the poultry facilities. BioSentry 904,
      ethylenediaminetetracetic acid (EDTA)-Tris, and a combination of the two were
      tested by this method against five field isolates of Pseudomonas aeruginosa at
      10(3), 10(6), and 10(9) colony-forming units (CFU)/ml. At the 10(9) CFU/ml
      concentration, most compounds failed to achieve a total kill with a contact time
      of 15 min. When tested at bacterial concentrations of 10(3) CFU/ml, the
      combination of EDTA-Tris mixed at a 1:1 ratio with BioSentry 904 killed the
      bacteria upon initial contact (< or = 0.05 min). This disinfectant mixture
      exhibited antagonistic, indifferent, or synergetic effects when exposed to
      different bacterial isolates at a concentration of 10(6) CFU/ml.

PMID- 12495043
TI  - Construction and immunogenicity studies of recombinant fowl poxvirus containing
      the S1 gene of Massachusetts 41 strain of infectious bronchitis virus.
AB  - The spike 1 (S1) surface glycoprotein of infectious bronchitis virus (IBV) is the
      major inducer of the generation of virus neutralizing antibodies, and the
      administration of purified S1 has been shown to elicit a protective immune
      response against virulent virus challenge. On the basis of these observations,
      recombinant fowl poxvirus (rFPV) containing a cDNA copy of the S1 gene of IBV
      Mass 41 (rFPV-S1) was constructed and its immunogenicity and vaccine potential
      were evaluated. Initially, rFPV-S1 was shown to express the S1 in vito by
      indirect immunofluorescence staining and western blot analyses. Later, in vivo
      expression was demonstrated by the detection of IBV-specific serum immunoglobulin
      G and neutralization antibodies in the sera of chickens immunized with rFPV-S1.
      That the recombinant virus elicited anti-IBV protective immunity was indicated by
      the manifested, relatively mild clinical signs of disease, decreased titers of
      recovered challenge virus, and less severe histologic changes of the tracheas in
      virulent IBV Mass 41-challenged chickens previously receiving rFPV-S1 as compared
      with parental fowl poxvirus (FPV)-vaccinated control birds. In contrast, chickens
      immunized with either recombinant or parental FPV were resistant to a subsequent
      virulent FPV challenge. As to a preferred method of immunization, wing web
      administration appeared to be superior to the subcutaneous route because a
      greater percentage of birds vaccinated by the former protocol exhibited an anti
      IBV humoral immune response. Thus, rFPV-S1 has potential as a poultry vaccine
      against both fowl pox and infectious bronchitis.

PMID- 12495044
TI  - Effects of dietary vitamin E on chickens infected with eimeria maxima:
      observations over time of primary infection.
AB  - Two trrials were conducted to define temporal changes in plasma D-alpha
      tocopherol (AT) caused by infection with Eimeria maxima in chickens that consumed
      either low (25 ppm) or high (225 ppm) levels of dietary DL-alpha-tocopheryl
      acetate (VE-AC) from 1 day of age. In both trials, rates of weight gain were
      depressed between days 5 and 7 post-inoculation (PI) and were not influenced by
      the level of dietary VE-AC. Plasma AT was consistently depressed at 5 and 7 days
      PI in chickens consuming either level of dietary VE-AC. The pattern and degree of
      plasma AT depression correlated with those of plasma carotenoids. Plasma levels
      of NO2- + NO3- were significantly increased at 5 and 7 days PI. In trial 1, the
      average increase during that period was not as high in chicks consuming 225 ppm
      VE-AC, but in trial 2, diet had no effect on the degree of increase. Also, there
      were no consistent effects of dietary VE-AC on lesion scores or amount of oocysts
      shed. These results are in general accord with findings of earlier experiments,
      and we conclude that feeding high levels of VE-AC to broiler chicks from 1 day of
      age is not effective in mitigating the pathology, including weight gain
      depression and development of mucosal lesions, during E. maxima infections or in
      modifying immune response events associated with phagocytosis as indexed by
      plasma NO2- + NO3-. The likely basis for the ineffectiveness of feeding this fat
      soluble form of vitamin E is that it is malabsorbed during E. maxima infection in
      the same manner as carotenoids and becomes less biologically available to
      infected tissues during the acute phase of infection.

PMID- 12495045
TI  - Nephropathogenic infectious bronchitis in Pennsylvania chickens 1997-2000.
AB  - Nephropathogenic infectious bronchitis (NIB) was diagnosed in 28 infectious
      bronchitis virus (IBV)-vaccinated commercial chicken flocks in Pennsylvania from
      December 1997 to July 2000. Early dinical signs were increased flock mortality
      and urinary water loss (polyuria and pollakiuria) leading to wet litter. Daily
      mortality ranged from 0.01% in layers to 2.45% in broilers, with total broiler
      mortality as high as 23%. Severe renal swelling and accumulation of urates in the
      tubules were commonly seen. Visceral gout and urolithiasis were less frequently
      observed. Histopathologic changes included characteristic tubular epithelial
      degeneration and sloughing with lymphoplasmacytic interstitial nephritis. Minimal
      respiratory disease signs were noted in broilers. Egg production and shell
      quality declined in layers. Confirmatory diagnosis of NIB was made by IBV antigen
      specific immunohistochemical staining of the renal tubular epithelium and virus
      isolation. Sequencing of the S1 subunit gene of 21 IBV isolates showed the NIB
      outbreak to be associated with two unique genotypes, PA/Wolgemuth/98 and
      PA/171/99. The cases from which the genotypes were isolated were clinically
      indistinguishable. The NIB viruses were unrelated to previously recognized
      endemic strains in Pennsylvania and were also dissimilar to each other. Genotype
      PA/Wolgemuth/98 was isolated almost exclusively during the first 14 mo of the
      outbreak, whereas PA/171/99 was recovered during the final 18 mo. The reason for
      the apparent replacement of PA/Wolgemuth/98 by PA/171/99 is not known.

PMID- 12495046
TI  - Molecular characterization of Spanish infectious bursal disease virus field
      isolates.
AB  - Nine Spanish isolates of infectious bursal disease virus (IBDV) were
      characterized and classified after reverse transcriptase-polymerase chain
      reaction of a 248-bp fragment of the VP2 gene hypervariable region and
      restriction fragment length polymorphism (RFLP). The restriction endonucleases
      (REs) used were BstNI, Sad, SspI, TaqI, DraI, and StyI. Sequencing of the
      amplified product and further comparison of these sequences with published
      sequence data from other IBDV strains were also performed. Very virulent and
      classic strains were identified. None of the strains identified had molecular
      characteristics similar to that of the American variant strains. Four very
      virulent strains (VG-248, 5939, 6145, and 7333) were digested by the TaqI, SspI,
      and StyI enzymes. The sequences of these strains were closely related to other
      European and Japanese very virulent IBDV (vvIBDV) strains. Strains VG-311, VG
      262, and VG-208 were digested by the BstNI and Sad REs and were classified as
      classic strains. Strains VG-276 and VG-313 had unique RFLP patterns. VG-276
      exhibited the SspI RE site, which has been reported as a characteristic of vvIBDV
      strains, whereas the VG-313 strain exhibited a Sad and StyI RE site indicative of
      the classic IBDV Edgar and 52-70 strains. However, nucleotide sequence analysis
      of the amplified hypervariable region strain VG-276 revealed a higher identity
      with the classic strains STC, 52/70, and 9109 IBDV strains, whereas strain VG-313
      exhibited a higher identity with the vvIBDV strains.

PMID- 12495047
TI  - Associations of interferon-gamma genotype and protein level with antibody
      response kinetics in chickens.
AB  - Although previous studies have demonstrated an association between interferon
      gamma (IFN-gamma) promoter genotype and antibody response kinetics in chickens,
      the protein levels that may mediate such a gene-trait association have not been
      determined. The objective of this study, therefore, was to determine the
      correlation of circulating IFN-gamma levels with both the IFN-gammaIFN-gamma
      promoter polymorphisms and antibody response in order to evaluate the potential
      role of IFN-gamma protein in mediating genetic control of antibody response in
      chickens. Antibody response after Salmonella enteritidis (SE) vaccination at day
      10, antibody response to sheep red blood cells (SRBCs) and killed Brucella
      abortus after immunizations at 19 wk and 22 wk, and serum IFN-gamma protein level
      were measured in an F2 population derived from inbred lines. A single nucleotide
      polymorphism in the IFN-gamma promoter region was associated with IFN-gamma
      protein expression as measured by an enzyme-linked immunosorbent assay after both
      primary and secondary immunizations. Higher IFN-gamma protein level was
      correlated with higher antibody level to SE and with increased maximum level and
      decreased time to reach the maximum secondary antibody response to SRBCs. These
      results suggest that one of the mechanisms by which promoter polymorphism of IFN
      gamma affects antibody production in chickens may involve the circulating level
      of IFN-gamma protein.

PMID- 12495048
TI  - Susceptibility of laughing gulls (Larus atricilla) to H5N1 and H5N3 highly
      pathogenic avian influenza viruses.
AB  - This investigation detailed the clinical disease, gross and histologic lesions,
      and distribution of viral antigen in juvenile laughing gulls (Larus atricilla)
      intranasally inoculated with either the A/tern/South Africa/61 (H5N3) (tern/SA)
      influenza virus or the A/chicken/Hong Kong/220/97 (H5N1) (chicken/HK) influenza
      virus, which are both highly pathogenic for chickens. Neither morbidity nor
      mortality was observed in gulls inoculated with either virus within the 14-day
      investigative period. Gross lesions resultant from infection with either virus
      were only mild, with the tern/SA virus causing decreased lucency of the air sacs
      (2/6), splenomegaly (2/6), and pancreatic mottling (1/6) and the chicken/HK virus
      causing only decreased lucency of the air sacs (2/8) and conjunctival edema
      (2/8). Histologic lesions in the tern/SA-inoculated gulls included a mild to
      moderate heterophilic to lymphoplasmacytic airsacculitis (6/6), mild to moderate
      interstitial pneumonia (3/6), and moderate necrotizing pancreatitis and hepatitis
      at 14 days postinoculation (DPI) (2/6). Immunohistochemical demonstration of
      viral antigen occurred only in association with lesions in the liver and
      pancreas. In contrast, viral antigen was not demonstrated in any tissues from the
      chicken/HK-inoculated gulls, and inflammatory lesions were confined to the air
      sac (3/8) and lungs (3/8). Both viruses were isolated at low titers (<10(1.68)
      mean embryo lethal dose) from oropharyngeal and cloacal swabs up to 7 days
      postinoculation (DPI), from the lung and kidney of one of two tern/SA-inoculated
      gulls at 14 DPI, and from the lung of one of two chicken/HK-inoculated gulls at 7
      DPI. Antibodies to influenza viruses as determined with the agar gel precipitin
      test at 14 DPI were detected only in the two tern/SA-inoculated gulls and not in
      the two chicken/HK-inoculated gulls.

PMID- 12495049
TI  - Subclinical effects and fenbendazole treatment of turkey ascaridiasis under
      simulated field conditions.
AB  - Under simulated natural conditions of bird production and parasite challenge, the
      effects of ascaridiasis and the effectiveness of fenbendazole treatment (6-day
      regimes in the feed at 16 ppm) were documented. Birds were artificially
      challenged with ascarid larvae on a daily basis from day 35 to 112, with bird
      grow out ending on day 119. Experimental groups, on a per pen basis, were
      infected control, treated with fenbendazole at days 63-69, treated with
      fenbendazole at days 63-69 and days 91-97, and uninfected control. In the same
      order as above, and on an experimental group mean bird basis, final weights were
      13.34, 13.47, 13.59, and 13.78 kg, average daily gains from day 7 to day 119 were
      117.8, 118.9, 120.1, and 121.8 g, and units gained per unit of feed consumed from
      day 7 to day 119 were 0.337, 0.341, 0.347, and 0.362. Infected control bird mean
      Ascaridia dissimilis burdens, with all stages combined, ranged from 351.1 on day
      63 to 117.2 on day 91, levels seen commonly with naturally infected commercial
      turkeys. Trial data dearly indicated that moderate A. dissimilis burdens
      negatively impacted animal performance (average daily gains and feed
      efficiencies) and that these parasite burdens are effectively removed by
      fenbendazole treatment.

PMID- 12495050
TI  - Experimental gizzard erosions in specific-pathogen-free chicks by serotype 1
      group I avian adenoviruses from broilers.
AB  - The pathogenicity of serotype 1 group I avian adenovirus (GIAAV) strains isolated
      from gizzard erosions for 1-wk-old specific-pathogen-free (SPF) chickens was
      investigated. In Experiment 1, SPF chickens inoculated orally with a serotype 1
      strain (Tokushima2000/GE) of GIAAV isolated from gizzard erosion in broilers were
      euthanatized and necropsied from 3 to 12 days after inoculation. Clinically,
      there were no significant signs in the chickens inoculated with Tokushima strain.
      The gizzards were found macroscopically to be dilated with liquefied contents.
      The koilin layer of the gizzard exhibited multifocal white lesions with
      occasional erosions. Gross lesions of the koilin layer (white foci and erosion)
      appeared at 3 days after inoculation and persisted until 12 days after
      inoculation. The gross lesions were most severe at 9 days after inoculation.
      Histologically, multifocal degeneration, necrosis, and loss of the glandular
      epithelial cells with intranuclear inclusions, liquefactive change of koilin
      substance, and erosive lesions of koilin layers and surface epithelium of the
      gizzards were observed. Macrophages increased in the focal areas of the lamina
      propriabelow the liquefactive koilin substances. Immunohistochemically,
      intranudear inclusions were positive against GIAAV antigen. Histologic lesions of
      gizzards were most severe at 7 and 9 days after inoculation, but the frequency of
      intranuclear inclusions was greatest at 5 days after inoculation. In Experiment
      2, the pathogenicities of four strains of serotype 1 GIAAV for 1-wk-old SPF
      chickens were compared. Three strains isolated from gizzard erosion had similar
      pathogenicities but one strain from a normal chicken was not pathogenic for
      chickens. These results suggest that gizzard erosions by serotype 1 GIAAV
      infection may occur in broiler chickens in Japan.

PMID- 12495051
TI  - Chronic effects of moniliformin in broiler and turkeys fed dietary treatments to
      market age.
AB  - Floor pen studies were conducted, with broilers from 1 to 7 wk of age and with
      turkeys from 1 to 14 wk of age, to evaluate the chronic effects of moniliformin
      (M). Fusarium fujikuroi (M-1214) culture material was added to typical corn
      soybean basal diets to supply 0, 25, or 50 mg M/kg diet (broilers) or 0, 12.5,
      25, 37.5, or 50 mg M/kg diet (turkeys). Compared with controls, chicks fed diets
      containing 50 mg M/kg consumed more feed, had lower body weight gain, were less
      efficient in converting feed to body weight gain, and had increased relative
      heart and proventriculus weights. Chicks fed the diet containing 50 mg M/kg also
      had significantly higher mortality and decreased mean corpuscular volumes
      compared with controls. Broilers fed 25 and 50 mg M/kg also had increased serum
      gamma glutamyltransferase activities. Feed intake, body weight gain, and feed
      conversion of turkeys fed dietary M were not affected. At 6 and 14 wk, turkeys
      fed 25, 37.5, or 50 mg M/kg diet had increased (P < 0.05) relative heart weights
      when compared with controls. At week 14, turkeys fed diets containing 37.5 or 50
      mg M/kg also had increased (P < 0.05) relative liver weights compared with
      turkeys fed 0, 12.5, or 25 mg M/kg diet. Lesions, observed only in the hearts of
      broilers and turkeys fed 50 mg M/kg, were loss of cardiomyocyte cross striations,
      increased cardiomyocyte nuclear size, and an increased number of cardiomyocyte
      mitotic figures (turkeys only). Results indicate that > or = 37.5 mg M/kg is
      hepatoxic and > or = 25 mg M/kg is cardiotoxic to turkeys and 50 mg M/kg diet is
      toxic to broilers fed to market age.

PMID- 12495052
TI  - Neuropathotyping: a new system to classify Marek's disease virus.
AB  - A statistical approach was used to establish a new classification system of
      Marek's disease virus (MDV) on the basis of neurologic responses. To develop the
      system, neurologic response data from 15x7 chickens inoculated with 30 strains of
      serotype 1 MDV were statistically analyzed by a cluster analysis. The goal was to
      identify a statistical system that would verify if three neurovirulence groups
      correlated with the three pathotypes previously described. The system was also
      validated in two additional strains of specific-pathogen-free (SPF) chickens,
      SPAFAS and line SC (Hy-Vac). The proposed system is based on analysis of three
      variables: 1) frequency of birds showing transient paralysis between 9 and 11
      days postinoculation (dpi), (2) mortality before 15 dpi, and (3) frequency of
      birds showing persistent neurologic disease between 21 and 23 dpi. By use of this
      system, a MDV may be classified in one of three groups, designated
      neuropathotypes A, B, and C, which roughly correspond to the virulent, very
      virulent, and very virulent plus pathotypes, respectively. However, correlation
      between neuropathotype and pathotype was not absolute, and neuropathotyping is
      more a complement to the current pathotyping system than a replacement for it.
      Our results showed that neuropathotyping studies can be conducted in two types of
      commercial SPF chickens by the use of the same variables, although the system
      would first have to be standardized by the use of prototype viruses.
      Neuropathotypes can also be estimated with our statistical analysis with
      reasonable accuracy. By use of this analysis, we established that MDV strains
      within the very virulent pathotype may be subdivided into neuropathotypes B and
      C, thus establishing a previously unrecognized pathotypic classification. This
      finding illustrates how neuropathotyping may extend important information not
      identified by conventional pathotyping.

PMID- 12495054
TI  - Induction of strong protection by vaccination with partially attenuated serotype
      1 Marek's disease viruses.
AB  - Studies were conducted to better understand the relationship among Marcek's
      disease (MD) vaccine strains between induction of protective immunity and the
      degree of attenuation (or virulence). To obtain viruses at different stages of
      attenuation, very virulent plus MD strains 584A and 648A and selected clones of
      these strains were serially passaged in chicken and duck cells. These viruses
      were considered fully attenuated after passage for 70-100 times in chicken embryo
      cell cultures until they no longer induced gross lesions in susceptible, maternal
      antibody-negative (ab-) chickens. Lower passages of the same strains were
      considered partially attenuated, provided their virulence was less than that of
      the parent strain. Four of five partially attenuated preparations derived from MD
      virus strains 584A and 648A or the previously attenuated Md11 strain induced 28%
      62% higher levels of protection in maternal antibody-positive (ab+) chickens
      against virulent MD challenge than the fully attenuated counterpart viruses. The
      partially attenuated 584A/d2/3 strain replicated in chickens but was totally
      nonprotective. Data from two subsequent trials in ab+ chickens confirmed that
      protection induced by the partly attenuated (passage 80) preparations was 79% and
      118% higher, respectively, than that induced by the fully attenuated (passage
      100) preparations of strain 648A. However, in one trial with ab- chickens, no
      difference in protection between partially and fully attenuated virus was
      observed. Strong protection (up to 85%) against highly virulent challenge also
      was provided by preparations of 648A at passages 40-60, which were moderately
      oncogenic when used alone. Partially attenuated strains tended to replicate to
      higher titers in both ab+ and ab- chickens compared with fully attenuated
      vaccines. Also, ab+ and ab- chickens vaccinated with partially attenuated strains
      developed three- to nine fold more extensive microscopic lesions in peripheral
      nerves at 14 and 22 days after virulent challenge than chickens vaccinated with
      fully attenuated strains. When measured in ab+ chickens, loss of lesion induction
      by 648A was achieved 30 passages earlier (at passage 70) than when measured in ab
      chickens. Thus, maternal antibodies appeared to abrogate the pathogenicity of
      some partially attenuated strains. These studies establish for MD the principle
      that at least some partially attenuated MD viruses may replicate better and
      induce stronger immunity against virulent challenge than fully attenuated
      preparations of the same strain, at least when tested in ab+ chickens. Moreover,
      depending on passage level, partially attenuated vaccine strains may be
      relatively innocuous for ab+ chickens, causing few or no lesions.

PMID- 12495053
TI  - Recovery of Campylobacter from segments of the reproductive tract of broiler
      breeder hens.
AB  - Three groups of >60-wk-old broiler breeder hens were assessed for the presence of
      Campylobacter within segments of the reproductive tract. In the first group,
      after stunned, the hens were bled, scalded, and defeathered, the reproductive
      tracts were aseptically excised from 18 hens, six from each of three adjacent
      floor pens that were feces positivefor Campylobacter. The reproductive tract
      segments (infundibulum, magnum-isthmus, shell gland, vagina, and cloaca) were
      pooled by pen. In the second group, 10 individual hens were sampled from the
      pens; the reproductive tract was divided into the following segments: magnum,
      isthmus, shell gland, vagina, and cloaca. For the third group, hens were obtained
      from two commercial farms that had been determined to be feces positive for
      Campylobacter, and the reproductive tract was divided into five segments, as
      described for the second group. Segments of the reproductive tract were placed
      into sterile plastic bags and suspended 1:3 (w/v) in Bolton enrichment broth, and
      serial dilutions were plated (0.1 ml) onto Campy-Cefex agar. The agar places were
      incubated at 42 C for 24 hr in a microaerobic atmosphere. In group 1, the pooled
      reproductive tract segments for hens from pen A were Campylobacter positive for
      the shell gland, vagina, and cloaca; hens from pen B were positive for the cloaca
      only; and hens from pen C were positive for the magnum-isthmus and doaca. In the
      second group, 9 of 10 cloaca samples were Campylobacter positive. Commercial hens
      in group 3 had campylobacter-positive cloaca samples (12/12), vagina (10/12),
      shell gland (7/12), isthmus (2/12), and magnum (4/12). Campylobacter colonization
      of the reproductive tract of the hen could enable vertical transmission of
      Campylobacter from the hen to the chick.

PMID- 12495055
TI  - Protection of chickens after live and inactivated virus vaccination against
      challenge with nephropathogenic infectious bronchitis virus PA/Wolgemuth/98.
AB  - Protection provided by live and inactivated virus vaccination against challenge
      with the virulent nephropathogenic infectious bronchitis virus (NIBV) strain
      PA/Wolgemuth/98 was assessed. Vaccinations with combinations of live attenuated
      strains Massachusetts (Mass) + Connecticut (Conn) or Mass + Arkansas (Ark) were
      given by eyedrop to 2-wk-old specific-pathogen-free leghorn chickens. After live
      infectious bronchitis virus (IBV) vaccination, some chickens at 6 wk of age
      received an injection of either an oil emulsion vaccine containing inactivated
      IBV strains Mass + Ark or an autogenous vaccine prepared from NIBV
      PA/Wolgemuth/98. Challenge with PA/Wolgemuth/98 was given via eyedrop at 10 wk of
      age. Serum IBV enzyme-linked immunosorbent assay antibody geometric mean titers
      (GMTs) after vaccination with the combinations of live attenuated strains were
      low, ranging from 184 to 1,354, prior to NIBV challenge at 10 wk of age. Both
      inactivated vaccines induced an anamnestic response of similar magnitudes with
      serum GMTs of 6,232-12,241. Assessment of protection following NIBV challenge was
      based on several criteria virus reisolation from trachea and kidney and renal
      microscopic pathology and IBV-specific antigen immunohistochemistry (IHC). Live
      attenuated virus vaccination alone with combinations of strains Mass + Conn or
      Mass + Ark did not protect the respiratory tract and kidney of chickens after
      PA/Wolgemuth/98 challenge. Chickens given a live combination vaccination of Mass
      + Conn and boosted with an inactivated Mass + Ark vaccine were also susceptible
      to NIBV challenge on the basis of virus isolation from trachea and kidney
      butshowed protection on the basis of renal microscopic pathology and IHC. Live
      IBV-primed chickens vaccinated with an autogenous inactivated PA/Wolgemuth/98
      vaccine had the highest protection against homologous virulent NIBV challenge on
      the basis of virus isolation.

PMID- 12495056
TI  - Comparison of a putative second serotype of chicken infectious anemia virus with
      a prototypical isolate I. Pathogenesis.
AB  - CIAV-7 is a virus with similar pathogenic and physicochemical characteristics to,
      but antigenically distinct from, chicken infectious anemia virus (CIAV). The
      pathogenesis of CIAV-7 was evaluated in a comparative study with a representative
      isolate of CIAV, the Del-Ros strain. The pathogenesis of CIAV-7 was similar to
      Del-Ros on the basis of the clinical disease induced and gross and microscopic
      lesions, although CIAV-7 produced fewer and less severe lesions overall. A second
      comparative pathogenesis study was performed with Del-Ros and CIAV-7, both alone
      and in combination with infectious bursal disease virus (IBDV). In this study,
      the pathogenesis of CIAV-7 was similar to Del-Ros in clinical, gross, and
      microscopic lesions in the bone marrow. However, thymic lesions were less severe
      in CIAV-7-inoculated birds. The interaction between Del-Ros and IBDV was
      synergistic, whereas there was no observed potentiation of CIAV-7-induced disease
      by IBDV. Progeny from breeder flocks from several geographic locations in the
      eastern United States were challenged with CIAV-7 or Del-Ros to assess protection
      by maternal antibodies. Some progeny from all flocks had protection against CIAV
      7 challenge, providing evidence for the presence of CIAV-7 in the field.
      Additionally, the number of birds protected against CIAV-7 or Del-Ros challenge
      varied within flocks, demonstrating that the agents are serologically distinct.

PMID- 12495057
TI  - Comparison of a putative second serotype of chicken infectious anemia virus with
      a prototypical isolate II. Antigenic and physicochemical characteristics.
AB  - A putative new serotype of chicken infectious anemia virus (CIAV) isolated from
      17-wk-old broiler breeder pullets was compared with a known, previously
      characterized CIAV isolate, the Del-Ros strain. Physicochemical characteristics
      evaluated induded thermal stability, size, pH, and chloroform sensitivity.
      Physicochemically, CIAV-7 was identical to CIAV. The virus isolates were compared
      antigenically by enzyme-linked immunosorbent assay, virus neutralization,
      immunofluorescence assay, and western blot. All four serologic assays
      demonstrated that CIAV-7 is antigenically distinct from the Del-Ros strain of
      CIAV. Additionally, polymerase chain reaction (PCR) and Southern blot were used
      to determine if there were similarities in genome sequence between the two
      viruses. CIAV-7 could not be detected with CIAV-specific PCR primers or a with
      CIAV-specific probe by Southern hybridization.

PMID- 12495058
TI  - Comparison of two formaldehyde administration methods of in ovo-injected eggs.
AB  - Formaldehyde administration in the hatchery can be very useful in decreasing
      microbial numbers. However, its use is controversial because of the adverse
      effects that can occur to chicks and people. This study was designed to look at
      alternative methods of application of formaldehyde in the hatchery. In addition,
      the study compared the effects of these methods of application on in ovo-and non
      in ovo-injected eggs. All in ovo-injected eggs were given diluent only with no
      vaccine or antibiotic added. In hatchers containing both in ovo-injected eggs and
      non-in ovo-injected eggs, formaldehyde was administered two ways, dose (DOSE) and
      constant rate infusion (CRI). In the DOSE hatcher, 12 ml of formaldehyde was
      administered at one time every 12 hr, whereas in the CRI hatcher, the same volume
      was administered at a rate of 1 ml/hr over a 12-hr period. A control (CONT)
      hatcher received 12 ml of distilled water at the same time that the DOSE hatcher
      was given formaldehyde. In the DOSE hatcher, a peak concentration of formaldehyde
      of 102 ppm was reached. The CRI was maintained at approximately 20 ppm of
      formaldehyde. At pipping, the aerosol bacterial load in the hatchers receiving
      formaldehyde (DOSE, 130 colony-forming units [CFU]/m3; CRI, 82.5 CFU/m3) was
      significantly less than in the CONT hatcher (235 CFU/m3). At hatch, the CRI
      (337.5 CFU/m3) was not able to control bacterial levels and only the DOSE hatcher
      (150 CFU/m3) had a significantly lower aerosol bacterial count. The CRI non-in
      ovo-injected eggs (93.39%) had a significantly higher percentage of hatch of
      fertile compared with non-in ovo-injected eggs exposed to water (84.27%). In ovo
      injected eggs in CONT and DOSE treatment groups contained significantly higher
      percentages of visual contamination than non-in on-injected eggs in the same
      hatchers. This difference had numerical significance only in the treatment groups
      within the CRI hatcher. The chicks were then placed into replicate treatment
      groups and grown for 14 days. Chicks from the CRI in ovo-injected eggs had a
      statistically significant improvement in feed conversion ratio (1.24) at 14 days
      when compared with chicks from CONT non-in ovo-injected eggs (1.29). All
      formaldehyde-exposed chicks had numerically lower feed conversion ratios compared
      with the CONT exposed chicks.

PMID- 12495059
TI  - Polymerase chain reaction for detection of avian leukosis virus subgroup J in
      feather pulp.
AB  - Feather pulp from experimentally infected chickens was used as a source of DNA
      for polymerase chain reaction (PCR) amplification of avian leukosis virus
      subgroup J (ALV-J) proviral DNA. A primer set that produces a large amplicon
      (approximately 2,125) was used to detect ALV-J proviral DNA. This primer set was
      used in lieu of previously published primers because it allows for sequencing of
      the entire envelope gene and because it was able to detect diagnostically a
      number of North American ALV-J isolates that could not be detected with
      previously published primers and PCR conditions. ALV-J proviral DNA was detected
      in feather pulp at 7 days of age in more than 90% of birds infected as embryos
      and 7 days postinoculation in over 50% of chickens infected at 3 days of age. The
      results obtained with PCR on feather pulp were compared with those of virus
      isolation. In the embryo-inoculated birds, the percentages of agreement between
      PCR and virus isolation were 92.5% at 7 days of age and 100% at 28, 42, 49, and
      56 days of age. However, the overall sensitivity of virus isolation in embryo
      infected birds was higher, particularly at 7 and 56 days of age. In chickens
      inoculated at 3 days of age, the percentages of agreement of detection between
      PCR and virus isolation ranged from 75% at 10 days of age to 100% at 42 days of
      age. Agreement of negative results of ALV-J detection by PCR and virus isolation
      in chickens infected posthatch ranged between 66.6% and 100% between the ages of
      10 and 42 days. Virus isolation requires chicken embryo fibroblasts of specific
      genetic lines, and the process takes onaverage 7-9 days. Aseptic collection of
      blood and tissues for virus isolation and molecular detection of ALV-J requires
      sterile necropsy instruments as well as syringes and needles for each individual
      chicken, whereas sterile microcentrifuge tubes and gloves are the only equipment
      necessary for aseptic feather pulp collection for ALV-J detection by PCR. PCR
      based detection of ALV-J in feather pulp is especially suitable when ALV-J
      infection must be diagnosed rapidly and unequivocally without killing the
      chicken(s) and in situations where crucial reagents or suitable virus propagation
      substrates are not readily available for isolation and propagation of ALV-J in
      cell culture.

PMID- 12495060
TI  - Lack of interaction between avian leukosis virus subgroup J and fowl adenovirus
      (FAV) in FAV-antibody-positive chickens.
AB  - Unfounded field speculation has suggested that avian leukosis virus subgroup J
      (ALV-J) predisposes young meat-type chickens to inclusion body hepatitis caused
      by fowl adenovirus (FAV). To address this hypothesis, we infected 1-day-old
      grandparent meat-type chickens carrying maternal antibodies against FAV with a
      field isolate of FAV associated with inclusion body hepatitis in broilers, ALV-J,
      or both FAV and ALV-J. We examined the effects of FAV alone or in combination
      with ALV-J on the basis of clinical signs, overall mortality, growth rate, and
      gross and microscopic lesions. With such criteria for evaluating possible
      interactions, we found no significant differences in the dually infected birds in
      comparison with chickens that received a monovalent challenge with either FAV or
      ALV-J.

PMID- 12495061
TI  - Campylobacter colonization of the crops of newly hatched leghorn chicks.
AB  - We have studied colonization of crops in newly hatched leghorn chicks (a layer
      breed) by wild-type and mutant strains of Campylobacter jejuni. We established
      that the wild-type parent strain forms a stable population level within the crop
      and that the mutant strains will do likewise. Concentrations of mutant strains in
      the crop were usually below that of the wild-type parent strain and ranged from
      10(3) to 10(5) colony-forming units. These results differ from results we have
      previously reported concerning cecal colonization, where these same mutant
      strains lacked colonizing ability. The present results, therefore, indicate that
      bacterial factors necessary for colonization of the crop are not the same as
      those needed for colonization of the cecum.

PMID- 12495062
TI  - Cold-induced ascites in broiler chickens and its improvement by temperature
      controlled rearing.
AB  - Pulmonary hypertension syndrome (PHS), also known as ascites, in broiler chickens
      prevailed in the local area of Ibaraki prefecture, Japan, and was investigated
      epidemiologically, serologically, and pathologically. PHS developed in chickens
      older than 35 days of age when rapid increase of body weight started.
      Approximately 90% of affected birds were males, in which weight increase was
      greater than in females. Serologic test revealed that PHS broilers had an
      increase of hematocrit value. Pathologic studies indicated that the heart of
      affected birds had an obese-induced pressure and cold exposure triggered
      congestion in the right ventricle/cava and an increase in peritoneal fluid. These
      changes were consistent with the previous reports of PHS, so we designed the
      experiment of effects on cold-induced PHS birds in a temperature-controlled
      house. After the 10 PHS birds at 55 days were reared for 14 days in a temperature
      controlled house at 20 +/- 5 C, ascites disappeared in eight birds and hematocrit
      values decreased to normal range in nine birds. Our finding indicated that
      temperature-controlled environment may be one solution to reduce mortality in PHS
      birds.

PMID- 12495063
TI  - Investigation of resistance of bacteria from commercial poultry sources to
      commercial disinfectants.
AB  - Concern by consumers about food safety has resulted in increased pressure on
      poultry companies to develop effective sanitation programs. Salmonella isolates
      in hatcheries are often the same species isolated from processing plants.
      Resistance develops in bacteria after prolonged exposure to disinfectants. The
      methods available in published literature to detect the efficacy of disinfectants
      are labor intensive and do not consider how bacteria behave when adhered to a
      solid surface. We used a recently developed technique, which utilizes the actual
      surfaces on which the disinfectant is to be applied, to evaluate the degree of
      resistance to four commercially available disinfectants of 17 bacterial isolates
      from poultry hatcheries. We found that bacterial isolates within the same genus
      and species have different sensitivities to the same disinfectant. In addition,
      disinfectants with similar but not identical chemical formulations have different
      efficacies against the same bacteria.

PMID- 12495064
TI  - Pathogenicity of embryo-adapted serotype 2 OH strain of infectious bursal disease
      virus in chickens and turkeys.
AB  - The pathogenicity of serotype 2 OH strain of infectious bursal disease virus
      (IBDV) to specific-pathogen-free (SPF) chicken embryos and 2-wk-old SPF chickens
      and turkey poults was investigated. The virus was pathogenic for chicken embryos
      after five passages as evidenced by pathologic changes in inoculated embryos. The
      embryo-adapted virus was not pathogenic for 2-wk-old SPF chickens and turkey
      poults as indicated by lack of clinical signs, gross or microscopic lesions in
      the bursa of Fabricius of inoculated birds. Bursa-to-body-weight ratios of the
      inoculated chickens and turkey poults were not significantly different from those
      of uninoculated controls. Virus-neutralizing antibodies to serotype 2 IBDV were
      detected in inoculated chickens and turkeys. Results of this study indicated that
      the embryo-adapted serotype 2 OH IBDV isolate that is pathogenic for chicken
      embryos is infectious but not pathogenic in chickens and turkeys.

PMID- 12495065
TI  - Effects of genetic selection for high or low antibody response on resistance to a
      variety of disease challenges and the relationship of resource allocation.
AB  - Lines of white leghorn chickens were selectively bred for either a high (H) or
      low (L) antibody response to sheep erythrocytes. The parental lines, HH and LL,
      and reciprocal crosses, HL (sire line cited first and dam line second) and LH,
      were compared for their responses to various diseases. High antibody titers were
      associated with reduced body weight. Lines and their crosses were challenged with
      infectious diseases. The LL line was most resistant to Mycobacterium avium,
      whereas the HH line was most susceptible. The HH line was most resistant to
      Mycoplasma gallisepticum, whereas the LL line was most susceptible. These
      findings indicate that defense against infectious diseases are resource
      expensive. In order to save resources, it is possible that different parts of a
      population might genetically devote high levels of resources against different
      types of diseases so that the entire population is not susceptible to a single
      infection.

PMID- 12495066
TI  - Survival of Ornithobacterium rhinotracheale in sterilized poultry litter.
AB  - Ornithobacterium rhinotracheale (ORT) has been associated with respiratory
      disease, increased mortality, retarded growth, and decreased egg production in
      chickens and turkeys. Surveillance of exposure to ORT infection in the field has
      shown that prevalence of the infection is higher during winter months. The
      ability of ORT to remain viable in the poultry litter was studied at different
      temperatures over time. Presterilized poultry litter was inoculated with 10(11)
      colony-forming units of ORT and kept at -12 C, 4 C, 22 C, 37 C, and 42 C.
      Reisolation and titration of ORT from litter was attempted at intervals. Results
      indicate that ORT survived for 1 day at 37 C, 6 days at 22 C, 40 days at 4 C, and
      at least 150 days at -12 C. ORT did not survive 24 hr at 42 C. The survival of
      ORT at lower temperatures may be associated with the higher incidence of ORT
      infection in poultry during winter months.

PMID- 12495067
TI  - Mucosal humoral immunity to experimental Salmonella enteritidis infection in the
      chicken crop.
AB  - In this report, we show that chickens, infected with Salmonella enteritidis (SE)
      by oral gavage, produce secretory immunoglobulin As (sIgAs) that specifically
      bind to numerous SE antigens. Chickens infected with SE showed strong sIgA
      response against flagella in both bile and crop. The optical density values of
      enzyme-linked immunosorbent assay (ELISA) tests in positive bile and crop were
      1.17 and 0.38, respectively, and were significantly different from those of
      negative samples. Western immunoblotting revealed that approximately 13.5-,
      approximately 56-, approximately 62-, approximately 80-, and approximately 143-kD
      polypeptides were immunodominant proteins in bile, whereas approximately 56-,
      approximately 62-, and approximately 80-kD polypeptides were found to be strong
      antigens in crop. These results indicate that the crop may function as another
      site for mucosal immunity, and the SE flagella-based ELISA of crop samples can
      provide a useful screening test of SE exposure in chickens.

PMID- 12495068
TI  - Risk factors associated with poult enteritis mortality syndrome-positive turkey
      flocks.
AB  - Poult enteritis mortality syndrome (PEMS) has been an economically devastating
      disease in North Carolina since the early 1990s. Though much is known about the
      disease, many questions remain unanswered about the syndrome, including its
      cause, transmission of causative agent(s), and control methods. This study was
      designed to investigate the association between PEMS and farm management factors.
      A prospective longitudinal study was conducted by collecting farm data and
      monitoring weekly mortality in 54 commercial turkey flocks raised in PEMS
      affected regions. Univariate and multivariate statistical analyses revealed that
      enhancing rodent control methods was negatively associated (P = 0.0228) with
      PEMS.

PMID- 12495069
TI  - Detection of avian pneumovirus in wild Canada (Branta canadensis) and blue-winged
      teal (Anas discors) geese.
AB  - Choanal cleft swab samples from 770 wild Canada geese (Branta canadensis) and 358
      blue-winged teal (Anas discors), captured for relocation or banding, were
      examined for the presence of avian pneumovirus (APV) RNA by reverse transcription
      (RT)-polymerase chain reaction (PCR) and for virus isolation. The swab samples
      were pooled into groups of 5 or 10. Sixty eight of 102 (66.7%) pooled goose
      samples were RT-PCR positive for APV RNA. Thirteen of 52 (25.0%) pooled blue
      winged teal samples were RT-PCR positive for APV RNA. APV RNA-positive samples
      were inoculated onto chick embryo fibroblasts (CEF) and QT-35 cells. Infectious
      APV was isolated from five Canada goose pooled samples in CEF and from one Canada
      goose pool in QT-35 cells but not from blue-winged teal.

PMID- 12495070
TI  - Virulent vaccine strains of infectious bursal disease virus not distinguishable
      from wild-type viruses with marker the use of a molecular.
AB  - Molecular techniques have not only made timely and accurate detection of
      infectious bursal disease viruses (IBDVs) possible but also have allowed the
      identification of viral strains. Previously, we identified a genetic marker that
      distinguished wild-type IBDV strains from vaccine strains of the virus. The
      marker was an NgoM IV restriction enzyme site in the VP2 gene that was present in
      10 wild-type viruses but not 16 vaccine strains of IBDV. On the basis of that
      study, we concluded that the NgoM IV marker could be useful in the identification
      of wild-type potentially pathogenic strains of this virus. Because virulent (hot)
      vaccine strains of IBDV are used to vaccinate commercial poultry, it was
      important to determine if the NgoM IV marker was present in these virulent
      vaccines. The infectious bursal disease Blen and Bursa Vac virulent vaccines were
      examined and determined to contain the marker. We concluded that the presence of
      this marker was not unique to wild-type strains of the virus. The absence of the
      NgoM IV marker, however, was consistent with some level of attenuation, and its
      presence appears to be consistent with virulent IBDV strains.

PMID- 12495071
TI  - Fertility and sperm quality of broiler breeder males infected with subgroup J
      avian leukosis virus.
AB  - In order to assess the effects of subgroup J avian leukosis virus (ALV-J) on
      semen quality, broiler breeder males were separated by ALV-J status (ALV-J
      positive = POS, ALV-J negative = NEG) at 44 wk of age. Of the 249 males
      originally placed at 1 day of age, 101 (40.6%) died by 43 wk of age. Observations
      of tumor expression and high mortality suggest that many of the males that died
      prior to 44 wk of age were infected with ALV-J. From 47 to 56 wk of age, hens
      were inseminated every third week with 7.5 x 10(7) sperm. Fertility and hatch
      data were collected by incubating eggs laid during the 2 wk postinsemination
      (WPI). The number of sperm that penetrated the perivitelline membrane of the ovum
      was determined from eggs laid on the eighth day postinsemination. Sperm mobility
      index (SMI) was determined at 58 and 60 wk of age from all males producing semen.
      Whereas SMI and sperm hole penetration measurements indicated that the sperm
      quality from treatments POS and NEG were similar, fertility was significantly
      greater in the POS treatment during the first (89.0% vs. 79.0%) and second WPI
      (59.3% vs. 45.0%). However, because of numerically higher hatch of fertile from
      the NEG group, the percentage of hatch of eggs set was similar between groups.
      These data suggest that ALV-J status of caged males has no influence on sperm
      quality or hatchability of eggs.

PMID- 12495072
TI  - Pododermatitis in turkeys.
AB  - Severe pododermatitis is a common lesion in turkeys, unlike in broiler chickens.
      Both dietary factors (soybean meal, biotin, methionine) and poor litter
      conditions (wet litter) are documented etiologies of footpad lesions. In the
      United States and United Kingdom both farm managers and processors monitor
      lesions. The United Kingdom reports an average footpad relative score higher than
      that of the United States. In both countries, incidence in toms is higher than in
      hens. There is no significant difference by country. Data support no consistent
      association with other lesions (i.e., breast blisters or condemnations), breed,
      or performance parameters (i.e., weight gain or age). The litter type used in the
      United Kingdom is either straw or wood shavings, whereas in the United States
      producers predominantly use wood shavings. In the United Kingdom, diets are
      formulated with a higher protein, which affects the excreta and subsequent litter
      conditions. British United Turkey is the predominate breed in the United Kingdom.
      In the United States, three breeds, British United Turkey of America, hybrid, and
      Nicholas, are common. Recent research has demonstrated the association between
      biotin levels and pododermatitis. Factors associated with pododermatitis (such as
      production systems, wet litter, and stocking density) are discussed. There are
      some indications that increased stocking density is associated with
      pododermatitis lesions. Further research is needed to identify what management
      factors are associated with pododermatitis.

PMID- 12495073
TI  - Characterization of Pseudomonas aeruginosa isolates associated with mortality in
      broiler chicks.
AB  - In mid-2000, a broiler chicken company in Alabama experienced high early
      mortality rates in chicks from two different hatcheries. Five isolates of
      Pseudomonas aeruginosa, obtained from these contaminated hatcheries and resulting
      broiler chicks with omphalitis, were selected to determine virulence of the
      bacteria. One-day-old specific-pathogen-free white leghorn chicks were placed
      into positive pressure isolation units (10 chicks per unit); feed and water were
      provided ad libitum. The five isolates of P. aeruginosa (1 x 10(1) or 1 x 10(1)
      colony-forming units/bird) were used to challenge two replicates of 10 chicks via
      yolk sac inoculation. Two control groups were injected with 0.1 ml of phosphate
      buffered saline, and two groups received no treatment. Mortality was recorded
      daily, and the chicks that died were necropsied and liver and yolk sacs were
      cultured. After 14 days, the remaining chickens were euthanatized and necropsied.
      Bacterial isolates retrieved from liver and yolk sacs were identified by the API
      20 NE typing system to confirm that they were the same as the challenge isolate.
      Virulence varied greatly among the isolates, resulting in mortality rates from 0
      to 90%. The challenge isolates produced different and often distinctive
      postmortem lesion patterns. Antibiotic sensitivity tests showed that all five
      isolates were resistant to sulfisoxazole, ceftiofur, penicillin, lincomycin,
      bacitracin, oxytetracycline, erythromycin, naladixic acid, and tetracycline. The
      isolates varied in sensitivity to other antibiotics, but all isolates were
      sensitive to gentamicin.

PMID- 12495074
TI  - Unidentified coryneform bacterial strain from cases of polyarthritis in chickens:
      phenotype and fatty acid profile.
AB  - We report isolation of a strain of fermentative coryneform bacteria from an
      outbreak of polyarthritis in chickens. This strain could not be assigned to any
      recognized bacterial taxon because its peculiar phenotype is not yet reported.
      The strain possessed phenotypic characteristics and fatty acid profile similar to
      Erysipelothrix but, on the other hand, exhibited temperature-dependent motility
      like Listeria. We found no evidence of either Mycoplasma synoviae or Chlamydia
      infection. Details of the phenotype and fatty acid profile of the isolate and
      measures undertaken to contain the outbreak have been described.

PMID- 12495075
TI  - Outbreak of avian tuberculosis in 48-week-old commercial layer hen flock.
AB  - This report describes an outbreak of tuberculosis in a flock of 38,500 48-wk-old
      layer hens. Clinical characteristics of the process included a gradual drop in
      egg production and feed intake, as well as an increased mortality rate. Two well
      defined clinical features were observed. On the one hand, a number of birds
      displayed good body condition and continued to lay but presented granulomatous
      nodular lesions, particularly in the infraorbital sinus, liver, and intestine. In
      contrast, other hens were emaciated and presented granulomatous lesions of
      various sizes throughout the internal organs. The lesions observed in the various
      organs of all the affected birds consisted of granulomas containing acid/alcohol
      fast bacilli. The presence of Mycobacterium avium was confirmed through
      polymerase chain reaction techniques. This report describes the epidemiologic and
      histopathologic characteristics of the outbreak.

PMID- 12495076
TI  - Internal papillomatosis with intrahepatic cholangiocarcinoma and gastrointestinal
      adenocarcinoma in a peach-fronted conure (Aratinga aurea).
AB  - A 17-yr-old pet female peach-fronted conure (Aratinga aurea) was presented with
      the chief complaints of mild lethargy and weight loss with increased appetite.
      Antemortem diagnostics included complete blood count, plasma biochemistry, and
      radiography. Abnormal findings included elevated inflammatory parameters
      (hyperfibrinogenemia) and a space-occupying mass in the region of the liver.
      Histologic examination of a liver biopsy sample indicated bile duct hyperplasia
      leading to a presumptive diagnosis of hepatoxicosis. The bird initially showed
      moderate improvement with supportive care, but its condition declined 9 days
      after the liver biopsy. Supportive care was attempted a second time, but the bird
      did not improve and euthanasia was elected. Abnormal gross necropsy findings were
      confined to the liver, which contained multiple tan nodules that exuded yellowish
      fluid on cut section. Histopathologic examination revealed multicentric bile duct
      hyperplasia and cholangiocarcinoma as well as segmental papillary hyperplasia and
      adenocarcinoma in the proventriculus, ventriculus, and throughout the intestinal
      tract. This is the first report of concurrent internal papillomatosis,
      gastrointestinal adenocarcinoma, and cholangiocarcinoma in a peach-fronted
      conure.

PMID- 12495077
TI  - Ingluvial squamous cell carcinoma in a game chicken.
AB  - A 4.5-yr-old rooster was presented for a "lump on the neck." The bird exhibited
      dyspnea immediately prior to death. Necropsy revealed a crateriform lesion in the
      crop. Histologically, the lesion was diagnosed as an invasive squamous cell
      carcinoma, extending almost the entire thickness of the crop. Polymerase chain
      reaction and ultrastructural examination failed to identify a viral component.
      Early vascular invasion was identified.

PMID- 12495078
TI  - Molecular epidemiology of human T-lymphotropic virus type II infection in
      Amerindian and urban populations of the Amazon region of Brazil.
AB  - Molecular characterization of human T-cell lymphotropic virus II (HTLV-II)
      isolates in North America and Europe has shown the existence of two principal
      subtypes of the virus, HTLV-IIa and HTLV-IIb. Subsequent studies on HTLV-II
      isolates from Brazil have suggested the existence of a unique variant
      phylogenetically related to HTLV-IIa but phenotypically similar to HTLV-IIb with
      respect to the transactivatory protein, Tax. This variant has been designated
      HTLV-IIc. To better clarify the variability and distribution of HTLV-II in
      Brazil, the viruses present in two population groups from the Amazon region were
      tested for the presence of HTLV-II using serological and molecular assays. The
      groups consisted of blood donors from three Amerindian communities and of HIV
      1/HTLV-II coinfected patients residing in Belem, an urban area. Nucleotide
      sequences and phylogenetic analysis confirmed the presence of HTLV-IIc subtype
      among Amerindian populations and, for the first time, the presence of the same
      virus among urban groups in Belem. The isolated occurrence of the HTLV-IIc
      subtype among Amerindian populations in the Amazon region could be attributed to
      (1) the different migratory pathways and founder effect, or (2) the local origin
      of a proto-HTLV-II carried by Amerindian ancestors who migrated to the Amazon
      circa 11,000 to 13,000 years ago. These results suggest that not only is HTLV-IIc
      unique to this region, but that its presence in urban areas of Brazil has
      resulted from admixture processes during the colonization of the country.

PMID- 12495079
TI  - Y-chromosome analysis in Egypt suggests a genetic regional continuity in
      Northeastern Africa.
AB  - The geographic location of Egypt, at the interface between North Africa, the
      Middle East, and southern Europe, prompted us to investigate the genetic
      diversity of this population and its relationship with neighboring populations.
      To assess the extent to which the modern Egyptian population reflects this
      intermediate geographic position, ten Unique Event Polymorphisms (UEPs), mapping
      to the nonrecombining portion of the Y chromosome, have been typed in 164 Y
      chromosomes from three North African populations. The analysis of these binary
      markers, which define 11 Y-chromosome lineages, were used to determine the
      haplogroup frequencies in Egyptians, Moroccan Arabs, and Moroccan Berbers and
      thereby define the Y-chromosome background in these regions. Pairwise comparisons
      with a set of 15 different populations from neighboring European, North African,
      and Middle Eastern populations and geographic analysis showed the absence of any
      significant genetic barrier in the eastern part of the Mediterranean area,
      suggesting that genetic variation and gene flow in this area follow the
      "isolation-by-distance" model. These results are in sharp contrast with the
      observation of a strong north-south genetic barrier in the western Mediterranean
      basin, defined by the Gibraltar Strait. Thus, the Y-chromosome gene pool in the
      modern Egyptian population reflects a mixture of European, Middle Eastern, and
      African characteristics, highlighting the importance of ancient and recent
      migration waves, followed by gene flow, in the region.

PMID- 12495080
TI  - Apolipoprotein E and H polymorphisms in Mongolian Buryat: allele frequencies and
      relationship with plasma lipid levels.
AB  - A Buryat population consisting of seven tribal groups in eastern Mongolia has
      been screened to determine the frequency distribution of different apolipoprotein
      E and H alleles (APOE and APOH, genes) coding for common isoforms and their
      association with quantitative plasma lipid levels. Allele frequencies at the APOE
      locus in 125 healthy Buryat aged 17 to 73 years were highest for APOE*3 (0.804),
      followed by APOE*4 (0.164) and APOE*2 (0.032). The APOH locus had high
      frequencies of APOH*2 (0.912) and APOH*3 (0.088). APOH*1 was not detected. No
      significant differences were observed in the overall APOE allele frequencies
      between the Buryat and the Siberian Evenki, Inuits, and Indians in Asia, or with
      some European whites. The frequency distribution of the overall APOH alleles of
      the Buryat was similar to that of the Japanese in Asia. Overall plasma lipid
      levels of the Buryat (males aged 20 to 73 years, females aged 21 to 64 years)
      were considerably lower, comparable to those of the Evenki. The APOE*4/E*3 males
      had significantly high total- and LDL-cholesterol levels compared with the
      APOE*3/E*3 males (p < 0.025 and p < 0.01, respectively). No significant effects
      of the APOH genotypes on any of the plasma lipid levels were observed. In
      particular, our data regarding APOE suggest that the Buryat are genetically close
      in allele frequencies to the Evenki and Inuits, but differ from them in the
      association of genotype APOE*4/E*3 with cholesterol levels.

PMID- 12495081
TI  - Genetic variation of apolipoproteins in North Indians.
AB  - Genetic variation at three apolipoprotein loci (APOA4, APOH, and APOE) has been
      examined in nine endogamous populations of Punjab, North India. The overall
      pattern of allele frequency variation at different loci is compatible with that
      of European populations, but observed microvariation differentiates the
      populations according to their position in the Indian caste structure. The most
      common allele at the APOA4 locus was APOA4*1 with a narrow frequency range (89%
      92%). APOH*2 allele frequency was highest in these populations (0.852-0.914).
      APOE*E4 allele frequency was relatively low (6%-10%) in the North Indian
      populations compared to its frequency in many European populations. The
      anthropological usage of these polymorphisms was evaluated using multivariate
      analyses. Genetic distance analysis and principal correspondence analysis showed
      that the North Indian populations are closest to Europeans, followed by Chinese
      and African populations. Overall, this study highlights the usefulness of
      apolipoproteins as genetic markers for clinical, population, and anthropological
      studies.

PMID- 12495082
TI  - Apolipoprotein E and presenilin-1 allelic variation and Alzheimer's disease in
      India.
AB  - As part of a larger epidemiological survey to study the prevalence of dementia in
      a suburb of Mumbai, Western India, we identified 78 cases with a Clinical
      Dementia Rating (CDR) > or = 1.0. Of these, 49 Alzheimer's disease (AD) cases
      were analyzed for risk association with APOE E*4 allele at apolipoprotein E gene
      (APOE) and presenilin-1 (PS-1) intron-8 polymorphism and were compared with 100
      age- and sex-matched nondemented controls. Genotype analysis confirmed the
      association of APOE E*4 allele with AD as has been reported by various studies.
      We report a low frequency of APOE E*4 allele, consistent with a low prevalence of
      AD in this study. Comparisons with other similar studies on APOE from India
      suggest common risk factors for AD in the Indian population, which is diverse in
      its ethnic and racial characteristics. The frequency for allele 1 at PS-1 intron
      8 polymorphism is the highest among all studies reported. This first report of PS
      1 intron-8 polymorphism and AD from India demonstrates no significant
      association.

PMID- 12495083
TI  - Twenty nuclear DNA polymorphisms in a Moroccan population: a comparison with
      seven other human populations.
AB  - A south central Moroccan sample was analyzed for 20 nuclear DNA polymorphisms
      (restriction fragment length polymorphisms). The population was chosen on the
      basis of available information on its history, making it suitable for comparisons
      with data from other European populations. The markers analyzed have been studied
      previously in several human groups from different continents, and data on African
      and European samples have been compared to evaluate the genetic affinity of the
      studied sample with other populations, especially with two Spanish groups:
      Basques and Andalusians. Heterozygosity levels showed intermediate values between
      the African and European groups and higher than those found so far in an African
      group for the studied markers. Genetic distances closely matched geographical
      relationships through neighbor-joining tree and correspondence analysis, the
      Moroccans being closer to the European groups than the sub-Saharan Africans
      included in the analysis. Allele distributions revealed specific population
      associations with large weight of several alleles in the differentiation of some
      groups. Gene flow from sub-Saharan Africa appears to be relevant in understanding
      the differentiation of present Moroccan populations.

PMID- 12495084
TI  - Comparison of populations as a function of confidence intervals of gene
      probability.
AB  - A new method for population comparison has been developed in order to determine
      the most discriminating systems in relation to diverse populations. The method
      compares pairs of populations on the basis of confidence intervals for allelic
      frequencies and does not require any previous assumption, such as normality of
      the population. A data set of 12 populations studied for Polymarker Kit (Roche)
      genetic systems, 13 biallelic systems (LDLR, GYPA, D7S8) and two systems with
      three alleles each (HBGG, GC), was considered. The analysis produced a total of
      144 confidence intervals (12 populations x 12 alleles). The raw data were then
      analyzed comparing pairs of populations, allele by allele, through their
      respective confidence intervals. The method calculates the matrix of similarity
      between pairs of populations for each allele and eventually for each genetic
      system. Finally, the 12 populations were classified depending on the number of
      nondiscriminating alleles. The results of this method are compared to those
      produced by such usual techniques as Principal Component Analysis.

PMID- 12495085
TI  - Mitochondrial diversity in linguistic isolates of the Alps: a reappraisal.
AB  - In Stenico et al. (1996) we reported unusually high levels of mitochondrial
      diversity in the Alps. In particular, two communities of Ladin speakers appeared
      the most extreme European mitochondrial outliers at that time. Recently, it has
      been observed that some rare nucleotide substitutions occur repeatedly among
      those sequences, raising the possibility of systematic sequencing errors. No
      biological material was left from the previous study, and hence we had to sample
      new individuals from the same communities. Here, we present the HVSI sequence
      variation, along with haplogroup assignment based on restriction fragment length
      polymorphism (RFLP), in 20 Ladin speakers of Colle Santa Lucia. None of the new
      sequences displays substitutions at the sites viewed as problematic. However,
      Ladins still show high levels of mtDNA diversity, both within their community and
      with respect to other Europeans, and they can still be considered one of the main
      European mitochondrial outliers.

PMID- 12495086
TI  - Atlas geburtshulflicher abbidungen, mit bezugnahme auf das lehrbuch der
      geburtskunde by Dietrich Wilhelm Heinrich Busch, 1788-1858. Berlin: August
      Hirschwalt, 1841.

PMID- 12495087
TI  - How oestrogen or progesterone might change a woman's susceptibility to HIV-1
      infection.
AB  - Worldwide, 18.5 million women are infected with the human immunodeficiency virus
      (HIV-1). At least 80% of these HIV infections have occurred as a result of sexual
      intercourse with an infected male partner. This review focuses on how HIV-1
      enters the human female reproductive tract, and how oestrogen or progesterone, by
      altering the cervicovaginal epithelium, might change a woman's susceptibility to
      HIV infection. Experiments on hysterectomised Rhesus monkeys suggest that the
      vagina, rather than the cervix or uterus, is the main site of viral entry. If
      ovariectomised monkeys are given systemic oestrogen treatment, this makes them
      completely resistant to infection by intravaginally administered simian
      immunodeficiency virus (SIV), whereas progesterone-treated animals, like the
      untreated controls, are extremely susceptible. Some studies have also shown that
      women on systemic long-acting gestagen-only contraceptives have a thinner vaginal
      epithelium and hence might be more susceptible to HIV infection; this is
      certainly true of post-menopausal women. The beneficial effects of oestrogen are
      thought to be due to increased thickness and cornification of the cervicovaginal
      epithelium, which prevents the virus from coming into contact with the target
      Langerhans cells (LCs). Topical vaginal oestrogen treatment is widely used as a
      safe and effective way of thickening and keratinising the vaginal epithelium in
      post-menopausal women. Perhaps this could be an exciting new way of protecting
      women from HIV infection.

PMID- 12495088
TI  - Is IVF becoming a band aid for social infertility?

PMID- 12495089
TI  - Outcome of pregnancy complicated by pre-gestational diabetes--improvement in
      outcomes.
AB  - Pre-gestational diabetes mellitus (DM) is associated with adverse fetal and
      maternal outcomes. We have previously reported outcomes for women with DM. To
      determine whether review, and discussion of the results, affected outcomes,
      pregnancies in women with DM from July 1998 to July 2001 were examined in a
      prospective cohort study. The results were then compared to the results from the
      previous review. METHODS: Thirty-five pregnancies were included (24 in 20 women
      with Type 1 DM, 11 in 11 with Type 2 DM). Type 1 women were more likely to be
      Caucasian (100% versus 22.2%, p < 0.0001), and had a longer duration of diabetes
      (13 +/- 6 versus 3 +/- 2 years, p < 0.0001). RESULTS: Pregnancy planning rates
      improved significantly for Type 1 DM (62.5% planned versus 18.9% in original
      study p = 0.01), and did not change for Type 2 DM. Caesarean section (LSCS) rate
      was high in the original study, particularly in Type 1 DM (77%), and was lower
      after review (47.6% in Type 1 DM p < 0.05 compared to original study, and 44.4%
      in Type2 DM, p = ns). Planning was associated with lower HbA1c before and during
      pregnancy (6.0 +/- 1.4% versus 8.1 +/- 1.8% (p = 0.0035), and 5.5 +/- 1 versus
      6.5 +/- 1.5% (p < 0.001)), greater gestational age at delivery (38.2 versus 36.2
      weeks p = 0.0318) and lower rate of LSCS (31.6% versus 72.7% (p = 0.0295)).
      CONCLUSIONS: It is important to continue improving pre-pregnancy planning.
      Extensive discussions involving a multi-disciplinary team improved planning rates
      and decreased the LSCS rate while maintaining outcomes.

PMID- 12495090
TI  - The prevalence of recalled low back pain during and after pregnancy: a South
      Australian population survey.
AB  - OBJECTIVE: To determine the prevalence of low back pain during pregnancy (LBPP)
      in an Australian population. DESIGN: A representative population-based survey of
      women aged 15 years and older. SETTING AND SAMPLE: Four thousand four hundred
      randomly selected South Australian households were visited by trained surveyors
      who interviewed 1531 women (69.7% response rate) using pre-tested questions.
      METHODS: The South Australian Health Omnibus survey was utilised. MAIN OUTCOME
      MEASURES: Demographic data were collected along with details of previous
      pregnancies, and degree of back pain during pregnancy treatment regimens, and
      persistence of back pain. RESULTS: Thirty-five and a half per cent of women
      recall having at least moderately severe back pain during pregnancy. Women who
      reported such back pain were younger, were more likely to report ill health and
      be unemployed. Increasing parity was not associated with current back pain. The
      most commonly used treatments were bed rest, pain killing medication,
      physiotherapy, and chiropractic treatment. Half of those with symptoms were
      untreated. Sixty-eight per cent of women who experienced moderate or worse low
      back pain during pregnancy continued to experience recurring low back pain with a
      self reported reduction in their health. CONCLUSIONS: Chronic low back pain is
      commonly associated with an onset in pregnancy subjectively contributing to long
      term morbidity The high prevalence may be an underestimate in view of the
      potential for recall bias in older women.

PMID- 12495091
TI  - Prenatal diagnosis of mosaic trisomy 20 in New Zealand.
AB  - OBJECTIVE: Mosaic trisomy 20 is not an uncommon finding on amniocentesis or CVS.
      Unlike other mosaic aneuploidies it is a relatively benign abnormality which,
      along with a lack of long-term follow-up of cases, has led to uncertainty when
      counselling parents. We aimed to identify known mosaic trisomy 20 pregnancies in
      New Zealand in the last 10 years and document their outcome. DESIGN:
      Retrospective database review with prospective clinical follow-up. METHODS: Cases
      were identified from the databases of the two clinical genetic services, as well
      as the four regional cytogenetics laboratories. Medical records were reviewed and
      where patients were available they were offered follow-up. RESULTS: Fourteen
      cases were identified (13 on amniocentesis, one on CVS), all with low levels of
      mosaicism (8-50%). In 12 cases, the children were physically and developmentally
      normal, with the longest follow-up being 10 years. Minor anomalies were noted in
      two cases. There were no major malformations noted in any of the cases and where
      repeat karyotypes were performed on blood or urine cytology these were normal.
      CONCLUSIONS: This series confirms a much lower incidence of phenotypic
      abnormalities associated with mosaic trisomy 20 compared to other forms of mosaic
      aneuploidy. Attempts to predict which of these pregnancies will have poor
      outcomes have not proven to be reliable. We recommend that, if a detailed anatomy
      scan is normal, parents be counselled that the risk of abnormality is less than
      10%. Further tests should be performed only on the basis of a clinical
      indication.

PMID- 12495092
TI  - The effect of hospitalisation on ambulatory blood pressure in pregnancy.
AB  - METHODS: Twenty-four-hour ambulatory blood pressure monitoring was performed on
      40 women (20 hypertensive, 20 normotensive) on a hospitalised and non
      hospitalised day. Mean blood pressure differences were calculated for the awake,
      sleeping and 24-hour periods on both days. RESULTS: Mean heart rate was higher at
      home (1.79, p = 0.04) than in hospital, but there were no significant differences
      in mean systolic (1.30 mmHg, p = 0.06), diastolic (0.78 mmHg, p = 0.21) or mean
      arterial blood pressure (0.81 mmHg, p = 0.19) between the hospitalised and non
      hospitalised day for the group overall. Nevertheless, the range of individual
      responses was wide (-8.5 mmHg to 15.4 mmHg mean arterial blood pressure).
      Hypertensive women receiving antihypertensive therapy had significantly greater
      differences in mean arterial blood pressure between the hospital and non-hospital
      day when compared to the rest of the group (5.8 mmHg, compared to 3.3 mm Hg, p =
      0.02). CONCLUSIONS: Although hospitalisation does not significantly lower blood
      pressure in pregnant women as a group, women receiving antihypertensive therapy
      demonstrate significant differences in blood pressure between hospital and home.
      Based on conventional blood pressure measurements alone, these women may be at
      risk of either under treatment, or over treatment, of blood pressure.

PMID- 12495093
TI  - Patterns of vitamin, mineral and herbal supplement use prior to and during
      pregnancy.
AB  - At the antenatal clinic, 211 women were interviewed to assess vitamin, mineral
      and herbal use pre-conceptually and in the three trimesters of pregnancy. The
      majority of women (62%) used both a vitamin or mineral supplement and a herbal
      preparation during the course of pregnancy. Folate (70%), iron (38%) and
      multivitamins (27%) were the vitamin and mineral supplements most frequently
      taken by pregnant women. Ginger (20%) and raspberry leaf (9%) were the most
      frequently used herbal preparations. Women relied on advice from friends and
      relatives in deciding to use herbal preparations.

PMID- 12495094
TI  - Epidemiology and predictive values of risk factors for neonatal group B
      streptococcal sepsis.
AB  - OBJECTIVES: To determine the incidence of and factors affecting risk factors for
      neonatal group B streptococcal (GBS) sepsis and their predictive values for
      intrapartum GBS carriage; to calculate the proportions of women eligible for
      intrapartum antibiotic prophylaxis (IAP) using different selection protocols.
      DESIGN: Cohort study. SETTING: Antenatal clinics and labour wards of a community
      hospital and a tertiary referral centre in western Sydney POPULATION: Women
      attending antenatal clinics during the study periods were invited to participate.
      METHODS: Approximately 500 women attending antenatal clinics were screened for
      GBS carriage at 26-32 weeks gestation and at delivery, using several screening
      methods. Clinical risk factors for neonatal sepsis were recorded during labour.
      MAIN OUTCOME MEASURES: Incidence of antenatal anovaginal GBS carriage and
      clinical risk factors during labour, their predictive values for intra-partum GBS
      carriage and their relationship, if any, to demographic and obstetric factors.
      RESULTS: Antenatal and intra-partum GBS carriage rates were similar but varied
      from 18% to 27%, depending on screening methods. The best positive and negative
      predictive values of antenatal GBS culture, for intra-partum carriage, were 69%
      (95% confidence interval (CI) 64-74) and 92% (95% CI 50-94) respectively Clinical
      risk factors occurred in similar proportions of GBS carriers and non-carriers.
      CONCLUSIONS: Neither early antenatal screening nor clinical risk factors are
      reliable predictors of intra-partum GBS carriage. Intra-partum antibiotic
      prophylaxis based on GBS carriage or risk factors when carrier status is unknown
      would involve approximately 35% of women, compared with approximately 16% if
      based on risk factors only Both strategies would prevent similar proportions of
      neonatal deaths from GBS sepsis. Compliance with a preventive protocol is the
      most likely determinant of its overall effectiveness.

PMID- 12495095
TI  - Women's preferences for reporting of Down syndrome screening results.
AB  - OBJECTIVE: The aim of this study was to determine whether women prefer the
      results of screening for Down syndrome tests to be reported as the risk of Down
      syndrome in early pregnancy at the time of the screening test or the risk at
      delivery (which takes into account the number of Down syndrome pregnancies that
      will be spontaneously lost before birth). DESIGN: A structured questionnaire.
      SETTING: A tertiary hospital antenatal clinic. SAMPLE: One hundred and fifteen
      English-speaking women who expressed an interest in having screening tests for
      Down syndrome performed. METHODS: A structured questionnaire exploring women's
      preferences for risk reporting was self administered by women attending for their
      first antenatal visit. MAIN OUTCOME MEASURES: Women's preference for reporting of
      screening test results as risk at time of test, risk at birth or both, and the
      reasons for this preference. RESULTS: The majority (n = 82) of women preferred to
      have both the risk of Down syndrome at the time of screening and at the time of
      birth reported. The most common reason (n = 60) given for this preference was a
      desire to have as much information available as possible so that an informed
      decision regarding further investigations could be made. CONCLUSIONS: The
      majority of women prefer to receive Down syndrome screening results as both the
      risk at the time of the test and the risk at birth.

PMID- 12495096
TI  - Uterine artery embolisation for the treatment of symptomatic uterine fibroids:
      short-term results of work in progress.
AB  - Bilateral uterine artery embolisation (UAE) was used to treat 11 women with
      symptomatic uterine fibroids. Uterine volume and dominant fibroid volume were
      assessed quantitatively by ultrasonography both before and at two and six months
      post procedure. Both uterine arteries were occluded effectively in all of the
      women, and the procedure was well tolerated, with hospital stays limited to 24-48
      hours in all cases. An improvement of symptoms occurred in 10 of the 11 women.
      There were no significant complications. The mean percentage reductions in
      uterine volume and dominant fibroid volume at six months following the procedure
      were 45.32% and 56.34%, respectively. Bilateral uterine artery embolisation for
      the treatment of uterine fibroids is a minimally invasive technique with very
      good clinical results. This procedure may be considered as an alternative to
      hysterectomy, or myomectomy in properly selected cases.

PMID- 12495097
TI  - Ten-year results of Marshall Marchetti Krantz and anterior colporraphy
      procedures.
AB  - OBJECTIVE: To evaluate subjective results of Marshall Marchetti Krantz (MMK) and
      anterior colporraphy (AC) procedures. STUDY DESIGN: Patients who had operations
      for genuine stress incontinence 10 years ago were surveyed regarding their
      current incontinence status. Results of both procedures were evaluated and
      compared. RESULTS: Fourteen of 28 patients in the MMK group and 21 of 67 patients
      in the AC group were evaluated at 10 years, the cure rates were found to be 64%
      and 38%, respectively. CONCLUSION: We conclude that the success rate of both
      procedures declines over time. The anterior colporraphy procedure appears to have
      a lower success rate than MMK, although this was not found to be statistically
      significant.

PMID- 12495098
TI  - Analgesic efficacy of continuous delivery of bupivacaine by an elastomeric
      balloon infusor after abdominal hysterectomy: a prospective randomised controlled
      trial.
AB  - OBJECTIVE: To investigate the analgesic efficacy and morphine-sparing effect of
      continuous bupivacaine wound infiltration after abdominal hysterectomy. DESIGN:
      Prospective, randomised controlled trial. SAMPLE: Fifty-two female ASA I or II
      patients were enrolled with 26 patients in each of the study and control groups.
      METHODS: The study group received 0.5% bupivacaine infusion into the incisional
      (Pfannenstiel) wound via an elastomeric infusor at 2 mL/hr for 48 hours
      postoperatively plus morphine via a patient controlled analgesia (PCA) pump. The
      control group had only PCA morphine. RESULTS: There were no significant
      differences in the visual analogue scores (VAS) for pain nor PCA morphine usage
      for 48 hours postoperatively CONCLUSION: That continuous infusion of the
      incisional wound with 0.5% bupivacaine did not confer additional analgesia over
      PCA morphine after abdominal hysterectomy

PMID- 12495099
TI  - Randomised controlled trial of glove perforation in single and double-gloving
      methods in gynaecologic surgery.
AB  - OBJECTIVE: To assess the value of double-gloving in gynaecological surgery.
      DESIGN: A prospective randomised controlled trial of glove perforation in single-
      and double-gloving methods. SETTING: Rajavithi Hospital between 1 September 1999
      to 31 August 2000. SAMPLE: Eighty-eight (88) and 82 primary surgeons were
      selected at random to make up single- and double-gloving groups, respectively,
      while performing total abdominal hysterectomy (TAH) with or without bilateral
      salpingo-oophorectomy (BSO). METHODS: The gloves were tested by immersion in
      water. RESULTS: The glove perforation rate was 6.09% and 22.73% in double-inner
      and single gloves, respectively, with this difference being statistically
      different (p < 0.05). There was no significant difference between the glove
      perforation rates in single gloves (22.73%) and in double-outer gloves (19.51%).
      There was matched perforation of the same finger of both outer and inner gloves
      in 1.22% of total double-inner gloves. CONCLUSIONS: The double-gloving methods
      significantly reduced the risk of surgeons' hands contacting blood, when compared
      with the single-gloving method, in TAH with/or without BSO.

PMID- 12495100
TI  - Vaginal childbirth and bladder neck mobility.
AB  - OBJECTIVE: Hypermobility of the bladder base is a predictor of stress urinary
      incontinence (SUI) in the female and at least partly due to pregnancy and vaginal
      childbirth. The purpose of this study was to quantify the effect of vaginal
      parity and birthweight on anterior compartment relaxation. DESIGN: Retrospective
      observational study. SETTING: Outpatient uroynaecological clinics. POPULATION:
      Five hundred and seventy three women seen for primary urogynaecological
      assessment. METHODS: Files of patients seen by the first author for assessment
      and translabial ultrasound imaging at urogynaecological units in Brisbane and
      Sydney, Australia, were reviewed for routinely-collected obstetric data and
      imaging results. MAIN OUTCOME MEASURES: Ultrasound parameters of anterior vaginal
      wall descent such as urethral rotation on Valsalva manoeuvre, bladder neck
      position on Valsalva, bladder neck descent and maximal descent of a cystocele on
      Valsalva. RESULTS: ANOVA analysis demonstrated a highly significant relationship
      between vaginal childbirth and bladder neck position on Valsalva (p < 0.001),
      bladder neck descent (p = 0.002) and maximal descent of a cystocele (p = 0.001).
      A large part of this effect was seen after one vaginal delivery. There was a
      trend towards increased bladder neck mobility (p = 0.065) with vaginal operative
      deliveries. Maximal recorded birthweight did not correlate with parameters of
      hypermobility. CONCLUSION: Vaginal childbirth is strongly associated with
      increased anterior vaginal wall descent, with most of this effect being due to
      the first vaginal delivery.

PMID- 12495101
TI  - Risk factors for strong regret and subsequent IVF request after having tubal
      ligation.
AB  - OBJECTIVES: To identify and describe pre-sterilisation characteristics most
      consistently associated with intensive post-sterilisation regret and subsequent
      request for IVF. DESIGN: Case control study. SETTING: Fertility clinic in a
      tertiary referral urban hospital, Sydney, Australia. SAMPLE CASES: Ninety-seven
      sterilised women who underwent evaluation for IVF during the period 1986-1996;
      CONTROLS: 101 sterilised women who remained satisfied with their tubal ligation.
      MAIN OUTCOME MEASURES: Variables known at the time of sterilisation including
      age, number of living children, history of abortion, underlying medical diseases,
      marital status, race, education, and timing of sterilisation. RESULTS: In the
      multivariate analysis of data, age at the time of sterilisation had the most
      pronounced effect on strong regret. Women younger than 30 years old at the time
      of sterilisation were more likely to request IVF treatment than women 30 to 34
      years old. A concurrent caesarean section was associated with a threefold risk
      (95% CI, 1.05-10.03) relative to an interval procedure. A strong protective
      effect (OR = 0.07; 95% CI, 0.01-0.65) was found for women with more than two
      children compared to childless women. The overwhelming reason stated by women
      requesting IVF was change in marital status, and the desire to have a child with
      the new partner. CONCLUSIONS: Women with such characteristics who are considering
      tubal ligation need further caution and counselling.

PMID- 12495102
TI  - Transvaginal sonography and saline infusion sonohysterography in the evaluation
      of abnormal uterine bleeding.
AB  - OBJECTIVE: To evaluate the accuracy of transvaginal sonography (TVS) and saline
      infusion sonohysterography (SIS) in diagnosing submucous fibroids and endometrial
      polyps in the patients of abnormal uterine bleeding (AUB). DESIGN: Prospective,
      comparative study. SETTING: Postgraduate Institute of Medical Sciences, Rohtak.
      POPULATION: Fifty patients with AUB underwent TVS and SIS prior to hysterectomy.
      MAIN OUTCOME MEASURES: Comparison of diagnosis of submucous fibroids and
      endometrial polyps at TVS and SIS with the final diagnosis at hysterectomy ie
      'gold standard'. RESULTS: Both procedures were helpful in detecting submucous
      fibroids and endometrial polyps. However, SIS was found to be more useful
      (sensitivity 89.5%, specificity 100%, likelihood ratios of the presence and
      absence of submucous fibroids of infinity and 0.1 respectively) than TVS
      (sensitivity 70% and specificity 96.6% and likelihood ratios of 21.2 and 0.3
      respectively) for submucous polyps. Saline infusion sonohysterography was also
      more accurate for endometrial polyps (sensitivity 100%, specificity 97.8%) than
      TVS (sensitivity 66.6%, specificity 100%). With SIS and TVS, the post-test
      probability with negative test was 0% and 4%, respectively, thus suggesting that
      no endometrial polyp would be missed on SIS. CONCLUSION: Saline infusion
      sonohysterography is more accurate in diagnosing submucous fibroids and
      endometrial polyps in the patients of abnormal uterine bleeding than is TVS. TVS
      should be included in the standard protocol for the management of AUB. Saline
      infusion sonohysterography should be reserved for those patients who have
      centrally located fibroids as they may be submucous.

PMID- 12495103
TI  - The place of bowel resection in initial debulking surgery for advanced ovarian
      cancer.
AB  - OBJECTIVE: To evaluate the efficacy and morbidity associated with bowel resection
      at the initial debulking procedure for patients with advanced ovarian cancer.
      DESIGN: Retrospective medical record and computerised database review. SETTING:
      John Hunter Hospital, Newcastle, New South Wales. SAMPLE: All women with FIGO
      stage III or IV epithelial ovarian cancer and with adequate case note
      documentation who underwent bowel resection as part of their primary debulking
      surgery at the John Hunter Hospital from 1991 to July 2000. MAIN OUTCOME
      MEASURES: Cumulative overall and disease free survival, optimal (residual disease
      < 1 cm) versus suboptimal cytoreduction and short (< 6 weeks) and long-term
      postoperative morbidity. RESULTS: For the optimally debulked patients the two and
      five-year overall and disease free survival rates were 49%, 30%, 19% and 8.9%
      respectively. The two-year overall survival rate for the suboptimally debulked
      patients was 20%. The major short-term morbidity rate was 17.6%. Long-term
      morbidity occurred in 10 of 51 patients; however, not all morbidity was surgery
      related. CONCLUSIONS: Cytoreductive surgery, including bowel resection, appears
      indicated in the treatment of patients with advanced ovarian cancer. The surgical
      morbidity rate from these procedures appears acceptable.

PMID- 12495104
TI  - A six-year audit of the management of ectopic pregnancy.
AB  - OBJECTIVE: To audit the management of ectopic pregnancy at National Women's
      Hospital over a six-year period to monitor changes in practice and assess
      adherence to hospital protocols. STUDY DESIGN: A retrospective audit of the
      management of women with a discharge diagnosis of ectopic pregnancy from 1996
      2001 at National Women's Hospital, Auckland, New Zealand. Information was
      collected regarding the demographics, risk factors for ectopic pregnancy, delay
      in diagnosis, management undertaken and failure and complications of initial
      treatment. RESULTS: Over a six-year period a total of 673 women had a discharge
      diagnosis of ectopic pregnancy. Surgery was the most frequent method of
      management but there was increasing utilisation of systemic methotrexate. The
      proportion of women who met the criteria for methotrexate varied from 27-54% over
      the six year period although the highest proportion who received methotrexate in
      any given year was only 24% (2001). The proportion of women who met the criteria
      for receiving methotrexate and had the option of methotrexate discussed with them
      increased from 12% in 1996 to 91% in 2001. Over the six year period 74 women
      received methotrexate and 14 (18.9%) failed and required surgical management.
      Surgical management was performed in 537 women and 30 (5.6%) required either
      further surgery or methotrexate or a combination of both. A laparoscopic
      procedure was performed in 86.5% (465/533) and 10.9% (51/465) converted to
      laparotomy CONCLUSIONS: Although there is evidence that methotrexate is an
      effective and safe option for a proportion of women with ectopic pregnancy, the
      majority of women still undergo surgical management.

PMID- 12495106
TI  - Respiratory symptoms as an indicator of undiagnosed bowel perforation following
      laparoscopic surgery--an observation.
AB  - Undiagnosed bowel perforation following diagnostic or operative laparoscopies is
      associated with significant morbidity and is indeed the primary cause of
      laparoscopy related mortality. The diagnosis of bowel perforation remains
      difficult, predominantly because of the highly varied clinical presentation.
      Respiratory symptoms have rarely been reported. We outline eight cases of
      undiagnosed bowel perforation in which the respiratory symptoms of dyspnoea and
      tachypnoea manifested themselves as an integral part of the clinical
      presentation. We believe these 'atypical' symptoms potentially further delayed
      the diagnosis and instigation of definitive management. Dyspnoea and other
      respiratory symptoms should be considered as additional warning signs of possible
      undiagnosed bowel perforation following laparoscopic surgery

PMID- 12495105
TI  - Is penicillin and/or erythromycin resistance present in clinical isolates of
      group B streptococcus in our community?
AB  - Traditionally group B streptococcus (GBS) has not exhibited resistance to the
      antibiotics penicillin and erythromycin. Recently there are reports from North
      America whereby some GBS isolates have exhibited resistance to erythromycin.
      There have been no studies reported to date to determine whether this resistance
      trend is also occurring in the Australian population. Over a period of six months
      from January to June 1999, 250 GBS isolates were collected at the Royal Women's
      Hospital, Melbourne. Sensitivity to penicillin, erythromycin and vancomycin was
      determined by disk diffusion. Any isolates that had reduced zones to penicillin,
      vancomycin or erythromycin had minimum inhibitory concentrations (MIC)
      determined. No isolates had reduced susceptibility to penicillin or vancomycin.
      Of the 250 isolates, seven (2.8%, 95% CI = 1.1-5.6%) had resistant MICs to
      erythromycin of > 1.0 microg/mL. These preliminary data suggest that penicillin
      therapy is still an effective first-line antibiotic for intrapartum
      chemoprophylaxis and that erythromycin resistance is low in our population.

PMID- 12495107
TI  - Pyoderma gangrenosum of the vulva.

PMID- 12495108
TI  - Lymphangioma vulva.

PMID- 12495109
TI  - Tuberous sclerosis in pregnancy: a case report and review of the literature.

PMID- 12495110
TI  - Benign cystic mesothelioma: a diagnostic dilemma.

PMID- 12495111
TI  - Staphylococcus septicaemia and massive vulvar oedema in pregnancy.

PMID- 12495112
TI  - Teratoma of the placenta.
AB  - Primary non-trophoblastic tumours of the placenta reported to date are
      chorioangioma and teratoma, both of which are extremely rare. A case of teratoma
      in a term placenta is reported.

PMID- 12495113
TI  - Parasitic ovarian dermoid tumour.

PMID- 12495114
TI  - Hymen re-formation after hymenotomy associated with pregnancy.

PMID- 12495115
TI  - Borderline mucinous tumour with mural nodule of signet ring adenocarcinoma.

PMID- 12495116
TI  - A case of splenic abscess in the postpartum period.

PMID- 12495117
TI  - Pregnancy ameliorates symptoms of insulinoma--a case report.

PMID- 12495118
TI  - Perineal endometriosis after vaginal delivery--clinical experience with 10
      patients.

PMID- 12495119
TI  - Spontaneous antenatal expulsion of fetal foot per vaginam--atypical presentation
      of congenital constriction band syndrome.

PMID- 12495120
TI  - Using naltrexone implants in the management of the pregnant heroin user.
AB  - OBJECTIVES: To describe the case history and associated obstetric and neonatal
      outcomes of eight women who had their heroin dependency managed over pregnancy by
      naltrexone implant (two x 1.8 g of naltrexone embedded in poly-DL-lactide acid)
      treatment. METHOD: Case data on maternal management associated with naltrexone
      implant were collected at the Australian Medical Procedures Research Foundation,
      Perth, Australia and three Perth hospitals. RESULTS: Despite earlier instability
      on oral naltrexone and repeated relapses back to dependent heroin use these
      women, following treatment with naltrexone implant, remained heroin free
      throughout their pregnancies. Neonatal and obstetric outcomes were unremarkable.
      CONCLUSIONS: This case series provides preliminary evidence that the pregnant
      heroin user can be managed by naltrexone implant without obvious risk to the
      mother or developing foetus. Importantly, the current case series suggests that
      the pregnant woman who finds it difficult to stabilise on oral naltrexone
      maintenance and returns to dependent heroin use may be managed using implantable
      naltrexone, thereby removing from her the onus for daily naltrexone medication
      compliance. The authors conclude that naltrexone implant may represent an
      important procedure for managing the pregnant heroin dependent patient who finds
      it difficult to shift away from her heroin use patterns. These preliminary
      findings require confirmation using a much larger controlled study.

PMID- 12495121
TI  - Delays in diagnosing breast cancer--the impact of concurrent pregnancy and
      lactation.

PMID- 12495122
TI  - Legal abortion in South Australia; a review of the first 30 years.

PMID- 12495123
TI  - Anatomy of the perineal membrane.

PMID- 12495124
TI  - DNA microarray experiments: biological and technological aspects.
AB  - DNA microarray technologies, such as cDNA and oligonucleotide microarrays,
      promise to revolutionize biological research and further our understanding of
      biological processes. Due to the complex nature and sheer amount of data produced
      from microarray experiments, biologists have sought the collaboration of experts
      in the analytical sciences, including statisticians, among others. However, the
      biological and technical intricacies of microarray experiments are not easily
      accessible to analytical experts. One aim for this review is to provide a bridge
      to some of the relevant biological and technical aspects involved in microarray
      experiments. While there is already a large literature on the broad applications
      of the technology, basic research on the technology itself and studies to
      understand process variation remain in their infancy. We emphasize the importance
      of basic research in DNA array technologies to improve the reliability of future
      experiments.

PMID- 12495125
TI  - Extended generalized estimating equations for binary familial data with
      incomplete families.
AB  - In this article, we assess the performance of two standard, but naive, methods
      for handling incomplete familial data in GEE2 analyses when the outcome is
      binary. We also propose a new method for analyzing such data using GEE2 when
      explanatory variables are discrete. Unlike the naive methods, the new method does
      not require the missing data process to be ignorable. We illustrate our method
      with an example that examines the familial aggregation of obesity.

PMID- 12495126
TI  - Marginally specified generalized linear mixed models: a robust approach.
AB  - Longitudinal data modeling is complicated by the necessity to deal appropriately
      with the correlation between observations made on the same individual. Building
      on an earlier nonrobust version proposed by Heagerty (1999, Biometrics 55, 688
      698), our robust marginally specified generalized linear mixed model (ROBMS-GLMM)
      provides an effective method for dealing with such data. This model is one of the
      first to allow both population-averaged and individual-specific inference. As
      well, it adopts the flexibility and interpretability of generalized linear mixed
      models for introducing dependence but builds a regression structure for the
      marginal mean, allowing valid application with time-dependent (exogenous) and
      time-independent covariates. These new estimators are obtained as solutions of a
      robustified likelihood equation involving Huber's least favorable distribution
      and a collection of weights. Huber's least favorable distribution produces
      estimates that are resistant to certain deviations from the random effects
      distributional assumptions. Innovative weighting strategies enable the ROBMS-GLMM
      to perform well when faced with outlying observations both in the response and
      covariates. We illustrate the methodology with an analysis of a prospective
      longitudinal study of laryngoscopic endotracheal intubation, a skill that
      numerous health-care professionals are expected to acquire. The principal goal of
      our research is to achieve robust inference in longitudinal analyses.

PMID- 12495127
TI  - Maximin D-optimal designs for longitudinal mixed effects models.
AB  - In this article, the optimal selection and allocation of time points in repeated
      measures experiments is considered. D-optimal cohort designs are computed
      numerically for the first- and second-degree polynomial models with random
      intercept, random slope, and first-order autoregressive serial correlations.
      Because the optimal designs are locally optimal, it is proposed to use a maximin
      criterion. It is shown that, for a large class of symmetric designs, the smallest
      relative efficiency over the model parameter space is substantial.

PMID- 12495128
TI  - A semiparametric likelihood approach to joint modeling of longitudinal and time
      to-event data.
AB  - Joint models for a time-to-event (e.g., survival) and a longitudinal response
      have generated considerable recent interest. The longitudinal data are assumed to
      follow a mixed effects model, and a proportional hazards model depending on the
      longitudinal random effects and other covariates is assumed for the survival
      endpoint. Interest may focus on inference on the longitudinal data process, which
      is informatively censored, or on the hazard relationship. Several methods for
      fitting such models have been proposed, most requiring a parametric
      distributional assumption (normality) on the random effects. A natural concern is
      sensitivity to violation of this assumption; moreover, a restrictive
      distributional assumption may obscure key features in the data. We investigate
      these issues through our proposal of a likelihood-based approach that requires
      only the assumption that the random effects have a smooth density. Implementation
      via the EM algorithm is described, and performance and the benefits for
      uncovering noteworthy features are illustrated by application to data from an HIV
      clinical trial and by simulation.

PMID- 12495129
TI  - Two-level proportional hazards models.
AB  - We extend the proportional hazards model to a two-level model with a random
      intercept term and random coefficients. The parameters in the multilevel model
      are estimated by a combination of EM and Newton-Raphson algorithms. Even for
      samples of 50 groups, this method produces estimators of the fixed effects
      coefficients that are approximately unbiased and normally distributed. Two
      different methods, observed information and profile likelihood information, will
      be used to estimate the standard errors. This work is motivated by the goal of
      understanding the determinants of contraceptive use among Nepalese women in the
      Chitwan Valley Family Study (Axinn, Barber, and Ghimire, 1997). We utilize a two
      level hazard model to examine how education and access to education for children
      covary with the initiation of permanent contraceptive use.

PMID- 12495130
TI  - Cohort case-control design and analysis for clustered failure-time data.
AB  - Cohort case-control design is an efficient and economical design to study risk
      factors for disease incidence or mortality in a large cohort. In the last few
      decades, a variety of cohort case-control designs have been developed and
      theoretically justified. These designs have been exclusively applied to the
      analysis of univariate failure-time data. In this work, a cohort case-control
      design adapted to multivariate failure-time data is developed. A risk set
      sampling method is proposed to sample controls from nonfailures in a large cohort
      for each case matched by failure time. This method leads to a pseudolikelihood
      approach for the estimation of regression parameters in the marginal proportional
      hazards model (Cox, 1972, Journal of the Royal Statistical Society, Series B 34,
      187-220), where the correlation structure between individuals within a cluster is
      left unspecified. The performance of the proposed estimator is demonstrated by
      simulation studies. A bootstrap method is proposed for inferential purposes. This
      methodology is illustrated by a data example from a child vitamin A
      supplementation trial in Nepal (Nepal Nutrition Intervention Project-Sarlahi, or
      NNIPS).

PMID- 12495131
TI  - Simultaneous inferences on the contrast of two hazard functions with censored
      observations.
AB  - In survival analysis, often times the pattern of instantaneous risk over time is
      more interesting than that of the cumulative risk. For this case, a nonparametric
      hazard function estimate is more appropriate for summarizing the risk experience
      of a group of patients than the corresponding Kaplan-Meier estimate. In comparing
      a new treatment with a standard therapy, it is important to know if the treatment
      loses it potency during the follow-up period, and if it does, one would like to
      know when it becomes ineffective. Unfortunately, with a plot of the differences
      of two Kaplan-Meier curves, it is rather difficult to capture such temporal
      trends. In this article, we propose simple procedures for constructing confidence
      bands for the contrast of two hazard functions with censored data. The
      simultaneous interval estimates are quite useful for identifying possible values
      of the contrast over time with a certain degree of confidence. The new proposals
      are illustrated with an example and a small simulation study.

PMID- 12495132
TI  - Penalized partial likelihood regression for right-censored data with bootstrap
      selection of the penalty parameter.
AB  - The Cox proportional hazards model is often used for estimating the association
      between covariates and a potentially censored failure time, and the corresponding
      partial likelihood estimators are used for the estimation and prediction of
      relative risk of failure. However, partial likelihood estimators are unstable and
      have large variance when collinearity exists among the explanatory variables or
      when the number of failures is not much greater than the number of covariates of
      interest. A penalized (log) partial likelihood is proposed to give more accurate
      relative risk estimators. We show that asymptotically there always exists a
      penalty parameter for the penalized partial likelihood that reduces mean squared
      estimation error for log relative risk, and we propose a resampling method to
      choose the penalty parameter. Simulations and an example show that the bootstrap
      selected penalized partial likelihood estimators can, in some instances, have
      smaller bias than the partial likelihood estimators and have smaller mean squared
      estimation and prediction errors of log relative risk. These methods are
      illustrated with a data set in multiple myeloma from the Eastern Cooperative
      Oncology Group.

PMID- 12495133
TI  - Estimation of integrated transition hazards and stage occupation probabilities
      for non-Markov systems under dependent censoring.
AB  - We propose nonparametric estimators of the stage occupation probabilities and
      transition hazards for a multistage system that is not necessarily Markovian,
      using data that are subject to dependent right censoring. We assume that the
      hazard of being censored at a given instant depends on a possibly time-dependent
      covariate process as opposed to assuming a fixed censoring hazard (independent
      censoring). The estimator of the integrated transition hazard matrix has a Nelson
      Aalen form where each of the counting processes counting the number of
      transitions between states and the risk sets for leaving each stage have an IPCW
      (inverse probability of censoring weighted) form. We estimate these weights using
      Aalen's linear hazard model. Finally, the stage occupation probabilities are
      obtained from the estimated integrated transition hazard matrix via product
      integration. Consistency of these estimators under the general paradigm of non
      Markov models is established and asymptotic variance formulas are provided.
      Simulation results show satisfactory performance of these estimators. An analysis
      of data on graft-versus-host disease for bone marrow transplant patients is used
      as an illustration.

PMID- 12495134
TI  - A measure of the proportion of treatment effect explained by a surrogate marker.
AB  - Randomized clinical trials with rare primary endpoints or long duration times are
      costly. Because of this, there has been increasing interest in replacing the true
      endpoint with an earlier measured marker. However, surrogate markers must be
      appropriately validated. A quantitative measure for the proportion of treatment
      effect explained by the marker in a specific trial is a useful concept. Freedman,
      Graubard, and Schatzkin (1992, Statistics in Medicine 11, 167-178) suggested such
      a measure of surrogacy by the ratio of regression coefficients for the treatment
      indicator from two separate models with or without adjusting for the surrogate
      marker. However, it has been shown that this measure is very variable and there
      is no guarantee that the two models both fit. In this article, we propose
      alternative measures of the proportion explained that adapts an idea in Tsiatis,
      DeGruttola, and Wulfsohn (1995, Journal of the American Statistical Association
      90, 27-37). The new measures require fewer assumptions in estimation and allow
      more flexibility in modeling. The estimates of these different measures are
      compared using data from an ophthalmology clinical trial and a series of
      simulation studies. The results suggest that the new measures are less variable.

PMID- 12495135
TI  - Bayesian modeling of incidence and progression of disease from cross-sectional
      data.
AB  - In the absence of longitudinal data, the current presence and severity of disease
      can be measured for a sample of individuals to investigate factors related to
      disease incidence and progression. In this article, Bayesian discrete-time
      stochastic models are developed for inference from cross-sectional data
      consisting of the age at first diagnosis, the current presence of disease, and
      one or more surrogates of disease severity. Semiparametric models are used for
      the age-specific hazards of onset and diagnosis, and a normal underlying variable
      approach is proposed for modeling of changes with latency time in disease
      severity. The model accommodates multiple surrogates of disease severity having
      different measurement scales and heterogeneity among individuals in disease
      progression. A Markov chain Monte Carlo algorithm is described for posterior
      computation, and the methods are applied to data from a study of uterine
      leiomyoma.

PMID- 12495136
TI  - Seamlessly expanding a randomized phase II trial to phase III.
AB  - A sequential Bayesian phase II/III design is proposed for comparative clinical
      trials. The design is based on both survival time and discrete early events that
      may be related to survival and assumes a parametric mixture model. Phase II
      involves a small number of centers. Patients are randomized between treatments
      throughout, and sequential decisions are based on predictive probabilities of
      concluding superiority of the experimental treatment. Whether to stop early,
      continue, or shift into phase III is assessed repeatedly in phase II. Phase III
      begins when additional institutions are incorporated into the ongoing phase II
      trial. Simulation studies in the context of a non-small-cell lung cancer trial
      indicate that the proposed method maintains overall size and power while usually
      requiring substantially smaller sample size and shorter trial duration when
      compared with conventional group-sequential phase III designs.

PMID- 12495137
TI  - Survival of bowhead whales, Balaena mysticetus, estimated from 1981-1998
      photoidentification data.
AB  - Annual survival probability of bowhead whales, Balaena mysticetus, was estimated
      using both Bayesian and maximum likelihood implementations of Cormack and Jolly
      Seber (JS) models for capture-recapture estimation in open populations and
      reduced-parameter generalizations of these models. Aerial photographs of
      naturally marked bowheads collected between 1981 and 1998 provided the data. The
      marked whales first photographed in a particular year provided the initial
      'capture' and 'release' of those marked whales and photographs in subsequent
      years the 'recaptures'. The Cormack model, often called the Cormack-Jolly-Seber
      (CJS) model, and the program MARK were used to identify the model with a single
      survival and time-varying capture probabilities as the most appropriate for these
      data. When survival was constrained to be one or less, the maximum likelihood
      estimate computed by MARK was one, invalidating confidence interval computations
      based on the asymptotic standard error or profile likelihood. A Bayesian Markov
      chain Monte Carlo (MCMC) implementation of the model was used to produce a
      posterior distribution for annual survival. The corresponding reduced-parameter
      JS model was also fit via MCMC because it is the more appropriate of the two
      models for these photoidentification data. Because the CJS model ignores much of
      the information on capture probabilities provided by the data, its results are
      less precise and more sensitive to the prior distributions used than results from
      the JS model. With priors for annual survival and capture probabilities uniform
      from 0 to 1, the posterior mean for bowhead survival rate from the JS model is
      0.984, and 95% of the posterior probability lies between 0.948 and 1. This high
      estimated survival rate is consistent with other bowhead life history data.

PMID- 12495138
TI  - Model selection for integrated recovery/recapture data.
AB  - Catchpole et al. (1998, Biometrics 54, 33-46) provide a novel scheme for
      integrating both recovery and recapture data analyses and derive sufficient
      statistics that facilitate likelihood computations. In this article, we
      demonstrate how their efficient likelihood expression can facilitate Bayesian
      analyses of these kinds of data and extend their methodology to provide a formal
      framework for model determination. We consider in detail the issue of model
      selection with respect to a set of recapture/recovery histories of shags
      (Phalacrocorax aristotelis) and determine, from the enormous range of
      biologically plausible models available, which best describe the data. By using
      reversible jump Markov chain Monte Carlo methodology, we demonstrate how this
      enormous model space can be efficiently and effectively explored without having
      to resort to performing an infeasibly large number of pairwise comparisons or
      some ad hoc stepwise procedure. We find that the model used by Catchpole et al.
      (1998) has essentially zero posterior probability and that, of the 477,144
      possible models considered, over 60% of the posterior mass is placed on three
      neighboring models with biologically interesting interpretations.

PMID- 12495139
TI  - Robust design and the use of auxiliary variables in estimating population size
      for an open population.
AB  - We consider the problem of estimating the population size for an open population
      where the data are collected over secondary periods within primary periods
      according to a robust design suggested by Pollock (1982, Journal of Wildlife
      Management 46, 757-760). A conditional likelihood is used to estimate the
      parameters associated with a generalized linear model in which the capture
      probability is assumed to have a logistic form depending on individual
      covariates. A Horvitz-Thompson-type estimator is used to estimate the population
      size for each primary period and the survival probabilities between primary
      periods. The asymptotic properties of the proposed estimators are investigated
      through simulation and are found to perform well. A data set for such a robust
      design of a small-mammal capture-recapture study conducted at Dummy Bottom within
      Browns Park National Wildlife Refuge is analyzed.

PMID- 12495140
TI  - Adaptive line transect sampling.
AB  - Adaptive line transect sampling offers the potential of improved population
      density estimation efficiency over conventional line transect sampling when
      populations are spatially clustered. In adaptive sampling, survey effort is
      increased when areas of high animal density are located, thereby increasing the
      number of observations. Its disadvantage is that the survey effort required is
      not known in advance. We develop an adaptive line transect methodology that, by
      varying the degree of adaptation, allows total effort to be fixed at the design
      stage. Relative to conventional line transect surveys, it also provides better
      survey coverage in the event of disruption in survey effort, e.g., due to poor
      weather. In analysis, sightings from the adaptive sections are downweighted in
      proportion to the increase in effort. We evaluate the methodology by simulation
      and report on surveys of harbor porpoise in the Gulf of Maine, in which the
      approach was compared with conventional line transect sampling.

PMID- 12495141
TI  - Segmented regression in the presence of covariate measurement error in main
      study/validation study designs.
AB  - This article considers the problem of segmented regression in the presence of
      covariate measurement error in main study/validation study designs. First, we
      derive a closed and interpretable form for the full likelihood. After that, we
      use the likelihood results to compute the bias of the estimated changepoint in
      the case when the measurement error is ignored. We find the direction of the bias
      in the estimated changepoint to be determined by the design distribution of the
      observed covariates, and the bias can be in either direction. We apply the
      methodology to data from a nutritional study that investigates the relation
      between dietary folate and blood serum homocysteine levels and find that the
      analysis that ignores covariate measurement error would have indicated a much
      higher minimum daily dietary folate intake requirement than is obtained in the
      analysis that takes covariate measurement error into account.

PMID- 12495142
TI  - Comparing the effects of continuous and discrete covariate mismeasurement, with
      emphasis on the dichotomization of mismeasured predictors.
AB  - It is well known that imprecision in the measurement of predictor variables
      typically leads to bias in estimated regression coefficients. We compare the bias
      induced by measurement error in a continuous predictor with that induced by
      misclassification of a binary predictor in the contexts of linear and logistic
      regression. To make the comparison fair, we consider misclassification
      probabilities for a binary predictor that correspond to dichotomizing an
      imprecise continuous predictor in lieu of its precise counterpart. On this basis,
      nondifferential binary misclassification is seen to yield more bias than
      nondifferential continuous measurement error. However, it is known that
      differential misclassification results if a binary predictor is actually formed
      by dichotomizing a continuous predictor subject to nondifferential measurement
      error. When the postulated model linking the response and precise continuous
      predictor is correct, this differential misclassification is found to yield less
      bias than continuous measurement error, in contrast with nondifferential
      misclassification, i.e., dichotomization reduces the bias due to mismeasurement.
      This finding, however, is sensitive to the form of the underlying relationship
      between the response and the continuous predictor. In particular, we give a
      scenario where dichotomization involves a trade-off between model fit and
      misclassification bias. We also examine how the bias depends on the choice of
      threshold in the dichotomization process and on the correlation between the
      imprecise predictor and a second precise predictor.

PMID- 12495143
TI  - Testing mutual independence between two discrete-valued spatial processes: a
      correction to pearson chi-squared.
AB  - A common feature of data collected in environmental and earth sciences is that
      they typically exhibit spatial autocorrelation. Violating the assumption of
      independent observations can have dramatic effects on inferences derived from
      standard statistical methods. In this article, we examine the consequences of
      spatial autocorrelation on Pearson's chi-squared test of mutual independence
      between two categorical responses with a general number of classes.
      Correspondingly, we suggest a simple modification to the standard test statistic
      that allows for spatial autocorrelation. Our modified statistic is based on a
      first-order correction factor and thus provides only an approximate test.
      However, we show by Monte Carlo simulation that this approximation results in
      satisfactory inferences in several situations of practical interest. The
      usefulness of the method is displayed through an application to categorical data
      arising in the study of the relationship between the distribution pattern of
      plant species and woodland age in a forest in northern Belgium.

PMID- 12495144
TI  - A hierarchical aggregate data model with spatially correlated disease rates.
AB  - The aggregate data study design (Prentice and Sheppard, 1995, Biometrika 82, 113
      125) estimates individual-level exposure effects by regressing population-based
      disease rates on covariate data from survey samples in each population group. In
      this work, we further develop the aggregate data model to allow for residual
      spatial correlation among disease rates across populations. Geographical
      variation that is not explained by model predictors and has a spatial component
      often arises in studies of rare chronic diseases, such as breast cancer. We
      combine the aggregate and Bayesian disease-mapping models to provide an intuitive
      approach to the modeling of spatial effects while drawing correct inference
      regarding the exposure effect. Based on the results of simulation studies, we
      suggest guidelines for use of the proposed model.

PMID- 12495145
TI  - Bayesian methods for a three-state model for rodent carcinogenicity studies.
AB  - The objective of a chronic rodent bioassay is to assess the impact of a chemical
      compound on the development of tumors. However, most tumor types are not
      observable prior to necropsy, making direct estimation of the tumor incidence
      rate problematic. In such cases, estimation can proceed only if the study
      incorporates multiple interim sacrifices or we make use of simplified parametric
      or nonparametric models. In addition, it is widely accepted that other factors,
      such as weight, can be related to both dose level and tumor onset, confounding
      the association of interest. However, there is not typically enough information
      in the current study to assess such effects. The addition of historical data can
      help alleviate this problem. In this article, we propose a novel Bayesian
      semiparametric model for the analysis of data from rodent carcinogenicity
      studies. We develop informative prior distributions for covariate effects through
      the use of historical control data and outline a Gibbs sampling scheme. We
      implement the model by analyzing data from a National Toxicology Program chronic
      rodent bioassay.

PMID- 12495146
TI  - On the use of historical control information for trend test in carcinogenesis.
AB  - In this article a new non-model-based significance test for detecting dose
      response relationship with the incorporation of historical control data is
      proposed. This non-model-based test is considered simpler from a regulatory
      perspective because it does not require validating any modeling assumptions.
      Moreover, our test is especially appropriate to those studies in which the
      intravenous doses for the investigational chemical are labeled as, e.g., low,
      medium and high or the dose labels do not suggest any obvious choices of dose
      scores. This test can be easily adopted for detecting general dose-response
      shape, such as an umbrella pattern. Simple adjustments will be proposed for
      better control of the actual Type I error. Data sets from two carcinogenesis
      studies will be used to illustrate our method. We also evaluate the performance
      of the proposed test and the famous model-based Tarone's trend test with respect
      to size and power.

PMID- 12495147
TI  - Estimators of tissue proportions from X-ray CT images.
AB  - Estimators are derived of tissue proportions from X-ray computed tomography (CT)
      images. These take into account that many pixels in such images are responses to
      mixtures of tissue types. The problem is motivated by an application involving
      estimation of sheep tissue weights. The standard estimator, a count of the number
      of pixels in a particular range of values, is compared with the maximum
      likelihood fit of a mixed-pixel distribution and a moment-based estimator. Both
      simulations and the application show the moment estimator to be best.

PMID- 12495148
TI  - Semiparametric modeling of labeled-cell kinetics, with application to isotope
      labeling of erythrocytes.
AB  - We propose a stochastic model for the kinetics of cells that have been tagged
      with a chemical label. The proposed model consists of two components: a
      parametrically specified distribution for the time to incorporation of the label
      into the cells and a nonparametric survival function reflecting the survival time
      of the label-cell combination. The target quantity of this modeling approach is
      the fraction of labeled cells among all cells, viewed as a function of time.
      Longitudinal measurements of this labeled-cell fraction are available from a
      recent experiment with folate-labeled red blood cells. The proposed
      semiparametric model is fitted to these data and some of the implications are
      explored. The proposed method also includes bootstrap-based inference.

PMID- 12495149
TI  - Profile-likelihood inference for highly accurate diagnostic tests.
AB  - We consider profile-likelihood inference based on the multinomial distribution
      for assessing the accuracy of a diagnostic test. The methods apply to ordinal
      rating data when accuracy is assessed using the area under the receiver operating
      characteristic (ROC) curve. Simulation results suggest that the derived
      confidence intervals have acceptable coverage probabilities, even when sample
      sizes are small and the diagnostic tests have high accuracies. The methods extend
      to stratified settings and situations in which the ratings are correlated. We
      illustrate the methods using data from a clinical trial on the detection of
      ovarian cancer.

PMID- 12495150
TI  - Sample size determination for establishing equivalence/noninferiority via ratio
      of two proportions in matched-pair design.
AB  - In this article, we propose approximate sample size formulas for establishing
      equivalence or noninferiority of two treatments in match-pairs design. Using the
      ratio of two proportions as the equivalence measure, we derive sample size
      formulas based on a score statistic for two types of analyses: hypothesis testing
      and confidence interval estimation. Depending on the purpose of a study, these
      formulas can be used to provide a sample size estimate that guarantees a
      prespecified power of a hypothesis test at a certain significance level or
      controls the width of a confidence interval with a certain confidence level. Our
      empirical results confirm that these score methods are reliable in terms of true
      size, coverage probability, and skewness. A liver scan detection study is used to
      illustrate the proposed methods.

PMID- 12495151
TI  - Ranked set sampling: cost and optimal set size.
AB  - McIntyre (1952, Australian Journal of Agricultural Research 3, 385-390)
      introduced ranked set sampling (RSS) as a method for improving estimation of a
      population mean in settings where sampling and ranking of units from the
      population are inexpensive when compared with actual measurement of the units.
      Two of the major factors in the usefulness of RSS are the set size and the
      relative costs of the various operations of sampling, ranking, and measurement.
      In this article, we consider ranking error models and cost models that enable us
      to assess the effect of different cost structures on the optimal set size for
      RSS. For reasonable cost structures, we find that the optimal RSS set sizes are
      generally larger than had been anticipated previously. These results will provide
      a useful tool for determining whether RSS is likely to lead to an improvement
      over simple random sampling in a given setting and, if so, what RSS set size is
      best to use in this case.

PMID- 12495152
TI  - Exact unconditional inference for risk ratio in a correlated 2 x 2 table with
      structural zero.
AB  - In this article, we consider small-sample statistical inference for rate ratio
      (RR) in a correlated 2 x 2 table with a structural zero in one of the off
      diagonal cells. Existing Wald's test statistic and logarithmic transformation
      test statistic will be adopted for this purpose. Hypothesis testing and
      confidence interval construction based on large-sample theory will be reviewed
      first. We then propose reliable small-sample exact unconditional procedures for
      hypothesis testing and confidence interval construction. We present empirical
      results to evince the better confidence interval performance of our proposed
      exact unconditional procedures over the traditional large-sample procedures in
      small-sample designs. Unlike the findings given in Lui (1998, Biometrics 54, 706
      711), our empirical studies show that the existing asymptotic procedures may not
      attain a prespecified confidence level even in moderate sample-size designs
      (e.g., n = 50). Our exact unconditional procedures on the other hand do not
      suffer from this problem. Hence, the asymptotic procedures should be applied with
      caution. We propose two approximate unconditional confidence interval
      construction methods that outperform the existing asymptotic ones in terms of
      coverage probability and expected interval width. Also, we empirically
      demonstrate that the approximate unconditional tests are more powerful than their
      associated exact unconditional tests. A real data set from a two-step
      tuberculosis testing study is used to illustrate the methodologies.

PMID- 12495153
TI  - A statistical model for investigating binding probabilities of DNA nucleotide
      sequences using microarrays.
AB  - There is considerable scientific interest in knowing the probability that a site
      specific transcription factor will bind to a given DNA sequence. Microarray
      methods provide an effective means for assessing the binding affinities of a
      large number of DNA sequences as demonstrated by Bulyk et al. (2001, Proceedings
      of the National Academy of Sciences, USA 98, 7158-7163) in their study of the DNA
      binding specificities of Zif268 zinc fingers using microarray technology. In a
      follow-up investigation, Bulyk, Johnson, and Church (2002, Nucleic Acid Research
      30, 1255-1261) studied the interdependence of nucleotides on the binding
      affinities of transcription proteins. Our article is motivated by this pair of
      studies. We present a general statistical methodology for analyzing microarray
      intensity measurements reflecting DNA-protein interactions. The log probability
      of a protein binding to a DNA sequence on an array is modeled using a linear
      ANOVA model. This model is convenient because it employs familiar statistical
      concepts and procedures and also because it is effective for investigating the
      probability structure of the binding mechanism.

PMID- 12495154
TI  - A pattern-mixture model for longitudinal binary responses with nonignorable
      nonresponse.
AB  - Longitudinal studies frequently incur outcome-related nonresponse. In this
      article, we discuss a likelihood-based method for analyzing repeated binary
      responses when the mechanism leading to missing response data depends on
      unobserved responses. We describe a pattern-mixture model for the joint
      distribution of the vector of binary responses and the indicators of nonresponse
      patterns. Specifically, we propose an extension of the multivariate logistic
      model to handle nonignorable nonresponse. This method yields estimates of the
      mean parameters under a variety of assumptions regarding the distribution of the
      unobserved responses. Because these models make unverifiable identifying
      assumptions, we recommended conducting sensitivity analyses that provide a range
      of inferences, each of which is valid under different assumptions for
      nonresponse. The methodology is illustrated using data from a longitudinal study
      of obesity in children.

PMID- 12495155
TI  - Flexible weighted log-rank tests optimal for detecting early and/or late survival
      differences.
AB  - At the present time, many AIDS clinical trials compare drug therapies by a time
      to-event primary endpoint that measures the durability of suppression of HIV
      replication. For such studies, survival differences tend to occur early and/or
      late in the follow-up period due to drug differences in initial potency and/or
      durability of efficacy, and detecting these differences is of primary interest.
      We propose a weighted log-rank statistic that emphasizes early and/or late
      survival differences. We also consider some versatile tests that also emphasize
      these differences but are sensitive to a wider range of alternatives. The
      performances of the new tests are evaluated in numerical studies. For the
      alternatives of interest, the new tests show greater power and flexibility than
      commonly used weighted log-rank tests and related versatile tests. When the main
      interest is in detecting early and/or late survival differences, these tests may
      be preferable to the other versatile and weighted log-rank tests that have been
      studied.

PMID- 12495156
TI  - P-value adjustment in sequential clinical trials.
AB  - Many randomized clinical trials utilize a group sequential monitoring procedure
      for assessing treatment efficacy during the course of the trial. For a group
      sequential trial in which the null hypothesis is ultimately rejected, the nominal
      p-value generally overstates the statistical significance of the result and some
      adjustment is required. Several orderings of the sample space have been proposed
      for performing this adjustment, each with unique operating characteristics. In
      this article, we compare four proposed methods with respect to the degree to
      which each captures the strength of evidence against the null hypothesis implied
      by the data. We conclude that the ordering of the sample space induced by the
      observed z-score has the most desirable operating characteristics.

PMID- 12495157
TI  - Weighted least-squares approach for comparing correlated kappa.
AB  - In the medical sciences, studies are often designed to assess the agreement
      between different raters or different instruments. The kappa coefficient is a
      popular index of agreement for binary and categorical ratings. Here we focus on
      testing for the equality of two dependent kappa coefficients. We use the weighted
      least-squares (WLS) approach of Koch et al. (1977, Biometrics 33, 133-158) to
      take into account the correlation between the estimated kappa statistics. We
      demonstrate how the SAS PROC CATMOD can be used to test for the equality of
      dependent Cohen's kappa coefficients and dependent intraclass kappa coefficients
      with nominal categorical ratings. We also test for the equality of dependent
      Cohen's kappa and dependent weighted kappa with ordinal ratings. The major
      advantage of the WLS approach is that it allows the data analyst a way of testing
      dependent kappa with popular SAS software. The WLS approach can handle any number
      of categories. Analyses of three biomedical studies are used for illustration.

PMID- 12495158
TI  - Overall concordance correlation coefficient for evaluating agreement among
      multiple observers.
AB  - Accurate and precise measurement is an important component of any proper study
      design. As elaborated by Lin (1989, Biometrics 45, 255-268), the concordance
      correlation coefficient (CCC) is more appropriate than other indices for
      measuring agreement when the variable of interest is continuous. However, this
      agreement index is defined in the context of comparing two fixed observers. In
      order to use multiple observers in a study involving large numbers of subjects,
      there is a need to assess agreement among these multiple observers. In this
      article, we present an overall CCC (OCCC) in terms of the interobserver
      variability for assessing agreement among multiple fixed observers. The OCCC
      turns out to be equivalent to the generalized CCC (King and Chinchilli, 2001,
      Statistics in Medicine 20, 2131-2147; Lin, 1989; Lin, 2000, Biometrics 56, 324
      325) when the squared distance function is used. We evaluated the OCCC through
      generalized estimating equations (Barnhart and Williamson, 2001, Biometrics 57,
      931-940) and U-statistics (King and Chinchilli, 2001) for inference. This article
      offers the following important points. First, it addresses the precision and
      accuracy indices as components of the OCCC. Second, it clarifies that the OCCC is
      the weighted average of all pairwise CCCs. Third, it is intuitively defined in
      terms of interobserver variability. Fourth, the inference approaches of GEE and
      the U-statistics are compared via simulations for small samples. Fifth, we
      illustrate the use of the OCCC by two medical examples with the GEE, U
      statistics, and bootstrap approaches.

PMID- 12495159
TI  - Probability models and the applicability of statistical procedures in the
      identification of chromosomal fragile sites.
AB  - Bohm et al. (1995, Human Genetics 95, 249-256) introduced a statistical model
      (named FSM--fragile site model) specifically designed for the identification of
      fragile sites from chromosomal breakage data. In response to claims to the
      contrary (Hou et al., 1999, Human Genetics 104, 350-355; Hou et al., 2001,
      Biometrics 57, 435-440), we show how the FSM model is correctly modified for
      application under the assumption that the probability of random breakage is
      proportional to chromosomal band length and how the purportedly alternative
      procedures proposed by Hou, Chang, and Tai (1999, 2001) are variations of the
      correctly modified FSM algorithm. With the exception of the test statistic
      employed, the procedure described by Hou et al. (1999) is shown to be
      functionally identical to the correctly modified FSM and the application of an
      incorrectly modified FSM is shown to invalidate all of the comparisons of FSM to
      the alternatives proposed by Hou et al. (1999, 2001). Last, we discuss the
      statistical implications of the methodological variations proposed by Hou et al.
      (2001) and emphasize the logical and statistical necessity for fragile site
      identifications to be based on data from single individuals.

PMID- 12495160
TI  - A note on estimating crude odds ratios in case-control studies with
      differentially misclassified exposure.
AB  - Morrissey and Spiegelman (1999, Biometrics 55, 338 344) provided a comparative
      study of adjustment methods for exposure misclassification in case-control
      studies equipped with an internal validation sample. In addition to the maximum
      likelihood (ML) approach, they considered two intuitive procedures based on
      proposals in the literature. Despite appealing ease of computation associated
      with the latter two methods, efficiency calculations suggested that ML was often
      to be recommended for the analyst with access to a numerical routine to
      facilitate it. Here, a reparameterization of the likelihood reveals that one of
      the intuitive approaches, the inverse matrix method, is in fact ML under
      differential misclassification. This correction is intended to alert readers to
      the existence of a simple closed-form ML estimator for the odds ratio in this
      setting so that they may avoid assuming that a commercially inaccessible
      optimization routine must be sought to implement ML.

PMID- 12495161
TI  - Antimicrobial activity of tigecycline (GAR-936) against Enterococcus faecium and
      Staphylococcus aureus used alone and in combination.
AB  - STUDY OBJECTIVE: To evaluate the antimicrobial properties of tigecycline, both
      alone and in combination with other antibiotics, against multidrug-resistant
      strains of Enterococcus faecium and Staphylococcus aureus. DESIGN: In vitro
      study. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS:
      Tigecycline, both alone and in combination with other antimicrobial agents, was
      evaluated against two strains of vancomycin-resistant E. faecium (VREF), three
      glycopeptide-intermediately resistant S. aureus strains, and one methicillin
      resistant S. aureus strain. Tigecycline's activity was compared with that of
      vancomycin, gentamicin, rifampin, and doxycycline, using time-kill studies and
      analysis of minimum inhibitory concentrations and minimum bactericidal
      concentrations. Tigecycline also was evaluated in combination with vancomycin,
      gentamicin, rifampin, and doxycycline in time-kill studies. The number of log10
      colony-forming units/ml at 24 hours was compared among treatment groups and
      growth control by analysis of variance. All isolates were susceptible to
      tigecycline, regardless of their susceptibilities to vancomycin or doxycycline.
      In time-kill studies, tigecycline significantly inhibited the bacterial inoculum
      of all isolates (p < 0.05). Although none of the tigecycline combinations studied
      had enhanced killing activity against VREF, when gentamicin was combined with
      tigecycline, improved effects were found against both strains. Against three of
      the S. aureus strains tested, the combination of gentamicin and tigecycline
      demonstrated enhanced or improved activity independently of each strain's
      susceptibility to gentamicin. CONCLUSION: The multidrug-resistant, gram-positive
      bacteria tested, including doxycycline-resistant isolates, were susceptible to
      tigecycline. The combination of tigecycline and gentamicin may have improved or
      enhanced activity against strains of vancomycin-resistant enterococci and S.
      aureus.

PMID- 12495162
TI  - Etiology and frequency of rhabdomyolysis.
AB  - STUDY OBJECTIVES: To describe the etiology and characteristics of patients with
      clinically diagnosed rhabdomyolysis in the United Kingdom General Practice
      Research Database (GPRD), and to estimate the risk of rhabdomyolysis in general
      and that associated with lipid-lowering agents in particular. DESIGN:
      Retrospective analysis. SETTING: The GPRD. PATIENTS: A base population of
      patients aged 20-75 years. Intervention. Patients hospitalized with a computer
      recorded code for acute myositis or myoglobinuria, or with "rhabdo" recorded in
      free text comments were reviewed for evidence of rhabdomyolysis. Lipid-lowering
      treatment among the base population also was calculated. MEASUREMENTS AND MAIN
      RESULTS: We identified 25 patients with rhabdomyolysis among 2.5 million in the
      base population between 1990 and 1999. Seven cases (28%) occurred after a drug
      overdose and 5 (20%) after septicemia. Among the 2935 concurrent users of statin
      and fibrate agents, one developed rhabdomyolysis. CONCLUSION: Only 25 patients
      out of 2.5 million were found to have rhabdomyolysis. Of those, only one patient
      was taking a statin and fibrate concurrently, out of almost 3000 concurrent
      users. The free-text comments field in the GPRD helped to identify patients with
      rhabdomyolysis.

PMID- 12495163
TI  - Comparison of gemfibrozil and fenofibrate in patients with dyslipidemic coronary
      heart disease.
AB  - STUDY OBJECTIVE: To compare the lipid-lowering effects of gemfibrozil and
      fenofibrate in patients with dyslipidemic coronary heart disease. DESIGN: Open
      label, fixed-dosage, retrospective-prospective, one-way crossover from
      gemfibrozil to fenofibrate. SETTING: University-affiliated outpatient clinics.
      PATIENTS: Eighty patients with coronary heart disease with a baseline low-density
      lipoprotein cholesterol (LDL) level above 130 mg/dl or a triglyceride level of
      200 mg/dl or higher who had been receiving gemfibrozil 600 mg twice/day. Thirty
      nine (49%) patients had received concomitant therapy with a 3-hydroxy-3
      methylglutaryl coenzyme A reductase inhibitor (statin) for a minimum of 9 months.
      INTERVENTION: All patients received gemfibrozil 600 mg twice/day for at least 3
      months before being switched to fenofibrate 201 mg/day. Patients receiving
      concomitant statin therapy before crossover continued the statin at the same
      dosage after crossover. Before crossover, a fasting lipid profile was determined
      and patients were queried about the side effects of lipid-lowering therapy. A
      repeat fasting lipid profile was obtained 12 weeks after the crossover.
      MEASUREMENTS AND MAIN RESULTS: Patients were stratified into those receiving
      versus those not receiving concomitant statin therapy. In both of these groups,
      fenofibrate was associated with significantly greater reductions in total
      cholesterol, LDL, and triglycerides than gemfibrozil (all p < 0.001). In
      addition, fenofibrate was associated with a significantly greater increase in
      high-density lipoprotein cholesterol (HDL) than gemfibrozil (p < 0.001). No
      patients reported new-onset adverse effects after the crossover. CONCLUSIONS:
      Compared with gemfibrozil, fenofibrate produced significantly greater reductions
      in total cholesterol, LDL, and triglycerides and significantly greater increases
      in HDL. These changes were evident in patients receiving and not receiving
      concomitant statin therapy.

PMID- 12495164
TI  - Improving blood pressure control in a pharmacist-managed hypertension clinic.
AB  - OBJECTIVE: To determine whether pharmaceutical care provided by a pharmacist
      managed hypertension clinic results in better treatment outcomes when compared
      with traditional health care from a primary care physician. DESIGN: Prospective,
      controlled study SETTING: Veterans Affairs Medical Center, Philadelphia,
      Pennsylvania. PATIENTS: Fifty six patients with essential hypertension; 27 were
      randomly assigned to the intervention group and 29 to the control group.
      INTERVENTION: Patients in the intervention group were scheduled monthly to meet
      with a clinical pharmacist who made appropriate changes in prescribed drugs,
      adjusted dosages, and provided drug counseling in accordance with the
      hypertension guidelines in the sixth report of the Joint National Committee on
      the Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).
      Patients in the control group received standard care from their physicians. The
      study period was 6 months. MEASUREMENTS AND MAIN RESULTS: Treatment outcomes were
      measured by changes in compliance, blood pressure, and patient satisfaction. The
      Short Form-36 health survey and a patient satisfaction survey were used to
      measure changes in patient satisfaction, and a compliance evaluation survey
      measured compliance. Twenty-one (81%) patients in the intervention group attained
      their blood pressure goal of below 140/90 mm Hg at the completion of the study
      versus only eight (30%) in the control group (p < 0.0001). Of 11 patients with
      diabetes in the intervention group, 10 (91%) attained their blood pressure goal
      (< 130/80 mm Hg) versus only two (12 %) of 16 patients with diabetes in the
      control group (p < 0.0001). No significant differences in patient satisfaction or
      compliance were reported between the intervention and control groups.
      CONCLUSIONS: Pharmaceutical care improves blood pressure control and results in
      more patients with hypertension reaching their blood pressure goal.

PMID- 12495165
TI  - Compliance with national guidelines in patients with diabetes in a family
      practice clinic.
AB  - STUDY OBJECTIVE: To assess whether clinicians are treating patients with both
      type 2 diabetes and hyperlipidemia according to national goals for blood
      pressure, low-density lipoprotein cholesterol (LDL), and glucose levels. DESIGN:
      Retrospective chart review. SETTING: University-based family medicine teaching
      practice. PATIENTS: One hundred twenty-four patients with both type 2 diabetes
      and hyperlipidemia. MEASUREMENTS AND MAIN RESULTS: Sixty-nine patients (58%) met
      the National Cholesterol Education Program Adult Treatment Panel II's goals for
      LDL (< 130 mg/dl for primary prevention and < 100 mg/dl for secondary
      prevention). Only 47 patients (38%) were in compliance with national standards
      for both systolic and diastolic blood pressures. The mean hemoglobin A1c (A1C)
      level was 8.6%; 27 patients (21.8%) had A1C levels below 7%. CONCLUSION: A high
      percentage of patients in our family practice clinic met their goals for reducing
      lipid levels, but more aggressive therapy is necessary to attain glucose and
      blood pressure goals. Data from this study emphasize the need for understanding
      which factors influence clinicians' treatment decisions.

PMID- 12495166
TI  - Implications of amyloid precursor protein and subsequent beta-amyloid production
      to the pharmacotherapy of Alzheimer's disease.
AB  - Alzheimer's disease is the most common type of dementia in older people. It is
      highly prevalent, affecting 35-45% of those aged 85 years or older. This disease
      has devastating consequences to patients, their families, caregivers, and the
      health care system. Much has been learned about its pathobiology, which has led
      to the beta-amyloid (Abeta) hypothesis. This hypothesis continues to be the
      predominant postulate of the pathobiology of Alzheimer's disease. Under this
      hypothesis, abnormal accumulation of Abeta is followed by a cascade of neurotoxic
      effects, which eventually result in neurodegeneration and development of
      Alzheimer's disease. This is thought to be the result of altered processing of
      the amyloid precursor protein (APP), preferentially by beta- and gamma-secretase
      enzymes rather than nonamyloidogenic processing by alpha-secretase. The growing
      body of knowledge regarding the processing of APP to various forms of Abeta has
      resulted in new approaches to the investigation of putative anti-Alzheimer's
      disease compounds, including immune-based therapies and various agents that can
      positively affect APP processing.

PMID- 12495167
TI  - Prevention of venous thromboembolism in acute medical illness.
AB  - Each year millions of patients experience a venous thromboembolic event. Due to
      the significant morbidity and mortality associated with venous thromboembolism
      (VTE), prevention is critical. Several groups, such as those undergoing
      orthopedic or general surgery, and patients experiencing acute myocardial
      infarction, are known to be at high risk for VTE. General medical patients-the
      medically ill-are also at risk, but they receive insufficient prophylaxis, which
      may be due to underestimation or lack of assessment of their risk. The American
      College of Chest Physicians recommends either unfractionated heparin or low
      molecular-weight heparin to prevent VTE in these patients. The different
      pharmacologic profiles and dosing methods of these two groups of agents suggest
      that efficacy and safety may not be equivalent. Due to heterogeneity of medically
      ill patients and variability in clinical trials, a detailed review of the
      literature was performed to assist clinicians in assessing risk and choice of a
      regimen to prevent VTE.

PMID- 12495168
TI  - National survey of pharmacist certified diabetes educators.
AB  - We sought to determine the demographics of pharmacists who were certified
      diabetes educators (CDEs) and information about their training, professional
      affiliations, and types of diabetes education services that they provide. We also
      queried these pharmacists about clinical activities, reimbursement, impact of
      certification, and intent to pursue CDE recertification. A list of pharmacists
      who were CDEs as of August 31, 2000, was obtained from the National Certification
      Board for Diabetes Educators. We then sent a six-page anonymous survey to 415
      pharmacist CDEs; 233 surveys (56.1%) were returned. Of these respondents, 140 are
      women and 93 are men, with a mean age of 41.5 years. Most reside in Southern or
      Western states. Average time since pharmacist licensure was 17 years, and average
      time as a CDE was 5 years. Most had completed postgraduate training, including
      residencies and/or fellowships; 52.8% had faculty appointments; 46.7% stated they
      were billing for their services; and 45.9% were obtaining reimbursement. Most
      pharmacists (84.4%) stated that they intended to pursue CDE recertification.
      Providing details about pharmacist CDEs and their clinical activities may
      motivate other pharmacists to pursue this credential. Pharmacists are often the
      most accessible of all health care providers, and earning the CDE credential may
      be an important contribution to diabetes care and education.

PMID- 12495169
TI  - Key articles and guidelines relative to intensive care unit pharmacology.
AB  - Compilations of key articles and guidelines in a particular clinical practice
      area are useful not only to clinicians who practice in that area, but to all
      clinicians. We compiled pertinent articles and guidelines pertaining to drug
      therapy in the intensive care unit setting from the perspective of an actively
      practicing critical care pharmacist. This document also may serve to stimulate
      other experienced clinicians to undertake a similar endeavor in their practice
      areas.

PMID- 12495170
TI  - Evaluation of the ability of seven herbal resources to answer questions about
      herbal products asked in drug information centers.
AB  - STUDY OBJECTIVE: To evaluate the ability of seven widely known herbal references
      and electronic databases to answer questions about herbal products asked at drug
      information centers. DESIGN: Cross-sectional study. SETTING: Five academic and
      institutional drug information centers. METHODS: Fifty-seven herbal-related
      questions were obtained from academic and institutional drug information centers.
      Seven herbal references and electronic databases were evaluated for their ability
      to answer these 57 questions: The Complete German Commission E Monographs:
      Therapeutic Guide to Herbal Medicines, 1st edition; Physicians' Desk Reference
      (PDR) for Herbal Medicines, 2001 edition; Tyler's Honest Herbal: A Sensible Guide
      to the Use of Herbs and Related Remedies, 4th edition; The Lawrence Review of
      Natural Products, 2001; Natural Medicines Comprehensive Database (electronically
      updated, 2001); The Natural Pharmacist (electronically updated, 2001); and
      AltMedDex (electronically updated, 2001). RESULTS: Natural Medicines
      Comprehensive Database outperformed all other products evaluated, providing
      direct answers to 61% of questions. AltMedDex and The Natural Pharmacist
      performed similarly to one another, answering 49% and 44% of questions,
      respectively. The Lawrence Review of Natural Products, PDR for Herbal Medicines,
      The Complete German Commission E Monographs, and Tyler's Honest Herbal were the
      least helpful in providing direct answers to the questions (24%, 21%, 11%, and
      9%, respectively). CONCLUSION: Natural Medicines Comprehensive Database,
      AltMedDex, and The Natural Pharmacist outperformed all other evaluated herbal
      references and electronic databases in their ability to answer questions about
      herbal products posed in clinical practice.

PMID- 12495171
TI  - Health-related quality of life in patients 7 months after a myocardial
      infarction: factors affecting the Short Form-12.
AB  - We assessed patients' health-related quality of life after myocardial infarction
      and identified related variables. Clinical data were obtained retrospectively
      from medical records of consecutive patients admitted to a Midwestern university
      affiliated medical center with diagnosis of myocardial infarction from July 1999
      July 2000. Telephone interviews 7 months after discharge were made to administer
      the Short Form-12 (SF-12) and obtain patient, disease, drug, and intervention
      data. Complete information was obtained from 200 patients (mean age 63.4 +/- 13.1
      yrs, 68% men). The mean Physical Component Summary (PCS)-12 score was 40.6 +/-
      12.0, and the mean Mental Component Summary (MCS)-12 score was 52.1 +/- 10.0.
      Based on univariate analyses, low PCS-12 scores were associated with women; non-Q
      wave infarctions; greater number of illnesses; history of myocardial infarction,
      chronic heart failure (CHF), transient ischemic attack (TIA), renal disease,
      peripheral vascular disease, or percutaneous coronary intervention (PCI);
      rehospitalization during the interim period; and unscheduled PCI since index
      myocardial infarction. Low MCS-12 scores were associated with age below 65 years,
      low overall self-reported drug therapy compliance, low self-reported compliance
      with angiotensin-converting enzyme inhibitor and lipid-lowering therapy, no
      history of coronary artery bypass graft, and no stress test since index
      myocardial infarction. A multivariate regression model for PCS-12 kept the
      following variables: greater number of illnesses, history of CHF or TIA, and
      rehospitalization since index myocardial infarction. The MCS-12 model contained
      age below 65 years, low overall compliance, and low compliance with lipid
      lowering therapy. Further work is necessary to determine noncardiovascular
      predictors of quality of life and whether interventions for these patients will
      result in improved quality of life.

PMID- 12495172
TI  - Modeling the cost-effectiveness of a smoking-cessation program in a community
      pharmacy practice.
AB  - OBJECTIVES: To describe some of the costs of providing a smoking-cessation
      program in a community pharmacy practice, and to model the program's cost
      effectiveness compared with that of a self-directed quit attempt. DESIGN AND
      SETTING: Data used were based primarily on results from a pharmacist-directed
      smoking-cessation program in a community pharmacy chain practice that achieved
      continuous abstinence for at least 1 year in 25% of patients. Baseline
      assumptions were formulated from a MEDLINE literature review and were varied in
      the sensitivity analysis. Overall costs were based on program costs and retail
      cost of the selected cessation method (cold turkey, nicotine patch, nicotine gum,
      or bupropion). PATIENTS: Forty-eight patients, more than two thirds of whom were
      women, aged 21-70 years, who had tried at least once to quit smoking.
      MEASUREMENTS AND MAIN RESULTS: Incremental cost-effectiveness was measured in
      terms of cost/successful quit attempt based on the payer's perspective. Cost/life
      year saved and cost/quality-adjusted life-year saved also were calculated for the
      societal perspective. Incremental cost for an additional patient to quit smoking
      using the pharmacist-directed program alternatives versus a self-directed quit
      attempt was $236 for the cold turkey method, $936 for nicotine patch, $1232 for
      nicotine gum, and $1150 for bupropion. Depending on the smoker's age at the time
      of cessation, the incremental discounted cost-effectiveness was $720-1418/life
      year saved. CONCLUSION: This analysis demonstrates that a pharmacist-directed
      cessation program is a cost-effective alternative to a self-directed quit attempt
      with respect to payers and society. Additional analyses conducted in community
      pharmacy practice are necessary to corroborate our results.

PMID- 12495173
TI  - Probable case of torsades de pointes induced by fluconazole.
AB  - A 25-year-old woman who was hospitalized for worsening endocarditis had a
      prolonged QT interval at baseline and developed monomorphic ventricular
      arrhythmias, which were managed successfully with pacing and antiarrhythmic
      therapy. Several days later, the patient started receiving high-dose fluconazole
      for fungemia and subsequently experienced episodes of torsades de pointes, a
      polymorphic ventricular arrhythmia associated with a prolonged QT interval or
      prominent U wave on the electrocardiogram. The arrhythmia developed in the
      presence of known risk factors. Clinicians should be aware of these risk factors
      and other relevant structural similarities with drugs that cause torsades de
      pointes so that they can recognize patients who may be at risk for fluconazole
      associated arrhythmia.

PMID- 12495174
TI  - Thrombotic complications after intravenous immunoglobulin therapy in two
      patients.
AB  - Although intravenous immunoglobulin (IVIg) generally is considered a safe
      treatment for various autoimmune and inflammatory disorders, rare cases of
      thrombosis may occur. We describe two patients who experienced thrombotic
      complications associated with IVIg therapy. A 54-year-old woman with idiopathic
      thrombocytopenia received IVIg 1 g/kg/day for 2 days. While receiving her
      infusion on day 2, she had an ischemic stroke with hemiparesis; 3 days later she
      developed deep vein thrombosis. A 33-year-old woman with Evans' syndrome received
      IVIg 400 mg/kg/day for 5 days and developed deep vein thrombosis 1 week after
      therapy was completed; she then received warfarin. Six months later, she received
      an additional course of IVIg for recurrent hemolytic anemia; 1 day later she died
      of pulmonary thromboembolism. We suggest that IVIg may promote thrombosis by
      increasing blood viscosity, activating platelets, or causing vasospasm and should
      be administered with caution.

PMID- 12495175
TI  - Patient detection of a drug dispensing error by use of physician-provided drug
      samples.

PMID- 12495176
TI  - Rickettsial infection in Dermacentor variabilis (Acari: Ixodidae) inhibits
      transovarial transmission of a second Rickettsia.
AB  - This study examined the ability of ticks to maintain multiple species of spotted
      fever group rickettsiae via transovarial transmission. Using a capillary feeding
      method, previously established Ricketisia montana- and Rickettsia rhipicephali
      infected cohorts of Dermacentor variabilis (Say) were exposed to R. rhipicephali
      and R. montana, respectively, in two reciprocal challenge experiments. Eggs
      collected from individual females, for two successive generations, of each cohort
      were assessed for rickettsial infection by polymerase chain reaction for each
      challenge experiment. Assessment of the eggs from challenged ticks identified
      that both B. montana- and R. rhipicephali-infected ticks were refractory to their
      respective challenge rickettsiae. The prechallenged infection rate for both F1
      and F2 generations (100%) of the B. montana-infected cohort was resistant to
      transovarial transmission of the second rickettsia species, and only R. montana
      was detected in the eggs of FL = (50%) and F2 = (74%) challenged females. The R.
      rhipicephali-infected cohort maintained a lower level of infection (20%) in the
      population and did not transovarially transmit the challenge species, however,
      detectable levels of infection were lost after the first generation. Second
      generation ticks, no longer infected with B. rhipicephali, became susceptible to
      infection with R. montana and female ticks (approximately 4%) were able to
      transmit R. montana to their progeny. The resistance of the ovaries to co
      infection and apparent host-specific nature of infection suggests that
      rickettsial infection of tick ovaries may alter the molecular expression of the
      oocytes so as to preclude secondary infection with other rickettsiae.

PMID- 12495177
TI  - Notes on parasitism by Amblyomma humerale (Acari: Ixodidae) in the state of
      Rondonia, western Amazon, Brazil.
AB  - The tick Amblyomma humerale Koch is endemic to South America. All host records
      refer to the adult stage parasitizing tortoises, mostly yellow-footed tortoise,
      Geochelone denticulata (L.), and red-footed tortoise, Geochelone carbonaria
      (Spix). The current study reports the presence of A. humerale in the state of
      Rondonia, Brazil. A total of 215 adult ticks (201 males, 14 females) was
      collected from six G denticulata in an Indian reserve and nine Geochelone sp. in
      rural Monte Negro County, giving an overall mean infestation of 14.3 +/- 12.0
      (range: 2-44) ticks per tortoise. Male ticks always outnumbered females on the
      host and nine tortoises had only male ticks. Male ticks were mostly attached in
      clusters on the ventral sides of the carapace near the anterior and posterior
      margins, and more rarely on the outer margin of the plastron. All females were
      found attached to the tortoise skin, at different sites such as head, neck,
      shoulders or legs. Male ticks were rarely observed attached to the body skin.
      Seven engorged nymphs collected on small vertebrates from Monte Negro County
      molted to adults of A. humerale. This included one nymph each on the seven
      colored lizard, Plica plica (L), green tree climber, Plica umbra (L.), and wide
      foraging lizard, Kentropyx calcarata Spix,three nymphs on the common opossum,
      Didelphis marsupialis L., and one nymph on the silky anteater, Cyclopes
      didactylus L. These constitute the first host records for the immature stages of
      the tick A. humerale.

PMID- 12495178
TI  - Population dynamics of adult fleas (Siphonaptera) on hosts and in nests of the
      California vole.
AB  - Microtus californicus (Peale, 1848) were live trapped or retrapped 887 times, and
      fleas were collected over a 2.5-yr period in the San Francisco Watershed and
      Wildlife Refuge. Also, 179 M. californicus nests were collected monthly with
      observations to identify the environment of fleas. The ratio of the mean number
      of fleas per nest to the mean number collected on voles was 4.7:1 for Malaraeus
      telchinus (Rothschild, 1905), 13:1 for Hystrichopsylla occidentalis linsdalei
      Holland, 1957,9:1 for Atyphloceras multidentatus multidentatus (C. Fox, 1909),
      and 76:1 for Catallagia wymani (C. Fox, 1909). The proportion of each flea
      species per nest to those per host was not closely associated seasonally or
      spatially. The average nest contained 37.5% moisture content in relation to its
      total weight and ranged between 3 and 92%. No relationship was observed between
      relative humidity of air within nests and flea number, but a significant
      relationship existed between the moisture of nesting materials and flea number.
      Malaraeus telchinus and A. m. multidentatus were collected in greatest numbers
      from nests having 30-39% moisture content by weight, and H. o. linsdalei and C.
      wymani were most numerous in nests that had 40-49% moisture content. Catallagia
      wymani had the greatest tolerance for high moisture and was severely affected by
      lack of moisture and nearly absent in drier nests. No ectoparasites were
      collected from nests that had <12% moisture content, and nests with >50% moisture
      content had few fleas. A static concept of nest fleas and host fleas as suggested
      by averages and often used in literature is questionable. In seasonal comparison
      of populations of fleas on hosts and in nests, M. telchinus and H. o. linsdalei
      reversed so that more of the flea population was on the host than in the nest for
      a short time during fall.

PMID- 12495179
TI  - Cyanobacteria associated with Anopheles albimanus (Diptera: Culicidae) larval
      habitats in southern Mexico.
AB  - Cyanobacteria associated with Anopheles albimanus Wiedemann larval habitats from
      southern Chiapas, Mexico, were isolated and identified from water samples and
      larval midguts using selective medium BG-11. Larval breeding sites were
      classified according to their hydrology and dominant vegetation. Cyanobacteria
      isolated in water samples were recorded and analyzed according to hydrological
      and vegetation habitat breeding types, and mosquito larval abundance. In total,
      19 cyanobacteria species were isolated from water samples. Overall, the most
      frequently isolated cyanobacterial taxa were Phormidium sp., Oscillatoria sp.,
      Aphanocapsa cf. littoralis, Lyngbya lutea, P. animalis, and Anabaena cf.
      spiroides. Cyanobacteria were especially abundant in estuaries, irrigation
      canals, river margins and mangrove lagoons, and more cyanobacteria were isolated
      from Brachiaria mutica, Ceratophyllum demersum, and Hymenachne amplexicaulis
      habitats. Cyanobacteria were found in habitats with low to high An. albimanus
      larval abundance, but Aphanocapsa cf. littoralis was associated with habitats of
      low larval abundance. No correlation was found between water chemistry parameters
      and the presence of cyanobacteria, however, water temperature (29.2-29.4 degrees
      C) and phosphate concentration (79.8-136.5 ppb) were associated with medium and
      high mosquito larvae abundance. In An. albimanus larval midguts, only six species
      of cyanobacteria were isolated, the majority being from the most abundant
      cyanobacteria in water samples.

PMID- 12495180
TI  - The effects of climatic factors on the distribution and abundance of malaria
      vectors in Kenya.
AB  - Since 1988 malaria epidemics have occurred in multiple sites in western Kenya
      highlands. Climatic variability has been associated with some of the recent
      epidemics. We examined influences of climatic factors on the distribution and
      abundance of three malaria vector species, Anopheles gambiae, Anopheles
      arabiensis, and Anopheles funestus in western Kenya and in the Great Rift Valley.
      Mosquito samples were collected from the lowland and highland areas with various
      climatic conditions. The three vector species were abundant in the lower part of
      western Kenya. An. arabiensis was not found in the areas above 1,400 m elevation
      in western Kenya Although An. gambiae and An. funestus were found in the sites
      above 1,700 m in western Kenya, their densities were < 1 per house. In the Great
      Rift Valley, An. gambiae was not recorded. An. funestus was more widely
      distributed than the other two species. A stepwise multiple regression analysis
      found that moisture index was the most important variable in shaping species
      composition of the An. gambiae complex. Relative abundance of An. gambiae was
      positively associated with moisture index, suggesting that An. gambiae is more
      adapted to moist climate. Seasonal differences in species composition were
      significant in western Kenya, and the proportion of An. funestus was higher in
      the dry season than the rainy season. Influence of temperature on vector density
      was significant for all three species. These results imply that climate changes
      alter the distribution and abundance of malaria vectors in future.

PMID- 12495181
TI  - Vertical movement and posture of blacklegged tick (Acari: Ixodidae) nymphs as a
      function of temperature and relative humidity in laboratory experiments.
AB  - We measured three components of the behavioral activity of blacklegged tick
      (Ixodes scapularis Say) nymphs under controlled conditions of daylength,
      temperature, and relative humidity in the laboratory. Temperature and relative
      humidity were experimentally manipulated among replicated treatment groups in two
      experiments. Humidity treatment had a significant effect on mean questing height,
      which was greater at 100% RH than at any lower humidity (P < 0.01), but it had no
      effect on mean distance moved between observations or the mean percentage of time
      in questing posture. Temperature had no effect on mean questing height, but
      significantly affected mean distance moved (P < 0.01) and the percentage of time
      in questing posture (P < 0.001). Mean distance moved and percentage of time in
      questing posture were both greater at 25 degrees C than at higher or lower
      temperatures. A mechanistic understanding of the factors affecting tick behavior
      is likely to be useful for interpreting field data, designing field studies, and
      predicting risk of exposure to tick-borne pathogens.

PMID- 12495182
TI  - Preprandial inhibition of re-mating in Ixodes ticks (Acari: Ixodidae).
AB  - Questing female blacklegged ticks, Ixodes scapularis, Say in Massachusetts rarely
      bear more than one endospermatophore in their reproductive tracts. We evaluated
      the cause of this nonrandom distribution by examining the stability of
      endospermatophore retention in females and the effect of prior insemination of
      females on the copulatory behavior of male ticks. Endospermatophores were
      retained without degradation in unfed female ticks for >1 yr at 5 degrees C and
      for at least 4 mo at 21 degrees C. Males were much more likely to abort
      preprandial (before feeding) copulations without inseminating females bearing
      endospermatophores. This remating inhibition activity persisted in unfed females
      for at least 2 mo after insemination. Perprandial (during feedng) copulations
      were less restrictive, particularly when females became partially engorged. Males
      were more likely to remain in copula with previously inseminated females that
      were engorged, but generally did not transfer spermatophores to them until their
      fifth day of attachment to a rabbit. Little inhibitory activity was evident
      during the final, rapid engorgement phase of feeding. Thus, remating inhibition
      appears to degrade as feeding progresses. In summary, an unknown factor
      associated with the previous insemination of females inhibits subsequent
      spermatophore transfer by causing mating pairs to interrupt copulation soon after
      initiation. Remating inhibition is strongest in unfed ticks and becomes less
      apparent as females become engorged.

PMID- 12495183
TI  - Temporal and geographic genetic variation in Culex nigripalpus theobald
      (Culicidae: Diptera), a vector of St. Louis encephalitis virus, from Florida.
AB  - A field population of Culex (Culex) nigripalpus Theobald from Vero Beach, FL
      sampled monthly over a period of 24 mo, a colony sample and 10 geographic samples
      were analyzed for genetic variation at 14 enzyme loci using polyacrylamide gel
      electrophoresis. The Cx. nigripalpus colony sample showed significantly lower
      genetic variation than the field-collected samples, measured by mean number of
      alleles per locus (colony 1.4 +/- 0.1 versus field 2.1 +/- 0.22), percentage of
      polymorphic loci (colony 35.7% versus field 54.8 +/- 7.7%), but mean observed
      heterozygosity (Ho = colony 0.16 +/- 0.07 versus field 0.17 +/- 0.03) and mean
      Hardy-Weinberg expected heterozygosity (He = colony 0.14 +/- 0.06 versus field
      0.18 +/- 0.02) did not differ significantly. Three of the 14 loci (Aldox, Gpd,
      and Gpi) from the Vero Beach field samples showed distinct temporal patterns in
      the frequency of the most common allele. Higher mean observed heterozygosity (Ho)
      occurred during months following high rainfall in the Vero Beach field samples
      than during months following low rainfall. The average Nm value of 3.6 indicated
      high gene flow among the temporally distributed samples of the Vero Beach
      population. Genetic variability values between geographic samples from Panhandle,
      FL and south Florida were not significant. Gene flow estimates based on F(ST) =
      0.039 provided a Nm of 6.2 indicating high levels of gene flow among the
      geographic samples of Cx. nigripalpus. The average Nei's and modified Rogers'
      genetic distances among the 10 populations were 0.009 +/- 0.001 and 0.081 +/-
      0.004, respectively. The cluster analysis did not suggest geographic clustering,
      Because Cx. nigripalpus is the vector of St. Louis encephalitis (SLE) in Florida,
      temporal and geographic genetic variation in this species is discussed in
      relation to the seasonal and geographic SLE virus activity in Florida.

PMID- 12495184
TI  - Evaluation of the Amazon River delta as a barrier to gene flow for the regional
      malaria vector, Anopheles aquasalis (Diptera: Culicidae) in northeastern Brazil.
AB  - The Neotropical malaria vector Anopheles aquasalis Curry is distributed
      predominantly along the Atlantic and Pacific Coasts because of its tolerance for
      breeding in salt water. We tested the hypothesis that the freshwater Amazon River
      acts as a barrier to gene flow in northeastern Brazil, by examining variation at
      a 588-nucleotide fragment of the mitochondrial cytochrome oxidase Igene from five
      populations. We identified 15 haplotypes of which 5 were shared both (1) between
      sample localities and (2) across the Amazon River Delta. Sequence divergence
      ranged from 0.0017-0.0272 (average = 0.0137). Estimates of genetic subdivision
      based on the presence of the Amazon Riverwere greatest within localities (phi =
      0.029) and among regions (phi = 0.018), followed by among localities (phi =
      0.011), but none were significant. Parsimony, neighbor-joining, and Nested Clade
      Analyses were used to estimate relationships among populations and infer
      evolutionary processes. Two phylogenetically distinct clusters of populations
      were moderately supported by parsimony. Neighbor-joining trees were poorly
      resolved, thus providing no geographical resolution and no support for the Amazon
      River as a barrier to migration. Phylogeographic structure as detected by the
      Nested Clade Analysis was consistent with restricted gene flow coupled with
      isolation by distance. Taken together, these analyses suggest that the localities
      within this region of northeastern Brazil constitute a single large population of
      An. aquasalis that spans the Amazon Delta.

PMID- 12495185
TI  - Detection of knockdown resistance mutations in Anopheles sacharovi (Diptera:
      Culicidae) and genetic distance with Anopheles gambiae (Diptera: Culicidae) using
      cDNA sequencing of the voltage-gated sodium channel gene.
AB  - The knockdown resistance (kdr) mutation in the voltage-gated sodium channel gene
      (VGSCG), an important resistance mechanism against pyrethroids, was studied in
      Anopheles sacharovi Favre. It was found that the specific primers Agd1 and Agd2
      used for polymerase chain reaction (PCR) amplification of Anopheles gambiae Giles
      VGSCG also amplified this genomic region in An. sacharovi. Comparison of the IIs4
      IIs6 domain segments of the gene indicated 70% nucleotides common to both species
      and a genetic distance of 0.255 between them. Four different samples of
      pyrethroid-resistant An. sacharovi produced three types of amino acid, serine
      (TCG),leucine (TTG),and phenylalanine (TTT) at the kdr mutation point, whereas
      only two kdr mutations, leucine to phenylalanine and leucine to serine, occur in
      An. gambiae.

PMID- 12495186
TI  - Water balance in two species of desert fleas, Xenopsylla ramesis and X. conformis
      (Siphonaptera: Pulicidae).
AB  - The role of water balance capabilities of fleas was examined in desert habitats.
      The fleas studied were Xenopsylla ramesis Rothschild and Xenopsylla conformis
      Wagner. Both fleas occur on Sundevall's jird, Meriones crassus, in the Negev
      Highlands of Israel but in different macro- and microhabitats. Because M. crassus
      occurs in several habitats of the highlands, it was used as a model for
      investigating the effect of habitat parameters on species composition of fleas
      within a host species. Water balance parameters investigated were the range of
      humidities over which active water uptake occurs in the larvae and prepupae of X.
      ramesis and X. conformis. Critical equilibrium humidity estimates were close to
      65% RH for larvae and prepupae of both species. Water loss rates were determined
      for each life stage, except eggs, and represented water loss from cuticular,
      respiratory, and other body openings) under conditions of little or no bulk air
      movement. When converted to a proportional rate (1.44 -2.37% mass loss h(-1))
      water loss rates did not differ significantly between stages or species. Thus,
      geographic separation of X. ramesis and X. conformis could not be explained by
      any difference in water uptake capabilities or water loss rates. Other factors
      that may be important include interspecific competition for resource availability
      among larval fleas and effect of soil texture on cocoon construction.

PMID- 12495187
TI  - Cross-resistance to pyrethroid and organophosphorus insecticides induced by
      selection with temephos in Aedes aegypti (Diptera: Culicidae) from Cuba.
AB  - A sample of Aedes aegypti (L.) from Santiago de Cuba, Cuba, with a high level of
      temephos resistance (19.58x at the 50% lethal concentration [LC50]), was
      subjected to temephos selection to evaluate the utility of this organophosphate
      insecticide for mosquito control. High resistance developed after six generations
      of selection (200.00x). Little or no cross-resistance was observed to the
      organophosphates, malathion and fenitrothion, but high cross-resistance was
      observed for the pyrethroid deltamethrin (337.5x) and the organophosphate
      fenthion (12.74x). Synergism tests implicated detoxifying esterases in temephos
      and fenthion resistance and deltamethrin resistance was associated with a
      cytochrome P450 monooxygenasa. Biochemical tests, polyacrylamide gel
      electrophoresis (PAGE), and inhibition studies confirmed the presence of elevated
      esterase activity associated with temephos resistance. Pyrethroid resistance
      could be associated with a glutathione-S-transferase mechanism but not the
      esterases. The cross-resistance to deltamethrin from temephos selection could
      limit the use of both insecticides for Ae. aegypti control.

PMID- 12495188
TI  - Comparative evaluation of juvenoids for control of cat fleas (Siphonaptera:
      Pulicidae) in topsoil.
AB  - The efficacy of a photostable formulation of methoprene and two photostable
      juvenoids, fenoxycarb and pyriproxyfen, and their residual activity in inhibiting
      the emergence of adult cat fleas, Ctenocephalides felis (Bouche), was studied in
      topsoil. Nursery pots composed of clay, peat, and plastic, and wooden flats were
      used to hold soil samples. Treated soil samples were exposed to sunlight during
      the 63-d study period. Methoprene was as effective as fenoxycarb and pyriproxyfen
      against cat fleas for up to 42 d in clay, peat, and plastic pots at a
      concentration of 64.56 mg (AI)/m2 (6 mg [AI]/ft2), but its activity declined
      significantly thereafter. In contrast, fenoxycarb and pyriproxyfen showed strong
      residual activity for the entire 63 d. The activity of methoprene declined even
      more rapidly over time in wooden flats, while at the same concentrations the
      other two juvenoids showed significant residual activity for 63 d. Clay, peat,
      and plastic pots were therefore considered to be equally effective for evaluating
      the outdoor efficacy of juvenoids in comparison to the wooden flats. However,
      results obtained with wooden flats may be more realistic when testing residual
      activity of volatile chemicals such as methoprene. Fenoxycarb and pyriproxyfen
      showed strong efficacy and residual activity at concentrations of 8.07, 16.14,
      and 32.28 mg (AI)/m2, whereas methoprene did not cause a significant reduction of
      adult emergence at levels below 64.56 mg (AI)/m2. LC50 values for methoprene,
      fenoxycarb, and pyriproxyfen needed for preventing flea emergence when applied to
      topsoil were estimated to be 0.643, 0.031, and 0.028 ppm, respectively.

PMID- 12495190
TI  - Modulation of bovine lymphocyte response by salivary gland extracts of the stable
      fly, Stomoxys calcitrans (Diptera: Muscidae).
AB  - The effect of salivary gland extract of the stable fly, Stomoxys calcitrans (L),
      on bovine lymphocyte proliferation was determined, and antibody reactivity to
      salivary gland proteins was characterized in cattle exposed to stable flies.
      Salivary glands were dissected from male and female flies (4-8 d after eclosion),
      and protein extracts were made by freeze-thaw cycles. Salivary gland extract
      (SGE, 1 and 5 microg) significantly inhibited mitogen-driven proliferation of
      bovine lymphocytes, compared with 1 and 5 microg of identically prepared midgut
      extract (ANOVA, P < 0.05). Phytohemagglutinin A (PHA) stimulated lymphocyte
      responses were suppressed by 61.7 and 79.5% (mean values) with 1 and 5 microg of
      SCE, whereas concanvalin A (Con A) stimulated responses were suppressed by 62.9
      and 77.1% (1 and 5 microg). In contrast, midgut extract (1 and 5 microg)
      minimally suppressed PHA (12.7% +/- 12.6 and 18.7% +/- 15.5) and Con A-driven
      responses (13.8% +/- 20.5 and 24.6% +/- 14.9), respectively. Viability studies
      using propidium iodide and flow cytometry demonstrated that SGE was not
      cytotoxic. Two-color immunofluorescence studies identified T and B lymphocytes as
      the nonviable cells in the cultures. Western blot analysis of serum collected
      from five dairy cows during periods of low and high fly exposure identified an
      immunodominant 27 kDa protein among the salivary gland proteins. These results
      indicate that exposure of cattle to stable fly saliva during blood feeding
      results in an antibody response to salivary proteins and that the saliva has a
      potential to modulate T lymphocyte function.

PMID- 12495189
TI  - Repellency of IR3535, KBR3023, para-menthane-3,8-diol, and deet to black salt
      marsh mosquitoes (Diptera: Culicidae) in the Everglades National Park.
AB  - IR3535, KBR3023, para-Menthane-3,8-diol (PMD), and deet were evaluated in
      controlled studies with human subjects (n = 5) for repellency to black salt marsh
      mosquitoes (Ochlerotatus taeniorhynchus Wiedemann), in the Everglades National
      Park, FL. In tests of 6-h duration, with an average mosquito biting pressure on
      exposed forearm skin of 19.5 (+/- 13.7) bites per minute, the mean percent
      repellencies (SE) for IR3535, KBR3023, PDM, and deet was 88.6 (3.2), 97.5 (1.7),
      89.2 (2.9), and 94.8 (2.5), respectively. Mean complete protection times (SE) for
      IR3535, KBR3023, PMD), mean deet were 3.0 (1.0), 5.4 (0.6), 3.8 (1.4), and 5.6
      (0.5) h, respectively. Untreated (ethanol) controls provided 0% repellency. When
      mosquito biting rates on the untreated forearm skin of repellent-treated subjects
      were compared with biting rates on the forearm skin of control subjects, the
      former were 23%-40% lower early in tests and as much as 22% higher late in tests.
      These differences cast doubt on the technical merit of test designs comprising
      evaluation of more than one repellent at a time on the same human subject while
      underscoring the importance of untreated subjects as negative controls in field
      repellent bioassays.

PMID- 12495191
TI  - Orientation of Onchocerca lienalis stiles (Filarioidea: Onchocercidae)
      microfilariae to black fly saliva.
AB  - Black flies (Simulium spp.) are intermediate hosts and vectors of parasitic
      nematodes belonging to the genus Onchocerca (Filarioidea Onchocercidae).
      Infection and subsequent transmission of infective third-stage larvae occur at
      the vertebrate host-skin interface. Experimental evidence presented here
      demonstrates that Onchocerca lienalis Stiles microfilariae orient to one or more
      components (microfilarial orientation factor [s]; MOF) in black fly saliva. MOFs
      may serve as a means for microfilariae to find and infect black flies during the
      act of blood-feeding. Directed movement through the host's skin to the bite site
      is necessary because Onchocerca spp. microfilariae do not circulate in the blood.
      The substance directing microfilarial orientation appears to be a salivary
      protein, but it is not the Simulium vittatum Zetterstedt erythema protein (SVEP)
      described from New World Simulium spp. These results support earlier field
      observations that associated increased numbers of cutaneous microfilariae with
      black fly feeding and indicate that a fundamental molecular mechanism linked to
      vector saliva may be key for the maintenance of the life cycle of Onchocerca spp.
      Salivary molecules that induce orientation of microfilariae to the bite site are
      potential targets for use in transmission-blocking vaccines to uncouple this
      primary vector infection step.

PMID- 12495192
TI  - Studies on the growth of Bartonella henselae in the cat flea (Siphonaptera:
      Pulicidae).
AB  - Two out of three pools of cat fleas, Ctenocephalides felis (Bouche), that were
      fed Bartonella henselae-positive cat blood for 3 d and then bovine blood for 3 d,
      were polymerase chain reaction (PCR) positive for B. henselae. In a second
      experiment, three cats were inoculated with a streptomycin-resistant strain of B.
      henselae. After the cats were inoculated, caged cat fleas were fed on the cats
      during three different periods, and then pooled and transferred to noninfected
      recipient cats. In the first trial, the bacteria in the flea feces were below
      level of detection when the fleas were transferred from the infected cats to the
      recipient cat. After the fleas had fed on the recipient cat for 6 d, a bacteria
      level of 4.00 x 10(3) CFU/ mg was detected in the flea feces. Subsequently, the
      bacteria level increased for 4 d and then declined. In another experiment, the
      bacteria level in the flea feces was 1.80 x 10(3) CFU/mg at 2 h after collection
      and 3.33 x 10(2) CFU/mg at 72 h after collection. These data indicated that this
      strain of B. henselae can persist in flea feces in the environment for at least 3
      d, and that B. henselae can multiply in the cat flea.

PMID- 12495195
TI  - The immune response of larvae and pupae of Calliphora vicina (Diptera:
      Calliphoridae), upon administered insult with Escherichia coli.
AB  - Adult blowflies, Calliphora vicina Robineau-Desvoidy, are exposed to bacteria
      laden decay as adults and larvae. They are protected from infections in such
      habitats by a family of lytic proteins called Cecropins. In this study, we
      explore the relationshipbetween the developmental stages of the blowfly and the
      strength of the immune response when insulted by an endogenous pathogen,
      Echerichia coli. Our data indicate that the protective function of Cecropin B
      varies with developmental stage. Pupae that were not fully tanned exhibited the
      greatest response to an insult by E coli. The expression of an increased immune
      response is due in part to an increased concentration of Cecropin B manufactured
      by this instar.

PMID- 12495193
TI  - Prevalence and distribution of Ochlerotatus japonicus (Diptera: Culicidae) in two
      counties in southern New York State.
AB  - The seasonal occurrence and abundance of a newly introduced mosquito in the
      United States, Ochlerotatus (Finlaya) japonicus (Theobald), are reported for
      Westchester and Putnam Counties in southern New York State. Adult mosquitoes were
      sampled at 39 sites distributed throughout the two counties. CDC (Centers
      forDisease Control and Prevention) light traps (2,107 trap nights) and gravid
      traps (1,813 trap nights) were used to collect a total of 44,428 mosquitoes from
      May through October 2000. Oc. japonicus was found at 97.4% of sites sampled and
      accounted for 9.8% of all specimens collected. Oc. japonicus was recovered from
      1.5% (n = 326) of the light trap collections and 18.1% (n = 4,026) of the gravid
      trap collections. Although gravid traps collected significantly more specimens
      than light traps, the seasonal activity patterns measured by each trap type were
      congruent. In all, 30 mosquito species were collected. Unlike other Ochlerotatus
      or Aedes species, Oc. japonicus was collected throughout the study, indicating a
      broad seasonal activity period. There was significant regional variation in Oc.
      japonicus abundance, with higher trap densities occurring in the northern-most
      trapping sites. This study demonstrates that Oc. Japonicus is established in
      southern New York State.

PMID- 12495194
TI  - Laboratory and field observations on duration of gonotrophic cycle of Anopheles
      albitarsis s.l. (Diptera: Culicidae) in southeastern Brazil.
AB  - Mark-release-recapture experiments were conducted to determine the duration of
      the gonotrophic cycle of Anopheles albitarsis s.l. in Ribeira Valley, State of
      Sao Paulo, Brazil. Separate experiments with females collected from the field
      were followed under laboratory conditions. A mean of 2.4 d was characteristic for
      the gonotrophic cycle for wild-caught females, whereas 4.4 d was characteristic
      for females in the laboratory conditions.

PMID- 12495196
TI  - Reduction of mosquito (Diptera: Culicidae) attacks on a human subject by
      combination of wind and vapor-phase DEET repellent.
AB  - In a Central Michigan wetland setting, air drawn through a DEET-impregnated
      screen using an electric fan and projected toward a human subject significantly
      reduced mosquito orientation by 74%, landing by 75%, and probing by 70%, relative
      to no applied wind or DEET. The DEET vapor effect was significant as revealed by
      a statistically significant wind/DEET interaction. The wind speed at the downwind
      human subject was 0.6 m/s and the DEET vapor concentration was estimated at 2
      microg/liter air. We suggest a combination of directed wind and volatile
      repellent might be developed as a mosquito deterrent strategy for the backyard
      setting.

PMID- 12495197
TI  - Susceptibility of Haematobia irritans (Diptera: Muscidae) to permethrin in
      dairies in Aguascalientes, Mexico.
AB  - The purpose of this study was to conduct a survey for the susceptibility of the
      horn fly, Hematobia irritans (L.), populations to permethrin on dairy cattle from
      Aguascalientes, Mexico. Samples of populations of horn flies at 25 dairies were
      exposed to two discriminating doses (2.5 and 6.0 microg/cm2) on permethrin
      treated filter papers and the percentage of mortality was compared with that of a
      susceptible strain treated with same doses of permethrin. The results show that
      there was a difference in the mortality from two discriminating doses and the
      mortality of the susceptible strain. Therefore, horn fly populations at all
      dairies tested in Aguascalientes, Mexico, were susceptible to permethrin. This
      insecticide, as well as other pyrethroids, could continue to be used to provide
      satisfactory control of horn flies in the study region.

PMID- 12495198
TI  - Unassisted isolated-pair mating of Anopheles gambiae (Diptera: Culicidae)
      mosquitoes.
AB  - Female Anopheles mosquitoes usually mate only once, but mating is seldom seen in
      small containers containing only one female and male. Therefore, matings are
      often performed among many adults in large cages or by forced copulation.
      Isolated-pair mating of Anopheles gambiae G3 strain-derived mosquitoes without
      forced copulation in small vials is described. We observed that the experimental
      variables eye color and male number were significant factors in the mating
      frequency. Females mated more frequently when three males were present over only
      one male. White-eyed females were more likely to be mated than wild-eyed females,
      but wild males mated more frequently than did white-eyed males. Experiments were
      also conducted to determine when mating was occurring by using wild-eye-color
      mosquitoes in isolated pairs. Almost no matings were observed before day 6 rather
      than the frequencies typically observed after 1-2 d in standard large-cage
      matings among large numbers of adults.

PMID- 12495199
TI  - Identification of 2,4-dichlorophenol in females of the American dog tick,
      Dermacentor variabilis (Acari: Ixodidae), and its possible role as a component of
      the attractant sex pheromone.
AB  - Presence of 2,4-dichlorophenol (2,4-DCP) in extracts of fed and nonfed adult
      female Dermacentor variabilis (Say) by gas chromatography and mass spectroscopy
      (GC/MS) is reported. 2,4-DCP was detected as part of a mixture with 2,6
      dichlorophenol, which is the attractant sex pheromone in this species in a 1:9
      ratio, respectively. Extracts did not contain the monochlorinated phenols, 2
      chlorophenol and 4-chlorophenol. None of these chlorophenols were detected in
      eggs. 2,4-DCP is comparable in efficacy to 2,6-DCP as an attractant sex
      pheromone, prompting attraction, arrestment and feeding posture behavior by fed
      males. It is also present in the female adult.

PMID- 12495200
TI  - An infestation of 2,055 brown recluse spiders (Araneae: Sicariidae) and no
      envenomations in a Kansas home: implications for bite diagnoses in nonendemic
      areas.
AB  - During a 6-mo period, 2,055 brown recluse spiders, Loxosceles reclusa Gertsch and
      Mulaik, were collected in a 19th-century-built, currently occupied home in
      Lenexa, KS. We conservatively estimate that at least 400 of these spiders were
      large enough to cause envenomation. Additional collections from more typically
      infested homes in Missouri and Oklahoma in 2001 yielded 45 and 30 brown recluse
      spiders, respectively. Despite these infestations, no envenomations of the
      inhabitants of these three homes occurred. Considering the levels of infestations
      with no bites in the homes presented here, nonendemic areas in the United States,
      which typically lack recluse spider populations and have had zero to few verified
      specimens of the spider, do not have sufficient numbers of brown recluse spiders
      to make envenomation a likely scenario. Despite this, physicians from nonendemic
      recluse areas often diagnose brown recluse bites which, therefore, are unlikely
      to be correct.

PMID- 12495201
TI  - Continuous oxygen monitoring of mammalian cell growth on space shuttle mission
      STS-93 with a novel radioluminescent oxygen sensor.
AB  - A compact, flow-through oxygen sensor device based on luminescence quenching was
      used to monitor dissolved oxygen levels during mammalian cell growth on the STS
      93 mission of the Columbia space shuttle. Excitation of an oxygen-sensitive
      ruthenium complex was provided by a radioluminescent light source (0.9 mm in
      diameter, 2.5 mm long), and the intensity of the resulting luminescence was
      measured by a simple photodiode detector. The use of radioluminescence for the
      excitation light source is a unique approach that provides many features
      important for long-term and remote monitoring applications. For the spaceflight
      experiment, human lung fibroblast cells (WI-38) were grown in hollow-fiber
      bioreactors. Oxygen concentration was measured in the flow path both before and
      after the bioreactor cartridge in order to gain information about the metabolism
      of the cells. The sensor was found to be nonperturbing to cell growth and
      withstood the challenging physical conditions of shuttle launch and landing while
      maintaining a stable calibration function. In addition, the sensor provided
      physically meaningful oxygen predictions.

PMID- 12495202
TI  - Sulfated polysaccharides from red microalgae have antiinflammatory properties in
      vitro and in vivo.
AB  - The primary goal of the present research was to determine whether sulfated
      polysaccharides derived from red microalgae possess antiinflammatory properties
      when directed against specific parameters of human skin inflammation. These
      unique biopolymers were studied in both in vitro and in vivo models of skin
      inflammation. Human subjects were recruited to participate in a study in which
      the polysaccharide material was applied topically and shown to inhibit cutaneous
      erythema induced by a known irritant. Leukocyte migration from capillary blood
      into sites of inflammation is an essential component of the inflammatory process
      and occurs in a series of steps, two of which are adhesion and chemotaxis. In
      vitro, the polysaccharide material primarily inhibited the migration of
      polymorphonuclear leukocytes (PMNs) toward a standard chemoattractant molecule
      and also partially blocked adhesion of PMNs to endothelial cells. The data
      obtained strongly suggest that sulfated polysaccharides derived from red
      microalgae have significant beneficial potential for use in topical products. In
      addition, the data suggested that the antiinflammatory mechanism for the
      polysaccharide was, at least in part, due to inhibition of circulating immune
      cell recruitment toward inflammatory stimuli.

PMID- 12495203
TI  - Effect of freeze-dried immobilized cells on delignified cellulosic material in
      low-temperature and ambient-temperature wine making.
AB  - In this article, we report on wine making by freeze-dried immobilized cells on
      delignified cellulosic material for ambient and low temperatures. Biocatalyst
      supported by freeze-dried delignified cellulosic (FDC) material recovered after
      the first repeated-batch fermentations the fermentation efficiency and startup,
      which become about equal to those of biocatalyst supported by wet delignified
      cellulosic material. The FDC biocatalyst was suitable for wine making at low
      temperatures (5-15 degrees C), and produced wine of 12% alcoholic degree, with
      the main volatiles contained in the wine and reduced by a decrease in
      temperature. The fermentation efficiency was not affected by total acidity of
      must, while an increase in initial Be density improved percentages of higher
      alcohols and ethyl acetate. The quality of the wine was validated by a
      preliminary taste test to be in the range of acceptable to excellent.

PMID- 12495204
TI  - Pretreatment of corn stover using wet oxidation to enhance enzymatic
      digestibility.
AB  - Corn stover is an abundant, promising raw material for fuel ethanol production.
      Although it has a high cellulose content, without pretreatment it resists
      enzymatic hydrolysis, like most lignocellulosic materials. Wet oxidation (water,
      oxygen, mild alkali or acid, elevated temperature and pressure) was investigated
      to enhance the enzymatic digestibility of corn stover. Six different combinations
      of reaction temperature, time, and pH were applied. The best conditions (60 g/L
      of corn stover, 195 degrees C, 15 min, 12 bar O2, 2 g/L of Na2CO3) increased the
      enzymatic conversion of corn stover four times, compared to untreated material.
      Under these conditions 60% of hemicellulose and 30% of lignin were solubilized,
      whereas 90% of cellulose remained in the solid fraction. After 24-h hydrolysis at
      50 degrees C using 25 filter paper units (FPU)/g of drymatter (DM) biomass, the
      achieved conversion of cellulose to glucose was about 85%. Decreasing the
      hydrolysis temperature to 40 degrees C increased hydrolysis time from 24 to 72 h.
      Decreasing the enzyme loading to 5 FPU/g of DM biomass slightly decreased the
      enzymatic conversion from 83.4 to 71%. Thus, enzyme loading can be reduced
      without significantly affecting the efficiency of hydrolysis, an important
      economical aspect.

PMID- 12495205
TI  - Modeling of the hydrolysis of sugar cane bagasse with hydrochloric acid.
AB  - Sugar cane bagasse was hydrolyzed under different concentrations of hydrochloric
      acid (2-6%), reaction times (0-300 min), and temperatures (100-128 degrees C).
      Sugars obtained (xylose, glucose, arabinose, and glucose) and degradation
      products (furfural and acetic acid) were determined. Based on the Saeman model
      and the two-fraction model, kinetic parameters for predicting these compounds in
      the hydrolysates were developed. The influence of temperature was studied using
      the Arrhenius equation. The optimal conditions selected were 128 degrees C, 2%
      HCl, and 51.1 min. Using these conditions, 22.6 g xylose/L, 3.31 g arabinose/L,
      3.77 g glucose/L, 3.59 g acetic acid/L, and 1.54 g furfural/L were obtained.

PMID- 12495206
TI  - Isolation of lipase producer and its performance in enantioselective hydrolysis
      of glycidyl butyrate.
AB  - A racemic glycidyl butyrate resolving strain, preliminarily identified as a
      Rhizopus sp., had been isolated from soil. Its extracellular lipase was found to
      enantioselectively hydrolyze the (S)-enantiomer of the chiral ester, with optimal
      activities at pH 5.3 and 42 degrees C. Higher enantioselectivity of the enzyme
      was observed at lower temperatures, while the best enantioselectivity was
      obtained at pH 5.5-6.0, with an E value (enantiomeric ratio) of 57.

PMID- 12495207
TI  - Effect of Mn2+, Co2+, Ni2+, and Cu2+ on horseradish peroxidase: activation,
      inhibition, and denaturation studies.
AB  - The effects of transition metal ions (M2+) such as Mn2+, Co2+, Ni2+, and Cu2+ on
      the functional and structural stabilities of horseradish peroxidase (HRP) were
      investigated with respect to reversible chemical denaturation, Michaelis-Menten
      kinetics, chemical modification and time-dependent catalytic activity.
      Conformational Gibbs free energy (deltaGo(H2O)) as a structural stability
      criterion and transition concentrations of metal ions ([M2+] 1/2) were estimated
      using a two-state chemical denaturation model. Activation and inhibitory
      concentration ranges for each metal ion were specified by the steady-state enzyme
      kinetics. Results of a pH-profile method confirmed by chemical modification
      indicate that a histidine residue interacts in the activation concentration
      range, whereas carboxylic residues (Asp and Glu) contribute to interaction in the
      inhibitory concentration range. Incubation of the enzyme with the metal ion at
      activation concentration leads to long-term functional stability of peroxidase.
      Thus, such metal ions as potent effectors induced the enhancement of
      conformational and functional stabilities of horseradish peroxidase.

PMID- 12495208
TI  - New millennium antivirals against pandemic and epidemic influenza: the
      neuraminidase inhibitors.
AB  - The mushroom shaped outer spike protein of influenza, neuraminidase, was first
      discovered nearly 60 years ago. Its importance in viral replication was soon
      recognised both at the point of viral release from the cell and also enabling
      passage of virus through nasal fluid to reach the cell. The enzyme active site
      was identified by x-ray crystallography, allowing an atomic study of interaction
      of enzyme with the sialic acid substrate. Analogues could then be identified and
      synthesized and became a focused target for antivirals. With the current threat
      of bioterrorism and the potential for the emergence of a new pandemic strain in
      the near future, efforts are underway to develop more potent second-generation
      anti-neuraminidase inhibitors with enhanced protective and therapeutic effects.
      Here we review older and newer neuraminidase inhibitors and the role that they
      will play in the fight against influenza in its epidemic and pandemic face.

PMID- 12495209
TI  - A sulphated fucan from the Laminaria abyssalis inhibits the human T cell
      lymphotropic virus type 1-induced syncytium formation in HeLa cells.
AB  - This work evaluated the effect of a sulphated fucan extracted from the Laminaria
      abyssalis marine algae on the human T cell lymphotropic virus type 1 (HTLV-1)
      induced syncytium formation. The experiments were carried out in HeLa cells
      cocultured with a HTLV-1-infected T cell line (C91/PL cells) in the presence of
      the sulphated polysaccharide at concentration below that corresponding to the
      ED50. The sulphated fucan inhibited almost 100% of the syncytium formation at
      concentration of 100 microg/mI and was still active (>95%) at a concentration of
      25 microg/ml. It was also observed that the best inhibition occurred when the
      compound was added in the first 2 h of the cell-to-cell contact. This is the
      first report showing that a purified sulphated polysaccharide, extracted from
      marine algae, is able to inhibit the cell-to-cell contact essential for the
      spreading of the HTLV-1.

PMID- 12495210
TI  - Antiviral properties of prodelphinidin B-2 3'-O-gallate from green tea leaf.
AB  - Prodelphinidin B-2 3-O-gallate, a proanthocyanidin gallate isolated from green
      tea leaf, was investigated for its anti-herpes simplex virus type 2 properties in
      vitro. Prodelphinidin B-2 3'-O-gallate exhibited antiviral activity with IC50 of
      5.0 +/-1.0 microM and 1.6 +/-0.3 pM for XTT and plaque reduction (PRA) assays,
      respectively. Cytotoxicity assay had shown that prodelphinidin B-2 3'-O-gallate
      possessed cytotoxic effect toward Vero cell at concentration higher than its
      IC50. The 50% cytotoxic concentration for cell growth (CC50) was 33.3 +/- 3.7
      microM. Thus, the selectivity index (SI) (ratio of IC50 to CC50) for XTT assay
      and PRA was 6.7 and 20.8, respectively. Prodelphinidin B-2 3'-O-gallate
      significantly reduced viral infectivity at concentrations 10 microM or more.
      Result of time-of-addition studies suggested that prodelphinidin B-2 3'-O-gallate
      affected the late stage of HSV-2 infection. In addition, it was also shown to
      inhibit the virus from attaching and penetrating into the cell. Thus,
      prodelphinidin B-2 3'-O-gallate was concluded to possess antiviral activity with
      mechanism of inhibiting viral attachment and penetration, and disturbing the late
      stage of viral infection.

PMID- 12495211
TI  - A combination of poor adherence and a low baseline susceptibility score is highly
      predictive for HAART failure.
AB  - The relationship between adherence, virological response to highly active
      antiretroviral therapy (HAART) and the presence and development of genotypic
      resistance was assessed in 41 HIV-infected patients on HAART. Four adherence
      parameters (drug taking adherence, dosing adherence, timing adherence and drug
      holidays) were scored prospectively using electronic event monitoring. Genotypic
      resistance at baseline and after therapy failure was scored retrospectively and a
      genotype-based susceptibility score was calculated. Overall median adherence
      rates were high. All adherence parameters were better in virological responders
      (n=31) compared to non-responders (n=10), drug taking adherence and number of
      drug holidays being significantly different. Responders had a significantly
      higher susceptibility score. Stepwise logistic regression showed that the number
      of drug holidays and a low susceptibility score were highly predictive for
      therapy failure. Despite the presence of a limited number of baseline resistance
      mutations, perfectly adherent patients can control virus replication for a
      prolonged period.

PMID- 12495212
TI  - Anti-HSV-1 activity of synthetic humic acid-like polymers derived from p
      diphenolic starting compounds.
AB  - A panel of ten humic-acid-like polymers was synthesized by oxidation of p
      diphenolic compounds and characterized by relative molecular weights, FT-IR
      spectra and functional group analysis. Using the XTT-based tetrazolium reduction
      assay EZ4U, both the low-molecular starting compounds and the synthesized
      polymers were examined for antiviral and cytotoxic activities in HSV-1-infected
      Vero cells. With the exception of hydroquinone, 2,5-dihydroxytoluene and 2,5
      dihydroxybenzoquinone, the starting compounds failed to inhibit herpesvirus
      replication. The polymeric oxidation products, however, developed anti-HSV-1
      activity with EC50 values in the range of 0.65 (2,5-DHPOP) and 322 microg/ml (2,5
      DHBQOP). The CC50 values of the polymers varied among 32.0 (TMHYDROP) and >512
      microg/ml (2,5-DHBQOP, HYDSULFOP). The most effective polymers were found to be
      2,5-DHPOP 2,5-DHTOP and GENOP (EC50: 0.65, 1.6 and 2.2 microg/ml, respectively,
      and SI: > or = 400, > or = 80 and > or = 58, respectively). Functional group
      analysis revealed that increasing numbers of carboxyl groups together with a high
      content of hydroxyl groups tend to enhance the antiviral activity of polymers
      derived from p-diphenolic compounds.

PMID- 12495213
TI  - Synthesis of methylenecyclobutane analogues of nucleosides with axial chirality
      and their phosphoralaninates: a new pronucleotide effective against Epstein-Barr
      virus.
AB  - Methylenecyclobutane analogues of 2'-deoxyadenosine, 2'-deoxyguanosine and 2'
      deoxycytidine, and the corresponding phosphoralaninate pronucleotides comprising
      adenine and guanine bases, were synthesized as potential antiviral agents.
      Phosphoralaninate of adenine methylenecyclobutane was a potent inhibitor of
      replication of Epstein-Barr virus (EBV) in Daudi cell culture. Phosphoralaninate
      of guanine analogue was inactive but both pronucleotides were substrates for
      porcine liver esterase. Adenine methylenecyclobutane analogue was deaminated by
      adenosine deaminase.

PMID- 12495214
TI  - The enhanced reactivity of endogenous biotin-like molecules by antigen retrieval
      procedures and signal amplification with tyramine.
AB  - In diagnostic pathology and immunocytochemical research, immunohistochemical
      techniques using the streptavidin-biotin-peroxidase system have played an
      extremely valuable role. This system, based on the high affinity of streptavidin
      for biotin, may, however, provoke false positive results because of endogenous
      streptavidin-binding sites in human tissues. With the advent of the antigen
      retrieval procedure and signal amplification method, this problem can be serious
      enough to cause mistakes in interpreting immunohistochemical staining results.
      Therefore, we examined the distribution of endogenous biotin-like molecules in
      various human tissues and the influence of various antigen retrieval procedures
      with or without signal amplification using biotinylated tyramine to reveal these
      biotin-like activities. We observed that endogenous biotin-like molecules were
      present in a wide range of tissues, and their activity was markedly enhanced by
      employing antigen retrieval procedures or signal amplification. Furthermore, the
      extent to which the activity of endogenous biotin-like activities was enhanced
      depended on the kinds of antigen retrieval procedures and signal amplification
      employed. Pressure cooking and tyramine amplification with microwave heating
      showed the highest activities. These results show that the antigen retrieval
      procedures and signal amplification with tyramine can enhance the activity of
      endogenous biotin or biotin-like molecules as well as antigenicity, which can be
      a pitfall in the interpretation of immunohistochemical data.

PMID- 12495215
TI  - In situ expression of heat shock proteins, Hsc73, Hsj2 and Hsp86 in the
      developing tooth germ of mouse lower first molar.
AB  - This study examined the detailed gene expression pattern of three different heat
      shock proteins (HSPs), Hsc73, Hsj2, and Hsp86, by means of an in situ
      hybridization method. Hsc73, Hsj2, and Hsp86 were shown in our previous study to
      be differentially expressed in the mouse embryonic mandible at day 10.5 (E10.5)
      gestational age. These HSP genes showed similar expression patterns during
      development of the mouse lower first molar. HSPs-expressing cells were widely
      distributed in both the epithelial and underlying ectomesenchymal cells at E10.5,
      and then were slightly localized at E12 in an area where the tooth germ of the
      lower first molar is estimated to be formed. A strong expression of HSPs was
      observed in the tooth germ at E13.5. At the cap stage, HSPs were expressed in the
      enamel organ and dental papilla. At the bell stage, HSPs were distinctly
      expressed in the inner enamel epithelium and dental papilla cells facing the
      inner enamel epithelial layer, which later differentiate into ameloblasts and
      odontoblasts, respectively. This study is the first report in which Hsc73, Hsj2,
      and Hsp86 were distinctly expressed in the developing tooth germ, thus suggesting
      these HSPs are related to the development and differentiation of odontogenic
      cells.

PMID- 12495216
TI  - Importance of N-linked sugar residues in the development of Auerbach's plexus in
      the rat colon: a lectin histochemical study.
AB  - The lectin-binding patterns in Auerbach's plexus in the distal portions of the
      rat colon from 15- to 21-day-old foetuses, newborns, and adults were examined by
      light and electron microscopy using 16 different lectins (ConA, RCA-1, WGA, PNA,
      SBA, UEA-1, DBA, LCA, PHA-L, DSA, GS-1, VVA, MPA, BPA, MAA, and PSA). The binding
      of ConA was shown to increase after day 19 of gestation in parallel with
      differentiation of Auerbach's plexus, whereas the staining intensity for DSA and
      RCA-1 increased after day 17 of gestation in accordance with the appearance of
      the plexus. At the electron microscopical level, DSA binding sites were observed
      to be localized mainly in the plasma membrane, Golgi apparatus, and nuclear
      membrane of nerve cells. Positive sites were also observed in the axolemma and in
      the plasma membrane of nerve cell processes, Schwann cells, and the surrounding
      smooth muscle cells. PSA, PHA-L, LCA, and WGA showed constant staining during the
      development after day 15 of gestation. Other lectins, most of which are specific
      for O-glycosidic mucin-type sugar residues, were essentially negative throughout
      the developmental stages. Moreover, N-glycanase digestion significantly
      diminished the positive reactions. N-linked oligosaccharides may thus play
      important roles in the development and maturation of the Auerbach's plexus, and
      may be involved in the developmental defect of the plexus, e.g. as occurs in
      Hirschsprung's disease.

PMID- 12495218
TI  - Evidence of regional differences in the lectin histochemistry along the ductus
      epididymis of the lizard, Podarcis sicula Raf.
AB  - The regional difference in the carbohydrate components of the ductus epididymis
      epithelium of a lizard was delineated by means of 13 lectins. Basal cells
      expressed only N-acetylglucosamine (GlcNAc). Throughout the ductus, the secretory
      cells showed oligosaccharides with terminal N-acetylneuraminic acid
      (Neu5Ac)alpha(2,6)galactose (Gal)/N-acetylgalactosamine (GalNAc) and internal
      mannose (Man) and/or glucose (Glc) in the whole cytoplasm, oligosaccharides
      terminating in Neu5Ac alpha(2,6)Gal beta(1,3)GalNAc, Neu5Ac alpha(2,6)Gal
      beta(1,4)GlcNAc, GalNAc, GlcNAc, and fucose (Fuc) in the supra-nuclear zone, and
      also glycans terminating in Neu5Ac alpha(2,3)Gal beta(1,4)GlcNAc, Neu5Ac
      alpha(2,6)Gal beta(1,3)GalNAc, Gal beta(1,4)GlcNAc on the luminal surface. In the
      caput and corpus regions, the supra-nuclear cytoplasm was characterized by
      terminal Gal beta(1,4)GlcNAc and alphaGalNAc, the luminal surface by alphaGalNAc
      and Gal. The Golgi zone, showing oligosaccharides with terminal Neu5Ac
      alpha(2,3)Gal beta(1,4)GlcNAc, Neu5Ac alpha(2,6)Gal beta(1,3)GalNAc, Neu5Ac
      alpha(2,6)Gal beta(1,4)GlcNAc, and internal GlcNAc, expressed terminal Gal
      beta(1,4)GlcNAc and alphaGalNAc in the caput, and terminal betaGalNAc in the
      corpus. The granules showed all the investigated carbohydrates in their
      peripheral zone except terminal betaGalNAc and Fuc, whereas internal Man/Glc and
      terminal Gal were expressed in the central core, and Fuc throughout the ductus,
      terminal GlcNAc in the caput and corpus, and terminal alphaGalNAc only in the
      corpus.

PMID- 12495217
TI  - Craniopharyngioma: a case report and comparative galectin histochemical analysis.
AB  - Craniopharyngioma is a rare benign tumour originating from Rathke's pouch. This
      paper reports a tumour case studied with a set of markers defining protein
      carbohydrate recognition. Expression of endogenous lectins and their reactive
      glycoligands is under differentiation-dependent control in many cell types. These
      parameters can be related to the degree of cell differentiation in tumours.
      Therefore, the expression patterns of endogenous lectins, namely galectins-1, -3,
      and -7, in the craniopharyngioma case were determined. Galectins-1 and -3 were
      also used to reveal glycoconjugates in cells and extracellular matrices, an
      approach that has heretofore relied largely on plant lectins. The staining
      pattern of craniopharyngioma is compared with that of two other types of
      ectodermally derived tumours, namely basal and squamous cell carcinomas. Clusters
      of polygonal and flattened cells with morphological characteristics of
      differentiated cells in the craniopharyngioma and the majority of poorly
      differentiated cells in squamous cell carcinomas were reactive with galectin-3.
      No binding of this probe was observed in cells of basal cell carcinomas and the
      majority of craniopharyngioma cells. In view of the lack of accessible binding in
      the basal layer of normal squamous epithelia where proliferative cells (including
      stem cells) are located, galectin-3 binding could be used to distinguish basal
      from suprabasal cells of squamous epithelial cells.

PMID- 12495219
TI  - Expression of heparan sulphate N-deacetylase/N-sulphotransferase by vascular
      smooth muscle cells.
AB  - Heparan sulphate is an important mediator in determining vascular smooth muscle
      cell (SMC) phenotype. The sulphation pattern of the heparan sulphate chains is
      critical to their function. We have examined the initial step in the biosynthesis
      of the sulphated domains mediated by the enzyme heparan sulphate N-deacetylase/N
      sulphotransferase (NDST). Rabbit aortic SMC in primary culture exhibited NDST
      enzyme activity and expressed NDST-1 in their Golgi apparatus, with maximal
      expression in SMC 2 days after dispersal in primary culture confirmed by Western
      blot analysis. Endothelial cells, macrophages and fibroblasts expressed NDST-1
      but had generally less intense staining than SMC, although SMC expression
      decreased with culture. The uninjured rat aorta also showed widespread expression
      of NDST-1. After balloon de-endothelialisation, NDST-1 could not be detected in
      SMC of the neointima in the early stages of neointimal formation, but was re
      expressed at later time points (after 12 weeks). In human coronary arteries, SMC
      of the media and the diffuse intimal thickening expressed NDST-1, while SMC in
      the atherosclerotic plaque were negative for NDST-1. We conclude that SMC may
      regulate their heparan sulphate sulphation at the level of expression of the
      enzyme heparan sulphate NDST in a manner related to their phenotypic state.

PMID- 12495220
TI  - Hepatocyte polarity and the peroxisomal compartment: a comparative study.
AB  - In search of factors that regulate the phenotype of the peroxisomal compartment
      in wild-type liver parenchymal cells, we compared hepatocyte polarity to
      peroxisome differentiation, using adult liver as the standard. Differentiation
      parameters were evaluated in a three-dimensional culture model (spheroid), in
      'sandwich' and monolayer primary hepatocyte cultures, and in 15.5 and 18.5-day
      old foetal rat liver. Peroxisomes, studied by immunohistochemistry, enzyme
      histochemistry, and catalase specific activity, were better differentiated
      depending on foetal age (day 18.5 > day 15.5) and culture type (spheroid >
      sandwich > monolayer). The hepatocyte polarity markers ATP-, ADP-, and AMP
      hydrolysing activities were, in all models, mislocalized at the lateral plasma
      membrane, whereas in contrast the multidrug resistance-associated protein 2
      (mrp2) antigen was always correctly immunolocalized at the apical membrane
      domain. In cultures, the correct secretion of fluorescein (mrp2-mediated) into
      bile canaliculi was observed. Bile canaliculi (branching, ultrastructure and
      immunolocalization of the tight-junction associated protein ZO-1), were better
      differentiated in 18.5 than in 15.5-day-old foetal liver and in spheroid >
      sandwich > monolayer cultures. Our results show a parallelism between changes of
      the peroxisomal compartment and bile canalicular structure together with mrp2
      mediated secretory function. Distinct polarization characteristics do not
      necessarily change simultaneously, suggesting different regulatory mechanisms.

PMID- 12495221
TI  - Selective binding of nucleotide probes by eosinophilic cationic protein during in
      situ hybridisation.
AB  - During in situ hybridisation on frozen and paraffin-embedded sections of bowel
      for IkappaB alpha, oligodeoxyribonucleotide probes were found to bind more avidly
      to eosinophils than target mRNA. This binding could not be obviated using
      strategies previously employed to block either binding of long DNA probes (200
      mers) to eosinophils in bone marrow smears, or of riboprobes to eosinophils in
      sections of bowel, without removing specific hybridisation of probes. That this
      binding could arise through interaction of anionic oligodeoxyribonucleotides with
      eosinophil cationic protein, which has an unusually high pI, and is abundant in
      cytoplasmic granules of eosinophils, was demonstrated in vitro using real-time
      biomolecular interaction analysis with a BiacoreX instrument. Finally, a
      relationship between probe hydrophobicity, measured by reverse phase ion-pair
      high performance liquid chromatography, and in situ binding of individual probes
      to eosinophils was demonstrated. Effective tissue penetration by hydrophobic
      probes and subsequent strong probe-eosinophilic cationic protein interactions
      therefore may confound the interpretation of in situ hybridisation performed with
      oligonucleotide probes in eosinophil-containing tissues, such as bowel and nasal
      polyps.

PMID- 12495222
TI  - Expression of apoptosis-inducing factor during early neural differentiation in
      the chick embryo.
AB  - The distribution of apoptosis-inducing factor (AIF) immunoreactivity has been
      studied in the developing somites and nervous system of the chick embryo at
      embryonic day 4. AIF was found to be expressed primarily in the cytoplasm of
      cells of the ventral motor roots, at the points of their insertion into the
      neural tube. Co-localization of mitochondrial AIF immunoreactivity with the
      epitopes recognized by the monoclonal antibodies HNK-1 and 1E8 suggests that the
      AIF may be present in Schwann cell precursors as well as in nerve fibres. AIF
      immunoreactivity was not observed in either cell bodies in the neural tube, or in
      the somitic tissue surrounding the ventral roots. The results are consistent with
      the hypothesis that AIF may be involved in neuronal cell death during
      development, and that target-derived neuronal survival factors may act by
      controlling AIF activity.

PMID- 12495223
TI  - Id-1 expression defines a subset of vimentin/S-100beta-positive, GFAP-negative
      astrocytes in the adult rat pineal gland.
AB  - Id proteins are dominant negative members of the helix-loop-helix (HLH)
      transcription factor family which are involved in the differentation of many cell
      types, including glia. We have recently identified the adult rat pineal gland as
      a major site of Id-1 and Id-3 expression. In the present study, double
      fluorescence immunocytochemical analysis was used to examine the co-localization
      of Id-1 and Id-3 with both neuronal (synaptophysin, betaIII-tubulin) and
      astrocytic markers (GFAP, vimentin, S-100beta) in the rat pineal. In addition to
      localizing Id-1 and Id-3 protein to the melatonin-producing pinealocytes, we have
      also made the novel observation that Id-1, but not Id-3, is highly expressed in a
      population of vimentin-positive/S-100beta-positive/GFAP-negative astrocytes.
      Surprisingly, Id-1 was primarily cytoplasmic in these cells, and expression
      extended throughout the cellular processes. The pineal has been recognized
      previously as a unique region of the central nervous system in which a vimentin
      positive/GFAP-negative glial phenotype is maintained in adult mammals. The
      exclusion of Id-1 from GFAP-positive cells, and expression in a population of
      vimentin-positive pineal astrocytes is evidence of a role for Id-1 in the adult
      stabilization of one form of astrocyte. These results identify the rat pineal
      gland as a model system for the functional analysis of Id-1.

PMID- 12495224
TI  - Endocrine cells in gastric carcinoma and adjacent mucosa. An immunohistochemical
      and ultrastructural study.
AB  - Endocrine cells are often found in human gastric carcinoma and may be recognized
      by the immunoreactivity of their chromogranin A, peptides and biogenic amines
      content. Anti-chromogranin A was used to investigate the morphology of endocrine
      cells using light and electron microscope immunohistochemical techniques. The
      hormone content of endocrine cells was examined in both tumour tissue and tumour
      adjacent mucosa. It was found that the endocrine cells in tumour tissue were
      malignant, often had amphocrine differentiation and did not resemble a normal
      cell type. The hormone content of endocrine cells in tumour tissue seldom
      corresponded to the hormonal content of endocrine cells in tumour-adjacent
      mucosa. In intestinal-type carcinoma and in some parts of diffuse-type gastric
      carcinomas, endocrine cell hyperplasia and an alteration of the differentiation
      in the tumour-adjacent mucosa were discovered. The distribution of endocrine
      cells in the tumour tissue was different in both types of gastric carcinoma. The
      results reported here suggest that endocrine cell differentiation of malignant
      endocrine cells in human gastric carcinoma develops in a different way from that
      of endocrine cells in tumour-adjacent mucosa, and as a result, diverse hormonal
      products may appear in tumour tissue.

PMID- 12495225
TI  - Co-localisation of nitric oxide synthase and endothelin in the rat supraoptic
      nucleus.
AB  - The co-localisation of neuronal nitric oxide synthase and endothelin-1 was
      studied in the rat supraoptic nucleus at the electron microscopy level. Double
      pre-embedding immunocytochemistry was performed using ExtrAvidin-horseradish
      peroxidase and immunogold-silver techniques. Immunoreactivities to neuronal
      nitric oxide synthase and endothelin-1 were co-localised in sub-populations of
      endocrine neurones (cell bodies) and dendrites. Double-labelled axon terminals
      making asymmetrical synapses on unlabelled dendrites were also observed. The
      findings are discussed in terms of the possible role and significance of nitric
      oxide and endothlin-1 in the hypothalamo-neurohypophysial system.

PMID- 12495226
TI  - Sociotropy-dependency and autonomy as predictors of eating disturbance among
      Canadian female college students.
AB  - The authors (a) tested the generalizability of A. Sugarman, D. Quinlan, and L.
      Devenis's (1982) psychodynamic account of eating disturbances, which posits that
      overt autonomy strivings associated with eating problems are a defense against
      unconscious dependency concerns, and (b) evaluated the degree to which autonomy
      and sociotropy had unique associations with eating disturbances. Canadian female
      college students (N= 286) completed self-report measures of autonomy, sociotropy,
      depression, and bulimia as well as the Rorschach Inkblot Test. Findings suggest,
      contrary to Sugarman and colleagues' psychodynamic account, that experiences of
      dependency related to self-reported eating pathology do not necessarily lie
      outside of conscious awareness. Moreover, reported bulimic symptoms were uniquely
      associated with sociotropy but not autonomy-self-criticism among the
      participants.

PMID- 12495227
TI  - Readdressing gender bias in the Coopersmith Self-Esteem Inventory-short form.
AB  - The short form of the Coopersmith Self-Esteem Inventory (SEI) was evaluated for
      gender bias. The authors replicated a study by L. Francis and D. James (1998) and
      administered the SEI to 361 middle and high school students (146 boys, 2l5
      girls). They found that gender bias existed in 6 of the 25 items on the SEI, with
      5 of those items favoring boys. Because recent literature indicates that male and
      female adolescents experience problems in different areas of their lives, the
      authors suggest that researchers consider such differences when selecting items
      for a standardized measure.

PMID- 12495228
TI  - The effect of self-observation on children's problem solving.
AB  - The effects of self-observation on children's problem solving were investigated.
      Children (N = 124) aged 6-8 years attempted to solve the 3-disc Tower of Hanoi
      problem. After pretesting, children were grouped into those who (a) practiced
      solving the(c) observed problem independently, (b) received instruction on the
      most efficient solution, a videotape recording of their previous attempt, and (d)
      served as a control. Subsequently, children were immediately tested on the 3-disc
      problem and a more difficult 4-disc problem. They were tested again 1 week later.
      Performance was most improved for children inwere maintained the practice and
      video conditions on the 4-disc problem. Improvements over the 1-week interval.
      Unique characteristics of video self-observation are discussed.

PMID- 12495229
TI  - The origin of conditional logic: does a cheater detection module exist?
AB  - The domain-specific hypothesis of L. Cosmides (1989) and L. Cosmides and J. Tooby
      (1989, 1992) positing that conditional logic has its origin in the evolution of
      social exchange and in the detection of potential cheaters was tested against a
      more domain-general hypothesis positing that adult reasoning is logical and that
      errors in conditional reasoning arise from misunderstandings, not from a lack of
      logicality. The results of 5 experiments with undergraduate students (n = 682 for
      Experiments 1-4; n = 188 for Experiment 5), which involved a series of selection
      tasks that yielded specific predictions about participant performance, were not
      consistent with the cheater detection hypothesis. Findings supported the
      misunderstandings hypothesis and imply that adults possess general-purpose
      logical competence versus domain-specific modules.

PMID- 12495230
TI  - Dyadic versus individual storytelling by preschool children.
AB  - A constructive model of recall and communication (D. Edwards & D. Middleton,
      1986) and certain whole-word approaches to learning (C. Pontecorvo & C.
      Zucchermaglio, 1989) were evaluated in conjunction with an investigation of the
      benefits of joint storytelling on children's cognitive processes. Preschoolers (N
      = 36, aged 30-62 months) were prompted to compose a story, working with a
      classmate (during which they talked together freely and generated a mutual
      narrative) or individually. Findings revealed that, although dyadically generated
      stories were longer, containing significantly more words, propositions, and
      additive conjunctions, stories told by individuals contained proportionally more
      logically connected statements and greater use of the past tense. Moreover,
      compared with dyadic stories, individually generated narratives contained fewer
      alterations of the protagonist.

PMID- 12495231
TI  - Young children's learning of size comparison strategies: effect of origami
      exercises.
AB  - The authors examined the process of change in size comparison strategies among
      preschool-age children. Twelve 5- and 6-year-old children were provided with
      origami exercises and size comparison tasks for 5 days consecutively, and another
      twelve 5- and 6-year-old children received size comparison tasks only. Children's
      strategies for the size comparison tasks were analyzed in terms of placement and
      adjustment. In contrast with the children in the control condition, the children
      who were provided with exercises in origami increased their use of
      superimposition and adjustment strategies by 2 dimensions across the 5 days. The
      authors argue that origami exercises helped the children connect their implicit
      understanding of relative size with the use of more effective strategies for size
      comparison.

PMID- 12495232
TI  - Motivation to hide emotion and children's understanding of the distinction
      between real and apparent emotions.
AB  - The authors investigated the extent to which children's understanding of the
      distinction between real and apparent emotions varied according to the motivation
      to hide emotions. Children, aged 6-7 and 10-11 years, were read stories designed
      to elicit either prosocial or self-protective motivated display rules and were
      asked to predict the facial expressions the protagonists would make to hide felt
      emotions. Children were found to understand the distinction between real and
      apparent emotions very well, independently of the type of motivation. Contrary to
      predictions, boys understood this distinction better than did girls when the
      motivation to hide positive emotions was prosocial. Children perceived
      neutralization as the most appropriate strategy to hide felt emotions, followed
      by masking.

PMID- 12495233
TI  - Family functioning and psychological well-being, school adjustment, and problem
      behavior in chinese adolescents with and without economic disadvantage.
AB  - Using an indigenously developed measure of family functioning, the author
      examined the association between family functioning and adolescent adjustment in
      1,519 Chinese adolescents. Results showed that family functioning was
      significantly related to measures of adolescent psychological well-being
      (existential well-being, life satisfaction, self-esteem, sense of mastery,
      general psychiatric morbidity), school adjustment (perceived academic
      performance, satisfaction with academic performance, and school conduct), and
      problem behavior (delinquent and substance abuse behavior). Family functioning
      was generally more strongly related to measures of adolescent adjustment for
      adolescents with economic disadvantage than for adolescents without economic
      disadvantage.

PMID- 12495234
TI  - The effects of children on parents: adoptee genetic dispositions and adoptive
      parent psychopathology.
AB  - Although the traditional focus in socialization research has been on the effect
      of parents on their children (Finley, 1999), recently, researchers have turned
      their attention to the effects of children on their parents (Ambert, 1992;
      Demick, Bursik, & Dibiase, 1993). An important confound in the study of the
      effects of children on parents, however, is shared genetic or biological
      heritage. One method of avoiding this confound is for researchers to study
      adoptees and adoptive parents who have no shared genetic heritage. We, therefore,
      designed the present secondary analysis to examine the effects of adopted
      children on their adoptive parents without confounding shared biological
      heritage.

PMID- 12495235
TI  - A six year progress report on full denture implants. 1954.

PMID- 12495236
TI  - Upper and lower implant dentures. 1954.

PMID- 12495237
TI  - Surgical, clinical and histopathologic notes on the human implant denture. 1954.

PMID- 12495238
TI  - Construction of the mandibular implant denture superstructure. 1954.

PMID- 12495239
TI  - Tracking and explanation of physical activity in young adults over a 7-year
      period.
AB  - Tracking and explaining physical activity in young adults was investigated in a 7
      year longitudinal design. From a representative sample of 980 respondents at
      baseline (M age = 21 years), 172 respondents, comprising 18% of the original
      sample, completed psychosocial questionnaires and were interviewed at home to
      assess their level of physical activity at follow-up. Psychosocial variables were
      grouped into four groups: social variables, self-efficacy, perceived benefits,
      and perceived barriers. Drop-out analyses showed no major differences between the
      baseline and follow-up samples. The aims of the present study were: (a) to
      investigate tracking in physical activity and psychosocial determinants over a 7
      year period, and (b) to examine baseline determinants and change in determinants
      in predicting physical activity change in men and women. No significant tracking
      of physical activity level was found for men. For women, moderate tracking scores
      were found for total energy expenditure and moderate-intensity energy expenditure
      (r = .34 and .41, respectively). There was higher tracking in psychosocial
      determinants than in physical activity. Relatively high tracking scores for
      perceived benefits and barriers suggest that cognitions related to physical
      activity are more stable than the behavior itself. Although baseline psychosocial
      variables were poor predictors of physical activity change, determinants'change
      scores accounted for 16-19% of the variance in physical activity in men and 7-24%
      in women. Significant predictors were different for men and women. Present
      results can inform the design of physical activity interventions for these
      populations.

PMID- 12495240
TI  - Age-related differences in vision and proprioception in a lower limb interceptive
      task: the effects of skill level and practice.
AB  - This study examined age-related differences in the role of visual proprioception
      during a lower limb interceptive action and how this varies as a function of
      skill and practice. In Experiment 1, skilled and less-skilled 8-, 10-, and 12
      year-old boys controlled a soccer ball using their preferred foot under full
      vision and when sight of the effector was occluded. With the exception of the
      high-skilled 12-year-olds and low-skilled 8-year-olds, participants showed a
      decrement in peformance when denied access to visual proprioception. In
      Experiment 2, the effect of practicing under different informational constraints
      was examined for 12 year-old boys. Children performed varying amounts of practice
      under full vision, or in a condition where sight of the foot was occluded, before
      being transferred to the alternative viewing condition. Participants who
      practiced under occluded viewing conditions showed greater relative improvement
      in performance over practice and transfer sessions compared with a full vision
      control group. Some support is provided for the manipulation of visual
      informational constraints as an effective pedagogical approach to motor learning.

PMID- 12495241
TI  - Change in throwing pattern: critical values for control parameter of velocity.
AB  - The purpose of this study was to determine the critical values at which throwing
      patterns change when scaling up on the control parameter of velocity. Thirty-six
      participants (ages: 6-12 years) were categorized into four throwing levels
      according to patterns represented by temporal joint lag. Each participant was
      required to complete 5 overhand throws at each of 10 relative velocities for a
      total of 50 trials per participant. The lowest velocity was 10% of maximum, with
      increases in increments of 10% up to a maximum effort. Quantitative and
      qualitative analyses indicated that critical values varied according to throwing
      category and joint. Generally, lower skilled throwers (Levels 1 and 2) had less
      stable joint lag and changed patterns at lower velocities than higher skilled
      (Levels 3 and 4) throwers.

PMID- 12495242
TI  - Self-controlled feedback: does it enhance learning because performers get
      feedback when they need it?
AB  - This paper examines whether self-controlled feedback schedules enhance learning,
      because they are more tailored to the performers' needs than externally
      controlled feedback schedules. Participants practiced a sequential timing task.
      One group of learners (self-control) was provided with feedback whenever they
      requested it, whereas another group (yoked) had no influence on the feedback
      schedule. The self-control group showed learning benefits on a delayed transfer
      test. Questionnaire results revealed that self-control learners asked for
      feedback primarily after good trials and yoked learners preferred to receive
      feedback after good trials. Analyses demonstrated that errors were lower on
      feedback than no-feedback trials for the self-control group but not for the yoked
      group. Thus, self-control participants appeared to use a strategy for requesting
      feedback. This might explain learning advantages of self-controlled practice.

PMID- 12495244
TI  - Exerted effort and performance in climbing among boys: the influence of
      achievement goals, perceived ability, and task difficulty.
AB  - In achievement contexts such as sport, achievement goal theory assumes that an
      individual's major concern is to demonstrate competence. However, competence may
      be expressed in two ways: as task and ego involvement (Nicholls, 1989). Seventy
      eight boys (M age = 13.6 years) performed five climbing courses, and the
      influence of achievement goals, perceived ability, and task difficulty on effort
      and performance was studied. According to the achievement goal theory: (a) task
      involved boys exerted more effort and performed better than ego-involved boys;
      and (b) exerted effort was determined by an interaction of one's achievement
      goal, perceived ability (PA), and task difficulty. Ego-high PA boys and task-low
      PA boys exerted the most effort on the moderate course; ego-low PA boys exerted
      least effort on the moderate and very difficult courses. Finally, task-high PA
      boys exerted more effort on the most difficult courses. The motivational
      processes underlying these findings are discussed.

PMID- 12495243
TI  - Comparison of 1 and 2 days per week of strength training in children.
AB  - The purpose of this study was to compare the effects of 1 and 2 days per week of
      strength training on upper body strength, lower body strength, and motor
      performance ability in children. Twenty-one girls and 34 boys between the ages of
      7.1 and 12.3 years volunteered to participate in this study. Participants
      strength trained either once per week (n = 22) or twice per week (n = 20) for 8
      weeks at a community-based youth fitness center. Each training session consisted
      of a single set of 10-15 repetitions on 12 exercises using child-size weight
      machines. Thirteen children who did not strength train served as age-matched
      controls. One repetition maximum (1RM) strength on the chest press and leg press,
      handgrip strength, long jump, vertical jump, and flexibility were assessed at
      baseline and posttraining. Only participants who strength trained twice per week
      made significantly greater gains in 1RM chest press strength, compared to the
      control group (11.5 and 4.4% respectively, p < .05). Participants who trained
      once and twice per week made gains in 1RM leg press strength (14.2 and 24.7%,
      respectively) that were significantly greater than control group gains (2.4%). On
      average, participants who strength trained once per week achieved 67% of the 1RM
      strength gains. No significant differences between groups were observed on other
      outcome measures. These findings support the concept that muscular strength can
      be improved during the childhood years and favor a training frequency of twice
      per week for children participating in an introductory strength training program.

PMID- 12495245
TI  - Evidence for the importance of openness to experience on performance of a fluid
      intelligence task by physically active and inactive participants.
AB  - The cross-sectional relationship between exercise training history and
      performance on a fluid intelligence test was examined. In addition, openness to
      experience was included as a potential trait-based contributor to predicting
      cognitive performance. Results supported past literature demonstrating that
      aerobically trained or active participants performed significantly better on the
      fluid intelligence task than aerobically untrained or inactive participants.
      Hierarchical regression analysis results revealed, as predicted, that openness to
      experience was a significant predictor of fluid intellectual performance. When
      entered into the hierarchical regression equation, openness to experience
      accounted for 16.0% of unique variance in Culture Fair Intelligence Test
      performance. By contrast, participants' exercise training history, which
      initially and significantly (p < .05) accounted for approximately 12.0% of the
      variance in cognitive performance, accounted for 5.0% (p > .05) after openness
      was entered. Participants were, on average, more open than inactive participants.
      Results are discussed in terms of the possible mechanisms aerobic exercise
      training and openness to experience share in regard to brain functioning and
      performance of fluid intelligence tasks. Future research is suggested that
      examines biological factors known to influence cognitive performance in exercise
      settings.

PMID- 12495246
TI  - Vertical ground reaction forces of children during one- and two-leg rope jumping.

PMID- 12495247
TI  - Within-participant variation in landing kinetics: movement behavior trait or
      transient?

PMID- 12495248
TI  - Neighborhood physical activity opportunity: a multilevel contextual model.

PMID- 12495249
TI  - The association between physical activity behavior and commonly reported barriers
      in a worksite population.

PMID- 12495250
TI  - Cross-validation of the revised motivation for physical activity measure in
      active women.

PMID- 12495251
TI  - Using concurrent visual feedback to focus attention in bimanual aiming movements.

PMID- 12495252
TI  - Single versus multiple sets for strength: a meta-analysis to address the
      controversy.

PMID- 12495253
TI  - The differential effects of human capital for male and female Division I
      basketball coaches.

PMID- 12495254
TI  - Nutrition and the extremes of life: dilemmas and enigmas of advanced old age.
AB  - Pre-term infants born four months before term have a very low birth weight; in an
      evolutionary sense, they were never 'meant' to survive through the evolutionary
      period preceding the technological age. In the same way, evolution failed to
      contemplate survival to ages 50, 60, 70 and beyond. Because peak reproductive
      performance comes before the vagaries of a given individual's survival is
      determined, and the fact of that survival conveys no advantage to disseminating
      the genetic make-up, natural selection cannot select for advantages related to
      longevity. Moreover, in the larger context of species survival and biodiversity,
      the crowding of the human ecosphere with older persons would seem to have had
      more liabilities than assets over evolution. We cannot learn from nature how to
      feed and nourish the oldest old. The lessons, if any, would be cruelly averse to
      our humanitarian values. However, we do have values and they guide us to the goal
      for quality of life for the assorted conditions of the extremely old. The choices
      are laissez faire or laissez aller. If we are ignorant about how to achieve the
      goals, perhaps the 'first do not harm' principle should be operative. Should we
      decide that prescription of diet and adjustment of nutritional stores are
      required, hypothesis-based research to provide evidence-based practices is
      required. We may be facing a true Heisenberg principle. The fact that ageing
      leads to the greatest heterogeneity among individuals complicates the generation
      of universal principles for prescriptive actions. Another quandary could be the
      fact that insufficient individuals within the age groups of interest are
      available for outcome research in any given area to provide statistically robust
      findings. Shifting once again to the lowest extreme of human survival, we know
      that what is good for the full-term infant is not the formula for the 600 g
      premature neonate. Failing to heed the distinction can be lethal. My suspicion is
      that what is good dietary practice for the younger adult is also not what is best
      for octogenarians. I would predict that a new intergenerational confrontation is
      in the offing as we recognise and raise the issues of alimentation of the
      extremely old. It is the tyranny of the preventive regimens of assorted
      guidelines to be imposed across the whole population that may exacerbate the
      tension between young and old, although the young's consuming a more healthful
      diet will presumably allow more of them to eventually reach the status of
      advanced age, and hopefully with greater health, vigour and function.

PMID- 12495255
TI  - Longitudinal study of diet and iron deficiency anaemia in infants during the
      first two years of life.
AB  - The objectives of this study were: (i) to investigate the energy, iron, zinc,
      calcium and vitamin C intakes of a group of healthy term Caucasian infants
      resident in Dunedin, New Zealand, prospectively from age 9 months to 2 years; and
      (ii) to determine the prevalence of iron deficiency anaemia among these infants.
      A self-selected sample of 74 Caucasian mothers and their infants born in Dunedin,
      New Zealand, between October 1995 and May 1996 were recruited. Dietary intake was
      determined using estimated diet records at 9, 12, 18 and 24 months of age.
      Haemoglobin concentration, mean corpuscular volume andzinc protoporphyrin
      concentration were determined at the same ages. The infants' zinc, calcium and
      vitamin C intakes appeared adequate. Their median iron intakes ranged from 4.3 mg
      (at 12 months) to 7.0 mg (at 9 months) per day and were below estimated
      requirements at all ages. At 9, 12 and 18 months of age, 7% (n = 4) of the
      infants had iron deficiency anaemia. None of the infants had iron deficiency
      anaemia at 24 months. The iron intakes of this group of Caucasian infants and
      young children appeared inadequate. However, their rate of iron deficiency
      anaemia was lower than has been reported in previous New Zealand studies.

PMID- 12495256
TI  - Nutrition problems of hospitalised children in a developing country: Thailand.
AB  - Nutritional assessment reveals the nutritional status of a patient. It thereby
      helps identify each patient's need for specific nutritional care and facilitates
      early intervention. Generally, the common nutrition and nutrition-related
      problems in hospitalised paediatric patients are: protein energy malnutrition in
      various degrees; vitamin deficiencies such as A, B1, B2, niacin, folic acid, K
      and E; mineral deficiencies such as Zn, Fe, Ca, Mg, P, K and Na; essential fatty
      acid deficiencies; carbohydrate intolerance; maldigestion and malabsorption; and
      overweight and obesity. However, there is limited information about nutritional
      status of hospitalised patients in some countries, especially in developing
      countries. In Thailand, it was found that the prevalence of hospital malnutrition
      in children aged 1-15 years in the paediatric ward was similar (50-60%) to that
      of a study conducted 10 years earlier. In another study of micronutrients in 45
      paediatric AIDS patients (aged 3-46 months), high prevalences of malnutrition,
      anaemia and mineral deficiencies were found. For convenience in clinical
      practice, body mass index (BMI) values for use as an indicator in the assessment
      of undernutrition in children whose heights are less than 145 cm have been
      published. These BMI values have been tested and retested using normal children
      and patients with various degrees of undernutrition and were found to be reliable
      and valid. Therefore, nutritional status must be assessed in all hospitalised
      patients. At the very least, weight and height (length) should be obtained.

PMID- 12495257
TI  - Effect of low-dosage vitamin A and riboflavin on iron-folate supplementation in
      anaemic pregnant women.
AB  - A double-blind, placebo, controlled trial was conducted in Banyudono subdistrict,
      Boyolali regency, Central Java province, Indonesia. The aim of the study was to
      determine whether adding low-dosage vitamin A and riboflavin can enhance the
      effect of iron-folate supplementation in anaemic pregnant women. From July to
      November 2000, 202 pregnant women were screened for anaemia (haemoglobin < 11.0
      g/dL). One hundred and three pregnant women (51%) were found to be anaemic and
      were then allocated alternately into four groups. Over a period of 60 days, group
      IF (n = 29) received iron-folate tablets (200 mg FeSO4 and 250 microg folic acid)
      + 5 mg glucose: group IFR (n = 22) received iron-folate tablets + 5 mg
      riboflavin; group IFA (n = 29) received iron-folate tablets + 2.75 mg retinyl
      palmitate (equal to 5000 IU vitamin A); and group IFRA (n = 23) received iron
      folate tablets + 5 mg riboflavin + 2.75 mg retinyl palmitate. At the end of the
      study 19 pregnant women (18.4%) were excluded from the analysis because of
      various reasons. Statistical analysis was based on 84 women (81.5%): group IF, n
      = 25; group IFR, n = 22; group IFA, n = 18; and group IFRA, n = 19. Haemoglobin
      measurements were carried out using the Technicon H1* (cyanmethaemoglobin
      method). All groups showed a significant increase in haemoglobin concentration (P
      < 0.05), except group IFA (P > 0.05), with the highest increment being in group
      FR. Multiple comparisons only showed significant differences between group IFR
      and group IFA (P < 0.05). It can be concluded that iron-folate supplementation
      can increase haemoglobin concentrations in anaemic pregnant women. Adding
      riboflavin tends to enhance the effect of iron-folate supplementation, but this
      is not the case with adding vitamin A.

PMID- 12495258
TI  - Impact of supplementary high calcium milk with additional magnesium on
      parathyroid hormone and biochemical markers of bone turnover in postmenopausal
      women.
AB  - The aim of this study was to investigate the impact of magnesium-enriched, high
      calcium milk on serum parathyroid hormone (PTH) and biochemical markers of bone
      turnover in postmenopausal women. We recruited 50 healthy postmenopausal women to
      take part in this randomised controlled study. Half of the women consumed two
      serves of high-calcium skim milk enriched with magnesium (milk group) and half
      consumed two serves apple drink per day (apple group), each for 4 weeks. The milk
      provided 1200 mg calcium and an additional 106 mg magnesium. We investigated the
      responses of serum PTH, as well as the serum and urinary calcium, magnesium and
      biochemical markers of bone turnover. There was no effect of time or drink on the
      clinical biochemistry, serum PTH or urine markers of bone resorption (free
      deoxypyridinoline and N-telopeptides). Serum C-telopeptides (CTX), another marker
      of bone resorption, did not change with time in the apple group. However, in the
      milk group, serum CTX deceased significantly from 0.43 +/- 0.04 ng/mL to 0.32 +/-
      0.02 at 2 weeks (p < 0.0001) and 0.28 +/- 0.02 at 4 weeks (p < 0.0001). In the
      milk group, urinary calcium and magnesium each increased during the night but not
      during the day. Overall, these data suggest that milk has an antiresorptive
      effect on bone, but that this is not accompanied by measurable changes in serum
      PTH.

PMID- 12495259
TI  - Dietary fibre content and nutrient claims relative to the faecal bulking efficacy
      of breakfast cereals.
AB  - The correspondence between the dietary fibre contents of 28 breakfast cereals and
      their faecal bulking efficacies was measured and used to assess criterion values
      controlling nutrient claims for dietary fibre. A valid, standardised rat assay
      was used to measure faecal bulking efficacy as the content of wheat bran
      equivalents for faecal bulk (WBEfb) in the cereals. Regression analysis of WBEfb
      content against dietary fibre content allowed the adequacy of criterion fibre
      values for claims of 'source of fibre,' 'high in fibre' and 'very high in fibre'
      to be assessed relative to a daily reference requirement of 63 WBEfb, based on
      human data. Faecal bulking by breakfast cereals was much lower than implied by
      the dietary fibre claims associated with them. Many more were claimed to be
      'high' or 'very high' in dietary fibre (n = 13) than were 'high' or 'very high'
      in faecal bulking efficacy (n = 4). Conversely, dietary fibre requirements per
      serving predicted from WBEfb requirements, as necessary to maintain adequate
      faecal bulk in the current Australian diet, were much higher (4.4 g) than the
      criterion fibre content (1.5 g) for the most modest claim, 'source of fibre'.
      After removing four high-bran cereals (>15% dietary fibre) from the analysis, a
      modest correlation of r = 0.62 between dietary fibre content and faecal bulk was
      obtained. It is concluded that, with respect to breakfast cereals, fibre values
      specified for nutrient claims are too low, dietary fibre content is not a
      reliable guide to faecal bulking efficacy and direct measures of faecal bulking
      capacity would be more useful than dietary fibre content in describing faecal
      bulking efficacy for evidence-based food choice.

PMID- 12495260
TI  - Bread enriched with microencapsulated tuna oil increases plasma docosahexaenoic
      acid and total omega-3 fatty acids in humans.
AB  - The aim of this study was to determine the acute and chronic effects of low doses
      of long chain (LC) n-3 polyunsaturated fatty acids (PUFA) (<100 mg per day) on
      plasma LC n-3 PUFA levels using a novel delivery form; bread containing
      microencapsulated tuna oil (MTO). Six omnivores (three men and three women)
      participated in the acute study, which involved ingesting a prototype MTO bread
      containing approximately 80 mg of LC n-3 PUFA/four slices. Plasma triacylglycerol
      fatty acid compositions were measured after an overnight fast and postprandially
      at 2 and 4 h. In the chronic study, 10 vegetarian subjects (nine men and one
      woman) consumed MTO bread at six to eight slices/day (comprising 60 mg of LC n-3
      PUFA) as the only dietary source of these PUFA for three weeks. Fasting plasma
      total and phospholipid fatty acid compositions were measured at baseline and
      endpoint. In the acute study, the proportions of 22:6 n-3 and total n-3 PUFA in
      plasma triacylglycerol were significantly increased (P < 0.05). In the chronic
      study, the proportions of 20:5 n-3, 22:5 n-3, 22:6 n-3, total n-3 PUFA in plasma,
      and 22:6 n-3 and total n-3 PUFA in plasma phospholipid fractions were
      significantly increased (P < 0.05) at the endpoint compared with the baseline.
      This study showed that a low dose of LC n-3 PUFA, consumed as MTO-enriched bread,
      was bioavailable, as measured by an increase in LC n-3 PUFA levels in the plasma
      of human subjects.

PMID- 12495262
TI  - Oxalate content and calcium binding capacity of tea and herbal teas.
AB  - Thirty-two commercially available teas consisting of green, oolong and black teas
      were bought from supermarkets in Christchurch, New Zealand in June 2001. Fifteen
      herbal teas were also purchased at the same time. The soluble oxalate content of
      the infusate made from each of the teas was determined using high pressure liquid
      chromatography. The mean soluble oxalate contents of black tea in tea bags and
      loose tea leaves were 4.68 and 5.11 mg/g tea, respectively, while green teas and
      oolong tea had lower oxalate contents, ranging from 0.23 to 1.15 mg/g tea. The
      soluble oxalate content of the herbal teas ranged from not detected to 3.00 mg/g
      tea. A regular tea drinker consuming six cups of tea/day would have an intake of
      between 26.46 and 98.58 mg soluble oxalate/day from loose black tea, 17.88 and
      93.66 mg soluble oxalate/day from black tea in tea bags and a maximum of 18.0
      mg/day from herbal teas. The oxalate intake from the regular daily consumption of
      black teas is modest when compared to the amounts of soluble oxalate that can be
      found in common foods. However, oxalate in black teas has the potential to bind
      to a significant proportion of calcium in the milk, which is commonly consumed
      with the black teas.

PMID- 12495261
TI  - Effect of green tea catechin on arachidonic acid cascade in chronic cadmium
      poisoned rats.
AB  - The purpose of this study was to investigate the effect of green tea catechin on
      the cyclooxygenase and lipoxygenase pathways in chronic cadmium-poisoned rats.
      Sprague-Dawley male rats weighing 100 +/- 10 g were randomly assigned to one
      normal and three cadmium-poisoned groups. The cadmium groups were classified as
      catechin-free diet group (Cd-0C), 0.25% catechin diet group (Cd-0.25C) and 0.5%
      catechin diet group (Cd-0.5C), in accordance with the level of catechin
      supplement. The phospholipase A2 activity was remarkably increased 117% in the Cd
      0C group and 60% in the Cd-0.25C group compared with the normal group, and the
      level in the Cd-0.5C group was the same as the normal group. Activity of platelet
      cyclooxygenase increased 284% in the Cd-0C group, 147% in the Cd-0.25C group and
      193% in the Cd-0.5C group. The synthesis of platelet thromboxane A2 (TXA2)
      increased 157% in the Cd-0C group and 105% in the Cd-0.25C group, compared with
      the normal group. The Cd-0.5C group showed the same level as the normal group.
      Prostacyclin (PGI2) formation in the aorta decreased 24% in the Cd-0C group and
      18% in the Cd-0.25C group. The ratio of PGI2/TXA2, the thrombocyte synthesis
      index, decreased 70% in the Cd-0C group and 59% in the Cd-0.25C group. The
      activity of 5'-lipoxygenase in the polymorphonuclear leukocyte was increased 40%
      in the Cd-0C group as compared with the normal group. Catechin-supplemented Cd
      0.25C and Cd-0.5C groups showed the level of the normal group. In this study, the
      observed content of leukotriene B4, which induces the inflammatory process,
      increased 54% in the Cd-0C group, and in catechin-supplemented groups, showed the
      same level as in the normal group. The serum peroxide value increased 60% in the
      Cd-0C group compared with the normal group; but in the Cd-0.5C group, it showed
      the level of the normal group. These results indicate that chronic cadmium
      poisoning in rats accelerates arachidonic acid metabolism. Inhibition of
      arachidonic acid metabolism due to catechin supplementation, however, decreases
      platelet aggregation and inflammatory action. In conclusion, it would appear that
      green tea catechin supplementation in chronic cadmium-poisoned rats inhibits the
      arachidonic acid cascade by regulating the activity of phospholipase A2.

PMID- 12495263
TI  - Body fat accumulation is greater in rats fed a beef tallow diet than in rats fed
      a safflower or soybean oil diet.
AB  - The effects of dietary fats , consisting of different fatty acids, on body fat
      accumulation and uncoupling protein (UCP) in interscapular brown adipose tissue
      were studied in rats. Metabolisable energy in experimental diets based on
      safflower oil, soybean oil or beef tallow was measured strictly (experiment 1).
      Male Wistar rats were then meal-fed an isoenergetic diet for 8 weeks (experiment
      2). Each group of rats showed the same weight gain during the 8-week experimental
      period. Carcass fat content was greater in rats fed the beef tallow diet than in
      those fed the with the safflower or soybean oil diets, whereas the weight of
      abdominal adipose tissue was the same for all three dietary groups. Gene
      expression of UCP1 and the UCP content of the interscapular brown adipose tissue
      was lower in the beef tallow diet group than in the other dietary groups. A
      negative correlation was observed between carcass fat content and n-6 unsaturated
      fatty acid content in dietary fats. These results suggest that the greater body
      fat accumulation in rats fed the beef tallow diet results from lower expression
      of UCP1 mRNA and lower UCP content in brown adipose tissue. n-6 Polyunsaturated
      fatty acids may be the most effective fatty acids in limiting body fat.

PMID- 12495264
TI  - Comparative effects of a tocotrienol-rich fraction and tocopherol in aspirin
      induced gastric lesions in rats.
AB  - This study examined the effects of a tocotrienol-rich fraction (TRF) obtained
      from palm oil on the healing of aspirin-induced gastric mucosal lesions. Thirty
      six male Sprague-Dawley rats (200-250 g) were randomly divided into three groups.
      Group I was fed a vitamin E-deficient diet (control), Group II was fed a vitamin
      E-deficient diet supplemented with tocopherol (300 mg/kg food) and Group III was
      fed a vitamin E-deficient diet supplemented with TRF (300 mg/kg food). After
      eight weeks, the control and treated groups received a single intragastric dose
      of 400 mg/kg body weight aspirin. The rats were killed 24 h after exposure to
      aspirin. Assessment of gastric lesions showed a lower gastric lesion index in the
      TRF (P = 0.0005) and tocopherol groups (P = 0.0008) compared to the control. The
      gastric malondialdehyde (MDA) content was also lower in the TRF (P = 0.025) and
      tocopherol groups (P = 0.025) compared to control. There were, however, no
      significant differences in the gastric lesion index and gastric MDA content
      between the TRF and tocopherol-fed groups. There were no significant differences
      in the adherent gastric mucous concentration and gastric acid concentration among
      all groups. We conclude that the TRF and tocopherol are equally effective in
      preventing aspirin-induced gastric lesions. The most probable mechanism is
      through their ability to limit lipid peroxidation, which is involved in aspirin
      induced gastric lesions.

PMID- 12495265
TI  - Effect of different curcumin dosages on human gall bladder.
AB  - Our previous study demonstrated that curcumin, an active compound of Curcuma
      xanthorrhiza and C. domestica, produces a positive cholekinetic effect. A 20 mg
      amount of curcumin is capable of contracting the gall bladder by up to 29% within
      an observation time of 2 h. The aim of the current study was to define the dosage
      of curcumin capable of producing a 50% contraction of the gall bladder, and to
      determine if there is a linear relationship between doubling the curcumin dosage
      and the doubling of gall bladder contraction. A randomised, single-blind, three
      phase, crossover-designed examination was carried out on 12 healthy volunteers.
      Ultrasonography was carried out serially to measure the gall bladder volume. The
      data obtained was analysed by analysis of variance (ANOVA). The fasting volumes
      of gall bladders were similar (P > 0.50), with 17.28 +/- 5.47 mL for 20 mg
      curcumin, 18.34 +/- 3.75 mL for 40 mg and 18.24 +/- 3.72 mL for 80 mg. The
      percentage decrease in gall bladder volume 2 h after administration of 20, 40 and
      80 mg was 34.10 +/- 10.16, 51.15 +/- 8.08 and 72.25 +/- 8.22, respectively, which
      was significantly different (P < 0.01). On the basis of the present findings, it
      appears that the dosage of cucumin capable of producing a 50% contraction of the
      bladder was 40 mg. This study did not show any linear relationship between
      doubling curcumin dosage and the doubling of gall bladder contraction.

PMID- 12495266
TI  - Metformin improves liver antioxidant potential in rats fed a high-fructose diet.
AB  - Increased lipid peroxidation plays a role in the pathology associated with
      fructose feeding. The present study reports the effects of metformin on the liver
      lipid peroxidation and antioxidant defence system of rats fed a high-fructose
      diet. The experimental animals were divided into two batches of 12 animals each.
      The control batch received a control diet containing 60% starch; the second batch
      was given a high-fructose diet containing 60% fructose as the sole source of
      carbohydrate. At the end of second week these were each subdivided into two
      groups. One was given metformin (50 mg/kg body weight/day in water) by
      intragastric intubation and the other group was left untreated. The rats were
      continued on the same dietary regimen for the next two weeks. After the
      experimental period of four weeks, liver lipid peroxidation and antioxidant
      status were quantified. Enhanced thiobarbituric acid-reactive substance
      reactivity and lipid hydroperoxides were observed in high-fructose-fed rats.
      However, the activities of enzymic antioxidants were lower in this group.
      Administration of metformin attenuated the rise in lipid peroxidation and
      improved the antioxidant potential in high-fructose-fed rats. Metformin did not
      have any effect on the antioxidant status of control rats. Attenuation of lipid
      peroxidation by metformin could be related to its insulin sensitising action.

PMID- 12495268
TI  - The organizational context of children's mental health services.
AB  - This paper reviews what is known about the organizational context of children's
      mental health services and describes organizational constructs, conceptual
      models, research methods, and intervention strategies that can be used to link
      organizational context to service quality and outcomes. Using evidence from
      studies of business and industrial organizations as well as studies of children's
      service organizations, the paper presents a model of organizational effectiveness
      that depends on several contextual characteristics that include organizational
      culture, structure, climate, and work attitudes. These characteristics are
      believed to affect the adoption of efficacious treatments (EBPs [evidence-based
      practices]), adherence to treatment protocols, therapeutic alliance, and the
      availability, responsiveness, and continuity of services. Finally, 10 components
      of the ARC(Availability Responsiveness and Continuity) organizational
      intervention are described as examples of strategies that can be used to develop
      organizational contexts with the prescribed characteristics. Mental health
      researchers are encouraged to consider including these constructs, conceptual
      models, research methods, and intervention strategies in dissemination,
      effectiveness, and implementation studies that address the gap between research
      based knowledge about mental health treatment and what is actually offered in the
      community.

PMID- 12495267
TI  - Towards a cognitive-behavioral model of PTSD in children and adolescents.
AB  - Posttraumatic stress disorder in children and adolescents has been studied only
      for the past 15-20 years and is the subject of a burgeoning corpus of research.
      Much research has focused on examining whether children and adolescents have the
      same responses to trauma as those experienced by adults. Many of the research
      tools used to investigate children's responses are taken from measures designed
      for use with adults, and these measures have proven to be useful. However, it has
      not been established that children's responses to traumatic events are related to
      the same underlying processes as are adults' responses. The possible application
      of 2 recent cognitive models of PTSD in adults to understanding PTSD in children
      and adolescents is discussed in this paper, within the context of what is already
      known about children's reaction to trauma and existing theoretical accounts of
      childhood PTSD. Particular attention is paid toward the nature of children's
      memories of traumatic events and how these memories relate to the reexperiencing
      symptoms of PTSD, and cognitive processes that may play a role in the maintenance
      of PTSD. It is proposed that the adoption of a more specific cognitive-behavioral
      framework in the study of this disorder may be beneficial and lead to better
      treatment outcomes.

PMID- 12495269
TI  - The effect of polygamous marital structure on behavioral, emotional, and academic
      adjustment in children: a comprehensive review of the literature.
AB  - Polygamy represents expanded family structures that are based on marriages
      involving a husband with 2 or more wives. Interestingly, polygamy is legally and
      widely practiced in 850 societies across the globe. In the last 2 decades,
      polygamy has been the focus of a significant growth in public, political, and
      academic awareness. Indeed, several quantitative and qualitative research
      articles and theoretical papers have emerged during this period, particularly
      concerning the effects of this form of marital structure on behavioral,
      emotional, and academic adjustment of children. However, to date, no researcher
      has provided a summary of the extant literature. Thus, the purpose of this
      comprehensive literature review is to summarize findings and to discuss
      implications of empirical studies that have examined whether polygamous marital
      structures are beneficial or harmful to children in comparison with children
      raised in monogamous marital structures. This review includes a summary of the
      findings from all quantitative and qualitative studies in the extant literature
      that have examined the effect of polygamy on children's outcomes.

PMID- 12495271
TI  - Fatty acids, calcium and bone metabolism.
AB  - Epidemiological, clinical and experimental evidence suggests that fatty acids may
      have an effect (due to their chemical structure) on calcium metabolism in animals
      and man. Fatty acid deficiency in animals can lead to a loss of bone calcium and
      matrix, resulting in marked bone demineralization, and treatment with a mixture
      of omega-3 and omega-6 polyunsaturated fatty acids can induce significant
      reduction in some biochemical markers of bone reabsorption. A relationship,
      between phospholipid fatty acid content, calcium-regulating hormones and
      intestinal, renal, and bone calcium metabolism alterations, has been reported in
      patients with renal stones and hypercalciuria. Recent studies have shown specific
      effects of fatty acids on the gene expression of some bone cytokines. Fatty acids
      might be involved in calcium metabolism influencing cellular calcium ion
      transport directly, as second messengers, or generating, through the
      cyclooxygenase pathway, potential biological mediators which have complex effects
      on bone remodeling. Experimental and clinical documentation of the specific and
      indirect effects of fatty acids on calcium and bone metabolism could open up new
      and interesting clinical prospects.

PMID- 12495270
TI  - The Good Behavior Game: a best practice candidate as a universal behavioral
      vaccine.
AB  - A "behavioral vaccine" provides an inoculation against morbidity or mortality,
      impacting physical, mental, or behavior disorders. An historical example of a
      behavioral vaccine is antiseptic hand washing to reduce childbed fever. In
      current society, issues with high levels of morbidity, such as substance abuse,
      delinquency, youth violence, and other behavioral disorders (multiproblems), cry
      out for a low-cost, widespread strategy as simple as antiseptic hand washing.
      Congruent research findings from longitudinal studies, twin studies, and other
      investigations suggest that a possibility might exist for a behavioral vaccine
      for multiproblem behavior. A simple behavioral strategy called the Good Behavior
      Game (GBG), which reinforces inhibition in a group context of elementary school,
      has substantial previous research to consider its use as a behavioral vaccine.
      The GBG is not a curriculum but rather a simple behavioral procedure from applied
      behavior analysis. Approximately 20 independent replications of the GBG across
      different grade levels, different types of students, different settings, and some
      with long-term follow-up show strong, consistent impact on impulsive, disruptive
      behaviors of children and teens as well as reductions in substance use or serious
      antisocial behaviors. The GBG, named as a "best practice" for the prevention of
      substance abuse or violent behavior by a number of federal agencies, is unique
      because it is the only practice implemented by individual teachers that is
      documented to have long-term effects. Presently, the GBG is only used in a small
      number of settings. However, near universal use of the GBG, in major political
      jurisdictions during the elementary years, could substantially reduce the
      incidence of substance use, antisocial behavior, and other adverse developmental
      or social consequences at a very modest cost, with very positive cost
      effectiveness ratios.

PMID- 12495272
TI  - Transplanting kidneys from donors with prior hepatitis B infection: one response
      to the organ shortage.
AB  - While the number of cadaveric organ donors remains relatively stable, the number
      of patients awaiting transplantation continues to increase, creating a shortage
      of donor organs. To address this imbalance, there is interest in transplanting
      organs formerly considered marginal or undesirable. Thus, more organs are
      currently transplanted from living donors, older donors, hemodynamically unstable
      donors, non-heart-beating donors and donors with markers of prior hepatitis B
      virus (HBV) infection. A large number (up to 93.8%) of liver transplant
      seronegative recipients from anti-HBc antibody positive donors have acquired
      HBsAg after liver transplantation in the absence of immunoprophylaxis. Based on
      experience in liver transplantation programs, transmission of HBV from donors
      without HBsAg but with antibody to HBV core antigen (anti-HBc), although
      conventionally defined as evidence of resolved infection, can have adverse
      consequences on both graft and recipient. On the contrary, HBV appears to be in
      frequently transmitted from HBsAg negative/anti-HBcAb positive kidney donors: the
      incidence of de novo HBsAg seropositivity after renal transplantation ranges
      between 0 and 5.2%. A significantly higher incidence of anti-HBc antibody
      seroconversion (without developing HBsAg) after renal transplantation with anti
      HBc antibody positive donors was seen. However, anti-HBc antibody positive renal
      allografts should be considered, especially for recipients who have been
      successfully immunized with HBV vaccine. Prospective long-term studies are in
      progress to assess the risk of de novo HBV infection (HBsAg seroconversion) in
      renal transplant recipients who have not been successfully immunized with vaccine
      against HBV.

PMID- 12495273
TI  - Glomerular size and global glomerulosclerosis in normal Caucasian donor kidneys:
      effects of aging and gender.
AB  - BACKGROUND: To assess the effects of aging and gender on glomerular size and
      global glomerulosclerosis (GS) and evaluate the relationship between glomerular
      size and GS in normal Caucasian donor kidneys. METHODS: All baseline graft
      biopsies between 1990 and 1998 were reviewed and sections with tissues containing
      at least 15 glomeruli were selected for morphometric analyses using a Digital
      Imaging Analyzer. Glomerular volumes (GV) were measured using the maximal profile
      area (MPA) method. The frequency of glomeruli with totally sclerotic lesions
      representing degree of global GS was expressed as a percentage of total number of
      glomeruli counted. RESULTS: 102 donor specimens (M/F, 46/56; mean age, 37.4 +/-
      17.3 yrs) were analyzed showing mean MPA of 27.8 +/- 6.6 (x 10(-3)mm2), mean GV
      of 3.6 +/- 1.2 (x 10(6)microm3) and mean GS% of 6 +/- 10%. GV was increased with
      increasing age (r2 = 0.32, p < 0.0001). There was a progressive increase in
      glomerular size between infancy and adolescence (2-18 years old). The rate of MPA
      growth over childhood appeared to be linear (n = 13, r2 = 0.66, p = 0.0004).
      However, MPA increased with age at a slower rate (n = 99, r2 = 0.66, p = 0.0004)
      in adults (excluding data for patients < 18 years) than in infancy and
      adolescence. There wasn't significant gender difference in GV. Age (r = 0.47, p <
      0.0001) and MPA (r = 0.31, p < 0.05) were both positively correlated with global
      GS. CONCLUSIONS: 1. Aging contributes to enlargement of glomerular size and
      global GS. 2. Gender had no significant effect on glomerular size. 3. Enlargement
      of glomerular size was associated with global GS in normal Caucasians.

PMID- 12495274
TI  - Risk factors for late renal allograft dysfunction: effects of baseline glomerular
      size.
AB  - BACKGROUND: Both alloantigen dependent and alloantigen independent factors
      contribute to late allograft dysfunction. Among the latter, the importance of the
      mass of the donor kidney is an issue of interest. We hypothesized that glomerular
      hypertrophy is a risk factor for deterioration of allograft function. The goal of
      this study was to examine the role of glomerular size in predicting late
      allograft dysfunction. METHODS: All baseline graft biopsies between 1990 and 1998
      were reviewed and sections containing at least 15 glomeruli were selected for
      morphometric analyses. Glomerular size was measured using the maximal profile
      area (MPA) method. Linear correlations between creatinine clearance (Ccr) and
      variables were evaluated. Covariates that tended to correlate with Ccr on
      univariate analysis (p < 0.2) were examined using multivariate analysis to
      determine the covariates associated with Ccr at 6 months (M) and 1, 2, 3, 4 years
      (yrs) after transplantation. RESULTS: Eighty-six patients were enrolled. Donor
      age, MPA, baseline Ccr, percent of global glomerulosclerosis (GS%), cyclosporin
      nephrotoxicity, cold ischemic time(CIT) and episodes of rejection were
      significantly correlated with interval Ccr in univariate analyses. MPA was a
      significant covariate at 6M, 1 yr, 3 yrs and 4 yrs. Other covariates
      significantly associated with interval Ccr included GS%, baseline Ccr, CIT and
      number of acute rejection episodes. CONCLUSIONS: Glomerular size in baseline
      biopsies is predictive of late allograft function, and the presence of
      hypertrophied glomeruli combined with other factors contributes to chronic renal
      allograft dysfunction.

PMID- 12495276
TI  - Role of myofibroblasts, macrophages, transforming growth factor-beta endothelin,
      angiotensin-II, and fibronectin in the progression of tubulointerstitial
      nephritis induced by gentamicin.
AB  - BACKGROUND: Animal models of aminoglycoside nephrotoxicity can show residual
      areas of interstitial fibrosis in the renal cortex. This study investigated the
      expression of fibronectin, alpha-smooth muscle actin (alpha-SM-actin),
      macrophages, endothelin,transforming growth factor-beta (TGF-beta) and
      angiotensin II (AII) in the renal cortex of rats, 5 and 30 days after stopping
      treatment with gentamicin, and the relationships with the histological features
      and renal function of these animals. METHODS: Forty-five female Wistar rats were
      injected with gentamicin, 40 mg/kg, twice a day for 9 days, and 11 controls were
      injected with 0.15 M NaCl solution. The animals were killed 5 or 30 days after
      these injections and the kidneys removed for histological examination, enzyme
      immunoassay and immunohistochemical studies. The histological and
      immunohistochemical results were evaluated by scores reflecting the extent of
      lesion or staining. The percentage of tubulointerstitial lesions was determined
      by morphometry. RESULTS: Gentamicin-treated rats presented a transitory increase
      in plasma creatinine levels. The immunohistochemical studies showed increased
      fibronectin, alpha-SM-actin, ED-1, endothelin, TGF-beta and AII staining in the
      renal cortex from rats 5 and 30 days after gentamicin compared to control (p <
      0.05). The animals killed on day 30 also presented fibrosis and increased TGF
      beta content in the renal cortex (p < 0.001), despite the recovery of renal
      function. The proportion of damaged areas was 23.17% +/- 5.23 in the renal cortex
      of these animals. CONCLUSIONS: Macrophages, myofibroblasts, TGF-beta, endothelin
      and AII may have contributed to the development of renal fibrosis in these rats.

PMID- 12495275
TI  - Pregnancy after renal transplantation in Italian patients: focus on fetal
      outcome.
AB  - BACKGROUND: In the last few years advances in surgical techniques and
      immunosuppression have improved not only survival, but also quality of life in
      organ transplanted patients. Hence, the number of women of child-bearing age who
      decide to have a child--which means resuming a normal life--has increased. This
      multicenter retrospective study describes pregnancies after kidney
      transplantation and is the first such survey in Italy. METHODS: We analyzed the
      outcomes from 56 pregnancies in 42 kidney transplant recipients from data
      collected in questionnaires, hospital records, and phone interviews. All
      recipients were maintained on cyclosporine (CsA), azathioprine (AZA),
      corticosteroids or tacrolimus (FK506) before and during pregnancy. RESULTS: The
      average time from transplantation to childbirth was 62 months (range 12 to 180).
      Complications arose during pregnancy in 16 out of 36 term pregnancies (44.4%).
      Four transplant rejections (11.8%) were documented, two of them irreversible.
      Thirty-six infants were born, and 20 abortions reported (35.7%). Of these 36
      babies, 16 (44.4%) were born at term, and 20 (55.6%) before term. Thirty-three
      Cesarean sections were performed (91.7%). Among the 20 pre-term babies, 11 can be
      grouped as follows: 5 low-birth-weight (LBW) (13.9%), 4 very low-birthweight
      (VLBW) (8.3%) and 2 extremely very low-birth-weight (EVLBW) (5.6%). The children
      were followed up for periods ranging from 2 months to 13 years. CONCLUSIONS: In
      kidney transplant recipients who became pregnant the incidence of spontaneous
      abortion and preterm delivery was increased. Newborns delivered to these patients
      had low birth weight, but no congenital defects were noted and their development
      was normal.

PMID- 12495278
TI  - Factors affecting outcome after percutaneous renal artery stent insertion.
AB  - BACKGROUND: Renal artery stenosis is increasingly being treated with the
      percutaneous insertion of stents. Little data are available to help select
      patients most likely to derive benefit from the procedure. METHODS: Data were
      gathered on all patients treated with renal artery stent insertion at the Royal
      Melbourne Hospital prior to 1998, and who were followed-up for at least 6 months
      or until death. Multivariate regression analysis was used to identify factors
      associated with patient survival and renal survival (survival free of dialysis).
      RESULTS: Adequate data were available on 148 of 198 patients treated during this
      time (75%). A baseline creatinine over 0.15 mmol/L and age over 70 were strongly
      associated with worse patient survival (Likelihood ratio(LR) 9.96, p < 0.0001 and
      3.4, p = 0.001 respectively) and renal survival (LR 7.8, p < 0.001 and 2.7, p <
      0.01 respectively). The presence of diabetes was also associated with worse
      overall survival (LR 2.2, p < 0.05) but not renal survival, while the presence of
      another nephropathic disorder was associated with worse renal survival (LR 2.8, p
      < 0.01) but not overall survival. The use of ACE inhibitors after the stenting
      procedure was associated with a significantly better renal survival (LR 0.46, p <
      0.05). CONCLUSIONS: Patients with baseline renal impairment, older age, diabetes
      or another coexistent renal disease have poor outcomes after renal artery stent
      insertion. A relatively conservative approach to revascularisation may be
      preferable in these patient groups. The use of ACE inhibitors after stent
      insertion is associated with a reduced likelihood of death or dialysis.

PMID- 12495277
TI  - Amplified biochemical activation of endothelial function in hypertension
      associated with moderate to severe renal failure.
AB  - BACKGROUND: Arterial hypertension and endothelial dysfunction have a role in the
      development of athero-sclerosis. This study assessed autocrine-paracrine
      endothelial function in patients with hypertension associated with renal failure.
      METHODS: Angiotensin II (Ang II), endothelin-1 ( ET-1), basic fibroblast growth
      factor (bFGF), transforming growth factor-beta (TGF-beta), soluble forms of
      adhesion molecules (ICAM-1, VCAM-1), E-selectin, von Willebrand factor (vWf) and
      nitric oxide (NO) were measured in 26 patients with hypertension and chronic
      renal failure (CRF), in 19 essential hypertensives (EH) and in 28 normotensive
      healthy subjects. RESULTS: Plasma concentrations of Ang-II, ET-1, ICAM-1, VCAM-1,
      E-selectin, bFGF and TGF-beta all were significantly higher in patients than in
      healthy subjects and EH. Furthermore, in CRF, serum creatinine correlated
      negatively with NO plasma levels (r = - 0.51; p < 0.0) and this relationship held
      true after adjusting the data for potential confounders. Plasma NO was inversely
      related with ET-1 and bFGF (P < 0.01). CONCLUSION: Hypertension in CRF is
      characterized by biochemical evidence of marked endothelial dysfunction,
      apparently more pronounced than in patients with EH. Amplified endothelial
      activation in CRF probably contributes to the high rate of atherosclerotic
      complications in CRF.

PMID- 12495279
TI  - Impact of volume control on left ventricular hypertrophy in dialysis patients.
AB  - BACKGROUND: Left ventricular hypertrophy (LVH), which strongly predicts cardiac
      mortality, is seen in more than 60% of end-stage renal disease patients. The aim
      of this study was to prospectively investigate the effect of salt restriction and
      strict volume control on blood pressure and LVH. METHOD: Nineteen hypertensive
      patients on chronic hemodialysis (HD) treatment (age 52 +/- 17 years, 7 women)
      were included in the study. Treatment consisted of 12-h HD per week, during which
      as much ultrafiltration (UF) was applied as possible without an excessive blood
      pressure (BP) drop. Special attention was given to dietary salt restriction.
      Predialysis mean BP (MBP), body weight (BW), cardio-thoracic index (CTI) and
      echocardiographic results were recorded at baseline and after 6 and 12 months.
      RESULTS: All patients reached acceptable BP (< 140/90 mmHg) within three months
      (10-75 days) with our strict volume control strategy. Mean pre-dialysis BP was
      127 +/- 17/78 +/- 9 mm Hg at baseline, 120 +/- 9/75 +/- 6 mm Hg at the 6th month
      and 118 +/- 11/73 +/- 5 mm Hgat the 12th month. The incidence of symptomatic
      hypotension gradually decreased from a mean of 22% to 11% and 7%, respectively
      during follow-up. Left ventricular mass index decreased from 164 +/- 64 to 112 +/
      36 g/m2. CTI, left atrial, left ventricular systolic and diastolic diameters
      significantly decreased in all patients. Inter-dialytic weight gain was 930 +/-
      70 g/day in the follow-up period. Hematocrit did not significantly differ at the
      first, second and last visits. CONCLUSION: Normal BP and improvement of cardiac
      structure, in particular a reduction of LVH could be reached in all our patients
      by intensifying salt restriction and UF.

PMID- 12495280
TI  - Many clinically silent access stenoses can be identified by ultrasonography.
AB  - BACKGROUND: Stenoses of vascular accesses are leading factors limiting access
      survival. Besides physical examination, screening of access stenoses is based
      mainly on the "dysfunction hypothesis", which states that progressive stenosis
      causes graft dysfunction, such as decreased flow. We tested whether Doppler
      ultrasonography could detect a number of clinically hidden access stenoses in
      otherwise well-managed patients. Indications from clinical evaluation regarding
      the presence of stenosis were compared with ultrasound findings. METHODS: We made
      258 examinations in 193 patients. Whole-length morphological ultrasound
      examinations of vascular access were done with a 7.5 MHz linear array transducer.
      The combination of > 50% stenosis in B-mode and at least doubling of peak
      systolic velocity was the criterion for significant stenosis. We compared the
      specificity and sensitivity of clinical diagnosis or ultrasound. RESULTS: The
      sensitivity and specificity of the clinical diagnosis of stenosis were 35.8% and
      92.8%, respectively. CONCLUSIONS: A considerable number of otherwise
      appropriately managed hemodialysis patients suffer from significant access
      stenosis. Wider use of Doppler ultrasonography would increase the proportion of
      clinically hidden stenoses diagnosed in time and thus might prolong access
      patency. Clinical suspicion of access stenosis is highly specific and such
      patients should be examined directly by angiography.

PMID- 12495281
TI  - Homocysteine and vascular access thrombosis in end-stage renal disease patients:
      a retrospective study.
AB  - BACKGROUND: Though pathology in end-stage renal disease (ESRD) patients with high
      total homocysteine (tHcy) can be established, the research findings with vascular
      access thrombosis (VAT) and tHcy are equivocal. Investigators have found
      significantly higher homocysteine levels in patients with recurrent VAT compared
      with one or less episodes of thrombosis. Initial prospective evidence supports an
      independent association between tHcy levels and access thrombosis. METHODS: One
      hundred and four patients undergoing dialysis were selected. The experimental
      group participants were identified as those having one or more vascular access
      thromboses (VAT) during the previous 14-month period (November 2000 to January
      2002) and the control group participants were those with no VAT during the same
      period. Additional sub-group analyses included the following: a) hypertensive vs.
      normotensive; b) diabetes mellitus, Type I, Type II, and none; c) gender; d) age.
      RESULTS: The Mann-Whitney U test for variance revealed no significant difference
      in tHcy values between VAT groups (U = 1580.5, p = 0.075), no significant
      differences in VAT and hypertension (U = 1009.0, p = 0.70), and no significant
      differences in VAT and Diabetes Mellitus (U = 1254.5, p = 0.67). A two-sample t
      Test revealed no significant differences in tHcy and age (F-ratio = 1.26, p =
      0.47). A Kolmogorov Smirnov test for normality revealed insufficient evidence
      that the tHcy distribution is not normal. Spearman Rank Correlations were
      calculated revealing low to moderate associations among variables. CONCLUSIONS:
      While some studies have demonstrated a relationship between tHcy and VAT, this
      study found chronically high homocysteine levels in patients with ESRD were not
      associated with incidence of VAT. There were no significant differences in the
      number of VAT's across additional variables of age, gender, and previous
      morbidity. No significant interactions were discovered.

PMID- 12495283
TI  - Hyperbaric oxygen therapy for calcific uremic arteriolopathy: a case series.
AB  - Calcific uremic arteriolopathy (CUA), also referred to as calciphylaxis, is a
      syndrome of small vessel calcification of unknown etiology causing painful
      violaceous skin lesions that progress to non-healing ulcers and gangrene. It is
      observed mainly in patients with end-stage renal disease, is associated with high
      morbidity and mortality and has no standard treatment at the present time.
      Although parathyroidectomy (PTX) has been advocated in some cases, other studies
      have not found this effective. Hyperbaric oxygen therapy (HOT) consists of
      breathing 100% O2 at higher than ambient pressure, with the patient inside a
      sealed chamber. HOT has been used with some success in the treatment of selected
      problem wounds (those that fail to respond to established medical and surgical
      management). They are often severely hypoxic; restoration of tissue PO2 to normal
      or above-normal enhances fibroblast proliferation and collagen production as well
      as angiogenesis. The present is the largest retrospective case series of CUA
      treated by means of HOT reported so far and comprises 11 chronic uremic patients
      on dialysis (9 hemo- and 2 peritoneal dialysis, 6 females and 5 males, mean age
      56 +/- 7 SD years, time on dialysis 163 +/- 84 SD months). Four patients had
      biopsy-proven CUA; 3 had diabetic nephropathy as a cause of uremia; 2 were obese
      and 3 had a consistent increase of serum calcium x phosphorus product; 3 patients
      had severe secondary hyperparathyroidism (II(nd) HPTH) and two had been submitted
      to subtotal PTX some years before CUA; two others had already had the limb
      amputated. Lesions were in the legs, except for one in a hand, and were
      prevalently ulcers and necrosis. The number of sessions in each HOT cycle ranged
      from a minimum of 20 to a maximum of 108 (mean 40.6 +/- 29.0). The results of two
      therapies cannot be evaluated (one was interrupted by the patient after 10
      sessions, and one ended with the death of the patient due to ventricular
      arrhythmia after eight sessions). Eight of the nine remaining had excellent
      results with healing of the skin ulcers, but the ninth got worse, making it
      advisable to amputate the foot. In conclusion, CUA appears to result from a
      multitude of predisposing and/or sensitizing events that are commonly present in
      the uremic milieu. The specific factors that induce this disorder in an
      individual patient are not known. The present retrospective study supports a role
      of HOT in many cases of CUA, especially considering that, in the absence of
      severe II(nd) HPTH, there are very few therapeutic options.

PMID- 12495282
TI  - The effect of long-term intravenous high dose B-complex vitamins with or without
      folic acid on serum homocysteine in hemodialysis patients.
AB  - BACKGROUND: Many regimens using different doses of folic acid (FA) alone or with
      supplementation of B-complex vitamins (BCV) have been tested for the reduction of
      total homocysteine (tHcy) levels in hemodialysis (HD) patients. BCV are usually
      administered orally and for a short period. In the present study, we assessed the
      effect of long-term intravenous (IV) BCV on serum tHCy levels in HD patients, and
      the effect produced by moderate oral supplementation with FA. METHODS: In a
      cohort of 37 patients under chronic HD treatment for a mean of 50.2 +/- 46.7
      months, serum concentrations of tHcy, folate and vitamin B12 were determined at
      the end of four sequential periods: (A) three months without any FA
      supplementation, (B) three months with oral supplementation of 5 mg of FA three
      times weekly, (C) six months without FA supplementation, and (D) three months
      without BVC or FA supplementation. From the start of HD treatment and throughout
      the study until the beginning of period D, patients received a standard IV dose
      of BCV (B1 250 mg + B6 250 mg + B12 1.5 mg) three times per week, post-dialysis.
      RESULTS: At the end of period B, mean serum tHcy levels were significantly lower
      than in periods A and C (13.7 +/- 3.6 micromol/L vs 19.6 +/- 10.8 micromol/L and
      21.3 +/- 9.4 micromol/L, respectively, p < 0.001) and mean serum folate levels
      were significantly higher (20.7 +/- 7.4 ng/mL vs 5.0 +/- 2.8 ng/mL and 4.5 +/-
      1.4 ng/mL, respectively, p < 0.01). At the end of period D, mean serum tHcy
      levels were significantly higher than in all the previons periods (29.3 +/- 13.5
      micromol/L, p < 0.001). Twenty-six of the 37 patients (70.2%) had normal (< 15
      micromol/L) serum tHcy levels at the end of period B and only one (2.7%) had
      normal tHcy at the end of period D. Mean serum vitamin B12 levels at the end of
      periods A, B and C were 100 times the usual normal values. At the end of period
      D, although significantly lowered (p < 0.001), they remained above the normal
      range. CONCLUSIONS: Long-term high-dose BCV IV three times a week post-dialysis
      reduced serum tHcy levels only when combined with oral FA supplementation.

PMID- 12495284
TI  - Safety profile of a high dose ferric gluconate in patients with severe chronic
      renal insufficiency.
AB  - BACKGROUND: Iron deficiency is a common and important cause of poor response to
      erythropoietin in patients with severe chronic renal failure (CRF). Oral iron
      supplements fail to correct iron deficiency in these patients. Ferric gluconate
      has a low side effect profile, however the recommended dose of 62.5 to 125 mg per
      treatment is not practical for patients who are not on hemodialysis (HD).
      METHODS: We retrospectively analyzed the incidence rate of side effects
      associated with 250 mg of ferric gluconate infused over 1 to 4 hrs. Seventy-nine
      treatments were administered to 40 patients who had severe CRF. Five patients had
      received treatments on consecutive days (2 to 4 treatments). RESULTS: Four
      treatments in two patients were associated with side effects, which included
      diarrhea, vomiting, low back pain, hypotension and burning sensation in feet. The
      duration of infusion did not influence the side effect profile. CONCLUSION: Our
      preliminary results suggest that 250 mg of ferric gluconate infused over 14 hrs
      may be safe with infrequent side effects (5%). It is also more convenient and
      practical for patients who are not on maintenance HD.

PMID- 12495285
TI  - Intermediate-dose (25mg/m2) IV melphalan for multiple myeloma with renal failure.
AB  - BACKGROUND: Multiple myeloma is a malignant plasma cell disorder which still
      bears a dramatic prognosis. Renal insufficiency is a frequent and severe
      complication directly related to prognosis. The aim of our study was to establish
      whether an intermediate dose of intravenous melphalan, 25 mg/m2, could be safely
      and efficiently administered to patients with multiple myeloma and renal
      impairment. METHODS: Between January 1990 and April 2000, 45 patients with
      multiple myeloma received a single intravenous dose of melphalan, 25 mg/m2.
      Survival was analysed, as well as the duration of response and potential
      toxicity. In addition, a melphalan pharmacokinetic study was performed. RESULTS:
      The overall median survival was 45 +/- 43 months after diagnosis. Based on the
      Cockcroft and Gault formula, 79% patients had renal impairment. For the 28 stage
      III patients, survival was no different whether renal insufficiency was present
      or not. Twenty-five out of 34 patients had leukopenia for an average of 13.8 +/-
      12 days, and the most frequent adverse effect was infection. The pharmacokinetic
      study showed that the melphalan area under the curve was positively correlated to
      the degree of renal insufficiency. However, this was not clinically relevant
      since patients with the most altered renal function, including those undergoing
      dialysis, did not present more episodes of leukopenia. DISCUSSION: The present
      study shows that renal impairment is not a contraindication for aggressive
      myeloma chemotherapy, even for patients undergoing dialysis. Intravenous
      melphalan, 25 mg/m2, is associated with good survival and acceptable side
      effects. A randomised trial seems needed to compare this melphalan dose with
      standard melphalan/prednisone or combination chemotherapies.

PMID- 12495286
TI  - Neuromuscular toxicity in nephrotic patients treated with fluvastatin.
AB  - Nephrotic dyslipidemia is a risk factor for the development of systemic
      atherosclerosis, and may aggravate glomerulosclerosis and enhance progression of
      glomerular disease. The greatest and most consistent reductions in LDL
      cholesterol are achieved with HMG-CoA reductase inhibitors but their efficacy and
      safety in long-term therapy need to be evaluated. In this study, we gave
      fluvastatin to 21 nephrotic patients and followed then up clinically,
      neurophysiologically and by laboratory tests. There was an improvement in the
      lipogram, with reductions of triglycerides (TG) (33%) and LDL (35%) at three
      months. There was no clinical manifestation of myopathy and CPK was normal.
      Electromyographic data showed significant decreases in the amplitude and duration
      of motor unit action potentials in the proximal muscles with statin therapy, but
      these changes did not amount to classic myopathy. We conclude that fluvastatin is
      a safe drug for long-term use in dyslipidemic nephrotic patients. However, we
      suggest further studies to verify whether the early electromyography (EMG)
      changes observed in this study may progress or not on its longer term use.

PMID- 12495287
TI  - Congenital nephrotic syndrome of the Finnish type in Italy: a molecular approach.
AB  - BACKGROUND: Congenital nephrotic syndrome of the Finnish type (CNF) is an
      autosomal recessive disorder mainly caused by mutations in the nephrin gene
      (NPHS1). The frequency of this gene is highest in Finland but the condition
      occurs in all populations, with and without Finnish ancestry. The NPHS1 gene is
      located in the chromosomal region 19q13.1 and consists of 29 exons. METHODS:
      Polymerase chain reaction (PCR), restriction and sequence analyses were used to
      screen 15 CNF Italian patients for mutations in this gene. RESULTS: No Italian
      patients had the typical Finnish mutations, a 2bp deletion in exon 2 (Fin-major)
      and a nonsense mutation in exon 26 (Fin-minor). We found 13 mutations including
      deletions, insertions, nonsense and missense mutations. Seven of these have never
      been described before. We also found one nucleotide change in the promoter region
      and one common polymorphism. NPHS1 missense mutations were confirmed by analysis
      of a healthy control population. CONCLUSIONS: Our study provides further evidence
      that loss of function of the nephrin gene is the main cause of congenital
      nephrotic syndrome of the Finnish type in Italian patients.

PMID- 12495288
TI  - Detection of enriched Thomsen-Friedenrich antigen on IgA1 from IgA nephropathy
      patients.
AB  - BACKGROUND: Human serum IgA1 has a mucin-like structure on its hinge portion
      which is composed of a mucin-type sugar chain and amino acid sequence rich in
      proline, serine and threonine. There are incompletely glycosylated O-linked
      oligosaccharide(s) on the IgA1 hinge region in some nephropathy patients.
      METHODS: We made a detailed analysis of the incompleteness of the sugar chain by
      digesting IgA1 with various glycosidases. To verify the incompleteness of the
      sugar chains, the galactosamine/glucosamine ratio (O/N ratio) was introduced as a
      specific value for each IgA1 preparation. RESULTS: When IgA1 from serum was
      treated with alpha-N-acetylgalactosaminidase and/or neuraminidase or endo-beta-N
      acetylglucosaminidase H (Endo-H), the O/N ratio did not change. However, endo
      alpha-N-acetylgalactosaminidase (Endo-A) reduced the O/N ratio of IgA1 from the
      IgA nephropathy patient whereas before treatment, the O/N ratio had been similar
      in the normal control and IgA nephropathy. CONCLUSIONS: This result means there
      is a small amount of the unsubstituted and the sialylated N-acetylgalactosamine
      residues (Tn and sialyl Tn antigen, respectively), and abundant asialo
      Galbeta1,3GalNAc (TF antigen) in the IgA1 molecule. In view of the incompleteness
      of the IgA1 sugar chain, the decrease in the sialic acid content of the mucin
      type sugar chain on IgA1 from an IgA nephropathy patient became obvious in this
      experiment.

PMID- 12495290
TI  - IgA nephropathy in a patient with chronic granulomatous disease.
AB  - We report the first documented case of X-linked chronic granulomatous disease
      (CGD) in association with IgA nephropathy in a 22 year old male with multiple
      soft tissue abscesses. The case highlights the potential role of staphylococcal
      infections in the pathogenesis of IgA nephropathy and suggests the hypothesis
      that the neutrophil defect in CGD predisposes to such infections which may
      trigger IgA immune complex formation.

PMID- 12495289
TI  - Acute renal failure in IgA nephropathy: aggravation by gross hematuria due to
      anticoagulant treatment.
AB  - IgA nephropathy is one of the most common forms of glomerulonephritis.
      Macroscopic or microscopic hematuria with mild proteinuria are the main symptoms.
      Without complicating factors, IgA nephropathy has a favourable long-term
      prognosis. We report a case of reversible acute renal failure (ARF) as a
      complication of mild IgA nephropathy while oral anticoagulants were administered.
      Diagnosis was based on a renal biopsy showing marked granular mesangial IgA
      deposition. In addition, numerous tubules were extended and completely obstructed
      by red blood cell casts. After hemodialysis treatment and parallel anti
      inflammatory steroids and after stopping anticoagulation, renal function
      gradually improved up to complete remission. This report indicates that
      anticoagulatory treatment may have negative effects on the long-term prognosis of
      IgA nephropathy with respect to development of ARF or tubulo-interstitial
      inflammation.

PMID- 12495291
TI  - ANCA-associated crescentic IgA glomerulonephritis in pregnancy.
AB  - Only a few reports have documented the presence of crescentic IgA nephropathy
      associated with antineutrophil cytoplasmic antibodies (ANCA), suggesting an
      overlap that has therapeutic significance as regards the patients' response to
      treatment. We report a case of rapidly progressive glomerulonephritis with P
      ANCA, with biopsyproven crescentic IgA glomerulonephritis in an 11-week pregnant
      woman who responded very well to cyclophosphamide and prednisone. Her 24-h urine
      protein dropped from 5400 mg/day to 516 mg/day and serum creatinine from 2.7
      mg/dL to 1.4 mg/dL. To the best of our knowledge, this is the first such case
      reported in pregnancy. Eighteen months after her initial presentation, she has no
      significant clinical problems and her laboratory work-up shows stable results.

PMID- 12495292
TI  - MPO-ANCA-associated pulmonary-renal vasculitis in a patient with diabetes
      mellitus.
AB  - Diabetes mellitus is one of the major causes of chronic renal failure. Typical
      findings of diabetic nephropathy are early hyperfiltration followed by
      microalbuminuria and overt proteinuria, resulting in a progressive decrease in
      glomerular filtration rate. Rapidly progressive glomerulonephritis has rarely
      been reported in patients with diabetes mellitus. Here, we describe a patient
      with MPO-ANCA-associated vasculitis, presenting with pulmonary-renal syndrome.
      Immunosuppressive treatment, including pulse methyl-prednisolone and
      cyclophosphamide, was administered and the disease was resolved.

PMID- 12495293
TI  - Abortion surveillance--United States, 1999.
AB  - PROBLEM/CONDITION: CDC began abortion surveillance in 1969 to document the number
      and characteristics of women obtaining legal induced abortions and to monitor
      unintended pregnancy. REPORTING PERIOD COVERED: This report summarizes and
      describes data reported to CDC regarding legal induced abortions obtained in the
      United States in 1999. DESCRIPTION OF SYSTEM: For each year since 1969, CDC has
      compiled abortion data by state or area of occurrence. From 1973 through 1997,
      data were received from or estimated for 52 reporting areas in the United States:
      50 states, the District of Columbia, and New York City. Beginning in 1998, CDC
      compiled abortion data from 48 reporting areas. Alaska, California, New
      Hampshire, and Oklahoma did not report, and data for these areas were not
      estimated. The availability of data regarding the characteristics of women who
      obtained an abortion in 1999 varied by state and by the number of states
      reporting each characteristic. The total number of legal induced abortions is
      reported by state of residence and also by state of occurrence for most areas;
      characteristics of women obtaining abortions in 1999 are reported by state of
      occurrence. RESULTS: A total of 861,789 legal induced abortions were reported to
      CDC for 1999, representing a 2.5% decrease from the 884,273 legal induced
      abortions reported by the same 48 reporting areas for 1998. The abortion ratio,
      defined as the number of abortions per 1,000 live births, was 256 in 1999,
      compared with 264 reported for 1998; the abortion rate for these 48 reporting
      areas was 17 per 1,000 women aged 15-44 years for 1999, the same as in 1997 and
      1998. The highest percentages of abortions were reported for women aged < 25
      years, women who were white, and unmarried women; slightly more than half were
      obtaining an abortion for the first time. Fifty-eight percent of all abortions
      for which gestational age was reported were performed at < or = 8 weeks of
      gestation, and 88% were performed before 13 weeks. From 1992 (when these data
      were first collected) through 1999, increases have occurred in the percentage of
      abortions performed at < or = 6 weeks of gestation. Few abortions were provided
      after 15 weeks of gestation; 4.3% were obtained at 16-20 weeks and 1.5% were
      obtained at > or = 21 weeks. A total of 27 reporting areas submitted data stating
      that they performed medical (nonsurgical) procedures (two of these areas
      categorized medical abortions with "other" procedures), making up < 1.0% of all
      procedures reported from all reporting areas. In 1998 (for which data have not
      been published previously and the most recent year for which such data are
      available), nine women died as a result of complications from known legal induced
      abortion; no deaths were associated with known illegal abortion. INTERPRETATION:
      From 1990 through 1997, the number of legal induced abortions gradually declined.
      In 1998 and in 1999, the number of abortions continued to decrease when comparing
      the same 48 reporting areas. In 1998, as in previous years, deaths related to
      legal induced abortions occurred rarely. PUBLIC HEALTH ACTION: Abortion
      surveillance in the United States should continue so that trends and
      characteristics of women who obtain legal induced abortions can be examined and
      efforts to prevent unintended pregnancy can be enhanced.

PMID- 12495294
TI  - Perspective: shifting sands. What gives?

PMID- 12495295
TI  - The role of the renin-angiotensin system in cholesterol and puromycin mediated
      renal injury.
AB  - BACKGROUND: Puromycin aminonucleoside (PAN) nephropathy is a widely studied model
      of glomerular sclerosis (GS) in the rat, and cholesterol feeding exacerbates the
      injury induced by PAN. The importance of the interaction of angiotensin II (Ang
      II) with the AT2 receptor is unclear. We investigated the role of the renin
      angiotensin system, particularly with regard to AT1 and AT2 receptor dynamics, in
      PAN and cholesterol-mediated GS. METHODS: Sprague-Dawley rats were given a 4%
      cholesterol diet (group II), subcutaneous PAN (group III), or a 4% cholesterol
      diet and PAN (group IV) and compared with a control group given PAN vehicle
      (group I). After 16 weeks, kidneys were harvested and tissue Ang II
      concentration, angiotensin-converting enzyme (ACE) activity, and ACE, AT1, and
      AT2 mRNA levels were determined. RESULTS: Compared with control rats, proteinuria
      was significantly higher in groups II to IV. Kidney ACE activity and ACE mRNA
      levels in groups III and IV were 2- and 3-fold higher than in groups I and II,
      respectively. Kidney Ang II concentration also was increased in the experimental
      groups. Whereas kidney AT1 mRNA was significantly lower in groups III and IV,
      kidney AT2 mRNA was significantly increased in groups II to IV. CONCLUSION: In
      these experimental models of GS, there is significant activation of the tissue
      based renin-angiotensin system. Puromycin with and without cholesterol decreased
      the AT1 receptor mRNA and increased the AT2 receptor mRNA. Up-regulation of AT2
      receptors may be important in ameliorating the proliferative effects of Ang II,
      which presumably occur through the AT1 receptor.

PMID- 12495296
TI  - Prenatal HIV counseling, testing, and antiretroviral prophylaxis by obstetric and
      family medicine providers in Alabama.
AB  - BACKGROUND: The study reported here assessed the implementation of
      recommendations for routine universal prenatal counseling and voluntary HIV
      testing among Alabama physicians who provide prenatal care and determined factors
      associated with noncompliance. METHODS: Voluntary, confidential mailed survey of
      obstetrics and family medicine practitioners. RESULTS: Of the 138 physicians who
      responded to a mailed survey in Alabama, 17 (12.3%) indicated that they did not
      offer universal HIV counseling and testing to pregnant women. Factors associated
      with failure to offer universal HIV counseling and testing included having more
      than 50% of patients refuse HIV counseling and testing when offered and never
      knowingly having given prenatal/perinatal care to women with HIV. Low/medium
      familiarity with the US Public Health Service recommendations for perinatal
      zidovudine use to reduce HIV transmission and physician specialty are also
      suggested as predictors of not offering universal testing. CONCLUSIONS: Despite
      the well-established benefits of antiretroviral prophylaxis to prevent vertical
      transmission of HIV, some physicians in Alabama have been slow to adopt universal
      testing of their pregnant patients for HIV in the prenatal period. Practitioner
      education is as important as patient education in eliminating pediatric HIV in
      the Deep South.

PMID- 12495297
TI  - Smoking and the genetics of signal transduction: an association study on
      retinopathy in type 1 diabetes.
AB  - BACKGROUND: Recent studies suggest a complex association between smoking and
      retinopathy that probably depends on the interaction between many variables. We
      have reported an association between ACP1 phenotype and retinopathy in type 1
      diabetes. Additionally, the deleterious effects of smoking on intrauterine growth
      are dependent on ACP1, a low-molecular-weight tyrosine phosphatase that modifies
      signal transduction. We examine here the interaction between smoking and ACP1 as
      a mediator of susceptibility to diabetic retinopathy in a sample of puerperae
      with type 1 diabetes. SUBJECTS AND METHODS: Seventy-eight women who had just
      delivered live infants were studied. ACP1 phenotype was determined by starch gel
      electrophoresis. Three-way contingency tables were analyzed. RESULTS: There is a
      significant epistatic interaction between smoking and ACP1 phenotype concerning
      their effects on retinopathy. In subjects with low ACP1 activity, frequency of
      retinopathy was slightly higher in smokers than in nonsmokers. However, in
      subjects with medium-high ACP1 activity, frequency of retinopathy was
      significantly lower in smokers than in nonsmokers. A logistic regression analysis
      using retinopathy as the dependent variable revealed that smoking, ACP1, and ACP1
      by smoking interaction, as well as the interaction between smoking and age of the
      women, are the most robust predictors of retinopathy. CONCLUSIONS: The effect of
      smoking on retinopathy in women with type 1 diabetes depends on many variables,
      which supports the hypothesis of complex interactions between smoking and other
      variables in the pathogenesis of this disease. Variability of genetic factors
      involved in signal transduction may affect endothelium proliferation through the
      regulation of growth factors and through regulation of glycemic levels. Because
      cigarette smoke influences signal transduction, its impact on diabetic
      retinopathy may be mediated by ACP1.

PMID- 12495298
TI  - Cardiology Grand Rounds from the University of North Carolina at Chapel Hill. The
      antioxidant vitamins and coronary heart disease: Part 1. Basic science background
      and clinical observational studies.

PMID- 12495299
TI  - Survival with serum sodium level of 180 mEq/L: permanent disorientation to place
      and time.
AB  - A 41-year-old woman who had undergone transfrontal craniotomy for a pituitary
      tumor 4 months before presentation was admitted with confusion and orientation
      only to self. She had a fever of 40 degrees C. Serum sodium and chloride levels
      on admission were 180 and 139 mEq/L, respectively. Measured serum osmolality was
      380 mOsmol/L with a urine osmolality of 360 mOsmol/L. Magnetic resonance imaging
      revealed a 1.5-cm mass in the sella turcica, which was nonfunctioning on
      endocrine evaluation. The "bright spot" of a normal posterior pituitary was
      absent. Central diabetes insipidus was confirmed by a 300% increase in urine
      osmolality with desmopressin. The patient survived her severe hypernatremia,
      which has 70% mortality with a serum sodium level of 160 mEq/L or above. However,
      she developed permanent (6 months) disorientation to time and place even when
      hypernatremia was corrected, which has not been described previously.

PMID- 12495300
TI  - A multihormonal pituitary adenoma with growth hormone and adrenocorticotropic
      hormone production, causing acromegaly and Cushing disease.
AB  - Pituitary adenoma with growth hormone (GH) and corticotropin (ACTH) production
      causing apparent acromegaly and Cushing disease is extremely rare. A 45-year-old
      woman had a pituitary macroadenoma and severe insulin resistance. Physical
      examination showed a fully developed acromegaly associated with mild Cushingoid
      features. Serum GH, insulin-like growth factor-I, ACTH, and cortisol levels were
      all elevated. Hormonal loading tests resulted in GH levels increasing
      paradoxically in response to thyrotropin-releasing hormone (TRH), but not
      corticotropin-releasing hormone (CRH). A similar unexpected increase in ACTH and
      cortisol levels occurred in response to TRH and GH-releasing hormone. After trans
      sphenoidal resection of the pituitary macroadenoma immunohistochemistry revealed
      the presence of either diffuse but faintly GH-positive cells or sparse but
      distinct ACTH-stained cells. A marked amelioration of insulin resistance was
      observed postoperatively. The elevated ACTH and cortisol levels should therefore
      be investigated by CRH and dexamethasone suppression tests for the coexistence of
      Cushing disease to exclude the possibility of underlying ACTH-producing tumors.

PMID- 12495301
TI  - A case of reversible dilated cardiomyopathy after alpha-interferon therapy in a
      patient with renal cell carcinoma.
AB  - A 47-year-old man with renal cell carcinoma underwent nephrectomy, and
      postoperative chemotherapy was performed with recombinant alpha-interferon. Five
      years later, he experienced dyspnea during physical exertion. An echocardiogram
      revealed dilatation and systolic dysfunction of the left ventricle, and thallium
      201 myocardial scintigraphy showed diffuse heterogeneous perfusion. We diagnosed
      congestive heart failure because of cardiomyopathy induced by alpha-interferon
      therapy. Withdrawal of interferon therapy and the combination of an angiotensin
      converting enzyme inhibitor, diuretics, and digitalis improved left ventricular
      systolic function. Furthermore, myocardial scintigraphy using [123I] beta-methyl
      p-iodophenylpentadecanoic acid (123I-BMIPP) or [123 I]metaiodobenzylguanidine
      (123I-MIBG) revealed normal perfusion after the improvement of congestive heart
      failure. This is a rare case of interferon-induced cardiomyopathy that resulted
      in normal myocardial images in 123I-BMIPP and 123I-MIBG scintigrams after
      withdrawal of interferon therapy.

PMID- 12495302
TI  - Two patients with arterial thromboembolism among 311 patients with adenocarcinoma
      of the pancreas.
AB  - PURPOSE: To examine the prevalence and characteristics of arterial
      thromboembolism in patients with adenocarcinoma of the pancreas. METHODS:
      Retrospective review of charts of all patients with cancer of the pancreas
      diagnosed and followed at a regional teaching hospital over a decade. RESULTS: In
      total, 320 patients were diagnosed and 311 were available for evaluation. Two
      patients with arterial thromboembolism were identified (0.65%) and studied. Both
      had extensive metastatic disease on diagnosis and, soon after, developed an acute
      arterial occlusion of the iliac and femoral arteries, with no identifiable
      embolic source (case 1) or acute intestinal infarction due to mesenteric and
      multiple other embolic arterial occlusions associated with nonbacterial
      thrombotic endocarditis (NBTE) of the mitral valve (case 2). Both cases had
      laboratory evidence of disseminated intravascular coagulation and succumbed to
      their illnesses within a very short time. CONCLUSION: Arterial occlusion in
      pancreatic cancer is a rare preterminal event that may be caused by cardiogenic
      emboli from NBTE or to thrombosis in situ. The pathogenesis is briefly reviewed.

PMID- 12495303
TI  - Intravascular lymphomatosis presenting as systemic inflammatory response
      syndrome.
AB  - Intravascular lymphomatosis is an unusual form of non-Hodgkin lymphoma
      characterized by intravascular proliferation of atypical lymphoid cells in
      multiple organs. It can cause systemic inflammatory response syndrome due to
      primary release of cytokines by the tumor cells or secondary release of cytokines
      after vascular occlusion by the tumor cells. It is a potentially fatal condition,
      because multiorgan failure can ensue due to thrombotic vascular occlusion. This
      is a very rare condition and most cases are diagnosed post mortem. We present a
      case of systemic inflammatory response syndrome and subsequent death from
      multiorgan failure in a patient with intravascular lymphoma.

PMID- 12495304
TI  - Rapid communication: acute renal failure associated with tenofovir: evidence of
      drug-induced nephrotoxicity.
AB  - Drug-induced renal failure is a relatively common event in patients infected with
      HIV. This group of patients receives a number of potentially nephrotoxic
      medications for a variety of illnesses. The acyclic nucleoside phosphonates
      cidofovir and adefovir are antivirals that possess significant nephrotoxicity.
      Interestingly, tenofovir disoproxil fumurate (DF) is structurally similar to
      these 2 agents, yet seems to be less nephrotoxic based on a few published studies
      in HIV patients with intact renal function. We present a case in which acute
      renal failure developed after therapy with tenofovir DF in a patient with HIV and
      stable chronic kidney disease.

PMID- 12495305
TI  - Franklin H Martin Memorial Lecture. From Mainz to modem with Martin in the
      middle.

PMID- 12495306
TI  - Laparoscopic resection of deep pelvic endometriosis with rectosigmoid
      involvement.
AB  - BACKGROUND: Adequate treatment of severe deep pelvic endometriosis requires
      complete excision of all implants, but formal bowel resection is not generally
      recommended. The purpose of this study was to describe our experience with
      planned complete laparoscopic management of deep pelvic endometriosis with bowel
      involvement. STUDY DESIGN: All patients presenting to the Department of
      Obstetrics and Gynecology and the Department of Colorectal Surgery at our
      institution with stage IV endometriosis and bowel involvement from February 1998
      to December 2001 were identified from a prospective database and were
      retrospectively analyzed. Data analysis included age, previous history of
      endometriosis, previous pregnancies, operative procedure, body mass index,
      operating room time, intra- and postoperative complications, length of stay, 30
      day readmission, and pain relief. Laparoscopic excision of all visible disease
      was planned. RESULTS: The series consisted of 51 patients with median age of 34
      years (range, 32 to 39 years), with history of earlier abdominal operation in
      66.7%. Preoperative symptoms were present as dysmenorrhea (85.3%), dyspareunia
      (55.9%), rectal pain (41.2%), constipation (44.1%), rectal bleeding (14.7%),
      bloating (29.4%), and tenesmus (8.8%). Management of the bowel disease included
      superficial excision of serosal endometriosis implants (n = 26), bowel resection
      (n = 18), and disc excision (n = 5). Five patients required management of disease
      other than rectosigmoid involvement. Median operating room time was 187 minutes
      (range, 145 to 277 minutes), and the median length of stay was 2 days (range, 1
      to 4 days). Thirty-three percent of excisions were outpatient procedures.
      Postoperative complications occurred in 10.3%: four cases (7.8%) were converted
      to formal laparotomy, and three patients (7.7%) were readmitted within 30 days.
      Only 7 of 47 patients with a uterus (14.9%) required abdominal hysterectomy or
      bilateral salpingo-oophorectomy. Postoperatively, 87% of patients reported a
      clinically significant improvement of their symptoms. CONCLUSIONS: Though
      technically demanding, complete radical laparoscopic excision of endometriotic
      implants can be accomplished with preservation of the reproductive organs and
      appropriate use of bowel resection in the majority of patients. The surgeon or
      gynecologist who plans to perform laparoscopic excision of deep pelvic
      endometriosis should have the ability or access to expertise for laparoscopic
      partial or segmental bowel resection or plan to convert to laparotomy when faced
      with this disease location.

PMID- 12495307
TI  - Prophylactic antibiotics alter the bacteriology of infected necrosis in severe
      acute pancreatitis.
AB  - BACKGROUND: Use of appropriate prophylactic antibiotics has been shown to
      decrease infectious complications and mortality rate in patients with severe
      acute pancreatitis, but its influence on the bacteriology of secondary pancreatic
      infection is poorly defined. STUDY DESIGN: Operative cultures from 61 consecutive
      patients with pancreatic necrosis treated during routine prophylactic antibiotic
      use (1993-2001) were compared with 34 consecutive patients with necrosis treated
      before routine antibiotic use (1977-1992). RESULTS: The two groups of patients
      were similar in demographics, etiology of pancreatitis, and severity of illness.
      All patients in the antibiotic group received prophylactic antibiotics compared
      with only 38% (13 of 34) in the control group. Routine broad-spectrum
      prophylactic antibiotics altered the bacteriology of secondary pancreatic
      infection in severe acute pancreatitis from predominantly gram-negative coliforms
      (56% versus 26%, p = 0.005) to predominately gram-positive organisms (23% versus
      52%, p = 0.009) without a significant increase in either the rate of beta-lactam
      resistance or fungal infections. The overall hospital stay in patients treated
      with prophylactic antibiotics was significantly reduced (61 +/- 24 days versus 41
      +/- 28 days, p = 0.002), and there was a trend toward a decline in mortality rate
      in the antibiotic treatment group. CONCLUSION: Routine broad-spectrum
      prophylactic antibiotic use has altered the bacteriology of secondary pancreatic
      infection in severe acute pancreatitis from predominantly gram-negative coliforms
      to predominantly gram-positive organisms without altering the rate of beta-lactam
      resistance or fungal superinfection.

PMID- 12495308
TI  - Laparoscopic colorectal resection: a safe option for elderly patients.
AB  - BACKGROUND: Open colorectal surgery in the elderly has been associated with
      higher morbidity and mortality rates. The favorable short-term outcomes of
      laparosocopic colorectal resection might reduce the morbidity in elderly
      patients. This study compares results of elderly patients (aged 70 and above) who
      underwent laparoscopic colorectal resection with those having open surgery. STUDY
      DESIGN: Consecutive patients aged 70 and above who had elective colorectal
      resection from June 2000 to December 2001 were included. Data concerning
      demographics, diseases, details of operations, and postoperative events were
      collected prospectively. Comparisons between results of laparoscopic surgery and
      open surgery were made. RESULTS: Sixty-five patients had laparoscopic colectomy
      and 89 had open surgery during the study period. Median ages were 77 years and 75
      years in the open and laparoscopic groups, respectively. Presence of premorbid
      medical conditions, American Society of Anesthesiology score, and incidence of
      previous surgery were similar in the two groups. Median operative time was longer
      (180 minutes versus 135 minutes, p < 0.001), but blood loss was less (100 mL
      versus 200 mL, p = 0.001) in the laparoscopic group. Conversion to open surgery
      occurred in eight patients. One patient died in the laparoscopic group and five
      died in the open group. Laparoscopic resection was associated with earlier return
      of bowel function (3 days versus 4 days, p = 0.004), earlier resumption of solid
      diet (3 days versus 5 days, p < 0.001), shorter hospital stay (7 days versus 9
      days, p = 0.001), and less cardiopulmonary morbidity (7.7% versus 22.4%, p =
      0.033) when compared with open colorectal resection. CONCLUSIONS: Laparoscopic
      colorectal resection is a safe option for elderly patients and is associated with
      more favorable short-term outcomes in terms of earlier return of bowel function,
      earlier resumption of diet, and shorter hospital stay. It is also associated with
      less cardiopulmonary morbidity, which is an important complication after
      colorectal surgery in the elderly.

PMID- 12495309
TI  - Pro- and antiinflammatory cytokine production after radiofrequency ablation of
      unresectable hepatic tumors.
AB  - BACKGROUND: Experience using radiofrequency ablation (RFA) for treating
      unresectable hepatic malignancies is expanding, with promising outcomes and fewer
      complications compared with cryotherapy. STUDY DESIGN: This study examined
      systemic inflammatory responses after RFA as measured by the appearance of
      postoperative symptoms and cytokine production. Seventeen patients (11 men, 6
      women) aged 40 to 85 years (mean 64.2 years) with unresectable primary and
      metastatic hepatic tumors underwent RFA. Mean liver volume treated with RFA was
      35.3% +/- 3.6% (SEM) (median 36.8%). Plasma cytokines (tumor necrosis factor
      alpha, interleukin [IL]-1beta, IL-1ra, IL-6, IL-8, IL-10, p55, and p75) were
      measured from anesthesia induction through 48 hours after RFA. Ex vivo whole
      blood cytokine production was measured at baseline, 24 hours, and 48 hours after
      RFA. RESULTS: Cytokine and cytokine-receptor production were not notably altered
      by RFA. Ex vivo whole-blood endotoxin stimulation indicated that intrinsic
      cellular immune function remained intact after treatment, although modest
      decreases in stimulated tumor necrosis factor alpha production were observed 24
      to 48 hours after RFA. Variceal bleeding, hepatic failure, and death occurred in
      one patient 30 days after RFA. None of the remaining patients exhibited
      tachycardia or hypotension. Fevers (> or = 38.5 degrees C) developed in three
      patients during the first 48 hours postoperatively. There was no association
      between plasma cytokines and postoperative complications. CONCLUSIONS: In
      contrast to previous reports using cryotherapy, systemic inflammatory responses
      as measured by increased cytokines were not observed after RFA. The cryotherapy
      induced "cryoshock" phenomenon was not observed in patients undergoing RFA in our
      study. We conclude that RFA ablation is fundamentally different than cryotherapy
      and apparently does not stimulate Kupffer and other hepatic macrophages to
      produce proinflammatory cytokines.

PMID- 12495310
TI  - Clinical outcomes and apomucin expression of intrahepatic cholangiocarcinoma
      according to gross morphology.
AB  - BACKGROUND: The clinicopathologic characteristics and the expression of apomucin
      (MUC) in intrahepatic cholangiocarcinoma (ICC) with respect to gross morphology
      have not been comprehensively examined. STUDY DESIGN: We reviewed the clinical
      data of 98 patients with ICC who underwent resection at Seoul National University
      Hospital from 1980 to 1998. We also examined the expression profiles of MUC1 and
      MUC2 in 30 ICC tissues by immunohistochemistry using mouse monoclonal antibodies.
      RESULTS: Of 98 cases, 42 were of the mass-forming type of ICC, 22 were of the
      periductal-infiltrating type, 21 were of the intraductal-growth (IG) type, and 13
      were of the mixed type, and the overall 5-year cumulative survival rate was 23.3%
      in the mass-forming type, 0% in the periductal-infiltrating type, and 76.2% in
      the IG type. MUC1 was expressed in all types (mass-forming type 75.0%, periductal
      infiltrating type 100%, and IG type 73.3%), but significantly, MUC2 was expressed
      only in the IG type (80.0%), which had better prognosis than the other types.
      CONCLUSIONS: It is apparent that the IG type of ICC should be distinguished from
      the other types of ICC because a favorable prognosis can be expected after
      complete surgical resection.

PMID- 12495311
TI  - A cost and outcomes comparison of a novel integrated pediatric air and ground
      transportation system.
AB  - BACKGROUND: The purpose of this study is to compare air transportation of
      critically ill pediatric patients with a mixed air-ground transportation system
      by evaluating timeliness, safety, and cost. The setting was a tertiary care "hub"
      center with three outlying-referral "spoke" facilities. STUDY DESIGN: Our study
      included 96 children transported between June and December 1997, with 45%
      constituting surgical admissions and 55% medical admissions. Data collected at
      the outlying facilities, en route, and at our institution included vital signs,
      laboratory values, and Glasgow coma scores. We evaluated transport time,
      transport cost, Pediatric Risk of Mortality scores, and Pediatric Index of
      Mortality of the children during transportation using ANOVA statistical analysis.
      We also compared adverse events in transportation, total hospital length of stay,
      and mortality at 24 and 72 hours in both the air and ground transport groups to
      determine differences in predicted and observed mortality. RESULTS: A total of 96
      children were transported (48% by ground and 52% by air) between June and
      December 1997. The time at the referring facility was significantly shorter in
      the ground group than in the air group (air, 55.4 minutes versus ground, 36.7
      minutes, p < 0.01). Total transport time differed by only 27 minutes between
      groups. No difference was identified in morbidity or mortality between air and
      ground groups. Actual mortality was not significantly different from predicted
      mortality in either group. The cost of ground transportation was significantly
      lower (air, $4,236 versus ground, $1,566). When our system of a combined air and
      ground group transport system is compared with a hypothetical 100% air transport
      system, we saved an average of more than $240,000 annually. CONCLUSIONS: We have
      demonstrated that a "hub-and-spoke" ground transportation system supplements air
      transportation in a safe, timely, and cost-effective manner.

PMID- 12495312
TI  - Spontaneous localized intestinal perforation in very-low-birth-weight infants: a
      distinct clinical entity different from necrotizing enterocolitis.
AB  - BACKGROUND: Idiopathic spontaneous intestinal perforation (SIP), a distinct
      clinical entity different from necrotizing enterocolitis (NEC), has an increasing
      prevalence in very-low-birth-weight infants. The aims of our study were to define
      patient characteristics and potential risk factors for premature infants with SIP
      compared with infants subjected to surgical treatment for NEC. STUDY DESIGN: The
      medical records of 29 premature infants with either SIP (n = 13) or NEC (n = 16)
      were reviewed retrospectively. RESULTS: Infants who experienced SIP were smaller
      at birth, had lower Apgar scores, and required more intensive neonatal
      resuscitation. An increased rate of premature rupture of membranes in infants
      with SIP (8/13 versus 6/16) was not associated with a higher rate of infection in
      mothers or infants. The onset of illness in SIP was significantly earlier than in
      NEC (p = 0.022). In contrast to patients with NEC (7/16), 11 of 13 patients in
      the SIP group had received indomethacin (p = 0.02). Bluish discoloration of the
      abdomen (8/13), a gasless abdomen (8/13), and the absence of pneumatosis
      intestinalis (0/13) were further significant markers in infants with SIP. At
      operation, SIP was always located in the terminal ileum in an antimesenteric
      position (13/13), and the remaining bowel appeared grossly normal. In most cases
      of SIP (10/13), the histologic investigation revealed an area of hemorrhagic
      necrosis without the typical coagulation necrosis seen predominantly in NEC.
      CONCLUSIONS: Based on clinical presentation and radiologic and intraoperative
      findings, SIP is a distinct pathologic entity in very-low-birth-weight infants
      and can be differentiated from classic NEC. Detected early, SIP can be treated by
      simple procedures (sutures, or resection and primary anastomosis) with a low rate
      of morbidity and mortality.

PMID- 12495313
TI  - Portal versus systemic drainage of small bowel allografts: comparative assessment
      of survival, function, rejection, and bacterial translocation.
AB  - BACKGROUND: Portal venous drainage of small bowel grafts is theoretically more
      physiologic than systemic drainage, but is technically more demanding.
      Comparisons in animal models have not demonstrated a clear advantage of one
      technique over the other, but clinical data are lacking. STUDY DESIGN: Clinical
      records of 36 patients who underwent 37 small bowel transplantation procedures
      from January 1995 to August 2001 were reviewed. Portal drainage was performed in
      19 patients (PD group). Systemic drainage was performed in 18 patients (SD
      group). Median followup was 531 days. RESULTS: PD and SD patients had similar ICU
      stays (median 7 versus 9 days) and endotracheal intubation durations (median 3
      versus 5 days). All current survivors, with the exception of one patient in each
      group, are independent from parenteral nutrition. Liver function tests were
      similar in both groups. There was a twofold increase in tacrolimus dosage in the
      PD group to achieve similar trough levels indicating a "first-pass" hepatic
      clearance effect. Cumulative incidence of acute rejection episodes and OKT3
      requiring rejection episodes were similar in both groups. To the contrary, a
      lower incidence of gram-negative rods of Enterococcus sp. in blood or
      bronchoalveolar lavage suggested that the clearance of translocated intestinal
      bacteria was more efficient in the PD group. Graft and patient survival rates
      were similar in both groups. CONCLUSIONS: Systemic venous drainage of small bowel
      transplants is a dependable technique, associated with similar results as portal
      venous drainage, in terms of overall mortality, morbidity, rejection, function,
      and patient and graft survival. But attention should be paid to an impaired
      clearance of intestinal bacterial translocation after systemic drainage.

PMID- 12495314
TI  - Surgeon volume as an indicator of outcomes after carotid endarterectomy: an
      effect independent of specialty practice and hospital volume.
AB  - BACKGROUND: High-volume hospitals have been shown to have superior outcomes after
      carotid endarterectomy (CEA), but the contribution of surgeon volume and
      specialty practice to CEA outcomes in a national sample is unknown. STUDY DESIGN:
      Using the National Inpatient Sample for 1996 and 1997, 35,821 patients who
      underwent CEA (ICD-9-CM code 3812) and had data for unique surgeon identification
      were studied. Surgeons were categorized in terms of annual CEA volume as low
      volume surgeons (< 10 procedures), medium-volume surgeons (10 to 29), and high
      volume surgeons (> or = 30). Data from cardiac, general, neurologic, and vascular
      surgical practices were analyzed. In-hospital mortality, postoperative stroke,
      and prolonged length of stay (> 4 days) were the primary outcomes variables.
      Unadjusted and case-mix adjusted analyses were performed. RESULTS: The overall in
      hospital mortality was 0.61%. CEA was performed annually by high-volume surgeons
      in 52% of patients, by medium-volume surgeons in 30% of patients, and by low
      volume surgeons in 18% of patients. Observed mortality by surgeon volume was
      0.44% for high-volume surgeons, 0.63% for medium-volume surgeons, and 1.1% for
      low-volume surgeons (p < 0.001). The postoperative stroke rate was 1.14% for high
      volume surgeons, 1.63% for medium-volume surgeons, and 2.03% for low-volume
      surgeons (p < 0.001). Surgeon specialty had no statistically significant effect
      on mortality or postoperative stroke. In the logistic regression model, increased
      risk of mortality was associated with emergent admission (odds ratio [OR] = 2.1;
      95% confidence interval [CI] 1.6 to 2.8, p < 0.001), patient age > 65 years (OR =
      2.0; 95% CI 1.3 to 3.1, p = 0.001), low-volume surgeon (OR = 1.9; 95% CI 1.4 to
      2.5, p < 0.001), and COPD (OR = 1.8; 95% CI 1.3 to 2.5, p = 0.001). Low hospital
      CEA volume (< 100) was not a significant risk factor in the multivariate
      analysis. CONCLUSIONS: More than 50% of the CEAs in the United States are
      performed by high-volume surgeons with superior outcomes. Health policy efforts
      should focus on reducing the number of low-volume surgeons, regardless of surgeon
      specialty or total hospital CEA volume.

PMID- 12495315
TI  - Comparative evaluation of duplex-derived parameters in patients with chronic
      venous insufficiency: correlation with clinical manifestations.
AB  - BACKGROUND: Quantification of venous reflux is still a matter of debate. Our goal
      was to compare the duplex-derived parameters between patients with early and
      advanced chronic venous insufficiency (CVI), and to determine indicative
      parameters reflecting the progression of CVI. STUDY DESIGN: A total of 1,132
      limbs in 914 patients with primary valvular incompetence were included. Clinical
      manifestations were categorized according to the CEAP (clinical, etiologic,
      anatomic, and pathophysiologic) classification, and the patients were divided
      into two groups: group I (those with relatively early CVI, C(1
      3)E(P),A(S,D,P),P(R)) and group II (those with advanced CVI, C(4
      6)E(P),A(S,D,P),P(R)). The distribution of venous insufficiency was determined,
      and the parameters assessed were the duration of reflux (s), the peak reflux
      velocity (cm/s), and the flow at peak reflux (mL/s). RESULTS: There was no
      notable difference in overall superficial venous reflux between the groups, and
      the frequency of isolated deep and perforator incompetence did not differ between
      the groups. The duration of reflux did not improve the discrimination power
      between the groups. In contrast, the peak reflux velocity had significant
      discrimination power at the saphenofemoral junction (p < 0.0001), the
      saphenopopliteal junction (p = 0.0002), in the greater saphenous vein (p <
      0.0001), in the superficial femoral vein (p = 0.0041), and in the popliteal vein
      (p = 0.003). The peak reflux flow was significantly higher in group II at the
      saphenofemoral junction (p < 0.0001), the saphenopopliteal junction (p = 0.0029),
      in the greater saphenous vein (p < 0.0001), in the common femoral vein (p =
      0.006), in the superficial femoral vein (p = 0.0005), and in the popliteal vein
      (p = 0.0003). CONCLUSIONS: Superficial venous insufficiency might play a major
      role in the development of advanced CVI. The peak reflux velocity and peak reflux
      volume improve discrimination power between early-stage and advanced CVI.

PMID- 12495316
TI  - Ocular and periocular injuries from orbital fractures.
AB  - BACKGROUND: Orbital fractures are associated with ocular and periocular injuries.
      The role of the ophthalmologist in the evaluation and management of facial
      trauma, including orbital fractures, has not been clearly defined. The purpose of
      this study is to identify and characterize ocular and periocular injuries
      associated with orbital fractures to define the role of the ophthalmologist in
      the management of facial trauma. STUDY DESIGN: Retrospective case review.
      RESULTS: Three hundred sixty-five patients with orbital fractures who were
      evaluated by an ophthalmologist as part of their initial trauma evaluation were
      studied. The majority of the patients with orbital fractures (74%) did not have
      associated ocular or periocular injuries. Twenty-three of 104 (22%) ocular
      injuries in 23 of 95 (24%) patients required immediate intervention by an
      ophthalmologist. CONCLUSIONS: Facial trauma and orbital fractures are associated
      with significant ocular and periocular injuries, the minority of which require
      immediate evaluation and treatment by an ophthalmologist. These results differ
      from those previously reported.

PMID- 12495317
TI  - What's new in general surgery: gastrointestinal conditions.

PMID- 12495318
TI  - Extended lymph node dissection in gastric carcinoma: where do we stand after the
      Dutch and British randomized trials?

PMID- 12495319
TI  - Carrel's war research hospital at Compiegne: prototype of a research facility at
      the front.

PMID- 12495320
TI  - Is this a bad day, or one of the last days? How to recognize and respond to
      approaching demise.

PMID- 12495321
TI  - Obstructing duodenal diverticula.

PMID- 12495322
TI  - Synchronous carcinoid tumor of the small bowel.

PMID- 12495323
TI  - Removal of hepatocellular carcinoma extending in the right atrium without
      extracorporal bypass.

PMID- 12495324
TI  - Technique of thymectomy by anterior-superior cervicomediastinal exenteration.

PMID- 12495325
TI  - Postoperative ileus after laparoscopic colectomy.

PMID- 12495326
TI  - Colon and rectal cancer in Filipinos.

PMID- 12495327
TI  - Lead as its own luminescent sensor.
AB  - Lead (II) in polar organic solvents such as acetone, acetonitrile, and
      propylenecarbonate with excess bromide generates the highly luminescent lead
      halide cluster Pb(4)Br(11)(3)(-). This in situ sensor does not rely on a host
      guest relationship and, thus, is intrinsically selective and sensitive, allowing
      for the detection of lead at nanomolar concentrations. The cluster's emission
      maximum and relaxation kinetics are temperature dependent and indicate a close
      spacing of intralead and intracluster electronic energy levels.

PMID- 12495328
TI  - New alkaline earth aluminum hydride with one-dimensional zigzag chains of [AlH6]:
      synthesis and crystal structure of BaAlH5.
AB  - The title hydride and its deuteride were successfully synthesized. The crystal
      structure of the deuteride was determined by time-of-flight neutron powder
      diffraction. BaAlD(5) crystallizes with a new orthorhombic structure in space
      group Pna2(1) (No. 33), cell parameters a = 9.194(1) A, b = 7.0403(9) A, and c =
      5.1061(6) A, Z = 4. BaAlH(5) is the first example that contains one-dimensional
      zigzag chains of [AlH(6)] along the crystallographic c axis.

PMID- 12495329
TI  - Influence of nonplanarity and extended conjugation on porphyrin basicity.
AB  - Thermodynamic basicities of several new nonplanar water soluble
      tetraaryltetracyclohexano- (Ar(4)TCHP) and tetraaryltetrabenzoporphyrins
      (Ar(4)TBP) have been measured and correlated with their structural parameters.
      While the degrees of nonplanarity in these porphyrins are similar, Ar(4)TCHPs
      exhibit significantly higher basicities than Ar(4)TBPs and than planar
      tetraarylporphyrins. Low basicities of distorted Ar(4)TBPs are believed to be due
      to extended pi-conjugation, which causes delocalization of the core electron
      density in these porphyrins and reduces negative charges at the protonation site.

PMID- 12495330
TI  - Highly bulky and electron-rich terminal ruthenium phosphido complexes: new donor
      ligands for palladium-catalyzed suzuki cross-couplings.
AB  - Secondary phosphine complexes of the formula [(eta(5)
      C(5)H(5))Ru(L)(2)(PHR(2))](+) BAr(F)(-) are prepared from cationic ruthenium N(2)
      complexes and PHR(2) (R = Ph (a), t-Bu (b), Cy (c)). Additions of t-BuOK or
      NaN(SiMe(3))(2) give the phosphido complexes (eta(5)-C(5)H(5))Ru(L)(2)(PR(2))
      ((L)(2) = (PEt(3))(2) (5a-c), depe (6a,b)) in high NMR yields. These rapidly
      oxidize in air to give isolable RuP(=O)R(2) species. Complex 5a is more basic
      than the rhenium analogue (eta(5)-C(5)H(5))Re(NO)(PPh(3))(PPh(2)), and 6b is more
      basic than P-t-Bu(3). Complexes 5a-c and 6b are effective ligands for palladium
      catalyzed Suzuki reactions. The catalyst from 6b is nearly as reactive as that
      from the benchmark ligand P-t-Bu(3).

PMID- 12495331
TI  - Stability and structure in alpha- and beta-Keggin Heteropolytungstates,
      [X(n)(+)W12O40)](8-n)(-), X = p-block cation.
AB  - beta-[SiW(12)O(40)](4)(-) (C(3)(v) symmetry) is sufficiently higher in energy
      than its alpha-isomer analogue that effectively complete conversion to alpha
      [SiW(12)O(40)](4)(-) (T(d)) is observed. By contrast, beta- and alpha
      [AlW(12)O(40)](5)(-) (beta- and alpha-1; C(3)(v) and T(d), respectively) are
      sufficiently close in energy that both isomers are readily seen in (27)Al NMR
      spectra of equilibrated (alpha-beta) mixtures. Recently published DFT
      calculations ascribe the stability of beta-1 to an electronic effect of the
      large, electron-donating [AlO(4)](5)(-) (T(d)) moiety encapsulated within the
      polarizable, fixed-diameter beta-W(12)O(36) (C(3)(v)) shell. Hence, no unique
      structural distortion of beta-1 is needed or invoked to explain its unprecedented
      stability. The results of these DFT calculations are confirmed by detailed
      comparison of the X-ray crystal structure of beta-1 (beta
      Cs(4.5)K(0.5)[Al(III)W(12)O(40)].7.5H(2)O; orthorhombic, space group Pmc2(1), a =
      16.0441(10) A, b = 13.2270(8) A, c = 20.5919(13) A, Z = 4 (T = 100(2) K)) with
      previously reported structures of alpha-1, alpha- and beta-[SiW(12)O(40)](4)(-),
      and beta(1)-[SiMoW(11)O(40)](4)(-).

PMID- 12495332
TI  - Identification of a near-linear supramolecular water dimer, (H2O)2, in the
      channel of an inorganic framework material.
AB  - Supramolecular water dimer, (H(2)O)(2), is fundamentally important. During the
      course of our work on polyoxometalates, we have been able to identify the
      existence of hydrogen-bonded, near-linear water dimers in the "sinuous" channels
      of an inorganic framework material,
      Na(3)(n)(H(2)O)(6)(n)[Al(OH)(6)Mo(6)O(18)](n)() x 2nH(2)O, 1. The three
      dimensional network structure of 1 in the solid state is assembled by the
      Anderson type of heteropolyanions as building blocks sharing sodium cations.
      Vibrational spectroscopy, X-ray powder diffraction technique, TG-DSC analyses,
      and single-crystal X-ray structure analysis have characterized this host-guest
      system, 1. Crystal data for 1: triclinic space group Ponemacr;, a = 12.0618 (3)
      A, b = 13.1570 (4) A, c = 14.1563 (4) A, alpha = 80.7850 (10) degrees, beta =
      75.2660 (10) degrees, gamma = 68.9210 (10) degrees, and Z = 3.

PMID- 12495333
TI  - Intramolecular "Aryl-metal chelate ring" pi,pi-interactions as structural
      evidence for metalloaromaticity in (aromatic alpha,alpha'-diimine)-copper(II)
      chelates: molecular and crystal structure of aqua(1,10-phenanthroline)(2
      benzylmalonato)copper(II) three-hydrate.
AB  - By reaction of Cu(2)CO(3)(OH)(2), 2-benzylmalonic acid (H(2)Bzmal), and 1,10
      phenanthroline (phen), [Cu(Bzmal)(phen)(H(2)O)] x 3H(2)O (compound 1) has been
      obtained and characterized by thermal, spectral, magnetic, and X-ray diffraction
      methods. The molecular structure of 1 is remarkably similar to that of
      [Cu(Bzmal)(bipy)(H(2)O)] x 2H(2)O (compound 2, bipy = 2,2'-bipyridine). In both
      complexes, the aryl(Bzmal) ring produces an unexpected pi,pi-stacking interaction
      with the Cu(II)-(aromatic alpha,alpha'-diimine) chelate ring, at an average
      distance d(pi)(-)(pi) of 3.40 A, involving roughly parallel and smoothly slipped
      rings. This insight is discussed as new structural evidence for
      metalloaromaticity of Cu(II)-(aromatic alpha,alpha'-diimine) chelate rings.
      Interestingly, 1 recognizes itself by a weak intermolecular pi,pi-stacking
      interaction between aryl(Bzmal) ligands to give pairs of complex molecules. In
      contrast, there is an intermolecular pyridyl-pyridyl pi,pi-stacking interaction
      also forming pairs of complex molecules in 2.

PMID- 12495334
TI  - Forty-five years of chemical discovery including a golden quarter-century.
AB  - Inorganic chemistry became a passion for me as a graduate student in the 1950s.
      It was exciting to be part of the renaissance of the discipline, and I am pleased
      to have contributed to its strength. Physical concepts applied to the
      understanding of the properties of transition metal compounds guided our work
      initially. In the 1970s, probably as a direct result of the world abandoning the
      gold standard, the chemistry of gold was awakened after a long sleep. Much of the
      chemistry covered in this review of our work relates to novel compounds of gold
      and the properties they display which have been uncovered during the last 25
      years of the 20th century. Stable metal-metal bonded Au(II) and organometallic
      Au(III) compounds, bi- and trimetallic oxidative addition, phosphorescent species
      with microsecond lifetimes, gold chains resulting from aurophilic bonding
      stronger than H-bonding, and recently, gold binding to organic pi acids have
      intrigued my group and other gold chemists during this period.

PMID- 12495335
TI  - Electronic spectra and structures of d2 molybdenum-oxo complexes. Effects of
      structural distortions on orbital energies, two-electron terms, and the mixing of
      singlet and triplet states.
AB  - Molybdenum-oxo ions of the type [Mo(IV)OL(4)Cl](+) (L = CNBu(t), PMe(3),
      (1)/(2)Me(2)PCH(2)CH(2)PMe(2)) have been studied by X-ray crystallography,
      vibrational spectroscopy, and polarized single-crystal electronic absorption
      spectroscopy (300 and ca. 20 K) in order to investigate the effects of the
      ancillary ligand geometry on the properties of the MotriplebondO bond. The
      idealized point symmetries of the [Mo(IV)OL(4)Cl](+) ions were established by X
      ray crystallographic studies of the salts [MoO(CNBu(t)())(4)Cl][BPh(4)]
      (C(4)(v)), [MoO(dmpe)(2)Cl]Cl.5H(2)O (C(2)(v)), and [MoO(PMe(3))(4)Cl][PF(6)]
      (C(2)(v)()); the lower symmetries of the phosphine derivatives are the result of
      the steric properties of the phosphine ligands. The Motbd1;O stretching
      frequencies of these ions (948-959 cm(-)(1)) are essentially insensitive to the
      nature and geometry of the equatorial ligands. In contrast, the electronic
      absorption bands arising from the nominal d(xy)() --> d(xz), d(yz) (n -->
      pi(MoO)) ligand-field transition exhibit a large dependence on the geometry of
      the equatorial ligands. Specifically, the electronic spectrum of
      [MoO(CNBu(t)())(4)Cl](+) exhibits a single (1)[n --> pi(xz)(,)(yz)] band, whereas
      the spectra of both [MoO(dmpe)(2)Cl](+) and [MoO(PMe(3))(4)Cl](+) reveal separate
      (1)[n --> pi(xz)] and (1)[n --> pi(yz)] bands. A general theoretical model of the
      n --> pi state energies of structurally distorted d(2) M(triplebondE)L(4)X
      chromophores is developed in order to interpret the electronic spectra of the
      phosphine derivatives. Analysis of the n --> pi transition energies using this
      model indicates that the d(xz) and d(yz) pi(MotriplebondO) orbitals are
      nondegenerate for the C(2)(v)-symmetry ions and the n --> pi(xz) and n --> pi(yz)
      excited states are characterized by different two-electron terms. These effects
      lead to a significant redistribution of intensity between certain spin-allowed
      and spin-forbidden absorption bands. The applicability of this model to the
      excited states produced by delta --> pi and pi --> delta symmetry electronic
      transitions of other chromophores is discussed.

PMID- 12495336
TI  - Intra- and intermolecular second-sphere coordination chemistry: formation of
      capsules, half-capsules, and extended structures with hexaaquo- and
      hexaamminemetal ions.
AB  - In the design of novel extended solids, particularly those based on weaker
      interactions, reliable "synthons" are a valuable commodity. This work concerns
      the hydrogen-bonded assemblies which result from the second-sphere coordination
      interactions between a highly preorganized trisulfonate ligand and hexaaquo metal
      ions. Significantly, supramolecular structural variation, which may be
      rationalized on the basis of the features of the molecular building blocks, is
      observed. The results are formation of second-sphere capsules with trivalent ions
      (Fe(3+), Cr(3+), Al(3+)), and half-capsules with divalent ions (Mg(2+), Zn(2+)).
      The divalent systems further assemble into extensively hydrogen-bonded hexagonal
      nets. Effects of geometrical variation of the building blocks are also observed
      when a Jahn-Teller-distorted divalent ion (Cu(2+)) is substituted for the
      perfectly octahedral species. The second-sphere effects on the stabilization of
      the primary coordination sphere are illustrated by TGA experiments. In these
      assemblies, the potential of a new supramolecular synthon is illustrated, that
      being the complementary cis-aquo sulfonate interaction. These complexes
      illustrate the general utility of second-sphere effects, both as an assembly tool
      and to stabilize metal complexes in the solid state. Finally, as a comparison, a
      hydrogen-bonded assembly with a hexaammine complex of a trivalent metal (Co(3+))
      is presented, which forms an extended network with a completely altered hydrogen
      bonding array.

PMID- 12495337
TI  - Mass effect on the equienergetic high-spin/low-spin states of spin-crossover in
      4,4'-bipyridine-bridged iron(II) polymeric compounds: synthesis, structure, and
      magnetic, Mossbauer, and theoretical studies.
AB  - The suitability of the system [Fe(4,4'-bipy)(H(2)O)(2)(NCX)(2)].(4,4'-bipy),
      where 4,4'-bipy stands for 4,4'-bipyridine and X = S (1) and Se (2), as a
      precursor for the synthesis of new polymeric spin-crossover compounds has been
      studied. The reaction of 1 or 2 with bt (2,2'-bithiazoline) afforded the
      polymeric compounds of formula [Fe(4,4'-bipy)(bt)(NCX)(2)] (X = S (3), Se (4)).
      Compounds 3 and 4 are isostructural, but only the crystal structure of 3 has been
      fully determined. It crystallizes in the orthorhombic system, Fdd2 space group, Z
      = 24, with a = 38.962(8) A, b = 11.545(2) A, c = 30.889(6) A, V = 13895(5) A(3).
      The structure consists of linear chains constituted by trans-4,4'-bipy linked
      iron(II) ions; two cis equatorial positions are occupied by two pseudohalide
      ligands, and the remaining positions are filled by the bidentate bt ligand.
      Investigation of their magnetic properties and Mossbauer spectra has revealed the
      occurrence of a low-spin (LS) <--> high-spin (HS) conversion involving 12% (3, S)
      and 20% (4, Se) of the Fe(II) ions. The thermal variation of the HS fraction is
      gradual with onset temperatures as low as 60 K. A theoretical approach based on
      the Ising-like model, completed with molecular vibrations, through harmonic
      oscillators, fits the data successfully, leading to an energy gap of 65 cm(-1)
      (3) and 86 cm(-1) (4) between the lowest LS and HS levels, and an average
      vibration frequency ohgrmacr;(LS) of 382 cm(-1) (3) and 365 cm(-1) (4) in the LS
      state. The ca. 1.05 omega(LS(3))/omega(LS(4)) ratio is close to the ca. 1.09 Se/S
      molar mass ratio. The simple electrovibrational Ising-like model permits us to
      explain, for the first time, a mass effect through the molecular vibrations in a
      spin-crossover complex that is in the unusual situation of equienergy among the
      HS and LS states.

PMID- 12495338
TI  - Synthesis and X-ray crystal structure determination of the first Copper(II)
      complexes of tetraazamacrocycle-glyoxal condensates.
AB  - Novel Cu(II) complexes CuLCl(2) (L = 1-4) have been synthesized containing the
      metal bound to a well-known type of tetracyclic bisaminal formed from the
      condensation of glyoxal and tetraazamacrocycles (1 = cyclam-glyoxal condensate, 2
      = [13]aneN4-glyoxal condensate, 3 = cyclen-glyoxal condensate, 4 = isocyclam
      glyoxal condensate). The four-coordinate complexes were characterized by X-ray
      crystallography, electronic spectroscopy, solid-state magnetic moments, and
      electron spin resonance spectroscopy. The tetracyclic bisaminals, although having
      four potential donor atoms, are bound in a cis-bidentate fashion to Cu(II) with
      two additional cis-chloride donors. The ligands take up folded conformations, and
      with the exception of ligand 4, only nonadjacent nitrogen atoms coordinate. As
      expected, ligand 2 in Cu(2)Cl(2) has a folded structure similar to those of the
      previously characterized 1 and 3. The conformation of 4 in the complex Cu(4)Cl(2)
      differs from 1-3 in that three nitrogens direct their lone pairs to one side of
      the folded tetracycle, with adjacent nitrogen atoms coordinated to Cu(II). This
      difference is probably caused by the presence of the more flexible seven-membered
      ring rather than the five- to six-membered rings in 1-3. Air oxidation of Cu(I)
      in the presence of 1 or 3 results in bis(mu-hydroxo) dimers as characterized by X
      ray crystal structures, suggesting dioxygen binding, followed by O-O bond
      splitting to give the Cu(2)O(2) diamond core.

PMID- 12495339
TI  - Reactivity investigation of dinuclear vanadium(IV,V)-citrate complexes in aqueous
      solutions. A closer look into aqueous vanadium-citrate interconversions.
AB  - Well-known vanadium(IV)- and vanadium(V)-citrate complexes have been employed in
      transformations involving vanadium redox as well as nonredox processes. The
      employed complexes include K(2)[V(2)O(4)(C(6)H(6)O(7))(2)] x 4H(2)O,
      K(4)[V(2)O(4)(C(6)H(5)O(7))(2)] x 5.6H(2)O,
      K(2)[V(2)O(2)(O(2))(2)(C(6)H(6)O(7))(2)] x 2H(2)O,
      K(4)[V(2)O(2)(C(6)H(4)O(7))(2)] x 6H(2)O,
      K(3)[V(2)O(2)(C(6)H(4)O(7))(C(6)H(5)O(7))] x 7H(2)O,
      (NH(4))(4)[V(2)O(2)(C(6)H(4)O(7))(2)] x 2H(2)O, and
      (NH(4))(6)[V(2)O(4)(C(6)H(4)O(7))(2)] x 6H(2)O. Reactions toward hydrogen
      peroxide at different vanadium(IV,V):H(2)O(2) ratios were crucial in delineating
      the routes leading to the interconversion of the various species. Equally
      important thermal transformations were critical in showing the linkage between
      pairs of dinuclear vanadium-citrate peroxo as well as nonperoxo complexes, for
      which the important vanadium(V)-assisted oxidative decarboxylation, leading to
      reduction of vanadium(V) to vanadium(IV), seemed to be a plausible pathway in
      place for all the cases examined. FT-IR spectroscopy and X-ray crystallography
      were instrumental in the identification of the arising products of all
      investigated reactions. Collectively, the data support the existence of chemical
      links between different and various structural forms of dinuclear vanadium(IV,V)
      citrate complexes in aqueous media. Furthermore, in corroboration of past
      studies, the examined interconversions lend credence to the notion that the
      involved species are active participants in the respective aqueous distributions
      of the metal ion in the presence of the physiological ligand citrate. The
      concomitant significance of structure-specific species relating to soluble and
      potentially bioavailable forms of vanadium is mentioned.

PMID- 12495340
TI  - Polytypism in columnar group 14 halide salts: structures of (Et2NH2)3Pb3X9 x nH2O
      (X = Cl, Br) and (beta-alaninium)2SnI4.
AB  - The crystal structures of three hybrid organoammonium metal halide salts composed
      of edge-sharing MX(6) octahedra have been determined. The genesis of these
      structures can be traced to the parent hexagonal MX(2) structure via dimensional
      reduction and recombination arguments. The structures of (Et(2)NH(2))(3)Pb(3)X(9)
      x nH(2)O (X = Br, I) contain unique columnar (Pb(3)X(9))(n)(3)(n)(-) structures,
      built up of edge-shared PbX(6) octahedra. The interaction of the Et(2)NH(2)(+)
      cations with the parent PbX(2) structures leads to a rearrangement of the lattice
      into the observed columnar structure. Groups of six Et(2)NH(2)(+) cations are
      hydrogen bonded to these columns, girdling them at their narrowest points. These
      hydrogen bonds contribute to the formation of the zigzag nature of the columnar
      inorganic framework. The resultant structures are recombinate analogues
      (polytypes) of the (Pb(3)X(9))(n)(3)(n)(-) stacks that would be obtained by the
      dimensional reduction process of the parent layer PbX(2) structure into simple
      edge-shared ribbons of PbX(6) octahedra. These structures can be described in
      terms of the stacking of planar bibridged Pb(3)X(8)(2-) units decorated with a
      single halide ion at a terminal lead ion site. In a similar fashion, (beta
      alaH)(2)Sn(2)I(6) contains corrugated (Sn(2)I(6))(n)(2)(n)(-) columns (beta-ala =
      beta-alanine), with the cations sitting in the clefts of the columns.

PMID- 12495341
TI  - Use of electrospray mass spectrometry (ESI-MS) for the study of europium(III)
      complexation with bis(dialkyltriazinyl)pyridines and its implications in the
      design of new extracting agents.
AB  - ESI mass spectrometry was used to investigate the europium complexation by
      tridentate ligands L identical with 2,6-bis(5,6-dialkyl-1,2,4-triazin-3-yl)
      pyridines (DATP) that have shown unique separation properties of actinides(III)
      from lanthanides(III) in nitric acid solutions. Complexes of three ligands,
      namely methyl (DMTP), n-propyl (DnPTP), and iso-propyl (DiPTP), have been
      investigated in acidic solutions to check the aqueous-phase stability of
      Eu(L)(3)(3+) ions identified previously in the solid state. The data obtained
      show, first, the presence of stable Eu(L)(3)(3+) ions with DnPTP (log
      beta(3)(app) = 12.0 +/- 0.5) and DiPTP (log beta(3)(app) = 14.0 +/- 0.6) in
      methanol/water (1:1 v/v) solutions under pH range 2.8-4.6 and, second, a
      mechanism whereby alkyl moieties contribute to a self-assembling process leading
      to the formation of Eu(L)(3)(3+) ions. Other complexes such as Eu(L)(2)(3+) ions
      are only observed for DnPTP (log beta(2)(app) = 6.7 +/- 0.5) and DMTP (log
      beta(2)(app) = 6.3 +/- 0.1) and Eu(L)(3+) only for DMTP (log beta(1)(app) = 2.9
      +/- 0.2). The log beta(n)(app) values for the Eu(L)(n)(3+) (n = 1-3) complexes
      were determined at pH 2.8. Better insight was given in this study concerning the
      role of the hydrophobic exterior of the ligands for the design of a new range of
      extracting agents.

PMID- 12495342
TI  - Kinetics and mechanism of chromate reduction with hydrogen peroxide in base.
AB  - [Cr(VI)O(4)](2)(-) is reduced to [Cr(V)(O(2))(4)](3)(-) by hydrogen peroxide in
      strongly basic media where the acid dissociation of H(2)O(2) (pK(a) = 11.65) is
      appreciable. The reaction is first order in chromium(VI) and inhibited by
      hydroxide. The hydrogen peroxide dependence is defined by the form of the
      effective pseudo-first-order rate constant: k(eff) = [H(2)O(2)](3)/(K(1) +
      K(2)[H(2)O(2)] + K(3)[HO(2)(-)]) with K(1) = 175(43) s x M(3), K(2) = 403(18) s x
      M(2), and K(3) = 1422(34) s x M(2). Hydrogen peroxide anion initially attacks
      chromate, and subsequent equilibrium steps that exchange oxo groups for three
      peroxo groups precede a rate-determining, one-electron, intramolecular reduction
      step.

PMID- 12495343
TI  - Gas phase structure of O-nitrobis(trifluoromethyl)hydroxylamine, (CF3)2NONO2: an
      extremely long O-N bond.
AB  - The gas phase structure of O-nitrobis(trifluoromethyl)hydroxylamine,
      (CF(3))(2)NONO(2), has been determined with gas electron diffraction and quantum
      chemical calculations (HF, MP2, and B3LYP with 6-31G basis sets). The
      calculations predict a structure with C(s) overall symmetry, a planar NONO(2)
      skeleton, and the NO(2) group oriented anti with respect to the CNC plane. The
      electron diffraction intensities are reproduced very well with such a model. The
      molecule possesses pyramidal configuration at the amino nitrogen atom, and the
      following geometric parameters (r(a) values with 3sigma uncertainties) were
      obtained for the NONO(2) skeleton: N-O = 1.392(18) A, O-N = 1.597(16) A,
      (N=O)(mean) = 1.192(4) A, N-O-N = 106.9(25) degrees, O=N=O = 138.4(24) degrees.
      The extremely long O-N distance is rationalized by very weak bonding between the
      two stable radicals (CF(3))(2)NO and NO(2). Whereas the ab initio methods HF (O-N
      = 1.395 A) and MP2 (O-N = 1.664 A) fail to reproduce this bond length correctly,
      the hybrid method B3LYP (O-N = 1.584 A) results in good agreement.

PMID- 12495344
TI  - Interplay of terminal amino group and coordinating side chains in directing
      regioselective cleavage of natural peptides and proteins with palladium(II)
      complexes.
AB  - Palladium(II) ions anchored to side chains of histidine and methionine residues
      in peptides and proteins in weakly acidic aqueous solutions promote hydrolytic
      cleavage of proximate amide bonds in the backbone. In this study, we determine
      how attachment of Pd(II) ions to histidine and methionine anchors and also to the
      terminal amino group in six natural peptides (chains A and B of insulin, segment
      11-14 of angiotensinogen, pentagastrin, angiotensin II, and segment 3-8 of
      angiotensin II) and two proteins (ubiquitin and cytochrome c) affects
      regioselectivity and rate of backbone cleavage. These Pd(II)-promoted reactions
      follow a clear pattern of regioselectivity, directed by the anchoring side
      chains. When the Pd(II) reagent is nonspecifically anchored to the terminal amino
      group, the ligating site that is present in almost all proteins, the cleavage is
      fortunately absent. When the reagent is anchored to a residue in positions 1, 2,
      or 3, cleavage is absent, because the terminal amino group and deprotonated amide
      nitrogen atom(s) interposed between it and the anchor "lock" the Pd(II) ion in
      hydrolytically inactive chelate complexes. When the reagent is anchored to
      residues in positions beyond 3, the second amide bond upstream from the anchor is
      regioselectively cleaved in all cases when the anchor was "isolated," that is,
      flanked by noncoordinating side chains. Segment 3-8 of angiotensin II undergoes
      additional cleavage, which we explain by determining the rate constants for the
      cleavage, identifying the rate-limiting displacement of ethylenediamine ligand
      from the Pd(II) ion, and detecting several intermediates. Experiments with
      cytochrome c demonstrate that the number of cleavage sites can be controlled by
      adjusting the mole ratio of the Pd(II) reagent to the substrate. Our inorganic
      peptidases are useful for biochemical applications because their regioselectivity
      and reactivity set them apart from proteolytic enzymes and organic chemical
      reagents.

PMID- 12495345
TI  - Structure and dynamics of ND3BF3 in the solid and gas phases: a combined NMR,
      neutron diffraction, and Ab initio study.
AB  - The decrease in D-->A bond lengths, previously reported for some Lewis acid/base
      complexes, in going from the gas to the solid phases is investigated by obtaining
      an accurate crystal structure of solid ND(3)BF(3) by powder neutron diffraction.
      The B-N internuclear distance is 1.554(3) A, 0.118 A shorter than the most recent
      gas-phase microwave value and 0.121 A shorter than the single molecule geometry
      optimized (1.672 A, CISD/6-311++G(d,p)) bond length. The crystal structure also
      shows N-D.F-B hydrogen bonds. The effects of this change in structure and of
      intermolecular hydrogen-bonding on nuclear magnetic shielding (i.e., chemical
      shifts) and the nuclear quadrupolar coupling constants (QCC) are investigated by
      ab initio molecular orbital and density functional theory calculations. These
      calculations show that the nitrogen ((15)N and (14)N) and boron ((11)B and (10)B)
      chemical shifts should be rather insensitive to changes in r(BN) and that the
      concomitant changes in molecular structure. Calculations on hydrogen-bonded
      clusters, based on the crystal structure, indicate that H-bonding should also
      have very little effect on the chemical shifts. On the other hand, the (11)B and
      (14)N QCCs show large changes because of both effects. An analysis of the
      (10)B[(19)F] line shape in solid ND(3)(10)BF(3) yields a (11)B QCC of +/-0.130
      MHz. This is reasonably close an earlier value of +/-0.080 MHz and the value of
      +/-0.050 MHz calculated for a [NH(3)BF(3)](4) cluster. The gas-phase value is
      1.20 MHz. Temperature-dependent deuterium T(1) measurements yield an activation
      energy for rotation of the ND(3) group in solid ND(3)BF(3) of 9.5 +/- 0.1 kJ/mol.
      Simulations of the temperature-dependent T(1) anisotropy gave an E(a) of 9.5 +/-
      0.2 kJ/mol and a preexponential factor, A, of 3.0 +/- 0.1 x 10(12) s(-)(1). Our
      calculated value for a [NH(3)BF(3)](4) cluster is 16.4 kJ/mol. Both are much
      higher than the previous value of 3.9 kJ/mol, from solid-state proton T(1)
      measurements.

PMID- 12495346
TI  - Cage compounds of heterotrimetallic mixed phosphanediide/silanolate aggregates
      with an alkaline Earth metal-centered phosphorus octahedron.
AB  - The lithiation of potassium triisopropylsilylphosphanide yields the corresponding
      phosphanediide. The subsequent metathesis reaction with SrI(2) and BaI(2) in the
      presence of hexamethyldisiloxane gives hexalithium hexapotassium strontium
      hexakis(triisopropylsilylphosphanediide)bis(trimethylsilanolate) (1) and the
      corresponding barium derivative (2), respectively. The alkaline earth metal atoms
      are surrounded octahedrally by the phosphanediide ligands. Six P(3) faces of the
      octahedron are capped by the K atoms, and the P-P edges of two opposite P(3)
      faces are bridged by the lithium atoms. The Li cations are also bonded to the
      Me(3)SiO substituents giving a coordination number of three for the alkali
      metals.

PMID- 12495347
TI  - Stereoselectivity of the secondary isotope effect in the aquation of
      [Co(NH3)5Cl]2+.
AB  - A careful kinetic study of the acid hydrolysis of [Co(NH(3))(5)Cl](2+) and the
      selectively deuterated species trans-[Co(NH(3))(4)(ND(3))Cl](2+), trans
      [Co(ND(3))(4)(NH(3))Cl](2+), and [Co(ND(3))(5)Cl](2+) reveals that N-deuteration
      reduces the hydrolysis rate at both the cis and trans sites. On a per-D basis,
      the rate reduction is three times more effective for trans-Cl deuteration. This
      result is contrary to conventional wisdom but has never been tested previously.
      It appears to be the first example of significant stereoselectivity for the
      secondary isotope effect in a substitution reaction, in either inorganic or
      organic systems. An explanation is offered in terms of the effect of D
      substitution on zero point energies, the different extents of coupling of NH(D)
      and Co-Cl vibrational modes according to their stereochemical relationship, and
      the view that the rate of acid hydrolysis of the [Co(NH(3))(5)Cl](2+) involves an
      aberrant Co-Cl vibration component.

PMID- 12495348
TI  - Determination of antiferromagnetic exchange coupling in the tetrahedral thiolate
      bridged diferrous complex [Fe2(SEt)6]2-.
AB  - Protein-bound iron-sulfur clusters and their synthetic analogues are
      characterized by tetrahedral metal sites, multiple oxidation levels, and exchange
      coupling. The recent attainment of several all-ferrous protein clusters and the
      presence of sulfide- and thiolate-bridged sites in the all-ferrous state of the
      nitrogenase P-cluster provides an imperative for determination of exchange
      coupling between tetrahedral Fe(II) sites with sulfur bridges. The cluster in the
      previously reported compound (Et(4)N)(2)[Fe(2)(SEt)(6)] is centrosymmetric with
      distorted tetrahedral coordination and a planar Fe(2)(mu-SEt)(2) bridge unit. The
      compound is diamagnetic at 4.2 K, indicating antiferromagnetic coupling. The
      lower limit J > 80 cm(-)(1) (H = JS(1).S(2)) is obtained by Mossbauer
      spectroscopy. Analysis of magnetic susceptibility data affords J = 165 +/- 15 cm(
      )(1). It is noteworthy that the J value of the diferrous pair obtained here is
      comparable to the J values reported for the mixed-valence state of plant-type
      Fe(2)S(2) ferredoxins. The near temperature independence of the quadrupole
      splitting (DeltaE(Q) = 3.25 mm/s at 4.2 K and 3.20 mm/s at 180 K) indicates that
      no excited orbital states are appreciably populated at temperatures less than 300
      K. The paramagnetism arises solely from thermal population of the S = 1 state of
      the spin ladder. This work provides the only measure of antiferromagnetic
      coupling by Fe(II) pairs in a tetrahedral sulfur environment.

PMID- 12495349
TI  - New oxovanadium bis(1,2-dithiolate) compounds that mimic the hydrogen-bonding
      interactions at the active sites of mononuclear molybdenum enzymes.
AB  - Reaction of VO(acac)(2) with 1,2-dithiols in the presence of triethylamine gives
      pentacoordinate oxovanadium complexes [HNEt(3)](2)[VO(bdt)(2)] (1),
      [HNEt(3)](2)[VO(tdt)(2)] (2), and [HNEt(3)](2)[VO(bdtCl(2))(2)] (3) (where
      H(2)bdt = 1,2-benzenedithiol, H(2)tdt = 3,4-toluenedithiol, and H(2)bdtCl(2) =
      3,6-dichloro-1,2-benzenedithiol). Compounds 1-3 have been characterized by IR,
      UV/visible, EPR, and mass spectroscopies. The X-ray crystal stuctures of 1 and 2
      show hydrogen-bonding interactions between the terminal oxo atom and
      triethylammonium counterions and between ligand sulfur atoms and the counterions.
      These interactions are comparable with those found at the active sites of
      mononuclear molybdenum enzymes.

PMID- 12495350
TI  - New quaternary bismuth sulfides: syntheses, structures, and band structures of
      AMBiS4 (A = Rb, Cs; M = Si, Ge).
AB  - Four new compounds, RbSiBiS(4), RbGeBiS(4), CsSiBiS(4), and CsGeBiS(4), have been
      synthesized by means of the reactive flux method. The isostructural compounds
      RbSiBiS(4), RbGeBiS(4), and CsGeBiS(4) crystallize in space group P2(1)/c of the
      monoclinic system with four formula units in cells of dimensions at 153 K of a =
      6.4714(4) A, b = 6.7999(4) A, c = 17.9058(11) A, and beta = 108.856(1) degrees
      for RbSiBiS(4), a = 6.5864(4) A, b = 6.8559(4) A, c = 17.9810(12) A, and beta =
      109.075(1) degrees for RbGeBiS(4), and a = 6.5474(4) A, b = 6.9282(4) A, c =
      18.8875(11) A, and beta = 110.173(1) degrees for CsGeBiS(4). CsSiBiS(4)
      crystallizes in a different structure type in space group P2(1)/c of the
      monoclinic system with four formula units in a cell of dimensions at 153 K of a =
      9.3351(7) A, b = 6.9313(5) A, c = 12.8115(10) A, and beta = 109.096(1) degrees.
      The two structure types are closely related and consist of [MBiS(4)(-)] (M = Si,
      Ge) layers separated by bicapped trigonal-prismatically coordinated alkali-metal
      atoms. In each, the M atom is coordinated to a tetrahedron of four S atoms and
      the Bi atom is coordinated to seven S atoms comprising five close S atoms at the
      corners of a square pyramid with Bi near the center of the basal plane and the
      sixth and seventh S atoms further away to complete a distorted monocapped
      trigonal prism. The optical band gaps of 2.23 eV for RbGeBiS(4) and 2.28 eV for
      CsGeBiS(4) were deduced from their diffuse reflectance spectra. From a band
      structure calculation, the optical absorption for RbGeBiS(4) originates from the
      [GeBiS(4)(-)] layer. The Ge 4p orbitals, Bi 6p orbitals, and S 3p orbitals are
      highly hybridized.

PMID- 12495351
TI  - A new two-dimensional molybdenum(V) nickel phosphate built up of
      [H18(Mo16O32)Ni16(PO4)26(OH)6(H2O)8]18- wheels.
AB  - The new molybdenum(V) nickel phosphate
      Na(6)Ni(6)[(Mo(2)O(4))(8)Ni(16)(H(2)PO(4))(4)(HPO(4))(10)(PO(4))(12)(OH)(6)(H(2)O
      (8)].66H(2)O (1) was synthesized hydrothermally. The structure (orthorhombic,
      space group Cccm; a = 23.999(4), b = 36.595(6), c = 20.445(4) A) was solved from
      single-crystal data. The framework structure of 1 consists of anionic inorganic
      sheets formed by the linkages of large polyoxomolybdate rings via nickel(II)
      octahedra. Charge-compensating sodium atoms are interleaved between the sheets.
      Magnetic studies of compound 1 revealed that among the 22 nickel(II) centers, 10
      are interacting. The chi(M)T = f(T) curve can be fitted using the dinuclear
      expression appropriate to the HDVV isotropic exchange Hamiltonian H = 
      2JS(1).S(2), with S(1) = S(2) = 1 and J = -24.1 cm(-)(1), showing that nickel is
      antiferromagnetically coupled within Ni(2) pairs.

PMID- 12495352
TI  - Silyl, hydrido-silylene, or other bonding modes: some unusual structures of
      [(dhpe)Pt(SiHR2)]+ (dhpe = H2P-CH2-CH2-PH2; R = H, Me, SiH3, Cl, OMe, NMe2) and
      [(dhpe)Pt(SiR3)](+) (R = Me, Cl) from DFT calculations.
AB  - DFT (B3LYP) calculations have been carried out in order to quantitatively
      evaluate the energies and stereochemistry of the accessible structures of
      [(dhpe)Pt(SiHR(2))](+) (dhpe = H(2)P-CH(2)-CH(2)-PH(2); R = H, CH(3), SiH(3), Cl,
      OMe, SMe, NMe(2)) and of [(dhpe)Pt(SiR(3))](+) (R = CH(3), Cl). A number of
      different isomers have been located. The expected terminal silyl or hydrido
      silylene complexes are often not the most stable complexes. An isomer in which an
      H or an R group bridges a Pt=SiHR or Pt=SiR(2) bond is found to compete with the
      terminal silyl or hydrido-silylene isomers. In some cases, isomers derived from
      cleavage of a C-H bond and formation of a silene or disilene ligand are obtained.
      The structures of the platinum silyls differ from that of the equivalent alkyl
      complex, calculated for [(dhpe)Pt(CH(3))](+).

PMID- 12495353
TI  - Synthesis, structure, and reactivity of some sterically hindered
      (Silylamino)phosphines.
AB  - A series of new (silylamino)phosphines that contain sterically bulky silyl groups
      on nitrogen were prepared by deprotonation/substitution reactions of the hindered
      disilylamines t-BuR(2)Si(Me(3)Si)NH (1, R = Me; 2, R = Ph) and (Et(3)Si)(2)NH
      (3). Sequential treatment of the N-lithio derivatives of 1-3 with PCl(3) or
      PhPCl(2) and MeLi gave the corresponding (silylamino)phosphines t
      BuR(2)Si(Me(3)Si)NP(R')Me (5, R = Me, R' = Ph; 6, R = Ph, R' = Me) and
      (Et(3)Si)(2)NP(R)Me (11, R = Me; 12, R = Ph) in high yields. Two of the P-chloro
      intermediates t-BuR(2)Si(Me(3)Si)NP(Ph)Cl (7, R = Ph; 9, R = Me) were also
      isolated and fully characterized. Hydrolysis of 7 afforded the crystalline PH
      substituted aminophosphine oxide t-BuPh(2)SiN(H)P(Ph)(=O)H (10). Thermal
      decomposition of 7 occurred with elimination of Me(3)SiCl and formation of a
      novel P(2)N(2) four-membered ring system (36) that contains both P(III) and P(V)
      centers. Reactions of the N-lithio derivatives of amines 1 and 2 with phosphorus
      trihalides afforded the thermally stable -PF(2) derivatives t
      BuR(2)Si(Me(3)Si)NPF(2) (13, R = Me; 14, R = Ph) and the unstable -PCl(2)
      analogue 17 (R = Ph). Reduction (using LiAlH(4)) of the SiPh-substituted
      dihalophosphines 14 and 17 gave the unstable parent phosphine t
      BuPh(2)Si(Me(3)Si)NPH(2) (15). The P-organo-substituted (silylamino)phosphines
      underwent oxidative bromination to afford high yields of the corresponding N
      silyl-P-bromophosphoranimines t-BuR(2)SiN=P(R')(Me)Br (18, R = R' = Me; 19, R =
      Me, R' = Ph; 20, R = Ph, R' = Me) and Et(3)SiN=P(R)(Me)Br (23, R = Me; 24, R =
      Ph). Subsequent treatment of these reactive PBr compounds with lithium
      trifluoroethoxide or phenoxide produced the corresponding PO derivatives t
      BuR(2)SiN=P(R')(Me)OR' ' (25 and 26, R' ' = CH(2)CF(3); 28-30, R' ' = Ph) and
      Et(3)SiN=P(R)(Me)OR' (31 and 33, R' = CH(2)CF(3); 32 and 34, R = Ph),
      respectively. Many of the new compounds containing the bulky tert
      butyldiphenylsilyl group, t-BuPh(2)Si, were solids that gave crystals suitable
      for X-ray diffraction studies. Consequently, the crystal structures of three
      (silylamino)phosphines (6, 7, and 14), one (silylamino)phosphine oxide (10), one
      N-silylphosphoranimine (30), and the cyclic compound 36 were determined. Among
      the (silylamino)phosphines, the P-N bond distances [6, N-PMe(2), 1.725(3) A; 7, N
      P(Ph)Cl, 1.68(1) A, 14, N-PF(2), 1.652(4) A] decreased significantly as the
      electron-withdrawing nature of the phosphorus substituents increased. The N
      silylphosphoranimine t-BuPh(2)SiN=PMe(2)OPh (30), which is a model system for
      poly(phosphazene) precursors, had a much shorter P=N distance of 1.512(6) A and a
      wide Si-N-P bond angle of 166.4(3) degrees. A similar P=N bond distance [1.514(7)
      A] and Si-N-P angle [169.9(6) degrees ] were observed for the exocyclic P=N-Si
      linkage in the ring compound 36, while the phosphine oxide 10 had P-N and P=O
      distances of 1.637(4) and 1.496(3) A, respectively, and a Si-N-P angle of
      134.3(2) degrees.

PMID- 12495354
TI  - Metal-promoted aromatic ring amination and deamination reactions at a diazo
      ligand coordinated to rhodium and ruthenium.
AB  - Reactions of MCl(3).3H(2)O (M = Rh and Ru) with the ligand 2-[(2-N
      arylamino)phenylazo]pyridine [HL(1); NH(4)C(5)N=NC(6)H(4)N(H)C(6)H(4)(H)
      (HL(1a)), NH(4)C(5)N=NC(6)H(4)N(H)C(6)H(4)(CH(3)) (HL(1b)), and
      NH(4)C(5)N=NC(6)H(4)N(H)C(5)H(4)N (HL(1c))] in the presence of dilute NEt(3)
      afforded multiple products. In the case of rhodium, two green compounds, viz.
      [Rh(L(1))(2)](+) ([2](+)) and [RhCl(pap)(L(1))](+) ([3](+)), where L(1) and pap
      stand for the conjugate base of [HL(1)] and 2-(phenylazo)pyridine, respectively,
      were separated on a preparative thin layer chromatographic plate. The reaction of
      RuCl(3).3H(2)O, on the other hand, produced two brown compounds, viz.
      [RuCl(HL(1))(L(1))] (4) and [RuCl(pap)(L(1))] (5), respectively, as the major
      products. The X-ray structures of the representative complexes are reported.
      Except for complex 2, and 4, the products are formed due to the cleavage of an
      otherwise unreactive C(phenyl)-N(amino) bond. In complex 4, one of the tridentate
      ligands (HL(1)) does not use its maximum denticity and coordinates as a neutral
      bidentate donor. Plausible reasons for the differences in their modes of
      coordination of the ligands as in 2 and 4 have been discussed. The ligand pap in
      the cationic mixed ligand complex [3](+) reacts instantaneously with ArNH(2) to
      produce an ink-blue compound, [RhCl(HL(2))(L(1))](+) ([6](+)) in a high yield.
      The ligand HL(2) is formed due to regioselective fusion of ArNH(2) residue at the
      para carbon of the phenyl ring (with respect to the azo fragment) of pap in
      [3](+). The above complexes are generally intensely colored and show strong
      absorptions in the visible region, which are assigned to intraligand charge
      transfer transitions. These complexes undergo multiple and successive one
      electron-transfer processes at the cathodic potentials. Electrogenerated cationic
      complexes of ruthenium(III), [4](+) and [5](+), showed rhombic EPR spectra at 77
      K.

PMID- 12495355
TI  - Methyloxorhenium(V) complexes with two bidentate ligands: syntheses and
      reactivity studies.
AB  - Four new methyloxorhenium(V) complexes were synthesized: MeReO(PA)(2) (1),
      MeReO(HQ)(2) (2), MeReO(MQ)(2) (3), and MeReO(diphenylphosphinobenzoate)(2) (4)
      (in which PAH = 2-picolinic acid, HQH = 8-hydroxyquinoline, and MQH = 8
      mercaptoquinoline). Although only one geometric structure has been identified
      crystallographically for 1, 2, and 3, two isomers of 3 and 4 in solution were
      detected by NMR spectroscopy. These compounds catalyze the sulfoxidation of
      thioethers by pyridine N-oxides and sulfoxides. The rate law for the reaction
      between pyridine N-oxides and thioethers, catalyzed by 1, shows a first-order
      dependence on the concentrations of pyridine N-oxide and 1. The second-order rate
      constants of a series of para-substituted pyridine N-oxides fall in the range of
      0.27-7.5 L mol(-)(1) s(-)(1). Correlation of these rate constants by the Hammett
      LFER method gave a large negative reaction constant, rho = -5.2. The next and
      rapid step does not influence the kinetics, but it could be explored with
      competition experiments carried out with a pair of methyl aryl sulfides,
      MeSC(6)H(4)-p-Y. The value of each rate was expressed relative to the reference
      compound that has Y = H. A Hammett analysis of k(Y)/k(H) gave rho = -1.9. Oxygen
      18 labeled 1 was used in a single turnover experiment for 4-picoline N-oxide and
      dimethyl sulfide. No (18)O-labeled DMSO was found. We suggest that the reaction
      proceeds by way of two intermediates that were not observed during the reaction.
      The first intermediate contains an opened PA-chelate ring; this allows the
      pyridine N-oxide to access the primary coordination sphere of rhenium. The second
      intermediate is a cis-dioxorhenium(VII) species, which the thioether then
      attacks. Oxygen-18 experiments were used to show that the two oxygens of this
      intermediate are not equivalent; only the new oxygen is attacked by, and
      transferred to, SR(2). Water inhibits the reaction because it hydrolyzes the
      rhenium(VII) intermediate.

PMID- 12495356
TI  - Photoluminescence switching of azobenzene-conjugated Pt(II) terpyridine complexes
      by trans-cis photoisomerization.
AB  - Pt(II) complexes with a terpyridylazobenzene ligand (tpyAB) were newly
      synthesized, and their photoluminescence properties by trans-cis isomerization of
      the azo moiety were investigated. In these complexes, upon excitation with 366-nm
      light in polar solvents such as DMF, DMSO, and propylene carbonate, trans-to-cis
      isomerization with significant UV-vis spectral changes occurred almost
      completely. Cis-to-trans isomerization was observed both by irradiation with
      visible light and by heat. The reduction peaks due to the terpyridine and the azo
      group in the cyclic voltammograms of the Pt complexes were shifted in the
      positive direction by trans-to-cis isomerization. Emission spectral changes due
      to trans-cis isomerization were observed for both the tpyAB and the Pt complexes.
      The significant differences in the emission properties of the complex compared to
      tpyAB include the observation that both the excitation and emission wavelengths
      were shifted to lower energy, located in the visible region. Moreover, the change
      in emission intensity between the trans and cis forms was more significant upon
      excitation with UV light, because the trans form of the complexes showed
      absolutely no emission. Accordingly, the azobenzene-conjugated Pt(II) terpyridine
      complexes promise to be doubly photofunctional materials, showing complete off-on
      switching of emission linked to the trans-cis conformation change.

PMID- 12495357
TI  - Copper(II) coordination to ligands immobilized on photoluminescent porous
      silicon.
AB  - Increased preorganization can be achieved by immobilizing ligands on solid
      supports. Photoluminescent porous silicon, which can undergo facile
      hydrosilylation, was used as a support for open chain neutral N- and O-donor
      ligands. The abilities of these ligands to bind the divalent metal ions Ni(2+),
      Cu(2+), Zn(2+), and Pb(2+) are examined. Immobilized ligands selectively
      complexed Cu(II) over the other metal ions studied. Ligands immobilized on
      photoluminescent porous silicon also removed a significant amount, up to 98%, of
      Cu(II) from copper(II)-spiked, organic-rich, seawater samples.

PMID- 12495358
TI  - Thermally inert metal ammines as light-inducible DNA-targeted agents. Synthesis,
      photochemistry, and photobiology of a prototypical rhodium(III)-intercalator
      conjugate.
AB  - The recent discovery of the promising tumor cell kill by a novel platinum
      acridine conjugate [Martins, E. T.; et al. J. Med. Chem. 2001, 44, 4492] has
      prompted us to explore the utility of analogous light-activatable rhodium(III)
      compounds as photocytotoxic agents. Here, the design and synthesis of
      [Rh(NH(3))(5)L](n)(+) complexes are described with L = 1,1,3,3
      tetramethylthiourea (tmtu) or 1-[2-(acridin-9-ylamino)ethyl]-1,3,3
      trimethylthiourea (2). The intercalator-based DNA-affinic carrier ligand 2 was
      synthesized from N-acridin-9-yl-N'-methylethane-1,2-diamine and
      dimethylthiocarbamoyl chloride and isolated as the hydrotriflate salt
      2(CF(3)SO(3)). [Rh(NH(3))(5)(tmtu)](3+) (1) and [Rh(NH(3))(5)(2)](4+) (3) were
      obtained from the reactions of the trifluoromethanesulfonato complex
      [Rh(NH(3))(5)(OSO(2)CF(3))](CF(3)SO(3))(2) with the appropriate thiourea in
      noncoordinating solvents. All compounds were characterized by (1)H NMR and UV-vis
      spectroscopies and by elemental analyses. The single-crystal X-ray structures of
      1(CF(3)SO(3))(3) x 2MeOH, 2(CF(3)SO(3)), and 3(CF(3)SO(3))(4) x H(2)O have been
      determined. Ligand-field photolysis of thermally inert 1 (lambda(max) = 378 nm)
      resulted in the aquation of 2 equiv of ammine ligand without noticeable release
      of sulfur-bound tmtu ((1)H NMR spectroscopy, NH(3)-sensitive electrode
      measurements). This was confirmed by (15)N[(1)H] NMR spectroscopy using (15)N
      labeled [Rh((15)NH(3))(5)(tmtu)](3+) (1), which also indicated photoisomerization
      of the [RhN(5)S] moiety. Despite greatly accelerated ligand exchange, rhodium in
      1 and 3 did not show light-enhanced formation of covalent adducts in calf thymus
      DNA. "Dark binding" levels of 3 in native DNA were slightly higher than for
      nontargeted 1, but significantly lower than those observed for analogous platinum
      acridine. Agarose gel electrophoresis revealed photocleavage of supercoiled pUC19
      plasmid DNA in the presence of hybrid 3 and its individual constituents 1 and 2.
      Simple 1 induced single-strand breaks while 3 produced complete degradation of
      the DNA after 24 h of continuous irradiation. Acridine 2 alone produced double
      strand breaks. The extent of DNA damage observed for 1-3 correlates with the
      photocytotoxicity of the compounds in human leukemia cells, suggesting that DNA
      might be the cellular target of these agents.

PMID- 12495359
TI  - Patients' understanding of risk associated with medication use: impact of
      European Commission guidelines and other risk scales.
AB  - Patients want and need comprehensive and accurate information about their
      medicines so that they can participate in decisions about their healthcare. In
      particular, they require information about the likely risks and benefits that are
      associated with the different treatment options. However, to provide this
      information in a form that people can readily understand and use is a
      considerable challenge to healthcare professionals. One recent attempt to
      standardise the language of risk has been to produce sets of verbal descriptors
      that correspond to specific probability ranges, such as those outlined in the
      European Commission (EC) Pharmaceutical Committee guidelines in 1998 for
      describing the incidence of adverse effects. This paper provides an overview of a
      number of studies involving members of the general public, patients, and hospital
      doctors, that evaluated the utility of the EC guideline descriptors (very common,
      common, uncommon, rare, very rare). In all studies it was found that people
      significantly over-estimated the likelihood of adverse effects occurring, given
      specific verbal descriptors. This in turn resulted in significantly higher
      ratings of their perceived risks to health and significantly lower ratings of
      their likelihood of taking the medicine. Such problems of interpretation are not
      restricted to the EC guideline descriptors. Similar levels of misinterpretation
      have also been demonstrated with two other recently advocated risk scales
      (Calman's verbal descriptor scale and Barclay, Costigan and Davies' lottery
      scale). In conclusion, the challenge for risk communicators and for future
      research will be to produce a language of risk that is sufficiently flexible to
      take into account different perspectives, as well as changing circumstances and
      contexts of illness and its treatments. In the meantime, we urge the EC and other
      legislative bodies to stop recommending the use of specific verbal labels or
      phrases until there is a stronger evidence base to support their use.

PMID- 12495360
TI  - Cytochrome P450 drug interactions within the HMG-CoA reductase inhibitor class:
      are they clinically relevant?
AB  - The present review outlines the clinical relevance of pharmacokinetic drug
      interactions within the HMG-CoA reductase inhibitor class. These interactions can
      result in markedly increased or decreased plasma concentrations of some drugs
      within this class. However, the relationship between altered plasma
      concentrations and adverse effects or toxicity may not be linear. It is likely
      that other variables affect this concentration-effect relationship including:
      rapid changes in the concentration, concomitant lipid-lowering therapy or host
      genetic factors that code for different forms or amounts of metabolising enzymes
      and drug receptors. It is not currently possible to predict which patients will
      manifest clinically important drug-drug interactions, nor what concentration of
      an HMG-CoA reductase inhibitor will cause rhabdomyolysis. Thus, until prescribers
      have better scientific information from which to develop a 'therapeutic range'
      for each agent, caution should be exercised. In particular, patients taking a
      CYP3A4-metabolised agent, e.g. atorvastatin, simvastatin and lovastatin, should
      not be started on a CYP3A4 inhibitor or inducer without close monitoring.

PMID- 12495361
TI  - Benefit-risk assessment of infliximab in the treatment of rheumatoid arthritis.
AB  - In the last decade, there have been substantial advances in the treatment of
      rheumatoid arthritis with the addition of several new disease-modifying agents to
      the therapeutic armamentarium. Biological agents targeting tumour necrosis factor
      (TNF) represent one such important addition. Infliximab, a chimeric anti-TNF
      monoclonal antibody, has shown remarkable promise in alleviating the signs and
      symptoms of rheumatoid arthritis in addition to retarding radiographic disease
      progression when used in combination with methotrexate. In its pivotal phase III
      trial, the addition of infliximab to patients with methotrexate-refractory
      disease was associated with substantial clinical benefit. Using American College
      of Rheumatology criteria for improvement, one-half of patients receiving
      infliximab (3 mg/kg every 8 weeks) plus methotrexate showed at least 20%
      improvement compared with only 20% of those receiving placebo plus methotrexate
      (p < 0.001) with over one-half of eventual responders obtaining criteria for
      improvement by the second week of observation. Although its use has been met with
      much deserved enthusiasm, recent reports have highlighted several potential
      serious adverse effects associated with infliximab (and other TNF antagonists),
      including infusion reactions, congestive heart failure, drug-induced lupus, and
      CNS demyelination. In addition, recent reports have cited the potential for
      reactivation of mycobacterial and fungal infection in patients receiving
      infliximab, mandating appropriate tuberculosis screening prior to drug
      initiation. Although the frequency of serious drug-related toxicity (requiring
      discontinuation of the agent) appears to be quite low, these reports underscore
      the need for caution and close surveillance with the administration of TNF
      inhibitors, particularly given that strategies aimed at preventing toxicity
      remain unproven. Despite its potential for toxicity, infliximab remains a
      valuable alternative for patients with rheumatoid arthritis.

PMID- 12495363
TI  - Adverse events associated with rofecoxib therapy: results of a large study in
      community-derived osteoarthritic patients.
AB  - OBJECTIVE: To evaluate the safety profile of rofecoxib, a selective cyclo
      oxygenase-2 inhibitor, in patients with osteoarthritis who are receiving care in
      non-hospital practice settings. DESIGN: All patients participating in a large 24
      week, open-label, nonpharmacological intervention trial were given rofecoxib for
      painful osteoarthritis of the knee or hip. They started at a dose of 12.5mg once
      daily for the first month, with the option of increasing to 25mg daily
      thereafter, if needed for efficacy. Adverse events were closely monitored. We
      considered all adverse events that occurred during treatment and within 14 days
      of discontinuation of rofecoxib. PATIENT GROUP STUDIED: 2896 patients (861 males
      and 2035 females) were involved in the safety analysis. Their mean (SD) age was
      66.8 (9.9) years, and 631 patients (21.8%) were aged >/=75 years. There were 913
      patients (31.5%) with hypertension and 151 (5.2%) with diabetes mellitus at the
      start of the study; 78 patients (2.7%) had a prior medical history of angina
      and/or myocardial infarction. The mean (SD) duration of rofecoxib treatment was
      139 (62) days. RESULTS: A total of 519 patients (17.9%) discontinued rofecoxib.
      The main reasons for discontinuation were dyspepsia (4.4%), nausea (2.4%) and
      dizziness (2.1%). The annualised incidence rates (95% CI) of complicated and
      uncomplicated upper gastrointestinal ulcers, myocardial infarction, and stroke
      were 1.36 (0.76-2.23), 0.09 (0-0.50) and 0.45 (0.16-1.05), respectively.
      CONCLUSION: This study conducted in conditions close to daily practice confirms
      that the use of rofecoxib is associated with a low rate of serious adverse events
      in patients with osteoarthritis.

PMID- 12495362
TI  - Aristolochic acid and 'Chinese herbs nephropathy': a review of the evidence to
      date.
AB  - Chinese herbs nephropathy (CHN) is a rapidly progressive interstitial nephropathy
      reported after the introduction of Chinese herbs in a slimming regimen followed
      by young Belgian women. It is characterised by early, severe anaemia, mild
      tubular proteinuria and initially normal arterial blood pressure in half of the
      patients. Renal histology shows unusual extensive, virtually hypocellular
      cortical interstitial fibrosis associated with tubular atrophy and global
      sclerosis of glomeruli decreasing from the outer to the inner cortex. Urothelial
      malignancy of the upper urinary tract develops subsequently in almost half of the
      patients. Suspicion that the disease was due to the recent introduction of
      Chinese herbs in the slimming regimen was reinforced by identification in the
      slimming pills of the nephrotoxic and carcinogenic aristolochic acid (AA)
      extracted from species of Aristolochia. This hypothesis was substantiated by the
      identification of premutagenic AA-DNA adducts in the kidney and ureteric tissues
      of CHN patients. Finally, induction of the clinical features (interstitial
      fibrosis and upper urothelial malignancy) typical of CHN in rodents given AA
      alone removed any doubt on the causal role of this phytotoxin in CHN, now better
      called aristolochic acid nephropathy (AAN). AAN is not restricted to the Belgian
      cases. Similar cases have been observed throughout the world, but AA is sometimes
      incriminated on the basis of the known content of AA in the herbs. The
      possibility remains that in some individuals in whom AA has not been
      demonstrated, other phytotoxins might be implicated. Biological and morphological
      features of AAN are strikingly similar to those reported in another fibrosing
      interstitial nephropathy of still unknown aetiology, Balkan endemic nephropathy
      (BEN). Interestingly, AA was incriminated as the cause of BEN many years ago, a
      hypothesis yet to be fully explored. The intake of AA and the presence of
      tissular AA-DNA adducts in patients with an unequivocal diagnosis of BEN remains
      to be demonstrated. The tragic phenomenon of CHN, recognised only 10 years ago,
      has been at the root of significant research and progress both in nephrology and
      oncology. It has provided a fascinating opportunity to understand the link
      between a fibrosing interstitial nephropathy and urothelial carcinoma. It allows
      the categorisation of interstitial nephritis on the basis of histological
      findings, of initiating toxic substances and of associated clinical features.
      Finally, it has led to the withdrawal in several countries of a previously
      unsuspected carcinogenic and nephrotoxic substance.

PMID- 12495364
TI  - Benefits and risks of pharmacotherapy for dysthymia: a systematic appraisal of
      the evidence.
AB  - BACKGROUND: Dysthymia is a prevalent form of subthreshold depressive disorder,
      associated with considerable disability and high co-morbidity. This paper
      systematically appraises the evidence for the efficacy and acceptability of the
      pharmacological treatment for this condition. METHODS: Randomised, controlled
      trials evaluating the efficacy of drug therapies for dysthymia were included. A
      comprehensive search of the literature was performed, aiming to avoid publication
      bias. Pooled relative risks (RR) and 95% CIs were calculated with the Random
      Effect Model method. The number needed to treat (NNT) and number needed to harm
      (NNH) were estimated for statistically significant results. RESULTS: Twenty-five
      trials were included for the main comparisons. Regarding placebo-controlled
      trials (n = 16), similar results were obtained in terms of efficacy for different
      groups of drugs, such as tricyclic antidepressants (TCAs), selective serotonin
      reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other drugs
      (sulpiride, amineptine, and ritanserin). The pooled RR for treatment response was
      0.68 (95% CI 0.57-0.81) for TCA and the NNT was 4.3 (95% CI 3.2-6.5); 0.68 (95%
      CI 0.56-0.82) for SSRIs (NNT 5.1; 95% CI 3.9-7.7); 0.59 (95% CI 0.48-0.71) for
      MAOIs (NNT 2.9; 95% CI 2.2-4.3). Other drugs (amisulpride, amineptine and
      ritanserin) showed similar results. The equivalent efficacy between
      antidepressants as found in trials where active medications were compared
      confirmed the efficacy findings from placebo trials. In general, patients treated
      with a TCA were more likely to report adverse events, compared with placebo and
      SSRIs. CONCLUSIONS: Pharmacotherapy for dysthymia appears to be an effective
      short-term treatment for dysthymic disorder. Newer antidepressants are equally
      effective and have better acceptability than TCAs, although their higher cost
      must be balanced against this assumed advantage.

PMID- 12495365
TI  - Defining the role of the caregiver in Alzheimer's disease treatment.
AB  - The day-to-day responsibility of caring for a person with dementia often exacts a
      toll upon the caregiver, which may be manifested psychologically, physically,
      socially and financially. The last decade has witnessed the advent of drug
      availability for the treatment of Alzheimer's disease, specifically the
      cholinesterase inhibitors. Caregivers are integral to the initiation,
      administration and monitoring of treatment. In particular, they provide
      substitute informed consent when patients are no longer competent to do so. While
      there is evidence that cholinesterase inhibitors may reduce caregiver burden and
      time spent assisting patients, there are also burdens associated with being the
      person responsible for administering medication. Caregivers are key to research
      into the use of medications for Alzheimer's disease. They have roles in
      recruitment and consent and monitoring response and adverse effects.
      Increasingly, caregivers themselves are recognised as legitimate targets for
      evaluating the efficacy of new pharmacological agents for Alzheimer's disease (as
      benefits have been demonstrated for them). Caregivers have responsibilities
      regarding the drug treatment of patients with Alzheimer's disease, and require
      information about the medications so that they can have realistic expectations.
      Doctors need to work in partnership with caregivers and patients when prescribing
      drugs for Alzheimer's disease.

PMID- 12495366
TI  - Background to and management of treatment-related bone loss in prostate cancer.
AB  - Prostate cancer is a common disease among older men. Androgen suppression by
      either orchiectomy or administration of luteinising hormone-releasing hormone
      (LHRH) analogues is the mainstay of treatment. Since the use of prostate-specific
      antigen (PSA) serum testing has become widespread, however, the timing of
      endocrine therapy has expanded considerably to include patients with limited
      involvement of extraprostatic sites and patients presenting an isolated elevation
      of PSA after radical treatments. These patients are expected to be treated for a
      long time, since they have a rather low risk of disease progression and there is
      no recommended time limit for LHRH analogue therapy. The long-term adverse
      effects of androgen deprivation therapy, therefore, deserve more attention than
      they have received in the past. Osteoporosis represents a special concern for men
      with prostate cancer receiving androgen deprivation therapy. The rate of bone
      loss in these men seems to markedly exceed that associated with menopause in
      women, and fractures occur more frequently than in the healthy elderly male
      population. Serial bone mineral density (BMD) evaluation could allow the
      detection of patients with prostate cancer who are at greater risk of
      osteoporosis and adverse skeletal events after androgen deprivation therapy, such
      as patients already osteopenic or osteoporotic at baseline and men with rapid
      bone loss during treatment. BMD evaluated during treatment could also be a
      potential surrogate parameter of antiosteoporotic therapeutic efficacy. Treatment
      of bone loss induced by androgen deprivation comprises general prevention
      measures, antiosteoporotic drugs and the use of alternative endocrine therapies.
      Optimising lifestyle and diet is important, although it cannot completely prevent
      bone loss. Patients with nonsevere bone disease may benefit from calcium and
      vitamin D supplements. Men who are osteoporotic before androgen deprivation or
      men becoming osteoporotic during treatment and/or experiencing adverse skeletal
      events may also require bisphosphonates. The effectiveness of these drugs in
      preventing fractures has been shown in a single randomised study involving
      patients with osteoporosis, but it has not yet been established in a prostatic
      cancer population without bone metastases given androgen deprivation therapy.
      Different forms of endocrine therapy such as low-dose estrogens, antiandrogens
      and intermittent androgen ablation are under investigation. They could offer the
      advantage of avoiding (or limiting) treatment-related bone loss. In our opinion,
      however, the data available so far are not robust enough to recommend these
      alternative endocrine therapies instead of standard androgen deprivation in
      routine clinical practice.

PMID- 12495369
TI  - Continuous low dose of melphalan and prednisone in patients with multiple myeloma
      of very old age or severe associated disease.
AB  - INTRODUCTION AND OBJECTIVE: The management of elderly patients with multiple
      myeloma is a relevant problem because it concerns a great number of patients.
      Patients with multiple myeloma who are very old or who have severe associated
      diseases have a dismal outcome. For these patients we retrospectively evaluated
      the effect of a mild approach with continuous low-dose melphalan and prednisone
      (cMP). DESIGN AND METHODS: 109 patients with multiple myeloma, observed between
      1985 and 2000, were treated with cMP; 67 were treated at time of diagnosis (group
      A; median age 78 years) and 42 as a second or subsequent line of therapy (group
      B; median age 72 years). The toxicity of the treatment was compared with a
      control group of 29 patients aged over 70 years, treated in the same institution
      with the conventional cyclical melphalan/prednisone regimen. RESULTS: Major or
      minor responses were obtained in 32% of patients in group A and 13% of patients
      in group B. Disease was stabilised in 45% of group A and 47% of group B and
      progressed in 5 and 18%, respectively. Median survival was, respectively, 19 and
      24 months in group A and B. Among the 42 patients who received cMP as a second
      line therapy (group B), 36 (86%) had previously been treated according to the
      standard cyclical melphalan/prednisone schedule; of these 12 (33%) obtained a
      better M protein reduction after cMP compared with the previous response to first
      line cyclical melphalan/prednisone. The cMP schedule was generally well
      tolerated, and the rate of haematological toxicity was lower than for a
      historical control group receiving cyclical melphalan/prednisone. CONCLUSION: The
      cMP treatment schedule is well tolerated and results in a high proportion of
      patients with stable disease, with acceptable survival even in patients with
      advanced disease.

PMID- 12495370
TI  - Several apparent errors surfaced on reading the article in the June 2002 issue of
      Alternative Medicine Review by Kodama et al. entitled "Can maitake MD-fraction
      aid cancer patients"?

PMID- 12495367
TI  - Treatment of acid-related diseases in the elderly with emphasis on the use of
      proton pump inhibitors.
AB  - Proton pump inhibitors (PPIs) have revolutionised the treatment of acid-related
      disorders, and they have also made it possible to define the spectrum of acid
      inhibition required for optimal treatment in each disorder. Five PPIs are now
      available: the older drugs, omeprazole, lansoprazole and pantoprazole, and the
      two newest, rabeprazole and esomeprazole. These agents have predominantly been
      developed in the younger adult population, and data for the elderly population
      are limited. Subtle differences have emerged between the old and the new PPIs in
      their pharmacokinetic, pharmacodynamic and efficacy profiles. The degree of
      clinical relevance of these differences in the adult population is in question.
      However, according to this review, based on the available data for the elderly
      and by inference from the adult population, the differences are highly relevant
      in the elderly population. Studies of the pharmacokinetics of older PPIs
      demonstrated considerable variation in drug clearance that was reflected in a
      wide range of efficacy related to acid suppression with standard dosages. The
      newer PPIs offer several advantages over older agents, particularly in terms of
      rapid, profound and consistent acid inhibition. Consistent acid inhibition is
      particularly important in the elderly since clinical response is often difficult
      to judge in this patient group. An individual's cytochrome P450 (CYP) 2C19
      genotype predicts the degree of acid suppression and consequently the clinical
      efficacy of the PPIs. The older PPIs are predominantly metabolised by CYP2C19,
      with this being of more importance for omeprazole and lansoprazole than
      pantoprazole. The hepatic metabolism of rabeprazole is predominantly by
      nonenzymatic reactions and minimally by CYP-mediated reactions, which therefore
      confers an advantage over older PPIs in that genetic polymorphisms for CYP2C19 do
      not significantly influence rabeprazole clearance, clinical efficacy or potential
      for drug interactions. The metabolism of esomeprazole involves CYP2C19 but to a
      lesser extent than its predecessor omeprazole. Furthermore, esomeprazole has a
      more rapid onset of action and less variation in clearance rates than omeprazole.
      Drug clearance decreases with age independently of CYP2C19 status, exaggerating
      some of the differences between the PPIs and increasing the risk of drug
      interactions.

PMID- 12495372
TI  - Mercury toxicity and antioxidants: Part 1: role of glutathione and alpha-lipoic
      acid in the treatment of mercury toxicity.
AB  - Mercury exposure is the second-most common cause of toxic metal poisoning. Public
      health concern over mercury exposure, due to contamination of fish with
      methylmercury and the elemental mercury content of dental amalgams, has long been
      a topic of political and medical debate. Although the toxicology of mercury is
      complex, there is evidence for antioxidant protection in the prevention of
      neurological and renal damage caused by mercury toxicity. Alpha-lipoic acid, a
      coenzyme of pyruvate and alpha-ketoglutarate dehydrogenase, has been used in
      Germany as an antioxidant and approved treatment for diabetic polyneuropathy for
      40 years. Research has attempted to identify the role of antioxidants,
      glutathione and alpha-lipoic acid specifically, in both mitigation of heavy metal
      toxicity and direct chelation of heavy metals. This review of the literature will
      assess the role of glutathione and alpha-lipoic acid in the treatment of mercury
      toxicity.

PMID- 12495368
TI  - Management strategies for the treatment of neuropathic pain in the elderly.
AB  - Pain caused by dysfunction or damage to the peripheral or central nervous system
      is typified by the symptoms described by patients with painful diabetic
      neuropathy, post-herpetic neuralgia and central poststroke pain. All these
      conditions are more common in the elderly. Neuropathic pain has long been
      recognised as one of the more difficult types of pain to treat; however, with the
      current emphasis on providing a multidisciplinary assessment and approach to
      management, more patients will be offered relief of their symptoms and an
      improved quality of life. Despite the use of combination drug therapy, adequate
      pain relief in the elderly is difficult to achieve without adverse effects. In an
      attempt to minimise these it is important to include non-drug treatment options
      in the management plan. Lifestyle changes and environmental modification,
      together with encouragement to adopt an appropriate exercise programme and an
      emphasis on maintaining mobility and independence should always be considered.
      Interventional therapy ranging from simple nerve blocks to intrathecal drug
      delivery can be of value. Drug treatment remains the mainstay of therapy.
      Tricyclic antidepressants such as amitriptyline, while having significant adverse
      effects in the elderly, have a number needed to treat (NNT) of 3.5 for 50% pain
      relief in diabetic neuropathy and 2.1 for 50% pain relief in postherpetic
      neuralgia. The newer antiepileptic drugs, such as gabapentin, appear to have a
      better adverse effect profile and provide similar efficacy with the NNT for
      treating painful diabetic neuropathy being 3.7 and 3.2 for treating pain in
      postherpetic neuralgia. As our understanding of the complexities of the pain
      processes increases, we are becoming more able to appropriately combine
      treatments to achieve not only improved pain relief but also improved function.

PMID- 12495373
TI  - Autism, an extreme challenge to integrative medicine. Part 2: medical management.
AB  - Autism and allied autistic spectrum disorders (ASD) present myriad behavioral,
      clinical, and biochemical abnormalities. Parental participation, advanced testing
      protocols, and eclectic treatment strategies have driven progress toward cure.
      Behavioral modification and structured education are beneficial but insufficient.
      Dietary restrictions, including removal of milk and other casein dairy products,
      wheat and other gluten sources, sugar, chocolate, preservatives, and food
      coloring are beneficial and prerequisite to benefit from other interventions.
      Individualized IgG or IgE testing can identify other troublesome foods but not
      non-immune mediated food sensitivities. Gastrointestinal improvement rests on
      controlling Candida and other parasites, and using probiotic bacteria and
      nutrients to correct dysbiosis and decrease gut permeability. Detoxification of
      mercury and other heavy metals by DMSA/DMPS chelation can have marked benefit.
      Documented sulfoxidation-sulfation inadequacies call for sulfur-sulfhydryl
      repletion and other liver p450 support. Many nutrient supplements are beneficial
      and well tolerated, including dimethylglycine (DMG) and a combination of
      pyridoxine (vitamin B6) and magnesium, both of which benefit roughly half of ASD
      cases. Vitamins A, B3, C, and folic acid; the minerals calcium and zinc; cod
      liver oil; and digestive enzymes, all offer benefit. Secretin, a triggering
      factor for digestion, is presently under investigation. Immune therapies
      (pentoxifyllin, intravenous immunoglobulin, transfer factor, and colostrum)
      benefit selected cases. Long-chain omega-3 fatty acids offer great promise.
      Current pharmaceuticals fail to benefit the primary symptoms and can have marked
      adverse effects. Individualized, in-depth clinical and laboratory assessments and
      integrative parent-physician-scientist cooperation are the keys to successful ASD
      management.

PMID- 12495374
TI  - The interaction of cigarette smoking and antioxidants. Part 2: alpha-tocopherol.
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, it would seem cigarette smokers would have an increased requirement for
      antioxidant nutrients. This review examines available evidence of alpha
      tocopherol supplementation by smokers and its effect clinically and on in vitro
      biomarkers of oxidative stress.

PMID- 12495375
TI  - Arginine: Clinical potential of a semi-essential amino acid..
AB  - Arginine, a semi-essential amino acid, is involved in numerous areas of human
      biochemistry, including ammonia detoxification, hormone secretion, and immune
      modulation. Arginine is also well known as a precursor to nitric oxide (NO), a
      key component of endothelial-derived relaxing factor, an endogenous messenger
      molecule involved in a variety of endothelium-dependent physiological effects in
      the cardiovascular system. Because of arginine's NO-stimulating effects, it can
      be utilized in therapeutic regimens for angina pectoris, congestive heart
      failure, hypertension, coronary heart disease, preeclampsia, intermittent
      claudication, and erectile dysfunction. In addition, arginine has been studied in
      the treatment of HIV/AIDS, athletic performance, burns and trauma, cancer,
      diabetes and syndrome X, gastrointestinal diseases, male and female infertility,
      interstitial cystitis, immunomodulation, and senile dementia. Toxicity, dosage
      considerations, and contraindications are also reviewed.

PMID- 12495376
TI  - Isatis tinctoria. Monograph.

PMID- 12495377
TI  - Niacinamide. Monograph.

PMID- 12495378
TI  - A piece of my mind. Not guilty.

PMID- 12495379
TI  - Snakevine leads scientists on sinuous drug trail.

PMID- 12495380
TI  - Addiction treatment strives for legitimacy.

PMID- 12495381
TI  - From the World Health Organization. Essential medicines: 25 years of better
      health.

PMID- 12495383
TI  - Effectiveness of over-the-counter nicotine replacement therapy.

PMID- 12495384
TI  - Effectiveness of over-the-counter nicotine replacement therapy.

PMID- 12495385
TI  - Effectiveness of over-the-counter nicotine replacement therapy.

PMID- 12495386
TI  - Effectiveness of over-the-counter nicotine replacement therapy.

PMID- 12495387
TI  - Risk of hemolytic uremic syndrome from antibiotic treatment of Escherichia coli
      O157:H7 colitis.

PMID- 12495388
TI  - Risk of hemolytic uremic syndrome from antibiotic treatment of Escherichia coli
      O157:H7 colitis.

PMID- 12495389
TI  - Risk of hemolytic uremic syndrome from antibiotic treatment of Escherichia coli
      O157:H7 colitis.

PMID- 12495391
TI  - Dual-chamber pacing or ventricular backup pacing in patients with an implantable
      defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial.
AB  - CONTEXT: Implantable cardioverter defibrillator (ICD) therapy with backup
      ventricular pacing increases survival in patients with life-threatening
      ventricular arrhythmias. Most currently implanted ICD devices provide dual
      chamber pacing therapy. The most common comorbid cause for mortality in this
      population is congestive heart failure. OBJECTIVE: To determine the efficacy of
      dual-chamber pacing compared with backup ventricular pacing in patients with
      standard indications for ICD implantation but without indications for
      antibradycardia pacing. DESIGN: The Dual Chamber and VVI Implantable
      Defibrillator (DAVID) Trial, a single-blind, parallel-group, randomized clinical
      trial. SETTING AND PARTICIPANTS: A total of 506 patients with indications for ICD
      therapy were enrolled between October 2000 and September 2002 at 37 US centers.
      All patients had a left ventricular ejection fraction (LVEF) of 40% or less, no
      indication for antibradycardia pacemaker therapy, and no persistent atrial
      arrhythmias. INTERVENTIONS: All patients had an ICD with dual-chamber, rate
      responsive pacing capability implanted. Patients were randomly assigned to have
      the ICDs programmed to ventricular backup pacing at 40/min (VVI-40; n = 256) or
      dual-chamber rate-responsive pacing at 70/min (DDDR-70; n = 250). Maximal
      tolerated medical therapy for left ventricular dysfunction, including angiotensin
      converting enzyme inhibitors and beta-blockers, was prescribed to all patients.
      MAIN OUTCOME MEASURE: Composite end point of time to death or first
      hospitalization for congestive heart failure. RESULTS: One-year survival free of
      the composite end point was 83.9% for patients treated with VVI-40 compared with
      73.3% for patients treated with DDDR-70 (relative hazard, 1.61; 95% confidence
      interval [CI], 1.06-2.44). The components of the composite end point, mortality
      of 6.5% for VVI-40 vs 10.1% for DDDR-70 (relative hazard, 1.61; 95% CI, 0.84
      3.09) and hospitalization for congestive heart failure of 13.3% for VVI-40 vs
      22.6% for DDDR-70 (relative hazard, 1.54; 95% CI, 0.97-2.46), also trended in
      favor of VVI-40 programming. CONCLUSION: For patients with standard indications
      for ICD therapy, no indication for cardiac pacing, and an LVEF of 40% or less,
      dual-chamber pacing offers no clinical advantage over ventricular backup pacing
      and may be detrimental by increasing the combined end point of death or
      hospitalization for heart failure.

PMID- 12495392
TI  - Benefit of an early invasive management strategy in women with acute coronary
      syndromes.
AB  - CONTEXT: Women who present with acute coronary syndromes (ACSs) have different
      characteristics than men. Reports have conflicted about whether different
      outcomes exist for women with use of a routine invasive management strategy.
      However, these studies were performed prior to the widespread use of platelet
      glycoprotein IIb/IIIa inhibitors and intracoronary stents. OBJECTIVE: To
      determine sex differences in baseline characteristics and outcomes in ACS and
      whether women benefit from a contemporary early invasive management strategy.
      DESIGN AND SETTING: Prospective analysis of women and men enrolled in the TACTICS
      TIMI 18 randomized trial, conducted December 1997 to December 1999 in 169 centers
      in 9 countries in North America and Europe, with follow-up at 1 and 6 months.
      PARTICIPANTS: A total of 2220 patients (757 women and 1463 men) with ACS.
      INTERVENTIONS: All patients received aspirin, 325 mg/d; intravenous
      unfractionated heparin; and tirofiban for 48 hours or until revascularization,
      with tirofiban administered for at least 12 hours after percutaneous coronary
      revascularization. Patients assigned to the early invasive strategy (n = 1114)
      underwent coronary angiography 4 to 48 hours after randomization and
      revascularization when appropriate. Patients assigned to the early conservative
      strategy (n = 1106) were treated medically and underwent coronary angiography and
      appropriate revascularization only if they met specified criteria. MAIN OUTCOME
      MEASURES: Baseline characteristics and the primary composite end point of death,
      myocardial infarction, or rehospitalization for ACS at 6 months in women and men
      assigned to early invasive vs conservative management. RESULTS: Women were older
      and more frequently had hypertension (P<.001 for both). Women less frequently had
      previous myocardial infarction, coronary artery bypass grafting, and elevations
      in cardiac markers (P<.001 for all), but there was no difference in distribution
      of TIMI risk scores (P =.76). Angiography and intervention rates were similar,
      but women had less severe coronary artery disease, including no critical lesions
      in 17% of women vs 9% of men (P<.001). Women had a 28% odds reduction in the
      primary end point with an early invasive strategy (adjusted odds ratio [OR],
      0.72; 95% confidence interval [CI], 0.47-1.11), similar to the benefit in men
      (adjusted OR, 0.64; 95% CI, 0.47-0.88; P =.60 for sex interaction). When adjusted
      for baseline characteristics, the benefit of invasive therapy in women with
      elevated troponin T levels was further enhanced (adjusted OR, 0.47; 95% CI, 0.26
      0.83). CONCLUSIONS: Despite differences between women and men in baseline
      characteristics, the benefit of an early invasive strategy incorporating
      tirofiban and intracoronary stents was similar in women and men and was enhanced
      in women presenting with markers of increased risk.

PMID- 12495393
TI  - Fish consumption and risk of stroke in men.
AB  - CONTEXT: The effect of fish consumption or long-chain omega-3 polyunsaturated
      fatty acid (PUFA) intake on risk of stroke remains uncertain. OBJECTIVE: To
      examine the relation of fish consumption and long-chain omega-3 PUFA intake and
      risk of stroke in men. DESIGN AND SETTING: The Health Professional Follow-up
      Study, a US prospective cohort study with 12 years of follow-up. PARTICIPANTS: A
      total of 43 671 men aged 40 to 75 years who completed a detailed and validated
      semiquantitative food frequency questionnaire and who were free of cardiovascular
      disease at baseline in 1986. MAIN OUTCOME MEASURE: Relative risk (RR) of stroke
      by subtype based on cumulative average fish consumption or long-chain omega-3
      PUFA intake, ascertained in 1986, 1990, and 1994. RESULTS: We documented 608
      strokes during the 12-year follow-up period, including 377 ischemic, 106
      hemorrhagic, and 125 unclassified strokes. Compared with men who consumed fish
      less than once per month, the multivariate RR of ischemic stroke was
      significantly lower among those who ate fish 1 to 3 times per month (RR, 0.57;
      95% confidence interval [CI], 0.35-0.95). However, a higher frequency of fish
      intake was not associated with further risk reduction; the RR was 0.54 (95% CI,
      0.31-0.94) for men who consumed fish 5 or more times per week. This lack of
      linearity was confirmed by spline analyses. By dichotomized fish intake, the
      multivariate RR for men who consumed fish at least once per month compared with
      those who ate fish less than once per month was 0.56 (95% CI, 0.38-0.83) for
      ischemic stroke and 1.36 (95% CI, 0.48-3.82) for hemorrhagic stroke. The inverse
      association between fish intake and risk of ischemic stroke was not materially
      modified by use of aspirin. No significant associations were found between fish
      or long-chain omega-3 PUFA intake and risk of hemorrhagic stroke. CONCLUSION: Our
      findings suggest that eating fish once per month or more can reduce the risk of
      ischemic stroke in men.

PMID- 12495394
TI  - Recent trends in disability and functioning among older adults in the United
      States: a systematic review.
AB  - CONTEXT: Several well-publicized recent studies have suggested that disability
      among older Americans has declined in the last decade. OBJECTIVES: To assess the
      quality, quantity, and consistency of recent evidence on US trends in the
      prevalence of self-rated old age disability and physical, cognitive, and sensory
      limitations during the late 1980s and 1990s and to evaluate the evidence on
      trends in disparities by major demographic groups. DATA SOURCES: We searched
      MEDLINE and AGELINE for relevant articles published from January 1990 through May
      2002 and reviewed reference lists in published articles. STUDY SELECTION: From
      more than 800 titles reviewed, we selected 16 articles based on 8 unique repeat
      cross-sectional and cohort surveys of US prevalence trends in disability or
      functioning among persons generally aged 65 or 70 years or older. DATA
      EXTRACTION: We evaluated survey quality according to 10 criteria, ranked the
      surveys as good, fair, or poor, and calculated for each outcome the average
      annual percent change. DATA SYNTHESIS: Among the 8 surveys, 2 were rated as good,
      4 as fair, 1 as poor, and 1 as mixed (fair or poor, depending on the outcome) for
      assessing trends. Analyses of surveys rated fair or good showed consistency of
      declines in any disability (-1.55% to -0.92% per year), instrumental activities
      of daily living disability (-2.74% to -0.40% per year), and functional
      limitations. Surveys provided limited evidence on cognition and conflicting
      evidence on self-reported ADL (changes ranged from -1.38% to 1.53% per year) and
      vision trends. Evidence on trends in disparities by age, sex, race, and education
      was limited and mixed, with no consensus yet emerging. CONCLUSIONS: Several
      measures of old age disability and limitations have shown improvements in the
      last decade. Research into the causes of these improvements is needed to
      understand the implications for the future demand for medical care.

PMID- 12495395
TI  - Reasonable accommodations for medical faculty with disabilities.
AB  - An unknown number of medical school faculty have disabilities, and their
      experiences have generally escaped notice and scrutiny. Although most medical
      schools offer long-term insurance and extended leaves of absence for disability,
      relatively few have policies explicitly addressing accommodations for faculty
      with disabilities as they perform teaching, research, and clinical duties. We
      discuss accommodating active medical school faculty with disabilities, drawing on
      University of Pennsylvania School of Medicine initiatives exploring the concerns
      of faculty with sensory and physical disabilities. Anecdotal reports suggest that
      many faculty, fearing reprisals, resist seeking job accommodations such as those
      mandated in the 1990 Americans with Disabilities Act (ADA). Although some faculty
      with disabilities have found supportive academic mentors, others report that lax
      institutional enforcement of ADA requirements, including physical access
      problems, demonstrates a tepid commitment to disabled staff. Potentially useful
      job accommodations include adjusting timelines for promotion decisions;
      reassessing promotions requirements that inherently require extensive travel;
      improving physical access to teaching, research, and clinical sites; and
      modifying clinical and teaching schedules. Faculty with disabilities bring
      identical intellectual and collegial benefits to medical schools as their
      nondisabled counterparts. In addition, they may offer special insights into how
      chronic illness and impairments affect daily life.

PMID- 12495396
TI  - Current controversies in vaccination: vaccine safety.

PMID- 12495397
TI  - Pathophysiology of physiologic cardiac pacing: advantages of leaving well enough
      alone.

PMID- 12495398
TI  - Acute coronary syndromes: does sex matter?

PMID- 12495399
TI  - Reducing disability in older age.

PMID- 12495400
TI  - Authorship for research groups.

PMID- 12495401
TI  - From the Centers for Disease Control and Prevention. Prevalence of self-reported
      arthritis or chronic joint symptoms among adults--United States, 2001.

PMID- 12495402
TI  - From the Centers for Disease Control and Prevention. Enterovirus surveillance-
      United States, 2000-2001.

PMID- 12495403
TI  - From the Centers for Disease Control and Prevention. Human rabies--Tennessee,
      2002.

PMID- 12495404
TI  - JAMA patient page. Heart disease and women.

PMID- 12495407
TI  - Does acetic acid iontophoresis accelerate the resorption of calcium deposits in
      calcific tendinitis of the shoulder?

PMID- 12495408
TI  - Prediction of postoperative pulmonary complications on the basis of preoperative
      risk factors in patients who had undergone coronary artery bypass graft surgery.
AB  - BACKGROUND AND PURPOSE: Pulmonary complications are among the most frequently
      reported complications after coronary artery bypass graft (CABG) surgery.
      However, the risks of postoperative pulmonary complications (PPCs) are not equal
      for all patients. The aim of this study was to develop a model, based on
      preoperative factors, for classifying patients with high and low risks for PPCs
      in order to implement tailored interventions. SUBJECTS AND METHODS: Postoperative
      pulmonary complications were examined in 117 adult patients who had undergone
      elective CABG surgery at the University Medical Centre Utrecht, Utrecht, the
      Netherlands. The presence of preoperative risk factors (N=12) that have been
      described in the literature was noted for each patient. A risk model was
      developed by use of logistic regression analysis. RESULTS: Preoperative risk
      factors for developing PPCs were an age of (>/=70 years, productive cough,
      diabetes mellitus, and a history of cigarette smoking. Protective factors against
      the development of PPCs were a predicted inspiratory vital capacity of (>/=75%
      and a predicted maximal expiratory pressure of (>/=75%. These risk and protective
      factors were included in the model (sensitivity=87% and specificity=56%), and a
      sum score for its clinical use was generated. DISCUSSION AND CONCLUSION: Six
      factors that can be determined easily before surgery, with need for only simple
      pulmonary testing, can provide a model for identifying patients at risk of
      developing PPCs after CABG surgery.

PMID- 12495409
TI  - Effect of electrical stimulation on chronic leg ulcer size and appearance.
AB  - BACKGROUND AND PURPOSE: Electrical current has been recommended for use on
      chronic pressure ulcers; however, the ability of this modality to improve healing
      of other types of chronic ulcers is less well established. The purpose of this
      study was to examine the effect of high-voltage pulsed current (HVPC) on healing
      of chronic leg ulcers. SUBJECTS: Twenty-seven people with 42 chronic leg ulcers
      participated in the study. METHODS: The subjects were separated into subgroups
      according to primary etiology of the wound (diabetes, arterial insufficiency,
      venous insufficiency) and then randomly assigned to receive either HVPC (100
      microseconds, 150 V, 100 Hz) or a sham treatment for 45 minutes, 3 times weekly,
      for 4 weeks. Wound surface area and wound appearance were assessed during an
      initial examination, following a 1- to 2-week period during which subjects
      received only conventional wound therapy, after 4 weeks of sham or HVPC
      treatment, and at 1 month following treatments. RESULTS: The results indicated
      that HVPC applied to chronic leg ulcers reduced the wound surface area over the 4
      week treatment period to approximately one half the initial wound size (mean
      decrease=44.3%, SD=8.8%, range=2.8%-100%), which was over 2 times greater than
      that observed in wounds treated with sham units (mean decrease=16.0%, SD=8.9%,
      range=-30.3%-83.7%). DISCUSSION AND CONCLUSION: The results of the study indicate
      that HVPC administered 3 times a week should be considered to accelerate wound
      closure of chronic leg ulcers.

PMID- 12495410
TI  - Use of anabolic steroids to attenuate the effects of glucocorticoids on the rat
      diaphragm.
AB  - BACKGROUND AND PURPOSE: Administration of glucocorticoids results in atrophy and
      contractile dysfunction in the rat diaphragm. Anabolic steroids may be useful in
      preventing atrophy and contractile dysfunction. The purpose of this study was to
      assess the effects of simultaneous administration of testosterone and
      glucocorticoids on morphological and contractile properties of the rat diaphragm.
      SUBJECTS: Eighty-eight adult female Sprague-Dawley rats were divided into 1 of 4
      groups: a control group that was given sham injections for 13 days (CONT group,
      n=23), a group that was given prednisolone injections (0.5 mg/100 g) for 10 days
      (PRED group, n=23), a group that was given testosterone injections (0.5 mg/100 g)
      for 13 days (TEST group, n=18), and a group that was given a combination of
      prednisolone and testosterone injections (0.5 mg/100 g) for 10 and 13 days,
      respectively (COMBO group, n=23). METHODS: The animals were weighed daily, and
      drug doses were adjusted to changes in body mass. Twenty-four hours following the
      final injection, animals were weighed and sacrificed and the diaphragm was
      removed and weighed. A small strip of diaphragm was attached to a force
      transducer to determine normalized maximal isometric tetanic tension (PO).
      RESULTS: Body weights in the PRED group were decreased by 26% as compared with
      body weights in the CONT group, and body weights in the COMBO group were
      decreased by 11% as compared with body weights in the CONT group. Diaphragm
      weights in the PRED and COMBO groups were decreased by 22% and 12%, respectively,
      as compared with diaphragm weights in the CONT group. Normalized maximal
      isometric tetanic tension was decreased by 11% in the PRED group as compared with
      PO in both the CONT and TEST groups and was decreased by 13% as compared with PO
      in the COMBO group. There was no difference in PO among the CONT, TEST, and COMBO
      groups. DISCUSSION AND CONCLUSION: The results support the hypothesis that
      simultaneous administration of testosterone with glucocorticoids would prevent a
      decrease in PO. The results indicate that simultaneous administration of
      testosterone with glucocorticoids prevented the loss in body weight and partially
      attenuated the loss in diaphragm weight that is commonly observed when
      glucocorticoids are given alone. These data support the notion that testosterone
      may be useful in the prevention of glucocorticoid-induced atrophy.

PMID- 12495411
TI  - Maximal voluntary and functional performance levels needed for independence in
      adults aged 65 to 97 years.
AB  - BACKGROUND AND PURPOSE: Age-related loss of muscle mass and cardiovascular
      endurance can lead to impairments in muscle force production and cardiac function
      that, in turn, limit performance in activities essential to everyday living. The
      purposes of this study were: (1) to identify the "breakpoint" or threshold of
      maximal voluntary performance and performance in ordinary daily function and (2)
      to evaluate the predictive validity of the threshold to identify the ability to
      live independently without self-reported functional limitation. SUBJECTS AND
      METHODS: Men and women (N=192; mean age=76 years, SD=7, range=65-97) were
      recruited from single-family community dwellings or retirement communities with
      multiple levels of care. Physical function was measured with the Continuous-Scale
      Physical Functional Performance Test (CS-PFP). Maximal voluntary performance
      measures included peak oxygen consumption (VO(2peak)) and isokinetic knee
      extensor torque (KET). Segmented linear regression models of the CS-PFP on the
      physical performance measures were used to determine the threshold values and
      their confidence intervals. A logistic regression model was used to evaluate the
      ability of the CS-PFP scores to identify those living independently and to
      further illustrate the concepts of threshold and physical reserve. RESULTS:
      Threshold values identified for VO(2peak) (20 mL x kg(-1) x min(-1)) and KET (2.5
      N x m/[kg x m(-1)]) were associated with an average of CS-PFP score of 57 units.
      The threshold accurately predicted individuals reporting functional limitations.
      DISCUSSION AND CONCLUSION: The thresholds provide a mechanism for easily
      estimating an individual's physical reserve, predicting dependency in living
      status, and providing unbiased guidance for intervention in late-life
      independence.

PMID- 12495412
TI  - The relationship of lower-extremity muscle torque to locomotor performance in
      people with stroke.
AB  - BACKGROUND AND PURPOSE: Improved walking is a common goal after stroke. The
      purpose of this study was to examine the relationship between the torque
      generated by the muscles of both lower extremities and 2 locomotor tasks: gait on
      level surfaces and stair climbing in people who had strokes. SUBJECTS: Twenty
      community-dwelling individuals (mean age=61.2 years, SD=8.4, range=52-82) who had
      strokes and who were able to walk independently participated in the study. The
      mean time since stroke was 4.0 years (SD=2.6, range=1.5-10.0). METHODS: Pearson
      correlations and multiple regression were used to measure the relationship
      between concentric isokinetic torque of the flexor and extensor muscles of the
      hip, knee, and ankle bilaterally and locomotor performance (gait on level
      surfaces and stair-climbing speed). RESULTS: The isokinetic torques of the
      paretic ankle plantar flexors, hip flexors, and knee flexors had moderate to high
      correlations (r=.5-.8) with gait and stair-climbing speeds. Muscle force could
      explain 66% to 72% of the variability in gait and stair-climbing speeds.
      Correlations for the nonparetic side were as high as or higher than those for the
      paretic side for some muscle groups. DISCUSSION AND CONCLUSION: Muscle
      performance measurements of both limbs should be included in the evaluation of
      locomotion and treatment of people following a stroke.

PMID- 12495414
TI  - When to use the manipulation?

PMID- 12495413
TI  - Occupational rehabilitation following open mesh surgical repair of an inguinal
      hernia.
AB  - BACKGROUND AND PURPOSE: The purpose of this case report is to describe an
      occupational rehabilitation program for a person whose work-related inguinal
      hernia was surgically repaired. CASE DESCRIPTION: A 35-year-old baggage service
      attendant acquired an inguinal hernia while lifting at work. Postoperatively, the
      patient had discomfort in the groin, weakness of the lower extremities and trunk,
      limited ability to walk, and a decreased ability to work due to impaired lifting
      tolerance. OUTCOMES: Following postoperative rehabilitation, the patient was able
      to return to full-time, full-duty work. DISCUSSION: This case report describes
      occupational rehabilitation as a method to treat patients with work-related
      inguinal hernias following surgical repair.

PMID- 12495415
TI  - Late stages of protein secretion in bacilli.
AB  - This review highlights the later stages of protein secretion in bacilli, which
      include protein release from the membrane and their translocation through the
      cell wall. Mechanisms of release of secreted polypeptides into the medium differ
      in Gram-positive and Gram-negative bacteria due to different structure of their
      cell envelope. Exogenous factors including molecular chaperons that can influence
      polypeptide folding may be also involved in later stages of protein secretion in
      bacilli. In Gram-positive bacteria protein secretion also depends on structural
      components of the cell wall. Certain evidence exists that maintenance of the
      secretory function is important for normal development of the sporulation process
      in these bacteria.

PMID- 12495416
TI  - Initiation of DNA replication in eukaryotes is an intriguing cascade of protein
      interactions.
AB  - Initiation of eukaryotic DNA replication is a complex process including the
      recognition of initiation sites on DNA, multi-step DNA preparation for
      duplication, and assembly of multi-protein complexes capable of beginning DNA
      synthesis at initiation sites. The process starts at the late M phase and lasts
      till the appropriate time of the S phase for each initiation site. A chain of
      interesting interactions between Orc1p-6p, Cdc6p, Mcm2p-7p, Mcm10p, Cdt1, Cdc45p,
      Dbf4/Cdc7p, RPA, and DNA polymerase alpha takes place during this period. The
      sequence of these interactions is controlled by cyclin-dependent kinases, as well
      as by ubiquitin-dependent proteolysis in the proteasome. This review summarizes
      the data on proteins initiating DNA replication and factors controlling their
      activities.

PMID- 12495417
TI  - On the involvement of the water-polaron mechanism in energy trapping by reaction
      centers of purple bacteria.
AB  - A locus for binding a mobile water molecule was searched for in the immediate
      vicinity of the special pair in the reaction center. Using the PROTEUS PC-program
      (a part of the GRASP package) atomic structures of the reaction centers were
      analyzed in purple bacteria Rhodopseudomonas viridis and Rhodobacter sphaeroides.
      In both structures the loci for binding mobile water molecules were found at the
      distance of about 4.5 A from the middle of the special pair in the reaction
      center. The reorientation of a hydrogen atom of this water molecule in the
      electric field of the excited special pair required energy of no less than 40 MeV
      that corresponded to predictions of the water-polarization model of trapping of
      electron excitation which was developed by M. V. Fok and one of the authors of
      this article.

PMID- 12495418
TI  - Sialidase activity in normal and atherosclerotic human aortic intima.
AB  - Sialidase activity has been determined in homogenates of human aortic intima by
      measuring the amount of GM1 formed during the incubation of ganglioside GD1a with
      the tissue homogenates. Areas with atherosclerotic lesions as well as adjacent
      areas without histological evidence of atherosclerosis were taken for comparison.
      The rate of GM1 formation from GD1a in the presence of homogenates of the
      atherosclerotic intima was 20 pmol/h per mg protein. Homogenates of the
      unaffected intima did not desialylate GD1a. Sialidase activity of the
      atherosclerotic intima was linear for 1.5 h at GD1a content up to 1.5 nmol and at
      homogenate protein up to 1 micro g. NH4Cl and NeuAc2en, inhibitors of lysosomal
      function and plasma membrane-bound sialidase, respectively, reduced sialidase
      activity of homogenates of the atherosclerotic intima by 94%. The results
      indicate that atherosclerotic lesions and unaffected intima differ in their
      activity and specificity of sialidases that cleave gangliosides.

PMID- 12495419
TI  - Recombinant human peroxiredoxin VI: preparation and protective properties in
      vitro.
AB  - cDNA of human peroxiredoxin VI, one of the recently discovered novel antioxidant
      proteins, was expressed in Escherichia coli cells. The expression product was
      obtained in water-soluble form and purified by a two-step chromatographic
      procedure using DEAE-Sepharose and Sephacryl S-200. According to CD data, the
      polypeptide chain of the recombinant human peroxiredoxin VI contains
      approximately 40% alpha-helical region and 30% beta-structure, which is the same
      as for native rat peroxiredoxin VI. The protective properties of the recombinant
      protein determined as its ability to prevent the inactivation of glutamine
      synthetase from E. coli in a model oxidation system were comparable with the
      protective properties of native rat peroxiredoxin VI.

PMID- 12495420
TI  - Effect of ethanol on the palmitate-induced uncoupling of oxidative
      phosphorylation in liver mitochondria.
AB  - The effect of ethanol on the uncoupling activity of palmitate and recoupling
      activities of carboxyatractylate and glutamate was studied in liver mitochondria
      at various Mg2+ concentrations and medium pH values (7.0, 7.4, and 7.8). Ethanol
      taken at concentration of 0.25 M had no effect on the uncoupling activity of
      palmitic acid in the presence of 2 mM MgCl2 and decreased the recoupling effects
      of carboxyatractylate and glutamate added to mitochondria either just before or
      after the fatty acid. However, ethanol did not modify the overall recoupling
      effect of carboxyatractylate and glutamate taken in combination. The effect of
      ethanol decreased as medium pH was decreased to 7.0. Elevated concentration of
      Mg2+ (up to 8 mM) inhibits the uncoupling effect of palmitate. Ethanol eliminates
      substantially the recoupling effect of Mg2+ under these conditions, but does not
      influence the recoupling effects of carboxyatractylate and glutamate. It is
      inferred that ADP/ATP and aspartate/glutamate antiporters are involved in
      uncoupling function as single uncoupling complex with the common fatty acid pool.
      Fatty acid molecules gain the ability to migrate under the action of ethanol:
      from ADP/ATP antiporter to aspartate/glutamate antiporter on addition of
      carboxyatractylate and in opposite direction on addition of glutamate. Possible
      mechanisms of fatty acid translocation from one transporter to another are
      discussed.

PMID- 12495421
TI  - Influence of acyl and plasmalogenic analogs of platelet activating factor on
      chemotaxis of human leukocytes in vitro and their inflammatory and
      antiinflammatory activity in vivo.
AB  - The effects of platelet activating factor (PAF) and its cell analogs 1-O-alk-1;
      enyl-2-acetyl-sn-glycero-3-phosphocholine (1-alkenyl-PAF) and 1-acyl-2-acetyl-sn
      glycero-3-phosphocholine (1-acyl-PAF) on chemotaxis of human leukocytes in vitro
      and their inflammatory and antiinflammatory activities in vivo were studied. Both
      analogs stimulated chemotaxis of human leukocytes in agarose gel. PAF and 1
      alkenyl-PAF induced rat paw edema in the range of doses 0.1-10 and 10-100 micro g
      per paw, respectively. Paw edema induced by 1-acyl-PAF (10-100 micro g per paw)
      was more pronounced than that induced by PAF or 1-alkenyl-PAF. The latter also
      exhibited significant antiinflammatory effect by inhibiting PAF- or carrageenan
      induced rat paw edema, and this effect exceeded that of dexamethasone. In these
      models of inflammation 1-acyl-PAF did not exhibit any antiinflammatory activity.
      The data suggest that PAF is not the only cell phospholipid mediating
      inflammation--its cell analogs, 1-acyl-PAF and 1-alkenyl-PAF, may also be
      involved into the inflammatory response. Possible interrelationships between
      cellular synthesis of 1-acyl-PAF, its formation in oxidized LDL, biological
      effects of lysolecithin, and penetration of LDL into the arterial wall are
      discussed.

PMID- 12495422
TI  - ATP binding to noncatalytic sites of chloroplast coupling factor CF1.
AB  - A kinetic analysis of ATP binding to noncatalytic sites of chloroplast coupling
      factor CF1 was made. The ATP binding proved to be unaffected by reduction of the
      disulfide bridge of the CF1 gamma-subunit. The first-order equation describing
      nucleotide binding to noncatalytic sites allowed for two vacant nucleotide
      binding sites different in their kinetics. As suggested by nucleotide
      concentration dependence of the rate of nucleotide binding, the tight binding was
      preceded by rapid reversible binding of nucleotides. Preincubation of CF1 with
      Mg2+ resulted in a decreased rate of ATP binding. ATP dissociation from
      noncatalytic sites was described by the first order equation for similar sites
      with a dissociation rate constant kd(ATP) approximately/= 10-3 min-1.
      Noncatalytic sites of CF1 were shown to be not homogeneous. One of them retained
      the major part of endogenous ADP after precipitation of CF1 with ammonium
      sulfate. Its two other sites differed in kinetic parameters and affinity for ATP.
      Anions of phosphate, sulfite, and especially, pyrophosphate inhibited the
      interaction between ATP and the noncatalytic sites.

PMID- 12495423
TI  - Comparative study of lipid composition and proliferative activity of rat
      cholangiocarcinoma RS1 and sarcoma M1 depending on the transplantation organ.
AB  - The proliferative activity and lipid composition (phospholipids, gangliosides)
      were studied in rat cholangiocarcinoma RS1 and sarcoma M1 transplanted
      subcutaneously or intrahepatically. The mitotic index was higher in the tumors
      transplanted into the heterologous organ. The total phospholipid and
      sphingomyelin contents were higher in the tumors transplanted intrahepatically.
      GM3 and GD3 were the main gangliosides in both variants of each tumor. A
      significant amount of GM3 ganglioside lactone was found in the intrahepatic
      variants whereas it was absent in the subcutaneous tumors. Both the mitotic index
      and lipid composition of the tumors studied depended on their microenvironment.

PMID- 12495424
TI  - Lucigenin-derived chemiluminescence in intact isolated mitochondria.
AB  - There are many data both in favor and against the use of lucigenin as a probe for
      superoxide anion (SA) in mitochondria, cells, and simple enzymatic systems. In
      the present work high concentrations (50-400 micro M) of lucigenin were used for
      continuous recording of rapid and reversible changes in the SA level in intact
      isolated mitochondria. The SA level in the presence of lucigenin rapidly and
      reversibly changed during the transition of the mitochondria from one functional
      state to another: under conditions of ATP synthesis from ADP and Pi, of Ca2+
      accumulation, and of reverse electron transfer. Induction of a Ca2+,cyclosporin A
      sensitive pore in mitochondria completely suppressed the lucigenin-derived
      chemiluminescence (LDC). The electron transfer in the Q-cycle of the respiratory
      chain complex III and high electric potential difference across the inner
      membrane of mitochondria were obligatory conditions for generation of a SA
      dependent chemiluminescent signal. Based on our own and literature data, a scheme
      of LDC generation is suggested. The origin of superoxide anion detected in intact
      mitochondria with lucigenin is discussed.

PMID- 12495425
TI  - Ionol (BHT) produces superoxide anion.
AB  - In aqueous medium etiolated wheat seedlings release superoxide anion (O2*-).
      Interaction of a synthetic antioxidant, butylated hydroxytoluene (BHT, ionol),
      with oxygen in the aqueous medium is accompanied by O2*- formation. This suggests
      that under certain conditions BHT behaves as a prooxidant. A natural antioxidant,
      superoxide dismutase (SOD), and also a wound healing preparation, emulsified
      denatured placenta (EDP), do not exhibit the prooxidant properties. In contrast
      to BHT, they reduce O2*- production by the etiolated wheat seedling system.

PMID- 12495426
TI  - Variability of hydrocarbon and fatty acid components in cultures of the
      filamentous cyanobacterium Scytonema sp. isolated from microbial community "black
      cover" of limestone walls in Jerusalem.
AB  - The hydrocarbon and lipid components of four strains of the filamentous
      cyanobacterium Scytonema sp. isolated from microbial community "Black Cover" of
      limestone walls in Jerusalem were identified by gas chromatography-mass
      spectrometry using serially coupled capillary columns. The dominant compounds
      were: 1-heptadecyne (1.5-8%), hexadecanoic acid (14-36%), (Z,Z)-9,12
      octadecadienoic acid (12-30%), (Z,Z,Z)-9,12,15-octadecatrienoic acid (6-12%), n
      heptadecane (4-16%), and 1-heptadecene (1.5-8%). In addition to unsaturated
      alkanes and fatty acids, the very long-chain (C30-C32) hydrocarbons, squalene
      (2.4-3.0%), and branched 4,8,12-trimethyl-C13:0 acid were also isolated. Two
      major hydrocarbons were detected in the cyanobacteria species using GC-MS and 13C
      NMR.

PMID- 12495427
TI  - Study of beta-amyloid peptide (Abeta40) insertion into phospholipid membranes
      using monolayer technique.
AB  - beta-Amyloid peptide (Abeta), a normal constituent of neuronal and non-neuronal
      cells, has been proved to be the major component of extracellular plaque of
      Alzheimer's disease (AD). The interaction of Abeta with lipid membranes may be
      essential for its neurotoxicity. Our previous study revealed that membrane
      insertion may provide a possible pathway by which Abeta prevents itself from
      aggregation and fibril formation. In the present work we studied the membrane
      insertion of Abeta and the factors that affect its insertion ability using a
      monolayer approach. The results show that Abeta is surface active and can insert
      into lipid monolayers. When a high level of cholesterol is present, Abeta40 can
      insert into the phospholipid mixtures simulating physiological membrane
      composition. Acidic pH enhances Abeta insertion, while the effect of ionic
      strength is rather complex. Abeta insertion ability may be ultimately relative to
      cholesterol-rich domains in the monolayers, which indicates strong interaction
      between Abeta and cholesterol.

PMID- 12495428
TI  - Evidence for the existence of an unfolding intermediate of thyroglobulin during
      denaturation by guanidine hydrochloride.
AB  - The unfolding of bovine thyroglobulin (Tg) in guanidine hydrochloride (GuHCl)
      solution was studied by following the fluorescence and circular dichroism. With
      increasing GuHCl concentrations, the emission maximum of the intrinsic
      fluorescence clearly red-shifted in two stages. At concentrations of GuHCl less
      than 1.2 M or more than 1.6 M, the red shift showed a cooperative manner. At
      concentrations of GuHCl between 1.2 and 1.6 M, an unfolding intermediate was
      observed. It was further characterized by the increased binding of the
      fluorescence probe 1-anilinonaphthalene-8-sulfonic acid (ANS). No significant
      changes of the secondary structure were indicated by CD spectra at the
      concentrations of GuHCl between 1.2 and 1.6 M. The conformation of this state has
      properties similar to those of a molten globule state which may exist in the
      folding pathway of the protein. Further changes in fluorescence properties
      occurred at concentrations of denaturant higher than 1.6 M with a significant red
      shift of the emission maximum from 340 to 347 nm and a marked decrease in ANS
      binding. This in vitro study gave a clue to understand the biochemical mechanism
      for the occurrence of aggregation and molecular chaperone binding during Tg
      maturation in vivo.

PMID- 12495429
TI  - Cloning, purification, and crystallization of a bacterial gene expression
      regulator--Hfq protein from Escherichia coli.
AB  - Thermostable RNA-binding protein Hfq (also denoted HF1) is a multifunctional
      expression regulator of many bacterial genes. The regulation takes place both at
      a translation level (directly) and transcription level (indirectly through the
      stimulation of bacterial RNA polymerase sigmaS-subunit translation). We have
      cloned and overexpressed the hfq gene from E. coli and developed a purification
      procedure for the protein. Using gel filtration and ultracentrifugation
      techniques it was shown that the obtained Hfq protein is highly homogeneous and
      well dissolved. It has been crystallized and can be used for structural
      investigations.

PMID- 12495430
TI  - Effect of isotope substitution and controlled dehydration on the photoinduced
      electron transport reactions of quinone acceptors and multiheme cytochrome C in
      bacterial photosynthetic reaction center.
AB  - Isotope substitution of H2O by 2H2O causes an increase in the rate of dark
      recombination between photooxidized bacteriochlorophyll (P+) and reduced primary
      quinone acceptor in Rhodobacter sphaeroides reaction centers (RC) at room
      temperature. The isotopic effect declines upon decreasing the temperature.
      Dehydration of RC complexes of Ectothiorhodospira shaposhnikovii chromatophores
      containing multiheme cytochrome c causes a decrease in the efficiency of transfer
      of a photomobilized electron between the primary and secondary quinone acceptors
      and from cytochrome to P+. In the case of H2O medium these effects are observed
      at a lower hydration than in 2H2O-containing medium. In the E. shaposhnikovii
      chromatophores subjected to dehydration in H2O, the rate of electron transfer
      from the nearest high-potential cytochrome heme to P+ is virtually independent of
      hydration within the P/P0 range from 0.1 to 0.5. In samples hydrated in 2H2O this
      rate is approximately 1.5 times lower than in H2O. However, the isotopic effect
      of this reaction disappears upon dehydration. The intramolecular electron
      transfer between two high-potential hemes of cytochrome c in samples with 2H2O is
      inhibited within this range of P/P0, whereas in RC samples with H2O there is a
      trend toward gradual inhibition of the interheme electron transfer with
      dehydration. The experimental results are discussed in terms of the effects of
      isotope substitution and dehydration on relaxation processes and charge state of
      RC on implementation of the reactive states of RC providing electron transfer
      control.

PMID- 12495431
TI  - Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm.
AB  - Phosphorylation plays a central role in regulating the activation and signalling
      lifetime of protein kinases A, B (also known as Akt) and C. These kinases share
      three conserved phosphorylation motifs: the activation loop segment, the turn
      motif and the hydrophobic motif. This review focuses on how phosphorylation at
      each of these sites regulates the maturation, signalling and down-regulation of
      PKC as a paradigm for how these sites control the function of the ABC kinases.

PMID- 12495432
TI  - Photolabelling the rat urotensin II/GPR14 receptor identifies a ligand-binding
      site in the fourth transmembrane domain.
AB  - A urotensin II (U-II) peptide analogue containing the photoreactive p -benzoyl-L
      phenylalanine (Bz-Phe) in the sixth position was used to identify ligand-binding
      sites of the rat U-II receptor, also known as GPR14. [Bz-Phe(6)]U-II bound the
      receptor expressed in COS-7 cells with high affinity (IC(50) 0.7 nM) and was as
      potent as U-II in the agonist-induced production of inositol phosphate.
      Photolabelling of the U-II receptor with (125)I-[Bz-Phe(6)]U-II resulted in the
      specific formation of a glycosylated (125)I-[Bz-Phe(6)]U-II-U-II receptor complex
      of 60 kDa. Digestion of the 60 kDa complex with endoproteinase Glu-C generated a
      fragment of 17 kDa circumscribing the labelled fragment to residues 148-286.
      Digestion of the ligand-receptor complex with endoproteinase Arg-C produced a
      short peptide of 4 kDa corresponding to fragments 125-148, 167-192 or 210-233.
      CNBr treatment of the endoproteinase-Glu-C and -Arg-C fragments yielded 2 kDa
      fragments, defining the labelling site to methionine residues 184/185 of the
      fourth transmembrane domain. Photolabelling of two mutant receptors, M184L/M185L
      and M184A/M185A, led to a significant decrease in the overall yield of covalent
      labelling. Taken together, our results indicate that position 6 of U-II normally
      occupied by phenylalanine would interact with Met(184) and/or Met(185) of the
      fourth transmembrane domain of the U-II receptor. This information should be of
      significant value in the study of the interactions between U-II and its cognate
      receptor.

PMID- 12495433
TI  - Novel splice variants of the receptor for advanced glycation end-products
      expressed in human vascular endothelial cells and pericytes, and their putative
      roles in diabetes-induced vascular injury.
AB  - The binding of advanced glycation end-products (AGE) to the receptor for AGE
      (RAGE) is known to deteriorate various cell functions and is implicated in the
      pathogenesis of diabetic vascular complications. In the present study, we show
      that the cellular constituents of small vessels, endothelial cells (EC) and
      pericytes express novel splice variants of RAGE mRNA coding for the isoforms that
      lack the N-terminal V-type immunoglobulin-like domain (N-truncated) or the C
      terminal transmembrane domain (C-truncated), as well as the known full-length
      mRNA. The ratio of the expression of the three variants was different between EC
      and pericytes; the content of the C-truncated form was highest in EC, whereas the
      full-length form was the most abundant in pericytes. Transfection experiments
      with COS-7 cells demonstrated that those variant mRNAs were translated into
      proteins as deduced; C-truncated RAGE was efficiently secreted into the culture
      media, and N-truncated RAGE was located mainly on the plasma membrane. The three
      isoforms were also detected in primary cultured human EC and pericytes. Further,
      full-length and C-truncated forms of RAGE bound to an AGE-conjugated column,
      whereas N-truncated RAGE did not. The AGE induction of extracellular-signal
      related kinase phosphorylation and vascular endothelial growth factor in EC and
      of the growth and cord-like structure formation of EC was abolished completely by
      C-truncated RAGE, indicating that this endogenous secretory receptor (endogenous
      secretory RAGE) is cytoprotective against AGE. The results may contribute to our
      understanding of the molecular basis for the diversity of cellular responses to
      AGE and for individual variations in the susceptibility to diabetic vascular
      complications.

PMID- 12495434
TI  - Regulation of tensin-promoted cell migration by its focal adhesion binding and
      Src homology domain 2.
AB  - Tensin1 is an actin- and phosphotyrosine-binding protein that localizes to focal
      adhesions. Recently, we have shown that both tensin1 and a new family member,
      tensin2, promote cell migration [Chen, Duncan, Bozorgchami and Lo (2002) Proc.
      Natl. Acad. Sci. U.S.A. 99, 733-738]. Since localization of proteins to
      particular intracellular compartments often regulates their functions, and Src
      homology domain 2 may mediate signals related to cell migration, we hypothesize
      that tensin-mediated cell migration is regulated by the focal adhesion
      localization and the Src homology domain 2 of tensin. To test this hypothesis, we
      have analysed the effects of a series of tensin1 mutants on cell migration. Our
      results have shown that (1) tensin1 contains two focal adhesion-binding sites,
      (2) the wild-type tensin1 significantly promotes cell migration, (3) mutants with
      one focal adhesion-binding site do not promote cell migration, (4) the non-focal
      adhesion localized mutant suppresses cell migration and (5) the mutant that is
      not able to bind to phosphotyrosine-containing proteins has no effect on cell
      migration. These results have indicated that focal adhesion localization of
      tensin1 and the phosphotyrosine-binding activity are two critical factors in
      regulating tensin-mediated cell migration.

PMID- 12495435
TI  - A relative value method for measuring and evaluating cardiac reserve.
AB  - BACKGROUND: Although a very close relationship between the amplitude of the first
      heart sound (S1) and the cardiac contractility have been proven by previous
      studies, the absolute value of S1 can not be applied for evaluating cardiac
      contractility. However, we were able to devise some indicators with relative
      values for evaluating cardiac function. METHODS: Tests were carried out on a
      varied group of volunteers. Four indicators were devised: (1) the increase of the
      amplitude of the first heart sound after accomplishing different exercise
      workloads, with respect to the amplitude of the first heart sound (S1)recorded at
      rest was defined as cardiac contractility change trend (CCCT). When the subjects
      completed the entire designed exercise workload (7000 J), the resulting CCCT was
      defined as CCCT(1); when only 1/4 of the designed exercise workload was
      completed, the result was defined as CCCT(1/4). (2) The ratio of S1 amplitude to
      S2 amplitude (S1/S2). (3) The ratio of S1 amplitude at tricuspid valve
      auscultation area to that at mitral auscultation area T1/M1 (4) the ratio of
      diastolic to systolic duration (D/S). Data were expressed as mean +/- SD.
      RESULTS: CCCT(1/4) was 6.36 +/- 3.01 (n = 67), CCCT(1) was 10.36 +/- 4.2 (n =
      33), S1/S2 was 1.89 +/- 0.94 (n = 140), T1/M1 was 1.44 +/- 0.99 (n = 144), and
      D/S was 1.68 +/- 0.27 (n = 172). CONCLUSIONS: Using indicators CCCT(1/4) and
      CCCT(1) may be beneficial for evaluating cardiac contractility and cardiac
      reserve mobilization level, S1/S2 for considering the factor for hypotension,
      T1/M1 for evaluating the right heart load, and D/S for evaluating diastolic
      cardiac blood perfusion time.

PMID- 12495436
TI  - Is the development of falciparum malaria in the human host limited by the
      availability of uninfected erythrocytes?
AB  - BACKGROUND: The development and propagation of malaria parasites in their
      vertebrate host is a complex process in which various host and parasite factors
      are involved. Sometimes the evolution of parasitaemia seems to be quelled by
      parasite load. In order to understand the typical dynamics of evolution of
      parasitaemia, various mathematical models have been developed. The basic premise
      ingrained in most models is that the availability of uninfected red blood cells
      (RBC) in which the parasite develops is a limiting factor in the propagation of
      the parasite population. PRESENTATION OF THE HYPOTHESIS: We would like to propose
      that except in extreme cases of severe malaria, there is no limitation in the
      supply of uninfected RBC for the increase of parasite population. TESTING THE
      HYPOTHESIS: In this analysis we examine the biological attributes of the parasite
      infected RBC such as cytoadherence and rosette formation, and the rheological
      properties of infected RBC, and evaluate their effects on blood flow and clogging
      of capillaries. We argue that there should be no restriction in the availability
      of uninfected RBC in patients. IMPLICATION OF THE HYPOTHESIS: There is no
      justification for the insertion of RBC supply as a factor in mathematical models
      that describe the evolution of parasitaemia in the infected host. Indeed, more
      recent models, that have not inserted this factor, successfully describe the
      evolution of parasitaemia in the infected host.

PMID- 12495437
TI  - Cellular immune response to Plasmodium falciparum after pregnancy is related to
      previous placental infection and parity.
AB  - BACKGROUND: Malaria in pregnancy is characterised by the sequestration of
      Plasmodium falciparum-infected erythrocytes in placental intervillous spaces.
      Placental parasites express a specific phenotype, which allows them to cytoadhere
      to chondroitin sulfate A expressed by syncytiotrophoblasts. Malaria infection
      during pregnancy allows the acquisition of antibodies against placental
      parasites, these antibodies are thought to be involved in protection during
      subsequent pregnancies. METHODS: To investigate the development of a cellular
      response to placental parasites during pregnancy, peripheral blood mononuclear
      cells were collected from women at the time of their confinement. The study was
      performed in Cameroon where malaria transmission is perennial. In vitro cell
      proliferation and cytokine production were measured in response to non-malarial
      activators (concanavalin A and PPD), a recombinant protein from P. falciparum MSP
      1, and erythrocytes infected by two P. falciparum lines, RP5 and W2. Like
      placental parasites, the RP5 line, but not W2, adheres to chondroitin sulfate A
      and to syncytiotrophoblasts. RESULTS: The proliferative response to all antigens
      was lower for cells obtained at delivery than 3 months later. Most interestingly,
      the cellular response to the RP5 line of P. falciparum was closely related to
      parity. The prevalence rate and the levels of response gradually increased with
      the number of previous pregnancies. No such relationship was observed with W2
      line, or MSP-1 antigen. CONCLUSIONS: This suggests the occurrence of an immune
      response more specific for the RP5 line in women having had multiple pregnancies,
      and who are likely to develop immunity to pregnancy-associated parasites. Both
      humoral and cellular mechanisms may account for the lower susceptibility of
      multigravidae to malaria.

PMID- 12495438
TI  - Examining the determinants of mosquito-avoidance practices in two Kenyan cities.
AB  - BACKGROUND: This study assesses the behavioural and socio-economic factors
      associated with avoiding mosquitoes and preventing malaria in urban environments
      in Kenya. METHODS: Data from two cities in Kenya were gathered using a household
      survey and a two-stage cluster sample design. The cities were stratified based on
      planning and drainage observed across the urban areas. This helped control for
      the strong environmental and topographical variation that we assumed influences
      mosquito ecology. Individual interviews given to each household included
      questions on socio-economic status, education, housing type, water source,
      rubbish disposal, mosquito-prevention practices and knowledge of mosquitoes. In
      multivariate regression, factors measuring wealth, education level, and the
      communities' level of planning and drainage were used to estimate the probability
      that a household engages in multiple mosquito-avoidance activities, or has all
      members sleeping under a bed net. RESULTS: Our analysis shows that people from
      wealthier, more educated households were more likely to sleep under a net, in
      Kisumu (OR = 6.88; 95% CI = 2.56,18.49) and Malindi (OR = 3.80; 95% CI =
      1.91,7.55). Similarly, the probability that households use several mosquito
      prevention activities was highest among the wealthiest, best-educated households
      in Kisumu (OR = 5.15; 95% CI = 2.04,12.98), while in Malindi household wealth
      alone is the major determinant. CONCLUSION: We demonstrate the importance of
      examining human-mosquito interaction in terms of how access to resources may
      enhance human activities. The findings illustrate that the poorest segments of
      society are already doing many things to protect themselves from being bitten,
      but they are doing less than their richer neighbours.

PMID- 12495439
TI  - Dissociation of DNA damage and mitochondrial injury caused by hydrogen peroxide
      in SV-40 transformed lung epithelial cells.
AB  - BACKGROUND: Since lung epithelial cells are constantly being exposed to reactive
      oxygen intermediates (ROIs), the alveolar surface is a major site of oxidative
      stress, and each cell type may respond differently to oxidative stress. We
      compared the extent of oxidative DNA damage with that of mitochondrial injury in
      lung epithelial cells at the single cell level. RESULT: DNA damage and
      mitochondrial injury were measured after oxidative stress in the SV-40
      transformed lung epithelial cell line challenged with hydrogen peroxide (H2O2).
      Single cell analysis of DNA damage was determined by assessing the number of 8
      oxo-2-deoxyguanosine (8-oxo-dG) positive cells, a marker of DNA modification, and
      the length of a comet tail. Mitochondrial membrane potential, DeltaPsim, was
      determined using JC-1. A 1 h pulse of H2O2 induced small amounts of apoptosis
      (3%). 8-oxo-dG-positive cells and the length of the comet tail increased within 1
      h of exposure to H2O2. The number of cells with reduced DeltaPsim increased after
      the addition of H2O2 in a concentration-dependent manner. In spite of a continual
      loss of DeltaPsim, DNA fragmentation was reduced 2 h after exposure to H2O2.
      CONCLUSION: The data suggest that SV-40 transformed lung epithelial cells are
      resistant to oxidative stress, showing that DNA damage can be dissociated from
      mitochondrial injury.

PMID- 12495440
TI  - Tripeptide analysis of protein structures.
AB  - BACKGROUND: An efficient building block for protein structure prediction can be
      tripeptides. 8000 different tripeptides from a dataset of 1220 high resolution
      (<or= 2.0 degrees A) structures from the Protein Data Bank (PDB) have been looked
      at, to determine which are structurally rigid and non-rigid. This data has been
      statistically analyzed, discussed and summarized. The entire data can be utilized
      for the building of protein structures. RESULTS: Tripeptides have been classified
      into three categories: rigid, non-rigid and intermediate, based on the relative
      structural rigidity between Calpha and Cbeta atoms in a tripeptide. We found that
      18% of the tripeptides in the dataset can be classified as rigid, 4% as non-rigid
      and 78% as intermediate. Many rigid tripeptides are made of hydrophobic residues,
      however, there are tripeptides with polar side chains forming rigid structures.
      The bulk of the tripeptides fall in the intermediate class while very small
      numbers actually fall in the non-rigid class. Structurally all rigid tripeptides
      essentially form two structural classes while the intermediate and non-rigid
      tripeptides fall into one structural class. This notion of rigidity and non
      rigidity is designed to capture side chain interactions but not secondary
      structures. CONCLUSIONS: Rigid tripeptides have no correlation with the secondary
      structures in proteins and hence this work is complementary to such studies.
      Tripeptide data may be used to predict plausible structures for oligopeptides and
      for denovo protein design.

PMID- 12495441
TI  - Modulatory effect of adenosine receptors on the ascending and descending neural
      reflex responses of rat ileum.
AB  - BACKGROUND: Adenosine is known to act as a neuromodulator by suppressing synaptic
      transmission in the central and peripheral nervous system. Both the release of
      adenosine within the small intestine and the presence of adenosine receptors on
      enteric neurons have been demonstrated. The aim of the present study was to
      characterize a possible involvement of adenosine receptors in the modulation of
      the myenteric reflex. The experiments were carried out on ileum segments 10 cm in
      length incubated in an single chambered organ bath, and the reflex response was
      initiated by electrical stimulation (ES). RESULTS: ES caused an ascending
      contraction and a descending relaxation followed by a contraction. All motility
      responses to ES were completely blocked by tetrodotoxin, indicating that they are
      mediated by neural mechanisms. Atropine blocked the contractile effects, whereas
      the descending relaxation was significantly increased. The A1 receptor agonist N6
      cyclopentyladenosine increased the ascending contraction, whereas the ascending
      contraction was reduced by the A1 receptor antagonist 8-cyclopentyl-1,3
      dipropylxanthine. Activation of the A1 receptor further reduced the descending
      relaxation and the latency of the peristaltic reflex. The A2B receptor antagonist
      alloxazine increased ascending contraction, whereas descending relaxation
      remained unchanged. For A2A and A3 receptors, we found contradictory effects of
      the agonists and antagonists, thus there is no clear physiological role for these
      receptors at this time. CONCLUSIONS: This study suggests that the myenteric
      ascending and descending reflex response of the rat small intestine is modulated
      by release of endogenous adenosine via A1 receptors.

PMID- 12495443
TI  - Mutations in the Lactococcus lactis Ll.LtrB group II intron that retain mobility
      in vivo.
AB  - BACKGROUND: Group II introns are mobile genetic elements that form conserved
      secondary and tertiary structures. In order to determine which of the conserved
      structural elements are required for mobility, a series of domain and sub-domain
      deletions were made in the Lactococcus lactis group II intron (Ll.LtrB) and
      tested for mobility in a genetic assay. Point mutations in domains V and VI were
      also tested. RESULTS: The largest deletion that could be made without severely
      compromising mobility was 158 nucleotides in DIVb(1-2). This mutant had a
      mobility frequency comparable to the wild-type Ll.LtrB intron (DeltaORF
      construct). Hence, all subsequent mutations were done in this mutant background.
      Deletion of DIIb reduced mobility to approximately 18% of wild-type, while
      another deletion in domain II (nts 404-459) was mobile to a minor extent. Only
      two deletions in DI and none in DIII were tolerated. Some mobility was also
      observed for a DIVa deletion mutant. Of the three point mutants at position G3 in
      DV, only G3A retained mobility. In DVI, deletion of the branch-point nucleotide
      abolished mobility, but the presence of any nucleotide at the branch-point
      position restored mobility to some extent. CONCLUSIONS: The smallest intron
      capable of efficient retrohoming was 725 nucleotides, comprising the DIVb(1-2)
      and DII(ii)a,b deletions. The tertiary elements found to be nonessential for
      mobility were alpha, kappa and eta. In DV, only the G3A mutant was mobile. A
      branch-point residue is required for intron mobility.

PMID- 12495442
TI  - A role for cryptochromes in sleep regulation.
AB  - BACKGROUND: The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the
      generation of circadian rhythms, as mice lacking both of these genes (cry1,2-/-)
      lack circadian rhythms. We studied sleep in cry1,2-/- mice under baseline
      conditions as well as under conditions of constant darkness and enforced
      wakefulness to determine whether cryptochromes influence sleep regulatory
      processes. RESULTS: Under all three conditions, cry1,2-/- mice exhibit the
      hallmarks of high non-REM sleep (NREMS) drive (i.e., increases in NREMS time,
      NREMS consolidation, and EEG delta power during NREMS). This unexpected phenotype
      was associated with elevated brain mRNA levels of period 1 and 2 (per1,2), and
      albumin d-binding protein (dbp), which are known to be transcriptionally
      inhibited by CRY1,2. To further examine the relationship between circadian genes
      and sleep homeostasis, we examined wild type mice and rats following sleep
      deprivation and found increased levels of per1,2 mRNA and decreased levels of dbp
      mRNA specifically in the cerebral cortex; these changes subsided with recovery
      sleep. The expression of per3, cry1,2, clock, npas2, bmal1, and casein-kinase
      1epsilon did not change with sleep deprivation. CONCLUSIONS: These results
      indicate that mice lacking cryptochromes are not simply a genetic model of
      circadian arrhythmicity in rodents and functionally implicate cryptochromes in
      the homeostatic regulation of sleep.

PMID- 12495444
TI  - Immunomodulation in stable renal transplant recipients with concomitant
      tacrolimus and sirolimus therapy.
AB  - BACKGROUND: Long term treatment with immunosuppressive agents results in
      nephrotoxicity in renal transplant recipients. We explored the effect of
      combination of Tacrolimus (TAC) and Sirolimus (SRL) on the immune system in renal
      transplant recipients. METHODS: 10 stable renal transplant recipients were
      selected to participate in a pharmacokinetic study with a combination of TAC and
      SRL. Blood was drawn on day zero and 14 days post treatment. Lymphocyte
      proliferation was quantified by 3H-thymidine uptake assay (results expressed as
      counts per minute). The mRNA expression was studied by RT-PCR and serum levels of
      cytokines were quantified by ELISA and a cytokine bead array system. RESULTS:
      Lymphocyte proliferative response to PHA (p < 0.05), Con A (p < 0.006) and Anti
      CD3 (p <0.005) were significantly decreased in patients who received both TAC and
      SRL compared to TAC alone. The mRNA expression of proinflammatory cytokines TNF
      alpha (p < 0.05), cyclins G (p < 0.01) and E (p < 05) were decreased, and of TGF
      beta (p < 0.03) and p21 (p < 0.05) were increased in patients treated with this
      combination. Circulating levels of IFN-gamma (p < 0.04), IL-4 (p < 0.02), and Il
      2 (p < 0.03) were significantly inhibited and elevation of TGF-beta (p < 0.04)
      was observed in patients treated with TAC and SRL combination. CONCLUSION: These
      novel findings demonstrate that addition of SRL to TAC therapy enhances immuno
      modulation and causes increased immunosuppression providing a rationale for this
      concomitant therapy.

PMID- 12495445
TI  - MHC class I expression protects rat colon carcinoma cells from hepatic natural
      killer cell-mediated apoptosis and cytolysis, by blocking the perforin/granzyme
      pathway.
AB  - BACKGROUND: Hepatic natural killer (NK) cells, the most cytotoxic cells of the
      natural occurring NK cells, are located in the liver sinusoids and are thus in a
      strategic position to kill arriving metastasising tumour cells, like colon
      carcinoma cells. It is known that major histocompatibility complex (MHC) class I
      on tumour cells negatively regulates NK cell-mediated cytolysis, but this is
      found using blood- or spleen-derived NK cells. Therefore, using isolated rat
      hepatic NK cells and the syngeneic colon carcinoma cell line CC531s, we
      investigated whether this protective role of MHC class I is also operative in
      hepatic NK cells, and addressed the mechanism of MHC class I protection. RESULTS:
      When MHC class I on CC531s cells was masked by preincubation with monoclonal
      antibody OX18, hepatic NK cell-mediated cytolysis (51Cr release) as well as
      apoptosis (DNA fragmentation, nucleus condensation and fragmentation) increased.
      When hepatic NK cells were preincubated with the granzyme inhibitor 3,4
      dichloroisocoumarin, or when extracellular Ca2+ was chelated by ethylene glycol
      bis(beta-aminoethyl ether)-N, N-tetraacetic acid, the enhanced cytolysis and
      apoptosis were completely inhibited. The involvement of the perforin/granzyme
      pathway was confirmed by showing that the enhanced cytolysis was caspase
      independent. CONCLUSIONS: MHC class I expression protects CC531s colon carcinoma
      cells from hepatic NK cell-mediated apoptosis and cytolysis, by blocking the
      perforin/granzyme pathway.

PMID- 12495446
TI  - Characteristic promoter hypermethylation signatures in male germ cell tumors.
AB  - BACKGROUND: Human male germ cell tumors (GCTs) arise from undifferentiated
      primordial germ cells (PGCs), a stage in which extensive methylation
      reprogramming occurs. GCTs exhibit pluripotentiality and are highly sensitive to
      cisplatin therapy. The molecular basis of germ cell (GC) transformation,
      differentiation, and exquisite treatment response is poorly understood. RESULTS:
      To assess the role and mechanism of promoter hypermethylation, we analyzed CpG
      islands of 21 gene promoters by methylation-specific PCR in seminomatous (SGCT)
      and nonseminomatous (NSGCT) GCTs. We found 60% of the NSGCTs demonstrating
      methylation in one or more gene promoters whereas SGCTs showed a near-absence of
      methylation, therefore identifying distinct methylation patterns in the two major
      histologies of GCT. DNA repair genes MGMT, RASSF1A, and BRCA1, and a
      transcriptional repressor gene HIC1, were frequently methylated in the NSGCTs.
      The promoter hypermethylation was associated with gene silencing in most
      methylated genes, and reactivation of gene expression occurred upon treatment
      with 5-Aza-2' deoxycytidine in GCT cell lines. CONCLUSIONS: Our results,
      therefore, suggest a potential role for epigenetic modification of critical tumor
      suppressor genes in pathways relevant to GC transformation, differentiation, and
      treatment response.

PMID- 12495448
TI  - Maternal exposure to low-level air pollution and pregnancy outcomes: a population
      based study.
AB  - BACKGROUND: Recent reports have shown that air pollution may increase the risk of
      adverse birth outcomes. We have evaluated the relationship between ambient air
      pollution and the occurrence of low birth weight and preterm delivery using
      routinely collected data in Lithuania. METHODS: This epidemiological study
      comprised all singleton newborns (N = 3,988), born to women in 1998, who resided
      in the City of Kaunas. Birth data and information on maternal characteristics
      were obtained from the Lithuanian National Birth Register. To estimate
      residential exposure levels, we used measurements of ambient nitrogen dioxide
      (NO2) and formaldehyde, which were collected at 12 monitoring posts. Multivariate
      logistic regression was used to estimate the effect that each pollutant would
      have on low birth weight (LBW) and premature birth while controlling for
      potential confounders. RESULTS: Adjusted odds ratios (OR) for LBW increased with
      increasing formaldehyde exposure (OR2nd tertile = 1.86, 95% CI 1.10-3.16; OR3rd
      tertile = 1.84, 95% CI 1.12-3.03). Adjusted ORs of preterm birth for the medium
      and high NO2 tertile exposures were OR = 1.14 (95% CI 0.77-1.68) and OR = 1.68
      (95% CI 1.15-2.46), respectively. The risk of preterm birth increased by 25%
      (adjusted OR = 1.25, 95% CI 1.07-1.46) per 10 microg/m3 increase in NO2
      concentrations. An analysis by trimester showed that pregnancy outcomes were
      associated with first-trimester exposure to air pollutants. However, there were
      no significant relationships in other pregnancy periods between preterm birth and
      exposure to formaldehyde or between LBW and NO2 exposure. CONCLUSION: Our
      findings suggest that in the City of Kaunas there might be a relationship between
      maternal exposure to ambient formaldehyde and the risk of LBW, as well as between
      NO2 exposure and the risk of preterm birth.

PMID- 12495447
TI  - Nuclear genes involved in mitochondria-to-nucleus communication in breast cancer
      cells.
AB  - BACKGROUND: The interaction of nuclear and mitochondrial genes is an essential
      feature in maintenance of normal cellular function. Of 82 structural subunits
      that make up the oxidative phosphorylation system in the mitochondria,
      mitochondrial DNA (mtDNA) encodes 13 subunits and rest of the subunits are
      encoded by nuclear DNA. Mutations in mitochondrial genes encoding the 13 subunits
      have been reported in a variety of cancers. However, little is known about the
      nuclear response to impairment of mitochondrial function in human cells. RESULTS:
      We isolated a Rho0 (devoid of mtDNA) derivative of a breast cancer cell line. Our
      study suggests that depletion of mtDNA results in oxidative stress, causing
      increased lipid peroxidation in breast cancer cells. Using a cDNA microarray we
      compared differences in the nuclear gene expression profile between a breast
      cancer cell line (parental Rho+) and its Rho0 derivative impaired in
      mitochondrial function. Expression of several nuclear genes involved in cell
      signaling, cell architecture, energy metabolism, cell growth, apoptosis including
      general transcription factor TFIIH, v-maf, AML1, was induced in Rho0 cells.
      Expression of several genes was also down regulated. These include phospholipase
      C, agouti related protein, PKC gamma, protein tyrosine phosphatase C,
      phosphodiestarase 1A (cell signaling), PIBF1, cytochrome p450, (metabolism) and
      cyclin dependent kinase inhibitor p19, and GAP43 (cell growth and
      differentiation). CONCLUSIONS: Mitochondrial impairment in breast cancer cells
      results in altered expression of nuclear genes involved in signaling, cellular
      architecture, metabolism, cell growth and differentiation, and apoptosis. These
      genes may mediate the cross talk between mitochondria and the nucleus.

PMID- 12495449
TI  - Influence of various factors on individual radiation exposure from the Chernobyl
      disaster.
AB  - BACKGROUND: The explosion at the Chernobyl Nuclear Power Plant was one of the
      greatest known nuclear disasters of the 20th century. To reduce individual
      exposure to ionizing radiation the Soviet Union government introduced a number of
      counter-measures. This article presents a description of how historical events
      conspired to disrupt these efforts and affect residents in exposed areas.
      METHODS: This study employed an extensive review of data on radionuclide
      deposition, contamination patterns and lifestyle characteristics. Data were
      obtained from the Ukraine Ministry of Health and the Ukraine Research Center for
      Radiation Medicine. RESULTS: Data are presented on annual contamination rates in
      selected locales as well as data on local food consumption patterns. Historical
      factors including economic and political circumstances are also highlighted.
      Results show the diminution of individual doses between 1987 and 1991 and then an
      increase between 1991 and 1994 and the relationship between this increase and
      changes in the lifestyle of the local population. CONCLUSION: A number of factors
      played direct and indirect roles in contributing to the populace's cumulative
      radiation exposure. Future post-contamination studies need to consider these
      factors when estimating individual exposures.

PMID- 12495450
TI  - A study of indoor carbon dioxide levels and sick leave among office workers.
AB  - BACKGROUND: A previous observational study detected a strong positive
      relationship between sick leave absences and carbon dioxide (CO2) concentrations
      in office buildings in the Boston area. The authors speculated that the observed
      association was due to a causal effect associated with low dilution ventilation,
      perhaps increased airborne transmission of respiratory infections. This study was
      undertaken to explore this association. METHODS: We conducted an intervention
      study of indoor CO2 levels and sick leave among hourly office workers employed by
      a large corporation. Outdoor air supply rates were adjusted periodically to
      increase the range of CO2 concentrations. We recorded indoor CO2 concentrations
      every 10 minutes and calculated a CO2 concentration differential as a measure of
      outdoor air supply per person by subtracting the 1-3 a.m. average CO2
      concentration from the same-day 9 a.m. - 5 a.m. average concentration. The metric
      of CO2 differential was used as a surrogate for the concentration of exhaled
      breath and for potential exposure to human source airborne respiratory pathogens.
      RESULTS: The weekly mean, workday, CO2 concentration differential ranged from 37
      to 250 ppm with a peak CO2 concentration above background of 312 ppm as compared
      with the American Society of Heating, Refrigeration and Air-conditioning
      Engineers (ASHRAE) recommended maximum differential of 700 ppm. We determined the
      frequency of sick leave among 294 hourly workers scheduled to work approximately
      49,804.2 days in the study areas using company records. We found no association
      between sick leave and CO2 differential CONCLUSIONS: The CO2 differential was in
      the range of very low values, as compared with the ASHRAE recommended maximum
      differential of 700 ppm. Although no effect was found, this study was unable to
      test whether higher CO2 differentials may be associated with increased sick
      leave.

PMID- 12495452
TI  - Functional foods: scientific and global perspectives. Proceedings of an
      international symposium. October 17-19, 2001. Paris, France.

PMID- 12495451
TI  - Serum organochlorines and urinary porphyrin pattern in a population highly
      exposed to hexachlorobenzene.
AB  - BACKGROUND: Porphyria cutanea tarda (PCT) is caused by hexachlorobenzene (HCB) in
      several species of laboratory mammals, but the human evidence is contradictory.
      In a study among adults of a population highly exposed to HCB (Flix, Catalonia,
      Spain), the prevalence of PCT was not increased. We aimed at analysing the
      association of individual urinary porphyrins with the serum concentrations of HCB
      and other organochlorine compounds in this highly exposed population. METHODS: A
      cross-sectional study on total porphyrins was carried out in 1994 on 604
      inhabitants of the general population of Flix, older than 14 years. Of them, 241
      subjects (comprising a random sample and the subgroup with the highest exposure)
      were included for the present study. The porphyrin profile was determined by high
      pressure liquid chromatography. Serum concentrations of HCB, as well as common
      organochlorine compounds, were determined by gas chromatography coupled to
      electron capture detection. RESULTS: Coproporphyrin I (CPI) and coproporphyrin
      III (CPIII) were the major porphyrins excreted, while uroporphyrins I and III
      were only detected in 2% and 36% of the subjects respectively, and
      heptaporphyrins I and III in 1% and 6%, respectively. CPI and CPIII decreased
      with increasing HCB concentrations (p < 0.05). This negative association was not
      explained by age, alcohol, smoking, or other organochlorine compounds. No
      association was found between uroporphyrin I and III excretion, nor
      heptaporphyrin excretion, and HCB. CPIII increased with smoking (p < 0.05).
      CONCLUSION: HCB exposure in this highly exposed population did not increase
      urinary concentrations of individual porphyrins.

PMID- 12495453
TI  - EU-funded research on functional foods.
AB  - Research on food and nutrition has been an important topic in all Framework
      Programmes for Research and Technological Development of the European Commission.
      From the Second Framework Programme (ECU 2 million for four projects on
      functional foods) to the Fifth Framework Programme (51 million for thirty-three
      projects on functional foods), the investment in research projects on functional
      foods has been increasing by quite an extent. In the early 1990s, the topics were
      fibres, pro-, pre- and synbiotics. Nowadays, the range of subjects has been
      broadened to antioxidative effects, vitamins, phyto-oestrogens and the socio
      economic area.

PMID- 12495454
TI  - Global view on functional foods: European perspectives.
AB  - In the context of this presentation, European means the European scientific
      community, which, over the last decade, has been working on the concepts for
      functional foods, producing a number of documents including a consensus paper,
      guidelines and scientific publications. The Functional Food Science in Europe
      (FUFOSE) project has been quite a unique attempt to establish a strong scientific
      framework to justify the functional food concept, to discover and develop new
      functional foods that are primarily function-driven, and to substantiate claims
      scientifically. Being clearly positioned as part of nutrition, the functional
      food concept is, however, quite distinct from other approaches like food
      supplementation or food fortification, and functional foods are different from
      nutraceuticals, pharmafoods, vitafoods and 'alicaments', all terms that are not
      defined conceptually. Functional foods are food products to be taken as part of
      the usual diet in order to have beneficial effects that go beyond what are known
      as traditional nutritional effects. Moreover, these beneficial effects have to be
      demonstrated scientifically to justify two specific types of claim: the enhanced
      function claim or the reduction of disease risk claim. Functional food is a key
      concept for the future of nutrition as a science because it results from the
      implementation in nutrition of all the basic scientific knowledge that has
      accumulated over the past two or three decades. To the benefit of public health
      this progress cannot be ignored, it needs to be recognized fully and used. But,
      today, functional food is still mainly a scientific concept that serves to
      stimulate research and the development of new products.

PMID- 12495455
TI  - Global view on functional foods: Asian perspectives.
AB  - There is an old Chinese thought meaning that medicine and food are isogenic. In
      Japan, a national research project started to endorse the thought scientifically,
      with the birth of functional foods that are now known to function to reduce the
      risk of life-style related diseases. The science gave rise to a national policy
      in which some functional foods were legally approved in terms of Foods for
      Specified Health Use. China has also constructed a unique system for approving
      some functional foods. This paper pinpoints a recent trend of functional foods
      characteristic to Asia, with special reference to relevant topics in Japan.

PMID- 12495456
TI  - Functional foods: Latin American perspectives.
AB  - The perspectives of Latin America as a potential producer and consumer of
      functional foods will depend largely on the level of information and income of
      the population, credibility of the products, research investments and regulatory
      practices. The characteristics of Latin America are diverse at the regional and
      sub-regional levels. However, as part of the demographic and epidemiological
      transition currently underway, common trends can be identified such as increasing
      urbanization and life expectancy, the occurrence of obesity and malnutrition,
      increasing incidences of chronic diseases and causes of mortality rates, all of
      which suggests the importance of diet and functional foods in public health
      policies. The Latin American population in general has no knowledge of functional
      foods, but in the more urbanized areas there is an increasingly health-conscious
      consumer, aware of the importance of food for health, due to the media and local
      traditions. More investment in research is important to explore the existing
      plant biodiversity that is a rich source of new foods and bioactive compounds,
      some of which are already used for health improvement and well-being. Clinical
      validation of functional foods should consider functional food science concepts
      and also the diverse cultural and genetic background of the local population. In
      Latin American scientific and regulatory communities, the functional foods
      concept has been associated with foods having health benefits beyond those of
      basic nutrition but is not defined officially in the emerging regulatory codes.
      Regulation existing in some countries is focused on safety and efficacy; both
      functional and health claims are allowed (risk reduction) provided they have
      scientific validation. This allowed introduction on the market of several
      products with health claims, some of them submitted to post-marketing
      surveillance.

PMID- 12495457
TI  - Functional foods and health: a US perspective.
AB  - Linkages between diet habits and the quality of life continue to surface on
      numerous fronts. Collectively these epidemiological, pre-clinical and clinical
      studies provide rather compelling evidence that numerous essential and non
      essential dietary components are capable of influencing growth, development and
      performance and disease prevention. Scientific discoveries and widespread
      interest in the potential medicinal benefits of foods and food components have
      fostered a variety of content, health and structure-function claims.
      Unfortunately, defining the ideal diet is complicated by the numerous and diverse
      components that may influence biological processes. Inconsistencies in the
      literature may reflect the multi-factorial nature of these processes and the
      specificity that individual dietary constituents have in modifying genetic and
      epigenetic events. New and emerging genomic and proteonomic approaches and
      technologies offer exciting opportunities for identifying molecular targets for
      dietary components and thus determining mechanisms by which they influence the
      quality of life. All cells have unique 'signatures' that are characterized by
      active and inactive genes and cellular products. It is plausible that bridging
      knowledge about unique cellular characteristics with molecular targets for
      nutrients can be used to develop strategies to optimize nutrition and minimize
      disease risk.

PMID- 12495458
TI  - Gastrointestinal physiology and functions.
AB  - While the health benefit of a functional food may be a metabolic response that
      lowers risk for disease, the actual target for the food or food component may be
      on the functioning of the gastrointestinal tract (GIT). For example, slowing
      absorption from the intestine, as measured by examining the appearance of the
      nutrient or food component in the blood, the hormone response associated with
      absorption of the compound or excretion of the compound, may provide a health
      benefit. However, the food component may slow absorption by delaying gastric
      emptying, altering the mixing within the intestinal contents or decreasing the
      availability of digestive enzymes in the intestine. These measures of GIT
      function provide validation of the mechanisms by which the functional food or
      food components affect metabolism. Bioavailability of physiologically active
      compounds from foods will be determined by the digestibility of foods that
      contain these compounds, their subsequent absorption and utilization by tissues.
      The physical structure of foods contributes to the functional effects of foods as
      well as to the availability of compounds from foods. For example, recent studies
      have demonstrated that changing the viscosity of the gut contents alters
      absorption and GIT response. Additionally, food structures such as the plant cell
      wall change the availability of absorbable compounds along the gastrointestinal
      contents. The areas of probiotics and prebiotics have highlighted the potential
      importance of gut microflora in health. While evidence suggests biological
      activity relevant to disease risk reduction, the long-term implications of the
      microbial activity have yet to be established.

PMID- 12495459
TI  - The immune system: a target for functional foods?
AB  - The immune system acts to protect the host from infectious agents that exist in
      the environment (bacteria, viruses, fungi, parasites) and from other noxious
      insults. The immune system is constantly active, acting to discriminate 'non
      self' from 'self'. The immune system has two functional divisions: the innate and
      the acquired. Both components involve various blood-borne factors (complement,
      antibodies, cytokines) and cells. A number of methodologies exist to assess
      aspects of immune function; many of these rely upon studying cells in culture ex
      vivo. There are large inter-individual variations in many immune functions even
      among the healthy. Genetics, age, gender, smoking habits, habitual levels of
      exercise, alcohol consumption, diet, stage in the female menstrual cycle, stress,
      history of infections and vaccinations, and early life experiences are likely to
      be important contributors to the observed variation. While it is clear that
      individuals with immune responses significantly below 'normal' are more
      susceptible to infectious agents and exhibit increased infectious morbidity and
      mortality, it is not clear how the variation in immune function among healthy
      individuals relates to variation in susceptibility to infection. Nutrient status
      is an important factor contributing to immune competence: undernutrition impairs
      the immune system, suppressing immune functions that are fundamental to host
      protection. Undernutrition leading to impairment of immune function can be due to
      insufficient intake of energy and macronutrients and/or due to deficiencies in
      specific micronutrients. Often these occur in combination. Nutrients that have
      been demonstrated (in either animal or human studies) to be required for the
      immune system to function efficiently include essential amino acids, the
      essential fatty acid linoleic acid, vitamin A, folic acid, vitamin B6, vitamin
      B12, vitamin C, vitamin E, Zn, Cu, Fe and Se. Practically all forms of immunity
      may be affected by deficiencies in one or more of these nutrients. Animal and
      human studies have demonstrated that adding the deficient nutrient back to the
      diet can restore immune function and resistance to infection. Among the nutrients
      studied most in this regard are vitamin E and Zn. Increasing intakes of some
      nutrients above habitual and recommended levels can enhance some aspects of
      immune function. However, excess amounts of some nutrients also impair immune
      function. There is increasing evidence that probiotic bacteria improve host
      immune function. The effect of enhancing immune function on host resistance to
      infection in healthy individuals is not clear.

PMID- 12495460
TI  - Functional foods and food supplements for athletes: from myths to benefit claims
      substantiation through the study of selected biomarkers.
AB  - The development of the sports food market and industrial involvement have led to
      numerous nutritional studies to define the type of nutrients that are most suited
      to support energy metabolism, fluid balance and muscle function. The key question
      in many of these studies was: 'Does the product lead to a significant
      product/consumer benefit that can be used as a claim on the package?' New methods
      and techniques have been developed, partly with sponsorship of the food industry,
      with the goal of measuring the effects of specific nutrients and supplements on
      athletic performance and metabolism. In line with this development, a wide
      variety of supplements and sports foods/drinks labelled with various performance
      or health benefit statements have been launched on the sports nutrition market.
      Although a variety of products have been tested clinically, there are also many
      products on the market with benefit claims that cannot be supported by sound
      nutritional and sports physiological science. The current short review highlights
      some of the methods and biomarkers that are used to substantiate product/consumer
      benefit claims for foods and drinks that are marketed as functional foods for
      athletes.

PMID- 12495461
TI  - Functional foods: psychological and behavioural functions.
AB  - It is easier to demonstrate the consistent effects of foods on satiety than on
      cognitive performance. This is understandable since the satiety system
      incorporates physiological signalling systems that mediate the effects of foods
      on function. Specific manipulations of proteins, carbohydrates and fats have the
      potential to act as functional foods for appetite control. Because of the
      importance of the optimal functioning of cognitions for survival, these functions
      are quite strongly protected against short-term dietary and physiological
      perturbances. Therefore, food manipulations may be better detected through the
      degree of effort exerted to maintain performance rather than via changes in the
      actual performance itself. This procedure has not been widely used hitherto. The
      concept of biomarkers may have to be interpreted differently from research on
      physiological systems or clinical endpoints. For satiety, adjustments in the
      profile of hunger could serve as a biomarker or surrogate endpoint. For
      cognitions, correlated physiological variables may be more difficult to measure
      than the functional endpoint itself. Changes related to unitary functions (such
      as tracking) could serve as biomarkers for more complex, integrated skills (such
      as car driving). Since food manipulations may affect multiple functions, the
      challenge is to design foods with good satiety control that do not impair mental
      performance; or alternatively to engineer foods that optimise cognitive
      performance without compromising satiety. This rapidly developing field has great
      potential for close collaboration between academia and industry in the production
      of commercially successful products that show clear improvements in human
      functioning with the capacity to protect against disease or impairment.

PMID- 12495462
TI  - Biomarkers and functional foods for obesity and diabetes.
AB  - Obesity has reached epidemic proportions in many countries around the world.
      Because of the close relationship between obesity and type 2 diabetes, an
      epidemic of diabetes is close behind the obesity epidemic. Preventing and
      treating obesity is becoming an increasing priority. In the United States, over
      60 % of the adult population is overweight or obese and thus at increased risk of
      developing diabetes and cardiovascular disease. While the aetiology of obesity
      and diabetes is complex, diet clearly plays an important role both in the
      development and management of these diseases. There is interest in functional
      foods that could help in prevention and/or management of obesity and type 2
      diabetes. This could involve food products that help management of 'hunger' or
      that increase 'satiety'. It could also involve foods that contribute to more
      inefficient use of ingested energy (i.e. foods that stimulate energy expenditure
      more than would be expected from their energy content). As the concept of insulin
      sensitivity becomes generally more accepted by health care professionals and the
      public, foods may be targeted towards maximizing insulin sensitivity and towards
      'prevention' of diabetes. In addition to foods that impact upon body weight,
      these may include foods that affect the glucose and/or insulin levels that are
      seen either following the ingestion of food or later in the day. The present
      paper reviews the complex aetiology of obesity and diabetes and considers a
      potential role for functional foods in prevention and treatment of obesity and
      diabetes.

PMID- 12495463
TI  - Scientific basis of biomarkers and benefits of functional foods for reduction of
      disease risk: cancer.
AB  - One of the most promising areas for the development of functional foods lies in
      modification of the activity of the gastrointestinal tract by use of probiotics,
      prebiotics and synbiotics. While a myriad of healthful effects have been
      attributed to the probiotic lactic acid bacteria, perhaps the most controversial
      remains that of anticancer activity. However, it must be emphasised that, to
      date, there is no direct experimental evidence for cancer suppression in man as a
      result of consumption of lactic cultures in fermented or unfermented dairy
      products, although there is a wealth of indirect evidence, based largely on
      laboratory studies. Presently, there are a large number of biomarkers available
      for assessing colon cancer risk in dietary intervention studies, which are
      validated to varying degrees. These include colonic mucosal markers, faecal water
      markers and immunological markers. Overwhelming evidence from epidemiological, in
      vivo, in vitro and clinical trial data indicates that a plant-based diet can
      reduce the risk of chronic disease, particularly cancer. It is now clear that
      there are components in a plant-based diet other than traditional nutrients that
      can reduce cancer risk. More than a dozen classes of these biologically active
      plant chemicals, now known as 'phytochemicals', have been identified. Although
      the vast number of naturally occurring health-enhancing substances appear to be
      of plant origin, there are a number of physiologically active components in
      animal products (such as the probiotics referred to above) that deserve attention
      for their potential role in cancer prevention.

PMID- 12495464
TI  - Biomarkers of bone health appropriate for evaluating functional foods designed to
      reduce risk of osteoporosis.
AB  - Osteoporosis is a growing global problem. The health care costs and decreased
      productivity and quality of life are staggering. Much research is invested in
      life-style approaches to build peak bone mass during growth to prevent
      osteoporosis as well as to treat the disease in later life. Functional foods have
      enjoyed a niche in bone health. Foods fortified with Ca are most popular. Other
      bone nutrients such as vitamin D, Mg and vitamin K are sometimes added. Future
      products are likely to include enhancers of Ca absorption such as inulin or whey
      proteins. Dietary factors that reduce urinary Ca loss (plant proteins) or
      suppress bone resorption (possibly phyto-oestrogens) are also gaining attention.
      Methodologies for evaluating the effectiveness of functional foods on bone health
      include measures of bone quality such as bone densitometry or measures of Ca
      metabolism, particularly absorption. Biochemical markers for bone turnover are
      less satisfactory for diet-related effects. Use of a rare isotope, 41Ca, and
      accelerator mass spectrometry offers a new approach for assessing the ability of
      functional foods to suppress bone resorption.

PMID- 12495465
TI  - Functional foods, trends and future.

PMID- 12495466
TI  - Serum insulin-like growth factors, insulin-like growth factor-binding protein-3,
      and risk of lung cancer death: a case-control study nested in the Japan
      Collaborative Cohort (JACC) Study.
AB  - To elucidate the roles of insulin-like growth factors (IGFs) in the development
      of lung cancer, we conducted a case-control study nested within the Japan
      Collaborative Cohort Study. Serum samples were collected at baseline from 39140
      men and women between 1988 and 1990. We measured serum IGF-I, IGF-II, and IGF
      binding protein-3 (IGFBP-3) in 194 case subjects who subsequently died from lung
      cancer during an 8-year follow-up and in 9351 controls. The odds ratios (ORs),
      adjusted for smoking and other covariates, were smaller with higher levels of IGF
      II and IGFBP-3. The ORs across quartiles were 0.41 (95% confidence interval [CI],
      0.27-0.63), 0.47 (0.31-0.71), and 0.67 (0.46-0.98) for IGF-II (trend P=0.018),
      and 0.55 (95% CI, 0.37-0.81), 0.54 (0.36-0.82), and 0.67 (0.45-1.01) for IGFBP-3
      (trend P=0.037). These peptides were not independently related to lung cancer
      risk when mutually adjusted. The risk was increased in the highest vs. the lowest
      quartile of IGF-I only after controlling for IGFBP-3 (OR, 1.74; 95% CI, 1.08
      2.81). Limiting subjects to those followed for 3 years strengthened the negative
      associations of IGF-II and IGFBP-3, whereas the ORs for IGF-I generally
      decreased. A higher level of circulating IGFBP-3 and / or IGF-II may decrease
      lung cancer risk. Elevated serum IGF-I may increase the risk, but this could
      partly be attributable to latent tumors.

PMID- 12495467
TI  - Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk
      factors for hepatocellular carcinoma in Haimen, China.
AB  - A case-control study was carried out to investigate the impact of factors
      including virus infection, aflatoxin B1, microcystins, smoking/drinking and
      dietary habits as well as genetic polymorphisms of aldehyde dehydrogenase 2
      (ALDH2) and cytochrome P4502E1 (CYP2E1), on susceptibility to hepatocellular
      carcinoma (HCC) in Haimen, China. A total of 248 patients with HCC and 248 sex-,
      age- and residence-matched population-based controls were recruited into the
      study. Virus infection, and ALDH2 and CYP2E1 gene polymorphisms were assessed in
      134 paired cases and controls. By univariate analysis, hepatitis B virus (HBV)
      infection (odds ratio [OR]=9.75; 95% confidence interval [CI]=4.71-20.2), history
      of intravenous injection (OR=1.50; 95%CI=1.02-2.22), average income (OR=0.63;
      95%CI=0.43-0.92), frequent intake of foods rich in protein, e.g., egg (OR=0.6;
      95%CI=0.42-0.87), chicken (OR=0.53; 95%CI=0.35-0.79), pork (OR=0.67; 95%CI=0.46
      0.98) and fresh fish (OR=0.58; 95%CI=0.39-0.87) significantly differed between
      cases and controls. However, peanut intake (OR=0.66; 95%CI=0.43-1.01), source of
      drinking water, including tap (OR=1.33; 95%CI=0.81-2.20), deep well (OR=0.94;
      95%CI=0.56-1.55), shallow well (OR=0.85; 95%CI=0.55=1.30), river (OR=0.95;
      95%CI=0.65-1.38), ditch (OR=1.09; 95%CI=0.76-1.55) and pond water (OR=1.0;
      95%CI=0.14-7.10) were not significantly associated with risk. Univariate analysis
      also indicated that the 1-1 genotype of ALDH2 (OR=1.38; 95%CI=0.86-2.23) as well
      as the Pst1- and Rsa1-digested c1/c1 genotype of CYP2E1 (OR=1.36; 95%CI=0.81
      2.28), was slightly more frequent in the case group. On multivariate analysis,
      HBV infection (OR=13.9; 95%CI=5.78-33.6) and history of intravenous injection
      (OR=2.72; 95%CI=1.24-6.00) were still associated with significantly increased
      risk of HCC, while frequent intake of fresh fish (OR=0.32; 95%CI=0.12-0.86)
      decreased this risk. These findings suggest that whereas peanut intake, water
      sources as well as genetic polymorphisms in ALDH2 and CYP2E1 do not significantly
      correlate with the risk of HCC, HBV infection is a main risk factor, and dietary
      items rich in protein, especially fresh fish, might protect against the risk of
      HCC in Haimen, China.

PMID- 12495468
TI  - Earlier Helicobacter pylori infection increases the risk for the N-methyl-N
      nitrosourea-induced stomach carcinogenesis in Mongolian gerbils.
AB  - Helicobacter pylori (H. pylori) is now well known to be associated with stomach
      cancer, with infection during childhood rather than as an adult considered to be
      more important for carcinogenesis. To evaluate the difference in susceptibility
      to stomach carcinogenesis in relation to age of acquisition of H. pylori
      infection, we designed an experiment involving inoculation of H. pylori ATCC43504
      followed by N-methyl-N-nitrosourea (MNU) treatment at different ages. Four-week
      old male Mongolian gerbils (MGs) were divided into twelve groups. H. pylori was
      inoculated at 4, 18 and 32 weeks of age, as representatives of early, middle and
      late infection, respectively. Two weeks later, the animals were treated with MNU.
      Groups without H. pylori and/or MNU were included as controls. The incidences of
      adenocarcinomas at 52 weeks after the inoculation in the early (H. pylori+MNU),
      middle (H. pylori+MNU), and late (H. pylori+MNU) group were 60% (12/20), 18.4%
      (2/11), and 10% (2/20), respectively. The corresponding figures were 14.8%
      (4/27), 0% (0/11), and 0% (0/21) in the MNU-alone groups. A higher titer of serum
      IgG for H. pylori and higher gastrin level were seen in the early-infected
      compared to the middle and the late groups (P<0.01). The results clearly
      demonstrated that early acquisition of H. pylori significantly increases gastric
      chemical carcinogenesis with MNU, as compared to the case with later infection,
      possibly because of differences in host gastric mucosal factors and immunologic
      responses.

PMID- 12495469
TI  - Effects of antioxidant 1-O-hexyl-2,3,5-trimethylhydroquinone or ascorbic acid on
      carcinogenesis induced by administration of aminopyrine and sodium nitrite in a
      rat multi-organ carcinogenesis model.
AB  - The effect of antioxidant, 0.25% 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) or
      0.25% ascorbic acid (AsA), on carcinogenesis induced by administration of 0.05%
      aminopyrine (AP) and 0.05% sodium nitrite (NaNO2), was examined using a rat multi
      organ carcinogenesis model. Groups of twenty F344 male rats were treated
      sequentially with an initiation regimen of N-diethylnitrosamine, N-methyl-N
      nitrosourea, N-butyl-N-(4-hydroxybutyl)nitrosamine, N,N'-dimethylhydrazine and
      2,2'-dihydroxy-di-n-propylnitrosamine during the first 4 weeks, followed by
      AP+NaNO2, AP+NaNO2+HTHQ, AP+NaNO2+AsA, NaNO2+HTHQ, NaNO2+AsA, each of the
      individual chemicals alone or basal diet and tap water as a control. All
      surviving animals were killed at week 28, and major organs were examined
      histopathologically for development of preneoplastic and neoplastic lesions. In
      the AP+NaNO2 group, the incidences of hepatocellular adenomas and
      hemangiosarcomas were 95% and 35%, respectively. When HTHQ or AsA was
      simultaneously administered, the incidences decreased to 58% and 11%, or to 80%
      and 15%, respectively. On the other hand, in the AP+NaNO2 group and the NaNO2
      alone group, when HTHQ, but not AsA, was simultaneously administered, the
      incidence of carcinomas in the forestomach significantly increased. The results
      suggest that HTHQ can prevent tumor production induced by AP and NaNO2 more
      effectively than AsA. On the other hand, an enhancing or possible carcinogenic
      effect of simultaneous administration of HTHQ and NaNO2 only on the forestomach
      is suggested, while simultaneous treatment with the same dose of AsA and NaNO2
      may not be carcinogenic to the forestomach or other organs.

PMID- 12495470
TI  - Primary malignant lymphoma of the brain: mutation pattern of rearranged
      immunoglobulin heavy chain gene.
AB  - Using reverse transcription-polymerase chain reaction (RT-PCR), six primary brain
      lymphomas, pathologically diagnosed as diffuse large B-cell lymphoma, were
      examined for rearranged VH-D-JH sequences of the immunoglobulin heavy chain gene,
      focusing on somatic mutations and intraclonal heterogeneity. The reliability of
      the isolated PCR clones was confirmed by in situ hybridization (ISH) with
      complementarity-determining region (CDR) 3 oligonucleotide probes. Sequence
      analysis of the PCR clones revealed a high frequency of somatic mutation, ranging
      from 8.8 to 27.3% (mean 18.2%) in the VH gene segments in all the lymphomas. A
      significantly lower frequency of replacement (R) mutations than expected was also
      seen in their frameworks (FRs) in all cases. These findings suggested that the
      precursor cells were germinal center (GC)-related cells in these lymphomas.
      However, despite extensive cloning experiments, intraclonal heterogeneity was not
      detected in any case except for one in which it could not be ruled out. Thus, it
      seemed likely that all of our brain lymphomas were derived from GC-related cells
      and that at least most of them were from post-GC cells.

PMID- 12495472
TI  - Costunolide triggers apoptosis in human leukemia U937 cells by depleting
      intracellular thiols.
AB  - We have previously demonstrated that costunolide, a biologically active compound
      that was isolated from the stem bark of Magnolia sieboldii, induced apoptosis in
      human cancer cells. In the present study, we investigated the underlying
      mechanisms and suggest that costunolide induces apoptosis in human promonocytic
      leukemia U937 cells by depleting the intracellular thiols. Costunolide treatment
      rapidly depleted the intracellular reduced glutathione (GSH) and protein thiols,
      and this preceded the occurrence of apoptosis. Pretreatment with sulfhydryl
      compounds such as GSH, N-acetyl-L-cysteine, dithiothreitol and 2-mercaptoethanol
      almost completely blocked the costunolide-induced apoptosis, highlighting the
      significance of the intracellular thiol level in the process. Furthermore,
      overexpression of Bcl-2 also significantly attenuated the effects of costunolide.
      The apoptosis-inducing activity of costunolide is likely to depend on the
      exomethylene moiety because derivatives in which this group was reduced, such as
      dihydrocostunolide and saussurea lactone, did not deplete the cellular thiols and
      showed no apoptotic activity. Taken together, the present study demonstrates that
      the costunolide-induced apoptosis depends on intracellular thiols contents, which
      are modulated by Bcl-2.

PMID- 12495471
TI  - Differential mechanisms of constitutive Akt/PKB activation and its influence on
      gene expression in pancreatic cancer cells.
AB  - Activated Akt/protein kinase B transmits oncogenic signals leading to inhibition
      of apoptosis, cellular proliferation, and tolerance to hypoxia. Presently,
      mutational inactivation of PTEN and activation of Ras are considered to be the
      major causes of Akt activation. Here we report differential mechanisms of
      constitutive Akt activation in 4 human pancreatic cancer cell lines (KMP-3, KMP
      4, PCI-66, and PCI-68). These 4 cell lines displayed phosphorylation and
      functional activation of Akt both in the presence and absence of serum, while
      three control cell lines (PCI-79, KMP-8, and PSN-1) did so only in the presence
      of serum in culture. All the 7 cell lines harbored K-Ras activated by mutations
      at codon 12 resulting in MAP kinase kinase (MEK1/2) phosphorylation, and all
      except one (KMP-8) had p53 mutations, indicating that these mutations are not
      sufficient for constitutive Akt activation. KMP-3 and KMP-4 had lost PTEN
      function owing to loss of expression or a mutation, but PCI-66 and PCI-68
      retained wild-type PTEN. Phosphorylation of Akt was inhibited by the
      phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and the tyrosine kinase
      inhibitor genistein in KMP-3 and KMP-4 cells, indicating that upstream signals
      are required for Akt activation in these two cell lines. In contrast, neither
      LY294002 nor genistein inhibited Akt activation in PCI-66 and PCI-68 cells,
      indicating the involvement of another unknown mechanism of Akt activation
      independent of PI3K-mediated signaling to Akt. Irrespective of the differential
      mechanisms, the 4 cell lines showed similar mRNA expression patterns of 49 genes
      assessed by cDNA array as compared to the 3 cell lines without Akt activation,
      suggesting that the mechanisms have the same consequences on the downstream
      signaling of the constitutive Akt activation.

PMID- 12495473
TI  - 1-beta-D-arabinofuranosylcytosine is cytotoxic in quiescent normal lymphocytes
      undergoing DNA excision repair.
AB  - We have sought to clarify the potential activity of the S-phase-specific
      antileukemic agent 1-beta-D-arabinofuranosylcytosine (ara-C), an inhibitor of DNA
      synthesis, in quiescent cells that are substantially non-sensitive to nucleoside
      analogues. It was hypothesized that the combination of ara-C with DNA damaging
      agents that initiate DNA repair will expand ara-C cytotoxicity to non-cycling
      cells. The repair kinetics, which included incision of damaged DNA, gap-filling
      by DNA synthesis and rejoining by ligation, were evaluated using the single cell
      gel electrophoresis (Comet) assay and the thymidine incorporation assay. When
      normal lymphocytes were treated with ultraviolet C or with 1,3-bis(2-chloroethyl)
      1-nitrosourea (BCNU), the processes of DNA excision repair were promptly
      initiated and rapidly completed. When the cells were incubated with ara-C prior
      to irradiation or BCNU treatment, the steps of DNA synthesis and rejoining in the
      repair processes were both inhibited. The ara-C-mediated inhibition of the repair
      processes was concentration-dependent, with the effect peaking at 10 microM. The
      combination of ara-C with these DNA repair initiators exerted subsequent
      cytotoxicity, which was proportional to the extent of the repair inhibition in
      the presence of ara-C. In conclusion, ara-C was cytotoxic in quiescent cells
      undergoing DNA repair. This might be attributed to unrepaired DNA damage that
      remained in the cells, thereby inducing lethal cytotoxicity. Alternatively, ara-C
      might exert its own cytotoxicity by inhibiting DNA synthesis in the repair
      processes. Such a strategy may be effective against a dormant subpopulation in
      acute leukemia that survives chemotherapy.

PMID- 12495474
TI  - Quantitative measurement of thymidylate synthase and dihydropyrimidine
      dehydrogenase mRNA level in gastric cancer by real-time RT-PCR.
AB  - We used real-time reverse-transcription polymerase chain reaction (RT-PCR) to
      assay expression of the mRNA of thymidylate synthase (TS) and dihydropyrimidine
      dehydrogenase (DPD) in gastric cancer tissue with the objective of establishing a
      system to measure TS and DPD in ultra-low-volume samples. Nude mouse xenografts
      of 5 human gastric cancer cell lines and 85 clinical samples were used as the
      specimens in this study. Sensitivity to 5-fluorouracil (5-FU) was determined on
      the basis of the relative tumor proliferation rate in mice and the results of ATP
      assay using serum-free cultures of the clinical samples. mRNA expression was
      measured in tumor tissue by real-time RT-PCR using the ABI PRISM 7700 system. The
      values for expression of the mRNA for TS and DPD were corrected according to the
      level of glyceraldehyde-3-phosphate dehydrogenase mRNA expression. The xenografts
      yielded correlations between TS and DPD mRNA expression and the activity of the
      enzymes (TS: rs=0.700, DPD: rs=0.900), and an inverse correlation was noted
      between the mRNA levels and sensitivity to 5-FU (TS: rs=-0.900, DPD: rs=-0.800).
      The clinical samples showed an inverse correlation between 5-FU sensitivity and
      mRNA expression (TS: rs=-0.518, DPD: rs=-0.564). Sensitivity to 5-FU was noted
      only in cases in which TS mRNA expression and DPD mRNA expression were both low.
      Real-time RT-PCR can provide a highly sensitive assessment of TS and DPD mRNA
      expression in gastric cancer, and it was useful for predicting 5-FU sensitivity.

PMID- 12495475
TI  - Estrogen receptor expression and estrogen receptor-independent cytotoxic effects
      of tamoxifen on malignant rhabdoid tumor cells in vitro.
AB  - Recent studies have shown that the antiestrogen tamoxifen (TAM) can be used in
      the treatment of malignant neoplasms other than breast cancer. In the present
      study, we investigated the expression of estrogen receptor (ER) in six malignant
      rhabdoid tumor (MRT) cell lines. Alterations in MRT cell growth in response to
      estrogen or antiestrogens (4-hydroxytamoxifen (4-OHT), TAM, and ICI 182 780) were
      also investigated. RT-PCR and western blotting showed that ER-alpha was expressed
      in three of the six MRT cell lines. While 17-beta-estradiol (E2) did not
      significantly alter MRT cell line proliferation, the hydroxylated tamoxifen
      metabolite 4-OHT significantly inhibited the growth of all 6 MRT cell lines.
      However, the steroidal antiestrogen ICI 182 780 did not alter the proliferation
      of any of the MRT cell lines. 4-OHT induced apoptosis in both ER-alpha-negative
      and ER-alpha-positive MRT cell lines, as assessed by nuclear morphology and DNA
      fragmentation. Neither growth inhibition nor induction of apoptosis due to 4-OHT
      was blocked by the addition of excess E2. Our data suggested that 4-OHT induced
      cytotoxic effects against MRT cells, and that these effects were independent of
      ER expression.

PMID- 12495476
TI  - Peroxisome proliferator-activated receptor gamma activation induces cell cycle
      arrest via the p53-independent pathway in human anaplastic thyroid cancer cells.
AB  - Anaplastic thyroid carcinoma is one of the most aggressive human malignancies.
      Outcomes of intensive multimodal therapy have been far from satisfactory.
      Furthermore, p53 gene dysfunction, often found in this type of cancer, is known
      to impair the efficacy of the therapeutic agents. Specific ligands for peroxisome
      proliferator activated receptor gamma (PPAR-gamma) induce growth suppression in
      some tumor cells. In this study, we investigated the role of PPAR-gamma in
      anaplastic thyroid cancer cell lines (OCUT-1, ACT-1). PPAR-gamma was expressed
      and functional in both cell lines. Activation of PPAR-gamma with its specific
      ligands, troglitazone and 15-deoxy-delta 12,14-prostaglandin J2, inhibited cell
      growth in a dose-dependent manner through inducing G1 cell cycle arrest. P53
      protein expression differed in OCUT-1 and in ACT-1, though the levels stayed
      constant irrespective of ligand exposure in both cell lines. In contrast, p21 and
      p27 proteins were induced in a dose-dependent manner in both situations. This
      study showed that PPAR-gamma ligands were able to induce growth suppression in
      anaplastic thyroid cancer cells via a p53-independent, but p21- and p27-dependent
      cytostatic pathway. These tumor-suppressive effects of PPAR-gamma may provide a
      novel approach to the treatment of anaplastic thyroid cancer.

PMID- 12495477
TI  - Impact of the p53 status of the tumor cells on the effect of reactor neutron beam
      irradiation, with emphasis on the response of intratumor quiescent cells.
AB  - Human head and neck squamous cell carcinoma cells transfected with mutant p53
      (SAS/mp53) or with neo vector as a control (SAS/neo) were inoculated
      subcutaneously into both the hind legs of Balb/cA nude mice. Tumor-bearing mice
      received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating
      (P) cells in the tumors. After administration of sodium borocaptate-10B (BSH) or
      p-boronophenylalanine-10B (BPA), the tumors were irradiated with neutron beams.
      The tumors not treated with 10B-compound were irradiated with neutron beams or
      gamma-rays. The tumors were then excised, minced and trypsinized. The tumor cell
      suspensions thus obtained were incubated with a cytokinesis blocker, and the
      micronucleus (MN) frequency in cells without BrdU labeling (=quiescent (Q) cells)
      was determined using immunofluorescence staining for BrdU. Meanwhile, 6 h after
      irradiation, tumor cell suspensions obtained in the same manner were used for
      determining the frequency of apoptosis in Q cells. The MN and apoptosis
      frequencies in total (P+Q) tumor cells were determined from the tumors that were
      not pretreated with BrdU. Without 10B-carriers, in both tumors, the relative
      biological effectiveness of neutrons was greater in Q cells than in total cells,
      and larger for low than high cadmium ratio neutrons. With 10B-carriers, the
      sensitivity was increased for each cell population, especially for total cells.
      BPA increased both frequencies for total cells more than BSH. Nevertheless, the
      sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q
      cells. These sensitization patterns in combination with 10B-carriers were clearer
      in SAS/neo than in SAS/mp53 tumors. The p53 status of the tumor cells had the
      potential to affect the response to reactor neutron beam irradiation following
      10B-carrier administration.

PMID- 12495478
TI  - Microarray-based analysis of anti-angiogenic activity of demethoxycurcumin on
      human umbilical vein endothelial cells: crucial involvement of the down
      regulation of matrix metalloproteinase.
AB  - cDNA microarray-based gene expression analysis has been successfully employed to
      explore the action mechanism and to validate the targets of several drugs. In the
      present study, we evaluated anti-angiogenic activity of demethoxycurcumin (DC), a
      structural analog of curcumin, isolated from Curcuma aromatica, and investigated
      the effect of DC on genetic reprogramming in cultured human umbilical vein
      endothelial cells (HUVECs) using cDNA microarray analysis. Of 1024 human cancer
      focused genes arrayed, 187 genes were up-regulated and 72 genes were down
      regulated at least 2-fold by DC. Interestingly, 9 angiogenesis-related genes were
      down-regulated over 5-fold in response to DC, suggesting that the genetic
      reprogramming was crucially involved in anti-angiogenesis by the compound. To
      verify the results obtained from cDNA microarray analysis, matrix
      metalloproteinase-9 (MMP-9), the product of one of the angiogenesis-related genes
      down-regulated over 5-fold by DC, was investigated using gelatin zymography. DC
      potently inhibited the expression of MMP-9, yet showed no direct effect on its
      activity. These data show that gene expressional change of MMP-9 is a major
      mediator for angiogenesis inhibition by DC. All genes identified and microarray
      data are available on the web at http://dasan.sejong.ac.kr/~bioprobe/.

PMID- 12495479
TI  - A novel theory to explain species diversity in landscapes: positive frequency
      dependence and habitat suitability.
AB  - Theories to explain the diversity of species have required that individual
      species occupy unique niches and/or vary in their response to environmental
      factors. Positive interactions within a species, although common in communities,
      have not been thought to maintain species diversity because in non-spatial models
      the more abundant species always outcompetes the rarer species. Here, we show,
      using a stochastic spatial model, that positive intraspecific interactions such
      as those caused by positive frequency dependence and/or priority effects, can
      maintain species diversity if interactions between individuals are primarily
      local and the habitat contains areas that cannot be colonized by any species,
      such as boulders or other physical obstructions. When intraspecific interactions
      are primarily neutral, species diversity will eventually erode to a single
      species. When the landscape is homogeneous (i.e. does not contain areas that
      cannot be colonized by any species), the presence of strong intraspecific
      interactions will not maintain diversity.

PMID- 12495480
TI  - Integration of alien plants into a native flower-pollinator visitation web.
AB  - Introduced alien species influence many ecosystem services, including pollination
      of plants by animals. We extend the scope of recent 'single species' studies by
      analysing how alien plant species integrate themselves into a native flower
      visitation web. Historical records for a community in central USA show that 456
      plant species received visits from 1429 insect and 1 hummingbird species,
      yielding 15 265 unique interactions. Aliens comprised 12.3% of all plant species,
      whereas only a few insects were alien. On average, the flowers of alien plants
      were visited by significantly fewer animal species than those of native plants.
      Most of these visitors were generalists, visiting many other plant species. The
      web of interactions between flowers and visitors was less richly connected for
      alien plants than for natives; nonetheless, aliens were well integrated into the
      native web. Because most visitors appear to be pollinators, this integration
      implies possible competitive and facilitative interactions between native and
      alien plants, mediated through animal visitors to flowers.

PMID- 12495481
TI  - Protected areas as biodiversity benchmarks for human impact: agriculture and the
      Serengeti avifauna.
AB  - Protected areas as biodiversity benchmarks allow a separation of the direct
      effects of human impact on biodiversity loss from those of other environmental
      changes. We illustrate the use of ecological baselines with a case from the
      Serengeti ecosystem, Tanzania. We document a substantial but previously unnoted
      loss of bird diversity in agriculture detected by reference to the immediately
      adjacent native vegetation in Serengeti. The abundance of species found in
      agriculture was only 28% of that for the same species in native savannah.
      Insectivorous species feeding in the grass layer or in trees were the most
      reduced. Some 50% of both insectivorous and granivorous species were not recorded
      in agriculture, with ground-feeding and tree species most affected. Grass-layer
      insect abundance and diversity was much reduced in agriculture, consistent with
      the loss of insectivorous birds. These results indicate that many species of
      birds will become confined to protected areas over time. We need to determine
      whether existing protected areas are sufficiently large to maintain viable
      populations of insectivorous birds likely to become confined to them. This study
      highlights the essential nature of baseline areas for assessing causes of change
      in human-dominated systems and for developing innovative strategies to restore
      biodiversity.

PMID- 12495482
TI  - An ounce of prevention or a pound of cure: bioeconomic risk analysis of invasive
      species.
AB  - Numbers of non-indigenous species--species introduced from elsewhere - are
      increasing rapidly worldwide, causing both environmental and economic damage.
      Rigorous quantitative risk-analysis frameworks, however, for invasive species are
      lacking. We need to evaluate the risks posed by invasive species and quantify the
      relative merits of different management strategies (e.g. allocation of resources
      between prevention and control). We present a quantitative bioeconomic modelling
      framework to analyse risks from non-indigenous species to economic activity and
      the environment. The model identifies the optimal allocation of resources to
      prevention versus control, acceptable invasion risks and consequences of invasion
      to optimal investments (e.g. labour and capital). We apply the model to zebra
      mussels (Dreissena polymorpha), and show that society could benefit by spending
      up to US$324 000 year(-1) to prevent invasions into a single lake with a power
      plant. By contrast, the US Fish and Wildlife Service spent US$825 000 in 2001 to
      manage all aquatic invaders in all US lakes. Thus, greater investment in
      prevention is warranted.

PMID- 12495483
TI  - Are you looking at me? Accuracy in processing line-of-sight in Turner syndrome.
AB  - The behavioural phenotype of women with Turner syndrome (X-monosomy, 45,X) is
      poorly understood, but includes reports of some social development anomalies.
      With this in mind, accuracy of direction of gaze detection was investigated in
      women with Turner syndrome. Two simple experimental tasks were used to test the
      prediction that the ability to ascertain gaze direction from face photographs
      showing small lateral angular gaze deviations would be impaired in this syndrome,
      compared with a control population of men and women. The prediction was confirmed
      and was found to affect both the detection of egocentric gaze from the eyes ('is
      the face looking at me?') and the detection of allocentric gaze, where the eyes
      in a photographed face inspected one of a number of locations of attention
      ('where is she looking?'). We suggest that dosage-sensitive X-linked genes
      contribute to the development of gaze-monitoring abilities.

PMID- 12495484
TI  - Noisy clues to the origin of life.
AB  - The origin of stable self-replicating molecules represents a fundamental obstacle
      to the origin of life. The low fidelity of primordial replicators places
      restrictions on the quantity of information encoded in a primitive nucleic acid
      alphabet. Further difficulties for the origin of life are the role of drift in
      small primordial populations, reducing the rate of fixation of superior
      replicators, and the hostile conditions increasing developmental noise. Thus,
      mutation, noise and drift are three different stochastic effects that are assumed
      to make the evolution of life improbable. Here we show, to the contrary, how
      noise present in hostile early environments can increase the probability of
      faithful replication, by amplifying selection in finite populations. Noise has
      negative consequences in infinite populations, whereas in finite populations, we
      observe a synergistic interaction among noise sources. Hence, two factors
      formerly considered inimical to the origin of life-developmental noise and drift
      in small populations-can in combination give rise to conditions favourable to
      robust replication.

PMID- 12495485
TI  - How old is the Hawaiian biota? Geology and phylogeny suggest recent divergence.
AB  - This study quantifies long-term landscape changes in the Hawaiian archipelago
      relating to dispersal, speciation and extinction. Accounting for volcano growth,
      subsidence and erosion, we modelled the elevations of islands at time intervals
      of 0.5 Myr for the last 32 Myr; we also assessed the variation in the spacing of
      volcanoes during this period. The size, spacing and total number of volcanic
      islands have varied greatly over time, with the current landscape of large,
      closely spaced islands preceded by a period with smaller, more distantly spaced
      islands. Considering associated changes in rates of dispersal and speciation,
      much of the present species pool is probably the result of recent colonization
      from outside the archipelago and divergence within contemporary islands, with
      limited dispersal from older islands. This view is in accordance with abundant
      phylogenetic studies of Hawaiian organisms that estimate the timing of
      colonization and divergence within the archipelago. Twelve out of 15 multi
      species lineages have diverged within the lifetime of the current high islands
      (last 5 Myr). Three of these, and an additional seven (mostly single-species)
      lineages, have colonized the archipelago within this period. The timing of
      colonization of other lineages remains uncertain.

PMID- 12495486
TI  - Incorporating spatial criteria in optimum reserve network selection.
AB  - Considering the spatial location of sites that are to be selected for inclusion
      in a protected reserve network may be necessary to facilitate dispersal and long
      term persistence of species in the selected sites. This paper presents an integer
      programming (IP) approach to the reserve network selection problem where spatial
      considerations based on intersite distances are taken into account when selecting
      reserve sites. The objective is to reduce the fragmentation of preserved sites
      and design a compact reserve network. Two IP formulations are developed which
      minimize the sum of pairwise distances and the maximum intersite distance between
      all sites in the reserve network, respectively, while representing all species
      under consideration. This approach is applied to a pond invertebrate dataset
      consisting of 131 sites containing 256 species in Oxfordshire, UK. The results
      show that significant reductions in reserve fragmentation can be achieved,
      compared with spatially unrestricted optimum reserve selection, at the expense of
      a small loss in reserve efficiency.

PMID- 12495487
TI  - Cyclic dynamics in simulated plant populations.
AB  - Despite the general interest in nonlinear dynamics in animal populations, plant
      populations are supposed to show a stable equilibrium that is attributed to
      fundamental differences compared with animals. Some studies find more complex
      dynamics, but empirical studies usually are too short and most modelling studies
      ignore important spatial aspects of local competition and establishment.
      Therefore, we used a spatially explicit individual-based model of a hypothetical,
      non-clonal perennial to explore which mechanisms might generate complex dynamics,
      i.e. cycles. The model is based on the field-of-neighbourhood approach that
      describes local competition and establishment in a phenomenological manner. We
      found cyclic population dynamics for a wide spectrum of model variants, provided
      that mortality is determined by local competition and recruitment is virtually
      completely suppressed within the zone of influence of established plants. This
      destabilizing effect of local processes within plant populations might have wide
      ranging implications for the understanding of plant community dynamics and
      coexistence.

PMID- 12495488
TI  - Association patterns and shoal fidelity in the three-spined stickleback.
AB  - We investigated pairwise association patterns and shoal fidelity in free-ranging,
      individual three-spine sticklebacks (Gasterosteus aculeatus) by capturing entire
      shoals of sticklebacks and tagging each shoal member with a unique individual
      mark before releasing the shoal at the point of capture. We recaptured tagged
      fishes in the study area on five subsequent days, noting their identity, their
      location and the individuals with which they were associated. Stable partner
      associations between fishes were observed which might provide the basis for shoal
      fidelity via social networks. These results suggest the potential for the kinds
      of inter-individual association patterns assumed by models of predator inspection
      and 'tit-for-tat' behaviours in free-ranging fishes.

PMID- 12495489
TI  - Major adaptive radiation in neritopsine gastropods estimated from 28S rRNA
      sequences and fossil records.
AB  - A well-supported phylogeny of the Neritopsina, a gastropod superorder archaic in
      origin, radiated ecologically and diverse in morphology, is reconstructed based
      on partial 28S rRNA sequences. The result (Neritopsidae (Hydrocenidae
      (Helicinidae + Neritiliidae) (Neritidae + Phenacolepadidae))) is highly congruent
      with the fossil records and the character distribution of reproductive tracts in
      extant taxa. We suggest that the Neritopsina originated in subtidal shallow
      waters, invaded the land and became fully terrestrial at least three times in
      different clades, by the extinct Dawsonellidae in the Late Palaeozoic and by the
      Helicinidae and Hydrocenidae in the Mesozoic. Invasion of fresh- and brackish
      waters is prevalent among the Neritopsina as the Jurassic and freshwater
      ancestory is most probable for helicinids. The Phenacolepadidae, a group
      exclusively inhabiting dysoxic environments, colonized deep-sea hydrothermal
      vents and seeps in the Late Cretaceous or Early Cenozoic. Submarine caves have
      served as refuges for the archaic Neritopsidae since the Early to Middle
      Cenozoic, and the marine neritopsine slug Titiscania represents a highly
      specialized but relatively recent offshoot of this family. The Neritiliidae is
      another clade to be found utilizing submarine caves as shelter by the Oligocene;
      once adapted to the completely dark environment, but some neritiliids have
      immigrated to surface freshwater habitats.

PMID- 12495490
TI  - The period gene and allochronic reproductive isolation in Bactrocera cucurbitae.
AB  - Clock genes that pleiotropically control circadian rhythm and the time of mating
      may cause allochronic reproductive isolation in the melon fly Bactrocera
      cucurbitae (Coquillett) (Diptera: Tephritidae). Flies with a shorter circadian
      period (ca. 22 h of locomotor activity rhythm) mated 5 h earlier in the day than
      those with a longer circadian period (ca. 30 h). Mate-choice tests demonstrated
      significant pre-mating isolation between populations with short and long
      circadian periods. Pre-mating isolation did not occur when the mating time was
      synchronized between the two populations by photoperiodic controls, indicating
      that reproductive isolation is due to variations in the time of mating and not
      any unidentified ethological difference between the two populations. We cloned
      the period (per) gene of B. cucurbitae that is homologous to the per gene in
      Drosophila. The relative level of per mRNA in the melon fly exhibited a robust
      daily fluctuation under light : dark conditions. The fluctuation of per
      expression under dark : dark conditions is closely correlated to the locomotor
      rhythm in B. cucurbitae. These results suggest that clock genes can cause
      reproductive isolation via the pleiotropic effect as a change of mating time.

PMID- 12495491
TI  - Competition for male reproductive investment elevates testosterone levels in
      female dunnocks, Prunella modularis.
AB  - In many songbirds, females occasionally sing in contexts of high female-female
      competition. Testosterone may be involved in the activation of song, because
      testosterone implants elicit female song in many species with rare female song. A
      possible mechanism for the hormonal control of female song is provided by the
      challenge hypothesis, which predicts a rise in testosterone in response to
      aggressive interactions during socially unstable situations. We tested this by
      comparing faecal testosterone levels in polygynandrous and monogamous female
      dunnocks. In groups with two to three females (polygynandry and polygyny) males
      provide less help at each nest than in groups with a single female (monogamy and
      polyandry). Polygynandrous and polygynous females are aggressive towards one
      another and attempt to expel rivals. Polygynandrous females had significantly
      higher testosterone levels than monogamous females. Competition between females
      that was induced by removal of males caused testosterone levels to rise. Further,
      female testosterone levels were correlated with the rate of 'tseep' calls, which
      are produced during aggressive encounters between females. Finally,
      polygynandrous and polygynous females sang significantly more than monogamous
      females. To the best of our knowledge, these results provide the first
      experimental support for the challenge hypothesis in female birds, and suggest
      that testosterone can regulate facultative female song in songbirds.

PMID- 12495492
TI  - Recent experience modulates forebrain gene-expression in response to mate-choice
      cues in European starlings.
AB  - Mate-choice decisions can be experience dependent, but we know little about how
      the brain processes stimuli that release such decisions. Female European
      starlings (Sturnus vulgaris) prefer males with long-bout songs over males with
      short-bout songs, and show higher expression of the immediate early gene (IEG)
      ZENK in the auditory forebrain when exposed to long-bout songs than when exposed
      to short-bout songs. We exposed female starlings to a short-day photoperiod for
      one of three durations and then, on an increased photophase, exposed them to one
      week of long-bout or short-bout song experience. We then examined their IEG
      response to novel long-bout versus novel short-bout songs by quantifying ZENK
      protein in two song-processing areas: the caudo-medial hyperstriatum ventrale and
      the caudo-medial neostriatum. ZENK expression in both areas increased with tenure
      on short-day photoperiods, suggesting that short days sensitize females to song.
      The ZENK response bias toward long-bout songs was greater in females with long
      bout experience than in females with short-bout experience, indicating that the
      forebrain response bias toward a preferred trait depends on recent experience
      with that category of trait. This surprising level of neuroplasticity is
      immediately relevant to the natural history and fitness of the organism, and may
      underlie a mechanism for optimizing mate-choice criteria amidst locally variable
      distributions of secondary sexual characteristics.

PMID- 12495493
TI  - Sex-biased dispersal in a salmonid fish.
AB  - We tested the hypothesis that dispersal is sex biased in an unexploited
      population of brook trout, Salvelinus fontinalis, on Cape Race, Newfoundland,
      Canada. Based on the assumptions that trout are promiscuous and that reproductive
      success is limited primarily by either number of mates (males) or fecundity
      (females), we predicted that males would disperse greater distances than females.
      We also tested the hypothesis that trout populations comprise stationary and
      mobile individuals, predicting that males have greater mobility than females.
      Based on a mark-recapture study of 943 individually tagged fishes, 191 of which
      were recaptured over 5 years, we find strong support for our hypothesis of male
      biased dispersal in brook trout. Averaged among all 11 resampling periods, males
      dispersed 2.5 times as far as females; during the spawning period only, male
      dispersal exceeded that by females almost fourfold. Both sexes were heterogeneous
      with respect to movement, with a lower incidence of mobility among females
      (29.6%) than males (41.1%); mobile males dispersed six times further than mobile
      females. We conclude that this sex bias reduces mate competition among male kin
      and decreases the probability that males will reproduce with related females.

PMID- 12495494
TI  - Testosterone increases perceived dominance but not attractiveness in human males.
AB  - Recent evidence suggests that certain features on the human face indicate
      hormonal levels during growth, and that women judge the attractiveness of
      potential partners based on the appearance of these features. One entrenched
      notion is male facial features that are affected by testosterone are used as
      direct cues in mate preference. Testosterone may be particularly revealing as it
      is purported to be an honest indicator of male fitness. Increased testosterone
      may impose an immunocompetence handicap on the bearer and only the best males can
      carry this handicap. To date, tests of this theory have been indirect, and have
      relied on digital manipulations that represent unrealistic continuums of
      masculine and feminine faces. We provide a much more direct test by manipulating
      digitally male faces to mimic known shape variation, caused by varying levels of
      testosterone through puberty. We produced a continuum of faces that ranged from
      low to high levels of testosterone in male faces and asked women to choose the
      points on the continuum that appeared most attractive and most physically
      dominant. Our data indicate that high testosterone faces reveal dominance.
      However, there is no evidence of directional selection for increased (or
      decreased) testosterone in terms of attractiveness to the opposite sex. We
      discuss the relevance and applicability of evolutionary interpretations of our
      data and, contrary to predictions, provide evidence of stabilizing selection
      acting on testosterone through mate preferences.

PMID- 12495495
TI  - Older males signal more reliably.
AB  - The hypothesis that females prefer older males because they have higher mean
      fitness than younger males has been the centre of recent controversy. These
      discussions have focused on the success of a female who prefers males of a
      particular age class when age cues, but not quality cues, are available. Thus, if
      the distribution of male quality changes with age, such that older males have on
      average genotypes with higher fitness than younger males, then a female who mates
      with older males has fitter offspring, which allows the female preference to
      spread through a genetic correlation. We develop a general model for male display
      in a species with multiple reproductive bouts that allows us to identify the
      conditions that promote reliable signalling within an age class. Because males
      have opportunities for future reproduction, they will reduce their levels of
      advertising compared with a semelparous species. In addition, because higher
      quality males have more future reproduction, they will reduce their advertising
      more than low-quality males. Thus, the conditions for reliable signalling in a
      semelparous organism are generally not sufficient to produce reliable signalling
      in species with multiple reproductive bouts. This result is due to the
      possibility of future reproduction so that, as individuals age and the
      opportunities for future reproduction fade, signalling becomes more reliable.
      This provides a novel rationale for female preference for older mates; older
      males reveal more information in their sexual displays.

PMID- 12495496
TI  - Sexual size dimorphism in anurans.
AB  - Several hypotheses have been proposed to explain the direction and extent of
      sexual size dimorphism in anurans (in which males are usually smaller than
      females) as a result of sexual selection. Here, we present an analysis to test
      the hypothesis that sexual dimorphism in anurans is largely a function of
      differences between the sexes in life-history strategies. Morphological and
      demographic data for anurans were collected from the literature, and the mean
      size and age in each sex were calculated for 51 populations, across 30 species
      and eight genera. Comparisons across 14 Rana species, eight Bufo species and
      across the genera showed a highly significant relationship between size
      dimorphism, measured using the female-male size ratio, and mean female-male age
      difference. A comparison of a subset of 17 of these species for which
      phylogenetic information was available, using the method of independent
      contrasts, yielded a similar result. These results indicate that most of the
      variation in size dimorphism in the anura can be explained in terms of
      differences in the age structure between the sexes in breeding populations. If
      sexual selection has an effect on size dimorphism in anurans, it is likely to be
      only a secondary one.

PMID- 12495497
TI  - Sexual selection and speciation in mammals, butterflies and spiders.
AB  - Recently refined evolutionary theories propose that sexual selection and
      reproductive conflict could be drivers of speciation. Male and female
      reproductive optima invariably differ because the potential reproductive rate of
      males almost always exceeds that of females: females are selected to maximize
      mate 'quality', while males can increase fitness through mate 'quantity'. A
      dynamic, sexually selected conflict therefore exists in which 'competitive' males
      are selected to override the preference tactics evolved by 'choosy' females. The
      wide variation across taxa in mating systems therefore generates variance in the
      outcome of intrasexual conflict and the strength of sexual selection: monandry
      constrains reproductive heterozygosity and allows female choice to select and
      maintain particular (preferred) genes; polyandry promotes reproductive
      heterozygosity and will more likely override female choice. Two different
      theories predict how sexual selection might influence speciation. Traditional
      ideas indicate that increased sexual selection (and hence conflict) generates a
      greater diversity of male reproductive strategies to be counteracted by female
      mate preferences, thus providing elevated potentials for speciation as more
      evolutionary avenues of male-female interaction are created. A less intuitively
      obvious theory proposes that increased sexual selection and conflict constrains
      speciation by reducing the opportunities for female mate choice under polyandry.
      We use a comparative approach to test these theories by investigating whether two
      general measures of sexual selection and the potential for sexual conflict have
      influenced speciation. Sexual size dimorphism (across 480 mammalian genera, 105
      butterfly genera and 148 spider genera) and degree of polyandry (measured as
      relative testes size in mammals (72 genera) and mating frequency in female
      butterflies (54 genera)) showed no associations with the variance in speciosity.
      Our results therefore show that speciation occurs independently of sexual
      selection.

PMID- 12495498
TI  - Mating system and sex ratios of a pollinating fig wasp with dispersing males.
AB  - Recent studies have used sex ratios to quantify the mating systems of organisms,
      the argument behind it being that more female-biased sex ratios are an indication
      of higher local mate competition, which goes hand-in-hand with higher levels of
      inbreeding. Although qualitative tests of the effects of mating systems on sex
      ratios abound, there is a dearth of studies that quantify both the mating system
      and the sex ratio. I use a colour dimorphism with a simple Mendelian inheritance
      to quantify the mating system of an unusual fig-pollinating wasp in which males
      disperse to obtain matings on non-natal mating patches. In qualitative agreement
      with initial expectations, the sex ratios of single foundresses are found to be
      higher than those of regular species. However, by quantifying the mating system,
      it is shown that the initial expectation is incorrect and this species' sex ratio
      is a poor predictor of its mating system (it underestimates the frequency of sib
      mating). The species has a very high variance in sex ratio suggesting that excess
      males can simply avoid local mate competition (and hence a lowered fitness to
      their mother) by dispersing to other patches.

PMID- 12495499
TI  - Egg-size evolution in aquatic environments: does oxygen availability constrain
      size?
AB  - Selection against large eggs has been proposed for aquatic environments,
      putatively because large eggs should have more difficulty obtaining the required
      oxygen. Here, we use brown trout (Salmo trutta) eggs to provide an experimental
      test of this hypothesis. At high levels of dissolved oxygen (14 mg l(-1)), egg
      survival was high and independent of egg size. At low oxygen levels (2.3 mg l(
      1)), survival decreased overall, and was higher for large-egged than small-egged
      siblings. Thus, contrary to conventional expectation, low oxygen levels selected
      for large rather than small eggs. A second experiment using Atlantic salmon (S.
      salar) eggs indicated that oxygen consumption increases relatively slowly with
      increasing egg mass (allometric constant = 0.44). The failure of the conventional
      'bigger is worse during incubation' hypothesis may thus be due to the erroneous
      assumption that oxygen consumption increases at a greater rate with increasing
      egg mass than does the egg surface area that is available for oxygen diffusion.
      We also demonstrate, using data from Atlantic salmon, that nest-specific oxygen
      consumption decreases with increasing egg size, but that this effect is more
      pronounced for large than for small females. This may help to explain the
      positive correlation between adult body size and egg size observed in fishes that
      cluster their eggs.

PMID- 12495500
TI  - Power of shell-rapping signals influences physiological costs and subsequent
      decisions during hermit crab fights.
AB  - Understanding the costs of signals used in fights is the key to understanding
      decisions made by contestants. Hermit crabs use shell rapping. This is a clearly
      defined agonistic signal, which can be quantified in temporal terms and in the
      power of the key shell-rapping signal component. We examine the relationship
      between the power expended by attacking hermit crabs and their consequent lactate
      levels. High power expenditure over the whole fight leads to high lactate, and
      attackers give up when lactate is high. Some defenders give up early in fights,
      particularly if the power of raps in early bouts they receive is high. These
      defenders and those not allowed to fight have low glucose, but those that
      successfully resist eviction have high glucose. Glucose is mobilized in an
      attempt to resist; nevertheless, some defenders that attempt resistance are still
      evicted by persistent attackers. Thus, early power of the signal is a major
      determinant of success for attackers, albeit at a cost. These data show the link
      between power, repetition of a signal, metabolic consequences and decisions of
      contestants in fights. The different activities, decisions and costs of the two
      roles are not adequately described by existing models of contests.

PMID- 12495501
TI  - Predictably simple: assemblages of caterpillars (Lepidoptera) feeding on
      rainforest trees in Papua New Guinea.
AB  - Predictability in the composition of tropical assemblages of insect herbivores
      was studied using a sample of 35,952 caterpillars (Lepidoptera) from 534 species,
      feeding on 69 woody species from 45 genera and 23 families in a lowland
      rainforest in Papua New Guinea. Caterpillar assemblages were strongly dominated
      by a single species (median 48% of individuals and 49% of biomass). They were
      spatially and temporally constant (median normalized expected species shared
      (NESS) similarity between assemblages from the same host was greater than or
      equal to 0.85 for three sites 8-17 km apart as well as for three four-month
      periods of the year). Further, the median presence of species was 11 months per
      year. Assemblages on hosts from different families and genera were virtually
      disjunct (NESS similarity less than 0.05) as the caterpillars were mostly
      specialized to a single plant family (77% of species) and, within families, to a
      single genus (66% of species), while capable of feeding on multiple congeneric
      hosts (89% of species). The dominance of caterpillar assemblages by a small
      number of specialized species, which also exhibited low spatial and temporal
      variability, permitted robust and reliable estimates of assemblage composition
      and between-assemblage similarity from small samples, typically less than 300
      individuals per host plant. By contrast, even considerably larger samples were
      insufficient for estimates of species richness. A sample of 300 individuals was
      typically obtained from 1,050 m(2) of foliage sampled during 596 tree inspections
      (i.e. a particular tree sampled at a particular time) in the course of 19
      sampling days (median values from 69 assemblages). These results demonstrate
      that, contrary to some previous suggestions, insect herbivore assemblages in
      tropical rainforests have a predictable structure and, as such, are amenable to
      study.

PMID- 12495502
TI  - Interspecific reciprocity explains mobbing behaviour of the breeding chaffinches,
      Fringilla coelebs.
AB  - When prey animals discover a predator close by, they mob it while uttering
      characteristic sounds that attract other prey individuals to the vicinity.
      Mobbing causes a predator to vacate its immediate foraging area, which gives an
      opportunity for prey individuals to continue their interrupted daily activity.
      Besides the increased benefits, mobbing behaviour also has its costs owing to
      injuries or death. The initiator of mobbing may be at increased risk of predation
      by attracting the predator's attention, especially if not joined by other
      neighbouring prey individuals. Communities of breeding birds have always been
      considered as temporal aggregations. Since an altruist could not prevent cheaters
      from exploiting its altruism in an anonymous community, this excluded any
      possibility of explaining mobbing behaviour in terms of reciprocal altruism.
      However, sedentary birds may have become acquainted since the previous non
      breeding season. Migrant birds, forming anonymous communities at the beginning of
      the breeding season, may also develop closer social ties during the course of the
      breeding season. We tested whether a male chaffinch, a migrant bird, would
      initiate active harassment of a predator both at the beginning of the breeding
      season and a week later when it has become a member of a non-anonymous multi
      species aggregation of sedentary birds. We expected that male chaffinches would
      be less likely to initiate a mob at the beginning of the breeding season when
      part of an anonymous multi-species aggregation of migratory birds. However, their
      mobbing activity should increase as the breeding season advances. Our results
      support these predictions. Cooperation among individuals belonging to different
      species in driving the predator away may be explained as interspecific
      reciprocity based on interspecific recognition and temporal stability of the
      breeding communities.

PMID- 12495503
TI  - Discovery of Aspidytidae, a new family of aquatic Coleoptera.
AB  - The six extant aquatic families of Hydradephaga (Coleoptera) known so far
      represent a diverse group of beetles morphologically highly modified for life in
      the water. We report the discovery of a new genus with two species from South
      Africa and China, which differ greatly from all extant families, but resemble the
      Jurassic-Cretaceous dagger Liadytidae (the dagger symbol indicates that the taxa
      are known only as fossils). Based on a combined phylogenetic analysis of
      molecular and morphological data we erect a new family, Aspidytidae, which is the
      sister group of Dytiscidae plus Hygrobiidae. We propose a new scenario for the
      evolution of swimming behaviour in adephagan beetles, in which the transition
      into the aquatic environment is followed by complex and repeated changes in
      lifestyles, including the secondary complete loss of swimming ability in
      Aspidytidae.

PMID- 12495504
TI  - The costs and benefits of being a chimera.
AB  - Most multicellular organisms are uniclonal. This is hypothesized to be because
      uniclonal organisms function better than chimeras (non-clonal organisms), owing
      to reduced levels of internal genetic conflict. We tested this idea using the
      social amoeba or slime mold Dictyostelium discoideum. When starving, the normally
      solitary amoebae aggregate to form a differentiated multicellular slug that
      migrates towards light and forms a fruiting body, facilitating the dispersal of
      spores. We added 10(7) amoebae to Petri plates containing 1, 2, 5 or 10 clones
      mixed together. We found an intrinsic cost to chimerism: chimeric slugs moved
      significantly less far than uniclonal slugs of the same size. However, in nature,
      joining with other clones to form a chimera should increase slug size, and larger
      slugs travel further. We incorporated this size effect into a second experiment
      by giving chimeras more cells than single clones (single clones had 10(6) cells,
      two-clone chimeras had 2 x 10(6) cells and so on). The uniclonal treatments then
      simulated a clone in a mixture that refuses to form chimeras. In this experiment,
      chimeras moved significantly further than the uniclonal slugs, in spite of the
      intrinsic cost. Thus, chimerism is costly, which may be why it evolves so seldom,
      but in D. discoideum the benefits of large size appear to compensate.

PMID- 12495505
TI  - Kinesin: a molecular motor with a spring in its step.
AB  - A key step in the processive motion of two-headed kinesin along a microtubule is
      the 'docking' of the neck linker that joins each kinesin head to the motor's
      dimerized coiled-coil neck. This process is similar to the folding of a protein
      beta-hairpin, which starts in a highly mobile unfolded state that has significant
      entropic elasticity and finishes in a more rigid folded state. We therefore
      suggest that neck-linker docking is mechanically equivalent to the thermally
      activated shortening of a spring that has been stretched by an applied load. This
      critical tension-dependent step utilizes Brownian motion and it immediately
      follows the binding of ATP, the hydrolysis of which provides the free energy that
      drives the kinesin cycle. A simple three-state model incorporating neck-linker
      docking can account quantitatively for both the kinesin force-velocity relation
      and the unusual tension-dependence of its Michaelis constant. However, we find
      that the observed randomness of the kinesin motor requires a more detailed four
      state model. Monte Carlo simulations of single-molecule stepping with this model
      illustrate the possibility of sub-8 nm steps, the size of which is predicted to
      vary linearly with the applied load.

PMID- 12495506
TI  - Functional and ecological significance of rDNA intergenic spacer variation in a
      clonal organism under divergent selection for production rate.
AB  - It has recently been hypothesized that variation in the intergenic spacer (IGS)
      of rDNA has considerable developmental, evolutionary and ecological significance
      through effects on growth rate and body C : N : P stoichiometry resulting from
      the role of the IGS in production of rRNA. To test these ideas, we assessed
      changes in size and structure of the repetitive region of the IGS, juvenile
      growth rate (JGR), RNA and phosphorus (P) contents in clonal lineages of Daphnia
      pulex derived from a single female and subjected to divergent selection on weight
      specific fecundity (WSF). As a result of selection, WSF diverged rapidly, with
      significant reductions within two generations. Other significant changes
      accompanying shifts in WSF were that juveniles produced by low-WSF females grew
      more rapidly and had higher RNA and P contents. An increased predominance of long
      IGS variants was observed in lineages with elevated JGRs and low WSF. The
      observed variations in IGS length were related to the number of subrepeat units
      carrying a promoter sequence in the repetitive region. These results strongly
      support the hypothesized relationships, indicate a genetic mechanism for the
      evolution of such associations and demonstrate that Daphnia (and perhaps other
      parthenogens) possess considerable potential for rapid adaptive change in major
      life-history traits.

PMID- 12495507
TI  - The evolution of anisogamy: a game-theoretic approach.
AB  - A popular theory has proposed that anisogamy originated through disruptive
      selection acting on an ancestral isogamous population, though recent work has
      emphasized the importance of other factors in its evolution. We re-examine the
      disruptive selection theory, starting from an isogamous population with two
      mating types and taking into account the functional relationship, g(m), between
      the fitness of a gamete and its size, m, as well as the relationship, f(S),
      between the fitness of a zygote and its size, S. Evolutionary game theory is used
      to determine the existence and continuous stability of isogamous and anisogamous
      strategies for the two mating types under various models for the two functions
      g(m) and f(S). In the ancestral unicellular state, these two functions are likely
      to have been similar; this leads to isogamy whether they are sigmoidal or
      concave, though in the latter case allowance must be made for a minimal gamete
      size. The development of multicellularity may leave g(m) relatively unchanged
      while f(S) moves to the right, leading to the evolution of anisogamy. Thus, the
      disruptive selection theory provides a powerful explanation of the origin of
      anisogamy, though other selective forces may have been involved in the subsequent
      specialization of micro- and macrogametes.

PMID- 12495509
TI  - Managing uncertainty: information and insurance under the risk of starvation.
AB  - In an uncertain world, animals face both unexpected opportunities and danger.
      Such outcomes can select for two potential strategies: collecting information to
      reduce uncertainty, or insuring against it. We investigate the relative value of
      information and insurance (energy reserves) under starvation risk by offering
      model foragers a choice between constant and varying food sources over finite
      foraging bouts. We show that sampling the variable option (choosing it when it is
      not expected to be good) should decline both with lower reserves and late in
      foraging bouts; in order to be able to reap the reduction in uncertainty
      associated with exploiting a variable resource effectively, foragers must be able
      to afford and compensate for an initial increase in the risk of an energetic
      shortfall associated with choosing the option when it is bad. Consequently,
      expected exploitation of the varying option increases as it becomes less
      variable, and when the overall risk of energetic shortfall is reduced. In
      addition, little activity on the variable alternative is expected until reserves
      are built up early in a foraging bout. This indicates that gathering information
      is a luxury while insurance is a necessity, at least when foraging on stochastic
      and variable food under the risk of starvation.

PMID- 12495510
TI  - Discrimination, discounting and impulsivity: a role for an informational
      constraint.
AB  - Feeding animals often prefer small, quickly delivered rewards over larger, more
      delayed rewards. Students of feeding behaviour typically explain this behaviour
      by saying that animals discount delayed benefits. Temporal discounting implies
      that delayed benefits are worth less than immediate benefits. This paper presents
      a new explanation of short-sighted decision-making called the discrimination
      advantage model that does not rely on discounting. A new model that includes
      several possible causes of discounting is developed. This model has many
      interesting features, but it cannot account for two empirical results: the
      strength of the 'discounting' effect and the fact that the time between choice
      presentations (the intertrial interval or ITI) has no effect. This leads to the
      conclusion that although discounting may be important it is probably not a
      complete explanation of the experimental facts. In the discrimination advantage
      model the observation that the ITI does not affect choice is seen as a strategy
      to make a cleaner discrimination between delayed alternatives in a noisy world. A
      simple example shows that when discrimination is imperfect a short-sighted choice
      rule can, in some situations, lead to a higher long-term rate than a rule that
      actually compares long-term rates. This idea is developed and extended in several
      ways.

PMID- 12495511
TI  - Behavioural and ecological consequences of limited attention.
AB  - Ecological research in the past few decades has shown that most animals acquire
      and respond adaptively to information that affects survival and reproduction. At
      the same time, neurobiological studies have established that the rate of
      information processing by the brain is much lower than the rate at which
      information is encountered in the environment, and that attentional mechanisms
      enable the brain to focus only on the most essential information at any given
      time. Recent integration of the ecological and neurobiological approaches helps
      us to understand key behaviours with broad ecological and evolutionary
      implications. Specifically, current data indicate that limited attention affects
      diet choice and constrains animals' ability simultaneously to feed and attend to
      predators. Recent experiments also suggest that limited attention influences
      social interactions, courtship and mating behaviour.

PMID- 12495512
TI  - Public information for the assessment of quality: a widespread social phenomenon.
AB  - We propose that the use of public information about the quality of environmental
      resources, obtained by monitoring the sampling behaviour of others, may be a
      widespread social phenomenon allowing individuals to make faster, more accurate
      assessments of their environment. To demonstrate this (i) we define public
      information and distinguish it from other kinds of social information; (ii) we
      review empirical work demonstrating the benefits and costs of using public
      information to estimate food patch quality; (iii) we examine recent work showing
      that individuals may also be using public information to improve their estimates
      of the quality of such disparate environmental parameters as breeding patches,
      opponents and mates; and finally (iv) we suggest avenues of future work to better
      understand the nature of public information use and when it might be used or
      ignored. Such work should lead to a more complete understanding of the behaviour
      of individuals in social aggregations.

PMID- 12495513
TI  - Potential disadvantages of using socially acquired information.
AB  - The acquisition and use of socially acquired information is commonly assumed to
      be profitable. We challenge this assumption by exploring hypothetical scenarios
      where the use of such information either provides no benefit or can actually be
      costly. First, we show that the level of incompatibility between the acquisition
      of personal and socially acquired information will directly affect the extent to
      which the use of socially acquired information can be profitable. When these two
      sources of information cannot be acquired simultaneously, there may be no benefit
      to socially acquired information. Second, we assume that a solitary individual's
      behavioural decisions will be based on cues revealed by its own interactions with
      the environment. However, in many cases, for social animals the only socially
      acquired information available to individuals is the behavioural actions of
      others that expose their decisions, rather than the cues on which these decisions
      were based. We argue that in such a situation the use of socially acquired
      information can lead to informational cascades that sometimes result in sub
      optimal behaviour. From this theory of informational cascades, we predict that
      when erroneous cascades are costly, individuals should pay attention only to
      socially generated cues and not behavioural decisions. We suggest three scenarios
      that might be examples of informational cascades in nature.

PMID- 12495514
TI  - Information flow, opinion polling and collective intelligence in house-hunting
      social insects.
AB  - The sharing and collective processing of information by certain insect societies
      is one of the reasons that they warrant the superlative epithet 'super-organisms'
      (Franks 1989, Am. Sci. 77, 138-145). We describe a detailed experimental and
      mathematical analysis of information exchange and decision-making in, arguably,
      the most difficult collective choices that social insects face: namely, house
      hunting by complete societies. The key issue is how can a complete colony select
      the single best nest-site among several alternatives? Individual scouts respond
      to the diverse information they have personally obtained about the quality of a
      potential nest-site by producing a recruitment signal. The colony then
      deliberates over (i.e. integrates) different incoming recruitment signals
      associated with different potential nest-sites to achieve a well-informed
      collective decision. We compare this process in honeybees and in the ant
      Leptothorax albipennis. Notwithstanding many differences - for example, honeybee
      colonies have 100 times more individuals than L. albipennis colonies - there are
      certain similarities in the fundamental algorithms these societies appear to
      employ when they are house hunting. Scout honeybees use the full power of the
      waggle dance to inform their nest-mates about the distance and direction of a
      potential nest-site (and they indicate the quality of a nest-site indirectly
      through the vigour of their dance), and yet individual bees perhaps only rarely
      make direct comparisons of such sites. By contrast, scouts from L. albipennis
      colonies often compare nest-sites, but they cannot directly inform one another of
      their estimation of the quality of a potential site. Instead, they discriminate
      between sites by initiating recruitment sooner to better ones. Nevertheless, both
      species do make use of forms of opinion polling. For example, scout bees that
      have formerly danced for a certain site cease such advertising and monitor the
      dances of others at random. That is, they act without prejudice. They neither
      favour nor disdain dancers that advocate the site they had formerly advertised or
      the alternatives. Thus, in general the bees are less well informed than they
      would be if they systematically monitored dances for alternative sites rather
      than spending their time reprocessing information they already have. However, as
      a result of their lack of prejudice, less time overall will be wasted in endless
      debate among stubborn and potentially biased bees. Among the ants, the opinions
      of nest-mates are also pooled effectively when scouts use a threshold population
      of their nest-mates present in a new nest-site as a cue to switch to more rapid
      recruitment. Furthermore, the ants' reluctance to begin recruiting to poor nest
      sites means that more time is available for the discovery and direct comparison
      of alternatives. Likewise, the retirement of honeybee scouts from dancing for a
      given site allows more time for other scouts to find potentially better sites.
      Thus, both the ants and the bees have time-lags built into their decision-making
      systems that should facilitate a compromise between thorough surveys for good
      nest-sites and relatively rapid decisions. We have also been able to show that
      classical mathematical models can illuminate the processes by which colonies are
      able to achieve decisions that are relatively swift and very well informed.

PMID- 12495515
TI  - Spectacular phenomena and limits to rationality in genetic and cultural
      evolution.
AB  - In studies of both animal and human behaviour, game theory is used as a tool for
      understanding strategies that appear in interactions between individuals. Game
      theory focuses on adaptive behaviour, which can be attained only at evolutionary
      equilibrium. We suggest that behaviour appearing during interactions is often
      outside the scope of such analysis. In many types of interaction, conflicts of
      interest exist between players, fuelling the evolution of manipulative
      strategies. Such strategies evolve out of equilibrium, commonly appearing as
      spectacular morphology or behaviour with obscure meaning, to which other players
      may react in non-adaptive, irrational ways. We present a simple model to show
      some limitations of the game-theory approach, and outline the conditions in which
      evolutionary equilibria cannot be maintained. Evidence from studies of biological
      interactions seems to support the view that behaviour is often not at
      equilibrium. This also appears to be the case for many human cultural traits,
      which have spread rapidly despite the fact that they have a negative influence on
      reproduction.

PMID- 12495516
TI  - Separating equilibria in continuous signalling games.
AB  - Much of the literature on costly signalling theory concentrates on separating
      equilibria of continuous signalling games. At such equilibria, every signaller
      sends a distinct signal, and signal receivers are able to exactly infer the
      signaller's condition from the signal sent. In this paper, we introduce a vector
      field solution method that simplifies the process of solving for separating
      equilibria. Using this approach, we show that continuous signalling games can
      have low-cost separating equilibria despite conflicting interests between
      signaller and receiver. We find that contrary to prior arguments, honesty does
      not require wasteful signals. Finally, we examine signalling games in which
      different signallers have different minimal-cost signals, and provide a
      mathematical justification for the argument that even non-signalling traits will
      be exaggerated beyond their phenotypic optimum when they are used by other
      individuals to judge condition or quality.

PMID- 12495517
TI  - Credible threats and promises.
AB  - We consider various implications of information about the other player in two
      player evolutionary games. A simple model of desertion shows that information
      about the partner's behaviour can be disadvantageous, and highlights the idea of
      credible threats. We then discuss the general issue of whether the partner can
      convince the focal player that it will behave in a specific way, i.e. whether the
      focal player can make credible threats or promises. We show that when desertion
      decisions depend on reserves, a player can manipulate its reserves so as to
      create a credible threat of desertion. We then extend previous work on the
      evolution of trust and commitment, discussing conditions under which it is
      advantageous to assume that a partner will behave in a certain way even though it
      is not in its best interest.

PMID- 12495518
TI  - Identifying the structure in cuttlefish visual signals.
AB  - The common cuttlefish (Sepia officinalis) communicates and camouflages itself by
      changing its skin colour and texture. Hanlon and Messenger (1988 Phil. Trans. R.
      Soc. Lond. B 320, 437-487) classified these visual displays, recognizing 13
      distinct body patterns. Although this conclusion is based on extensive
      observations, a quantitative method for analysing complex patterning has obvious
      advantages. We formally define a body pattern in terms of the probabilities that
      various skin features are expressed, and use Bayesian statistical methods to
      estimate the number of distinct body patterns and their visual characteristics.
      For the dataset of cuttlefish coloration patterns recorded in our laboratory,
      this statistical method identifies 12-14 different patterns, a number consistent
      with the 13 found by Hanlon and Messenger. If used for signalling these would
      give a channel capacity of 3.4 bits per pattern. Bayesian generative models might
      be useful for objectively describing the structure in other complex biological
      signalling systems.

PMID- 12495520
TI  - Modulation of the auditory cortex during speech: an MEG study.
AB  - Several behavioral and brain imaging studies have demonstrated a significant
      interaction between speech perception and speech production. In this study,
      auditory cortical responses to speech were examined during self-production and
      feedback alteration. Magnetic field recordings were obtained from both
      hemispheres in subjects who spoke while hearing controlled acoustic versions of
      their speech feedback via earphones. These responses were compared to recordings
      made while subjects listened to a tape playback of their production. The
      amplitude of tape playback was adjusted to match the amplitude of self-produced
      speech. Recordings of evoked responses to both self-produced and tape-recorded
      speech were obtained free of movement-related artifacts. Responses to self
      produced speech were weaker than were responses to tape-recorded speech.
      Responses to tones were also weaker during speech production, when compared with
      responses to tones recorded in the presence of speech from tape playback.
      However, responses evoked by gated noise stimuli did not differ for recordings
      made during self-produced speech versus recordings made during tape-recorded
      speech playback. These data suggest that during speech production, the auditory
      cortex (1) attenuates its sensitivity and (2) modulates its activity as a
      function of the expected acoustic feedback.

PMID- 12495519
TI  - No accident: genetic codes freeze in error-correcting patterns of the standard
      genetic code.
AB  - The standard genetic code poses a challenge in understanding the evolution of
      information processing at a fundamental level of biological organization. Genetic
      codes are generally coadapted with, or 'frozen' by, the protein-coding genes that
      they translate, and so cannot easily change by natural selection. Yet the
      standard code has a significantly non-random pattern that corrects common errors
      in the transmission of information in protein-coding genes. Because of the
      freezing effect and for other reasons, this pattern has been proposed not to be
      due to selection but rather to be incidental to other evolutionary forces or even
      entirely accidental. We present results from a deterministic population genetic
      model of code-message coevolution. We explicitly represent the freezing effect of
      genes on genetic codes and the perturbative effect of changes in genetic codes on
      genes. We incorporate characteristic patterns of mutation and translational
      error, namely, transition bias and positional asymmetry, respectively. Repeated
      selection over small successive changes produces genetic codes that are
      substantially, but not optimally, error correcting. In particular, our model
      reproduces the error-correcting patterns of the standard genetic code. Aspects of
      our model and results may be applicable to the general problem of adaptation to
      error in other natural information-processing systems.

PMID- 12495521
TI  - Components of switching intentional set.
AB  - Despite the intuition that we can shift cognitive set on instruction, some
      behavioral studies have suggested that set shifting might only be accomplished
      once we engage in performance of the new task. It is possible that set switching
      consists of more than one component cognitive process and that the component
      processes might segregated in time. We recorded event-related potentials (ERPs)
      during two set-switching tasks to test whether different component processes were
      responsible for (i) set initiation and reconfiguration when presented with the
      instruction to switch, and (ii) the implementation of the new set once subjects
      engaged in performing the new task. The response switching (RS) task required
      shifts of intentional set; subjects selected between responses according to one
      of two conflicting intentional sets. The results demonstrated the existence of
      more than one constituent process. Some of the processes were linked to the
      initiation and reconfiguration of the set prior to actual performance of the new
      task. Other processes were time locked to performance of new task items. Set
      initiation started with modulation of medial frontal ERPs and was followed by
      modulation over parietal electrodes. Implementation of intentional set was
      associated with modulation of response-related ERPs.

PMID- 12495522
TI  - Paradoxical interhemispheric summation in the split brain.
AB  - We measured simple reaction time (RT) to light flashes, presented either singly
      or in pairs, in two people who had undergone callosotomy, one person with
      agenesis of the corpus callosum, and 17 normal subjects. The three split-brained
      subjects' RTs were decreased to bilateral pairs beyond predictions based on a
      simple race between independent unilateral processes, while those of the normal
      subjects were actually longer than predicted by the race model. This effect was
      present whether the bilateral pairs were in mirror-image locations or not, but
      was not present when the pairs were presented unilaterally. Since summation does
      not depend on close spatial correspondence, and also occurs when inputs are
      staggered in time, we suggest that it is due to cortical projection to a
      subcortical arousal system, and is normally inhibited by the corpus callosum.

PMID- 12495523
TI  - EMPATH: a neural network that categorizes facial expressions.
AB  - There are two competing theories of facial expression recognition. Some
      researchers have suggested that it is an example of "categorical perception." In
      this view, expression categories are considered to be discrete entities with
      sharp boundaries, and discrimination of nearby pairs of expressive faces is
      enhanced near those boundaries. Other researchers, however, suggest that facial
      expression perception is more graded and that facial expressions are best thought
      of as points in a continuous, low-dimensional space, where, for instance,
      "surprise" expressions lie between "happiness" and "fear" expressions due to
      their perceptual similarity. In this article, we show that a simple yet
      biologically plausible neural network model, trained to classify facial
      expressions into six basic emotions, predicts data used to support both of these
      theories. Without any parameter tuning, the model matches a variety of
      psychological data on categorization, similarity, reaction times, discrimination,
      and recognition difficulty, both qualitatively and quantitatively. We thus
      explain many of the seemingly complex psychological phenomena related to facial
      expression perception as natural consequences of the tasks' implementations in
      the brain.

PMID- 12495524
TI  - Blindsight modulation of motion perception.
AB  - Monkey data suggest that of all perceptual abilities, motion perception is the
      most likely to survive striate damage. The results of studies on motion
      blindsight in humans, though, are mixed. We used an indirect strategy to examine
      how responses to visible stimuli were modulated by blind-field stimuli. In a 26
      year-old man with focal striate lesions, discrimination of visible optic flow was
      enhanced about 7% by blind-field flow, even though discrimination of optic flow
      in the blind field alone (the direct strategy) was at chance. Pursuit of an
      imagined target using peripheral cues showed reduced variance but not increased
      gain with blind-field cues. Preceding blind-field prompts shortened reaction
      times to visible targets by about 10 msec, but there was no attentional crowding
      of visible stimuli by blind-field distractors. A similar efficacy of indirect
      blind-field optic flow modulation was found in a second patient with residual
      vision after focal striate damage, but not in a third with more extensive medial
      occipito-temporal damage. We conclude that indirect modulatory strategies are
      more effective than direct forced-choice methods at revealing residual motion
      perception after focal striate lesions.

PMID- 12495525
TI  - Localization of executive functions in dual-task performance with fMRI.
AB  - We report a study that investigated the neuroanatomical correlates of executive
      functions in dual-task performance with functional magnetic resonance imaging.
      Participants performed an auditory and a visual three-choice reaction task either
      separately as single tasks or concurrently as dual tasks. In the dual-task
      condition, two stimuli were presented in rapid succession to ensure interference
      between the component tasks (psychological refractory period). The behavioral
      data showed considerable performance decrements in the dual-task compared to the
      single-task condition. Dual-task-related activation was detected with two
      different neuroimaging methods. First, we determined dual-task-related activation
      according to the method of cognitive subtraction. For that purpose, activation in
      the dual-task was compared directly with activation in the single-task
      conditions. This analysis revealed that cortical areas along the inferior frontal
      sulcus (IFS), the middle frontal gyrus (MFG), and the intraparietal sulcus (IPS)
      are involved in dual-task performance. The results of the subtraction method were
      validated with the method of parametric manipulation. For this purpose, a second
      dual-task condition was introduced, where the difficulty of the dual-task
      coordination was increased compared with the first dual-task condition. As
      expected, behavioral dual-task performance decreased with increased dual-task
      difficulty. Furthermore, the increased dual-task difficulty led to an increase of
      activation in those cortical regions that proved to be dual-task related with the
      subtraction method, that is, the IFS, the MFG, and the IPS. These results support
      the conclusion that dorsolateral prefrontal and superior parietal cortices are
      involved in the coordination of concurrent and interfering task processing.

PMID- 12495526
TI  - Extensive individual differences in brain activations associated with episodic
      retrieval are reliable over time.
AB  - The localization of brain functions using neuroimaging techniques is commonly
      dependent on statistical analyses of groups of subjects in order to identify
      sites of activation, particularly in studies of episodic memory. Exclusive
      reliance on group analysis may be to the detriment of understanding the true
      underlying cognitive nature of brain activations. In the present study, we found
      that the patterns of brain activity associated with episodic retrieval are very
      distinct for individual subjects from the patterns of brain activity at the group
      level. These differences go beyond the relatively small variations due to
      cyctoarchitectonic differences or spatial normalization. We quantify this
      individual variability by cross-correlating volumes of brain images. We
      demonstrate that individual patterns of brain activity are reliable over time
      despite their extensive variability. We suggest that varied but reliable
      individual patterns of significant brain activity may be indicative of different
      cognitive strategies used to produce a recognition response. We believe that
      individual analysis in conjunction with group analysis may be critical to fully
      understanding the relationship between retrieval processes and underlying brain
      regions.

PMID- 12495528
TI  - When action turns into words. Activation of motor-based knowledge during
      categorization of manipulable objects.
AB  - Functional imaging studies have demonstrated that processing of man-made objects
      activate the left ventral premotor cortex, which is known to be concerned with
      motor function. This has led to the suggestion that the comprehension of man-made
      objects may rely on motor-based knowledge of object utilization (action
      knowledge). Here we show that the left ventral premotor cortex is activated
      during categorization of "both" fruit/vegetables and articles of clothing,
      relative to animals and nonmanipulable man-made objects. This observation
      suggests that action knowledge may not be important for the processing of man
      made objects per se, but rather for the processing of manipulable objects in
      general, whether natural or man-made. These findings both support
      psycholinguistic theories suggesting that certain lexical categories may evolve
      from, and the act of categorization rely upon, motor-based knowledge of action
      equivalency, and have important implications for theories of category
      specificity. Thus, the finding that the processing of vegetables/fruit and
      articles of clothing give rise to similar activation is difficult to account for
      should knowledge representations in the brain be truly categorically organized.
      Instead, the data are compatible with the suggestion that categories differ in
      the weight they put on different types of knowledge.

PMID- 12495527
TI  - Rethinking feelings: an FMRI study of the cognitive regulation of emotion.
AB  - The ability to cognitively regulate emotional responses to aversive events is
      important for mental and physical health. Little is known, however, about neural
      bases of the cognitive control of emotion. The present study employed functional
      magnetic resonance imaging to examine the neural systems used to reappraise
      highly negative scenes in unemotional terms. Reappraisal of highly negative
      scenes reduced subjective experience of negative affect. Neural correlates of
      reappraisal were increased activation of the lateral and medial prefrontal
      regions and decreased activation of the amygdala and medial orbito-frontal
      cortex. These findings support the hypothesis that prefrontal cortex is involved
      in constructing reappraisal strategies that can modulate activity in multiple
      emotion-processing systems.

PMID- 12495529
TI  - Two corticotectal areas facilitate multisensory orientation behavior.
AB  - It had previously been shown that influences from two cortical areas, the
      anterior ectosylvian sulcus (AES) and the rostral lateral suprasylvian sulcus
      (rLS), play critical roles in rendering superior colliculus (SC) neurons capable
      of synthesizing their cross-modal inputs. The present studies examined the
      consequences of selectively eliminating these cortical influences on SC-mediated
      orientation responses to cross-modal stimuli. Cats were trained to orient to a
      low-intensity modality-specific cue (visual) in the presence or absence of a
      neutral cue from another modality (auditory). The visual target could appear at
      various locations within 45 degrees of the midline, and the stimulus
      effectiveness was varied to yield an average of correct orientation responses of
      approximately 45%. Response enhancement and depression were observed when the
      auditory cue was coupled with the target stimulus: A substantially enhanced
      probability in correct responses was evident when the cross-modal stimuli were
      spatially coincident, and a substantially decreased response probability was
      obtained when the stimuli were spatially disparate. Cryogenic blockade of either
      AES or rLS disrupted these behavioral effects, thereby eliminating the enhanced
      performance in response to spatially coincident cross-modal cues and degrading
      the depressed performance in response to spatially disparate cross-modal cues.
      These disruptive effects on targets contralateral to the deactivated cortex were
      restricted to multisensory interactive processes. Orientation to modality
      specific targets was unchanged. Furthermore, the pattern of orientation errors
      was unaffected by cortical deactivation. These data bear striking similarities to
      the effects of AES and rLS deactivation on multisensory integration at the level
      of individual SC neurons. Presumably, eliminating the critical influences from
      AES or rLS cortex disrupts SC multisensory synthesis that, in turn, disables SC
      mediated multisensory orientation behaviors.

PMID- 12495530
TI  - Contribution of the primate superior colliculus to inhibition of return.
AB  - The phenomenon of inhibition of return (IOR) has generated considerable interest
      in cognitive neuroscience because of its putative functional role in visual
      search, that of placing inhibitory tags on objects that have been recently
      inspected so as to direct further search to novel items. Many behavioral
      parameters of this phenomenon have been clearly delineated, and based on indirect
      but converging evidence, the widely held consensus is that the midbrain superior
      colliculus (SC) is involved in the generation of IOR. We had previously trained
      monkeys on a saccadic IOR task and showed that they displayed IOR in a manner
      similar to that observed in humans. Here we recorded the activity of single
      neurons in the superficial and intermediate layers of the SC while the monkeys
      performed this IOR task. We found that when the target was presented at a
      previously cued location, the stimulus-related response was attenuated and the
      magnitude of this response was correlated with subsequent saccadic reaction
      times. Surprisingly, this observed attenuation of activity during IOR was not
      caused by active inhibition of these neurons because (a) they were, in fact, more
      active following the presentation of the cue in their response field, and (b)
      when we repeated the same experiment while using the saccadic response time
      induced by electrical micro-stimulation of the SC to judge the level of
      excitability of the SC circuitry during the IOR task, we found faster saccades
      were elicited from the cued location. Our findings demonstrate that the primate
      SC participates in the expression of IOR; however, the SC is not the site of the
      inhibition. Instead, the reduced activity in the SC reflects a signal reduction
      that has taken place upstream.

PMID- 12495531
TI  - Impaired recognition of social emotions following amygdala damage.
AB  - Lesion, functional imaging, and single-unit studies in human and nonhuman animals
      have demonstrated a role for the amygdala in processing stimuli with emotional
      and social significance. We investigated the recognition of a wide variety of
      facial expressions, including basic emotions (e.g., happiness, anger) and social
      emotions (e.g., guilt, admiration, flirtatiousness). Prior findings with a
      standardized set of stimuli indicated that recognition of social emotions can be
      signaled by the eye region of the face and is disproportionately impaired in
      autism (Baron-Cohen, Wheelwright, & Jolliffe, 1997). To test the hypothesis that
      the recognition of social emotions depends on the amygdala, we administered the
      same stimuli to 30 subjects with unilateral amygdala damage (16 left, 14 right),
      2 with bilateral amygdala damage, 47 brain-damaged controls, and 19 normal
      controls. Compared with controls, subjects with unilateral or bilateral amygdala
      damage were impaired when recognizing social emotions; moreover, they were more
      impaired in recognition of social emotions than in recognition of basic emotions,
      and, like previously described patients with autism, they were impaired also when
      asked to recognize social emotions from the eye region of the face alone. The
      findings suggest that the human amygdala is relatively specialized to process
      stimuli with complex social significance. The results also provide further
      support for the idea that some of the impairments in social cognition seen in
      patients with autism may result from dysfunction of the amygdala.

PMID- 12495532
TI  - Editorial.

PMID- 12495533
TI  - Psychiatric emergency outreach: a report on the first 2 years of functioning in
      Copenhagen.
AB  - The purpose of the study was to evaluate psychiatric emergency outreach after
      functioning for a period of 2 years in Copenhagen, Denmark. Psychiatric emergency
      outreach was staffed by a psychiatrist and an ambulance driver, and the target
      group was defined as mentally ill and persons in severe crisis. For each of 935
      calls covering 777 different patients, a registration form with social and
      clinically relevant data was filled out. After the 2-year period, patients were
      looked up in the National Cause of Death Register and the National Psychiatric
      Case Register. A total of 66% were previously registered as psychiatric patients,
      and in 37% of all calls, the patient had psychotic symptoms. In 25% of the calls,
      the patient was admitted to psychiatric hospital; 38% of the admissions were
      involuntary. Forty-eight per cent of the calls were initiated by relatives,
      friends or neighbours. Suicidal behaviour was frequent. There were significantly
      more calls in socially deprived areas. Standard Mortality Rates were high for all
      causes of death (5.00), and especially for suicide (31.98). In conclusion,
      psychiatric emergency outreach seems to fulfil some of its purpose.

PMID- 12495534
TI  - Stability of perceived ward atmosphere over time, diagnosis and gender for
      patients with psychosis.
AB  - In this study the focus was on patients with psychosis treated in a psychiatric
      rehabilitation unit in southern Sweden. The study described the stability of the
      ward atmosphere over 2 years, as well as differences between subgroups of
      patients regarding gender and diagnosis. Furthermore, the perceived ward
      atmosphere was compared with what has been recommended in the literature. The
      ward atmosphere was measured by The Community-Oriented Programs Environment Scale
      (COPES) five times during a 2-year period. The ward atmosphere was fairly stable
      over time, and in several respects it met the recommendations suggested for
      psychotic patients. There were few differences between schizophrenia patients and
      patients with other psychoses. No difference was found in perceived ward
      atmosphere with respect to gender. The study showed that the investigated unit,
      admitting almost only patients with psychosis, could provide a ward atmosphere
      accordance with the recommendations, probably due to a carefully planned program
      with a psychodynamically oriented supportive treatment milieu.

PMID- 12495535
TI  - Quality of life and mental health of parents of children with mental health
      problems.
AB  - Mental health of parents and their quality of life is likely to be affected when
      a child in the family has a psychiatric disorder. The purpose of this study is to
      assess quality of life and mental health of parents of referred children waiting
      for service at the only child psychiatric service in Iceland, with reassessment
      at least 3 months after first attendance to the service. In order to do so, 208
      parents of 123 children waiting for psychiatric care were sent the Icelandic
      Quality of Life (IQL), the General Health Questionnaire (GHQ-30) and the CAGE
      screen for alcoholism. For reassessment, responders in the first phase were
      assessed again with the IQL and GHQ-30, at least 3 months after initiation of
      child psychiatric interventions. A total of 120 of the 208 parents (58%)
      responded in the first phase of the study, 49 fathers and 71 mothers. The mean
      (+/- s, standard deviation) standardized IQL T-score was for the fathers 51+/-
      7.5 but significantly lower for the mothers or 45 +/-11.5 (P = 0.001) compared to
      normal sample of same-age women (T-scores of 50 are normal). Nearly 55% of women
      compared with 26% of men were psychiatric cases, scoring 5 or higher on the GHQ.
      According to a CAGE score of 2 and above 16% of fathers and 14% of mother abused
      alcohol. No significant change occurred in parents GHQ-30 or IQL before and after
      initiation of treatment. We conclude that mothers of children with mental
      disorders have poor quality of life, and high prevalence of mental disorders;
      hence child psychiatry clinics need to ensure that mothers receive appropriate
      care along with the child.

PMID- 12495536
TI  - Symptoms profile and quality of life in rural and urban patients with chronic
      psychoses.
AB  - The symptoms profile (modified Positive and Negative Syndrome Scale, PANSS) and
      the quality of life (Lancashire Quality of Life Profile, LQLP, and the Quality of
      Life Scale 100, QLS-100) were compared between two groups of patients with
      chronic psychoses: a rural group of 19 patients living in villages with < or =300
      10,000 inhabitants and far away from a large city, and an urban group of 19
      patients living in a major city with 250,000 inhabitants. The patients were
      matched pair-wise for sex, age, global assessment of functioning (GAF) and
      psychiatric symptoms (modified PANSS, total score). Seventeen of the pairs were
      diagnosed with schizophrenia, and two pairs with delusional disorder. The
      symptoms profile indicated more negative symptoms and less positive symptoms for
      the rural group, compared with the urban group, with a significantly lower degree
      of spontaneity in the rural group. No group differences were found in the QLS
      100, or in the specific quality of life variables according to LQLP. However, the
      rural group had significantly higher self-rating of the general quality of life
      variables of the LQLP, i.e. satisfaction with well-being, general health and
      mental health. The results are discussed in view of a possible relation between
      negative symptoms and impairments in social cognition and insight.

PMID- 12495537
TI  - Neurological soft signs (NSS) in 200 treatment-naive cases with schizophrenia: a
      community-based study in a rural setting.
AB  - Several studies have reported neurological soft signs (NSS) to be common in
      individuals with schizophrenia. The majority of these studies are based on
      clinical samples exposed to neuroleptic treatment. The present study reports on
      200 treatment-naive and community-identified cases of schizophrenia and 78
      healthy individuals from the same area, evaluated using the Neurological
      Evaluation Scale (NES). The median NES score was 5.0 for cases of schizophrenia
      and 1.5 for healthy subjects. The impairment rate of NSS in cases with
      schizophrenia was 65.0% against 50.0% in healthy subjects, and the difference was
      statistically significant (chi2 = 5.30; df = 1; P < 0.021). NSS abnormality is as
      common in treatment-naive cases as reported in many studies in those on
      neuroleptic medication. There was no significant relation between the NSS
      impairment and duration of illness, remission status, positive symptoms, negative
      symptoms and disorganized symptoms.

PMID- 12495538
TI  - Perceived coercion among patients admitted to acute wards in Norway.
AB  - Several studies suggest that the patient's experience of being coerced, during
      the admission process to mental hospitals, does not necessarily correspond with
      their legal status. Rather, perceived coercion appears to be associated with
      having experienced force and/or threats (negative pressures), as well as feeling
      that their views were not taken into consideration in the admission process
      (process exclusion). We investigated perceived coercion, among patients admitted
      both voluntarily and involuntarily, to acute wards in Norway. We used a visual
      analogue scale (the Coercion Ladder, CL) and the MacArthur Perceived Coercion
      Scale (MPCS), a five-item questionnaire, to measure perceived coercion. Two
      hundred and twenty-three consecutively admitted patients to four acute wards were
      included and interviewed within 5 days of admission. Many patients reported high
      levels of perceived coercion in the admission process, with the involuntary group
      experiencing significantly higher levels than the voluntary group. However, 32%
      of voluntarily admitted patients perceived high levels, and 41% of involuntarily
      admitted patients perceived low levels of coercion. Legal status did not
      significantly predict perceived coercion on either the MPCS or the CL after
      taking negative pressures and process exclusion into account. Applying a visual
      analogue scale (CL) seems to provide a useful measure of patients' perception of
      coercion and one that largely parallels the MPCS.

PMID- 12495539
TI  - Behavioral activation or inhibition during emotional stress-implications for
      exercise habits and emotional problems among young females.
AB  - According to the defense-defeat model of stress, the defense reaction is
      associated with behavioral activation and the defeat reaction with behavioral
      inhibition. The aim of this study was to investigate the associations of stress
      induced changes of physical activity to certain psychological and behavioral
      problems among young females. A random sample of 726 females, aged 18-23 years,
      responded on a self-report questionnaire. Groups were defined by the given
      response on an item addressing changed levels of physical activity during periods
      of emotional stress. Groups of increased, decreased and unchanged drive to
      activity were compared regarding the results on various items. Subjects reporting
      stress-induced behavioral activation reported significantly higher amounts of
      habitual physical exercise and activity than did compared groups. They were also
      more prone to engage in compensatory activities against being overweight.
      Conversely, subjects reporting stress-induced behavioral inhibition during
      emotional stress reported more frequent depressive symptoms. Stress-induced
      changes of physical activity seem to be associated with certain patterns of
      emotional and behavioral problems among young females.

PMID- 12495540
TI  - Self-image of anorexic and bulimic female adolescents.
AB  - The purpose of this study was to assess the self-concept using the Offer Self
      Image Questionnaire (OSIQ) in groups of Finnish adolescent girls with anorexia
      nervosa and bulimia nervosa, and a normal control group without an eating
      disorder. A total of 135 adolescent girls aged 16-21 (10 with anorexia nervosa,
      10 with bulimia nervosa and 115 normal controls) were investigated using the
      OSIQ. In comparisons, girls with bulimia nervosa differed significantly from both
      girls with anorexia nervosa and normal controls with regard to severity on almost
      all of the OSIQ scales. Girls with anorexia nervosa differed from normal controls
      only in Emotional Tone and Sexual Attitudes. The findings suggest that anorexia
      nervosa and bulimia nervosa should be handled as different groups in assessing
      self-image with the OSIQ.

PMID- 12495541
TI  - Determinants of attempted suicide in urban environment.
AB  - This paper investigates, first, the differences in attempted-suicide rates among
      men and women between urban districts and, second, the association between
      regional characteristics and attempted-suicide rates. The data cover all
      attempted suicides referred to healthcare in 1989 and 1997 in Helsinki, Finland.
      There are clear and persistent differences in the attempted-suicide rates between
      the studied districts. Although female rates increased in all seven districts
      from 1989 to 1997, their mutual relationships remain similar. There are more
      changes among men both within and between the districts. Socio-economic
      disadvantage within the districts was associated with higher attempted-suicide
      rates. We conclude that socio-economic characteristics and their changes over
      time in the districts are likely to affect the suicidal behaviour of men more
      than women. Improving the employment status and structural position, especially
      of men, would probably prove to be important for the prevention of attempted
      suicide.

PMID- 12495542
TI  - The changing standard of care in medicine. E-health, medical errors, and
      technology add new obstacles.

PMID- 12495543
TI  - Privacy versus the public's right to know. Presidential health and the White
      House physician.

PMID- 12495544
TI  - HMOs, accountability, and the death of ERISA preemption.

PMID- 12495545
TI  - Radioprotection: the non-steroidal anti-inflammatory drugs (NSAIDs) and
      prostaglandins.
AB  - Clinical and experimental studies of the acute and late effects of radiation on
      cells have enhanced our knowledge of radiotherapy and have led to the
      optimisation of radiation treatment schedules and to more precise modes of
      radiation delivery. However, as both normal and cancerous tissues have similar
      response to radiation exposure, radiation-induced injury on normal tissues may
      present either during, or after the completion of, the radiotherapy treatment.
      Studies on both NSAIDs and prostaglandins have indeed shown some evidence of
      radioprotection. Both have the potential to increase the survival of cells but by
      entirely different mechanisms. Studies of cell kinetics reveal that cells in the
      mitotic (M) and late G2 phases of the cell cycle are generally most sensitive to
      radiation compared with cells in the early S and G1/G0 phases. Furthermore,
      radiation leads to a mitotic delay in the cell cycle. Thus, chemical agents that
      either limit the proportion of cells in the M and G2 phases of the cell cycle or
      enhance rapid cell growth could in principle be exploited for their potential use
      as radioprotectors to normal tissue during irradiation. NSAIDs have been shown to
      exert anti-cancer effects by causing cell-cycle arrest, shifting cells towards a
      quiescence state (G0/G1). The same mechanism of action was observed in
      radioprotection of normal tissues. An increase in arachidonic acid concentrations
      after exposure to NSAIDs also leads to the production of an apoptosis-inducer
      ceramide. NSAIDs also elevate the level of superoxide dismutase in cells.
      Activation of heat shock proteins by NSAIDs increases cell survival by alteration
      of cytokine expression. A role for NSAIDs with respect to inhibition of cellular
      proliferation possibly by an anti-angiogenesis mechanism has also been suggested.
      Several in-vivo studies have provided evidence suggesting that NSAIDs may protect
      normal tissues from radiation injury. Prostaglandins do not regulate the cell
      cycle, but they do have a variety of effects on cell growth and differentiation.
      PGE(2) mediates angiogenesis, increasing the supply of oxygen and nutrients,
      essential for cellular survival and growth. Accordingly, PGE(2) at sufficiently
      high plasma concentrations enhances cellular survival by inhibiting pro
      inflammatory cytokines such as TNF-alpha and IL-1beta. Thus, PGE(2) acts as a
      modulator, rather than a mediator, of inflammation. Prospective studies have
      suggested the potential use of misoprostol, a PGE(1) analogue, before
      irradiation, in prevention of radiation-induced side effects. The current
      understanding of the pharmacology of NSAIDs and prostaglandins shows great
      potential to minimise the adverse effects of radiotherapy on normal tissue.

PMID- 12495546
TI  - Solubilization of the lichen metabolite (+)-usnic acid for testing in tissue
      culture.
AB  - The pharmacological testing of natural products can often be hampered by the poor
      solubility of such compounds in non-toxic solvents. There is thus a need for a
      suitable agent for solubilization of natural substances to allow testing on a
      variety of cell lines in-vitro. Such an agent should ideally have no direct
      effects on any of the commonly used cell lines from a variety of tissues and
      mammalian species to allow proper comparison. In this study, the lichen
      metabolite (+)-usnic acid, a dibenzofuran derivative, was used as a prototype for
      an insoluble natural product with the aim of finding a solvent that was both
      capable of solubilizing usnic acid and was free of direct activity against a test
      cell line. Solubilization was measured at different pH values in various
      concentrations of co-solvents (glycofurol 75, propylene glycol, polyethylene
      glycol 400), surfactants (polysorbate 20 and Cremophor RH40), and the complexing
      agent 2-hydroxypropyl-beta-cyclodextrin. The solubility achieved in a 20% aqueous
      solution was 0.11 mg mL(-1) for propylene glycol, 0.19 for PEG 400, 0.27 for
      glycofurol 75, 0.57 for Cremophor RH40, 0.68 for 2-hydroxypropyl-beta
      cyclodextrin and 0.84 for polysorbate 20. The direct effects of the various
      solvent systems were tested on the human leukaemia cell line K-562 in a standard
      proliferation assay. Most of the solvents proved toxic with the exception of
      propylene glycol, PEG 400 and 2-hydroxypropyl-beta-cyclodextrin. Anti
      proliferative activity of usnic acid could be demonstrated with an ED50 (amount
      of substance required to reduce thymidine uptake to 50% of uptake by untreated
      control culture) of 4.7 microg mL(-1) using PEG 400 and 2-hydroxypropyl-beta
      cyclodextrin but only the latter gave satisfactory solubility. 2-Hydroxypropyl
      beta-cyclodextrin was thus identified as a solubilizing agent that fulfilled both
      set criteria of solubility and lack of toxicity against the test cells.

PMID- 12495547
TI  - Physically cross-linked chitosan hydrogels as topical vehicles for hydrophilic
      drugs.
AB  - Physically cross-linked chitosan hydrogels with lauric, myristic, palmitic or
      stearic acid were prepared by freeze-drying and have been studied for topical
      use. This study selected propranolol hydrochloride as a hydrophilic model drug to
      design a transdermal delivery system. We evaluated the effect of the nature of
      the cross-linker on drug permeation through porcine skin and the main permeation
      parameters (diffusion coefficient, flux and lag time) were calculated. All the
      chitosan hydrogels analysed provided more transcutaneous permeation of
      propranolol hydrochloride than the corresponding solution of the commercial drug.
      Among the different chitosan vehicles, chitosan-laurate and chitosan-myristate
      hydrogels enhanced lyophilised drug diffusion through the skin with respect to
      chitosan-palmitate and chitosan-stearate hydrogels. This can been explained by
      the interaction of the hydrogels with the stratum corneum, increasing the
      solubility of the drug in the skin.

PMID- 12495548
TI  - Covalent coupling of concanavalin A to a Carbopol 934P and 941P carrier in
      glucose-sensitive gels for delivery of insulin.
AB  - A novel glucose-sensitive gel formulation, containing concanavalin A and specific
      polysaccharides, was stabilised via covalent coupling to two structurally
      different carbomers. The bonding was done to minimise leaching of gel components
      thereby preventing toxicity and preserving the working mechanism of the gel.
      Increased gel stability was introduced by covalently bonding amine groups present
      on the lysine residues of concanavalin A to carboxylic moieties on Carbopol 934P
      NF and 941P NF using carbodiimide chemistry. The introduction of dextran then
      produced a glucose-sensitive formulation that transformed from gel to sol in the
      presence of free glucose. Rheological examination of glucose-sensitive gels
      stabilised in this way and containing varying concentrations of glucose was
      conducted with a cone and plate viscometer used in continual rotation mode. A
      decrease in viscosity over the chosen glucose concentration range was exhibited
      by both carbomer-stabilised formulations. The subsequent testing of such
      formulations in in-vitro diffusion experiments revealed that the leaching of
      concanavalin A from the covalently coupled gels is restricted significantly with
      respect to non-coupled formulations. In addition, insulin delivery in response to
      glucose in the physiologically relevant glucose concentration range has been
      demonstrated using the carbomer-stabilised gels at 37 degrees C. The performance
      of this self-regulating drug delivery system has been improved in terms of
      increased gel stability with reduced component leaching.

PMID- 12495549
TI  - Enhanced anaerobic degradation of polymeric azo compounds by Escherichia coli in
      the presence of low-molecular-weight redox mediators.
AB  - The effects of the redox mediator lawsone (2-hydroxy-1,4-naphthoquinone) on the
      ability of Escherichia coli to reduce anaerobically polymeric azo compounds were
      analysed. Two types of polymeric azo compounds were tested, that have been
      proposed as putative tools for the site-specific targeting of drugs to the colon.
      The first group of polymers consisted basically of linear chains of
      polymethacrylic acid or polymethylmethacrylate which were interrupted by subunits
      of 4,4'-bis(methacryloylamino)azobenzene. These polymers differed significantly
      in their hydrophilicity according to the relative proportion of polymethacrylic
      acid used for the polymerization procedure. The second group of polymers
      consisted of almost water-insoluble poly(ether-ester)azo polymers that were
      composed of 4-(6-hydroxyhexyl)oxy-phenylazobenzoate and 16-hydroxyhexadecanoate.
      The addition of lawsone to the anaerobically incubated cultures of E. coli
      resulted in a pronounced increase in the reduction rates of the water-soluble
      poly(methacrylate-co-4,4'-bis(methacryloylamino)azobenzene) and in a much
      smaller, but significant, increase in the reduction rates of the hydrophobic
      poly(ether-ester)azo polymers. An increase in the amount of azo groups resulted,
      for the hydrophobic poly(ether-ester)azo polymers, in an increased reduction rate
      in the presence of the redox mediator lawsone.

PMID- 12495550
TI  - Human skin sandwich for assessing shunt route penetration during passive and
      iontophoretic drug and liposome delivery.
AB  - This work explored the role of skin appendages (shunt route) in passive and
      iontophoretic drug and liposome penetration. The technique used an epidermis and
      stratum corneum sandwich from the same skin donor with the additional stratum
      corneum forming the top layer of the sandwich. Penetration was monitored during
      occluded passive and iontophoretic (0.5 mA cm(-2)) delivery of mannitol and
      estradiol solutions, and ultradeformable liposomes containing estradiol. The
      shunt route had a significant role during passive penetration of mannitol
      (hydrophilic compound), but was negligible during penetration of estradiol
      (lipophilic drug) and liposomes. In iontophoresis, the shunt route significantly
      contributed to the overall flux of all preparations, being highest for mannitol.
      However, shunts were not the only pathway for iontophoretic drug delivery and
      evidence was observed for the creation of new aqueous pathways via
      disorganization of the intercellular lipid domain of stratum corneum. The skin
      sandwich technique should prove valuable for general studies on routes of skin
      penetration.

PMID- 12495551
TI  - Effect of gentamicin on pharmacokinetics of lysozyme in rats: interaction between
      megalin substrates in the kidney.
AB  - To investigate the pharmacokinetic interaction between substrates of megalin, a
      600-kDa endocytic receptor abundantly expressed in the renal proximal tubules, we
      examined the effect of gentamicin infusion on the pharmacokinetics of fluorescein
      isothiocyanate (FITC)-lysozyme in rats. Infusion of gentamicin did not affect the
      plasma concentration-time profile of FITC-lysozyme. On the other hand, gentamicin
      significantly decreased the accumulation of FITC-lysozyme in the renal cortex and
      medulla, whereas the accumulation in the renal papilla, liver, brain and lung was
      not changed. Urinary excretion of FITC-lysozyme was increased by gentamicin,
      whereas there was no change in the biliary excretion of FITC-lysozyme or its
      degradation products. Gentamicin infusion had little influence on the ATP content
      in the renal cortex and urinary excretion of glucose, indicating that
      nephrotoxicity is not induced by short-term infusion of gentamicin. These
      findings suggest that lysozyme and gentamicin interact with each other in their
      reabsorption processes in the renal proximal tubules, probably by competing for
      their binding to megalin expressed in the apical membrane of the renal proximal
      tubules.

PMID- 12495552
TI  - Poly(L-lysine) as a model drug macromolecule with which to investigate secondary
      structure and microporous membrane transport, part 2: diffusion studies.
AB  - Peptide drugs are hydrophilic in nature and so their preferred pathway of
      membrane transport is by the paracellular route, which primarily involves passive
      diffusion across intercellular pores. The objective of the present study was to
      investigate the effect of secondary structure on the aqueous diffusion of a model
      polypeptide, poly(L-lysine), through a microporous membrane. The primary aim was
      to systematically evaluate the variables (e.g. viscosity and/or hydrodynamic
      radius) that may contribute to the difference, if any, in the calculated values
      of the aqueous diffusion coefficient (D(aq)) for each conformer of poly(L
      lysine). Variations in pH and temperature of the medium were used to induce
      secondary structural changes in poly(L-lysine). Transport studies were conducted
      for 3 h at 25 or 37 degrees C using side-by-side diffusion cells. Hydrophilic
      microporous polyester membranes with a 1-microm pore diameter were used to
      measure the free diffusion of each conformer. The values for the apparent
      permeability (P(app)) and D(aq) were calculated using standard equations. The
      viscosity of each conformer solution was determined and the hydrodynamic radius
      of each conformer was then estimated. At 25 degrees C, both P(app) and D(aq) of
      the alpha-helix conformer were approximately the same as those of the random coil
      conformer. In contrast, at 37 degrees C, the P(app) and the D(aq) of the beta
      sheet conformer were significantly (P < 0.05) less than those of the random coil
      conformer. At 25 degrees C, the solutions containing primarily either the random
      coil or the-helix conformers had approximately the same viscosity. On the other
      hand, at 37 degrees C, the solutions containing the beta-sheet conformer had a
      significantly (P < 0.05) higher viscosity than when this conformer was absent.
      The random coil and the alpha-helix conformers appeared to have comparable sizes,
      whereas the hydrodynamic radius estimated for the beta-sheet conformer was
      significantly (P < 0.05) larger than those for the other two conformers. In
      summary, changing the secondary structure of poly(L-lysine) from the random coil
      to the alpha-helix did not affect its P(app) and intrinsic D(aq). On the other
      hand, appearance of the beta-sheet conformer significantly decreased the values
      of P(app) and D(aq). The differences appeared to result from the significantly
      higher solution viscosity as well as the extended structure associated with the
      beta-sheet conformer of poly(L-lysine). This strategy may represent a potential
      mechanism to sustain the delivery of therapeutic peptide drugs from a controlled
      drug delivery device.

PMID- 12495553
TI  - Influence of pharmaceutical quality on the bioavailability of active components
      from Ginkgo biloba preparations.
AB  - To be effective, herbal medicinal products are expected to meet comparable
      standards concerning the assessment of efficacy, safety and biopharmaceutical
      quality as chemically defined synthetic drugs as food supplements. However, these
      requirements are often not fulfilled, particularly regarding the characterization
      of biopharmaceutical properties such as in-vitro dissolution and in-vivo
      bioavailability. With respect to the relevance of biopharmaceutical quality of
      herbal medicinal products, two different Ginkgo biloba brands (test product:
      Ginkgo biloba capsules; reference product: Ginkgold) were analysed for
      dissolution rates and bioavailability of the most relevant active ingredients.
      Dissolution rates at pH 1 and 4.5 were determined according to the USP 23. The
      relative bioavailability of ginkgolide A, ginkgolide B and bilobalide was
      investigated after single oral administration of 120 mg Ginkgo biloba extract as
      tablets or capsules. Bioavailability data (area under the curve and peak
      concentration in plasma) were clearly different and did not show bioequivalence
      of test and reference products. The slow in-vitro dissolution of the test product
      resulted in a large decrease in bioavailability. These results indicate for the
      first time that the pharmaceutical properties of a herbal medicinal product have
      a significant impact on the rate and extent of drug absorption, and very likely
      on efficacy in humans.

PMID- 12495554
TI  - Antihypertensive, vasodilator and antioxidant effects of a vinifera grape skin
      extract.
AB  - Cumulative evidence suggests that moderate wine consumption exerts a
      cardioprotective effect. We investigated the occurrence of an antihypertensive
      effect of an alcohol-free hydroalcoholic grape skin extract (GSE) obtained from
      skins of a vinifera grape (Vitis labrusca) in experimental rodent hypertension
      models. The vasodilator effect of GSE (polyphenols concentration 55.5 mg g(-1))
      was also assessed in the isolated mesenteric vascular bed of Wistar rats and the
      antioxidant effect was studied on lipid peroxidation of hepatic microsomes. Oral
      administration of GSE significantly reduced systolic, mean and diastolic arterial
      pressure in Wistar rats with desoxycorticosterone acetate-salt and N(G)-nitro-L
      arginine methyl ester (L-NAME) induced experimental hypertension. In the rat
      isolated mesenteric vascular bed pre-contracted with norepinephrine, bolus
      injections of GSE induced endothelium-dependent vasodilatation that was
      substantially inhibited by L-NAME, but not by indometacin, tetraethylammonium or
      glibenclamide. Lipid peroxidation of hepatic microsomes estimated as
      malondialdehyde production was concentration-dependently inhibited by GSE. In
      conclusion, the antihypertensive effect of GSE might be owing to a combination of
      vasodilator and antioxidant actions of GSE. These findings also suggest that the
      beneficial effect of moderate red wine consumption could be owing to an
      antihypertensive action induced by compounds occurring in the skin of vinifera
      grapes.

PMID- 12495555
TI  - Assessment of estrogenic activity in some common essential oil constituents.
AB  - Estrogenic responses have not only been associated with endocrine function, but
      also with cognitive function. Several studies have indicated that estrogen
      replacement therapy has favourable effects on cognition, and may have potential
      in the prevention and treatment of Alzheimer's disease. Thus, ligands for the
      estrogen receptor, that have a better efficacy and adverse-effect profile than
      drugs currently available, require investigation. This study was undertaken to
      investigate the potential estrogenic activity of a number of essential oil
      constituents. Initially, estrogenic activity was determined by a sensitive and
      specific bioassay using recombinant yeast cells expressing the human estrogen
      receptor. At high concentrations, estrogenic activity was detected for citral
      (geranial and neral), geraniol, nerol and trans-anethole, while eugenol showed
      anti-estrogenic activity. Molecular graphics studies were undertaken to identify
      the possible mechanisms for the interaction of geranial, neral, geraniol, nerol
      and eugenol with the ligand-binding domain of the estrogen alpha-receptor, using
      the computer program HyperChem. Citral, geraniol, nerol and eugenol were also
      able to displace [(3)H]17beta-estradiol from isolated alpha- and beta-human
      estrogen receptors, but none of these compounds showed estrogenic or anti
      estrogenic activity in the estrogen-responsive human cell line Ishikawa Var I at
      levels below their cytotoxic concentrations, and none showed activity in a yeast
      screen for androgenic and anti-androgenic activity. The potential in-vivo
      estrogenic effects of citral and geraniol were examined in ovariectomized mice,
      but neither compound showed any ability to stimulate the characteristic
      estrogenic responses of uterine hypertrophy or acute increase in uterine vascular
      permeability. These results show that very high concentrations of some commonly
      used essential oil constituents appear to have the potential to interact with
      estrogen receptors, although the biological significance of this is uncertain.

PMID- 12495556
TI  - Rapid effect of progesterone on the contraction of rat aorta in-vitro.
AB  - Progesterone induced rapid relaxation of KCl-induced contraction of rat aortic
      rings. The relaxant effect of progesterone on aortic rings was concentration
      dependent (over the range of 10(-10) to 10(-5) M) and partially dependent on the
      endothelium. Application of a nitric oxide (NO) synthase antagonist N(G)
      monomethyl-L-arginine (L-NMMA, 10(-5) M) after progesterone treatment partially
      inhibited the relaxant effects of progesterone. This suggested that part of the
      effect was through the production of nitric oxide. Washing out the steroid
      hormone in the bath solutions could quickly reverse the inhibitory effects of
      progesterone on phasic tension generation in aortic rings. Five minutes after
      washout, the tension generation in aortic rings was completely restored. Cultured
      endothelial cells from rat aorta increased release of NO into culture media in
      response to a 60-min exposure to progesterone. Aldosterone and dexamethasone were
      also tested, and failed to relax KCl-induced contraction of aortic rings. These
      data suggest that the vascular effects of progesterone are not mediated by a
      genomic action of this steroid, and that the vascular effects are mediated
      partially through endothelial NO production.

PMID- 12495557
TI  - Participation of various kinases in staurosporine induced apoptosis of RAW 264.7
      cells.
AB  - Staurosporine induced apoptosis of RAW 264.7 cells, a mouse macrophage-like cell
      line, as determined by DNA fragmentation, the increase of annexin V-stained
      cells, and the cleavage of poly(ADP-ribose)polymerase (PARP), a substrate of
      caspase. Analysis of the increase in the percentage of sub-G(1) cells revealed
      that the DNA fragmentation occurred in a time- and concentration-dependent manner
      at 0.021-2.1 microM of staurosporine. Staurosporine induced phosphorylation of
      p38 mitogen-activated protein kinase (MAPK) but suppressed spontaneous
      phosphorylation of p44/42 MAPK. The p38 MAPK inhibitor SB203580, the
      MAPK/extracellular signal-regulated kinase kinase inhibitor PD98059 and the
      phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 potentiated the
      staurosporine-induced PARP cleavage and DNA fragmentation. The protein kinase A
      (PKA) inhibitor H-89 potentiated the staurosporine-induced DNA fragmentation
      without potentiating the PARP cleavage. In contrast, the protein kinase C (PKC)
      inhibitor Ro-31-8425 suppressed the PARP cleavage and DNA fragmentation. These
      findings suggested that staurosporine induces apoptosis via the caspase cascade
      in RAW 264.7 cells. The staurosporine-induced apoptosis is positively regulated
      by PKC, negatively regulated by p38 MAPK, p44/42 MAPK and PI3K via the caspase
      cascade, and negatively regulated by PKA without regulation of caspase
      activation.

PMID- 12495558
TI  - Inhibition and possible induction of rat CYP2D after short- and long-term
      treatment with antidepressants.
AB  - The aim of this study was to investigate the influence of tricyclic
      antidepressants (imipramine, amitriptyline, clomipramine, desipramine), selective
      serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel
      antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2D, measured
      as a rate of ethylmorphine O-deethylation. The reaction was studied in control
      liver microsomes in the presence of the antidepressants, as well as in microsomes
      of rats treated intraperitoneally for one day or two weeks (twice a day) with
      pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine,
      nefazodone 10 mg kg(-1) i.p.; desipramine, fluoxetine, sertraline 5 mg kg(-1)
      i.p.; mirtazapine 3 mg kg(-1) i.p.), in the absence of the antidepressants in
      vitro. Antidepressants decreased the activity of the rat CYP2D by competitive
      inhibition of the enzyme, the potency of their inhibitory effect being as
      follows: clomipramine (K(i) = 14 microM) > sertraline approximate, equals
      fluoxetine (K(i) = 17 and 16 microM, respectively) > imipramine approximate,
      equals amitriptyline (K(i) = 26 and 25 microM, respectively) > desipramine (K(i)
      = 44 microM) > nefazodone (K(i) = 55 microM) > mirtazapine (K(i) = 107 microM). A
      one-day treatment with antidepressants caused a significant decrease in the CYP2D
      activity after imipramine, fluoxetine and sertraline. After prolonged
      administration of antidepressants, the decreased CYP2D activity produced by
      imipramine, fluoxetine and sertraline was still maintained. Moreover,
      amitriptyline and nefazodone significantly decreased, while mirtazapine increased
      the activity of the enzyme. Desipramine and clomipramine did not produce any
      effect when administered in-vivo. The obtained results indicate three different
      mechanisms of the antidepressants-CYP2D interaction: firstly, competitive
      inhibition of CYP2D shown in-vitro, the inhibitory effects of tricyclic
      antidepressants and SSRIs being stronger than those of novel drugs; secondly, in
      vivo inhibition of CYP2D produced by both one-day and chronic treatment with
      tricyclic antidepressants (except for desipramine and clomipramine) and SSRIs,
      which suggests inactivation of the enzyme apoprotein by reactive metabolites; and
      thirdly, in-vivo inhibition by nefazodone and induction by mirtazapine of CYP2D
      produced only by chronic treatment with the drugs, which suggests their influence
      on the enzyme regulation.

PMID- 12495559
TI  - Influence of hydroxypropyl-beta-cyclodextrin on photo-induced free radical
      production by the sunscreen agent, butyl-methoxydibenzoylmethane.
AB  - The aim of the study was to investigate the effect of hydroxypropyl-beta
      cyclodextrin (HP-beta-CD) on the photo-induced production of free radicals by the
      sunscreen agent, butyl-methoxydibenzoylmethane (BMDBM). Spin-trapping/electron
      paramagnetic resonance spectroscopy was used to evaluate the formation of
      radicals and the extent of BMDBM photodegradation was measured by high
      performance liquid chromatography. The stable 2,2,6,6-tetramethylpiperidine-1
      oxyl, nitroxide radical (TEMPO) was used as spin-trap. Any free radicals
      generated during irradiation of the sunscreen agent will couple with the TEMPO
      radicals giving diamagnetic species and thus a decrease of the signal intensity
      in the electron paramagnetic resonance spectrum. Following 2-h illumination with
      simulated sunlight, the solution containing free BMDBM exhibited a 93.9% decrease
      of the intensity of the TEMPO signal. Under the same irradiation conditions, only
      a 12.2% reduction of the TEMPO concentration was measured in the sample
      containing BMDBM complexed with HP-beta-CD. Moreover, the decrease of the spin
      trap level observed for the HP-beta-CD/BMDBM complex was not significantly
      different from that produced when solutions containing TEMPO only or TEMPO in the
      presence of HP-beta-CD alone were subjected to irradiation. In addition, the
      photodegradation of the sunscreen agent was reduced by complexation with HP-beta
      CD (the extent of degradation was 27.6% for the complex compared with 63.1% for
      free BMDBM). The results obtained indicate that the free radicals generated by
      BMDBM when exposed to simulated sunlight are effectively scavenged by inclusion
      complexation of the sunscreen agent with HP-beta-CD.

PMID- 12495560
TI  - Effects of histamine H(2)-receptor antagonists on human plasma levels of
      calcitonin gene-related peptide, substance P and vasoactive intestinal peptide.
AB  - The effects of the histamine H(2)-receptor antagonists (H(2)-antagonists),
      ranitidine, nizatidine, cimetidine and famotidine, on plasma levels of
      gastrointestinal peptides, calcitonin gene-related peptide (CGRP), substance P
      (SP), and vasoactive intestinal peptide (VIP) was investigated with respect to
      regulation of gastric mucosal blood flow, in healthy volunteers. H(2)-Antagonists
      or placebo was orally administered to five healthy male volunteers. Venous blood
      samples were taken before and after drug administration. The levels of plasma
      gastrointestinal peptides were determined by enzyme immunoassay. The
      administration of ranitidine and nizatidine caused significant increases in
      plasma CGRP and SP levels at 30 to 120 min compared with the placebo group. Peak
      plasma CGRP levels (39.8+/-3.1 and 40.6+/-3.6 pg mL(-1)) were achieved 60 min
      after administration of ranitidine and nizatidine, respectively. Maximum plasma
      SP levels (21.3+/-5.2 and 22.8+/-4.2 pg mL(-1)) were reached 60 min after
      administration of ranitidine and nizatidine, respectively. However, all H(2)
      antagonists did not alter the levels of VIP. The released CGRP and SP by
      ranitidine and nizatidine administration may produce a gastroprotective effect,
      increase mucosal blood flow, and inhibit acid secretion in the gastrointestinal
      tract.

PMID- 12495561
TI  - Diazepam does not reduce infarct size in rats subjected to transient occlusion of
      the middle cerebral artery when normothermia is maintained.
AB  - Activation of the gamma-amino butyric acid (GABA)-ergic system might protect
      against the damage that occurs after cerebral ischaemia. We examined this
      hypothesis by administering diazepam to rats subjected to transient middle
      cerebral artery occlusion (MCAO) using the intraluminal thread method. Diffusion
      MRI (DWI) and perfusion imaging (PI) were acquired during MCAO to assess brain
      tissue status and haemodynamics, respectively. Rats were intraperitoneally
      injected with either 10 mg kg(-1) diazepam (n = 5) or vehicle (n = 5) both 30 min
      and 90 min after the onset of MCAO. To exclude the possibility that
      neuroprotection was due to the hypothermic action of the drug, body temperature
      was maintained at 37-38 degrees C for up to 7 h postischaemia with a feed-back
      controlled thermoregulatory unit. Infarct volumes quantified 2 days after MCAO
      from T(2)-weighted images were similar in ischaemic control rats and in ischaemic
      rats treated with diazepam. We conclude that diazepam-induced enhancement of
      GABA(A) activity does not effectively protect against neuronal damage that occurs
      after transient MCAO in normothermic rats.

PMID- 12495562
TI  - The dimensionality of speaking and writing: a multilevel factor analysis of
      situational, task and school effects.
AB  - BACKGROUND: This article addresses the question whether communication
      apprehension (CA) should be regarded as a unidimensional or alternatively as a
      multidimensional construct. The answer is not only interesting from a theoretical
      point of view. There might also be practical implications for the treatment of
      CA. If CA were to appear to be unidimensional and a student's level of CA were to
      be the same across situations and tasks, there would be no need to tailor the
      treatment to particular speaking situations or specific writing problems. If,
      however, CA appeared to be multi-dimensional and a student might have a variety
      of different levels and types of CA, one type of treatment might be more
      effective for one student than for another one. AIM: To examine the effects of
      situational, task and school effects on speaking and writing apprehension.
      SAMPLE: Use was made of the dataset of the 1987-1988 National Assessment of
      Language Performance in the Netherlands. The nationally representative sample
      consisted of 1448 students from 184 secondary schools; 52% of the students were
      boys and 48% were girls; the mean age of the students was 15 years 6 months.
      METHOD: Speaking and writing apprehension were measured by means of self-report
      measures in grade 9. Multilevel factor analysis (MLFA) was used to determine the
      dimensionality of the measurement of speaking and writing apprehension. RESULTS
      AND CONCLUSIONS: First, all seven speaking situations and three out of four
      writing problems could be distinguished empirically. Speaking and writing
      apprehension are clearly multidimensional constructs that depend on the speaking
      situation and the writing task. Second, correlations between speaking and writing
      apprehension were rather low. Speaking and writing apprehension seem to represent
      skill-specific constructs, which cannot be considered as equivalent forms of
      communication apprehension. Third, differences between schools in the level of
      speaking and writing apprehension were very small compared to measurements of
      speaking and writing performance.

PMID- 12495563
TI  - Developing deep learning approaches and personal teaching efficacy within a
      preservice teacher education context.
AB  - BACKGROUND: University students' approaches to learning have been demonstrated to
      affect learning outcomes across a wide range of courses, favouring the use of a
      deep approach. Interventions to promote the use of deep approaches have had mixed
      success, with the most successful interventions involving large-scale course
      redesign. AIMS: This paper describes a study in which contextual modifications
      were implemented in an existing preservice teacher education programme to
      increase students' use of deep approaches to learning and reduce their reliance
      on the use of surface approaches, without the need for major redesign. Students'
      perceptions of their competence in performing the tasks of teaching (personal
      teaching efficacy) were also expected to improve in response to improvements in
      quality learning. SAMPLE: Three cohorts of students (N = 134), enrolled in a
      preservice teacher education degree programme at a rural university in New South
      Wales, Australia participated in the study. METHOD: A longitudinal quasi
      experimental design was used, with Cohort 1 acting as a control while Cohorts 2
      and 3 represented treatment groups. Repeated measures were taken on Biggs'
      (1987b) Study Process Questionnaire, a modified version of Gibson and Dembo's
      (1984) Teacher Efficacy Scale and the Academic subscale within Lefcourt's (1981)
      Multidimensional-Multiattributional Causality Scale. An action research paradigm
      was embedded to enable the development and refinement of the altered teaching
      approaches. RESULTS: Results indicated that the modifications to teaching
      methods, task requirements and assessment processes applied to the treatment
      group encouraged changes in students' approaches to learning by firstly reducing
      their use of surface approaches and later increasing the use of deep approaches.
      While both treatment and contrast groups exhibited equivalent growth in teaching
      efficacy, differences between cohorts were noted in the sources that informed
      personal teaching efficacy at the conclusion of the course. CONCLUSIONS: These
      findings suggest that the study succeeded in its major goal of improving the
      quality of teaching and learning in this teacher education programme. The results
      conform to the findings of previous research and are consistent with learning
      approach theory. While the specific contextual modifications used in the current
      study may not necessarily be transferable to other settings, the processes
      employed in the generation of those modifications could find wider applicability.

PMID- 12495564
TI  - Reading, language and memory skills: a comparative longitudinal study of children
      with Down syndrome and their mainstream peers.
AB  - BACKGROUND: Many of today's young adults with Down syndrome never had the
      opportunity to learn to read. However, an increasing number of children with Down
      syndrome are currently attending mainstream schools and being taught to read. As
      a consequence, it is now possible to systematically study reading development in
      children with Down syndrome. AIMS: The aim of this study was to chart the
      development of reading, language, and memory skills in children with Down
      syndrome and to investigate the relationships between these abilities. SAMPLE:
      Twenty-four children with Down syndrome aged between 4 and 12 were followed over
      two years and compared to 31 children matched for reading age, and 42 children of
      average reading ability, selected from the same mainstream classes as the
      children with Down syndrome. METHOD: Standardised assessments were administered
      annually to obtain measures of reading, spelling, language, memory, and general
      intelligence. RESULTS: The children with Down syndrome had relatively advanced
      single word reading ability compared to their other cognitive skills. The reading
      progress of the children with Down syndrome did not differ significantly from
      that of the reading matched group even after two years. Different cognitive
      abilities were highly correlated with one another in all groups. However, after
      controlling for age, many of the partial correlations between reading and the
      other measures were reduced to non-significant levels. CONCLUSIONS: Most children
      with Down syndrome are capable of learning to read single words. However, there
      was no evidence over this two-year period to support the hypothesis that learning
      to read will help to enhance language and memory development in children with
      Down syndrome.

PMID- 12495565
TI  - Relaxed conditions can provide memory cues in both undergraduates and primary
      school children.
AB  - BACKGROUND: Memory can be impaired by changes between the contexts of learning
      and retrieval (context-dependent memory, CDM). However, the reminder properties
      of context have usually been investigated by experimental manipulation of cues in
      isolation, underestimating CDM that results from interactions between cues. AIMS:
      To test whether CDM can be demonstrated using multiple contextual cues combined
      to create relaxing versus neutral contexts at separate learning and memory
      testing stages of the experiments. SAMPLE: Forty university undergraduates (in
      Experiment 1), and forty 9-10 year-olds (in Experiment 2). METHODS: All
      participants were given age-appropriate tasks under either relaxing or neutral
      conditions. The next day they were tested for retrieval or practice effects,
      under the same or different (relaxing versus neutral) conditions. RESULTS: For
      both age groups, there was a (mostly asymmetric) CDM effect with performance
      generally best in the relaxing-relaxing condition. There was also some overall
      benefit of having learned under relaxed conditions. CONCLUSION: A relaxed
      learning environment can provide effective retrieval cues, as well as improve
      learning. COMMENT: For both primary school children and university students, the
      educational implication of these findings is that learning can be improved in a
      relaxed state. For this benefit to be fully manifest, the assessment of learning
      should also take place under relaxed conditions.

PMID- 12495566
TI  - General cognitive ability in children with reading comprehension difficulties.
AB  - BACKGROUND: Children with specific reading comprehension difficulties read
      accurately and fluently but are poor at understanding what they read. AIMS: This
      study investigated cognitive ability in children with poor reading comprehension
      with a view to determining the relationship between general cognitive ability and
      specific reading comprehension difficulty. SAMPLE: Twenty-five poor comprehenders
      and 24 control children, matched for chronological age and word reading ability,
      participated in this study. METHODS: General conceptual ability (GCA) was
      assessed using the British Ability Scales (2(nd) edition; BAS-II); good and poor
      comprehenders' performance on different subscales was compared and related to
      underlying skills in reading accuracy, reading comprehension and number. RESULTS:
      There was a general tendency for poor comprehenders to achieve lower scores on
      verbal tasks than on non-verbal and spatial tasks. Although the poor
      comprehenders scored significantly below the control children across most
      subtests, most obtained GCA scores within the normal range. For these children,
      reading comprehension was significantly below GCA-expected levels. A subset of
      poor comprehenders with below average GCA showed a clear hyperlexic profile in
      which comprehension was not unexpectedly poor but rather, reading accuracy was
      surprisingly good. CONCLUSIONS: These findings highlight the heterogeneity of
      children presenting with poor reading comprehension. Although most poor
      comprehenders have weaknesses that appear to be restricted to the verbal domain,
      a minority have more general cognitive impairments.

PMID- 12495567
TI  - Teaching children to recognise rhyme does not directly promote phonemic
      awareness.
AB  - BACKGROUND: Rhyming ability and phoneme awareness both predict aspects of reading
      development, with rhyming emerging earlier than phoneme awareness in most
      children. This study employed an experimental technique to elucidate the causal
      connections between these two aspects of phonological sensitivity. AIMS: The
      purpose of this study was to examine whether teaching preschool children to
      detect rhyme promotes their ability to detect phoneme relations. SAMPLE, METHODS,
      RESULTS: An experimental group of 23 children was successfully taught to rhyme,
      and compared to an untaught control group of 23 children in the ability to detect
      phonemes. Neither group showed any increase in phonemic awareness on an immediate
      or a delayed post-test. CONCLUSIONS: The results do not support the hypothesis
      that rhyme sensitivity is a causal precursor of phoneme sensitivity. We conclude
      that teaching children to rhyme remains an important preliteracy activity, but
      not because it directly promotes phonemic awareness.

PMID- 12495568
TI  - Measuring self-reported studying and learning for university students: linking
      attitudes and behaviours on the same scale.
AB  - BACKGROUND: The relationships between self-reported Approaches to Studying and
      Self-concept, Self-capability and Studying and Learning Behaviour are usually
      studied by measuring the variables separately (using factor analysis and Cronbach
      Alphas) and then using various correlation techniques (such as multiple
      regression and path analysis). This procedure has measurement problems and is
      called into question. AIMS: To create a single scale of Studying and Learning
      using a model with subsets of ordered stem-items based on a Deep Approach, a
      Surface Approach and a Strategic Approach, integrated with three self-reported
      aspects (an Ideal Self-view, a Capability Self-view and a Studying and Learning
      Behaviour Self-view). SAMPLES: The stem-item sample was 33, all answered in three
      aspects, that produced an effective item sample of 99. The person convenience
      sample was 431 students in education (1(st) to 4(th) year) at an Australian
      university during 2000. METHOD: The latest Rasch Unidimensional Measurement Model
      Computer Program (Andrich, Lyne, Sheridan, & Luo, 2000) was used to analyse the
      data and create a single scale of Studying and Learning. RESULTS: Altogether 77
      items fitted a Rasch Measurement Model and formed a scale in which the
      'difficulties' of the items were ordered from 'easy' to 'hard' and the student
      measures of Studying and Learning were ordered from 'low' to 'high'. The
      proportion of observed student variance considered true was 0.96. The response
      categories were answered consistently and logically and the results supported
      many, but not all, the conceptualised ordering of the subscales. Students found
      it 'easy' to report a high Ideal Self-view, 'much harder' to report a high
      Capability Self-view, and 'harder still' to report a high Studying and Learning
      Behaviour for the stem-items, in accordance with the model, where items fit the
      measurement model. The Ideal Self-view Surface Approach items provided the most
      non-fit to the model. CONCLUSION: This method was highly successful in producing
      a single scale of Studying and Learning from self-reported Self-concepts, Self
      capabilities, and Studying and Learning Behaviours, based on a Deep Approach, a
      Surface Approach and a Strategic Approach.

PMID- 12495569
TI  - Controversies about databases.

PMID- 12495571
TI  - Database analyses: a reply.

PMID- 12495570
TI  - Limitations of inferences from observational databases in amyotrophic lateral
      sclerosis: all that glitters is not gold.
AB  - Data from three observational databases have suggested that survival in patients
      with ALS who take riluzole is far greater than that reported in randomized
      controlled studies. This editorial discusses why therapeutic efficacy cannot be
      inferred from observational databases. Data in these databases cannot control for
      biases in treatment assignment or for differences in intensity of follow-up or
      supportive care. The retrospective riluzole data, as presented so far, have not
      demonstrated comparability between the treated and untreated groups across all
      known prognostic factors, including vital capacity at the start of the
      observation period. Furthermore, the similarity of untreated patients to
      historical cohorts likely reflects adverse selection. Optimization of analysis in
      retrospective studies may be accomplished by allowing full access to data to all
      interested parties.

PMID- 12495572
TI  - SOD1 activity and protective factors in familial ALS patients with L84F SOD1
      mutation.
AB  - METHOD: The activity and amount of SOD1 in erythrocyte lysates and the plasma
      amino acid content were evaluated in four familial ALS patients bearing the L84F
      SOD1 mutation (fALS), in an asymptomatic family member with the mutation
      (L84F(5)), in sporadic ALS patients (sALS) and controls. Three of the fALS
      patients and the L84F(5) subject were tested once a year for three consecutive
      years. RESULTS: At the first evaluation SOD1 activity was similar in controls,
      sALS and fALS; the amount of SOD1 protein was lower (P < 0.01) in fALS. In the
      subsequent 2 years, 34% and 52% decrease of SOD1 activity was recorded in fALS
      patients. The plasma amino acid pattern did not differ between controls and sALS,
      whereas fALS patients displayed high levels of plasma aspartate and glutamate.
      Aspartate was in the normal range but glutamate was still elevated in the
      subsequent evaluations. The L84F(5) subject had remarkably low levels of
      aspartate, glutamate and branched-chain amino acids. CONCLUSIONS: The method of
      measuring mutant SOD1 amount is indirect but the results are indicative of a
      reduction of mutant SOD1 taking place during fast-worsening phases of the
      disease. Since the disease onset of fALS patients is 42.8 +/- 11.3 years and the
      L84F(5) family member is asymptomatic at the age of 66, low levels of excitotoxic
      and branched-chain amino acids in plasma may constitute a protective factor
      against disease development.

PMID- 12495573
TI  - Correlates of Quality of Life in people with motor neuron disease (MND).
AB  - OBJECTIVES: Previous work has not found correlations between standardized
      questionnaire measures of quality of life (QoL) and physical strength/functional
      ability in people with motor neuron disease (MND). Little is known about the
      relationship between ratings on an abbreviated self-generated measure of QoL, the
      Schedule for Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL
      DW), and measures of functional status such as the Sickness Impact Profile (SIP),
      although the former has been rated by people with MND as providing a more valid
      measure of their own QoL than the latter. The aim of this study was to examine
      whether self-generated ratings of QoL correlated with measures of physical
      impairment and self-reported functional status, psychological wellbeing and self
      reported cognitive functioning, and with factors such as social support, which
      elsewhere has been reported to be a determinant of QoL in MND. DESIGN: The
      present cross-sectional study investigated between SEIQoL-DW ratings and SIP and
      the relationship ALS Severity Scale (ALSSS) scores, as well as with self-reported
      anxiety, depression, social support and everyday cognitive functioning in 31
      people with MND. RESULTS: Overall QoL ratings on the SEIQoL-DW failed to
      correlate with any of the ALSSS or SIP subscale scores. This was despite the fact
      that health was nominated as an important QoL-related category by 64.5% of the
      sample. QoL scores were, however, found to correlate positively with the
      existence of confiding and emotional support; they also correlated negatively
      with the presence of self-rated everyday cognitive difficulties but not with
      affective state. CONCLUSIONS: Current findings support recent observations that
      individuals' ratings of their QoL cannot simply be equated with their physical
      impairment and functional limitations, and that support systems may be important.
      Cognitive functioning, known to be impaired in some people with MND, should also
      be considered when evaluating QoL.

PMID- 12495574
TI  - F-Waves and the corticospinal lesion in amyotrophic lateral sclerosis.
AB  - INTRODUCTION: In upper motor neuron (UMN) syndromes, F-waves are of higher
      amplitude, increased duration, and increased latency. Increased F-wave frequency
      in UMN syndromes is not well documented. We have studied the effect of
      corticospinal lesion on F-wave frequency, M-wave amplitude, distal motor latency
      and on the Neurophysiological Index (CMAP amplitude/DML x % F-wave frequency)
      which we have described previously in amyotrophic lateral sclerosis (ALS).
      METHOD: We studied 145 abductor digiti minimi (ADM) muscles in 75 patients with
      ALS. Six groups of hands were defined, based on strength of the ADM, as assessed
      clinically by the MRC scale, and the presence or absence of UMN signs in the same
      upper limb. RESULTS: CMAP amplitude and area were decreased, and DML increased,
      in weaker muscles (MRC < 3) causing a change in the ALS Neurophysiological Index.
      In general, UMN signs were not correlated with increased F-wave frequency. In
      five weak hands F-responses were studied in individual motor units. A larger
      number of responding motor units in these weak limbs with UMN signs was observed.
      CONCLUSION: F-wave excitability is largely dependent on the size of the lower
      motor neuron pool.

PMID- 12495575
TI  - Baroreflex stimulation shows impaired cardiovagal and preserved vasomotor
      function in early-stage amyotrophic lateral sclerosis.
AB  - OBJECT: In ALS patients, autonomic nervous system dysfunction might account for
      an additional reduction of the quality and expectancy of life of individual
      patients and contribute to unexpected early fatalities. This study was undertaken
      to assess baroreflex-mediated vagal and sympathetic cardiovascular control of the
      heart and blood vessels in ALS patients. METHODS: In 12 early-stage ALS patients
      (age 54 +/- 4 years) and 12 controls (age 55 +/- 3 years) we assessed resting
      baroreflex sensitivity (BRS) by spectral analysis, then stimulated the carotid
      baroreflex by oscillating neck suction at 0.1 Hz to assess the autonomic
      modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of
      parasympathetic stimulation on the heart. RESULTS: Resting heart rate was
      significantly higher in the ALS patients than in the controls (P < 0.05), but
      resting baroreflex sensitivity did not differ significantly between the groups.
      Stimulation at 0.2 Hz induced an oscillation in R-R interval that was
      significantly smaller (P < 0.05) in ALS patients than in controls. R-R interval
      responses to 0.1 Hz stimulation were significantly (P < 0.01) reduced in ALS
      patients compared to controls. Responses of blood vessels to 0.1 Hz stimulation
      did not differ significantly between the groups. CONCLUSION: In early-stage ALS
      patients, BRS might be normal at rest. Only baroreflex activation reveals
      impaired cardiovagal responses while sympathetic vasomotor control is preserved.
      Treatment to restore sympathetic-parasympathetic balance to the heart could
      prevent early cardiovascular fatalities in some ALS patients.

PMID- 12495576
TI  - Non-invasive ventilation in motor neuron disease: current UK practice.
AB  - OBJECTIVE: To evaluate the clinical application of non-invasive ventilation (NIV)
      in motor neuron disease (MND) in the UK. METHOD: We conducted a postal survey of
      the current clinical practice of all consultant neurologists in the UK, with a
      second mailing to non-responders after 6 weeks. The principal outcome measures
      assessed were: 1. the percentage of patients with MND receiving NIV, 2. access to
      a NIV service, 3. routine monitoring of respiratory function, and 4. influence of
      symptoms, respiratory function, rate of disease progression, level of disability
      and bulbar involvement on referral for NIV. RESULTS: The response rate was 76%,
      1719 new patients had been diagnosed in the preceding 12 months and a total of
      2280 patients were under review. Of these, 126 were currently receiving NIV (5.5%
      of patients under review, estimated 2.6-3.5% of all MND patients). Most
      neurologists (172/265) had referred no patients for NIV in the preceding year,
      while three neurologists made 30% of all referrals nationally. Referral was based
      primarily on symptoms, and was influenced by the number of MND patients under
      review, level of disability, rate of disease progression and availability of a
      NIV service. Bulbar involvement was considered a relative contra-indication to
      NIV by 51% of responders. CONCLUSIONS: In the UK, few patients with MND are
      treated with NIV. There is marked variation in clinical practice. This may
      reflect uncertainty about the role of non-invasive ventilation in MND, and
      emphasizes the need for a randomized controlled trial to assess the impact of NIV
      on quality of life and survival.

PMID- 12495577
TI  - Synergistic effects of low level stressors in an oxidative damage model of spinal
      motor neuron degeneration.
AB  - BACKGROUND: An increase in reactive oxygen species (ROS) burden and subsequent
      oxidative damage to nucleic acids, proteins, and lipids, occurs during the normal
      aging process of cells, including neurons. OBJECTIVE: With this in mind we
      hypothesize that an oxidative stress which leads to an increased state of
      oxidation, but is not itself lethal, nonetheless renders the motor neuron more
      vulnerable to other sublethal stressors. METHOD AND RESULTS: We have combined
      paraquat-induced oxidative stress with sublethal increased exogenous glutamate,
      or thermal stress, or a combination of both, and demonstrate a synergistic effect
      of low-level stressors on the viability of motor neurons. CONCLUSION: This model
      of low-level oxidative stress reveals the subsequent vulnerability of motor
      neurons to genetic or environmental stressors and may in part explain the mid
      life/late-life symptom onset in both familial and sporadic ALS patients.

PMID- 12495578
TI  - Motor neuron disease presenting with slow saccades and dementia.
AB  - A 46-year-old man with a 2-year history of dementia presented with very slow
      saccades and tongue fasciculations. The diagnosis of amyotrophic lateral
      sclerosis (ALS) was established by electrophysiologic studies and ultimately on
      autopsy. Rarely, slowed saccades may be present in ALS, and slow saccades in a
      relatively young demented patient should prompt consideration of ALS.

PMID- 12495579
TI  - Juvenile familial amyotrophic lateral sclerosis: two siblings.

PMID- 12495580
TI  - Kessnich Family MDA ALS Center.

PMID- 12495581
TI  - Beyond hope?

PMID- 12495582
TI  - PC-SPES.

PMID- 12495583
TI  - Composition, red blood cell uptake, and serum protein binding of phytoestrogens
      extracted from commercial kudzu-root and soy preparations.
AB  - Kudzu-root and soy phytoestrogens have been associated with anti-cancer and anti
      intoxication activities. Sales of capsules containing kudzu-root and soy extracts
      through health food stores and the Internet are unregulated. To compare efficacy,
      the amount of phytoestrogens present in commercial preparations and their fate in
      biological samples must be determined. In this study, the levels and composition
      of phytoestrogens in kudzu-root and soy extracts were studied using high
      performance liquid chromatography with ultraviolet light detection. The
      bioavailability of phytoestrogens was studied by measuring red blood cell (RBC)
      uptake and serum protein binding ability. Phytoestrogen levels in acidified kudzu
      root samples were 5- to 10-fold greater than those in nonacidified samples.
      Puerarin accounted for 80% of total phytoestrogens in kudzu-root. In soy extract,
      puerarin was absent while genistin, glycetein, and daidzin or daidzein were the
      major phytoestrogens. The RBC uptake depended on the phytoestrogen's polarity and
      molecular length. When serum was dialyzed with phytoestrogen standards in a
      buffer, the protein binding of phytoestrogens correlated negatively with their
      polarity. However, when serum was dialyzed with kudzu-root or soy extract, almost
      all of the phytoestrogens present in the extract bound to serum protein.
      Therefore, this study suggests differences in the bioavailability of
      phytoestrogens when they are ingested as purified compounds compared with crude
      plant extract. The differential composition of phytoestrogens in kudzu-root and
      soy may account for the differences in their therapeutic activities.

PMID- 12495584
TI  - Radioprotective effects in vivo of phenolics extracted from Olea europaea L.
      leaves against X-ray-induced chromosomal damage: comparative study versus several
      flavonoids and sulfur-containing compounds.
AB  - The radioprotective effects of a polyphenolic extract of Olea europaea L. leaves
      (OL); the flavonoids diosmin and rutin, which are widely used as pharmaceuticals;
      and the sulfur-containing compounds dimethylsulfoxide (DMSO) and 6-n-propyl-2
      thiouracil (PTU) were determined by using the micronucleus test for
      anticlastogenic activity, evaluating the reduction of the frequency of
      micronucleated polychromatic erythrocytes (MnPCEs) in bone marrow of mouse before
      and after X-ray irradiation. With treatment before X-irradiation, the most
      effective compounds were, in order, rutin > DMSO > OL > PTU > diosmin. These
      results showed, for the polyphenols studied, a linear correlation (r(2) = 0.965)
      between anticlastogenic activity and antioxidant capacity. The magnitude of
      protection with treatment after X-irradiation were lower, and the most effective
      compounds were, in order, OL > diosmin > rutin; DMSO and PTU lacked
      radioprotective activity. Therefore, OL is the only substance that showed a
      significant anticlastogenic activity both before and after X-ray irradiation
      treatments. Structurally, the free oxygen radicals and lipoperoxyradicals
      scavenging capacity and, consequently, the anticlastogenic activity of these
      polyphenolic compounds are based principally on the presence of specific
      functional groups, mainly catechol groups (rutin, oleuropein, hydroxytyrosol,
      verbascoside, luteolin), that also increase the stability of the aroxyl
      polyphenol radical generated in the above processes.

PMID- 12495585
TI  - Nutrient composition of rose (Rosa canina L.) seed and oils.
AB  - Rose seeds were evaluated for weight of 100 seeds, moisture, crude protein, ash,
      crude oil, energy, and mineral content. Also, fatty acid composition was
      determined in the seed oils. The weight of 100 seeds, moisture, crude oil,
      energy, and iron (Fe) content of Ermenek rose seeds were found to be higher than
      those of other regions. The major fatty acids identified by gas chromatography of
      rose seed oils growing wild in the Hadim, Taskent, and Ermenek regions in Turkey
      were, respectively, as follows: palmitic (3.17%, 1.71%, and 2.14%), stearic
      (2.47%, 2.14%, and 1.69%), oleic (16.73%, 18.42%, and 14.71%), linoleic (54.41%,
      51.71%, and 48,64%), linolenic (17.14%, 16.42%, and 18.41%), and arachidic
      (2.11%, 1.87%, and 2.61%). The seeds were rich in oil and minerals. The oil may
      be valuable for food and other uses because of its high unsaturated content.

PMID- 12495586
TI  - Nutritional supplementation with Chlorella pyrenoidosa for mild to moderate
      hypertension.
AB  - Pharmacological treatment of hypertension reduces the risk of cardiovascular
      disease; however, randomized, controlled clinical trials and population studies
      have also shown that abnormally high blood pressure (BP) can be lowered with diet
      modification and exercise. The objective of this pilot study was to determine
      whether daily dietary supplementation with 10 g Chlorella tablets and 100 ml
      Chlorella extract for 2 months would reduce BP in subjects with a mean sitting
      diastolic BP (SiDBP) between 90 and 115 mm Hg. Thirty-three people were enrolled
      and underwent a 4-week washout period from all antihypertensive medications,
      during which they consumed placebo. At completion of this washout/placebo period,
      24 subjects were considered evaluable (i.e., had a SiDBP between 90 and 115 mm
      Hg) and were continued in the study. After 1 or 2 months of dietary Chlorella
      supplementation, the average heart rate, sitting systolic BP, and SiDBP changed
      only slightly; after 2 months of Chlorella consumption, the group's mean SiDBP
      was 96.5 +/- 6.6. However, a heterogenous response pattern to Chlorella existed,
      with 25% (6/24) of the subjects achieving their BP goal (SiDBP less than 90 mm
      Hg). Furthermore, the BP of nonresponders did not increase significantly above
      washout values. Quality-of-life questionnaires indicated an overall perception
      that health had significantly improved in conjunction with Chlorella consumption.
      The results indicate that, for some subjects with mild to moderate hypertension,
      a daily dietary supplement of Chlorella reduced or kept stable their SiDBP.

PMID- 12495587
TI  - Melatonin, serotonin, and tryptamine in some egyptian food and medicinal plants.
AB  - The mammalian pineal hormone melatonin (N-acetyl-5-methoxytryptamine), an
      aminoindole produced by the metabolism of serotonin (5-hydroxytryptamine), has
      been shown to be a potent scavenger for the highly toxic hydroxyl radical. Three
      substances that are very important in animal physiology (e.g., in brain
      metabolism) are noradrenaline, histamine, and serotonin; all three occur in
      plants. Here we report that serotonin, tryptamine, and melatonin were found in
      some edible and medicinal plants in Egypt. The results of this screening showed
      that the pulp of underripe and ripe yellow banana contains 5-hydroxytryptamine at
      concentrations of 31.4 and 18.5 ng/g, respectively. Corn, rice, barley grains,
      and ginger showed the highest concentrations of melatonin, at 187.8, 149.8, 87.3,
      142.3 ng/100 g, respectively. On the other hand, potato samples were free from
      all indolamines. Pomegranate and strawberry showed a low level of indolamines (8
      12 microg/g serotonin, 4-9 microg/g tryptamine, and 13-29 ng/100 g melatonin).

PMID- 12495588
TI  - Chicken egg yolk antibodies as therapeutics in enteric infectious disease: a
      review.
AB  - Passive immunization by oral administration of specific antibodies has been an
      attractive approach against gastrointestinal (GI) pathogens in both humans and
      animals. Recently, laying chickens have attracted considerable attention as an
      alternative source of antibodies for the prevention and treatment of infectious
      GI diseases. After immunization, the specific antibodies (called IgY) are
      transported to the egg yolk, from which the IgY then can be separated without
      sacrificing chickens. A chicken usually lays about 280 eggs in a year, and egg
      yolk contains 100-150 mg of IgY per yolk, suggesting that more than 40 g of IgY
      per year can be obtained from each chicken through eggs. IgY is also an
      alternative to antibiotics for treatment of enteric antibiotic-resistant
      pathogens. Oral administration of IgY has proved successful for treatment of a
      variety of GI infections, such as bovine and human rotaviruses, bovine
      coronavirus, Yersinia ruckeri, enterotoxigenic Escherichia coli, Salmonella spp.,
      Edwardsiella tarda, Staphylococcus, and Pseudomonas. The IgY technology offers
      great future opportunities for designing prophylactic strategies against
      infectious GI diseases in humans and animals. However, there is still controversy
      regarding the stability of IgY through the GI tract. Finding an effective way to
      protect the antibodies from degradation in the GI tract would open the door for
      significant advances in IgY technology and nutraceutical applications.

PMID- 12495589
TI  - Hepatoprotective activity of Moringa oleifera on antitubercular drug-induced
      liver damage in rats.
AB  - Moringa oleifera Lam (Moringaceae), commonly known as "Drumstick," is used in
      Indian folk medicine for the treatment of various illness. We have evaluated the
      hepatoprotective effect of an ethanolic extract of M. oleifera leaves on liver
      damage induced by antitubercular drugs such as isoniazid (INH), rifampicin (RMP),
      and pyrazinamide (PZA) in rats. Oral administration of the extract showed a
      significant protective action made evident by its effect on the levels of
      glutamic oxaloacetic transaminase (aspartate aminotransferase), glutamic pyruvic
      transaminase (alanine aminotransferase), alkaline phosphatase, and bilirubin in
      the serum; lipids, and lipid peroxidation levels in liver. This observation was
      supplemented by histopathological examination of liver sections. The results of
      this study showed that treatment with M. oleifera extracts or silymarin (as a
      reference) appears to enhance the recovery from hepatic damage induced by
      antitubercular drugs.

PMID- 12495590
TI  - Control of silica exposure in construction: scabbling concrete.

PMID- 12495591
TI  - Using the internet to achieve your workplace training objectives.

PMID- 12495592
TI  - On-site measurement of blood-lead concentrations using field-portable
      electroanalysis.

PMID- 12495594
TI  - Biomarkers of toluene diisocyanate exposure.
AB  - Biomarkers are very useful tools when the metabolic fate of the compound or the
      etiology of a resultant disease is completely understood. They may contribute to
      confusion if it is not possible to distinguish between markers of exposure and
      markers of disease. Such is the case for biomarkers used in the assessment of
      diisocyanate exposure. Biomarkers for diisocyanate exposure result from both
      direct and indirect effects. Molecules such as hemoglobin, albumin, tubulin,
      glutathione, and laminin have been implicated as having been directly modified as
      a result of exposure to toluene diisocyanate (TDI). In addition, indirect
      biomarkers have included profiles of molecules such as antibodies, cytokines,
      cell accumulation or proliferation, and markers of oxidative stress. While a
      brief presentation of each of these markers is provided here, the focus is
      primarily on immunological markers as an example of the difficulties with using
      biomarkers in assessing diisocyanate exposure in general, and TDI specifically.
      Compiled data will be used to demonstrate where gaps exist in our understanding
      of how the results of measured biomarkers are used with regard to isocyanate
      exposure, and whether it may be possible to develop these tools to define
      thresholds between exposure and disease. Issues addressed include whether the
      marker represents a measure of exposure or disease, whether the methods are
      sufficiently uniform between labs to be able to compare between studies, and
      whether the ambiguities are the result of the complexity of the isocyanate
      reactivity in the biological system, or our inability to accurately measure the
      end point of the reactions.

PMID- 12495595
TI  - Toxicology of toluene diisocyanate.
AB  - In studies on animals, toluene diisocyanate (TDI) was a contact and respiratory
      sensitizer, was not toxic by the oral or dermal routes, but was irritating, and
      toxic by inhalation. The respiratory tract was the target in acute, subchronic,
      and chronic exposure studies. Typically, at concentrations of above 0.1 ppm
      (parts per million), clinical signs of nasal irritation were evident, and
      histopathological investigations revealed rhinitis and epithelial hyperplasia of
      nasal passages. With increasing concentration, effects were more severe; affected
      the larynx, trachea, and lung; and, eventually, affected body weight and
      survival. The carcinogenicity of TDI to rats and mice was investigated. By
      inhalation, there was no treatment-related increase in tumor incidence in either
      species at the highest concentration tested (0.15 ppm). Effects of TDI were seen
      as rhinitis in nasal turbinates of both species, and as reduced body weight gain
      in mice. Through oral administration of TDI dissolved in corn oil to rats and
      mice (up to 120 mg/kg/day), increased incidence of a number of tumor types was
      seen. This route is of questionable relevance to occupational exposure. The
      dosing solutions were known to have degraded, and TDI would hydrolyze to
      diaminotoluene in the acidic stomach environment. Several in vitro tests for
      genotoxicity gave positive results, which can be ascribed to degradation of TDI
      by solvents. In properly conducted assays, in vivo TDI was negative for
      genotoxicity. In a two-generation reproduction study in rats, there were no
      effects on reproductive indices at the highest exposure concentration of 0.3 ppm
      TDI, which elicited toxicity in both generations. In a developmental toxicity
      study in rats, there was evidence of minimal fetotoxicity in the presence of
      maternal toxicity at 0.5 ppm, with no effects at 0.1 ppm. No treatment-related
      embryotoxicity or teratogenicity was observed.

PMID- 12495596
TI  - Experience with early detection of toluene diisocyanate-associated occupational
      asthma.
AB  - There is good reason to expect that regular respiratory surveillance and early
      removal of workers who develop toluene diisocyanate (TDI)-associated occupational
      asthma can effectively protect these workers from accelerated pulmonary function
      decline. Application of this simple principle in operating industrial workplaces
      presents numerous challenges. The experience of one corporation is presented. One
      approach is to remove from future diisocyanate work, all workers who develop
      symptoms consistent with occupational asthma. However, the experience within this
      one corporation concurs with earlier, more carefully controlled investigations
      that such a strategy would be unduly restrictive of workers' occupational
      options. Fewer than half of the workers, who might have triggered such a
      practice, have required removal after more thorough occupational medical
      evaluation. Diisocyanates are such well known occupational asthmagens that other
      exposures tend to be ignored when considering respiratory health problems in a
      workplace. A small series of workers with work-related respiratory symptoms will
      be discussed. The usual industrial hygiene air monitoring demonstrated excellent
      control of the polyisocyanate hazard. Further investigation demonstrated poor
      control of a mold-release solution. Control of that exposure has allowed
      previously restricted workers to return to their former work making polyurethane
      parts. The number of cases available for analysis and discussion from this
      single, albeit large, corporation is small. Significant advances in understanding
      whether time-weighted average (TWA), task-specific, or dermal exposures to TDI
      and other polyisocyanates are most hazardous will require either many more years
      of experience within one corporation, or pooling of experience across the
      industry.

PMID- 12495597
TI  - Industrial hygiene sampling for airborne TDI in six flexible slabstock foam
      manufacturing facilities in the United States: a comparison of the short-term and
      long-term sampling data.
AB  - A majority of all the flexible polyurethane foams are produced by the continuous
      slabstock process using toluene diisocyanate (TDI) and polyether polyol. The
      commercially available TDI product is predominantly an 80:20 mixture of the 2,4
      TDI and 2,6-TDI isomers. TDI can be used in many applications, but the market is
      dominated by the flexible slabstock foam industry. Even though there has been a
      considerable amount of industrial hygiene sampling conducted for airborne TDI in
      this industry, the focus of the sampling has generally included long-term (time
      weighted average) monitoring with a limited amount of sampling for short-term
      (peak) episodes. By conducting only long-term sampling, which averages the
      exposure over some extended time period, these short-term episodes (i.e., tasks
      or activities) of peak exposure were often not characterized. To investigate
      whether long-term sampling was adequately predictive of short-term excursions,
      simultaneous (side-by-side) short-term and long-term breathing zone samples were
      collected on 31 flexible slabstock foam line employees at six manufacturing
      facilities throughout the United States. Four hundred three short-term samples
      averaging 15 minutes in length, and 78 long-term samples averaging 124 minutes in
      length were collected for four operator categories. From these 78 long-term
      samples, 31 eight-hour TWAs were projected (assuming no further exposure to
      airborne TDI for the remainder of the work shift) for comparison to the short
      term samples. Based on the data collected, compliance with the current ACGIH TLV
      TWA of 5 ppb would also ensure compliance with the OSHA PEL-C of 20 ppb in a
      majority of the cases associated with the flexible slabstock foam industry
      provided that (1) the TLV TWA accounted for the 2,6-TDI isomer in addition to the
      2,4-TDI isomer (at this time, exposure limits are published for only the 2,4-TDI
      isomer), and (2) the TLV TWA was compared to the partial shift TWA measured over
      the operational time of the workday rather than as an average over an eight-hour
      workday. Further, exceedences of the 20 ppb PEL-C did occur (e.g., when the foam
      line tunnel was entered, where there was an "upset" condition, or where there was
      close contact with hot [fresh cut] buns), but can be protected against with (1)
      improved work practices, (2) engineering controls, and (3) respiratory
      protection.

PMID- 12495598
TI  - Frequency and trends of occupational asthma due to toluene diisocyanate: a
      critical review.
AB  - In recent years, occupational asthma has become the most frequent occupational
      lung disease in many countries. Reports and statements on the frequency of
      occupational asthma due to isocyanates are quite contradictory. In order to
      clarify the issue, a critical review of the medical literature of the past half
      century worldwide has been performed, with special emphasis on toluene
      diisocyanate (TDI) as the main representative of the isocyanate family. Nine
      longitudinal workplace studies of 2,751 persons under risk allow calculation of
      incidences of occupational asthma due to toluene diisocyanate. Annual incidences
      had repeatedly been above five percent before 1980, and have decreased to zero to
      0.7 percent since 1980. There is a downward trend during the last half century
      that clearly parallels the downward trend of toluene diisocyanate exposure in
      some studies. Prevalences of occupational asthma due to toluene diisocyanate can
      be estimated from 10 cross-sectional studies, based on 788 persons. Prevalences
      had repeatedly been above 10 percent before 1985, and have been mostly between
      zero and 10 percent in recent years.

PMID- 12495599
TI  - Critical review of methods for sampling, analysis, and monitoring of vapor-phase
      toluene diisocyanate.
AB  - This article is a critical review of some of the methods that have been used for
      the sampling, analysis, and monitoring of vapor-phase toluene diisocyanate (TDI).
      Only some of the methods that have received relatively widespread application
      have been addressed in this article. This review includes a "tutorial style"
      discussion of basic definitions and basic principles and procedures of quality
      control and metrology for sampling, analysis, and monitoring. One critical issue
      that is addressed: Are there methods and monitoring instruments available that
      are capable of sampling and analyzing or monitoring TDI vapor with sufficient
      speed and sensitivity to satisfy the requirements of the current ACGIH threshold
      limit values (TLVs) for TDI vapor?

PMID- 12495600
TI  - Occupational asthma, lung function decrement, and toluene diisocyanate (TDI)
      exposure: a critical review of exposure-response relationships.
AB  - An extensive amount of clinical/epidemiological literature exists regarding the
      effects of toluene diisocyanate (TDI) exposure on respiratory health. This review
      presents an evaluation and synthesis of that literature with an emphasis on
      assessing exposure-response relationships in the workplace. The key respiratory
      disorders examined are bronchial asthma and an accelerated decline in lung
      function. In the early years of the industry, annual incidence rates of TDI
      induced occupational asthma (OA) were as high as 5-6 percent. In settings where
      mean TDI concentrations have been maintained below 5 ppb based on 8-hr personal
      samples, OA incidence rates have declined to < 1 percent annually. Recent data
      also suggest that overexposure incidents may play an important role in inducing
      OA, particularly in work environments engineered to minimize routine ambient air
      concentrations. Fourteen studies were reviewed that examined lung function
      decrement. Early studies from the 1960s and 1970s provided evidence of transient
      or fixed lung function loss (measured as a decline in forced expiratory volume in
      one second [FEV1]) during periods of ongoing exposure among employees
      experiencing high rates of work-related symptoms of OA. Such findings would not
      be unexpected in that modest FEV1 declines have been demonstrated in general
      population studies of persons with bronchial hyperresponsiveness or persistent
      non-occupational asthma. More recent workplace studies have provided no
      consistent evidence of accelerated FEV1 loss among employees exposed up to 5 ppb
      TDI (8-hr TWA) even with documented routine short-term TDI concentrations
      exceeding 20 ppb TDI.

PMID- 12495601
TI  - Diisocyanate-induced asthma: diagnosis, prognosis, and effects of medical
      surveillance measures.
AB  - Diisocyanates have been the most commonly identified cause for occupational
      asthma (OA) in industrialized areas. Asthma among diisocyanate workers may be
      true occupational asthma, caused by a high level of irritant exposure at work or
      by sensitization to diisocyanates. Alternatively, asthma may be coincidental to
      or may be aggravated by work exposures. A clear diagnosis usually requires a
      combination of investigations (serial peak expiratory flow recordings,
      methacholine challenges, and/or diisocyanate challenges), but it is important to
      provide the best management by identifying whether workplace changes are needed
      for the worker. Preventive measures to reduce the risk of occupational asthma
      from diisocyanates have not been prospectively evaluated. The introduction of a
      medical surveillance program (in Ontario, Canada) in 1983 was followed by
      retrospective assessments to determine benefits. Between 1980 and 1993, the
      proportion of all accepted compensation claims for OA that were attributed to
      diisocyanates, classified by year of symptom onset in the province with the
      program, rose to 64 percent by 1988, then fell significantly down to 29 percent
      in 1992 and 35 percent in 1993. Besides the medical surveillance program for
      diisocyanates, possible factors contributing to this reduction may include
      reduced diisocyanates exposures and better awareness of diisocyanate-induced
      asthma, both by workers and physicians. Compared with OA caused by other agents,
      those with OA due to diisocyanates had a significantly earlier onset of asthma
      after the start of the exposure (mean 5 yr vs. 7 yr), were younger and less
      likely to be atopic and to have smoked. The mean duration of asthma before the
      main medical assessment for compensation was significantly shorter among those
      with diisocyanate-induced asthma (mean 2 yr vs. 3 yr), and the severity was
      milder as assessed by medication use and pulmonary function. Those with
      diisocyanate-induced asthma were significantly less likely to be hospitalized for
      asthma. Among the subset whose outcome was determined at a mean of 2.1 years
      after the main medical assessment, the outcome severity was less for those with
      diisocyanate-induced OA. Among those with diisocyanate-induced OA, an earlier
      diagnosis and a trend to better outcome was found in workers from companies that
      were identified to be in compliance with surveillance measures.

PMID- 12495602
TI  - A multicenter comparative study of cefepime versus broad-spectrum antibacterial
      therapy in moderate and severe bacterial infections.
AB  - The safety and efficacy of cefepime empiric monotherapy compared with standard
      broad-spectrum combination therapy for hospitalized adult patients with moderate
      to severe community-acquired bacterial infections were evaluated. In an open
      label, multicenter study, 317 patients with an Acute Physiology and Chronic
      Health Evaluation (APACHE II) score ranging from >5 to =19 were enrolled with
      documented pneumonia (n=196), urinary tract infection (n=65), intra-abdominal
      infection (n=38), or sepsis (n=18). Patients were randomly assigned 1:1 to
      receive cefepime 1 to 2 g IV twice daily or three times a day or IV ampicillin,
      cephalothin, or ceftriaxone +/-aminoglycoside therapy for 3 to 21 days. For both
      treatment groups, metronidazole, vancomycin, or macrolide therapy was added as
      deemed necessary. The primary efficacy variable was clinical response at the end
      of therapy. Two hundred ninety-six (93%) patients met evaluation criteria and
      were included in the efficacy analysis. Diagnoses included the following: 180
      pneumonias (90 cefepime, 90 comparator), 62 urinary tract infections (29
      cefepime, 33 comparator), 37 intra-abdominal infections (19 cefepime, 18
      comparator), and 17 sepses (8 cefepime, 9 comparator). At the end of therapy,
      overall clinical success rates were 131/146 (90%) for patients treated with
      cefepime vs 125/150 (83%) for those treated with comparator (95% confidence
      interval [CI]: -2.6% to 16.3%). The clinical success rate for patients with
      community-acquired pneumonia, the most frequent infection, was 86% for both
      treatment groups. Among the patients clinically evaluated, 162 pathogens were
      isolated and identified before therapy. The most commonly isolated pathogens were
      Escherichia coli (n=49), Streptococcus pneumoniae (n=29), Haemophilus influenzae
      (n=14), and Staphylococcus aureus (n=11). Bacteriologic eradication/presumed
      eradication was 97% for cefepime vs 94% for comparator-treated patients. Drug
      related adverse events were reported in 16% of cefepime patients and 19% of
      comparator patients. In conclusion, cefepime had higher cure rates compared with
      broad-spectrum combination therapy as an initial empiric treatment for
      hospitalized patients with moderate to severe community-acquired infections,
      including urinary tract infections, intra-abdominal infections, and sepsis.

PMID- 12495603
TI  - Effect of host-related factors on the intensity of liver fibrosis in patients
      with chronic hepatitis C virus infection.
AB  - There is increasing interest in the identification of factors associated with
      liver disease progression in patients infected with hepatitis C virus (HCV). We
      assessed host-related factors associated with a histologically advanced stage of
      this disease and determined the rate of liver fibrosis progression in HCV
      infected patients. We included patients submitted to liver biopsy, who were anti
      HCV and HCV RNA positive, who showed a parenteral risk factor (blood transfusion
      or intravenous drug use), and who gave information about alcohol consumption.
      Patients were divided into two groups for analysis: group 1 - grades 0 to 2;
      group 2 - grades 3 to 4. The groups were compared in terms of sex, age at the
      time of infection, estimated duration of infection and alcoholism. The rate of
      fibrosis progression (index of fibrosis) was determined based on the relationship
      between disease stage and duration of infection (years). Logistic regression
      analysis revealed that age at the time of infection (P<0.01; 95% CI 1.06-1.22)
      and the duration of infection (P<0.01; 95% CI 1.06-1.32) were independently
      associated with a more advanced stage of hepatitis C. The median index of
      fibrosis was 0.14 for the group as a whole. A significant difference in the index
      of fibrosis was observed between patients aged < 40 years at infection (median =
      0.11) and patients aged > or = 40 years (median = 0.47). The main factors
      associated with a more rapid fibrosis progression were age at the time of
      infection and the estimated duration of infection. Patients who acquired HCV
      after 40 years of age showed a higher rate of fibrosis progression.

PMID- 12495604
TI  - Seroprevalence of hepatitis a antibodies in a group of normal and Down syndrome
      children in Porto Alegre, southern Brazil.
AB  - The high incidence of Hepatitis A and B in institutionalized patients with Down
      Syndrome (DS) is not fully understood. Under poor hygienic conditions,
      immunological alterations might predispose individuals to these infections. Sixty
      three DS children between 1 and 12 years old living at home with their families
      were examined for anti-HAV and compared to age-matched controls (64 healthy
      children). This cross-sectional study was carried out from May 1999 to April 2000
      at the Hospital de Clinicas of Porto Alegre, southern Brazil. Groups were
      compared in terms of age, sex, skin color, and family income (> R$ 500 and < R $
      500/month) by the chi-square test, with Yates' correction and for the prevalence
      of anti-HAV (Fisher's exact test). In the DS group (n=63), the mean age was 4.4
      +/- 3.3 years, 94% of the patients were white and 51% were female. Family income
      was < or = R$ 500/month in 40 cases (63%). In the control group (n=64), the mean
      age was 4.8 +/- 2.7 years, 81% of the patients were white and 56% were female.
      Family income was < or = R$ 500 in 20 patients (31%). DS children's families had
      a significantly lower income (P<0.0005). In the DS group there were 6 positive
      (9.5%) anti-HAV cases, and all came from low-income families (less than R$ 500/
      month). In the control group, 3 cases (4.7%) were positive for anti-HAV (two were
      from a low-income family and one was from a higher income family). These
      differences were not significant. Our data indicate that Hepatitis A is not a
      special risk for mentally retarded DS outpatients, even in a developing country
      like Brazil.

PMID- 12495605
TI  - Estimated prevalence of immunity to poliomyelitis in the city of Sao Paulo,
      Brazil: a population-based survey.
AB  - Objectives. Estimate the prevalence of immunity to poliomyelitis (anti-polio
      antibodies) in the city of Sao Paulo/Brazil through a population-based survey.
      Methods. A quantitative and inductive method was used to draw a representative
      sample of the population. Randomization and stratification (based on sex, age and
      residence region) was done, and 1,059 individuals were studied on a home-visit
      basis (structured questionnaires and blood samples). A microneutralization test
      was performed to detect anti-polio antibodies against serotypes 1, 2 and 3.
      Results. The estimated prevalence of immunity to poliomyelitis was high, with
      94.6% prevalence of anti-polio 1 antibodies, 98.8% anti-polio 2 and 91.9% anti
      polio 3. Despite this high prevalence, there were significantly lower prevalence
      levels in some groups, specially among age and residence region groups.
      Discussion. Routine child immunization and NIDs with OPV have provided excellent
      levels of serological immunity to poliomyelitis in the population of the city of
      Sao Paulo, Brazil. However, there may be specific groups with a lower prevalence
      of immunity. Estimations of the prevalence of immunity to poliomyelitis were made
      in a population-based survey, which could be used as an auxiliary tool for
      supporting the polio eradication program.

PMID- 12495606
TI  - Prevalence and antimicrobial susceptibility of Salmonella serotypes in patients
      from Ribeirao Preto, Sao Paulo, Brazil, between 1985 and 1999.
AB  - Salmonella strains isolated from 1,138 samples representing 28,199 biological
      materials (stool, urine, blood and other fluids), collected between January 1985
      and January 1999 at a reference University Hospital in Ribeirao Preto, Sao Paulo,
      Brazil, were studied. The most frequently detected serotypes were Salmonella
      enterica subspecies enterica serotype 4,5,12:i:- (S. I 4,5,12:i:) (21.2%), S.
      agona (15.8%) and S. enteritidis (11.3%). A changing pattern of Salmonella
      serotypes was observed between 1985-1999. S. agona, which represented 27% of
      Salmonella serotypes isolated from 1985-1989, declined to 4% during the period
      from 1995 to 1999. S. enteritidis isolation remained below 1% until 1989; rose to
      5.9% between 1990 and 1994, and increased to 32.3% between 1995-1999. S. I
      4,5,12:i:-; S. enteritidis; S. typhimurium; S. dublin and S. infantis, showed low
      to moderate resistance profiles to most antimicrobial drugs. Nalidixic acid and
      tetracycline were the most and the least effective drugs, respectively, in the
      disk diffusion tests. We encountered changes in salmonellosis epidemiology in
      this geographical region.

PMID- 12495607
TI  - Low incidence of colonization and no cases of disseminated Mycobacterium avium
      complex infection (DMAC) in Brazilian AIDS patients in the HAART era.
AB  - OBJECTIVE: Evaluate the incidence of mycobacterial disease and the colonization
      of the respiratory and gastrointestinal tracts by Mycobacterium avium complex
      (MAC) bacteria in AIDS patients. METHODS:  INCLUSION CRITERIA: HIV-positive
      individuals with at least one CD(4)(+) count < 100 cells/mm(3). EXCLUSION
      CRITERIA: Mycobacterial disease and MAC prophylaxis. Stool, sputum, and blood
      cultures were prospectively obtained every month from September, 1997, to
      December, 1999. The incidence was calculated using Poisson regression. Survival
      was estimated by the Kaplan Meier method and the Cox proportional hazard model.
      RESULTS: We followed-up 79 patients during a median period of 428 days. Blood
      cultures (n = 742) were negative for all mycobacteria. Positive cultures (25
      samples) were obtained from non-sterile sites: Stools (19/703 specimens = 2.7%)
      and sputum (14/742 specimens = 1.9%). MAC was isolated in 7/703 stool samples
      (1%) and 1/32 sputum specimens (0.1%). The incidence of patient colonization with
      MAC was 0.09 /year (CI=0.05-0.18). CD4 counts in patients colonized with MAC were
      below 100 cells/mm(3) in only 2 out of 8 cases. Restoration of CD(4)(+) counts
      >100 cells/mm(3) (HR = 0.18; CI = 0.05-0.70) predicted a lower risk of death
      (P<0.05) but was not protective for MAC colonization (HR=0.52;CI =0.62-4.35,
      P=0.55). CONCLUSION: The absence of DMAC infection in colonized individuals
      argues in favor of a HAART protective effect against; DMAC; however, restoration
      of CD(4) counts did not protect patients against MAC colonization.

PMID- 12495608
TI  - Expansion of gammadelta T Cells in patients infected with cutaneous leishmaniasis
      with and without glucantime therapy.
AB  - The expansion of gammadelta T cells in patients with active cutaneous
      leishmaniasis, with or without glucantime therapy, was investigated. Twenty
      patients with local cutaneous leishmaniasis including glucantime-treated (n=10)
      and untreated (n=10) patients were selected. The controls were healthy
      individuals (n=10) living in endemic areas. Whole blood was obtained and the T
      cell subpopulations were analyzed by flow cytometry. Significantly more
      gammadelta CD(3)(+) T cells were observed in untreated patients (15.9% +/-5.9),
      when compared with glucantime-treated patients (4.6% +/-1.4) and controls (5.3%
      +/-2.3). On the other hand, when the percentages of alphabeta CD(3)(+) T-cells
      were analyzed different results were obtained. A significant increase in
      alphabeta T cells was seen in glucantime-treated patients (62.4% +/-7.6), when
      compared to the untreated patients (55.7% +/-5.5) and controls (55.1% +/-9.6).
      The percentage of total CD(3)(+) T cells was statistically greater in both
      glucantime-treated (68.8% +/-7.4) and untreated patients (73.4% +/-5.9) when
      compared to the controls (61% +/-10.3). These results are consistent with
      previous results on the expansion of gammadelta T cells during the course of
      cutaneous leishmaniasis. They also indicate that glucantime therapy can reverse
      the expansion of gammadelta T cells and as a result increase the percentages of
      alphabeta ab CD(3)(+) T cells.

PMID- 12495609
TI  - Plasmodium vivax malaria presenting with severe thrombocytopenia.
AB  - Plasmodium falciparum and Plasmodium vivax malaria are endemic infections in
      India and are commonly associated with mild hematological abnormalities. Severe
      thrombocytopenia is common in isolated falciparum and mixed falciparum/vivax
      malaria, but is very rare in isolated P.vivax infection. We hereby report a case
      of severe thrombocytopenia (platelet count of 8x10(9)/L) in a case of vivax
      malaria. This is only the second case ever reported in the literature of such
      profound thrombocytopenia in a case of isolated P.vivax malaria.

PMID- 12495610
TI  - Current aspects of antibiotic prophylaxis for upper gastrointestinal bleeding in
      cirrhosis patients.
AB  - Bacterial infection is a common complication in cirrhotic patients. The portal
      hypertension as well as the immune depression observed in these patients can
      explain this high incidence of bacterial infection. Because of the high
      probability of cirrhotic patients to develop infections, antibiotic prophylaxis
      is warranted in some conditions, such as upper gastrointestinal bleeding or after
      spontaneous bacterial peritonitis. Nevertheless, antibiotic prophylaxis is not
      widely recommended for cirrhotic patients.

PMID- 12495611
TI  - Low prevalence of hepatitis B and C markers in non-amazonian indigenous
      population.

PMID- 12495612
TI  - Curb antimicrobial resistance: use the right antibiotic first!

PMID- 12495613
TI  - Developmental neurotransmitters?
AB  - Previous studies support an early role for neurotransmitter signaling before
      synaptogenesis, but puzzlingly, a neurological phenotype is absent in embryonic
      mice that lack vesicular release. Demarque et al. (in this issue of Neuron) now
      report that early release of transmitter is unconventional in not requiring
      action potentials, Ca(2+) entry, or vesicle fusion, thus potentially reconciling
      the discrepancy.

PMID- 12495614
TI  - PKG and the neural basis for behavioral phenotypes.
AB  - Cyclic GMP-dependent protein kinase (PKG) has been implicated in the regulation
      of diverse aspects of vertebrate and insect behavior, yet the mechanisms
      underlying these effects are poorly understood. In this issue of Neuron, Fujiwara
      et al. and L'Etoile et al. address the neural basis for PKG function in C.
      elegans and demonstrate the power of behavioral genetic analysis in simple
      systems in the elucidation of neuronal signaling mechanisms in vivo.

PMID- 12495615
TI  - The negative BOLD signal unmasked.
AB  - Many fMRI experiments show regions of cortex that seem to respond in antiphase
      with the primary stimulus. In this issue of Neuron, Shmuel et al. show that this
      "negative BOLD response" is spatially and temporally linked to reductions in
      blood flow. By combining BOLD and blood flow data to model the energy consumption
      in cortex, they conclude that the NBR is primarily due to active neuronal
      inhibition.

PMID- 12495616
TI  - Two B or not two B? Questioning the rotational symmetry of tetrameric ion
      channels.
AB  - Members of the voltage-gated family of ion channels generally demonstrate
      rotational symmetry about their pore regions. Recent evidence suggests that a
      subset of this family, the cyclic nucleotide-gated channels, may deviate from
      this pattern of rotational symmetry by having 3A:1B subunit stoichiometry. This
      finding raises many questions about the function, assembly, and trafficking of
      these and related ion channels and about the functional nonequivalence of
      subunits with identical amino acid sequences.

PMID- 12495617
TI  - Big ben rings in a lesson on biological clocks.

PMID- 12495619
TI  - EGF converts transit-amplifying neurogenic precursors in the adult brain into
      multipotent stem cells.
AB  - Neural stem cells in the subventricular zone (SVZ) continue to generate new
      neurons in the adult brain. SVZ cells exposed to EGF in culture grow to form
      neurospheres that are multipotent and self-renewing. We show here that the
      majority of these EGF-responsive cells are not derived from relatively quiescent
      stem cells in vivo, but from the highly mitotic, Dlx2(+), transit-amplifying C
      cells. When exposed to EGF, C cells downregulate Dlx2, arrest neuronal
      production, and become highly proliferative and invasive. Killing Dlx2(+) cells
      dramatically reduces the in vivo response to EGF and neurosphere formation in
      vitro. Furthermore, purified C cells are 53-fold enriched for neurosphere
      generation. We conclude that transit-amplifying cells retain stem cell competence
      under the influence of growth factors.

PMID- 12495618
TI  - Parkin protects against the toxicity associated with mutant alpha-synuclein:
      proteasome dysfunction selectively affects catecholaminergic neurons.
AB  - One hypothesis for the etiology of Parkinson's disease (PD) is that subsets of
      neurons are vulnerable to a failure in proteasome-mediated protein turnover. Here
      we show that overexpression of mutant alpha-synuclein increases sensitivity to
      proteasome inhibitors by decreasing proteasome function. Overexpression of parkin
      decreases sensitivity to proteasome inhibitors in a manner dependent on parkin's
      ubiquitin-protein E3 ligase activity, and antisense knockdown of parkin increases
      sensitivity to proteasome inhibitors. Mutant alpha-synuclein also causes
      selective toxicity to catecholaminergic neurons in primary midbrain cultures, an
      effect that can be mimicked by the application of proteasome inhibitors. Parkin
      is capable of rescuing the toxic effects of mutant alpha-synuclein or proteasome
      inhibition in these cells. Therefore, parkin and alpha-synuclein are linked by
      common effects on a pathway associated with selective cell death in
      catecholaminergic neurons.

PMID- 12495620
TI  - A role for neuregulin1 signaling in muscle spindle differentiation.
AB  - The maturation of synaptic structures depends on inductive interactions between
      axons and their prospective targets. One example of such an interaction is the
      influence of proprioceptive sensory axons on the differentiation of muscle
      spindles. We have monitored the expression of three transcription factors, Egr3,
      Pea3, and Erm, that delineate early muscle spindle development in an assay of
      muscle spindle-inducing signals. We provide genetic evidence that Neuregulin1
      (Nrg1) is required for proprioceptive afferent-evoked induction of muscle spindle
      differentiation in the mouse. Ig-Nrg1 isoforms are preferentially expressed by
      proprioceptive sensory neurons and are sufficient to induce muscle spindle
      differentiation in vivo, whereas CRD-Nrg1 isoforms are broadly expressed in
      sensory and motor neurons but are not required for muscle spindle induction.

PMID- 12495621
TI  - Paracrine intercellular communication by a Ca2+- and SNARE-independent release of
      GABA and glutamate prior to synapse formation.
AB  - GABA and glutamate receptors are expressed in immature "silent" CA1 pyramidal
      neurons prior to synapse formation, but their function is unknown. We now report
      the presence of tonic, spontaneous, and evoked currents in embryonic and neonatal
      CA1 neurons mediated primarily by the activation of GABA(A) receptors. These
      currents are mediated by a nonconventional release of transmitters, as they
      persist in the presence of calcium channel blockers or botulinium toxin and are
      observed in Munc18-1-deficient mice in which vesicular release is abolished. This
      paracrine communication is modulated by glutamate but not GABA transporters,
      which do not operate during this period of life. Thus, a Ca(2+)- and SNARE
      independent release of transmitters underlies a paracrine mode of communication
      before synapse formation.

PMID- 12495622
TI  - Axonal transport of mitochondria to synapses depends on milton, a novel
      Drosophila protein.
AB  - A protein required to localize mitochondria to Drosophila nerve terminals has
      been identified genetically. Photoreceptors mutant for milton show aberrant
      synaptic transmission despite normal phototransduction. Without Milton, synaptic
      terminals and axons lack mitochondria, although mitochondria are numerous in
      neuronal cell bodies. In contrast, synaptic vesicles continue to be transported
      to and concentrated at synapses. Milton protein is associated with mitochondria
      and is present primarily in axons and synapses. A likely explanation of the
      apparent trafficking defect is offered by the coimmunoprecipitation of Milton and
      kinesin heavy chain. Transfected into HEK293T cells, Milton induces a
      redistribution of mitochondria within the cell. We propose that Milton is a
      mitochondria-associated protein required for kinesin-mediated transport of
      mitochondria to nerve terminals.

PMID- 12495623
TI  - The cyclic GMP-dependent protein kinase EGL-4 regulates olfactory adaptation in
      C. elegans.
AB  - Prolonged odor exposure causes a specific, reversible adaptation of olfactory
      responses. A genetic screen for negative regulators of olfaction uncovered
      mutations in the cGMP-dependent protein kinase EGL-4 that disrupt olfactory
      adaptation in C. elegans. G protein-coupled olfactory receptors within the AWC
      olfactory neuron signal through cGMP and a cGMP-gated channel. The cGMP-dependent
      kinase functions in AWC neurons during odor exposure to direct adaptation to AWC
      sensed odors, suggesting that adaptation is a cell intrinsic process initiated by
      cGMP. A predicted phosphorylation site on the beta subunit of the cGMP-gated
      channel is required for adaptation after short odor exposure, suggesting that
      phosphorylation of signaling molecules generates adaptation at early time points.
      A predicted nuclear localization signal within EGL-4 is required for adaptation
      after longer odor exposure, suggesting that nuclear translocation of EGL-4
      triggers late forms of adaptation.

PMID- 12495624
TI  - Regulation of body size and behavioral state of C. elegans by sensory perception
      and the EGL-4 cGMP-dependent protein kinase.
AB  - The growth and behavior of higher organisms depend on the accurate perception and
      integration of sensory stimuli by the nervous system. We show that defects in
      sensory perception in C. elegans result in abnormalities in the growth of the
      animal and in the expression of alternative behavioral states. Our analysis
      suggests that sensory neurons modulate neural or neuroendocrine functions,
      regulating both bodily growth and behavioral state. We identify genes likely to
      be required for these functions downstream of sensory inputs. Here, we
      characterize one of these genes as egl-4, which we show encodes a cGMP-dependent
      protein kinase. We demonstrate that this cGMP-dependent kinase functions in
      neurons of C. elegans to regulate multiple developmental and behavioral processes
      including the orchestrated growth of the animal and the expression of particular
      behavioral states.

PMID- 12495625
TI  - alpha- and betaCaMKII. Inverse regulation by neuronal activity and opposing
      effects on synaptic strength.
AB  - We show that alpha and betaCaMKII are inversely regulated by activity in
      hippocampal neurons in culture: the alpha/beta ratio shifts toward alpha during
      increased activity and beta during decreased activity. The swing in ratio is
      approximately 5-fold and may help tune the CaMKII holoenzyme to changing
      intensities of Ca(2+) signaling. The regulation of CaMKII levels uses
      distinguishable pathways, one responsive to NMDA receptor blockade that controls
      alphaCaMKII alone, the other responsive to AMPA receptor blockade and involving
      betaCaMKII and possibly further downstream effects of betaCaMKII on alphaCaMKII.
      Overexpression of alphaCaMKII or betaCaMKII resulted in opposing effects on
      unitary synaptic strength as well as mEPSC frequency that could account in part
      for activity-dependent effects observed with chronic blockade of AMPA receptors.
      Regulation of CaMKII subunit composition may be important for both activity
      dependent synaptic homeostasis and plasticity.

PMID- 12495626
TI  - Interaction of postsynaptic receptor saturation with presynaptic mechanisms
      produces a reliable synapse.
AB  - Synapses that reliably activate their postsynaptic targets typically release
      neurotransmitter with high probability, are not very sensitive to changes in
      calcium entry, and depress. We have determined the mechanisms that give rise to
      these characteristic features at the climbing fiber to Purkinje cell synapse. We
      find that saturation of presynaptic calcium entry, of presynaptic release, and of
      postsynaptic receptors combine to produce a postsynaptic response that is near
      maximal. Postsynaptic receptor saturation also accelerates recovery from
      depression, in part by accentuating a rapid calcium-dependent recovery phase.
      Thus, postsynaptic receptor saturation interacts with presynaptic mechanisms to
      produce highly reliable synapses that can effectively drive their targets even
      during sustained activation.

PMID- 12495627
TI  - Optimizing synaptic architecture and efficiency for high-frequency transmission.
AB  - Bursts of neuronal activity are transmitted more effectively as synapses mature.
      However, the mechanisms that control synaptic efficiency during development are
      poorly understood. Here, we study postnatal changes in synaptic ultrastructure
      and exocytosis in a calyx-type nerve terminal. Vesicle pool size, exocytotic
      efficiency (amount of exocytosis per Ca influx), Ca current facilitation, and the
      number of active zones (AZs) increased with age, whereas AZ area, number of
      docked vesicles per AZ, and release probability decreased with age. These changes
      led to AZs that are less prone to multivesicular release, resulting in reduced
      AMPA receptor saturation and desensitization. A greater multiplicity of small AZs
      with few docked vesicles, a larger pool of releasable vesicles, and a higher
      efficiency of release thus promote prolonged high-frequency firing in mature
      synapses.

PMID- 12495628
TI  - Cerebellar long-term synaptic depression requires PKC-mediated activation of CPI
      17, a myosin/moesin phosphatase inhibitor.
AB  - Cerebellar LTD requires brief activation of PKC and is expressed as a functional
      downregulation of AMPA receptors. Modulation of vascular smooth-muscle
      contraction by G protein-coupled receptors (called Ca(2+) sensitization) also
      involves PKC phosphorylation and activation of a specific inhibitor of
      myosin/moesin phosphatase (MMP). This inhibitor, called CPI-17, is also expressed
      in brain. Here, we tested the hypothesis that LTD, like Ca(2+) sensitization,
      employs a PKC/CPI-17 cascade. Introduction of activated recombinant CPI-17 into
      cells produced a use-dependent attenuation of glutamate-evoked responses and
      occluded subsequent LTD. Moreover, the requirement for endogenous CPI-17 in LTD
      was demonstrated with neutralizing antibodies plus gene silencing by siRNA. These
      interventions had no effect on basal synaptic strength but blocked LTD induction.
      Thus, a biochemical circuit that involves PKC-mediated activation of CPI-17
      modulates the distinct physiological processes of vascular contractility and
      cerebellar LTD.

PMID- 12495629
TI  - Climbing fiber activation of metabotropic glutamate receptors on cerebellar
      purkinje neurons.
AB  - In the cerebellum, metabotropic glutamate receptors (mGluRs) are required for
      distinct forms of synaptic plasticity expressed at parallel fiber (PF) and
      climbing fiber (CF) synapses. At PF synapses, mGluR activation generates a slow
      synaptic current and triggers intracellular calcium release; at CF synapses,
      mGluR activation has not been observed. This has led some investigators to
      propose that mGluR-dependent changes in CF synaptic strength are induced
      heterosynaptically. Here we describe an mGluR-mediated response to CF stimulation
      consisting of two parallel signaling pathways: one leading to a slow synaptic
      conductance and the other leading to internal calcium release. This additional
      target for glutamate broadens the signaling capabilities of CF synapses and
      raises the possibility that changes in CF strength are homosynaptically
      triggered.

PMID- 12495630
TI  - Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron-A
      potential mechanism for orchestrating the hypothalamic arousal system.
AB  - Neurons that release hypocretin/orexin modulate sleep, arousal, and energy
      homeostasis; the absence of hypocretin results in narcolepsy. Here we present
      data on the physiological characteristics of these cells, identified with GFP in
      transgenic mouse brain slices. Hypocretin-1 and -2 depolarized hypocretin neurons
      by 15mV and evoked an increase in spike frequency (+366% from a 1-3 Hz baseline).
      The mechanism for this appears to be hypocretin-mediated excitation of local
      glutamatergic neurons that regulate hypocretin neuron activity, in part by
      presynaptic facilitation of glutamate release. This represents a possible
      mechanism for orchestrating the output of the diffuse hypothalamic arousal
      system. No direct effect of hypocretin on membrane properties of hypocretin cells
      was detected. Norepinephrine and serotonin, transmitters of other arousal
      systems, decreased spike frequency and evoked outward currents, whereas
      acetylcholine and histamine had little effect.

PMID- 12495631
TI  - Memory of sequential experience in the hippocampus during slow wave sleep.
AB  - Rats repeatedly ran through a sequence of spatial receptive fields of hippocampal
      CA1 place cells in a fixed temporal order. A novel combinatorial decoding method
      reveals that these neurons repeatedly fired in precisely this order in long
      sequences involving four or more cells during slow wave sleep (SWS) immediately
      following, but not preceding, the experience. The SWS sequences occurred
      intermittently in brief ( approximately 100 ms) bursts, each compressing the
      behavioral sequence in time by approximately 20-fold. This rapid encoding of
      sequential experience is consistent with evidence that the hippocampus is crucial
      for spatial learning in rodents and the formation of long-term memories of events
      in time in humans.

PMID- 12495633
TI  - Viewing lip forms: cortical dynamics.
AB  - Viewing other persons' actions automatically activates brain areas belonging to
      the mirror-neuron system (MNS) assumed to link action execution and observation.
      We followed, by magnetoencephalographic cortical dynamics, subjects who observed
      still pictures of lip forms, on-line imitated them, or made similar forms in a
      self-paced manner. In all conditions and in both hemispheres, cortical activation
      progressed in 20-70 ms steps from the occipital cortex to the superior temporal
      region (where the strongest activation took place), the inferior parietal lobule,
      and the inferior frontal lobe (Broca's area), and finally, 50-140 ms later, to
      the primary motor cortex. The signals of Broca's area and motor cortex were
      significantly stronger during imitation than other conditions. These results
      demonstrate that still pictures, only implying motion, activate the human MNS in
      a well-defined temporal order.

PMID- 12495632
TI  - Sustained negative BOLD, blood flow and oxygen consumption response and its
      coupling to the positive response in the human brain.
AB  - Most fMRI studies are based on the detection of a positive BOLD response (PBR).
      Here, we demonstrate and characterize a robust sustained negative BOLD response
      (NBR) in the human occipital cortex, triggered by stimulating part of the visual
      field. The NBR was spatially adjacent to but segregated from the PBR. It depended
      on the stimulus and thus on the pattern of neuronal activity. The time courses of
      the NBR and PBR were similar, and their amplitudes covaried both with increasing
      stimulus duration and increasing stimulus contrast. The NBR was associated with
      reductions in blood flow and with decreases in oxygen consumption. Our findings
      support the contribution to the NBR of (1) a significant component of reduction
      in neuronal activity and (2) possibly a component of hemodynamic changes
      independent of the local changes in neuronal activity.

PMID- 12495634
TI  - The role of medial temporal lobe structures in implicit learning: an event
      related FMRI study.
AB  - The medial temporal lobe (MTL) has been associated with declarative learning of
      flexible relational rules and the basal ganglia with implicit learning of
      stimulus-response mappings. It remains an open question of whether MTL or basal
      ganglia are involved when learning flexible relational contingencies without
      awareness. We studied learning of an explicit stimulus-response association with
      fMRI. Embedded in this explicit task was a hidden structure that was learnt
      implicitly. Implicit learning of the sequential regularities of the "hidden rule"
      activated the ventral perirhinal cortex, within the MTL, whereas learning the
      fixed stimulus-response associations activated the basal ganglia, indicating that
      the function of the MTL and the basal ganglia depends on the learned material and
      not necessarily on the participants' awareness.

PMID- 12495636
TI  - Chemokines: attractive mediators of the immune response.
AB  - An effective inflammatory immune response first requires the recruitment of cells
      to the site of inflammation and then their appropriate activation and regulation.
      Chemokines are critical in this response since they are both chemotactic and
      immunoregulatory molecules. In this regard, the interaction between CCL5 and CCR5
      may be critical in regulating T cell functions, by mediating their recruitment
      and polarization, activation, and differentiation. Various tyrosine
      phosphorylation signaling cascades can be engaged following chemokine receptor
      aggregation on T cells, including the Jak-Stat pathway, FAK activation, the MAP
      kinase pathway, PI3-kinase activation, and transactivation of the T cell
      receptor. This review will address specific aspects related to chemokine-T cell
      interactions and the molecular signaling mechanisms that influence T cell
      function in an inflammatory immune response.

PMID- 12495637
TI  - Chemokines and chemokine receptors in rheumatoid arthritis.
AB  - Chemokines are chemotactic cytokines involved in a number of pathological
      processes, including inflammatory conditions. Chemokines play a role in the
      pathogenesis of various inflammatory diseases. Based on a burgeoning body of
      literature, RA was chosen as a prototype to discuss this issue. In this review,
      the authors give a detailed introduction to the classification and function of
      chemokines and their receptors. This is followed by a discussion of the role of
      chemokines and chemokine receptors in RA. Chemokines interact with other
      inflammatory mediators, such as cytokines. Thus, the regulation of chemokine
      production and the place of chemokines in the network of inflammatory mediators
      present in the rheumatoid synovium are also reviewed. Finally, potential
      strategies using anti-chemokine or anti-chemokine receptor biologicals in anti
      rheumatic therapy are discussed.

PMID- 12495638
TI  - The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental
      autoimmune encephalomyelitis (EAE).
AB  - Multiple sclerosis (MS) is the commonest inflammatory demyelinating disease of
      the human central nervous system (CNS). In MS, CNS inflammation is associated
      with demyelination and axonal degeneration, which leads to clinical presentation.
      Expression and cellular localization of CCL2/MCP-1 and CCR2 in MS have been
      described in the three compartments: brain, cerebrospinal fluid (CSF) and blood.
      Evidence from descriptive, transgenic, knockout and neutralizing studies of
      experimental autoimmune encephalomyelitis (EAE) points towards a nonredundant
      role of CCL2 and CCR2 in the recruitment of inflammatory infiltrate into the CNS.
      Hence, CCL2 and CCR2 may be targets for specific and effective treatment in MS.

PMID- 12495639
TI  - The role of chemokines and chemokine receptors in alloantigen-independent and
      alloantigen-dependent transplantation injury.
AB  - Transplantation injury and rejection involves the interplay of innate and
      acquired immune responses. Immune-related injury manifests itself in three
      temporal phases: early innate immune driven alloantigen-independent injury,
      acquired immune driven alloantigen-dependent injury, and chronic injury.
      Sequential waves of chemokine expression play a central role in regulating graft
      injury through the recruitment of phagocytes shortly after transplantation and
      activated lymphocytes and phagocytes in the weeks and years following
      transplantation. This review focuses on recent studies demonstrating the role of
      chemokines in transplantation.

PMID- 12495640
TI  - Chemokine biology in cancer.
AB  - Many human cancers possess a complex chemokine network that may influence the
      extent and phenotype of the leukocyte infiltrate, angiogenesis, tumor cell
      growth, survival and migration. Restricted expression of chemokine receptors on
      leukocytes may allow concise control of cell movement and retention at the tumor
      site. Restricted and specific expression of chemokine receptors on tumor cells
      may be involved in the characteristic patterns of metastasis, and may promote
      tumor cell growth and survival. Detailed study of chemokine and chemokine
      receptor antagonists in experimental cancer models is warranted. Manipulation of
      the tumor chemokine network could have therapeutic potential in malignant
      disease.

PMID- 12495642
TI  - Parents' caregiving approaches: facing a new treatment alternative in severe
      intractable childhood epilepsy.
AB  - Parents of children with severe and intractable epilepsy face profound caregiving
      challenges, dealing with their child's frequent and intense seizures,
      accompanying physical, social and psychological problems, and ongoing quest for
      seizure control through a variety of medications, diet and surgery. With the
      advent of a new, surgical treatment for epilepsy, vagus nerve stimulation (VNS),
      these parents have been presented with a renewed possibility of seizure control
      for their children. While many studies have investigated the effects of VNS on
      seizure frequency and intensity, none have looked at parents' experiences in
      facing this potentially life changing treatment for their child. This multiple
      case study addresses this gap by exploring the experiences of nine parents of
      children receiving VNS. Collected over a 6-month period following parents in the
      hospital, clinic and in their homes, data from 22 in-depth interviews revealed
      that parents facing a new treatment alternative for their child experienced
      uncertainty around treatment efficacy and had a need to exert control over their
      expectations. Ongoing caregiving approaches adopted by these parents were
      consistent with existing literature on families living with childhood chronic
      illness, however, new insights were gained from parents' sharing of positive life
      perspectives gained through their experiences. These findings provide guidance
      for health care professionals working with the parents of children with severe,
      intractable epilepsy.

PMID- 12495641
TI  - Strategies for chemokine antagonists as therapeutics.
AB  - Chemokines are responsible for specific recruitment of leukocytes that are
      involved both in homing as well as in inflammation. Dysregulation of the system
      results in excessive recruitment to inflammatory sites and thus prevention of
      this recruitment is an effective anti-inflammatory strategy. Chemokine receptors
      are not limited only to cellular recruitment but are also the essential co-factor
      along with CD4 that enable HIV-1 viruses to infect cells. In this review we
      discuss the various points of intervention that can be addressed to provide anti
      inflammatory and anti-HIV infectivity therapeutics. These include prevention of
      the receptor-ligand interaction, prevention of the chemokine-glycosaminoglycan
      interaction, interfering with the signaling pathways that are induced upon
      receptor activation, and modification of receptor trafficking pathways. We
      summarize the status of the approaches that have been undertaken to produce
      therapeutics that block chemokine action.

PMID- 12495643
TI  - Patient's perspective on epilepsy: self-knowledge among Omanis.
AB  - Improving patients' knowledge has been suggested to improve their symptoms and
      prognosis. Very little is known about epileptic patient's knowledge of their
      illness in cross-cultural settings. This pilot study investigated what Omani
      patients know about their disorder. Patients attending a tertiary hospital
      completed a structured knowledge questionnaire to elicit information pertaining
      to aetiology, safety, compliance with medication regimes, legal and employment
      issues concerning epilepsy.Although correctly endorsing issues related to their
      medication, this cross-cultural sample was found to have limited knowledge about
      their condition. In particular, most patients were unable to give accurate
      indications of epilepsy, neither were they able to give correct responses to
      questions pertaining to safety and compliance. There is a need for improving
      patient's knowledge. As with other chronic disorders, people with epilepsy in
      Oman should receive systematic health education about how to manage the condition
      most effectively.

PMID- 12495644
TI  - Magnetoencephalographic localization of peritumoral temporal epileptic focus
      previous surgical resection.
AB  - Magnetoencephalography (MEG) is suggested as a localizing technique of
      epileptogenic areas in drug-resistant seizure patients due to intracraneal
      lesions. A male 42-year-old patient who begins at 26 with partial complex drug
      resistant seizures is put forward. MRI shows a 9 mm diameter lesion located in
      left superior temporal gyrus which seems compatible with cavernoma. Both
      conventional and sleep deprivation EEGs have proved normal. Sleep EEG shows sharp
      waves in left temporal region. MEG helps to localize interictal spike and spike
      wave activity, as well as wide slow wave (2-7 Hz) activity areas. Craniotomy
      under analgesia and aware sedation conditions is carried out. Intrasurgery
      cortical electric stimulation assisted by neuronavigator causes a limited partial
      complex seizure which the patient recognizes to be exactly like his. Thus, MEG
      localization of the epileptogenic area is confirmed. Surgical resection of both
      the lesion and the epileptogenic area is carried out. The patient remains free
      from seizures 9 months after surgery. A control MEG study reveals no
      epileptogenic nor slow wave activity. CONCLUSION: in this particular case, MEG
      has proven to be a useful presurgical evaluation technique to localize
      epileptogenic activity, validated by intrasurgical cortical stimulation.

PMID- 12495645
TI  - Stroke and status epilepticus: stroke type, type of status epilepticus, and
      prognosis.
AB  - Even though stroke is known to be a common cause of status epilepticus (SE), the
      types of stroke or SE that may be associated are not yet clearly defined. The
      aims of this study were to assess the timing and type of SE in stroke patients
      and to observe the effects of stroke and the type of SE on the response to
      treatment and mortality. From May 1998 to May 2001 a total of 121 patients were
      admitted with SE. Among these, 30 cases (24.8%) of poststroke SE were identified
      and evaluated. There were 20 early-onset, and 10 late-onset SE. All stroke types
      were evenly distributed within the early-onset group, whereas only ischaemic
      stroke was found in the late-onset group. Posterior cerebral artery (PCA)
      infarcts were significantly more common within the latter (P: 0.0017).
      Nonconvulsive SE (NCS) was more frequent than convulsive SE (CS) in the early
      onset group (P: 0.0352). There was a delay in the time-to-treatment for NCS
      compared to CS (P: 0.0007). Without, however any effect on the rate of response
      to first step treatment (intravenous diazepam and phenytoin; P: 0.6334). Thirteen
      patients died (43.3%) during hospitalisation. Disability was significantly
      associated with higher mortality in the early-onset group (P: 0.0201). As a
      conclusion, NCS seems to be an important issue in stroke, thus requiring a high
      degree of suspicion in an acute stroke setting to avoid further neuronal injury
      and morbidity.

PMID- 12495646
TI  - The absorption of gabapentin following high dose escalation.
AB  - Gabapentins (GBP) is structurally similar to GABA yet its mode of action remains
      uncertain. It is water-soluble and GI tract absorption occurs via the L-amino
      acid transport system in the proximal small bowel. It has been suggested that
      this transportation is capacity limited, thus decreasing GBP bioavailability at
      higher doses. GBP is not protein bound, therefore, salivary levels might be
      expected to be similar to those in serum; also the drug does not induce hepatic
      enzymes and is excreted unmetabolised by the kidney. Within the dose-range
      normally prescribed, it is devoid of pharmacokinetic (PK) drug interactions with
      all other anti-epileptic drugs. This study assesses two things in patients with
      epilepsy: (a) bioavailability of higher doses of GBP (1200-4800 mg per day), and
      (b) the influence of high dose GBP on between-dose serum concentrations of co
      prescribed anti-epileptic drugs. After stabilising at each dosage, a sequence of
      serum and saliva samples were collected within the dosage interval; GBP and co
      medication concentrations were determined and the results subjected to PK
      modelling. Meaned results from 10 patients indicate that GBP continues to be
      absorbed in a reasonably linear manner relative to dose up to 4800 mg per day.
      The study also shows that GBP is transported into saliva, however, salivary
      concentrations are only 5-10% of those in plasma. Furthermore, the results
      indicate that GBP, in higher than recommended doses, did not change plasma
      concentrations of lamotrigine, carbamazepine, carbamazepine-epoxide, vigabatrin,
      primidone, phenobarbitone or phenytoin when added to treatment. It is concluded
      that larger than recommended doses of GBP can be efficiently absorbed by some
      patients and also that GBP plasma levels do not fluctuate greatly between dosage
      intervals, therefore, twice daily dosage is a possibility.

PMID- 12495647
TI  - Vagal nerve stimulation--the Norwegian experience.
AB  - The purpose of this open retrospective study was to analyze the efficacy and
      tolerability of vagal nerve stimulation (VNS) in a Norwegian cohort of referral
      patients with refractory epileptic seizures. A total of 47 patients have been
      assessed after a mean follow-up time of 2.7 years. Mean age was 34.4 years, mean
      duration of epilepsy was 25.3 years. Forty-two patients (89%) had localization
      related epilepsy, 36 patients (77%) had daily seizures. The patients had tried on
      average 9.5 antiepileptic drugs, and 12 patients (26%) had undergone epilepsy
      surgery. Sixteen patients (34%) had >50% reduction of seizure frequency with VNS,
      of which one patient became seizure free. The stimulation was generally well
      tolerated, but three patients requested the device removed because of troublesome
      side effects. We conclude that VNS is an efficacious and safe mode of treatment
      that should be offered to patients with medically and surgically refractory
      seizures.

PMID- 12495648
TI  - A paradoxical effect of levetiracetam may be seen in both children and adults
      with refractory epilepsy.
AB  - The aim of this prospective, uncontrolled clinical study was to evaluate the
      tolerability and the efficacy of levetiracetam as add-on treatment in 78 adults
      and 44 children with intractable epilepsy. The patients' seizure frequency in the
      8 weeks baseline period was compared to their seizure frequency after a mean
      follow-up of 8 months of treatment.A greater than 50% reduction in seizure
      frequency was achieved in 31 adults (40%) and 9 children (20%), of whom 7 adults
      (9%) and 3 children (7%) became seizure free. Most often levetiracetam was well
      tolerated, somnolence being the most frequently reported side effect (18% in
      adults and 7% in children). However, in 14 adults (18%) and 19 children (43%)
      levetiracetam was associated with an increase (>25%) in seizure frequency. Such a
      paradoxical effect, including the development of status epilepticus in three
      adults and four children, appeared most often in mentally retarded patients
      during the first 2 months of treatment, and on relatively high doses. Two
      children developed status epilepticus after 5 and 7 months, respectively. In
      conclusion, levetiracetam is usually well tolerated as add-on treatment in
      patients with difficult-to-treat partial onset seizures. By using a lower initial
      dose and a slower dose escalation than recommended by the manufacturer, a
      paradoxical effect may perhaps be avoided. In children, doses >20 mgkg(-1) per
      day should be introduced with caution.

PMID- 12495649
TI  - Epilepsy in mainstream and special educational primary school settings.
AB  - This population based study compared the prevalence, nature and management of
      epilepsy between primary school children in mainstream education and those
      attending a special educational placement (children with special needs). The
      overall prevalence of epilepsy was 4.3/1000, but was 30 times higher in children
      with special needs, many of whom also had severe physical disabilities. Seizure
      types and the proportion of subjects with multiple seizures were similar in
      mainstream children and those with special needs. Epilepsy syndromes were
      identified in 74% of children. Although seizures were better controlled in
      children at mainstream school, 44% of these children did not have well controlled
      seizures. Children with epilepsy are an educationally vulnerable group and both
      education and health staff need to be aware of the additional support that many
      of these children require in all types of primary educational settings.

PMID- 12495650
TI  - Treatment of out-of-hospital status epilepticus with diazepam rectal gel.
AB  - Intravenous access cannot always be promptly obtained when treating status
      epilepticus outside the hospital. We compared the efficacy and safety of diazepam
      rectal gel to IV lorazepam in our long-term care facility for adults with
      developmental disabilities. Diazepam rectal gel was given more quickly and
      reliably, reducing total seizure time, potential neuronal injury and other
      complications. A treatment protocol for treating status epilepticus with diazepam
      rectal gel is given.

PMID- 12495651
TI  - Graphogenic epilepsy: a variant of language-induced epilepsy distinguished from
      reading- and praxis-induced epilepsy.
AB  - We report a case of graphogenic epilepsy as a variant of language-induced
      epilepsy. A 25-year-old, right-handed woman had noticed for the previous 10 years
      that writing almost always provoked jerks or a jerking sensation in her right
      hand. No other triggers, including facets of language function such as reading
      and speaking, elicited any epileptic seizures. Ictal EEG demonstrated an initial
      left central abnormality. In our report, we stress that graphogenic seizures as
      an expression of language-induced epilepsy should not be confused with those that
      are manifestations of juvenile myoclonic epilepsy, and that writing and reading
      trigger different facets of motor manifestations.

PMID- 12495652
TI  - Emotional facial paresis in temporal lobe epilepsy: its prevalence and
      lateralizing value.
AB  - The selection of patients with medically refractory temporal lobe epilepsy (TLE)
      for surgery depends on the concordance of data from clinical, imaging and
      electroencephalographic evaluation. Though clinical examination is often normal,
      emotional facial paresis has been described in patients with TLE. Utilizing a
      well-characterized group of mesial TLE (MTLE) patients, who have achieved
      excellent seizure outcome following anterior temporal lobectomy with
      amygdalohippocampectomy (ATL), we investigated the prevalence, predictive value
      and associations of emotional facial paresis. When compared to 8 out of 50
      control subjects (16%), 36 out of 50 MTLE patients (72%) exhibited unilateral
      emotional facial paresis; the difference was highly significant (P<0.0001). The
      presence of contralateral emotional facial paresis correctly predicted the side
      of ATL in 86.1% patients. The occurrence of emotional facial paresis was
      significantly associated with longer duration of epilepsy prior to ATL and left
      ATL. Our observations confirm that emotional facial parersis contralateral to the
      side of mesial temporal sclerosis (MTS) is a valuable localizing sign in
      correctly predicting the epileptogenic temporal lobe. We hypothesize that the
      presence of an intact right hemisphere and pathological changes more extensive
      than MTS may be required for emotional facial paresis to readily manifest.

PMID- 12495653
TI  - Carbon monoxide disposition and permeability-surface area product in the foetal
      circulation of the perfused term human placenta.
AB  - In order to estimate the placental barrier to gas transfer, a novel carbon
      monoxide (CO) wash-in method was used to estimate the permeability-surface area
      (PS) product for the transfer of gas across the foetal circulation in the
      perfused human term placenta. The PS product for CO was 0.0096+/-0.006 ml/s/g or
      0.012+/-0.007 ml/s/g using compartmental or Crone-Renkin analysis, respectively.
      Using this result and a published estimate of the placental capillary surface
      area, the permeability coefficient to CO across the foetal circulation was found
      to be approximately 4 x 10(-5)cm/s. This result is compatible with the hypothesis
      that the foetal circulation of the human placenta imposes a potentially
      significant barrier to gas transfer.

PMID- 12495654
TI  - Changes in umbilical artery flow velocity waveforms following maternal
      administration of betamethasone.
AB  - In a retrospective cohort study we have previously shown that administration of
      betamethasone to women with a pregnancy complicated by absent end-diastolic flow
      in the umbilical artery (UA) is associated with altered UA flow velocity
      waveforms. To examine this phenomenon further we undertook a prospective study of
      30 similar singleton pregnancies. Umbilical artery FVWs were recorded before and
      after betamethasone administration using real-time pulsed wave colour flow
      Doppler. The results of this prospective cohort were similar to those of the
      retrospective study allowing pooling of the data. Of the 55 total pregnancies
      with umbilical artery AEDF studied betamethasone administration was associated
      with the return of end-diastolic flow in 39 (71 per cent; 95 per centCI: 59-83
      per cent). The median (range) duration of this change was 3 (1-10) days. There is
      no evidence that this change has either a beneficial or detrimental effect on
      foetal health. Administration of betamethasone to women with a pregnancy
      complicated by umbilical artery AEDF is associated with the transient return of
      end-diastolic flow in most cases. While the mechanisms underlying this effect are
      yet to be fully elucidated it has implications for foetal surveillance in these
      high-risk pregnancies.

PMID- 12495655
TI  - Pharmacological identification of P2X1, P2X4 and P2X7 nucleotide receptors in the
      smooth muscles of human umbilical cord and chorionic blood vessels.
AB  - To ascertain the role of extracellular adenosine 5'-triphosphate (ATP) receptors
      in human placenta circulation, we identified and pharmacologically characterized
      the P2X receptor population in its superficial vessels. Total RNA was extracted
      from segments of chorionic and umbilical arteries and veins of terminal placentae
      delivered by vaginal or Caesarian births. Polymerase chain reaction (PCR),
      followed by sequencing of the products, identified the presence of P2X 1, 4, 5,
      6, and 7mRNAs in smooth muscle from chorionic and umbilical arteries and veins.
      Umbilical vessels proximal to the fetus expressed the same population of P2X
      subtypes, except for the P2X(5), but additionally expressed the P2X(2). Rings of
      chorionic vessels contracted upon addition of nucleotides and analogs with the
      following relative rank order of potencies in arteries and veins: alpha,beta
      methyleneATP>beta,gamma-methyleneATP>PNP>ATP=diBzATP>2-MeSATP>ADP>AMP; in
      umbilical vessels alpha,beta-methyleneATP was at least 100-fold more potent than
      ATP. Nucleotide potency was less than that of PGF(2alpha) or endothelin-2, but
      had the same magnitude as serotonin. ATP-desensitized receptors evidenced cross
      desensitization to alpha,beta-methyleneATP, 2-MeSATP and diBzATP, effect not
      observed when desensitization was elicited by alpha,beta-methyleneATP, confirming
      the presence of various P2X receptor subtypes in the smooth muscles of these
      vessels. The vasocontractile efficacy of alpha,beta-methyleneATP was unaltered by
      endothelium removal, while that of ATP was significantly attenuated and those
      elicited by 2-MeSATP were blunted, indicating the presence of additional
      endothelial nucleotide receptors. These results suggest that P2X receptors
      participate in the humoral regulation of placental blood flow.

PMID- 12495656
TI  - Asymmetrical transport of glucose across the in vitro perfused human placenta.
AB  - The transplacental flux of glucose together with the consumption by the tissue
      was studied in human term placenta using the dual in vitro perfusion of an
      isolated cotyledon. The effect of different transplacental glucose gradients
      going either from the maternal to the foetal side or in the opposite direction
      was tested. A linear correlation between uptake from the donor circuit as well as
      transplacental flux and concentration difference of glucose between the two sides
      was found in both directions. At comparable gradients both uptake and flux were
      significantly higher with the gradient going from the maternal to the foetal side
      as compared to the other direction. For the non-metabolizable 2-deoxy-analog of D
      -glucose no asymmetry of flux was seen. The large fraction of glucose uptake,
      which is metabolized by placental tissue together with the difference in membrane
      transport capacity across the microvillous as compared to the basal membrane of
      the syncytiotrophoblast could be an explanation for the asymmetry in
      transplacental glucose flux.

PMID- 12495657
TI  - Placental composition and surface area but not vascularization are altered by
      maternal protein restriction in the rat.
AB  - Amino acids are essential nutrients for foetal growth and development, and
      maternal protein restriction decreases foetal growth despite increasing placental
      size. To determine if placental structure is altered so as to impair function
      despite increased size, the effect of maternal protein restriction on the
      composition and vascularization of the placenta in the rat was determined.
      Pregnant rats were randomized to receive either a normal protein (20 per cent) or
      an isocaloric low (8 per cent) protein diet. Placentae were studied at day 18 of
      gestation. Tissue sections were stained with biotinylated Bandeiraea
      simplicifolia (BS-1) lectin to allow identification of foetal capillaries, and
      analysed using stereological techniques. Protein restriction increased total
      placental volume, but decreased the proportion of the placental volume composed
      of labyrinth. Consequently the total volumes of labyrinthine tissue and of foetal
      and maternal blood space were not different between the two groups. Protein
      restriction increased the surface area density and total surface area of the
      materno-foetal interface, but did not alter foetal capillary surface area,
      diameter or length. This study found that maternal protein restriction is
      associated with an increase in placental size, and that this enlargement is
      accompanied by increases in some, but not all, structural correlates of function.

PMID- 12495658
TI  - Semi quantitative expression analysis of MDR3, FIC1, BSEP, OATP-A, OATP-C,OATP-D,
      OATP-E and NTCP gene transcripts in 1st and 3rd trimester human placenta.
AB  - Using real time RT-PCR, we have detected expression of seven genes that influence
      bile acid transport,MDR3, FIC1, BSEP, OATP-A, OATP-C, OATP-D and OATP-E, in
      normal human placenta. With the exception of OATP-C and OATP-E these genes were
      found to be differentially expressed in 1st trimester and 3rd trimester
      placentae. MDR3 gene expression was found to be up regulated four fold in 3rd
      trimester placentae compared to 1st trimester, OATP-A gene expression was down
      regulated eight fold, OATP-D was down regulated 17 fold, while FIC1 expression
      was reduced by 33 fold in the 3rd trimester. OATP-C and BSEP gene expression was
      not detected in the 3rd trimester placenta, while low levels of transcripts were
      detected in the 1st trimester placentae. Transcripts of the hepatic sinusoidal
      bile acid transporter, NTCP, were not detected in placenta.

PMID- 12495659
TI  - The presence of inducible cytochrome P450 types 1A1 and 1A2 in the BeWo cell
      line.
AB  - The activity and inducibility of cytochrome P450 systems (CYP1A1:1A2) of the
      human placenta were assessed in a representative human trophoblast-like cell
      line, BeWo. The activity of CYP1A1 and CYP1A2 in microsome preparations from
      human liver, placenta, primary cultures of human cytotrophoblast, and BeWo cells
      was measured by O -dealkylation of 7-ethoxyresorufin (EROD) and 7
      methoxyresorufin O -demethylation (MROD), respectively. Results indicated high
      EROD and MROD activity associated with human liver microsomes, sometimes
      comparable activities in human placenta microsomes prepared from smokers, and
      relatively low activities in human placenta microsomes from nonsmokers and in the
      primary cultures of cytotrophoblasts isolated from nonsmokers. Microsomes from
      BeWo cell monolayers exhibited the lowest EROD and MROD activities relative to
      all other microsome preparations. However, compared to primary cultures of normal
      trophoblasts, the EROD activity of the BeWo cells was far more sensitive to
      typical inducers, 3-methylcholanthrene, 1,2-benzanthracene, and beta
      naphthoflavone. EROD activity in BeWo cells was induced approximately 200-fold by
      3-methylcholanthrene. Both EROD and MROD activity in BeWo cells was readily
      induced by 1,2-benzanthracene, 100-fold and 60-fold, respectively. After
      induction with 1,2-benzanthracene, the CYP1A1 selective inhibitor, alpha
      naphthoflavone, and the CYP1A2 selective inhibitor, furafylline, effectively
      inhibited enzyme activities with IC(50)s of 2.4 microM and 12.8 microM,
      respectively, in microsomes from both trophoblasts culture systems. These results
      show that major cytochrome P450 forms present in human placenta are present and
      inducible in BeWo cells, a potential model for investigation of drug metabolism
      mechanisms in the human trophoblast.

PMID- 12495660
TI  - Expression and activity of matrix metalloproteinase 2 and 9 in human
      trophoblasts.
AB  - Indiscriminate invasion upon the endometrium by normal trophoblasts is strictly
      regulated unlike that by choriocarcinoma cells. In this study, we focused on the
      activity of matrix metalloproteinase (MMP)-2 and MMP-9 as parameters of invasion
      in normal human placenta. In situ hybridization (ISH), immunohistochemical
      staining (IH) and film in situ zymography (FIZ) were performed to identify cells
      having MMP-2 or MMP-9 expression and activity. Purified cytotrophoblasts (CTs)
      were used to examine the expression and activity of MMP-2 and MMP-9, and their
      invasive ability. In first trimester placental tissue, the MMP-2 expression was
      observed in extravillous trophoblasts (EVTs), and MMP-9 mainly in villous
      cytotrophoblasts (VCTs). FIZ revealed marked gelatinase activity in the EVTs
      which MMP-2 expression was observed in. In full-term placental tissue, the MMP-2
      expressions was observed in the EVTs similar to that in first trimester, whereas
      the gelatinase activity in these cells was decreased or completely lost. Using
      purified CTs, the gelatinase activity was marked in early CTs, but not term CTs.
      Invasive ability of early CTs was inhibited by tissue inhibitor of
      metalloproteinase (TIMP)-2 and MMP-2 antibody in a dose dependent manner. These
      suggests that the invasive ability of trophoblasts may be regulated by the enzyme
      activity of gelatinases, especially MMP-2.

PMID- 12495661
TI  - Survivin inhibits apoptosis in cytotrophoblasts.
AB  - Survivin, a protein that inhibits apoptosis, is expressed in a variety of tumour
      cells. We detected survivin-specific mRNA and protein in normal placental
      tissues, two human choriocarcinoma cell lines (JEG-3 and BeWo), and a
      trophoblastic cell line (tPA30-1) by reverse transcription-polymerase chain
      reaction (RT-PCR), Northern blotting, and Western blotting.
      Immunohistochemically, survivin was localized to normal villous cytotrophoblasts,
      normal extravillous trophoblasts, cytotrophoblasts in hydatidiform mole, and
      choriocarcinoma cells. Antisense oligonucleotides for survivin dose-dependently
      induced apoptosis in two choriocarcinoma cell lines (JEG-3 and BeWo) and a
      trophoblastic cell line (tPA30-1), while sense oligonucleotides showed little
      effect. These findings suggest that survivin antagonizes apoptosis in
      cytotrophoblasts, extravillous trophoblasts, and choriocarcinoma cells.

PMID- 12495662
TI  - Effect of hypoxia on placental activin A, inhibin A and follistatin synthesis.
AB  - Placental activin A and inhibin A output is increased in pre-eclampsia, a
      condition characterized by placental hypoxaemia, whereas follistatin secretion is
      unaltered. We investigated whether hypoxia was the basis for elevated placental
      activin A and inhibin A output. First trimester and term placental explants were
      grown in 5-6% dissolved O(2) (n=10/trimester) and 200 microM cobalt chloride
      (CoCl(2),n =6/trimester) to simulate environmental and cellular hypoxia
      respectively, for up to 72 h. Activin A, inhibin A and follistatin production
      were compared with control cultures grown in standard media at 20% O(2). In first
      trimester and term placenta, activin A output declined significantly under 5-6%
      O(2) (P=0.006 and 0.001 after 48 h respectively). Inhibin A declined
      significantly under 5-6% O(2), mainly in first trimester placenta (P=0.03, 24h).
      CoCl(2) significantly elevated activin A production in term placenta (P=0.003, 48
      h), whereas inhibin A output was unaffected. Neither low O(2) or CoCl(2) altered
      follistatin output from first trimester or term placenta. These findings suggest
      that there may be novel O(2) sensing mechanism/s that down regulate activin A and
      inhibin A in the placenta and that low O(2) is not the mechanism behind increased
      placental inhibin A or activin A output in pre-eclampsia.

PMID- 12495663
TI  - Matrix metalloprotease-9, placental syncytiotrophoblast and the endothelial
      dysfunction of pre-eclampsia.
AB  - The maternal syndrome of pre-eclampsia is caused by generalized maternal
      endothelial cell dysfunction, arising directly or indirectly from factors of
      placental origin. Syncytiotrophoblast membrane microvesicular particles are shed
      from the placental surface into maternal blood in increased amounts in pre
      eclampsia and, in vitro, both inhibit endothelial cell proliferation and cause
      marked changes in the morphology of the cultured cell monolayers. Because there
      is evidence that proteolytic activation and degradation of the underlying matrix
      can cause the same morphological changes, we tested the hypothesis that proteases
      intrinsic to syncytiotrophoblast microvillous membranes (STBM) are the cause of
      the in vitro endothelial changes. Purified STBM were analysed by zymography and
      western blotting. Although we could confirm the presence of urokinase plasminogen
      activator (uPA) in STBM we could demonstrate no intrinsic activity presumably
      because of its association with the plasminogen activator inhibitor-2 (PAI-2)
      which is also a component of STBM. We detected gelatinase activity and showed
      that it was due to the matrix metalloproteinase-9 (MMP-9). Its presence was
      confirmed in this location by immunohistocytochemistry. Protease inhibitors
      caused a small reversal of the effects of STBM on morphology and no effect on
      inhibition of proliferation. We conclude that the effect of STBM on endothelial
      cells is unlikely to be caused by intrinsic proteases.

PMID- 12495664
TI  - Placental leptin receptor isoforms in normal and pathological pregnancies.
AB  - Alternate mRNA splicing of human leptin receptor generates four membrane isoforms
      with different C-terminal sequences. They differ by the length of their
      intracellular domain which include specific motifs crucial for the specificity of
      leptin signalling. As a step towards functional studies, we have characterized
      leptin receptors in human placenta from normal pregnancies and pregnancies
      associated with diabetes and pre-eclampsia. Leptin and leptin receptors were
      visualized by immunohistochemistry of placentas obtained from first and third
      trimester pregnancies. Antibodies against N and C-terminal epitopes showed
      signals in the apical membrane of the syncytiotrophoblast in early and term
      placental villi as well as in JAr and BeWo derived trophoblast cells. In
      addition, a distinct isoform recognized by its extracellular juxtamembrane
      epitope was exclusively localized in cytotrophoblast cells and likely stains the
      soluble receptor. At contrast with the transmembrane receptors, the expression of
      this isoform is increased in placentas of pre-eclamptic and diabetic women which
      synthesize more leptin than placenta from uncomplicated pregnancy. These data
      demonstrate that short and long transmembrane leptin receptors are expressed in
      the trophoblast and indicate that leptin synthetized within the placenta can act
      locally through both receptor isoforms. Being also accessible to leptin from
      maternal origin, these transmembrane receptors may signal differently in
      pregnancy with normal and increased leptin production. The co-localization of
      leptin and the soluble receptor isoform suggests that this isoform serves for
      modulating maternal free leptin levels through modification of leptin binding
      capacities.

PMID- 12495665
TI  - Macrophage inhibitory cytokine-1 in gestational tissues and maternal serum in
      normal and pre-eclamptic pregnancy.
AB  - Macrophage inhibitory cytokine-1 (MIC-1), a divergent member of transforming
      growth factor-beta superfamily, has been recently shown to be produced by the
      human placenta with detectable levels in maternal serum. In this study, using
      immunohistochemistry, we have localized MIC-1 in placenta, decidua and foetal
      membranes across pregnancy and, using an enzyme-linked immunoassay, measured MIC
      1 in maternal serum in normal pregnancy, in association with labour and pre
      eclampsia. In the placenta MIC-1 was principally localized to the
      syncytiotrophoblast while in the foetal membranes MIC-1 was present in the
      amniotic epithelium, chorionic trophoblasts and adherent decidual cells. There
      were no differences in MIC-1 staining distribution or intensity in the placentae
      between women in labour and not in labour, or between healthy and pre-eclamptic
      pregnancies. MIC-1 staining in the foetal membranes was slightly stronger after a
      labour and delivery compared to those delivered by elective Caesarean section.
      MIC-1 levels in the maternal serum increased with advancing gestation but there
      were no significant differences in maternal serum levels associated with either
      labour or pre-eclampsia.These observations would be consistent with MIC-1 having
      roles at the maternal-foetal interface, perhaps in the establishment and/or
      maintenance of pregnancy. Our data argue against MIC-1 having a significant role
      in the regulation of labour or in the pathophysiology of pre-eclampsia.

PMID- 12495666
TI  - A mola hydatidosa coexistent with a foetus in a bovine freemartin pregnancy.
AB  - Molar transformations of the bovine placenta are extremly rare phenomenona and
      the aetiology of this genuine placental disease is still unknown. In the present
      study, an uncommon case of a German Holstein Friesian foetus co-twinned with a
      hydatidiform mole is described. Cytogenetic and fluorescence in situ
      hybridization analysis of cell cultures as well as prove of the presence of the
      SRY gene sequence revealed a heterosexual twin pregnancy. A chimeric condition of
      the mole was also established. In addition, an XO cell population was detected in
      the co-twin as well as in the mole. Upon examination of microsatellites of the
      parents, the mole and the co-twin an androgenetic origin of the mole is
      suggested, supporting the hypothesis that molar transformation of the bovine
      placenta may be caused by an androgenetic origin. Furthermore, the present
      observation demonstrates that the freemartin condition in cattle can be induced
      even in cases where severe placental transformations had subsequently occurred
      and no foetus proper could be detected at delivery.

PMID- 12495667
TI  - Umbilical cord blood: the role of apoptosis in the control of CD34+ cell counts.
AB  - BACKGROUND AND OBJECTIVE: Cord blood obtained at delivery can be used for
      hematopoietic precursor cells (HPC) transplantation. The major limit for its
      success is represented by the low cellular yield of the stem cell population. The
      objective of this study was to determine the role played by apoptosis in the
      numerical control of CD34+ cell counts. DESIGN AND METHODS: Umbilical cord blood
      samples were collected from 15 women at the time of the delivery and cord blood
      units processed. Cells, collected following 24h and 48h of incubation, were
      analysed by flow cytometry using the gating strategy. RESULTS: Remarkable levels
      of apoptosis were detected in the stem cell population and a significant
      difference between apoptosis mean values at 24h and 48h within CD34+ cells were
      found. The difference between the percentage of apoptosis in CD34+ cells and that
      in the remaining population was significant both at 24h and at 48h. CONCLUSIONS:
      CD34+ cells have a higher likelihood to undergo apoptosis in comparison to the
      remaining ones present in umbilical cord blood. This process of cellular death
      plays a major role in the control of CD34+ cell counts in placental blood and
      influence, for this reason, the possibility of success of a cord blood
      transplantation.

PMID- 12495668
TI  - How many paraffin blocks are necessary to detect villitis?

PMID- 12495670
TI  - 'Imprinting and Growth Congress' 2002, London, UK.

PMID- 12495672
TI  - Bovine lymphocytes express functional receptors for Escherichia coli Shiga toxin
      1.
AB  - Interactions of Shiga toxins (Stxs) and immune cells contribute to the
      pathogenesis of diseases due to Stx-producing Escherichia coli (STEC) infections
      in humans and facilitate the persistence of infection in asymptomatically
      infected cattle. Our recent findings that bovine B and T lymphocytes express
      Gb(3)/CD77, the human Stx-receptor, prompted us to determine whether the bovine
      homologue also mediates binding and internalization of Stx1. In fact, Stx1
      holotoxin and recombinant B subunit (rStxB1) bound to stimulated bovine
      peripheral blood mononuclear cells, especially to those subpopulations (B cells,
      BoCD8(+) T cells) that are highly sensitive to Stx1. Competition and HPTLC
      binding studies confirmed that Stx1 binds to bovine Gb(3), but different receptor
      isoforms with varying affinities for rStxB1 were expressed during the course of
      lymphocyte activation. At least one of these isoforms mediated toxin uptake. An
      anti-StxB1 mouse monoclonal antibody, used as a model for bovine serum antibodies
      specific for Stx1, modulated rather than generally prevented rStxB1 binding to
      and internalization by the receptors. The presence of functional Stx1-receptors
      on bovine lymphocytes explains the immunomodulatory effect of Stx1 observed in
      cattle at a molecular level. Furthermore, expression of such receptors by bovine
      but not human T cells enlightens the background for the differential outcome of
      STEC infections in cattle and man, i.e., persistent infection and development of
      disease, respectively.

PMID- 12495673
TI  - Type IV pili are not specifically required for contact dependent translocation of
      exoenzymes by Pseudomonas aeruginosa.
AB  - The type III secretion system (TTSS) of the opportunistic pathogen Pseudomonas
      aeruginosa enables the bacterium to deliver exoenzymes directly into the
      eukaryotic cell. In this study we have investigated the role of key factors
      involved in this process. We could demonstrate that the translocators PopB, PopD
      and PcrV are absolutely required for delivery of Exoenzyme S into host cells. By
      analyzing different Tfp (type IV pili) mutants we could establish a correlation
      between the frequency of bacteria binding to the host cell and the levels of
      translocated ExoS, thereby verifying that the process is contact dependent.
      However, there was no absolute requirement for the Tfp per se, since the pilus
      could be substituted with a different type of adhesin, the non-fimbrial adhesin
      pH6 antigen of Yersinia pestis. Taken together, our results demonstrate that
      binding to establish close contact between the type III secretion organelle and
      the host cell is essential for translocation, while the additional activities of
      Tfp are not essential for the delivery of TTSS proteins.

PMID- 12495674
TI  - Cytopathic effects observed upon expression of a repressed collagenase gene
      present in Salmonella and related pathogens: mimicry of a cytotoxin from multiple
      antibiotic-resistant Salmonella enterica serotype Typhimurium phagetype DT104.
AB  - Recently, we reported that certain strains of Salmonella enterica serovar
      Typhimurium phagetype DT104 (DT104) secrete a putative cytotoxin. While searching
      for the gene that encodes this toxin, we noted a previously reported but
      uncharacterized DNA fragment (clg) in Salmonella that could be potentially
      relevant to cytotoxin-like activity. Therefore, we cloned and expressed clg in
      cytotoxin-negative Escherichia coli and Salmonella and subsequently assessed the
      bioactivity of Clg in vitro and in vivo. Lysates containing Clg from both
      expression hosts exerted cytopathic effects on murine enterocytes while semi
      purified Clg was determined to be cytopathic to HEp-2 cells. Sequence and RT-PCR
      analyses of the clg gene indicated that a homologue of clg exists in different
      Gram-negative bacteria although the gene is not expressed in vitro. Although Clg
      mediated lesions are similar to those mediated by the DT104 cytotoxin, further
      investigations are necessary to examine the relationship between these two
      proteins in DT104. Nonetheless, we report here a defined Salmonella protein that
      is capable of inflicting damage on tissue culture cells and murine enterocytes.

PMID- 12495676
TI  - Leptospira interrogans binds to the CR3 receptor on mammalian cells.
AB  - Pathogenic leptospires adhere to phagocytes even in the absence of specific
      antibodies; we demonstrate that the CR3 integrin (known as Mac-1 or CD11b/CD18
      receptor), expressed on neutrophils and CHO Mac-1 transfected cells, recognizes
      and binds leptospires. The I-domain of the molecule seems to be involved in the
      recognition and data suggest that this occurs via fibronectin absorbed at the
      Leptospira surface. On the other hand, since N-acetyl-D-glucosamine does not
      behave as antagonist of the binding, the lectin-like domain of the receptor is
      not involved in the recognition.

PMID- 12495675
TI  - Identification of genomic differences between Escherichia coli strains pathogenic
      for poultry and E. coli K-12 MG1655 using suppression subtractive hybridization
      analysis.
AB  - Diseases of poultry caused by Escherichia coli result in significant economic
      loss every year. Specific virulence factors associated with E. coli strains
      pathogenic for poultry have been identified, but it is likely that others remain
      to be identified. To identify unique DNA fragments associated with avian strains
      we used suppression subtractive hybridization. The genome of E. coli K-12 strain
      MG1655 was subtracted from the genomes of two avian E. coli strains resulting in
      the identification of 62 fragments specific to the two avian strains. Sequence
      homology analysis was done and four types of fragments were identified: plasmid
      sequences, phage sequences, sequences with known function and sequences without
      any currently known function. Two E. coli collections, a reference collection of
      diverse strains (ECOR) and a collection of 41 avian isolates, were screened for
      the presence of 25 of the 62 fragments. We identified nine fragments present in
      significantly more of the avian strains than of the ECOR strains. Five fragments
      were in significantly more of the ECOR strains than the avian strains. These
      results suggested that the nine fragments could play a role in the pathogenesis
      of E. coli as it relates to diseases of poultry.

PMID- 12495677
TI  - Induction of NF-kappaB nuclear translocation in human respiratory epithelial
      cells by group A streptococci.
AB  - The activation of the transcription factor NF-kappaB and the production of
      inflammatory mediators play an essential role in the host response to pathogenic
      organisms. The objective of this study was to investigate the ability of group A
      streptococci (GAS) to stimulate the nuclear translocation of NF-kappaB in
      cultured human epithelial (HEp-2) cells. Infection of HEp-2 cells with a strain
      of Streptococcus pyogenes capable to efficiently internalize HEp-2 cells (strain
      A40) resulted in translocation of NF-kappaB during the first 15 min of infection,
      reaching a peak after 30 min that persisted at slightly lower levels 1h
      thereafter. Inhibition of bacterial internalization by cytochalasin D resulted in
      lower levels of nuclear NF-kappaB at 30 min and 1h of infection, however, it did
      not affect the initial nuclear translocation of NF-kappaB observed at 15 min
      postinfection. These results suggest that adhesion of S. pyogenes alone might be
      sufficient to stimulate nuclear translocation of NF-kappaB, however, bacterial
      internalization is required for a sustained nuclear translocation of this
      transcriptional factor.

PMID- 12495678
TI  - General outbreaks of infectious intestinal disease (IID) in hospitals, England
      and Wales, 1992-2000.
AB  - Between 1992 and 2000, 26.6% (1,396/5,257) of all general outbreaks of infectious
      intestinal disease (IID) reported to the Public Health Laboratory Service (PHLS)
      Communicable Disease Surveillance Centre (CDSC) occurred in hospitals. Over
      29,000 patients and staff were affected and the mortality risk was higher than
      for outbreaks in other settings [relative risk 2.00 (95% CI: 1.52-2.63) P<0.001].
      Person-to-person spread was the predominant mode of transmission. The mortality
      risk was highest in foodborne disease outbreaks [relative risk 3.22 (95% CI: 1.41
      7.36); P=0.003]. Most outbreaks occurred between November and April. The
      pathogens most frequently reported were Norwalk-like virus (NLV) (54%) and
      Clostridium difficile (12.6%). These findings emphasize the public health
      importance of outbreaks of IID in hospitals, especially during the winter when
      pressures on hospitals are at their height.

PMID- 12495679
TI  - Infections in a burn intensive care unit: experience of seven years.
AB  - The objective of this study is to describe infections in a specialized burns
      intensive care unit from 1993 to 1999. The criteria for admission to the unit
      are: children with burns involving at least 10% or adults with burns involving at
      least 20% of total body surface; burns affecting face, perineum or feet;
      suspected or proven airway injury; electric or chemical burns; age less than one
      year or above 50; or pre-existing disease with any extent of burns. Surveillance
      of hospital-acquired infection was prospective. Hospital-acquired infection
      criteria used were those modified from the Centers for Disease Control and
      Prevention. Diagnosis of infection using skin biopsy was not done. Over the study
      period, 320 patients were admitted to our burns intensive care unit. One hundred
      and seventy-five (55%) developed 388 hospital-acquired infections. The rate for
      vascular catheter-associated bloodstream infections was 34 per 1,000 central line
      days. The rate of ventilator associated pneumonia was 26 infections per 1,000
      ventilator-days. Primary bloodstream was the most common infection with 189
      episodes (49%); followed by 83 burn wound infections (21%) and 56 pneumonias
      (14%). In 76% of these infections and in 97% of the primary bloodstream
      infections, aetiological agents were identified. The micro-organisms causing
      infections were S taphylococcus aureus (24%), Pseudomonas aeruginosa (18%),
      Acinetobacter spp. (14%) and coagulase-negative staphylococci (12%). Candida spp.
      caused 8% of infections. Gram-positive and Gram-negative organisms exhibited
      resistance to most antimicrobial agents used for therapy. During the first three
      days of hospitalization in the burns intensive care unit there were eight
      infections caused by S. aureus and three of these were resistant to oxacillin.
      These data provide background information regarding extensive burn patients on
      which decisions for control and prevention of hospital-acquired infections can be
      made.

PMID- 12495680
TI  - A monthly systematic bacteriological report improves accuracy of identification
      of hospital-acquired infections in an ICU.
AB  - A prospective cohort study with retrospective validation was initiated in order
      to assess whether a monthly bacteriological report improves the accuracy in
      detecting hospital-acquired infections (HAI). The setting was a 14-bed medical
      intensive care unit (ICU) in a 821 bed French university affiliated hospital. One
      thousand, six hundred and two patients were admitted during the two-year study
      period, the mean age was 58+/-19 years, the mean Simplified Acute Physiology
      Score 2 (SAPS 2) was 34+/-21, and ICU mortality was 14%. The microbiology
      laboratory sent monthly bacteriological reports of urine samples and central
      venous catheter (CVC) tips back to the intensive-care unit physician in charge of
      the HAI surveillance programme. This enabled a comparison to be made between
      prospectively and retrospectively diagnosed hospital-acquired urinary tract
      infections (HAUTI) and CVC-related infections (HACVCI), HAUTI were prospectively
      identified in 51 cases (incidence density=10.03/1,000 days) and 23 more cases
      were found after receiving the monthly bacteriological report (final HAUTI
      incidence density=14.6/1,000 days, P<0.05). HACVCI were prospectively recognized
      in 13 cases (incidence density=4/1,000 days) and eight more cases were discovered
      (final HACVCI incidence density=6.52/1,000 days,P >0.1). All retrospectively
      diagnosed HAI occurred during the last 48 h of the patients' ICU stay. We
      conclude that the routine HAI surveillance programme is reliable, except for the
      last 48 h in the ICU. The monthly bacteriological report improved the accuracy of
      the HAI reporting rate.

PMID- 12495681
TI  - Reappraisal of attributable mortality in critically ill patients with nosocomial
      bacteraemia involving Pseudomonas aeruginosa.
AB  - In a retrospective study, population characteristics and outcome were
      investigated in intensive care unit (ICU) patients with hospital-acquired
      Pseudomonas aeruginosa bacteraemia admitted over a seven-year period (January
      1992 through December 1998). A matched cohort study was performed in which all
      ICU patients with P. aeruginosa bacteraemia were defined as cases (N=53).
      Matching (1:2 ratio) of the controls (N=106) was based on the APACHE II
      classification: an equal APACHE II score (+/-1 point) and an equal diagnostic
      category. Patients with P. aeruginosa bacteraemia had a higher incidence of acute
      respiratory failure, haemodynamic instability, a longer ICU stay and length of
      ventilator dependence (P<0.05). In-hospital mortalities for cases and controls
      were 62.3 vs. 47.2% respectively (P=0.073). Thus, the attributable mortality was
      15.1% (95% confidence intervals: -1.0-31.2). In a multivariate survival analysis
      the APACHE II score was the only variable independently associated with
      mortality. In conclusion, P. aeruginosa bacteraemia is associated with a
      clinically relevant attributable mortality (15%). However, we could not find
      statistical evidence of P. aeruginosa being an independent predictor of
      mortality.

PMID- 12495682
TI  - Risk factors for nosocomial infections in a neonatal intensive-care unit.
AB  - The clinical records a years cohort of 280 newborn infants consecutively
      hospitalized for 48 h or more in our neonatal intensive-care unit (NICU) were
      reviewed. Information on the infants' conditions during the first 12h of life,
      and on the procedures used in the NICU, were collected. Statistical significance
      was tested by univariate analysis with the chi(2) test and by multivariate
      logistic regression analysis with the software program SPSS (Version 10). Over
      the one-year period reviewed, 90 hospital-acquired infections (HAIs) were
      contracted; 55 (19.6%) of infants had at least one infection during their stay.
      The overall in-hospital mortality was 7.1%, and mortality was higher in infants
      in whom at least one infection developed than in non-infected infants (12.7 vs.
      5.8% P=0.13). Very low birthweight infants (VLBW<1,501 g) who had more severe
      clinical conditions on admission [clinical risk index for babies (CRIB) score
      >/=5] had an almost two-fold higher risk of contracting a HAI. In the
      multivariate regression analysis, the onset of a HAI was strongly associated with
      a low gestational age and the presence of an intravascular catheter. HAIs
      frequently complicate hospitalization in NICUs and are associated with increased
      mortality. Our findings also suggest that CRIB could be predictive for the risk
      of infection in VLBW infants.

PMID- 12495683
TI  - Successful control of an Acinetobacter baumannii outbreak in a neonatal intensive
      care unit.
AB  - We describe an outbreak of Acinetobacter baumannii in a neonatal intensive care
      unit (NICU), and our investigation to determine the source and mode of
      transmission and identify the population at risk. A case (infected infant) was
      defined as a patient hospitalized in the NICU during the outbreak period, with
      clinical signs of sepsis and isolation of A. baumannii. In colonized infants, A.
      baumannii was isolated from body surfaces without signs of infection. Infected
      infants were separated and treated by a different medical team. Cultures were
      taken from working surfaces and along the infant's admission passage from the
      delivery room to the NICU. The outbreak strain was identified by pulsed-field gel
      electrophoresis (PFGE). Nine cases and eight colonized infants met the definition
      criteria. Cases were younger than colonized infants with regard to gestational
      age and age of diagnosis and had lower birthweights (P<0.01). The outbreak strain
      was only isolated from hygroscopic bandages used on skin under the ventilation
      tube and umbilical catheters. Discontinuing the use of the bandages put an end to
      the outbreak. We conclude that a rapid and thorough investigation of the
      environment during an outbreak of A. baumannii is essential to finding the source
      of the infection, and that hygroscopic bandages may be a source of such
      outbreaks.

PMID- 12495684
TI  - Risk factors in the acquisition of extended-spectrum beta-lactamase Klebsiella
      pneumoniae: a case-control study in a district teaching hospital in Taiwan.
AB  - A case-control study was performed to find the risk factors in the acquisition of
      extended-spectrum beta-lactamase (ESBL) Klebsiella pneumoniae. From 1 May 2001 to
      30 September 2001, 422 isolates ofK. pneumoniae identified by the microbiological
      laboratory in Hsin-Chu hospital were collected, 59 of which were ESBL-producing
      strains. The prevalence rate was 14% (59/422). There were 43 case patients (ESBL
      producing K. pneumoniae) and 86 controls (non-ESBL-producing K. pneumoniae).
      Tracheostomy, insertion of a Foley catheter, endotracheal tube, nasogastric tube
      and central venous catheter were found to be risk factors in the acquisition of
      K. pneumoniae with ESBLs by univariate analysis. Tracheostomy (odds ratio, 5.13;
      95% CI, 1.24-21.1;P =0.023) and ceftazidime use (odds ratio, 13.40; 95% CI, 1.21
      148.85; P=0.035) remained as risk factors by multivariate analysis with logistic
      regression. Other anti-pseudomonal agents should be used as empirical therapy to
      treat possible Pseudomonas aeruginosa infection in order to reduce ceftazidime
      use and thereby decrease the prevalence of ESBL producing strains of
      Enterobacteriaceae.

PMID- 12495685
TI  - Device-related sources of bacteraemia in English hospitals--opportunities for the
      prevention of hospital-acquired bacteraemia.
AB  - Between 1997 and 2001, 17 teaching and 56 non-teaching acute English hospitals
      conducted hospital-wide surveillance of hospital-acquired bacteraemia (HAB) using
      a standard protocol drawn up by the Nosocomial Infection National Surveillance
      Scheme (NINSS). The sources of organisms, the incidence of device-related HAB,
      and the distribution of HABs from individual device-related sources by specialty
      and type of hospital were determined for 6,956 HABs in order to identify where
      resources should best be targeted to reduce these infections. The overall
      incidence of HAB was higher in teaching than in non-teaching hospitals: 5.39 and
      2.83 HABs per 1,000 patients at risk, respectively (P<0.001). Device-related
      sources were responsible for 52.4 and 43.2% of all HABs in teaching and non
      teaching hospitals, respectively (P<0.001), and central lines were the commonest
      source, causing 38.3% of HABs in teaching versus 22.3% in non-teaching hospitals
      (P<0.001). In teaching hospitals, general intensive care units (ICUs),
      haematology, special care baby units (SCBUs), nephrology, and oncology accounted
      for only 6.1% of the population surveyed, but had the highest incidence of HAB,
      and contributed 47.8% of 2091 HABs and 56.9% of 1,095 device-related
      bacteraemias. Of 623 device-related bacteraemias in these high-risk specialties,
      554 (88.9%) were from central lines. Thus, in teaching hospitals, resources
      should be targeted primarily at the prevention of central line-related
      bacteraemia in these five high-risk specialties, and the surveillance should
      include data on central line use. In non-teaching hospitals, nearly two thirds
      (63.3%) of 4,865 HABs and 60.7% of 2,103 device-related bacteraemias were from a
      few specialties with a low incidence of bacteraemia, but large numbers of
      patients, namely general medicine, general surgery, geriatric medicine and
      urology. These specialties accounted for 50.5% of the population surveyed.
      Central lines were the most common source of bacteraemia in general medicine and
      surgery, and together accounted for 23.3% of all device-related bacteraemias.
      However, in geriatric medicine and urology, central line sources were infrequent,
      accounting for only 1.7% of all device-related bacteraemias. On the other hand,
      bacteraemia from catheter-associated UTI were common in all these four
      specialties accounting for 20.9% of all device-related bacteraemias. Thus, in non
      teaching hospitals, resources should be targeted primarily at these low-risk
      specialties and surveillance should include, at least, bacteraemia from central
      lines and from catheter-associated UTI. Further benefit can be obtained by
      including central line-related bacteraemias from general ICU and haematology
      patients, as they contributed 17.0% of all device-related bacteraemias in non
      teaching hospitals.

PMID- 12495687
TI  - Biofilm removal from silicone tubing: an assessment of the efficacy of dialysis
      machine decontamination procedures using an in vitro model.
AB  - The aim of this study was to assess the efficacy of 21 decontamination
      procedures, for the removal of a multispecies biofilm. Experiments were performed
      on five-day-old biofilms grown inside silicone tubing, using a reactor system
      that mimics a dialysis machine. The treatments were tested on 5 cm tubing
      samples. Effects of treatment were measured using direct microscopy following
      staining. Bacterial viability and endotoxin removal were determined using
      conventional microbiological methods following biofilm detachment by scraping.
      The 21 procedures were classified into four groups based on the amount of biofilm
      removed. The most effective treatment was an acid pre-treatment, followed by use
      of a concentrated bleach solution. Acid pre-treatment removes calcium and
      magnesium carbonate crystals that are always found in dialysis biofilms.
      Treatments performed at high temperature did not increase the efficacy of biofilm
      removal. Most treatments caused at least a 10(5)-fold reduction in bacterial
      viability with a few resulting in complete kill. Autoclaved and bleach-treated
      samples gave the best results for viability reduction, with both treatments
      providing an equally effective and complete kill. In addition, autoclaving led to
      a significant decrease in endotoxin level (removal of 99.99%).

PMID- 12495686
TI  - Combination therapy with polymyxin B-immobilized fibre haemoperfusion and
      teicoplanin for sepsis due to methicillin-resistant Staphylococcus aureus.
AB  - The aim of the present study was to determine whether treatment with polymyxin B
      immobilized fibre (PMX-F) haemoperfusion, teicoplanin, or both in combination is
      effective in patients with methicillin-resistant Staphylococcus aureus (MRSA)
      sepsis. Sixty patients with MRSA sepsis were randomly assigned to one of four
      treatments: (A) PMX-F treatment (N=15), (B) teicoplanin treatment (N=15), (C) PMX
      F and teicoplanin in combination (N=20) and (D) conventional therapy (N=10). PMX
      F treatment was repeated twice. Teicoplanin was administered by intravenous
      injection. Plasma endotoxin levels were determined by endospecy test. Plasma
      endotoxin levels were reduced in groups A and C (P<0.05). Survival rates were 53,
      47, 90, and 20% in groups A, B, C and D, respectively (group C versus group A,
      P<0.05; group C versus group B, P<0.01; group C versus group D,P <0.001). The
      mean duration of stay was 44, 42, 28 and 56 days in groups A, B, C and D,
      respectively. Our data suggest that combination therapy with PMX-F and
      teicoplanin is effective for sepsis caused by MRSA.

PMID- 12495688
TI  - The risk of hospital-acquired GB virus C infection: a pilot case-control study.
AB  - The risk of hospital-acquired infection with GB virus C (GBV-C) was explored
      among 42 patients. The factors independently associated with detection of GBV-C
      RNA in serum were bronchoscopic examination [adjusted odds ratio (OR)=18.1 (95%
      confidence interval 1.3-255.3), P=0.03] and a history of illicit drug use
      [OR=14.5 (1.0-218.7), P=0.05]. In this cohort of patients, invasive procedures
      appear to be associated with GBV-C infection but not with hepatitis C virus (HCV)
      infection.

PMID- 12495689
TI  - Use of random amplified polymorphic DNA to assess repeated isolates of
      Acinetobacter baumannii.

PMID- 12495690
TI  - Non-touch fittings in hospitals: a possible source of Pseudomonas aeruginosa and
      Legionella spp.

PMID- 12495691
TI  - A possible grading system for healthcare-associated infection surveillance.

PMID- 12495692
TI  - Aspergillus terreus in a cystic fibrosis clinic: environmental distribution and
      patient colonization pattern.

PMID- 12495693
TI  - Proper meals in transition: young married couples on the nature of eating
      together.
AB  - Most people get married or spend time living with a partner at some stage in
      their lives. But what effect does this change have, if any, on their eating
      habits? The transition from bachelor or spinster to young couple represents a
      major lifecourse change and this paper looks at the role that eating together
      plays in the lives of a group of young Scottish couples recently married or
      cohabiting with their partner. The key question here is what role do meals play
      in all of this and how are eating activities arranged in these households. In an
      attempt to move the debate on meals beyond the "traditional family unit" it
      considers what eating "properly" meant for these couples. The paper looks at the
      importance of the evening meal as a site for sociability in married and
      cohabiting couples and examines the process of social interaction, focusing on
      temporal and spatial aspects of eating together as a couple. It reports on what
      men and women said in individual interviews and recorded in personal food
      diaries, contrasting this with their behaviour when they were living separately
      from their partners.

PMID- 12495694
TI  - Achieving "proper" satiety in different social contexts--qualitative
      interpretations from a cross-disciplinary project, sociomaet.
AB  - In nutritional research, the sensations of appetite have mostly been studied as a
      physiological phenomenon. However, in order to understand the significance of
      appetite for everyday eating habits, it is pertinent to include the social
      dimension. In a qualitative interview study, using qualitative semi-structured in
      depth interviews, we investigated how appetite was experienced and handled in the
      context of everyday life among 20 men and women. This report examines how
      qualitative dimensions of appetite are experienced and conceptualised in everyday
      life. Achieving what was described as proper satiety was found to be of decisive
      importance for daily eating habits. The experience of being full up, the duration
      of satiety and the sensuous pleasure of eating were all found to be central
      dimensions of proper satiety, the definition of which varied according to
      different social contexts. Whether one ate one's fill in the company of others,
      alone, at work or in one's spare time turned out to be of decisive importance. A
      more elaborate understanding of the social dimensions of appetite may help to
      improve endeavours to prevent overweight and obesity.

PMID- 12495695
TI  - Effectiveness of trained peer models to encourage food acceptance in preschool
      children.
AB  - The present study examined the effectiveness of trained peer models to encourage
      food acceptance in children during preschool meals, and one month later. It also
      considered whether trained peer models risk the over-justification effects
      proposed to reduce later food acceptance after reinforcement has been offered for
      eating a specific food. Three novel foods were presented to eight tables of 38
      children during five preschool meals. After three baseline meals, 16 children
      were trained to serve as peer models of food acceptance for one of the foods in
      exchange for small toy reinforcements, with each food assigned to either no
      model, girl model, or boy model conditions during the next two meals. The
      remaining 22 children served as observers whose food bites were recorded during
      baseline and modeled meals. Girl models were more effective than boy models to
      increase food acceptance from baseline to modeled meals for children of either
      gender. One month later, child interviews measured delayed food acceptance using
      food preference ratings and number of bites consumed. For observers, delayed food
      acceptance did not differ according to the food's previous modeling condition,
      suggesting that effectiveness of trained peer models does not last beyond the
      modeled meals. Trained peer models gave the highest preference ratings to the
      specific food they had eaten in exchange for toy reinforcements one month before,
      and they ate as much of this food as other foods, offering no evidence for
      detrimental over-justification effects on food acceptance as a result of serving
      as peer models.

PMID- 12495704
TI  - Propolis, an old remedy used in modern medicine.
AB  - Propolis is one of the few natural remedies that has maintained its popularity
      over a long period of time. The pharmacologically active molecules in the
      propolis are flavonoids and phenolic acids and their esters. These components
      have multiple effects on bacteria, fungi and viruses. In addition, propolis and
      its components have anti-inflammatory and immunomodulatory activities. Moreover,
      propolis has been shown to lower blood pressure and cholesterol levels. However,
      clinical studies to substantiate these claims are required.

PMID- 12495705
TI  - Analytical methods for quality control of propolis.
AB  - Propolis is a resinous substance collected by honeybees from leaf buds and cracks
      in the bark of various plants, and it is composed of 50% resin (composed of
      flavonoids and related phenolic acids), 30% wax, 10% essential oils, 5% pollen
      and 5% various organic compounds. Propolis cannot be used as raw material, and it
      must be purified by extraction with solvents. This process should remove the
      inert material and preserve the polyphenolic fraction, which is considered to
      contribute more to the observed healing effects than the other propolis
      constituents. Therefore, the assay of propolis polyphenols is of interest, and
      this paper describes the results obtained in the analysis of propolis by means of
      a gradient HPLC or mass spectrometry. HPLC in the gradient mode and coupled with
      photodiode array detection remains the method of choice for the assay of most
      relevant components of propolis. Direct analysis by APCI-IT-MS represents a
      valuable alternative to obtain typical fingerprints of propolis and a reliable
      identification of a large number of propolis components.

PMID- 12495706
TI  - Antioxidant activity of propolis: role of caffeic acid phenethyl ester and
      galangin.
AB  - Propolis, a natural product produced by the honeybee, has been used for thousands
      of years in folk medicine for several purposes. The extract contains amino acids,
      phenolic acids, phenolic acid esters, flavonoids, cinnamic acid, terpenes and
      caffeic acid. It possesses several biological activities such as
      antiinflammatory, immunostimulatory, antiviral and antibacterial. The exact mode
      of physiological or biochemical mechanisms responsible for the medical effects,
      however, is yet to be determined. In this work, we have investigated the
      antioxidant activity of a propolis extract deprived of caffeic acid phenethyl
      ester (CAPE). In addition, the activity of CAPE and galangin was also examined.
      Propolis extract (with and without CAPE) and its active components showed a dose
      dependent free radical scavenging effect, a significant inhibition of xanthine
      oxidase activity, and an antilipoperoxidative capacity. Propolis extract with
      CAPE was more active than propolis extract without CAPE. CAPE, used alone,
      exhibited a strong antioxidant activity, higher than galangin. The experimental
      evidence, therefore, suggests that CAPE plays an important role in the
      antioxidant activity of propolis.

PMID- 12495708
TI  - Effect of a propolis extract and caffeic acid phenethyl ester on formation of
      aberrant crypt foci and tumors in the rat colon.
AB  - We have studied the effect of propolis and its main active ingredient caffeic
      acid phenetyl ester (CAPE) on formation of aberrant crypt foci (ACF) and tumors
      in the rat colon in vivo. CAPE (50 mg/kg i.p.) reduced the formation of ACF and
      tumor induced by azoxymethane, while propolis ethanolic extract was without
      effect. These results suggest a potential anti-carcinogenesis of CAPE but not
      propolis.

PMID- 12495707
TI  - The role of the phenethyl ester of caffeic acid (CAPE) in the inhibition of rat
      lung cyclooxygenase activity by propolis.
AB  - In this study we investigated the effect of an ethanolic extract of propolis,
      with and without CAPE, and some of its components on cyclooxygenase (COX)
      activity. Propolis (0.00003-0.03%) significantly and concentration-dependently
      inhibited COX activity from lung homogenate of saline- or LPS-treated rats. Same
      results were obtained with CAPE (0.1-100 microM). COX activity from lung
      homogenate of saline- or LPS-treated rats was also inhibited by galangin (0.1-100
      microM), although the inhibition induced by the lowest concentration was not
      significant. Caffeic, ferulic, cinnamic and chlorogenic acids and pinocembrin,
      (0.1-100 microM) did not affect COX activity. The inhibition curves showed that
      CAPE and propolis were equipotent inhibitors, whereas galangin was significantly
      (P<0.001) less potent than propolis and CAPE. In order to better investigate the
      role of CAPE, we tested the action of an ethanolic extract of propolis (0.00003
      0.03%) without CAPE. This extract significantly and concentration-dependently
      inhibited COX activity from lung homogenate of saline- or LPS-treated rats,
      however, it resulted to be approximately 10 times less potent than the extract
      containing CAPE. The analysis of the inhibition curves of the extract with and
      without CAPE showed a significant (P<0.001) difference. These results suggest
      that both CAPE and galangin contribute to the overall activity of propolis, CAPE
      being more effective.

PMID- 12495709
TI  - In vitro permeation through porcine buccal mucosa of caffeic acid phenetyl ester
      (CAPE) from a topical mucoadhesive gel containing propolis.
AB  - Recent studies have shown that propolis has on the oral cavity appreciable
      antibacterial, antifungal and antiviral actions, as well as anti-inflammatory,
      anaesthetic and cytostatic properties. In light of these studies, an assessment
      of the diffusion and permeation of caffeic acid phenetyl ester (CAPE) through
      porcine buccal mucosa was considered useful as a possible application in the
      stomatological field. To do so, a mucoadhesive topical gel was prepared to apply
      to the buccal mucosa. The gel was formulated in such a way as to improve the
      solubility of the propolis, conducting to an increase of the flux. The mucosal
      permeation of CAPE from the formulation was evaluated using Franz cells, with
      porcine buccal mucosa as septum between the formulation (donor compartment) and
      the receptor phase chamber. The diffusion through the membrane was determined by
      evaluating the amount of CAPE present in the receiving solution, the flux and the
      permeation coefficient (at the steady state) in the different formulations at set
      intervals. Qualitative and quantitative determinations were done by HPLC
      analysis. From the results, CAPE allowed a high permeability coefficient in
      comparison to the coefficient of other molecules, as expected from its physical
      chemical structure. Moreover, the developed gel improved the CAPE flux
      approximately 35 times more with respect to an ethanol solution formulated at the
      same gel concentration. The developed gel was also tested in order to evaluate
      the mucoadhesive behaviour and comfort in vivo on 10 volunteers in a period of 8
      h. The in vivo evaluation of mucoadhesive gel revealed adequate comfort and non
      irritancy during the period of study and it was well accepted by the volunteers.

PMID- 12495710
TI  - Phytochemical compounds involved in the anti-inflammatory effect of propolis
      extract.
AB  - Two ethanolic propolis extracts (EPE) with and without the caffeic acid phenethyl
      ester (CAPE), CAPE and galangin (major components of propolis) were investigated
      for anti-inflammatory activity in rats using carrageenin foot oedema, carrageenin
      pleurisy and adjuvant arthritis. In our experiments, EPE with CAPE and CAPE alone
      significantly inhibited carrageenin oedema, carrageenin pleurisy and adjuvant
      arthritis. In contrast EPE without CAPE and galangin did not exhibit anti
      inflammatory effects in acute and chronic inflammation. These results suggest
      that the anti-inflammatory activity of propolis is due to CAPE.

PMID- 12495712
TI  - Etiology and pathogenetic mechanisms of the anti-phospholipid syndrome unraveled.

PMID- 12495713
TI  - Harm or heal--divergent effects of autoimmune neuroinflammation?

PMID- 12495715
TI  - NK cells: a lesson from mismatched hematopoietic transplantation.

PMID- 12495717
TI  - Lessons from history: dysfunctional APCs, inherent dangers of STI and an
      important goal, as yet unmet.

PMID- 12495719
TI  - Paracrine relationships between adipose and lymphoid tissues: implications for
      the mechanism of HIV-associated adipose redistribution syndrome.
AB  - The adipocytes anatomically associated with lymph nodes and omental milky spots
      have site-specific properties that equip them to interact locally with lymphoid
      cells. Paracine provisioning of peripheral immune responses improves their
      efficiency and emancipates activated lymphocytes from competition with other
      tissues for blood-borne nutrients. Prolonged disruption to such paracine
      interactions might contribute to the HIV-associated adipose redistribution
      syndrome, causing selective hypertrophy of the mesentery, omentum and other
      lymphoid tissue-containing adipose depots, while nodeless depots atrophy.

PMID- 12495720
TI  - Evolutionary clues to the functions of the Toll-like family as surveillance
      receptors.
AB  - The origin of the Toll-like family of receptors pre-dates the evolutionary split
      between the plant and animal kingdoms. These receptors are remarkably conserved
      across the taxonomic kingdoms and have fundamental roles in triggering immune
      responses. How they trigger such responses, and how these mechanisms arose in
      evolution, is a topic of extensive debate. We postulate a surveillance model:
      these receptors "keep watch" for both endogenous and exogenous molecules that
      indicate tissue injury, infection and remodeling. Furthermore, we suggest that
      the first Toll-like family receptors that arose in evolution might have acted in
      both development and immunity by recognizing the degradation of endogenous
      macromolecules.

PMID- 12495721
TI  - IL-6: a regulator of the transition from neutrophil to monocyte recruitment
      during inflammation.
AB  - The origin of the Toll-like family of receptors pre-dates the evolutionary split
      between the plant and animal kingdoms. These receptors are remarkably conserved
      across the taxonomic kingdoms and have fundamental roles in triggering immune
      responses. How they trigger such responses, and how these mechanisms arose in
      evolution, is a topic of extensive debate. We postulate a surveillance model:
      these receptors "keep watch" for both endogenous and exogenous molecules that
      indicate tissue inquiry, infection and remodeling. Furthermore, we suggest that
      the first Toll-like family receptors that arose in evolution might have acted in
      both development and immunity by recognizing the degradation of endogenous
      macromolecules.

PMID- 12495722
TI  - Malaria-specific antibody subclasses in immune individuals: a key source of
      information for vaccine design.
AB  - Immunity against the blood stage of Plasmodium falciparum malaria is associated
      with protective-type antibodies of certain classes and subclasses. Field studies
      have demonstrated the differential regulation of various IgG subclasses depending
      on the dynamics of parasite transmission and on the immune status of the
      individuals tested. The intrinsic properties of each IgG subclass has a crucial
      role in protection, both because immunoglobulin levels are dependent on their
      production and clearance from blood and because antibodies are actively used for
      parasite clearance. In vitro models using B cells obtained from P. falciparum
      immune adults have enabled study of the production of various antibody subclasses
      depending on the individual and on the antigens used. Ex vivo and in vitro
      observations from immune donors have helped to extend our understanding of the
      development and regulation of the antibody response and to design more effective
      vaccine strategies.

PMID- 12495723
TI  - The dual role of IL-10.
AB  - Classification of cytokines as pro-versus anti-inflammatory might not apply to
      the pleiotropic effects of interleukin-10 (IL-10). Several reports suggest that
      IL-10 enhances the function of natural killer cells, which leads, through
      pathogen destruction, to increased antigen availability. In addition, by
      inhibiting the maturation of antigen-presenting cells (APCs), IL-10 preserves
      their ability for antigen uptake while simultaneously hampering their migration
      to draining lymph nodes. This review suggests that this "antigen-loading" phase
      might constitute an important component of the innate immune reaction to a
      pathogen. Additional proinflammatory stimuli might subsequently lead to
      maturation of "loaded" APCs that could migrate to draining lymph nodes or recruit
      and activate adaptive immune effectors locally.

PMID- 12495724
TI  - Granulomas in schistosome and mycobacterial infections: a model of local immune
      responses.
AB  - Granulomatous immune responses are interesting models for the effector phase of
      immunity, in that granulomas can be part of both immune protection and disease
      pathology during the course of various infectious and autoimmune diseases.
      Focusing mainly on granulomas induced by Schistosoma or Mycobacterium infection,
      this article reviews T-cell recruitment, local cytokine networks and the
      regulation of cytokine networks by neuropeptides in granulomas. In addition,
      different activation pathways for macrophages residing in granulomas are
      discussed. Granulomas are unique inflammatory sites that offer a challenging and
      rewarding model to study immunity.

PMID- 12495726
TI  - Mammalian Toll-like receptors.

PMID- 12495727
TI  - Drosophila immunity: paths and patterns.

PMID- 12495728
TI  - Resistance gene signaling in plants--complex similarities to animal innate
      immunity.

PMID- 12495729
TI  - New insights into the mechanism of IL-1beta maturation.

PMID- 12495730
TI  - Macrophage regulation by Tyro 3 family receptors.

PMID- 12495731
TI  - Innate immune recognition by stimulatory immunoreceptors.

PMID- 12495732
TI  - Natural killer cells and viral infections.

PMID- 12495733
TI  - Ringing the interferon alarm: differential regulation of gene expression at the
      interface between innate and adaptive immunity.

PMID- 12495734
TI  - Death and survival: viral regulation of TNF signaling pathways.

PMID- 12495735
TI  - Antigen processing and recognition.

PMID- 12495736
TI  - Using the World Wide Web for predicting CTL epitopes.

PMID- 12495737
TI  - Assembly and export of MHC class I peptide ligands.

PMID- 12495738
TI  - Cross priming or direct priming: is that really the question?

PMID- 12495739
TI  - ISO: a critical evaluation of the role of peptides in heat shock/chaperone
      protein-mediated tumor rejection.

PMID- 12495740
TI  - CD1-restricted antigen presentation: an oily matter.

PMID- 12495741
TI  - Transcriptional regulation of the MHC class II antigen presentation pathway.

PMID- 12495742
TI  - Interaction of bacteria with antigen presenting cells: influences on antigen
      presentation and antibacterial immunity.